Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family.
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. ASIC4 subfamily.
Expressed in pituitary gland. Weakly expressed in brain, vestibular system and organ of Corti.
Homotrimer or heterotrimer with other ASIC proteins.
Probable cation channel with high affinity for sodium. In vitro, has no proton-gated channel activity.
Induces activation of MAPK14/p38 cascade, when overexpressed (PubMed:28688764). Induces apoptosis, when overexpressed (PubMed:19969290).
Interacts with RELT, RELL1 and OXSR1 (PubMed:16389068). Interacts with PLSCR1 (PubMed:22052202). Interacts with TRAF2 (PubMed:19969290).
Primarily expressed in spleen, thymus, testis, peripheral blood leukocytes, brain and placenta. Not detected in prostate, ovary, small intestine, colon, heart, lung, liver, skeletal muscle, kidney and pancreas.
Breakpoint hotspot for the Prader-Willi/Angelman syndromes and may be implicated in autism. Commonly altered in tumors.
Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit is an adapter between EIF4E and FMR1. Promotes the translation repression activity of FMR1 in brain probably by mediating its association with EIF4E and mRNA (By similarity). Regulates formation of membrane ruffles and lamellipodia. Plays a role in axon outgrowth. Binds to F-actin but not to RNA. Part of the WAVE complex that regulates actin filament reorganization via its interaction with the Arp2/3 complex. Actin remodeling activity is regulated by RAC1. Regulator of epithelial morphogenesis. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes (By similarity). May act as an invasion suppressor in cancers.
Component of the WAVE1 complex composed of ABI2, CYFIP1 or CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Within the complex, a heterodimer containing NCKAP1 and CYFIP1 interacts with a heterotrimer formed by WAVE1, ABI2 and BRK1. Component of the CYFIP1-EIF4E-FMR1 complex which is composed of CYFIP, EIF4E and FMR1. Interacts with FMR1 but does not bind to related proteins FXR1 or FXR2. Interaction with EIF4E stimulates FMR1 binding. Component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1/NAP1 (NCKAP1l/HEM1 in hematopoietic cells) and WASF2/WAVE2 (PubMed:16417406). Interacts with the active GTP-bound form of RAC1. Interacts through its C-terminus with the C-terminus of DPYSL2/CRMP2 which is necessary for DPYSL2-induced axon outgrowth. Interacts with NYAP1, NYAP2 and MYO16. Interacts with TMEM108 (via N-terminus); the interaction associates TMEM108 with the WAVE1 complex (By similarity).
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'- and 'Lys-48'-, as well as 'Lys-63'-linked polyubiquitination. Participates in the regulation of transepithelial sodium transport in renal cells. May be involved in cell growth arrest.
Belongs to the ubiquitin-conjugating enzyme family.
The ubiquitin-loaded form interacts specifically with importin-11 (IPO11), leading to its import into the nucleus. Interacts with NEDD4L.
Ubiquitously expressed at low levels. Highly expressed in skeletal muscle.
Belongs to the G-protein coupled receptor 1 family.
Expression largely restricted to adipose tissue and spleen.
Receptor for 3-OH-octanoid acid mediates a negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in beta-oxidation rates. Acts as a low affinity receptor for nicotinic acid. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet.
May play a role in stabilizing dense microtubular networks or in vesicular trafficking.
Regulator of G protein-coupled receptor (GPCR) signaling in phototransduction. Participates in the recovery phase of visual transduction via its interaction with RGS9-1 isoform. Acts as a membrane-anchor that mediates the targeting of RGS9-1 to the photoreceptor outer segment, where phototransduction takes place. Enhances the ability of RGS9-1 to stimulate G protein GTPase activity, allowing the visual signal to be terminated on the physiologically time scale. It also controls the proteolytic stability of RGS9-1, probably by protecting it from degradation (By similarity).
Specifically interacts with isoform RGS9-1 of RGS9. Component of the RGS9-1-Gbeta5 complex composed of RGS9-1, Gbeta5 (GNB5) and RGS9BP (By similarity).
The disease is caused by variants affecting the gene represented in this entry.
Interacts with BCAS3; the interaction is requrired for the association with the phagophore.
Plays a regulatory role in autophagic activity. In complex with BCAS3, associates with the autophagosome formation site during both non-selective and selective autophagy.
Was originally (Ref.1) thought to be a lin-10 homolog.
Belongs to the iodothyronine deiodinase family.
May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. The UGA codon in position 34 may either function as a selenocysteine codon or a translation termination codon.
May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. The UGA codon in position 59 may either function as a selenocysteine codon or a translation termination codon.
Responsible for the deiodination of T4 (3,5,3',5'-tetraiodothyronine) into T3 (3,5,3'-triiodothyronine) and of T3 into T2 (3,3'-diiodothyronine). Plays a role in providing a source of plasma T3 by deiodination of T4 in peripheral tissues such as liver and kidney.
Responsible for the deiodination of T4 (3,5,3',5'-tetraiodothyronine).
The UGA codon in position 83 may either function as a selenocysteine codon or a translation termination codon.
Guanine nucleotide exchange factor (GEF) which may activate RAB9A and RAB9B. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form.
Interacts with ITSN1 and GRB2 (PubMed:29030480). Isoform 1 interacts with the SH3 domain of ABL1.
May be involved in cytoskeletal organization and tumorogenicity. Seems to be involved in a signaling transduction pathway leading to activation of MAPK1/ERK2. Plays a role in EGFR trafficking from recycling endosomes back to the cell membrane (PubMed:29030480).
May block ERK2 activation stimulated by ABL1 (Probable). May alter cell morphology and cell growth (Probable).
Phosphorylated. Phosphorylation decreases ITSN1 binding.
Produced by alternative splicing of isoform 1.
Widely expressed with the exception of peripheral blood lymphocytes. Isoform 1 is expressed in several epithelial and fibroblast (including tumorigenic) but absent in lymphoid cell lines (at protein level). Isoform 3 is expressed in primary cell or weakly tumorigenic but not in tumorigenic cell lines (at protein level).
Expressed at high levels in the kidney and pancreas. Moderate expression seen in the skeletal muscle, liver and heart. A weak expression seen in the brain, lung, uterus, prostate, testis, small intestine and colon.
Interacts (when myristoylated) with UNC119 and UNC119B; interaction is required for localization to cilium.
Detected in cerebellum, heart, placenta, spleen, stomach, testis and thymus.
Potential ligand of the IGFLR1 cell membrane receptor.
Belongs to the glycerophosphoryl diester phosphodiesterase family.
Hydrolyzes lysoglycerophospholipids to produce lysophosphatidic acid (LPA) and the corresponding amines (PubMed:27637550, PubMed:25596343). Shows a preference for 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF), lysophosphatidylethanolamine (lyso-PE) and lysophosphatidylcholine (lyso-PC) (PubMed:27637550, PubMed:25596343). May be involved in bioactive N-acylethanolamine biosynthesis from both N-acyl-lysoplasmenylethanolamin (N-acyl-lysoPlsEt) and N-acyl-lysophosphatidylethanolamin (N-acyl-lysoPE) (PubMed:27637550, PubMed:25596343). In addition, hydrolyzes glycerophospho-N-acylethanolamine to N-acylethanolamine (PubMed:27637550). Does not display glycerophosphodiester phosphodiesterase activity, since it cannot hydrolyze either glycerophosphoinositol or glycerophosphocholine (By similarity).
Lysophospholipase D activity is increased by magnesium and manganese and inhibited by calcium in a concentration dependent manner (PubMed:27637550). Loss of lysophospholipase D activity by addition of EDTA (By similarity).
Widely expressed with high expression level in testis.
Belongs to the Nudix hydrolase family. NudF subfamily.
Hydrolyzes ADP-ribose (ADPR) to AMP and ribose 5'-phosphate.
Inhibited by fluoride and N-acetyl-p-benzoquinoneimine.
Ubiquitously expressed but isoform 1 is the most predominant isoform.
Expressed in pancreatic duct cells. Expressed in several tumor cell lines of neuroendocrine origin including pheochromocytoma, medullary thyroid carcinoma, insulinoma, medulloblastoma, retinoblastoma, pheochromacytoma, medullary thyroid carcinoma and small cell lung carcinoma.
Interacts (via the SNAG domain) with HDAC1 (PubMed:16569215). Interacts (via the SNAG domain) with HDAC2 (By similarity). Interacts (via the SNAG domain) with KDM1A (PubMed:23721412). Interacts (via the SNAG domain) with RCOR1. Interacts with SORBS1 (By similarity). Interacts (via the N-terminal region) with CCND1 (via cyclin N-terminal domain); the interaction competes with the binding of CCND1 to CDK4 during cell cycle progression and increases its transcriptional repressor activity (PubMed:16569215, PubMed:18417529, PubMed:19124461). Interacts with HDAC3; the interaction increases its transcriptional repressor activity (PubMed:16569215, PubMed:18417529).
Sequence-specific DNA-binding transcriptional regulator that plays a key role in neurogenesis and neuroendocrine cell differentiation during embryonic and/or fetal development. Binds to the consensus sequence 5'-[TG][TC][TC][TT][GA]GGG[CG]A-3' in target promoters. Acts as a transcriptional repressor of NEUROD1 and INS expression via its interaction with cyclin CCND1 in a cell cycle-independent manner. Negatively regulates skeletal muscle-specific gene expression in endocrine cells of the pituitary by inhibiting the Notch signaling pathway. Represses target gene transcription by recruiting chromatin-modifying factors, such as HDAC1, HDAC2, HDAC3, KDM1A and RCOR1 histone deacetylases. Binds to its own promoter, suggesting autoregulation as a self-control feedback mechanism. Competes with histone H3 for the same binding site on the histone demethylase complex formed by KDM1A and RCOR1, and thereby inhibits demethylation of histone H3 at 'Lys-4' (PubMed:23721412). Promotes the generation and expansion of neuronal basal progenitor cells in the developing neocortex. Involved in the differentiation of endocrine cells of the developing anterior pituitary gland, of the pancreas and intestine, and of sympatho-adrenal cells in the peripheral nervous system. Promotes cell cycle signaling arrest and inhibition of cellular proliferation.
The C-terminal region is necessary for NEUROD1 promoter DNA-binding and transcriptional repressor activity.
Up-regulated by transcription factors, such as MASH1, NEUROD1, NEUROG3, NGN3 and TCF3.
An intronic variant that affects alternative splicing of REST into isoform 3 and inactivation of REST repressor activity is associated with progressive hearing loss and deafness.
Binds to the 3' region of the neuron-restrictive silencer element (NRSE), with lower affinity than full-length REST isoform 1 (By similarity). Exhibits weaker repressor activity compared to isoform 1 (PubMed:11779185). May negatively regulate the repressor activity of isoform 1 by binding to isoform 1, thereby preventing its binding to NRSE and leading to derepression of target genes (PubMed:11779185). However, in another study, does not appear to be implicated in repressor activity of a NRSE motif-containing reporter construct nor in inhibitory activity on the isoform 1 transcriptional repressor activity (PubMed:11741002). Post-transcriptional inactivation of REST by SRRM4-dependent alternative splicing into isoform 3 is required in mechanosensory hair cells in the inner ear for derepression of neuronal genes and hearing (By similarity).
Contaminating sequence. Potential poly-A sequence.
Controversial data exists concerning the repressor activity of isoform 3. A study showed that isoform 3 exhibits weak repressor activity of a NRSE motif-containing reporter construct (PubMed:11779185). Another report, however, does not observe any isoform 3 transcriptional repressor activity of a NRSE motif-containing reporter construct (PubMed:11741002). Controversial data also exists regarding the function of isoform 3 on the negative regulation of isoform 1. It was shown that isoform 3 negatively regulates the repressor activity of isoform 1 by binding to isoform 1, thereby preventing its binding to NRSE and leading to derepression of target genes (PubMed:11779185). Another study, however, did not observe any inhibitory activity of isoform 3 on the isoform 1 transcriptional repressor activity (PubMed:11741002).
Disease susceptibility is associated with variants affecting the gene represented in this entry.
Expressed in neurons of the prefrontal cortex, in hippocampal pyramidal neurons, dentate gyrus granule neurons and cerebellar Purkinje and granule neurons (at protein level) (PubMed:24670762). Expressed in dopaminergic neurons of the substantia nigra (at protein level) (PubMed:30684677). Expressed in neural progenitor cells (at protein level) (PubMed:21258371). In patients suffering from Alzheimer disease, frontotemporal dementia or dementia with Lewy bodies, decreased nuclear levels have been observed in neurons of the prefrontal cortex and the hippocampus, but not in neurons of the dentate gyrus and cerebellum (at protein level) (PubMed:24670762). In patients with Parkinson disease or dementia with Lewy bodies, decreased nuclear levels have been observed in dopaminergic neurons and in cortical neurons and localization to Lewy bodies and pale bodies was detected (at protein level) (PubMed:30684677). Expressed at higher levels in weakly invasive breast cancer cell lines and at lower levels in highly invasive breast cancer lines (at protein level) (PubMed:26053433). Ubiquitous (PubMed:8568247). Expressed at higher levels in the tissues of the lymphocytic compartment, including spleen, thymus, peripheral blood lymphocytes and ovary (PubMed:8568247).
Expression is cell cycle-dependent with decreased levels in G2 phase; mediated by proteasomal degradation (at protein level) (PubMed:18354482). In aged individuals, increased expression in hippocampal CA1, CA3 and CA4 pyramidal neurons and in dentate granule cell neurons, but not in the cerebellum (PubMed:24670762).
Isoform 1 and isoform 3 form heterodimers (By similarity). Isoform 3: Forms homodimers and homooligomers; binds to the neuron-restrictive silencer element (NRSE) as monomer (By similarity). Interacts with SIN3A, SIN3B and RCOR1 (PubMed:10449787, PubMed:10734093, PubMed:16288918). Interacts with CDYL (PubMed:19061646). Interacts with EHMT1 and EHMT2 only in the presence of CDYL (PubMed:19061646). Part of a complex containing at least CDYL, REST, WIZ, SETB1, EHMT1 and EHMT2 (PubMed:19061646). Interacts (via zinc-finger DNA-binding domain) with ZFP90 (via N- and C-termini); the interaction inhibits REST repressor activity (PubMed:21284946). Interacts (via C2H2-type zinc finger 5) with PRICKLE1 (PubMed:14645515, PubMed:16442230). Interacts with FBXW11 and BTRC (PubMed:18354482). Interacts with USP7 (PubMed:21258371).
Phosphorylated; phosphorylation is required for ubiquitination.
Produced by SRRM4-dependent alternative splicing in neurons and inner ear hair cells (By similarity). Lacks the four C-terminal zinc fingers and the RCOR1 corepressor interaction site found in full length REST isoform 1, which are required for full DNA-binding and repressive activity (PubMed:11741002).
The C2H2-type zinc finger 5 is required for nuclear localization.
The disease may be caused by variants affecting the gene represented in this entry. An intronic variant that affects alternative splicing of REST and inactivation of REST repressor activity fully segregates with deafness in a 3-generation family.
Transcriptional repressor which binds neuron-restrictive silencer element (NRSE) and represses neuronal gene transcription in non-neuronal cells (PubMed:12399542, PubMed:26551668, PubMed:7697725, PubMed:7871435, PubMed:8568247, PubMed:11741002, PubMed:11779185). Restricts the expression of neuronal genes by associating with two distinct corepressors, SIN3A and RCOR1, which in turn recruit histone deacetylase to the promoters of REST-regulated genes (PubMed:10449787, PubMed:10734093). Mediates repression by recruiting the BHC complex at RE1/NRSE sites which acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier (By similarity). Transcriptional repression by REST-CDYL via the recruitment of histone methyltransferase EHMT2 may be important in transformation suppression (PubMed:19061646). Represses the expression of SRRM4 in non-neural cells to prevent the activation of neural-specific splicing events and to prevent production of REST isoform 3 (By similarity). Repressor activity may be inhibited by forming heterodimers with isoform 3, thereby preventing binding to NRSE or binding to corepressors and leading to derepression of target genes (PubMed:11779185). Also maintains repression of neuronal genes in neural stem cells, and allows transcription and differentiation into neurons by dissociation from RE1/NRSE sites of target genes (By similarity). Thereby is involved in maintaining the quiescent state of adult neural stem cells and preventing premature differentiation into mature neurons (PubMed:21258371). Plays a role in the developmental switch in synaptic NMDA receptor composition during postnatal development, by repressing GRIN2B expression and thereby altering NMDA receptor properties from containing primarily GRIN2B to primarily GRIN2A subunits (By similarity). Acts as a regulator of osteoblast differentiation (By similarity). Key repressor of gene expression in hypoxia; represses genes in hypoxia by direct binding to an RE1/NRSE site on their promoter regions (PubMed:27531581). May also function in stress resistance in the brain during aging; possibly by regulating expression of genes involved in cell death and in the stress response (PubMed:24670762). Repressor of gene expression in the hippocampus after ischemia by directly binding to RE1/NRSE sites and recruiting SIN3A and RCOR1 to promoters of target genes, thereby promoting changes in chromatin modifications and ischemia-induced cell death (By similarity). After ischemia, might play a role in repression of miR-132 expression in hippocampal neurons, thereby leading to neuronal cell death (By similarity). Negatively regulates the expression of SRRM3 in breast cancer cell lines (PubMed:26053433).
Ubiquitinated; ubiquitination is mediated by BTRC and leads to proteasomal degradation in G2 phase (PubMed:18354482, PubMed:21258371). Ubiquitination increases during neuronal differentiation (PubMed:21258371). Deubiquitinated by USP7; leading to its stabilization and promoting the maintenance of neural progenitor cells (PubMed:21258371).
Up-regulated by Wnt signaling (PubMed:24670762). Up-regulated in the brain of aging individuals but not in Alzheimer disease patients (PubMed:24670762). Up-regulated by oxidative stress (PubMed:24670762). Down-regulated during neural progenitor cell differentiation (PubMed:21258371).
Interacts with RAF1, RAB2L and RAL GTPase proteins.
May function as an adapter protein or regulator of Ras signaling pathways.
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.1/SCN1A subfamily.
Inactivation of this channel is specifically inhibited by the spider toxins Hm1a and Hm1b (H.maculata, AC P60992 and AC P0DOC5) in somatosensory neurons to elicit acute pain and mechanical allodynia.
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:14672992). Plays a key role in brain, probably by regulating the moment when neurotransmitters are released in neurons. Involved in sensory perception of mechanical pain: activation in somatosensory neurons induces pain without neurogenic inflammation and produces hypersensitivity to mechanical, but not thermal stimuli.
Phosphorylation at Ser-1516 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents.
SCN1A mutations may be involved in Panayiotopoulos syndrome, a benign age-related focal seizure disorder occurring in early and mid-childhood. It is characterized by seizures, often prolonged, with predominantly autonomic symptoms, and by an electroencephalogram that shows shifting and/or multiple foci, often with occipital predominance. Autonomic seizures in Panayiotopoulos syndrome consist of episodes of disturbed autonomic function with emesis as the predominant symptom. Cardiorespiratory arrest is exceptional.
The S3b-S4 and S1-S2 loops of repeat IV are targeted by H.maculata toxins Hm1a and Hm1b, leading to inhibit fast inactivation of Nav1.1/SCN1A. Selectivity for H.maculata toxins Hm1a and Hm1b depends on S1-S2 loops of repeat IV.
The sequence contains 4 internal repeats, each with 5 hydrophobic segments (S1, S2, S3, S5, S6) and one positively charged segment (S4). Segments S4 are probably the voltage-sensors and are characterized by a series of positively charged amino acids at every third position.
The voltage-sensitive sodium channel consists of an ion conducting pore forming alpha-subunit regulated by one or more beta-1 (SCN1B), beta-2 (SCN2B), beta-3 (SCN3B) and/or beta-4 (SCN4B). Beta-1 (SCN1B) and beta-3 (SCN3B) are non-covalently associated with alpha, while beta-2 (SCN2B) and beta-4 (SCN4B) are covalently linked by disulfide bonds. Interacts with FGF13 (PubMed:21566136). Interacts with SCN1B (PubMed:17928445, PubMed:15525788). Interacts with the conotoxin GVIIJ (PubMed:24497506). Interacts with the spider beta/delta-theraphotoxin-Pre1a (PubMed:28428547).
Guanine nucleotide exchange factor (GEF) for RAP1A, RAP2A and MRAS/M-Ras-GTP. Its association with MRAS inhibits Rap1 activation.
Widely expressed with highest levels in brain.
Abundantly expressed in whole adult brain and in all individual brain regions examined, including spinal cord. Weakly expressed in ovary, testis, fetal brain and small intestine.
Interacts with MCHR1 (PubMed:16945926). Interacts with SEMA4C (By similarity). Interacts with DIAPH1 (via FH3 domain) (By similarity). Interacts with GRM5 (By similarity).
Palmitoylated. Palmitoylation by ZDHHC1, ZDHHC3 and ZDHHC11 regulates the association of NCDN with endosome membranes. May also be palmitoylated by ZDHHC7.
Probably involved in signal transduction in the nervous system, via increasing cell surface localization of GRM5/mGluR5 and positively regulating its signaling (PubMed:33711248). Required for the spatial learning process. Acts as a negative regulator of Ca(2+)-calmodulin-dependent protein kinase 2 (CaMK2) phosphorylation. May play a role in modulating melanin-concentrating hormone-mediated functions via its interaction with MCHR1 that interferes with G protein-coupled signal transduction. May be involved in bone metabolism. May also be involved in neurite outgrowth (Probable).
Component of the multisubunit TRAPP (transport protein particle) complex, which includes at least TRAPPC2, TRAPPC2L, TRAPPC3, TRAPPC3L, TRAPPC4, TRAPPC5, TRAPPC8, TRAPPC9, TRAPPC10, TRAPPC11 and TRAPPC12.
Involved in endoplasmic reticulum to Golgi apparatus trafficking at a very early stage.
Belongs to the immunoglobulin superfamily. CEA family.
PSBG are produced in high quantity during pregnancy.
Activated by histamine, L-adrenaline, L- and D-histidine, and L- and D-phenylalanine. Inhibited by coumarins, sulfonamide derivatives such as acetazolamide (AZA), by saccharin and Foscarnet (phosphonoformate trisodium salt).
Belongs to the alpha-carbonic anhydrase family.
Belongs to the potassium channel family. D (Shal) (TC 1.A.1.2) subfamily. Kv4.1/KCND1 sub-subfamily.
Homotetramer or heterotetramer with KCND2 and/or KCND3. Associates with the regulatory subunits KCNIP1, KCNIP2, KCNIP3 and KCNIP4 (By similarity). Interacts with DPP10 (Probable).
Pore-forming (alpha) subunit of voltage-gated rapidly inactivating A-type potassium channels. May contribute to I(To) current in heart and I(Sa) current in neurons. Channel properties are modulated by interactions with other alpha subunits and with regulatory subunits.
The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino acids at every third position.
Widely expressed. Highly expressed in brain, in particular in cerebellum and thalamus; detected at lower levels in the other parts of the brain.
Expression occurs preferentially during late G1, S, G2 and M phases of the cell cycle, while in cells in G0 phase the antigen cannot be detected (at protein level) (PubMed:6206131). Present at highest level in G2 phase and during mitosis (at protein level). In interphase, forms fiber-like structures in fibrillarin-deficient regions surrounding nucleoli (PubMed:2674163, PubMed:8799815).
Interacts with KIF15 (PubMed:10878014). Interacts (via the FHA domain) with NIFK (PubMed:11342549, PubMed:14659764, PubMed:16244663). Interacts with PPP1CC (PubMed:24867636). Component of a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY, MKI67, RBBP5, ASH2L and WDR5; the complex is formed as a result of interactions between components of a nuclear receptor-mediated transcription complex and a histone methylation complex (PubMed:19131338). Interacts with ZNF335 (PubMed:19131338, PubMed:23178126).
Phosphorylated. Hyperphosphorylated in mitosis (PubMed:10502411, PubMed:10653604). Hyperphosphorylated form does not bind DNA.
Required to maintain individual mitotic chromosomes dispersed in the cytoplasm following nuclear envelope disassembly (PubMed:27362226). Associates with the surface of the mitotic chromosome, the perichromosomal layer, and covers a substantial fraction of the chromosome surface (PubMed:27362226). Prevents chromosomes from collapsing into a single chromatin mass by forming a steric and electrostatic charge barrier: the protein has a high net electrical charge and acts as a surfactant, dispersing chromosomes and enabling independent chromosome motility (PubMed:27362226). Binds DNA, with a preference for supercoiled DNA and AT-rich DNA (PubMed:10878551). Does not contribute to the internal structure of mitotic chromosomes (By similarity). May play a role in chromatin organization (PubMed:24867636). It is however unclear whether it plays a direct role in chromatin organization or whether it is an indirect consequence of its function in maintaining mitotic chromosomes dispersed (Probable).
Was thought to play a key role in cell proliferation, and is commonly used as a marker of cell proliferation (PubMed:6339421, PubMed:21960707). However, its primary function is uncoupled from cell proliferation: it is required to maintain mitotic chromosomes dispersed by forming a steric and electrostatic charge barrier (PubMed:27362226).
Widely used as a marker to assess cell proliferation, as it is detected in the nucleus of proliferating cells only (PubMed:6339421, PubMed:21960707). In cancer research field for example, MKI67 is the most widely used marker for comparing proliferation between tumor samples (PubMed:21960707, PubMed:26680267).
Adapter or scaffold protein which participates in the assembly of numerous protein complexes and is involved in several cellular processes such as cell fate determination, cytoskeletal organization, repression of gene transcription, cell-cell adhesion, cell differentiation, proliferation and migration. Positively regulates microRNA (miRNA)-mediated gene silencing and is essential for P-body formation and integrity. Acts as a hypoxic regulator by bridging an association between the prolyl hydroxylases and VHL enabling efficient degradation of HIF1A. Acts as a transcriptional corepressor for SNAI1- and SNAI2/SLUG-dependent repression of E-cadherin transcription. Negatively regulates the Hippo signaling pathway and antagonizes phosphorylation of YAP1. Inhibits E2F-mediated transcription, and suppresses the expression of the majority of genes with E2F1-responsive elements. Regulates osteoblast development, function, differentiation and stress osteoclastogenesis. Enhances the ability of TRAF6 to activate adapter protein complex 1 (AP-1) and negatively regulates the canonical Wnt receptor signaling pathway in osteoblasts. May act as a tumor suppressor by inhibiting cell proliferation.
Expressed in normal and breast cancer tissues (at protein level). Ubiquitous.
Interacts (via LIM domains) with TRAF6. Found in a complex with TRAF6, PRKCZ and SQSTM1. Interacts (via LIM domains) SNAI2/SLUG (via SNAG domain) and SCRT1 (via SNAG domain) (By similarity). Interacts with SQSTM1 and RB1. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with EIF4E, AGO1, AGO2, DCP2, DDX6, LATS1, LATS2, EGLN1/PHD2, EGLN2/PHD1 and EGLN3/PHD3. Interacts (via LIM zinc-binding 2) with isoform 1 and isoform 3 of VHL. Interacts (via LIM domains) with SNAI1 (via SNAG domain).
Cohesin complexes are composed of a heterodimer between a SMC1 protein (SMC1A or SMC1B) and SMC3, which are attached via their hinge domain, and RAD21 which link them at their heads, and one STAG protein (STAG1, STAG2 or STAG3) (PubMed:11076961, PubMed:22628566, PubMed:32409525). In cohesin complexes, STAG1 is mutually exclusive with STAG2 and STAG3 (PubMed:11076961). Interacts directly with RAD21 in cohesin complex (By similarity). The cohesin complex interacts with the cohesin loading complex subunits NIPBL/Scc2 (via HEAT repeats) and MAU2/Scc4. NIPBL directly contacts all members of the complex, RAD21, SMC1A/B, SMC3 and STAG1 (PubMed:32409525).
Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate.
Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis.
Part of the cohesin complex which is composed of a heterodimer between a SMC1 protein (SMC1A or SMC1B) and SMC3, which are attached via their hinge domain, and RAD21 which link them at their heads, and one STAG protein.
Phosphorylated by PLK1. The large dissociation of cohesin from chromosome arms during prophase is partly due to its phosphorylation (By similarity).
Expressed in goblet cells of the intestines and colon (at protein level). Expressed by goblet cells of small and large intestinal epithelia and also by the uterus. Also expressed in the hypothalamus where it is detected in paraventricular, periventricular and supraoptic nuclei (at protein level).
Involved in the maintenance and repair of the intestinal mucosa. Promotes the mobility of epithelial cells in healing processes (motogen).
Acetylation regulates its nuclear translocation and corepressive activity (By similarity). Acetylation abolishes interaction with CTBP1. Phosphorylation enhances interaction with YWHAH.
Contains 9 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs, which have different affinities for nuclear receptors. The C-terminal LTKTNPILYYMLQK motif is required for ligand-dependent interaction with RAAR and RXRB homodimers and heterodimers, for the corepressor activity, and for the formation of an HDAC3 complex with RARA/RXRB (By similarity). Contains at least four autonomous repression domains (RD1-4). RD1 functions via a histone deacetylase (HDAC)-independent mechanism, whereas RD2, RD3 and RD4 can function by HDAC-dependent or independent mechanisms, depending on cell type. RD2 is dependent on CTBP binding.
Expressed in a circadian manner in the liver (at protein level).
Interacts with RARA and RXRB homodimers and RARA/RXRB heterodimers in the presence of ligand. Interacts with HDAC1 and HDAC3 via its N-terminal domain. Interacts with NR2C1 (sumoylated form and via the ligand-binding domain); the interaction results in promoting the repressor activity of NR2C1 (By similarity). Interacts with CTBP1, CTBP2, ESR1, HDAC1, HDAC2, HDAC5, HDAC6, NR2C2, NR3C1, NR3C2, YWHAH, JUN and FOS. Found in a complex with both NR3C1 and YWHAH. Interacts with ZNF366. Interacts with RORA.
Modulates transcriptional activation by steroid receptors such as NR3C1, NR3C2 and ESR1. Also modulates transcriptional repression by nuclear hormone receptors. Positive regulator of the circadian clock gene expression: stimulates transcription of BMAL1, CLOCK and CRY1 by acting as a coactivator for RORA and RORC. Involved in the regulation of ovarian function (By similarity). Plays a role in renal development (PubMed:28381549).
Belongs to the glutamine synthetase family.
By glucocorticoids. Vitamin D and the Wnt signaling pathway inhibit its expression and activity.
Decamer; composed of two pentamers (PubMed:18005987). Interacts with PALMD (By similarity). Interacts with RHOJ (PubMed:30158707).
Glutamine synthetase activity is inhibited by methionine sulfoximine (MSO).
Glutamine synthetase that catalyzes the ATP-dependent conversion of glutamate and ammonia to glutamine (PubMed:30158707, PubMed:16267323). Its role depends on tissue localization: in the brain, it regulates the levels of toxic ammonia and converts neurotoxic glutamate to harmless glutamine, whereas in the liver, it is one of the enzymes responsible for the removal of ammonia (By similarity). Essential for proliferation of fetal skin fibroblasts (PubMed:18662667). Independently of its glutamine synthetase activity, required for endothelial cell migration during vascular development: acts by regulating membrane localization and activation of the GTPase RHOJ, possibly by promoting RHOJ palmitoylation (PubMed:30158707). May act as a palmitoyltransferase for RHOJ: able to autopalmitoylate and then transfer the palmitoyl group to RHOJ (PubMed:30158707). Plays a role in ribosomal 40S subunit biogenesis (PubMed:26711351).
Palmitoylated; undergoes autopalmitoylation.
Belongs to the ubiquitin family. SUMO subfamily.
Cleavage of precursor form by SENP1, SENP2 or SENP5 is necessary for function.
Covalently attached to a number of proteins. Interacts with BMAL1 (By similarity). Interacts with USP25 (via ts SIM domain); the interaction sumoylates USP25 and inhibits its ubiquitin hydrolyzing activity. Interacts with SAE2 and UBE2I.
Polymeric chains can be formed through Lys-11 cross-linking.
Ubiquitin-like protein which can be covalently attached to target lysines either as a monomer or as a lysine-linked polymer. Does not seem to be involved in protein degradation and may function as an antagonist of ubiquitin in the degradation process. Plays a role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Covalent attachment to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by an E3 ligase such as PIAS1-4, RANBP2 or CBX4 (PubMed:11451954, PubMed:18538659, PubMed:21965678). Plays a role in the regulation of sumoylation status of SETX (PubMed:24105744).
Belongs to the peptidase C19 family. USP20/USP33 subfamily.
Deubiquitinating enzyme involved in various processes such as centrosome duplication, cellular migration and beta-2 adrenergic receptor/ADRB2 recycling. Involved in regulation of centrosome duplication by mediating deubiquitination of CCP110 in S and G2/M phase, leading to stabilize CCP110 during the period which centrioles duplicate and elongate. Involved in cell migration via its interaction with intracellular domain of ROBO1, leading to regulate the Slit signaling. Plays a role in commissural axon guidance cross the ventral midline of the neural tube in a Slit-dependent manner, possibly by mediating the deubiquitination of ROBO1. Acts as a regulator of G-protein coupled receptor (GPCR) signaling by mediating the deubiquitination of beta-arrestins (ARRB1 and ARRB2) and beta-2 adrenergic receptor (ADRB2). Plays a central role in ADRB2 recycling and resensitization after prolonged agonist stimulation by constitutively binding ADRB2, mediating deubiquitination of ADRB2 and inhibiting lysosomal trafficking of ADRB2. Upon dissociation, it is probably transferred to the translocated beta-arrestins, leading to beta-arrestins deubiquitination and disengagement from ADRB2. This suggests the existence of a dynamic exchange between the ADRB2 and beta-arrestins. Deubiquitinates DIO2, thereby regulating thyroid hormone regulation. Mediates deubiquitination of both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.
Increased expression in S and early G2 phases and lower levels in late G2 and M phases.
Interacts with VHL, leading to its ubiquitination and subsequent degradation (PubMed:11739384). Interacts with ARRB1 and ARRB2 (PubMed:19363159). Interacts with ADRB2 (PubMed:19424180). Interacts with DIO2 (PubMed:12865408). Interacts with ROBO1. Interacts with SELENBP1; in a selenium-dependent manner (PubMed:19118533). Interacts with CCP110 (PubMed:23486064). Interacts with ADRB2 (PubMed:23166351).
The UBP-type zinc finger binds 3 zinc ions. However, it does not bind ubiquitin, probably because the conserved Arg in position 86 is replaced by a Glu residue.
Ubiquitinated via a VHL-dependent pathway for proteasomal degradation.
Belongs to the HAD-like hydrolase superfamily. EYA family.
Highly expressed in heart and skeletal muscle.
Interacts with SIX3; translocates EYA4 from the cytoplasm to the nucleus and promotes activation of their target genes.
May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Tyrosine phosphatase that specifically dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph). 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress. Promotes efficient DNA repair by dephosphorylating H2AX, promoting the recruitment of DNA repair complexes containing MDC1. Its function as histone phosphatase probably explains its role in transcription regulation during organogenesis. May be involved in development of the eye (By similarity).
Monomer and homooligomer (PubMed:23615443). Interacts with TTN/titin (PubMed:12482578). Interacts with SVIL (PubMed:18639526). Interacts (via nebulin repeats 160-164) with DES (PubMed:23615443).
Muscle specific. Located in the thin filament of striated muscle.
This giant muscle protein may be involved in maintaining the structural integrity of sarcomeres and the membrane system associated with the myofibrils. Binds and stabilize F-actin.
Part of the core SMN complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP (PubMed:18984161, PubMed:16314521, PubMed:17178713). Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG (PubMed:18984161, PubMed:16314521). Interacts with GEMIN3; the interaction is direct (PubMed:18984161, PubMed:17178713). Interacts with GEMIN5 (PubMed:33963192). Interacts with GEMIN8; the interaction is direct (PubMed:17178713). Interacts with several snRNP SM core proteins, including SNRPB, SNRPD1, SNRPD2, SNRPD3 and SNRPE (PubMed:18984161). Interacts with PPP4R2 (PubMed:12668731).
The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs. Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (Sm core). In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP. To assemble core snRNPs, the SMN complex accepts the trapped 5Sm proteins from CLNS1A forming an intermediate. Binding of snRNA inside 5Sm triggers eviction of the SMN complex, thereby allowing binding of SNRPD3 and SNRPB to complete assembly of the core snRNP.
Major isoform, represents 80% of transcripts.
Predominantly expressed in thyroid tissue.
Probable S-adenosyl-L-methionine-dependent methyltransferase that acts as a component of the wybutosine biosynthesis pathway. Wybutosine is a hyper modified guanosine with a tricyclic base found at the 3'-position adjacent to the anticodon of eukaryotic phenylalanine tRNA (By similarity).
Altered in its ability to trans-activate compared to isoform B.
Belongs to the POU transcription factor family. Class-1 subfamily.
Interacts with PITX1 (PubMed:26612202). Interacts with LHX3 (PubMed:26612202). Interacts with ELK1 (PubMed:26612202).
The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.
Transcription factor involved in the specification of the lactotrope, somatotrope, and thyrotrope phenotypes in the developing anterior pituitary. Specifically binds to the consensus sequence 5'-TAAAT-3'. Activates growth hormone and prolactin genes (PubMed:22010633, PubMed:26612202).
Binds 3 Ca(2+) ions per subunit. The ions are bound to the C2 domains.
Exhibits calcium-dependent phospholipid and inositol polyphosphate binding properties (By similarity). May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003).
Expressed at the neuromuscular junction (PubMed:33659639). Expressed in melanocytes (PubMed:23999003).
Homotetramer (Probable). Heterodimer; heterodimerizes with SYT1 in presence of calcium (By similarity). Interacts with STON2 (PubMed:11381094). Interacts with SCAMP5 (PubMed:19234194). Interacts with PRRT2 (By similarity).
Phosphorylation at Thr-199 by WNK1, changes the calcium requirement for SYT2-binding to phospholipid membranes.
The first C2 domain mediates Ca(2+)-dependent phospholipid binding.
The second C2 domain mediates interaction with Stonin 2. The second C2 domain mediates phospholipid and inositol polyphosphate binding in a calcium-independent manner.
Belongs to the krueppel C2H2-type zinc-finger protein family.
May be involved in transcriptional regulation.
Negatively regulates cilia formation by recruiting the CP110-CEP97 complex (a negative regulator of ciliogenesis) at the distal end of the mother centriole in ciliary cells (PubMed:30375385). At the beginning of cilia formation, MPHOSPH9 undergoes TTBK2-mediated phosphorylation and degradation via the ubiquitin-proteasome system and removes itself and the CP110-CEP97 complex from the distal end of the mother centriole, which subsequently promotes cilia formation (PubMed:30375385).
TTBK2-mediated phosphorylation at Ser-781 and Ser-788, promotes its ubiquitination at Lys-784 leading to proteasomal degradation, loss of MPHOSPH9 facilitates the removal of the CP110-CEP97 complex from the mother centrioles, promoting the initiation of ciliogenesis (PubMed:30375385). Phosphorylated in M (mitotic) phase (PubMed:8885239).
Ubiquitinated at Lys-784, leading to proteasomal degradation.
Probably functions as a spermatogenesis-specific component of the DNA-binding general transcription factor complex TFIID, a multimeric protein complex that plays a central role in mediating promoter responses to various activators and repressors. May play a role in spermatogenesis (By similarity).
TFIID is composed of TATA binding protein (TBP) and a number of TBP-associated factors (TAFs). TAF7L may replace TAF7 in a spermatogenesis-specific form of TFIID. Interacts with TBP; the interaction occurs in a sub-population of cells (pachytene and haploid round spermatids) and is developmentally regulated through differential intracellular localization of the two proteins. Interacts with TAF1 (By similarity).
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.
Component of a protein kinase signal transduction cascade. Activates the CSBP2, P38 and JNK MAPK pathways, but not the ERK pathway. Specifically phosphorylates and activates MAP2K4 and MAP2K6.
Expressed at high levels in heart, placenta, skeletal muscle and pancreas, and at lower levels in other tissues.
Monomer and homodimer. Homodimerization enhances kinase activity. Interacts with TRAF4; this promotes homodimerization (PubMed:16157600). Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with AXIN1 and DIXDC1; interaction with DIXDC1 prevents interaction with AXIN1 (PubMed:15262978). Interacts with GADD45 and MAP2K6 (PubMed:12052864). Interacts with ZFP36; this interaction enhances the association with SH3KBP1/CIN85 (PubMed:20221403). Interacts with SH3KBP1; this interaction enhances the association with ZFP36 (PubMed:20221403). Interacts with CDC42 (By similarity).
N-terminal autoinhibitory domain interacts with the C-terminal kinase domain, inhibiting kinase activity, and preventing interaction with its substrate, MAP2K6. The GADD45 proteins activate the kinase by binding to the N-terminal domain. Activated by phosphorylation on Thr-1505.
Directly interacts with tubulin-gamma; this interaction determines centrosomal localization.
Plays a role in the organization of both preexisting and nascent microtubules in interphase cells. During mitosis, required for the organization and orientation of the mitotic spindle.
The coiled-coil domains may be important for tubulin-gamma-binding and hence for centrosomal localization.
Oligomeric complex that consists of at least the alpha, beta, beta', gamma, delta, epsilon and zeta subunits. Interacts with ZNF289/ARFGAP2 through its C-terminal appendage domain. Interacts with EGFR upon EGF treatment; interaction is essential for regulation of EGF-dependent nuclear transport of EGFR by retrograde trafficking from the Golgi to the ER. Interacts with COPB1. Interacts with TMED10 (via C-terminus). Interacts with TMED2, TMED3, TMED7 and TMED9.
The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. Coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. In mammals, the coatomer can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins; the complex also influences the Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors. Required for limiting lipid storage in lipid droplets. Involved in lipid homeostasis by regulating the presence of perilipin family members PLIN2 and PLIN3 at the lipid droplet surface and promoting the association of adipocyte triglyceride lipase (PNPLA2) with the lipid droplet surface to mediate lipolysis (By similarity).
The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:25043029, PubMed:26083744). In the context of the APC/C complex, directly interacts with UBE2C and UBE2S (PubMed:27259151). Interacts (via cullin domain) with ANAPC11 and with UBCH10 (PubMed:11739784). Interacts with NEUROD2 (By similarity). Interacts with FBXO43; the interaction is direct.
Together with the RING-H2 protein ANAPC11, constitutes the catalytic component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. The CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. CDC20-APC/C-induced degradation of NEUROD2 drives presynaptic differentiation.
Belongs to the intercrine beta (chemokine CC) family.
Chemotactic for lymphocytes and monocytes. Is a ligand for CCR1, CCR3 and CCR5. Is an inhibitor of HIV-1-infection. The processed form LD78-beta(3-70) shows a 20-fold to 30-fold higher chemotactic activity and is a very potent inhibitor of HIV-1-infection. LD78-beta(3-70) is also a ligand for CCR1, CCR3 and CCR5.
The N-terminal processed forms LD78-beta(3-70) and LD78-beta(5-70) are produced by proteolytic cleavage after secretion from peripheral blood monocytes. The cleavage to yield LD78-beta(3-70) is probably achieved by DPP4.
The copy number of the CCL3L1 gene varies among individuals; most individuals have 1-6 copies in the diploid genome, although rare individuals have zero or more than 6 copies.
Inhibits factor X (X(a)) directly and, in a Xa-dependent way, inhibits VIIa/tissue factor activity, presumably by forming a quaternary Xa/LACI/VIIa/TF complex. It possesses an antithrombotic action and also the ability to associate with lipoproteins in plasma.
This inhibitor contains three inhibitory domains. The first domain interacts with VIIa and TF, the second one with Xa.
After T-cell activation, becomes hyperphosphorylated on Ser and Thr residues and phosphorylated on Tyr residues.
Cell adhesion molecule that mediates cell-cell contacts and regulates T-cell responses via its interaction with ALCAM/CD166 (PubMed:15048703, PubMed:15294938, PubMed:16352806, PubMed:16914752, PubMed:24945728, PubMed:24584089). Contributes to signaling cascades triggered by activation of the TCR/CD3 complex (PubMed:24584089). Functions as costimulatory molecule; promotes T-cell activation and proliferation (PubMed:15294938, PubMed:16352806, PubMed:16914752). Contributes to the formation and maturation of the immunological synapse (PubMed:15294938, PubMed:16352806). Functions as calcium-dependent pattern receptor that binds and aggregates both Gram-positive and Gram-negative bacteria. Binds both lipopolysaccharide (LPS) from Gram-negative bacteria and lipoteichoic acid from Gram-positive bacteria (PubMed:17601777). LPS binding leads to the activation of signaling cascades and down-stream MAP kinases (PubMed:17601777). Mediates activation of the inflammatory response and the secretion of pro-inflammatory cytokines in response to LPS (PubMed:17601777).
Detected on thymocytes (PubMed:15294938). Detected on peripheral blood T-cells (PubMed:15048703, PubMed:16352806). Detected on natural killer (NK) cells (PubMed:16352806). Soluble CD6 is detected in blood serum (at protein level) (PubMed:17601777). Detected in spleen, thymus, appendix, lymph node and peripheral blood leukocytes (PubMed:9013954). Expressed by thymocytes, mature T-cells, a subset of B-cells known as B-1 cells, and by some cells in the brain.
Interacts (via extracellular domain) with ALCAM/CD166 (via extracellular domain) (PubMed:15048703, PubMed:16352806, PubMed:16914752, PubMed:24945728, PubMed:26146185). Interacts with the TCR/CD3 complex subunit CD3E (PubMed:15294938). Interacts (via tyrosine phosphorylated C-terminus) with LCP2 (via SH2 domain) (PubMed:16914752). Interacts with VAV1 (By similarity). Interacts (via glycosylated extracellular domain) with LGALS1 and LGALS3 (PubMed:24945728). Interaction with LGALS1 or LGALS3 inhibits interaction with ALCAM (PubMed:24945728).
Lacks conserved residue(s) required for the propagation of feature annotation.
Lacks the third SRCR domain and doesn't bind ALCAM/CD166. Doesn't localize to the immunological synapse.
Lacks the third SRCR domain and doesn't bind ALCAM/CD166. Doesn't localize to the immunological synapse. Constitutes the only expressed species in a small percentage of T-cells.
Belongs to the intermediate filament family.
Has a role in hair formation. Specific component of keratin intermediate filaments in the inner root sheath (IRS) of the hair follicle (Probable).
Heterotetramer of two type I and two type II keratins.
Highly expressed in hair follicles from scalp and eyebrow. Also expressed in palmoplantar epidermis. Not expressed in face skin despite the presence of fine hairs histologically. In hair, it is specifically present in the inner root sheath (IRS) of the hair follicle. Present in the IRS cuticle, but not in Henle or Huxley layers of the IRS. In the IRS cuticle, its presence is delayed up to the height of the apex of the dermal papilla (at protein level).
There are two types of cytoskeletal and microfibrillar keratin, I (acidic) and II (neutral to basic) (40-55 and 56-70 kDa, respectively).
Was initially thought to be the ortholog of mouse KRT71.
Activated by RNAs having enough uridines.
Belongs to the Toll-like receptor family.
Endosomal receptor that plays a key role in innate and adaptive immunity (PubMed:25297876, PubMed:32433612). Controls host immune response against pathogens through recognition of RNA degradation products specific to microorganisms that are initially processed by RNASET2 (PubMed:31778653). Recognizes GU-rich single-stranded RNA (GU-rich RNA) derived from SARS-CoV-2, SARS-CoV-1 and HIV-1 viruses (PubMed:33718825). Upon binding to agonists, undergoes dimerization that brings TIR domains from the two molecules into direct contact, leading to the recruitment of TIR-containing downstream adapter MYD88 through homotypic interaction (PubMed:23520111, PubMed:25599397, PubMed:26929371, PubMed:33718825). In turn, the Myddosome signaling complex is formed involving IRAK4, IRAK1, TRAF6, TRAF3 leading to activation of downstream transcription factors NF-kappa-B and IRF7 to induce pro-inflammatory cytokines and interferons, respectively (PubMed:16737960, PubMed:17932028, PubMed:29155428).
Expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells.
Homodimer (PubMed:23520111, PubMed:25599397, PubMed:26929371, PubMed:29155428). Interacts with MYD88 via their respective TIR domains (Probable). Interacts with UNC93B1 (By similarity). Interacts with BTK (PubMed:17932028). Interacts with SMPDL3B (By similarity).
Proteolytic processing occurs in monocytes and monocyte-derived macrophages by both furin-like proprotein convertase and cathepsins (PubMed:25297876). The cleavage is necessary for dimer formation and subsequent activation (PubMed:26929371).
Ubiquitinated by RNF216; leading to degradation by the proteasome.
(Microbial infection) Interacts with adenovirus hexon-interlacing protein; this interaction leads to capsid disruption at the nuclear pore complex during virus entry into host cell.
Belongs to the kinesin light chain family.
Found in a variety of tissues. Mostly abundant in brain and spine.
It is uncertain whether Met-1 or Met-5 is the initiator.
Kinesin is a microtubule-associated force-producing protein that may play a role in organelle transport (PubMed:21385839). The light chain may function in coupling of cargo to the heavy chain or in the modulation of its ATPase activity (By similarity).
Kinesin is a microtubule-associated force-producing protein that play a role in organelle transport.
Oligomeric complex composed of two heavy chains and two light chains.
Oligomeric complex composed of two heavy chains and two light chains. Interacts with SPAG9 (By similarity). Interacts with ATCAY; may link mitochondria to KLC1 and regulate mitochondria localization into neuron projections (By similarity). Interacts (via TPR repeats) with TOR1A; the interaction associates TOR1A with the kinesin oligomeric complex (PubMed:14970196). Interacts with BORCS5 (PubMed:25898167). Interacts with MAPK8IP3/JIP3 and NTRK2/TRKB; interaction with NTRK2/TRKB is mediated by MAPK8IP3/JIP3 (By similarity). Interacts with CLSTN1; phosphorylation at Ser-460 inhibits interaction with CLSTN1 (PubMed:21385839).
Phosphorylation at Ser-460 by ERK inhibits interaction with CLSTN1 and localization to cytoplasmic vesicles.
May mediate a process in spermatogenesis or may play a role in sex ratio distortion.
Belongs to the RIN (Ras interaction/interference) family.
Interacts with CD2AP, RAB5B, RAB31 and BIN1.
Ras effector protein that functions as a guanine nucleotide exchange (GEF) for RAB5B and RAB31, by exchanging bound GDP for free GTP. Required for normal RAB31 function.
May be involved in signal transduction as a component of a multimeric receptor complex.
Belongs to the nucleotide-sugar transporter family. SLC35A subfamily.
Interacts with SLC35A3; the interaction is reduced in the presence of SLC35A4 (PubMed:23089177, PubMed:28167211). Found in a complex with SLC35A3 and SLC35A4 (PubMed:28167211).
Transports uridine diphosphate galactose (UDP-galactose) from the cytosol into the Golgi apparatus, functioning as an antiporter that exchanges UDP-galactose for UMP (PubMed:9010752, PubMed:12682060). It is also able to exchange UDP-galactose for AMP and CMP, and to transport UDP-N-acetylgalactosamine (UDP-GalNAc) and other nucleotide sugars (PubMed:12682060, PubMed:11784306). As a provider of UDP-galactose to galactosyltransferases present in the Golgi apparatus, it is necessary for globotriaosylceramide/globoside (Gb3Cer) synthesis from lactosylceramide (PubMed:30817854).
Dephosphorylation results in its dissociation from CAPZA2.
Highly expressed in skeletal muscle and more weakly in cardiac muscle. Also expressed in several lymphoid organs, including spleen, thymus, peripheral blood leukocytes, lymph node and bone marrow.
Stress-induced phosphorylation of CAPZIP may regulate the ability of F-actin-capping protein to remodel actin filament assembly.
Monomer (PubMed:24821723, PubMed:24272907). Homodimer (PubMed:24821723, PubMed:24272907). Interacts with type III, type IV and type X collagens (PubMed:24821723).
PPIase which accelerates the folding of proteins during protein synthesis. Has a preference for substrates containing 4-hydroxylproline modifications, including type III collagen. May also target type VI and type X collagens.
Contrary to isoforms 1 and 2, isoforms 3 and 4 do not contain any BH3 motif.
Essential mediator of p53/TP53-dependent and p53/TP53-independent apoptosis (PubMed:11463391, PubMed:23340338). Promotes partial unfolding of BCL2L1 and dissociation of BCL2L1 from p53/TP53, releasing the bound p53/TP53 to induce apoptosis (PubMed:23340338). Regulates ER stress-induced neuronal apoptosis (By similarity).
Interacts with MCL1 and BCL2A1 (By similarity). Interacts (via BH3 domain) with BCL2 (PubMed:11463391). Interacts with BCL2L1/BCL-XL (PubMed:23340338). Interacts (via BH3 domain) with NOL3/ARC (via CARD domain); this interaction prevents BBC3 association with BCL2 and results in CASP8 activation (By similarity).
The BH3 motif is intrinsically disordered in the absence of a binding partner but folds upon binding (PubMed:23340338). Folds when bound to BCL2L1 (PubMed:23340338). Also folds when bound to MCL1 (By similarity).
Up-regulated by TP53 (PubMed:11463392, PubMed:11572983). Up-regulated by DNA damage, glucocorticoid treatment and growth factor deprivation (PubMed:11572983). Up-regulated by ER stress in a DDIT3/CHOP-dependent manner (PubMed:22761832).
A chromosomal aberration involving CHIC2 is found in a form of acute myeloid leukemia (AML). Translocation t(4;12)(q12;p13) with ETV6.
Palmitoylation in the CHIC motif is required for membrane association.
Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers (By similarity). Binds to the barbed end of the actin filament and slows down actin polymerization and depolymerization (By similarity). Required for cytokinesis, and transcriptional activation of the serum response factor (By similarity). DFR proteins couple Rho and Src tyrosine kinase during signaling and the regulation of actin dynamics (By similarity). Functions as a scaffold protein for MAPRE1 and APC to stabilize microtubules and promote cell migration (By similarity). Has neurite outgrowth promoting activity. Acts in a Rho-dependent manner to recruit PFY1 to the membrane (By similarity). In hear cells, it may play a role in the regulation of actin polymerization in hair cells (PubMed:20937854, PubMed:21834987, PubMed:26912466). The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854, PubMed:21834987). It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity (PubMed:20937854, PubMed:21834987). In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (PubMed:20937854, PubMed:21834987). Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape (PubMed:20937854, PubMed:21834987). Plays a role in brain development (PubMed:24781755). Also acts as an actin nucleation and elongation factor in the nucleus by promoting nuclear actin polymerization inside the nucleus to drive serum-dependent SRF-MRTFA activity (By similarity).
Belongs to the formin homology family. Diaphanous subfamily.
Expressed in brain, heart, placenta, lung, kidney, pancreas, liver, skeletal muscle and cochlea. Expressed in platelets (PubMed:26912466).
Homodimer (By similarity). Interacts with the GTP-bound form of RHOA (PubMed:23325789). Interacts with RHOC, PFY1, MAPRE1 and BAIAP2 (By similarity). Interacts with APC; acts as a scaffold protein for MAPRE1 and APC to stabilize microtubules and promote cell migration (By similarity). Interacts with SCAI (By similarity). Interacts with DCAF7, via FH2 domain (By similarity). Interacts with NCDN (By similarity). Interacts with OSBPL10, OSBPL2, VIM, TUBB and DYN1 (PubMed:23325789).
Phosphorylation at Thr-768 is stimulated by cAMP and regulates stability, complex formation and mitochondrial movement.
Strongly expressed in ventricular and subventricular zone progenitor cells of the neocortical wall at 12 weeks post-conception.
The DAD domain regulates activation via by an autoinhibitory interaction with the GBD/FH3 domain (By similarity). This autoinhibition is released upon competitive binding of an activated GTPase (By similarity). The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments (By similarity).
Belongs to the UDP-glycosyltransferase family.
Expressed in many tissues. Present in liver, prostate and testis.
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:7835232, PubMed:9295060, PubMed:16595710, PubMed:18719240, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:7835232). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (testosterone, androsterone) and estrogens (estradiol, epiestradiol, estriol, catechol estrogens) (PubMed:7835232, PubMed:9295060, PubMed:16595710, PubMed:18719240, PubMed:23288867). Displays glucuronidation activity toward several classes of xenobiotic substrates, including phenolic compounds (eugenol, 4-nitrophenol, 4-hydroxybiphenyl) and phenylpropanoids (naringenin, coumarins) (PubMed:7835232). Catalyzes the glucuronidation of monoterpenoid alcohols such as borneol, menthol and isomenthol, a class of natural compounds used in essential oils (By similarity).
Auxiliary enzyme of beta-oxidation. Participates in the degradation of unsaturated fatty enoyl-CoA esters having double bonds in both even- and odd-numbered positions in peroxisome. Catalyzes the NADP-dependent reduction of 2,4-dienoyl-CoA to yield trans-3-enoyl-CoA. Has activity towards short and medium chain 2,4-dienoyl-CoAs, but also towards 2,4,7,10,13,16,19-docosaheptaenoyl-CoA, suggesting that it does not constitute a rate limiting step in the peroxisomal degradation of docosahexaenoic acid.
Belongs to the short-chain dehydrogenases/reductases (SDR) family. 2,4-dienoyl-CoA reductase subfamily.
Cooperates with CIITA to promote transcription of MHC class I and MHC class II genes.
May be expressed in brain, heart, kidney, liver, lung, muscle and placenta.
Self-associates. Interacts with ZXDC and CIITA.
Component of the sarcomeric M-band which plays a role in myocyte response to biomechanical stress. May regulate expression of other M-band proteins via an SRF-dependent pathway. Important for normal contractile function in heart.
Highly expressed in skeletal muscle and heart. Not detected in other tissues tested.
Component of the SCF-like E3 ubiquitin-protein ligase complex which contains CUL3, RBX1, ELOB, ELOC and ZSWIM8.
Substrate recognition component of a SCF-like E3 ubiquitin-protein ligase complex that promotes target-directed microRNA degradation (TDMD), a process that mediates degradation of microRNAs (miRNAs) (PubMed:33184234, PubMed:33184237). The SCF-like E3 ubiquitin-protein ligase complex acts by catalyzing ubiquitination and subsequent degradation of AGO proteins (AGO1, AGO2, AGO3 and/or AGO4), thereby exposing miRNAs for degradation (PubMed:33184234, PubMed:33184237). Specifically recognizes and binds AGO proteins when they are engaged with a TDMD target (PubMed:33184234). May also act as a regulator of axon guidance: specifically recognizes misfolded ROBO3 and promotes its ubiquitination and subsequent degradation (PubMed:24012004).
Ensures normal bone formation, through the negative regulation of bone morphogenetic protein (BMP) signaling in osteoblast lineage cells by blocking cytoplasm-nucleus translocation of phosphorylated SMAD1/5/9 proteins.
The CR1 and CR2 motifs mediate sequence-specific DNA binding, and are important for binding to the MYOD1 enhancer.
Transcription factor which binds to RE2 sequence elements in the MYOD1 enhancer.
Acts as a transcriptional regulator. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3'). Associates with chromatin to enhancer regulatory elements in genes encoding key transcriptional regulators of neurogenesis (By similarity).
Efficient DNA binding requires dimerization with another bHLH protein.
Expression restricted to the embryonic nervous system.
(Microbial infection) Acts as a target for S.flexneri infection by binding to the bacterium, possibly via bacterial surface proteins, and thereby augmenting infectivity via enhanced bacterial adhesion and invasion of epithelial cells and tissues.
(Microbial infection) The disulfide bridges and homodimerization are a prerequisite for the enhancement of S.flexneri adhesion and invasion.
Expressed in the gastrointestinal, reproductive, and urinary tracts (at protein level) (PubMed:1429669, PubMed:12021776, PubMed:9588893, PubMed:22359618). Expressed in Paneth cells of the small intestine (at protein level) (PubMed:1429669, PubMed:12021776). Expressed throughout the urothelium of the lower urinary tract and in the collecting tubules of the kidney (at protein level) (PubMed:22359618). Expressed in stratified squamous epithelial cells of the female genital tract epithelia, such as in vagina, ectocervix, endocervix, endometrium, and fallopian tube (at protein level) (PubMed:9588893). Endometrial expression correlates with stages of the menstrual cycle: Expression is low during the early proliferative phase, increased during the mid- to late proliferative phase, peaks during the early secretory phase of the cycle, and decreases during the mid- to late secretory phase (PubMed:9588893).
Homodimer (PubMed:17088326, PubMed:22573326, PubMed:25782105, PubMed:29858013). Homotetramer (PubMed:23163963). Interacts with B.antracis lef/lethal factor (PubMed:22573326).
Host-defense peptide that maintains sterility in the urogenital system (PubMed:12021776, PubMed:12660734, PubMed:15616305, PubMed:22359618, PubMed:25354318, PubMed:30808760, PubMed:19589339, PubMed:22573326, PubMed:25782105). Has antimicrobial activity against a wide range of bacteria, including Gram-negative E.coli, P.aeruginosa and S.typhimurium, and Gram-positive E.aerogenes, S.aureus, B.cereus, E.faecium and L.monocytogenes (PubMed:12021776, PubMed:15616305, PubMed:22359618, PubMed:25354318, PubMed:30808760, PubMed:19589339, PubMed:22573326). Confers resistance to intestinal infection by S.typhimurium (PubMed:12660734). Exhibits antimicrobial activity against enteric commensal bacteria such as B.adolescentis, L.acidophilus, B.breve, L.fermentum, B.longum and S.thermophilus (PubMed:25354318). Binds to bacterial membranes and causes membrane disintegration (PubMed:25782105). Induces the secretion of the chemokine IL-8 by intestinal epithelial cells (PubMed:19589339). Binds to B.antracis lef/lethal factor, a major virulence factor from B.anthracis, and neutralizes its enzymatic activity (PubMed:22573326).
It was shown by two studies that dimerization of DEFA5 is crucial for antimicrobial activity (PubMed:17088326, PubMed:22573326). Another study, however, states that dimer formation is not indispensable for antimicrobial activity of DEFA5 (PubMed:25782105).
Proteolytically cleaved at Arg-62 by trypsin (PubMed:12021776). Both the propeptide form proHD5/HD5(20-94) and HD5(56-94) are cleaved into the lumenal peptide form HD5(63-94) by trypsin (PubMed:12021776). Unprocessed proHD5 exerts antimicrobial activities, but peptide potency is enhanced by peptide processing (PubMed:12021776). Proteolytically cleaved in duodenal fluid; derived fragments are antimicrobially active against commensal bacteria (in vitro) (PubMed:30808760).
Up-regulated in fallopian tubes upon infection (PubMed:9588893). Increased expression in kidneys with pyelonephritis (PubMed:22359618).
Belongs to the GST superfamily. Pi family.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Involved in the formation of glutathione conjugates of both prostaglandin A2 (PGA2) and prostaglandin J2 (PGJ2) (PubMed:9084911). Participates in the formation of novel hepoxilin regioisomers (PubMed:21046276). Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
Ap4A synthesis is inhibited by tRNA, via the disruption of the second ATP-binding site by direct blocking and/or by tRNA-induced conformational change.
Belongs to the class-II aminoacyl-tRNA synthetase family.
Catalyzes the ATP-dependent ligation of glycine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP) (PubMed:17544401, PubMed:28675565, PubMed:24898252). Also produces diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways, by direct condensation of 2 ATPs. Thereby, may play a special role in Ap4A homeostasis (PubMed:19710017).
Expressed in brain, spinal cord, muscle, heart and spleen.
Expressed in brain, spinal cord, muscle, heart, spleen and liver.
Human GlyRS uses direct ATP condensation to synthesize Ap4A, a unique amino acid-independent mechanism, in contrast to the classical amino acid-dependent mechanism for synthesis of Ap4A by a tRNA synthetase, that involves the generation of an enzyme-bound aminoacyl-AMP which is then attacked by ATP to form Ap4A.
The isoform 2 translation is regulated by an Internal Ribosome Entry Site (IRES) and an upstream Open Reading Frame. Both are important in hindering the synthesis of the mitochondrial GARS and target the translation of the cytosolic enzyme to ER-bound ribosomes.
Widely expressed, including in brain and spinal cord.
Belongs to the peptidase S1 family. Plasma kallikrein subfamily.
Forms a heterodimer with SERPINA5. The zymogen is activated by factor XIIa, which cleaves the molecule into a light chain, which contains the active site, and a heavy chain, which associates with HMW kininogen. These chains are linked by one or more disulfide bonds.
The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin.
Highly expressed in kidney, lung and skeletal muscle. Expressed at intermediate levels in brain, heart, placenta, liver and pancreas. Isoform 1 is predominant, while isoform 2 and isoform 3 are expressed at lower levels.
Interacts with PARD6B. Interacts with INSC/inscuteable.
Putative adapter protein involved in asymmetrical cell division and cell polarization processes. May play a role in the formation of epithelial tight junctions.
The N-terminal part (1-351) part blocks the association of the tight junction marker TJP1 with the cell-cell boundary when it is overexpressed.
Expressed in all tissues examined. High levels seen in the ovary, kidney and placenta while low levels seen in thymus and skeletal muscle.
Proteolytic enzyme possibly involved in normal cellular protein degradation and turnover.
Expressed in cardiac and skeletal muscle.
Interacts with actin, alpha-actinin, KLHL41, TLN1 and VCL. Interacts with CSRP3.
May be involved in anchoring the terminal actin filaments in the myofibril to the membrane and in transmitting tension from the myofibrils to the extracellular matrix.
Expressed in visceral and subcutaneous adipose tissue.
Putative transcription factor that appears to regulate lipid metabolism.
Up-regulated in both visceral and subcutaneous adipose tissue of diabetic individuals.
Belongs to the glucose-6-phosphatase family.
Genetic variations in G6PC2 define the fasting plasma glucose levels quantitative trait locus 1 (FGQTL1) [MIM:612108]. The normal fasting plasma glucose level in the plasma is defined as less than 100 mg per deciliter (5.55 mmol per liter). Higher fasting plasma glucose levels predict type 2 diabetes in young adults and increases the risk of mortality.
May hydrolyze glucose-6-phosphate to glucose in the endoplasmic reticulum. May be responsible for glucose production through glycogenolysis and gluconeogenesis (By similarity).
N-glycosylated; the non-glycosylated form is more unstable and is degraded through the proteasome.
Specifically expressed in pancreas and also detected to a lower extent in testis. Expressed by most islet cells in the pancreas (at protein level).
Preferentially expressed in teratocarcinoma rather than in normal testis.
Belongs to the DNA/RNA non-specific endonuclease family.
Interacts with RNF26; this interaction is important to modulate innate immune signaling through the cGAS-STING pathway (PubMed:32614325).
May act as a DNase and a RNase. Plays a role in the modulation of innate immune signaling through the cGAS-STING pathway by interacting with RNF26.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family.
Interacts (via residues 1146-1167) with KANK1 (via ankyrin repeats 1-5) and KANK2 (via ankyrin repeats 1-5).
Microtubule-binding motor protein probably involved in neuronal axonal transport. In vitro, has a plus-end directed motor activity.
Highly expressed in primary hepatocarcinoma. Detected in lung, liver and blood leukocytes.
Homodimer. Interacts with GRIA1 and GRIA2 (By similarity).
May regulate AMPA receptor content at nascent synapses, and have a role in postsynaptic development and maturation.
Addition of GM2A stimulates the hydrolysis of sulfated glycosphingolipid SM2 and the ganglioside GM2.
Belongs to the glycosyl hydrolase 20 family.
Hydrolyzes the non-reducing end N-acetyl-D-hexosamine and/or sulfated N-acetyl-D-hexosamine of glycoconjugates, such as the oligosaccharide moieties from proteins and neutral glycolipids, or from certain mucopolysaccharides (PubMed:11707436, PubMed:9694901, PubMed:8672428, PubMed:8123671). The isozyme B does not hydrolyze each of these substrates, however hydrolyzes efficiently neutral oligosaccharide (PubMed:11707436). Only the isozyme A is responsible for the degradation of GM2 gangliosides in the presence of GM2A (PubMed:9694901, PubMed:8672428, PubMed:8123671). During fertilization is responsible, at least in part, for the zona block to polyspermy. Present in the cortical granules of non-activated oocytes, is exocytosed during the cortical reaction in response to oocyte activation and inactivates the sperm galactosyltransferase-binding site, accounting for the block in sperm binding to the zona pellucida (By similarity).
N-linked glycans at Asn-142 and Asn-190 consist of Man(3)-GlcNAc(2) and Man(5 to 7)-GlcNAc(2), respectively.
The beta-A and beta-B chains are produced by proteolytic processing of the precursor beta chain.
There are 3 forms of beta-hexosaminidase: hexosaminidase A is an heterodimer composed of one subunit alpha and one subunit beta (chain A and B); hexosaminidase B is an homodimer of two beta subunits (two chains A and B); hexosaminidase S is a homodimer of two alpha subunits (By similarity). The composition of the dimer (isozyme A versus isozyme S) has a significant effect on the substrate specificity of the alpha subunit active site (PubMed:8672428).
(Microbial infection) Interacts with HBV protein X.
Belongs to the archaeal Rpo5/eukaryotic RPB5 RNA polymerase subunit family.
Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively (PubMed:9852112, PubMed:16809778). In RNA Pol II, this subunit is present in 2-fold molar excess over the other subunits (PubMed:9852112). Component of the PAQosome complex which is responsible for the biogenesis of several protein complexes and which consists of R2TP complex members RUVBL1, RUVBL2, RPAP3 and PIH1D1, URI complex members PFDN2, PFDN6, PDRG1, UXT and URI1 as well as ASDURF, POLR2E and DNAAF10/WDR92 (PubMed:31738558). Interacts with URI1 (PubMed:9819440).
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2E/RPB5 is part of the lower jaw surrounding the central large cleft and thought to grab the incoming DNA template. Seems to be the major component in this process (By similarity).
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2E/RPB5 is part of the lower jaw surrounding the central large cleft and thought to grab the incoming DNA template. Seems to be the major component in this process.
Dubious isoform produced through aberrant splice sites.
Expressed abundantly in the stomach, the Clara cells of the lung and activated B-lymphocytes, and at lower levels in lymph nodes, skin and spleen. Not expressed in resting B-lymphocytes.
Glycosylated. The nature of the carbohydrate chain varies between cell types. In fibroblasts, the proenzyme contains a high mannose-type oligosaccharide, while the mature enzyme contains a complex-type oligosaccharide. In erythrocyte membranes, both the proenzyme and mature enzyme contain a complex-type oligosaccharide.
May have a role in immune function. Probably involved in the processing of antigenic peptides during MHC class II-mediated antigen presentation. May play a role in activation-induced lymphocyte depletion in the thymus, and in neuronal degeneration and glial cell activation in the brain.
Two forms are produced by autocatalytic cleavage, form I begins at Ile-54, form II begins at Thr-57.
Belongs to the Golgi pH regulator (TC 1.A.38) family.
Homotrimer (PubMed:18794847). Interacts with RABL3; the interaction stabilizes GPR89A (By similarity).
Homotrimer (PubMed:18794847). Interacts with RABL3; the interaction stabilizes GPR89B (By similarity).
Voltage dependent anion channel required for acidification and functions of the Golgi apparatus that may function in counter-ion conductance (PubMed:12761501, PubMed:18794847). Plays a role in lymphocyte development, probably by acting as a RABL3 effector in hematopoietic cells (By similarity).
Voltage dependent anion channel required for acidification and functions of the Golgi apparatus that may function in counter-ion conductance (PubMed:18794847). Plays a role in lymphocyte development, probably by acting as a RABL3 effector in hematopoietic cells (By similarity).
A family of highly similar proteins (GOLGA8A, GOLGA8B, GOLGA8C, GOLGA8D, GOLGA8E, GOLGA8F, GOLGA8G) are encoded by a repeated region on chromosome 15q11-15q13. Our sequences are in agreement with HGNC nomenclature.
May be involved in maintaining Golgi structure.
By activation of the Notch signaling pathway.
Downstream effector of Notch signaling which may be required for cardiovascular development (By similarity). Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGTG-3' (By similarity). Represses transcription by the cardiac transcriptional activators GATA4 and GATA6.
Self-associates. Interacts with GATA4, GATA6, HES1, HEY1 and HEY2. Interacts with HDAC1, NCOR1 and SIN3A.
Belongs to the bZIP family. Maf subfamily.
Expressed in the islets of Langerhans (at protein level).
Forms homodimers or heterodimers (PubMed:12011435, PubMed:23148532). Monomers and dimers are able to bind DNA, but the off-rate is faster for monomers (PubMed:23148532). Interacts with NEUROD1 and PDX1 (By similarity). May interact with MAFB, FOS, JUN and PCAF (By similarity).
Transcription factor that activates insulin gene expression (PubMed:15993959, PubMed:12011435). Acts synergistically with NEUROD1/BETA2 and PDX1 (PubMed:15993959). Binds the insulin enhancer C1/RIPE3b element (PubMed:12011435). Binds to consensus TRE-type MARE 5'-TGCTGACTCAGCA-3' DNA sequence (PubMed:23148532, PubMed:29339498).
Ubiquitinated, leading to its degradation by the proteasome.
Deubiquitinating enzyme that functions as negative regulator of the innate immune system (PubMed:17991829, PubMed:22245969, PubMed:23827681, PubMed:33523931). Has peptidase activity towards 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains (PubMed:22245969). Can also cleave 'Lys-11'-linked ubiquitin chains (in vitro) (PubMed:22245969). Acts via TRAF3 deubiquitination and subsequent suppression of type I interferon (IFN) production (PubMed:17991829). Controls neuroectodermal differentiation through cleaving 'Lys-48'-linked ubiquitin chains to counteract degradation of select chromatin regulators such as ARID1A, HDAC2 and HCF1 (PubMed:33523931). Acts as a positive regulator of mTORC1 and mTORC2 signaling following phosphorylation by MTOR: acts by mediating deubiquitination of BTRC, leading to its stability (PubMed:33110214).
Expressed in various tissues, including the liver and placenta, as well as in peripheral blood leukocytes.
Phosphorylation at Ser-177 is required for deubiquitinating activity (PubMed:22245969, PubMed:33523931). Phosphorylation at Ser-328, Ser-337 and Ser-508 by MTOR promotes its activity (PubMed:33110214).
Up-regulated by bacterial lipopolysaccharide (LPS) in bone marrow-derived macrophages.
Homodimer at neutral pH and homooctamer at acidic pH. Exists both as a single chain of 58 kDa (component A) or as a chain of 50 kDa (component B) linked by disulfide bond(s) to a 7 kDa chain (component C). Interacts with SUMF1.
Inhibited by phosphate. The phosphate forms a covalent bond with the active site 3-oxoalanine.
The conversion to 3-oxoalanine (also known as C-formylglycine, FGly), of a serine or cysteine residue in prokaryotes and of a cysteine residue in eukaryotes, is critical for catalytic activity. This post-translational modification is severely defective in multiple sulfatase deficiency (MSD).
The metal cofactor was first identified as magnesium ion, based on the structure of the recombinant protein, but when purified from human placenta, the protein contains 1 calcium ion per subunit.
The protein represented in this entry is involved in disease pathogenesis. Arylsulfatase A activity is impaired in multiple sulfatase deficiency due to mutations in SUMF1 (PubMed:15146462). SUMF1 mutations result in defective post-translational modification of ARSA at residue Cys-69 that is not converted to 3-oxoalanine (PubMed:7628016).
Belongs to the Nudix hydrolase family. DIPP subfamily.
Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate) and [PP]2-InsP4 (bisdiphosphoinositol tetrakisphosphate), suggesting that it may play a role in signal transduction (PubMed:12370170, PubMed:9822604, PubMed:10585413). InsP6 (inositol hexakisphosphate) is not a substrate (PubMed:9822604). Acts as a negative regulator of the ERK1/2 pathway (By similarity). Also able to catalyze the hydrolysis of dinucleoside oligophosphates, with diadenosine 5',5'''-P1,P6-hexaphosphate (Ap6A) and diadenosine 5',5'''- P1,P5-pentaphosphate (Ap5A) being the preferred substrates (PubMed:12370170, PubMed:10419486). The major reaction products are ADP and p4a from Ap6A and ADP and ATP from Ap5A (PubMed:12370170). Also able to hydrolyze 5-phosphoribose 1-diphosphate (PubMed:12370170). Acts as a decapping enzyme that modulates the stability of a subset of mRNAs implicated in cell motility (PubMed:26932476). Hydrolyzes monomethylated capped RNA after both the alpha- and beta-phosphates generating m7GMP + ppRNA and m7GDP + pRNA (PubMed:32727897). Can hydrolyze unmethylated capped RNAs (By similarity). Divalent cations zinc, magnesium and manganese determine its substrate specificity (PubMed:34788624). Exhibits diphosphoinositol polyphosphate phosphohydrolase in the presence of magnesium ions, diadenosine hexaphosphate hydrolase activity in the presence of manganese ions and endopolyphosphatase activity in the presence of zinc ions (PubMed:34788624). Plays an important role in limiting DNA damage and maintaining cell survival upon oxidative stress via its endopolyphosphatase activity (PubMed:34788624).
Endopolyphospahatase activity is inhibited by NaF, NaPPi, beta-glycerol phosphate and heparin (PubMed:34788624). 5-diphosphoinositol pentakisphosphate (5-InsP7) inhibits its mRNA decapping activity (PubMed:32727897).
Widely expressed. Expressed at higher level in brain, heart, pancreas and liver. Also expressed in placenta, lung and kidney.
Heterodimer of a catalytic (light) chain and a multidomain (heavy) chain linked by a disulfide bond.
Responsible for initiating activation of pancreatic proteolytic proenzymes (trypsin, chymotrypsin and carboxypeptidase A). It catalyzes the conversion of trypsinogen to trypsin which in turn activates other proenzymes including chymotrypsinogen, procarboxypeptidases, and proelastases.
The chains are derived from a single precursor that is cleaved by a trypsin-like protease.
Detected in placenta, lung, liver,heart and pancreas.
Homooligomer. Interacts with EGFR (By similarity).
May be involved in several stages of intracellular trafficking. Plays a role in protein transport from early to late endosomes. Plays a role in protein transport to the lysosome. Promotes degradation of EGFR after EGF signaling. Plays a role in intracellular transport of vesicular stomatitis virus nucleocapsids from the endosome to the cytoplasm.
The PX domain mediates interaction with membranes enriched in phosphatidylinositol 3-phosphate.
(Microbial infection) Interacts with hepatitis C virus/HCV non-structural protein NS5A; promotes the ubiquitin-mediated proteasomal degradation of NS5A.
Acetylation at Lys-68 and Lys-71 increases stability through impairment of APC/C-mediated proteolysis and promotes cytoplasmic retention. Deacetylated by SIRT3.
Part of a SCF(SKP2) complex consisting of CUL1, RBX1, SKP1 and SKP2. Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Interacts directly with CUL1 and SKP1. Interacts with CKS1. Interacts with ASB2 which is the substrate-recognition component of a probable ECS E3 ubiquitin-protein ligase complex; ASB2 is likely to bridge the formation of dimeric E3-ubiquitin-protein ligase complexes composed of an ECS complex and an SCF(SKP2) complex (PubMed:21119685). Interacts with the cyclin-A-CDK2 complex. Interacts with ORC1, phosphorylated CDT1, phosphorylated RBL2, ELF4, phosphorylated RAG2, FOXO1, UBP43, MYC, TOB1, TAL1 and KMT2A/MLL1. Interacts with TRIM21. Interacts with cyclin-E (By similarity). Interacts with IFI27; promotes the ubiquitin-mediated proteasomal degradation of hepatitis C virus/HCV non-structural protein NS5A (PubMed:27194766). Interacts with CARM1 (By similarity).
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins involved in cell cycle progression, signal transduction and transcription (PubMed:11931757, PubMed:12435635, PubMed:12769844, PubMed:12840033, PubMed:15342634, PubMed:15668399, PubMed:15949444, PubMed:16103164, PubMed:16262255, PubMed:16581786, PubMed:16951159, PubMed:17908926, PubMed:17962192, PubMed:22770219, PubMed:32267835). Specifically recognizes phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition (By similarity). Degradation of CDKN1B/p27kip also requires CKS1. Recognizes target proteins ORC1, CDT1, RBL2, KMT2A/MLL1, CDK9, RAG2, FOXO1, UBP43, YTHDF2, and probably MYC, TOB1 and TAL1 (PubMed:11931757, PubMed:12435635, PubMed:12769844, PubMed:12840033, PubMed:15342634, PubMed:15668399, PubMed:15949444, PubMed:16103164, PubMed:17962192, PubMed:16581786, PubMed:16951159, PubMed:17908926, PubMed:32267835). Degradation of TAL1 also requires STUB1 (PubMed:17962192). Recognizes CDKN1A in association with CCNE1 or CCNE2 and CDK2 (PubMed:16262255). Promotes ubiquitination and destruction of CDH1 in a CK1-dependent manner, thereby regulating cell migration (PubMed:22770219).
Through the ubiquitin-mediated proteasomal degradation of hepatitis C virus non-structural protein 5A, has an antiviral activity towards that virus.
Ubiquitinated by the APC/C complex, leading to its degradation by the proteasome. Deubiquitinated by USP13.
Catalyzes the hydrolysis of nucleoside triphosphates and diphosphates in a calcium- or magnesium-dependent manner, with a preference for pyrimidines. Preferentially hydrolyzes UTP and TTP. AMP, ADP, ATP and UMP are not substrates (PubMed:10858452, PubMed:9556635). Preferentially activated by Ca(2+) over Mg(2+) (PubMed:10858452).
Has a broad substrate specificity with the ability of cleaving all nucleotide di- and triphosphates with the exception of adenosine di- and triphosphate (ADP and ATP). Preferentially hydrolyzes CTP, UDP, CDP, GTP and GDP. Can use either Ca(2+) or Mg(2+) equally.
Ubiquitous. Highest expression in testis and lowest in bladder.
Belongs to the vitamin K-dependent gamma-carboxylase family.
Mediates the vitamin K-dependent carboxylation of glutamate residues to calcium-binding gamma-carboxyglutamate (Gla) residues with the concomitant conversion of the reduced hydroquinone form of vitamin K to vitamin K epoxide (PubMed:17073445). Catalyzes gamma-carboxylation of various proteins, such as blood coagulation factors (F2, F7, F9 and F10), osteocalcin (BGLAP) or matrix Gla protein (MGP) (PubMed:17073445).
Monomer (PubMed:11570873). May interact with CALU (By similarity).
The vitamin K-dependent protein substrates of carboxylase have usually a propeptide that binds to a high-affinity site on the carboxylase. CO(2), O(2) and reduced vitamin K are cosubstrates.
Plays an essential role in the protection and maintenance of transcriptional and developmental programs. Protects many bivalent promoters and poised enhancers from hypermethylation, showing a marked preference for these regulatory elements over other types of promoters or enhancers. Mechanistically, cooperates with TET1 and binds to DNA in a common complex to inhibit the binding of DNMT3A/3B and therefore de novo methylation.
Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, enables phosphorylation of Thr-436 and allows the kinase domain to adopt an active structure (By similarity).
Autophosphorylated when activated by CDC42/p21.
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.
Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Shows highly specific binding to the SH3 domains of phospholipase C-gamma and of adapter protein NCK. Interacts with the C-terminal of APP (By similarity). Interacts with ARHGEF6 and ARHGEF7. Interacts with GIT1 and GIT2 (PubMed:10896954).
Restricted to the nervous system. Highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus.
Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation. Plays a role in dendrite spine morphogenesis as well as synapse formation and plasticity. Acts as downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Additionally, phosphorylates TNNI3/troponin I to modulate calcium sensitivity and relaxation kinetics of thin myofilaments. May also be involved in early neuronal development. In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC) (By similarity).
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIC subfamily.
Specifically expressed in testis. Found in very low levels in skeletal muscle. Expressed in mature sperm (at protein level).
Specifically inhibited by an endogenous cardiac glycoside, ouabain.
The sodium/potassium-transporting ATPase is composed of a catalytic alpha subunit, an auxiliary non-catalytic beta subunit and an additional regulatory subunit.
This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients. Plays a role in sperm motility.
Acts as a nuclear transcription factor that positively regulates the expression of heat shock genes. Binds to heat shock promoter elements (HSE).
Expressed strongly in testis and brain and weakly in prostate, spleen, pancreas and uterus.
The N-terminus is necessary for nuclear localization. The C-terminus is necessary for transcriptional activity.
A number of inactive tetrameric holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. The cAMP-dependent protein kinase catalytic subunit binds PJA2. Both isoforms 1 and 2 forms activate cAMP-sensitive PKAI and PKAII holoenzymes by interacting with regulatory subunit (R) of PKA, PRKAR1A/PKR1 and PRKAR2A/PKR2, respectively. Interacts with PRKAR1A and PRKAR2B (PubMed:33058759). Interacts with NFKB1, NFKB2 and NFKBIA in platelets; these interactions are disrupted by thrombin and collagen. Binds to ABL1 in spermatozoa and with CDC25B in oocytes. Interacts with APOBEC3G and AICDA. Interacts with RAB13; downstream effector of RAB13 involved in tight junction assembly. Found in a complex at least composed of MROH2B, PRKACA isoform 2 and TCP11 (By similarity). Interacts with MROH2B (By similarity). Isoform 2 interacts with TCP11 (By similarity). Interacts with HSF1 (PubMed:21085490). Interacts with TBC1D31; in regulation of OFD1 (PubMed:33934390). Interacts in free form with SMO (via C-terminus); the interaction leads to sequestration of PRKACA at the membrane, preventing PRKACA-mediated phosphorylation of GLI transcription factors (By similarity).
Allosterically activated by various compounds, including ATP. Activated by cAMP; the nucleotide acts as a dynamic and allosteric activator by coupling the two lobes of apo PKA, enhancing the enzyme dynamics synchronously and priming it for catalysis. Inhibited by H89 (N-[2-[[3-(4-Bromophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulfonamide), spiroindoline, azole-based inhibitors, (3s)-amino-aminomethylbenzamide analogs, ARC-1032 (6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}-N-[(1R)-4-carbamimidamido-1-carbamoylbutyl]hexanamide), ARC-1034 (6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}-N-[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]hexanamide), ARC-582, ARC-902 (Adc-6-aminohexanoic acid-(D-Arg)(6)-NH(2)), ARC-1012 ((2R)-6-amino-2-(6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}hexanamido)-N-(5-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]carbamoyl}pentyl)hexanamide) and ARC-1039 (6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}-N-[(1R)-1-[(5-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]carbamoyl}pentyl)carbamoyl]ethyl]he xanamide).
Asn-3 is partially deaminated to Asp-3 giving rise to 2 major isoelectric variants, called CB and CA respectively.
Autophosphorylated. Phosphorylation is enhanced by vitamin K(2) (PubMed:12372837, PubMed:17909264). Phosphorylated on threonine and serine residues. Phosphorylation on Thr-198 is required for full activity (PubMed:16765046, PubMed:20137943, PubMed:20481595, PubMed:20732331, PubMed:21774789, Ref.43). Phosphorylated at Tyr-331 by activated receptor tyrosine kinases EGFR and PDGFR; this increases catalytic efficiency (By similarity).
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cAMP subfamily.
Isoform 1 is ubiquitous. Isoform 2 is sperm-specific and is enriched in pachytene spermatocytes but is not detected in round spermatids.
Phosphorylates a large number of substrates in the cytoplasm and the nucleus (PubMed:15642694, PubMed:15905176, PubMed:16387847, PubMed:17333334, PubMed:17565987, PubMed:17693412, PubMed:18836454, PubMed:19949837, PubMed:20356841, PubMed:21085490, PubMed:21514275, PubMed:21812984, PubMed:31112131). Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, SOX9 and VASP (PubMed:15642694, PubMed:15905176, PubMed:16387847, PubMed:17333334, PubMed:17565987, PubMed:17693412, PubMed:18836454, PubMed:19949837, PubMed:20356841, PubMed:21085490, PubMed:21514275, PubMed:21812984). Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis (PubMed:21423175). RORA is activated by phosphorylation (PubMed:21514275). Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts (PubMed:19949837). Involved in chondrogenesis by mediating phosphorylation of SOX9 (By similarity). Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP (PubMed:15642694, PubMed:20356841). Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated (PubMed:17333334). RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+) (PubMed:17693412). PSMC5/RPT6 activation by phosphorylation stimulates proteasome (PubMed:17565987). Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation (PubMed:15905176). NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding (PubMed:15642694). Required for phosphorylation of GLI transcription factors which inhibits them and prevents transcriptional activation of Hedgehog signaling pathway target genes (By similarity). GLI transcription factor phosphorylation is inhibited by interaction of PRKACA with SMO which sequesters PRKACA at the cell membrane (By similarity). Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis most probably through the regulation of OFD1 in ciliogenesis (PubMed:33934390). Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation (By similarity). May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT) (By similarity). Phosphorylates APOBEC3G and AICDA (PubMed:16387847, PubMed:18836454). Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock (PubMed:21085490). Acts as a negative regulator of mTORC1 by mediating phosphorylation of RPTOR (PubMed:31112131).
Phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation.
When myristoylated, Ser-11 is autophosphorylated probably in conjunction with deamidation of Asn-3.
Binds to nucleoporins. Found in a complex with XPO7, EIF4A1, ARHGAP1, VPS26A, VPS29, VPS35 and SFN. Interacts with ARHGAP1 and SFN. Interacts with Ran and cargo proteins in a GTP-dependent manner.
Mediates the nuclear export of proteins (cargos) with broad substrate specificity. In the nucleus binds cooperatively to its cargo and to the GTPase Ran in its active GTP-bound form. Docking of this trimeric complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the cargo from the export receptor. XPO7 then return to the nuclear compartment and mediate another round of transport. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus.
Strong expression in testis, thyroid and bone marrow, low expression in lung, liver and small intestine, no expression in thymus, and remaining tissues studied have moderate expression. Expressed in red blood cells; overexpressed in red blood cells (cytoplasm) of patients with hereditary non-spherocytic hemolytic anemia of unknown etiology.
Belongs to the SCAMP family. SCAMP5 subfamily.
Expressed both by neuronal and non-neuronal tissues. Expressed in brain, stomach, thyroid, spinal cord, lymph node, trachea, adrenal gland, bone marrow and in the different parts of brain. In thyroid tissues, it is expressed by the follicular epithelial cells. In the adrenal gland tissues it is detected in the zona fasciculata of the cortex region (at protein level).
Interacts (via C-terminal part) with SYT1 and SYT2; interaction with synaptotagmins making a link with the SNARE molecules. Interacts with SLC9A7.
Required for the calcium-dependent exocytosis of signal sequence-containing cytokines such as CCL5. Probably acts in cooperation with the SNARE machinery. May play a role in accumulation of expanded polyglutamine (polyQ) protein huntingtin (HTT) in case of endoplasmic reticulum stress by inhibiting the endocytosis pathway.
Probable chemokine receptor. Alternative coreceptor with CD4 for HIV-1 infection.
As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). Involved in the cytoskeletal anchoring of DLG4 in excitatory synapses (By similarity).
Component of the minor spliceosome. Within this complex, interacts with RNF113A, as well as with SF3B1/SF3b155, SF3B2/SF3b145 and PHF5A/SF3b14b (PubMed:33509932). Interacts with TUBB1. Interacts strongly with the PDZ3 domain of members of the DLG4 family. Associates with microtubules (By similarity). Interacts with DLG4.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Kinesin subfamily.
Composed of three structural domains: a large globular N-terminal domain which is responsible for the motor activity of kinesin (it hydrolyzes ATP and binds microtubule), a central alpha-helical coiled coil domain that mediates the heavy chain dimerization; and a small globular C-terminal domain which interacts with other proteins (such as the kinesin light chains), vesicles and membranous organelles.
Disease susceptibility is associated with variants affecting the gene represented in this entry. The mutation NM_004984.2:c.33019A>G encoding the predicted missence variant p.Arg1007Gly, may also affect splicing and induce the skipping of exon 27, resulting in a frameshift and a premature stop codon producing a truncated protein p.Asn999Valfs*39.
Distributed throughout the CNS but is highly enriched in subsets of neurons.
Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL). Can induce formation of neurite-like membrane protrusions in non-neuronal cells in a ZFYVE27-dependent manner. The ZFYVE27-KIF5A complex contributes to the vesicular transport of VAPA, VAPB, SURF4, RAB11A, RAB11B and RTN3 proteins in neurons. Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation.
Oligomer composed of two heavy chains and two light chains. Interacts with GRIP1. Interacts with FMR1 (via C-terminus); this interaction is increased in a mGluR-dependent manner. Interacts with ZFYVE27. Interacts with VAPA, VAPB, SURF4, RAB11A (GDP-bound form), RAB11B (GDP-bound form) and RTN3 in a ZFYVE27-dependent manner (By similarity). Interacts with BORCS5 (PubMed:25898167). Interacts with BICD2 (PubMed:20386726). Interacts with DTNB (By similarity).
Component of the conserved oligomeric Golgi complex which is composed of eight different subunits and is required for normal Golgi morphology and localization. Interacts with TMEM115.
Widely expressed with highest levels in pancreas and testis and lowest levels in lung.
Active thioredoxin with a redox potential of about -250 mV.
Component of the 19S regulatory cap of the 26S proteasome. Interacts with PSMD14/RPN11. Interacts with, and reduces EEF1A1.
3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholestanate (THCA) inhibits the activation of cholate.
Belongs to the ATP-dependent AMP-binding enzyme family.
May mediate the import of long-chain fatty acids (LCFA) by facilitating their transport across cell membranes (PubMed:20448275, PubMed:20530735). Also catalyzes the ATP-dependent formation of fatty acyl-CoA using LCFA and very-long-chain fatty acids (VLCFA) as substrates (PubMed:10479480). Mainly functions as a bile acyl-CoA synthetase catalyzing the activation of bile acids via ATP-dependent formation of bile acid CoA thioesters which is necessary for their subsequent conjugation with glycine or taurine (PubMed:10749848, PubMed:11980911). Both primary bile acids (cholic acid and chenodeoxycholic acid) and secondary bile acids (deoxycholic acid and lithocholic acid) are the principal substrates (PubMed:10749848, PubMed:11980911). In vitro, activates 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholestanate ((25R)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-oate or THCA), the C27 precursor of cholic acid deriving from the de novo synthesis from cholesterol (PubMed:11980911). Plays an important role in hepatic fatty acid uptake and bile acid reconjugation and recycling but not in de novo synthesis of bile acids (By similarity).
Interacts with cytolethal distending toxin.
Mediates action of cytolethal distending toxins (CDT), which are secreted by many pathogenic bacteria. Expression level of TMEM181 is rate-limiting for intoxication.
Chemotactic factor that attracts monocytes, lymphocytes, basophils and eosinophils, but not neutrophils. Signals through CCR2B and CCR3 receptors. Plays a role in the accumulation of leukocytes at both sides of allergic and non-allergic inflammation. May be involved in the recruitment of monocytes into the arterial wall during the disease process of atherosclerosis. May play a role in the monocyte attraction in tissues chronically exposed to exogenous pathogens.
One major form (form long), and two minor forms (short chain and medium chain) are produced by differential signal peptide cleavage. The medium chain is about 30-fold less active than the long chain.
Widely expressed. Found in small intestine, thymus, colon, lung, trachea, stomach and lymph node. Low levels seen in the pulmonary artery smooth muscle cells.
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MNB/DYRK subfamily.
Dual-specificity protein kinase that promotes disassembly of several types of membraneless organelles during mitosis, such as stress granules, nuclear speckles and pericentriolar material (PubMed:29973724). Dual-specificity tyrosine-regulated kinases (DYRKs) autophosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues (PubMed:9748265, PubMed:29634919). Acts as a central dissolvase of membraneless organelles during the G2-to-M transition, after the nuclear-envelope breakdown: acts by mediating phosphorylation of multiple serine and threonine residues in unstructured domains of proteins, such as SRRM1 and PCM1 (PubMed:29973724). Does not mediate disassembly of all membraneless organelles: disassembly of P-body and nucleolus is not regulated by DYRK3 (PubMed:29973724). Dissolution of membraneless organelles at the onset of mitosis is also required to release mitotic regulators, such as ZNF207, from liquid-unmixed organelles where they are sequestered and keep them dissolved during mitosis (PubMed:29973724). Regulates mTORC1 by mediating the dissolution of stress granules: during stressful conditions, DYRK3 partitions from the cytosol to the stress granule, together with mTORC1 components, which prevents mTORC1 signaling (PubMed:23415227). When stress signals are gone, the kinase activity of DYRK3 is required for the dissolution of stress granule and mTORC1 relocation to the cytosol: acts by mediating the phosphorylation of the mTORC1 inhibitor AKT1S1, allowing full reactivation of mTORC1 signaling (PubMed:23415227). Also acts as a negative regulator of EPO-dependent erythropoiesis: may place an upper limit on red cell production during stress erythropoiesis (PubMed:10779429). Inhibits cell death due to cytokine withdrawal in hematopoietic progenitor cells (PubMed:10779429). Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1: this in turn inhibits p53/TP53 activity and apoptosis (PubMed:20167603).
Isoform 1: Highly expressed in testis and in hematopoietic tissue such as fetal liver, and bone marrow (PubMed:10779429). Isoform 1: Predominant form in fetal liver and bone marrow (PubMed:10779429). Isoform 1: Present at low levels in heart, pancreas, lymph node and thymus (PubMed:10779429). Isoform 2: Highly expressed in testis and in hematopoietic tissue such as fetal liver, and bone marrow (PubMed:10779429). Isoform 2: Predominant form in testis. Isoform 2: Present at low levels in heart, pancreas, lymph node and thymus (PubMed:10779429).
Protein kinase activity is activated following autophosphorylation at Tyr-369 (Probable). Autophosphorylation at Ser-350 stabilizes the protein and enhances the protein kinase activity (PubMed:9748265).
Protein kinase activity is activated following autophosphorylation at Tyr-369 (PubMed:9748265). Inhibited by harmine, an ATP competitive inhibitor (PubMed:29634919). Inhibited by small-compound GSK-626616 (PubMed:29973724).
The N-terminal domain, which is intrinsically disordered, is required for stress granule localization.
Ubiquitinated at anaphase by the anaphase-promoting complex (APC/C), leading to its degradation by the proteasome.
Could be involved in cell-cell and/or cell-matrix interactions necessary for normal growth control. Pro-apoptotic protein that functions intracellularly upstream of JNK activation and cytochrome c release.
Mainly expressed in stratified squamous epithelium.
Belongs to the peroxisomal membrane protein PXMP2/4 family.
Non-selective channel that modulates the membrane potential under normal conditions and oxidative stress, and is involved in mitochondrial homeostasis (PubMed:25861990). Involved in mitochondrial deoxynucleoside triphosphates (dNTP) pool homeostasis and mitochondrial DNA (mtDNA) maintenance (PubMed:26760297). May be involved in the regulation of reactive oxygen species metabolism and the control of oxidative phosphorylation (By similarity).
Ubiquitous. Expressed in pancreas, kidney, muscle, liver, lung, placenta, brain and heart.
Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily.
Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses. Interacts (phosphorylated at position Tyr-602) with FYN. Interacts with CDK5, CDK5R1 and NGEF; upon activation by EFNA1 induces NGEF phosphorylation by the kinase CDK5. Interacts with CHN1; effector of EPHA4 in axon guidance linking EPHA4 activation to RAC1 regulation (By similarity). Interacts (via PDZ motif) with SIPA1L1 (via PDZ domain); controls neuronal morphology through regulation of the RAP1 (RAP1A or RAP1B) and RAP2 (RAP2A, RAP2B or RAP2C) GTPases. Forms a ternary complex composed of ADAM10, CADH1 and EPHA4; within the complex, CADH1 is cleaved by ADAM10 which disrupts adherens junctions (By similarity).
Receptor tyrosine kinase which binds membrane-bound ephrin family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Highly promiscuous, it has the unique property among Eph receptors to bind and to be physiologically activated by both GPI-anchored ephrin-A and transmembrane ephrin-B ligands including EFNA1 and EFNB3. Upon activation by ephrin ligands, modulates cell morphology and integrin-dependent cell adhesion through regulation of the Rac, Rap and Rho GTPases activity. Plays an important role in the development of the nervous system controlling different steps of axonal guidance including the establishment of the corticospinal projections. May also control the segregation of motor and sensory axons during neuromuscular circuit development. In addition to its role in axonal guidance plays a role in synaptic plasticity. Activated by EFNA1 phosphorylates CDK5 at 'Tyr-15' which in turn phosphorylates NGEF regulating RHOA and dendritic spine morphogenesis. In the nervous system, also plays a role in repair after injury preventing axonal regeneration and in angiogenesis playing a role in central nervous system vascular formation. Additionally, its promiscuity makes it available to participate in a variety of cell-cell signaling regulating for instance the development of the thymic epithelium. During development of the cochlear organ of Corti, regulates pillar cell separation by forming a ternary complex with ADAM10 and CADH1 which facilitates the cleavage of CADH1 by ADAM10 and disruption of adherens junctions (By similarity). Phosphorylates CAPRIN1, promoting CAPRIN1-dependent formation of a membraneless compartment (By similarity).
The protein kinase domain mediates interaction with NGEF.
Interacts with ATPAF2 (PubMed:28719601).
Plays a role in the assembly/stability of the mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) (PubMed:28719601).
Cleaved by signal peptidase at Ser-14 but the peptide does not act as a signal peptide. Cleavage is inhibited by ceramide which inverts the orientation of TM4SF20 in membranes exposing the N-terminus to the cytosol and not to the endoplasmic reticulum lumen.
Expressed in the brain, with high levels in the parietal lobe, hippocampus, pons, white matter and cerebellum.
Glycosylated at Asn-132, Asn-148 and Asn-163 in presence of ceramide which inverts the orientation of TM4SF20 in membranes exposing these residues to the endoplasmic reticulum lumen.
Polytopic transmembrane protein that inhibits regulated intramembrane proteolysis (RIP) of CREB3L1, inhibiting its activation and the induction of collagen synthesis (PubMed:25310401, PubMed:27499293). In response to ceramide, which alters TM4SF20 membrane topology, stimulates RIP activation of CREB3L1 (PubMed:27499293). Ceramide reverses the direction through which transmembrane helices are translocated into the endoplasmic reticulum membrane during translation of TM4SF20, this mechanism is called 'regulated alternative translocation' (RAT) and regulates the function of the transmembrane protein (PubMed:27499293).
TGFB1 inhibits TM4SF20 expression to activate CREB3L1 (PubMed:25310401).
The first transmembrane helix plays a critical role for the insertion orientation in the endoplasmic reticulum membrane.
(Microbial infection) Interaction with influenza B NS1 protein inhibits its conjugation.
(Microbial infection) Interacts (via C-terminus) with Crimean-Congo hemorrhagic fever virus (CCHFV) RNA-directed RNA polymerase L (via N-terminus); the deISGylase activity of the viral protein interferes with antiviral signaling pathways mediated by NF-kappaB and IRF signalings.
(Microbial infection) Interacts with vaccinia virus protein E3.
Both the Ubiquitin-like 1 and Ubiquitin-like 2 domains are required for its efficient conjugation to cellular proteins. The two domains play different roles in the ISGylation pathway: Ubiquitin-like 2 domain is necessary for the first two steps allowing the linking of ISG15 to the E1 and E2 enzymes while Ubiquitin-like 1 domain is essential for the final, E3-mediated transfer of ISG15, from the E2 to the Lys of the target protein (PubMed:18356159).
Detected in lymphoid cells, striated and smooth muscle, several epithelia and neurons. Expressed in neutrophils, monocytes and lymphocytes. Enhanced expression seen in pancreatic adenocarcinoma, endometrial cancer, and bladder cancer, as compared to non-cancerous tissue. In bladder cancer, the increase in expression exhibits a striking positive correlation with more advanced stages of the disease.
Homodimer; disulfide-linked (PubMed:2440890). Interacts with, and is conjugated to its targets by UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme) (PubMed:11157743, PubMed:15131269). Interacts with NEDD4 (PubMed:18305167).
Induced as an inactive, precursor protein that is cleaved by specific proteases to expose the C-terminal diglycine (LRLRGG) motif. This motif is essential not only for its conjugation to substrates but also for its recognition by the relevant processing proteases.
S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins.
Strongly induced upon exposure to type I interferons, viruses, LPS, and other stresses, including certain genotoxic stresses.
Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein (PubMed:33727702). Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Isgylation of the viral sensor IFIH1/MDA5 promotes IFIH1/MDA5 oligomerization and triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses (PubMed:33727702). Can also isgylate: EIF2AK2/PKR which results in its activation, RIGI which inhibits its function in antiviral signaling response, EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity, UBE2N and UBE2E1 which negatively regulates their activity, IRF3 which inhibits its ubiquitination and degradation and FLNB which prevents its ability to interact with the upstream activators of the JNK cascade thereby inhibiting IFNA-induced JNK signaling. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag and host TSG101 and disrupts their interaction, thereby preventing assembly and release of virions from infected cells. Inhibits Ebola virus budding mediated by the VP40 protein by disrupting ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISGylates influenza A virus NS1 protein which causes a loss of function of the protein and the inhibition of virus replication. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity. The secreted form acts through the integrin ITGAL/ITGB2 receptor to initiate activation of SRC family tyrosine kinases including LYN, HCK and FGR which leads to secretion of IFNG and IL10; the interaction is mediated by ITGAL (PubMed:29100055).
Binds to the promoters of target genes and functions as repressor. Promotes cell proliferation and antagonizes cell death. Promotes phosphorylation of AKT1 at 'Ser-473'.
Component of a histone deacetylase complex that contains HDAC2, KDM1A, CTBP1 and ZNF217. May be a component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST, PHF21A/BHC80, ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I. Interacts with CTBP1 and CTBP2.
Homodimer. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins. Interacts directly with PER1, PER2, CRY1, CRY2, and TIMELESS; interaction with CRY1 and CRY2 is weak and not rhythmic. Interacts with FBXW11 and BTRC.
Originally described as a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1, NR1D2, RORA, RORB and RORG, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. Has a redundant role with the other PER proteins PER1 and PER2 and is not essential for the circadian rhythms maintenance. In contrast, plays an important role in sleep-wake timing and sleep homeostasis probably through the transcriptional regulation of sleep homeostasis-related genes, without influencing circadian parameters. Can bind heme.
Phosphorylation by CSNK1E is weak and appears to require association with PER1 and translocation to the nucleus.
The number of repeats of 18 amino acids in positions 966 to 1055 is polymorphic and varies among at least 2 different alleles. Alleles corresponding in size to a 4 (PER3.4) and 5 (PER3.5) repeats have been described. The sequence shown is that of allele PER3.5. In most populations around 10% of individuals are homozygous for the 5-repeat (PER3.5), whereas approximately 50% are homozygous for the 4-repeat (PER3.4). In some populations in Papua New Guinea the prevalence of the various genotypes appears to be reversed. These repeats and polymorphism are not present in non-primate mammals. Homozygosity for PER3.5 is more likely to show morning preference, whereas homozygosity for the PER3.4 associates with evening preferences. PER3.5 homozygous show vulnerability to sleep loss with a greater cognitive decline in response to total sleep deprivation (PubMed:11306557, PubMed:17346965, PubMed:19716732, PubMed:24439663, PubMed:24577121).
Belongs to the 5-formyltetrahydrofolate cyclo-ligase family.
Cytoskeletal protein involved in actin-membrane attachment at sites of cell adhesion to the extracellular matrix (focal adhesion). Recruits other proteins such as TRIM15 to focal adhesion.
Interacts in vitro with VCL/vinculin as well as to the SH3 domain of SRC and, when tyrosine phosphorylated, to the SH2 domain of CRK (PubMed:7534286). Interacts with GIT1 (PubMed:10938112). Interacts with NUDT16L1/SDOS (By similarity). Interacts with PTK2/FAK1 (PubMed:14527389). Interacts with PTK2B/PYK2 (PubMed:19358827). Interacts with ASAP2 (PubMed:10749932). Interacts with unphosphorylated ITGA4 (PubMed:10604475). Interacts with RNF5 (PubMed:12861019). Interacts with PDCD10 (PubMed:20489202). Interacts with NEK3, the interaction is prolactin-dependent (PubMed:17297458). Interacts with PTK6 (PubMed:15572663). Interacts with TGFB1I1 (By similarity). Interacts with SORBS1 (PubMed:17462669). Interacts with PARVB (PubMed:22869380). Interacts (via LD motif 4) with PARVA/PARVIN (PubMed:15817463, PubMed:18508764, PubMed:18940607). Interacts (via LD motif 4) with ILK (PubMed:15817463, PubMed:18508764, PubMed:18940607). Interacts (via cytoplasmic domain) with CEACAM1; the interaction is phosphotyrosyl-dependent (PubMed:11035932). Interacts with LIMA1; this complex stabilizes actin dynamics (PubMed:24694988). Interacts with CD36 (via C-terminus) (PubMed:20037584). Interacts with TRIM15 (PubMed:25015296).
Interacts strongly with PTK2/FAK1 and weakly with VCL/vinculin.
Interacts strongly with VCL/vinculin but only weakly with PTK2/FAK1.
Phosphorylated by MAPK1/ERK2 (By similarity). Phosphorylated on tyrosine residues during integrin-mediated cell adhesion, embryonic development, fibroblast transformation and following stimulation of cells by mitogens. Phosphorylation at Ser-244 by CDK5 reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Phosphorylation at Tyr-31 and Tyr-118 by PTK6 promote the activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. Phosphorylation at Ser-250 by SLK is required for PXN redistribution and cell motility (PubMed:23128389).
Regulates intracellular cholesterol distribution from recycling endosomes to the trans-Golgi network through interactions with RAB11 and OSBP (PubMed:29514919). Functions in membrane tethering and promotes OSBP-mediated cholesterol transfer between RAB11-bound recycling endosomes and OSBP-bound Golgi-like membranes (PubMed:29514919).
Expressed in gastric cancer cell lines and gastric cancer tissues (at protein level). Detected in the apical gland region of the gastric foveolar epithelium (at protein level).
Ligand for members of the frizzled family of seven transmembrane receptors.
Ligand for members of the frizzled family of seven transmembrane receptors. Probable developmental protein. May be a signaling molecule which affects the development of discrete regions of tissues. Is likely to signal over only few cell diameters. Together with CAV1 may promote chemoresistance of gastric cancer cells to DNA-damaging anthracycline drugs through the activation of the canonical Wnt receptor signaling pathway.
Palmitoleoylation is required for efficient binding to frizzled receptors. Depalmitoleoylation leads to Wnt signaling pathway inhibition.
Belongs to the PtdIns transfer protein family. PI transfer class IIA subfamily.
Catalyzes the transfer of phosphatidylinositol (PI) between membranes (PubMed:22822086, PubMed:10531358). Binds PI, phosphatidylcholine (PC) and phosphatidic acid (PA) with the binding affinity order of PI > PA > PC (PubMed:22822086). Regulates RHOA activity, and plays a role in cytoskeleton remodeling (PubMed:11909959). Necessary for normal completion of cytokinesis (PubMed:15125835). Plays a role in maintaining normal diacylglycerol levels in the Golgi apparatus (PubMed:15723057). Necessary for maintaining the normal structure of the endoplasmic reticulum and the Golgi apparatus (PubMed:15545272). Required for protein export from the endoplasmic reticulum and the Golgi (PubMed:15723057). Binds calcium ions (PubMed:10022914).
Interacts with PIK4CA (By similarity). Interacts with PTK2B via its C-terminus. Interacts with RHOA. Has higher affinity for the inactive, GDP-bound form of RHOA. The CDK1-phosphorylated form interacts with PLK1. Interacts with VAPB.
Phosphorylated on multiple sites by CDK1 at the onset of mitosis. Phosphorylation facilitates dissociation from the Golgi complex and is required for interaction with PLK1.
Phosphorylated on threonine residues upon treatment with oleic acid.
Phosphorylated on tyrosine residues by PTK2B.
Allows the formation of correctly charged Gln-tRNA(Gln) through the transamidation of misacylated Glu-tRNA(Gln) in the mitochondria. The reaction takes place in the presence of glutamine and ATP through an activated gamma-phospho-Glu-tRNA(Gln).
Belongs to the GatB/GatE family. GatB subfamily.
Predominantly expressed in tissues characterized by high rates of oxidative phosphorylation (OxPhos), including muscle and heart.
Subunit of the heterotrimeric GatCAB amidotransferase (AdT) complex, composed of A (QRSL1), B (GATB) and C (GATC) subunits.
The disease may be caused by variants affecting the gene represented in this entry.
Available under the names Novarel (Ferring) and Profasi (Serono). Used as adjunctive therapy in the treatment of obesity. There is no substantial evidence that it increases weight loss beyond that resulting from caloric restriction, that it causes a more attractive or 'normal' distribution of fat, or that it decreases the hunger and discomfort associated with calorie-restricted diets.
Belongs to the glycoprotein hormones subunit beta family.
Beta subunit of the human chorionic gonadotropin (hCG). hCG is a complex glycoprotein composed of two glycosylated subunits alpha and beta which are non-covalently associated. The alpha subunit is identical to those in the pituitary gonadotropin hormones (LH, FSH and TSH). The beta subunits are distinct in each of the hormones and confer receptor and biological specificity. Has an essential role in pregnancy and maternal adaptation. Stimulates the ovaries to synthesize the steroids that are essential for the maintenance of pregnancy.
Encoded by a cluster of genes that have evolved by duplication from LHB. HCG-beta is encoded by six non-allelic genes (CGB) clustered on chromosome 19q13.3 and named CGB1, CGB2, CGB3, CGB5, CGB7 and CGB8. Two specific hCGb proteins that differ by three amino acids in positions 2,4 and 117 have been described: type 1 (CGB7) and type 2 (CGB3, CGB5, CGB8). The CGB gene first arose in the common ancestor of the anthropoid primates.
Expressed continuously during the whole pregnancy with a peak during the first trimester.
Heterodimer of a common alpha chain identical in LH, FSH, TSH and HCG and a unique beta chain distinct in each of the hormones.
High expression in the placenta throughout pregnancy.
Allosterically activated by various compounds including ATP, 2,3-BPG/2,3-Bisphosphoglyceric acid and Ap4A/P1,P4-bis(5'-adenosyl) tetraphosphate (PubMed:1659319, PubMed:10092873, PubMed:21396942). Binding of an allosteric activator is a prerequisiste to magnesium and substrate binding (PubMed:21396942). Inhibited by inorganic phosphate (PubMed:10092873).
Belongs to the 5'(3')-deoxyribonucleotidase family.
Broad specificity cytosolic 5'-nucleotidase that catalyzes the dephosphorylation of 6-hydroxypurine nucleoside 5'-monophosphates (PubMed:1659319, PubMed:9371705, PubMed:10092873, PubMed:12907246). In addition, possesses a phosphotransferase activity by which it can transfer a phosphate from a donor nucleoside monophosphate to an acceptor nucleoside, preferably inosine, deoxyinosine and guanosine (PubMed:1659319, PubMed:9371705). Has the highest activities for IMP and GMP followed by dIMP, dGMP and XMP (PubMed:1659319, PubMed:9371705, PubMed:10092873, PubMed:12907246). Could also catalyze the transfer of phosphates from pyrimidine monophosphates but with lower efficiency (PubMed:1659319, PubMed:9371705). Through these activities regulates the purine nucleoside/nucleotide pools within the cell (PubMed:1659319, PubMed:9371705, PubMed:10092873, PubMed:12907246).
Belongs to the palmitoyl-protein thioesterase family.
Broadly expressed, with highest levels in skeletal muscle.
Catalytically inactive due to lack of His-283. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Removes thioester-linked fatty acyl groups from various substrates including S-palmitoyl-CoA. Has the highest S-thioesterase activity for the acyl groups palmitic and myristic acid followed by other short- and long-chain acyl substrates. However, because of structural constraints, is unable to remove palmitate from peptides or proteins.
Was originally referred as a palmitoyl-protein thioesterase (palmitoyl-protein hydrolase).
(Microbial infection) Acts as a receptor for Measles virus; also including isoform 4.
(Microbial infection) Interacts with measles hemagglutinin protein.
Constitutively expressed on peripheral blood memory T-cells, T-cell clones, immature thymocytes and a proportion of B-cells, and is rapidly induced on naive T-cells after activation (PubMed:7617038). Activated B-cells express isoform 1, isoform 3 and a cytoplasmic isoform (PubMed:9091591). Isoform 4 is expressed in B-cells, primary T-cells, dendritic cells and macrophages. Isoform 4 is expressed in tumors of the central nervous system (PubMed:25710480).
Interacts (via cytoplasmic domain) with SH2D1A and SH2D1B; SH2D1A mediates association with FYN; SH2D1A binds to phosphorylated and not phosphorylated ITSM 1 (PubMed:9774102, PubMed:11313386, PubMed:11806999, PubMed:12458214). Interacts (via cytoplasmic domain phosphorylated on tyrosine residues) with INPP5D and PTPN11; presence of SH2D1A facilitates binding to INPP5D (PubMed:11313386, PubMed:12458214). Interacts with MAP4K1 (PubMed:20231852). Interacts with PIK3C3, BECN1 and UVRAG; indicative for an association with PI3K complex II (PI3KC3-C2) (PubMed:20818396).
Phosphorylated on tyrosine residues by FYN.
Self-ligand receptor of the signaling lymphocytic activation molecule (SLAM) family. SLAM receptors triggered by homo- or heterotypic cell-cell interactions are modulating the activation and differentiation of a wide variety of immune cells and thus are involved in the regulation and interconnection of both innate and adaptive immune response. Activities are controlled by presence or absence of small cytoplasmic adapter proteins, SH2D1A/SAP and/or SH2D1B/EAT-2. SLAMF1-induced signal-transduction events in T-lymphocytes are different from those in B-cells. Two modes of SLAMF1 signaling seem to exist: one depending on SH2D1A (and perhaps SH2D1B) and another in which protein-tyrosine phosphatase 2C (PTPN11)-dependent signal transduction operates. Initially it has been proposed that association with SH2D1A prevents binding to inhibitory effectors including INPP5D/SHIP1 and PTPN11/SHP-2 (PubMed:11806999). However, signaling is also regulated by SH2D1A which can simultaneously interact with and recruit FYN which subsequently phosphorylates and activates SLAMF1 (PubMed:12458214). Mediates IL-2-independent proliferation of activated T-cells during immune responses and induces IFN-gamma production (By similarity). Downstreaming signaling involves INPP5D, DOK1 and DOK2 leading to inhibited IFN-gamma production in T-cells, and PRKCQ, BCL10 and NFKB1 leading to increased T-cell activation and Th2 cytokine production (By similarity). Promotes T-cell receptor-induced IL-4 secretion by CD4(+) cells (By similarity). Inhibits antigen receptor-mediated production of IFN-gamma, but not IL-2, in CD4(-)/CD8(-) T-cells (By similarity). Required for IL-4 production by germinal centers T follicular helper (T(Fh))cells (By similarity). May inhibit CD40-induced signal transduction in monocyte-derived dendritic cells (PubMed:16317102). May play a role in allergic responses and may regulate allergen-induced Th2 cytokine and Th1 cytokine secretion (By similarity). In conjunction with SLAMF6 controls the transition between positive selection and the subsequent expansion and differentiation of the thymocytic natural killer T (NKT) cell lineage. Involved in the peripheral differentiation of indifferent natural killer T (iNKT) cells toward a regulatory NKT2 type (By similarity). In macrophages involved in down-regulation of IL-12, TNF-alpha and nitric oxide in response to lipopolysaccharide (LPS) (By similarity). In B-cells activates the ERK signaling pathway independently of SH2D1A but implicating both, SYK and INPP5D, and activates Akt signaling dependent on SYK and SH2D1A (By similarity). In B-cells also activates p38 MAPK and JNK1 and JNK2 (PubMed:20231852). In conjunction with CD84/SLAMF5 and SLAMF6 may be a negative regulator of the humoral immune response (By similarity). Involved in innate immune response against Gram-negative bacteria in macrophages; probably recognizes OmpC and/or OmpF on the bacterial surface, regulates phagosome maturation and recruitment of the PI3K complex II (PI3KC3-C2) leading to accumulation of PdtIns(3)P and NOX2 activity in the phagosomes (PubMed:20818396).
The ITSMs (immunoreceptor tyrosine-based switch motifs) with the consensus sequence T-X-Y-X-X-[VI] present in SLAM family receptors have overlapping specificity for activating and inhibitory SH2 domain-containing binding partners. Especially they mediate the interaction with the SH2 domain of SH2D1A and SH2D1B. For SLAMF1 a 'two-out-of-three-pronged' mechanism is proposed involving threonine (position -2), phosphorylated tyrosine (position 0) and valine/isoleucine (position +3). SH2D1A binding is mediated by either three 'prongs' (for high affinity binding involving ITSM 1) or a combination of any two also including non-phosphorylated Tyr-281 of ITSM 1 thus providing a positive feedback loop implicating SH2D1A-dependent recruitment of activating FYN. ITSM 2 needs to be phosphorylated on Tyr-327 for SH2D1A binding.
Belongs to the UbiA prenyltransferase family.
Converts protoheme IX and farnesyl diphosphate to heme O.
Belongs to the class IV-like SAM-binding methyltransferase superfamily.
Depletion with RNAi causes a significant accumulation of cells in later prometaphase with misaligned chromosomes.
Required for association of the centrosomes with the poles of the bipolar mitotic spindle during metaphase (PubMed:20813266, PubMed:25657325). Also involved in chromosome alignment (PubMed:20813266). May promote centrosome maturation probably by recruiting A-kinase anchor protein AKAP9 to centrosomes in early mitosis (PubMed:25657325). Binds specifically to miRNA MIR145 hairpin, regulates MIR145 expression at a postranscriptional level (PubMed:28431233).
Abundantly expressed in the differentiating cortex of growing (anagen) hair. Expression is restricted to the keratinocytes of the hair cortex and is absent from inner root sheath and medulla. Expressed in malignant lymph node tissue in breast carcinoma tissue.
There are two types of hair/microfibrillar keratin, I (acidic) and II (neutral to basic).
Belongs to the SIMIBI class G3E GTPase family. ZNG1 subfamily.
Zinc chaperone that directly transfers zinc cofactor to target metalloproteins, thereby activating them. Catalyzes zinc insertion into the active site of methionine aminopeptidase METAP1, which function to cleave the initiator methionine from polypeptides during or after protein translation. Mechanistically, the N-terminal psi-PxLVp motif binds to the C6H2-type zinc finger of inactive form of METAP1. After formation of the docked complex, zinc is transferred from the CXCC motif in the GTPase domain of ZNG1E to the zinc binding site in the peptidase domain of METAP1 in a process requiring GTP hydrolysis. GTP/GDP exchange is required for release of active METAP1.
A chromosomal aberration involving DEK is found in a subset of acute myeloid leukemia (AML); also known as acute non-lymphocytic leukemia (PubMed:1549122). Translocation t(6;9)(p23;q34) with NUP214/CAN (PubMed:1549122). It results in the formation of a DEK-NUP214 fusion gene (PubMed:1549122).
Found in a mRNA splicing-dependent exon junction complex (EJC) with DEK, RBM8A, RNPS1, SRRM1 and ALYREF/THOC4. Interacts with histones H2A, H2B, H3, H4, acetylated histone H4, non-phosphorylated DAXX and HDAC2. Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21. Binds DNA.
Phosphorylated by CK2. Phosphorylation fluctuates during the cell cycle with a moderate peak during G(1) phase, and weakens the binding of DEK to DNA.
Ubiquitous. Expressed at relatively high levels.
Plays a critical role in tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway (PubMed:27736875). May play a role in development or function of the auditory system (PubMed:22678063).
Component of the DCX(DCAF12) E3 ubiquitin ligase complex, at least composed of CUL4 (CUL4A or CUL4B), DDB1, DCAF12 and RBX1.
Highly expressed in lung cancer tissues and some cancer cell lines (PubMed:18957058). Restricted expression in normal testis (PubMed:18957058).
Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:16949367, PubMed:16964240, PubMed:29779948). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (PubMed:29779948). The DCX(DCAF12) complex specifically recognizes proteins with a diglutamate (Glu-Glu) at the C-terminus, such as MAGEA3, MAGEA6 and CCT5, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:31267705). Ubiquitination of MAGEA3, MAGEA6 by DCX(DCAF12) complex is required for starvation-induced autophagy (PubMed:31267705). Also directly recognizes the C-terminal glutamate-leucine (Glu-Leu) degron as an alternative degron in proteins such as MOV10, leading to their ubiquitination and degradation. Controls the protein level of MOV10 during spermatogenesis and in T cells, especially after their activation (PubMed:34065512).
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. S6 kinase subfamily.
Belongs to the intercrine alpha (chemokine CxC) family.
Chemotactic for neutrophil granulocytes. Signals through binding and activation of its receptors (CXCR1 and CXCR2). In addition to its chemotactic and angiogenic properties, it has strong antibacterial activity against Gram-positive and Gram-negative bacteria (90-fold-higher when compared to CXCL5 and CXCL7).
Homodimer and heterodimer with SSTR2. Heterodimerization with SSTR2 inactivates SSTR3 receptor function (By similarity).
Phosphorylated. Phosphorylation increases upon somatostatin binding (By similarity).
Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase.
Belongs to the glycosyl hydrolase 47 family.
Expressed ubiquitously in all tissues tested with slightly higher levels detected in small intestine and peripheral blood leukocytes and weakest levels in brain and skeletal muscle.
Has similarity to alpha 1,2-mannosidases, but the catalytic activity of this protein is controversial (PubMed:15537790, PubMed:25092655). One study shows that it is important for a specific oligosaccharide trimming step from Man9GlcNAc2 to Man8GlcNAc2, suggesting activity as a mannosidase (PubMed:25092655). However, another study reports that this protein has no mannosidase activity (PubMed:15537790).
Involved in the endoplasmic reticulum-associated degradation (ERAD) pathway that targets misfolded glycoproteins for degradation in an N-glycan-dependent manner (PubMed:15537790, PubMed:25092655). May initiate ERAD by promoting the first mannose trimming step of ERAD substrates, from Man9GlcNAc2 to Man8GlcNAc2 (PubMed:25092655). Seems to recognize and bind to exposed hydrophobic regions in target proteins (By similarity).
Belongs to the nuclear hormone receptor family. NR3 subfamily.
Binds DNA as a homodimer. Can form a heterodimer with ESR1. Interacts with NCOA1, NCOA3, NCOA5 and NCOA6 coactivators, leading to a strong increase of transcription of target genes. Interacts with UBE1C. Interacts with AKAP13. Interacts with DNTTIP2. Interacts with isoform 4 of TXNRD1. Interacts with CCDC62 in the presence of estradiol/E2; this interaction seems to enhance the transcription of target genes, including cyclin-D1/CCND1 AP-1 promoter. Interacts with DNAAF4 (By similarity). Interacts with PRMT2. Interacts with CCAR2 (via N-terminus) in a ligand-independent manner. Interacts with RBM39, in the presence of estradiol (E2) (By similarity).
Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.
Expressed in spleen, thymus, testis and ovary and at a lower level in skeletal muscle, prostate, colon, small intestine, leukocytes, bone marrow, mammary gland and uterus.
Expressed in testis and ovary, and at a lower level in heart, brain, placenta, liver, skeletal muscle, spleen, thymus, prostate, colon, bone marrow, mammary gland and uterus. Also found in uterine bone, breast, and ovarian tumor cell lines, but not in colon and liver tumors.
Expressed in testis, and at a lower level in spleen, thymus, ovary, mammary gland and uterus.
Expressed in testis, placenta, skeletal muscle, spleen and leukocytes, and at a lower level in heart, lung, liver, kidney, pancreas, thymus, prostate, colon, small intestine, bone marrow, mammary gland and uterus. Not expressed in brain.
Had previously been shown to interact with PELP1. However this paper was retracted as cell-based data was viewed as unreliable.
Lacks ligand binding ability and has no or only very low ERE binding activity resulting in the loss of ligand-dependent transactivation ability.
Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1/ER-alpha, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560).
Phosphorylation at Ser-87 and Ser-105 recruits NCOA1.
Preferentially forms a heterodimer with ESR1 rather than ESR2 isoform 1 and inhibits DNA-binding by ESR1.
Belongs to the MICOS complex subunit Mic13 family.
Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane.
Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane. Constituent of mature MICOS complex, it is required for the formation of cristae junction (CJ) and maintenance of cristae morphology. Required for the incorporation of MICOS10/MIC10 into the MICOS complex.
Component of the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOO/MIC26, MICOS13/MIC13, APOOL/MIC27 and IMMT/MIC60. The MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1 and MTX2 (together described as components of the mitochondrial outer membrane sorting assembly machinery (SAM) complex) and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9. The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both membranes termed the mitochondrial intermembrane space bridging (MIB) complex.
Component of the mitochondrial contact site and cristae organizing system (MICOS) complex.
(Microbial infection) Interacts with Staphylococcus aureus protein SSL5.
Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C6 complex is the foundation upon which the lytic complex is assembled.
An association study of C5 haplotypes and genotypes in individuals with chronic hepatitis C virus infection shows that individuals homozygous for the C5_1 haplotype have a significantly higher stage of liver fibrosis than individuals carrying at least 1 other allele.
C5 precursor is first processed by the removal of 4 basic residues, forming two chains, beta and alpha, linked by a disulfide bond. C5 convertase activates C5 by cleaving the alpha chain, releasing C5a anaphylatoxin and generating C5b (beta chain + alpha' chain). Interacts with the tick complement inhibitors OmCI, RaCI1 and CirpT1 (PubMed:18536718, PubMed:27018802, PubMed:31871188). Interacts with cobra venom factor (CVF) (PubMed:21217642).
C5 variants are responsible for poor response to eculizumab [MIM:615749]. Eculizumab is a monoclonal antibody highly effective in reducing intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria. It specifically binds to the terminal complement protein C5, inhibits its cleavage into C5a and C5b, and prevents the formations of the cytolytic complement pore (PubMed:24521109).
Derived from proteolytic degradation of complement C5, C5a anaphylatoxin is a mediator of local inflammatory process. Binding to the receptor C5AR1 induces a variety of responses including intracellular calcium release, contraction of smooth muscle, increased vascular permeability, and histamine release from mast cells and basophilic leukocytes (PubMed:8182049). C5a is also a potent chemokine which stimulates the locomotion of polymorphonuclear leukocytes and directs their migration toward sites of inflammation.
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
Arginine methylation in the ITAM domain may interfere with the binding of SYK. It promotes signals leading to B-cell differentiation (By similarity).
Heterodimer of alpha and beta chains; disulfide-linked. Part of the B-cell antigen receptor complex where the alpha/beta chain heterodimer is non-covalently associated with an antigen-specific membrane-bound surface immunoglobulin of two heavy chains and two light chains. Interacts through its phosphorylated ITAM domain with the SH2 domains of SYK which stimulates SYK autophosphorylation and activation. Also interacts, when phosphorylated on Tyr-210, with the SH2 domain of BLNK/SLP65, bringing BLNK into proximity with SYK and allowing SYK to phosphorylate BLNK which is necessary for trafficking of the BCR to late endosomes. Interacts with Src-family tyrosine kinases including FYN and LYN, increasing their activity (By similarity).
Phosphorylated on tyrosine, serine and threonine residues upon B-cell activation. Phosphorylation of tyrosine residues by Src-family kinases is an early and essential feature of the BCR signaling cascade. The phosphorylated tyrosines serve as docking sites for SH2-domain containing kinases, leading to their activation which in turn leads to phosphorylation of downstream targets. Phosphorylated by LYN. Phosphorylation of serine and threonine residues may prevent subsequent tyrosine phosphorylation.
Required in cooperation with CD79B for initiation of the signal transduction cascade activated by binding of antigen to the B-cell antigen receptor complex (BCR) which leads to internalization of the complex, trafficking to late endosomes and antigen presentation. Also required for BCR surface expression and for efficient differentiation of pro- and pre-B-cells. Stimulates SYK autophosphorylation and activation. Binds to BLNK, bringing BLNK into proximity with SYK and allowing SYK to phosphorylate BLNK. Also interacts with and increases activity of some Src-family tyrosine kinases. Represses BCR signaling during development of immature B-cells.
The disease is caused by variants affecting the gene represented in this entry. Two different mutations, one at the splice donor site of intron 2 and the other at the splice acceptor site for exon 3, have been identified. Both mutations give rise to a truncated protein.
Interacts with MYCBP and AKAP1. Part of a complex containing MYCBP, AKAP1 and PRKAR2B.
Involved in sperm flagellum axonemal organization and function (PubMed:12223483, PubMed:32161152). May regulate cilium motility through its role in the assembly of the axonemal radial spokes (By similarity).
May be produced by alternative promoter usage.
Widely expressed, but strongly expressed in all spermatogenesis-related tissues, including the testis, the epithelium of cauda and the corpus epididymis, as well as the spermatid and mature sperm. Also expressed in Leydig cells.
Cleaves the propeptides of type II collagen prior to fibril assembly. Does not act on types I and III collagens.
Glycosylated. Can be O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS family members. Can also be C-glycosylated with one or two mannose molecules on tryptophan residues within the consensus sequence W-X-X-W of the TPRs, and N-glycosylated. These other glycosylations can also facilitate secretion (By similarity).
Has sometimes been referred to as ADAMTS4.
The precursor is cleaved by a furin endopeptidase.
The spacer domain and the TSP type-1 domains are important for a tight interaction with the extracellular matrix.
Activator of the NOTCH1 pathway. May mediate neuron-glia interaction during astrocytogenesis (By similarity).
Expressed in brain, spinal cord and adrenal gland.
Interacts with AP1G1. Interacts with NOTCH1 (By similarity).
Expressed in benign prostatic hyperplasia.
Homodimeric or heterodimeric through association with alpha and beta subunits, linked by one or more disulfide bonds. Inhibins are heterodimers of one alpha and one beta subunit. Activins are homo- or heterodimers of beta subunits only (By similarity).
Inhibins and activins inhibit and activate, respectively, the secretion of follitropin by the pituitary gland. Inhibins/activins are involved in regulating a number of diverse functions such as hypothalamic and pituitary hormone secretion, gonadal hormone secretion, germ cell development and maturation, erythroid differentiation, insulin secretion, nerve cell survival, embryonic axial development or bone growth, depending on their subunit composition. Inhibins appear to oppose the functions of activins.
Interacts with TFF2 (By similarity). Heterodimer with TFF1; disulfide linked.
Not detected before gestational days 53-54. Expressed in the eye at gestational week 10.
(Microbial infection) Interacts with Shigella flexneri ipah9.8; the interaction promotes polyubiquitination of IKBKG.
Inhibits NF-kappa-B activation and TNF-induced NF-kappa-B-dependent gene expression by regulating TAX1BP1 and A20/TNFAIP3-mediated deubiquitination of IKBKG; proposed to link A20/TNFAIP3 to ubiquitinated IKBKG (PubMed:21885437). Involved in regulation of EGF-induced ERK1/ERK2 signaling pathway; blocks MAPK3/MAPK1 nuclear translocation and MAPK1-dependent transcription. Increases cell surface CD4(T4) antigen expression. Involved in the anti-inflammatory response of macrophages and positively regulates TLR-induced activation of CEBPB. Involved in the prevention of autoimmunity; this function implicates binding to polyubiquitin. Involved in leukocyte integrin activation during inflammation; this function is mediated by association with SELPLG and dependent on phosphorylation by SRC-family kinases. Interacts with HIV-1 matrix protein and is packaged into virions and overexpression can inhibit viral replication. May regulate matrix nuclear localization, both nuclear import of PIC (Preintegration complex) and export of GAG polyprotein and viral genomic RNA during virion production. In case of infection, promotes association of IKBKG with Shigella flexneri E3 ubiquitin-protein ligase ipah9.8 p which in turn promotes polyubiquitination of IKBKG leading to its proteasome-dependent degradation and thus is perturbing NF-kappa-B activation during bacterial infection.
Interacts with TNFAIP3 and IKBKG (polyubiquitinated); facilitates TNFAIP3-mediated de-ubiquitination of NEMO/IKBKG. Interacts with polyubiquitin. Interacts with MAPK1, SELPLG and PIK3CD. Interacts with IRAK1 (polyubiquitinated). Interacts with MYD88; the interaction is indicative for participation in an activated TLR-signaling complex. Interacts with HIV-1 matrix protein. Interacts with TAX1BP1 (PubMed:21885437).
Less effective in the NF-kappa-B inhibitory effect.
Phosphorylation at Tyr-552 by SRC-family kinases recruits phosphoinositide-3-kinase (PI3K) PIK3CD:p85 heterodimer which results in integrin activation and leukocyte adhesion to activated endothelium during inflammation.
Ubiquitous. Strongly expressed in peripheral blood lymphocytes, spleen and skeletal muscle, and is weakly expressed in the brain. In peripheral blood mononucleocytes, isoform 4 is mainly expressed and isoform 1 and isoform 7 are almost not expressed. Expression of isoform 1 and isoform 7 increases in leukemic cells.
Belongs to the serpin family. Ov-serpin subfamily.
In human bone marrow, present in all CD45+ populations. Expression levels are highest in the neutrophil lineage, intermediate in monocytic, and lowest in lymphocytic lineage. Within the neutrophil lineage, expression is highest in promyelocytes.
Monomer (PubMed:23269243). Interacts (via C-terminus) with CASP1; CASP4 (via CARD domain) and CASP5; these interactions regulate the activity of inflammatory caspases (PubMed:30692621). Interacts with PRTN3 (PubMed:30692621). Interacts with GZMH (PubMed:23269243).
Neutrophil serine protease inhibitor that plays an essential role in the regulation of the innate immune response, inflammation and cellular homeostasis (PubMed:30692621). Acts primarily to protect the cell from proteases released in the cytoplasm during stress or infection. These proteases are important in killing microbes but when released from granules, these potent enzymes also destroy host proteins and contribute to mortality. Regulates the activity of the neutrophil proteases elastase, cathepsin G, proteinase-3, chymase, chymotrypsin, and kallikrein-3 (PubMed:11747453, PubMed:30692621). Acts also as a potent intracellular inhibitor of GZMH by directly blocking its proteolytic activity (PubMed:23269243). During inflammation, limits the activity of inflammatory caspases CASP1, CASP4 and CASP5 by suppressing their caspase-recruitment domain (CARD) oligomerization and enzymatic activation (PubMed:30692621). When secreted, promotes the proliferation of beta-cells via its protease inhibitory function (PubMed:26701651).
Reactive bond 1 is specific for reaction with chymotrypsin-like protease such as cathepsin G, chymotrypsin, chymase or granzyme H, while reactive bond 2 is specific for reaction with elastase-like protease such as neutrophil elastase, proteinase-3, pancreatic elastase or PSA.
Inhibits generation of IL-1-beta by interacting with caspase-1 and preventing its association with RIP2. Down-regulates the release of IL1B.
Interacts with pro-CASP1. Interacts with CARD8.
Primarily expressed in the heart and placenta.
Up-regulated in response to TNF and bacterial lipopolysaccharides (LPS).
Belongs to the gamma-glutamyltransferase family.
Cleaved by autocatalysis into a large and a small subunit and the autocatalytic cleavage is essential to the functional activation of the enzyme.
Heterodimer composed of the light and heavy chains. The active site is located in the light chain.
Hydrolyzes and transfers gamma-glutamyl moieties from glutathione and other gamma-glutamyl compounds to acceptors.
Expressed at high levels in the placenta and, at mucher lower, in testis and fetal liver (PubMed:16971064). Isoform 1 is only detected in placenta and in moderately and poorly differentiated hepatocellular carcinoma cells (at protein level). Isoform 2 is detected in fetal liver, non-tumor liver tissues, as well as well-differentiated tumor tissues (at protein level). Tends to be up-regulated in triple-negative (ER-,PR-,HER2-) breast tumors, as well as in liver, ovarian, and thyroid carcinomas (PubMed:22118463).
Might be negatively regulated by the microRNA let-7b.
Suppressor of microRNA (miRNA) biogenesis, including that of let-7 and possibly of miR107, miR-143 and miR-200c. Binds primary let-7 transcripts (pri-let-7), including pri-let-7g and pri-let-7a-1, and sequester them in the nucleolus, away from the microprocessor complex, hence preventing their processing into mature miRNA (PubMed:22118463). Does not act on pri-miR21 (PubMed:22118463). The repression of let-7 expression is required for normal development and contributes to maintain the pluripotent state of embryonic stem cells by preventing let-7-mediated differentiation. When overexpressed, recruits ZCCHC11/TUT4 uridylyltransferase to pre-let-7 transcripts, leading to their terminal uridylation and degradation (PubMed:19703396). This activity might not be relevant in vivo, as LIN28B-mediated inhibition of let-7 miRNA maturation appears to be ZCCHC11-independent (PubMed:22118463). Interaction with target pre-miRNAs occurs via an 5'-GGAG-3' motif in the pre-miRNA terminal loop. Mediates MYC-induced let-7 repression (By similarity). When overexpressed, isoform 1 stimulates growth of the breast adenocarcinoma cell line MCF-7. Isoform 2 has no effect on cell growth.
The tandem zinc fingers, also referred as zinc knuckle domain (ZKD), mediate specific binding to the GGAG/GGUG motif while the CSD shows only limited pyrimidine-rich sequence specificity. Both domains bind single-stranded nucleic acids.
According to PubMed:2168892, this sequence initiates from a non-AUG codon; N-terminal ACG codon did serve as a start codon.
Activated by magnesium and inorganic phosphate.
Belongs to the ribose-phosphate pyrophosphokinase family.
Catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) that is essential for nucleotide synthesis.
Homodimer. The active form is probably a hexamer composed of 3 homodimers (By similarity).
Activated by EGF (PubMed:8912711). Arachidonic acid conversion is inhibited by (13S,14S)-epoxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate (13S,14S-epoxy-DHA) (PubMed:23504711). Arachidonate 12-lipoxygenase activity is decreased when PH decreases from 7.4 to 6 (By similarity).
Catalyzes the regio and stereo-specific incorporation of molecular oxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species (PubMed:17493578, PubMed:1851637, PubMed:8319693, PubMed:8500694, PubMed:18311922, PubMed:32404334). Mainly converts arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) to the specific bioactive lipid (12S)-hydroperoxyeicosatetraenoate/(12S)-HPETE (PubMed:17493578, PubMed:22984144, PubMed:24282679, PubMed:8319693, PubMed:8500694). Through the production of bioactive lipids like (12S)-HPETE it regulates different biological processes including platelet activation (PubMed:8319693, PubMed:8500694). It can also catalyze the epoxidation of double bonds of polyunsaturated fatty acids such as (14S)-hydroperoxy-docosahexaenoate/(14S)-HPDHA resulting in the formation of (13S,14S)-epoxy-DHA (PubMed:23504711). Furthermore, it may participate in the sequential oxidations of DHA ((4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate) to generate specialized pro-resolving mediators (SPMs) like resolvin D5 ((7S,17S)-diHPDHA) and (7S,14S)-diHPDHA, that actively down-regulate the immune response and have anti-aggregation properties with platelets (PubMed:32404334). An additional function involves a multistep process by which it transforms leukotriene A4/LTA4 into the bioactive lipids lipoxin A4/LXA4 and lipoxin B4/LXB4, both are vasoactive and LXA4 may regulate neutrophil function via occupancy of specific recognition sites (PubMed:8250832). Can also peroxidize linoleate ((9Z,12Z)-octadecadienoate) to (13S)-hydroperoxyoctadecadienoate/ (13S-HPODE) (By similarity). Due to its role in regulating both the expression of the vascular endothelial growth factor (VEGF, an angiogenic factor involved in the survival and metastasis of solid tumors) and the expression of integrin beta-1 (known to affect tumor cell migration and proliferation), it can be regarded as protumorigenic (PubMed:9751607, PubMed:16638750, PubMed:22237009). Important for cell survival, as it may play a role not only in proliferation but also in the prevention of apoptosis in vascular smooth muscle cells (PubMed:23578768).
Disease susceptibility may be associated with variants affecting the gene represented in this entry. Gln at position 261 may confer interindividual susceptibility to colorectal cancer (PubMed:17460548).
Disease susceptibility may be associated with variants affecting the gene represented in this entry. Gln at position 261 may confer interindividual susceptibility to esophageal cancer (PubMed:17460548).
Down-regulated upon starvation, by UV-irradiation and 15-lipoxygenase metabolites.
Expressed in vascular smooth muscle cells.
Possible transcription factor. Specifically binds to the CT/GC-rich region of the interleukin-3 promoter and mediates tax transactivation of IL-3.
Ubiquitously expressed. Highest levels in skeletal muscle and kidney.
Belongs to the calycin superfamily. Lipocalin family.
Binds all-trans retinoic acid and may act as a retinoid carrier protein within the epididymis. May play a role in male fertility (By similarity).
Calcium-dependent lectin that acts as a pattern recognition receptor (PRR) of the innate immune system: recognizes damage-associated molecular patterns (DAMPs) of abnormal self and pathogen-associated molecular patterns (PAMPs) of bacteria and fungi (PubMed:18509109, PubMed:23602766). The PAMPs notably include mycobacterial trehalose 6,6'-dimycolate (TDM), a cell wall glycolipid with potent adjuvant immunomodulatory functions (PubMed:23602766, PubMed:24101491). Interacts with signaling adapter Fc receptor gamma chain/FCER1G to form a functional complex in myeloid cells (By similarity). Binding of mycobacterial trehalose 6,6'-dimycolate (TDM) to this receptor complex leads to phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of FCER1G, triggering activation of SYK, CARD9 and NF-kappa-B, consequently driving maturation of antigen-presenting cells and shaping antigen-specific priming of T-cells toward effector T-helper 1 and T-helper 17 cell subtypes (By similarity). Also recognizes alpha-mannose residues on pathogenic fungi of the genus Malassezia and mediates macrophage activation (By similarity). Through recognition of DAMPs released upon nonhomeostatic cell death, enables immune sensing of damaged self and promotes inflammatory cell infiltration into the damaged tissue (By similarity).
Monomer and homodimer (PubMed:18509109). Interacts with signaling adapter Fc receptor gamma chain/FCER1G to form a functional complex; the interaction is direct (By similarity). Alternatively, acts as a bridge for interaction between CLEC4D and FCER1G. A heterodimer of CLEC4E and CLEC4D associates with FCER1G to form a functional complex (By similarity). Interacts with SAP130 nuclear protein that is released from necrotic cells; the interaction is direct (By similarity).
Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. Ligand for CD36 mediating antiangiogenic properties.
High expression in invertebral disk tissue.
Homotrimer; disulfide-linked. Interacts (via the TSP type I repeats) with CD36; the interaction conveys an antiangiogenic effect. Interacts (via the TSP type I repeats) with HRG; the interaction blocks the antiangiogenic effect of THBS2 with CD36 (By similarity). Can bind to fibrinogen, fibronectin, laminin and type V collagen.
Belongs to the glycosyl hydrolase 56 family.
Detected in placenta and skeletal muscle.
Endo-hyaluronidase that degrades hyaluronan to smaller oligosaccharide fragments. Has also chondroitin sulfate hydrolase activity, The best substrate being the galactosaminidic linkage in the sequence of a trisulfated tetrasaccharide.
May play a role in cell-cell or cell-ligand interactions during synaptogenesis and other events in the brain.
Part of the multisubunit axonemal dynein complex formed at least of two heavy chains and a number of intermediate and light chains. Associated with axonemal dynein subunits such as, DNAH2, DNAI3, and DYNLT1. Interacts with DYNLT1.
Plays a critical role in the assembly of axonemal dynein complex, thereby playing a role in ciliary motility.
Expression peaks in late G2/S phase of the cell cycle.
Interacts with TP53BP1 (when phosphorylated by ATM) (PubMed:23333306, PubMed:28241136). May interact with TRF2 (By similarity). Interacts with SHLD2 (PubMed:29789392). Interacts with ERCC6 (via WHD region) (PubMed:29203878).
Key regulator of TP53BP1 that plays a key role in the repair of double-strand DNA breaks (DSBs) in response to DNA damage: acts by promoting non-homologous end joining (NHEJ)-mediated repair of DSBs (PubMed:15342490, PubMed:28241136). In response to DNA damage, interacts with ATM-phosphorylated TP53BP1 (PubMed:23333306, PubMed:28241136). Interaction with TP53BP1 leads to dissociate the interaction between NUDT16L1/TIRR and TP53BP1, thereby unmasking the tandem Tudor-like domain of TP53BP1 and allowing recruitment to DNA DSBs (PubMed:28241136). Once recruited to DSBs, RIF1 and TP53BP1 act by promoting NHEJ-mediated repair of DSBs (PubMed:23333306). In the same time, RIF1 and TP53BP1 specifically counteract the function of BRCA1 by blocking DSBs resection via homologous recombination (HR) during G1 phase (PubMed:23333306). Also required for immunoglobulin class-switch recombination (CSR) during antibody genesis, a process that involves the generation of DNA DSBs (By similarity). Promotes NHEJ of dysfunctional telomeres (By similarity).
Binds to the U5 repressive element (U5RE) of the human T cell leukemia virus type I long terminal repeat. It recognizes the 5'-TCCACCCC-3' sequence as a core motif and exerts a strong repressive effect on HTLV-I LTR-mediated expression.
The sequence shown here is derived from an EMBL/GenBank/DDBJ whole genome shotgun (WGS) entry which is preliminary data.
Belongs to the G-protein coupled receptor 1 family. Mas subfamily.
Mainly expressed in mast cells. Has a limited expression profile, both peripheral and within the central nervous system, with highest levels in dorsal root ganglion (PubMed:12915402). Detected in blood vessels, scattered lymphocytes, and gastrointestinal ganglia (at protein level) (PubMed:16161007).
Mast cell-specific receptor for basic secretagogues, i.e. cationic amphiphilic drugs, as well as endo- or exogenous peptides, consisting of a basic head group and a hydrophobic core (PubMed:25517090). Recognizes and binds small molecules containing a cyclized tetrahydroisoquinoline (THIQ), such as non-steroidal neuromuscular blocking drugs (NMBDs), including tubocurarine and atracurium. In response to these compounds, mediates pseudo-allergic reactions characterized by histamine release, inflammation and airway contraction (By similarity). Acts as a receptor for a number of other ligands, including peptides and alkaloids, such as cortistatin-14, proadrenomedullin N-terminal peptides PAMP-12 and, at lower extent, PAMP-20, antibacterial protein LL-37, PMX-53 peptide, beta-defensins, and complanadine A.
Component of the GET- and EMC-like (GEL) complex, composed of RAB5IF/OPTI and TMCO1 (PubMed:36261522). The GEL complex is part of the multi-pass translocon (MPT) complex, composed of three subcomplexes, the GEL complex (composed of RAB5IF/OPTI and TMCO1), the BOS complex (composed of NCLN/Nicalin, NOMO and TMEM147) and the PAT complex (composed of WDR83OS/Asterix and CCDC47) (PubMed:36261522). The MPT complex associates with the SEC61 complex (PubMed:36261522). Interacts with NDUFS3, NDUFA4, NDUFV1, NDUFA9 and NDUFS8 of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) (PubMed:31536960). Interacts with UQCRC2 of the ubiquinol-cytochrome c reductase complex (Complex III) (PubMed:31536960). Interacts with COX5A and COX7C of the cytochrome c oxidase complex (Complex IV) (PubMed:31536960).
Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes (PubMed:36261522). The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions (PubMed:36261522). Within the MPT complex, the GEL subcomplex may mediate insertion of transmembrane regions into the membrane (PubMed:36261522). In addition to its role in multi-pass membrane insertion, RAB5IF/OPTI also acts as an assembly factor for mitochondrial respiratory complexes (PubMed:31536960).
Expressed in embryonic stem cells and differentiated neuronal cells.
The disease may be caused by variants affecting the gene represented in this entry. Loss of RAB5IF in fibroblasts from a CFSMR2 patient carrying RAB5IF variant p.Trp25ter and negative for TMCO1 pathogenic variants, is associated with lack of TMCO1 expression. This suggests a possible functional relation between the two proteins and involvement in a common disease mechanism.
Belongs to the RNase H2 subunit B family.
Non catalytic subunit of RNase H2, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids. Participates in DNA replication, possibly by mediating the removal of lagging-strand Okazaki fragment RNA primers during DNA replication. Mediates the excision of single ribonucleotides from DNA:RNA duplexes.
The RNase H2 complex is a heterotrimer composed of the catalytic subunit RNASEH2A and the non-catalytic subunits RNASEH2B and RNASEH2C.
Belongs to the tumor necrosis factor family.
Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be an important regulator of interactions between T-cells and dendritic cells and may play a role in the regulation of the T-cell-dependent immune response. May also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy (PubMed:22664871). Induces osteoclastogenesis by activating multiple signaling pathways in osteoclast precursor cells, chief among which is induction of long lasting oscillations in the intracellular concentration of Ca (2+) resulting in the activation of NFATC1, which translocates to the nucleus and induces osteoclast-specific gene transcription to allow differentiation of osteoclasts. During osteoclast differentiation, in a TMEM64 and ATP2A2-dependent manner induces activation of CREB1 and mitochondrial ROS generation necessary for proper osteoclast generation (By similarity).
Highest in the peripheral lymph nodes, weak in spleen, peripheral blood Leukocytes, bone marrow, heart, placenta, skeletal muscle, stomach and thyroid.
Homotrimer (By similarity). Interacts with TNFRSF11B (PubMed:22664871). Interacts with TNFRSF11A. Interacts with FBN1 (via N-terminal domain) in a Ca(+2)-dependent manner (By similarity). Interacts with TNFAIP6 (via both Link and CUB domains).
The soluble form of isoform 1 derives from the membrane form by proteolytic processing (By similarity). The cleavage may be catalyzed by ADAM17.
Up-regulated by T-cell receptor stimulation.
Binds to the consensus sequence 5'-AGAGTG-3' and has transcriptional activator activity (By similarity). May have a tumor-suppressor function. May play a role in apoptosis.
Ubiquitous. Most abundantly expressed in lung, placenta, skeletal muscle, pancreas and leukocyte. Frequently down-regulated in lung, kidney, liver and colon cancers compared with their corresponding normal tissues.
(Microbial infection) Interacts with HIV-1 Rev.
Belongs to the importin beta family. Importin beta-3 subfamily.
Functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus (By similarity). Mediates the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5 (PubMed:9687515, PubMed:11682607). In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones. Binds to CPEB3 and mediates its nuclear import following neuronal stimulation (By similarity). In case of HIV-1 infection, binds and mediates the nuclear import of HIV-1 Rev.
Interacts with RPS7 and RPL5 (PubMed:9687515). Interacts with RPL23A (via BIB domain) (PubMed:9687515, PubMed:11682607). Interacts with H2A, H2B, H3 and H4 histones (By similarity). Interacts with CPEB3; this mediates CPEB3 nuclear import following neuronal stimulation which enhances the interaction in a RAN-regulated manner (PubMed:22730302). Interacts with AIFM2; this interaction likely mediates the translocation of AIFM2 into the nucleus upon oxidative stress. Interacts with STX3 (isoform 3) (PubMed:29475951). Interacts with SRP19 (PubMed:11682607).
Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability.
Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters.
Butyrylation of histones marks active promoters and competes with histone acetylation. It is present during late spermatogenesis.
Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription.
Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.
Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.
Dopaminylated by TGM2 at Gln-6 (H3Q5dop) in ventral tegmental area (VTA) neurons (PubMed:32273471). H3Q5dop mediates neurotransmission-independent role of nuclear dopamine by regulating relapse-related transcriptional plasticity in the reward system (By similarity).
Expressed during S phase, then expression strongly decreases as cell division slows down during the process of differentiation.
HIST1H3B or HIST1H3C mutations affecting residue Lys-37 of histone H3.1 are involved in the pathogenesis of pediatric undifferentiated soft tissue sarcomas. The mechanism through which mutations lead to tumorigenesis involves altered histones methylation with gain of global H3K27 methylation, altered Polycomb repressive complex 1 (PRC1) activity, aberrant epigenetic regulation of gene expression and impaired differentiation of mesenchimal progenitor cells.
Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.
Lysine deamination at Lys-5 (H3K4all) to form allysine is mediated by LOXL2. Allysine formation by LOXL2 only takes place on H3K4me3 and results in gene repression.
Methylation at Lys-5 (H3K4me), Lys-37 (H3K36me) and Lys-80 (H3K79me) are linked to gene activation. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are linked to gene repression. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication.
Monoubiquitinated by RAG1 in lymphoid cells, monoubiquitination is required for V(D)J recombination (By similarity). Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins.
Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 or isoform M2 of PKM (PKM2) is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Thr-12 (H3T11ph) by chromatin-associated CHEK1 regulates the transcription of cell cycle regulatory genes by modulating acetylation of Lys-10 (H3K9ac). Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin.
Serine ADP-ribosylation by PARP1 or PARP2 constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:30257210, PubMed:34874266). Serine ADP-ribosylation at Ser-11 (H3S10ADPr) promotes recruitment of CHD1L (PubMed:34874266). H3S10ADPr is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac) (PubMed:30257210).
Serotonylated by TGM2 at Gln-6 (H3Q5ser) during serotonergic neuron differentiation (PubMed:30867594). H3Q5ser is associated with trimethylation of Lys-5 (H3K4me3) and enhances general transcription factor IID (TFIID) complex-binding to H3K4me3, thereby facilitating transcription (PubMed:30867594).
Succinylation at Lys-80 (H3K79succ) by KAT2A takes place with a maximum frequency around the transcription start sites of genes (PubMed:29211711). It gives a specific tag for epigenetic transcription activation (PubMed:29211711). Desuccinylation at Lys-123 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair (PubMed:27436229).
The gene represented in this entry is involved in disease pathogenesis. HIST1H3B mutations affecting residue Lys-28 involved in post-translational modifications of histone H3.1 are recurrent in malignant, aggressive gliomas including pediatric non-brain stem glioblastoma and diffuse intrinsic pontine glioma (DIPG) (PubMed:22286216). The mechanism through which mutations lead to tumorigenesis involves altered histone methylation, impaired regulation of Polycomb repressive complex 2 (PRC2) activity, and aberrant epigenetic regulation of gene expression (PubMed:23603901).
The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Interacts with TONSL; CHAF1A; CHAF1B; MCM2 and DNAJC9 (PubMed:33857403).
The original paper reporting lysine deamination at Lys-5 by LOXL2 has been retracted due to inappropriate manipulation of figure data (PubMed:22483618, PubMed:27392148). However, this modification was confirmed in a subsequent publication (PubMed:27735137).
This histone is only present in mammals and is enriched in acetylation of Lys-15 and dimethylation of Lys-10 (H3K9me2).
Interacts with CPLANE1. Interacts with FUZ and WDPCP; FUZ, INTU and WDPCP probably form the core CPLANE (ciliogenesis and planar polarity effectors) complex (By similarity). Interacts with NPHP4 and DAAM1; INTU is mediating the interaction between NPHP4 and DAAM1 (PubMed:26644512).
Plays a key role in ciliogenesis and embryonic development. Regulator of cilia formation by controlling the organization of the apical actin cytoskeleton and the positioning of the basal bodies at the apical cell surface, which in turn is essential for the normal orientation of elongating ciliary microtubules. Plays a key role in definition of cell polarity via its role in ciliogenesis but not via conversion extension. Has an indirect effect on hedgehog signaling (By similarity). Proposed to function as core component of the CPLANE (ciliogenesis and planar polarity effectors) complex involved in the recruitment of peripheral IFT-A proteins to basal bodies (PubMed:27158779).
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. SRTD7/20 can be caused by co-occurrence of WDR35 variant p.Trp311Leu and INTU p.Gln276Ter. One such patient has been reported.
Associates with the phosphorylated CTD domain of POLR2A /RNA polymerase II.
Component of pre-mRNA cleavage complex II, which promotes transcription termination by RNA polymerase II.
Phosphorylation at Ser-120 and/or Thr-121 by WNK1 weakens its association with POLR2A/RNA polymerase II, promoting transcript release from the chromatin template and mRNA export to the cytoplasm.
Belongs to the SLC12A transporter family.
Electroneutral sodium and chloride ion cotransporter, which acts as a key mediator of sodium and chloride reabsorption in kidney distal convoluted tubules (PubMed:21613606, PubMed:18270262, PubMed:22009145, PubMed:36351028, PubMed:36792826). Also acts as a receptor for the pro-inflammatory cytokine IL18, thereby contributing to IL18-induced cytokine production, including IFNG, IL6, IL18 and CCL2 (By similarity). May act either independently of IL18R1, or in a complex with IL18R1 (By similarity).
Homodimer (PubMed:36351028, PubMed:36792826). Interacts with KLHL3 (PubMed:22406640). Interacts with IL18R1; this interaction is increased by IL18 treatment (By similarity).
Interaction between the cytoplasmic N-terminal and C-terminal domains (NTD and CTD, respectively) is essential for SLC12A3/NCC transporter activity (PubMed:36792826). Phosphorylation by OXSR1/OSR1 and STK39/SPAK may activate SLC12A3/NCC by facilitating this interaction (PubMed:36792826).
Phosphorylated at Thr-46, Thr-55, Thr-60 and Ser-91 by OXSR1/OSR1 and STK39/SPAK downstream of WNK4, promoting its activity (PubMed:18270262). Phosphorylated in response to IL18 (By similarity).
Phosphorylation by OXSR1/OSR1 and STK39/SPAK in kidney distal convoluted tubules downstream of WNK4 promotes its activity (PubMed:18270262). Also activated by OXSR1/OSR1 and STK39/SPAK downstream of WNK3 (PubMed:21613606). Target of thiazide diuretics used in the treatment of high blood pressure (PubMed:8528245, PubMed:36792826). Thiazide drugs, such as polythiazide, specifically inhibit SLC12A3/NCC transporter activity by competing with chloride for binding and by locking SLC12A3/NCC in an outward-facing conformation (PubMed:36792826).
Predominantly expressed in the kidney (at protein level) (PubMed:29993276, PubMed:8812482). Localizes to the distal convoluted tubules (at protein level)(PubMed:29993276). Not detected in normal aorta, but abundantly expressed in fatty streaks and advanced atherosclerotic lesions (at protein level) (PubMed:26099046).
Ubiquitinated; ubiquitination is essential for regulation of endocytosis. The BCR(KLHL3) complex was initially identified as a candidate ubiquitin ligase for SLC12A3 (PubMed:22406640). However, it was later shown that it is not the case.
Adaptor protein complex 1 (AP-1) is a heterotetramer composed of two large adaptins (gamma-type subunit AP1G1 and beta-type subunit AP1B1), a medium adaptin (mu-type subunit AP1M1 or AP1M2) and a small adaptin (sigma-type subunit AP1S1 or AP1S2 or AP1S3).
Belongs to the adaptor complexes small subunit family.
Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules.
Up-regulated in response to enterovirus 71 (EV71) infection.
Plays a role in processing of mitochondrial RNA precursors and in stabilization of a subset of mature mitochondrial RNA species, such as MT-CO1, MT-CO2, MT-CYB, MT-CO3, MT-ND3, MT-ND5 and MT-ATP8/6. May play a role in cell cycle progression (PubMed:9383053).
RAP domain is required for TBRG4 function in mRNA stability and translation.
Ubiquitously expressed (PubMed:12759187). Expression detected in spleen, thymus, testis, ovary, colon, heart, smooth muscle, kidney, brain, lung, liver and white adipose tissue with highest expression in smooth muscle (PubMed:20869947).
Belongs to the proteasome subunit p55 family.
Component of the 19S proteasome regulatory particle complex (PubMed:27428775, PubMed:27342858). The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:27428775, PubMed:27342858). The regulatory particle is made of a lid composed of 9 subunits including PSMD12, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Interacts with ERCC6 (PubMed:26030138).
Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.
Down-regulated in oral tongue squamous cell carcinomas.
May be involved in mediating calcium-activated chloride conductance.
Primarily expressed in the digestive tract, mainly in colon. Detected in smaller amounts in brain, urogenital organs, testis, and salivary and mammary glands. Highly expressed in the epithelial layer and submucosal gland of the inferior turbinate mucosa. Lower levels in the epithelial layer of nasal polyp.
The metalloprotease region is responsible for autoproteolytic processing. It can also cross-cleave other CLCA substrates.
The translation product is autoproteolytically cleaved by the metalloprotease domain in the endoplasmic reticulum into a N-terminal and a C-terminal products that remain physically associated with each other. The cleavage is necessary for calcium-activated chloride channel (CaCC) activation activity.
Belongs to the membrane-bound acyltransferase family. HHAT subfamily.
Inhibited by NaCl concentrations above 150 mM.
Palmitoyl acyltransferase that catalyzes N-terminal palmitoylation of SHH; which is required for SHH signaling (PubMed:18534984, PubMed:31875564, PubMed:24784881). It also catalyzes N-terminal palmitoylation of DHH (PubMed:24784881). Promotes the transfer of palmitoyl-CoA from the cytoplasmic to the luminal side of the endoplasmic reticulum membrane, where SHH palmitoylation occurs (PubMed:31875564). It is an essential factor for proper embryonic development and testicular organogenesis (PubMed:24784881).
Widely expressed. Expressed in fetal ovary and testis, with high levels of expression observed in Sertoli cells (PubMed:24784881).
Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex (PubMed:16622420). Plays an important role in chromosome congression and in the recruitment of CENP-O complex (which comprises CENPO, CENPP, CENPQ and CENPU), CENPE and PLK1 to the kinetochores (PubMed:25395579).
Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex interacts with the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU.
Phosphorylation at Ser-50 is essential for CENPE recruitment to kinetochores and orderly chromosome congression.
At 24 weeks of gestation, fragments of radial glial fibers are positive within the cortical plate and subplate of allocortical areas. These positive fragments often appear enlarged as varicosities and some of them terminate at blood vessels. Between 28 and 30 weeks of gestation, all iso- and allocortical areas contain immunolabeled radial glial fibers revealing curvature next to sulci. After 32 weeks of gestation, radial glial fibers gradually disappear; instead positive transitional stages between radial glia and astrocytes were found.
Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. Is coupled to both the G(i/0)alpha and G(12) subclass of heteromeric G-proteins (By similarity). May play a regulatory role in the transformation of radial glial cells into astrocytes and may affect proliferative activity of these cells.
Widely expressed in the brain, most prominently in the corpus callosum, which is predominantly white matter. Detected in spleen, peripheral blood leukocytes, placenta, lung, aorta and fetal spleen. Low-level signal detected in many tissue extracts. Overexpressed in leukemic large granular lymphocytes. Isoform 1 is predominantly expressed in peripheral tissues. Isoform 2 is expressed in brain, spleen and peripheral blood leukocytes.
Component of the U5 snRNP complex that is required for spliceosome assembly and for pre-mRNA splicing.
Interacts with PRPF8 (via RNase H homology domain) (PubMed:26527271). Component of a U5 snRNP complex that contains PRPF8 (By similarity).
Adaptor protein complex 3 (AP-3) is a heterotetramer composed of two large adaptins (delta-type subunit AP3D1 and beta-type subunit AP3B1 or AP3B2), a medium adaptin (mu-type subunit AP3M1 or AP3M2) and a small adaptin (sigma-type subunit APS1 or AP3S2) (Probable). AP-3 associates with the BLOC-1 complex (By similarity). Interacts with KIF3A; interaction is direct; interaction is impaired by pyrophosphorylation of AP3B1 (PubMed:19934039).
Belongs to the adaptor complexes large subunit family.
Pyrophosphorylation by 5-diphosphoinositol pentakisphosphate (5-IP7) impairs interaction with KIF3A (PubMed:19934039). Serine pyrophosphorylation is achieved by Mg(2+)-dependent, but enzyme independent transfer of a beta-phosphate from a inositol pyrophosphate to a pre-phosphorylated serine residue (PubMed:19934039).
Subunit of non-clathrin- and clathrin-associated adaptor protein complex 3 (AP-3) that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. AP-3 appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles. In concert with the BLOC-1 complex, AP-3 is required to target cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals.
Belongs to the methyltransferase superfamily. LCMT family.
Methylates the carboxyl group of the C-terminal leucine residue of protein phosphatase 2A catalytic subunits to form alpha-leucine ester residues.
Exclusively expressed in epididymis, in the corpus region.
Genetic variations in BHLHE41 are associated with the familial natural short sleep 1 (FNSS1) phenotype, an autosomal dominant trait [MIM:612975]. Individuals with this trait require less sleep in any 24-hour period than is typical for their age group.
Highly expressed in skeletal muscle and brain, moderately expressed in pancreas and heart, weakly expressed in placenta, lung, liver and kidney.
Homodimer (By similarity). Heterodimer with BHLHE40/DEC1 (PubMed:15193144). Interacts with CIART and BMAL1 (By similarity). Interacts with RXRA (PubMed:19786558). Interacts with NR0B2 and HNF1A (By similarity).
Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes (PubMed:11278948, PubMed:14672706, PubMed:15193144, PubMed:15560782, PubMed:18411297, PubMed:19786558, PubMed:25083013). Acts as the negative limb of a novel autoregulatory feedback loop (DEC loop) which differs from the one formed by the PER and CRY transcriptional repressors (PER/CRY loop). Both these loops are interlocked as it represses the expression of PER1 and in turn is repressed by PER1/2 and CRY1/2. Represses the activity of the circadian transcriptional activator: CLOCK-BMAL1 heterodimer by competing for the binding to E-box elements (5'-CACGTG-3') found within the promoters of its target genes (PubMed:25083013). Negatively regulates its own expression and the expression of DBP and BHLHE41/DEC2. Acts as a corepressor of RXR and the RXR-LXR heterodimers and represses the ligand-induced RXRA/B/G, NR1H3/LXRA, NR1H4 and VDR transactivation activity. Inhibits HNF1A-mediated transactivation of CYP1A2, CYP2E1 AND CYP3A11 (By similarity).
Expressed in breast epithelial cell lines.
Interacts with the nuclear localization signal of BRCA1 and with the N-terminal of KSR1. The C-terminal portion of BCRA1 interacts with DDB1.
Negatively regulates MAP kinase activation by limiting the formation of Raf/MEK complexes probably by inactivation of the KSR1 scaffold protein. Also acts as a Ras responsive E3 ubiquitin ligase that, on activation of Ras, is modified by auto-polyubiquitination resulting in the release of inhibition of Raf/MEK complex formation. May also act as a cytoplasmic retention protein with a role in regulating nuclear transport.
Belongs to the eukaryotic ribosomal protein eS25 family.
Component of the small ribosomal subunit (PubMed:23636399). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399).
Component of the small ribosomal subunit.
Inhibits phosphatase activity of protein phosphatase 1 (PP1) complexes.
Highly expressed in liver. Expressed in brain and pancreas. Not observed in heart, placenta, lung, skeletal muscle and kidney. Expression is significantly reduced in hepatocellular carcinomas.
Homotetramer, dimer of dimers (Probable). Does not assemble into higher oligomers (By similarity). Interacts with the PDZ domain of the syntrophin SNTA1. Interacts with the PDZ domain of TAX1BP3 (PubMed:11163757).
Plays an important role in the regulation of glutamine catabolism. Promotes mitochondrial respiration and increases ATP generation in cells by catalyzing the synthesis of glutamate and alpha-ketoglutarate. Increases cellular anti-oxidant function via NADH and glutathione production. May play a role in preventing tumor proliferation.
Up-regulated by P53 (at protein and mRNA level) under both stressed and non-stressed conditions.
A conserved histidine residue in the third TMD (His-115) may play an essential role in the pH sensitivity of SLCO1B3/OATP1B3-mediated substrate transport.
Belongs to the organo anion transporter (TC 2.A.60) family.
Highly expressed in liver, in particular at the basolateral membrane of hepatocytes near the central vein (PubMed:10779507, PubMed:15159445). Expressed in the placenta (PubMed:12409283). In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed in Leydig cells and within the tubules (PubMed:35307651).
Mediates the Na(+)-independent uptake of organic anions (PubMed:15159445, PubMed:17412826, PubMed:10779507). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:15159445, PubMed:17412826, PubMed:10779507, PubMed:12568656, PubMed:11159893, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16627748, PubMed:16624871).
Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4 with high specificity (PubMed:7937884, PubMed:27791009, PubMed:27365393, PubMed:9153254, PubMed:23409838). Can also catalyze the transfer of a glutathionyl group from glutathione (GSH) to 13(S),14(S)-epoxy-docosahexaenoic acid to form maresin conjugate in tissue regeneration 1 (MCTR1), a bioactive lipid mediator that possess potent anti-inflammatory and proresolving actions (PubMed:27791009).
Detected in lung, platelets and the myelogenous leukemia cell line KG-1 (at protein level). LTC4S activity is present in eosinophils, basophils, mast cells, certain phagocytic mononuclear cells, endothelial cells, vascular smooth muscle cells and platelets.
Homotrimer (PubMed:17632548, PubMed:17632546). Interacts with ALOX5AP and ALOX5 (PubMed:19233132).
LTC4 synthase deficiency is associated with a neurometabolic developmental disorder characterized by muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.
Phosphorylation at Ser-36 by RPS6KB1 inhibits the leukotriene-C4 synthase activity.
Belongs to the N-acetylmuramoyl-L-alanine amidase 2 family.
Detected in skin epidermis, eccrine sweat glands and ducts, ciliary body epithelial cells of the eye, in small intestine, colon, stomach and in mature epithelial cells of the tongue (at protein level). Highly expressed in skin and esophagus, expressed also in tonsils and thymus and to a much lesser extent in the stomach, descending colon, rectum and brain.
Monomer. Homodimer; disulfide-linked. Heterodimer with PGLYRP4; disulfide-linked.
Pattern receptor that binds to murein peptidoglycans (PGN) of Gram-positive bacteria. Has bactericidal activity towards Gram-positive bacteria. May kill Gram-positive bacteria by interfering with peptidoglycan biosynthesis. Binds also to Gram-negative bacteria, and has bacteriostatic activity towards Gram-negative bacteria. Plays a role in innate immunity.
Up-regulated by exposure to Gram-positive and Gram-negative bacteria.
Expressed in columnar epithelial cells of the colon (at protein level) (PubMed:10436421). Strongly down-regulated in colonic adenocarcinomas.
Directly interacts with DKC1 alone, but not in the context of the core trimer composed of DKC1, NOP10 and NHP2, nor in the presence of NAF1. Does not interact with NAF1.
Required for the quantitative accumulation of H/ACA ribonucleoproteins (RNPs), including telomerase, probably through the stabilization of DKC1, from the time of its synthesis until its association with NOP10, NHP2, and NAF1 at the nascent H/ACA RNA.
Component of a topoisomerase 6 complex specifically required for meiotic recombination. Together with SPO11, mediates DNA cleavage that forms the double-strand breaks (DSB) that initiate meiotic recombination. The complex promotes relaxation of negative and positive supercoiled DNA and DNA decatenation through cleavage and ligation cycles.
Contains a signal peptide sequence at position 1-23.
Despite a weak sequence similarity, retains most of the structural features of the ancestral archaeal Top6B subunit (AC O05207), including the transducer domain that interacts with the SPO11 subunit and the ATP-binding fold, also named GHKL fold.
Detected in lung, spleen,colon and in skeletal muscle. Expressed in the ovaries, Fallopian tubes and uterus (PubMed:30388401).
Expansion of a polymorphic CGG repeat within the 5'-UTR of this gene may be the cause of folate-sensitive fragile site FRA11A. The expansion is identified in the 15-year-old proband with intellectual disability as well as in phenotypically normal members of the family.
Heterotetramer of SPO11 and 2 TOP6BL chains. Interacts with SPO11.
Antiviral protein which inhibits the replication of viruses by recruiting the cellular RNA degradation machineries to degrade the viral mRNAs. Binds to a ZAP-responsive element (ZRE) present in the target viral mRNA, recruits cellular poly(A)-specific ribonuclease PARN to remove the poly(A) tail, and the 3'-5' exoribonuclease complex exosome to degrade the RNA body from the 3'-end. It also recruits the decapping complex DCP1-DCP2 through RNA helicase p72 (DDX17) to remove the cap structure of the viral mRNA to initiate its degradation from the 5'-end. Its target viruses belong to families which include retroviridae: human immunodeficiency virus type 1 (HIV-1), moloney and murine leukemia virus (MoMLV) and xenotropic MuLV-related virus (XMRV), filoviridae: ebola virus (EBOV) and marburg virus (MARV), togaviridae: sindbis virus (SINV) and Ross river virus (RRV). Specifically targets the multiply spliced but not unspliced or singly spliced HIV-1 mRNAs for degradation. Isoform 1 is a more potent viral inhibitor than isoform 2. Isoform 2 acts as a positive regulator of RIGI signaling resulting in activation of the downstream effector IRF3 leading to the expression of type I IFNs and IFN stimulated genes (ISGs).
By type I interferon (IFN) and viruses. Isoform 2 is up-regulated by 3'-PPP-RNA.
Homodimer or homooligomer. Homooligomerization is essential for its antiviral activity. Interacts with EXOSC5 (By similarity). Interacts (via N-terminal domain) with DDX17 in an RNA-independent manner (By similarity). Interacts with EXOSC3, EXOSC7, DCP2 and DCP1A. Interacts with PARN in an RNA-independent manner. Interacts with XRN1 in an RNA-dependent manner. Isoform 2 interacts (via zinc-fingers) with RIGI in an RNA-dependent manner. Interacts (via N-terminal domain) with DHX30 (via N-terminus) in an RNA-independent manner.
Phosphorylation at Ser-275 is essential for sequential phosphorylation of Ser-271, Ser-267, Ser-263 and Ser-257 by GSK3-beta. Phosphorylation by GSK3-beta enhances its antiviral activity (By similarity).
The N-terminal domain is sufficient to bind to viral RNAs and promote their degradation. The second and fourth zinc fingers are involved in binding to specific viral RNAs (PubMed:20451500). Contains a divergent PARP homology ADP-ribosyltransferase domain which lacks the structural requirements for NAD[+] binding (PubMed:25635049). It is therefore inactive (PubMed:25043379, PubMed:25635049).
Cleaved by tolloid proteases; cleavage participates in dorsoventral patterning during early development.
Dorsalizing factor. Key developmental protein that dorsalizes early vertebrate embryonic tissues by binding to ventralizing TGF-beta family bone morphogenetic proteins (BMPs) and sequestering them in latent complexes (By similarity).
Dorsalizing factor. Key developmental protein that dorsalizes early vertebrate embryonic tissues by binding to ventralizing TGF-beta family bone morphogenetic proteins (BMPs) and sequestering them in latent complexes.
Expressed at the highest level in liver.
Belongs to the ammonium transporter (TC 2.A.49) family. Rh subfamily.
Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane (PubMed:35835865). Mediates the primary membrane attachment site for ANK1 when associated with RHAG (PubMed:35835865). May participate in the ammonium and carbon dioxide transport through the heterotrimer form (Probable).
Heterotrimer; a RHCE monomer interacts with a RHAG homodimer (PubMed:35835865). Component of the ankyrin-1 complex in the erythrocyte, composed of ANK1, RHCE, RHAG, SLC4A1, EPB42, GYPA, GYPB and AQP1 (PubMed:35835865). Interacts (via the N- and C-terminal) with ANK1 (via ANk 1-5 repeats); mediates the primary membrane attachment site for ANK1 (PubMed:35835865).
Restricted to tissues or cell lines expressing erythroid characters. Isoform 4g and isoform RhPI-Alpha are expressed in immature erythroblasts but not in mature erythroblasts.
RhCE and RhD are responsible for the RH blood group system. The molecular basis of the E=Rh3/e=Rh5 blood group antigens is a single variation in position 226; Pro-226 corresponds to Rh3 and Ala-226 to Rh5. The molecular basis of the C=Rh2/c=Rh4 blood group antigens is a single variation in position 103; Ser-103 corresponds to Rh2 and Pro-103 to Rh4.
Fetal kidney, fetal liver, and adult pancreas, brain, lung, jejunum and stomach.
Receptor for somatostatin with higher affinity for somatostatin-14 than -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and Na(+)/H(+) exchanger via pertussis toxin insensitive G proteins.
It is uncertain whether Met-1 or Met-64 is the initiator.
Interacts with SHANK2 (By similarity). Interacts with LPAR2 (PubMed:15143197).
The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family.
Motor protein that may participate in process critical to neuronal development and function such as cell migration, neurite outgrowth and vesicular transport.
Represents an unconventional myosin. This protein should not be confused with the conventional myosin-1 (MYH1).
Belongs to the mitochondrial carrier (TC 2.A.29) family.
Catalyzes the electroneutral exchange or flux of physiologically important metabolites such as dicarboxylates (malonate, malate, succinate), inorganic sulfur-containing anions, and phosphate, across mitochondrial inner membrane (PubMed:29211846). Plays an important role in gluconeogenesis, fatty acid metabolism, urea synthesis, and sulfur metabolism, particularly in liver, by supplying the substrates for the different metabolic processes. Regulates fatty acid release from adipocytes, and contributes to systemic insulin sensitivity (By similarity).
Present in high amounts in liver and kidney, and at lower levels in all the other tissues analyzed.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EF-Tu/EF-1A subfamily.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. ERF3 subfamily.
Component of the eRF1-eRF3-GTP ternary complex, composed of ETF1/ERF1 and ERF3 (GSPT1/ERF3A or GSPT2/ERF3B) and GTP (PubMed:19417105, PubMed:27863242). Component of the transient SURF (SMG1-UPF1-eRF1-eRF3) complex (PubMed:19417104). The ETF1-GSPT1 complex interacts with JMJD4 (PubMed:24486019). Interacts with PABPC1 (By similarity). Interacts with SHFL (PubMed:30682371).
GTPase component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons UAA, UAG and UGA (PubMed:2511002, PubMed:15987998, PubMed:19417105, PubMed:27863242). GSPT1/ERF3A mediates ETF1/ERF1 delivery to stop codons: The eRF1-eRF3-GTP complex binds to a stop codon in the ribosomal A-site (PubMed:27863242). GTP hydrolysis by GSPT1/ERF3A induces a conformational change that leads to its dissociation, permitting ETF1/ERF1 to accommodate fully in the A-site (PubMed:16777602, PubMed:27863242). Component of the transient SURF complex which recruits UPF1 to stalled ribosomes in the context of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons (PubMed:24486019). Required for SHFL-mediated translation termination which inhibits programmed ribosomal frameshifting (-1PRF) of mRNA from viruses and cellular genes (PubMed:30682371).
eRF3 antibodies used in PubMed:19417104 do not differentiate between GSPT1/ERF3A and GSPT2/ERF3B.
(Microbial infection) Binds to the HIV-1 TAR RNA which is located in the long terminal repeat (LTR) of HIV-1, and stimulates translation of TAR-containing RNAs (PubMed:2011739, PubMed:11438532, PubMed:12475984). This is achieved in part at least by binding to and inhibiting EIF2AK2/PKR, thereby reducing phosphorylation and inhibition of EIF2S1/eIF-2-alpha (PubMed:11438532). May also promote translation of TAR-containing RNAs independently of EIF2AK2/PKR (PubMed:12475984). Mediates recruitment of FTSJ3 methyltransferase to HIV-1 RNA, leading to 2'-O-methylation of the viral genome, allowing HIV-1 to escape the innate immune system (PubMed:30626973).
(Microbial infection) Interacts with FTSJ3; forms a complex with FTSJ3 and HIV-1 TAR RNA.
(Microbial infection) Interacts with ebolavirus VP30; this interaction, which occurs only in the presence of siRNA, prevents TARBP2 binding to DICER1 and thus allows the virus to counteract host RNA silencing.
(Microbial infection) Interacts with ebolavirus VP35; this interaction prevents TARBP2 binding to DICER1 and thus allows the virus to counteract host RNA silencing.
A paper describing truncating mutations of TARBP2 in tumor cells and resultant effects on DICER1 stability and miRNA processing has been retracted, due to concerns of image duplication in some of the figures.
Required for formation of the RNA induced silencing complex (RISC). Component of the RISC loading complex (RLC), also known as the micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, AGO2 and TARBP2. Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto AGO2. AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. May also play a role in the production of short interfering RNAs (siRNAs) from double-stranded RNA (dsRNA) by DICER1 (By similarity) (PubMed:15973356, PubMed:16142218, PubMed:16271387, PubMed:16357216, PubMed:16424907, PubMed:17452327, PubMed:18178619). Binds in vitro to the PRM1 3'-UTR (By similarity). Seems to act as a repressor of translation (By similarity). For some pre-miRNA substrates, may also alter the choice of cleavage site by DICER1 (PubMed:23063653). Negatively regulates IRF7-mediated IFN-beta signaling triggered by viral infection by inhibiting the phosphorylation of IRF7 and promoting its 'Lys'-48-linked ubiquitination and degradation (PubMed:30927622).
Self-associates. Component of the RISC loading complex (RLC), or micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, AGO2 and TARBP2. Note that the trimeric RLC/miRLC is also referred to as RISC. Interacts with EIF2AK2/PKR and inhibits its protein kinase activity. Interacts with DHX9 and PRKRA. Interacts with DICER1, AGO2, MOV10, EIF6 and RPL7A (60S ribosome subunit); they form a large RNA-induced silencing complex (RISC) (PubMed:17507929). Interacts with IRF7; this interaction prevents IRF7 phosphorylation and activation (PubMed:30927622).
Expressed in heart, liver, skeletal muscle and pancreas. At very low levels expressed in brain, placenta and lung.
Phosphorylation by CK2 is required for efficient degradation of NFKBIA and CDKN1B.
Probable component of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins involved in cell cycle progression, signal transduction and transcription (PubMed:10851089). CRLs complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins, ARIH1 mediating addition of the first ubiquitin on CRLs targets (By similarity). Through the RING-type zinc finger, seems to recruit the E2 ubiquitination enzyme to the complex and brings it into close proximity to the substrate. Promotes the neddylation of CUL5 via its interaction with UBE2F. May play a role in protecting cells from apoptosis induced by redox agents.
Probable part of SCF complexes, which consist of SKP1, CUL1, RNF7/RBX2 and a F-box protein. Interacts (preferentially) with CUL5. Also interacts (with lower preference) with CUL1, CUL2, CUL3, CUL4A and CUL4B. Interacts with UBE2F. Interacts with CSNK2B, the interaction is not affected by phosphorylation by CK2. May also interact with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5 (PubMed:26906416).
The RING-type zinc finger domain is essential for ubiquitin ligase activity. It coordinates an additional third zinc ion.
Belongs to the major facilitator superfamily. Proton-dependent oligopeptide transporter (POT/PTR) (TC 2.A.17) family.
Expressed in osteoblast cell lines. Well expressed in ovary, heart, pancreas, skeletal muscle, lung, and fetal kidney and lung and only at the basal levels in the other tissues examined including adult kidney. More expressed in S-type neuroblastoma cells than in N-type neuroblastoma cells.
Involved in bone homeostasis. Acts as a negative regulator of RANKL-induced osteoclast precursor differentiation from bone marrow precursors (By similarity).
Acts at E2F-responsive promoters as coregulator to integrate signals provided by PHD- and/or bromodomain-containing transcription factors. May act as coactivator as well as corepressor of E2F1-TFDP1 and E2F4-TFDP1 complexes on E2F consensus binding sites, which would activate or inhibit E2F-target genes expression. Modulates fat storage by down-regulating the expression of key genes involved in adipocyte lipolysis, thermogenesis and oxidative metabolism.
Interacts with XPO1; which mediates nuclear export. Interacts with TFDP1; modulates transactivation activity of TFDP1/E2F complexes.
Polyubiquitinated, which promotes proteasomal degradation.
Transcript levels remain constant in all phases of the cell cycle. In contrast, protein levels accumulate at the G1/S phase boundary and decrease progressively through S phase until G2/M phase is reached, residual expression is observed in the G2/M and early G1 phases.
Belongs to the phosphatase 2A regulatory subunit B family.
PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules (By similarity). Interacts with IER5 (PubMed:25816751).
The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment.
The EMBL entry for PubMed:10574460 is not complete, the paper shows the rest of the sequence (residues 1 to 23).
Belongs to the TMEM97/sigma-2 receptor family.
Intracellular orphan receptor that binds numerous drugs and which is highly expressed in various proliferating cancer cells (PubMed:28559337). Corresponds to the sigma-2 receptor, which is thought to play important role in regulating cell survival, morphology and differentiation (PubMed:23922215, PubMed:25620095). Under investigation for its potential diagnostic and therapeutic uses (PubMed:23922215, PubMed:25620095). May play a role as a regulator of cellular cholesterol homeostasis (PubMed:19583955). May function as sterol isomerase (PubMed:25566323). May alter the activity of some cytochrome P450 proteins (PubMed:22292588).
Potentially useful for cancer diagnostics or as target for anticancer therapeutics or adjuvant anticancer treatment agents (PubMed:23922215). Some exogenous ligands display a neuroprotective effect (PubMed:25620095).
Sigma receptors are classified into two subtypes (Sigma-1 and Sigma-2) based on their different pharmacological profile. Sigma-2 receptors are identified by radioligand-binding studies as a binding site with high affinity for di-o-tolylguanidine (DTG) and haloperidol.
The molecular identity of the sigma-2 receptor has been unclear for a long time. It is now identified as TMEM97 (PubMed:28559337). Previously identified as PGRMC1 (AC O00264) (PubMed:22292588, PubMed:28007569).
Up-regulated in ovarian surface epithelial (OSE) cells with progesterone.
Widely expressed in normal tissues. Expressed in pancreatic, renal, breast, colon, ovarian surface epithelial (OSE) cells. Highly expressed in various proliferating cancer cells (PubMed:23922215).
Interacts with SEC5. The interaction occurs only in the presence of magnesium or manganese and is stimulated by dCTP or GTP.
Probable guanine nucleotide exchange factor (GEF), which may be involved in the secretion process.
Acts as a growth inhibitor. Can activate p53/TP53, causes G1 arrest and collaborates with CDKN2A to restrict proliferation, but does not require either protein to inhibit DNA synthesis. Redistributes CDKN2A into the nucleoplasm. Involved in maintaining chromosomal stability.
Ubiquitinated; mediated by MDM2 and leading to its subsequent proteasomal degradation.
Widely expressed at low levels in most tissues, with highest levels in pancreas, lung and liver. Expression is decreased in primary tumors including lung, liver, breast, pancreas and kidney carcinomas, chronic lymphocytic leukemia and diffuse large B-cell lymphoma.
A chromosomal aberration involving MLLT6 is associated with acute leukemias. Translocation t(11;17)(q23;q21) with KMT2A/MLL1. The result is a rogue activator protein.
Interacts with histone H3; interaction is necessary for MLLT6 binding to nucleosomes; interaction is inhibited by histone H3 'Lys-27' methylations (H3K27me1, H3K27me2 and H3K27me3).
Belongs to the arylamine N-acetyltransferase family.
N-acetylation polymorphism is determined by a low or high NAT activity in liver and has been implicated in the action and toxicity of amine-containing drugs. Slow acetylation genotypes have been associated with significant lung cancer risk. Candidate risk factor for susceptibility to neural tube defects. The NAT1*10 allele has been associated with increased risk of colon and urinary bladder cancers and with higher levels of N-acetyltransferase activity and DNA adducts in aromatic amine tumor target organs such as colon and urinary bladder (PubMed:7585580).
NAT1 was historically considered to be monomorphic in nature but reports of allelic variations at the NAT1 locus suggest that it is a polymorphically expressed enzyme.
Participates in the detoxification of a plethora of hydrazine and arylamine drugs. Catalyzes the N- or O-acetylation of various arylamine and heterocyclic amine substrates and is able to bioactivate several known carcinogens.
The allelic variation Ile-149 designated as NAT1*17 is part of the NAT1*11 allelic variation as reported by the nomenclature committee.
Allosterically regulated (Probable); feedback inhibited by cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac), the end product of neuraminic acid biosynthesis. Activity is dependent on oligomerization. The monomer is inactive, whereas the dimer catalyzes only the phosphorylation of N-acetylmannosamine; the hexamer is fully active for both enzyme activities (By similarity). Up-regulated after PKC-dependent phosphorylation.
Highest expression in liver and placenta. Also found in heart, brain, lung, kidney, skeletal muscle and pancreas. Isoform 1 is expressed in heart, brain, kidney, liver, placenta, lung, spleen, pancreas, skeletal muscle and colon. Isoform 2 is expressed mainly in placenta, but also in brain, kidney, liver, lung, pancreas and colon. Isoform 3 is expressed at low level in kidney, liver, placenta and colon.
In the C-terminal section; belongs to the ROK (NagC/XylR) family.
In the N-terminal section; belongs to the UDP-N-acetylglucosamine 2-epimerase family.
Regulates and initiates biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids. Plays an essential role in early development (By similarity). Required for normal sialylation in hematopoietic cells. Sialylation is implicated in cell adhesion, signal transduction, tumorigenicity and metastatic behavior of malignant cells.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A11 subfamily.
GABA transport is inhibited by SNAP-5114.
Mediates sodium- and chloride-dependent transport of gamma-aminobutyric acid (GABA) (PubMed:7874447). Can also mediate transport of beta-alanine and to a lower extent that of taurine and hypotaurine (By similarity).
Belongs to the Odd C2H2-type zinc-finger protein family.
Expressed in adult colon, small intestine, prostate, testis, and fetal lung.
Transcription factor that plays a role in the regulation of embryonic heart and urogenital development.
Highly expressed in prostate. Very low levels may be detected in some other tissues, such as placenta, skeletal muscle, heart, ovary and testis. Up-regulated in prostate cancers.
Expressed in skin fibroblasts (at protein level). Expressed in airway epithelial cells (PubMed:36191189).
Interacts with PIERCE1 and PIERCE2; the interactions link outer dynein arms docking complex (ODA-DC) to the internal microtubule inner proteins (MIP) in cilium axoneme.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (PubMed:36191189). May play a role in the beating of primary cilia and thereby be involved in the establishment of organ laterality during embryogenesis (PubMed:26531781).
Belongs to the cyclic nucleotide phosphodiesterase family. PDE8 subfamily.
Binds 2 divalent metal cations per subunit. Site 1 may preferentially bind zinc ions, while site 2 has a preference for magnesium and/or manganese ions.
Composed of a C-terminal catalytic domain containing two putative divalent metal sites and an N-terminal regulatory domain.
Expressed in most tissues except thymus and peripheral blood leukocytes. Highest levels in testis, ovary, small intestine and colon.
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes (PubMed:18983167). May be involved in maintaining basal levels of the cyclic nucleotide and/or in the cAMP regulation of germ cell development (PubMed:18983167). Binding to RAF1 reduces RAF1 'Ser-259' inhibitory-phosphorylation and stimulates RAF1-dependent EGF-activated ERK-signaling (PubMed:23509299). Protects against cell death induced by hydrogen peroxide and staurosporine (PubMed:23509299).
Inhibited by dipyridimole. Insensitive to selective PDE inhibitors including rolipram and zaprinast as well as to the non-selective inhibitor, IBMX. Unaffected by cGMP.
Interacts with RAF1. The interaction promotes RAF1 activity.
Phosphorylated at Ser-359 by PKA under elevated cAMP conditions, this enhances catalytic activity.
Homodimer (Probable). Interacts with RAC1 and RAC2. Interacts with CRKL and VAV. Interacts with CD3Z.
Involved in cytoskeletal rearrangements required for lymphocyte migration in response of chemokines. Activates RAC1 and RAC2, but not CDC42, by functioning as a guanine nucleotide exchange factor (GEF), which exchanges bound GDP for free GTP. May also participate in IL2 transcriptional activation via the activation of RAC2.
Specifically expressed in hematopoietic cells. Highly expressed in peripheral blood leukocytes, and expressed at intermediate level in thymus and spleen. Expressed at very low level in the small intestine and colon.
Splicing donor and acceptor sites between exon 6 and exon 7 are not canonical.
The DOCKER domain may mediate the GEF activity.
Broadly expressed in the immune system. Highly expressed in T cells (PubMed:31308374).
Interacts with ZAP70 (By similarity). Interacts with IRF4, activated RAC1 and F-actin. Both the phosphorylated and non-phosphorylated forms bind phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3). Interacts with RAB11A (PubMed:31308374).
Phosphatidylinositol 3,4,5-trisphosphate-dependent guanine nucleotide exchange factor (GEF) which plays a role in the activation of Rho GTPases RAC1, RhoA and CDC42 (PubMed:12651066, PubMed:15023524). Can regulate cell morphology in cooperation with activated RAC1 (By similarity). Involved in immune homeostasis by ensuring proper trafficking and availability of T-cell regulator CTLA-4 at T-cell surface (PubMed:31308374). Plays a role in Th2 (T helper cells) development and/or activation, perhaps by interfering with ZAP70 signaling (By similarity).
The PH domain is essential for phosphatidylinositol 3,4,5-trisphosphate binding.
Tyrosine-phosphorylated by tyrosine-protein kinase LCK in response to T-cell activation.
A conserved histidine residue in the third TMD (His-191) may play an essential role in the pH sensitivity of SLCO4A1/OATP4A1-mediated substrate transport.
Expressed in fetal brain, heart, kidney, liver, lung, skeletal muscle, spleen and pancreas (PubMed:10873595).
Organic anion antiporter with apparent broad substrate specificity. Recognizes various substrates including thyroid hormones 3,3',5-triiodo-L-thyronine (T3), L-thyroxine (T4) and 3,3',5'-triiodo-L-thyronine (rT3), conjugated steroids such as estrone 3-sulfate and estradiol 17-beta glucuronide, bile acids such as taurocholate and prostanoids such as prostaglandin E2, likely operating in a tissue-specific manner (PubMed:10873595, PubMed:19129463, PubMed:30343886). May be involved in uptake of metabolites from the circulation into organs such as kidney, liver or placenta. Possibly drives the selective transport of thyroid hormones and estrogens coupled to an outward glutamate gradient across the microvillous membrane of the placenta (PubMed:30343886). The transport mechanism, its electrogenicity and potential tissue-specific counterions remain to be elucidated (Probable).
Widely expressed (PubMed:10873595, PubMed:11316767). Expressed in placental trophoblasts (PubMed:10873595, PubMed:12409283). Expressed in pancreas, kidney, skeletal muscle, liver, lung, brain, heart, colon, small intestine, ovary, testis, prostate, thymus and spleen. In testis, primarily localized to Leydig cells (PubMed:35307651).
Carboxypeptidase that may play an important role in the hydrolysis of circulating peptides. Catalyzes the hydrolysis of dipeptides with unsubstituted terminals into amino acids. May play a role in the liberation of thyroxine hormone from its thyroglobulin (Tg) precursor.
Homodimer. The monomeric form is inactive while the homodimer is active.
Mainly detected in blood plasma. Abundant in placenta and kidney. Present at low level in muscles, liver and skin fibroblasts. Not detected in brain or white blood cells (at protein level).
N-glycosylated. The secreted form is modified by hybrid or complex type oligosaccharide chains (By similarity).
Up-regulated in the majority of hepatitis C virus-associated hepatocellular carcinoma.
Probable substrate-specific adapter of an E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
(Microbial infection) Interacts with Hantaan hantavirus nucleoprotein; this interaction prevents the breakdown of the viral glycoprotein N by virus-triggered autophagy.
(Microbial infection) The interaction with STX17 is decreased in presence of SARS coronavirus-2/SARS-CoV-2 ORF3A protein.
Forms a SNARE complex, composed of VAMP8, SNAP29 and STX17, involved in fusion of autophagosome with lysosome (PubMed:23217709, PubMed:25686604). Interacts with multiple syntaxins including STX6 (By similarity). Interacts with EIPR1 (PubMed:27440922). Interacts with STX17; this interaction is increased in the absence of TMEM39A (PubMed:31806350, PubMed:33422265).
Found in brain, heart, kidney, liver, lung, placenta, skeletal muscle, spleen and pancreas.
SNAREs, soluble N-ethylmaleimide-sensitive factor-attachment protein receptors, are essential proteins for fusion of cellular membranes. SNAREs localized on opposing membranes assemble to form a trans-SNARE complex, an extended, parallel four alpha-helical bundle that drives membrane fusion. SNAP29 is a SNARE involved in autophagy through the direct control of autophagosome membrane fusion with the lysososome membrane. Also plays a role in ciliogenesis by regulating membrane fusions.
Binds clathrin heavy chain and AP-2 (PubMed:12213833, PubMed:12429846, PubMed:12538641). Interacts with VTI1B (PubMed:18033301). Interacts with GGA2 (via GAE domain) (PubMed:12213833, PubMed:14665628). Interacts with AP1G1 (via GAE domain) (PubMed:12213833, PubMed:12429846, PubMed:12538641, PubMed:14665628). Interacts with AP1G2 (via GAE domain) (PubMed:14665628).
Binds to membranes enriched in phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). May have a role in transport via clathrin-coated vesicles from the trans-Golgi network to endosomes. Stimulates clathrin assembly.
Genetic variations in CLINT1 may contribute to susceptibility to schizophrenia (SCZD1) and psychotic disorders in some populations.
Ubiquitously expressed at low to intermediate levels.
Expressed in several human tissues including brain, testis, heart, lung, pancreas and spleen (at protein level).
Expressed in lung, liver, pancreas and thymus. Lower expression in heart, placenta, spleen, prostate, ovary, small intestine and colon. No expression seen in brain, skeletal muscle, kidney, testis and peripheral blood leukocyte.
Inhibitory receptor on lymphocytes that negatively regulates antigen receptor signaling via PTPN6/SHP-1 and PTPN11/SHP-2 (PubMed:12796776, PubMed:14652006, PubMed:15568026, PubMed:18193050). May interact in cis (on the same cell) or in trans (on other cells) with TNFRSF14 (PubMed:19915044). In cis interactions, appears to play an immune regulatory role inhibiting in trans interactions in naive T cells to maintain a resting state. In trans interactions, can predominate during adaptive immune response to provide survival signals to effector T cells (PubMed:19915044).
Interacts with tyrosine phosphatases PTPN6/SHP-1 and PTPN11/SHP-2 (PubMed:12796776, PubMed:14652006). Interacts with TNFRSF14/HVEM (via cysteine-rich domain 1) (PubMed:15568026, PubMed:18193050, PubMed:19915044).
Phosphorylated on Tyr residues by TNFRSF14 and by antigen receptors cross-linking, both inducing association with PTPN6 and PTPN11.
Adapter protein with E3 ligase activity that is involved in many diverse biological processes including cell proliferation, migration, differentiation, DNA repair, platelet activation or apoptosis (PubMed:30352854, PubMed:31076633, PubMed:32268273, PubMed:33991522). Promotes EGFR-mediated signaling by facilitating the dimerization of EGFR and downstream AKT activation thereby promoting cell proliferation (PubMed:30352854). Ubiquitinates SMURF2 through 'Lys-48'-linked ubiquitin chain leading to SMURF2 degradation through the proteasome and subsequently osteogenic differentiation (PubMed:31076633). Promotes 'Lys-63'-mediated ubiquitination of CHK1 which in turn activates cell cycle arrest and activation of DNA repair (PubMed:32357935). In addition, promotes an atypical 'Lys-29'-linked ubiquitination at the C-terminal end of IRS1 which is crucial for insulin-like growth factor (IGF) signal transduction (PubMed:33991522). Regulates activation of NF-kappa-B in response to signaling through Toll-like receptors. Required for normal skeleton development, and for normal development of the respiratory tract (By similarity). Required for activation of RPS6KB1 in response to TNF signaling. Modulates TRAF6 functions. Inhibits adipogenic differentiation by activating pyruvate kinase PKM activity and subsequently the beta-catenin signaling pathway (PubMed:32268273).
Belongs to the TNF receptor-associated factor family. B subfamily.
Expressed in epithelial cells of thymus, dendritic cells of lymph node, and in the basal cell layer of epithelia such as epidermis, nasopharynx, respiratory tract, salivary gland, and esophagus.
Homotrimer (Probable). Interacts with LTBR/TNFRSF3, NGFR/TNFRSF16, RPS6KB1 and TGFB1I1. Interacts with SMURF1. Interacts (via TRAF domain) with MAP3K4 (via kinase domain). Interacts with NCF1, TICAM1, IRAK1 and TRAF6, and is probably part of a complex containing TRAF4, NCF1, TICAM1, IRAK1 and TRAF6. Interacts (via MATH domain) with GP6 and GP1BB (PubMed:20946164, PubMed:29073066). Interacts with EGFR (via C-terminal region); this interaction promotes the formation of EGFR asymmetric dimers (PubMed:30352854). Interacts with PKM; this interaction promotes PKM kinase activity (PubMed:32268273).
Polyubiquitinated, leading to its proteasomal degradation (PubMed:19937093). Ubiquitinated at Lys-263 by the SCF(FBXL2) complex, leading to its degradation by the proteasome (By similarity).
The MATH/TRAF domain binds to receptor cytoplasmic domains.
The coiled coil domain mediates homo- and hetero-oligomerization.
Up-regulated by bacterial lipopolysaccharides (LPS) and by single-stranded CpG oligodeoxynucleotide.
A publication reported that a complex is formed with TGFB1 (PubMed:7798248). According to another report, there is no association with TGFB1 (PubMed:10930463).
Contains hydroxylated asparagine residues.
Expressed in the aorta (at protein level). Expressed in lung, weakly expressed in heart, placenta, liver and skeletal muscle.
Forms part of the large latent transforming growth factor beta precursor complex; removal is essential for activation of complex (PubMed:7798248). Interacts with SDC4 (PubMed:20382221). Interacts (via C-terminal domain) with FBN1 (via N-terminal domain) in a Ca(+2)-dependent manner (PubMed:17293099).
May play an integral structural role in elastic-fiber architectural organization and/or assembly.
Component of the ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, a VPS37 protein (VPS37A to -D) and MVB12A or MVB12B in a 1:1:1:1 stoichiometry. Interacts with CD2AP and CIN85/SH3KBP1. Interacts with CD2AP (via one of the SH3 domains). Interacts with TSG101; the association appears to be mediated by the TSG101-VPS37 binary subcomplex. Interacts with VPS28. Interacts with VPS37B; the association appears to be mediated by the TSG101-VPS37 binary subcomplex. Interacts with VPS37C; the association appears to be mediated by the TSG101-VPS37 binary subcomplex. Interacts with VPS37D; the association appears to be mediated by the TSG101-VPS37 binary subcomplex. Interacts with CEP55.
Component of the ESCRT-I complex, a regulator of vesicular trafficking process. Required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies. May be involved in the ligand-mediated internalization and down-regulation of EGF receptor.
Phosphorylated on Tyr-204 upon EGF stimulation. Phosphorylation is required for interaction with CD2AP and CIN85/SH3KBP1.
Ubiquitously expressed except in skeletal muscle.
Belongs to the sodium:solute symporter (SSF) (TC 2.A.21) family.
Choline uptake activity is regulated by SLC5A7/CHT1 internalization (inactive form) from the cell surface and recycling of internalized SLC5A7/CHT1 into the cell surface (active form) (PubMed:12969261, PubMed:15953352) (Probable). Activated by extracellular chloride ion (PubMed:11068039, PubMed:17005849, PubMed:12237312). Specifically inhibited by nanomolar concentrations of hemicholinium 3 (PubMed:11027560, PubMed:11068039, PubMed:12969261, PubMed:17005849, PubMed:23132865, PubMed:12237312).
Expressed in putamen, spinal cord and medulla (PubMed:11027560, PubMed:11068039). Expressed in cholinergic neurons (PubMed:27569547).
High-affinity Na(+)-coupled choline transmembrane symporter (PubMed:11027560, PubMed:11068039, PubMed:12969261, PubMed:17005849, PubMed:23141292, PubMed:23132865, PubMed:12237312, PubMed:27569547). Functions as an electrogenic, voltage-dependent transporter with variable charge/choline stoichiometry (PubMed:17005849). Choline uptake and choline-induced current is also Cl(-)-dependent where Cl(-) is likely a regulatory ion rather than cotransported ion (PubMed:11068039, PubMed:17005849, PubMed:12237312). Plays a critical role in acetylcholine (ACh) synthesis by taking up the substrate choline from the synaptic cleft into the presynaptic nerve terminals after neurotransmitter release (PubMed:27569547). SLC5A7/CHT1-mediated choline high-affinity transport in cholinergic neurons is the rate-limiting step for production of ACh, thereby facilitating communication by subsequent action potentials (PubMed:11027560). Localized predominantly in presynaptic terminal intracellular organelles, and translocated to the plasma membrane in active form in response to neuronal activity (PubMed:12969261, PubMed:15953352).
Homooligomerizes at cell surface (PubMed:23132865). Interacts with SEC14L1; may regulate SLC5A7 (PubMed:17092608).
The C-terminal dileucine-like motif (DKTILV) controls SLC5A7/CHT1 internalization in clathrin-coated vesicles to early endosomes as well as choline transporter activity.
Binds to the plus end of microtubules and regulates the dynamics of the microtubule cytoskeleton. Promotes microtubule growth and microtubule bundling. Links cytoplasmic vesicles to microtubules and thereby plays an important role in intracellular vesicle trafficking. Plays a role macropinocytosis and endosome trafficking.
Detected in dendritic cells (at protein level). Highly expressed in the Reed-Sternberg cells of Hodgkin disease.
Interacts with MTOR; phosphorylates and regulates CLIP1 (PubMed:12231510). Interacts (via CAP-Gly domains) with tubulin (PubMed:17563362, PubMed:17889670). Interacts with SLAIN2 (PubMed:21646404). Interacts (via zinc finger) with DCTN1 (PubMed:17828275, PubMed:20679239). Interacts with TUBA1B, MAPRE1 and MAPRE3 (PubMed:17563362). Binds preferentially to tyrosinated microtubules, and only marginally to detyrosinated microtubules (By similarity).
Intramolecular interaction between the zinc finger domain and the CAP-Gly domains may inhibit interaction with tubulin.
Phosphorylated. Phosphorylation induces conformational changes by increasing the affinity of the N-terminus for C-terminus, resulting in inhibition of its function thus decreasing its binding to microtubules and DCTN1. Exhibits a folded, autoinhibited conformation when phosphorylated and an open conformation when dephosphorylated with increased binding affinity to microtubules and DCTN1. Phosphorylation regulates its recruitment to tyrosinated microtubules and the recruitment of vesicular cargo to microtubules in neurons (By similarity). Phosphorylation by MTOR may positively regulate CLIP1 association with microtubules (PubMed:12231510).
Although it belongs to the tubulin--tyrosine ligase family, the TTL domain lacks some of the ATP binding sites predicted to be essential for TTL activity (PubMed:23251473). Lacks tyrosine ligase activity in vitro (PubMed:23251473). Lacks glutamylation activity in vitro (By similarity). Although TTLL12 contains a potential SET-like domain in the N-terminus, it does not have lysine methyltransferase activity towards histone in vitro (PubMed:23251473).
Belongs to the tubulin--tyrosine ligase family.
Expressed in the basal layer of prostate and endothelial cells. Increased expression in prostatic intraepithelial neoplasia and metastatic lesions.
Interacts with MAVS; the interaction prevents MAVS binding to TBK1 and IKBKE (PubMed:28011935). Interacts (via N-terminus) with TBK1 (via protein kinase domain) (PubMed:28011935). Interacts (via TTL domain) with IKBKE (via protein kinase domain) (PubMed:28011935). Interacts with tubulin alpha (PubMed:23251473). Interacts with histone H3 and histone H4 (when trimethylated at 'Lys-20' (H4K20me3)) (PubMed:23251473). Interacts with CBX3 (PubMed:23251473).
Negatively regulates post-translational modifications of tubulin, including detyrosination of the C-terminus and polyglutamylation of glutamate residues (PubMed:20162578, PubMed:23251473). Also, indirectly promotes histone H4 trimethylation at 'Lys-20' (H4K20me3) (PubMed:23251473). Probably by controlling tubulin and/or histone H4 post-translational modifications, plays a role in mitosis and in maintaining chromosome number stability (PubMed:20162578, PubMed:23251473). During RNA virus-mediated infection, acts as a negative regulator of the RIG-I pathway by preventing MAVS binding to TBK1 and IKBKE (PubMed:28011935).
Moderately selective excitatory receptor for orexin-A and, with a lower affinity, for orexin-B neuropeptide (PubMed:9491897, PubMed:26950369). Triggers an increase in cytoplasmic Ca(2+) levels in response to orexin-A binding (PubMed:9491897, PubMed:26950369).
The N-terminal region is required for orexin signaling.
The antagonists suvorexant and SB-674042 bind at the cognate neuropeptide binding site that is situated between the transmembrane helices and accessible from the extracellular side of the membrane.
Belongs to the gamma type-C retroviral envelope protein family.
Cleaved by some metalloproteinase at 432-Gln-Arg-433 (mainly) or 433-Arg-Gln-434, leading to release the secreted form (Endogenous retroviral envelope protein HEMO, secreted form) in the extracellular medium.
Endogenous envelope proteins originate from retroviral envelope proteins, which mediate receptor recognition and membrane fusion during early infection. Endogenous envelope proteins may have kept, lost or modified their original function during evolution.
Expressed at high level in the placenta and stem cells (at protein level) (PubMed:28739914). Also expressed in the kidney but at a lower level (PubMed:28739914). Endogenous retroviral envelope protein HEMO, secreted form: Present in the blood of pregnant women (at protein level) (PubMed:28739914).
Component of a multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9.
Component of the coenzyme Q biosynthetic pathway. May play a role in organizing a multi-subunit COQ enzyme complex required for coenzyme Q biosynthesis. Required for steady-state levels of other COQ polypeptides.
Expressed ubiquitously, but at high levels in liver, lung and pancreas.
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:7574697, PubMed:9866708, PubMed:9435160, PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:7574697, PubMed:9866708, PubMed:9435160, PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:7574697, PubMed:15766564, PubMed:19965576, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9866708, PubMed:9435160). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRID2 subfamily.
Receptor for glutamate. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. Promotes synaptogenesis and mediates the D-Serine-dependent long term depression signals and AMPA receptor endocytosis of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses through the beta-NRX1-CBLN1-GRID2 triad complex (PubMed:27418511).
Tetramer; dimer of dimers (PubMed:27418511). Interacts with EML2, MAGI2 (via PDZ domains) and AP4M1 (By similarity). Interacts with BECN1, GOPC, GRID2IP, SHANK1 and SHANK2. Interacts with CBLN2, but not with CBLN4 (By similarity). Interacts with CBLN1 (via C1q domain); the interaction is CBLN1-NRX1 complex formation-dependent; CBLN1-binding is calcium-independent; CBLN1 hexamers anchor GRID2 N-terminal domain dimers to monomeric NRXN1 isoform beta; promotes synaptogenesis and mediates the D-Serine-dependent long term depression signals and AMPA receptor endocytosis (PubMed:27418511).
The PDZ-binding motif mediates interaction with GOPC.
(Microbial infection) Regulates SARS coronavirus-2/SARS-CoV-2 entry and replication in lung epithelial cells probably through the post-transcriptional regulation of ACE2 and interferon-stimulated gene expression.
Acetylated on Lys-538 by CLOCK during the repression phase of the circadian cycle. Acetylation facilitates recruitment of CRY1 protein and initiates the repression phase of the circadian cycle. Acetylated at Lys-538 by KAT5 during the activation phase of the cycle, leading to recruitment of the positive transcription elongation factor b (P-TEFb) and BRD4, followed by productive elongation of circadian transcripts. Deacetylated by SIRT1, which may result in decreased protein stability.
CLOCK-BMAL1 double mutations within the PAS domains result in synergistic desensitization to high levels of CRY on repression of CLOCK-BMAL1 transcriptional activity of PER1 and, disrupt circadian rhythmicity.
Component of the circadian clock oscillator which includes the CRY1/2 proteins, CLOCK or NPAS2,BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER1/2/3 proteins (By similarity). Forms a heterodimer with CLOCK (PubMed:9616112, PubMed:23229515). The CLOCK-BMAL1 heterodimer is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and, for phosphorylation of both CLOCK and BMAL1 (By similarity). Part of a nuclear complex which also includes RACK1 and PRKCA; RACK1 and PRKCA are recruited to the complex in a circadian manner (By similarity). Interacts with NPAS2 (By similarity). Interacts with EZH2 (By similarity). Interacts with SUMO3 (By similarity). Interacts with SIRT1 (By similarity). Interacts with AHR (PubMed:9079689). Interacts with ID1, ID2 and ID3 (By similarity). Interacts with DDX4 (By similarity). Interacts with OGT (By similarity). Interacts with EED and SUZ12 (By similarity). Interacts with MTA1 (By similarity). Interacts with CIART (PubMed:24385426). Interacts with HSP90 (PubMed:9079689). Interacts with KAT2B and EP300 (PubMed:14645221). Interacts with BHLHE40/DEC1 and BHLHE41/DEC2 (By similarity). Interacts with RELB and the interaction is enhanced in the presence of CLOCK (By similarity). Interacts with PER1, PER2, CRY1 and CRY2 and this interaction requires a translocation to the nucleus (By similarity). Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits transcription activation (By similarity). Interaction of the CLOCK-BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (By similarity). The CLOCK-BMAL1 heterodimer interacts with GSK3B (By similarity). Interacts with KDM5A (PubMed:21960634). Interacts with KMT2A; in a circadian manner (By similarity). Interacts with UBE3A (PubMed:24728990). Interacts with PRKCG (By similarity). Interacts with MAGEL2 (By similarity). Interacts with NCOA2 (By similarity). Interacts with THRAP3 (By similarity). The CLOCK-BMAL1 heterodimer interacts with PASD1 (PubMed:25936801). Interacts with PASD1 (PubMed:25936801). Interacts with USP9X (PubMed:29626158). Interacts with PIWIL2 (via PIWI domain) (PubMed:28903391). Interacts with HDAC3 (By similarity). Interacts with HNF4A (PubMed:30530698).
Hair follicles (at protein level). Highly expressed in the adult brain, skeletal muscle and heart.
O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents protein degradation by inhibiting ubiquitination. It also stabilizes the CLOCK-BMAL1 heterodimer thereby increasing CLOCK-BMAL1-mediated transcription of genes in the negative loop of the circadian clock such as PER1/2/3 and CRY1/2.
Phosphorylated upon dimerization with CLOCK. Phosphorylation enhances the transcriptional activity, alters the subcellular localization and decreases the stability of the CLOCK-BMAL1 heterodimer by promoting its degradation. Phosphorylation shows circadian variations in the liver with a peak between CT10 to CT14. Phosphorylation at Ser-90 by CK2 is essential for its nuclear localization, its interaction with CLOCK and controls CLOCK nuclear entry (By similarity). Dephosphorylation at Ser-78 is important for dimerization with CLOCK and transcriptional activity (PubMed:23229515).
Sumoylated on Lys-259 upon dimerization with CLOCK. Predominantly conjugated to poly-SUMO2/3 rather than SUMO1 and the level of these conjugates undergo rhythmic variation, peaking at CT9-CT12. Sumoylation localizes it exclusively to the PML body and promotes its ubiquitination in the PML body, ubiquitin-dependent proteasomal degradation and the transcriptional activity of the CLOCK-BMAL1 heterodimer.
There is conflicting data about the effect of NAD cofactors on activity. PubMed:11441146 suggests that the redox state of the cell can modulate the transcriptional activity of the CLOCK-BMAL1 heterodimer; NADH and NADPH enhance the DNA-binding activity of the heterodimer. PubMed:23229515 reports that NADH and NADPH have no significant effect on DNA-binding activity of the CLOCK-BMAL1 heterodimer.
Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repressBMAL1 transcription, respectively.BMAL1 positively regulates myogenesis and negatively regulates adipogenesis via the transcriptional control of the genes of the canonical Wnt signaling pathway. Plays a role in normal pancreatic beta-cell function; regulates glucose-stimulated insulin secretion via the regulation of antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C inflammatory monocytes; rhythmic recruitment of the PRC2 complex imparts diurnal variation to chemokine expression that is necessary to sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2, STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes involved in hair growth. Plays an important role in adult hippocampal neurogenesis by regulating the timely entry of neural stem/progenitor cells (NSPCs) into the cell cycle and the number of cell divisions that take place prior to cell-cycle exit. Regulates the circadian expression of CIART and KLF11. The CLOCK-BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. The NPAS2-BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. The preferred binding motif for the CLOCK-BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking adenine nucleotide at the 3-prime end of the canonical 6-nucleotide E-box sequence (PubMed:23229515). CLOCK specifically binds to the half-site 5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3' (PubMed:23229515). The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (PubMed:23229515). Essential for the rhythmic interaction of CLOCK with ASS1 and plays a critical role in positively regulating CLOCK-mediated acetylation of ASS1 (PubMed:28985504). Plays a role in protecting against lethal sepsis by limiting the expression of immune checkpoint protein CD274 in macrophages in a PKM2-dependent manner (By similarity). Regulates the diurnal rhythms of skeletal muscle metabolism via transcriptional activation of genes promoting triglyceride synthesis (DGAT2) and metabolic efficiency (COQ10B) (By similarity).
Ubiquitinated, leading to its proteasomal degradation (PubMed:24728990). Deubiquitinated by USP9X (PubMed:29626158).
Undergoes lysosome-mediated degradation in a time-dependent manner in the liver.
Belongs to the small GTPase superfamily. Rab family.
Endoplasmic reticulum-Golgi intermediate compartment membrane
Interacts with PRKCI (PubMed:14570876). Interacts with TRIP11 (PubMed:25473115). Interacts (in GTP-bound form) with GARIN1B (By similarity).
Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase.
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between active GTP-bound and inactive GDP-bound states. In their active state, drive transport of vesicular carriers from donor organelles to acceptor organelles to regulate the membrane traffic that maintains organelle identity and morphology. Required for protein transport from the endoplasmic reticulum to the Golgi complex. Regulates the compacted morphology of the Golgi.
Binds to DNA sequences containing the consensus nucleotide core sequence 5'-GGAA.-3'.
Interacts (via C-terminal) with ZMYM5 (via N-terminal 120 amino acid region).
Despite its name, it does not contain a canonical C2H2-type zinc-finger, seems to be a partial inverted duplication of ZNF674.
Expressed in brain, ovary, testis, prostate, tonsil, heart, bone marrow, colon, breast and kidney.
Catalyzes several different glutathione-dependent reactions (PubMed:8703034, PubMed:9278457, PubMed:23409838, PubMed:26656251, PubMed:26066610). Catalyzes the glutathione-dependent reduction of lipid hydroperoxides, such as 5-HPETE (PubMed:9278457, PubMed:23409838). Has glutathione transferase activity, toward xenobiotic electrophiles, such as 1-chloro-2, 4-dinitrobenzene (CDNB) (PubMed:23409838, PubMed:8703034). Catalyzes also the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4 (LTC4) (PubMed:23409838, PubMed:26656251). Involved in oxidative DNA damage induced by ER stress and anticancer agents by activating LTC4 biosynthetic machinery in nonimmune cells (PubMed:26656251).
Each monomer can bind on GSH molecule but only one subunit is catalytically active.
Liver, spleen, skeletal muscle, heart, adrenals, pancreas, prostate, testis, fetal liver, and fetal spleen. Very low expression in lung, brain, placenta and bone marrow (PubMed:8703034). Abundantly expressed in human umbilical vein endothelial cells (at protein level) (PubMed:11322876).
Upon ER stress with brefeldin A or with tunicamycin, MGST2 is down-regulated, in several non-haematopoietic cell types, during the early, protective phase of the unfolded protein response (UPR), and up-regulated at the late, death-promoting phase of the unfolded protein response (UPR).
Component of the GPI transamidase complex, necessary for transfer of GPI to proteins (PubMed:34576938). Mediates GPI anchoring in the endoplasmic reticulum, by replacing a protein's C-terminal GPI attachment signal peptide with a pre-assembled GPI. During this transamidation reaction, the GPI transamidase forms a carbonyl intermediate with the substrate protein.
Forms a complex with PIGT, PIGS, PIGU and GAA1.
The disulfide bond between PIGK/GPI8 and PIGT is important for normal enzyme activity.
Aryl sulfonamide anticancer drugs change the substrate specificity of DCAF15 by acting as a molecular glue that promotes binding between DCAF15 and weak affinity interactors, such as RBM39.
Binding of aryl sulfonamide anticancer drugs, such as indisulam (E7070) or E7820, change the substrate specificity of the DCX(DCAF15) complex, leading to promote ubiquitination and degradation of splicing factor RBM39 (PubMed:28437394, PubMed:28302793, PubMed:31693891, PubMed:31452512). RBM39 degradation results in splicing defects and death in cancer cell lines (PubMed:28437394, PubMed:28302793, PubMed:31693891). Aryl sulfonamide anticancer drugs change the substrate specificity of DCAF15 by acting as a molecular glue that promotes binding between DCAF15 and weak affinity interactor RBM39 (PubMed:31686031, PubMed:31819272). Aryl sulfonamide anticancer drugs also promote ubiquitination and degradation of RBM23 and PRPF39 (PubMed:31693891, PubMed:31626998, PubMed:31686031).
Component of the DCX(DCAF15) complex, also named CLR4(DCAF15) complex, composed of DCAF15, DDB1, cullin-4 (CUL4A or CUL4B), DDA1 and RBX1.
Substrate-recognition component of the DCX(DCAF15) complex, a cullin-4-RING E3 ubiquitin-protein ligase complex that mediates ubiquitination and degradation of target proteins (PubMed:16949367, PubMed:31452512). The DCX(DCAF15) complex acts as a regulator of the natural killer (NK) cells effector functions, possibly by mediating ubiquitination and degradation of cohesin subunits SMC1A and SMC3 (PubMed:31452512). May play a role in the activation of antigen-presenting cells (APC) and their interaction with NK cells (PubMed:31452512).
Belongs to the bZIP family. ATF subfamily.
Binds DNA as a dimer (PubMed:2516827). Interacts with HIPK2 and CDK3 (PubMed:18794154, PubMed:20980392). Interacts with MOTS-c, a peptide produced by the mitochondrially encoded 12S rRNA MT-RNR1; the interaction occurs in the nucleus following metabolic stress (PubMed:29983246).
Phosphorylated at Ser-198 by HIPK2 in response to genotoxic stress. This phosphorylation promotes transcription repression of FTH1 and other antioxidant detoxification genes. The CDK3-mediated phosphorylation at Ser-63 promotes its transactivation and transcriptional activities. Phosphorylated at Ser-63 by RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli.
The gene represented in this entry may be involved in disease pathogenesis. Chromosomal aberrations involving ATF1 are found in patients with angiomatoid fibrous histiocytoma. Translocation t(12;16)(q13;p11.2) with FUS generates a chimeric ATF1/FUS protein. Translocation t(12;22)(q13;q12) with EWSR1 generates a chimeric ATF1/EWSR1 protein.
This protein binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Binds to the Tax-responsive element (TRE) of HTLV-I. Mediates PKA-induced stimulation of CRE-reporter genes. Represses the expression of FTH1 and other antioxidant detoxification genes. Triggers cell proliferation and transformation.
Involved in both transcriptional activation and repression. Interaction with SIRT7 leads to recruitment and stabilization of SIRT7 at promoters, followed by deacetylation of histone H3 at 'Lys-18' (H3K18Ac) and subsequent transcription repression. Forms a ternary complex with the serum response factor (SRF). Requires DNA-bound SRF for ternary complex formation and makes extensive DNA contacts to the 5'side of SRF, but does not bind DNA autonomously.
Belongs to the uridine kinase family. NRK subfamily.
Catalyzes the phosphorylation of nicotinamide riboside (NR) and nicotinic acid riboside (NaR) to form nicotinamide mononucleotide (NMN) and nicotinic acid mononucleotide (NaMN). Reduces laminin matrix deposition and cell adhesion to laminin, but not to fibronectin. Involved in the regulation of PXN at the protein level and of PXN tyrosine phosphorylation. May play a role in the regulation of terminal myogenesis.
Down-regulated during myoblast differentiation.
Monomer (By similarity). Interacts with ITGB1 alone or when associated with alpha-7, but not with alpha-5.
Predominantly expressed in skeletal muscle and, at a much lower level, in the heart (at protein level). No expression in brain, kidney, liver, lung, pancreas nor placenta.
Belongs to the TRAFAC class YlqF/YawG GTPase family. LSG1 subfamily.
GTPase required for the XPO1/CRM1-mediated nuclear export of the 60S ribosomal subunit. Probably acts by mediating the release of NMD3 from the 60S ribosomal subunit after export into the cytoplasm (Probable).
In contrast to other GTP-binding proteins, this family is characterized by a circular permutation of the GTPase motifs described by a G4-G1-G3 pattern.
Component of the MIS12 complex composed of MIS12, DSN1, NSL1 and PMF1. Also interacts with KNL1, CBX3, CBX5, NDC80 and ZWINT.
Part of the MIS12 complex which is required for normal chromosome alignment and segregation and for kinetochore formation during mitosis (PubMed:12515822, PubMed:15502821, PubMed:16585270). Essential for proper kinetochore microtubule attachments (PubMed:23891108).
Expression starts early in spermiogenesis and finishes in the late spermatid phase.
Interacts with ODC1 and thereby sterically blocks ODC homodimerization (By similarity). Interacts with AZIN2; this interaction disrupts the interaction between the antizyme and ODC1 (PubMed:17900240). Interacts with GGN (By similarity).
Ornithine decarboxylase (ODC) antizyme protein that negatively regulates ODC activity and intracellular polyamine biosynthesis and uptake in response to increased intracellular polyamine levels. Binds to ODC monomers, inhibiting the assembly of the functional ODC homodimers. Does not target the ODC monomers for degradation, which allows a protein synthesis-independent restoration of ODC activity (PubMed:17900240). Stabilizes AZIN2 by interfering with its ubiquitination. Involved in the translocation of AZNI2 from ER-Golgi intermediate compartment (ERGIC) to the cytosol. Probably plays a key role in spermatogenesis by regulating the intracellular concentration of polyamines in haploid germ cells (By similarity).
Unusual initiator. The initiator methionine is coded by a non-canonical CTG leucine codon.
Expressed at low level in many tissues. Not expressed in 80% of tumor cell lines tested.
May play a role in tumorigenesis as a tumor suppressor. Altered expression of this protein and disruption of the molecular pathway it is involved in, may contribute directly to or modify tumorigenesis.
It is uncertain whether Met-1 or Met-14 is the initiator.
By IL1B/interleukin-1 beta and TNF in bronchial smooth muscle cells and fibroblasts. By IL10/interleukin-10 and IFNG/IFN-gamma in monocyte-derived dendritic cells.
Expressed exclusively in tissues with a high content of epithelial cells. Highly expressed in salivary gland, mammary gland, prostate, and lung. Weakly expressed in kidney and colon. Not detected in heart, brain, placenta, liver, skeletal muscle, spleen, thymus, testis, ovary, small intestine or peripheral blood leukocytes.
The PNT domain acts as a transcriptional activator.
Transcriptional activator that may play a role in regulating epithelial cell differentiation and proliferation. May act as a repressor for a specific subset of ETS/AP-1-responsive genes and as a modulator of the nuclear response to mitogen-activated protein kinase signaling cascades. Binds to DNA sequences containing the consensus nucleotide core sequence GGAA. Involved in regulation of TNFRSF10B/DR5 expression through Ets-binding sequences on the TNFRSF10B/DR5 promoter. May contribute to development and carcinogenesis by acting as a tumor suppressor gene or anti-oncogene.
High expression in ovary. Not detected in the brain regions thalamus, putamen, caudate, frontal cortex, pons, hypothalamus and hippocampus.
Receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities. Transduces a signal by increasing the intracellular calcium ions and by stimulating adenylyl cyclase activity. The rank order of potency for agonists of this receptor is 1-oleoyl- > 1-stearoyl- > 1-palmitoyl- > 1-myristoyl- > 1-alkyl- > 1-alkenyl-LPA.
(Microbial infection) Interacts with vaccinia virus protein F17; this interaction dysregulates mTOR.
Part of the mechanistic target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR (PubMed:15268862, PubMed:15467718, PubMed:17461779, PubMed:17599906, PubMed:34519268). Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Binds directly to MTOR and PRR5 within the TORC2 complex; interaction with MTOR is enhanced by deubiquitination of RICTOR by USP9X (PubMed:15268862, PubMed:17461779, PubMed:17599906, PubMed:33378666). Interaction with MAPKAP1 is not enhanced by RICTOR deubiquitination by USP9X (PubMed:33378666). Interacts with CCDC28B (PubMed:23727834). Interacts with NBN (PubMed:23762398). Interacts with PRR5L (PubMed:17461779, PubMed:21964062). Interacts with SIK3 (PubMed:30232230). Interacts with NCKAP1L (PubMed:32647003). Interacts with kinases GSK3A and GSK3B; the interactions lead to phosphorylation of RICTOR at 'Thr-1695' which facilitates its FBXW7-mediated ubiquitination and subsequent degradation (PubMed:25897075). Interacts with FBXW7; the interaction is enhanced by GSK3-mediated phosphorylation of 'Thr-1695' and results in RICTOR ubiquitination and degradation (PubMed:25897075). Interacts with USP9X; the interaction results in deubiquitination of RICTOR and protection from proteasomal degradation, thus promoting mTORC2 complex assembly (PubMed:33378666). Interacts with ARMH4 (via cytoplasmic tail); this interaction bridges ARMH4 to the mTORC2 complex and inhibits the mTORC2 kinase activity (By similarity).
Phosphorylated by MTOR; when part of mTORC2 (PubMed:15467718). Phosphorylated at Thr-1135 by RPS6KB1; phosphorylation of RICTOR inhibits mTORC2 and AKT1 signaling (PubMed:19995915). Phosphorylated at Thr-1695 by GSK3A and GSK3B which facilitates RICTOR ubiquitination and subsequent degradation (PubMed:25897075).
Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Plays an essential role in embryonic growth and development.
Ubiquitinated by the SCF(FBXW7) complex, leading to its degradation by the proteasome (PubMed:25897075). Deubiquitinated by USP9X; deubiquitination stabilizes RICTOR and enhances its binding to MTOR, thus promoting mTORC2 complex assembly (PubMed:33378666).
Acetyl-CoA transporter that mediates active acetyl-CoA import through the endoplasmic reticulum (ER) membrane into the ER lumen where specific ER-based acetyl-CoA:lysine acetyltransferases are responsible for the acetylation of ER-based protein substrates, such as BACE1 (PubMed:24828632, PubMed:20826464). Necessary for O-acetylation of gangliosides (PubMed:9096318).
Belongs to the SLC33A transporter family.
Expression is induced in presence of ceramide.
Ubiquitous. Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. With strongest signals in pancreas.
Belongs to the WD repeat Groucho/TLE family.
Found predominantly in muscle, heart and Placenta. In fetal tissues, abundantly expressed in the heart, lung, kidney, brain and liver.
Homooligomer and heterooligomer with other family members. Binds TCF7 (By similarity). Binds the NF-kappa-B subunit RELA. Interacts with PHF12. Interacts (via Q domain) with SIX3. Interacts with SIX6.
Transcriptional corepressor. Acts as dominant repressor towards other family members. Inhibits NF-kappa-B-regulated gene expression. May be required for the initiation and maintenance of the differentiated state. Essential for the transcriptional repressor activity of SIX3 during retina and lens development.
Predominantly expressed in osteoclasts (bones) (PubMed:7805878). Expressed in thyroid epithelial cells (PubMed:11082042).
Thiol protease involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. Involved in the release of thyroid hormone thyroxine (T4) by limited proteolysis of TG/thyroglobulin in the thyroid follicle lumen (PubMed:11082042).
Endonuclease that preferentially catalyzes the cleavage of double-stranded 5-hydroxymethylcytosine (5hmC)-modified DNA (PubMed:25355512). The 5hmC-modified nucleotide does not increase the binding affinity, but instead increases the efficiency of cutting and specifies the site of cleavage for the modified DNAs (By similarity). Shows significantly higher affinity for four-stranded Holliday junction over duplex and single-stranded DNAs (By similarity). Promotes conservative recombination when the DNA is 5hmC-modified (PubMed:25355512). Promotes autophagy through the suppression of mTOR by its phosphorylation-mediated interaction with YWHAG and its endonuclease activity-mediated DNA damage response (PubMed:33473107). GSK3-beta mediated phosphorylation of ENDOG enhances its interaction with YWHAG, leading to the release of TSC2 and PIK3C3 from YWHAG resulting in mTOR pathway suppression and autophagy initiation (PubMed:33473107). Promotes cleavage of mtDNA in response to oxidative and nitrosative stress, in turn inducing compensatory mtDNA replication (PubMed:29719607).
GSK3-beta-mediated dual phosphorylations at Thr-128 and Ser-288 is necessary for its interaction with YWHAG and the induction of autophagy.
Homodimer; disulfide-linked (By similarity). Homodimerization is essential for enzyme activity (By similarity). Interacts with YWHAG (PubMed:33473107).
Belongs to the PA-phosphatase related phosphoesterase family.
Has most probably no phospholipid phosphatase activity (By similarity). This is supported by the fact that the phosphatase sequence motifs as well as the His residue acting as a nucleophile in active phosphatases of the PA-phosphatase related phosphoesterase family are not conserved (By similarity).
It is uncertain whether Met-1 or Met-3 is the initiator.
Plays a role in the regulatory network through which muscle cells coordinate their structural and functional states during growth, adaptation, and repair.
Preferentially and abundantly expressed in heart and skeletal muscle.
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Interacts with DDX21, NCL, NOP2 and EBNA1BP2 (PubMed:23848194).
Scaffold component of the nucleolar structure. Required for localization of DDX21 and NCL to the granular compartment of the nucleolus (PubMed:23848194). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.
Expressed in epididymis (at protein level).
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts with EXOC3L1 (By similarity). Interacts with BIRC6/bruce. Interacts with MYRIP (By similarity). Interacts with SLC6A9 (By similarity).
A PH-like domain is involved in phosphatidylinositol phosphate binding.
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.
Highly expressed in heart followed by skeletal muscle, pancreas and kidney. Weakly expressed in placenta, lung and liver.
Interacts with the cytoplasmic domain of ITGB1 (PubMed:10712922). Could also interact with integrin ITGB2, ITGB3 and/or ITGB5 (PubMed:10712922). Interacts (via ANK repeats) with LIMS1 and LIMS2 (PubMed:12167643, PubMed:19074270, PubMed:19117955). Interacts with PARVA (via C-terminus) and PARVB; these compete for the same binding site (PubMed:11402068, PubMed:15284246, PubMed:15817463, PubMed:20005845, PubMed:20117114). Interacts probably also with TGFB1I1 (By similarity). Interacts (via ANK repeats) with EPHA1 (via SAM domain); stimulated by EFNA1 but independent of the kinase activity of EPHA1 (PubMed:19118217). Interacts with FERMT2 (By similarity). Interacts with LIMD2; leading to activate the protein kinase activity (PubMed:24590809). Interacts with PXN/PAXILLIN (via LD motif 4) (PubMed:15817463). Interacts with CCDC25 (via cytoplasmic region); initiating the ILK-PARVB cascade to induce cytoskeleton rearrangement and directional migration of cells (PubMed:32528174).
Probable cloning artifact. Was originally thought to be distinct gene (ILK2) (PubMed:10871859).
Receptor-proximal protein kinase regulating integrin-mediated signal transduction (PubMed:8538749, PubMed:9736715). May act as a mediator of inside-out integrin signaling (PubMed:10712922). Focal adhesion protein part of the complex ILK-PINCH (PubMed:10712922). This complex is considered to be one of the convergence points of integrin- and growth factor-signaling pathway (PubMed:10712922). Could be implicated in mediating cell architecture, adhesion to integrin substrates and anchorage-dependent growth in epithelial cells (PubMed:10712922). Regulates cell motility by forming a complex with PARVB (PubMed:32528174). Phosphorylates beta-1 and beta-3 integrin subunit on serine and threonine residues, but also AKT1 and GSK3B (PubMed:8538749, PubMed:9736715).
Stimulated rapidly but transiently by both cell fibronectin interactions, as well as by insulin, in a PI3-K-dependent manner, likely via the binding of PtdIns(3,4,5)P3 with a PH-like domain of ILK. The protein kinase activity is stimulated by LIMD2 (PubMed:24590809).
Highly expressed in leukocytes, liver, spleen and thymus, with lower expression in brain, lung and skeletal muscle.
No UPRTase activity has been detected in vitro and the uracil binding region known from UPRTases is missing.
Cross-linked to tightly form both dimers and trimers by TGM2. Cross-linking enhances the activation of EGF receptor-mediated signaling pathway (PubMed:30458214). Cross-linking is inhibited by EGF (PubMed:30458214).
Expressed in epithelial cells (at protein level) (PubMed:29987896). Isoform 3 expression is highly increased in colorectal cancer cells (PubMed:29987896).
Homodimer and homotrimer; forms tight forms of dimers and trimers.
Ubiquitinated. EGF increases ubiquitination.
WD6 repeat is required for cross-linking by TGM2.
When cross-linked to form dimers and trimers, it has a regulatory effect on ERK signaling pathway activity in response to EGF stimulation. Colocalizes with the EGF receptor in WDR54-specific vesicle where it sustains the internalization and controls the degradation of the EGF receptor after EGF stimulation.
Belongs to the ABC transporter superfamily. ABCF family. EF3 subfamily.
Isoform 2 interacts (via N-terminus) with EIF2S1; the interaction is independent of its phosphorylated status. Isoform 2 associates (via both ABC transporter domains) with the ribosomes.
Isoform 2 is phosphorylated at phosphoserine and phosphothreonine. Isoform 2 phosphorylation on Ser-109 and Ser-140 by CK2 inhibits association of EIF2 with ribosomes.
Isoform 2 is required for efficient Cap- and IRES-mediated mRNA translation initiation. Isoform 2 is not involved in the ribosome biogenesis.
Component of the axonemal radial spoke complex 1 (RS1), at least composed of spoke head proteins RSPH1, RSPH3, RSPH9 and the cilia-specific component RSPH4A or sperm-specific component RSPH6A, spoke stalk proteins RSPH14, DNAJB13, DYDC1, ROPN1L and NME5, and the anchor protein IQUB (By similarity). Interacts with IQUB (By similarity).
Functions as part of axonemal radial spoke complexes that play an important part in the motility of sperm and cilia. Does not seem to have NDK kinase activity. Confers protection from cell death by Bax and alters the cellular levels of several antioxidant enzymes including Gpx5. May play a role in spermiogenesis by increasing the ability of late-stage spermatids to eliminate reactive oxygen species (By similarity).
Specifically expressed in testis germinal cells.
Contaminating sequence. Potential vector sequence at the N-terminus.
Part of the TFIIIC subcomplex TFIIIC2, consisting of six subunits, GTF3C1, GTF3C2, GTF3C3, GTF3C4, GTF3C5 and GTF3C6 (PubMed:19299493). Interacts with IGHMBP2. Interacts with MAF1 (PubMed:18377933).
Required for RNA polymerase III-mediated transcription. Component of TFIIIC that initiates transcription complex assembly on tRNA and is required for transcription of 5S rRNA and other stable nuclear and cytoplasmic RNAs. Binds to the box B promoter element.
Belongs to the Mediator complex subunit 30 family.
Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.
Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.
Expressed in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle.
Belongs to the paired homeobox family. Bicoid subfamily.
Expressed predominantly in fetal and adult brain and skeletal muscle. Expression is specific to the telencephalon and ventral thalamus. There is an absence of expression in the cerebellum throughout development and also in adult.
The disease is caused by variants affecting the gene represented in this entry. Also called X-linked lissencephaly with abnormal genitalia (XLAG).
Transcription factor (PubMed:22194193, PubMed:31691806). Binds to specific sequence motif 5'-TAATTA-3' in regulatory elements of target genes, such as histone demethylase KDM5C (PubMed:22194193, PubMed:31691806). Positively modulates transcription of KDM5C (PubMed:31691806). Activates expression of KDM5C synergistically with histone lysine demethylase PHF8 and perhaps in competition with transcription regulator ZNF711; synergy may be related to enrichment of histone H3K4me3 in regulatory elements (PubMed:31691806). Required for normal brain development (PubMed:11889467, PubMed:12379852, PubMed:14722918). Plays a role in neuronal proliferation, interneuronal migration and differentiation in the embryonic forebrain (By similarity). May also be involved in axonal guidance in the floor plate (By similarity).
Belongs to the PPP phosphatase family. PP-1 subfamily.
Inhibited by the toxins okadaic acid, tautomycin and microcystin Leu-Arg (By similarity). The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.
PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, which is folded into its native form by inhibitor 2 and glycogen synthetase kinase 3, and then complexed to one or several targeting or regulatory subunits. The targeting or regulatory subunits determine the substrate specificity of PP1. PPP1R12A, PPP1R12B and PPP1R12C mediate binding to myosin. PPP1R3A (in skeletal muscle), PPP1R3B (in liver), PPP1R3C, PPP1R3D and PPP1R3F (in brain) mediate binding to glycogen. Part of a complex containing PPP1R15B, PP1 and NCK1/2 (By similarity). Interacts with PPP1R7 and PPP1R12C. PPP1R15A and PPP1R15B mediate binding to EIF2S1. Interacts with PPP1R16B. Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1R8. Interacts with TRIM28; the interaction is weak. Interacts with PPP1R12A and NUAK1; the interaction is direct. Interacts with FOXP3. Interacts with RRP1B (PubMed:20926688). Interacts with SERPINE1 (PubMed:28296156). Interacts with LZTR1 (PubMed:30368668).
Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase (PP1) is essential for cell division, it participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T-cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208).
Up-regulated in synovial fluid mononuclear cells and peripheral blood mononuclear cells from patients with rheumatoid arthritis.
Was originally thought to be part of the MLL5-L complex, at least composed of KMT2E, STK38, PPP1CA, PPP1CB, PPP1CC, HCFC1, ACTB and OGT (PubMed:19377461). However, the corresponding article has been retracted (PubMed:24336203).
The gene coding for this protein is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes.
Potential calcium-dependent cell-adhesion protein. May be involved in the establishment and maintenance of specific neuronal connections in the brain.
Belongs to the Sp1 C2H2-type zinc-finger protein family.
Binds to GT and GC boxes promoters elements. Probable transcriptional activator.
The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. In SP4, the motif is inactive.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.
Inhibited by the ATP-competitive kinase inhibitor, SP600125.
Interacts with TPR; the interactions occurs in a microtubule-independent manner (PubMed:19273613). Interacts with MAD1L1 and MAD2L1 (PubMed:29162720).
Phosphorylates proteins on serine, threonine, and tyrosine (PubMed:18243099, PubMed:29162720). Probably associated with cell proliferation (PubMed:18243099). Phosphorylates MAD1L1 to promote mitotic checkpoint signaling (PubMed:29162720). Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint (PubMed:18243099).
Present in rapidly proliferating cell lines.
Interacts with TFIIIB subunits BRF1 and BRF2 (PubMed:17505538, PubMed:18377933). Interacts with Pol III subunit POLR3F. Interacts with TFIIIC subunit GTF3C1 (PubMed:18377933).
Phosphorylated at Ser-60, Ser-68 and Ser-75; the major sites of phosphorylation. Nuclear accumulation correlates with a concomitant dephosphorylation. Phosphorylation may attenuate its RNA polymerase III-repressive function.
Plays a role in the repression of RNA polymerase III-mediated transcription in response to changing nutritional, environmental and cellular stress conditions to balance the production of highly abundant tRNAs, 5S rRNA, and other small non-coding RNAs with cell growth and maintenance (PubMed:18377933, PubMed:20233713, PubMed:20516213, PubMed:20543138). Also plays a key role in cell fate determination by promoting mesorderm induction and adipocyte differentiation (By similarity). Mechanistically, associates with the RNA polymerase III clamp and thereby impairs its recruitment to the complex made of the promoter DNA, TBP and the initiation factor TFIIIB (PubMed:20887893, PubMed:17505538). When nutrients are available and mTOR kinase is active, MAF1 is hyperphosphorylated and RNA polymerase III is engaged in transcription. Stress-induced MAF1 dephosphorylation results in nuclear localization, increased targeting of gene-bound RNA polymerase III and a decrease in the transcriptional readout (PubMed:26941251). Additionally, may also regulate RNA polymerase I and RNA polymerase II-dependent transcription through its ability to regulate expression of the central initiation factor TBP (PubMed:17499043).
Sumoylated with SUMO1 and SUMO2, mainly on Lys-35. Desumoylated by SENP1. SUMOylation promotes the ability of MAF1 to repress transcription and suppress colony formation.
Belongs to the DEAD box helicase family. DEAH subfamily.
Identified in the spliceosome C complex.
Cargo receptor involved in protein vesicular trafficking and quality control in the endoplasmic reticulum (ER) and Golgi (PubMed:10052452, PubMed:11726511, PubMed:16641999, PubMed:17288597, PubMed:19296914, PubMed:20427317, PubMed:21219331, PubMed:27569046). The p24 protein family is a group of transmembrane proteins that bind coat protein complex I/COPI and coat protein complex II/COPII involved in vesicular trafficking between the membranes (PubMed:10052452). Acts at the lumenal side for incorporation of secretory cargo molecules into transport vesicles and involved in vesicle coat formation at the cytoplasmic side (PubMed:20427317, PubMed:27569046). Mainly functions in the early secretory pathway and cycles between the ER, ER-Golgi intermediate compartment (ERGIC) and Golgi, mediating cargo transport through COPI and COPII-coated vesicles (PubMed:10052452, PubMed:10852829, PubMed:12237308). In COPII vesicle-mediated anterograde transport, involved in the transport of GPI-anchored proteins by acting together with TMED2 as their cargo receptor; the function specifically implies SEC24C and SEC24D of the COPII vesicle coat and lipid raft-like microdomains of the ER (PubMed:20427317, PubMed:27569046). Recognizes GPI anchors structural remodeled in the ER by the GPI inositol-deacylase/PGAP1 and the metallophosphoesterase MPPE1/PGAP5 (By similarity). In COPI vesicle-mediated retrograde transport, involved in the biogenesis of COPI vesicles and vesicle coat recruitment (PubMed:11726511). Involved in trafficking of amyloid beta A4 protein and soluble APP-beta release (independent from the modulation of gamma-secretase activity) (PubMed:17288597). Involved in the KDELR2-mediated retrograde transport of the toxin A subunit (CTX-A-K63)together with COPI and the COOH terminus of KDELR2 (By similarity). On Golgi membranes, acts as primary receptor for ARF1-GDP, a GTP-binding protein involved in COPI-vesicle formation (PubMed:11726511). Increases coatomer-dependent GTPase-activating activity of ARFGAP2 which mediates the hydrolysis of ARF1-bound GTP and therefore modulates protein trafficking from the Golgi apparatus (PubMed:19296914). Involved in the exocytic trafficking of G protein-coupled receptors F2LR1/PAR2 (trypsin and tryspin-like enzyme receptor), OPRM1 (opioid receptor) and P2RY4 (UTD and UDP receptor) from the Golgi to the plasma membrane, thus contributing to receptor resensitization (PubMed:21219331). In addition to its cargo receptor activity, may also act as a protein channel after oligomerization, facilitating the post-translational entry of leaderless cytoplasmic cargo into the ERGIC (PubMed:32272059). Involved in the translocation into ERGIC, the vesicle entry and the secretion of leaderless cargos (lacking the secretion signal sequence), including the mature form of interleukin 1/IL-1 family members, the alpha-crystallin B chain HSPB5, the carbohydrate-binding proteins galectin-1/LGALS1 and galectin-3/LGALS3, the microtubule-associated protein Tau/MAPT, and the annexin A1/ANXA1; the translocation process is dependent on cargo protein unfolding and enhanced by chaperones HSP90AB1 and HSP90B1/GRP9 (PubMed:32272059). Could also associates with the presenilin-dependent gamma-secretase complex in order to regulate gamma-cleavages of the amyloid beta A4 protein to yield amyloid-beta 40/Abeta40 (PubMed:16641999).
Ectopic expression of TMED10 alone does not result in its proper cis-Golgi network localization (PubMed:10852829). Interaction of TMED10 with TMED2 is both necessary and sufficient for transport of the couple to the cis-Golgi network, and TMED3 and/or TMED9 contribute to facilitating the process (PubMed:10852829).
Predominantly dimeric and to a lesser extent monomeric in the ER (PubMed:12237308). Monomer and dimer in ERGIC and cis-Golgi network (PubMed:12237308). Forms homooligomer (via GOLD domain); the assembly is promoted by direct binding with leaderless cargos and may form a protein channel that facilitates cargo entry into the ERGIC (PubMed:32272059). Forms heterooligomeric complexes with other members of the p24 family such as TMED2, TMED7 and TMED9 (PubMed:9472029, PubMed:10359607, PubMed:20427317, PubMed:32272059). Interacts (via GOLD domain) with TMED2 (via GOLD domain); the complex is required for export of TMED10 from the ER to the cis-Golgi network; the complex is proposed to be involved in cis-Golgi network dynamics and / or biogenesis (PubMed:10852829, PubMed:27569046). Associates with the COPI vesicle coat subunits (coatomer) (PubMed:9472029, PubMed:11056392, PubMed:16940185). Tetramerization of the cytoplasmic domain at the Golgi membrane in vitro; the complex is proposed to interact with COPI coatomer and induce budding of the vesicles (By similarity). Interacts with COPG1; the interaction involves TMED10 homodimer (PubMed:16940185). Interacts with ARF1 (GDP-bound); the interaction probably involves a TMED10 oligomer (PubMed:11726511). Interacts with SEC23A, SEC24B, SEC24C and SEC24D components of the coat protein complex II/COPII, indicative of an association of TMED10 with the COPII vesicle coat (PubMed:9472029). Interacts with CD59 (PubMed:20427317). Interacts with MPPE1/PGAP5; the complex might recruit and sort GPI-anchored proteins to the ER-exit site, or the interaction might lead to recycling of PGAP5 between the ER and the Golgi (PubMed:19837036). Interacts with F2LR1/PAR2 (PubMed:21219331). Interacts with KDELR2/ERD2; the interaction is disrupted by KDELR2 ligand (By similarity). Found in a complex composed at least of SURF4, TMED2 and TMED10 (PubMed:18287528). Associates with the presenilin-dependent gamma-secretase complex (PubMed:16641999). Interacts with STX17; the interaction is direct (PubMed:21545355). Interacts with IL-1; the interaction is direct (PubMed:32272059). Interacts with RAB21 (active GTP-bound form); the interaction is indirect and regulates TMED10 abundance and localization at the Golgi (PubMed:31455601).
The GOLD domain is required for proper p24 heterooligomeric complex formation and efficient transport of GPI-anchored proteins.
The lumenal domain mediates localization to the plasma membrane by partially overriding the ER retention by the cytoplasmic domain.
Belongs to the V-ATPase G subunit family.
Kidney; localizes to early distal nephron, encompassing thick ascending limbs and distal convoluted tubules (at protein level) (PubMed:29993276). Ubiquitous (PubMed:12384298).
Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:33065002, PubMed:32001091). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (PubMed:32001091). In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation (PubMed:28296633).
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex (PubMed:33065002). The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H (PubMed:33065002). The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR (PubMed:33065002).
Has a stimulatory effect on the ATPase activity of HSP70 in a dose-dependent and time-dependent manner and hence acts as a co-chaperone of HSP70 (PubMed:10954706, PubMed:28233300). Plays an indispensable role in the organization of KRT8/KRT18 filaments (PubMed:10954706). Acts as an endogenous molecular chaperone for neuronal proteins including huntingtin (PubMed:11896048, PubMed:22366786). Suppresses aggregation and toxicity of polyglutamine-containing, aggregation-prone proteins (PubMed:20159555, PubMed:22366786). Also reduces cellular toxicity and caspase-3 activity (PubMed:11896048).
Homooligomer (PubMed:22366786). Interacts with BAG3, HSPB8 and STUB1 (PubMed:22366786). Interacts with ALKBH1 (By similarity). Interacts with HSP70, KRT18 and PTTG (PubMed:10954706, PubMed:9915854).
Interacts with histone deacetylases HDAC4, HDAC6, and SIRT2, HDAC activity is required for antiaggregation.
Isoform B but not isoform A inhibits huntingtin aggregation.
The antiaggregation activity of isoform B resides in the serine-rich region and the C-terminus.
The disease is caused by variants affecting the gene represented in this entry. There is evidence that LGMDD1 is caused by dysfunction of isoform B (PubMed:22366786).
Widely expressed. Highest levels in testis and brain, and lower levels in heart, spleen, intestine, ovary, placenta, lung, kidney, pancreas, thymus, prostate, skeletal muscle, liver and leukocytes. In testis, expressed in germ cells in the earlier stages of differentiation pathway as well as in spermatids. In brain, expressed at a higher level in hippocampus and thalamus and a lower level in amygdala, substantia nigra, corpus callosum and caudate nucleus.
It is uncertain whether Met-1 or Met-52 is the initiator.
Acetyltransferase required for the establishment of sister chromatid cohesion (PubMed:15958495, PubMed:18614053). Couples the processes of cohesion and DNA replication to ensure that only sister chromatids become paired together. In contrast to the structural cohesins, the deposition and establishment factors are required only during S phase. Acts by mediating the acetylation of cohesin component SMC3 (PubMed:18614053).
Belongs to the acetyltransferase family. ECO subfamily.
It is uncertain whether Met-1 or Met-2 is the initiator.
Phosphorylated during mitosis, when associated with chromosomes.
The N-terminal region seems to be responsible for association with chromosomes, thus excluding any involvement of the Zn finger in this process.
The subunit structure is controversial. Monomer (PubMed:27803161). Homodimer (PubMed:27112597).
Widely expressed. Expressed in heart, brain, liver, placenta, lung, kidney and pancreas. Highly expressed in muscle.
SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. Substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Inhibits EGF signaling by mediating the degradation of the Tyr-phosphorylated EGF receptor/EGFR.
The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes.
Acts as a chaperone during the assembly of the 26S proteasome, specifically of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD10:PSMC4:PSMC5:PAAF1 module which probably assembles with a PSMD5:PSMC2:PSMC1:PSMD2 module. Independently of the proteasome, regulates EGF-induced AKT activation through inhibition of the RHOA/ROCK/PTEN pathway, leading to prolonged AKT activation. Plays an important role in RAS-induced tumorigenesis.
Acts as an proto-oncoprotein by being involved in negative regulation of tumor suppressors RB1 and p53/TP53. Overexpression is leading to phosphorylation of RB1 and proteasomal degradation of RB1. Regulates CDK4-mediated phosphorylation of RB1 by competing with CDKN2A for binding with CDK4. Facilitates binding of MDM2 to p53/TP53 and the mono- and polyubiquitination of p53/TP53 by MDM2 suggesting a function in targeting the TP53:MDM2 complex to the 26S proteasome. Involved in p53-independent apoptosis. Involved in regulation of NF-kappa-B by retaining it in the cytoplasm. Binds to the NF-kappa-B component RELA and accelerates its XPO1/CRM1-mediated nuclear export.
Part of transient complex containing PSMD10, PSMC4, PSMC5 and PAAF1 formed during the assembly of the 26S proteasome. Stays associated throughout the assembly of the PA700/19S RC and is released upon association with the 20S core. Interacts with PSMC4. Interacts with RB1. Interacts with CDK4. Interacts with MDM2. Interacts with RELA. Associates with a CDK4:CCND2 serine/threonine kinase complex. Interacts with ARHGDIA and increases the interaction between ARHGDIA and RHOA, hence promotes ARHGDIA inactivation of RHOA and ROCK.
Tends to be up-regulated in cancer cells with RAS mutations, including lung cancers and adenocarconimas (at protein level).
Was initially identified as a genuine component of the 26S proteasome.
(Microbial infection) Interacts with human herpes virus 1 (HHV-1) transcriptional regulator ICP22.
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.
Cleaved isoform SV9 (p110C) binds to the serine/threonine kinase PAK1 and RANBP9. p110C interacts with RNPS1. Isoform 7, but not isoform SV9, nor its cleavage product p110C, interacts with CCND3. Interacts with CCNL1 and CCNL2. Forms complexes with pre-mRNA-splicing factors, including at least SRSF1, SRSF2 and SRSF7/SLU7. Interacts with isoform 5 of MYO18A (PubMed:25965346).
Duplicated gene. CDK11A and CDK11B encode almost identical protein kinases of 110 kDa that contain at their C-termini the open reading frame of a smaller 58 kDa isoform which is expressed following IRES-mediated alternative initiation of translation.
During FAS- or TNF-induced apoptosis, isoform SV9 is cleaved by caspases to produce p110C, a fragment that contains the C-terminal kinase domain.
Expressed ubiquitously. Some evidence of isoform-specific tissue distribution.
Isoform 7 is induced in G2/M phase of the cell cycle.
Many references talk about 'p110 isoforms' but it is not yet known if this refers to CDK11A and/or CDK11B or one/some of the isoforms of each.
Phosphorylation at Ser-115 creates a binding site for 14-3-3 proteins. p110C can be autophosphorylated.
Phosphorylation at Thr-448 or Tyr-449 inactivates the enzyme, while phosphorylation at Thr-595 activates it.
Plays multiple roles in cell cycle progression, cytokinesis and apoptosis. Involved in pre-mRNA splicing in a kinase activity-dependent manner. Isoform 7 may act as a negative regulator of normal cell cycle progression.
Produced by alternative initiation at Met-357 of isoform SV9 via an internal ribosomal entry site (IRES).
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family. MOCOS subfamily.
Sulfurates the molybdenum cofactor. Sulfation of molybdenum is essential for xanthine dehydrogenase (XDH) and aldehyde oxidase (ADO) enzymes in which molybdenum cofactor is liganded by 1 oxygen and 1 sulfur atom in active form. In vitro, the C-terminal domain is able to reduce N-hydroxylated prodrugs, such as benzamidoxime.
Atypical type III intermediate filament (IF) protein that may play a supportive role in the efficient coupling of mechanical stress between the myofibril and fiber exterior. May facilitate lateral force transmission during skeletal muscle contraction. Does not form homofilaments nor heterofilaments with other IF proteins.
May link the dystrophin-associated glycoprotein complex (DAPC) to intracellular desmin (DES) filaments. Interacts with DES and DTNA.
Up-regulated at the sarcolemma in individuals with various forms of neuromuscular disease.
Catalyzes the transfer of the lipoyl group from lipoyl-AMP to the specific lysine residue of lipoyl domains of lipoate-dependent enzymes.
Highly expressed in skeletal muscle and heart, moderately in kidney and pancreas, and detected at lower levels in liver, brain, placenta and lung.
Broadly expressed at low levels. Expressed at high levels in heart, skeletal muscle and placenta.
Interacts with PSRC1; recruited by PSRC1 to the spindle during mitosis (PubMed:26820536).
Phosphorylated during mitosis (PubMed:26820536).
Required for normal progression through mitosis. Involved in chromosome alignment and cytokinesis via regulation of microtubules polymerization.
Dual histone methylation reader specific for PRDM9-catalyzed histone marks (H3K4me3 and H3K36me3) (PubMed:32744506, PubMed:20826339). Facilitates the repair of PRDM9-induced meiotic double-strand breaks (DSBs) (By similarity). Essential for male fertility and spermatogenesis (By similarity). Required for meiosis prophase I progression in male but not in female germ cells (By similarity).
The CW-TYPE zinc finger mediates its binding to trimethylated histone H3K4me3.
Serotonylation of Gln-67 by TGM2 during activation and aggregation of platelets leads to constitutive activation of GTPase activity.
Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state (By similarity). Protein transport. Probably involved in vesicular traffic (By similarity). Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets (By similarity).
Belongs to the metallo-dependent hydrolases superfamily. Hydantoinase/dihydropyrimidinase family.
Carboxylation allows a single lysine to coordinate two zinc ions.
Catalyzes the second step of the reductive pyrimidine degradation, the reversible hydrolytic ring opening of dihydropyrimidines. Can catalyze the ring opening of 5,6-dihydrouracil to N-carbamyl-alanine and of 5,6-dihydrothymine to N-carbamyl-amino isobutyrate.
Maximum levels during G(1) phase. Levels decrease through S and G(2) phases.
Present in respiratory cells (at protein level).
Specifically required for generation of multiciliated cells, possibly by promoting a cell cycle state compatible with centriole amplification and maturation. Acts downstream of MCIDAS to promote mother centriole amplification and maturation in preparation for apical docking.
The disease is caused by variants affecting the gene represented in this entry. Marked reduction of cilia in multiciliate cells due to defective mother centriole generation and placement. Remaining cilia correctly express axonemal motor proteins, are motile and do not show beating defects. Defects are probably caused by a strong reduction in the number of multiple motile cilia covering the cell surface in respiratory epithelial cells (PubMed:24747639).
Was originally thought to have uracil-DNA glycosylase (UDG) activity and wrongly named UNG2 and UDG2 (PubMed:2001396). It was later shown that it is a member of the cyclin family (PubMed:8419333). UNG2 corresponds to the isoform 2 of UNG gene.
Belongs to the ankyrin SOCS box (ASB) family.
Expressed in the eye. The highest expression is observed in the iris, with moderate levels in the trabecular meshwork (TM), the lamina, and the optic nerve; slightly lower levels in the ciliary body, retina, and choroid; and very low levels in the lens.
May be a substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin-protein ligase complexes.
Acts as a phosphoinositide 5- and phosphoinositide 6-phosphatase and regulates cellular levels of inositol pentakisphosphate (InsP5) and inositol hexakisphosphate (InsP6) (PubMed:33257696). Also acts as a 2,3-bisphosphoglycerate 3-phosphatase, by mediating the dephosphorylation of 2,3-bisphosphoglycerate (2,3-BPG) to produce phospho-D-glycerate without formation of 3-phosphoglycerate. May play a role in bone development (endochondral ossification). May play a role in the transition of chondrocytes from proliferation to hypertrophy (By similarity). Through the regulation of intracellular inositol polyphosphates, may control intracellular cation homeostasis, including that of calcium and iron, hence affecting free cation availability required for neural cell signaling (PubMed:33257696).
Belongs to the histidine acid phosphatase family. MINPP1 subfamily.
Widely expressed with highest levels in kidney, liver, cerebellum and placenta.
Forms oligomers. Interacts with 6 of the 7 known isoforms of 14-3-3 proteins.
Guanine nucleotide exchange factor (GEF) activating RAB12. Promotes the exchange of GDP to GTP, converting inactive GDP-bound RAB12 into its active GTP-bound form (PubMed:20937701). Regulates autophagy in response to starvation through RAB12 activation. Starvation leads to ULK1/2-dependent phosphorylation of Ser-472 and Ser-490, which in turn allows recruitment of 14-3-3 adapter proteins and leads to up-regulation of GEF activity towards RAB12 (By similarity). Also plays a role in protein transport from recycling endosomes to lysosomes, regulating, for instance, the degradation of the transferrin receptor and of the amino acid transporter PAT4 (PubMed:20937701). Starvation also induces phosphorylation at Tyr-858, which leads to up-regulated GEF activity and initiates autophagy (By similarity).
Inactive DENND3 is found in a closed conformation, in which the linker region interacts with the DENN domain. Phosphorylation of Tyr-858 in the linker region intereferes with this interaction leading to an open conformation and enhances the GEF activity of the protein towards RAB12.
As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (PubMed:36084634). Plays a role in the regulation of primary cilia length and Hedgehog signaling (PubMed:36084634).
Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932, PubMed:17656373). Within this complex, interacts with RNF113A, as well as with SF3B1/SF3b155, SF3B2/SF3b145, SF3B3/SF3b130 and CDC5L (PubMed:33509932). May interact with LUC7L2 and SNRNP70 (By similarity).
The disease is caused by variants affecting the gene represented in this entry. The genetic variation producing the missense variant p.P51Q, associated with OFD19, has been shown to create a new acceptor splice site, leading to the deletion of 31 nucleotides, resulting in a frameshift and an early termination codon (p.F42YfsTer8). The variant mRNA is predicted to undergo nonsense-mediated mRNA decay.
Belongs to the class IV-like SAM-binding methyltransferase superfamily. TRM10 family.
Expressed in embryonic and fetal brain. It is expressed throughout the dorsal telencephalon at 8 and 11 weeks of gestation, with highest expression in ventricular zone and marginal zone. Detected in cerebellar cortex and nuclei, but not in dorsal telencephalon, at later stages.
S-adenosyl-L-methionine-dependent guanine N(1)-methyltransferase that catalyzes the formation of N(1)-methylguanine at position 9 (m1G9) in tRNAs (PubMed:23042678, PubMed:25053765). Probably not able to catalyze formation of N(1)-methyladenine at position 9 (m1A9) in tRNAs (PubMed:23042678).
Belongs to the SLC13A/DASS transporter (TC 2.A.47) family. NADC subfamily.
Expression is highest in kidney (PubMed:16331647). Detected in placenta, brain, liver and pancreas.
High-affinity sodium-dicarboxylate cotransporter that accepts a range of substrates with 4-6 carbon atoms, such as the citric acid cycle intermediates succinate and alpha-ketoglutarate (2-oxoglutarate), as well as other compounds including N-acetyl-L-aspartate (PubMed:10794676, PubMed:10992006, PubMed:15561973, PubMed:17426067, PubMed:17356845, PubMed:24247155, PubMed:30635937). Transports the dicarboxylate into the cell with a probable stoichiometry of 3 Na(+) for 1 divalent dicarboxylate, rendering the process electrogenic (PubMed:10794676, PubMed:10992006). Can transport citrate in a Na(+)-dependent manner, recognizing the divalent form of citrate rather than the trivalent form which is normally found in blood (PubMed:10794676).
Li(+) decreases succinate transport in the presence of Na(+).
Belongs to the type I cytokine receptor family. Type 3 subfamily.
Binds to CNTF. The alpha subunit provides the receptor specificity. Receptor for heterodimeric neurotropic cytokine composed of CLCF1/CLC and CRLF1/CLF-1 (PubMed:26858303). Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL6ST/GP130 and IL27RA/WSX1 (PubMed:19386761).
Forms a heterotrimer with LIFR and IL6ST. Interacts with heterodimeric neurotropic cytokine composed of CLCF1/CLC and CRLF1/CLF-1 (PubMed:26858303). Either alone or in complex with the heterodimer CLCF1-CRLF1 interacts with SORL1; this interaction may promote internalization and lysosomal degradation (PubMed:26858303). Component of a receptor complex composed of IL6ST/GP130, IL27RA/WSX1 and CNTFR which interacts with the neuroprotective peptide humanin (PubMed:19386761).
The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.
Heterohexamer; composed of 3 copies of TIMM8A and 3 copies of TIMM13, named soluble 70 kDa complex. Associates with the TIM22 complex, whose core is composed of TIMM22.
Highly expressed in fetal and adult brain, followed by fetal lung, liver and kidney. Also expressed in heart, placenta, lung, liver, kidney, pancreas, skeletal muscle and heart.
Mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane. Also required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. Acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space. The TIMM8-TIMM13 complex mediates the import of proteins such as TIMM23, SLC25A12/ARALAR1 and SLC25A13/ARALAR2, while the predominant TIMM9-TIMM10 70 kDa complex mediates the import of much more proteins. Probably necessary for normal neurologic development.
The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space. However, during the transit of TIMM8A from cytoplasm into mitochondrion, the Cys residues probably coordinate zinc, thereby preventing folding and allowing its transfer across mitochondrial outer membrane (By similarity).
Chemotactic activity for lymphocytes but not for monocytes or neutrophils. In thymus, mediates medullary accumulation of thymic dendritic cells and contributes to regulatoy T cell development, playing a role in self-tolerance establishment.
Highest level in spleen, lower in peripheral leukocytes and very low levels in lung, colon and small intestine.
Acts as a mediator of epithelial dynamics and organ branching by promoting cleft progression. Induced following accumulation of fibronectin in forming clefts, leading to local expression of the cell-scattering SNAIL2 and suppression of E-cadherin levels, thereby altering cell morphology and reducing cell-cell adhesion. This stimulates cell separation at the base of forming clefts by local, dynamic intercellular gap formation and promotes cleft progression (By similarity).
Belongs to the glycosyltransferase 2 family. GalNAc-T subfamily.
Probably catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor.
The ricin B-type lectin domain binds to GalNAc and contributes to the glycopeptide specificity.
There are two conserved domains in the glycosyltransferase region: the N-terminal domain (domain A, also called GT1 motif), which is probably involved in manganese coordination and substrate binding and the C-terminal domain (domain B, also called Gal/GalNAc-T motif), which is probably involved in catalytic reaction and UDP-Gal binding.
Widely expressed. Expressed in heart, skeletal muscle, kidney, liver, small intestine and placenta. Weakly expressed in colon, thymus, spleen, lung and leukocyte.
Interacts with UBTF. Interacts with the NuRD complex component RBBP4 (via the nucleolar localization motif), the interaction mediates transcriptional repression activity.
The PHD-type zinc finger 1 mediates both nucleolar localization and interaction with UBTF.
The ePHD2 domain folds as an integrated structural module comprizing the C2HC pre-PHD-type 2 zinc finger and the PHD-type 2 zinc finger. It mediates non-specific binding to dsDNA, but doesn't bind histones in contrast to many PHD-type zinc fingers.
Transcriptional regulator that associates with ribosomal RNA promoters and suppresses ribosomal RNA (rRNA) transcription.
Functions as an intracellular leucine sensor that negatively regulates the mTORC1 signaling pathway through the GATOR complex (PubMed:18692468, PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:26612684, PubMed:26586190, PubMed:31586034, PubMed:35114100, PubMed:35831510, PubMed:36528027). In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents mTORC1 signaling (PubMed:18692468, PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:26612684, PubMed:26586190, PubMed:31586034, PubMed:35114100, PubMed:35831510, PubMed:36528027). Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:26449471, PubMed:26586190, PubMed:35114100, PubMed:35831510, PubMed:36528027). This stress-inducible metabolic regulator also plays a role in protection against oxidative and genotoxic stresses. May negatively regulate protein translation in response to endoplasmic reticulum stress, via mTORC1 (PubMed:24947615). May positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1 (PubMed:23274085). May also mediate TP53 inhibition of TORC1 signaling upon genotoxic stress (PubMed:18692468). Moreover, may prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein (PubMed:26612684). Was originally reported to contribute to oxidative stress resistance by reducing PRDX1 (PubMed:15105503). However, this could not be confirmed (PubMed:19113821).
Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated by leucine (PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:35114100, PubMed:35831510, PubMed:36528027). Conveys leucine availability via direct interaction with SEH1L and WDR24 components of the GATOR2 complex (PubMed:35831510, PubMed:36528027). Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them (PubMed:25259925). May interact with the TORC2 complex (By similarity). Interacts with KEAP1, RBX1, SQSTM and ULK1; to regulate the degradation of KEAP1 (PubMed:23274085, PubMed:25040165). May also associate with the complex composed of TSC1, TSC2 and the AMP-responsive protein kinase/AMPK to regulate TORC1 signaling (PubMed:18692468). May interact with PRDX1 (PubMed:15105503).
Phosphorylated by ULK1 at multiple sites.
The C-terminal domain mediates interaction with GATOR2 through which it regulates TORC1 signaling.
The N-terminal domain has an alkylhydroperoxide reductase activity.
Ubiquitinated at Lys-175 by RNF167 via 'Lys-63'-linked polyubiquitination in response to leucine deprivation: ubiquitination promotes SESN2-interaction with the GATOR2 complex, leading to inhibit the TORC1 signaling pathway (PubMed:35114100). Deubiquitinated at Lys-175 by STAMBPL1, promoting the TORC1 signaling pathway (PubMed:35114100). Ubiquitinated by RNF186; ubiquitination mediates proteasomal degradation (PubMed:31586034).
Up-regulated by hypoxia and DNA damage (PubMed:12203114). Up-regulated by treatments inducing endoplasmic reticulum stress (PubMed:24947615).
Component of the antigen processing and presentation pathway, which binds to MHC class I coupled with beta2-microglobulin/B2M. Association between TAPBPR and MHC class I occurs in the absence of a functional peptide-loading complex (PLC).
Has reduced cell surface expression, and does not down-regulate MHC class I surface expression as efficiently as isoform alpha.
Interacts with peptide-free HLA-A*02-B2M complexes or those loaded with low affinity peptides, likely facilitating peptide exchange onto higher affinity peptides.
A chromosomal aberration involving FCRL5 has been found in cell lines with 1q21 abnormalities derived from Burkitt lymphoma. Duplication dup(1)(q21q32).
Contains 2 copies of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM).
Expressed in marginal zone B-cells, immunoblasts, tonsillar germinal center centrocytes and in the intraepithelial and interfollicular regions of the tonsil. Expressed in many lymphoma cell lines and on hairy cell leukemia cells. Isoform 1, isoform 3, isoform 4 and isoform 5 are detected in lymph node, spleen, bone marrow, and small intestine with preponderance of isoform 3. Expressed in mature and memory B-cells and down-regulated in germinal center cells (at protein level).
May be involved in B-cell development and differentiation in peripheral lymphoid organs and may be useful markers of B-cell stages. May have an immunoregulatory role in marginal zone B-cells. May play a role in fertilization (By similarity).
Belongs to the seminal plasma protein family.
Binds to spermatozoa upon ejaculation and may play a role in sperm capacitation. Has phosphorylcholine-binding activity (By similarity).
Detected in cauda epididymidal fluid and on sperm membrane (at protein level).
A connexon is composed of a hexamer of connexins.
A connexon is composed of a hexamer of connexins. Interacts with TJP1 (By similarity).
Belongs to the connexin family. Gamma-type subfamily.
Expressed in central nervous system, in sciatic nerve and sural nerve. Also detected in skeletal muscles.
It is uncertain whether Met-1 or Met-4 is the initiator.
One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. May play a role in myelination in central and peripheral nervous systems.
Acts as a negative regulator of NEK2 to maintain the centrosome integrity in interphase. Suppresses centrosome disjunction by inhibiting NEK2 kinase activity (PubMed:26220856).
Abundantly expressed in the majority of tissues examined, including brain and skeletal muscle.
Belongs to the tigger transposable element derived protein family.
Probable calcium-dependent phospholipid-binding protein that may play a role in calcium-mediated intracellular processes.
Expressed strongly in kidney and skeletal muscle, followed by liver, placenta, pancreas, and lung, with low amounts in heart and only traces in brain (PubMed:11085536). Widely expressed with ubiquitous expression in epithelial tissues (at protein level) (PubMed:17973242).
Homooligomer (PubMed:24806965). Interacts with COPB1 (PubMed:24806965). May interact with LMAN1 (PubMed:24806965). Interacts with the COG complex; probably through COG3 (PubMed:24806965).
May play a role in retrograde transport of proteins from the Golgi to the endoplasmic reticulum. May indirectly play a role in protein glycosylation in the Golgi.
(Microbial infection) Interacts with E3 14.7 kDa protein of group C human adenovirus (PubMed:9488477). Interacts with Bluetongue virus protein NS3 (PubMed:27538435).
(Microbial infection) May constitute a cellular target for various viruses, such as adenovirus E3 14.7 or Bluetongue virus, to inhibit innate immune response (PubMed:9488477, PubMed:27538435). During RNA virus infection, such as that of Sendai virus, negatively regulates the induction of IFNB1 (PubMed:20174559).
(Microbial infection) Up-regulated in response to Sendai virus infection or double stranded RNA treatment (at protein level); the up-regulation is direct and not mediated through a response to type I interferons; this may negatively regulate the interferon response to RNA-activated antiviral signaling pathways.
Phosphorylated by TBK1, leading to restrict bacterial proliferation in case of infection. Phosphorylation is induced by phorbol esters and decreases its half-time.
Plays an important role in the maintenance of the Golgi complex, in membrane trafficking, in exocytosis, through its interaction with myosin VI and Rab8 (PubMed:27534431). Links myosin VI to the Golgi complex and plays an important role in Golgi ribbon formation (PubMed:27534431). Plays a role in the activation of innate immune response during viral infection. Mechanistically, recruits TBK1 at the Golgi apparatus, promoting its trans-phosphorylation after RLR or TLR3 stimulation (PubMed:27538435). In turn, activated TBK1 phosphorylates its downstream partner IRF3 to produce IFN-beta/IFNB1. Plays a neuroprotective role in the eye and optic nerve. May act by regulating membrane trafficking and cellular morphogenesis via a complex that contains Rab8 and hungtingtin (HD). Mediates the interaction of Rab8 with the probable GTPase-activating protein TBC1D17 during Rab8-mediated endocytic trafficking, such as that of transferrin receptor (TFRC/TfR); regulates Rab8 recruitment to tubules emanating from the endocytic recycling compartment (PubMed:22854040). Autophagy receptor that interacts directly with both the cargo to become degraded and an autophagy modifier of the MAP1 LC3 family; targets ubiquitin-coated bacteria (xenophagy), such as cytoplasmic Salmonella enterica, and appears to function in the same pathway as SQSTM1 and CALCOCO2/NDP52.
Present in aqueous humor of the eye (at protein level). Expressed in the trabecular meshwork (at protein level) (PubMed:11834836, PubMed:12379221, PubMed:12646749). Expressed in nonpigmented ciliary epithelium (at protein level) (PubMed:11834836). Expressed at high levels in skeletal muscle, also detected in heart, brain, pancreas, kidney, placenta and liver (PubMed:9488477). Expressed in dermal fibroblasts (at protein level) (PubMed:11834836).
Self-associates (PubMed:23669351). Interacts with HD (PubMed:9700202, PubMed:11137014). Interacts with GTF3A (PubMed:10756201). Interacts with MYO6 (PubMed:31371777). Interacts (via UBAN) with ubiquitinated TFRC (PubMed:20085643). Interacts with GTP-bound Rab8 (RAB8A and/or RAB8B) (PubMed:11137014, PubMed:20085643, PubMed:22854040). Interacts with TBC1D17 (PubMed:22854040). Interacts with TBK1 (PubMed:20174559, PubMed:27538435, PubMed:23669351). Interacts with TRAF3 (PubMed:20174559). Binds to linear ubiquitin chains (PubMed:20085643). Interacts with LC3 family members MAP1LC3A, MAP1LC3B, GABARAP, GABARAPL1 and GABARAPL2; OPTN phosphorylation increases the association (at least with MAP1LC3B). Interacts with RAB12; the interaction may be indirect. Interacts with TBK1; this interaction leads to the Golgi localization of TBK1 and its subsequent activation. Interacts with palmitoyltransferase ZDHHC17/HIP14; the interaction does not lead to palmitoylation of OPTN (PubMed:24705354). Interacts with CYLD (PubMed:32185393). Interacts with TOM1; the interaction is indirect and is mediated by MYO6, which acts as a bridge between TOM1 and OPTN (PubMed:31371777).
The LIR (LC3-interacting region) motif mediates the interaction with ATG8 family proteins.
Ubiquitin-binding motif (UBAN), also called UBD, is essential for subcellular localization to recycling endosomes and for proper trafficking of transferrin to the juxtanuclear region. It is involved in interaction with ubiquitinated TFRC.
Up-regulated by TNF (PubMed:9488477, PubMed:10807909, PubMed:12379221). Up-regulated by IFNG. TNF and IFNG act synergistically to stimulate OPTN expression (PubMed:10807909). Induced by glucocorticoids, such as dexamethasone (PubMed:12379221). In an in vitro experimental setting, in which donor eyes are subjected to increased perfusion pressure (10 to 30 mm Hg) in the anterior chamber, there is no up-regulation in the trabecular meshwork at the transcript level for periods ranging between 1 and 24 hours (PubMed:12646749). However, exposure to continuous elevated pressure for several days shows an induction of OPTN expression, with a 56% increase after 7 days (PubMed:12379221).
(Microbial infection) Acts as a receptor for Epstein-Barr virus on lymphocytes.
(Microbial infection) Interacts with Epstein-Barr virus gp42 protein.
(Microbial infection) Interacts with Staphylococcus aureus enterotoxin A/entA, enterotoxin B/entB, enterotoxin C1/entC1, enterotoxin D/entD and enterotoxin H/entH. Enterotoxins bind outside the peptide-binding cleft of MHCII: enterotoxin H/entH interacts via the beta-1 domain of MHCII and in a zinc-dependent way, whereas enterotoxin B/entB interacts primarily via the alpha-1 domain.
A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the alpha chain HLA-DRA, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DRB1-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells (PubMed:29884618, PubMed:22327072, PubMed:27591323, PubMed:8642306, PubMed:15265931, PubMed:31495665, PubMed:16148104). Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:8145819). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (PubMed:31495665). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (PubMed:17182262, PubMed:23783831). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self-peptides (PubMed:25413013). The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (PubMed:8145819).
Allele DRB1*01:01: Displays an immunodominant epitope derived from Bacillus anthracis pagA/protective antigen, PA (KLPLYISNPNYKVNVYAVT), to both naive and PA-specific memory CD4-positive T cells (PubMed:22327072). Presents immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (PHQFINLRSNNSATLIVPYV), contributing to viral clearance (PubMed:27591323). Displays commonly recognized peptides derived from IAV external protein HA (PKYVKQNTLKLAT and SNGNFIAPEYAYKIVK) and from internal proteins M, NP and PB1, with M-derived epitope (GLIYNRMGAVTTEV) being the most immunogenic (PubMed:8145819, PubMed:9075930, PubMed:25413013, PubMed:32668259). Presents a self-peptide derived from COL4A3 (GWISLWKGFSF) to TCR (TRAV14 biased) on CD4-positive, FOXP3-positive regulatory T cells and mediates immune tolerance to self (PubMed:28467828). May present peptides derived from oncofetal trophoblast glycoprotein TPBG 5T4, known to be recognized by both T-helper 1 and regulatory T cells (PubMed:31619516). Displays with low affinity a self-peptide derived from MBP (VHFFKNIVTPRTP) (PubMed:9075930).
Allele DRB1*03:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Displays self-peptides derived from retinal SAG (NRERRGIALDGKIKHE) and thyroid TG (LSSVVVDPSIRHFDV) (PubMed:25413013). Presents viral epitopes derived from HHV-6B gH/U48 and U85 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection (PubMed:31020640). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and long-term protection (PubMed:19830726).
Allele DRB1*04:01: Presents an immunodominant bacterial epitope derived from M. tuberculosis esxB/culture filtrate antigen CFP-10 (EISTNIRQAGVQYSR), eliciting CD4-positive T cell effector functions such as IFNG production and cytotoxic activity (PubMed:15265931). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Presents tumor epitopes derived from melanoma-associated TYR antigen (QNILLSNAPLGPQFP and DYSYLQDSDPDSFQD), triggering CD4-positive T cell effector functions such as GMCSF production (PubMed:8642306). Displays preferentially citrullinated self-peptides derived from VIM (GVYATR/citSSAVR and SAVRAR/citSSVPGVR) and ACAN (VVLLVATEGR/ CitVRVNSAYQDK) (PubMed:24190431). Displays self-peptides derived from COL2A1 (PubMed:9354468).
Allele DRB1*04:02: Displays native or citrullinated self-peptides derived from VIM.
Allele DRB1*04:04: May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (HIVMQYMYVPPGAPIPTTRN) and VP2 (RGDSTITSQDVANAVVGYGV), contributing to viral clearance (PubMed:27591323). Displays preferentially citrullinated self-peptides derived from VIM (SAVRAR/citSSVPGVR) (PubMed:24190431).
Allele DRB1*04:05: May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies.
Allele DRB1*05:01: Presents an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load.
Allele DRB1*07:01: Upon EBV infection, presents latent antigen EBNA2 peptide (PRSPTVFYNIPPMPLPPSQL) to CD4-positive T cells, driving oligoclonal expansion and selection of a dominant virus-specific memory T cell subset with cytotoxic potential to directly eliminate virus-infected B cells (PubMed:31308093). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (VPYVNAVPMDSMVRHNNWSL), contributing to viral clearance (PubMed:27591323). In the context of tumor immunesurveillance, may present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (MTEYKLVVVGAVGVGKSALTIQLI), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:22929521). In metastatic epithelial tumors, presents to intratumoral CD4-positive T cells a KRAS neoantigen (MTEYKLVVVGAVGVGKSALTIQLI) carrying G12V hotspot driver mutation and may mediate tumor regression (PubMed:30282837).
Allele DRB1*11:01: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SDRIIQITRGDSTITSQDVA), contributing to viral clearance (PubMed:27591323). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and longterm protection (PubMed:19830726). In the context of tumor immunesurveillance, may present tumor-derived neoantigens to CD4-positive T cells and trigger anti-tumor helper functions (PubMed:31495665).
Allele DRB1*13:01: Presents viral epitopes derived from HHV-6B antigens to polyfunctional CD4-positive T cells implicated in control of HHV-6B infection.
Allele DRB1*15:01 is associated with increased susceptibility to Goodpasture syndrome. Can present a self-peptide derived from COL4A3 (GWISLWKGFSF) on TCR (TRAV19 biased) in pathogenic CD4-positive T-helper 1 and T-helper 17 cells, triggering autoimmune inflammation.
Allele DRB1*15:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SNNSATLIVPYVNAVPMDSM), contributing to viral clearance (PubMed:27591323). Displays a self-peptide derived from MBP (ENPVVHFFKNIVTPR) (PubMed:9782128, PubMed:25413013). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies.
Allele DRB1*15:02: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:19120973).
Disease susceptibility is associated with variants affecting the gene represented in this entry. Alleles DRB1*04:01; DRB1*04:04; DRB1*04:05; DRB1*04:08; DRB1*10:01; DRB1*01:01 and DRB1*01:02 are associated with increased susceptibility to rheumatoid arthritis, where affected individuals have antibodies to cyclic citrullinated peptide (anti-CCP-positive rheumatoid arthritis). Variations at position 40 in the peptide-binding cleft of these alleles explain most of the association to rheumatoid arthritis risk.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Alleles DRB1*04:02, DRB1*11:01 and DRB1*12:01 are associated with sarcoidosis. Allele DRB1*04:02 is significantly associated with specific sarcodosis phenotypes such as eye, parotid and salivary gland involvement.
Disease susceptibility is associated with variants affecting the gene represented in this entry. In populations of European descent, allele DRB1*15:01 has the strongest association with multiple sclerosis among all HLA class II alleles. Additional risk is associated with the strongly linked alleles DRB1*03:01 and DQB1*02:01 as well as with allele DRB1*13:03 (PubMed:21833088). It is postulated that bacterial or viral infection triggers the autoimmune MS. Microbial peptides having low affinity crossreactivity to MBP autoantigen, may stimulate autoreactive T cells via molecular mimicry and initiate the autoimmune inflammation (PubMed:19303388).
Expressed in professional APCs: monocyte/macrophages, dendritic cells and B cells (at protein level) (PubMed:31495665, PubMed:23783831, PubMed:19830726). Expressed in thymic epithelial cells (at protein level) (PubMed:23783831).
Heterotrimer that consists of an alpha chain HLA-DRA, a beta chain HLA-DRB1 and a peptide (peptide-MHCII) (PubMed:7477400, PubMed:9354468, PubMed:9782128, PubMed:31619516, PubMed:32668259). Newly synthesized alpha and beta chains forms a heterodimer (MHCII) that associates with the CD74/invariant chain (Ii) in the endoplasmic reticulum (ER). Ii is a trimer composed of three subunits and each subunit interacts with one MHCII dimer, blocking the peptide-binding cleft. As a result, MHCII molecules cannot bind peptides present in the ER (PubMed:7479981). The complex of MHCII and CD74/Ii is transported in vesicles from ER to Golgi to lysosomes, where it encounters antigenic peptides generated via proteolysis of endocytosed antigens. MHCII dimers are dissociated from CD74/Ii by the combined action of proteolysis and HLA-DM (PubMed:25413013). Lysosomal enzymes such as cathepsin, degrade CD74/Ii leaving a 24 amino acid remnant called class II-associated Ii or CLIP. Interacts (via the peptide binding cleft) with CLIP; this interaction inhibits antigen peptide binding before entry in the endosomal compartment (PubMed:7477400, PubMed:9075930). The displacement of CLIP and replacement by a high affinity peptide in lysosomes is performed by HLA-DM heterodimer. HLA-DM catalyzes CLIP dissociation from MHCII, stabilizes empty MHCII and mediates the selection of high affinity peptides (PubMed:23260142, PubMed:11070170, PubMed:9075930). Interacts with HLA-DM heterodimer; this interaction is direct (PubMed:25413013). Interacts with TCR (via CDR3) (PubMed:29884618). Interacts (via beta-2 domain) with CD4 coreceptor (via Ig-like V-type domain); this interaction is of exceptionally low affinity yet necessary for optimal recognition of antigenic peptides (PubMed:21900604, PubMed:27114505).
Highly polymorphic. Polymorphic residues encode for the beta-1 domain of the peptide-binding cleft, where they contribute to variations in peptide binding and TCR recognition among different alleles. The sequence shown is that of DRB1*15:01. The sequences of common representative alleles of serologically distinct allele groups as defined in the catalog of common and well-documented HLA alleles, are described as variants of DRB1*15:01 (PubMed:23510415). In the context of hematological malignancy and T cell transplantation, alleles DRB1*03:01 and DRB1*13:01 present minor histocompatibility antigens derived respectively from host MTHFD1 and LY75 proteins, contributing to T cell-mediated graft-versus-leukemia effect and complete remission (PubMed:19706888).
In populations of European descent, allele DRB1*01:03 is associated with increased susceptibility to Crohn disease and colonic ulcerative colitis. Decreased heterozygosity in individuals with colonic ulcerative colitis suggests that it acts as a recessive risk allele.
The beta-1 domain is a structural part of the peptide-binding cleft. It contains one alpha helix and 4 beta sheets, respectively forming part of the wall and the floor of the peptide-binding cleft. The other 4 beta sheets of the floor and the second alpha helix wall is formed by the alpha-1 domain of HLA-DRA. Forms hydrogen bonds with the peptide main chain via conserved amino acid in most HLA-DRB molecules. The polymorphic residues accomodate the side chains of the peptide conferring peptide specificity to distinct HLA-DRB1 alleles (PubMed:8145819, PubMed:28467828, PubMed:9782128, PubMed:9354468). The peptide-bound beta-1 domain forms hydrogen bonds with CDR2 and CDR3 alpha-domains of TCR (PubMed:19303388).
The beta-2 Ig-like domain mediates the interaction with CD4 coreceptor.
Ubiquitinated by MARCHF1 and MARCHF8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHCII.
Belongs to the type-B carboxylesterase/lipase family.
Detected in blood plasma (at protein level). Present in most cells except erythrocytes.
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Homotetramer; disulfide-linked. Dimer of dimers.
Inhibited by mercury. Inhibited by Tabun. Tabun forms a covalent adduct with Ser-226 that becomes irreversible upon aging.
N-glycosylated. No other PTM detected (PubMed:20946535). The major N-glycan structures are of the complex diantennary type with 1 and 2 N-acetylneuraminic acid molecules (Neu5Ac) making up approximately 33% and 47% of the total N-glycans, respectively. Only low amounts of fucosylated diantennary N-glycans are detected (approximately 2%). Triantennary N-glycans with or without fucose amount to approximately 13%, whereas 5% of the total N-glycans are of the oligomannosidic or hybrid type.
Component of the GINS complex which is a heterotetramer of GINS1, GINS2, GINS3 and GINS4. Forms a stable subcomplex with GINS1. GINS complex interacts with DNA primase in vitro (PubMed:17170760, PubMed:17417653, PubMed:17545466, PubMed:17557111, PubMed:17652513, PubMed:28414293, PubMed:32453425). Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex (PubMed:34700328, PubMed:34694004, PubMed:32453425).
Required for correct functioning of the GINS complex, a complex that plays an essential role in the initiation of DNA replication, and progression of DNA replication forks (PubMed:17417653, PubMed:28414293). GINS complex is a core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built (PubMed:32453425, PubMed:34694004, PubMed:34700328, PubMed:35585232).
Significantly up-regulated in aggressive melanomas.
Has intrinsic E3 ubiquitin ligase activity and promotes ubiquitination.
Spleen, small intestine, ovary, peripheral blood, lung, kidney and pancreas. Expressed at low levels in the thymus, prostate, testis, colon, heart, brain, placenta and liver.
Up-regulated by FGF2 in gastric cancer cells.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. GB1/RHD3 GTPase family.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. GB1/RHD3 GTPase family. GB1 subfamily.
Expressed predominantly in the adult and fetal central nervous system. Measurable expression in all tissues examined, although expression in adult brain is at least 50-fold higher than in other tissues. Detected predominantly in pyramidal neurons in the cerebral cortex and the hippocampus of the brain. Expressed in upper and lower motor neurons (at protein level).
GTPase tethering membranes through formation of trans-homooligomers and mediating homotypic fusion of endoplasmic reticulum membranes. Functions in endoplasmic reticulum tubular network biogenesis (PubMed:27619977). May also regulate Golgi biogenesis. May regulate axonal development.
Monomer as apoprotein and in the GDP-bound form. Homodimer in the GTP-bound form. Interacts (via N-terminal region) with MAP4K4 (via CNH regulatory domain). Interacts with REEP5, RTN3 and RTN4 (via the transmembrane region). Interacts with SPAST; interaction is direct. May interact with TMED2. Interacts with REEP1. Interacts with CPT1C. Interacts with ARL6IP1 (By similarity). Interacts with ZFYVE27 (PubMed:23969831).
Synthesized by syncytiotrophoblast of the placenta.
CCNA2/CDK2 regulatory protein that transiently maintains CCNA2 in the cytoplasm.
Expressed at each stage of the cell cycle, including G0, although the expression is somewhat higher in late G1 and S phases.
Interacts with CCNA2/CDK2 complex, but not with CCNA2/CDC2, CCNB1/CDC2 or CCNE1/CDK2 complexes, at multiple phases of the cell cycle, including S and G2/M.
Phosphorylated in vitro by the CCNA2/CDK2 complex.
Widely expressed with high expression in testis. Isoform 1 is detected in various tissues, including retina, fetal and adult brain. Isoform 2 is expressed in the retina at high levels, and in the brain at very low levels (PubMed:28794130).
Belongs to the splicing factor SR family.
A rare polymorphic frameshift in position 451 produces a protein of 545 residues.
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is clonidine > norepinephrine > epinephrine = oxymetazoline > dopamine > p-tyramine = phenylephrine > serotonin > p-synephrine / p-octopamine. For antagonists, the rank order is yohimbine > chlorpromazine > phentolamine > mianserine > spiperone > prazosin > alprenolol > propanolol > pindolol.
Belongs to the G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRA2B sub-subfamily.
Interacts with RAB26 (PubMed:23105096). Interacts with PPP1R9B (PubMed:24114805). Interacts with GGA1, GGA2 and GGA3 (PubMed:27901063, PubMed:26811329).
Cytokine produced by various cells such as eosinophils, T-helper type 2 (Th2) cells or epithelial cells that plays a role in internal safety of adaptive immune responses by regulating cytokine production (PubMed:25821217, PubMed:15860795). Promotes and augments T-helper type 2 responses locally or systemically (PubMed:25821217). Exerts its activity via its receptor composed of IL17RA and IL17RB for signal transduction (By similarity). In turn, stimulates the JAK2-STAT5A pathway and promotes the secretion of type-2 associated cytokines including IL4, IL9 and IL13 (PubMed:25821217). Induces also the release of IL8, and IL6 from eosinophils through the combined activation of MAPK and NF-kappa-B pathways (PubMed:15860795). Inhibits the differentiation of T-helper (Th17) cells via the production of IL4, IL5 and IL13 (PubMed:11754819).
Expressed at low levels in several tissues, including brain, kidney, lung, prostate, testis, spinal cord, adrenal gland, and trachea.
Functions as a receptor for the Fc fragment of IgA and IgM. Binds IgA and IgM with high affinity and mediates their endocytosis. May function in the immune response to microbes mediated by IgA and IgM.
Up-regulated by IFNG/IFN-gamma in mesangial cells.
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.
Bone morphogenetic protein (BMP) type I receptor that is involved in a wide variety of biological processes, including bone, heart, cartilage, nervous, and reproductive system development and regulation (PubMed:20628059, PubMed:22977237). As a type I receptor, forms heterotetrameric receptor complexes with the type II receptors AMHR2, ACVR2A or ACVR2B (PubMed:17911401). Upon binding of ligands such as BMP7 or GDF2/BMP9 to the heteromeric complexes, type II receptors transphosphorylate ACVR1 intracellular domain (PubMed:25354296). In turn, ACVR1 kinase domain is activated and subsequently phosphorylates SMAD1/5/8 proteins that transduce the signal (PubMed:9748228). In addition to its role in mediating BMP pathway-specific signaling, suppresses TGFbeta/activin pathway signaling by interfering with the binding of activin to its type II receptor (PubMed:17911401). Besides canonical SMAD signaling, can activate non-canonical pathways such as p38 mitogen-activated protein kinases/MAPKs (By similarity). May promote the expression of HAMP, potentially via its interaction with BMP6 (By similarity).
Expressed in normal parenchymal cells, endothelial cells, fibroblasts and tumor-derived epithelial cells.
Interacts with FKBP1A (PubMed:22484487, Ref.14). Interacts with FCHO1 (PubMed:22484487). Interacts with CLU (PubMed:8555189). Interacts with type II receptors AMHR2 and ACVR2A (PubMed:17911401). Interacts with BMP7 (PubMed:9748228). Interacts with GDF2/BMP9 (PubMed:20628059). Interacts with BMP6 (when glycosylated); the interaction may induce HAMP expression (PubMed:18070108, PubMed:31800957). Interacts with TSC22D1/TSC-22 (PubMed:21791611).
Expressed in placenta, ovary and small intestine, as well as in heart and pancreas. Also expressed in peripheral blood mononuclear cells and dendritic cells.
May play a role in early endosome fusion upstream of RAB5, hence regulating receptor trafficking and fluid-phase transport. Enhances cellular sensitivity to TNF-induced apoptosis (PubMed:18288467).
The PH and FYVE domains may be important for TNF-induced localization to the endoplasmic reticulum and for enhanced cellular sensitivity to TNF-induced apoptosis (PubMed:18288467). The FYVE domain is important for binding to the endosomal membrane.
Up-regulated by TNF, bacterial lipopolysaccharides (LPS) and phorbol myristate acetate (PMA) (at protein level).
Interacts (via C-terminus) with SMAD2. Interacts (via C-terminus) with SMAD3 (via MH2 domain). Interacts with LHX2 (via LIM domains). Interacts with WT1 (By similarity). Interacts (via C-terminus) with EP300 (via CH1 domain); the interaction is stimulated in response to hypoxia. Interacts with PPARA. Interacts (via C-terminus) with TFAP2A, TFAP2B and TFAP2C.
Transcriptional coactivator of the p300/CBP-mediated transcription complex. Acts as a bridge, linking TFAP2 transcription factors and the p300/CBP transcriptional coactivator complex in order to stimulate TFAP2-mediated transcriptional activation. Positively regulates TGF-beta signaling through its association with the SMAD/p300/CBP-mediated transcriptional coactivator complex. Stimulates the peroxisome proliferator-activated receptors PPARA transcriptional activity. Enhances estrogen-dependent transactivation mediated by estrogen receptors. Acts also as a transcriptional corepressor; interferes with the binding of the transcription factors HIF1A or STAT2 and the p300/CBP transcriptional coactivator complex. Participates in sex determination and early gonad development by stimulating transcription activation of SRY. Plays a role in controlling left-right patterning during embryogenesis; potentiates transcriptional activation of NODAL-mediated gene transcription in the left lateral plate mesoderm (LPM). Plays an essential role in differentiation of the adrenal cortex from the adrenogonadal primordium (AGP); stimulates WT1-mediated transcription activation thereby up-regulating the nuclear hormone receptor NR5A1 promoter activity. Associates with chromatin to the PITX2 P1 promoter region.
Anchoring protein that mediates the subcellular compartmentation of cAMP-dependent protein kinase (PKA type II) (PubMed:9473338). Acts as an anchor for a PKA-signaling complex onto mitotic chromosomes, which is required for maintenance of chromosomes in a condensed form throughout mitosis. Recruits condensin complex subunit NCAPD2 to chromosomes required for chromatin condensation; the function appears to be independent from PKA-anchoring (PubMed:10601332, PubMed:10791967, PubMed:11964380). May help to deliver cyclin D/E to CDK4 to facilitate cell cycle progression (PubMed:14641107). Required for cell cycle G2/M transition and histone deacetylation during mitosis. In mitotic cells recruits HDAC3 to the vicinity of chromatin leading to deacetylation and subsequent phosphorylation at 'Ser-10' of histone H3; in this function may act redundantly with AKAP8L (PubMed:16980585). Involved in nuclear retention of RPS6KA1 upon ERK activation thus inducing cell proliferation (PubMed:22130794). May be involved in regulation of DNA replication by acting as scaffold for MCM2 (PubMed:12740381). Enhances HMT activity of the KMT2 family MLL4/WBP7 complex and is involved in transcriptional regulation. In a teratocarcinoma cell line is involved in retinoic acid-mediated induction of developmental genes implicating H3 'Lys-4' methylation (PubMed:23995757). May be involved in recruitment of active CASP3 to the nucleus in apoptotic cells (PubMed:16227597). May act as a carrier protein of GJA1 for its transport to the nucleus (PubMed:26880274). May play a repressive role in the regulation of rDNA transcription. Preferentially binds GC-rich DNA in vitro. In cells, associates with ribosomal RNA (rRNA) chromatin, preferentially with rRNA promoter and transcribed regions (PubMed:26683827). Involved in modulation of Toll-like receptor signaling. Required for the cAMP-dependent suppression of TNF-alpha in early stages of LPS-induced macrophage activation; the function probably implicates targeting of PKA to NFKB1 (By similarity).
Binds to the PKA RII-alpha regulatory subunit PRKAR2A (phosphorylated at 'Thr-54') during mitosis (PubMed:9473338, PubMed:10601332, PubMed:10764601, PubMed:11591814). Interacts (via C-terminus) with FIGN (By similarity). Interacts with NCAPD2, CCND1, MCM2, RPS6KA1, PDE4A (PubMed:10601332, PubMed:11964380, PubMed:11591814, PubMed:12740381, PubMed:14641107, PubMed:15470020, PubMed:22130794). Interacts with CCND3, CCNE1, DDX5, CASP3. Interacts with NFKB1; detetcted in the cytoplasm. Interacts with MYCBP; MYCBP is translocated to the nucleus and the interaction prevents the association of the PKA catalytic subunit leading to suppression of PKA activity (By similarity). Interacts with DPY30; mediating AKAP8 association with at least the MLL4/WBP7 HMT complex (PubMed:23995757). Interacts with HDAC3; increased during mitosis (PubMed:16980585). Interacts with GJA1; in the nucleus and in the nuclear membrane; the nuclear association increases with progress of cell cycle G1, S and G2 phase and decreases in M phase (PubMed:26880274).
Highly expressed in heart, liver, skeletal muscle, kidney and pancreas. Expressed in mature dendritic cells.
Phosphorylated on tyrosine residues probably by SRC subfamily protein kinases; multiple phosphorylation is leading to dissociation from nuclear structures implicated in chromatin structural changes.
Expressed in the blood vessel walls. Detected in colon, brain and pancreas islets of Langerhans (at protein level). Detected in brain, and at lower levels in pancreas islet beta cells.
Interacts with neurexins NRXN1, NRXN2 and NRXN3 (By similarity). Interaction with neurexins is mediated by heparan sulfate glycan modification on neurexin (By similarity). Interacts (via its C-terminus) with DLG4/PSD-95 (via PDZ domain 3) (PubMed:9278515). Interacts with PATJ (By similarity). Interacts with GPHN (By similarity). Interacts with MDGA1 and MDGA2 (By similarity). Found in a complex with MAGI2 and IGSF9B, where it interacts with MAGI2 (via WW 1, WW 2 and PDZ 2 domains) (PubMed:23751499). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3 (By similarity). Interacts with LHFPL4; leading to mutual regulation of the protein level and synaptic clustering (By similarity). Interacts with NLGN2 (By similarity).
Transmembrane scaffolding protein involved in cell-cell interactions via its interactions with neurexin family members. Mediates cell-cell interactions both in neurons and in other types of cells, such as Langerhans beta cells. Plays a role in synapse function and synaptic signal transmission, especially via gamma-aminobutyric acid receptors (GABA(A) receptors). Functions by recruiting and clustering synaptic proteins. Promotes clustering of postsynaptic GABRG2 and GPHN. Promotes clustering of postsynaptic LHFPL4 (By similarity). Modulates signaling by inhibitory synapses, and thereby plays a role in controlling the ratio of signaling by excitatory and inhibitory synapses and information processing. Required for normal signal amplitude from inhibitory synapses, but is not essential for normal signal frequency. May promote the initial formation of synapses, but is not essential for this. In vitro, triggers the de novo formation of presynaptic structures. Mediates cell-cell interactions between Langerhans beta cells and modulates insulin secretion (By similarity).
ATPase activity is enhanced in the presence of homomeric poly(U) RNAs, but not by double-stranded DNA (dsDNA), double-stranded RNA (dsRNA) and tRNA.
Found in a multi-helicase-TICAM1 complex at least composed of DHX36, DDX1, DDX21 and TICAM1; this complex exists in resting cells with or without dsRNA poly(I:C) ligand stimulation (By similarity). Interacts (via C-terminus) with TICAM1 (via TIR domain) (By similarity). Interacts (via C-terminus) with DDX21; this interaction serves as bridges to TICAM1 (By similarity). Interacts with TERT; this interaction is dependent on the ability of DHX36 to bind to the G-quadruplex RNA (G4-RNA) structure present in the telomerase RNA template component (TERC) (PubMed:21846770). Interacts with DKC1; this interaction is dependent on the ability of DHX36 to bind to the G4-RNA structure present in TERC (PubMed:21846770). Interacts with PARN; this interaction stimulates PARN to enhance uPA mRNA decay (PubMed:14731398). Interacts with EXOSC3; this interaction occurs in a RNase-insensitive manner (PubMed:14731398). Interacts with EXOSC10; this interaction occurs in a RNase-insensitive manner (PubMed:14731398). Interacts with ILF3; this interaction occurs in a RNA-dependent manner (PubMed:14731398). Interacts with ELAVL1; this interaction occurs in an RNA-dependent manner (PubMed:14731398, PubMed:26489465). Interacts with DDX5; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts with DDX17; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts with HDAC1; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts with HDAC3; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts with HDAC4 (By similarity). Interacts with AGO1 (PubMed:17932509). Interacts with AGO2 (PubMed:17932509). Interacts with ERCC6 (PubMed:26030138).
Multifunctional ATP-dependent helicase that unwinds G-quadruplex (G4) structures (PubMed:16150737, PubMed:18854321, PubMed:20472641, PubMed:21586581). Plays a role in many biological processes such as genomic integrity, gene expression regulations and as a sensor to initiate antiviral responses (PubMed:14731398, PubMed:18279852, PubMed:21993297, PubMed:22238380, PubMed:25579584). G4 structures correspond to helical structures containing guanine tetrads (By similarity). Binds with high affinity to and unwinds G4 structures that are formed in nucleic acids (G4-ADN and G4-RNA) (PubMed:16150737, PubMed:18842585, PubMed:20472641, PubMed:21586581, PubMed:24369427, PubMed:26195789). Plays a role in genomic integrity (PubMed:22238380). Converts the G4-RNA structure present in telomerase RNA template component (TREC) into a double-stranded RNA to promote P1 helix formation that acts as a template boundary ensuring accurate reverse transcription (PubMed:20472641, PubMed:21149580, PubMed:21846770, PubMed:22238380, PubMed:24151078, PubMed:25579584). Plays a role in transcriptional regulation (PubMed:21586581, PubMed:21993297). Resolves G4-DNA structures in promoters of genes, such as YY1, KIT/c-kit and ALPL and positively regulates their expression (PubMed:21993297). Plays a role in post-transcriptional regulation (PubMed:27940037). Unwinds a G4-RNA structure located in the 3'-UTR polyadenylation site of the pre-mRNA TP53 and stimulates TP53 pre-mRNA 3'-end processing in response to ultraviolet (UV)-induced DNA damage (PubMed:27940037). Binds to the precursor-microRNA-134 (pre-miR-134) terminal loop and regulates its transport into the synapto-dendritic compartment (By similarity). Involved in the pre-miR-134-dependent inhibition of target gene expression and the control of dendritic spine size (By similarity). Plays a role in the regulation of cytoplasmic mRNA translation and mRNA stability (PubMed:24369427, PubMed:26489465). Binds to both G4-RNA structures and alternative non-quadruplex-forming sequence within the 3'-UTR of the PITX1 mRNA regulating negatively PITX1 protein expression (PubMed:24369427). Binds to both G4-RNA structure in the 5'-UTR and AU-rich elements (AREs) localized in the 3'-UTR of NKX2-5 mRNA to either stimulate protein translation or induce mRNA decay in an ELAVL1-dependent manner, respectively (PubMed:26489465). Binds also to ARE sequences present in several mRNAs mediating exosome-mediated 3'-5' mRNA degradation (PubMed:14731398, PubMed:18279852). Involved in cytoplasmic urokinase-type plasminogen activator (uPA) mRNA decay (PubMed:14731398). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines via the adapter molecule TICAM1 (By similarity). Required for early embryonic development and hematopoiesis. Involved in the regulation of cardioblast differentiation and proliferation during heart development. Involved in spermatogonia differentiation. May play a role in ossification (By similarity).
The DHX36-specific motif (DSM) form folds into a DNA-binding-induced alpha-helix that together with the oligonucleotide and oligosaccharide-binding-fold-like (OB-fold-like) subdomain, selectively bind to Myc-promoter G4-DNA-containing structure in an ATP-dependent manner. Upon G4-DNA-binding, DHX36 pulls on DSM in the 3'-direction, inducing rearrangement of the RecA-like 1 and 2 and the degenerate-winged-helix (WH) regions; these rearrangements are propbably responsible for the ATP-independent repetitive G4-DNA unfolding activity, one residue at a time. Upon resolving of G4-DNA into separate nucleotide strands, and ATP hydrolysis, the apoprotein of DHX36 seems incompatible with G4-DNA-binding (By similarity). The N-terminus is necessary for its recruitment to cytoplasmic stress granules (SGs) upon arsenite-induced treatment (PubMed:18854321).
Belongs to the MICOS complex subunit Mic10 family.
Component of the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOOL/MIC27, IMMT/MIC60, APOO/MIC23/MIC26 and MICOS13/MIC13. This complex was also known under the names MINOS or MitOS complex. The MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1 and MTX2 (together described as components of the mitochondrial outer membrane sorting assembly machinery (SAM) complex) and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9. The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both membranes termed the mitochondrial intermembrane space bridging (MIB) complex. Interacts with IMMT/MIC60 and MICOS13/MIC13. Interacts with APOO/MIC23/MIC26 and APOOL/MIC27. Interacts with ARMC1 (PubMed:31644573).
In brain, may be required for corpus callosum development.
The disease is caused by variants affecting the gene represented in this entry. A variant resulting in a GUG start codon may be able to produce some protein because of a consensus Kozak sequence, although less efficiently than the wild type. This would explain the phenotypic variability observed.
Ubiquitously expressed, with higher expression in lung and fetal brain.
Component of the CAVIN complex composed of CAVIN1, CAVIN2, CAVIN3 and CAVIN4. Homotrimer (By similarity). Interacts with TTF1 (PubMed:9582279). Interacts with RNA polymerase I. Binds the 3' end of pre-rRNA. Interacts with transcription factor ZNF148 (By similarity). Interacts with LIPE in the adipocyte cytoplasm (PubMed:17026959). Interacts with CAV1 and CAVIN3 (By similarity). Interacts with CAVIN2 (PubMed:19525939, PubMed:24567387). Interacts with CAVIN4 and CAV3 (PubMed:24567387).
Five truncated forms are found in the caveolae. These are thought to be the result of proteolysis and may be phosphorylation-dependent.
Phosphorylated. Present in active and inactive forms. Changes in phosphorylation pattern may alter activity. Phosphorylation at Tyr-156 is essential for its functionin the regulation of ribosomal transcriptional activity.
Plays an important role in caveolae formation and organization. Essential for the formation of caveolae in all tissues (PubMed:18056712, PubMed:18191225, PubMed:19726876). Core component of the CAVIN complex which is essential for recruitment of the complex to the caveolae in presence of calveolin-1 (CAV1). Essential for normal oligomerization of CAV1. Promotes ribosomal transcriptional activity in response to metabolic challenges in the adipocytes and plays an important role in the formation of the ribosomal transcriptional loop. Dissociates transcription complexes paused by DNA-bound TTF1, thereby releasing both RNA polymerase I and pre-RNA from the template (By similarity) (PubMed:18056712, PubMed:18191225, PubMed:19726876). The caveolae biogenesis pathway is required for the secretion of proteins such as GASK1A (By similarity).
The leucine-zipper domain 1 is essential for its localization in the caveolae.
Acts both as a chaperone in the cytosol and as a chromatin regulator in the nucleus. When cytosolic, acts as a molecular chaperone: component of the ribosome-associated complex (RAC), a complex involved in folding or maintaining nascent polypeptides in a folding-competent state. In the RAC complex, stimulates the ATPase activity of the ribosome-associated pool of Hsp70-type chaperones HSPA14 that bind to the nascent polypeptide chain. When nuclear, mediates the switching from polycomb-repressed genes to an active state: specifically recruited at histone H2A ubiquitinated at 'Lys-119' (H2AK119ub), and promotes the displacement of the polycomb PRC1 complex from chromatin, thereby facilitating transcription activation.
Component of ribosome-associated complex (RAC), a heterodimer composed of Hsp70/DnaK-type chaperone HSPA14 and Hsp40/DnaJ-type chaperone DNAJC2 (PubMed:16002468). Interacts (via ZRF1-UBD region) with ID1 (By similarity).
Constitutes a myeloid leukemia-associated antigen and might be a target for leukemia T-cell therapy.
Expression is repressed by CEBPA. Strongly overexpressed in leukemic cells.
The ZRF1-UBD region specifically recognizes and binds H2AK119ub. The ZRF1-UBD region is also involved in protein-protein interactions with other proteins, suggesting that it may be masked by some regulator, thereby preventing its association with H2AK119ub.
Acetylated in the endoplasmic reticulum at Lys-126, Lys-275, Lys-279, Lys-285, Lys-299, Lys-300 and Lys-307. Acetylation by NAT8 and NAT8B is transient and deacetylation probably occurs in the Golgi. Acetylation regulates the maturation, the transport to the plasma membrane, the stability and the expression of the protein.
DXXLL motif is required for a proper endocytosis and retrograde transport to the trans-Golgi network, as well as for regulation of lysosomal degradation.
Expressed at high levels in the brain and pancreas. In the brain, expression is highest in the substantia nigra, locus coruleus and medulla oblongata.
Monomer. Interacts (via DXXLL motif) with GGA1, GGA2 and GGA3 (via their VHS domain); the interaction highly increases when BACE1 is phosphorylated at Ser-498 (PubMed:14567678, PubMed:15886016). Interacts with RTN1; RTN2; RTN3 and RTN4; the interaction leads to inhibition of amyloid precursor protein processing (PubMed:15286784, PubMed:16965550, PubMed:16979658). Interacts with SNX6 (PubMed:20354142). Interacts with PCSK9 (PubMed:18660751). Interacts with NAT8 and NAT8B (PubMed:19011241). Interacts with BIN1 (PubMed:27179792). Interacts (via extracellular domain) with ADAM10 (via extracellular domain) (By similarity). Interacts with SORL1; this interaction may affect binding with APP and hence reduce APP cleavage (PubMed:16407538). Interacts with NRDC AND NRG1 (By similarity).
N-Glycosylated (PubMed:11083922, PubMed:17425515). Addition of a bisecting N-acetylglucosamine by MGAT3 blocks lysosomal targeting, further degradation and is required for maintaining stability under stress conditions (By similarity).
Palmitoylation mediates lipid raft localization.
Phosphorylation at Ser-498 is required for interaction with GGA1 and retrograded transport from endosomal compartments to the trans-Golgi network. Non-phosphorylated BACE1 enters a direct recycling route to the cell surface.
Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase (PubMed:10656250, PubMed:10677483, PubMed:20354142). Cleaves CHL1 (By similarity).
The transmembrane domain is necessary for its activity. It determines its late Golgi localization and access to its substrate, APP.
Ubiquitinated at Lys-501, ubiquitination leads to lysosomal degradation (PubMed:27302062, PubMed:16033761, PubMed:20484053, PubMed:23109336). Monoubiquitinated and 'Lys-63'-linked polyubitinated (PubMed:20484053). Deubiquitnated by USP8; inhibits lysosomal degradation (PubMed:27302062).
Up-regulated by the Ca(2+)-regulated transcription factor NFATC4.
Core histones chaperone involved in chromatin reprogramming, specially during fertilization and early embryonic development. Probably involved in sperm DNA decondensation during fertilization.
Homopentamer, when bound to H2A-H2B dimers only. Homodecamer of two stacked pentamers, when bound to H2A-H2B dimers and H3-H4 tetramers simultaneously.
The acidic tract A2 mediates histone binding.
Belongs to the DNA polymerase type-X family.
DPOLM has a reduced ability to distinguish dNTP and rNTP as substrates, and elongates them on DNA primer strand with a similar efficiency. It is able to polymerize nucleotides on RNA primer strands.
Expressed in a number of tissues. Abundant in thymus.
Gap-filling polymerase involved in repair of DNA double-strand breaks by non-homologous end joining (NHEJ). Participates in immunoglobulin (Ig) light chain gene rearrangement in V(D)J recombination.
Binds medium- and long-chain acyl-CoA esters and may function as an intracellular carrier of acyl-CoA esters.
Putative receptor for purines coupled to G-proteins.
Belongs to the glycosyltransferase group 1 family. Glycosyltransferase 4 subfamily.
Ubiquitous. Expressed at high levels in the lung, brain, spleen, testis, placenta. ovary, pancreas, spleen and peripheral blood leukocytes. Expressed at low level in the colon, small intestine, kidney, skeletal muscle and thymus. Expressed at high level in colon adenocarcinoma.
Belongs to the ligand-gated ion channel (TC 1.A.9) family.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRB3 sub-subfamily.
GABRB3 variants may be associated with insomnia, a condition of inability to initiate or maintain sleep [MIM:137192].
Heteropentamer, formed by a combination of alpha, beta, gamma, delta and rho chains (PubMed:22243422, PubMed:18281286, PubMed:18514161, PubMed:24909990). Can form functional homopentamers (in vitro) (PubMed:22303015). Interacts with UBQLN1 (By similarity). May interact with KIF21B (By similarity). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3 (By similarity). Interacts with LHFPL4 (By similarity). Interacts with GIT1; this interaction is required for synaptic GABRB3 surface stability and inhibitory synapse strength (By similarity).
Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:18514161, PubMed:22303015, PubMed:26950270, PubMed:22243422, PubMed:24909990). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (PubMed:25489750). The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the synaptogenic effect of this subunit is influenced by the type of alpha and beta subunits present in the receptor pentamer (By similarity). The alpha1/beta3/gamma2 receptor exhibits synaptogenic activity (PubMed:25489750). The alpha2/beta3/gamma2 receptor shows very little or no synaptogenic activity (By similarity). Functions also as histamine receptor and mediates cellular responses to histamine (PubMed:18281286). Plays an important role in somatosensation and in the production of antinociception (By similarity).
A chromosomal aberration involving TNFRSF17 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(4;16)(q26;p13) with IL2.
Associates with TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6.
Expressed in mature B-cells, but not in T-cells or monocytes.
Receptor for TNFSF13B/BLyS/BAFF and TNFSF13/APRIL. Promotes B-cell survival and plays a role in the regulation of humoral immunity. Activates NF-kappa-B and JNK.
Belongs to the SLC35F solute transporter family.
Cell adhesion protein that promotes adhesion and outgrowth of hippocampal embryonic neurons. Binds directly to bacteria and their components and functions as an opsonin for macrophage phagocytosis of bacteria. Essential in the initiation of the innate immune response and represents a unique pattern-recognition molecule in the ECM for microbial pathogens (By similarity). Binds bacterial lipopolysaccharide (LPS).
Expressed in normal lung tissue but not in lung carcinoma cell lines.
Protein-disulfide reductase of the endoplasmic reticulum that promotes disulfide bond formation in client proteins through its thiol-disulfide oxidase activity.
Expressed in most tissues. High levels were found in liver, kidney, heart, ovary, spleen, testes, skeletal muscle and peripheral blood leukocytes. Expression was absent or low in colon and small intestine. Expression is relatively high in the tumor cell lines chronic myologenous leukemia K-562 and the colorectal adenocarcinoma SW480. Expression is moderate in the cervical carcinoma HeLa, the Burkitt's lymphoma Raji, the lung carcinoma A-549, and the melanoma G-361. In contrast, two leukemia cell lines, HL-60 (promyelocytic leukemia) and MOLT-4 (lymphoblastic leukemia), show relatively low levels.
Interactions with CASP8 and CASP10 are mediated by the DED domain.
Interacts with CASP8, CASP10 and GTF3C3. Homodimerizes and heterodimerizes with DEDD.
May play a critical role in death receptor-induced apoptosis and may target CASP8 and CASP10 to the nucleus. May regulate degradation of intermediate filaments during apoptosis. May play a role in the general transcription machinery in the nucleus and might be an important regulator of the activity of GTF3C3.
ADP-ribosyltransferase that mediates mono-ADP-ribosylation of glutamate residues on target proteins (PubMed:16061477, PubMed:27796300, PubMed:18851833, PubMed:25043379). In contrast to PARP1 and PARP2, it is not able to mediate poly-ADP-ribosylation (PubMed:25043379). Has been shown to catalyze the mono-ADP-ribosylation of STAT1 at 'Glu-657' and 'Glu-705', thus decreasing STAT1 phosphorylation which negatively regulates pro-inflammatory cytokine production in macrophages in response to IFNG stimulation (PubMed:27796300). However, the role of ADP-ribosylation in the prevention of STAT1 phosphorylation has been called into question and it has been suggested that the inhibition of phosphorylation may be the result of sumoylation of STAT1 'Lys-703' (PubMed:29858569). Mono-ADP-ribosylates STAT6; enhancing STAT6-dependent transcription (PubMed:27796300). In macrophages, positively regulates MRC1 expression in response to IL4 stimulation by promoting STAT6 phosphorylation (PubMed:27796300). Mono-ADP-ribosylates PARP9 (PubMed:27796300).
Interacts with STAT6 (By similarity). Interacts with PARP10 (PubMed:23473667). Interacts with PARP9 in IFNG-stimulated macrophages; the interaction prevents PARP14-mediated STAT1 and STAT6 ADP-riboslylation (PubMed:27796300).
The role of PARP14-mediated ADP-ribosylation of STAT1 in the prevention of STAT1 phosphorylation has been called into question and it has been suggested that the inhibition of phosphorylation may be the result of sumoylation of STAT1 'Lys-703'.
Up-regulated by IFNG in macrophages. Down-regulated by IL4 in macrophages.
A report observed N-glycosylation at Asn-493 (PubMed:19139490). However, as the protein is predicted to act as a DNA-binding transcription activator, additional evidence is required to confirm this result.
May act as transcription activator that binds DNA elements with the sequence 5'-CCCTATCGATCGATCTCTACCT-3'. May play a role in spermatogenesis (By similarity).
(Microbial infection) Interacts (via FHA domain) with phosphorylated human herpesvirus 1 ICP0 protein; leading to RNF8 degradation by the proteasome.
According to a well-established model, RNF8 initiate H2A 'Lys-63'-linked ubiquitination leading to recruitment of RNF168 to amplify H2A 'Lys-63'-linked ubiquitination (PubMed:19203578, PubMed:19203579). However, other data suggest that RNF168 is the priming ubiquitin ligase by mediating monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub respectively) (PubMed:22980979). These data suggest that RNF168 might be recruited to DSBs sites in a RNF8-dependent manner by binding to non-histone proteins ubiquitinated via 'Lys-63'-linked and initiates monoubiquitination of H2A, which is then amplified by RNF8 (PubMed:22980979). Additional evidence is however required to confirm these data.
Autoubiquitinated through 'Lys-48' and 'Lys-63' of ubiquitin. 'Lys-63' polyubiquitination is mediated by UBE2N. 'Lys-29'-type polyubiquitination is also observed, but it doesn't require its own functional RING-type zinc finger.
E3 ubiquitin-protein ligase that plays a key role in DNA damage signaling via 2 distinct roles: by mediating the 'Lys-63'-linked ubiquitination of histones H2A and H2AX and promoting the recruitment of DNA repair proteins at double-strand breaks (DSBs) sites, and by catalyzing 'Lys-48'-linked ubiquitination to remove target proteins from DNA damage sites. Following DNA DSBs, it is recruited to the sites of damage by ATM-phosphorylated MDC1 and catalyzes the 'Lys-63'-linked ubiquitination of histones H2A and H2AX, thereby promoting the formation of TP53BP1 and BRCA1 ionizing radiation-induced foci (IRIF). Also controls the recruitment of UIMC1-BRCC3 (RAP80-BRCC36) and PAXIP1/PTIP to DNA damage sites. Also recruited at DNA interstrand cross-links (ICLs) sites and catalyzes 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Promotes the formation of 'Lys-63'-linked polyubiquitin chains via interactions with the specific ubiquitin-conjugating UBE2N/UBC13 and ubiquitinates non-histone substrates such as PCNA. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation. Also catalyzes the formation of 'Lys-48'-linked polyubiquitin chains via interaction with the ubiquitin-conjugating UBE2L6/UBCH8, leading to degradation of substrate proteins such as CHEK2, JMJD2A/KDM4A and KU80/XRCC5: it is still unclear how the preference toward 'Lys-48'- versus 'Lys-63'-linked ubiquitination is regulated but it could be due to RNF8 ability to interact with specific E2 specific ligases. For instance, interaction with phosphorylated HERC2 promotes the association between RNF8 and UBE2N/UBC13 and favors the specific formation of 'Lys-63'-linked ubiquitin chains. Promotes non-homologous end joining (NHEJ) by promoting the 'Lys-48'-linked ubiquitination and degradation the of KU80/XRCC5. Following DNA damage, mediates the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF168, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites (PubMed:11322894, PubMed:14981089, PubMed:17724460, PubMed:18001824, PubMed:18001825, PubMed:18006705, PubMed:18077395, PubMed:18337245, PubMed:18948756, PubMed:19015238, PubMed:19124460, PubMed:19202061, PubMed:19203578, PubMed:19203579, PubMed:20550933, PubMed:21558560, PubMed:21857671, PubMed:21911360, PubMed:22266820, PubMed:22373579, PubMed:22531782, PubMed:22705371, PubMed:22865450, PubMed:22980979). Following DNA damage, mediates the ubiquitination and degradation of POLD4/p12, a subunit of DNA polymerase delta. In the absence of POLD4, DNA polymerase delta complex exhibits higher proofreading activity (PubMed:23233665). In addition to its function in damage signaling, also plays a role in higher-order chromatin structure by mediating extensive chromatin decondensation. Involved in the activation of ATM by promoting histone H2B ubiquitination, which indirectly triggers histone H4 'Lys-16' acetylation (H4K16ac), establishing a chromatin environment that promotes efficient activation of ATM kinase. Required in the testis, where it plays a role in the replacement of histones during spermatogenesis. At uncapped telomeres, promotes the joining of deprotected chromosome ends by inducing H2A ubiquitination and TP53BP1 recruitment, suggesting that it may enhance cancer development by aggravating telomere-induced genome instability in case of telomeric crisis. Promotes the assembly of RAD51 at DNA DSBs in the absence of BRCA1 and TP53BP1 Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. May be required for proper exit from mitosis after spindle checkpoint activation and may regulate cytokinesis. May play a role in the regulation of RXRA-mediated transcriptional activity. Not involved in RXRA ubiquitination by UBE2E2 (PubMed:11322894, PubMed:14981089, PubMed:17724460, PubMed:18001824, PubMed:18001825, PubMed:18006705, PubMed:18077395, PubMed:18337245, PubMed:18948756, PubMed:19015238, PubMed:19124460, PubMed:19202061, PubMed:19203578, PubMed:19203579, PubMed:20550933, PubMed:21558560, PubMed:21857671, PubMed:21911360, PubMed:22266820, PubMed:22373579, PubMed:22531782, PubMed:22705371, PubMed:22865450, PubMed:22980979).
Homodimer. Forms a E2-E3 ubiquitin ligase complex composed of the RNF8 homodimer and a E2 heterodimer of UBE2N and UBE2V2. Interacts with class III E2s, including UBE2E1, UBE2E2, and UBE2E3 and with UBE2N. Interacts with RXRA. Interacts (via FHA domain) with ATM-phosphorylated MDC1. Interacts (via FHA domain) with 'Thr-4827' phosphorylated HERC2 (via C-terminus). Interacts with PIWIL1; leading to sequester RNF8 in the cytoplasm (By similarity). Interacts with WRAP53/TCAB1 (PubMed:25512560).
Low levels at the G1-S boundary increase in intensity during S phase and until the end of the G2 phase. Abruptly decreases in late mitosis (at protein level). Barely detectable in anaphase.
The FHA domain specifically recognizes and binds ATM-phosphorylated MDC1 and 'Thr-4827' phosphorylated HERC2 (PubMed:18001824). This domain is required for proper recruitment to DNA damage sites after UV irradiation, ionizing radiation, or treatment with an alkylating agent (PubMed:23233665).
Ubiquitous. In fetal tissues, highest expression in brain, thymus and liver. In adult tissues, highest levels in brain and testis, lowest levels in peripheral blood cells.
Expressed in liver. Expression is either down-regulated or lost in hepatocellular carcinomas (HCC).
Product of a dubious CDS prediction. Encoded by the 3'-UTR of HEPACAM.
Belongs to the glycosyltransferase 14 family.
Branching enzyme that converts linear into branched poly-N-acetyllactosaminoglycans. Introduces the blood group I antigen during embryonic development. It is closely associated with the development and maturation of erythroid cells.
Determines the expression of the blood group I antigen in erythrocytes.
Expression increases dramatically during development and oncogenesis.
GCNT2 is involved in determining the blood group I system (Ii) [MIM:110800]. The i (fetal) and I (adult) antigens are determined by linear and branched poly-N-acetyllactosaminoglycans, respectively. A replacement during development of i by I is dependent on the appearance of a beta-1,6-N-acetylglucosaminyltransferase, the I-branching enzyme. The expression of the blood group I antigen in erythrocytes is determined by isoform C of GCNT2.
During intrathymic development, transcript levels strongly increase from pro-DN1 thymocytes to DN3a cells, in which they peak, and drop immediately after beta-selection in their DN3b successors. The subcellular location of the protein also varies, from punctate cytoplasmic structures in DN1 and DN2 cells to large crescent-shaped membrane structures in DN3 cells, which preferentially localize in cell-to-cell contact zones.
Membrane-associated form that antagonizes canonical Wnt signaling by triggering lysosome-dependent degradation of Wnt-activated LRP6. Regulates thymocyte proliferation.
Component of the outer core of AMPAR complex. AMPAR complex consists of an inner core made of 4 pore-forming GluA/GRIA proteins (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged in a twofold symmetry. One of the two pairs of distinct binding sites is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR complex is complemented by outer core constituents binding directly to the GluA/GRIA proteins at sites distinct from the interaction sites of the inner core constituents. Outer core constituents include at least PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the inner and outer core serve as a platform for other, more peripherally associated AMPAR constituents. Alone or in combination, these auxiliary subunits control the gating and pharmacology of the AMPAR complex and profoundly impact their biogenesis and protein processing (By similarity).
Expressed in adult and fetal brain. Very weak expression in medulla, spinal cord and in adult ovary.
Important modulator of glutamate signaling pathway.
Named FRRS1L by HGNC because it shares limited sequence similarity with FRRS1. However, sequence similarities lie outside of the reductase region, suggesting it has no oxidoreductase activity.
Catalyzes the ferrous insertion into protoporphyrin IX.
Homodimer (PubMed:17261801, PubMed:30765471). Interacts with PGRMC1; the interaction results in decreased FECH activity (PubMed:27599036). Interacts with ABCB10 and SLC25A37; this interaction forms an oligomeric complex (By similarity). Forms a complex with ABCB7 and ABCB10, where a dimeric FECH bridges ABCB7 and ABCB10 homodimers; this complex may be required for cellular iron homeostasis, mitochondrial function and heme biosynthesis (PubMed:30765471). Interacts with ABCB7 and ABCB10 (PubMed:30765471).
Inhibited by nitric oxide (NO). The 2Fe-2S cluster could act as a NO sensor.
Belongs to the class V-like SAM-binding methyltransferase superfamily.
Expressed in embryonic stem cells. Tends to be overexpressed in breast cancer (at protein level).
The first 5 zinc fingers, but not the last one, are required for DNA-binding and transcriptional activity.
Transcription factor that has both positive and negative roles on transcription. Required for the maintenance of embryonic stem cell identity and the reacquisition of pluripotency in somatic cells. May play an essential role in germ cell development at 2 levels: the reacquisition of potential pluripotency, including SOX2 up-regulation, and successful epigenetic reprogramming, characterized by EHMT1 repression. Its association with CBFA2T2 is required for the functions in pluripotency and germ cell formation (By similarity). Directly up-regulates the expression of pluripotency gene POU5F1 through its proximal enhancer. Binds to the DNA consensus sequence 5'-GGTC[TC]CTAA-3'.
By TNF, IL1/interleukin-1 and bacterial lipopolysaccharides (LPS).
Expressed at high levels in peripheral blood leukocytes and lung, at moderate levels in liver, placenta, and at low levels in spleen, kidney, skeletal muscle and heart.
Interacts with NFKB1/p50 (PubMed:16513645). Interacts with RELA (PubMed:16513645). Interacts with AKIRIN2 (By similarity).
Involved in regulation of NF-kappa-B transcription factor complexes (PubMed:16513645, PubMed:16622025). Inhibits NF-kappa-B activity without affecting its nuclear translocation upon stimulation (PubMed:16513645). Inhibits DNA-binding of RELA and NFKB1/p50, and of the NF-kappa-B p65-p50 heterodimer and the NF-kappa-B p50-p50 homodimer (PubMed:16513645). Seems also to activate NF-kappa-B-mediated transcription (PubMed:16622025). In vitro, upon association with NFKB1/p50 has transcriptional activation activity and, together with NFKB1/p50 and RELA, is recruited to LCN2 promoters (PubMed:16622025). Promotes transcription of LCN2 and DEFB4 (PubMed:16622025). Is recruited to IL-6 promoters and activates IL-6 but decreases TNF-alpha production in response to LPS (By similarity). Seems to be involved in the induction of inflammatory genes activated through TLR/IL-1 receptor signaling (By similarity). Involved in the induction of T helper 17 cells (Th17) differentiation upon recognition of antigen by T cell antigen receptor (TCR) (By similarity).
Interacts (via C-terminus) with both free and 20S proteasome-bound forms of the proteasome activator complex subunit PSME3; the interaction is direct.
Phosphorylation by CK2 stabilizes the interaction with PSME3.
Promotes the association of the proteasome activator complex subunit PSME3 with the 20S proteasome and regulates its activity. Inhibits PSME3-mediated degradation of some proteasome substrates, probably by affecting their diffusion rate into the catalytic chamber of the proteasome. Also inhibits the interaction of PSME3 with COIL, inhibits accumulation of PSME3 in Cajal bodies and positively regulates the number of Cajal bodies in the nucleus.
A proteolytic cleavage generates a new N-terminus that functions as a tethered ligand (PubMed:10831593, PubMed:19864598, PubMed:9020112, PubMed:10805786, PubMed:16478888). Activating serine proteases include trypsin, mast cell tryptase, coagulation factors VII and Xa, myeloblastin/PRTN3 and membrane-type serine protease 1/ST14 (PubMed:10831593, PubMed:19864598, PubMed:9020112, PubMed:10805786, PubMed:16478888, PubMed:23202369). Subsequent cleavage by serine proteases, including neutrophil elastase and cathepsin G, leads to receptor deactivation (PubMed:12594060). At least in part, implicated proteases are also shown to activate the receptor; the glycosylation status of the receptor is thought to contribute to the difference (PubMed:12171601). In addition to conventional trypsin-like proteases activated by other proteases and glycosidases derived from bacteria, fungi and insects (PubMed:11447194, PubMed:11441110, PubMed:17404307, PubMed:18474671, PubMed:19864598). Activated by serine protease allergens such as dust mite Der p3 and Der p9 and mold Pen c13 (PubMed:11441110, PubMed:17404307). Activated by P.gingivalis arginine-specific (trypsin-like) cysteine proteinases called gingipains (PubMed:11447194). Activated by S.griseus exogenous chitinase (PubMed:18474671). Activated by A.alternata aspartate protease; the cleavage generates non-conventional processed forms (PubMed:19864598).
Activated upon interaction by mucunain, a cowhage (Mucuna pruriens) plant cysteine proteinase.
Interacts with TLR4, COPS5 and TMED2. Interacts with GNAQ, GNA11, GNA12, GNA13 and GNA14 (By similarity).
Monoubiquitinated by CBL at the plasma membrane and in early endosomes; not required for receptor endocytosis but for translocation to late endosomes or lysosomes. Deubiquitination involves STAMBP and USP8; required for lysosomal trafficking and receptor degradation.
Multiple phosphorylated on serine and threonine residues in the cytoplasmic region upon receptor activation; required for receptor desensitization and recruitment of beta-arrestin.
Receptor for trypsin and trypsin-like enzymes coupled to G proteins (PubMed:28445455). Its function is mediated through the activation of several signaling pathways including phospholipase C (PLC), intracellular calcium, mitogen-activated protein kinase (MAPK), I-kappaB kinase/NF-kappaB and Rho (PubMed:28445455). Can also be transactivated by cleaved F2R/PAR1. Involved in modulation of inflammatory responses and regulation of innate and adaptive immunity, and acts as a sensor for proteolytic enzymes generated during infection. Generally is promoting inflammation. Can signal synergistically with TLR4 and probably TLR2 in inflammatory responses and modulates TLR3 signaling. Has a protective role in establishing the endothelial barrier; the activity involves coagulation factor X. Regulates endothelial cell barrier integrity during neutrophil extravasation, probably following proteolytic cleavage by PRTN3 (PubMed:23202369). Proposed to have a bronchoprotective role in airway epithelium, but also shown to compromise the airway epithelial barrier by interrupting E-cadherin adhesion (PubMed:10086357). Involved in the regulation of vascular tone; activation results in hypotension presumably mediated by vasodilation. Associates with a subset of G proteins alpha subunits such as GNAQ, GNA11, GNA14, GNA12 and GNA13, but probably not with G(o)-alpha, G(i) subunit alpha-1 and G(i) subunit alpha-2. However, according to PubMed:21627585 can signal through G(i) subunit alpha. Believed to be a class B receptor which internalizes as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptor, for extended periods of time. Mediates inhibition of TNF-alpha stimulated JNK phosphorylation via coupling to GNAQ and GNA11; the function involves dissociation of RIPK1 and TRADD from TNFR1. Mediates phosphorylation of nuclear factor NF-kappa-B RELA subunit at 'Ser-536'; the function involves IKBKB and is predominantly independent of G proteins. Involved in cellular migration. Involved in cytoskeletal rearrangement and chemotaxis through beta-arrestin-promoted scaffolds; the function is independent of GNAQ and GNA11 and involves promotion of cofilin dephosphorylation and actin filament severing. Induces redistribution of COPS5 from the plasma membrane to the cytosol and activation of the JNK cascade is mediated by COPS5. Involved in the recruitment of leukocytes to the sites of inflammation and is the major PAR receptor capable of modulating eosinophil function such as pro-inflammatory cytokine secretion, superoxide production and degranulation. During inflammation promotes dendritic cell maturation, trafficking to the lymph nodes and subsequent T-cell activation. Involved in antimicrobial response of innate immune cells; activation enhances phagocytosis of Gram-positive and killing of Gram-negative bacteria. Acts synergistically with interferon-gamma in enhancing antiviral responses. Implicated in a number of acute and chronic inflammatory diseases such as of the joints, lungs, brain, gastrointestinal tract, periodontium, skin, and vascular systems, and in autoimmune disorders.
Synthetic PAR agonist peptides (APs) that mimic the first six amino acids of the newly formed N-terminus activate the native, uncleaved receptor nonenzymatically by binding directly to the corresponding second extracellular loop to mediate signaling.
Widely expressed in tissues with especially high levels in pancreas, liver, kidney, small intestine, and colon (PubMed:7556175, PubMed:8615752). Moderate expression is detected in many organs, but none in brain or skeletal muscle (PubMed:7556175, PubMed:8615752). Expressed in endothelial cells (PubMed:23202369).
Accumulates in brains affected by autosomal-recessive juvenile parkinsonism, idiopathic Parkinson disease and diffuse Lewy body disease.
Part of the multisynthetase complex (MSC), a multisubunit complex that groups tRNA ligases for Arg (RARS1), Asp (DARS1), Gln (QARS1), Ile (IARS1), Leu (LARS1), Lys (KARS1), Met (MARS1) the bifunctional ligase for Glu and Pro (EPRS1) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18 (PubMed:24312579, PubMed:19131329, PubMed:19289464). Interacts (via N-terminus) with KARS1 (PubMed:9878398, PubMed:15220430, PubMed:18029264, PubMed:23159739, PubMed:26074468). Interacts with EPRS1 (PubMed:26472928). Forms a linear complex that contains MARS1, EEF1E1, EPRS1 and AIMP2 that is at the core of the multisubunit complex (PubMed:26472928). Binds FUBP1 (via C-terminus). Interacts in both its unphosphorylated and phosphorylated forms with p53/TP53 (via N-terminus) in the nucleus following UV irradiation. Interacts (via N-terminus) with PRKN/parkin (via first RING-type domain) (PubMed:16135753). Interacts with TARS3 (PubMed:24312579).
Phosphorylated on serine residues in response to UV irradiation.
Required for assembly and stability of the aminoacyl-tRNA synthase complex (PubMed:19131329). Mediates ubiquitination and degradation of FUBP1, a transcriptional activator of MYC, leading to MYC down-regulation which is required for aveolar type II cell differentiation. Blocks MDM2-mediated ubiquitination and degradation of p53/TP53. Functions as a proapoptotic factor.
Ubiquitinated by PRKN, leading to its degradation by the proteasome. Mutant PRKN fails to ubiquitinate AIMP2 efficiently, allowing its accumulation which may contribute to neurodegeneration associated with Parkinson disease.
Belongs to the acetyltransferase family.
Enzyme which catalyzes the acetylation of polyamines (PubMed:15283699, PubMed:16455797, PubMed:17516632). Substrate specificity: norspermidine = spermidine >> spermine > N(1)-acetylspermine (PubMed:17516632). This highly regulated enzyme allows a fine attenuation of the intracellular concentration of polyamines (PubMed:16455797). Also involved in the regulation of polyamine transport out of cells (PubMed:16455797). Also acts on 1,3-diaminopropane and 1,5-diaminopentane (PubMed:16455797, PubMed:17516632).
Overexpression of SAT1 and the consequent putrescine accumulation might play a role in the pathogenesis of keratosis follicularis spinulosa decalvans.
Testis specific. Expressed in cancer cell lines.
Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.
Belongs to the complex I NDUFA11 subunit family.
Complex I is composed of 45 different subunits.
May be involved in the initiation of hepatocyte growth.
Adaptor protein complex 2 (AP-2) is a heterotetramer composed of two large adaptins (alpha-type subunit AP2A1 or AP2A2 and beta-type subunit AP2B1), a medium adaptin (mu-type subunit AP2M1) and a small adaptin (sigma-type subunit AP2S1). Binds EPN1, EPS15, AMPH, SNAP91 and BIN1 (By similarity). Interacts with HIP1 (PubMed:11532990). Interacts with DGKD (By similarity). Interacts with DENND1A, DENND1B and DENND1C (By similarity). Interacts with FCHO1 and DAB2 (PubMed:22484487). Interacts with ATAT1; this interaction is required for efficient alpha-tubulin acetylation by ATAT1 (PubMed:24097348). Interacts with KIAA1107 (PubMed:29262337). Together with AP2B1 and AP2M1, it interacts with ADAM10; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons (PubMed:23676497). Interacts with CLN3 (via dileucine motif) (PubMed:15598649). Interacts with ABCB11; this interaction regulates cell membrane expression of ABCB11 through its internalization in a clathrin-dependent manner and its subsequent degradation (PubMed:22262466).
Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. During long-term potentiation in hippocampal neurons, AP-2 is responsible for the endocytosis of ADAM10 (PubMed:23676497). The AP-2 alpha subunit binds polyphosphoinositide-containing lipids, positioning AP-2 on the membrane. The AP-2 alpha subunit acts via its C-terminal appendage domain as a scaffolding platform for endocytic accessory proteins. The AP-2 alpha and AP-2 sigma subunits are thought to contribute to the recognition of the [ED]-X-X-X-L-[LI] motif (By similarity).
Expressed in the brain (at protein level).
Mediates the import of long-chain fatty acids (LCFA) into the cell by facilitating their transport at the plasma membrane (PubMed:12556534). Also functions as an acyl-CoA ligase catalyzing the ATP-dependent formation of fatty acyl-CoA using LCFA and very-long-chain fatty acids (VLCFA) as substrates (By similarity). Plays a pivotal role in regulating available LCFA substrates from exogenous sources in tissues undergoing high levels of beta-oxidation such as the heart (PubMed:12556534).
Strongly expressed in heart and localizes to cardiac myocytes (PubMed:12556534). Expressed at moderate levels in placenta, testis, and adrenal glands. Expressed at very low levels in kidney, bladder and uterus.
Despite its name, does not contain a real coiled coil domain region: predicted coiled coil regions are the result of the Glu-rich region.
Expressed at higher levels in fetal brain and skeletal muscle. Lower expression is detected in fetal kidney, liver, spleen, thymus, heart and lung.
Belongs to the major facilitator superfamily. Organophosphate:Pi antiporter (OPA) (TC 2.A.1.4) family.
Expressed in numerous tissues, with highest expression in pancreas, kidney, bone marrow, spleen, liver, small intestine, as well as in fetal brain, liver and spleen.
Inhibited by vanadate but not by chlorogenic acid.
Inorganic phosphate and glucose-6-phosphate antiporter. May transport cytoplasmic glucose-6-phosphate into the lumen of the endoplasmic reticulum and translocate inorganic phosphate into the opposite direction. Independent of a lumenal glucose-6-phosphatase. May not play a role in homeostatic regulation of blood glucose levels.
Expressed in endothelial cells, and in certain larger vessels, in mural cells. In the brain, possibly expressed in microglia. Expressed in peripheral blood mononuclear cells (at protein level).
Alpha-2-HS glycoprotein derives from this precursor, when the connecting peptide is cleaved off. The two chains A and B are held together by a single disulfide bond.
O- and N-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. N-glycan at Asn-156: Hex5HexNAc4; N-glycan heterogeneity at Asn-176: Hex5HexNAc4 (major) and Hex6HexNAc5 (minor).
Phosphorylated by FAM20C in the extracellular medium.
Promotes endocytosis, possesses opsonic properties and influences the mineral phase of bone. Shows affinity for calcium and barium ions.
Synthesized in liver and selectively concentrated in bone matrix. Secreted in plasma. It is also found in dentin in much higher quantities than other plasma proteins.
There are two common alleles, AHSG*1 and AHSG*2. AHSG*1 has Thr-248/Thr-256; AHSG*2 has Met-248/Ser-256.
It is uncertain whether Met-1 or Met-20 is the initiator.
Transcriptional activator. Activates the transcription of a number of liver genes such as HNF3B.
Involved in pre-mRNA splicing as component of the activated spliceosome. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
Part of the activated spliceosome B/catalytic step 1 spliceosome, one of the forms of the spliceosome which has a well-formed active site but still cannot catalyze the branching reaction and is composed of at least 52 proteins, the U2, U5 and U6 snRNAs and the pre-mRNA. Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932).
E3 ubiquitin-protein ligase that acts in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, which targets misfolded proteins that accumulate in the endoplasmic reticulum (ER) for ubiquitination and subsequent proteasome-mediated degradation. Protects cells from ER stress-induced apoptosis.
Expressed at highest levels in testis, lower levels in heart, liver, lung, and kidney (PubMed:17074343). Not detected in brain, ovary, and uterus (PubMed:17074343). Down-regulated in testis from patients with maturation arrest (MA) or Sertoli cell-only syndrome (SCOS) (PubMed:17074343). Ubiquitously expressed with high expression in testis (PubMed:27485036).
Up-regulated by endoplasmic reticulum (ER) stress triggered by thapsigargin or tunicamycin.
Belongs to the shaker potassium channel beta subunit family.
Cytoplasmic potassium channel subunit that modulates the characteristics of the channel-forming alpha-subunits (PubMed:7649300, PubMed:11825900). Contributes to the regulation of nerve signaling, and prevents neuronal hyperexcitability (By similarity). Promotes expression of the pore-forming alpha subunits at the cell membrane, and thereby increases channel activity (By similarity). Promotes potassium channel closure via a mechanism that does not involve physical obstruction of the channel pore (PubMed:7649300, PubMed:11825900). Promotes KCNA4 channel closure (PubMed:7649300, PubMed:11825900). Modulates the functional properties of KCNA5 (By similarity). Enhances KCNB2 channel activity (By similarity). Binds NADPH and has NADPH-dependent aldoketoreductase activity (By similarity). Has broad substrate specificity and can catalyze the reduction of methylglyoxal, 9,10-phenanthrenequinone, prostaglandin J2, 4-nitrobenzaldehyde, 4-nitroacetophenone and 4-oxo-trans-2-nonenal (in vitro) (By similarity).
Detected in myelinated nerve fibers in the spinal cord, in the juxtaparanodal region of the nodes of Ranvier, but also in the paranodal region (PubMed:11086297). Detected in hippocampus (at protein level) (PubMed:21357749). Detected in hippocampus (PubMed:7649300).
Homotetramer (By similarity). Interaction with tetrameric potassium channel alpha subunits gives rise to a heterooctamer (By similarity). Identified in potassium channel complexes containing KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNAB1 and KCNAB2 (By similarity). Interacts with KCNA1 (PubMed:11086297). Interacts with KCNA2 (PubMed:11086297). Interacts with KCNA4 and KCND3 (By similarity). Interacts with KCNA5 (By similarity). Interacts with KCNB2 (By similarity). Interacts (in unphosphorylated form) with MAPRE1 (By similarity). Forms a ternary complex with SQSTM1 and PRKCZ (By similarity).
In contrast to KCNAB1, the shorter N-terminal domain of KCNAB2 cannot mediate closure of delayed rectifier potassium channels by physically obstructing the pore.
Phosphorylated by PRKCZ; may be regulated by incorporation in a complex composed of PRKCZ and SQSTM1.
Interacts with ATP6V1D; may play a role in ciliogenesis.
Probable phosphoinositide-binding protein involved in protein sorting and membrane trafficking in endosomes. Plays a role in cilium biogenesis through regulation of the transport and the localization of proteins to the cilium. Required for the localization to the cilium of V-ATPase subunit ATP6V1D and ATP6V0D1, and RAB8A. Involved in osteoclast differentiation and therefore bone resorption.
In vitro can degrade the fibrinogen alpha chain of as well as pro-urokinase-type plasminogen activator.
Predominantly detected in testis, liver, heart and ovary, as well as in several tumor cell lines.
Catalytically inactive, shows enhanced binding to IGBP1, and does not interact with the scaffolding subunit PPP2R1A.
PP2A consists of a common heterodimeric core enzyme, composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits (PubMed:17055435, PubMed:18394995, PubMed:30595372). Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules (PubMed:18394995, PubMed:30595372). Interacts with NXN; the interaction is direct (By similarity). Interacts with KCTD20 (By similarity). Interacts with BTBD10 (By similarity). Interacts with SGO1 and SGO2 (PubMed:16580887, PubMed:16541025, PubMed:17485487). Interacts with TP53 (PubMed:17245430). Interacts with AXIN1; the interaction dephosphorylates AXIN1 (PubMed:9920888). Interacts with PIM3; this interaction promotes dephosphorylation, ubiquitination and proteasomal degradation of PIM3 (PubMed:12473674). Interacts with RAF1 (PubMed:10801873). Interaction with IGBP1 protects unassembled PPP2CA from degradative ubiquitination (PubMed:9647778, PubMed:19818709, PubMed:20092282). Interacts with GSK3B (via C2 domain) (PubMed:20080667). Interacts with MFHAS1; retains PPP2CA into the cytoplasm and excludes it from the nucleus (PubMed:28609714). Interacts with PABIR1/FAM122A (PubMed:27588481). Interacts with ADCY8; interaction is phosphatase activity-dependent; antagonizes interaction between ADCY8 and calmodulin (PubMed:16258073). Interacts with CRTC3 (when phosphorylated at 'Ser-391') (PubMed:30611118). Interacts with SPRY2; the interaction is inhibited by TESK1 interaction with SPRY2, possibly by vesicular sequestration of SPRY2 (PubMed:17974561). Interacts with TRAF3IP3 (PubMed:30115741). Interacts with AMBRA1 (via PxP motifs); enhancing interaction between PPP2CA and MYC or FOXO3 (PubMed:25438055, PubMed:30513302). Forms a complex with AMBRA1 and BECN1; AMBRA1 and BECN1 components of the complex regulate MYC stability via different pathways (PubMed:25803737).
PP2A is the major phosphatase for microtubule-associated proteins (MAPs) (PubMed:22613722). PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase (PubMed:22613722). Cooperates with SGO2 to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I (By similarity). Can dephosphorylate SV40 large T antigen and p53/TP53 (PubMed:17245430). Activates RAF1 by dephosphorylating it at 'Ser-259' (PubMed:10801873). Mediates dephosphorylation of WEE1, preventing its ubiquitin-mediated proteolysis, increasing WEE1 protein levels, and promoting the G2/M checkpoint (PubMed:33108758). Mediates dephosphorylation of MYC; promoting its ubiquitin-mediated proteolysis: interaction with AMBRA1 enhances interaction between PPP2CA and MYC (PubMed:25438055). Mediates dephosphorylation of FOXO3; promoting its stabilization: interaction with AMBRA1 enhances interaction between PPP2CA and FOXO3 (PubMed:30513302). Catalyzes dephosphorylation of the pyrin domain of NLRP3, promoting assembly of the NLRP3 inflammasome (By similarity).
Phosphorylation of either threonine (by autophosphorylation-activated protein kinase) or tyrosine results in inactivation of the phosphatase. Auto-dephosphorylation has been suggested as a mechanism for reactivation.
Polyubiquitinated, leading to its degradation by the proteasome.
Reversibly methyl esterified on Leu-309 by leucine carboxyl methyltransferase 1 (LCMT1) and protein phosphatase methylesterase 1 (PPME1). Carboxyl methylation influences the affinity of the catalytic subunit for the different regulatory subunits, thereby modulating the PP2A holoenzyme's substrate specificity, enzyme activity and cellular localization.
Acetylation of Gly-2 converts Hb F to the minor Hb F1.
Expressed until four or five weeks after birth.
Gamma chains make up the fetal hemoglobin F, in combination with alpha chains.
Heterotetramer of two alpha chains and two gamma chains in fetal hemoglobin (Hb F).
Zinc chaperone that directly transfers zinc cofactor to target metalloproteins, thereby activating them. Catalyzes zinc insertion into the active site of methionine aminopeptidase METAP1, which function to cleave the initiator methionine from polypeptides during or after protein translation. Mechanistically, the N-terminal psi-PxLVp motif binds to the C6H2-type zinc finger of inactive form of METAP1. After formation of the docked complex, zinc is transferred from the CXCC motif in the GTPase domain of ZNG1C to the zinc binding site in the peptidase domain of METAP1 in a process requiring GTP hydrolysis. GTP/GDP exchange is required for release of active METAP1.
Interacts with neddylated CUL2, ubiquitinated HIF1A, and VCP/p97.
The UBA domain is required for binding ubiquitinated-protein substrates.
The UBX domain mediates interaction with VCP/p97.
The UIM (ubiquitin-interacting motif) is required to engage the NEDD8 modification on cullins.
Ubiquitin-binding adapter that links a subset of NEDD8-associated cullin ring ligases (CRLs) to the segregase VCP/p97, to regulate turnover of their ubiquitination substrates.
Unlikely isoform. Aberrant splice sites.
Interacts through its PDZ domains with ANO2 and NETO1 (By similarity). Interacts through its first two PDZ domains with GRIN2A, GRIN2B, GRIN2C, GRIN2D (By similarity). Interacts with ASIC3 (By similarity). Interacts with SEMA4C (By similarity). Interacts with CXADR (By similarity). Interacts with KCND2 (By similarity). Interacts with SYNGAP1 (By similarity). Interacts with LRRC4 and LRRC4B (By similarity). Interacts with ERBB4 (PubMed:10725395). Interacts with KCNA1, KCNA2, KCNA3 and KCNA4 (PubMed:7477295). Interacts through its first PDZ domain with GRIK2, KCNA4 and CRIPT (PubMed:11744724). Interacts through its second PDZ domain with the PDZ domain of NOS1 or the C-terminus of CAPON (By similarity). Interacts through its third PDZ domain with NLGN1 and CRIPT, and probably with NLGN2 and NLGN3 (PubMed:9278515). Interacts through its guanylate kinase-like domain with KIF13B (PubMed:10859302). Interacts through its guanylate kinase-like domain with DLGAP1/GKAP, DLGAP2, DLGAP3, DLGAP4, MAP1A, BEGAIN and SIPA1L1 (By similarity). Isoform 2 interacts through an L27 domain with HGS/HRS and the first L27 domain of CASK (PubMed:12151521). Interacts with ADR1B and ANKS1B (By similarity). May interact with HTR2A (By similarity). Interacts with ADAM22 (PubMed:27066583). Interacts with KLHL17 and LGI1 (By similarity). Interacts with FRMPD4 (via C-terminus) (PubMed:19118189). Interacts with LRFN1, LRFN2 and LRFN4 (PubMed:16630835). Interacts (via N-terminal tandem pair of PDZ domains) with GPER1 (via C-terminus tail motif); the interaction is direct and induces the increase of GPER1 protein levels residing at the plasma membrane surface in a estradiol-independent manner (By similarity). Interacts (via N-terminus tandem pair of PDZ domains) with NOS1 (via N-terminal domain) (By similarity). Interacts with SHANK3 (By similarity). Interacts with KCNJ4 (By similarity). Interacts with GPR85 (PubMed:25780553). Interacts with CACNG2 and MPP2 (via the SH3-Guanylate kinase-like sub-module) (By similarity). Interacts with ADGRB1 (PubMed:23782696). Found in a complex with PRR7 and GRIN1 (By similarity). Interacts (via PDZ3 domain and to lesser degree via PDZ2 domain) with PRR7 (By similarity). Component of the postsynaptic hippocampal AMPA-type glutamate receptor (AMPAR) complex, at least composed of pore forming AMPAR subunits GRIA1, GRIA2 and GRIA3 and AMPAR auxiliary proteins SHISA6 and SHISA7. Interacts (via its first two PDZ domains) with SHISA6 and SHISA7 (via PDZ-binding motif); the interaction is direct (By similarity). Interacts with RPH3A and GRIN2A; this ternary complex regulates NMDA receptor composition at postsynaptic membranes (By similarity). Interacts with ABR and BCR (PubMed:20962234). Interacts with DGKI (via PDZ-binding motif); controls the localization of DGKI to the synapse (PubMed:21119615). Interacts with C9orf72, SMCR8 and RAB39B (By similarity). Interacts with ZDHHC5 (PubMed:26334723). Interacts with PTEN (via PDZ domain-binding motif); the interaction is induced by NMDA and is required for PTEN location at postsynaptic density (By similarity).
Palmitoylated (PubMed:26701913). Palmitoylation is required for targeting to postsynaptic density, plasma membrane and synapses (By similarity). Palmitoylation by ZDHHC2 occurs when the synaptic activity decreases and induces DLG4 synaptic clustering (By similarity). Palmitoylation by ZDHHC15 regulates trafficking to the postsynaptic density and function in synaptogenesis (By similarity). Palmitoylation may play a role in glutamate receptor GRIA1 synapse clustering (By similarity). Depalmitoylated by ABHD17A and ABHD17B and to a lesser extent by ABHD17C, ABHD12, ABHD13, LYPLA1 and LYPLA2 (PubMed:26701913). Undergoes rapid synaptic palmitoylation/depalmitoylation cycles during neuronal development which slow down in mature neurons (By similarity).
Postsynaptic scaffolding protein that plays a critical role in synaptogenesis and synaptic plasticity by providing a platform for the postsynaptic clustering of crucial synaptic proteins. Interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels. Required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. May reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. May regulate the intracellular trafficking of ADR1B. Also regulates AMPA-type glutamate receptor (AMPAR) immobilization at postsynaptic density keeping the channels in an activated state in the presence of glutamate and preventing synaptic depression (By similarity). Under basal conditions, cooperates with FYN to stabilize palmitoyltransferase ZDHHC5 at the synaptic membrane through FYN-mediated phosphorylation of ZDHHC5 and its subsequent inhibition of association with endocytic proteins (PubMed:26334723).
The L27 domain near the N-terminus of isoform 2 is required for HGS/HRS-dependent targeting to postsynaptic density.
The PDZ domain 3 mediates interaction with ADR1B.
Ubiquitinated by MDM2 in response to NMDA receptor activation, leading to proteasome-mediated degradation of DLG4 which is required for AMPA receptor endocytosis.
Associates with secreted ligand-bound IL1R2 and increases the affinity of secreted IL1R2 for IL1B; this complex formation may be the dominant mechanism for neutralization of IL1B by secreted/soluble receptors (PubMed:12530978). Enhances the ability of secreted IL1R1 to inhibit IL-33 signaling (By similarity).
Belongs to the interleukin-1 receptor family.
Coreceptor for IL1RL2 in the IL-36 signaling system (By similarity). Coreceptor with IL1R1 in the IL-1 signaling system. Associates with IL1R1 bound to IL1B to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. Recruits TOLLIP to the signaling complex. Does not bind to interleukin-1 alone; binding of IL1RN to IL1R1, prevents its association with IL1R1 to form a signaling complex. The cellular response is modulated through a non-signaling association with the membrane IL1R2 decoy receptor. Coreceptor for IL1RL1 in the IL-33 signaling system. Can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to PTPRD (By similarity). May play a role in IL1B-mediated costimulation of IFNG production from T-helper 1 (Th1) cells (Probable).
Detected in liver, skin, placenta, thymus and lung. Isoform 4 is predominantly expressed in brain. Overexpressed on candidate chronic myeloid leukemia (CML) stem cells, hematopoietic stem cells and mononuclear cells of patients with acute myeloid leukemia (AML). Overexpressed in patients with chronic obstructive pulmonary disease (COPD). Expressed in T-helper 1 (Th1) and T-helper 2 (Th2) cell subsets (PubMed:10653850).
Isoform 1 is down-regulated by phorbol ester treatment. Isoform 2 is induced by phorbol ester treatment.
The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity.
The interleukin-36 receptor complex is a heterodimer of IL1RL2 and IL1RAP; the association is inhibited by IL36RN (By similarity). The interleukin-1 receptor complex is a heterodimer of IL1R1 and IL1RAP. Associates with IL1R2 to form a non-signaling interleukin-1 receptor complex. Isoform 4 interacts with IL1R1 in an interleukin-1-dependent manner. Interacts with IL-33-bound IL1RL1 to form the minimal interleukin-33 signaling complex with a 1:1:1 stoichiometry. Interacts with KIT (independently of stimulation with KITLG/SCF). A mast cell-specific KITLG/SCF-induced interleukin-33 signaling complex contains IL1RL1, IL1RAP, KIT and MYD88 (By similarity). Interacts (via the first immunoglobilin domain) with PTPRD (via the third immunoglobilin domain); induces pre- and postsynaptic differentiation of neurons (By similarity).
Unable to mediate canonical IL-1 signaling (PubMed:19481478). Required for Src phosphorylation by IL1B. May be involved in IL1B-potentiated NMDA-induced calcium influx in neurons (By similarity).
Oligomeric complex that consists of at least the alpha, beta, beta', gamma, delta, epsilon and zeta subunits. Probably interacts with PEX11A. Interacts with SCYL1 (By similarity). Interacts with JAGN1 (PubMed:25129144).
The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. Coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. In mammals, the coatomer can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins; the complex also influences the Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors.
This coatomer complex protein, essential for Golgi budding and vesicular trafficking, is a selective binding protein (RACK) for protein kinase C, epsilon type. It binds to Golgi membranes in a GTP-dependent manner (By similarity).
Myoblast-specific protein that mediates myoblast fusion, an essential step for the formation of multi-nucleated muscle fibers (PubMed:28569745, PubMed:35642635). Involved in membrane fusion downstream of the lipid mixing step mediated by MYMK (By similarity). Acts by generating membrane stresses via its extracellular C-terminus, leading to drive fusion pore formation. Acts independently of MYMK (By similarity). Involved in skeletal muscle regeneration in response to injury by mediating the fusion of satellite cells, a population of muscle stem cells, with injured myofibers (By similarity).
The AxLyCxL motif is required for myoblast fusion.
Although PubMed:12724401 reports that it contains a PHD-type zinc finger, it contains a RING-type zinc finger. Moreover, PHD-type zinc fingers do not have any ubiquitin ligase activity.
Interacts with GGN (By similarity). Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM (PubMed:12973351, PubMed:15502827, PubMed:16116422, PubMed:22343915). The complex is not found in FA patients. In complex with FANCF, FANCA and FANCG, but not with FANCC, nor FANCE, interacts with HES1; this interaction may be essential for the stability and nuclear localization of FA core complex proteins (PubMed:18550849). Interacts with FANCI (PubMed:21775430). Directly interacts (via the RING-type zinc finger) with UBE2T and UBE2W (PubMed:16916645, PubMed:17938197, PubMed:19111657, PubMed:21775430, PubMed:24389026).
The RING-type zinc finger domain is monoubiquitinated in the presence of UBE2T and UBE2W.
The UBC-RWD region (URD) region mediates interaction with FANCI and FANCD2.
Ubiquitin ligase protein that mediates monoubiquitination of FANCD2 in the presence of UBE2T, a key step in the DNA damage pathway (PubMed:12973351, PubMed:16916645, PubMed:17938197, PubMed:19111657, PubMed:24389026). Also mediates monoubiquitination of FANCI (PubMed:19589784). May stimulate the ubiquitin release from UBE2W. May be required for proper primordial germ cell proliferation in the embryonic stage, whereas it is probably not needed for spermatogonial proliferation after birth.
Belongs to the Tim17/Tim22/Tim23 family.
Component of the TIM23 complex at least composed of TIMM23, TIMM17 (TIMM17A or TIMM17B) and TIMM50. The complex interacts with the TIMM44 component of the PAM complex and with DNAJC15.
Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane.
Expression is abundant in heart and skeletal muscle, intermediate in brain, and weak in pancreas, placenta, kidney and liver.
Belongs to the histone deacetylase family. HD type 2 subfamily.
Interacts with AHRR, BAHD1, BCOR, HDAC7, HDAC9, CTBP1, MEF2C, NCOR2, NRIP1, PHB2 and a 14-3-3 chaperone protein. Interacts with BCL6, DDIT3/CHOP, GRK5, KDM5B and MYOCD. Interacts with EP300 in the presence of TFAP2C. Interacts with ANKRA2. Interacts with CUL7 (as part of the 3M complex); negatively regulated by ANKRA2. Interacts with ZBTB7B; the interaction allows the recruitment of HDAC4 on CD8 loci for deacetylation and possible inhibition of CD8 genes expression (By similarity). Interacts with RARA (PubMed:28167758).
Phosphorylated by AMPK, CaMK1, SIK1 and PRKD1 at Ser-259 and Ser-498. The phosphorylation is required for the export to the cytoplasm and inhibition. Phosphorylated by the PKC kinases PKN1 and PKN2, impairing nuclear import. Phosphorylated by GRK5, leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription (By similarity).
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Serves as a corepressor of RARA and causes its deacetylation (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758).
The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm.
Ubiquitinated. Polyubiquitination however does not lead to its degradation.
Belongs to the immunoglobulin superfamily. BTN/MOG family.
Belongs to the G-protein coupled receptor 1 family. Opsin subfamily.
Detected in brain and retina and cell lines derived from neural retina.
G-protein coupled receptor which selectively activates G(i) type G proteins via ultraviolet A (UVA) light-mediated activation in the retina (By similarity). Preferentially binds the chromophore 11-cis retinal and is a bistable protein that displays emission peaks at 380 nm (UVA light) and 470 nm (blue light) (PubMed:22043319). Required for the light-response in the inner plexiform layer, and contributes to the regulation of the light-response in the nerve fiber layer, via phosphorylated DAT/SLC6A3 dopamine uptake (By similarity). Involved in local corneal and retinal circadian rhythm photoentrainment via modulation of the UVA light-induced phase-shift of the retina clock (By similarity). Acts as a circadian photoreceptor in the outer ear, via modulation of circadian clock-gene expression in response to violet light during the light-to-dark transition phase and night phase of the circadian cycle (By similarity). Required in the retina to negatively regulate hyaloid vessel regression during postnatal development via light-dependent OPN5-SLC32A1-DRD2-VEGFR2 signaling (By similarity). Involved in the light-dependent regulation of retina and vitreous compartment dopamine levels (By similarity).
It is uncertain whether Cys-315 or Cys-316 is palmitoylated.
Acts as a basic transcriptional regulator. Represses basic transcription driven by several virus and cellular promoters. When associated with BRD7, activates transcription of glucocorticoid-responsive promoter in the absence of ligand-stimulation. Also plays a role in mRNA processing and transport. Binds avidly to poly(G) and poly(C) RNA homopolymers in vitro.
Interacts with the adenovirus type 5 (Ad5) E1B-55 kDa, BRD7, PRMT2, TP53 and NXF1. Associates with histones and BRD7.
Its methylation is enhanced in the late phase of adenoviral infection.
(Microbial infection) Acts as a receptor for P.sordellii toxin TcsL in the in the vascular endothelium.
(Microbial infection) Interacts with P.sordellii toxin TcsL; semaphorins SEMA6A and SEMA6B constitute the major host receptors for TcsL in the vascular endothelium.
Active as a homodimer or oligomer (By similarity). The SEMA6A homodimer interacts with a PLXNA2 homodimer, giving rise to a heterotetramer (By similarity). Interacts with EVL (PubMed:10993894).
Cell surface receptor for PLXNA2 that plays an important role in cell-cell signaling. Required for normal granule cell migration in the developing cerebellum. Promotes reorganization of the actin cytoskeleton and plays an important role in axon guidance in the developing central nervous system. Can act as repulsive axon guidance cue. Has repulsive action towards migrating granular neurons. May play a role in channeling sympathetic axons into the sympathetic chains and controlling the temporal sequence of sympathetic target innervation.
Belongs to the calcium channel flower family.
Interacts with the SLBP/pre-mRNA complex but not with SLBP alone. Interacts with LSM11 in a U7 snRNP-dependent manner.
Involved in histone 3'-end pre-mRNA processing by associating with U7 snRNP and interacting with SLBP/pre-mRNA complex. Increases histone 3'-end pre-mRNA processing but has no effect on U7 snRNP levels, when overexpressed. Required for cell cycle progression from G1 to S phases.
The C2H2-type zinc finger 2 to 6 are necessary and sufficient for discrete Cajal bodies localization. The C2H2-type zinc finger 5 to 10 are necessary and sufficient for interaction with LSM11. The C2H2-type zinc finger 2 to 8 are necessary for interaction with the SLBP/RNA complex in the histone pre-mRNAs. The C2H2-type zinc finger 2 to 10 confer activity in histone pre-mRNA processing.
Belongs to the cytochrome c oxidase VIIa family.
Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with PET100 (PubMed:22356826).
Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.
(Microbial infection) Interacts with human cytomegalovirus protein UL32.
Accumulates steadily during G2 and is abruptly destroyed at mitosis. Not detected during the G1 phase of the cell cycle. It accumulates during the DNA synthesis/S phase and disappears as cells progress into mitosis, between prophase and metaphase (at protein level).
Belongs to the cyclin family. Cyclin AB subfamily.
Cyclin which controls both the G1/S and the G2/M transition phases of the cell cycle. Functions through the formation of specific serine/threonine protein kinase holoenzyme complexes with the cyclin-dependent protein kinases CDK1 or CDK2. The cyclin subunit confers the substrate specificity of these complexes and differentially interacts with and activates CDK1 and CDK2 throughout the cell cycle.
Interacts with the CDK1 and CDK2 protein kinases to form serine/threonine kinase holoenzyme complexes (PubMed:1312467, PubMed:7630397, PubMed:8684460, PubMed:8756328). Interacts with CDK1 (hyperphosphorylated form in G1 and underphosphorylated forms in S and G2) (PubMed:1312467). Interacts with CDK2; the interaction increases from G1 to G2 (PubMed:1312467). Interacts (associated with CDK2 but not with CDK1) with SCAPER; regulates the activity of CCNA2/CDK2 by transiently maintaining CCNA2 in the cytoplasm (PubMed:17698606). Forms a ternary complex with CDK2 and CDKN1B; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements (PubMed:8684460). Interacts with INCA1 (PubMed:21540187).
Polyubiquitinated via 'Lys-11'-linked ubiquitin by the anaphase-promoting complex (APC/C), leading to its degradation by the proteasome. Deubiquitinated and stabilized by USP37 enables entry into S phase.
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Gamma/CHRNG sub-subfamily.
Pentamer of two alpha chains, and one each of the beta, delta, and gamma (in immature muscle) or epsilon (in mature muscle) chains.
Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer.
Belongs to the protein kinase superfamily. Tyr protein kinase family. FAK subfamily.
Detected in B and T-lymphocytes. Isoform 1 and isoform 6 are detected in lung fibroblasts (at protein level). Ubiquitous. Expressed in epithelial cells (at protein level) (PubMed:31630787).
Detected in cultured cells, immediately after seeding and before formation of focal adhesions (at protein level).
Interacts (via first Pro-rich region) with CAS family members (via SH3 domain), including BCAR1, BCAR3, and CASS4. Interacts with NEDD9 (via SH3 domain) (PubMed:9360983). Interacts with GIT1. Interacts with SORBS1. Interacts with ARHGEF28. Interacts with SHB. Part of a complex composed of THSD1, PTK2/FAK1, TLN1 and VCL (PubMed:29069646). Interacts with PXN and TLN1. Interacts with STAT1. Interacts with DCC. Interacts with WASL. Interacts with ARHGEF7. Interacts with GRB2 and GRB7 (By similarity). Component of a complex that contains at least FER, CTTN and PTK2/FAK1. Interacts with BMX. Interacts with TGFB1I1. Interacts with STEAP4. Interacts with ZFYVE21. Interacts with ESR1. Interacts with PIK3R1 or PIK3R2. Interacts with SRC, FGR, FLT4 and RET. Interacts with EPHA2 in resting cells; activation of EPHA2 recruits PTPN11, leading to dephosphorylation of PTK2/FAK1 and dissociation of the complex. Interacts with EPHA1 (kinase activity-dependent). Interacts with CD4; this interaction requires the presence of HIV-1 gp120. Interacts with PIAS1. Interacts with ARHGAP26 and SHC1. Interacts with RB1CC1; this inhibits PTK2/FAK1 activity and activation of downstream signaling pathways. Interacts with P53/TP53 and MDM2. Interacts with LPXN (via LD motif 3). Interacts with MISP. Interacts with CIB1 isoform 2. Interacts with CD36. Interacts with EMP2; regulates PTK2 activation and localization (PubMed:19494199). Interacts with DSCAM (By similarity). Interacts with AMBRA1 (By similarity). Interacts (when tyrosine-phosphorylated) with tensin TNS1; the interaction is increased by phosphorylation of TNS1 (PubMed:20798394).
Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.
Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Phosphorylates NEDD9 following integrin stimulation (PubMed:9360983). Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.
Phosphorylated on tyrosine residues upon activation, e.g. upon integrin signaling. Tyr-397 is the major autophosphorylation site, but other kinases can also phosphorylate this residue. Phosphorylation at Tyr-397 promotes interaction with SRC and SRC family members, leading to phosphorylation at Tyr-576, Tyr-577 and at additional tyrosine residues. FGR promotes phosphorylation at Tyr-397 and Tyr-576. FER promotes phosphorylation at Tyr-577, Tyr-861 and Tyr-925, even when cells are not adherent. Tyr-397, Tyr-576 and Ser-722 are phosphorylated only when cells are adherent. Phosphorylation at Tyr-397 is important for interaction with BMX, PIK3R1 and SHC1. Phosphorylation at Tyr-925 is important for interaction with GRB2. Dephosphorylated by PTPN11; PTPN11 is recruited to PTK2 via EPHA2 (tyrosine phosphorylated). Microtubule-induced dephosphorylation at Tyr-397 is crucial for the induction of focal adhesion disassembly; this dephosphorylation could be catalyzed by PTPN11 and regulated by ZFYVE21. Phosphorylation on tyrosine residues is enhanced by NTN1 (By similarity).
Subject to autoinhibition, mediated by interactions between the FERM domain and the kinase domain. Activated by autophosphorylation at Tyr-397. This promotes interaction with SRC and phosphorylation at Tyr-576 and Tyr-577 in the kinase activation loop. Phosphorylation at Tyr-576 and Tyr-577 is required for maximal kinase activity. Inhibited by TAC544, TAE226, PF-573,228 and PF-562,271.
Sumoylated; this enhances autophosphorylation.
The C-terminal region is the site of focal adhesion targeting (FAT) sequence which mediates the localization of FAK1 to focal adhesions.
The Pro-rich regions interact with the SH3 domain of CAS family members, such as BCAR1 and NEDD9, and with the GTPase activating protein ARHGAP26.
Associates with the EF-Tu.GDP complex and induces the exchange of GDP to GTP. It remains bound to the aminoacyl-tRNA.EF-Tu.GTP complex up to the GTP hydrolysis stage on the ribosome.
Expressed in all tissues, with the highest levels of expression in skeletal muscle, liver and kidney.
Activated by dimerization. Not activated by EGF, TGF-alpha and amphiregulin. Interaction with PTK6 increases its intrinsic kinase activity.
Autophosphorylated. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit (Probable). Ligand-binding increases phosphorylation on tyrosine residues (PubMed:27134172, PubMed:33497358). Signaling via SEMA4C promotes phosphorylation at Tyr-1248 (PubMed:17554007). Dephosphorylated by PTPN12 (PubMed:27134172).
Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily.
Chromosomal aberrations involving ERBB2 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with CDK12, leading to CDK12-ERBB2 fusion leading to truncated CDK12 protein not in-frame with ERBB2.
Expressed in a variety of tumor tissues including primary breast tumors and tumors from small bowel, esophagus, kidney and mouth.
Homodimer (PubMed:21454582). Heterodimer with EGFR, ERBB3 and ERBB4 (PubMed:10358079, PubMed:15093539, PubMed:21190959, PubMed:16978839). Part of a complex with EGFR and either PIK3C2A or PIK3C2B. May interact with PIK3C2B when phosphorylated on Tyr-1196 (PubMed:10805725). Interacts with PLXNB1 (PubMed:15210733). Interacts (when phosphorylated on Tyr-1248) with MEMO1 (PubMed:15156151). Interacts with MUC1; the interaction is enhanced by heregulin (HRG) (PubMed:12939402). Interacts (when phosphorylated on Tyr-1139) with GRB7 (via SH2 domain) (PubMed:12975581). Interacts (when phosphorylated on Tyr-1248) with ERBIN (PubMed:12444095). Interacts with KPNB1, RANBP2, EEA1, CRM1 and CLTC (PubMed:16314522). Interacts with PTK6 (PubMed:18719096). Interacts with RPA194 and ACTB (PubMed:21555369). Interacts with PRKCABP, SRC and MYOC (By similarity). Interacts (preferentially with the tyrosine phosphorylated form) with CPNE3; this interaction occurs at the cell membrane and is increased in a growth factor heregulin-dependent manner (PubMed:20010870). Interacts with HSP90AA1 and HSP90AB1 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity (PubMed:26517842). Interacts with SORL1; this interaction regulates ERBB2 subcellular distribution by promoting its recycling after internalization from endosomes back to the plasma membrane, hence stimulates ERBB2-mediated signaling (PubMed:31138794). Interacts with SH3BGRL (PubMed:32381043).
In the nucleus is involved in transcriptional regulation. Associates with the 5'-TCAAATTC-3' sequence in the PTGS2/COX-2 promoter and activates its transcription. Implicated in transcriptional activation of CDKN1A; the function involves STAT3 and SRC. Involved in the transcription of rRNA genes by RNA Pol I and enhances protein synthesis and cell growth.
Produced by alternative initiation at Met-611 of isoform 1.
Produced by alternative initiation at Met-687 of isoform 1.
Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization.
The gene represented in this entry is involved in disease pathogenesis.
The protein represented in this entry is involved in disease pathogenesis.
There are four alleles due to the variations in positions 654 and 655. Allele B1 (Ile-654/Ile-655) has a frequency of 0.782; allele B2 (Ile-654/Val-655) has a frequency of 0.206; allele B3 (Val-654/Val-655) has a frequency of 0.012.
Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Regulator of Hedgehog (Hh), required for both activation and inhibition of the Hh pathway in the patterning of the neural tube. During neural tube development, it is required for formation of the most ventral cell types and for full Hh pathway activation. Functions in Hh signal transduction to fully activate the pathway in the presence of high Hh levels and to repress the pathway in the absence of Hh signals. Modulates Hh signal transduction downstream of SMO and RAB23 (By similarity).
Part of the tectonic-like complex (also named B9 complex).
Directly interacts with F-actin and ABRA.
Expressed predominantly in heart and brain.
May act as scaffold protein. May stimulate ABRA activity and ABRA-dependent SRF transcriptional activity.
Belongs to the metallophosphoesterase superfamily. LOC643853 family.
A chromosomal aberration involving TPR has been found in papillary thyroid carcinomas (PTCs). Intrachromosomal rearrangement that links the 5'-end of the TPR gene to the protein kinase domain of NTRK1 forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the carboxy terminus of the NTRK1 protein.
Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. Functions as a scaffolding element in the nuclear phase of the NPC essential for normal nucleocytoplasmic transport of proteins and mRNAs, plays a role in the establishment of nuclear-peripheral chromatin compartmentalization in interphase, and in the mitotic spindle checkpoint signaling during mitosis. Involved in the quality control and retention of unspliced mRNAs in the nucleus; in association with NUP153, regulates the nuclear export of unspliced mRNA species bearing constitutive transport element (CTE) in a NXF1- and KHDRBS1-independent manner. Negatively regulates both the association of CTE-containing mRNA with large polyribosomes and translation initiation. Does not play any role in Rev response element (RRE)-mediated export of unspliced mRNAs. Implicated in nuclear export of mRNAs transcribed from heat shock gene promoters; associates both with chromatin in the HSP70 promoter and with mRNAs transcribed from this promoter under stress-induced conditions. Modulates the nucleocytoplasmic transport of activated MAPK1/ERK2 and huntingtin/HTT and may serve as a docking site for the XPO1/CRM1-mediated nuclear export complex. According to some authors, plays a limited role in the regulation of nuclear protein export (PubMed:22253824, PubMed:11952838). Also plays a role as a structural and functional element of the perinuclear chromatin distribution; involved in the formation and/or maintenance of NPC-associated perinuclear heterochromatin exclusion zones (HEZs). Finally, acts as a spatial regulator of the spindle-assembly checkpoint (SAC) response ensuring a timely and effective recruitment of spindle checkpoint proteins like MAD1L1 and MAD2L1 to unattached kinetochore during the metaphase-anaphase transition before chromosome congression. Its N-terminus is involved in activation of oncogenic kinases.
Expressed in esophagus, ovary, liver, skin, smooth muscles, cerebrum and fetal cerebellum (at protein level). Highest in testis, lung, thymus, spleen and brain, lower levels in heart, liver and kidney.
Interacts with IFI204 (via C-terminal region). Interacts with IFI203 (By similarity). Homodimer. Part of the nuclear pore complex (NPC). Associates with the XPO1/CRM1-mediated nuclear export complex, the Importin alpha/Importin beta receptor and the dynein 1 complex. Interacts (via C-terminal domain) with the KPNB1; the interaction occurs in a RanGTP-dependent manner. Interacts (via C-terminal regionand phosphorylated form) with MAPK1/ERK2 (via phosphorylated form); the interaction requires dimerization of MAPK1/ERK2 and increases following EGF stimulation. Interacts with MAPK3/ERK1; the interaction increases following EGF stimulation. Interacts (via coiled coil region) with NUP153; the interaction is direct. Interacts with HSF1; the interaction increases in a stress-responsive manner and stimulates export of stress-induced HSP70 mRNA. Interacts with huntingtin/HTT; the interaction is inhibited by aggregated huntingtin/HTT forms with expanded polyglutamine stretch. Interacts with MAD1L1 (via N-terminal region), MAD2L1, and TTK; the interactions occurs in a microtubule-independent manner. Interacts (via middle region) with DYNLL1. Interacts with DCTN1, dynein, NUP153 and tubulin. Interacts with MTA1.
Involved in tumorigenic rearrangements with the MET.
Phosphorylated. Phosphorylation occurs on serine and threonine residues (comprised in the C-terminal region) by MAPK1/ERK2 and stabilizes the interaction between these two proteins.
Proteolytically degraded after poliovirus (PV) infection; degradation is restricted to its unfolded C-terminal tail domain whereas its coiled-coil domain containing NCP- and NUP153-binding domains withstand degradation.
The N-terminal domain mediates intranuclear attachment to the nuclear pore complex. The C-terminal domain mediates its nuclear import.
(Microbial infection) Interacts (via coiled coil domain) with hepatitis C virus (HCV) NS5A.
(Microbial infection) Required for efficient replication of hepatitis C virus (HCV) by promoting the interaction between VAPA and HCV virus protein NS5A.
Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:11931768, PubMed:19858209, PubMed:21240272). Interacts (when sumoylated at Lys-71) with TBL1X; leading to protect GPS2 from degradation by the proteasome (PubMed:24943844, PubMed:21240272). Interacts with UBE2N; leading to inhibit UBE2N/Ubc13 activity (By similarity). Interacts with TRAF1 (By similarity). Interacts with TRAF2 (By similarity). Interacts with TRAF6 (By similarity). Interacts with PPARG (when in the liganded conformation) (By similarity). Interacts with (sumoylated) NR1H2; interaction with sumoylated NR1H2 and NR5A2 onto hepatic acute phase protein promoters prevents N-Cor corepressor complex dissociation (PubMed:20159957). Interacts with (sumoylated) NR5A2; interaction with sumoylated NR1H2 and NR5A2 onto hepatic acute phase protein promoters prevents N-Cor corepressor complex dissociation (PubMed:20159957). Interacts with NR1H3 (PubMed:19481530). Interacts with RFX4 (By similarity). Interacts with ANKRD26 (PubMed:22666460).
Down-regulated in liposarcoma (PubMed:27460081). Down-regulated in macrophages of patients with adipose tissue inflammation and type-2 diabetes (PubMed:27270589).
Key regulator of inflammation, lipid metabolism and mitochondrion homeostasis that acts by inhibiting the activity of the ubiquitin-conjugating enzyme UBE2N/Ubc13, thereby inhibiting 'Lys-63'-linked ubiquitination (By similarity). In the nucleus, can both acts as a corepressor and coactivator of transcription, depending on the context (PubMed:24943844). Acts as a transcription coactivator in adipocytes by promoting the recruitment of PPARG to promoters: acts by inhibiting the activity of the ubiquitin-conjugating enzyme UBE2N/Ubc13, leading to stabilization of KDM4A and subsequent histone H3 'Lys-9' (H3K9) demethylation (By similarity). Promotes cholesterol efflux by acting as a transcription coactivator (PubMed:19481530). Acts as a regulator of B-cell development by inhibiting UBE2N/Ubc13, thereby restricting the activation of Toll-like receptors (TLRs) and B-cell antigen receptors (BCRs) signaling pathways (By similarity). Acts as a key mediator of mitochondrial stress response: in response to mitochondrial depolarization, relocates from the mitochondria to the nucleus following desumoylation and specifically promotes expression of nuclear-encoded mitochondrial genes (PubMed:29499132). Promotes transcription of nuclear-encoded mitochondrial genes by inhibiting UBE2N/Ubc13 (PubMed:29499132). Can also act as a corepressor as part of the N-Cor repressor complex by repressing active PPARG (PubMed:19858209, PubMed:24943844). Plays an anti-inflammatory role in macrophages and is required for insulin sensitivity by acting as a corepressor (By similarity). Plays an anti-inflammatory role during the hepatic acute phase response by interacting with sumoylated NR1H2 and NR5A2 proteins, thereby preventing N-Cor corepressor complex dissociation (PubMed:20159957). In the cytosol, also plays a non-transcriptional role by regulating insulin signaling and pro-inflammatory pathways (By similarity). In the cytoplasm, acts as a negative regulator of inflammation by inhibiting the pro-inflammatory TNF-alpha pathway; acts by repressing UBE2N/Ubc13 activity (By similarity). In the cytoplasm of adipocytes, restricts the activation of insulin signaling via inhibition of UBE2N/Ubc13-mediated ubiquitination of AKT (By similarity). Able to suppress G-protein- and mitogen-activated protein kinase-mediated signal transduction (PubMed:8943324). Acts as a tumor-suppressor in liposarcoma (PubMed:27460081).
Methylated at Arg-312 and Arg-323 by PRMT6. Methylation at Arg-323 protects from degradation by the proteasome.
Sumoylation regulates its subcellular location (PubMed:24943844). Sumoylation at Lys-45 and Lys-71 regulates the shuttling between the cytoplasm and the nucleus (PubMed:24943844). Sumoylation at Lys-71 is required for interaction with TBL1X (By similarity). Sumoylated at Lys-45 and Lys-71 in mitochondrion (By similarity). Desumoylation by SENP1 leads to relocation from the mitochondria to the nucleus (By similarity).
Ubiquitinated at the C-terminus by SIAH2; leading to its degradation by the proteasome. Interaction with TBL1X and methylation at Arg-323 protect GPS2 against ubiquitination and degradation.
Interacts with PLEKHM1 (via N- and C-terminus) (By similarity). Interacts with YWHAE. Interacts directly with NEFL and indirectly with NEFH. Interacts with microtubules (By similarity). Self-associates. Interacts with DISC1, dynein, dynactin, tubulin gamma, KATNA1, KATNB1, PAFAH1B1, PCM1 and PCNT. Interacts (via C-terminus) with CENPF. Interacts with ZNF365.
Palmitoylation at Cys-273 reduces affinity for dynein.
Phosphorylated in mitosis. Can be phosphorylated by CDK1, CDK5 and MAPK1. Phosphorylation by CDK5 promotes interaction with KATNA1 and YWHAE.
Required for organization of the cellular microtubule array and microtubule anchoring at the centrosome. May regulate microtubule organization at least in part by targeting the microtubule severing protein KATNA1 to the centrosome. Also positively regulates the activity of the minus-end directed microtubule motor protein dynein. May enhance dynein-mediated microtubule sliding by targeting dynein to the microtubule plus ends. Required for several dynein- and microtubule-dependent processes such as the maintenance of Golgi integrity, the centripetal motion of secretory vesicles and the coupling of the nucleus and centrosome. Also required during brain development for the migration of newly formed neurons from the ventricular/subventricular zone toward the cortical plate. Plays a role, together with DISC1, in the regulation of neurite outgrowth. Required for mitosis in some cell types but appears to be dispensible for mitosis in cortical neuronal progenitors, which instead requires NDE1. Facilitates the polymerization of neurofilaments from the individual subunits NEFH and NEFL. Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts (By similarity).
Was originally thought to function as an oligopeptidase (NUDEL-oligopeptidase or endooligopeptidase A) which could regulate peptide levels relevant to brain function.
A particular signal processing and glycosylation pattern may differentiate the UpI2 RNase, found specifically in pregnant women urine, from other nonsecretory RNases.
Belongs to the pancreatic ribonuclease family.
Interacts with and forms a tight 1:1 complex with RNH1. Dimerization of two such complexes may occur.
Liver, lung, spleen, leukocytes and body fluids.
The N-terminal region is necessary for mediating chemotactic activity.
This is a non-secretory ribonuclease. It is a pyrimidine specific nuclease with a slight preference for U. Cytotoxin and helminthotoxin. Selectively chemotactic for dendritic cells. Possesses a wide variety of biological activities.
Appears to be expressed ubiquitously. The Tyr-9 phosphorylated form is markedly increased in diseased tissue compared with normal tissue from lung, liver, colon and breast.
Autophosphorylated; autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PDPK1 subfamily.
Homodimer in its autoinhibited state. Active as monomer. Interacts with NPRL2, PPARG, PAK1, PTK2B, GRB14, PKN1 (via C-terminus), STRAP and IKKB. The Tyr-9 phosphorylated form interacts with SRC, RASA1 and CRK (via their SH2 domains). Interacts with SGK3 in a phosphorylation-dependent manner. The tyrosine-phosphorylated form interacts with PTPN6. The Ser-241 phosphorylated form interacts with YWHAH and YWHAQ. Binds INSR in response to insulin. Interacts (via PH domain) with SMAD3, SMAD4 and SMAD7. Interacts with PKN2; the interaction stimulates PDPK1 autophosphorylation, its PI(3,4,5)P3-dependent kinase activity toward 'Ser-473' of AKT1 but also activates its kinase activity toward PRKCD and PRKCZ.
Homodimerization regulates its activity by maintaining the kinase in an autoinhibitory conformation. NPRL2 down-regulates its activity by interfering with tyrosine phosphorylation at the Tyr-9, Tyr-373 and Tyr-376 residues. The 14-3-3 protein YWHAQ acts as a negative regulator by association with the residues surrounding the Ser-241 residue. STRAP positively regulates its activity by enhancing its autophosphorylation and by stimulating its dissociation from YWHAQ. SMAD2, SMAD3, SMAD4 and SMAD7 also positively regulate its activity by stimulating its dissociation from YWHAQ. Activated by phosphorylation on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to insulin.
Monoubiquitinated in the kinase domain, deubiquitinated by USP4.
Phosphorylation on Ser-241 in the activation loop is required for full activity. PDPK1 itself can autophosphorylate Ser-241, leading to its own activation. Autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2 (By similarity). Tyr-9 phosphorylation is critical for stabilization of both PDPK1 and the PDPK1/SRC complex via HSP90-mediated protection of PDPK1 degradation. Angiotensin II stimulates the tyrosine phosphorylation of PDPK1 in vascular smooth muscle in a calcium- and SRC-dependent manner. Phosphorylated on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to insulin. Palmitate negatively regulates autophosphorylation at Ser-241 and palmitate-induced phosphorylation at Ser-529 and Ser-501 by PKC/PRKCQ negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylation at Thr-354 by MELK partially inhibits kinase activity, the inhibition is cooperatively enhanced by phosphorylation at Ser-394 and Ser-398 by MAP3K5.
Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive.
Stimulated by insulin, and the oxidants hydrogen peroxide and peroxovanadate.
The PH domain plays a pivotal role in the localization and nuclear import of PDPK1 and is also essential for its homodimerization.
The PIF-pocket is a small lobe in the catalytic domain required by the enzyme for the binding to the hydrophobic motif of its substrates. It is an allosteric regulatory site that can accommodate small compounds acting as allosteric inhibitors.
(Microbial infection) Interacts (via N-terminus) with Hantaan hantavirus nucleoprotein.
(Microbial infection) Interacts (via N-terminus) with Tula hantavirus nucleoprotein.
(Microbial infection) Interacts with Epstein-barr virus BGLF4.
Cleavage of precursor form by SENP1 or SENP2 is necessary for function.
Covalently attached to KCNB1; UBE2I increases cross-linking with KCNB1 and PIAS1 decreases cross-links with KCNB1 (PubMed:19223394, PubMed:15931224). Interacts with SAE2, RANBP2, PIAS1 and PIAS2 (PubMed:10961991, PubMed:15608651, PubMed:15660128, PubMed:16204249, PubMed:15931224). Interacts with PRKN (PubMed:16955485). Covalently attached to a number of proteins such as IKFZ1, PML, RANGAP1, HIPK2, SP100, p53, p73-alpha, MDM2, JUN, DNMT3B and TDG (PubMed:10961991, PubMed:15931224, PubMed:15959518, PubMed:17099698). Also interacts with HIF1A, HIPK2, HIPK3, CHD3, EXOSC9, RAD51 and RAD52 (PubMed:10961991, PubMed:12565818). Interacts with USP25 (via ts SIM domain); the interaction weakly sumoylates USP25 (PubMed:18538659). Interacts with SIMC1, CASP8AP2, RNF111 and SOBP (via SIM domains) (PubMed:23086935). Interacts with BHLHE40/DEC1 (PubMed:21829689). Interacts with RWDD3 (PubMed:17956732). Interacts with UBE2I/UBC9 and this interaction is enhanced in the presence of RWDD3 (PubMed:12924945, PubMed:17956732). Interacts with MTA1 (PubMed:21965678). Interacts with SENP2 (PubMed:15296745). Interacts with HINT1 (By similarity).
Polymeric SUMO1 chains undergo polyubiquitination by RNF4.
The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving SUMO1 is the cause of OFC10. Translocation t(2;8)(q33.1;q24.3). The breakpoint occurred in the SUMO1 gene and resulted in haploinsufficiency confirmed by protein assays.
Ubiquitin-like protein that can be covalently attached to proteins as a monomer or a lysine-linked polymer. Covalent attachment via an isopeptide bond to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by E3 ligases such as PIAS1-4, RANBP2 or CBX4. This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Involved for instance in targeting RANGAP1 to the nuclear pore complex protein RANBP2. Covalently attached to the voltage-gated potassium channel KCNB1; this modulates the gating characteristics of KCNB1 (PubMed:19223394). Polymeric SUMO1 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins. May also regulate a network of genes involved in palate development. Covalently attached to ZFHX3 (PubMed:24651376).
Binds the armadillo repeat of CTNNB1 and forms a stable complex (By similarity). Interacts with DAZAP2 (PubMed:19304756).
Detected in hair follicles and skin keratinocytes, and at lower levels in stomach epithelium.
Participates in the Wnt signaling pathway. Binds to DNA and acts as a repressor in the absence of CTNNB1, and as an activator in its presence. Necessary for the terminal differentiation of epidermal cells, the formation of keratohyalin granules and the development of the barrier function of the epidermis (By similarity). Down-regulates NQO1, leading to increased mitomycin c resistance.
The putative Groucho interaction domain between the N-terminal CTNNB1 binding domain and the HMG-box is necessary for repression of the transactivation mediated by TCF7L1 and CTNNB1.
Glycosylation is required for cell surface expression.
Monomer in the presence of Ca(2+); it oligomerizes in absence of Ca(2+) (PubMed:18854159). Forms homooligomers and heterooligomers with STIM2 (PubMed:11463338, PubMed:11983428, PubMed:18854159, PubMed:22451904, PubMed:24351972, PubMed:24069340). Interacts (via the transmembrane region and the SOAR/CAD domain) with SPPL3; the interaction promotes the binding of STIM1 to ORAI1 (PubMed:25384971). Interacts with ORAI1 (PubMed:17905723, PubMed:19249086, PubMed:27185316, PubMed:24351972, PubMed:28219928, PubMed:30481768). Interacts with MAPRE1; probably required for targeting to the growing microtubule plus ends (PubMed:19632184). Interacts with CRACR2A/EFCAB4B; the interaction is direct and takes place in absence of Ca(2+) (PubMed:20418871). Forms a complex with CRACR2A/EFCAB4B and ORAI1 at low concentration of Ca(2+), the complex dissociates at elevated Ca(2+) concentrations (PubMed:20418871). Interacts with SARAF, promoting a slow inactivation of STIM1-dependent SOCE activity, possibly by facilitating the deoligomerization of STIM1 (PubMed:22464749, PubMed:30481768). Interacts with EFHB; the interaction takes place upon Ca(2+)-store depletion and inhibits the association with SARAF (PubMed:30481768). Interacts with ASPH (isoform 8) (PubMed:22586105). Interacts with SLC35G1; intracellular Ca(2+)-dependent. May interact with ATP1A1, ATP2A2, ATP2B1, ATP2B4, KPNB1 and XPO1; through SLC35G1 (PubMed:22084111). Interacts with TMEM203 (PubMed:25996873). Interacts with STIMATE, promoting STIM1 conformational switch (PubMed:26322679). Interacts with TMEM178A (By similarity). Interacts with CASQ1 (via C-terminal end and preferentially with the monomeric form); this interaction increases in response to a depletion of intracellular Ca(2+), decreases both STIM1 aggregation and clustering, interaction of STIM1 with ORAI1 and store-operated Ca(2+) entry (SOCE) activity (PubMed:27185316). Interacts with ADCY8 (PubMed:22494970).
Phosphorylated predominantly on Ser residues.
Plays a role in mediating store-operated Ca(2+) entry (SOCE), a Ca(2+) influx following depletion of intracellular Ca(2+) stores (PubMed:15866891, PubMed:16005298, PubMed:16208375, PubMed:16537481, PubMed:16733527, PubMed:16766533, PubMed:16807233, PubMed:18854159, PubMed:19249086, PubMed:22464749, PubMed:24069340, PubMed:24351972, PubMed:24591628, PubMed:26322679, PubMed:25326555, PubMed:28219928). Acts as Ca(2+) sensor in the endoplasmic reticulum via its EF-hand domain. Upon Ca(2+) depletion, translocates from the endoplasmic reticulum to the plasma membrane where it activates the Ca(2+) release-activated Ca(2+) (CRAC) channel subunit ORAI1 (PubMed:16208375, PubMed:16537481). Involved in enamel formation (PubMed:24621671). Activated following interaction with STIMATE, leading to promote STIM1 conformational switch (PubMed:26322679).
The STIM1 Orai1-activating region/CRAC-activating domain (SOAR/CAD) mediates interaction with ORAI1 to activate the channel.
The microtubule tip localization signal (MtLS) motif; mediates interaction with MAPRE1 and targeting to the growing microtubule plus ends.
Transfection of STIM1 into cells derived from a rhabdoid tumor and from a rhabdomyosarcoma that do not express detectable levels of STIM1 can induce cell death, suggesting a possible role in the control of rhabdomyosarcomas and rhabdoid tumors.
Ubiquitously expressed in various human primary cells and tumor cell lines.
Component of a complex with RUVBL1 and PSMC5.
Specifically deubiquitinates histone H2B at 'Lys-120' (H2BK120Ub). H2BK120Ub is a specific tag for epigenetic transcriptional activation and acts as a regulator of mRNA splicing. Deubiquitination is required for efficient cotranscriptional splicing of a large set of exons.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv12.3/KCNH4 sub-subfamily.
Detected only in brain, in particular in the telencephalon. Detected in putamen and caudate nucleus, and at lower levels in cerebral cortex, occipital and hippocampus.
Pore-forming (alpha) subunit of voltage-gated potassium channel. Elicits an outward current, but shows no inactivation. Channel properties may be modulated by cAMP and subunit assembly.
The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming alpha subunits that can associate with modulating beta subunits.
Expressed in the periderm of fetal skin from 16th week gestational age and in the granular and horny layers of the epidermis at 24th week gestational age and thereafter (at protein level).
Expressed in the upper layer of epidermis and psoriasis (at protein level). Expressed in the upper layer of epidermis and psoriasis.
Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. AIG1/Toc34/Toc159-like paraseptin GTPase family. IAN subfamily.
Monomer in the presence of bound GDP and in the absence of bound nucleotide. Homodimer in the presence of bound GTP. Heterodimer with GIMAP2.
Most abundantly expressed in spleen, lymph nodes, and fetal kidney, but also present in the heart and the small intestine. Lower expression levels are found in lung, kidney, liver, and thyroid, salivary, and mammary glands. Also detected in the thymus (PubMed:15474311). Detected in T-cells (PubMed:23454188).
The dimer has GTPase activity; the active site contains residues from both subunits.
Mitochondrial membrane carrier protein that mediates the import of NAD(+) into mitochondria (PubMed:32906142). Compared to SLC25A51, SLC25A52-mediated transport is not essential for the import of NAD(+) in mitochondria (PubMed:32906142). The transport mechanism, uniport or antiport, its electrogenicity and substrate selectivity, remain to be elucidated.
Belongs to the bile acid:sodium symporter (BASS) (TC 2.A.28) family.
Detected in the heart and vertebrae in embryos at 8 weeks of gestation (Carnegie stage 16), and in the long-bone cartilage at 9 weeks (Carnegie stages 19).
Involved in teeth and skeletal development. Has an essential role in the biosynthesis and trafficking of glycosaminoglycans and glycoproteins, to produce a proper functioning extracellular matrix. Required for extracellular matrix mineralization (PubMed:30082715, PubMed:29878199). Also involved in the regulation of cellular calcium homeostasis (PubMed:30082715, PubMed:31191616). Does not show transport activity towards bile acids or steroid sulfates (including taurocholate, cholate, chenodeoxycholate, estrone-3-sulfate, dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate).
Widely expressed (PubMed:15932064, PubMed:17628207). Expressed at high levels in liver and at lower levels in prostate, placenta, kidney, heart, lung, thymus and spleen (PubMed:15932064, PubMed:17628207). Strongly expressed in testis and also detected in brain, ovary, colon and small intestine (PubMed:17628207). Weakly expressed in testis and not detected in brain, ovary, colon or small intestine (PubMed:15932064). Isoform 1: Expressed in liver, testis and placenta (PubMed:17628207). Isoform 4: Expressed in liver, testis and placenta (PubMed:17628207).
Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3).
Binds to the SH3 domain of the YES kinase. Binds to WBP1 and WBP2 (PubMed:9202023). Binds, in vitro, through the WW1 domain, to neural isoforms of ENAH that contain the PPSY motif (By similarity). The phosphorylated form interacts with YWHAB (PubMed:17974916). Interacts (via WW domains) with LATS1 (via PPxY motif 2) (PubMed:18158288). Interacts with LATS2 (PubMed:18158288). Interacts with TEAD1, TEAD2, TEAD3 and TEAD4 (PubMed:18579750, PubMed:20123905, PubMed:20123908). Interacts with TP73 (PubMed:18280240). Interacts with RUNX1 (PubMed:18280240). Interacts with HCK (PubMed:17535448). Interacts (via WW domains) with PTPN14 (via PPxY motif 2); this interaction leads to the cytoplasmic sequestration of YAP1 and inhibits its transcriptional coactivator activity (PubMed:22525271). Interacts (when phosphorylated at Ser-127) with SMAD2, SMAD3 and WWTR1 (By similarity). Interacts with PRRG2 (via cytoplasmic domain) (PubMed:17502622). Interacts (via WW domains) with PRRG4 (via cytoplasmic domain) (PubMed:23873930). Interacts (phosphorylated) with CLDN18; the interaction sequesters YAP1 away from the nucleus and thereby restricts transcription of YAP1 target genes (By similarity). Interacts with SMAD1 (PubMed:21685363).
Highest expression in ovary and placenta, lowest in skeletal muscle and brain.
Increased expression seen in some liver and prostate cancers. Isoforms lacking the transactivation domain found in striatal neurons of patients with Huntington disease (at protein level).
Interacts (via WW domain 1) with isoform 3 of ERBB4 (via PPxY motif 2).
Phosphorylated by LATS1 and LATS2; leading to cytoplasmic translocation and inactivation (PubMed:18158288, PubMed:20048001). Phosphorylated by ABL1; leading to YAP1 stabilization, enhanced interaction with TP73 and recruitment onto proapoptotic genes; in response to DNA damage (PubMed:18280240). Phosphorylation at Ser-400 and Ser-403 by CK1 is triggered by previous phosphorylation at Ser-397 by LATS proteins and leads to YAP1 ubiquitination by SCF(beta-TRCP) E3 ubiquitin ligase and subsequent degradation (PubMed:20048001). Phosphorylated at Thr-119, Ser-138, Thr-154, Ser-367 and Thr-412 by MAPK8/JNK1 and MAPK9/JNK2, which is required for the regulation of apoptosis by YAP1 (PubMed:21364637).
The first coiled-coil region mediates most of the interaction with TEAD transcription factors.
Transcriptional regulator which can act both as a coactivator and a corepressor and is the critical downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:17974916, PubMed:18280240, PubMed:18579750, PubMed:21364637, PubMed:30447097). The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ (PubMed:18158288). Plays a key role in tissue tension and 3D tissue shape by regulating cortical actomyosin network formation. Acts via ARHGAP18, a Rho GTPase activating protein that suppresses F-actin polymerization (PubMed:25778702). Plays a key role in controlling cell proliferation in response to cell contact. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration (PubMed:18158288). The presence of TEAD transcription factors are required for it to stimulate gene expression, cell growth, anchorage-independent growth, and epithelial mesenchymal transition (EMT) induction (PubMed:18579750). Suppresses ciliogenesis via acting as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1 (PubMed:25849865). In conjunction with WWTR1, involved in the regulation of TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation (By similarity).
Ubiquitinated by SCF(beta-TRCP) E3 ubiquitin ligase.
Binds DNA as a dimer. Can form homodimers or heterodimers with other AP-2 family members. Interacts with WWOX. Interacts with CITED4. Interacts with UBE2I. Interacts with RALBP1 in a complex also containing EPN1 and NUMB during interphase and mitosis. Interacts with KCTD1; this interaction represses transcription activation. Interacts (via C-terminus) with CITED2 (via C-terminus); the interaction stimulates TFAP2A-transcriptional activation. Interacts (via N-terminus) with EP300 (via N-terminus); the interaction requires CITED2. Interacts with KCTD15; this interaction inhibits TFAP2A transcriptional activation.
May be an aberrantly processed form with no significant distribution in vivo.
Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes. AP-2 factors bind to the consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development. They also suppress a number of genes including MCAM/MUC18, C/EBP alpha and MYC. AP-2-alpha is the only AP-2 protein required for early morphogenesis of the lens vesicle. Together with the CITED2 coactivator, stimulates the PITX2 P1 promoter transcription activation. Associates with chromatin to the PITX2 P1 promoter region.
Sumoylated on Lys-10; which inhibits transcriptional activity.
The PPxY motif mediates interaction with WWOX.
Belongs to the glycosyltransferase 2 family.
Expressed in pancreas, placenta, liver, heart, brain, kidney, skeletal muscle, and lung.
Required for the assembly of lipid-linked oligosaccharides in kidney epithelial cells, and protein N-glycosylation. Required for polycystin-1 (PKD1) glycosylation and maturation.
(Microbial infection) Interacts with molluscum contagiosum virus protein MC148.
Chemoattractant active on T-lymphocytes and monocytes but not neutrophils. Activates the C-X-C chemokine receptor CXCR4 to induce a rapid and transient rise in the level of intracellular calcium ions and chemotaxis. SDF-1-beta(3-72) and SDF-1-alpha(3-67) show a reduced chemotactic activity. Binding to cell surface proteoglycans seems to inhibit formation of SDF-1-alpha(3-67) and thus to preserve activity on local sites. Also binds to atypical chemokine receptor ACKR3, which activates the beta-arrestin pathway and acts as a scavenger receptor for SDF-1. Binds to the allosteric site (site 2) of integrins and activates integrins ITGAV:ITGB3, ITGA4:ITGB1 and ITGA5:ITGB1 in a CXCR4-independent manner (PubMed:29301984). Acts as a positive regulator of monocyte migration and a negative regulator of monocyte adhesion via the LYN kinase. Stimulates migration of monocytes and T-lymphocytes through its receptors, CXCR4 and ACKR3, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for beta-2 integrins. SDF1A/CXCR4 signaling axis inhibits beta-2 integrin LFA-1 mediated adhesion of monocytes to ICAM-1 through LYN kinase. Inhibits CXCR4-mediated infection by T-cell line-adapted HIV-1. Plays a protective role after myocardial infarction. Induces down-regulation and internalization of ACKR3 expressed in various cells. Has several critical functions during embryonic development; required for B-cell lymphopoiesis, myelopoiesis in bone marrow and heart ventricular septum formation. Stimulates the proliferation of bone marrow-derived B-cell progenitors in the presence of IL7 as well as growth of stromal cell-dependent pre-B-cells (By similarity).
Isoform Alpha and isoform Beta are ubiquitously expressed, with highest levels detected in liver, pancreas and spleen. Isoform Gamma is mainly expressed in heart, with weak expression detected in several other tissues. Isoform Delta, isoform Epsilon and isoform Theta have highest expression levels in pancreas, with lower levels detected in heart, kidney, liver and spleen.
Isoform Alpha is ubiquitously expressed in fetal tissues. Isoform Beta and isoform Delta have more limited expression patterns, with highest levels detected in fetal spleen and fetal liver, respectively. Isoform Gamma and isoform Theta are weakly detected in fetal kidney.
Monomer or homodimer; in equilibrium. Dimer formation is induced by non acidic pH and the presence of multivalent anions, and by binding to CXCR4 or heparin. Monomeric form is required for full chemotactic activity and resistance to ischemia/reperfusion injury, whereas the dimeric form acts as a partial agonist of CXCR4, stimulating Ca2+ mobilization but with no chemotactic activity and instead acts as a selective antagonist that blocks chemotaxis induced by the monomeric form. Interacts with the N-terminus of ACKR3. Interacts with integrin subunit ITGB3 (via the allosteric site (site 2)) (PubMed:29301984). Interacts with TNFAIP6 (via Link domain).
Processed forms SDF-1-beta(3-72) and SDF-1-alpha(3-67) are produced after secretion by proteolytic cleavage of isoforms Beta and Alpha, respectively. The N-terminal processing is probably achieved by DPP4. Isoform Alpha is first cleaved at the C-terminus to yield a SDF-1-alpha(1-67) intermediate before being processed at the N-terminus. The C-terminal processing of isoform Alpha is reduced by binding to heparin and, probably, cell surface proteoglycans.
Essential for Golgi structural integrity.
Up-regulated by Golgi stress-inducing agent nigericin.
Belongs to the SLC29A/ENT transporter (TC 2.A.57) family.
Bidirectional uniporter involved in the facilitative transport of nucleosides and nucleobases, and contributes to maintaining their cellular homeostasis (PubMed:9396714, PubMed:9478986, PubMed:12527552, PubMed:10722669, PubMed:12590919, PubMed:21795683, PubMed:16214850). Functions as a Na(+)-independent, passive transporter (PubMed:9478986). Involved in the transport of nucleosides such as inosine, adenosine, uridine, thymidine, cytidine and guanosine (PubMed:9396714, PubMed:9478986, PubMed:12527552, PubMed:10722669, PubMed:12590919, PubMed:21795683, PubMed:16214850). Also able to transport purine nucleobases (hypoxanthine, adenine, guanine) and pyrimidine nucleobases (thymine, uracil) (PubMed:21795683, PubMed:16214850). Involved in nucleoside transport at basolateral membrane of kidney cells, allowing liver absorption of nucleoside metabolites (PubMed:12527552). Mediates apical nucleoside uptake into Sertoli cells, thereby regulating the transport of nucleosides in testis across the blood-testis-barrier (PubMed:23639800). Mediates both the influx and efflux of hypoxanthine in skeletal muscle microvascular endothelial cells to control the amount of intracellular hypoxanthine available for xanthine oxidase-mediated ROS production (By similarity).
Highly expressed in skeletal muscle (PubMed:9478986). Expressed in liver, lung, placenta, brain, heart, kidney and ovarian tissues (PubMed:9478986). Expressed in testis at the blood-brain-barrier (PubMed:23639800).
Non functional nucleoside transporter protein for adenosine or thymidine tranport. Does not express on cell membrane.
The nuclear function of SLC29A2/ENT2 is unclear. A study reported that under proliferative conditions, two SLC29A2/ENT2 nuclear isoforms recruited SLC29A2/ENT2 to the nuclear envelope in order to translocate nucleosides into the nucleus for incorporation into DNA during replication (PubMed:27271752). However, the physiological existence of these isoforms has yet to be proven.
Transport activity is insensitive to nanomolar concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR) (PubMed:9396714, PubMed:9478986, PubMed:10722669, PubMed:12590919, PubMed:21795683). Inhibited by higher concentrations of NBMPR (1uM-10uM) (PubMed:9396714, PubMed:9478986, PubMed:10722669, PubMed:12590919).
Belongs to the class I-like SAM-binding methyltransferase superfamily. NNMT/PNMT/TEMT family.
Catalyzes the N-methylation of nicotinamide using the universal methyl donor S-adenosyl-L-methionine to form N1-methylnicotinamide and S-adenosyl-L-homocysteine, a predominant nicotinamide/vitamin B3 clearance pathway (PubMed:8182091, PubMed:21823666, PubMed:23455543). Plays a central role in regulating cellular methylation potential, by consuming S-adenosyl-L-methionine and limiting its availability for other methyltransferases. Actively mediates genome-wide epigenetic and transcriptional changes through hypomethylation of repressive chromatin marks, such as H3K27me3 (PubMed:26571212, PubMed:23455543, PubMed:31043742). In a developmental context, contributes to low levels of the repressive histone marks that characterize pluripotent embryonic stem cell pre-implantation state (PubMed:26571212). Acts as a metabolic regulator primarily on white adipose tissue energy expenditure as well as hepatic gluconeogenesis and cholesterol biosynthesis. In white adipocytes, regulates polyamine flux by consuming S-adenosyl-L-methionine which provides for propylamine group in polyamine biosynthesis, whereas by consuming nicotinamide controls NAD(+) levels through the salvage pathway (By similarity). Via its product N1-methylnicotinamide regulates protein acetylation in hepatocytes, by repressing the ubiquitination and increasing the stability of SIRT1 deacetylase (By similarity). Can also N-methylate other pyridines structurally related to nicotinamide and play a role in xenobiotic detoxification (PubMed:30044909).
Predominantly expressed in the liver. A lower expression is seen in the kidney, lung, skeletal muscle, placenta and heart. Not detected in the brain or pancreas.
Prominently expressed in the stroma of high-grade serous carcinomas (PubMed:31043742). In tumorigenesis, regulates the epigenetic reprograming of cancer cells associated with increased cell migration and metastasis (PubMed:23455543, PubMed:31043742).
In bronchial mucosa, mainly expressed in ciliated and basal epithelial cells and weakly in alveolar cells (at protein level). Tends to be down-regulated in lung cancers, immortalized bronchial epithelial cell lines and precancerous lesions.
It is uncertain whether Met-1 or Met-6 is the initiator.
Receptor for the C-C type chemokine CCL20 (PubMed:9169459). Binds to CCL20 and subsequently transduces a signal by increasing the intracellular calcium ion levels (PubMed:20068036). Although CCL20 is its major ligand it can also act as a receptor for non-chemokine ligands such as beta-defensins (PubMed:25585877). Binds to defensin DEFB1 leading to increase in intracellular calcium ions and cAMP levels. Its binding to DEFB1 is essential for the function of DEFB1 in regulating sperm motility and bactericidal activity (PubMed:25122636). Binds to defensins DEFB4 and DEFB4A/B and mediates their chemotactic effects (PubMed:20068036). The ligand-receptor pair CCL20-CCR6 is responsible for the chemotaxis of dendritic cells (DC), effector/ memory T-cells and B-cells and plays an important role at skin and mucosal surfaces under homeostatic and inflammatory conditions, as well as in pathology, including cancer and various autoimmune diseases. CCR6-mediated signals are essential for immune responses to microbes in the intestinal mucosa and in the modulation of inflammatory responses initiated by tissue insult and trauma (PubMed:21376174). CCR6 is essential for the recruitment of both the pro-inflammatory IL17 producing helper T-cells (Th17) and the regulatory T-cells (Treg) to sites of inflammation. Required for the normal migration of Th17 cells in Peyers-patches and other related tissue sites of the intestine and plays a role in regulating effector T-cell balance and distribution in inflamed intestine. Plays an important role in the coordination of early thymocyte precursor migration events important for normal subsequent thymocyte precursor development, but is not required for the formation of normal thymic natural regulatory T-cells (nTregs). Required for optimal differentiation of DN2 and DN3 thymocyte precursors. Essential for B-cell localization in the subepithelial dome of Peyers-patches and for efficient B-cell isotype switching to IgA in the Peyers-patches. Essential for appropriate anatomical distribution of memory B-cells in the spleen and for the secondary recall response of memory B-cells (By similarity). Positively regulates sperm motility and chemotaxis via its binding to CCL20 (PubMed:23765988).
Sperm. Mainly localized in the tail and in the postacrosomal region but is also found in the midpiece and basal region in a small percentage of sperm cells. Reduced levels found in the sperms of asthenozoospermia and leukocytospermia patients (at protein level). Spleen, lymph nodes, appendix, and fetal liver. Expressed in lymphocytes, T-cells and B-cells but not in natural killer cells, monocytes or granulocytes.
Acts as a transcriptional activator. Involved in neurogenesis. Plays important roles in the early stage of organogenesis of the CNS, as well as during dorsal spinal cord development and maturation of the cerebellum. Involved in the spatial distribution of mossy fiber (MF) neurons within the pontine gray nucleus (PGN). Plays a role in the regulation of MF axon pathway choice. Promotes MF migration towards ipsilaterally-located cerebellar territories. May have a role in shear flow mechanotransduction in osteocytes. Retains nuclear GLI1 and GLI3 in the cytoplasm. Binds to the minimal GLI-consensus sequence 5'-TGGGTGGTC-3' (By similarity).
Belongs to the GLI C2H2-type zinc-finger protein family.
CNS. A high level expression is seen in the cerebellum. Detected in the nuclei of the cerebellar granule cell lineage from the progenitor cells of the external germinal layer to the postmigrated cells of the internal granular layer. Detected in medulloblastoma (26/29 cases), but not present in all other tumors examined.
Interacts (via the C2H2-type domains 3, 4 and 5) with MDFIC (via the C2H2-type domains 3, 4 and 5). Interacts with GLI1; the interaction enhances transcription activation. Interacts with GLI2. Interacts with GLI3; the interaction enhances transcription activation (By similarity).
The C2H2-type 3, 4 and 5 zinc finger domains are necessary for transcription activation.
Belongs to the Mediator complex subunit 9 family.
Belongs to the cation channel sperm-associated (TC 1.A.1.19) family.
Component of the CatSper complex or CatSpermasome composed of the core pore-forming members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 as well as auxiliary members CATSPERB, CATSPERG, CATSPERD, CATSPERE, CATSPERZ, C2CD6/CATSPERT, TMEM249, TMEM262 and EFCAB9 (By similarity). HSPA1 may be an additional auxiliary complex member (By similarity). The core complex members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 form a heterotetrameric channel. The auxiliary CATSPERB, CATSPERG, CATSPERD and CATSPERE subunits form a pavilion-like structure over the pore which stabilizes the complex through interactions with CATSPER4, CATSPER3, CATSPER1 and CATSPER2 respectively (By similarity). TMEM262/CATSPERH interacts with CATSPERB, further stabilizing the complex. C2CD6/CATSPERT interacts at least with CATSPERD and is required for targeting the CatSper complex in the flagellar membrane (By similarity).
In mouse, Slco6c1 is an additional auxiliary subunit of the CatSper complex. It is unclear if the related SLCO6A1 protein performs the same role in non-rodent species.
The CatSper calcium channel is indirectly activated by extracellular progesterone and prostaglandins following the sequence: progesterone > PGF1-alpha = PGE1 > PGA1 > PGE2 >> PGD2 (PubMed:21412338, PubMed:21412339, PubMed:26989199). The CatSper calcium channel is directly inhibited by endocannabinoid 2-arachidonoylglycerol (2AG) (PubMed:26989199). Indirect activation by progesterone takes place via the following mechanism: progesterone binds and activates the acylglycerol lipase ABHD2, which in turn mediates hydrolysis of 2AG inhibitor, relieving inhibition of the CatSper channel (PubMed:26989199). The primary effect of progesterone activation is to shift voltage dependence towards more physiological, negative membrane potentials; it is not mediated by metabotropic receptors and second messengers (PubMed:21412338, PubMed:21412339). Sperm capacitation enhances the effect of progesterone by providing additional negative shift. Also activated by the elevation of intracellular pH (PubMed:21412338, PubMed:21412339).
Voltage-gated calcium channel that plays a central role in calcium-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the oocyte.
Belongs to the PtdIns transfer protein family. PI transfer class I subfamily.
Catalyzes the transfer of phosphatidylinositol and phosphatidylcholine between membranes (PubMed:10531358, PubMed:18636990, PubMed:20332109). Also catalyzes the transfer of sphingomyelin (By similarity). Required for COPI-mediated retrograde transport from the Golgi to the endoplasmic reticulum; phosphatidylinositol and phosphatidylcholine transfer activity is essential for this function (PubMed:20332109).
Constitutive phosphorylation of Ser-262 has no effect on phospholipid transfer activity but is required for Golgi targeting.
Phosphatidylinositol transfer activity is inhibited by N-ethylmaleimide.
Widely expressed in various tissues including brain.
PPIases accelerate the folding of proteins during protein synthesis.
Belongs to the universal ribosomal protein uL18 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25278503). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins.
Together with thiosulfate sulfurtransferase (TST), acts as a mitochondrial import factor for the cytosolic 5S rRNA. The precursor form shows RNA chaperone activity; is able to fold the 5S rRNA into an import-competent conformation that is recognized by rhodanese (TST). Both the cytoplasmic and mitochondrial forms are able to bind to the helix IV-loop D in the gamma domain of the 5S rRNA.
May be involved in transcriptional regulation. May play a role in DNA repair process.
Although 2 transmembrane domains are predicted, PubMed:19269366 showed that it only contains one transmembrane domain. The other predicted transmembrane region is probably a hairpin-type region embedded into the membrane, which does not cross the membrane. It is unclear which of the 2 predicted transmembrane regions is the transmembrane or the hairpin-type region.
Belongs to the MIA/OTOR family. Tango1 subfamily.
Broadly expressed, except in bone marrow and peripheral blood mononuclear cells. Down-regulated in melanoma tissue.
Interacts with MIA2 (PubMed:21525241). Interacts (via SH3 domain) with COL7A1 (PubMed:19269366). Interacts with the COPII coat subunits SEC23A, SEC23B and maybe SEC24C (PubMed:19269366, PubMed:27551091, PubMed:28442536). May interact with APOB and MIA2 (PubMed:27138255). Isoform 1 and isoform 4 interact with SEC16A (PubMed:28442536).
Plays a role in the transport of cargos that are too large to fit into COPII-coated vesicles and require specific mechanisms to be incorporated into membrane-bound carriers and exported from the endoplasmic reticulum. This protein is required for collagen VII (COL7A1) secretion by loading COL7A1 into transport carriers. It may participate in cargo loading of COL7A1 at endoplasmic reticulum exit sites by binding to COPII coat subunits Sec23/24 and guiding SH3-bound COL7A1 into a growing carrier. Does not play a role in global protein secretion and is apparently specific to COL7A1 cargo loading. However, it may participate in secretion of other proteins in cells that do not secrete COL7A1. It is also specifically required for the secretion of lipoproteins by participating in their export from the endoplasmic reticulum (PubMed:27138255, PubMed:19269366). Required for correct assembly of COPII coat components at endoplasmic reticulum exit sites (ERES) and for the localization of SEC16A and membrane-bound ER-resident complexes consisting of MIA2 and PREB/SEC12 to ERES (PubMed:28442536).
The proline-rich domain (PRD) contains repeated PPP motifs. A single PPP motif is necessary and sufficient to mediate interaction with the COPII coat subunits SEC23A and SEC23B.
Extracts misfolded glycoproteins, but not glycoproteins undergoing productive folding, from the calnexin cycle. It is directly involved in endoplasmic reticulum-associated degradation (ERAD) and targets misfolded glycoproteins for degradation in an N-glycan-independent manner, probably by forming a complex with SEL1L. It has low mannosidase activity, catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2.
Interacts with DNAJC10 (By similarity). Interacts with DERL2 and DERL3. Binds to SEL1L.
Expressed in fetal liver, adult brain and pancreatic islet as well as in kidney tumors, uterus cancer and pancreatic cancer.
Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
Laminin is a complex glycoprotein, consisting of three different polypeptide chains (alpha, beta, gamma), which are bound to each other by disulfide bonds into a cross-shaped molecule comprising one long and three short arms with globules at each end. Alpha-2 is a subunit of laminin-2 (laminin-211 or merosin), laminin-4 (laminin-221 or S-merosin) and laminin-12 (laminin-213). Interacts with FBLN1, FBLN2 and NID2.
Placenta, striated muscle, peripheral nerve, cardiac muscle, pancreas, lung, spleen, kidney, adrenal gland, skin, testis, meninges, choroid plexus, and some other regions of the brain; not in liver, thymus and bone.
The alpha-helical domains I and II are thought to interact with other laminin chains to form a coiled coil structure.
Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions.
Apolipoprotein C-I is present in acidic (APOC1A) and basic (APOC1B) forms in P.paniscus, P.abelii and P.troglodytes and perhaps also in baboons and macaques. The two genes for ApoC-I arose through a duplication process that occurred after the divergence of New World monkeys from the human lineage. In human, the acidic form has become a pseudogene sometime between the divergence of bonobos and chimpanzees from the human lineage and the appearance of the Denisovans. Pseudogenization resulted when the codon for the penultimate amino acid in the signal sequence was changed to a stop codon.
Belongs to the apolipoprotein C1 family.
Inhibitor of lipoprotein binding to the low density lipoprotein (LDL) receptor, LDL receptor-related protein, and very low density lipoprotein (VLDL) receptor. Associates with high density lipoproteins (HDL) and the triacylglycerol-rich lipoproteins in the plasma and makes up about 10% of the protein of the VLDL and 2% of that of HDL. Appears to interfere directly with fatty acid uptake and is also the major plasma inhibitor of cholesteryl ester transfer protein (CETP). Binds free fatty acids and reduces their intracellular esterification. Modulates the interaction of APOE with beta-migrating VLDL and inhibits binding of beta-VLDL to the LDL receptor-related protein.
Synthesized mainly in liver and to a minor degree in intestine. Also found in the lung and spleen.
Belongs to the amino acid/polyamine transporter 2 family.
Putative sodium-dependent amino acid/proton antiporter.
Belongs to the metallothionein superfamily. Type 1 family.
Class I metallothioneins contain 2 metal-binding domains: four divalent ions are chelated within cluster A of the alpha domain and are coordinated via cysteinyl thiolate bridges to 11 cysteine ligands. Cluster B, the corresponding region within the beta domain, can ligate three divalent ions to 9 cysteines.
Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids.
Binds ubiquitinated proteins via its RanBP2-type zinc finger.
Expressed at highest levels in brain, heart, skeletal muscle, kidney and fetal liver.
Heterodimer with UFD1 (PubMed:11574150, PubMed:26471729). The heterodimer binds ubiquitinated proteins (By similarity). The heterodimer binds to VCP and inhibits Golgi membrane fusion (PubMed:11574150, PubMed:26471729). Interacts with ZFAND2B; probably through VCP (PubMed:24160817).
The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope (By similarity). Acts as a negative regulator of type I interferon production via the complex formed with VCP and UFD1, which binds to RIGI and recruits RNF125 to promote ubiquitination and degradation of RIGI (PubMed:26471729).
Component of the fork protection machinery required to protect stalled/damaged replication forks from uncontrolled DNA2-dependent resection. Acts by stabilizing RAD51 at stalled replication forks and protecting RAD51 nucleofilaments from the antirecombinogenic activities of FBH1 and BLM (PubMed:26166705, PubMed:29937342). Does not regulate spindle orientation (PubMed:26166705).
Interacts (via COMPASS-Shg1 domain) with SETD1A at stalled replication forks; this interaction mediates FANCD2-dependent nucleosome remodeling at reversed forks protecting them from nucleolytic degradation.
Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the helicase ATP-binding and the helicase C-terminal domain of INO80. Interacts with RP9.
Induces growth and cell cycle arrests at the G1 phase of the cell cycle.
Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.
Homodimer. Forms a signaling complex with LCK; PTK2B/PYK2 and PI3-kinase upon activation by EFNA1; regulates T-lymphocytes migration. Interacts (via SAM domain) with ILK (via ANK repeats); stimulated by EFNA1 but independent of the kinase activity of EPHA1. Interacts (kinase activity-dependent) with PTK2/FAK1.
Phosphorylated. Autophosphorylation is stimulated by its ligand EFNA1.
Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Binds with a low affinity EFNA3 and EFNA4 and with a high affinity to EFNA1 which most probably constitutes its cognate/functional ligand. Upon activation by EFNA1 induces cell attachment to the extracellular matrix inhibiting cell spreading and motility through regulation of ILK and downstream RHOA and RAC. Also plays a role in angiogenesis and regulates cell proliferation. May play a role in apoptosis.
Binds to the dendritic targeting element and may play a role in mRNA trafficking (By similarity). Part of a ternary complex that binds to the downstream control sequence (DCS) of the pre-mRNA. Mediates exon inclusion in transcripts that are subject to tissue-specific alternative splicing. May interact with single-stranded DNA from the far-upstream element (FUSE). May activate gene expression. Also involved in degradation of inherently unstable mRNAs that contain AU-rich elements (AREs) in their 3'-UTR, possibly by recruiting degradation machinery to ARE-containing mRNAs.
Detected in neural and non-neural cell lines.
KH domains KH 3 and KH 4 behave as independent binding modules and can interact with different regions of the AU-rich RNA targets of degradation.
Part of a ternary complex containing FUBP2, PTBP1, PTBP2 and HNRPH1 (PubMed:11003644). Interacts with PARN (PubMed:15175153). Interacts with PQBP1 (PubMed:21933836).
Phosphorylation at Ser-193 leads to the unfolding of the unstable KH domain 1, creating a site for 14-3-3 YWHAZ binding, which promotes nuclear localization and impairs the RNA degradation function.
Expressed preferentially in cartilaginous tissues and pancreas. Highly expressed in the liver, kidney, heart, brain and skeletal muscle. Weakly expressed in the lung, small intestine and spleen.
Has a negative effect on cell proliferation.
Interacts with FGF2 with a low affinity.
In contrast to the ortholog protein in primates, human KIF25 protein is shorter at the N-terminus. While the kinesin motor domain is intact, it is unknown whether the absence of the N-terminus affects the microtubule-dependent motor activity.
Minus-end microtubule-dependent motor protein (By similarity). Acts as a negative regulator of centrosome separation required to prevent premature centrosome separation during interphase (PubMed:28263957). Required to maintain a centered nucleus to ensure that the spindle is stably oriented at the onset of mitosis (PubMed:28263957). May also act as a negative regulator of amino acid starvation-induced autophagy (PubMed:22354037).
Highly expressed in placenta, pancreas and hepatoma cells. Lower levels found in skeletal muscle, heart and colon carcinoma and melanoma cell lines.
There are 3 carboxypeptidase-like domains. Only the first two domains seem to have kept a catalytic activity.
Expressed in placenta, maternal decidua and fetal membranes. Within placenta, expressed in trophoblasts, stromal cells, villous endothelium, syncytiotrophoblast apical membrane and villous stroma. Within fetal membranes, expressed in amnion, chorioamniotic mesenchyma and chorion (at protein level). Expressed in cardiac, smooth, and skeletal muscle, neurons, thymus, kidney and hematopoietic cells.
Homodimer. Binds LGALS3BP. Interacts with CD2, CD3, CD4, CD6, CD7, CD43, ALCAM and CD45. Interacts with laminin (via poly-N-acetyllactosamine). Interacts with SUSD2. Interacts with cargo receptor TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion (PubMed:32272059).
Lectin that binds beta-galactoside and a wide array of complex carbohydrates. Plays a role in regulating apoptosis, cell proliferation and cell differentiation. Inhibits CD45 protein phosphatase activity and therefore the dephosphorylation of Lyn kinase. Strong inducer of T-cell apoptosis.
Belongs to the NFYA/HAP2 subunit family.
Component of the sequence-specific heterotrimeric transcription factor (NF-Y) which specifically recognizes a 5'-CCAAT-3' box motif found in the promoters of its target genes. NF-Y can function as both an activator and a repressor, depending on its interacting cofactors. NF-YA positively regulates the transcription of the core clock component BMAL1.
Heterotrimeric transcription factor composed of three components, NF-YA, NF-YB and NF-YC. NF-YB and NF-YC must interact and dimerize for NF-YA association and DNA binding. Interacts with SP1; the interaction is inhibited by glycosylation of SP1. Interacts with ZHX1. Interacts (via N-terminus) with ZHX2 (via homeobox domain). Interacts with ZFX3.
E3 ubiquitin-protein ligase that participates in multiple biological processes including cell survival, differentiation, apoptosis, and in particular, the innate immune response (PubMed:27981609, PubMed:28747347). Participates in the activation of interferon-gamma signaling by promoting proteasomal degradation of the repressor SOCS1 (PubMed:12163497). Plays a positive role in the TNFalpha and IL-1beta signaling pathways. Mechanistically, induces the 'Lys-63'-linked polyubiquitination of MAP3K7/TAK1 component leading to the activation of NF-kappa-B (PubMed:22084099, PubMed:23152791, PubMed:27981609, PubMed:34871740). Modulates also STAT3 activity through negative regulation of PIAS3, either by degradation of PIAS3 through the ubiquitin-proteasome pathway or exclusion of PIAS3 from the nucleus (PubMed:20516148). Negatively regulates TLR3/4-mediated innate immune response by catalyzing 'Lys-6'- and 'Lys-33'-linked polyubiquitination of TICAM1 and thereby disrupting the TICAM1-TBK1 interaction (PubMed:28747347).
Homodimer. Interacts with SOCS1 (via) SH2 domain and SOCS box (PubMed:12163497). Interacts with HSP90AB1; prevents nucleus translocation of phosphorylated STAT3 and HSP90AB1. Interacts with MAP3K7/TAK1 (PubMed:22084099). Interacts with PIAS3 (PubMed:20516148). Interacts with TICAM1 (PubMed:28747347). Interacts with TRIM15; this interaction prevents TRIM8 cytoplasmic translocation (PubMed:34871740).
The coiled coil domain is required for homodimerization.
The region immediately C-terminal to the RING motif is sufficient to mediate the interaction with SOCS1.
Widely expressed. Expressed in glomerular podocytes of kidneys.
Antibodies against GM88 are present in serum from a patient with Sjoegren syndrome. Sera from patients with Sjoegren syndrome often contain antibodies that react with normal components of the Golgi complex.
Extended rod-like protein with coiled-coil domains.
Highly expressed in brain, heart and kidney. Detected at lower levels in liver, thymus, spleen, lung and peripheral blood leukocytes.
Interacts through its PDZ domain with the C-terminal regions of VANGL1 and VANGL2. Interacts with Rac. Interacts with ARRB1; the interaction is enhanced by phosphorylation of DVL1 (By similarity). Can form large oligomers (via DIX domain). Interacts (via DIX domain) with DIXDC1 (via DIX domain). Interacts (via DEP domain) with AP2M1 and the AP-2 complex (By similarity). Interacts with DACT1 and FAM105B/otulin. Interacts with DCDC2. Interacts (when phosphorylated) with FOXK1 and FOXK2; the interaction induces DVL2 nuclear translocation (PubMed:25805136). Interacts with MAPK15 (By similarity). Interacts with PKD1 (via extracellular domain) (PubMed:27214281). Interacts with LMBR1L (By similarity).
Phosphorylated by CSNK1D (PubMed:21422228, PubMed:9192851). WNT3A induces DVL2 phosphorylation by CSNK1E and MARK kinases (PubMed:25805136).
Plays a role in the signal transduction pathways mediated by multiple Wnt genes. Participates both in canonical and non-canonical Wnt signaling by binding to the cytoplasmic C-terminus of frizzled family members and transducing the Wnt signal to down-stream effectors. Promotes internalization and degradation of frizzled proteins upon Wnt signaling.
The DIX domain mediates homooligomerization.
A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children.
Belongs to the SRC/p160 nuclear receptor coactivator family.
Contains 7 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. LXXLL motifs 3, 4 and 5 are essential for the association with nuclear receptors. LXXLL motif 7, which is not present in isoform 2, increases the affinity for steroid receptors in vitro.
Interacts with PPARA; the interaction is direct (PubMed:11698662). Interacts with PPARG; the interaction is direct (PubMed:11698662, PubMed:9744270). Interacts with ESRRG; the interaction is direct (PubMed:11864604). Interacts with STAT5A (via FDL motif) (PubMed:12954634). Interacts with STAT5B (via FDL motif) (PubMed:12954634). Interacts with STAT6 (via LXXLL motif) (PubMed:12138096). Interacts (via LXXLL 1, 2 and 3 motifs) with RORC (via AF-2 motif) (By similarity). Interacts with ASXL1 (PubMed:16606617). Interacts with the methyltransferase CARM1 (By similarity). Interacts with COPS5 (PubMed:10722692). Interacts with the histone acetyltransferase CREBBP (By similarity). Interacts with DDX5 (PubMed:11250900). Interacts with the histone acetyltransferase EP300 (By similarity). Interacts with ESR1 (PubMed:7481822). Interacts with GCCR (PubMed:7481822). Interacts with the basal transcription factor GTF2B (PubMed:8754792). Interacts with NCOA6 (PubMed:10567404). Interacts with NCOA2 (PubMed:10594042). Interacts with NR3C1 (PubMed:12917342). Interacts with NR4A1/Nur77 (PubMed:18690216). Interacts with NR4A3 (By similarity). Interacts with PCAF (PubMed:9296499). Interacts with PGR (PubMed:7481822). Interacts with PRMT2 (PubMed:12039952). Interacts with PRMT6 (PubMed:20047962). Interacts with PSMB9 (PubMed:16957778). Interacts with RXRA, the interaction is ligand-dependent (PubMed:19786558, PubMed:7481822). Interacts with STAT3 following IL-6 stimulation (PubMed:11773079). Interacts with TRA (PubMed:7481822). Interacts with TRIP4 (PubMed:25219498). Interacts with TTLL5/STAMP (PubMed:17116691). Interacts with UBE2L3; they functionally interact to regulate progesterone receptor transcriptional activity (PubMed:15367689). Interacts with VDR (PubMed:28698609).
Major form. Contains a domain at its C-terminus (1241-1399) that is able to mediate transactivation.
Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.
Sumoylated; sumoylation increases its interaction with PGR and prolongs its retention in the nucleus. It does not prevent its ubiquitination and does not exert a clear effect on the stability of the protein.
The C-terminal (1107-1441) part mediates the histone acetyltransferase (HAT) activity.
Ubiquitinated; leading to proteasome-mediated degradation. Ubiquitination and sumoylation take place at different sites.
(Microbial infection) Acts as a receptor for human cytomegalovirus protein UL11 and mediates binding of UL11 to T-cells, leading to reduced induction of tyrosine phosphorylation of multiple signaling proteins upon T-cell receptor stimulation and impaired T-cell proliferation.
(Microbial infection) Interacts with human cytomegalovirus protein UL11; the interaction is required for binding of UL11 to T-cells.
Belongs to the protein-tyrosine phosphatase family. Receptor class 1/6 subfamily.
Binds GANAB and PRKCSH (By similarity). Interacts with SKAP1 (PubMed:11909961). Interacts with DPP4; the interaction is enhanced in an interleukin-12-dependent manner in activated lymphocytes (PubMed:12676959).
Disease susceptibility may be associated with variants affecting the gene represented in this entry.
Isoform 1: Detected in thymocytes. Isoform 2: Detected in thymocytes. Isoform 3: Detected in thymocytes. Isoform 4: Not detected in thymocytes. Isoform 5: Detected in thymocytes. Isoform 6: Not detected in thymocytes. Isoform 7: Detected in thymocytes. Isoform 8: Not detected in thymocytes.
Isoform 1: During T-cell development, expressed at the CD3-CD4-CD8- and CD3+CD4+CD8- stages but barely detectable at the CD3-CD4+CD8+ stage. Isoform 2: During T-cell development, expressed at low levels at the CD3-CD4-CD8- and CD3-CD4+CD8- stages but up-regulated at the CD3+CD4+CD8+ and CD3+CD4+CD8- stages. Isoform 3: During T-cell development, expressed at the CD3-CD4-CD8- and CD3+CD4+CD8- stages but barely detectable at the CD3-CD4+CD8+ stage. Isoform 5: During T-cell development, expressed at the CD3-CD4-CD8- and CD3+CD4+CD8- stages but barely detectable at the CD3-CD4+CD8+ stage. Isoform 7: Consistently expressed at high levels at all stages of T-cell development.
Protein tyrosine-protein phosphatase required for T-cell activation through the antigen receptor. Acts as a positive regulator of T-cell coactivation upon binding to DPP4. The first PTPase domain has enzymatic activity, while the second one seems to affect the substrate specificity of the first one. Upon T-cell activation, recruits and dephosphorylates SKAP1 and FYN. Dephosphorylates LYN, and thereby modulates LYN activity (By similarity).
The first PTPase domain interacts with SKAP1.
Acts as guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases. Binding of APC may activate RAC1 GEF activity. The APC-ARHGEF4 complex seems to be involved in cell migration as well as in E-cadherin-mediated cell-cell adhesion. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression.
Expressed at high levels in the brain, skeletal muscle and testis and at low levels in the kidney, lung, small intestine, ovary and prostate. Expression is aberrantly enhanced in most colorectal tumors.
In an autoinhibited form the SH3 domain binds intramolecularly to the DH domain, thus blocking the Rac-binding site.
Isoform 3 interacts with RHOA and RAC1, and (via ABR domain) with APC. Found in a complex consisting of ARHGEF4, APC and CTNNB1.
Abundant in hepatoma cells and fetal cochlea, ovary, eye, heart, adrenal gland, liver and kidney. Low levels present in adult peripheral blood leukocytes and fetal brain, thymus, spleen, skeletal muscle, lung and tongue.
Belongs to the aldehyde dehydrogenase family.
Multifunctional enzyme mediating important protective effects. Metabolizes betaine aldehyde to betaine, an important cellular osmolyte and methyl donor. Protects cells from oxidative stress by metabolizing a number of lipid peroxidation-derived aldehydes. Involved in lysine catabolism.
Ammonium transporter involved in the maintenance of acid-base homeostasis. Transports ammonium and its related derivative methylammonium across the plasma membrane of epithelial cells likely contributing to renal transepithelial ammonia transport and ammonia metabolism. Postulated to primarily mediate an electroneutral bidirectional transport of NH3 ammonia species according to a mechanism that implies interaction of an NH4(+) ion with acidic residues of the pore entry followed by dissociation of NH4(+) into NH3 and H(+). As a result NH3 transits through the central pore and is protonated on the extracellular side reforming NH4(+) (PubMed:11062476, PubMed:14761968, PubMed:15929723, PubMed:16477434, PubMed:16580862, PubMed:24077989). May act as a CO2 channel providing for renal acid secretion (PubMed:24077989).
Expressed in brain, testis, placenta, pancreas, esophagus and prostate. Expressed in squamous epithelial tissues (at protein level). Expressed in kidney.
Belongs to the 1-acyl-sn-glycerol-3-phosphate acyltransferase family.
Exhibits acyltransferase activity (PubMed:21498505, PubMed:18156367). Exhibits acetyltransferase activity (By similarity). Activity is calcium-independent (By similarity). Catalyzes the conversion of lysophosphatidylcholine (1-acyl-sn-glycero-3-phosphocholine or LPC) into phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine or PC) (PubMed:21498505, PubMed:18156367). Catalyzes the conversion 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone (By similarity). Displays a clear preference for saturated fatty acyl-CoAs, and 1-myristoyl or 1-palmitoyl LPC as acyl donors and acceptors, respectively (By similarity). Involved in platelet-activating factor (PAF) biosynthesis by catalyzing the conversion of the PAF precursor, 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) into 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) (By similarity). May synthesize phosphatidylcholine in pulmonary surfactant, thereby playing a pivotal role in respiratory physiology (By similarity). Involved in the regulation of lipid droplet number and size (PubMed:25491198).
The HXXXXD motif is essential for acyltransferase activity and may constitute the binding site for the phosphate moiety of the glycerol-3-phosphocholine.
The di-lysine motif may confer endoplasmic reticulum localization.
(Microbial infection) Monomeric actin is cross-linked by V.cholerae toxins RtxA and VgrG1 in case of infection: bacterial toxins mediate the cross-link between Lys-52 of one monomer and Glu-272 of another actin monomer, resulting in formation of highly toxic actin oligomers that cause cell rounding (PubMed:19015515). The toxin can be highly efficient at very low concentrations by acting on formin homology family proteins: toxic actin oligomers bind with high affinity to formins and adversely affect both nucleation and elongation abilities of formins, causing their potent inhibition in both profilin-dependent and independent manners (PubMed:26228148).
ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, premature onset coronary artery disease (CAD), premature ischemic strokes and Moyamoya disease.
Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
In vertebrates 3 main groups of actin isoforms, alpha, beta and gamma have been identified. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins coexist in most cell types as components of the cytoskeleton and as mediators of internal cell motility.
Monomethylation at Lys-86 (K84me1) regulates actin-myosin interaction and actomyosin-dependent processes. Demethylation by ALKBH4 is required for maintaining actomyosin dynamics supporting normal cleavage furrow ingression during cytokinesis and cell migration.
N-terminal cleavage of acetylated cysteine of intermediate muscle actin by ACTMAP.
Oxidation of Met-46 and Met-49 by MICALs (MICAL1, MICAL2 or MICAL3) to form methionine sulfoxide promotes actin filament depolymerization. MICAL1 and MICAL2 produce the (R)-S-oxide form. The (R)-S-oxide form is reverted by MSRB1 and MSRB2, which promotes actin repolymerization.
Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to 4 others.
Binds to heparin, dermatan sulfate and chondroitin sulfate.
CETN2-binding regions contains a conserved Trp residue in their C-terminal ends, which seems critical for interaction with CETN2.
It is uncertain whether Met-1 or Met-24 is the initiator.
Plays a role in the dynamic structure of centrosome-associated contractile fibers via its interaction with CETN2.
Belongs to the DNA2/NAM7 helicase family.
Contains 5 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. These motifs are not required for interaction with PPARG.
Expressed in various tissues including heart, pancreas, skeletal muscle, colon, spleen, liver, kidney, lung, peripheral blood and placenta.
Helicase that acts as a transcriptional coactivator for a number of nuclear receptors including PPARA, PPARG, THRA, THRB and RXRA.
Interacts with PPARA (via DNA-binding domain) and PPARG; the interaction stimulates the transcriptional activity of PPARA and PPARG. Interacts with THRAP3; the interaction is direct and HELZ2 and THRAP3 synergistically enhance the transcriptional activity of PPARG. It is probably part of the peroxisome proliferator activated receptor alpha interacting complex (PRIC).
More abundantly expressed than isoform 2.
PubMed:12189208 experiments have been carried out partly in rat and partly in human.
Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol (PubMed:9407135, PubMed:25375833). Exhibits almost no acyl chain preference for PA, showing no discrimination for the sn-1/sn-2 acyl chain composition of PAs (PubMed:25375833). Plays an important role in regulating the growth of lipid droplets which are storage organelles at the center of lipid and energy homeostasis (PubMed:26946540, PubMed:31548309). Positively regulates the differentiation and development of adipocytes (By similarity).
Expressed in adult tissues such as placenta, brain, small intestine, ovary, testis and prostate. Highly expressed in fetal kidney, lung and brain. Lower level in fetal liver.
Homodimer (By similarity). Interacts with FOS; this interaction may enhance catalytic activity (By similarity).
Inhibited by its anionic phospholipid end products, with phosphatidylinositol-(4,5)- bisphosphate showing the strongest inhibition.
Expressed at very low level in most fetal tissues, but at higher levels in skeletal muscle and lung.
Interacts with AP2B1 (By similarity). Interacts with ZFYVE26. Interacts with AP1G1 and AP1G2.
Plus end-directed microtubule-dependent motor protein involved in intracellular transport and regulating various processes such as mannose-6-phosphate receptor (M6PR) transport to the plasma membrane, endosomal sorting during melanosome biogenesis and cytokinesis. Mediates the transport of M6PR-containing vesicles from trans-Golgi network to the plasma membrane via direct interaction with the AP-1 complex. During melanosome maturation, required for delivering melanogenic enzymes from recycling endosomes to nascent melanosomes by creating peripheral recycling endosomal subdomains in melanocytes. Also required for the abcission step in cytokinesis: mediates translocation of ZFYVE26, and possibly TTC19, to the midbody during cytokinesis.
Widely expressed, with highest levels in heart, brain and skeletal muscle.
Has also a catalytic activity and catalyzes two steps in the biosynthesis of the molybdenum cofactor. In the first step, molybdopterin is adenylated. Subsequently, molybdate is inserted into adenylated molybdopterin and AMP is released.
Homotrimer, homodimer and homooligomer (PubMed:26613940). Interacts with GABARAP (By similarity). Interacts with SRGAP2 (via SH3 domain) (By similarity). Interacts with GABRA3 (PubMed:26613940). Interacts with GLRB (PubMed:26613940, PubMed:12684523). GABRA3 and GLRB occupy overlapping binding sites (By similarity). Interacts with ARHGAP32; IQSEC3, INSYN1 and INSYN2A (By similarity).
In the C-terminal section; belongs to the MoeA family.
In the N-terminal section; belongs to the MoaB/Mog family.
Microtubule-associated protein involved in membrane protein-cytoskeleton interactions. It is thought to anchor the inhibitory glycine receptor (GLYR) to subsynaptic microtubules (By similarity). Acts as a major instructive molecule at inhibitory synapses, where it also clusters GABA type A receptors (PubMed:25025157, PubMed:26613940).
Palmitoylated (PubMed:25025157). Palmitoylation is stimulated by GABA type A receptors activity (By similarity). Palmitoylation by ZDHHC12 regulates clustering at synapses (PubMed:25025157).
Expressed in single blastomeres from 8-cell stage embryos.
Transcription factor that acts as repressor.
Belongs to the Dus family. Dus1 subfamily.
Catalyzes the synthesis of dihydrouridine, a modified base found in the D-loop of most tRNAs.
May play a role in meiotic resumption and pronuclear formation, mediated by a WW domain-signaling pathway during fertilization.
Expressed in appendix, brain, colon, fetal liver, heart, ovary, pancreas, placenta, prostate, skeletal muscle, small intestine, spleen, testis and thymus.
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Interacts with FBL and PPP1R26 (PubMed:16053918, PubMed:17498821).
Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. Involved in 18S pre-rRNA processing. Associates with U3 snoRNA.
A chromosomal aberration involving BTG1 may be a cause of a form of B-cell chronic lymphocytic leukemia. Translocation t(8;12)(q24;q22) with MYC.
Its expression is associated with the early G1 phase of the cell cycle.
Belongs to the major facilitator superfamily. Monocarboxylate porter (TC 2.A.1.13) family.
Proton-linked monocarboxylate transporter. May catalyze the transport of monocarboxylates across the plasma membrane.
Plays an important role in regulating the size of autophagosomes during the formation process.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-, as well as 'Lys-63'-linked polyubiquitination. May be involved in degradation of muscle-specific proteins. Mediates polyubiquitination of CYP3A4.
Widely expressed, mainly in skeletal muscle.
Expressed in many tissues, including the stomach, intestine and hypothalamus.
Zn(2+) acts as an agonist. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated mainly through G(q)-alpha and G(12)/G(13) proteins. Involved in regulation of body weight, gastrointestinal mobility, hormone secretion and cell death (By similarity).
Basal expression under nonstress conditions; expression increases transiently after endoplasmic reticulum (ER) stress.
Elevated expression in medulloblastomas (PubMed:12800201). Patients with cancer had 2 to 12-fold higher frequencies of antibodies against this antigen (PubMed:12800201).
Interacts with RNF5 and MAPK8, but not with MAPK9. Binding to MAPK8 occurs before and after exposure to stress, such as UV irradiation. After exposure to stress, interacts with phosphorylated MAPK8. Competes with DUSP10 for MAPK8 binding. Associates with multiple components of the proteasome and with ERAD regulatory proteins including AMFR/GP78, CANX, PSMC1, PSMC2, PSMC3/TBP1, PSMC5, PSMC6, PSMD8, SEC61-ALPHA and UFD1 (By similarity). Interacts with DERL1 (in the presence of misfolded protein CFTR(F508del)) (PubMed:18784250).
Regulates the duration of MAPK8 activity in response to various stress stimuli (By similarity). Facilitates degradation of misfolded endoplasmic reticulum (ER) proteins through the recruitment of components of the proteasome and endoplasmic reticulum-associated degradation (ERAD) system (PubMed:18784250).
Ubiquitinated by RNF5 via 'Lys-63'-linked ubiquitin linkage in a UBE2N-dependent manner. Ubiquitination decreases association with components of the proteasome and ERAD.
Functions as a transcriptional repressor. May repress OTX2-mediated transactivation by forming a heterodimer with OTX2 on the P3C (5'-TAATCCGATTA-3') sequence. Required for brain development (By similarity).
Homodimer or heterodimer. Forms heterodimers with OTX2 (By similarity).
(Microbial infection) Activated by Aichi virus protein 3A, this activation is sensitized by ACBD3.
(Microbial infection) Interacts with Aichi virus protein 3A. Part of a complex Aichi virus protein 3A/ACBD3/PI4KB that allows the synthesis of PI4P at the viral RNA replication sites.
(Microbial infection) Plays an essential role in Aichi virus RNA replication (PubMed:22124328, PubMed:27989622, PubMed:22258260). Recruited by ACBD3 at the viral replication sites (PubMed:22124328, PubMed:27989622).
(Microbial infection) Required for cellular spike-mediated entry of human coronavirus SARS-CoV.
Belongs to the PI3/PI4-kinase family. Type III PI4K subfamily.
Expressed in 11-week old fetal inner ear.
Inhibited by wortmannin and adenosine (PubMed:11277933). Increased kinase activity upon interaction with NCS1/FREQ (By similarity).
Interacts with ARF1 and ARF3 in the Golgi complex, but not with ARF4, ARF5 or ARF6 (PubMed:17555535). Interacts with NCS1/FREQ in a calcium-independent manner. Interacts with CALN1/CABP8 and CALN2/CABP7; in a calcium-dependent manner; this interaction competes with NCS1/FREQ binding (By similarity). Interacts with ACBD3 (PubMed:23572552, PubMed:27009356, PubMed:27989622, PubMed:22124328, PubMed:22258260). Interacts with ARMH3, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ, YWHAZ and SFN (PubMed:23572552). Interacts with GGA2 (via VHS domain); the interaction is important for PI4KB location at the Golgi apparatus membrane (PubMed:28289207). Interacts with ATG9A (PubMed:30917996).
Phosphorylates phosphatidylinositol (PI) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate (PIP). May regulate Golgi disintegration/reorganization during mitosis, possibly via its phosphorylation. Involved in Golgi-to-plasma membrane trafficking (By similarity) (PubMed:10559940, PubMed:11277933, PubMed:12749687, PubMed:9405935). May play an important role in the inner ear development.
Widely expressed with highest levels in heart, skeletal muscle, pancreas, testis and ovary. Weakly expressed in liver (PubMed:9020160, PubMed:9405935, PubMed:9405938). Expressed in the innear ear in the epithelium of the spinal organ of corti.
Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1CC. Interacts with PPP1CA, WDR82 and TOX4 (By similarity).
Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Phosphorylated on Ser-398 by PKA within the region necessary for interaction with PPP1CA.
Scaffold protein which mediates the formation of the PTW/PP1 phosphatase complex by providing a binding platform to each component of the complex. The PTW/PP1 phosphatase complex plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Mediates interaction of WDR82 and PPP1CA. Inhibitor of PPP1CA and PPP1CC phosphatase activities. Has inhibitory activity on PPP1CA only when phosphorylated. Binds to mRNA, single-stranded DNA (ssDNA), poly(A) and poly(G) homopolymers (By similarity).
Scaffold protein which mediates the formation of the PTW/PP1 phosphatase complex by providing a binding platform to each component of the complex. The PTW/PP1 phosphatase complex plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Mediates interaction of WDR82 and PPP1CA. Inhibitor of PPP1CA and PPP1CC phosphatase activities. Has inhibitory activity on PPP1CA only when phosphorylated. Binds to mRNA, single-stranded DNA (ssDNA), poly(A) and poly(G) homopolymers.
Contaminating sequence. Sequence of unknown origin in the N-terminal part.
Dendrite-specific motor protein which, in association with the Apba1-containing complex (LIN-10-LIN-2-LIN-7 complex), transports vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules.
Homodimer (By similarity). Interacts with APBA1 (via PDZ domain); the interaction is direct and is required for association of KIF17 with the cargo that is to be transported (By similarity). Interacts with IFT B complex components IFT52 and IFT57 (By similarity). Interacts with IFT70B (By similarity). Interacts with PIWIL1 (By similarity). Interacts with TBATA (By similarity).
Adapter protein that interacts with the cytoplasmic domain of numerous receptor kinases and modulates down-stream signaling. Promotes activation of down-stream protein kinases, including STAT3, AKT1, MAPK1 and/or MAPK3. Promotes activation of HRAS. Plays a role in signal transduction in response to EGF. Plays a role in the regulation of cell proliferation and cell migration. Plays a role in the assembly and stability of RNA stress granules. Binds to the 5'UTR of target mRNA molecules and represses translation of target mRNA species, when not phosphorylated. Phosphorylation impairs RNA binding and promotes stress granule disassembly during recovery after cellular stress (By similarity).
Homodimer. Interacts (via SH2 domain) with EGFR, ERBB2, ERBB3 (when phosphorylated), ERBB4 (when phosphorylated), EPHB1, INSR, FGFR1, PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated). Interacts with SHC1. Interacts with RND1. Interacts (when tyrosine phosphorylated) with FHL2 and HAX1 (By similarity). Interacts (via SH2 domain) with RET and PTK2/FAK1. Interacts (when not phosphorylated) with ELAVL1. In stressed cells, but not in normal cells, part of a complex that contains at least GRB7, PTK2/FAK1, STAU1, ELAVL1 and TIA1. Interacts (via SH2 domain) with KIT (phosphorylated). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (By similarity).
Phosphorylated on serine and threonine residues in response to heregulin. Phosphorylated on tyrosine residues by TEK/TIE2. Phosphorylated on tyrosine residues in response to NTN1 signaling. Phosphorylation promotes stress granule disassembly during recovery after cellular stress (By similarity). Phosphorylated on tyrosine residues by PTK2/FAK1, and possibly also other kinases. Phosphorylation is enhanced by activation of receptor kinases. Tyrosine phosphorylation is essential for activation of down-stream protein kinases.
The PH domain mediates interaction with membranes containing phosphoinositides.
An hexuronic acid was shown to be linked to Ser-33 in about 40% of the polypeptides. Neither the structure of the carbohydrate (whether glucuronic acid or an isomer of), nor the linkage (whether a glycoside or an ester) has been definitely established.
PRP's act as highly potent inhibitors of crystal growth of calcium phosphates. They provide a protective and reparative environment for dental enamel which is important for the integrity of the teeth.
Proteolytically cleaved; PRP-2, PRP-1, PIF-S and Db-S yield PRP-4, PRP-3 (protein A), PIF-F and Db-F, respectively.
Sequence shown is that of allele PRH1-PIF, which is the most frequent allele (68% of the population). The PRH1-DB allele (about 16% of the population) has an insertion of 21 repeated amino acids compared to the PRH1-PIF allele. Allele PRH2-2, also known as PR-2, allele PRH2-1 is also known as PR-1 or protein C, and allele PRH2-3 as PR-1'. In contrast to all other PRH1 and PRH2 alleles, the PRH1-PA allele (16%) is not proteolytically cleaved.
Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity (PubMed:14699129, PubMed:14738735). Required for kinetochore integrity and the organization of stable microtubule binding sites in the outer plate of the kinetochore (PubMed:14738735, PubMed:14699129). The NDC80 complex synergistically enhances the affinity of the SKA1 complex for microtubules and may allow the NDC80 complex to track depolymerizing microtubules (PubMed:23085020).
Component of the NDC80 complex, which consists of NDC80/HEC1, CDCA1, SPBC24 and SPBC25. The NDC80 complex is formed by two subcomplexes composed of NDC80/HEC1-CDCA1 and SPBC24-SPBC25. Each subcomplex is formed by parallel interactions through the coiled-coil domains of individual subunits. Formation of a tetrameric complex is mediated by interactions between the C-terminal regions of both subunits of the NDC80/HEC1-CDCA1 subcomplex and the N-terminal regions of both subunits of the SPBC24-SPBC25 complex. The tetrameric NDC80 complex has an elongated rod-like structure with globular domains at either end.
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL3) composed of CUL1, SKP1, RBX1 and FBXL3 (By similarity). Interacts with CRY1 and CRY2 (phosphorylated) (PubMed:17463251). Interacts with HDAC3 (By similarity). Interacts with KDM8 (By similarity).
Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex involved in circadian rhythm function. Plays a key role in the maintenance of both the speed and the robustness of the circadian clock oscillation (PubMed:17463251, PubMed:23452855, PubMed:27565346). The SCF(FBXL3) complex mainly acts in the nucleus and mediates ubiquitination and subsequent degradation of CRY1 and CRY2 (PubMed:17463251, PubMed:23452855, PubMed:27565346). Activity of the SCF(FBXL3) complex is counteracted by the SCF(FBXL21) complex (PubMed:23452855).
Undergoes autophagy-mediated degradation in the liver in a time-dependent manner.
Belongs to the 3-hydroxyacyl-CoA dehydrogenase family.
Has high L-gulonate 3-dehydrogenase activity. It also exhibits low dehydrogenase activity toward L-3-hydroxybutyrate (HBA) and L-threonate.
Widely expressed, with highest levels in liver and kidney.
Belongs to the G-protein coupled receptor T2R family.
Expressed in subsets of taste receptor cells of the tongue and exclusively in gustducin-positive cells.
Most taste cells may be activated by a limited number of bitter compounds; individual taste cells can discriminate among bitter stimuli.
Receptor that may play a role in the perception of bitterness and is gustducin-linked. May play a role in sensing the chemical composition of the gastrointestinal content. The activity of this receptor may stimulate alpha gustducin, mediate PLC-beta-2 activation and lead to the gating of TRPM5 (By similarity). Activated by the sulfonyl amide sweeteners saccharin and acesulfame K.
Heterochromatin component that specifically recognizes and binds methylated 'Lys-9' of histone H3 (H3K9me) and promotes recruitment of proteins that mediate epigenetic repression (PubMed:20871592, PubMed:26022416). Mediates recruitment of the HUSH complex to H3K9me3 sites: the HUSH complex is recruited to genomic loci rich in H3K9me3 and is required to maintain transcriptional silencing by promoting recruitment of SETDB1, a histone methyltransferase that mediates further deposition of H3K9me3, as well as MORC2 (PubMed:26022416, PubMed:28581500). Binds H3K9me and promotes DNA methylation by recruiting DNMT3A to target CpG sites; these can be situated within the coding region of the gene (PubMed:20871592). Mediates down-regulation of CDH1 expression (PubMed:20871592). Also represses L1 retrotransposons in collaboration with MORC2 and, probably, SETDB1, the silencing is dependent of repressive epigenetic modifications, such as H3K9me3 mark. Silencing events often occur within introns of transcriptionally active genes, and lead to the down-regulation of host gene expression (PubMed:29211708). The HUSH complex is also involved in the silencing of unintegrated retroviral DNA by being recruited by ZNF638: some part of the retroviral DNA formed immediately after infection remains unintegrated in the host genome and is transcriptionally repressed (PubMed:30487602).
Homodimer (PubMed:21419134, PubMed:22022377, PubMed:22086334). Interacts (via chromo domain) with histone H3K9me3 (PubMed:20871592). Has the highest affinity for H3K9me3, and lesser affinity for H3K9me2 and H3K9me1 (PubMed:20871592). Component of the HUSH complex; at least composed of TASOR, PPHLN1 and MPHOSPH8 (PubMed:26022416). Interacts with DNMT3, EHMT1 and SETDB1 (PubMed:20871592, PubMed:22086334). Interacts with MORC2; the interaction associateS MORC2 with the HUSH complex which recruits MORC2 to heterochromatic loci (PubMed:28581500). Interacts with ZNF638; leading to recruitment of the HUSH complex to unintegrated retroviral DNA (PubMed:30487602). Interacts with TASOR (By similarity). Interacts with humanin (PubMed:23532874).
Phosphorylated in M (mitotic) phase. Phosphorylation by CDK1 promotes dissociation from chromatin.
The chromo domain mediates interaction with methylated 'Lys-9' of histone H3 (H3K9me), with the highest affinity for the trimethylated form (H3K9me3).
Activated by Ca(2+)/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows phosphorylation of Thr-177 within the activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-177 results in several fold increase in total activity. Unlike CaMK4, is unable to exhibit autonomous activity after Ca(2+)/calmodulin activation.
Belongs to the protein kinase superfamily.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily.
Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, regulates transcription activators activity, cell cycle, hormone production, cell differentiation, actin filament organization and neurite outgrowth. Recognizes the substrate consensus sequence [MVLIF]-x-R-x(2)-[ST]-x(3)-[MVLIF]. Regulates axonal extension and growth cone motility in hippocampal and cerebellar nerve cells. Upon NMDA receptor-mediated Ca(2+) elevation, promotes dendritic growth in hippocampal neurons and is essential in synapses for full long-term potentiation (LTP) and ERK2-dependent translational activation. Downstream of NMDA receptors, promotes the formation of spines and synapses in hippocampal neurons by phosphorylating ARHGEF7/BETAPIX on 'Ser-694', which results in the enhancement of ARHGEF7 activity and activation of RAC1. Promotes neuronal differentiation and neurite outgrowth by activation and phosphorylation of MARK2 on 'Ser-91', 'Ser-92', 'Ser-93' and 'Ser-294'. Promotes nuclear export of HDAC5 and binding to 14-3-3 by phosphorylation of 'Ser-259' and 'Ser-498' in the regulation of muscle cell differentiation. Regulates NUMB-mediated endocytosis by phosphorylation of NUMB on 'Ser-276' and 'Ser-295'. Involved in the regulation of basal and estrogen-stimulated migration of medulloblastoma cells through ARHGEF7/BETAPIX phosphorylation (By similarity). Is required for proper activation of cyclin-D1/CDK4 complex during G1 progression in diploid fibroblasts. Plays a role in K(+) and ANG2-mediated regulation of the aldosterone synthase (CYP11B2) to produce aldosterone in the adrenal cortex. Phosphorylates EIF4G3/eIF4GII. In vitro phosphorylates CREB1, ATF1, CFTR, MYL9 and SYN1/synapsin I.
Monomer. Interacts with XPO1 (By similarity). Interacts with MARK2, ARHGEF7/BETAPIX and GIT1.
Phosphorylated by CaMKK1 and CaMKK2 on Thr-177.
Polybiquitinated by the E3 ubiquitin-protein ligase complex SCF(FBXL12), leading to proteasomal degradation.
The autoinhibitory domain overlaps with the calmodulin binding region and interacts in the inactive folded state with the catalytic domain as a pseudosubstrate.
Widely expressed. Expressed in cells of the zona glomerulosa of the adrenal cortex.
Activated monocytes and activated T lymphocytes.
Chemotactic for resting T-lymphocytes, and eosinophils (PubMed:9104803, PubMed:9365122). Has lower chemotactic activity for neutrophils but none for monocytes and activated lymphocytes (PubMed:9104803, PubMed:9365122). Is a strong suppressor of colony formation by a multipotential hematopoietic progenitor cell line (PubMed:9104803, PubMed:9365122). Binds to CCR3 (PubMed:9104803, PubMed:9365122).
Activation of peripheral blood leukocytes with phytohemagglutinin induces strong expression of the membrane isoform followed by the release of the secreted isoform.
Involved in the initial immune cell clustering during inflammatory response and may regulate chemotactic activity of chemokines. May play a role in melanocortin signaling pathways that regulate energy homeostasis and hair color. Low-affinity receptor for agouti (By similarity). Has a critical role in normal myelination in the central nervous system (By similarity).
Isoform 2 is detected in plasma (at protein level). Expressed and secreted by activated T-lymphocytes. Expressed at low to moderate levels in peripheral blood leukocytes, spleen, lymph node, tonsil, bone marrow and fetal liver. At very low levels found in thymus. Isoform 2 is the major isoform in peripheral blood leukocytes.
Was originally (PubMed:7539799, PubMed:9736737) thought to have dipeptidase activity but it was shown later to lack that activity.
ATPase activity is decreased by cholesterol and ceramide. ATPase activity is stimulated by phosphatidylserine, phosphatidylcholine and sphingomyelin, but phosphatidylserine is more effective.
Belongs to the ABC transporter superfamily. ABCA family.
Catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of membrane coupled to the hydrolysis of ATP (PubMed:24097981). Transports preferentially phosphatidylserine over phosphatidylcholine (PubMed:24097981). Plays a role in lipid homeostasis and macrophage-mediated phagocytosis (PubMed:14592415, PubMed:12917409, PubMed:12925201, PubMed:14570867). Binds APOA1 and may function in apolipoprotein-mediated phospholipid efflux from cells (PubMed:12917409, PubMed:14570867, PubMed:14592415). May also mediate cholesterol efflux (PubMed:14570867). May regulate cellular ceramide homeostasis during keratinocyte differentiation (PubMed:12925201). Involved in lipid raft organization and CD1D localization on thymocytes and antigen-presenting cells, which plays an important role in natural killer T-cell development and activation (By similarity). Plays a role in phagocytosis of apoptotic cells by macrophages (By similarity). Macrophage phagocytosis is stimulated by APOA1 or APOA2, probably by stabilization of ABCA7 (By similarity). Also involved in phagocytic clearance of amyloid-beta by microglia cells and macrophages (By similarity). Further limits amyloid-beta production by playing a role in the regulation of amyloid-beta A4 precursor protein (APP) endocytosis and/or processing (PubMed:26260791). Amyloid-beta is the main component of amyloid plaques found in the brains of Alzheimer patients (PubMed:26260791).
Expressed in fetal tissues. Strongly expressed in fetal liver.
Expressed in leukocytes (at protein level) (PubMed:10873640). Widely expressed (PubMed:10873640). Highly expressed in myelo-lymphatic tissues including peripheral leukocytes, thymus, spleen and bone marrow (PubMed:10873640, PubMed:11435699). Expressed in the hippocampus and the cerebellum (PubMed:27472885). Isoform 2: Abundant in lymph node, spleen, thymus and trachea (PubMed:14592415). Isoform 1: Strongly expressed in brain and bone marrow (PubMed:14592415).
Inactive for apoA-I-mediated lipid release.
There are conflicting results concerning the role of ABCA7 in lipid transport. ABCA7 was described to play a role in apolipoprotein-mediated phospholipid and cholesterol efflux when expressed in HEK293 cells (PubMed:12917409, PubMed:27472885). However, another report shows that ABCA7 deficiency does not influence cholesterol and phospholipid efflux in mouse primary macrophages, but leads to lower serum HDL cholesterol levels and a reduction in fat mass in female mice (By similarity).
Up-regulated in macrophages upon cholesterol uptake and inversely regulated upon cholesterol deloading from the cells (at protein level). Up-regulated in keratinocytes during terminal differentiation.
Does not interact with sperm-egg fusion proteins IZUMO1 or IZUMO1R/JUNO.
Sperm protein required for fusion of sperm with the egg membrane during fertilization.
Belongs to the peptidase C19 family. USP12/USP46 subfamily.
Deubiquitinating enzyme that plays a role in behavior, possibly by regulating GABA action. May act by mediating the deubiquitination of GAD1/GAD67 (By similarity). Has almost no deubiquitinating activity by itself and requires the interaction with WDR48 to have a high activity (PubMed:19075014, PubMed:26388029). Not involved in deubiquitination of monoubiquitinated FANCD2 (PubMed:19075014).
Interacts with WDR48 (PubMed:19075014, PubMed:26388029). Interacts with WDR20 (PubMed:20147737).
Belongs to the universal ribosomal protein uL16 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379, PubMed:25278503). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins.
Detected at low levels in heart, liver, kidney, skeletal muscle, pancreas, testis, ovary and prostate. Detected at even lower levels in mammary epithelial cells and breast cancer cells.
Repressor that binds to DNA sequences containing a bipartite element consisting of a direct repeat of the sequence 5'-AAAGTTT-3' separated by 2-9 nucleotides. Represses basal transcription activity from target promoters (By similarity). Inhibits colony formation in cultured breast cancer cells.
Belongs to the anion exchanger (TC 2.A.31) family.
Electrogenic sodium/bicarbonate cotransporter with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3. May regulate bicarbonate influx/efflux at the basolateral membrane of cells and regulate intracellular pH.
Expressed in the corneal endothelium cells (at protein level). Expressed in pancreas and to a lower extent in heart, skeletal muscle, liver, parotid salivary glands, prostate, colon, stomach, thyroid, brain and spinal chord.
Homodimer (PubMed:29500354). Interacts with CA2/carbonic anhydrase 2 and CA4/carbonic anhydrase 4 which may regulate transporter activity (PubMed:12411514, PubMed:14567693, PubMed:15218065, PubMed:15563508). Isoform 1 but not isoform 2 interacts with AHCYL1 (via PEST domain when phosphorylated); the interaction increases SLC4A4 isoform 1 activity (PubMed:16769890). Interacts with AHCYL2 (By similarity).
Loss of interaction with and stimulation by CA4 is the cause of retinitis pigmentosa type 17 (RP17).
N-glycosylated. May not be necessary for the transporter basic functions.
Phosphorylation of Ser-1026 by PKA increases the binding of CA2 and changes the Na(+):HCO3(-) stoichiometry of the transporter from 3:1 to 2:1 (PubMed:11744745, PubMed:12411514, PubMed:12730338). Phosphorylated in presence of STK39 and dephosphorylated in presence of PP1 phosphatase; phosphorylation seems to inhibit SLC4A4 activity (By similarity).
Specifically expressed in kidney at the level of proximal tubules.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.
In the hair cortex, hair keratin intermediate filaments are embedded in an interfilamentous matrix, consisting of hair keratin-associated proteins (KRTAP), which are essential for the formation of a rigid and resistant hair shaft through their extensive disulfide bond cross-linking with abundant cysteine residues of hair keratins. The matrix proteins include the high-sulfur and high-glycine-tyrosine keratins.
Restricted to a narrow region of the hair fiber cuticle, lying approximately 20 cell layers above the apex of the dermal papilla of the hair root; not detected in any other tissues.
A structural component of the cornified envelope of the stratum corneum involved in innate cutaneous host defense (Probable). Possesses defensin-like antimicrobial activity against a broad spectrum of Gram-positive and Gram-negative bacteria, both aerobic and anaerobic species. Upon inflammation, may regulate skin barrier repair by shaping cutaneous microbiota composition and immune response to bacterial antigens (PubMed:28634035).
Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.
Hydrolyzes UDP-glucose to glucose 1-phosphate and UMP and UDP-galactose to galactose 1-phosphate and UMP. Preferred substrate is UDP-glucose.
Belongs to the sulfotransferase 1 family. Gal/GlcNAc/GalNAc subfamily.
May serve as an anti-inflammatory target.
Specifically expressed in HEV. Weakly expressed in spleen. Not expressed in other tissues. Expressed in colonic mucinous adenocarcinoma.
Sulfotransferase involved in SELL/L-selectin ligand biosynthesis pathway. Catalyzes the transfer of the sulfate group from 3'-phospho-5'-adenylyl sulfate (PAPS) onto the hydroxyl group at C-6 position of the non-reducing N-acetylglucosamine (GlcNAc) residue within O-linked mucin-type glycans. Contributes to generate sialyl 6-sulfo Lewis X determinant (also known as MECA-79 epitope) for SELL recognition, a prerequisite for continuous lymphocyte homing into peripheral lymph nodes and antigen immune surveillance (PubMed:11439191, PubMed:12107080, PubMed:10330415, PubMed:11726653). Transfers the sulfate group primarily on core 2 GlcNAcbeta1-6(Galbeta1-3)GalNAcalphaSer/Thr and extended core 1 GlcNAcbeta1-3Galbeta1-3GalNAcalphaSer/Thr based O-linked glycans on CD34 and GLYCAM1 peripheral node addressins (PNAds) expressed on the lumenal side of high endothelial venules (HEVs) (PubMed:11439191). The recognition of PNAds by SELL initiates a multistep process comprising tethering and rolling of blood lymphocytes on HEVs against the blood flow, followed by chemokine signaling, integrin-mediated lymphocyte adhesion onto endothelial cells and lymphocyte transendothelial migration. Modulates rolling velocity and differential T and B lymphocyte recruitment into peripheral lymph nodes, with a major role in B lymphocyte homing. Might be redundant in sulfation of MADCAM1 and lymphocyte trafficking to mesenteric lymph nodes (By similarity). Can also sulfonate core 3 GlcNAcbeta1-3GalNAc-R based glycans as well as GlcNAcbeta1-3Galbeta1-Glc, GlcNAcbeta1-6ManOMe and GlcNAcbeta1-2Man oligosaccharides, which might be ectopically expressed during tumorigenesis (PubMed:12107080, PubMed:11439191, PubMed:11726653).
Upon cytokine activation, it is expressed at low level.
Binds MYO5A, MYO7A and F-actin (By similarity). Binds RAB27A that has been activated by GTP-binding via its N-terminus. Interacts with PRKAR2A. Interacts with components of the exocyst complex, including EXOC3 and EXOC4 (By similarity).
Detected in brain, skin, heart, adrenal medulla, pancreas, intestine, liver, kidney, muscle and testis.
Rab effector protein involved in melanosome transport. Serves as link between melanosome-bound RAB27A and the motor proteins MYO5A and MYO7A. May link RAB27A-containing vesicles to actin filaments. Functions as a protein kinase A-anchoring protein (AKAP). May act as a scaffolding protein that links PKA to components of the exocytosis machinery, thus facilitating exocytosis, including insulin release (By similarity).
Defects in TUBB2B may be involved in cerebellar ataxia, intellectual disability, and dysequilibrium syndrome (CAMRQ).
Dimer of alpha and beta chains (PubMed:23001566, PubMed:28013290, PubMed:26732629). A typical microtubule is a hollow water-filled tube with an outer diameter of 25 nm and an inner diameter of 15 nM. Alpha-beta heterodimers associate head-to-tail to form protofilaments running lengthwise along the microtubule wall with the beta-tubulin subunit facing the microtubule plus end conferring a structural polarity. Microtubules usually have 13 protofilaments but different protofilament numbers can be found in some organisms and specialized cells.
Dimer of alpha and beta chains. A typical microtubule is a hollow water-filled tube with an outer diameter of 25 nm and an inner diameter of 15 nM. Alpha-beta heterodimers associate head-to-tail to form protofilaments running lengthwise along the microtubule wall with the beta-tubulin subunit facing the microtubule plus end conferring a structural polarity. Microtubules usually have 13 protofilaments but different protofilament numbers can be found in some organisms and specialized cells.
Phosphorylated on Ser-172 by CDK1 during the cell cycle, from metaphase to telophase, but not in interphase. This phosphorylation inhibits tubulin incorporation into microtubules.
Some glutamate residues at the C-terminus are monoglycylated but not polyglycylated due to the absence of functional TTLL10 in human. Monoglycylation is mainly limited to tubulin incorporated into cilia and flagella axonemes, which is required for their stability and maintenance. Flagella glycylation controls sperm motility. Both polyglutamylation and monoglycylation can coexist on the same protein on adjacent residues, and lowering glycylation levels increases polyglutamylation, and reciprocally.
Some glutamate residues at the C-terminus are polyglutamylated, resulting in polyglutamate chains on the gamma-carboxyl group (PubMed:26875866). Polyglutamylation plays a key role in microtubule severing by spastin (SPAST). SPAST preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity by SPAST increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold (PubMed:26875866). Glutamylation is also involved in cilia motility (By similarity).
The MREI motif is common among all beta-tubulin isoforms and may be critical for tubulin autoregulation.
Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers (PubMed:23001566, PubMed:28013290, PubMed:26732629). Microtubules grow by the addition of GTP-tubulin dimers to the microtubule end, where a stabilizing cap forms. Below the cap, tubulin dimers are in GDP-bound state, owing to GTPase activity of alpha-tubulin. Plays a critical role in proper axon guidance in both central and peripheral axon tracts (PubMed:23001566). Implicated in neuronal migration (PubMed:19465910).
Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers. Microtubules grow by the addition of GTP-tubulin dimers to the microtubule end, where a stabilizing cap forms. Below the cap, tubulin dimers are in GDP-bound state, owing to GTPase activity of alpha-tubulin.
ATP-depletion almost completely abolishes SLC9A5 activity. Inhibited by amiloride compounds.
Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.
Interacts with CHP1 and CHP2 (By similarity). Interacts with ARRB2; facilitates the endocytosis of SLC9A5 from the plasma membrane (PubMed:15699339, PubMed:21296876). Interacts with RACK1; this interaction positively regulates SLC9A5 activity and promotes SLC9A5 localization to focal adhesions (PubMed:24006492). Interacts with SCAMP2; this interaction regulates SLC9A5 cell-surface targeting and SLC9A5 activity (PubMed:19276089).
Mainly expressed in brain (PubMed:7759094, PubMed:9933641). Expressed in neurons of the central and peripheral nervous system (PubMed:21551074, PubMed:9933641). Expressed also in testis, spleen, and skeletal muscle (PubMed:7759094).
Phosphorylated by PRKAA2; promotes its accumulation at the cell surface (PubMed:24936055). Phosphorylated by CSNK2A1 in a manner favoring its beta-arrestin binding and endocytosis (PubMed:21296876).
Plasma membrane Na(+)/H(+) antiporter. Mediates the electroneutral exchange of intracellular H(+) ions for extracellular Na(+) in 1:1 stoichiometry, thus regulating intracellular pH homeostasis, in particular in neural tissues (PubMed:9933641, PubMed:10692428, PubMed:19276089, PubMed:24936055). Acts as a negative regulator of dendritic spine growth (PubMed:21551074). Plays a role in postsynaptic remodeling and signaling (PubMed:24006492, PubMed:21551074). Can also contribute to organellar pH regulation, with consequences for receptor tyrosine kinase trafficking (PubMed:24936055).
(Microbial infection) Interacts with human adenovirus 5 protein E1A; this interaction inhibits RBX1-CUL1-dependent elongation reaction of ubiquitin chains by the SCF(FBW7) complex.
E3 ubiquitin ligase component of multiple cullin-RING-based E3 ubiquitin-protein ligase (CRLs) complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins, including proteins involved in cell cycle progression, signal transduction, transcription and transcription-coupled nucleotide excision repair (PubMed:10230407, PubMed:10579999, PubMed:15983046, PubMed:16678110, PubMed:19112177, PubMed:19679664, PubMed:23455478, PubMed:27565346, PubMed:29769719, PubMed:11961546, PubMed:22748924). CRLs complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins, ARIH1 mediating addition of the first ubiquitin on CRLs targets (PubMed:27565346). The functional specificity of the E3 ubiquitin-protein ligase complexes depends on the variable substrate recognition components. As a component of the CSA complex promotes the ubiquitination of ERCC6 resulting in proteasomal degradation. Recruits the E2 ubiquitin-conjugating enzyme CDC34 to the complex and brings it into close proximity to the substrate. Probably also stimulates CDC34 autoubiquitination. May be required for histone H3 and histone H4 ubiquitination in response to ultraviolet and for subsequent DNA repair. Promotes the neddylation of CUL1, CUL2, CUL4 and CUL4 via its interaction with UBE2M. Involved in the ubiquitination of KEAP1, ENC1 and KLHL41. In concert with ATF2 and CUL3, promotes degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. As part of a multisubunit complex composed of elongin BC complex (ELOB and ELOC), elongin A/ELOA, RBX1 and CUL5; polyubiquitinates monoubiquitinated POLR2A (PubMed:19920177).
Part of a SCF complex consisting of CUL1, RBX1, SKP1 and SKP2 (PubMed:10230406, PubMed:11961546). Part of a SCF-like complex consisting of CUL7, RBX1, SKP1 and FBXW8. Part of CBC(VHL) complexes with elongin BC complex (ELOB and ELOC), CUL2 or CUL5 and VHL (PubMed:10213691). Part of the CSA complex (DCX(ERCC8) complex), a DCX E3 ubiquitin-protein ligase complex containing ERCC8, RBX1, DDB1 and CUL4A; the CSA complex interacts with RNA polymerase II; upon UV irradiation it interacts with the COP9 signalosome and preferentially with the hyperphosphorylated form of RNA polymerase II (PubMed:12732143). Part of multisubunit E3 ubiquitin ligase complexes with elongin BC complex (ELOB and ELOC), CUL2 and MED8; elongin BC complex (ELOB and ELOC), CUL5 and MUF1 (PubMed:11384984, PubMed:12149480). Part of multisubunit complexes with elongin BC complex (ELOB and ELOC), SOCS1 or WSB1 and CUL5. Part of a multisubunit ubiquitin ligase complex consisting of elongin BC complex (ELOB and ELOC), elongin A/ELOA, RBX1 and CUL5 (PubMed:19920177). Interacts directly with CUL1 and probably also with CUL2, CUL3, CUL4A, CUL4B, CUL5 and CUL7 (PubMed:10230407, PubMed:12481031). Interacts with CDC34 (PubMed:22748924). Interacts with GLMN. GLMN competes for the binding site of the E2 ubiquitin-conjugating enzyme CDC34 and disrupts CDC34 binding (PubMed:22748924). Interacts with COPS6 (PubMed:11337588). Component of the DCX DET1-COP1 ubiquitin ligase complex at least composed of RBX1, DET1, DDB1, CUL4A and COP1 (PubMed:14739464). Part of an E3 ligase complex composed of RBX1, DDB1, DDB2 and CUL4A or CUL4B (PubMed:16678110). Interacts with UBE2M (PubMed:19250909). Part of a SCF complex consisting of CUL1, FBXO3, RBX1 and SKP1; this complex interacts with PML via FBXO3 (PubMed:18809579). Component of the SCF(Cyclin F) complex consisting of CUL1, RBX1, SKP1 and CCNF (PubMed:20596027). Identified in a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex together with HINT1 and CDC34 (PubMed:19112177). Component of multiple BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes formed of CUL3, RBX1 and a variable BTB domain-containing protein (PubMed:15983046). Part of the BCR(ENC1) complex containing ENC1 (PubMed:15983046). Part of the BCR(GAN) complex containing GAN (PubMed:15983046). Part of the BCR(KLHL41) complex containing KLHL41 (PubMed:15983046). Part of the BCR(KEAP1) complex containing KEAP1 (PubMed:15983046). Interacts with SESN1 and SESN2 (PubMed:23274085). Interacts with NOTCH2 (PubMed:29149593). Component of the BCR(KLHL22) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL22 and RBX1 (PubMed:23455478). Interacts with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5 (PubMed:26906416, PubMed:24192928, PubMed:25349211). Component of a BCR3 (BTB-CUL3-RBX1) E3 ubiquitin ligase complex, also named Cul3-RING ubiquitin ligase complex CUL3(KBTBD6/7), composed of CUL3, RBX1, KBTBD6 and KBTBD7 (PubMed:25684205). Component of the ECS(LRR1) complex with the substrate recognition component LRR1 (PubMed:34700328).
The RING-type zinc finger domain is essential for ubiquitin ligase activity (PubMed:10230407). It coordinates an additional third zinc ion (PubMed:11961546, PubMed:22748924).
6-O-sulfation enzyme which catalyzes the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to position 6 of the N-sulfoglucosamine residue (GlcNS) of heparan sulfate.
Belongs to the sulfotransferase 6 family.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class dual specificity subfamily.
Monomer (PubMed:29106959). Interacts with MAP3K5/ASK1; may compete with AKT1 preventing MAP3K5/ASK1 phosphorylation by AKT1.
Probable protein tyrosine phosphatase. Has phosphatase activity with synthetic substrates (PubMed:15252030, PubMed:29106959). Has a phosphatase activity-independent regulatory role in MAP3K5/ASK1-mediated apoptosis, preventing MAP3K5/ASK1 inhibition by AKT1. Shows no phosphatase activity on MAPK1/ERK2, MAPK8/JNK, MAPK14/p38 and MAP3K5/ASK1.
May participate in the translocation of transit peptide-containing proteins across the mitochondrial inner membrane. the PAM complex (By similarity).
Exhibits a potent RNase activity (PubMed:12244054, PubMed:12527768, PubMed:17150966). Has broad-spectrum antimicrobial activity against many pathogenic microorganisms including uropathogenic E.coli (UPEC), and remarkably potent activity (lethal dose of 90% < 30 nM) against a vancomycin resistant Enterococcus faecium (PubMed:12244054, PubMed:12527768, PubMed:25075772, PubMed:33818125, PubMed:17150966). Causes loss of bacterial membrane integrity (PubMed:17150966). Probably contributes to urinary tract sterility (PubMed:25075772). Bactericidal activity is independent of RNase activity (PubMed:17150966).
Expressed in collecting ducts in kidney, and in apical uroepithelium in bladder (at protein level) (PubMed:25075772). Expressed in various epithelial tissues including skin, respiratory tract, genito-urinary tract and, at a low level, in the gut (PubMed:12244054). Expressed in liver, kidney, skeletal muscle and heart (PubMed:12527768).
Up-regulated in response to the cytokines IL1B, IFNG and TNF (PubMed:12244054). Strongly up-regulated in response to the bacterium P.aeruginosa (PubMed:12244054). Moderately up-regulated in response to S.aureus, E.coli and S.pyogenes (PubMed:12244054). Up-regulated in kidney in response to infection (PubMed:25075772).
By IFNG/IFN-gamma, mitogens and IL1/interleukin-1.
Chemotactic factor that attracts monocytes, lymphocytes, basophils and eosinophils. May play a role in neoplasia and inflammatory host responses. This protein can bind heparin. The processed form MCP-2(6-76) does not show monocyte chemotactic activity, but inhibits the chemotactic effect most predominantly of CCL7, and also of CCL2 and CCL5 and CCL8.
Highest expression found in the small intestine and peripheral blood cells. Intermediate levels seen in the heart, placenta, lung, skeletal muscle, thymus, colon, ovary, spinal cord and pancreas. Low levels seen in the brain, liver, spleen and prostate.
N-terminal processed form MCP-2(6-76) is produced by proteolytic cleavage after secretion from peripheral blood monocytes.
By GDNF/glial cell line-derived neurotrophic factor.
The KRAB domain mediates interaction with TRIM28 and is required for transcriptional repressor activity.
Transcriptional repressor that plays a role in cell proliferation. Requires TRIM28 for its activity.
Histone binding-protein that regulates chromatin dynamics and minichromosome maintenance (MCM) loading at replication origins, possibly by promoting chromatin openness (PubMed:25990725).
Induced by E2F transcription factors (PubMed:14990995).
Interacts with METTL18 (PubMed:23349634). Interacts with CDT1; origin binding of GRWD1 is dependent on CDT1 (PubMed:25990725). Interacts with CDC6; origin binding of GRWD1 is dependent on CDC6 (PubMed:25990725). Binds to histone H2A-H2B and H3-H4 complexes (PubMed:25990725).
Interacts with microtubules. Interacts with 4 subunits of the katanin complex: KATNA1, KATNAL1, KATNB1 and KATNBL1.
May influence the stability of microtubules (MT), possibly through interaction with the MT-severing katanin complex.
Interacts with iRhom1/RHBDF1 and iRhom2/RHBDF2 (via cytoplasmic N-termini); this interaction leads to mutual protein stabilization (PubMed:29897333). Interacts with ADAM17; this interaction is indirect and mediated by iRhom proteins (PubMed:29897333, PubMed:29897336). Interacts with LRP6; this interaction affects LRP6-binding to AXIN1 (PubMed:19572019).
Promotes the cell surface stability of iRhom1/RHBDF1 and iRhom2/RHBDF2 and prevents their degradation via the endolysosomal pathway. By acting on iRhoms, involved in ADAM17-mediated shedding of TNF, amphiregulin/AREG, HBEGF and TGFA from the cell surface (PubMed:29897333, PubMed:29897336). Negatively regulates Wnt signaling, possibly by antagonizing the recruitment of AXIN1 to LRP6 (PubMed:19572019).
Widely expressed, with high expression in heart and spleen.
Cilium- and flagellum-associated protein (PubMed:29606301). In the olfactory epithelium, regulates the speed of activation and termination of the odor response and thus contributes to the robustness of olfactory transduction pathways (By similarity). Required for sperm flagellum assembly and stability (PubMed:29606301).
Highly expressed in the testis, specifically in sperm (at protein level) (PubMed:29606301). Expressed in the brain, kidney, liver, lung, and intestine (PubMed:29606301).
Belongs to the two pore domain potassium channel (TC 1.A.1.8) family.
Potassium channel displaying weak inward rectification in symmetrical K(+) solution.
The current is enhanced by arachidonic acid and inhibited by halothane.
Belongs to the major facilitator superfamily. Sugar transporter (TC 2.A.1.1) family. Glucose transporter subfamily.
Extracellular glucose and urate accelerate urate efflux (PubMed:22647630, PubMed:18842065). Intracellular urate, glucose and fructose accelerate urate influx (PubMed:22647630).
Genetic variations in SLC2A9 influence the variance in serum uric acid concentrations and define the serum uric acid concentration quantitative trait locus 2 (UAQTL2) [MIM:612076] with pronounced sex-specific effects. The proportion of the variance of serum uric acid concentrations explained by genotypes is about 1.2% in men and 6% in women, and the percentage accounted for by expression levels is 3.5% in men and 15% in women (PubMed:18327257, PubMed:18327256, PubMed:18842065). Excess serum accumulation of uric acid can lead to the development of gout (PubMed:18327257, PubMed:18327256).
High-capacity urate transporter that was first described as a fructose and glucose transporter. Also described in the literature as high-affinity and low-capacity glucose and fructose transporter (PubMed:18327257, PubMed:17710649, PubMed:18842065). However, another group could not confirm transporter activity for glucose or fructose (PubMed:28083649).
High-capacity urate transporter, which may play a role in the urate reabsorption by proximal tubules (PubMed:18327257, PubMed:28083649, PubMed:22647630, PubMed:18701466, PubMed:36749388). May have a residual high-affinity, low-capacity glucose and fructose transporter activity (PubMed:18842065, PubMed:18327257, PubMed:18701466). Transports urate at rates 45- to 60-fold faster than glucose (PubMed:18842065). Does not transport galactose (PubMed:28083649). May mediate small uptake of adenine but not of other nucleobases (PubMed:22647630).
Most strongly expressed in basolateral membranes of proximal renal tubular cells, liver and placenta. Also detected in lung, blood leukocytes, heart skeletal muscle and chondrocytes from articular cartilage. Detected in kidney membrane (at protein level).
No effect of extracellular urate, glucose or fructose on urate efflux. Intracellular urate and fructose slightly accelerate urate influx.
Only detected in the apical membranes of polarized renal tubular cells and placenta. Detected in kidney membrane (at protein level).
Belongs to the class I-like SAM-binding methyltransferase superfamily. Glycine N-methyltransferase family.
Catalyzes the methylation of glycine by using S-adenosylmethionine (AdoMet) to form N-methylglycine (sarcosine) with the concomitant production of S-adenosylhomocysteine (AdoHcy), a reaction regulated by the binding of 5-methyltetrahydrofolate. Plays an important role in the regulation of methyl group metabolism by regulating the ratio between S-adenosyl-L-methionine and S-adenosyl-L-homocysteine.
Expressed only in liver, pancreas, and prostate.
Inhibited by 5-methyltetrahydrofolate monoglutamate and by 5-methyltetrahydrofolate pentaglutamate, inhibition is much more effective by the pentaglutamate form than by the monoglutamate form. Two molecules of 5-methyltetrahydrofolate are bound per tetramer. The binding sites are localized between subunits. Inhibitor binding may preclude movements of the polypeptide chain that are necessary for enzyme activity.
Highly homologous to GCUD2 but localized to a distinct locus.
A 55 kDa form is produced by proteolytic cleavage.
Expression is generally absent in normal colon and other normal body tissues, but it is induced an average of 78-fold in Stage II, III, and IV colon cancers, as well as in colon adenomas and colon cancer cell lines.
May be used as a serological marker for colon neoplasia.
An N-terminal amphipathic helix, the BAR domain and a second amphipathic helix inserted into helix 1 of the BAR domain (N-BAR domain) induce membrane curvature and bind curved membranes. The BAR domain dimer forms a rigid crescent shaped bundle of helices with the pair of second amphipathic helices protruding towards the membrane-binding surface.
Brain, mostly in frontal cortex. Expressed at high level in fetal cerebellum.
HeLa cells expressing the N-BAR domain of SH3GL2 show tubulation of the plasma membrane. The N-BAR domain binds liposomes and induces formation of tubules from liposomes. The N-terminal amphipathic helix is required for liposome binding. The second amphipathic helix enhances liposome tubulation.
Implicated in synaptic vesicle endocytosis. May recruit other proteins to membranes with high curvature. Required for BDNF-dependent dendrite outgrowth. Cooperates with SH3GL2 to mediate BDNF-NTRK2 early endocytic trafficking and signaling from early endosomes.
Monomer; in cytoplasm. Homodimer; when associated with membranes (By similarity). Interacts with OPHN1 (By similarity). Interacts with SYNJ1 (PubMed:10542231). Interacts with DNM1 (By similarity). Interacts with MAP4K3; the interaction appears to regulate MAP4K3-mediated JNK activation (By similarity). Interacts with PDCD6IP (PubMed:17350572). Interacts with ATXN2 (PubMed:18602463). Interacts with ADAM9 and ADAM15 cytoplasmic tails (PubMed:10531379). Interacts with BIN2 (PubMed:23285027). Interacts with TMEM108 (By similarity). Interacts with ADGRB2 (PubMed:28891236).
Acetylation of Lys-748 might play a role in catalytic activity regulation.
Homotetramer (PubMed:18297087). Interacts (via the biotin carboxylation domain) with SIRT4 (PubMed:23438705).
Pyruvate carboxylase catalyzes a 2-step reaction, involving the ATP-dependent carboxylation of the covalently attached biotin in the first step and the transfer of the carboxyl group to pyruvate in the second. Catalyzes in a tissue specific manner, the initial reactions of glucose (liver, kidney) and lipid (adipose tissue, liver, brain) synthesis from pyruvate.
Has activity against the synthetic substrates Boc-Phe-Ser-Arg-Mec, Boc-Leu-Thr-Arg-Mec, Boc-Gln-Ala-Arg-Mec and Boc-Val-Pro-Arg-Mec. The single-chain form is more active than the two-chain form against all of these substrates.
Occurs in a single-chain form and a two-chain form, produced by proteolytic cleavage after Arg-122.
Sulfation at Tyr-154 increases selectivity towards basic versus apolar residues at the P2' position of inhibitors that bind in a substrate-like fashion. Although the increase in selectivity is relatively small, it may facilitate digestion of a broader range of dietary proteins.
Tyr-154 was proposed to be phosphorylated (PubMed:8683601) but it has been shown (PubMed:17087724) to be sulfated instead. Phosphate and sulfate groups are similar in mass and size, and this can lead to erroneous interpretation of the results.
Catalyzes the last step of the oxidative degradation of choline to glycine. Converts sarcosine into glycine.
Expressed in pancreas, liver and kidney.
Component of the condensin-2 complex, which contains the SMC2 and SMC4 heterodimer, and 3 non SMC subunits that probably regulate the complex: NCAPH2, NCAPD3 and NCAPG2.
Regulatory subunit of the condensin-2 complex, a complex which establishes mitotic chromosome architecture and is involved in physical rigidity of the chromatid axis.
Expressed in hair follicle (at protein level).
May play a role in the early stages of epithelial differentiation or in apoptosis.
Heterodimer of a type I and a type II keratin. May associate with KRT17.
Highly expressed in hair follicles from scalp. Specifically expressed in the of the hair companion layer follicle, a single layered band of flat and vertically oriented cells between the cuboidal outer root sheath (ORS) cells and the inner root sheath (IRS) that stretches from the lowermost bulb region to the isthmus of the follicle. Also expressed in medullated hairs. In nails, it is almost exclusively present in the nail bed (at protein level).
May be used as a marker of hair differentiation.
Plays a central role in hair and nail formation. Essential component of keratin intermediate filaments in the companion layer of the hair follicle.
The Thr-161 variant may increase risk to develop pseudofolliculitis barbae (PFB) [MIM:612318]. PFB is a common hair disorder characterized by a pustular foreign body inflammatory reaction that is induced by ingrown hairs of the facial and submental (barbea) regions after regular shaving. It occurs predominantly in black males, while it is rather rare and usually far less severe in Caucasian males.
(Microbial infection) Integrin ITGA3:ITGB1 may act as a receptor for R.delemar CotH7 in alveolar epithelial cells, which may be an early step in pulmonary mucormycosis disease progression.
Antibodies against integrin alpha-3 ITGA3 protects epithelial cells from invasion by the fungus R.delemar, a causative agent of mucormycosis, and could thus potentially be used to treat mucormycosis disease.
Belongs to the integrin alpha chain family.
Heterodimer of an alpha and a beta subunit. The alpha subunit is composed of a heavy and a light chain linked by a disulfide bond. Alpha-3 associates with beta-1. Interacts with HPS5. Interacts with FAP (seprase); the interaction occurs at the cell surface of invadopodia membrane in a collagen-dependent manner.
Integrin alpha-3/beta-1 is a receptor for fibronectin, laminin, collagen, epiligrin, thrombospondin and CSPG4. Integrin alpha-3/beta-1 provides a docking site for FAP (seprase) at invadopodia plasma membranes in a collagen-dependent manner and hence may participate in the adhesion, formation of invadopodia and matrix degradation processes, promoting cell invasion. Alpha-3/beta-1 may mediate with LGALS3 the stimulation by CSPG4 of endothelial cells migration.
Isoform 1 is widely expressed. Isoform 2 is expressed in brain and heart. In brain, both isoforms are exclusively expressed on vascular smooth muscle cells, whereas in heart isoform 1 is strongly expressed on vascular smooth muscle cells, isoform 2 is detected only on endothelial vein cells.
Isoform 1, but not isoform 2, is phosphorylated on serine residues. Phosphorylation increases after phorbol 12-myristate 13-acetate stimulation.
Expressed in subsets of taste receptor cells of the tongue and palate epithelium and exclusively in gustducin-positive cells.
Receptor that may play a role in the perception of bitterness and is gustducin-linked. May play a role in sensing the chemical composition of the gastrointestinal content. The activity of this receptor may stimulate alpha gustducin, mediate PLC-beta-2 activation and lead to the gating of TRPM5.
Belongs to the major facilitator (TC 2.A.1) superfamily. Organic cation transporter (TC 2.A.1.19) family.
Contains one proline-rich sequence (Pro-Glu-Ser-Pro-Arg) that may be involved in tyrosine-protein kinase YES1 binding and is required for the activation of substrate transport.
Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:9260930, PubMed:9687576). Functions as a Na(+)-independent, bidirectional uniporter (PubMed:9687576, PubMed:21128598). Cation cellular uptake or release is driven by the electrochemical potential, i.e. membrane potential and concentration gradient (PubMed:9260930, PubMed:9687576, PubMed:15212162). However, may also engage electroneutral cation exchange when saturating concentrations of cation substrates are reached (By similarity). Predominantly expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (PubMed:15783073). Implicated in monoamine neurotransmitters uptake such as histamine, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, serotonin and tyramine, thereby supporting a physiological role in the central nervous system by regulating interstitial concentrations of neurotransmitters (PubMed:9687576, PubMed:16581093, PubMed:17460754). Also capable of transporting dopaminergic neuromodulators cyclo(his-pro), salsolinol and N-methyl-salsolinol, thereby involved in the maintenance of dopaminergic cell integrity in the central nervous system (PubMed:17460754). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Also transports guanidine and endogenous monoamines such as vitamin B1/thiamine, creatinine and N-1-methylnicotinamide (NMN) (PubMed:9260930, PubMed:12089365, PubMed:15212162, PubMed:17072098, PubMed:24961373). Mediates the uptake and efflux of quaternary ammonium compound choline (PubMed:9260930). Mediates the bidirectional transport of polyamine agmatine and the uptake of polyamines putrescine and spermidine (PubMed:12538837, PubMed:21128598). Able to transport non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). Also involved in the uptake of xenobiotic 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:12395288, PubMed:16394027). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable).
In contrast with isoform 1, not able to transport guanidine, creatinine, cimetidine and metformin.
Mainly expressed in kidney, bone marrow and testis (PubMed:12089365). Expressed in colon, skeletal muscle, spinal cord, placenta and liver (PubMed:12089365).
Mainly expressed in kidney, in the cortex and medulla (PubMed:9260930, PubMed:12089365, PubMed:11912245). Localized in testis, mostly to peritubular myoid cells and Leydig cells and also detected along the basal membrane of Sertoli cells (PubMed:12089365, PubMed:35307651). Expressed in brain, in neurons of the cerebral cortex and in various subcortical nuclei (PubMed:9260930, PubMed:12089365, PubMed:9687576). In the brain, also detected in the dopaminergic regions of the substantia nigra (PubMed:17460754). Expressed in tracheal and bronchial ciliated epithelium in the respiratory tract (PubMed:15817714). Also detected in secretory phase endometrium, in scattered stromal cells (PubMed:17393420). Expressed in spleen, placenta, small intestine and spinal cord (PubMed:9260930, PubMed:12089365). Weakly expressed in prostate, uterus and lung (PubMed:12089365).
May be down-regulated in diabetic patients.
Mediates the renal secretion of many clinically used cationic drugs (PubMed:12089365, PubMed:16272756). Transports drugs such as diabetes treatment medicine metformin, 1-methyl-4-phenylpyridinium (MPP(+)), famotidine, ranitidine, amantadine, acriflavine, amiloride, memantine, cimetidine, platinum-based drugs cisplatin and oxaliplatin, 3'-azido-3'-deoxythymidine (AZT) and tetraethylammonium (TEA) (PubMed:9260930, PubMed:12089365, PubMed:15496291, PubMed:16314463, PubMed:16272756, PubMed:16006492, PubMed:15783073, PubMed:16394027, PubMed:16951202, PubMed:16914559, PubMed:16581093, PubMed:24961373). Mediates the bidirectional transport of MPP(+) (PubMed:9260930, PubMed:12089365, PubMed:9687576). Metformin competitively inhibits OCT1-mediated thiamine uptake, leading to a decrease in hepatic steatosis (PubMed:24961373). Plays a predominant role in the anticancer activity of cisplatin and oxaliplatin and may contribute to antitumor specificity (PubMed:16951202, PubMed:16914559). Involved in cisplatin-induced nephrotoxicity (By similarity).
Most authors have deduced a localization at the basolateral membrane of proximal tubules (PubMed:11912245). Other studies demonstrated a localization to the luminal membrane in the distal tubule (PubMed:9260930).
Tyrosine phosphorylated by tyrosine-protein kinase YES1.
Tyrosine phosphorylation of the transporter leads to activation of the transport activity (PubMed:26979622). TEA uptake is activated by tyrosine phosphorylation (PubMed:26979622). Inhibited by cGMP, most likely through a cGMP-binding protein that interacts with OCT2 (PubMed:12395288).
Expressed in bacteria requires high concentrations of kosmotropic salts to be activated (PubMed:15301553). The mature and the intermediate form differ in activity towards synthetic caspase substrates: the p17/p10 mature form but not the p20/p8 intermediate form is active on WEHD-MCA; p20/p8 is active on a number of other caspase substrates without any marked preference (VEID-AFC, DEVD-AFC, LEVD-AFC and LEHD-AFC) (PubMed:22825846).
Expressed in keratinocytes of adult skin suprabasal layers (from spinous layers to the stratum granulosum and stratum corneum) (at protein level). Expressed in keratinocytes of hair shaft and sebaceous glands (at protein level). In psoriatic skin only expressed at very low levels (PubMed:11175259). The p17/10 mature form is expressed in epidermis stratum corneum, the p20/p8 intermediate form in epidermis upper granular cells of the stratum granulosum (PubMed:22825846).
Heterodimer of a large and a small subunit, both processed from the precursor; the mature active form is a p17/p10 dimer and the intermediate form a p20/p8 dimer.
In undifferentiated keratinocytes under postconfluency growth conditions (in vitro) (PubMed:11175259). By high glucose in retinal pigment epithelia cells (PubMed:25121097).
Inhibited by caspase-1 inhibitor YVAD-FMK and the pan-caspase inhibitor VAD-FMK.
Maturation by proteolytic processing appears to be a two-step process. The precursor is processed by KLK7 to yield the p20/p8 intermediate form which acts on the precursor to yield the p17/p10 mature form (PubMed:22825846). Initially, cleavage between Ile-152 and Lys-153 has been proposed to yield the large and small subunits of the active enzyme (PubMed:12200134).
Non-apoptotic caspase involved in epidermal differentiation. Is the predominant caspase in epidermal stratum corneum (PubMed:15556625). Seems to play a role in keratinocyte differentiation and is required for cornification. Regulates maturation of the epidermis by proteolytically processing filaggrin (By similarity). In vitro has a preference for the substrate [WY]-X-X-D motif and is active on the synthetic caspase substrate WEHD-ACF (PubMed:16854378, PubMed:19960512). Involved in processing of prosaposin in the epidermis (By similarity). May be involved in retinal pigment epithelium cell barrier function (PubMed:25121097). Involved in DNA degradation in differentiated keratinocytes probably by cleaving DFFA/ICAD leading to liberation of DFFB/CAD (PubMed:24743736).
Belongs to the small heat shock protein (HSP20) family.
Acts as a positive regulator in the activation of the canonical Wnt/beta-catenin signaling pathway by stabilizing cytoplasmic beta-catenin (By similarity). Involved in transcription activation of Wnt target gene expression (By similarity). Plays a role in symmetric division of blastomeres in the early stages of embryogenesis via regulation of mitotic spindle central positioning and organization of the F-actin filament network (By similarity). Plays a role in regulating the distribution of cellular organelles, via modulation of cytoskeletal dynamics and cytoplasmic lattice formation (By similarity).
Associates with the subcortical maternal complex (SCMC) composed of at least NLRP5, KHDC3L, OOEP, and TLE6 via interaction with NLRP5 and TLE6 (By similarity). Interacts with AXIN1; the interaction is direct, enhanced by protein kinase GSK3B and casein kinase CSNK1E activities and decreases GSK3B-induced beta-catenin serine and threonine phosphorylations (By similarity).
Induced in blood plasma by hyperglycemia (PubMed:24283382). Decreased in blood plasma by hyperinsulinemia (PubMed:24283382).
Secreted in blood plasma, and expressed in skeletal muscle and adipose tissue (at protein level).
Belongs to the Schlafen family. Subgroup III subfamily.
Endoribonuclease that cleaves tRNAs and rRNAs (PubMed:29563550). Cleaves tRNAs 11 nucleotides from the 3'-terminus at the acceptor stem (PubMed:29563550). Does not act on tRNA(Sec) (PubMed:29563550). Able to restrict HIV-1 virus replication; ability to inhibit HIV-1 replication is dependent on endoribonuclease activity (PubMed:29563550).
Shows a pseudo-dimeric U-pillow-shaped architecture of the SLFN13 N'-domain that may clamp base-paired RNAs.
Belongs to the calcineurin regulatory subunit family. CHP subfamily.
Both N-myristoylation and calcium-mediated conformational changes are essential for its function in exocytic traffic (By similarity). N-myristoylation is required for its association with microtubules and interaction with GAPDH, but not for the constitutive association to membranes.
Calcium-binding protein involved in different processes such as regulation of vesicular trafficking, plasma membrane Na(+)/H(+) exchanger and gene transcription. Involved in the constitutive exocytic membrane traffic. Mediates the association between microtubules and membrane-bound organelles of the endoplasmic reticulum and Golgi apparatus and is also required for the targeting and fusion of transcytotic vesicles (TCV) with the plasma membrane. Functions as an integral cofactor in cell pH regulation by controlling plasma membrane-type Na(+)/H(+) exchange activity. Affects the pH sensitivity of SLC9A1/NHE1 by increasing its sensitivity at acidic pH. Required for the stabilization and localization of SLC9A1/NHE1 at the plasma membrane. Inhibits serum- and GTPase-stimulated Na(+)/H(+) exchange. Plays a role as an inhibitor of ribosomal RNA transcription by repressing the nucleolar UBF1 transcriptional activity. May sequester UBF1 in the nucleoplasm and limit its translocation to the nucleolus. Associates to the ribosomal gene promoter. Acts as a negative regulator of the calcineurin/NFAT signaling pathway. Inhibits NFAT nuclear translocation and transcriptional activity by suppressing the calcium-dependent calcineurin phosphatase activity. Also negatively regulates the kinase activity of the apoptosis-induced kinase STK17B. Inhibits both STK17B auto- and substrate-phosphorylations in a calcium-dependent manner.
Endoplasmic reticulum-Golgi intermediate compartment
Monomer. Interacts with STK17B; the interaction occurs in a calcium-independent manner and induces the translocation of CHP1 from the Golgi to the nucleus. Interacts with GAPDH; the interaction is direct, occurs in a N-myristoylation-dependent manner and facilitates the ability of CHP1 to bind microtubules. Interacts with KIF1B (via the C-terminal end of the kinesin-motor domain); the interaction occurs in a calcium-dependent manner. Associates (via C-terminal domain) with microtubules; the association occurs with polymerized microtubules during the cell cycle in a myristoylation- and calcium-independent manner and is enhanced by GAPDH (By similarity). Interacts with PPP3CA. Interacts with SLC9A1/NHE1 (via the C-terminal domain); the interaction occurs at the plasma membrane in a calcium-dependent manner and at a domain that is critical for growth factor stimulation of the exchanger (PubMed:8901634, PubMed:11350981, PubMed:15035633, PubMed:34108458, PubMed:35613257). Interacts with SLC9A3; increases SLC9A3 trafficking and activity at the plasma membrane (PubMed:35613257).
Phosphorylated; decreased phosphorylation is associated with an increase in SLC9A1/NHE1 Na(+)/H(+) exchange activity. Phosphorylation occurs in serum-dependent manner. The phosphorylation state may regulate the binding to SLC9A1/NHE1.
Ubiquitously expressed. Has been found in fetal eye, lung, liver, muscle, heart, kidney, thymus and spleen.
Homodimer; disulfide-linked (PubMed:8483502, PubMed:22528658). Interacts with IL5RA (PubMed:1495999, PubMed:22153509). Interacts with CSF2RB (PubMed:1495999).
Homodimeric cytokine expressed predominantly by T-lymphocytes and NK cells that plays an important role in the survival, differentiation, and chemotaxis of eosinophils (PubMed:2653458, PubMed:9010276). Acts also on activated and resting B-cells to induce immunoglobulin production, growth, and differentiation (By similarity). Mechanistically, exerts its biological effects through a receptor composed of IL5RA subunit and the cytokine receptor common subunit beta/CSF2RB (PubMed:1495999, PubMed:22528658). Binding to the receptor leads to activation of various kinases including LYN, SYK and JAK2 and thereby propagates signals through the RAS-MAPK and JAK-STAT5 pathways respectively (PubMed:7613138).
Belongs to the AB hydrolase superfamily. Lipase family.
May function as inhibitor of dietary triglyceride digestion. Lacks detectable lipase activity towards triglycerides, diglycerides, phosphatidylcholine, galactolipids or cholesterol esters (in vitro) (By similarity).
Belongs to the dynein heavy chain family.
Consists of at least two heavy chains and a number of intermediate and light chains.
Dynein heavy chains probably consist of an N-terminal stem (which binds cargo and interacts with other dynein components), and the head or motor domain. The motor contains six tandemly-linked AAA domains in the head, which form a ring. A stalk-like structure (formed by two of the coiled coil domains) protrudes between AAA 4 and AAA 5 and terminates in a microtubule-binding site. A seventh domain may also contribute to this ring; it is not clear whether the N-terminus or the C-terminus forms this extra domain. There are four well-conserved and two non-conserved ATPase sites, one per AAA domain. Probably only one of these (within AAA 1) actually hydrolyzes ATP, the others may serve a regulatory function (By similarity).
Expressed primarily in trachea and testis, 2 tissues containing axonemal structures. Also expressed in brain (PubMed:11175280).
Force generating protein of cilia required for sperm flagellum motility. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Required in spermatozoa for the formation of the inner dynein arms and biogenesis of the axoneme (PubMed:24360805).
Component of the 60-80S U3 small nucleolar ribonucleoprotein (U3 snoRNP). Required for the early cleavages during pre-18S ribosomal RNA processing (PubMed:12655004). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Component of a heterotrimeric complex containing IMP3, IMP4 and MPHOSPH10. Interacts with MPHOSPH10 (PubMed:12655004).
Belongs to the eIF-2B gamma/epsilon subunits family.
Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP.
Complex of five different subunits; alpha, beta, gamma, delta and epsilon. Interacts with RGS2.
Phosphorylated at Ser-544 by DYRK2; this is required for subsequent phosphorylation by GSK3B (By similarity). Phosphorylated on serine and threonine residues by GSK3B; phosphorylation inhibits its function.
Belongs to the HpcH/HpaI aldolase family. Citrate lyase beta subunit-like subfamily.
Mitochondrial citramalyl-CoA lyase indirectly involved in the vitamin B12 metabolism (PubMed:29056341). Converts citramalyl-CoA into acetyl-CoA and pyruvate in the C5-dicarboxylate catabolism pathway (PubMed:29056341). The C5-dicarboxylate catabolism pathway is required to detoxify itaconate, a vitamin B12-poisoning metabolite (PubMed:29056341). Also acts as a malate synthase in vitro, converting glyoxylate and acetyl-CoA to malate (PubMed:29056341, PubMed:24334609). Also displays malyl-CoA thioesterase activity (PubMed:29056341). Also acts as a beta-methylmalate synthase in vitro, by mediating conversion of glyoxylate and propionyl-CoA to beta-methylmalate (PubMed:24334609, PubMed:29056341). Also has very weak citramalate synthase activity in vitro (PubMed:24334609, PubMed:29056341).
The protein is absent in 2.7% of the human population due to a loss-of-function polymorphism (rs41281112) that changes Arg-259 to a premature stop codon, leading to loss of the protein product (PubMed:23754956, PubMed:24334609). This polymorphism is associated with reduction of circulating vitamin B12 (PubMed:23754956, PubMed:24334609). The reduction of circulating vitamin B12 is caused by accumulation of citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that includes itaconate (PubMed:29056341). Itaconate acting as a vitamin B12-poisoning metabolite that inactivates the mitochondrial methylglutaconyl-CoA hydratase (AUH) enzyme (PubMed:29056341).
This organism lacks the other subunits that are necessary for ATP-independent citrate lyase activity. Even though this protein has clear similarity to citrate lyase beta subunit, it is expected to have a somewhat different enzyme activity.
Activated by X-ray, histamine, L-adrenaline, L- and D-phenylalanine, L- and D-histidine, L-His-OMe and beta-Ala-His (carnosine). Competitively inhibited by saccharin, thioxolone, coumarins, 667-coumate, celecoxib (Celebrex), valdecoxib (Bextra), SC-125, SC-560, diclofenac, acetate, azide, bromide, sulfonamide derivatives such as acetazolamide (AZA), methazolamide (MZA), ethoxzolamide (EZA), dichlorophenamide (DCP), brinzolamide, dansylamide, thiabendazole-5-sulfonamide, trifluoromethane sulfonamide and N-hydroxysulfamide, fructose-based sugar sulfamate RWJ-37497, and Foscarnet (phosphonoformate trisodium salt). Repressed strongly by hydrogen sulfide(HS) and weakly by nitrate (NO(3)). Esterase activity weakly reduced by cyanamide. N-hydroxyurea interfers with zinc binding and inhibit activity.
Catalyzes the reversible hydration of carbon dioxide (PubMed:1909891, PubMed:1910042, PubMed:1336460, PubMed:8485129, PubMed:8399159, PubMed:8218160, PubMed:8262987, PubMed:8451242, PubMed:7901850, PubMed:7761440, PubMed:8639494, PubMed:9265618, PubMed:17330962, PubMed:9398308, PubMed:11327835, PubMed:12056894, PubMed:17346964, PubMed:12171926, PubMed:15453828, PubMed:16214338, PubMed:15865431, PubMed:16106378, PubMed:15300855, PubMed:15667203, PubMed:18942852, PubMed:11831900, PubMed:17251017, PubMed:17314045, PubMed:18618712, PubMed:1336460, PubMed:11802772, PubMed:14736236, PubMed:16290146, PubMed:16759856, PubMed:16807956, PubMed:16686544, PubMed:17705204, PubMed:17127057, PubMed:17540563, PubMed:17588751, PubMed:18266323, PubMed:18024029, PubMed:18162396, PubMed:18374572, PubMed:18640037, PubMed:18481843, PubMed:19170619, PubMed:19186056, PubMed:19206230, PubMed:19778001, PubMed:19520834). Can also hydrate cyanamide to urea (PubMed:10550681, PubMed:11015219). Stimulates the chloride-bicarbonate exchange activity of SLC26A6 (PubMed:15990874). Essential for bone resorption and osteoclast differentiation (PubMed:15300855). Involved in the regulation of fluid secretion into the anterior chamber of the eye. Contributes to intracellular pH regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption.
Interacts with SLC4A4 (PubMed:14567693, PubMed:15218065). Interaction with SLC4A7 regulates SLC4A7 transporter activity (PubMed:14736710). Interacts with SLC26A6 isoform 4 (via C-terminus cytoplasmic domain) (PubMed:15990874).
Target of drugs used in treatments against glaucoma disorder and breast cancer.
Zinc. Can also use cobalt(II) with lower efficiency, but not copper(II), nickel(II) and manganese(II).
Binds differentially to the SH3 domains of certain proteins of signal transduction pathways. Binds to phosphatidylinositols; linking the hemopoietic tyrosine kinase fes to the cytoplasmic membrane in a phosphorylation dependent mechanism.
Expressed in a variety of tissues including lung, liver, skeletal muscle, kidney and pancreas.
Phosphorylated. Phosphorylation at Tyr-448 may stimulate the activity of the LYN kinase (By similarity).
May be a structural component of the sperm flagellum.
Belongs to the ureohydrolase superfamily. Arginase family.
Highly expressed in liver and kidney. Also found in skeletal muscle, fetal liver, brain, testis, skin and the gastrointestinal tract. Within brain, expression is higher in the cerebral cortex with lower levels in the medulla and spinal cord.
Hydrolyzes linear guanidino acids to form urea and the corresponding amines. Displays specificity for substrates having a negatively charged head group and short chains including taurocyamine, guanidino propanoic and butanoic acids. May protect cells by detoxifying potentially harmful amounts of guanidino acids. Metabolizes L-arginine with low efficiency.
Initially proposed to function as agmatinase but this activity was not proved when using the purified enzyme. A recent study showed that it rather functions as a guanidino acid hydrolase.
Acetylation at Lys-70 may increase chaperone activity.
Alpha-crystallin A 1-172 is found at nearly twofold higher levels in diabetic lenses than in age-matched control lenses.
Contributes to the transparency and refractive index of the lens (PubMed:18302245). In its oxidized form (absence of intramolecular disulfide bond), acts as a chaperone, preventing aggregation of various proteins under a wide range of stress conditions (PubMed:22120592, PubMed:31792453, PubMed:18199971, PubMed:19595763). Required for the correct formation of lens intermediate filaments as part of a complex composed of BFSP1, BFSP2 and CRYAA (PubMed:28935373).
Deamidation of Asn-101 in lens occurs mostly during the first 30 years of age, followed by a small additional amount of deamidation (approximately 5%) during the next approximately 38 years, resulting in a maximum of approximately 50% deamidation during the lifetime of the individual.
Expressed in the eye lens (at protein level).
Heteropolymer composed of three CRYAA and one CRYAB subunits (PubMed:20836128). Inter-subunit bridging via zinc ions enhances stability, which is crucial as there is no protein turn over in the lens (PubMed:22890888). Can also form homodimers and homotetramers (dimers of dimers) which serve as the building blocks of homooligomers (PubMed:17909943, PubMed:31792453, PubMed:23255486). Within homooligomers, the zinc-binding motif is created from residues of 3 different molecules. His-100 and Glu-102 from one molecule are ligands of the zinc ion, and His-107 and His-154 residues from additional molecules complete the site with tetrahedral coordination geometry (By similarity). Part of a complex required for lens intermediate filament formation composed of BFSP1, BFSP2 and CRYAA (PubMed:28935373).
In young individuals and during the first approximately 30 years of life, less than half molecules contain an intramolecular disulfide bond (oxidized form), while in the remaining fraction the cysteines are in the free sulfhydryl form (reduced form). With aging, the amount of oxidized form increases up to 90% and it becomes a major constituent of high molecular weight aggregates, concomitant with an age-dependent loss of its chaperone activity. The reduced form is undetectable in cataractous lenses.
O-glycosylated; contains N-acetylglucosamine side chains.
Phosphorylation on Ser-122 seems to be developmentally regulated. Absent in the first months of life, it appears during the first 12 years of human lifetime. The relative amount of phosphorylated form versus unphosphorylated form does not change over the lifetime of the individual.
Undergoes age-dependent proteolytical cleavage at the C-terminus. Alpha-crystallin A(1-172) is the most predominant form produced most rapidly during the first 12 years of age and after this age is present in approximately 50% of the lens molecules.
A chromosomal aberration involving MAPK10 has been found in a single patient with pharmacoresistant epileptic encephalopathy. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation.
Activated by threonine and tyrosine phosphorylation by two dual specificity kinases, MAP2K4 and MAP2K7. MAP2K7 phosphorylates MAPK10 on Thr-221 causing a conformational change and a large increase in Vmax. MAP2K4 then phosphorylates Tyr-223 resulting in a further increase in Vmax. Inhibited by dual specificity phosphatases, such as DUSP1. Inhibited by HDAC9.
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.
Dually phosphorylated on Thr-221 and Tyr-223 by MAP2K4 and MAP2K7, which activates the enzyme. MAP2K7 shows a strong preference for Thr-221 while MAP2K4 phosphorylates Tyr-223 preferentially. Weakly autophosphorylated on threonine and tyrosine residues in vitro.
Interacts with MAPKBP1 (By similarity). Interacts with MAPK8IP1/JIP-1 and MAPK8IP3/JIP-3/JSAP1 (By similarity). Interacts with SPAG9/MAPK8IP4/JIP4 (PubMed:15693750). Interacts with HDAC9 (PubMed:16611996). Interacts with ARRB2; the interaction enhances MAPK10 activation by MAP3K5 (PubMed:18435604). Interacts with SARM1 (By similarity). Interacts with JUND; interaction is inhibited in the presence of MEN1 (PubMed:22327296).
Palmitoylation regulates subcellular location and axonal development.
Responds to activation by environmental stress and pro-inflammatory cytokines by phosphorylating a number of transcription factors, and thus regulates transcriptional activity.
Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as pro-inflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the amyloid-beta precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-BMAL1 heterodimer and plays a role in the photic regulation of the circadian clock (PubMed:22441692). Phosphorylates JUND and this phosphorylation is inhibited in the presence of MEN1 (PubMed:22327296).
Specific to a subset of neurons in the nervous system. Present in the hippocampus and areas, cerebellum, striatum, brain stem, and weakly in the spinal cord. Very weak expression in testis and kidney.
The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
Brain-specific. Expressed in fetal and adult brain. Up-regulated in synovial carcinomas.
Allosterically regulated by S-adenosylmethionine (SAM).
Belongs to the methylenetetrahydrofolate reductase family.
Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine (PubMed:29891918). Represents a key regulatory connection between the folate and methionine cycles (Probable).
Contains a serine-rich phosphorylation region at the N-terminal and an eukaryote-only S-adenosylmethionine (SAM)-binding domain at the C-terminal. Through asymmetric homodimerization, the two regions are positioned next to each other and N-terminal phosphorylation increases sensitivity to SAM binding and inhibition.
Genetic variation in MTHFR influences susceptibility to occlusive vascular disease, neural tube defects (NTD), colon cancer and acute leukemia.
Phosphorylation of an N-terminal serine-rich phosphorylation region increases sensitivity to S-adenosylmethionine and inhibition.
Not expressed in normal tissues, except in germ cells in the seminiferous tubules and in Purkinje cells of the cerebellum. Expressed in various tumors, including melanoma, lymphoma, as well as pancreatic cancer, mammary gland cancer, non-small cell lung cancer and liver cancer. In hepatocellular carcinoma, there is an inverse correlation between tumor differentiation and protein expression, i.e. the lower the differentiation, the higher percentage of expression.
Proposed to enhance ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases. In vitro enhances ubiquitin ligase activity of TRIM28 and stimulates p53/TP53 ubiquitination in presence of Ubl-conjugating enzyme UBE2H leading to p53/TP53 degradation. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzymes (E2) at the E3:substrate complex.
Strongly expressed in spermatogonia and primary spermatocytes. At later stages of maturation, expression gradually decreases and becomes undetectable in mature spermatids.
(Microbial infection) Monomeric actin is cross-linked by V.cholerae toxins RtxA and VgrG1 in case of infection: bacterial toxins mediate the cross-link between Lys-50 of one monomer and Glu-270 of another actin monomer, resulting in formation of highly toxic actin oligomers that cause cell rounding (PubMed:19015515). The toxin can be highly efficient at very low concentrations by acting on formin homology family proteins: toxic actin oligomers bind with high affinity to formins and adversely affect both nucleation and elongation abilities of formins, causing their potent inhibition in both profilin-dependent and independent manners (PubMed:26228148).
Defects in ACTG1 has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea.
Monomethylation at Lys-84 (K84me1) regulates actin-myosin interaction and actomyosin-dependent processes. Demethylation by ALKBH4 is required for maintaining actomyosin dynamics supporting normal cleavage furrow ingression during cytokinesis and cell migration.
N-terminal acetylation by NAA80 affects actin filament depolymerization and elongation, including elongation driven by formins (PubMed:29581253). In contrast, filament nucleation by the Arp2/3 complex is not affected (PubMed:29581253).
N-terminal cleavage of acetylated methionine of immature cytoplasmic actin by ACTMAP.
Oxidation of Met-44 and Met-47 by MICALs (MICAL1, MICAL2 or MICAL3) to form methionine sulfoxide promotes actin filament depolymerization. MICAL1 and MICAL2 produce the (R)-S-oxide form. The (R)-S-oxide form is reverted by MSRB1 and MSRB2, which promote actin repolymerization.
Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to 4 others. Interacts with TWF1, CAPZB, cofilin and profilin (PubMed:28493397).
During interphase, required for microtubule organizing and anchoring activities. During mitosis, required for the organization and stabilization of the spindle pole (PubMed:28394342). Isoform 2/alpha is particularly important for the regulation of microtubule anchoring, microtubule stability, spindle architecture and spindle orientation, compared to isoform 1/beta (PubMed:28394342). May promote cell cycle arrest by enhancing the inhibition of CDK2 activity by CDKN1A. May be required for repair of DNA damage by homologous recombination in conjunction with BRCA2. May not be involved in non-homologous end joining (NHEJ).
Expressed at high levels in testis and skeletal muscle and at lower levels in brain, heart, kidney, liver, lung, ovary, pancreas, placenta, and spleen.
HT1080 cells that constitutively express low levels of BCCIP display increased levels of spontaneous single-stranded DNA and double-strand breaks.
Interacts with BRCA2, CDKN1A and MTDH/LYRIC (PubMed:10878006, PubMed:11313963, PubMed:14726710, PubMed:15713648, PubMed:18440304). Isoform 2/alpha, but not isoform 1/beta, interacts with DCTN1/p150-glued and ACTR1A/ARP1 (PubMed:28394342). Both isoform 1 and isoform 2 interact with alpha-, beta- and gamma-tubulins (PubMed:28394342). Interacts with TENT5C; the interaction has no effect on TENT5C poly(A) polymerase function (PubMed:28931820).
Isoform 1 is expressed throughout the cell cycle. Isoform 2 is expressed following mitosis and peaks in the G1/S phase of the cell cycle.
A chromosomal aberration involving BCL6 may be a cause of a form of B-cell leukemia. Translocation t(3;11)(q27;q23) with POU2AF1/OBF1.
A chromosomal aberration involving BCL6 may be a cause of lymphoma. Translocation t(3;4)(q27;p11) with ARHH/TTF.
Acetylated at Lys-379 by EP300 which inhibits the interaction with NuRD complex and the transcriptional repressor function. Deacetylated by HDAC- and SIR2-dependent pathways.
Chromosomal aberrations involving BCL6 are a cause of B-cell non-Hodgkin lymphomas (B-cell NHL), including diffuse large B-cell lymphoma and follicular lymphoma. Approximately 40% of diffuse large B-cell lymphomas and 5 to 10% of follicular lymphomas are associated with chromosomal translocations that deregulate expression of BCL6 by juxtaposing heterologous promoters to the BCL6 coding domain (PubMed:10469447, PubMed:10753856, PubMed:12414651, PubMed:11821949). Translocation t(3;14)(q27;q32). Translocation t(3;22)(q27;q11) with immunoglobulin gene regions (PubMed:11821949). Translocation t(3;7)(q27;p12) with IKZF1 gene 5'non-coding region (PubMed:10753856). Translocation t(3;6)(q27;p21) with Histone H4 (PubMed:12414651). Translocation t(3;16)(q27;p11) with IL21R. Translocation t(3;13)(q27;q14) with LCP1 (PubMed:10469447).
Down-regulated during maturation of dendritic cells by selective stimuli such as bacterial lipopolysaccharides (LPS), CD40LG and zymosan. Protein levels decreases upon genotoxic stress in a dose- and time-dependent way.
Expressed in germinal center T- and B-cells and in primary immature dendritic cells.
Homodimer. Interacts (via BTB domain) with the corepressors BCOR, NCOR1 and SMRT/NCOR2; the interactions are direct. Forms preferably ternary complexes with BCOR and SMRT/NCOR2 on target gene promoters but, on enhancer elements, interacts with SMRT/NCOR2 and HDAC3 to repress proximal gene expression. Interacts with histone deacetylases HDAC2, HDAC5 and HDAC9 (via the catalytic domain). Interacts with ZBTB7 and BCL6B. Interacts with SCF(FBXO11) complex; the interaction is independent of phosphorylation and promotes ubiquitination. Interacts (when phosphorylated) with PIN1; the interaction is required for BCL6 degradation upon genotoxic stress. Interacts with ZBTB17; inhibits ZBTB17 transcriptional activity. Interacts with CTBP1, autoinhibits its transcriptional expression. Interacts with NOTCH1 NCID and SIRT1; leads to a epigenetic repression of selective NOTCH1-target genes. Interacts (nor via BTB domain neither acetylated) with the NuRD complex components CHD4, HDAC1, MBD3 and MTA3; the interaction with MTA3 inhibits BCL6 acetylation and is required for BCL6 transpriptional repression.
Phosphorylated by MAPK1 in response to antigen receptor activation at Ser-333 and Ser-343. Phosphorylated by ATM in response to genotoxic stress. Phosphorylation induces its degradation by ubiquitin/proteasome pathway.
Polyubiquitinated (PubMed:9649500, PubMed:22113614, PubMed:30190310). Polyubiquitinated by SCF(FBXO11), leading to its degradation by the proteasome (PubMed:22113614). Ubiquitinated by the SCF(FBXL17) complex, leading to its degradation by the proteasome: ubiquitination by the SCF(FBXL17) complex takes place when aberrant BTB domain dimers are formed (PubMed:30190310).
The BTB domain mediates homodimerization. Its dimer interface mediates peptide binding such as to corepressors BCOR and NCOR2 (PubMed:18212045). Interaction with corepressors through the BTB domain is needed to facilitate the rapid proliferation and survival of GC B-cells but is not involved in the T(FH) formation and BCL6-mediated suppression of T(H)2 and T(H)17 differentiationrequired for GC formation (By similarity).
Transcriptional repressor mainly required for germinal center (GC) formation and antibody affinity maturation which has different mechanisms of action specific to the lineage and biological functions. Forms complexes with different corepressors and histone deacetylases to repress the transcriptional expression of different subsets of target genes. Represses its target genes by binding directly to the DNA sequence 5'-TTCCTAGAA-3' (BCL6-binding site) or indirectly by repressing the transcriptional activity of transcription factors. In GC B-cells, represses genes that function in differentiation, inflammation, apoptosis and cell cycle control, also autoregulates its transcriptional expression and up-regulates, indirectly, the expression of some genes important for GC reactions, such as AICDA, through the repression of microRNAs expression, like miR155. An important function is to allow GC B-cells to proliferate very rapidly in response to T-cell dependent antigens and tolerate the physiological DNA breaks required for immunglobulin class switch recombination and somatic hypermutation without inducing a p53/TP53-dependent apoptotic response. In follicular helper CD4(+) T-cells (T(FH) cells), promotes the expression of T(FH)-related genes but inhibits the differentiation of T(H)1, T(H)2 and T(H)17 cells. Also required for the establishment and maintenance of immunological memory for both T- and B-cells. Suppresses macrophage proliferation through competition with STAT5 for STAT-binding motifs binding on certain target genes, such as CCL2 and CCND2. In response to genotoxic stress, controls cell cycle arrest in GC B-cells in both p53/TP53-dependedent and -independent manners. Besides, also controls neurogenesis through the alteration of the composition of NOTCH-dependent transcriptional complexes at selective NOTCH targets, such as HES5, including the recruitment of the deacetylase SIRT1 and resulting in an epigenetic silencing leading to neuronal differentiation.
Component of the outer alpha-ring of the 20S proteasome core which is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The catalytic chamber with the active sites is on the inside of the barrel. Interacts with canonical subunits of the spermatoproteasome, including proteasome activators PSME4 (also called PA200) and PSME3 (also called PA28-gamma). Interacts with proteasome-interacting proteins chaperones, ubiquitin ligases and ubiquitin specific proteases. Interacts with meiotic proteins cyclin dependent kinase CDK1 and the ATPase TRIP13 as well as proteins of the synaptonemal complex SIX6OS1 and SYCE3.
Component of the spermatoproteasome, a proteasome specifically found in testis that promotes acetylation-dependent degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. The proteasome is a protein complex that degrades unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Required for 20S core proteasome assembly, essential for the degradation of meiotic proteins RAD51 and RPA1 at late prophase I and the progression of meiosis I during spermatogenesis. Localizes to the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I.
Belongs to the RRM HNRPC family. RALY subfamily.
Belongs to the connexin family. Delta-type subfamily.
Homodimer (via BAR domain). Interacts with ADAM15. Interacts with FASLG. Interacts (via SH3 domain) with DNM1 and DNM2. Interacts with WASL. Interacts with FCHSD1 (via the F-BAR domain) (By similarity).
Plays a role in the reorganization of the cytoskeleton, endocytosis and cellular vesicle trafficking via its interactions with membranes, WASL, DNM1 and DNM2. Acts both during interphase and at the end of mitotic cell divisions. Required for efficient progress through mitosis and cytokinesis. Required for normal formation of the cleavage furrow at the end of mitosis. Modulates endocytosis of cell-surface proteins, such as APP and PRNP; this then modulates the secretion of APP and PRNP peptides. Promotes membrane tubulation (in vitro). May promote the formation of macropinosomes.
The PX and BAR domains mediate association with membranes and are required for membrane tubulation.
A paper describing an additional role for this protein in a base excision repair pathway that is not coupled to transcription has been retracted, because some of the experimental data were incorrect.
Belongs to the XPG/RAD2 endonuclease family. XPG subfamily.
Binds 2 magnesium ions per subunit. They probably participate in the reaction catalyzed by the enzyme. May bind an additional third magnesium ion after substrate binding.
Both nuclear localization signals 1 and 2 act as a monopartite signal which binds to the high affinity site on KPNA2/importin-alpha.
Both the spacer region (also known as the recognition (R) domain) and C-terminal domain are required for stable binding to the DNA repair bubble (PubMed:16246722). However, both domains are dispensable for incision of DNA bubble structures (PubMed:16246722, PubMed:32821917, PubMed:32522879).
Includes a cryptic exon found in intron 6.
Induced by replication stress caused by DNA double-strand breaks (DBS).
Monomer (PubMed:32522879). Homodimer (PubMed:32522879). Component of the homologous recombination repair (HR) complex composed of ERCC5/XPG, BRCA2, PALB2, DSS1 and RAD51 (PubMed:26833090). Within the complex, interacts with BRCA2 and PALB2 (PubMed:26833090). Interacts with RNA polymerase II (PubMed:16246722). Interacts (via C-terminus) with ERCC6/CSB; the interaction stimulates ERCC6/CSB binding to the DNA repair bubble and ERCC6/CSB ATPase activity (PubMed:16246722). May form a complex composed of RNA polymerase II, ERCC6/CSB and ERCC5/XPG which associates with the DNA repair bubble during transcription-coupled nucleotide excision repair (PubMed:16246722). Interacts with BRCA1; the interaction promotes the release of BRCA1 from DNA (PubMed:26833090). Interacts with PCNA (PubMed:9305916). Interacts with NTHL1; the interaction stimulates NTHL1 activity and NTHL1 binding to its DNA substrate (PubMed:9927729).
Single-stranded structure-specific DNA endonuclease involved in DNA excision repair (PubMed:8206890, PubMed:8090225, PubMed:8078765, PubMed:7651464, PubMed:32821917, PubMed:32522879). Makes the 3'incision in DNA nucleotide excision repair (NER) (PubMed:8090225, PubMed:8078765, PubMed:32821917, PubMed:32522879). Binds and bends DNA repair bubble substrate and breaks base stacking at the single-strand/double-strand DNA junction of the DNA bubble (PubMed:32522879). Plays a role in base excision repair (BER) by promoting the binding of DNA glycosylase NTHL1 to its substrate and increasing NTHL1 catalytic activity that removes oxidized pyrimidines from DNA (PubMed:9927729). Involved in transcription-coupled nucleotide excision repair (TCR) which allows RNA polymerase II-blocking lesions to be rapidly removed from the transcribed strand of active genes (PubMed:16246722). Functions during the initial step of TCR in cooperation with ERCC6/CSB to recognized stalled RNA polymerase II (PubMed:16246722). Also, stimulates ERCC6/CSB binding to the DNA repair bubble and ERCC6/CSB ATPase activity (PubMed:16246722). Required for DNA replication fork maintenance and preservation of genomic stability (PubMed:26833090, PubMed:32522879). Involved in homologous recombination repair (HRR) induced by DNA replication stress by recruiting RAD51, BRCA2, and PALB2 to the damaged DNA site (PubMed:26833090). During HRR, binds to the replication fork with high specificity and stabilizes it (PubMed:32522879). Also, acts upstream of HRR, to promote the release of BRCA1 from DNA (PubMed:26833090).
Autophosphorylated. Phosphorylated by MAP2K6//MAPKK6, leading to PAK6 activation.
Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1 (By similarity). Interacts with the androgen receptor AR and the estrogen receptor ESR1. Interacts with IQGAP1 and PPM1B.
Selectively expressed in brain and testis, with lower levels in multiple tissues including prostate and breast.
Serine/threonine protein kinase that plays a role in the regulation of gene transcription. The kinase activity is induced by various effectors including AR or MAP2K6/MAPKK6. Phosphorylates the DNA-binding domain of androgen receptor/AR and thereby inhibits AR-mediated transcription. Inhibits also ESR1-mediated transcription. May play a role in cytoskeleton regulation by interacting with IQGAP1. May protect cells from apoptosis through phosphorylation of BAD.
Acetylated at Lys-540, Lys-546 and Lys-554 by KAT2B/PCAF (PubMed:23932781). Acetylation is promoted by glucose and stabilizes the protein, probably by preventing ubiquitination at the same sites (PubMed:23932781). Acetylation promotes de novo lipid synthesis (PubMed:23932781). Deacetylated by SIRT2.
Catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA, the latter serving as common substrate for de novo cholesterol and fatty acid synthesis.
In the C-terminal section; belongs to the succinate/malate CoA ligase alpha subunit family.
In the N-terminal section; belongs to the succinate/malate CoA ligase beta subunit family.
Phosphorylated by PKA and GSK3 in a sequential manner; phosphorylation results in activation of its activity (PubMed:10653665). Phosphorylation on Thr-447 and Ser-451 depends on the phosphorylation state of Ser-455 (By similarity). Phosphorylation on Ser-455 is decreased by prior phosphorylation on the other 2 residues (By similarity).
Phosphorylation results in activation of its activity (PubMed:10653665). Glucose 6-phosphate, fructose 6-phosphate, fructose 2,6-bisphosphate, ribulose 5-phosphate, and fructose 1,6-bisphosphate also act as activators (PubMed:10653665).
Ubiquitinated at Lys-540, Lys-546 and Lys-554 by the BCR(KLHL25) E3 ubiquitin ligase complex and UBR4, leading to its degradation (PubMed:23932781, PubMed:27664236, PubMed:34491895). Ubiquitination is probably inhibited by acetylation at same site (PubMed:23932781). BCR(KLHL25)-mediated degradation of ACLY promotes fatty acid oxidation and is required for differentiation of inducible regulatory T (iTreg) cells (PubMed:34491895).
(Microbial infection) Interacts with C.difficile toxin TcdB, suggesting that it may act as a receptor for TcdB.
Detected in fibroblasts (at protein level) (PubMed:36213313). Detected in placenta (at protein level) (PubMed:32337544). Detected in malignant melanoma cells.
Interacts with the first PDZ domain of MPDZ. Interacts with PRKCA. Binds TNC, laminin-1, COL5A1 and COL6A2. Interacts with PLG and angiostatin. Binds FGF2 and PDGFA. Interacts with GRIP1, GRIP2 and GRIA2. Forms a ternary complex with GRIP1 and GRIA2 (By similarity). Interacts with LGALS3 and the integrin composed of ITGB1 and ITGA3. Interacts with ITGA4 through its chondroitin sulfate glycosaminoglycan. Interacts with BCAR1, CDC42 and ACK1. Interacts with MMP16.
O-glycosylated; contains glycosaminoglycan chondroitin sulfate which are required for proper localization and function in stress fiber formation (By similarity). Involved in interaction with MMP16 and ITGA4.
Phosphorylation by PRKCA regulates its subcellular location and function in cell motility.
Proteoglycan playing a role in cell proliferation and migration which stimulates endothelial cells motility during microvascular morphogenesis. May also inhibit neurite outgrowth and growth cone collapse during axon regeneration. Cell surface receptor for collagen alpha 2(VI) which may confer cells ability to migrate on that substrate. Binds through its extracellular N-terminus growth factors, extracellular matrix proteases modulating their activity. May regulate MPP16-dependent degradation and invasion of type I collagen participating in melanoma cells invasion properties. May modulate the plasminogen system by enhancing plasminogen activation and inhibiting angiostatin. Functions also as a signal transducing protein by binding through its cytoplasmic C-terminus scaffolding and signaling proteins. May promote retraction fiber formation and cell polarization through Rho GTPase activation. May stimulate alpha-4, beta-1 integrin-mediated adhesion and spreading by recruiting and activating a signaling cascade through CDC42, ACK1 and BCAR1. May activate FAK and ERK1/ERK2 signaling cascades.
Valuable marker for several incompletely differentiated precursor cells.
Belongs to the eukaryotic ribosomal protein eL36 family.
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25901680, PubMed:25957688, PubMed:32669547).
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25901680, PubMed:25957688, PubMed:32669547). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:12962325, PubMed:23636399, PubMed:25901680, PubMed:25957688, PubMed:32669547).
Adaptor protein complex 1 (AP-1) is a heterotetramer composed of two large adaptins (gamma-type subunit AP1G1 and beta-type subunit AP1B1), a medium adaptin (mu-type subunit AP1M1 or AP1M2) and a small adaptin (sigma-type subunit AP1S1 or AP1S2 or AP1S3). Interacts with P2X4 (By similarity).
Belongs to the adaptor complexes medium subunit family.
Phosphorylation of membrane-bound AP1M1/AP1M2 increases its affinity for sorting signals.
Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the trans-Golgi network (TGN) and endosomes. The AP complexes mediate the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules.
Catalyzes the degradation of hydrogen peroxide (H(2)O(2)) generated by peroxisomal oxidases to water and oxygen, thereby protecting cells from the toxic effects of hydrogen peroxide (PubMed:7882369). Promotes growth of cells including T-cells, B-cells, myeloid leukemia cells, melanoma cells, mastocytoma cells and normal and transformed fibroblast cells (PubMed:7882369).
Homotetramer (PubMed:21976670, PubMed:10666617, PubMed:10656833). Interacts (via microbody targeting signal) with PEX5, monomeric form interacts with PEX5, leading to its translocation into peroxisomes (PubMed:21976670).
Occurs in almost all aerobically respiring organisms and serves to protect cells from the toxic effects of hydrogen peroxide.
Belongs to the peptidase M67A family. CSN5 subfamily.
Component of the CSN complex, composed of COPS1/GPS1, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7 (COPS7A or COPS7B), COPS8 and COPS9 isoform 1 (PubMed:26456823). In the complex, it probably interacts directly with COPS1, COPS2, COPS4, COPS6 and COPS7 (COPS7A or COPS7B) and COPS9 isoform 1 (PubMed:26456823). Interacts with COPS9 isoform 2 (PubMed:23776465). The CSN complex interacts with the BRISC complex. Also exists as monomeric form. Interacts with TP53, MIF, JUN, UCHL1, NCOA1, HIF1A, CDKN1B, BCL3, GFER, PGR, LHCGR, SMAD4, SMAD7, ID1, ID3, ITGB2 and TOP2A. Part of a complex consisting of RANBP9, Ran, DYRK1B and COPS5. Interacts with IFIT3. Interacts with BRSK2. Interacts with ZDHHC16 (PubMed:17123647). Interacts with MINDY3 (PubMed:21499297). Interacts with FANK1; regulates the phosphorylation of JUN and the transcriptional activity of AP-1 (PubMed:20978819). Interacts with NUPR1; this interaction allows COPS5-dependent CDKN1B nuclear to cytoplasm translocation (PubMed:16300740).
Probable protease subunit of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of the SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. In the complex, it probably acts as the catalytic center that mediates the cleavage of Nedd8 from cullins. It however has no metalloprotease activity by itself and requires the other subunits of the CSN complex. Interacts directly with a large number of proteins that are regulated by the CSN complex, confirming a key role in the complex. Promotes the proteasomal degradation of BRSK2.
The CSN complex is associated with some 'Lys-63'-specific deubiquitination. Such activity is however not mediated by the core CSN complex but by the BRCC3/BRCC36 component of the BRISC complex.
The JAMM motif is essential for the protease activity of the CSN complex resulting in deneddylation of cullins. It constitutes the catalytic center of the complex (By similarity).
Binds free ubiquitin non-covalently via its RING-type zinc finger. Ubiquitin-binding leads to enhance the E3 ubiquitin-protein ligase activity by stabilizing the ubiquitin-conjugating enzyme E2 (donor ubiquitin) in the 'closed' conformation and activating ubiquitin transfer (PubMed:26656854).
E3 ubiquitin-protein ligase that acts as a regulator of motor axon elongation. Required for efficient motor axon extension in the dorsal forelimb by enhancing the transcriptional responses of the SMAD1/SMAD5/SMAD8 effectors, which are activated downstream of BMP. Acts by mediating ubiquitination and degradation of SMAD inhibitors such as SMAD6, SMAD7, SKI and SNON isoform of SKIL.
Monomer; binding to the ubiquitin-conjugating enzyme E2 does not trigger homodimerization (PubMed:26656854).
The RING-type zinc finger mediates the E3 ubiquitin-protein ligase activity and binds directly to free ubiquitin (PubMed:26656854). Non-covalent ubiquitin-binding stabilizes the ubiquitin-conjugating enzyme E2 (donor ubiquitin) in the 'closed' conformation and stimulates ubiquitin transfer (PubMed:26656854).
Belongs to the transient receptor (TC 1.A.4) family. TrpV subfamily. TRPV5 sub-subfamily.
Constitutively active calcium selective cation channel thought to be involved in Ca(2+) reabsorption in kidney and intestine (PubMed:11549322, PubMed:18768590). Required for normal Ca(2+) reabsorption in the kidney distal convoluted tubules (By similarity). The channel is activated by low internal calcium level and the current exhibits an inward rectification (PubMed:11549322, PubMed:18768590). A Ca(2+)-dependent feedback regulation includes fast channel inactivation and slow current decay (By similarity). Heteromeric assembly with TRPV6 seems to modify channel properties. TRPV5-TRPV6 heteromultimeric concatemers exhibit voltage-dependent gating (By similarity).
Expressed at high levels in kidney, small intestine and pancreas, and at lower levels in testis, prostate, placenta, brain, colon and rectum.
Homotetramer and probably heterotetramer with TRPV6. Interacts with TRPV6 (By similarity). Interacts with S100A10 and probably with the ANAX2-S100A10 heterotetramer. The interaction with S100A10 is required for the trafficking to the plasma membrane. Interacts with calmodulin. Interacts with BSPRY, which results in its inactivation.
Forms a heterodimer with TCF3 isoform E47; interaction may be required for DNA-binding in certain situations.
The disease is caused by variants affecting the gene represented in this entry. A 6.5 kb deletion that spans a remote cis regulatory element 20 kb upstream from ATOH7 has been found in PHPVAR patients (PubMed:21441919).
Transcription factor that binds to DNA at the consensus sequence 5'-CAG[GC]TG-3' (PubMed:31696227). Dimerization with TCF3 isoform E47 may be required in certain situations (PubMed:31696227). Binds to gene promoters and enhancer elements, and thereby regulates a transcriptional program of retinal ganglion cell (RGC) determinant genes (By similarity). Although the exact mechanism is not certain, retinal transcription regulation by ATOH7 has a role in RGC determination and survival, photoreceptor population development, targeting of RGC axons to the optic nerve and development of the retino-hypothalamic tract (By similarity). Binds to its own promoter and enhancer sequences, suggesting autoregulation of ATOH7 transcription (By similarity). Required for retinal circadian rhythm photoentrainment (By similarity). Plays a role in brainstem auditory signaling and binaural processing (By similarity).
Phosphorylated. Phosphorylation at Ser-107 and Ser-109 mediates the interaction with spliceosome proteins.
Probably acts as a spliceosomal factor that contributes to spliceosome assembly and regulates the isoform switching of proteins such as PARP6.
Acts as a transcriptional activator: mediates transcriptional activation by binding to E box-containing promoter consensus core sequences 5'-CANNTG-3'. Associates with the p300/CBP transcription coactivator complex to stimulate transcription of the secretin gene as well as the gene encoding the cyclin-dependent kinase inhibitor CDKN1A. Contributes to the regulation of several cell differentiation pathways, like those that promote the formation of early retinal ganglion cells, inner ear sensory neurons, granule cells forming either the cerebellum or the dentate gyrus cell layer of the hippocampus, endocrine islet cells of the pancreas and enteroendocrine cells of the small intestine. Together with PAX6 or SIX3, is required for the regulation of amacrine cell fate specification. Also required for dendrite morphogenesis and maintenance in the cerebellar cortex. Associates with chromatin to enhancer regulatory elements in genes encoding key transcriptional regulators of neurogenesis (By similarity).
Efficient DNA-binding requires dimerization with another bHLH protein (By similarity). Heterodimer with TCF3/E47; the heterodimer is inhibited in presence of ID2, but not NR0B2, to E-box element (PubMed:14752053). Interacts with EP300; the interaction is inhibited by NR0B2 (PubMed:14752053). Interacts with RREB1 (PubMed:12482979). Interacts with ATOH8 (By similarity).
Phosphorylated. In islet cells, phosphorylated on Ser-274 upon glucose stimulation; which may be required for nuclear localization. In activated neurons, phosphorylated on Ser-335; which promotes dendritic growth. Phosphorylated by MAPK1; phosphorylation regulates heterodimerization and DNA-binding activities. Phosphorylation on Ser-266 and Ser-274 increases transactivation on the insulin promoter in glucose-stimulated insulinoma cells (By similarity).
Metallocarboxypeptidase that mediates deglutamylation of tubulin and non-tubulin target proteins. Catalyzes the removal of polyglutamate side chains present on the gamma-carboxyl group of glutamate residues within the C-terminal tail of tubulin protein. Specifically cleaves tubulin long-side-chains, while it is not able to remove the branching point glutamate. Also catalyzes the removal of polyglutamate residues from the carboxy-terminus of non-tubulin proteins such as MYLK. May catalyze the hydrolysis of aspartate from the carboxy-terminus of target proteins. Does not show detyrosinase or deglycylase activities from the carboxy-terminus of target proteins.
Metallocarboxypeptidase that mediates tubulin deglutamylation.
Up-regulated by inducers of the unfolded protein response (UPR), including tunicamycin and thapsigargin.
Expressed in hair root but not in skin. Expressed also in lung, pancreas, ovary, testis.
In the hair cortex, hair keratin intermediate filaments are embedded in an interfilamentous matrix, consisting of hair keratin-associated protein (KRTAP), which are essential for the formation of a rigid and resistant hair shaft through their extensive disulfide bond cross-linking with abundant cysteine residues of hair keratins. The matrix proteins include the high-sulfur and high-glycine-tyrosine keratins.
ADP-ribosylation during genotoxic stress promotes accumulation in nuclear speckles.
Associated with the large multiprotein complex TRAP (Mediator complex-like). Interacts with SFPQ; the interaction is dependent on SFPQ phosphorylation at 'Thr-687' and inhibits binding of SFPQ to an ESS1 exonic splicing silencer element-containing RNA. Interacts with NXF1. Component of the SNARP complex which consists at least of SNIP1, SNW1, THRAP3, BCLAF1 and PNN. Associated with spliced mRNP complexes. Interacts with HELZ2 and PPARG. Interacts with CLOCK and BMAL1 (By similarity). Component of a MACOM-like complex, named WTAP complex, composed of WTAP, ZC3H13, CBLL1, KIAA1429, RBM15, BCLAF1 and THRAP3.
Involved in pre-mRNA splicing. Remains associated with spliced mRNA after splicing which probably involves interactions with the exon junction complex (EJC). Can trigger mRNA decay which seems to be independent of nonsense-mediated decay involving premature stop codons (PTC) recognition. May be involved in nuclear mRNA decay. Involved in regulation of signal-induced alternative splicing. During splicing of PTPRC/CD45 is proposed to sequester phosphorylated SFPQ from PTPRC/CD45 pre-mRNA in resting T-cells. Involved in cyclin-D1/CCND1 mRNA stability probably by acting as component of the SNARP complex which associates with both the 3'end of the CCND1 gene and its mRNA. Involved in response to DNA damage. Is excluced from DNA damage sites in a manner that parallels transcription inhibition; the function may involve the SNARP complex. Initially thought to play a role in transcriptional coactivation through its association with the TRAP complex; however, it is not regarded as a stable Mediator complex subunit. Cooperatively with HELZ2, enhances the transcriptional activation mediated by PPARG, maybe through the stabilization of the PPARG binding to DNA in presence of ligand. May play a role in the terminal stage of adipocyte differentiation. Plays a role in the positive regulation of the circadian clock. Acts as a coactivator of the CLOCK-BMAL1 heterodimer and promotes its transcriptional activator activity and binding to circadian target genes (PubMed:24043798).
Belongs to the Mrp/NBP35 ATP-binding proteins family.
Highest expression in liver and kidney. expressed at significant levels in small intestine and brain (at protein level).
Required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I). May deliver of one or more Fe-S clusters to complex I subunits.
Interacts with SKP1 (PubMed:26171402). Interacts with CUL1 (By similarity). Interacts with IL22RA1 (PubMed:26171402).
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex (PubMed:26171402). Promotes degradation of interleukin-22 receptor subunit IL22RA1 in resting and IL22-stimulated conditions by facilitating its ubiquitination (PubMed:26171402). Functions as a cell growth suppressor (PubMed:26171402).
Functions as a dosage-dependent inducer in mitotic control. Tyrosine protein phosphatase required for progression of the cell cycle.
Interacts with MAPK14 and 14-3-3 proteins.
Phosphorylated by BRSK1 in vitro. Phosphorylated by CHEK1, which inhibits the activity of this protein. Phosphorylation at Ser-353 by AURKA might locally participate in the control of the onset of mitosis. Phosphorylation by MELK at Ser-169 promotes localization to the centrosome and the spindle poles during mitosis. Phosphorylation at Ser-323 and Ser-375 by MAPK14 is required for binding to 14-3-3 proteins.
Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Required for G2/M phases of the cell cycle progression and abscission during cytokinesis in a ECT2-dependent manner. Directly dephosphorylates CDK1 and stimulates its kinase activity. The three isoforms seem to have a different level of activity.
Belongs to the Mediator complex subunit 28 family.
Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. May be part of a complex containing NF2/merlin that participates in cellular signaling to the actin cytoskeleton downstream of tyrosine kinase signaling pathways.
Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Forms a ternary complex with NF2/merlin and GRB2. Binds to actin.
Up-regulated by endothelial cells when exposed to tumor conditional media.
Widely expressed. Highly expressed in vascular tissues such as placenta, testis and liver.
Acts as guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases. Regulates cell migration and adhesion assembly and disassembly through a RAC1, PI3K, RHOA and AKT1-dependent mechanism. Increases both RAC1 and CDC42 activity, but decreases the amount of active RHOA. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression.
Both the ABR and the SH3 domains contribute to maintaining the protein in an inhibited conformation by associating with the C-terminal tail. Binding of these domains to the C-terminal tail inhibits the activity of the protein by blocking a region that is required for its GEF activity.
Expressed at high levels in the placenta, spleen and kidney, at moderate levels in lung, small intestine, liver, brain and heart, and at low levels in skeletal muscle. Expression is aberrantly enhanced in most colorectal tumors.
Interacts (via ABR and SH3 domain) with APC. The binding of APC enhances its GEF activity by relieving it from an autoinhibitory conformation, in which the ABR and SH3 domains are associated with the C-terminal tail. Interacts (via C-terminal tail) with PPP1R9B (via C-terminus). Interacts with RAC1.
The C-terminal tail is required for its GEF activity.
Required for the transport of GPI-anchored proteins to the plasma membrane (PubMed:24367057). Probable acetyltransferase, which acetylates the inositol ring of phosphatidylinositol during biosynthesis of GPI-anchor. Acetylation during GPI-anchor biosynthesis is not essential for the subsequent mannosylation and is usually removed soon after the attachment of GPIs to proteins (By similarity).
Belongs to the GST superfamily. Alpha family.
Catalyzes the conjugation of glutathione to a large variety of electrophilic compounds.
Homodimer or heterodimer of GSTA1 and GSTA2.
Belongs to the ZIP transporter (TC 2.A.5) family.
Cleaved on the N-terminus before locating to the plasma membrane.
Highly expressed in the breast, prostate, placenta, kidney, pituitary and corpus callosum (PubMed:12839489). Weakly expressed in heart and intestine. Also highly expressed in cells derived from an adenocarcinoma of the cervix and lung carcinoma (PubMed:12839489).
Interacts with SLC39A10; which triggers cells to undergo EMT and mitosis (PubMed:27274087). Found in a complex with SLC39A6, SLC39A10 and with the 'Ser-727' phosphorylated form of STAT3 throughout mitosis (PubMed:32797246). Found in a complex with SLC39A6, SLC39A10 and with NCAM1; this complex controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition (EMT) (By similarity). Found in a complex with SLC39A6, SLC39A10 and with GSK3B that controls NCAM1 phosphorylation (By similarity).
Phosphorylated by ZAP70 in response to TCR stimulation leading to its activation.
Up-regulated by estrogen in breast cancer cells lines (PubMed:2903103, PubMed:23919497). Decreased protein level in response to zinc treatment (PubMed:18272141). Increased upon T cell activation (PubMed:30552163). Induced by STAT3 (PubMed:23919497).
Zinc-influx transporter which plays a role in zinc homeostasis and in the induction of epithelial-to-mesenchymal transition (EMT) (PubMed:27274087, PubMed:18272141, PubMed:21422171, PubMed:34394081, PubMed:23919497, PubMed:12839489). When associated with SLC39A10, the heterodimer formed by SLC39A10 and SLC39A6 mediates cellular zinc uptake to trigger cells to undergo epithelial- to-mesenchymal transition (EMT) (PubMed:27274087). The SLC39A10-SLC39A6 heterodimer also controls NCAM1 phosphorylation and its integration into focal adhesion complexes during EMT (By similarity). Zinc influx inactivates GSK3B, enabling unphosphorylated SNAI1 in the nucleus to down-regulate adherence genes such as CDH1, causing loss of cell adherence (PubMed:23919497). In addition, the SLC39A10-SLC39A6 heterodimer plays an essentiel role in initiating mitosis by importing zinc into cells to initiate a pathway resulting in the onset of mitosis (PubMed:32797246). Participates in the T-cell receptor signaling regulation by mediating cellular zinc uptake into activated lymphocytes (PubMed:30552163, PubMed:21422171, PubMed:34394081). Regulates the zinc influx necessary for proper meiotic progression to metaphase II (MII) that allows the oocyte-to-egg transition (PubMed:25143461).
(Microbial infection) Interacts with attenuated rabies virus protein G; this interaction is required for virally-induced apoptosis.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class subfamily.
Cleaved and activated by calpain I/CAPN1.
Highly phosphorylated on serine and threonine residues but not on tyrosines.
Interacts with MAPK12 (via C-terminus); this interaction abolishes PTPN4 catalytic autoinhibition and thus activates the phosphatase activity.
Phosphatase that plays a role in immunity, learning, synaptic plasticity or cell homeostasis (PubMed:25825441, PubMed:27246854). Regulates neuronal cell homeostasis by protecting neurons against apoptosis (PubMed:20086240). Negatively regulates TLR4-induced interferon beta production by dephosphorylating adapter TICAM2 and inhibiting subsequent TRAM-TRIF interaction (PubMed:25825441). Dephosphorylates also the immunoreceptor tyrosine-based activation motifs/ITAMs of the TCR zeta subunit and thereby negatively regulates TCR-mediated signaling pathway (By similarity). May act at junctions between the membrane and the cytoskeleton.
Belongs to the eukaryotic ribosomal protein eS27 family.
Was named 'duranin' in honor of Marinus Duran, who first described L-2-hydroxyglutaric aciduria.
Widely expressed. Highly expressed in brain, testis and muscle. Expressed to a lower extent in lymphocytes, fibroblasts, keratinocytes, placenta, bladder, small intestine, liver and bone marrow.
Expressed in lung, kidney, spleen, liver and brain with lowest expression in kidney.
Homo- and heterodimer. Associates with pre-60S ribosomal particles (PubMed:32669547). Interacts with MELK and MYBL2 (PubMed:11802789, PubMed:12645566). Interacts with DNAJC21 (PubMed:27346687).
Phosphorylated by MELK. The phosphorylation may redirect the protein to the nucleus.
Pre-60S-associated cytoplasmic factor involved in the cytoplasmic maturation of the 60S subunit.
Ubiquitinated by HECTD1, leading to its degradation.
Interacts with CEP63 (PubMed:24613305). Interacts with WDR62 (PubMed:26297806). Forms a complex with OFD1 and CEP20/FOR20 (PubMed:26643951). Interacts with PCM1 (PubMed:26297806, PubMed:26643951).
Involved in centriole duplication (PubMed:24613305, PubMed:26297806). Positively regulates CEP63 centrosomal localization (PubMed:24613305, PubMed:26297806). Required for WDR62 centrosomal localization and promotes the centrosomal localization of CDK2 (PubMed:24613305, PubMed:26297806). May play a role in cilium assembly.
Adapter protein that plays a role in the intracellular membrane trafficking of ubiquitinated proteins, thereby participating in autophagy, ubiquitination-dependent signaling and receptor recycling pathways (PubMed:14563850, PubMed:15047686, PubMed:23023224, PubMed:25588840, PubMed:26320582, PubMed:31371777). Acts as a MYO6/Myosin VI adapter protein that targets MYO6 to endocytic structures (PubMed:23023224). Together with MYO6, required for autophagosomal delivery of endocytic cargo, the maturation of autophagosomes and their fusion with lysosomes (PubMed:23023224). MYO6 links TOM1 with autophagy receptors, such as TAX1BP1; CALCOCO2/NDP52 and OPTN (PubMed:31371777). Binds to polyubiquitinated proteins via its GAT domain (PubMed:14563850). In a complex with TOLLIP, recruits ubiquitin-conjugated proteins onto early endosomes (PubMed:15047686). The Tom1-Tollip complex may regulate endosomal trafficking by linking polyubiquitinated proteins to clathrin (PubMed:14563850, PubMed:15047686). Mediates clathrin recruitment to early endosomes by ZFYVE16 (PubMed:15657082). Modulates binding of TOLLIP to phosphatidylinositol 3-phosphate (PtdIns(3)P) via binding competition; the association with TOLLIP may favor the release of TOLLIP from endosomal membranes, allowing TOLLIP to commit to cargo trafficking (PubMed:26320582). Acts as a phosphatidylinositol 5-phosphate (PtdIns(5)P) effector by binding to PtdIns(5)P, thereby regulating endosomal maturation (PubMed:25588840). PtdIns(5)P-dependent recruitment to signaling endosomes may block endosomal maturation (PubMed:25588840). Also inhibits Toll-like receptor (TLR) signaling and participates in immune receptor recycling (PubMed:15047686, PubMed:26320582).
Found in a complex with TOLLIP; interacts (via GAT domain) with TOLLIP (via N-terminus); the interactions leads to TOM1-recruitment to endosomes and inhibition of TOLLIP binding to PtdIns(3)P (PubMed:14563850, PubMed:15047686, PubMed:31263572, PubMed:26320582). Interacts (via GAT domain and the C-terminal part of the VHS domain) with UBC/ubiquitin (PubMed:14563850, PubMed:15047686, PubMed:16199040, PubMed:31263572). Interacts (via clathrin box and C-terminus) with clathrin heavy chain (PubMed:14563850, PubMed:15657082). Interacts with MYO6 (PubMed:23023224, PubMed:31371777). Interacts with TAX1BP1; CALCOCO2/NDP52 and OPTN; the interaction is indirect and is mediated by MYO6, which acts as a bridge between TOM1 and the three autophagy receptors (PubMed:31371777). Interacts (via C-terminus) with ZFYVE16 (via C-terminus); interaction is required to target TOM1 and clathrin to endosomes (PubMed:14613930, PubMed:15657082). Interacts with LRBA (PubMed:31263572).
The GAT domain and the VHS domain are required for the interaction with polyubiquitinated proteins.
The VHS domain binds to phosphatidylinositol monophosphates (PubMed:25588840). The KRKK motif within the VHS domain is required for binding to phosphatidylinositol monophosphates, with a preference for phosphatidylinositol 5-phosphate (PtdIns(5)P) (PubMed:25588840).
Widely expressed. Highly expressed in skeletal muscle, heart, placenta and liver.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 envelope glycoprotein B/gB. Interacts also with the trimeric complex gH-gL-gO. Trimer-PDGFRA interaction has an inhibitory effect on PDGFRA signaling (PubMed:33626330).
A chromosomal aberration involving PDGFRA is found in some cases of hypereosinophilic syndrome. Interstitial chromosomal deletion del(4)(q12q12) causes the fusion of FIP1L1 and PDGFRA (FIP1L1-PDGFRA). Mutations that cause overexpression and/or constitutive activation of PDGFRA may be a cause of hypereosinophilic syndrome.
Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation at Tyr-731 and Tyr-742 is important for interaction with PIK3R1. Phosphorylation at Tyr-720 and Tyr-754 is important for interaction with PTPN11. Phosphorylation at Tyr-762 is important for interaction with CRK. Phosphorylation at Tyr-572 and Tyr-574 is important for interaction with SRC and SRC family members. Phosphorylation at Tyr-988 and Tyr-1018 is important for interaction with PLCG1.
Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily.
Detected in platelets (at protein level). Widely expressed. Detected in brain, fibroblasts, smooth muscle, heart, and embryo. Expressed in primary and metastatic colon tumors and in normal colon tissue.
Interacts with homodimeric PDGFA, PDGFB and PDGFC, and with heterodimers formed by PDGFA and PDGFB. Monomer in the absence of bound ligand. Interaction with dimeric PDGFA, PDGFB and/or PDGFC leads to receptor dimerization, where both PDGFRA homodimers and heterodimers with PDGFRB are observed. Interacts (tyrosine phosphorylated) with SHB (via SH2 domain) (By similarity). Interacts (tyrosine phosphorylated) with SHF (via SH2 domain). Interacts (tyrosine phosphorylated) with SRC (via SH2 domain). Interacts (tyrosine phosphorylated) with PIK3R1. Interacts (tyrosine phosphorylated) with PLCG1 (via SH2 domain). Interacts (tyrosine phosphorylated) with CRK, GRB2 and GRB7.
Present in an inactive conformation in the absence of bound ligand. Binding of PDGFA and/or PDGFB leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by imatinib, nilotinib and sorafenib.
The gene represented in this entry may be involved in disease pathogenesis. Mutations causing PDGFRA constitutive activation have been found in gastrointestinal stromal tumors lacking KIT mutations (PubMed:12522257).
Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. Depending on the context, promotes or inhibits cell proliferation and cell migration. Plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. Required for normal skeleton development and cephalic closure during embryonic development. Required for normal development of the mucosa lining the gastrointestinal tract, and for recruitment of mesenchymal cells and normal development of intestinal villi. Plays a role in cell migration and chemotaxis in wound healing. Plays a role in platelet activation, secretion of agonists from platelet granules, and in thrombin-induced platelet aggregation. Binding of its cognate ligands - homodimeric PDGFA, homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFC -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PIK3R1, PLCG1, and PTPN11. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylates PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and thereby mediates activation of the AKT1 signaling pathway. Mediates activation of HRAS and of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3 and STAT5A and/or STAT5B. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor.
Ubiquitinated, leading to its internalization and degradation.
Activated by RHOA binding. Inhibited by Y-27632 (By similarity).
Activated by RHOA binding. Inhibited by Y-27632.
An interaction between Thr-414 and Asp-48 is essential for kinase activity and dimerization.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family.
Cleaved by granzyme B during apoptosis. This leads to constitutive activation of the kinase and membrane blebbing.
Homodimer (By similarity). Interacts with IRS1 (By similarity). Interacts with RAF1 (By similarity). Interacts with RHOA (activated by GTP), RHOB and RHOC (By similarity). Interacts with PPP1R12A (PubMed:10579722, PubMed:19131646). Interacts with EP300 (PubMed:16574662). Interacts with CHORDC1 (PubMed:20230755). Interacts with BRCA2 (PubMed:21084279). Interacts with NPM1; this interaction enhances ROCK2 activity (PubMed:17015463). Interacts with SORL1 (PubMed:21147781). Interacts with PJVK (By similarity).
Phosphorylation at Tyr-722 reduces its binding to RHOA and is crucial for focal adhesion dynamics. Dephosphorylation by PTPN11 stimulates its RHOA binding activity.
Protein kinase which is a key regulator of actin cytoskeleton and cell polarity.
Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus. Plays an important role in generating the circadian rhythm of the aortic myofilament Ca(2+) sensitivity and vascular contractility by modulating the myosin light chain phosphorylation.
Expressed predominantly in the liver. Also detected in endothelial cells and spinal cord neurons.
Homodimer (PubMed:25372031). Interacts with and forms a tight 1:1 complex with RNH1. Dimerization of two such complexes may occur.
Low level expression in the developing fetus, increased in the neonate, and maximal in the adult.
Ribonuclease that cleaves tRNA within anticodon loops to produce tRNA-derived stress-induced fragments (tiRNAs) which inhibit protein synthesis and triggers the assembly of stress granules (SGs) (PubMed:1400510, PubMed:21855800). Binds to actin on the surface of endothelial cells; once bound, angiogenin is endocytosed and translocated to the nucleus (PubMed:8127865). Stimulates ribosomal RNA synthesis including that containing the initiation site sequences of 45S rRNA (PubMed:12051708). Angiogenin induces vascularization of normal and malignant tissues (PubMed:19354288). Angiogenic activity is regulated by interaction with RNH1 in vivo (PubMed:19354288).
Highly expressed in lung, heart and skeletal muscle.
Interacts with components of the lysosomal V-ATPase complex (PubMed:28024296). Interacts with ATP6V0A1 (PubMed:28024296). Interacts with ATP6V0A2 (PubMed:28024296).
Negative regulator of amino acid sensing and mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels and amino acids (PubMed:28024296). Negatively regulates mTORC1 activation by inhibiting recruitment of mTORC1 to lysosomes upon stimulation with amino acids: acts by promoting the formation of a tightly bound supercomplex composed of the lysosomal V-ATPase, Ragulator and Rag GTPases, preventing recruitment of mTORC1 (PubMed:28024296). Acts as a regulator of muscle regeneration following injury by regulating mTORC1 activation (By similarity).
Plays a role in the apoptotic process and has a pro-apoptotic activity.
In epidermis, primarily detected in cells of the basal or immediately suprabasal layers (at protein level) (PubMed:16891417). In hair follicles, mainly expressed in the outer root sheath (at protein level) (PubMed:8034748). Expressed in epidermis, testis and foreskin, and to a lower extent in thymus, spleen, mammary glands, placenta, brain and heart (PubMed:9687312). Expressed in the ovary, notably in oocytes (PubMed:30010909).
Phosphorylation on Ser-537 and Ser-541 leads to cytoplasmic localization.
Transcriptional activator (By similarity). It is likely involved in the regulation of keratinocytes terminal differentiation in squamous epithelia and hair follicles (PubMed:8034748). Required for the maintenance of spermatogenesis (By similarity). It is involved in the positive regulation of oocyte maturation, probably acting through the control of BMP15 levels and regulation of AKT signaling cascade (PubMed:30010909). May also play a role in the early development of embryos (By similarity).
In contrast to other ubiquitin-conjugating enzymes E2, residues essential for lysine reactivity are absent: Pro and a His residues are present instead of an Asp and an Asp residues in positions 88 and 119, respectively.
Interacts with PRKN; involved in ubiquitination and degradation of misfolded proteins. Interacts with UBE3A; used by the papilloma virus HPV-16 E6 protein to ubiquitinate p53/TP53. Interacts with CCNB1IP1, CBL, ZAP70, RNF19A, RNF19B and RNF144B. Interacts with ARIH1. Interacts with ARIH2 (via RING-type 1). Interacts with NCOA1; they functionally interact to regulate progesterone receptor transcriptional activity. May interact with NR3C1. Interacts with NDFIP1 (via N-terminus); the interaction mediates recruitment of UBE2L3 to ITCH and causes MAP3K7 ubiquitination (PubMed:25632008).
PubMed:10760570 reported that UBE2L1, UBE2L2 and UBE2L4 are most likely pseudogenes and the only expressed member of this subfamily seems to be UBE2L3.
Ubiquitin-conjugating enzyme E2 that specifically acts with HECT-type and RBR family E3 ubiquitin-protein ligases. Does not function with most RING-containing E3 ubiquitin-protein ligases because it lacks intrinsic E3-independent reactivity with lysine: in contrast, it has activity with the RBR family E3 enzymes, such as PRKN, RNF31 and ARIH1, that function like RING-HECT hybrids. Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'-linked polyubiquitination. Involved in the selective degradation of short-lived and abnormal proteins. Down-regulated during the S-phase it is involved in progression through the cell cycle. Regulates nuclear hormone receptors transcriptional activity. May play a role in myelopoiesis.
Ubiquitinated. The alteration of UBE2L3 protein levels during the S-phase of the cell cycle is due to ubiquitin-dependent proteasomal degradation. Autoubiquitinated in vitro (PubMed:22496338).
Ubiquitous, with highest expression in testis.
Cleaves C-terminal arginine or lysine residues from biologically active peptides such as kinins or anaphylatoxins in the circulation thereby regulating their activities. Down-regulates fibrinolysis by removing C-terminal lysine residues from fibrin that has already been partially degraded by plasmin.
N-glycosylated. N-glycan at Asn-108: Hex5HexNAc4.
TAFI/CPB2 is unique among carboxypeptidases in that it spontaneously inactivates with a short half-life, a property that is crucial for its role in controlling blood clot lysis. The zymogen is stabilized by interactions with the activation peptide. Release of the activation peptide increases a dynamic flap mobility and in time this leads to conformational changes that disrupt the catalytic site and expose a cryptic thrombin-cleavage site present at Arg-324.
Mainly expressed in ileum and kidney, lower expression in cecum.
Plays a critical role in the sodium-dependent reabsorption of bile acids from the lumen of the small intestine (PubMed:7592981, PubMed:9458785, PubMed:9856990). Transports various bile acids, unconjugated or conjugated, such as cholate and taurocholate (PubMed:7592981, PubMed:9458785, PubMed:9856990). Also responsible for bile acid transport in the renal proximal tubules, a salvage mechanism that helps conserve bile acids (Probable). Works collaboratively with the Na(+)-taurocholate cotransporting polypeptide (NTCP), the organic solute transporter (OST), and the bile salt export pump (BSEP), to ensure efficacious biological recycling of bile acids during enterohepatic circulation (PubMed:33222321).
Interacts through its PDZ domains with NETO1, GRIN2B and SYNGAP1. Interacts through its guanylate kinase-like domain with DLGAP1, DLGAP2, DLGAP3 and DLGAP4. Interacts with FLTP/C1orf192 (By similarity). Interacts through its PDZ domains with APC. Interacts through its first two PDZ domains with ERBB4. Interacts through its third PDZ domain with NLGN1, and probably with NLGN2 and NLGN3. Interacts with FRMPD4 (via C-terminus). Interacts with LRFN1, LRFN2 and LRFN4. Interacts with DGKI (via PDZ-binding motif) (By similarity).
Required for learning most likely through its role in synaptic plasticity following NMDA receptor signaling.
Belongs to the mitochondrion-specific ribosomal protein mL39 family.
Isoform 1 is ubiquitously expressed. Isoform 2 is heart-specific.
Ref.1 indicates C21orf8 as a synonym for this orf, this is incorrect, C21orf8 is already assigned to another chromosome 21 region.
Accumulates steadily during G2 and is abruptly destroyed at mitosis.
Essential for the control of the cell cycle at the G2/M (mitosis) transition.
Interacts with the CDK1 protein kinase to form a serine/threonine kinase holoenzyme complex also known as maturation promoting factor (MPF). The cyclin subunit imparts substrate specificity to the complex.
Inhibited by TGFB1 (Probable). Down-regulated by LPS (PubMed:21907835).
Interacts with PPP1CA, PPP1CB and MSN. Interacts (via its fourth ankyrin repeat) with the mature dimeric form of RPSA/LAMR1 (PubMed:16263087, PubMed:18586956). Interacts with EEF1A1 (PubMed:26497934). Interacts with PTEN (PubMed:25007873). Interacts with ECE1 (By similarity).
Phosphorylated by PKA and, after PKA priming, by GSK3B. Phosphorylation by GSK3B reduces its association with PP1C and enhances PP1C activity. Dephosphorylation by its associated PP1C results in enhanced association with PP1C, but reduced PP1C activity (By similarity).
Regulator of protein phosphatase 1 (PP1) that acts as a positive regulator of pulmonary endothelial cell (EC) barrier function (PubMed:18586956). Involved in the regulation of the PI3K/AKT signaling pathway, angiogenesis and endothelial cell proliferation (PubMed:25007873). Regulates angiogenesis and endothelial cell proliferation through the control of ECE1 dephosphorylation, trafficking and activity (By similarity). Protects the endothelial barrier from lipopolysaccharide (LPS)-induced vascular leakage (By similarity). Involved in the regulation of endothelial cell filopodia extension (By similarity). May be a downstream target for TGF-beta1 signaling cascade in endothelial cells (PubMed:16263087, PubMed:18586956). Involved in PKA-mediated moesin dephosphorylation which is important in EC barrier protection against thrombin stimulation (PubMed:18586956). Promotes the interaction of PPP1CA with RPSA/LAMR1 and in turn facilitates the dephosphorylation of RPSA/LAMR1 (PubMed:16263087). Involved in the dephosphorylation of EEF1A1 (PubMed:26497934).
Interacts (via J domain) with HSPA5. Interacts (via cytosolic domain) with ribosomes (By similarity). Interacts (via SANT 2 domain) with SERPINA3; the interaction delays the formation of the covalent inhibitory complex SERPINA3-chymotrypsin, but does not alter the catalytic activity of SERPINA3. Interacts (via SANT 2 domain) with ITIH4 (via C-terminus); the interaction protects ITIH4 against in vitro cleavage by kallikrein.
E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins. Involved in chromosome segregation and cell cycle regulation (PubMed:28087737). May play a role in the acrosome reaction and fertilization.
Highly expressed in testis, prostate and brain (PubMed:15145053). Weakly expressed in kidney, lung and heart (PubMed:15145053). Expressed in fetal tissues (PubMed:28087737).
As part of the alternative replication protein A complex, aRPA, binds single-stranded DNA and probably plays a role in DNA repair. Compared to the RPA2-containing, canonical RPA complex, may not support chromosomal DNA replication and cell cycle progression through S-phase. The aRPA may not promote efficient priming by DNA polymerase alpha but could support DNA polymerase delta synthesis in the presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange.
Belongs to the replication factor A protein 2 family.
Component of the aRPA, the alternative replication protein A complex, a trimeric complex similar to the replication protein A complex/RPA but where RPA1 and RPA3 are associated with RPA4 instead of RPA2. Interacts with RPA1 and RPA3.
Preferentially expressed in placental and colon mucosa. Widely expressed at intermediate or lower levels.
'Armus' means hinge, linker in Latin and ancient Greek.
Acts as GTPase-activating protein for RAB7A. Signal effector acting as a linker between RAC1 and RAB7A, leading to RAB7A inactivation and subsequent inhibition of cadherin degradation and reduced cell-cell adhesion.
Expressed in a broad range of tissues, especially in kidney, liver, lung and placenta. Also expressed in keratinocytes and epithelia-containing organs. Isoform 2 is differentially expressed in prostate normal and cancer cells (at protein level).
A cytochrome P450 monooxygenase involved in epidermal ceramide biosynthesis. Hydroxylates the terminal carbon (omega-hydroxylation) of ultra-long-chain fatty acyls (C28-C36) prior to ceramide synthesis (PubMed:26056268). Contributes to the synthesis of three classes of omega-hydroxy-ultra-long chain fatty acylceramides having sphingosine, 6-hydroxysphingosine and phytosphingosine bases, all major lipid components that underlie the permeability barrier of the stratum corneum (PubMed:26056268). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:26056268).
A second transmembrane domain at positions 95-115 is predicted by three programs ESKW, MEMSAT and Phobius. However experimental evidence supports the presence of a single signal-anchor transmembrane domain at the N-terminus.
(Microbial infection) Interacts with hepatitis C virus/HCV core protein.
Belongs to the AspA/AstE family. Aspartoacylase subfamily.
Exists as a mixture of homodimers and homotetramer, both catalytically active.
Plays an important role in deacetylating mercapturic acids in kidney proximal tubules. Also acts on N-acetyl-aromatic amino acids (By similarity).
Arginine methylation by PRMT1 in the Arg/Gly-rich region impedes RNA binding.
Associates with the 40S ribosomal subunit, the 80S ribosome and with polysomes.
Binds G-rich elements in target mRNA coding sequences (PubMed:28329689). Prevents G-quadruplex structure formation in vitro, suggesting a role in supporting translation by resolving stable structures on mRNAs (PubMed:28329689).
Expressed in the liver, kidney, spleen, testis, lung, muscle and adrenal glands.
Single-stranded DNA-binding protein that preferentially binds to the sterol regulatory element (SRE) sequence 5'-GTGCGGTG-3', and thereby mediates transcriptional repression (PubMed:2562787). Has a role as transactivator of the Myc promoter (By similarity). Binds single-stranded RNA in a sequence-specific manner (By similarity).
The disease is caused by variants affecting the gene represented in this entry. The causative mutation is a CCTG expansion (mean approximately 5000 repeats) located in intron 1 of the CNBP gene.
Transcriptionally up-regulated by sterol treatment.
Dephosphorylates both phosphorylated Thr and Tyr residues in MAPK1, and dephosphorylation of phosphotyrosine is slightly faster than that of phosphothreonine (PubMed:8107850). Can dephosphorylate MAPK1 (By similarity).
Interacts with MAPK14; this interaction does not lead to catalytic activation of DUSP2 and dephosphrylation of MAPK14.
Binds to CDK2-bound cyclins and inhibits the kinase activity of CDK2; binding to cyclins is critical for its function as CDK inhibitor (PubMed:21540187). Inhibits cell growth and cell proliferation and may play a role in cell cycle control (By similarity). Required for ING5-mediated regulation of S-phase progression, enhancement of Fas-induced apoptosis and inhibition of cell growth (By similarity).
Detected in testis, and at lower levels in ovary. Detected at very low levels in testis tumors (PubMed:15159402). Down-regulated in bone marrow cells in acute myeloid and lymphoid leukemia patients as compared with normal bone marrow cells (PubMed:21540187).
Interacts with CCNA1 (PubMed:21540187, PubMed:15159402). Interacts with CCNA2, CCNB1 and CCNE1 (PubMed:21540187). Found in a complex with CCNA1 and CDK2 (PubMed:15159402). Interacts with ZNF16; the interaction inhibits INCA1 activity and induces the cell cycle process (PubMed:21874239). Interacts with SPACA9 (PubMed:18756329). Interacts with the CCNA1/CDK2 complex (PubMed:21540187). Interacts with ING5, DAZAP2, RNF26, USP15, SPOUT1, DPH7, TRIM26 and RAB5C (PubMed:21750715).
Phosphorylated when part of a complex with CCNA1 and CDK2. Strongly phosphorylated by CDK2 on its C-terminal region spanning amino acid 149-221. Less intensively phosphorylated by CDK2 on its first 75 amino acid residues.
Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the N-terminus of INO80.
Putative regulatory component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.
Forms a homodimer or heterodimer with other members of the family.
Belongs to the major facilitator superfamily. Spinster (TC 2.A.1.49) family.
Associated component of the mechanistic target of rapamycin complex 1 (mTORC1), which contains core MTOR, MLST8 and RPTOR (PubMed:17510057, PubMed:17386266, PubMed:17277771, PubMed:29236692, PubMed:31601764). Dissociates from mTORC1 in response to insulin treatment (PubMed:17386266, PubMed:18372248). mTORC1 binds to and is inhibited by FKBP12-rapamycin (PubMed:31601764, PubMed:17277771). Interacts (via TOS motif) with RPTOR; interaction is direct (PubMed:17510057, PubMed:17517883, PubMed:17386266). The phosphorylated form interacts with 14-3-3 proteins (PubMed:12524439, PubMed:18372248).
Negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1), an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth (PubMed:17510057, PubMed:17386266, PubMed:17277771, PubMed:29236692). In absence of insulin and nutrients, AKT1S1 associates with the mTORC1 complex and directly inhibits mTORC1 activity by blocking the MTOR substrate-recruitment site (PubMed:29236692). In response to insulin and nutrients, AKT1S1 dissociates from mTORC1 (PubMed:17386266, PubMed:18372248). Its activity is dependent on its phosphorylation state and binding to 14-3-3 (PubMed:16174443, PubMed:18372248). May also play a role in nerve growth factor-mediated neuroprotection (By similarity).
Phosphorylated by AKT1; phosphorylation takes place in response to insulin treatment and promotes AKT1S1 interaction with 14-3-3 proteins, leading to relieve its inhibitor activity (PubMed:12524439, PubMed:17386266). Phosphorylated by MTOR following mTORC1 activation, inhibiting AKT1S1 inhibitor activity: phosphorylation by MTOR probably serves as a feedback loop that relieves inhibition from AKT1S1 in response to mTORC1 inactivation (PubMed:17517883). Phosphorylation at Thr-246 by DYRK3 relieves inhibitory function on mTORC1 (PubMed:23415227).
The TOS motif mediates interaction with RPTOR, leading to promote phosphorylation by mTORC1 complex.
Widely expressed with highest levels of expression in liver and heart. Expressed at higher levels in cancer cell lines (e.g. A-549 and HeLa) than in normal cell lines (e.g. HEK293).
Binds MBD2 and a histone deacetylase complex. Interacts with NPAT.
Transcriptional repressor that binds to the consensus sequence 5'-CGGACGTT-3' and to the RB1 promoter. Transcriptional activator that promotes histone H4 gene transcription at the G1/S phase transition in conjunction with NPAT. Also activates transcription of the ATM and PRKDC genes. Autoregulates its expression by associating with its own promoter.
Ubiquitinated. Ubiquitination may lead to proteasome-mediated degradation.
Ubiquitous. Highly expressed in brain, heart, skeletal muscle, spleen, kidney, small intestine, placenta and liver.
(Microbial infection) Acts as a receptor for Pseudorabies virus.
(Microbial infection) Acts as a receptor for poliovirus. May play a role in axonal transport of poliovirus, by targeting virion-PVR-containing endocytic vesicles to the microtubular network through interaction with DYNLT1. This interaction would drive the virus-containing vesicle to the axonal retrograde transport.
(Microbial infection) Interacts with human cytomegalovirus /HHV-5 UL141 protein.
(Microbial infection) Interacts with poliovirus capsid proteins.
(Microbial infection) Interacts with pseudorabies virus gD protein.
(Microbial infection) Is prevented to reach cell surface upon infection by Human cytomegalovirus /HHV-5, presumably to escape immune recognition of infected cell by NK cells.
Can form trans-heterodimers with NECTIN3. The extracellular domain interacts with VTN, CD226 and CD96. The cytoplasmic domain interacts with DYNLT1. Binds with high affinity to TIGIT.
Contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases.
Mediates NK cell adhesion and triggers NK cell effector functions. Binds two different NK cell receptors: CD96 and CD226. These interactions accumulates at the cell-cell contact site, leading to the formation of a mature immunological synapse between NK cell and target cell. This may trigger adhesion and secretion of lytic granules and IFN-gamma and activate cytotoxicity of activated NK cells. May also promote NK cell-target cell modular exchange, and PVR transfer to the NK cell. This transfer is more important in some tumor cells expressing a lot of PVR, and may trigger fratricide NK cell activation, providing tumors with a mechanism of immunoevasion. Plays a role in mediating tumor cell invasion and migration.
N-glycosylated. N-glycan at Asn-120: Hex5HexNAc4.
Phosphorylated by Src kinases on tyrosine residues in the ITIM motif upon ligation. Interaction with TIGIT is required for Phosphorylation.
The V-type domain is necessary and sufficient for virus binding and uptake.
Involved in nucleolar processing of pre-18S ribosomal RNA.
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3.
Ribosome biogenesis factor. Involved in nucleolar processing of pre-18S ribosomal RNA. Required for optimal pre-ribosomal RNA transcription by RNA polymerase I (PubMed:17699751). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Expressed in skeletal muscle, liver, heart and kidney.
Homooligomer. Interacts with PNPLA2; prevents interaction of PNPLA2 with ABHD5. Interacts with ABHD5; targets ABHD5 to lipid droplets and promotes interaction of ABHD5 with PNPLA2. Interacts with LIPE (By similarity).
Increased by endurance and sprint interval training.
Lipid droplet-associated protein that maintains the balance between lipogenesis and lipolysis and also regulates fatty acid oxidation in oxidative tissues. Recruits mitochondria to the surface of lipid droplets and is involved in lipid droplet homeostasis by regulating both the storage of fatty acids in the form of triglycerides and the release of fatty acids for mitochondrial fatty acid oxidation. In lipid droplet triacylglycerol hydrolysis, plays a role as a scaffolding protein for three major key lipolytic players: ABHD5, PNPLA2 and LIPE. Reduces the triacylglycerol hydrolase activity of PNPLA2 by recruiting and sequestering PNPLA2 to lipid droplets. Phosphorylation by PKA enables lipolysis probably by promoting release of ABHD5 from the perilipin scaffold and by facilitating interaction of ABHD5 with PNPLA2. Also increases lipolysis through interaction with LIPE and upon PKA-mediated phosphorylation of LIPE (By similarity).
Phosphorylated by PKA. Phosphorylated on serine in skeletal muscle at rest or upon lipolytic stimulation (By similarity).
By polyamine analogs in analog-sensitive H157 cells.
Component of the MIS12 complex composed of MIS12, DSN1, NSL1 and PMF1. Interacts with COPS7A. Interacts via its coiled-coil domain with the leucine-zipper domain of NFE2L2. The interaction with NFE2L2 is required for the transcriptional regulation of SSAT.
Highest levels of expression in heart and skeletal muscle, with significant levels expressed in kidney and liver.
Part of the MIS12 complex which is required for normal chromosome alignment and segregation and kinetochore formation during mitosis. May act as a cotranscription partner of NFE2L2 involved in regulation of polyamine-induced transcription of SSAT.
A lower molecular weight form (around 43 kDa) is present in patients with papillary thyroid carcinoma.
Belongs to the PDGF/VEGF growth factor family.
Expressed in the fallopian tube, vascular smooth muscle cells in kidney, breast and colon and in visceral smooth muscle of the gastrointestinal tract. Highly expressed in retinal pigment epithelia. Expressed in medulloblastoma. In the kidney, constitutively expressed in parietal epithelial cells of Bowman's capsule, tubular epithelial cells and in arterial endothelial cells (at protein level). Highly expressed in the platelets, prostate, testis and uterus. Higher expression is observed in uterine leiomyomata. Weaker expression in the spleen, thymus, heart, pancreas, liver, ovary cells and small intestine, and negligible expression in the colon and peripheral blood leukocytes.
Growth factor that plays an essential role in the regulation of embryonic development, cell proliferation, cell migration, survival and chemotaxis. Potent mitogen and chemoattractant for cells of mesenchymal origin. Required for normal skeleton formation during embryonic development, especially for normal development of the craniofacial skeleton and for normal development of the palate. Required for normal skin morphogenesis during embryonic development. Plays an important role in wound healing, where it appears to be involved in three stages: inflammation, proliferation and remodeling. Plays an important role in angiogenesis and blood vessel development. Involved in fibrotic processes, in which transformation of interstitial fibroblasts into myofibroblasts plus collagen deposition occurs. The CUB domain has mitogenic activity in coronary artery smooth muscle cells, suggesting a role beyond the maintenance of the latency of the PDGF domain. In the nucleus, PDGFC seems to have additional function.
Homodimer; disulfide-linked. Interacts with PDGFRA homodimers, and with heterodimers formed by PDGFRA and PDGFRB. Interacts (via CUB domain) with PLAT (via kringle domain).
In the fetal kidney, detected in the developing mesangium, ureteric bud epithelium and the undifferentiated mesenchyme (at protein level).
Proteolytic removal of the N-terminal CUB domain releasing the core domain is necessary for unmasking the receptor-binding epitopes of the core domain. Cleavage after basic residues in the hinge region (region connecting the CUB and growth factor domains) gives rise to the receptor-binding form. Cleaved by PLAT and PLG.
Up-regulated by EWS-FLI1 chimeric transcription factor in tumor derived cells. Up-regulated in podocytes and interstitial cells after injury/activation of these cells. FGF2 activates PDGFC transcription via EGR1. Up-regulated by TGFB1 in concert with FGF2.
Homotrimer (PubMed:17215869). May form an octadecamer consisting of an elementary trimer unit. Does not interact with fibronectin, elastin or zymosan. Interacts with MASP1 and MASP2.
Liver and lung. In liver it is produced by bile duct epithelial cells and hepatocytes. In lung it is produced by both ciliated bronchial epithelial cells and type II alveolar epithelial cells.
May function in innate immunity through activation of the lectin complement pathway. Calcium-dependent and GlcNAc-binding lectin. Has affinity with GalNAc, GlcNAc, D-fucose, as mono/oligosaccharide and lipopolysaccharides from S.typhimurium and S.minnesota.
Interacts with PRR19; this interaction promotes crossover formation. Interacts with RFC3 and RFC4; these interactions facilitate crossover formation. Interacts with CDC34; this interaction regulates the cell-cycle progression.
Plays a role in the different steps of crossover formation during meiotic recombination. Participates in the crossover differentiation step of crossover-specific recombination intermediates through its interaction with PRR19. In addition, stimulates crossover formation through the interactions with RFC3 and RFC4 and simultaneously regulates cell-cycle progression through interactions with CDC34 and subsequent ubiquitination of WEE1. May also participates in an active deselection process that destabilizes or removes excess pre-CO intermediates.
A cytochrome P450 monooxygenase that catalyzes the conversion of C19 androgens, androst-4-ene-3,17-dione (androstenedione) and testosterone to the C18 estrogens, estrone and estradiol, respectively (PubMed:27702664, PubMed:2848247). Catalyzes three successive oxidations of C19 androgens: two conventional oxidations at C19 yielding 19-hydroxy and 19-oxo/19-aldehyde derivatives, followed by a third oxidative aromatization step that involves C1-beta hydrogen abstraction combined with cleavage of the C10-C19 bond to yield a phenolic A ring and formic acid (PubMed:20385561). Alternatively, the third oxidative reaction yields a 19-norsteroid and formic acid. Converts dihydrotestosterone to delta1,10-dehydro 19-nordihydrotestosterone and may play a role in homeostasis of this potent androgen (PubMed:22773874). Also displays 2-hydroxylase activity toward estrone (PubMed:22773874). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:20385561, PubMed:22773874).
Phosphorylated in vitro by PKA and PKG/PRKG1. These phosphorylations inhibit the catalytic activity as measured by estrone synthesis from androstenedione (36% decrease for PKA and 30% for PKG/PRKG1).
Widely expressed, including in adult and fetal brain, placenta, skin fibroblasts, adipose tissue and gonads.
Belongs to the FAD-binding oxidoreductase/transferase type 4 family.
Expressed moderately in heart and liver and at lower levels in skeletal muscle and kidney.
Involved in D-lactate, but not L-lactate catabolic process.
Broad specificity; small intestine, colon, colonic tumors, heart, liver, thymus, prostate, pancreas and gall bladder.
Highly O-glycosylated and probably also N-glycosylated.
Major glycoprotein component of a variety of mucus gels. Thought to provide a protective, lubricating barrier against particles and infectious agents at mucosal surfaces. May be involved in ligand binding and intracellular signaling.
This sequence is incomplete at 5' and 3' ends and extensively differs from that shown.
Has low activity towards the organophosphate paraxon and aromatic carboxylic acid esters. Rapidly hydrolyzes lactones such as statin prodrugs (e.g. lovastatin). Hydrolyzes aromatic lactones and 5- or 6-member ring lactones with aliphatic substituents but not simple lactones or those with polar substituents.
Predominantly expressed in macrophages. Present in the spleen, small and large intestine, lung and brain (at protein level). Highly expressed in peripheral leukocytes, ovary, retina, spleen and stomach. Moderately expressed in thymus, uterus and platelets, as well as some brain tissues, such as thalamus and fetal brain.
Serine protease that has amidolytic activity, cleaving its substrates before Arg residues.
Up-regulated by phorbol myristate acetate (PMA).
Belongs to the cyclic nucleotide phosphodiesterase family. PDE4 subfamily.
Binds 2 divalent metal cations per subunit (PubMed:17727341, Ref.20). Site 2 has a preference for magnesium and/or manganese ions (By similarity).
Binds 2 divalent metal cations per subunit. Site 1 may preferentially bind zinc ions.
Efficiently hydrolyzes cAMP. The phosphodiesterase activity is not affected by calcium, calmodulin or cyclic GMP (cGMP) levels. Does not hydrolyze cGMP.
Expressed at high levels in the heart and small intestine. It is also found in the brain, kidney, spleen, colon, salivary gland, ovary and peripheral blood lymphocytes.
Expressed in lymphoid cell subsets including CD8-positive T cells and T-helper 2 cells. Expressed in dendritic cells.
Expressed predominantly in skeletal muscle and brain and at lower levels in the testis. Found in specific neuronal subpopulations including cortical pyramidal neurons, horn neurons in the spinal cord and Purkinje cells in cerebellum (at protein level).
Highly expressed in liver, stomach, testis, thyroid and adrenal glands and at a lower extent in placenta, kidney, pancreas, ovary, uterus and skin. Expressed in myeloid cell subsets including dendritic cells, monocytes, macrophages, eosinophils and mast cells. Expressed in natural killer cells. Expressed in bronchial smooth muscle.
Hydrolyzes the second messenger 3',5'-cyclic AMP (cAMP), which is a key regulator of many important physiological processes.
Inhibited by rolipram, cilomilast, Ro 20-1724, roflumilast and denbufylline.
Interacts with LYN (via SH3 domain). Interacts with ARRB2.
May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Probably represents a non-functional splice isoform.
It is uncertain whether Met-1 or Met-12 is the initiator.
Adapter protein involved in invadopodia and podosome formation, extracellular matrix degradation and invasiveness of some cancer cells. Binds matrix metalloproteinases (ADAMs), NADPH oxidases (NOXs) and phosphoinositides. Acts as an organizer protein that allows NOX1- or NOX3-dependent reactive oxygen species (ROS) generation and ROS localization. In association with ADAM12, mediates the neurotoxic effect of amyloid-beta peptide.
Found in several cancer cell lines, particularly invasive breast carcinomas and melanomas.
Gene prediction based on similarity to mouse ortholog and partial transcript data.
Interacts (via N-terminus) with CYBA (By similarity). Interacts with ADAM12, ADAM15 and ADAM19. Interacts with NOXO1. Interacts (via SH3 domains) with NOXA1. Interacts with FASLG.
The PX domain is required for podosome localization because of its ability to bind phosphatidylinositol 3-phosphate (PtdIns(3)P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) and, to a lesser extent, phosphatidylinositol 4-phosphate (PtdIns(4)P), phosphatidylinositol 5-phosphate (PtdIns(5)P), and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Binds to the third intramolecular SH3 domain (By similarity).
The fifth SH3 domain mediates binding with ADAM12, ADAM15 and ADAM19.
Tyrosine phosphorylated by SRC. Phosphorylation plays a regulatory role in the protein localization. The intramolecular interaction of the PX domain with the third SH3 domain maintains the protein in the cytoplasm and phosphorylation disrupts this interaction, resulting in the redistribution of the protein from cytoplasm to the perimembrane region. Phosphorylated on serine upon DNA damage, probably by ATM or ATR.
Belongs to the bacterial ribosomal protein bS16 family.
Component of the mitochondrial small ribosomal subunit (mt-SSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. bS16m has a zinc binding site.
Belongs to the short-chain dehydrogenases/reductases (SDR) family. ERG27 subfamily.
Bifunctional enzyme involved in steroid-hormone metabolism and cholesterol biosynthesis (PubMed:12574203, PubMed:12732193, PubMed:12829805, PubMed:20659585, PubMed:19772289, PubMed:11165030). Catalyzes the NADP(H)-dependent reduction of estrogens and androgens and regulates the biological potency of these steroids. Converts estrone (E1) to a more potent estrogen, 17beta-estradiol (E2) (PubMed:12574203, PubMed:12732193, PubMed:19772289). Converts dihydrotestosterone (DHT) to its inactive form 5a-androstane-3b,17b-diol (PubMed:12574203, PubMed:12732193, PubMed:19772289). Converts moderately progesterone to 3beta-hydroxypregn-4-ene-20-one, leading to its inactivation (PubMed:12574203, PubMed:12732193). Additionally, participates in the post-squalene cholesterol biosynthesis, as a 3-ketosteroid reductase (PubMed:12829805, PubMed:20659585, PubMed:11165030).
Binds to the short form of prolactin receptor.
Does not have enzymatic activities toward E1 and DHT.
Estradiol 17-beta-dehydrogenase and dihydrotestosterone oxidoreductase activities are selectively inhibited by 4-methyl-4-aza-5alpha-androstane derivatives, such as 17beta-[(N-Heptyl)methylamino]-4-aza-5r-androstan-3-one and 17beta-(N-Decylformamido)-4-aza-5r-androstan-3-one.
Expressed in eye ciliary epithelial cells and neuroendocrine cells.
Highly expressed in adrenal gland, liver, lung and thymus. Expressed in breast, ovaries, pituitary gland, pregnant uterus, prostate, kidney, lymph node, small intestine, spinal cord and trachea. Weakly expressed in all other tissues tested.
It is uncertain whether Met-1, Met-13 or Met-31 is the initiator.
Belongs to the Mediator complex subunit 15 family.
By 12-O-tetradecanoylphorbol-13-acetate (TPA).
Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Required for cholesterol-dependent gene regulation. Positively regulates the Nodal signaling pathway.
Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with SMAD2, SMAD3, SREBF1 and SREBF2. Interacts with WWTR1. Interacts with TRIM11.
Expressed in all tissues examined, including heart, brain, lung, spleen, thymus, pancreas, blood leukocyte and placenta. However, the level of expression varied, with highest expression in the placenta and peripheral blood and lowest in the pancreas and kidney.
The poly-Gln region from amino acids 235-262 of PCQAP is polymorphic. There are from 15 to 18 repeats in the Italian population.
Ubiquitinated by TRIM11, leading to proteasomal degradation.
Associates with SLC3A2/4F2hc to form a functional heterodimeric complex that translocates small neutral L- and D-amino acids across the plasma membrane. Preferentially mediates exchange transport, but can also operate via facilitated diffusion (By similarity) (PubMed:10863037). Acts as a major transporter for glycine, L- and D-serine in the central nervous system. At the spinal cord and brainstem regulates glycine metabolism and glycinergic inhibitory neurotransmission by providing for glycine de novo synthesis from L-serine and glycine recycling from astrocytes to glycinergic motor neurons (By similarity). At Schaffer collateral-CA1 synapses mediates D-serine and glycine release that modulates post-synaptic activation of NMDA receptors and excitatory glutamatergic transmission (By similarity). May regulate D-serine release from mesenchymal progenitors located in developing subcutaneous adipose tissue, favoring white adipocyte over thermogenic beige adipocyte lineage commitment (By similarity).
Belongs to the amino acid-polyamine-organocation (APC) superfamily.
Disulfide-linked heterodimer with the amino acid transport protein SLC3A2/4F2hc.
Expressed in brain, heart, kidney, liver, lung, pancreas, placenta, and skeletal muscle.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Glycine at position 9 results in gain of function and is associated with susceptibility to essential tremor.
Disease susceptibility may be associated with variants affecting the gene represented in this entry. Glycine at position 9 results in gain of function and may be a risk factor for schizophrenia.
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. Promotes cell proliferation.
Interacts with CLIC6 (By similarity). Interacts with GRK4 (PubMed:19520868). Interacts with PALM (PubMed:16386234). Interacts with FLNA (via filamin repeat 21); increases PKA-mediated phosphorylation of FLNA (PubMed:26460884).
Phosphorylated by GRK4 (GRK4-alpha and GRK4-gamma).
Belongs to the glycosyltransferase 6 family.
Common alleles GBGT1*01N.01 and GBGT1*01N.02 do not synthesize Forssman glycolipid antigen (FORS1). A rare allele encoding an arginine to glutamine change at residue 296 is associated with the ability to synthesize Forssman antigen, which is expressed in erythrocytes and is inheritable, thus defining a new histo-blood group FORS, also known as Apae. This variation might have arised as a consequence of the selective pressure exerted by microorganisms. For instance, the uropathogenic E.coli expressing prsG adhesin only binds and agglutinates FORS1-expressing erythrocytes. Thus, FORS1-positive individuals might be more susceptible to certain pathogens.
Has lost the ability to synthesize Forssman glycolipid antigen (FORS1/FG) (PubMed:10506200). Might have acquired an alternative function in glycosphingolipid metabolism, but it remains to be established. It appears to have drifted more slowly than confirmed pseudogenes in the glycosyltransferase 6 family, suggesting that it has remained under evolutionary pressure.
The Forssman antigen (FORS1) is normally expressed on erythrocytes of some non-primate mammals. However, in rare cases it is expressed on human erythrocytes of histo-blood group FORS carriers.
The conserved DXD motif is involved in cofactor binding. The manganese ion interacts with the beta-phosphate group of UDP and may also have a role in catalysis (By similarity).
Widely expressed. Expressed at higher level in placenta, ovary and peripheral blood leukocyte, whereas it is weakly expressed in liver, thymus, and testis (PubMed:10506200). Expressed in bone marrow erythroid cells (PubMed:23255552).
Belongs to the MINDY deubiquitinase family. FAM63 subfamily.
Hydrolase that can remove 'Lys-48'-linked conjugated ubiquitin from proteins (PubMed:27292798). Binds to polyubiquitin chains of different linkage types, including 'Lys-6', 'Lys-11', 'Lys-29', 'Lys-33', 'Lys-48' and 'Lys-63' (PubMed:28082312). May play a regulatory role at the level of protein turnover (PubMed:27292798).
Part of the neuronal tubulin polyglutamylase complex which contains TPGS1, TPGS2, TTLL1, LRRC49 and NICN1 (Probable). Interacts with PCM1, CSTPP1 and LRRC49 (PubMed:34782749).
Subunit of the tubulin polyglutamylase complex (TPGC). The complex mediates cilia and flagella polyglutamylation which is essential for their biogenesis and motility (Probable). May act in the targeting of the tubulin polyglutamylase complex. Required for the development of the spermatid flagellum (By similarity).
As part of the CUL3(KBTBD6/7) E3 ubiquitin ligase complex functions as a substrate adapter for the RAC1 guanine exchange factor (GEF) TIAM1, mediating its 'Lys-48' ubiquitination and proteasomal degradation (PubMed:25684205). By controlling this ubiquitination, regulates RAC1 signal transduction and downstream biological processes including the organization of the cytoskeleton, cell migration and cell proliferation (PubMed:25684205). Ubiquitination of TIAM1 requires the membrane-associated protein GABARAP which may restrict locally the activity of the complex (PubMed:25684205).
Core component of a BCR3 (BTB-CUL3-RBX1) E3 ubiquitin ligase complex, also named Cul3-RING ubiquitin ligase complex CUL3(KBTBD6/7), composed of CUL3, RBX1, KBTBD6 and KBTBD7 (PubMed:25684205). Interacts with GABARAP; the interaction is direct and is required for the ubiquitination of TIAM1 (PubMed:25684205). Interacts with GABARAPL1, GABARAPL2 and MAP1LC3B; the interaction is direct (PubMed:25684205).
The ATG8 interaction motif (AIM) mediates interaction with proteins of the ATG8 family including GABARAP.
The BTB domain is required for interaction with CUL3.
The Kelch repeats mediate interaction with TIAM1, a CUL3(KBTBD6/7) E3 ubiquitin ligase substrate.
ATP and calmodulin are essential for its activation. Channel activity is inhibited by CFTR protein and by chloride inhibitors such as niflumic acid (NFA) and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS). Activated by heat with activation seen at temperatures above 44 degrees Celsius (By similarity). Activated by BDNF in radial glial cells (By similarity).
By IL13 (PubMed:33026825). By IL4, likely as a result of IL4-induced cell proliferation (PubMed:31732694). By wounding in airway epithelial cells with levels decreasing significantly during the healing process (PubMed:31732694).
Calcium-activated chloride channel (CaCC) (PubMed:20056604, PubMed:22178883, PubMed:21984732, PubMed:22946059, PubMed:32487539). Plays a role in transepithelial anion transport and smooth muscle contraction. Required for the normal functioning of the interstitial cells of Cajal (ICCs) which generate electrical pacemaker activity in gastrointestinal smooth muscles. Acts as a major contributor to basal and stimulated chloride conductance in airway epithelial cells and plays an important role in tracheal cartilage development. Required for CFTR activation by enhancing endoplasmic reticulum Ca(2+) store release and is also required for CFTR membrane expression (PubMed:28963502). Required for basal and ATP-dependent mucus secretion in airways and intestine, probably by controlling exocytosis of mucus-filled granules by providing Ca(2+) to an apical signaling compartment (By similarity). Contributes to airway mucus expression induced by interleukins IL3 and IL8 and by the asthma-associated protein CLCA1 and is required for expression of mucin MUC5AC (PubMed:33026825). However, was shown in another study not to be required for MUC5AC expression (PubMed:31732694). Plays a role in the propagation of Ca(2+) waves in Kolliker's organ in the cochlea and contributes to the refinement of auditory brainstem circuitries prior to hearing onset (By similarity). In vomeronasal sensory neurons, modulates spontaneous firing patterns in the absence of stimuli as well as the firing pattern of pheromone-evoked activity (By similarity). Responsible for calcium-activated chloride channel activity in type I taste cells of the vallate papillae (By similarity). Acts as a heat sensor in nociceptive neurons (By similarity). In dorsal root ganglion neurons, plays a role in mediating non-histaminergic Mas-related G-protein coupled receptor (MRGPR)-dependent itching, acting as a downstream effector of MRGPRs (By similarity). In the developing brain, required for the Ca(2+)-dependent process extension of radial glial cells (By similarity).
Calcium-activated chloride channel (CaCC). Contributes to calcium-activated chloride secretion in human sweat gland epithelial cells. Shows increased basal chloride permeability and decreased Ca(2+)-induced chloride permeability.
Calcium-activated chloride channel (CaCC). Shows increased sensitivity to intracellular Ca(2+).
Contains ten transmembrane regions, not eight as predicted.
Expressed in nasal epithelial cells (at protein level) (PubMed:32487539). In the kidney, expressed in the collecting duct (at protein level) (PubMed:24913262). Broadly expressed with higher levels in liver, skeletal muscle and gastrointestinal muscles (PubMed:16906560, PubMed:15215166). Expressed in eccrine sweat glands (PubMed:25220078).
Homodimer (PubMed:21056985, PubMed:28559167). Interacts with CFTR (PubMed:22178883, PubMed:28963502). Interacts with TRPV4 (By similarity).
In airway epithelial cells, highly expressed during cell proliferation with levels decreasing as cell differentiation progresses (at protein level).
The region spanning the fifth and sixth transmembrane domains probably forms the pore-forming region.
The term 'anoctamin' was coined because these channels are anion selective and are predicted to have eight (OCT) transmembrane segments. There is some dissatisfaction in the field with the Ano nomenclature because it is not certain that all the members of this family are anion channels or have the 8-transmembrane topology.
Highly expressed in placenta, small intestine, spleen, kidney, thymus, liver, salivary gland and testes. Weakly expressed in breast, skeletal muscle and colon. Highly expressed in breast cancer upon interaction between tumor cells and stromal cells in vitro. Expressed in blood mononuclear cells from patients with systemic lupus erythematosus (SLE).
Intron retention. Authors have ignored retained intron when translating.
Plays a role in M1 macrophage polarization and is required for the proper regulation of gene expression during M1 versus M2 macrophage differentiation (By similarity). Might play a role in RELA/p65 and STAT1 phosphorylation and nuclear localization upon activation of macrophages (By similarity).
Belongs to the transcription factor STAT family.
Carries out a dual function: signal transduction and activation of transcription. Involved in IL4/interleukin-4- and IL3/interleukin-3-mediated signaling.
Forms a homodimer or a heterodimer with a related family member (By similarity). Interacts with NCOA1 via its C-terminal LXXLL motif.
Tyrosine phosphorylated on Tyr-641 following stimulation by IL4/interleukin-4 (PubMed:27796300). Tyrosine phosphorylated following stimulation by IL3/interleukin-3 (By similarity). Dephosphorylation on tyrosine residues by PTPN2 negatively regulates the IL4/interleukin-4 mediated signaling (PubMed:17210636).
Belongs to the class-I pyridoxal-phosphate-dependent aminotransferase family.
Transaminase involved in tyrosine breakdown. Converts tyrosine to p-hydroxyphenylpyruvate.
Transaminase involved in tyrosine breakdown. Converts tyrosine to p-hydroxyphenylpyruvate. Can catalyze the reverse reaction, using glutamic acid, with 2-oxoglutarate as cosubstrate (in vitro). Has much lower affinity and transaminase activity towards phenylalanine.
Calcium appears to inhibit ligand binding to the receptor, most probably by interacting with a distinct calcium-binding protein which then inhibits the receptor.
Homotetramer (By similarity). Interacts with CABP1 (PubMed:12032348). Interacts with BOK; regulates ITPR2 expression (By similarity). Interacts with BCL2L10 (PubMed:27995898). Interacts with TRPC4 (By similarity).
Isoform Short is found in skeletal muscle and heart.
Phosphorylation by cAMP-dependent PKA on Ser-937 increases calcium release.
Receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium. This release is regulated by cAMP both dependently and independently of PKA (By similarity).
The receptor contains a calcium channel in its C-terminal extremity. Its large N-terminal cytoplasmic region has the ligand-binding site in the N-terminus and modulatory sites in the middle portion immediately upstream of the channel region.
Expressed at highest levels during the G1 to S transition of the cell cycle.
Highest amounts are found in placenta, lung and heart.
Single-stranded DNA binding protein that interacts with the region upstream of the MYC gene. Binds specifically to the DNA sequence motif 5'-[AT]CT[AT][AT]T-3'. Probably has a role in DNA replication.
(Microbial infection) Recruited to the promoters of adenovirus 12 E1A gene in case of infection, possibly leading to regulate its expression.
Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. SET2 subfamily.
Histone methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' (H3K36me2) as substrate (PubMed:16118227, PubMed:19141475, PubMed:21526191, PubMed:21792193, PubMed:23043551, PubMed:27474439). It is capable of trimethylating unmethylated H3K36 (H3K36me0) in vitro (PubMed:19332550). Represents the main enzyme generating H3K36me3, a specific tag for epigenetic transcriptional activation (By similarity). Plays a role in chromatin structure modulation during elongation by coordinating recruitment of the FACT complex and by interacting with hyperphosphorylated POLR2A (PubMed:23325844). Acts as a key regulator of DNA mismatch repair in G1 and early S phase by generating H3K36me3, a mark required to recruit MSH6 subunit of the MutS alpha complex: early recruitment of the MutS alpha complex to chromatin to be replicated allows a quick identification of mismatch DNA to initiate the mismatch repair reaction (PubMed:23622243). Required for DNA double-strand break repair in response to DNA damage: acts by mediating formation of H3K36me3, promoting recruitment of RAD51 and DNA repair via homologous recombination (HR) (PubMed:24843002). Acts as a tumor suppressor (PubMed:24509477). H3K36me3 also plays an essential role in the maintenance of a heterochromatic state, by recruiting DNA methyltransferase DNMT3A (PubMed:27317772). H3K36me3 is also enhanced in intron-containing genes, suggesting that SETD2 recruitment is enhanced by splicing and that splicing is coupled to recruitment of elongating RNA polymerase (PubMed:21792193). Required during angiogenesis (By similarity). Required for endoderm development by promoting embryonic stem cell differentiation toward endoderm: acts by mediating formation of H3K36me3 in distal promoter regions of FGFR3, leading to regulate transcription initiation of FGFR3 (By similarity). In addition to histones, also mediates methylation of other proteins, such as tubulins and STAT1 (PubMed:27518565, PubMed:28753426). Trimethylates 'Lys-40' of alpha-tubulins such as TUBA1B (alpha-TubK40me3); alpha-TubK40me3 is required for normal mitosis and cytokinesis and may be a specific tag in cytoskeletal remodeling (PubMed:27518565). Involved in interferon-alpha-induced antiviral defense by mediating both monomethylation of STAT1 at 'Lys-525' and catalyzing H3K36me3 on promoters of some interferon-stimulated genes (ISGs) to activate gene transcription (PubMed:28753426).
Specifically inhibited by sinefungin derivatives. N-propyl sinefungin (Pr-SNF) interacts preferentially with SETD2.
Specifically interacts with hyperphosphorylated C-terminal domain (CTD) of RNA polymerase II large subunit (POLR2A): binds to CTD heptad repeats doubly phosphorylated on 'Ser-2' and 'Ser-5' of each heptad (PubMed:16118227, PubMed:16314571). Interacts with HTT (PubMed:11461154, PubMed:9700202, PubMed:10958656). Interacts with IWS1 (PubMed:19141475). Interacts with p53/TP53; leading to regulate p53/TP53 target genes (PubMed:18585004). Component of a complex with HNRNPL (PubMed:19332550, PubMed:36537238). Interacts with TUBA1A; the interaction is independent on alpha-tubulin acetylation on 'Lys-40' (PubMed:27518565). Interacts with STAT1 (PubMed:28753426).
The catalytic SET domain binds histone H3 (PubMed:27474439, PubMed:28256625). It is also able to bind oncogenic histone H3 K36M/I found in a number of cancer types, in which histone H3 'Lys-36' is replaced by a Met or an Ile residue. When binding the oncogenic variant histone H3 K36M/I, the SET domain undergoes dramatic conformational change to accommodate the histone H3 peptide, leading to sequester and inhibit SETD2 activity and block global H3K36 methylation (PubMed:27474439, PubMed:28256625).
The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry.
The disease may be caused by variants affecting the gene represented in this entry. Defects of SETD2 are associated with loss of DNA methylation at non-promoter regions (PubMed:23792563). SETD2 defects lead to aberrant and reduced nucleosome compaction and chromatin association of key replication proteins, such as MCM7 and DNA polymerase delta, leading to hinder replication fork progression and prevent loading of RAD51 homologous recombination repair factor at DNA breaks (PubMed:25728682).
The low charge region mediates the transcriptional activation activity.
Interacts with POC1A (PubMed:23015594). Interacts with FAM161A (PubMed:25018096). Interacts with CEP44; the interaction is direct and recruits POC1B to centriolar microtubules (PubMed:32060285).
Phosphorylated in mitotic cells that may be mediated by CDK1.
Plays an important role in centriole assembly and/or stability and ciliogenesis (PubMed:20008567, PubMed:32060285). Involved in early steps of centriole duplication, as well as in the later steps of centriole length control (PubMed:19109428). Acts in concert with POC1A to ensure centriole integrity and proper mitotic spindle formation (PubMed:32060285). Required for primary cilia formation, ciliary length and also cell proliferation (PubMed:23015594). Required for retinal integrity (PubMed:25044745).
Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways. May be involved in coupling from immunoreceptor to Ras signaling. Acts as a negative regulator of cytokine signaling in collaboration with CBL. Binds to EPOR and suppresses EPO-induced STAT5 activation, possibly through a masking effect on STAT5 docking sites in EPOR. Suppresses PDGF-induced mitogenesis. May induce cytoskeletal reorganization via interaction with VAV3.
Expressed in spleen, prostate, testis, uterus, small intestine and skeletal muscle. Among hematopoietic cell lines, expressed exclusively in B-cells. Not expressed in most tumor cell lines.
Homodimer. Interacts with KIT/c-KIT, SHC1, EPOR, PDGFR, VAV1 and VAV3. Interacts (via N-terminal region) with SHC1. Interacts (via the phosphorylated C-terminus) with GRB2. Interacts (via its SH2 domain) with EPOR, INSR and KIT. Interacts with GRB2 after B-cell antigen receptor stimulation. Interacts (via PH domain) with VAV3. Interacts with NTRK1, NTRK2 and NTRK3 (phosphorylated); after stimulation of the receptor by its extracellular ligand and subsequent autophosphorylation of the receptor. Binds INSR, GRB2, ASB6 and CAP. Insulin stimulation leads to dissociation of CAP. Binds CBS only when SH2B2/APS has become phosphorylated. INSR binding does not depend on the phosphorylation of SH2B2/APS (By similarity).
Tyrosine phosphorylated by JAK2, KIT and other kinases activated by B-cell receptor in response to stimulation with cytokines, IL3, IL5, PDGF, IGF1, IGF2, CSF2/GM-CSF and cross-linking of the B-cell receptor complex.
Belongs to the eukaryotic RPA34 RNA polymerase subunit family.
Component of the RNA polymerase I (Pol I) complex consisting of at least 13 subunits. Interacts with TAF1A thereby associates with the SL1 complex. Interacts with UBTF. Interacts with POLR1E/PRAF1 through its N-terminal region (By similarity). Isoform 2 interacts with CD3E.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase I which synthesizes ribosomal RNA precursors. Isoform 1 is involved in UBTF-activated transcription, presumably at a step following PIC formation.
Has sharply different functional characteristics.
Isoform 1 is phosphorylated on tyrosine residues in initiation-competent Pol I-beta complexes but not in Pol I-alpha complexes.
Isoform 2 has been described as a component of preformed T-cell receptor (TCR) complex.
Isoform 2 undergoes tyrosine phosphorylation upon T-cell receptor (TCR) stimulation. This phosphorylation has not been confirmed by other groups.
It is in an antisense orientation to and overlaps the gene of the DNA repair enzyme ERCC1. This gene overlap is conserved in mouse, suggesting an important biological function.
It is not known whether the so-called human ASE1 and human CAST proteins represent two sides of a single gene product with sharply different functional characteristics. Experiments done with the mouse homolog protein are in favor of an implication of this gene in rRNA transcription instead of T-cell receptor signaling.
Antibodies against PHF20 are present in sera from patients with hepatocellular carcinoma, glioblastoma and childhood medulloblastula.
Expressed in heart, kidney, liver, lung, pancreas, placenta, spleen and testis. Not expressed in brain, skeletal muscle, colon, ovary, prostate, small intestine and thymus. Expressed in colon and ovary cancer cell lines while it is not expressed in the respective normal tissues.
Homodimer; disulfide-linked. Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1.
Methyllysine-binding protein, component of the MOF histone acetyltransferase protein complex. Not required for maintaining the global histone H4 'Lys-16' acetylation (H4K16ac) levels or locus specific histone acetylation, but instead works downstream in transcriptional regulation of MOF target genes (By similarity). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. Contributes to methyllysine-dependent p53/TP53 stabilization and up-regulation after DNA damage.
The Tudor domain 1 doesn't bind dimethyl-lysine residues, due to an atypical and occluded aromatic cage.
The Tudor domain 2 mediates reading of dimethyl-lysine residues.
Ubiquitinated by TRIM26; leading to proteasomal degradation.
Belongs to the G-protein coupled receptor 2 family. Adhesion G-protein coupled receptor (ADGR) subfamily.
Detected in fetal retina. Highly expressed in normal enterochromaffin cells and in neuroendocrine carcinoma. Detected in normal liver; highly expressed in primary liver carcinoma.
Expressed in many tissues. Highly expressed in ovary, testis, pancreas, brain, heart and prostate.
May function as a transcription factor involved in cell differentiation.
An intronic G-to-A transition (rs2535913) has been associated with leukocyte telomere length. The minor A allele is associated with shorter telomeres and lower expression in lymphoblastoid cells and in sun-exposed skin (PubMed:25624462).
May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex.
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
Genetic variations in CYP2D6 are the cause of poor drug metabolism CYP2D6-related [MIM:608902]. The CYP2D6 gene is highly polymorphic. CYP2D6 activity ranges widely within a population comprising ultrarapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizer phenotypes. UM and PM are those most at risk for treatment failure or dose-dependent drug toxicity, respectively. Of the Caucasian populations of Europe and North America, 5%-10% are of the PM phenotype and are unable to metabolize the antihypersensitive drug debrisoquine and numerous other drugs. Different alleles are known, including CYP2D6*1 (PubMed:15768052), CYP2D6*2 (PubMed:25469868), CYP2D6*6B/6C (PubMed:7868129), CYP2D6*7 also known CYP2D6E (PubMed:7845481), CYP2D6*9 also known CYP2D6C (PubMed:1844820), CYP2D6*10 also known CYP2D6J (PubMed:8287064, PubMed:25469868), CYP2D6*12 (PubMed:8655150), CYP2D6*14 (PubMed:10064570), CYP2D6*17 also known CYP2D6Z (PubMed:8971426), CYP2D6*41B (PubMed:15768052), CYP2D6*45A (PubMed:15768052), CYP2D6*45B (PubMed:15768052), CYP2D6*46 (PubMed:15768052), CYP2D6*87 (PubMed:25469868), CYP2D6*88 (PubMed:25469868), CYP2D6*89 (PubMed:25469868), CYP2D6*90 (PubMed:25469868), CYP2D6*91 (PubMed:25469868), CYP2D6*93 (PubMed:25469868), C CYP2D6*94 (PubMed:25469868), CYP2D6*97 (PubMed:25469868) and CYP2D6*98 (PubMed:25469868). Isozymes CYP2D6.45 (Lys-155, Cys-296 and Thr-486) and CYP2D6.46 (His-26, Lys-155, Cys-296 and Thr-486) are functional (PubMed:15768052). The sequence shown is that of isozyme CYP2D6.1 corresponding to allele CYP2D6*1.
Expressed in the heart and skeletal muscle.
Plays an important role in cardiomyocyte hypertrophy via activation of the calcineurin/NFAT signaling pathway.
May be a DNA-binding protein with a regulatory function. May play an important role in cell death and/or in regulation of cell proliferation.
Ubiquitinated by PRKN, promoting proteasomal degradation.
Does not exhibit APOBEC1 complementation activity.
Essential component of the apolipoprotein B mRNA editing enzyme complex which is responsible for the postranscriptional editing of a CAA codon for Gln to a UAA codon for stop in APOB mRNA. Binds to APOB mRNA and is probably responsible for docking the catalytic subunit, APOBEC1, to the mRNA to allow it to deaminate its target cytosine. The complex also protects the edited APOB mRNA from nonsense-mediated decay.
Major isoform found in 66-78% of cDNA clones.
Minor isoform found in 2-3% of cDNA clones.
Part of the apolipoprotein B mRNA editing complex with APOBEC1 (PubMed:10781591, PubMed:10669759). Interacts with TNPO2; TNPO2 may be responsible for transport of A1CF into the nucleus (PubMed:12896982). Interacts with SYNCRIP (PubMed:11134005). Interacts with CELF2/CUGBP2 (PubMed:11577082). Interacts with RBM47 (PubMed:24916387).
The RRM domains are necessary but not sufficient for binding to APOB mRNA. Additional residues in the pre-RRM and C-terminal regions are required for RNA-binding and for complementing APOBEC1 activity.
Widely expressed with highest levels in brain, liver, pancreas, colon and spleen.
Interacts (via N-terminus) with RAB2B (in GTP-bound form).
RAB2B effector protein which promotes cytosolic DNA-induced innate immune responses. Regulates IFN responses against DNA viruses by regulating the CGAS-STING signaling axis.
Binds to actin and affects the structure of the cytoskeleton. Slightly reduces actin polymerization. Binds to poly-L-proline, phosphatidylinositol 3-phosphate (PtdIns(3)P), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 4-phosphate (PtdIns(4)P). May be involved in spermatogenesis.
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
Contaminating sequence. The N-terminus matches the 2q37.3 region.
Found in the Intron Large (IL) complex, a post-mRNA release spliceosomal complex containing the excised intron, U2, U5 and U6 snRNPs, and splicing factors (PubMed:24304693). Interacts with TFIP11 and DHX15 (PubMed:24304693).
Involved in pre-mRNA splicing through regulating spliceosome C complex formation (PubMed:24304693). May play a role during late-stage splicing events and turnover of excised introns (PubMed:24304693).
Was originally thought to be a DNA-binding transcriptional repressor. However, later work showed that the original sequence was a chimera and that the DNA-binding activity was derived from the incorrect N-terminal sequence.
Widely expressed in tissues and cell lines.
Deubiquitinase that plays a role in different processes including cell cycle regulation, DNA replication or DNA damage response (PubMed:26299517, PubMed:27296872, PubMed:31911859, PubMed:34509474). Antagonizes the anaphase-promoting complex (APC/C) during G1/S transition by mediating deubiquitination of cyclin-A (CCNA1 and CCNA2), thereby promoting S phase entry. Specifically mediates deubiquitination of 'Lys-11'-linked polyubiquitin chains, a specific ubiquitin-linkage type mediated by the APC/C complex. Phosphorylation at Ser-628 during G1/S phase maximizes the deubiquitinase activity, leading to prevent degradation of cyclin-A (CCNA1 and CCNA2) (PubMed:21596315). Plays an important role in the regulation of DNA replication by stabilizing the licensing factor CDT1 (PubMed:27296872). Plays also an essential role beyond S-phase entry to promote the efficiency and fidelity of replication by deubiquitinating checkpoint kinase 1/CHK1, promoting its stability (PubMed:34509474). Sustains the DNA damage response (DDR) by deubiquitinating and stabilizing the ATP-dependent DNA helicase BLM (PubMed:34606619). Mechanistically, DNA double-strand breaks (DSB) promotes ATM-mediated phosphorylation of USP37 and enhances the binding between USP37 and BLM (PubMed:34606619). Promotes cell migration by deubiquitinating and stabilizing the epithelial-mesenchymal transition (EMT)-inducing transcription factor SNAI (PubMed:31911859). Plays a role in the regulation of mitotic spindle assembly and mitotic progression by associating with chromatin-associated WAPL and stabilizing it through deubiquitination (PubMed:26299517).
Induced by E2F transcription factors in G1.
Induced in G1 phase, accumulates at G1/S transition, and degraded in late mitosis following ubiquitination and degradation by the APC(CDH1) complex.
Interacts with FZR1/CDH1 (PubMed:21596315). Interacts with CDT1 (PubMed:27296872).
Phosphorylated at Ser-628 by CDK2 during G1/S phase but not during mitosis; phosphorylation at Ser-628 is required for deubiquitinase activity. Also polyubiquitinated during early G1 phase, without leading to degradation (PubMed:21596315). Phosphorylated at Ser-114 by ATM following DNA damage, which in turn increases its deubiquitination activity towards BLM (PubMed:34606619).
Polyubiquitinated via 'Lys-11'-linked ubiquitin by the APC(CDH1) complex during late mitosis, leading to its degradation. Able to mediate auto-deubiquitination.
The KEN box 3 is required for interaction with FZR1/CDH1 and is essential for APC(CDH1)-mediated ubiquitination.
Interacts with BIK and RNF183 (PubMed:26567849). Interacts with IMMT/MIC60and EMD (PubMed:27402544).
Involved in the regulation of endoplasmic reticulum (ER)-mitochondria coupling. Negatively regulates the ER-mitochondria distance and Ca(2+) transfer from ER to mitochondria possibly implicating it in the regulation of apoptosis (PubMed:27402544). May collaborate with RNF183 to restrain BIK protein levels thus regulating apoptotic signaling (PubMed:26567849).
Testis-specific in fetus (aged from 6 to 11 weeks). In adult, expressed predominantly in testis, with some expression in lung, heart, kidney, adrenal gland and whole brain (PubMed:11694338). Highly expressed in certain types of cancer tissues such as hepatocellular carcinoma, colon and gastric cancer. Weakly expressed in normal pancreas (PubMed:12865919).
Although related to other DMRT proteins, it does not contain a canonical DM DNA-binding domain.
Predominantly expressed in kidney, pancreas, ovary and testis. Detected in brain and in many other tissues.
In T-helper 2 (Th2) cells, regulates the magnitude of NFAT-driven transcription of a specific subset of cytokine genes, including IL3, IL4, IL5 and IL13, but not IL2. Recruits PRMT1 to the IL4 promoter; this leads to enhancement of histone H4 'Arg-3'-methylation and facilitates subsequent histone acetylation at the IL4 locus, thus promotes robust cytokine expression (By similarity). Down-regulates formation of poly-SUMO chains by UBE2I/UBC9 (By similarity).
Interacts with NFATC2, TRAF1, TRAF2 and PRMT1. Interacts with UBE2I/UBC9 (By similarity).
Methylation at the N-terminus by PRMT1 modulates interaction with the NFAT complex and results in augmented cytokine production.
Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13.
Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation.
Belongs to the immunoglobulin superfamily. IgLON family.
Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CNIH2, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8 (By similarity).
Expression is up-regulated in dorsolateral prefrontal cortex of patients with schizophrenia (postmortem brain study).
Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by regulating their rates of activation, deactivation and desensitization.
Binds MYD88 via their respective TIR domains (By similarity). Homodimer (Potential).
Highly expressed in spleen, lymph node, thymus, tonsil and at lower levels in lung. Highly expressed in promyelocytic HL-60 cells and in B-cell lines.
In some plant proteins and in human SARM1, the TIR domain has NAD(+) hydrolase (NADase) activity (By similarity). However, despite the presence of the catalytic Asp residue, the isolated TIR domain of human TLR4 lacks NADase activity (By similarity). Based on this, it is unlikely that Toll-like receptors have NADase activity.
Participates in the innate immune response to microbial agents. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (By similarity).
Interacts with MAP2K7 and GTP-bound NRAS.
Negatively regulates stress-induced JNK activation and apoptosis by promoting MAP2K7 phosphorylation and inhibiting its ability to activate JNK. Following prolonged stress, anti-apoptotic effect stops because of degradation of RASSF7 protein via the ubiquitin-proteasome pathway. Required for the activation of AURKB and chromosomal congression during mitosis where it stimulates microtubule polymerization.
Polyubiquitinated and degraded by the proteasome upon prolonged stress stimuli.
Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Binds single-stranded DNA. Required for maximal induction of heat-shock genes. Required for the trimethylation of histone H3 'Lys-4' (H3K4me3) on genes involved in stem cell pluripotency; this function is synergistic with CXXC1 indicative for an involvement of a SET1 complex (By similarity).
Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8; the association of RTF1 appears to be less stable than that of other subunits. At least in HeLa cells a N-terminal shorter form of RTF1 is also found in the complex (PubMed:20178742). The PAF1 complex interacts with PHF5A (By similarity).
It is uncertain whether Met-1 or Met-41 is the initiator.
The Plus3 domain mediates single-stranded DNA-binding.
Chromatin reader that recognizes dual histone modifications such as histone H3.1 dimethylated at 'Lys-36' and histone H4 acetylated at 'Lys-16' (H3.1K36me2-H4K16ac) and histone H3 methylated at 'Lys-4' and histone H4 acetylated at 'Lys-14' (H3K4me1-H3K14ac) (PubMed:26655721, PubMed:31965980, PubMed:36064715, PubMed:27477906). May act as a transcriptional corepressor for KDM5D by recognizing the dual histone signature H3K4me1-H3K14ac (PubMed:27477906). May also act as a transcriptional corepressor for KDM5C and EZH2 (PubMed:33323928). Recognizes acetylated histone H4 and recruits the NuRD chromatin remodeling complex to damaged chromatin for transcriptional repression and double-strand break repair by homologous recombination (PubMed:30134174, PubMed:25593309, PubMed:27732854). Also activates transcription elongation by RNA polymerase II through recruiting the P-TEFb complex to target promoters (PubMed:30134174, PubMed:26655721). Localizes to H3.1K36me2-H4K16ac marks at all-trans-retinoic acid (ATRA)-responsive genes and positively regulates their expression (PubMed:26655721). Promotes neuronal differentiation by associating with regulatory regions within the MAPT gene, to enhance transcription of a protein-coding MAPT isoform and suppress the non-coding MAPT213 isoform (PubMed:36064715, PubMed:35916866, PubMed:30134174). Suppresses breast cancer, and prostate cancer cell invasion and metastasis (PubMed:27477906, PubMed:31965980, PubMed:33323928).
Expressed in neurons (at protein level) (PubMed:36064715). Absent in astrocytes (at protein level) (PubMed:36064715). Expressed in all tissues examined with highest expression in brain, lung, pancreas, and placenta (PubMed:11003709, PubMed:35916866). Expressed in cutaneous T-cell lymphomas (CTCL) (PubMed:11149944).
Highly expressed in fetal brain, with decreasing expression in postnatal stages.
Induced by all-trans-retinoic acid (ATRA) (at protein level).
Monomer and homodimer (PubMed:30134174). Interacts with NuRD subcomplexes containing GATAD2A (PubMed:27732854). Interacts with the histone deacetylase NuRD complex subunit CHD4; the interaction is direct, appears to occur with monomeric ZMYND8, and is increased following DNA damage (PubMed:30134174, PubMed:25593309, PubMed:36064715). Interacts (via N-terminus) with the P-TEFb complex subunit CCNT1 (via central region); the interaction is direct and the association appears to occur between homodimeric ZMYND8 and the activated form of the P-TEFb complex (PubMed:30134174). Interacts (via N-terminus) with DBN1 (via ADF-H domain); the interaction leads to sequestering of ZMYND8 in the cytoplasm (PubMed:28966017, PubMed:35916866). Interacts with the P-TEFb complex subunit CDK9; the association appears to occur between homodimeric ZMYND8 and the activated form of the P-TEFb complex (PubMed:30134174). Interacts with EZH2; the interaction is dependent on the presence of chromatin (PubMed:33323928, PubMed:36064715). Interacts (via MYND domain) with the NuRD complex subunit GATAD2A (PubMed:35916866, PubMed:27732854). Interacts with histone H3 (via N-terminus) that is both methylated at 'Lys-4' (H3K4me1) and acetylated at 'Lys-14' (H3K14ac), with histone H3 (via N-terminus) unmodified at 'Lys-4' (H3K4me0) and acetylated at 'Lys-14' (H3K14ac), and with histone H3 (via N-terminus) di-methylated at 'Lys-36' (H3K36me2) (PubMed:27477906, PubMed:25593309, PubMed:26655721, PubMed:31965980). Interacts (via Bromo domain) with histone H4 acetylated at 'Lys-16' (H4K16ac) (PubMed:25593309, PubMed:26655721, PubMed:31965980). Interacts with HDAC1 (PubMed:25593309, PubMed:36064715). Interacts with HDAC2 (PubMed:25593309). Interacts with KDM1A (PubMed:27477906, PubMed:25593309). Interacts with KDM5C (PubMed:33323928). Interacts with KDM5D (PubMed:27477906). Interacts in vitro with PRKCB (PubMed:11003709). Interacts with RNA polymerase II subunit POLR2A phosphorylated at 'Ser-5' (PubMed:26655721). Interacts with ZNF592 (PubMed:30134174). Interacts with ZNF687 (PubMed:30134174). Does not interact with GATAD2B (PubMed:27732854).
Mutations in ZMYND8 may be the cause of syndromic intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies.
The MYND-type zinc finger domain is required for localization to DNA damage sites.
The PWWP domain is required for interaction with histone H3.1K36me2.
The bromo domain is required for interaction with histone H4K16ac.
The bromo domain is required for localization to DNA damage sites.
Belongs to the immunoglobulin superfamily. AMIGO family.
May mediate heterophilic cell-cell interaction. May contribute to signal transduction through its intracellular domain (By similarity).
May play a scavenger role by digesting biologically active peptidoglycan (PGN) into biologically inactive fragments. Has no direct bacteriolytic activity.
Strongly expressed in liver and fetal liver, and secreted into serum. Expressed to a much lesser extent in transverse colon, lymph nodes, heart, thymus, pancreas, descending colon, stomach and testis. Isoform 2 is not detected in the liver or serum.
Homotetramer. Interacts with HSC70 as well as DNAJ homologs and HSP90 (By similarity). Interacts (via the C-terminus 303- 319 AA) with GRK5.
One HIP oligomer binds the ATPase domains of at least two HSC70 molecules dependent on activation of the HSC70 ATPase by HSP40. Stabilizes the ADP state of HSC70 that has a high affinity for substrate protein. Through its own chaperone activity, it may contribute to the interaction of HSC70 with various target proteins (By similarity).
Belongs to the phosphatase 2A regulatory subunit B56 family.
PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with SGO1.
Widely expressed with the highest expression in heart and skeletal muscle.
Binds to both calcium-free and calcium-bound calmodulin. The affinity for the calcium-bound form is 50-fold greater.
Functions as a modulator of calcium-binding by calmodulin. Thereby, regulates calmodulin activity and the different processes it controls (PubMed:19106096, PubMed:23204517, PubMed:27876793). For instance, may play a role in neuronal differentiation through activation of calmodulin-dependent kinase signaling pathways (PubMed:21491429).
Mostly intrinsically disordered, with residual structure localized to the IQ domain which mediates the interaction with calmodulin.
Abundantly expressed in lacrimal gland where it found in the secretory endpieces. Also expressed at modest levels in the submandibular gland.
Opiorphin is an endogenous inhibitor of neprilysin and aminopeptidase N. Inhibits the breakdown of substance P, Mca-BK2 and Met-enkephalin by neprilysin in vitro with IC(50) values of 29 uM, 33 uM and 33 uM respectively. Inhibits the breakdown of Ala-pNA by aminopeptidase N in vitro with an IC(50) of 65 uM. Has a potent analgesic effect when administered to rats by intravenous injection.
Contaminating sequence. Premature poly-A sequence.
Highly expressed in fetal brain. Weakly expressed in adult brain and prostate.
Interacts (via N-terminus) with adapter protein complex AP-2 subunits alpha (AP2A1) and beta (AP2B1).
Involved in clathrin-mediated endocytosis at the synapse. Plays a role in neuronal development and in synaptic vesicle recycling in mature neurons, a process required for normal synaptic transmission.
Mesodermal transcription factor that plays a key role in somitogenesis and is specifically required for sclerotome development. Required for maintenance of the sclerotome polarity and formation of the cranio-cervical joints (PubMed:23290072, PubMed:24073994). Binds specifically to the promoter of target genes and regulates their expression. Activates expression of NKX3-2 in the sclerotome. Activates expression of CDKN1A and CDKN2A in endothelial cells, acting as a regulator of vascular cell proliferation. While it activates CDKN1A in a DNA-dependent manner, it activates CDKN2A in a DNA-independent manner. Required for hematopoietic stem cell (HSCs) induction via its role in somitogenesis: specification of HSCs occurs via the deployment of a specific endothelial precursor population, which arises within a sub-compartment of the somite named endotome.
Belongs to the TRAFAC class translation factor GTPase superfamily. Bms1-like GTPase family. TSR1 subfamily.
Required during maturation of the 40S ribosomal subunit in the nucleolus.
Decapping enzyme for NAD-capped RNAs: specifically hydrolyzes the nicotinamide adenine dinucleotide (NAD) cap from a subset of RNAs by removing the entire NAD moiety from the 5'-end of an NAD-capped RNA (PubMed:28283058). The NAD-cap is present at the 5'-end of some RNAs and snoRNAs (PubMed:28283058). In contrast to the canonical 5'-end N7 methylguanosine (m7G) cap, the NAD cap promotes mRNA decay (PubMed:28283058). Preferentially acts on NAD-capped transcripts in response to environmental stress (PubMed:31101919). Also acts as a non-canonical decapping enzyme that removes the entire cap structure of m7G capped or incompletely capped RNAs and mediates their subsequent degradation (By similarity). Specifically degrades pre-mRNAs with a defective 5'-end m7G cap and is part of a pre-mRNA capping quality control (By similarity). Has decapping activity toward incomplete 5'-end m7G cap mRNAs such as unmethylated 5'-end-capped RNA (cap0), while it has no activity toward 2'-O-ribose methylated m7G cap (cap1) (PubMed:29601584). In contrast to canonical decapping enzymes DCP2 and NUDT16, which cleave the cap within the triphosphate linkage, the decapping activity releases the entire cap structure GpppN and a 5'-end monophosphate RNA (By similarity). Also has 5'-3' exoribonuclease activities: The 5'-end monophosphate RNA is then degraded by the 5'-3' exoribonuclease activity, enabling this enzyme to decap and degrade incompletely capped mRNAs (PubMed:29601584). Also possesses RNA 5'-pyrophosphohydrolase activity by hydrolyzing the 5'-end triphosphate to release pyrophosphates (By similarity). Exhibits decapping activity towards FAD-capped RNAs (PubMed:32374864). Exhibits decapping activity towards dpCoA-capped RNAs in vitro (By similarity).
Decapping enzyme for NAD-capped RNAs: specifically hydrolyzes the nicotinamide adenine dinucleotide (NAD) cap from a subset of RNAs by removing the entire NAD moiety from the 5'-end of an NAD-capped RNA.
Belongs to the Integrator subunit 6 family.
Belongs to the multiprotein complex Integrator, at least composed of INTS1, INTS2, INTS3, INTS4, INTS5, INTS6, INTS7, INTS8, INTS9/RC74, INTS10, INTS11/CPSF3L and INTS12.
Component of the Integrator (INT) complex, a complex involved in the small nuclear RNAs (snRNA) U1 and U2 transcription and in their 3'-box-dependent processing. The Integrator complex is associated with the C-terminal domain (CTD) of RNA polymerase II largest subunit (POLR2A) and is recruited to the U1 and U2 snRNAs genes (Probable). Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the INT complex (PubMed:23904267). May have a tumor suppressor role; an ectopic expression suppressing tumor cell growth (PubMed:15254679, PubMed:16239144).
Frequently down-regulated in nonsmall cell lung carcinomas and prostate cancers. Down-regulation in prostate cancer is due to CpG hypermethylation of its promoter. However, some involvement in cancer is unclear.
Widely expressed. Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Expressed exclusively in the central nervous system. Highest level in the in amygdala, hippocampus, thalamus and cerebral cortex. In the rest of the brain a basal expression seems to be always present. Up-regulated in substantia nigra neurons from Parkinson disease patients.
Functional component of the Nogo receptor signaling complex (RTN4R/NGFR) in RhoA activation responsible for some inhibition of axonal regeneration by myelin-associated factors (PubMed:14966521, PubMed:15694321). Is also an important negative regulator of oligodentrocyte differentiation and axonal myelination (PubMed:15895088). Acts in conjunction with RTN4 and RTN4R in regulating neuronal precursor cell motility during cortical development (By similarity).
Homotetramer (PubMed:17005555). Forms a ternary complex with RTN4R/NGFR and RTN4R/TNFRSF19 (PubMed:14966521, PubMed:15694321, PubMed:17005555). Interacts with NGRF and MYT1L (By similarity). Interacts with RTN4R (PubMed:19052207).
N-glycosylated. Contains predominantly high-mannose glycans.
The intracellular domain of LINGO1 interacts with MYT1L.
AIM-100 (4-amino-5,6-biaryl-furo[2,3-d]pyrimidine) suppresses TNK2-mediated phosphorylation at Tyr-269. Inhibits the binding of the Tyr-269 phosphorylated form to androgen-responsive enhancers (AREs) and its transcriptional activity.
Belongs to the nuclear hormone receptor family.
Binds DNA as a homodimer. Part of a ternary complex containing AR, EFCAB6/DJBP and PARK7. Interacts with HIPK3 and NR0B2 in the presence of androgen. The ligand binding domain interacts with KAT7/HBO1 in the presence of dihydrotestosterone. Interacts with EFCAB6/DJBP, PQBP1, RANBP9, RBAK, SPDEF, SRA1, TGFB1I1 and RREB1. Interacts with ZMIZ1/ZIMP10 and ZMIZ2/ZMIP7 which both enhance its transactivation activity. Interacts with SLC30A9 and RAD54L2/ARIP4. Interacts with MACROD1 (via macro domain) (PubMed:19022849). Interacts via the ligand-binding domain with LXXLL and FXXLF motifs from NCOA1, NCOA2, NCOA3, NCOA4 and MAGEA11. The AR N-terminal poly-Gln region binds Ran resulting in enhancement of AR-mediated transactivation. Ran-binding decreases as the poly-Gln length increases. Interacts with HIP1 (via coiled coil domain). Interacts (via ligand-binding domain) with TRIM68. Interacts with TNK2. Interacts with USP26. Interacts with RNF6. Interacts (regulated by RNF6 probably through polyubiquitination) with RNF14; regulates AR transcriptional activity. Interacts with PRMT2 and TRIM24. Interacts with RACK1. Interacts with RANBP10; this interaction enhances dihydrotestosterone-induced AR transcriptional activity. Interacts with PRPF6 in a hormone-independent way; this interaction enhances dihydrotestosterone-induced AR transcriptional activity. Interacts with STK4/MST1. Interacts with ZIPK/DAPK3. Interacts with LPXN. Interacts with MAK. Part of a complex containing AR, MAK and NCOA3. Interacts with CRY1. Interacts with CCAR1 and GATA2. Interacts with ZNF318 (By similarity). Interacts with BUD31 (PubMed:25091737). Interacts with ARID4A (PubMed:23487765). Interacts with ARID4B (By similarity). Interacts (via NR LBD domain) with ZBTB7A; the interaction is direct and androgen-dependent (PubMed:20812024). Interacts with NCOR1 (PubMed:20812024). Interacts with NCOR2 (PubMed:20812024). Interacts with CRY2 in a ligand-dependent manner (By similarity).
Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. In the presence of bound steroid the ligand-binding domain interacts with the N-terminal modulating domain, and thereby activates AR transcription factor activity. Agonist binding is required for dimerization and binding to target DNA. The transcription factor activity of the complex formed by ligand-activated AR and DNA is modulated by interactions with coactivator and corepressor proteins (PubMed:25091737). Interaction with RANBP9 is mediated by both the N-terminal domain and the DNA-binding domain. Interaction with EFCAB6/DJBP is mediated by the DNA-binding domain.
Defects in AR may play a role in metastatic prostate cancer. The mutated receptor stimulates prostate growth and metastases development despite of androgen ablation. This treatment can reduce primary and metastatic lesions probably by inducing apoptosis of tumor cells when they express the wild-type receptor.
Expressed in basal and stromal cells of the prostate (at protein level).
In the absence of ligand, steroid hormone receptors are thought to be weakly associated with nuclear components; hormone binding greatly increases receptor affinity. The hormone-receptor complex appears to recognize discrete DNA sequences upstream of transcriptional start sites.
Lacks the C-terminal ligand-binding domain and may therefore constitutively activate the transcription of a specific set of genes independently of steroid hormones.
Mainly expressed in heart and skeletal muscle.
Minor isoform identified in prostate cancer cells.
Minor isoform up-regulated in prostate cancer cells.
Palmitoylated by ZDHHC7 and ZDHHC21. Palmitoylation is required for plasma membrane targeting and for rapid intracellular signaling via ERK and AKT kinases and cAMP generation.
Phosphorylated in prostate cancer cells in response to several growth factors including EGF. Phosphorylation is induced by c-Src kinase (CSK). Tyr-535 is one of the major phosphorylation sites and an increase in phosphorylation and Src kinase activity is associated with prostate cancer progression. Phosphorylation by TNK2 enhances the DNA-binding and transcriptional activity and may be responsible for androgen-independent progression of prostate cancer. Phosphorylation at Ser-83 by CDK9 regulates AR promoter selectivity and cell growth. Phosphorylation by PAK6 leads to AR-mediated transcription inhibition.
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues (PubMed:19022849). Transcription factor activity is modulated by bound coactivator and corepressor proteins like ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024). Transcription activation is also down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.
Sumoylated on Lys-388 (major) and Lys-521. Ubiquitinated. Deubiquitinated by USP26. 'Lys-6' and 'Lys-27'-linked polyubiquitination by RNF6 modulates AR transcriptional activity and specificity.
The disease is caused by variants affecting the gene represented in this entry. Caused by trinucleotide CAG repeat expansion. In SMAX1 patients the number of Gln ranges from 38 to 62. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.
The level of tyrosine phosphorylation may serve as a diagnostic tool to predict patient outcome in response to hormone-ablation therapy. Inhibition of tyrosine phosphorylation may be an effective intervention target for hormone-refractory prostate cancer.
The poly-Gln region of AR is highly polymorphic and the number of Gln varies in the population (from 17 to 26). A smaller size of the poly-Gln region may be associated with the development of prostate cancer. Long poly-Gln alleles (>23) may be associated with higher testosterone levels and severe clinical outcome in COVID-19 disease (PubMed:33647767).
The poly-Gly region of AR is polymorphic and ranges from 24 to 31 Gly. A poly-Gly region shorter or equal to 23 may be associated with the development of androgenetic alopecia.
Transcriptional activity is enhanced by binding to RANBP9.
Expressed in articular chondrocytes but not in knee meniscal cartilage cells (PubMed:12746903). Localizes to the intermediate to deep zone of articular cartilage (PubMed:21880736).
May be cleaved into 2 chains possibly by a furin-like protease upon or preceding secretion.
May play a role in cartilage scaffolding.
ERMAP is responsible for the Scianna/Radin blood group system which comprises seven different antigens (PubMed:12393480). The Sc1 and Sc2 antigens are resulting from a single variation in position 57; Arg-57 corresponds to the Sc2 antigen and Gly-57 to the Sc1 antigen. The Sc2 antigen is rare with an occurrence of less than 1% in the population while Sc1 is more frequent. Sc3 is not expressed by individuals homozygous for a null allele encoding a truncated protein lacking its extracellular part (Sc-3). The Sc4 antigen corresponding to the previously defined Radin blood group antigen (Rd) is due to a single variation in position 60; Ala-60 corresponds to Sc4/Rd(+), the antigenic form of the protein. Sc4 is found in less than 1% of the population. Sc5/STAR, Sc6/SCER and Sc7/SCAN antigens are due to single variations in positions 47, 81 and 35 respectively. Alloantibodies to the low frequency Sc2 and Sc4 antigens are the cause of hemolytic disease in the newborn (PubMed:15660834, PubMed:16371048).
Expressed in erythroid-enriched bone marrow (at protein level). Highly expressed in bone marrow and to a lower extent in leukocytes, thymus, lymph node and spleen.
Expressed in fetal liver blood cells (at protein level). Highly expressed in fetal liver.
Possible role as a cell-adhesion or receptor molecule of erythroid cells.
Highly expressed as a 3.0 kb transcript in brain, ovary, testis, heart, prostate and peripheral Leukocytes. Lower levels in pancreas and small intestine. A 2.3 kb transcript was also found in peripheral Leukocytes. In brain regions, detected as a 3.0 kb transcript in all regions tested. Highest levels in the caudate nucleus, putamen, hippocampus and subthalamic nucleus. Lowest level in the cerebellum.
Orphan receptor. Possible candidate for amine-like G-protein coupled receptor.
Forms either a homodimer or a heterodimer with a related family member (By similarity). Interacts with SIX1 (PubMed:27923061).
Transcription factor that, in osteoblasts, activates the decoy receptor for RANKL, TNFRSF11B, which in turn regulates osteoclast differentiation. Acts in synergy with the Wnt-responsive LEF1/CTNNB1 pathway. Recognizes variations of the palindromic sequence 5'-ATTCCCNNGGGAATT-3' (By similarity).
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 virus protein ORF8.
(Microbial infection) Receptor for SARS coronavirus-2/SARS-CoV-2 virus protein ORF8, leading to IL17 pathway activation and an increased secretion of pro-inflammatory factors through activating NF-kappa-B signaling pathway.
Forms heterodimers with IL17RC; the heterodimer binds IL17A and IL17F homodimers as well as the heterodimer formed by IL17A and IL17F (PubMed:16785495, PubMed:18684971, PubMed:32187518). Forms complexes with 2:1 binding stoichiometry: two receptor chains for one interleukin molecule (PubMed:32187518). IL17A homodimer preferentially drives the formation of IL17RA-IL17RC heterodimeric receptor complex, whereas IL17F homodimer forms predominantly complexes with IL17RC homodimer (PubMed:32187518). IL17A homodimer adopts an asymmetrical ternary structure with one IL17RA molecule, allowing for high affinity interactions of one IL17A monomer with one IL17RA molecule (via D1 and D2 domains), while disfavoring binding of a second IL17RA molecule on the other IL17A monomer (PubMed:23695682). IL17A-IL17F forms complexes with IL17RA-IL17RC, but with lower affinity when compared to IL17A homodimer (PubMed:32187518). IL17RA chain cannot distinguish between IL17A and IL17F molecules, potentially enabling the formation of topologically distinct complexes (PubMed:28827714). Interacts with TRAF3IP2 (PubMed:24120361). Forms heterodimers with IL17RE; the heterodimer binds IL17C (PubMed:21993848, PubMed:16785495, PubMed:18684971).
Receptor for IL17A and IL17F, major effector cytokines of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity. Receptor for IL17A (PubMed:17911633, PubMed:9367539). Receptor for IL17F (PubMed:19838198, PubMed:17911633). Binds to IL17A with higher affinity than to IL17F (PubMed:17911633). Binds IL17A and IL17F homodimers as part of a heterodimeric complex with IL17RC (PubMed:16785495). Also binds heterodimers formed by IL17A and IL17F as part of a heterodimeric complex with IL17RC (PubMed:18684971). Cytokine binding triggers homotypic interaction of IL17RA and IL17RC chains with TRAF3IP2 adapter, leading to TRAF6-mediated activation of NF-kappa-B and MAPkinase pathways, ultimately resulting in transcriptional activation of cytokines, chemokines, antimicrobial peptides and matrix metalloproteinases, with potential strong immune inflammation (PubMed:16785495, PubMed:24120361, PubMed:17911633, PubMed:18684971, PubMed:21350122). Involved in antimicrobial host defense primarily promoting neutrophil activation and recruitment at infection sites to destroy extracellular bacteria and fungi (By similarity). In secondary lymphoid organs, contributes to germinal center formation by regulating the chemotactic response of B cells to CXCL12 and CXCL13, enhancing retention of B cells within the germinal centers, B cell somatic hypermutation rate and selection toward plasma cells (By similarity). Plays a role in the maintenance of the integrity of epithelial barriers during homeostasis and pathogen infection. Stimulates the production of antimicrobial beta-defensins DEFB1, DEFB103A, and DEFB104A by mucosal epithelial cells, limiting the entry of microbes through the epithelial barriers (By similarity). Involved in antiviral host defense through various mechanisms. Enhances immunity against West Nile virus by promoting T cell cytotoxicity. Contributes to Influenza virus clearance by driving the differentiation of B-1a B cells, providing for production of virus-specific IgM antibodies at first line of host defense (By similarity). Receptor for IL17C as part of a heterodimeric complex with IL17RE (PubMed:21993848).
Soluble isoform lacking the transmembrane segment.
Calcium-dependent lectin displaying mannose-binding specificity. Induces the formation of Birbeck granules (BGs); is a potent regulator of membrane superimposition and zippering. Binds to sulfated as well as mannosylated glycans, keratan sulfate (KS) and beta-glucans. Facilitates uptake of antigens and is involved in the routing and/or processing of antigen for presentation to T cells. Major receptor on primary Langerhans cells for Candida species, Saccharomyces species, and Malassezia furfur. Protects against human immunodeficiency virus-1 (HIV-1) infection. Binds to high-mannose structures present on the envelope glycoprotein which is followed by subsequent targeting of the virus to the Birbeck granules leading to its rapid degradation.
Exclusively expressed by Langerhans cells. Expressed in astrocytoma and malignant ependymoma, but not in normal brain tissues.
The C-type lectin domain mediates dual recognition of both sulfated and mannosylated glycans.
Belongs to the peptidase S8 family. Furin subfamily.
Serine endopeptidase which is involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. Responsible for the release of glucagon from proglucagon in pancreatic A cells.
Interacts with PIK3R/p85, SHP2 and GRAP2/MONA (By similarity). May interact with Grb2.
Phosphorylated on tyrosine residue(s) after macrophage colony-stimulating factor (M-CSF) receptor stimulation.
Expressed in brain, especially in striatum.
Gs-coupled receptor activated by antipsychotics reserpine leading to an increase in intracellular cAMP and its internalization (PubMed:24587241). May play a role in locomotor activity through modulation of dopamine, NMDA and ADORA2A-induced locomotor activity. These behavioral changes are accompanied by modulation of the dopamine receptor signaling pathway in striatum (PubMed:24587241). Modulates HTT level via cAMP-dependent but PKA independent mechanisms throught activation of RAB39B that translocates HTT to the endoplasmic reticulum, thus avoiding proteasome degradation (PubMed:25738228).
Expressed in some signet-ring cell carcinoma, especially those showing high invasion and metastatic activity (at protein level).
Belongs to the enoyl-CoA hydratase/isomerase family.
Highly expressed in liver and kidney, also detected in heart, muscle and brain (at protein level). Not detected in lung.
Hydrolyzes 3-hydroxyisobutyryl-CoA (HIBYL-CoA), a saline catabolite. Has high activity toward isobutyryl-CoA. Could be an isobutyryl-CoA dehydrogenase that functions in valine catabolism. Also hydrolyzes 3-hydroxypropanoyl-CoA.
Acts as a transcriptional transactivator of TCEA1 elongation activity (By similarity). Acts as a transcriptional transactivator of ELL and ELL2 elongation activities. Potent inducer of apoptosis in prostatic and non-prostatic cell lines. Inhibits prostate tumor growth in vivo.
Expressed in heart, brain, placenta, lung, skeletal muscle, kidney, pancreas, spleen, prostate, testis, small intestine, colon, adrenal, bone marrow, lymph node, spinal gland, stomach, thyroid, trachea, thymus, liver and leukocytes.
Isoform 1 and isoform 2 interact with TCEA1 (By similarity). Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3). Interacts with ELL and ELL2.
Can bind about 5 Ca(2+) ions per subunit.
May play an important role in the progression of epithelial malignancies.
Specifically expressed in stromal cells of breast carcinomas.
The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.
May function as a growth factor receptor.
Placenta, pancreatic carcinoma cell lines.
Highly expressed in skeletal muscle. Expressed in heart, fibroblast, placenta and liver. Weakly expressed in brain and lung. Expressed in the cortex of the kidney (highly expressed in tubular epithelial cells but low expression in the glomerulus).
Homodimer (PubMed:24244371). Interacts with PER2; the interaction inhibits termination of circadian target genes (By similarity). Interacts with CHD4, POLR2A, PRKDC and TRIM28 (PubMed:23149945). Does not interact with C14orf178 (PubMed:24244371). Interacts with UBE2I (PubMed:24105744). Interacts (via N-terminus domain) with EXOSC9 (via C-terminus region); the interaction enhances SETX sumoylation (PubMed:24105744). Interacts with NCL (via N-terminus domain) (PubMed:19515850). Interacts with PABPN1, PABPC1 and SF3B1 (PubMed:19515850). Interacts with SMN1/SMN2 and POLR2A; SMN1/SMN2 recruits SETX to POLR2A (PubMed:19515850, PubMed:26700805).
Probable RNA/DNA helicase involved in diverse aspects of RNA metabolism and genomic integrity. Plays a role in transcription regulation by its ability to modulate RNA Polymerase II (Pol II) binding to chromatin and through its interaction with proteins involved in transcription (PubMed:19515850, PubMed:21700224). Contributes to the mRNA splicing efficiency and splice site selection (PubMed:19515850). Required for the resolution of R-loop RNA-DNA hybrid formation at G-rich pause sites located downstream of the poly(A) site, allowing XRN2 recruitment and XRN2-mediated degradation of the downstream cleaved RNA and hence efficient RNA polymerase II (RNAp II) transcription termination (PubMed:19515850, PubMed:21700224, PubMed:26700805). Required for the 3' transcriptional termination of PER1 and CRY2, thus playing an important role in the circadian rhythm regulation (By similarity). Involved in DNA double-strand breaks damage response generated by oxidative stress (PubMed:17562789). In association with RRP45, targets the RNA exosome complex to sites of transcription-induced DNA damage (PubMed:24105744). Plays a role in the development and maturation of germ cells: essential for male meiosis, acting at the interface of transcription and meiotic recombination, and in the process of gene silencing during meiotic sex chromosome inactivation (MSCI) (By similarity). May be involved in telomeric stability through the regulation of telomere repeat-containing RNA (TERRA) transcription (PubMed:21112256). Plays a role in neurite outgrowth in hippocampal cells through FGF8-activated signaling pathways. Inhibits retinoic acid-induced apoptosis (PubMed:21576111).
Sumoylated preferentially with SUMO2 or SUMO3 (PubMed:24105744, PubMed:24244371).
The N-terminus domain is necessary for S/G2 nuclear foci localization (PubMed:23149945).
Belongs to the polypeptide deformylase family.
Removes the formyl group from the N-terminal Met of newly synthesized proteins.
Required for the activation of AURKA at the onset of mitosis.
Expressed in the interterritorial matrix of articular deep zone cartilage (at protein level). Isoform 1 and isoform 2 are expressed in brain. Isoform 1 is detected in lung and chondrocytes. Detected in cartilage, bone, cultured chondrocytes and lung, and at low levels in heart. Not detected in osteoblasts.
Shares an exon with the neighboring tail-to-tail oriented gene GOLGA7B.
Up-regulated by BMP4 (at protein level). Up-regulated in mesenchymal stem cells undergoing chondrogenic differentiation and by BMP4.
May associate with the nuclear pore complex.
Auto-ubiquitinated. Poly-ubiquitinated in cultured cells, whereas it is monoubiquitinated in vitro.
Brain. Highly expressed in the cerebral cortex (at protein level). Severely decreased in the affected brain areas in Parkinson disease and dementia with Lewy bodies.
E3 ubiquitin-protein ligase which ubiquitinates itself in cooperation with an E2 enzyme UBE2D2/UBC4 and serves as a targeting signal for proteasomal degradation. May play a role in regulation of neuronal functions and may also participate in the formation or breakdown of abnormal inclusions in neurodegenerative disorders. May act as a regulator of synaptic vesicle exocytosis by controlling the availability of SNAP25 for the SNARE complex formation.
May be due to a competing donor splice site, to exon inclusion and to intron retention.
The coiled coil domain mediates the interaction with the N-terminal t-SNARE domain of SNAP25.
Component of pre-catalytic, catalytic and post-catalytic spliceosomes (PubMed:10197984, PubMed:28502770, PubMed:30705154). Associates with the spliceosome prior to recognition of the 3'-splice site for step II, probably during catalysis of step I (PubMed:10197984).
Required for pre-mRNA splicing as component of the spliceosome (PubMed:10197984, PubMed:28502770, PubMed:30705154). Participates in the second catalytic step of pre-mRNA splicing, when the free hydroxyl group of exon I attacks the 3'-splice site to generate spliced mRNA and the excised lariat intron. Required for holding exon 1 properly in the spliceosome and for correct AG identification when more than one possible AG exists in 3'-splicing site region. May be involved in the activation of proximal AG. Probably also involved in alternative splicing regulation.
The CCHC-type zinc finger is required to retain the protein within the nucleus and prevent its shuttle back to the cytoplasm via the CRM1 pathway.
Although homologous to serine proteases, it has lost all essential catalytic residues and has no enzymatic activity.
As a result of hemolysis, hemoglobin is found to accumulate in the kidney and is secreted in the urine. Haptoglobin captures, and combines with free plasma hemoglobin to allow hepatic recycling of heme iron and to prevent kidney damage. Haptoglobin also acts as an antioxidant, has antibacterial activity and plays a role in modulating many aspects of the acute phase response. Hemoglobin/haptoglobin complexes are rapidly cleared by the macrophage CD163 scavenger receptor expressed on the surface of liver Kupfer cells through an endocytic lysosomal degradation pathway.
As a result of hemolysis, hemoglobin is found to accumulate in the kidney and is secreted in the urine. Haptoglobin captures, and combines with free plasma hemoglobin to allow hepatic recycling of heme iron and to prevent kidney damage. Haptoglobin also acts as an antioxidant, has antibacterial activity, and plays a role in modulating many aspects of the acute phase response. Hemoglobin/haptoglobin complexes are rapidly cleared by the macrophage CD163 scavenger receptor expressed on the surface of liver Kupfer cells through an endocytic lysosomal degradation pathway.
Expressed by the liver and secreted in plasma.
In human populations there are two major allelic forms, alpha-1 (1-1) with 83 residues and alpha-2 (2-2) with 142 residues. These alleles determine 3 possible genotypes, homozygous (1-1 or 2-2) and heterozygous (2-1), and 3 major phenotypes HP*1F/HP*1S and HP*2FS. The two main alleles of HP*1 are called HP*1F (fast) and HP*1S (slow). The alleles exhibit different oligomerization properties. In healthy males, but not in females, the Hp 2-2 phenotype is associated with higher serum iron, decreased antimicrobial and antioxidant capability, and less efficient clearance from the circulation, than Hp 1-1 and 2-1. The sequence displayed in this entry corresponds to allele alpha-2 (2-2).
Tetramer of two alpha and two beta chains; disulfide-linked (By similarity). The hemoglobin/haptoglobin complex is composed of a haptoglobin dimer bound to two hemoglobin alpha-beta dimers (By similarity). Interacts with CD163 (By similarity). Interacts with ERGIC3.
Tetramer of two alpha and two beta chains; disulfide-linked (PubMed:6997877, PubMed:4573324). The hemoglobin/haptoglobin complex is composed of a haptoglobin dimer bound to two hemoglobin alpha-beta dimers (By similarity). Interacts with CD163 (By similarity). Interacts with ERGIC3 (PubMed:31142615).
The uncleaved form of allele alpha-2 (2-2), known as zonulin, plays a role in intestinal permeability, allowing intercellular tight junction disassembly, and controlling the equilibrium between tolerance and immunity to non-self antigens.
Interacts with WT1. Interacts with DEPDC1A.
May be involved in transcriptional regulation as a transcriptional repressor. The DEPDC1A-ZNF224 complex may play a critical role in bladder carcinogenesis by repressing the transcription of the A20 gene, leading to transport of NF-KB protein into the nucleus, resulting in suppression of apoptosis of bladder cancer cells.
Ubiquitous. Mainly expressed in fetal tissues.
Homodimer (PubMed:32169171). Interacts with LONP2 (PubMed:18281296).
Involved in the initial and rate-limiting step of peroxisomal beta-oxidation of straight-chain saturated and unsaturated very-long-chain fatty acids (PubMed:7876265, PubMed:15060085, PubMed:17458872, PubMed:17603022, PubMed:32169171, PubMed:33234382). Catalyzes the desaturation of fatty acyl-CoAs such as palmitoyl-CoA (hexadecanoyl-CoA) to 2-trans-enoyl-CoAs ((2E)-enoyl-CoAs) such as (2E)-hexadecenoyl-CoA, and donates electrons directly to molecular oxygen (O(2)), thereby producing hydrogen peroxide (H(2)O(2)) (PubMed:7876265, PubMed:17458872, PubMed:17603022).
Is active against a much broader range of substrates and shows activity towards long-chain fatty acyl-CoAs.
Isoform 1 and isoform 2 can reverse the Acox1 null phenotype in mouse which is characterized by severe microvesicular hepatic steatosis, sustained activation of PPARA, spontaneous massive peroxisome proliferation and eventual development of hepatocellular carcinomas. Isoform 2 is more effective in reversal of the phenotype than isoform 1 (PubMed:20195242).
Shows highest activity against medium-chain fatty acyl-CoAs. Shows optimum activity with a chain length of 10 carbons (decanoyl-CoA) in vitro.
Widely expressed with highest levels of isoform 1 and isoform 2 detected in testis. Isoform 1 is expressed at higher levels than isoform 2 in liver and kidney while isoform 2 levels are higher in brain, lung, muscle, white adipose tissue and testis. Levels are almost equal in heart.
May be involved in MAP kinase activation, epithelial sodium channel (ENaC) down-regulation and cell cycling.
Belongs to the tetraspanin (TM4SF) family.
Expansion of a polymorphic CGG repeat within the 5'-UTR of FRA10AC1 results in expression of the folate-sensitive fragile site FRA10A. The number of the CGG repeats normally varies in the population from 8 to 14. In contrast, individuals cytogenetically expressing the fragile site have at least 200 CGG repeats (PubMed:15203205). No distinct phenotype has been associated with expression of FRA10A. Nevertheless, some studies have proposed that this fragile site expression might be associated with intellectual disability, tumorigenesis, or neurological disorders. However, these associations can be attributed to ascertainment bias.
Ubiquitously expressed with higher expression in brain, heart, skeletal muscle, kidney and liver.
Electrogenic proton-coupled amino-acid transporter that transports oligopeptides of 2 to 4 amino acids with a preference for dipeptides. Transports neutral and monovalently charged peptides with a proton to peptide stoichiometry of 1:1 or 2:1 (PubMed:7896779, PubMed:9835627, PubMed:8914574, PubMed:15521010, PubMed:18367661, PubMed:19685173, PubMed:26320580) (By similarity). Primarily responsible for the absorption of dietary di- and tripeptides from the small intestinal lumen (By similarity). Mediates transepithelial transport of muramyl and N-formylated bacterial dipeptides contributing to recognition of pathogenic bacteria by the mucosal immune system (PubMed:9835627, PubMed:15521010).
Interacts (via extracellular domain region) with trypsin.
The extracellular domain (ECD) region specifically binds trypsin.
Adipocyte-secreted protein (adipokine) that regulates adipogenesis, metabolism and inflammation through activation of the chemokine-like receptor 1 (CMKLR1). Acts also as a ligand for CMKLR2. Can also bind to C-C chemokine receptor-like 2 (CCRL2), but with a lower affinity than it does to CMKLR1 or CMKLR2 (PubMed:27716822). Positively regulates adipocyte differentiation, modulates the expression of adipocyte genes involved in lipid and glucose metabolism and might play a role in angiogenesis, a process essential for the expansion of white adipose tissue. Also acts as a pro-inflammatory adipokine, causing an increase in secretion of pro-inflammatory and prodiabetic adipokines, which further impair adipose tissue metabolic function and have negative systemic effects including impaired insulin sensitivity, altered glucose and lipid metabolism, and a decrease in vascular function in other tissues. Can have both pro- and anti-inflammatory properties depending on the modality of enzymatic cleavage by different classes of proteases. Acts as a chemotactic factor for leukocyte populations expressing CMKLR1, particularly immature plasmacytoid dendritic cells, but also immature myeloid DCs, macrophages and natural killer cells. Exerts an anti-inflammatory role by preventing TNF/TNFA-induced VCAM1 expression and monocytes adhesion in vascular endothelial cells. The effect is mediated via inhibiting activation of NF-kappa-B and CRK/p38 through stimulation of AKT1/NOS3 signaling and nitric oxide production. Its dual role in inflammation and metabolism might provide a link between chronic inflammation and obesity, as well as obesity-related disorders such as type 2 diabetes and cardiovascular disease. Exhibits an antimicrobial function in the skin.
Expressed at the highest levels in placenta, liver, and white adipose tissue (WAT), and to a lesser extent in many other tissues such as lung, brown adipose tissue, heart, ovary, kidney, skeletal muscle and pancreas. Within WAT, expression is enriched in adipocytes as compared to the stromal vascular fraction. Expression and secretion increases dramatically with adipogenesis. Highly expressed in skin (basal and suprabasal layers of the epidermis, hair follicles and endothelial cells). Expression is elevated in numerous metabolic and inflammatory diseases including psoriasis, obesity, type 2 diabetes, metabolic syndrome and cardiovascular disease.
Inhibited in psoriatic lesions. Activated by tazarotene in skin rafts and in the epidermis of psoriatic lesions.
Secreted in an inactive precursor form, prochemerin, which is proteolytically processed by a variety of extracellular proteases to generate forms with differing levels of bioactivity. For example, the removal of six amino acids results in chemerin-157, which exhibits the highest activity, while removal of seven amino acids results in chemerin-156 which has slightly less activity. Some proteases are able to cleave at more than one site and chemerin forms may be sequentially processed by different enzymes to modulate activity levels. The coordinated expression and activity of chemerin-modifying enzymes is essential for regulating its bioactivation, inactivation and, consequently, biological function. Cathepsin G cleaves seven C-terminal amino acids from prochemerin (chemerin-156), elastase is able to cleave six (chemerin-157), eight (chemerin-155) or eleven (chemerin-152), plasmin cleaves five amino acids (chemerin-158), and tryptase cleaves five (chemerin-158) or eight (chemerin-155). Multiple cleavages might be required to fully activate chemerin, with an initial tryptase cleavage resulting in chemerin with low activity (chemerin-158), and a second cleavage by carboxypeptidase N or B producing highly active chemerin (chemerin-157).
Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits (PubMed:10637334, PubMed:16778766, PubMed:19558367, PubMed:22977175). In the complex, interacts directly with CNOT6, CNOT6L, CNOT7 or CNOT8 (PubMed:10637334, PubMed:16778766, PubMed:22977175). Interacts in a ligand-dependent fashion with ESR1 and RXRA (PubMed:16778766). Interacts with NANOS2, TOB1 and ZFP36 (PubMed:18377426, PubMed:21278420, PubMed:23644599). Interacts with TNRC6A, TNRC6B or TNRC6C; the interactions are direct (PubMed:21981923, PubMed:21984185). Interacts with YTHDF2; the interaction is direct and promotes recruitment of the CCR4-NOT complex to N6-methyladenosine (m6A)-containing mRNAs, leading to their deadenylation and subsequent degradation (PubMed:27558897). Interacts with EIF4ENIF1/4E-T (PubMed:26027925, PubMed:27342281, PubMed:32354837, PubMed:26489469).
Contains Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs, a motif known to be important for the association with nuclear receptors.
Scaffolding component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Its scaffolding function implies its interaction with the catalytic complex module and diverse RNA-binding proteins mediating the complex recruitment to selected mRNA 3'UTRs. Involved in degradation of AU-rich element (ARE)-containing mRNAs probably via association with ZFP36. Mediates the recruitment of the CCR4-NOT complex to miRNA targets and to the RISC complex via association with TNRC6A, TNRC6B or TNRC6C. Acts as a transcriptional repressor. Represses the ligand-dependent transcriptional activation by nuclear receptors. Involved in the maintenance of embryonic stem (ES) cell identity.
Strongly expressed in brain, heart, thymus, spleen, kidney, liver, placenta and lung. Weakly expressed in skeletal muscle and colon.
Expressed in various tissues except brain. Expression is more intense in liver, kidney, peripheral leukocyte, lung, and spleen than in other tissues. Highly expressed in eosinophils, neutrophils, and lung macrophages.
Receptor for eicosanoids and polyunsaturated fatty acids such as 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-OXO-ETE), 5(S)-hydroperoxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5(S)-HPETE) and arachidonic acid. Seems to be coupled to the G(i)/G(o), families of heteromeric G proteins.
Adapter protein in a cytoplasmic complex linking beta-integrins to the actin cytoskeleton, bridges the complex to cell surface receptor tyrosine kinases and growth factor receptors. Involved in the regulation of cell survival, cell proliferation and cell differentiation.
Expressed in most tissues except in the brain.
Interacts (via LIM zinc-binding 5) with TGFB1I1 (By similarity). Interacts with integrin-linked protein kinase 1 (ILK) via the first LIM domain, and in competition with LIMS2. Part of the heterotrimeric IPP complex composed of integrin-linked kinase (ILK), LIMS1 or LIMS2, and PARVA. Interacts with SH3/SH2 adapter NCK2, thereby linking the complex to cell surface receptors.
Binds polysaccharides in a Ca(2+)-independent manner with a preferentially binding to fucoidan, beta-glucans and galactans (PubMed:26170455).
Dectected in all cell lines tested and in peripheral blood cells.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Trm1 family.
Dimethylates a single guanine residue at position 26 of most tRNAs using S-adenosyl-L-methionine as donor of the methyl groups.
Expressed in spermatids (PubMed:23436708). Detected in liver cancer (at protein level) (PubMed:23436708).
Probable regulator of microtubule dynamics required for sperm motility (Probable). In contrast to other members of the family, has no microtubule bundling activity (PubMed:17105200).
In the C-terminal section; belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family.
In the N-terminal section; belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family.
Interacts (via C-terminus) with ESPN. Interacts (via C-terminus) with ESPNL.
Probable actin-based motor with a protein kinase activity. Required for normal cochlear hair bundle development and hearing. Plays an important role in the early steps of cochlear hair bundle morphogenesis. Influences the number and lengths of stereocilia to be produced and limits the growth of microvilli within the forming auditory hair bundles thereby contributing to the architecture of the hair bundle, including its staircase pattern. Involved in the elongation of actin in stereocilia tips by transporting the actin regulatory factor ESPN to the plus ends of actin filaments.
Could act as a modulator of transcription.
Testis-specific. Expressed in a melanoma cell line.
As part of a multisubunit complex composed of elongin BC complex (ELOB and ELOC), elongin A/ELOA, RBX1 and CUL5; polyubiquitinates monoubiquitinated POLR2A.
Heterotrimer of an A (ELOA, ELOA2 or ELOA3P), ELOB and ELOC subunit (By similarity). Part of a multisubunit ubiquitin ligase complex consisting of elongin BC complex (ELOB and ELOC), elongin A/ELOA, RBX1 and CUL5 (PubMed:19920177). Interacts with ERCC6; the interaction is induced by DNA damaging agents or inhibitors of RNA polymerase II elongation (By similarity). Interacts (via BC-box) with CUL5 (By similarity).
It is uncertain whether Met-1 or Met-27 is the initiator.
SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex).
The BC-box, which mediates binding to the elongin BC complex, has the consensus sequence [APST]-L-x(3)-C-x(3)-[AILV].
Belongs to the glycosyltransferase group 1 family.
Interacts with RAC1 (PubMed:1644792). Forms a complex composed of at least WDR26, a G-beta:gamma unit, and PLCB2 (PubMed:23625927).
The receptor-mediated activation of PLC-beta-2 is most effectively mediated by one G-protein alpha subunit, alpha-16.
Acetylated in the C-terminus. Acetylation decreases interaction with NUDT21 and KPNB1, and inhibits nuclear localization through inhibiting binding to the importin alpha/beta complex (By similarity).
Belongs to the poly(A) polymerase family.
Binds 2 magnesium ions. Also active with manganese.
Hyperphosphorylation on multiple CDK2 consensus and non-consensus sites in the C-terminal Ser/Thr-rich region represses PAP activity in late M-phase. Phosphorylation/dephosphorylation may regulate the interaction between PAP and CPSF (By similarity).
Monomer. Found in a complex with CPSF1, FIP1L1 and PAPOLA. Interacts with AHCYL1 and FIP1L1; the interaction with AHCYL1 seems to increase interaction with FIP1L1 (PubMed:19224921). Interacts with NUDT21; the interaction is diminished by acetylation. Interacts with KPNB1; the interaction promotes PAP nuclear import and is inhibited by acetylation of PAP (By similarity).
Polymerase that creates the 3'-poly(A) tail of mRNA's. Also required for the endoribonucleolytic cleavage reaction at some polyadenylation sites. May acquire specificity through interaction with a cleavage and polyadenylation specificity factor (CPSF) at its C-terminus.
Polysumoylated. Varying sumoylation depending on tissue- and cell-type. Highly sumoylated in bladder and NIH 3T3 cells. Sumoylation is required for nuclear localization and enhances PAP stability. Desumoylated by SENP1. Inhibits polymerase activity (By similarity).
(Microbial infection) Interacts with HIV-2 Capsid protein p24; interacts with high affinity (PubMed:30270045). Interacts with HIV-1 Capsid protein p24; interacts with low affinity (PubMed:30270045).
A chromosomal aberration involving NONO may be a cause of papillary renal cell carcinoma (PRCC). Translocation t(X;X)(p11.2;q13.1) with TFE3.
DNA- and RNA binding protein, involved in several nuclear processes (PubMed:11525732, PubMed:12403470, PubMed:26571461). Binds the conventional octamer sequence in double-stranded DNA (PubMed:11525732, PubMed:12403470, PubMed:26571461). Also binds single-stranded DNA and RNA at a site independent of the duplex site (PubMed:11525732, PubMed:12403470, PubMed:26571461). Involved in pre-mRNA splicing, probably as a heterodimer with SFPQ (PubMed:11525732, PubMed:12403470, PubMed:26571461). Interacts with U5 snRNA, probably by binding to a purine-rich sequence located on the 3' side of U5 snRNA stem 1b (PubMed:12403470). Together with PSPC1, required for the formation of nuclear paraspeckles (PubMed:22416126). The SFPQ-NONO heteromer associated with MATR3 may play a role in nuclear retention of defective RNAs (PubMed:11525732). The SFPQ-NONO heteromer may be involved in DNA unwinding by modulating the function of topoisomerase I/TOP1 (PubMed:10858305). The SFPQ-NONO heteromer may be involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination and may stabilize paired DNA ends (PubMed:15590677). In vitro, the complex strongly stimulates DNA end joining, binds directly to the DNA substrates and cooperates with the Ku70/G22P1-Ku80/XRCC5 (Ku) dimer to establish a functional preligation complex (PubMed:15590677). NONO is involved in transcriptional regulation. The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional activity (PubMed:11897684). NONO binds to an enhancer element in long terminal repeats of endogenous intracisternal A particles (IAPs) and activates transcription (By similarity). Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer (By similarity). Important for the functional organization of GABAergic synapses (By similarity). Plays a specific and important role in the regulation of synaptic RNAs and GPHN/gephyrin scaffold structure, through the regulation of GABRA2 transcript (By similarity). Plays a key role during neuronal differentiation by recruiting TET1 to genomic loci and thereby regulating 5-hydroxymethylcytosine levels (By similarity). Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728, PubMed:30270045). Promotes activation of the cGAS-STING pathway in response to HIV-2 infection: acts by interacting with HIV-2 Capsid protein p24, thereby promoting detection of viral DNA by CGAS, leading to CGAS-mediated inmmune activation (PubMed:30270045). In contrast, the weak interaction with HIV-1 Capsid protein p24 does not allow activation of the cGAS-STING pathway (PubMed:30270045).
Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Also found in a number of breast tumor cell lines.
Monomer and component of the SFPQ-NONO complex, which is probably a heterotetramer of two 52 kDa (NONO) and two 100 kDa (SFPQ) subunits (PubMed:8439294, PubMed:15590677). NONO is a component of spliceosome and U5.4/6 snRNP complexes (PubMed:12403470). Interacts with CPNE4 (via VWFA domain) (By similarity). Forms heterodimers with PSPC1; this involves formation of a coiled coil domain by helices from both proteins (PubMed:16148043, PubMed:22416126). Part of complex consisting of SFPQ, NONO and MATR3 (PubMed:11525732). Part of a complex consisting of SFPQ, NONO and NR5A1 (PubMed:11897684). Part of a complex consisting of SFPQ, NONO and TOP1 (PubMed:9756848). Interacts with SPI1 and SPIB (By similarity). Interacts with RNF43 (PubMed:18655028). Interacts with PER1 and PER2 (By similarity). Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA (PubMed:28712728). Interacts (via second RRM domain) with WASL; the interaction is direct (PubMed:16767080). Component of a multiprotein complex with WASL and SFPQ (PubMed:16767080). Interacts with ERCC6 (PubMed:26030138). Interacts (via DNA-binding domain) with TET1 (By similarity).
Acts as decoy receptor for TNFSF11/RANKL and thereby neutralizes its function in osteoclastogenesis. Inhibits the activation of osteoclasts and promotes osteoclast apoptosis in vitro. Bone homeostasis seems to depend on the local ratio between TNFSF11 and TNFRSF11B. May also play a role in preventing arterial calcification. May act as decoy receptor for TNFSF10/TRAIL and protect against apoptosis. TNFSF10/TRAIL binding blocks the inhibition of osteoclastogenesis.
Highly expressed in adult lung, heart, kidney, liver, spleen, thymus, prostate, ovary, small intestine, thyroid, lymph node, trachea, adrenal gland, testis, and bone marrow. Detected at very low levels in brain, placenta and skeletal muscle. Highly expressed in fetal kidney, liver and lung.
Homodimer. Interacts with TNFSF10 and TNFSF11.
N-glycosylated. Contains sialic acid residues.
Up-regulated by increasing calcium-concentration in the medium and estrogens. Down-regulated by glucocorticoids.
Belongs to the thiolase-like superfamily. Thiolase family.
Contains a putative mitochondrial transit peptide at positions 1-20.
Expression at protein level is almost abolished in Zellweger syndrome. Cholesterol transfer from the endoplasmic reticulum to the plasma membrane was reduced in patient fibroblasts compared to controls.
In the N-terminal section; belongs to the thiolase-like superfamily. Thiolase family.
Interacts with PEX5; the interaction is essential for peroxisomal import.
Mediates the transfer of all common phospholipids, cholesterol and gangliosides from the endoplasmic reticulum to the plasma membrane. May play a role in regulating steroidogenesis (PubMed:17157249, PubMed:8300590, PubMed:7642518). Stimulates the microsomal conversion of 7-dehydrocholesterol to cholesterol (By similarity). Also binds fatty acids and fatty acyl Coenzyme A (CoA) such as phytanoyl-CoA. Involved in the regulation phospholipid synthesis in endoplasmic reticulum enhancing the incorporation of exogenous fatty acid into glycerides. Seems to stimulate the rate-limiting step in phosphatidic acid formation mediated by GPAT3. Isoforms SCP2 and SCPx cooperate in peroxisomal oxidation of certain naturally occurring tetramethyl-branched fatty acyl-CoAs (By similarity).
Plays a crucial role in the peroxisomal oxidation of branched-chain fatty acids (PubMed:10706581). Catalyzes the last step of the peroxisomal beta-oxidation of branched chain fatty acids and the side chain of the bile acid intermediates di- and trihydroxycoprostanic acids (DHCA and THCA) (PubMed:10706581). Also active with medium and long straight chain 3-oxoacyl-CoAs. Stimulates the microsomal conversion of 7-dehydrocholesterol to cholesterol and transfers phosphatidylcholine and 7-dehydrocholesterol between membrances, in vitro (By similarity). Isoforms SCP2 and SCPx cooperate in peroxisomal oxidation of certain naturally occurring tetramethyl-branched fatty acyl-CoAs (By similarity).
preSCP2, a protein with a molecular mass of about 15 kDa, is processed into its mature form (SCP2) by proteolytic cleavage of a 20 residue leader sequence after translocation into peroxisomes.
According to a report, can also be a component of ESCRT-I complexes containing VPS37B, VPS37C or VPS37D (PubMed:22405001). However, another publication showed that UBAP1 has specificity for complexes containing VPS37A and not VPS37 paralogs (PubMed:24284069).
Component of an ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, VPS37A and UBAP1 in a 1:1:1:1 stoichiometry (PubMed:21757351, PubMed:24284069, PubMed:22405001, PubMed:31203368) (Probable). Interacts with PTPN23 (PubMed:21757351, PubMed:27839950). Interacts (via UBA domains) with ubiquitinated proteins (PubMed:22405001, PubMed:30929741).
Component of the ESCRT-I complex, a regulator of vesicular trafficking process (PubMed:21757351, PubMed:22405001, PubMed:31203368). Binds to ubiquitinated cargo proteins and is required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies (MVBs) (PubMed:21757351, PubMed:22405001). Plays a role in the proteasomal degradation of ubiquitinated cell-surface proteins, such as EGFR and BST2 (PubMed:24284069, PubMed:22405001, PubMed:31203368).
The UMA domain mediates association with the ESCRT-I complex.
Ubiquitous. Highly expressed in heart, brain, placenta, lung, liver, skeletal muscle and pancreas.
Deubiquitinating enzyme that regulates the degradation of various proteins. Deubiquitinates and prevents proteasomal degradation of RNF123 which in turn stimulates CDKN1B ubiquitin-dependent degradation thereby playing a role in cell proliferation. Involved in decreased protein synthesis in atrophying skeletal muscle. Modulates transcription of major myofibrillar proteins. Also involved in turnover of endoplasmic-reticulum-associated degradation (ERAD) substrates. Regulates the stability of BIRC2/c-IAP1 and BIRC3/c-IAP2 by preventing their ubiquitination. Required for cells to mount an appropriate response to hypoxia and rescues HIF1A from degradation in a non-catalytic manner. Plays an important role in 17 beta-estradiol (E2)-inhibited myogenesis. Decreases the levels of ubiquitinated proteins during skeletal muscle formation and acts to repress myogenesis. Exhibits a preference towards 'Lys-63'-linked ubiquitin chains.
Interacts with RNF123 (By similarity). Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with HIF1A (via N-terminus).
Homodimer. Interacts with myosin (By similarity).
Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Activated by dopamine, but also by epinephrine and norepinephrine, and by numerous synthetic agonists and drugs (PubMed:9003072, PubMed:16423344, PubMed:27659709, PubMed:29051383). Agonist binding triggers signaling via G proteins that inhibit adenylyl cyclase (PubMed:7512953, PubMed:7643093, PubMed:16423344, PubMed:27659709, PubMed:29051383). Modulates the circadian rhythm of contrast sensitivity by regulating the rhythmic expression of NPAS2 in the retinal ganglion cells (By similarity).
Forms homo- and heterooligomers with DRD2. D4.7 allele exhibits higher affinity for homodimers compared to DRD2 heterodimers, while alleles D42. and 4.4 have similar affinities for both. The interaction with DRD2 may modulate agonist-induced downstream signaling (PubMed:21184734). Interacts with CLIC6 (By similarity). Interacts with GPRASP1 (PubMed:12142540). May interact with ADORA2A (PubMed:20836733). Interacts with KLHL12 (PubMed:18303015).
Highly expressed in retina. Detected at much lower levels in brain, in amygdala, thalamus, hypothalamus, cerebellum and pituitary.
Palmitoylated. Palmitoylation of the C-terminal Cys is important for normal expression at the cell membrane.
Polyubiquitinated by the BCR(KLHL12) E3 ubiquitin ligase complex: polyubiquitination does not lead to degradation of DRD4 protein.
Signaling in response to agonists such as dopamine, epinephrine and norepinephrine is modulated by Na(+); lower Na(+) levels result in higher receptor activity (in vitro).
The number of repeats of 16 amino acids in the third cytoplasmic loop is highly polymorphic and varies among different alleles. Alleles corresponding in size to a 2 (D4.2), 3 (D4.3), 4 (D4.4), 5 (D4.5), 6 (D4.6), 7 (D4.7) and 9 (D4.9) repeats have been described. The sequence shown is that of allele D4.4. The polymorphic repeat sequence has little influence on DRD4-binding profiles and might not be essential for G protein interaction.
Belongs to the universal ribosomal protein uS15 family.
Component of the small ribosomal subunit. Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797).
Component of the small ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Ubiquitinated at Lys-27 by RNF14 and RNF25 in response to ribosome collisions (ribosome stalling).
Belongs to the metallo-dependent hydrolases superfamily. NagA family.
Binds 1 divalent metal cation per subunit.
Hydrolyzes the N-glycolyl group from N-glycolylglucosamine 6-phosphate (GlcNGc-6-P) in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway. Although human is not able to catalyze formation of Neu5Gc due to the inactive CMAHP enzyme, Neu5Gc is present in food and must be degraded.
Component of the nexin-dynein regulatory complex (N-DRC) (By similarity). Interacts (via IQ domain) with CALM when calcium levels are low. Does not interact with CALM in the presence of Ca(2+). Interacts with the HSP70 proteins HSPA1L and HSPA8 (PubMed:24787902). May form a complex with CAMK4 and HSP70 (By similarity).
Component of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes. Binds calmodulin when cellular Ca(2+) levels are low and thereby contributes to the regulation of calcium and calmodulin-dependent protein kinase IV (CAMK4) activity; contributes to the regulation of CAMK4 signaling cascades. Required for normal axoneme assembly in sperm flagella, normal sperm tail formation and for male fertility.
The IQ domain mediates interaction with calmodulin when cellular Ca(2+) levels are low.
Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9, FANCM, FAAP24 and FAAP100. Forms a subcomplex with FANCB and FANCL.
Plays a role in Fanconi anemia-associated DNA damage response network. Regulates FANCD2 monoubiquitination and the stability of the FA core complex. Induces chromosomal instability as well as hypersensitivity to DNA cross-linking agents, when repressed.
Expressed in the ventral part of the optic vesicles at 7 week dpc.
Transcription factor that may function in dorsoventral specification of the forebrain. Regulates the expression of Wnt signaling antagonists including the expression of a truncated TCF7L2 isoform that cannot bind CTNNB1 and acts therefore as a potent dominant-negative Wnt antagonist. Plays a crucial role in eye development and, in particular, in the specification of the ventral optic vesicle (By similarity). May be a regulator of axial polarization in the retina.
(Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes. Association with CLDN1 and the CLDN1-CD81 receptor complex is essential for HCV entry into host cell.
(Microbial infection) Involved in SAMHD1-dependent restriction of HIV-1 replication. May support early replication of both R5- and X4-tropic HIV-1 viruses in T cells, likely via proteasome-dependent degradation of SAMHD1.
(Microbial infection) Plays a critical role in HCV attachment and/or cell entry by interacting with HCV E1/E2 glycoproteins heterodimer.
(Microbial infection) Specifically required for Plasmodium falciparum infectivity of hepatocytes, controlling sporozoite entry into hepatocytes via the parasitophorous vacuole and subsequent parasite differentiation to exoerythrocytic forms.
Binds cholesterol in a cavity lined by the transmembrane spans.
Expressed on B cells (at protein level) (PubMed:20237408). Expressed in hepatocytes (at protein level) (PubMed:12483205). Expressed in monocytes/macrophages (at protein level) (PubMed:12796480). Expressed on both naive and memory CD4-positive T cells (at protein level) (PubMed:22307619).
Homodimer (PubMed:20375010). Part of a complex composed of CD19, CR2/CD21, CD81 and IFITM1/CD225 in the membrane of mature B cells. Interacts (via the second extracellular domain) with CD19; this interaction is initiated early during biosynthesis in the ER and enables trafficking of only properly folded CD19 (PubMed:16449649, PubMed:1383329). Part of a complex that includes MHC class II/HLA-DR molecules and IFITM1 (PubMed:8409388). Interacts with IFITM1 (PubMed:2398277, PubMed:26354436). Interacts with IFITM2 and IFITM3 (By similarity). Part of integrin-tetraspanin complex composed of CD9, CD81, beta-1 and beta-2 integrins in the membrane of monocyte/macrophages (PubMed:12796480). Interacts (via the second extracellular domain) with integrin ITGAV:ITGB3 (PubMed:27993971). Interacts with CD247/CD3 zeta, ICAM1 and CD9 at the immune synapse on T cell membrane (PubMed:23858057). Part of a GPCR-tetraspanin complex consisting at least of ADGRG1, CD81, possibly CD9, and GNA11 in which CD81 enhances the association of ADGRG1 with GNA11 (PubMed:15004227). Part of a complex composed of CD9, CD81, PTGFRN and IGSF8 (By similarity). Interacts directly with IGSF8 (PubMed:11504738). Interacts with CD53 and SCIMP (PubMed:21930792). Interacts with SAMHD1 (via its C-terminus) (PubMed:28871089). Interacts with glypican GPC3 and with the transcriptional repressor HHEX; binding to GPC3 decreases the availability of free CD81 for binding to HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (By similarity). Interacts with CLDN1 (PubMed:20375010, PubMed:21516087). Interacts with CLDN6 and CLDN9 (PubMed:20375010).
Likely constitutively palmitoylated at low levels. Protein palmitoylation is up-regulated upon coligation of BCR and CD9-C2R-CD81 complexes in lipid rafts.
Structural component of specialized membrane microdomains known as tetraspanin-enriched microdomains (TERMs), which act as platforms for receptor clustering and signaling. Essential for trafficking and compartmentalization of CD19 receptor on the surface of activated B cells (PubMed:20237408, PubMed:27881302, PubMed:16449649). Upon initial encounter with microbial pathogens, enables the assembly of CD19-CR2/CD21 and B cell receptor (BCR) complexes at signaling TERMs, lowering the threshold dose of antigen required to trigger B cell clonal expansion and antibody production (PubMed:15161911, PubMed:20237408). In T cells, facilitates the localization of CD247/CD3 zeta at antigen-induced synapses with B cells, providing for costimulation and polarization toward T helper type 2 phenotype (PubMed:22307619, PubMed:23858057, PubMed:8766544). Present in MHC class II compartments, may also play a role in antigen presentation (PubMed:8409388, PubMed:8766544). Can act both as positive and negative regulator of homotypic or heterotypic cell-cell fusion processes. Positively regulates sperm-egg fusion and may be involved in acrosome reaction (By similarity). In myoblasts, associates with CD9 and PTGFRN and inhibits myotube fusion during muscle regeneration (By similarity). In macrophages, associates with CD9 and beta-1 and beta-2 integrins, and prevents macrophage fusion into multinucleated giant cells specialized in ingesting complement-opsonized large particles (PubMed:12796480). Also prevents the fusion of mononuclear cell progenitors into osteoclasts in charge of bone resorption (By similarity). May regulate the compartmentalization of enzymatic activities. In T cells, defines the subcellular localization of dNTPase SAMHD1 and permits its degradation by the proteasome, thereby controlling intracellular dNTP levels (PubMed:28871089). Also involved in cell adhesion and motility. Positively regulates integrin-mediated adhesion of macrophages, particularly relevant for the inflammatory response in the lung (By similarity).
Belongs to the glycosyltransferase 54 family.
Expressed in testis. Poorly expressed in testis biopsies from men with impaired spermatogenesis.
May play a role in male spermatogenesis. In vitro acts as inhibitor of MGAT1 activity causing cell surface proteins to carry mainly high mannose N-glycans. The function is mediated by its lumenal domain and occurs specifically in the Golgi. A catalytic glucosyltransferase activity is not detected. May be involved in regulation of Sertoli-germ cell interactions during specific stages of spermatogenesis.
May self-associate; specifically in the endoplasmic reticulum prior to its translocation to the Golgi. Interacts with MGAT1, MGAT3 and MAN2A2; may interact with MGTA1 specifically in the Golgi.
Belongs to the glycosyltransferase 23 family.
Catalyzes the addition of fucose in alpha 1-6 linkage to the first GlcNAc residue, next to the peptide chains in N-glycans.
Seems to be only expressed in retina, inactive as a fucosyltransferase.
Belongs to the proteasome subunit S3 family.
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD3, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with ERCC6 (PubMed:26030138).
Homodimer; disulfide-linked. Interacts with GRB2 and GRB7 in a phosphorylation-dependent manner.
May play a role in the downstream signal transduction pathways involving GRB2 and GRB7.
Detected in platelets (at protein level). Dysplastic nevi, radial growth phase primary melanomas, hematopoietic cells, tissue macrophages.
Functions as cell surface receptor for TIMP1 and plays a role in the activation of cellular signaling cascades. Plays a role in the activation of ITGB1 and integrin signaling, leading to the activation of AKT, FAK/PTK2 and MAP kinases. Promotes cell survival, reorganization of the actin cytoskeleton, cell adhesion, spreading and migration, via its role in the activation of AKT and FAK/PTK2. Plays a role in VEGFA signaling via its role in regulating the internalization of KDR/VEGFR2. Plays a role in intracellular vesicular transport processes, and is required for normal trafficking of the PMEL luminal domain that is essential for the development and maturation of melanocytes. Plays a role in the adhesion of leukocytes onto endothelial cells via its role in the regulation of SELP trafficking. May play a role in mast cell degranulation in response to Ms4a2/FceRI stimulation, but not in mast cell degranulation in response to other stimuli.
Interacts with TIMP1 and ITGB1 and recruits TIMP1 to ITGB1 (PubMed:16917503, PubMed:24635319). Interacts with CD9. Identified in a complex with CD9 and ITGB3 (PubMed:19640571). Interacts with PMEL (PubMed:21962903). Interacts with KDR/VEGFR2; identified in a complex with ITGB1 and KDR/VEGFR2 and is required to recruit KDR to ITGB1 complexes (PubMed:23632027). Interacts with SYT7 (By similarity).
Lack of expression of CD63 in platelets has been observed in a patient with Hermansky-Pudlak syndrome (HPS). Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous, rare, autosomal recessive disorder characterized by oculocutaneous albinism, bleeding due to platelet storage pool deficiency, and lysosomal storage defects. This syndrome results from defects of diverse cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes. Ceroid storage in the lungs is associated with pulmonary fibrosis, a common cause of premature death in individuals with HPS.
Palmitoylated at a low, basal level in unstimulated platelets. The level of palmitoylation increases when platelets are activated by thrombin (in vitro).
This antigen is associated with early stages of melanoma tumor progression.
May be involved in the control of adherens junction integrity.
Interacts (via chromo domain) with histone H3K9me3.
The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. Coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. The zeta subunit may be involved in regulating the coat assembly and, hence, the rate of biosynthetic protein transport due to its association-dissociation properties with the coatomer complex.
GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
Highly expressed in kidney and placenta. Also expressed in colon, skeletal muscle, small intestine, stomach, and testis. Not detected in brain, liver or spleen. Overexpressed in the majority of colorectal tumors examined.
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Essential in early embryonic development to prevent apoptotic death.
Predominantly expressed in brain, liver, kidney, testes and ovary.
Ubiquitin ligase activity is mediated by two distinct domains, PHD-type zinc fingers 2 and 3. The use of these distinct domains may allow ubiquitination of different targets by each domain. The HECT domain is catalytically inactive and does not contribute to this activity.
Up-regulated approximately 4-fold in G2 when compared to S phase. Down-regulated approximately 3-fold by gamma-irradiation.
Activated in cardiovascular cells and Hela cells following exposure to hypoxia. Inhibited by polynitrogen compounds probably by chelation to Fe(2+) ions.
Induced by hypoxia in a number of cells including neutrophils and certain cancer cell lines. Up-regulated 10-fold in pancreatic cancers.
Interacts with BCL2 (via its BH4 domain); the interaction disrupts the BAX-BCL4 complex inhibiting the anti-apoptotic activity of BCL2 (PubMed:20849813). Interacts with WDR83; the interaction leads to almost complete elimination of HIF-mediated reporter activity (By similarity). Interacts with ADRB2; the interaction hydroxylates ADRB2 facilitating its ubiquitination by the VHL-E3 ligase complex (PubMed:19584355). Interacts with PAX2; the interaction targets PAX2 for destruction (PubMed:21575608). Interacts with PKM; the interaction hydroxylates PKM in hypoxia (PubMed:21620138, PubMed:21483450). Interacts with LIMD1, WTIP and AJUBA (PubMed:22286099).
Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as PKM, TELO2, ATF4 and HIF1A (PubMed:19584355, PubMed:21620138, PubMed:21483450, PubMed:22797300, PubMed:20978507, PubMed:21575608). Target proteins are preferentially recognized via a LXXLAP motif. Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins (PubMed:11595184, PubMed:12181324). Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A (PubMed:11595184, PubMed:12181324). Also hydroxylates HIF2A (PubMed:11595184, PubMed:12181324). Has a preference for the CODD site for both HIF1A and HIF2A (PubMed:11595184, PubMed:12181324). Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site (PubMed:11595184, PubMed:12181324). Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex (PubMed:11595184, PubMed:12181324). Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes (PubMed:11595184, PubMed:12181324). ELGN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis (PubMed:21620138, PubMed:21483450). Under normoxia, hydroxylates and regulates the stability of ADRB2 (PubMed:19584355). Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex (PubMed:20849813). In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity (PubMed:16098468). Also essential for hypoxic regulation of neutrophilic inflammation (PubMed:21317538). Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway (PubMed:22797300). Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4 (Probable).
The Beta(2)beta(3) 'finger-like' loop domain is important for substrate (HIFs' CODD/NODD) selectivity.
Ubiquitinated by SIAH1 and/or SIAH2 in response to the unfolded protein response (UPR), leading to its degradation.
Widely expressed at low levels. Expressed at higher levels in adult heart (cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle), lung and placenta, and in fetal spleen, heart and skeletal muscle. Also expressed in pancreas. Localized to pancreatic acini and islet cells.
Probable potassium channel subunit. No channel activity observed in heterologous systems. May need to associate with another protein to form a functional channel (By similarity).
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. SCNN1B subfamily.
Detected in placenta, lung and kidney (PubMed:7762608). Expressed in kidney (at protein level) (PubMed:22207244).
Heterotrimer containing an alpha/SCNN1A, a beta/SCNN1B and a gamma/SCNN1G subunit. An additional delta/SCNN1D subunit exists only in some organisms and can replace the alpha/SCNN1A subunit to form an alternative channel with specific properties (PubMed:7499195, PubMed:16423824). Interacts with NEDD4 (via WW domains) (PubMed:11244092, PubMed:12167593). Interacts with NEDD4L (via WW domains) (PubMed:11244092). Interacts with WWP1 (via WW domains) (PubMed:9169421). Interacts with WWP2 (via WW domains) (PubMed:9169421, PubMed:12167593). Interacts with the full-length immature form of PCSK9 (pro-PCSK9) (PubMed:22493497). Interacts (N-glycosylated) with BPIFA1; the interaction is direct and inhibits the proteolytic processing of SCNN1A and SCNN1G and the activation of ENaC (PubMed:24124190, PubMed:24043776).
N-glycosylated. N-glycosylation is required for interaction with BPIFA1.
Phosphorylated on serine and threonine residues. Aldosterone and insulin increase the basal level of phosphorylation.
Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride. Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells. Plays an essential role in electrolyte and blood pressure homeostasis, but also in airway surface liquid homeostasis, which is important for proper clearance of mucus. Controls the reabsorption of sodium in kidney, colon, lung and sweat glands. Also plays a role in taste perception.
The disease is caused by variants affecting the gene represented in this entry. The degree of channel function impairment differentially affects the renin-aldosterone system and urinary Na/K ratios, resulting in distinct genotype-phenotype relationships in PHA1 patients. Loss-of-function mutations are associated with a severe clinical course and age-dependent hyperactivation of the renin-aldosterone system. This feature is not observed in patients with missense mutations that reduce but do not eliminate channel function. Markedly reduced channel activity results in impaired linear growth and delayed puberty (PubMed:18634878).
Expressed in various diffuse-type gastric cancers. Detected at lower levels in skeletal muscle.
Interacts with the GTP form of RRAGA, RRAGC and RRAGD. Interacts with NIP7. Interacts with DDX18; the interaction is RNA-dependent. Interacts with DDX47; the interaction is RNA-dependent.
Plays an essential role in the survival of diffuse-type gastric cancer cells. Acts as a nucleolar anchoring protein for DDX47. May be involved in regulation of gene expression at the post-transcriptional level or in ribosome biogenesis in cancer cells.
Up-regulated in diffuse-type gastric cancers.
May function in nuclear protein import as nuclear transport receptor.
Homodimer. Interacts with NOSIP and NOSTRIN (PubMed:11149895, PubMed:12446846). Interacts with HSP90AB1 (PubMed:23585225, PubMed:11149895, PubMed:12446846) (By similarity). Forms a complex with ASL, ASS1 and SLC7A1; the complex regulates cell-autonomous L-arginine synthesis and citrulline recycling while channeling extracellular L-arginine to nitric oxide synthesis pathway (By similarity).
Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1.
Phosphorylation by AMPK at Ser-1177 in the presence of Ca(2+)-calmodulin (CaM) activates activity. In absence of Ca(2+)-calmodulin, AMPK also phosphorylates Thr-495, resulting in inhibition of activity (By similarity). Phosphorylation of Ser-114 by CDK5 reduces activity.
Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway (PubMed:1378832). NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets.
Stimulated by calcium/calmodulin. Inhibited by NOSIP and NOSTRIN.
Tetrahydrobiopterin (BH4). May stabilize the dimeric form of the enzyme.
Variation Asp-298 in NOS3 may be associated with susceptibility to coronary spasm.
Catalyzes the oxidation of ferrous iron(II) to ferric iron(III) and stores iron in a soluble, non-toxic, readily available form (PubMed:11323407, PubMed:15201052). Important for iron homeostasis (PubMed:11323407, PubMed:15201052). Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation (PubMed:11323407, PubMed:15201052).
Detected in testis and erythroleukemia. Expression is very low or not detectable in brain, colon, heart, kidney, liver, lung, muscle, placental, spleen and small intestine.
Homooligomer of 24 subunits. The functional molecule is roughly spherical and contains a central cavity into which the polymeric mineral iron core is deposited.
Forms homo- or heterooligomeric complexes. The central region of MAPK8IP3 interacts with the C-terminal of MAPK8IP2 but not MAPK8IP1. Binds specific components of the JNK signaling pathway namely MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3 to the N-terminal region, MAP2K4/MKK4 and MAP2K7/MKK7 to the central region and MAP3K11 to the C-terminal region. Binds the TPR motif-containing C-terminal of kinesin light chain, KLC1. Pre-assembled MAPK8IP1 scaffolding complexes are then transported as a cargo of kinesin, to the required subcellular location. Interacts with ROCK1 and this interaction is enhanced by ultraviolet-B (UVB) radiation. Interacts with SH3RF2 (By similarity). Interacts with NTRK2/TRKB and NTRK3/TRKC (By similarity).
Phosphorylation by ROCK1 is crucial for the recruitment of JNK.
The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module (PubMed:12189133). May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity). Promotes neuronal axon elongation in a kinesin- and JNK-dependent manner. Activates cofilin at axon tips via local activation of JNK, thereby regulating filopodial dynamics and enhancing axon elongation. Its binding to kinesin heavy chains (KHC), promotes kinesin-1 motility along microtubules and is essential for axon elongation and regeneration. Regulates cortical neuronal migration by mediating NTRK2/TRKB anterograde axonal transport during brain development (By similarity). Acts as an adapter that bridges the interaction between NTRK2/TRKB and KLC1 and drives NTRK2/TRKB axonal but not dendritic anterograde transport, which is essential for subsequent BDNF-triggered signaling and filopodia formation (PubMed:21775604).
Belongs to the G-protein coupled receptor 1 family. FSH/LSH/TSH subfamily.
Receptor for lutropin-choriogonadotropic hormone (PubMed:11847099). The activity of this receptor is mediated by G proteins which activate adenylate cyclase (PubMed:11847099).
May form homophilic interactions that could regulate cell-cell interaction. Interacts with CACNB2, DST, MIA and NCKIPSD. Interacts with HHLA2.
Plays a role in cell-cell interaction, cell migration, and angiogenesis. Through interaction with HHLA2, costimulates T-cells in the context of TCR-mediated activation. Enhances T-cell proliferation and cytokine production via an AKT-dependent signaling cascade.
Repetitive stimulation of naive T-cells, including with IL2 and antibodies against CD3 and CD28 or repetitive antigenic exposure, leads to progressive and irreversible loss of expression.
Widely expressed, mainly by epithelial and endothelial cells, including bronchial epithelial cells of lung, breast glandular and lobular epithelia cells, urothelium of the bladder, skin epidermis, epithelium of gastrointestinal, rectum, endometrial glands of the uterus, ureter, fallopian tube epithelium, colonic epithelium, small bowl epithelium, stomach epithelium, including both chief and parietal cells, trophoblastic epithelium of placenta, and pancreatic acinar cells (at protein level). Consistently expressed in veins and arteries (at protein level). Not detected in thyroid, cerebellum, cerebral cortex and thymus (at protein level). Expressed in lymphoid organs, with highest levels in thymus, spleen, peripheral blood lymphocytes and liver. In the thymus, expressed in CD4+ and CD8+ single- and double-positive cells, but not in immature CD4- and CD8- double-negative cells (at protein level). In peripheral blood mononuclear cells, highly expressed on CD56+ or CD16+ natural killer cells and CD3+ T-cells(at protein level). Not detected on B-cells(at protein level). Expressed in tonsils (at protein level).
Mediates post-translational transport of precursor polypeptides across endoplasmic reticulum (ER). Proposed to act as a targeting receptor for small presecretory proteins containing short and apolar signal peptides. Targets and properly positions newly synthesized presecretory proteins into the SEC61 channel-forming translocon complex, triggering channel opening for polypeptide translocation to the ER lumen.
The ER translocon complex that consists of channel-forming core components SEC61A1, SEC61B and SEC61G and different auxiliary components such as SEC62 and SEC63. Interacts with SEC61B.
Essential component of the Ost-alpha/Ost-beta complex, a heterodimer that acts as the intestinal basolateral transporter responsible for bile acid export from enterocytes into portal blood (PubMed:16317684). Modulates SLC51A glycosylation, membrane trafficking and stability activities (PubMed:16317684). The Ost-alpha/Ost-beta complex efficiently transports the major species of bile acids (taurocholate) (PubMed:16317684). Taurine conjugates are transported more efficiently across the basolateral membrane than glycine-conjugated bile acids (By similarity). Can also transport steroids such as estrone 3-sulfate and dehydroepiandrosterone 3-sulfate, therefore playing a role in the enterohepatic circulation of sterols (PubMed:16317684). Able to transport eicosanoids such as prostaglandin E2 (By similarity).
Interacts with SLC51A. The Ost-alpha/Ost-beta complex is a heterodimer composed of alpha (SLC51A) and beta (SLC51B) subunit; induces the transport of SLC51A from the reticulum endoplasmic to the plasma membrane (By similarity).
The transmembrane domain (TM) is the major site of interaction with SLC51A. The extracellular-membrane interface is absolutely required for transport activity. The intracellular-membrane interface is necessary for establishing the correct membrane orientation that is essential for the heterodimer Ost-alpha/Ost-beta complex formation and transport activity at the cell membrane surface (By similarity).
Widely expressed with a high expression in ileum. Expressed in testis, colon, liver, small intestine, kidney, ovary and adrenal gland; and at low levels in heart, lung, brain, pituitary, thyroid gland, uterus, prostate, mammary gland and fat.
Belongs to the cytochrome c oxidase VIII family.
Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I, COX5A, COX5B, COX6A, COX6B, COX6C, COX7A, COX7B, COX7C, COX8 and NDUFA4, which are encoded in the nuclear genome. The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)).
Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695).
Activated by phosphorylation at Ser-53. Mutagenesis of Ser-54 abolishes activation.
Binds 2 divalent metal cations per subunit (PubMed:15260978, PubMed:15576036). Site 2 has a preference for magnesium and/or manganese ions (By similarity).
Detected in brain, placenta, lung and kidney.
Expressed in colonic epithelial cells (at protein level). Widespread; most abundant in skeletal muscle.
Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution.
Homodimer for the long isoforms. Isoforms with truncated N-termini are monomeric. Isoform 3 is part of a ternary complex containing PRKAR2A, PRKAR2B and AKAP9. Interacts with PDE4DIP. Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1) (By similarity). Isoform 5, isoform N3 and isoform 12 bind RACK1 via their unique N-terminus. Binds ARRB2. Interacts (via N-terminal region) with SHANK2 (via proline-rich region); the interaction is increased in a PKA-dependent manner.
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Inhibited by rolipram. Activated by phosphatidic acid.
Long isoforms that share a conserved PKA phosphorylation site in the N-terminus are activated by PKA through phosphorylation (By similarity). Isoform 3 and isoform 7 are activated by phosphorylation (in vitro), but not isoform 6. Isoform N3 and isoform 12 are phosphorylated on Ser-49, Ser-51, Ser-55 and Ser-59.
Sumoylation of long isoforms by PIAS4 augments their activation by PKA phosphorylation and represses their inhibition by ERK phosphorylation.
Allosterically activated by benzodiazepines (PubMed:29950725). Allosterically activated by the anesthetic etomidate (By similarity). Inhibited by the antagonist bicuculline (PubMed:29950725).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRB2 sub-subfamily.
Heteropentamer, formed by a combination of alpha, beta, gamma, delta and rho chains (PubMed:8264558, PubMed:29950725). Interacts with UBQLN1 (By similarity). Interacts with KCTD8, KCTD12 and KCTD16; this interaction determines the pharmacology and kinetics of the receptor response, the KCTD proteins markedly accelerating the GABA-B response, although to different extents (By similarity). May interact with KIF21B (By similarity). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3 (By similarity).
Isoform 1 and isoform 2 show reduced expression in schizophrenic brain. Isoform 3 shows increased expression in schizophrenic and bipolar disorder brains while isoform 4 shows reduced expression.
Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:8264558, PubMed:19763268, PubMed:27789573, PubMed:29950725). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (PubMed:23909897, PubMed:25489750). The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the synaptogenic effect of this subunit is influenced by the type of alpha and beta subunits present in the receptor pentamer (By similarity). The alpha1/beta2/gamma2 receptor and the alpha2/beta2/gamma2 receptor exhibit synaptogenic activity (PubMed:23909897, PubMed:25489750). Functions also as histamine receptor and mediates cellular responses to histamine (By similarity).
The extracellular domain contributes to synaptic contact formation.
(Microbial infection) Acts as an interaction partner for human coronaviruses SARS-CoV and, probably, SARS-CoV-2 envelope protein E which results in delayed formation of tight junctions and disregulation of cell polarity.
(Microbial infection) Interacts (via PDZ domain) with human coronaviruses SARS-CoV and, probably, SARS-CoV-2 envelope small membrane protein E (via C-terminus); this inhibits the interaction between PALS1 and CRB3.
Expressed at the outer limiting membrane in the retina (at protein level) (PubMed:15914641, PubMed:15558731, PubMed:16519681, PubMed:17584769). Expressed in T lymphocytes (at protein level) (PubMed:21479189). Expressed in the kidney (at protein level) (PubMed:17584769).
Heterodimer with MPP1 (PubMed:17584769). Forms a heterotrimeric complex composed of PALS1, LIN7B and PATJ; the N-terminal L27 domain of PALS1 interacts with the L27 domain of PATJ and the C-terminal L27 domain of PALS1 interacts with the L27 domain of LIN7B (PubMed:22337881). Component of a complex composed of PALS1, CRB1 and MPP4 (PubMed:15914641). Component of a complex whose core is composed of ARHGAP17, AMOT, PALS1, PATJ and PARD3/PAR3 (PubMed:16678097). Component of a complex composed of PALS1, CRB1 and EPB41L5 (PubMed:17920587). Within the complex, interacts (via HOOK domain) with EPB41L5 (via FERM domain), and interacts with CRB1 (via intracellular domain) (PubMed:17920587). Component of a complex composed of PALS1, MPP3 and CRB1; PALS1 acts as a bridging protein between MPP3 (via guanylate kinase-like domain) and CRB1 (PubMed:16519681). Component of a complex composed of CRB3, PALS1 and PATJ (By similarity). Interacts (via PDZ domain) with PATJ (via N-terminus) (PubMed:12527193). Interacts with EZR (By similarity). Interacts (via PDZ domain) with CRB1 (via C-terminal ERLI motif) (PubMed:25385611, PubMed:25760605). While the PDZ domain is sufficient for interaction with CRB1, the adjacent SH3 and guanylate kinase-like domains are likely to contribute to a high affinity interaction (PubMed:25385611). Interacts with WWTR1/TAZ (via WW domain) (PubMed:21145499). Interacts with MPP7 (PubMed:16678097, PubMed:17332497). Interacts (via PDZ domain) with CRB3 (via C-terminus) (By similarity). Interacts with LIN7C (By similarity). Interacts with MPDZ (By similarity). Interacts with PARD6B (By similarity). Interacts with SC6A1 (By similarity). Interacts with CDH5; the interaction promotes PALS1 localization to cell junctions and is required for CDH5-mediated vascular lumen formation and endothelial cell (PubMed:27466317). Interacts with NPHP1 (via coiled coil and SH3 domains) (PubMed:19755384). Interacts with NPHP4 (PubMed:19755384). Interacts with CRB2 (By similarity).
Plays a role in tight junction biogenesis and in the establishment of cell polarity in epithelial cells (PubMed:16678097, PubMed:25385611). Also involved in adherens junction biogenesis by ensuring correct localization of the exocyst complex protein EXOC4/SEC8 which allows trafficking of adherens junction structural component CDH1 to the cell surface (By similarity). Plays a role through its interaction with CDH5 in vascular lumen formation and endothelial membrane polarity (PubMed:27466317). Required during embryonic and postnatal retinal development (By similarity). Required for the maintenance of cerebellar progenitor cells in an undifferentiated proliferative state, preventing premature differentiation, and is required for cerebellar histogenesis, fissure formation, cerebellar layer organization and cortical development (By similarity). Plays a role in neuronal progenitor cell survival, potentially via promotion of mTOR signaling (By similarity). Plays a role in the radial and longitudinal extension of the myelin sheath in Schwann cells (By similarity). May modulate SC6A1/GAT1-mediated GABA uptake by stabilizing the transporter (By similarity). Plays a role in the T-cell receptor-mediated activation of NF-kappa-B (PubMed:21479189). Required for localization of EZR to the apical membrane of parietal cells and may play a role in the dynamic remodeling of the apical cytoskeleton (By similarity). Required for the normal polarized localization of the vesicular marker STX4 (By similarity). Required for the correct trafficking of the myelin proteins PMP22 and MAG (By similarity). Involved in promoting phosphorylation and cytoplasmic retention of transcriptional coactivators YAP1 and WWTR1/TAZ which leads to suppression of TGFB1-dependent transcription of target genes such as CCN2/CTGF, SERPINE1/PAI1, SNAI1/SNAIL1 and SMAD7 (By similarity).
The L27 domain 1 functions in targeting to the tight junctions by binding to and stabilizing PATJ.
The PDZ domain binds to the C-terminus of SC6A1.
Binds 1 Mg(2+) ion per subunit. Can also utilize other divalent metal cations, such as Ca(2+), Mn(2+) and Co(2+).
Binds 1 thiamine pyrophosphate per subunit.
Catalyzes the transfer of a two-carbon ketol group from a ketose donor to an aldose acceptor, via a covalent intermediate with the cofactor thiamine pyrophosphate.
Binds microtubules. Together with MAPRE1 may target the microtubule depolymerase KIF2C to the plus-end of microtubules. May regulate the dynamics of microtubules at their growing distal tip.
Detected in embryonic stem cells differentiating to cardiomyocytes.
Homodimer. Interacts with KIF2C and MAPRE1; the interaction is direct and probably targets MTUS2 and KIF2C to microtubules.
In the C-terminal section; belongs to the MTUS1 family.
Belongs to the 2-oxoacid dehydrogenase family.
Delipoylated at Lys-132 and Lys-259 by SIRT4, delipoylation decreases the PHD complex activity.
Part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (subunits PDH1A and PDHB, E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules (PubMed:14638692, PubMed:20361979). Interacts with PDK2 and PDK3 (PubMed:15861126, PubMed:17532006, PubMed:17683942, PubMed:18387944). Interacts with SIRT4 (PubMed:25525879). Interacts with PDHB (PubMed:20160912).
Primary biliary cirrhosis is a chronic, progressive cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients' serum. It manifests with inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis. Patients with primary biliary cirrhosis show autoantibodies against the E2 component of pyruvate dehydrogenase complex.
The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle.
The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2).
Receptor for chemokines SCYC1 and SCYC2. Subsequently transduces a signal by increasing the intracellular calcium ions level. Receptor for XCL1/Lymphotactin.
According to PubMed:12370122, it has no hydrolytic activity.
Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum. May form with the glucose-6-phosphate transporter (SLC37A4/G6PT) a ubiquitously expressed complex responsible for glucose production through glycogenolysis and gluconeogenesis. Probably required for normal neutrophil function.
Ubiquitously expressed. Highly expressed in skeletal muscle, at intermediate levels in heart, brain, placenta, kidney, colon, thymus, spleen and pancreas. Also detected in testis, prostate, ovary, liver, lung, small intestine and peripheral blood lymphocytes.
Interacts with RP1; has a synergistic effect with RP1 in photoreceptor differentiation.
Required for the differentiation of photoreceptor cells. Plays a role in the organization of outer segment of rod and cone photoreceptors (By similarity).
Retinal-specific; expressed in photoreceptor.
The C-terminal part contains a large repetitive region which contains an unusually high percentage of glutamine, glycine and above all glutamic acid residues.
The exact length of RP1L1 is variable between individuals due to the presence of several length polymorphisms. The sequence shown here is that of allele RP1L1-1 and includes 3 repeats (from aa 1292-1342) with a length of 16 amino acids. The number of repeats is highly polymorphic and varies among different alleles, ranging from 3 to 8.
Monomer (Probable). Interacts with NECAP1, TSG101, UBC and AFTPH/aftiphilin. Interacts with CNST (By similarity). Interacts with GGA1 and GGA3 (PubMed:14638859). Binds to clathrin and activated ARFs, such as ARF1, ARF5 and ARF6 (PubMed:11301005, PubMed:11950392). Binds RABEP1 and RABGEF1 (PubMed:12505986). Interacts with the type-I membrane proteins LRP3, M6PR/CD-MPR, IGF2R/CI-MPR and BACE1 (PubMed:11390366, PubMed:11387475, PubMed:11886874, PubMed:14567678). Interacts (via N-terminal VHS domain) with SORL1/sorLA and SORT1 (via C-terminal cytosolic domain) (PubMed:11331584, PubMed:11390366, PubMed:11821067). Binds the accessory proteins CCDC91, P200, SYNRG, EPN4 and NECAP2 (PubMed:10814529, PubMed:12429846, PubMed:12808037, PubMed:14665628). Interacts with ADRA2B (PubMed:27901063). Interacts (via VHS domain) with PIK4B; the interaction is important for PIK4B location at the Golgi apparatus membrane (PubMed:28289207).
Plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. Mediates the ARF-dependent recruitment of clathrin to the TGN and binds ubiquitinated proteins and membrane cargo molecules with a cytosolic acidic cluster-dileucine (DXXLL) motif (PubMed:10747088). Mediates export of the GPCR receptor ADRA2B to the cell surface (PubMed:27901063). Regulates retrograde transport of phosphorylated form of BACE1 from endosomes to the trans-Golgi network (PubMed:15615712).
The GAE domain binds accessory proteins regulating GGAs function.
The GAT domain is responsible for interaction with ARF-GTP, UBC and RABEP1. Required for recruitment to the TGN it prevents ARF-GTP hydrolysis.
The VHS domain functions as a recognition module for sorting signals composed of an acidic cluster followed by two leucines (DXXLL motif).
The unstructured hinge region contains clathrin-binding but no autoinhibitory (DXXLL) motifs.
Ribonuclease that plays an essential role in innate immune response by recognizing and degrading RNAs from microbial pathogens that are subsequently sensed by TLR8 (PubMed:31778653). Cleaves preferentially single-stranded RNA molecules between purine and uridine residues, which critically contributes to the supply of catabolic uridine and the generation of purine-2',3'-cyclophosphate-terminated oligoribonucleotides (PubMed:31778653). In turn, RNase T2 degradation products promote the RNA-dependent activation of TLR8 (PubMed:31778653). Also plays a key role in degradation of mitochondrial RNA and processing of non-coding RNA imported from the cytosol into mitochondria (PubMed:28730546, PubMed:30184494). Participates as well in degradation of mitochondrion-associated cytosolic rRNAs (PubMed:30385512).
Ubiquitous. Higher expression levels observed in the temporal lobe and fetal brain.
Belongs to the 5'-nucleotidase type 3 family.
Catalyzes the hydrolysis of nucleotide monophosphates, releasing inorganic phosphate and the corresponding nucleoside, AMP is the major substrate.
Highly expressed in testis, placenta and pancreas. Detected at lower levels in heart, kidney, liver and lung.
Interacts (via N-terminus) with LMNA isoform C (via C-terminus) (in vitro) (PubMed:16339967). Interacts (via LEM domain) with BANF1 (PubMed:32494070). Interacts (via C-terminus) with CHMP7 (PubMed:28242692). Interacts (via N-terminus) with tubulin; the interaction causes microtubule bundling and stabilization (in vitro) (PubMed:32494070).
Nuclear lamina-associated inner nuclear membrane protein that is involved in nuclear structure organization, maintenance of nuclear envelope (NE) integrity and NE reformation after mitosis (PubMed:16339967, PubMed:17097643, PubMed:28242692, PubMed:32494070). Plays a role as transmembrane adapter for the endosomal sorting complexes required for transport (ESCRT), and is thereby involved in ESCRT-mediated NE reformation (PubMed:28242692, PubMed:32494070). Promotes ESCRT-mediated NE closure by recruiting CHMP7 and downstream ESCRT-III proteins IST1/CHMP8 and CHMP2A to the reforming NE during anaphase (PubMed:28242692). During nuclear reassembly, condenses into a liquid-like coating around microtubule spindles and coassembles with CHMP7 to form a macromolecular O-ring seal at the confluence between membranes, chromatin, and the spindle to facilitate early nuclear sealing (PubMed:32494070). Plays a role in the organization of heterochromatin associated with the NE and in the maintenance of NE organization under mechanical stress (By similarity). Required for embryonic development and involved in regulation of several signaling pathways such as MAPK and AKT (By similarity). Required for myoblast differentiation involving regulation of ERK signaling (By similarity). Essential for cardiac homeostasis and proper heart function (By similarity).
Phosphorylated; strongly phosphorylated in mitosis compared to G1/S.
The LEM domain is required for inner nuclear membrane (INM) localization and contains a BANF1 conserved binding motif which allows localization to chromatin (PubMed:16339967, PubMed:32494070). In late anaphase, as the reforming nuclear envelope (NE) surrounds the chromatin disk, both the LEM domain and the disordered regions are necessary for localization to the NE core (PubMed:32494070).
The disordered regions, also named low complexity domain, confer the ability to phase separate (PubMed:32494070). In late anaphase, as the reforming nuclear envelope (NE) surrounds the chromatin disk, both the LEM domain and the disordered regions are necessary for localization to the NE core (PubMed:32494070). During NE reformation, the proline-arginine-rich sequence within the disordered region binds microtubules, targeting LEM2 condensation to spindle microtubules traversing the nascent NE (PubMed:32494070).
The winged-helix (WH) region (residues 395-503) activates the ESCRT-II/ESCRT-III hybrid protein CHMP7 to form co-oligomeric rings around spindle microtubules to facilitate early nuclear sealing.
Ubiquitously expressed, including bone marrow, brain, kidney, colon, skeletal muscle, thymus, testis and uterus.
Belongs to the peptidase S1 family. Kallikrein subfamily.
Expressed at high levels in serum, ascites fluid and tumor cytosol of advanced stage ovarian cancer patients and may serve as a marker of ovarian cancer.
Inhibited by a range of serine protease inhibitors including antipain, aprotinin, leupeptin, benzamidine and soybean trypsin inhibitor.
Isoform 1 is predominantly expressed in the pancreas. Isoform 2 is expressed in adult brain and hippocampus. Isoform 1 and isoform 2 are found in fetal brain and placenta. Detected in salivary gland, uterus, thymus, breast, testis and kidney but not in spleen, liver, lung or normal ovarian tissue. Displays an 11.5-fold increase in Alzheimer disease hippocampus compared to controls and is overexpressed in some ovarian carcinomas. Expressed at low levels in normal skin while high levels are found in psoriasis vulgaris, seborrheic keratosis, lichen planus and squamous cell carcinoma skin samples. Expressed in the keratinocytes.
Produced as a result of a human-specific mutation which is not found in other primates.
Serine protease which is capable of degrading a number of proteins such as casein, fibrinogen, kininogen, fibronectin and collagen type IV. Also cleaves L1CAM in response to increased neural activity. Induces neurite outgrowth and fasciculation of cultured hippocampal neurons. Plays a role in the formation and maturation of orphan and small synaptic boutons in the Schaffer-collateral pathway, regulates Schaffer-collateral long-term potentiation in the hippocampus and is required for memory acquisition and synaptic plasticity. Involved in skin desquamation and keratinocyte proliferation. Plays a role in the secondary phase of pathogenesis following spinal cord injury.
Belongs to the glycosyltransferase 31 family.
Beta-1,3-N-acetylglucosaminyltransferase that plays a key role in the synthesis of lacto- or neolacto-series carbohydrate chains on glycolipids, notably by participating in biosynthesis of HNK-1 and Lewis X carbohydrate structures. Has strong activity toward lactosylceramide (LacCer) and neolactotetraosylceramide (nLc(4)Cer; paragloboside), resulting in the synthesis of Lc(3)Cer and neolactopentaosylceramide (nLc(5)Cer), respectively. Probably plays a central role in regulating neolacto-series glycolipid synthesis during embryonic development.
Up-regulated by stimulation with retinoic acid and down-regulated with 12-O-tetradecanoylphorbol-13-acetate (TPA).
Widely expressed. Highly expressed in lung, colon, placenta, testis, pituitary gland and cerebellum. Weakly expressed in brain, liver, spleen, lymph node and thymus.
Heterodimer with MEIS1 (PubMed:28473536). Heterodimer with MEIS2 (Ref.8).
Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. Binds preferentially to methylated DNA (PubMed:28473536).
(Microbial infection) Interacts with hepatitis C virus (HCV) envelope glycoprotein E2; this interaction is required for HCV infectivity and production.
(Microbial infection) Through its interaction with HCV envelope glycoprotein E2, participates in the attachment of HCV to HSPGs and other receptors (LDLr, VLDLr, and SR-B1) on the cell surface and to the assembly, maturation and infectivity of HCV viral particles (PubMed:25122793, PubMed:29695434). This interaction is probably promoted via the up-regulation of cellular autophagy by the virus (PubMed:29695434).
APOE exists as multiple glycosylated and sialylated glycoforms within cells and in plasma (PubMed:29516132). The extent of glycosylation and sialylation are tissue and context specific (PubMed:29516132). Plasma APOE undergoes desialylation and is less glycosylated and sialylated than the cellular form (PubMed:2498325, PubMed:19838169, PubMed:20511397, PubMed:23234360). Glycosylation is not required for proper expression and secretion (PubMed:2498325). O-glycosylated with core 1 or possibly core 8 glycans. Thr-307 and Ser-314 are minor glycosylation sites compared to Ser-308 (PubMed:19838169, PubMed:23234360).
APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids (PubMed:6860692, PubMed:1911868, PubMed:14754908). APOE is a core component of plasma lipoproteins and is involved in their production, conversion and clearance (PubMed:6860692, PubMed:2762297, PubMed:1911868, PubMed:1917954, PubMed:9395455, PubMed:14754908, PubMed:23620513). Apolipoproteins are amphipathic molecules that interact both with lipids of the lipoprotein particle core and the aqueous environment of the plasma (PubMed:6860692, PubMed:2762297, PubMed:9395455). As such, APOE associates with chylomicrons, chylomicron remnants, very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) but shows a preferential binding to high-density lipoproteins (HDL) (PubMed:6860692, PubMed:1911868). It also binds a wide range of cellular receptors including the LDL receptor/LDLR, the LDL receptor-related proteins LRP1, LRP2 and LRP8 and the very low-density lipoprotein receptor/VLDLR that mediate the cellular uptake of the APOE-containing lipoprotein particles (PubMed:2762297, PubMed:1917954, PubMed:7768901, PubMed:8939961, PubMed:12950167, PubMed:20030366, PubMed:2063194, PubMed:8756331, PubMed:20303980, PubMed:1530612, PubMed:7635945). Finally, APOE has also a heparin-binding activity and binds heparan-sulfate proteoglycans on the surface of cells, a property that supports the capture and the receptor-mediated uptake of APOE-containing lipoproteins by cells (PubMed:9395455, PubMed:9488694, PubMed:23676495, PubMed:7635945). A main function of APOE is to mediate lipoprotein clearance through the uptake of chylomicrons, VLDLs, and HDLs by hepatocytes (PubMed:1911868, PubMed:1917954, PubMed:9395455, PubMed:23676495, PubMed:29516132). APOE is also involved in the biosynthesis by the liver of VLDLs as well as their uptake by peripheral tissues ensuring the delivery of triglycerides and energy storage in muscle, heart and adipose tissues (PubMed:2762297, PubMed:29516132). By participating in the lipoprotein-mediated distribution of lipids among tissues, APOE plays a critical role in plasma and tissues lipid homeostasis (PubMed:2762297, PubMed:1917954, PubMed:29516132). APOE is also involved in two steps of reverse cholesterol transport, the HDLs-mediated transport of cholesterol from peripheral tissues to the liver, and thereby plays an important role in cholesterol homeostasis (PubMed:9395455, PubMed:14754908, PubMed:23620513). First, it is functionally associated with ABCA1 in the biogenesis of HDLs in tissues (PubMed:14754908, PubMed:23620513). Second, it is enriched in circulating HDLs and mediates their uptake by hepatocytes (PubMed:9395455). APOE also plays an important role in lipid transport in the central nervous system, regulating neuron survival and sprouting (PubMed:8939961, PubMed:25173806). APOE is also involved in innate and adaptive immune responses, controlling for instance the survival of myeloid-derived suppressor cells (By similarity). Binds to the immune cell receptor LILRB4 (PubMed:30333625). APOE may also play a role in transcription regulation through a receptor-dependent and cholesterol-independent mechanism, that activates MAP3K12 and a non-canonical MAPK signal transduction pathway that results in enhanced AP-1-mediated transcription of APP (PubMed:28111074).
Belongs to the apolipoprotein A1/A4/E family.
Binds to and activates LILRB4 on acute myeloid leukemia (AML) cells which leads to suppression of T cell proliferation and promotion of AML cell migration and infiltration.
Disease susceptibility is associated with variants affecting the gene represented in this entry. The APOE*4 allele (APOE form E4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer disease. Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE*4 alleles in 42 families with late onset AD. Thus APOE*4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE*4 was virtually sufficient to cause AD by age 80. The mechanism by which APOE*4 participates in pathogenesis is not known.
Glycated in plasma VLDL of normal subjects, and of hyperglycemic diabetic patients at a higher level (2-3 fold).
Homotetramer (PubMed:8340399). May interact with ABCA1; functionally associated with ABCA1 in the biogenesis of HDLs (PubMed:14754908). May interact with APP/A4 amyloid-beta peptide; the interaction is extremely stable in vitro but its physiological significance is unclear (PubMed:8367470, PubMed:23620513). May interact with MAPT (PubMed:7972031). May interact with MAP2 (PubMed:7891887). In the cerebrospinal fluid, interacts with secreted SORL1 (PubMed:30448281). Interacts with PMEL; this allows the loading of PMEL luminal fragment on ILVs to induce fibril nucleation.
Produced by several tissues and cell types and mainly found associated with lipid particles in the plasma, the interstitial fluid and lymph (PubMed:25173806). Mainly synthesized by liver hepatocytes (PubMed:25173806). Significant quantities are also produced in brain, mainly by astrocytes and glial cells in the cerebral cortex, but also by neurons in frontal cortex and hippocampus (PubMed:3115992, PubMed:10027417). It is also expressed by cells of the peripheral nervous system (PubMed:10027417, PubMed:25173806). Also expressed by adrenal gland, testis, ovary, skin, kidney, spleen and adipose tissue and macrophages in various tissues (PubMed:25173806).
The disease is caused by variants affecting the gene represented in this entry. The vast majority of the patients are homozygous for APOE*2 alleles. More severe cases of HLPP3 have also been observed in individuals heterozygous for rare APOE variants. The influence of APOE on lipid levels is often suggested to have major implications for the risk of coronary artery disease (CAD). Individuals carrying the common APOE*4 variant are at higher risk of CAD.
There are three common APOE alleles identified: APOE*2/APOE-epsilon2/E2, APOE*3/APOE-epsilon3/E3, and APOE*4/APOE-epsilon4/E4. The corresponding ApoE2, ApoE3 and ApoE4 isoforms differentially present Cys and Arg residues at positions 130 and 176. The most common allele in the human population is APOE*3 which sequence is the one displayed in that entry with a Cys at position 130 and an Arg at position 176. Common APOE variants influence lipoprotein metabolism in healthy individuals. Additional variants have been described and are described relative to the three common alleles. Allele APOE*4 is strongly associated with risk for severe COVID-19, increases susceptibility to SARS-CoV-2 infection in neurons and astrocytes (PubMed:33450186).
Undergoes C-terminal proteolytic processing in neurons. C-terminally truncated APOE has a tendency to form neurotoxic intracellular neurofibrillary tangle-like inclusions in neurons.
Belongs to the short-chain dehydrogenases/reductases (SDR) family.
Homotetramer (PubMed:15342248, PubMed:20077426, PubMed:25925575). Component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3 (PubMed:18984158, PubMed:25925575, PubMed:26950678, PubMed:28888424). Interacts with TRMT10C/MRPP1; forming the MRPP1-MRPP2 subcomplex of the mitochondrial ribonuclease P complex (PubMed:23042678, PubMed:29040705).
In addition to mitochondrial dehydrogenase activity, moonlights as a component of mitochondrial ribonuclease P, a complex that cleaves tRNA molecules in their 5'-ends (PubMed:18984158, PubMed:24549042, PubMed:25925575, PubMed:26950678, PubMed:28888424). Together with TRMT10C/MRPP1, forms a subcomplex of the mitochondrial ribonuclease P, named MRPP1-MRPP2 subcomplex, which displays functions that are independent of the ribonuclease P activity (PubMed:23042678, PubMed:29040705). The MRPP1-MRPP2 subcomplex catalyzes the formation of N(1)-methylguanine and N(1)-methyladenine at position 9 (m1G9 and m1A9, respectively) in tRNAs; HSD17B10/MRPP2 acting as a non-catalytic subunit (PubMed:23042678, PubMed:25925575, PubMed:28888424). The MRPP1-MRPP2 subcomplex also acts as a tRNA maturation platform: following 5'-end cleavage by the mitochondrial ribonuclease P complex, the MRPP1-MRPP2 subcomplex enhances the efficiency of 3'-processing catalyzed by ELAC2, retains the tRNA product after ELAC2 processing and presents the nascent tRNA to the mitochondrial CCA tRNA nucleotidyltransferase TRNT1 enzyme (PubMed:29040705). Associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly.
Mitochondrial dehydrogenase involved in pathways of fatty acid, branched-chain amino acid and steroid metabolism (PubMed:9553139, PubMed:10600649, PubMed:12917011, PubMed:20077426, PubMed:18996107, PubMed:19706438, PubMed:25925575, PubMed:26950678, PubMed:28888424). Acts as (S)-3-hydroxyacyl-CoA dehydrogenase in mitochondrial fatty acid beta-oxidation, a major degradation pathway of fatty acids. Catalyzes the third step in the beta-oxidation cycle, namely the reversible conversion of (S)-3-hydroxyacyl-CoA to 3-ketoacyl-CoA. Preferentially accepts straight medium- and short-chain acyl-CoA substrates with highest efficiency for (3S)-hydroxybutanoyl-CoA (PubMed:9553139, PubMed:10600649, PubMed:12917011, PubMed:25925575, PubMed:26950678). Acts as 3-hydroxy-2-methylbutyryl-CoA dehydrogenase in branched-chain amino acid catabolic pathway. Catalyzes the oxidation of 3-hydroxy-2-methylbutanoyl-CoA into 2-methyl-3-oxobutanoyl-CoA, a step in isoleucine degradation pathway (PubMed:20077426, PubMed:18996107, PubMed:19706438). Has hydroxysteroid dehydrogenase activity toward steroid hormones and bile acids. Catalyzes the oxidation of 3alpha-, 17beta-, 20beta- and 21-hydroxysteroids and 7alpha- and 7beta-hydroxy bile acids (PubMed:10600649, PubMed:12917011). Oxidizes allopregnanolone/brexanolone at the 3alpha-hydroxyl group, which is known to be critical for the activation of gamma-aminobutyric acid receptors (GABAARs) chloride channel (PubMed:19706438, PubMed:28888424). Has phospholipase C-like activity toward cardiolipin and its oxidized species. Likely oxidizes the 2'-hydroxyl in the head group of cardiolipin to form a ketone intermediate that undergoes nucleophilic attack by water and fragments into diacylglycerol, dihydroxyacetone and orthophosphate. Has higher affinity for cardiolipin with oxidized fatty acids and may degrade these species during the oxidative stress response to protect cells from apoptosis (PubMed:26338420). By interacting with intracellular amyloid-beta, it may contribute to the neuronal dysfunction associated with Alzheimer disease (AD) (PubMed:9338779). Essential for structural and functional integrity of mitochondria (PubMed:20077426).
The phospholipase C-like activity toward cardiolipin is inhibited by amyloid-beta peptide.
Ubiquitously expressed in normal tissues but is overexpressed in neurons affected in AD.
Interacts with DERL1 and (via VIM motif) with VCP, suggesting that it forms a membrane complex with DERL1 that serves as a receptor for VCP. Also interacts with DERL2, DERL3 and SELENOK. The SELENOK-SELENOS complex interacts with VCP. Interacts with CCDC47 (By similarity).
Involved in the degradation process of misfolded endoplasmic reticulum (ER) luminal proteins. Participates in the transfer of misfolded proteins from the ER to the cytosol, where they are destroyed by the proteasome in a ubiquitin-dependent manner. Probably acts by serving as a linker between DERL1, which mediates the retrotranslocation of misfolded proteins into the cytosol, and the ATPase complex VCP, which mediates the translocation and ubiquitination.
Truncated SELENOS proteins produced by failed UGA/Sec decoding are ubiquitinated by the CRL2(KLHDC2) and CRL2(KLHDC3) complexes, which recognizes the glycine (Gly) at the C-terminus of truncated SELENOS proteins (PubMed:26138980, PubMed:30526872). Truncated SELENOS proteins produced by failed UGA/Sec decoding are also ubiquitinated by the CRL5(KLHDC1) complex (PubMed:32200094).
3'-to-5'exoribonuclease that preferentially degrades DNA and RNA oligonucleotides composed of only two nucleotides (PubMed:31588022, PubMed:30926754, PubMed:32365187, PubMed:23741365). Binds and degrades longer oligonucleotides with a lower affinity (PubMed:31588022, PubMed:30926754, PubMed:32365187). Plays dual roles in mitochondria, scavenging nanoRNAs (small RNA oligonucleotides of <5 nucleotides) that are produced by the degradosome and clearing short RNAs that are generated by RNA processing (PubMed:31588022, PubMed:30926754, PubMed:32365187). Essential for correct initiation of mitochondrial transcription, degrading mitochondrial RNA dinucleotides to prevent RNA-primed transcription at non-canonical sites in the mitochondrial genome (PubMed:31588022). Essential for embryonic development (By similarity).
3'-to-5'exoribonuclease that preferentially degrades DNA and RNA oligonucleotides composed of only two nucleotides.
Belongs to the oligoribonuclease family.
Expressed in fetal liver, lung and kidney.
Highly expressed in the heart and at lower levels in the lymph nodes, brain, lung, liver, spleen and thymus.
Homodimer (PubMed:31588022, PubMed:30926754, PubMed:32365187). Homotetramer (PubMed:23741365).
Inhibited by adenosine 3',5'-bisphosphate.
Catalyzes the irreversible transamination of the L-tryptophan metabolite L-kynurenine to form kynurenic acid (KA). As a member of the malate-aspartate shuttle, it has a key role in the intracellular NAD(H) redox balance. Is important for metabolite exchange between mitochondria and cytosol, and for amino acid metabolism. Facilitates cellular uptake of long-chain free fatty acids.
In eukaryotes there are cytoplasmic, mitochondrial and chloroplastic isozymes.
Up-regulated by long-time exposure to alcohol.
RTL6 is one of at least 11 genes called Mar or Mart related to long terminal repeat retrotransposons. They do not correspond to functional retrotransposons, but rather to neofunctionalized retrotransposons genes.
Component of the XAB2 complex, a multimeric protein complex composed of XAB2, PRPF19, AQR, ZNF830, ISY1, and PPIE; this complex binds preferentially to RNA. Interacts with XAB2 (PubMed:17981804). Identified in a pentameric intron-binding (IB) complex composed of AQR, XAB2, ISY1, ZNF830 and PPIE that is incorporated into the spliceosome as a preassembled complex (PubMed:25599396). The IB complex does not contain PRPF19 (PubMed:25599396).
May play a role in pre-mRNA splicing as component of the spliceosome (PubMed:25599396). Acts as an important regulator of the cell cycle that participates in the maintenance of genome integrity. During cell cycle progression in embryonic fibroblast, prevents replication fork collapse, double-strand break formation and cell cycle checkpoint activation. Controls mitotic cell cycle progression and cell survival in rapidly proliferating intestinal epithelium and embryonic stem cells. During the embryo preimplantation, controls different aspects of M phase. During early oocyte growth, plays a role in oocyte survival by preventing chromosomal breaks formation, activation of TP63 and reduction of transcription (By similarity).
Phosphorylated in response to DNA damage by the cell cycle checkpoint kinases ATR/ATM.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. 5-hydroxytryptamine receptor (TC 1.A.9.2) subfamily. HTR3B sub-subfamily.
Expressed in the brain cortex, in the caudate nucleus, the hippocampus, the thalamus and the amygdala. Detected in the kidney and testis as well as in monocytes of the spleen, small and large intestine, uterus, prostate, ovary and placenta.
Forms homopentameric as well as heteropentameric serotonin-activated cation-selective channel complexes with HTR3A. The homomeric complex is not functional. Heteropentameric complexes display properties which resemble that of neuronal serotonin-activated channels in vivo.
Forms serotonin (5-hydroxytryptamine/5-HT3)-activated cation-selective channel complexes, which when activated cause fast, depolarizing responses in neurons.
N-glycosylation required for membrane localization.
The HA-stretch region of HTR3B seems to confer increased conductance to HTR3A/HTR3B heteromers compared to that of HTR3A homomers.
Highly expressed in testis, but not in testicular carcinoma. Lower amounts present in most other tissues.
Insulin-regulated facilitative hexose transporter that mediates the transport of glucose and fructose (By similarity). Facilitates hepatic influx of dietary trehalose, which in turn inhibits glucose and fructose influx triggering a starvation signal and hepatic autophagy through activation of AMPK and ULK1 (PubMed:27922102). Also able to mediate the transport of dehydroascorbate.
Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor.
Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway. May be involved in the binding of an intermediate of Fe/S cluster assembly.
Required for biogenesis of the 60S ribosomal subunit.
Belongs to the VWA-containing collagen family.
Trimer or homomer. Secreted as a 135 kDa monomer under reducing conditions and as a homotrimer under non-reducing conditions (By similarity).
Expressed in prostate, skeletal muscle, kidney and placenta (at protein level) (PubMed:11706037). Expressed in brain, cartilage, colon, heart, intestine, kidney, liver, lung, muscle, placenta, and prostate (PubMed:11706037). Also detected in thyroid, trachea and adrenal gland (PubMed:17911633). Low expression in thymus and leukocytes (PubMed:11706037).
Homodimer; disulfide-linked (PubMed:32187518). Heterodimer with IL17RA (PubMed:16785495, PubMed:18684971). Heterodimerization with IL17RA is independent of the cytoplasmic tail (By similarity). Associates with non-glycosylated IL17RA constitutively (By similarity). Binding of IL17A and IL17F induces association with glycosylated IL17RA (By similarity). Forms complexes with 2:1 binding stoichiometry: two receptor chains for one interleukin molecule (PubMed:32187518, PubMed:28827714). IL17A homodimer preferentially drives the formation of IL17RA-IL17RC heterodimeric receptor complex, whereas IL17F homodimer forms predominantly complexes with IL17RC homodimer (PubMed:32187518). IL17A-IL17F forms complexes with IL17RA-IL17RC, but with lower affinity when compared to IL17A homodimer (PubMed:32187518). IL17RC chain cannot distinguish between IL17A and IL17F molecules, potentially enabling the formation of topologically distinct complexes (PubMed:28827714). Interacts (through SEFIR domain and extended downstream region) with TRAF3IP2/ACT1 (phosphorylated) (PubMed:24120361).
Receptor for IL17A and IL17F, major effector cytokines of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity (By similarity). Receptor for IL17A and IL17F, major effector cytokines of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity. Receptor for IL17A and IL17F homodimers as part of a heterodimeric complex with IL17RA (PubMed:16785495). Receptor for the heterodimer formed by IL17A and IL17B as part of a heterodimeric complex with IL17RA (PubMed:18684971). Has also been shown to be the cognate receptor for IL17F and to bind IL17A with high affinity without the need for IL17RA (PubMed:17911633). Upon binding of IL17F homodimer triggers downstream activation of TRAF6 and NF-kappa-B signaling pathway (PubMed:16785495, PubMed:32187518). Induces transcriptional activation of IL33, a potent cytokine that stimulates group 2 innate lymphoid cells and adaptive T-helper 2 cells involved in pulmonary allergic response to fungi (By similarity). Promotes sympathetic innervation of peripheral organs by coordinating the communication between gamma-delta T cells and parenchymal cells. Stimulates sympathetic innervation of thermogenic adipose tissue by driving TGFB1 expression (By similarity). Binding of IL17A-IL17F to IL17RA-IL17RC heterodimeric receptor complex triggers homotypic interaction of IL17RA and IL17RC chains with TRAF3IP2 adapter through SEFIR domains. This leads to downstream TRAF6-mediated activation of NF-kappa-B and MAPkinase pathways ultimately resulting in transcriptional activation of cytokines, chemokines, antimicrobial peptides and matrix metalloproteinases, with potential strong immune inflammation (PubMed:18684971, PubMed:17911633). Primarily induces neutrophil activation and recruitment at infection and inflammatory sites (By similarity). Stimulates the production of antimicrobial beta-defensins DEFB1, DEFB103A, and DEFB104A by mucosal epithelial cells, limiting the entry of microbes through the epithelial barriers (By similarity).
Antigenic tumor-specific truncated splice form.
By IFNG in endothelial cells and in LPS-primed macrophages.
Expressed in peripheral blood monocytes (at protein level).
Homodimer; homodimerizes upon GTP-binding (PubMed:20180847). GDP-bound form remains homodimeric (PubMed:20180847).
Homodimer; homodimerizes upon GTP-binding (PubMed:20180847). GDP-bound is monomeric (PubMed:20180847).
Homodimer; homodimerizes upon GTP-binding, forming a close face-to-face dimer (PubMed:20180847, PubMed:21151871, PubMed:33876762). Heterodimer with other family members, including GBP1, GBP2, GBP3 and GBP4 (PubMed:21151871). May also form tetramers (dimer of dimers) in the presence of GTP (PubMed:20180847). Interacts with NLRP3, possibly in its tetrameric form, and promotes PYCARD/ASC polymerization (PubMed:22461501).
Interferon (IFN)-inducible GTPase that plays important roles in innate immunity against a diverse range of bacterial, viral and protozoan pathogens (By similarity). Hydrolyzes GTP, but in contrast to other family members, does not produce GMP (PubMed:20180847). Following infection, recruited to the pathogen-containing vacuoles or vacuole-escaped bacteria and acts as a positive regulator of inflammasome assembly by promoting the release of inflammasome ligands from bacteria (By similarity). Acts by promoting lysis of pathogen-containing vacuoles, releasing pathogens into the cytosol (By similarity). Following pathogen release in the cytosol, promotes recruitment of proteins that mediate bacterial cytolysis: this liberates ligands that are detected by inflammasomes, such as lipopolysaccharide (LPS) that activates the non-canonical CASP4/CASP11 inflammasome or double-stranded DNA (dsDNA) that activates the AIM2 inflammasome (By similarity). As an activator of NLRP3 inflammasome assembly: promotes selective NLRP3 inflammasome assembly in response to microbial and soluble, but not crystalline, agents (PubMed:22461501). Independently of its GTPase activity, acts as an inhibitor of various viruses infectivity, such as HIV-1, Zika and influenza A viruses, by inhibiting FURIN-mediated maturation of viral envelope proteins (PubMed:26996307, PubMed:31091448).
Isoprenylation is required for proper subcellular location.
Component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1.
Identified in the CTLH complex that contains GID4, RANBP9 and/or RANBP10, MKLN1, MAEA, RMND5A (or alternatively its paralog RMND5B), GID8, ARMC8, WDR26 and YPEL5 (PubMed:17467196, PubMed:29911972). Within this complex, MAEA, RMND5A (or alternatively its paralog RMND5B), GID8, WDR26, and RANBP9 and/or RANBP10 form the catalytic core, while GID4, MKLN1, ARMC8 and YPEL5 have ancillary roles (PubMed:29911972).
AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3).
Belongs to the 5'-AMP-activated protein kinase beta subunit family.
Non-catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Beta non-catalytic subunit acts as a scaffold on which the AMPK complex assembles, via its C-terminus that bridges alpha (PRKAA1 or PRKAA2) and gamma subunits (PRKAG1, PRKAG2 or PRKAG3).
Phosphorylated when associated with the catalytic subunit (PRKAA1 or PRKAA2). Phosphorylated by ULK1 and ULK2; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1, ULK2 and AMPK.
In reproductive tissues the expression of isoform A and isoform B varies as a consequence of developmental and hormonal status. Isoform A and isoform B are expressed in comparable levels in uterine glandular epithelium during the proliferative phase of the menstrual cycle. Expression of isoform B but not of isoform A persists in the glands during mid-secretory phase. In the stroma, isoform A is the predominant form throughout the cycle. Heterogeneous isoform expression between the glands of the endometrium basalis and functionalis is implying region-specific responses to hormonal stimuli.
Increases mitochondrial membrane potential and cellular respiration upon stimulation by progesterone.
Interacts with SMARD1 and UNC45A. Interacts with CUEDC2; the interaction promotes ubiquitination, decreases sumoylation, and represses transcriptional activity. Interacts with PIAS3; the interaction promotes sumoylation of PR in a hormone-dependent manner, inhibits DNA-binding, and alters nuclear export. Interacts with SP1; the interaction requires ligand-induced phosphorylation on Ser-345 by ERK1/2 MAPK. Interacts with PRMT2. Isoform A interacts with NCOR2. Isoform B (but not isoform A) interacts with NCOA2 and NCOA1. Isoform B (but not isoform A) interacts with KLF9. Interacts with GTF2B (PubMed:1517211).
Ligand-dependent transdominant repressor of steroid hormone receptor transcriptional activity including repression of its isoform B, MR and ER. Transrepressional activity may involve recruitment of corepressor NCOR2.
Phosphorylated on multiple serine sites. Several of these sites are hormone-dependent. Phosphorylation on Ser-294 occurs preferentially on isoform B, is highly hormone-dependent and modulates ubiquitination and sumoylation on Lys-388. Phosphorylation on Ser-102 and Ser-345 also requires induction by hormone. Basal phosphorylation on Ser-81, Ser-162, Ser-190 and Ser-400 is increased in response to progesterone and can be phosphorylated in vitro by the CDK2-A1 complex. Increased levels of phosphorylation on Ser-400 also in the presence of EGF, heregulin, IGF, PMA and FBS. Phosphorylation at this site by CDK2 is ligand-independent, and increases nuclear translocation and transcriptional activity. Phosphorylation at Ser-162 and Ser-294, but not at Ser-190, is impaired during the G(2)/M phase of the cell cycle. Phosphorylation on Ser-345 by ERK1/2 MAPK is required for interaction with SP1.
Produced by alternative splicing of isoform B.
Sumoylation is hormone-dependent and represses transcriptional activity. Sumoylation on all three sites is enhanced by PIAS3. Desumoylated by SENP1. Sumoylation on Lys-388, the main site of sumoylation, is repressed by ubiquitination on the same site, and modulated by phosphorylation at Ser-294.
The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Depending on the isoform, progesterone receptor functions as transcriptional activator or repressor.
Transcriptional activator of several progesteron-dependent promoters in a variety of cell types. Involved in activation of SRC-dependent MAPK signaling on hormone stimulation.
Ubiquitination is hormone-dependent and represses sumoylation on the same site. Promoted by MAPK-mediated phosphorylation on Ser-294.
Belongs to the glycosyl hydrolase 31 family.
Belongs to the small GTPase superfamily. Rho family.
Binds GRB7 and PLXNB1. Interacts with UBXD5. Interacts with PLXNA2.
Lacks intrinsic GTPase activity. Has a low affinity for GDP, and constitutively binds GTP. Controls rearrangements of the actin cytoskeleton. Induces the Rac-dependent neuritic process formation in part by disruption of the cortical actin filaments. Causes the formation of many neuritic processes from the cell body with disruption of the cortical actin filaments.
(Microbial infection) Glycosylated at Arg-117 by enteropathogenic E.coli protein NleB1, C.rodentium protein NleB and S.typhimurium protein Ssek1: arginine GlcNAcylation prevents recruitment of caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors.
(Microbial infection) Interacts with human papillomavirus 16/HPV16 protein E6.
(Microbial infection) Interacts with molluscum contagiosum virus proteins MC159L/v-CFLAR and MC160L.
Apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors (PubMed:7538907, PubMed:23955153, PubMed:19118384, PubMed:20935634, PubMed:16762833, PubMed:24025841). The resulting aggregate called the death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation (PubMed:7538907, PubMed:19118384, PubMed:20935634, PubMed:16762833). Active caspase-8 initiates the subsequent cascade of caspases mediating apoptosis (PubMed:16762833). Involved in interferon-mediated antiviral immune response, playing a role in the positive regulation of interferon signaling (PubMed:21109225).
Can self-associate (PubMed:19118384, PubMed:20935634). Interacts with CFLAR, PEA15 and MBD4 (PubMed:10442631, PubMed:12702765). When phosphorylated, part of a complex containing HIPK3 and FAS (PubMed:11034606). May interact with MAVS/IPS1 (PubMed:16127453). Interacts with MOCV v-CFLAR protein and PIDD1 (PubMed:10825539). Interacts (via death domain) with FAS (via death domain) (PubMed:21109225, PubMed:16762833, PubMed:20935634). Interacts with CASP8 (PubMed:16762833). Interacts directly (via DED domain) with NOL3 (via CARD domain); inhibits death-inducing signaling complex (DISC) assembly by inhibiting the increase in FAS-FADD binding induced by FAS activation (By similarity). Interacts with RIPK1, TRADD and CASP8 (By similarity). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity). Interacts with stimulated TNFRSF10B (PubMed:18846110). Interacts with stimulated TNFRSF10B (By similarity).
Contains a death domain involved in the binding of the corresponding domain within Fas receptor.
Expressed in a wide variety of tissues, except for peripheral blood mononuclear leukocytes.
The interaction between the FAS and FADD death domains is crucial for the formation of the death-inducing signaling complex (DISC).
Component of the axonemal radial spoke 1 (RS1) and 2 (RS2) complexes, at least composed of spoke head proteins RSPH1, RSPH3, RSPH9 and the cilia-specific component RSPH4A or sperm-specific component RSPH6A, spoke stalk proteins RSPH14, DNAJB13, DYDC1, ROPN1L and NME5, and the RS1 complex-specific anchor protein IQUB (By similarity). Interacts with RSPH3B (By similarity). Interacts with RSPH4A (By similarity). Interacts with RSPH6A (By similarity).
Expressed in trachea, lungs, airway brushings, and testes.
Functions as part of axonemal radial spoke complexes that play an important part in the motility of sperm and cilia.
The disease is caused by variants affecting the gene represented in this entry. RSPH1 mutations result in a primary ciliary diskinesia phenotype with defects of the radial spokes and the axonemal central pair of microtubules (PubMed:23993197).
Expressed in keratinocytes (at protein level) (PubMed:29043977). Detected in brain (PubMed:16806267).
Protein phosphatase involved in the inactivation of MAP kinases. Has a specificity for the MAPK11/MAPK12/MAPK13/MAPK14 subfamily. It preferably dephosphorylates p38.
Belongs to the glycosyltransferase 29 family.
Expressed in fetal and adult brain, adult heart and skeletal muscle.
Expressed in fetal and adult brain, not detected in adult heart and skeletal muscle.
Involved in the synthesis of gangliosides GD1c, GT1a, GQ1b, GP1c and GT3 from GD1a, GT1b, GM1b and GD3 respectively.
Catalyzes the dephosphorylation and concomitant reactivation of the alpha subunit of the E1 component of the pyruvate dehydrogenase complex.
Heterodimer of a catalytic subunit and a FAD protein of unknown function.
Interacts with VAPA and VAPB. Interaction with VAPB is less efficient than with VAPA (PubMed:16895911). Interacts (via FFAT motif) with MOSPD2 (via MSP domain) (PubMed:29858488).
Phosphorylation on Ser-132 decreases the affinity toward phosphatidylinositol 4-phosphate at Golgi membranes and reduces ceramide transfer activity. Inactivated by hyperphosphorylation of serine residues by CSNK1G2/CK1 that triggers dissociation from the Golgi complex, thus down-regulating ER-to-Golgi transport of ceramide and sphingomyelin synthesis.
Shelters ceramides and diacylglycerol lipids inside its START domain and mediates the intracellular trafficking of ceramides and diacylglycerol lipids in a non-vesicular manner.
The FFAT motif is required for interaction with VAPA, VAPB and MOSPD2.
The PH domain targets the Golgi apparatus.
The START domain recognizes ceramides and diacylglycerol lipids, interacts with membranes, and mediates the intermembrane transfer of ceramides and diacylglycerol lipids.
Was originally reported to have a protein kinase activity and to phosphorylate on Ser and Thr residues the Goodpasture autoantigen (in vitro).
(Microbial infection) Interacts with HIV-1 Tat protein.
Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB7 displays a trypsin-like activity.
Component of the proteasome, a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity.
Expressed at a low level in colonic mucosa. Up-regulated in colorectal cancer tissues.
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.
Converts glycerol-3-phosphate to 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) by incorporating an acyl moiety at the sn-1 position of the glycerol backbone (PubMed:17170135). Also converts LPA into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone (PubMed:19318427). Protects cells against lipotoxicity (PubMed:30846318).
The HXXXXD motif is essential for acyltransferase activity and may constitute the binding site for the phosphate moiety of the glycerol-3-phosphate.
Widely expressed. Expressed in liver, kidney, testis, brain, heart, skeletal muscle, thyroid, prostate, thymus and placenta. Also expressed lung and adipose tissue.
Binds 2 manganese ions per subunit (By similarity). Mn(2+) is inhibitory below pH 8 and activating above pH 8 (PubMed:24892992).
In colorectal cancer tissue, expression is highest in the surface epithelium of normal colonic mucosa adjacent to the cancer tissue but is largely excluded from the crypt bases. Expression is lost or significantly decreased in 78% of tested tumors (at protein level). Ubiquitously expressed in non-cancerous tissues.
Insensitive to okadaic acid (PubMed:15808505). Deubiquitination by WDR48-USP12 complex positively regulates PHLPP1 stability (PubMed:24145035).
Interacts with the nucleotide free form of K-Ras (KRAS) via its LRR repeats (By similarity). Interacts with AKT2, AKT3, PRKCB isoform beta-II, STK4, RPS6KB1, RAF1 (PubMed:17386267, PubMed:18162466, PubMed:19732725, PubMed:21986499, PubMed:24530606). Isoform 1 (predominantly) and isoform 2 interact with BRAP (PubMed:25820252). Interacts with FKBP5; FKBP5 acts as a scaffold for PHLPP1 and Akt (PubMed:19732725). Interacts with SCRIB; SCRIB acts as a scaffold for PHLPP1 and Akt (PubMed:21701506). Interacts with NHERF1; NHERF1 scaffolds a heterotrimeric complex with PTEN at the plasma membrane (PubMed:21804599). Interacts with WDR48 and USP12 (PubMed:24145035).
Protein phosphatase involved in regulation of Akt and PKC signaling. Mediates dephosphorylation in the C-terminal domain hydrophobic motif of members of the AGC Ser/Thr protein kinase family; specifically acts on 'Ser-473' of AKT2 and AKT3, 'Ser-660' of PRKCB and 'Ser-657' of PRKCA (PubMed:15808505, PubMed:17386267, PubMed:18162466). Isoform 2 seems to have a major role in regulating Akt signaling in hippocampal neurons (By similarity). Akt regulates the balance between cell survival and apoptosis through a cascade that primarily alters the function of transcription factors that regulate pro- and antiapoptotic genes. Dephosphorylation of 'Ser-473' of Akt triggers apoptosis and suppression of tumor growth. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation (PubMed:18162466). Dephosphorylates STK4 on 'Thr-387' leading to STK4 activation and apoptosis (PubMed:20513427). Dephosphorylates RPS6KB1 and is involved in regulation of cap-dependent translation (PubMed:21986499). Inhibits cancer cell proliferation and may act as a tumor suppressor (PubMed:19079341). Dephosphorylates RAF1 inhibiting its kinase activity (PubMed:24530606). May act as a negative regulator of K-Ras signaling in membrane rafts (By similarity). Involved in the hippocampus-dependent long-term memory formation (By similarity). Involved in circadian control by regulating the consolidation of circadian periodicity after resetting (By similarity). Involved in development and function of regulatory T-cells (By similarity).
The PH domain is required for interaction with PRKCB and its dephosphorylation.
Associates with the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication (PubMed:27939641). Enhances transcription activation by YY1 (PubMed:14744866). Plays a role in cell cycle regulation (PubMed:17541814, PubMed:27939641).
Interacts with YY1. Interacts with MAD2L2. Interacts with INO80.
Ubiquitous. Detected in small intestine, skeletal muscle, lung, pancreas, brain, stomach, spleen, colon and heart. Detected at very low levels in healthy liver. Highly expressed in most liver carcinomas.
Belongs to the eukaryotic RPB7/RPC8 RNA polymerase subunit family.
Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits. RPB4 and RPB7 form a subcomplex that protrudes from the 10-subunit Pol II core complex.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB7 is part of a subcomplex with RPB4 that binds to a pocket formed by RPB1, RPB2 and RPB6 at the base of the clamp element. The RPB4-RPB7 subcomplex seems to lock the clamp via RPB7 in the closed conformation thus preventing double-stranded DNA to enter the active site cleft. The RPB4-RPB7 subcomplex binds single-stranded DNA and RNA (By similarity). Binds RNA.
Found in a post-splicing messenger ribonucleoprotein (mRNP) complex. Associates with the exon junction complex (EJC). Interacts with SMG1, EST1A, UPF1, UPF3A, UPF3B, EIF4A1 and EIF1.
Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by associating with the nuclear exon junction complex (EJC). Recruited by UPF3B associated with the EJC core at the cytoplasmic side of the nuclear envelope and the subsequent formation of an UPF1-UPF2-UPF3 surveillance complex (including UPF1 bound to release factors at the stalled ribosome) is believed to activate NMD. In cooperation with UPF3B stimulates both ATPase and RNA helicase activities of UPF1. Binds spliced mRNA.
Organ-common type isozyme is found in many different tissues.
Catalyzes the attachment of threonine to tRNA(Thr) in a two-step reaction: threonine is first activated by ATP to form Thr-AMP and then transferred to the acceptor end of tRNA(Thr). Also edits incorrectly charged tRNA(Thr) via its editing domain.
Identified in a complex containing STX6, STX12, VAMP4 and VTI1A (PubMed:17159904). Binds EEA1 (By similarity). Interacts with VPS45A (By similarity). Interacts with MARCHF2; the interaction promotes MARCHF2-mediated ubiquitination and degradation of CFTR (PubMed:23818989). Interacts with MARCHF3 (By similarity). Interacts with GOPC (PubMed:11384996). Interacts with BLTP3B (via C-terminal coiled-coil domain) (PubMed:20163565, PubMed:35499567). Interacts with BAIAP3; this interaction is increased in the presence of calcium (PubMed:28626000). Interacts with VPS13B (By similarity).
SNARE promoting movement of transport vesicles to target membranes. Targets endosomes to the trans-Golgi network, and may therefore function in retrograde trafficking. Together with SNARE STX12, promotes movement of vesicles from endosomes to the cell membrane, and may therefore function in the endocytic recycling pathway.
Belongs to the G-protein coupled receptor 2 family.
Receptor for GRF, coupled to G proteins which activate adenylyl cyclase. Stimulates somatotroph cell growth, growth hormone gene transcription and growth hormone secretion.
A paper describing ATG4D tissue expression has been retracted, due to concerns of image duplication in some of the figures.
Cleaved by CASP3 during apoptosis which leads to increased activity (PubMed:19549685, PubMed:22441018). The cleavage by CASP3 reveals a cryptic mitochondrial targeting sequence immediately downstream of their canonical caspase cleavage sites which leads to mitochondrial import of the protein (PubMed:19549685, PubMed:22441018).
Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins (PubMed:21177865, PubMed:29458288, PubMed:30661429). The protease activity is required for proteolytic activation of ATG8 family proteins: cleaves the C-terminal amino acid of ATG8 proteins MAP1LC3 and GABARAPL2, to reveal a C-terminal glycine (PubMed:21177865). Exposure of the glycine at the C-terminus is essential for ATG8 proteins conjugation to phosphatidylethanolamine (PE) and insertion to membranes, which is necessary for autophagy (By similarity). In addition to the protease activity, also mediates delipidation of ATG8 family proteins (PubMed:29458288, PubMed:33909989). Catalyzes delipidation of PE-conjugated forms of ATG8 proteins during macroautophagy (PubMed:29458288, PubMed:33909989). Also involved in non-canonical autophagy, a parallel pathway involving conjugation of ATG8 proteins to single membranes at endolysosomal compartments, by catalyzing delipidation of ATG8 proteins conjugated to phosphatidylserine (PS) (PubMed:33909989). ATG4D plays a role in the autophagy-mediated neuronal homeostasis in the central nervous system (By similarity). Compared to other members of the family (ATG4A, ATG4B or ATG4C), constitutes the major protein for the delipidation activity, while it promotes weak proteolytic activation of ATG8 proteins (By similarity). Involved in phagophore growth during mitophagy independently of its protease activity and of ATG8 proteins: acts by regulating ATG9A trafficking to mitochondria and promoting phagophore-endoplasmic reticulum contacts during the lipid transfer phase of mitophagy (PubMed:33773106).
Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins.
Plays a role as an autophagy regulator that links mitochondrial dysfunction with apoptosis. The mitochondrial import of ATG4D during cellular stress and differentiation may play important roles in the regulation of mitochondrial physiology, ROS, mitophagy and cell viability.
The cryptic mitochondrial transit peptide is revealed after cleavage by caspase upon oxidative stress and cell death (PubMed:22441018). It acts then as a functional transit peptide, and allows the import of the cleaved protein into the mitochondria (PubMed:22441018).
A chromosomal aberration involving USP16 is a cause of Chronic myelomonocytic leukemia. Inversion inv(21) (q21;q22) with RUNX1/AML1.
Belongs to the peptidase C19 family. USP16 subfamily.
Homotetramer (PubMed:17914355). Associates with late pre-40S ribosomes (PubMed:32129764).
Phosphorylated at the onset of mitosis and dephosphorylated during the metaphase/anaphase transition. Phosphorylation by AURKB enhances the deubiquitinase activity.
Present in all the tissues examined including fetal brain, lung, liver, kidney, and adult heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Specifically deubiquitinates 'Lys-120' of histone H2A (H2AK119Ub), a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator (PubMed:17914355). Deubiquitination of histone H2A is a prerequisite for subsequent phosphorylation at 'Ser-11' of histone H3 (H3S10ph), and is required for chromosome segregation when cells enter into mitosis (PubMed:17914355). In resting B- and T-lymphocytes, phosphorylation by AURKB leads to enhance its activity, thereby maintaining transcription in resting lymphocytes. Regulates Hox gene expression via histone H2A deubiquitination (PubMed:17914355). Prefers nucleosomal substrates (PubMed:17914355). Does not deubiquitinate histone H2B (PubMed:17914355). Also deubiquitinates non-histone proteins, such as ribosomal protein RPS27A: deubiquitination of monoubiquitinated RPS27A promotes maturation of the 40S ribosomal subunit (PubMed:32129764).
The UBP-type zinc finger binds 3 zinc ions that form a pair of cross-braced ring fingers encapsulated within a third zinc finger in the primary structure. It recognizes the C-terminal tail of free ubiquitin.
USP16 may contribute to somatic stem cell defects observed in Down syndrome. USP16 is triplicated in Down syndrome and its overexpression may contribute to proliferation defects in stem cells. Reduction of USP16 levels results in increased proliferation capacity of Down syndrome fibroblasts (PubMed:24025767).
Brain, heart, liver, lung, kidney, skin and placenta.
Catalyzes the NAD(P)(+)-dependent oxidative decarboxylation of the C4 methyl groups of 4-alpha-carboxysterols in post-squalene cholesterol biosynthesis (By similarity). Also plays a role in the regulation of the endocytic trafficking of EGFR (By similarity).
Among normal tissues, present only in Leydig cells. Strongly up-regulated in breast cancers and in brain cancer distant metastasis (at protein level). Up-regulated in prostate cancer cells and in the higher grades of prostate adenocarcinoma (at protein level).
Increases cell migration by inducing filopodia formation at the leading edge of migrating cells. Plays a role in regulation of apoptosis, possibly through control of CASP3. May be involved in a redox-related process.
Isoprenylation facilitates association with the plasma membrane and enhances the migratory phenotype of cells by inducing increased filopodia formation.
Insulin-regulated facilitative glucose transporter, which plays a key role in removal of glucose from circulation. Response to insulin is regulated by its intracellular localization: in the absence of insulin, it is efficiently retained intracellularly within storage compartments in muscle and fat cells. Upon insulin stimulation, translocates from these compartments to the cell surface where it transports glucose from the extracellular milieu into the cell.
Insulin-stimulated phosphorylation of TBC1D4 is required for GLUT4 translocation.
Interacts with NDUFA9 (By similarity). Binds to DAXX (PubMed:11842083). Interacts via its N-terminus with SRFBP1 (PubMed:16647043). Interacts with TRARG1; the interaction is required for proper SLC2A4 recycling after insulin stimulation (By similarity).
Palmitoylated (PubMed:28057756). Palmitoylation by ZDHHC7 controls the insulin-dependent translocation of GLUT4 to the plasma membrane (PubMed:28057756).
Skeletal and cardiac muscles; brown and white fat.
The dileucine internalization motif is critical for intracellular sequestration.
Belongs to the V-ATPase C subunit family.
Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:33065002). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (By similarity). Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is likely to have a specific function in its catalytic activity (By similarity).
Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment. Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is likely to have a specific function in its catalytic activity.
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex. The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H. The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and two accessory subunits.
Probable component of the Integrator (INT) complex, a complex involved in the small nuclear RNAs (snRNA) U1 and U2 transcription and in their 3'-box-dependent processing.
Strongly expressed in numerous cancer cells compared with their non-cancerous counterparts (lung, prostate, colon, stomach and skin).
Acyl-CoA thioesterases are a group of enzymes that catalyze the hydrolysis of acyl-CoAs to the free fatty acid and coenzyme A (CoASH), providing the potential to regulate intracellular levels of acyl-CoAs, free fatty acids and CoASH. Active on long chain acyl-CoAs.
Belongs to the acyl coenzyme A hydrolase family.
Mediates the intracellular transfer of ceramide-1-phosphate (C1P) between organelle membranes and the cell membrane. Required for normal structure of the Golgi stacks. Can bind phosphoceramides with a variety of aliphatic chains, but has a preference for lipids with saturated C16:0 or monounsaturated C18:1 aliphatic chains, and is inefficient with phosphoceramides containing lignoceryl (C24:0). Plays a role in the regulation of the cellular levels of ceramide-1-phosphate, and thereby contributes to the regulation of phospholipase PLA2G4A activity and the release of arachidonic acid. Has no activity with galactosylceramide, lactosylceramide, sphingomyelin, phosphatidylcholine, phosphatidic acid and ceramide. C1P transfer is stimulated by phosphatidylserine in C1P source vesicles (PubMed:28011644). Regulates autophagy, inflammasome mediated IL1B and IL18 processing, and pyroptosis, but not apoptosis (PubMed:29164996).
Ubiquitous. Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes.
Belongs to the WD repeat neurobeachin family.
Binds to type II regulatory subunits of protein kinase A and anchors/targets them to the membrane. May anchor the kinase to cytoskeletal and/or organelle-associated proteins (By similarity).
Predominant in many brain structures. Also expressed at medium levels in spleen, thymus, prostate, testis and ovary. Low level expression is seen in heart, kidney, pancreas, skeletal muscle and intestine.
RII-alpha binding site, predicted to form an amphipathic helix, could participate in protein-protein interactions with a complementary surface on the R-subunit dimer.
Mediates a firm binding of versican V2 to hyaluronic acid. May play a pivotal role in the formation of the hyaluronan-associated matrix in the central nervous system (CNS) which facilitates neuronal conduction and general structural stabilization. Binds to hyaluronic acid (By similarity).
Belongs to the TALE/MEIS homeobox family.
Expressed in the proliferative zones of the fetal neocortex. Expressed at a very high level in the developing ganglionic eminence and at a more moderate level in the cortical plate.
Expressed in various tissues. Expressed at high level in the lymphoid organs of hematopoietic tissues. Also expressed in some regions of the brain, such as the putamen.
Involved in transcriptional regulation. Binds to HOX or PBX proteins to form dimers, or to a DNA-bound dimer of PBX and HOX proteins and thought to have a role in stabilization of the homeoprotein-DNA complex. Isoform 3 is required for the activity of a PDX1:PBX1b:MEIS2b complex in pancreatic acinar cells involved in the transcriptional activation of the ELA1 enhancer; the complex binds to the enhancer B element and cooperates with the transcription factor 1 complex (PTF1) bound to the enhancer A element; MEIS2 is not involved in complex DNA-binding. Probably in complex with PBX1, is involved in transcriptional regulation by KLF4. Isoform 3 and isoform 4 can bind to a EPHA8 promoter sequence containing the DNA motif 5'-CGGTCA-3'; in cooperation with a PBX protein (such as PBX2) is proposed to be involved in the transcriptional activation of EPHA8 in the developing midbrain. May be involved in regulation of myeloid differentiation. Can bind to the DNA sequence 5'-TGACAG-3'in the activator ACT sequence of the D(1A) dopamine receptor (DRD1) promoter and activate DRD1 transcription; isoform 5 cannot activate DRD1 transcription.
Monomer and homodimer (PubMed:26550823). Heterodimer with HOXB13 (Ref.16). Isoform 2 interacts with TLX1. Isoform 3 interacts with HOXA13 and PBX1 isoform PBX1b. Isoform 4 interacts with SP1, SP3 and KLF4. Isoform 4 and isoform 5 interact with PBX1 isoform PBX1a; the interaction partially relieves MEIS2 autoinhibition. Isoform 3 also known as MEIS2b is part of a PDX1:PBX1b:Meis2B complex; Meis2B is recruited by PBX1b and can be replaced by isoform 4 in a small fraction of complexes. Can form trimeric complexes including HOXB8 and PBX2 or PBX3.
This protein is a transcriptional activator. It may play a role in the formation of segmented structures of the embryo. May play an important role in the normal development of the vertebral column (By similarity).
Belongs to the eukaryotic ATPase subunit F6 family.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(0) seems to have nine subunits: a, b, c, d, e, f, g, F6 and 8 (or A6L). Component of an ATP synthase complex composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5PD, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and MP68 (By similarity).
Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(0) domain and the peripheric stalk, which acts as a stator to hold the catalytic alpha(3)beta(3) subcomplex and subunit a/ATP6 static relative to the rotary elements. Also involved in the restoration of oligomycin-sensitive ATPase activity to depleted F1-F0 complexes.
Binds various proteins from the extracellular matrix.
Promotes matrix assembly and cell adhesiveness (By similarity). Can stimulate endothelial cell proliferation, migration, as well as angiogenesis.
Facilitates bidirectional transport of amino acids. May act as a glutamate sensor that regulates glutamate-glutamine cycle and mTOR signaling in the brain. The transport mechanism remains to be elucidated.
Belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM5 sub-subfamily.
Strongly expressed in fetal brain, liver and kidney, and in adult prostate, testis, ovary, colon and peripheral blood leukocytes. Also expressed in a large proportion of Wilms' tumors and rhabdomyosarcomas. In monochromosomal cell lines shows exclusive paternal expression.
Voltage-modulated Ca(2+)-activated, monovalent cation channel (VCAM) that mediates a transient membrane depolarization and plays a central role in taste transduction. Monovalent-specific, non-selective cation channel that mediates the transport of Na(+), K(+) and Cs(+) ions equally well. Activated directly by increases in intracellular Ca(2+), but is impermeable to it. Gating is voltage-dependent and displays rapid activation and deactivation kinetics upon channel stimulation even during sustained elevations in Ca(2+). Also activated by a fast intracellular Ca(2+) increase in response to inositol 1,4,5-triphosphate-producing receptor agonists. The channel is blocked by extracellular acidification. External acidification has 2 effects, a fast reversible block of the current and a slower irreversible enhancement of current inactivation. Is a highly temperature-sensitive, heat activated channel showing a steep increase of inward currents at temperatures between 15 and 35 degrees Celsius. Heat activation is due to a shift of the voltage-dependent activation curve to negative potentials. Activated by arachidonic acid in vitro. May be involved in perception of bitter, sweet and umami tastes. May also be involved in sensing semiochemicals.
Expressed in fetal heart and brain tumors.
Has a particular type of basic domain (presence of a helix-interrupting proline) that binds to the N-box (CACNAG), rather than the canonical E-box (CANNTG).
The C-terminal WRPW motif is a transcriptional repression domain necessary for the interaction with Groucho/TLE family members, transcriptional corepressors recruited to specific target DNA by Hairy-related proteins.
Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family.
Transcriptional repressor of genes that require a bHLH protein for their transcription. Plays an important role as neurogenesis negative regulator (By similarity).
Belongs to the eukaryotic ribosomal protein eL32 family.
Component of the large ribosomal subunit (PubMed:23636399, PubMed:32669547). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399, PubMed:32669547).
Component of the large ribosomal subunit.
B-cell receptor specific for TNFSF13B/TALL1/BAFF/BLyS. Promotes the survival of mature B-cells and the B-cell response.
Highly expressed in spleen and lymph node, and in resting B-cells. Detected at lower levels in activated B-cells, resting CD4+ T-cells, in thymus and peripheral blood leukocytes.
Interacts with M-Ras/MRAS, and RAF1 (PubMed:16630891, PubMed:25137548). Forms a multiprotein complex with Ras (M-Ras/MRAS), Raf (RAF1) and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC) (PubMed:16630891, PubMed:25137548). Interacts with ERBIN; disrupts the interaction with RAF1 and Ras, leading to prevent activation of the Ras signaling pathway (PubMed:16301319). Specifically binds K-Ras/KRAS, M-Ras/MRAS and N-Ras/NRAS but not H-Ras/HRAS (PubMed:9674433). Interacts with LZTR1 (PubMed:30368668).
Regulatory subunit of protein phosphatase 1 (PP1c) that acts as a M-Ras/MRAS effector and participates in MAPK pathway activation. Upon M-Ras/MRAS activation, targets PP1c to specifically dephosphorylate the 'Ser-259' inhibitory site of RAF1 kinase and stimulate RAF1 activity at specialized signaling complexes.
Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells. May play an important role in AUM-cytoskeleton interaction in terminally differentiated urothelial cells. It also contributes to the formation of urothelial glycocalyx which may play an important role in preventing bacterial adherence (By similarity).
Belongs to the acid sphingomyelinase family.
Interacts with TLR4, TLR7, TLR8 and TLR9.
Lipid-modulating phosphodiesterase (PubMed:26095358). Active on the surface of macrophages and dendritic cells and strongly influences macrophage lipid composition and membrane fluidity. Acts as a negative regulator of Toll-like receptor signaling (By similarity). Has in vitro phosphodiesterase activity, but the physiological substrate is unknown (PubMed:26095358). Lacks activity with phosphocholine-containing lipids, but can cleave CDP-choline, and can release phosphate from ATP and ADP (in vitro) (By similarity).
Belongs to the immunoglobulin superfamily. MyBP family.
MYBPC3 mutations may be involved in restrictive cardiomyopathy (RCM), a rare non-ischemic myocardial disease. RCM is characterized by restrictive ventricular-filling physiology in the presence of normal or reduced diastolic and/or systolic volumes (of 1 or both ventricles), biatrial enlargement, and normal ventricular wall thickness.
Substrate for phosphorylation by PKA and PKC. Reversible phosphorylation appears to modulate contraction (By similarity).
Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands. In vitro it binds MHC, F-actin and native thin filaments, and modifies the activity of actin-activated myosin ATPase. It may modulate muscle contraction or may play a more structural role.
Able to mediate mobilization of P-elements when transfected in Drosophila.
Active transposase that specifically recognizes the bipartite 5'-TXXGGGX(A/T)-3' consensus motif and mediates transposition.
A polymorphic GGC triplet repeat located in the 5'-UTR region of RELN gene, which harbors in the normal population 8 to 10 repeats, is significantly increased in autistic patients to carry 4 to 23 additional repeats.
Abundantly produced during brain ontogenesis by the Cajal-Retzius cells and other pioneer neurons located in the telencephalic marginal zone and by granule cells of the external granular layer of the cerebellum. In adult brain, preferentially expressed in GABAergic interneurons of prefrontal cortices, temporal cortex, hippocampus and glutamatergic granule cells of cerebellum. Expression is reduced to about 50% in patients with schizophrenia. Also expressed in fetal and adult liver.
Expressed in fetal and postnatal brain and liver. Expression in postnatal human brain is high in the cerebellum.
Extracellular matrix serine protease that plays a role in layering of neurons in the cerebral cortex and cerebellum. Regulates microtubule function in neurons and neuronal migration. Affects migration of sympathetic preganglionic neurons in the spinal cord, where it seems to act as a barrier to neuronal migration. Enzymatic activity is important for the modulation of cell adhesion. Binding to the extracellular domains of lipoprotein receptors VLDLR and LRP8/APOER2 induces tyrosine phosphorylation of DAB1 and modulation of TAU phosphorylation (By similarity).
Oligomer of disulfide-linked homodimers. Binds to the ectodomains of VLDLR and LRP8/APOER2 (By similarity).
The basic C-terminal region is essential for secretion.
Abundantly expressed in retina, in photoreceptor synapses and inner segments. Expressed in a much lesser extent in several other tissues.
According to some authors, acts by extracting target proteins from membranes (PubMed:21642972). According to a another report, rather acts by targeting proteins to membranes (PubMed:22085962).
Adopts an immunoglobulin-like beta-sandwich fold forming a hydrophobic cavity that captures N-terminally myristoylated target peptides (PubMed:21642972). Phe residues within the hydrophobic beta sandwich are required for myristate binding (PubMed:22085962).
Defects in UNC119 may be a cause of cone-rod dystrophy. A mutation was found in a 57-year-old woman with late-onset cone-rod dystrophy: from 40 year old, the patient suffered from poor night vision, defective color vision and light-sensitivity. At 57 year old, she displayed reduced visual acuity, myopa, macular atrophy and pericentral ring scotomas. The disease was caused by a heterozygous mutation causing premature termination and truncated UNC119 protein with dominant-negative effect.
Interacts with CABP4; in the absence of calcium (By similarity). Interacts with DNM1; leading to a decrease of DNM1 GTPase activity (By similarity). May interact with GTP-bound ARL1. Interacts with ARL2 and ARL3 (GTP-bound forms); this promotes the release of myyristoylated cargo proteins (PubMed:22960633, PubMed:30945270). Found in a complex with ARL3, RP2 and UNC119; RP2 induces hydrolysis of GTP ARL3 in the complex, leading to the release of UNC119. Interacts with NPHP3 (when myristoylated). Interacts with CYS1 (when myristoylated). Interacts with MACIR; interaction only takes place when UNC119 is not liganded with myristoylated proteins. Interacts with LCK; this interaction plays a crucial role in activation of LCK. Interacts with FYN. Interacts with RAB11A; in a cell cycle-dependent manner. Interacts with LYN (via SH2 and SH3 domains); leading to LYN activation. Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases. Interacts with CD44; leading to Shigella invasion. Interacts with KLHL18 (via kelch repeats) (PubMed:31696965). Interacts with PPP3CA, PPP3CB and PPP3CC (By similarity).
Involved in synaptic functions in photoreceptor cells, the signal transduction in immune cells as a Src family kinase activator, endosome recycling, the uptake of bacteria and endocytosis, protein trafficking in sensory neurons and as lipid-binding chaperone with specificity for a diverse subset of myristoylated proteins. Specifically binds the myristoyl moiety of a subset of N-terminally myristoylated proteins and is required for their localization. Binds myristoylated GNAT1 and is required for G-protein localization and trafficking in sensory neurons. Probably plays a role in trafficking proteins in photoreceptor cells. Plays important roles in mediating Src family kinase signals for the completion of cytokinesis via RAB11A.
Phosphorylation suppresses its interaction with KLHL18 and down-regulates its KLHL18-mediated degradation (PubMed:31696965). Phosphorylated more under light conditions than dark conditions (PubMed:31696965). Dephosphorylated by calcineurin (PubMed:31696965).
Bifunctional enzyme that catalyzes the post-translational modification of inactive peptidylglycine precursors to the corresponding bioactive alpha-amidated peptides, a terminal modification in biosynthesis of many neural and endocrine peptides (PubMed:12699694). Alpha-amidation involves two sequential reactions, both of which are catalyzed by separate catalytic domains of the enzyme. The first step, catalyzed by peptidyl alpha-hydroxylating monooxygenase (PHM) domain, is the copper-, ascorbate-, and O2- dependent stereospecific hydroxylation (with S stereochemistry) at the alpha-carbon (C-alpha) of the C-terminal glycine of the peptidylglycine substrate (PubMed:12699694). The second step, catalyzed by the peptidylglycine amidoglycolate lyase (PAL) domain, is the zinc-dependent cleavage of the N-C-alpha bond, producing the alpha-amidated peptide and glyoxylate (PubMed:12699694). Similarly, catalyzes the two-step conversion of an N-fatty acylglycine to a primary fatty acid amide and glyoxylate (By similarity).
In the C-terminal section; belongs to the peptidyl-alpha-hydroxyglycine alpha-amidating lyase family.
In the N-terminal section; belongs to the copper type II ascorbate-dependent monooxygenase family.
PAM activity is inhibited by EDTA, phenylglyoxal and diethyl pyrocarbonate (PubMed:12699694). PAL activity is stimulated by cadmium and inhibited by mercury (By similarity).
Expressed in monocytic cell lines and primary macrophages but not in B or T cells.
Functions as an inhibitor of DNA virus-induced activation of AIM2-like receptors (ALR) inflammasome through interaction with AIM2.
Interacts with AIM2; disrupts assembly of the ALR inflammasome complex (PubMed:24531343). Interacts with IFI16 (PubMed:24531343). Interacts with NLRP3 (PubMed:24531343).
Up-regulated in response to IFNB1 or virus infection.
Atypical homeodomain protein which does not bind DNA and is required to modulate cardiac growth and development. Acts via its interaction with SRF, thereby modulating the expression of SRF-dependent cardiac-specific genes and cardiac development. Prevents SRF-dependent transcription either by inhibiting SRF binding to DNA or by recruiting histone deacetylase (HDAC) proteins that prevent transcription by SRF. Overexpression causes cardiac hypertrophy (By similarity). May act as a tumor suppressor. Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and assists in chaperone-mediated protein refolding (PubMed:27708256).
Interacts with serum response factor (SRF). Component of a large complex containing histone deacetylases such as HDAC2 (By similarity). Interacts with the acetylated forms of HSPA1A and HSPA1B. Interacts with HSPA8 (PubMed:27708256).
Widely expressed. Expressed in the heart, brain, placenta, lung, skeletal and smooth muscles, uterus, urinary bladder, kidney and spleen. Down-regulated in some types of cancer such as lung cancer, choriocarcinoma, head and neck squamous cell carcinoma and oral squamous cell carcinoma.
Interacts with DDRGK1 (By similarity). Interacts with TRIP4; deufmylates TRIP4 (PubMed:25219498).
Thiol-dependent isopeptidase that recognizes and hydrolyzes the peptide bond at the C-terminal Gly of UFM1, a ubiquitin-like modifier protein bound to a number of target proteins (PubMed:25219498, PubMed:32160526). Does not hydrolyze SUMO1 or ISG15 ubiquitin-like proteins (PubMed:25219498). Through TRIP4 deufmylation may regulate intracellular nuclear receptors transactivation and thereby regulate cell proliferation and differentiation (PubMed:25219498).
Belongs to the SNF2/RAD54 helicase family. RAD16 subfamily.
Has both helicase and E3 ubiquitin ligase activities. Possesses intrinsic ATP-dependent nucleosome-remodeling activity; This activity may be required for transcriptional activation or repression of specific target promoters (By similarity). These may include the SERPINE1 and HIV-1 promoters and the SV40 enhancer, to which this protein can bind directly. Plays a role in error-free postreplication repair (PRR) of damaged DNA and maintains genomic stability through acting as a ubiquitin ligase for 'Lys-63'-linked polyubiquitination of chromatin-bound PCNA.
In contrast with other SMARC proteins, there is currently no evidence that it associates with actin or actin-related proteins. It may rather act as a sequence-specific DNA binding ATPase, whose precise function remains to be fully characterized.
Interacts with SP1 and SP3 independently of DNA; the interaction with these transcriptional factors may be required for basal transcription of target genes. Interacts with EGR1; the interaction requires prior binding to DNA and represses c-Rel via a DNA looping mechanism (By similarity). Interacts with GATA4 (By similarity). Interacts with PCNA; the interaction promotes polyubiquitination of PCNA through association with the UBE2B-RAD18 and UBE2V2-UBE2N ubiquitin ligase complexes. Interacts with RAD18, SHPRH, UBE2V2 and UBE2N.
Subject to frequent epigenetic inactivation by promoter methylation in colon cancer.
Binds to and modulates brain Na,K-ATPase subunits ATP1B1 and ATP1B3 and may thereby participate in the regulation of electrical excitability and synaptic transmission. May not display kinase activity.
The protein kinase domain is predicted to be catalytically inactive.
Widely expressed in all tissues examined except in heart. Isoform 1 is expressed in high levels in the brain, skeletal muscle, spleen and testis. Isoform 7 expression has yet to be demonstrated.
(Microbial infection) Interacts with (and methylates) HIV-1 Tat, Rev and Nucleocapsid protein p7 (NC).
(Microbial infection) Interacts with human cytomegalovirus protein UL69.
Arginine methyltransferase that can catalyze the formation of both omega-N monomethylarginine (MMA) and asymmetrical dimethylarginine (aDMA), with a strong preference for the formation of aDMA (PubMed:17898714, PubMed:18077460, PubMed:18079182, PubMed:19405910, PubMed:30420520). Preferentially methylates arginyl residues present in a glycine and arginine-rich domain and displays preference for monomethylated substrates (PubMed:17898714, PubMed:18077460, PubMed:18079182, PubMed:19405910). Specifically mediates the asymmetric dimethylation of histone H3 'Arg-2' to form H3R2me2a (PubMed:17898714, PubMed:18079182, PubMed:18077460). H3R2me2a represents a specific tag for epigenetic transcriptional repression and is mutually exclusive with methylation on histone H3 'Lys-4' (H3K4me2 and H3K4me3) (PubMed:17898714, PubMed:18077460). Acts as a transcriptional repressor of various genes such as HOXA2, THBS1 and TP53 (PubMed:19509293). Repression of TP53 blocks cellular senescence (By similarity). Also methylates histone H2A and H4 'Arg-3' (H2AR3me and H4R3me, respectively). Acts as a regulator of DNA base excision during DNA repair by mediating the methylation of DNA polymerase beta (POLB), leading to the stimulation of its polymerase activity by enhancing DNA binding and processivity (PubMed:16600869). Methylates HMGA1 (PubMed:16157300, PubMed:16159886). Regulates alternative splicing events. Acts as a transcriptional coactivator of a number of steroid hormone receptors including ESR1, ESR2, PGR and NR3C1. Promotes fasting-induced transcriptional activation of the gluconeogenic program through methylation of the CRTC2 transcription coactivator (By similarity). May play a role in innate immunity against HIV-1 in case of infection by methylating and impairing the function of various HIV-1 proteins such as Tat, Rev and Nucleocapsid protein p7 (NC) (PubMed:17267505). Methylates GPS2, protecting GPS2 from ubiquitination and degradation (By similarity). Methylates SIRT7, inhibiting SIRT7 histone deacetylase activity and promoting mitochondria biogenesis (PubMed:30420520).
Automethylation enhances its stability and antiretroviral activity.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Protein arginine N-methyltransferase family. PRMT6 subfamily.
Amino acids 31-34, 96-99 and 241-244 are necessary for interaction with the Importin alpha/Importin beta receptor. The first 18 amino acids, amino acids 69-76 and 179-182 are necessary for interaction with TNPO3. Amino acids 31-34, 96-99 and 241-244 are necessary for nuclear localization.
Monomer (PubMed:22439849). SLBP/pre-mRNA complex interacts with ZNF473 (PubMed:11782445). Interacts with the Importin alpha/Importin beta receptor, LSM1, MIF4GD, TNPO3 and UPF1 (PubMed:15829567, PubMed:16086026, PubMed:18025107). Interaction with LSM1 occurs when histone mRNA is being rapidly degraded during the S phase (PubMed:18172165). Found in a ternary complex with ERI1 and the stem-loop structure of the 3' end of histone mRNA (PubMed:16912046). Associates with polyribosomes (PubMed:12588979). Identified in a histone pre-mRNA complex, at least composed of ERI1, LSM11, SLBP, SNRPB, SYNCRIP and YBX1 (By similarity). Binds in a cooperative manner with ERI1 to the mature 3'-end of histone mRNAs (By similarity).
Phosphorylated on Thr-61 and Thr-62 in the S-phase. Phosphorylation of Thr-62 by CDK1 primes phosphorylation of Thr-61 by CK2. Phosphorylation of Thr-62 is required for its degradation by the proteasome at the end of the S phase. Its degradation is not required for histone mRNA degradation at the end of the S phase. All the phosphorylated forms detected are present in the cytoplasm. Both unphosphorylated and phosphorylated forms bind the stem-loop structure of histone mRNAs. Phosphorylation at Thr-171 increases affinity for histone mRNAs.
RNA-binding protein involved in the histone pre-mRNA processing (PubMed:8957003, PubMed:9049306, PubMed:12588979, PubMed:19155325). Binds the stem-loop structure of replication-dependent histone pre-mRNAs and contributes to efficient 3'-end processing by stabilizing the complex between histone pre-mRNA and U7 small nuclear ribonucleoprotein (snRNP), via the histone downstream element (HDE) (PubMed:8957003, PubMed:9049306, PubMed:12588979, PubMed:19155325). Plays an important role in targeting mature histone mRNA from the nucleus to the cytoplasm and to the translation machinery (PubMed:8957003, PubMed:9049306, PubMed:12588979, PubMed:19155325). Stabilizes mature histone mRNA and could be involved in cell-cycle regulation of histone gene expression (PubMed:8957003, PubMed:9049306, PubMed:12588979, PubMed:19155325). Involved in the mechanism by which growing oocytes accumulate histone proteins that support early embryogenesis (By similarity). Binds to the 5' side of the stem-loop structure of histone pre-mRNAs (By similarity).
Regulated during the cell cycle: protein levels increase 10 to 20 fold in the late G1 and decrease at the S/G2 border.
Ubiquitinated by the CRL2(FEM1A), CRL2(FEM1B) and CRL2(FEM1C) complexes, leading to its degradation.
(Microbial infection) Involved in the endolysosomal trafficking of human coronavirus SARS-CoV-2.
Expressed in liver, kidney, prostate, testis and uterus.
Monomer (PubMed:33758062). Dimer (PubMed:33758062). Interacts with TPCN1 (PubMed:33758061).
Nicotinic acid adenine dinucleotide phosphate (NAADP) binding protein required for NAADP-evoked intracellular calcium release (PubMed:33758061, PubMed:33758062). Confers NAADP-sensitivity to the two pore channels (TPCs) complex (PubMed:33758061). Enables NAADP to activate Ca(2+) release from the endoplasmic reticulum through ryanodine receptors (PubMed:33758062).
Up-regulated in squamous cell carcinoma (SCC) adenocarcinoma (AC), adenosquamous cell carcinoma (ASCC), bronchioalveolar carcinoma (BAC), breast and uterus tumors.
Expressed in brain neurons (at protein level) (PubMed:27333034). Expressed in testis (PubMed:10512762).
Interacts with CTSD; this leads to activation of CTSD.
Plays a role in lysosomal amyloid precursor protein (APP) processing by cleaving and activating CTSD/cathepsin D which leads to APP degradation (PubMed:27333034).
Belongs to the GTR/RAG GTP-binding protein family.
Forms a heterodimer with RRAGA in a sequence-independent manner and RRAGB (PubMed:11073942, PubMed:14660641). Heterodimerization stabilizes RRAG proteins (PubMed:11073942, PubMed:14660641, PubMed:25561175, PubMed:25567906). The GDP-bound form of RRAGD (in complex with the GTP-bound form of RRAGA or RRAGB), interacts with RPTOR, thereby promoting recruitment of mTORC1 to the lysosomes (PubMed:18497260). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator (By similarity). Interacts with NOL8 (PubMed:14660641). Interacts with SH3BP4; the interaction with this negative regulator is most probably direct, preferentially occurs with the inactive GDP-bound form of RRAGD and is negatively regulated by amino acids (PubMed:22575674). The Rag heterodimer interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Interacts with SESN1, SESN2 and SESN3 (PubMed:25259925). The GDP-bound form interacts with TFEB (By similarity). The GDP-bound form interacts with TFE3 (PubMed:32612235).
Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade (PubMed:20381137, PubMed:24095279, PubMed:34607910). Forms heterodimeric Rag complexes with RagA/RRAGA or RagB/RRAGB and cycles between an inactive GTP-bound and an active GDP-bound form: RagD/RRAGD is in its active form when GDP-bound RagD/RRAGD forms a complex with GTP-bound RagA/RRAGA (or RagB/RRAGB) and in an inactive form when GTP-bound RagD/RRAGD heterodimerizes with GDP-bound RagA/RRAGA (or RagB/RRAGB) (PubMed:24095279). In its active form, promotes the recruitment of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB (PubMed:20381137, PubMed:24095279). This is a crucial step in the activation of the MTOR signaling cascade by amino acids (PubMed:20381137, PubMed:24095279). Also plays a central role in the non-canonical mTORC1 complex, which acts independently of RHEB and specifically mediates phosphorylation of MiT/TFE factors TFEB and TFE3: GDP-bound RagD/RRAGD mediates recruitment of MiT/TFE factors TFEB and TFE3 (PubMed:32612235).
The activation of RagD/RRAGD is mediated by a GTPase activating protein (GAP) (PubMed:24095279). In high-amino acid conditions, activated by GTPase activating protein FLCN that stimulates RRAGD GTPase activity to turn it into its active GDP-bound form (PubMed:24095279). In response to amino acid depletion, the GATOR1 complex inactivates RagC/RRAGC by securing the GTP-bound inactive form (By similarity).
Contributes to various developmental events and other processes such as wound healing and cholesterol homeostasis through its interactions with multiple signaling pathways. Wnt signaling inhibitor which competes with WNT2B for binding to Wnt receptor FZD4 and represses WNT2B-dependent development of the peripheral eye. Plays a role in regulating the hair cycle by controlling TGFB1 signaling. Required for the development of the anterior commissure in the brain by inhibiting neurite outgrowth. Essential for terminal differentiation of hippocampal neural stem cells. Plays a role in regulating bone elongation and bone mass by modulating growth plate chondrocyte function and overall body size. Required for development of the inner ear through its involvement in stereocilia formation in inner hair cells. Facilitates wound healing by inhibiting secretion of TGFB1 from macrophages which prevents myofibroblast differentiation, maintaining inflammatory cell quiescence. Plays a role in cholesterol homeostasis by reducing circulating high-density lipoprotein cholesterol, lowering cholesterol efflux capacity and decreasing cholesterol-to-bile acid conversion in the liver. In one study, shown to negatively regulate sympathetic innervation in brown fat, leading to reduced energy expenditure. In another study, shown not to affect brown fat thermogenic capacity, body weight gain or glucose homeostasis.
Interacts with FZD4 (via FZ domain); competes with WNT2B for binding to FZD4, inhibiting Wnt signaling and repressing peripheral eye development (By similarity). Interacts with TGFB1; the interaction contributes to regulation of the hair cycle (By similarity). Interacts with netrin (By similarity). Interacts with CCN2 (PubMed:30232710).
This factor is named 'Tsukushi' because its expression pattern in chick embryos is similar to the shape of the Japanese horsetail plant, tsukushi.
Homodimer; disulfide-linked (PubMed:1610568). Forms a homotetramer (By similarity). Forms a heterotetramer with PRPH2 (By similarity). Homotetramer and heterotetramer core complexes go on to form higher order complexes by formation of intermolecular disulfide bonds (By similarity). Interacts with STX3 (By similarity). Interacts with SNAP25 (By similarity).
Plays a role in rod outer segment (ROS) morphogenesis (By similarity). May play a role with PRPH2 in the maintenance of the structure of ROS curved disks (By similarity). Plays a role in the organization of the ROS and maintenance of ROS disk diameter (By similarity). Involved in the maintenance of the retina outer nuclear layer (By similarity).
Retina photoreceptors (at protein level) (PubMed:1610568, PubMed:8504299). In rim region of ROS disks (PubMed:1610568).
The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry. A digenic form of retinitis pigmentosa 7 results from a mutation in the PRPH2 gene and a null mutation of the ROM1 gene has been reported (PubMed:8202715).
Belongs to the damage-control phosphatase family. Sugar phosphate phosphatase III subfamily.
Has been reportedly associated with a protein carboxyl methyltransferase activity, but whether this protein indeed has such an activity remains to be determined (PubMed:25732820). It has been later shown to belong to a family of metal-dependent phosphatases implicated in metabolite damage-control (PubMed:27322068).
Metal-dependent phosphatase that shows phosphatase activity against several substrates, including fructose-1-phosphate and fructose-6-phosphate (By similarity). Its preference for fructose-1-phosphate, a strong glycating agent that causes DNA damage rather than a canonical yeast metabolite, suggests a damage-control function in hexose phosphate metabolism (By similarity). Has also been shown to have O-methyltransferase activity that methylates glutamate residues of target proteins to form gamma-glutamyl methyl ester residues (PubMed:25732820). Possibly methylates PCNA, suggesting it is involved in the DNA damage response (PubMed:25732820).
Metal-dependent phosphatase that shows phosphatase activity against several substrates, including fructose-1-phosphate and fructose-6-phosphate. Its preference for fructose-1-phosphate, a strong glycating agent that causes DNA damage rather than a canonical yeast metabolite, suggests a damage-control function in hexose phosphate metabolism. Has also been shown to have O-methyltransferase activity that methylates glutamate residues of target proteins to form gamma-glutamyl methyl ester residues. Possibly methylates PCNA, suggesting it is involved in the DNA damage response.
Subfamily III proteins have a conserved RTxK motif about 40-50 residues from the C-terminus; the threonine may be replaced by serine or cysteine.
ARHGAP11B arose from partial duplication of ARHGAP11A on the human lineage after separation from the chimpanzee lineage, but before the divergence from Neandertals.
Although it contains a Rho-GAP domains, does not have GTPase activator activity (PubMed:25721503, PubMed:27957544). The absence of GTPase activator activity is required to promote amplification of basal progenitors (PubMed:27957544). Restoring this activity abolishes ability to promote amplification of basal progenitors during neocortex development (PubMed:27957544).
Hominin-specific protein that promotes development and evolutionary expansion of the brain neocortex (PubMed:25721503, PubMed:27957544, PubMed:30484771, PubMed:32554627, PubMed:33938018). Able to promote amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis, thereby playing a key role in neocortex expansion (PubMed:25721503). Promotes the proliferation of basal progenitors by inhibiting the mitochondrial permeability transition pore (mPTP): delays the opening of the mPTP via interaction with ADP:ATP translocase, thereby increasing mitochondrial Ca(2+) concentration and inducing glutamine catabolism, which is required for basal progenitor proliferation (PubMed:31883789). Does not possess GTPase activator activity: the absence of GTPase activator activity is required to promote amplification of basal progenitors during neocortex development (PubMed:25721503, PubMed:27957544).
Interacts with ADP:ATP translocase components SLC25A4/ANT1 and SLC25A5/ANT2.
Specifically expressed in radial glia cells of cortical neural stem and progenitor cells (NPCs) during neocortex development. Preferentially expressed in apical and basal radial glia (PubMed:25721503). Not detected in cortical neurons and cortical plate (PubMed:25721503).
When expressed in embryonic mouse neocortex, promotes basal progenitor generation and self-renewal, and can increase cortical plate area and induce gyrification (PubMed:25721503, PubMed:33938018). Mice exhibit increased neocortical size and upper-layer neuron numbers persisting into adulthood (PubMed:33938018). Moreover, mice display altered neurobehaviour, characterized by an increased memory flexibility and a reduced anxiety level (PubMed:33938018). When expressed in the developing neocortex of the gyrencephalic ferret, strongly increases proliferative basal radial glia, a progenitor cell type thought to be instrumental for neocortical expansion, resulting in extension of the neurogenic period and an increase in upper-layer neurons (PubMed:30484771). As consequence, the postnatal ferret neocortex displays increased neuron density in the upper cortical layers and expands in both the radial and tangential dimensions (PubMed:30484771). Expression in fetal neocortex of the common marmoset increases the numbers of upper-layer neurons, promoting enlargement of the neocortex and inducing its folding (PubMed:32554627).
Belongs to the grh/CP2 family. Grainyhead subfamily.
Binds DNA as homodimer (PubMed:29309642). Homodimer, also forms heterodimers with GRHL2 or GRHL3 (PubMed:12175488, PubMed:12549979, PubMed:29309642, PubMed:35013237).
GRHL genes (GRHL1, GRHL2 and GRHL3) show a paradoxical lack of redundancy despite their extensive sequence identity in the DNA-binding and protein dimerization domains and the fact that the core consensus DNA binding sites are identical. They have related but remarkably different functions during embryogenesis because of their differential spatiotemporal expression patterns during development.
Isoform 1 is highly expressed in brain, pancreas, tonsil, placenta and kidney. Isoform 2 is highly expressed in brain and liver. Expressed at very low levels in non-steroidogenic cells.
May function as a repressor in tissues where both isoform 1 and isoform 2 are expressed.
Methylation at Arg-9 and Lys-116 may be involved in regulating transcriptional activation.
Transcription factor involved in epithelial development. Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' (PubMed:12175488, PubMed:18288204, PubMed:29309642). Important regulator of DSG1 in the context of hair anchorage and epidermal differentiation, participates in the maintenance of the skin barrier. There is no genetic interaction with GRHL3, nor functional cooperativity due to diverse target gene selectivity during epithelia development (By similarity). May play a role in regulating glucose homeostasis and insulin signaling.
Belongs to the RecA family. RAD51 subfamily.
Essential for the homologous recombination (HR) pathway of DNA repair. Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. Part of the RAD51 paralog protein complexes BCDX2 and CX3 which act at different stages of the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, BCDX2 seems to act downstream of BRCA2 recruitment and upstream of RAD51 recruitment; CX3 seems to act downstream of RAD51 recruitment; both complexes bind predominantly to the intersection of the four duplex arms of the Holliday junction (HJ) and to junction of replication forks. The BCDX2 complex was originally reported to bind single-stranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA. The BCDX2 subcomplex RAD51B:RAD51C exhibits single-stranded DNA-dependent ATPase activity suggesting an involvement in early stages of the HR pathway. Involved in RAD51 foci formation in response to DNA damage suggesting an involvement in early stages of HR probably in the invasion step. Has an early function in DNA repair in facilitating phosphorylation of the checkpoint kinase CHEK2 and thereby transduction of the damage signal, leading to cell cycle arrest and HR activation. Participates in branch migration and HJ resolution and thus is important for processing HR intermediates late in the DNA repair process; the function may be linked to the CX3 complex. Part of a PALB2-scaffolded HR complex containing BRCA2 and which is thought to play a role in DNA repair by HR. Protects RAD51 from ubiquitin-mediated degradation that is enhanced following DNA damage. Plays a role in regulating mitochondrial DNA copy number under conditions of oxidative stress in the presence of RAD51 and XRCC3. Contributes to DNA cross-link resistance, sister chromatid cohesion and genomic stability. Involved in maintaining centrosome number in mitosis.
Expressed in a variety of tissues, with highest expression in testis, heart muscle, spleen and prostate.
Part of the RAD51 paralog protein complexes BCDX2 and CX3; the complexes have a ring-like structure arranged into a flat disc around a central channel (PubMed:12427746, PubMed:11751635, PubMed:11751636, PubMed:11842112, PubMed:11842113, PubMed:14704354). The BCDX2 complex consits of RAD51B, RAD51C, RAD51D and XRCC2; the CX3 complex consists of RAD51C and XRCC3 (PubMed:11751635, PubMed:11842113, PubMed:14704354). The BCDX2 subcomplex RAD51B:RAD51C interacts with RAD51 (PubMed:12427746, PubMed:16395335). Interacts with SWSAP1; involved in homologous recombination repair (PubMed:21965664). Interacts directly with PALB2 which may serve as a scaffold for a HR complex containing PALB2, BRCA2, RAD51C, RAD51 and XRCC3 (PubMed:24141787). Interacts with HELQ (PubMed:24005041).
Stress-induced increase in the mitochondrial levels is seen.
Part of the multisubunit TRAPP (transport protein particle) complex.
Belongs to the WD repeat IPI3/WDR18 family.
Component of the 5FMC complex, at least composed of PELP1, LAS1L, TEX10, WDR18 and SENP3; the complex interacts with methylated CHTOP and ZNF148. Interacts with NOL9. Component of the PELP1 complex, composed of at least PELP1, TEX10 and WDR18. The complex interacts with pre-60S ribosome particles (PubMed:21326211).
Functions as a component of the Five Friends of Methylated CHTOP (5FMC) complex; the 5FMC complex is recruited to ZNF148 by methylated CHTOP, leading to desumoylation of ZNF148 and subsequent transactivation of ZNF148 target genes (PubMed:22872859). Component of the PELP1 complex involved in the nucleolar steps of 28S rRNA maturation and the subsequent nucleoplasmic transit of the pre-60S ribosomal subunit (PubMed:21326211). May play a role during development (By similarity).
Expressed strongly in colorectal cancer cells (PubMed:28040436). Expressed strongly in colorectal cancer tissues compared to wild-type colon samples (at protein level) (PubMed:28040436). Expressed strongly in colorectal cancer tissues compared to wild-type colon samples (PubMed:28040436).
Interacts (via N- and C-terminus) with DDX1 (PubMed:28040436). Interacts (via N- and C-terminus) with C14orf166 (PubMed:28040436). Interacts with FAM98B (PubMed:28040436). Interacts with PLEKHM1 (via N- and C-terminus) (By similarity).
Positively stimulates PRMT1-induced protein arginine methylation (PubMed:28040436). Involved in skeletal homeostasis (By similarity). Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts (By similarity).
Acts as transcriptional activator. Required in the earliest stages in both axial midline development and left-right (LR) asymmetry specification. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'.
Interacts (via the C2H2-type domains 3, 4 and 5) with MDFIC (via the C2H2-type domains 3, 4 and 5); the interaction reduces its transcriptional activity (By similarity). Interacts with KPNA1 and KPNA6. Interacts (via C2H2-type domains 3, 4 and 5) with GLI3; the interaction enhances its transcriptional activity.
Calcium-independent receptor of low affinity for alpha-latrotoxin, an excitatory neurotoxin present in black widow spider venom which triggers massive exocytosis from neurons and neuroendocrine cells. Receptor probably implicated in the regulation of exocytosis.
Expressed very widely in all normal tissues tested. Expression is variable in tumor cell lines, apparently elevated in some lines and absent or markedly reduced in others.
Forms a heterodimer, consisting of a large extracellular region non-covalently linked to a seven-transmembrane moiety.
Proteolytically cleaved into 2 subunits, an extracellular subunit and a seven-transmembrane subunit.
Plays a key role in the organization of epithelial monolayers by regulating the actin cytoskeleton. May be involved in ovary development.
Expressed in a broad spectrum of adult tissues (PubMed:12270931).
Forms homooligomers. Forms heterooligomers with SCUBE1. Forms heterooligomers with SCUBE3 (PubMed:33308444). Interacts with SHH via the cholesterol anchor of the dually lipid-modified SHH (ShhNp) (PubMed:19480626, PubMed:22902404). Interacts with PTCH1 (PubMed:19480626, PubMed:22902404). Interacts with VEGFR2 (PubMed:27834687).
It is unclear how SCUBE2 binds the dilipidated SHH. According to a report, the SHH cholesterol-anchor, but not palmitate, seems to be both necessary and sufficient for SCUBE2-mediated SHH release from the cell membrane (PubMed:22902404). According to a second paper, palmitoylation accelerates the rate of SCUBE2-mediated release (PubMed:22677548). Cholesterol modification is sufficient for a heterologous protein to bind to SCUBE2 and to be secreted in a SCUBE2-dependent manner (PubMed:22902404).
Lipid-binding protein required for SHH long-range signaling by binding to the dually lipid-modified SHH (ShhNp) and by promoting ShhNp mobilization, solubilization and release from the cell membrane (PubMed:22902404, PubMed:22677548). Acts by enhancing the proteolytic processing (shedding) of the lipid-modified N- and C- terminal of ShhNp at the cell surface (PubMed:24522195). Synergizes with DISP1 to increase SHH secretion (PubMed:22902404). Probable cell surface coreceptor for VEGFR2 involved in VEGFR2-mediated angiogenesis (PubMed:27834687).
The CUB domain is important for the interaction with the cholesterol-anchor of SHH. The CUB domain regulates protease recruitment and activation during SHH shedding.
Belongs to the ABC transporter superfamily. ABCD family. Peroxisomal fatty acyl CoA transporter (TC 3.A.1.203) subfamily.
Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that catalyzes the transport of long-chain fatty acids (LCFA)-CoA, dicarboxylic acids-CoA, long-branched-chain fatty acids-CoA and bile acids from the cytosol to the peroxisome lumen for beta-oxydation (PubMed:11248239, PubMed:25168382, PubMed:24333844, PubMed:29397936). Has fatty acyl-CoA thioesterase and ATPase activities (PubMed:29397936). Probably hydrolyzes fatty acyl-CoAs into free fatty acids prior to their ATP-dependent transport into peroxisomes (By similarity). Thus, play a role in regulation of LCFAs and energy metabolism namely, in the degradation and biosynthesis of fatty acids by beta-oxidation (PubMed:25944712, PubMed:24333844).
Homodimers (PubMed:17609205). Can form heterodimers with ABCD1 and ABCD2 (PubMed:10777694, PubMed:10551832, PubMed:17609205). Dimerization is necessary to form an active transporter (PubMed:17609205). Interacts with PEX19; mediates the targeting of ABCD3 to peroxisomes (PubMed:10704444, PubMed:16344115, PubMed:17761678).
Mutation in ABCD3 have been found in two individuals affected by Zellweger syndrome (PubMed:1301993). Later studies, however, showed unambiguously that a PEX1 defect was the underlying cause of the defect in peroxisome biogenesis in these patients (PubMed:9539740).
Ubiquitinated by PEX2 during pexophagy in response to starvation, leading to its degradation.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily.
Constitutively activated by phosphorylation at Ser-232, Ser-372, and Ser-389 in serum-starved cells. Does not require growth factor stimulation for significant kinase activity.
Constitutively active serine/threonine-protein kinase that exhibits growth-factor-independent kinase activity and that may participate in p53/TP53-dependent cell growth arrest signaling and play an inhibitory role during embryogenesis.
Forms a complex with MAPK3/ERK1 but not with MAPK9 or MAPK14 in serum-starved cells.
Phosphorylated at Ser-232, Ser-372, and Ser-389 in serum-starved cells.
Belongs to the SIX/Sine oculis homeobox family.
Expression is detected in Rathke's pouch and overlying ventral diencephalon at carnegie stage 17 and in the anterior and posterior lobes of the pituitary at carnegie stage 20. At fetal stage, expression is observed in the anterior pituitary, and the ventricular zones of the hypothalamus and telencephalic vesicles.
Interacts with EYA4; translocates EYA4 from the cytoplasm to the nucleus and promotes activation of their target genes (By similarity). Interacts with MTA1 and HDAC2; represses its own transcription (By similarity). Interacts with MTA1; facilitates the binding of SIX3 to the core DNA motif of SIX3 promoter (By similarity). Interacts with EYA1; promotes EYA1 translocation to the nucleus (By similarity). Interacts with TLE1 and TLE5 (via Q domain); can act in combination with either TLE1 and/or TLE5 leading to transcriptional repression or activation, respectively. Interacts (via homeobox) with NR4A3; differentially regulates the transcriptional activities NR4A3. Interacts with GMNN. Interacts with TLE4.
Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes. During forebrain development represses WNT1 expression allowing zona limitans intrathalamica formation and thereby ensuring proper anterio-posterior patterning of the diencephalon and formation of the rostral diencephalon. Acts as a direct upstream activator of SHH expression in the rostral diencephalon ventral midline and that in turn SHH maintains its expression. In addition, Six3 activity is required for the formation of the telencephalon. During postnatal stages of brain development is necessary for ependymal cell maturation by promoting the maturation of radial glia into ependymal cells through regulation of neuroblast proliferation and migration. Acts on the proliferation and differentiation of neural progenitor cells through activating transcription of CCND1 and CCND2. During early lens formation plays a role in lens induction and specification by activating directly PAX6 in the presumptive lens ectoderm. In turn PAX6 activates SIX3 resulting in activation of PDGFRA and CCND1 promoting cell proliferation. Also is required for the neuroretina development by directly suppressing WNT8B expression in the anterior neural plate territory. Its action during retina development and lens morphogenesis is TLE5 and TLE4-dependent manner. Furthermore, during eye development regulates several genes expression. Before and during early lens development represses the CRYGF promoter by binding a SIX repressor element. Directly activates RHO transcription, or cooperates with CRX or NRL. Six3 functions also in the formation of the proximodistal axis of the optic cup, and promotes the formation of optic vesicles-like structures. During pituitary development, acts in parallel or alternatively with HESX1 to control cell proliferation through Wnt/beta-catenin pathway (By similarity). Plays a role in eye development by suppressing WNT1 expression and in dorsal-ventral patterning by repressing BMP signaling pathway.
Belongs to the KCNMB (TC 8.A.14.1) family. KCNMB3 subfamily.
Interacts with KCNMA1 tetramer. There are probably 4 molecules of KCMNB3 per KCNMA1 tetramer.
Isoform 1, isoform 3 and isoform 4 are widely expressed. Isoform 2 is expressed placenta, pancreas, kidney and heart. Isoform 1 and isoform 3 are highly expressed in pancreas and testis.
Isoform 4 cytoplasmic N-terminal domain participates in the partial inactivation of KCNMA1, possibly by binding to a receptor site.
Regulatory subunit of the calcium activated potassium KCNMA1 (maxiK) channel. Modulates the calcium sensitivity and gating kinetics of KCNMA1, thereby contributing to KCNMA1 channel diversity. Alters the functional properties of the current expressed by the KCNMA1 channel. Isoform 2, isoform 3 and isoform 4 partially inactivate the current of KCNBMA. Isoform 4 induces a fast and incomplete inactivation of KCNMA1 channel that is detectable only at large depolarizations. In contrast, isoform 1 does not induce detectable inactivation of KCNMA1. Two or more subunits of KCNMB3 are required to block the KCNMA1 tetramer.
The extracellular domain contains disulfide bond essential for the gating mechanism.
The extracellular domain forms gates to block ion permeation, providing a mechanism by which current can be rapidly diminished upon cellular repolarization.
AM and PAMP are potent hypotensive and vasodilatator agents. Numerous actions have been reported most related to the physiologic control of fluid and electrolyte homeostasis. In the kidney, am is diuretic and natriuretic, and both am and pamp inhibit aldosterone secretion by direct adrenal actions. In pituitary gland, both peptides at physiologically relevant doses inhibit basal ACTH secretion. Both peptides appear to act in brain and pituitary gland to facilitate the loss of plasma volume, actions which complement their hypotensive effects in blood vessels.
Highest levels found in pheochromocytoma and adrenal medulla. Also found in lung, ventricle and kidney tissues.
Proton-linked monocarboxylate transporter. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucine, valine and isoleucine, and the ketone bodies acetoacetate, beta-hydroxybutyrate and acetate (By similarity).
Previous published data showed conflicting results on the intracellular location of TANGO2. Has been reported to be located in the Golgi apparatus (PubMed:26805781). However, another study was unable to detect Golgi localization (PubMed:32909282). Has been reported to be located in the mitochondrion by several recent studies (PubMed:32909282, PubMed:36961129, PubMed:35197517). However, no mitochondrial localization was detected in a study which reported that the protein is primarily cytoplasmic (PubMed:31276219).
(Microbial infection) Interacts with HTLV1 Tax protein, possibly affecting the transformation ability of Tax.
(Microbial infection) Interacts with human papillomavirus/HPV type 16 and 18 E6 proteins.
Acts as a scaffolding protein at cell-cell junctions, thereby regulating various cellular and signaling processes. Cooperates with PTEN to modulate the kinase activity of AKT1. Its interaction with PTPRB and tyrosine phosphorylated proteins suggests that it may link receptor tyrosine phosphatase with its substrates at the plasma membrane. In polarized epithelial cells, involved in efficient trafficking of TGFA to the cell surface. Regulates the ability of LPAR2 to activate ERK and RhoA pathways. Regulates the JNK signaling cascade via its interaction with FZD4 and VANGL2.
Interacts with ADRB1, FZD4, FZD7, PTPRB, TGFA and VANGL2. Interacts with unidentified tyrosine phosphorylated proteins (By similarity). Interacts with ADGRB1, LPAR2/EDG4, GRIN2B and PTEN. Does not interact with HTLV TAX2 or TAX3 proteins. Interacts with DLL1 (By similarity). Interacts with PRRG4 (via cytoplasmic domain) (PubMed:23873930).
MAGI3 PDZ domains are used to design peptide ligands that bind and inhibit PDZ domains.
Ubiquitinated following interaction with HPV E6 protein, leading to its degradation by the proteasome. Degradation is independent of E6AP ubiquitin ligase complex.
Belongs to the universal ribosomal protein uL15 family.
Expressed in retinal pigmented epithelial cells.
Uniporter that mediates the transport of neutral amino acids like L-tryptophan, proline and alanine (PubMed:21097500). The transport activity is sodium ions-independent, electroneutral and therefore functions via facilitated diffusion (PubMed:21097500).
The sodium/potassium-transporting ATPase is composed of a catalytic alpha subunit, an auxiliary non-catalytic beta subunit and an additional regulatory subunit. Interacts with regulatory subunit FXYD1.
This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium, providing the energy for active transport of various nutrients.
Belongs to the RFamide neuropeptide family.
Expressed widely in the brain with highest expression levels in the cerebellum, medulla, pituitary, retina, vestibular nucleus, and white matter. Also expressed in the bladder, colon, coronary artery, parathyroid gland, prostate, testis, and thyroid.
Ligand for the G-protein coupled receptor QRFPR/GPR103.
Stimulates feeding behavior, metabolic rate and locomotor activity and increases blood pressure. May have orexigenic activity. May promote aldosterone secretion by the adrenal gland (By similarity).
(Microbial infection) Interacts with JC virus small t antigen.
Belongs to the retinoblastoma protein (RB) family.
During G0 and early G1 phase of the cell cycle, phosphorylated on Ser-639 and on 5 sites within the domain B. Phosphorylation on Ser-672 in G1 leads to its ubiquitin-dependent proteolysis.
Interacts with AATF. Interacts with KMT5B, KMT5C and USP4 (By similarity). Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2. The complex exists in quiescent cells where it represses cell cycle-dependent genes. It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2. Interacts with RINT1. Interacts with PML (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5). Interacts with RBBP9 (By similarity).
Key regulator of entry into cell division. Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases KMT5B and KMT5C, leading to epigenetic transcriptional repression. Controls histone H4 'Lys-20' trimethylation. Probably acts as a transcription repressor by recruiting chromatin-modifying enzymes to promoters. Potent inhibitor of E2F-mediated trans-activation, associates preferentially with E2F5. Binds to cyclins A and E. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein. May act as a tumor suppressor.
Cadherins are calcium-dependent cell adhesion proteins. FAT4 plays a role in the maintenance of planar cell polarity as well as in inhibition of YAP1-mediated neuroprogenitor cell proliferation and differentiation (By similarity).
Heterophilic interaction with DCHS1; this interaction affects their respective protein levels. Interacts (via cytoplasmic domain) with MPDZ. Forms a complex with PALS1 and MPDZ.
In embryos at 9 weeks the strongest expression is detected in the apical neuroepithelium, with weaker staining being present in the subventricular zone and within the cortical plate.
Widely expressed. Expressed in fetal brain, infant brain, brain tumor and colorectal cancer.
Highly glycosylated in the Golgi apparatus during spermiogenesis.
Plays an essential role in anchoring sperm head to the tail. Is responsible for the attachment of the coupling apparatus to the sperm nuclear envelope.
Probable homotrimer. Interacts with DNAJB13.
Sperm (at protein level) (PubMed:27640305). Widely expressed (PubMed:12621555). Conflictingly shown to be specifically expressed in testis (PubMed:21711156).
Medium-wave-sensitive opsin genes vary in number among individuals and, together with a single red pigment gene, reside in a head-to-tail tandem array within the X chromosome. In the GRCh38 reference genome assembly, there are 3 genes in tandem coding for identical proteins AC P04001, AC P0DN77 and P0DN78.
N-glycosylated (PubMed:30948514). O-glycosylated (PubMed:30948514).
Phosphorylated on some or all of the serine and threonine residues present in the C-terminal region.
The three color pigments are found in the cone photoreceptor cells.
Visual pigments are the light-absorbing molecules that mediate vision. They consist of an apoprotein, opsin, covalently linked to cis-retinal.
The GPIb-V-IX complex functions as the vWF receptor and mediates vWF-dependent platelet adhesion to blood vessels. The adhesion of platelets to injured vascular surfaces in the arterial circulation is a critical initiating event in hemostasis.
Actin-binding protein that contains 2 major actin binding sites (PubMed:21685497, PubMed:23184945). Organizes filamentous actin into parallel bundles (PubMed:20393565, PubMed:21685497, PubMed:23184945). Plays a role in the organization of actin filament bundles and the formation of microspikes, membrane ruffles, and stress fibers (PubMed:22155786). Important for the formation of a diverse set of cell protrusions, such as filopodia, and for cell motility and migration (PubMed:20393565, PubMed:21685497, PubMed:23184945). Mediates reorganization of the actin cytoskeleton and axon growth cone collapse in response to NGF (PubMed:22155786).
Composed of four fascin beta-trefoil domains.
Interacts with RUFY3 (via N-terminus); the interaction induces neuron axon development (By similarity). Interacts with NGFR (By similarity). Associates with CTNNB1 (By similarity). Interacts with PLXNB3 (PubMed:21706053).
Phosphorylation at Ser-39 inhibits actin-binding (PubMed:8647875, PubMed:8999969). Phosphorylation is required for the reorganization of the actin cytoskeleton in response to NGF (PubMed:22155786).
Catalytic subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation (PubMed:31831667, PubMed:34653363). N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity. This subunit contains the active site and the acceptor peptide and donor lipid-linked oligosaccharide (LLO) binding pockets (By similarity). STT3A is present in the majority of OST complexes and mediates cotranslational N-glycosylation of most sites on target proteins, while STT3B-containing complexes are required for efficient post-translational glycosylation and mediate glycosylation of sites that have been skipped by STT3A (PubMed:19167329).
Component of the oligosaccharyltransferase (OST) complex (PubMed:31831667). OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits (PubMed:23606741, PubMed:25135935, PubMed:31831667). STT3A complex assembly occurs through the formation of 3 subcomplexes. Subcomplex 1 contains RPN1 and TMEM258, subcomplex 2 contains the STT3A-specific subunits STT3A, DC2/OSTC, and KCP2 as well as the core subunit OST4, and subcomplex 3 contains RPN2, DAD1, and OST48. The STT3A complex can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes (By similarity).
Despite low primary sequence conservation between eukaryotic catalytic subunits and bacterial and archaeal single subunit OSTs (ssOST), structural comparison revealed several common motifs at spatially equivalent positions, like the DXD motif 1 on the external loop 1 and the DXD motif 2 on the external loop 2 involved in binding of the metal ion cofactor and the carboxamide group of the acceptor asparagine, the conserved Glu residue of the TIXE/SVSE motif on the external loop 5 involved in catalysis, as well as the WWDYG and the DK/MI motifs in the globular domain that define the binding pocket for the +2 Ser/Thr of the acceptor sequon. In bacterial ssOSTs, an Arg residue was found to interact with a negatively charged side chain at the -2 position of the sequon. This Arg is conserved in bacterial enzymes and correlates with an extended sequon requirement (Asp-X-Asn-X-Ser/Thr) for bacterial N-glycosylation.
Expressed at high levels in placenta, liver, muscle and pancreas, and at very low levels in brain, lung and kidney. Expressed in skin fibroblasts (at protein level).
Interacts with AP1G1 and AP2A1 components of the adapter protein complexes AP-1 and AP-2. Interacts with the GAE domain proteins GGA1, GGA2 and GGA3 (By similarity).
The WXXF motifs mediate binding of accessory proteins to the ear-domain of AP-1, GGAs and AP-2 through hydrophobic interactions. Selective binding to the GAE domains of AP-1 or to the alpha-ear domain of AP-2 is tuned by the acidic context surrounding the motif and the properties of the second residue of the motif itself. The WXXF motif 1, which is preceded by an acidic residue and has a glycine in second position mediates specific interaction with AP-1. The WXXF motif 2, which is followed by the C-terminal carboxyl group negative charge, allows specific interaction with AP-2 (By similarity).
Interacts with SMARCB1, SIN3B and DDX4. Interacts with piRNA-associated proteins TDRD1, PIWIL1 and PIWIL2 (By similarity). Interacts with TEX19 (By similarity).
Plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. Its association with piP-bodies suggests a participation in the secondary piRNAs metabolic process. Required for the localization of germ-cell factors to the meiotic nuage (By similarity).
Plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. Its association with piP-bodies suggests a participation in the secondary piRNAs metabolic process. Required for the localization of germ-cell factors to the meiotic nuage.
Testis-specific. Expressed in various cancer cell lines, probably due to demethylation of its promoter.
Expressed in spleen, prostate, testis and uterus.
Interacts (via N-terminus) with ATRIP. Interacts with ATM, ATR and MDC1. Interacts with XPA (via N-terminus) upon UV irradiation. Interacts with CEP83, CCDC92, TTBK2, DVL3, NPHP3 and weakly with NPHP4. Interacts with DZIP1 (By similarity).
Phosphorylation at Ser-186 is induced upon DNA-damage caused by treatment with IR irradiation, UV irradiation, hydroxyurea or amphidicolin. Also MDC1-mediated chromatin remodeling is critical for DNA damage-induced phosphorylation.
Plays a role in microtubule organization and/or maintenance for the formation of primary cilia (PC), a microtubule-based structure that protrudes from the surface of epithelial cells. Plays a critical role in G2/M checkpoint and nuclear divisions. A key player in the DNA damage-activated ATR/ATM signaling cascade since it is required for the proper phosphorylation of H2AX, RPA, CHEK2 and CHEK1. Plays a critical role in chromosome segregation, acting as a mediator required for the maintenance of genomic stability through modulation of MDC1, RPA and CHEK1.
Belongs to the prefoldin subunit alpha family.
Binds specifically to cytosolic chaperonin (c-CPN) and transfers target proteins to it. Binds to nascent polypeptide chain and promotes folding in an environment in which there are many competing pathways for nonnative proteins. Represses the transcriptional activity of MYC.
Does not repress transcription activity of MYC.
Heterohexamer of two PFD-alpha type and four PFD-beta type subunits. Binds to MYC; interacts with its N-terminal domain.
Highly expressed in pancreas and skeletal muscle and moderately in other tissues.
Coreceptor for SEMA3A, SEMA3C, SEMA3F and SEMA6D. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, invasive growth and cell migration. Class 3 semaphorins bind to a complex composed of a neuropilin and a plexin. The plexin modulates the affinity of the complex for specific semaphorins, and its cytoplasmic domain is required for the activation of down-stream signaling events in the cytoplasm (By similarity).
Detected in fetal brain, lung, liver and kidney.
Interacts directly with NRP1 and NRP2. Interacts with FARP2, RND1 and KDR/VEGFR2. Binding of SEMA3A leads to dissociation of FARP2 (By similarity).
Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion.
Epidermis, tongue, tonsil, esophagus and carcinomas. Expressed in skin and mucosa (at protein level) (PubMed:30528827).
Pemphigus vulgaris (PV) is a potentially lethal skin disease in which epidermal blisters occur as the result of the loss of cell-cell adhesion caused by the action of autoantibodies against desmoglein 3.
Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain.
Belongs to the transglutaminase superfamily. Transglutaminase family.
By 12-O-tetradecanoylphorbol-13-acetate (TPA) and calcium in NHEK cells.
Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Contributes to the formation of the cornified cell envelope of keratinocytes.
An N-terminal amphipathic helix, the BAR domain and a second amphipathic helix inserted into helix 1 of the BAR domain (N-BAR domain) induce membrane curvature and bind curved membranes.
Implicated in endocytosis. May recruit other proteins to membranes with high curvature (By similarity).
Interacts with ARC (By similarity). Interacts with DNM1, SGIP1 and SYNJ1. Interacts with the huntingtin exon 1 protein (HDEX1P) containing a glutamine repeat in the pathological range and promotes formation of insoluble polyglutamine-containing aggregates in vivo. Interacts with DYDC1. Interacts with FASLG. Interacts with ATXN2. Interacts with BIN2.
Consistent with the observation that mTORC1 signaling regulates cell growth and size in many species, TMEM127 knockdown cells are larger and proliferate at higher rates compared to control cell lines. In contrast, cell proliferation is reduced in cells overexpressing TMEM127 (PubMed:20154675).
Controls cell proliferation acting as a negative regulator of TOR signaling pathway mediated by mTORC1. May act as a tumor suppressor.
Plays a role in motile cilium function, possibly by acting on outer dynein arm assembly (PubMed:24094744). Seems to be important for initiation rather than maintenance of cilium motility (By similarity). Required for correct positioning of the cilium at the apical cell surface, suggesting an additional role in the planar cell polarity (PCP) pathway (By similarity). May suppress canonical Wnt signaling activity (By similarity).
The disease is caused by variants affecting the gene represented in this entry. Cilia in nasal epithelia show the absence of both outer and inner dynein-arm components and complete paralysis.
Authors have revised their sequence, but have not submitted the revised DNA sequence.
Mesenchymal cells of the endometrial stroma.
Required for left-right (L-R) asymmetry determination of organ systems in mammals. May play a role in endometrial bleeding.
The processing of the protein may also occur at the second R-X-X-R site located at AA 132-135. Processing appears to be regulated in a cell-type specific manner.
Transiently expressed before and during menstrual bleeding.
(Microbial infection) Interacts (via N-terminus) with HCV non-structural protein 5A (via N-terminus); this interaction seems to regulate the association of HCV particles with ApoE.
(Microbial infection) Involved in Hepatatis C virus (HCV) assembly and required for HCV entry into hepatocytes.
Highly expressed in liver and small intestine and, at lower levels, in colon, kidney and spleen.
Interacts with DFFA (PubMed:10619428). Interacts with DFFB; inhibited by DFFB (PubMed:10619428). Interacts with APOB. Interacts with PREB/SEC12; facilitating loading of SCAP-SREBP into COPII vesicles (By similarity).
Lipid transferase specifically expressed in hepatocytes, which promotes unilocular lipid droplet formation by mediating lipid droplet fusion (PubMed:35939579). Lipid droplet fusion promotes their enlargement, restricting lipolysis and favoring lipid storage (PubMed:35939579). Localizes on the lipid droplet surface, at focal contact sites between lipid droplets, and mediates atypical lipid droplet fusion by promoting directional net neutral lipid transfer from the smaller to larger lipid droplets (By similarity). The transfer direction may be driven by the internal pressure difference between the contacting lipid droplet pair (By similarity). Promotes lipid exchange and lipid droplet fusion in both small and large lipid droplet-containing hepatocytes (By similarity). In addition to its role in lipid droplet fusion, also involved in cytoplasmic vesicle biogenesis and transport (By similarity). Required for very-low-density lipoprotein (VLDL) lipidation and maturation (By similarity). Probably involved in the biogenesis of VLDL transport vesicles by forming a COPII vesicle coat and facilitating the formation of endoplasmic reticulum-derived large vesicles (By similarity). Also involved in sterol-regulated export of the SCAP-SREBP complex, composed of SCAP, SREBF1/SREBP1 and SREBF2/SREBP2, by promoting loading of SCAP-SREBP into COPII vesicles (By similarity). May also activate apoptosis (PubMed:10619428).
Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex (PubMed:34700328, PubMed:34694004, PubMed:32453425). Associated with ORC2. Interacts with HELB (PubMed:25933514).
Required for initiation of chromosomal DNA replication. Core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built.
Transcript peaks at G1-S transition, but total protein remains constant throughout the cell cycle. Expressed in multiple tissues during embryogenesis, including neural crest-derived structures.
Widely expressed, highest levels are found in adult testis and thymus and in fetal liver.
Acetylation at Lys-6 (H4K5ac), Lys-9 (H4K8ac), Lys-13 (H4K12ac) and Lys-17 (H4K16ac) occurs in coding regions of the genome but not in heterochromatin.
Butyrylation of histones marks active promoters and competes with histone acetylation.
Chromosomal aberrations involving HISTONE H4 is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;6)(q27;p21), with BCL6.
Citrullination at Arg-4 (H4R3ci) by PADI4 impairs methylation.
Glutarylation at Lys-92 (H4K91glu) destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes.
Monomethylated, dimethylated or trimethylated at Lys-21 (H4K20me1, H4K20me2, H4K20me3) (PubMed:12086618, PubMed:15964846, PubMed:17967882). Monomethylation is performed by KMT5A/SET8 (PubMed:15964846). Dimethylation and trimethylation is performed by KMT5B and KMT5C and induces gene silencing (By similarity). Monomethylated at Lys-13 (H4K12me1) by N6AMT1; H4K12me1 modification is present at the promoters of numerous genes encoding cell cycle regulators (PubMed:31061526).
Monomethylation and asymmetric dimethylation at Arg-4 (H4R3me1 and H4R3me2a, respectively) by PRMT1 favors acetylation at Lys-9 (H4K8ac) and Lys-13 (H4K12ac). Demethylation is performed by JMJD6. Symmetric dimethylation on Arg-4 (H4R3me2s) by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.
Phosphorylated by PAK2 at Ser-48 (H4S47ph). This phosphorylation increases the association of H3.3-H4 with the histone chaperone HIRA, thus promoting nucleosome assembly of H3.3-H4 and inhibiting nucleosome assembly of H3.1-H4.
Sumoylated, which is associated with transcriptional repression.
The disease is caused by variants affecting the gene represented in this entry. TEBIVANED1 is caused by variants in H4C3.
The disease is caused by variants affecting the gene represented in this entry. TEBIVANED2 is caused by variants in H4C11.
The disease is caused by variants affecting the gene represented in this entry. TEBIVANED3 is caused by variants in H4C5.
The disease is caused by variants affecting the gene represented in this entry. TEBIVANED4 is caused by variants in H4C9.
The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA (By similarity). Found in a co-chaperone complex with DNJC9, MCM2 and histone H3.3-H4 dimers (PubMed:33857403). Within the complex, interacts with DNJC9 (via C-terminus); the interaction is direct (PubMed:33857403).
The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.
Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins. Monoubiquitinated at Lys-92 of histone H4 (H4K91ub1) in response to DNA damage. The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 Lys-21 methylation (H4K20me).
Ufmylated; monofmylated by UFL1 at Lys-32 (H4K31Ufm1) in response to DNA damage.
Autophosphorylated (PubMed:28202711, PubMed:28720718, PubMed:29127255, PubMed:29212815, PubMed:30635421). Phosphorylation of Ser-910 and either Ser-935 or Ser-1444 facilitates interaction with YWHAG (PubMed:28202711). Phosphorylation of Ser-910 and/or Ser-935 facilitates interaction with SFN (PubMed:28202711).
Expressed in pyramidal neurons in all cortical laminae of the visual cortex, in neurons of the substantia nigra pars compacta and caudate putamen (at protein level). Expressed in neutrophils (at protein level) (PubMed:29127255). Expressed in the brain. Expressed throughout the adult brain, but at a lower level than in heart and liver. Also expressed in placenta, lung, skeletal muscle, kidney and pancreas. In the brain, expressed in the cerebellum, cerebral cortex, medulla, spinal cord occipital pole, frontal lobe, temporal lobe and putamen. Expression is particularly high in brain dopaminoceptive areas.
Homodimer (PubMed:22952686, PubMed:18230735, PubMed:30635421). Interacts with PRKN, PRDX3, and TPCN2 (PubMed:16352719, PubMed:21850687, PubMed:22012985). Interacts with VPS35 and RAB29 (PubMed:23395371). Interacts (via ROC domain) with SEC16A (PubMed:25201882). Interacts with APP; interaction promotes phosphorylation of 'Thr-743' of APP (PubMed:28720718). Interacts with MAPT (PubMed:26014385). Interacts with RAB8A, RAB10, and RAB12 (PubMed:26824392). Interacts with YWHAG; this interaction is dependent on phosphorylation of Ser-910 and either Ser-935 or Ser-1444 (PubMed:28202711). Interacts with SFN; this interaction is dependent on phosphorylation of Ser-910 and/or Ser-935 (PubMed:28202711).
Kinase activity is regulated by the GTPase activity of the ROC domain (PubMed:29212815, PubMed:18230735). GTP-bound LLRK2 kinase activity is stimulated by RAB29 (PubMed:29212815). Inhibited by small molecule inhibitor MLi-2 (PubMed:26824392, PubMed:29127255).
Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, innate immunity, autophagy, and vesicle trafficking (PubMed:20949042, PubMed:22012985, PubMed:26824392, PubMed:27830463, PubMed:29125462, PubMed:28720718, PubMed:29127255, PubMed:30398148, PubMed:29212815, PubMed:30635421, PubMed:21850687, PubMed:23395371, PubMed:17114044, PubMed:24687852, PubMed:26014385, PubMed:25201882). Is a key regulator of RAB GTPases by regulating the GTP/GDP exchange and interaction partners of RABs through phosphorylation (PubMed:26824392, PubMed:28720718, PubMed:29127255, PubMed:30398148, PubMed:29212815, PubMed:29125462, PubMed:30635421). Phosphorylates RAB3A, RAB3B, RAB3C, RAB3D, RAB5A, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB35, and RAB43 (PubMed:26824392, PubMed:28720718, PubMed:29127255, PubMed:30398148, PubMed:29212815, PubMed:29125462, PubMed:30635421, PubMed:23395371). Regulates the RAB3IP-catalyzed GDP/GTP exchange for RAB8A through the phosphorylation of 'Thr-72' on RAB8A (PubMed:26824392). Inhibits the interaction between RAB8A and GDI1 and/or GDI2 by phosphorylating 'Thr-72' on RAB8A (PubMed:26824392). Regulates primary ciliogenesis through phosphorylation of RAB8A and RAB10, which promotes SHH signaling in the brain (PubMed:29125462, PubMed:30398148). Together with RAB29, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose-6-phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner (PubMed:23395371). Regulates neuronal process morphology in the intact central nervous system (CNS) (PubMed:17114044). Plays a role in synaptic vesicle trafficking (PubMed:24687852). Plays an important role in recruiting SEC16A to endoplasmic reticulum exit sites (ERES) and in regulating ER to Golgi vesicle-mediated transport and ERES organization (PubMed:25201882). Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway (PubMed:22012985). The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes (PubMed:22012985). Phosphorylates PRDX3 (PubMed:21850687). By phosphorylating APP on 'Thr-743', which promotes the production and the nuclear translocation of the APP intracellular domain (AICD), regulates dopaminergic neuron apoptosis (PubMed:28720718). Acts as a positive regulator of innate immunity by mediating phosphorylation of RIPK2 downstream of NOD1 and NOD2, thereby enhancing RIPK2 activation (PubMed:27830463). Independent of its kinase activity, inhibits the proteasomal degradation of MAPT, thus promoting MAPT oligomerization and secretion (PubMed:26014385). In addition, has GTPase activity via its Roc domain which regulates LRRK2 kinase activity (PubMed:18230735, PubMed:26824392, PubMed:29125462, PubMed:28720718, PubMed:29212815).
The Roc domain mediates homodimerization and regulates kinase activity.
The seven-bladed WD repeat region is critical for synaptic vesicle trafficking and mediates interaction with multiple vesicle-associated presynaptic proteins (PubMed:24687852). It also mediates homodimerization and regulates kinase activity (PubMed:30635421).
Ubiquitinated by TRIM1; undergoes 'Lys-48'-linked polyubiquitination leading to proteasomal degradation.
Alternates between an inactive form bound to GDP and an active form bound to GTP.
Belongs to the small GTPase superfamily. Ras family.
Interacts with AFDN, the C-terminal domain of RALGDS and RLF, but not with RIN1 and PIK3CA. RLF binds exclusively to the active GTP-bound form. Strongly interacts with BRAF, but only weakly with RAF1. BARF and RAF1 association is dependent upon the GTP-bound state. Interacts with RGL3 (By similarity).
Plays a crucial role in coupling NGF stimulation to the activation of both EPHB2 and MAPK14 signaling pathways and in NGF-dependent neuronal differentiation. Involved in ELK1 transactivation through the Ras-MAPK signaling cascade that mediates a wide variety of cellular functions, including cell proliferation, survival, and differentiation.
Shows rapid uncatalyzed guanine nucleotide dissociation rates, which are much faster than those of most Ras subfamily members.
Stimulation of the NGF and EGF receptor signaling pathways results in rapid and prolonged activation.
Activated by autocatalytic proteolytical processing upon acidification (PubMed:11054422, PubMed:19038966, PubMed:19038967). N-glycosylation is required for processing and activity (PubMed:19038966, PubMed:19038967).
Detected in all tissues examined with highest levels in heart and placenta and relatively similar levels in other tissues.
Incorrectly indicated as originating from bovine.
Inhibited by diisopropyl fluorophosphate (DFP).
Lysosomal serine protease with tripeptidyl-peptidase I activity (PubMed:11054422, PubMed:19038966, PubMed:19038967). May act as a non-specific lysosomal peptidase which generates tripeptides from the breakdown products produced by lysosomal proteinases (PubMed:11054422, PubMed:19038966, PubMed:19038967). Requires substrates with an unsubstituted N-terminus (PubMed:19038966).
Monomer (PubMed:19038967). Interacts with CLN5 (PubMed:19941651). Interacts with CLN3 (PubMed:17237713).
Expressed in pancreas, kidney, liver, placenta, and lung.
Protease-inhibitor that contains multiple distinct protease inhibitor domains. Probably has serine protease- and metalloprotease-inhibitor activity (By similarity).
The second BPTI/Kunitz inhibitor domain is able to inhibit trypsin. It has however no activity toward chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator.
Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. Suvar4-20 subfamily.
Histone methyltransferase that specifically methylates monomethylated 'Lys-20' (H4K20me1) and dimethylated 'Lys-20' (H4K20me2) of histone H4 to produce respectively dimethylated 'Lys-20' (H4K20me2) and trimethylated 'Lys-20' (H4K20me3) and thus regulates transcription and maintenance of genome integrity (PubMed:24396869, PubMed:28114273). In vitro also methylates unmodified 'Lys-20' (H4K20me0) of histone H4 and nucleosomes (PubMed:24396869). H4 'Lys-20' trimethylation represents a specific tag for epigenetic transcriptional repression. Mainly functions in pericentric heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin in these regions. KMT5C is targeted to histone H3 via its interaction with RB1 family proteins (RB1, RBL1 and RBL2) (By similarity). Facilitates TP53BP1 foci formation upon DNA damage and proficient non-homologous end-joining (NHEJ)-directed DNA repair by catalyzing the di- and trimethylation of 'Lys-20' of histone H4 (PubMed:28114273). May play a role in class switch reconbination by catalyzing the di- and trimethylation of 'Lys-20' of histone H4 (By similarity).
Homodimer (By similarity). Interacts with HP1 proteins CBX1, CBX3 and CBX5. Interacts with RB1 family proteins RB1, RBL1 and RBL2 (By similarity).
Inhibited by 6,7-Dichloro-N-cyclopentyl-4-(pyridin-4-yl)phthalazin-1-amine (A-196) with an IC(50) of 144 nM.
Binds UBE2I/UBC9 and two SUMO2 molecules via its N-terminus. The most N-terminal region interacts with the SUMO2 chain that is covalently bound to the UBE2I/UBC9 active site, while the second region interacts with another SUMO2 that is non-covalently associated with the same UBE2I/UBC9 chain.
E3 SUMO-protein ligase; facilitates UBE2I/UBC9-mediated SUMO2 modification of target proteins (PubMed:26524493).
Belongs to the snRNP Sm proteins family.
Component of the precatalytic spliceosome (spliceosome B complex) (PubMed:11991638, PubMed:28781166). Component of the U4/U6-U5 tri-snRNP complex, a building block of the precatalytic spliceosome (spliceosome B complex) (PubMed:10523320, PubMed:28781166, PubMed:26912367). The U4/U6-U5 tri-snRNP complex is composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39, plus LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 (PubMed:26912367). LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 form a heptameric, ring-shaped subcomplex (the LSM2-8 complex) that is part of the U4/U6-U5 tri-snRNP complex and the precatalytic spliceosome (PubMed:10523320, PubMed:26912367, PubMed:28781166).
Plays a role in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex that is involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex) (PubMed:28781166). The heptameric LSM2-8 complex binds specifically to the 3'-terminal U-tract of U6 snRNA (PubMed:10523320).
Defects in MYO1F has been found in a patient with a form of non-syndromic sensorineural hearing loss.
Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Their highly divergent tails are presumed to bind to membranous compartments, which would be moved relative to actin filaments (By similarity).
Involved in down-regulation of E-cadherin which results in reduced cell adhesion. Promotes metastasis.
Belongs to the zona pellucida-binding protein Sp38 family.
Is implicated in sperm-oocyte interaction during fertilization.
Alkaline phosphatase that can hydrolyze various phosphate compounds.
Belongs to the alkaline phosphatase family.
In most mammals there are four different isozymes: placental (ALPP), germ cell (ALPG), intestinal (ALPI) and tissue non-specific (liver/bone/kidney) (ALPL/TNAP).
Higher expression in normal tissues than in tumor cell lines. Highly expressed in peripheral blood lymphocytes, spleen, skeletal muscle, placenta, lung and heart.
Receptor for the cytotoxic ligand TRAIL. Lacks a cytoplasmic death domain and hence is not capable of inducing apoptosis. May protect cells against TRAIL mediated apoptosis by competing with TRAIL-R1 and R2 for binding to the ligand.
Mainly expressed in heart, skeletal muscle and brown adipose tissues.
May be involved in the energy metabolism. Could be a molecular link between myofibrillar stretch-induced signaling pathways and muscle gene expression.
Broadly expressed in different tissues, but high in B- and T-lymphocytes. In brain, expression is restricted to amygdala and frontal cortex.
Catalyzes the hydrolyze of the acetyl group at the sn-2 position of platelet-activating factor (PAF) and its analogs, leading to their inactivation (PubMed:9494101). Hydrolyzes propionyl and butyroyl moieties approximately half as effectively as PAF (By similarity). Also catalyzes transacetylation of the acetyl group from platelet-activating factor (PAF) to lysoplasmalogen and to sphingosine, producing plasmalogen analogs of PAF and N-acetylsphingosine (C2-ceramide) respectively. Has a marked selectivity for phospholipids with short acyl chains at the sn-2 position (By similarity).
Inhibited by phenylmethanesulfonyl fluoride, 3,4,dichloroisocoumarin, diisopropyl fluorophosphate (DFP) and diethyl p-nitrophenyl phosphate (DENP).
Acidic protein which may be involved in interactions with other proteins or DNA.
Belongs to the nucleosome assembly protein (NAP) family.
'Hikeshi' is a traditional Japanese compound word used for a firefighter, smokejumper, or troubleshooter.
Acts as a specific nuclear import carrier for HSP70 proteins following heat-shock stress: acts by mediating the nucleoporin-dependent translocation of ATP-bound HSP70 proteins into the nucleus. HSP70 proteins import is required to protect cells from heat shock damages. Does not translocate ADP-bound HSP70 proteins into the nucleus.
Forms an asymmetric homodimer; required for binding and nuclear import of HSP70 proteins (PubMed:25760597). Interacts with ATP-bound HSP70 proteins (PubMed:22541429). Interacts with NUP62 and NUP153 (via F-X-F-G repeats) (PubMed:22541429). Interacts with HSPA8 (PubMed:25760597).
Belongs to the glycosyltransferase 61 family.
Catalyzes the transfer of a single N-acetylglucosamine from UDP-GlcNAc to a serine or threonine residue in extracellular proteins resulting in their modification with a beta-linked N-acetylglucosamine (O-GlcNAc). Specifically glycosylates the Thr residue located between the fifth and sixth conserved cysteines of folded EGF-like domains.
Imprinted. Promoter methylation of the paternal allele may restrict expression to the maternal allele in leukocytes.
Functions as a GC-rich promoter-specific transactivating transcription factor.
Interacts with GTF2B, GTF2F2, RNA polymerase II and TBP.
Widely expressed. Some isoforms may be specifically expressed in veins and arteries (at protein level). Isoform 4 is widely expressed. Isoform 1, isoform 2 and isoform 3 may be specifically expressed in vascular smooth muscle cells.
Encoded on a bicistronic transcript that code for two proteins, SNRPN and SNURF.
Encoded on a bicistronic transcript that code for two proteins, SNRPN and SNURF. In addition to the primary 1.6-kb bicistronic SNURF-SNRPN transcript, SNURF-only transcript is also detected.
Expressed in heart, skeletal muscle and lymphoblasts (at protein level). Expressed in brain, pancreas, heart, liver, lung, kidney and skeletal muscle.
May be involved in tissue-specific alternative RNA processing events.
Patients with the autoimmune disease systemic lupus erythematosus (SLE) have autoantibodies directed against some of the individual snRNP polypeptides. The most common autoantigen is called Sm. N bears Sm epitopes.
By IFNG/IFN-gamma. Negatively regulated by microRNA-155 (miR155).
Interacts (via C-terminus) with TRIM21 (via C-terminus). Interacts with the BATF-JUNB heterodimer. Interacts with BATF (via bZIP domain); the interaction is direct (By similarity). Interacts with COPS2. Interacts with SPI1 (PubMed:33951726).
Predominantly expressed in lymphoid tissues.
Sumoylated with SUMO3. Desumoylated by SENP1.
Transcription factor that specifically binds to the upstream regulatory region of type I interferon (IFN) and IFN-inducible MHC class I genes (the interferon consensus sequence (ICS)) (PubMed:25122610). Can both act as a transcriptional activator or repressor (By similarity). Plays a negative regulatory role in cells of the immune system (By similarity). Involved in CD8(+) dendritic cell differentiation by forming a complex with the BATF-JUNB heterodimer in immune cells, leading to recognition of AICE sequence (5'-TGAnTCA/GAAA-3'), an immune-specific regulatory element, followed by cooperative binding of BATF and IRF8 and activation of genes (By similarity). Required for the development of plasmacytoid dendritic cells (pDCs), which produce most of the type I IFN in response to viral infection (By similarity). Positively regulates macroautophagy in dendritic cells (PubMed:29434592). Acts as a transcriptional repressor of osteoclast differentiation factors such as NFATC1 and EEIG1 (By similarity).
Ubiquitinated (PubMed:25122610). Ubiquitination by TRIM21 in macrophages, a process that is strongly increased upon interferon gamma stimulation, leds to the enhanced transcriptional activity of target cytokine genes (By similarity). Ubiquitination leads to its degradation by the proteasome (PubMed:25122610).
(Microbial infection) Interacts with hepatitis E virus capsid protein ORF2.
Expressed exclusively in hepatic parenchymal cells.
Mediates the endocytosis of plasma glycoproteins to which the terminal sialic acid residue on their complex carbohydrate moieties has been removed. The receptor recognizes terminal galactose and N-acetylgalactosamine units. After ligand binding to the receptor, the resulting complex is internalized and transported to a sorting organelle, where receptor and ligand are disassociated. The receptor then returns to the cell membrane surface.
The functioning ligand-binding unit of this receptor is thought to be at least a dimer. Interacts with LASS2.
Predominantly expressed in the CNS, particularly in the medulla oblongata, pontine reticular formation, spinal cord, and thalamus. High level in testis whereas lower levels are present in a variety of peripheral tissues including the gastrointestinal tract, genitourinary tract, liver, pancreas, adrenal gland, thyroid gland, lung, trachea, spleen and thymus.
Receptor for the neuromedin-U and neuromedin-S neuropeptides.
Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. In the complex, plays a role in the release of the mitotic checkpoint complex (MCC) from the APC/C: not required for APC/C activity itself, but promotes the turnover of CDC20 and MCC on the APC/C, thereby participating in the responsiveness of the spindle assembly checkpoint. Also required for degradation of CDC20.
The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5.
(Microbial infection) Interacts with adenovirus type 2 PIII.
A cysteine residue is required for ubiquitin-thioester formation.
Activated by NDFIP1- and NDFIP2-binding.
Autoubiquitinated. Ubiquitinated by the SCF(FBXL15) complex, leading to its degradation by the proteasome.
Detected in heart, throughout the brain, placenta, lung, liver, muscle, kidney and pancreas. Also detected in spleen and peripheral blood leukocytes.
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it to proteasomal degradation; in embryonic stem cells (ESCs) the ubiquitination is proposed to regulate POU5F1 protein level. Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T-cells the ubiquitination inhibits activation-induced cell death. Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of NDFIP1 and NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal degradation.
Highly expressed in undifferentiated embryonic stem cells and expression is reduced after embryoid body (EB) formation. Not detectable at day 13 of EB formation; low levels are again detected at day 18 of EB formation.
Interacts with POU5F1, RBP1, EGR2 and SLC11A2 (By similarity). Interacts with SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2 and ATN1. Interacts with ERBB4, NDFIP1 and NDFIP2. Interacts with ARRDC4 (PubMed:23236378). Interacts (via WW domains) with ARRDC1 (via PPxY motifs); ubiquitinates ARRDC1 (PubMed:22315426, PubMed:21191027). Interacts (via WW domains) with ARRDC2 and ARRDC3 (PubMed:21191027).
The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain.
The WW domains mediate interaction with PPxY motif-containing proteins.
Expressed in testis and epididymis (at protein level) (PubMed:12384147, PubMed:12089149, PubMed:15963465). Expressed in endometrium (at protein level); highly expressed during the normal secretory phase, but expression is significantly reduced in the proliferative phase (PubMed:17197897). Expressed at lower levels in adult tissues including bone marrow (at protein level) (PubMed:12372408, PubMed:12384147, PubMed:15963465). Expressed in hematopoietic cells, including CD34(+) leukocytes (PubMed:12384147). Expressed in fetal liver (at protein level), brain, lung, kidney, heart, skeletal muscle, spleen and thymus (PubMed:12372408, PubMed:12384147, PubMed:15963465). Expressed in leukemia cells (PubMed:12384147). Abundantly expressed in ovarian cancer clear-cell adenocarcinoma (PubMed:17581421).
Facilitative organic cation transporter that mediates the transport of carnitine as well as the polyamine spermidine (PubMed:12089149, PubMed:20037140). Mediates the partially Na(+)-dependent bidirectional transport of carnitine (PubMed:12089149). May mediate L-carnitine secretion from testis epididymal epithelium into the lumen which is involved in the maturation of spermatozoa (PubMed:12089149).
Involved in the uptake of clinically used drugs such as anticancer agents doxorubicin and bleomycin.
Forms mixed disulfides with both ERO1A and ERO1B and cargo folding intermediates; the interactions with ERO1A and ERO1B result in their retention in the endoplasmic reticulum (PubMed:11847130, PubMed:29858230). Directly interacts with ITPR1 in a pH-, redox state- and calcium-dependent manner, but not with ITPR2 or ITPR3 (PubMed:15652484). The strength of this interaction inversely correlates with calcium concentration (By similarity).
Mediates thiol-dependent retention in the early secretory pathway, forming mixed disulfides with substrate proteins through its conserved CRFS motif (PubMed:11847130, PubMed:14517240). Inhibits the calcium channel activity of ITPR1 (PubMed:15652484). May have a role in the control of oxidative protein folding in the endoplasmic reticulum (PubMed:11847130, PubMed:29858230, PubMed:14517240). Required to retain ERO1A and ERO1B in the endoplasmic reticulum (PubMed:11847130, PubMed:29858230).
Up-regulated by inducers of the unfolded protein response (UPR), including tunicamycin and dithiothreitol.
(Microbial infection) Interacts with hepatitis C/HCV protein NS5A.
Binds the immunosuppressant FK506 only in its calmodulin/calcium activated form.
Constitutively inactive PPiase, which becomes active when bound to calmodulin and calcium. Seems to act as a chaperone for BCL2, targets it to the mitochondria and modulates its phosphorylation state. The BCL2/FKBP8/calmodulin/calcium complex probably interferes with the binding of BCL2 to its targets. The active form of FKBP8 may therefore play a role in the regulation of apoptosis. Involved in the inhibition of viral infection by influenza A viruses (IAV) (PubMed:28169297).
Homomultimers or heteromultimers (Potential). Forms heterodimer with calmodulin. When activated by calmodulin and calcium, interacts with the BH4 domain of BCL2 and weakly with BCL2L1/BCLX isoform Bcl-X(L). Does not bind and inhibit calcineurin. Interacts with ZFYVE27; may negatively regulate ZFYVE27 phosphorylation.
It is uncertain whether Met-1 or Met-58 is the initiator.
The first part of the cDNA maps to the same locus, but in opposite orientation.
Ubiquitinated by PRKN during mitophagy, leading to its degradation and enhancement of mitophagy. Deubiquitinated by USP30.
Widely expressed. Highest levels seen in the brain. Highly abundant in the retina.
Belongs to the protein kinase superfamily. Tyr protein kinase family.
Belongs to the protein kinase superfamily. Tyr protein kinase family. CSK subfamily.
Could play a significant role in the signal transduction of hematopoietic cells. May regulate tyrosine kinase activity of SRC-family members in brain by specifically phosphorylating their C-terminal regulatory tyrosine residue which acts as a negative regulatory site. It may play an inhibitory role in the control of T-cell proliferation.
Expressed in various myeloid cell lines, detected in brain and lung.
Strongly expressed in testis, low expression in placenta, and very low expression in brain.
Autoubiquitinated, leading to its subsequent proteasomal degradation.
Down-regulated by miR-15b (PubMed:26202983). Down-regulated in BRAFi resistant melanomas, leading to increased levels of JAK1 and possibly promoting BRAFi resistance.
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins, such as RIGI, MAVS/IPS1, IFIH1/MDA5, JAK1 and p53/TP53 (PubMed:15843525, PubMed:17460044, PubMed:17643463, PubMed:26027934, PubMed:26471729, PubMed:25591766, PubMed:27411375). Acts as a negative regulator of type I interferon production by mediating ubiquitination of RIGI at 'Lys-181', leading to RIGI degradation (PubMed:17460044, PubMed:26471729). Mediates ubiquitination and subsequent degradation of p53/TP53 (PubMed:25591766). Mediates ubiquitination and subsequent degradation of JAK1 (PubMed:26027934). Acts as a positive regulator of T-cell activation (PubMed:15843525).
Interacts with UBE2D1 (PubMed:27411375). Interacts with VCP/p97; leading to recruit RNF125 to RIGI and promote ubiquitination of RIGI (PubMed:26471729).
Predominantly expressed in lymphoid tissues, including bone marrow, spleen and thymus. Also weakly expressed in other tissues. Predominant in the CD4(+) and CD8(+) T-cells, suggesting that it is preferentially confined to T-cells.
The C2HC RNF-type zinc finger and the linker region stabilize the RING-type zinc finger, leading to promote binding of the RING-type zinc finger to the ubiquitin-conjugating enzyme E2 (donor ubiquitin) (PubMed:27411375).
Apoptotic regulator capable of exerting proapoptotic and anti-apoptotic activities and plays crucial roles in apoptosis, cell proliferation, and cell cycle control (PubMed:11162435, PubMed:11024045, PubMed:11084335, PubMed:16729033, PubMed:17294084). Its anti-apoptotic activity is mediated through the inhibition of CASP3, CASP7 and CASP9, as well as by its E3 ubiquitin-protein ligase activity (PubMed:11024045, PubMed:16729033). As it is a weak caspase inhibitor, its anti-apoptotic activity is thought to be due to its ability to ubiquitinate DIABLO/SMAC targeting it for degradation thereby promoting cell survival (PubMed:16729033). May contribute to caspase inhibition, by blocking the ability of DIABLO/SMAC to disrupt XIAP/BIRC4-caspase interactions (PubMed:16729033). Protects against apoptosis induced by TNF or by chemical agents such as adriamycin, etoposide or staurosporine (PubMed:11162435, PubMed:11084335, PubMed:11865055). Suppression of apoptosis is mediated by activation of MAPK8/JNK1, and possibly also of MAPK9/JNK2 (PubMed:11865055). This activation depends on TAB1 and MAP3K7/TAK1 (PubMed:11865055). In vitro, inhibits CASP3 and proteolytic activation of pro-CASP9 (PubMed:11024045).
Autoubiquitinated and undergoes proteasome-mediated degradation.
Binds to CASP9. Interaction with DIABLO/SMAC via the BIR domain disrupts binding to CASP9 and apoptotic suppressor activity. Interacts with TAB1. In vitro, interacts with CASP3 and CASP7 via its BIR domain.
Blocks etoposide-induced apoptosis (PubMed:11162435, PubMed:11322947). Protects against natural killer (NK) cell-mediated killing (PubMed:18034418).
Blocks staurosporine-induced apoptosis (PubMed:11322947). Promotes natural killer (NK) cell-mediated killing (PubMed:18034418).
Isoform 1 and isoform 2 are expressed at very low levels or not detectable in most adult tissues. Detected in adult heart, placenta, lung, lymph node, spleen and ovary, and in several carcinoma cell lines. Isoform 2 is detected in fetal kidney, heart and spleen, and at lower levels in adult brain, skeletal muscle and peripheral blood leukocytes.
The RING domain is essential for autoubiquitination.
The truncated protein (tLivin) not only loses its anti-apoptotic effect but also acquires a pro-apoptotic effect.
Interacts with MYOZ1, MYOZ2 and MYOZ3. Interacts with CSRP3. Interacts directly with the N-terminal Ig-like domains of 2 titin (TTN) molecules. Interacts with ANKRD2; the interaction is direct.
Muscle assembly regulating factor. Mediates the antiparallel assembly of titin (TTN) molecules at the sarcomeric Z-disk.
The C-terminal domain appears to be unstructured in solution. It may promote the assembly of higher-order TTN complexes.
Exhibits arylsulfatase activity towards the artificial substrate 4-methylumbelliferyl sulfate (PubMed:7720070, PubMed:9497243). May be essential for the correct composition of cartilage and bone matrix during development (PubMed:7720070). Has no activity toward steroid sulfates (PubMed:7720070).
Expressed in the pancreas, liver and kidney.
Inhibited by millimolar concentrations of warfarin.
The conversion to 3-oxoalanine (also known as C-formylglycine, FGly), of a serine or cysteine residue in prokaryotes and of a cysteine residue in eukaryotes, is critical for catalytic activity.
(Microbial infection) Interaction with HTLV-1 TAX protein favors NFKB1 activation.
Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).
Down-regulated by antioxidants BO-653 and probucol.
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits.
Belongs to the very long-chain fatty acids dehydratase HACD family.
Catalyzes the third of the very long-chain fatty acids (VLCFA) elongation four-step cycle (condensation, reduction, dehydration, and reduction). This endoplasmic reticulum-elongation process is characterized by the addition of two carbons to the lipid chain through each cycle. This enzyme catalyzes the dehydration of the 3-hydroxyacyl-CoA intermediate into trans-2,3-enoyl-CoA, within each cycle of elongation. Therefore, it participates in the production of various VLCFAs involved in multiple biological processes as precursors of membrane lipids and lipid mediators.
Highly expressed in testis, spleen, prostate, colon and heart, followed by moderate expression in thymus, ovary, small intestine, peripheral blood leukocytes, liver, skeletal muscle and pancreas. Weakly detected in kidney, placenta, brain and lung.
May interact with enzymes of the ELO family (including ELOVL1); with those enzymes that mediate condensation, the first of the four steps of the reaction cycle responsible for fatty acids elongation, may be part of a larger fatty acids elongase complex (PubMed:18554506). Interacts with BCAP31 (PubMed:15024066).
Shares some similarity with tyrosine phosphatase proteins but it has probably no phosphatase activity.
Turns over rapidly through degradation by the proteasome system.
Activated by phosphorylation on Ser-486 by an unknown kinase (may be mTORC2 but not confirmed), transforming it into a substrate for PDPK1 which then phosphorylates it on Thr-320.
Expressed in most tissues with highest levels in pancreas, kidney liver, heart and brain and lower levels in lung, placenta and skeletal muscle. Expression is higher in ER-positive breast tumors than ER-negative breast tumors.
Induced by estrogen/ER in breast cancer cells.
Interacts with GSK3B and FLII. Interacts with PDPK1 in a phosphorylation-dependent manner.
Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, proliferation, survival and migration. Up-regulates Na(+) channels: SCNN1A/ENAC and SCN5A, K(+) channels: KCNA3/KV1.3, KCNE1, KCNQ1 and KCNH2/HERG, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channel: BSND, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, amino acid transporters: SLC1A5/ASCT2 and SLC6A19, glutamate transporters: SLC1A3/EAAT1, SLC1A6/EAAT4 and SLC1A7/EAAT5, glutamate receptors: GRIA1/GLUR1 and GRIK2/GLUR6, Na(+)/H(+) exchanger: SLC9A3/NHE3, and the Na(+)/K(+) ATPase. Plays a role in the regulation of renal tubular phosphate transport and bone density. Phosphorylates NEDD4L and GSK3B. Positively regulates ER transcription activity through phosphorylation of FLII. Negatively regulates the function of ITCH/AIP4 via its phosphorylation and thereby prevents CXCR4 from being efficiently sorted to lysosomes.
Two specific sites, one in the kinase domain (Thr-320) and the other in the C-terminal regulatory region (Ser-486), need to be phosphorylated for its full activation.
Associated with ribosomes but is not required for canonical ribosome function and has extra-ribosomal functions (PubMed:14567916, PubMed:17218275, PubMed:23636399, PubMed:32669547). Component of the GAIT (gamma interferon-activated inhibitor of translation) complex which mediates interferon-gamma-induced transcript-selective translation inhibition in inflammation processes (PubMed:23071094). Upon interferon-gamma activation and subsequent phosphorylation dissociates from the ribosome and assembles into the GAIT complex which binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and suppresses their translation (PubMed:23071094). In the GAIT complex interacts with m7G cap-bound eIF4G at or near the eIF3-binding site and blocks the recruitment of the 43S ribosomal complex (PubMed:23071094). Involved in methylation of rRNA (PubMed:17921318).
Belongs to the universal ribosomal protein uL13 family.
Component of the 60S ribosome (PubMed:14567916, PubMed:12962325, PubMed:23636399, PubMed:32669547). Component of the GAIT complex (PubMed:15479637). Interacts with EIF4G1 (PubMed:17218275).
Phosphorylation at Ser-77 upon interferon-gamma treatment in monocytes involves a DAPK1-DAPK3 kinase cascade and is causing release from the ribosome, association with the GAIT complex and subsequent involvement in transcript-selective translation inhibition.
Contributes to oxidative stress resistance by reducing cysteine-sulfinic acid formed under exposure to oxidants in the peroxiredoxins PRDX1, PRDX2, PRDX3 and PRDX4 (PubMed:15448164, PubMed:15590625). Does not act on PRDX5 or PRDX6 (PubMed:15448164, PubMed:15590625). May catalyze the reduction in a multi-step process by acting both as a specific phosphotransferase and a thioltransferase (PubMed:15448164, PubMed:15590625).
Widely expressed with highest levels in kidney, lung, spleen and thymus.
Colon, colon carcinoma cell lines, normal cervical epithelium, carcinomas of the uterine cervix and peripheral blood leukocytes.
In the C-terminal section; belongs to the LDH/MDH superfamily.
In the N-terminal section; belongs to the ubiquitin-conjugating enzyme family. UEV subfamily.
Possible negative regulator of polyubiquitination.
Interacts with soluble adenylyl cyclase (sAC).
Sperm-specific sodium/hydrogen exchanger involved in intracellular pH regulation of spermatozoa. Required for sperm motility and fertility. Involved in sperm cell hyperactivation, a step needed for sperm motility which is essential late in the preparation of sperm for fertilization. Required for the expression and bicarbonate regulation of the soluble adenylyl cyclase (sAC) (By similarity).
The ion transport-like region is related to the membrane segments of voltage-gated ion channels. Its function is unknown (By similarity).
Activated by Ca(2+)/calmodulin. Binding of calmodulin is thought to result in a conformational change and leads to activation through phosphorylation by CAMKK1 (By similarity).
Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade. In vitro phosphorylates transcription factor CREB1 (By similarity).
Mainly expressed in brain with small amounts in skeletal muscles, kidney, spleen and liver. Strongly expressed in forebrain neocortex, striatum and limbic system.
Functions as a dual-specificity transcription factor, regulating the expression of both MAX-network and T-box family target genes. Functions as a repressor or an activator. Binds to 5'-AATTTCACACCTAGGTGTGAAATT-3' core sequence and seems to regulate MYC-MAX target genes. Suppresses transcriptional activation by MYC and inhibits MYC-dependent cell transformation. Function activated by heterodimerization with MAX. This heterodimerization serves the dual function of both generating an E-box-binding heterodimer and simultaneously blocking interaction of a corepressor (By similarity).
Interacts with MAX. Requires dimerization with MAX for E-box binding (By similarity). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Interacts with ZMYND11.
Transcription repression is enhanced or dependent on the presence of the T-box DNA-binding domain.
Heterodimer of an alpha and a beta subunit. Alpha-10 associates with beta-1.
Integrin alpha-10/beta-1 is a receptor for collagen.
The integrin I-domain (insert) is a VWFA domain. Integrins with I-domains do not undergo protease cleavage.
Widely expressed with highest expression in muscle and heart. Found in articular cartilage.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv12.2/KCNH3 sub-subfamily.
Detected only in brain, in particular in the telencephalon. Detected in the cerebral cortex, occipital pole, frontal and temporal lobe, putamen, amygdala, hippocampus and caudate nucleus.
Pore-forming (alpha) subunit of voltage-gated potassium channel. Elicits an outward current with fast inactivation. Channel properties may be modulated by cAMP and subunit assembly.
(Microbial infection) Interacts with SV40 virus large T antigen and this interaction is required for efficient viral replication and sustained viral gene expression in restrictive cell types.
(Microbial infection) May directly function at replication forks, explaining why Simian virus 40 (SV40) interacts with FAM111A to overcome host range restriction.
Autocatalytically cleaved; activating the protein (PubMed:32165630). Autocatalytic cleavage takes place in trans (PubMed:32165630).
Interacts (via PIP-box) with PCNA; then interaction is direct.
Regulated in a cell cycle dependent manner with the lowest expression during G0 or the quiescent phase and with peak expression during G2/M phase (at protein level).
Single-stranded DNA-binding serine protease that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity (PubMed:32165630). DPCs are highly toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription, and which are induced by reactive agents, such as UV light or formaldehyde (PubMed:32165630). Protects replication fork from stalling by removing DPCs, such as covalently trapped topoisomerase 1 (TOP1) adducts on DNA lesion, or poly(ADP-ribose) polymerase 1 (PARP1)-DNA complexes trapped by PARP inhibitors (PubMed:32165630). Required for PCNA loading on replication sites (PubMed:24561620). Promotes S-phase entry and DNA synthesis (PubMed:24561620).
The PIP-box mediates the interaction with PCNA.
Myosin is a hexamer of 2 heavy chains and 4 light chains: interacts with myosin heavy chain MYO19.
Myosin regulatory subunit that plays an important role in regulation of both smooth muscle and nonmuscle cell contractile activity via its phosphorylation. Phosphorylation triggers actin polymerization in vascular smooth muscle. Implicated in cytokinesis, receptor capping, and cell locomotion.
Phosphorylation increases the actin-activated myosin ATPase activity and thereby regulates the contractile activity. It is required to generate the driving force in the migration of the cells but not necessary for localization of myosin-2 at the leading edge. Phosphorylation is reduced following epigallocatechin-3-O-gallate treatment.
Ubiquitously expressed in various hematopoietic cells.
Specifically expressed in prostate and testis.
Component of the DRB sensitivity-inducing factor complex (DSIF complex), which regulates mRNA processing and transcription elongation by RNA polymerase II. DSIF positively regulates mRNA capping by stimulating the mRNA guanylyltransferase activity of RNGTT/CAP1A. DSIF also acts cooperatively with the negative elongation factor complex (NELF complex) to enhance transcriptional pausing at sites proximal to the promoter. Transcriptional pausing may facilitate the assembly of an elongation competent RNA polymerase II complex. DSIF and NELF promote pausing by inhibition of the transcription elongation factor TFIIS/S-II. TFIIS/S-II binds to RNA polymerase II at transcription pause sites and stimulates the weak intrinsic nuclease activity of the enzyme. Cleavage of blocked transcripts by RNA polymerase II promotes the resumption of transcription from the new 3' terminus and may allow repeated attempts at transcription through natural pause sites. DSIF can also positively regulate transcriptional elongation and is required for the efficient activation of transcriptional elongation by the HIV-1 nuclear transcriptional activator, Tat. DSIF acts to suppress transcriptional pausing in transcripts derived from the HIV-1 LTR and blocks premature release of HIV-1 transcripts at terminator sequences.
Interacts with SUPT4H1 to form DSIF. DSIF interacts with the positive transcription elongation factor b complex (P-TEFb complex), which is composed of CDK9 and cyclin-T (CCNT1 or CCNT2). DSIF interacts with RNA polymerase II, and this interaction is reduced by phosphorylation of the C-terminal domain (CTD) of POLR2A by P-TEFb. DSIF also interacts with the NELF complex, which is composed of NELFA, NELFB, NELFD and NELFE, and this interaction occurs following prior binding of DSIF to RNA polymerase II. DSIF also interacts with PRMT1/HRMT1L2, HTATSF1/TATSF1, RNGTT/CAP1A, PRMT5/SKB1, SUPT6H, and can interact with PIN1. Component of a complex which is at least composed of HTATSF1/Tat-SF1, the P-TEFb complex components CDK9 and CCNT1, RNA polymerase II, SUPT5H, and NCL/nucleolin. Interacts with MCM3AP isoform GANP (PubMed:23652018).
Methylated by PRMT1/HRMT1L2 and PRMT5/SKB1. Methylation negatively regulates interaction with P-TEFb and RNA polymerase II.
Phosphorylated by CDK7 and CDK9. Phosphorylation by P-TEFb alleviates transcriptional pausing and can stimulate transcriptional elongation from the HIV-1 LTR. P-TEFb dependent phosphorylation is stimulated by the HIV-1 Tat protein. Phosphorylation may also stimulate interaction with PIN1. Bulk phosphorylation occurs predominantly in mitosis.
Catalyzes the phosphorylation of hexose to hexose 6-phosphate, although at very low level compared to other hexokinases (PubMed:30517626). Has low glucose phosphorylating activity compared to other hexokinases (PubMed:30517626). Involved in glucose homeostasis and hepatic lipid accumulation. Required to maintain whole-body glucose homeostasis during pregnancy; however additional evidences are required to confirm this role (By similarity).
Widely expressed (PubMed:27459389, PubMed:29401404). Highly expressed in the brush border, surface epithelium and the myenteric plexus of the small and large intestines; the acinar centrocytes and interlobular ducts of the pancreas; and the alveolar macrophages in the lungs (at protein level) (PubMed:29401404). Present at moderate level in the thyroid follicular epithelium (at protein level) (PubMed:29401404).
A chromosomal aberration involving NFKB2 is found in a case of B-cell non Hodgkin lymphoma (B-NHL). Translocation t(10;14)(q24;q32) with IGHA1. The resulting oncogene is also called Lyt-10C alpha variant.
A chromosomal aberration involving NFKB2 is found in a cutaneous T-cell leukemia (C-TCL) cell line. This rearrangement produces the p80HT gene which codes for a truncated 80 kDa protein (p80HT).
Component of the NF-kappa-B RelB-p52 complex. Homodimer; component of the NF-kappa-B p52-p52 complex. Component of the NF-kappa-B p65-p52 complex. Component of the NF-kappa-B p52-c-Rel complex. NFKB2/p52 interacts with NFKBIE. Component of a complex consisting of the NF-kappa-B p50-p50 homodimer and BCL3. Directly interacts with MEN1.
Constitutive processing is tightly suppressed by its C-terminal processing inhibitory domain, named PID, which contains the death domain.
In B-cell leukemia (B-CLL) cell line, LB40 and EB308, can be found after heterogeneous chromosomal aberrations, such as internal deletions.
NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. In a non-canonical activation pathway, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. The NF-kappa-B heterodimeric RelB-p52 complex is a transcriptional activator. The NF-kappa-B p52-p52 homodimer is a transcriptional repressor. NFKB2 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p100 and generation of p52 by a cotranslational processing. The proteasome-mediated process ensures the production of both p52 and p100 and preserves their independent function. p52 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. p52 and p100 are respectively the minor and major form; the processing of p100 being relatively poor. Isoform p49 is a subunit of the NF-kappa-B protein complex, which stimulates the HIV enhancer in synergy with p65. In concert with RELB, regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer.
Subsequent to MAP3K14-dependent serine phosphorylation, p100 polyubiquitination occurs then triggering its proteasome-dependent processing.
The C-terminus of p100 might be involved in cytoplasmic retention, inhibition of DNA-binding by p52 homodimers, and/or transcription activation.
The glycine-rich region (GRR) appears to be a critical element in the generation of p52.
While translation occurs, the particular unfolded structure after the GRR repeat promotes the generation of p52 making it an acceptable substrate for the proteasome. This process is known as cotranslational processing. The processed form is active and the unprocessed form acts as an inhibitor (I kappa B-like), being able to form cytosolic complexes with NF-kappa B, trapping it in the cytoplasm. Complete folding of the region downstream of the GRR repeat precludes processing.
Expressed during embryogenesis and in adult kidney.
Forms a DNA-binding heterodimer with transcription factor PBX1.
Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. Also binds to its own promoter. Binds specifically to the motif 5'-CYYNATTA[TG]Y-3'.
Calcium-regulated non-lysosomal thiol-protease.
The VTT domain was previously called the SNARE-assoc domain. As there is no evidence that this domain associates with SNARE proteins, it was renamed as VMP1, TMEM41, and TVP38 (VTT) domain.
Highly expressed in adult T-cell leukemia cell line.
Interacts with MCL1 (PubMed:15694340, PubMed:17374615, PubMed:17389404). Interacts with BCL2A1 (Ref.11). Interacts with BAX (PubMed:15705586). Interacts with BCL2L10 (PubMed:23563182).
Promotes activation of caspases and apoptosis. Promotes mitochondrial membrane changes and efflux of apoptogenic proteins from the mitochondria. Contributes to p53/TP53-dependent apoptosis after radiation exposure. Promotes proteasomal degradation of MCL1. Competes with BAK1 for binding to MCL1 and can displace BAK1 from its binding site on MCL1 (By similarity). Competes with BIM/BCL2L11 for binding to MCL1 and can displace BIM/BCL2L11 from its binding site on MCL1.
The BH3 motif is essential for pro-apoptotic activity.
Up-regulated by p53/TP53, phorbol esters, double-stranded RNA, IFNB1/IFN-beta and viruses.
(Microbial infection) Antiviral activity is antagonized by oncoproteins, such as papillomavirus (HPV) protein E7 and adenovirus early E1A protein (PubMed:26405230). Such oncoproteins prevent the ability to sense cytosolic DNA (PubMed:26405230).
(Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1 on both 'Lys-48' and 'Lys-63'-linked ubiquitin chains; leading to inhibition of cGAS-STING signaling.
(Microbial infection) Interacts with Chikungunya virus non-structural protein 1; this interaction results in inhibition of cGAS-STING signaling and increased levels of palmitoylated nsP1 and protein stabilization.
(Microbial infection) Interacts with adenovirus early E1A protein.
(Microbial infection) Interacts with herpes simplex virus 1 protein ICP34.5; this interaction inhibits the intracellular DNA sensing pathway.
(Microbial infection) Interacts with human cytomegalovirus proteins UL94, UL42 and UL138; these interactions result in the inhibition of cGAS-STING signaling.
(Microbial infection) Interacts with human papillomavirus (HPV) protein E7.
(Microbial infection) Interacts with varivella virus protein 39; this interaction results in the inhibition of cGAS-STING signaling.
Activated upon binding to the hydrolysis-resistant 2'3'-cG(s)A(s)MP, an analog of cGAMP, in which phosphodiester linkages are replaced by phosphothioate linkages (PubMed:25344812). Specifically inhibited by small-molecule H-151 (N-(4-ethylphenyl)-N'-1H-indol-3-yl-urea), which covalently binds Cys-91 and prevents palmitoylation and subsequent activation of STING1 (PubMed:29973723, PubMed:35045565). In contrast to mouse protein, not activated by anticancer molecule 5,6-dimethylxanthenone 4-acetic acid (DMXAA) (PubMed:26669264, PubMed:23910378, PubMed:25199835). Inhibited by compound 18 ([(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]acetate), a competitive inhibitor with slow dissociation kinetics and good oral bioavailability (PubMed:30655953).
Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta) (PubMed:18724357, PubMed:18818105, PubMed:19433799, PubMed:19776740, PubMed:23027953, PubMed:23910378, PubMed:23747010, PubMed:29973723, PubMed:30842659, PubMed:35045565, PubMed:27801882, PubMed:36808561). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm (PubMed:26300263). Acts by binding cyclic dinucleotides: recognizes and binds cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced by CGAS in response to DNA virus in the cytosol (PubMed:21947006, PubMed:23258412, PubMed:23707065, PubMed:23722158, PubMed:26229117, PubMed:23910378, PubMed:23747010, PubMed:30842659). Upon binding of c-di-GMP or cGAMP, STING1 oligomerizes, translocates from the endoplasmic reticulum and is phosphorylated by TBK1 on the pLxIS motif, leading to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent anti-viral state (PubMed:22394562, PubMed:25636800, PubMed:29973723, PubMed:30842653, PubMed:35045565). In addition to promote the production of type I interferons, plays a direct role in autophagy (PubMed:30568238, PubMed:30842662). Following cGAMP-binding, STING1 buds from the endoplasmic reticulum into COPII vesicles, which then form the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) (PubMed:30842662). The ERGIC serves as the membrane source for WIPI2 recruitment and LC3 lipidation, leading to formation of autophagosomes that target cytosolic DNA or DNA viruses for degradation by the lysosome (PubMed:30842662). The autophagy- and interferon-inducing activities can be uncoupled and autophagy induction is independent of TBK1 phosphorylation (PubMed:30568238, PubMed:30842662). Autophagy is also triggered upon infection by bacteria: following c-di-GMP-binding, which is produced by live Gram-positive bacteria, promotes reticulophagy (By similarity). Exhibits 2',3' phosphodiester linkage-specific ligand recognition: can bind both 2'-3' linked cGAMP (2'-3'-cGAMP) and 3'-3' linked cGAMP but is preferentially activated by 2'-3' linked cGAMP (PubMed:26300263, PubMed:23910378, PubMed:23747010). The preference for 2'-3'-cGAMP, compared to other linkage isomers is probably due to the ligand itself, whichs adopts an organized free-ligand conformation that resembles the STING1-bound conformation and pays low energy costs in changing into the active conformation (PubMed:26150511). May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons (PubMed:18724357). May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II) (By similarity).
Homodimer; forms a homodimer in absence of cyclic nucleotide (c-di-GMP or cGAMP); 'Lys-63'-linked ubiquitination at Lys-150 is required for homodimerization (PubMed:22579474, PubMed:22705373, PubMed:22728658, PubMed:22728660, PubMed:22728659, PubMed:19285439, PubMed:30842659). Homotetramer; in presence of cyclic nucleotide (c-di-GMP or cGAMP), forms tetramers and higher-order oligomers through side-by-side packing (Probable). Interacts (when phosphorylated) with IRF3; following activation and phosphorylation on the pLxIS motif by TBK1, recruits IRF3 (PubMed:22394562, PubMed:25636800, PubMed:28331227, PubMed:27302953). Interacts with RIGI, MAVS and SSR2 (PubMed:18818105, PubMed:18724357). Interacts with RNF5 and TRIM56 (PubMed:19285439, PubMed:21074459). Interacts with TBK1; when homodimer, leading to subsequent production of IFN-beta (PubMed:19416887). Interacts with IFIT1 and IFIT2 (PubMed:19416887). Interacts with TRIM29; this interaction induces STING1 ubiquitination and subsequent degradation (PubMed:29038422). Associates with the MHC-II complex (By similarity). Interacts with STEEP; the interaction is increased upon cGAMP binding and promotes STING1 translocation to COPII vesicles (PubMed:32690950). Interacts with SEC24A, SEC24B, and SEC24C; promoting translocation to COPII vesicles (PubMed:32690950, PubMed:30842662). Interacts (when ubiquitinated) with SQSTM1; leading to relocalization to autophagosomes (By similarity). Interacts with SURF4 (PubMed:29251827). Interacts with HNRNPA2B1 (PubMed:31320558). Interacts with ZDHHC1; ZDHHC1 constitutively interacts with STING1 and in presence of DNA viruses activates it by promoting its cGAMP-induced oligomerization and the recruitment of downstream signaling components (PubMed:25299331). Interacts with ZDHHC11; in presence of DNA viruses promotes the recruitment of IRF3 to STING1 (PubMed:28331227). Interacts with TOMM70 (PubMed:20628368). Interacts with isoform IFI16-beta of IFI16 (PubMed:30104205).
In absence of cGAMP, the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly (By similarity). In absence of cyclic nucleotide (c-di-GMP or cGAMP), the protein is autoinhibited by an intramolecular interaction between the cyclic dinucleotide-binding domain (CBD) and the C-terminal tail (CTT) (PubMed:22579474, PubMed:22705373, PubMed:22728658, PubMed:22728660, PubMed:22728659). Following cGAMP-binding, the cyclic dinucleotide-binding domain (CBD) is closed, leading to a 180 degrees rotation of the CBD domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the CBD dimer, which leads to the formation of the STING1 tetramer and higher-order oligomers through side-by-side packing (By similarity). The N-terminal part of the CBD region was initially though to contain a fifth transmembrane region (TM5) but is part of the folded, soluble CBD (PubMed:22579474, PubMed:22705373, PubMed:22728658, PubMed:22728660, PubMed:22728659).
Palmitoylation takes place in the Golgi apparatus and creates a platform for the recruitment of TBK1.
Phosphorylation by TBK1 leads to activation and production of IFN-beta (PubMed:18818105, PubMed:19433799, PubMed:25636800, PubMed:30842659, PubMed:30842653, PubMed:27302953). Following cyclic nucleotide (c-di-GMP or cGAMP)-binding, activation and translocation from the endoplasmic reticulum, STING1 is phosphorylated by TBK1 at Ser-366 in the pLxIS motif (PubMed:25636800, PubMed:32690950). The phosphorylated pLxIS motif constitutes an IRF3-binding motif, leading to recruitment of the transcription factor IRF3 to induce type-I interferons and other cytokines (PubMed:25636800). The phosphorylated pLxIS motif facilitates SENP2 recruitment during late phase of viral infection (By similarity). Phosphorylated on tyrosine residues upon MHC-II aggregation (By similarity). Dephosphorylation by PPP6C leads to inactivation and decreased production of IFN-beta (PubMed:32753499). Phosphorylation at Ser-358 is also required to activate IRF3 (PubMed:25636800).
Sumoylated at Lys-338 by TRIM38 during the early phase of viral infection, promoting its stability by preventing its relocalization to autophagosomes and subsequent degradation. Desumoylated by SENP2 during the late phase of viral infection.
The N-terminal domain interacts with glycerophospholipids and phospholipids.
The cGAS-STING signaling pathway drives sterile inflammation leading to type I interferon immunopathology in severe COVID-19 disease caused by SARS-CoV-2 virus infection (PubMed:35045565). Tissue damages in the lung and skin lesions are caused by activation of the cGAS-STING signaling leading to aberrant inflammation (PubMed:35045565). Endothelial cell damage is also caused by activation of the cGAS-STING pathway: SARS-CoV-2 infection triggers mitochondrial DNA release into the cytosol (PubMed:35045565). Released mitochondrial DNA is then detected by CGAS, leading to activation of the cGAS-STING pathway, triggering type-I interferon production and autoinflammation (PubMed:35045565).
The pLxIS motif constitutes an IRF3-binding motif: following phosphorylation by TBK1, the phosphorylated pLxIS motif of STING1 recruits IRF3 (PubMed:25636800). IRF3 is then phosphorylated and activated by TBK1 to induce type-I interferons and other cytokines (PubMed:25636800).
Ubiquitinated (PubMed:19285439, PubMed:19433799, PubMed:21074459, PubMed:25254379). Ubiquitinated via 'Lys-63'-linked ubiquitin chains in response to double-stranded DNA treatment, leading to relocalization to autophagosomes and subsequent degradation; this process is dependent on SQSTM1 (By similarity). 'Lys-63'-linked ubiquitination mediated by TRIM56 at Lys-150 promotes homodimerization and recruitment of the antiviral kinase TBK1 and subsequent production of IFN-beta (PubMed:21074459). 'Lys-48'-linked polyubiquitination at Lys-150 occurring after viral infection is mediated by RNF5 and leads to proteasomal degradation (PubMed:19285439). 'Lys-11'-linked polyubiquitination at Lys-150 by RNF26 leads to stabilize STING1: it protects STING1 from RNF5-mediated 'Lys-48'-linked polyubiquitination (PubMed:25254379). 'Lys-33'-linked and 'Lys-48'-linked deubiquitinated by USP20; leading to its stabilization and promotion of innate antiviral response (PubMed:27801882). 'Lys-48'-linked deubiquitinated by USP44; leading to its stabilization and promotion of innate antiviral response (PubMed:31968013). Deubiquitinated by USP13; leading to inhibition of innate antiviral response (PubMed:28534493).
Ubiquitously expressed. Expressed in skin endothelial cells, alveolar type 2 pneumocytes, bronchial epithelium and alveolar macrophages.
The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. In KLF7, the motif is inactive.
The acidic N-terminal part may favor interaction with the basic domain of transcription factors.
Transcriptional factor (PubMed:9774444, PubMed:16339272). Plays a critical role in neuronal morphogenesis and survival of sensory neurons (By similarity). Represses the corneal epithelium differentiation (PubMed:28916725). Acts also as a metabolic regulator, by modulating insulin sensitivity in pancreatic beta cells and skeletal muscle cells (PubMed:16339272). Inhibits transcriptional inducers of adipogenesis and has a repressive role in the expression of several adipokines, including leptin (PubMed:16339272).
Interacts with CDT1 and ATPase VCP/p97 (PubMed:26842564). Interacts (via UBA domain) with FAS (via death domain) (PubMed:10462485). Interacts (via UBA domain) with NLRP12 (via DAPIN/PYRIN domain) (PubMed:21978668).
Most abundant in testis, slightly less abundant in skeletal muscle and heart, followed by prostate, thymus, ovary, small intestine, and colon. Not detected in the peripheral blood leukocytes.
Ubiquitin-binding protein (PubMed:19722279). Required for the progression of DNA replication forks by targeting DNA replication licensing factor CDT1 for degradation (PubMed:26842564). Potentiates but cannot initiate FAS-induced apoptosis (By similarity).
Belongs to the fibril-associated collagens with interrupted helices (FACIT) family.
Homotrimer. Interacts with FBN1, fibronectin and integrins ITGA1/ITGB1 and ITGA2/ITGB1. Integrin ITGA1/ITGB1 binds to a unique site within COL16A1 located close to its C-terminal end between collagenous domains COL1-COL3.
In papillary dermis, is a component of specialized fibrillin-1-containing microfibrils, whereas in territorial cartilage matrix, it is localized to a discrete population of thin, weakly banded collagen fibrils in association with other collagens (at protein level). In the placenta, where it is found in the amnion, a membranous tissue lining the amniotic cavity. Within the amnion, it is found in an acellular, relatively dense layer of a complex network of reticular fibers. Also located to a fibroblast layer beneath this dense layer. Exists in tissues in association with other types of collagen.
Involved in mediating cell attachment and inducing integrin-mediated cellular reactions, such as cell spreading and alterations in cell morphology.
Prolines at the third position of the tripeptide repeating unit (G-X-Y) are hydroxylated in some or all of the chains.
This sequence defines eighteen different domains, nine triple-helical domains (COL9 to COL1) and ten non-triple-helical domains (NC10 to NC1). The numerous interruptions in the triple helix may make this molecule either elastic or flexible.
Transiently elevated expression during gestation, and decrease at term.
Based on a readthrough transcript which may produce a PTGES3L-AARSD1 fusion protein.
Belongs to the class-II aminoacyl-tRNA synthetase family. Alax-L subfamily.
Functions in trans to edit the amino acid moiety from incorrectly charged tRNA(Ala).
Maps to a duplicated region on chromosome 15; the gene is present in at least 3 almost identical copies.
(Microbial infection) Promotes viral gene expression and replication of polyomavirus SV40: acts by binding to N6-methyladenosine (m6A)-containing viral RNAs (PubMed:29447282).
(Microbial infection) Promotes viral gene expression and virion production of kaposis sarcoma-associated herpesvirus (KSHV) at some stage of the KSHV life cycle (in iSLK.219 and iSLK.BAC16 cells) (PubMed:29659627). Acts by binding to N6-methyladenosine (m6A)-containing viral RNAs (PubMed:29659627).
Belongs to the YTHDF family. YTHDF2 subfamily.
Highly expressed in induced pluripotent stem cells (iPSCs) and down-regulated during neural differentiation.
Interacts with CNOT1; interaction is direct and promotes recruitment of the CCR4-NOT complex (PubMed:27558897, PubMed:32492408). Interacts with YTHDF3 (PubMed:28106072). Interacts with RIDA/HRSP12; interaction leads to recruitment of the ribonuclease P/MRP complex (PubMed:30930054).
Previous studies suggested the 3 different paralogs (YTHDF1, YTHDF2 and YTHDF3) have unique functions with limited redundancy (PubMed:26046440). However, later studies showed that YTHDF1, YTHDF2 and YTHDF3 paralogs have redundant functions to a profound extent and directly promote degradation of m6A-containing mRNAs (PubMed:32492408).
Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, and regulates their stability (PubMed:24284625, PubMed:26046440, PubMed:26318451, PubMed:32492408). M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in mRNA stability and processing (PubMed:22575960, PubMed:24284625, PubMed:32492408, PubMed:25412658, PubMed:25412661). Acts as a regulator of mRNA stability by promoting degradation of m6A-containing mRNAs via interaction with the CCR4-NOT and ribonuclease P/MRP complexes, depending on the context (PubMed:24284625, PubMed:26046440, PubMed:27558897, PubMed:30930054, PubMed:32492408). The YTHDF paralogs (YTHDF1, YTHDF2 and YTHDF3) share m6A-containing mRNAs targets and act redundantly to mediate mRNA degradation and cellular differentiation (PubMed:28106072, PubMed:32492408). M6A-containing mRNAs containing a binding site for RIDA/HRSP12 (5'-GGUUC-3') are preferentially degraded by endoribonucleolytic cleavage: cooperative binding of RIDA/HRSP12 and YTHDF2 to transcripts leads to recruitment of the ribonuclease P/MRP complex (PubMed:30930054). Other m6A-containing mRNAs undergo deadenylation via direct interaction between YTHDF2 and CNOT1, leading to recruitment of the CCR4-NOT and subsequent deadenylation of m6A-containing mRNAs (PubMed:27558897). Required maternally to regulate oocyte maturation: probably acts by binding to m6A-containing mRNAs, thereby regulating maternal transcript dosage during oocyte maturation, which is essential for the competence of oocytes to sustain early zygotic development (By similarity). Also required during spermatogenesis: regulates spermagonial adhesion by promoting degradation of m6A-containing transcripts coding for matrix metallopeptidases (By similarity). Also involved in hematopoietic stem cells specification by binding to m6A-containing mRNAs, leading to promote their degradation (PubMed:30065315). Also acts as a regulator of neural development by promoting m6A-dependent degradation of neural development-related mRNA targets (By similarity). Inhibits neural specification of induced pluripotent stem cells by binding to methylated neural-specific mRNAs and promoting their degradation, thereby restraining neural differentiation (PubMed:32169943). Regulates circadian regulation of hepatic lipid metabolism: acts by promoting m6A-dependent degradation of PPARA transcripts (PubMed:30428350). Regulates the innate immune response to infection by inhibiting the type I interferon response: acts by binding to m6A-containing IFNB transcripts and promoting their degradation (PubMed:30559377). May also act as a promoter of cap-independent mRNA translation following heat shock stress: upon stress, relocalizes to the nucleus and specifically binds mRNAs with some m6A methylation mark at their 5'-UTR, protecting demethylation of mRNAs by FTO, thereby promoting cap-independent mRNA translation (PubMed:26458103). Regulates mitotic entry by promoting the phase-specific m6A-dependent degradation of WEE1 transcripts (PubMed:32267835). Promotes formation of phase-separated membraneless compartments, such as P-bodies or stress granules, by undergoing liquid-liquid phase separation upon binding to mRNAs containing multiple m6A-modified residues: polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their disordered regions and thereby leading to phase separation (PubMed:31388144, PubMed:31292544, PubMed:32451507, PubMed:31642031). The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated membraneless compartments, such as P-bodies, stress granules or neuronal RNA granules (PubMed:31292544). May also recognize and bind RNAs modified by C5-methylcytosine (m5C) and act as a regulator of rRNA processing (PubMed:31815440).
The disordered regions have the ability to interact with each other and to 'phase separate' into liquid droplets within the cytosol following binding to mRNAs containing multiple m6A-modified residues (PubMed:31292544). This leads to the partition of m6A-containing mRNAs into membraneless compartments, where mRNAs may be stored, degraded or used to transport mRNAs to dendritic arbors in neurons (PubMed:31292544).
The role of YTHDF2 and N6-methyladenosine (m6A) in virus expression and replication is unclear (PubMed:29109479, PubMed:29447282, PubMed:29659627, PubMed:30559377). According to some reports, YTHDF2 promotes viral gene expression and replication of polyomavirus SV40 and herpesvirus (KSHV) by binding to N6-methyladenosine (m6A)-containing viral RNAs (PubMed:29447282, PubMed:29659627). Another report however suggests that YTHDF2 regulates virus expression and replication indirectly, via its ability to inhibit the type I interferon response, thereby promoting virus expression (PubMed:30559377). Indirect regulation via inhibition of type I interferon response might explain why contradictory results have been reported for its role in KSHV virus replication (PubMed:29109479, PubMed:29659627).
Ubiquitinated by the SCF(SKP2) complex, leading to its degradation.
(Microbial infection) Promotes Zika virus replication by mediating envelope protein E ubiquitination.
Auto-ubiquitinates via 'Lys-63'-linked polyubiquitination.
E3 ubiquitin-protein ligase that have both tumor-promoting and tumor-suppressing activities and functions in several biological processes including innate immunity, regulation of ferroptosis as well as cell proliferation and migration (PubMed:25851810, PubMed:32853985, PubMed:34062120). Acts as an antiviral effector against multiple viruses by targeting specific viral proteins for ubiquitination and degradation including norovirus NTPase protein or SARS-CoV-2 NSP5 and NSP8 proteins (PubMed:34062120, PubMed:35982226). Mechanistically, recognizes the C-terminal glutamine-containing motif usually generated by viral proteases that process the polyproteins and trigger their ubiquitination and subsequent degradation (PubMed:35982226, PubMed:35867826, PubMed:35893676). Mediates 'Lys-63'-linked polyubiquitination and stabilization of the JUN coactivator RNF187 in response to growth factor signaling via the MEK/ERK pathway, thereby regulating JUN transactivation and cellular proliferation (PubMed:25851810). Promotes the TLR4-mediated signaling activation through its E3 ligase domain leading to production of pro-inflammatory cytokines and type I interferon (By similarity). Also plays a negative role in the regulation of exogenous cytosolic DNA virus-triggered immune response. Mechanistically, enhances the 'Lys-48'-linked ubiquitination of STING1 leading to its proteasome-dependent degradation (PubMed:32126128). Mediates the ubiquitination of the SIN3-HDAC chromatin remodeling complex component BRMS1 (PubMed:32853985). Modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells by ubiquitinating NCOA4, leading to its degradation (PubMed:36067704).
Forms homodimers (PubMed:35893676). Interacts with GNIP2 (PubMed:14984203, PubMed:25851810). Interacts with GYG1 (PubMed:11916970, PubMed:14984203, PubMed:33989636). Interacts with RNF187 (via C-terminus) (PubMed:25851810).
Phosphorylated at Ser-107 by RPS6KA5/MSK1, which stimulates the ubiquitin ligase activity.
Skeletal muscle and placenta, at lower levels in heart, brain and pancreas. Isoform 1 is widely expressed with high level in testis, kidney and heart.
The B30.2 domain mediates interaction with GYG1.
The coiled-coil region mediates homodimerization and heterodimerization.
Belongs to the calycin superfamily. Fatty-acid binding protein (FABP) family.
Cytosolic CRABPs may regulate the access of retinoic acid to the nuclear retinoic acid receptors.
Forms a beta-barrel structure that accommodates hydrophobic ligands in its interior.
Phosphorylates thymidine, deoxycytidine, and deoxyuridine in the mitochondrial matrix (PubMed:9989599, PubMed:11687801). In non-replicating cells, where cytosolic dNTP synthesis is down-regulated, mtDNA synthesis depends solely on TK2 and DGUOK (PubMed:9989599). Widely used as target of antiviral and chemotherapeutic agents (PubMed:9989599).
Predominantly expressed in liver, pancreas, muscle, and brain.
Involved in the cross-linking of microtubules and microfilaments (PubMed:12584248, PubMed:24706950). Regulates microtubule dynamics and stability by interacting with microtubule plus-end tracking proteins, such as MAPRE1, to regulate microtubule growth along actin stress fibers (PubMed:24706950).
Highly expressed in testis, the expression is observed precisely in seminiferous tubules.
May play a role in apoptosis regulation.
(Microbial infection) Interacts (via both extracellular domains) with Clostridium perfringens enterotoxin CPE; the interaction may disrupt claudin assembly in tight junctions.
CLDN4 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region.
Channel-forming tight junction protein that mediates paracellular chloride transport in the kidney. Plays a critical role in the paracellular reabsorption of filtered chloride in the kidney collecting ducts. Claudins play a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.
Directly interacts with TJP1/ZO-1 (PubMed:16236711). Interacts with TJP2/ZO-2 and TJP3/ZO-3 (By similarity). Interacts with EPHA2; phosphorylates CLDN4 and may regulate tight junctions (PubMed:16236711). Interacts with CLDN1 (PubMed:20375010). Interacts with CLDN8 (By similarity).
Expressed in the lungs from 23 weeks of gestation till birth.
Phosphorylated. Phosphorylation by EPHA2 is stimulated by EFNA1 and alters interaction with TJP1.
Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.
Appears to be a novel specific biomarker for blastic plasmocytoid dendritic cells neoplasia.
Expressed in plasmocytoid dendritic cells. Expressed in suprabasal skin keratinocytes and squamous cells (at protein level). Expressed in the brain and weakly in spleen and skin. Expressed in plasmocytoid dendritic cells.
Plays a role in short-term synaptic plasticity in a subset of GABAergic neurons in the brain.
Up-regulated upon CpG dinucleotides activation. Down-regulated upon activation by Toll-like receptor (TLR) ligands.
Expressed in pancreas (PubMed:25497100). Expressed in pancreatic beta-cells (insulin-positive cells) and alpha-cells (glucagon-positive cells) (at protein level). Specifically expressed in pancreas, small intestine and colon (PubMed:20148032). Expressed in endocrine cells in the islets (PubMed:25497100).
Transcription factor required to direct islet cell differentiation during endocrine pancreas development. Specifically required for the differentiation of 4 of the 5 islet cell types and for the production of insulin (PubMed:20148032, PubMed:25497100). Not required for pancreatic PP (polypeptide-producing) cells differentiation. Acts downstream of NEUROG3 and regulates the transcription factors involved in beta-cell maturation and function, thereby restricting the expression of the beta-cell differentiation and specification genes, and thus the beta-cell fate choice. Activates transcription by forming a heterodimer with RFX3 and binding to the X-box in the promoter of target genes (PubMed:20148032). Involved in glucose-stimulated insulin secretion by promoting insulin and L-type calcium channel gene transcription (PubMed:25497100).
High in intestine and in peripheral blood mononuclear cells; low in lung, kidney, thymus, uterus, vasculature and brain. Not found in liver, heart, retina oe skeletal muscle.
Phosphorylation mediates agonist-mediated desensitization by promoting cytoplasmic retention.
Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. Has a relaxing effect on smooth muscle. May play an important role in regulating renal hemodynamics, intestinal epithelial transport, adrenal aldosterone secretion, and uterine function.
Was originally designated as the EP2 subtype.
(Microbial infection) Glycosylated on arginine residues by S.typhimurium protein Ssek3.
Interacts with SGSM1 and SGSM3 (By similarity). Interacts with PIK3CB (By similarity). Interacts with GDI1; this promotes dissociation from membranes; phosphorylation at Ser-84 disrupts this interaction (PubMed:23815289, PubMed:29125462). Interacts with GDI2; phosphorylation at Ser-84 disrupts the interaction (PubMed:29125462). Interacts with EEA1 (PubMed:10491193, PubMed:20534488). Interacts with RIN1 and GAPVD1, which regulate its pathway, probably by acting as a GEF (PubMed:11703925, PubMed:16410077). Interacts with RINL. Interacts with ALS2CL, SUN2, ZFYVE20 and RUFY1 (PubMed:10818110, PubMed:11062261, PubMed:15388334, PubMed:14617813, PubMed:16034420). Interacts with RABEP1; one RABEP1 homodimer binds two RAB5A chains, but at opposite sides of the dimer (PubMed:15378032). Interacts with OCRL (PubMed:25869668). Interacts with INPP5F. May be a component of a complex composed of RAB5A, DYN2 and PIK3C3 (By similarity). Does not interact with BLOC-3 complex (heterodimer of HPS1 and HPS4) (By similarity). Interacts with CLN5 (PubMed:22431521). Interacts with APPL2 (By similarity). Interacts with F8A1/F8A2/F8A3 (By similarity). Found in a complex with F8A1/F8A2/F8A3, HTT and RAB5A; mediates the recruitment of HTT by RAB5A onto early endosomes (By similarity). Interacts with ATP9A (PubMed:36604604).
Phosphorylation of Ser-84 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including RAB GDP dissociation inhibitors GDI1 and GDI2.
Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP.
Small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate cellular responses such as of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Active GTP-bound form is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. RAB5A is required for the fusion of plasma membranes and early endosomes (PubMed:10818110, PubMed:14617813, PubMed:16410077, PubMed:15378032). Contributes to the regulation of filopodia extension (PubMed:14978216). Required for the exosomal release of SDCBP, CD63, PDCD6IP and syndecan (PubMed:22660413). Regulates maturation of apoptotic cell-containing phagosomes, probably downstream of DYN2 and PIK3C3 (By similarity).
Acetylation at Lys-1097 by EP300/p300 in response to leucine metabolite acetyl-coA promotes its activity, leading to activation of the mTORC1 complex (PubMed:30197302, PubMed:32561715). Acetylation is decreased in response to fasting (By similarity).
Component of the mechanistic target of rapamycin complex 1 (mTORC1), an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth (PubMed:12150925, PubMed:12150926, PubMed:12747827, PubMed:24403073, PubMed:26588989, PubMed:32561715). In response to nutrients, growth factors or amino acids, mTORC1 is recruited to the lysosome membrane and promotes protein, lipid and nucleotide synthesis by phosphorylating several substrates, such as ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) (PubMed:12150925, PubMed:12150926, PubMed:12747827, PubMed:24403073, PubMed:26588989). In the same time, it inhibits catabolic pathways by phosphorylating the autophagy initiation components ULK1 and ATG13, as well as transcription factor TFEB, a master regulators of lysosomal biogenesis and autophagy (PubMed:12150925, PubMed:12150926, PubMed:12747827, PubMed:24403073, PubMed:32561715). The mTORC1 complex is inhibited in response to starvation and amino acid depletion (PubMed:12150925, PubMed:12150926, PubMed:12747827, PubMed:24403073). Within the mTORC1 complex, RPTOR acts both as a molecular adapter, which (1) mediates recruitment of mTORC1 to lysosomal membranes via interaction with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD), and a (2) substrate-specific adapter, which promotes substrate specificity by binding to TOS motif-containing proteins and direct them towards the active site of the MTOR kinase domain for phosphorylation (PubMed:12747827, PubMed:24403073, PubMed:26588989). mTORC1 complex regulates many cellular processes, such as odontoblast and osteoclast differentiation or neuronal transmission (By similarity). mTORC1 complex in excitatory neuronal transmission is required for the prosocial behavior induced by the psychoactive substance lysergic acid diethylamide (LSD) (By similarity).
Highly expressed in skeletal muscle, and in a lesser extent in brain, lung, small intestine, kidney and placenta.
Insulin-stimulated phosphorylation at Ser-863 by MTOR and MAPK8 regulates mTORC1 activity (PubMed:19864431). Phosphorylated at Ser-863 by NLK in response to stress, disrupting the interaction with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD), thereby preventing lysosome recruitment and activation of the mTORC1 complex (PubMed:26588989). Osmotic stress also induces phosphorylation at Ser-696, Thr-706 and Ser-863 by MAPK8 (PubMed:19864431, PubMed:22493283). Ser-863 phosphorylation is required for phosphorylation at Ser-855 and Ser-859 (PubMed:19864431). In response to nutrient limitation, phosphorylated at Ser-722 and Ser-792 by AMPK; phosphorylation promotes interaction with 14-3-3 proteins, leading to negative regulation of the mTORC1 complex (PubMed:18439900). In response to growth factors, phosphorylated at Ser-719, Ser-721 and Ser-722 by RPS6KA1, which stimulates mTORC1 activity (PubMed:18722121, PubMed:18439900). Phosphorylation at Ser-791 by PKA downstream of cAMP inhibits the mTORC1 complex (PubMed:31112131). Phosphorylated at Ser-877 by TBK1, leading to negative regulation of the mTORC1 complex (PubMed:31530866).
Part of the mechanistic target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8 and RPTOR (PubMed:12408816, PubMed:24403073, PubMed:25940091, PubMed:27909983, PubMed:29236692, PubMed:31601764, PubMed:31601708, PubMed:36697823). mTORC1 associates with AKT1S1/PRAS40, which inhibits its activity (PubMed:17386266, PubMed:31601764). mTORC1 associates with DEPTOR, which regulates its activity (PubMed:34519269, PubMed:34519268). mTORC1 binds to and is inhibited by FKBP12-rapamycin (PubMed:12408816, PubMed:15066126). Forms a complex with MTOR under both leucine-rich and -poor conditions (PubMed:12408816, PubMed:25940091, PubMed:31601764, PubMed:31601708). Interacts with (via TOS motifs) EIF4EBP1 and RPS6KB1; interaction is independent of its association with MTOR (PubMed:12150925, PubMed:12150926, PubMed:12747827, PubMed:24403073). Binds preferentially to poorly or non-phosphorylated forms of EIF4EBP1, and this binding is critical to the ability of MTOR to catalyze phosphorylation (PubMed:12747827, PubMed:24403073). Interacts with ULK1 in a nutrient-dependent manner; the interaction is reduced during starvation (PubMed:19211835). Interacts with GTP-bound form of RagA/RRAGA or RagB/RRAGB and GDP-bound form of RagC/RRAGC or RagD/RRAGD, promoting recruitment of mTORC1 to the lysosomes (PubMed:31601764, PubMed:31601708). Interacts (when phosphorylated by AMPK) with 14-3-3 protein, leading to inhibition of its activity (PubMed:18439900). Interacts with SPAG5; SPAG5 competes with MTOR for RPTOR-binding, resulting in decreased mTORC1 formation (PubMed:23953116). Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). Interacts with G3BP1 (PubMed:23953116). The complex formed with G3BP1 and SPAG5 is increased by oxidative stress (PubMed:23953116). Interacts with HTR6 (PubMed:23027611). Interacts with PIH1D1 (PubMed:24036451). Interacts with LARP1 (PubMed:25940091). Interacts with BRAT1 (PubMed:25657994). Interacts with SIK3 (PubMed:30232230). Interacts with SLC38A7; this interaction mediates the recruitment of mTORC1 to the lysosome and its subsequent activation (PubMed:35561222).
Ubiquitinated, leading to its degradation by the proteasome (PubMed:34290272, PubMed:35927303). Deubiquitinated by OTUB1 via a non-catalytic mechanism (PubMed:35927303). Ubiquitinated by an E3 ubiquitin ligase complex containing VHL (PubMed:34290272).
Widely expressed, with highest levels in nasal mucosa and pituitary and lowest in spleen.
Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles. Fibrillin-containing microfibrils provide long-term force bearing structural support.
Predominantly expressed in connective tissues such as skeletal muscle, tendon, skin, perichondrium and periosteum. Highly expressed in fetal lung, brain, kidney. Expressed at low level in prostate, testis, mammary gland, uterus, ovary, placenta, bladder, adrenal gland, thyroid, fetal thymus, fetal liver, liver, fetal heart and heart.
Probably forms intermolecular disulfide bonds either with other FBN3 molecules or with other components of the microfibrils.
Highly expressed in liver, placenta and adrenal gland. Moderately expressed in small intestine, lung, stomach and prostate. Weakly expressed in trachea and spleen.
Lectin that binds to various sugars: galactose > mannose = fucose > N-acetylglucosamine > N-acetylgalactosamine (PubMed:10224141). Acts as a chemoattractant, probably involved in the regulation of cell migration (PubMed:28301481).
Interacts with PI4KB. This binding competes with FREQ/NCS1 binding in a calcium-dependent manner (By similarity).
Negatively regulates Golgi-to-plasma membrane trafficking by interacting with PI4KB and inhibiting its activity.
The C-terminal transmembrane domain (TMD) is necessary and sufficient for membrane targeting.
It is uncertain whether Met-1 or Met-25 is the initiator.
Exhibits adenosine 5'-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5'monophosphoramidate (AMP-NH2) to yield AMP and NH2 (PubMed:16762638, PubMed:31990367). Hydrolyzes adenosine 5'-O-p-nitrophenylphosphoramidate (AMP-pNA) (PubMed:16762638). Hydrolyzes fluorogenic purine nucleoside tryptamine phosphoramidates in vitro (PubMed:31990367). May be involved in steroid biosynthesis (PubMed:18653718). May play a role in apoptosis (PubMed:16762638).
High expression in liver and pancreas. Expression is significantly down-regulated in hepatocellular carcinoma (HCC) patients.
Preferentially expressed in heart, skeletal muscle and testis. Expressed at low levels in the developing brain. Expressed in megakaryocytes and platelets (PubMed:34704371).
The C-terminal phenylalanine residue is cleaved by KIAA0895L/MATCAP.
The MREC motif may be critical for tubulin autoregulation.
This tubulin does not have a C-terminal tyrosine; however, its C-terminal phenylalanine residue can be cleaved.
Arg-186 is the main determinant for regioselectivity, which segregates between initiases and elongases in all tubulin--tyrosine ligase family. A glutamine residue at this position is found in elongases TTLL6, TTLL9, TTLL11, TTLL13, TTLL10 and favors glutamate-chain elongation, whereas an arginine residue is found in initiases TTLL2, TTLL4, TTLL5, TTLL3, TTLL8 and favors initiation.
Expressed in the retina, found in the rod and cone photoreceptors (at protein level). Widely expressed with highest levels in heart and skeletal muscle and low levels in other tissues.
Interacts with the transcriptional coactivators NCOA1/SRC-1 and NCOA2/TIF2.
Polyglutamylase which modifies tubulin, generating polyglutamate side chains on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of tubulin. Preferentially mediates ATP-dependent initiation step of the polyglutamylation reaction over the elongation step. Preferentially modifies the alpha-tubulin tail over a beta-tail (By similarity). Required for CCSAP localization to both polyglutamylated spindle and cilia microtubules (PubMed:22493317). Increases the effects of transcriptional coactivator NCOA2/TIF2 in glucocorticoid receptor-mediated repression and induction and in androgen receptor-mediated induction (PubMed:17116691).
The flexible c-MTBD (cationic microtubule binding domain) region mediates binding to microtubules. It is positively charged and becomes ordered when bound to microtubules: it interacts with a negatively charged patch on tubulin. The presence of positive charges in the c-MTBD region is essential for proper binding.
Belongs to the Integrator subunit 3 family.
Belongs to the multiprotein complex Integrator, at least composed of INTS1, INTS2, INTS3, INTS4, INTS5, INTS6, INTS7, INTS8, INTS9/RC74, INTS10, INTS11/CPSF3L and INTS12. Component of the SOSS complex, composed of SOSS-B (SOSS-B1/NABP2 or SOSS-B2/NABP1), SOSS-A/INTS3 and SOSS-C/INIP. SOSS complexes containing SOSS-B1/NABP2 are more abundant than complexes containing SOSS-B2/NABP1. Interacts with SOSS-B1/NABP2, SOSS-B2/NABP1 and SOSS-C/INIP; the interaction is direct. Interacts with NBN/NBS1.
Component of the Integrator (INT) complex. The Integrator complex is involved in the small nuclear RNAs (snRNA) U1 and U2 transcription and in their 3'-box-dependent processing. The Integrator complex is associated with the C-terminal domain (CTD) of RNA polymerase II largest subunit (POLR2A) and is recruited to the U1 and U2 snRNAs genes (Probable). Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the INT complex (PubMed:23904267).
Component of the SOSS complex, a multiprotein complex that functions downstream of the MRN complex to promote DNA repair and G2/M checkpoint. The SOSS complex associates with single-stranded DNA at DNA lesions and influences diverse endpoints in the cellular DNA damage response including cell-cycle checkpoint activation, recombinational repair and maintenance of genomic stability. The SOSS complex is required for efficient homologous recombination-dependent repair of double-strand breaks (DSBs) and ATM-dependent signaling pathways. In the SOSS complex, it is required for the assembly of the complex and for stabilization of the complex at DNA damage sites.
Antibodies against TNRC6A are found in sera from patients with Sjoegren syndrome (SS), ataxia and sensor neuropathy diseases that developed autoantibodies against protein of the GWB structure. Autoantibodies were mapped to the GW-rich mid-part, the non-GW-rich region and the C-terminus of the protein.
By exogenous short interfering RNA (siRNA).
Interacts with AGO2 (PubMed:16284623, PubMed:16284622, PubMed:18690212, PubMed:19304925, PubMed:19324964, PubMed:19383768). Interacts with AGO1, AGO3 and AGO4 (PubMed:19324964, PubMed:19383768). Interacts with CNOT1; the interaction is direct and mediates the association with the CCR4-NOT complex (PubMed:21981923). Interacts with ZC3H12A (PubMed:26134560). Interacts with SND1 (PubMed:28546213). Interacts with GARRE1 (PubMed:29395067).
Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs). Required for miRNA-dependent repression of translation and for siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins. As a scaffolding protein, associates with argonaute proteins bound to partially complementary mRNAs, and can simultaneously recruit CCR4-NOT and PAN deadenylase complexes.
2-oxoglutarate dehydrogenase (E1-like) component of the 2-oxoglutarate dehydrogenase multienzyme complex (OGDHC) which mediates the decarboxylation of alpha-ketoglutarate in the tricarboxylic acid cycle. The OGDHC complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2) while reducing NAD(+) to NADH (By similarity). The OGDHC complex is mainly active in the mitochondrion (By similarity). Involved in the inhibition of cell proliferation and in apoptosis (PubMed:23152800, PubMed:31175094).
Belongs to the alpha-ketoglutarate dehydrogenase family.
Post-transcriptionally repressed by microRNA miR-214 in cancer cells.
The OGDHC complex comprises multiple copies of three catalytic enzyme components, the 2-oxoglutarate dehydrogenase (OGDH/E1), the dihydrolipoamide dehydrogenase (DLST/E2) and the dihydrolipoamide dehydrogenase (DLD/E3). OGDHL/E1-like isoenzyme may replace OGDH in the OGDHC complex in the brain. The presence of either ODGH/E1 or ODGHL/E1-like isoenzyme in the complex may depend on its tissular distribution.
Binds 2 magnesium ions, but the ions interact each with only 1 or 2 residues.
Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits; the complex contains two deadenylase subunits, CNOT6 or CNOT6L, and CNOT7 or CNOT8 (PubMed:17452450, PubMed:18377426, PubMed:19558367). Interacts with CNOT1, CNOT3, CNOT7, CNOT8 and CNOT9 (PubMed:17452450). Interacts with TOB1 (PubMed:18377426). Interacts with NANOS2 (By similarity). Interacts with ZFP36 (By similarity). Interacts with ZFP36L2 (PubMed:34611029). Interacts with RBM46 (By similarity).
Depletion of CNOT6L causes cell growth defect.
Has 3'-5' poly(A) exoribonuclease activity for synthetic poly(A) RNA substrate. Catalytic component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. May be involved in the deadenylation-dependent degradation of mRNAs through the 3'-UTR AU-rich element-mediated mechanism. Involved in deadenylation-dependent degradation of CDKN1B mRNA. Its mRNA deadenylase activity can be inhibited by TOB1. Mediates cell proliferation and cell survival and prevents cellular senescence.
Highly expressed in placenta, skeletal muscle, pancreas, testis and leukocytes. Weakly expressed in heart, spleen and thymus.
Inhibited by free AMP, and with lesser efficiency also by CMP, GMP, UMP, ATP and neomycin.
Divalent cation-dependent acid DNA endonuclease involved in the breakdown of the nucleus during corneocyte formation of epidermal keratinocytes. May play an immune role by eliminating harmful DNA released into the extracellular environment by damaged epidermal cells.
Preferentially expressed in the skin and up-regulated during keratinocytes differentiation. Highly abundant (at protein level) in the stratum granulosum.
Specifically expressed in peripheral blood leukocytes.
(Microbial infection) Interacts with N.meningitidis serogroup B adhesin A (nadA). Interaction is stabilized by ADP and 17-AAG (17-N-allylamino-17-demethoxygeldanamycin) and inhibited by ATP. Decreasing HSP90 levels increases adhesion and entry of bacterial into human Chang cells; increasing its levels leads to decreased adhseion and invasion.
(Microbial infection) Interacts with herpes simplex virus 1 protein US11; this interaction inhibits TBK1-induced interferon production.
(Microbial infection) Seems to interfere with N.meningitidis NadA-mediated invasion of human cells. Decreasing HSP90 levels increases adhesion and entry of E.coli expressing NadA into human Chang cells; increasing its levels leads to decreased adhesion and invasion.
Belongs to the heat shock protein 90 family.
Homodimer (PubMed:7588731, PubMed:8289821, PubMed:18400751, PubMed:29127155). Identified in NR3C1/GCR steroid receptor-chaperone complexes formed at least by NR3C1, HSP90AA1 and a variety of proteins containing TPR repeats such as FKBP4, FKBP5, PPID, PPP5C or STIP1 (PubMed:15383005, PubMed:9195923). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex (PubMed:29127155). The closed form interacts (via the middle domain and TPR repeat-binding motif) with co-chaperone TSC1 (via C-terminus) (PubMed:29127155). Interacts with TOM34 (PubMed:9660753). Interacts with TERT; the interaction, together with PTGES3, is required for correct assembly and stabilization of the TERT holoenzyme complex (PubMed:11274138, PubMed:9817749). Interacts with CHORDC1 and DNAJC7 (PubMed:12853476, PubMed:19875381). Interacts with STUB1 and UBE2N; may couple the chaperone and ubiquitination systems (PubMed:16307917, PubMed:27353360). Interacts (via TPR repeat-binding motif) with PPP5C (via TPR repeats); the interaction is direct and activates PPP5C phosphatase activity (PubMed:15383005, PubMed:15577939, PubMed:16531226, PubMed:27353360). Following LPS binding, may form a complex with CXCR4, GDF5 and HSPA8 (PubMed:11276205). Interacts with KSR1 (PubMed:10409742). Interacts with co-chaperone CDC37 (via C-terminus); the interaction inhibits HSP90AA1 ATPase activity (PubMed:23569206, PubMed:27353360). May interact with NWD1 (PubMed:24681825). Interacts with FNIP1 and FNIP2; the interaction inhibits HSP90AA1 ATPase activity (PubMed:17028174, PubMed:27353360). Interacts with co-chaperone AHSA1 (phosphorylated on 'Tyr-223'); the interaction activates HSP90AA1 ATPase activity and results in the dissociation of TSC1 from HSP90AA1 (PubMed:12604615, PubMed:27353360, PubMed:29127155). Interacts with FLCN in the presence of FNIP1 (PubMed:27353360). Interacts with HSP70, STIP1 and PTGES3 (PubMed:27353360). Interacts with SMYD3; this interaction enhances SMYD3 histone-lysine N-methyltransferase (PubMed:15235609, PubMed:25738358). Interacts with SGTA (via TPR repeats) (PubMed:15708368). Interacts with TTC1 (via TPR repeats) (PubMed:15708368). Interacts with HSF1 in an ATP-dependent manner (PubMed:11583998, PubMed:26517842). Interacts with MET; the interaction suppresses MET kinase activity (PubMed:26517842). Interacts with ERBB2 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity (PubMed:26517842). Interacts with HIF1A, KEAP1 and RHOBTB2 (PubMed:26517842). Interacts with HSF1; this interaction is decreased in a IER5-dependent manner, promoting HSF1 accumulation in the nucleus, homotrimerization and DNA-binding activities (PubMed:26754925). Interacts with STUB1 and SMAD3 (PubMed:24613385). Interacts with HSP90AB1; interaction is constitutive (PubMed:20353823). Interacts with HECTD1 (via N-terminus) (By similarity). Interacts with NR3C1 (via domain NR LBD) and NR1D1 (via domain NR LBD) (By similarity). Interacts with NLPR12 (PubMed:30559449, PubMed:17947705). Interacts with PDCL3 (By similarity). Interacts with TOMM70; the interaction is required for preprotein mitochondrial import (PubMed:12526792). Interacts with TOMM70, IRF3 and TBK1; the interactions are direct and mediate the association of TOMM70 with IRF3 and TBK1 (PubMed:20628368). Forms a complex with ASL, ASS1 and NOS2; the complex regulates cell-autonomous L-arginine synthesis and citrulline recycling while channeling extracellular L-arginine to nitric oxide synthesis pathway.
In the resting state, through the dimerization of its C-terminal domain, HSP90 forms a homodimer which is defined as the open conformation (PubMed:18400751). Upon ATP-binding, the N-terminal domain undergoes significant conformational changes and comes in contact to form an active closed conformation (PubMed:18400751). After HSP90 finishes its chaperoning tasks of assisting the proper folding, stabilization and activation of client proteins under the active state, ATP molecule is hydrolyzed to ADP which then dissociates from HSP90 and directs the protein back to the resting state (PubMed:18400751). Co-chaperone TSC1 promotes ATP binding and inhibits HSP90AA1 ATPase activity (PubMed:29127155). Binding to phosphorylated AHSA1 promotes HSP90AA1 ATPase activity (PubMed:29127155). Inhibited by geldanamycin, Ganetespib (STA-9090) and SNX-2112 (PubMed:29127155, PubMed:12526792).
Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity which is essential for its chaperone activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function (PubMed:11274138, PubMed:15577939, PubMed:15937123, PubMed:27353360, PubMed:29127155, PubMed:12526792). Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself (PubMed:29127155). Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone. After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle (PubMed:27295069, PubMed:26991466). Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70 (PubMed:12526792). Apart from its chaperone activity, it also plays a role in the regulation of the transcription machinery. HSP90 and its co-chaperones modulate transcription at least at three different levels (PubMed:25973397). In the first place, they alter the steady-state levels of certain transcription factors in response to various physiological cues(PubMed:25973397). Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment (PubMed:25973397). Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression (PubMed:25973397). Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205). Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation (PubMed:24613385). Mediates the association of TOMM70 with IRF3 or TBK1 in mitochondrial outer membrane which promotes host antiviral response (PubMed:20628368, PubMed:25609812).
S-nitrosylated; negatively regulates the ATPase activity and the activation of eNOS by HSP90AA1.
The TPR repeat-binding motif mediates interaction with TPR repeat-containing proteins like the co-chaperone STUB1.
Ubiquitinated via 'Lys-63'-linked polyubiquitination by HECTD1. Ubiquitination promotes translocation into the cytoplasm away from the membrane and secretory pathways.
Belongs to the calcineurin regulatory subunit family.
Forms a complex composed of a calmodulin-dependent catalytic subunit (also known as calcineurin A) and a regulatory Ca(2+)-binding subunit (also known as calcineurin B). There are three catalytic subunits, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two regulatory subunits which are also encoded by separate genes (PPP3R1 and PPP3R2) (By similarity). Interacts with SPATA33 (via PQIIIT motif) (PubMed:34446558).
Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity.
This protein has four functional calcium-binding sites.
Product of a polymorphic gene which also produces a longer 410-residue protein due to a polymorphism which affects Met-1, resulting in a longer protein starting at an upstream Met.
The function of this enzyme is unclear as allantoicase activity is not known to exist in mammals.
Acts as a transcriptional repressor. Increases DNMT3B-mediated repressive transcriptional activity when DNMT3B is tethered to DNA. May link molecule between DNMT3B and other co-repressor proteins.
Forms homodimers. Heterodimer (via HD1 domain) with ZHX2 (via HD1 domain). Also forms a heterodimer with ZHX3 which is a prerequisite for repressor activity. Interacts with ATF7IP and NFYA. Interacts (via homeobox domains) with DNMT3B (via PWWP domain).
Ubiquitously expressed. Expressed in podocytes.
Belongs to the cytidine and deoxycytidylate deaminase family.
Cytidine deaminase catalyzing the cytidine to uridine postranscriptional editing of a variety of mRNAs (PubMed:30844405). Form complexes with cofactors that confer differential editing activity and selectivity. Responsible for the postranscriptional editing of a CAA codon for Gln to a UAA codon for stop in the apolipoprotein B mRNA (PubMed:24916387). Also involved in CGA (Arg) to UGA (Stop) editing in the NF1 mRNA (PubMed:11727199). May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation (By similarity).
Expressed exclusively in the small intestine.
Homodimer (PubMed:8078915). Interacts with A1CF; form an mRNA editing complex (PubMed:30844405). Interacts with RBM47; form an mRNA editing complex (PubMed:24916387, PubMed:30844405). Found in a complex with CELF2/CUGBP2 and A1CF. Interacts with HNRPAB (PubMed:8999813). Interacts with SYNCRIP (PubMed:11352648).
Cell surface receptor for LCN2 (24p3) that plays a key role in iron homeostasis and transport. Able to bind iron-bound LCN2 (holo-24p3), followed by internalization of holo-24p3 and release of iron, thereby increasing intracellular iron concentration and leading to inhibition of apoptosis. Also binds iron-free LCN2 (apo-24p3), followed by internalization of apo-24p3 and its association with an intracellular siderophore, leading to iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration and resulting in apoptosis (By similarity).
Expression is activated by RUNX3. Repressed by the oncoprotein BCR-ABL; BCR-ABL misregulates expression by inducing a switch in binding from RUNX3 to RUNX1, a repressor of 24p3R expression, through a Ras signaling pathway.
Authors show that FZD9 is responsible for the cellular phenotype found in neural progenitor cells (NPCs) derived from Williams syndrome patients namely increased apoptosis of neural progenitor cells (NPCs).
Belongs to the G-protein coupled receptor Fz/Smo family.
Expressed predominantly in adult and fetal brain, testis, eye, skeletal muscle and kidney. Moderately expressed in pancreas, thyroid, adrenal cortex, small intestine and stomach. Detected in fetal liver and kidney. Expressed in neural progenitor cells (PubMed:27509850).
Has been first described as FZD3 in literature.
Lys-Thr-X-X-X-Trp motif interacts with the PDZ domain of Dvl (Disheveled) family members and is involved in the activation of the Wnt/beta-catenin signaling pathway.
Receptor for WNT2 that is coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes (By similarity). Plays a role in neuromuscular junction (NMJ) assembly by negatively regulating the clustering of acetylcholine receptors (AChR) through the beta-catenin canonical signaling pathway (By similarity). May play a role in neural progenitor cells (NPCs) viability through the beta-catenin canonical signaling pathway by negatively regulating cell cycle arrest leading to inhibition of neuron apoptotic process (PubMed:27509850). During hippocampal development, regulates neuroblast proliferation and apoptotic cell death. Controls bone formation through non canonical Wnt signaling mediated via ISG15. Positively regulates bone regeneration through non canonical Wnt signaling (By similarity).
The FZ domain is involved in binding with Wnt ligands.
Ubiquitinated by ZNRF3, leading to its degradation by the proteasome.
Component of SWI/SNF chromatin remodeling complexes, in some of which it can be mutually exclusive with ARID1B/BAF250B (PubMed:12672490, PubMed:22952240, PubMed:26601204, PubMed:12200431, PubMed:11988099, PubMed:15170388). The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B) and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific (PubMed:11734557, PubMed:22952240, PubMed:26601204). Component of the BAF (SWI/SNF-A) complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C (PubMed:18765789). In muscle cells, the BAF complex also contains DPF3. Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin (By similarity). Component of a SWI/SNF-like EBAFb complex, at least composed of SMARCA4/BRG1/BAF190A, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, SMARCC1/BAF155, SMARCC2/BAF170, ARID1B/BAF250B, MLLT1/ENL and actin (PubMed:12665591). Interacts through its C-terminus with SMARCA2/BRM/BAF190B and SMARCA4/BRG1/BAF190A (PubMed:12200431, PubMed:11988099, PubMed:15170388). Interacts with SMARCC1/BAF155 (PubMed:15170388).
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Binds DNA non-specifically (PubMed:14982958, PubMed:15170388).
Produced by alternative initiation at Met-84 of isoform 5.
The poly-Gln region is polymorphic and the number of Gln varies in the population (from 17 to 23).
Widely expressed with high levels in heart, skeletal muscle and kidney.
May be a specific regulator of miRNA biogenesis. Binds to microRNAs MIR7-1, MIR16-2 and MIR29A hairpins recognizing the 3'-ATA(A/T)-5' motif in the apical loop.
Interacts with ERBB2 (By similarity). Interacts with EGFR.
Levels are very low in quiescent cells. Up-regulated by mitogens.
Negative regulator of EGFR signaling in skin morphogenesis. Acts as a negative regulator for several EGFR family members, including ERBB2, ERBB3 and ERBB4. Inhibits EGFR catalytic activity by interfering with its dimerization. Inhibits autophosphorylation of EGFR, ERBB2 and ERBB4. Important for normal keratinocyte proliferation and differentiation. Plays a role in modulating the response to steroid hormones in the uterus. Required for normal response to progesterone in the uterus and for fertility. Mediates epithelial estrogen responses in the uterus by regulating ESR1 levels and activation. Important for regulation of endometrium cell proliferation. Important for normal prenatal and perinatal lung development (By similarity).
The EGFR-binding region prevents binding of a cyclin-like activator to the EGFR kinase domain, and thereby keeps EGFR in an inactive conformation. Also maintains EGFR in an inactive conformation by preventing formation of an asymmetric homodimer.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. NCD subfamily.
Binds NUBP1 and NUBP2. Interacts with PPP1R42 (By similarity).
HeLa cells lacking KIFC1 show multipolar mitotic spindles and a defect in chromosome congression and chromosome alignment during mitosis.
Minus end-directed microtubule-dependent motor required for bipolar spindle formation (PubMed:15843429). May contribute to movement of early endocytic vesicles (By similarity). Regulates cilium formation and structure (By similarity).
Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) (PubMed:27499296). Required to stabilize NDUFAF5 (PubMed:27499296).
Abundant in 18-24 week old fetal brain. Postnatally its expression decline and only minimal levels were present in adulthood.
May participate in the maintenance of segment identity in the hindbrain and pituitary development, and maturation or maintenance of the overall structure of the nervous system. May function as a regulatory subunit of ion channels.
Acts as a cofactor for XPO1/CRM1-mediated nuclear export, perhaps as export complex scaffolding protein. Bound to XPO1/CRM1, stabilizes the XPO1/CRM1-cargo interaction. In the absence of Ran-bound GTP prevents binding of XPO1/CRM1 to the nuclear pore complex. Binds to CHC1/RCC1 and increases the guanine nucleotide exchange activity of CHC1/RCC1. Recruits XPO1/CRM1 to CHC1/RCC1 in a Ran-dependent manner. Negative regulator of TGF-beta signaling through interaction with the R-SMAD proteins, SMAD2 and SMAD3, and mediating their nuclear export.
Interacts with CHC1 in a Ran-stimulated manner. Interacts with XPO1. Interacts (via its C-terminal R domain) with SMAD2 (dephosphorylated form via its MH1 and MH2 domains); the interaction results in the nuclear export of SMAD2 and termination of the TGF-beta signaling. Interacts (via its C-terminal R domain) with SMAD3 (dephosphorylated form via its MH1 domain); the interaction results in the nuclear export of SMAD3 and termination of the TGF-beta signaling.
Widely expressed with high levels in testis and heart.
Cleaved by CASP3 during apoptosis. In intact cells cleavage occurs preferentially after Asp-127, yielding a pro-apoptotic 28 kDa C-terminal fragment.
Expression increases early during phorbol ester-induced differentiation along the monocyte/macrophage pathway in myeloid leukemia cell line ML-1. Rapidly up-regulated by CSF2 in ML-1 cells. Up-regulated by heat shock-induced differentiation. Expression increases early during retinoic acid-induced differentiation.
Interacts with HIF3A (via C-terminus domain) (By similarity). Interacts with BAD, BOK, BIK and BMF (By similarity). Interacts with PMAIP1 (PubMed:17389404). Interacts with BBC3 (By similarity). Isoform 1 interacts with BAX, BAK1 and TPT1 (PubMed:10837489, PubMed:12149273, PubMed:15077116). Heterodimer of isoform 1 and isoform 2. Homodimers of isoform 1 or isoform 2 are not detected. Isoform 2 does not interact with pro-apoptotic BCL2-related proteins (PubMed:10837489). Interacts with RTL10/BOP (PubMed:23055042). Interacts with BCL2L11; may sequester BCL2L11 to prevent its pro-apoptotic activity (PubMed:10837489, PubMed:27013495, PubMed:17389404, PubMed:20562877). Interacts with GIMAP5 and HSPA8/HSC70; the interaction between HSPA8 and MCL1 is impaired in the absence of GIMAP5 (By similarity).
Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.
Phosphorylated on Ser-159, by GSK3, in response to IL3/interleukin-3 withdrawal. Phosphorylation at Ser-159 induces ubiquitination and proteasomal degradation, abrogating the anti-apoptotic activity. Treatment with taxol or okadaic acid induces phosphorylation on additional sites.
Rapidly degraded in the absence of phosphorylation on Thr-163 in the PEST region.
Ubiquitinated. Ubiquitination is induced by phosphorylation at Ser-159 (PubMed:16543145). Deubiquitinated by USP20; leading to increased stability (PubMed:35063767).
Belongs to the protease inhibitor I47 (latexin) family.
Hardly reversible, non-competitive, and potent inhibitor of CPA1, CPA2 and CPA4. May play a role in inflammation.
Highly expressed in heart, prostate, ovary, kidney, pancreas, and colon, moderate or low in other tissues including brain.
(Microbial infection) Interacts with human cytomegalovirus UL135.
Component of the WAVE complex composed of ABI2, CYFIP1 or CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Within the complex, a heterodimer containing NCKAP1 and CYFIP1 interacts with a heterotrimer formed by WAVE1, ABI2 and BRK1. CYFIP2 binds to activated RAC1 which causes the complex to dissociate, releasing activated WASF1 (PubMed:21107423). Interacts (via SH3 domain) with ABL1 and ABL2 (PubMed:7590236, PubMed:8649853).
Regulator of actin cytoskeleton dynamics underlying cell motility and adhesion. Functions as a component of the WAVE complex, which activates actin nucleating machinery Arp2/3 to drive lamellipodia formation (PubMed:21107423). Acts as regulator and substrate of nonreceptor tyrosine kinases ABL1 and ABL2 involved in processes linked to cell growth and differentiation. Positively regulates ABL1-mediated phosphorylation of ENAH, which is required for proper polymerization of nucleated actin filaments at the leading edge (PubMed:7590236, PubMed:8649853, PubMed:10498863). Contributes to the regulation of actin assembly at the tips of neuron projections. In particular, controls dendritic spine morphogenesis and may promote dendritic spine specification toward large mushroom-type spines known as repositories of memory in the brain (By similarity). In hippocampal neurons, may mediate actin-dependent BDNF-NTRK2 early endocytic trafficking that triggers dendrite outgrowth (By similarity). Participates in ocular lens morphogenesis, likely by regulating lamellipodia-driven adherens junction formation at the epithelial cell-secondary lens fiber interface (By similarity). Also required for nascent adherens junction assembly in epithelial cells (PubMed:15572692).
The SH3 domain is critical for binding to ABL1 and ABL2.
Widely expressed. Abundant in testes, ovary, thymus, and colon, with lower but detectable levels in prostate, peripheral blood leukocytes, and spleen.
Inhibitor of PPP1CA. Has over 50-fold higher inhibitory activity when phosphorylated (By similarity).
Phosphorylated primarily on Thr-57 by PKC (in vitro). An unknown Ser is also phosphorylated by PKC (in vitro) (By similarity).
Controls the classical pathway of complement activation. It binds as a cofactor to C3b/C4b inactivator (C3bINA), which then hydrolyzes the complement fragment C4b. It also accelerates the degradation of the C4bC2a complex (C3 convertase) by dissociating the complement fragment C2a. It also interacts with anticoagulant protein S and with serum amyloid P component. The beta chain binds protein S.
Disulfide-linked complex of alpha and beta chains of 3 possible sorts: a 570 kDa complex of 7 alpha chains and 1 beta chain, a 530 kDa homoheptamer of alpha chains or a 500 kDa complex of 6 alpha chains and 1 beta chain. The central body of the alpha chain homomer supports tentacles, each with the binding site for C4b at the end.
Expressed specifically in skeletal and cardiac muscles.
Plays an important role in the process of myofiber differentiation and maturation. Probable substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex, which mediates the ubiquitination of proteins. Probably contributes to catalysis through recognition and positioning of the substrate and the ubiquitin-conjugating enzyme. During myogenesis, controls the ubiquitination and degradation of the specific pool of CTNNB1/beta-catenin located at the sarcolemma (By similarity).
Probable component the ECS(NEURL2) E3 ubiquitin-protein ligase complex consisting of ELOB/Elongin B, ELOC/Elongin C, CUL5, RBX1 and NEURL2. Interacts with CTNNB1 (By similarity).
The SOCS domain mediates the interaction with ELOB and ELOC, while the NHR domain may be involved in ubiquitination substrate binding.
(Microbial infection) Interacts with SARS-CoV nucleoprotein.
Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced by TGF-beta.
Monomer; in the absence of TGF-beta (PubMed:9670020). Homooligomer; in the presence of TGF-beta (PubMed:9670020). Heterotrimer; forms a heterotrimer in the presence of TGF-beta consisting of two molecules of C-terminally phosphorylated SMAD2 or SMAD3 and one of SMAD4 to form the transcriptionally active SMAD2/SMAD3-SMAD4 complex (PubMed:9670020, PubMed:11224571, PubMed:15799969, PubMed:15350224). Part of a complex consisting of MAGI2/ARIP1, ACVR2A, ACVR1B and SMAD3 (PubMed:9892009). Forms a complex with SMAD2 and TRIM33 upon addition of TGF-beta (PubMed:16751102). Found in a complex composed of SMAD3, RAN and XPO4; within the complex interacts directly with XPO4 (PubMed:16449645). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta (PubMed:9732876, PubMed:10995748). Part of a ternary complex composed of SMAD3, ITCH/AIP4 and NEDD9/HEF1; within the complex NEDD9/HEF1 interacts (via N-terminus) with ITCH/AIP4; the complex mediates ubiquitination and proteasomal degradation of NEDD9/HEF1 (PubMed:15051726). Interacts with NEDD9; the interaction promotes NEDD9 ubiquitination and proteasomal degradation (PubMed:15051726). Interacts (via an N-terminal domain) with JUN (via its basic DNA binding and leucine zipper domains); this interaction is essential for DNA binding and cooperative transcriptional activity in response to TGF-beta (PubMed:9732876, PubMed:10995748). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts with PPM1A; the interaction dephosphorylates SMAD3 in the C-terminal SXS motif leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export and termination of TGF-beta signaling (PubMed:16751101). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD3 inhibitors (PubMed:9311995). Interacts (dephosphorylated form via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling (PubMed:19289081). Interacts (via MH2 domain) with LEMD3; the interaction represses SMAD3 transcriptional activity through preventing the formation of the heteromeric complex with SMAD4 and translocation to the nucleus (PubMed:15601644, PubMed:15647271). Interacts (via the linker region) with EP300 (C-terminal); the interaction promotes SMAD3 acetylation and is enhanced by TGF-beta phosphorylation in the C-terminal of SMAD3 (PubMed:9843571, PubMed:15588252). This interaction can be blocked by competitive binding of adenovirus oncoprotein E1A to the same C-terminal site on EP300, which then results in partially inhibited SMAD3/SMAD4 transcriptional activity (PubMed:9843571, PubMed:15588252). Interacts with TGFBR1 (PubMed:9311995). Interacts with TGFB1I1 (PubMed:15561701). Interacts with PRDM16 (PubMed:19049980). Interacts with SNW1 (PubMed:11278756). Interacts (via MH2 domain) with ZFYVE9 (PubMed:9865696, PubMed:12154125). Interacts with HDAC1 (PubMed:19049980). Interacts with TGIF2 (PubMed:11427533). Interacts with SKOR1 (PubMed:17292623). Interacts with SKOR2 (PubMed:16200078). Interacts with DACH1; the interaction inhibits the TGF-beta signaling (PubMed:14525983). Interacts with RBPMS (PubMed:17099224). Interacts (via MH2 domain) with MECOM (PubMed:9665135, PubMed:15897867). Interacts with WWTR1 (via its coiled-coil domain) (PubMed:18568018). Interacts with SKI; the interaction represses SMAD3 transcriptional activity (PubMed:19049980). Interacts with MEN1 (PubMed:11274402). Interacts with IL1F7 (PubMed:20935647). Interaction with CSNK1G2 (PubMed:18794808). Interacts with PDPK1 (via PH domain) (PubMed:17327236). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation (PubMed:11387212). Interacts with USP15 (PubMed:21947082). Interacts with PPP5C; the interaction decreases SMAD3 phosphorylation and protein levels (PubMed:22781750). Interacts with LDLRAD4 (via the SMAD interaction motif) (PubMed:24627487). Interacts with PMEPA1 (PubMed:20129061). Interacts with ZNF451 (PubMed:24324267). Interacts with ZFHX3 (PubMed:25105025). Interacts weakly with ZNF8 (PubMed:12370310). Interacts with STUB1, HSPA1A, HSPA1B, HSP90AA1 and HSP90AB1 (PubMed:24613385). Interacts with YAP1 (when phosphorylated at 'Ser-127') (By similarity). Interacts with MAGI2/ARIP1 (By similarity). Interacts (via MH2 domain) with CITED2 (via C-terminus) (By similarity). Interacts with HGS (By similarity). Interacts with WWP1 (By similarity). Interacts with TTRAP (By similarity). Interacts with FOXL2 (By similarity). Interacts with PML (By similarity). Interacts with NEDD4L; the interaction requires TGF-beta stimulation (By similarity). Interacts with ZC3H3 (By similarity). Interacts with TGIF. Interacts with CREBBP. Interacts with ATF2. Interacts with NEDD9; the interaction is inhibited by oxidation of NEDD9 (PubMed:29899023).
Phosphorylated on serine and threonine residues. Enhanced phosphorylation in the linker region on Thr-179, Ser-204 and Ser-208 on EGF and TGF-beta treatment. Ser-208 is the main site of MAPK-mediated phosphorylation. CDK-mediated phosphorylation occurs in a cell-cycle dependent manner and inhibits both the transcriptional activity and antiproliferative functions of SMAD3. This phosphorylation is inhibited by flavopiridol. Maximum phosphorylation at the G(1)/S junction. Also phosphorylated on serine residues in the C-terminal SXS motif by TGFBR1 and ACVR1. TGFBR1-mediated phosphorylation at these C-terminal sites is required for interaction with SMAD4, nuclear location and transactivational activity, and appears to be a prerequisite for the TGF-beta mediated phosphorylation in the linker region. Dephosphorylated in the C-terminal SXS motif by PPM1A. This dephosphorylation disrupts the interaction with SMAD4, promotes nuclear export and terminates TGF-beta-mediated signaling. Phosphorylation at Ser-418 by CSNK1G2/CK1 promotes ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Phosphorylated by PDPK1.
Poly-ADP-ribosylated by PARP1 and PARP2. ADP-ribosylation negatively regulates SMAD3 transcriptional responses during the course of TGF-beta signaling.
Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.
The MH1 domain is required for DNA binding. Also binds zinc ions which are necessary for the DNA binding.
The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.
The disease is caused by variants affecting the gene represented in this entry. SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource.
The linker region is required for the TGFbeta-mediated transcriptional activity and acts synergistically with the MH2 domain.
Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding (PubMed:21947082). Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082). Ubiquitinated by RNF111, leading to its degradation: only SMAD3 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD3 and regulating its turnover (By similarity). Undergoes STUB1-mediated ubiquitination and degradation (PubMed:24613385).
Binds Ca(2+). The ions are bound to the C2 1 domain.
Calcium/phospholipid-binding protein that plays a role in the plasmalemma repair mechanism of endothelial cells that permits rapid resealing of membranes disrupted by mechanical stress. Involved in endocytic recycling. Implicated in VEGF signal transduction by regulating the levels of the receptor KDR (By similarity).
Expressed in myoblast and endothelial cells (at protein level). Highly expressed in cardiac and skeletal muscles. Also present in lung, and at very low levels in kidney, placenta and brain.
Interacts with DNM2 and KDR. Interacts with EHD1 (By similarity). Interacts with EHD2; the interaction is direct (PubMed:18502764). Interacts with RIPOR2 (PubMed:24687993).
The C2 domain 1 associates with lipid membranes in a calcium-dependent manner.
Expressed in various lymphoid tissues and activated B- and T-lymphocytes, strongly up-regulated in B-cells infected with Epstein-Barr virus and T-cells infected with herpesvirus 6 or 7.
Receptor for the MIP-3-beta chemokine. Probable mediator of EBV effects on B-lymphocytes or of normal lymphocyte functions.
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family.
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1S subfamily.
Channel activity is blocked by dihydropyridines (DHP), phenylalkylamines, and by benzothiazepines.
Component of a calcium channel complex consisting of a pore-forming alpha subunit (CACNA1S) and the ancillary subunits CACNB1 or CACNB2, CACNG1 and CACNA2D1. The channel complex contains alpha, beta, gamma and delta subunits in a 1:1:1:1 ratio, i.e. it contains either CACNB1 or CACNB2 (By similarity). CACNA1S channel activity is modulated by the auxiliary subunits (CACNB1 or CACNB2, CACNG1 and CACNA2D1). Interacts with DYSF and JSRP1 (By similarity). Interacts with RYR1 (By similarity). Interacts with STAC, STAC2 and STAC3 (via their SH3 domains) (PubMed:29078335). Interacts with CALM (PubMed:19473981).
Each of the four internal repeats contains five hydrophobic transmembrane segments (S1, S2, S3, S5, S6) and one positively charged transmembrane segment (S4). S4 segments probably represent the voltage-sensor and are characterized by a series of positively charged amino acids at every third position.
Phosphorylated. Phosphorylation by PKA activates the calcium channel. Both the minor and major forms are phosphorylated in vitro by PKA. Phosphorylation at Ser-1575 is involved in beta-adrenergic-mediated regulation of the channel.
Pore-forming, alpha-1S subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle. Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle via their interaction with RYR1, which triggers Ca(2+) release from the sarcoplasmic reticulum and ultimately results in muscle contraction. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group.
The alpha-1S subunit is found in two isoforms in the skeletal muscle: a minor form of 212 kDa containing the complete amino acid sequence, and a major form of 190 kDa derived from the full-length form by post-translational proteolysis close to Phe-1690.
The loop between repeats II and III interacts with the ryanodine receptor, and is therefore important for calcium release from the endoplasmic reticulum necessary for muscle contraction.
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death.
May play a role in sperm development and fertilization This is a non-catalytic metalloprotease-like protein.
Abundant in the putamen and caudate nucleus regions of brain and testis, moderately expressed in the thyroid gland, pituitary gland, thalamus and cerebellum.
Belongs to the cyclic nucleotide phosphodiesterase family.
Composed of a C-terminal catalytic domain containing two divalent metal sites and an N-terminal regulatory domain which contains one cyclic nucleotide-binding region.
Inhibited by dipyridamole and moderately by IBMX. cGMP acts as an allosteric activator.
Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides (PubMed:10373451, PubMed:10393245, PubMed:16330539, PubMed:27058447, PubMed:17389385). Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate (PubMed:10373451, PubMed:10393245, PubMed:27058447, PubMed:17389385). May play a critical role in regulating cAMP and cGMP levels in the striatum, a region of the brain that contributes to the control of movement and cognition (PubMed:27058447).
The tandem GAF domains bind cAMP, and regulate enzyme activity. The binding of cAMP stimulates enzyme activity.
Forms homodimers (PubMed:34642815). Interacts with PACS1 (PubMed:34642815). Interacts with PACS2 (PubMed:34642815).
Required for normal ER Ca2+ handling in lymphocytes. Together with PACS1, it plays an essential role in stabilizing peripheral lymphocyte populations.
Transcriptional activator of MEF2C involved in the regulation of adult muscle fiber type identity and skeletal muscle regeneration (By similarity). Plays an important role in spermatogenesis (By similarity). Required for the survival of spermatogonia and participates in spermatocyte meiosis (By similarity).
Binds preferentially and cooperatively to pyrimidine rich single-stranded DNA (ss-DNA) (PubMed:21953457, PubMed:23290262, PubMed:31550240). In vitro, required to maintain the copy number of mitochondrial DNA (mtDNA) and plays a crucial role during mtDNA replication by stimulating the activity of the replisome components POLG and TWNK at the replication fork (PubMed:21953457, PubMed:12975372, PubMed:26446790, PubMed:15167897, PubMed:31550240). Promotes the activity of the gamma complex polymerase POLG, largely by organizing the template DNA and eliminating secondary structures to favor ss-DNA conformations that facilitate POLG activity (PubMed:26446790, PubMed:21953457, PubMed:31550240). In addition it is able to promote the 5'-3' unwinding activity of the mtDNA helicase TWNK (PubMed:12975372). May also function in mtDNA repair (PubMed:23290262).
Expressed in retinal ganglion cells, photoreceptors, pigmented epithelium and fibroblasts (at protein level).
Homotetramer (PubMed:23290262, PubMed:31550240). Interacts with MPG/AAG, through inhibition of its glycosylase activity it potentially prevents formation of DNA breaks in ssDNA, ensuring that base removal primarily occurs in dsDNA (PubMed:23290262). Interacts with POLDIP2 (PubMed:16428295). Interacts with PRIMPOL (PubMed:25550423).
May have a role in sperm development and fertilization.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WEE1 subfamily.
Expressed in oocytes (at protein level) (PubMed:29606300). May also be expressed in testis (PubMed:11029659).
Oocyte-specific protein tyrosine kinase that phosphorylates and inhibits CDK1/CDC2 and acts as a key regulator of meiosis during both prophase I and metaphase II (PubMed:29606300). Required to maintain meiotic arrest in oocytes during the germinal vesicle (GV) stage, a long period of quiescence at dictyate prophase I, by phosphorylating CDK1 at 'Tyr-15', leading to inhibit CDK1 activity and prevent meiotic reentry. Also required for metaphase II exit during egg activation by phosphorylating CDK1 at 'Tyr-15', to ensure exit from meiosis in oocytes and promote pronuclear formation (By similarity).
Phosphorylated on serine residues (PubMed:29606300). Phosphorylation leads to increase its activity (By similarity).
Acts as androgen receptor coregulator that increases androgen receptor activity by modulating the receptors interdomain interaction. May play a role in embryonal development and tumor transformation or aspects of tumor progression.
Expressed in tumors of several types, such as melanoma, head and neck squamous cell carcinoma, lung carcinoma and breast carcinoma. Expressed in testis, ovary, prostate, cancerous prostate, breast and adrenal tissue.
Belongs to the fibrillar collagen family.
The C-terminal propeptide, also known as COLFI domain, have crucial roles in tissue growth and repair by controlling both the intracellular assembly of procollagen molecules and the extracellular assembly of collagen fibrils. It binds a calcium ion which is essential for its function (By similarity).
Trimers of two alpha 1(V) and one alpha 2(V) chains in most tissues and trimers of one alpha 1(V), one alpha 2(V), and one alpha 3(V) chains in placenta. Interacts with CSPG4.
Type V collagen is a member of group I collagen (fibrillar forming collagen). It is a minor connective tissue component of nearly ubiquitous distribution. Type V collagen binds to DNA, heparan sulfate, thrombospondin, heparin, and insulin.
Interacts with TGFB1I1 (By similarity). Interacts with LIMS1 (via LD motifs) (PubMed:11331308). Interacts with ARHGAP31 (PubMed:16860736). Interacts with the actin cytoskeleton (PubMed:11331308). Interacts (via C-terminus) with ILK (PubMed:11331308, PubMed:15284246, PubMed:15817463, PubMed:20005845). Interacts (via C-terminus) with TESK1 (via C-terminus); the interaction inhibits TESK1 kinase activity (PubMed:15817463). Interacts with PXN/PAXILLIN (via LD motif 4) (PubMed:15817463, PubMed:18508764, PubMed:18940607).
Plays a role in sarcomere organization and in smooth muscle cell contraction. Required for normal development of the embryonic cardiovascular system, and for normal septation of the heart outflow tract. Plays a role in sprouting angiogenesis and is required for normal adhesion of vascular smooth muscle cells to endothelial cells during blood vessel development (By similarity). Plays a role in the reorganization of the actin cytoskeleton, formation of lamellipodia and ciliogenesis. Plays a role in the establishment of cell polarity, cell adhesion, cell spreading, and directed cell migration.
Widely expressed, with highest levels in heart, skeletal muscle, kidney and liver.
Belongs to the phosphatidylethanolamine-binding protein family.
It was previously reported that PEBP4 is a lysosomal protein which is highly expressed in tumor cells, and may promote cellular resistance to TNF-induced apoptosis. However the paper has since been retracted by the journal due to concerns of image manipulation.
Promotes AKT phosphorylation, suggesting a possible role in the PI3K-AKT signaling pathway.
Expressed in bone marrow and in monocytic and immature erythroid cell lines.
May function as a transcription factor. Seem to have a transcriptional repression activity.
Belongs to the nucleotide pyrophosphatase/phosphodiesterase family.
Expressed on the surface of vascular endothelia.
Hydrolyzes extracellular Ap3A into AMP and ADP, and Ap4A into AMP and ATP. Ap3A and Ap4A are diadenosine polyphosphates thought to induce proliferation of vascular smooth muscle cells. Acts as a procoagulant, mediating platelet aggregation at the site of nascent thrombus via release of ADP from Ap3A and activation of ADP receptors.
Collagen type III occurs in most soft connective tissues along with type I collagen. Involved in regulation of cortical development. Is the major ligand of ADGRG1 in the developing brain and binding to ADGRG1 inhibits neuronal migration and activates the RhoA pathway by coupling ADGRG1 to GNA13 and possibly GNA12.
O-linked glycan consists of a Glc-Gal disaccharide bound to the oxygen atom of a post-translationally added hydroxyl group.
Proline residues at the third position of the tripeptide repeating unit (G-X-Y) are hydroxylated in some or all of the chains.
The C-terminal propeptide, also known as COLFI domain, have crucial roles in tissue growth and repair by controlling both the intracellular assembly of procollagen molecules and the extracellular assembly of collagen fibrils. It binds a calcium ion which is essential for its function.
Trimers of identical alpha 1(III) chains. The chains are linked to each other by interchain disulfide bonds. Trimers are also cross-linked via hydroxylysines. Interacts with ADGRG1 (PubMed:28258187).
Highly expressed in heart, liver, skeletal muscle, pancreas, adrenal medulla and cortex, thyroid, testis, spleen, appendix, peripheral blood lymphocytes and bone marrow. Lower expression found in brain, placenta, lung, kidney, ovary, small intestine, stomach, lymph node, thymus and fetal liver. Expression is up-regulated in dorsolateral prefrontal cortex of patients with schizophrenia (postmortem brain study).
Interacts with AREG immature precursor and with immature TGFA, i.e. with a prosegment and lacking full N-glycosylation, but not with the fully N-glycosylated form. In the Golgi apparatus, may form a complex with GORASP55 and transmembrane TGFA.
Involved in the selective transport and maturation of TGF-alpha family proteins.
Binds PTPN6 when phosphorylated (PubMed:9285411). Binds FCER1A and FCGR1A (PubMed:9842885, PubMed:11907092). Interacts with human cytomegalovirus/HHV-5 protein UL18 (PubMed:10591185). Interacts with peptide-bound HLA-G-B2M complex (PubMed:16455647). Interacts with peptide-bound HLA-F-B2M complex but not with peptide-free HLA-F open conformer. It does not probe the peptide sequence directly (PubMed:28636952).
Contains 4 copies of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases.
Expressed in B cells, monocytes and various dendritic cell (DC) subsets including myeloid, plasmacytoid and tolerogenic DCs (at protein level) (PubMed:20448110, PubMed:9285411, PubMed:9842885, PubMed:24453251). Expressed in decidual macrophages (at protein level) (PubMed:19304799). Expressed in decidual NK cells (at protein level) (PubMed:29262349).
May act as dominant negative regulator and block the interaction between membrane-associated isoforms and HLA-class I.
Phosphorylated on tyrosine residues. Dephosphorylated by PTPN6.
Receptor for class I MHC antigens. Recognizes a broad spectrum of HLA-A, HLA-B, HLA-C, HLA-G and HLA-F alleles (PubMed:16455647, PubMed:28636952). Receptor for H301/UL18, a human cytomegalovirus class I MHC homolog. Ligand binding results in inhibitory signals and down-regulation of the immune response. Engagement of LILRB1 present on natural killer cells or T-cells by class I MHC molecules protects the target cells from lysis. Interaction with HLA-B or HLA-E leads to inhibition of FCER1A signaling and serotonin release. Inhibits FCGR1A-mediated phosphorylation of cellular proteins and mobilization of intracellular calcium ions (PubMed:11907092, PubMed:9285411, PubMed:9842885). Recognizes HLA-G in complex with B2M/beta-2 microglobulin and a nonamer self-peptide (PubMed:16455647). Upon interaction with peptide-bound HLA-G-B2M complex, triggers secretion of growth-promoting factors by decidual NK cells (PubMed:29262349, PubMed:19304799). Reprograms B cells toward an immune suppressive phenotype (PubMed:24453251).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRID1 subfamily.
Dimer. Interacts (via extracellular N-terminal domain) with CBLN1 (via C1q domain), and more weakly with CBLN2.
Receptor for glutamate that functions as a ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system.
Receptor for glutamate. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists.
A chromosomal aberration involving ZNF41 has been found in a patient with severe intellectual disability. Translocation t(X;7)(p11.3;q11.21).
Although ZNF41 has been reported to be involved in X-linked intellectual disability (PubMed:14628291), its pathological role is questionable (PubMed:23871722).
Expressed in the heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Based on a naturally occurring readthrough transcript which produces a JMJD7-PLA2G4B fusion protein.
Calcium-dependent phospholipase A1 and A2 and lysophospholipase that may play a role in membrane phospholipid remodeling.
Calcium-dependent phospholipase A1 and A2 and lysophospholipase. Cleaves the ester bond of the fatty acyl group attached to the sn-1 or sn-2 position of diacyl phospholipids (phospholipase A1 and A2 activity, respectively), producing lysophospholipids that may be used in deacylation-reacylation cycles. Can further hydrolyze lysophospholipids enabling complete deacylation. Has no activity toward alkylacyl phospholipids.
Calcium-dependent phospholipase A2 and lysophospholipase. Cleaves the ester bond of the fatty acyl group attached to the sn-2 position of phosphatidylethanolamines, producing lysophospholipids that may be used in deacylation-reacylation cycles. Hydrolyzes lysophosphatidylcholines with low efficiency but is inefficient toward phosphatidylcholines.
Most tissues also express read-through transcripts from this gene into the upstream gene (JMJD7), some of which may encode fusion proteins.
The N-terminal C2 domain associates with lipid membranes upon calcium binding. It modulates enzyme activity by presenting the active site to its substrate in response to elevations of cytosolic Ca(2+) (By similarity).
Widely expressed. Expressed at higher level in brain, heart, liver, cerebellum and pancreas.
Expressed predominantly in cortical thymic epithelial cells.
Protease that may play a role in T-cell development.
Highly expressed in testis. Detected at low levels in pancreas. Not detected in the other tissues tested.
The MBD3L proteins are encoded by strongly repeated regions of the 19p13 chromosome. The exact number of functional copies is unclear, and some of them may represent pseudogenes.
The N-terminal half of the protein mediates transcription repression.
Belongs to the plakin or cytolinker family.
May function as a co-chaperone towards HSPA9/mortalin which, by itself, is prone to self-aggregation.
Oligomerizes in a concentration-dependent fashion. Interacts with HSPA9.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family.
Dual phosphorylation of Thr-244 and Thr-249 activates the kinase. Phosphorylation of Thr-379 activates the kinase. Phosphorylated upon arsenic trioxide As(2)O(3) treatment. Phosphorylated by MAPK1/ERK2, MAPK11 and MAPK14. Dephosphorylated by PP2A.
Inhibited by CGP57380 and staurosporine. Activated by phosphorylation in a negative-feedback regulatory manner in response to chemotherapy (e.g. cytarabine) and thus impairs the generation of antileukemic responses.
Monomer. Interacts with the C-terminal regions of EIF4G1 and EIF4G2; this interaction is promoted when MAPK pathways are repressed but repressed upon ERK proteins activation. Also binds to dephosphorylated MAPK3/ERK1 and MAPK1/ERK2. Isoform 1 interaction with phosphorylated MAPK3/ERK1 and MAPK1/ERK2 protects it from dephosphorylation and inactivation. Isoform 2 interacts with ESR2 and EIF4E in the nucleus.
Serine/threonine-protein kinase that phosphorylates SFPQ/PSF, HNRNPA1 and EIF4E. May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Required for mediating PP2A-inhibition-induced EIF4E phosphorylation. Triggers EIF4E shuttling from cytoplasm to nucleus. Isoform 1 displays a high basal kinase activity, but isoform 2 exhibits a very low kinase activity. Acts as a mediator of the suppressive effects of IFNgamma on hematopoiesis. Negative regulator for signals that control generation of arsenic trioxide As(2)O(3)-dependent apoptosis and anti-leukemic responses. Involved in anti-apoptotic signaling in response to serum withdrawal.
Ubiquitously expressed in all tissues examined. Isoform 2 is expressed at higher levels in the ovary than is isoform 1.
Acetylation at Met-1 seems to be important for proper folding and native oligomeric structure.
Genetic alterations of SNCA resulting in aberrant polymerization into fibrils, are associated with several neurodegenerative diseases (synucleinopathies). SNCA fibrillar aggregates represent the major non A-beta component of Alzheimer disease amyloid plaque, and a major component of Lewy body inclusions. They are also found within Lewy body (LB)-like intraneuronal inclusions, glial inclusions and axonal spheroids in neurodegeneration with brain iron accumulation type 1.
Hallmark lesions of neurodegenerative synucleinopathies contain alpha-synuclein that is modified by nitration of tyrosine residues and possibly by dityrosine cross-linking to generated stable oligomers.
Highly expressed in presynaptic terminals in the central nervous system. Expressed principally in brain.
Neuronal protein that plays several roles in synaptic activity such as regulation of synaptic vesicle trafficking and subsequent neurotransmitter release (PubMed:28288128, PubMed:30404828, PubMed:20798282, PubMed:26442590). Participates as a monomer in synaptic vesicle exocytosis by enhancing vesicle priming, fusion and dilation of exocytotic fusion pores (PubMed:28288128, PubMed:30404828). Mechanistically, acts by increasing local Ca(2+) release from microdomains which is essential for the enhancement of ATP-induced exocytosis (PubMed:30404828). Acts also as a molecular chaperone in its multimeric membrane-bound state, assisting in the folding of synaptic fusion components called SNAREs (Soluble NSF Attachment Protein REceptors) at presynaptic plasma membrane in conjunction with cysteine string protein-alpha/DNAJC5 (PubMed:20798282). This chaperone activity is important to sustain normal SNARE-complex assembly during aging (PubMed:20798282). Also plays a role in the regulation of the dopamine neurotransmission by associating with the dopamine transporter (DAT1) and thereby modulating its activity (PubMed:26442590).
Phosphorylated, predominantly on serine residues. Phosphorylation by CK1 appears to occur on residues distinct from the residue phosphorylated by other kinases. Phosphorylation of Ser-129 is selective and extensive in synucleinopathy lesions. In vitro, phosphorylation at Ser-129 promoted insoluble fibril formation. Phosphorylated on Tyr-125 by a PTK2B-dependent pathway upon osmotic stress.
Soluble monomer. Homotetramer (PubMed:21841800). A dynamic intracellular population of tetramers and monomers coexists normally and the tetramer plays an essential role in maintaining homeostasis (PubMed:21841800). Interacts with UCHL1 (By similarity). Interacts with phospholipase D and histones. Interacts (via N-terminus) with synphilin-1/SNCAIP; this interaction promotes formation of SNCA inclusions in the cytoplasm (PubMed:19762560). Interacts with CALM1 (PubMed:23607618). Interacts with STXBP1; this interaction controls SNCA self-replicating aggregation (PubMed:27597756). Interacts with SNARE components VAMP2 and SNAP25; these interactions allows SNARE complex assembly and integrity (PubMed:20798282). Interacts with RPH3A and RAB3A (PubMed:15207266). Interacts with SERF1A; this interaction promotes the aggregation of SNCA (PubMed:22854022, PubMed:31034892). Interacts with SEPTIN4 (By similarity).
The 'non A-beta component of Alzheimer disease amyloid plaque' domain (NAC domain) is involved in fibrils formation. The middle hydrophobic region forms the core of the filaments. The C-terminus may regulate aggregation and determine the diameter of the filaments.
Ubiquitinated. The predominant conjugate is the diubiquitinated form.
Binds to actin filaments in muscle and non-muscle cells (PubMed:23170982). Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction (PubMed:23170982). Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments.
Detected in primary breast cancer tissues but undetectable in normal breast tissues in Sudanese patients. Isoform 1 is expressed in adult and fetal skeletal muscle and cardiac tissues, with higher expression levels in the cardiac tissues. Isoform 10 is expressed in adult and fetal cardiac tissues, but not in skeletal muscle.
Homodimer (PubMed:23170982). Heterodimer of an alpha (TPM1, TPM3 or TPM4) and a beta (TPM2) chain (By similarity). Interacts with HRG (via the HRR domain); the interaction contributes to the antiangiogenic properties of the histidine/proline-rich region (HRR) of HRG (By similarity). Interacts (via N-terminus) with LMOD2 (via N-terminus) and TMOD1 (via N-terminus) (PubMed:26873245).
Phosphorylated at Ser-283 by DAPK1 in response to oxidative stress and this phosphorylation enhances stress fiber formation in endothelial cells.
The molecule is in a coiled coil structure that is formed by 2 polypeptide chains. The sequence exhibits a prominent seven-residues periodicity.
Chromatin reader that specifically recognizes and binds histone H3 both trimethylated at 'Lys-4' and asymmetrically dimethylated at 'Arg-8' (H3K4me3 and H3R8me2a) and acts as an activator of Wnt signaling pathway downstream of PRMT2. In case of cancer, promotes cell cancer proliferation via activation of the Wnt signaling pathway (PubMed:24589551). Overexpression induces metaphase arrest and chromosomal instability. Localizes to active rDNA loci and promotes the expression of rRNA genes (PubMed:21960006). May play a role in cell-cycle regulation during the transition from gamete to embryo. Involved in oocyte meiotic resumption, a process that takes place before ovulation to resume meiosis of oocytes blocked in prophase I: may act by regulating maternal transcripts to control meiotic resumption.
Highly expressed in ovarian cancer tissues.
Homodimer; may form higher-order oligomers (PubMed:17082182). Interacts with TCF7L2/TCF4; the interaction is direct (PubMed:22258766, PubMed:24589551, PubMed:29061846). Interacts with HABP4 and SERBP1 (By similarity). Interacts with C11orf84/SPINDOC (PubMed:29061846).
Phosphorylated during oocyte meiotic maturation.
The 3 tudor-like domains (also named Spin/Ssty repeats) specifically recognize and bind methylated histones (PubMed:23077255, PubMed:24589551). H3K4me3 and H3R8me2a are recognized by tudor-like domains 2 and 1, respectively (PubMed:24589551).
Gustducin-coupled receptor implicated in the perception of bitter compounds in the oral cavity and the gastrointestinal tract. Signals through PLCB2 and the calcium-regulated cation channel TRPM5.
Several bitter taste receptors are expressed in a single taste receptor cell.
(Microbial infection) Interacts with the vesicular stomatitis virus matrix protein/M; the interaction inhibits viral propagation.
Binds calmodulin. Interacts with NDUFAF3.
Expression is low in quiescent cells and is induced in exponentially proliferating cultures. Expression is also induced when prolactin is added to stationary cells. Induced by dietary differentiating agents such as butyrate and retinoic acid.
Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I) (PubMed:18179882, PubMed:28853723). May be involved in cell proliferation and survival of hormone-dependent tumor cells. May be a regulator of breast tumor cell invasion.
Phosphorylated on serine. Prolactin stimulate serine phosphorylation (By similarity).
E3 ubiquitin-protein ligase that participates in multiple biological processes including cell death, glucose metabolism, and in particular, the innate immune response. Mediates 'Lys-63'-linked polyubiquitination of TRAF3 thereby promoting type I interferon production via RIG-I signaling pathway (PubMed:32562145). Can also catalyze 'Lys-48'-linked polyubiquitination and proteasomal degradation of viral proteins such as influenza virus PB2 (PubMed:32562145). Acts as a negative feedback regulator of TLR7- and TLR9-triggered signaling. Mechanistically, promotes the 'Lys-48'-linked ubiquitination of IRF7 and induces its degradation via a proteasome-dependent pathway (PubMed:25907537). Reduces FGFR1-dependent tyrosine phosphorylation of PKM, inhibiting PKM-dependent lactate production, glucose metabolism, and cell growth (PubMed:25263439).
Interacts with PKM isoform M2, but not isoform M1; this interaction may compete with that between PKM and FGFR1, and hence reduces FGFR1-dependent tyrosine phosphorylation of PKM (PubMed:25263439). Interacts with IRF7; this interaction promotes IRF7 proteasomal degradation (PubMed:25907537). Interacts with TRAF3; this interaction promotes TRAF3 activation (PubMed:32562145).
The RING finger domain and the coiled-coil region are required for the apoptosis-inducing activity.
Belongs to the protein-tyrosine phosphatase family.
Farnesylated. Farnesylation is required for membrane targeting (By similarity).
Inhibited by sodium orthovanadate and peroxovanadium compounds, and by pentamidine.
Mainly expressed in cardiomyocytes and skeletal muscle; also found in pancreas. Consistently overexpressed in colon cancer metastasis.
Protein tyrosine phosphatase which stimulates progression from G1 into S phase during mitosis. Enhances cell proliferation, cell motility and invasive activity, and promotes cancer metastasis. May be involved in the progression of cardiac hypertrophy by inhibiting intracellular calcium mobilization in response to angiotensin II.
In muscle, parvalbumin is thought to be involved in relaxation after contraction. It binds two calcium ions.
Homodimer (By similarity). Interacts with GCSH (By similarity). The glycine cleavage system is composed of four proteins: P (GLDC), T (GCST), L (DLD) and H (GCSH).
Stimulated by lipoic acid. Inhibited in presence of methylamine (By similarity).
The glycine cleavage system catalyzes the degradation of glycine. The P protein (GLDC) binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor; CO(2) is released and the remaining methylamine moiety is then transferred to the lipoamide cofactor of the H protein (GCSH).
Forms part of the large latent transforming growth factor beta precursor complex; removal is essential for activation of complex. Interacts with EFEMP2 (PubMed:27339457).
Isoform 2: Expressed prominently in heart, skeletal muscle, prostate, testis, small intestine and ovary (PubMed:12154076). Isoform 1: Strongly expressed in pancreas and liver (PubMed:12154076).
Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space. Associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGF-beta, and regulates integrin-dependent activation of TGF-beta.
Two intrachain disulfide bonds from the TB3 domain are rearranged upon TGFB1 binding, and form interchain bonds with TGFB1 propeptide, anchoring it to the extracellular matrix.
Homooligomer and heterooligomer with HEXIM1; probably dimeric (PubMed:15713661, PubMed:15994294). Core component of the 7SK RNP complex, at least composed of 7SK RNA, LARP7, MEPCE, HEXIM1 (or HEXIM2) and P-TEFb (composed of CDK9 and CCNT1/cyclin-T1) (PubMed:15713661, PubMed:15713662, PubMed:15994294). Interacts with CCNT2 (PubMed:19883659).
The coiled-coil domain mediates oligomerization.
Transcriptional regulator which functions as a general RNA polymerase II transcription inhibitor (PubMed:15713661, PubMed:15713662). Core component of the 7SK RNP complex: in cooperation with 7SK snRNA sequesters P-TEFb in a large inactive 7SK snRNP complex preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation (PubMed:15713661, PubMed:15713662).
Ubiquitously expressed with higher expression in testis. HEXIM1 and HEXIM2 are differentially expressed.
Up-regulated by HMBA (hexamethylene bisacetamide) (at protein level).
Acetylation stimulates the transcriptional activity.
Belongs to the nuclear hormone receptor family. NR5 subfamily.
Binds DNA as a monomer. Interacts with NR0B2 and PPARGC1A (By similarity). Part of a complex consisting of SFPQ, NONO and NR5A1. Interacts with NCOA2. Interacts with DGKQ and CDK7. Binds to and activated by HIPK3.
High expressed in the adrenal cortex, the ovary, the testis, and the spleen (PubMed:9177385).
Phosphorylated on Ser-203 by CDK7. This phosphorylation promotes transcriptional activity.
Sumoylation reduces CDK7-mediated phosphorylation on Ser-203.
Transcriptional activator. Essential for sexual differentiation and formation of the primary steroidogenic tissues (PubMed:27378692). Binds to the Ad4 site found in the promoter region of steroidogenic P450 genes such as CYP11A, CYP11B and CYP21B. Also regulates the AMH/Muellerian inhibiting substance gene as well as the AHCH and STAR genes. 5'-YCAAGGYC-3' and 5'-RRAGGTCA-3' are the consensus sequences for the recognition by NR5A1 (PubMed:27378692). The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional activity. Binds phosphatidylcholine (By similarity). Binds phospholipids with a phosphatidylinositol (PI) headgroup, in particular PI(3,4)P2 and PI(3,4,5)P3. Activated by the phosphorylation of NR5A1 by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation.
Interacts with OTOF. Interacts with SYT6 and SYT8; the interaction is Ca(2+)-dependent (By similarity).
Potentially involved in docking of synaptic vesicles at presynaptic active zones. May mediate Ca(2+)-regulation of exocytosis acrosomal reaction in sperm (By similarity).
The glycine-rich C-terminus serves as an unconventional nuclear localization signal.
Activated by guanine nucleotide-exchange factors (GEF) EPAC and EPAC2 in a cAMP-dependent manner, and GFR.
Found in a complex, at least composed of ITGB1BP1, KRIT1 and RAP1A (PubMed:17916086). Interacts (active GTP-bound form preferentially) with KRIT1 (via C-terminus FERM domain); the interaction does not induce the opening conformation of KRIT1 (PubMed:17916086). In its GTP-bound form interacts with PLCE1 and RADIL (PubMed:11022048, PubMed:12444546, PubMed:17704304). Interacts with SGSM1, SGSM2 and SGSM3 (PubMed:17509819). Interacts (via GTP-bound active form) with RAPGEF2 (via Ras-associating domain) (PubMed:11359771, PubMed:10608844). Interacts with TBC1D21 (By similarity). Interacts with RAP1GDS1 (PubMed:20709748).
Induces morphological reversion of a cell line transformed by a Ras oncogene. Counteracts the mitogenic function of Ras, at least partly because it can interact with Ras GAPs and RAF in a competitive manner. Together with ITGB1BP1, regulates KRIT1 localization to microtubules and membranes. Plays a role in nerve growth factor (NGF)-induced neurite outgrowth. Plays a role in the regulation of embryonic blood vessel formation. Involved in the establishment of basal endothelial barrier function. May be involved in the regulation of the vascular endothelial growth factor receptor KDR expression at endothelial cell-cell junctions.
Facilitates proton transport across the inner mitochondrial membrane and may dissipate excessive proton gradient associated with oxidative and metabolic stress at neuronal synapses. Regulates glutamate-induced proton conductance in astrocytes, shifting the energy metabolism toward aerobic glycolysis and lactate transfer to neurons for ATP synthesis. Can transport chloride ions with lower efficiency. The transport mechanism remains to be elucidated.
Found in adult and fetal brain. Present in most of the brain tissues, with low levels in spinal chord, corpus callosum and substantia nigra.
Proton conductance is up-regulated by unsaturated long-chain fatty acids and inhibited by purine nucleotides ATP and ADP. The transport of chloride ions is partially inhibited by long-chain fatty acids.
Expressed in fetal brain, heart, intestine and kidney.
Functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus (By similarity). Mediates the nuclear import of UBC9, the RBM8A/MAGOH complex, PAX6 and probably other members of the paired homeobox family. Also mediates nuclear export of eIF-1A, and the cytoplasmic release of eIF-1A is triggered by the loading of import substrates onto IPO13.
Interacts with UBC9, RAN, RBM8A, eIF-1A and PAX6.
Belongs to the potassium channel family. Calcium-activated (TC 1.A.1.3) subfamily. KCa5.1/KCNU1 sub-subfamily.
Homotetramer; which constitutes the calcium-activated potassium channel. May interact with LRRC52; this interaction may change channel gating properties, such as shifting gating to more negative potentials at a given pH.
Testis-specific potassium channel activated by both intracellular pH and membrane voltage that mediates export of K(+). May represent the primary spermatozoan K(+) current. In contrast to KCNMA1/SLO1, it is not activated by Ca(2+) or Mg(2+). Critical for fertility. May play an important role in sperm osmoregulation required for the acquisition of normal morphology and motility when faced with osmotic challenges, such as those experienced after mixing with seminal fluid and entry into the vagina.
The C-terminal cytosolic region confers the pH-dependence.
The RCK N-terminal domain mediates the homotetramerization, thereby promoting the assembly of monomers into functional potassium channel.
The S4 segment, which is characterized by a series of positively charged amino acids at every third position, is part of the voltage-sensor.
The pore-forming domain (also referred as P region) is imbedded into the membrane, and forms the selectivity filter of the pore. It contains the signature sequence of potassium channels that displays selectivity to potassium (By similarity).
Belongs to the HFCD (homooligomeric flavin containing Cys decarboxylase) superfamily.
Catalyzes the decarboxylation of the cysteine moiety of 4-phosphopantothenoylcysteine to form 4'-phosphopantotheine and this reaction forms part of the biosynthesis of coenzyme A.
The Met-1 codon is associated with a polymorphism (dbSNP:rs2304899) that replaces the initiation ATG codon by an ATA codon.
At least three different alleles exist. The allele defined by Arg-6 and Glu-89 is associated with a risk of gastric cancer.
Testis and very low level in placenta and in some uterus samples. Observed in 25-50% of tumor samples of melanomas, non-small-cell lung carcinomas, bladder, prostate and head and neck cancers.
Belongs to the 'GDXG' lipolytic enzyme family.
Binds 2 divalent metal cations per subunit with RNAase activity being higher in presence of Mn(2+) than of Mg(2+) or Co(2+).
Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits; the complex contains two deadenylase subunits, CNOT6 or CNOT6L, and CNOT7 or CNOT8 (PubMed:19558367). In the complex, interacts directly with CNOT1 (PubMed:21336257). Interacts with AGO2 (By similarity). Interacts with TOB1; recruited by TOB1 to a ternary complex with CPEB3 which is required for mRNA deadenylation and decay (PubMed:21336257, PubMed:23236473, PubMed:19276069). Interacts with BTG1 (By similarity). Interacts with BTG2 (PubMed:23236473). Interacts with NANOS2 (By similarity). Interacts with ZFP36, ZFP36L1 and ZFP36L2; these interactions are inhibited in response to phorbol 12-myristate 13-acetate (PMA) treatment in a p38 MAPK-dependent manner (PubMed:25106868). Interacts with TARDBP (PubMed:30520513). Interacts with BTG4 (PubMed:32502391). Interacts with EIF4E; this interaction is increased by CNOT7 interaction with BTG4 (By similarity).
Has 3'-5' poly(A) exoribonuclease activity for synthetic poly(A) RNA substrate (PubMed:20634287, PubMed:31439799, PubMed:19276069). Its function seems to be partially redundant with that of CNOT8 (PubMed:19605561). Catalytic component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation (PubMed:20634287, PubMed:31439799, PubMed:19276069). During miRNA-mediated repression the complex seems also to act as translational repressor during translational initiation (PubMed:20065043). Additional complex functions may be a consequence of its influence on mRNA expression (PubMed:23236473, PubMed:19276069). Associates with members of the BTG family such as TOB1 and BTG2 and is required for their anti-proliferative activity (PubMed:23236473, PubMed:19276069).
Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase.
Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3.
Multi-mono-ubiquitinated by OBI1; ubiquitination is important for efficient DNA replication origin site activation. Ubiquitination levels are low in mitotic and early G1-phAse cells and are induced in late G1-/early S-phase, peaking in S-phase and decrease toward the end of the cell cycle.
Expressed in HVS transformed T-cells but not other T-cell lines or primary stimulated T-cells. Expressed in colonic T-cells including Th17 inflammatory T-cells; the expression is significantly increased in serum of patients with Crohn's disease (at protein level).
May play a role in local mechanisms of mucosal immunity and seems to have a pro-inflammatory function. May play a role in inflammatory bowel disease. Activates STAT1 and STAT3, MAPK1/3 (ERK1/2), JUN and AKT. Induces expression of SOCS3, TNF-alpha and IL-8, secretion of IL-8 and IL-10 and surface expression of ICAM1. Decreases proliferation of intestinal epithelial cells. Is inhibited by heparin.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class 1 subfamily.
Expressed in keratinocytes (at protein level).
Interacts with EPHA3 (phosphorylated); dephosphorylates EPHA3 and may regulate its trafficking and function. Interacts with MET.
Oxidized on Cys-215; the Cys-SOH formed in response to redox signaling reacts with the alpha-amido of the following residue to form a sulfenamide cross-link, triggering a conformational change that inhibits substrate binding and activity. The active site can be restored by reduction.
S-nitrosylation of Cys-215 inactivates the enzyme activity.
Ser-50 is the major site of phosphorylation as compared to Ser-242 and Ser-243. Activated by phosphorylation at Ser-50.
Sulfhydration at Cys-215 following endoplasmic reticulum stress inactivates the enzyme activity, promoting EIF2AK3/PERK activity.
Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response. Mediates dephosphorylation of EIF2AK3/PERK; inactivating the protein kinase activity of EIF2AK3/PERK. May play an important role in CKII- and p60c-src-induced signal transduction cascades. May regulate the EFNA5-EPHA3 signaling pathway which modulates cell reorganization and cell-cell repulsion. May also regulate the hepatocyte growth factor receptor signaling pathway through dephosphorylation of MET.
Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors, which acts as a key regulator of angiogenesis. Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway. Acts as a ligand for frizzled FZD8 and LRP6. May negatively regulate the TGF-beta pathway (PubMed:21727895, PubMed:21909076, PubMed:22615920). Acts as a key regulator of angiogenesis by controlling vascular stability and pruning: acts by activating the non-canonical Wnt signaling pathway in endothelial cells (By similarity) (PubMed:21727895, PubMed:21909076, PubMed:22615920). Can also amplify Wnt signaling pathway independently of LGR4-6 receptors, possibly by acting as a direct antagonistic ligand to RNF43 and ZNRF3 (PubMed:29769720).
Interacts with the extracellular domain of FZD8 and LRP6 (By similarity). It however does not form a ternary complex with FZD8 and LRP6 (By similarity). Interacts with WNT1 (By similarity). Binds heparin. Interacts with LGR4, LGR5 and LGR6 (PubMed:21727895, PubMed:21909076, PubMed:22615920).
The FU repeats are required for activation and stabilization of beta-catenin.
Ubiquitously expressed. Expressed at higher level in placenta, small intestine, fetal thymus and lymph node (PubMed:12463421). Highly expressed in endothelial cells (PubMed:26766444).
Belongs to the heparin-binding growth factors family.
In adults expression is restricted to the gonads.
Monomer. Homodimer. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.
Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration. Required for normal brain, eye, ear and limb development during embryogenesis. Required for normal development of the gonadotropin-releasing hormone (GnRH) neuronal system (PubMed:16384934, PubMed:16597617, PubMed:8663044). Plays a role in neurite outgrowth in hippocampal cells (PubMed:21576111).
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in FGF8 as well as in other HH-associated genes including FGFR1 (PubMed:23643382).
The gene represented in this entry is involved in disease pathogenesis. Duplications encompassing the FGF8 locus have been found in unrelated families with isolated bilateral hypoplasia of the femoral and pelvic bone. The phenotype is most likely the result of position effects causing altered FGF8 expression rather than gene dosage.
Acts specifically as a negative regulator of skeletal muscle growth.
Homodimer; disulfide-linked (PubMed:27625211). Interacts with WFIKKN2, leading to inhibit its activity (PubMed:12595574). Interacts with FST3 (PubMed:17878677).
Homodimer; disulfide-linked. Interacts with WFIKKN2, leading to inhibit its activity. Interacts with FSTL3.
Synthesized as large precursor molecule that undergoes proteolytic cleavage to generate an N-terminal propeptide and a disulfide linked C-terminal dimer, which is the biologically active molecule. The circulating form consists of a latent complex of the C-terminal dimer and other proteins, including its propeptide, which maintain the C-terminal dimer in a latent, inactive state. Ligand activation requires additional cleavage of the prodomain by a tolloid-like metalloproteinase.
Predominantly expressed in thymus, spleen, lymph nodes, small intestine, lung, placenta and peripheral blood leukocytes.
Receptor for the glycosphingolipid psychosine (PSY) and several related glycosphingolipids (PubMed:11309421). Plays a role in immune response by maintaining lysosome function and supporting phagocytosis-mediated intracellular bacteria clearance (PubMed:27287411). May have a role in activation-induced cell death or differentiation of T-cells (By similarity).
Autophosphorylated on serine/threonine residues. Activated by dephosphorylation.
Belongs to the FAST protein kinase family.
Interacts with TIA1; the interactions leads to TIA1 phosphorylation (PubMed:7544399, PubMed:17135269). Interacts with TIAR (PubMed:7544399, PubMed:17135269).
Phosphorylates the splicing regulator TIA1, thereby promoting the inclusion of FAS exon 6, which leads to an mRNA encoding a pro-apoptotic form of the receptor.
Required for the biogenesis of some mitochondrial-encoded mRNAs, specifically stabilizes ND6 (NADH dehydrogenase complex subunit 6) mRNA, and regulates its levels.
The RAP domain is essential for RNA-binding.
Homodimer (PubMed:25869669). Interacts with OCRL and RAB5A (PubMed:25869668). Interacts with INPP5B and INPP4A (PubMed:25869668). Interacts with STAT3; the interaction is independent of STAT3 'Tyr-705' phosphorylation status (PubMed:25476455).
INPP5F has been initially described as an inositol polyphosphate 5-phosphatase.
Inositol 4-phosphatase which mainly acts on phosphatidylinositol 4-phosphate. May be functionally linked to OCRL, which converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol, for a sequential dephosphorylation of phosphatidylinositol 4,5-bisphosphate at the 5 and 4 position of inositol, thus playing an important role in the endocytic recycling (PubMed:25869669). Regulator of TF:TFRC and integrins recycling pathway, is also involved in cell migration mechanisms (PubMed:25869669). Modulates AKT/GSK3B pathway by decreasing AKT and GSK3B phosphorylation (PubMed:17322895). Negatively regulates STAT3 signaling pathway through inhibition of STAT3 phosphorylation and translocation to the nucleus (PubMed:25476455). Functionally important modulator of cardiac myocyte size and of the cardiac response to stress (By similarity). May play a role as negative regulator of axon regeneration after central nervous system injuries (By similarity).
Ubiquitous (PubMed:11274189). Highly expressed in brain (PubMed:26203138).
Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41 and VPS72/YL1. The NuA4 complex interacts with MYC and the adenovirus E1A protein. MORF4L1 may also participate in the formation of NuA4 related complexes which lack the KAT5/TIP60 catalytic subunit, but which include the SWI/SNF related protein SRCAP. Component of the MSIN3A histone deacetylase complex, which includes SIN3A, HDAC2, ARID4B, MORF4L1, RBBP4/RbAp48, and RBBP7/RbAp46. Interacts with MRFAP1 and RB1. May also interact with one or more as yet undefined members of the TLE (transducin-like enhancer of split) family of transcriptional repressors.
Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histone H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. NuA4 may also play a direct role in DNA repair when directly recruited to sites of DNA damage. Also a component of the MSIN3A complex which acts to repress transcription by deacetylation of nucleosomal histones.
A chromosomal aberration involving FRYL is found in treatment-related acute lymphoblastic leukemia (ALL). Translocation t(4;11)(p12;q23) that forms a KMT2A/MLL1-FRYL fusion protein.
Plays a key role in maintaining the integrity of polarized cell extensions during morphogenesis, regulates the actin cytoskeleton and plays a key role in patterning sensory neuron dendritic fields by promoting avoidance between homologous dendrites as well as by limiting dendritic branching (By similarity). May function as a transcriptional activator.
Widely expressed with higher expression in colon, placenta, brain and cells of lymphoid origin.
Expressed abundantly in the pancreas and heart and at high levels in brain, placenta, spleen, uterus and small intestine.
Function as phospholipase selective for phosphatidylcholine (PubMed:8530346, PubMed:9582313, PubMed:25936805). Implicated as a critical step in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis. May be involved in the regulation of perinuclear intravesicular membrane traffic (By similarity).
Stimulated by phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate, activated by the phosphokinase C-alpha, by the ADP-ribosylation factor-1 (ARF-1), and to a lesser extent by GTP-binding proteins: RHO A, RAC-1 and CDC42. Inhibited by oleate.
Belongs to the nucleoporin Nup85 family.
Component of the nuclear pore complex (NPC) (PubMed:12196509). Component of the NPC Nup107-160 subcomplex, consisting of at least NUP107, NUP98/Nup96, NUP160, NUP133, NUP85, NUP37, NUP43 and SEC13 (PubMed:15146057). Interacts with NUP160, NUP133 and SEC13 (PubMed:12718872, PubMed:30179222). Interacts with NUP37, NUP107 and NUP43 (PubMed:15146057). Interacts with CCR2 (PubMed:15995708).
Component of the nuclear pore complex (NPC).
Essential component of the nuclear pore complex (NPC) that seems to be required for NPC assembly and maintenance (PubMed:12718872). As part of the NPC Nup107-160 subcomplex plays a role in RNA export and in tethering NUP96/Nup98 and NUP153 to the nucleus (PubMed:12718872). The Nup107-160 complex seems to be required for spindle assembly during mitosis (PubMed:16807356). NUP85 is required for membrane clustering of CCL2-activated CCR2 (PubMed:15995708). Seems to be involved in CCR2-mediated chemotaxis of monocytes and may link activated CCR2 to the phosphatidyl-inositol 3-kinase-Rac-lammellipodium protrusion cascade (PubMed:15995708). Involved in nephrogenesis (PubMed:30179222).
Functions as a component of the nuclear pore complex (NPC).
Forms homodimers or heterodimers with ARFIP1 (PubMed:21239483). Interacts with RAC1 (PubMed:11346801). Specifically binds to GTP-bound ARF1 and ARF6, but binds to RAC1.GTP and RAC1.GDP with similar affinities. Interacts with ARL1 (PubMed:11303027, PubMed:22679020, PubMed:26507660). Interacts (via N-terminus) with IKBKB and IKBKG; these interactions inhibit activation of NF-kappa-B (PubMed:26296658).
Plays a role in constitutive metalloproteinase (MMP) secretion from the trans Golgi network (PubMed:26507660). May have important functions during vesicle biogenesis at certain cargo subdomains, which could be predominantly utilized by secreted MMPs, such as MMP7 and MMP2 (PubMed:26507660). Also involved in autophagy by regulating the starvation-dependent trafficking of ATG9A vesicles which deliver the phosphatidylinositol 4-kinase beta (PI4KB) to the autophagosome initiation site (PubMed:31204568, PubMed:30917996). Involved in phagophore growth during mitophagy by regulating ATG9A trafficking to mitochondria (PubMed:33773106). In addition, plays a role in NF-kappa-B inhibition by interacting with IKBKB and IKBKG (PubMed:26296658).
Associates with PML and SP100 in the PML NB complex. Associates with survival motor neuron protein (SMN)-containing macromolecular nuclear complexes and U1 and U2 snRNAs and U3 snoRNA.
Highly expressed in peripheral blood leukocytes, spleen, thymus, colon and lung. Up regulated by E2 in estrogen receptor-positive breast cancer lines.
Induced by interferons alpha and beta. Weaker induction was seen with interferon gamma. Increased expression was seen at the transcriptional level.
Interferon-induced antiviral exoribonuclease that acts mainly on single-stranded RNA (PubMed:11401564, PubMed:12594219, PubMed:16033969). Exhibits antiviral activity against RNA viruses including hepatitis C virus (HCV), hepatitis A virus (HAV) and yellow fever virus (YFV) (PubMed:16514659, PubMed:21036379). Inhibition of several viruses such as chikungunya virus (CHIKV) does not involve the degradation of viral RNAs, but rather the inhibition of translation of viral proteins (By similarity). Exerts a translational control over a large panel of non-self RNA substrates while sparing endogenous transcripts. This activity correlates with the protein's ability to localize in cytoplasmic processing bodies (PubMed:31600344). May also act as master regulator of over hundred interferon stimulated genes leading to viral genome translation inhibition (By similarity). May play additional roles in the maturation of snRNAs and rRNAs, and in ribosome biogenesis (PubMed:16514659).
Binds single-stranded RNA. Has a high affinity for G-rich and U-rich regions of hnRNA. Also binds to APOB mRNA transcripts around the RNA editing site.
Dimethylation at Arg-322 is probably asymmetric.
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with APOBEC1.
Induced by pro-inflammatory cytokines such as TNF and IL1B, via NF-kappaB signaling (PubMed:16730711, PubMed:19684084). Induced by cellular stresses such as heat shock, TPA, lipopolysaccharide and UV (PubMed:17603013). Induced by mitogens such as thrombin (PubMed:18959821).
Monomer. Interacts with NOTCH2 (via ANK repeats), the interaction inhibits the nuclear translocation of NOTCH2 N2ICD (PubMed:25985737). Interacts (C-terminus) with CBY1 (C-terminus), TCIM competes with CTNNB1 for the interaction with CBY1 (PubMed:16424001).
Seems to be involved in the regulation of cell growth an differentiation, may play different and opposite roles depending on the tissue or cell type. May enhance the WNT-CTNNB1 pathway by relieving antagonistic activity of CBY1 (PubMed:16424001, PubMed:16730711). Enhances the proliferation of follicular dendritic cells (PubMed:16730711). Plays a role in the mitogen-activated MAPK2/3 signaling pathway, positively regulates G1-to-S-phase transition of the cell cycle (PubMed:18959821). In endothelial cells, enhances key inflammatory mediators and inflammatory response through the modulation of NF-kappaB transcriptional regulatory activity (PubMed:19684084). Involved in the regulation of heat shock response, seems to play a positive feedback with HSF1 to modulate heat-shock downstream gene expression (PubMed:17603013). Plays a role in the regulation of hematopoiesis even if the mechanisms are unknown (By similarity). In cancers such as thyroid or lung cancer, it has been described as promoter of cell proliferation, G1-to-S-phase transition and inhibitor of apoptosis (PubMed:15087392, PubMed:24941347). However, it negatively regulates self-renewal of liver cancer cells via suppresion of NOTCH2 signaling (PubMed:25985737).
Ubiquitous. Expressed in thyroid papillary carcinoma. Expressed in liver, expression levels decrease in hepatocellular carcinoma (PubMed:25985737). Slightly detected in normal lung, its expression is highly induced in lung cancer cells (at protein level) (PubMed:24941347).
Fatty acylated. Heavily palmitoylated in the cysteine string motif.
Highest expression in lung. Placenta, liver and heart also express high levels of GAIP.
Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Binds to G-alpha subfamily 1 members, with the order G(i)a3 > G(i)a1 > G(o)a >> G(z)a/G(i)a2. Activity on G(z)-alpha is inhibited by phosphorylation and palmitoylation of the G-protein.
Interacts with GIPC PDZ domain. Interacts with GNAO1 (PubMed:34685729).
Phosphorylated, mainly on serine residues.
Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B), and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific (PubMed:22952240). Component of the BAF complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM, SMARCA4/BRG1, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C (PubMed:18765789). In muscle cells, the BAF complex also contains DPF3. Component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin (ACTB) (PubMed:22952240, PubMed:26601204). Interacts with UNKL (PubMed:20148946). Interacts with CEBPE (PubMed:28369036).
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner (PubMed:22952240, PubMed:26601204). Critical regulator of myeloid differentiation, controlling granulocytopoiesis and the expression of genes involved in neutrophil granule formation (PubMed:28369036).
Ubiquitinated through a signaling process involving RAC1 and the RING finger protein UNKL.
Interacts (via SAM domain) with INPPL1/SHIP2.
Phosphatidylinositol 3,4,5-trisphosphate-dependent GTPase-activating protein that modulates actin cytoskeleton remodeling by regulating ARF and RHO family members. Is activated by phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) binding. Can be activated by phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4,5)P2) binding, albeit with lower efficiency. Acts on ARF6, RAC1, RHOA and CDC42. Plays a role in the internalization of anthrax toxin.
Tyrosine phosphorylated at a low basal level. PDGF treatment stimulates phosphorylation. Tyrosine phosphorylation is increased in cells that are in the process of becoming attached to a substrate and that start spreading and flattening (By similarity).
Interacts (via N-terminus) with U2AF1 and SRSF5; acts to bridge the two. Interacts (via C-terminus) with EP400 and DDX1; acts to bridge the two (By similarity). Component of splicing factor SF3B complex which is composed of at least eight subunits; SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6, PHF5A and DDX42 (PubMed:12234937, PubMed:12738865, PubMed:27720643, PubMed:28541300). Within the SF3B complex interacts directly with SF3B1 and SF3B3 (PubMed:27720643). The SF3B complex composed of SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6 and PHF5A interacts with U2AF2 (PubMed:27720643). SF3B associates with the splicing factor SF3A and a 12S RNA unit to form the U2 small nuclear ribonucleoproteins complex (U2 snRNP) (PubMed:12234937). Component of the minor spliceosome, also called U12-type spliceosome, which splices U12-type introns. Within this complex, interacts with CRIPT (PubMed:15146077, PubMed:33509932). Interacts with the PAF1 complex (PAF1C) composed of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8. Within the PAF1C interacts directly with CDC73 and SKIC8. Interacts with RNA polymerase II (By similarity).
Involved with the PAF1 complex (PAF1C) in transcriptional elongation by RNA polymerase II, and in regulation of development and maintenance of embryonic stem cell (ESC) pluripotency. Required for maintenance of ESCs self-renewal and cellular reprogramming of stem cells. Maintains pluripotency by recruiting and stabilizing PAF1C on pluripotency genes loci, and by regulating the expression of the pluripotency genes. Regulates the deposition of elongation-associated histone modifications, including dimethylated histone H3 'Lys-79' (H3K79me2) and trimethylated histone H3 'Lys-36' (H3K36me3), on PAF1C targets, self-renewal and pluripotency genes. Regulates RNA polymerase II promoter-proximal pause release of the PAF1C targets and self-renewal genes, and the levels of elongating ('Ser-2' phosphorylated) RNA polymerase II in their gene bodies. Regulates muscle specification in adult stem cells by stabilizing PAF1C in chromatin to promote myogenic differentiation (By similarity). Involved in pre-mRNA splicing as a component of the splicing factor SF3B complex (PubMed:27720643, PubMed:28541300). SF3B complex is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA (PubMed:12234937). Acts as a transcriptional regulator by binding to the GJA1/Cx43 promoter and enhancing its up-regulation by ESR1/ER-alpha (By similarity). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
Belongs to the AB hydrolase superfamily. Monoacylglycerol lipase family.
Converts monoacylglycerides to free fatty acids and glycerol (PubMed:19029917, PubMed:20079333, PubMed:21049984, PubMed:22969151, PubMed:24368842). Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain (PubMed:19029917, PubMed:20079333, PubMed:21049984, PubMed:22969151, PubMed:24368842). Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth (PubMed:20079333).
Detected in adipose tissue, lung, liver, kidney, brain and heart.
Short-term inhibition causes analgesia, while long-term inhibition causes tolerance to endocannabinoids acting on brain cannabinoid receptor CNR1, and a reduction in brain cannabinoid receptor CNR1 activity.
CARD is critical for both extrinsic and intrinsic apoptotic pathways (By similarity). CARD domain mediates a protective effect against myocardial ischemia/reperfusion, oxidative stress and TNF-induced necrosis (PubMed:15004034). The C-terminal domain (amino acids 99 to 208) is involved in calcium binding and plays a protective role in calcium-mediated cell death (PubMed:15509781).
Functions as an apoptosis repressor that blocks multiple modes of cell death. Inhibits extrinsic apoptotic pathways through two different ways. Firstly by interacting with FAS and FADD upon FAS activation blocking death-inducing signaling complex (DISC) assembly (By similarity). Secondly by interacting with CASP8 in a mitochondria localization- and phosphorylation-dependent manner, limiting the amount of soluble CASP8 available for DISC-mediated activation (By similarity). Inhibits intrinsic apoptotic pathway in response to a wide range of stresses, through its interaction with BAX resulting in BAX inactivation, preventing mitochondrial dysfunction and release of pro-apoptotic factors (PubMed:15004034). Inhibits calcium-mediated cell death by functioning as a cytosolic calcium buffer, dissociating its interaction with CASP8 and maintaining calcium homeostasis (PubMed:15509781). Negatively regulates oxidative stress-induced apoptosis by phosphorylation-dependent suppression of the mitochondria-mediated intrinsic pathway, by blocking CASP2 activation and BAX translocation (By similarity). Negatively regulates hypoxia-induced apoptosis in part by inhibiting the release of cytochrome c from mitochondria in a caspase-independent manner (By similarity). Also inhibits TNF-induced necrosis by preventing TNF-signaling pathway through TNFRSF1A interaction abrogating the recruitment of RIPK1 to complex I (By similarity). Finally through its role as apoptosis repressor, promotes vascular remodeling through inhibition of apoptosis and stimulation of proliferation, in response to hypoxia (By similarity). Inhibits too myoblast differentiation through caspase inhibition (By similarity).
Highly expressed in heart and skeletal muscle. Detected at low levels in placenta, liver, kidney and pancreas.
Oligomerizes (via CARD doamin). Interacts (via CARD domain) with CASP2; inhibits CASP2 activity in a phosphorylation-dependent manner. Interacts with CASP8; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium. Interacts with TFPT; translocates NOL3 into the nucleus and negatively regulated TFPT-induced cell death (By similarity). Interacts directly (via CARD domain) with FAS and FADD (via DED domain); inhibits death-inducing signaling complex death-inducing signaling complex (DISC) assembly by inhibiting the increase in FAS-FADD binding induced by FAS activation (By similarity). Interacts (via CARD domain) with BAX (via a C-terminal 33 residues); inhibits BAX activation and translocation and consequently cytochrome c release from mitochondria. Interacts with PPM1G; may dephosphorylate NOL3 (By similarity). Interacts (via CARD domain) with BBC3 (via BH3 domain); preventing the association of BBC3 with BCL2 and resulting in activation of CASP8 (By similarity). Interacts (via CARD domain) with BAD(via BH3 domain); preventing the association of BAD with BCL2 (By similarity). Interacts directly (via CARD domain) with TNFRSF1A; inhibits TNF-signaling pathway (By similarity). Isoform 1 binds to SFRS9/SRp30C.
Phosphorylation at Thr-149 is required for its antiapoptotic effect by blocking death-inducing signaling complex death-inducing signaling complex (DISC) activity through the control of interaction with CASP8. Phosphorylation at Thr-149 results in translocation to mitochondria and this translocation enables the binding to CASP8. Dephosphorylated at Thr-149 by calcineurin; doesn't inhibit the association between FADD and CASP8 and the consequent apoptosis.
Polyubiquitinated by MDM2; promoting proteasomal-dependent degradation in response to apoptotic stimuli.
Protein expression decreases in hearts failure patients (PubMed:16505176) and in response to oxidative stress (PubMed:17142452).
May be involved in transcriptional regulation as a repressor.
Seems ubiquitous. Seen in the heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Acrosomal protein that maintains proacrosin (pro-ACR) as an enzymatically inactive zymogen in the acrosome. Involved also in the acrosome formation.
Binds proacrosin (pro-ACR). Does not bind the mature form of ACR.
Expression restricted to testis in normal tissue. Expressed in a wide spectrum of cancers, including bladder, breast, liver, lung and colon cancers.
Phosphorylated on Tyr residues in capacitated sperm.
Synthesized as a 60-kDa precursor, the 32-kDa mature form is post-translationally produced by the removal of the N-terminal half of the precursor during sperm maturation in the testis and/or epididymis.
Interacts with palmitoyltransferase ZDHHC17/HIP14; the interaction leads to palmitoylation of SPRED3.
Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase (By similarity). Inhibits fibroblast growth factor (FGF)-induced retinal lens fiber differentiation, probably by inhibiting FGF-mediated phosphorylation of ERK1/2 (By similarity). Inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells (By similarity).
Limited proteolysis of myosin heavy chain produces 1 light meromyosin (LMM) and 1 heavy meromyosin (HMM). HMM can be further cleaved into 2 globular subfragments (S1) and 1 rod-shaped subfragment (S2).
Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2).
Represents a conventional myosin. This protein should not be confused with the unconventional myosin-4 (MYO4).
The rodlike tail sequence is highly repetitive, showing cycles of a 28-residue repeat pattern composed of 4 heptapeptides, characteristic for alpha-helical coiled coils.
A chromosomal aberration involving FOXO4 is found in acute leukemias. Translocation t(X;11)(q13;q23) with KMT2A/MLL1. The result is a rogue activator protein.
A constitutively active FOXO4 mutant where phosphorylation sites Thr-32, Ser-197 and Ser-262 have been mutated to alanine may have therapeutic potential in ERBB2/HER2-overexpressing cancers as it inhibits ERBB2-mediated cell survival, transformation and tumorigenicity.
Acetylation by CREBBP/CBP, which is induced by peroxidase stress, inhibits transcriptional activity. Deacetylation by SIRT1 is NAD-dependent and stimulates transcriptional activity.
Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform zeta is most abundant in the liver, kidney, and pancreas.
Interacts with CREBBP/CBP, CTNNB1, MYOCD, SIRT1, SRF and YWHAZ. Acetylated by CREBBP/CBP and deacetylated by SIRT1. Binding of YWHAZ inhibits DNA-binding. Interacts with USP7; the interaction is enhanced in presence of hydrogen peroxide and occurs independently of TP53. Interacts with NLK, and this inhibits monoubiquitination and transcriptional activity. Interacts with FOXK1; the interaction inhibits MEF2C transactivation activity (By similarity).
Monoubiquitinated; monoubiquitination is induced by oxidative stress and reduced by deacetylase inhibitors; results in its relocalization to the nucleus and its increased transcriptional activity. Deubiquitinated by USP7; deubiquitination is induced by oxidative stress; enhances its interaction with USP7 and consequently, deubiquitination; increases its translocation to the cytoplasm and inhibits its transcriptional activity. Hydrogene-peroxide-induced ubiquitination and USP7-mediated deubiquitination have no major effect on its protein stability.
Phosphorylation by PKB/AKT1 inhibits transcriptional activity and is responsible for cytoplasmic localization. May be phosphorylated at multiple sites by NLK.
Transcription factor involved in the regulation of the insulin signaling pathway. Binds to insulin-response elements (IREs) and can activate transcription of IGFBP1. Down-regulates expression of HIF1A and suppresses hypoxia-induced transcriptional activation of HIF1A-modulated genes. Also involved in negative regulation of the cell cycle. Involved in increased proteasome activity in embryonic stem cells (ESCs) by activating expression of PSMD11 in ESCs, leading to enhanced assembly of the 26S proteasome, followed by higher proteasome activity.
A chromosomal aberration involving ELL is found in acute leukemias. Translocation t(11;19)(q23;p13.1) with KMT2A/MLL1. The result is a rogue activator protein.
Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3). Component of the little elongation complex (LEC), at least composed of ELL (ELL, ELL2 or ELL3), ZC3H8, ICE1 and ICE2. Interacts with AFF4; the interaction is direct. Interacts with EAF1 and EAF2. Interacts with ICE1 (via N-terminus domain). Interacts with ICE2. Interacts with USPL1 (PubMed:24413172).
Elongation factor component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. Elongation factor component of the little elongation complex (LEC), a complex required to regulate small nuclear RNA (snRNA) gene transcription by RNA polymerase II and III (PubMed:22195968, PubMed:23932780). Specifically required for stimulating the elongation step of RNA polymerase II- and III-dependent snRNA gene transcription (PubMed:23932780). ELL also plays an early role before its assembly into in the SEC complex by stabilizing RNA polymerase II recruitment/initiation and entry into the pause site. Required to stabilize the pre-initiation complex and early elongation.
Expressed in all tissues tested. Highest levels found in placenta, skeletal muscle, testis and peripheral blood leukocytes.
Efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with TCF3.
Transcription factor that plays a key role in neuronal differentiation: acts as a pioneer transcription factor, accessing closed chromatin to allow other factors to bind and activate neural pathways. Directly binds the E box motif (5'-CANNTG-3') on promoters and promotes transcription of neuronal genes. The combination of three transcription factors, ASCL1, POU3F2/BRN2 and MYT1L, is sufficient to reprogram fibroblasts and other somatic cells into induced neuronal (iN) cells in vitro. Plays a role at early stages of development of specific neural lineages in most regions of the CNS, and of several lineages in the PNS. Essential for the generation of olfactory and autonomic neurons. Acts synergistically with FOXN4 to specify the identity of V2b neurons rather than V2a from bipotential p2 progenitors during spinal cord neurogenesis, probably through DLL4-NOTCH signaling activation. Involved in the regulation of neuroendocrine cell development in the glandular stomach (By similarity).
Homotetramer; forms a two-fold symmetric tetramer in solution (PubMed:28963344). Interacts with CUL3; interaction is direct and forms a 5:5 heterodecamer (PubMed:28963344). Component of the BCR(BACURD3) E3 ubiquitin ligase complex, at least composed of CUL3, KCTD10/BACURD3 and RBX1 (By similarity). Interacts with DNA polymerase delta subunit 2/POLD2 (By similarity). Interacts with PCNA (PubMed:19125419).
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex. The BCR(BACURD3) E3 ubiquitin ligase complex mediates the ubiquitination of target proteins, leading to their degradation by the proteasome (By similarity).
Expressed in fibroblasts, heart, brain, liver, and skeletal muscle but not in placenta, lung, kidney and pancreas.
Inhibits calcineurin-dependent transcriptional responses by binding to the catalytic domain of calcineurin A. Could play a role during central nervous system development.
The C-terminal AMOP domain plays an important role in the anti-angiogenic function of ISM1.
Interacts with RAB3A and RAB3B that have been activated by GTP-binding. Interacts with RAB3C, RAB3D and RAB26. Interacts with TSPOAP1 and RIMBP2. Interacts with PPFIA3 and PPFIA4. Interacts via its zinc finger with the first C2 domain of UNC13A. Forms a complex consisting of UNC13A, RIMS2 and RAB3A. Heterodimer with PCLO. Part of a ternary complex involving PCLO and EPAC2 (By similarity).
Rab effector involved in exocytosis. May act as scaffold protein. Plays a role in dendrite formation by melanocytes (PubMed:23999003).
Widely expressed (PubMed:32470375). Expressed in melanocytes (PubMed:23999003). In fetal tissues, predominantly expressed in the brain (PubMed:32470375). In the retina, expressed in the outer plexiform layer (at protein level) (PubMed:32470375). In the cerebellum, expressed in Purkinje cells (at protein level) (PubMed:32470375). In the pancreas, expressed in Langerhans islets (at protein level) (PubMed:32470375).
Exhibits adenosine 5'-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5'monophosphoramidate (AMP-NH2) to yield AMP and NH2 (PubMed:15703176, PubMed:16835243, PubMed:17337452, PubMed:17217311, PubMed:23614568, PubMed:28691797, PubMed:29787766, PubMed:31990367, PubMed:22329685). Hydrolyzes adenosine 5'monophosphomorpholidate (AMP-morpholidate) and guanosine 5'monophosphomorpholidate (GMP-morpholidate) (PubMed:15703176, PubMed:16835243). Hydrolyzes lysyl-AMP (AMP-N-epsilon-(N-alpha-acetyl lysine methyl ester)) generated by lysine tRNA ligase, as well as Met-AMP, His-AMP and Asp-AMP, lysyl-GMP (GMP-N-epsilon-(N-alpha-acetyl lysine methyl ester)) and AMP-N-alanine methyl ester (PubMed:15703176, PubMed:22329685, PubMed:17337452). Hydrolyzes 3-indolepropionic acyl-adenylate, tryptamine adenosine phosphoramidate monoester and other fluorogenic purine nucleoside tryptamine phosphoramidates in vitro (PubMed:17337452, PubMed:23614568, PubMed:29787766, PubMed:17217311, PubMed:28691797, PubMed:31990367). Can also convert adenosine 5'-O-phosphorothioate and guanosine 5'-O-phosphorothioate to the corresponding nucleoside 5'-O-phosphates with concomitant release of hydrogen sulfide (PubMed:30772266). In addition, functions as scaffolding protein that modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex and by the complex formed with MITF and CTNNB1 (PubMed:16014379, PubMed:22647378). Modulates p53/TP53 levels and p53/TP53-mediated apoptosis (PubMed:16835243). Modulates proteasomal degradation of target proteins by the SCF (SKP2-CUL1-F-box protein) E3 ubiquitin-protein ligase complex (PubMed:19112177). Also exhibits SUMO-specific isopeptidase activity, deconjugating SUMO1 from RGS17 (PubMed:31088288). Deconjugates SUMO1 from RANGAP1 (By similarity).
Homodimer. Interacts with CDK7. Interacts with RUVBL1 and RUVBL2 and is associated with the LEF1/TCF1-CTNNB1 complex and with a KAT5 histone acetyltransferase complex. Identified in a complex with MITF and CTNNB1. Interacts with CDC34 and RBX1, and is part of a SCF (SKP2-CUL1-F-box protein) E3 ubiquitin-protein ligase complex (PubMed:19112177). Interacts with SUMO1, SUMO2 and RGS17 (By similarity). Interacts with the Ten-1 ICD form of TENM1 (By similarity). Interacts with CALM1; interaction increases in the presence of calcium ions (By similarity).
Was originally thought to be a protein kinase C inhibitor and to bind zinc in solution. Both seem to be incorrect.
Interacts with AKT1; AKT2 and AKT3 (By similarity). Associates with PP2CA (By similarity). Part of a complex containing MARK4 (PubMed:14676191).
Promotes the phosphorylation of AKT family members.
(Microbial infection) Interacts with Rabies virus protein M; this interaction promotes virion uncoating.
(Microbial infection) Plays an important role in virion uncoating during Rabies virus replication after membrane fusion. Specifically, participates in the dissociation of incoming viral matrix M proteins uncoating through direct interaction.
ATP hydrolysis occurs at the interface between the nucleotide-binding domains of subunits A and B (By similarity). ATP hydrolysis triggers a conformational change in the subunits D and F, which induces a shift of subunit d (By similarity). The c-ring is subsequently rotated and results in a continuous proton translocation across the membrane (By similarity).
Belongs to the ATPase alpha/beta chains family.
Catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:8463241). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (PubMed:32001091). In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation (PubMed:28296633). May play a role in neurite development and synaptic connectivity (PubMed:29668857).
Phosphorylation at Ser-384 by AMPK down-regulates its enzyme activity.
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex (PubMed:33065002). The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H (PubMed:33065002). The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR (PubMed:33065002). Interacts with the V0 complex V-ATPase subunit a4 ATP6V0A4 (By similarity). Interacts with WFS1 (PubMed:23035048). Interacts with alpha-crystallin B chain/CRYAB and with MTOR, forming a ternary complex (PubMed:31786107).
Part of the SNAPc complex composed of 5 subunits: SNAPC1, SNAPC2, SNAPC3, SNAPC4 and SNAPC5. SNAPC1 interacts with SNAPC3, SNAPC4 and TBP.
Part of the SNAPc complex required for the transcription of both RNA polymerase II and III small-nuclear RNA genes. Binds to the proximal sequence element (PSE), a non-TATA-box basal promoter element common to these 2 types of genes. Recruits TBP and BRF2 to the U6 snRNA TATA box.
Detected in pancreas, brain, liver, placenta, trachea, kidney, spinal cord, stomach and fetal brain. In the adult brain region expression is detected in the hippocampus, striatum, amygdala and thalamus.
The mouse and rat orthologous proteins do not exist.
Zinc-activated ligand-gated ion channel.
Belongs to the eukaryotic ribosomal protein P1/P2 family.
Heterodimer with RPLP2 at the lateral ribosomal stalk of the large ribosomal subunit.
Plays an important role in the elongation step of protein synthesis.
Ubiquitinated at Lys-92 and Lys-93 by RNF14 and RNF25 in response to ribosome collisions (ribosome stalling).
Belongs to the fatty acid desaturase CarF family.
Down-regulated during differentiation of cultured colon adenocarcinoma cells.
Has no ubiquitin ligase activity on its own. The UBE2V1-UBE2N heterodimer catalyzes the synthesis of non-canonical poly-ubiquitin chains that are linked through Lys-63. This type of poly-ubiquitination activates IKK and does not seem to involve protein degradation by the proteasome. Plays a role in the activation of NF-kappa-B mediated by IL1B, TNF, TRAF6 and TRAF2. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes. Together with RNF135 and UBE2N, catalyzes the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIGI to activate the downstream signaling pathway that leads to interferon beta production (PubMed:31006531). UBE2V1-UBE2N together with TRAF3IP2 E3 ubiquitin ligase mediate 'Lys-63'-linked polyubiquitination of TRAF6, a component of IL17A-mediated signaling pathway.
Heterodimer with UBE2N (PubMed:11057907, PubMed:16307917, PubMed:16893187). Interacts (UBE2V2-UBE2N heterodimer) with the E3 ligase STUB1 (via the U-box domain); the complex has a specific 'Lys-63'-linked polyubiquitination activity (PubMed:16307917). Interacts with TRAF6 (PubMed:11057907, PubMed:16307917).
Highly expressed in thyroid, pancreas, spinal cord, lymph node, trachea, adrenal gland, bone marrow and pancreas. Detected at low levels in heart, breast, placenta, brain, liver, kidney, stomach and lung.
Histidine box-1 and -2 together with other histidine residues are essential for catalytic activity.
In human, PESD1 and UBE2V1 are adjacent genes which can produce independent proteins and can also be fused to form a PESD1-UBE2V1 hybrid protein.
In human, PESD1/KUA and UBE2V1/UEV1 are adjacent genes which can produce independent proteins and can also be fused to form a PESD1-UBE2V1 hybrid protein.
Plasmanylethanolamine desaturase involved in plasmalogen biogenesis in the endoplasmic reticulum membrane (PubMed:31604315, PubMed:32209662, PubMed:33859415). Plasmalogens are glycerophospholipids with a hydrocarbon chain linked by a vinyl ether bond at the glycerol sn-1 position, and are involved in antioxidative and signaling mechanisms (PubMed:31604315).
Adapter molecule that plays a key role in the activation of pro-inflammatory NF-kappa-B signaling following detection of bacterial pathogen-associated molecular pattern metabolites (PAMPs) (PubMed:12566447, PubMed:15492226, PubMed:26068852, PubMed:28877472, PubMed:28222186, PubMed:30111836). Promotes activation of an innate immune response by inducing the oligomerization and polyubiquitination of TRAF6, which leads to the activation of TAK1 and IKK through a proteasome-independent mechanism (PubMed:15492226, PubMed:26068852). TIFA-dependent innate immune response is triggered by ADP-D-glycero-beta-D-manno-heptose (ADP-Heptose), a potent PAMP present in all Gram-negative and some Gram-positive bacteria: ADP-Heptose is recognized by ALPK1, which phosphorylates TIFA at Thr-9, leading to TIFA homooligomerization and subsequent activation of pro-inflammatory NF-kappa-B signaling (PubMed:30111836).
D-glycero-beta-D-manno-heptose 1,7-bisphosphate (HBP) was initially thought to constitute the bacterial pathogen-associated molecular pattern metabolite (PAMP) triggering the ALPK1-TIFA innate immunune response (PubMed:26068852, PubMed:28877472, PubMed:28222186). It was however shown that ADP-D-glycero-beta-D-manno-heptose (ADP-Heptose) constitutes the main PAMP that activates the kinase activity of ALPK1, promoting phosphorylation of TIFA (PubMed:30111836).
Homooligomer; homooligomerizes following phosphorylation at Thr-9 (PubMed:12566447, PubMed:22566686, PubMed:26068852, PubMed:26389808). Interacts with IRAK1, TRAF2 and TRAF6 (PubMed:12566447). Interacts with TIFAB; binding to TIFAB inhibits TRAF6 activation, possibly by inducing a conformational change in TIFA (PubMed:15047173). Interacts with ZCCHC11; binding to ZCCHC11 suppresses the TRAF6-dependent activation of NF-kappa-B (PubMed:16643855).
Phosphorylated at Thr-9 following detection of ADP-D-glycero-beta-D-manno-heptose (ADP-Heptose) by ALPK1 (PubMed:30111836). Phosphorylation at Thr-9 by ALPK1 leads to the formation of an intermolecular binding between the FHA domain and phosphorylated Thr-9, promoting TIFA oligomerization and TIFA-mediated NF-kappa-B activation (PubMed:22566686, PubMed:30111836, PubMed:26389808).
The FHA domain recognizes and binds phosphorylated Thr-9, promoting homooligomerization and subsequent activation of NF-kappa-B.
Affinity and transport activity are regulated by a phosphorylation switch state at Ser-274 and Ser-297; increasing of affinity and amino acid transport activity via dephosphorylation at Ser-274 and phosphorylation at Ser-297.
Belongs to the SLC43A transporter (TC 2.A.1.44) family.
Dephosphorylation at Ser-274 and phosphorylation at Ser-297 increase affinity and amino acid transport activity (PubMed:30379325). Phosphorylation-dephosphorylation cycle is regulated by food-entrained diurnal rhythm and dietary proteins (By similarity).
Detected in several tissues with higher expression in placenta, kidney and peripheral blood leukocytes (PubMed:15659399). In the kidney, is detected in epithelial cells of the distal tubule and collecting duct (PubMed:15659399). In the intestine, is expressed mainly in crypt cells of the intestinal microvilli and epithelial cells in the base of the villus (PubMed:15659399).
Uniporter that mediates the transport of the stereospecific L-phenylalanine, L-methionine and L-branched-chain amino acids, between the extracellular space and the cytoplasm and may control the transepithelial (re)absorption of neutral amino acid in kidney and small intestine (PubMed:30379325, PubMed:15659399). The transport activity is mediated through facilitated diffusion and is sodium ions-, chloride ions- and pH-independent (PubMed:15659399).
Interacts with GLUT1 (C-terminus), ACTN1, KIF1B, MYO6, PLEKHG5, SDC4/syndecan-4 and SEMA4C/semaphorin-4C (By similarity). Interacts with RGS19 C-terminus. Interacts with HTLV-I Tax through the PDZ domain.
May be involved in G protein-linked signaling.
The disease may be caused by variants affecting the gene represented in this entry. GGC repeat expansions in the 5'-UTR ranging from 73 to 164 were reported in patients, compared with a normal range from 12 to 32 in unaffected individuals. Patient skeletal muscle showed similar protein levels to those of unaffected individuals.
Widely expressed (PubMed:9770488). Expressed in skeletal muscle (at protein level) (PubMed:32413282).
(Microbial infection) In contrast to DERL1, it is not involved in the degradation of MHC class I heavy chains following infection by cytomegaloviruses.
Forms homo- and heterooligomers with DERL3 and, to a lesser extent, with DERL1 (PubMed:16186509). Interacts with the SEL1L/SYVN1 and VCP/SELENOS protein complexes (PubMed:16186509). Mediates association between VCP and EDEM1, as well as that between VCP and the misfolded glycoproteins (PubMed:16449189). Interacts with OS9 (PubMed:19084021). Interacts with SELENOK and SELENOS (PubMed:22016385). Interacts with the signal recognition particle/SRP and the SRP receptor; in the process of endoplasmic reticulum stress-induced pre-emptive quality control (PubMed:26565908). Interacts with CCDC47 (By similarity).
Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal glycoproteins, but not that of misfolded nonglycoproteins. May act by forming a channel that allows the retrotranslocation of misfolded glycoproteins into the cytosol where they are ubiquitinated and degraded by the proteasome. May mediate the interaction between VCP and misfolded glycoproteins (PubMed:16186509, PubMed:16449189). May also be involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation (PubMed:26565908).
Ubiquitous. Overexpressed in various hepatocarcinomas.
Up-regulated in response to endoplasmic reticulum stress via the ERN1-XBP1 pathway of the unfolded protein response (UPR).
Homooligomer (By similarity). Central component of a complex containing at least ANKS6, INVS, NEK8 and NPHP3 (PubMed:23793029). ANKS6 may organize complex assembly by linking INVS and NPHP3 to NEK8 and INVS may target the complex to the proximal ciliary axoneme (PubMed:23793029). Interacts (via SAM domain) with BICC1 (via KH domains) in an RNA-dependent manner (By similarity). Interacts (via SAM domain) with ANKS3 (via SAM domain) (PubMed:24998259).
Hydroxylated at Asn-138, most probably by HIF1AN. This hydroxylation results in decreased NEK8-binding.
The SAM domain mediates interaction with the SAM domain of ANKS3.
The ankyrin repeats are necessary and sufficient for NEK8-binding.
In lung, HT-29 colonic epithelial cells, Raji B-lymphoblasts. Lesser extent in brain, heart, kidney, liver and placenta. Not expressed in CD4+ or CD8+ T-cells. Expressed in the T-cell lines HARRIS, HuT 78, Jurkat and SUP-T1, but not in the T-cell lines Peer, MOLT-4, HSB and YT.
This is a receptor for VIP. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. The affinity is VIP = PACAP-27 > PACAP-38.
Belongs to the eukaryotic ribosomal protein eL24 family.
Component of the large ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell.
Mono-ADP-ribosylation at Glu-4 by PARP16 inhibits polysome assembly and mRNA loading, thereby inhibiting protein translation.
Interacts with POLR2A (via the C-terminal domain).
Expressed at low levels in most fetal tissues, adult ovaries and at high levels in adult testis, where it is localized in germ cells (PubMed:10806483). Expressed in respiratory epithelial cells of the lung (PubMed:28543983).
Interacts with GLI1, GLI2 and GLI3 (PubMed:10806483). Interacts with SPAG16 and KIF27.
Serine/threonine protein kinase which plays an important role in the sonic hedgehog (Shh) pathway by regulating the activity of GLI transcription factors (PubMed:10806483). Controls the activity of the transcriptional regulators GLI1, GLI2 and GLI3 by opposing the effect of SUFU and promoting their nuclear localization (PubMed:10806483). GLI2 requires an additional function of STK36 to become transcriptionally active, but the enzyme does not need to possess an active kinase catalytic site for this to occur (PubMed:10806483). Required for postnatal development, possibly by regulating the homeostasis of cerebral spinal fluid or ciliary function. Essential for construction of the central pair apparatus of motile cilia.
Catalyzes a step in lysosomal heparan sulfate degradation.
Deiminated on Arg-4 in granulocytes upon calcium entry.
Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).
Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.
Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.
Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.
The HB-6, CDW75, and CD76 differentiation antigens are cell-surface carbohydrate determinants generated by this enzyme.
The soluble form derives from the membrane form by proteolytic processing.
Transfers sialic acid from CMP-sialic acid to galactose-containing acceptor substrates.
Belongs to the WD repeat peroxin-7 family.
Interacts with PEX5; interaction only takes place when PEX7 is associated with cargo proteins (PubMed:11546814, PubMed:33389129, PubMed:25538232). Interacts with VWA8 (PubMed:30204880).
Receptor required for the peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal (PubMed:9090381, PubMed:11931631, PubMed:22057399, PubMed:25538232). Specifically binds to cargo proteins containing a PTS2 peroxisomal targeting signal in the cytosol (PubMed:11931631, PubMed:22057399, PubMed:25538232). Cargo protein-binding triggers interaction with PEX5 and formation of a ternary complex composed of PEX5 and PEX7 along with PTS2-containing cargo proteins, which is tranlocated into peroxisomes by passing through the PEX13-PEX14 docking complex (PubMed:11546814, PubMed:25538232).
Ubiquitous (PubMed:9090381). Highest expression in pancreas, skeletal muscle and heart (PubMed:9090381).
A cytochrome P450 monooxygenase involved in the metabolism of arachidonic acid and its conjugates (PubMed:14660610, PubMed:24563460). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:14660610, PubMed:24563460). Acts as an omega and omega-1 hydroxylase for arachidonic acid and possibly for other long chain fatty acids. May modulate the arachidonic acid signaling pathway and play a role in other fatty acid signaling processes (PubMed:14660610, PubMed:24563460). May down-regulate the biological activities of N-arachidonoyl-serotonin, an endocannabinoid that has anti-nociceptive effects through inhibition of fatty acid amide hydrolase FAAH, TRPV1 receptor and T-type calcium channels. Catalyzes C-2 oxidation of the indole ring of N-arachidonoyl-serotonin forming a less active product 2-oxo-N-arachidonoyl-serotonin (PubMed:24563460).
Widely expressed with stronger expression in thymus, heart and cerebellum.
By changes in energy balance: down-regulated following very low-calorie diet, whereas refeeding elevates the mRNA level.
Polymorphic variation at position 148 influences insulin secretion levels and obesity. In obese subjects the body mass index and waist are higher in carriers of the Ile-148 allele. The Ile-148 carriers also display decreased insulin secretion in response to oral glucose tolerance test. Met-148 allele carriers are seemingly more insulin resistant at a lower body mass index.
Specifically catalyzes coenzyme A (CoA)-dependent acylation of 1-acyl-sn-glycerol 3-phosphate (2-lysophosphatidic acid/LPA) to generate phosphatidic acid (PA), an important metabolic intermediate and precursor for both triglycerides and glycerophospholipids. Does not esterify other lysophospholipids. Acyl donors are long chain (at least C16) fatty acyl-CoAs: arachidonoyl-CoA, linoleoyl-CoA, oleoyl-CoA and at a lesser extent palmitoyl-CoA (PubMed:22560221). Additionally possesses low triacylglycerol lipase and CoA-independent acylglycerol transacylase activities and thus may play a role in acyl-chain remodeling of triglycerides (PubMed:15364929, PubMed:20034933, PubMed:22560221). In vitro may express hydrolytic activity against glycerolipids triacylglycerol, diacylglycerol and monoacylglycerol, with a strong preference for oleic acid as the acyl moiety (PubMed:21878620). However, the triacylglycerol hydrolase activity is controversial and may be very low (PubMed:22560221). Possesses phospholipase A2 activity (PubMed:15364929).
The triglyceride lipase activity is inhibited by BEL ((E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one), a suicide substrate inhibitor.
Peroxisomal 2-OH acyl-CoA lyase involved in the cleavage (C1 removal) reaction in the fatty acid alpha-oxydation in a thiamine pyrophosphate (TPP)-dependent manner (PubMed:28289220, PubMed:21708296, PubMed:10468558). Involved in the degradation of 3-methyl-branched fatty acids like phytanic acid and the shortening of 2-hydroxy long-chain fatty acids (PubMed:28289220, PubMed:21708296, PubMed:10468558). Plays a significant role in the biosynthesis of heptadecanal in the liver (By similarity).
Interacts with the APC/C complex (By similarity). Interacts with the chromatin-bound cohesin complex; the interaction is indirect, occurs after DNA replication and requires acetylation of the cohesin component SMC3. Interacts (via the FGF motif) with PDS5A and PDS5B; the interaction is direct and prevents the interaction of PDS5A with WAPL.
Named sororin after the Latin word 'soror', which means 'sister', because of its critical role in sister chromatid cohesion.
Phosphorylated. Phosphorylation, as cells enter mitosis, disrupts the interaction with PDS5A and relieves the inhibition of WAPL by CDCA5.
Regulator of sister chromatid cohesion in mitosis stabilizing cohesin complex association with chromatin. May antagonize the action of WAPL which stimulates cohesin dissociation from chromatin. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair. Required for efficient DNA double-stranded break repair.
The KEN box is required for the association with the APC/C complex.
Ubiquitinated by the APC/C complex in G1, leading to its degradation.
ppGpp hydrolyzing enzyme involved in starvation response.
(Microbial infection) Interacts with ebolavirus protein VP24.
Consists of an N-terminal hydrophilic region, a hydrophobic central region composed of 10 repeats, and a short hydrophilic C-terminus. The N-terminal hydrophilic region contains the importin beta binding domain (IBB domain), which is sufficient for binding importin beta and essential for nuclear protein import.
Forms a complex with importin subunit beta-1.
Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Mediates nuclear import of STAT1 homodimers and STAT1/STAT2 heterodimers by recognizing non-classical NLSs of STAT1 and STAT2 through ARM repeats 8-9. Recognizes influenza A virus nucleoprotein through ARM repeat 7-9 In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS.
The IBB domain is thought to act as an intrasteric autoregulatory sequence by interacting with the internal autoinhibitory NLS. Binding of KPNB1 probably overlaps the internal NLS and contributes to a high affinity for cytoplasmic NLS-containing cargo substrates. After dissociation of the importin/substrate complex in the nucleus the internal autohibitory NLS contributes to a low affinity for nuclear NLS-containing proteins (By similarity).
The major and minor NLS binding sites are mainly involved in recognition of simple or bipartite NLS motifs. Structurally located within in a helical surface groove they contain several conserved Trp and Asn residues of the corresponding third helices (H3) of ARM repeats which mainly contribute to binding (By similarity).
Part of the AP-3 complex, an adaptor-related complex which is not clathrin-associated. The complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and may be directly involved in trafficking to lysosomes. In concert with the BLOC-1 complex, AP-3 is required to target cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals.
Homodimer and heterodimer. Multiple DAZL RRMs can bind to a single RNA containing multiple GUU triplets (By similarity). Forms a heterodimer with DAZ. Interacts with BOLL, DAZAP1 and DAZAP2. Interacts with PUM2.
RNA-binding protein, which is essential for gametogenesis in both males and females. Plays a central role during spermatogenesis. Acts by binding to the 3'-UTR of mRNA, specifically recognizing GUU triplets, and thereby regulating the translation of key transcripts (By similarity).
The DAZ domain mediates the interaction with DAZAP1 and DAZAP2.
Forms functional complexes with BSG/CD147 or EMB/GP70 ancillary proteins.
Monocarboxylate transporter selective for taurine. May associate with BSG/CD147 or EMB/GP70 ancillary proteins to mediate facilitative efflux or influx of taurine across the plasma membrane. The transport is pH- and sodium-independent. Rather low-affinity, is likely effective for taurine transport in tissues where taurine is present at high concentrations.
(Microbial infection) Critical macrophage receptor for dengue virus serotypes 1-4 (PubMed:18496526, PubMed:21566123). The binding of dengue virus to CLEC5A triggers signaling through the phosphorylation of TYROBP (PubMed:18496526). This interaction does not result in viral entry, but stimulates pro-inflammatory cytokine release (PubMed:18496526).
(Microbial infection) Interacts with dengue virus envelope protein E (PubMed:18496526, PubMed:21566123).
Acts as a key regulator of synovial injury and bone erosion during autoimmune joint inflammation when its activation leads to enhanced recruitment of inflammatory macrophages and neutrophils to the joints.
Functions as a positive regulator of osteoclastogenesis (By similarity). Cell surface receptor that signals via TYROBP (PubMed:10449773). Regulates inflammatory responses (By similarity).
Highly expressed in bone marrow with lower levels in synovium, lung and bronchus (PubMed:20212065). Expressed in peripheral blood monocytes and in the monocyte/macrophage cell lines U-937 and Mono-Mac-6, but not in cell lines of other origins (PubMed:10449773). Expression is down-regulated when monocytes differentiate into dendritic cells (PubMed:10449773).
Monomer (PubMed:21566123). Homodimer (PubMed:21566123). The majority of CLEC5A is expressed as a monomeric form on macrophages (PubMed:21566123). Interacts with TYROBP/DAP12 (PubMed:10449773). The interaction with TYROBP is required for CLEC5A cell surface expression (PubMed:10449773). Interacts with HCST/DAP10 (By similarity). Forms a CLEC5A/TYROBP/HCST trimolecular complex depending almost solely on TYROBP (By similarity).
(Microbial infection) Binds to the HIV-1 TAR RNA which is located in the long terminal repeat (LTR) of HIV-1.
(Microbial infection) The NELF complex is involved in HIV-1 latency possibly involving recruitment of PCF11 to paused RNA polymerase II.
Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II (PubMed:10199401, PubMed:27256882). The NELF complex, which acts via an association with the DSIF complex and causes transcriptional pausing, is counteracted by the P-TEFb kinase complex (PubMed:11940650, PubMed:12612062, PubMed:27256882). Provides the strongest RNA binding activity of the NELF complex and may initially recruit the NELF complex to RNA (PubMed:18303858, PubMed:27282391, PubMed:27256882).
Phosphorylated by the P-TEFb complex at sites next to its RNA recognition motif, promoting its release from chromatin.
Poly-ADP-ribosylated by PARP1, thereby preventing RNA-binding and relieving transcription pausing.
The NELF complex is composed of NELFA, NELFB, NELFCD (isoform NELF-C or isoform NELF-D) and NELFE (PubMed:10199401, PubMed:27282391). Interacts with NELFB (By similarity).
The RRM domain interacts with RNA, and is essential for NELF complex function. It is however not required for the NELF complex formation.
Widely expressed. Expressed in heart, brain, lung, placenta, liver, skeletal muscle, kidney and pancreas.
Belongs to the adenylate kinase family. AK3 subfamily.
Consists of three domains, a large central CORE domain and two small peripheral domains, NMPbind and LID, which undergo movements during catalysis. The LID domain closes over the site of phosphoryl transfer upon GTP/ATP binding. Assembling and dissambling the active center during each catalytic cycle provides an effective means to prevent GTP/ATP hydrolysis.
Highly expressed in kidney, moderately expressed in heart and liver and weakly expressed in brain.
Involved in maintaining the homeostasis of cellular nucleotides by catalyzing the interconversion of nucleoside phosphates (PubMed:19073142, PubMed:19766732, PubMed:23416111, PubMed:24767988). Efficiently phosphorylates AMP and dAMP using ATP as phosphate donor, but phosphorylates only AMP when using GTP as phosphate donor (PubMed:19073142, PubMed:19766732, PubMed:23416111). Also displays broad nucleoside diphosphate kinase activity (PubMed:19073142, PubMed:19766732, PubMed:23416111). Plays a role in controlling cellular ATP levels by regulating phosphorylation and activation of the energy sensor protein kinase AMPK (PubMed:24767988, PubMed:26980435). Plays a protective role in the cellular response to oxidative stress (PubMed:19130895, PubMed:23474458, PubMed:26980435).
Monomer (Ref.17). Interacts with SLC25A5/ANT2 (PubMed:19130895).
Some studies have failed to detect adenylate kinase activity (PubMed:11485571, PubMed:19130895). However, kinase activity has been demonstrated in a number of other studies (PubMed:19766732, PubMed:23416111).
Involved in directing the movement of organelles along actin filaments.
MYO1A mutations have been reported to cause autosomal dominant non-syndromic hearing loss DFNA48 (PubMed:12736868). It was later shown that MYO1A is not associated with DFNA48 (PubMed:24616153).
By hypoxia, directly activated by HIF1A. Expression is regulated by PRMT7.
Dioxygenase that demethylates RNA by oxidative demethylation: specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes (PubMed:23177736, PubMed:24489119, PubMed:24616105, PubMed:24778178). Can also demethylate N(6)-methyladenosine in single-stranded DNA (in vitro) (PubMed:24616105). Requires molecular oxygen, alpha-ketoglutarate and iron (PubMed:21264265, PubMed:23177736, PubMed:24489119, PubMed:24616105, PubMed:24778178). Demethylation of m6A mRNA affects mRNA processing and export (PubMed:23177736). Required for the late meiotic and haploid phases of spermatogenesis by mediating m6A demethylation in spermatocytes and round spermatids: m6A demethylation of target transcripts is required for correct splicing and the production of longer 3'-UTR mRNAs in male germ cells (By similarity).
Widely expressed, with highest expression in lung, followed by testis, pancreas, spleen and ovary.
Highly expressed in testis, weakly expressed in spleen, thymus, prostate, ovary, small intestine colon and peripheral blood leukocytes.
Interacts with actin and this stimulates phosphatase activity. Also interacts with LIMK1 and with the 14-3-3 proteins YWHAB, YWHAG, YWHAQ, and YWHAZ. Interaction with 14-3-3 proteins inhibits phosphatase activity and also blocks recruitment to lamellipodia and stimulation by actin.
Phosphorylated. Inhibitory phosphorylation by PAK4 promotes binding to YWHAZ. Phosphorylation at Ser-978 is decreased by stimuli which promote actin reorganization and lamellipodia formation. Can be dephosphorylated and activated by PPP3CA/calcineurin A. Phosphorylation decreases immediately prior to telophase.
Protein phosphatase which regulates actin filament dynamics. Dephosphorylates and activates the actin binding/depolymerizing factor cofilin, which subsequently binds to actin filaments and stimulates their disassembly. Inhibitory phosphorylation of cofilin is mediated by LIMK1, which may also be dephosphorylated and inactivated by this protein.
Tyrosine phosphatase activity has not been demonstrated for this protein to date.
Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Although it displays a much weaker activity toward all substrates tested compared to GALNT2, it is able to transfer up to seven GalNAc residues to the Muc5AC peptide, suggesting that it can fill vicinal Thr/Ser residues in cooperation with other GALNT proteins. Prefers Muc1a as substrate.
Was originally termed Galnt15/pp-GaNTase 15.
Widely expressed. Highly expressed in small intestine, placenta, spleen, cerebral cortex and ovary. Expressed at intermediate level in uterus, mammary gland, stomach, cerebellum and whole brain. Weakly expressed in fetal brain, bone marrow, thyroid gland, thymus, heart, skeletal muscle, lung, liver, colon, pancreas, kidney and testis. Not expressed in leukocyte. Expressed in both normal and osteoarthritic cartilage. Expressed at low level in chondrocytes in all zones of both normal and osteoarthritic cartilage.
Receptor that may play a role in the perception of bitterness and is gustducin-linked. May play a role in sensing the chemical composition of the gastrointestinal content. The activity of this receptor may stimulate alpha gustducin, mediate PLC-beta-2 activation and lead to the gating of TRPM5 (By similarity).
Oligomer of 24 subunits (PubMed:9159481). There are two types of subunits: L (light) chain and H (heavy) chain (PubMed:9159481). The major chain can be light or heavy, depending on the species and tissue type. In the human liver, the heavy chain is predominant (PubMed:9159481). The functional molecule forms a roughly spherical shell with a diameter of 12 nm and contains a central cavity into which the insoluble mineral iron core is deposited (PubMed:9159481).
Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Has ferroxidase activity (PubMed:9003196). Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation (PubMed:9003196). Also plays a role in delivery of iron to cells (By similarity). Mediates iron uptake in capsule cells of the developing kidney (By similarity).
The disease is caused by variants affecting the gene represented in this entry. In a Japanese family affected by HFE5, a single point mutation has been detected in the iron-responsive element (IRE) in the 5'-UTR of FTH1 mRNA. This mutation leads to an increased binding affinity for iron regulatory protein and thereby to the efficient suppression of mRNA translation.
Belongs to the biopterin-dependent aromatic amino acid hydroxylase family.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Naturally occurring variants of TPH2 with impaired enzyme activity could cause deficiency of serotonin production and result in an increased risk of developing behavioral disorders.
Modulates the kinetic properties of both isoforms.
Detected on umbilical veil endothelial cells (PubMed:10625079). Detected in placenta (at protein level) (PubMed:1692830). Detected on endothelial cells (PubMed:1692830).
Homodimer; disulfide-linked (PubMed:8370410, PubMed:1326540, PubMed:21737454, PubMed:22347366, PubMed:28564608). Forms a heteromeric complex with the signaling receptors for transforming growth factor-beta: TGFBR1 and/or TGFBR2 (PubMed:1326540). It is able to bind TGFB1 and TGFB2 with high affinity, but not TGFB3 (PubMed:8370410, PubMed:1326540). Interacts with GDF2, forming a heterotetramer with a 2:2 stoichiometry (PubMed:21737454, PubMed:22347366, PubMed:28564608). Interacts with ACVRL1 (PubMed:22347366, PubMed:28564608). Can form a heteromeric complex with GDF2 and ACVRL1 (PubMed:28564608). Interacts with BMP10 (PubMed:21737454). Interacts with DYNLT4 (PubMed:16982625). Interacts with ARRB2 (PubMed:17540773).
The N-terminal OR region is composed of two intertwined domains (OR1 and OR2) with a common, novel fold. Each contains 12 beta-strands that form a parallel beta-helix-like structure, plus a single alpha-helix. The OR1 region mediates interaction with GDF2.
Vascular endothelium glycoprotein that plays an important role in the regulation of angiogenesis (PubMed:21737454, PubMed:23300529). Required for normal structure and integrity of adult vasculature (PubMed:7894484). Regulates the migration of vascular endothelial cells (PubMed:17540773). Required for normal extraembryonic angiogenesis and for embryonic heart development (By similarity). May regulate endothelial cell shape changes in response to blood flow, which drive vascular remodeling and establishment of normal vascular morphology during angiogenesis (By similarity). May play a critical role in the binding of endothelial cells to integrins and/or other RGD receptors (PubMed:1692830). Acts as TGF-beta coreceptor and is involved in the TGF-beta/BMP signaling cascade that ultimately leads to the activation of SMAD transcription factors (PubMed:8370410, PubMed:21737454, PubMed:22347366, PubMed:23300529). Required for GDF2/BMP9 signaling through SMAD1 in endothelial cells and modulates TGFB1 signaling through SMAD3 (PubMed:21737454, PubMed:22347366, PubMed:23300529).
Belongs to the MICU1 family. MICU3 subfamily.
May play a role in mitochondrial calcium uptake.
Belongs to the glycosyl hydrolase 18 family. Chitinase class II subfamily.
Degrades chitin and chitotriose. May participate in the defense against nematodes, fungi and other pathogens. Plays a role in T-helper cell type 2 (Th2) immune response. Contributes to the response to IL-13 and inflammation in response to IL-13. Stimulates chemokine production by pulmonary epithelial cells. Protects lung epithelial cells against apoptosis and promotes phosphorylation of AKT1. Its function in the inflammatory response and in protecting cells against apoptosis is inhibited by allosamidin, suggesting that the function of this protein depends on carbohydrate binding.
Detected in lung epithelial cells from asthma patients (at protein level). Highly expressed in stomach. Detected at lower levels in lung.
Up-regulated in lung epithelial cells from asthma patients.
Antibodies against GOLGA4 are present in sera from patients with Sjoegren syndrome. Sera from patients with Sjoegren syndrome often contain antibodies that react with normal components of the Golgi complex.
Homodimer (PubMed:14718928). Interacts with RAB6A (PubMed:10209123). Interacts with GTP-bound ARL1 and ARL3 (PubMed:11303027, PubMed:14580338, PubMed:14718928). Interacts with MACF1 (PubMed:15265687). Directly interacts with TBC1D23 (PubMed:29084197). Interacts with FAM91A1; this interaction may be mediated by TBC1D23 (PubMed:29084197).
Involved in vesicular trafficking at the Golgi apparatus level. May play a role in delivery of transport vesicles containing GPI-linked proteins from the trans-Golgi network through its interaction with MACF1. Involved in endosome-to-Golgi trafficking (PubMed:29084197).
Belongs to the universal ribosomal protein uL29 family.
Chimeric cDNA. Seems to include a portion of the orthologous murine sequence.
Interacts with OSBPL9 (PubMed:22906437). Interacts with DIAPH1 (PubMed:23325789).
Polymorphisms are associated with dyslipidemia. Variant Asn-254 is associated with LDL-cholesterol levels in Japanese population (PubMed:20224571). Association with peripheral arterial disease has also been observed (PubMed:20610895).
Probable lipid transporter involved in lipid countertransport between the endoplasmic reticulum and the plasma membrane. Its ability to bind phosphatidylserine, suggests that it specifically exchanges phosphatidylserine with phosphatidylinositol 4-phosphate (PI4P), delivering phosphatidylserine to the plasma membrane in exchange for PI4P (PubMed:23934110) (Probable). Plays a role in negative regulation of lipid biosynthesis (PubMed:19554302). Negatively regulates APOB secretion from hepatocytes (PubMed:19554302, PubMed:22906437). Binds cholesterol and acidic phospholipids (PubMed:22906437). Also binds 25-hydroxycholesterol (PubMed:17428193). Binds phosphatidylserine (PubMed:23934110).
The C-terminal region binds cholesterol, 25-hydroxysterol and acidic phospholipids and is required for localization to microtubules.
The PH domain selectively interacts with phosphatidylinositol-4-phosphate.
May play a role in organizing the actin cytoskeleton of the brain cells.
An adhesion molecule that interacts with extracellular matrix molecules in developing teeth and may play important roles in differentiation and maintenance of odontoblasts as well as in dentin formation.
Interacts with heparin, FBLN1, FN1 and DSPP. Preferentially binds dental mesenchyme cells and odontoblasts but not dental epithelial cells or nondental cells. Binding requires a heparan sulfate-containing receptor on the cell surface as well as an integrin (By similarity).
May modulate the function of nicotinic acetylcholine receptors. May enhance sperm motility.
Specifically expressed in prostate, testis and spinal cord. Present in the acrosomal region of sperm cells. Present in apical epithelial cells of prostatic duct.
Interacts with SRPK1 (PubMed:19240134). Interacts with HSP70 (HSPA1A or HSPA1B) (PubMed:27133716).
Suppresses polyglutamine (polyQ) aggregation of ATXN3 in neuronal cells (PubMed:27133716).
Homodimer (PubMed:27673746). Interacts with hepatitis C virus/HCV non-structural protein NS5A; promotes the ubiquitin-mediated proteasomal degradation of NS5A (PubMed:27194766). Interacts with SKP2; promotes the ubiquitin-mediated proteasomal degradation of NS5A (PubMed:27194766). Interacts with NR4A1 (PubMed:22427340). May interact with BCL2 (PubMed:27673746).
Probable adapter protein involved in different biological processes (PubMed:22427340, PubMed:27194766). Part of the signaling pathways that lead to apoptosis (PubMed:18330707, PubMed:27673746, PubMed:24970806). Involved in type-I interferon-induced apoptosis characterized by a rapid and robust release of cytochrome C from the mitochondria and activation of BAX and caspases 2, 3, 6, 8 and 9 (PubMed:18330707, PubMed:27673746). Also functions in TNFSF10-induced apoptosis (PubMed:24970806). May also have a function in the nucleus, where it may be involved in the interferon-induced negative regulation of the transcriptional activity of NR4A1, NR4A2 and NR4A3 through the enhancement of XPO1-mediated nuclear export of these nuclear receptors (PubMed:22427340). May thereby play a role in the vascular response to injury (By similarity). In the innate immune response, has an antiviral activity towards hepatitis C virus/HCV (PubMed:27194766, PubMed:27777077). May prevent the replication of the virus by recruiting both the hepatitis C virus non-structural protein 5A/NS5A and the ubiquitination machinery via SKP2, promoting the ubiquitin-mediated proteasomal degradation of NS5A (PubMed:27194766, PubMed:27777077). Promotes also virus-induced pyroptosis by activating CASP3 in the mitochondria after 'Lys-6'-linked ubiquitination by TRIM21 (PubMed:36426955).
Ubiquitinated by TRIM21 via 'Lys-6'-linked ubiquitin chains leading to IFI27 mitochondrial migration.
Up-regulated by type-I and type-II interferons.
Expressed predominantly in brain. Deposited preferentially in primitive or neuritic amyloid plaques which are typical of Alzheimer disease.
Forms homodimers and homotrimers. Binds to the fibrillized forms of amyloid-beta protein 40 (beta-APP40) and amyloid-beta protein 42 (beta-APP42). Found associated with beta-APP42 more frequently than with beta-APP40.
Hydroxylated on 11% of proline residues and 49% of lysine residues.
Inhibits fibrillization of amyloid-beta peptide during the elongation phase. Has also been shown to assemble amyloid fibrils into protease-resistant aggregates. Binds heparin.
The pyrrolidone carboxylic acid reported in PubMed:11927537 probably formed artifactually from Glu-113 during the extraction procedure in 70% formic acid. In PubMed:15522881, the protein was found to have unblocked Glu at the N-terminus.
Undergoes proteolytic cleavage by furin protease to yield the soluble collagen-like Alzheimer amyloid plaque component.
Acts as a molecular scaffold that plays a key role in the organization of the endoplasmic reticulum exit sites (ERES), also known as transitional endoplasmic reticulum (tER). SAR1A-GTP-dependent assembly of SEC16A on the ER membrane forms an organized scaffold defining an ERES. Required for secretory cargo traffic from the endoplasmic reticulum to the Golgi apparatus (PubMed:17192411, PubMed:17005010, PubMed:17428803, PubMed:21768384, PubMed:22355596). Mediates the recruitment of MIA3/TANGO to ERES (PubMed:28442536). Regulates both conventional (ER/Golgi-dependent) and GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of CFTR to cell membrane (PubMed:28067262). Positively regulates the protein stability of E3 ubiquitin-protein ligases RNF152 and RNF183 and the ER localization of RNF183 (PubMed:29300766). Acts as a RAB10 effector in the regulation of insulin-induced SLC2A4/GLUT4 glucose transporter-enriched vesicles delivery to the cell membrane in adipocytes (By similarity).
Plays a role in the organization of the endoplasmic reticulum exit sites (ERES), also known as transitional endoplasmic reticulum (tER). Required for secretory cargo traffic from the endoplasmic reticulum to the Golgi apparatus.
SEC16A and SEC16B are each present in multiple copies in a heteromeric complex (PubMed:17192411, PubMed:22355596). Interacts with SEC23A (PubMed:17192411, PubMed:17428803). Interacts with RNF183 and RNF152 (PubMed:29300766). Interacts with LRRK2 (via ROC domain) (PubMed:25201882). Interacts with SEC13 (PubMed:25201882, PubMed:19638414, PubMed:17428803). Interacts with RAB10 (By similarity). Interacts with MIA3 (PubMed:28442536). Interacts with GORASP2 in response to ER stress (PubMed:28067262).
SEC16A and SEC16B are each present in multiple copies in a heteromeric complex.
Ubiquitous. Expressed at higher levels in the pancreas.
GRO-beta(5-73) is available under the name Garnocestim as immunomodulator. It is used prior to hematopoietic transplantation for peripheral blood stem cell mobilization and reduction of incidence, duration, and/or severity of chemotherapy induced cytopenias.
Produced by activated monocytes and neutrophils and expressed at sites of inflammation. Hematoregulatory chemokine, which, in vitro, suppresses hematopoietic progenitor cell proliferation. GRO-beta(5-73) shows a highly enhanced hematopoietic activity.
The N-terminal processed form GRO-beta(5-73) is produced by proteolytic cleavage after secretion from bone marrow stromal cells.
Belongs to the G-protein coupled receptor 3 family.
G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity.
Widely expressed in the brain. Expression is increased in the superior frontal cortex of alcoholics, but not in the motor cortex or cerebellum.
Belongs to the TPT transporter family. SLC35E subfamily.
Belongs to the synaptophysin/synaptobrevin family.
Intrinsic membrane protein of small synaptic vesicles. Probable vesicular channel protein (By similarity).
Highly expressed in lung, breast, colon and ovarian carcinomas. It is also present on some normal cells, endothelial cells in particular.
Present in high molecular weight complexes in tumor cells. Interacts with SDCBP2 (PubMed:11102519).
Expressed at high level in fetal and adult lung tissues but repressed in most human lung cancers (PubMed:9857033, PubMed:18000218). Constitutively expressed in fetal kidney and adult placenta, kidney, prostate, testis, ovary, small intestine, colon, stomach, and spinal cord at low to moderate levels. Not detectable in fetal heart, brain, and liver and adult heart, brain, liver, skeletal muscle, pancreas, spleen, thymus, and peripheral leukocytes. According to PubMed:10783259, expressed at low but detectable level in pancreas and heart.
Interacts (via its transmembrane domain) with EGFR.
Orphan receptor. Could be involved in modulating differentiation and maintaining homeostasis of epithelial cells. This retinoic acid-inducible GPCR provide evidence for a possible interaction between retinoid and G-protein signaling pathways. Functions as a negative modulator of EGFR signaling (By similarity). May act as a lung tumor suppressor (PubMed:18000218).
Phosphorylated in two conserved double-tyrosine motifs, Tyr-317/Tyr-320 and Tyr-347/Tyr-350, by EGFR; leading to inactivation of the tumor suppressive function of GPRC5A in lung cancer cells. Tyr-317 and Tyr-320 are the preferred residues responsible for EGFR-mediated GPRC5A phosphorylation.
A cytosolic factor (probably pyrophosphate, polytriphosphate, polyP4, polyP25, polyP45, and/or polyP65) is necessary for TRPA1 activation by irritants (PubMed:17567811). Such factor acts by keeping TRPA1 in a agonist-sensitive state (PubMed:17567811). Inhibited by the potent blocker of TRPV channels ruthenium red, A-967079, AP-18, HC-030031, and aryl sulfonamide derivative (S)-N-(4-chlorobenzyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide (ASD) (PubMed:17567811, PubMed:21873995, PubMed:21402443, PubMed:30878828, PubMed:20547126). Non-covalently activated by the scorpion wasabi receptor toxin (PubMed:31447178). Activated by benzyl isothiocyanate (BITC), iodoacetamide, sulfhydryl reactive agent MTSEA, N-methyl maleimide (NMM), N-ethylmaleimide (NEM), and 2-aminoethyldiphenylborinate (2-APB) (PubMed:17164327, PubMed:17567811, PubMed:21873995, PubMed:27241698). Also activated by hyperoxia (PubMed:21873995).
Belongs to the transient receptor (TC 1.A.4) family.
C-terminal helices from the four subunits associate to form atypical coiled coil structure; this region is probably involved in binding the inositol polyphosphates that are required for optimal channel activity (in vitro).
Expressed at very low levels in fibroblasts.
Expressed in embryos at 12 weeks of age.
Homotetramer (PubMed:25389312, PubMed:25855297). Interacts with TMEM100 (By similarity). Interacts with EGLN1 (By similarity). Interacts with the scorpion wasabi receptor toxin at the same site that electrophiles but in a non-covalent manner (PubMed:31447178).
Hydroxylation is required for TRPA1 activity inhibition in normoxia. In hypoxia, the decrease in oxygen concentration diminishes the activity of the hydroxylase EGLN1, thus relieving TRPA1 from inhibition and ultimately leading to channel activation.
Oxidation of Cys-633 and Cys-856 in hyperoxia may override the hydroxylase EGLN1-mediated inhibition, causing TRPA1 activation.
Receptor-activated non-selective cation channel involved in pain detection and possibly also in cold perception, oxygen concentration perception, cough, itch, and inner ear function (PubMed:21873995, PubMed:23199233, PubMed:25389312, PubMed:25855297). Shows 8-fold preference for divalent over monovalent cations (PubMed:31447178). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of irritants, such as allylthiocyanate (AITC) from mustard oil or wasabi, cinnamaldehyde, diallyl disulfide (DADS) from garlic, and acrolein, an irritant from tears gas and vehicle exhaust fumes (PubMed:25389312, PubMed:27241698, PubMed:30878828, PubMed:20547126). Acts also as an ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). Is activated by a large variety of structurally unrelated electrophilic and non-electrophilic chemical compounds. Electrophilic ligands activate TRPA1 by interacting with critical N-terminal Cys residues in a covalent manner, whereas mechanisms of non-electrophilic ligands are not well determined. May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity).
TRPA1 activation by electrophiles occurs though covalent modification of specific cysteine residues in the N-terminal cytoplasmic domain (PubMed:25389312).
The ANK repeat domain consists of a convex stem structure formed by five ANK repeats and 11 additional ANK repeats that form a crescent-shaped structure that surrounds the protein core.
Expressed in the liver, stomach, kidney, prostate, thyroid and rectum.
Sodium-independent anion exchanger which mediates the electroneutral exchange of chloride for bicarbonate ions across the cell membrane (PubMed:15184086, PubMed:34668226). Plays an important role in osteoclast differentiation and function (PubMed:34668226). Regulates bone resorption and calpain-dependent actin cytoskeleton organization in osteoclasts via anion exchange-dependent control of pH (By similarity). Essential for intracellular pH regulation in CD8(+) T-cells upon CD3 stimulation, modulating CD8(+) T-cell responses (By similarity).
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily.
Expressed in the testis and placenta. In the testis, restrictedly expressed in outer cell layer of seminiferous tubules.
Phosphorylated; in a cell-cycle dependent manner at mitosis.
Phosphorylates MAP kinase p38. Seems to be active only in mitosis. May also play a role in the activation of lymphoid cells. When phosphorylated, forms a complex with TP53, leading to TP53 destabilization and attenuation of G2/M checkpoint during doxorubicin-induced DNA damage.
Forms both hetero- and homodimers with SOHLH2.
Transcription regulator of both male and female germline differentiation. Suppresses genes involved in spermatogonial stem cells maintenance, and induces genes important for spermatogonial differentiation. Coordinates oocyte differentiation without affecting meiosis I (By similarity).
Binds to the underphosphorylated form of RB. May interact with other transcription factors in order to regulate specific genes. Interacts with RUNX1.
In fetal tissues, it is highly expressed in heart, lung liver and kidney, and weakly expressed in brain. In adult, it is highly expressed in pancreas, spleen, thymus and peripheral blood leukocytes, expressed at moderate levels in heart, placenta, lung, liver, skeletal muscle, kidney, prostate, ovary, small intestine and colon, and weakly expressed in brain and testis.
Transcription factor that activates the LYN and BLK promoters. Appears to be required for the T-cell-receptor-mediated trans activation of HIV-2 gene expression. Binds specifically to two purine-rich motifs in the HIV-2 enhancer.
Found in the basement membranes (major component).
Laminin is a complex glycoprotein, consisting of three different polypeptide chains (alpha, beta, gamma), which are bound to each other by disulfide bonds into a cross-shaped molecule comprising one long and three short arms with globules at each end. Beta-3 is a subunit of laminin-5 (laminin-332 or epiligrin/kalinin/nicein). Interacts with ECM1.
Involved in vesicular protein trafficking, mainly in the early secretory pathway. targeting. Involved in the maintenance of the Golgi apparatus. Appears to play a role in the biosynthesis of secreted cargo including processing. Involved in endoplasmic reticulum stress response. May play a role in the regulation of heat-shock response and apoptosis (By similarity).
Abundant in liver, heart and skeletal muscle. A weak expression is seen in the brain, placenta, lung, kidney and pancreas.
Belongs to the ETF beta-subunit/FixA family.
Heterodimer composed of ETFA and ETFB (PubMed:25023281, PubMed:25416781, PubMed:8962055, PubMed:15159392, PubMed:15975918). Identified in a complex that contains ETFA, ETFB and ETFRF1 (PubMed:27499296). Interacts with ACADM (PubMed:15159392, PubMed:15975918).
Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase (PubMed:25416781, PubMed:15159392, PubMed:15975918). It transfers the electrons to the main mitochondrial respiratory chain via ETF-ubiquinone oxidoreductase (Probable). Required for normal mitochondrial fatty acid oxidation and normal amino acid metabolism (PubMed:12815589, PubMed:7912128). ETFB binds an AMP molecule that probably has a purely structural role (PubMed:8962055, PubMed:15159392, PubMed:15975918).
Methylated. Trimethylation at Lys-200 and Lys-203 may negatively regulate the activity in electron transfer from acyl-CoA dehydrogenases.
The recognition loop recognizes a hydrophobic patch at the surface of interacting dehydrogenases and acts as a static anchor at the interface.
Interacts with STX17 (By similarity). Component of two distinct SNARE complexes consisting of STX5, GOSR2/BOS1, BET1 and SEC22B or STX18, USE1L, BNIP1/SEC20L and SEC22B. YKT6 can probably replace SEC22B in either complex. Interacts with the COPII Sec23/24 complex composed of SEC23A and SEC24A; recruits SEC22B into COPII-coated vesicles to allow its transport from the endoplasmic reticulum to the Golgi (PubMed:17499046, PubMed:18843296).
SNARE involved in targeting and fusion of ER-derived transport vesicles with the Golgi complex as well as Golgi-derived retrograde transport vesicles with the ER.
Associated component of the mechanistic target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8 and RPTOR (PubMed:19446321, PubMed:25936805, PubMed:34519269, PubMed:34519268). Associated component of the mechanistic target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PROTOR1, RICTOR, MAPKAP1 and DEPTOR (PubMed:19446321, PubMed:34519268). Interacts (via PDZ domain) with MTOR; interacts with MTOR within both mTORC1 and mTORC2 (PubMed:19446321). Interacts (via PDZ domain) with MINAR1 (via N-terminus) (PubMed:30080879). Interacts with SIK3 (PubMed:30232230).
Expression is negatively regulated by both mTORC1 and mTORC2 (at protein level).
Inhibited upon phosphatidic acid-binding: phosphatidic acid produced upon mitogenic stimulation promotes DEPTOR dissociatiom from the mTORC1 and mTORC2 complexes, leading to their activation (PubMed:25936805, PubMed:33865870). Specifically binds unsaturated phosphatidic acid, such as 16:0-18:1, 18:0-18:1 and di-18:1 (PubMed:25936805). Inhibited when nutrients are present via a feedback loop: phosphorylation by MTOR promotes DEPTOR ubiquitination and degradation (PubMed:22017875, PubMed:22017876, PubMed:22017877).
Negative regulator of the mTORC1 and mTORC2 complexes: inhibits the protein kinase activity of MTOR, thereby inactivating both complexes (PubMed:19446321, PubMed:22017875, PubMed:22017876, PubMed:22017877, PubMed:25936805, PubMed:29382726, PubMed:34519269, PubMed:34519268). DEPTOR inhibits mTORC1 and mTORC2 to induce autophagy (PubMed:22017875, PubMed:22017876, PubMed:22017877). In contrast to AKT1S1/PRAS40, only partially inhibits mTORC1 activity (PubMed:34519269, PubMed:34519268).
Phosphorylation weakens interaction with MTOR within mTORC1 and mTORC2 (PubMed:19446321). Phosphorylated at Ser-286, Ser-287 and Ser-291 in response to mitogenic stimulation by MTOR: DEPTOR is either directly phosphorylated by MTOR or indirectly via proteins kinases that are activated by MTOR, such as CK1/CSNK1A1 (PubMed:22017875, PubMed:22017876, PubMed:22017877). Phosphorylation at Ser-286, Ser-287 and Ser-291 promotes ubiquitination by the SCF(BTRC) complex, followed by degradation (PubMed:22017875, PubMed:22017876, PubMed:22017877). Phosphorylation at Ser-235 by MAPK3/ERK1 promotes deubiquitination by USP7, enhancing its stability (PubMed:35216969). Phosphorylation at Tyr-289 by SYK impairs its interaction with MTOR, promoting mTORC1 and mTORC2 signaling (PubMed:34634301).
Ubiquitinated; leading to proteasomal degradation (PubMed:22017875, PubMed:22017876, PubMed:22017877, PubMed:30080879, PubMed:33110214). Ubiquitination by the SCF(BTRC) and SCF(FBXW11) complexes following phosphorylation at Ser-286, Ser-287 and Ser-291 by MTOR, leads to its degradation by the proteasome (PubMed:22017875, PubMed:22017876, PubMed:22017877, PubMed:33110214). Deubiquitinated by OTUB1 in response to amino acid via a non-canonical mechanism, leading to DEPTOR stability (PubMed:29382726). Deubiquitinated by USP7 following phosphorylation at Ser-235, promoting its stability (PubMed:35216969).
This sequence lacks full-length transcript support.
Belongs to the glycosyltransferase 22 family. PIGB subfamily.
Mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the third alpha-1,2-mannose to Man2-GlcN-acyl-PI during GPI precursor assembly.
Belongs to the complex I NDUFB5 subunit family.
Belongs to the TRAPP small subunits family. BET3 subfamily.
May play a role in vesicular transport from endoplasmic reticulum to Golgi.
(Microbial infection) Acts as a receptor for Vesicular stomatitis virus.
(Microbial infection) Acts as a receptor for hepatitis C virus in hepatocytes, but not through a direct interaction with viral proteins.
(Microbial infection) In case of HIV-1 infection, may function as a receptor for extracellular Tat in neurons, mediating its internalization in uninfected cells.
(Microbial infection) Interacts with C.difficile toxin TcdA, suggesting that it may contribute to TcdA toxin entry into cells.
(Microbial infection) Interacts with vesicular stomatitis virus glycoprotein.
(Microbial infection) May interact with HIV-1 Tat.
Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits.
Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif (By similarity). Interacts (via NPXY motif) with LDLRAP1 (via PID domain) (PubMed:12221107, PubMed:22509010). Interacts with ARRB1 (PubMed:12944399). Interacts with SNX17 (PubMed:14739284). Interacts with the full-length immature form of PCSK9 (via C-terminus) (PubMed:17461796, PubMed:21149300).
The NPXY motif mediates the interaction with the clathrin adapter DAB2 and with LDLRAP1 which are involved in receptor internalization. A few residues outside the motif also play a role in the interaction.
Ubiquitinated by MYLIP leading to degradation.
3-beta-HSD is a bifunctional enzyme, that catalyzes the oxidative conversion of Delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids. The 3-beta-HSD enzymatic system plays a crucial role in the biosynthesis of all classes of hormonal steroids.
Expressed in adrenal gland, testis and ovary.
Mild HSD3B2 deficiency in hyperandrogenic females is associated with characteristic traits of polycystic ovary syndrome, such as insulin resistance and luteinizing hormone hypersecretion.
Binds DNA as a dimer. Can form homodimers or heterodimers with other AP-2 family members. Interacts with CITED4. Interacts with UBE2I. Interacts with KCTD1; this interaction represses transcription activation. Interacts with CITED2 (via C-terminus); the interaction stimulates TFAP2B-transcriptional activity.
Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes. AP-2 factors bind to the consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development. They also suppress a number of genes including MCAM/MUC18, C/EBP alpha and MYC. AP-2-beta appears to be required for normal face and limb development and for proper terminal differentiation and function of renal tubular epithelia.
Sumoylated on Lys-21; which inhibits transcriptional activity.
Expressed exclusively in thymus and spleen.
Inhibited in cells after FCER1A triggering.
Monomer. Interacts with MAPK1, MAPK3 and several other MAP kinases.
Oxidized at active site cysteine. Treatment with pervanadate (vanadate and H(2)O(2)) or with antigen enhanced oxidation of active site cysteine (By similarity).
Phosphorylated on serine residues in resting T-cells. Phosphorylation increases upon exposure to stimuli that increase intracellular cAMP levels. Phosphorylation leads to dissociation of bound MAP kinases.
Protein phosphatase that acts preferentially on tyrosine-phosphorylated MAPK1. Plays a role in the regulation of T and B-lymphocyte development and signal transduction.
Belongs to the L-seryl-tRNA(Sec) kinase family.
Specifically phosphorylates seryl-tRNA(Sec) to O-phosphoseryl-tRNA(Sec), an activated intermediate for selenocysteine biosynthesis.
May be involved in apoptosis regulation.
Belongs to the tRNA methyltransferase O family.
S-adenosyl-L-methionine-dependent methyltransferase responsible for the addition of the methyl group in the formation of N6-methyl-N6-threonylcarbamoyladenosine at position 37 (m(6)t(6)A37) of the tRNA anticodon loop of tRNA(Ser)(GCU) (PubMed:25063302). The methyl group of m(6)t(6)A37 may improve the efficiency of the tRNA decoding ability (By similarity).
Endopeptidase that degrades various components of the extracellular matrix, such as fibrin. May be involved in the activation of membrane-bound precursors of growth factors or inflammatory mediators, such as tumor necrosis factor-alpha. May also be involved in tumoral process. Cleaves pro-TNF-alpha at the '74-Ala-|-Gln-75' site. Not obvious if able to proteolytically activate progelatinase A. Does not hydrolyze collagen types I, II, III, IV and V, gelatin, fibronectin, laminin, decorin nor alpha1-antitrypsin.
Expressed in brain, leukocytes, colon, ovary testis and breast cancer. Expressed also in many transformed and non-transformed cell types.
Major isotype in brain, where it represents 46% of all beta-tubulins. In the brain, highest expression levels in the cerebellum, followed by putamen and white matter. Moderate levels in testis. Very low levels, if any, in other tissues.
The highly acidic C-terminal region may bind cations such as calcium.
Interacts with BCL2 and BCL2L1. Interacts with C1QBP.
The BH3 motif is required for the induction of cell death.
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of NUMB. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates ubiquitination of isoform p66 and isoform p72 of NUMB, but not that of isoform p71 or isoform p65.
Expressed in heart, placenta, kidney, pancreas and brain.
Interacts with the phosphotyrosine interaction domain of all isoforms of NUMB (By similarity). Interacts with MAGEB18 and MAGEF1. Interacts with the Coxsackievirus and adenovirus receptor CXADR. Interacts with endogenous retrovirus K protein Np9. IGSF5/JAM4 interacts with isoform 2 through the second PDZ domain, other isoforms may also interact with IGSF5/JAM4 (By similarity).
Isoform 2 provides an endocytic scaffold for IGSF5/JAM4.
The NPXY motif is required for the interaction with the PID domain of NUMB. It is however not sufficient.
The PDZ 1 domain participates in the interaction with the PID domain of NUMB, and participates in the isoform-specific ubiquitination of NUMB. The PDZ 2 domain of isoform 2 participates in the interaction with IGSF5/JAM4, other isoforms containing this domain may also interact with IGSF5/JAM4 (By similarity).
Controls the flux of glucose into the hexosamine pathway. Most likely involved in regulating the availability of precursors for N- and O-linked glycosylation of proteins. Regulates the circadian expression of clock genes BMAL1 and CRY1 (By similarity). Has a role in fine tuning the metabolic fluctuations of cytosolic UDP-GlcNAc and its effects on hyaluronan synthesis that occur during tissue remodeling (PubMed:26887390).
Homotetramer (Probable), may also exist as homodimers.
Isoform 1 is predominantly expressed in skeletal muscle. Not expressed in brain. Seems to be selectively expressed in striated muscle.
Heterotrimer of KIFAP3, KIF3A and KIF3B. Interacts with RAP1GDS1/SMG GDS. Interacts with SMC3 subunit of the cohesin complex.
Involved in tethering the chromosomes to the spindle pole and in chromosome movement. Binds to the tail domain of the KIF3A/KIF3B heterodimer to form a heterotrimeric KIF3 complex and may regulate the membrane binding of this complex (By similarity).
Phosphorylated on tyrosine residues by SRC in vitro; this reduces the binding affinity of the protein for RAP1GDS1.
Expression is down-regulated in ovarian tumors (at protein level). Widely expressed with highest levels in placenta and heart. Expressed in the retina. Not detected in brain or thymus.
Plays a role in the initiation of autophagy. In the retina, might be involved in the process of photoreceptor cells renewal and recycling to preserve visual function. Induces apoptotic cell death when coexpressed with DRAM1.
Belongs to the AB hydrolase superfamily.
Demethylates proteins that have been reversibly carboxymethylated. Demethylates PPP2CB (in vitro) and PPP2CA. Binding to PPP2CA displaces the manganese ion and inactivates the enzyme.
Phosphorylated by SIK1 following increases in intracellular sodium, leading to dissociation from the protein phosphatase 2A (PP2A) complex and subsequent dephosphorylation of sodium/potassium-transporting ATPase ATP1A1.
Acts as a signaling transduction factor of the EPO-EPOR signaling pathway promoting erythroid cell differentiation (PubMed:25092874).
Expressed in the proerythroblasts (at protein level) (PubMed:25092874). Expressed strongly in the kidney (PubMed:25092874). Expressed weakly in the pancreas, liver and lung (PubMed:25092874). Expressed strongly in erythroid progenitor cells (EPCs) (PubMed:25092874). Expressed weakly in T-cells and neutrophils (PubMed:25092874).
Interacts with EPOR; this interaction occurs in a erythropoietin (EPO)-dependent manner (PubMed:25092874). Interacts with JAK2; this interaction occurs in a erythropoietin (EPO)-dependent manner (PubMed:25092874). Interacts (via tyrosine-phosphorylated form) with GRB2 (PubMed:25092874).
Phosphorylated. Phosphorylation on Tyr-132 and Tyr-141 occurs in a erythropoietin (EPO)-dependent manner (PubMed:25092874).
Up-regulated during erythroid differentiation (PubMed:25092874).
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC5 and few additional components (PubMed:27428775, PubMed:27342858). Component of a complex with USP49 and RUVBL1 (PubMed:23824326). Interacts with PRPF19. Interacts with TRIM5 (PubMed:22078707). Interacts with NDC80 (PubMed:9295362, PubMed:10409732). Interacts with PAAF1 (PubMed:15831487). Interacts, in vitro, with the thyroid hormone receptor (in a thyroid hormone T3-dependent manner) and with retinoid X receptor (RXR) (By similarity). Interacts with ERCC6 (PubMed:26030138).
Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC5 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.
Activated by divalent cations (PubMed:16527816). Activated by bile acids and their conjugates, except for lithocholic acid which is rather inhibitory. Binding of deoxycholic acid favors the selective release of anandamide and likely other unsatured long FAEs (PubMed:27571266, PubMed:25684574). Inhibited by phosphatidylethanolamines (PubMed:25684574).
Binds 2 zinc divalent cations per subunit.
D-type phospholipase that hydrolyzes N-acyl-phosphatidylethanolamines (NAPEs) to produce bioactive N-acylethanolamines/fatty acid ethanolamides (NAEs/FAEs) and phosphatidic acid (PubMed:14634025, PubMed:16527816, PubMed:27571266, PubMed:25684574). Cleaves the terminal phosphodiester bond of diacyl- and alkenylacyl-NAPEs, primarily playing a role in the generation of long-chain saturated and monounsaturated NAEs in the brain (By similarity). May control NAPE homeostasis in dopaminergic neuron membranes and regulate neuron survival, partly through RAC1 activation (By similarity). As a regulator of lipid metabolism in the adipose tissue, mediates the crosstalk between adipocytes, gut microbiota and immune cells to control body temperature and weight. In particular, regulates energy homeostasis by promoting cold-induced brown or beige adipocyte differentiation program to generate heat from fatty acids and glucose. Has limited D-type phospholipase activity toward N-acyl lyso-NAPEs (By similarity).
Homodimer. Bile acids promote the assembly of inactive monomers into an active dimer and enable catalysis.
Widely expressed. Highest expression in brain, kidney and testis (at protein level). Expressed in adipose tissue (at protein level).
(Microbial infection) Interacts with Simian virus 5 protein V.
(Microbial infection) Interacts with hepatitis B virus protein HBX; the viral protein contains a short helical motif that competes for the same binding site as the N-terminal helical motif found in endogenous DCAF proteins.
(Microbial infection) Interacts with human cytomegalovirus protein UL145; this interaction promotes STAT2 degradation.
Acetylated, promoting interaction with CUL4 (CUL4A or CUL4B) and subsequent formation of DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes (PubMed:28886238). Deacetylation by SIRT7 impairs the interaction with CUL4 (CUL4A or CUL4B) and formation of DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes (PubMed:28886238).
Component of the UV-DDB complex which includes DDB1 and DDB2; the heterodimer dimerizes to give rise to a heterotetramer when bound to damaged DNA (PubMed:9632823, PubMed:16223728, PubMed:16527807, PubMed:19109893, PubMed:22822215). The UV-DDB complex interacts with monoubiquitinated histone H2A and binds to XPC via the DDB2 subunit (PubMed:16473935). Component of numerous DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which consist of a core of DDB1, CUL4A or CUL4B and RBX1 (PubMed:11673459, PubMed:12732143, PubMed:15882621, PubMed:16678110, PubMed:18593899, PubMed:28886238, PubMed:28437394, PubMed:28302793, PubMed:31693891, PubMed:31686031, PubMed:31819272, PubMed:31693911). DDB1 may recruit specific substrate targeting subunits to the DCX complex (PubMed:11673459, PubMed:12732143, PubMed:15882621, PubMed:18593899, PubMed:28886238). These substrate targeting subunits are generally known as DCAF (DDB1- and CUL4-associated factor) or CDW (CUL4-DDB1-associated WD40-repeat) proteins (PubMed:17079684, PubMed:16949367, PubMed:18606781, PubMed:19608861, PubMed:16964240, PubMed:19966799). Interacts with AMBRA1, ATG16L1, BTRC, CRBN, DCAF1, DCAF4, DCAF5, DCAF6, DCAF7, DCAF8, DCAF9, DCAF10, DCAF11, DCAF12, DCAF15, DCAF16, DCAF17, DDA1, DET1, DTL, ERCC8, FBXW5, FBXW8, GRWD1, KATNB1, NLE1, NUP43, PAFAH1B1, PHIP, PWP1, RBBP4, RBBP5, RBBP7, COP1, SNRNP40, DCAF1, WDR5, WDR5B, WDR12, WDR26, WDR39, WDR42, WDR53, WDR59, WDR61, WSB1, WSB2, LRWD1 and WDTC1 (PubMed:14739464, PubMed:17079684, PubMed:16949367, PubMed:17041588, PubMed:18606781, PubMed:22935713, PubMed:23478445, PubMed:22118460, PubMed:25043012, PubMed:25108355). DCX complexes may associate with the COP9 signalosome, and this inhibits the E3 ubiquitin-protein ligase activity of the complex (PubMed:15448697, PubMed:16260596). Interacts with NF2, TSC1 and TSC2 (PubMed:18332868, PubMed:18381890). Interacts with AGO1 and AGO2 (PubMed:17932509). Associates with the E3 ligase complex containing DYRK2, EDD/UBR5, DDB1 and DCAF1 proteins (EDVP complex) (PubMed:19287380). Interacts directly with DYRK2 (PubMed:19287380). DCX(DTL) complex interacts with FBXO11; does not ubiquitinate and degradate FBXO11 (PubMed:19287380). Interacts with TRPC4AP (PubMed:19966799). Interacts with CRY1 and CRY2 (By similarity). The DDB1-CUL4A complex interacts with CRY1 (PubMed:26431207). May also interact with DCUN1D1, DCUN1D2, DCUN1D3 and DCUN1D5 (PubMed:26906416). Component of the DCX(DCAF13) E3 ubiquitin ligase complex, at least composed of CUL4 (CUL4A or CUL4B), DDB1, DCAF13 and RBX1. Interacts with DCAF13 (via WD40 domain) (PubMed:30111536, PubMed:31492966).
Protein, which is both involved in DNA repair and protein ubiquitination, as part of the UV-DDB complex and DCX (DDB1-CUL4-X-box) complexes, respectively (PubMed:15448697, PubMed:14739464, PubMed:16260596, PubMed:16482215, PubMed:17079684, PubMed:16407242, PubMed:16407252, PubMed:16940174). Core component of the UV-DDB complex (UV-damaged DNA-binding protein complex), a complex that recognizes UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair (PubMed:15448697, PubMed:16260596, PubMed:16407242, PubMed:16940174). The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches (PubMed:15448697, PubMed:16260596, PubMed:16407242, PubMed:16940174). Also functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:14739464, PubMed:16407252, PubMed:16482215, PubMed:17079684, PubMed:25043012, PubMed:25108355, PubMed:18332868, PubMed:18381890, PubMed:19966799, PubMed:22118460, PubMed:28886238). The functional specificity of the DCX E3 ubiquitin-protein ligase complex is determined by the variable substrate recognition component recruited by DDB1 (PubMed:14739464, PubMed:16407252, PubMed:16482215, PubMed:17079684, PubMed:25043012, PubMed:25108355, PubMed:18332868, PubMed:18381890, PubMed:19966799, PubMed:22118460). DCX(DDB2) (also known as DDB1-CUL4-ROC1, CUL4-DDB-ROC1 and CUL4-DDB-RBX1) may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage (PubMed:16678110, PubMed:17041588, PubMed:16473935, PubMed:18593899). The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair (PubMed:16678110, PubMed:17041588, PubMed:16473935, PubMed:18593899). DCX(DDB2) also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER (PubMed:15882621). DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication (PubMed:17041588). DCX(ERCC8) (the CSA complex) plays a role in transcription-coupled repair (TCR) (PubMed:12732143). The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1 (PubMed:26431207). DDB1-mediated CRY1 degradation promotes FOXO1 protein stability and FOXO1-mediated gluconeogenesis in the liver (By similarity). By acting on TET dioxygenses, essential for oocyte maintenance at the primordial follicle stage, hence essential for female fertility (By similarity). Maternal factor required for proper zygotic genome activation and genome reprogramming (By similarity).
The core of the protein consists of three WD40 beta-propeller domains.
Ubiquitinated by CUL4A. Subsequently degraded by ubiquitin-dependent proteolysis.
Belongs to the Mediator complex subunit 18 family.
Adhesion molecule that engages in homo- and heterophilic interactions with the other nectin-like family members, leading to cell aggregation. Important for synapse organization, providing regulated trans-synaptic adhesion. Preferentially binds to oligodendrocytes.
Belongs to the glycosyl hydrolase 1 family.
Belongs to the glycosyl hydrolase 1 family. Klotho subfamily.
Contains 2 glycosyl hydrolase 1 regions. However, the first region lacks the essential Glu active site residue at position 241, and the second one lacks the essential Glu active site residue at position 889. These domains are therefore predicted to be inactive.
Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. Probably inactive as a glycosidase. Increases the ability of FGFR1 and FGFR4 to bind FGF21 (By similarity).
Interacts with FGFR1 and FGFR4 (By similarity). Interacts with FGF19; this interaction is direct. Interacts (via C-terminus) with FGF21; this interaction is direct.
Belongs to the protein kinase superfamily. ADCK protein kinase family.
The function of this protein is not yet clear. It is not known if it has protein kinase activity and what type of substrate it would phosphorylate (Ser, Thr or Tyr).
Associates with Polycomb group (PcG) multiprotein complexes; the complex class is required to maintain the transcriptionally repressive state of some genes.
Interacts with the SAM domain of PHC1 via its SAM domain in vitro (By similarity). Associates with a PRC1-like complex.
Strongly expressed in heart, muscle and pancreas. Weakly expressed in brain, placenta, lung, liver and kidney.
Highly expressed in the CNS, in particular in putamen, spinal cord, medulla and subthalamic nucleus. A strong signal was also detected in uterine subepithelial cells and around renal blood vessels. Detected at lower levels in amygdala, caudate, thalamus, pancreas and skeletal muscle. Detected at very low levels in substantia nigra, cerebellum, cortex, corpus callosum and hippocampus.
May contribute to the degradation of peptide hormones and be involved in the inactivation of neuronal peptides.
The disease is caused by variants affecting the gene represented in this entry. ECEL1 mutations have also been found in patients with arthrogryposis, significant ophthalmoplegia, and refractive errors (PubMed:23808592).
Shows particularly broad specificity; although bonds involving phenylalanine and leucine are preferred, many others are also cleaved to some extent.
Interacts with RIGI (via tandem CARD domain); the interaction is direct (PubMed:23843640). Interacts (via GOLD domain) with SLC18A3; the interaction is direct (PubMed:17092608). Interacts with SLC5A7 (via GOLD domain); the interaction is direct (PubMed:17092608).
May play a role in innate immunity by inhibiting the antiviral RIG-I signaling pathway. In this pathway, functions as a negative regulator of RIGI, the cytoplasmic sensor of viral nucleic acids. Prevents the interaction of RIGI with MAVS/IPS1, an important step in signal propagation (PubMed:23843640). May also regulate the SLC18A3 and SLC5A7 cholinergic transporters (PubMed:17092608).
By alpha and beta interferons, but not by gamma interferons.
This protein aggregates to form microtubular structures.
Belongs to the pseudouridine synthase RluA family.
Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling (PubMed:11439091, PubMed:16314507, PubMed:16854980, PubMed:21362118, PubMed:29884772). Specifically recognizes PEX5 monoubiquitinated at 'Cys-11', and pulls it out of the peroxisome lumen through the PEX2-PEX10-PEX12 retrotranslocation channel (PubMed:29884772). Extraction by the PEX1-PEX6 AAA ATPase complex is accompanied by unfolding of the TPR repeats and release of bound cargo from PEX5 (PubMed:29884772).
Homooligomer; homooligomerizes in the cytosol, interaction with PEX6 promotes dissociation of the homooligomer (PubMed:16854980). Interacts with PEX6; forming the PEX1-PEX6 AAA ATPase complex, which is composed of a heterohexamer formed by a trimer of PEX1-PEX6 dimers (PubMed:12717447, PubMed:16854980, PubMed:21362118). Interacts indirectly with PEX26, via its interaction with PEX6 (PubMed:12717447).
Dimeric, linked by one or more disulfide bonds. Inhibin A is a dimer of alpha and beta-A. Inhibin B is a dimer of alpha and beta-B. Activin A is a homodimer of beta-A. Activin B is a homodimer of beta-B. Activin AB is a dimer of beta-A and beta-B. Interacts with FST and FSTL3.
Belongs to the alpha/beta interferon family.
Interferons alpha-1 and alpha-13 have identical protein sequences.
Produced by macrophages, IFN-alpha have antiviral activities. Interferon stimulates the production of two enzymes: a protein kinase and an oligoadenylate synthetase.
Two forms exist; alpha-1a (shown here) and alpha-1b (PubMed:11032395).
Component of the RNA exosome complex (PubMed:29906447). Specifically part of the catalytically inactive RNA exosome core (Exo-9) complex which is believed to associate with catalytic subunits EXOSC10, and DIS3 or DIS3L in cytoplasmic- and nuclear-specific RNA exosome complex forms. Exo-9 is formed by a hexameric ring of RNase PH domain-containing subunits specifically containing the heterodimers EXOSC4-EXOSC9, EXOSC5-EXOSC8 and EXOSC6-EXOSC7, and peripheral S1 domain-containing components EXOSC1, EXOSC2 and EXOSC3 located on the top of the ring structure. Interacts with DDX60.
Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC4 binds to ARE-containing RNAs.
The six exosome core subunits containing a RNase PH-domain are not phosphorolytically active.
Plays a role as an intracellular lectin in the early secretory pathway. Interacts with N-acetyl-D-galactosamine and high-mannose type glycans and may also bind to O-linked glycans. Involved in the transport and sorting of glycoproteins carrying high mannose-type glycans (By similarity).
Appears to be a negative regulator of type-1 angiotensin II receptor-mediated signaling by regulating receptor internalization as well as mechanism of receptor desensitization such as phosphorylation. Induces also a decrease in cell proliferation and angiotensin II-stimulated transcriptional activity.
Interacts with RACK1, and with the C-terminal region of AGTR1.
Ubiquitous but more abundant in kidney, heart, pancreas and thyroid.
Belongs to the POU transcription factor family. Class-3 subfamily.
Transcription factor that acts synergistically with SOX11 and SOX4. Plays a role in neuronal development (PubMed:31303265). Is implicated in an enhancer activity at the embryonic met-mesencephalic junction; the enhancer element contains the octamer motif (5'-ATTTGCAT-3') (By similarity).
Orphan receptor with constitutive G(i) signaling activity that activate cyclic AMP.
Ubiquitous with highest levels in intestinal tissues. In the brain detected in thalamus, putamen, and caudate, but not in frontal cortex, pons and hypothalamus.
Expressed in heart, placenta, lung and liver.
Interacts with subunit of G(i) alpha proteins and regulates the activation of G(i) alpha proteins.
The GoLoco 1 and/or GoLoco 3 domains exhibit GDI activity towards GDP-bound G(i) alpha protein, but not the GoLoco 2 domain.
By p53/TP53; expression is directly activated by TP53. TP53 phosphorylation on 'Ser-15' is required to activate the PHLDA3 promoter.
PHLDA3 genomic locus is frequently observed in primary lung cancers, suggesting a role in tumor suppression.
The PH domain binds phosphoinositides with a broad specificity. It competes with the PH domain of AKT1 and directly interferes with AKT1 binding to phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3), preventing AKT1 association to membrane lipids and subsequent activation of AKT1 signaling.
Widely expressed with lowest expression in liver and spleen.
p53/TP53-regulated repressor of Akt/AKT1 signaling. Represses AKT1 by preventing AKT1-binding to membrane lipids, thereby inhibiting AKT1 translocation to the cellular membrane and activation. Contributes to p53/TP53-dependent apoptosis by repressing AKT1 activity. Its direct transcription regulation by p53/TP53 may explain how p53/TP53 can negatively regulate AKT1. May act as a tumor suppressor.
Belongs to the WD repeat WDR3/UTP12 family.
Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome.
Highly expressed in heart, skeletal muscle and pancreas and, to a lesser extent, in brain, placenta, kidney, liver and lung.
Involved in GM1/GD1B/GA1 ganglioside biosynthesis.
Atypical histone H2A which can replace conventional H2A in some nucleosomes and is associated with active transcription and mRNA processing. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. Nucleosomes containing this histone are less rigid and organize less DNA than canonical nucleosomes in vivo. They are enriched in actively transcribed genes and associate with the elongating form of RNA polymerase. They associate with spliceosome components and are required for mRNA splicing. May participate in spermatogenesis.
In contrast to other H2A histones, it does not contain the conserved residues that are the target of post-translational modifications.
The docking domain is responsible for the weaker heterodimerization with H2B.
The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. May be incorporated into a proportion of nucleosomes, replacing one or more H2A molecules.
Acts as transcriptional coactivator. Increases ligand-dependent transcriptional activity of AR and promotes AR sumoylation. The stimulation of AR activity is dependent upon sumoylation (PubMed:14609956, PubMed:26522984). Also functions as a transcriptional coactivator in the TGF-beta signaling pathway by increasing the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850). Involved in transcriptional activation of a subset of NOTCH1 target genes including MYC. Involved in thymocyte and T cell development (By similarity). Involved in the regulation of postmitotic positioning of pyramidal neurons in the developing cerebral cortex (PubMed:30639322).
Expressed most abundantly in ovary and, at lower levels, in prostate, spleen and testis. Weak expression, if any, in thymus, small intestine, colon and peripheral blood leukocytes.
Interacts with AR, but not with ESR1, NR3C1, PGR, THRB nor VDR. Interacts with NOTCH1 and RBPJ (PubMed:14609956, PubMed:26522984). Interacts with SMARCA4 (By similarity). Interacts (via SP-RING-type domain) with SMAD3 and SMAD4 (via MH2 domain) (PubMed:16777850).
The C-terminal proline-rich domain possesses a significant intrinsic transcriptional activity. This activity is inhibited by the N-terminus in the full-length protein.
The SP-RING-type domain mediates interaction with SMAD3 and SMAD4.
Associates with the MITRAC complex (PubMed:29381136). Interacts with MT-CO2/COX; specifically interacts with newly synthesized MT-CO2/COX (PubMed:29355485, PubMed:29381136). Interacts with SCO1, SCO2 and COA6 (PubMed:29381136).
No COX16 mutations have been detected in patients with cytochrome c oxidase (COX) deficiency.
Required for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase (PubMed:29355485, PubMed:29381136, PubMed:33169484). Promotes the insertion of copper into the active site of cytochrome c oxidase subunit II (MT-CO2/COX2) (PubMed:29355485, PubMed:29381136). Interacts specifically with newly synthesized MT-CO2/COX and its copper center-forming metallochaperones SCO1, SCO2 and COA6 (PubMed:29381136). Probably facilitates MT-CO2/COX2 association with the MITRAC assembly intermediate containing MT-CO1/COX1, thereby participating in merging the MT-CO1/COX1 and MT-CO2/COX2 assembly lines (PubMed:29381136).
Widely expressed. Expressed at higher level in skeletal muscle, heart and liver.
Expressed in various tissues including heart, kidney, liver, lung, pancreas, placenta, skeletal muscle, prostate, ovary, colon and small intestine. Not detected in lymphoid organs and brain (PubMed:10455175, PubMed:10681567). Expressed in platelets (at protein level) (PubMed:25082876).
Group II phospholipase A2 is found in many cells and also extracellularly. The membrane-bound and secreted forms are identical and are encoded by a single gene.
Interaction with integrin ITGA4:ITGB3 is inhibited by a number of synthetic peptides including R-Ala-Trp-Asp-Ile and R-Gly-Arg-Gly-Asp-Asp-Asp which bind to PLA2G2A and disrupt its integrin-binding activity.
Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids with implications in host antimicrobial defense, inflammatory response and tissue regeneration (PubMed:10455175, PubMed:10681567, PubMed:2925633). Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) with preference for phosphatidylethanolamines and phosphatidylglycerols over phosphatidylcholines (PubMed:10455175, PubMed:10681567). Contributes to lipid remodeling of cellular membranes and generation of lipid mediators involved in pathogen clearance. Displays bactericidal activity against Gram-positive bacteria by directly hydrolyzing phospholipids of the bacterial membrane (PubMed:11694541, PubMed:10358193). Upon sterile inflammation, targets membrane phospholipids of extracellular mitochondria released from activated platelets, generating free unsaturated fatty acids such as arachidonate that is used by neighboring leukocytes to synthesize inflammatory eicosanoids such as leukotrienes. Simultaneously, by compromising mitochondrial membrane integrity, promotes the release in circulation of potent damage-associated molecular pattern molecules that activate the innate immune response (PubMed:25082876). Plays a stem cell regulator role in the intestinal crypt. Within intracellular compartment mediates Paneth cell differentiation and its stem cell supporting functions by inhibiting Wnt signaling pathway in intestinal stem cell (ICS). Secreted in the intestinal lumen upon inflammation, acts in an autocrine way and promotes prostaglandin E2 synthesis that stimulates Wnt signaling pathway in ICS cells and tissue regeneration (By similarity). May play a role in the biosynthesis of N-acyl ethanolamines that regulate energy metabolism and inflammation. Hydrolyzes N-acyl phosphatidylethanolamines to N-acyl lysophosphatidylethanolamines, which are further cleaved by a lysophospholipase D to release N-acyl ethanolamines (PubMed:14998370). Independent of its catalytic activity, acts as a ligand for integrins (PubMed:18635536, PubMed:25398877). Binds to and activates integrins ITGAV:ITGB3, ITGA4:ITGB1 and ITGA5:ITGB1 (PubMed:18635536, PubMed:25398877). Binds to a site (site 2) which is distinct from the classical ligand-binding site (site 1) and induces integrin conformational changes and enhanced ligand binding to site 1 (PubMed:25398877). Induces cell proliferation in an integrin-dependent manner (PubMed:18635536).
Interacts with EFTUD2, a component of the spliceosome U5 complex (PubMed:32703943). Interacts with DDX41, a component of the spliceosome C complex (PubMed:32703943).
Probably involved in the regulation of pre-mRNA splicing.
Widely expressed in fetal and adult tissues. Mostly abundant in fetal brain, liver and kidney; in the adult, high levels were also observed in heart, skeletal muscle, spleen, thymus, prostate and small intestine. Expressed in fetal cerebellum and hypothalamus. Low expression is observed in fetal temporal lobe (PubMed:32703943).
Activated by both the alpha and the beta-gamma G proteins following stimulation of G protein-coupled receptors (GPCRs). Activation by GPCRs is assisted by the regulatory subunits (PIK3R5 or PIK3R6) leading to the translocation from the cytosol to the plasma membrane and to kinase activation. Inhibited by AS-604850 and AS-605240.
Autophosphorylation at Ser-1101 has no effect on the phosphatidylinositol-4,5-bisphosphate 3-kinase activity.
Candidate target in therapy for inflammatory diseases. Selective inhibitors and protein ablation are anti-inflammatory in multiple disease models such as asthma, rheumatoid arthritis, allergy, systemic lupus erythematosus, airway inflammation, lung injury and pancreatitis (PubMed:18278175).
Heterodimer of a catalytic subunit PIK3CG and a PIK3R5 or PIK3R6 regulatory subunit. Interacts with GRK2 through the PIK helical domain. Interaction with GRK2 is required for targeting to agonist-occupied receptor. Interacts with PDE3B; regulates PDE3B activity and thereby cAMP levels in cells (By similarity). Interacts with TPM2. Interacts with EPHA8; regulates integrin-mediated cell adhesion to substrate. Interacts with HRAS; the interaction is required for membrane recruitment and beta-gamma G protein dimer-dependent activation of the PI3K gamma complex PIK3CG:PIK3R6 (By similarity).
Pancreas, skeletal muscle, liver and heart.
Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation, activation, and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to GRK2 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.
Expressed at low level in most tissues, except in adult testis, where it is highly expressed. Overexpressed in many patients suffering from pituitary adenomas, primary epithelial neoplasias, and esophageal cancer.
Interacts with RPS10 and DNAJA1 (By similarity). Interacts with the caspase-like ESPL1, and prevents its protease activity probably by covering its active site. Interacts with TP53 and blocks its activity probably by blocking its binding to DNA. Interacts with the Ku 70 kDa subunit of ds-DNA kinase. Interacts with PTTG1IP.
Low level during G1 and S phases. Peaks at M phase. During anaphase, it is degraded.
Phosphorylated at Ser-165 by CDK1 during mitosis.
Phosphorylated in vitro by ds-DNA kinase.
Regulatory protein, which plays a central role in chromosome stability, in the p53/TP53 pathway, and DNA repair. Probably acts by blocking the action of key proteins. During the mitosis, it blocks Separase/ESPL1 function, preventing the proteolysis of the cohesin complex and the subsequent segregation of the chromosomes. At the onset of anaphase, it is ubiquitinated, conducting to its destruction and to the liberation of ESPL1. Its function is however not limited to a blocking activity, since it is required to activate ESPL1. Negatively regulates the transcriptional activity and related apoptosis activity of TP53. The negative regulation of TP53 may explain the strong transforming capability of the protein when it is overexpressed. May also play a role in DNA repair via its interaction with Ku, possibly by connecting DNA damage-response pathways with sister chromatid separation.
The N-terminal destruction box (D-box) acts as a recognition signal for degradation via the ubiquitin-proteasome pathway.
The TEK-boxes are required for 'Lys-11'-linked ubiquitination and facilitate the transfer of the first ubiquitin and ubiquitin chain nucleation. TEK-boxes may direct a catalytically competent orientation of the UBE2C/UBCH10-ubiquitin thioester with the acceptor lysine residue.
Ubiquitinated through 'Lys-11' linkage of ubiquitin moieties by the anaphase promoting complex (APC) at the onset of anaphase, conducting to its degradation. 'Lys-11'-linked ubiquitination is mediated by the E2 ligase UBE2C/UBCH10.
Acts as a ligand for the urokinase plasminogen activator surface receptor. Plays a role in angiogenesis by inducing endothelial cell migration and the formation of vascular network (cords). Involved in cellular migration and adhesion. Increases the phosphorylation levels of FAK. Interacts with and increases the mitogenic activity of HGF. Promotes synapse formation. May have a role in the perisylvian region, critical for language and cognitive development.
Expressed in neurons of the rolandic area of the brain (at protein level). Highly expressed in the brain, placenta, lung, trachea, uterus, adrenal gland, heart, ovary and placenta. Weakly expressed in the peripheral blood, brain and bone marrow. Expressed in numerous cancer cell lines and in gastrointestinal cancer cells. Higher levels found in colorectal cancers than in normal colonic mucosa.
Forms homooligomers (By similarity). Interacts with PLAUR (via the UPAR/Ly6 domains), ADAMTS4 and CTSB. Interacts with HGF; the interaction increases the mitogenic activity of HGF.
Expressed at low levels in normal tissues, with highest expression levels in placenta and testis. Expression is significantly increased in subset of diffuse large B-cell lymphomas.
Histone methylation reader which binds to non-methylated (H3K4me0), monomethylated (H3K4me1), dimethylated (H3K4me2) and trimethylated (H3K4me3) 'Lys-4' on histone H3 (PubMed:26933034). The order of binding preference is H3K4me3 > H3K4me2 > H3K4me1 > H3K4me0 (PubMed:26933034).
May be involved in forming the receptor site for cardiac glycoside binding or may modulate the transport function of the sodium ATPase.
Regulatory subunit of the sodium/potassium-transporting ATPase which is composed of a catalytic alpha subunit, an auxiliary non-catalytic beta subunit and an additional regulatory subunit.
Found in a complex with XPOT, Ran and tRNA. Probably found in a complex with nucleoporins. Interacts with Ran and tRNA in a GTP-dependent manner.
Mediates the nuclear export of aminoacylated tRNAs. In the nucleus binds to tRNA and to the GTPase Ran in its active GTP-bound form. Docking of this trimeric complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the tRNA from the export receptor. XPOT then return to the nuclear compartment and mediate another round of transport. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus.
A chromosomal aberration involving KNL1 is associated with acute myeloblastic leukemia (AML). Translocation t(11;15)(q23;q14) with KMT2A. May give rise to a KMT2A-KNL1 fusion protein.
Highly expressed in testis, where it is localized in germ cells, in particular in spermatocytes and in the pre-acrosome of round spermatids. Detected in the acrosome of ejaculated spermatozoa. Detected in adult thymus, bone marrow, colon, small intestine, appendix and placenta, and in fetal liver and thymus.
Interacts with DSN1, MIS12, BUB1, BUB1B, NSL1 and ZWINT.
Performs two crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Required for attachment of the kinetochores to the spindle microtubules. Directly links BUB1 and BUB1B to kinetochores. Part of the MIS12 complex, which may be fundamental for kinetochore formation and proper chromosome segregation during mitosis. Acts in coordination with CENPK to recruit the NDC80 complex to the outer kinetochore.
A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:20972997, PubMed:19965576). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307).
Genetic variation in CYP2C19 is responsible for poor drug metabolism [MIM:609535]. Individuals can be characterized as either extensive metabolizers (EM) or poor metabolizers (PM). The PM phenotype is inherited in an autosomal recessive manner, with the EM phenotype comprising both homozygous dominant and heterozygote genotypes. There are marked interracial differences in the frequency of this polymorphism. Poor metabolizers represent 2-5% of Caucasians, 13-23% of Asian populations, and as many as 38-79% of individuals of some of the islands of Polynesia and Micronesia. At least 38 different alleles are known including CYP2C19*1A, CYP2C19*1B, CYP2C19*1C, CYP2C19*2A (CYP2C19m1 or CYP2C19m1A), CYP2C19*2B (CYP2C19m1B), CYP2C19*2C (CYP2C19*21), CYP2C19*3A (CYP2C19m2), CYP2C19*3B (CYP2C19*20), CYP2C19*4 (CYP2C19m3), CYP2C19*5A (CYP2C19m4), CYP2C19*5B, CYP2C19*6, CYP2C19*7, CYP2C19*8, CYP2C19*9, CYP2C19*10, CYP2C19*11 CYP2C19*12, CYP2C19*13, CYP2C19*14 CYP2C19*15, CYP2C19*16, CYP2C19*18 and CYP2C19*19. Defective CYP2C19*2 and CYP2C19*3 alleles are characterized by a splice mutation and a stop codon, respectively, and account for most of the PM alleles. The sequence shown is that of allele CYP2C19*1A.
P450 can be induced to high levels in liver and other tissues by various foreign compounds, including drugs, pesticides, and carcinogens.
P450-254C was originally listed as a separate gene (CYP2C17). Resequencing demonstrated that it is not a separate gene, but a chimera. The 5'-portion corresponds to a partial 2C18 clone, and the 3'-portion corresponds to a partial 2C19 clone.
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Component of the SWAP complex that consists of NPM1, NCL/nucleolin, PARP1 and SWAP70 (By similarity). Component of a complex which is at least composed of HTATSF1/Tat-SF1, the P-TEFb complex components CDK9 and CCNT1, RNA polymerase II, SUPT5H, and NCL/nucleolin (PubMed:10393184). Interacts with AICDA (By similarity). Interacts with APTX (PubMed:15044383). Interacts with C1QBP (PubMed:21536856). Interacts with ERBB4 (PubMed:20858735). Interacts (via C-terminus) with FMR1 isoform 6 (via N-terminus) (PubMed:24658146). Interacts with GZF1; this interaction is important for nucleolar localization of GZF1 (PubMed:17674968). Interacts with NSUN2 (PubMed:17215513). Interacts with NVL (PubMed:21474449). Interacts (via N-terminus domain) with SETX (PubMed:21700224). Interacts (via RRM1 and C-terminal RRM4/Arg/Gly-rich domains) with TERT; the interaction is important for nucleolar localization of TERT (PubMed:15371412). Interacts with WDR46 (PubMed:23848194). Interacts with ZFP36 (PubMed:20221403). Interacts with LRRC34 (By similarity). Interacts with RRP1B (PubMed:19710015). Interacts with HNRNPU; this interaction occurs during mitosis (PubMed:21242313). Interacts with RIOK1; RIOK1 recruits NCL to PRMT5 for symmetrically methylation (PubMed:21081503). Interacts with ZBTB7B (By similarity). Interacts with MDK; this interaction promotes NCL clustering and lateral movements of this complex into lipid rafts leading to MDK internalization (PubMed:12147681). Interacts with HDGF (isoform 1) (PubMed:26845719). Interacts with ALKBH2.
Nucleolin is the major nucleolar protein of growing eukaryotic cells. It is found associated with intranucleolar chromatin and pre-ribosomal particles. It induces chromatin decondensation by binding to histone H1. It is thought to play a role in pre-rRNA transcription and ribosome assembly. May play a role in the process of transcriptional elongation. Binds RNA oligonucleotides with 5'-UUAGGG-3' repeats more tightly than the telomeric single-stranded DNA 5'-TTAGGG-3' repeats.
Some glutamate residues are glycylated by TTLL8. This modification occurs exclusively on glutamate residues and results in a glycine chain on the gamma-carboxyl group (By similarity).
Deubiquitinase involved in innate antiviral immunity by mediating 'Lys-48'-linked deubiquitination of CGAS, thereby promoting its stabilization.
Functions in post-Golgi recycling pathways. Acts as a recycling carrier to the cell surface.
Interacts with SLC6A4 and SLC9A7 (PubMed:15840657, PubMed:16870614). Interacts with SLC9A5; this interaction regulates SLC9A5 cell-surface targeting and SLC9A5 activity (PubMed:19276089).
Catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate in the presence of divalent cations, acting as a rate-limiting enzyme in gluconeogenesis. Plays a role in regulating glucose sensing and insulin secretion of pancreatic beta-cells. Appears to modulate glycerol gluconeogenesis in liver. Important regulator of appetite and adiposity; increased expression of the protein in liver after nutrient excess increases circulating satiety hormones and reduces appetite-stimulating neuropeptides and thus seems to provide a feedback mechanism to limit weight gain.
Subject to complex allosteric regulation. The enzyme can assume an active R-state, or an inactive T-state. Intermediate conformations may exist. AMP acts as allosteric inhibitor. AMP binding affects the turnover of bound substrate and not the affinity for substrate. Fructose 2,6-bisphosphate acts as competitive inhibitor. Fructose 2,6-bisphosphate and AMP have synergistic effects.
Up-regulated in pancreatic islets of individuals with type 2 diabetes.
Binds two metal ions per subunit. Two metal binding sites with different affinities are located in the enzyme active site and can be occupied in vitro by different metals: site 1 is occupied by Zn(2+), Mn(2+), Mg(2+) or Co(2+), while the tight binding site 2 can be occupied by only Zn(2+) or Co(2+). One Zn(2+) ion is tightly bound to site 2 and essential for enzyme activity in vivo, while site 1 can be occupied by different metals to give different enzymatic activities. Mn(2+) is required for Cys-Gly hydrolysis activity. A third metal binding site may serve a structural role, possibly stabilizing part of the interface between the N-terminal and the catalytic domain.
Cytosolic metallopeptidase that catalyzes the removal of unsubstituted N-terminal hydrophobic amino acids from various peptides. The presence of Zn(2+) ions is essential for the peptidase activity, and the association with other cofactors can modulate the substrate spectificity of the enzyme. For instance, in the presence of Mn(2+), it displays a specific Cys-Gly hydrolyzing activity of Cys-Gly-S-conjugates. Involved in the metabolism of glutathione and in the degradation of glutathione S-conjugates, which may play a role in the control of the cell redox status.
Calcium-binding protein. Binds one calcium ion per monomer (PubMed:17030513). Can promote differentiation of adipocytes (in vitro) (By similarity). Overexpression in preadipocytes increases their proliferation, enhances adipogenesis and reduces insulin-stimulated glucose uptake (By similarity).
Homodimer (PubMed:17030513, PubMed:21046186). Interacts with TP53 (By similarity).
S100A16 proteins, but not other S100 proteins, have only one functional Ca(2+) binding site per monomer. Upon Ca(2+) binding, undergoes conformational changes leading to the exposure of hydrophobic patches which could be implicated in the Ca(2+) -dependent nuclear export. Binds Zn(2+). Ca(2+) and Zn(2+) do not bind to the same site. Does not bind Cu(2+).
Ubiquitous (PubMed:14684152). Highly expressed in esophagus, adipose tissues and colon. Expressed at lower level in lung, brain, pancreas and skeletal muscle. Expression is up-regulated in tumors of bladder, lung, thyroid gland, pancreas and ovary (PubMed:14684152). Expressed in astrocytes (PubMed:17030513).
Identified in the spliceosome B complex (PubMed:28781166). Identified in the spliceosome C complex (PubMed:11991638). Associates with the U5 snRNP particle (PubMed:10788320). Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39, LSm proteins LSm2-8 and Sm proteins (PubMed:16723661, PubMed:26912367, PubMed:28781166). Interacts with ARAF (PubMed:10848612). Interacts with AR and NR3C1, but not ESR1, independently of the presence of hormones (PubMed:12039962). Interacts with USH1G (PubMed:34023904).
Involved in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex, one of the building blocks of the spliceosome (PubMed:28781166, PubMed:21549338). Enhances dihydrotestosterone-induced transactivation activity of AR, as well as dexamethasone-induced transactivation activity of NR3C1, but does not affect estrogen-induced transactivation.
The disease may be caused by variants affecting the gene represented in this entry. Cells from RP60 patients show intron retention for pre-mRNA bearing specific splicing signals.
Lysosomal integral membrane protein that may regulate MTORC1 complex translocation to lysosomes.
Component of the biogenesis of lysosome-related organelles complex-2 (or BLOC2) composed of HPS3, HPS5 and HPS6.
Component of the biogenesis of lysosome-related organelles complex-2 (or BLOC2) composed of HPS3, HPS5 and HPS6. Interacts with HPS5 (PubMed:15030569). Interacts with HPS6 (PubMed:15030569, PubMed:25189619).
Involved in early stages of melanosome biogenesis and maturation.
Widely expressed. Higher levels of expression are observed in kidney, liver and placenta.
Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19261746, PubMed:19261749, PubMed:19261748, PubMed:21282113). In the BRCA1-A complex, interacts directly with ABRAXAS1 and BABAM2 (PubMed:19261749, PubMed:19261748). Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19214193, PubMed:21282113, PubMed:24075985, PubMed:25283148). Identified in a complex with SHMT2 and the other subunits of the BRISC complex (PubMed:24075985).
Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX. In the BRCA1-A complex, it is required for the complex integrity and its localization at DSBs. Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:24075985, PubMed:26195665). In these 2 complexes, it is probably required to maintain the stability of BABAM2 and help the 'Lys-63'-linked deubiquitinase activity mediated by BRCC3/BRCC36 component. The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985).
The VWFA-like region is similar to the VWFA domain. Its presence reveals similarities between the structure of the 19S proteasome and the BRCA1-A complexes.
May interact with the exon junction complex (EJC) composed at least of CASC3, EIF4A3, MAGOH and RBM8A.
Arg-502 is dimethylated, probably to asymmetric dimethylarginine.
Belongs to the DEAD box helicase family. DDX5/DBP2 subfamily.
DDX5 was reported to be a transcriptional coactivator of ESR1. However, this study has been retracted due to concerns of image manipulation.
Identified in the spliceosome C complex (PubMed:11991638). Component of a ribonucleoprotein complex containing mRNAs and RNA-binding proteins including DDX5, HNRNPH2 and SRSF1 as well as splicing regulator ARVCF (PubMed:24644279). Interacts with RBM4; the interaction occurs in an RNA-independent manner. Interacts with AGO1 and AGO2. Interacts with ESR1, AR, EP300, CREBBP, POLR2A, TP53, RUNX2 and HDAC1. Self-associates. Interacts with DDX17. Interacts with BRDT. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (active). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts with NUPR1 (By similarity). Interacts with ERCC6 (PubMed:26030138). Interacts with DDX3X in the cytoplasm; this interaction may be more efficient when both proteins are unphosphorylated (PubMed:22034099).
Involved in the alternative regulation of pre-mRNA splicing; its RNA helicase activity is necessary for increasing tau exon 10 inclusion and occurs in a RBM4-dependent manner. Binds to the tau pre-mRNA in the stem-loop region downstream of exon 10. The rate of ATP hydrolysis is highly stimulated by single-stranded RNA. Involved in transcriptional regulation; the function is independent of the RNA helicase activity. Transcriptional coactivator for androgen receptor AR but probably not ESR1. Synergizes with DDX17 and SRA1 RNA to activate MYOD1 transcriptional activity and involved in skeletal muscle differentiation. Transcriptional coactivator for p53/TP53 and involved in p53/TP53 transcriptional response to DNA damage and p53/TP53-dependent apoptosis. Transcriptional coactivator for RUNX2 and involved in regulation of osteoblast differentiation. Acts as transcriptional repressor in a promoter-specific manner; the function probably involves association with histone deacetylases, such as HDAC1. As component of a large PER complex is involved in the inhibition of 3' transcriptional termination of circadian target genes such as PER1 and NR1D1 and the control of the circadian rhythms.
Polyubiquitinated, leading to proteasomal degradation.
Sumoylated; sumoylation, promoted by PIAS1, promotes interaction with HDAC1 and transcriptional repression activity. Sumoylation also significantly increases stability, and reduces polyubiquitination.
Weakly phosphorylated in the G1/S phase of the cell cycle and much more at G2/M, especially at Thr and Tyr residues.
Gla residues are produced after subsequent post-translational modifications of glutamate by a vitamin K-dependent gamma-carboxylase.
Cell cycle associated protein capable of promoting cell proliferation through the activation of CDK2 at the G1/S phase transition.
Ubiquitously expressed with highest expression in the mammary gland and large intestine. Highly expressed in cancer tissues and cancer cell lines. During cell cycle progression expression is high in G1/S, low in the middle of S phase, and increases again in S/G2 phase.
ADP-ribosylated by tankyrase TNKS and TNKS2. Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination.
Detected in adrenal gland (PubMed:9129147).
Interacts with GORASP2. Interacts with the GTP-bound form of RAB2, but not with other Golgi Rab proteins (PubMed:11739401). Identified in a complex with RAB2 and GORASP2 (PubMed:11739401).
Required for normal Golgi structure and for protein transport from the endoplasmic reticulum (ER) through the Golgi apparatus to the cell surface.
The tankyrase-binding motif (also named TBD) is required for interaction with tankyrase TNKS and TNKS2.
Ubiquitinated by RNF146 when poly-ADP-ribosylated, leading to its degradation.
Was originally identified as a potential transcription factor, because of the presence of a potential basic motif and leucine-zipper domain, and because isoform 1 is detected in the nucleus upon heterologous expression. However, homology at several typical position for basic or hydrophobic residues is missing. Besides, another publication showed it is important for normal Golgi apparatus structure and function.
Heterodimer of a 32 kDa chain and a 20 kDa chain; disulfide-linked.
Protective protein appears to be essential for both the activity of beta-galactosidase and neuraminidase, it associates with these enzymes and exerts a protective function necessary for their stability and activity. This protein is also a carboxypeptidase and can deamidate tachykinins.
(Microbial infection) Glycosylated residues by S.typhimurium protein Ssek1: arginine GlcNAcylation promotes microtubule stability.
Binds to alpha-tubulin folding intermediates after their interaction with cytosolic chaperonin in the pathway leading from newly synthesized tubulin to properly folded heterodimer (PubMed:9265649). Involved in regulation of tubulin heterodimer dissociation. May function as a negative regulator of axonal growth (By similarity).
Phosphorylation by PAK1 is required for normal function.
Supercomplex made of cofactors A to E. Cofactors A and D function by capturing and stabilizing tubulin in a quasi-native conformation. Cofactor E binds to the cofactor D-tubulin complex; interaction with cofactor C then causes the release of tubulin polypeptides that are committed to the native state (PubMed:9265649). Cofactors B and E can form a heterodimer which binds to alpha-tubulin and enhances their ability to dissociate tubulin heterodimers (By similarity). Interacts with GAN (PubMed:16303566). Interacts with DCTN1 (PubMed:22777741).
Ubiquitinated in the presence of GAN which targets it for degradation by the proteasome.
Expressed in subsets of taste receptor cells of the tongue and palate epithelium and exclusively in gustducin-positive cells. Expressed in testis (PubMed:16720576).
May be involved in cytochrome c oxidase biogenesis.
Isoform 1 and isoform 2 are N-glycosylated.
Lectin involved in the quality control of the secretory pathway. As a member of the endoplasmic reticulum-associated degradation lumenal (ERAD-L) surveillance system, targets misfolded endoplasmic reticulum lumenal glycoproteins for degradation.
May form a complex with OS9, HSPA5, SYVN1, and SEL1L with which it interacts directly. Interacts (via PRKCSH 2 domain) with KREMEN2 (when glycosylated). Interacts with HSPA5.
Probable lectin that binds selectively to improperly folded lumenal proteins. May function in endoplasmic reticulum quality control and endoplasmic reticulum-associated degradation (ERAD) of both non-glycosylated proteins and glycoproteins.
Guanine nucleotide exchange factor (GEF) for Ral-A. Potential effector of GTPase HRas and Ras-related protein M-Ras. Negatively regulates Elk-1-dependent gene induction downstream of HRas and MEKK1 (By similarity).
Interacts with GTP-bound forms of RIT1, HRAS and MRAS.
The Ras-associating domain plays a central role in the activation of Ral-A GDP/GTP exchange activity.
Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter PRAME (PubMed:21822215, PubMed:23460923, PubMed:26138980). Interacts with RARA (via the ligand-binding domain); the interaction is direct and ligand (retinoic acid)-dependent (PubMed:16179254). Interacts with EZH2; required to repress RAR signaling (PubMed:16179254).
Expressed in testis. Detected in samples of kidney, brain and skin.
Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex, which mediates ubiquitination of target proteins, leading to their degradation (PubMed:21822215, PubMed:26138980). The CRL2(PRAME) complex mediates ubiquitination and degradation of truncated MSRB1/SEPX1 selenoproteins produced by failed UGA/Sec decoding (PubMed:26138980). In the nucleus, the CRL2(PRAME) complex is recruited to epigenetically and transcriptionally active promoter regions bound by nuclear transcription factor Y (NFY) and probably plays a role in chromstin regulation (PubMed:21822215). Functions as a transcriptional repressor, inhibiting the signaling of retinoic acid through the retinoic acid receptors RARA, RARB and RARG: prevents retinoic acid-induced cell proliferation arrest, differentiation and apoptosis (PubMed:16179254).
Tumor antigen recognized by cytolytic T lymphocytes.
Up-regulated in response to interferon gamma (IFNG) treatment and exposure to bacterial PAMPs (pathogen associated molecular patterns).
Binds calcium and zinc ions; this stabilizes the protein fold and is essential for protein-protein interactions mediated by this domain.
Interacts with HHATL/GUP1 which negatively regulates HHAT-mediated palmitoylation of the SHH N-terminus (By similarity). Interacts with BOC and CDON (By similarity). Interacts with HHIP (PubMed:19561609). Interacts with DISP1 via its cholesterol anchor (PubMed:22902404, PubMed:22677548). Interacts with SCUBE2 (PubMed:24522195, PubMed:22677548). Interacts with glypican GPC3 (By similarity).
N-palmitoylation by HHAT of ShhN is required for sonic hedgehog protein N-product multimerization and full activity (By similarity). It is a prerequisite for the membrane-proximal positioning and the subsequent shedding of this N-terminal peptide (PubMed:24522195).
The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity (By similarity). Both activities result in the cleavage of the full-length protein and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-terminal fragment (ShhN) (By similarity). Cholesterylation is required for the sonic hedgehog protein N-product targeting to lipid rafts and multimerization (PubMed:24522195, PubMed:26875496). ShhN is the active species in both local and long-range signaling, whereas the C-product (ShhC) is degraded in the reticulum endoplasmic (By similarity).
The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity (By similarity). Both activities result in the cleavage of the full-length protein into two parts (ShhN and ShhC) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated ShhN (By similarity). Both activities occur in the reticulum endoplasmic (By similarity). Once cleaved, ShhC is degraded in the endoplasmic reticulum (By similarity).
The Cardin-Weintraub (CW) motif is required for heparan sulfate binding of the solubilized ShhNp (PubMed:23118222). The N-terminal palmitoylated peptide is cleaved at the heparan sulfate-binding Cardin-Weintraub (CW) motif site (PubMed:24522195). The cleavage reduced the interactions with heparan sulfate. The cleavage is enhanced by SCUBE2 (PubMed:24522195).
The dually lipidated sonic hedgehog protein N-product (ShhNp) is a morphogen which is essential for a variety of patterning events during development. Induces ventral cell fate in the neural tube and somites (PubMed:24863049). Involved in the patterning of the anterior-posterior axis of the developing limb bud (By similarity). Essential for axon guidance (By similarity). Binds to the patched (PTCH1) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes (PubMed:10753901). In the absence of SHH, PTCH1 represses the constitutive signaling activity of SMO (PubMed:10753901).
The gene represented in this entry is involved in disease pathogenesis. Abnormal SHH limb expression with pathological consequences is caused by duplications (16-75 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5 (PubMed:24456159).
The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences (PubMed:12837695).
The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences.
The gene represented in this entry is involved in disease pathogenesis. SHH expression is altered due to disease-causing variants located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH.
The lipidated N- and C-terminal peptides of ShhNp can be cleaved (shedding)(PubMed:24522195). The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub (CW) motif site (PubMed:24522195). The cleavage reduced the interactions with heparan sulfate. The cleavage is enhanced by SCUBE2 (PubMed:24522195, PubMed:23118222).
The several steps and mechanisms that permit controlled Shh dispersion and gradient formation remain controversial. The ShhNC C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity resulting in the cleavage and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-terminal fragment (ShhN). The protein is further modified by covalent addition of palmitate at the N-terminal of ShhN, resulting to the dual-lipidated Shh (ShhNp). ShhNp is firmly tethered to the cell membrane where it forms multimers. Further solubilization and release from the cell surface seem to be achieved through different mechanisms, including the interaction with DISP1 and SCUBE2, movement by lipoprotein particles, transport by cellular extensions called cytonemes or by proteolytic removal of both terminal lipidated peptides (PubMed:26875496). Once released, the fully processed Shh can signal within embryonic tissues both at short and long-range.
Interacts with PLXNA4 (By similarity). Interacts with RAB1B (PubMed:15694364, PubMed:27552051). Interacts with MAPK1/ERK2 (By similarity). Interacts with RAB35, RAB8A, RAB10, RAB13 and RAB15 (in their GTP-bound forms); binding to RAB35 is of low affinity compared to other Rab proteins; at least in case of RAB8A may bind 2 molecules of RAB8A simultaneously through a high and a low affinity binding site, respectively (PubMed:27552051). May interact with MAPK1/ERK2 (By similarity). Interacts with CORO1C; this interaction recruits MICAL2 to the actin filaments (PubMed:34106209).
Methionine monooxygenase that promotes depolymerization of F-actin by mediating oxidation of residues 'Met-44' and 'Met-47' on actin to form methionine-sulfoxide, resulting in actin filament disassembly and preventing repolymerization (PubMed:24440334, PubMed:29343822). Regulates the disassembly of branched actin networks also by oxidizing ARP3B-containing ARP2/3 complexes leading to ARP3B dissociation from the network (PubMed:34106209). Acts as a key regulator of the SRF signaling pathway elicited by nerve growth factor and serum: mediates oxidation and subsequent depolymerization of nuclear actin, leading to increase MKL1/MRTF-A presence in the nucleus and promote SRF:MKL1/MRTF-A-dependent gene transcription. Does not activate SRF:MKL1/MRTF-A through RhoA (PubMed:24440334).
Specifically inhibited by CCG-1423, a small molecule inhibitor of SRF:MKL1/MRTF-A-dependent transcription.
The C-terminal RAB-binding domain (RBD) (1796-1945), also described as bivalent Mical/EHBP Rab binding (bMERB) domain, mediates binding to predominantly RAB8A, RAB10, RAB13 and RAB15 (in their GTP-bound forms).
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, eicosanoids and vitamins (PubMed:18577768, PubMed:10833273, PubMed:10660572, PubMed:11997390, PubMed:17341693, PubMed:18574070). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase). Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of long- and very long-chain fatty acids. Displays high omega-hydroxylase activity toward polyunsaturated fatty acids (PUFAs) (PubMed:18577768). Participates in the conversion of arachidonic acid to omega-hydroxyeicosatetraenoic acid (20-HETE), a signaling molecule acting both as vasoconstrictive and natriuretic with overall effect on arterial blood pressure (PubMed:10660572, PubMed:17341693, PubMed:18574070). Plays a role in the oxidative inactivation of eicosanoids, including both pro-inflammatory and anti-inflammatory mediators such as leukotriene B4 (LTB4), lipoxin A4 (LXA4), and several HETEs (PubMed:8026587, PubMed:9799565, PubMed:10833273, PubMed:10660572, PubMed:17341693, PubMed:18574070, PubMed:18577768). Catalyzes omega-hydroxylation of 3-hydroxy fatty acids (PubMed:18065749). Converts monoepoxides of linoleic acid leukotoxin and isoleukotoxin to omega-hydroxylated metabolites (PubMed:15145985). Contributes to the degradation of very long-chain fatty acids (VLCFAs) by catalyzing successive omega-oxidations and chain shortening (PubMed:16547005, PubMed:18182499). Plays an important role in vitamin metabolism by chain shortening. Catalyzes omega-hydroxylation of the phytyl chain of tocopherols (forms of vitamin E), with preference for gamma-tocopherols over alpha-tocopherols, thus promoting retention of alpha-tocopherols in tissues (PubMed:11997390). Omega-hydroxylates and inactivates phylloquinone (vitamin K1), and menaquinone-4 (MK-4, a form of vitamin K2), both acting as cofactors in blood coagulation (PubMed:19297519, PubMed:24138531).
Disease susceptibility may be associated with variants affecting the gene represented in this entry. The variant Met-433 is associated with coumarin (the brand name of warfarin) resistance by increasing coumarin maintenance dose in patients on this anti-coagulant therapy. This is probably due to decreased activity of the phylloquinone omega-hydroxylase activity, leading to an increase in hepatic vitamin K levels that warfarin must antagonize (PubMed:24138531).
Liver. Also present in kidney: specifically expressed in the S2 and S3 segments of proximal tubules in cortex and outer medulla (PubMed:10660572).
Adhesion molecule that promotes lamina-specific synaptic connections in the retina. Expressed in specific subsets of interneurons and retinal ganglion cells (RGCs) and promotes synaptic connectivity via homophilic interactions.
Dysregulation of this protein may play an important role in podocyte dysfunction in HIV-associated nephropathy.
Homodimer; mediates homophilic interactions to promote cell adhesion.
Ig-like C2-type domains 1 and 2 mediate homophilic interactions.
Up-regulated in glomeruli in HIV-associated nephropathy. In diseased glomeruli, significantly overexpressed and the expression is no longer restricted to mesangial cells but includes podocytes and parietal epithelial cells (PubMed:15213259).
Component of a Wnt-signaling complex that contains a WNT protein, a FZD protein and LRP5 or LRP6. Interacts directly with LRP5 or LRP6; the interaction is promoted by Wnt-binding and signaling and inhibited by DKK1. Interacts with GPOC, RSPO1 and RSPO3 (By similarity). Interacts with glypican GPC3 (PubMed:24496449).
Most abundant in fetal kidney, followed by brain and lung. In adult tissues, expressed in kidney, heart, pancreas and skeletal muscle.
Receptor for Wnt proteins. Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalosomes. The beta-catenin canonical signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Coreceptor along with RYK of Wnt proteins, such as WNT1.
Belongs to the teashirt C2H2-type zinc-finger protein family.
Expressed in brain; strongly reduced in post-mortem elderly subjects with Alzheimer disease.
Interacts (via homeobox domain) with APBB1 (via PID domain 1).
Probable transcriptional regulator involved in developmental processes. May act as a transcriptional repressor (Potential).
The sequence differs from that shown due translation of a 3'-UTR region.
Detected on marginal zone and germinal center B cells in lymph nodes (PubMed:2463100). Detected on blood B cells (at protein level) (PubMed:2463100, PubMed:16672701).
Functions as coreceptor for the B-cell antigen receptor complex (BCR) on B-lymphocytes. Decreases the threshold for activation of downstream signaling pathways and for triggering B-cell responses to antigens (PubMed:2463100, PubMed:1373518, PubMed:16672701). Activates signaling pathways that lead to the activation of phosphatidylinositol 3-kinase and the mobilization of intracellular Ca(2+) stores (PubMed:9382888, PubMed:9317126, PubMed:12387743, PubMed:16672701). Is not required for early steps during B cell differentiation in the blood marrow (PubMed:9317126). Required for normal differentiation of B-1 cells (By similarity). Required for normal B cell differentiation and proliferation in response to antigen challenges (PubMed:2463100, PubMed:1373518). Required for normal levels of serum immunoglobulins, and for production of high-affinity antibodies in response to antigen challenge (PubMed:9317126, PubMed:12387743, PubMed:16672701).
Interacts with CR2/CD21 (PubMed:1702139). Part of a complex composed of CD19, CR2/CD21, CD81 and IFITM1/CD225 in the membrane of mature B-cells (PubMed:1383329). Interacts directly with CD81 (via the second extracellular domain); this interaction is initiated early during biosynthesis in the ER/pre-Golgi compartments and is essential for trafficking and compartmentalization of CD19 receptor on the cell surface of activated B cells (PubMed:16449649). Interacts with VAV (PubMed:10706702). Interacts with GRB2 and SOS when phosphorylated on Tyr-348 and/or Tyr-378. Interacts with PLCG2 when phosphorylated on Tyr-409 (PubMed:10706702). Interacts with LYN (PubMed:7687428). Interacts (when tyrosine phosphorylated) with the regulatory p85 subunit of phosphatidylinositol 3-kinase (PIK3R1 or PIK3R2) (PubMed:7684160).
Phosphorylated on tyrosine following B-cell activation (PubMed:7684160, PubMed:7687539, PubMed:10706702, PubMed:12387743). Phosphorylated on tyrosine residues by LYN (PubMed:7687428). Tyrosine residues are phosphorylated sequentially after activation of the B cell receptor. Phosphorylation of Tyr-531 is extremely rapid, followed by phosphorylation at Tyr-409. In contrast, phosphorylation of Tyr-500 appears more slowly and is more transient, returning rapidly to basal levels (By similarity).
Specifically expressed in meiotic tissues. Highly expressed in testis.
Forms a soluble 1:1 complex with AFM; this prevents oligomerization and is required for prolonged biological activity (PubMed:26902720). The complex with AFM may represent the physiological form in body fluids (PubMed:26902720).
Ligand for members of the frizzled family of seven transmembrane receptors. Plays a role in embryonic patterning.
Palmitoleoylation is required for efficient binding to frizzled receptors (By similarity). Depalmitoleoylation leads to Wnt signaling pathway inhibition (By similarity).
Proteolytic processing by TIKI1 and TIKI2 promotes oxidation and formation of large disulfide-bond oligomers, leading to inactivation of WNT8A.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 glycoprotein UL16; this interaction causes sequestration of MICB in the endoplasmic reticulum and increases resistance to KLRK1-mediated cytotoxicity.
A GC to AG nucleotide substitution in intron 1 generates a splice junction which gives rise to an additional exon between exons 1 and 2. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Belongs to the MHC class I family. MIC subfamily.
By heat shock, oxidative stress, retinoic acid, IFN-alpha and the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine. Induction by IFN-alpha is impaired in patients with chronic hepatitis C virus infection. Down-regulated by human cytomegalovirus UL112 microRNA during viral infection which leads to decreased binding of KLRK1/NKG2D and reduced killing by natural killer cells.
Disease susceptibility is associated with variants affecting the gene represented in this entry. The MICB*004 allele is associated with rheumatoid arthritis.
Genetic variation in MICB is associated with cytomegalovirus and herpes simplex virus I seropositivity and this may be associated with schizophrenia risk.
Proteolytically cleaved and released from the cell surface of tumor cells.
Seems to have no role in antigen presentation. Acts as a stress-induced self-antigen that is recognized by gamma delta T cells. Ligand for the KLRK1/NKG2D receptor. Binding to KLRK1 leads to cell lysis.
The following alleles of MICB are known: MICB*001, MICB*002, MICB*003, MICB*004, MICB*005, MICB*006, MICB*007, MICB*008, MICB*009N, MICB*010, MICB*011, MICB*012, MICB*013, MICB*014, MICB*015, MICB*016, MICB*018, MICB*019, MICB*020, MICB*021N and MICB*022. MICB*009N and MICB*021N are null alleles which are not expressed. The three most common MICB alleles in the human population could be MICB*005, MICB*004, and MICB*002. The sequence shown is that of MICB*004.
Unlike classical MHC class I molecules, does not form a heterodimer with beta-2-microglobulin. Binds as a monomer to a KLRK1/NKG2D homodimer. KLRK1 forms a complex with HCST/DAP10 in which KLRK1 binds MICB while HCST acts as an adapter molecule which enables signal transduction. Receptor-ligand interaction induces clustering of both proteins in ordered structures called immune synapses and also leads to their intercellular transfer. This is associated with a reduction in the cytotoxicity of KLRK1-expressing cells.
Widely expressed with the exception of the central nervous system where it is absent. Expressed in many, but not all, epithelial tumors of lung, breast, kidney, ovary, prostate and colon. In hepatocellular carcinomas, expressed in tumor cells but not in surrounding non-cancerous tissue.
Highly expressed in the liver and at lower levels in the heart, lung and pancreas.
Tautomerization of D-dopachrome with decarboxylation to give 5,6-dihydroxyindole (DHI).
Belongs to the GST superfamily. Omega family.
Exhibits glutathione-dependent thiol transferase activity. Has high dehydroascorbate reductase activity and may contribute to the recycling of ascorbic acid. Participates in the biotransformation of inorganic arsenic and reduces monomethylarsonic acid (MMA).
Expressed in a range of tissues, including the liver, kidney, skeletal muscle and prostate. Strongest expression in the testis.
Interacts with RNMT; this interaction enhances mRNA binding and cap methyltransferase activity.
Regulatory subunit of the mRNA-capping methyltransferase RNMT:RAMAC complex that methylates the N7 position of the added guanosine to the 5'-cap structure of mRNAs (PubMed:22099306, PubMed:27422871). Promotes the recruitment of the methyl donor, S-adenosyl-L-methionine, to RNMT (PubMed:27422871). Regulates RNMT expression by a post-transcriptional stabilizing mechanism (PubMed:22099306). Binds RNA (PubMed:22099306).
Binds DNA. Interacts with SUMO conjugating enzyme UBC9/UBE2I. Interacts with the telomeric protein TERF2IP.
Liver, skeletal and heart muscle, mammary cells. Very low levels in brain, lung, placenta and kidney. Strongly overexpressed in many pancreas and colorectal cancers. Increased gene copy numbers are detected in 3 of 12 tumor cell lines and 2 of 12 primary pancreatic carcinomas. Overexpressed in 80% of colorectal cancers.
Transmembrane component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Required for ciliogenesis and sonic hedgehog/SHH signaling (By similarity).
Belongs to the POU transcription factor family. Class-5 subfamily.
Could be the product of a pseudogene. Several pseudogenes of POU5F1 have been described on chromosomes 1, 3, 8, 10 and 12. Two of them, localized on chromosomes 8 and 10 have been shown to be preferentially transcribed in cancer tissues and may be involved in the regulation of POU5F1 gene activity in carcinogenesis.
Detected at the mRNA level in several cancer tissues (breast, uterine cervix, lung, thyroid gland, esophagus, colon, urinary bladder, and glioma), but absent in normal tissues.
Shows weak transcriptional activator activity.
Belongs to the immunoglobulin superfamily. L1/neurofascin/NgCAM family.
Cell adhesion, ankyrin-binding protein which may be involved in neurite extension, axonal guidance, synaptogenesis, myelination and neuron-glial cell interactions.
Homophilic adhesion is primarily mediated by the interaction of the second Ig-like domains.
Horseshoe-shaped homodimer. Probable constituent of a NFASC/NRCAM/ankyrin-G complex. Associates with the sodium channel beta-1 (SCN1B) and beta-3 (SCN3B) subunits. Interacts with GLDN/gliomedin (By similarity). Interacts with MYOC.
Efficient DNA binding requires dimerization with another basic helix-loop-helix (bHLH) protein. Forms heterodimers with bHLH transcription factor TCF3. May not heterodimerise with bHLH protein HAND1.
Expressed in the ectoderm but not in the mesoderm or endoderm of the fetus at the second trimester (PubMed:12099555). At the second trimester, expressed in photoreceptor, bipolar, and ganglion cells of the retina, and in developing skin cells (PubMed:12099555). Expressed in developing neuronal cells of the brain and the spinal cord, but not in the peripheral nerves (PubMed:12099555).
Expressed in the placenta at a stage between the first and second trimesters and when it matures, at about 32-36 weeks (PubMed:12099555). Expressed in the extravillous trophoblasts, the intermediate trophoblasts, and at lower levels in the cytotrophoblasts and stroma of chorionic villi of the developing placenta (PubMed:9175731, PubMed:12099555). Expressed in follicular T-helper (Tfh) cells (PubMed:24463518).
In contrast to the mouse ortholog, the ASCL2 locus is not imprinted in human placenta.
Transcription factor. Binds to E-box motifs 5'-CANNTG-3' in the regulatory elements of target genes, probably as a heterodimer with another basic helix-loop-helix (bHLH) protein such as the transcription factor TCF3. May bind both open and closed chromatin, acting as a pioneer transcription factor to allow other factors to bind and activate lineage-specific genes. Required during post-implantation development for the generation of some differentiated trophoblast cell types. Transcriptional activity of ASCL2 may be antagonised in a subset of trophoblast cells by bHLH transcription factor HAND1, perhaps by competing for dimerization with other bHLH proteins. Involved in differentiation and function of follicular T-helper (Tfh) cells, thereby playing a role in germinal center responses; probably modulates expression of genes involved in Tfh cell function, such as BCL6. May also act as a suppressor of Th1-, Th2- and Th17-cell differentiation. Induces the formation of stem cells in intestinal crypts in vitro, synergistically activating transcription of target genes, such as SOX9, together with TCF4/beta-catenin. May form a bistable transcriptional switch, controlling expression of its own gene together with Wnt/R-spondin signaling, and thereby maintaining stem cell characteristics (By similarity). Modulates expression of target genes, including perhaps down-regulating EGR1/Krox24 and chemokine CXCL10/Mob-1 and up-regulating CXCR4 and CDKN1C/p57kip2, in Schwann cells. May play a role in reducing proliferation of Schwann cells, perhaps acting via modulation of expression of CDKN1C (By similarity). May be dispensable for blastocyst formation and later embryonic function (By similarity). May be involved in the determination of neuronal precursors (By similarity).
Homotrimer. Binds to PKC beta-1 (By similarity). Interacts with ATRAID; the interaction promotes osteoblast cell differentiation and mineralization.
Plays a role in the control of cell growth and differentiation. Promotes osteoblast cell differentiation and terminal mineralization.
Extracellular matrix protein required for maintenance of the integrity of the skin epithelium and for maintenance of renal epithelia (PubMed:15838507). Required for epidermal adhesion (PubMed:15838507). Involved in the development of eyelids and the anterior segment of the eyeballs (PubMed:29688405, PubMed:30802441).
The Calx-beta domains bind calcium with high affinity and undergo a major conformational shift upon binding.
(Microbial infection) Binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I.
Binds DNA as a homodimer and as a heterodimer (PubMed:11018027). Heterodimer; heterodimerizes with CEBPB (PubMed:11018027). Heterodimer; heterodimerizes with DDIT3/CHOP (PubMed:18940792). Interacts with CEP290 (via an N-terminal region) (PubMed:16682973). Interacts with NEK6, DAPK2 (isoform 2) and ZIPK/DAPK3 (PubMed:20873783, PubMed:21408167). Interacts (via its leucine zipper domain) with GABBR1 and GABBR2 (via their C-termini) (By similarity). Forms a heterodimer with TXLNG in osteoblasts (PubMed:15911876). Interacts (via its DNA binding domain) with FOXO1 (C-terminal half); the interaction occurs in osteoblasts and regulates glucose homeostasis through suppression of beta-cell proliferation and a decrease in insulin production (By similarity). Interacts with SATB2; the interaction results in enhanced DNA binding and transactivation by these transcription factors (By similarity). Interacts with ABRAXAS2 (PubMed:22974638). Interacts with TRIB3, inhibiting the transactivation activity of ATF4 (By similarity). Interacts with DISC1; which inhibits ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding (By similarity). Interacts with EP300/p300; EP300/p300 stabilizes ATF4 and increases its transcriptional activity independently of its catalytic activity by preventing its ubiquitination (PubMed:16219772).
Hydroxylated by PHD3, leading to decreased protein stability.
Phosphorylation at Ser-245 by RPS6KA3/RSK2 in osteoblasts enhances transactivation activity and promotes osteoblast differentiation (PubMed:15109498). Phosphorylated on the betaTrCP degron motif at Ser-219, followed by phosphorylation at Thr-213, Ser-224, Ser-231, Ser-235 and Ser-248, promoting interaction with BTRC and ubiquitination (By similarity). Phosphorylation is promoted by mTORC1 (By similarity). Phosphorylation at Ser-215 by CK2 decreases its stability (PubMed:23123191). Phosphorylated by NEK6 (PubMed:20873783).
Regulated at the translational level in response to various stress such as endoplasmic reticulum stress, amino acid starvation or oxidative stress (PubMed:27629041, PubMed:33384352). In the absence of stress, ribosomes re-initiate translation at an inhibitory open reading frame (uORF) upstream of the ATF4 transcript, which precludes AFT4 translation. In response to stress and subsequent EIF2S1/eIF-2-alpha phosphorylation, ribosomes bypass the inhibitory uORF and re-initiate translation at the AFT4 coding sequence (PubMed:27629041).
The BetaTrCP degron motif promotes binding to BTRC when phosphorylated.
Transcription factor that binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3') and displays two biological functions, as regulator of metabolic and redox processes under normal cellular conditions, and as master transcription factor during integrated stress response (ISR) (PubMed:17684156, PubMed:16682973, PubMed:31444471, PubMed:32132707). Binds to asymmetric CRE's as a heterodimer and to palindromic CRE's as a homodimer (By similarity). Core effector of the ISR, which is required for adaptation to various stress such as endoplasmic reticulum (ER) stress, amino acid starvation, mitochondrial stress or oxidative stress (PubMed:32132707). During ISR, ATF4 translation is induced via an alternative ribosome translation re-initiation mechanism in response to EIF2S1/eIF-2-alpha phosphorylation, and stress-induced ATF4 acts as a master transcription factor of stress-responsive genes in order to promote cell recovery (PubMed:32132706, PubMed:32132707). Promotes the transcription of genes linked to amino acid sufficiency and resistance to oxidative stress to protect cells against metabolic consequences of ER oxidation (By similarity). Activates the transcription of NLRP1, possibly in concert with other factors in response to ER stress (PubMed:26086088). Activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress (PubMed:11960987). However, when associated with DDIT3/CHOP, the transcriptional activation of the ASNS gene is inhibited in response to amino acid deprivation (PubMed:18940792). Together with DDIT3/CHOP, mediates programmed cell death by promoting the expression of genes involved in cellular amino acid metabolic processes, mRNA translation and the terminal unfolded protein response (terminal UPR), a cellular response that elicits programmed cell death when ER stress is prolonged and unresolved (By similarity). Together with DDIT3/CHOP, activates the transcription of the IRS-regulator TRIB3 and promotes ER stress-induced neuronal cell death by regulating the expression of BBC3/PUMA in response to ER stress (PubMed:15775988). May cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis which is critical for cell viability in response to ER stress (PubMed:33384352). In the absence of stress, ATF4 translation is at low levels and it is required for normal metabolic processes such as embryonic lens formation, fetal liver hematopoiesis, bone development and synaptic plasticity (By similarity). Acts as a regulator of osteoblast differentiation in response to phosphorylation by RPS6KA3/RSK2: phosphorylation in osteoblasts enhances transactivation activity and promotes expression of osteoblast-specific genes and post-transcriptionally regulates the synthesis of Type I collagen, the main constituent of the bone matrix (PubMed:15109498). Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production (By similarity). Activates transcription of SIRT4 (By similarity). Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4 (By similarity). Binds in a circadian time-dependent manner to the cAMP response elements (CRE) in the SLC6A4 and PER2 promoters and periodically activates the transcription of these genes (By similarity). Mainly acts as a transcriptional activator in cellular stress adaptation, but it can also act as a transcriptional repressor: acts as a regulator of synaptic plasticity by repressing transcription, thereby inhibiting induction and maintenance of long-term memory (By similarity). Regulates synaptic functions via interaction with DISC1 in neurons, which inhibits ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding (PubMed:31444471).
Ubiquitinated by SCF(BTRC) in response to mTORC1 signal, followed by proteasomal degradation and leading to down-regulate expression of SIRT4 (PubMed:11238952). Interaction with EP300/p300 inhibits ubiquitination by SCF(BTRC) (PubMed:16219772).
Part of a SCF (SKP1-cullin-F-box) protein ligase complex.
Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation.
Homotrimer (via collagen-like domains). Interacts with NRCAM and NFASC/neurofascin (PubMed:27616481). Interaction with glial NRCAM enhances interaction with axonal NFASC. Interacts with MYOC.
Ligand for NRCAM and NFASC/neurofascin that plays a role in the formation and maintenance of the nodes of Ranvier on myelinated axons. Mediates interaction between Schwann cell microvilli and axons via its interactions with NRCAM and NFASC. Nodes of Ranvier contain clustered sodium channels that are crucial for the saltatory propagation of action potentials along myelinated axons. During development, nodes of Ranvier are formed by the fusion of two heminodes. Required for normal clustering of sodium channels at heminodes; not required for the formation of mature nodes with normal sodium channel clusters. Required, together with NRCAM, for maintaining NFASC and sodium channel clusters at mature nodes of Ranvier.
Proteolytic proccessing by a furin-like protease causes shedding of the ectodomain. Further cleavage by BMP1 releases the olfactomedin-like domain.
Specifically expressed in spinal cord, brain, placenta and sciatic nerve. More abundant in peripheral than central nervous system.
The olfactomedin-like domain mediates NFASC/neurofascin and NRCAM binding.
Belongs to the dynactin subunit 3 family.
Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules (By similarity). Together with dynein may be involved in spindle assembly and cytokinesis (PubMed:9722614).
Subunit of dynactin, a multiprotein complex part of a tripartite complex with dynein and a adapter, such as BICDL1, BICD2 or HOOK3. The dynactin complex is built around ACTR1A/ACTB filament and consists of an actin-related filament composed of a shoulder domain, a pointed end and a barbed end. Its length is defined by its flexible shoulder domain. The soulder is composed of 2 DCTN1 subunits, 4 DCTN2 and 2 DCTN3. The 4 DCNT2 (via N-terminus) bind the ACTR1A filament and act as molecular rulers to determine the length. The pointed end is important for binding dynein-dynactin cargo adapters. Consists of 4 subunits: ACTR10, DCNT4, DCTN5 and DCTN6. The barbed end is composed of a CAPZA1:CAPZB heterodimers, which binds ACTR1A/ACTB filament and dynactin and stabilizes dynactin.
Ubiquitously expressed. Highly expressed in muscle and pancreas and detected at lower levels in brain.
A palmitoylation site was proposed at Cys-93, but it was later shown that this cysteine is engaged in a disulfide bond.
Forms a soluble 1:1 complex with AFM; this prevents oligomerization and is required for prolonged biological activity (PubMed:26902720). The complex with AFM may represent the physiological form in body fluids (PubMed:26902720). Interacts with PORCN. Interacts with RSPO1, RSPO2 and RSPO3 (By similarity). Interacts with WLS (By similarity).
Genetic variations in WNT1 define the bone mineral density quantitative trait locus 16 (BMND16) [MIM:615221]. Variance in bone mineral density influences bone mass, contributes to size determination in the general population, and is a susceptibility factor for osteoporotic fractures.
Ligand for members of the frizzled family of seven transmembrane receptors (Probable). Acts in the canonical Wnt signaling pathway by promoting beta-catenin-dependent transcriptional activation (PubMed:23499309, PubMed:26902720, PubMed:28528193, PubMed:23656646). In some developmental processes, is also a ligand for the coreceptor RYK, thus triggering Wnt signaling (By similarity). Plays an essential role in the development of the embryonic brain and central nervous system (CNS) (By similarity). Has a role in osteoblast function, bone development and bone homeostasis (PubMed:23499309, PubMed:23656646).
Palmitoleoylation is required for efficient binding to frizzled receptors. Palmitoleoylation is necessary for proper trafficking to cell surface (Probable). Depalmitoleoylated by NOTUM, leading to inhibit Wnt signaling pathway (By similarity).
Interacts with RARRES1, KIF11 AND MAPRE1.
Metallocarboxypeptidase that mediates deglutamylation of tubulin and non-tubulin target proteins. Catalyzes the removal of polyglutamate side chains present on the gamma-carboxyl group of glutamate residues within the C-terminal tail of tubulin protein. Specifically cleaves tubulin long-side-chains, while it is not able to remove the branching point glutamate. Also catalyzes the removal of polyglutamate residues from the carboxy-terminus of non-tubulin proteins such as MYLK.
Was initially shown to catalyze the removal of carboxy-terminus tyrosine from alpha-tubulin (PubMed:21303978). However, later studies did not identified any detyrosinase or deglycylase activities from the carboxy-terminus of tubulin (By similarity).
Was originally thought to have detyrosinating activity from C-terminal positions on tubulin.
Homodimer, and heterodimer with OIP5/MIS18B (PubMed:17199038, PubMed:26921242). Identified in a complex containing MIS18A, OIP5/MIS18B, MIS18BP1, RBBP7 and RBBP4 (PubMed:17199038).
Required for recruitment of CENPA to centromeres and normal chromosome segregation during mitosis.
(Microbial infection) Interacts with ebolavirus protein VP35; this interaction stabilizes VP35 N-terminal oligomerization domain and enhances viral RNA synthesis.
(Microbial infection) Interacts with human spumaretrovirus Gag protein; this interaction is critical for intracellular microtubule-dependent viral genome transport toward the centrosome.
Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. May play a role in changing or maintaining the spatial distribution of cytoskeletal structures.
Belongs to the dynein light chain family.
Binds and inhibits the catalytic activity of neuronal nitric oxide synthase/NOS1.
Homodimer. Monomer; the monomeric form is incapable of binding to target proteins. The cytoplasmic dynein 1 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs); the composition seems to vary in respect to the IC, LIC and LC composition. The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits. The ICs and LICs bind directly to the HC dimer and the LCs assemble on the IC dimer. Interacts with TXNDC17. Interacts with WWC1 and ESR1. The WWC1-DYNLL1 interaction is mandatory for the recruitment and transactivation functions of ESR1 or DYNLL1 to the target chromatin. Interacts with BCL2L11 isoform 1 and isoform 2. Interacts with BCL2; the interaction is greatly enhanced in the nucleus and in mitochondria upon induction of apoptosis. Interacts with PAK1; the interaction requires dimeric DYNLL1. Interacts with MYZAP. Part of an astrin (SPAG5)-kinastrin (SKAP) complex containing KNSTRN, SPAG5, PLK1, DYNLL1 and SGO2. Interacts with ATMIN; this interaction inhibits ATMIN transcriptional activity and hence may play a role in a feedback loop whereby DYNLL1 inhibits transactivation of its own promoter by ATMIN. Interacts with NEK9 (not phosphorylated at 'Ser-944'). Interacts with BICD2 (By similarity). Interacts with BCAS1 (By similarity). Interacts with Basson/BSN. Interacts with HDAC6 (PubMed:31505170). Interacts with TPPP (PubMed:31505170). Interacts with AMBRA1 (via TQT motifs); tethering AMBRA1 to the cytoskeleton (PubMed:20921139). Interacts with FAM83D/CHICA (via C-terminus) (PubMed:22965910). Interacts with HMMR, SPAG5/Astrin and KNSTRN/Kinastrin (PubMed:22965910). Interacts with TLK2 (PubMed:29955062, PubMed:33323470). Interacts with NOS1 (By similarity).
Phosphorylation at Ser-88 appears to control the dimer-monomer transition. According to PubMed:15193260, it is phosphorylated at Ser-88 by PAK1, however, according to PubMed:18650427, the DYNLL1 dimer is not accessible for PAK1 and the phosphorylation could not be demonstrated in vitro.
Promotes transactivation functions of ESR1 and plays a role in the nuclear localization of ESR1.
Regulates apoptotic activities of BCL2L11 by sequestering it to microtubules. Upon apoptotic stimuli the BCL2L11-DYNLL1 complex dissociates from cytoplasmic dynein and translocates to mitochondria and sequesters BCL2 thus neutralizing its antiapoptotic activity.
Ubiquitous (PubMed:8628263). Expressed in testis (PubMed:22965910).
Up-regulated by ATMIN, PAK1 and estrogen.
Dominant determinant of sensitivity to DNA-damaging anticancer drugs: acts by mediating cell death in response to DNA damage induced by anticancer drugs (PubMed:29395061). Down-regulated in a number of chemoresistant tumors (PubMed:26625211, PubMed:28196596, PubMed:27440269, PubMed:28212573).
Down-regulated in small cell lung cancer (SCLC) cells resistant to PARP inhibitor drugs (PubMed:26625211, PubMed:28196596, PubMed:27440269, PubMed:28212573). Up-regulated by type I interferons, poly-IC and poly-dAdT (PubMed:20956525, PubMed:23000900).
Exhibits a wider expression range in ovarian and colon adenocarcinoma than in their corresponding healthy tissues.
Inhibitor of DNA replication that promotes cell death in response to DNA damage (PubMed:22927417, PubMed:26658330, PubMed:29395061). Acts as a guardian of the genome by killing cells with defective replication (PubMed:29395061). Persistently blocks stressed replication forks by opening chromatin across replication initiation sites at stressed replication forks, possibly leading to unwind DNA ahead of the MCM helicase and block fork progression, ultimately leading to cell death (PubMed:29395061). Acts independently of ATR (PubMed:29395061). Also acts as an interferon (IFN)-induced antiviral protein which acts as an inhibitor of retrovirus protein synthesis (PubMed:23000900). Specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1) by acting as a specific inhibitor of the synthesis of retroviruses encoded proteins in a codon-usage-dependent manner (PubMed:23000900). Binds to tRNAs and exploits the unique viral codon bias towards A/T nucleotides (PubMed:23000900). The exact inhibition mechanism is unclear: may either sequester tRNAs, prevent their maturation via post-transcriptional processing or may accelerate their deacylation (PubMed:23000900). Does not inhibit reverse transcription, integration or production and nuclear export of viral RNA (PubMed:23000900).
Interacts with MCM3 (PubMed:29395061). Interacts with DHX9 (PubMed:26625211, PubMed:29395061). Interacts with RPA1 (PubMed:26658330, PubMed:29395061).
In the C-terminal section; belongs to the actin family.
In the N-terminal section; belongs to the POTE family.
C1 is a calcium-dependent trimolecular complex of C1q, C1r and C1s in the molar ration of 1:2:2. Activated C1s is an disulfide-linked heterodimer of a heavy chain and a light chain.
C1s B chain is a serine protease that combines with C1q and C1r to form C1, the first component of the classical pathway of the complement system. C1r activates C1s so that it can, in turn, activate C2 and C4.
The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains.
Expressed in secretory granules of many acinar cells in lacrimal gland and in scattered acinar cells of salivary glands.
Modulates secretion by lacrimal acinar cells.
Homotrimer; disulfide-linked (PubMed:20956340, PubMed:25912189). Interacts with MASP1; probably triggers the lectin pathway of complement (PubMed:20956340).
Lectin that plays a role in innate immunity, apoptosis and embryogenesis (PubMed:23954398, PubMed:25912189, PubMed:21258343). Calcium-dependent lectin that binds self and non-self glycoproteins presenting high mannose oligosaccharides with at least one terminal alpha-1,2-linked mannose epitope (PubMed:25912189). Primarily recognizes the terminal disaccharide of the glycan (PubMed:25912189). Also recognizes a subset of fucosylated glycans and lipopolysaccharides (PubMed:17179669, PubMed:25912189). Plays a role in innate immunity through its ability to bind non-self sugars presented by microorganisms and to activate the complement through the recruitment of MAPS1 (PubMed:20956340, PubMed:25912189). Also plays a role in apoptosis through its ability to bind in a calcium-independent manner the DNA present at the surface of apoptotic cells and to activate the complement in response to this binding (Probable). Finally, plays a role in development, probably serving as a guidance cue during the migration of neural crest cells and other cell types during embryogenesis (PubMed:21258343, PubMed:28301481).
Ubiquitous (PubMed:17179669). Detected in adrenal gland, kidney, liver, ovaries and testis (at protein level) (PubMed:20956340).
Homodimer (PubMed:24098481). Interacts with ARL1, ARL2 and ARL3 (PubMed:11303027). Directly interacts with FEZ1 and UVRAG (PubMed:22354037, PubMed:24098481). The interaction with UVRAG is reduced by amino acid starvation, but the complex is stabilized in the presence of FEZ1. Interacts with NRBF2 (PubMed:22354037).
Positive regulator of amino acid starvation-induced autophagy.
Widely expressed with highest levels in brain, heart and skeletal muscle.
Heterodimerizes with MAU2/SCC2 to form the cohesin loading complex (PubMed:16682347, PubMed:16802858, PubMed:21934712, PubMed:28167679, PubMed:22628566). The NIPBL-MAU2 heterodimer interacts with the SMC1A-SMC3 heterodimer and with the cohesin complex composed of SMC1A, SMC3, RAD21 and STAG1 (PubMed:22628566).
Plays an important role in the loading of the cohesin complex on to DNA. Forms a heterodimeric complex (also known as cohesin loading complex) with NIPBL/SCC2 which mediates the loading of the cohesin complex onto chromatin (PubMed:28167679, PubMed:22628566). Plays a role in sister chromatid cohesion and normal progression through prometaphase (PubMed:16802858, PubMed:16682347).
Homodimer. Forms higher-order oligomers under interphase but not mitotic conditions. Dimers of the protein on one membrane might be able to interact with dimers on another and so stack cisternae (PubMed:26363069). Interacts with the C-terminus of GOLGA2/GM130 under both mitotic and non-mitotic conditions (PubMed:16489344, PubMed:26363069). The interaction is critical for the correct targeting of both proteins to the cis-Golgi. Interacts with TMED2 and TMED3 (By similarity).
Key structural protein of the Golgi apparatus (PubMed:33301566). The membrane cisternae of the Golgi apparatus adhere to each other to form stacks, which are aligned side by side to form the Golgi ribbon (PubMed:33301566). Acting in concert with GORASP2/GRASP55, is required for the formation and maintenance of the Golgi ribbon, and may be dispensable for the formation of stacks (PubMed:33301566). However, other studies suggest that GORASP1 plays an important role in assembly and membrane stacking of the cisternae, and in the reassembly of Golgi stacks after breakdown during mitosis (By similarity). Caspase-mediated cleavage of GORASP1 is required for fragmentation of the Golgi during apoptosis (By similarity). Also mediates, via its interaction with GOLGA2/GM130, the docking of transport vesicles with the Golgi membranes (PubMed:16489344). Mediates ER stress-induced unconventional (ER/Golgi-independent) trafficking of core-glycosylated CFTR to cell membrane (PubMed:21884936).
Phosphorylated by CDC2/B1 and PLK kinases during mitosis. Phosphorylation cycle correlates with the cisternal stacking cycle. Phosphorylation of the homodimer prevents the association of dimers into higher-order oligomers, leading to cisternal unstacking.
Target for caspase-3 cleavage during apoptosis. The cleavage contributes to Golgi fragmentation and occurs very early in the execution phase of apoptosis.
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent degradation of DVL1. Also targets the mutant SOD1 protein involved in familial amyotrophic lateral sclerosis (FALS). Forms cytotoxic aggregates with DVL1, SSR3 and mutant SOD1 that lead to motor neuron death in FALS.
Interacts with DVL1 and SSR3. Also interacts with mutant SOD1.
Predominantly expressed in neurons of adult and fetal brain. Weakly expressed in the kidney.
By phytohemagglutinin (PHA) in peripheral CD8(+) T cells.
Homodimer; non-disulfide-linked. Interacts with KLRB1. Interacts with KLRF2.
Mainly expressed in skin. Also expressed in keratinocytes, spleen, thymus, small intestine, peripheral blood monocytes, bone marrow, ovary, testis and skin. High expression in CD8(+), B-lymphocytes and naive CD4(+) T-cells. Restricted mostly to proliferating lymphocytes. Not detected in myeloid leukocytes or natural killer (NK) cells.
Plays a role in modulating the extent of T-cell expansion. Enhances the expansion of TCR-stimulated T-cells by increasing their survival through enhanced expression of anti-apoptotic proteins. May modulate the capacity of T-cells to home to lymph nodes through SELL. Facilitates dedicated immune recognition of keratinocytes via interaction with its receptor KLRF2 by stimulating natural killer cell mediated cytotoxicity.
Mediates the transport of organic anions such as steroids (estrone 3-sulfate, chenodeoxycholate, glycocholate) and thyroid hormones (3,3',5-triiodo-L-thyronine (T3), L-thyroxine (T4)), in the kidney (PubMed:14993604, PubMed:19129463, PubMed:20610891). Capable of transporting cAMP and pharmacological substances such as digoxin, ouabain and methotrexate (PubMed:14993604). Transport is independent of sodium, chloride ion, and ATP (PubMed:14993604). Transport activity is stimulated by an acidic extracellular environment due to increased substrate affinity to the transporter (PubMed:19129463). The driving force for this transport activity is currently not known (By similarity). The role of hydrogencarbonate (HCO3(-), bicarbonate) as the probable counteranion that exchanges for organic anions is still not well defined (PubMed:19129463). Functions as an uptake transporter at the apical membrane, suggesting a role in renal reabsorption (By similarity). Involved in the renal secretion of the uremic toxin ADMA (N(omega),N(omega)-dimethyl-L-arginine or asymmetrical dimethylarginine), which is associated to cardiovascular events and mortality, and the structurally related amino acids L-arginine and L-homoarginine (a cardioprotective biomarker) (PubMed:30865704). Can act bidirectionally, suggesting a dual protective role of this transport protein; exporting L-homoarginine after being synthesized in proximal tubule cells, and mediating uptake of ADMA from the blood into proximal tubule cells where it is degraded by the enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) (PubMed:30865704, PubMed:32642843). May be involved in sperm maturation by enabling directed movement of organic anions and compounds within or between cells (By similarity). This ion-transporting process is important to maintain the strict epididymal homeostasis necessary for sperm maturation (By similarity). May have a role in secretory functions since seminal vesicle epithelial cells are assumed to secrete proteins involved in decapacitation by modifying surface proteins to facilitate the acquisition of the ability to fertilize the egg (By similarity).
Predominantly expressed in kidney but also weakly expressed in both fetal liver and kidney.
SLCO4C1-mediated digoxin uptake is inhibited by digoxin itself and related compounds such as ouabain, digitoxin and digoxigenin.
Belongs to the LDH/MDH superfamily. LDH family.
Fermentation of pyruvate to lactate is inhibited when bound to folliculin FLCN, perhaps partly by FLCN preventing binding of cofactor NADH (PubMed:34381247).
Homotetramer (PubMed:11276087). Interacts with PTEN upstream reading frame protein MP31 (PubMed:33406399). Interacts with folliculin FLCN; the interaction is direct and inhibits enzymatic activity (PubMed:34381247).
Interconverts simultaneously and stereospecifically pyruvate and lactate with concomitant interconversion of NADH and NAD(+).
Predominantly expressed in anaerobic tissues such as skeletal muscle and liver.
Expressed in a number of retinoblastoma cell lines.
Autophosphorylates following homodimerization, leading to activation of the protein.
Highly expressed in rapidly proliferating tissues (spleen, placenta, and peripheral blood leukocytes). Also expressed in brain, heart, skeletal muscle, colon, thymus, kidney, liver, small intestine and lung.
Homodimer; homodimerization is required for activation segment autophosphorylation.
Inhibited by the pyrrole-indolinone inhibitor SU11274 (K00593): intercalates between the ATP-binding Lys-65 and alpha-C glutamate (Glu-81), resulting in a partial disordering of the lysine side chain. Also specifically inhibited by erlotinib. Slightly inhibited by gefitinib.
Inhibition by erlotinib, an orally administered EGFR tyrosine kinase inhibitor used for treatment, enhances STK10-dependent lymphocytic responses, possibly leading to the aggravation of skin inflammation observed upon treatment by erlotinib.
Serine/threonine-protein kinase involved in regulation of lymphocyte migration. Phosphorylates MSN, and possibly PLK1. Involved in regulation of lymphocyte migration by mediating phosphorylation of ERM proteins such as MSN. Acts as a negative regulator of MAP3K1/MEKK1. May also act as a cell cycle regulator by acting as a polo kinase kinase: mediates phosphorylation of PLK1 in vitro; however such data require additional evidences in vivo.
Although related to histone H2AB1 in mouse (AC Q9CQ70), it is unclear whether human and mouse H2AB1 proteins are involved in similar processes. In mouse, histone H2AB1 is specifically required to direct the transformation of dissociating nucleosomes to protamine in male germ cells during spermatogenesis. It is however unclear whether human protein, which participates in mRNA processing and is associated with active transcription, is also involved in nucleosomes to protamine replacement (PubMed:22795134).
Atypical histone H2A which can replace conventional H2A in some nucleosomes and is associated with active transcription and mRNA processing (PubMed:22795134). Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability (PubMed:15257289, PubMed:16287874, PubMed:16957777, PubMed:17591702, PubMed:17726088, PubMed:18329190, PubMed:22795134). Nucleosomes containing this histone are less rigid and organize less DNA than canonical nucleosomes in vivo (PubMed:15257289, PubMed:16957777, PubMed:17591702, PubMed:24336483). They are enriched in actively transcribed genes and associate with the elongating form of RNA polymerase (PubMed:17591702, PubMed:24753410). They associate with spliceosome components and are required for mRNA splicing (PubMed:22795134).
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. Component of an ATP synthase complex composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5PD, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and ATP5MJ (By similarity). Interacts with PRICKLE3 (PubMed:32516135).
Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(0) domain. Minor subunit located with subunit a in the membrane (By similarity).
Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(0) domain. Minor subunit located with subunit a in the membrane.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry.
Isoform A is the predominant isoform in spleen, caudate and hippocampus. Isoform B is expressed at lower levels. Isoform D is a minor isoform in terms of expression.
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase.
Expressed in skeletal and cardiac muscles but not in other tissues.
Interacts with beta-1 integrin subunit. This interaction is regulated by divalent cations, and it occurs only in absence of calcium.
May play a role during maturation and/or organization of muscles cells.
The tail domain binds to the cytoplasmic domain of both integrin beta-1a and beta-1d isoforms. The presence of Ca(2+) ions does not prevent binding of a fragment consisting of the second cysteine rich repeat and the tail domain but prevents the binding of the full-length protein.
E3 ubiquitin-protein ligase. Ubiquitinates BRAF, inducing its proteasomal degradation.
The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.
Heterotetramer of two type I and two type II keratins. Keratin-3 associates with keratin-12.
There are two types of cytoskeletal and microfibrillar keratin: I (acidic; 40-55 kDa) and II (neutral to basic; 56-70 kDa).
Mono-ADP-ribosyltransferase that mediates mono-ADP-ribosylation of target proteins (PubMed:25043379, PubMed:25673562). Plays a role in nuclear envelope stability and nuclear remodeling during spermiogenesis (By similarity).
Belongs to the dynactin subunit 4 family.
Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules.
Subunit of dynactin, a multiprotein complex part of a tripartite complex with dynein and a adapter, such as BICDL1, BICD2 or HOOK3. The dynactin complex is built around ACTR1A/ACTB filament and consists of an actin-related filament composed of a shoulder domain, a pointed end and a barbed end. Its length is defined by its flexible shoulder domain. The soulder is composed of 2 DCTN1 subunits, 4 DCTN2 and 2 DCTN3. The 4 DCNT2 (via N-terminus) bind the ACTR1A filament and act as molecular rulers to determine the length. The pointed end is important for binding dynein-dynactin cargo adapters. Consists of 4 subunits: ACTR10, DCNT4, DCTN5 and DCTN6. The barbed end is composed of a CAPZA1:CAPZB heterodimers, which binds ACTR1A/ACTB filament and dynactin and stabilizes dynactin (By similarity). Interacts with ATP7B, but not ATP7A, in a copper-dependent manner (PubMed:16554302). Interacts with ANK2; this interaction is required for localization at costameres (By similarity).
(Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 infection, the interaction with non-structural protein 2 (nsp2) with GIGYF2 enhances GIGYF2 binding to EIF4E2 and increases repression of translation initiation of genes involved in antiviral innate immune response such as IFNB1.
Belongs to the eukaryotic initiation factor 4E family.
Component of the 4EHP-GYF2 complex, a multiprotein complex that acts as a repressor of translation initiation (PubMed:22751931, PubMed:35878012). In association with GIGYF2, assists ribosome-associated quality control (RQC) by sequestering the mRNA cap, blocking ribosome initiation and decreasing the translational load on problematic messages. Part of a pathway that works in parallel to RQC-mediated degradation of the stalled nascent polypeptide. GIGYF2 and EIF4E2 work downstream and independently of ZNF598, which seems to work as a scaffold that can recruit them to faulty mRNA even if alternative recruitment mechanisms may exist (PubMed:32726578).
ISGylation enhances its cap structure-binding activity and translation-inhibition activity.
Interacts with EIF4EBP1, EIF4EBP2 and EIF4EBP3 (PubMed:15153109, PubMed:17368478). Does not interact with eIF4G (EIF4G1, EIF4G2 or EIF4G3) (By similarity). Component of the 4EHP-GYF2 complex, at least composed of EIF4E2, GIGYF2 and ZNF598 (PubMed:22751931, PubMed:32726578). Interacts with GIGYF2 (via the 4EHP-binding motif); the interaction is direct (PubMed:22751931, PubMed:32726578, PubMed:33581076). Interacts with EIF4ENIF1/4E-T (via YXXXXLphi motif); increasing affinity for the 7-methylguanosine-containing mRNA cap (PubMed:23991149, PubMed:28487484).
Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation. Acts as a repressor of translation initiation (PubMed:17368478, PubMed:22751931, PubMed:25624349, PubMed:33581076, PubMed:9582349). In contrast to EIF4E, it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3), suggesting that it acts by competing with EIF4E and block assembly of eIF4F at the cap (By similarity). In P-bodies, component of a complex that promotes miRNA-mediated translational repression (PubMed:28487484). Involved in virus-induced host response by mediating miRNA MIR34A-induced translational silencing which controls IFNB1 production by a negative feedback mechanism (PubMed:28487484, PubMed:33581076).
Ubiquitinated by ARIH1 (PubMed:14623119, PubMed:25624349). The consequences of ubiquitination are however unclear: according to a report, EIF4E2 ubiquitination leads to promote EIF4E2 cap-binding and protein translation arrest (PubMed:25624349). According to another report ubiquitination leads to its subsequent degradation (PubMed:14623119).
Homodimer, and heterodimer with AMIGO2 and AMIGO3. Interacts with KCNB1.
Promotes growth and fasciculation of neurites from cultured hippocampal neurons. May be involved in fasciculation as well as myelination of developing neural axons. May have a role in regeneration as well as neural plasticity in the adult nervous system. May mediate homophilic as well as heterophilic cell-cell interaction and contribute to signal transduction through its intracellular domain. Assembled with KCNB1 modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1.
The LRR repeat region mediates homodimerization.
A model for self-activation in which residue Thr-21 serves as nucleophile and Lys-53 as proton donor/acceptor has been proposed. Subunit processing of mammalian beta-subunits proceeds via a novel ordered two-step mechanism involving autocatalysis.
Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.
Highly expressed in immature dendritic cells (at protein level).
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB6. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.
The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB6 by PSMB9 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues.
Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Up-regulated by tumor necrosis factor-alpha (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by heat shock treatment. Up-regulated by CD40L via the NFKB1 pathway in cancer cells.
May be necessary to recruit DLD/E3 to the mitochondrial 2-oxoglutarate dehydrogenase complex (OGDC) core composed of OGDH/E1-DLST/E2, hence stabilizes the complex.
Probable component of the 2-oxoglutarate dehydrogenase complex (OGDC), composed of OGDH (2-oxoglutarate dehydrogenase; also called E1 subunit), DLST (dihydrolipoamide succinyltransferase; also called E2 subunit) and DLD (dihydrolipoamide dehydrogenase; also called E3 subunit). Within OGDC, may interact (via N-terminus) with E3 subunit and (via C-terminus) with the complex core formed by E1 and E2 subunits.
Was originally identified in the small subunit (28S) of mitochondrial ribosomes that were purified on sucrose gradients (By similarity). This observation has been challenged by experiments showing MRPS36 copurification with the oxoglutarate dehydrogenase complex (OGDC), also called alpha-ketoglutarate dehydrogenase complex (KGDH). Both mitochondrial ribosome 28S subunit and OGDC have a similar size and OGDC is highly abundant, therefore OGDC has been found to contaminate ribosomal preparations performed by sequential centrifugation steps (By similarity). In addition, MRPS36 could not be located in the structure of the human mitochondrial ribosome, supporting the hypothesis that it is not a mitoribosomal protein (PubMed:25838379).
As cone-specific cGMP phosphodiesterase, it plays an essential role in light detection and cone phototransduction by rapidly decreasing intracellular levels of cGMP.
Composed of two alpha' subunits that are associated with 3 smaller proteins of 11, 13, and 15 kDa.
Belongs to the eukaryotic ribosomal protein eL8 family.
Common component of the spliceosome and rRNA processing machinery.
Identified in the spliceosome B complex (PubMed:28781166). Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, WDR57, SNRNP40, DDX23, CD2BP2, PPIH, NHP2L1, EFTUD2, SART1 and USP39 (PubMed:16723661, PubMed:26912367). Interacts with RAD17 and PRPF31 (PubMed:10593953, PubMed:17412961, PubMed:21784869). The complex formed by SNU13 and PRPF31 binds U4 snRNA (PubMed:17412961). The complex formed by SNU13 and PRPF31 binds also U4atac snRNA, a characteristic component of specific, less abundant spliceosomal complexes (PubMed:21784869). Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797).
Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797). Involved in pre-mRNA splicing as component of the spliceosome (PubMed:28781166). Binds to the 5'-stem-loop of U4 snRNA and thereby contributes to spliceosome assembly (PubMed:10545122, PubMed:17412961). The protein undergoes a conformational change upon RNA-binding (PubMed:17412961, PubMed:10545122, PubMed:28781166).
Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Required for proper control of cellular levels of GMNN expression.
Homodimer. Component of a PRC1-like complex (PubMed:12167701, PubMed:19636380, PubMed:21282530). Interacts with RNF2 and CBX7 (By similarity). Interacts with PHC2, PHC2 and BMI1 (By similarity).
The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different PRC1-like complexes.
Belongs to the calycin superfamily. Lipocalin family. Highly divergent.
Interacts with LRP2; LRP2 mediates APOM renal uptake and subsequent lysosomal degradation.
Plasma protein. Expressed in liver and kidney.
Probably involved in lipid transport. Can bind sphingosine-1-phosphate, myristic acid, palmitic acid and stearic acid, retinol, all-trans-retinoic acid and 9-cis-retinoic acid.
Adapter protein that binds to and probably organizes the subcellular localization of a variety of proteins. May link various receptors to the actin cytoskeleton and the dystrophin glycoprotein complex (By similarity).
Interacts with the dystrophin protein DMD and related proteins DTNA and DTNB.
The association with dystrophin or related proteins probably leaves the PDZ domain available to recruit proteins to the membrane.
Widely expressed. Strong expression in brain and testis. In CNS, it is expressed in the perikaryon and proximal portion of the neuronal processes. Strong expression in the hippocampus, neuron-rich dendate granule cells, and pyramidal cell layers. Highly expressed in neurons of the cerebral cortex. Also expressed in the cerebellar cortex, deep cerebellar nuclei, thalamus, and basal ganglia.
Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. May play a role in binding dynein to membranous organelles or chromosomes.
Belongs to the dynein light intermediate chain family.
Homodimer. The cytoplasmic dynein 1 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs); the composition seems to vary in respect to the IC, LIC and LC composition. The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits. The ICs and LICs bind directly to the HC dimer and the LCs assemble on the IC dimer. Interacts with DYNC1H1; DYNC1LI1 and DYNC1LI2 bind mutually exclusive to DYNC1H.
Homodimer. The cytoplasmic dynein 1 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs).
Homooligomer (PubMed:9590177). Interacts with M6PR (via the cytoplasmic domain) (PubMed:9590177). Interacts with IGF2R (via the cytoplasmic domain) (PubMed:9590177).
Phosphorylation at Tyr-251 by isoform 1 of CHKA (CHKalpha2) promotes dissociation from lipid droplets: dissociation is followed by recruitment of autophagosome machinery to lipid droplets and subsequent lipid droplet lipolysis.
Structural component of lipid droplets, which is required for the formation and maintenance of lipid storage droplets (PubMed:34077757). Required for the transport of mannose 6-phosphate receptors (MPR) from endosomes to the trans-Golgi network (PubMed:9590177).
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodium ions.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-4/CHRNA4 sub-subfamily.
Neuronal AChR is composed of two different types of subunits: alpha and beta. Alpha-4 subunit can be combined to beta-2 or beta-4 to give rise to functional receptors, complexes with beta-2 may be heteropentamers (PubMed:22361591). Interacts with RIC3; which is required for proper folding and assembly (PubMed:16120769). Interacts with LYPD6 (PubMed:27344019). The heteropentamer alpha-4-beta-2 interacts with alpha-conotoxins PnIA, GID and MII (By similarity).
Does not have retinol/retinal dehydrogenase activity in vitro.
Has retinol/retinal dehydrogenase activity in vitro.
Highly expressed in the liver (PubMed:29562163). Also detected in ovary, bone marrow, kidney, brain, lung, skeletal muscle, bladder and testis.
Plays a pivotal role in hepatic lipid metabolism (PubMed:29562163). In vitro, it catalyzes the oxidation of a variety of lipid substrates, including 17beta-estradiol, retinol, retinal, and leukotriene B4 (PubMed:29562163, PubMed:30415504, PubMed:32973038).
The insertion of an adenine adjacent to the donor splice site of exon 6 (dbSNP:rs72613567) is associated with reduced risk of non-alcoholic fatty liver disease and protection from chronic liver disease [MIM:620116]. It is also associated with reduced risk of hepatocellular carcinoma (PubMed:29562163, PubMed:34930143). Variant rs72613567 alters mRNA splicing and results in the synthesis of a truncated, unstable protein. Liver samples from variant carriers contain reduced levels of isoform 1 and isoform 2 transcripts (PubMed:29562163).
Monomer. Homodimer only upon binding to a DNA (By similarity). Efficient DNA binding requires dimerization with another bHLH protein. Interacts with TACC3 (By similarity). Interacts with HIF1A, EPAS1, NPAS1 and NPAS3; forms a heterodimer that binds core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (PubMed:20699359, PubMed:16181639) (By similarity). Forms a heterodimer with AHRR, as well as with other bHLH proteins (Probable). Interacts with NOCA7 (PubMed:10395741). Interacts with TACC3 (By similarity). Interacts with AHR; the heterodimer ARNT:AHR binds to core DNA sequence 5'-TGCGTG-3' within the dioxin response element (DRE) of target gene promoters and activates their transcription (PubMed:28396409, PubMed:34521881). Interacts with SIM1 and NPAS4 (By similarity).
Required for activity of the AHR. Upon ligand binding, AHR translocates into the nucleus, where it heterodimerizes with ARNT and induces transcription by binding to xenobiotic response elements (XRE). Not required for the ligand-binding subunit to translocate from the cytosol to the nucleus after ligand binding (PubMed:34521881). The complex initiates transcription of genes involved in the regulation of a variety of biological processes, including angiogenesis, hematopoiesis, drug and lipid metabolism, cell motility and immune modulation (Probable). The heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters and functions as a transcriptional regulator of the adaptive response to hypoxia (By similarity). The heterodimer ARNT:AHR binds to core DNA sequence 5'-TGCGTG-3' within the dioxin response element (DRE) of target gene promoters and activates their transcription (PubMed:28396409).
Autoubiquitinated leading to degradation (short half-life).
By binding to and ubiquitinating two ALS1 variants of SOD1 (mSOD1 variants Arg-86 and Ala-94) it attenuates their cytotoxicity.
Expressed in brain, heart, liver, lung, spleen, stomach, testis, skeletal and muscle.
Mitochondrial E3 ubiquitin-protein ligase that plays a crucial role in the control of mitochondrial morphology by acting as a positive regulator of mitochondrial fission. May play a role in the prevention of cell senescence acting as a regulator of mitochondrial quality control. Promotes ubiquitination of FIS1, DNM1L and MFN1.
Monomer and homodimer. Interacts with MFN1, MFN2, DNM1L and FIS1.
The RING-CH-type zinc finger domain is required for E3 ligase activity.
(Microbial infection) Interacts via its globular head domain with the central portion of S.flexneri IcsA (also called VirG).
Acetylated; mainly by myristic acid but also by a small amount of palmitic acid.
Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion. Regulates cell-surface E-cadherin expression and potentiates mechanosensing by the E-cadherin complex. May also play important roles in cell morphology and locomotion.
Belongs to the vinculin/alpha-catenin family.
Exhibits self-association properties. Part of a complex composed of THSD1, PTK2/FAK1, TLN1 and VCL (PubMed:29069646). Interacts with APBB1IP and NRAP (By similarity). Interacts with TLN1. Interacts with CTNNB1 and this interaction is necessary for its localization to the cell-cell junctions and for its function in regulating cell surface expression of E-cadherin (By similarity). Interacts with SYNM. Interacts with SORBS1 (By similarity). Interacts with CTNNA1 (PubMed:26691986). Binds to ACTN4; this interaction triggers conformational changes (PubMed:15988023).
Exists in at least two conformations. When in the closed, 'inactive' conformation, extensive interactions between the head and tail domains prevent detectable binding to most of its ligands. It takes on an 'active' conformation after cooperative and simultaneous binding of two different ligands. This activation involves displacement of the head-tail interactions and leads to a significant accumulation of ternary complexes. The active form then binds a number of proteins that have both signaling and structural roles that are essential for cell adhesion.
Phosphorylated; on serines, threonines and tyrosines. Phosphorylation on Tyr-1133 in activated platelets affects head-tail interactions and cell spreading but has no effect on actin binding nor on localization to focal adhesion plaques (By similarity).
The N-terminal globular head (Vh) comprises of subdomains D1-D4. The C-terminal tail (Vt) binds F-actin and cross-links actin filaments into bundles. In isoform 2 (metavinculin) a 68 residue insertion in the tail domain promotes actin severing instead of bundling. An intramolecular interaction between Vh and Vt masks the F-actin-binding domain located in Vt. The binding of talin and alpha-actinin to the D1 subdomain of vinculin induces a helical bundle conversion of this subdomain, leading to the disruption of the intramolecular interaction and the exposure of the cryptic F-actin-binding domain of Vt. Vt inhibits actin filament barbed end elongation without affecting the critical concentration of actin assembly.
Component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP ACD and POT1. Forms heterodimers with POT1. Identified in a complex with POT1 and single-stranded telomeric DNA. Interacts with STN1 and TINF2.
Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends. Without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Promotes binding of POT1 to single-stranded telomeric DNA. Modulates the inhibitory effects of POT1 on telomere elongation. The ACD-POT1 heterodimer enhances telomere elongation by recruiting telomerase to telomeres and increasing its processivity. May play a role in organogenesis.
Cleaves peptide substrates on the N-terminus of arginine residues in dibasic pairs. Is a critical activator of BACE1- and ADAM17-mediated pro-neuregulin ectodomain shedding, involved in the positive regulation of axonal maturation and myelination. Required for proper functioning of 2-oxoglutarate dehydrogenase (OGDH) (By similarity).
Primarily in adult heart, skeletal muscle, and testis and at much lower levels in other tissues.
Acts as an epigenetic regulator of myogenesis in cooperation with DPF3a (isoform 2 of DPF3/BAF45C) (PubMed:32459350). Associates with the BAF complex via its interaction with DPF3a and HDGFL2-DPF3a activate myogenic genes by increasing chromatin accessibility through recruitment of SMARCA4/BRG1/BAF190A (ATPase subunit of the BAF complex) to myogenic gene promoters (PubMed:32459350). Promotes the repair of DNA double-strand breaks (DSBs) through the homologous recombination pathway by facilitating the recruitment of the DNA endonuclease RBBP8 to the DSBs (PubMed:26721387). Preferentially binds to chromatin regions marked by H3K9me3, H3K27me3 and H3K36me2 (PubMed:26721387, PubMed:32459350). Involved in cellular growth control, through the regulation of cyclin D1 expression (PubMed:25689719).
Interacts with HDGF (By similarity). Interacts with trimethylated 'Lys-36' of histone H3 (H3K36me3). Interacts with trimethylated 'Lys-79' of histone H3 (H3K79me3), but has higher affinity for H3K36me3. Interacts with IWS1 (PubMed:25689719). Interacts with H2AX, POGZ, RBBP8 and CBX1 (PubMed:26721387). Interacts with histones H3K9me3, H3K27me3 and H3K36me2 (PubMed:26721387, PubMed:32459350). Interacts with DPF3a (isoform 2 of DPF3/BAF45C) (PubMed:32459350). Interacts with SMARCA4/BRG1/BAF190A, SMARCC1/BAF155 and SMARCD1/BAF60A in a DPF3a-dependent manner (PubMed:32459350).
Widely expressed. High expression is found in heart, skeletal muscle, ovary and testis. Overexpression is frequently observed in hepatocellular carcinoma samples.
Basement membrane-associated chondroitin sulfate proteoglycan (CSPG). Has prolyl 3-hydroxylase activity catalyzing the post-translational formation of 3-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens, especially types IV and V. May be involved in the secretory pathway of cells. Has growth suppressive activity in fibroblasts.
The disease is caused by variants affecting the gene represented in this entry. A splice site mutation leading to the absence of isoform 1 has been reported in 2 OI8 patients. Isoform 1 is the only form predicted to be located in the endoplasmic reticulum, which the appropriate location for the catalysis of collagen hydroxylation. These patients show indeed severely reduced COL1A1 hydroxylation (PubMed:19088120).
Essential for the proper assembly of type I and type II keratin protein complexes and formation of keratin intermediate filaments in the inner root sheath (irs) (By similarity). Plays a role in the cytoskeleton organization (PubMed:26902920).
Heterodimer of a type I and a type II keratin (PubMed:26902920). Heterodimer with type II keratin KRT5 leading to the formation of keratin intermediate filament (KIF) network (PubMed:28899683). Interacts with KRT6A to form filaments (By similarity).
Strongly expressed in skin and scalp, and weak expression observed in thymus and tongue. In the hair follicle, expressed in Henle layer, Huxley layer and in the inner root sheath cuticle of the hair follicle. Expression extends from the bulb region up to the point of differentiation into the three layers. Also present in the medulla of beard hair (at protein level).
(Microbial infection) Binds HIV-2 protein vpx and thereby promotes the nuclear translocation of the lentiviral genome (in vitro).
(Microbial infection) FG repeats mediates interaction with HIV-1 capsid protein p24 (CA).
(Microbial infection) Interacts (via C-terminus) with HIV-1 capsid protein p24 (CA) (via N-terminus).
(Microbial infection) Interacts with Epstein-barr virus BGLF4; this interaction allows BGLF4 nuclear entry.
(Microbial infection) Interacts with HIV-1 caspid protein P24 and thereby promotes the integration of the virus in the nucleus of non-dividing cells (in vitro).
(Microbial infection) Interacts with HIV-1 integrase; this interaction might play a role in nuclear import of HIV pre-integration complex.
(Microbial infection) Interacts with HIV-2 virus protein vpx; this interaction might promote vpx nuclear entry.
(Microbial infection) Interacts with hepatitis B virus capsid protein; this interaction probably plays a role in nuclear import of HBV genome.
Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. Functions as a scaffolding element in the nuclear phase of the NPC essential for normal nucleocytoplasmic transport of proteins and mRNAs. Involved in the quality control and retention of unspliced mRNAs in the nucleus; in association with TPR, regulates the nuclear export of unspliced mRNA species bearing constitutive transport element (CTE) in a NXF1- and KHDRBS1-independent manner. Mediates TPR anchoring to the nuclear membrane at NPC. The repeat-containing domain may be involved in anchoring other components of the NPC to the pore membrane. Possible DNA-binding subunit of the nuclear pore complex (NPC).
Contains FG repeats. FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC. FG repeat regions are highly flexible and lack ordered secondary structure. The overall conservation of FG repeats regarding exact sequence, spacing, and repeat unit length is limited.
Interacts with RAN; the interaction occurs in a GTP- and GDP-independent manner (By similarity). Part of the nuclear pore complex (NPC). Interacts with TPR (via coiled coil region); the interaction is direct and provides a link between the core structure and the TPR-containing nuclear basket of the nuclear pore complex (NPC). Interacts with HIKESHI, SENP2 and XPO5. Interacts with MCM3AP isoform GANP; this interaction is required for GANP localization at the nuclear pore complex (PubMed:20005110, PubMed:23652018).
O-glycosylated during cytokinesis at sites identical or close to phosphorylation sites, this interferes with the phosphorylation status.
Phosphorylated in interphase, hyperphosphorylated during mitosis. May play a role in the reversible disassembly of the nuclear pore complex during mitosis (By similarity).
Proteolytically degraded after poliovirus (PV) infection; degradation is partial and NCP- and TPR-binding domains withstand degradation.
Colipase is a cofactor of pancreatic lipase. It allows the lipase to anchor itself to the lipid-water interface. Without colipase the enzyme is washed off by bile salts, which have an inhibitory effect on the lipase.
Enterostatin has a biological activity as a satiety signal.
Forms a 1:1 stoichiometric complex with pancreatic lipase.
Variant Cys-109 is statistically significantly associated with an increased risk of type 2 diabetes.
The 3-beta-HSD enzymatic system plays a crucial role in the biosynthesis of all classes of hormonal steroids. HSD VII is active against four 7-alpha-hydroxylated sterols. Does not metabolize several different C(19/21) steroids as substrates. Involved in bile acid synthesis (PubMed:11067870). Plays a key role in cell positioning and movement in lymphoid tissues by mediating degradation of 7-alpha,25-dihydroxycholesterol (7-alpha,25-OHC): 7-alpha,25-OHC acts as a ligand for the G protein-coupled receptor GPR183/EBI2, a chemotactic receptor for a number of lymphoid cells.
An N-terminally truncated L27 domain is predicted in isoform 2 at positions 1 through 27.
Interacts through its PDZ domains with NETO1 (By similarity). Interacts with NOS1/nNOS through second PDZ domain (By similarity). Interacts with KCNJ2/Kir2.1 (via C-terminus) through one of its PDZ domains (PubMed:15304517). Interacts with KCNJ4 (By similarity), Interacts with FRMPD4 (via C-terminus) (PubMed:19118189). Interacts with LRFN1, LRFN2 and LRFN4 (PubMed:16630835). Interacts with FASLG (PubMed:19807924). Interacts with KCNJ4 (By similarity). Interacts with ADAM22 (By similarity). Interacts with DGKI (via PDZ-binding motif) (By similarity).
Palmitoylation of isoform 1 is not required for targeting to postsynaptic density.
Required for perception of chronic pain through NMDA receptor signaling. Regulates surface expression of NMDA receptors in dorsal horn neurons of the spinal cord. Interacts with the cytoplasmic tail of NMDA receptor subunits as well as inward rectifying potassium channels. Involved in regulation of synaptic stability at cholinergic synapses. Part of the postsynaptic protein scaffold of excitatory synapses (By similarity).
(Microbial infection) Interacts with E.coli effector protein EspF(U) (PubMed:19366662, PubMed:22921828). Identified in a complex containing at least WASL, BAIAP2L1 and E.coli EspF(U) (PubMed:22921828).
(Microbial infection) Interacts with Shigella flexneri protein IcsA (PubMed:9582270, PubMed:10491394). The interaction with IcsA enhances the affinity of WASL for Arp2/3, thus assembling a tight complex which has maximal activity in actin assembly (PubMed:9582270, PubMed:10491394).
Binds actin and the Arp2/3 complex (PubMed:22847007). Interacts with CDC42 (PubMed:9422512). Interacts with FCHSD1 (By similarity). Interacts with FCHSD2 (PubMed:29887380). Binds to SH3 domains of GRB2. Interacts with the C-terminal SH3 domain of DNMBP (PubMed:19767742, PubMed:24332715, PubMed:17015620). Interacts with SNX9 (By similarity). Interacts with the WW domains of PRPF40A/FBP11 (By similarity). Interacts with PTK2/FAK1 (By similarity). Interacts with PACSIN1, PACSIN2 and PACSIN3 (By similarity). Interacts with NOSTRIN (PubMed:16234328). Binds to TNK2 (PubMed:16257963). Interacts with SNX33 (PubMed:19487689). Interacts with NONO (via second RRM domain); the interaction is direct (PubMed:16767080). Component of a multiprotein complex with NONO and SFPQ; associates with the complex via direct interaction with NONO (PubMed:16767080).
Phosphorylation at Ser-242, Tyr-256, Ser-484 and Ser-485 enhances actin polymerization activity.
Regulates actin polymerization by stimulating the actin-nucleating activity of the Arp2/3 complex (PubMed:9422512, PubMed:16767080, PubMed:19366662, PubMed:19487689, PubMed:22847007, PubMed:22921828). Involved in various processes, such as mitosis and cytokinesis, via its role in the regulation of actin polymerization (PubMed:9422512, PubMed:19366662, PubMed:19487689, PubMed:22847007, PubMed:22921828). Together with CDC42, involved in the extension and maintenance of the formation of thin, actin-rich surface projections called filopodia (PubMed:9422512). In addition to its role in the cytoplasm, also plays a role in the nucleus by regulating gene transcription, probably by promoting nuclear actin polymerization (PubMed:16767080). Binds to HSF1/HSTF1 and forms a complex on heat shock promoter elements (HSE) that negatively regulates HSP90 expression (By similarity). Plays a role in dendrite spine morphogenesis (By similarity). Decreasing levels of DNMBP (using antisense RNA) alters apical junction morphology in cultured enterocytes, junctions curve instead of being nearly linear (PubMed:19767742).
Belongs to the eukaryotic ribosomal protein eS10 family.
Belongs to the parathyroid hormone family.
Highly expressed in fetal and adult brain, cerebellum and trachea. Weakly expressed in spinal cord, fetal liver, kidney and heart.
Ligand of high affinity for the PTH2 receptor (PTH2R).
Plays a role as a potent and selective agonist of PTH2R resulting in adenyl cyclase activation and intracellular calcium levels elevation. Induces protein kinase C beta activation, recruitment of beta-arrestin and PTH2R internalization. May inhibit cell proliferation via its action on PTH2R activation. Neuropeptide which may also have a role in spermatogenesis. May activate nociceptors and nociceptive circuits.
Expressed in the cortical brain, pancreas, spleen, and testis with weaker expression in the peripheral nerve (at protein level). Highly expressed in gray matter (at protein level).
Farnesylation is important for trafficking to lysosomes.
Homooligomer (By similarity). Interacts with DCTN1, KIF3A, RAB7A and RILP (PubMed:22261744). Interacts with CLN5 (PubMed:19941651, PubMed:14699076). May interact with HOOK1 (PubMed:15471887). Interacts with KCNIP3; this interaction is disrupted by intracellular increase of calcium level (PubMed:17189291). Interacts with TPP1, CLN6 and CLN8 (PubMed:17237713). Interacts with MYH10; this interaction may play a role in regulation of cytoskeleton organization (PubMed:20850431). Interacts with SBDS (PubMed:20015955). Interacts with sodium/potassium-transporting ATPase complex (via ATP1A1) and fodrin heteromer (via SPTAN1); this interaction regulates their localization at the plasma membrane (Probable). Interacts with HSPA5 (Probable). Interacts (via dileucine motif) with AP3D1 and AP1G1; this interaction facilitates lysosomal targeting (PubMed:15598649). Interacts (via dileucine motif) with AP2A2 (PubMed:15598649).
Mao et al suggest that CLN3 has five transmembranes with a long lumenal N-terminus because their antibody does not immunoprecipitate the N-terminus in the presence of microsomes.
Mediates microtubule-dependent, anterograde transport connecting the Golgi network, endosomes, autophagosomes, lysosomes and plasma membrane, and participates in several cellular processes such as regulation of lysosomal pH, lysosome protein degradation, receptor-mediated endocytosis, autophagy, transport of proteins and lipids from the TGN, apoptosis and synaptic transmission (PubMed:10924275, PubMed:18817525, PubMed:18317235, PubMed:22261744, PubMed:15471887, PubMed:20850431). Facilitates the proteins transport from trans-Golgi network (TGN)-to other membrane compartments such as transport of microdomain-associated proteins to the plasma membrane, IGF2R transport to the lysosome where it regulates the CTSD release leading to regulation of CTSD maturation and thereby APP intracellular processing (PubMed:10924275, PubMed:18817525). Moreover regulates CTSD activity in response to osmotic stress (PubMed:23840424, PubMed:28390177). Also binds galactosylceramide and transports it from the trans Golgi to the rafts, which may have immediate and downstream effects on cell survival by modulating ceramide synthesis (PubMed:18317235). At the plasma membrane, regulates actin-dependent events including filopodia formation, cell migration, and pinocytosis through ARF1-CDC42 pathway and also the cytoskeleton organization through interaction with MYH10 and fodrin leading to the regulation of the plasma membrane association of Na+, K+ ATPase complex (PubMed:20850431). Regulates synaptic transmission in the amygdala, hippocampus, and cerebellum through regulation of synaptic vesicles density and their proximity to active zones leading to modulation of short-term plasticity and age-dependent anxious behavior, learning and memory (By similarity). Regulates autophagic vacuoles (AVs) maturation by modulating the trafficking between endocytic and autophagolysosomal/lysosomal compartments, which involves vesicle fusion leading to regulation of degradation process (By similarity). Participates also in cellular homeostasis of compounds such as, water, ions, amino acids, proteins and lipids in several tissue namely in brain and kidney through regulation of their transport and synthesis (PubMed:17482562).
Phosphorylated on both serine and threonine residues by PKA, PKG and CK2.
The C-terminal (153-438) mediates KCNIP3 interaction and the cytoprotective activity (PubMed:17189291). the dileucine motif mediates AP1G1 and AP3D1 interaction (PubMed:15598649).
Embryonic stem (ES) cell-specific transcription factor required to regulate ES cell pluripotency. Binds telomeres and plays a key role in genomic stability in ES cells by regulating telomere elongation. Acts as an activator of spontaneous telomere sister chromatid exchange (T-SCE) and telomere elongation in undifferentiated ES cells (By similarity).
Able to form oligomers (By similarity). Interacts with ODAD1 (PubMed:30148830).
Expressed in nasal respiratory epithelium and in the sperm.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (PubMed:36191189). May play a role in the control of meiotic division and germ cell differentiation through regulation of pairing and recombination during meiosis. Required for sperm flagella assembly (By similarity). May play a role in the assembly and function of the outer dynein arm-docking complex (ODA-DC). ODA-DC mediates outer dynein arms (ODA) binding onto the axonemal doublet microtubules (PubMed:30148830).
Belongs to the DNA mismatch repair MutS family. MSH3 subfamily.
Component of the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1 (PubMed:26300262). Heterodimer consisting of MSH2-MSH3 (MutS beta) (PubMed:8942985). Forms a ternary complex with MutL alpha (MLH1-PMS1). Interacts with EXO1 (PubMed:11427529). Interacts with MCM9 (PubMed:26300262).
Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS beta which binds to DNA mismatches thereby initiating DNA repair. When bound, the MutS beta heterodimer bends the DNA helix and shields approximately 20 base pairs. MutS beta recognizes large insertion-deletion loops (IDL) up to 13 nucleotides long. After mismatch binding, forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis.
(Microbial infection) Interacts with herpes simplex virus 1 UL46.
In response to a variety of growth factors, isoform p46Shc and isoform p52Shc bind to phosphorylated Trk receptors through their phosphotyrosine binding (PID) and/or SH2 domains. The PID and SH2 domains bind to specific phosphorylated tyrosine residues in the Asn-Pro-Xaa-Tyr(P) motif of the Trk receptors. Isoform p46Shc and isoform p52Shc are in turn phosphorylated on three tyrosine residues within the extended proline-rich domain. These phosphotyrosines act as docking site for GRB2 and thereby are involved in Ras activation (By similarity).
Interacts with CPNE3; this interaction may mediate the binding of CPNE3 with ERBB2 (PubMed:20010870). Interacts with the NPXY motif of tyrosine-phosphorylated IGF1R and INSR in vitro via the PID domain. Once activated, binds to GRB2. Interacts with tyrosine-phosphorylated CD3T and DDR2. Interacts with the N-terminal region of SH2B2. Interacts with phosphorylated LRP1 and IRS4. Interacts with INPP5D/SHIP1 and INPPL1/SHIP2. Interacts with TRIM31. Interacts with PTPN6/SHP (tyrosine phosphorylated). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTT (By similarity). Interacts with ALK, GAB2, GRB7 and KIT. Interacts with FLT4 (tyrosine-phosphorylated). Interacts with EPHB1 and GRB2; activates the MAPK/ERK cascade to regulate cell migration. Interacts with PDGFRB (tyrosine-phosphorylated). Interacts with ERBB4. Interacts with TEK/TIE2 (tyrosine-phosphorylated). Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; in a phosphotyrosine-dependent manner. Interacts with PTK2/FAK1. Interacts with CEACAM1; this interaction is CEACAM1-phosphorylation-dependent and mediates interaction with EGFR or INSR resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 pathway (By similarity). Interacts (via PID domain) with PEAK1 (when phosphorylated at 'Tyr-1188') (PubMed:23846654, PubMed:35687021). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (PubMed:23846654).
Phosphorylated by activated epidermal growth factor receptor. Phosphorylated in response to FLT4 and KIT signaling. Isoform p46Shc and isoform p52Shc are phosphorylated on tyrosine residues of the Pro-rich domain. Isoform p66Shc is phosphorylated on Ser-36 by PRKCB upon treatment with insulin, hydrogen peroxide or irradiation with ultraviolet light (By similarity). Tyrosine phosphorylated in response to FLT3 signaling (By similarity). Tyrosine phosphorylated by activated PTK2B/PYK2 (By similarity). Tyrosine phosphorylated by ligand-activated ALK. Tyrosine phosphorylated by ligand-activated PDGFRB. Tyrosine phosphorylated by TEK/TIE2. May be tyrosine phosphorylated by activated PTK2/FAK1; tyrosine phosphorylation was seen in an astrocytoma biopsy, where PTK2/FAK1 kinase activity is high, but not in normal brain tissue. Isoform p52Shc dephosphorylation by PTPN2 may regulate interaction with GRB2.
Regulated by epigenetic modifications of its promoter region.
Signaling adapter that couples activated growth factor receptors to signaling pathways. Participates in a signaling cascade initiated by activated KIT and KITLG/SCF. Isoform p46Shc and isoform p52Shc, once phosphorylated, couple activated receptor tyrosine kinases to Ras via the recruitment of the GRB2/SOS complex and are implicated in the cytoplasmic propagation of mitogenic signals. Isoform p46Shc and isoform p52Shc may thus function as initiators of the Ras signaling cascade in various non-neuronal systems. Isoform p66Shc does not mediate Ras activation, but is involved in signal transduction pathways that regulate the cellular response to oxidative stress and life span. Isoform p66Shc acts as a downstream target of the tumor suppressor p53 and is indispensable for the ability of stress-activated p53 to induce elevation of intracellular oxidants, cytochrome c release and apoptosis. The expression of isoform p66Shc has been correlated with life span (By similarity). Participates in signaling downstream of the angiopoietin receptor TEK/TIE2, and plays a role in the regulation of endothelial cell migration and sprouting angiogenesis.
Widely expressed. Expressed in neural stem cells but absent in mature neurons.
Acts on GalNAc. Also acts as a galactokinase when galactose is present at high concentrations. May be involved in a salvage pathway for the reutilization of free GalNAc derived from the degradation of complex carbohydrates.
Belongs to the GHMP kinase family. GalK subfamily.
4-guanidinobutyrate and guanidinoethyl sulfonate inhibit the transport activity.
Extracellular pH-and Na(+)-sensitive low-affinity creatine transporter (PubMed:31784090). Functions also as a pH-independent carnitine efflux transporter (PubMed:21886157).
A chromosomal aberration involving BCR has been found in patients with chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with ABL1. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
Autophosphorylated. Phosphorylated by FES/FPS on tyrosine residues, leading to down-regulation of the BCR kinase activity. Phosphorylation at Tyr-177 by HCK is important for interaction with GRB2.
Homotetramer. Interacts with PDZK1 (PubMed:15494376). May interact with CCPG1 (By similarity). Interacts with FES/FPS, ABL1, PIK3R1 and GRB2 (PubMed:15302586, PubMed:1712671, PubMed:9407116). Interacts with HCK (PubMed:9407116). Interacts with SH2D5 (PubMed:25331951). Interacts with DLG4 (PubMed:20962234).
Protein with a unique structure having two opposing regulatory activities toward small GTP-binding proteins. The C-terminus is a GTPase-activating protein (GAP) domain which stimulates GTP hydrolysis by RAC1, RAC2 and CDC42. Accelerates the intrinsic rate of GTP hydrolysis of RAC1 or CDC42, leading to down-regulation of the active GTP-bound form (PubMed:7479768, PubMed:1903516, PubMed:17116687). The central Dbl homology (DH) domain functions as guanine nucleotide exchange factor (GEF) that modulates the GTPases CDC42, RHOA and RAC1. Promotes the conversion of CDC42, RHOA and RAC1 from the GDP-bound to the GTP-bound form (PubMed:7479768, PubMed:23940119). The amino terminus contains an intrinsic kinase activity (PubMed:1657398). Functions as an important negative regulator of neuronal RAC1 activity (By similarity). Regulates macrophage functions such as CSF1-directed motility and phagocytosis through the modulation of RAC1 activity (PubMed:17116687). Plays a major role as a RHOA GEF in keratinocytes being involved in focal adhesion formation and keratinocyte differentiation (PubMed:23940119).
The DH domain is involved in interaction with CCPG1.
The amino terminus contains an intrinsic kinase activity. The central Dbl homology (DH) domain functions as guanine nucleotide exchange factor (GEF) that modulates the GTPases CDC42, RHOA and RAC1. Promotes the conversion of CDC42, RHOA and RAC1 from the GDP-bound to the GTP-bound form. The C-terminus is a Rho-GAP domain which stimulates GTP hydrolysis by RAC1, RAC2 and CDC42. The protein has a unique structure having two opposing regulatory activities toward small GTP-binding proteins.
The region involved in binding to ABL1 SH2-domain is rich in serine residues and needs to be Ser/Thr phosphorylated prior to SH2 binding. This region is essential for the activation of the ABL1 tyrosine kinase and transforming potential of the chimeric BCR-ABL oncogene.
Expression in poorly metastatic human melanoma cell lines; no expression in highly metastatic human melanoma cell lines.
High expression in kidney medulla, placenta and spleen; low in kidney cortex, liver, prostate and gut. Not expressed in normal skin, expression is high in melanocytes and in 3 out of 11 melanoma metastases tested.
Negatively regulates TGF-beta signaling.
The N- and C-terminal domains are separated by a 2-repeat G-Q region.
Transcription factor. Plays a role in the epithelialization of somitic mesoderm and in the development of cardiac mesoderm. Defines the rostrocaudal patterning of the somites by participating in distinct Notch pathways (By similarity).
Belongs to the nuclear hormone receptor family. NR4 subfamily.
Expressed in a number of cell lines of T-cell, B-cell and fibroblast origin. Strong expression in brain tissue.
Interacts with SFPQ, NCOR2, SIN3A and HADC1. The interaction with NCOR2 increases in the absence of PITX3. Interacts with PER2 (By similarity).
Interacts with SFPQ, NCOR2, SIN3A and HADC1. The interaction with NCOR2 increases in the absence of PITX3. Interacts with PER2.
Rapidly and only very transiently expressed after cell activation, during the G0-G1 transition of the cell cycle.
Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development (PubMed:17184956, PubMed:15716272). It is crucial for expression of a set of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons (By similarity).
the ligand-binding domain (LBD) contains no cavity as a result of the tight packing of side chains from several bulky hydrophobic residues in the region normally occupied by ligands. NR4A2 lacks a 'classical' binding site for coactivators (PubMed:12774125).
Expressed in both pancreatic alpha- and beta-cells (at protein level). Expressed at higher levels in the pancreas than other somatostatin receptors. Also expressed in the cerebrum and kidney and, in lesser amounts, in the jejunum, colon and liver. In the developing nervous system, expressed in the cortex where it is located in the preplate at early stages and is enriched in the outer part of the germinal zone at later stages. In the cerebellum, expressed in the deep part of the external granular layer at gestational week 19. This pattern persists until birth but disappears at adulthood.
Homodimer and heterodimer with SSTR3 and SSTR5. Heterodimerization with SSTR3 inactivates SSTR3 receptor function. Heterodimerization with SSTR5 is enhanced by agonist stimulation of SSTR2 and increases SSTR2 cell growth inhibition activity. Following agonist stimulation, homodimers dissociate into monomers which is required for receptor internalization. Interacts with beta-arrestin; this interaction is necessary for receptor internalization and is destabilized by heterodimerization with SSTR5 which results in increased recycling of SSTR2 to the cell surface. Interacts (via C-terminus) with SHANK1 (via PDZ domain).
Phosphorylated on serine and threonine residues in response to agonist stimulation, leading to receptor desensitization and rapid internalization. Phosphorylated to a greater extent on serine than threonine residues. Threonine phosphorylation is required for arrestin binding and receptor endocytosis but is not necessary for desensitization (By similarity).
Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and PLC via pertussis toxin insensitive as well as sensitive G proteins. Inhibits calcium entry by suppressing voltage-dependent calcium channels. Acts as the functionally dominant somatostatin receptor in pancreatic alpha- and beta-cells where it mediates the inhibitory effect of somatostatin-14 on hormone secretion. Inhibits cell growth through enhancement of MAPK1 and MAPK2 phosphorylation and subsequent up-regulation of CDKN1B. Stimulates neuronal migration and axon outgrowth and may participate in neuron development and maturation during brain development. Mediates negative regulation of insulin receptor signaling through PTPN6. Inactivates SSTR3 receptor function following heterodimerization.
Transcriptional regulator with a possible role in patterning of mesoderm during development.
May play a role in copper homeostasis. Can bind one Cu(1+) per subunit.
A chromosomal aberration involving SEPTIN11 may be a cause of chronic neutrophilic leukemia. Translocation t(4;11)(q21;q23) with KMT2A/MLL1.
Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. Septin GTPase family.
Filament-forming cytoskeletal GTPase. May play a role in cytokinesis (Potential). May play a role in the cytoarchitecture of neurons, including dendritic arborization and dendritic spines, and in GABAergic synaptic connectivity (By similarity). During Listeria monocytogenes infection, not required for the bacterial entry process, but restricts its efficacy.
Septins polymerize into heterooligomeric protein complexes that form filaments, and can associate with cellular membranes, actin filaments and microtubules. Forms homooligomers. GTPase activity is required for filament formation. Interacts with SEPTIN7, SEPTIN9 and SEPTIN12.
Septins polymerize into heterooligomeric protein complexes that form filaments.
Detected in prenatal liver nuclear extracts (12.4-27 weeks estimated gestational age). Not detected in postnatal liver samples.
Expressed in erythroleukemia and hepatoma cell lines and in liver and pancreas. Not expressed in any other cell lines or tissues examined.
Transcription factor that is thought to act as a 'pioneer' factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites (By similarity). Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis; binds to and activates transcription from the G6PC1 promoter. Binds to the CYP3A4 promoter and activates its transcription in cooperation with CEBPA. Binds to the CYP3A7 promoter together with members of the CTF/NF-I family. Involved in regulation of neuronal-specific transcription. May be involved in regulation of spermatogenesis.
Forms homooligomers (By similarity). Interacts (via C-terminal PDZ domain) with MYO15A; this interaction is necessary for localization of WHRN to stereocilia tips (By similarity). Interacts (via C-terminal PDZ domain) with MPP1/p55 (PubMed:17584769). Interacts with LRRC4C/NGL1. Interacts with MYO7A. Interacts with RPGR. Interacts with EPS8 (By similarity). Interacts with CASK (By similarity). Interacts with CIB2 (PubMed:23023331). Component of USH2 complex, composed of ADGRV1, PDZD7, USH2A and WHRN. Interacts (via PDZ domains) with PDZD7; the interaction is direct. Interacts (via N-terminal PDZ domain) with USH2A (via cytoplasmic region) (PubMed:16434480). Interacts with ADGRV1/MASS1 (via cytoplasmic region) (PubMed:16434480).
Involved in hearing and vision as member of the USH2 complex. Necessary for elongation and maintenance of inner and outer hair cell stereocilia in the organ of Corti in the inner ear. Involved in the maintenance of the hair bundle ankle region, which connects stereocilia in cochlear hair cells of the inner ear. In retina photoreceptors, required for the maintenance of periciliary membrane complex that seems to play a role in regulating intracellular protein transport.
A cysteine-rich region homologous to part of the regulatory domain of protein kinase C may be important in interactions of this protein with the lipid bilayer.
Postsynaptic protein required for clustering of nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction. It may link the receptor to the underlying postsynaptic cytoskeleton, possibly by direct association with actin or spectrin.
Ubiquitinated by the BCR(KLHL8) complex, leading to its degradation.
Component of the EKC/KEOPS complex composed of at least GON7, TP53RK, TPRKB, OSGEP and LAGE3; the whole complex dimerizes.
Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine (PubMed:22912744, PubMed:27903914). The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37 (PubMed:22912744, PubMed:27903914). LAGE3 functions as a dimerization module for the complex (PubMed:22912744, PubMed:27903914).
Expressed in the apical radial glial cells in the developing brain.
Nucleolar protein that is involved in ribosomal RNA (rRNA) processing (PubMed:33199730). Also plays a role in primary cilia resorption, and cell cycle progression in neurogenesis and neocortex development (PubMed:33199730). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Interacts with NOL6; required for NOL6 localization to nucleolus.
Detected in T-cell lines and fetal and adult lung.
May have a role in hematopoietic cell differentiation.
Belongs to the prickle / espinas / testin family.
Expressed in a broad range of normal tissues as well as in hepatocellular carcinoma, breast cancer and prostate cancer tissues.
Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (By similarity).
Monoubiquitination of Lys-120 (H2AXK119ub) gives a specific tag for epigenetic transcriptional repression. Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties (By similarity).
Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription (By similarity).
S-adenosyl-L-methionine-dependent methyltransferase that mediates mRNA cap2 2'-O-ribose methylation to the 5'-cap structure of mRNAs. Methylates the ribose of the second nucleotide of a m(7)GpppG-capped mRNA and small nuclear RNA (snRNA) (cap0) to produce m(7)GpppRmpNm (cap2). Recognizes a guanosine cap on RNA independently of its N(7) methylation status. Display cap2 methylation on both cap0 and cap1. Displays a preference for cap1 RNAs.
As the regulatory component of the serine/threonine-protein phosphatase 2A (PP2A) holoenzyme, modulates substrate specificity, subcellular localization, and responsiveness to phosphorylation. The phosphorylated form mediates the interaction between PP2A and AKT1, leading to AKT1 dephosphorylation.
By retinoic acid; in neuroblastoma cell lines.
Component of the serine/threonine-protein phosphatase 2A complex (PP2A). This complex consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant scaffold subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules (PubMed:23135275). Interacts with SGO1 (PubMed:16541025). Interacts with AKT1 (PubMed:21329884). Interacts with CUL3 and KLHL15; this interaction leads to proteasomal degradation (PubMed:23135275).
Ubiquitinated by E3 CUL3-KLHL15 complex; this modification leads to proteasomal degradation.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRR1 sub-subfamily.
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. Rho-1 GABA receptor could play a role in retinal neurotransmission.
Generally pentameric. There are five types of GABA(A) receptor chains: alpha, beta, gamma, delta, and rho. Interacts with SQSTM1 (By similarity).
Highly expressed in the retina and in a lesser extent in brain, lung and thymus.
Autophosphorylated at the conserved aspartate of the P-type ATPase signature sequence.
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IV subfamily.
Catalytic component of a P4-ATPase flippase complex, which catalyzes the hydrolysis of ATP coupled to the transport of glucosylceramide (GlcCer) from the outer to the inner leaflet of lysosome membranes. Plays an important role in the maintenance of lysosome membrane integrity and function in cortical neurons.
Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit ATP10B and an accessory beta subunit TMEM30A.
Expressed in predominantly in brain structures including medulla oblongata, substantia nigra and basal ganglia. Expressed in the gastrointestinal system with highest levels in the small intestine and colon. Also expressed at low levels in testis and thymus.
Fatty acylated. Heavily palmitoylated in the cysteine string motif (By similarity).
Forms a complex with G(alpha)z/i2 subunits and mu-opioid receptors; the formation of this complex results in mu-opioid receptor desensitization. Interacts with OPRM1 (By similarity).
Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Binds selectively to G(z)-alpha and G(alpha)-i2 subunits, accelerates their GTPase activity and regulates their signaling activities. The G(z)-alpha activity is inhibited by the phosphorylation and palmitoylation of the G-protein. Negatively regulates mu-opioid receptor-mediated activation of the G-proteins (By similarity).
Isoform 5 is expressed in brain at high levels in the caudate nucleus and temporal lobe.
N- and O-glycosylated in synapsomal membranes.
Serine phosphorylated in synapsomal membranes.
Sumoylated with SUMO1 and SUMO2 in synaptosomes. The sumoylated forms act as a scaffold for sequestering mu-opioid receptor-activated G(alpha) subunits (By similarity).
Enhances the transcriptional activities of several nuclear receptors. Involved in the coactivation of different nuclear receptors, such as ESR1, THRB, PPARG and RARA.
Highly expressed in brain. Weakly expressed in mammary gland, ovary, uterus, prostate, stomach, bladder, spinal cord and pancreas. Expressed in cancer cell line.
Interacts with ESR1, ESR2A, ESR2B, THRB, PPARG and RARA in a ligand-inducible manner. Interacts with the heterodimer AHR-ARNT.
Catalyzes the phosphorylation of nicotinamide riboside (NR) and nicotinic acid riboside (NaR) to form nicotinamide mononucleotide (NMN) and nicotinic acid mononucleotide (NaMN). The enzyme also phosphorylates the antitumor drugs tiazofurin and 3-deazaguanosine.
G proteins are composed of 3 units, alpha, beta and gamma.
Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.
Expressed in cornea. Mainly expressed in brain. Also expressed in spinal cord and trachea.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues of keratan (PubMed:11352640, PubMed:11278593, PubMed:12218059, PubMed:17690104). Cooperates with B4GALT4 galactosyltransferase and B3GNT7 N-acetylglucosaminyltransferase to construct and elongate the sulfated disaccharide unit [->3Galbeta1->4(6-sulfoGlcNAcbeta)1->] within keratan sulfate polymer. Involved in biosynthesis of keratan sulfate in cornea, with an impact on proteoglycan fibril organization and corneal transparency (PubMed:17690104, PubMed:11278593, PubMed:12218059). Involved in sulfation of endothelial mucins such as GLYCAM1 (PubMed:11352640).
The disease is caused by variants affecting the gene represented in this entry. CHST6 homozygous missense mutations have been observed in patients with macular corneal dystrophy type I, while type II patients show a large deletion and replacement in the upstream region of CHST6. The only missense mutation for type II is Cys-50, which is heterozygous with a replacement in the upstream region on the other allele of CHST6.
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1E subfamily.
Expressed in neuronal tissues and in kidney.
Interacts with EFHC1. Voltage-dependent calcium channels are multisubunit complexes, consisting of alpha-1, alpha-2, beta and delta subunits in a 1:1:1:1 ratio. The channel activity is directed by the pore-forming and voltage-sensitive alpha-1 subunit. In many cases, this subunit is sufficient to generate voltage-sensitive calcium channel activity. The auxiliary subunits beta and alpha-2/delta linked by a disulfide bridge regulate the channel activity.
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells (PubMed:30343943). They are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1E gives rise to R-type calcium currents. R-type calcium channels belong to the 'high-voltage activated' (HVA) group and are blocked by nickel. They are however insensitive to dihydropyridines (DHP). Calcium channels containing alpha-1E subunit could be involved in the modulation of firing patterns of neurons which is important for information processing.
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1E gives rise to R-type calcium currents.
Belongs to the G-protein coupled receptor 3 family. TAS1R subfamily.
Putative taste receptor. TAS1R1/TAS1R3 responds to the umami taste stimulus (the taste of monosodium glutamate). Sequence differences within and between species can significantly influence the selectivity and specificity of taste responses.
Interacts with POU5F1/OCT4 and SOX2 (By similarity). Interacts with MUC1 (via the C-terminal domain) (PubMed:17308127). Interacts with MEIS2 isoform 4 and PBX1 isoform PBX1a (PubMed:21746878). Interacts with ZNF296 (By similarity). Interacts with GLIS1 (PubMed:21654807). Interacts with BTRC; this interaction leads to KLF4 ubiquitination and subsequent degradation (By similarity). Interacts with IPO7; the interaction facilitates nuclear translocation of KLF4 in dental papilla cells (By similarity).
POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4 are the four Yamanaka factors. When combined, these factors are sufficient to reprogram differentiated cells to an embryonic-like state designated iPS (induced pluripotent stem) cells. iPS cells exhibit the morphology and growth properties of ES cells and express ES cell marker genes.
Polyglutamylated by TTLL1 and TTLL4 at Glu-411, which inhibits KLF4 binding with E3 ligase component BTRC, thereby impeding ubiquitination. Deglutamylated by CCP1 and CCP6; deglutamylation promotes KLF4 ubiquitination. KLF4 glutamylation state plays a critical role in the regulation of its function in cell reprogramming, pluripotency maintenance and embryogenesis.
Transcription factor; can act both as activator and as repressor. Binds the 5'-CACCC-3' core sequence. Binds to the promoter region of its own gene and can activate its own transcription. Regulates the expression of key transcription factors during embryonic development. Plays an important role in maintaining embryonic stem cells, and in preventing their differentiation. Required for establishing the barrier function of the skin and for postnatal maturation and maintenance of the ocular surface. Involved in the differentiation of epithelial cells and may also function in skeletal and kidney development. Contributes to the down-regulation of p53/TP53 transcription.
Ubiquitinated. 'Lys-48'-linked ubiquitinated and targeted for proteasomal degradation by the SCF(BTRC) E3 ubiquitin-protein ligase complex, thereby negatively regulating cell pluripotency maintenance and embryogenesis.
Activated by phospholipids including cardiolipin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and phosphatidylserine.
Contains the RXG motif, which is important for substrate binding and prenyltransferase activity. The catalytic site at NUS1-DHDDS interface accomodates both the allylic and the homoallylic IPP substrates to the S1 and S2 pockets respectively. The beta-phosphate groups of IPP substrates form hydrogen bonds with the RXG motif of NUS1 and four conserved residues of DHDDS (Arg-85, Arg-205, Arg-211 and Ser-213), while the allylic isopentenyl group is pointed toward the hydrophobic tunnel of the S1 pocket where the product elongation occurs.
Forms an active dehydrodolichyl diphosphate synthase complex with DHDDS (NUS1-DHDDS) (PubMed:28842490, PubMed:19723497, PubMed:25066056, PubMed:32817466). Interacts with NPC2 (PubMed:21572394).
NUS1 seems to exist in two topological orientations, a minor glycosylated species with its C-terminus oriented towards the lumen regulating NPC2 stability, and a major fraction oriented with its C-terminus directed towards the cytosol where it regulates cis-IPTase activity.
With DHDDS, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery. Both subunits contribute to enzymatic activity, i.e. condensation of multiple copies of isopentenyl pyrophosphate (IPP) to farnesyl pyrophosphate (FPP) to produce dehydrodolichyl diphosphate (Dedol-PP), a precursor of dolichol phosphate which is utilized as a sugar carrier in protein glycosylation in the endoplasmic reticulum (ER) (PubMed:21572394, PubMed:25066056, PubMed:28842490, PubMed:32817466). Synthesizes long-chain polyprenols, mostly of C95 and C100 chain length (PubMed:32817466). Regulates the glycosylation and stability of nascent NPC2, thereby promoting trafficking of LDL-derived cholesterol. Acts as a specific receptor for the N-terminus of Nogo-B, a neural and cardiovascular regulator (PubMed:16835300).
Belongs to the AB hydrolase superfamily. Epoxide hydrolase family.
Autophosphorylated. Binding of FGF family members together with heparan sulfate proteoglycan or heparin promotes receptor dimerization and autophosphorylation on tyrosine residues. Autophosphorylation occurs in trans between the two FGFR molecules present in the dimer and proceeds in a highly ordered manner. Initial autophosphorylation at Tyr-653 increases the kinase activity by a factor of 50 to 100. After this, Tyr-583 becomes phosphorylated, followed by phosphorylation of Tyr-463, Tyr-766, Tyr-583 and Tyr-585. In a third stage, Tyr-654 is autophosphorylated, resulting in a further tenfold increase of kinase activity. Phosphotyrosine residues provide docking sites for interacting proteins and so are crucial for FGFR1 function and its regulation.
Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily.
Chromosomal aberrations involving FGFR1 are a cause of chromosome 8p11 myeloproliferative syndrome. Translocation t(8;13)(p11;q12) with ZMYM2. Translocation t(6;8)(q27;p11) with CEP43. Insertion ins(12;8)(p11;p11p22) with FGFR1OP2. Translocation t(8;9)(p12;q33) with CNTRL. Translocation t(2;8)(q12;p11) with RANBP2. Chromosome 8p11 myeloproliferative syndrome is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins FGFR1OP2-FGFR1, CEP43-FGFR1 or FGFR1-CEP43 may exhibit constitutive kinase activity and be responsible for the transforming activity. The fusion protein CNTRL-FGFR1 is found in the cytoplasm, exhibits constitutive kinase activity and may be responsible for the transforming activity.
Detected in astrocytoma, neuroblastoma and adrenal cortex cell lines. Some isoforms are detected in foreskin fibroblast cell lines, however isoform 17, isoform 18 and isoform 19 are not detected in these cells.
Monomer. Homodimer after ligand binding. Interacts predominantly with FGF1 and FGF2, but can also interact with FGF3, FGF4, FGF5, FGF6, FGF8, FGF10, FGF19, FGF21, FGF22 and FGF23 (in vitro) (PubMed:1697263, PubMed:1722683, PubMed:8663044, PubMed:9655399, PubMed:12181353, PubMed:16597617, PubMed:17623664). Ligand specificity is determined by tissue-specific expression of isoforms, and differences in the third Ig-like domain are crucial for ligand specificity. Affinity for fibroblast growth factors (FGFs) is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Likewise, KLB increases the affinity for FGF19, FGF21 and FGF23 (PubMed:19966287). Interacts (phosphorylated on Tyr-766) with PLCG1 (via SH2 domains) (PubMed:1656221, PubMed:1379697, PubMed:21765395). Interacts with FRS2 (PubMed:21765395). Interacts with RPS6KA1 (PubMed:15117958). Interacts (via C-terminus) with NEDD4 (via WW3 domain) (PubMed:21765395). Interacts with KL (By similarity). Interacts with SHB (via SH2 domain) (PubMed:12181353). Interacts with GRB10 (PubMed:10454568). Interacts with ANOS1; this interaction does not interfere with FGF2-binding to FGFR1, but prevents binding of heparin-bound FGF2 (PubMed:19696444). Interacts with SOX2 and SOX3. Interacts with FLRT1, FLRT2 and FLRT3 (By similarity). Found in a ternary complex with FGF1 and ITGAV:ITGB3 (PubMed:20422052, PubMed:18441324).
N-glycosylated in the endoplasmic reticulum. The N-glycan chains undergo further maturation to an Endo H-resistant form in the Golgi apparatus.
Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by sequential autophosphorylation on tyrosine residues. Inhibited by ARQ 069; this compound maintains the kinase in an inactive conformation and inhibits autophosphorylation. Inhibited by PD173074.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in FGFR1 also have a mutation other HH-associated genes including DUSP6, FGF8, FGF17, FLRT3, GNRH1, GNRHR, HS6ST1, IL17RD, ANOS1, KISS1R, NSMF, PROKR2, SPRY4 and TACR3 (PubMed:23643382).
The second and third Ig-like domains directly interact with fibroblast growth factors (FGF) and heparan sulfate proteoglycans. Isoforms lacking the first Ig-like domain have higher affinity for fibroblast growth factors (FGF) and heparan sulfate proteoglycans than isoforms with all three Ig-like domains.
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation.
Ubiquitinated. FGFR1 is rapidly ubiquitinated by NEDD4 after autophosphorylation, leading to internalization and lysosomal degradation. CBL is recruited to activated FGFR1 via FRS2 and GRB2, and mediates ubiquitination and subsequent degradation of FGFR1.
Gamma-carboxylation is controversial. Gamma-carboxyglutamated; gamma-carboxyglutamate residues are formed by vitamin K dependent carboxylation; this may be required for calcium binding (PubMed:18450759). According to a more recent report, does not contain vitamin K-dependent gamma-carboxyglutamate residues (PubMed:26273833).
Homodimer (PubMed:29754429). Interacts with BMP1 and fibronectin.
Induces cell attachment and spreading and plays a role in cell adhesion (PubMed:12235007). Enhances incorporation of BMP1 in the fibronectin matrix of connective tissues, and subsequent proteolytic activation of lysyl oxidase LOX (By similarity).
Widely expressed with highest levels in aorta, stomach, lower gastrointestinal tract, placenta, uterus, thyroid tissue and breast. Up-regulated in epithelial ovarian tumors. Not expressed in normal ovaries. Also highly expressed at the tumor periphery of lung carcinoma tissue but not within the tumor. Overexpressed in breast cancers.
Associates with the IFT complex A (IFT-A) (PubMed:20889716, PubMed:27932497). Interacts with SIRT1 (PubMed:35397207).
Expressed at high levels in testis, ovaries, thyroid, and spinal chord.
Negative regulator of the Shh signaling transduction pathway: recruited to primary cilia via association with the IFT complex A (IFT-A) and is required for recruitment of G protein-coupled receptor GPR161 to cilia, a promoter of PKA-dependent basal repression machinery in Shh signaling. Binds to phosphorylated inositide (phosphoinositide) lipids. Both IFT-A- and phosphoinositide-binding properties are required to regulate ciliary G protein-coupled receptor trafficking. During adipogenesis, regulates ciliary trafficking of FFAR4 in preadipocytes.
Identified in the spliceosome B complex (PubMed:28781166). Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:28076346). Present in a spliceosome complex assembled in vitro, and composed of SNRPB2, HPRP8BP and CRNKL1 (PubMed:12084575). Contributes to the binding of stem loop IV of U2 snRNA with SNRPP1 (PubMed:9716128).
Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28502770, PubMed:28781166, PubMed:28076346). Associated with sn-RNP U2, where it contributes to the binding of stem loop IV of U2 snRNA (PubMed:9716128).
Patients with systemic lupus erythematosus produce antibodies which interact with snRNP proteins.
Part of BBSome complex, that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10. Interacts with PCM1. Interacts with CCDC28B. Interacts with PKD1 (PubMed:24939912).
The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia. The BBSome complex is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Firstly the BBSome associates with the ciliary membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and promotes docking and fusion of carrier vesicles to the base of the ciliary membrane. The BBSome complex, together with the LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. Required for proper BBSome complex assembly and its ciliary localization.
Auxiliary protein of the large-conductance, voltage and calcium-activated potassium channel (BK alpha). Modulates gating properties by producing a marked shift in the BK channel's voltage dependence of activation in the hyperpolarizing direction, and in the absence of calcium.
Mainly expressed in adrenal gland, thymus and skeletal muscle.
The transmembrane domain is necessary for interaction with KCNMA1.
Highest expression in liver. Expressed in pancreas, kidney, intestine, testis, fibroblasts and lymphoblasts. Very low expression in brain and skeletal muscle. The relative expression of isoform 2 (at mRNA level) is highest in heart (30%), skeletal muscle (22%), and brain (14%).
Homodimer; disulfide-linked. Can also form homotetramers.
Mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase that catalyzes a cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in ketogenesis. Terminal step in leucine catabolism. Ketone bodies (beta-hydroxybutyrate, acetoacetate and acetone) are essential as an alternative source of energy to glucose, as lipid precursors and as regulators of metabolism.
Stimulated by reducing agents such as dithiothreitol (DTT).
The transcript is not translated, but would result in a catalytically impaired product if it was.
Very low expression. The transcript is not translated, but would result in a catalytically inactive product if it was.
(Microbial infection) Interacts with Epstein-Barr virus LMP2A.
(Microbial infection) Interacts with Human cytomegalovirus (HCMV) protein UL42; this interaction induces ubiquitination and degradation of ITCH.
(Microbial infection) Interacts with ebola virus protein VP40; this interaction is required for efficient viral egress from the infected cell.
(Microbial infection) Interacts with herpesvirus 1 (HHV-1) UL56 protein; this interaction induces ubiquitination and probably degradation of ITCH.
(Microbial infection) Interacts with herpesvirus 2 (HHV-2) UL56 protein.
(Microbial infection) Interacts with herpesvirus 6A (HHV-6A) U24 protein.
(Microbial infection) Interacts with influenza A virus matrix protein 1.
(Microbial infection) Interacts with varicella-zoster virus (VZV) Orf0 protein.
Activated by NDFIP1- and NDFIP2-binding (PubMed:25631046). Activated by PI4K2A-binding (PubMed:23146885). Inhibited by DTX3L-binding (PubMed:24790097). Inhibited by N4BP1 binding (By similarity).
Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:14602072, PubMed:17028573, PubMed:16387660, PubMed:18718448, PubMed:18718449, PubMed:11046148, PubMed:19592251, PubMed:19116316, PubMed:19881509, PubMed:20491914, PubMed:20392206, PubMed:20068034, PubMed:23146885, PubMed:24790097, PubMed:25631046, PubMed:15051726). Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation (PubMed:17028573, PubMed:18718448, PubMed:19131965, PubMed:19881509). Involved in the control of inflammatory signaling pathways (PubMed:19131965). Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways (PubMed:19131965). Promotes the association of the complex after TNF stimulation (PubMed:19131965). Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains (PubMed:19131965). This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1 (PubMed:19131965). Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (PubMed:19592251). Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response (PubMed:18718448, PubMed:20491914). Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages (PubMed:18718448). Mediates JUN ubiquitination and degradation (By similarity). Mediates JUNB ubiquitination and degradation (PubMed:16387660). Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation (By similarity). Involved in the negative regulation of MAVS-dependent cellular antiviral responses (PubMed:19881509). Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (PubMed:19881509). Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity (PubMed:23146885). Ubiquitinates PI4K2A and negatively regulates its catalytic activity (PubMed:23146885). Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4 to the degradative endocytic pathway following ligand stimulation by ubiquitinating endosomal sorting complex required for transport ESCRT-0 components HGS and STAM (PubMed:14602072, PubMed:23146885, PubMed:34927784). Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (PubMed:17028573, PubMed:18628966, PubMed:23886940). Ubiquitinates SNX9 (PubMed:20491914). Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation (By similarity). Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (PubMed:20068034). Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID (PubMed:20392206). Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). Inhibits the replication of influenza A virus (IAV) via ubiquitination of IAV matrix protein 1 (M1) through 'Lys-48'-linked conjugation resulting in M1 proteasomal degradation (PubMed:30328013). Ubiquitinates NEDD9/HEF1, resulting in proteasomal degradation of NEDD9/HEF1 (PubMed:15051726).
Monomer. Part of a ternary complex composed of SMAD3, ITCH/AIP4 and NEDD9/HEF1; within the complex NEDD9/HEF1 interacts (via N-terminus) with ITCH/AIP4 (via WW domains); the complex mediates ubiquitination and proteasomal degradation of NEDD9/HEF1 (PubMed:15051726). Interacts (via WW domains) with OCNL (By similarity). Interacts (via WW domains) with NOTCH1 (By similarity). Interacts (via WW domains) with JUN (By similarity). Interacts with JUNB; the interaction promotes ITCH-mediated ubiquitination and degradation of JUNB (PubMed:16387660). Interacts with FYN; the interaction phosphorylates ITCH on Tyr-420 decreasing binding of JUNB (PubMed:16387660). Interacts (via WW domain 2) with N4BP1; the interaction inhibits the E3 ubiquitin-protein ligase activity (By similarity). Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes (By similarity). Interacts with ARHGEF7 (PubMed:17652093). Interacts with RNF11 (PubMed:14559117, PubMed:19131965). Interacts (via the WW 1 domain) with NFE2 (via the PXY motif 1); the interaction promotes 'Lys-63'-linked ubiquitination of NFE2, retains it in the cytoplasm and prevents its transactivation activity (PubMed:11318614, PubMed:18718448). Interacts (via WW domains) with CXCR4 (via C-terminus); the interaction depends on CXCR4 phosphorylation (PubMed:19116316). Found in a complex with E3 ligase DTX3L and ESCRT-0 components HGS and STAM (PubMed:24790097). Interacts with DTX3L (via C-terminus); the interaction is increased upon CXCL12 stimulation and inhibits ITCH catalytic activity (the interaction is direct) (PubMed:24790097). Interacts with HGS (PubMed:14602072). Interacts (via WW domains) with PCBP2 within a complex containing ITCH, MAVS and PCBP2 (PubMed:19881509). Interacts (via WW domains) with TXNIP (via C-terminus) (PubMed:20068034). Interacts with p15 BID (PubMed:20392206). Interacts with ERBB4 (PubMed:20858735). Interacts with DTX1 (PubMed:17028573). Interacts with SPART (PubMed:19580544). Interacts with SNX9 and SNX18 (PubMed:20491914). Interacts (via its WW domains) with ATN1 (PubMed:9647693). Interacts (via WW domains) with SGK3 (PubMed:16888620). Interacts with CBLC (PubMed:12226085). Interacts with OTUD7B (PubMed:22179831). Interacts (via WW domain 1,2 and 3) with PI4K2A; the interaction inhibits PI4K2A catalytic activity and promotes ITCH catalytic activity (PubMed:23146885). Interacts with ARRDC4 (PubMed:23236378). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (By similarity). Interacts with UBE2L3; the interaction is mediated by NDFIP1 (PubMed:25632008). Interacts with MAPK8/JNK1 (By similarity). Interacts (via WW domains) with ARRDC1 (via PPxY motifs); the interaction is direct and participates in the recruitment of the ubiquitin-protein ligase ITCH to the NOTCH1 receptor (PubMed:21191027, PubMed:23886940). Interacts (via WW domains) with ARRDC2 (PubMed:21191027). Interacts (via WW domains) with ARRDC3 (PubMed:21191027, PubMed:23886940). Interacts directly with LDLRAD3; this interaction promotes ITCH auto-ubiquitination leading to its degradation (PubMed:26854353). Interacts with ENTREP1; enhances the ubiquitination of CXCR4 by ITCH and its subsequent endocytosis (PubMed:34927784).
Monoubiquitinated (PubMed:19116316). Autopolyubiquitinated with 'Lys-63' linkages which does not lead to protein degradation (PubMed:18718449, PubMed:23146885, PubMed:24790097).
On T-cell activation, phosphorylation by the JNK cascade on serine and threonine residues surrounding the PRR domain accelerates the ubiquitination and degradation of JUN and JUNB. The increased ITCH catalytic activity due to phosphorylation by JNK1 may occur due to a conformational change disrupting the interaction between the PRR/WW motifs domain and the HECT domain and, thus exposing the HECT domain (By similarity). Phosphorylation by FYN reduces interaction with JUNB and negatively controls JUN ubiquitination and degradation.
The WW domain 4 mediates interaction with ENTREP1.
All seven C2 domains associate with lipid membranes in a calcium-dependent manner. Domains C2 1 and 3 have the highest affinity for calcium, the C2 domain 1 seems to be largely unstructured in the absence of bound ligands. The C2 domain 1 from isoform 14 does not bind calcium in the absence of bound phospholipid (PubMed:24239457, PubMed:24461013).
Expressed in skeletal muscle, myoblast, myotube and in the syncytiotrophoblast (STB) of the placenta (at protein level). Ubiquitous. Highly expressed in skeletal muscle. Also found in heart, brain, spleen, intestine, placenta and at lower levels in liver, lung, kidney and pancreas.
Expression in limb tissue from 5-6 weeks embryos; persists throughout development.
Interacts with CACNA1S. Interacts with ANXA1; the interaction is Ca(2+)- and injury state-dependent. Interacts with ANXA2; the interaction is Ca(2+)- and injury state-dependent. Interacts with CACNA1S and PARVB. Interacts with TRIM72/MG53; interaction is required for transport to sites of cell injury during repair patch formation (By similarity). Interacts with RIPOR2; this interaction occurs during early myogenic differentiation (PubMed:24687993). Interacts with CAV3 and PARVB. Interacts with AHNAK; the interaction is direct and Ca(2+)-independent. Interacts with AHNAK2; the interaction is direct and Ca(2+)-independent.
Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion. Plays a role in the sarcolemma repair mechanism of both skeletal muscle and cardiomyocytes that permits rapid resealing of membranes disrupted by mechanical stress (By similarity).
Acts as an accessory subunit for the core Polycomb repressive complex 2 (PRC2), which mediates histone H3K27 (H3K27me3) trimethylation on chromatin leading to transcriptional repression of the affected target gene (PubMed:15225548, PubMed:31959557, PubMed:29499137). Plays a role in nucleosome localization of the PRC2 complex (PubMed:29499137).
Belongs to the AEBP2/jing C2H2-type zinc-finger family.
Self-associates (PubMed:15225548). Associates with the PRC2 complex, which consists of the core components EED, EZH1 or EZH2, SUZ12, and RBBP4, and various combinations of accessory subunits including AEBP2, JARID2, PHF19, MTF2 and EPOP (PubMed:12351676, PubMed:15225548, PubMed:31959557, PubMed:29499137). Found in a monomeric PRC2.2 (class 2) complex consisting of at least SUZ12, RBBP4, AEBP2 and JARID2 (PubMed:29499137). Within the PRC2 complex, interacts directly with SUZ12; competes with PHF19 for SUZ12 binding (PubMed:12351676, PubMed:29499137). Interacts with EED, EZH2, and RBBP4 (PubMed:12351676, PubMed:15225548). May also interact with RBBP7 (PubMed:12351676).
(Microbial infection) In case of infection by cytomegaloviruses, it plays a central role in the export from the ER and subsequent degradation of MHC class I heavy chains via its interaction with US11 viral protein, which recognizes and associates with MHC class I heavy chains. Also participates in the degradation process of misfolded cytomegalovirus US2 protein.
(Microbial infection) Interacts with the cytomegalovirus US11 protein.
Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins (PubMed:15215856, PubMed:33658201). Forms homotetramers which encircle a large channel traversing the endoplasmic reticulum (ER) membrane (PubMed:33658201). This allows the retrotranslocation of misfolded proteins from the ER into the cytosol where they are ubiquitinated and degraded by the proteasome (PubMed:33658201). The channel has a lateral gate within the membrane which provides direct access to membrane proteins with no need to reenter the ER lumen first (PubMed:33658201). May mediate the interaction between VCP and the misfolded protein (PubMed:15215856). Also involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation (PubMed:26565908). By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333).
Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins. May act by forming a channel that allows the retrotranslocation of misfolded proteins into the cytosol where they are ubiquitinated and degraded by the proteasome.
Homotetramer (PubMed:33658201). The four subunits of the tetramer are arranged in a twofold symmetry (PubMed:33658201). Forms heterooligomers with DERL2 and DERL3; binding to DERL3 is poorer than that between DERL2 and DERL3. Interacts (via SHP-box motif) with VCP (PubMed:16289116, PubMed:16186510, PubMed:16186509, PubMed:16449189, PubMed:27714797). Interacts with AMFR, SELENOS, SEL1L, SELENOK and SYVN1, as well as with SEL1L-SYVN1 and VCP-SELENOS protein complexes; this interaction is weaker than that observed between DERL2 and these complexes. Interacts with NGLY1 and YOD1. Does not bind to EDEM1. Interacts with DNAJB9. Interacts with RNF103 (PubMed:15215856, PubMed:16055502, PubMed:16186509, PubMed:16186510, PubMed:16289116, PubMed:16449189, PubMed:18675248, PubMed:19818707, PubMed:22016385). Interacts with HM13 (PubMed:25239945). Interacts with XBP1 isoform 1 (via luminal/ectodomain domain); the interaction obviates the need for ectodomain shedding prior HM13/SPP-mediated XBP1 isoform 1 cleavage (PubMed:25239945). Interacts with the signal recognition particle/SRP and the SRP receptor; in the process of endoplasmic reticulum stress-induced pre-emptive quality control (PubMed:26565908). May interact with UBXN6 (PubMed:19275885). Interacts with ZFAND2B; probably through VCP (PubMed:24160817). Interacts with CCDC47 (By similarity). Interacts with C18orf32 (PubMed:29275994). May interact with TRAM1 (PubMed:19121997).
Cooperates with AGTR2 to inhibit ERK2 activation and cell proliferation. May be required for AGTR2 cell surface expression. Together with PTPN6, induces UBE2V2 expression upon angiotensin-II stimulation. Isoform 1 inhibits breast cancer cell proliferation, delays the progression of mitosis by prolonging metaphase and reduces tumor growth.
Down-regulated in invasive breast carcinomas (at protein level).
Expressed at very low levels in most tissues.
Homodimer. Interacts with AGTR2. Interacts with PTPN6 (By similarity). Isoform 1 associates with microtubules.
The gene represented in this entry may be involved in disease pathogenesis.
Ubiquitously expressed (at protein level). Highly expressed in brain. Down-regulated in ovarian carcinoma, pancreas carcinoma, colon carcinoma and head and neck squamous cell carcinoma (HNSCC). Isoform 1 is the major isoform in most peripheral tissues. Isoform 2 is abundant in most peripheral tissues. Isoform 3 is the major isoform in brain, female reproductive tissues, thyroid and heart. Within brain it is highly expressed in corpus callosum and pons. Isoform 6 is brain-specific, it is the major isoform in cerebellum and fetal brain.
Acetylation modifies enzyme activity in response to alterations of extracellular nutrient availability. Acetylation increased with trichostin A (TSA) or with nicotinamide (NAM). Glucose increases acetylation by about a factor of 3 with decreasing enzyme activity. Acetylation on Lys-288 is decreased on the addition of extra amino acids resulting in activation of enzyme activity.
Belongs to the lyase 1 family. Argininosuccinate lyase subfamily.
Catalyzes the reversible cleavage of L-argininosuccinate to fumarate and L-arginine, an intermediate step reaction in the urea cycle mostly providing for hepatic nitrogen detoxification into excretable urea as well as de novo L-arginine synthesis in nonhepatic tissues (PubMed:11747433, PubMed:11747432, PubMed:9045711, PubMed:22081021, PubMed:2263616). Essential regulator of intracellular and extracellular L-arginine pools. As part of citrulline-nitric oxide cycle, forms tissue-specific multiprotein complexes with argininosuccinate synthase ASS1, transport protein SLC7A1 and nitric oxide synthase NOS1, NOS2 or NOS3, allowing for cell-autonomous L-arginine synthesis while channeling extracellular L-arginine to nitric oxide synthesis pathway (PubMed:22081021).
Enzyme activity is regulated by acetylation.
Homotetramer (PubMed:11747433). Forms tissue-specific complexes with ASS1, SLC7A1, HSP90AA1 and nitric oxide synthase NOS1, NOS2 or NOS3; the complex maintenance is independent of ASL catalytic function (By similarity).
The disease is caused by variants affecting the gene represented in this entry. The phenotype heterogeneity among patients is associated with interallelic complementation resulting in either complete loss of activity or partial regeneration of functional active sites in the heterotetrameric mutant protein.
Higher expression in fetus than in adult.
In fetal skin, highest expression found in cells of mesodermal origin within the dermal papilla of the developing hair shaft. Not detected in epidermis or dermis. In adult skin, weakly expressed within the basal layers of the epidermis. Not expressed in dermis.
May play a role in the scarless healing of cutaneous wounds during the first two trimesters of development.
Belongs to the peptidase S1 family. Elastase subfamily.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Loss-of-function CTRC variants predispose to pancreatitis by diminishing its protective trypsin-degrading activity (PubMed:18059268). They cause loss of function by one or more of three mechanisms: reduced secretion, catalytic defect and increased degradation by trypsin (PubMed:22942235).
Regulates activation and degradation of trypsinogens and procarboxypeptidases by targeting specific cleavage sites within their zymogen precursors. Has chymotrypsin-type protease activity and hypocalcemic activity.
Seems to be expressed in prostate and less abundantly in adult brain, fetal liver, and fetal kidney.
Expressed in the cerebral cortex of the brain and at higher levels in some astrocytic brain tumors such as astrocytomas, glioblastomas and primitive neuroectodermal tumors.
Interacts (via LRR 1 and 2 repeats) with PTPRD (via extracellular domain).
It is involved in synaptogenesis and promotes synapse differentiation (PubMed:27812321). Suppresses neurite outgrowth (By similarity).
Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family.
Each subunit can be divided into 4 domains that are consecutive along the polypeptide chain. Domains 1 and 2 bind FAD and NADPH, respectively. Domain 4 forms the interface.
Expressed at very high levels in peripheral blood.
Maintains high levels of reduced glutathione in the cytosol.
Produced by alternative initiation of isoform Mitochondrial.
The active site is a redox-active disulfide bond.
(Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein HBZ; this interaction modulates HBZ stability.
Binds TOPBP1. Associates with CDK9 and TFIIS/TCEA1 and forms a transcription regulatory complex made of CDK9, RNAP II, UBR5 and TFIIS/TCEA1 that can stimulate target gene transcription (e.g. gamma fibrinogen/FGG) by recruiting their promoters. Associates with the E3 ligase complex containing DYRK2, EDD/UBR5, DDB1 and DCAF1 proteins (EDVP complex). Interacts directly with DYRK2. Interacts with PIH1D1 (PubMed:24656813).
E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation (By similarity). Involved in maturation and/or transcriptional regulation of mRNA by activating CDK9 by polyubiquitination. May play a role in control of cell cycle progression. May have tumor suppressor function. Regulates DNA topoisomerase II binding protein (TopBP1) in the DNA damage response. Plays an essential role in extraembryonic development. Ubiquitinates acetylated PCK1. Also acts as a regulator of DNA damage response by acting as a suppressor of RNF168, an E3 ubiquitin-protein ligase that promotes accumulation of 'Lys-63'-linked histone H2A and H2AX at DNA damage sites, thereby acting as a guard against excessive spreading of ubiquitinated chromatin at damaged chromosomes.
Widely expressed. Most abundant in testis and expressed at high levels in brain, pituitary and kidney.
Broadly expressed. High levels in brain, cerebellum, testis and whole blood.
Component of the multisubunit TRAPP II complex, which includes at least TRAPPC1, TRAPPC2, TRAPPC2L, TRAPPC3, TRAPPC4, TRAPPC5, TRAPPC6A/B, TRAPPC9, TRAPPC10 and TRAPPC14. TRAPPC9, TRAPPC10 and TRAPPC14 are specific subunits of the TRAPP II complex (PubMed:31467083). Interacts with alpha-tubulin during mitosis (PubMed:30715179). Interacts with RAB3IP (via the N-terminal region); this interaction mediates RAB3IP association with the TRAPP II complex (PubMed:31467083). Interacts with TRAPPC10 (PubMed:31467083). Interacts with FBF1 (PubMed:31467083).
Specific subunit of the TRAPP (transport protein particle) II complex, a highly conserved vesicle tethering complex that functions in late Golgi trafficking as a membrane tether (PubMed:31467083, PubMed:30715179). TRAPP II complex has also GEF activity toward RAB1A (By similarity). TRAPPC14 is dispensable for TRAPPII complex integrity but mediates RAB3IP preciliary vesicle trafficking to the mother centriole during ciliogenesis (PubMed:31467083). Modulates YAP1 activity as transcriptional regulator (PubMed:30447097).
(Microbial infection) Interacts with human adenovirus 5 hexon protein; this interaction probably allows virus intracellular transport.
Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. May play a role in binding dynein to membranous organelles or chromosomes. Probably involved in the microtubule-dependent transport of pericentrin. Is required for progress through the spindle assembly checkpoint. The phosphorylated form appears to be involved in the selective removal of MAD1L1 and MAD1L2 but not BUB1B from kinetochores. Forms a functional Rab11/RAB11FIP3/dynein complex onto endosomal membrane that regulates the movement of peripheral sorting endosomes (SE) along microtubule tracks toward the microtubule organizing center/centrosome, generating the endosomal recycling compartment (ERC) (PubMed:20026645).
Homodimer (By similarity). The cytoplasmic dynein 1 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs); the composition seems to vary in respect to the IC, LIC and LC composition. The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits. The ICs and LICs bind directly to the HC dimer and the LCs assemble on the IC dimer. Self-associates. Interacts with DYNC1H1; DYNC1LI1 and DYNC1LI2 bind mutually exclusive to DYNC1H1. Interacts with PCNT (By similarity). Forms a complex with RAB11FIP3 and RAB11A1; the interaction between DYNC1LI1 and RAB11FIP3 is direct and induces DYNC1LI1 localization onto endosomal membrane; the complex regulates endocytic trafficking (PubMed:20026645).
Phosphorylated during mitosis but not in interphase.
Belongs to the peptidase C19 family. USP17 subfamily.
Phe-89 is present instead of the conserved Cys which is expected to be an active site residue suggesting that this protein has lost its catalytic activity.
The RS447 megasatellite DNA is a highly polymorphic conserved tandem repetitive sequence which contains a copy of the USP17 gene. It is present with an interindividual variation in copy number, ranging from 20 to 103, and can be found in the genome both on chromosome 4 and chromosome 8. The high similarity between the UPS17-like genes makes impossible to clearly assign data to one of the genes of the family. Oligonucleotides designed in RNAi experiments are for instance not specific of a given UPS17-like gene.
Belongs to the class-I aminoacyl-tRNA synthetase family.
(Microbial infection) Essential factor for the splicing of the pre-mRNAs of human parvovirus B19 (B19V) and for the expression of B19V 11-kDa protein, which enhances viral replication.
By p53/TP53 family. Directly induced by p53/TP53, TP63/p63 and TP73/p73.
RNA-binding protein that specifically bind the 3'-UTR of CDKN1A transcripts, leading to maintain the stability of CDKN1A transcripts, thereby acting as a mediator of the p53/TP53 family to regulate CDKN1A. CDKN1A is a cyclin-dependent kinase inhibitor transcriptionally regulated by the p53/TP53 family to induce cell cycle arrest. Isoform 1, but not isoform 2, has the ability to induce cell cycle arrest in G1 and maintain the stability of CDKN1A transcripts induced by p53/TP53. Also acts as a mRNA splicing factor. Specifically regulates the expression of FGFR2-IIIb, an epithelial cell-specific isoform of FGFR2. Plays a role in myogenic differentiation.
Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when directly recruited to sites of DNA damage. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome.
Expressed in brain, heart, kidney, liver, lung, ovaries, placenta, prostate, skeletal muscle, small intestine, spleen, testis and thymus.
Interacts with H3K4me3 and to a lesser extent with H3K4me2. Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6. The NuA4 complex interacts with MYC and the adenovirus E1A protein. HTATTIP/TIP60, EPC1, and ING3 together constitute a minimal HAT complex termed Piccolo NuA4. Component of a SWR1-like complex.
The PHD-type zinc finger mediates the binding to H3K4me3.
Acts as an E2-dependent E3 ubiquitin-protein ligase, probably involved in the ER-associated protein degradation pathway.
Highly expressed in the normal cerebellum but not in the cerebral cortex.
Abundantly expressed in the heart, skeletal muscle and kidney. Expressed at lower level other tissues.
Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:28076346). Interacts with CCNDBP1 (PubMed:11118353).
Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28502770, PubMed:28076346).
Expressed during embryonic development, expression decreases at blastocyst stage.
N-terminal domain is required for nucleoplasm location and C-terminal domain for nucleolus location.
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). May be a component of the proposed t-UTP subcomplex of the ribosomal small subunit (SSU) processome containing at least UTP4, WDR43, HEATR1, UTP15, WDR75 (PubMed:17699751, PubMed:22916032). Binds to RNA; binding is required for its chromatin association. Interacts with CDK9, DDX21 and SUPT6H. Interacts with RNA polymerase II (By similarity). Interacts directly with UTP4 and UTP15 (PubMed:24219289).
Ribosome biogenesis factor that coordinates hyperactive transcription and ribogenesis (PubMed:17699751). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. Involved in nucleolar processing of pre-18S ribosomal RNA. Required for optimal pre-ribosomal RNA transcription by RNA polymerase I (PubMed:17699751, PubMed:34516797). Essential for stem cell pluripotency and embryonic development. In the nucleoplasm, recruited by promoter-associated/nascent transcripts and transcription to active promoters where it facilitates releases of elongation factor P-TEFb and paused RNA polymerase II to allow transcription elongation and maintain high-level expression of its targets genes (By similarity).
Associates with the PRC2 complex, which consists of the core components EED, EZH1 or EZH2, SUZ12, and RBBP4, and various combinations of accessory subunits including AEBP2, JARID2, PHF19, MTF2 and EPOP (PubMed:24550272, PubMed:29499137). Within the complex, interacts with SUZ12 (via C2H2 zinc finger domain); competes with JARID2 for SUZ12 binding (PubMed:29499137). Associates with the elongin BC complex (By similarity). Interacts with USP7 (By similarity).
Scaffold protein that serves as a bridging partner between the PRC2/EZH2 complex and the elongin BC complex: required to fine-tune the transcriptional status of Polycomb group (PcG) target genes in embryonic stem cells (ESCs). Plays a key role in genomic regions that display both active and repressive chromatin properties in pluripotent stem cells by sustaining low level expression at PcG target genes: acts by recruiting the elongin BC complex, thereby restricting excessive activity of the PRC2/EZH2 complex. Interaction with USP7 promotes deubiquitination of H2B at promoter sites. Acts as a regulator of neuronal differentiation.
The BC-box, which mediates binding to the elongin BC complex.
Component of the BCR(KBTBD8) E3 ubiquitin ligase complex, at least composed of CUL3, KBTBD8 and RBX1 (PubMed:26399832).
Down-regulated in differentiating embryonic stem cells (ESCs) (at protein level).
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of neural crest specification (PubMed:26399832). The BCR(KBTBD8) complex acts by mediating monoubiquitination of NOLC1 and TCOF1: monoubiquitination promotes the formation of a NOLC1-TCOF1 complex that acts as a platform to connect RNA polymerase I with enzymes responsible for ribosomal processing and modification, leading to remodel the translational program of differentiating cells in favor of neural crest specification (PubMed:26399832).
Component of the GINS complex which is a heterotetramer of GINS1, GINS2, GINS3 and GINS4 (PubMed:17417653, PubMed:17545466, PubMed:17557111, PubMed:17652513, PubMed:32453425). Forms a stable subcomplex with GINS3. GINS complex interacts with DNA primase in vitro (PubMed:17417653, PubMed:17545466, PubMed:17557111, PubMed:17652513). Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex (PubMed:34700328, PubMed:34694004, PubMed:32453425).
Required for correct functioning of the GINS complex, a complex that plays an essential role in the initiation of DNA replication, and progression of DNA replication forks (PubMed:17417653). GINS complex is a core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built (PubMed:32453425, PubMed:34694004, PubMed:34700328, PubMed:35585232).
Confers susceptibility to xenotropic murine leukemia retrovirus (X-MLV) infection in vitro, but it is unclear whether its ability to act as a receptor for xenotropic and polytropic murine leukemia retroviruses is relevant in vivo and whether such viruses can infect human.
Inorganic ion transporter that mediates phosphate ion export across plasma membrane. Plays a major role in phosphate homeostasis, preventing intracellular phosphate accumulation and possible calcium phosphate precipitation, ultimately preserving calcium signaling. The molecular mechanism of phosphate transport, whether electrogenic, electroneutral or coupled to other ions, remains to be elucidated (PubMed:23791524, PubMed:25938945, PubMed:31043717) (By similarity). Binds inositol hexakisphosphate (Ins6P) and similar inositol polyphosphates, such as 5-diphospho-inositol pentakisphosphate (5-InsP7), important intracellular signaling molecules involved in regulation of phosphate flux (PubMed:27080106).
The SPX domain has high affinity for inositol polyphosphates, such as myo-inositol hexakisphosphate and 5-diphospho-myo-inositol pentakisphosphate (5-InsP7). Its affinity for inorganic phosphate is tow to three orders of magnitude lower.
Widely expressed. Detected in spleen, lymph node, thymus, leukocytes, bone marrow, heart, kidney, pancreas and skeletal muscle.
Belongs to the immunoglobulin superfamily.
Receptor on natural killer (NK) cells for HLA-C alleles (HLA-Cw1, HLA-Cw3 and HLA-Cw7). Inhibits the activity of NK cells thus preventing cell lysis.
Belongs to the fatty acid desaturase type 1 family.
The N-terminus contains a duplication of the repeated 'MEPTEP' sequence. It is unclear whether such duplication is due to a sequencing error or a polymorphism.
Activated in chronic T-cell leukemias (T-CLL) carrying rearrangements of the 14q32.1 region.
Enhances the phosphorylation and activation of AKT1 and AKT2.
Expressed in a variety of tissues including placenta and testis.
Interacts with AKT1 and AKT2 (via PH domain). Does not interact with AKT3.
Interacts with DYRK1A, DYRK1B and DIAPH1. Interacts with DDB1. Interacts with ZNF703. Interacts with human adenovirus 5 E1A protein (PubMed:23864635).
Involved in craniofacial development. Acts upstream of the EDN1 pathway and is required for formation of the upper jaw equivalent, the palatoquadrate. The activity required for EDN1 pathway function differs between the first and second arches (By similarity). Associates with DIAPH1 and controls GLI1 transcriptional activity. Could be involved in normal and disease skin development. May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex.
Class-IV neuronal intermediate filament that is able to self-assemble. It is involved in the morphogenesis of neurons. It may form an independent structural network without the involvement of other neurofilaments or it may cooperate with NEFL to form the filamentous backbone to which NEFM and NEFH attach to form the cross-bridges. May also cooperate with the neuronal intermediate filament protein PRPH to form filamentous networks (By similarity).
Expressed in brain as early as the 16th week of gestation, and increased rapidly and reached a steady state level by the 18th week of gestation.
Forms homodimers (in vitro) (By similarity). Forms heterodimers with NEFL, NEFM or NEFH (in vitro) (By similarity).
Belongs to the ZIP transporter (TC 2.A.5) family. KE4/Catsup subfamily.
Methylation at some His residue by METTL9 leads to reduced zinc-binding.
Phosphorylation activates zinc transport activity.
Rapidly phosphorylated by CK2 following Zn(2+) treatment. This phosphorylation is required for efficient cytosolic Zn(2+) release.
Transports Zn(2+) from the endoplasmic reticulum (ER)/Golgi apparatus to the cytosol, playing an essential role in the regulation of cytosolic zinc levels (PubMed:14525538, PubMed:15705588, PubMed:29980658, PubMed:28205653). Acts as gatekeeper of zinc release from intracellular stores, requiring post-translational activation by phosphorylation, resulting in activation of multiple downstream pathways leading to cell growth and proliferation (PubMed:29980658, PubMed:22317921, PubMed:28205653). Has an essential role in B cell development and is required for proper B cell receptor signaling (PubMed:30718914). Plays an important role in maintaining intestinal epithelial homeostasis and skin dermis development by regulating ER function (By similarity). Controls cell signaling pathways involved in glucose metabolism in skeletal muscle (By similarity). Has a protective role against ER stress in different biological contexts (PubMed:29980658, PubMed:30237509). Mediates Zn(2+)-induced ferroptosis (PubMed:33608508).
Adenine glycosylase active on G-A mispairs.
Binds 1 [4Fe-4S] cluster. The cluster does not appear to play a role in catalysis, but is probably involved in the proper positioning of the enzyme along the DNA strand.
Involved in oxidative DNA damage repair. Initiates repair of A*oxoG to C*G by removing the inappropriately paired adenine base from the DNA backbone. Possesses both adenine and 2-OH-A DNA glycosylase activities.
The gene represented in this entry may be involved in disease pathogenesis. Somatic mutations contribute to the development of a sub-set of sporadic gastric cancers in carriers of Helicobacter pylori (PubMed:15273732).
Belongs to the thymidylate synthase family.
Catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate (dUMP) to thymidine 5'-monophosphate (dTMP), using the cosubstrate, 5,10- methylenetetrahydrofolate (CH2H4folate) as a 1-carbon donor and reductant and contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Expressed both in normal and cancerous tissues.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. TYMS germline variants in the presence of a common ENOSF1 haplotype (defined by rs699517, rs2790 and rs1512643) result in severe thymidylate synthase deficiency and disease. The pathogenic mechanism involves increased expression of ENOSF1 relative to TYMS, and post-transcriptional inhibition of TYMS translation through ENOSF1-TYMS RNA-RNA interactions.
Interacts directly with isoform p52shc of SHC1 via its SH2 domain (By similarity). Interacts with TRIM71; leading to enhanced SHCBP1 protein stability (By similarity). Interacts with both members of the centralspindlin complex, KIF23 and RACGAP1 (PubMed:21187330).
May play a role in signaling pathways governing cellular proliferation, cell growth and differentiation. May be a component of a novel signaling pathway downstream of Shc. Acts as a positive regulator of FGF signaling in neural progenitor cells.
May function as an activating coreceptor in B-cells. May function in B-cells activation and differentiation.
Phosphorylated on tyrosines upon activation.
Primarily expressed in secondary lymphoid tissues by mature subsets of B-cells. Detected in spleen, lymph node, heart, skeletal muscle, kidney, liver and placenta. Specifically expressed by mature B lineage cells with higher expression in naive versus memory B-cells (at protein level).
Heterodimer with PPIH. Interacts with PRPF4 and with the spliceosome. Part of a complex containing U4/U6 snRNPs.
Participates in the second step of pre-mRNA splicing.
Belongs to the bacterial ribosomal protein bL36 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. bL36m has a zinc binding site.
Component of the ER membrane protein complex (EMC) (PubMed:22119785, PubMed:29242231, PubMed:32439656, PubMed:32459176, PubMed:33964204). Interacts with WNK1 (via amphipathic alpha-helix region); promoting the ER membrane protein complex assembly by preventing EMC2 ubiquitination (PubMed:33964204).
Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins (PubMed:30415835, PubMed:29809151, PubMed:29242231, PubMed:32459176, PubMed:32439656, PubMed:33964204). Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues (PubMed:30415835, PubMed:29809151, PubMed:29242231). Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices (PubMed:30415835, PubMed:29809151). It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes (PubMed:29809151, PubMed:29242231). By mediating the proper cotranslational insertion of N-terminal transmembrane domains in an N-exo topology, with translocated N-terminus in the lumen of the ER, controls the topology of multi-pass membrane proteins like the G protein-coupled receptors (PubMed:30415835). By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes (Probable).
Ubiquitinated when soluble in the cytoplasm, leading to its degradation by the proteasome (PubMed:33964204). Interaction with EMC2 prevents its ubiquitination and degradation (PubMed:33964204).
Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules. Modulates NOTCH1 activity by modifying O-fucose residues at specific EGF-like domains resulting in enhancement of NOTCH1 activation by DLL1 and JAG1. May be involved in limb formation and in neurogenesis.
Interacts with DST (isoform 1). Interacts with SH3GL2. Interacts (via N-terminus) with CYFIP1 and CYFIP2; the interactions associate TMEM108 with the WAVE1 complex.
Transmembrane protein required for proper cognitive functions. Involved in the development of dentate gyrus (DG) neuron circuitry, is necessary for AMPA receptors surface expression and proper excitatory postsynaptic currents of DG granule neurons. Regulates the organization and stability of the microtubule network of sensory neurons to allow axonal transport. Through the interaction with DST, mediates the docking of the dynein/dynactin motor complex to vesicle cargos for retrograde axonal transport. In hippocampal neurons, required for BDNF-dependent dendrite outgrowth. Cooperates with SH3GL2 and recruits the WAVE1 complex to facilitate actin-dependent BDNF:NTRK2 early endocytic trafficking and mediate signaling from early endosomes.
Bifunctional enzyme that acts both as an endopeptidase and 2-oxoglutarate-dependent monooxygenase (PubMed:28847961, PubMed:29459673, PubMed:28982940, PubMed:29563586). Endopeptidase that cleaves histones N-terminal tails at the carboxyl side of methylated arginine or lysine residues, to generate 'tailless nucleosomes', which may trigger transcription elongation (PubMed:28847961, PubMed:29459673, PubMed:28982940). Preferentially recognizes and cleaves monomethylated and dimethylated arginine residues of histones H2, H3 and H4. After initial cleavage, continues to digest histones tails via its aminopeptidase activity (PubMed:28847961, PubMed:29459673). Upon DNA damage, cleaves the N-terminal tail of histone H3 at monomethylated lysine residues, preferably at monomethylated 'Lys-9' (H3K9me1). The histone variant H3F3A is the major target for cleavage (PubMed:28982940). Additionnally, acts as Fe(2+) and 2-oxoglutarate-dependent monooxygenase, catalyzing (R)-stereospecific hydroxylation at C-3 of 'Arg-137' of RPS6 and 'Arg-141' of RCCD1, but the biological significance of this activity remains to be established (PubMed:29563586). Regulates mitosis through different mechanisms: Plays a role in transcriptional repression of satellite repeats, possibly by regulating H3K36 methylation levels in centromeric regions together with RCCD1. Possibly together with RCCD1, is involved in proper mitotic spindle organization and chromosome segregation (PubMed:24981860). Negatively regulates cell cycle repressor CDKN1A/p21, which controls G1/S phase transition (PubMed:24740926). Required for G2/M phase cell cycle progression. Regulates expression of CCNA1/cyclin-A1, leading to cancer cell proliferation (PubMed:20457893). Also, plays a role in regulating alpha-tubulin acetylation and cytoskeletal microtubule stability involved in epithelial to mesenchymal transition (PubMed:28455245). Regulates the circadian gene expression in the liver (By similarity). Represses the transcriptional activator activity of the CLOCK-BMAL1 heterodimer in a catalytically-independent manner (PubMed:30500822). Negatively regulates the protein stability and function of CRY1; required for AMPK-FBXL3-induced CRY1 degradation (PubMed:30500822).
Can form homodimers (via JmjC domain) (PubMed:24100311, PubMed:28982940). Found in a complex with RCCD1 (PubMed:24981860). Interacts (via N-terminus) with RCCD1 (via N-terminus); this interaction stimulates H3K36me3 and H3K36me2 demethylation (PubMed:28455245, PubMed:24981860). Interacts (via JmjC domain) with H3C1 (PubMed:28982940). Interacts with FBXL3 and PSMD2 (By similarity). Interacts with CRY1 in a FBXL3-dependent manner (By similarity).
The demethylase activity of JMJD5 is controversial. Demethylase activity toward H3K36me2 was observed in vivo and in vitro (PubMed:20457893). In addition, demethylase activity toward H3K36me3 when in a complex with RCCD1 has been observed (PubMed:24981860). In contrast, in other studies, JMJD5 was shown not to display any demethylase activity toward methylated H3K36 nor toward other methyllysines in the N-terminal tails of H3 and H4 in vitro (PubMed:28982940, PubMed:22851697, PubMed:24100311).
Up-regulated upon starvation, DNA replication stress, UV treatment and by camptothecin and etoposide treatment.
Weakly expressed in most cells. Highly expressed in breast cancer cells (PubMed:20457893). Expressed in embryonic stem cells (PubMed:24740926).
Co-chaperone for HSPA8/Hsc70 (PubMed:10816573). Stimulates ATP hydrolysis, but not the folding of unfolded proteins mediated by HSPA1A (in vitro) (PubMed:24318877). Plays a role in protein transport into mitochondria via its role as co-chaperone. Functions as co-chaperone for HSPA1B and negatively regulates the translocation of BAX from the cytosol to mitochondria in response to cellular stress, thereby protecting cells against apoptosis (PubMed:14752510). Promotes apoptosis in response to cellular stress mediated by exposure to anisomycin or UV (PubMed:24512202).
Identified in a complex with HSPA1B and BAX (PubMed:14752510). Interacts with RNF207 (PubMed:25281747).
Ubiquitous. Isoform 2 is highly expressed in testis and lung, but detected at low levels in thymus, prostate, colon and liver.
Disease susceptibility is associated with variants affecting the gene represented in this entry. A deletion encompassing CFHR1 and CFHR3 is associated with an increased risk of atypical hemolytic uremic syndrome, likely due to a defective regulation of complement activation (PubMed:17367211). Some patients carrying the deletion have serum anti-CFH autoantibodies (PubMed:18006700).
Might be involved in complement regulation.
Detected in blood plasma (PubMed:2340307, PubMed:11893776, PubMed:12641539). Detected in milk (at protein level) (PubMed:2340307).
Homodimer (PubMed:16179346, PubMed:26725083, PubMed:11893776) (Probable). Interacts with GPIHBP1 with 1:1 stoichiometry (PubMed:17997385, PubMed:27929370, PubMed:26725083, PubMed:27811232, PubMed:29899144, PubMed:30559189). Interacts with APOC2; the interaction activates LPL activity in the presence of lipids (By similarity). Interaction with heparan sulfate proteoglycans is required to protect LPL against loss of activity (PubMed:11342582). Associates with lipoprotein particles in blood plasma (PubMed:11342582, PubMed:11893776). Interacts with LMF1 and SEL1L; interaction with SEL1L is required to prevent aggregation of newly synthesized LPL in the endoplasmic reticulum (ER), and for normal export of LPL from the ER to the extracellular space (PubMed:25066055). Interacts with SORL1; SORL1 acts as a sorting receptor, promoting LPL localization to endosomes and later to lysosomes, leading to degradation of newly synthesized LPL (PubMed:21385844).
Homodimer. Interacts with APOC2; the interaction activates LPL activity in the presence of lipids.
Key enzyme in triglyceride metabolism. Catalyzes the hydrolysis of triglycerides from circulating chylomicrons and very low density lipoproteins (VLDL), and thereby plays an important role in lipid clearance from the blood stream, lipid utilization and storage (PubMed:8675619, PubMed:11342582, PubMed:27578112). Although it has both phospholipase and triglyceride lipase activities it is primarily a triglyceride lipase with low but detectable phospholipase activity (PubMed:7592706, PubMed:12032167). Mediates margination of triglyceride-rich lipoprotein particles in capillaries (PubMed:24726386). Recruited to its site of action on the luminal surface of vascular endothelium by binding to GPIHBP1 and cell surface heparan sulfate proteoglycans (PubMed:11342582, PubMed:27811232).
Key enzyme in triglyceride metabolism. Catalyzes the hydrolysis of triglycerides from circulating chylomicrons and very low density lipoproteins (VLDL), and thereby plays an important role in lipid clearance from the blood stream, lipid utilization and storage. Mediates margination of triglyceride-rich lipoprotein particles in capillaries. Recruited to its site of action on the luminal surface of vascular endothelium by binding to GPIHBP1 and cell surface heparan sulfate proteoglycans.
The apolipoprotein APOC2 acts as a coactivator of LPL activity (PubMed:12032167). Ca(2+) binding promotes protein stability and formation of the active homodimer (PubMed:16179346). Interaction with GPIHBP1 protects LPL against inactivation by ANGPTL4 (PubMed:27929370, PubMed:29899144). Inhibited by NaCl (PubMed:12032167).
Tyrosine nitration after lipopolysaccharide (LPS) challenge down-regulates the lipase activity.
Probably involved in maintaining Golgi structure.
Belongs to the kynurenine formamidase family.
Catalyzes the hydrolysis of N-formyl-L-kynurenine to L-kynurenine, the second step in the kynurenine pathway of tryptophan degradation. Kynurenine may be further oxidized to nicotinic acid, NAD(H) and NADP(H). Required for elimination of toxic metabolites.
The main chain amide nitrogen atoms of the second glycine and its adjacent residue in the HGGXW motif define the oxyanion hole, and stabilize the oxyanion that forms during the nucleophilic attack by the catalytic serine during substrate cleavage.
Although predominant among the water-soluble brain proteins, S100 is also found in a variety of other tissues.
Dimer of either two alpha chains, or two beta chains, or one alpha and one beta chain (PubMed:12480931, PubMed:20950652). The S100B dimer binds two molecules of STK38 (By similarity). Interacts with CACYBP in a calcium-dependent manner (By similarity). Interacts with ATAD3A; this interaction probably occurs in the cytosol prior to ATAD3A mitochondrial targeting (PubMed:20351179). Interacts with S100A6 (PubMed:9925766). The S100B dimer interacts with two molecules of CAPZA1 (PubMed:12480931). Interacts with AGER (PubMed:20943659). Interacts with PPP5C (via TPR repeats); the interaction is calcium-dependent and modulates PPP5C activity (PubMed:22399290). Interacts with TPPP; this interaction inhibits TPPP dimerization (PubMed:33831707). Interacts with isoform CLSTN3beta of CLSTN3; interaction promotes secretion (By similarity).
Small zinc- and- and calcium-binding protein that is highly expressed in astrocytes and constitutes one of the most abundant soluble proteins in brain (PubMed:6487634, PubMed:20950652). Weakly binds calcium but binds zinc very tightly-distinct binding sites with different affinities exist for both ions on each monomer (PubMed:6487634, PubMed:20950652). Physiological concentrations of potassium ion antagonize the binding of both divalent cations, especially affecting high-affinity calcium-binding sites (By similarity). Acts as a neurotrophic factor that promotes astrocytosis and axonal proliferation (By similarity). Involved in innervation of thermogenic adipose tissue by acting as an adipocyte-derived neurotrophic factor that promotes sympathetic innervation of adipose tissue (By similarity). Binds to and initiates the activation of STK38 by releasing autoinhibitory intramolecular interactions within the kinase (By similarity). Interaction with AGER after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Could assist ATAD3A cytoplasmic processing, preventing aggregation and favoring mitochondrial localization (PubMed:20351179). May mediate calcium-dependent regulation on many physiological processes by interacting with other proteins, such as TPR-containing proteins, and modulating their activity (PubMed:22399290).
Expressed in stomach (at protein level). No expression is detected in cancer tissue or gastric cancer cell lines.
Has mitogenic activity and may be involved in maintaining the integrity of the gastric mucosal epithelium.
Intron retention. The N-terminal region arises from intron retention.
Phosphorylated on serine and threonine residues.
Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fission of tubules that serve as transport intermediates during endosome sorting.
Component of the WASH core complex also described as WASH regulatory complex (SHRC) composed of WASH (WASHC1, WASH2P or WASH3P), WASHC2 (WASHC2A or WASHC2C), WASHC3, WASHC4 and WASHC5. The WASH core complex associates via WASHC2 with the F-actin-capping protein dimer (formed by CAPZA1, CAPZA2 or CAPZA3 and CAPZB) in a transient or substoichiometric manner which was initially described as WASH complex.
One study reported a nucleation-promoting factor (NPF) activity towards the Arp2/3 complex using partially purified samples of the WASH complex (PubMed:19922875). In another study, the in vitro reconstituted and purified recombinant WASH core complex, consisting of WASHC3, WASHC4, WASHC5, WASHC1 and the N-terminal residues 1-356 of WASHC2, did not show activity toward Arp2/3 complex (PubMed:20498093).
AP-3 associates with the BLOC-1 complex (By similarity). Adaptor protein complex 3 (AP-3) is a heterotetramer composed of two large adaptins (delta-type subunit AP3D1 and beta-type subunit AP3B1 or AP3B2), a medium adaptin (mu-type subunit AP3M1 or AP3M2) and a small adaptin (sigma-type subunit APS1 or AP3S2) (By similarity). Interacts with SLC30A2 (PubMed:25808614). Interacts with CLN3 (via dileucine motif); this interaction facilitates lysosomal targeting (PubMed:15598649).
Contaminating sequence. Presence of an unrelated sequence found on chromosome 7.
Lack of 8 exons and truncation of 2 other exons in the C- terminus. Alternative splicing seems doubtful, since exon-intron junctions are not the consensus ones.
Part of the AP-3 complex, an adaptor-related complex which is not clathrin-associated. The complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and may be directly involved in trafficking to lysosomes. Involved in process of CD8+ T-cell and NK cell degranulation (PubMed:26744459). In concert with the BLOC-1 complex, AP-3 is required to target cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals (By similarity).
Present in all adult tissues examined with the highest levels in skeletal muscle, heart, pancreas and testis.
Belongs to the WD repeat PROPPIN family.
Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation (PubMed:23435086, PubMed:28561066). Binds phosphatidylinositol 3-phosphate (PtdIns3P) (PubMed:28561066). Activated by the STK11/AMPK signaling pathway upon starvation, WDR45 is involved in autophagosome assembly downstream of WIPI2, regulating the size of forming autophagosomes (PubMed:28561066). Together with WIPI1, promotes ATG2 (ATG2A or ATG2B)-mediated lipid transfer by enhancing ATG2-association with phosphatidylinositol 3-monophosphate (PI3P)-containing membranes (PubMed:31271352). Probably recruited to membranes through its PtdIns3P activity (PubMed:28561066).
Interacts with WIPI1 (PubMed:28561066). Interacts with WIPI2 (PubMed:28561066). Interacts with ATG2A and ATG2B (PubMed:28820312, PubMed:28561066, PubMed:32483132). Interacts with ULK1 (PubMed:28561066). May interact with the PRKAA1, PRKAA2, PRKAB1 and PRKAG1 subunits of the AMPK kinase (PubMed:28561066). May interact with NUDC (PubMed:28561066).
The L/FRRG motif is required for recruitment to PtdIns3P.
Ubiquitously expressed, with high expression in skeletal muscle and heart. Weakly expressed in liver and placenta. Expression is down-regulated in pancreatic and in kidney tumors.
Belongs to the complexin/synaphin family.
Binds to the SNARE core complex containing SNAP25, VAMP2 and STX1A.
Nervous system. In hippocampus and cerebellum, expressed mainly by inhibitory neurons. Overexpressed in substantia nigra from patients with Parkinson disease.
Positively regulates a late step in exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles (PubMed:21785414). Organizes the SNAREs into a cross-linked zigzag topology that, when interposed between the vesicle and plasma membranes, is incompatible with fusion, thereby preventing SNAREs from releasing neurotransmitters until an action potential arrives at the synapse (PubMed:21785414). Also involved in glucose-induced secretion of insulin by pancreatic beta-cells. Essential for motor behavior.
Aryl sulfonamide anticancer drugs, such as indisulam (E7070) or E7820, promote ubiquitination and subsequent degradation by the DCX(DCAF15) complex (PubMed:31693891, PubMed:31686031, PubMed:31819272). Aryl sulfonamide anticancer drugs change the substrate specificity of DCAF15 by acting as a molecular glue that promotes binding between DCAF15 and weak affinity interactor RBM23 (PubMed:31686031, PubMed:31819272).
Highly expressed in placenta, liver, skeletal muscle, heart and kidney (PubMed:15694343). Expressed at lower levels in the colon, thymus, spleen, small intestine and lung (PubMed:15694343).
RNA-binding protein that acts both as a transcription coactivator and pre-mRNA splicing factor (PubMed:15694343). Regulates steroid hormone receptor-mediated transcription, independently of the pre-mRNA splicing factor activity (PubMed:15694343).
Adapter protein that associates with PIDD1 and the caspase CASP2 to form the PIDDosome, a complex that activates CASP2 and triggers apoptosis (PubMed:9044836, PubMed:15073321, PubMed:16652156, PubMed:17159900, PubMed:17289572). Also recruits CASP2 to the TNFR-1 signaling complex through its interaction with RIPK1 and TRADD and may play a role in the tumor necrosis factor-mediated signaling pathway (PubMed:8985253).
Constitutively expressed in most tissues, with particularly high expression in adult heart, testis, liver, skeletal muscle, fetal liver and kidney.
Forms a complex named the PIDDosome with PIDD1 and CASP2 (PubMed:9044836, PubMed:8985253, PubMed:15073321, PubMed:16652156, PubMed:17159900, PubMed:17289572). Interacts (via Death domain) with RIPK1 (via Death domain); the interaction is direct (PubMed:9044836). Interacts with TRADD (PubMed:8985253). Interacts with TNFRSF1A (PubMed:8985253).
The CARD domain mediates a direct interaction with CASP2.
The Death domain mediates the interaction with PIDD1 and the formation of a complex composed of 5 PIDD1 and 7 CRADD proteins which in turn probably recruit 7 CASP2 to form the PIDDosome (PubMed:17289572). The Death domain mediates a direct interaction with the Death domain of RIPK1 (PubMed:9044836).
Cholesterol transporter that mediates non-vesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER) (By similarity). Contains unique domains for binding cholesterol and the PM, thereby serving as a molecular bridge for the transfer of cholesterol from the PM to the ER (By similarity). Plays a crucial role in cholesterol homeostasis and has the unique ability to localize to the PM based on the level of membrane cholesterol (By similarity). In lipid-poor conditions localizes to the ER membrane and in response to excess cholesterol in the PM is recruited to the endoplasmic reticulum-plasma membrane contact sites (EPCS) which is mediated by the GRAM domain (By similarity). At the EPCS, the sterol-binding VASt/ASTER domain binds to the cholesterol in the PM and facilitates its transfer from the PM to ER (By similarity). May play a role in tumor progression (By similarity). Plays a role in autophagy regulation and is required for biogenesis of the autophagosome (PubMed:31222192). This function in autophagy requires its cholesterol-transfer activity (PubMed:31222192).
GRAM domain binds phosphatidylserine in the PM and mediates protein recruitment to endoplasmic reticulum-plasma membrane contact sites (EPCS) in response to excess cholesterol in the PM.
Up-regulated in hepatocellular carcinoma tissues.
VASt (VAD1 Analog of StAR-related lipid transfer) domain, also known as ASTER (Greek for star) domain is a sterol-binding domain.
Involved in the early to middle stages of 60S ribosomal subunit biogenesis. Core component of box C/D small nucleolar ribonucleoprotein (snoRNP) particles. Required for the biogenesis of box C/D snoRNAs such U3, U8 and U14 snoRNAs (PubMed:12777385, PubMed:15574333). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Part of a large pre-ribosomal ribonucleoprotein (RNP) complex, that consists of at least 62 ribosomal proteins, 45 nonribosomal proteins and both pre-rRNA and mature rRNA species. Within this complex directly interacts with TCOF1 in an RNA-independent manner. Core component of box C/D small nucleolar ribonucleoprotein (snoRNP) particles; the core proteins SNU13, NOP56, NOP58 and FBL assemble stepwise onto the snoRNA. Interacts with NOP1 and NOP58. Interacts with NUFIP1, RUVBL1 and RUVBL2; RUVBL1:RUVBL2 seem to bridge the association of NOP56 with NUFIP1. Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797).
The disease is caused by variants affecting the gene represented in this entry. Caused by large hexanucleotide CGCCTG repeat expansions within intron 1. These expansions induce RNA foci and sequester the RNA-binding protein SRSF2. In addition, the transcription of MIR1292, a microRNA gene located just 19 bp 3' of the GGCCTG repeat, is significantly decreased.
Belongs to the IMPDH/GMPR family. GuaC type 1 subfamily.
Catalyzes the irreversible NADPH-dependent deamination of GMP to IMP. It functions in the conversion of nucleobase, nucleoside and nucleotide derivatives of G to A nucleotides, and in maintaining the intracellular balance of A and G nucleotides (PubMed:12009299, PubMed:12669231, PubMed:16359702, PubMed:22037469). Plays a role in modulating cellular differentiation (PubMed:12669231).
Catalyzes the irreversible NADPH-dependent deamination of GMP to IMP. It functions in the conversion of nucleobase, nucleoside and nucleotide derivatives of G to A nucleotides, and in maintaining the intracellular balance of A and G nucleotides.
Highly expressed in heart, skeletal muscle, kidney, brain, liver, prostate, spleen, placenta, testis and ovary. Low expression in colon, thymus and peripheral blood leukocytes.
Transcriptional repressor of the myelin basic protein gene (MBP). Binds to the proximal MB1 element 5'-TTGTCC-3' of the MBP promoter. Its binding to MB1 and function are inhibited by PURA (By similarity).
UDP-glucuronosyltransferases catalyze phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase water solubility and enhance excretion. They are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds (By similarity).
Belongs to the cytochrome b5 family. MAPR subfamily.
Component of a progesterone-binding protein complex (PubMed:28396637). Binds progesterone (PubMed:25675345). Has many reported cellular functions (heme homeostasis, interaction with CYPs). Required for the maintenance of uterine histoarchitecture and normal female reproductive lifespan (By similarity). Intracellular heme chaperone. Regulates heme synthesis via interactions with FECH and acts as a heme donor for at least some hemoproteins (PubMed:27599036).
Detected in urine (at protein level) (PubMed:36213313). Expressed by endometrial glands and stroma (at protein level) (PubMed:23793472). Widely expressed, with highest expression in liver and kidney.
Homodimer. Forms stable homodimer through hydrophobic heme-heme stacking interactions (PubMed:26988023, PubMed:28396637). Interacts with FECH; the interaction results in decreased FECH activity (PubMed:27599036). Interacts with EGFR, CYP1A1 and CYP3A4; the interactions require PGRMC1 homodimerization (PubMed:28396637).
Non-classical progesterone receptors involved in extranuclear signaling are classified in 2 groups: the class II progestin and adipoQ receptor (PAQR) family (also called mPRs) (PAQR5, PAQR6, PAQR7, PAQR8 and PAQR9) and the b5-like heme/steroid-binding protein family (also called MAPRs) (PGRMC1, PGRMC2, NENF and CYB5D2).
O-glycosylated; contains chondroitin sulfate attached to Ser-54. Ser-54 is in the cytoplasmic domain but the glycosylated form was detected in urine, suggesting that the membrane-bound form is cleaved, allowing for production of a secreted form which is glycosylated.
The cytochrome b5 heme-binding domain lacks the conserved iron-binding His residues at positions 107 and 131.
Was initially identified as sigma-2 receptor, which is thought to play important role in regulating cell survival, morphology and differentiation (PubMed:21730960, PubMed:22292588, PubMed:28007569). However, it was later shown that it is not the case (PubMed:28007569). The sigma-2 receptor has been identified as TMEM97 (AC Q5BJF2) (PubMed:28559337).
Expressed in heart, skeletal muscle, testis, and all specific brain regions examined. Slightly lower expression was detected in ovary and kidney, and intermediate expression was detected in lung, pancreas, spleen and liver.
Expression does not vary in normal patients compared to patients with acute monocytic leukemia.
Represents a conventional myosin. This protein should not be confused with the unconventional myosin-7 (MYO7).
The cardiac alpha isoform is a 'fast' ATPase myosin, while the beta isoform is a 'slow' ATPase.
This protein sequence has been named 'Slow A' MYH14, but it also appears also as 'Slow B' MYH15 within the reference.
Expressed in heart, placenta and skeletal muscle and to a lesser extent in pancreas. Very low expression in brain, lung, liver and kidney.
Putative Notch ligand involved in the mediation of Notch signaling. Involved in limb development (By similarity).
In contrast to isoform 1, does not bind poly-ADP-ribose (PubMed:15902274). Represses SOD3 gene expression (PubMed:23022728).
In contrast to other Macro-domain containing proteins, lacks ADP-ribose glycohydrolase activity.
Isoform that specifically binds poly-ADP-ribose and O-acetyl-ADP-ribose and plays a key role in NAD(+) metabolism (PubMed:15902274). Able to bind to the ends of poly-ADP-ribose chains created by PARP1 and cap them (By similarity). This prevents PARP1 from further addition of ADP-ribose and thus limits the consumption of nuclear NAD(+), allowing the cell to maintain proper NAD(+) levels in both the nucleus and the mitochondria to promote proper mitochondrial respiration (By similarity). Increases the expression of genes involved in redox metabolism, including SOD3 (PubMed:23022728).
Monoubiquitinated at either Lys-116 or Lys-117. May also be polyubiquitinated. Ubiquitination is mediated by the CUL3/SPOP E3 complex and does not promote proteasomal degradation. Instead, it is required for enrichment in inactive X chromosome chromatin.
Preferentially expressed over isoform 2 in the absence of DDX5/DDX17.
The macro domain specifically binds poly-ADP-ribose.
The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. Interacts with HDAC1 and HDAC2 (PubMed:16107708). Interacts with SPOP (PubMed:15897469, PubMed:19818708). Part of a complex consisting of MACROH2A1, CUL3 and SPOP (PubMed:15897469, PubMed:19818708).
The preferential expression of isoform 2 over that of isoform 1 requires the presence of DDX5/DDX17.
Variant histone H2A which replaces conventional H2A in a subset of nucleosomes where it represses transcription (PubMed:12718888, PubMed:15621527, PubMed:16428466). Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template (PubMed:15897469). Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability (PubMed:15897469). DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. Involved in stable X chromosome inactivation (PubMed:15897469). Inhibits the binding of transcription factors, including NF-kappa-B, and interferes with the activity of remodeling SWI/SNF complexes (PubMed:12718888, PubMed:16428466). Inhibits histone acetylation by EP300 and recruits class I HDACs, which induces a hypoacetylated state of chromatin (PubMed:16428466, PubMed:16107708).
Homodimer and heterodimer with VANGL1. Interacts through its C-terminal region with the N-terminal half of DVL1, DVL2 and DVL3. The PDZ domain of DVL1, DVL2 and DVL3 is required for the interaction. Also interacts with the PDZ domains of MAGI3, SCRIB/SCRB1 and FZD3 (By similarity). Interacts with PRICKLE3 (By similarity).
Involved in the control of early morphogenesis and patterning of both axial midline structures and the development of neural plate. Plays a role in the regulation of planar cell polarity, particularly in the orientation of stereociliary bundles in the cochlea. Required for polarization and movement of myocardializing cells in the outflow tract and seems to act via RHOA signaling to regulate this process. Required for cell surface localization of FZD3 and FZD6 in the inner ear (By similarity).
Belongs to the SPTSS family. SPTSSA subfamily.
Component of the serine palmitoyltransferase (SPT) complex, which is composed of SPTLC1, SPTLC2 or SPTLC3 and SPTSSA or SPTSSB (PubMed:19416851, PubMed:33558761, PubMed:33558762, PubMed:37308477). The heterodimer consisting of SPTLC1 and SPTLC2/SPTLC3 forms the catalytic core of the enzyme, while SPTSSA or SPTSSB subunits determine substrate specificity (PubMed:33558762, PubMed:37308477). SPT also interacts with ORMDL proteins, especially ORMDL3, which negatively regulate SPT activity in the presence of ceramides (PubMed:33558762, PubMed:37308477). Interacts with MBOAT7; the interaction plays a role in MBOAT7 localization to mitochondria-associated membranes (PubMed:23510452).
Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-chain bases (PubMed:19416851). The SPT complex is composed of SPTLC1, SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this complex, the heterodimer consisting of SPTLC1 and SPTLC2/SPTLC3 forms the catalytic core (PubMed:19416851). Within the SPT complex, SPTSSA stimulates the catalytic activity and plays a role in substrate specificity, which depends upon the overall complex composition (PubMed:19416851, PubMed:33558761). The SPTLC1-SPTLC2-SPTSSA complex shows a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as substrates, with a slight preference for C14-CoA (PubMed:19416851). Independently of its action as a SPT component, may be involved in MBOAT7 localization to mitochondria-associated membranes, a membrane bridge between the endoplasmic reticulum and mitochondria, may hence affect MBOAT7-catalyzed incorporation of arachidonic acid into phosphatidylinositol (PubMed:23510452).
Highly expressed in heart, stomach, jejunum, kidney, liver, and adrenal gland. Expression was generally higher in adult organs than in fetal tissues, particularly in heart, kidney, and liver.
Interacts (via COMM domain) with COMMD1 (via COMM domain). Interacts with RELA, RELB, NFKB1/p105. Interacts with CCDC22, CCDC93, SCNN1B, CUL2, CUL3, CUL4A, CUL4B, CUL7.
May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes (PubMed:21778237). Negatively regulates cell proliferation. Negatively regulates cell cycle G2/M phase transition probably by transactivating p21/CDKN1A through the p53/TP53-independent signaling pathway. Involved in kidney proximal tubule morphogenesis (By similarity). Down-regulates activation of NF-kappa-B (PubMed:15799966).
Acetylation is essential for its transcriptional coactivator activity.
Binds to ESR1 and sequesters it in the cytoplasm and enhances its non-genomic responses.
Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5 (PubMed:33283408, PubMed:9885572, PubMed:28977666, PubMed:16428440). The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes (PubMed:33283408, PubMed:16428440, PubMed:28977666). Interacts with RBBP4; the interaction is direct (PubMed:24920672). Interacts with BMAL1 (By similarity). Interacts with CLOCK (By similarity). Interacts with COP1 (PubMed:19805145). Interacts with CSNK1G2 in the cytoplasm (PubMed:15077195). Interacts with EP300 (PubMed:16617102). Interacts with HDAC2 (PubMed:17671180, PubMed:19805145, PubMed:21965678, PubMed:24970816). Interacts with IFI16 (PubMed:24413532). Interacts with ITGB3BP/CENPR (PubMed:15254226). Interacts with MBD3L2 (PubMed:15701600). Interacts with MDM2 (PubMed:19837670). Interacts with NACC2 (PubMed:22926524). Interacts with p53/TP53 (PubMed:19837670). Interacts with PIAS1 (PubMed:21965678). Interacts with PIAS3 (PubMed:21965678). Interacts with PIAS4 (PubMed:21965678). Interacts with PWWP2A (PubMed:30327463). Interacts with PWWP2B (By similarity). Interacts with SENP1 (PubMed:21965678). Interacts with SENP2 (PubMed:21965678). Interacts with SIX3; facilitates the binding of SIX3 to the core DNA motif of SIX3 promoter (PubMed:20682799). Interacts with SUMO1 (PubMed:21965678). Interacts with SUMO2 (PubMed:21965678). Interacts with TFCP2L1; which is indispensable for TFCP2L1-mediated self-renewal-promoting effect and endoderm-inhibiting action (By similarity). Interacts with TFAP2C (PubMed:24413532). Interacts with TPR (PubMed:24970816). Interacts with UBE2I/UBC9 (PubMed:21965678).
Involved in the epigenetic regulation of ESR1 expression in breast cancer in a TFAP2C, IFI16 and HDAC4/5/6-dependent manner.
Isoform Short contains a Leu-Arg-Ile-Leu-Leu motif (ER binding motif).
Phosphorylation by CSNK1G2/CK1 triggered by estrogen enhances corepression of estrogen receptor (ER).
Sumoylation positively regulates its transcriptional corepressor activity but does not affect the protein stability. Sumoylated preferentially by SUMO2 or SUMO3 than SUMO1. Sumoylation is enhanced by PIAS1/3/4 and preferentially sumoylated by SUMO2 in the presence of PIAS1/3/4. Desumoylated by SENP1.
Transcriptional coregulator which can act as both a transcriptional corepressor and coactivator (PubMed:16617102, PubMed:17671180, PubMed:17922032, PubMed:21965678, PubMed:24413532). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:28977666). In the NuRD complex, regulates transcription of its targets by modifying the acetylation status of the target chromatin and cofactor accessibility to the target DNA (PubMed:17671180). In conjunction with other components of NuRD, acts as a transcriptional corepressor of BRCA1, ESR1, TFF1 and CDKN1A (PubMed:17922032, PubMed:24413532). Acts as a transcriptional coactivator of BCAS3, and SUMO2, independent of the NuRD complex (PubMed:21965678, PubMed:17671180, PubMed:16617102). Stimulates the expression of WNT1 by inhibiting the expression of its transcriptional corepressor SIX3 (By similarity). Regulates p53-dependent and -independent DNA repair processes following genotoxic stress (PubMed:19837670). Regulates the stability and function of p53/TP53 by inhibiting its ubiquitination by COP1 and MDM2 thereby regulating the p53-dependent DNA repair (PubMed:19837670). Plays a role in the regulation of the circadian clock and is essential for the generation and maintenance of circadian rhythms under constant light and for normal entrainment of behavior to light-dark (LD) cycles (By similarity). Positively regulates the CLOCK-BMAL1 heterodimer mediated transcriptional activation of its own transcription and the transcription of CRY1 (By similarity). Regulates deacetylation of BMAL1 by regulating SIRT1 expression, resulting in derepressing CRY1-mediated transcription repression (By similarity). With TFCP2L1, promotes establishment and maintenance of pluripotency in embryonic stem cells (ESCs) and inhibits endoderm differentiation (By similarity).
Ubiquitinated by COP1, which leads to proteasomal degradation.
Widely expressed. High expression in brain, liver, kidney, and cardiac muscle, ovaries, adrenal glands and virgin mammary glands. Higher in tumors than in adjacent normal tissue from the same individual. Up-regulated in a wide variety of cancers including breast, liver, ovarian, and colorectal cancer and its expression levels are closely correlated with tumor aggressiveness and metastasis.
Forms a heterodimer with BOLL and DAZL. Interacts with PUM2, DAZAP1, DAZAP2, DZIP1 and DZIP3.
RNA-binding protein that plays an essential role in spermatogenesis. May act by binding to the 3'-UTR of mRNAs and regulating their translation.
The DAZ domains are essential and mediate the interaction with DAZAP1 and DAZAP2.
The DAZ proteins (DAZ, DAZ2, DAZ4 and DAZ4) are all encoded by a strongly repeated region of the Y chromosome, in two clusters each comprising an inverted pair of DAZ genes. They are very similar, which gives their indidual characterization difficult. Thus, most experiments do not discriminate between the different members. One can therefore suppose that reported interactions with a DAZ protein involve all the 4 proteins.
The disease may be caused by variants affecting the gene represented in this entry. AZFc deletions in the Yq11.23 region including the DAZ genes are the most common known genetic cause of human male infertility.
The number as well as the precise structure of the DAZ proteins probably differs within the population.
Belongs to the DZIP C2H2-type zinc-finger protein family.
Interacts with SEPTIN2 (PubMed:28530676).
Involved in primary cilium formation (PubMed:19852954, PubMed:28530676). Probably acts as a transition zone protein required for localization of PKD1/PC1 and PKD2/PC2 to the ciliary membrane (PubMed:28530676).
Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6. Component of a NuA4-related complex which contains EP400, TRRAP/PAF400, SRCAP, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, actin, ACTL6A/BAF53A, VPS72 and YEATS4/GAS41. DMAP1 also forms a complex with DNMT1 and HDAC2. Throughout S phase it interacts directly with the N-terminus of DNMT1, which serves to recruit DMAP1 to replication foci. DMAP1 interacts with ING1, a component of the mSin3A transcription repressor complex, although this interaction is not required for recruitment of ING1 to heterochromatin. Interacts directly with the transcriptional corepressor TSG101. Interacts with the pro-apoptotic protein DAXX. Interacts with URI1.
Involved in transcription repression and activation. Its interaction with HDAC2 may provide a mechanism for histone deacetylation in heterochromatin following replication of DNA at late firing origins. Can also repress transcription independently of histone deacetylase activity. May specifically potentiate DAXX-mediated repression of glucocorticoid receptor-dependent transcription. Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage. Participates in the nuclear localization of URI1 and increases its transcriptional corepressor activity.
Plays a role in mast cell degranulation.
Acts as a negative regulator of hedgehog signaling.
Belongs to the gamma-glutamylcyclotransferase family. ChaC subfamily.
Catalyzes the cleavage of glutathione into 5-oxo-L-proline and a Cys-Gly dipeptide. Acts specifically on glutathione, but not on other gamma-glutamyl peptides.
Although related to peptidase S1 family, lacks the essential His, Asp, and Ser residues of the catalytic triad at positions 83, 129 and 221 and is therefore predicted to have lost protease activity.
Belongs to the POU transcription factor family. Class-4 subfamily.
Expressed in the brain (PubMed:7691107). Expressed in the ganglion cell layer of the retina (PubMed:7691107).
Interacts with POU4F1; this interaction inhibits both POU4F1 DNA-binding and transcriptional activities. Interacts (C-terminus) with ESR1 (via DNA-binding domain); this interaction increases the estrogen receptor ESR1 transcriptional activity in a DNA- and ligand 17-beta-estradiol-independent manner. Interacts (via C-terminus) with TP53 (via N-terminus). Interacts with DLX1 (via homeobox DNA-binding domain); this interaction suppresses DLX1-mediated transcriptional activity in postnatal retina enhancing retinal ganglion cell (RGC) differentiation. Interacts with DLX2 (via homeobox DNA-binding domain); this interaction enhances RGC differentiation. Interacts (via C-terminus) with ISL1 (via C-terminus). Interacts with ISL2. Interacts with LHX2.
The N-terminal transcriptional activation region is sufficient to induce transcriptional activity.
The POU-specific domain and POU homeodomain regions are necessary for DNA-binding activity and transcriptional repression.
The polyhistidine motif acts as a targeting signal to nuclear speckles.
Tissue-specific DNA-binding transcription factor involved in the development and differentiation of target cells (PubMed:19266028, PubMed:23805044). Functions either as activator or repressor modulating the rate of target gene transcription through RNA polymerase II enzyme in a promoter-dependent manner (PubMed:19266028, PubMed:23805044). Binds to the consensus octamer motif 5'-AT[A/T]A[T/A]T[A/T]A-3' of promoter of target genes. Plays a fundamental role in the gene regulatory network essential for retinal ganglion cell (RGC) differentiation. Binds to an octamer site to form a ternary complex with ISL1; cooperates positively with ISL1 and ISL2 to potentiate transcriptional activation of RGC target genes being involved in RGC fate commitment in the developing retina and RGC axon formation and pathfinding. Inhibits DLX1 and DLX2 transcriptional activities preventing DLX1- and DLX2-mediated ability to promote amacrine cell fate specification. In cooperation with TP53 potentiates transcriptional activation of BAX promoter activity increasing neuronal cell apoptosis. Negatively regulates BAX promoter activity in the absence of TP53. Acts as a transcriptional coactivator via its interaction with the transcription factor ESR1 by enhancing its effect on estrogen response element (ERE)-containing promoter. Antagonizes the transcriptional stimulatory activity of POU4F1 by preventing its binding to an octamer motif. Involved in TNFSF11-mediated terminal osteoclast differentiation (By similarity).
Belongs to the eukaryotic ribosomal protein eL22 family.
Binds to Epstein-Barr virus small RNAs and to heparin.
TBL2 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of TBL2 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.
Belongs to the ubiquitin-activating E1 family.
Catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation through the ubiquitin-proteasome system (PubMed:1606621, PubMed:1447181, PubMed:33108101). Activates ubiquitin by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a ubiquitin-E1 thioester and free AMP (PubMed:1447181). Essential for the formation of radiation-induced foci, timely DNA repair and for response to replication stress. Promotes the recruitment of TP53BP1 and BRCA1 at DNA damage sites (PubMed:22456334).
Detected in erythrocytes (at protein level). Ubiquitous.
Monomer (By similarity). Interacts with GAN (via BTB domain).
The disease is caused by variants affecting the gene represented in this entry. Somatic variants affecting the initiator methionine of isoform 2 are recurrently found in VEXAS patients. These variants cause loss of isoform 2 and production of a shorter isoform with strongly reduced enzymatic activity from a downstream methionine (Met-67).
The first 11 amino acids are essential for phosphorylation and exclusive nuclear localization.
There are two active sites within the E1 molecule, allowing it to accommodate two ubiquitin moieties at a time, with a new ubiquitin forming an adenylate intermediate as the previous one is transferred to the thiol site.
Actin-associated protein that may play a role in modulating actin-based shape and motility of dendritic spines and renal podocyte foot processes. Seems to be essential for the formation of spine apparatuses in spines of telencephalic neurons, which is involved in synaptic plasticity (By similarity).
Interacts with BAIAP1. Interacts with actin (By similarity). Interacts (via PPxY motifs) with WWC1 (via WW domains).
Depletion of isoform 2 results in cell apoptosis while its overexpression in cells leads to accelerated growth rate and tumorogenicity.
Expressed in all tissues tested with higher expression in placenta, liver, kidney, heart and brain.
Interacts with the DNA-binding domain of p53/TP53.
May play a role in cell survival and cell growth. May suppress the transcriptional activity of p53/TP53.
Calcium-independent and membrane-bound phospholipase, that catalyzes the esterolytic cleavage of fatty acids from glycerophospholipids to yield free fatty acids and lysophospholipids, hence regulating membrane physical properties and the release of lipid second messengers and growth factors (PubMed:10833412, PubMed:10744668, PubMed:15695510, PubMed:15908428, PubMed:17213206, PubMed:18171998, PubMed:28442572). Hydrolyzes phosphatidylethanolamine, phosphatidylcholine and probably phosphatidylinositol with a possible preference for the former (PubMed:15695510). Has also a broad substrate specificity in terms of fatty acid moieties, hydrolyzing saturated and mono-unsaturated fatty acids at nearly equal rates from either the sn-1 or sn-2 position in diacyl phosphatidylcholine (PubMed:10833412, PubMed:10744668, PubMed:15695510, PubMed:15908428). However, has a weak activity toward polyunsaturated fatty acids at the sn-2 position, and thereby favors the production of 2-arachidonoyl lysophosphatidylcholine, a key branch point metabolite in eicosanoid signaling (PubMed:15908428). On the other hand, can produce arachidonic acid from the sn-1 position of diacyl phospholipid and from the sn-2 position of arachidonate-containing plasmalogen substrates (PubMed:15908428). Therefore, plays an important role in the mobilization of arachidonic acid in response to cellular stimuli and the generation of lipid second messengers (PubMed:15695510, PubMed:15908428). Can also hydrolyze lysophosphatidylcholine (PubMed:15695510). In the mitochondrial compartment, catalyzes the hydrolysis and release of oxidized aliphatic chains from cardiolipin and integrates mitochondrial bioenergetics and signaling. It is essential for maintaining efficient bioenergetic mitochondrial function through tailoring mitochondrial membrane lipid metabolism and composition (PubMed:28442572).
Calcium-independent phospholipase (PubMed:10833412, PubMed:10744668). Inhibited by (E)-6-bromomethylene-3-1-naphthalenyl-2H-tetrahydropyran-2-one (BEL) (PubMed:10744668, PubMed:15908428, PubMed:18171998). The activity toward 1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine is stimulated by cardiolipin (PubMed:28442572).
Expressed in parenchymal tissues including heart, skeletal muscle, placenta, brain, liver and pancreas. Also expressed in bronchial epithelial cells and kidney. Highest expression is observed in skeletal muscle and heart.
Belongs to the UPF0184 (EST00098) family.
Essential for intermediate filament organization in intestinal cells, interacts with intermediate filament and regulates intestinal lumen morphology.
Belongs to the bZIP family. CNC subfamily.
Homodimer; disulfide-linked (PubMed:22194330). Heterodimer of BACH2 and Maf-related transcription factors (By similarity).
Phosphorylation at Ser-521 downstream of the PI-3K pathway promotes nuclear export.
The reversible disulfide bond may provide a mechanism to regulate the activity in oxidative stress responses.
Transcriptional regulator that acts as repressor or activator (By similarity). Binds to Maf recognition elements (MARE) (By similarity). Plays an important role in coordinating transcription activation and repression by MAFK (By similarity). Induces apoptosis in response to oxidative stress through repression of the antiapoptotic factor HMOX1 (PubMed:17018862). Positively regulates the nuclear import of actin (By similarity). Is a key regulator of adaptive immunity, crucial for the maintenance of regulatory T-cell function and B-cell maturation (PubMed:28530713).
Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1-like complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:25519132). Component of a PRC1-like complex that mediates monoubiquitination of histone H2A 'Lys-119' on the X chromosome and is required for normal silencing of one copy of the X chromosome in XX females. May stimulate ubiquitination of histone H2A 'Lys-119' by recruiting the complex to target sites (By similarity). Inhibits ubiquitination and subsequent degradation of TP53, and thereby plays a role in regulating transcription of TP53 target genes (PubMed:19098711). May also regulate the ubiquitin-mediated proteasomal degradation of other proteins like FANK1 to regulate apoptosis (PubMed:14765135, PubMed:27060496). May be implicated in the regulation of the transcription as a repressor of the transcriptional activity of E4TF1 (PubMed:11953439). May bind to DNA (By similarity). May play a role in the repression of tumor growth and metastasis in breast cancer by down-regulating SRRM3 (PubMed:27748911).
Down-regulated in breast cancer tissues and in several breast cancer cell lines (at protein level) (PubMed:27748911). Widely expressed with highest levels in lymphoid tissues and placenta.
Intrinsically unstructured in the absence of binding partners. Folds upon binding to DNA or RNF2 (By similarity).
Monomer. Component of repressive BCOR complex containing Polycomb group subcomplex at least composed of BCOR, PCGF1, RING1 and RNF2/RING2 (PubMed:16943429). Component of PCR1-like complexes (PubMed:26687479, PubMed:20696397). Interacts with PCGF1 (PubMed:26687479). Part of a PCR1-like complex that contains AUTS2, PCGF5, RNF2, CSNK2B and RYBP (PubMed:25519132). Interacts with RNF2; the interaction is direct (PubMed:20696397). Interacts with CBX2, YAF2, RING1 and RNF2 (By similarity). Interacts with ubiquitin and ubiquitinated proteins (By similarity). Interacts with ubiquitinated histone H2A (By similarity). Interacts with apoptin, DEDD, FADD, CASP8, CASP10, YY1 and GABPB1 (PubMed:11395500, PubMed:11953439, PubMed:14765135). Together with GABPB1 and YY1, it forms a ternary complex, probably being the bridge factor between these two transcription factors (PubMed:11953439). Interacts with MDM2, and thereby inhibits ubiquitination of TP53 (PubMed:19098711). Identified in a ternary complex containing MDM2, TP53 and RYBP (PubMed:19098711). Interacts with FANK1; may prevent the ubiquitin-mediated proteasomal degradation of FANK1 (PubMed:27060496). Interacts with IFT57 (By similarity).
Component of the outer dynein arm-docking complex (ODA-DC) that mediates outer dynein arms (ODA) binding onto the doublet microtubule. Seems to regulate the assembly of both ODAs and their axonemal docking complex onto ciliary microtubules (By similarity). Regulates ciliary and flagellar motility and is required for cilia-driven determination of body laterality (By similarity).
Component of the outer dynein arm-docking complex along with ODAD1, ODAD2, ODAD3 and ODAD4.
Component of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex composed at least by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2 (PubMed:16162815, PubMed:9463366). Interacts with PIGQ (PubMed:9463366). Interacts with the heterodimer PIGA:PIGH (PubMed:9463366).
Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis.
Plays an essential role in the maturation of presomitic mesoderm cells by individual attenuation of both FGF and WNT signaling.
Channel opening is brought about by a conformation change that involves buckling of the second transmembrane helix and affects the position and orientation of the fourth transmembrane helix.
Voltage-insensitive potassium channel (PubMed:22282805). Channel opening is triggered by mechanical forces that deform the membrane (PubMed:22282805, PubMed:25471887, PubMed:25500157, PubMed:30290154). Channel opening is triggered by raising the intracellular pH to basic levels (By similarity). The channel is inactive at 24 degrees Celsius (in vitro); raising the temperature to 37 degrees Celsius increases the frequency of channel opening, with a further increase in channel activity when the temperature is raised to 42 degrees Celsius (By similarity). Plays a role in the perception of pain caused by heat (By similarity). Plays a role in the sensory perception of pain caused by pressure (By similarity).
Belongs to the LCE cluster present on 1q21.
Precursors of the cornified envelope of the stratum corneum.
Belongs to the cytochrome c oxidase subunit 5B family.
Numerous size polymorphism are present in KRTAP4 gene family, which are mainly due to variations in the sequence encoding cysteine-rich repeat segments (PubMed:15955084).
Involved in endoplasmic reticulum (ER) stress-induced cell death pathway.
Belongs to the cyclin family. Cyclin L subfamily.
Contains a RS region (arginine-serine dipeptide repeat) within the C-terminal domain which is the hallmark of the SR family of splicing factors. This region probably plays a role in protein-protein interactions (By similarity).
Interacts with CDK11A, CDK11B, CDK12, CDK13 and POLR2A, the hyperphosphorylated C-terminal domain (CTD) of RNA polymerase II (PubMed:14684736, PubMed:18216018). May form a ternary complex with CDK11B and casein kinase II (CKII) (PubMed:18216018). Interacts with pre-mRNA-splicing factors, including at least SRSF1, SRSF2 AND SRSF7/SLU7 (PubMed:14684736, PubMed:18216018).
Involved in pre-mRNA splicing. May induce cell death, possibly by acting on the transcription and RNA processing of apoptosis-related factors.
Belongs to the PI3/PI4-kinase family. Type II PI4K subfamily.
Inhibited by phenylarsine oxide and adenosine (PubMed:11923287). Activation through membrane association is stimulated by active RAC1 (PubMed:12324459).
Together with PI4K2A and the type III PI4Ks (PIK4CA and PIK4CB) it contributes to the overall PI4-kinase activity of the cell (PubMed:11923287, PubMed:12324459). This contribution may be especially significant in plasma membrane, endosomal and Golgi compartments (PubMed:11923287, PubMed:12324459). The phosphorylation of phosphatidylinositol (PI) to PI4P is the first committed step in the generation of phosphatidylinositol 4,5-bisphosphate (PIP2), a precursor of the second messenger inositol 1,4,5-trisphosphate (InsP3) (PubMed:11923287, PubMed:12324459). Contributes to the production of InsP3 in stimulated cells and is likely to be involved in the regulation of vesicular trafficking.
Involved in the biosynthesis of gangliosides GM2, GD2, GT2 and GA2 from GM3, GD3, GT3 and GA3, respectively.
Behaves as a cytokine, promoting IL17A secretion by CD4+ T-cells, and differentiation and activation of IL17 producing helper T-cells (TH17).
Contains 2 copies of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases. Both motives are required for full inhibition of FCER1A-mediated degranulation.
Expressed on myeloid (neutrophils, eosinophils and monocytes) but not on lymphoid cells.
Inhibitory immune receptor involved in the regulation of phagocytes.
Mainly detected in immune tissues and cells.
Belongs to the leukocyte receptor cluster (LRC) present on 19q13.4.
Interacts (via its N-terminal region) with PLK1; controls PLK1 kinase activity (PubMed:34260926). Interacts (via the KVVXF motif) with PPP1CC; controls PLK1 kinase activity (PubMed:34260926). Interacts with FIGNL1; may regulate homologous recombination (PubMed:29608566).
Phosphorylation at Ser-43 by PLK1 strengthens FIRRM-PLK1 interaction (PubMed:34260926). Phosphorylation at Ser-744 by PLK1 negatively regulates its interaction with PPP1CC (PubMed:34260926).
Regulates PLK1 kinase activity at kinetochores and promotes faithful chromosome segregation in prometaphase by bridging kinase and phosphatase activities (PubMed:34260926). Phosphorylation of FIRRM by PLK1 negatively regulates its interaction with the phosphatase, PPP1CC, thus creating a negative feedback loop for maintaining proper PLK1 kinase activity during mitosis (PubMed:34260926). In complex with FIGL1 may regulate homologous recombination (PubMed:29608566).
Belongs to the methyltransferase superfamily. METTL21 family.
Interacts with heat shock protein 70 family members; at least some of these proteins are methylation substrates (PubMed:23349634, PubMed:23921388).
Protein-lysine methyltransferase that selectively trimethylates residues in heat shock protein 70 (HSP70) family members. Contributes to the in vivo trimethylation of Lys residues in HSPA1 and HSPA8. In vitro methylates 'Lys-561' in HSPA1, 'Lys-564' in HSPA2, 'Lys-585' in HSPA5, 'Lys-563' in HSPA6 and 'Lys-561' in HSPA8.
Transcriptional regulator that plays a key role in germ cell development. Determines the oogenic fate by activating key genes for the oogenic program and meiotic prophase entry. Acts downstream of bone morphogenetic protein (BMP) by regulating expression of genes required for the oogenic programs, which are repressed by Polycomb activities in sexually uncommitted germ cells. Regulates expression of STRA8, a central downstream effector for the meiotic program. Acts independently of retinoic acid (RA). In males, not required for germ-cell sex determination, but required to allow the spermatogonia to efficiently accomplish the meiotic prophase.
Expressed in the vascular smooth muscle of coronary artery.
Interacts with EPHB2 (By similarity). Interacts with EPHA4.
Phosphorylated on tyrosine residues upon EFNA1 stimulation. EPHB2-dependent phosphorylation at Tyr-353 triggers UBE3A-mediated ubiquitination (By similarity).
Specific GEF for RhoA activation. Does not activate RAC1 or CDC42. Regulates vascular smooth muscle contractility. Negatively regulates excitatory synapse development by suppressing the synapse-promoting activity of EPHB2.
Ubiquitinated; UBE3A-mediated ubiquitination and degradation by the proteasome promotes EFNB1-dependent synapse formation.
Belongs to the phosphatase and actin regulator family.
Acetylcholine receptors incorporating that alpha subunit do not bind alpha-bungarotoxin.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-1/CHRNA1 sub-subfamily.
Is able to interact with other subunits of the acetylcholine receptor but is not assembled into functional acetylcholine-gated cation-selective channels.
Isoform 1 is only expressed in skeletal muscle. Isoform 2 is constitutively expressed in skeletal muscle, brain, heart, kidney, liver, lung and thymus.
Non functional acetylcholine receptor alpha subunit which is not integrated into functional acetylcholine-gated cation-selective channels.
One of the alpha chains that assemble within the acetylcholine receptor, a pentamer of two alpha chains, a beta, a delta, and a gamma (in immature muscle) or epsilon (in mature muscle) chains. The muscle heteropentamer composed of alpha-1, beta-1, delta, epsilon subunits interacts with the alpha-conotoxin ImII (PubMed:15609996).
The alpha subunit is the main focus for antibody binding in myasthenia gravis. Myasthenia gravis is characterized by sporadic muscular fatigability and weakness, occurring chiefly in muscles innervated by cranial nerves, and characteristically improved by cholinesterase-inhibiting drugs.
Upon acetylcholine binding, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
Induced in early phase of liver regeneration.
Interacts with GPIHBP1 (PubMed:17997385). Interacts with SORL1; this interaction leads to APOA5 internalization and sorting either to lysosomes and degradation, or to the trans-Golgi network (PubMed:17326667, PubMed:18603531).
Minor apolipoprotein mainly associated with HDL and to a lesser extent with VLDL. May also be associated with chylomicrons. Important determinant of plasma triglyceride (TG) levels by both being a potent stimulator of apo-CII lipoprotein lipase (LPL) TG hydrolysis and an inhibitor of the hepatic VLDL-TG production rate (without affecting the VLDL-apoB production rate) (By similarity). Activates poorly lecithin:cholesterol acyltransferase (LCAT) and does not enhance efflux of cholesterol from macrophages. Binds heparin (PubMed:17326667).
Three common alleles are known: allele APOA5*1, APOA5*2 and APOA5*3. The APOA5*2 haplotype, which consists of 3 non-coding SNPs, is present in approximately 16% of Caucasians and is associated with increased plasma triglyceride concentrations. APOA5*3 haplotype is defined by the rare Ser-19-Trp substitution. Together, the APOA5*2 and APOA5*3 haplotypes are found in 25 to 50% of African Americans, Hispanics, and Caucasians.
Up-regulated by PPARA agonists, which are used clinically to lower serum TG (such as fibrates).
Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation. Sperm cell hyperactivation is needed for sperm motility which is essential late in the preparation of sperm for fertilization. Required for CATSPER1 stability before intraflagellar transport and/or incorporation of the CatSper complex channel into the flagellar membrane.
Component of the CatSper complex or CatSpermasome composed of the core pore-forming members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 as well as auxiliary members CATSPERB, CATSPERG, CATSPERD, CATSPERE, CATSPERZ, C2CD6/CATSPERT, TMEM249, TMEM262 and EFCAB9 (By similarity). HSPA1 may be an additional auxiliary complex member (By similarity). The core complex members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 form a heterotetrameric channel. The auxiliary CATSPERB, CATSPERG, CATSPERD and CATSPERE subunits form a pavilion-like structure over the pore which stabilizes the complex through interactions with CATSPER4, CATSPER3, CATSPER1 and CATSPER2 respectively. TMEM262/CATSPERH interacts with CATSPERB, further stabilizing the complex. C2CD6/CATSPERT interacts at least with CATSPERD and is required for targeting the CatSper complex in the flagellar membrane (By similarity).
Binds (via the RRM domain) to the 3'-untranslated region (UTR) of CDKN1A mRNA.
Catalyzes the NAD-dependent dehydrogenation (oxidation) of a broad array of hydroxylated polyunsaturated fatty acids (mainly eicosanoids and docosanoids, including prostaglandins, lipoxins and resolvins), yielding their corresponding keto (oxo) metabolites (PubMed:8086429, PubMed:10837478, PubMed:16828555, PubMed:16757471, PubMed:21916491, PubMed:25586183). Decreases the levels of the pro-proliferative prostaglandins such as prostaglandin E2 (whose activity is increased in cancer because of an increase in the expression of cyclooxygenase 2) and generates oxo-fatty acid products that can profoundly influence cell function by abrogating pro-inflammatory cytokine expression (PubMed:25586183, PubMed:15574495). Converts resolvins E1, D1 and D2 to their oxo products, which represents a mode of resolvin inactivation. Resolvin E1 plays important roles during the resolution phase of acute inflammation, while resolvins D1 and D2 have a unique role in obesity-induced adipose inflammation (PubMed:16757471, PubMed:22844113).
Detected in colon epithelium (at protein level).
Down-regulated by cortisol, dexamethasone and betamethasone. Down-regulated in colon cancer. Up-regulated by TGFB1.
May be involved in cell cycle regulation by chromatin remodeling.
Ubiquitously expressed (PubMed:11306461, PubMed:27486781). In the retina, present in the nerve fiber layer and to a lesser extent in the inner and outer plexiform layers (at protein level) (PubMed:27486781).
Belongs to the anaerobic coproporphyrinogen-III oxidase family. HemW subfamily.
May be a heme chaperone, appears to bind heme. Homologous bacterial proteins do not have oxygen-independent coproporphyrinogen-III oxidase activity (Probable). Binds 1 [4Fe-4S] cluster. The cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine (By similarity).
Might carry two S-adenosyl-L-methionine binding sites with only one binding to the iron-sulfur cluster.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ14 subfamily.
Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. KCNJ14 gives rise to low-conductance channels with a low affinity to the channel blockers Barium and Cesium (By similarity).
A chromosomal aberration involving DDX6 may be a cause of hematopoietic tumors such as B-cell lymphomas. Translocation t(11;14)(q23;q32).
Belongs to the DEAD box helicase family.
Belongs to the DEAD box helicase family. DDX6/DHH1 subfamily.
Essential for the formation of P-bodies, cytosolic membrane-less ribonucleoprotein granules involved in RNA metabolism through the coordinated storage of mRNAs encoding regulatory functions (PubMed:25995375, PubMed:27342281, PubMed:31422817). Plays a role in P-bodies to coordinate the storage of translationally inactive mRNAs in the cytoplasm and prevent their degradation (PubMed:27342281). In the process of mRNA degradation, plays a role in mRNA decapping (PubMed:16364915). Blocks autophagy in nutrient-rich conditions by repressing the expression of ATG-related genes through degradation of their transcripts (PubMed:26098573).
Interacts with LSM14A, LSM14B, EIF4ENIF1/4E-T, PATL1, EDC3 and EDC4 (PubMed:26027925, PubMed:31422817, PubMed:27342281, PubMed:28216671, PubMed:32354837, PubMed:26489469, PubMed:29510985, PubMed:31439631). Forms a complex with DCP1A, DCP2, EDC3 and EDC4/HEDLS (PubMed:16364915, PubMed:19285948). Interacts with LIMD1, WTIP and AJUBA (PubMed:20616046). Interacts with APOBEC3G in an RNA-dependent manner (PubMed:16699599). Interacts with RC3H1 (By similarity). Interacts with ATXN2L (PubMed:23209657). Interacts with MCRIP1 (PubMed:26184334). Interacts with MCRIP2 (PubMed:26184334). Interacts with NUFIP2 (PubMed:26184334). Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner (PubMed:23125361). Interacts with GIGYF1 and GIGYF2 (PubMed:31439631).
Catalyzes the biosynthesis and metabolism of eicosanoids. Catalyzes the isomerization of prostaglandin H2 to prostacyclin (= prostaglandin I2), a potent mediator of vasodilation and inhibitor of platelet aggregation (PubMed:18032380, PubMed:25623425, PubMed:12372404, PubMed:15115769). Additionally, displays dehydratase activity, toward hydroperoxyeicosatetraenoates (HPETEs), especially toward (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (15(S)-HPETE) (PubMed:17459323).
Widely expressed; particularly abundant in ovary, heart, skeletal muscle, lung and prostate.
Interacts with the Rho-GAP domain of RACGAP1 (PubMed:12590651). Interacts with UBXD5 (PubMed:11940653). Interacts with PRAG1 (By similarity).
May be specifically involved in neuronal and hepatic functions. Is a C3 toxin-insensitive member of the Rho subfamily (By similarity).
Part of the tectonic-like complex (also named B9 complex). Interacts with TMEM107.
A report observed N-glycosylation at Asn-58 (PubMed:19139490). However, as the protein is not predicted to localize in an extracellular compartment of the cell, additional evidence is required to confirm this result.
Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation. Sperm cell hyperactivation is needed for sperm motility which is essential late in the preparation of sperm for fertilization. Required for a distribution of the CatSper complex in linear quadrilateral nanodomains along the flagellum, maximizing fertilization inside the mammalian female reproductive tract. Together with EFCAB9, associates with the CatSper channel pore and is required for the two-row structure of each single CatSper channel.
Component of the CatSper complex or CatSpermasome composed of the core pore-forming members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 as well as auxiliary members CATSPERB, CATSPERG, CATSPERD, CATSPERE, CATSPERZ, C2CD6/CATSPERT, TMEM249, TMEM262 and EFCAB9 (By similarity). HSPA1 may be an additional auxiliary complex member (By similarity). The core complex members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 form a heterotetrameric channel (By similarity). The auxiliary CATSPERB, CATSPERG, CATSPERD and CATSPERE subunits form a pavilion-like structure over the pore which stabilizes the complex through interactions with CATSPER4, CATSPER3, CATSPER1 and CATSPER2 respectively (By similarity). TMEM262/CATSPERH interacts with CATSPERB, further stabilizing the complex. C2CD6/CATSPERT interacts at least with CATSPERD and is required for targeting the CatSper complex in the flagellar membrane (By similarity). Interacts with EFCAB9; the interaction is direct, Ca(2+)-dependent and connects EFCAB9 with the CatSper complex (By similarity). Dissociates from EFCAB9 at elevated pH (By similarity).
Plays a role in the control of cellular growth (PubMed:18285427). May have a role in epidermal development. May act as a receptor for Sonic hedgehog (SHH).
Interacts with PRKCABP, and disrupts the interaction between GRIA2 and PRKCABP, leading to the internalization of GRIA2 (By similarity). Found in a complex with VAMP8 (By similarity). Component of a SNARE-like complex that contains at least ZW10, USE1L, RINT1, STX18 and NAPA/SNAP-alpha (PubMed:15029241). Interacts with VTI1A (By similarity). Interacts with STX12 (By similarity). Interacts with GNA12 (via N-terminus); the interaction promotes CDH5 localization to plasma membrane (PubMed:15980433).
Required for vesicular transport between the endoplasmic reticulum and the Golgi apparatus (Probable). Together with GNA12 promotes CDH5 localization to plasma membrane (PubMed:15980433).
Binds 3 zinc ions per subunit. The zinc ions have a structural role (PubMed:24315485).
Broadly expressed. Highly expressed in hematopoietic cells; highest expression observed in granulocytes. Expression is reduced in granulocytes from peripheral blood of patients affected by myelodysplastic syndromes.
Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation. Has a preference for 5-hydroxymethylcytosine in CpG motifs. Also mediates subsequent conversion of 5hmC into 5-formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC probably constitutes the first step in cytosine demethylation. Methylation at the C5 position of cytosine bases is an epigenetic modification of the mammalian genome which plays an important role in transcriptional regulation. In addition to its role in DNA demethylation, also involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT.
Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in epigenetic chromatin reprogramming during embryonic development.
Interacts with HCFC1 (PubMed:23353889). Interacts with OGT (PubMed:23353889, PubMed:23222540). Interacts with PROSER1; this interaction mediates TET2 O-GlcNAcylation and stability by promoting the interaction between OGT and TET2 (PubMed:34667079). Directly interacts (via C-terminus) with the DCAF1 component of the CRL4(VprBP) E3 ubiquitin-protein ligase complex (PubMed:24357321, PubMed:25557551).
May be glycosylated. It is unclear whether interaction with OGT leads to GlcNAcylation. According to a report, it is not GlcNAcylated by OGT (PubMed:23353889). In contrast, another group reports GlcNAcylation by OGT in mouse ortholog.
Monoubiquitinated at Lys-1299 by the DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex called CRL4(VprBP) or CUL4A-RBX1-DDB1-DCAF1/VPRBP complex; this modification promotes binding to DNA.
Subsequent steps in cytosine demethylation are subject to discussion. According to a first model cytosine demethylation occurs through deamination of 5hmC into 5-hydroxymethyluracil (5hmU) and subsequent replacement by unmethylated cytosine by the base excision repair system. According to another model, cytosine demethylation is rather mediated via conversion of 5hmC into 5fC and 5caC, followed by excision by TDG (PubMed:21817016).
TET2 is frequently mutated in myeloproliferative disorders (MPD). These constitute a heterogeneous group of disorders, also known as myeloproliferative diseases or myeloproliferative neoplasms (MPN), characterized by cellular proliferation of one or more hematologic cell lines in the peripheral blood, distinct from acute leukemia. Included diseases are: essential thrombocythemia, polycythemia vera, primary myelofibrosis (chronic idiopathic myelofibrosis). Bone marrow samples from patients display uniformly low levels of hmC in genomic DNA compared to bone marrow samples from healthy controls as well as hypomethylation relative to controls at the majority of differentially methylated CpG sites.
TET2 is frequently mutated in systemic mastocytosis; also known as systemic mast cell disease. A condition with features in common with myeloproliferative diseases. It is a clonal disorder of the mast cell and its precursor cells. The clinical symptoms and signs of systemic mastocytosis are due to accumulation of clonally derived mast cells in different tissues, including bone marrow, skin, the gastrointestinal tract, the liver, and the spleen.
The disease is caused by variants affecting the gene represented in this entry. Bone marrow samples from patients display uniformly low levels of hmC in genomic DNA compared to bone marrow samples from healthy controls as well as hypomethylation relative to controls at the majority of differentially methylated CpG sites.
(Microbial infection) Cleaved at two different sites by enterovirus 71 protease 3C, leading to impaired PML-Nuclear bodies formation.
(Microbial infection) Immediate early protein IE1 of human cytomegalovirus (HHV-5) interferes with the sumoylation of PML (PubMed:15163746, PubMed:10233977, PubMed:27903803). Immediate early protein IE1 inhibits PML de novo sumoylation (PubMed:27903803).
(Microbial infection) Interacts with Lassa virus Z protein and rabies virus phosphoprotein.
(Microbial infection) Interacts with human cytomegalovirus (HHV-5) immediate early protein IE1; this interaction mediates PML desumoylation and PML-mediated sumoylation of IE1.
(Microbial infection) Isoform PML-1 interacts with herpes simplex virus-1/HHV-1 ICP0.
(Microbial infection) Isoform PML-2 interacts with human adenovirus 2 E1A and this interaction stimulates E1A-dependent transcriptional activation.
(Microbial infection) Isoform PML-3 interacts (via RING-type zinc finger) with human foamy virus bel1/tas and bet.
(Microbial infection) Isoform PML-4 and isoform PML-5 interact with human adenovirus 5 E1B-55K protein; these interactions promote efficient subnuclear targeting of E1B-55K to PML nuclear bodies.
(Microbial infection) Isoform PML-4 interacts with VZV capsid protein VP26/ORF23 capsid protein.
(Microbial infection) Isoform PML-6 interacts with moloney murine leukemia virus (MoMLV) integrase (IN) and reverse transcriptase (RT).
(Microbial infection) The RING-type zinc finger is necessary for the sumoylation of human cytomegalovirus (HHV-5) immediate early protein IE1.
(Microbial infection) The sumoylated isoform PML-4 interacts with encephalomyocarditis virus (EMCV) RNA-directed RNA polymerase 3D-POL (P3D-POL).
(Microbial infection) Upon infection with Epstein-Barr virus, phosphorylated by CK2. Viral EBNA1 increases the association of CK2 with PML proteins, which increases PML phosphorylation by CK2, triggering the USP7-dependent polyubiquitylation and degradation of PML.
A chromosomal aberration involving PML may be a cause of acute promyelocytic leukemia (APL). Translocation t(15;17)(q21;q21) with RARA. The PML breakpoints (type A and type B) lie on either side of an alternatively spliced exon.
Acetylation at Lys-487 is essential for its nuclear localization. Deacetylated at Lys-487 by SIRT1 and this deacetylation promotes PML control of PER2 nuclear localization.
Binds arsenic via the RING-type zinc finger.
By interferons alpha, beta and gamma. Up-regulated by IRF3 and p53/TP53.
Exhibits antiviral activity against both DNA and RNA viruses. The antiviral activity can involve one or several isoform(s) and can be enhanced by the permanent PML-NB-associated protein DAXX or by the recruitment of p53/TP53 within these structures. Isoform PML-4 restricts varicella zoster virus (VZV) via sequestration of virion capsids in PML-NBs thereby preventing their nuclear egress and inhibiting formation of infectious virus particles. The sumoylated isoform PML-4 restricts rabies virus by inhibiting viral mRNA and protein synthesis. The cytoplasmic isoform PML-14 can restrict herpes simplex virus-1 (HHV-1) replication by sequestering the viral E3 ubiquitin-protein ligase ICP0 in the cytoplasm. Isoform PML-6 shows restriction activity towards human cytomegalovirus (HHV-5) and influenza A virus strains PR8(H1N1) and ST364(H3N2). Sumoylated isoform PML-4 and isoform PML-12 show antiviral activity against encephalomyocarditis virus (EMCV) by promoting nuclear sequestration of viral polymerase (P3D-POL) within PML NBs. Isoform PML-3 exhibits antiviral activity against poliovirus by inducing apoptosis in infected cells through the recruitment and the activation of p53/TP53 in the PML-NBs. Isoform PML-3 represses human foamy virus (HFV) transcription by complexing the HFV transactivator, bel1/tas, preventing its binding to viral DNA. PML may positively regulate infectious hepatitis C viral (HCV) production and isoform PML-2 may enhance adenovirus transcription. Functions as an E3 SUMO-protein ligase that sumoylates (HHV-5) immediate early protein IE1, thereby participating in the antiviral response (PubMed:20972456, PubMed:28250117). Isoforms PML-3 and PML-6 display the highest levels of sumoylation activity (PubMed:20972456, PubMed:28250117).
Functions via its association with PML-nuclear bodies (PML-NBs) in a wide range of important cellular processes, including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms. Acts as the scaffold of PML-NBs allowing other proteins to shuttle in and out, a process which is regulated by SUMO-mediated modifications and interactions. Inhibits EIF4E-mediated mRNA nuclear export by reducing EIF4E affinity for the 5' 7-methylguanosine (m7G) cap of target mRNAs (PubMed:11500381, PubMed:11575918, PubMed:18391071). Isoform PML-4 has a multifaceted role in the regulation of apoptosis and growth suppression: activates RB1 and inhibits AKT1 via interactions with PP1 and PP2A phosphatases respectively, negatively affects the PI3K pathway by inhibiting MTOR and activating PTEN, and positively regulates p53/TP53 by acting at different levels (by promoting its acetylation and phosphorylation and by inhibiting its MDM2-dependent degradation). Isoform PML-4 also: acts as a transcriptional repressor of TBX2 during cellular senescence and the repression is dependent on a functional RBL2/E2F4 repressor complex, regulates double-strand break repair in gamma-irradiation-induced DNA damage responses via its interaction with WRN, acts as a negative regulator of telomerase by interacting with TERT, and regulates PER2 nuclear localization and circadian function. Isoform PML-6 inhibits specifically the activity of the tetrameric form of PKM. The nuclear isoforms (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5) in concert with SATB1 are involved in local chromatin-loop remodeling and gene expression regulation at the MHC-I locus. Isoform PML-2 is required for efficient IFN-gamma induced MHC II gene transcription via regulation of CIITA. Cytoplasmic PML is involved in the regulation of the TGF-beta signaling pathway. PML also regulates transcription activity of ELF4 and can act as an important mediator for TNF-alpha- and IFN-alpha-mediated inhibition of endothelial cell network formation and migration.
Key component of PML bodies. PML bodies are formed by the interaction of PML homodimers (via SUMO-binding motif) with sumoylated PML, leading to the assembly of higher oligomers. Several types of PML bodies have been observed. PML bodies can form hollow spheres that can sequester target proteins inside. Interacts (via SUMO-binding motif) with sumoylated proteins. Interacts (via C-terminus) with p53/TP53. Recruits p53/TP53 and CHEK2 into PML bodies, which promotes p53/TP53 phosphorylation at 'Ser-20' and prevents its proteasomal degradation. Interacts with MDM2, and sequesters MDM2 in the nucleolus, thereby preventing ubiquitination of p53/TP53. Interaction with PML-RARA oncoprotein and certain viral proteins causes disassembly of PML bodies and abolishes the normal PML function. Interacts with HIPK2, TERT, SIRT1, TOPBP1, TRIM27 and TRIM69. Interacts with ELF4 (via C-terminus). Interacts with ITPR3. Interacts (in the cytoplasm) with TGFBR1, TGFBR2 and PKM. Interacts (via the coiled-coil domain and when sumoylated) with SATB1. Interacts with UBE2I; the interaction is enhanced by arsenic binding. Interacts (PML-RARA oncoprotein, via the coiled-coil domain) with UBE2I; the interaction is enhanced by arsenic binding and is required for PML-RARA oncoprotein sumoylation and inhibition of RARA transactivational activity. Interacts with RB1, PPP1A, SMAD2, SMAD3, DAXX, RPL11 and MTOR. Interacts with PPARGC1A and KAT2A. Interacts with CSNK2A1 and CSNK2A3. Interacts with ANKRD2; the interaction is direct. Interacts (via SUMO-interacting motif) with sumoylated MORC3 (PubMed:20501696). Isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4, isoform PML-5 and isoform PML-6 interact with RNF4. Isoform PML-1 interacts with NLRP3. Isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5 interact with MAGEA2, RBL2, PER2 and E2F4. Isoform PML-2 interacts with CIITA. Isoform PML-2, isoform PML-3 and isoform PML-4 interact with TBX2. Isoform PML-4 interacts with RANBP2, HDAC7, KAT6A, WRN, PIN1, TBX3 and phosphorylated MAPK1/ERK2. Isoform PML-4 interacts with the CTNNB1 and TCF7L2/TCF4 complex. Isoform PML-4 preferentially interacts with MAPK7/BMK1 although other isoforms (isoform PML-1, isoform PML-2, isoform PML-3 and isoform PML-6) also interact with it. Isoform PML-12 interacts with PIAS1, PIAS2 (isoform PIAS2-alpha) and CSNK2A1/CK2. Interacts with TRIM16. Interacts with PRDM1/Blimp-1 (PubMed:28842558). Interacts (via RING-type zinc finger) with EIF4E; the interaction results in conformational changes of both interacting proteins and reduces EIF4E affinity for the 5' m7G cap of mRNA, thus reducing EIF4E-mediated mRNA nuclear export (PubMed:11500381, PubMed:11575918).
Non-canonical splice sites. Might alternatively represent a polymorphic variation.
Phosphorylation is a major regulatory mechanism that controls PML protein abundance and the number and size of PML nuclear bodies (PML-NBs). Phosphorylated in response to DNA damage, probably by ATR (PubMed:15195100). HIPK2-mediated phosphorylation at Ser-8, Ser-36 and Ser-38 leads to increased accumulation of PML protein and its sumoylation and is required for the maximal pro-apoptotic activity of PML after DNA damage (PubMed:19015637). CHEK2-mediated phosphorylation at Ser-117 is important for PML-mediated apoptosis following DNA damage (PubMed:12402044). MAPK1-mediated phosphorylations at Ser-403, Ser-505, Ser-527 and Ser-530 and CDK1/2-mediated phosphorylation at Ser-518 promote PIN1-dependent PML degradation (PubMed:22033920, PubMed:21840486). CK2-mediated phosphorylation at Ser-565 primes PML ubiquitination via an unidentified ubiquitin ligase (PubMed:22406621, PubMed:20719947).
Sumoylation regulates PML's: stability in response to extracellular or intracellular stimuli, transcription directly and indirectly, through sequestration of or dissociation of the transcription factors from PML-NBs, ability to regulate apoptosis and its anti-viral activities. It is also essential for: maintaining proper PML nuclear bodies (PML-NBs) structure and normal function, recruitment of components of PML-NBs, the turnover and retention of PML in PML-NBs and the integrity of PML-NBs. Undergoes 'Lys-11'-linked sumoylation. Sumoylation on all three sites (Lys-65, Lys-160 and Lys-490) is required for nuclear body formation. Sumoylation on Lys-160 is a prerequisite for sumoylation on Lys-65. Lys-65 and Lys-160 are sumoylated by PISA1 and PIAS2. PIAS1-mediated sumoylation of PML promotes its interaction with CSNK2A1/CK2 and phosphorylation at Ser-565 which in turn triggers its ubiquitin-mediated degradation. PIAS1-mediated sumoylation of PML-RARA promotes its ubiquitin-mediated degradation. The PML-RARA fusion protein requires the coiled-coil domain for sumoylation. Sumoylation at Lys-490 by RANBP2 is essential for the proper assembly of PML-NBs. SUMO1P1/SUMO5 conjugated PML at Lys-160, Lys-380, Lys-400, Lys-490 and Lys-497, but Lys-380, Lys-400 and Lys-497 are not key acceptor lysines. SUMO1P1/SUMO5 forms polymeric chain on Lys-160 of PML by successive conjugation at 'Lys-18'; facilitating recruitment of PML-NB components, which enlarges PML. SUMO1P1/SUMO5 conjugation of PML increases SUMO2/3 conjugation, which leads to the recruitment of RNF4 and ubiquitin-dependent disintegration of PML-NBs. SUMO1P1/SUMO5 monoconjugated Lys-490 (PubMed:27211601). DNA damage triggers its sumoylation while some but not all viral infections can abolish sumoylation. Desumoylated by SENP1, SENP2, SENP3, SENP5 and SENP6 (PubMed:27211601, PubMed:12419228, PubMed:21148299). Arsenic induces PML and PML-RARA polysumoylation and their subsequent RNF4-dependent ubiquitination and proteasomal degradation, and is used as treatment in acute promyelocytic leukemia (APL). The nuclear isoforms (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4, isoform PML-5 and isoform PML-6) show an increased sumoylation in response to arsenic trioxide. The cytoplasmic isoform PML-7 is not sumoylated.
The B box-type zinc binding domain and the coiled-coil domain mediate its interaction with PIAS1.
The Sumo interaction motif (SIM) is required for efficient ubiquitination, recruitment of proteasome components within PML-NBs and PML degradation in response to arsenic trioxide.
The coiled-coil domain mediates a strong homo/multidimerization activity essential for core assembly of PML-NBs. Interacts with PKM via its coiled-coil domain (PubMed:18298799).
The unique C-terminal domains of isoform PML-2 and isoform PML-5 play an important role in regulating the localization, assembly dynamics, and functions of PML-NBs.
Ubiquitinated; mediated by RNF4, RNF111, UHRF1, UBE3A/E6AP, BCR(KLHL20) E3 ubiquitin ligase complex E3 ligase complex, SIAH1 or SIAH2 and leading to subsequent proteasomal degradation (PubMed:18408734, PubMed:21840486, PubMed:22033920). Ubiquitination by BCR(KLHL20) E3 ubiquitin ligase complex E3 ligase complex requires CDK1/2-mediated phosphorylation at Ser-518 which in turn is recognized by prolyl-isopeptidase PIN1 and PIN1-catalyzed isomerization further potentiates PML interaction with KLHL20 (PubMed:21840486, PubMed:22033920). 'Lys-6'-, 'Lys-11'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination by RNF4 is polysumoylation-dependent (PubMed:18408734). Ubiquitination by RNF111 is polysumoylation-dependent (By similarity).
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In association with the E3 enzyme BRE1 (RNF20 and/or RNF40), it plays a role in transcription regulation by catalyzing the monoubiquitination of histone H2B at 'Lys-120' to form H2BK120ub1. H2BK120ub1 gives a specific tag for epigenetic transcriptional activation, elongation by RNA polymerase II, telomeric silencing, and is also a prerequisite for H3K4me and H3K79me formation. In vitro catalyzes 'Lys-11', as well as 'Lys-48'-linked polyubiquitination. Required for postreplication repair of UV-damaged DNA.
Interacts with RAD18 and WAC (PubMed:21329877). Interacts with RFPL4A and CCNB1 (By similarity).
Phosphorylation at Ser-120 by CDK9 increases activity towards histone H2B.
Expressed in bone marrow. Not detected in placenta.
Possesses similar cytotoxic and cytostimulatory activities to PRG2/MBP. In vitro, stimulates neutrophil superoxide production and IL8 release, and histamine and leukotriene C4 release from basophils.
Collagen-like protein specifically expressed in the inner ear, which provides an organic scaffold for otoconia, a calcium carbonate structure in the saccule and utricle of the ear. Acts as a scaffold for biomineralization: sequesters calcium and forms interconnecting fibrils between otoconia that are incorporated into the calcium crystal structure. Together with OC90, modulates calcite crystal morphology and growth kinetics.
Homooligomer; disulfide-linked; probably forms homotrimers. Interacts with OC90. Interacts with CBLN1.
The C1q domain mediates calcium-binding.
Belongs to the mitochondrion-specific ribosomal protein mL37 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379, PubMed:25278503). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. mL37 forms a heterodimer with mL65.
Expressed specifically in the cerebellum.
Interacts with activated forms of GNAO1 and GNAZ.
Associates with the mitochondrial ribosome large subunit; the association occurs in a GTP-dependent manner.
Belongs to the TRAFAC class OBG-HflX-like GTPase superfamily. OBG GTPase family.
Plays a role in the regulation of the mitochondrial ribosome assembly and of translational activity. Displays GTPase activity. Involved in the ribosome maturation process.
Belongs to the eukaryotic RPC34/RPC39 RNA polymerase subunit family.
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits. RPC3/POLR3C, RPC6/POLR3F and RPC7/POLR3G form a Pol III subcomplex (By similarity). Directly interacts with POLR3C (PubMed:21358628). Interacts with TBP and TFIIIB90 and GTF3C4 (By similarity) (PubMed:10523658). Interacts with MAF1 (PubMed:18377933). As part of the RNA polymerase III (Pol III) complex, interacts with PKP2 (PubMed:11416169).
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Specific peripheric component of RNA polymerase III which synthesizes small RNAs, such as 5S rRNA and tRNAs.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Specific peripheric component of RNA polymerase III which synthesizes small RNAs, such as 5S rRNA and tRNAs. May direct RNA Pol III binding to the TFIIIB-DNA complex. Plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses, including varicella zoster virus (PubMed:30211253). Acts as nuclear and cytosolic DNA sensor detecting AT-rich DNA, involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF- Kappa-B through the RIG-I pathway. Preferentially binds double-stranded DNA (dsDNA) (PubMed:21358628).
Belongs to the acyl-CoA dehydrogenase family.
Competitively inhibited by valproyl-CoA.
Short and branched chain specific acyl-CoA dehydrogenase that catalyzes the removal of one hydrogen from C-2 and C-3 of the fatty acyl-CoA thioester, resulting in the formation of trans-2-enoyl-CoA (PubMed:7698750, PubMed:11013134, PubMed:21430231, PubMed:10832746). Among the different mitochondrial acyl-CoA dehydrogenases, acts specifically on short and branched chain acyl-CoA derivatives such as (S)-2-methylbutyryl-CoA as well as short straight chain acyl-CoAs such as butyryl-CoA (PubMed:7698750, PubMed:11013134, PubMed:21430231, PubMed:10832746). Plays an important role in the metabolism of L-isoleucine by catalyzing the dehydrogenation of 2-methylbutyryl-CoA, one of the steps of the L-isoleucine catabolic pathway (PubMed:11013134, PubMed:10832746). Can also act on valproyl-CoA, a metabolite of valproic acid, an antiepileptic drug (PubMed:8660691).
(Microbial infection) Interacts (via C-terminus) with HCV envelope glycoprotein E1. Interacts (via C-terminus) with HCV non-structural protein 5A; this interaction targets NS5A for ubiquitination and degradation.
Component of the probable ECS(SPSB2) E3 ubiquitin-protein ligase complex which contains CUL5, RNF7/RBX2, Elongin BC complex and SPSB2 (PubMed:15601820). Interacts with CUL5, RNF7, ELOB and ELOC (PubMed:15601820). Interacts with MET (PubMed:15713673). Interacts (via B30.2/SPRY domain) with PAWR; this interaction occurs in association with the Elongin BC complex (PubMed:16498413, PubMed:20561531). Interacts with NOS2 (PubMed:21199876).
Substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:15601820, PubMed:21199876). Negatively regulates nitric oxide (NO) production and limits cellular toxicity in activated macrophages by mediating the ubiquitination and proteasomal degradation of NOS2 (PubMed:21199876). Acts as a bridge which links NOS2 with the ECS E3 ubiquitin ligase complex components ELOC and CUL5 (PubMed:21199876).
The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes (By similarity). Essential for its ability to link NOS2 and the ECS E3 ubiquitin ligase complex components ELOC and CUL5.
(Microbial infection) Glycosylated at Arg-352 by enteropathogenic E.coli protein NleB1.
Abundantly expressed in thymocytes and lymphocytes. Detected in lymphocyte-rich tissues such as thymus, colon, intestine, and spleen. Also found in the prostate.
Homodimer. Interacts strongly via the death domains with TNFRSF1 and TRADD to activate at least two distinct signaling cascades, apoptosis and NF-kappa-B signaling. Interacts with BAG4.
Receptor for TNFSF12/APO3L/TWEAK. Interacts directly with the adapter TRADD. Mediates activation of NF-kappa-B and induces apoptosis. May play a role in regulating lymphocyte homeostasis.
Forms a complex with the beta and gamma subunits of the GTP-binding protein, transducin. Interacts with CRX.
Light-induced changes in cyclic nucleotide levels modulate the phosphorylation of this protein by cAMP kinase.
May participate in the regulation of visual phototransduction or in the integration of photoreceptor metabolism. Inhibits the transcriptional activation activity of the cone-rod homeobox CRX.
Activation requires multiple phosphorylation events on serine/threonine residues. Activation appears to be first mediated by phosphorylation of multiple sites in the autoinhibitory domain, which facilitates phosphorylation at Thr-412, disrupting the autoinhibitory mechanism and allowing phosphorylation of Thr-252 by PDPK1. The active conformation of the kinase is believed to be stabilized by a mechanism involving three conserved phosphorylation sites located in the kinase domain activation loop (Thr-252) and in the AGC-kinase C-terminal domain (Ser-394 in the middle of the tail/linker region and Thr-412 within a hydrophobic motif at its end). Activated by mTORC1; isoform Alpha I and isoform Alpha II are sensitive to rapamycin, which inhibits activating phosphorylation at Thr-412. Activated by PDPK1.
Interacts with PPP1R9A/neurabin-1 (By similarity). Interacts with RPTOR (PubMed:12150926). Interacts with IRS1 (PubMed:18952604). Interacts with EIF3B and EIF3C (PubMed:16286006). Interacts with TRAF4 (PubMed:12801526). Interacts with POLDIP3 (PubMed:15341740). Interacts (via N-terminus) with IER5 (PubMed:26496226).
Phosphorylation at Thr-412 is regulated by mTORC1. The phosphorylation at this site is maintained by an agonist-dependent autophosphorylation mechanism (PubMed:29236692, PubMed:18925875, PubMed:19085255, PubMed:22017876, PubMed:23429703). Activated by phosphorylation at Thr-252 by PDPK1 (PubMed:9445476, PubMed:19864428). Dephosphorylation by PPP1CC at Thr-412 in mitochondrion (PubMed:17936702).
Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression (PubMed:11500364, PubMed:12801526, PubMed:14673156, PubMed:15071500, PubMed:15341740, PubMed:16286006, PubMed:17052453, PubMed:17053147, PubMed:17936702, PubMed:18952604, PubMed:19085255, PubMed:19720745, PubMed:19935711, PubMed:19995915, PubMed:23429703, PubMed:28178239, PubMed:22017876). Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD (PubMed:11500364, PubMed:12801526, PubMed:14673156, PubMed:15071500, PubMed:15341740, PubMed:16286006, PubMed:17052453, PubMed:17053147, PubMed:17936702, PubMed:18952604, PubMed:19085255, PubMed:19720745, PubMed:19935711, PubMed:19995915, PubMed:23429703, PubMed:28178239, PubMed:22017876). Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex (PubMed:16286006). Upon mitogenic stimulation, phosphorylation by the mechanistic target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation (PubMed:16286006). The active form then phosphorylates and activates several substrates in the pre-initiation complex, including the EIF2B complex and the cap-binding complex component EIF4B (PubMed:16286006). Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis (PubMed:17053147). Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR (PubMed:15341740). In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2 (PubMed:11500364). Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling (PubMed:19720745, PubMed:19935711, PubMed:19995915). Also involved in feedback regulation of mTORC1 and mTORC2 by phosphorylating DEPTOR (PubMed:22017876). Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function (By similarity). Phosphorylates mitochondrial URI1 leading to dissociation of a URI1-PPP1CC complex (PubMed:17936702). The free mitochondrial PPP1CC can then dephosphorylate RPS6KB1 at Thr-412, which is proposed to be a negative feedback mechanism for the RPS6KB1 anti-apoptotic function (PubMed:17936702). Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1 (PubMed:18952604). In cells lacking functional TSC1-2 complex, constitutively phosphorylates and inhibits GSK3B (PubMed:17052453). May be involved in cytoskeletal rearrangement through binding to neurabin (By similarity). Phosphorylates and activates the pyrimidine biosynthesis enzyme CAD, downstream of MTOR (PubMed:23429703). Following activation by mTORC1, phosphorylates EPRS and thereby plays a key role in fatty acid uptake by adipocytes and also most probably in interferon-gamma-induced translation inhibition (PubMed:28178239).
The TOS (TOR signaling) motif is essential for activation by mTORC1.
The autoinhibitory domain is believed to block phosphorylation within the AGC-kinase C-terminal domain and the activation loop.
Highly expressed in dendritic cells and primary leukemia cells, especially those of myeloid lineage.
Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin.
Acts as a backup for CMTM6 to regulate plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. May protect PD-L1/CD274 from being polyubiquitinated and targeted for degradation.
Belongs to the chemokine-like factor family.
Highly expressed in testis and prostate.
Detected at comparable levels in heart, lung, brain, skeletal muscle, pancreas and placenta. Weakly expressed in liver and kidney.
Homotetramer, formed by a dimer of dimers (PubMed:11013134, PubMed:14752098). May be part of the large multiprotein complex ARC/DRIP (PubMed:10235267).
Isobutyryl-CoA dehydrogenase which catalyzes the conversion of 2-methylpropanoyl-CoA to (2E)-2-methylpropenoyl-CoA in the valine catabolic pathway (PubMed:11013134, PubMed:12359132, PubMed:16857760). To a lesser extent, also able to catalyze the oxidation of (2S)-2-methylbutanoyl-CoA (PubMed:11013134, PubMed:12359132).
Abundantly expressed in subthalamic nucleus but undetectable in other brain regions tested (hypothalamus was not tested) and in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Binds to orexin receptor HCRTR2/OX2R only (By similarity). Stimulates food intake (By similarity). Modulates pituitary luteinizing hormone secretion in an ovarian steroid-dependent manner (By similarity).
Binds to orexin receptors HCRTR1/OX1R and HCRTR2/OX2R with a high affinity (By similarity). Stimulates food intake (By similarity). Modulates pituitary luteinizing hormone secretion in an ovarian steroid-dependent manner (By similarity).
Neuropeptides that play a significant role in the regulation of food intake and sleep-wakefulness, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions. A broader role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and the regulation of body fluids, is also suggested.
Specific enzymatic cleavages at paired basic residues yield the different active peptides.
The disease is caused by variants affecting the gene represented in this entry. Human narcolepsy is associated with a deficient orexin system. Orexins are absent and/or greatly diminished in the brain and cerebrospinal fluid (CSF) of most narcoleptic patients.
Expressed in many tumors of several types, such as melanoma, head and neck squamous cell carcinoma, lung carcinoma and breast carcinoma, but not in normal tissues except for testes.
Interacts with TRIM28 and UBE2H. Interacts with HDAC3. Interacts with PML (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5).
Reduces p53/TP53 transactivation function through recruitment of HDAC3 to p53/TP53 transcription sites. Also represses p73/TP73 activity. Proposed to enhance ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases. In vitro enhances ubiquitin ligase activity of TRIM28 and stimulates p53/TP53 ubiquitination by TRIM28 potentially in presence of Ubl-conjugating enzyme UBE2H. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex. May play a role in embryonal development and tumor transformation or aspects of tumor progression. In vitro promotes cell viability in melanoma cell lines. Antigen recognized on a melanoma by autologous cytolytic T-lymphocytes. Negatively regulates acetylation and sumoylation of PML and represses PML-induced p53/TP53 acetylation and activation.
Has abundant triacylglycerol lipase activity.
No differential expression during adipocyte differentiation.
May prevent inappropriate targeting of non-secretory polypeptides to the endoplasmic reticulum (ER). May bind to nascent polypeptide chains as they emerge from the ribosome and block their interaction with the signal recognition particle (SRP), which normally targets nascent secretory peptides to the ER. May also reduce the inherent affinity of ribosomes for protein translocation sites in the ER membrane (M sites) (By similarity).
Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane (PubMed:23229899, PubMed:25608530, PubMed:26571211). The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (Probable). In the complex, EFR3A probably acts as the membrane-anchoring component (PubMed:23229899). Also involved in responsiveness to G-protein-coupled receptors; it is however unclear whether this role is direct or indirect (PubMed:25380825).
Component of a phosphatidylinositol 4-kinase (PI4K) complex, composed of PI4KA, EFR3 (EFR3A or EFR3B), TTC7 (TTC7A or TTC7B) and HYCC (HYCC1 or HYCC2) (PubMed:26571211).
Genetic variations in EFR3A may be associated with susceptibility to autism.
Palmitoylated at its N-terminus, anchoring the protein to the plasma membrane.
Receptor for the hormone galanin (PubMed:25691535). Receptor for the hormone spexin-1 (PubMed:24517231).
Binds 1 Mg(2+) ion per subunit. May bind a second metal ion at a regulatory site, or after substrate binding.
Endonuclease that specifically degrades the RNA of RNA-DNA hybrids (PubMed:10497183). Plays a role in RNA polymerase II (RNAp II) transcription termination by degrading R-loop RNA-DNA hybrid formation at G-rich pause sites located downstream of the poly(A) site and behind the elongating RNAp II (PubMed:21700224).
Endonuclease that specifically degrades the RNA of RNA-DNA hybrids.
In the presence of magnesium, manganese is inhibitory.
Expressed in placenta. Localizes primarily to differentiated syncytiotrophoblast throughout gestation as well as to a small population of villous cytotrophoblasts. Also detected in maternal blood and rapidly disappears following delivery, but is not detected in other adult or fetal tissues examined.
May play a role in placental development.
Up-regulated during trophoblast differentiation and by FGF7 in trophoblast cells.
Belongs to the GST superfamily. Mu family.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Participates in the formation of novel hepoxilin regioisomers (PubMed:21046276).
Widely expressed, with highest levels in brain.
Expressed in the heart (at protein level). Expressed in many tissues with highest abundance in skeletal muscle.
Interacts with GATA1 and GATA4 (By similarity). Interacts with beta-dystroglycan. Interacts with GATA6.
The LIM zinc-binding domains and the Cys-rich region mediate interaction with GATA6.
Transcriptional cofactor that restricts GATA6 function by inhibiting DNA-binding, resulting in repression of GATA6 transcriptional activation of downstream target genes. Represses GATA6-mediated trans activation of lung- and cardiac tissue-specific promoters. Inhibits DNA-binding by GATA4 and GATA1 to the cTNC promoter (By similarity). Plays a critical role in the development of cardiac hypertrophy via activation of calcineurin/nuclear factor of activated T-cells signaling pathway.
AP-1 family transcription factor that controls the differentiation of lineage-specific cells in the immune system: specifically mediates the differentiation of T-helper 17 cells (Th17), follicular T-helper cells (TfH), CD8(+) dendritic cells and class-switch recombination (CSR) in B-cells. Acts via the formation of a heterodimer with JUNB that recognizes and binds DNA sequence 5'-TGA[CG]TCA-3'. The BATF-JUNB heterodimer also forms a complex with IRF4 (or IRF8) in immune cells, leading to recognition of AICE sequence (5'-TGAnTCA/GAAA-3'), an immune-specific regulatory element, followed by cooperative binding of BATF and IRF4 (or IRF8) and activation of genes. Controls differentiation of T-helper cells producing interleukin-17 (Th17 cells) by binding to Th17-associated gene promoters: regulates expression of the transcription factor RORC itself and RORC target genes such as IL17 (IL17A or IL17B). Also involved in differentiation of follicular T-helper cells (TfH) by directing expression of BCL6 and MAF. In B-cells, involved in class-switch recombination (CSR) by controlling the expression of both AICDA and of germline transcripts of the intervening heavy-chain region and constant heavy-chain region (I(H)-C(H)). Following infection, can participate in CD8(+) dendritic cell differentiation via interaction with IRF4 and IRF8 to mediate cooperative gene activation. Regulates effector CD8(+) T-cell differentiation by regulating expression of SIRT1. Following DNA damage, part of a differentiation checkpoint that limits self-renewal of hematopoietic stem cells (HSCs): up-regulated by STAT3, leading to differentiation of HSCs, thereby restricting self-renewal of HSCs (By similarity).
Expressed at highest levels in lung, and at lower levels in placenta, liver, kidney, spleen, and peripheral blood. Detected in SW480 colorectal cancer cell line and several hematopoietic tumor cell lines, including Raji Burkitt's lymphoma. Strongly expressed in mature B- and T-lymphocytes. Also expressed in moderate levels in lymph node and appendix and at low levels in thymus and bone marrow (PubMed:10777209).
Heterodimer; mainly heterodimerizes with JUNB. The BATF-JUNB heterodimer interacts with IRF4 and IRF8. Interacts (via bZIP domain) with IRF4 and IRF8; the interaction is direct (By similarity). Also forms heterodimers with JUN and JUND. Also interacts with IFI35.
Phosphorylated on serine and threonine residues and at least one tyrosine residue. Phosphorylation at Ser-43 inhibit DNA binding activity and transforms it as a negative regulator of AP-1 mediated transcription (By similarity).
Up-regulated by PDCD1 following infection by HIV-1 virus, leading to inhibit T-cell functions and exhaust T-cells. Up-regulated by Epstein-Barr virus (EBV) protein EBNA2 following infection by EBV.
Plays a role in biomineralization. Seems to regulate the formation of crystallites during the secretory stage of tooth enamel development. Thought to play a major role in the structural organization and mineralization of developing enamel.
Transiently but abundantly expressed by ameloblasts during tooth development. Amelogenin is the predominant protein in developing dental enamel.
Genetic variations in C3orf58 may be associated with susceptibility to autism (PubMed:18621663).
May play a role in cardiomyocyte proliferation through paracrine signaling and activation of the PPI3K-AKT-CDK7 signaling cascade.
Interacts with RHO/rhodopsin; the interaction promotes PRCD stability.
Palmitoylated at Cys-2 (PubMed:27613864). Palmitoylation is essential for protein stability and trafficking to the photoreceptor outer segment, but does not appear to be essential for membrane localization (PubMed:27613864). Probably palmitoylated by ZDHHC3 (PubMed:27613864).
ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells. Mediates ATP-dependent transport of endogenous metabolites such as cAMP and cGMP, folic acid and N-lactoyl-amino acids (in vitro) (PubMed:10893247, PubMed:15899835, PubMed:25964343, PubMed:17229149, PubMed:12695538, PubMed:12637526). Acts also as a general glutamate conjugate and analog transporter that can limit the brain levels of endogenous metabolites, drugs, and toxins (PubMed:26515061). Confers resistance to the antiviral agent PMEA (PubMed:12695538). Able to transport several anticancer drugs including methotrexate, and nucleotide analogs in vitro, however it does with low affinity, thus the exact role of ABCC5 in mediating resistance still needs to be elucidated (PubMed:10840050, PubMed:15899835, PubMed:12435799, PubMed:12695538). Acts as a heme transporter required for the translocation of cytosolic heme to the secretory pathway (PubMed:24836561). May play a role in energy metabolism by regulating the glucagon-like peptide 1 (GLP-1) secretion from enteroendocrine cells (By similarity).
Although other labs have confirmed the ability of ABCC5 to transport cGMP in an ATP-dependent manner, they obtained a much lower affinity for this substrate (PubMed:12637526, PubMed:12695538). The authors conclude that ABCC5 is a low-affinity cyclic nucleotide transporter a major function in cGMP excretion is unlikely (PubMed:12637526, PubMed:12695538).
Belongs to the ABC transporter superfamily. ABCC family. Conjugate transporter (TC 3.A.1.208) subfamily.
Predominant isoform in retinal pigment epithelium, bladder, and stomach.
Ubiquitously expressed, but levels in brain and muscle are especially high (PubMed:9827529, PubMed:10438534, PubMed:15501592). All isoforms are equally expressed in retina (PubMed:17521428).
cGMP transport is highly sensitive to inhibitors of cGMP phosphodiesterase, such as zaprinast, trequinsin and sildenafil.
Belongs to the protein kinase superfamily. NEK Ser/Thr protein kinase family. NIMA subfamily.
Highest expression in thyroid, adrenal gland and skin. Low levels in spleen, colon and uterus. Overexpressed in breast tumors, with highest expression in infiltrating ductal carcinomas and moderate levels in mucinous adenocarcinoma.
Interacts with PKD2; may regulate PKD2 targeting to the cilium (By similarity). Component of a complex containing at least ANKS6, INVS, NEK8 and NPHP3 (PubMed:23418306, PubMed:23793029). ANKS6 may organize complex assembly by linking INVS and NPHP3 to NEK8 and INVS may target the complex to the proximal ciliary axoneme (PubMed:23418306, PubMed:23793029). Interacts with ANKS3 (PubMed:26188091).
Required for renal tubular integrity. May regulate local cytoskeletal structure in kidney tubule epithelial cells. May regulate ciliary biogenesis through targeting of proteins to the cilia (By similarity). Plays a role in organogenesis and is involved in the regulation of the Hippo signaling pathway.
Abundantly expressed in many tissues. Expressed in brain, colon, heart, kidney, liver, lung, liver, pancreas, placenta, skeletal muscle, testis and thymus. Highest expression in colon, testis, lung, placenta and brain.
(Microbial infection) Acts as a receptor for Ebolavirus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope.
(Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope.
(Microbial infection) Promotes Zika virus entry in glial cells, Sertoli cells and astrocytes (PubMed:28076778, PubMed:29379210, PubMed:31311882). Additionally, Zika virus potentiates AXL kinase activity to antagonize type I interferon signaling and thereby promotes infection (PubMed:28076778). Interferon signaling inhibition occurs via an SOCS1-dependent mechanism (PubMed:29379210).
AXL and its ligand GAS6 are highly expressed in thyroid carcinoma tissues, and might thus be involved in thyroid tumorigenesis. Overexpression of AXL and its ligand was also detected in many other cancers such as myeloproliferative disorders, prostatic carcinoma cells, or breast cancer.
Activated by GAS6-binding and subsequent autophosphorylation.
Belongs to the protein kinase superfamily. Tyr protein kinase family. AXL/UFO subfamily.
Heterodimer and heterotetramer with ligand GAS6. Interacts with CBL, GRB2, LCK, NCK2, PIK3R1, PIK3R2, PIK3R3, PLCG1, SOCS1 and TNS2. Part of a complex including AXL, TNK2 and GRB2, in which GRB2 promotes AXL recruitment by TNK2.
Highly expressed in metastatic colon tumors. Expressed in primary colon tumors. Weakly expressed in normal colon tissue.
Monoubiquitinated upon GAS6-binding. A very small proportion of the receptor could be subjected to polyubiquitination in a very transient fashion.
Phosphorylated at tyrosine residues by autocatalysis, which activates kinase activity.
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of AXL. Following activation by ligand, AXL binds and induces tyrosine phosphorylation of PI3-kinase subunits PIK3R1, PIK3R2 and PIK3R3; but also GRB2, PLCG1, LCK and PTPN11. Other downstream substrate candidates for AXL are CBL, NCK2, SOCS1 and TNS2. Recruitment of GRB2 and phosphatidylinositol 3 kinase regulatory subunits by AXL leads to the downstream activation of the AKT kinase. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. Also plays an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response.
Deubiquitinating enzyme that may play a role in the ubiquitin-dependent regulation of protein synthesis, downstream of mTORC1 (PubMed:21267069, PubMed:27864334). May associate with the protein synthesis initiation complex and modify its ubiquitination to repress translation (PubMed:27864334). May also repress DNA synthesis and modify different cellular targets thereby regulating cell growth and proliferation (PubMed:27864334). May also play a role in proteasome assembly and function (PubMed:28343629).
Initially, no deubiquitinase activity could be detected when tested (PubMed:23827681). Other studies, show an obvious deubiquitinase activity (PubMed:21267069, PubMed:28343629, PubMed:27864334).
Interacts with the eukaryotic translation initiation factor 4F complex.
Stimulates protein synthesis. Influences the expression of CCND1/cyclin D1 by promoting its translation and regulates MYC/c-Myc protein stability.
Cleaved by CASP1 (Probable). The N-terminal cleavage product localizes to the nucleus as a filamentous network and to the cytoplasm, interacts more strongly with RELA and NFKBIA than the full-length protein, enhances the nuclear localization of RELA and induces NFKBIA proteolysis. The C-terminal cleavage product localizes to the cytoplasm (Probable).
Degraded along with the delivery of its substrates to autolysosomal compartments (at protein level).
Expressed in peripheral blood leukocytes, particularly in mature granulocytes and to a lesser extent in monocytes but not in lymphocytes. Detected in spleen, lung and muscle, probably as a result of leukocyte infiltration in these tissues. Not expressed in thymus, prostate, testis, ovary, small intestine, colon, heart, brain, placenta, liver, kidney, pancreas. Expression detected in several myeloid leukemic, colon cancer, and prostate cancer cell lines.
First detected in bone marrow promyelocytes. Expression increases throughout myelocyte differentiation and peaks in the mature myelomonocytic cells.
Homotrimer. Interacts (via the B box-type zinc finger) with PSTPIP1 (PubMed:14595024, PubMed:17964261, PubMed:19109554, PubMed:28835462). Interacts (via the B30.2/SPRY domain) with several components of the inflammasome complex, including CASP1 p20 and p10 subunits, CASP5, PYCARD, NLRP1, NLRP2 and NLRP3, as well as with unprocessed IL1B; this interaction may lead to autophagic degradation of these proteins (PubMed:11498534, PubMed:16785446, PubMed:17431422, PubMed:17964261, PubMed:26347139). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity). Interacts with NFKBIA and RELA (PubMed:18577712). Interacts weakly with VASP and ACTR3 (PubMed:19109554). Interacts with active ULK1 (phosphorylated on 'Ser-317') and BECN1 simultaneously. Also interacts with ATG16L1 (via WD repeats), and with ATG8 family members, including GABARAP, GABARAPL1 and, to a lesser extent, GABARAPL2, MAP1LC3A/LC3A and MAP1LC3C/LC3C. Interacts with TRIM21 (PubMed:26347139, PubMed:28835462). Interacts with YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ and YWHAZ; the interaction is required for the down-regulation of pyrin pro-inflammatory activity (PubMed:27030597, PubMed:28835462).
In monocytes, up-regulated by treatment with colchicine and IFN-alpha, by the pro-inflammatory cytokines IFNG/IFN-gamma and TNF, by bacterial lipopolysaccharides (LPS) and by retroviral infection. Repressed in monocytes by the anti-inflammatory cytokines IL10/interleukin-10, TGFB1 and IL4/interleukin-4. In neutrophils and macrophages, up-regulated by IFNG/IFN-gamma with a peak after 8 hours of treatment.
Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma (PubMed:10807793, PubMed:11468188, PubMed:17964261, PubMed:18577712, PubMed:19109554, PubMed:19584923, PubMed:16037825, PubMed:27030597, PubMed:28835462, PubMed:16785446, PubMed:17431422, PubMed:26347139). Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1, ATG16L1, and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy (PubMed:16785446, PubMed:17431422, PubMed:26347139). Acts as an autophagy receptor for the degradation of several inflammasome components, including CASP1, NLRP1 and NLRP3, hence preventing excessive IL1B- and IL18-mediated inflammation (PubMed:16785446, PubMed:17431422, PubMed:26347139). However, it can also have a positive effect in the inflammatory pathway, acting as an innate immune sensor that triggers PYCARD/ASC specks formation, caspase-1 activation, and IL1B and IL18 production (PubMed:16037825, PubMed:27030597, PubMed:28835462). Together with AIM2, also acts as a mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an integral part of host defense against pathogens, in response to bacterial infection (By similarity). It is required for PSTPIP1-induced PYCARD/ASC oligomerization and inflammasome formation (PubMed:10807793, PubMed:11468188, PubMed:17964261, PubMed:18577712, PubMed:19109554, PubMed:19584923). Recruits PSTPIP1 to inflammasomes, and is required for PSTPIP1 oligomerization (PubMed:10807793, PubMed:11468188, PubMed:17964261, PubMed:18577712, PubMed:19109554, PubMed:19584923).
Phosphorylation at Ser-242 is required for the interaction with 14-3-3 proteins and down-regulation of pyrin pro-inflammatory activity.
The B box-type zinc finger interacts, possibly intramolecularly, with the pyrin domain; this may be an autoinhibitory mechanism released by PSTPIP1 binding.
The disease is caused by variants affecting the gene represented in this entry. The disease-associated mutations in the B30.2/SPRY domain perturb ULK1 recruitment and autophagic degradation of inflammasome components, including NLRP3, and hence may contribute to the inflammatory phenotype associated with ARFMF.
Dynein-attachment factor required for cilia motility.
E3 ligase that regulates nuclear lamina integrity and the association of viral chromatin with transcriptionally-active host chromatin. Acts thereby as a herpesvirus-specific antiviral factor and mediates the ubiquitination-dependent proteasomal degradation of PCNT.
GTPase-activating protein that catalyzes the conversion of active GTP-bound Rho GTPases to their inactive GDP-bound form, thus suppressing various Rho GTPase-mediated cellular processes (PubMed:11432776). Also converts Cdc42 to an inactive GDP-bound state (PubMed:11432776). Essential for PTKB2 regulation of cytoskeletal organization via Rho family GTPases. Inhibits PAK2 proteolytic fragment PAK-2p34 kinase activity and changes its localization from the nucleus to the perinuclear region. Stabilizes PAK-2p34 thereby increasing stimulation of cell death (By similarity). Associates with MICAL1 on the endosomal membrane to promote Rab8-Rab10-dependent tubule extension. After dissociation with MICAL1, recruits WDR44 which connects the endoplasmic reticulum (ER) with the endosomal tubule, thereby participating in the export of a subset of neosynthesized proteins (PubMed:32344433).
High levels of expression in heart and skeletal muscle.
Interacts with PKN3 (PubMed:11432776). Interacts with caspase-activated PAK2 proteolytic fragment PAK-2p34; the interaction does not affect GRAF2/ARHGAP10 GTPase activation activity towards RHOA and CDC42 (By similarity). Interacts via its SH3 domain with PTK2/FAK1 (By similarity). Interacts with PTK2B/PYK2; the interaction negatively regulates GRAF2/ARHGAP10 GTPase-activating activity (By similarity). Interacts with MICAL1 and WDR44; complex formation might transit from GRAF2/ARHGAP10-MICAL1 to GRAF2/ARHGAP10-WDR44 complexes (PubMed:32344433).
Phosphorylated. Phosphorylated in vitro by constitutive active PKN3.
The BAR domain is important to associate RAB8A (or RAB8B) and RAB10 to endosomal membrane to promote tubule extension. The BAR domain is also important to recruit WDR44 to endosomal tubules.
Actin-binding component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF) (PubMed:9230079). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility (PubMed:9230079). In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA (PubMed:29925947). The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs) (PubMed:29925947).
Component of the Arp2/3 complex composed of ACTR2/ARP2, ACTR3/ARP3, ARPC1B/p41-ARC, ARPC2/p34-ARC, ARPC3/p21-ARC, ARPC4/p20-ARC and ARPC5/p16-ARC.
Maps to a tandemly repeated region on chromosome Yp11; additionally at least one copy is reported originating from Yq. The gene is thought to be present with an inter-individual variation in copy number and between 20 and 60 copies per Y chromosome are expected. 35 tandemly repeated gene copies on Yp11 originating from one individual have been reported (PubMed:12815422).
May be involved in sperm differentiation and proliferation.
Belongs to the AAA ATPase family. DRC11 subfamily.
Component of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes.
Component of the nexin-dynein regulatory complex (N-DRC).
According to a report, displays histone acetyltransferase activity while localized in the Golgi apparatus (PubMed:21981917). May mediate acetylation of free histone H4 and promote nucleosome assembly (PubMed:21981917). Such results are however unclear in vivo and recent reports strongly suggest that it acts as a N-alpha-acetyltransferase that specifically targets N-terminal residues of transmembrane proteins (PubMed:21750686, PubMed:25732826).
Acetylated: autoacetylation is required for optimal acetyltransferase activity.
Belongs to the acetyltransferase family. NAA60 subfamily.
In placenta and leukocytes, expressed from the maternal allele, due to imprinting of the paternal allele.
Isoform 2: Imprinted (PubMed:21593219). Promoter methylation of the paternal allele may restrict expression to the maternal allele in placenta and leukocytes (PubMed:21593219). Isoform 1: Biallelically expressed (PubMed:21593219).
Monomer and homodimer; monomer in presence of substrate and homodimer in its absence (PubMed:27320834).
N-alpha-acetyltransferase that specifically mediates the acetylation of N-terminal residues of the transmembrane proteins, with a strong preference for N-termini facing the cytosol (PubMed:25732826). Displays N-terminal acetyltransferase activity towards a range of N-terminal sequences including those starting with Met-Lys, Met-Val, Met-Ala and Met-Met (PubMed:21750686, PubMed:25732826, PubMed:27550639, PubMed:27320834). Required for normal chromosomal segregation during anaphase (PubMed:21750686). May also show histone acetyltransferase activity; such results are however unclear in vivo and would require additional experimental evidences (PubMed:21981917).
Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. Also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Has a promiscuous chemokine-binding profile, interacting with inflammatory chemokines of both the CXC and the CC subfamilies but not with homeostatic chemokines. Acts as a receptor for chemokines including CCL2, CCL5, CCL7, CCL11, CCL13, CCL14, CCL17, CXCL5, CXCL6, IL8/CXCL8, CXCL11, GRO, RANTES, MCP-1 and TARC. May regulate chemokine bioavailability and, consequently, leukocyte recruitment through two distinct mechanisms: when expressed in endothelial cells, it sustains the abluminal to luminal transcytosis of tissue-derived chemokines and their subsequent presentation to circulating leukocytes; when expressed in erythrocytes, serves as blood reservoir of cognate chemokines but also as a chemokine sink, buffering potential surges in plasma chemokine levels.
Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. Also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Has a promiscuous chemokine-binding profile, interacting with inflammatory chemokines of both the CXC and the CC subfamilies but not with homeostatic chemokines. Acts as a receptor for chemokines including CCL2, CCL5, CCL7, CCL11, CCL13, CCL14, CCL17, CXCL5, CXCL6, IL8/CXCL8, CXCL11, GRO, RANTES, MCP-1, TARC and also for the malaria parasites P.vivax and P.knowlesi. May regulate chemokine bioavailability and, consequently, leukocyte recruitment through two distinct mechanisms: when expressed in endothelial cells, it sustains the abluminal to luminal transcytosis of tissue-derived chemokines and their subsequent presentation to circulating leukocytes; when expressed in erythrocytes, serves as blood reservoir of cognate chemokines but also as a chemokine sink, buffering potential surges in plasma chemokine levels.
Belongs to the G-protein coupled receptor 1 family. Atypical chemokine receptor subfamily.
DARC is responsible for the Duffy blood group system (FY) [MIM:110700]. The molecular basis of the Fy(A)=Fy1/Fy(B)=Fy2 blood group antigens is a single variation in position 42; Gly-42 corresponds to Fy(A) and Asp-42 to Fy(B). Individuals that do not produce the Duffy antigen (FY(A-B-)) are more resistant to infection by the malarial parasite Plasmodium vivax. This allele is found predominantly in population of African origin [MIM:611162].
Found in adult kidney, adult spleen, bone marrow and fetal liver. In particular, it is expressed along postcapillary venules throughout the body, except in the adult liver. Erythroid cells and postcapillary venule endothelium are the principle tissues expressing duffy. Fy(-A-B) individuals do not express duffy in the bone marrow, however they do, in postcapillary venule endothelium.
Genetic variations in DARC define the white blood cell count quantitative trait locus 1 (WBCQ1) [MIM:611862]. Peripheral white blood cell count (WBC) is a common clinical measurement, used to determine evidence of acute inflammation or infection. Peripheral WBC is the sum of several cell types including neutrophils and lymphocytes, which are the most common types of WBC, as well as less common cell types such as eosinophils, basophils, and monocytes. Elevated WBC has been associated with risk of coronary heart disease, cancer, and all-cause mortality. White blood cell levels have widespread clinical applications including assessment of patients undergoing chemotherapy and evaluation of infection.
Appears to be involved in myelination. Could also participate in ion transport events as addition of plasmolipin to lipid bilayers induces the formation of ion channels, which are voltage-dependent and K(+)-selective (By similarity).
Hexamer arranged as a trimer of two plasmolipin subunits.
Mediates the hydrolysis of oxidized nucleoside diphosphate derivatives. Hydrolyzes 8-oxo-7,8-dihydroguanine (8-oxo-Gua)-containing deoxyribo- and ribonucleoside diphosphates to the monophosphates. Hydrolyzes 8-oxo-dGDP and 8-oxo-GDP with the same efficiencies. Hydrolyzes also 8-OH-dADP and 2-OH-dADP. Exhibited no or minimal hydrolysis activity against 8-oxo-dGTP, 8-oxo-GTP, dGTP, GTP, dGDP and GDP. Probably removes oxidized guanine nucleotides from both the DNA and RNA precursor pools.
Expressed in breast tumors with a higher expression level in estrogen receptor-positive cancers (PubMed:22341523, PubMed:28915724).
Interacts with 14-3-3 proteins (PubMed:28915724).
May regulate the transcriptional function of androgen and estrogen receptors.
Up-regulated in breast cancers (PubMed:22341523).
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type V subfamily.
ADP-ribosyltransferase activity is regulated via an allosteric activation mechanism (PubMed:34108479). In absence of activation signal, PARP2 is autoinhibited by the PARP alpha-helical domain (also named HD region), which prevents effective NAD(+)-binding (PubMed:34108479). Activity is highly stimulated by signals, which unfold the PARP alpha-helical domain, relieving autoinhibition (PubMed:34108479). Poly-ADP-ribosyltransferase activity is tightly regulated and PARP2 is removed from damaged chromatin following initial poly-ADP-ribosylation of chromatin to avoid prolonged residence (trapping) that has cytotoxic consequences (PubMed:33275888). CHD1L promotes PARP2 removal from chromatin (PubMed:33275888). ADP-ribosyltransferase activity is inhibited by a number of PARP inhibitors (PARPi) compounds, that are used the treatment of breast or ovarian cancers that have defects in DNA repair by homologous recombination (PubMed:35349716). PARPi molecules (niraparib, talazoparib, and, to a lesser extent, olaparib) also trap PARP2 at DNA damage sites (PubMed:33275888, PubMed:35349716).
Acetylation reduces DNA binding and enzymatic activity.
Auto poly-ADP-ribosylated on serine residues, leading to dissociation of the PARP2-HPF1 complex from chromatin (PubMed:32939087, PubMed:34108479). Poly-ADP-ribosylated by PARP1 (By similarity).
Component of a base excision repair (BER) complex, containing at least XRCC1, PARP1, POLB and LRIG3 (By similarity). Homo- and heterodimer with PARP1 (PubMed:20092359). Interacts (via the PARP catalytic domain) with HPF1 (PubMed:27067600, PubMed:28190768, PubMed:32028527, PubMed:32939087, PubMed:33141820, PubMed:34108479). Interacts with core nucleosomes (PubMed:32939087, PubMed:33141820).
Poly-ADP-ribosyltransferase that mediates poly-ADP-ribosylation of proteins and plays a key role in DNA repair (PubMed:10364231, PubMed:25043379, PubMed:27471034, PubMed:30104678, PubMed:32028527, PubMed:32939087, PubMed:34486521, PubMed:34874266, PubMed:34108479). Mediates glutamate, aspartate or serine ADP-ribosylation of proteins: the ADP-D-ribosyl group of NAD(+) is transferred to the acceptor carboxyl group of target residues and further ADP-ribosyl groups are transferred to the 2'-position of the terminal adenosine moiety, building up a polymer with an average chain length of 20-30 units (PubMed:25043379, PubMed:30104678, PubMed:30321391). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:32939087). Mediates glutamate and aspartate ADP-ribosylation of target proteins in absence of HPF1 (PubMed:25043379). Following interaction with HPF1, catalyzes serine ADP-ribosylation of target proteins; HPF1 conferring serine specificity by completing the PARP2 active site (PubMed:28190768, PubMed:32028527, PubMed:34486521, PubMed:34874266, PubMed:34108479). PARP2 initiates the repair of double-strand DNA breaks: recognizes and binds DNA breaks within chromatin and recruits HPF1, licensing serine ADP-ribosylation of target proteins, such as histones, thereby promoting decompaction of chromatin and the recruitment of repair factors leading to the reparation of DNA strand breaks (PubMed:10364231, PubMed:32939087, PubMed:34108479). HPF1 initiates serine ADP-ribosylation but restricts the polymerase activity of PARP2 in order to limit the length of poly-ADP-ribose chains (PubMed:34732825, PubMed:34795260). Specifically mediates formation of branched poly-ADP-ribosylation (PubMed:30104678). Branched poly-ADP-ribose chains are specifically recognized by some factors, such as APLF (PubMed:30104678). In addition to proteins, also able to ADP-ribosylate DNA: preferentially acts on 5'-terminal phosphates at DNA strand breaks termini in nicked duplex (PubMed:27471034, PubMed:29361132).
Proteolytically cleaved by caspase-8 (CASP8) in response to apoptosis, leading to its inactivation.
The N-terminal disordered region does not act as a key DNA-binding domain (PubMed:26704974). The WGR and PARP catalytic domains function together to recruit PARP2 to sites of DNA breaks. The N-terminal disordered region is only required for activation on specific types of DNA damage (PubMed:26704974).
The N-terminal region (NTR) recognizes and binds poly-ADP-ribose chains produced by PARP1, leading to its recruitment to DNA damage sites.
The PARP alpha-helical domain (also named HD region) prevents effective NAD(+)-binding in absence of activation signal (PubMed:34108479). Binding to damaged DNA unfolds the PARP alpha-helical domain, relieving autoinhibition (PubMed:34108479).
The WGR domain bridges two nucleosomes, with the broken DNA aligned in a position suitable for ligation (PubMed:30321391, PubMed:32939087, PubMed:33141820). The bridging induces structural changes in PARP2 that signal the recognition of a DNA break to the catalytic domain of PARP2, promoting HPF1 recruitment and subsequent activation of PARP2, licensing serine ADP-ribosylation of target proteins (PubMed:32939087).
Widely expressed, mainly in actively dividing tissues (PubMed:10364231). The highest levels are in the brain, heart, pancreas, skeletal muscle and testis; also detected in kidney, liver, lung, placenta, ovary and spleen; levels are low in leukocytes, colon, small intestine, prostate and thymus (PubMed:10364231).
Although it belongs to the sodium:solute symporter (SSF) (TC 2.A.21) family, lacks Na(+)/glucose symporter activity.
Does not function as sodium/D-glucose symporter (PubMed:13130073, PubMed:20421923, PubMed:22766068). However, may function as a D-glucose sensor by generating a D-glucose-induced depolarization which is pH-independent, Na(+)-dependent at neutral pH and probably H(+)-dependent at acidic pH (PubMed:13130073, PubMed:22766068, PubMed:17110502, PubMed:20421923).
Expressed in skeletal muscle, where it may localize to the neuromuscular junction (at protein level) (PubMed:13130073). Expressed in small intestine where it may localize to cholinergic neurons of the submucosal plexus and myenteric plexus (at protein level) (PubMed:13130073). Detected in kidney (at protein level) (PubMed:22766068).
Expressed abundantly in brain and pancreas. Also expressed in the testis.
This is a specific receptor for parathyroid hormone. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. PTH2R may be responsible for PTH effects in a number of physiological systems. It may play a significant role in pancreatic function. PTH2R presence in neurons indicates that it may function as a neurotransmitter receptor (By similarity).
Enhances the ATPase activity of DHX15 in vitro.
Belongs to the type I cytokine receptor family. Type 1 subfamily.
Contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases.
Erythroid cells and erythroid progenitor cells. Isoform EPOR-F is the most abundant form in EPO-dependent erythroleukemia cells and in late-stage erythroid progenitors. Isoform EPOR-S and isoform EPOR-T are the predominant forms in bone marrow. Isoform EPOR-T is the most abundant from in early-stage erythroid progenitor cells.
Forms homodimers on EPO stimulation. The tyrosine-phosphorylated form interacts with several SH2 domain-containing proteins including LYN (By similarity), the adapter protein SH2B2, PTPN6 (By similarity), PTPN11, JAK2, PI3 kinases, STAT5A/B, SOCS3, CRKL (By similarity). Interacts with INPP5D/SHIP1 (By similarity). The N-terminal SH2 domain of PTPN6 binds Tyr-454 and inhibits signaling through dephosphorylation of JAK2 (By similarity). SH2B2 binding also inhibits the JAK-STAT signaling. Binding to PTPN11, preferentially through the N-terminal SH2 domain, promotes mitogenesis and phosphorylation of PTPN11 (By similarity). Binding of JAK2 (through its N-terminal) promotes cell-surface expression (By similarity). Interacts with RHEX; this interaction occurs in a erythropoietin (EPO)-dependent manner (PubMed:25092874). Interaction with the ubiquitin ligase NOSIP mediates EPO-induced cell proliferation. Interacts with ATXN2L.
Isoform EPOR-T acts as a dominant-negative receptor of EPOR-mediated signaling.
On EPO stimulation, phosphorylated on C-terminal tyrosine residues by JAK2. The phosphotyrosine motifs are also recruitment sites for several SH2-containing proteins and adapter proteins which mediate cell proliferation. Phosphorylation on Tyr-454 is required for PTPN6 interaction, Tyr-426 for PTPN11. Tyr-426 is also required for SOCS3 binding, but Tyr-454/Tyr-456 motif is the preferred binding site.
Receptor for erythropoietin. Mediates erythropoietin-induced erythroblast proliferation and differentiation. Upon EPO stimulation, EPOR dimerizes triggering the JAK2/STAT5 signaling cascade. In some cell types, can also activate STAT1 and STAT3. May also activate the LYN tyrosine kinase.
The box 1 motif is required for JAK interaction and/or activation.
Ubiquitination at Lys-281 mediates receptor internalization, whereas ubiquitination at Lys-453 promotes trafficking of activated receptors to the lysosomes for degradation (By similarity). Ubiquitinated by NOSIP; appears to be either multi-monoubiquitinated or polyubiquitinated. Ubiquitination mediates proliferation and survival of EPO-dependent cells.
Appears to be the dominant isoform in peripheral blood cell fractions. Contains a transmembrane helix.
Associates with BCL10 by CARD-CARD interaction (PubMed:15637807).
Expressed in ovary, testis, placenta, skeletal muscle, kidney, lung, heart and liver (at protein level). Expressed in thymus and brain.
Plays a role in inhibiting the effects of BCL10-induced activation of NF-kappa-B. May inhibit the phosphorylation of BCL10 in a CARD-dependent manner.
Acetylation leads to protein stability. Acetylated in vitro on Lys-141, Lys-154, Lys-161 and Lys-163. Deacetylation by HDAC1 is prevented by competitive binding of C10orf90/FATS to HDAC1 (By similarity).
Activated by p53/TP53, mezerein (antileukemic compound) and IFNB1. Repressed by HDAC1.
Expressed in all adult tissues, with 5-fold lower levels observed in the brain.
Interacts with HDAC1; the interaction is prevented by competitive binding of C10orf90/FATS to HDAC1 facilitating acetylation and protein stabilization of CDKN1A/p21 (By similarity). Interacts with MKRN1 (PubMed:19536131). Interacts with PSMA3 (PubMed:11350925). Interacts with PCNA (PubMed:11595739, PubMed:18794347, PubMed:18703516, PubMed:8861913). Component of the ternary complex, cyclin D-CDK4-CDKN1A. Interacts (via its N-terminal domain) with CDK4; the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4 (PubMed:9106657). Binding to CDK2 leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair (PubMed:19445729). Interacts with PIM1 (PubMed:12431783). Interacts with STK11 and NUAK1 (PubMed:25329316). Interacts wih DTL (PubMed:23213251). Interacts with isoform 1 and isoform 2 of TRIM39 (PubMed:23213251).
Phosphorylation of Thr-145 by Akt or of Ser-146 by PKC impairs binding to PCNA. Phosphorylation at Ser-114 by GSK3-beta enhances ubiquitination by the DCX(DTL) complex. Phosphorylation of Thr-145 by PIM2 enhances CDKN1A stability and inhibits cell proliferation. Phosphorylation of Thr-145 by PIM1 results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. UV radiation-induced phosphorylation at Thr-80 by LKB1 and at Ser-146 by NUAK1 leads to its degradation.
Plays an important role in controlling cell cycle progression and DNA damage-induced G2 arrest (PubMed:9106657). Involved in p53/TP53 mediated inhibition of cellular proliferation in response to DNA damage. Also involved in p53-independent DNA damage-induced G2 arrest mediated by CREB3L1 in astrocytes and osteoblasts (By similarity). Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression. Functions in the nuclear localization and assembly of cyclin D-CDK4 complex and promotes its kinase activity towards RB1. At higher stoichiometric ratios, inhibits the kinase activity of the cyclin D-CDK4 complex. Inhibits DNA synthesis by DNA polymerase delta by competing with POLD3 for PCNA binding (PubMed:11595739).
The C-terminal is required for nuclear localization of the cyclin D-CDK4 complex.
The PIP-box K+4 motif mediates both the interaction with PCNA and the recruitment of the DCX(DTL) complex: while the PIP-box interacts with PCNA, the presence of the K+4 submotif, recruits the DCX(DTL) complex, leading to its ubiquitination.
Ubiquitinated by MKRN1; leading to polyubiquitination and 26S proteasome-dependent degradation. Ubiquitinated by the DCX(DTL) complex, also named CRL4(CDT2) complex, leading to its degradation during S phase or following UV irradiation. Ubiquitination by the DCX(DTL) complex is essential to control replication licensing and is PCNA-dependent: interacts with PCNA via its PIP-box, while the presence of the containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to its degradation. Ubiquitination at Ser-2 leads to degradation by the proteasome pathway. Ubiquitinated by RNF114; leading to proteasomal degradation.
Interacts with APP beta-APP42 (amyloid-beta protein 42).
May participate in amyloid-beta-induced apoptosis via its interaction with beta-APP42.
Was originally (PubMed:11278849) thought to modulate amyloid-beta toxicity by coupling to G protein. However, PubMed:12836168 showed that this effect is not direct.
Isoform 1: Homodimer; disulfide-linked via the cysteine motif. Isoform 1: Can also form heterodimers with SYT3, SYT7, SYT9 and SYT10. Isoform 1: Interacts with STX1A, STX1B and STX2; the interaction is Ca(2+)-dependent. Isoform 2: Is not able to form homodimer and heterodimers.
May be involved in Ca(2+)-dependent exocytosis of secretory vesicles through Ca(2+) and phospholipid binding to the C2 domain or may serve as Ca(2+) sensors in the process of vesicular trafficking and exocytosis. May mediate Ca(2+)-regulation of exocytosis in acrosomal reaction in sperm (By similarity).
The cysteine motif mediates homo- or heterodimer formation via formation of disulfide bonds.
Induced in breast cancer tissue (at protein level). Up-regulated in liver tumor tissues.
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187). Interacts with NOTCH3 (PubMed:17292860). Interacts with ZFAND1 (PubMed:29804830).
'Lys-63'-linked polyubiquitination by TRAF6 is required for activation.
(Microbial infection) Activated upon coronavirus SARS-CoV-2 infection.
Homodimer, when phosphorylated (PubMed:25326418, PubMed:18836453). Interacts with TASL (via pLxIS motif); interaction takes place downstream of TLR7, TLR8 or TLR9, leading to its activation (PubMed:32433612). Interacts with MYD88 and TRAF6 (By similarity).
Maintained as a monomer in an autoinhibited state (PubMed:25326418, PubMed:18836453, PubMed:22412986). Phosphorylation and activation follow the following steps: innate adapter protein TASL recruits IRF5, thereby licensing IRF5 for phosphorylation by IKBKB (PubMed:32433612). Phosphorylated IRF5 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce IFNs (PubMed:25326418, PubMed:32433612).
Phosphorylation of serine and threonine residues by IKBKB in a C-terminal autoinhibitory region, stimulates dimerization, transport into the nucleus, assembly with the coactivator CBP/EP300 and initiation of transcription.
Transcription factor that plays a critical role in innate immunity by activating expression of type I interferon (IFN) IFNA and INFB and inflammatory cytokines downstream of endolysosomal toll-like receptors TLR7, TLR8 and TLR9 (PubMed:11303025, PubMed:15695821, PubMed:22412986, PubMed:25326418, PubMed:32433612). Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters (By similarity). Can efficiently activate both the IFN-beta (IFNB) and the IFN-alpha (IFNA) genes and mediate their induction downstream of the TLR-activated, MyD88-dependent pathway (By similarity). Key transcription factor regulating the IFN response during SARS-CoV-2 infection (PubMed:33440148).
Interacts with KIF16B (By similarity). Interacts with ZFYVE20.
Involved in membrane trafficking between the Golgi complex and endosomes during early embryonic development. Regulates the Golgi to endosome transport of FGFR-containing vesicles during early development, a key process for developing basement membrane and epiblast and primitive endoderm lineages during early postimplantation development. May act by modulating the kinesin KIF16B-cargo association to endosomes (By similarity). Regulates, together with its guanine nucleotide exchange factor DENND6A, the specific endocytic transport of ADAM10, N-cadherin/CDH2 shedding and cell-cell adhesion.
Belongs to the anion channel-forming bestrophin (TC 1.A.46) family. Calcium-sensitive chloride channel subfamily.
Forms calcium-sensitive chloride channels. Permeable to bicarbonate.
Mainly confined to the retinal pigment epithelium and colon.
Expressed at higher levels in tumor tissues such as carcinoma.
Inhibited by the natural product emetine produced by the ipecac root.
Interacts with RB1; the interaction disrupts RB1 binding to E2F1 (PubMed:21689726). Interacts with RBL1 and RBL2 (By similarity).
Plays a role in maintaining pluripotency in human stem cells in vitro.
Serine hydrolase whose substrates have not been identified yet (PubMed:19329999, PubMed:20080647). May negatively regulate basal or autocrine TGF-beta signaling by suppressing SMAD2-SMAD3 phosphorylation (PubMed:20080647). May play a role in the transformation process due to its capacity to confer resistance to the growth-inhibitory effects of TGF-beta through interaction with RB1 and the subsequent displacement of E2F1 (PubMed:9697699).
Belongs to the secreted frizzled-related protein (sFRP) family.
Expressed in mesenchymal cells. Highly expressed in the stroma of proliferative endometrium. Expressed in cardiomyocytes. Shows moderate to strong expression in ovarian tumors with expression increasing as the tumor stage increases. In ovarian tumors, expression levels are inversely correlated with expression of CTNNB1 (at protein level).
Increased levels in failing myocardium. Up-regulated in several tumor types including ostomalacia-associated tumors and endometrial and breast carcinomas.
Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts. They have a role in regulating cell growth and differentiation in specific cell types (By similarity). SFRP4 plays a role in bone morphogenesis. May also act as a regulator of adult uterine morphology and function. May also increase apoptosis during ovulation possibly through modulation of FZ1/FZ4/WNT4 signaling (By similarity). Has phosphaturic effects by specifically inhibiting sodium-dependent phosphate uptake (PubMed:12952927).
Belongs to the glycoprotein hormones subunit alpha family.
Functions as a heterodimeric glycoprotein hormone with GPHB5 able to bind and activate the thyroid-stimulating hormone receptor (TSHR), leading to increased cAMP production (PubMed:12045258). Plays a central role in controlling thyroid cell metabolism (PubMed:12045258).
Heterodimer with GPHB5; this heterodimer interacts with thyroid-stimulating hormone receptor (TSHR), and hence stimulates cAMP production.
Chromosomal aberrations involving CDK12 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with ERBB2, leading to CDK12-ERBB2 fusion leading to trunctated CDK12 protein not in-frame with ERBB2.
Cyclin-dependent kinase that phosphorylates the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A), thereby acting as a key regulator of transcription elongation. Regulates the expression of genes involved in DNA repair and is required for the maintenance of genomic stability. Preferentially phosphorylates 'Ser-5' in CTD repeats that are already phosphorylated at 'Ser-7', but can also phosphorylate 'Ser-2'. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogen inhibitors.
Inhibited by the ATP analog flavopiridol, purvalanol A, purvalanol B, staurosporine and CR8.
Interacts with CCNL1 and CCNL2 (By similarity). Interacts with CCNK.
Phosphorylation at Thr-893 increases kinase activity.
(Microbial infection) Cleavage by S.pyogenes cysteine protease SpeB promotes its activation independently of CASP1 (PubMed:28331908, PubMed:32719155). SpeB-mediated maturation of IL1B plays a dual role depending on infection site: while IL1B inflammatory response prevents bacterial growth during invasive skin infections, it promotes streptococcal infection of the nasopharynx by disrupting colonization resistance mediated by the microbiota (PubMed:28331908, PubMed:32719155).
(Microbial infection) Cleavage by S.pyogenes cysteine protease SpeB promotes its activation independently of CASP1.
Activation of the IL1B precursor involves a CASP1-catalyzed proteolytic cleavage. Processing and secretion are temporarily associated.
By LPS (PubMed:15192144). Transcription and translation induced by M.tuberculosis and a number of different M.tuberculosis components in macrophages; EsxA is the most potent activator tested (at protein level) (PubMed:20148899). In pancreatic islets, release is increased by high glucose treatment. In pancreatic islets and macrophages, release is also increased by endocannabinoid anandamide/AEA (PubMed:23955712).
Expressed in activated monocytes/macrophages (at protein level).
Monomer. In its precursor form, weakly interacts with full-length MEFV; the mature cytokine does not interact at all (PubMed:17431422). Interacts with integrins ITGAV:ITGBV and ITGA5:ITGB1; integrin-binding is required for IL1B signaling (PubMed:29030430). Interacts with cargo receptor TMED10; the interaction is direct and is required for the secretion of IL1B mature form (PubMed:32272059). Interacts with HSP90AB1; the interaction facilitates cargo translocation into the ERGIC (PubMed:32272059). Interacts with HSP90B1; the interaction facilitates cargo translocation into the ERGIC (PubMed:32272059).
Potent pro-inflammatory cytokine (PubMed:3920526, PubMed:10653850, PubMed:12794819, PubMed:28331908). Initially discovered as the major endogenous pyrogen, induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, B-cell activation and antibody production, and fibroblast proliferation and collagen production (PubMed:3920526). Promotes Th17 differentiation of T-cells. Synergizes with IL12/interleukin-12 to induce IFNG synthesis from T-helper 1 (Th1) cells (PubMed:10653850). Plays a role in angiogenesis by inducing VEGF production synergistically with TNF and IL6 (PubMed:12794819). Involved in transduction of inflammation downstream of pyroptosis: its mature form is specifically released in the extracellular milieu by passing through the gasdermin-D (GSDMD) pore (PubMed:33377178, PubMed:33883744). Acts as a sensor of S.pyogenes infection in skin: cleaved and activated by pyogenes SpeB protease, leading to an inflammatory response that prevents bacterial growth during invasive skin infection (PubMed:28331908).
The IL1B production occurs in 2 steps, each being controlled by different stimuli. First, inflammatory signals, such as LPS, stimulate the synthesis and promote the accumulation of cytosolic stores of pro-IL1B (priming). Then additional signals are required for inflammasome assembly, leading to CASP1 activation, pro-IL1B processing and eventually secretion of the active cytokine. IL1B processing and secretion are temporarily associated.
Heterodimer with RABGEF1. The dimer binds RAB5A that has been activated by GTP-binding. Interacts with SDCCAG8; this interaction is important for ciliogenesis regulation (PubMed:27224062). Interacts with RAB4A; this interaction may mediate VEGFR2 cell surface expression (PubMed:29425100).
Plays a role in membrane trafficking and in homotypic early endosome fusion (PubMed:9524116). Participates in arteriogenesis by regulating vascular endothelial growth factor receptor 2/VEGFR2 cell surface expression and endosomal trafficking (PubMed:29425100). By interacting with SDCCAG8, localizes to centrosomes and plays a critical role in ciliogenesis (PubMed:27224062).
Interacts with the phosphotyrosine interaction domain of NUMB.
O-glycosylated; contains chondroitin sulfate and heparan sulfate.
Plays a role in formation of mast cell secretory granules and mediates storage of various compounds in secretory vesicles. Required for storage of some proteases in both connective tissue and mucosal mast cells and for storage of granzyme B in T-lymphocytes. Plays a role in localizing neutrophil elastase in azurophil granules of neutrophils. Mediates processing of MMP2. Plays a role in cytotoxic cell granule-mediated apoptosis by forming a complex with granzyme B which is delivered to cells by perforin to induce apoptosis. Regulates the secretion of TNF-alpha and may also regulate protease secretion. Inhibits bone mineralization.
Associates with PLCG1, VAV1 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with VAV3, PLCG2 and GRB2. Interacts through its SH2 domain with CD79A. Interacts (via SH2 domain) with SYK; phosphorylated and activated by SYK. Interacts (via SH2 domain) with SCIMP; this interaction is dependent on phosphorylation of SCIMP 'Tyr-131' (PubMed:21930792).
Expressed in B-cell lineage and fibroblast cell lines (at protein level). Highest levels of expression in the spleen, with lower levels in the liver, kidney, pancreas, small intestines and colon.
Following BCR activation, phosphorylated on tyrosine residues by SYK and LYN. When phosphorylated, serves as a scaffold to assemble downstream targets of antigen activation, including PLCG1, VAV1, GRB2 and NCK1. Phosphorylation of Tyr-84, Tyr-178 and Tyr-189 facilitates PLCG1 binding. Phosphorylation of Tyr-96 facilitates BTK binding. Phosphorylation of Tyr-72 facilitates VAV1 and NCK1 binding. Phosphorylation is required for both Ca(2+) and MAPK signaling pathways.
Functions as a central linker protein, downstream of the B-cell receptor (BCR), bridging the SYK kinase to a multitude of signaling pathways and regulating biological outcomes of B-cell function and development. Plays a role in the activation of ERK/EPHB2, MAP kinase p38 and JNK. Modulates AP1 activation. Important for the activation of NF-kappa-B and NFAT. Plays an important role in BCR-mediated PLCG1 and PLCG2 activation and Ca(2+) mobilization and is required for trafficking of the BCR to late endosomes. However, does not seem to be required for pre-BCR-mediated activation of MAP kinase and phosphatidyl-inositol 3 (PI3) kinase signaling. May be required for the RAC1-JNK pathway. Plays a critical role in orchestrating the pro-B cell to pre-B cell transition. May play an important role in BCR-induced B-cell apoptosis.
Expressed in neutrophils (at protein level) (PubMed:2843187, PubMed:2500436, PubMed:2501794). Expressed in bone marrow (PubMed:8469233).
Homodimer; homodimerization seems to be required for killing S.aureus, but not E.coli (PubMed:17088326, PubMed:30658057). Interacts with CD4 (PubMed:15620707). Interacts with HIV-1 surface protein gp120; homodimerization is required for the interaction (PubMed:15620707, PubMed:30658057). Interacts with Bacillus anthracis lef; homodimerization is required for the interaction (PubMed:30658057).
Host-defense peptide that has antimicrobial activity against Gram-negative bacteria, and to a lesser extent also against Gram-positive bacteria and fungi (PubMed:2500436, PubMed:2501794, PubMed:15317502, PubMed:15616305, PubMed:30658057). Exhibits antimicrobial activity against Gram-negative E.coli and E.aerogenes and Gram-positive S.faecalis, S.aureus and B.cereus and the yeast C.albicans (in vitro) (PubMed:2500436, PubMed:2501794, PubMed:15317502, PubMed:15616305, PubMed:17088326, PubMed:30658057). Interacts with pathogenic surface proteins and toxins, such as HIV-1 surface protein gp120 and B.anthracis anthrax lethal factor lef (PubMed:15620707, PubMed:30658057). Protects blood cells against infection with HIV-1 (in vitro) (PubMed:15620707). Inhibits enzymatic activity of B.anthracis lef/anthrax lethal factor (in vitro) (PubMed:30658057). Inhibits corticotropin (ACTH)-stimulated corticosterone production (in vitro) (PubMed:2843187).
The three-dimensional structure formed by the three intramolecular disulfide bridges is indispensable for effective bacterial killing.
Binds to AT-rich stretches in the modulator region upstream of the human cytomegalovirus major intermediate early gene enhancer. May act as repressor and down-regulate enhancer-dependent gene expressison (PubMed:8649988). May positively regulate chondrocyte-specific transcription such as of COL2A1 in collaboration with SOX9 and positively regulate histone H3 acetylation at chondrocyte-specific genes. May stimulate early-stage chondrocyte differentiation and inhibit later stage differention (By similarity). Can repress ESR1-mediated transcriptional activation; proposed to act as corepressor for selective nuclear hormone receptors (PubMed:15941852). As RNA-binding protein involved in the regulation of inflammatory response by stabilizing selective inflammation-related mRNAs, such as IL6, STAT3 and TBX21. Binds to stem loop structures located in the 3'UTRs of IL6, STAT3 and TBX21 mRNAs; at least for STAT3 prevents binding of ZC3H12A to the mRNA stem loop structure thus inhibiting its degradation activity. Contributes to elevated IL6 levels possibly implicated in autoimmunity processes. IL6-dependent stabilization of STAT3 mRNA may promote differentiation of naive CD4+ T-cells into T-helper Th17 cells. In CD4+ T-cells may also inhibit RORC-induced Th17 cell differentiation independently of IL6 signaling. Stabilization of TBX21 mRNA contributes to elevated interferon-gamma secretion in Th1 cells possibly implicated in the establishment of septic shock (By similarity). Stabilizes TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in its 3'UTR; thereby competing with the mRNA-destabilizing functions of RC3H1 and endoribonuclease ZC3H12A (By similarity).
Interacts with SOX9 (By similarity). Interacts with ESR1 (PubMed:15941852). Interacts with RORC (By similarity).
Phosphorylated by MAPK14 on serine residues involving a TLR4 signaling pathway upon lipopolysaccharide (LPS) stimulation leading to its ubiquitination and proteasomal degradation.
Ubiquitinated leading to proteasomal degradation; involving WWP1 linked to MAPK14-mediated phosphorylation upon LPS stimulation.
(Microbial infection) Required early in hepatitis C virus (HCV) infection to initiate RNA replication, and later in the infection to support infectious virus production.
Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs). Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway. Binds cholesterol and may promote ER retention of the SCAP-SREBF complex (PubMed:24217618).
Expressed in heart, placenta, liver, kidney, pancreas, prostate, testis, ovary and small intestine.
Forms a heteromeric complex with ERLIN2 (PubMed:19240031). In complex with ERLIN2, interacts with RNF170 (PubMed:21610068). Interacts with AMFR and SYVN1 (PubMed:21343306).
ELN is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of ELN may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease (PubMed:8812460).
Elastin is formed through the cross-linking of its soluble precursor tropoelastin. Cross-linking is initiated through the action of lysyl oxidase on exposed lysines to form allysine. Subsequent spontaneous condensation reactions with other allysine or unmodified lysine residues result in various bi-, tri-, and tetrafunctional cross-links. The most abundant cross-links in mature elastin fibers are lysinonorleucine, allysine aldol, desmosine, and isodesmosine.
Expressed within the outer myometrial smooth muscle and throughout the arteriolar tree of uterus (at protein level). Also expressed in the large arteries, lung and skin.
Hydroxylation on proline residues within the sequence motif, GXPG, is most likely 4-hydroxy as this fits the requirement for 4-hydroxylation in vertebrates.
Major structural protein of tissues such as aorta and nuchal ligament, which must expand rapidly and recover completely. Molecular determinant of the late arterial morphogenesis, stabilizing arterial structure by regulating proliferation and organization of vascular smooth muscle (By similarity).
Major structural protein of tissues such as aorta and nuchal ligament, which must expand rapidly and recover completely. Molecular determinant of the late arterial morphogenesis, stabilizing arterial structure by regulating proliferation and organization of vascular smooth muscle.
The polymeric elastin chains are cross-linked together into an extensible 3D network. Forms a ternary complex with BGN and MFAP2. Interacts with MFAP2 via divalent cations (calcium > magnesium > manganese) in a dose-dependent and saturating manner. Interacts with FBLN5 (PubMed:15790312, PubMed:17035250). Interacts with FBN1 (PubMed:15790312). Forms a ternary complex with FBN1 and FBLN2 or FBLN5 (PubMed:17255108). Interacts with MFAP4 in a Ca (2+)-dependent manner; this interaction promotes ELN self-assembly (By similarity) (PubMed:15790312, PubMed:17035250, PubMed:17255108). Interacts with EFEMP2 with moderate affinity (PubMed:16478991).
Expressed in theca cells in ovary and in Leydig cells in testis (at protein level). Also expressed in brain and mammary gland.
Interacts with APOA1 (PubMed:23719382). Binds to HDL (PubMed:17533573).
May accelerate cholesterol efflux from endothelial cells to high-density lipoprotein (HDL) and thereby regulates angiogenesis. May orchestrate hematopoietic stem and progenitor cell emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. YJEFN3-mediated cholesterol efflux activates endothelial SREBF2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates NOTCH and promotes hematopoietic stem and progenitor cell emergence (By similarity). May play a role in spermiogenesis and oogenesis (PubMed:17533573).
Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription (PubMed:21063504). Might be involved in transcriptional regulation by modulating the binding of the RARA nuclear receptor to RARE DNA elements (PubMed:28167758).
Ubiquitinated. Polyubiquitination involves WWP1 and leads to proteasomal degradation of this protein (By similarity).
Belongs to the universal ribosomal protein uS5 family.
Component of the mitochondrial small ribosomal subunit (mt-SSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins.
(Microbial infection) Interacts directly with herpes virus HHV-1 protein ICP0.
Antibodies against CENPA are present in sera from patients with autoimmune diseases that developed autoantibodies against centrosomal proteins.
Component of centromeric nucleosomes, where DNA is wrapped around a histone octamer core (PubMed:23818633, PubMed:26878239, PubMed:20739937, PubMed:21743476). The octamer contains two molecules each of H2A, H2B, CENPA and H4 assembled in one CENPA-H4 heterotetramer and two H2A-H2B heterodimers (PubMed:23818633, PubMed:26878239, PubMed:20739937, PubMed:21743476). CENPA modulates the DNA-binding characteristics of nucleosomes so that protruding DNA ends have higher flexibility than in nucleosomes containing conventional histone H3 (PubMed:27499292, PubMed:21743476). Inhibits binding of histone H1 to nucleosomes, since histone H1 binds preferentially to rigid DNA linkers that protrude from nucleosomes (PubMed:27499292). Nucleosomes containing CENPA also contain histone H2A variants such as MACROH2A and H2A.Z/H2AZ1 (Probable). The CENPA-H4 heterotetramer is more compact and structurally more rigid than corresponding H3-H4 heterotetramers (PubMed:15282608, PubMed:20739937). Can assemble into nucleosomes that contain both CENPA and histone H3.3; these nucleosomes interact with a single CENPC chain (PubMed:25408271). Heterotrimer composed of HJURP, CENPA and histone H4, where HJURP interacts with the dimer formed by CENPA and histone H4 and prevents tetramerization of CENPA and H4 (PubMed:21478274). Component of the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU (PubMed:16622419). Interacts (via CATD domain) with HJURP; the interaction is direct and is required for its localization to centromeres (PubMed:15282608, PubMed:19410544, PubMed:19410545, PubMed:23818633, PubMed:25556658). Interacts with CENPC, CENPN and CENPT; interaction is direct. Part of a centromere complex consisting of CENPA, CENPT and CENPW (PubMed:19533040). Identified in centromere complexes containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:27499292). Can self-associate (PubMed:9024683). The CENPA-H4 heterotetramer can bind DNA by itself (in vitro) (PubMed:20739937). Interacts with CDK1, PPP1CA and RBBP7 (PubMed:25556658).
Expression varies across the cell cycle, with high levels in G2 phase (at the mRNA level).
Histone H3-like nucleosomal protein that is specifically found in centromeric nucleosomes (PubMed:7962047, PubMed:9024683, PubMed:11756469, PubMed:14667408, PubMed:15702419, PubMed:15475964, PubMed:15282608, PubMed:17651496, PubMed:19114591, PubMed:27499292, PubMed:20739937). Replaces conventional H3 in the nucleosome core of centromeric chromatin that serves as an assembly site for the inner kinetochore (PubMed:18072184). The presence of CENPA subtly modifies the nucleosome structure and the way DNA is wrapped around the nucleosome and gives rise to protruding DNA ends that are less well-ordered and rigid compared to nucleosomes containing histone H3 (PubMed:27499292, PubMed:26878239). May serve as an epigenetic mark that propagates centromere identity through replication and cell division (PubMed:15475964, PubMed:15282608, PubMed:26878239, PubMed:20739937, PubMed:21478274). Required for recruitment and assembly of kinetochore proteins, and as a consequence required for progress through mitosis, chromosome segregation and cytokinesis (PubMed:11756469, PubMed:14667408, PubMed:18072184, PubMed:23818633, PubMed:25556658, PubMed:27499292).
Phosphorylated by CDK1 at Ser-68 during early mitosis; this abolishes association with chromatin and centromeres, prevents interaction with HJURP and thereby prevents premature assembly of CENPA into centromeres (PubMed:25556658). Dephosphorylated at Ser-68 by PPP1CA during late mitosis (PubMed:25556658). Phosphorylation of Ser-7 by AURKA and AURKB during prophase is required for localization of AURKA and AURKB at inner centromere and is essential for normal cytokinesis (PubMed:11756469, PubMed:14667408, PubMed:18239465). Initial phosphorylation during prophase is mediated by AURKA and is maintained by AURKB.
The CATD (CENPA targeting domain) region is responsible for the more compact structure of nucleosomes containing CENPA (PubMed:15282608). It is necessary and sufficient to mediate the localization into centromeres (PubMed:7962047, PubMed:15282608).
Trimethylated by NTMT1 at the N-terminal glycine after cleavage of Met-1. Methylation is low before incorporation into nucleosomes and increases with cell cycle progression, with the highest levels in mitotic nucleosomes.
Ubiquitinated (Probable). Interaction with herpes virus HSV-1 ICP0 protein, leads to its degradation by the proteasome pathway.
Inhibited by transition metal ions including Ni(2+), Zn(2+), and Cu(2+) and by sulfhydryl-blocking agents.
Removes 5-oxoproline from various penultimate amino acid residues except L-proline.
Belongs to the major facilitator superfamily.
(Microbial infection) Interacts with HTLV-1 accessory protein p12I.
Belongs to the V-ATPase proteolipid subunit family.
Proton-conducting pore forming subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:33065002). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (By similarity).
Ubiquitinated by RNF182, leading to its degradation via the ubiquitin-proteasome pathway.
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex (PubMed:33065002). The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H (PubMed:33065002). The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR (PubMed:33065002). Interacts with the V0 complex V-ATPase subunit a4 ATP6V0A4 (By similarity). Interacts with LASS2 (PubMed:11543633). Interacts with RNF182; this interaction leads to ubiquitination and degradation via the proteasome pathway (PubMed:18298843).
Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed to be not involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.
Mammalian complex I is composed of 45 different subunits.
Interacts (via VWFA domain) with ACTB, BCOR, BICD2, CCDC22, CDC42BPB, CEP162, MYCBP2, NONO, PDCD6, PITPNM2, RDX, SKIL, SKT, SPTBN1, UBE2O and WTAP (PubMed:12522145).
Widely expressed (PubMed:12670487, PubMed:12949241). Expressed strongly in the brain, heart and prostate (PubMed:12670487, PubMed:12949241). Expressed strongly in peripheral blood leukocytes (PubMed:12949241).
Associates with IL12B to form the pro-inflammatory cytokine IL-23 that plays different roles in innate and adaptive immunity (PubMed:11114383). Released by antigen-presenting cells such as dendritic cells or macrophages, binds to a heterodimeric receptor complex composed of IL12RB1 and IL23R to activate JAK2 and TYK2 which then phosphorylate the receptor to form a docking site leading to the phosphorylation of STAT3 and STAT4 (PubMed:32474165, PubMed:29287995, PubMed:33606986). This process leads to activation of several pathways including p38 MAPK or NF-kappa-B and promotes the production of pro-inflammatory cytokines such as interleukin-17A/IL17A (PubMed:12023369). In turn, participates in the early and effective intracellular bacterial clearance (PubMed:32474165). Promotes the expansion and survival of T-helper 17 cells, a CD4-positive helper T-cell subset that produces IL-17, as well as other IL-17-producing cells (PubMed:17676044).
Heterodimer with IL12B; disulfide-linked (PubMed:11114383, PubMed:18680750). The heterodimer is known as interleukin IL-23 (PubMed:11114383, PubMed:18680750). Interacts with IL23R; this interaction enables recruitment of IL12RB1 (PubMed:29287995, PubMed:33606986).
Secreted by activated dendritic and phagocytic cells and keratinocytes. Also expressed by dermal Langerhans cells (at protein level).
Up-regulated by a wide array of pathogens and pathogen-products together with self-signals for danger or injury. Up-regulated in psoriatic dermal tissues, in dendritic cells of multiple sclerosis patients and in tumors.
According to PubMed:12498782, expressed predominantly in the brain and in kidney (PubMed:12498782). Low levels in heart, skeletal muscle, liver, placenta, pancreas and lung (PubMed:12498782). According to PubMed:12972431, predominant expression in brain, and only marginal in kidney (PubMed:12972431). In brain, present throughout all cortical layers, highest levels in GABAergic neurons (based on morphology and distribution pattern) (PubMed:12972431).
Adipose-specific isoform that plays a key role in adaptive thermogenesis. Facilitates the efficient use of stored triglyceride by promoting multilocular morphology of thermogenic adipocytes: acts by inhibiting the activity of CIDEA and CIDEC on lipid droplets, thereby preventing lipid droplet fusion and facilitating lipid utilization. May also participate in adaptive thermogenesis by promoting sympathetic innervation of thermogenic adipose tissue: acts by driving secretion of neurotrophic factor S100B from brown adipocytes, stimulating neurite outgrowth from sympathetic neurons.
Expression is restricted to adipose tissue, with high expression in multilocular thermogenic adipocytes (brown adipose tissue).
Interacts (via cadherin domains) with both alpha and beta isoforms of neurexins (NRXN1, NRXN2 and NRXN3) (By similarity). Directly interacts with APBA2 (PubMed:12972431). Forms a tripartite complex with APBA2 and APP (PubMed:12972431). Interacts with low affinity with KLC1 (By similarity). Interacts with SLC23A2/SVCT2 (PubMed:34673103).
Interacts with CIDEA; inhibiting the lipid transferase activity of CIDEA (By similarity). Interacts with CIDEC; inhibiting the lipid transferase activity of CIDEC (By similarity).
Postsynaptic adhesion molecule that binds to presynaptic neurexins to mediate both excitatory and inhibitory synapse formation (PubMed:25352602). Promotes synapse development by acting as a cell adhesion molecule at the postsynaptic membrane, which associates with both neurexin-alpha and neurexin-beta proteins at the presynaptic membrane (PubMed:25352602). Regulates the balance between excitatory and inhibitory synapses by inhibiting formation of excitatory parallel-fiber synapses and promoting formation of inhibitory synapses in the same neuron (By similarity). May also be involved in ascorbate (vitamin C) uptake via its interaction with SLC23A2/SVCT2 (PubMed:34673103). Complex formation with APBA2 and APP, stabilizes APP metabolism and enhances APBA2-mediated suppression of beta-APP40 secretion, due to the retardation of intracellular APP maturation (PubMed:12972431) (Probable).
Proteolytically processed under normal cellular conditions (PubMed:15037614). A primary zeta-cleavage generates a large extracellular (soluble) N-terminal domain (sAlc) and a short C-terminal transmembrane fragment (CTF1) (PubMed:15037614). A secondary cleavage catalyzed by gamma-secretase within the transmembrane domain releases the beta-Alc-beta chain in the extracellular milieu and produces an intracellular fragment (AlcICD) (PubMed:15037614). This processing is strongly suppressed in the tripartite complex formed with APBA2 and APP, which seems to prevent the association with gamma-secretase (PubMed:15037614).
The cytoplasmic domain binds synaptic Ca(2+).
Ubiquitinated: endoplasmic reticulum-localized protein is ubiquitinated and degraded by the endoplasmic reticulum-associated degradation (ERAD) pathway.
Belongs to the WWC family. KIBRA subfamily.
Expressed in mammary epithelial cells and breast cancer cell lines. Found in the luminal epithelium surrounding the ducts in the normal breast. In the brain, expressed in somatodendritic compartment of neurons in the cortex and hippocampus and in the cerebellum it is found in the Purkinje cells and some granule cells (at protein level). Detected in brain, heart, colon and kidney. In the kidney, expressed in glomerular podocytes, in some tubules and in the collecting duct.
Genetic variations in WWC1 define the memory quantitative trait locus (MEMRYQTL) [MIM:615602].
Homodimer. Interacts with DDN. Interacts with DYNLL1 and histone H3. The interaction with DYNLL1 is mandatory for the recruitment and transactivation functions of ESR1 or DYNLL1 to the target chromatin and the interaction with histone H3 ensures proper regulatory interaction of WWC1-DYNLL1-ESR1 complexes with target chromatin. Interacts (via WW domains) with DDR1 (via PPxY motif) in a collagen-regulated manner. Interacts with PRKCZ (via the protein kinase domain). Forms a tripartite complex with DDR1 and PRKCZ, but predominantly in the absence of collagen. Interacts (via the ADDV motif) with PATJ (via PDZ domain 8). Interacts (via WW domains) with SYNPO (via PPxY motifs). Interacts with NF2 and SNX4.
Phosphorylation at Ser-542 and Ser-931 by CDK1 in response to spindle damage stress regulates mitotic exit, these two sites are dephosphorylated by CDC14B.
Probable regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in tumor suppression by restricting proliferation and promoting apoptosis. Along with NF2 can synergistically induce the phosphorylation of LATS1 and LATS2 and can probably function in the regulation of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway. Acts as a transcriptional coactivator of ESR1 which plays an essential role in DYNLL1-mediated ESR1 transactivation. Regulates collagen-stimulated activation of the ERK/MAPK cascade. Modulates directional migration of podocytes. Acts as a substrate for PRKCZ. Plays a role in cognition and memory performance (PubMed:15081397, PubMed:16684779, PubMed:18190796, PubMed:18596123, PubMed:18672031, PubMed:20159598, PubMed:23778582). Plays an important role in regulating AMPA-selective glutamate receptors (AMPARs) trafficking underlying synaptic plasticity and learning (By similarity).
Strongly up-regulated by progestin treatment.
The C2-domain mediates homodimerization. It is a calcium-sensitive lipid-binding domain with preference for PI(3)P.
(Microbial infection) The PAF1 complex interacts with Dengue virus DENV2 16681 non-structural protein 5/NS5 (PubMed:30550790). The PAF1 complex interacts with Dengue virus DENV4 Dominica/814669/1981 non-structural protein 5/NS5 (PubMed:30550790). The interaction with viral NS5 proteins may reduce the antiviral immune response by inhibiting the recruitment of the PAF1 complex to interferon-stimulated genes, thus preventing their transcription (PubMed:30550790).
(Microbial infection) The PAF1 complex interacts with Zika virus French Polynesia 10087PF/2013 non-structural protein 5/NS5 (PubMed:30550790). The interaction with viral NS5 proteins may reduce the antiviral immune response by inhibiting the recruitment of the PAF1 complex to interferon-stimulated genes, thus preventing their transcription (PubMed:30550790).
Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Required for mono- and trimethylation on histone H3 'Lys-4' (H3K4me3) and dimethylation on histone H3 'Lys-79' (H3K4me3). Required for Hox gene transcription. Required for the trimethylation of histone H3 'Lys-4' (H3K4me3) on genes involved in stem cell pluripotency; this function is synergistic with CXXC1 indicative for an involvement of the SET1 complex. Involved in transcriptional regulation of IL6-responsive genes and in JAK-STAT pathway; may regulate DNA-association of STAT3 (By similarity).
Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8 (PubMed:16024656, PubMed:19952111, PubMed:20178742). The PAF1 complex interacts with PHF5A (By similarity). Interacts with KMT2A/MLL1 (PubMed:20541477). Interacts with STAT3 (By similarity). Interacts with SETD5 (By similarity). Interacts with ERCC6 (PubMed:26030138).
Ligand for members of the frizzled family of seven transmembrane receptors (Probable). Functions in the canonical Wnt/beta-catenin signaling pathway (By similarity). Plays a role in normal ectoderm development (PubMed:17847007, PubMed:28589954). Required for normal tooth development (PubMed:17847007, PubMed:29178643, PubMed:28589954). Required for normal postnatal development and maintenance of tongue papillae and sweat ducts (PubMed:28589954). Required for normal proliferation of basal cells in tongue filiform papillae, plantar epithelium and sweat ducts. Required for normal expression of keratins in tongue papillae (By similarity). Required for normal expression of KRT9 in foot plant epithelium (PubMed:28589954). Required for normal hair follicle function (PubMed:28589954).
Adapter protein which acts downstream of several membrane receptors including cytokine, antigen, hormone, cell matrix and growth factor receptors to regulate multiple signaling pathways. Regulates osteoclast differentiation mediating the TNFRSF11A/RANK signaling. In allergic response, it plays a role in mast cells activation and degranulation through PI-3-kinase regulation. Also involved in the regulation of cell proliferation and hematopoiesis.
Part of a complex composed of EEIG1, TNFRSF11A/RANK, PLCG2, GAB2, TEC and BTK; complex formation increases in the presence of TNFSF11/RANKL (PubMed:23478294). Interacts with SHC1; may mediate interaction with receptors (By similarity). Interacts with SYK (By similarity). Interacts with PI-3 kinase. Interacts with GRB2 (via SH3 2 domain). Interacts (phosphorylated) with PTPN11. Interacts with TNFRSF11A (via cytoplasmic domain). Interacts (phosphorylated) with 14-3-3 family proteins SFN, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ and YWHAZ; prevents interaction with GRB2 and attenuates GAB2 signaling. Interacts with HCK.
Phosphorylated on tyrosine residue(s) by the thrombopoietin receptor (TPOR), stem cell factor receptor (SCFR), and T-cell and B-cell antigen receptors, gp130, IL-2R and IL-3R (By similarity). Phosphorylated upon stimulation of TNFRSF11A/RANK by TNFSF11/RANKL (By similarity). Phosphorylated upon EGF stimulation. Phosphorylated on tyrosine residues by HCK upon IL6 signaling.
The PH domain mediates phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate binding.
The SH3-binding motifs mediate interaction with SHC1 and GRB2.
Expressed in all cell lines and normal tissues tested, including the thymus.
Histone-binding protein, which is part of various corepressor complexes. Mediates the recruitment of corepressor complexes to target genes, followed by chromatin compaction and repression of transcription. Plays a role during myogenesis: required for the maintenance of undifferentiated states of myogenic progenitor cells via interaction with MYOD1. Interaction with MYOD1 leads to the recruitment of associated corepressors and silencing of MYOD1 target genes. Part of the SLC complex in germ cells, where it may play a role during spermatogenesis.
Interacts with MYOD1 (By similarity). Component of the SLC (SFMBT1-LSD1-CoREST) corepressor complex, which also contains KDM1A/LSD1 and RCOR1/CoREST. Interacts with KDM1A/LSD1 and RCOR1/CoREST. Interacts with L3MBTL3 (By similarity).
The MBT repeats mediate binding to histones tails; however, in contrast to other MBT repeats, does not bind specific histone lysine modifications. The MBT repeats lack the conserved Asp and aromatic cage at conserved positions (PubMed:23592795).
Interacts with TERT, PPP2CA and SMG1. Part of a complex that contains SMG1, SMG5, SMG7, PPP2CA, a short isoform of UPF3A (isoform UPF3AS, but not isoform UPF3AL) and phosphorylated UPF1. Not detected in complexes that contain unphosphorylated UPF1.
Plays a role in nonsense-mediated mRNA decay. Does not have RNase activity by itself. Promotes dephosphorylation of UPF1. Together with SMG7 is thought to provide a link to the mRNA degradation machinery involving exonucleolytic pathways, and to serve as an adapter for UPF1 to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation. Necessary for TERT activity.
Belongs to the cytidine and deoxycytidylate deaminase family. ADAT3 subfamily.
Val-225 is present instead of the conserved Glu which is an active site in the cytidine and deoxycytidylate deaminase family of enzymes. It is suggested that this protein may act as a regulatory subunit.
Homodimer (via coiled-coil domain) (PubMed:28218432). Interacts (via coiled-coil domain) with ATG14 (via coiled-coil domain); this interaction is tighter than BECN2 self-association (PubMed:23954414, PubMed:28218432). Interacts with AMBRA1, UVRAG and PIK3C3/VPS34; these interactions are not disrupted by starvation (PubMed:23954414). Does not interact with RUBCN (PubMed:23954414). Interacts (via N-terminus) with GPRASP1/GASP1; the interaction is direct (PubMed:23954414).
Involved in 2 distinct lysosomal degradation pathways: acts as a regulator of autophagy and as a regulator of G-protein coupled receptors turnover. Regulates degradation in lysosomes of a variety of G-protein coupled receptors via its interaction with GPRASP1/GASP1.
Present in fetal and adult brain (at protein level).
According to the Genome Reference Consortium, the reference genome GRCh38/hg38 is in conflict with the sequence shown here.
Down-regulated in Sjoegren syndrome patients (at protein level).
Expressed corneal epithelial cells, conjunctival goblet and epithelial cells and lacrimal gland cells (at protein level). Expressed by mucous cells of the submandibular gland and submucosal gland of the trachea. Expressed by middle ear epithelial cells.
May function in ocular mucus homeostasis.
Autocitrullination at Arg-372 and Arg-374 inactivates the enzyme.
Belongs to the protein arginine deiminase family.
Catalyzes the citrullination/deimination of arginine residues of proteins such as histones, thereby playing a key role in histone code and regulation of stem cell maintenance (PubMed:15339660, PubMed:15345777, PubMed:16567635, PubMed:21245532). Citrullinates histone H1 at 'Arg-54' (to form H1R54ci), histone H3 at 'Arg-2', 'Arg-8', 'Arg-17' and/or 'Arg-26' (to form H3R2ci, H3R8ci, H3R17ci, H3R26ci, respectively) and histone H4 at 'Arg-3' (to form H4R3ci) (PubMed:15339660, PubMed:15345777, PubMed:16567635, PubMed:21245532). Acts as a key regulator of stem cell maintenance by mediating citrullination of histone H1: citrullination of 'Arg-54' of histone H1 (H1R54ci) results in H1 displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance (PubMed:15339660, PubMed:15345777, PubMed:16567635, PubMed:21245532). Promotes profound chromatin decondensation during the innate immune response to infection in neutrophils by mediating formation of H1R54ci (PubMed:18209087). Required for the formation of neutrophil extracellular traps (NETs); NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation (By similarity). Citrullination of histone H3 prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription (PubMed:15345777). Citrullinates EP300/P300 at 'Arg-2142', which favors its interaction with NCOA2/GRIP1 (PubMed:15731352).
Expressed in eosinophils and neutrophils, not expressed in peripheral monocytes or lymphocytes.
Strongly Inhibited by F-amidine and N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine). These inhibitors are however not specific to PADI4 and also inhibit other members of the family (PubMed:17002273). Incorporation of a carboxylate ortho to the backbone amide of Cl-amidine results in inhibitors with increased specificity for PADI4: N-alpha-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-L-ornithine amide (o-F-amidine) and N-alpha-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-L-ornithine amide (o-Cl-amidine) (PubMed:21882827). Strongly and specifically inhibited by Thr-Asp-F-amidine (TDFA); other members of the family are not inhibited (PubMed:22004374).
The gene represented in this entry may be involved in disease pathogenesis. The association to rheumatoid arthritis was initially thought to result from increased citrullination of target proteins (PubMed:12833157). However, variants that have been associated to rheumatoid arthritis (Ser-55, Ala-82 and Ala-112) do not affect the catalytic activity or the citrullination activity of PADI4, suggesting that these variants may affect the mRNA stability rather than the protein (PubMed:21245532).
Belongs to the eukaryotic initiation factor 4G family.
Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome (PubMed:9418880). Functional homolog of EIF4G1 (PubMed:9418880).
Following infection by certain enteroviruses, rhinoviruses and aphthoviruses, EIF4G1 is cleaved by the viral protease 2A, or the leader protease in the case of aphthoviruses. This shuts down the capped cellular mRNA transcription.
Interacts with EIF4A, EIF4E, eIF3 and PABPC1 (PubMed:9418880). Part of a complex with EIF4E (By similarity). eIF4F is a multi-subunit complex, the composition of which varies with external and internal environmental conditions (By similarity). It is composed of at least EIF4A, EIF4E and EIF4G1/EIF4G3. EIF4G1/EIF4G3 interacts through its C-terminus with the serine/threonine kinases MKNK1, and with MKNK2. Appears to act as a scaffold protein, holding these enzymes in place to phosphorylate eIF4E. Non-phosphorylated EIF4EBP1 competes with EIF4G1/EIFG3 to interact with EIF4E; insulin stimulated MAP-kinase (MAPK1 and MAPK3) phosphorylation of EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation. EIF4G1/EIF4G3 interacts with PABPC1 to bring about circularization of the mRNA (By similarity). Interacts with FXR1; promoting translation of FXR1 target mRNAs (By similarity).
Cleaves the vWF multimers in plasma into smaller forms thereby controlling vWF-mediated platelet thrombus formation.
Genetic variations in ADAMTS13 coding region influence plasmatic ADAMTS13 activity levels. Dependent on the sequence context, the same polymorphisms might be either positive or negative modifiers of gene expression, thereby altering the phenotype of ADAMTS13 deficiency.
Glycosylated. O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS13. May also be C-glycosylated on tryptophan residues within the consensus sequence W-X-X-W of the TPRs, and also N-glycosylated. These other glycosylations can also facilitate secretion.
The globular cysteineless spacer domain adopts a jelly-roll topology, and is necessary to recognize and cleave vWF. The C-terminal TSP type-1 and CUB domains may modulate this interaction.
The precursor is processed by a furin endopeptidase which cleaves off the pro-domain.
The pro-domain is not required for folding or secretion and does not perform the common function of maintening enzyme latency.
Zinc and calcium ions cooperatively modulate enzyme activity. The cleavage of the pro-domain is not required for protease activity. Dependence on calcium for proteolytic activity is mediated by the high affinity site.
Isoform 1 interacts (through WDR repeats) with NVL; the interaction is independent of RNA or pre-60S ribosome particles. Isoform 2 does not interact with NVL (PubMed:28416111). Interacts with MTREX; the interaction dissociation in a late stage of rRNA synthesis is required for appropriate maturation of pre-60S particles and depends on the ATPase activity of NVL (PubMed:26456651, PubMed:29107693).
Regulatory protein of the MTREX-exosome complex involved in the synthesis of the 60S ribosomal subunit (PubMed:26456651). Participates in an early cleavage of the pre-rRNA processing pathway in cooperation with NVL (PubMed:29107693). Required for blastocyst formation, is necessary for RNA transcription, processing and/or stability during preimplantation development (By similarity).
Belongs to the class I-like SAM-binding methyltransferase superfamily. RsmB/NOP family.
S-adenosyl-L-methionine-dependent methyltransferase that specifically methylates the C5 position of cytosine 72 in tRNA(Thr)(TGT) and tRNA(Cys)(GCA) (PubMed:26160102, PubMed:27703015, PubMed:28531330). In vitro also methylates tRNA(Thr)(AGT) (PubMed:27703015, PubMed:26160102). Methylation requires, in the acceptor stem region, the presence of the 3'-CCA terminus, the target site C72, the discriminator base U73, and the second and third base pairs (2:71 and 3:70) in the tRNA substrates (PubMed:26160102, PubMed:27703015).
The PUA domain plays a role in tRNA recognition through precisely recognizing the CCA end and the D-stem region of tRNA.
Auxillary subunit of the N-terminal acetyltransferase A (NatA) complex which displays alpha (N-terminal) acetyltransferase activity.
Component of the N-terminal acetyltransferase A (NatA) complex composed of NAA10 and NAA16.
Binds to EPS15 (a clathrin coat-associated protein) via a C-terminal domain containing three Asn-Pro-Phe (NPF) repeats.
Concentrated at clathrin-coated endocytic intermediates in nerve terminals. Isoform 1 is more enriched than isoform 2 in developing brain as well as non-neuronal cells. Isoform 2 is very abundant in nerve terminals.
In the central section; belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family.
Interacts with ASH/GRB2. Interacts with PACSIN1, PACSIN2 and PACSIN3 (By similarity). Binds AMPH, SH3GL1, SH3GL2 and SH3GL3 (PubMed:10542231). Interacts with MYO1E (via SH3 domain) (PubMed:17257598). Interacts with BIN1 and DNM1 (By similarity).
Phosphatase that acts on various phosphoinositides, including phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate (PubMed:27435091). Has a role in clathrin-mediated endocytosis (By similarity). Hydrolyzes PIP2 bound to actin regulatory proteins resulting in the rearrangement of actin filaments downstream of tyrosine kinase and ASH/GRB2 (By similarity).
The C-terminal proline-rich region mediates binding to a variety of SH3 domain-containing proteins including AMPH, SH3GL1, SH3GL2, SH3GL3 and GRB2.
Belongs to the carbon-nitrogen hydrolase superfamily. BTD/VNN family.
Catalytic release of biotin from biocytin, the product of biotin-dependent carboxylases degradation.
It is uncertain whether Met-1 or Met-21 is the initiator.
Functions as a tRNA-binding adapter to mediate NAT10-dependent tRNA acetylation modifying cytidine to N4-acetylcytidine (ac4C) (PubMed:25653167, PubMed:35196516).
Interacts with NAT10 (PubMed:25653167). Binds tRNA (PubMed:35196516).
Part of a complex that contains SMG5, SMG7, PPP2CA, a short isoform of UPF3A (isoform UPF3AS, but not isoform UPF3AL) and phosphorylated UPF1 (PubMed:14636577). Interacts with DHX34; the interaction is RNA-independent (PubMed:25220460).
Plays a role in nonsense-mediated mRNA decay.
Plays a role in nonsense-mediated mRNA decay. Recruits UPF1 to cytoplasmic mRNA decay bodies. Together with SMG5 is thought to provide a link to the mRNA degradation machinery involving exonucleolytic pathways, and to serve as an adapter for UPF1 to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation.
Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions (PubMed:2430973, PubMed:6489349, PubMed:15014436, PubMed:18285447). Multifunctional, involved in inflammation, angiogenesis, wound healing, reactive oxygen species (ROS) signaling, nitrous oxide (NO) signaling, apoptosis, senescence, aging, cellular self-renewal, stemness, and cardiovascular and metabolic homeostasis (PubMed:14568985, PubMed:1371676, PubMed:10613822, PubMed:11134179, PubMed:24511121, PubMed:29042481, PubMed:32679764). Negatively modulates dendritic cell activation and cytokine release, as part of an autocrine feedback loop, contributing to the resolution of inflammation and immune homeostasis (PubMed:14568985). Ligand for receptor CD47 (PubMed:8550562, PubMed:19004835). Modulates nitrous oxide (NO) signaling via CD47, hence playing a role as a pressor agent, supporting blood pressure (By similarity). Plays a role in endothelial cell senescence, acting via CD47, by increasing the abundance and activation of NADPH oxidase NOX1, and so generating excess ROS (PubMed:29042481). Inhibits stem cell self-renewal, acting via CD47 signaling, probably by regulation of the stem cell transcription factors POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4 (By similarity). Negatively modulates wound healing, acting via CD47 (By similarity). Ligand for receptor CD36 (PubMed:1371676, PubMed:10613822, PubMed:11134179). Involved in inducing apoptosis in podocytes in response to elevated free fatty acids, acting via CD36 (By similarity). Plays a role in suppressing angiogenesis, acting, depending on context, via CD36 or CD47 (PubMed:1371676, PubMed:10613822, PubMed:32679764, PubMed:11134179). Promotes cellular senescence in a TP53-CDKN1A-RB1 signaling-dependent manner (PubMed:29042481). Ligand for immunoglobulin-like cell surface receptor SIRPA (PubMed:24511121). Involved in ROS signaling in non-phagocytic cells, stimulating NADPH oxidase-derived ROS production, acting via interaction with SIRPA (PubMed:24511121). Plays a role in metabolic dysfunction in diet-induced obesity, perhaps acting by exacerbating adipose inflammatory activity; its effects may be mediated, at least in part, through enhanced adipocyte proliferation (By similarity). Plays a role in ER stress response, via its interaction with the activating transcription factor 6 alpha (ATF6) which produces adaptive ER stress response factors (By similarity). May be involved in age-related conditions, including metabolic dysregulation, during normal aging (PubMed:29042481, PubMed:32679764).
Expressed by platelets (at protein level) (PubMed:101549). Expressed by monocyte-derived immature and mature dendritic cells (at protein level) (PubMed:14568985).
Expression is induced by PGE2, S.aureus and lipopolysaccharide (PubMed:14568985). Induced in arteries and lung parenchyma following injury or stress (PubMed:27742621). Expression in vasculature, including arteries, increases in normal aging (PubMed:32679764, PubMed:29042481).
Homotrimer; disulfide-linked (PubMed:101549, PubMed:18285447). Can bind to fibrinogen, fibronectin, laminin, type V collagen and integrins alpha-V/beta-1, alpha-V/beta-3 and alpha-IIb/beta-3 (PubMed:6489349, PubMed:6693501, PubMed:2478219). Binds heparin (PubMed:101549, PubMed:16407063, PubMed:18065761). Interacts (via the C-terminal domain) with CD47 (PubMed:8550562, PubMed:19004835). Interacts (via the TSP type I repeats) with CD36; the interaction conveys an antiangiogenic effect (PubMed:1371676, PubMed:10613822). Interacts (via the TSP type I repeats) with HRG; the interaction blocks the antiangiogenic effect of THBS1 with CD36 (PubMed:11134179). Interacts with ATF6 (via lumenal domain) (By similarity). Interacts with FN1; this interaction is enhanced by TNFAIP6, which may act as a bridging molecule between FN1 and THBS1 (PubMed:18042364). Interacts with SIRPA; the interaction stimulates phosphorylation of SIRPA (PubMed:24511121).
Component of the circadian core oscillator, which includes the CRY proteins, CLOCK, or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins. Interacts directly with CLOCK to form the BMAL2-CLOCK transactivator. Can form heterodimers or homodimers which interact directly with CLOCK to form the transcription activator. Interacts with NPAS2 and HIF1A. Interacts with PER2 (By similarity).
Constitutively expressed. Has no circadian rhythm expression pattern.
Expressed in fetal brain. Highly expressed in brain and placenta. Lower levels in heart, liver, thymus, kidney and lung. Located to endothelial cells and neuronal cells of the suprachiasmatic nucleus (SCN). Also detected in endothelial cells of the heart, lung and kidney. In the brain, specifically expressed in the thalamus, hippocampus and amygdala.
Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. The CLOCK-BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1.
Belongs to the glycosyl hydrolase 18 family.
Binds to oocyte zona pellucida in vivo. May play a role in the fertilization process and/or early embryonic development.
Defects in NOX1 may play a role in the pathogenesis of very early onset inflammatory bowel disease (VEOIBD), a chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology diagnosed before 6 years of age. VEOIBD is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but the phenotype of children with onset of Crohn disease occurring younger than the age of 10 is predominantly colonic, with a lower risk of ileal disease. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints.
NOH-1L is detected in colon, uterus, prostate, and colon carcinoma, but not in peripheral blood leukocytes. NOH-1S is detected only in colon and colon carcinoma cells.
NOH-1S is a voltage-gated proton channel that mediates the H(+) currents of resting phagocytes and other tissues. It participates in the regulation of cellular pH and is blocked by zinc. NOH-1L is a pyridine nucleotide-dependent oxidoreductase that generates superoxide and might conduct H(+) ions as part of its electron transport mechanism, whereas NOH-1S does not contain an electron transport chain.
NOX1, NOXA1, NOXO1, RAC1 and CYBA forms a functional multimeric complex supporting reactive oxygen species (ROS) production. Interacts with NOXA1 and NOXO1.
The oxidase activity is potentiated by NOXA1 and NOXO1.
Paired receptors consist of highly related activating and inhibitory receptors and are widely involved in the regulation of the immune system. PILRB is thought to act as a cellular signaling activating receptor that associates with ITAM-bearing adapter molecules on the cell surface.
Required to maintain a pool of extrasynaptic AMPA-regulated glutamate receptors (AMPAR) which is necessary for synapse development and function. Regulates basal AMPAR function and synaptic transmission during development but is dispensable at mature hippocampal synapses. Plays a role in regulating basal phosphorylation levels of glutamate receptor GRIA1 and promotes GRIA1 and GRIA2 cell surface expression.
(Microbial infection) Over-expressed following infection by Epstein-Barr virus.
Component of the telomerase holoenzyme complex composed of one molecule of TERT, one molecule of WRAP53/TCAB1, two molecules of H/ACA ribonucleoprotein complex subunits DKC1, NOP10, NHP2 and GAR1, and a telomerase RNA template component (TERC) (PubMed:19179534, PubMed:20351177, PubMed:26170453, PubMed:29695869). The telomerase holoenzyme complex is associated with TEP1, SMG6/EST1A and POT1 (PubMed:19179534). Interacts with the chaperonin-containing T-complex (TRiC) complex; which mediates the folding of WRAP53/TCAB1 (PubMed:25467444). Interacts with COIL (PubMed:21072240). Interacts with SMN1 (PubMed:21072240). Interacts with RNF8 (PubMed:25512560). Interacts with histone H2AX (PubMed:26734725, PubMed:27715493).
Expressed in all tissues and cell lines examined.
Phosphorylated at Ser-64 by ATM in response to DNA damage, promoting its interaction with histone H2AX and localization to sites of DNA double-strand breaks.
RNA chaperone that plays a key role in telomere maintenance and RNA localization to Cajal bodies (PubMed:29804836, PubMed:29695869). Specifically recognizes and binds the Cajal body box (CAB box) present in both small Cajal body RNAs (scaRNAs) and telomerase RNA template component (TERC) (PubMed:19285445, PubMed:20351177, PubMed:29804836, PubMed:29695869). Essential component of the telomerase holoenzyme complex, a ribonucleoprotein complex essential for the replication of chromosome termini that elongates telomeres in most eukaryotes (PubMed:19179534, PubMed:20351177, PubMed:26170453, PubMed:29695869). In the telomerase holoenzyme complex, required to stimulate the catalytic activity of the complex (PubMed:27525486, PubMed:29804836). Acts by specifically binding the CAB box of the TERC RNA and controlling the folding of the CR4/CR5 region of the TERC RNA, a critical step for telomerase activity (PubMed:29804836). In addition, also controls telomerase holoenzyme complex localization to Cajal body (PubMed:22547674). During S phase, required for delivery of TERC to telomeres during S phase and for telomerase activity (PubMed:29804836). In addition to its role in telomere maintenance, also required for Cajal body formation, probably by mediating localization of scaRNAs to Cajal bodies (PubMed:19285445, PubMed:21072240). Also plays a role in DNA repair: phosphorylated by ATM in response to DNA damage and relocalizes to sites of DNA double-strand breaks to promote the repair of DNA double-strand breaks (PubMed:25512560, PubMed:27715493). Acts by recruiting the ubiquitin ligase RNF8 to DNA breaks and promote both homologous recombination (HR) and non-homologous end joining (NHEJ) (PubMed:25512560, PubMed:27715493).
The mRNA encoding this protein plays a critical role in the regulation of p53/TP53 expression at the post-transcriptional level; it is involved both in maintaining basal p53/TP53 mRNA levels and in p53/TP53 induction upon DNA damage.
Belongs to the metallo-dependent hydrolases superfamily. TatD-type hydrolase family.
Binds 2 divalent metal cations per subunit.
Deoxyribonuclease which catalyzes (in vitro) the decatenation of kinetoplast DNA, which are circular DNA catenated to each other, producing linear DNA molecules (By similarity). Plays an important role in chromosomal segregation and cell cycle progression during eye development probably via its DNA decatenation activity (By similarity).
Its physiological role is not yet clear.
AC 1 and AC 2 (clusters of acidic amino acids) contain sorting information. AC 1 directs TGN localization and interacts with the TGN sorting protein PACS-1 (By similarity).
Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. Likely functions in the constitutive and regulated secretory pathways. Plays an essential role in pregnancy establishment by proteolytic activation of a number of important factors such as BMP2, CALD1 and alpha-integrins.
The propeptide domain acts as an intramolecular chaperone assisting the folding of the zymogen within the endoplasmic reticulum.
Expressed in testis, placenta and skin. Expressed at lower level in mammary gland and stomach.
Tumor-associated antigen found in several cutaneous T-cell lymphoma (CTCL). Also found in colorectal and breast carcinomas, head and neck squamous cell carcinomas and melanoma.
Belongs to the ROX family. MINA53 subfamily.
Expressed in liver, skeletal muscle, heart, pancreas, and placenta. Not detected in brain, lung or kidney. Expressed in several lung cancer tissues, but is barely detected in the adjacent non-cancerous tissues. Also highly expressed in several esophageal squamous cell carcinoma (ESCC), and colon cancer tissues, and in various cancer cell lines.
Oxygenase that can act as both a histone lysine demethylase and a ribosomal histidine hydroxylase.
Oxygenase that can act as both a histone lysine demethylase and a ribosomal histidine hydroxylase. Is involved in the demethylation of trimethylated 'Lys-9' on histone H3 (H3K9me3), leading to an increase in ribosomal RNA expression. Also catalyzes the hydroxylation of 60S ribosomal protein L27a on 'His-39'. May play an important role in cell growth and survival. May be involved in ribosome biogenesis, most likely during the assembly process of pre-ribosomal particles.
Up-regulated in response to MYC, in alveolar macrophages from coal miners and in silica particle-treated A549 lung cancer cells.
Belongs to the sirtuin family. Class IV subfamily.
Interacts with UBTF and the RNA polymerase I complex (PubMed:16618798, PubMed:19174463). Interacts with components of the B-WICH complex, such as MYBBP1A, SMARCA5/SNF2H and BAZ1B/WSTF (PubMed:22586326). Interacts with ELK4, leading to stabilization at target promoters for H3K18Ac deacetylation (PubMed:22722849). Interacts with histone H2A and/or histone H2B (PubMed:22722849). Interacts with DNMT1 (By similarity). Interacts with SIRT1 (By similarity).
Methylation at Arg-388 by PRMT6 inhibits the H3K18Ac histone deacetylase activity, promoting mitochondria biogenesis and maintaining mitochondria respiration.
NAD-dependent protein-lysine deacetylase and deacylase activities are activated by nucleic acids (PubMed:26907567, PubMed:27997115). Histone deacetylase activity is activated by DNA and nucleosomes (PubMed:27997115, PubMed:35939806). Protein-lysine deacylase activity is activated by RNA (PubMed:26907567). H3K18Ac histone deacetylase activity is inhibited by methylation at Arg-388 (PubMed:30420520). H3K18Ac histone deacetylase activity is inhibited by deubiquitination by USP7 (PubMed:28655758).
NAD-dependent protein-lysine deacylase that can act both as a deacetylase or deacylase (desuccinylase, depropionylase, deglutarylase and dedecanoylase), depending on the context (PubMed:22722849, PubMed:26907567, PubMed:30653310, PubMed:31542297, PubMed:35939806). Specifically mediates deacetylation of histone H3 at 'Lys-18' (H3K18Ac) (PubMed:22722849, PubMed:30420520, PubMed:35939806). In contrast to other histone deacetylases, displays strong preference for a specific histone mark, H3K18Ac, directly linked to control of gene expression (PubMed:22722849, PubMed:30653310). H3K18Ac is mainly present around the transcription start site of genes and has been linked to activation of nuclear hormone receptors; SIRT7 thereby acts as a transcription repressor (PubMed:22722849). Moreover, H3K18 hypoacetylation has been reported as a marker of malignancy in various cancers and seems to maintain the transformed phenotype of cancer cells (PubMed:22722849). Also able to mediate deacetylation of histone H3 at 'Lys-36' (H3K36Ac) in the context of nucleosomes (PubMed:30653310). Also mediates deacetylation of non-histone proteins, such as ATM, CDK9, DDX21, DDB1, FBL, FKBP5/FKBP51, GABPB1, RAN, RRP9/U3-55K and POLR1E/PAF53 (PubMed:24207024, PubMed:26867678, PubMed:28147277, PubMed:28886238, PubMed:28426094, PubMed:30540930, PubMed:31075303, PubMed:30944854, PubMed:28790157). Enriched in nucleolus where it stimulates transcription activity of the RNA polymerase I complex (PubMed:16618798, PubMed:19174463, PubMed:24207024). Acts by mediating the deacetylation of the RNA polymerase I subunit POLR1E/PAF53, thereby promoting the association of RNA polymerase I with the rDNA promoter region and coding region (PubMed:16618798, PubMed:19174463, PubMed:24207024). In response to metabolic stress, SIRT7 is released from nucleoli leading to hyperacetylation of POLR1E/PAF53 and decreased RNA polymerase I transcription (PubMed:24207024). Required to restore the transcription of ribosomal RNA (rRNA) at the exit from mitosis (PubMed:19174463). Promotes pre-ribosomal RNA (pre-rRNA) cleavage at the 5'-terminal processing site by mediating deacetylation of RRP9/U3-55K, a core subunit of the U3 snoRNP complex (PubMed:26867678). Mediates 'Lys-37' deacetylation of Ran, thereby regulating the nuclear export of NF-kappa-B subunit RELA/p65 (PubMed:31075303). Acts as a regulator of DNA damage repair by mediating deacetylation of ATM during the late stages of DNA damage response, promoting ATM dephosphorylation and deactivation (PubMed:30944854). Suppresses the activity of the DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes by mediating deacetylation of DDB1, which prevents the interaction between DDB1 and CUL4 (CUL4A or CUL4B) (PubMed:28886238). Activates RNA polymerase II transcription by mediating deacetylation of CDK9, thereby promoting 'Ser-2' phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (PubMed:28426094). Deacetylates FBL, promoting histone-glutamine methyltransferase activity of FBL (PubMed:30540930). Acts as a regulator of mitochondrial function by catalyzing deacetylation of GABPB1 (By similarity). Regulates Akt/AKT1 activity by mediating deacetylation of FKBP5/FKBP51 (PubMed:28147277). Required to prevent R-loop-associated DNA damage and transcription-associated genomic instability by mediating deacetylation and subsequent activation of DDX21, thereby overcoming R-loop-mediated stalling of RNA polymerases (PubMed:28790157). In addition to protein deacetylase activity, also acts as protein-lysine deacylase (PubMed:27436229, PubMed:27997115, PubMed:31542297). Acts as a protein depropionylase by mediating depropionylation of Osterix (SP7), thereby regulating bone formation by osteoblasts (By similarity). Acts as a histone deglutarylase by mediating deglutarylation of histone H4 on 'Lys-91' (H4K91glu); a mark that destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes (PubMed:31542297). Acts as a histone desuccinylase: in response to DNA damage, recruited to DNA double-strand breaks (DSBs) and catalyzes desuccinylation of histone H3 on 'Lys-122' (H3K122succ), thereby promoting chromatin condensation and DSB repair (PubMed:27436229). Also promotes DSB repair by promoting H3K18Ac deacetylation, regulating non-homologous end joining (NHEJ) (By similarity). Along with its role in DNA repair, required for chromosome synapsis during prophase I of female meiosis by catalyzing H3K18Ac deacetylation (By similarity). Involved in transcriptional repression of LINE-1 retrotransposon via H3K18Ac deacetylation, and promotes their association with the nuclear lamina (PubMed:31226208). Required to stabilize ribosomal DNA (rDNA) heterochromatin and prevent cellular senescence induced by rDNA instability (PubMed:29728458). Acts as a negative regulator of SIRT1 by preventing autodeacetylation of SIRT1, restricting SIRT1 deacetylase activity (By similarity).
Overexpressed in thyroid carcinoma cell lines and tissues, but not in adenomas.
Ubiquitinated via 'Lys-63'-linked ubiquitin chains (PubMed:28655758). Deubiquitinated by USP7, inhibiting the H3K18Ac histone deacetylase activity and regulating gluconeogenesis (PubMed:28655758). Ubiquitinated by E3 ubiquitin-protein ligase complex containing FBXO7; leading to proteasomal degradation.
Was originally termed SIR-T8/SIRT8 (PubMed:11953824). This was later retracted (PubMed:12454780, PubMed:12454781).
Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.
The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:25043029). The C-terminus of APC10 binds to CDC27/APC3 (PubMed:11524682). Interacts with PIWIL1; interaction only takes place when PIWIL1 binds piRNA (By similarity). Interacts with FBXO43; the interaction is direct.
Contains a tandem atypical propeller in EMLs (TAPE) domain. The N-terminal beta-propeller is formed by canonical WD repeats; in contrast, the second beta-propeller contains one blade that is formed by discontinuous parts of the polypeptide chain.
Homotrimer; self-association is mediated by the N-terminal coiled coil (By similarity). Does not interact with EML3 (PubMed:25740311). Binds repolymerizing microtubules (PubMed:24859200). Binds unpolymerized tubulins via its WD repeat region (PubMed:24706829). Interacts with TASOR (By similarity).
Modulates the assembly and organization of the microtubule cytoskeleton, and probably plays a role in regulating the orientation of the mitotic spindle and the orientation of the plane of cell division. Required for normal proliferation of neuronal progenitor cells in the developing brain and for normal brain development. Does not affect neuron migration per se.
The N-terminal coiled coil is required for association with microtubules.
Ubiquitous; expressed in most tissues with the exception of thymus and peripheral blood lymphocytes.
Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. The full-length GLI3 form (GLI3FL) after phosphorylation and nuclear translocation, acts as an activator (GLI3A) while GLI3R, its C-terminally truncated form, acts as a repressor. A proper balance between the GLI3 activator and the repressor GLI3R, rather than the repressor gradient itself or the activator/repressor ratio gradient, specifies limb digit number and identity. In concert with TRPS1, plays a role in regulating the size of the zone of distal chondrocytes, in restricting the zone of PTHLH expression in distal cells and in activating chondrocyte proliferation. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'.
Is expressed in a wide variety of normal adult tissues, including lung, colon, spleen, placenta, testis, and myometrium.
Phosphorylated on multiple sites by protein kinase A (PKA) and phosphorylation by PKA primes further phosphorylation by CK1 and GSK3. Phosphorylated by DYRK2 (in vitro). Phosphorylation is essential for its proteolytic processing.
The full-length GLI3 form (GLI3FL) interacts with SUFU and this interaction regulates the formation of either repressor or activator forms of GLI3. Its association with SUFU is regulated by Hh signaling and dissociation of the SUFU-GLI3 interaction requires the presence of the ciliary motor KIF3A (By similarity). Interacts with KIF7. The activator form of GLI3 (GLI3A) but not the repressor form (GLI3R) can interact with TRPS1. The phosphorylated form interacts with BTRC. Interacts with ZIC1. Interacts with ZIC3 (via C2H2-type domains 3, 4 and 5); the interaction enhances its transcriptional activity. Interacts with WRD11; the interaction associates EMX1 with GLI3 (PubMed:29263200). Interacts with DZIP1; retains GLI3 within the cytoplasm (PubMed:23955340).
Transcriptional repressor GLI3R, a C-terminally truncated form, is generated from the full-length GLI3 protein (GLI3FL/GLI3-190) through proteolytic processing. This process requires PKA-primed phosphorylation of GLI3, ubiquitination of GLI3 and the presence of BTRC. GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state. Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R. GLI3R formation leads to its dissociation from SUFU, allowing it to translocate into the nucleus, and repress Hh target genes. When Hh signaling is initiated, SUFU dissociates from GLI3FL and this has two consequences. First, GLI3R production is halted. Second, free GLI3FL translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A). Phosphorylated in vitro by ULK3.
A soluble form arises by proteolytic removal of the membrane anchor.
Detected in proximal tubules in the kidney cortex (at protein level) (PubMed:14576052, PubMed:29402915). Long isoforms are highly expressed in small intestine, colon and kidney (renal proximal tubule epithelial cells). Shorter isoforms are detected at lower levels in testis, thymus and peripheral blood leukocytes.
Interacts (via extracellular region) with CUBN/cubilin, giving rise to a huge complex containing one AMN chain and three CUBN chains.
Membrane-bound component of the endocytic receptor formed by AMN and CUBN (PubMed:14576052, PubMed:30523278, PubMed:29402915). Required for normal CUBN glycosylation and trafficking to the cell surface (PubMed:14576052, PubMed:29402915). The complex formed by AMN and CUBN is required for efficient absorption of vitamin B12 (PubMed:12590260, PubMed:14576052, PubMed:26040326). Required for normal CUBN-mediated protein transport in the kidney (Probable).
The complex formed by AMN and CUBN is composed of a 400 Angstrom long stem and a globular crown region. The stem region is probably formed by AMN and the CUBN N-terminal region, including the EGF-like domains. The crown is probably formed by the CUBN CUB domains.
The role of Amn in embryonic development seems to be species specific. In mice, null mutations lead to embryonic lethality. Human mutations give rise to much milder symptoms.
Belongs to the glutathione peroxidase family.
Could play a major role in protecting mammals from the toxicity of ingested organic hydroperoxides (PubMed:8428933). Tert-butyl hydroperoxide, cumene hydroperoxide and linoleic acid hydroperoxide but not phosphatidycholine hydroperoxide, can act as acceptors (PubMed:8428933).
Mostly in liver and gastrointestinal tract, not found in heart or kidney.
Homotrimer. Interacts (via C-type lectin domain) with IGHE (via CH3 region); this interaction regulates IgE homeostasis. Interacts (via the C-terminus) with CR2/CD21 (via Sushi domain 1 and 2).
Low-affinity receptor for immunoglobulin E (IgE) and CR2/CD21. Has essential roles in the regulation of IgE production and in the differentiation of B cells. On B cells, initiates IgE-dependent antigen uptake and presentation to T cells (PubMed:2167225). On macrophages, upon IgE binding and antigen cross-linking induces intracellular killing of parasites through activation of L-Arginine-nitric oxide pathway (PubMed:7544003).
The secreted form sCD23 is produced by ADAM10-mediated ectodomain shedding.
There are two kinds of Fc receptors for IgE, which differ in both structure and function: high affinity receptors on basophils and mast cells and low affinity receptors on lymphocytes and monocytes.
By TNF, IL1B/interleukin-1 beta and bacterial lipopolysaccharides (LPS).
Component of the BCR(TNFAIP1) E3 ubiquitin ligase complex, at least composed of CUL3, TNFAIP1/BACURD2 and RBX1. Interacts with RHOA; with a preference for RhoA-GDP. Interacts with RHOB. Interacts with PCNA. Interacts with CSNK2B.
Phosphorylation at Ser-280 by CK2 facilitates the nucleus localization and increases interaction with PCNA.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex involved in regulation of cytoskeleton structure. The BCR(TNFAIP1) E3 ubiquitin ligase complex mediates the ubiquitination of RHOA, leading to its degradation by the proteasome, thereby regulating the actin cytoskeleton and cell migration. Its interaction with RHOB may regulate apoptosis. May enhance the PCNA-dependent DNA polymerase delta activity.
Plays a role in microtubule organization.
(Microbial infection) Interacts directly with HIV-1 virus GAG protein (PubMed:12756246, PubMed:15220430).
(Microbial infection) Interacts with HIV-1 virus GAG protein, facilitating the selective packaging of tRNA(3)(Lys), the primer for reverse transcription initiation.
Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA (PubMed:9278442, PubMed:18029264, PubMed:18272479). When secreted, acts as a signaling molecule that induces immune response through the activation of monocyte/macrophages (PubMed:15851690). Catalyzes the synthesis of the signaling molecule diadenosine tetraphosphate (Ap4A), and thereby mediates disruption of the complex between HINT1 and MITF and the concomitant activation of MITF transcriptional activity (PubMed:5338216, PubMed:14975237, PubMed:19524539, PubMed:23159739).
Homodimer and tetradimer (PubMed:18272479, PubMed:23159739, PubMed:26074468, PubMed:28887846). Part of the multisynthetase complex (MSC), a multisubunit complex that groups tRNA ligases for Arg (RARS), Asp (DARS), Gln (QARS), Ile (IARS), Leu (LARS), Lys (KARS), Met (MARS) the bifunctional ligase for Glu and Pro (EPRS) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18 (PubMed:19131329, PubMed:19289464, PubMed:24312579, PubMed:23159739). Interacts with AIMP2 (via N-terminus) and MITF (PubMed:9878398, PubMed:14975237, PubMed:15220430, PubMed:23159739, PubMed:26074468, PubMed:31116475). Interacts with TARSL2 (PubMed:24312579).
Mitochondrial precursor. Contains a mitochondrial transit peptide at positions 1-16.
Phosphorylated on a serine residue after mast cell stimulation with immunoglobulin E (IgE).
Shares a bidirectional promoter with TERF2IP/RAP1.
The N-terminal domain (1-65) of the cytoplasmic isoform is a functional tRNA-binding domain, is required for nuclear localization, is involved in the interaction with DARS, but has a repulsive role in the binding to EEF1A1. A central domain (208-259) is involved in homodimerization and is required for interaction with HIV-1 GAG and incorporation into virions. The C-terminal domain (452-597) is not required for interaction with AIMP2.
Up-regulated by DARS and EEF1A1, but not by AIMP2.
Ubiquitously expressed with highest level in pancreas and lowest in skeletal muscle.
Adenylyltransferase activity is specifically phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2).
Associates with the cleavage and polyadenylation specificity factor (CPSF) complex (PubMed:21102410). Interacts with CPSF1 and CPSF3; the interaction is direct (PubMed:21102410). Interacts with PIP5K1A (PubMed:18288197).
Belongs to the DNA polymerase type-B-like family.
Phosphorylated by CK1 in the proline-rich (Pro-rich) region.
Poly(A) polymerase that creates the 3'-poly(A) tail of specific pre-mRNAs (PubMed:18288197, PubMed:21102410). Localizes to nuclear speckles together with PIP5K1A and mediates polyadenylation of a select set of mRNAs, such as HMOX1 (PubMed:18288197). In addition to polyadenylation, it is also required for the 3'-end cleavage of pre-mRNAs: binds to the 3'UTR of targeted pre-mRNAs and promotes the recruitment and assembly of the CPSF complex on the 3'UTR of pre-mRNAs (PubMed:21102410). In addition to adenylyltransferase activity, also has uridylyltransferase activity (PubMed:16790842, PubMed:18288197, PubMed:28589955). However, the ATP ratio is higher than UTP in cells, suggesting that it functions primarily as a poly(A) polymerase (PubMed:18288197). Acts as a specific terminal uridylyltransferase for U6 snRNA in vitro: responsible for a controlled elongation reaction that results in the restoration of the four 3'-terminal UMP-residues found in newly transcribed U6 snRNA (PubMed:16790842, PubMed:18288197, PubMed:28589955). Not involved in replication-dependent histone mRNA degradation.
The RRM domain is required for terminal uridylyltransferase activity (PubMed:28589955). Together with the zinc-finger domain, binds the 5'-area of U6 snRNA (PubMed:28589955).
The proline-rich region is dispensable for terminal uridylyltransferase activity.
The zinc-finger domain is required for terminal uridylyltransferase activity (PubMed:28589955). Together with the RRM domain, binds the 5'-area of U6 snRNA (PubMed:28589955).
A chromosomal aberration involving OBSCN has been found in Wilms tumor. Translocation t(1;7)(q42;p15) with PTHB1.
Autophosphorylated by protein kinase domains 1 and 2.
Initially the name obscurin was used to describe isoform 3 which lacks the kinase domains.
Interacts (via protein kinase domain 2) with CDH2 and (via protein kinase domain 1) with ATP1B1 (By similarity). Isoform 3 interacts with TTN/titin and calmodulin (PubMed:11448995, PubMed:11717165). Isoform 3 interacts with ANK1 isoform Mu17/ank1.5 (PubMed:12527750).
Lacks the kinase domain. Initially described as obscurin.
Structural component of striated muscles which plays a role in myofibrillogenesis. Probably involved in the assembly of myosin into sarcomeric A bands in striated muscle (PubMed:11448995, PubMed:16205939). Has serine/threonine protein kinase activity and phosphorylates N-cadherin CDH2 and sodium/potassium-transporting ATPase subunit ATP1B1 (By similarity). Binds (via the PH domain) strongly to phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), and to a lesser extent to phosphatidylinositol 3-phosphate (PtdIns(3)P), phosphatidylinositol 4-phosphate (PtdIns(4)P), phosphatidylinositol 5-phosphate (PtdIns(5)P) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) (PubMed:28826662).
Expressed predominantly in the heart and in the skeletal muscle.
Important for the maintenance of cardiac function. Plays a regulatory function in heart rate dynamics mediated, at least in part, through cAMP-binding and, probably, by increasing cell surface expression of the potassium channel KCNK2 and enhancing current density.
Weakly expressed in placenta, fetal kidney, fetal lung, adult pancreas, adult kidney and adult lung.
Guanine nucleotide exchange factor (GEF) for Ras and Rap1.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRG3 sub-subfamily.
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Generally pentameric. There are five types of GABA(A) receptor chains: alpha, beta, gamma, delta, and rho.
This subunit carries the benzodiazepine binding site.
Belongs to the NF-kappa-B inhibitor family.
Interacts with NFKB1, RELA and RELB; in the nucleus.
Regulates the expression of IL-2, IL-6, and other cytokines through regulation on NF-kappa-B activity. Functions in the regulation of inflammatory responses. Involved in the induction of T helper 17 cells (Th17) differentiation upon recognition of antigen by T cell antigen receptor (TCR). May also regulate TCR-induced negative selection of thymocytes.
Brain-specific. Predominantly expressed in neurons, in their axons, and at the synapses of motoneurons in the spinal cord.
Defects in TMPRSS5 may be a cause of deafness.
Binds PARK7. Part of a ternary complex containing PARK7, EFCAB6/DJBP and AR.
Negatively regulates the androgen receptor by recruiting histone deacetylase complex, and protein DJ-1 antagonizes this inhibition by abrogation of this complex (PubMed:12612053). Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (Probable).
Functions in hedgehog (Hh) signaling. Regulates the release and extracellular accumulation of cholesterol-modified hedgehog proteins and is hence required for effective production of the Hh signal (By similarity). Synergizes with SCUBE2 to cause an increase in SHH secretion (PubMed:22902404).
Interacts with SHH via the cholesterol anchor of the dually lipid-modified SHH (ShhNp) (PubMed:22902404).
F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units. Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of corepressor complexes that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of transcription repressor complexes, thereby allowing cofactor exchange (By similarity).
Fetal brain and prostate. Expressed in the cochlear spiral ganglion neurons, and in outer and inner hair cells (PubMed:30341416).
Probable component of the N-Cor repressor complex and some E3 ubiquitin ligase complex. Interacts with NCOR2 (PubMed:30341416).
The F-box-like domain is related to the F-box domain, and apparently displays the same function as component of ubiquitin E3 ligase complexes.
Belongs to the protein-tyrosine phosphatase family. Receptor class 2B subfamily.
Expressed in colon, lung, heart and testis, as well as in fetal and adult brain. Not detected in muscle and peripheral blood leukocytes.
May be involved in both signal transduction and cellular adhesion in the CNS.
Acetylated by EP300 ina stimuli-specific manner; protecting it from XIAP-mediated proteasomal degradation and required for interaction with RElA in response to stress.
Monomer, homodimer. Can form heterodimers with other COMM domain-containing proteins but only certain combinations may exist in vivo (PubMed:23563313). Interacts (via COMM domain) with COMMD2, COMMD3, COMMD4, COMMD5, COMMD6, COMMD7, COMMD8 and COMMD10 (via COMM domain). Identified in a complex with an E3 ubiquitin ligase complex composed of TCEB1/elongin C, CUL2, SOCS1 and RBX1; in the complex interacts directly with SOCS1 and CUL2. Interacts directly with ATP7B (via the N-terminal region). Interacts with CCS, CDKN2A, RELA, REL, RELB, NFKB1/p105, NFKB2/p100, NFKBIB, SCNN1D, SCNN1B, CFTR, CLU, SGK1, AKT1, CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, CUL7, HIF1A. Identified in a complex with NF-kappa-B. Interacts directly with SLC12A2. Interacts with CCDC22 and CCDC93; proposed to be a component of the CCC (COMMD/CCDC22/CCDC93) complex which contains at least COMMD1 (and possibly other COMM domain-containing proteins), CCDC22, CCDC93 (PubMed:25355947, PubMed:28892079). Interacts with VPS35L; the interaction associates CCC complex with retriever complex (PubMed:28892079, PubMed:25355947). Interacts with ATP7A (PubMed:21667063). Interacts with FAM107A; this interaction stabilizes COMMD1 in the nucleus (PubMed:28604741).
Proposed scaffold protein that is implicated in diverse physiological processes and whose function may be in part linked to its ability to regulate ubiquitination of specific cellular proteins. Can modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes by displacing CAND1; in vitro promotes CRL E3 activity and dissociates CAND1 from CUL1 and CUL2 (PubMed:21778237). Promotes ubiquitination of NF-kappa-B subunit RELA and its subsequent proteasomal degradation. Down-regulates NF-kappa-B activity (PubMed:15799966, PubMed:17183367, PubMed:20048074). Involved in the regulation of membrane expression and ubiquitination of SLC12A2 (PubMed:23515529). Modulates Na(+) transport in epithelial cells by regulation of apical cell surface expression of amiloride-sensitive sodium channel (ENaC) subunits and by promoting their ubiquitination presumably involving NEDD4L. Promotes the localization of SCNN1D to recycling endosomes (PubMed:14645214, PubMed:20237237, PubMed:21741370). Promotes CFTR cell surface expression through regulation of its ubiquitination (PubMed:21483833). Down-regulates SOD1 activity by interfering with its homodimerization (PubMed:20595380). Plays a role in copper ion homeostasis. Involved in copper-dependent ATP7A trafficking between the trans-Golgi network and vesicles in the cell periphery; the function is proposed to depend on its association within the CCC complex and cooperation with the WASH complex on early endosomes (PubMed:25355947). Can bind one copper ion per monomer (PubMed:17309234). May function to facilitate biliary copper excretion within hepatocytes. Binds to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) (PubMed:18940794). Involved in the regulation of HIF1A-mediated transcription; competes with ARNT/Hif-1-beta for binding to HIF1A resulting in decreased DNA binding and impaired transcriptional activation by HIF-1 (PubMed:20458141). Negatively regulates neuroblastoma G1/S phase cell cycle progression and cell proliferation by stimulating ubiquitination of NF-kappa-B subunit RELA and NF-kappa-B degradation in a FAM107A- and actin-dependent manner (PubMed:28604741).
Ubiquitinated; undergoes both 'Lys-63'- and 'Lys-48'-linked polyubiquitination. Ubiquitinated by XIAP, leading to its proteasomal degradation.
Ubiquitous. Highest expression in the liver, with lower expression in brain, lung, placenta, pancreas, small intestine, heart, skeletal muscle, kidney and placenta. Down-regulated in cancer tissues.
Belongs to the immunoglobulin superfamily. DCC family.
Found in axons of the central and peripheral nervous system and in differentiated cell types of the intestine. Not expressed in colorectal tumor cells that lost their capacity to differentiate into mucus producing cells.
Inactivation of DCC due to allelic deletion and/or point mutations is related to lymphatic and hematogenous metastatic tumor dissemination.
Interacts with the cytoplasmic part of UNC5A, UNC5B, UNC5C and probably UNC5D (By similarity). Interacts with DSCAM (By similarity). Interacts with PTK2/FAK1 and MAPK1 (By similarity). Interacts with NTN1 (By similarity). Interacts with MYO10 (PubMed:21642953). Interacts with CBLN4; this interaction can be competed by NTN1 (By similarity). Interacts with SIAH1 and SIAH2 (PubMed:9334332).
Receptor for netrin required for axon guidance. Mediates axon attraction of neuronal growth cones in the developing nervous system upon ligand binding. Its association with UNC5 proteins may trigger signaling for axon repulsion. It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand. Implicated as a tumor suppressor gene.
Ubiquitinated; mediated by SIAH1 or SIAH2 and leading to its subsequent proteasomal degradation.
Alpha 3 and alpha 4 type IV collagens are colocalized and present in kidney, eye, basement membranes of lens capsule, cochlea, lung, skeletal muscle, aorta, synaptic fibers, fetal kidney and fetal lung. PubMed:8083201 reports similar levels of expression of alpha 3 and alpha 4 type IV collagens in kidney, but PubMed:7523402 reports that in kidney levels of alpha 3 type IV collagen are significantly lower than those of alpha 4 type IV collagen. According to PubMed:8083201, alpha 3 type IV collagen is not detected in heart, brain, placenta, liver, pancreas, extrasynaptic muscle fibers, endoneurial and perineurial nerves, fetal brain, fetal heart and fetal liver. According to PubMed:7523402, alpha 3 type IV collagen is strongly expressed in pancreas, neuroretina and calvaria and not expressed in adrenal, ileum and skin. Isoform 1 and isoform 3 are strongly expressed in kidney, lung, suprarenal capsule, muscle and spleen, in each of these tissues isoform 1 is more abundant than isoform 3. Isoform 1 and isoform 3 are expressed at low levels in artery, fat, pericardium and peripherical nerve, but not in placenta, mesangium, skin, pleura and cultured umbilical endothelial cells.
Alpha chains of type IV collagen have a non-collagenous domain (NC1) at their C-terminus, frequent interruptions of the G-X-Y repeats in the long central triple-helical domain (which may cause flexibility in the triple helix), and a short N-terminal triple-helical 7S domain.
Autoantibodies against the NC1 domain of alpha 3(IV) are found in Goodpasture syndrome, an autoimmune disease of lung and kidney.
Isoform 2 contains an additional N-linked glycosylation site.
Phosphorylated. Thought to be phosphorylated by CERT, but CERT does not have kinase activity.
The epitopes recognized by the Goodpasture autoantibodies are sequestered within the NC1 hexamer of the type IV collagen network.
The trimeric structure of the NC1 domains is stabilized by covalent bonds between Lys and Met residues.
There are six type IV collagen isoforms, alpha 1(IV)-alpha 6(IV), each of which can form a triple helix structure with 2 other chains to generate type IV collagen network. The alpha 3(IV) chain forms a triple helical protomer with alpha 4(IV) and alpha 5(IV); this triple helical structure dimerizes through NC1-NC1 domain interactions such that the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains of one protomer connect with the alpha 5(IV), alpha 4(IV) and alpha 3(IV) chains of the opposite promoter, respectively (PubMed:12193605). Interacts with ITGB3 (PubMed:12682293). Associates with LAMB2 at the neuromuscular junction and in GBM (By similarity).
Tumstatin, a cleavage fragment corresponding to the collagen alpha 3(IV) NC1 domain, possesses both anti-angiogenic and anti-tumor cell activity; these two anti-tumor properties may be regulated via RGD-independent ITGB3-mediated mechanisms.
Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen.
Type IV collagens contain numerous cysteine residues which are involved in inter- and intramolecular disulfide bonding. 12 of these, located in the NC1 domain, are conserved in all known type IV collagens.
Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits. The complex is composed of 3 respiratory subunits cytochrome b, cytochrome c1 and Rieske protein UQCRFS1, 2 core protein subunits UQCRC1/QCR1 and UQCRC2/QCR2, and 6 low-molecular weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, UQCR10/QCR9, UQCR11/QCR10 and subunit 9, the cleavage product of Rieske protein UQCRFS1 (By similarity). The complex exists as an obligatory dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and cytochrome c oxidase (complex IV, CIV), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695).
Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. The cytochrome b-c1 complex catalyzes electron transfer from ubiquinol to cytochrome c, linking this redox reaction to translocation of protons across the mitochondrial inner membrane, with protons being carried across the membrane as hydrogens on the quinol. In the process called Q cycle, 2 protons are consumed from the matrix, 4 protons are released into the intermembrane space and 2 electrons are passed to cytochrome c.
Component of the TFIID basal transcription factor complex, composed of TATA-box-binding protein TBP, and a number of TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473). Interacts with TBP, and more strongly with TAF10 and TAF11 (PubMed:9695952).
The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription (PubMed:33795473, PubMed:9695952). TFIID recognizes and binds promoters via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC) (PubMed:33795473). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473). TAF13, together with TAF11 and TBP, play key roles during promoter binding by the TFIID and TFIIA transcription factor complexes (PubMed:33795473).
The binding of TAF10 and TAF11 requires distinct domains of TAF13.
It is uncertain whether Met-1 or Met-17 is the initiator.
Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.
Involved in the regulation of growth and apoptosis. Mediates activation of stress-responsive MTK1/MEKK4 MAPKKK.
Expressed in the liver, breast and kidney.
Lack UDP-glucuronosyltransferase (UGT) activity.
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:11300766). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:11300766). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (androsterone, 3alpha-androstanediol) and estrogens (estradiol, estrone) (PubMed:11300766). Catalyzes the glucuronidation of bile acid substrates, which are natural detergents for dietary lipids absorption (PubMed:11300766). Displays glucuronidation activity toward the phenolic compounds eugenol (PubMed:11300766).
Because IMPDH activity is tightly linked with cell proliferation, it has been recognized as a target for cancer and viral chemotherapy and as a target for immunosuppressive drugs. The activities of the antitumor drug tiazofurin, the antiviral drug ribavirin, and the immunosuppressive drugs mizoribine and mycophenolic acid (MPA) are attributed to the inhibition of IMPDH. In addition, bacterial and parasitic IMPDH's differ significantly from mammalian enzymes, which makes it a suitable target for anti-infective drugs.
Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism. It may also have a role in the development of malignancy and the growth progression of some tumors.
IMP type I is the main species in normal leukocytes and type II predominates over type I in the tumor.
Mycophenolic acid (MPA) is a non-competitive inhibitor that prevents formation of the closed enzyme conformation by binding to the same site as the amobile flap. In contrast, mizoribine monophosphate (MZP) is a competitive inhibitor that induces the closed conformation. MPA is a potent inhibitor of mammalian IMPDHs but a poor inhibitor of the bacterial enzymes. MZP is a more potent inhibitor of bacterial IMPDH.
Mycophenolic acid (MPA) is a non-competitive inhibitor that prevents formation of the closed enzyme conformation by binding to the same site as the amobile flap. In contrast, mizoribine monophosphate (MZP) is a competitive inhibitor that induces the closed conformation. MPA is a potent inhibitor of mammalian IMPDHs but a poor inhibitor of the bacterial enzymes. MZP is a more potent inhibitor of bacterial IMPDH. Subject to product inhibition by XMP and NADH. Also inhibited by ADP.
Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade. In vitro phosphorylates CREB1 and SYN1/synapsin I. Phosphorylates and activates CAMK1 (By similarity).
(Microbial infection) Activated by human cytomegalovirus (HCMV) UL38 in order to provide the virus with glycosyl building blocks.
During ontogenesis, there is a transition from the alpha/alpha homodimer to the alpha/beta heterodimer in striated muscle cells, and to the alpha/gamma heterodimer in nerve cells.
Has neurotrophic and neuroprotective properties on a broad spectrum of central nervous system (CNS) neurons. Binds, in a calcium-dependent manner, to cultured neocortical neurons and promotes cell survival (By similarity).
Levels of ENO2 increase dramatically in cardiovascular accidents, cerebral trauma, brain tumors and Creutzfeldt-Jakob disease.
Mammalian enolase is composed of 3 isozyme subunits, alpha, beta and gamma, which can form homodimers or heterodimers which are cell-type and development-specific.
Mg(2+) is required for catalysis and for stabilizing the dimer.
The alpha/alpha homodimer is expressed in embryo and in most adult tissues. The alpha/beta heterodimer and the beta/beta homodimer are found in striated muscle, and the alpha/gamma heterodimer and the gamma/gamma homodimer in neurons.
Expressed in the small intestine and at much lower levels in the large intestine. Highest expression levels in the jejunum.
FABPs are thought to play a role in the intracellular transport of long-chain fatty acids and their acyl-CoA esters. FABP2 is probably involved in triglyceride-rich lipoprotein synthesis. Binds saturated long-chain fatty acids with a high affinity, but binds with a lower affinity to unsaturated long-chain fatty acids. FABP2 may also help maintain energy homeostasis by functioning as a lipid sensor.
Forms a beta-barrel structure that accommodates the hydrophobic ligand in its interior.
Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). During the base subcomplex assembly is part of an intermediate PSMD9:PSMC6:PSMC3 module, also known as modulator trimer complex; PSMD9 is released during the further base assembly process.
Belongs to the proteasome subunit p27 family.
Expressed in all tissues tested, highly expressed in liver and kidney.
Interacts with PSMC3. Part of a transient complex (modulator) containing PSMD9, PSMC6 and PSMC3 formed during the assembly of the 26S proteasome.
Was initially identified as a component of the 26S proteasome.
Expressed at high levels in brain, with lower levels in kidney, intestine, and testis. Detected in lung.
Interacts (via FERM domain) with CADM1 (PubMed:12234973, PubMed:21131357). Interacts (via FERM domain) with PRMT3; the interaction is direct and inhibits the protein-arginine N-methyltransferase activity of PRMT3 (PubMed:15334060). Interacts with PRMT5 (PubMed:15334060, PubMed:15737618). Interacts with PRMT6 (PubMed:15334060).
Tumor suppressor that inhibits cell proliferation and promotes apoptosis. Modulates the activity of protein arginine N-methyltransferases, including PRMT3 and PRMT5.
Acts as an inhibitor of serine/threonine-protein phosphatase 2A (PP2A) activity (PubMed:27588481, PubMed:33108758). Potentiates ubiquitin-mediated proteasomal degradation of serine/threonine-protein phosphatase 2A catalytic subunit alpha (PPP2CA) (PubMed:27588481). Inhibits PP2A-mediated dephosphorylation of WEE1, promoting ubiquitin-mediated proteolysis of WEE1, thereby releasing G2/M checkpoint (PubMed:33108758).
CHEK1-mediated phosphorylation at Ser-37 negatively regulates its ability to inhibit serine/threonine-protein phosphatase 2A (PP2A) activity. Phosphorylation leads to its release from the PP2A complex and its sequestration by 14-3-3 proteins in the cytoplasm resulting in its inability to translocate to the nucleus, where it otherwise inhibits PP2A.
Interacts with PPP2CA and PPP2R1A (PubMed:27588481). Interacts with PPP2R2A (PubMed:27588481, PubMed:33108758). The CHEK1-mediated Ser-37 phosphorylated form interacts with 14-3-3 proteins (PubMed:33108758).
Orphan receptor. May regulate nociceptor function and/or development, including the sensation or modulation of pain.
Detected in adult heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, thymus, prostate, testis, ovary, small intestine and colon. In the fetus, expressed in brain, lung, liver and kidney.
Rare non-synonymous variants in FZD6 may contribute to neural tube defects, congenital malformations of the central nervous system and adjacent structures related to defective neural tube closure during the first trimester of pregnancy.
Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Together with FZD3, is involved in the neural tube closure and plays a role in the regulation of the establishment of planar cell polarity (PCP), particularly in the orientation of asymmetric bundles of stereocilia on the apical faces of a subset of auditory and vestibular sensory cells located in the inner ear (By similarity).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type B (BoNT/B, botB) which probably hydrolyzes the 78-Gln-|-Phe-79 bond and inhibits neurotransmitter release (PubMed:22289120).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type D (BoNT/D, botD) which probably hydrolyzes the 61-Arg-|-Leu-62 bond and inhibits neurotransmitter release (PubMed:22289120). BoNT/D has low catalytic activity on this protein due to its sequence (PubMed:22289120). Note that humans are not known to be infected by C.botulinum type D.
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type F (BoNT/F, botF) which probably hydrolyzes the 60-Gln-|-Lys-61 bond and inhibits neurotransmitter release (PubMed:22289120).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type X (BoNT/X) which probably hydrolyzes the 68-Arg-|-Ala-69 bond and inhibits neurotransmitter release (PubMed:29540745). It remains unknown whether BoNT/X is ever produced, or what organisms it targets.
Involved in the targeting and/or fusion of transport vesicles to their target membrane.
Nervous system, skeletal muscle and adipose tissue.
The disease is caused by variants affecting the gene represented in this entry. A mutation affecting a critical donor site for the splicing of VAMP1 isoforms leads to the loss of neuron-specific isoform 1 and subsequently results in haploinsufficiency (PubMed:22958904). Therefore, there would be less neurotransmitter exocytosis in specific regions of the brain, causing the symptoms of SPAX1.
Belongs to the glycosyltransferase 28 family.
Contains 1 OTU domain with intact active sites. No deubiquitinase activity has been detected when tested (PubMed:23827681).
May be involved in protein N-glycosylation, second step of the dolichol-linked oligosaccharide pathway.
Possible multifunctional enzyme with both glycosyltransferase and deubiquitinase activities.
Acts as a transcriptional repressor. Interacts with MXI1 to repress MYC responsive genes and antagonize MYC oncogenic activities. Interacts with MAD-MAX heterodimers by binding to MAD. The heterodimer then represses transcription by tethering SIN3B to DNA. Also forms a complex with FOXK1 which represses transcription. With FOXK1, regulates cell cycle progression probably by repressing cell cycle inhibitor genes expression.
Interacts with FOXK1/MNF, MXI, MAD, NCOR1 and SAP30. Interaction with SUDS3 enhances the interaction with HDAC1 to form a complex. Interacts with CRY1, HCFC1, MAD3, MAD4, MAEL, REST, RNF220 and SETDB1. Interacts with C6orf89 (PubMed:23460338). Interacts with MYT1L (By similarity).
Ubiquitinated by RNF220 that leads to proteasomal degradation.
Cooperates with PPP2CA to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I. Has a crucial role in protecting REC8 at centromeres from cleavage by separase. During meiosis, protects centromeric cohesion complexes until metaphase II/anaphase II transition, preventing premature release of meiosis-specific REC8 cohesin complexes from anaphase I centromeres. Is thus essential for an accurate gametogenesis. May act by targeting PPP2CA to centromeres, thus leading to cohesin dephosphorylation (By similarity). Essential for recruiting KIF2C to the inner centromere and for correcting defective kinetochore attachments. Involved in centromeric enrichment of AUKRB in prometaphase.
Directly interacts with PPP2CA. Part of an astrin (SPAG5) -kinastrin (SKAP) complex containing KNSTRN, SPAG5, PLK1, DYNLL1 and SGO2. Interacts with CDCA8.
Shugoshin is Japanese for guardian spirit (as it is known to be a protector of centromeric cohesin).
Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C (PubMed:9930701). Activated by inositol 1,4,5-triphosphate receptors (ITPR) with bound IP3 (PubMed:10611319). May be activated by internal calcium store depletion. Inhibited by intracellular Ca(2+) (PubMed:35051376).
Belongs to the transient receptor (TC 1.A.4) family. STrpC subfamily. TRPC3 sub-subfamily.
Expressed predominantly in brain and at much lower levels in ovary, colon, small intestine, lung, prostate, placenta and testis.
Forms a receptor-activated non-selective calcium permeant cation channel (PubMed:8646775, PubMed:9417057, PubMed:9930701, PubMed:20095964, PubMed:30139744, PubMed:29726814, PubMed:35051376). May be operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors (PubMed:8646775).
Homotetramer (PubMed:29700422, PubMed:30139744, PubMed:29726814, PubMed:35051376). Interacts with ITPR1 (PubMed:9853757). Interacts with ITPR3 (PubMed:10611319). Interacts with MX1 (PubMed:15757897). Interacts with RNF24 (PubMed:17850865). Interacts with JPH2; the interaction is involved in maintaining Ca(2+) homeostasis in skeletal muscle and is mediated by JPH2 'Ser-165' phosphorylation (PubMed:20095964).
The cytoplasmic portion of the protein is required for channel assembly and gating.
E3 ubiquitin-protein ligase that catalyzes monoubiquitination of 40S ribosomal proteins RPS2/us5 and RPS3/us3 in response to ribosome stalling (PubMed:34348161, PubMed:34469731). Part of a ribosome quality control that takes place when ribosomes have stalled during translation initiation (iRQC): RNF10 acts by mediating monoubiquitination of RPS2/us5 and RPS3/us3, promoting their degradation by the proteasome (PubMed:34348161, PubMed:34469731). Also promotes ubiquitination of 40S ribosomal proteins in response to ribosome stalling during translation elongation (PubMed:34348161). The action of RNF10 in iRQC is counteracted by USP10 (PubMed:34469731). May also act as a transcriptional factor involved in the regulation of MAG (Myelin-associated glycoprotein) expression (By similarity). Acts as a regulator of Schwann cell differentiation and myelination (By similarity).
Expressed in developing cortex at all stages examined but most strikingly at 12 gestational weeks. Expression is found in both progenitor (ventricular zone) and neuronal (intermediate zone and cortical plate) compartments. Also selectively expressed within the choroid plexus within the cerebral ventricles.
Interacts with the COPII coat components Sec23 (SEC23A and/or SEC23B) and Sec24 (SEC24A and/or SEC24B) (PubMed:11489904). Interacts with YIF1A (PubMed:15990086). May interact with RAB1A (PubMed:15611160). Interacts with YIPF3 and YIPF4 (PubMed:27999994).
Plays a role in transport between endoplasmic reticulum and Golgi. In pancreatic beta cells, required to transport proinsulin from endoplasmic reticulum into the Golgi (PubMed:33164986).
Ubiquitously expressed with abundant expression in pancreatic tissue, islets, beta cells, and brain. Highly expressed in coronary smooth muscles.
Belongs to the PIH1 family. Kintoun subfamily.
Interacts with CFAP300 (PubMed:29727693). Interacts with DNAAF4 (PubMed:23872636). Interacts with DNAAF6/PIH1D3 (PubMed:28041644). Interacts with DNAI2 and HSPA1A (By similarity).
Required for cytoplasmic pre-assembly of axonemal dyneins, thereby playing a central role in motility in cilia and flagella. Involved in pre-assembly of dynein arm complexes in the cytoplasm before intraflagellar transport loads them for the ciliary compartment.
In the N-terminal section; belongs to the FGAMS family.
Phosphoribosylformylglycinamidine synthase involved in the purines biosynthetic pathway. Catalyzes the ATP-dependent conversion of formylglycinamide ribonucleotide (FGAR) and glutamine to yield formylglycinamidine ribonucleotide (FGAM) and glutamate.
(Microbial infection) Acts as a receptor for Coxsackievirus A21 capsid proteins.
(Microbial infection) Acts as a receptor for major receptor group rhinovirus A-B capsid proteins.
(Microbial infection) Interacts with Coxsackievirus A21 capsid proteins (PubMed:11160747, PubMed:16004874, PubMed:9539703).
(Microbial infection) Interacts with major receptor group rhinovirus A-B capsid proteins (PubMed:1968231, PubMed:2538243).
(Microbial infection) Upon Kaposi's sarcoma-associated herpesvirus/HHV-8 infection, is degraded by viral E3 ubiquitin ligase MIR2, presumably to prevent lysis of infected cells by cytotoxic T-lymphocytes and NK cell.
Belongs to the immunoglobulin superfamily. ICAM family.
Homodimer (Probable). Interacts with MUC1 and promotes cell aggregation in epithelial cells. Interacts with ARHGEF26/SGEF. Interacts (on T cell side) with CD81, CD247 and CD9 at immunological synapses between antigen-presenting cells and T cells.
Homozygotes with ICAM1-Kalifi Met-56 seem to have an increased risk for cerebral malaria [MIM:611162].
ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L/beta-2). During leukocyte trans-endothelial migration, ICAM1 engagement promotes the assembly of endothelial apical cups through ARHGEF26/SGEF and RHOG activation.
Monoubiquitinated, which is promoted by MARCH9 and leads to endocytosis.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. Dynamin/Fzo/YdjA family.
Interacts with CAV1 and SH3GLB1. Binds SH3GL1, SH3GL2 and SH3GL3 (By similarity). Interacts with PHOCN. Interacts with PACSIN1, PACSIN2 and PACSIN3 (By similarity). Interacts with SNX9. Interacts with MYO1E (via SH3 domain). Interacts with SNX33 (via SH3 domain). Interacts with UNC119; leading to a decrease of DNM1 GTPase activity (By similarity). Interacts with DIAPH1 (PubMed:23325789). Interacts with AMPH, BIN1 and SYNJ1 (By similarity).
Microtubule-associated force-producing protein involved in producing microtubule bundles and able to bind and hydrolyze GTP. Most probably involved in vesicular trafficking processes. Involved in receptor-mediated endocytosis.
A chromosomal aberration involving RHOH is found in a non-Hodgkin lymphoma cell line. Translocation t(3;4)(q27;p11) with BCL6.
By CSF2/GM-CSF. Down-regulated by phorbol myristate acetate (PMA).
Expressed only in hematopoietic cells. Present at very high levels in the thymus, less abundant in the spleen, and least abundant in the bone marrow. Expressed at a higher level in the TH1 subtype of T-helper cells than in the TH2 subpopulation. Expressed in neutrophils under inflammatory conditions, such as cystic fibrosis, ulcerative colitis and appendicitis.
Interacts with ZAP70 (via SH2 domains) and the interaction is enhanced by its phosphorylation by LCK. Interacts with SYK and the interaction is enhanced by its phosphorylation by FYN (By similarity). Interacts with GDI1 and GDI2. Interacts with PAK5 (By similarity).
Negative regulator of hematopoietic progenitor cell proliferation, survival and migration. Critical regulator of thymocyte development and T-cell antigen receptor (TCR) signaling by mediating recruitment and activation of ZAP70. Required for phosphorylation of CD3Z, membrane translocation of ZAP70 and subsequent activation of the ZAP70-mediated pathways. Essential for efficient beta-selection and positive selection by promoting the ZAP70-dependent phosphorylation of the LAT signalosome during pre-TCR and TCR signaling. Crucial for thymocyte maturation during DN3 to DN4 transition and during positive selection. Plays critical roles in mast cell function by facilitating phosphorylation of SYK in Fc epsilon RI-mediated signal transduction. Essential for the phosphorylation of LAT, LCP2, PLCG1 and PLCG2 and for Ca(2+) mobilization in mast cells (By similarity). Binds GTP but lacks intrinsic GTPase activity and is resistant to Rho-specific GTPase-activating proteins. Inhibits the activation of NF-kappa-B by TNF and IKKB and the activation of CRK/p38 by TNF. Inhibits activities of RAC1, RHOA and CDC42. Negatively regulates leukotriene production in neutrophils.
Phosphorylated on tyrosine by LCK. Phosphorylated by FYN. Phosphorylation enhances the interactions with ZAP70 and SYK and is critical for its function in thymocyte development (By similarity).
The region involved in interaction with ZAP70 is a non-canonical immunoreceptor tyrosine-based activation motif (ITAM).
Expressed neural retina, cornea, sclera and optic nerve.
Serine protease required during eye development.
Expressed in vestibule of the inner ear, eye and small intestine.
Part of a complex composed of USH1C, USH1G and MYO7A (PubMed:21709241, PubMed:21311020). Interacts with USH1C (via the first PDZ domain) (PubMed:20142502, PubMed:12588794). Interacts with PDZD7 (PubMed:19028668). Interacts with CDH23 and PCDH15; these interactions may recruit USH1G to the plasma membrane (By similarity). Interacts with intraflagellar transport proteins IFT20, IFT52 and IFT57 (PubMed:31637240). Interacts with splicing factors SF3B1, PRPF6, PRPF31 and SON (PubMed:34023904). Interacts with the U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complex in the presence of pre-mRNAs (PubMed:34023904). Interacts (via SAM domain) with MAGI2 (via PDZ 6 domain); the interaction is triggered by phosphorylation of USH1G by CK2 and negatively regulates MAGI2-mediated endocytosis (PubMed:24608321).
Plays a role in pre-mRNA splicing by regulating the release and transfer of U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complexes from their assembly site in Cajal bodies to nuclear speckles, thereby contributing to the assembly of the pre-catalytic spliceosome on target pre-mRNAs (PubMed:34023904). May also participate in recycling of snRNPs back to Cajal bodies during splicing (PubMed:34023904). Plays a role in regulating MAGI2-mediated endocytosis (PubMed:24608321). Anchoring/scaffolding protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal development and maintenance of cochlear hair cell bundles. Required for normal hearing.
The first cases with non-syndromic sensorineural hearing loss based on mutations in USH1G. The hearing loss has an onset during early childhood, is progressive, and has a downsloping audiogram configuration. Ophthalmic and vestibular abnormalities are absent.
Acts as a sequence-specific transcriptional repressor in association with BCL6. May function in a narrow stage or be related to some events in the early B-cell development.
Associates with BCL6 through the BTB domain.
Ubiquitously expressed with higher expression found in heart and placenta.
In the C-terminal section; belongs to the PNT beta subunit family.
In the N-terminal section; belongs to the AlaDH/PNT family.
The transhydrogenation between NADH and NADP is coupled to respiration and ATP hydrolysis and functions as a proton pump across the membrane (By similarity). May play a role in reactive oxygen species (ROS) detoxification in the adrenal gland (PubMed:22634753).
Widely expressed with expression most readily detectable in adrenal, heart, kidney, thyroid and adipose tissues.
Belongs to the lipase maturation factor family.
Involved in the maturation of specific proteins in the endoplasmic reticulum. May be required for maturation and transport of active lipoprotein lipase (LPL) through the secretory pathway (By similarity).
Component of the SKI complex which consists of SKIC2, SKIC3 and SKIC8 (PubMed:16024656, PubMed:32006463, PubMed:35120588). Interacts with PAF1 (PubMed:16024656).
Component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways (PubMed:16024656, PubMed:32006463, PubMed:35120588). The SKI complex catalyzes mRNA extraction from 80S ribosomal complexes in the 3'-5' direction and channels mRNA to the cytosolic exosome for degradation (PubMed:32006463, PubMed:35120588). SKI-mediated extraction of mRNA from stalled ribosomes allow binding of the Pelota-HBS1L complex and subsequent ribosome disassembly by ABCE1 for ribosome recycling (PubMed:32006463). In the nucleus, the SKI complex associates with transcriptionally active genes in a manner dependent on PAF1 complex (PAF1C) (PubMed:16024656).
Widely expressed with the highest levels observed in vascular tissues, lymph node, pituitary, lung and intestine. Not expressed in the liver.
Belongs to the complex I NDUFA3 subunit family.
Apoptosis regulator that functions through different apoptotic signaling pathways (PubMed:27076518, PubMed:15102863, PubMed:20673843). Plays a roles as pro-apoptotic protein that positively regulates intrinsic apoptotic process in a BAX- and BAK1-dependent manner or in a BAX- and BAK1-independent manner (PubMed:27076518, PubMed:15102863). In response to endoplasmic reticulum stress promotes mitochondrial apoptosis through downstream BAX/BAK1 activation and positive regulation of PERK-mediated unfolded protein response (By similarity). Activates apoptosis independently of heterodimerization with survival-promoting BCL2 and BCL2L1 through induction of mitochondrial outer membrane permeabilization, in a BAX- and BAK1-independent manner, in response to inhibition of ERAD-proteasome degradation system, resulting in cytochrome c release (PubMed:27076518). In response to DNA damage, mediates intrinsic apoptotic process in a TP53-dependent manner (PubMed:15102863). Plays a role in granulosa cell apoptosis by CASP3 activation (PubMed:20673843). Plays a roles as anti-apoptotic protein during neuronal apoptotic process, by negatively regulating poly ADP-ribose polymerase-dependent cell death through regulation of neuronal calcium homeostasis and mitochondrial bioenergetics in response to NMDA excitation (By similarity). In addition to its role in apoptosis, may regulate trophoblast cell proliferation during the early stages of placental development, by acting on G1/S transition through regulation of CCNE1 expression (PubMed:19942931). May also play a role as an inducer of autophagy by disrupting interaction between MCL1 and BECN1 (PubMed:24113155).
BH4 domain mediates interaction with ITPR1.
Expressed mainly in oocytes; weak expression in granulosa cells of the developing follicles. In adult human ovaries, expressed in granulosa cells at all follicular stages, but expression in primordial/primary follicles granulosa cell is stronger than in secondary and antral follicles.
Isoform 1: at 5-7 weeks of gestation, detected primarily in the cytotrophoblast layer. By 10-13 weeks, expression becomes restricted primarily to the apical border of the syncytiotrophoblast (PubMed:19942931). Isoform 2: expression significantly increased around 6-8 weeks (PubMed:15775999).
Monomer; positively regulates apoptotic process. Homodimer (By similarity). Heterodimer (By similarity). Oligomer; promoted by apoptotic stimuli and BH3-only proteins; mediates constitutive activation (PubMed:15868100). Interacts (via BH4 domain) with ITPR1; enhances BOK expression and stabilization; limits apoptosis and prevents ubiquitination and then degradation; protects ITPR1 from proteolysis by CASP3 during apoptosis (PubMed:23884412). Interacts with ITPR2 and ITPR3; binds most strongly to ITPR2, and barely to ITPR3; regulates their expression (By similarity). Interacts with XPO1; translocates to the cytoplasm (PubMed:16302269). Interacts with BNIP3; promotes oligomerization (PubMed:15868100).
Pro-apoptotic molecule exerting its function through the mitochondrial pathway.
Ubiquitinated by AMFR/gp78 E3 ubiquitin ligase complex; mediates degradation by ubiquitin-proteasome pathway in a VCP/p97-dependent manner; prevents from pro-apoptotic activity; promotes degradation of newly synthesized proteins that are not ITPR1 associated.
Belongs to the cation diffusion facilitator (CDF) transporter (TC 2.A.4) family. SLC30A subfamily.
Electroneutral proton-coupled antiporter concentrating zinc ions into a variety of intracellular organelles including endosomes, zymogen granules and mitochondria. Thereby, plays a crucial role in cellular zinc homeostasis to confer upon cells protection against its potential cytotoxicity (PubMed:21289295, PubMed:25808614, PubMed:25657003, PubMed:30893306, PubMed:17065149, PubMed:22733820). Regulates the zinc concentration of milk, through the transport of zinc ions into secretory vesicles of mammary cells (PubMed:19496757). By concentrating zinc ions into lysosomes participates to lysosomal-mediated cell death during early mammary gland involution (PubMed:25808614).
Electroneutral proton-coupled antiporter mediating the efflux of zinc ions through the plasma membrane.
Homodimer (PubMed:22733820). Interacts (via lysosomal targeting motif) with AP3D1; in AP-3-mediated transport to lysosomes (PubMed:25808614). Interacts with TMEM163 (PubMed:36204728).
Phosphorylated at Ser-296. Phosphorylation at Ser-296 prevents localization to lysosomes. Dephosphorylation of Ser-296 which triggers localization to lysosomes, accumulation of zinc into lysosomes and lysosomal-mediated cell death is induced by TNF-alpha.
Belongs to the class I fructose-bisphosphate aldolase family.
Homotetramer. Interacts with ATP6V1E1. May interact with PLD2.
In vertebrates, three forms of this ubiquitous glycolytic enzyme are found, aldolase A in muscle, aldolase B in liver and aldolase C in brain.
Expression is restricted to the brain, and more specifically to the forebrain.
Ligand for members of the frizzled family of seven transmembrane receptors. May play an important role in the development and differentiation of certain forebrain structures, notably the hippocampus.
Proteolytic processing by TIKI1 and TIKI2 promotes oxidation and formation of large disulfide-bond oligomers, leading to inactivation of WNT8B.
Interacts with CD72/LYB-2. Interacts with PTPN6/SHP-1 (By similarity).
May act as a receptor in regulating T-cell proliferation.
Phosphorylated on tyrosine residues by LYN; this creates binding sites for PTPN6/SHP-1.
Bornavirus is a non-retroviral RNA virus that does not generate DNA forms during viral replication. Therefore, integration of EBLN-1 must have occur through a mechanism relying on an endogenous reverse transcriptase activity.
Expression detected by RT-PCR in a few cell lines, including OL, HEK293T and MOLT-4. Not observed in HeLa cells (PubMed:20054395).
May act as an RNA-binding protein. Highly homologous to the bornavirus nucleocapsid N protein that binds viral RNA and oligomerizes (By similarity).
Acetylated following deubiquitination by VCPIP1, leading to recruitment to chromatin and DNA damage sites.
Autocatalytically cleaved in response to double-stranded DNA-binding: autocatalytic cleavage takes place in trans and leads to inactivation.
DNA-binding activates the protease activity: single-stranded DNA-binding specifically activates ability to cleave covalent DNA-protein cross-links (DPCs) (PubMed:27871366, PubMed:27871365, PubMed:30893605). In contrast, double-stranded DNA-binding specifically activates autocatalytic cleavage, and subsequent inactivation (PubMed:27852435, PubMed:27871365, PubMed:30893605).
DNA-dependent metalloendopeptidase that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity (PubMed:27852435, PubMed:27871366, PubMed:27871365, PubMed:32649882, PubMed:30893605). DPCs are highly toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription, and which are induced by reactive agents, such as UV light or formaldehyde (PubMed:27852435, PubMed:27871366, PubMed:27871365, PubMed:32649882). Associates with the DNA replication machinery and specifically removes DPCs during DNA synthesis (PubMed:27852435, PubMed:27871366, PubMed:27871365, PubMed:32649882). Acts as a pleiotropic protease for DNA-binding proteins cross-linked with DNA, such as TOP1, TOP2A, histones H3 and H4 (PubMed:27871366). Mediates degradation of DPCs that are not ubiquitinated, while it is not able to degrade ubiquitinated DPCs (By similarity). SPRTN activation requires polymerase collision with DPCs followed by helicase bypass of DPCs (By similarity). Involved in recruitment of VCP/p97 to sites of DNA damage (PubMed:22902628, PubMed:23042605, PubMed:23042607, PubMed:32152270). Also acts as an activator of CHEK1 during normal DNA replication by mediating proteolytic cleavage of CHEK1, thereby promoting CHEK1 removal from chromatin and subsequent activation (PubMed:31316063). Does not activate CHEK1 in response to DNA damage (PubMed:31316063). May also act as a 'reader' of ubiquitinated PCNA: recruited to sites of UV damage and interacts with ubiquitinated PCNA and RAD18, the E3 ubiquitin ligase that monoubiquitinates PCNA (PubMed:22681887, PubMed:22894931, PubMed:22902628, PubMed:22987070). Facilitates chromatin association of RAD18 and is required for efficient PCNA monoubiquitination, promoting a feed-forward loop to enhance PCNA ubiquitination and translesion DNA synthesis (PubMed:22681887).
Homodimer (PubMed:30893605). Interacts (VIA PIP-box) with PCNA (when ubiquitinated) (PubMed:22894931, PubMed:22902628, PubMed:22681887, PubMed:23042605, PubMed:23042607, PubMed:22987070, PubMed:27084448). Interacts (via its SHP-box) with VCP/p97 (PubMed:22902628, PubMed:23042605, PubMed:23042607). Interacts with RAD18 (PubMed:22681887). Interacts with KCTD13 and POLD3 (PubMed:22902628).
Monoubiquitinated; monoubiquitination promotes exclusion from chromatin (PubMed:27871365, PubMed:32649882). Deubiquitinated by VCPIP1: deubiquitination is required for subsequent acetylation and recruitment to chromatin and DNA damage sites (PubMed:27871365, PubMed:32649882).
Phosphorylation by CHEK1 promotes recruitment to chromatin.
Predominantly expressed during S- and G2-phases and early M-phase (PubMed:23042605). It then drops, and is probably degraded by the APC/C complex (PubMed:23042605).
The PIP-box mediates the interaction with PCNA, while the UBZ4-type zinc finger mediates binding to 'Lys-48'- and 'Lys-63'-linked polyubiquitin.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Unc-104 subfamily.
KIF1A dysfunction is associated with a large spectrum of neurologic disorders, including HSN2C, SPG30 and NESCAVS. It has been proposed to collectively name them KIF1A-Associated Neurological Disorder (KAND). Some variants reported here are based on this broad classification.
Monomer. Interacts with PPFIA1 and PPFIA4 (By similarity). Interacts with CALM1; the interaction is increased in presence of calcium and increases neuronal dense core vesicles motility (PubMed:30021165). Interacts with PPFIA2 and TANC2; both interactions allow the recruitment of neuronal dense core vesicles to dendritic spines and decrease in presence of calcium (PubMed:30021165). Interacts with SYT4 (unphosphorylated) and SYT11; both interactions increase in presence of calcium (By similarity). Interacts with MADD (By similarity).
Motor for anterograde axonal transport of synaptic vesicle precursors (PubMed:33880452). Also required for neuronal dense core vesicles (DCVs) transport to the dendritic spines and axons. The interaction calcium-dependent with CALM1 increases vesicle motility and interaction with the scaffolding proteins PPFIA2 and TANC2 recruits DCVs to synaptic sites.
Probable cloning artifact leading to C-terminal exon with non-canonical splice junction.
Directly interacts with ATG5 and associates with the ATG12-ATG5-ATG16L complex (PubMed:20417604). Interacts with p62/SQSTM1; this interaction is required to recruit WDFY3 to cytoplasmic bodies and to PML bodies (PubMed:20168092, PubMed:20971078). Directly interacts with GABARAP, GABARAPL1 and GABARAPL2; the interaction with GABARAP is required for WDFY3 recruitment to MAP1LC3B-positive p62/SQSTM1 bodies. Weakly interacts with MAP1LC3C; this interaction is direct. Does not interact with MAP1LC3A, nor MAP1LC3B (PubMed:24668264). Interacts with TRAF6 (By similarity).
Expressed in osteoclast and their mononuclear precursors (at protein level).
Required for selective macroautophagy (aggrephagy). Acts as an adapter protein by linking specific proteins destined for degradation to the core autophagic machinery members, such as the ATG5-ATG12-ATG16L E3-like ligase, SQSTM1 and LC3 (PubMed:20417604). Along with p62/SQSTM1, involved in the formation and autophagic degradation of cytoplasmic ubiquitin-containing inclusions (p62 bodies, ALIS/aggresome-like induced structures). Along with SQSTM1, required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed:20168092). Important for normal brain development. Essential for the formation of axonal tracts throughout the brain and spinal cord, including the formation of the major forebrain commissures. Involved in the ability of neural cells to respond to guidance cues. Required for cortical neurons to respond to the trophic effects of netrin-1/NTN1 (By similarity). Regulates Wnt signaling through the removal of DVL3 aggregates, likely in an autophagy-dependent manner. This process may be important for the determination of brain size during embryonic development (PubMed:27008544). May regulate osteoclastogenesis by acting on the TNFSF11/RANKL - TRAF6 pathway (By similarity). After cytokinetic abscission, involved in midbody remnant degradation (PubMed:24128730). In vitro strongly binds to phosphatidylinositol 3-phosphate (PtdIns3P) (PubMed:15292400).
The FYVE domain mediates binding to phosphatidylinositol 3-phosphate (PtdIns3P).
The LIR (LC3-interacting region) motif mediates the interaction with MAP1LC3C and other ATG8 family members.
May be involved in endosome fusion. Mediates down-regulation of growth factor signaling via internalization of growth factor receptors.
The disease is caused by variants affecting the gene represented in this entry. Germline variants in SAMD9L with a suppressive effect on the cell cycle are associated with somatic loss of the chromosome 7 harboring the mutant allele. This results in the deletion of several genes and predisposes to the development of myelodysplastic syndrome and acute myelogenous leukemia.
Widely expressed in adult and fetal tissues. Expressed in the cerebellum (PubMed:35310830). Variable expression in tumors. Down-regulated in breast cancer.
Highly expressed in the capillary loop stage and very faintly in the S-shaped body stage of glomerulus in fetal kidney of 16 weeks of gestation.
Ubiquitously expressed in fetus and adult (PubMed:9722952). Highest expression in adult pancreas, liver, skeletal muscle (PubMed:9722952, PubMed:12930836). In fetus, highest expression in liver and lower levels in kidney, and lung (PubMed:12930836). Exclusively expressed in the glomeruli along the glomerular capillary walls (PubMed:19443642).
Uniport that mediates the transport of neutral amino acids such as L-leucine, L-isoleucine, L-valine, and L-phenylalanine (PubMed:12930836). The transport activity is sodium ions-independent, electroneutral and mediated by a facilitated diffusion (PubMed:12930836).
Expressed in the pancreas, kidney, liver, lung, placenta, brain and heart.
Acts as a regulatory protein that associates with GUCY2C and negatively modulates its heat-stable enterotoxin-mediated activation (PubMed:11950846). Stimulates SLC9A3 activity in the presence of elevated calcium ions (PubMed:19088451).
Expressed in kidney and the gastrointestinal tract. Not detected in brain, heart, skeletal muscle or cells of hematopoietic origin.
Interacts with the C-terminal region of GUCY2C (PubMed:11950846). Interacts with the C-terminal region SLC9A3 and the interactions decrease in response to elevated calcium ion levels (PubMed:19088451). Interacts with the C-terminal region of SLC34A1 (By similarity). Interacts with USP2 isoform 4 (PubMed:26756164). Interacts (via the third PDZ domain) with SLC26A3 (via PDZ-binding motif); interaction leads to decreased expression of SLC26A3 on the cell membrane resulting in its reduced exchanger activity (PubMed:22627094).
Phosphorylation at Ser-395 negatively regulates its interaction with SLC26A3.
Highly expressed in fetal and adult brain, predominantly in the cerebral cortex and the cerebellum. Also expressed in other tissues but to a lesser extent.
Involved in neurite outgrowth by regulating cell-cell adhesion via the N-cadherin signaling pathway. May act by regulating expression of protein-coding genes, such as N-cadherins and integrin beta-1 (ITGB1).
The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving NEXMIF is found in patients with severe intellectual disability. Pericentric inversion inv(X)(p22.3;q13.2) with P2RY8 leading to inactivation of NEXMIF (PubMed:15466006). XLID98 transmission pattern is consistent with X-linked recessive inheritance (PubMed:23615299). In some cases, de novo heterozygous loss-of-function mutations have been found in affected females, while some female carriers are asymptomatic (PubMed:26576034, PubMed:27358180, PubMed:27568816). The female phenotype partially overlaps with the reported male phenotype but includes epilepsy as a relevant feature. The variability of disease manifestation in female carriers is probably due to skewed X inactivation with differential expression in the brain (PubMed:26576034, PubMed:27358180, PubMed:27568816).
Probable cell surface receptor that plays a role in cellular fusion and cell differentiation. Cooperates with DCSTAMP in modulating cell-cell fusion in both osteoclasts and foreign body giant cells (FBGCs). Involved in osteoclast bone resorption. Promotes osteoclast differentiation and may play a role in the multinucleated osteoclast maturation (By similarity).
Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class III subfamily.
Expressed in cartilage and synovial membranes (at protein level) (PubMed:18164633, PubMed:23845380). Expressed in the retina, iris, ligament, skin and fetal liver (at protein level) (PubMed:12019215, PubMed:25136834). Expressed in the retinal pigment epithelium (at protein level) (PubMed:25136834). Expressed in synovial fibroblasts and subchondral bone osteoblasts (PubMed:18164633).
Inhibits angiogenesis in the vitreous humor of the eye, and therefore represses neovascularization (By similarity). Binds collagen fibrils (By similarity). May be involved in collagen fiber organization via regulation of other members of the small leucine-rich repeat proteoglycan superfamily (By similarity).
Proteolytically cleaved by MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, ADAMTS4, and ADAMTS5 (PubMed:23845380). Proteolytically cleaved by MMP13 (By similarity). The degradation of OPTC by proteases may contribute to osteoarthritis pathophysiology (PubMed:23845380).
Defects in FOXR1 may be the cause of a severe neurological disorder characterized by postnatal microcephaly, progressive brain atrophy and global developmental delay.
Transcription factor which acts as both an activator and a repressor (PubMed:34723967). Activates transcription of a number of genes including the heat shock chaperones HSPA1A and HSPA6 and the antioxidant NADPH-dependent reductase DHRS2 which are involved in protection against oxidative stress (PubMed:34723967). Required for normal brain development (By similarity).
Expressed in brain. Tends to be down-regulated in astrocytic gliomas due to promoter methylation. Methylation occurs early in gliomagenesis and the extent of methylation parallels with higher glioma grades, so that methylation is observed in close to 70% WHO grade IV primary glioblastomas, but not in grade I astrocytomas.
Plays an important role in regulating embryonic neurogenesis.
May be part of an oligomeric complex which is likely to have a transport or channel function in the erythrocyte membrane.
RHD and RHCE are responsible for the Rh blood group system. The molecular basis of the Tar=Rh40 blood group antigen is a variant in position 110. Homozygous deletion of the RHD gene results in Rh-negative (dd) individuals (PubMed:1824267, PubMed:10845894). Some polymorhisms lead to weak RHD expression. This phenotype called weak D, formerly known as D(u), is observed in about 0.2% to 1% of Caucasians (PubMed:9864185). Moderately decreased RHD expression results in a phenotype called DHMi (PubMed:9864185).
Restricted to tissues or cell lines expressing erythroid characters.
Upon bacterial lipopolysaccharide stimulation, mediates clathrin-dependent internalization of TLR4 in dendritic cells, resulting in activation of TICAM1-mediated signaling and subsequent IFNB1 production. May regulate B-cell antigen receptor-mediated signaling.
The polyhistidine repeat acts as a targeting signal to nuclear speckles.
Belongs to the amino acid-polyamine-organocation (APC) superfamily. Cationic amino acid transporter (CAT) (TC 2.A.3.3) family.
Imports 4-aminobutanoate (GABA) into lysosomes. May act as a GABA sensor that regulates mTORC2-dependent INS signaling and gluconeogenesis. The transport mechanism and substrate selectivity remain to be elucidated.
Initially postulated to transport L-arginine based on studies with a chimeric protein, which was not confirmed by other groups using the wild-type protein. It was latter shown to rather function as a GABA importer.
Belongs to the peptidase C19 family. USP10 subfamily.
Deubiquitinating enzyme that removes conjugated ubiquitin from specific proteins to regulate different cellular processes.
Following DNA damage. Down-regulated in renal cell carcinomas.
Found in a deubiquitination complex with TANK, USP10 and ZC3H12A; this complex inhibits genotoxic stress- or interleukin-1-beta (IL1B)-mediated NF-kappa-B activation by promoting IKBKG or TRAF6 deubiquitination (PubMed:25861989). Interacts with IKBKG; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with TRAF6; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with G3BP1 (via NTF2 domain) and G3BP2 (via NTF2 domain); inhibiting stress granule formation (PubMed:11439350, PubMed:23279204, PubMed:27022092, PubMed:32302570, PubMed:31981475, PubMed:36183834, PubMed:36279435).
Hydrolase that can remove conjugated ubiquitin from target proteins such as p53/TP53, RPS2/us5, RPS3/us3, RPS10/eS10, BECN1, SNX3 and CFTR (PubMed:11439350, PubMed:18632802, PubMed:31981475). Acts as an essential regulator of p53/TP53 stability: in unstressed cells, specifically deubiquitinates p53/TP53 in the cytoplasm, leading to counteract MDM2 action and stabilize p53/TP53 (PubMed:20096447). Following DNA damage, translocates to the nucleus and deubiquitinates p53/TP53, leading to regulate the p53/TP53-dependent DNA damage response (PubMed:20096447). Component of a regulatory loop that controls autophagy and p53/TP53 levels: mediates deubiquitination of BECN1, a key regulator of autophagy, leading to stabilize the PIK3C3/VPS34-containing complexes (PubMed:21962518). In turn, PIK3C3/VPS34-containing complexes regulate USP10 stability, suggesting the existence of a regulatory system by which PIK3C3/VPS34-containing complexes regulate p53/TP53 protein levels via USP10 and USP13 (PubMed:21962518). Does not deubiquitinate MDM2 (PubMed:20096447). Plays a key role in 40S ribosome subunit recycling when a ribosome has stalled during translation: acts both by inhibiting formation of stress granules, which store stalled translation pre-initiation complexes, and mediating deubiquitination of 40S ribosome subunits (PubMed:27022092, PubMed:31981475, PubMed:34348161, PubMed:34469731). Acts as a negative regulator of stress granules formation by lowering G3BP1 and G3BP2 valence, thereby preventing G3BP1 and G3BP2 ability to undergo liquid-liquid phase separation (LLPS) and assembly of stress granules (PubMed:11439350, PubMed:27022092, PubMed:32302570). Promotes 40S ribosome subunit recycling following ribosome dissociation in response to ribosome stalling by mediating deubiquitination of 40S ribosomal proteins RPS2/us5, RPS3/us3 and RPS10/eS10, thereby preventing their degradation by the proteasome (PubMed:31981475, PubMed:34348161, PubMed:34469731). Part of a ribosome quality control that takes place when ribosomes have stalled during translation initiation (iRQC): USP10 acts by removing monoubiquitination of RPS2/us5 and RPS3/us3, promoting 40S ribosomal subunit recycling (PubMed:34469731). Deubiquitinates CFTR in early endosomes, enhancing its endocytic recycling (PubMed:19398555). Involved in a TANK-dependent negative feedback response to attenuate NF-kappa-B activation via deubiquitinating IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage (PubMed:25861989). Deubiquitinates TBX21 leading to its stabilization (PubMed:24845384).
Phosphorylated by ATM following DNA damage, leading to stablization and translocation it to the nucleus.
Specifically inhibited by spautin-1 (specific and potent autophagy inhibitor-1), a derivative of MBCQ that binds to USP10 and inhibits deubiquitinase activity. Regulated by PIK3C3/VPS34-containing complexes.
Ubiquitinated. Deubiquitinated by USP13.
Isoform 1 acts as a transcriptional repressor.
Belongs to the peptidase S9B family. DPPIV subfamily.
Found in serum, T-cells and brain (at protein level). Expressed in brain, pancreas, spinal cord and adrenal glands.
Gly-651 is present instead of the conserved Ser which is expected to be an active site residue suggesting that this protein has no peptidase activity.
May form oligomers. Interacts with KCND1 (Probable). Interacts with KCND2.
N-glycosylation is important for cell surface expression, specially at Asn-257, which is crucial.
Promotes cell surface expression of the potassium channel KCND2 (PubMed:15454437). Modulates the activity and gating characteristics of the potassium channel KCND2 (PubMed:15454437). Has no dipeptidyl aminopeptidase activity (PubMed:12662155).
Involved in the mineralization and structural organization of enamel.
Present in the extracellular enamel and is mainly associated with the crystal component.
Serine protease that cleaves extracellular substrates, and contributes to the proteolytic processing of growth factors, such as HGF and MST1/HGFL (PubMed:21875933, PubMed:15839837). Plays a role in cell growth and maintenance of cell morphology (PubMed:8346233, PubMed:21875933). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). Mediates the proteolytic cleavage of urinary UMOD that is required for UMOD polymerization (PubMed:26673890).
Deubiquitinating enzyme that removes conjugated ubiquitin from specific proteins to regulate different cellular processes that may include cell proliferation, progression through the cell cycle, apoptosis, cell migration, and the cellular response to viral infection.
The RS447 megasatellite DNA is a highly polymorphic conserved tandem repetitive sequence which contains a copy of the USP17 gene. It is present with an interindividual variation in copy number, ranging from 20 to 103, and can be found in the genome on chromosome 4 and chromosome 8. The high similarity between the UPS17-like genes makes it impossible to specifically assign data to a particular gene of the family. Oligonucleotides designed in RNAi experiments are for instance not specific for a given UPS17-like gene.
Belongs to the beta/gamma-crystallin family.
Crystallins are the dominant structural components of the vertebrate eye lens.
Has a two-domain beta-structure, folded into four very similar Greek key motifs.
Anti-terminator protein required to prevent early mRNA termination during transcription (PubMed:31104839). Together with SCAF8, acts by suppressing the use of early, alternative poly(A) sites, thereby preventing the accumulation of non-functional truncated proteins (PubMed:31104839). Mechanistically, associates with the phosphorylated C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit (POLR2A), and subsequently binds nascent RNA upstream of early polyadenylation sites to prevent premature mRNA transcript cleavage and polyadenylation (PubMed:31104839). Independently of SCAF8, also acts as a suppressor of transcriptional readthrough (PubMed:31104839).
Interacts with POLR2A; via C-terminal heptapeptide repeat domain (CTD) phosphorylated at 'Ser-2' and 'Ser-5'.
Belongs to the V-ATPase V0D/AC39 subunit family.
Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (By similarity). May play a role in coupling of proton transport and ATP hydrolysis (By similarity). Regulator of osteoclast fusion and bone formation (By similarity).
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex. The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H. The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR.
Homodimer. Interacts with BCL2, ARHGAP1, MIF and GFER.
Isoform 2 is expressed in placenta and lung.
May be a bridge molecule between BCL2 and ARHGAP1/CDC42 in promoting cell death.
A chromosomal aberration involving TCTA is associated with T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(1;3)(p34;p21).
May be required for cellular fusion during osteoclastogenesis.
Ubiquitous. Highest level of expression in kidney. Present in monocytes, osteoclasts, macrophages, synoviocytes and synovial lining cells (at protein level).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-3/CHRNA3 sub-subfamily.
Genetic variations in CHRNA3 have been associated with susceptibility to smoking-related behavioral traits and lung cancer, contributing to the smoking quantitative trait locus 3 (SQTL3) [MIM:612052].
Neuronal AChR is composed of two different types of subunits: alpha and beta. Alpha-3 subunit can be combined to beta-2 or beta-4 to give rise to functional receptors. Interacts with RIC3; which is required for proper folding and assembly (PubMed:16120769). Interacts with LYPD6 (PubMed:27344019). The heteropentamer alpha-3-beta-2 interacts with alpha-conotoxins ImI and ImII (PubMed:15609996). The heteropentamer alpha-3-beta-2 interacts with alpha-conotoxins ImI, ImII, PnIA, GID and MII (By similarity). The heteropentamer alpha-3-beta-4 interacts with the alpha-conotoxin ImI (PubMed:15609996).
Expressed in neuronal, neuroblastoma and embryonic kidney cell lines (at protein level).
Interacts with PPP1CA and NCOA5. Forms a complex with ILF2, ILF3, KHDRBS1, RBMX, NCOA5 and PPP1CA (By similarity).
Plays a role in the reduction of telomerase activity during differentiation of embryonic stem cells by binding to the core promoter of TERT and controlling its down-regulation.
Transfers mannosyl residues to the hydroxyl group of serine or threonine residues. The 4 members of the TMTC family are O-mannosyl-transferases dedicated primarily to the cadherin superfamily, each member seems to have a distinct role in decorating the cadherin domains with O-linked mannose glycans at specific regions. Also acts as O-mannosyl-transferase on other proteins such as PDIA3.
Belongs to the type I cytokine receptor family. Type 5 subfamily.
Cell surface receptor for IL3 expressed on hematopoietic progenitor cells, monocytes and B-lymphocytes that controls the production and differentiation of hematopoietic progenitor cells into lineage-restricted cells (PubMed:10527461). Ligand stimulation rapidly induces hetrodimerization with IL3RB, phosphorylation and enzyme activity of effector proteins such as JAK2 and PI3K that play a role in signaling cell proliferation and differentiation. Activation of JAK2 leads to STAT5-mediated transcriptional program (By similarity).
Interacts with IL3 (PubMed:29374162). Heterodimer of an alpha and a beta subunit. The beta subunit is common to the IL3, IL5 and GM-CSF receptors.
Ubiquitinated by RNFT2 in response to IL3. Ubiquitination leads ligand-induced degradation by the proteasome.
By disease-causing laminin A mutants also inducing CBX5 and CBX1 proteasomal degradation.
Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Overexpression is leading to degradation of CBX5 and CBX1.
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.
Acetylated. Deacetylated by SIRT1, resulting in decreased protein stability. Deacetylated by SIRT6, preventing its degradation by the proteasome, resulting in increased protein stability.
Homodimer. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts with CLOCK-BMAL1 (off DNA).Interacts with BMAL2. Interacts directly with PER1 and PER3, and through a C-terminal domain, with CRY1 and CRY2. Interacts (via PAS 2 domain) with TIMELESS (PubMed:31138685). Interacts with NFIL3. Different large complexes have been identified with different repressive functions. The core of PER complexes is composed of at least PER1, PER2, PER3, CRY1, CRY2, CSNK1D and/or CSNK1E. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (active). The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A. The large PER complex involved in the histone methylation is composed of at least PER2, CBX3, TRIM28, SUV39H1 and/or SUV39H2; CBX3 mediates the formation of the complex. Interacts with SETX; the interaction inhibits termination of circadian target genes. Interacts with the nuclear receptors HNF4A, NR1D1, NR4A2, RORA, PPARA, PPARG and THRA; the interaction with at least PPARG is ligand dependent. Interacts with PML. Interacts (phosphorylated) with BTRC and FBXW11; the interactions trigger proteasomal degradation. Interacts with NONO and SFPQ. Interacts with CAVIN3 (By similarity). Interacts with MAGEL2 (By similarity). Interacts with MAP1LC3B (By similarity). Interacts with HNF4A (PubMed:30530698).
Oscillates diurnally. Rhythmic levels are critical for the generation of circadian rhythms in central as well as peripheral clocks. Targeted degradation of PER and CRY proteins enables the reactivation of CLOCK-BMAL1, thus initiating a new circadian transcriptional cycle with an intrinsic period of 24 hours.
Phosphorylated by CSNK1E and CSNK1D. Phosphorylation results in PER2 protein degradation. May be dephosphorylated by PP1.
Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndrome and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. PER1 and PER2 proteins transport CRY1 and CRY2 into the nucleus with appropriate circadian timing, but also contribute directly to repression of clock-controlled target genes through interaction with several classes of RNA-binding proteins, helicases and others transcriptional repressors. PER appears to regulate circadian control of transcription by at least three different modes. First, interacts directly with the CLOCK-BMAL1 at the tail end of the nascent transcript peak to recruit complexes containing the SIN3-HDAC that remodel chromatin to repress transcription. Second, brings H3K9 methyltransferases such as SUV39H1 and SUV39H2 to the E-box elements of the circadian target genes, like PER2 itself or PER1. The recruitment of each repressive modifier to the DNA seems to be very precisely temporally orchestrated by the large PER complex, the deacetylases acting before than the methyltransferases. Additionally, large PER complexes are also recruited to the target genes 3' termination site through interactions with RNA-binding proteins and helicases that may play a role in transcription termination to regulate transcription independently of CLOCK-BMAL1 interactions. Recruitment of large PER complexes to the elongating polymerase at PER and CRY termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. May propagate clock information to metabolic pathways via the interaction with nuclear receptors. Coactivator of PPARA and corepressor of NR1D1, binds rhythmically at the promoter of nuclear receptors target genes like BMAL1 or G6PC1. Directly and specifically represses PPARG proadipogenic activity by blocking PPARG recruitment to target promoters and thereby inhibiting transcriptional activation. Required for fatty acid and lipid metabolism, is involved as well in the regulation of circulating insulin levels. Plays an important role in the maintenance of cardiovascular functions through the regulation of NO and vasodilatatory prostaglandins production in aortas. Controls circadian glutamate uptake in synaptic vesicles through the regulation of VGLUT1 expression. May also be involved in the regulation of inflammatory processes. Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1 and ATF4. Negatively regulates the formation of the TIMELESS-CRY1 complex by competing with TIMELESS for binding to CRY1.
Ubiquitinated, leading to its proteasomal degradation. Ubiquitination may be inhibited by CRY1.
Widely expressed. Found in heart, brain, placenta, lung, liver, skeleatal muscle, kidney and pancreas. High levels in skeletal muscle and pancreas. Low levels in lung. Isoform 2 is expressed in keratinocytes (at protein level).
(Microbial infection) Binds to Neisseria transferrin-binding protein A (tbpA or tbp1). Forms a large complex with TbpA and TbpB.
(Microbial infection) Binds to Neisseria transferrin-binding protein B (tbpb or tbp2).
(Microbial infection) Binds to Neisseria transferrin-binding proteins A and B via its C-terminal lobe only. The L3 helix finger of TbpA inserts into the C-terminal lobe of TF, altering its conformation and probably disturbing the coordination of iron 2. Electron microscopy suggests that in the TbpA-TbpB-TF complex, TF is captured directly above the loop domain of TbpA in a chamber of about 1000 Angstroms(3) formed by the 3 proteins, where interactions between the proteins serve to abstract iron 2 from TF (PubMed:22343719, PubMed:22327295). Binding to TbpB does not alter the conformation of the C-terminal lobe (PubMed:22343719).
(Microbial infection) Serves as an iron source for Neisseria species, which capture the protein and extract its iron for their own use.
(Microbial infection) Serves as an iron source for parasite T.brucei (strain 427), which capture TF via its own transferrin receptor ESAG6:ESAG7 and extract its iron for its own use.
Different polymorphic variants of transferrin are known. The sequence shown is the predominant electrophoretic variant (C1 or TF*C1).
Has a bilobed structure, each lobe binds a single Fe(3+) ion. Does not always bind 2 Fe(3+) ions.
Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate. It is responsible for the transport of iron from sites of absorption and heme degradation to those of storage and utilization. Serum transferrin may also have a further role in stimulating cell proliferation.
Alpha-inhibin-92 and alpha-inhibin-31, derived from the proteolytic degradation of semenogelin, inhibit the secretion of pituitary follicle-stimulating hormone.
Occurs in disulfide-linked complexes which may also contain two less abundant 71- and 76-kDa semenogelin-related polypeptides. Interacts with EPPIN (via C-terminus); Cys-239 is a critical amino acid for both binding to EPPIN.
Predominant protein in semen. It participates in the formation of a gel matrix entrapping the accessory gland secretions and ejaculated spermatozoa. Fragments of semenogelin and/or fragments of the related proteins may contribute to the activation of progressive sperm movements as the gel-forming proteins are fragmented by KLK3/PSA.
Rapidly cleaved after ejaculation by KLK3/PSA, resulting in liquefaction of the semen coagulum and the progressive release of motile spermatozoa.
ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell (PubMed:15670820) (By similarity). Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane (By similarity). Specifically required during spermatogenesis, probably to mediate ADP:ATP exchange in spermatocytes (PubMed:17137571). Large ATP supplies from mitochondria may be critical for normal progression of spermatogenesis during early stages of meiotic prophase I, including DNA double-strand break repair and chromosomal synapsis (By similarity). In addition to its ADP:ATP antiporter activity, also involved in mitochondrial uncoupling and mitochondrial permeability transition pore (mPTP) activity (By similarity). Plays a role in mitochondrial uncoupling by acting as a proton transporter: proton transport uncouples the proton flows via the electron transport chain and ATP synthase to reduce the efficiency of ATP production and cause mitochondrial thermogenesis (By similarity). Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A31/ANT4 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity) (By similarity). Proton transporter activity requires free fatty acids as cofactor, but does not transport it (By similarity). Among nucleotides, may also exchange ADP for dATP and dADP (PubMed:15670820). Also plays a key role in mPTP opening, a non-specific pore that enables free passage of the mitochondrial membranes to solutes of up to 1.5 kDa, and which contributes to cell death (By similarity). It is however unclear if SLC25A31/ANT4 constitutes a pore-forming component of mPTP or regulates it (By similarity).
Expressed in brain, liver, sperm and testis (PubMed:15670820, PubMed:17137571). In testis, expressed at higher level in spermatocytes, while it is expressed at lower level in spermatogonial cells (PubMed:17681941). Expressed in erythrocytes (at protein level) (PubMed:27641616).
The matrix-open state (m-state) is inhibited by the membrane-permeable bongkrekic acid (BKA). The cytoplasmic-open state (c-state) is inhibited by the membrane-impermeable toxic inhibitor carboxyatractyloside (CATR) (By similarity). Proton transporter activity is inhibited by ADP:ATP antiporter activity (By similarity).
The transmembrane helices are not perpendicular to the plane of the membrane, but cross the membrane at an angle. Odd-numbered transmembrane helices exhibit a sharp kink, due to the presence of a conserved proline residue.
(Microbial infection) Interacts with human cytomegalovirus protein UL148; this interaction retains immature CD58 intracellularly.
Interacts with CD2 (PubMed:10380930, PubMed:3309127). Interacts with CMTM6 (PubMed:28813417).
Ligand of the T-lymphocyte CD2 glycoprotein. This interaction is important in mediating thymocyte interactions with thymic epithelial cells, antigen-independent and -dependent interactions of T-lymphocytes with target cells and antigen-presenting cells and the T-lymphocyte rosetting with erythrocytes. In addition, the LFA-3/CD2 interaction may prime response by both the CD2+ and LFA-3+ cells.
Ancillary protein that assembles as a beta subunit with a voltage-gated potassium channel complex of pore-forming alpha subunits. Modulates the gating kinetics and enhances stability of the channel complex. Assembled with KCNB1 modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1 (PubMed:19219384). Assembled with KCNQ1/KVLQT1 is proposed to form the slowly activating delayed rectifier cardiac potassium (IKs) channel. The outward current reaches its steady state only after 50 seconds. Assembled with KCNH2/HERG may modulate the rapidly activating component of the delayed rectifying potassium current in heart (IKr).
Belongs to the potassium channel KCNE family.
Expressed in lung, kidney, testis, ovaries, small intestine, peripheral blood leukocytes. Expressed in the heart (PubMed:19219384). Not detected in pancreas, spleen, prostate and colon. Restrictively localized in the apical membrane portion of epithelial cells.
Interacts with KCNB1. Interacts with KCNC2 (By similarity). Associates with KCNH2/HERG (PubMed:9230439). Interacts with KNCQ1; targets the complex KNCQ1-KCNE1 to the membrane raft (PubMed:20533308). The complex KNCQ1-KNCE1 interacts with the scolopendra toxin SSD609 (PubMed:26307551).
N-glycosylation at Asn-26 occurs post-translationally, and requires prior cotranslational glycosylation at Asn-5.
Phosphorylation inhibits the potassium current.
An interstitial deletion causing the fusion of exon 10 of CTL4 with the 3'-UTR of NEU has been detected in two patients affected by sialidosis.
Belongs to the CTL (choline transporter-like) family.
Choline transporter that plays a role in the choline-acetylcholine system and is required to the efferent innervation of hair cells in the olivocochlear bundle for the maintenance of physiological function of outer hair cells and the protection of hair cells from acoustic injury (By similarity) (PubMed:23651124, PubMed:28013291). Also described as a thiamine pyrophosphate transporter in colon, may mediate the absorption of microbiota-generated thiamine pyrophosphate and contribute to host thiamine (vitamin B1) homeostasis (PubMed:24379411, PubMed:26741288).
Has also thiamine pyrophosphate transporter activity.
Highly expressed in colon, also detected in prostate, trachea and lung (PubMed:24379411). Isoform 3 is also expressed in colon but a lower levels (PubMed:24379411).
N-glycosylated; N-glycosylation of Asn-69, Asn-155 and Asn-393 is required for a proper thiamine pyrophosphate uptake.
High relative levels in skeletal muscle, testis and pancreas. Lower levels of expression in the heart, brain, placenta, lung, liver, kidney, spleen, thymus, prostate, ovary, small intestine, colon and leukocytes. Expression is coregulated with MRPL43.
Homohexamer (via C-terminus) which assembled in a ring-like structure (PubMed:18039713, PubMed:17324440, PubMed:22383523, PubMed:25824949, PubMed:30496414, PubMed:18971204). Homoheptamer which assembled in a ring-like structure (PubMed:25824949, PubMed:30496414). Oligomerization is Mg(2+), nucleotide and DNA-independent, however, Mg(2+) and nucleotide stabilize the homohexameric form (PubMed:18039713). Interacts with POLG in vitro (PubMed:15167897).
In vitro, can catalyze the hydrolysis of different nucleotide triphosphate (NTP) substrates with different efficiency.
Lack DNA unwinding and ATP hydrolysis activities (PubMed:18039713). Does not bind single-stranded or double-stranded DNA (PubMed:18039713).
Mitochondrial helicase involved in mtDNA replication and repair (PubMed:12975372, PubMed:15167897, PubMed:17324440, PubMed:18039713, PubMed:18971204, PubMed:25824949, PubMed:26887820, PubMed:27226550). Might have a role in mtDNA repair (PubMed:27226550). Has DNA strand separation activity needed to form a processive replication fork for leading strand synthesis which is catalyzed by the formation of a replisome complex with POLG and mtSDB (PubMed:12975372, PubMed:15167897, PubMed:18039713, PubMed:22383523, PubMed:26887820, PubMed:27226550). Preferentially unwinds DNA substrates with pre-existing 5'-and 3'- single-stranded tails but is also active on a 5'- flap substrate (PubMed:12975372, PubMed:15167897, PubMed:18039713, PubMed:22383523, PubMed:26887820, PubMed:27226550). Can dissociate the invading strand of immobile or mobile D-loop DNA structures irrespective of the single strand polarity of the third strand (PubMed:27226550). In addition to its DNA strand separation activity, also has DNA strand annealing, DNA strand-exchange and DNA branch migration activities (PubMed:22383523, PubMed:26887820, PubMed:27226550).
Monomer (PubMed:18039713). Does not form oligomers (PubMed:18039713).
N-terminus enhances protein stability and hexamer formation, which is important for DNA binding, and is required for DNA helicase activity and, ultimately, for mtDNA replisome processivity.
Strand annealing activity is inhibited by 150 mM NaCl (in vitro).
The N-terminus contains a putative primase-like domain; however the absence of the zinc binding domain and other motifs important for catalysis suggests that TWNK lacks primase activity.
Highly expressed in testis, uterus and small intestine, and weakly expressed in colon and prostate. Also expressed in skin, primary keratinocytes, immortalized keratinocytes, and HeLa and HEK293 cells. Not detected in blood, thymus, spleen or Hep-G2 cells.
In a 7-week embryo, expressed in the urogenital sinus, the precursor of the bladder, and its outflow tract. The most prominent expression is in the primitive urothelium, and there is weaker expression in the surrounding mesenchyme. Expression also detected in the urothelium of the adult male urethra.
Probable transcription factor specific for skin keratinocytes. May play a role in the differentiation of spermatozoa and oocytes (PubMed:14988505). May also play an important role in early urinary-tract development (PubMed:31051115).
Adapter protein that binds to and probably organizes the subcellular localization of a variety of membrane proteins. May link various receptors to the actin cytoskeleton and the dystrophin glycoprotein complex.
Monomer and homodimer (Probable). Interacts with the other members of the syntrophin family SNTA1 and SNTB2; with the sodium channel proteins SCN4A and SCN5A (By similarity). Interacts with the viral HTLV-1 TAX protein and with dystrophin protein DMD and related proteins DTNA and UTRN. Interacts with DTNB (By similarity).
The PDZ domain binds to the last three or four amino acids of ion channels and receptor proteins. The association with dystrophin or related proteins probably leaves the PDZ domain available to recruit proteins to the membrane (By similarity).
The PH 1 domain mediates the oligomerization in a calcium dependent manner.
The SU domain binds calmodulin in a calcium-dependent manner.
Eight non disease-associated alleles are known: CYP2F1*1, CYP2F1*2A, CYP2F1*2B, CYP2F1*3, CYP2F1*4, CYP2F1*5A, CYP2F1*5B and CYP2F1*6. The sequence shown corresponds to allele CYP2F1*1.
Expressed in lung. Rarely detected in liver and placenta.
May be involved in the metabolism of various pneumotoxicants including naphthalene. Is able to dealkylate ethoxycoumarin, propoxycoumarin, and pentoxyresorufin but possesses no activity toward ethoxyresorufin and only trace dearylation activity toward benzyloxyresorufin. Bioactivates 3-methylindole (3MI) by dehydrogenation to the putative electrophile 3-methylene-indolenine.
Belongs to the major facilitator superfamily. Vesicular transporter family.
Electrogenic antiporter that exchanges one cationic monoamine with two intravesicular protons across the membrane of secretory and synaptic vesicles. Uses the electrochemical proton gradient established by the V-type proton-pump ATPase to accumulate high concentrations of monoamines inside the vesicles prior to their release via exocytosis. Transports a variety of catecholamines such as dopamine, adrenaline and noradrenaline, histamine, and indolamines such as serotonin (PubMed:8643547, PubMed:23363473). Regulates the transvesicular monoaminergic gradient that determines the quantal size. Mediates somatodendritic dopamine release in hippocampal neurons, likely as part of a regulated secretory pathway that integrates retrograde synaptic signals (By similarity). Acts as a primary transporter for striatal dopamine loading ensuring impulse-dependent release of dopamine at the synaptic cleft (By similarity). Responsible for histamine and serotonin storage and subsequent corelease from mast cell granules (PubMed:8860238) (By similarity).
Expressed in neuronal and neuroendocrine tissues. Detected in central and peripheral nervous system in particular in axonal and dendritic processes in dopaminergic cells of substantia nigra, histaminergic neuronal cell bodies of substantia nigra and tuberomammillary nucleus, in ganglion cells of sympathetic glia and in peripheral sympathetic nerve terminals in stomach and duodenum (at protein level). Highly expressed in chromaffin cells of the adrenal medulla and histamine-storing enterochromaffin-like cells of oxyntic mucosa (at protein level).
Strongly inhibited by reserpine and tetrabenazine (PubMed:8643547, PubMed:8860238). Also inhibited to a lesser extent by ketanserin and fenfluramine. Inhibited by tetrabenazine.
Expressed in breast, placenta, kidney, liver and pancreas.
Homodimer upon hormone binding. Interacts with SMARCA1. Interacts with GH1. Interacts with CSH. Interacts with NEK3 and VAV2 and this interaction is prolactin-dependent.
Includes exon 11. Does not transduce prolactin signaling.
Produced by deletion of part of exon 10 and frameshift.
SF1b with deletion of exon 4. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Soluble isoform that appears specific for the BT-474 breast cancer cell line.
This is a receptor for the anterior pituitary hormone prolactin (PRL). Acts as a prosurvival factor for spermatozoa by inhibiting sperm capacitation through suppression of SRC kinase activation and stimulation of AKT. Isoform 4 is unable to transduce prolactin signaling. Isoform 6 is unable to transduce prolactin signaling.
Component of a mRNP complex containing PIWIL2, TDRD1 and piRNAs. Component of the PET complex, at least composed of EXD1, PIWIL2, TDRD12 and piRNAs.
Probable ATP-binding RNA helicase required during spermatogenesis to repress transposable elements and preventing their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. Involved in the secondary piRNAs metabolic process. Acts via the PET complex, a multiprotein complex required during the secondary piRNAs metabolic process for the PIWIL2 slicing-triggered loading of PIWIL4 piRNAs.
May play a role in the organization of the cytoskeleton.
Heme-binding protein which promotes neuronal but not astrocyte differentiation.
The cytochrome b5 heme-binding domain was proven to bind heme, although it lacks the conserved iron-binding His residues at position 73 and 106.
Expressed in placenta, cultured skin fibroblasts and in osteoblast cell line MG-63.
Probable peripherally associated component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. Involved in cytokinesis. Involved in recruiting VPS4A and/or VPS4B to the midbody of dividing cells. May also be involved in chromosome condensation. Targets the Polycomb group (PcG) protein BMI1/PCGF4 to regions of condensed chromatin. May play a role in stable cell cycle progression and in PcG gene silencing.
Probable peripherally associated component of the endosomal sorting required for transport complex III (ESCRT-III). ESCRT-III components are thought to multimerize to form a flat lattice on the perimeter membrane of the endosome. Several assembly forms of ESCRT-III may exist that interact and act sequentially. Self-associates. Interacts with CHMP1B. Interacts with VPS4A. Interacts with VPS4B. Interacts with PHF1. Interacts with IST1. Interacts with MITD1.
Was originally (PubMed:8863740) thought to be a metalloprotease (PRSM1). This was based on a wrong translation of the ORF which gave rise to a putative protein of 318 AA containing a pattern reminiscent of zinc metalloproteases.
Belongs to the ADP-ribosylglycohydrolase family.
Specifically acts as an arginine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to arginine residues on proteins.
Accessory subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, regulating their cell-surface expression and cyclic nucleotide dependence.
Belongs to the peroxisomal targeting signal receptor family.
Interacts with RAB8B. Forms an obligate 4:4 complex with HCN2 (By similarity). May interact with the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type); the relevance of such interaction is however unclear (PubMed:11463335). Interacts with HCN3 (By similarity).
Mainly expressed in brain. Also expressed in pancreas, testis and pituitary.
Catalyzes the attachment of threonine to tRNA(Thr) in a two-step reaction: threonine is first activated by ATP to form Thr-AMP and then transferred to the acceptor end of tRNA(Thr) (PubMed:25824639, PubMed:31374204). Also edits incorrectly charged tRNA(Thr) via its editing domain, at the post-transfer stage (By similarity).
Inhibited by borrelidin (BN, IC 50 is 7 nM), which binds to 4 distinct subsites in the protein, preventing binding of all 3 substrates (PubMed:25824639).
(Microbial infection) Directly interacts with hepatitis C virus (HCV) core protein in the cytoplasm.
(Microbial infection) Facilitates Dengue virus (DENV) replication.
(Microbial infection) Facilitates HIV-1 replication (PubMed:15507209, PubMed:18583960, PubMed:21589879, PubMed:22872150, PubMed:29899501). Acts as a cofactor for XPO1-mediated nuclear export of HIV-1 Rev RNAs (PubMed:15507209, PubMed:18583960, PubMed:29899501). This function is strongly stimulated in the presence of TBK1 and requires DDX3X ATPase activity (PubMed:18583960).
(Microbial infection) Facilitates Venezuelan equine encephalitis virus (VEEV) replication.
(Microbial infection) Facilitates Zika virus (ZIKV) replication.
(Microbial infection) Facilitates hepatitis C virus (HCV) replication (PubMed:29899501). During infection, HCV core protein inhibits the interaction between MAVS and DDX3X and therefore impairs MAVS-dependent INFB induction and might recruit DDX3X to HCV replication complex (PubMed:21170385).
(Microbial infection) Interacts with HIV-1 protein Rev.
(Microbial infection) Interacts with Venezuelan equine encephalitis virus non-structural protein 3.
(Microbial infection) Interacts with hepatitis B virus (HBV) polymerase in the cytoplasm; this interaction may inhibit DDX3X interaction with the IKBKE/TBK1 complex, and hence impair IKBKE/TBK1-mediated increase in IFNB production.
(Microbial infection) Interacts with vaccinia virus (VACV) protein K7.
Belongs to the DEAD box helicase family. DDX3/DED1 subfamily.
Encoded by an chromosome X-linked gene which may escape X chromosome inactivation in females. DDX3Y, its homolog on chromosome Y, is located on the Y non-recombinant portion.
Homodimer; can bind RNA as a monomer and as a dimer/oligomer (PubMed:27546789, PubMed:31300642). Interacts with TDRD3 (PubMed:18632687). Interacts (when phosphorylated at Ser-102) with IRF3; the interaction facilitates the phosphorylation and activation of IRF3 by IKBKE (PubMed:23478265, PubMed:27980081). Directly interacts with XPO1/CRM1 (PubMed:15507209, PubMed:30131165, PubMed:31575075). The interaction with XPO1/CMR1 is dependent on the DDX3X nuclear export signal motif and XPO1 interaction with GTPase RAN in its active GTP-bound form (PubMed:31575075, PubMed:30131165). Weakly interacts with TBKBP1/SINTBAD (PubMed:27980081). Directly interacts with TRAF3; this interaction stimulates TRAF3 'Lys-63' ubiquitination (PubMed:27980081). Interacts with CSNK1E in a Wnt-dependent manner; this interaction greatly enhances CSNK1E affinity for ATP, stimulates its kinase activity and promotes CSNK1E-mediated DVL2 phosphorylation (PubMed:23413191, PubMed:29222110). In the presence of RNA, the interaction is decreased (PubMed:29222110). Also interacts with CSNK1D and stimulates its kinase activity (PubMed:23413191, PubMed:29222110). Interacts with TRPV4; this interaction is decreased when the TRPV4 channel is activated, leading to DDX3X relocalization to the nucleus (PubMed:29899501). Interacts with MAP3K14/NIK (PubMed:30341167). Directly interacts with CHUK/IKKA after physiological activation of the TLR7 and TLR8 pathways; this interaction enhances CHUK autophosphorylation (PubMed:30341167). May associate with EIF4F complex, composed of at least EIF4A, EIF4E and EIF4G1/EIF4G3 (Probable). Directly interacts with EIF4E in an RNA-independent manner; this interaction enhances EIF4E cap-binding ability (PubMed:17667941, PubMed:21883093, PubMed:28733330). Directly interacts with EIF4G1 in an RNA-independent manner (PubMed:22872150). DDX3X competes with EIF4G1 for interaction with EIF4E (PubMed:17667941, PubMed:21883093). Interacts with EIF4A1 and EIF2S1 in an RNA-independent manner (PubMed:18596238, PubMed:22323517). Associates with the eukaryotic translation initiation factor 3 (eIF-3) complex, including with EIF3B and EIF3C subunits (PubMed:18628297, PubMed:22323517). Directly interacts with IKBKE/IKKE; this interaction stimulates IKBKE activating autophosphorylation and is induced upon viral infection (PubMed:18636090, PubMed:20657822, PubMed:23478265, PubMed:27980081). Interacts with TBK1 (PubMed:20375222). Interacts with SP1; this interaction potentiates SP1-induced CDKN1A/WAF1/CIP1 transcription (PubMed:16818630). Interacts with GSK3A and GSK3B (PubMed:18846110). Interacts with several death receptors, inclusing FAS, TNFRSF10A and TNFRSF10B (PubMed:18846110). Recruited to TNFRSF10B in the absence of receptor stimulation. When TNFRSF10B is stimulated, further recruited to the receptor and cleaved by caspases. A large proteolytic fragment remains associated with TNFRSF10B (PubMed:18846110). Interacts (via C-terminus) with NXF1/TAP; this interaction may be partly involved in DDX3X nuclear export and in NXF1 localization to stress granules (PubMed:18596238). Identified in an mRNP complex, composed of at least DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1/2, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1 (PubMed:19029303). The interaction with IGF2BP1/2 is RNA-dependent (PubMed:22323517). Directly interacts with PABPC1/PABP1 in an RNA-independent manner (PubMed:18596238, PubMed:21883093, PubMed:22872150, PubMed:28733330). This interaction increases in stressed cells and decreases during cell recovery (PubMed:21883093). Interacts (via C-terminus) with MAVS/IPS-1; this interaction occurs rapidly, but transiently after Sendai virus infection (PubMed:20127681, PubMed:21170385, PubMed:27980081). The interaction potentiates MAVS-mediated IFNB induction (PubMed:20127681, PubMed:21170385). Interacts with ERCC6/CBS (PubMed:26030138). Interacts with DHX33 in an RNA-independent manner (PubMed:26100019). Interacts with DDX5 in the cytoplasm; this interaction may be more efficient when both proteins are unphosphorylated (PubMed:22034099). Interacts with RIGI/RIG-1 (PubMed:20127681). Interacts with IFIH1/MDA5 (PubMed:20127681). Interacts with NCAPH; this interaction may be important for the NCAPH localization at condensing chromosomes during mitosis (PubMed:21730191). Interacts with NLRP3 (via NACHT domain) under inflammasome-activating conditions (By similarity). Interacts with CAPRIN1 (PubMed:28733330). Interacts with HNF4A and NR0B2/SHP in an RNA-independent manner; this interaction disrupts the interaction between HNF4 and NR0B2 that forms inactive heterodimers and enhances the formation of active HNF4 homodimers (PubMed:28128295). Interacts with CREBBP/CBP (PubMed:28128295). Interacts with EP300/p300 (PubMed:28128295). Interacts with gamma-tubulin (PubMed:28842590). Interacts with phosphorylated TP53 (PubMed:28842590). Directly interacts with RELA/p65; this interaction may trap RELA in the cytoplasm, impairing nuclear relocalization upon TNF activating signals (PubMed:27736973).
Multifunctional ATP-dependent RNA helicase (PubMed:17357160, PubMed:21589879, PubMed:31575075). The ATPase activity can be stimulated by various ribo-and deoxynucleic acids indicative for a relaxed substrate specificity (PubMed:29222110). In vitro can unwind partially double-stranded DNA with a preference for 5'-single-stranded DNA overhangs (PubMed:17357160, PubMed:21589879). Binds RNA G-quadruplex (rG4s) structures, including those located in the 5'-UTR of NRAS mRNA (PubMed:30256975). Involved in many cellular processes, which do not necessarily require its ATPase/helicase catalytic activities (Probable). Involved in transcription regulation (PubMed:16818630, PubMed:18264132). Positively regulates CDKN1A/WAF1/CIP1 transcription in an SP1-dependent manner, hence inhibits cell growth. This function requires its ATPase, but not helicase activity (PubMed:16818630, PubMed:18264132). CDKN1A up-regulation may be cell-type specific (PubMed:18264132). Binds CDH1/E-cadherin promoter and represses its transcription (PubMed:18264132). Potentiates HNF4A-mediated MTTP transcriptional activation; this function requires ATPase, but not helicase activity. Facilitates HNF4A acetylation, possibly catalyzed by CREBBP/EP300, thereby increasing the DNA-binding affinity of HNF4 to its response element. In addition, disrupts the interaction between HNF4 and SHP that forms inactive heterodimers and enhances the formation of active HNF4 homodimers. By promoting HNF4A-induced MTTP expression, may play a role in lipid homeostasis (PubMed:28128295). May positively regulate TP53 transcription (PubMed:28842590). Associates with mRNPs, predominantly with spliced mRNAs carrying an exon junction complex (EJC) (PubMed:17095540, PubMed:18596238). Involved in the regulation of translation initiation (PubMed:18628297, PubMed:17667941, PubMed:22872150). Not involved in the general process of translation, but promotes efficient translation of selected complex mRNAs, containing highly structured 5'-untranslated regions (UTR) (PubMed:20837705, PubMed:22872150). This function depends on helicase activity (PubMed:20837705, PubMed:22872150). Might facilitate translation by resolving secondary structures of 5'-UTRs during ribosome scanning (PubMed:20837705). Alternatively, may act prior to 43S ribosomal scanning and promote 43S pre-initiation complex entry to mRNAs exhibiting specific RNA motifs, by performing local remodeling of transcript structures located close to the cap moiety (PubMed:22872150). Independently of its ATPase activity, promotes the assembly of functional 80S ribosomes and disassembles from ribosomes prior to the translation elongation process (PubMed:22323517). Positively regulates the translation of cyclin E1/CCNE1 mRNA and consequently promotes G1/S-phase transition during the cell cycle (PubMed:20837705). May activate TP53 translation (PubMed:28842590). Required for endoplasmic reticulum stress-induced ATF4 mRNA translation (PubMed:29062139). Independently of its ATPase/helicase activity, enhances IRES-mediated translation; this activity requires interaction with EIF4E (PubMed:17667941, PubMed:22323517). Independently of its ATPase/helicase activity, has also been shown specifically repress cap-dependent translation, possibly by acting on translation initiation factor EIF4E (PubMed:17667941). Involved in innate immunity, acting as a viral RNA sensor. Binds viral RNAs and promotes the production of type I interferon (IFN-alpha and IFN-beta) (PubMed:31575075, PubMed:20127681, PubMed:21170385). Potentiate MAVS/RIGI-mediated induction of IFNB in early stages of infection (PubMed:20127681, PubMed:21170385). Enhances IFNB1 expression via IRF3/IRF7 pathway and participates in NFKB activation in the presence of MAVS and TBK1 (PubMed:18583960, PubMed:18636090, PubMed:21170385, PubMed:27980081, PubMed:19913487). Involved in TBK1 and IKBKE-dependent IRF3 activation leading to IFNB induction, acts as a scaffolding adapter that links IKBKE and IRF3 and coordinates their activation (PubMed:23478265). Involved in the TLR7/TLR8 signaling pathway leading to type I interferon induction, including IFNA4 production. In this context, acts as an upstream regulator of IRF7 activation by MAP3K14/NIK and CHUK/IKKA. Stimulates CHUK autophosphorylation and activation following physiological activation of the TLR7 and TLR8 pathways, leading to MAP3K14/CHUK-mediated activatory phosphorylation of IRF7 (PubMed:30341167). Also stimulates MAP3K14/CHUK-dependent NF-kappa-B signaling (PubMed:30341167). Negatively regulates TNF-induced IL6 and IL8 expression, via the NF-kappa-B pathway. May act by interacting with RELA/p65 and trapping it in the cytoplasm (PubMed:27736973). May also bind IFNB promoter; the function is independent of IRF3 (PubMed:18583960). Involved in both stress and inflammatory responses (By similarity). Independently of its ATPase/helicase activity, required for efficient stress granule assembly through its interaction with EIF4E, hence promotes survival in stressed cells (PubMed:21883093). Independently of its helicase activity, regulates NLRP3 inflammasome assembly through interaction with NLRP3 and hence promotes cell death by pyroptosis during inflammation. This function is independent of helicase activity (By similarity). Therefore DDX3X availability may be used to interpret stress signals and choose between pro-survival stress granules and pyroptotic NLRP3 inflammasomes and serve as a live-or-die checkpoint in stressed cells (By similarity). In association with GSK3A/B, negatively regulates extrinsic apoptotic signaling pathway via death domain receptors, including TNFRSF10B, slowing down the rate of CASP3 activation following death receptor stimulation (PubMed:18846110). Cleavage by caspases may inactivate DDX3X and relieve the inhibition (PubMed:18846110). Independently of its ATPase/helicase activity, allosteric activator of CSNK1E. Stimulates CSNK1E-mediated phosphorylation of DVL2, thereby involved in the positive regulation of Wnt/beta-catenin signaling pathway. Also activates CSNK1A1 and CSNK1D in vitro, but it is uncertain if these targets are physiologically relevant (PubMed:23413191, PubMed:29222110). ATPase and casein kinase-activating functions are mutually exclusive (PubMed:29222110). May be involved in mitotic chromosome segregation (PubMed:21730191).
Phosphorylated by TBK1; the phosphorylation is required for the synergistic induction of IFNB mediated by TBK1 and DDX3X (PubMed:18583960). Phosphorylated by IKBKE at Ser-102 after ssRNA viral infection; enhances the induction of INFB promoter by IRF3 (PubMed:18583960, PubMed:23478265). The cytoplasmic form is highly phosphorylated in the G1/S phase of the cell cycle and much less at G2/M (PubMed:22034099). Phosphorylation by CSNK1E may inhibit RNA-stimulated ATPase activity (PubMed:29222110).
The C-terminus (residues 536-662) is dispensable for DDX3X trafficking.
The role of the nuclear export signal (NES) motif in XPO1-mediated DDX3X export is controversial (PubMed:30131165, PubMed:31575075, PubMed:15507209). In one study, NES has been found dispensable for DDX3X export while the helicase domain mediates the interaction with XPO1 (PubMed:15507209). However, in two other studies, DDX3X nuclear export is dependent on both NES and Ran in its GTP-bound form while the helicase domain is not required (PubMed:30131165, PubMed:31575075).
Upon stimulation of death receptors, including TNFRSF10B, recruited to receptors and cleaved by caspases. Proteolytic fragments remain associated with the receptors. This cleavage presumably inactivates DDX3X anti-apoptotic function.
Widely expressed (PubMed:15294876). In testis, expressed in spermatids (PubMed:15294876). Expressed in epidermis and liver (at protein level) (PubMed:16818630, PubMed:16301996).
Involved in peroxisome biosynthesis and integrity. Assembles membrane vesicles before the matrix proteins are translocated. As a docking factor for PEX19, is necessary for the import of peroxisomal membrane proteins in the peroxisomes.
Negatively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. Positively regulates a late step in exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles. Also involved in mast cell exocytosis (By similarity).
Nervous system. In hippocampus and cerebellum, expressed mainly by excitatory neurons. Down-regulated in brain cortex from patients suffering from Huntington disease, bipolar disorder or major depression. Down-regulated in cerebellum from patients with schizophrenia.
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.5/KCNA5 sub-subfamily.
Homotetramer and heterotetramer of potassium channel proteins. Interacts with DLG1, which enhances channel currents. Forms a ternary complex with DLG1 and CAV3 (By similarity). Interacts with KCNAB1 (PubMed:12130714). Interacts with UBE2I (PubMed:17261810).
Sumoylated on Lys-221, and Lys-536, preferentially with SUMO3. Sumoylation regulates the voltage sensitivity of the channel.
The amino terminus may be important in determining the rate of inactivation of the channel while the C-terminal PDZ-binding motif may play a role in modulation of channel activity and/or targeting of the channel to specific subcellular compartments.
The transmembrane segment S4 functions as voltage-sensor and is characterized by a series of positively charged amino acids at every third position. Channel opening and closing is effected by a conformation change that affects the position and orientation of the voltage-sensor paddle formed by S3 and S4 within the membrane. A transmembrane electric field that is positive inside would push the positively charged S4 segment outwards, thereby opening the pore, while a field that is negative inside would pull the S4 segment inwards and close the pore. Changes in the position and orientation of S4 are then transmitted to the activation gate formed by the inner helix bundle via the S4-S5 linker region.
Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:12130714). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (PubMed:12130714). Homotetrameric channels display rapid activation and slow inactivation (PubMed:8505626, PubMed:12130714). May play a role in regulating the secretion of insulin in normal pancreatic islets. Isoform 2 exhibits a voltage-dependent recovery from inactivation and an excessive cumulative inactivation (PubMed:11524461).
Binds to all human somatostatin receptor (SSTR) subtypes. It also inhibits cAMP production induced by forskolin through SSTRs.
Expressed in a subset of GABAergic cells in the cortex and hippocampus.
Component of a chromatin complex, at least composed of KDM5A, GATAD1 and EMSY.
Component of some chromatin complex recruited to chromatin sites methylated 'Lys-4' of histone H3 (H3K4me), with a preference for trimethylated form (H3K4me3).
Ubiquitously expressed among various tissue types. Expressed in left ventricular myocytes.
Belongs to the glycosyltransferase 10 family.
By T-cell activation (PubMed:8666674). Up-regulated by LIF (PubMed:19455659). Induced by IL1B (PubMed:29138114). Induced at higher levels by interleukin 12 in activated T cells (PubMed:9858509). Down-regulated by IL4 (PubMed:9858509).
Catalyzes the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to the N-acetyl glucosamine (GlcNAc) of a distal alpha2,3 sialylated lactosamine unit of a glycoprotein or a glycolipid-linked sialopolylactosamines chain through an alpha-1,3 glycosidic linkage and participates in the final fucosylation step in the biosynthesis of the sialyl Lewis X (sLe(x)), a carbohydrate involved in cell and matrix adhesion during leukocyte trafficking and fertilization (PubMed:8207002, PubMed:8752218, PubMed:8666674, PubMed:9299472, PubMed:9405391, PubMed:9473504, PubMed:9499379, PubMed:9461592, PubMed:15632313, PubMed:15926890, PubMed:18553500, PubMed:18402946, PubMed:11404359, PubMed:29593094). In vitro, also synthesizes sialyl-dimeric-Lex structures, from VIM-2 structures and both di-fucosylated and trifucosylated structures from mono-fucosylated precursors (PubMed:9499379). However does not catalyze alpha 1-3 fucosylation when an internal alpha 1-3 fucosylation is present in polylactosamine chain and the fucosylation rate of the internal GlcNAc residues is reduced once fucose has been added to the distal GlcNAc (PubMed:9473504, PubMed:9499379). Also catalyzes the transfer of a fucose from GDP-beta-fucose to the 6-sulfated a(2,3)sialylated substrate to produce 6-sulfo sLex mediating significant L-selectin-dependent cell adhesion (PubMed:10200296, PubMed:8752218). Through sialyl-Lewis(x) biosynthesis, can control SELE- and SELP-mediated cell adhesion with leukocytes and allows leukocytes tethering and rolling along the endothelial tissue thereby enabling the leukocytes to accumulate at a site of inflammation (PubMed:10386892, PubMed:29138114, PubMed:8666674, PubMed:9473504, PubMed:9834120). May enhance embryo implantation through sialyl Lewis X (sLeX)-mediated adhesion of embryo cells to endometrium (PubMed:18402946, PubMed:18553500). May affect insulin signaling by up-regulating the phosphorylation and expression of some signaling molecules involved in the insulin-signaling pathway through SLe(x) which is present on the glycans of the INSRR alpha subunit (PubMed:17229154).
Inhibited by NaCl (Probable). Inhibited by GDP in a concentration dependent manner, with an IC(50) value of 93 uM (PubMed:9405391, PubMed:15632313). Also inhibited by GMP and GTP (PubMed:9405391). Inhibited by N-ethylmaleimide (Probable). Activated by poly(ethylene glycol) by enhancing the thermal stability of FUT7 (PubMed:9405391). Activated by Mn2+, Ca2+, and Mg2+ (PubMed:9405391). Both panosialin A and B inhibit activity with IC(50) values of 4.8 and 5.3 ug/ml, respectively (PubMed:10386892). Inhibited by gallic acid (GA) and (-)-epigallocatechin gallate (EGCG) in a time-dependent and irreversible manner with IC(50) values of 60 and 700 nM, respectively (PubMed:15081893).
Expressed in subsets of taste receptor cells of the tongue and exclusively in gustducin-positive cells. Expressed on ciliated airway epithelium.
Receptor that may play a role in the perception of bitterness and is gustducin-linked. May play a role in sensing the chemical composition of the gastrointestinal content. The activity of this receptor may stimulate alpha gustducin, mediate PLC-beta-2 activation and lead to the gating of TRPM5 (By similarity). In airway epithelial cells, binding of bitter compounds increases the intracellular calcium ion concentration and stimulates ciliary beat frequency (By similarity).
Has transcriptional repressor activity. Overexpression inhibits the transcriptional activities of AP-1, p53/TP53 and CDKN1A.
Widely expressed in embryonic and adult tissues.
Heterodimers with GPN1 or GPN3 (By similarity). Binds to RNA polymerase II (RNAPII) (PubMed:20864038).
Small GTPase required for proper localization of RNA polymerase II and III (RNAPII and RNAPIII). May act at an RNAP assembly step prior to nuclear import.
Activated by Ca(2+)/calmodulin. Regulated by a locking mechanism, involving autophosphorylation at Ser-308 and calmodulin binding. In the inactive state, Ser-308 is phosphorylated. Activation involves its dephosphorylation and a release-of-autoinhibition mechanism where binding of calmodulin induces a conformational change that relieves the steric block of the active site by the autoinhibitory domain. Activity is modulated by UNC5B and NTN1. UNC5B activates it by inhibiting the phosphorylation at Ser-308, whereas NTN1 inhibits UNC5B-mediated activation of DAPK1. Endoplasmic-stress activates by causing Ser-308 dephosphorylation.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. DAP kinase subfamily.
Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. Phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. Phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. Phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. Phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. Phosphorylates RPS6, MYL9 and DAPK3. Acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca(2+) influx through NMDA receptor channels, resulting in an irreversible neuronal death. Required together with DAPK3 for phosphorylation of RPL13A upon interferon-gamma activation which is causing RPL13A involvement in transcript-selective translation inhibition.
Contaminating sequence. Sequence of unknown origin in the C-terminal part.
In response to mitogenic stimulation (PMA or EGF), phosphorylated at Ser-289; phosphorylation suppresses DAPK1 pro-apoptotic function. Autophosphorylation at Ser-308 inhibits its catalytic activity. Phosphorylation at Ser-734 by MAPK1 increases its catalytic activity and promotes cytoplasmic retention of MAPK1. Endoplasmic-stress can cause dephosphorylation at Ser-308.
Interacts with KLHL20 (PubMed:20389280). Interacts (via death domain) with MAPK1 and MAPK3 (PubMed:15616583). Interacts with MAP1B (via N-terminus) (PubMed:18195017). Interacts with PRKD1 in an oxidative stress-regulated manner (PubMed:17703233). Interacts with PIN1, PDCD6, BECN1, TSC2 and STX1A (PubMed:12730201, PubMed:16132846, PubMed:18974095, PubMed:19180116, PubMed:21497122). Interacts (via kinase domain) with DAPK3 (via kinase domain) (PubMed:15367680). Interacts with GRINB (By similarity). Interacts (via death domain) with UNC5B (via death domain) (PubMed:15729359). Interacts with UNC5C (via death domain) (PubMed:27068745).
Isoform 2 cannot induce apoptosis but can induce membrane blebbing.
Isoform 2 is expressed in normal intestinal tissue as well as in colorectal carcinomas.
Removal of the C-terminal tail of isoform 2 (corresponding to amino acids 296-337 of isoform 2) by proteolytic cleavage stimulates maximally its membrane-blebbing function.
The autoinhibitory domain sterically blocks the substrate peptide-binding site by making both hydrophobic and electrostatic contacts with the kinase core.
Ubiquitinated by the BCR(KLHL20) E3 ubiquitin ligase complex, leading to its degradation by the proteasome.
Up-regulated following treatment with IFNG/IFN-gamma.
Belongs to the protein phosphatase inhibitor 2 family.
Phosphorylation on Thr-73 by GSK3 activates PP1 by dissociating the PP1-PPP1R2 complex (By similarity). Phosphorylation on Ser-44 by ATM activates PP1 by dissociating the PP1-PPP1R2 complex.
Interacts with GEM through its N-terminal.
Stimulates, in vitro and in vivo, the GTPase activity of RhoA.
Part of an E3 ubiquitin-protein ligase complex with Elongin BC (ELOB and ELOC), CUL5 and ANKRD9 (PubMed:30293565). Interacts with IMPDH2; leading to ubiquitination of IMPDH2 and its subsequent proteasomal degradation (PubMed:31337707).
Substrate receptor subunit of a cullin-RING superfamily E3 ligase complex (CUL5-based E3 ubiquitin ligase complex) which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:30293565). Depending of the metabolic state of the cell, promotes the proteasomal degradation of IMPDH2, the rate-limiting enzyme in GTP biosynthesis or protects IMPDH2 by stabilizing IMPDH2 filaments assembly (PubMed:30293565, PubMed:31337707). Implicated in different cellular processes, like copper homeostasis and cell proliferation (PubMed:24522796, PubMed:30293565).
Interacts with POU1F1 (PubMed:26612202).
Sequence-specific transcription factor that binds gene promoters and activates their transcription. May play a role in the development of anterior structures, and in particular, the brain and facies and in specifying the identity or structure of hindlimb.
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving the PITX1 locus results in LBNBG. Translocation t(5;18)(q31.1;q12.3). Additionally, two chromosome 5 deletions located 5'of PITX1 have been found in LBNBG patients. These structural variations cause altered expression of PITX1 in the forelimb via the activation of ectopic enhancers (PubMed:23022097).
Outer dense fibers are filamentous structures located on the outside of the axoneme in the midpiece and principal piece of the mammalian sperm tail. May help to maintain the passive elastic structures and elastic recoil of the sperm tail.
(Microbial infection) Interacts with Epstein-Barr virus (EBV) tegument protein BGLF2; this interaction leads to STAT1 dephosphorylation and inhibition.
(Microbial infection) Interacts with HCV core protein; the interaction results in STAT1 degradation.
(Microbial infection) Interacts with Nipah virus P, V and W proteins preventing activation of ISRE and GAS promoter.
(Microbial infection) Interacts with Rabies virus phosphoprotein preventing activation of ISRE and GAS promoter.
(Microbial infection) Interacts with Sendai virus C', C, Y1 and Y2 proteins, preventing activation of ISRE and GAS promoter.
(Microbial infection) Ubiquitinated by Herpes simplex virus 2 E3 ubiquitin ligase ICP22.
Deubiquitinated by USP13; leading to STAT1 stabilization and positive regulation of type I and type II IFN signalings.
Has been shown to be mono-ADP-ribosylated at Glu-657 and Glu-705 by PARP14 which prevents phosphorylation at Tyr-701 (PubMed:27796300). However, the role of ADP-ribosylation in the prevention of phosphorylation has been called into question (PubMed:29858569). It has been suggested that the lack of phosphorylation may be due to sumoylation of Lys-703 (PubMed:29858569).
Isoform alpha homodimerizes upon IFN-gamma induced phosphorylation (PubMed:8605877, PubMed:28753426). Heterodimer with STAT2 upon IFN-alpha/beta induced phosphorylation (PubMed:8605877). The heterodimer STAT1:STAT2 forms the interferon-stimulated gene factor 3 complex (ISGF3) with IRF9 (By similarity). Interacts (phosphorylated at Ser-727) with PIAS1; the interaction results in release of STAT1 from its target gene (PubMed:9724754, PubMed:17897103). Interacts with IFNAR1; the interaction requires the phosphorylation of IFNAR1 at 'Tyr-466' (PubMed:9121453). Interacts with IFNAR2 (PubMed:9121453). Found in a complex with NMI and CREBBP/CBP (PubMed:9989503). Interacts with NMI which is required for CREBBP/CBP recruitment to the complex (PubMed:9989503). Interacts with PTK2/FAK1 (PubMed:11278462). Interacts with SRC (By similarity). Interacts with ERBB4 (phosphorylated) (PubMed:18721752). Interacts with PARP9 and DTX3L independently of IFN-beta or IFN-gamma-mediated STAT1 'Tyr-701' phosphorylation (PubMed:26479788). Interacts with histone acetyltransferase EP300/p300 in response to INF-gamma stimulation (PubMed:16257975, PubMed:26479788). Interacts with OTOP1 (By similarity). Interacts with IFNGR1 (PubMed:8156998). Interacts with STAT4 (PubMed:34508746).
Mono-ADP-ribosylated at Glu-657 and Glu-705 by PARP14; ADP-ribosylation prevents phosphorylation at Tyr-701 (PubMed:27796300). However, the role of ADP-ribosylation in the prevention of phosphorylation has been called into question and the lack of phosphorylation may be due to sumoylation of Lys-703 (PubMed:29858569).
Monomethylated at Lys-525 by SETD2; monomethylation is necessary for phosphorylation at Tyr-701, translocation into the nucleus and activation of the antiviral defense.
Phosphorylated on tyrosine and serine residues in response to a variety of cytokines/growth hormones including IFN-alpha, IFN-gamma, PDGF and EGF (PubMed:28753426, PubMed:26479788). Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus (PubMed:21135090). Upon EGF stimulation, phosphorylation on Tyr-701 (lacking in beta form) by JAK1, JAK2 or TYK2 promotes dimerization and subsequent translocation to the nucleus (PubMed:7657660, PubMed:28753426). Growth hormone (GH) activates STAT1 signaling only via JAK2 (PubMed:7657660). Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:17561467, PubMed:19088846). Phosphorylation on Ser-727 by several kinases including MAPK14, ERK1/2, CAMK2/CAMKII and CK2 in response to IFN-gamma stimulation, is required for maximal transcriptional activity (PubMed:7543024, PubMed:15322115, PubMed:16799645, PubMed:17897103). Phosphorylated on Ser-727 by CAMK2/CAMKII in response to IFN-gamma stimulation and calcium mobilization, promoting activity (PubMed:11972023, PubMed:16257975). Phosphorylated by CAMK2/CAMKII in response to IFN-beta stimulation and calcium mobilization in epithelial cells, promoting activity (PubMed:35568036). Phosphorylation on Ser-727 promotes sumoylation though increasing interaction with PIAS (PubMed:17897103). Phosphorylation on Ser-727 by PRKCD induces apoptosis in response to DNA-damaging agents (PubMed:15322115). Phosphorylated on tyrosine residues when PTK2/FAK1 is activated; most likely this is catalyzed by a SRC family kinase (PubMed:11278462). Dephosphorylation on tyrosine residues by PTPN2 negatively regulates interferon-mediated signaling (PubMed:12138178). Upon viral infection or IFN induction, phosphorylation on Ser-708 occurs much later than phosphorylation on Tyr-701 and is required for the binding of ISGF3 on the ISREs of a subset of IFN-stimulated genes IKBKE-dependent (PubMed:22065572). Phosphorylation at Tyr-701 and Ser-708 are mutually exclusive, phosphorylation at Ser-708 requires previous dephosphorylation of Tyr-701 (PubMed:22065572).
Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors (PubMed:9724754, PubMed:12855578, PubMed:12764129, PubMed:15322115, PubMed:34508746, PubMed:35568036, PubMed:23940278). Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize and associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus (PubMed:28753426, PubMed:35568036). ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of IFN-stimulated genes (ISG), which drive the cell in an antiviral state (PubMed:28753426, PubMed:35568036). In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated (PubMed:26479788). It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state (PubMed:8156998). Becomes activated in response to KITLG/SCF and KIT signaling (PubMed:15526160). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:19088846). Involved in food tolerance in small intestine: associates with the Gasdermin-D, p13 cleavage product (13 kDa GSDMD) and promotes transcription of CIITA, inducing type 1 regulatory T (Tr1) cells in upper small intestine (By similarity).
Sumoylated with SUMO1, SUMO2 and SUMO3. Sumoylation is enhanced by IFN-gamma-induced phosphorylation on Ser-727, and by interaction with PIAS proteins. Enhances the transactivation activity.
The disease is caused by variants affecting the gene represented in this entry. STAT1 mutations in patients with autosomal dominant candidiasis lead to defective responses of type 1 and type 17 helper T-cells, characterized by reduced production of interferon-alpha, interleukin-17, and interleukin-22. These cytokines are crucial for the antifungal defense of skin and mucosa (PubMed:21714643).
The anchoring of this receptor to the plasma membrane is probably mediated by the palmitoylation of a cysteine residue.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in TACR3 as well as in other HH-associated genes including FGFR1, SPRY4 and KAL1 (PubMed:23643382).
This is a receptor for the tachykinin neuropeptide neuromedin-K (neurokinin B). It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: neuromedin-K > substance K > substance P.
Expressed in placenta, gall bladder and colon.
Transports dicarboxylates across the inner membranes of mitochondria by a counter-exchange mechanism (PubMed:11083877). Can transport 2-oxoadipate (2-oxohexanedioate), 2-oxoglutarate, adipate (hexanedioate), glutarate, and to a lesser extent, pimelate (heptanedioate), 2-oxopimelate (2-oxoheptanedioate), 2-aminoadipate (2-aminohexanedioate), oxaloacetate, and citrate (PubMed:11083877). Plays a central role in catabolism of lysine, hydroxylysine, and tryptophan, by transporting common metabolite intermediates (such as 2-oxoadipate) into the mitochondria, where it is converted into acetyl-CoA and can enter the citric acid (TCA) cycle (Probable).
Belongs to the histone-like Alba family.
Component of nuclear RNase P and RNase MRP complexes (PubMed:9630247, PubMed:15096576, PubMed:16723659, PubMed:20215441, PubMed:30454648). RNase P consists of a catalytic RNA moiety and 10 different protein chains; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40 (PubMed:9630247, PubMed:16723659, PubMed:30454648). Within the RNase P complex, POP1, POP7 and RPP25 form the 'finger' subcomplex, POP5, RPP14, RPP40 and homodimeric RPP30 form the 'palm' subcomplex, and RPP21, POP4 and RPP38 form the 'wrist' subcomplex. All subunits of the RNase P complex interact with the catalytic RNA (PubMed:30454648). Several subunits of RNase P are also part of the RNase MRP complex. RNase MRP consists of a catalytic RNA moiety and about 8 protein subunits; POP1, POP7, RPP25, RPP30, RPP38, RPP40 and possibly also POP4 and POP5 (PubMed:15096576, PubMed:16723659, PubMed:28115465). Interacts with SMN1 (PubMed:14715275). POP7 forms a heterodimer with RPP25 that binds to the P3 stem loop of the catalytic RNA (PubMed:15096576, PubMed:20215441, PubMed:29625199).
Component of ribonuclease P, a ribonucleoprotein complex that generates mature tRNA molecules by cleaving their 5'-ends (PubMed:9630247, PubMed:30454648). Also a component of the MRP ribonuclease complex, which cleaves pre-rRNA sequences (PubMed:28115465).
Preferentially expressed in skeletal muscle. Lower levels in pancreas, placenta, and heart.
Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds specifically and non-cooperatively to the Sph and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription. Binds to the M-CAT motif.
Unusual initiator. The initiator methionine is coded by a non-canonical ATA isoleucine codon.
(Microbial infection) Functions as an E3 ligase for ISGylation of hepatitis B virus protein X leading to enhanced viral replication due to increased interferon resistance.
Binds to CCNA1, CCNB1, CCND1 and CCNE1. Interacts with UBE2L6. Interacts with IRF3, this interaction is marginal in resting cells but enhanced upon viral infection. Interacts with influenza A virus NS1.
By IFNB1/IFN-beta. In endothelial cells, by TNF, IL1B/interleukin-1B and by bacterial lipopolysaccharides (LPS), hardly induced in other cells of the vascular wall such as primary smooth muscle cells and fibroblasts. By viral infection.
Expressed in testis and to a lesser degree in brain, ovary and placenta. Found in most tissues at low levels.
Major E3 ligase for ISG15 conjugation (PubMed:27534820, PubMed:34572049, PubMed:37279284). Acts as a positive regulator of innate antiviral response in cells induced by interferon. Functions as part of the ISGylation machinery that recognizes target proteins in a broad and relatively non-specific manner. Catalyzes ISGylation of IRF3 which results in sustained activation, it attenuates IRF3-PIN1 interaction, which antagonizes IRF3 ubiquitination and degradation, and boosts the antiviral response. Mediates ISGylation of the phosphatase PTEN leading to its degradation, thus alleviating its suppression of the PI3K-AKT signaling pathway and promoting the production of cytokines that facilitate bacterial clearance (PubMed:37279284). Interferes with the function of key viral structural proteins such as ebolavirus structural protein VP40 or HIV-1 protein GAG (PubMed:22093708, PubMed:34572049). Catalyzes ISGylation of influenza A viral NS1 which attenuates virulence; ISGylated NS1 fails to form homodimers and thus to interact with its RNA targets. Catalyzes ISGylation of papillomavirus type 16 L1 protein which results in dominant-negative effect on virus infectivity. Physically associated with polyribosomes, broadly modifies newly synthesized proteins in a cotranslational manner. In an interferon-stimulated cell, newly translated viral proteins are primary targets of ISG15. Promotes parkin/PRKN ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation (PubMed:27534820).
Was thought to be a ubiquitin ligase ubiquitinated by UBE2D1, but was confirmed by numerous studies that it's main function is as E3 ISG15 ligase.
involved in nervous system development, important for striatal morphology and motor regulation.
Component of a topoisomerase 6 complex specifically required for meiotic recombination. Together with TOP6BL, mediates DNA cleavage that forms the double-strand breaks (DSB) that initiate meiotic recombination. The complex promotes relaxation of negative and positive supercoiled DNA and DNA decatenation through cleavage and ligation cycles. Essential for the phosphorylation of SMC3, HORMAD1 and HORMAD2.
Heterotetramer of SPO11 and 2 TOP6BL chains. Interacts with TOP6BL.
Interacts with ZW10 and MIS12. Interacts with the NDC80 subunit of the NDC80 complex specifically during mitosis. Also interacts with KNL1, CETN3, DSN1 and PMF1.
Part of the MIS12 complex, which is required for kinetochore formation and spindle checkpoint activity. Required to target ZW10 to the kinetochore at prometaphase.
Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins (By similarity). Can also reduce fatty acid hydroperoxide, cholesterol hydroperoxide and thymine hydroperoxide (By similarity). Plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation (By similarity). Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron-dependent accumulation of lipid reactive oxygen species (PubMed:24439385). The presence of selenocysteine (Sec) versus Cys at the active site is essential for life: it provides resistance to overoxidation and prevents cells against ferroptosis (By similarity). The presence of Sec at the active site is also essential for the survival of a specific type of parvalbumin-positive interneurons, thereby preventing against fatal epileptic seizures (By similarity). May be required to protect cells from the toxicity of ingested lipid hydroperoxides (By similarity). Required for normal sperm development and male fertility (By similarity). Essential for maturation and survival of photoreceptor cells (By similarity). Plays a role in a primary T-cell response to viral and parasitic infection by protecting T-cells from ferroptosis and by supporting T-cell expansion (By similarity). Plays a role of glutathione peroxidase in platelets in the arachidonic acid metabolism (PubMed:11115402). Reduces hydroperoxy ester lipids formed by a 15-lipoxygenase that may play a role as down-regulator of the cellular 15-lipoxygenase pathway (By similarity).
Monomer. Has a tendency to form higher mass oligomers.
Present primarily in testis. Expressed in platelets (at protein level) (PubMed:11115402).
Binds 2 magnesium or manganese ions per subunit.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRB1 sub-subfamily.
Binds UBQLN1 (By similarity). Heteropentamer, formed by a combination of alpha, beta, gamma, delta and rho chains. Interacts with KCTD8, KCTD12 and KCTD16; this interaction determines the pharmacology and kinetics of the receptor response, the KCTD proteins markedly accelerating the GABA-B response, although to different extents (By similarity).
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel.
Absence of the mitochondrial target sequence which may lead to miss-localization.
Belongs to the methylthiotransferase family. MiaB subfamily.
Binds 2 [4Fe-4S] clusters. One cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.
CDK5RAP1 was proposed to act on both nuclear and mitochondrial RNA (PubMed:22422838). However, another study shows that ms2i6A is a mitochondrial tRNA specific modification and is absent from nuclear encoded RNA species, implying that there is no methylthiotransferase activity on nuclear RNA (PubMed:28981754).
Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas (PubMed:10721722). Expressed in neurons of central nervous tissue (PubMed:10721722, PubMed:11882646).
Interacts with CDK5R1 (p35 form). CDK5RAP1, CDK5RAP2 and CDK5RAP3 show competitive binding to CDK5R1. Forms a complex with CDK5R1 and CDK5.
Mainly expressed in brain, placenta and testis.
Methylthiotransferase that catalyzes the conversion of N6-(dimethylallyl)adenosine (i(6)A) to 2-methylthio-N6-(dimethylallyl)adenosine (ms(2)i(6)A) at position 37 (adjacent to the 3'-end of the anticodon) of four mitochondrial DNA-encoded tRNAs (Ser(UCN), Phe, Tyr and Trp) (PubMed:22422838, PubMed:25738458, PubMed:28981754). Essential for efficient and highly accurate protein translation by the ribosome (PubMed:22422838, PubMed:25738458, PubMed:28981754). Specifically inhibits CDK5 activation by CDK5R1 (PubMed:11882646). Essential for efficient mitochondrial protein synthesis and respiratory chain; shows pathological consequences in mitochondrial disease (PubMed:25738458).
Belongs to the glycosyltransferase 25 family.
Beta-galactosyltransferase that transfers beta-galactose to hydroxylysine residues of type I collagen (PubMed:19075007, PubMed:22216269, PubMed:27402836). By acting on collagen glycosylation, facilitates the formation of collagen triple helix (PubMed:27402836). Also involved in the biosynthesis of collagen type IV (PubMed:30412317).
Ubiquitous with higher levels in placenta, heart, lung and spleen.
Homodimer, and heterodimer with NHERF1. Binds PDZK1. Found in a complex with EZR, PODXL and NHERF2 (By similarity). Interacts (via the PDZ domains) with PODXL (via the C-terminal PDZ-binding motif DTHL); interaction is detected in glomerular epithelium cells (By similarity). Binds ADRB2, SLC9A3, P2RY1, P2YR2, SRY, RDX and LPAR2. Interacts with MCC and PODXL. Interacts with SGK1 and KCNJ1/ROMK1. Interacts (via the PDZ domains) with SLC26A6 isoform 4 and isoform 5.
Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3 (PubMed:18829453). May also act as scaffold protein in the nucleus.
Component of ribonucleosomes, which are complexes of at least 20 other different heterogeneous nuclear ribonucleoproteins (hnRNP). hnRNP play an important role in processing of precursor mRNA in the nucleus.
Identified in the spliceosome C complex. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with GTPBP1.
Does not function as a metalloreductase due to the absence of binding sites for the electron-donating substrate NADPH. Promotes Fe(3+) reduction when fused to the NADPH-binding domain of STEAP4.
Ubiquitously expressed. Highly expressed in prostate tumors.
(Microbial infection) Facilitates Dengue virus (DENV) replication, possibly through its action on DDX3X.
(Microbial infection) Facilitates Zika virus (ZIKV) replication, possibly through its action on DDX3X.
(Microbial infection) Facilitates hepatitis C virus (HCV) replication, possibly through its action on DDX3X.
Belongs to the transient receptor (TC 1.A.4) family. TrpV subfamily. TRPV4 sub-subfamily.
Channel activation is inhibited by binding to phosphatidylinositol-4,5-bisphosphate, and to a much lesser degree by phosphatidylinositol-3,4,5-trisphosphate. Not inhibited by phosphatidylinositol-3,4-bisphosphate and phosphatidylinositol-3,5-bisphosphate.
Found in the synoviocytes from patients with (RA) and without (CTR) rheumatoid arthritis (at protein level).
Genetic variations in TRPV4 determine the sodium serum level quantitative trait locus 1 (SSQTL1) [MIM:613508]. In some populations, variant Pro19Ser has been shown to be significantly associated with hyponatremia defined as serum sodium concentration below or equal to 135 mEq/L.
Homotetramer (Probable). Self-associates in an isoform-specific manner (PubMed:16293632). Isoform 1 and isoform 5 can oligomerize, but isoform 2, isoform 4 and isoform 6 cannot oligomerize (PubMed:16293632). Interacts with calmodulin (PubMed:12724311). Interacts with Map7 and Src family Tyr protein kinases LYN, SRC, FYN, HCK, LCK and YES (By similarity). Interacts with CTNNB1 (By similarity). The TRPV4 and CTNNB1 complex can interact with CDH1 (By similarity). Interacts with PACSIN1, PACSIN2 and PACSIN3 (via SH3 domain) (By similarity). Part of a complex containing MLC1, AQP4, HEPACAM and ATP1B1 (PubMed:22328087). Interacts with ITPR3 (PubMed:18826956). Interacts with AQP5; the interaction is probably indirect and regulates TRPV4 activation by hypotonicity (By similarity). Interacts with ANO1 (By similarity). Interacts (via C-terminus) with PKD2 (via C-terminus) (PubMed:18695040). Interacts with DDX3X; this interaction is decreased when the channel is activated (PubMed:29899501).
Lacks channel activity, due to impaired oligomerization and intracellular retention.
Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification (PubMed:18826956, PubMed:18695040, PubMed:29899501). Also activated by heat, low pH, citrate and phorbol esters (PubMed:16293632, PubMed:18826956, PubMed:18695040, PubMed:25256292, PubMed:20037586, PubMed:21964574). Increase of intracellular Ca(2+) potentiates currents. Channel activity seems to be regulated by a calmodulin-dependent mechanism with a negative feedback mechanism (PubMed:12724311, PubMed:18826956). Promotes cell-cell junction formation in skin keratinocytes and plays an important role in the formation and/or maintenance of functional intercellular barriers (By similarity). Acts as a regulator of intracellular Ca(2+) in synoviocytes (PubMed:19759329). Plays an obligatory role as a molecular component in the nonselective cation channel activation induced by 4-alpha-phorbol 12,13-didecanoate and hypotonic stimulation in synoviocytes and also regulates production of IL-8 (PubMed:19759329). Together with PKD2, forms mechano- and thermosensitive channels in cilium (PubMed:18695040). Negatively regulates expression of PPARGC1A, UCP1, oxidative metabolism and respiration in adipocytes (By similarity). Regulates expression of chemokines and cytokines related to pro-inflammatory pathway in adipocytes (By similarity). Together with AQP5, controls regulatory volume decrease in salivary epithelial cells (By similarity). Required for normal development and maintenance of bone and cartilage (PubMed:26249260). In its inactive state, may sequester DDX3X at the plasma membrane. When activated, the interaction between both proteins is affected and DDX3X relocalizes to the nucleus (PubMed:29899501).
Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification. Also activated by phorbol esters. Has the same channel activity as isoform 1, and is activated by the same stimuli.
The ANK repeat region mediates interaction with Ca(2+)-calmodulin and ATP binding (By similarity). The ANK repeat region mediates interaction with phosphatidylinositol-4,5-bisphosphate and related phosphatidylinositides (PubMed:25256292).
Catalytic component of a P4-ATPase flippase complex, which catalyzes the hydrolysis of ATP coupled to the transport of glucosylceramide (GlcCer) from the outer to the inner leaflet of the plasma membrane.
Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit ATP10A and an accessory beta subunit TMEM30A.
Expressed in placenta and, to a lesser extent, in kidney.
Functions as a heterodimeric glycoprotein hormone with GPHA2 able to bind and activate the thyroid-stimulating hormone receptor (TSHR), leading to increased cAMP production. Plays a central role in controlling thyroid cell metabolism.
Heterodimer with GPHA2; this heterodimer interacts with thyroid-stimulating hormone receptor (TSHR), and hence stimulates cAMP production.
Highly expressed in brain and at low levels in pituitary. Also found in retina, testis and skin but not in pancreas, parotid, kidney, stomach, liver, colon, small intestine, thyroid, brain or adrenal gland. In pituitary, colocalizes with ACTH, suggesting that it is located in corticotrophs.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Epsilon/CHRNE sub-subfamily.
Pentamer of two alpha chains, and one each of the beta, delta, and gamma (in immature muscle) or epsilon (in mature muscle) chains. The muscle heteropentamer composed of alpha-1, beta-1, delta, epsilon subunits interacts with the alpha-conotoxin ImII (PubMed:15609996).
The muscle AChR is the major target antigen in the autoimmune disease myasthenia gravis. Myasthenia gravis is characterized by sporadic muscular fatigability and weakness, occurring chiefly in muscles innervated by cranial nerves, and characteristically improved by cholinesterase-inhibiting drugs.
Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) and O4-methylthymine (O4-MeT) in DNA. Repairs the methylated nucleobase in DNA by stoichiometrically transferring the methyl group to a cysteine residue in the enzyme. This is a suicide reaction: the enzyme is irreversibly inactivated.
This enzyme catalyzes only one turnover and therefore is not strictly catalytic. According to one definition, an enzyme is a biocatalyst that acts repeatedly and over many reaction cycles.
Belongs to the calcium channel subunit alpha-2/delta family.
Binds gabapentin, an antiepileptic drug.
Dimer formed of alpha-2-2 and delta-2 chains; disulfide-linked. Voltage-dependent calcium channels are multisubunit complexes, consisting of alpha-1 (CACNA1), alpha-2 (CACNA2D), beta (CACNB) and delta (CACNA2D) subunits in a 1:1:1:1 ratio (By similarity).
May be proteolytically processed into subunits alpha-2-2 and delta-2 that are disulfide-linked. It is however unclear whether such cleavage really takes place in vivo and has a functional role (By similarity).
Predominantly present in cerebellar cortex. Present in various lung tumor cell lines, while it is absent in normal lung (at protein level). Highly expressed in heart, lung, testis, pancreas and skeletal muscle. Also expressed in kidney, liver, placenta and brain.
The MIDAS-like motif in the VWFA domain binds divalent metal cations and is required to promote trafficking of the alpha-1 (CACNA1) subunit to the plasma membrane by an integrin-like switch.
The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-type calcium channel (CACNA1A), N-type (CACNA1B), L-type (CACNA1C OR CACNA1D) and possibly T-type (CACNA1G) (PubMed:15111129, PubMed:23339110). Overexpression induces apoptosis.
Interacts (via the homeobox) with NRL (via the leucine-zipper domain). Interacts with PDC, RAX2, RORB and SCA7.
Transcription factor that binds and transactivates the sequence 5'-TAATC[CA]-3' which is found upstream of several photoreceptor-specific genes, including the opsin genes. Acts synergistically with other transcription factors, such as NRL, RORB and RAX, to regulate photoreceptor cell-specific gene transcription. Essential for the maintenance of mammalian photoreceptors.
By bacterial infection and by IFNG/IFN-gamma.
Exhibits antimicrobial activity against Gram-positive bacteria S.aureus and S.pyogenes, Gram-negative bacteria P.aeruginosa and E.coli and the yeast C.albicans. Kills multiresistant S.aureus and vancomycin-resistant E.faecium. No significant hemolytic activity was observed.
Highly expressed in skin and tonsils, and to a lesser extent in trachea, uterus, kidney, thymus, adenoid, pharynx and tongue. Low expression in salivary gland, bone marrow, colon, stomach, polyp and larynx. No expression in small intestine.
In 23-week-old embryo found in epithelial podocytes of the periphery of mature and developing glomeruli.
Interacts with CD2AP (via C-terminal domain). Interacts with MAGI1 (via PDZ 2 and 3 domains) forming a tripartite complex with IGSF5/JAM4. Interacts with DDN; the interaction is direct. Self-associates (via the Ig-like domains). Also interacts (via the Ig-like domains) with KIRREL1/NEPH1 and KIRREL2; the interaction with KIRREL1 is dependent on KIRREL1 glycosylation. Interacts with KIRREL3. Forms a complex with ACTN4, CASK, IQGAP1, MAGI2, SPTAN1 and SPTBN1 (By similarity). Interacts with NPHS2 (PubMed:11562357). Interacts with phosphatidylinositol 3-kinase regulatory subunit PIK3R1; the interaction is reduced by high glucose levels (PubMed:28955049).
Phosphorylated at Tyr-1193 by FYN, leading to the recruitment and activation of phospholipase C-gamma-1/PLCG1 (By similarity). Tyrosine phosphorylation is reduced by high glucose levels (PubMed:28955049). Dephosphorylated by tensin TNS2 which leads to reduced binding of NPHN1 to PIK3R1 (PubMed:28955049).
Seems to play a role in the development or function of the kidney glomerular filtration barrier. Regulates glomerular vascular permeability. May anchor the podocyte slit diaphragm to the actin cytoskeleton. Plays a role in skeletal muscle formation through regulation of myoblast fusion (By similarity).
Specifically expressed in podocytes of kidney glomeruli.
Interacts with (symmetrically methylated) PIWIL1, PIWIL2 and PIWIL4.
Participates in the primary piRNA biogenesis pathway and is required during spermatogenesis to repress transposable elements and prevent their mobilization, which is essential for the germline integrity. The piRNA metabolic process mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons. Required for the final steps of primary piRNA biogenesis by participating in the processing of 31-37 nt intermediates into mature piRNAs. May act in pi-bodies and piP-bodies by transferring piRNA precursors or intermediates to or between these granules.
Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form (PubMed:9034191). Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein (PubMed:12441351). Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT) (PubMed:24226769). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain (By similarity). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R, leading to the release of secreted form of IL6R (PubMed:26876177, PubMed:28060820). Mediates the proteolytic cleavage and shedding of FCGR3A upon NK cell stimulation, a mechanism that allows for increased NK cell motility and detachment from opsonized target cells.
Interacts with MAD2L1, MAPK14 and MUC1 (PubMed:12441351, PubMed:20188673). Interacts with iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333). Interacts with FRMD8 via its interaction with iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333).
Must be membrane anchored to cleave the different substrates. The cytoplasmic domain is not required for the this activity. Only the catalytic domain is essential to shed TNF and p75 TNFR (By similarity).
Phosphorylated. Stimulation by growth factor or phorbol 12-myristate 13-acetate induces phosphorylation of Ser-819 but decreases phosphorylation of Ser-791. Phosphorylation at Thr-735 by MAPK14 is required for ADAM17-mediated ectodomain shedding.
Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney. Expressed in natural killer cells (at protein level) (PubMed:24337742).
As a member of the subcortical maternal complex (SCMC), plays an essential role for zygotes to progress beyond the first embryonic cell divisions via regulation of actin dynamics (By similarity). Required for the formation of F-actin cytoplasmic lattices (CPL) in oocytes, which in turn are responsible for symmetric division of zygotes via the regulation of mitotic spindle formation and positioning (By similarity). Required for the localization of cortical granules to the cortex of oocytes, via association with the cortical actin scaffold (By similarity). Required for cortical actin clearance prior to oocyte exocytosis (By similarity). Involved in regulating post-fertilization Ca(2+) release and endoplasmic reticulum (ER) storage via regulation of ER localization (By similarity). May be involved in the localization of mitochondria to the cytoplasm and perinuclear region in oocytes and early stage embryos, independent of its role in CPL formation (By similarity).
Component of the subcortical maternal complex (SCMC), at least composed of NLRP5, KHDC3, OOEP, and TLE6 isoform 1 (PubMed:25542835). Within the complex, interacts with OOEP, KHDC3L and TLE6 (PubMed:25542835). The SCMC may facilitate translocation of its components between the nuclear and cytoplasmic compartments (PubMed:25542835). As part of the SCMC interacts with the SCMC-associated protein ZBED3 (By similarity). As part of the SCMC interacts with the SCMC-associated protein CFL1/Cofilin-1 (By similarity). Interacts with PRKCE (PubMed:19542546). Interacts with TUBB3 at cytoskeleton microtubules (PubMed:24374158).
Expressed at all stages during oocyte maturation, additionally expressed in granulosa cells and cumulus oophorus cells (PubMed:19192343). Expressed primarily with other SCMC components in the subcortex of oocytes and early embryos (PubMed:25542835). Expression is excluded from cell-cell contact regions after the 2-cell stage (PubMed:25542835).
Expressed in cumulus cells (at protein level) (PubMed:19542546). Highly abundant in oocytes and early embryos, however poorly expressed in somatic tissues such as the liver and spinal cord (PubMed:11925379, PubMed:30877238).
NLRP5 variants have been found in a spectrum of phenotypes characterized by aberrant methylation of multiple imprinted loci, a condition known as multi-locus imprinting defect or multi-locus imprinting disturbance (MLID). MLID-related phenotype spectrum ranges from intrauterine death to different types of imprinting disorders, including Beckwith-Wiedemann syndrome (BWS), Silver-Russell syndrome (SRS), and non-specific developmental and behavioral manifestations. MLID has also been observed in individuals without overt clinical manifestations. Recurrent pregnancy loss has been reported in healthy women carrying NLRP5 variants.
According to a report, AIM2 is autoinhibited in absence of double-stranded DNA (dsDNA) due to an interaction between the pyrin and HIN-200 domains that induce a closed conformation (PubMed:22483801). However, it was later shown that AIM2 is not autoinhibited and that dsDNA acts as a molecular ruler to promote its homooligomerization (PubMed:26197926).
Also acts as a tumor suppressor independently of its role in inflammatory response (PubMed:16432157). Able to suppress overt cell proliferation in enterocytes: restricts stem cell proliferation in the intestinal mucosa in an inflammasome-independent manner, contributing to a decrease in the likelihood of colorectal cancer development (By similarity). AIM2 suppresses cell proliferation by inhibiting phosphorylation of AKT1 at 'Ser-473', preventing AKT1 activation and AKT-mTOR signaling pathway (By similarity). Inhibits AKT1 phosphorylation both by inhibiting the activity of PRKDC/DNA-PK kinase and promoting dephosphorylation by PP2A phosphatase (By similarity). Also acts as a key regulator of regulatory T-cells (Treg) homeostasis by promoting their stability: acts by preventing AKT1 activation (By similarity). Its role in Treg homeostasis is important to restain autoimmune diseases (By similarity).
Defects in AIM2 may be a cause of microsatellite unstable colon cancers.
Degraded via selective autophagy following interaction with TRIM11.
Expressed in spleen, small intestine, peripheral blood leukocytes, and testis.
Inactive in absence of double-stranded DNA (dsDNA) (PubMed:26197926, PubMed:22483801). Homooligomerizes upon binding to dsDNA, dsDNA serving as an oligomerization platform (PubMed:26197926, PubMed:33980849). AIM2 requires large dsDNA to generate a structural template that couples dsDNA ligand-binding and homooligomerization (PubMed:26197926). Homooligomerization is followed by recruitment of PYCARD/ASC to initiate speck formation (nucleation) (PubMed:26197926, PubMed:29440442, PubMed:22483801, PubMed:33980849). AIM2 and PYCARD/ASC homooligomer filaments assemble bidirectionally and the recognition between AIM2 and PYCARD/ASC oligomers occurs in a head-to-tail manner (PubMed:33980849). Clustered PYCARD/ASC nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization and activation (PubMed:19158675, PubMed:19158676). Active CASP1 then specifically processes protein precursors, such as gasdermin-D (GSDMD), IL1B and IL18, leading to the release of mature cytokines in the extracellular milieu or pyroptosis, depending on cell type (PubMed:16432157, PubMed:19158676, PubMed:19158675). AIM2 can be activated in response to events that cause genomic DNA (HIV protease inhibitor nelfinavir) or mitochondrial DNA release in the cytoplasm (such as Perfluoroalkyl substance pollutants or cholesterol overload) (By similarity). Activation of the AIM2 inflammasome is inhibited by isoform IFI16-beta of IFI16, which prevents the interaction between AIM2 and PYCARD/ASC (PubMed:30104205). Activation of the AIM2 inflammasome is inhibited by TRIM11, which promotes autophagy-dependent degradation of AIM2 (PubMed:27498865).
Self-associates; forms homooligomers in response to cytosolic double-stranded DNA (dsDNA) and the dsDNA seems to serve as oligomerization platform (PubMed:15582594, PubMed:19158676, PubMed:26197926, PubMed:29440442, PubMed:24406744, PubMed:26583071, PubMed:33980849). Component of AIM2 inflammasome, which consists of a signal sensor component (AIM2), an adapter (PYCARD/ASC), which recruits an effector pro-inflammatory caspase (CASP1) (PubMed:22869553, PubMed:22483801, PubMed:33980849). Interacts (via pyrin domain) with PYCARD/ASC (via pyrin domain); interaction is direct (PubMed:19158675, PubMed:19158679, PubMed:29440442, PubMed:23530044, PubMed:33980849). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity). Interacts with PYDC5; disrupts assembly of the AIM2 inflammasome complex (PubMed:24531343). Interacts with EIF2AK2/PKR (PubMed:22801494). Interacts with MAPRE1 (PubMed:22869553). Interacts with IFI16 (PubMed:22046441). Interacts with isoform IFI16-beta of IFI16; preventing the interaction between AIM2 and PYCARD/ASC (PubMed:30104205). Interacts with RACK1; promoting association with PP2A phosphatase and dephosphorylation of AKT1 (By similarity). Interacts with TRIM11; promoting AIM2 recruitment to autophagosomes and autophagy-dependent degradation (PubMed:27498865).
Sensor component of the AIM2 inflammasome, which mediates inflammasome activation in response to the presence of double-stranded DNA (dsDNA) in the cytosol, leading to subsequent pyroptosis (PubMed:17726700, PubMed:19158675, PubMed:19158676, PubMed:19158679, PubMed:20566831, PubMed:26197926, PubMed:29440442, PubMed:23530044, PubMed:26583071, PubMed:33980849). Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (PubMed:17726700, PubMed:19158675, PubMed:19158676, PubMed:19158679, PubMed:20566831, PubMed:26197926, PubMed:29440442, PubMed:33980849). Acts as a recognition receptor (PRR): specifically recognizes and binds dsDNA in the cytosol, and mediates the formation of the inflammasome polymeric complex composed of AIM2, CASP1 and PYCARD/ASC (PubMed:17726700, PubMed:19158675, PubMed:19158676, PubMed:19158679, PubMed:20566831, PubMed:26197926, PubMed:29440442, PubMed:33980849). Recruitment of pro-caspase-1 (proCASP1) to the AIM2 inflammasome promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), promoting cytokine secretion (PubMed:17726700, PubMed:19158675, PubMed:19158676, PubMed:19158679, PubMed:20566831). In some cells, CASP1 activation mediates cleavage and activation of GSDMD, triggering pyroptosis without promoting cytokine secretion (PubMed:19158675, PubMed:19158676). Detects cytosolic dsDNA of viral and bacterial origin in a non-sequence-specific manner (PubMed:17726700, PubMed:19158675, PubMed:19158676, PubMed:19158679, PubMed:20566831, PubMed:26197926, PubMed:29440442, PubMed:26583071, PubMed:33980849). Involved in the DNA damage response caused by acute ionizing radiation by mediating pyroptosis of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks (By similarity). Mechanistically, AIM2 senses DNA damage in the nucleus to mediate inflammasome assembly and inflammatory cell death (By similarity). Also acts as a regulator of neurodevelopment via its role in the DNA damage response: acts by promoting neural cell death in response to DNA damage in the developing brain, thereby purging genetically compromised cells of the central nervous system (By similarity). Pyroptosis mediated by the AIM2 inflammasome in response to DNA damage is dependent on GSDMD without involving IL1B and IL18 cytokine secretion (By similarity). Also acts as a mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an integral part of host defense against pathogens, in response to bacterial infection (By similarity). Can also trigger PYCARD/ASC-dependent, caspase-1-independent cell death that involves caspase-8 (CASP8) (By similarity).
The HIN-200 domain mediates dsDNA binding via electrostatic interactions.
The pyrin domain mediates homotypic interaction with PYCARD/ASC (PubMed:19158676, PubMed:19158675).
A mutation in COL6A1 is the cause of autosomal recessive limb-girdle muscular dystrophy. The affected individual with a homozygous recessive COL6A1 mutation showed progressive muscle weakness with an onset at the age of 4 years and loss of ambulation at the age of 15 years. Muscle biopsy showed end stage dystrophy.
Collagen VI acts as a cell-binding protein.
Trimers composed of three different chains: alpha-1(VI), alpha-2(VI), and alpha-3(VI) or alpha-5(VI) or alpha-6(VI).
Interacts with TSSK2. Interacts with HSP90; this interaction stabilizes TSSK1 (By similarity).
Kinase activity is specifically inhibited by 2 classes of compounds: biphenyl compounds (1,1'-(biphenyl-4,4'-diyl)bis(2,2-dihydroxyethanone)) and 1,2,7-trialky-1H-imidazo[4,5-g]quinoxalin-6-one. Activated by phosphorylation on Thr-174 and potentially by autophosphorylation.
TSSK1B might be used as a target for male contraception or and intra-vaginal spermicides.
Testis-specific serine/threonine-protein kinase required during spermatid development. Phosphorylates 'Ser-288' of TSKS. Involved in the late stages of spermatogenesis, during the reconstruction of the cytoplasm. During spermatogenesis, required for the transformation of a ring-shaped structure around the base of the flagellum originating from the chromatoid body.
Testis-specific. Present in sperm (at protein level).
Ubiquitinated; HSP90 activity negatively regulates ubiquitination and degradation.
Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly.
Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, the core components of this complex being COA3/MITRAC12 and COX14. Interacts with COA3.
Expressed in the fetus (at protein level).
Actin stress fibers-associated protein that activates non-muscle myosin IIa. Activates the non-muscle myosin IIa complex by promoting the phosphorylation of its regulatory subunit MRLC/MYL9. Through the activation of non-muscle myosin IIa, positively regulates actin stress fibers assembly and stabilizes focal adhesions. It therefore negatively regulates cell spreading and cell migration.
Interacts with MYH9; independently of the integration of MYH9 into the myosin complex.
Binding of Ca(2+) triggers a conformation change that is essential for catalytic activity.
Catalyzes the deimination of arginine residues of proteins.
Detected in keratinocytes in epidermis (at protein level).
Highly expressed in brain, spleen and peripheral blood leukocytes.
Probable sugar transporter that acts as a regulator of glycolysis in macrophages (Probable). Does not transport glucose (PubMed:30431159).
Was initially thought to act as a glucose transporter (PubMed:10970791). However, later studies demonstrated that it does not transport glucose (PubMed:30431159).
Was named GLUT9 by a report, but this gene name has already been used for SLC2A9.
Interacts with DLG4 and DLGAP1 and forms a ternary complex.
May sustain the structure of the postsynaptic density (PSD).
Homodimer and heterodimer (PubMed:15683364). Able to interact with SPRED2 to form heterodimers (PubMed:15683364). Interacts (via C-terminus) with TAOK1/MARKK (via C-terminus); the interaction does not affect TAOK1 kinase activity (PubMed:18216281). Interacts (via C-terminus) with TESK1 (via C-terminus); the interaction inhibits TESK1 kinase activity (PubMed:18216281). Interacts with CAV1 (PubMed:16115197). Interacts with RAS (By similarity). Interacts with palmitoyltransferase ZDHHC17/HIP14; the interaction leads to palmitoylation of SPRED1 (PubMed:24705354).
Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase (By similarity). Negatively regulates hematopoiesis of bone marrow (By similarity). Inhibits fibroblast growth factor (FGF)-induced retinal lens fiber differentiation, probably by inhibiting FGF-mediated phosphorylation of ERK1/2 (By similarity). Attenuates actin stress fiber formation via inhibition of TESK1-mediated phosphorylation of cofilin (PubMed:18216281). Inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells (By similarity).
Weakly expressed in embryonic cell line HEK293.
Expressed in skeletal and cardiac muscle and brain.
Interacts with HDAC7 (By similarity). Heterodimer. Interacts with HDAC9.
Transcriptional activator which binds specifically to the MEF2 element, 5'-YTA[AT](4)TAR-3', found in numerous muscle-specific genes. Activates transcription via this element. May be involved in muscle-specific and/or growth factor-related transcription.
Hydrolyzes ADP-ribose, IDP-ribose, CDP-glycerol, CDP-choline and CDP-ethanolamine, but not other non-reducing ADP-sugars or CDP-glucose. May be involved in immune cell signaling as suggested by the second-messenger role of ADP-ribose, which activates TRPM2 as a mediator of oxidative/nitrosative stress (By similarity).
Found in a complex with at least ARL2, PPP2CB; PPP2R1A, PPP2R2A, PPP2R5E and TBCD (By similarity). PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with SGO1.
May be involved in the negative control of osteogenic differentiation of osteochondrogenic precursor cells in peripheral zones of fetal cartilage and at the cartilage-bone interface.
Predominantly expressed in resting chondrocytes.
Proteolytically cleaved by a furin-like convertase to generate a persistent C-terminal fragment found in almost the entire cartilage matrix, and affecting osteoblast differentiation.
Available under the name Actimmune (Genentech). Used for reducing the frequency and severity of serious infections associated with chronic granulomatous disease (CGD).
Belongs to the type II (or gamma) interferon family.
By cytokines, most notably interleukin IL-12, secreted by professional antigen-presenting cells such as monocytes/macrophages and dendritic cells.
Homodimer (PubMed:1902591). Interacts with IFNGR1 (via extracellular domain); this interaction promotes IFNGR1 dimerization (PubMed:8349687).
Proteolytic processing produces C-terminal heterogeneity, with proteins ending alternatively at Gly-150, Met-157 or Gly-161.
Released primarily from activated T lymphocytes.
Type II interferon produced by immune cells such as T-cells and NK cells that plays crucial roles in antimicrobial, antiviral, and antitumor responses by activating effector immune cells and enhancing antigen presentation (PubMed:16914093, PubMed:8666937). Primarily signals through the JAK-STAT pathway after interaction with its receptor IFNGR1 to affect gene regulation (PubMed:8349687). Upon IFNG binding, IFNGR1 intracellular domain opens out to allow association of downstream signaling components JAK2, JAK1 and STAT1, leading to STAT1 activation, nuclear translocation and transcription of IFNG-regulated genes. Many of the induced genes are transcription factors such as IRF1 that are able to further drive regulation of a next wave of transcription (PubMed:16914093). Plays a role in class I antigen presentation pathway by inducing a replacement of catalytic proteasome subunits with immunoproteasome subunits (PubMed:8666937). In turn, increases the quantity, quality, and repertoire of peptides for class I MHC loading (PubMed:8163024). Increases the efficiency of peptide generation also by inducing the expression of activator PA28 that associates with the proteasome and alters its proteolytic cleavage preference (PubMed:11112687). Up-regulates as well MHC II complexes on the cell surface by promoting expression of several key molecules such as cathepsins B/CTSB, H/CTSH, and L/CTSL (PubMed:7729559). Participates in the regulation of hematopoietic stem cells during development and under homeostatic conditions by affecting their development, quiescence, and differentiation (By similarity).
Type II interferon produced by immune cells such as T-cells and NK cells that plays crucial roles in antimicrobial, antiviral, and antitumor responses by activating effector immune cells and enhancing antigen presentation. Primarily signals through the JAK-STAT pathway after interaction with its receptor IFNGR1 to affect gene regulation. Upon IFNG binding, IFNGR1 intracellular domain opens out to allow association of downstream signaling components JAK2, JAK1 and STAT1, leading to STAT1 activation, nuclear translocation and transcription of IFNG-regulated genes. Many of the induced genes are transcription factors such as IRF1 that are able to further drive regulation of a next wave of transcription. Plays a role in class I antigen presentation pathway by inducing a replacement of catalytic proteasome subunits with immunoproteasome subunits. In turn, increases the quantity, quality, and repertoire of peptides for class I MHC loading. Increases the efficiency of peptide generation also by inducing the expression of activator PA28 that associates with the proteasome and alters its proteolytic cleavage preference. Up-regulates as well MHC II complexes on the cell surface by promoting expression of several key molecules such as cathepsins B/CTSB, H/CTSH, and L/CTSL. Participates in the regulation of hematopoietic stem cells during development and under homeostatic conditions by affecting their development, quiescence, and differentiation.
(Microbial infection) Interacts with Hantaan hantavirus glycoprotein N; this interaction contributes to the virus-induced degradation of mitochondria by autophagy, which leads to degradation of MAVS and inhibition of type I interferon (IFN) responses.
(Microbial infection) Interacts with human parainfluenza virus 3 matrix protein; this interaction inhibits RLR-mediated type I interferon production while promoting autophagy.
Interacts with NLRX1 (PubMed:22749352). Interacts with ATG16L1 (PubMed:22749352).
Promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis. Also plays a role in the regulation of autophagy and innate immunity. Recruits ATG5-ATG12 and NLRX1 at mitochondria and serves as a checkpoint of the RIGI-MAVS pathway. In turn, inhibits RLR-mediated type I interferon while promoting autophagy.
This protein promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis.
Isoform 1 is detected in testis. Isoform 4 is detected in testis and brain, and at lower levels in kidney, heart, pancreas, thyroid, ovary, adrenal gland, spinal cord, trachea and liver.
Necessary for sperm flagellar function. Plays a role in motile ciliogenesis. May help to recruit STK36 to the cilium or apical surface of the cell to initiate subsequent steps of construction of the central pair apparatus of motile cilia (By similarity).
Frontal cortex, hippocampus, hypothalamus, pons and liver.
Interacts with C3 (the anaphylatoxin peptide C3a and the adipogenic hormone ASP); the interaction occurs with higher affinity for ASP, enhancing the phosphorylation and activation of GPR77, recruitment of ARRB2 to the cell surface and endocytosis of GRP77.
Receptor for the chemotactic and inflammatory C3a, C4a and C5a anaphylatoxin peptides and also for their dearginated forms ASP/C3adesArg, C4adesArg and C5adesArg respectively. Couples weakly to G(i)-mediated signaling pathways.
Forms a complex with RGP1; the interaction enhances RAB6A GTPase activity (PubMed:16112082). Interacts (via central domain) with RGP1 (PubMed:16112082). Interacts with RAB6A; the interaction is direct with a preference for RAB6A-GDP (PubMed:16112082). Interacts (via C-terminus domain) with RAB33B; the interaction is direct with a preference for RAB33B-GTP (PubMed:16112082). Interacts with GJA1 (PubMed:23091056).
Present in kidney and various cell lines (at protein level). Widely expressed at low level.
The RIC1-RGP1 complex acts as a guanine nucleotide exchange factor (GEF), which activates RAB6A by exchanging bound GDP for free GTP, and may thereby be required for efficient fusion of endosome-derived vesicles with the Golgi compartment (PubMed:23091056). The RIC1-RGP1 complex participates in the recycling of mannose-6-phosphate receptors (PubMed:23091056). Required for phosphorylation and localization of GJA1 (PubMed:16112082). Is a regulator of procollagen transport and secretion, and is required for correct cartilage morphogenesis and development of the craniofacial skeleton (PubMed:31932796).
Interacts with UBTF and PIK3CA (By similarity). Interacts (via phosphorylated YXXM motifs) with PIK3R1 (By similarity). Interacts with ROCK1 and FER (By similarity). Interacts (via PH domain) with PHIP (By similarity). Interacts with GRB2 (By similarity). Interacts with SOCS7 (PubMed:16127460). Interacts (via IRS-type PTB domain) with IGF1R and INSR (via the tyrosine-phosphorylated NPXY motif) (PubMed:7541045, PubMed:7559478, PubMed:7537849). Interacts with ALK (PubMed:15226403, PubMed:16878150). Interacts with EIF2AK2/PKR (By similarity). Interacts with GKAP1 (By similarity). Interacts with DGKZ in the absence of insulin; insulin stimulation decreases this interaction (By similarity). Found in a ternary complex with DGKZ and PIP5K1A in the absence of insulin stimulation (By similarity). Interacts with SQSTM1; the interaction is disrupted by the presence of tensin TNS2 (PubMed:25101860).
May mediate the control of various cellular processes by insulin. When phosphorylated by the insulin receptor binds specifically to various cellular proteins containing SH2 domains such as phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit (By similarity).
Serine phosphorylation of IRS1 is a mechanism for insulin resistance. Ser-312 phosphorylation inhibits insulin action through disruption of IRS1 interaction with the insulin receptor (By similarity). Phosphorylation of Tyr-896 is required for GRB2-binding (By similarity). Phosphorylated by ALK. Phosphorylated at Ser-270, Ser-307, Ser-636 and Ser-1101 by RPS6KB1; phosphorylation induces accelerated degradation of IRS1 (PubMed:18952604). Phosphorylated on tyrosine residues in response to insulin (PubMed:23401856). In skeletal muscles, dephosphorylated on Tyr-612 by TNS2 under anabolic conditions; dephosphorylation results in the proteasomal degradation of IRS1 (PubMed:23401856).
The Arg-971 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, and glycogen synthesis by affecting the PI3K/AKT1/GSK3 signaling pathway. The polymorphism at Arg-971 may contribute to the in vivo insulin resistance observed in carriers of this variant. Arg-971 could contribute to the risk for atherosclerotic cardiovascular diseases associated with non-insulin-dependent diabetes mellitus (NIDDM) by producing a cluster of insulin resistance-related metabolic abnormalities. In insulin-stimulated human endothelial cells from carriers of the Arg-971 polymorphism, genetic impairment of the IRS1/PI3K/PDPK1/AKT1 insulin signaling cascade results in impaired insulin-stimulated nitric oxide (NO) release and suggested that this may be a mechanism through which the Arg-971 polymorphism contributes to the genetic predisposition to develop endothelial dysfunction and cardiovascular disease. The Arg-971 polymorphism not only reduces phosphorylation of the substrate but allows IRS1 to act as an inhibitor of PI3K, producing global insulin resistance.
Ubiquitinated by the Cul7-RING(FBXW8) complex in a mTOR-dependent manner, leading to its degradation: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2).
Component of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex composed at least by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2 (PubMed:16162815). Interacts directly with PIGA and PIGQ (PubMed:10944123).
Belongs to the zinc-containing alcohol dehydrogenase family. Quinone oxidoreductase subfamily.
Catalyzes the NADPH-dependent reduction of quinones (PubMed:19349281). Exhibits a low enzymatic activity with beta-naphthoquinones, with a strong preference for the ortho-quinone isomer (1,2-beta-naphthoquinone) over the para isomer (1,4-beta-naphthoquinone). Also displays a low reductase activity for non-quinone compounds such as diamine and 2,6-dichloroindophenol (in vitro) (PubMed:19349281). Involved in the generation of reactive oxygen species (ROS) (PubMed:19349281).
Isoform 1 and isoform 2 are both activated by p53/TP53, doxorubicin, etoposide and ionizing radiation. Isoform 2 is highly activated by UV radiation.
Major isoform under UV light exposure. Undergoes rapid proteolytic degradation by the proteasome.
Major isoform under normal light conditions.
Forms homooligomers and, to a much smaller extent, heterooligomers with DDHD1.
It is uncertain whether Met-1 or Met-31 is the initiator.
Phospholipase that hydrolyzes preferentially phosphatidic acid, including 1,2-dioleoyl-sn-phosphatidic acid, and phosphatidylethanolamine. Specifically binds to phosphatidylinositol 3-phosphate (PI(3)P), phosphatidylinositol 4-phosphate (PI(4)P), phosphatidylinositol 5-phosphate (PI(5)P) and possibly phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). May be involved in the maintenance of the endoplasmic reticulum and/or Golgi structures. May regulate the transport between Golgi apparatus and plasma membrane.
SAM and DDHD domains together are required for phospholipid binding.
Belongs to the helicase family. RecQ subfamily.
DNA helicase that plays an important role in DNA replication, transcription and repair (PubMed:20643585, PubMed:22973052). Binds to the RNA polymerase II subunit POLR2A during transcription elongation and suppresses transcription-associated genomic instability (PubMed:20231364). Associates also with POLR1A and enforces the stability of ribosomal DNA arrays (PubMed:27502483). Plays an important role in mitotic chromosome separation after cross-over events and cell cycle progress (PubMed:22013166). Mechanistically, removes RAD51 filaments protecting stalled replication forks at common fragile sites and stimulates MUS81-EME1 endonuclease leading to mitotic DNA synthesis (PubMed:28575661). Required for efficient DNA repair, including repair of inter-strand cross-links (PubMed:23715498). Stimulates DNA decatenation mediated by TOP2A. Prevents sister chromatid exchange and homologous recombination.
Monomer. Interacts with TOP2A, TOP3A and TOP3B (PubMed:20231364, PubMed:10710432). Isoform beta interacts with RNA polymerase II subunit POLR2A (PubMed:20348101, PubMed:20231364, PubMed:23748380). Identified in a complex with the RNA polymerase II core bound to DNA (PubMed:20348101, PubMed:20231364). Interacts (via C-terminus) with POLR1A (PubMed:27502483). Isoform beta interacts with RAD51 (PubMed:20348101, PubMed:20231364). Interacts with WRN; this interaction stimulates WRN helicase activity on DNA fork duplexes (PubMed:23180761). Interacts with MUS1; this interaction promotes MUS81-dependent mitotic DNA synthesis (PubMed:28575661).
Phosphorylated by CDK1 at Ser-727; this phosphorylation is required for RECQL5-mediated disruption of RAD51 filaments on stalled replication forks.
Located in the 'azoospermia factor a' (AZFa) region on chromosome Y which is deleted in Sertoli cell-only syndrome. This is an infertility disorder in which no germ cells are visible in seminiferous tubules leading to azoospermia.
Probable ATP-dependent RNA helicase. During immune response, may enhance IFNB1 expression via IRF3/IRF7 pathway (By similarity).
Widely expressed at the mRNA level, with highest levels in testis (PubMed:9381176). Testis-specific (at protein level). Expressed predominantly in spermatogonia, but occasionally detected in some pre-leptotene/leptotene spermatocytes (PubMed:15294876).
Belongs to the major facilitator superfamily. Sodium/anion cotransporter family. VGLUT subfamily.
Expressed in amygdala, cerebellum, hippocampus, medulla, spinal cord and thalamus.
Multifunctional transporter that transports L-glutamate as well as multiple ions such as chloride, sodium and phosphate (PubMed:33440152, PubMed:12151341). At the synaptic vesicle membrane, mainly functions as an uniporter that mediates the uptake of L-glutamate into synaptic vesicles at presynaptic nerve terminals of excitatory neural cells (PubMed:12151341). The L-glutamate uniporter activity is electrogenic and is driven by the proton electrochemical gradient, mainly by the electrical gradient established by the vacuolar H(+)-ATPase across the synaptic vesicle membrane (PubMed:12151341). In addition, functions as a chloride channel that allows a chloride permeation through the synaptic vesicle membrane that affects the proton electrochemical gradient and promotes synaptic vesicles acidification (By similarity). At the plasma membrane, following exocytosis, functions as a symporter of Na(+) and phosphate from the extracellular space to the cytoplasm allowing synaptic phosphate homeostasis regulation (Probable). The symporter activity is electrogenic (PubMed:33440152). Moreover, operates synergistically with SLC18A3/VACHT under a constant H(+) gradient, thereby allowing striatal vesicular acetylcholine uptake (By similarity).
The L-glutamate uniporter activity exhibits a biphasic dependence on chloride concentration. Chloride channel activity is allosterically activated by lumenal H(+) and Cl(-) leading to synaptic vesicles acidification. The glutamate transport activity is allosterically activated by lumenal H(+) and Cl(-), preventing non-vesicular L-glutamate release.
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types.
Belongs to the X(+)/potassium ATPases subunit beta family.
Mediates cell adhesion of neurons and astrocytes, and promotes neurite outgrowth.
The C-terminal lobe folds into an immunoglobulin-like domain and mediates cell adhesion properties.
The sodium/potassium-transporting ATPase is composed of a catalytic alpha subunit, an auxiliary non-catalytic beta subunit and an additional regulatory subunit. Interacts with isoform 2 of BSG (By similarity).
This is the non-catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of Na(+) and K(+) ions across the plasma membrane. The exact function of the beta-2 subunit is not known.
Forms an interface between the RNA polymerase II enzyme and chaperone/scaffolding protein, suggesting that it is required to connect RNA polymerase II to regulators of protein complex formation. Required for interaction of the RNA polymerase II complex with acetylated histone H3.
Part of an RNA polymerase II complex that contains POLR2A, POLR2B, POLR2C, POLR2D, POLR2E, POLR2F, POLR2G, POLR2H, POLR2I, POLR2J, POLR2K, POLR2L, RPAP1, FCP1 plus the general transcription factors TFIIB and TFIIF.
Heterodimer of an alpha and a beta subunit. The alpha subunit is composed of a heavy and a light chain linked by a disulfide bond (By similarity). Alpha-6 associates with either beta-1 (ITGB1) or beta-4 (ITGB4) to form ITGA6:ITGB1 and ITGA6:ITGB4, respectively (By similarity). ITGA6:ITGB1 is found in a complex with CD9; interaction takes place in oocytes and is involved in sperm-egg fusion (By similarity). ITGA6:ITGB4 is found in a ternary complex with NRG1 and ERBB3 (PubMed:20682778). ITGA6:ITGB4 is found in a ternary complex with IGF1 and IGF1R (PubMed:22351760). ITGA6:ITGB4 interacts with IGF2 (PubMed:28873464). Interacts with ADAM9 (By similarity). Interacts with RAB21 (PubMed:16754960). Interacts with MDK (PubMed:15466886). ITGA6:ITGB1 interacts with MDK; this interaction mediates MDK-induced neurite outgrowth (PubMed:15466886).
Integrin alpha-6/beta-1 (ITGA6:ITGB1) is a receptor for laminin on platelets (By similarity). Integrin alpha-6/beta-1 (ITGA6:ITGB1) is present in oocytes and is involved in sperm-egg fusion (By similarity). Integrin alpha-6/beta-4 (ITGA6:ITGB4) is a receptor for laminin in epithelial cells and it plays a critical structural role in the hemidesmosome (By similarity). ITGA6:ITGB4 binds to NRG1 (via EGF domain) and this binding is essential for NRG1-ERBB signaling (PubMed:20682778). ITGA6:ITGB4 binds to IGF1 and this binding is essential for IGF1 signaling (PubMed:22351760). ITGA6:ITGB4 binds to IGF2 and this binding is essential for IGF2 signaling (PubMed:28873464).
Integrin alpha-6/beta-4 is predominantly expressed by epithelia. Isoforms containing segment X1 are ubiquitously expressed. Isoforms containing segment X1X2 are expressed in heart, kidney, placenta, colon, duodenum, myoblasts and myotubes, and in a limited number of cell lines; they are always coexpressed with the ubiquitous isoform containing segment X1. In some tissues (e.g. Salivary gland), isoforms containing cytoplasmic segment A and isoforms containing segment B are detected while in others, only isoforms containing one cytoplasmic segment are found (segment A in epidermis and segment B in kidney). Processed integrin alpha-6: Expressed at low levels in normal prostate tissue with elevated levels in prostate cancer tissue (at protein level) (PubMed:15023541).
Isoforms containing segment A, but not segment B, are the major targets for PMA-induced phosphorylation. Phosphorylation occurs on 'Ser-1103' of isoform alpha-6X1X2A. Phosphorylation is not required for the induction of integrin alpha-6A/beta-1 high affinity but may reduce the affinity for ligand.
Palmitoylation by DHHC3 enhances stability and cell surface expression.
Undergoes PLAU-mediated cleavage at residues Arg-634-635-Arg in a time-dependent manner to produce processed integrin alpha-6 (alpha6p) (PubMed:11359780, PubMed:15023541, PubMed:17303120). Production of alpha6p enhances prostate cancer cell invasion and migration (PubMed:17303120).
Expressed in all fetal and adult tissues examined. Among fetal tissues, highest levels of expression detected in heart, lung, liver and kidney, and lower levels in brain. Among adult tissues, highest levels of expression detected in heart, placenta, lung, skeletal muscle, spleen, thymus, testis and ovary. Moderate expression in prostate, small intestine, kidney, liver and pancreas, and weak expression in colon, brain and peripheral blood lymphocytes.
Interacts with the LIM domains of LMO2 (By similarity). Interacts via its N-terminal region with RUNX1.
Isoform 1 transcriptionally activates the LYN and BLK promoters and acts synergistically with RUNX1 to transactivate the BLK promoter.
Isoform 2 may function in repression of RUNX1-mediated transactivation.
(Microbial infection) Interacts with human papillomavirus type 16 protein E6.
(Microbial infection) Protects APC and human papillomavirus type 16 protein E6 against degradation via the ubiquitin proteasome pathway.
A homodimer structure has been reported; however it is unclear whether the protein form a homodimer in vivo (PubMed:22001210). Identified in a complex with the COP9 signalosome complex (CSN) (PubMed:16005295). Interacts with SMAD1, SMAD2 and SMAD3; the interaction is direct (PubMed:21947082). Forms a complex with SMURF2 and SMAD7 (PubMed:22344298). Interacts with TGFBR1 (PubMed:22344298). Interacts with SART3; the interaction is direct (PubMed:24526689). May interact with RNF20 and RNF40 (PubMed:24526689). May interact with PRKN (PubMed:24852371). Interacts with INCA1 (PubMed:21750715).
Expressed in skeletal muscle, kidney, heart, placenta, liver, thymus, lung, and ovary, with little or no expression in other tissues.
Hydrolase that removes conjugated ubiquitin from target proteins and regulates various pathways such as the TGF-beta receptor signaling, NF-kappa-B and RNF41/NRDP1-PRKN pathways (PubMed:21947082, PubMed:22344298, PubMed:24852371, PubMed:16005295, PubMed:17318178, PubMed:19826004, PubMed:19576224). Acts as a key regulator of TGF-beta receptor signaling pathway, but the precise mechanism is still unclear: according to a report, acts by promoting deubiquitination of monoubiquitinated R-SMADs (SMAD1, SMAD2 and/or SMAD3), thereby alleviating inhibition of R-SMADs and promoting activation of TGF-beta target genes (PubMed:21947082). According to another reports, regulates the TGF-beta receptor signaling pathway by mediating deubiquitination and stabilization of TGFBR1, leading to an enhanced TGF-beta signal (PubMed:22344298). Able to mediate deubiquitination of monoubiquitinated substrates, 'Lys-27'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains (PubMed:33093067). May also regulate gene expression and/or DNA repair through the deubiquitination of histone H2B (PubMed:24526689). Acts as an inhibitor of mitophagy by counteracting the action of parkin (PRKN): hydrolyzes cleavage of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains attached by parkin on target proteins such as MFN2, thereby reducing parkin's ability to drive mitophagy (PubMed:24852371). Acts as an associated component of COP9 signalosome complex (CSN) and regulates different pathways via this association: regulates NF-kappa-B by mediating deubiquitination of NFKBIA and deubiquitinates substrates bound to VCP (PubMed:16005295, PubMed:17318178, PubMed:19826004, PubMed:19576224). Involved in endosome organization by mediating deubiquitination of SQSTM1: ubiquitinated SQSTM1 forms a molecular bridge that restrains cognate vesicles in the perinuclear region and its deubiquitination releases target vesicles for fast transport into the cell periphery (PubMed:27368102). Acts as a negative regulator of antifungal immunity by mediating 'Lys-27'-linked deubiquitination of CARD9, thereby inactivating CARD9 (PubMed:33093067).
Phosphorylated. Phosphorylation protects against ubiquitination and subsequent degradation by the proteasome.
Ubiquitinated, leading to degradation by the proteasome.
May regulate calcium-dependent activities in the endoplasmic reticulum lumen or post-ER compartment.
O-glycosylated. O-mannosylated by POMT1 and POMT2 and elongated by POMGNT1.
This protein has four functional calcium-binding sites; potential sites II and VI have lost affinity for calcium.
Exhibits enhanced expression in matured epithelial layers (PubMed:23608536). Apical leptin, Staphylococcus aureus alpha-toxin and Pseudomonas aeruginosa acyl-homoserine lactone 3O-C12-HSl lower expression levels, altering junctional integrity in intestinal cells (PubMed:20434232, PubMed:22354024, PubMed:24314862).
Interacts with occludin OCLN, claudins and TPJ1 (By similarity). Interacts with PATJ (By similarity). Interacts with UBN1 (PubMed:20434232). Interacts with FASLG (PubMed:19807924). Interacts with CCND1 (PubMed:21411630).
TJP1, TJP2, and TJP3 are closely related scaffolding proteins that link tight junction (TJ) transmembrane proteins such as claudins, junctional adhesion molecules, and occludin to the actin cytoskeleton (PubMed:16129888). The tight junction acts to limit movement of substances through the paracellular space and as a boundary between the compositionally distinct apical and basolateral plasma membrane domains of epithelial and endothelial cells. Binds and recruits PATJ to tight junctions where it connects and stabilizes apical and lateral components of tight junctions (PubMed:16129888). Promotes cell-cycle progression through the sequestration of cyclin D1 (CCND1) at tight junctions during mitosis which prevents CCND1 degradation during M-phase and enables S-phase transition (PubMed:21411630). With TJP1 and TJP2, participates in the junctional retention and stability of the transcription factor DBPA, but is not involved in its shuttling to the nucleus (By similarity). Contrary to TJP2, TJP3 is dispensable for individual viability, embryonic development, epithelial differentiation, and the establishment of TJs, at least in the laboratory environment (By similarity).
Acetylation on multiple lysines, mainly by KAT2B/PCAF, regulates cell cycle G(2)/M transition. Deacetylation of Lys-1349 and Lys-1415 by SIRT1 increases methyltransferase activity.
Belongs to the class I-like SAM-binding methyltransferase superfamily. C5-methyltransferase family.
Homodimer (PubMed:19173286). Forms a stable complex with E2F1, BB1 and HDAC1 (PubMed:10888886). Forms a complex with DMAP1 and HDAC2, with direct interaction (PubMed:10888872). Interacts with the PRC2/EED-EZH2 complex (PubMed:16357870). Probably part of a corepressor complex containing ZNF304, TRIM28, SETDB1 and DNMT1 (PubMed:24623306). Interacts with UHRF1; promoting its recruitment to hemimethylated DNA (PubMed:21745816). Interacts with USP7, promoting its deubiquitination (PubMed:21745816). Interacts with PCNA (PubMed:9302295). Interacts with MBD2 and MBD3 (PubMed:10947852). Interacts with DNMT3A and DNMT3B (PubMed:12145218). Interacts with UBC9 (PubMed:19450230). Interacts with CSNK1D (By similarity). Interacts with HDAC1 (By similarity). Interacts with BAZ2A/TIP5 (By similarity). Interacts with SIRT7 (By similarity). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (PubMed:32051553). Interacts with L3MBTL3 and DCAF5; the interaction requires DNMT1 methylation at Lys-142 and is necessary to target DNMT1 for ubiquitination by the CRL4-DCAF5 E3 ubiquitin ligase complex and proteasomal degradation (PubMed:29691401). Interacts with PHF20L1; the interaction requires DNMT1 methylation at Lys-142 and protects DNMT1 from ubiquitination and proteasomal degradation (PubMed:24492612).
Its abundance is reduced to non detectable levels at the G0 phase of the cell cycle and is dramatically induced upon entrance into the S-phase of the cell cycle.
Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2. In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9. Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells (PubMed:24623306). Also required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs) (PubMed:24623306). Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing (PubMed:24623306). Promotes tumor growth (PubMed:24623306).
Methylation at Lys-142 by SETD7 is necessary for the regulation of DNMT1 proteasomal degradation.
Phosphorylation of Ser-154 by CDKs is important for enzymatic activity and protein stability. Phosphorylation of Ser-143 by AKT1 prevents methylation by SETD7 therebye increasing DNMT1 stability.
Sumoylated; sumoylation increases activity.
The CXXC-type zinc finger specifically binds to unmethylated CpG dinucleotides, positioning the autoinhibitory linker between the DNA and the active site, thus providing a mechanism to ensure that only hemimethylated CpG dinucleotides undergo methylation.
The N-terminal part is required for homodimerization and acts as a regulatory domain.
Ubiquitinated by UHRF1; interaction with USP7 counteracts ubiquitination by UHRF1 by promoting deubiquitination and preventing degradation by the proteasome.
Ubiquitous; highly expressed in fetal tissues, heart, kidney, placenta, peripheral blood mononuclear cells, and expressed at lower levels in spleen, lung, brain, small intestine, colon, liver, and skeletal muscle. Isoform 2 is less expressed than isoform 1.
APC mutations have led to some interesting observations. (1) the great majority of the mutations found to date would result in truncation of the APC product. (2) almost all the mutations have occurred within the first half of the coding sequence, and somatic mutations in colorectal tumors are further clustered in a particular region, called MCR (mutation cluster region). (3) most identified point mutations in the APC gene are transitions from cytosine to other nucleotides. (4) the location of germline mutations tends to correlate with the number of colorectal polyps in FAP1 patients. Inactivation of both alleles of the APC gene seems to be required as an early event to develop most adenomas and carcinomas in the colon and rectum as well as some of those in the stomach.
Belongs to the adenomatous polyposis coli (APC) family.
Expressed in a variety of tissues: brain, small intestine, colon, thymus, skeletal muscle, heart, prostate, lung, spleen, ovary, testis kidney, placenta, blood and liver (PubMed:21643010, PubMed:27217144). Isoform 1A: Very strongly expressed in brain but has relatively low expression levels in other tissues (PubMed:19527921, PubMed:21643010, PubMed:27217144). Isoform 1B: Predominant form in all tissues except for brain, including gastric mucosa and blood (PubMed:19527921, PubMed:21643010, PubMed:27217144).
Forms homooligomers (Probable). Found in a complex consisting of ARHGEF4, APC and CTNNB1 (PubMed:10947987). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (By similarity). The complex composed, at least, of APC, CTNNB1 and GSK3B interacts with JPT1; the interaction requires the inactive form of GSK3B (phosphorylated at 'Ser-9') (PubMed:25169422). Interacts with APC2 (PubMed:11691822). Interacts with DLG1 (via PDZ domains) and DLG3 (via PDZ domains) (PubMed:8638125, PubMed:9188857). Interacts with alpha- and beta-catenins (PubMed:8259519). Interacts with AXIN1 (via RGS domain) (PubMed:10811618). Interacts with ARHGEF4 (via N-terminus) (PubMed:10947987). Interacts (via C-terminal residues 2674-2843) with MAPRE1 (via C-terminal residues 206-211); the interaction inhibits association with and bundling of F-actin (PubMed:17293347, PubMed:14514668, PubMed:19632184). Interacts with MAPRE2 and MAPRE3 (via C-terminus) (PubMed:14514668). Interacts with DIAPH1; DIAPH1 acts as a scaffold protein for MAPRE1 and APC to stabilize microtubules and promote cell migration (By similarity). Interacts with DIAPH2 (By similarity). Interacts with SCRIB; may mediate APC targeting to adherens junctions of epithelial cells (PubMed:16611247). Interacts with SPATA13 (via N-terminus and SH3 domain) (PubMed:17599059). Interacts with ASAP1 (via SH3 domain) (PubMed:20509626). Interacts (at the cell membrane) with AMER1 and AMER2 (via ARM repeats) (PubMed:21498506, PubMed:22128170). Interacts with KHDRBS1 (PubMed:22000517). Interacts with actin; binds both to F-actin and actin filament bundles (PubMed:17293347).
Phosphorylated; phosphorylation enhances the F-actin bundling activity (PubMed:17293347). Phosphorylated by GSK3B.
The basic region (residues 2167-2674) mediates the association with both microtubule and actin proteins and promotes the bundling of F-actin.
Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. APC activity is correlated with its phosphorylation state. Activates the GEF activity of SPATA13 and ARHGEF4. Plays a role in hepatocyte growth factor (HGF)-induced cell migration. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Associates with both microtubules and actin filaments, components of the cytoskeleton (PubMed:17293347). Plays a role in mediating the organization of F-actin into ordered bundles (PubMed:17293347). Functions downstream of Rho GTPases and DIAPH1 to selectively stabilize microtubules (By similarity). Acts as a mediator of ERBB2-dependent stabilization of microtubules at the cell cortex. It is required for the localization of MACF1 to the cell membrane and this localization of MACF1 is critical for its function in microtubule stabilization.
Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is facilitated by Axin. Deubiquitinated by ZRANB1/TRABID.
May be involved in transcriptional regulation. Involved in cell differentiation and/or proliferation.
Component of the BCR(KBTBD13) E3 ubiquitin ligase complex, at least composed of CUL3 and KBTBD13 and RBX1. Interacts with CUL3.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex.
The BCB domain mediates the interaction with CUL3.
Component of the IFT complex B, at least composed of IFT20, IFT25, IFT27, IFT52, IFT57, IFT74, IFT81, IFT88 and TRAF3IP1 (PubMed:25443296). Interacts with IFT25 (By similarity). Interacts with IFT70B (By similarity). Interacts with RABL2/RABL2A; binding is equal in the presence of GTP or GDP (By similarity). Interacts with ARL6; recognizes and binds with the GTP-free form of ARL6 (PubMed:25443296).
Small GTPase-like component of the intraflagellar transport (IFT) complex B that promotes the exit of the BBSome complex from cilia via its interaction with ARL6 (PubMed:25443296). Not involved in entry of the BBSome complex into cilium. Prevents aggregation of GTP-free ARL6 (PubMed:25443296). Required for hedgehog signaling. Forms a subcomplex within the IFT complex B with IFT25. Its role in intraflagellar transport is mainly seen in tissues rich in ciliated cells such as kidney and testis. Essential for male fertility, spermiogenesis and sperm flagella formation. Plays a role in the early development of the kidney. May be involved in the regulation of ureteric bud initiation (By similarity).
Chemotactic factor that attracts T-cells and monocytes, but not neutrophils, eosinophils, or B-cells. Acts mainly via CC chemokine receptor CCR1. Also binds to CCR3. CCL15(22-92), CCL15(25-92) and CCL15(29-92) are more potent chemoattractants than the CCL15.
Most abundant in heart, skeletal muscle and adrenal gland. Lower levels in placenta, liver, pancreas and bone marrow. CCL15(22-92), CCL15(25-92) and CCL15(29-92) are found in high levels in synovial fluids from rheumatoid patients.
The N-terminal is proteolytically cleaved by proteases associated with inflammatory responses. The processed forms CCL15(22-92), CCL15(25-92) and CCL15(29-92) exhibit increase in CCR1-mediated signaling and chemotaxis assays in vitro.
Acts as an important adapter that promotes epithelial cell polarity and tight junction formation via its interaction with DLG1. Involved in the assembly of protein complexes at sites of cell-cell contact.
Down-regulated in patients suffering of passive Heymann nephritis (at protein level).
Heterodimer; able to heterodimerize via its C-terminal L27 domain with LIN7A, LIN7B and LIN7C. Forms a tripartite complex composed of DLG1, MPP7 and LIN7 (LIN7A or LIN7C). Interacts with DLG1 via its N-terminal L27 domain. Interacts with PALS1 and PATJ.
Phosphorylated by aPKC which promotes dissociation from the cell cortex.
The phospho-regulated basic and hydrophobic (PRBH) motif is sufficient and important for interaction with phospholipids permitting cortical localization (PubMed:26481050). Phosphorylation of the PRBH motif by aPKC inhibits the association of the protein with the cortical membrane (PubMed:26481050).
Efficient protease with alanine specificity but only little elastolytic activity.
Interacts with CTTN/cortactin; this interaction may redistribute CTTN to stress fibers (By similarity). May form homomers. May interact with MOB4, PPP2R1A, PPP2CB, STK24, STK25, STK26, STRN4, STRIP1 and STRIP2.
Regulates lamellipodial actin dynamics in a CTTN-dependent manner.
Interacts (via SH3 domains) with the calcium channels CACNA1S and CACNA1C (PubMed:29078335). Component of a calcium channel complex with CACNA1S and CACNB1. Component of a calcium channel complex with CACNA1C and CACNB1 (By similarity).
Required for normal excitation-contraction coupling in skeletal muscle and for normal muscle contraction in response to membrane depolarization. Required for normal Ca(2+) release from the sarcplasmic reticulum, which ultimately leads to muscle contraction. Probably functions via its effects on muscle calcium channels (PubMed:23736855, PubMed:29078335). Increases CACNA1S channel activity, in addition to its role in enhancing the expression of CACNA1S at the cell membrane. Has a redundant role in promoting the expression of the calcium channel CACNA1S at the cell membrane (By similarity). Slows down the inactivation rate of the calcium channel CACNA1C (PubMed:29078335).
Genetic variations in PIR might have a sex-specific influence on bone mineral density differences in some populations, as reported by PubMed:19766747. In a cohort of 4000 Chinese, a significant statistical association has been identified, in women but not in men, between the intronic SNP rs5935970 and lumbar spine bone mineral density, and between a haplotype composed of three SNPs with bone mineral density at other sites.
Highly expressed in a subset of melanomas. Detected at very low levels in most tissues (at protein level). Expressed in all tissues, with highest level of expression in heart and liver.
Inhibited by kojic acid, sodium diethyldithiocarbamate and 1,10-phenanthroline monohydrochloride.
May interact with NF1/CTF1. Interacts with BCL3. Identified in a complex comprised of PIR, BLC3, NFKB1 and target DNA.
Transcriptional coregulator of NF-kappa-B which facilitates binding of NF-kappa-B proteins to target kappa-B genes in a redox-state-dependent manner. May be required for efficient terminal myeloid maturation of hematopoietic cells. Has quercetin 2,3-dioxygenase activity (in vitro).
Up-regulated in CD34(+) cells upon myelomonocytic differentiation. Down-regulated in many acute myeloid leukemias. Up-regulated in primary bronchial epithelial cells exposed to cigarette smoke extract.
Adaptor protein complex 3 (AP-3) is a heterotetramer composed of two large adaptins (delta-type subunit AP3D1 and beta-type subunit AP3B1 or AP3B2), a medium adaptin (mu-type subunit AP3M1 or AP3M2) and a small adaptin (sigma-type subunit APS1 or AP3S2). Interacts with AGAP1. AP-3 associates with the BLOC-1 complex (By similarity).
Associates with the spliceosome. Component of a large chromatin remodeling complex, at least composed of MYSM1, PCAF, RBM10 and KIF11/TRIP5.
May be involved in post-transcriptional processing, most probably in mRNA splicing. Binds to RNA homopolymers, with a preference for poly(G) and poly(U) and little for poly(A) (By similarity). May bind to specific miRNA hairpins (PubMed:28431233).
RBM10 transcripts also code for an alternative open reading frame (alt-ORF) coding for the MINAS-60 (AC P0DW28) protein (Probable). MINAS-60 and RBM10 ORFs are overlapping and are formed by shifting the reading frame (Probable).
Interacts with WWP1. Interacts with ANP32B; this interaction induces promoter region-specific histone incorporation and inhibition of histone acetylation by ANP32B.
Transcription factor that binds to GC box promoter elements. Activates the transcription of these genes.
Ubiquitinated. Polyubiquitination involves WWP1 and leads to proteasomal degradation of this protein (PubMed:15735697). Deubiquitinated by ATXN3L (PubMed:26079537).
Autophosphorylated on tyrosine residues.
Expressed in all umbilical cord blood, bone marrow and adult blood cell sub-populations and in several leukemia cell lines. Highly expressed in fetal blood, brain, lung, liver and kidney. Detected at lower levels in adult prostate, testis, ovary, small intestine and colon. Not expressed in adult lung, liver, kidney or brain.
Interacts with the SH3 domain of PLCG1 via its Pro-rich domain.
Involved in negative regulation of cell growth. Has tumor suppressor properties. Plays a negative regulatory role in the Ras-MAPK pathway. May function in signaling pathways utilized broadly during fetal development and more selectively in adult tissues and in cells of the lymphohematopoietic system. Could specifically be involved in phospholipid signal transduction.
Catalyzes the de novo synthesis of acetyl-CoA in vitro (By similarity). Promotes acetylation of CTTN, possibly by providing the acetyl donor, ensuring correct dendritic spine morphology and synaptic transmission (By similarity). Binds to follistatin-related protein FSTL1 and may act as a cell surface receptor for FSTL1, contributing to AKT activation and subsequent FSTL1-induced survival and function of endothelial cells and cardiac myocytes (PubMed:20054002).
Interacts with FSTL1; DIP2A may act as a cell surface receptor for FSTL1 (PubMed:20860622, PubMed:20054002). Interacts (via N-terminus) with CTTN (via SH3 domain); the interaction promotes acetylation of CTTN and is required for proper synaptic transmission (By similarity). Interacts with SHANK3 (By similarity).
Three OR2J2 alleles are known: 6M1-6*01, 6M1-6*02 and 6M1-6*03. The sequence shown is that of allele 6M1-6*01.
Belongs to the dTDP-4-dehydrorhamnose reductase family. MAT2B subfamily.
Heterotrimer; composed of a catalytic MAT2A homodimer that binds one regulatory MAT2B chain (PubMed:10644686, PubMed:23189196). Heterohexamer; composed of a central, catalytic MAT2A homotetramer flanked on either side by a regulatory MAT2B chain (PubMed:25075345). NADP binding increases the affinity for MAT2A (PubMed:23189196).
Heterotrimer; composed of a catalytic MAT2A homodimer that binds one regulatory MAT2B chain. Heterohexamer; composed of a central, catalytic MAT2A homotetramer flanked on either side by a regulatory MAT2B chain. NADP binding increases the affinity for MAT2A.
Its expression in hepatoma cell lines may lead to increase DNA synthesis and thereby participate in cell proliferation.
Regulatory subunit of S-adenosylmethionine synthetase 2, an enzyme that catalyzes the formation of S-adenosylmethionine from methionine and ATP. Regulates MAT2A catalytic activity by changing its kinetic properties, increasing its affinity for L-methionine (PubMed:10644686, PubMed:23189196, PubMed:25075345). Can bind NADP (in vitro) (PubMed:23189196, PubMed:23425511).
Regulatory subunit of S-adenosylmethionine synthetase 2, an enzyme that catalyzes the formation of S-adenosylmethionine from methionine and ATP. Regulates MAT2A catalytic activity by changing its kinetic properties, increasing its affinity for L-methionine.
As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex involved in the connection between the nuclear lamina and the cytoskeleton (PubMed:18039933, PubMed:18396275). The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning (By similarity). Required for interkinetic nuclear migration (INM) and essential for nucleokinesis and centrosome-nucleus coupling during radial neuronal migration in the cerebral cortex and during glial migration (By similarity). Involved in telomere attachment to nuclear envelope in the prophase of meiosis implicating a SUN1/2:KASH5 LINC complex in which SUN1 and SUN2 seem to act at least partial redundantly (By similarity). Required for gametogenesis and involved in selective gene expression of coding and non-coding RNAs needed for gametogenesis (By similarity). Helps to define the distribution of nuclear pore complexes (NPCs) (By similarity). Required for efficient localization of SYNE4 in the nuclear envelope (By similarity). May be involved in nuclear remodeling during sperm head formation in spermatogenesis (By similarity). May play a role in DNA repair by suppressing non-homologous end joining repair to facilitate the repair of DNA cross-links (PubMed:24375709).
Core component of the LINC complex which is composed of inner nuclear membrane SUN domain-containing proteins coupled to outer nuclear membrane KASH domain-containing nesprins. SUN and KASH domain-containing proteins seem to bind each other promiscuously; however, differentially expression of LINC complex constituents is giving rise to specific assemblies. At least SUN1/2-containing core LINC complexes are proposed to be hexameric composed of three protomers of each KASH and SUN domain-containing protein. Interacts with KASH5 (via the last 22 amino acids); this interaction mediates KASH5 telomere localization by forming a SUN1:KASH5 LINC complex. May interact with SYNE3. Interacts with SYNE2 and SYNE1; probably forming respective LINC complexes. Interacts with A-type lamin with a strong preference for unprocessed A-type lamin compared with the mature protein. Interaction with lamins B1 and C is hardly detectable. Interacts with NAT10. Interacts with EMD and TSNAX. Associates with the nuclear pore complex (NPC). Interacts with CCDC79/TERB1; promoting the accumulation of the LINC complex complexes at the telomere-nuclear envelope attachment sites. Interacts (via KASH domain) with TMEM258 (PubMed:28716842).
The SUN domain may play a role in nuclear anchoring and/or migration.
The coiled coil domains differentially mediate trimerization required for binding to nesprins and are proposed to dynamically regulate the oligomeric state by locking the SUN domain in an inactive confirmation. The coiled coil domains are proposed to be involved in load-bearing and force transmission from the cytoskeleton.
The disulfide bond with KASH domain-containing nesprins is required for stability of the respective LINC complexes under tensile forces.
Phosphorylation of Ser-333 and Ser-334 is a key step in agonist-dependent desensitization and loss of surface P2RY4. This phosphorylation does not involve PKC, nor other calcium activated kinases.
Receptor for UTP and UDP coupled to G-proteins that activate a phosphatidylinositol-calcium second messenger system. Not activated by ATP or ADP.
Belongs to the ATP synthase subunit s family.
Homotetramer. Associates with ATP synthase.
Involved in regulation of mitochondrial membrane ATP synthase. Necessary for H(+) conduction of ATP synthase. Facilitates energy-driven catalysis of ATP synthesis by blocking a proton leak through an alternative proton exit pathway.
It is uncertain whether Met-1 or Met-16 is the initiator.
Expressed in KYSE-150 esophageal carcinoma, HeLa cervical carcinoma and U2OS osteosarcoma cells. Expression is regulated in a cell cycle-dependent manner and peaks during G2/M phase (at protein level). Expressed in fetal heart, skeletal muscle, liver, lung and cochlea, and in adult brain, testis, kidney and retina.
Interacts with gamma-tubulin and TUBGCP4. Interacts with anaphase promoting complex/cyclosome (APC/C). Interacts with CDC20 and FZR1. Isoform 2 interacts with LCA5 and USH2A. Isoform 2 interacts with DZANK1 (PubMed:26485514).
Involved in the microtubule organization in interphase cells. Overexpression induces the fragmentation of the Golgi, and causes lysosomes to disperse toward the cell periphery; it also interferes with mitotic spindle assembly. Involved in vesicle transport in photoreceptor cells (By similarity). May play a role in ovarian carcinogenesis.
Phosphorylated by PLK1 which disrupts its centrosome association and interaction with gamma-tubulin.
The KEN and D (destructive) boxes are required for the cell cycle-controlled NINL degradation by the APC/C pathway.
Ubiquitinated by the APC/C complex leading to its degradation.
A chimeric transcript, characterized by the first third of PPAN exon 12 joined to P2RY11 exon 2, has been detected. It is possibly produced by trans-splicing. The chimeric transcript is widely expressed and can be induced by retinoic acid during the granulocytic differentiation of the HL-60 cell line. The resulting chimeric protein shows a much lower activity than the non-chimeric P2RY11 gene product, but qualitatively indistinguishable (PubMed:11278528).
Belongs to the methyltransferase superfamily. Arsenite methyltransferase family.
Catalyzes the transfer of a methyl group from AdoMet to trivalent arsenicals producing methylated and dimethylated arsenicals (PubMed:16407288, PubMed:25997655). It methylates arsenite to form methylarsonate, Me-AsO(3)H(2), which is reduced by methylarsonate reductase to methylarsonite, Me-As(OH)2 (PubMed:16407288, PubMed:25997655). Methylarsonite is also a substrate and it is converted into the much less toxic compound dimethylarsinate (cacodylate), Me(2)As(O)-OH (PubMed:16407288, PubMed:25997655).
Belongs to the small membrane AKAP family.
Binds to type I regulatory subunits of protein kinase A (PKA-RI) and may anchor/target them to the plasma membrane.
Belongs to the myo-inositol 1-phosphate synthase family.
By glucose and lovastain. Up-regulation is prevented by mevalonic acid, farnesol, and geranylgeraniol. Up-regulated by E2F1.
Highly expressed in testis, ovary, heart, placenta and pancreas. Weakly expressed in blood leukocyte, thymus, skeletal muscle and colon.
Inhibited by mood-stabilizing drugs such as valproate (VPA) and lithium.
Key enzyme in myo-inositol biosynthesis pathway that catalyzes the conversion of glucose 6-phosphate to 1-myo-inositol 1-phosphate in a NAD-dependent manner (PubMed:15024000, PubMed:23902760). Rate-limiting enzyme in the synthesis of all inositol-containing compounds (PubMed:15024000).
Phosphorylation at Ser-279 and Ser-357 may be associated with a decrease in activity.
ATP-dependent RNA helicase. Binds to partially double-stranded RNAs (dsRNAs) in order to unwind RNA secondary structures. Unwinding is promoted in the presence of single-strand binding proteins. Mediates also RNA duplex formation thereby displacing the single-strand RNA binding protein. ATP and ADP modulate its activity: ATP binding and hydrolysis by DDX42 triggers RNA strand separation, whereas the ADP-bound form of the protein triggers annealing of complementary RNA strands. Involved in the survival of cells by interacting with TP53BP2 and thereby counteracting the apoptosis-stimulating activity of TP53BP2. Relocalizes TP53BP2 to the cytoplasm.
Belongs to the DEAD box helicase family. DDX42 subfamily.
Component of splicing factor SF3B complex which is composed of at least eight subunits; SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6, PHF5A/SF3B14B, and DDX42/SF3B125. Interacts (via the C-terminus) with TP53BP2; the interaction is not inhibitied by TP53BP2 ubiquitination and is independent of p53/TP53.
Expressed in several cell lines (at protein level). Expressed in liver, lung, tonsil, thymus, muscle and pancreatic islets.
NAT16 is the ortholog of the ectothermic vertebrates enzyme HISAT (AC I3J7Q8) responsible for the synthesis of N-acetyl-histidine (NAH). NAT16 protein, unlike fish HISAT, has only trace enzyme activity for NAH synthesis.
Probable N-acetyltransferase. Shows only trace activity toward L-His and no N-acetyltransferase activity toward other amino acids. The physiological substrate of this enzyme is unknown.
Belongs to the THEM4/THEM5 thioesterase family.
Has acyl-CoA thioesterase activity towards long-chain (C16 and C18) fatty acyl-CoA substrates, with a preference for linoleoyl-CoA and other unsaturated long-chain fatty acid-CoA esters (PubMed:22586271). Plays an important role in mitochondrial fatty acid metabolism, and in remodeling of the mitochondrial lipid cardiolipin (PubMed:22586271). Required for normal mitochondrial function (PubMed:22586271).
Belongs to the myotilin/palladin family.
Component of a complex of multiple actin cross-linking proteins. Involved in the control of myofibril assembly and stability at the Z lines in muscle cells.
Expressed in skeletal muscle (at protein level). Expressed in skeletal muscle, heart, bone marrow and thyroid gland.
Homodimer. Interacts with ACTA1, ACTN1, FLNA, FLNB, FLNC and MYOZ2. Interacts with the C-terminal region of MYOZ1.
(Microbial infection) Cleaved and inactivated by the protease 3C of poliovirus, Coxsackievirus B3 and Human rhinovirus 14, allowing the virus to shutoff the host cell translation.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. IF-2 subfamily.
Binds 1 monovalent cation per monomer in the active site. Structural cofactor that stabilizes the GTP-bound 'on' state. May also act as a transition state stabilizer of the hydrolysis reaction.
Interacts through its C-terminal domain (CTD) with the CTD of eIF1A (EIF1AX) or with the CTD of EIF5 (mutually exclusive) through a common binding site (PubMed:30211544). Interacts with eIF1A (EIF1AX) from the location of the start codon by the 43S complex until the formation of the 80S complex (PubMed:12569173, PubMed:35732735). Interacts with ANXA5 in a calcium and phospholipid-dependent manner (By similarity).
Plays a role in translation initiation (PubMed:10659855, PubMed:35732735). Ribosome-dependent GTPase that promotes the joining of the 60S ribosomal subunit to the pre-initiation complex to form the 80S initiation complex with the initiator methionine-tRNA in the P-site base paired to the start codon (PubMed:10659855, PubMed:35732735). Together with eIF1A (EIF1AX), actively orients the initiator methionine-tRNA in a conformation that allows 60S ribosomal subunit joining to form the 80S initiation complex (PubMed:12569173, PubMed:35732735). Is released after formation of the 80S initiation complex (PubMed:35732735). Its GTPase activity is not essential for ribosomal subunits joining, but GTP hydrolysis is needed for eIF1A (EIF1AX) ejection quickly followed by EIF5B release to form elongation-competent ribosomes (PubMed:10659855, PubMed:35732735). In contrast to its procaryotic homolog, does not promote recruitment of Met-rRNA to the small ribosomal subunit (PubMed:10659855).
Belongs to the DEAD box helicase family. DDX41 subfamily.
Identified in the spliceosome C complex (PubMed:11991638, PubMed:25920683). Interacts with ERCC6 (PubMed:26030138). Interacts with FAM50A (PubMed:32703943).
Probable ATP-dependent RNA helicase. Is required during post-transcriptional gene expression. May be involved in pre-mRNA splicing.
Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres. CENPN is the first protein to bind specifically to CENPA nucleosomes and the direct binding of CENPA nucleosomes by CENPN is required for centromere assembly. Required for chromosome congression and efficiently align the chromosomes on a metaphase plate.
Component of the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU (PubMed:16622420, PubMed:16622419). The CENPA-NAC complex interacts with the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. Interacts directly with CENPA (PubMed:19543270). Identified in a centromere complex containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:27499292).
Acts as a heparin receptor in vascular cells (By similarity). May be involved in vesicle transport in exocrine cells and Sertoli cells (By similarity).
Expressed in vascular cells (at protein level).
Probable cloning artifact. Aberrant splice sites.
Receptor for ATP and ADP coupled to G-proteins that activate both phosphatidylinositol-calcium and adenylyl cyclase second messenger systems. Not activated by UTP or UDP.
Activates pre-mRNA splicing. May inhibit PP1 phosphatase activity.
Interacts with PPP1CA, PPP1CB and PPP1CC (By similarity). Interacts via the PGR motif with PQBP1 in the nucleus. Interacts with the WW domains of WBP4.
Ubiquitous. Highly expressed in the heart, pancreas, kidney skeletal muscle, placenta and brain (at protein level). Weakly expressed in liver and lung.
Belongs to the archaeal Rpo11/eukaryotic RPB11/RPC19 RNA polymerase subunit family.
Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits. Interacts with AATF.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB11 is part of the core element with the central large cleft (By similarity).
Ubiquitously expressed. High expression was found in heart and skeletal muscle.
Highly expressed in proliferating tissue and tumor cell lines but not in normal cell lines.
Interacts (via TPR repeats) with HSP90AB1 (PubMed:18320024). Interacts with HSPA8 and CDC6 (PubMed:18320024). Interacts with TBK1 (PubMed:29251827). Interacts with MSL1 (By similarity).
May act as a co-chaperone for HSP90AB1 (PubMed:18320024). Promotes Sendai virus (SeV)-induced host cell innate immune responses (PubMed:29251827).
Component of nuclear coiled bodies, also known as Cajal bodies or CBs, which are involved in the modification and assembly of nucleoplasmic snRNPs.
Interacts with ANKS1B (PubMed:15862129). Interacts with SMN1 (via Tudor domain) (PubMed:11641277). Interacts (via C-terminus) with AK6 (PubMed:16079131). Interacts with WRAP53/TCAB1 (PubMed:21072240). Interacts with HMBOX1 (PubMed:23685356). Interacts with PSME3; the interaction is inhibited by PSME3IP1 (PubMed:29934401). Interacts wit UBL5 (PubMed:23726919).
Phosphorylation during mitosis is associated with disassembly of CBs.
Symmetrical dimethylation of arginine residues within the RG repeat region enhances affinity for SMN, and thus localization of SMN complexes to CBs.
The atypical Tudor domain at the C-terminus contains two large unstructured loops, and does not bind methylated residues.
Acts as an anti-inflammatory factor in the intestine and colon. Binds to and acts on macrophages to down-regulate pro-inflammatory gene expression. Affects key macrophage functions, including phagocytosis, by down-regulating many key pathways for macrophage activation, partly via by STAT3 activation and signaling. May be required to dampen the immunological response in colitis.
Up-regulated in colon cells of patients with inflammatory bowel disease (IBD).
Belongs to the class-I aminoacyl-tRNA synthetase family. Glutamate--tRNA ligase type 1 subfamily.
Catalyzes the attachment of glutamate to tRNA(Glu) in a two-step reaction: glutamate is first activated by ATP to form Glu-AMP and then transferred to the acceptor end of tRNA(Glu).
A chromosomal aberration involving MIPOL1 is found in a patient with mirror-image polydactyly of hands and feet without other anomalies (MIP). Translocation t(2;14)(p23.3;q13). MIP is a very rare congenital anomaly characterized by mirror-image duplication of digits. MIP is occasionally associated with dimelia of the ulna and fibula, tibial and/or fibular hypoplasia, nasal abnormality and other malformations. Most MIP cases are sporadic, but very rare parent-child transmissions observed in familial cases suggest an autosomal mode of inheritance.
Expressed very weakly in heart, liver, skeletal muscle, kidney, pancreas and fetal kidney. Not detected in brain, placenta and lung.
May be due to a competing acceptor splice site.
Binds the C-terminal sequence motif K-D-E-L in a hydrophilic cavity between the transmembrane domains. This triggers a conformation change that exposes a Lys-rich patch on the cytosolic surface of the protein (By similarity). This patch mediates recycling from the Golgi to the endoplasmic reticulum, probably via COPI vesicles (By similarity).
Membrane receptor that binds the K-D-E-L sequence motif in the C-terminal part of endoplasmic reticulum resident proteins and maintains their localization in that compartment by participating to their vesicle-mediated recycling back from the Golgi (PubMed:1325562, PubMed:18086916, PubMed:33053334). Binding is pH dependent, and is optimal at pH 5-5.4 (By similarity).
Isoform 2 is widely expressed. Isoform 3 is only expressed in CD34(+) cells.
May play a role in hematopoietic stem/progenitor cell differentiation. May play a role as a DNA binding-dependent transcriptional repressor.
Probable target of nonsense-mediated mRNA decay. The proposed CDS is dubious.
Probable target of nonsense-mediated mRNA decay. The proposed CDS is dubious. Isoform produced through aberrant splice sites.
The KRAB domain mediates interaction with TRIM28.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ10 subfamily.
Heterodimer with Kir5.1/KCNJ16; this interaction is required for KCNJ16 localization to the basolateral membrane in kidney cells. Interacts with MAGI1, alone and possibly as a heterodimer with KCNJ16; this interaction may facilitate KCNJ10/KCNJ16 potassium channel expression at the basolateral membrane in kidney cells (PubMed:24561201). Interacts with PATJ (By similarity).
May be responsible for potassium buffering action of glial cells in the brain. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium and cesium (By similarity). In the kidney, together with KCNJ16, mediates basolateral K(+) recycling in distal tubules; this process is critical for Na(+) reabsorption at the tubules.
Defects in NOTCH2NLA may be a cause of chromosome 1q21.1 deletion/duplication syndrome (PubMed:29856954). Deletions of NOTCH2NL (NOTCH2NLA, NOTCH2NLB and/or NOTCH2NLC) are present in patients affected by microcephaly, whereas macrocephaly is observed in patients with NOTCH2NL duplications (PubMed:29856954).
Expressed at low levels at 7-9 gestational weeks and then increases at later stages, including in the non-cortical plate region at gestational week 21, containing the outer-subventricular zone (PubMed:29856955). Expressed at lower level than NOTCH2NLB (PubMed:29856955).
Human-specific protein that promotes neural progenitor proliferation and evolutionary expansion of the brain neocortex by regulating the Notch signaling pathway (PubMed:29856954, PubMed:29856955, PubMed:29561261). Able to promote neural progenitor self-renewal, possibly by down-regulating neuronal differentiation genes, thereby delaying the differentiation of neuronal progenitors and leading to an overall final increase in neuronal production (PubMed:29856954). Acts by enhancing the Notch signaling pathway via two different mechanisms that probably work in parallel to reach the same effect (PubMed:29856954). Enhances Notch signaling pathway in a non-cell-autonomous manner via direct interaction with NOTCH2 (PubMed:29856954). Also promotes Notch signaling pathway in a cell-autonomous manner through inhibition of cis DLL1-NOTCH2 interactions, which promotes neuronal differentiation (By similarity).
Interacts with ELANE (PubMed:14673143). Interacts with NOTCH2 (PubMed:29856954). Interacts with DLL1; the interaction is direct (By similarity).
Widely expressed with higher levels in leukocytes and lymph nodes (PubMed:14673143). Expressed in radial glia neural stem cells during cortical development (PubMed:29856954).
About 40% of KLK11 is inactivated by internal cleavage after Arg-188. This proteolytic inactivation may be effected by plasminogen.
Expressed in brain, skin and prostate. Isoform 1 is expressed preferentially in brain. Isoform 2 is expressed in prostate. Present in seminal plasma at concentrations ranging from 2 to 37 microg/mL (at protein level).
Localized in the prostate secretory epithelium.
Possible multifunctional protease. Efficiently cleaves 'bz-Phe-Arg-4-methylcoumaryl-7-amide', a kallikrein substrate, and weakly cleaves other substrates for kallikrein and trypsin. Cleaves synthetic peptides after arginine but not lysine residues.
By androgen-bound AR and glucocorticoid-bound NR3C1 in a prostate cancer cell line (LNCaP).
Cholesterol bound to SSD domain of SCAP or oxysterol bound to INSIG (INSIG1 or INSIG2) leads to masking of an ER export signal (also named MELADL motif) on SCAP possibly by moving the signal further away from the ER membrane.
Escort protein required for cholesterol as well as lipid homeostasis (By similarity). Regulates export of the SCAP-SREBP complex from the endoplasmic reticulum to the Golgi upon low cholesterol, thereby regulating the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (By similarity). At high sterol concentrations, formation of a ternary complex with INSIG (INSIG1 or INSIG2) leads to mask the ER export signal in SCAP, promoting retention of the complex in the endoplasmic reticulum (By similarity). Low sterol concentrations trigger release of INSIG, a conformational change in the SSD domain of SCAP, unmasking of the ER export signal, promoting recruitment into COPII-coated vesicles and transport of the SCAP-SREBP to the Golgi: in the Golgi, SREBPs are then processed, releasing the transcription factor fragment of SREBPs from the membrane, its import into the nucleus and up-regulation of LDLR, INSIG1 and the mevalonate pathway (By similarity). Binds cholesterol via its SSD domain (By similarity).
Loop-1 binds to loop-7, enabling interaction with COPII-coated vesicles. When levels of cholesterol in the endoplasmic reticulum increase, Loop-1 binds to cholesterol instead, thereby disrupting direct binding between the two loops and preventing the SCAP-SREBP complex from exiting the endoplasmic reticulum.
Membrane region forms a homotetramer (By similarity). Component of the SCAP-SREBP complex (composed of SCAP and SREBF1/SREBP1 or SREBF2/SREBP2); interacts with SREBF1/SREBP1 or SREBF2/SREBP2 through its C-terminal cytoplasmic domain (By similarity). Forms a ternary complex with INSIG1 or INSIG2 through its transmembrane domains at high sterol concentrations (PubMed:17428920, PubMed:26160948). Interacts with the SEC23-SEC24 complex in a SAR1-GTP-dependent manner through an ER export signal in its third cytoplasmic loop (By similarity). Interacts with RNF139; the interaction inhibits the interaction of SCAP with SEC24B and hampering the ER to Golgi transport of the SCAP-SREBP complex (PubMed:19706601). Interacts with SPRING1 (PubMed:32111832).
Ubiquitinated at Lys-454 and Lys-466. RNF145 triggers ubiquitination of SCAP, likely inhibiting SCAP-SREBP complex transport to the Golgi apparatus and the subsequent processing/maturation of SREBF2/SREBP2.
Inhibited by 3-isobutyl-1-methylxanthine (IBMX), zaprinast and dipyridamole. cGMP acts as an allosteric activator. Weakly inhibited by Sildenafil (Viagra) and Tadalafil (Cialis); however, the fact that the protein is probably absent from testis, suggests that it is not biologically relevant and is not related with erectile dysfunction.
Isoform 1 is present in prostate, pituitary, heart and liver. It is however not present in testis nor in penis, suggesting that weak inhibition by Tadalafil (Cialis) is not relevant (at protein level). Isoform 2 may be expressed in testis. Isoform 4 is expressed in adrenal cortex.
Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides cAMP and cGMP (PubMed:10725373, PubMed:10906126, PubMed:11050148, PubMed:16330539). Catalyzes the hydrolysis of both cAMP and cGMP to 5'-AMP and 5'-GMP, respectively (PubMed:10725373, PubMed:10906126, PubMed:11050148).
The tandem GAF domains bind cGMP, and regulate enzyme activity. The binding of cGMP stimulates enzyme activity.
Detected in liver, kidney and esophagus (at protein level). Ubiquitous.
May contribute to the regulation of cell proliferation.
The rat protein was reported to play a role in DNA repair (PubMed:9406864), based on its ability to complement E.coli deficient in the DNA repair enzyme mutT that hydrolyzes oxidized guanine nucleotides. PubMed:17569023 found no such activity, neither for the human nor the rat protein.
This protein is coded from a FGF2 (BFGF) gene antisense transcript.
Acts as a transcriptional repressor. May function in the assembly and/or enzymatic activity of the mSin3A corepressor complex or in mediating interactions between the complex and other regulatory complexes.
Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3/SAP45, ARID4B/SAP180, HDAC1 and HDAC2. Interacts (released by dead or dying cells) with CLEC4E (By similarity).
The C-terminus may interact with HDAC-dependent and HDAC-independent corepressors.
The N-terminus may interact with a transcriptional coactivator.
Alpha-L-fucosidase is responsible for hydrolyzing the alpha-1,6-linked fucose joined to the reducing-end N-acetylglucosamine of the carbohydrate moieties of glycoproteins.
Belongs to the glycosyl hydrolase 29 family.
There are two common alleles of FUCA1; FUCA1*1; also known as Fu1; has Arg-281 and FUCA1*2; also known as Fu2; has Gln-281.
Translation of X01390 sequence produces a larger peptide than that shown in CAA25646.1.
A processed pseudogene with 96% sequence identity was found in the BRCA1 (113705) region of 17q21.
Farnesylated. Farnesylation is required for membrane targeting and for interaction with RABGGTB. Unfarnesylated forms are redirected to the nucleus and cytosol.
In contrast to PTP4A1 and PTP4A3, does not interact with tubulin. Interacts with RABGGTB.
Inhibited by sodium orthovanadate and pentamidine.
Protein tyrosine phosphatase which stimulates progression from G1 into S phase during mitosis. Promotes tumors. Inhibits geranylgeranyl transferase type II activity by blocking the association between RABGGTA and RABGGTB.
Ubiquitously expressed, with highest levels in skeletal muscle, heart and thymus. Overexpressed in prostate tumor tissue.
ATP- and membrane-binding protein that controls membrane reorganization/tubulation upon ATP hydrolysis. In vitro causes vesiculation of endocytic membranes (PubMed:24019528). Acts in early endocytic membrane fusion and membrane trafficking of recycling endosomes (PubMed:15020713, PubMed:17233914, PubMed:20801876). Recruited to endosomal membranes upon nerve growth factor stimulation, indirectly regulates neurite outgrowth (By similarity). Plays a role in myoblast fusion (By similarity). Involved in the unidirectional retrograde dendritic transport of endocytosed BACE1 and in efficient sorting of BACE1 to axons implicating a function in neuronal APP processing (By similarity). Plays a role in the formation of the ciliary vesicle (CV), an early step in cilium biogenesis. Proposed to be required for the fusion of distal appendage vesicles (DAVs) to form the CV by recruiting SNARE complex component SNAP29. Is required for recruitment of transition zone proteins CEP290, RPGRIP1L, TMEM67 and B9D2, and of IFT20 following DAV reorganization before Rab8-dependent ciliary membrane extension. Required for the loss of CCP110 form the mother centriole essential for the maturation of the basal body during ciliogenesis (PubMed:25686250).
Belongs to the TRAFAC class dynamin-like GTPase superfamily. Dynamin/Fzo/YdjA family. EHD subfamily.
Homooligomer, and heterooligomer with EHD2, EHD3 and EHD4, ATP-binding is required for heterooligomerization (PubMed:16251358, PubMed:17233914, PubMed:18331452). Interacts (via EH domain) with MICALL1 (via NPF1 motif); the interaction is direct and recruits EHD1 to membranes (PubMed:19864458, PubMed:20106972). Interacts with RAB35; the interaction is indirect through MICALL1 and recruits EHD1 to membranes (By similarity). Interacts (via EH domain) with PACSIN2 (via NPF motifs); regulates localization to tubular recycling endosome membranes (PubMed:23596323). Interacts with PACSIN1 (By similarity). Interacts with RAB8A (PubMed:19864458). Interacts with FER1L5 (via second C2 domain) (By similarity). Interacts with MYOF (By similarity). Interacts with ZFYVE20 (PubMed:15020713). Interacts (via EH domain) with RAB11FIP2 (PubMed:16251358).
The EH domain interacts with Asn-Pro-Phe (NPF) motifs of target proteins.
Belongs to the metallo-dependent hydrolases superfamily. Peptidase M19 family.
Homodimer; disulfide-linked (PubMed:32325220). Interacts with TEX101; co-localized on the cell surface of spermatocytes, spermatids, and testicular spermatozoa, co-localized only in cytoplasmic droplets of caput and corpus epididymal sperm (By similarity).
Lacks dipeptidase activity and is unable to hydrolyze cystinyl-bis-glycine, leukotriene D4 and the beta-lactam antibiotic imipenem (PubMed:32325220). The absence of activity may be due to the inability of asparagine (instead of aspartate found in DPEP1/2) at position 359 to function as the acid/base catalyst and activate the nucleophilic water/hydroxide (PubMed:32325220). A tyrosine (instead of histidine) at position 269 reduces affinity for the beta zinc and may cause substrate steric hindrance (PubMed:32325220).
Actin-binding protein involved in motile and morphological processes. Inhibits actin polymerization, likely by sequestering G-actin. By capping the barbed ends of filaments, it also regulates motility. Seems to play an important role in clathrin-mediated endocytosis and distribution of endocytic organelles. May play a role in regulating the mature length of the middle and short rows of stereocilia (By similarity).
Belongs to the actin-binding proteins ADF family. Twinfilin subfamily.
In vitro, phosphorylated by PRKCZ, CK2 and SRC.
Interacts with G-actin; ADP-actin form and capping protein (CP). May also be able to interact with TWF1 and phosphoinositides, PI(4,5)P2. When bound to PI(4,5)P2, it is down-regulated. Interacts with MYO7A (By similarity).
Ubiquitously expressed (at protein level).
Excess hnRNP L activates NMD of its own mRNA by promoting the inclusion of a 'poison exon' containing a premature stop codon and leading to nonsense-mediated decay. It also cross-regulates inclusion of an analogous 'poison exon' in the hnRNP L-like pre-mRNA (PubMed:19124611).
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Interacts with HNRNPLL (PubMed:18669861). Interacts with APEX1; the interaction is DNA-dependent (PubMed:11809897). Component of a complex with SETD2 (PubMed:19332550, PubMed:36537238). Interacts with ELAVL1 (PubMed:18161049). Part of a transcription inhibitory ribonucleoprotein complex composed at least of the circular RNA circZNF827, ZNF827 and HNRNPK (PubMed:33174841). Interacts with CHD8 in an RNA-dependent manner.
Phosphorylation at Ser-544 by CaMK4 enhances interaction with a CaMK4-responsive RNA element (CaRRE1), and prevents inclusion of the stress axis-regulated exon (STREX) of the KCNMA1 potassium channel transcripts upon membrane depolarization.
RRM domain 2 has moderate RNA-binding affinity. RRM domains 3 and 4 may facilitate RNA looping when binding to two appropriately separated binding sites within the same target pre-mRNA (PubMed:23782695).
Several isoelectric forms of the L protein are probably the results of post-translational modifications.
Splicing factor binding to exonic or intronic sites and acting as either an activator or repressor of exon inclusion. Exhibits a binding preference for CA-rich elements (PubMed:11809897, PubMed:22570490, PubMed:24164894, PubMed:25623890, PubMed:26051023). Component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes and associated with most nascent transcripts (PubMed:2687284). Associates, together with APEX1, to the negative calcium responsive element (nCaRE) B2 of the APEX2 promoter (PubMed:11809897). As part of a ribonucleoprotein complex composed at least of ZNF827, HNRNPK and the circular RNA circZNF827 that nucleates the complex on chromatin, may negatively regulate the transcription of genes involved in neuronal differentiation (PubMed:33174841). Regulates alternative splicing of a core group of genes involved in neuronal differentiation, likely by mediating H3K36me3-coupled transcription elongation and co-transcriptional RNA processing via interaction with CHD8.
Gastric, colon, rectal, and pancreatic carcinomas.
Highly expressed in pancreas (PubMed:11245983). Also expressed in stomach, adrenal cortex and brain (PubMed:11245983). In brain, expressed in cells throughout the cortex (PubMed:34610277).
Receptor for gastrin-releasing peptide (GRP) (PubMed:1655761). Signals via association with G proteins that activate a phosphatidylinositol-calcium second messenger system, resulting in Akt phosphorylation. Contributes to the regulation of food intake. Contributes to the perception of prurient stimuli and transmission of itch signals in the spinal cord that promote scratching behavior, but does not play a role in the perception of pain. Contributes primarily to nonhistaminergic itch sensation. In one study, shown to act in the amygdala as part of an inhibitory network which inhibits memory specifically related to learned fear (By similarity). In another study, shown to contribute to disinhibition of glutamatergic cells in the auditory cortex via signaling on vasoactive intestinal peptide-expressing cells which leads to enhanced auditory fear memories (By similarity). Contributes to the induction of sighing through signaling in the pre-Botzinger complex, a cluster of several thousand neurons in the ventrolateral medulla responsible for inspiration during respiratory activity (By similarity).
Could be involved with bystin and trophinin in a cell adhesion molecule complex that mediates an initial attachment of the blastocyst to uterine epithelial cells at the time of the embryo implantation.
Directly binds bystin, and indirectly trophinin.
Strong expression at implantation sites. Was exclusively localized to the apical side of the syncytiotrophoblast. Also found in macrophages.
Highly expressed in the hypothalamus (PubMed:23161870). Also expressed in spinal cord, kidney and testis.
Plasma membrane progesterone (P4) receptor coupled to G proteins (PubMed:23763432). Seems to act through a G(i) mediated pathway (PubMed:23763432). May be involved in oocyte maturation (By similarity). Also binds dehydroepiandrosterone (DHEA), pregnanolone, pregnenolone and allopregnanolone (PubMed:23161870).
Binds to the catalytic subunit of the cyclin dependent kinases and is essential for their biological function.
Forms a homohexamer that can probably bind six kinase subunits.
Expressed in prostate, breast, testis and salivary gland.
C2H2-type zinc-finger domains 5 and 6 are important for the interaction with SOX9.
Transcriptional regulator (PubMed:14621294, PubMed:19549071). Recognizes and binds 2 copies of the core DNA sequence motif 5'-GGGGG-3' (PubMed:14621294). Binds to the HMGN1 promoter and may repress HMGN1 expression (PubMed:14621294). Regulates SNCA expression in primary cortical neurons (PubMed:19549071). Binds to the COL2A1 promoter and activates COL2A1 expression, as part of a complex with SOX9 (By similarity). Plays a role in chondrocyte differentiation (By similarity).
Expressed in fetal lung and kidney and in adult prostate and ovary.
(Microbial infection) Interacts with Rev of HIV-1.
(Microbial infection) Interacts with Severe acute respiratory syndrome coronavirus (SARS-CoV) (via N-terminus) (PubMed:20573827). Interacts (via C-terminus) with the replicase polyprotein 1ab Nsp14 of the Avian infectious bronchitis virus (IBV).
(Microbial infection) Required for Coronavirus IBV replication.
(Microbial infection) Required for HIV-1 Rev function as well as for HIV-1 and coronavirus IBV replication. Binds to the RRE sequence of HIV-1 mRNAs.
According to some authors the unwinding activity is ADP-dependent and not ATP-dependent.
Acts as an ATP-dependent RNA helicase, able to unwind both RNA-RNA and RNA-DNA duplexes. Possesses 5' single-stranded RNA overhang nuclease activity. Possesses ATPase activity on various RNA, but not DNA polynucleotides. May play a role in RNA clearance at DNA double-strand breaks (DSBs), thereby facilitating the template-guided repair of transcriptionally active regions of the genome. Together with RELA, acts as a coactivator to enhance NF-kappa-B-mediated transcriptional activation. Acts as a positive transcriptional regulator of cyclin CCND2 expression. Binds to the cyclin CCND2 promoter region. Associates with chromatin at the NF-kappa-B promoter region via association with RELA. Binds to poly(A) RNA. May be involved in 3'-end cleavage and polyadenylation of pre-mRNAs. Component of the tRNA-splicing ligase complex required to facilitate the enzymatic turnover of catalytic subunit RTCB: together with archease (ZBTB8OS), acts by facilitating the guanylylation of RTCB, a key intermediate step in tRNA ligation (PubMed:24870230). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines via the adapter molecule TICAM1. Specifically binds (via helicase ATP-binding domain) on both short and long poly(I:C) dsRNA (By similarity).
Belongs to the DEAD box helicase family. DDX1 subfamily.
Found in a multi-helicase-TICAM1 complex at least composed of DHX36, DDX1, DDX21 and TICAM1; this complex exists in resting cells with or without poly(I:C) RNA ligand stimulation. Interacts with DHX36. Interacts (via B30.2/SPRY domain) with DDX21 (via N-terminus); this interaction serves as bridges to TICAM1 (By similarity). Interacts with FAM98A (via N- and C-terminus) (PubMed:28040436). Interacts with MBNL1 (PubMed:18335541). Interacts with CSTF2 (PubMed:11598190). Interacts with HNRNPK (PubMed:12183465). Interacts with ATM (PubMed:18710941). Interacts with RELA (via C-terminus) (PubMed:19058135). Component of the tRNA-splicing ligase complex (PubMed:21311021, PubMed:24870230). Interacts with PQBP1 (PubMed:21933836). Interacts with PHF5A (via C-terminus) (By similarity). Interacts with ERCC6 (PubMed:26030138).
Highest levels of transcription in 2 retinoblastoma cell lines and in tissues of neuroectodermal origin including the retina, brain, and spinal cord.
Phosphorylated by ATM kinase; phosphorylation is increased in response to ionizing radiation (IR).
The helicase domain is involved in the stimulation of RELA transcriptional activity.
Defects in WWOX may be involved in several cancer types. The gene spans the second most common chromosomal fragile site (FRA16D) which is frequently altered in cancers (PubMed:10861292). Alteration of the expression and expression of some isoforms is associated with cancers. However, it is still unclear if alteration of WWOX is directly implicated in cancerogenesis or if it corresponds to a secondary effect (PubMed:10861292, PubMed:11572989, PubMed:15266310, PubMed:15073125, PubMed:15131042).
Interacts with TP53, p73/TP73 and MAPK8. Interacts with MAPT/TAU, RUNX2 and HYAL2 (By similarity). Forms a ternary complex with TP53 and MDM2. Interacts with ERBB4, LITAF and WBP1. Interacts with DVL1, DVL2 and DVL3. May interact with FAM189B and SCOTIN. Interacts with TNK2. Interacts with TMEM207. Interacts (via WW domain) with VOPP1 (PubMed:30285739).
Phosphorylated upon genotoxic stress. Phosphorylation of Tyr-33 regulates interaction with TP53, TP73 and MAPK8. May also regulate proapoptotic activity. Phosphorylation by TNK2 is associated with polyubiquitination and degradation.
Putative oxidoreductase. Acts as a tumor suppressor and plays a role in apoptosis. Required for normal bone development (By similarity). May function synergistically with p53/TP53 to control genotoxic stress-induced cell death. Plays a role in TGFB1 signaling and TGFB1-mediated cell death. May also play a role in tumor necrosis factor (TNF)-mediated cell death. Inhibits Wnt signaling, probably by sequestering DVL2 in the cytoplasm.
The WW 1 domain mediates interaction with TP53, and probably TP73, TFAP2C, LITAF and WBP1.
Ubiquitinated when phosphorylated by TNK2, leading to its degradation.
Widely expressed. Strongly expressed in testis, prostate, and ovary. Overexpressed in cancer cell lines. Isoform 5 and isoform 6 may only be expressed in tumor cell lines.
Keratin-binding protein required for epithelial cell polarization. Involved in apical junction complex (AJC) assembly via its interaction with PARD3. Required for ciliogenesis.
May interact with FAS cytoplasmic domain (By similarity). Interacts with PARD3 (By similarity) (PubMed:18838552). Interacts with TRAPPC14 (PubMed:31467083).
Present in various epithelial cells (at protein level).
Belongs to the ClpA/ClpB family. Torsin subfamily.
Homohexamer. Interacts with TOR1B; the interaction may be specific of neural tissues. Interacts (ATP-bound) with TOR1AIP1 and TOR1AIP2; the interactions induce ATPase activity. Interacts with KLHL14; preferentially when ATP-free. Interacts with KLC1 (via TPR repeats); the interaction associates TOR1A with the kinesin oligomeric complex. Interacts with COPS4; the interaction associates TOR1A with the CSN complex. Interacts with SNAPIN; the interaction is direct and associates SNAPIN with the CSN complex. Interacts with STON2. Interacts (ATP-bound) with SYNE3 (via KASH domain); the interaction is required for SYNE3 nuclear envelope localization. Interacts with VIM; the interaction associates TOR1A with the cytoskeleton. Interacts with PLEC. Interacts (ATP-bound) with SLC6A3; regulates SLC6A3 transport to the plasma membrane.
Protein with chaperone functions important for the control of protein folding, processing, stability and localization as well as for the reduction of misfolded protein aggregates. Involved in the regulation of synaptic vesicle recycling, controls STON2 protein stability in collaboration with the COP9 signalosome complex (CSN). In the nucleus, may link the cytoskeleton with the nuclear envelope, this mechanism seems to be crucial for the control of nuclear polarity, cell movement and, specifically in neurons, nuclear envelope integrity. Participates in the cellular trafficking and may regulate the subcellular location of multipass membrane proteins such as the dopamine transporter SLC6A3, leading to the modulation of dopamine neurotransmission. In the endoplasmic reticulum, plays a role in the quality control of protein folding by increasing clearance of misfolded proteins such as SGCE variants or holding them in an intermediate state for proper refolding. May have a redundant function with TOR1B in non-neural tissues.
Widely expressed. Highest levels in kidney and liver. In the brain, high levels found in the dopaminergic neurons of the substantia nigra pars compacta, as well as in the neocortex, hippocampus and cerebellum. Also highly expressed in the spinal cord.
Belongs to the prokaryotic/mitochondrial release factor family.
Expressed in skeletal muscle (at protein level).
Methylation of glutamine in the GGQ triplet by HEMK1 is conserved from bacteria to mammals.
Mitochondrial peptide chain release factor that directs the termination of translation in response to the peptide chain termination codons UAA and UAG.
The GGQ domain interacts with the peptidyltransferase center (PTC) of the large ribosomal subunit to trigger nascent chain hydrolysis.
Was initially thought to promote the termination of non-canonical termination stop codons AGG and AGA in addition to canonical termination codons UAA and UAG (PubMed:20075246). However, it was later shown that termination of non-canonical termination stop codons AGG and AGA is mediated by MTRF1 (PubMed:37141370).
Component of the CAVIN complex composed of CAVIN1, CAVIN2, CAVIN3 and CAVIN4. Interacts with PRKCD and with phosphatidylserine. Phosphatidylserine may form a bridge between PKC and PKC-binding partners and stabilize the binding. Interacts with PER2. Interacts with CAVIN1 (By similarity). Interacts (via leucine-zipper domain) with CAV1 in a cholesterol-sensitive manner (PubMed:19262564). Interacts with EPS15L1 (PubMed:19262564).
Down-regulated in breast and lung cancer cell lines.
Regulates the traffic and/or budding of caveolae (PubMed:19262564). Plays a role in caveola formation in a tissue-specific manner. Required for the formation of caveolae in smooth muscle but not in the lung and heart endothelial cells. Regulates the equilibrium between cell surface-associated and cell surface-dissociated caveolae by promoting the rapid release of caveolae from the cell surface. Plays a role in the regulation of the circadian clock. Modulates the period length and phase of circadian gene expression and also regulates expression and interaction of the core clock components PER1/2 and CRY1/2 (By similarity).
Skeletal muscle, liver, stomach, lung, kidney and heart (at protein level). Strongly expressed in mammary and epithelial cells.
The leucine-zipper domain is essential for its localization in the caveolae and for its interaction with CAV1 and EPS15L1.
It is uncertain whether Met-1 or Met-39 is the initiator. Met-1 does not seem to exist in orthologs.
Autophosphorylated at multiple residues, Thr-348 being the major site. Phosphorylated by AMP-activated protein kinase AMPK at Ser-398 leading to EEF2K activation and protein synthesis inhibition. Phosphorylated by TRPM7 at Ser-78 resulting in improved protein stability, higher EE2F phosphorylated and subsequently reduced rate of protein synthesis. Phosphorylation by other kinases such as CDK1 and MAPK13 at Ser-359 or RPS6KA1 and RPS6KB1 at Ser-366 instead decrease EEF2K activity and promote protein synthesis.
Belongs to the protein kinase superfamily. Alpha-type protein kinase family.
Monomer or homodimer (Probable). Interacts with Calmodulin/CALM1; this interaction is strictly required for phosphorylation activity (PubMed:11015200).
Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation. Upon activation by a variety of upstream kinases including AMPK or TRPM7, phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive. In turn, the rate of protein synthesis is reduced.
Undergoes calcium/calmodulin-dependent intramolecular autophosphorylation, and this results in it becoming partially calcium/calmodulin-independent.
Readthrough transcript which is the product of an upstream read-through pseudogene (SUGT1P4-STRA6LP) with CCDC180.
Binds to SUMO2 and SUMO3 (PubMed:15296745). Interacts with the C-terminal domain of NUP153 via its N-terminus (PubMed:11896061, PubMed:12192048). Interacts with MTA1 (PubMed:21965678).
Polyubiquitinated; which leads to proteasomal degradation.
Protease that catalyzes two essential functions in the SUMO pathway (PubMed:11896061, PubMed:12192048, PubMed:20194620, PubMed:21965678, PubMed:15296745). The first is the hydrolysis of an alpha-linked peptide bond at the C-terminal end of the small ubiquitin-like modifier (SUMO) propeptides, SUMO1, SUMO2 and SUMO3 leading to the mature form of the proteins (PubMed:15296745). The second is the deconjugation of SUMO1, SUMO2 and SUMO3 from targeted proteins, by cleaving an epsilon-linked peptide bond between the C-terminal glycine of the mature SUMO and the lysine epsilon-amino group of the target protein (PubMed:20194620, PubMed:21965678, PubMed:15296745). May down-regulate CTNNB1 levels and thereby modulate the Wnt pathway (By similarity). Deconjugates SUMO2 from MTA1 (PubMed:21965678). Plays a dynamic role in adipogenesis by desumoylating and promoting the stabilization of CEBPB (PubMed:20194620). Acts as a regulator of the cGAS-STING pathway by catalyzing desumoylation of CGAS and STING1 during the late phase of viral infection (By similarity).
The N-terminus is necessary and sufficient for nuclear envelope targeting.
Belongs to the class I-like SAM-binding methyltransferase superfamily. mRNA cap 0 methyltransferase family.
Catalytic subunit of the mRNA-capping methyltransferase RNMT:RAMAC complex that methylates the N7 position of the added guanosine to the 5'-cap structure of mRNAs (PubMed:9790902, PubMed:9705270, PubMed:10347220, PubMed:11114884, PubMed:22099306, PubMed:27422871). Binds RNA containing 5'-terminal GpppC (PubMed:11114884).
In the N-terminal section; belongs to the dsDNA virus mRNA guanylyltransferase family.
Interacts with importin alpha, leading to stimulate both RNA-binding and methyltransferase activity (PubMed:11114884). Interaction with importin alpha and beta is required for its nuclear localization, importin beta dissociating in response to RanGTP, allowing RNMT-importin alpha to bind RNA substrates (PubMed:11114884). Interacts with elongating form of polymerase II and RNGTT (PubMed:9705270). Interacts with RAMAC, this interaction significantly enhances RNA-binding and cap methyltransferase activity (PubMed:22099306, Ref.14).
Methyltransferase activity is activated by RAMAC (PubMed:27422871).
Interacts with PEX5, probably required to target it into peroxisomes.
Participates in chain elongation of fatty acids. Catalyzes the reduction of trans-2-enoyl-CoAs of varying chain lengths from 6:1 to 16:1, having maximum activity with 10:1 CoA. Has no 2,4-dienoyl-CoA reductase activity.
Component of the FTS/Hook/FHIP complex (FHF complex) (PubMed:18799622, PubMed:32073997). The FHF complex may function to promote vesicle trafficking and/or fusion via the homotypic vesicular protein sorting complex (the HOPS complex) (PubMed:18799622). FHF complex promotes the distribution of AP-4 complex to the perinuclear area of the cell (PubMed:32073997). Required for spermatid differentiation. Probably involved in the positioning of the microtubules of the manchette and the flagellum in relation to the membrane skeleton (By similarity).
Self-associates (PubMed:18799622, PubMed:32073997). Component of the FTS/Hook/FHIP complex (FHF complex), composed of AKTIP/FTS, FHIP1B, and one or more members of the Hook family of proteins HOOK1, HOOK2, and HOOK3 (PubMed:18799622, PubMed:32073997). Interacts directly with AKTIP/FTS, HOOK2 and HOOK3 (PubMed:18799622, PubMed:32073997). Associates with several subunits of the homotypic vesicular sorting complex (the HOPS complex) including VPS16, VPS18, VPS39 and VPS41; these interactions may be indirect (PubMed:18799622). Interacts with CCDC181 (By similarity). Interacts (via coiled-coil region) with RIMBP3 (via C-terminus) (By similarity). Interacts with LRGUK (via guanylate kinase-like domain) (By similarity). Interacts with microtubules (PubMed:11238449). May interact with CLN3 (PubMed:15471887). Interacts with AP4M1; the interaction is direct, mediates the interaction between FTS-Hook-FHIP (FHF) complex and AP-4 and the perinuclear distribution of AP-4 (PubMed:32073997).
Efficient DNA binding requires dimerization with another bHLH protein (By similarity). Heterodimer with NPAS4 (PubMed:24465693). Heterodimer with SIM1 (By similarity). Heterodimer with the aryl hydrocarbon receptor (AHR) or the SIM1 protein (By similarity). Interacts with TACC3 (By similarity).
Transcription factor that plays a role in the development of the hypothalamo-pituitary axis, postnatal brain growth, and visual and renal function (PubMed:24022475). Specifically recognizes the xenobiotic response element (XRE).
Belongs to the FPP/GGPP synthase family.
Heterotetramer composed of 2 PDSS1/DPS1 and 2 PDSS2/DLP1 subunits.
Heterotetrameric enzyme that catalyzes the condensation of farnesyl diphosphate (FPP), which acts as a primer, and isopentenyl diphosphate (IPP) to produce prenyl diphosphates of varying chain lengths and participates in the determination of the side chain of ubiquinone (PubMed:16262699). Supplies nona and decaprenyl diphosphate, the precursors for the side chain of the isoprenoid quinones ubiquinone-9 (Q9) and ubiquinone-10 (Q10) respectively (PubMed:16262699). The enzyme adds isopentenyl diphosphate molecules sequentially to farnesyl diphosphate with trans stereochemistry (PubMed:16262699). May play a role during cerebellar development (By similarity). May regulate mitochondrial respiratory chain function (By similarity).
Arg-291 is dimethylated, probably to asymmetric dimethylarginine.
Phosphorylated at Ser-84 by MAPKAPK2 in response to LPS treatment, promoting stabilization of GADD45A mRNA.
mRNA-binding component of ribonucleosomes. Specifically binds AU-rich element (ARE)-containing mRNAs. Involved in post-transcriptional regulation of cytokines mRNAs.
(Microbial infection) N- and C-terminal domains are required for AAV transduction.
(Microbial infection) Plays an essential function in adeno-associated virus (AAV) transduction across multiple serotypes except AAV5. May play a critical role in mediating the endosomal virus escape or in the AAV virions trafficking from endosomes to the nucleus.
May play a role in intracellular immune modulation by activating NF-kappaB response and attenuating Toll-like-receptor response.
Belongs to the zinc-containing alcohol dehydrogenase family.
Catalyzes the NAD-dependent oxidation of all-trans-retinol and its derivatives such as all-trans-4-hydroxyretinol and may participate in retinoid metabolism (PubMed:15369820, PubMed:16787387). In vitro can also catalyzes the NADH-dependent reduction of all-trans-retinal and its derivatives such as all-trans-4-oxoretinal (PubMed:15369820, PubMed:16787387). Catalyzes in the oxidative direction with higher efficiency (PubMed:16787387). Has the same affinity for all-trans-4-hydroxyretinol and all-trans-4-oxoretinal (PubMed:15369820).
Dimer of identical or non-identical chains of three types; alpha, beta and gamma.
There are 7 different ADH's isozymes in human: three belongs to class-I: alpha, beta, and gamma, one to class-II: pi, one to class-III: chi, one to class-IV: ADH7 and one to class-V: ADH6.
Three alleles are known: ADH1B*1 (ADH2*1) corresponding to variant beta-1, ADH1B*2 (ADH2*2) corresponding to variant beta-2, ADH1B*3 (ADH2*3) corresponding to variant beta-3. The sequence shown is that of allele ADH1B*2. The ADH1B*2 allele frequency in orientals is approximately 75%, whereas it is less than 5% in most Caucasian populations. The ADH1B*2 allele is associated with a lower risk of alcoholism. ADH1B variations have been associated with protection against alcohol dependence and alcohol-related aerodigestive tract cancer [MIM:103720].
Expressed in adipose tissue, heart, brain, skeletal muscle, pancreas, thymus, prostate, testis, ovary, small intestine and colon. Highest levels in adipose tissue, small intestine and colon.
Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts. They have a role in regulating cell growth and differentiation in specific cell types. SFRP2 may be important for eye retinal development and for myogenesis.
Required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in mitochondrial tRNAs that read codons beginning with adenine. Probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37. Involved in mitochondrial genome maintenance.
Widely expressed, with maximum expression in pituitary gland, prostate, rectum and uterus.
Belongs to the histidine acid phosphatase family. VIP1 subfamily.
Bifunctional inositol kinase that acts in concert with the IP6K kinases IP6K1, IP6K2 and IP6K3 to synthesize the diphosphate group-containing inositol pyrophosphates diphosphoinositol pentakisphosphate, PP-InsP5, and bis-diphosphoinositol tetrakisphosphate, (PP)2-InsP4. PP-InsP5 and (PP)2-InsP4, also respectively called InsP7 and InsP8, regulate a variety of cellular processes, including apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, insulin signaling and neutrophil activation. Phosphorylates inositol hexakisphosphate (InsP6) at position 1 to produce PP-InsP5 which is in turn phosphorylated by IP6Ks to produce (PP)2-InsP4. Alternatively, phosphorylates PP-InsP5 at position 1, produced by IP6Ks from InsP6, to produce (PP)2-InsP4. Activated when cells are exposed to hyperosmotic stress.
The C-terminal acid phosphatase-like domain binds PtdIns(3,4,5)P3 and InsP6. Despite its similarity with the phosphatase domain of histidine acid phosphatases, it has no phosphatase activity.
Widely expressed, with a higher expression in skeletal muscle, heart and brain.
Cell-cycle regulated. Increases during G2/M phase and then reduces after exit from M phase.
Cells lacking CDCA8 display a slight decrease in histone H3 'Ser-10' phosphorylation, suggesting that the CPC complex mediates phosphorylation of 'Ser-10' of histone H3.
Component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Major effector of the TTK kinase in the control of attachment-error-correction and chromosome alignment.
May form homooligomers and homodimers. Component of the chromosomal passenger complex (CPC) composed of at least BIRC5/survivin, CDCA8/borealin, INCENP, AURKB or AURKC; in the complex forms a triple-helix bundle-based subcomplex with INCENP and BIRC5 (PubMed:17956729). Interacts with SENP3, UBE2I and RANBP2. Interacts (phosphorylated) with SGO1 and SGO2; the association is dependent on CDK1.
Phosphorylated by TTK, essentially at Thr-88, Thr94, Thr-169 and Thr-230. Phosphorylation (probably by CDK1) promotes targeting of the CPC to centromeric DNA.
Sumoylated by UBE2I and RANBP2. Desumoylated by SENP3 through the removal of SUMO2 and SUMO3.
The C-terminal region (aa 207-280) represents the dimerization motif.
Can interact with DNA and histones and may scavenge nuclear material released from damaged circulating cells. May also function as a calcium-dependent lectin.
Homopentamer. Pentaxin (or pentraxin) have a discoid arrangement of 5 non-covalently bound subunits.
Homopentamer. Pentraxin (or pentaxin) have a discoid arrangement of 5 non-covalently bound subunits.
N-glycosylated with a complex biantennary oligosaccharide chain with a sialic acid at the end (disialo-SAP). Monosialo-SAP as well as asioalo-SAP are also detected (PubMed:15174148).
SAP is a precursor of amyloid component P which is found in basement membrane and associated with amyloid deposits.
Defect in TMEM263 has been found in a fetus with severe lethal skeletal dysplasia. The homozygous frameshift mutation found in this fetus results in the creation of a premature stop codon at Lys-68.
Belongs to the pectinacetylesterase family. Notum subfamily.
Carboxylesterase that acts as a key negative regulator of the Wnt signaling pathway by specifically mediating depalmitoleoylation of WNT proteins. Serine palmitoleoylation of WNT proteins is required for efficient binding to frizzled receptors (PubMed:25731175).
Rarely expressed in adult normal tissues.
The molecular function of NOTUM has remained unclear for many years. It was initially thought to hydrolyze glycosaminoglycan (GAG) chains of glypicans, thereby affecting glypicans ability to interact with Wnt ligands. It was later reported to trigger glypican shedding, by mediating cleavage of their GPI-anchor. However, while NOTUM specifically inhibit the Wnt signaling pathway, more pleiotropic effects would be expected from an enzyme affecting glypicans. It was finally shown that it requires glypicans to suppress Wnt signaling, but does not cleave their GPI-anchor. It acts by mediating depalmitoleoylation of WNT proteins, impairing WNT binding to frizzled receptors (PubMed:25731175).
Up-regulated in hepatocellular carcinoma (HCC) with high intracellular beta-catenin.
Belongs to the constitutive coactivator of PPAR-gamma family.
Functions as a transactivator of PPARG and ESR1. Functions in adipogenesis through PPARG activation (By similarity).
Interacts with ESR1 and RXRA. Interacts with PPARG; in a ligand-independent manner (By similarity).
Expressed moderately in spleen, kidney, bone marrow, small intestine and leukocytes. Expressed weakly in testis, trachea and colon.
Homodimer. Forms heterodimers with TFE3. Forms heterodimers with MITF (By similarity). Interacts with MITF (By similarity).
Transcriptional regulator that acts as a repressor or an activator. Acts as a transcriptional repressor on minimal promoter containing element F (that includes an E-box sequence). Binds to element F in an E-box sequence-specific manner. Acts as a transcriptional transactivator on the proximal promoter region of the tartrate-resistant acid phosphatase (TRAP) E-box containing promoter (By similarity). Collaborates with MITF in target gene activation (By similarity). Acts as a transcriptional repressor on minimal promoter containing mu E3 enhancer sequence (By similarity). Binds to mu E3 DNA sequence of the immunoglobulin heavy-chain gene enhancer (By similarity). Binds DNA in a homo- or heterodimeric form.
Plays a role in the organization of the endoplasmic reticulum exit sites (ERES), also known as transitional endoplasmic reticulum (tER). Required for secretory cargo traffic from the endoplasmic reticulum to the Golgi apparatus (PubMed:17192411, PubMed:21768384, PubMed:22355596). Involved in peroxisome biogenesis. Regulates the transport of peroxisomal biogenesis factors PEX3 and PEX16 from the ER to peroxisomes (PubMed:21768384).
SEC16A and SEC16B are each present in multiple copies in a heteromeric complex (PubMed:17192411, PubMed:22355596). Interacts with TFG (PubMed:21478858). Interacts with SEC13 (PubMed:22355596).
Contains an N-terminal anti-parallel coiled coil formed by two BRMS1 chains; this region can form homohexamers.
Expression levels are higher in term placentas than in early placentas. Low levels of expression observed in normal pregnancies and in molar pregnancies.
Homohexamer (Potential). Interacts with SNX6, HDAC1 and RELA. Interacts with ARID4A. Identified in mSin3A corepressor complexes together with SIN3A, SIN3B, RBBP4, RBBP7, SAP30, SUDS3, ARID4A, HDAC1 and HDAC2. Interacts with SPOP; this recruits the protein to a ubiquitin ligase complex containing SPOP and CUL3.
Transcriptional repressor. Down-regulates transcription activation by NF-kappa-B by promoting the deacetylation of RELA at 'Lys-310'. Promotes HDAC1 binding to promoter regions. Down-regulates expression of anti-apoptotic genes that are controlled by NF-kappa-B. Promotes apoptosis in cells that have inadequate adherence to a substrate, a process called anoikis, and may thereby inhibit metastasis. May be a mediator of metastasis suppression in breast carcinoma.
Ubiquitinated by a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing SPOP, leading to proteasomal degradation.
Has no constitutive proton transporter activity and has to be activated by long-chain fatty acids/LCFAs (PubMed:28781081). Inhibited by purine nucleotides (PubMed:28781081). Both purine nucleotides and LCFAs bind the cytosolic side of the transporter and directly compete to activate or inhibit it (PubMed:28781081). Activated by noradrenaline and reactive oxygen species. Despite lacking canonical translational encoding for selenocysteine, a small pool of the protein has been observed to selectively incorporate selenocysteine at 'Cys-254'. Selenocysteine-modified protein is highly sensitive to redox modification and may constitute a pool of protein highly sensitive to activation by elevated levels of reactive oxygen species (ROS).
May undergo sulfenylation upon cold exposure. May increase the sensitivity of UCP1 thermogenic function to the activation by noradrenaline probably through structural effects.
May undergo ubiquitin-mediated proteasomal degradation.
Mitochondrial protein responsible for thermogenic respiration, a specialized capacity of brown adipose tissue and beige fat that participates in non-shivering adaptive thermogenesis to temperature and diet variations and more generally to the regulation of energy balance (By similarity). Functions as a long-chain fatty acid/LCFA and proton symporter, simultaneously transporting one LCFA and one proton through the inner mitochondrial membrane (PubMed:24196960, PubMed:28781081). However, LCFAs remaining associated with the transporter via their hydrophobic tails, it results in an apparent transport of protons activated by LCFAs. Thereby, dissipates the mitochondrial proton gradient and converts the energy of substrate oxydation into heat instead of ATP. Regulates the production of reactive oxygen species/ROS by mitochondria (By similarity).
Mitochondrial protein responsible for thermogenic respiration, a specialized capacity of brown adipose tissue and beige fat that participates in non-shivering adaptive thermogenesis to temperature and diet variations and more generally to the regulation of energy balance. Functions as a long-chain fatty acid/LCFA and proton symporter, simultaneously transporting one LCFA and one proton through the inner mitochondrial membrane. However, LCFAs remaining associated with the transporter via their hydrophobic tails, it results in an apparent transport of protons activated by LCFAs. Thereby, dissipates the mitochondrial proton gradient and converts the energy of substrate oxydation into heat instead of ATP. Regulates the production of reactive oxygen species/ROS by mitochondria.
Most probably functions as a monomer. Binds one purine nucleotide per monomer (By similarity). However, has also been suggested to function as a homodimer or a homotetramer (PubMed:24196960). Tightly associates with cardiolipin in the mitochondrion inner membrane; may stabilize and regulate its activity (PubMed:24196960).
Expressed in brain, kidney, heart, pancreas and placenta. Not detected in skeletal muscle or liver.
Guanine nucleotide exchange factor (GEF) which may activate RAB8A and RAB8B (PubMed:12221131, PubMed:26824392). Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form (PubMed:12221131, PubMed:26824392). Mediates the release of GDP from RAB8A and RAB8B but not from RAB3A or RAB5 (PubMed:20937701, PubMed:26824392). Modulates actin organization and promotes polarized transport of RAB8A-specific vesicles to the cell surface (PubMed:12221131). Together with RAB11A, RAB8A, the exocyst complex, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis (PubMed:20890297). Part of the ciliary targeting complex containing Rab11, ASAP1, RAB3IP and RAB11FIP3 and ARF4 that promotes RAB3IP preciliary vesicle trafficking to mother centriole and ciliogenesis initiation (PubMed:31204173, PubMed:25673879).
Homodimer (PubMed:26258637). Interacts with the N-terminal region of SSX2 (PubMed:12007189). Interacts with the GDP-bound forms of RAB8A and RAB8B (PubMed:26824392, PubMed:12221131). The interaction with RAB8A is prevented by phosphorylation of RAB8A at 'Thr-72' (PubMed:26824392). Interacts with the GDP-bound forms of RAB3A and RAB3D (PubMed:12221131). Interacts with DCDC1 (PubMed:22159412, PubMed:12007189, PubMed:12221131, PubMed:26824392). Interacts (via the N-terminal region) with TRAPPC14; this interaction mediates RAB3IP association with the TRAPP II complex (PubMed:31467083). Forms a heterotetramer with RAB11A where RAB3IP homodimer binds two RAB11A subunits (PubMed:26258637). Forms a complex with RAB11A and RAB11FIP3, probably a heterohexamer with two of each protein subunit, where Rabin8/RAB3IP and RAB11FIP3 simultaneously bind to RAB11A; the complex promotes preciliary trafficking (PubMed:26258637, PubMed:31204173). Forms a complex containing RAB11A, ASAP1, RAB3IP, RAP11FIP3 and ARF4; the complex promotes preciliary trafficking; the complex binds to RHO in photoreceptor cells and promotes RHO ciliary transport (PubMed:25673879).
Phosphorylated by AKT1; the phosphorylation alters its GEF activity.
Phosphorylation by ATK1 alters its GEF activity (PubMed:31204173). Complex formation with RAB11A and RAB11FIP3 and ciliogenesis function are competitively inhibited by RAB11A-WDR44 interaction (PubMed:31204173).
Belongs to the olfactory marker protein family.
May act as a modulator of the olfactory signal-transduction cascade.
Uniquely associated with mature olfactory receptor neurons.
Expressed during cranofacial development as well as in heart.
Expressed in heart, skeletal muscle, liver, lung, bone marrow fibroblast, pancreas and placenta.
May be a growth regulator and have a role in specifying neural systems involved in processing somatosensory information, as well as in face and body structure formation.
Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis (PubMed:27626371, PubMed:32385911, PubMed:33153867). Complex I functions in the transfer of electrons from NADH to the respiratory chain (PubMed:27626371). The immediate electron acceptor for the enzyme is believed to be ubiquinone (PubMed:27626371).
Belongs to the complex I NDUFA8 subunit family.
Contains four C-X9-C motifs that are predicted to form a helix-coil-helix structure, permitting the formation of intramolecular disulfide bonds.
May contain intrachain disulfide bonds, as evidenced by its electrophoretic mobility under reducing vs non-reducing conditions.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL69.
(Microbial infection) The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production.
Belongs to the DEAD box helicase family. DECD subfamily.
Homodimer, and heterodimer with DDX39A (PubMed:11675789, PubMed:15833825, PubMed:14667819). Component of the transcription/export (TREX) complex at least composed of ALYREF/THOC4, DDX39B, SARNP/CIP29, CHTOP and the THO subcomplex; TREX seems to have dynamic structure involving ATP-dependent remodeling; in the complex bridges ALYREF/THOC4 and the THO complex, and, in a ATP-dependent manner, ALYREF/THOC4 and SARNP/CIP29 (PubMed:11675789, PubMed:15833825, PubMed:14667819, PubMed:15998806, PubMed:17984224, PubMed:20844015, PubMed:23299939). Component of the spliceosome. Interacts directly with U2AF2 (PubMed:9242493). Interacts with RBM8A, RNPS1 and SRRM1, FYTTD1/UIF, THOC1, MX1 and POLDIP3 (PubMed:12944400, PubMed:15870275, PubMed:19836239, PubMed:21859714, PubMed:22928037). Interacts with LUZP4 (PubMed:25662211).
Involved in nuclear export of spliced and unspliced mRNA. Assembling component of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NFX1 pathway. May undergo several rounds of ATP hydrolysis during assembly of TREX to drive subsequent loading of components such as ALYREF/THOC and CHTOP onto mRNA. Also associates with pre-mRNA independent of ALYREF/THOC4 and the THO complex. Involved in the nuclear export of intronless mRNA; the ATP-bound form is proposed to recruit export adapter ALYREF/THOC4 to intronless mRNA; its ATPase activity is cooperatively stimulated by RNA and ALYREF/THOC4 and ATP hydrolysis is thought to trigger the dissociation from RNA to allow the association of ALYREF/THOC4 and the NXF1-NXT1 heterodimer. Involved in transcription elongation and genome stability.
Splice factor that is required for the first ATP-dependent step in spliceosome assembly and for the interaction of U2 snRNP with the branchpoint. Has both RNA-stimulated ATP binding/hydrolysis activity and ATP-dependent RNA unwinding activity. Even with the stimulation of RNA, the ATPase activity is weak. Can only hydrolyze ATP but not other NTPs. The RNA stimulation of ATPase activity does not have a strong preference for the sequence and length of the RNA. However, ssRNA stimulates the ATPase activity much more strongly than dsRNA. Can unwind 5' or 3' overhangs or blunt end RNA duplexes in vitro. The ATPase and helicase activities are not influenced by U2AF2; the effect of ALYREF/THOC4 is reported conflictingly with [PubMed:23299939] reporting a stimulatory effect.
The helicase C-terminal domain mediates interaction with ALYREF/THOC4.
Protease which processes procollagen C-propeptides, such as chordin, pro-biglycan and pro-lysyl oxidase. Required for the embryonic development. Predominant protease, which in the development, influences dorsal-ventral patterning and skeletogenesis.
A beta-galactoside alpha2-3 sialyltransferase primarily involved in terminal sialylation of ganglio and globo series glycolipids (PubMed:8920913, PubMed:9266697). Catalyzes the transfer of sialic acid (N-acetyl-neuraminic acid; Neu5Ac) from the nucleotide sugar donor CMP-Neu5Ac onto acceptor Galbeta-(1->3)-GalNAc-terminated glycoconjugates through an alpha2-3 linkage (PubMed:8920913, PubMed:9266697, PubMed:25916169). Sialylates GM1/GM1a, GA1/asialo-GM1 and GD1b gangliosides to form GD1a, GM1b and GT1b, respectively (PubMed:8920913, PubMed:9266697). Together with ST3GAL3, primarily responsible for biosynthesis of brain GD1a and GT1b that function as ligands for myelin-associated glycoprotein MAG on axons, regulating MAG expression and axonal myelin stability and regeneration (By similarity). Via GT1b regulates TLR2 signaling in spinal cord microglia in response to nerve injury (By similarity). Responsible for the sialylation of the pluripotent stem cell- and cancer stem cell-associated antigen SSEA3, forming SSEA4 (PubMed:12716912). Sialylates with low efficiency asialofetuin, presumably onto O-glycosidically linked Galbeta-(1->3)-GalNAc-O-Ser (PubMed:9266697, PubMed:25916169).
Highly expressed in skeletal muscle and heart and to a much lesser extent in brain, placenta, liver and pancreas. Scarcely detectable in lung and kidney.
Homodimer; disulfide-linked. Homodimer formation occurs in the endoplasmic reticulum.
N-glycosylated; necessary for proper exit from endoplasmic reticulum and trafficking to the Golgi apparatus.
Expressed primarily in the granular layer of the epidermis and inner root sheath of hair follicles. In psoriatic skin, expressed throughout the stratum corneum. In ulcerated skin, expressed in the stratum granulosum of intact epidermis but almost absent from ulcerated regions. Expressed in differentiated areas of squamous cell carcinomas but not in undifferentiated tumors.
It is uncertain whether Met-1 or Met-85 is the initiator.
Protease responsible for filaggrin processing, essential for the maintenance of a proper epidermis organization.
Undergoes autocleavage which is necessary for activation of the protein.
Binds both calcium and zinc. May be involved in calcium-dependent cuticle cell differentiation, hair shaft and hair cuticular barrier formation.
Homodimer and homotetramer for the citrullinated form.
More than half of the arginine residues undergo citrullination by PAD1 and PAD2. Arg-51 is specifically citrullinated by PAD3 and promotes tetramerization.
Skin specific, specifically expressed at the inner endocuticle of hair fibers.
(Microbial infection) Eliminates nuclear HIV-1 cDNA, thereby suppressing immune sensing and proviral hyper-integration.
(Microbial infection) Sumoylation of BLM is decreased by HIV-1 Vpu protein, unleashing end degradation of viral cDNA.
ATP-dependent DNA helicase that unwinds single- and double-stranded DNA in a 3'-5' direction (PubMed:9388193, PubMed:24816114, PubMed:25901030). Participates in DNA replication and repair (PubMed:12019152, PubMed:21325134, PubMed:23509288, PubMed:34606619). Involved in 5'-end resection of DNA during double-strand break (DSB) repair: unwinds DNA and recruits DNA2 which mediates the cleavage of 5'-ssDNA (PubMed:21325134). Negatively regulates sister chromatid exchange (SCE) (PubMed:25901030). Stimulates DNA 4-way junction branch migration and DNA Holliday junction dissolution (PubMed:25901030). Binds single-stranded DNA (ssDNA), forked duplex DNA and DNA Holliday junction (PubMed:20639533, PubMed:24257077, PubMed:25901030). Recruited by the KHDC3L-OOEP scaffold to DNA replication forks where it is retained by TRIM25 ubiquitination, it thereby promotes the restart of stalled replication forks (By similarity).
Monomer (PubMed:28228481). Homodimer (via N-terminus) (PubMed:28228481). Homotetramer (via N-terminus); dimer of dimers (PubMed:28228481). Homohexamer (via N-terminus) (PubMed:28228481). Self-association negatively regulates DNA unwinding amplitude and rate. Oligomeric complexes dissociate into monomer in presence of ATP (PubMed:28228481). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with RMI complex. Interacts directly with RMI1 (via N-terminal region) component of RMI complex. Found in a complex, at least composed of BLM, RAD51 and SPIDR; the complex formation is mediated by SPIDR. Interacts with the KHDC3L/FILIA-OOEP/FLOPED scaffold complex and TRIM25 at DNA replication forks (By similarity). Interacts with ubiquitinated FANCD2 (PubMed:15257300). Interacts with SUPV3L1 (PubMed:17961633). Interacts with TOP3A (via N-terminal region). Interacts with SPIDR (via C-terminal region); the interaction is direct and required to target BLM to sites of DNA damage.
Phosphorylated in response to DNA damage. Phosphorylation requires the FANCA-FANCC-FANCE-FANCF-FANCG protein complex, as well as the presence of RMI1.
Poly-ubiquitinated by TRIM25 at Lys-259 (By similarity). Deubiquitinated by USP37; leading to stabilization in order to sustain the DNA damage response (PubMed:34606619).
The N-terminal region mediates dimerization and homooligomerization (PubMed:28228481). Both the helicase ATP-binding domain and the helicase C-terminal domain form intramolecular interactions with the HRDC domain in a ATP-dependent manner (PubMed:25901030). The HRDC domain is required for single-stranded DNA (ssDNA) and DNA Holliday junction binding (PubMed:20639533).
Amplified and overexpressed in a number of cancers (at protein level).
In the context of cancer, overexpression of the METTL1-WDR4 methyltransferase complex promotes cancer progression by driving oncogenic transformation (PubMed:34352207, PubMed:34352206, PubMed:34371184). The METTL1-WDR4 methyltransferase complex drives oncogenesis by mediating the formation of N(7)-methylguanine at position 46 (m7G46) in some tRNAs, in particular Arg-TCT-4-1 (TRR-TCT4-1), leading to increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon (PubMed:34352207, PubMed:34352206, PubMed:34371184).
Non-catalytic component of the METTL1-WDR4 complex, composed of METTL1 and WDR4 (PubMed:12403464, PubMed:26751069, PubMed:36599982, PubMed:36599985, PubMed:37379838). Interacts with FEN1; the interaction is direct (PubMed:26751069).
Non-catalytic component of the METTL1-WDR4 methyltransferase complex required for the formation of N(7)-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs) (PubMed:12403464, PubMed:31031084, PubMed:31031083, PubMed:36599982, PubMed:36599985, PubMed:37369656). In the METTL1-WDR4 methyltransferase complex, WDR4 acts as a scaffold for tRNA-binding (PubMed:36599982, PubMed:36599985, PubMed:37369656). Required for the formation of N(7)-methylguanine at position 46 (m7G46) in a large subset of tRNAs that contain the 5'-RAGGU-3' motif within the variable loop (PubMed:12403464, PubMed:34352207, PubMed:34352206, PubMed:36599982, PubMed:36599985, PubMed:37369656). M7G46 interacts with C13-G22 in the D-loop to stabilize tRNA tertiary structure and protect tRNAs from decay (PubMed:36599982, PubMed:36599985). Also required for the formation of N(7)-methylguanine at internal sites in a subset of mRNAs (PubMed:31031084, PubMed:37379838). Also required for methylation of a specific subset of miRNAs, such as let-7 (PubMed:31031083). Independently of METTL1, also plays a role in genome stability: localizes at the DNA replication site and regulates endonucleolytic activities of FEN1 (PubMed:26751069).
Auxillary component of the NALCN sodium channel complex, a channel that regulates the resting membrane potential and controls neuronal excitability.
Component of the NALCN channel complex. NALCN complex consists of NALCN and auxiliary subunits, UNC79, UNC80 and NACL1. These auxiliary subunits are essential for the NALCN channel function.
Bifunctional phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazole succinocarboxamide synthetase catalyzing two reactions of the de novo purine biosynthetic pathway.
In the C-terminal section; belongs to the AIR carboxylase family. Class II subfamily.
In the N-terminal section; belongs to the SAICAR synthetase family.
At least 2 different SAA2 alleles have been described: SAA2.1 (SAA2alpha) and SAA2.2 (SAA2beta). We use here the revised nomenclature described in PubMed:10211414. The sequence shown is that of SAA2.2.
Expressed by the liver; secreted in plasma.
Reactive, secondary amyloidosis is characterized by the extracellular accumulation in various tissues of the SAA2 protein. These deposits are highly insoluble and resistant to proteolysis; they disrupt tissue structure and compromise function.
Exhibits microtubule-destabilizing activity, which is antagonized by STAT3.
Interacts with STAT3. Interacts with CLU (secreted form); this interaction may act as an important modulator during neuronal differentiation (By similarity).
N-terminal palmitoylation promotes specific anchoring to the cytosolic leaflet of Golgi membranes and subsequent vesicular trafficking along dendrites and axons. Neuronal Stathmins are substrates for palmitoyltransferases ZDHHC3, ZDHHC7 and ZDHHC15.
Genetic variations in MC3R define the body mass index quantitative trait locus 9 (BMIQ9) [MIM:602025]. Variance in body mass index is a susceptibility factor for obesity.
Receptor for MSH (alpha, beta and gamma) and ACTH. This receptor is mediated by G proteins which activate adenylate cyclase. Required for expression of anticipatory patterns of activity and wakefulness during periods of limited nutrient availability and for the normal regulation of circadian clock activity in the brain.
Belongs to the glycosyltransferase 47 family.
Glycosyltransferase required for the biosynthesis of heparan-sulfate and responsible for the alternating addition of beta-1-4-linked glucuronic acid (GlcA) and alpha-1-4-linked N-acetylglucosamine (GlcNAc) units to nascent heparan sulfate chains.
Gene prediction based on partial mRNA data.
Interacts (via second C2 domain) with EHD1 and EHD2.
Plays a role in myoblast fusion; probable mediator of endocytic recycling for membrane trafficking events during myotube formation.
(Microbial infection) In case of infection by influenza virus A (IVA), is involved in viral replication (PubMed:21900157).
(Microbial infection) Interacts with influenza A virus (IAV) RNA polymerase subunits PA, PB1 and PB2, and nucleocapsid NP (PubMed:21900157, PubMed:26864902). Associates with IAV polymerase complexes both in the nucleus and cytosol (PubMed:26864902). Associates with IAV ribonucleoproteins (vRNP) packaged in virions (PubMed:26864902). Interacts with hepatitis C virus core protein p19 (PubMed:21823664).
(Microbial infection) Up-regulated specifically following influenza A virus (IAV) infection in a viral replication-dependent manner (at protein level) (PubMed:26864902).
Homodimer (Probable). Interacts with FAM98A (via N- and C-terminus) (PubMed:28040436). Interacts with NIN; which may prevent phosphorylation of NIN (PubMed:15147888). Interacts with POLR2A (PubMed:16950395). Component of a tRNA-splicing ligase complex with FAM98B, DDX1 and RTCB (PubMed:21311021, PubMed:24870230, PubMed:24608264).
RNA-binding protein involved in modulation of mRNA transcription by Polymerase II (PubMed:16950395). Component of the tRNA-splicing ligase complex and is required for tRNA ligation (PubMed:24870230). May be required for RNA transport (PubMed:24608264).
Widely expressed. Expressed at high level in heart and skeletal muscle. Expressed at intermediate level in liver, pancreas, fetal brain and fetal lung. Weakly expressed in adult brain, adult lung, placenta, fetal liver and fetal kidney. Overexpressed in many brain tumors.
By cold exposure and repressed by heat exposure.
Has an acyl-CoA thioesterase activity with a preference for the long chain fatty acyl-CoA thioesters hexadecanoyl-CoA/palmitoyl-CoA and tetradecanoyl-CoA/myristoyl-CoA which are the main substrates in the mitochondrial beta-oxidation pathway.
Isoform 1 is predominantly expressed in skeletal muscle, liver, testis, stomach, spleen, lung and brain. Isoform 2 is predominantly expressed in kidney, uterus, hibernoma and white adipose tissue.
Abundantly expressed in lacrimal gland where it is found in the acinar cells but not in the intralobular ducts. Also found in the submandibular gland, the parotid and sublingual glands.
Binds DNA as a homodimer or as a heterodimer with JUN or ATF2/CREBP1.
Binds to the cAMP response element and activates transcription.
Interacts (via its cytoplasmic domain) with PEX6; interaction is direct and is ATP-dependent (PubMed:12717447, PubMed:21362118). Interacts with PEX1; interaction is indirect and is mediated via interaction with PEX6 (PubMed:12717447).
Peroxisomal docking factor that anchors PEX1 and PEX6 to peroxisome membranes (PubMed:12717447, PubMed:12851857, PubMed:16854980, PubMed:21362118, PubMed:16763195, PubMed:16257970). PEX26 is therefore required for the formation of the PEX1-PEX6 AAA ATPase complex, a complex that mediates the extraction of the PEX5 receptor from peroxisomal membrane (PubMed:12717447, PubMed:12851857, PubMed:16854980, PubMed:21362118, PubMed:16763195, PubMed:16257970).
Widely expressed (PubMed:12851857). Highly expressed in kidney, liver, brain and skeletal muscles (PubMed:12851857). Expressed at intermediate level in pancreas, placenta and heart (PubMed:12851857). Weakly expressed in lung (PubMed:12851857).
Highest expression in brain, lower in heart, kidney, pancreas, placenta, lung and skeletal muscle.
May function to confer stability and plasticity to neuronal membrane via multiple interactions, including the spectrin-actin-based cytoskeleton, integral membrane channels and membrane-associated guanylate kinases.
Belongs to the type II pantothenate kinase family.
Cytoplasmic isoform that catalyzes the phosphorylation of pantothenate to generate 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis.
Expressed in the brain (at protein level) (PubMed:15659606, PubMed:17825826). Ubiquitous (PubMed:11479594). Highly expressed in the testis (PubMed:17825826). Expressed in the umbilical vein endothelial cells (HUVEC) (PubMed:30221726).
May be produced by alternative initiation at Leu-111 of isoform 1.
Mitochondrial isoform that catalyzes the phosphorylation of pantothenate to generate 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis (PubMed:15659606, PubMed:17825826, PubMed:17242360, PubMed:16272150). Required for angiogenic activity of umbilical vein of endothelial cells (HUVEC) (PubMed:30221726).
Produced by alternative initiation at Met-124 of isoform 1.
Strongly inhibited by acetyl-CoA and its thioesters (PubMed:15659606, PubMed:17825826, PubMed:17242360, PubMed:16272150). Activated by palmitoylcarnitine (PubMed:17825826, PubMed:17242360).
Synthesized as a 62-kDa precursor which is proteolytically processed by the mitochondrial-processing peptidase (MPP) via a 59-kDa intermediate to yield the mature mitochondrial 48-kDa subunit.
The HSS syndrome has been proposed to be renamed because of the unethical activities of Julius Hallervorden and Hugo Spatz during world war II.
Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala). Also edits incorrectly charged tRNA(Ala) via its editing domain.
Consists of three domains; the N-terminal catalytic domain, the editing domain and the C-terminal C-Ala domain. The editing domain removes incorrectly charged amino acids, while the C-Ala domain, along with tRNA(Ala), serves as a bridge to cooperatively bring together the editing and aminoacylation centers thus stimulating deacylation of misacylated tRNAs.
Expressed in vein endothelial cells. Isoform 4 is expressed in lung, kidney, spleen, thymus and skeletal muscle.
N-glycosylated. Isoform 4 is glycosylated at Asn-154.
Shares a common promoter with APAF1 from which the 2 genes are transcribed in opposite directions.
Target of p53/TP53 with pro-apoptotic function.
(Microbial infection) AMPylation at Tyr-32 and Thr-35 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo.
(Microbial infection) Glucosylated at Thr-35 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:7777059, PubMed:7775453, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453).
(Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-35 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274).
(Microbial infection) Glycosylated at Tyr-32 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of CDC42 and leads to actin disassembly.
Belongs to the small GTPase superfamily. Rho family. CDC42 subfamily.
Interacts with CDC42EP1, CDC42EP2, CDC42EP3, CDC42EP4, CDC42EP5, CDC42SE1, CDC42SE2, PARD6A, PARD6B and PARD6G (in a GTP-dependent manner) (PubMed:10490598, PubMed:10816584, PubMed:10954424, PubMed:11260256). Interacts with activated CSPG4 and with BAIAP2 (PubMed:10587647, PubMed:11130076). Interacts with activated CSPG4 and with BAIAP2 (By similarity). Interacts with DOCK11/Zizimin2; the interaction activates CDC42 by exchanging GDP for GTP (By similarity). Interacts with DOCK9; the interaction activates CDC42 by exchanging GDP for GTP (PubMed:12172552, PubMed:19745154). Interacts with DOCK8 (via DHR-2 domain); the interaction activates CDC42 by exchanging GDP for GTP (PubMed:12172552). Interacts with IQGAP1 (By similarity). Interacts with NET1 and ARHGAP33/TCGAP (By similarity). Part of a complex with PARD3, PARD6A or PARD6B and PRKCI or PRKCZ (PubMed:11260256). The GTP-bound form interacts with CCPG1 (By similarity). Interacts with USP6 (PubMed:12612085). Interacts with NEK6 (PubMed:20873783). Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas (PubMed:17038317). Interacts with ITGB1BP1 (PubMed:11807099). Interacts with ARHGDIA; this interaction inactivates and stabilizes CDC42 (PubMed:23434736). Interacts with ARHGDIB; this maintains CDC42 in the inactive, GDP-bound form (PubMed:7512369). Interacts (in GTP-bound form) with FNBP1L and ABI1, but only in the presence of FNBP1L (PubMed:19798448). May interact with ARHGEF16; responsible for the activation of CDC42 by the viral protein HPV16 E6 (PubMed:21139582).
Phosphorylated by SRC in an EGF-dependent manner, this stimulates the binding of the Rho-GDP dissociation inhibitor RhoGDI.
Plasma membrane-associated small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses. Involved in epithelial cell polarization processes. Regulates the bipolar attachment of spindle microtubules to kinetochores before chromosome congression in metaphase (PubMed:15642749). Regulates cell migration (PubMed:17038317). In neurons, plays a role in the extension and maintenance of the formation of filopodia, thin and actin-rich surface projections (PubMed:14978216). Required for DOCK10-mediated spine formation in Purkinje cells and hippocampal neurons. In podocytes, facilitates filopodia and podosomes formation upon DOCK11-activation (PubMed:33523862). Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Also plays a role in phagocytosis through organization of the F-actin cytoskeleton associated with forming phagocytic cups (PubMed:26465210).
(Microbial infection) Interacts (via fourth PDZ domain) with tick-borne encephalitis virus RNA-directed RNA polymerase NS5; this interaction targets viral NS5 to the cell membrane periphery and nucleus and prevents STAT1 phosphorylation, and thus, the activation of the JAK-STAT signaling pathway (PubMed:18042258). Interacts with HPV E6 (PubMed:11027293).
Belongs to the LAP (LRR and PDZ) protein family.
Expressed in kidney, skeletal muscles, liver, lung, breast, intestine, placenta and skin mainly in epithelial cells (at protein level).
Interacts with UBE3A (PubMed:11027293). Interacts with PAK1 and PAK2 (PubMed:18716323). Interacts (via PDZ domains) with VANGL2 (By similarity). Interacts (via PDZ domains) with LPP and TRIP6; the interaction is direct (PubMed:15649318, PubMed:16137684). Interacts (via PDZ domains) with TJP2 (PubMed:15975580). Interacts (via PDZ domains) with APC; may mediate APC targeting to adherens junctions of epithelial cells (PubMed:16611247). Interacts (via PDZ domains) with TSHR; regulates TSHR trafficking and function (PubMed:15775968). Interacts with ARHGEF7 and GIT1; interacts directly with ARHGEF7 (PubMed:15182672). Interacts with CTNNB1 (By similarity). Interacts with MAPK12 (By similarity). Interacts (via PDZ domains 1 and 3) with MCC (PubMed:19555689, PubMed:22480440). Interacts with DLG5 (PubMed:28169360). Interacts with STK4/MST1 and LATS1 in the presence of DLG5 (PubMed:28169360). Interacts (via PDZ domain 3) with CRTAM (via PDZ-binding motif); the interaction promotes CRTAM and SCRIB polarization in a subset of CD4+ T-cells (By similarity).
Palmitoylated (PubMed:27380321). Could be depalmitoylated by LYPLA1 and/or LYPLA2 (PubMed:27380321). Palmitoylation of SCRIB by ZDHHC7 is required for its localization to cell-cell junctions, function in the establishement of epithelial cell polarity and the regulation of downstream signaling pathways important for epithelial cell differentiation (PubMed:27380321).
Scaffold protein involved in different aspects of polarized cell differentiation regulating epithelial and neuronal morphogenesis and T-cell polarization (PubMed:15182672, PubMed:16344308, PubMed:19041750, PubMed:18716323, PubMed:18641685, PubMed:16965391, PubMed:27380321). Via its interaction with CRTAM, required for the late phase polarization of a subset of CD4+ T-cells, which in turn regulates TCR-mediated proliferation and IFNG and IL22 production (By similarity). Most probably functions in the establishment of apico-basal cell polarity (PubMed:16344308, PubMed:19041750). May function in cell proliferation regulating progression from G1 to S phase and as a positive regulator of apoptosis for instance during acinar morphogenesis of the mammary epithelium (PubMed:16965391, PubMed:19041750). May also function in cell migration and adhesion and hence regulate cell invasion through MAPK signaling (PubMed:18716323, PubMed:18641685). May play a role in exocytosis and in the targeting of synaptic vesicles to synapses (PubMed:15182672). Functions as an activator of Rac GTPase activity.
Ubiquitinated; targeted for UBE3A-dependent multiubiquitination in the presence of high-risk HPV E6 proteins and degraded.
Interacts with USP20 and USP33. Interacts with MARCHF6.
Isoform 1 is expressed in the lung, trachea, kidney, heart, skeletal muscle, placenta, fetal brain and several regions of the adult brain (PubMed:8755651, PubMed:11165050). Isoform 2 is expressed in the brain, heart, kidney and trachea (PubMed:11165050).
Responsible for the deiodination of T4 (3,5,3',5'-tetraiodothyronine) into T3 (3,5,3'-triiodothyronine). Essential for providing the brain with appropriate levels of T3 during the critical period of development.
Ubiquitinated by MARCHF6, leading to its degradation by the proteasome. Deubiquitinated by USP20 and USP33.
E3 ubiquitin ligase that ubiquitinates APBB1 for its degradation by the proteasome and thus prevents apoptosis and promotes survival of neurons (PubMed:25342469). Has a dual role in neurons as it is also required for dendrite growth and maintenance for which its ligase activity is not critical (PubMed:25342469). May act as a scaffold molecule to regulate this process (PubMed:25342469). Acts as a downstream effector of the interconnected PI3K and MAPK signaling pathways and thus participates in the regulation of the cell cycle (PubMed:28655764).
Expression is cell cycle-specific with higher levels in cells arrested in G1/S and G2/M (PubMed:28655764).
Interacts with APBB1 (PubMed:25342469). Interacts with CHD1; CHD1-binding controls RNF157 stability (PubMed:28655764). Interacts with ATRN, MEGF8, TECR, MSI2, PLRG1, BYSL, MTERF3, PSMA1, MRPS18B, PRPF4, FASTKD2, SLC25A1, SMU1, CNOT9, MRPS2, MAGT1, FXR2, EMD, PSMD8, HDAC1, RAN, HSD17B12, TXNDC5 and MRPL19 (PubMed:28655764).
Phosphorylation at Ser-660, Ser-661, Ser-662 and Ser-663 downstream of the PI3K and MAPK pathways influences the E3 ligase activity and stability of RNF157 during the cell cycle in an anaphase-promoting complex/cyclosome-CDH1-dependent manner (PubMed:28655764).
The D-box motifs play a key role in RNF157 stabilization (PubMed:28655764).
Activated by phosphorylation on threonine and tyrosine by dual specificity kinases, MAP2K3/MKK3, MAP2K6/MKK6, MAP2K4/MKK4 and MAP2K7/MKK7. Activation by ultraviolet radiation, hyperosmotic shock, anisomycin or by TNF-alpha is mediated by MAP2K3/MKK3. Inhibited by dual specificity phosphatase DUSP1.
Dually phosphorylated on Thr-180 and Tyr-182 by MAP2K3/MKK3, MAP2K4/MKK4, MAP2K6/MKK6 and MAP2K7/MKK7, which activates the enzyme. Dephosphorylated by dual specificity phosphatase DUSP1.
Expressed in testes, pancreas, small intestine, lung and kidney. Abundant in macrophages, also present in neutrophils, CD4+ T-cells, and endothelial cells.
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK13 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as pro-inflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK13 is one of the less studied p38 MAPK isoforms. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in the regulation of protein translation by phosphorylating and inactivating EEF2K. Involved in cytoskeletal remodeling through phosphorylation of MAPT and STMN1. Mediates UV irradiation induced up-regulation of the gene expression of CXCL14. Plays an important role in the regulation of epidermal keratinocyte differentiation, apoptosis and skin tumor development. Phosphorylates the transcriptional activator MYB in response to stress which leads to rapid MYB degradation via a proteasome-dependent pathway. MAPK13 also phosphorylates and down-regulates PRKD1 during regulation of insulin secretion in pancreatic beta cells.
Belongs to the mitochondrion-specific ribosomal protein mL49 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379, PubMed:25278503). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (PubMed:11551941, PubMed:25278503, PubMed:25838379). Interacts with OXA1L (By similarity).
It has been suggested that DPY19L2P1 is an inactive pseudogene from which DPY19L2 has evolved by duplication. However, expressed transcript sequences derived from the DPY19L2P1 locus are known to exist.
Probable C-mannosyltransferase that mediates C-mannosylation of tryptophan residues on target proteins.
Required during spermatogenesis for sperm head elongation and acrosome formation (PubMed:21397063, PubMed:21397064). Also plays a role in acrosome attachment to the nuclear envelope (By similarity).
The disease is caused by variants affecting the gene represented in this entry. Deletions in DPY19L2 are probably the major cause of SPGF9.
Widely expressed with high expression in testis. Not detectable in ejaculated sperm (at protein level).
It is unsure whether Met-1 or Met-3 is the initiator.
Expressed at high levels in the lung, liver, and kidney, while weakly expressed in intestine, brain, muscle, cholecyst, heart, and pancreas.
May function as a transcription factor. May be involved in the development of multiple embryonic organs.
Belongs to the WD repeat WDR5/wds family.
May function as a substrate receptor for CUL4-DDB1 ubiquitin E3 ligase complex.
Probable part of a cullin-RING E3 protein ligase complex containing CUL4B-DDB1 and a substrate-recruiting component (DCAF). Interacts with CUL4B and DDB1 (By similarity).
Abundantly expressed in fetal liver. Expressed at lower levels in bone marrow, testis, colon, and placenta.
Decreased phosphorylation levels are associated with the differentiation of intestinal epithelial cells.
Elevated levels of expression detected in the G2/M phase of synchronized cultures of HeLa cells.
Interacts with CDK1. Interacts with the C-terminal proline-rich region of FBXO7. Recruited by FBXO7 to a SCF (SKP1-CUL1-F-box) protein complex in a CDK1/Cyclin B-phosphorylation dependent manner. Interacts with CDH1.
It was localized to the spindle and the spindle pole (PubMed:12527899) but was later found to be localized to the spindle and to be excluded from the spindle pole (PubMed:15561729).
Potential cell cycle regulator that may play a role in carcinogenesis of cancer cells. Mitotic phosphoprotein regulated by the ubiquitin-proteasome pathway. Key regulator of adherens junction integrity and differentiation that may be involved in CDH1-mediated adhesion and signaling in epithelial cells.
Ubiquitinated, leading to its degradation.
A cytochrome P450 monooxygenase involved in the metabolism of retinoates (RAs), the active metabolites of vitamin A, and critical signaling molecules in animals (PubMed:14532297). RAs exist as at least four different isomers: all-trans-RA (atRA), 9-cis-RA, 13-cis-RA, and 9,13-dicis-RA, where atRA is considered to be the biologically active isomer, although 9-cis-RA and 13-cis-RA also have activity (Probable). Catalyzes the oxidation of atRA primarily at C-4 (PubMed:14532297). Oxidation of atRA limits its biological activity and initiates a degradative process leading to its eventual elimination, thereby contributes to the regulation of atRA homeostasis and signaling (Probable). Able to metabolize other RAs such as 9-cis with high efficiency (PubMed:14532297). Can oxidize all-trans-13,14-dihydroretinoate (DRA) to metabolites which could include all-trans-4-oxo-DRA, all-trans-4-hydroxy-DRA, all-trans-5,8-epoxy-DRA, and all-trans-18-hydroxy-DRA (By similarity). Shares sequence similarity with other CYP26 family members, but has higher affinity to 9-cis-RA and is much less sensitive to the inhibitory effects of ketoconazole (PubMed:14532297). In cooperation with Cyp26a1, contributes to the CNS patterning and the development of regions of higher visual acuity (By similarity).
Detected in most tissues at very low level.
Belongs to the carotenoid oxygenase family.
Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins. Catalyzes the cleavage and isomerization of all-trans-retinyl fatty acid esters to 11-cis-retinol which is further oxidized by 11-cis retinol dehydrogenase to 11-cis-retinal for use as visual chromophore (PubMed:16116091). Essential for the production of 11-cis retinal for both rod and cone photoreceptors (PubMed:17848510). Also capable of catalyzing the isomerization of lutein to meso-zeaxanthin an eye-specific carotenoid (PubMed:28874556). The soluble form binds vitamin A (all-trans-retinol), making it available for LRAT processing to all-trans-retinyl ester. The membrane form, palmitoylated by LRAT, binds all-trans-retinyl esters, making them available for IMH (isomerohydrolase) processing to all-cis-retinol. The soluble form is regenerated by transferring its palmitoyl groups onto 11-cis-retinol, a reaction catalyzed by LRAT (By similarity).
Interacts with MYO7A; this mediates light-dependent intracellular transport of RPE65.
Palmitoylation by LRAT regulates ligand binding specificity; the palmitoylated form (membrane form) specifically binds all-trans-retinyl-palmitate, while the soluble unpalmitoylated form binds all-trans-retinol (vitamin A) (By similarity).
Retina (at protein level). Retinal pigment epithelium specific.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.
Heterodimer (via C-terminus) with MTMR9 (via coiled coil domain); the interaction enhances MTMR7 catalytic activity (By similarity). Does not homodimerize (By similarity). Interacts with RAB1B (in GDP-bound form) (By similarity).
Interaction with MTMR9 increases phosphatase activity.
Phosphatase that specifically dephosphorylates phosphatidylinositol 3-phosphate (PtdIns(3)P) and inositol 1,3-bisphosphate (Ins(1,3)P2).
Abundant expression in the intestinal tract. Expressed in colonic intraepithelial neuroendocrine cells.
G-protein-coupled receptor for long-chain fatty acids (LCFAs) with a major role in adipogenesis, energy metabolism and inflammation. Signals via G-protein and beta-arrestin pathways (PubMed:22282525, PubMed:24742677, PubMed:27852822, PubMed:24817122, PubMed:22343897). LCFAs sensing initiates activation of phosphoinositidase C-linked G proteins GNAQ and GNA11 (G(q)/G(11)), inducing a variety of cellular responses via second messenger pathways such as intracellular calcium mobilization, modulation of cyclic adenosine monophosphate (cAMP) production, and mitogen-activated protein kinases (MAPKs) (PubMed:27852822, PubMed:22343897, PubMed:22282525, PubMed:24742677). After LCFAs binding, associates with beta-arrestin ARRB2 that acts as an adapter protein coupling the receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis (PubMed:22282525, PubMed:24817122). In response to dietary fats, plays an important role in the regulation of adipocyte proliferation and differentiation (By similarity). Acts as a receptor for omega-3 polyunsaturated fatty acids (PUFAs) at primary cilium of perivascular preadipocytes, initiating an adipogenic program via cAMP and CTCF-dependent chromatin remodeling that ultimately results in transcriptional activation of adipogenic genes and cell cycle entry (By similarity). Induces differentiation of brown adipocytes probably via autocrine and endocrine functions of FGF21 hormone (By similarity). Activates brown adipocytes by initiating intracellular calcium signaling that leads to mitochondrial depolarization and fission, and overall increased mitochondrial respiration (By similarity). Consequently stimulates fatty acid uptake and oxidation in mitochondria together with UCP1-mediated thermogenic respiration, eventually reducing fat mass (By similarity). Regulates bi-potential differentiation of bone marrow mesenchymal stem cells toward osteoblasts or adipocytes likely by up-regulating distinct integrins (By similarity). In response to dietary fats regulates hormone secretion and appetite (By similarity). Stimulates GIP and GLP1 secretion from enteroendocrine cells as well as GCG secretion in pancreatic alpha cells, thereby playing a role in the regulation of blood glucose levels (By similarity). Negatively regulates glucose-induced SST secretion in pancreatic delta cells (By similarity). Mediates LCFAs inhibition of GHRL secretion, an appetite-controlling hormone (By similarity). In taste buds, contributes to sensing of dietary fatty acids by the gustatory system (By similarity). During the inflammatory response, promotes anti-inflammatory M2 macrophage differentiation in adipose tissue (By similarity). Mediates the anti-inflammatory effects of omega-3 PUFAs via inhibition of NLRP3 inflammasome activation (PubMed:23809162). In this pathway, interacts with adapter protein ARRB2 and inhibits the priming step triggered by Toll-like receptors (TLRs) at the level of TAK1 and TAB1 (By similarity). Further inhibits the activation step when ARRB2 directly associates with NLRP3, leading to inhibition of pro-inflammatory cytokine release (PubMed:23809162). Mediates LCFAs anti-apoptotic effects (By similarity).
Genetic variations in FFAR4 define the body mass index quantitative trait locus 10 (BMIQ10) [MIM:607514]. Variance in body mass index is a susceptibility factor for obesity.
Interacts (via C-terminus) with ARRB2 following LCFAs stimulation.
Low expression is detected in preadipocytes, mainly localized in primary cilium.
Phosphorylated at two clusters of Ser and Thr residues located in the intracellular C-terminus, a prerequisite for FFAR4 internalization via an ARRB2-dependent pathway.
Receptor for LCFAs decoupled from G-protein signaling. May signal through beta-arrestin pathway. After LCFAs binding, associates with beta-arrestin ARRB2 that may act as an adapter protein coupling the receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis.
The predominant isoform in human tissues. Expressed in adipose tissue, pancreatic islets, lung and brain. Expressed in alpha cells of pancreatic islets (PubMed:24742677). Expressed in primary cilia of perivascular preadipocytes of white adipose tissue (at protein level) (PubMed:31761534).
Mainly expressed in brain. Found in certain nerve cell lines, such as retinoblasts, glioma cells and neuroblasts.
Belongs to the nuclear hormone receptor family. NR2 subfamily.
Expressed in aortic endothelial cells (at protein level) (PubMed:28167758). Expressed in monocytes (PubMed:26463675). Expressed in a variety of tumor cell lines.
Homodimer (in vitro) (PubMed:11782480). Heterodimer with other retinoic acid receptor family members. Binds DNA preferentially as a RAR/RXR heterodimer (PubMed:1310259). Interacts with NR1H3 (PubMed:12970175). Interacts with AKAP13 (By similarity).
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE).
During primary cilia disassembly, involved in cilia disassembly. Required specifically to control cilia retraction as well as the liberation and duplication of the basal body/centrosome. May act by stimulating AURKA activity at the basal body in a cell cycle-dependent manner.
Interacts with proteins involved in ciliary transport, including ARL13B, CETN1, KIF3A, RAB6A, RAB8A, TUBB1 and TUBG1. Interacts with AURKA.
Highly expressed in fetal brain, kidney and heart and to a much lesser extent in adult heart and thymus.
May transfer sialic acid through alpha-2,8-linkages to the alpha-2,3-linked and alpha-2,6-linked sialic acid of N-linked oligosaccharides of glycoproteins and may be involved in PSA (polysialic acid) expression.
Inhibited by histatin-3 1/24 (histatin-5).
Interacts (via the C-terminal hemopexin-like domains-containing region) with the integrin alpha-V/beta-3; the interaction promotes vascular invasion in angiogenic vessels and melamoma cells. Interacts (via the C-terminal PEX domain) with TIMP2 (via the C-terminal); the interaction inhibits the degradation activity. Interacts with GSK3B.
Mediates the proteolysis of CHUK/IKKA and initiates a primary innate immune response by inducing mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-kappaB, NFAT and IRF transcriptional pathways.
PEX, the C-terminal non-catalytic fragment of MMP2, posseses anti-angiogenic and anti-tumor properties and inhibits cell migration and cell adhesion to FGF2 and vitronectin. Ligand for integrinv/beta3 on the surface of blood vessels.
Phosphorylation on multiple sites modulates enzymatic activity. Phosphorylated by PKC in vitro.
Produced by normal skin fibroblasts. PEX is expressed in a number of tumors including gliomas, breast and prostate.
The propeptide is processed by MMP14 (MT-MMP1) and MMP16 (MT-MMP3). Autocatalytic cleavage in the C-terminal produces the anti-angiogenic peptide, PEX. This processing appears to be facilitated by binding integrinv/beta3.
Ubiquitinous metalloproteinase that is involved in diverse functions such as remodeling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rupture. As well as degrading extracellular matrix proteins, can also act on several nonmatrix proteins such as big endothelial 1 and beta-type CGRP promoting vasoconstriction. Also cleaves KISS at a Gly-|-Leu bond. Appears to have a role in myocardial cell death pathways. Contributes to myocardial oxidative stress by regulating the activity of GSK3beta. Cleaves GSK3beta in vitro. Involved in the formation of the fibrovascular tissues in association with MMP14.
A disulfide-bonded peptide called proline/arginine-rich protein or PARP is released from the N-terminus during extracellular processing and is subsequently retained in the cartilage matrix from which it can be isolated in significant amounts.
May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
Trimers composed of three different chains: alpha 1(XI), alpha 2(XI), and alpha 3(XI). Alpha 3(XI) is a post-translational modification of alpha 1(II). Alpha 1(V) can also be found instead of alpha 3(XI)=1(II).
Down-regulated in neutrophils after treatment with LPS and TNF.
Expressed in neutrophils. Isoforms 1 and 5 are expressed at high levels in the colon, lung,testis, lymph nodes and thyroid tissue. Isoform 5, but not isoform 1, is detected in spleen.
May stimulate primary immune response. Acts on T-cell stimulated sub-optimally through the TCR/CD3 complex stimulating their proliferation and cytokine production.
Highly expressed in heart, placenta, pancreas, lung and liver and weakly expressed in spleen, lymph nodes and thymus.
Involved in the costimulatory signal, essential for T-cell proliferation and IFNG production in a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell proliferation by blocking cell cycle progression and cytokine production (By similarity).
Up-regulated by IFNG/IFN-gamma stimulation in monocytes and induced on dendritic cells grown from peripheral blood mononuclear cells with CSF2 and IL4/interleukin-4.
Belongs to the LDH/MDH superfamily. MDH type 2 family.
Available under the names Nutropin or Protropin (Genentech), Norditropin (Novo Nordisk), Genotropin (Pharmacia Upjohn), Humatrope (Eli Lilly) and Saizen or Serostim (Serono). Used for the treatment of growth hormone deficiency and for Turner's syndrome.
Belongs to the somatotropin/prolactin family.
Circulating GH shows a great heterogeneity due to alternative splicing, differential post-translational modifications of monomeric forms, oligomerization, optional binding to 2 different GH-binding proteins, and potentially proteolytic processing.
Monomer, dimer, trimer, tetramer and pentamer, disulfide-linked or non-covalently associated, in homomeric and heteromeric combinations. Can also form a complex either with GHBP or with the alpha2-macroglobulin complex.
Plays an important role in growth control. Its major role in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-1. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues.
Interacts with IQGAP1; this interaction promotes phosphorylation and nuclear translocation of IQGAP1.
Mainly expressed in the outer subventricular zone (OSVZ) of the fetal brains.
Primate-specific protein involved in cortical expansion and folding in the developing neocortex. May drive neural progenitor proliferation through nuclear translocation of IQGAP1, which in turn promotes G1/S cell cycle transitions.
When expressed in embryonic mouse neocortex, induces intermediate progenitor cells and outer radial glia expansion, cortical thickening and induces gyrification (PubMed:29033352).
A translocation t(3;10)(p24;q23) located 215 kb 3' to the EOMES gene but leading to loss of its expression was identified in a large consanguineous family. Homozygous silencing produces microcephaly associated with corpus callosum agenesis, bilateral polymicrogyria, ventricular dilatation and a small cerebellum.
Detected at 7 weeks of development in the forebrain floorplate of the CNS. Expressed within the mantle layer and migrating neuroblasts of the telencephalon at 12.5 weeks of development.
Functions as a transcriptional activator playing a crucial role during development. Functions in trophoblast differentiation and later in gastrulation, regulating both mesoderm delamination and endoderm specification. Plays a role in brain development being required for the specification and the proliferation of the intermediate progenitor cells and their progeny in the cerebral cortex. Also involved in the differentiation of CD8+ T-cells during immune response regulating the expression of lytic effector genes.
Up-regulated in CD8+ T-cells simultaneously stimulated with TGFB1 and IL4/interleukin-4.
Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as the source of nitrogen. Constitutes the rate-limiting enzyme in the synthesis of cytosine nucleotides.
Autoinhibited by the ariadne domain, which masks the second RING-type zinc finger that contains the active site and inhibits the E3 activity (PubMed:23707686). Inhibition is relieved upon binding to neddylated cullin-RING ubiquitin ligase complexes, which activate the E3 ligase activity of ARIH1 (PubMed:24076655, PubMed:27565346).
Belongs to the RBR family. Ariadne subfamily.
Defects in ARIH1 have been found in several individuals with thoracic aortic aneurysms and cerebrovascular disease.
E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3 (PubMed:15236971, PubMed:21532592, PubMed:24076655, PubMed:27565346, PubMed:23707686). Acts as an atypical E3 ubiquitin-protein ligase by working together with cullin-RING ubiquitin ligase (CRL) complexes and initiating ubiquitination of CRL substrates: associates with CRL complexes and specifically mediates addition of the first ubiquitin on CRLs targets (PubMed:27565346). The initial ubiquitin is then elongated by CDC34/UBE2R1 and UBE2R2 (PubMed:27565346). E3 ubiquitin-protein ligase activity is activated upon binding to neddylated cullin-RING ubiquitin ligase complexes (PubMed:24076655, PubMed:27565346). Plays a role in protein translation in response to DNA damage by mediating ubiquitination of EIF4E2, the consequences of EIF4E2 ubiquitination are however unclear (PubMed:25624349). According to a report, EIF4E2 ubiquitination leads to promote EIF4E2 cap-binding and protein translation arrest (PubMed:25624349). According to another report EIF4E2 ubiquitination leads to its subsequent degradation (PubMed:14623119). Acts as the ligase involved in ISGylation of EIF4E2 (PubMed:17289916). In vitro, controls the degradation of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex member SUN2 and may therefore have a role in the formation and localization of the LINC complex, and as a consequence, nuclear subcellular localization and nuclear morphology (PubMed:29689197).
Interacts (via the first RING-type zinc finger) with UBE2L3 (PubMed:11278816, PubMed:21532592, PubMed:24076655, PubMed:23707686). Associates with cullin-RING ubiquitin ligase (CRL) complexes containing CUL1, CUL2 and CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL1 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL2 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL4A (PubMed:24076655).
Members of the RBR family are atypical E3 ligases. They interact with the E2 conjugating enzyme UBE2L3 and function like HECT-type E3 enzymes: they bind E2s via the first RING-type zinc finger, but require an obligate trans-thiolation step during the ubiquitin transfer, requiring a conserved active site Cys residue in the second RING-type zinc finger (PubMed:21532592, PubMed:23707686). The active site probably forms a thioester intermediate with ubiquitin taken from the active-site cysteine of the E2 before ultimately transferring it to a Lys residue on the substrate (PubMed:21532592, PubMed:23707686).
The Ariadne domain inhibits activity by masking the second RING-type zinc finger that contains the active site (PubMed:23707686).
The RING-type 2 zinc finger was initially reported to only bind 1 zinc ion instead of 2 compared to classical RING-types (PubMed:15236971). But it was later shown that it is not the case and binds 2 zinc ions (PubMed:24058416, PubMed:23707686).
Up-regulated following DNA damage (PubMed:25624349).
Expressed in macrophages but not in other leukocytes. Abundantly expressed in heart and kidney. Also expressed in spleen, leukocytes, and placenta.
May be involved in the digestion of phagocytosed particles in the lysosome, participation in an inflammatory protease cascade, and trimming of peptides for antigen presentation.
Contrary to IGLL1, not expressed in pre-B-cells.
Located within the immunoglobulin lambda locus, but does not require somatic rearrangement for expression.
May play a role in carrying and orienting carbohydrate, as well as having a more specific role.
Broadly expressed in fetal tissues. Expressed in adult liver and placenta.
Catalyzes the peptide bond hydrolysis in dipeptides, displaying a non-redundant activity toward threonyl dipeptides (By similarity). Mediates threonyl dipeptide catabolism in a tissue-specific way (By similarity). Has high dipeptidase activity toward cysteinylglycine, an intermediate metabolite in glutathione metabolism (PubMed:19346245, PubMed:12473676). Metabolizes N-lactoyl-amino acids, both through hydrolysis to form lactic acid and amino acids, as well as through their formation by reverse proteolysis (PubMed:25964343). Plays a role in the regulation of cell cycle arrest and apoptosis (PubMed:17121880, PubMed:24395568).
Inhibited by p-hydroxymercurybenzoate. The inhibitory concentration 50% (IC(50)) is 13 uM. Inhibited by bestatin. The inhibitory concentration 50% (IC(50)) is 7 nM at pH 9.5.
The reverse proteolysis is not negligible in vivo as long as the substrates are present in considerable concentrations, such as upon physical exercice. N-lac-Phe plasma levels are increased in patients with PKU with increased plasma Phe levels. N-lactoyl-amino acids are present in many tissues.
Ubiquitously expressed with higher levels in kidney and liver (at protein level). Expressed in peripheral blood leukocytes (PubMed:12473676). Expressed in gastric mucosa and down-regulated in gastric cancer mucosal tissues (at protein level) (PubMed:24395568).
Interacts with PI4KB. This binding competes with FREQ/NCS1 binding in a calcium-dependent manner.
Negatively regulates Golgi-to-plasma membrane trafficking by interacting with PI4KB and inhibiting its activity. May play a role in the physiology of neurons and is potentially important in memory and learning.
(Microbial infection) Acts as a receptor for human coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus NL63/HCoV-NL63.
(Microbial infection) In airway epithelial cells, expression is increased upon influenza A virus infection (PubMed:32413319).
(Microbial infection) In airway epithelial cells, expression is induced by viruses such rhinoviruses and influenza virus.
(Microbial infection) Induced by human coronavirus SARS-CoV-2.
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 spike protein (via RBD domain).
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 spike protein; the interaction is increased by AVP/Arg-vasopressin with which they may form a complex.
(Microbial infection) Interacts with SARS coronavirus/SARS-CoV spike protein.
(Microbial infection) Interacts with human coronavirus NL63 spike protein.
(Microbial infection) Interacts with human coronavirus NL63/HCoV-NL63 spike glycoprotein.
(Microbial infection) Non-functional as a receptor for human coronavirus SARS-CoV-2.
An engeneered stable, dimeric and secreted receptor with combined mutations that increase the affinity for human coronavirus SARS-CoV-2 spike protein shows potent SARS-CoV and SARS-CoV-2 neutralization in vitro.
Essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis (PubMed:27217402). Converts angiotensin I to angiotensin 1-9, a nine-amino acid peptide with anti-hypertrophic effects in cardiomyocytes, and angiotensin II to angiotensin 1-7, which then acts as a beneficial vasodilator and anti-proliferation agent, counterbalancing the actions of the vasoconstrictor angiotensin II (PubMed:10969042, PubMed:10924499, PubMed:11815627, PubMed:19021774, PubMed:14504186). Also removes the C-terminal residue from three other vasoactive peptides, neurotensin, kinetensin, and des-Arg bradykinin, but is not active on bradykinin (PubMed:10969042, PubMed:11815627). Also cleaves other biological peptides, such as apelins (apelin-13, [Pyr1]apelin-13, apelin-17, apelin-36), casomorphins (beta-casomorphin-7, neocasomorphin) and dynorphin A with high efficiency (PubMed:11815627, PubMed:27217402, PubMed:28293165). In addition, ACE2 C-terminus is homologous to collectrin and is responsible for the trafficking of the neutral amino acid transporter SL6A19 to the plasma membrane of gut epithelial cells via direct interaction, regulating its expression on the cell surface and its catalytic activity (PubMed:18424768, PubMed:19185582).
Expressed in endothelial cells from small and large arteries, and in arterial smooth muscle cells (at protein level) (PubMed:15141377). Expressed in enterocytes of the small intestine, Leydig cells and Sertoli cells (at protein level) (PubMed:15141377). Expressed in the renal proximal tubule and the small intestine (at protein level) (PubMed:18424768). Expressed in heart, kidney, testis, and gastrointestinal system (at protein level) (PubMed:10969042, PubMed:10924499, PubMed:15231706, PubMed:12459472, PubMed:15671045, PubMed:32715618, PubMed:32170560). In lung, expressed at low levels in some alveolar type 2 cells, the expression seems to be individual-specific (at protein level) (PubMed:32425701, PubMed:15141377, PubMed:32715618, PubMed:32170560, PubMed:33432184). Expressed in nasal epithelial cells (at protein level) (PubMed:33432184, PubMed:32333915). Coexpressed with TMPRSS2 within some lung alveolar type 2 cells, ileal absorptive enterocytes, intestinal epithelial cells, cornea, gallbladder and nasal goblet secretory cells (PubMed:32413319, PubMed:32327758, PubMed:32358202). Coexpressed with TMPRSS4 within mature enterocytes (PubMed:32404436).
Expressed in nasal and bronchial epithelial cells (at protein level).
Expression is induced by interferons such as IFNA, IFNB and IFNG. It seems that isoform 2 is an interferon-stimulated gene (ISG) but not isoform 1.
Homodimer (PubMed:32132184). Interacts with the catalytically active form of TMPRSS2 (PubMed:21068237). Interacts with SLC6A19; this interaction is essential for expression and function of SLC6A19 in intestine (By similarity). Interacts with ITGA5:ITGB1 (PubMed:15276642, PubMed:33102950). Probably interacts (via endocytic sorting signal motif) with AP2M1; the interaction is inhibited by phosphorylation of Tyr-781 (PubMed:33436498). Interacts (via PDZ-binding motif) with NHERF1 (via PDZ domains); the interaction may enhance ACE2 membrane residence (PubMed:34189428).
N-glycosylation on Asn-90 may limit SARS infectivity.
Not induced by interferons such as IFNA, IFNB and IFNG.
Phosphorylated. Phosphorylation at Tyr-781 probably inhibits interaction with AP2M1 and enables interactions with proteins containing SH2 domains.
Proteolytic cleavage by ADAM17 generates a secreted form (PubMed:15983030, PubMed:33713620). Also cleaved by serine proteases: TMPRSS2, TMPRSS11D and HPN/TMPRSS1.
Regulated by chloride and fluoride, but not bromide (PubMed:11815627). Chloride increases angiotensin I and decreases angiotensin II cleavage (PubMed:19021774). Inhibited by MLN-4760, cFP_Leu, and EDTA (PubMed:15231706, PubMed:10924499), but not by the ACE inhibitors lisinopril, captopril and enalaprilat (PubMed:10969042, PubMed:10924499). Highly potent and selective in vitro ACE2 inhibitors were identified (PubMed:12358520).
The cytoplasmic tail contains several linear motifs such as LIR, PDZ-binding, PTB and endocytic sorting signal motifs that would allow interaction with proteins that mediate endocytic trafficking and autophagy.
The extracellular region of the ACE2 enzyme is composed of two domains. The first is a zinc metallopeptidase domain (residues 19-611). The second domain is located at the C-terminus (residues 612-740) and is 48% identical to human collectrin.
Up-regulated in failing heart (PubMed:14504186, PubMed:15151696, PubMed:15671045). Expression is induced by IFNA and IFNG (PubMed:32413319, PubMed:32425701). Exposure to cigarette smoke increases expression in lungs (PubMed:32425701). Expression is decreased in nasal and bronchial epithelium of individuals with allergy after allergen challenge (PubMed:32333915). IL13 stimulation decreases expression in nasal and bronchial epithelium (PubMed:32333915).
Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency (PubMed:16307923, PubMed:19952111, PubMed:20178742). PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1 (PubMed:16307923, PubMed:19952111, PubMed:20178742). PAF1C is required for transcription of Hox and Wnt target genes (PubMed:16307923, PubMed:19952111, PubMed:20178742). PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL (PubMed:16307923, PubMed:19952111, PubMed:20178742). PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3) (PubMed:16307923, PubMed:19952111, PubMed:20178742). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription (PubMed:16307923, PubMed:19952111, PubMed:20178742). PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors (PubMed:16307923, PubMed:19952111, PubMed:20178742). In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription (PubMed:16307923, PubMed:19952111, PubMed:20178742). Required for mono- and trimethylation on histone H3 'Lys-4' (H3K4me3), dimethylation on histone H3 'Lys-79' (H3K4me3). Required for Hox gene transcription (PubMed:16307923, PubMed:19952111, PubMed:20178742). Also acts as a component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways (PubMed:16024656, PubMed:32006463, PubMed:35120588). The SKI complex catalyzes mRNA extraction from 80S ribosomal complexes in the 3'-5' direction and channels mRNA to the cytosolic exosome for degradation (PubMed:32006463, PubMed:35120588). SKI-mediated extraction of mRNA from stalled ribosomes allow binding of the Pelota-HBS1L complex and subsequent ribosome disassembly by ABCE1 for ribosome recycling (PubMed:32006463).
Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8 (PubMed:16024656, PubMed:19952111, PubMed:20178742). The PAF1 complex interacts with PHF5A (By similarity). Within the PAF1 complex interacts directly with PHF5A (By similarity). Component of the SKI complex which consists of SKIC2, SKIC3 and SKIC8 (PubMed:16024656, PubMed:32006463, PubMed:35120588).
Anti-apoptotic protein that modulates a caspase-10 dependent mitochondrial caspase-3/9 feedback amplification loop.
Calcium-independent ATP-Mg/Pi exchanger that catalyzes the electroneutral exchange of Mg-ATP or free ADP against an hydrogenphosphate and participates in the net transport of adenine nucleotides across the mitochondria inner membrane.
Expressed in fetal skeletal muscle and kidney.
Acts as a transcriptional repressor for zinc finger transcription factors EGR1 and EGR2.
Homomultimers may associate with EGR1 bound to DNA.
Isoform Short is found in myeloid leukemia cell line KG-1.
The NAB conserved domain 1 (NCD1) interacts with EGR1 inhibitory domain and mediates multimerization.
The NAB conserved domain 2 (NCD2) is necessary for transcriptional repression.
Lipase that preferentially hydrolysis medium-chain saturated monoacylglycerols including 2-arachidonoylglycerol (PubMed:22969151). Through 2-arachidonoylglycerol degradation may regulate endocannabinoid signaling pathways (By similarity). Also has a lysophosphatidyl lipase activity with a preference for lysophosphatidylglycerol among other lysophospholipids (By similarity). Also able to degrade bis(monoacylglycero)phosphate (BMP) and constitutes the major enzyme for BMP catabolism (PubMed:26491015). BMP, also known as lysobisphosphatidic acid, is enriched in late endosomes and lysosomes and plays a key role in the formation of intraluminal vesicles and in lipid sorting (PubMed:26491015).
Component of the DCX(AMBRA1) E3 ubiquitin ligase complex, also named CRL4(AMBRA1), at least composed of CUL4 (CUL4A or CUL4B), DDB1, AMBRA1 and RBX1 (PubMed:25499913, PubMed:16949367, PubMed:30166453, PubMed:33854232, PubMed:33854239). Interacts with BECN1 (PubMed:21358617, PubMed:25438055). Probably forms a complex with BECN1 and PIK3C3 (By similarity). Interacts with BECN2 (PubMed:23954414). Interacts with BCL2; leading to prevent interaction with BCN1 and autophagy, interaction is disrupted upon autophagy induction (PubMed:21358617). Interacts with ULK1 (PubMed:25438055). Interacts (via PxP motifs) with PPP2CA; enhancing interaction between PPP2CA and MYC or FOXO3 (PubMed:25438055, PubMed:30513302). Forms a complex with PPP2CA and BECN1; AMBRA1 and BECN1 components of the complex regulate MYC stability via different pathways (PubMed:25803737). Interacts (TQT motifs) with DYNLL1 and DYNLL2; tethering AMBRA1 and the BECN1-PIK3C3 complex in absence of autophagy (PubMed:20921139). Interacts with TRAF6; interaction is required to mediate 'Lys-63'-linked ubiquitination of ULK1 (PubMed:23524951). Interacts with TRIM32; promoting activation of ULK1 by TRIM32 via unanchored 'Lys-63'-linked polyubiquitin chains (PubMed:31123703). Interacts with PRKN (By similarity). Interacts (via LIR motif) with LC3 (MAP1LC3A, MAP1LC3B or MAP1LC3C) (PubMed:25215947, PubMed:30217973). Interacts with HUWE1 (PubMed:30217973). Interacts with PTK2/FAK (By similarity). Interacts with SRC; required for SRC trafficking to autophagosomes (By similarity).
Negatively regulated by microRNA 7-3HG (miR7-3HG), which targets the 3' untranslated (3'-UTR) region of AMBRA1 transcripts, leading to a decrease of AMBRA1 mRNA and protein levels, thereby inhibiting autophagy (PubMed:28059583). Strongly up-regulated during egulatory T-cells (Treg) differentiation (PubMed:30513302).
Phosphorylation at Ser-52 by MTOR inhibits its ability to regulate autophagy and mediate ubiquitination of ULK1 (PubMed:23524951). Phosphorylation by ULK1 in response to autophagy induction abolishes interaction with DYNLL1 and DYNLL2, releasing AMBRA1 from the cytoskeletal docking site to induce autophagosome nucleation (PubMed:20921139). Phosphorylation by MTOR inhibits interaction with PPP2CA and subsequent dephosphorylation of MYC (PubMed:25438055). Phosphorylation at Ser-1043 by CHUK/IKKA promotes its interaction with ATG8 family proteins GABARAP and MAP1LC3B and its mitophagic activity (PubMed:30217973).
Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex involved in cell cycle control and autophagy (PubMed:20921139, PubMed:23524951, PubMed:24587252, PubMed:33854232, PubMed:33854235, PubMed:33854239, PubMed:32333458). The DCX(AMBRA1) complex specifically mediates the polyubiquitination of target proteins such as BECN1, CCND1, CCND2, CCND3, ELOC and ULK1 (PubMed:23524951, PubMed:33854232, PubMed:33854235, PubMed:33854239). Acts as an upstream master regulator of the transition from G1 to S cell phase: AMBRA1 specifically recognizes and binds phosphorylated cyclin-D (CCND1, CCND2 and CCND3), leading to cyclin-D ubiquitination by the DCX(AMBRA1) complex and subsequent degradation (PubMed:33854232, PubMed:33854235, PubMed:33854239). By controlling the transition from G1 to S phase and cyclin-D degradation, AMBRA1 acts as a tumor suppressor that promotes genomic integrity during DNA replication and counteracts developmental abnormalities and tumor growth (PubMed:33854232, PubMed:33854235, PubMed:33854239). AMBRA1 also regulates the cell cycle by promoting MYC dephosphorylation and degradation independently of the DCX(AMBRA1) complex: acts via interaction with the catalytic subunit of protein phosphatase 2A (PPP2CA), which enhances interaction between PPP2CA and MYC, leading to MYC dephosphorylation and degradation (PubMed:25803737, PubMed:25438055). Acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes (PubMed:25499913, PubMed:30166453). Acts as a key regulator of autophagy by modulating the BECN1-PIK3C3 complex: controls protein turnover during neuronal development, and regulates normal cell survival and proliferation (PubMed:21358617). In normal conditions, AMBRA1 is tethered to the cytoskeleton via interaction with dyneins DYNLL1 and DYNLL2 (PubMed:20921139). Upon autophagy induction, AMBRA1 is released from the cytoskeletal docking site to induce autophagosome nucleation by mediating ubiquitination of proteins involved in autophagy (PubMed:20921139). The DCX(AMBRA1) complex mediates 'Lys-63'-linked ubiquitination of BECN1, increasing the association between BECN1 and PIK3C3 to promote PIK3C3 activity (By similarity). In collaboration with TRAF6, AMBRA1 mediates 'Lys-63'-linked ubiquitination of ULK1 following autophagy induction, promoting ULK1 stability and kinase activity (PubMed:23524951). Also activates ULK1 via interaction with TRIM32: TRIM32 stimulates ULK1 through unanchored 'Lys-63'-linked polyubiquitin chains (PubMed:31123703). Also acts as an activator of mitophagy via interaction with PRKN and LC3 proteins (MAP1LC3A, MAP1LC3B or MAP1LC3C); possibly by bringing damaged mitochondria onto autophagosomes (PubMed:21753002, PubMed:25215947). Also activates mitophagy by acting as a cofactor for HUWE1; acts by promoting HUWE1-mediated ubiquitination of MFN2 (PubMed:30217973). AMBRA1 is also involved in regulatory T-cells (Treg) differentiation by promoting FOXO3 dephosphorylation independently of the DCX(AMBRA1) complex: acts via interaction with PPP2CA, which enhances interaction between PPP2CA and FOXO3, leading to FOXO3 dephosphorylation and stabilization (PubMed:30513302). May act as a regulator of intracellular trafficking, regulating the localization of active PTK2/FAK and SRC (By similarity). Also involved in transcription regulation by acting as a scaffold for protein complexes at chromatin (By similarity).
The LIR motif (LC3-interacting region) is required for the interaction with the ATG8 family proteins GABARAP and MAP1LC3B.
The PxP motifs mediate interaction with the catalytic subunit of protein phosphatase 2A (PPP2CA).
The TQT motifs mediate interaction with the dynein light chain proteins DYNLL1 and DYNLL2, tethering AMBRA1 to the cytoskeleton in absence of autophagy.
Ubiquitinated by RNF2 via 'Lys-48'-linkage in unstressed cells, leading to its degradation by the proteasome (PubMed:25499913). Induction of autophagy promotes stabilization via interaction with CUL4 (CUL4A or CUL4B) and DDB1 (PubMed:25499913). Upon prolonged starvation, ubiquitinated and degraded, terminating the autophagy response (PubMed:25499913).
Undergoes proteolytic processing by caspase-6 (CASP6), caspase-7 (CASP7) and caspase-8 (CASP8) during apoptosis, resulting in the dismantling of the autophagic machinery and the accomplishment of the programmed cell death program (PubMed:22441670). Also cleaved by calpains during apoptosis, which mediate a complete proteolytic degradation (PubMed:22441670).
Interacts with RMDN3. Isoform 1 interacts with TMED9. Isoform 1 interacts with STX17; dephosphorylates STX17. Interacts with ITGA1 (via cytoplasmic domain); activates the phosphatase activity towards EGFR. Interacts with TRAF2; probably involved in tumor necrosis factor-mediated signaling. Interacts with MET.
Major isoform. Contains a nuclear location signal at positions 377-381 (PubMed:7593185) and an autoinhibitory region acting through intramolecular interactions is found at positions 353-387.
Non-receptor type tyrosine-specific phosphatase that dephosphorylates receptor protein tyrosine kinases including INSR, EGFR, CSF1R, PDGFR. Also dephosphorylates non-receptor protein tyrosine kinases like JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3 and STAT6 either in the nucleus or the cytoplasm. Negatively regulates numerous signaling pathways and biological processes like hematopoiesis, inflammatory response, cell proliferation and differentiation, and glucose homeostasis. Plays a multifaceted and important role in the development of the immune system. Functions in T-cell receptor signaling through dephosphorylation of FYN and LCK to control T-cells differentiation and activation. Dephosphorylates CSF1R, negatively regulating its downstream signaling and macrophage differentiation. Negatively regulates cytokine (IL2/interleukin-2 and interferon)-mediated signaling through dephosphorylation of the cytoplasmic kinases JAK1, JAK3 and their substrate STAT1, that propagate signaling downstream of the cytokine receptors. Also regulates the IL6/interleukin-6 and IL4/interleukin-4 cytokine signaling through dephosphorylation of STAT3 and STAT6 respectively. In addition to the immune system, it is involved in anchorage-dependent, negative regulation of EGF-stimulated cell growth. Activated by the integrin ITGA1/ITGB1, it dephosphorylates EGFR and negatively regulates EGF signaling. Dephosphorylates PDGFRB and negatively regulates platelet-derived growth factor receptor-beta signaling pathway and therefore cell proliferation. Negatively regulates tumor necrosis factor-mediated signaling downstream via MAPK through SRC dephosphorylation. May also regulate the hepatocyte growth factor receptor signaling pathway through dephosphorylation of the hepatocyte growth factor receptor MET. Also plays an important role in glucose homeostasis. For instance, negatively regulates the insulin receptor signaling pathway through the dephosphorylation of INSR and control gluconeogenesis and liver glucose production through negative regulation of the IL6 signaling pathways. May also bind DNA.
Specifically phosphorylated in a cell cycle-dependent manner by cyclin-dependent kinases CDK1 and CDK2. Probably activated through phosphorylation by PKR.
Ubiquitously expressed. Isoform 2 is probably the major isoform. Isoform 1 is expressed in T-cells and in placenta.
Up-regulated by IL4/interleukin-4 (at protein level).
Detected in heart, liver, adrenal glands, and at low levels in skeletal muscle, kidney, pancreas and brain.
May be attached to the ER membrane by its C-terminus segment.
NADPH-dependent oxidoreductase which catalyzes the reduction of steroids (estrone, androstene-3,17-dione and cortisone) as well as prostaglandin E1, isatin and xenobiotics in vitro (PubMed:30031147). May have a role in steroid and/or xenobiotic metabolism (PubMed:30031147).
Restricted to hair root, not detected in any other tissues.
Highest level of expression in spleen and leukocytes.
Homodimer (PubMed:28074300). Interacts with S100P (PubMed:11747429).
Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site (PubMed:10373424). Involved in the terminal differentiation of keratinocytes through prostasin (PRSS8) activation and filaggrin (FLG) processing (PubMed:18843291). Proteolytically cleaves and therefore activates TMPRSS13 (PubMed:28710277).
Interacts with CDCP1. May interact with TMEFF1.
Interacts with AP5Z1, AP5B1, AP5S1 and SPG11. Interacts with TTC19 and KIF13A.
Phosphatidylinositol 3-phosphate-binding protein required for the abcission step in cytokinesis: recruited to the midbody during cytokinesis and acts as a regulator of abcission. May also be required for efficient homologous recombination DNA double-strand break repair.
Strongest expression in the adrenal gland, bone marrow, adult brain, fetal brain, lung, placenta, prostate, skeletal muscle, testis, thymus, and retina. Intermediate levels are detected in other structures, including the spinal cord.
The FYVE-type zinc finger mediates binding to phosphatidylinositol 3-phosphate and recruitment to the midbody during cytokinesis.
AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Gamma non-catalytic subunit mediates binding to AMP, ADP and ATP, leading to activate or inhibit AMPK: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive.
AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2.
Belongs to the 5'-AMP-activated protein kinase gamma subunit family.
Isoform B is ubiquitously expressed except in liver and thymus. The highest level is detected in heart with abundant expression in placenta and testis.
Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK.
The 4 CBS domains mediate binding to nucleotides. Of the 4 potential nucleotide-binding sites, 3 are occupied, designated as sites 1, 3, and 4 based on the CBS modules that provide the acidic residue for coordination with the 2'- and 3'-hydroxyl groups of the ribose of AMP. Of these, site 4 appears to be a structural site that retains a tightly held AMP molecule (AMP 3). The 2 remaining sites, 1 and 3, can bind either AMP, ADP or ATP. Site 1 (AMP, ADP or ATP 1) is the high-affinity binding site and likely accommodates AMP or ADP. Site 3 (AMP, ADP or ATP 2) is the weakest nucleotide-binding site on the gamma subunit, yet it is exquisitely sensitive to changes in nucleotide levels and this allows AMPK to respond rapidly to changes in cellular energy status. Site 3 is likely to be responsible for protection of a conserved threonine in the activation loop of the alpha catalytic subunit through conformational changes induced by binding of AMP or ADP.
The AMPK pseudosubstrate motif resembles the sequence around sites phosphorylated on target proteins of AMPK, except the presence of a non-phosphorylatable residue in place of Ser. In the absence of AMP this pseudosubstrate sequence may bind to the active site groove on the alpha subunit (PRKAA1 or PRKAA2), preventing phosphorylation by the upstream activating kinase STK11/LKB1.
Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Involved in down-regulation of MYB- and JUN-dependent transcription. May play a role in cell differentiation (By similarity). Can bind oligonucleotides, such as poly-G, poly-C or poly-T (in vitro), but the physiological relevance of this is not certain. Does not bind poly-A. Enhances ligand-dependent transcriptional activity of nuclear hormone receptors, including RARA, expect ESR1-mediated transcription that is not only slightly increased, if at all.
Detected in spleen, thymus, prostate, testis, ovary and intestine.
Homodimer. Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits. Interacts with MYB, ATF2, RARA, RARB, RARG, RXRA, RXRB and RXRG. Identified in a complex with ATF2 bound to target DNA (By similarity). Interacts with NANOS2 (By similarity). Directly interacts with ZNF335.
Acts as a calcium sensor for mitochondrial flash (mitoflash) activation, an event characterized by stochastic bursts of superoxide production (PubMed:26975899). May play a role in neuronal differentiation (By similarity).
Acts as GTPase-activating protein for RAB27A, but not for RAB2A, RAB3A, nor RAB4A.
Binds to the first PDZ domain of NHERF1 and NHERF2.
Exists in both phosphorylated and non-phosphorylated state.
The arginine and glutamine fingers are critical for the GTPase-activating mechanism, they pull out Rab's 'switch 2' glutamine and insert in Rab's active site.
Potential calcium-dependent cell-adhesion protein.
As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning. Probable anchoring protein which tethers the nucleus to the cytoskeleton by binding PLEC which can associate with the intermediate filament system. Plays a role in the regulation of aortic epithelial cell morphology, and is required for flow-induced centrosome polarization and directional migration in aortic endothelial cells.
Core component of LINC complexes which are composed of inner nuclear membrane SUN domain-containing proteins coupled to outer nuclear membrane KASH domain-containing nesprins. SUN and KASH domain-containing proteins seem to bind each other promiscuously; however, differentially expression of LINC complex constituents can give rise to specific assemblies. Interacts with SUN1 and SUN2; probably forming respective LINC complexes. Interacts with PLEC (via actin-binding domain). Interacts with DST. Interacts with SYNE1 via spectrin repeats. Interacts (via KASH domain) with TOR1A (ATP-bound); the interaction is required for SYNE3 nuclear envelope localization.
Expressed in aortic endothelial cells (at protein level).
The KASH domain is involved in the binding to SUN1 and SUN2 through recognition of their SUN domains.
The disulfid bond with SUN1 or SUN2 is required for stability of the respective LINC complex under tensile forces.
ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen (PubMed:11248239, PubMed:15682271, PubMed:16946495, PubMed:18757502, PubMed:21145416, PubMed:23671276, PubMed:29397936, PubMed:33500543). Coupled to the ATP-dependent transporter activity has also a fatty acyl-CoA thioesterase activity (ACOT) and hydrolyzes VLCFA-CoA into VLCFA prior their ATP-dependent transport into peroxisomes, the ACOT activity is essential during this transport process (PubMed:33500543, PubMed:29397936). Thus, plays a role in regulation of VLCFAs and energy metabolism namely, in the degradation and biosynthesis of fatty acids by beta-oxidation, mitochondrial function and microsomal fatty acid elongation (PubMed:23671276, PubMed:21145416). Involved in several processes; namely, controls the active myelination phase by negatively regulating the microsomal fatty acid elongation activity and may also play a role in axon and myelin maintenance. Controls also the cellular response to oxidative stress by regulating mitochondrial functions such as mitochondrial oxidative phosphorylation and depolarization. And finally controls the inflammatory response by positively regulating peroxisomal beta-oxidation of VLCFAs (By similarity).
Can form homodimers and heterodimers with ABCD2 and ABCD3. Dimerization is necessary to form an active transporter (PubMed:17609205, PubMed:10551832) (Probable). The minimal functional unit is a homodimer but the major oligomeric form in peroxisomal membrane is a homotetramer (By similarity). Forms heterotramers with ABCD2 (By similarity). Interacts with PEX19; facilitates ABCD1 insertion into the peroxisome membrane (PubMed:10777694, PubMed:10704444).
The NH2-terminal transmembrane domaine (TMD) is involved in the recognition of substrates, and undergoes a conformational change upon ATP binding to the COOH-terminal nucleotide binding domain (NBD).
The cysteine-reactive reagent p-chloromercuribenzoic acid (pCMB) strongly decreased the ACOT activity. The serine esterase inhibitors phenylmethylsulfonyl fluoride (PMSF), diisopropylfluorophosphate (DFP) and bis-(4-nitrophenyl)phosphate (BNPP) moderately reduced the ACOT activity. The histidine-reacting reagent diethyl pyrocarbonate (DEPC) has no effect on the ACOT activity.
The promoter region of ABCD1 is deleted in the chromosome Xq28 deletion syndrome which involves ABCD1 and the neighboring gene BCAP31.
Up-regulated by degradation or export of cholesterol.
Variants Trp-88, Cys-152, Cys-181, Ser-343, Pro-503, Arg-514 and His-554 have original been associated with ALD. However this paper was retracted due to inconsistencies in a confirmation immunoblot that could not be validated from the originally published data.
Appears to have no transporter activity.
Electrogenic Na+-coupled sugar symporter that actively transports D-mannose or D-fructose at the plasma membrane, with a Na+ to sugar coupling ratio of 1:1. Transporter activity is driven by a transmembrane Na+ electrochemical gradient set by the Na+/K+ pump. Exclusively recognizes sugar substrates having a pyranose ring with an axial hydroxyl group on carbon 2 (PubMed:24573086, PubMed:22212718, PubMed:23451068). Has likely evolved to enable renal reabsorption of D-mannose, an important constituent of oligosaccharide chains of glycoproteins. Contributes to dietary D-fructose reabsorption from glomerular filtrate across the brush border of the kidney (PubMed:22212718, PubMed:23451068).
Predominantly expressed at high levels in kidney. Very low expression is detected in testes.
The most abundant isoform expressed in kidney.
May be a serine protease inhibitor (By similarity). Essential for sperm maturation and fertility. Inhibits sperm acrosome reaction, protecting sperm from premature reaction (By similarity).
Ubiquitously expressed. Highest expression in stomach, salivary glands and lymph nodes. Isoform 2 is expressed in placenta.
Found at low level in a wide range of tissues, but significantly expressed in lung, kidney, bone and nervous system.
Proton-sensing receptor involved in pH homeostasis. May represents an osteoblastic pH sensor regulating cell-mediated responses to acidosis in bone. Mediates its action by association with G proteins that stimulates inositol phosphate (IP) production or Ca(2+) mobilization. The receptor is almost silent at pH 7.8 but fully activated at pH 6.8. Also functions as a metastasis suppressor gene in prostate cancer (By similarity).
Was originally (PubMed:10806476) thought to be a receptor for sphingosylphosphorylcholine (SPC). However, this work has been retracted (PubMed:16508674).
Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin.
Component of centriolar satellites contributing to the building of a complex and dynamic network required to regulate cilia/flagellum formation (PubMed:17954613, PubMed:24185901). In proliferating cells, MIB1-mediated ubiquitination induces its sequestration within centriolar satellites, precluding untimely cilia formation initiation (PubMed:24121310). In contrast, during normal and ultraviolet or heat shock cellular stress-induced ciliogenesis, its non-ubiquitinated form is rapidly displaced from centriolar satellites and recruited to centrosome/basal bodies in a microtubule- and p38 MAPK-dependent manner (PubMed:24121310, PubMed:26616734). Acts also as a negative regulator of BBSome ciliary trafficking (PubMed:24550735). Plays a role in sperm flagellar formation; may be involved in the regulation of intraflagellar transport (IFT) and/or intramanchette (IMT) trafficking, which are important for axoneme extension and/or cargo delivery to the nascent sperm tail (By similarity). Required for optimal cell proliferation and cell cycle progression; may play a role in the regulation of genome stability in non-ciliogenic cells (PubMed:22797915, PubMed:26297806). Involved in centriole duplication (By similarity). Required for CEP152, WDR62 and CEP63 centrosomal localization and promotes the centrosomal localization of CDK2 (PubMed:26297806). Essential for maintaining proper centriolar satellite integrity (PubMed:30804208).
MAPKAPK2-dependent phosphorylation at Ser-47 and Ser-78 occurs in response to cellular stress such as exposure to ultraviolet irradiation and promotes binding to 14-3-3 proteins which leads to cytoplasmic sequestration of CEP131 and blocks formation of new centriolar satellites (PubMed:26616734). Phosphorylation at Ser-78 mediated by PLK4 is essential for proper organization and integrity of centriolar satellites but is dispensable for its localization to centrioles and its function in ciliogenesis (PubMed:30804208).
Self-associates. Associates with the centriolar satellite BBSome protein complex. Interacts with BBS4; the interaction limits BBS4 availability for association with the BBSome complex, and hence negatively regulates ciliary localization of the BBSome complex (PubMed:24550735). Interacts with MIB1 (PubMed:24121310). Interacts with PCM1; the interaction increases in response to ultraviolet light (UV) radiation (PubMed:22797915, PubMed:24121310). Associates with microtubules; association with microtubules is reduced in response to cellular stress, such as UV stimulation, in a process that requires p38 MAP kinase signaling (PubMed:24121310). Interacts with CEP290, DCTN1, PCNT, PCM1 and CEP152. Interacts with 14-3-3 proteins following UV-induced phosphorylation by MAPKAPK2; this inhibits formation of novel centriolar satellites (PubMed:26616734). Interacts with SDCCAG8 (PubMed:27224062). Interacts with CCDC61 (PubMed:31789463). Interacts with PLK4 (PubMed:30804208).
Transient cell cultured-based knock-down (by RNAi) of CEP131 leads to a reduction in ciliogenesis (PubMed:17954613, PubMed:24121310). However, analysis of mice with chronic absence of CEP131 following genetic deletion (knockout) shows that cilia develop and function normally in vivo. This suggests that CEP131 is not essential for ciliogenesis, except for the modified cilia of the developing sperm flagella, and that there is an alternative mechanism to compensate for the lack of CEP131.
Ubiquitinated. Undergoes monoubiquitination catalyzed by the E3 ubiquitin-protein ligase MIB1 in proliferating cells, preventing cilia formation. Monoubiquitination by MIB1 is inhibited in response to cellular stress, such as ultraviolet light (UV) radiation or heat shock, resulting in cilia formation initiation.
Up-regulated by the transcription factor SP1.
Belongs to the SEC23/SEC24 family. SEC23 subfamily.
COPII is composed of at least five proteins: the Sec23/24 complex, the Sec13/31 complex and Sar1 (PubMed:17499046). Interacts with SEC23IP. Interacts with HTR4 (By similarity). Interacts with SEC16A (PubMed:17192411). Interacts with SLC6A4 (By similarity). Interacts (as part of the Sec23/24 complex) with SEC22B; recruits SEC22B into COPII-coated vesicles and allows the transport of this cargo from the endoplasmic reticulum to the Golgi (PubMed:17499046). Interacts (via Gelsolin-like repeat) with MIA2 and MIA3; specifically involved in the transport of large cargos like the collagen COL7A1 (PubMed:27551091, PubMed:28442536). Interacts with DDHD1 (By similarity). Interacts with TMEM39A (PubMed:31806350). Interacts with SACM1L; this interaction is reduced in the absence of TMEM39A (PubMed:31806350). Interacts with kinase FAM20C; transport of FAM20C from the endoplasmic reticulum to the Golgi is likely to be mediated by COPII vesicles (PubMed:34349020).
Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules for their transport to the Golgi complex. Required for the translocation of insulin-induced glucose transporter SLC2A4/GLUT4 to the cell membrane (By similarity).
The Gelsolin-like repeat mediates interaction with proteins containing PPP motifs that include MIA2, MIA3 but also SEC31A. These interactions are probably competitive.
Belongs to the glycosyl hydrolase 13 family.
Calcium-binding enzyme that initiates starch digestion in the oral cavity (PubMed:12527308). Catalyzes the hydrolysis of internal (1->4)-alpha-D-glucosidic bonds, yielding a mixture of maltose, isomaltose, small amounts of glucose as well as small linear and branched oligosaccharides called dextrins (PubMed:12527308).
Three distinct genes (AMY1A, AMY1B and AMY1C), located in a gene cluster on 1p21, encode proteins sharing the same peptidic sequence.
Probable substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes TNFRSF1B.
High-level and epididymis-specific expression (PubMed:12600824). Most abundant in the epithelium of the caput and present in the epididymis lumen and bound to sperm (PubMed:12600824). Also expressed in pancreas (PubMed:12600824).
Host defense peptide that exhibits antimicrobial activity against both Gram-negative bacteria, such as E.coli and S.typhimurium, and Gram-positive bacteria, such as S.aureus and B.subtilis (PubMed:15033915, PubMed:33224970). Inhibits cell adhesion of E.coli on intestinal epithelial enterocytes (PubMed:33224970). Causes rapid permeabilization of both the outer and inner membrane of E.coli, leading to morphological alterations on the bacterial surface (PubMed:15033915). Binds to bacterial lipopolysaccharides (LPS) with high affinity, and may thereby be involved in immunoregulation through LPS neutralization (PubMed:33181266). May contribute to epididymal innate immunity and protect the sperm against attack by microorganisms (PubMed:15033915).
The three-dimensional structure formed by the three intramolecular disulfide bridges is indispensable for antimicrobial activity.
A single nucleotide deletion at position Leu-229 in the gene coding for this protein is responsible for functional diversity thus producing a pseudogene. The deletion is more frequent in African-Americans than in non-Africans.
BBS5 may interact genetically with BBS1.
Part of BBSome complex, that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10. Binds to phosphoinositides. Interacts with CCDC28B. Interacts with SMO; the interaction is indicative for the association of SMO with the BBsome complex to facilitate ciliary localization of SMO. Interacts with PKD1 (PubMed:24939912). Interacts with DLEC1 (PubMed:33144677).
The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia. The BBSome complex is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Firstly the BBSome associates with the ciliary membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and promotes docking and fusion of carrier vesicles to the base of the ciliary membrane. The BBSome complex, together with the LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. Required for BBSome complex ciliary localization but not for the proper complex assembly.
Belongs to the immunoglobulin superfamily. SIGLEC (sialic acid binding Ig-like lectin) family.
Expressed by peripheral blood leukocytes (eosinophils, monocytes and a natural killer cell subpopulation). Isoform 5 is found to be the most abundant isoform. Found in lymph node, lung, ovary and appendix. Isoform 1 is found at high levels and isoform 2 at lower levels in bone marrow, spleen and spinal chord. Isoform 2 is also found in brain. Isoform 4 is specifically found in natural killer cells.
Interacts with PTPN6/SHP-1 upon phosphorylation (PubMed:12163025). Interacts with NCF1 (By similarity). Interacts with CD24; the probable CD24:SIGLEC10 complex is proposed to inhibit HGMB1-mediated tissue damage immune response. Interacts with HMGB1; the interaction is dependent on CD24 (PubMed:19264983). Interacts with RIGI, CBL and PTPN11 (By similarity).
Phosphorylation of Tyr-667 is involved in binding to PTPN6.
Putative adhesion molecule that mediates sialic-acid dependent binding to cells. Preferentially binds to alpha-2,3- or alpha-2,6-linked sialic acid (By similarity). The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface. In the immune response, seems to act as an inhibitory receptor upon ligand induced tyrosine phosphorylation by recruiting cytoplasmic phosphatase(s) via their SH2 domain(s) that block signal transduction through dephosphorylation of signaling molecules (PubMed:11284738, PubMed:12163025). Involved in negative regulation of B-cell antigen receptor signaling. The inhibition of B cell activation is dependent on PTPN6/SHP-1 (By similarity). In association with CD24 may be involved in the selective suppression of the immune response to danger-associated molecular patterns (DAMPs) such as HMGB1, HSP70 and HSP90 (By similarity). In association with CD24 may regulate the immune repsonse of natural killer (NK) cells (PubMed:25450598). Plays a role in the control of autoimmunity (By similarity). During initiation of adaptive immune responses by CD8-alpha(+) dendritic cells inhibits cross-presentation by impairing the formation of MHC class I-peptide complexes. The function seems to implicate recruitment of PTPN6/SHP-1, which dephosphorylates NCF1 of the NADPH oxidase complex consequently promoting phagosomal acidification (By similarity).
Belongs to the GSK-3-binding protein family.
Binds DVL1. Binds GSK-3 and prevent GSK-3-dependent phosphorylation.
Positively regulates the Wnt signaling pathway by stabilizing beta-catenin through the association with GSK-3. May play a role in tumor progression and collaborate with PIM1 and MYC in lymphomagenesis.
Belongs to the glycosyl hydrolase 79 family.
Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extracellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up-regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis.
Escapes proteolytic cleavage, devoid of HS degradation activity.
Heterodimer; heterodimer formation between the 8 kDa and the 50 kDa subunits is required for enzyme activity. Interacts with TF; the interaction, inhibited by heparin, enhances the generation of activated factor X and activates coagulation. Interacts with HRG; the interaction is enhanced at acidic pH, partially inhibits binding of HPSE to cell surface receptors and modulates its enzymatic activity. Interacts with SDC1; the interaction enhances the shedding of SDC1. Interacts with HPSE2.
Highly expressed in placenta and spleen and weakly expressed in lymph node, thymus, peripheral blood leukocytes, bone marrow, endothelial cells, fetal liver and tumor tissues. Also expressed in hair follicles, specifically in both Henle's and Huxley's layers of inner the root sheath (IRS) at anagen phase.
Inhibited by EDTA, laminarin sulfate and, to a lower extent, by heparin and sulfamin and activated by calcium and magnesium.
N-glycosylated. Glycosylation of the 50 kDa subunit appears to be essential for its solubility.
Proteolytically processed. The cleavage of the 65 kDa form leads to the generation of a linker peptide, and 8 kDa and 50 kDa products. The active form, the 8/50 kDa heterodimer, is resistant to degradation. Complete removal of the linker peptide appears to be a prerequisite to the complete activation of the enzyme.
A chromosomal aberration involving SATB2 is found in a patient with classical features of Toriello-Carey syndrome. Translocation t(2;14)(q33;q22).
Binds to DNA, at nuclear matrix- or scaffold-associated regions. Thought to recognize the sugar-phosphate structure of double-stranded DNA. Transcription factor controlling nuclear gene expression, by binding to matrix attachment regions (MARs) of DNA and inducing a local chromatin-loop remodeling. Acts as a docking site for several chromatin remodeling enzymes and also by recruiting corepressors (HDACs) or coactivators (HATs) directly to promoters and enhancers. Required for the initiation of the upper-layer neurons (UL1) specific genetic program and for the inactivation of deep-layer neurons (DL) and UL2 specific genes, probably by modulating BCL11B expression. Repressor of Ctip2 and regulatory determinant of corticocortical connections in the developing cerebral cortex. May play an important role in palate formation. Acts as a molecular node in a transcriptional network regulating skeletal development and osteoblast differentiation.
Chromosomal aberrations involving SATB2 are found in isolated cleft palate. Translocation t(2;7); translocation t(2;11).
High expression in adult brain, moderate expression in fetal brain, and weak expression in adult liver, kidney, and spinal cord and in select brain regions, including amygdala, corpus callosum, caudate nucleus, and hippocampus.
Interacts with ATF4 and RUNX2; resulting in enhanced DNA binding and transactivation by these transcription factors (By similarity). Interacts with PIAS1.
Sumoylated by PIAS1. Sumoylation promotes nuclear localization, but represses transcription factor activity.
Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3. Interacts with RAB11FIP2, RAB11A, and RAB8A. Found in a complex with CFTR and RAB11A. Interacts with NPC1L1; (PubMed:19542231). Interacts with LIMA1 (PubMed:29880681).
May be involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation. Required in a complex with RAB11A and RAB11FIP2 for the transport of NPC1L1 to the plasma membrane. Together with RAB11A participates in CFTR trafficking to the plasma membrane and TF (transferrin) recycling in nonpolarized cells. Together with RAB11A and RAB8A participates in epithelial cell polarization. Together with RAB25 regulates transcytosis. Required for proper localization of bile salt export pump ABCB11 at the apical/canalicular plasma membrane of hepatocytes (PubMed:34816459).
Autoubiquitinated in the presence of CDC34/UBCH3.
Binds 1 divalent metal cation per subunit. Mg(2+) or Mn(2+).
Catalytic component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination. V(D)J recombination assembles a diverse repertoire of immunoglobulin and T-cell receptor genes in developing B and T-lymphocytes through rearrangement of different V (variable), in some cases D (diversity), and J (joining) gene segments. In the RAG complex, RAG1 mediates the DNA-binding to the conserved recombination signal sequences (RSS) and catalyzes the DNA cleavage activities by introducing a double-strand break between the RSS and the adjacent coding segment. RAG2 is not a catalytic component but is required for all known catalytic activities. DNA cleavage occurs in 2 steps: a first nick is introduced in the top strand immediately upstream of the heptamer, generating a 3'-hydroxyl group that can attack the phosphodiester bond on the opposite strand in a direct transesterification reaction, thereby creating 4 DNA ends: 2 hairpin coding ends and 2 blunt, 5'-phosphorylated ends. The chromatin structure plays an essential role in the V(D)J recombination reactions and the presence of histone H3 trimethylated at 'Lys-4' (H3K4me3) stimulates both the nicking and haipinning steps. The RAG complex also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. The introduction of DNA breaks by the RAG complex on one immunoglobulin allele induces ATM-dependent repositioning of the other allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. In addition to its endonuclease activity, RAG1 also acts as an E3 ubiquitin-protein ligase that mediates monoubiquitination of histone H3. Histone H3 monoubiquitination is required for the joining step of V(D)J recombination. Mediates polyubiquitination of KPNA1 (By similarity).
Homodimer. Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2. Interacts with DCAF1, leading to recruitment of the CUL4A-RBX1-DDB1-DCAF1/VPRBP complex to ubiquitinate proteins and limit error-prone repair during V(D)J recombination (By similarity).
The NBD (nonamer binding) DNA-binding domain mediates the specific binding to the nonamer RSS motif by forming a tightly interwoven homodimer that binds and synapses 2 nonamer elements, with each NBD making contact with both DNA molecules. Each RSS is composed of well-conserved heptamer (consensus 5'-CACAGTG-3') and nonamer (consensus 5'-ACAAAAACC-3') sequences separated by a spacer of either 12 bp or 23 bp.
The RING-type zinc finger mediates the E3 ubiquitin-protein ligase activity.
Acts as a ligand for C-C chemokine receptor CCR2 (PubMed:9837883, PubMed:10587439, PubMed:10529171). Signals through binding and activation of CCR2 and induces a strong chemotactic response and mobilization of intracellular calcium ions (PubMed:9837883, PubMed:10587439). Exhibits a chemotactic activity for monocytes and basophils but not neutrophils or eosinophils (PubMed:8627182, PubMed:9792674, PubMed:8195247). May be involved in the recruitment of monocytes into the arterial wall during the disease process of atherosclerosis (PubMed:8107690).
Expressed in the seminal plasma, endometrial fluid and follicular fluid (at protein level) (PubMed:23765988). Expressed in monocytes (PubMed:2513477).
Genetic variations in CCL2 determine Mycobacterium tuberculosis susceptibility [MIM:607948].
Monomer or homodimer; in equilibrium (PubMed:8898111, PubMed:9837883, PubMed:15033992, PubMed:8989326). Is tethered on endothelial cells by glycosaminoglycan (GAG) side chains of proteoglycans (PubMed:9792674). Interacts with TNFAIP6 (via Link domain).
Processing at the N-terminus can regulate receptor and target cell selectivity (PubMed:8627182). Deletion of the N-terminal residue converts it from an activator of basophil to an eosinophil chemoattractant (PubMed:8627182).
Up-regulated upon hypertonic conditions (PubMed:23233732). In pancreatic islets, secretion is stimulated by IL1B (PubMed:23955712).
Channel activity is regulated by phosphorylation (PubMed:16551655, PubMed:20881056, PubMed:26269590). Channel activity is regulated by intracellular Ca(2+) (PubMed:11854751).
Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B (PubMed:27214281). Can also form a functional, homotetrameric ion channel (PubMed:29899465). Functions as a cation channel involved in fluid-flow mechanosensation by the primary cilium in renal epithelium (PubMed:18695040). Functions as outward-rectifying K(+) channel, but is also permeable to Ca(2+), and to a much lesser degree also to Na(+) (PubMed:11854751, PubMed:15692563, PubMed:27071085, PubMed:27991905). May contribute to the release of Ca(2+) stores from the endoplasmic reticulum (PubMed:11854751, PubMed:20881056). Together with TRPV4, forms mechano- and thermosensitive channels in cilium (PubMed:18695040). PKD1 and PKD2 may function through a common signaling pathway that is necessary to maintain the normal, differentiated state of renal tubule cells. Acts as a regulator of cilium length, together with PKD1. The dynamic control of cilium length is essential in the regulation of mechanotransductive signaling. The cilium length response creates a negative feedback loop whereby fluid shear-mediated deflection of the primary cilium, which decreases intracellular cAMP, leads to cilium shortening and thus decreases flow-induced signaling. Also involved in left-right axis specification via its role in sensing nodal flow; forms a complex with PKD1L1 in cilia to facilitate flow detection in left-right patterning. Detection of asymmetric nodal flow gives rise to a Ca(2+) signal that is required for normal, asymmetric expression of genes involved in the specification of body left-right laterality (By similarity).
Detected in fetal and adult kidney (PubMed:10770959). Detected at the thick ascending limb of the loop of Henle, at distal tubules, including the distal convoluted tubule and cortical collecting tubules, with weak staining of the collecting duct (PubMed:10770959). Detected on placenta syncytiotrophoblasts (at protein level) (PubMed:26269590). Strongly expressed in ovary, fetal and adult kidney, testis, and small intestine. Not detected in peripheral leukocytes.
Homotetramer (PubMed:20881056, PubMed:27768895, PubMed:27991905, PubMed:28092368, PubMed:29899465). Heterotetramer with PKD1, giving rise to a complex formed by one PKD1 chain and three PKD2 chains (PubMed:20881056, PubMed:19556541, PubMed:27214281, PubMed:30093605). Interaction with PKD1 is required for ciliary localization (By similarity) Isoform 1 interacts with PKD1 while isoform 3 does not (By similarity). Interacts with PKD1L1. Interacts with CD2AP (PubMed:10913159). Interacts with HAX1 (PubMed:10760273). Interacts with NEK8 (By similarity). Part of a complex containing AKAP5, ADCY5, ADCY6 and PDE4C (By similarity). Interacts (via C-terminus) with TRPV4 (via C-terminus) (PubMed:18695040). Interacts (via C-terminal acidic region) with PACS1 and PACS2; these interactions retain the protein in the endoplasmic reticulum and prevent trafficking to the cell membrane (PubMed:15692563). Interacts with TMEM33 (By similarity).
N-glycosylated. The four subunits in a tetramer probably differ in the extent of glycosylation; simultaneous glycosylation of all experimentally validated sites would probably create steric hindrance. Thus, glycosylation at Asn-305 is not compatible with glycosylation at Asn-328; only one of these two residues is glycosylated at a given time.
Phosphorylated. Phosphorylation is important for protein function; a mutant that lacks the N-terminal phosphorylation sites cannot complement a zebrafish pkd2-deficient mutant (PubMed:16551655). PKD-mediated phosphorylation at the C-terminus regulates its function in the release of Ca(2+) stores from the endoplasmic reticulum (PubMed:20881056). PKA-mediated phosphorylation at a C-terminal site strongly increases the open probability of the channel, but does not increase single channel conductance (PubMed:26269590).
The C-terminal coiled-coil domain is involved in oligomerization and the interaction with PKD1 (PubMed:18694932, PubMed:19556541). The isolated coiled-coil domain forms a homotrimer in vitro; the homotrimer interacts with a single PKD1 chain (PubMed:19556541). The coiled-coil domain binds calcium and undergoes a calcium-induced conformation change (in vitro) (PubMed:18694932).
The mechanisms that govern channel opening are complex and still under debate; heterologous expression of PKD2 by itself or together with PKD1 gives rise to very low or undetectable spontaneous ion channel activity, in spite of its presence at the cell membrane.
Interacts with adapter protein complex 1 (AP-1) and AP-2, but not AP-3 and AP-4 (By similarity). Interacts with LAMP2 (PubMed:27046251).
Mediates the translocation of RNA and DNA across the lysosomal membrane during RNA and DNA autophagy (RDA), a process in which RNA or DNA is directly imported into lysosomes in an ATP-dependent manner, and degraded (PubMed:27046251, PubMed:27846365). Involved in the uptake of single-stranded oligonucleotides by living cells, a process called gymnosis (PubMed:28277980). In vitro, mediates the uptake of linear DNA more efficiently than that of circular DNA, but exhibits similar uptake efficacy toward RNA and DNA. Binds long double-stranded RNA (dsRNA) (500 - 700 base pairs), but not dsRNA shorter than 100 bp (By similarity).
Belongs to the CDKN2 cyclin-dependent kinase inhibitor family.
Interacts strongly with CDK4 and CDK6 and inhibits them.
By wounding; increased levels are observed in hematopoietic cells 48 hours after wounding (PubMed:30609079). Following wounding, repressed by infection with S.aureus (PubMed:30609079). Isoform 1: By lipopolysaccharide and TNF (PubMed:28705375). Isoform 2: By lipopolysaccharide and TNF (PubMed:28705375).
Expressed constitutively in a variety of cell types including macrophages, natural killer cells, neutrophils, keratinocytes and monocytes (PubMed:26402460, PubMed:28705375, PubMed:7888681). In skin, expressed in both hematopoietic and non-hematopoietic cells with expression detected in a variety of cell types including keratinocytes, fibroblasts and endothelial cells (PubMed:30609079).
Forms arc- and ring-shaped pre-pores on top of the membrane at neutral to slightly acidic pH conditions and converts to pores upon acidification (PubMed:31537793). Undergoes transition from the pre-pore to the pore in a processive clockwise hand-over-hand process (By similarity). In the pore state, 2 alpha-helical regions refold into transmembrane hairpins (TMH1 and TMH2) in each protomer that form in the ensemble complex giant beta-barrel transmembrane pores (PubMed:31537793).
Homooligomer (PubMed:31537793). Predominantly forms a homooligomeric arc-shaped pore complex instead of complete rings of 16 subunits (By similarity).
Lacks the C-terminal transmembrane domain.
Monoubiquitinated in response to bacterial infection; ubiquitination is required for vesicular localization and antibacterial activity and can be blocked by bacterial cell cycle inhibiting factor (cif) (By similarity).
Pore-forming protein involved in both innate and adaptive immunity (PubMed:23753625, PubMed:26402460, PubMed:28422754, PubMed:30609079, PubMed:31537793, PubMed:33224153). Plays a central role in antigen cross-presentation in dendritic cells by forming a pore in antigen-containing compartments, thereby promoting delivery of antigens for cross-presentation (By similarity). Also involved in innate immune response following bacterial infection; shows antibacterial activity against a wide spectrum of Gram-positive, Gram-negative and acid-fast bacteria (PubMed:23753625, PubMed:26402460, PubMed:28422754, PubMed:30609079, PubMed:33224153). Reduces the viability of the intracytosolic pathogen L.monocytogenes by inhibiting acidification of the phagocytic vacuole of host cells which restricts bacterial translocation from the vacuole to the cytosol (By similarity). Required for the antibacterial activity of reactive oxygen species and nitric oxide (By similarity).
Pore-forming protein that plays a central role in antigen cross-presentation in dendritic cells by mediating delivery of antigens for cross-presentation (By similarity). Dendritic cells bridge innate and adaptive immunity by capturing exogenous antigens on MHC class-I molecules and presenting them to naive CD8(+) T-cells (By similarity). Acts by forming a pore in antigen-containing compartments, promoting the release of antigens into the cytosol, enabling generation of MHCI:peptide complexes and T-cell priming (By similarity).
Proteolytically processed in two steps to generate the Macrophage-expressed gene 1 protein, processed form: cleaved by trypsin in proximity of the helical transmembrane domain releases the ectodomain into the lysosomal lumen to orient the pore-forming domain toward the endogenous membranes, and processed by the asparagine endopeptidase (LGMN).
The MACPF domain includes the central machinery of pore formation: acidification causes a significant structural rearrangement, leading to oligomerization and deployment of the transmembrane beta-strands (named TMH1 and TMH2) that enter the membrane as amphipathic beta-hairpins.
The P2 region contains beta-hairpins to interact with target membranes.
Activated by phosphorylation on Thr-208.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.
Phosphorylated at Thr-208 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39 (PubMed:14976552). Autophosphorylation is also possible at Thr-208 (PubMed:32845958).
Stress-activated kinase involved in tolerance to glucose starvation. Induces cell-cell detachment by increasing F-actin conversion to G-actin. Expression is induced by CD95 or TNF-alpha, via NF-kappa-B. Protects cells from CD95-mediated apoptosis and is required for the increased motility and invasiveness of CD95-activated tumor cells. Phosphorylates LATS1 and LATS2. Plays a key role in neural tube closure during embryonic development through LATS2 phosphorylation and regulation of the nuclear localization of YAP1 a critical downstream regulatory target in the Hippo signaling pathway (PubMed:32845958).
Forms a heterodimer with SLX1A/GIYD1. Interacts with ERCC4/XPF; catalytic subunit of the ERCC4-ERCC1 endonuclease. Interacts with MUS81; catalytic subunit of the MUS81-EME1 endonuclease. Interacts with MSH2; component of the MSH2-MSH3 mismatch repair complex. Interacts with TERF2-TERF2IP. Interacts with PLK1 and SLX4IP.
Regulatory subunit that interacts with and increases the activity of different structure-specific endonucleases. Has several distinct roles in protecting genome stability by resolving diverse forms of deleterious DNA structures originating from replication and recombination intermediates and from DNA damage. Component of the SLX1-SLX4 structure-specific endonuclease that resolves DNA secondary structures generated during DNA repair and recombination. Has endonuclease activity towards branched DNA substrates, introducing single-strand cuts in duplex DNA close to junctions with ss-DNA. Has a preference for 5'-flap structures, and promotes symmetrical cleavage of static and migrating Holliday junctions (HJs). Resolves HJs by generating two pairs of ligatable, nicked duplex products. Interacts with the structure-specific ERCC4-ERCC1 endonuclease and promotes the cleavage of bubble structures. Interacts with the structure-specific MUS81-EME1 endonuclease and promotes the cleavage of 3'-flap and replication fork-like structures. SLX4 is required for recovery from alkylation-induced DNA damage and is involved in the resolution of DNA double-strand breaks.
Expressed in skin, including primary keratinocytes, spleen, kidney, leukocytes, testis, lung, small intestine and prostate.
Isoform 4 is expressed at low level in kidney, testis and fetal thymus. Isoform 3 is expressed at low level in prostate, testis and fetal thymus.
(Microbial infection) May interact with the MA protein of HIV-1.
Component of the PRC2/EED-EZH2 complex, which includes EED, EZH2, SUZ12, RBBP4 and RBBP7 and possibly AEBP2. The minimum components required for methyltransferase activity of the PRC2/EED-EZH2 complex are EED, EZH2 and SUZ12. Component of the PRC2/EED-EZH1 complex, which includes EED, EZH1, SUZ12, RBBP4 and AEBP2. The PRC2 complex may also interact with DNMT1, DNMT3A, DNMT3B and PHF1 via the EZH2 subunit and with SIRT1 via the SUZ12 subunit. Interacts with HDAC, HDAC2, histone H1 and YY1. May interact with ITGA4, ITGAE and ITGB7. Interacts with CDYL. Interacts with BMAL1. Interacts with KMT2A/MLL1 (By similarity).
Expressed in brain, colon, heart, kidney, liver, lung, muscle, ovary, peripheral blood leukocytes, pancreas, placenta, prostate, spleen, small intestine, testis, thymus and uterus. Appears to be overexpressed in breast and colon cancer.
Expression is induced by E2F1, E2F2 and E2F3.
Expression peaks at the G1/S phase boundary.
Methylated. Binding to histone H1 'Lys-26' promotes mono-, di-, and trimethylation of internal lysines.
Polycomb group (PcG) protein. Component of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' and 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Also recognizes 'Lys-26' trimethylated histone H1 with the effect of inhibiting PRC2 complex methyltransferase activity on nucleosomal histone H3 'Lys-27', whereas H3 'Lys-27' recognition has the opposite effect, enabling the propagation of this repressive mark. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1 and CDKN2A.
The WD repeat domain mediates recognition of trimethylated histone peptides at the consensus sequence Ala-Arg-Lys-Ser. This is achieved through an aromatic cage encircling the methyllysine, and involving Phe-97, Tyr-148 and Tyr-365.
Two variants of the PRC2 complex have been described, termed PRC3 and PRC4. Each of the three complexes may include a different complement of EED isoforms, although the precise sequences of the isoforms in each complex have not been determined. The PRC2 and PRC4 complexes may also methylate 'Lys-26' of histone H1 in addition to 'Lys-27' of histone H3 (PubMed:15099518, PubMed:15684044), although other studies have demonstrated no methylation of 'Lys-26' of histone H1 by PRC2 (PubMed:16431907).
A publication reported some nucleolar localization (PubMed:32199293). However, the protein used in this publication used a N-terminal tag, which possibly interferes with the mitochondrial targeting (PubMed:34774131).
Belongs to the methyltransferase superfamily. METL family.
Mitochondrial S-adenosyl-L-methionine-dependent methyltransferase that mediates N(3)-methylcytidine modification of residue 32 of the tRNA anticodon loop of mitochondrial tRNA(Ser)(UCN) and tRNA(Thr) (PubMed:34774131, PubMed:35017528). N(3)-methylcytidine methylation modification regulates mitochondrial translation efficiency and is required for activity of the respiratory chain (PubMed:34774131, PubMed:35017528). N(3)-methylcytidine methylation of mitochondrial tRNA(Ser)(UCN) requires the formation of N(6)-dimethylallyladenosine(37) (i6A37) by TRIT1 as prerequisite (PubMed:34774131, PubMed:35017528). May also mediate N(3)-methylcytidine modification of mRNAs (PubMed:28655767). The existence of N(3)-methylcytidine modification on mRNAs is however unclear, and additional evidences are required to confirm the role of the N(3)-methylcytidine-specific mRNA methyltransferase activity of METTL8 in vivo (PubMed:34774131, PubMed:33313824).
S-adenosyl-L-methionine-dependent methyltransferase.
The existence of N(3)-methylcytidine on mRNA is unclear (PubMed:34774131, PubMed:33313824). A report was unable to detect N(3)-methylcytidine formation in mammalian mRNAs using a nucleotide-resolution sequencing approach (PubMed:33313824). According to another publication, METTL8 has no activity on mRNAs and specifically methylates mitochondrial tRNAs (PubMed:34774131).
Cleaved by a furin endopeptidase in the trans-Golgi network.
Interacts (via PDZ-binding motif) with APBA3 (via PDZ domain). Interacts with GRIP1 and GRIP2 (By similarity).
Metalloprotease that mediates cleavage of N-cadherin (CDH2) and acts as a regulator of neuro-immune interactions and neural stem cell quiescence. Involved in cell-cell interactions between nociceptive neurites and mast cells, possibly by mediating cleavage of CDH2, thereby acting as a mediator of peripheral thermal nociception and inflammatory hyperalgesia. Key regulator of neural stem cells quiescence by mediating cleavage of CDH2, affecting CDH2-mediated anchorage of neural stem cells to ependymocytes in the adult subependymal zone, leading to modulate their quiescence. May play a role in axonal growth. Able to activate progelatinase A. May also be a proteoglycanase involved in degradation of proteoglycans, such as dermatan sulfate and chondroitin sulfate proteoglycans. Cleaves partially fibronectin, but not collagen type I, nor laminin (By similarity).
Predominantly expressed in brain, kidney, pancreas and lung. Overexpressed in a series of brain tumors, including astrocytomas and glioblastomas.
The PDZ-binding motif (also named EWV motif) is required for interaction with PDZ domains of APBA3 and recycling through the trans-Golgi network.
Activates Rho-GTPases by promoting the exchange of GDP for GTP. May be involved in epithelial barrier permeability, cell motility and polarization, dendritic spine morphology, antigen presentation, leukemic cell differentiation, cell cycle regulation, innate immune response, and cancer. Binds Rac-GTPases, but does not seem to promote nucleotide exchange activity toward Rac-GTPases, which was uniquely reported in PubMed:9857026. May stimulate instead the cortical activity of Rac. Inactive toward CDC42, TC10, or Ras-GTPases. Forms an intracellular sensing system along with NOD1 for the detection of microbial effectors during cell invasion by pathogens. Required for RHOA and RIP2 dependent NF-kappaB signaling pathways activation upon S.flexneri cell invasion. Involved not only in sensing peptidoglycan (PGN)-derived muropeptides through NOD1 that is independent of its GEF activity, but also in the activation of NF-kappaB by Shigella effector proteins (IpgB2 and OspB) which requires its GEF activity and the activation of RhoA. Involved in innate immune signaling transduction pathway promoting cytokine IL6/interleukin-6 and TNF-alpha secretion in macrophage upon stimulation by bacterial peptidoglycans; acts as a signaling intermediate between NOD2 receptor and RIPK2 kinase. Contributes to the tyrosine phosphorylation of RIPK2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Overexpression activates Rho-, but not Rac-GTPases, and increases paracellular permeability (By similarity). Involved in neuronal progenitor cell division and differentiation (PubMed:28453519). Involved in the migration of precerebellar neurons (By similarity).
Found in a complex composed at least of ARHGEF2, NOD2 and RIPK2. Interacts with RIPK2; the interaction mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK. Interacts with RIPK1 and RIPK3. Interacts with YWHAZ/14-3-3 zeta; when phosphorylated at Ser-886. Interacts with the kinases PAK4, AURKA and MAPK1. Interacts with RHOA and RAC1. Interacts with NOD1. Interacts (via the N-terminal zinc finger) with CAPN6 (via domain II). Interacts with DYNLT1 (By similarity).
Phosphorylation of Ser-886 by PAK1 induces binding to protein YWHAZ, promoting its relocation to microtubules and the inhibition of its activity. Phosphorylated by AURKA and CDK1 during mitosis, which negatively regulates its activity. Phosphorylation by MAPK1 or MAPK3 increases nucleotide exchange activity. Phosphorylation by PAK4 releases GEF-H1 from the microtubules. Phosphorylated on serine, threonine and tyrosine residues in a RIPK2-dependent manner.
Sequence differs at a large extent from the sequence shown in the paper.
The DH (DBL-homology) domain interacts with and promotes loading of GTP on RhoA. Promotes tyrosine phosphorylation of RIPK2.
The PH domain has no affinity for phosphoinositides suggesting that it does not interact directly with membranes.
The phorbol-ester/DAG-type zinc-finger and the C-terminal coiled-coil domains (606-986) are both important for association with microtubules.
Up-regulated by bacterial peptidoglycans stimulation, such as muramyl dipeptide and in biopsies from inflamed mucosal areas of Crohn's disease patients.
Predominantly expressed in lung, where it is detected in type II pneumocytes in the alveolus, and in nonciliated epithelium in bronchioli (at protein level). Also detected at lower levels in cervix, esophagus, stomach, testis and kidney.
Catalytically inactive protein kinase that acts as a scaffold protein. Functions as an effector of the small GTPase RND2, which stimulates RhoA activity and inhibits NGF-induced neurite outgrowth (By similarity). Promotes Src family kinase (SFK) signaling by regulating the subcellular localization of CSK, a negative regulator of these kinases, leading to the regulation of cell morphology and motility by a CSK-dependent mechanism (By similarity). Acts as a critical coactivator of Notch signaling (By similarity).
Despite of the presence of a putative ATP-binding motif, this protein does not bind ATP, suggesting that it has no protein kinase activity.
Homodimer (PubMed:29079850). Dimerization leads to the catalytic activation of CSK (By similarity). Interacts (via C-terminus) with RND2 (By similarity). Interacts with CSK (via SH2 domain) in a Tyr-413 phosphorylation-dependent manner; this interaction potentiates kinase activity of CSK (By similarity). Interacts with PEAK1 (PubMed:29079850). Interacts with NOTCH1 intracellular domain (N1ICD) (By similarity). Forms a complex with N1ICD and MAML1, in a MAML1-dependent manner (By similarity).
Phosphorylated by CSK on Tyr-253, Tyr-365, and Tyr-413; Tyr-413 is a primary site of phosphorylation.
The dimerization region encompasses helices both from the N- and C-terminal of the protein kinase domain.
Involved in the synthesis of the Sd(a) antigen (Sia-alpha2,3-[GalNAc-beta1,4]Gal-beta1,4-GlcNAc), a carbohydrate determinant expressed on erythrocytes, the colonic mucosa and other tissues. Transfers a beta-1,4-linked GalNAc to the galactose residue of an alpha-2,3-sialylated chain.
The Sd(a) antigen on red blood cells defines the SID blood group system. There is considerable variability in the strength of antigen expression, ranging from ordinary Sd(a+) to strong Sd(a++) expression [MIM:615018]. Lack of Sd(a) antigen results in the Sd(a-) phenotype, due to genetic variants in B4GALNT2.
Widely expressed. Highly expressed in colon and to a lesser extent in kidney, stomach, ileum and rectum.
Component of a ciliary calcium channel that controls calcium concentration within primary cilia without affecting cytoplasmic calcium concentration. Forms a heterodimer with PKD2L1 in primary cilia and forms a calcium-permeant ciliary channel that regulates sonic hedgehog/SHH signaling and GLI2 transcription. Does not constitute the pore-forming subunit. Also involved in left/right axis specification downstream of nodal flow: forms a complex with PKD2 in cilia to facilitate flow detection in left/right patterning.
Detected in testis and in fetal and adult heart.
Heterodimer; heterodimerizes with PKD2 proteins to form a calcium channel. Interacts with PKD2L1; to form ciliary calcium channel. Interacts with PKD2.
In association with mitochondrial contact site and cristae organizing system (MICOS) complex components and mitochondrial outer membrane sorting assembly machinery (SAM) complex components may regulate mitochondrial dynamics playing a role in determining mitochondrial length, distribution and motility.
Interacts with mitochondrial contact site and cristae organizing system (MICOS) complex components IMMT/MIC60 and MICOS10/MIC10 (PubMed:31644573). Interacts with mitochondrial outer membrane sorting assembly machinery (SAM) complex components SAMM50 and MTX1 (PubMed:31644573).
E3 ubiquitin-protein ligase that cooperates with the microRNAs (miRNAs) machinery and promotes embryonic stem cells proliferation and maintenance (Probable). Binds to miRNAs and associates with AGO2, participating in post-transcriptional repression of transcripts such as CDKN1A (By similarity). In addition, participates in post-transcriptional mRNA repression in a miRNA independent mechanism (PubMed:23125361). Facilitates the G1-S transition to promote rapid embryonic stem cell self-renewal by repressing CDKN1A expression. Required to maintain proliferation and prevent premature differentiation of neural progenitor cells during early neural development: positively regulates FGF signaling by controlling the stability of SHCBP1 (By similarity). Specific regulator of miRNA biogenesis. Binds to miRNA MIR29A hairpin and postranscriptionally modulates MIR29A levels, which indirectly regulates TET proteins expression (PubMed:28431233).
Interacts (via NHL repeats) with AGO2; the interaction increases in presence of RNA (PubMed:23125361). Interacts with HSP90AA1. Interacts (via NHL repeats) with MOV10, PABPC1, PUM1, PUM2, STAU2, XRN1 and XRN2 in an RNA-dependent manner (PubMed:23125361). Interacts with SHCBP1; leading to enhance its stability (By similarity).
Negatively regulated by the microRNA (miRNA) let-7 which causes degradation of the mRNA encoding this protein. This requires a let-7 complementary site (LCS) in the 3'-UTR of the mRNA encoding this protein (PubMed:17890240, PubMed:24239284). Down-regulated by retinoic acid in Tera-2 cells (PubMed:15722555).
Promotes reprogramming of differentiated cells to an embryonic-like state designated iPS (induced pluripotent stem) cells. iPS cells exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Inhibits translation of the prodifferentiation transcription factor EGR1 through binding to its mRNA and regulates a broad array of differentiation genes.
The NHL domain, containing the 6 NHL repeats, is necessary and sufficient to target RNA but not to repress mRNA. The minimal region needed to execute repression consists of the coiled coil domain and the Filamin repeat. The RING-type domain is dispensable for mRNA repression.
Interaction with integrins is heparin- and cell-type-dependent and promotes cell adhesion. In skin fibroblasts it binds ITGA6/ITGB1, in endothelial cells, binds ITGAV/ITGB3 and in platelets, ITGA2B/ITGB3. Binds, in vitro, ITGAV/ITGB5.
Promotes cell proliferation, chemotaxis, angiogenesis and cell adhesion. Appears to play a role in wound healing by up-regulating, in skin fibroblasts, the expression of a number of genes involved in angiogenesis, inflammation and matrix remodeling including VEGA-A, VEGA-C, MMP1, MMP3, TIMP1, uPA, PAI-1 and integrins alpha-3 and alpha-5. CCN1-mediated gene regulation is dependent on heparin-binding. Down-regulates the expression of alpha-1 and alpha-2 subunits of collagen type-1. Promotes cell adhesion and adhesive signaling through integrin alpha-6/beta-1, cell migration through integrin alpha-v/beta-5 and cell proliferation through integrin alpha-v/beta-3.
Ubiquitous. Most abundant in cardiac and skeletal muscle.
Acetylation of alpha chains at Lys-40 is located inside the microtubule lumen. This modification has been correlated with increased microtubule stability, intracellular transport and ciliary assembly.
Detyrosination is involved in metaphase plate congression by guiding chromosomes during mitosis: detyrosination promotes interaction with CENPE, promoting pole-proximal transport of chromosomes toward the equator (PubMed:25908662). Detyrosination increases microtubules-dependent mechanotransduction in dystrophic cardiac and skeletal muscle. In cardiomyocytes, detyrosinated microtubules are required to resist to contractile compression during contraction: detyrosination promotes association with desmin (DES) at force-generating sarcomeres, leading to buckled microtubules and mechanical resistance to contraction (By similarity).
Expressed in the cornea, sclera, and peripheral blood (PubMed:29051577).
Methylation of alpha chains at Lys-40 is found in mitotic microtubules and is required for normal mitosis and cytokinesis contributing to genomic stability.
Nitration of Tyr-450 is irreversible and interferes with normal dynein intracellular distribution.
Tyrosination promotes microtubule interaction with CAP-Gly domain-containing proteins such as CLIP1, CLIP2 and DCTN1 (By similarity). Tyrosination regulates the initiation of dynein-dynactin motility via interaction with DCTN1, which brings the dynein-dynactin complex into contact with microtubules (PubMed:26972003). In neurons, tyrosinated tubulins mediate the initiation of retrograde vesicle transport (By similarity).
Undergoes a tyrosination/detyrosination cycle, the cyclic removal and re-addition of a C-terminal tyrosine residue by the enzymes tubulin tyrosine carboxypeptidase (KIAA0895L/MATCAP, VASH1 or VASH2) and tubulin tyrosine ligase (TTL), respectively.
Interacts with LIN28A in the presence of pre-let-7 RNA (PubMed:19703396, PubMed:22118463, PubMed:31036859). Interacts with T2BP (PubMed:16643855). Interacts with MOV10; the interaction is RNA-dependent (PubMed:30122351).
Uridylyltransferase that mediates the terminal uridylation of mRNAs with short (less than 25 nucleotides) poly(A) tails, hence facilitating global mRNA decay (PubMed:25480299, PubMed:31036859). Essential for both oocyte maturation and fertility. Through 3' terminal uridylation of mRNA, sculpts, with TUT7, the maternal transcriptome by eliminating transcripts during oocyte growth (By similarity). Involved in microRNA (miRNA)-induced gene silencing through uridylation of deadenylated miRNA targets. Also functions as an integral regulator of microRNA biogenesis using 3 different uridylation mechanisms (PubMed:25979828). Acts as a suppressor of miRNA biogenesis by mediating the terminal uridylation of some miRNA precursors, including that of let-7 (pre-let-7), miR107, miR-143 and miR-200c. Uridylated miRNAs are not processed by Dicer and undergo degradation. Degradation of pre-let-7 contributes to the maintenance of embryonic stem (ES) cell pluripotency (By similarity). Also catalyzes the 3' uridylation of miR-26A, a miRNA that targets IL6 transcript. This abrogates the silencing of IL6 transcript, hence promoting cytokine expression (PubMed:19703396). In the absence of LIN28A, TUT7 and TUT4 monouridylate group II pre-miRNAs, which includes most of pre-let7 members, that shapes an optimal 3' end overhang for efficient processing (PubMed:25979828). Adds oligo-U tails to truncated pre-miRNAS with a 5' overhang which may promote rapid degradation of non-functional pre-miRNA species (PubMed:25979828). May also suppress Toll-like receptor-induced NF-kappa-B activation via binding to T2BP (PubMed:16643855). Does not play a role in replication-dependent histone mRNA degradation (PubMed:18172165). Due to functional redundancy between TUT4 and TUT7, the identification of the specific role of each of these proteins is difficult (PubMed:25979828, PubMed:25480299, PubMed:16643855, PubMed:19703396, PubMed:18172165) (By similarity). TUT4 and TUT7 restrict retrotransposition of long interspersed element-1 (LINE-1) in cooperation with MOV10 counteracting the RNA chaperonne activity of L1RE1. TUT7 uridylates LINE-1 mRNAs in the cytoplasm which inhibits initiation of reverse transcription once in the nucleus, whereas uridylation by TUT4 destabilizes mRNAs in cytoplasmic ribonucleoprotein granules (PubMed:30122351).
Utilizes two multidomain functional modules during the switch from monouridylation to oligouridylation. The catalytic module (containing the 3 CCHC-type Zinc finger domains) is essential for both activities while the Lin28-interacting module (LIM) at the N-termail part is indispensable for oligouridylation.
Defects in TANC2 has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea.
Interacts with KIF1A; the interaction decreases in presence of calcium.
Scaffolding protein in the dendritic spines which acts as immobile postsynaptic posts able to recruit KIF1A-driven dense core vesicles to dendritic spines.
Highly expressed in cerebellum and brain. Expression is down-regulated in medulloblastoma.
Homopentamer. Interacts with KCTD11; KCTD6 and KCTD11 may associate in pentameric assemblies. Interacts (via BTB domain) with CUL3; initially a 4:4 stoichiometry has been reported, however, electron microscopy revealed pentameric states with a five-pointed pinwheel shape. The interaction with CUL3 is indicative for a participation in a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex. Interacts with HDAC1; probably indirect as the interaction is requires the presence of KCTD11 (PubMed:21472142, PubMed:24307990, PubMed:25974686, PubMed:27152988). Interacts with USP21 (preferentially catalytic inactive form) (PubMed:27621083). Interacts with ANK1 isoform Mu17; detected in striated muscle (PubMed:22573887). Interacts with USP11 (PubMed:29293652).
Probable substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex mediating the ubiquitination and subsequent proteasomal degradation of target proteins. Promotes the ubiquitination of HDAC1; the function seems to depend on KCTD11:KCTD6 oligomerization. Can function as antagonist of the Hedgehog pathway by affecting the nuclear transfer of transcription factor GLI1; the function probably occurs via HDAC1 down-regulation, keeping GLI1 acetylated and inactive. Inhibits cell growth and tumorigenicity of medulloblastoma (MDB) (PubMed:21472142). Involved in regulating protein levels of ANK1 isoform Mu17 probably implicating CUL3-dependent proteasomal degradation (PubMed:22573887).
Belongs to the bacterial ribosomal protein bL20 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (PubMed:25278503, PubMed:25838379). Interacts with OXA1L (By similarity).
A number of inactive tetrameric holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits (By similarity). Interacts with PRKAR1A and PRKAR2B (PubMed:33058759). The cAMP-dependent protein kinase catalytic subunit binds PJA2 (PubMed:21423175). Interacts with GPKOW (PubMed:21880142).
Asn-3 is partially deaminated to Asp giving rise to 2 major isoelectric variants, called CB and CA respectively.
Isoform 1 is most abundant in the brain, with low level expression in kidney. Isoform 2 is predominantly expressed in thymus, spleen and kidney. Isoform 3 and isoform 4 are only expressed in the brain.
Mediates cAMP-dependent signaling triggered by receptor binding to GPCRs (PubMed:12420224, PubMed:21423175, PubMed:31112131). PKA activation regulates diverse cellular processes such as cell proliferation, the cell cycle, differentiation and regulation of microtubule dynamics, chromatin condensation and decondensation, nuclear envelope disassembly and reassembly, as well as regulation of intracellular transport mechanisms and ion flux (PubMed:12420224, PubMed:21423175). Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis (PubMed:12420224, PubMed:21423175). Phosphorylates GPKOW which regulates its ability to bind RNA (PubMed:21880142). Acts as a negative regulator of mTORC1 by mediating phosphorylation of RPTOR (PubMed:31112131).
Acts as an E3 ubiquitin-protein ligase able to ubiquitinate p53/TP53 which promotes its relocalization to discrete foci associated with PML nuclear bodies. Exhibits preference for UBE2D2 as a E2 enzyme.
Widely expressed with highest levels in testis.
Expressed in breast cancer cell lines and primary cancer.
Required for normal development of intervertebral disks.
Essential for gene silencing: has a role in the structure of silenced chromatin. Plays a role in the developing brain (By similarity). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Defects in CFHR5 have been found in patients with atypical hemolytic uremic syndrome and may contribute to the disease. Atypical hemolytic uremic syndrome is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.
Head-to-tail homodimer and heterodimer with CFHR1 or CFHR2. Binds C3b in vitro.
Involved in complement regulation. The dimerized forms have avidity for tissue-bound complement fragments and efficiently compete with the physiological complement inhibitor CFH.
Bornavirus is a non-retroviral RNA virus that does not generate DNA forms during viral replication. Therefore, integration of EBLN-2 must have occur through a mechanism relying on an endogenous reverse transcriptase activity.
May act as an RNA-binding protein. The C-terminal region is highly homologous to the bornavirus nucleocapsid N protein that binds viral RNA and oligomerizes. The viral protein also possesses a nuclear import and a nuclear export signal. These 2 signals seem absent in EBLN-2 supporting an unrelated function in Human.
Belongs to the immunoglobulin superfamily. LISCH7 family.
Defects in LSR may be the cause of familial intrahepatic cholestasis.
Homotrimer or homotetramer (By similarity). Assembles into cell-cell contacts. Interacts (via the cytoplasmic domain) with MARVELD2 (via C-terminal cytoplasmic domain); the interaction is required to recruit MARVELD2 to tricellular contacts. Interacts with OCLN (By similarity).
In contrast to the rodent orthologous protein, it is longer in N-terminus and no signal sequence is detected by any prediction method.
Phosphorylation at Ser-365 by MAPK8/JNK1 and MAPK9/JNK2 may be required for exclusive localization at tricellular tight junstions.
Probable role in the clearance of triglyceride-rich lipoprotein from blood. Binds chylomicrons, LDL and VLDL in presence of free fatty acids and allows their subsequent uptake in the cells (By similarity). Maintains epithelial barrier function by recruiting MARVELD2/tricellulin to tricellular tight junctions (By similarity).
Cadherins are calcium-dependent cell adhesion proteins.
Calcium-dependent cell adhesion protein; preferentially mediates homotypic cell-cell adhesion by dimerization with a CDH2 chain from another cell. Cadherins may thus contribute to the sorting of heterogeneous cell types. Acts as a regulator of neural stem cells quiescence by mediating anchorage of neural stem cells to ependymocytes in the adult subependymal zone: upon cleavage by MMP24, CDH2-mediated anchorage is affected, leading to modulate neural stem cell quiescence. Plays a role in cell-to-cell junction formation between pancreatic beta cells and neural crest stem (NCS) cells, promoting the formation of processes by NCS cells (By similarity). Required for proper neurite branching. Required for pre- and postsynaptic organization (By similarity). CDH2 may be involved in neuronal recognition mechanism. In hippocampal neurons, may regulate dendritic spine density.
Cleaved by MMP24. Ectodomain cleavage leads to the generation of a soluble 90 kDa N-terminal soluble fragment and a 45 kDa membrane-bound C-terminal fragment 1 (CTF1), which is further cleaved by gamma-secretase into a 35 kDa (By similarity). Cleavage in neural stem cells by MMP24 affects CDH2-mediated anchorage of neural stem cells to ependymocytes in the adult subependymal zone, leading to modulate neural stem cell quiescence (By similarity).
Homodimer (via extracellular region). Can also form heterodimers with other cadherins (via extracellular region). Dimerization occurs in trans, i.e. with a cadherin chain from another cell (By similarity). Interacts with CDCP1 (PubMed:16007225). Interacts with PCDH8; this complex may also include TAOK2 (By similarity). The interaction with PCDH8 may lead to internalization through TAOK2/p38 MAPK pathway (By similarity). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. May interact with OBSCN (via protein kinase domain 2) (By similarity). Interacts with FBXO45 (PubMed:32341084).
Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain. Calcium-binding sites are occupied sequentially in the order of site 3, then site 2 and site 1.
Forms a complex with CDC7. Note that CDC7 forms distinct complex either with DBF4A or DBF4B. Such complexes are stable upon replication stress. Interacts with MEN1, MCM2, ORC2, ORC4 and ORC6. Interacts (via IBM motifs) with PSIP1 (via IBD domain); phosphorylation increases its affinity for PSIP1 (PubMed:29997176).
Highly expressed in testis and thymus. Expressed also in most cancer cells lines.
Induced in G1 phase at low level, increased during G1-S phase and remain high during S and G2-M phase.
Phosphorylation increases its interaction with PSIP1.
Regulatory subunit for CDC7 which activates its kinase activity thereby playing a central role in DNA replication and cell proliferation. Required for progression of S phase. The complex CDC7-DBF4A selectively phosphorylates MCM2 subunit at 'Ser-40' and 'Ser-53' and then is involved in regulating the initiation of DNA replication during cell cycle.
Autoinhibited. Intramolecular binding of the interdomains A and B (also called linker region) to parts of the catalytic domain keep the catalytic center in an inactive conformation. The phosphorylation of the interdomains or the binding of the SH2 domains with dually phosphorylated ITAM domains on transmembrane proteins disrupt those intramolecular interactions allowing the kinase domain to adopt an active conformation. The phosphorylation of SYK and of the ITAM domains which is responsible for SYK activation is essentially mediated by SRC subfamily kinases, like LYN, upon transmembrane receptors engagement. May also be negatively regulated by PTPN6 through dephosphorylation. Downstream signaling adapters and intermediates like BLNK or RHOH may mediate positive and/or negative feedback regulation. Negatively regulated by CBL and CBLB through ubiquitination and probable degradation. Phosphorylates SH3BP2 which in turn may regulate SYK through LYN (By similarity).
Autophosphorylated. Phosphorylated on tyrosine residues by LYN following receptors engagement. Phosphorylation on Tyr-323 creates a binding site for CBL, an adapter protein that serves as a negative regulator of BCR-stimulated calcium ion signaling. Phosphorylation at Tyr-348 creates a binding site for VAV1. Phosphorylation on Tyr-348 and Tyr-352 enhances the phosphorylation and activation of phospholipase C-gamma and the early phase of calcium ion mobilization via a phosphoinositide 3-kinase-independent pathway (By similarity). Phosphorylated on tyrosine residues in response to IL15 (PubMed:15123770). Phosphorylation on Ser-297 is very common, it peaks 5 minutes after BCR stimulation, and creates a binding site for YWHAG. Phosphorylation at Tyr-630 creates a binding site for BLNK. Dephosphorylated by PTPN6.
Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily.
Interacts with LYN; phosphorylates SYK (By similarity). Interacts with RHOH (phosphorylated); regulates mast cells activation (By similarity). Interacts with NFAM1 (phosphorylated); probably involved in BCR signaling (By similarity). Interacts with VAV1 (via SH2 domain); phosphorylates VAV1 upon BCR activation. Interacts with GAB2 (phosphorylated); probably involved in IgE Fc receptor signaling (By similarity). Interacts (via its SH2 domains) with CD79A (via its phosphorylated ITAM domain); the interaction stimulates SYK autophosphorylation and activation (By similarity). Interacts with FCRL3 (PubMed:19843936, PubMed:11162587). Interacts (via SH2 domains) with FCER1G (via ITAM domain); activates SYK and mediates neutrophils and macrophages integrin-mediated activation (By similarity). Interaction with FCER1G in basophils triggers IL3-induced IL4 production (By similarity). Interacts with ITGB2 and FGR; involved in ITGB2 downstream signaling (By similarity). Interacts with ITGB3; upon activation by ITGB3 promotes platelet adhesion. Interacts (via SH2 domains) with TYROBP (via ITAM domain); involved in neutrophils and macrophages integrin-mediated activation (By similarity). Interacts with MSN and SELPLG; mediates the selectin-dependent activation of SYK by SELPLG. Interacts with BLNK (via SH2 domain). Interacts (via the second SH2 domain) with USP25 (via C-terminus); phosphorylates USP25 and regulates USP25 intracellular levels. Interacts (via SH2 domains) with CLEC1B (dimer). Interacts with CLEC7A; participates in leukocyte activation in presence of fungal pathogens. Interacts (phosphorylated) with SLA; may regulate SYK through CBL recruitment. Interacts with YWHAG; attenuates BCR-induced membrane translocation and activation of SYK. Interacts (via SH2 domains) with GCSAM; the interaction increases after B-cell receptor stimulation, resulting in enhanced SYK autophosphorylation and activity. Interacts with TNS2; leading to the phosphorylation of SYK (PubMed:22019427). Interacts with FLNA (via filamin repeat 5); docks SYK to the plasma membrane (PubMed:20713593). Interacts with CEACAM1; lipopolysaccharide activated neutrophils induce phosphorylation of SYK resulting in the formation of a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, leading to a reduction of the inflammasome activity (By similarity). Interacts (via SH2 domains) with CEACAM20 (phosphorylated form); the interaction further enhances CEACAM20 phosphorylation (By similarity). Interacts with IL15RA (PubMed:15123770).
Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development (PubMed:12387735, PubMed:33782605). Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include DEPTOR, VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK (PubMed:12456653, PubMed:15388330, PubMed:8657103, PubMed:34634301). Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition (PubMed:12456653). Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR also plays a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade (By similarity). Required for the stimulation of neutrophil phagocytosis by IL15 (PubMed:15123770). Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Involved in interleukin-3/IL3-mediated signaling pathway in basophils (By similarity). Also functions downstream of receptors mediating cell adhesion (PubMed:12387735). Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Also plays a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. Together with CEACAM20, enhances production of the cytokine CXCL8/IL-8 via the NFKB pathway and may thus have a role in the intestinal immune response (By similarity).
The SH2 domains mediate the interaction of SYK with the phosphorylated ITAM domains of transmembrane proteins. Some proteins like CLEC1B have a partial ITAM domain (also called hemITAM) containing a single YxxL motif. The interaction with SYK requires CLEC1B homodimerization.
Ubiquitinated by CBLB after BCR activation; which promotes proteasomal degradation.
Widely expressed in hematopoietic cells (at protein level) (PubMed:8163536). Expressed in neutrophils (at protein level) (PubMed:15123770). Within the B-cell compartment, expressed from pro- and pre-B cells to plasma cells (PubMed:8163536).
In the C-terminal section; belongs to the class I-like SAM-binding methyltransferase superfamily. Cation-independent O-methyltransferase family.
In the N-terminal section; belongs to the Maf family. YhdE subfamily.
Nucleoside triphosphate pyrophosphatase that hydrolyzes dTTP and UTP. Can also hydrolyze CTP and the modified nucleotides pseudo-UTP, 5-methyl-UTP (m(5)UTP) and 5-methyl-CTP (m(5)CTP). Has weak activity with dCTP, 8-oxo-GTP and N(4)-methyl-dCTP (PubMed:24210219). May have a dual role in cell division arrest and in preventing the incorporation of modified nucleotides into cellular nucleic acids (PubMed:24210219). In addition, the presence of the putative catalytic domain of S-adenosyl-L-methionine binding in the C-terminal region argues for a methyltransferase activity (Probable).
Pyrophosphatase activity requires a divalent metal cation.
The gene coding for this protein is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes. It represents a unique fusion product of 2 different genes of different evolutionary origin and function. The N-terminus is homologous to the bacterial maf/orfE genes and the C-terminus is homologous to ASMT. Exon duplication, exon shuffling and gene fusion seem to be common characteristics of the PAR1 region.
Widely expressed. In adult, highly expressed in pancreas, placenta, fibroblast, thymus, prostate, testis, ovary and colon. Expressed at lower levels in spleen, small intestine and leukocytes. In fetus, expressed at high levels in the lung and kidney and at lower level in brain and liver.
Associates primarily with CDK7 and cyclin H to form the CAK complex. CAK can further associate with the core-TFIIH to form the TFIIH basal transcription factor.
Highest levels in colon and testis. Moderate levels are present thymus, prostate, ovary, and small intestine. The lowest levels are found in spleen and leukocytes.
Stabilizes the cyclin H-CDK7 complex to form a functional CDK-activating kinase (CAK) enzymatic complex.
Stabilizes the cyclin H-CDK7 complex to form a functional CDK-activating kinase (CAK) enzymatic complex. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Involved in cell cycle control and in RNA transcription by RNA polymerase II.
O-glycosylated (PubMed:30078215). O-GlcNAcylation may occur in response to increasing glucose levels and affect transcription factor activity (PubMed:30078215).
Sumoylated (PubMed:12370286). Sumoylation increases its half-life, possibly by blocking ubiquitin-mediated degradation (PubMed:12370286).
The five zinc finger domains are necessary and sufficient to bind to DNA.
Transcription factor that binds to the sequence motif 5'-CATCCCATAATA-3', and is specifically required to silence expression of fetal hemoglobin in adult erythroid cells (PubMed:33859416, PubMed:33301730). Prevents expression of fetal hemoglobin genes HBG1 and HBG2 through CHD4: acts as a direct transcriptional activator of CHD4, a central component of the NuRD complex that represses transcription of fetal hemoglobin genes HBG1 and HBG2 in erythroid cells (PubMed:33859416, PubMed:33301730). May also activate transcription of matrix-remodeling genes such as MMP1 during fibroblast senescence (PubMed:12370286). May activate transcription of the gap junction gene GJC1, perhaps in response to increasing glucose (PubMed:30078215). However, recent studies suggest that ZNF410 is dedicated to regulate expression of a single gene: CHD4 (PubMed:33859416, PubMed:33301730).
(Microbial infection) Interacts with Chikungunya virus non-structural protein 3 (via C-terminus).
(Microbial infection) Interacts with hepatitis virus protein NS5A (via C-terminus); this interaction sequesters NAP1L1 in the cytoplasm, blocking its nuclear translocation.
(Microbial infection) Interacts with human herpesvirus 8 protein LANA1 (via N-terminus); this interaction is required for LANA1-dependent DNA replication.
(Microbial infection) Positively regulates Epstein-Barr virus reactivation in epithelial cells through the induction of viral BZLF1 expression.
(Microbial infection) Together with human herpesvirus 8 protein LANA1, assists the proper assembly of the nucleosome on the replicated viral DNA.
Histone chaperone that plays a role in the nuclear import of H2A-H2B and nucleosome assembly (PubMed:20002496, PubMed:21211722, PubMed:26841755). Participates also in several important DNA repair mechanisms: greatly enhances ERCC6-mediated chromatin remodeling which is essential for transcription-coupled nucleotide excision DNA repair (PubMed:28369616). Stimulates also homologous recombination (HR) by RAD51 and RAD54 which is essential in mitotic DNA double strand break (DSB) repair (PubMed:24798879). Plays a key role in the regulation of embryonic neurogenesis (By similarity). Promotes the proliferation of neural progenitors and inhibits neuronal differentiation during cortical development (By similarity). Regulates neurogenesis via the modulation of RASSF10; regulates RASSF10 expression by promoting SETD1A-mediated H3K4 methylation at the RASSF10 promoter (By similarity).
Homodimer (PubMed:26841755). The dimer binds strongly and sequentially to single and double H2A-H2B heterodimers (PubMed:26841755). Interacts with ERCC6; this interaction increases ERCC6 processivity (PubMed:28369616). Interacts with RAD54 (PubMed:24798879). Interacts with SETD1A (By similarity).
Monoglycylated on glutamate residues. Cannot be polyglycylated due to the absence of functional TTLL10 in human (By similarity).
Polyglutamylated by TTLL4 on glutamate residues, resulting in polyglutamate chains on the gamma-carboxyl group. Both polyglutamylation and monoglycylation modifications can coexist on the same protein on adjacent residues, and lowering polyglycylation levels increases polyglutamylation, and reciprocally.
The NAP1L motif is required for the histone chaperone activity.
The acidic domains are probably involved in the interaction with histones.
A subset of epithelial cells including normal human mammary epithelial cells and keratinocytes.
By growth factors in early G1 phase and probably by cell-cycle regulation in S phase. DNA methylation probably plays a direct negative role in suppressing S100L gene expression in tumor cells.
Homodimer. Interacts with FKBP4. Interacts with PPP5C (via TPR repeats); the interaction is calcium-dependent and modulates PPP5C activity. Interacts with TPPP; this interaction inhibits TPPP dimerization (PubMed:33831707).
May function as calcium sensor and modulator, contributing to cellular calcium signaling. May function by interacting with other proteins, such as TPR-containing proteins, and indirectly play a role in many physiological processes. May also play a role in suppressing tumor cell growth.
Preferentially expressed in normal human mammary epithelial cells as opposed to tumor-derived ones. The level of S100L was shown to correlate inversely with tumor progression.
Detected in fetal cartilage and calvaria, in chondrocytes of hypertrophic cartilage in vertebrae and in the dorsal end of ribs undergoing ossification, as well as in osteoblasts and periosteal cells below the inner periosteal region of ossified ribs. Detected in chondrocytes from in joint cartilage that have been treated with TNF and IL1B, but not in untreated chondrocytes. Detected in T lymphocytes. Detected in breast carcinoma tissue.
Inhibited by TIMP1, TIMP2 and TIMP3. Inhibited by acetohydroxamic acid and other zinc chelators.
Monomer. Interacts with TIMP1, TIMP2 and TIMP3. Binds (via the C-terminal region) to collagen.
Plays a role in the degradation of extracellular matrix proteins including fibrillar collagen, fibronectin, TNC and ACAN. Cleaves triple helical collagens, including type I, type II and type III collagen, but has the highest activity with soluble type II collagen. Can also degrade collagen type IV, type XIV and type X. May also function by activating or degrading key regulatory proteins, such as TGFB1 and CCN2. Plays a role in wound healing, tissue remodeling, cartilage degradation, bone development, bone mineralization and ossification. Required for normal embryonic bone development and ossification. Plays a role in the healing of bone fractures via endochondral ossification. Plays a role in wound healing, probably by a mechanism that involves proteolytic activation of TGFB1 and degradation of CCN2. Plays a role in keratinocyte migration during wound healing. May play a role in cell migration and in tumor cell invasion.
The C-terminal region binds to collagen.
The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme (By similarity).
The proenzyme is activated by removal of the propeptide; this cleavage can be effected by other matrix metalloproteinases, such as MMP2, MMP3 and MMP14 and may involve several cleavage steps. Cleavage can also be autocatalytic, after partial maturation by another protease or after treatment with 4-aminophenylmercuric acetate (APMA) (in vitro).
Able to bind hyaluronan. However, its intracellular localization suggests that this interaction may not be relevant in vivo.
Associates with ribosomes; promoting ribosome stabilization (PubMed:21771594). Interacts with EEF2/eEF2; promoting ribosome stabilization (By similarity). Interacts with FMR1 (PubMed:21771594). Interacts with FXR1 and FXR2 (PubMed:21771594). Interacts with CHD3 (via C-terminus) (PubMed:12505151). Interacts (via C-terminus) with RACK1 (PubMed:14699138). Interacts with p53/TP53 (PubMed:16455055). Interacts (via N-terminus) with SRSF9; this interaction is direct (PubMed:19523114). Interacts with SYNCRIP; this interaction is direct (PubMed:19523114). Interacts with MEF2C (via N-terminus); this interaction decreases DNA-binding activity of MEF2C in myocardial cells in response to mechanical stress (PubMed:15862299). Interacts with PRMT1 (via N-terminus) (PubMed:16879614). Interacts with SPIN1 (By similarity).
Highly expressed in brain, heart, and kidney, and moderately expressed in skeletal muscle. Also expressed in a variety of tumor cell lines and in activated but not resting leukocytes.
Methylated (PubMed:16879614). Methylation is decreased by phorbol 12-myristate 13-acetate (PMA)-activated PKC, in vitro (PubMed:16879614).
Phosphorylated by phorbol 12-myristate 13-acetate (PMA)-activated PKC isoforms at Thr-354 and Thr-375.
Ribosome-binding protein that promotes ribosome hibernation, a process during which ribosomes are stabilized in an inactive state and preserved from proteasomal degradation (By similarity). Acts via its association with EEF2/eEF2 factor at the A-site of the ribosome, promoting ribosome stabilization in an inactive state compatible with storage (By similarity). Plays a key role in ribosome hibernation in the mature oocyte by promoting ribosome stabilization (By similarity). Ribosomes, which are produced in large quantities during oogenesis, are stored and translationally repressed in the oocyte and early embryo (By similarity). Also binds RNA, regulating transcription and pre-mRNA splicing (PubMed:14699138, PubMed:16455055, PubMed:21771594, PubMed:19523114). Binds (via C-terminus) to poly(U) RNA (PubMed:19523114). Seems to play a role in PML-nuclear bodies formation (PubMed:28695742). Negatively regulates DNA-binding activity of the transcription factor MEF2C in myocardial cells in response to mechanical stress (By similarity).
The C-terminal region is necessary for nucleus and cytoplasmic localization (PubMed:19523114). The N-terminal region is necessary for nucleus and nuclear bodies localization (PubMed:19523114). Regions containing Arg-Gly-Gly repeats (RGG/RXR-box) may be preferentially methylated by PRMT1 (PubMed:16879614).
The interaction with RACK1 is abolished upon activation of L540 tumor cells with PMA, which results in phosphorylation and exit of HABP4 from the nucleus.
Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Displays activity toward mucin-derived peptide substrates such as Muc2, Muc5AC, Muc7, and Muc13 (-58). May be involved in O-glycosylation in kidney.
Detected in renal tubules (at protein level). Highly expressed in fetal and adult kidney. Widely expressed at low level. Weakly expressed in whole brain, cerebellum, thymus, lung, mammary gland, liver, stomach, small intestine, colon, pancreas, spleen, bladder, uterus, placenta, testis, ovary, skeletal muscle, leukocyte, B-cell, bone marrow, fetal brain, fetal thymus, fetal lung, fetal liver, fetal small intestine, fetal spleen, fetal skeletal and fetus. Detected in renal tubules (at protein level).
(Microbial infection) Acts as a receptor for rubella virus.
(Microbial infection) Interacts with rubella virus E2 glycoprotein.
Do not confuse myelin-oligodendrocyte glycoprotein (MOG) with oligodendrocyte-myelin glycoprotein (OMG).
Found exclusively in the CNS, where it is localized on the surface of myelin and oligodendrocyte cytoplasmic membranes.
Homodimer (By similarity). May form heterodimers between the different isoforms (By similarity).
Mediates homophilic cell-cell adhesion (By similarity). Minor component of the myelin sheath. May be involved in completion and/or maintenance of the myelin sheath and in cell-cell communication.
Minor component of the myelin sheath. May be involved in completion and/or maintenance of the myelin sheath and in cell-cell communication. Mediates homophilic cell-cell adhesion.
Not functionally active. May be expressed at low level in the adult.
Acts as a GTPase-activating protein for RAB5A and RAB43. Involved in receptor trafficking. In complex with EPS8 inhibits internalization of EGFR. Involved in retrograde transport from the endocytic pathway to the Golgi apparatus. Involved in the transport of Shiga toxin from early and recycling endosomes to the trans-Golgi network. Required for structural integrity of the Golgi complex.
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 non-structural protein 2 (nsp2); the interaction enhances GIGYF2 binding to EIF4E2.
(Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 infection, the interaction with non-structural protein 2 (nsp2) enhances GIGYF2 binding to EIF4E2 and increases repression of translation initiation of genes involved in antiviral innate immune response such as IFNB1.
Component of the 4EHP-GYF2 complex, at least composed of EIF4E2, GIGYF2 and ZNF598 (PubMed:22751931, PubMed:31439631, PubMed:32726578). Interacts (via the 4EHP-binding motif) with EIF4E2; the interaction is direct (PubMed:22751931, PubMed:31439631, PubMed:32726578). Interacts with ZFP36/TTP (via P-P-P-P-G repeats); the interaction is direct (PubMed:31439631). Interacts with GRB10 (By similarity). Interacts (via DDX6 motif) with DDX6 (via RecA-like domain 2) (PubMed:31439631).
Disease susceptibility may be associated with variants affecting the gene represented in this entry. Its association with Parkinson disease is however unclear. According to a number of studies, variations affecting this gene are not a frequent cause of Parkinson disease, suggesting that GIGYF2 does not play a major role in Parkinson disease etiology (PubMed:19279319, PubMed:19429085, PubMed:19638301, PubMed:19482505, PubMed:20004041, PubMed:19321232, PubMed:20060621).
Key component of the 4EHP-GYF2 complex, a multiprotein complex that acts as a repressor of translation initiation (PubMed:22751931, PubMed:31439631, PubMed:35878012). In the 4EHP-GYF2 complex, acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking translation repression with mRNA decay (PubMed:31439631). Also recruits and bridges the association of the 4EHP complex with the decapping effector protein DDX6, which is required for the ZFP36/TTP-mediated down-regulation of AU-rich mRNA (PubMed:31439631). May act cooperatively with GRB10 to regulate tyrosine kinase receptor signaling, including IGF1 and insulin receptors (PubMed:12771153). In association with EIF4E2, assists ribosome-associated quality control (RQC) by sequestering the mRNA cap, blocking ribosome initiation and decreasing the translational load on problematic messages. Part of a pathway that works in parallel to RQC-mediated degradation of the stalled nascent polypeptide (PubMed:32726578). GIGYF2 and EIF4E2 work downstream and independently of ZNF598, which seems to work as a scaffold that can recruit them to faulty mRNA even if alternative recruitment mechanisms may exist (PubMed:32726578).
Highly expressed in liver and placenta. Also expressed in peripheral blood, lung, kidney and brain. Detected at lower levels in colon. High expression is detected in brain and testis.
Lysophospholipid acyltransferase involved in fatty acyl chain remodeling of glycerophospholipids in the endoplasmic reticulum membrane (By similarity). Selectively catalyzes the transfer and esterification of saturated long-chain fatty acids from acyl-CoA to the sn-1 position of 1-lyso-2-acyl phosphatidylethanolamines (1-lyso-PE, LPE), with a preference for stearoyl CoA over palmitoyl CoA as acyl donor (PubMed:36049524). Acts in concert with an unknown phospholipase A1 to convert palmitate phosphatidylethanolamine (PE) species into stearate ones. Provides substrates to the PE methylation pathway, controlling stearate/palmitate composition of PE and phosphatidylcholine (PC) species with an overall impact on de novo hepatic lipid synthesis, body fat content and life span (By similarity). Can acylate lysophosphatidylglycerols (LPG) using various saturated fatty acyl-CoAs as acyl donors (PubMed:15485873). Can also acylate monoacylglycerols with a preference for 2-monoacylglycerols over 1-monoacylglycerols (By similarity). Has no activity toward lysophosphatidic acids (LPA) (By similarity).
The role in phosphatidylglycerols remodeling and cardiolipin synthesis is questioned as both processes occur in mitochondria. The monoacylglycerol acyltransferase activity is also weak and a direct role in triacylglycerol synthesis appears unlikely.
Detected at low levels in all tissues analyzed. Detected in fetal and adult brain, lens, retina, retinal pigment epithelium, placenta, lymphocytes and fibroblasts. Levels in retinal pigment epithelium, placenta, lymphocytes, and fibroblasts are very low. Expressed also in kidney, lung and thymus.
Interacts with the tight junction protein TJP1/ZO-1. Associates with actin-rich structures. Interacts with BRK1 and with all three members of the WAVE protein family, WASF1, WASF2 and WASF3.
May function in cell morphology by maintaining the integrity of the circumferential actin ring and controlling lamellipod formation. Involved in the regulation eye, tooth, brain and craniofacial development.
The disease is caused by variants affecting the gene represented in this entry. Caused by copy number variations predicted to result in altered transcriptional regulation of the NHS gene: a 0.8 Mb segmental duplication-triplication encompassing the NHS, SCML1 and RAI2 genes, and an 4.8 kb intragenic deletion in NHS intron 1.
Highly expressed in prostate and testis. Also detected in placenta, muscle, colon, peripheral blood leukocytes and skin.
Constitutes a precursor of the transcription factor. Mediates the autocatalytic cleavage that releases the Myelin regulatory factor, N-terminal component that specifically activates transcription of central nervous system (CNS) myelin genes (PubMed:23966832).
Expressed in lung, ARPE-19 cell line, brainstem, uterus and, to a lesser extent, in basal ganglion and liver. Weakly expressed in cerebellum and retina.
Follows autocatalytic cleavage via the peptidase S74 domain. Autoprocessing is apparently constitutive and is essential for transcriptional activity (PubMed:23966832). Autocatalytic cleavage is inhibited by interaction with TMEM98 (By similarity).
Homotrimer (PubMed:23966832). Interacts (via C-terminal region) with TMEM98; the interaction inhibits MYRF self-cleavage (By similarity).
Membrane-bound part that has no transcription factor activity and remains attached to the endoplasmic reticulum membrane following cleavage.
The nuclear localization signals mediate translocation to the nucleus.
The peptidase S74 domain, also named Intramolecular Chaperone Auto-processed (ICA) domain or Intramolecular Chaperone Domain (ICD), has protease activity and mediates autocatalytic processing of the protein to generate the Myelin regulatory factor, N-terminal active transcription factor and the Myelin regulatory factor, C-terminal components.
Transcription factor that specifically activates expression of myelin genes such as MBP, MOG, MAG, DUSP15 and PLP1 during oligodendrocyte (OL) maturation, thereby playing a central role in oligodendrocyte maturation and CNS myelination. Specifically recognizes and binds DNA sequence 5'-CTGGYAC-3' in the regulatory regions of myelin-specific genes and directly activates their expression. Not only required during oligodendrocyte differentiation but is also required on an ongoing basis for the maintenance of expression of myelin genes and for the maintenance of a mature, viable oligodendrocyte phenotype (PubMed:23966832).
By UV irradiation and carcinogenic agents. During squamous differentiation of epidermal keratinocytes.
Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane.
Expressed during differentiation of squamous cells.
Suprabasal layers of squamous-differentiated tissues such as epidermis, esophagus, tongue and trachea.
Autopalmitoylated (PubMed:15603740, PubMed:18794299). Autopalmitoylation has a regulatory role in ZDHHC17-mediated Mg(2+) transport (PubMed:18794299).
Belongs to the DHHC palmitoyltransferase family. AKR/ZDHHC17 subfamily.
Expressed in all brain regions. Expression is highest in the cortex, cerebellum, occipital lobe and caudate and lowest in the spinal cord. Expression is also seen in testis, pancreas, heart and kidney.
Interacts (via ANK repeats) with numerous proteins (via the consensus sequence motif [VIAP]-[VIT]-x-x-Q-P) (PubMed:28882895). Interacts (via ANK repeats) with CLIP3 (PubMed:26198635, PubMed:28882895). Interacts (via ANK repeats) with HTT; this interaction is inversely correlated to the length of the polyglutamine tract added to the huntingtin protein in Huntington disease (PubMed:12393793, PubMed:9700202, PubMed:26198635, PubMed:28882895, PubMed:28757145). Interacts (via ANK repeats) with DNAJC5 (via C-terminus) (PubMed:28882895). Interacts (via ANK repeats) with MAP6 (PubMed:26198635). Interacts (via ANK repeats) with SNAP23 (PubMed:28882895). Interacts (via ANK repeats) with SNAP25 (PubMed:28882895, PubMed:28757145). Interacts (via ANK repeats) with EVL (PubMed:28882895). Interacts with SPRED1 and SPRED3 (PubMed:24705354). Interacts with GPM6A and OPTN (PubMed:24705354). May interact (via ANK repeats) with SPRED2 (By similarity). May interact with NTRK1; may regulate its localization and function (By similarity).
Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates and is involved in a variety of cellular processes (PubMed:15489887, PubMed:15603740, PubMed:24705354, PubMed:27911442, PubMed:28757145). Has no stringent fatty acid selectivity and in addition to palmitate can also transfer onto target proteins myristate from tetradecanoyl-CoA and stearate from octadecanoyl-CoA (By similarity). Palmitoyltransferase specific for a subset of neuronal proteins, including SNAP25, DLG4/PSD95, GAD2, SYT1 and HTT (PubMed:15603740, PubMed:15489887, PubMed:19139280, PubMed:28757145). Also palmitoylates neuronal protein GPM6A as well as SPRED1 and SPRED3 (PubMed:24705354). Could also play a role in axonogenesis through the regulation of NTRK1 and the downstream ERK1/ERK2 signaling cascade (By similarity). May be involved in the sorting or targeting of critical proteins involved in the initiating events of endocytosis at the plasma membrane (PubMed:12393793). May play a role in Mg(2+) transport (PubMed:18794299). Could also palmitoylate DNAJC5 and regulate its localization to the Golgi membrane (By similarity). Palmitoylates CASP6, thereby preventing its dimerization and subsequent activation (PubMed:27911442).
The DHHC domain is required for palmitoyltransferase activity.
Thought to palmitoylate MPP1 (PubMed:22496366). This work was later retracted due to image manipulation.
(Microbial infection) Critical host factor required for infection by human coronaviruses SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E, as well as all flaviviruses tested such as Zika virus and Yellow fever virus (PubMed:33382968, PubMed:33338421). Required post-entry of the virus to facilitate the ER membrane remodeling necessary to form replication organelles (PubMed:33382968).
(Microbial infection) Interacts with Zika virus NS4A protein and Yellow fever virus NS4B protein.
(Microbial infection) VTT domain is required for flavivirus infection.
Interacts with VMP1 (PubMed:30093494). Interacts with COPA, COPB1, VDAC1 and ERLIN2 (PubMed:30352685). Interacts with ATG2A (PubMed:33850023). Interacts with SURF4 (PubMed:34015269).
Phospholipid scramblase involved in lipid homeostasis and membrane dynamics processes (PubMed:34015269, PubMed:33929485, PubMed:33850023). Has phospholipid scramblase activity toward cholesterol and phosphatidylserine, as well as phosphatidylethanolamine and phosphatidylcholine (PubMed:34015269, PubMed:33929485, PubMed:33850023). Required for autophagosome formation: participates in early stages of autophagosome biogenesis at the endoplasmic reticulum (ER) membrane by reequilibrating the leaflets of the ER as lipids are extracted by ATG2 (ATG2A or ATG2B) to mediate autophagosome assembly (PubMed:30093494, PubMed:30126924, PubMed:30933966, PubMed:34015269, PubMed:33929485, PubMed:34043740, PubMed:33850023). In addition to autophagy, involved in other processes in which phospholipid scramblase activity is required (PubMed:33850023). Required for normal motor neuron development (By similarity).
Acts as component of the GARP complex that is involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN). The GARP complex is required for the maintenance of the cycling of mannose 6-phosphate receptors between the TGN and endosomes, this cycling is necessary for proper lysosomal sorting of acid hydrolases such as CTSD (PubMed:15878329, PubMed:18367545). Acts as component of the EARP complex that is involved in endocytic recycling. The EARP complex associates with Rab4-positive endosomes and promotes recycling of internalized transferrin receptor (TFRC) to the plasma membrane (PubMed:25799061).
Component of the Golgi-associated retrograde protein (GARP) complex, also called VFT (VPS fifty-three) complex, composed of VPS51, VPS52, VPS53 and VPS54 (PubMed:27440922, PubMed:15878329). Component of the endosome-associated retrograde protein (EARP) complex, composed of VPS51, VPS52, VPS53 and VPS50/Syndetin (PubMed:25799061, PubMed:27440922). EIPR1 interacts with both EARP and GARP complexes and mediates the recruitment of the GARP complex to the trans-Golgi network (PubMed:27440922). Interacts with VPS50 in an EIPR1-independent manner (PubMed:31721635).
Detected in pancreas (at protein level).
Monomer. Binds to the sea anemone inhibitor helianthamide (PubMed:27066537).
A chromosomal translocation involving SIPA1L3 is found in a patient with bilateral severe ocular abnormalities including congenital cataracts, corneal clouding, iridocorneal and lenticular adhesions and microphthalmia. Chromosomal translocation t(2;19)(q37.3;q13.1). In addition to translocation, missense variant has been found in patient with bilateral congenital cataracts (PubMed:26231217).
Plays a critical role in epithelial cell morphogenesis, polarity, adhesion and cytoskeletal organization in the lens (PubMed:26231217).
Expressed in lung and dermal fibroblasts.
May play a role in the process of maturation of dendritic cells. Required for the development of cerebellar granule cells (By similarity).
Up-regulated in fibrotic lung. Down-regulated in activated dendritic cells.
Aquaporins contain two tandem repeats each containing three membrane-spanning domains and a pore-forming loop with the signature motif Asn-Pro-Ala (NPA).
Belongs to the MIP/aquaporin (TC 1.A.8) family.
Expressed in collecting tubules in kidney medulla (at protein level) (PubMed:7510718). Detected in kidney (PubMed:7510718).
Forms a water-specific channel that provides the plasma membranes of renal collecting duct with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient (PubMed:8140421, PubMed:7524315, PubMed:7510718, PubMed:15509592). Plays an essential role in renal water homeostasis (PubMed:8140421, PubMed:7524315, PubMed:15509592).
Homotetramer (PubMed:24733887). Interacts with micropeptide MIAC; the interaction leads to a reduction of filamentous actin fibers and inhibition of the EREG/EGFR signaling pathway (PubMed:32176498, PubMed:36117171).
Ser-256 phosphorylation is necessary and sufficient for expression at the apical membrane. Endocytosis is not phosphorylation-dependent.
Interacts (via coiled coil) with TRIM17 (via coiled coil).
May play a role in the process of differentiation and maturation of neuronal cells (By similarity). May regulate the activity of TRIM17. Is a negative regulator of PAX6 expression (PubMed:26394807).
Isoform 1 and isoform 2 are ubiquitously expressed (PubMed:11290418). Detected in heart and brain (PubMed:21621375).
May regulate the intracellular trafficking of RAN (PubMed:11290418). Promotes guanine nucleotide release from RAN and inhibits binding of new GTP by preventing the binding of the RAN guanine nucleotide exchange factor RCC1 (PubMed:29040603). Regulates the levels of GTP-bound RAN in the nucleus, and thereby plays a role in the regulation of RAN-dependent mitotic spindle dynamics (PubMed:29040603). Enhances the expression of SCN5A at the cell membrane in cardiomyocytes (PubMed:18184654, PubMed:23420830, PubMed:21621375).
Monomer. Interacts with RAN, both RAN-GTP and RAN-GDP (PubMed:11290418, PubMed:29040603). Competes with RCC1 for a common binding site on RAN and thereby inhibits RCC1-mediated nucleotide exchange (PubMed:29040603). Forms a complex with RAN-GTP and RANBP1 (By similarity). Interacts with the cytoplasmic loop 2 of SCN5A (PubMed:18184654).
Overexpression can rescue the trafficking defect caused by some SCN5A mutations that impair trafficking to the cell membrane.
Cleavage of HGF is inhibited by SPINT1/HAI-1 via the BPTI/Kunitz inhibitor 1 domain.
Expressed in lung, placenta, pancreas, and prostate (PubMed:11267681). Weakly expressed in testis and peripheral blood lymphocytes (PubMed:11267681).
Interacts with SPINT1/HAI-1; the interaction promotes the phosphorylation and cell membrane localization of TMPRSS13 (PubMed:28710277). Interacts with SPINT2/HAI-2; the interaction promotes the phosphorylation and cell membrane localization of TMPRSS13 (PubMed:28710277, PubMed:34562451).
N-glycosylation of Asn-405 and Asn-445 is required for exit from the endoplasmic reticulum and trafficking to the cell surface (PubMed:28710277, PubMed:34562451). Also required for autocleavage of the zymogen, activation and secretion of the mature protein (PubMed:34562451).
Phosphorylation is required for localization at the cell surface (PubMed:28710277, PubMed:34562451). Phosphorylation increases following inhibition of protease activity by SPINT2/HAI-2 (PubMed:35796294).
Predominantly expressed in lung, placenta, pancreas, and prostate.
Serine protease (PubMed:20977675, PubMed:28710277, PubMed:34562451). Cleaves the proform of PRSS8/prostasin to form the active protein (PubMed:34562451). Cleaves the proform of HGF to form the active protein which promotes MAPK signaling (PubMed:20977675). Promotes the formation of the stratum corneum and subsequently the epidermal barrier in embryos (By similarity).
The inactive zymogen is post-translationally modified and then trafficked to the cell surface, whereby it undergoes autocatalytic cleavage resulting in an activated form that is released extracellularly.
The repeat A-S-P-A-[GLQR] is polymorphic and the number of copies varies between 12 to 14.
Shows weak transcriptional activatory activity.
May act as a protease inhibitor to modulate the host immune response against tumor cells.
Maps to a tandemly repeated region on chromosome Yp11; additionally at least one copy is reported originating from Yq. The gene is thought to be present with an inter-individual variation in copy number and between 20 and 60 copies per Y chromosome are expected. PubMed:12815422 reports 35 tandemly repeated gene copies on Yp11 originating from one individual.
Sequence of unknown origin inserted in the coding sequence.
Specifically expressed in testicular tissues. Isoform 1 and isoform 2 are expressed in spermatogonia and spermatocytes. Found in early testicular carcinoma in situ, spermatogonial cells in testicular tissues of 46,X,Y female and in prostate cancer cell lines.
TSPY is located in the gonadoblastoma critical region and is preferentially expressed in tumor germ cells of gonadoblastoma specimens. Expression also correlates with testicular seminoma and tumorigenesis of the prostate gland.
Up-regulated by androgen in a prostate cancer cell line.
Variants Val-Glu-Val-Val-Ala-Glu-79 Ins and Arg-195 are shown to be present in a number of TSPY1 copies of the Yp11 loci. Variant Arg-195 is shown to be present at least in one TSPY1 copy of the Yq locus.
Along with COX14, core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex (Probable) (PubMed:23260140). Interacts with MT-CO1/COX1, SMIM20, SURF1 and TIMM21 (PubMed:26321642).
Core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. MITRAC complexes regulate both translation of mitochondrial encoded components and assembly of nuclear-encoded components imported in mitochondrion. Required for efficient translation of MT-CO1 and mitochondrial respiratory chain complex IV assembly.
A chromosomal aberration involving GAS7 is found in acute myeloid leukemia. Translocation t(11;17)(q23;p13) with KMT2A/MLL1.
May play a role in promoting maturation and morphological differentiation of cerebellar neurons.
Exhibits strong synaptogenic activity, restricted to excitatory presynaptic differentiation, acting at both pre- and postsynaptic level.
Predominantly expressed in forebrain regions including thalamus and cerebral cortex.
This gene is imprinted, being predominantly expressed from the paternal allele and showing a variable pattern of maternal down-regulation. May be associated paternally with handedness and schizophrenia.
Expressed as early as 6 weeks of gestation (Carnegie stage 16). Ubiquitously expressed during fetal development and postnatally in all adult tissues tested.
Interacts with CCP110, CEP290, CEP97, KIF24.
Required for ciliogenesis and sonic hedgehog/SHH signaling. Required for the centrosomal recruitment of RAB8A and for the targeting of centriole satellite proteins to centrosomes such as of PCM1. May play a role in early ciliogenesis in the disappearance of centriolar satellites that preceeds ciliary vesicle formation (PubMed:24421332). Involved in regulation of cell intracellular organization. Involved in regulation of cell polarity (By similarity). Required for asymmetrical localization of CEP120 to daughter centrioles (By similarity).
The disease is caused by variants affecting the gene represented in this entry. Some patients with biallelic KIAA0586 mutations manifest a disease phenotype with features of Joubert syndrome and additional findings of a small thorax and respiratory problems consistent with Jeune syndrome (Joubert-Jeune ciliopathy).
Ubiquitously expressed (PubMed:26386044). Expressed in photoreceptor cells (at protein level) (PubMed:26386247).
Receptor with an affinity for galactose and fucose. Could be involved in endocytosis (By similarity).
Binds to numerous extracellular matrix proteins.
Mainly expressed in testis, small intestine, colon, blood leukocytes and in pancreatic adenocarcinoma cells.
Ubiquitinated by the CRL2(FEM1B) complex, leading to its degradation.
Expressed in brain, placenta, skeletal muscle, pancreas, testis, uterus, and small intestine. Reduced expression in pancreatic cancer cells.
Activated T-cells, mast cells, natural killer cells.
Cytokine secreted predominantly by activated T-lymphocytes as well as mast cells and osteoblastic cells that controls the production and differentiation of hematopoietic progenitor cells into lineage-restricted cells (PubMed:2556442). Stimulates also mature basophils, eosinophils, and monocytes to become functionally activated (PubMed:10779277, PubMed:32889153). In addition, plays an important role in neural cell proliferation and survival (PubMed:23226269). Participates as well in bone homeostasis and inhibits osteoclast differentiation by preventing NF-kappa-B nuclear translocation and activation (PubMed:12816992). Mechanistically, exerts its biological effects through a receptor composed of IL3RA subunit and a signal transducing subunit IL3RB (PubMed:29374162). Receptor stimulation results in the rapid activation of JAK2 kinase activity leading to STAT5-mediated transcriptional program (By similarity). Alternatively, contributes to cell survival under oxidative stress in non-hematopoietic systems by activating pathways mediated by PI3K/AKT and ERK (PubMed:27862234).
Upon activation of the T-cell receptor/CD3 pathway and can be augmented by coactivation of the CD3 and CD28 pathways.
Contributes to tetrahydrofolate metabolism. Helps regulate carbon flow through the folate-dependent one-carbon metabolic network that supplies carbon for the biosynthesis of purines, thymidine and amino acids. Catalyzes the irreversible conversion of 5-formyltetrahydrofolate (5-FTHF) to yield 5,10-methenyltetrahydrofolate.
Belongs to the small GTPase superfamily. Arf family.
Down-regulated by HIV-1 Tat or phorbol ester (TPA) treatment in endothelial cells (at mRNA and protein levels).
Expressed in brain, liver, lung, kidney and heart (at protein level). Ubiquitously expressed. More abundant in heart, pancreas, liver, intestine and adipose tissues.
Expressed in fetal tissues. More abundant in kidney.
Interacts with TBP and the transcription factor IID (TFIID) complex, NR5A2, NR1H3 and PPARG. Interaction with TBP is regulated by phosphorylation. Binds NR5A1, ATF1, FOS and JUN via their conserved basic region. Binding to calmodulin is regulated by calcium and phosphorylation of the IQ motif.
The IQ motif, which is involved in calmodulin binding, overlaps with the binding domain for nuclear receptors and transcription factors. Its phosphorylation probably allows a switch between the two activities of the protein (By similarity).
Transcriptional coactivator stimulating NR5A1 and ligand-dependent NR1H3/LXRA and PPARG transcriptional activities. Enhances the DNA-binding activity of ATF1, ATF2, CREB1 and NR5A1. Regulates nitric oxid synthase activity probably by sequestering calmodulin in the cytoplasm. May function in endothelial cells differentiation, hormone-induced cardiomyocytes hypertrophy and lipid metabolism.
Belongs to the ubiquitin-conjugating enzyme family. FTS subfamily.
Component of the FTS/Hook/FHIP complex (FHF complex) (PubMed:32073997). The FHF complex may function to promote vesicle trafficking and/or fusion via the homotypic vesicular protein sorting complex (the HOPS complex). Regulates apoptosis by enhancing phosphorylation and activation of AKT1. Increases release of TNFSF6 via the AKT1/GSK3B/NFATC1 signaling cascade. FHF complex promotes the distribution of AP-4 complex to the perinuclear area of the cell (PubMed:32073997).
Component of the FTS/Hook/FHIP complex (FHF complex), composed of AKTIP/FTS, FHIP1B, and one or more members of the Hook family of proteins HOOK1, HOOK2, and HOOK3. Interacts directly with HOOK1, HOOK2 and HOOK3 (PubMed:18799622, PubMed:32073997). The FHF complex associates with the homotypic vesicular sorting complex (the HOPS complex) (PubMed:18799622). Also interacts with AKT1. May interact with FHIP1A (PubMed:32073997).
Lacks the conserved Cys residue necessary for ubiquitin-conjugating enzyme E2 activity.
Has a glutathione-disulfide oxidoreductase activity in the presence of NADPH and glutathione reductase. Reduces low molecular weight disulfides and proteins.
Cleaved into two subunits, alpha and beta, probably between the first EGF domain and the SEA domain. Beta subunit contains the cytoplasmic tail and alpha subunit the extracellular tail. The homooligomerization into dimers is dependent on intrachain disulfide bonds.
Epithelial and hemopoietic transmembrane mucin that may play a role in cell signaling.
Highly expressed in epithelial tissues, particularly those of the gastrointestinal and respiratory tracts, such as large intestine and trachea, followed by kidney, small intestine, appendix and stomach.
Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. The intermediate chains mediate the binding of dynein to dynactin via its 150 kDa component (p150-glued) DCTN1. May play a role in mediating the interaction of cytoplasmic dynein with membranous organelles and kinetochores.
Belongs to the dynein intermediate chain family.
Homodimer (By similarity). The cytoplasmic dynein 1 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs); the composition seems to vary in respect to the IC, LIC and LC composition. The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits. The ICs and LICs bind directly to the HC dimer and the LCs assemble on the IC dimer. Interacts with DYNC1H1. Interacts with DYNLT1 and DYNLT3. Interacts with DCTN1 (By similarity).
Cell autonomous antagonist of the canonical Wnt signaling pathway. May activate a second Wnt signaling pathway that controls planar cell polarity (By similarity). Required for processing of TGFA and for targeting of TGFA to the basolateral membrane of polarized epithelial cells.
Expressed in kidney, lung, pancreas and spleen.
Interacts with DVL1, DVL2, DVL3 and PPP2R3A (By similarity). Interacts with RNF25 and TGFA (via cytoplasmic domain).
The N-terminal domain comprising the first 217 amino acid residues is mostly unstructured.
Ubiquitinated, leading to rapid proteasomal degradation. Interaction with TGFA interferes with RNF25 binding and protects against ubiquitination mediated by RNF25.
Interacts with actin at the FH2 domain. Interacts with DAAM2 (PubMed:33232676).
Phosphate inhibits both the depolymerization and severing activities.
Regulated by autoinhibition due to intramolecular GBD-DAD binding.
Severs actin filaments and accelerates their polymerization and depolymerization.
The WH2 domain acts as the DAD (diaphanous autoregulatory) domain and binds to actin monomers.
The severing activity is dependent on covalent attachment of the FH2 domain to the C-terminus.
Widely expressed. In the kidney, expression is apparent in podocytes and some tubule cells.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ12 subfamily.
Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium.
Probably phosphorylated by PKC; decreases single-channel open probability.
Specifically expressed in skeletal muscle.
Adhesive protein that mediates cell-to-cell interactions (PubMed:11509594, PubMed:15383453). Acts as receptor for thrombospondin THBS1 and as modulator of integrin signaling through the activation of heterotrimeric G proteins (PubMed:19004835, PubMed:8550562, PubMed:7691831). Involved in signal transduction, cardiovascular homeostasis, inflammation, apoptosis, angiogenesis, cellular self-renewal, and immunoregulation (PubMed:27742621, PubMed:19004835, PubMed:8550562, PubMed:11509594, PubMed:7691831, PubMed:32679764, PubMed:15383453). Plays a role in modulating pulmonary endothelin EDN1 signaling (PubMed:27742621). Modulates nitrous oxide (NO) signaling, in response to THBS1, hence playing a role as a pressor agent, supporting blood pressure (By similarity). Plays an important role in memory formation and synaptic plasticity in the hippocampus (By similarity). Receptor for SIRPA, binding to which prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells (PubMed:11509594). Interaction with SIRPG mediates cell-cell adhesion, enhances superantigen-dependent T-cell-mediated proliferation and costimulates T-cell activation (PubMed:15383453). Positively modulates FAS-dependent apoptosis in T-cells, perhaps by enhancing FAS clustering (By similarity). Plays a role in suppressing angiogenesis and may be involved in metabolic dysregulation during normal aging (PubMed:32679764). In response to THBS1, negatively modulates wound healing (By similarity). Inhibits stem cell self-renewal, in response to THBS1, probably by regulation of the stem cell transcription factors POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4 (By similarity). May play a role in membrane transport and/or integrin dependent signal transduction (PubMed:7691831). May prevent premature elimination of red blood cells (By similarity).
Induced in pulmonary artery and lung parenchyma following injury or stress (PubMed:27742621). Expression in arteries increases in normal aging (PubMed:32679764).
Monomer (PubMed:18657508). Interacts with THBS1 (via the C-terminal domain) (PubMed:8550562, PubMed:19004835). Interacts with SIRPA (PubMed:11509594). Interacts with FAS/CD95; interaction may be enhanced by functional activation (PubMed:15917238). Interacts with SIRPG, UBQLN1 and UBQLN2 (PubMed:10549293, PubMed:15383453, PubMed:18657508). May interact with fibrinogen (PubMed:22079249).
Very broadly distributed on normal adult tissues, as well as ovarian tumors, being especially abundant in some epithelia and the brain.
Interacts with microtubules. Interacts with CKAP5 independently of clathrin. Interacts with CKAP5 and clathrin forming the TACC3/ch-TOG/clathrin complex located at spindle inter-microtubules bridges; TACC3 (phosphorylated at Ser-558 by AURKA) and CLTC are proposed to form a composite microtubule interaction surface (PubMed:21297582, PubMed:23918938, PubMed:25596274). Interacts with CCDC100/CEP120. The coiled coil C-terminal region interacts with AH receptor nuclear translocator protein (ARNT) and ARNT2 (By similarity). Interacts with GCN5L2 and PCAF (PubMed:14767476).
Plays a role in the microtubule-dependent coupling of the nucleus and the centrosome. Involved in the processes that regulate centrosome-mediated interkinetic nuclear migration (INM) of neural progenitors (By similarity). Acts as component of the TACC3/ch-TOG/clathrin complex proposed to contribute to stabilization of kinetochore fibers of the mitotic spindle by acting as inter-microtubule bridge. The TACC3/ch-TOG/clathrin complex is required for the maintenance of kinetochore fiber tension (PubMed:21297582, PubMed:23532825). May be involved in the control of cell growth and differentiation. May contribute to cancer (PubMed:14767476).
Up-regulated in various cancer cell lines.
'Lys-63'-linked polyubiquitinated at Lys-30 and Lys-401 by TRAF2:BIRC2 and TRAF2:BIRC3 complexes. Ubiquitination is induced by LPS, TNFA and interleukin-1 and required for full kinase activity and KF-kappa-B pathway activation.
(Microbial infection) Interacts (via Protein kinase domain) with arenavirus protein N; the interaction inhibits IKBKE kinase function.
(Microbial infection) Interacts with Ebola virus protein VP35; the interaction leads to inhibition of cellular antiviral response by blocking necessary interactions between the IKBKE and MAVS/IPS as well as its substrates IRF3 and IRF7.
(Microbial infection) Interacts with Epstein-Barr virus (EBV) protein NEC2/BFRF1; this interaction inhibits IKBKE kinase activity and IRF3 nuclear translocation.
(Microbial infection) Interacts with Severe fever with thrombocytopenia virus (SFTSV) NSs; this interaction this interaction sequesters IKBKE in NSs-induced cytoplasmic inclusion bodies thereby inhibiting the IFN responses.
(Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein HBZ.
Autophosphorylated and phosphorylated by IKBKB/IKKB. Phosphorylation at Ser-172 is enhanced by the interaction with DDX3X. Phosphorylated at Thr-501 upon IFN activation.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.
Highly expressed in spleen followed by thymus, peripheral blood leukocytes, pancreas, placenta. Weakly expressed in lung, kidney, prostate, ovary and colon.
Homodimer. Interacts with MAVS/IPS1 (PubMed:16177806, PubMed:28011935, PubMed:27980081). Interacts (via protein kinase domain) with TTLL12 (via N-terminus); the interaction prevents MAVS binding to IKBKE (PubMed:28011935). Interacts with the adapter proteins AZI2/NAP1, TANK and TBKBP1/SINTBAD (PubMed:17568778). Interacts with SIKE1 (PubMed:16281057, PubMed:14560022). Interacts with TICAM1/TRIF, IRF3 and RIGI; interactions are disrupted by the interaction between IKBKE and SIKE1 (PubMed:14739303, PubMed:16281057, PubMed:23478265). Interacts with TOPORS; induced by DNA damage (PubMed:20188669). Interacts with CYLD (PubMed:18636086). Interacts (when polyubiquitinated) with IKBKB, IKBKG and MYD88 (PubMed:23453969). Interacts with IFIH1 (PubMed:17600090). Interacts with DDX3X; the interaction may be induced upon virus infection (PubMed:18636090, PubMed:20657822, PubMed:23478265, PubMed:27980081). Interacts with TRIM6 (via SPRY box) (PubMed:24882218). Interacts with unanchored K48-linked polyubiquitin chains; this leads to IKBKE activation (PubMed:24882218). Interacts with TBK1 (PubMed:29251827). Interacts with FKBP5 (PubMed:26101251, PubMed:31434731).
Induced by lipopolysaccharide (LPS) and TNFA.
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the type I IFN, NF-kappa-B and STAT signaling. Also involved in TNFA and inflammatory cytokines, like Interleukin-1, signaling. Following activation of viral RNA sensors, such as RIG-I-like receptors, associates with DDX3X and phosphorylates interferon regulatory factors (IRFs), IRF3 and IRF7, as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRF3 leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNB. In order to establish such an antiviral state, IKBKE forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including IPS1/MAVS, TANK, AZI2/NAP1 or TBKBP1/SINTBAD can be recruited to the IKBKE-containing-complexes. Activated by polyubiquitination in response to TNFA and interleukin-1, regulates the NF-kappa-B signaling pathway through, at least, the phosphorylation of CYLD. Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. In addition, is also required for the induction of a subset of ISGs which displays antiviral activity, may be through the phosphorylation of STAT1 at 'Ser-708'. Phosphorylation of STAT1 at 'Ser-708' seems also to promote the assembly and DNA binding of ISGF3 (STAT1:STAT2:IRF9) complexes compared to GAF (STAT1:STAT1) complexes, in this way regulating the balance between type I and type II IFN responses. Protects cells against DNA damage-induced cell death. Also plays an important role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Phosphorylates AKT1.
Sumoylation by TOPORS upon DNA damage is required for protection of cells against DNA damage-induced cell death. Desumoylated by SENP1.
Converts unsaturated trans-2-enoyl-CoA species ((2E)-enoyl-CoA) to the corresponding (3S)-3hydroxyacyl-CoA species through addition of a water molecule to the double bond (PubMed:25125611, PubMed:26251176). Catalyzes the hydration of medium- and short-chained fatty enoyl-CoA thioesters from 4 carbons long (C4) up to C16 (PubMed:26251176). Has high substrate specificity for crotonyl-CoA ((2E)-butenoyl-CoA) and moderate specificity for acryloyl-CoA, 3-methylcrotonyl-CoA (3-methyl-(2E)-butenoyl-CoA) and methacrylyl-CoA ((2E)-2-methylpropenoyl-CoA) (PubMed:26251176). Can bind tiglyl-CoA (2-methylcrotonoyl-CoA), but hydrates only a small amount of this substrate (PubMed:26251176). Plays a key role in the beta-oxidation spiral of short- and medium-chain fatty acid oxidation (PubMed:25125611, PubMed:26251176). At a lower rate than the hydratase reaction, catalyzes the isomerase reaction of trans-3-enoyl-CoA species (such as (3E)-hexenoyl-CoA) to trans-2-enoyl-CoA species (such as (2E)-hexenoyl-CoA), which are subsequently hydrated to 3(S)-3-hydroxyacyl-CoA species (such as (3S)-hydroxyhexanoyl-CoA) (By similarity).
Liver, fibroblast, muscle. Barely detectable in spleen and kidney.
Belongs to the G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRB3 sub-subfamily.
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. Beta-3 is involved in the regulation of lipolysis and thermogenesis.
The variant Arg-64 seems to be associated with weight gain (obesity) and is also associated with susceptibility to non-insulin-dependent diabetes mellitus (NIDDM).
Could function in transport of proteins into the mitochondrion.
Part of a large protein complex spanning both mitochondrial membranes termed the mitochondrial intermembrane space bridging (MIB) complex.
Chimeric cDNA. The N-terminal part is identical to the product of the KRTAP2-3 gene.
In the hair cortex, hair keratin intermediate filaments are embedded in an interfilamentous matrix, consisting of hair keratin-associated proteins (KRTAP), which are essential for the formation of a rigid and resistant hair shaft through their extensive disulfide bond cross-linking with abundant cysteine residues of hair keratins. The matrix proteins include the high-sulfur and high-glycine-tyrosine keratins (By similarity).
Enhances the tyrosine carboxypeptidase activity of VASH1 and VASH2, thereby promoting the removal of the C-terminal tyrosine residue of alpha-tubulin (PubMed:29146869, PubMed:31270470, PubMed:31235911, PubMed:31324789, PubMed:31171830, PubMed:31235910). This activity is critical for spindle function and accurate chromosome segregation during mitosis since microtubule detyronisation regulates mitotic spindle length and postioning (PubMed:31171830). Also required to enhance the solubility and secretion of VASH1 and VASH2 (PubMed:20736312, PubMed:27879017, PubMed:30607023). Plays a role in axon and excitatory synapse formation (PubMed:31235911).
Interacts with EFNB1, EFNB3, GRIA2, GRIA3, CSPG4 and GRIPAP1. Can form homomultimers and heteromultimers with GRIP1 (By similarity). Interacts with the C-terminal tail of PRLHR.
May play a role as a localized scaffold for the assembly of a multiprotein signaling complex and as mediator of the trafficking of its binding partners at specific subcellular location in neurons.
PDZ 5 mediates the C-terminal binding of GRIA2 and GRIA3. PDZ 6 mediates interaction with the PDZ recognition motif of EFNB1. PDZ 7 mediates interaction with CSPG4 (By similarity).
Interacts with the GTP-bound form of RAP2A.
May act as an effector of RAP2A in neuronal cells.
Acts as a UDP-D-xylose:ribitol-5-phosphate beta1,4-xylosyltransferase, which catalyzes the transfer of UDP-D-xylose to ribitol 5-phosphate (Rbo5P) to form the Xylbeta1-4Rbo5P linkage on O-mannosyl glycan (PubMed:27733679, PubMed:29477842) (Probable). Participates in the biosynthesis of the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3-N-acetylglucosamine-beta-4-(phosphate-6-)mannose), a carbohydrate structure present in alpha-dystroglycan (DAG1), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity (PubMed:25279699, PubMed:27601598, PubMed:27733679) (Probable).
Forms a complex composed of FKTN/fukutin, FKRP and RXYLT1/TMEM5.
Amphipathic helix regions act as an anchoring domain for PKA, and appear to be responsible of the interaction between myospryn and PRKAR2A.
Down-regulated in muscle cell lines derived from patients with Duchenne muscular dystrophy (DMD).
Expressed in skeletal muscle; at a strong level and in heart.
Interacts with PRKAR2A. Interacts with ACTN2 and DTNBP1/dysbindin (By similarity). Interacts with DES (PubMed:17872945). Interacts with DMD/dystrophin (By similarity). Interacts with the calcineurin catalytic subunit PPP3CA (By similarity). Interacts with TTN (PubMed:20634290). Interacts with CAPN3; this interaction, which results in CMYA5 proteolysis, may protect CAPN3 from autolysis (PubMed:20634290). Interacts with FSD2 (By similarity). Identified in a complex composed of FSD2, CMYA5 and RYR2 (By similarity).
May serve as an anchoring protein that mediates the subcellular compartmentation of protein kinase A (PKA) via binding to PRKAR2A (By similarity). May function as a repressor of calcineurin-mediated transcriptional activity. May attenuate calcineurin ability to induce slow-fiber gene program in muscle and may negatively modulate skeletal muscle regeneration (By similarity). Plays a role in the assembly of ryanodine receptor (RYR2) clusters in striated muscle (By similarity).
Ligand for members of the frizzled family of seven transmembrane receptors. Probable developmental protein. May be a signaling molecule which affects the development of discrete regions of tissues. Is likely to signal over only few cell diameters (By similarity).
Belongs to the glycosyltransferase 32 family.
Catalyzes the transfer of N-acetylglucosamine (GlcNAc) to core 2 branched O-glycans (PubMed:10430883). Necessary for the synthesis of type III mucin which is specifically produced in the stomach, duodenum, and pancreatic duct (PubMed:10430883). May protect against inflammation-associated gastric adenocarcinomas (By similarity).
The conserved DXD motif is involved in enzyme activity.
Chemotactic factor that attracts skin-associated memory T-lymphocytes. May play a role in mediating homing of lymphocytes to cutaneous sites. Binds to CCR10.
Monomer, dimer, and tetramer. Heparin avidly promotes oligomerization. Interacts with TNFAIP6 (via Link domain).
Testis, thymus, placenta, ovary and skin.
Homodimer. Binds to heparin and chondroitin sulfate E (By similarity).
Belongs to the GST superfamily. Zeta family.
Bifunctional enzyme showing minimal glutathione-conjugating activity with ethacrynic acid and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole and maleylacetoacetate isomerase activity. Has also low glutathione peroxidase activity with T-butyl and cumene hydroperoxides. Is able to catalyze the glutathione dependent oxygenation of dichloroacetic acid to glyoxylic acid.
Glutathione is required for the MAAI activity.
Mostly expressed in liver followed by kidney, skeletal muscle and brain. Also expressed in melanocytes, synovium, placenta, breast and fetal liver and heart.
Abundantly expressed in retina with lower levels of expression in most other tissues.
Interacts with GNAI1 and GNAQ (PubMed:18434541). Interacts with GNAI2, GNAI3 and GNAO1 (By similarity).
Phosphorylated. Phosphorylation at Tyr-168 by EGFR enhances GTPase accelerating (GAP) activity toward GNAI1.
Regulates G protein-coupled receptor signaling cascades. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form (PubMed:11602604, PubMed:18434541). Plays an important role in the phototransduction cascade by regulating the lifetime and effective concentration of activated transducin alpha. May regulate extra and intracellular mitogenic signals (By similarity).
Expressed only in heart and skeletal muscle.
Probable substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex that may function in myogenesis.
The expression decreases in the dystrophic muscle of Limb-girdle muscular dystrophy (LGMD) patient.
Dimer (PubMed:23964685). Can also form higher oligomers (PubMed:23964685). Interacts with LCN1; this interaction mediates the endocytosis of LCN1 (PubMed:11287427, PubMed:12591932, PubMed:23964685). Interacts with UBAC2, FAF2, VCP, AMFR, ZNRF3, CTNNB1, LRP6, GSK3A and GSK3B (PubMed:31073040). Interacts with DVL2 and RNF43 (By similarity). Interaction with SCGB1A1 has been observed in PubMed:16423471, but not in PubMed:23964685 (PubMed:16423471, PubMed:23964685). Interaction with LGB which mediates the endocytosis of LGB has been observed in PubMed:17991420, but not in PubMed:23964685 (PubMed:17991420, PubMed:23964685).
Expressed in testis, pituitary gland, adrenal gland, trachea, placenta, thymus, cerebellum, stomach, mammary gland, spinal cord. A weaker expression is detected in colon, pancreas, and prostate.
Plays an essential role in lymphocyte development by negatively regulating the canonical Wnt signaling pathway (By similarity). In association with UBAC2 and E3 ubiquitin-protein ligase AMFR, promotes the ubiquitin-mediated degradation of CTNNB1 and Wnt receptors FZD6 and LRP6 (By similarity). LMBR1L stabilizes the beta-catenin destruction complex that is required for regulating CTNNB1 levels (By similarity). Acts as a LCN1 receptor and can mediate its endocytosis (PubMed:11287427, PubMed:12591932, PubMed:23964685).
Expressed in liver, kidney, colon, esophagus and small intestine.
Homodimer (PubMed:17179145). Homooligomer (Probable). Interacts with UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8 and UGT1A10 to form heterodimers (PubMed:17179145). Isoform 1 interacts with isoform 2/i2 suggesting that oligomerization is involved in negative regulation of transferase activity by isoform 2. Isoform 1 also interacts with respective i2 isoforms of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8 and UGT1A10 (PubMed:20610558).
Lacks UGT glucuronidation activity but acts as a negative regulator of isoform 1.
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15472229, PubMed:15470161, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:19545173). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:20610558). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212).
UGT1A9 isoform is part of the UGT1A complex locus which displays alternative use of promoters, first exons and terminal exons. The locus is defined by 13 first exons, which are alternatively spliced to 3 other common exons and 2 alternative terminal exons 5. From the 27 possible mRNA isoforms, 9 produce functionally active polypeptides (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9 and 1A10) called isoforms 1 (i1). Use of an alternative exon 5 (5b) as terminal exon is leading to 9 additional alternatively spliced products termed isoforms i2 and which lack transferase activity.
Binds RPS6KA3, MAPK3 and MAPK1. Transient interaction with PLD1 and PLD2 (By similarity). Interacts with CASP8 and FADD.
Blocks Ras-mediated inhibition of integrin activation and modulates the ERK MAP kinase cascade. Inhibits RPS6KA3 activities by retaining it in the cytoplasm (By similarity). Inhibits both TNFRSF6- and TNFRSF1A-mediated CASP8 activity and apoptosis. Regulates glucose transport by controlling both the content of SLC2A1 glucose transporters on the plasma membrane and the insulin-dependent trafficking of SLC2A4 from the cell interior to the surface.
Phosphorylated by protein kinase C and calcium-calmodulin-dependent protein kinase. These phosphorylation events are modulated by neurotransmitters or hormones.
Ubiquitously expressed. Most abundant in tissues such as heart, brain, muscle and adipose tissue which utilize glucose as an energy source. Lower expression in glucose-producing tissues. Higher levels of expression are found in tissues from individuals with type 2 diabetes than in controls.
Component of the ER membrane protein complex (EMC).
Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins (PubMed:30415835, PubMed:29809151, PubMed:29242231, PubMed:32459176, PubMed:32439656). Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues (PubMed:30415835, PubMed:29809151, PubMed:29242231). Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices (PubMed:30415835, PubMed:29809151). It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes (PubMed:29809151, PubMed:29242231). By mediating the proper cotranslational insertion of N-terminal transmembrane domains in an N-exo topology, with translocated N-terminus in the lumen of the ER, controls the topology of multi-pass membrane proteins like the G protein-coupled receptors (PubMed:30415835). By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes (Probable).
Plays a role in transcriptional regulation (PubMed:24623306). Involved in activated KRAS-mediated transcriptional activation of PRKD1 in colorectal cancer (CRC) cells (PubMed:24623306). Binds to the PRKD1 promoter in colorectal cancer (CRC) cells (PubMed:24623306). Could play a role in the terminal differentiation of the intestine. Binds preferentially to methylated DNA (PubMed:28473536).
Associates with TBP to form B-TFIID. Binds DRAP1.
Belongs to the SNF2/RAD54 helicase family.
Regulates transcription in association with TATA binding protein (TBP). Removes TBP from the TATA box in an ATP-dependent manner.
Belongs to the protein kinase superfamily. PAN3 family.
Contains a pseudokinase domain. The protein kinase domain is predicted to be catalytically inactive because some of the residues important for catalytic activity are substituted and it lacks the equivalent of the binding site for a peptide substrate. However, it has retained an ATP-binding site and ATP-binding is required for mRNA degradation, stimulating the activity of the PAN2 nuclease in vitro. The nucleotide-binding site is juxtaposed to the RNase active site of PAN2 in the complex and may actually bind nucleosides of a poly(A) RNA rather than ATP, feeding the poly(A)-tail to the active site of the deadenylase and thus increasing the efficiency with which this distributive enzyme degrades oligo(A) RNAs.
Decreases PAN2-mediated deadenylation, possibly by preventing progression into the second CCR4-NOT mediated stage of biphasic deadenylation. Has a significant effect on mRNA stability, generally stabilizing a subset of the transcriptome. Stabilizes mRNAs degraded by the AU-rich element (ARE)-mediated mRNA decay pathway but promotes degradation of mRNAs by the microRNA-mediated pathway (PubMed:28559491). Its activity influences mRNP remodeling, specifically reducing formation of a subset of P-bodies containing GW220, an isoform of TNRC6A (PubMed:28559491).
Enhances PAN2 deadenylase activity and has an extensive effect on mRNA stability, generally enhancing mRNA decay across the transcriptome by multiple pathways, including the AU-rich element (ARE)-mediated pathway, microRNA-mediated pathway and the nonsense-mediated pathway (NMD) (PubMed:28559491). Its activity is required for efficient P-body formation (PubMed:28559491). May be involved in regulating mRNAs of genes involved in cell cycle progression and cell proliferation (PubMed:28559491).
Homodimer (PubMed:23932717). Forms a heterotrimer with a catalytic subunit PAN2 to form the poly(A)-nuclease (PAN) deadenylation complex (PubMed:14583602, PubMed:23932717). Interacts (via PAM-2 motif) with poly(A)-binding protein PABPC1 (via PABC domain), conferring substrate specificity of the enzyme complex (PubMed:17595167, PubMed:18056425). Interacts with the GW182 family proteins TNRC6A, TNRC6B and TNRC6 (PubMed:21981923). Interacts with YTHDF3 (By similarity).
Interacts with PAN2 (PubMed:28559491). Interacts (via N-terminus) with PABPC1 at higher efficiency than isoform 1 (PubMed:28559491).
Interacts with PAN2 (PubMed:28559491). Interacts (via N-terminus) with PABPC1 at lower efficiency than isoform 3 (PubMed:28559491).
Regulatory subunit of the poly(A)-nuclease (PAN) deadenylation complex, one of two cytoplasmic mRNA deadenylases involved in general and miRNA-mediated mRNA turnover. PAN specifically shortens poly(A) tails of RNA and the activity is stimulated by poly(A)-binding protein (PABP). PAN deadenylation is followed by rapid degradation of the shortened mRNA tails by the CCR4-NOT complex. Deadenylated mRNAs are then degraded by two alternative mechanisms, namely exosome-mediated 3'-5' exonucleolytic degradation, or deadenylation-dependent mRNA decapping and subsequent 5'-3' exonucleolytic degradation by XRN1. PAN3 acts as a regulator for PAN activity, recruiting the catalytic subunit PAN2 to mRNA via its interaction with RNA and PABP, and to miRNA targets via its interaction with GW182 family proteins.
The N-terminal zinc finger binds to poly(A) RNA.
The pseudokinase domain, the coiled-coil (CC), and C-terminal knob domain (CK) form a structural unit (PKC) that forms an extensive high-affinity interaction surface for PAN2.
Receptor for extracellular UDP > UTP > ATP. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system.
Actin-organizing protein that may cause stress fiber formation together with cell elongation (By similarity). Isoform 4 may play a role in actin filament polymerization in cardiomyocytes.
Expressed in the heart, kidney and brain. May be down-regulated in various types of heart diseases, including idiopathic dilated, ventricular dilated, familial dilated and perinatal dilated cardiomyopathies, as well as ischemic heart disease (at protein level).
Interacts with nestin/NES-based interfilament (IF) (By similarity). Interacts with SQSTM1; isoform 4 threonine phosphorylation disrupts SQSTM1-binding.
Phosphorylated on Thr-1474 and Thr-1476 by CK2.
The DAD domain regulates activation via by an autoinhibitory interaction with the GBD/FH3 domain. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments (By similarity).
Homodimer. Interacts with PIEZO1 and PIEZO2.
Required for the function of many mechanoreceptors. Modulate mechanotransduction channels and acid-sensing ion channels (ASIC) proteins. Potentiates PIEZO1 and PIEZO2 function by increasing their sensitivity to mechanical stimulations.
Can form oligomers with SYN1 (PubMed:23406870). Interacts with CAPON.
Neuronal phosphoprotein that coats synaptic vesicles, binds to the cytoskeleton, and is believed to function in the regulation of neurotransmitter release. May play a role in noradrenaline secretion by sympathetic neurons (By similarity).
Phosphorylation at Ser-10 dissociates synapsins from synaptic vesicles. Phosphorylation at Ser-425 by MAPK1/ERK2 and/or MAPK3/ERK1 may play a role in noradrenaline secretion by sympathetic neurons (By similarity).
The A region binds phospholipids with a preference for negatively charged species.
There are several mRNAs and ESTs supporting this gene model. However, the genome sequence encoding the N-terminal part contains several sequence discrepancies.
Cleaved by caspase-7 in response to apoptosis to produce EMAP-II.
Homodimer. Part of the multisynthetase complex (MSC), a multisubunit complex that groups tRNA ligases for Arg (RARS1), Asp (DARS1), Gln (QARS1), Ile (IARS1), Leu (LARS1), Lys (KARS1), Met (MARS1) the bifunctional ligase for Glu and Pro (EPRS1) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18 (PubMed:24312579, PubMed:19131329, PubMed:19289464). Interacts (via N-terminus) with RARS1 (via N-terminus) (PubMed:10358004, PubMed:17443684). Part of a complex composed of RARS1, QARS1 and AIMP1 (PubMed:25288775). Interacts (via C-terminus) with SMURF2. Interacts (via N-terminus) with HSP90B1/gp96 (via C-terminus) (By similarity). Interacts with PSMA7 (PubMed:19362550). Interacts with TARS3 (PubMed:24312579).
Non-catalytic component of the multisynthase complex. Stimulates the catalytic activity of cytoplasmic arginyl-tRNA synthase (PubMed:10358004). Binds tRNA. Possesses inflammatory cytokine activity (PubMed:11306575). Negatively regulates TGF-beta signaling through stabilization of SMURF2 by binding to SMURF2 and inhibiting its SMAD7-mediated degradation (By similarity). Involved in glucose homeostasis through induction of glucagon secretion at low glucose levels (By similarity). Promotes dermal fibroblast proliferation and wound repair (PubMed:16472771). Regulates KDELR1-mediated retention of HSP90B1/gp96 in the endoplasmic reticulum (By similarity). Plays a role in angiogenesis by inducing endothelial cell migration at low concentrations and endothelian cell apoptosis at high concentrations (PubMed:12237313). Induces maturation of dendritic cells and monocyte cell adhesion (PubMed:11818442). Modulates endothelial cell responses by degrading HIF-1A through interaction with PSMA7 (PubMed:19362550).
Belongs to the Mrp/NBP35 ATP-binding proteins family. NUBP2/CFD1 subfamily.
Binds 4 [4Fe-4S] clusters per heterotetramer. Contains two stable clusters in the N-termini of NUBP1 and two labile, bridging clusters between subunits of the NUBP1-NUBP2 heterotetramer.
Component of the cytosolic iron-sulfur (Fe/S) protein assembly (CIA) machinery. Required for maturation of extramitochondrial Fe-S proteins. The NUBP1-NUBP2 heterotetramer forms a Fe-S scaffold complex, mediating the de novo assembly of an Fe-S cluster and its transfer to target apoproteins. Negatively regulates cilium formation and structure.
Expressed in fetal brain, lung, liver and kidney.
Heterotetramer of 2 NUBP1 and 2 NUBP2 chains (By similarity). Interacts with KIFC1 (By similarity). Interacts with NUBP1 (PubMed:18573874).
Widely expressed with highest expression in skeletal muscle.
DNA glycosylase which prefers single-stranded DNA (ssDNA), or partially ssDNA structures such as bubble and fork structures, to double-stranded DNA (dsDNA) (PubMed:12433996, PubMed:19170771, PubMed:22569481, PubMed:23755964). Mediates interstrand cross-link repair in response to replication stress: acts by mediating DNA glycosylase activity, cleaving one of the two N-glycosyl bonds comprising the interstrand cross-link, which avoids the formation of a double-strand break but generates an abasic site that is bypassed by translesion synthesis polymerases (By similarity). In vitro, displays strong glycosylase activity towards the hydantoin lesions spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh) in both ssDNA and dsDNA; also recognizes FapyA, FapyG, 5-OHU, 5-OHC, 5-OHMH, Tg and 8-oxoA lesions in ssDNA (PubMed:12433996, PubMed:19170771, PubMed:22569481, PubMed:23755964). No activity on 8-oxoG detected (PubMed:12433996, PubMed:19170771, PubMed:22569481, PubMed:23755964). Also shows weak DNA-(apurinic or apyrimidinic site) lyase activity (PubMed:12433996, PubMed:19170771, PubMed:22569481, PubMed:23755964). In vivo, appears to be the primary enzyme involved in removing Sp and Gh from ssDNA in neonatal tissues (PubMed:12433996, PubMed:19170771, PubMed:22569481, PubMed:23755964).
Expressed in keratinocytes and embryonic fibroblasts (at protein level). Also detected in thymus, testis and fetal lung primary fibroblasts.
The N-terminal region (2-281) contains the glycosylase and lyase activities.
The RanBP2-type zinc-finger, also named NZF zinc finger, recognizes and binds ubiquitinated CMG helicase complex. The GRF-type zinc-fingers recognize single-stranded DNA (ssDNA), possibly on the lagging strand template.
Up-regulated during early S phase of the cell cycle, and sustained through G/M phase. Low expression levels in quiescent cells.
Was originally thought to be inactive as a glycosylase (PMID:12200441,PMID:19121397), but recent reports (PMID:22569481, PMID:20185759) demonstrate that cleavage of the initiator methionine is essential for catalytic activity.
(Microbial infection) Interacts with Epstein-Barr virus protein EBNA6; this interaction inhibits TP73-mediated apoptotic pathway.
Activated and stabilized by interaction with RANBP9.
Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression.
Expressed in striatal neurons of patients with Huntington disease (at protein level). Brain, kidney, placenta, colon, heart, liver, spleen, skeletal muscle, prostate, thymus and pancreas. Highly expressed in fetal tissue. Expressed in the respiratory epithelium (PubMed:34077761).
Found in a complex with p53/TP53 and CABLES1. The C-terminal oligomerization domain binds to the ABL1 tyrosine kinase SH3 domain. Interacts with HECW2. Isoform Beta interacts homotypically and with p53/TP53, whereas isoform Alpha does not. Isoform Gamma interacts homotypically and with all p73 isoforms. Isoform Delta interacts with isoform Gamma, isoform Alpha, and homotypically. Isoforms Alpha and Beta interact with HIPK2. Isoform Alpha interacts with RANBP9. Isoform Beta interacts with WWOX. Interacts (via SAM domain) with FBXO45 (via B30.2/SPRY domain). Interacts with YAP1 (phosphorylated form). Interacts with HCK (via SH3 domain); this inhibits TP73 activity and degradation. Interacts (via SAM domain) with NQO1; this interaction is NADH-dependent, stabilizes TP73 in response to oxidative stress and protects it from ubiquitin-independent degradation by the 20S proteasome.
Higher levels of phosphorylation seen in the brain from patients with Huntington disease.
Isoform alpha (but not isoform beta) is sumoylated on Lys-627, which potentiates proteasomal degradation but does not affect transcriptional activity. Phosphorylation by PLK1 and PLK3 inhibits the transcription regulator activity and pro-apoptotic function.
Maps to a chromosome region frequently mutated in diverse cell lines of human cancer. Appears not to be frequently mutated in human cancers, in contrast to p53/TP53. Hemizygosity is observed in neuroblastoma and oligodendroglioma.
Not induced by DNA damage. Isoforms lacking the transactivation domain block gene induction.
Participates in the apoptotic response to DNA damage. Isoforms containing the transactivation domain are pro-apoptotic, isoforms lacking the domain are anti-apoptotic and block the function of p53 and transactivating p73 isoforms. May be a tumor suppressor protein. Is an activator of FOXJ1 expression (By similarity). It is an essential factor for the positive regulation of lung ciliated cell differentiation (PubMed:34077761).
Polyubiquitinated by RCHY1/PIRH2; leading to its degradation by the proteasome.
Possesses an acidic transactivation domain, a central DNA binding domain and a C-terminal oligomerization domain that binds to the ABL1 tyrosine kinase SH3 domain.
Produced by alternative splicing of isoform Alpha.
Produced by alternative splicing of isoform Alpha. The splicing of exon 11 results in a frameshift from the original reading frame.
Produced by alternative splicing of isoform Alpha. The splicing of exon 11 results in a frameshift from the original reading frame. The splicing of exon 13 reverts the reading frame to the sequence of isoform Alpha.
Produced by alternative splicing of isoform dN-Alpha.
Monomer. Homodimer (via N-terminus). Associates with the Golgi-associated retrograde protein (GARP) complex. Interacts with GARP complex component VPS52 (PubMed:20163565). Interacts (via C-terminal coiled-coil domain) with STX6 (PubMed:20163565, PubMed:35499567).
Tube-forming lipid transport protein which mediates the transfer of lipids between membranes at organelle contact sites (PubMed:35499567). Required for retrograde traffic of vesicle clusters in the early endocytic pathway to the Golgi complex (PubMed:35499567, PubMed:20163565).
Alpha-helical parts of the C-terminal intracellular region mediate heterodimeric interaction with GABBR2 (PubMed:9872744). The linker region between the transmembrane domain 3 (TM3) and the transmembrane domain 4 (TM4) probably plays a role in the specificity for G-protein coupling (PubMed:9844003).
Belongs to the G-protein coupled receptor 3 family. GABA-B receptor subfamily.
Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2 (PubMed:9872316, PubMed:9872744, PubMed:15617512, PubMed:18165688, PubMed:22660477, PubMed:24305054). Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins (PubMed:18165688). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase (PubMed:10906333, PubMed:10773016, PubMed:10075644, PubMed:9872744, PubMed:24305054). Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis (PubMed:10075644). Calcium is required for high affinity binding to GABA (By similarity). Plays a critical role in the fine-tuning of inhibitory synaptic transmission (PubMed:9844003). Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials (PubMed:9844003, PubMed:9872316, PubMed:10075644, PubMed:9872744, PubMed:22660477). Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception (Probable). Activated by (-)-baclofen, cgp27492 and blocked by phaclofen (PubMed:9844003, PubMed:9872316, PubMed:24305054).
Heterodimer of GABBR1 and GABBR2 (PubMed:9872316, PubMed:10773016, PubMed:9872744, PubMed:15617512, PubMed:18165688, PubMed:22660477, PubMed:24305054). Homodimers may form, but are inactive (PubMed:9872316, PubMed:15617512). Isoform 1E (without C-terminal intracellular domain) is unable to dimerize via a coiled-coil interaction with GABBR2 (PubMed:10906333). Interacts (via C-terminus) with ATF4 (via leucine zipper domain) (By similarity). Interacts with JAKMIP1 (PubMed:14718537).
Highly expressed in brain (PubMed:9844003, PubMed:9753614, PubMed:9872744). Weakly expressed in heart, small intestine and uterus. Isoform 1A: Mainly expressed in granular cell and molecular layer (PubMed:9844003). Isoform 1B: Mainly expressed in Purkinje cells (PubMed:9844003). Isoform 1E: Predominantly expressed in peripheral tissues as kidney, lung, trachea, colon, small intestine, stomach, bone marrow, thymus and mammary gland (PubMed:10906333).
Isoform 1E may regulate the formation of functional GABBR1/GABBR2 heterodimers by competing for GABBR2 binding. This could explain the observation that certain small molecule ligands exhibit differential affinity for central versus peripheral sites.
Major isoform in almost all peripheral tissues, although containing a premature stop codon in the mRNA and thus being a potential target for nonsense-mediated mRNA decay. May act as an antagonist of GABA-B receptors, being able to disrupt the normal association between isoform 1A and GABBR2.
Interacts with YIPF6; this interaction may stabilize YIPF2. May also form a ternary complex with YIPF1 and YIPF6.
Component of heterochromatin. Recognizes and binds histone H3 tails methylated at 'Lys-9', leading to epigenetic repression. Interaction with lamin B receptor (LBR) can contribute to the association of the heterochromatin with the inner nuclear membrane.
Expressed in all adult and embryonic tissues.
Homodimer (By similarity). Interacts directly with CHAF1A, EMSY, LBR, TIF1/TIF1A and TRIM28/TIF1B PXVXL motif via the chromoshadow domain (PubMed:14651845, PubMed:16615912). Interacts directly with histone H3 methylated at 'Lys-9' via the chromo domain (By similarity). Interacts with SUV39H1 and SETDB1, KMT5B and KMT5C (PubMed:10202156, PubMed:15899859). Interacts with PRDM6 (By similarity). Interacts with POGZ (PubMed:20850016, PubMed:20562864). Interacts with CHAMP1 (PubMed:20850016). Interacts with INCENP (PubMed:21346195). Interacts with SGO1; the CBX1 homodimer binds to one molecule of SGO1 (PubMed:21346195). Interacts with LRIF1 (via PxVxL motif) (PubMed:23542155). Interacts with HDGFL2 (PubMed:26721387). Interacts with CHD3 (PubMed:28977666). Interacts with CHD4 (PubMed:28977666).
Was previously reported to interact with ASXL1. However, this publication has been retracted.
Interacts (via guanylate kinase-like domain) with RIMBP3 (via coiled-coil region). Interacts (via guanylate kinase-like domain) with HOOK2. Interacts (via LRRCT domain) with KLC3. Interacts with HOOK1 and HOOK3.
Involved in multiple aspects of sperm assembly including acrosome attachment, shaping of the sperm head and in the early aspects of axoneme development. Not essential for primary cilium biogenesis.
Belongs to the multi antimicrobial extrusion (MATE) (TC 2.A.66.1) family.
Mediates the efflux of cationic compounds such as the model cations, tetraethylammonium (TEA), the neurotoxin 1-methyl-4-phenylpyridinium (MPP), the platinum-based drugs cisplatin and oxaliplatin, the drugs procainamide, acyclovir and topotecan, or weak bases that are positively charged at physiological pH, such as cimetidine or the antidiabetic drug metformin.
Multidrug efflux pump that functions as a H(+)/organic cation antiporter (PubMed:16330770, PubMed:17509534). Plays a physiological role in the excretion of cationic compounds including endogenous metabolites, drugs, toxins through the kidney and liver, into urine and bile respectively (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). Mediates the efflux of endogenous compounds such as creatinine, vitamin B1/thiamine, agmatine and estrone-3-sulfate (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). May also contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier (Probable).
Widely expressed. The highest expression is found in adrenal gland, and to a lower extent in liver, skeletal muscle and kidney. In testis, primarily localized throughout the adluminal compartment of the seminiferous tubules with expression at the peritubular myoid cells and Leydig cells (PubMed:35307651).
Belongs to the PUR DNA-binding protein family.
Defects in PURB may be a cause of progression of myelodysplastic syndrome (MDS) towards acute myelogenous leukemia (AML). MDS refers to a heterogeneous group of closely related hematopoietic disorders. All are characterized by a cellular marrow with impaired morphology and maturation (dysmyelopoiesis) and peripheral blood cytopenias, resulting from ineffective blood cell production. Some patients with MDS develop acute myelogenous leukemia (AML), a malignant disease in which hematopoietic precursors are arrested in an early stage of development.
Expressed in myocardium of heart failure patients.
Has capacity to bind repeated elements in single-stranded DNA such as the purine-rich single strand of the PUR element located upstream of the MYC gene. Plays a role in the control of vascular smooth muscle (VSM) alpha-actin gene transcription as repressor in myoblasts and fibroblasts. Participates in transcriptional and translational regulation of alpha-MHC expression in cardiac myocytes by binding to the purine-rich negative regulatory (PNR) element. Modulates constitutive liver galectin-3 gene transcription by binding to its promoter. May play a role in the dendritic transport of a subset of mRNAs (By similarity).
Homodimer, heterodimer with PURA and heterotrimer with PURA and YBX1/Y-box protein 1.
Interacts with TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7.
May play a role in TRPCs intracellular trafficking.
Associated with AP-1 and AP-2 complexes.
May be involved in endocytic recycling of growth factor receptors such as EGFR.
Widely expressed, including in skin and keratinocytes, with highest levels in adrenal gland, rectum and thymus.
Autoinhibited by its C-terminal basic region.
Binds via its PH domain to the inositol head group of phosphatidylinositol 3,4,5-trisphosphate.
Expressed predominantly in peripheral blood leukocytes.
Promotes guanine-nucleotide exchange on ARF1 and ARF5. Promotes the activation of ARF factors through replacement of GDP with GTP.
Catalyzes the ATP-dependent transport of phospholipids such as phosphatidylcholine and phosphoglycerol from the cytoplasm into the lumen side of lamellar bodies, in turn participates in the lamellar bodies biogenesis and homeostasis of pulmonary surfactant (PubMed:16959783, PubMed:17574245, PubMed:28887056, PubMed:31473345, PubMed:27177387). Transports preferentially phosphatidylcholine containing short acyl chains (PubMed:27177387). In addition plays a role as an efflux transporter of miltefosine across macrophage membranes and free cholesterol (FC) through intralumenal vesicles by removing FC from the cell as a component of surfactant and protects cells from free cholesterol toxicity (PubMed:26903515, PubMed:25817392, PubMed:27177387).
Expressed in brain, pancreas, skeletal muscle and heart (PubMed:8706931). Highly expressed in the lung in an AT2-cell-specific manner (PubMed:11718719, PubMed:8706931). Weakly expressed in placenta, kidney and liver (PubMed:8706931). Also expressed in medullary thyroid carcinoma cells (MTC) and in C-cell carcinoma (PubMed:8706931).
Multifunctional polypeptide with two homologous halves, each containing a hydrophobic membrane-anchoring domain and an ATP binding cassette (ABC) domain.
N-glycosylated (PubMed:16959783, PubMed:24142515, PubMed:27177387). Localization at intracellular vesicles is accompanied by processing of oligosaccharide from high mannose type to complex type (PubMed:16959783, PubMed:27177387). N-linked glycosylation at Asn-124 and Asn-140 is required for stability and efficient anterograde trafficking and prevents from proteasomal degradation (PubMed:24142515).
Proteolytically cleaved by CTSL and to a lower extent by CTSB within multivesicular bodies (MVB) and lamellar bodies (LB) leading to a mature form of 150 kDa.
The ATP-dependent phosphatidylcholine transport is competitively inhibited by miltefosine.
Up-regulated in Leishmania Viannia (L.V.) panamensis-infected macrophages exposed to miltefosine (PubMed:26903515). Down-regulated by L. V. panamensis infection (PubMed:26903515).
By 3-methylcholanthrene (3-MC) in MNCs from adults. By the heterodimer AHR/ARNT.
Highly expressed in testis, lung, ovary, spleen and pancreas. Highly expressed in mononuclear cells (MNCs) from umbilical cord blood. Isoform 3 is highly expressed in lung, kidney, spleen and thymus. Down-regulated malignant tissue from different anatomical origins, including colon, breast, lung, stomach, cervix, and ovary.
Interacts with ANKRA2, HDAC4 and HDAC5. Interacts with ARNT; forms a heterodimer with ARNT (PubMed:28904176).
Mediates dioxin toxicity and is involved in regulation of cell growth and differentiation. Represses the transcription activity of AHR by competing with this transcription factor for heterodimer formation with the ARNT and subsequently binding to the xenobiotic response element (XRE) sequence present in the promoter regulatory region of variety of genes. Represses CYP1A1 by binding the XRE sequence and recruiting ANKRA2, HDAC4 and/or HDAC5. Autoregulates its expression by associating with its own XRE site.
The Ala-189 allele may be a susceptibility factor for dioxin-related male infertility. Homozygosity for Ala-189 is observed in azoospermic individuals at higher frequency than in normozoospermic individuals (PubMed:15474075, PubMed:17559847). Might also be associated with susceptibility to and severity of endometriosis.
The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers.
Variant histone H2A which replaces conventional H2A in a subset of nucleosomes where it represses transcription. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. May be involved in stable X chromosome inactivation.
Constitutively phosphorylated on serine, threonine and tyrosine residues within the head and tail regions of noncapacitated spermatozoa. Phosphorylation on tyrosine residues increases upon sperm capacitation within the acrosomal region in a protein kinase A (PKA)-dependent signaling pathway.
Found in a complex at least composed of MROH2B, PRKACA isoform 2 and TCP11. Interacts with MROH2B. Interacts with PRKACA isoform 2 (By similarity). Isoform 2 and isoform 3 interact with ODF1 (via leucine zipper motif) (PubMed:21597245).
Isoform 2 and isoform 3 are expressed in sperm. Isoform 1 is not detected in sperm (at protein level) (PubMed:21597245). Testis-specific (PubMed:11756566). Isoform 1, isoform 2 and isoform 3 are expressed in sperm (PubMed:21597245).
Plays a role in the process of sperm capacitation and acrosome reactions. Probable receptor for the putative fertilization-promoting peptide (FPP) at the sperm membrane that may modulate the activity of the adenylyl cyclase cAMP pathway.
May help orchestrate cytoskeletal arrangement. Contribute to lamellipodia formation.
Requires phosphatidylcholine as an allosteric activator for enzymatic activity.
Interacts with cytoplasmic tails of a variety of G-protein coupled receptors such as muscarinic acetylcholine receptor M1/CHRM1 and calcitonin receptor/CALCR.
May play a role in regulation of a variety of G-protein coupled receptors.
(Microbial infection) Interacts with herpes virus 8/HHV-8 protein vIRF-1; this interaction induces ubiquitination and degradation of SYNCRIP.
(Microbial infection) Interacts with minute virus of mice (MVM) NS1 protein.
Contaminating sequence. Potential poly-A sequence starting in position 413.
Heterogenous nuclear ribonucleoprotein (hnRNP) implicated in mRNA processing mechanisms. Component of the CRD-mediated complex that promotes MYC mRNA stability. Isoform 1, isoform 2 and isoform 3 are associated in vitro with pre-mRNA, splicing intermediates and mature mRNA protein complexes. Isoform 1 binds to apoB mRNA AU-rich sequences. Isoform 1 is part of the APOB mRNA editosome complex and may modulate the postranscriptional C to U RNA-editing of the APOB mRNA through either by binding to A1CF (APOBEC1 complementation factor), to APOBEC1 or to RNA itself. May be involved in translationally coupled mRNA turnover. Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain. Interacts in vitro preferentially with poly(A) and poly(U) RNA sequences. Isoform 3 may be involved in cytoplasmic vesicle-based mRNA transport through interaction with synaptotagmins. Component of the GAIT (gamma interferon-activated inhibitor of translation) complex which mediates interferon-gamma-induced transcript-selective translation inhibition in inflammation processes. Upon interferon-gamma activation assembles into the GAIT complex which binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and suppresses their translation; seems not to be essential for GAIT complex function.
Isoform 1 is a component of the APOB mRNA editosome complex and interacts with APOBEC1 and A1CF (APOBEC1 complementation factor). Part of a complex associated with the FOS mCRD domain and consisting of PABPC1, PAIP1, CSDE1/UNR, HNRPD and SYNCRIP. Isoform 3 interacts with HNRPR. Interacts with POLR2A hyperphosphorylated C-terminal domain. Isoform 1, isoform 2 and isoform 3 interact with SMN. Isoform 3 interacts through its C-terminal domain with SYT7, SYT8 and SYT9 (By similarity). The non-phosphorylated and phosphorylated forms are colocalized with PAIP1 in polysomes (By similarity). Interacts with HABP4 (PubMed:19523114). Identified in a histone pre-mRNA complex, at least composed of ERI1, LSM11, SLBP, SNRPB, SYNCRIP and YBX1 (By similarity). Identified in the spliceosome C complex. Component of the coding region determinant (CRD)-mediated complex, composed of DHX9, HNRNPU, IGF2BP1, SYNCRIP and YBX1. Identified in a mRNP complex, at least composed of DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1. Identified in a mRNP granule complex, at least composed of ACTB, ACTN4, DHX9, ERG, HNRNPA1, HNRNPA2B1, HNRNPAB, HNRNPD, HNRNPL, HNRNPR, HNRNPU, HSPA1, HSPA8, IGF2BP1, ILF2, ILF3, NCBP1, NCL, PABPC1, PABPC4, PABPN1, RPLP0, RPS3, RPS3A, RPS4X, RPS8, RPS9, SYNCRIP, YBX1 and untranslated mRNAs. Interacts with GTPBP1. Component of the GAIT complex; in humans the complex assembly seems to be a two-step process in which EPRS1 first associates with SYNCRIP to form a pre-GAIT complex which is deficient in GAIT element binding.
May be due to a competing donor splice site and to an exon inclusion.
May be due to a competing donor splice site.
Phosphorylated on tyrosine. The membrane-bound form found in microsomes is phosphorylated in vitro by insulin receptor tyrosine kinase (INSR). Phosphorylation is inhibited upon binding to RNA, whereas the cytoplasmic form is poorly phosphorylated (By similarity).
The domain containing eight Arg-Gly-Gly repeats (RGG/RXR-box) may be involved in RNA-binding and protein-protein interactions. It is methylated by PRMT1, and essential for nuclear localization.
Ubiquitously expressed. Detected in heart, brain, pancreas, placenta, spleen, lung, liver, skeletal muscle, kidney, thymus, prostate, uterus, small intestine, colon, peripheral blood and testis.
Belongs to the WD repeat KIAA0329 family.
Detected in skin fibroblast (at protein level).
Interacts with the ATG8 family members GABARAP, GABARAPL1, GABARAPL2, MAP1LC3B and MAP1LC3C.
Probably plays a role as positive regulator of autophagy.
Belongs to the cytidylyltransferase family.
Catalyzes the key rate-limiting step in the CDP-choline pathway for phosphatidylcholine biosynthesis.
Expressed in brain, liver and fetal lung.
Highly expressed in testis, placenta, brain, ovary, liver and fetal lung.
Interacts (via COMM domain) with COMMD1 (via COMM domain) (PubMed:15799966). Interacts with RELA, RELB, NFKB1/p105, NFKB2/p100. Interacts with CCDC22, CCDC93, SCNN1B, CUL3, CUL4B, CUL5, CUL7 (PubMed:28892079, PubMed:15799966, PubMed:21778237, PubMed:23563313, PubMed:23637203, PubMed:25355947).
May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes (PubMed:21778237). May down-regulate activation of NF-kappa-B (PubMed:15799966).
Functions as a cytoplasmic linker protein. Involved in TGN-endosome dynamics. May modulate the cellular compartmentalization of AKT kinase family and promote its cell membrane localization, thereby playing a role in glucose transport in adipocytes.
Homodimer. Interacts with AKT1 and AKT2; when AKT1 and AKT2 are phosphorylated and activated, affinity is higher for AKT2 (PubMed:19139280). Interacts with ZDHHC13 (via ANK repeats) (PubMed:26198635). Interacts with ZDHHC17 (via ANK repeats) (PubMed:26198635, PubMed:28882895).
Microtubule association is inhibited by the ANK repeats and the Golgi localization region (GoLD).
Palmitoylation by ZDHHC17 regulates association with the plasma membrane.
The N-terminal half is dispensable for proper Golgi targeting, whereas the GoLD region is required.
Positively regulates hepatic SREBP signaling pathway by modulating the proper localization of SCAP (SREBP cleavage-activating protein) to the endoplasmic reticulum, thereby controlling the level of functional SCAP.
Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate (PubMed:29162720, PubMed:15024386). In the closed conformation (C-MAD2) forms a heterotetrameric complex with MAD1L1 at unattached kinetochores during prometaphase, the complex recruits open conformation molecules of MAD2L1 (O-MAD2) and then promotes the conversion of O-MAD2 to C-MAD2 (PubMed:29162720). Required for the execution of the mitotic checkpoint which monitors the process of kinetochore-spindle attachment and inhibits the activity of the anaphase promoting complex by sequestering CDC20 until all chromosomes are aligned at the metaphase plate (PubMed:10700282, PubMed:11804586, PubMed:15024386).
Monomer and homodimer (PubMed:18022367, PubMed:18318601). Heterodimerizes with MAD2L1 in order to form a tetrameric MAD1L1-MAD2L1 core complex (PubMed:12574116, PubMed:18981471, PubMed:12006501, PubMed:15024386). In the closed and open conformation, interacts with MAD1L1 (PubMed:29162720). Formation of a heterotetrameric core complex containing two molecules each of MAD1L1 and of MAD2L1 promotes binding of another molecule of MAD2L1 to each MAD2L1, resulting in a heterohexamer (PubMed:12006501). Interacts with MAD2L1BP (PubMed:12456649, PubMed:18022368). Interacts with ADAM17/TACE (PubMed:10527948). Interacts with CDC20 (PubMed:9637688, PubMed:12574116, PubMed:18981471, PubMed:10700282). Dimeric MAD2L1 in the closed conformation interacts with CDC20 (PubMed:29162720). Monomeric MAD2L1 in the open conformation does not interact with CDC20 (PubMed:11804586). CDC20 competes with MAD1L1 for MAD2L1 binding (PubMed:11804586). In the closed conformation, interacts with BUB1B (PubMed:29162720). Interacts with TTK (PubMed:29162720). Interacts with TPR (PubMed:18981471). Binds to UBD (via ubiquitin-like 1 domain) during mitosis (PubMed:16495226, PubMed:25422469). Interacts with isoform 1 and isoform 2 of NEK2 (PubMed:20034488). Interacts with HSF1; this interaction occurs in mitosis (PubMed:18794143). Interacts with isoform 3 of MAD1L1; this interaction leads to the cytoplasmic sequestration of MAD2L1 (PubMed:19010891).
Phosphorylated on multiple serine residues. The level of phosphorylation varies during the cell cycle and is highest during mitosis. Phosphorylation abolishes interaction with MAD1L1 and reduces interaction with CDC20. Phosphorylated by NEK2.
The protein has two highly different native conformations, an inactive open conformation that cannot bind CDC20 and that predominates in cytosolic monomers, and an active closed conformation. The protein in the closed conformation preferentially dimerizes with another molecule in the open conformation, but can also form a dimer with a molecule in the closed conformation. Formation of a heterotetrameric core complex containing two molecules of MAD1L1 and of MAD2L1 in the closed conformation promotes binding of another molecule of MAD2L1 in the open conformation and the conversion of the open to the closed form, and thereby promotes interaction with CDC20.
Adapter that functions to localize a calcium-sensitive signal transduction machinery in sperm to a calcium-permeable ion channel (By similarity). Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (PubMed:36191189).
Binds calmodulin via its IQ domain. Interacts with TRPC1, TRPC2, TRPC5, but not TRPC3 (By similarity). Interacts with CFAP45 (PubMed:33139725).
The IQ motif is involved in calmodulin binding.
Belongs to the class VI-like SAM-binding methyltransferase superfamily. Isoprenylcysteine carboxyl methyltransferase family.
Catalyzes the post-translational methylation of isoprenylated C-terminal cysteine residues.
Competitively inhibited by N-acetyl-S-trans,trans-farnesyl-l-cysteine (AFC).
Ubiquitously expressed. Expressed at higher levels in the cerebellum and putamen than in other brain regions. Abundant expression seen in the Purkinje cells and pontine neurons.
Genetic variation in SLC11A1 is associated with susceptibility to infection with Mycobacterium ulcerans [MIM:610446].
Genetic variations in SLC11A1 determine Mycobacterium tuberculosis susceptibility [MIM:607948].
In response to lymphokine or bacterial products.
Macrophage-specific antiporter that fluxes metal ions in either direction against a proton gradient. Localized to late endosomal lysosomal membranes, delivers bivalent cations from the cytosol into these acidic compartments where they may directly affect antimicrobial activity (PubMed:11237855). Involved in iron metabolism and host natural resistance to infection with intracellular parasites. Pathogen resistance involves sequestration of Fe(2+) and Mn(2+), cofactors of both prokaryotic and eukaryotic catalases and superoxide dismutases, not only to protect the macrophage against its own generation of reactive oxygen species, but to deny the cations to the pathogen for synthesis of its protective enzymes (Probable).
Macrophages; peripheral blood leukocytes, lung, spleen and liver.
Cleaves aggrecan, a cartilage proteoglycan, at the '1938-Glu-|-Leu-1939' site (within the chondroitin sulfate attachment domain), and may be involved in its turnover (By similarity). Has angiogenic inhibitor activity. Active metalloprotease, which may be associated with various inflammatory processes as well as development of cancer cachexia. May play a critical role in follicular rupture.
Available under the name Osigraft (Stryker). Its use is indicated in the treatment of tibial non-union of at least 9 months duration, secondary to trauma, in skeletally mature patients, in cases where autograft has failed or is unfeasible.
Expressed in the developing eye, brain and ear during embryogenesis.
Expressed in the kidney and bladder. Lower levels seen in the brain.
Growth factor of the TGF-beta superfamily that plays important role in various biological processes, including embryogenesis, hematopoiesis, neurogenesis and skeletal morphogenesis (PubMed:31208997). Initiates the canonical BMP signaling cascade by associating with type I receptor ACVR1 and type II receptor ACVR2A (PubMed:9748228, PubMed:12667445). Once all three components are bound together in a complex at the cell surface, ACVR2A phosphorylates and activates ACVR1. In turn, ACVR1 propagates signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act as activators and repressors of transcription of target genes (PubMed:12478285). For specific functions such as growth cone collapse in developing spinal neurons and chemotaxis of monocytes, uses also BMPR2 as type II receptor (PubMed:31208997). Can also signal through non-canonical pathways such as P38 MAP kinase signaling cascade that promotes brown adipocyte differentiation through activation of target genes, including members of the SOX family of transcription factors (PubMed:27923061). Promotes the expression of HAMP, this is repressed by its interaction with ERFE (PubMed:30097509).
Homodimer; disulfide-linked (PubMed:8570652). Interacts with SOSTDC1 (PubMed:15020244). Interacts with TWSG1 (By similarity). Interacts with FBN1 (via N-terminal domain) and FBN2 (PubMed:18339631). Interacts with type I receptor ACVR1 (PubMed:9748228). Interacts with type II receptor ACVR2A (PubMed:12667445). Interacts with NOG; this interaction inhibits canonical BMP signaling (PubMed:12478285). Interacts with SCUBE3 (PubMed:33308444). Interacts with ERFE; the interaction inhibits BMP-induced transcription of HAMP (PubMed:30097509).
Several N-termini starting at positions 293, 300, 315 and 316 have been identified by direct sequencing resulting in secretion of different mature forms.
Interacts with kinesin, dynein, APLP1, APLP2, TENT2/GLD2 and APP. Both phosphorylated and non phosphorylated forms interact with APLP1 (By similarity). Interacts with TENT4B; the interaction is required for TENT4B-mediated translational control (PubMed:28383716).
Isoform 1 is expressed in immature oocytes, ovary, brain and heart. Isoform 2 is expressed in brain and heart. Isoform 3 and isoform 4 are expressed in brain. Expressed in breast tumors and several tumor cell lines.
Phosphorylated on serine/threonine residues by AURKA within positions 166 and 197. Phosphorylation and dephosphorylation on Thr-172 regulates cytoplasmic polyadenylation and translation of CPE-containing mRNAs. Phosphorylation on Thr-172 by AURKA and CAMK2A activates CPEB1. Phosphorylation on Thr-172 may be promoted by APLP1. Phosphorylation increases binding to RNA (By similarity).
Sequence-specific RNA-binding protein that regulates mRNA cytoplasmic polyadenylation and translation initiation during oocyte maturation, early development and at postsynapse sites of neurons. Binds to the cytoplasmic polyadenylation element (CPE), an uridine-rich sequence element (consensus sequence 5'-UUUUUAU-3') within the mRNA 3'-UTR. RNA binding results in a clear conformational change analogous to the Venus fly trap mechanism (PubMed:24990967). In absence of phosphorylation and in association with TACC3 is also involved as a repressor of translation of CPE-containing mRNA; a repression that is relieved by phosphorylation or degradation (By similarity). Involved in the transport of CPE-containing mRNA to dendrites; those mRNAs may be transported to dendrites in a translationally dormant form and translationally activated at synapses (By similarity). Its interaction with APLP1 promotes local CPE-containing mRNA polyadenylation and translation activation (By similarity). Induces the assembly of stress granules in the absence of stress. Required for cell cycle progression, specifically for prophase entry (PubMed:26398195).
The 2 RRM domains and the C-terminal region mediate interaction with CPE-containing RNA (PubMed:24990967). The interdomain linker (411-429) acts as a hinge to fix the relative orientation of the 2 RRMs (PubMed:24990967). The ZZ domain (509-566) coordinates 2 Zn ions and is probably implicated in mediating interactions with other proteins in addition to increasing the affinity of the RRMs for the CPEs (PubMed:23500490, PubMed:24990967). A continuous hydrophobic interface is formed between the 2 RRMs (PubMed:24990967).
Acetylation alters the phosphorylation pattern. Deacetylated by SIRT3 (By similarity).
Heterotetramer of two PDHA1 and two PDHB subunits. The heterotetramer interacts with DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules.
Phosphorylation at Ser-232, Ser-293 and Ser-300 by PDK family kinases inactivates the enzyme; for this phosphorylation at a single site is sufficient. Dephosphorylation at all three sites, i.e. at Ser-232, Ser-293 and Ser-300, is required for reactivation.
Pyruvate dehydrogenase activity is inhibited by phosphorylation of PDHA1; it is reactivated by dephosphorylation.
Belongs to the pseudouridine synthase TruB family.
Catalytic subunit of H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA (PubMed:25219674). This involves the isomerization of uridine such that the ribose is subsequently attached to C5, instead of the normal N1 (PubMed:25219674). Each rRNA can contain up to 100 pseudouridine ('psi') residues, which may serve to stabilize the conformation of rRNAs. Required for ribosome biogenesis and telomere maintenance (PubMed:19179534, PubMed:25219674). Also required for correct processing or intranuclear trafficking of TERC, the RNA component of the telomerase reverse transcriptase (TERT) holoenzyme (PubMed:19179534).
Part of the H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which contains NHP2/NOLA2, GAR1/NOLA1, NOP10/NOLA3, and DKC1/NOLA4, which is presumed to be the catalytic subunit (PubMed:15044956). The complex contains a stable core formed by binding of one or two NOP10-DKC1 heterodimers to NHP2; GAR1 subsequently binds to this core via DKC1 (PubMed:15044956). The complex binds a box H/ACA small nucleolar RNA (snoRNA), which may target the specific site of modification within the RNA substrate (PubMed:15044956). During assembly, the complex contains NAF1 instead of GAR1/NOLA1 (PubMed:16601202, PubMed:16618814). The complex also interacts with TERC, which contains a 3'-terminal domain related to the box H/ACA snoRNAs. Specific interactions with snoRNAs or TERC are mediated by GAR1 and NHP2. Associates with NOLC1/NOPP140 (PubMed:15044956). H/ACA snoRNPs interact with the SMN complex, consisting of SMN1 or SMN2, GEMIN2/SIP1, DDX20/GEMIN3, and GEMIN4. This is mediated by interaction between GAR1 and SMN1 or SMN2. The SMN complex may be required for correct assembly of the H/ACA snoRNP complex (PubMed:15044956). Component of the telomerase holoenzyme complex composed of one molecule of TERT, one molecule of WRAP53/TCAB1, two molecules of H/ACA ribonucleoprotein complex subunits DKC1, NOP10, NHP2 and GAR1, and a telomerase RNA template component (TERC) (PubMed:11074001, PubMed:19179534, PubMed:20351177, PubMed:29695869). The telomerase holoenzyme complex is associated with TEP1, SMG6/EST1A and POT1 (PubMed:19179534). Interacts with SHQ1; this interaction may lead to the stabilization of DKC1, from the time of its synthesis until its association with NOP10, NHP2, and NAF1 at the nascent H/ACA RNA (PubMed:19734544, PubMed:19383767). Interacts with HMBOX1 (PubMed:23685356). Interacts with DHX36 (PubMed:21846770).
Promotes cell to cell and cell to substratum adhesion, increases the cell proliferation rate and leads to cytokeratin hyper-expression.
The disease is caused by variants affecting the gene represented in this entry. Reduced rRNA pseudouridine levels in cells from patients (PubMed:25219674).
Almost absent from healthy skin; especially in epidermal keratinocytes, skin fibroblasts or endothelial cells and is barely detectable in benign melanocytic naevi. Expressed in the stroma close to skin tumors, in the tumor cells themselves and in the epidermis of psoriasis.
By TGFB1 present in the melanoma cell conditioned medium (MCCM).
It is uncertain whether Met-1 or Met-53 is the initiator.
May be an activator of G protein signaling.
Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. May be involved in cell migration processes that are specific for lymphocytes.
Specifically expressed in fetal and adult lymphoid and hematopoietic tissue as well as in lung. Considerable level of expression in adult and fetal spleen as well as adult peripheral leukocytes and lung. Lower expression in adult thymus, lymph node, bone marrow, and appendix as well as in fetal liver, thymus, and lung.
Heterodimer (named alpha-thrombin) of a light and a heavy chain; disulfide-linked. Forms a heterodimer with SERPINA5. In plasma, interacts (via N-terminus) with alpha-1-microglobulin with molar ratio 1:2 and 1:1; this interaction does not prevent the activation of prothrombin to thrombin.
In the penultimate step of the coagulation cascade, prothrombin is converted to thrombin by the prothrombinase complex composed of factor Xa (F10), cofactor Va (F5), and phospholipids. This activation requires factor Xa-catalyzed sequential cleavage at 2 sites, Arg-314 and Arg-363, along 2 possible pathways. In the first pathway, the first cleavage occurs at Arg-314, leading to the formation of the inactive intermediate prethrombin-2. This pathway preferentially occurs on platelets and in the absence of cofactor Va. In the second pathway, the first cleavage occurs at Arg-363, which separates protease domain into 2 chains that remain connected through a disulfide bond and generates the active intermediate meizothrombin. The presence of cofactor Va directs activation along the meizothrombin pathway and greatly accelerates the rate of cleavage at Arg-363, but has a smaller effect on the cleavage of meizothrombin at Arg-314. Meizothrombin accumulates as an intermediate when prothrombinase is assembled on the membrane of red blood cells.
It is not known whether 1 or 2 smaller activation peptides, with additional cleavage after Arg-314, are released in natural blood clotting.
N-glycosylated. N-glycan heterogeneity at Asn-121: Hex3HexNAc3 (minor), Hex4HexNAc3 (minor) and Hex5HexNAc4 (major). At Asn-143: Hex4HexNAc3 (minor) and Hex5HexNAc4 (major).
The cleavage after Arg-198, observed in vitro, does not occur in plasma.
The disease is caused by variants affecting the gene represented in this entry. A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis.
The gamma-carboxyglutamyl residues, which bind calcium ions, result from the carboxylation of glutamyl residues by a microsomal enzyme, the vitamin K-dependent carboxylase. The modified residues are necessary for the calcium-dependent interaction with a negatively charged phospholipid surface, which is essential for the conversion of prothrombin to thrombin.
The peptide TP508 also known as Chrysalin (Orthologic) could be used to accelerate repair of both soft and hard tissues.
Thrombin can itself cleave the N-terminal fragment (fragment 1) of the prothrombin, prior to its activation by factor Xa.
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing.
A chromosomal aberration involving KAT6B may be a cause acute myeloid leukemias. Translocation t(10;16)(q22;p13) with CREBBP.
Autoacetylated (PubMed:10497217, PubMed:11965546). Autoacetylation at Lys-815 is required for proper function.
Component of the MOZ/MORF complex composed at least of ING5, KAT6A, KAT6B, MEAF6 and one of BRPF1, BRD1/BRPF2 and BRPF3. Interacts with RUNX1 and RUNX2.
Histone acetyltransferase which may be involved in both positive and negative regulation of transcription. Required for RUNX2-dependent transcriptional activation. May be involved in cerebral cortex development. Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity.
The N-terminus is involved in transcriptional activation while the C-terminus is involved in transcriptional repression.
Ubiquitously expressed, with high levels in heart, pancreas, testis and ovary.
Component of the MAJIN-TERB1-TERB2 complex, composed of MAJIN, TERB1 and TERB2.
Meiosis-specific telomere-associated protein involved in meiotic telomere attachment to the nucleus inner membrane, a crucial step for homologous pairing and synapsis. Component of the MAJIN-TERB1-TERB2 complex, which promotes telomere cap exchange by mediating attachment of telomeric DNA to the inner nuclear membrane and replacement of the protective cap of telomeric chromosomes: in early meiosis, the MAJIN-TERB1-TERB2 complex associates with telomeric DNA and the shelterin/telosome complex. During prophase, the complex matures and promotes release of the shelterin/telosome complex from telomeric DNA.
Expressed in white adipose tissue (at protein level) (PubMed:11201732). Widely expressed, with particularly strong expression in lung, bone marrow, breast and peripheral blood (PubMed:15248836). Expressed strongly in bone marrow and at lower levels in lung, but not detected in other tissues (PubMed:15064728). Isoform 2 is detected in adipose tissue, bone marrow, brain, lung, peripheral blood, placenta and thymus (PubMed:15248836).
Homodimer; disulfide-linked (By similarity). Interacts with DEFA1 (PubMed:15064728).
Hormone that seems to suppress insulin ability to stimulate glucose uptake into adipose cells (By similarity). Potentially links obesity to diabetes (By similarity). Promotes chemotaxis in myeloid cells (PubMed:15064728).
(Microbial infection) Interacts with human papillomavirus 16/HPV16 protein E7.
Arg-20 is dimethylated, probably to asymmetric dimethylarginine.
Blocks interferon-dependent interphase and stimulates DNA synthesis in cells. Involved in the translational regulation of the human papillomavirus type 16 E7 mRNA (HPV16 E7).
Expressed in cultured epidermal, bronchial and mesothelial cells but absent in colon, ectocervix and liver. Observed throughout the glandular cells in the junction between stomach and esophagus but is absent in the esophagus.
Heterotetramer of two type I and two type II keratins. Interacts with eukaryotic translation initiator factor 3 (eIF3) subunit EIF3S10. Interacts with GPER1.
Expressed in circumvallate papillae and testis (PubMed:16720576). Expressed in the retina. Isoform 1 is predominantly present in mature optic cups. Isoform 1 expression is confined to the cell body and inner segment of developing rod photoreceptor cells (PubMed:27889058).
Interacts with STX3 (By similarity). Interacts with clathrin (By similarity).
Required for correct function and survival of retinal photoreceptors (PubMed:27889058). Required for retinal development (By similarity). In rod photoreceptors, facilitates stability and/or trafficking of guanylate cyclases and is required to maintain endoplasmic reticulum and mitochondrial homeostasis (By similarity). May play a role in clathrin-coated intracellular vesicle trafficking of proteins from the endoplasmic reticulum to the retinal rod plasma membrane (By similarity).
Associates with Ikaros at centromeric heterochromatin.
Belongs to the Ikaros C2H2-type zinc-finger protein family.
Component of the pre-catalytic and catalytic spliceosome complexes (PubMed:11991638, PubMed:28502770, PubMed:28076346, PubMed:29361316, PubMed:29360106, PubMed:29301961). Component of the postcatalytic spliceosome P complex (PubMed:30705154). Interacts with PPIL1; this interaction leads to CDC40 isomerization (PubMed:33220177).
Required for pre-mRNA splicing as component of the activated spliceosome (PubMed:33220177). Plays an important role in embryonic brain development; this function does not require proline isomerization (PubMed:33220177).
Undergoes isomerization of the peptide bond between Gly-94 and Pro-95. The reaction is catalyzed by PPIL1.
Belongs to the ZP domain family. ZPB subfamily.
Component of the zona pellucida, an extracellular matrix surrounding oocytes which mediates sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy. The zona pellucida is composed of 3 to 4 glycoproteins, ZP1, ZP2, ZP3, and ZP4. ZP1 ensures the structural integrity of the zona pellucida.
Expressed in oocytes (at protein level).
Polymers of ZP2 and ZP3 organized into long filaments cross-linked by ZP1 homodimers (By similarity). Interacts with ZP3 (PubMed:28886344).
Proteolytically cleaved before the transmembrane segment to yield the secreted ectodomain incorporated in the zona pellucida.
The ZP domain is involved in the polymerization of the ZP proteins to form the zona pellucida.
By 12-O-tetradecanoylphorbol-13-acetate (TPA) in myeloid leukemia cells.
Histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code (PubMed:17825402, PubMed:17851529, PubMed:17713478, PubMed:18003914). Demethylates trimethylated and dimethylated H3 'Lys-27' (PubMed:17825402, PubMed:17851529, PubMed:17713478, PubMed:18003914). Plays a central role in regulation of posterior development, by regulating HOX gene expression (PubMed:17851529). Involved in inflammatory response by participating in macrophage differentiation in case of inflammation by regulating gene expression and macrophage differentiation (PubMed:17825402). Plays a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression by acting as a link between T-box factors and the SMARCA4-containing SWI/SNF remodeling complex (By similarity).
Interacts with TLE1 (By similarity). Component of the MLL4 complex, at least composed of KMT2B/MLL4, ASH2L, RBBP5, WDR5, and KDM6B (PubMed:17825402). Interacts with TBX21, SMARCA4, SMARCC1 and SMARCC2 (By similarity).
Involved in efficient integration of the N-module into mitochondrial respiratory chain complex I.
(Microbial infection) Interacts with HIV-1 Gag polyprotein p55.
(Microbial infection) Was initially reported to enhance infectivity of retroviruses, such as HIV-1, by stabilizing the capsid of retroviruses (PubMed:20573829, PubMed:24554657). However, it was later shown that PDZD8 is not absolutely required for HIV-1 infection, suggesting that its role in retroviral infection is probably indirect (PubMed:25771112).
Molecular tethering protein that connects endoplasmic reticulum and mitochondria membranes (PubMed:29097544). PDZD8-dependent endoplasmic reticulum-mitochondria membrane tethering is essential for endoplasmic reticulum-mitochondria Ca(2+) transfer (PubMed:29097544). In neurons, involved in the regulation of dendritic Ca(2+) dynamics by regulating mitochondrial Ca(2+) uptake in neurons (PubMed:29097544). Plays an indirect role in the regulation of cell morphology and cytoskeletal organization (PubMed:21834987). May inhibit herpes simplex virus 1 infection at an early stage (PubMed:21549406).
The SMP-LTD domain is a barrel-like domain that binds phospholipids.
RAB2B effector protein required for the compacted Golgi morphology, probably through interaction with small GTPase RAB2B.
Belongs to the ATP:guanido phosphotransferase family.
Dimer of identical or non-identical chains, which can be either B (brain type) or M (muscle type). With MM being the major form in skeletal muscle and myocardium, MB existing in myocardium, and BB existing in many tissues, especially brain.
Reversibly catalyzes the transfer of phosphate between ATP and various phosphogens (e.g. creatine phosphate). Creatine kinase isoenzymes play a central role in energy transduction in tissues with large, fluctuating energy demands, such as skeletal muscle, heart, brain and spermatozoa.
Belongs to the endothelin/sarafotoxin family.
EDN1 genetic variants may influence high density lipoprotein cholesterol (HDLC) levels in some populations and in a sex-specific manner, defining the high density lipoprotein cholesterol level quantitative trait locus 7 (HDLCQ7) [MIM:618979].
Endothelins are endothelium-derived vasoconstrictor peptides (By similarity). Probable ligand for G-protein coupled receptors EDNRA and EDNRB which activates PTK2B, BCAR1, BCAR3 and, GTPases RAP1 and RHOA cascade in glomerular mesangial cells (PubMed:19086031). Also binds the DEAR/FBXW7-AS1 receptor (PubMed:17446437).
Expressed in lung, placental stem villi vessels and in cultured placental vascular smooth muscle cells.
ACTH and MSH are produced by the pituitary gland.
Anorexigenic peptide. Increases the pigmentation of skin by increasing melanin production in melanocytes.
Increases the pigmentation of skin by increasing melanin production in melanocytes.
O-glycosylated; reducing sugar is probably N-acetylgalactosamine.
Stimulates the adrenal glands to release cortisol.
(Microbial infection) Interacts with human cytomegalovirus protein UL135.
Consists of an N-terminal FERM domain linked via a short unstructured region to a large flexible C-terminal rod which contains 13 amphipathic helical bundles (R1-R13). The rod begins with a five-helix bundle (R1) followed by three four-helix bundles (R2-R4). These are followed by a series of eight five-helix bundles (R5-R7 and R9-R13) in which the N- and C-termini are positioned at opposite ends of the bundle, creating a linear chain. The four-helix bundle R8 does not disrupt the chain because it is inserted into a loop in the R7 five-helix bundle. The uneven distribution of four- and five-helix bundles creates two distinctly different zones: a compact N-terminal region sensitive to stretch and a linear C-terminal region that is optimal for force transmission.
Expressed at low to non-detectable levels in many tissues but highly expressed in skin and pancreas with other tissues including kidney cortex, endocervix, testis, pituitary, liver, and spleen also showing robust expression.
Expression in cancer cells is associated with altered drug responses. Cells show increased sensitivity to EGFR inhibitors but are resistant to drugs targeting PI3K signaling and cytoskeleton regulation.
High molecular weight cytoskeletal protein concentrated at regions of cell-substratum contact and, in lymphocytes, at cell-cell contacts (By similarity). Involved in connections of major cytoskeletal structures to the plasma membrane (By similarity).
Interacts with VCL; shows enhanced VCL binding compared to isoform 1 (PubMed:36880935). Interacts with APBB1IP; shows similar level of binding compared to isoform 1 (PubMed:36880935).
Interacts with VCL; shows reduced VCL binding compared to isoform 2 (PubMed:36880935). Interacts with APBB1IP; shows similar level of binding compared to isoform 2 (PubMed:36880935).
Part of a complex composed of THSD1, PTK2/FAK1, TLN1 and VCL (PubMed:29069646). Interacts with THSD1 (PubMed:27895300, PubMed:29069646); this promotes interaction with PTK2/FAK1 and VCL. Binds with high affinity to VCL and with low affinity to integrins (PubMed:15070891). Interacts with APBB1IP; this inhibits VCL binding. Interacts with PTK2/FAK1 (By similarity). Interacts with PIP5K1C and NRAP (PubMed:10320340, PubMed:12422220). Interacts with LAYN (By similarity). Interacts with SYNM (PubMed:18342854). Interacts with ITGB1; the interaction is prevented by competitive binding of ITGB1BP1 (PubMed:21768292, PubMed:12473654).
Shows reduced mechanical stability compared to isoform 1 (PubMed:36880935). Shows altered focal adhesion formation compared to isoform 1 with cells having a greater number of small adhesions compared to those expressing isoform 1 (PubMed:36880935).
Involved in the lipid remodeling steps of GPI-anchor maturation. Required for stable expression of GPI-anchored proteins at the cell surface.
This isoform is predicted to contain an additional transmembrane domain at position 85-105. If this domain exists, the topology of the protein would be modified, possibly challenging the GPI-anchor remodeling function of the protein.
Ubiquitously expressed, with highest levels in testis and pancreas.
Heterochromatin protein that acts as a transcription repressor and has the ability to promote the formation of large heterochromatic domains. May act by recruiting heterochromatin proteins such as CBX5 (HP1 alpha), HDAC5 and MBD1. Represses IGF2 expression by binding to its CpG-rich P3 promoter and recruiting heterochromatin proteins. At specific stages of Listeria infection, in complex with TRIM28, corepresses interferon-stimulated genes, including IFNL1, IFNL2 and IFNL3.
Interacts with CBX5 (HP1 alpha), HDAC5, MBD1 and SP1. Forms a transcription silencing complex with at least CBX3 (HP1 gamma), HDAC1, HDAC2 and TRIM28. Interacts with L.monocytogenes LntA; this interaction, occurring at a late Listeria infection stage, relieves transcription repression, mostly that of interferon-stimulated genes. Interacts with FBXO11 (PubMed:33156908).
The BAH domain is required for localization at H3K27me3.
Ubiquitinated in a FBXO11-dependent manner; leading to degradation.
Expressed in fetal ovaries (PubMed:26742488). Expressed in testis (PubMed:28380054).
Expression first detected in wpf (week post-fertilization) 11 and is highest in wpf 22.
Interacts with YTHDC2; binds transcript that regulate the mitotic cell cycle inhibiting progression into metaphase, thereby allowing meiotic prophase to proceed normally. Interacts with RBM46.
Is required for meiosis completion in both male and female germ cells. Confers stability to numerous meiotic mRNAs in gonads allowing proper initiation and progression into meiosis prophase I. The function may involve YTHDC2 and is independent of induction by retinoic acid (RA). Maintains an extended meiotic prophase I by properly promoting the transition from a mitotic to a meiotic cell cycle program by binding transcripts through its interaction with YTHDC2 that regulate the mitotic cell cycle.
(Microbial infection) Acts as a receptor for human cytomegalovirus pentamer-dependent entry in epithelial and endothelial cells.
(Microbial infection) Interacts with human cytomegalovirus proteins gL, UL128, UL130 and UL131A.
High affinity receptor for semaphorins 3C, 3F, VEGF-165 and VEGF-145 isoforms of VEGF, and the PLGF-2 isoform of PGF.
The tandem CUB domains mediate binding to semaphorin, while the tandem F5/8 domains are responsible for heparin and VEGF binding.
A splice site deletion resulting in a five amino acid in-frame insertion in SARS1, is associated with autosomal dominant complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly.
Belongs to the class-II aminoacyl-tRNA synthetase family. Type-1 seryl-tRNA synthetase subfamily.
Catalyzes the attachment of serine to tRNA(Ser) in a two-step reaction: serine is first activated by ATP to form Ser-AMP and then transferred to the acceptor end of tRNA(Ser) (PubMed:22353712, PubMed:24095058, PubMed:9431993, PubMed:26433229, PubMed:28236339, PubMed:34570399, PubMed:36041817). Is probably also able to aminoacylate tRNA(Sec) with serine, to form the misacylated tRNA L-seryl-tRNA(Sec), which will be further converted into selenocysteinyl-tRNA(Sec) (PubMed:9431993, PubMed:26433229, PubMed:28236339, PubMed:34570399). In the nucleus, binds to the VEGFA core promoter and prevents MYC binding and transcriptional activation by MYC (PubMed:24940000). Recruits SIRT2 to the VEGFA promoter, promoting deacetylation of histone H4 at 'Lys-16' (H4K16). Thereby, inhibits the production of VEGFA and sprouting angiogenesis mediated by VEGFA (PubMed:19423848, PubMed:19423847, PubMed:24940000).
Consists of two distinct domains, a catalytic core and a N-terminal extension that is involved in tRNA binding.
Homodimer (PubMed:22353712, PubMed:26433229). The tRNA molecule may bind across the dimer (PubMed:26433229). Interacts with SIRT2 (PubMed:24940000). Interacts with METTL6; interaction is required for the tRNA N(3)-methylcytidine methyltransferase activity of METTL6 (PubMed:28655767, PubMed:34268557).
Although CCL17 was shown to bind to CCR8, additional studies demonstrated that CCR4, not CCR8, was the bona fide CCL17 receptor.
Chemokine, which displays chemotactic activity for T lymphocytes, preferentially Th2 cells, but not monocytes or granulocytes. Therefore plays an important role in a wide range of inflammatory and immunological processes (PubMed:8702936, PubMed:9169480). Acts by binding to CCR4 at T-cell surface (PubMed:9169480, PubMed:10540332). Mediates GM-CSF/CSF2-driven pain and inflammation (PubMed:27525438). In the brain, required to maintain the typical, highly branched morphology of hippocampal microglia under homeostatic conditions. May be important for the appropriate adaptation of microglial morphology and synaptic plasticity to acute lipopolysaccharide (LPS)-induced neuroinflammation (By similarity). Plays a role in wound healing, mainly by inducing fibroblast migration into the wound (By similarity).
Constitutively expressed in thymus. Detected at lower levels in the lung, colon and small intestine (PubMed:8702936). Expressed in stimulated peripheral blood mononuclear cells, but not in resting cells (PubMed:8702936).
In monocytes, up-regulated by IL4 and by GM-CSF/CSF2 in an IRF4-dependent manner (at protein level).
Was originally thought to be a ligand for CCR8.
It is uncertain whether Met-1 or Met-19 is the initiator.
Belongs to the cytochrome c oxidase VIIb family.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro able to promote polyubiquitination using all 7 ubiquitin Lys residues, but may prefer 'Lys-11' and 'Lys-48'-linked polyubiquitination.
Autoantibodies against RPP38 are found in sera from scleroderma patients.
Component of nuclear RNase P and RNase MRP ribonucleoproteins (PubMed:9037013, PubMed:10444065, PubMed:9630247, PubMed:16723659, PubMed:30454648). RNase P consists of a catalytic RNA moiety and about 10 protein subunits; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40 (PubMed:9037013, PubMed:9630247, PubMed:10444065, PubMed:16723659, PubMed:30454648). Within the RNase P complex, POP1, POP7 and RPP25 form the 'finger' subcomplex, POP5, RPP14, RPP40 and homodimeric RPP30 form the 'palm' subcomplex, and RPP21, POP4 and RPP38 form the 'wrist' subcomplex. All subunits of the RNase P complex interact with the catalytic RNA (PubMed:30454648). Several subunits of RNase P are also part of the RNase MRP complex. RNase MRP consists of a catalytic RNA moiety and about 8 protein subunits; POP1, POP7, RPP25, RPP30, RPP38, RPP40 and possibly also POP4 and POP5 (PubMed:16723659, PubMed:28115465).
Component of ribonuclease P, a ribonucleoprotein complex that generates mature tRNA molecules by cleaving their 5'-ends (PubMed:9037013, PubMed:9630247, PubMed:10444065, PubMed:30454648). Also a component of the MRP ribonuclease complex, which cleaves pre-rRNA sequences (PubMed:28115465).
Belongs to the thymidylate kinase family.
By interferon-alpha (PubMed:30083606). IRF1 is crucial for the transcriptional activation of CMPK2 (PubMed:36930652).
High levels are observed in myeloid, lymphoid and mesenchymal tissues.
Mitochondrial nucleotide monophosphate kinase needed for salvage dNTP synthesis that mediates immunomodulatory and antiviral activities through IFN-dependent and IFN-independent pathways (PubMed:17999954, PubMed:30083606, PubMed:36930652, PubMed:37075076). Restricts the replication of multiple viruses including flaviviruses or coronaviruses (PubMed:30083606, PubMed:36930652, PubMed:37075076). Together with viperin/RSAD2 and ddhCTP, suppresses the replication of several coronaviruses through inhibition of the viral RNA-dependent RNA polymerase activities (PubMed:36930652). Concerning flaviviruses, restricts RNA translation when localized to the mitochondria independently of its kinase activity (PubMed:37075076). Is able to phosphorylate dUMP, dCMP, CMP, UMP and monophosphates of the pyrimidine nucleoside analogs ddC, dFdC, araC, BVDU and FdUrd with ATP as phosphate donor. Efficacy is highest for dUMP followed by dCMP while CMP and UMP are poor substrates. Controls therefore mitochondrial DNA synthesis by supplying required deoxyribonucleotides (By similarity). CMPK2-dependent mitochondrial DNA synthesis is necessary for the production of oxidized mitochondrial DNA fragments after exposure to NLRP3 activators (By similarity). In turn, cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation (By similarity).
LIAT1 proteins of some primates, from macaques to humans, contain tandem repeats of a 10-residue sequence, whereas LIAT1 proteins of other mammals contain a single copy of this motif. Quantities of these repeats are, in general, different in LIAT1 of different primates. For example, there are 1, 4, 13, 13, 17, and 17 repeats in the gibbon, gorilla, orangutan, bonobo, neanderthal, and human LIAT1, respectively.
Participates in nucleolar liquid-liquid phase separation (LLPS) through its N-terminal intrinsically disordered region (IDR). May be involved in ATE1-mediated N-terminal arginylation.
Post-translationally modified by JMJD6 lysyl-hydroxylase activity at its Lys-rich domain, which inhibits its self-association and nucleolar localization.
Self-associates (via Lys-rich domain); targets LIAT1 to the nucleolus. Interacts with ATE1; it is not a substrate of ATE1, the interaction takes place in the cytoplasm and seems to increase ATE1 arginyltransferase activity. Interacts with JMJD6 and MRPS14.
The N-terminal intrinsically disordered region (IDR) facilitates its liquid-liquid phase separation (LLPS) in the nucleolus. In the IDR, the lysine-rich domain mediates self-association and targeting to the nucleolus.
Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6.
Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine) (PubMed:29332244). The elongator complex catalyzes formation of carboxymethyluridine in the wobble base at position 34 in tRNAs (PubMed:22854966, PubMed:29332244). Involved in cell migration (By similarity).
The elongator complex was originally thought to play a role in transcription elongation. However, it is no longer thought to play a direct role in this process and its primary function is thought to be in tRNA modification.
(Microbial infection) Acetylation of Ser-174, Ser-176 and Ser-178 by Yersinia YopJ prevents phosphorylation and activation, thereby promoting cell death.
Autophosphorylated (PubMed:16824733, PubMed:21123652, PubMed:29452636, PubMed:28545134). Phosphorylated at Ser-176, either via autophosphorylation or by LRRK2, enhancing activity (PubMed:16824733, PubMed:27830463). Autophosphorylation at Tyr-474 is required for effective NOD2 signaling (PubMed:21123652). Autophosphorylation is however not essential for NOD2 signaling (PubMed:29452636). Phosphorylation at Tyr-381 by Src kinase CSK occurs in a ARHGEF2-dependent manner and is required for NOD2-dependent innate immune activation (PubMed:21887730).
Contains an N-terminal kinase domain and a C-terminal caspase activation and recruitment domain (CARD) that mediates the recruitment of CARD-containing proteins.
Degraded via selective autophagy following interaction with IRGM (PubMed:36221902). IRGM promotes NOD1/NOD2-RIPK2 RIPosome recruitment to autophagosome membranes (PubMed:36221902). RIPK2 biquitinated via 'Lys-63'-linked chains is then recognized by SQSTM1/p62, leading to the SQSTM1/p62-dependent autophagic degradation of the NOD1/NOD2-RIPK2 RIPosome (PubMed:36221902).
Detected in heart, brain, placenta, lung, peripheral blood leukocytes, spleen, kidney, testis, prostate, pancreas and lymph node.
In the inactive state, the helix alphaC is packed against the helical, non-phosphorylated activation segment (AS) (PubMed:28545134). Upon activation, helix alphaC is displaced and the phosphorylated AS becomes disordered (PubMed:28545134). Specifically inhibited by GSK583, which blocks NOD2 signaling by interfering with XIAP binding to RIPK2 (PubMed:29452636). Specifically inhibited by CSLP37 and CSLP43, which blocks NOD2 signaling by interfering with XIAP binding to RIPK2 (PubMed:30026309).
Interacts (via CARD domain) with NOD2 (via CARD domain) (PubMed:15044951, PubMed:17355968, PubMed:19592251, PubMed:21887730, PubMed:27812135, PubMed:30279485, PubMed:30478312). Interacts (via CARD domain) with NOD1 (via CARD domain) (PubMed:17054981, PubMed:30478312). Homooligomer; following interaction with NOD1 or NOD2, homooligomerizes via its CARD domain and forms long filaments named RIPosomes (PubMed:30279485, PubMed:30478312). Found in a signaling complex consisting of at least ARHGEF2, NOD2 and RIPK2 (PubMed:21887730). Interacts with ARHGEF2; the interaction mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK (PubMed:21887730). Interacts with MAP3K4; this interaction sequesters RIPK2 from the NOD2 signaling pathway (PubMed:18775659). Interacts with IKBKG/NEMO (PubMed:18079694). The polyubiquitinated protein interacts with MAP3K7/TAK1; interaction is indirect and is mediated by TAB2 and TAB3 that bind to polyubiquitin chains attached to RIPK2 (PubMed:18079694). Binds to CFLAR/CLARP and CASP1 via their CARD domains (PubMed:9575181). Binds to BIRC3/c-IAP1 and BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6 (PubMed:21931591). Interacts with NLRP10 (PubMed:22672233). Interacts with CARD9 (By similarity). Interacts with INAVA; the interaction takes place upon PRR stimulation (PubMed:28436939). Interacts (via CARD domain) with NGFR (via death domain) (PubMed:26646181). Interacts with IRGM; promoting RIPK2 degradation (PubMed:36221902).
Polyubiquitinated via both 'Lys-63'- and 'Met-1'-linked polyubiquitin following recruitment by NOD1 or NOD2, creating docking sites for downstream effectors, triggering activation of the NF-kappa-B and MAP kinases signaling (PubMed:22607974, PubMed:29452636, PubMed:30026309). 'Lys-63'-linked polyubiquitination by XIAP is essential for NOD2 signaling and promotes recruitment of the LUBAC complex (PubMed:22607974, PubMed:29452636, PubMed:30026309). Also polyubiquitinated with 'Lys-63'-linked chains by PELI3, BIRC2/c-IAP1 and BIRC3/c-IAP2 (PubMed:19464198, PubMed:21931591). Ubiquitinated on Lys-209 via 'Lys-63'-linked by ITCH (PubMed:18079694, PubMed:19592251). Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to attenuate NOD2-mediated inflammation and tissue damage (By similarity). Polyubiquitinated with 'Lys-63'-linked chains in response to Shigella infection, promoting its SQSTM1/p62-dependent autophagic degradation (PubMed:36221902). Undergoes 'Met-1'-linked polyubiquitination; the head-to-tail linear polyubiquitination is mediated by the LUBAC complex in response to NOD2 stimulation 'Met-1'-linked polyubiquitination (PubMed:23806334). 'Lys-63'-linked polyubiquitination by XIAP is required for recruimtent of the LUBAC complex and subsequent (PubMed:22607974). Linear polyubiquitination is restricted by FAM105B/otulin, probably to limit NOD2-dependent pro-inflammatory signaling activation of NF-kappa-B (PubMed:23806334). Ubiquitination at Lys-503 by ZNRF4 via 'Lys-48'-linked polyubiquitination promotes RIPK2 degradation by the proteasome; ubiquitination by ZNRF4 takes place during both acute and NOD2 tolerance conditions (PubMed:28656966).
Serine/threonine/tyrosine-protein kinase that plays an essential role in modulation of innate and adaptive immune responses (PubMed:9575181, PubMed:9642260, PubMed:14638696, PubMed:21123652, PubMed:17054981, PubMed:28656966). Acts as a key effector of NOD1 and NOD2 signaling pathways: upon activation by bacterial peptidoglycans, NOD1 and NOD2 oligomerize and recruit RIPK2 via CARD-CARD domains, leading to the formation of RIPK2 filaments (PubMed:17562858, PubMed:21123652, PubMed:17054981, PubMed:22607974, PubMed:28656966, PubMed:29452636, PubMed:30026309). Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3, as well as 'Met-1'-linked (linear) polyubiquitination by the LUBAC complex, becoming a scaffolding protein for downstream effectors (PubMed:22607974, PubMed:29452636, PubMed:28545134, PubMed:30279485, PubMed:30478312, PubMed:30026309). 'Met-1'-linked polyubiquitin chains attached to RIPK2 recruit IKBKG/NEMO, which undergoes 'Lys-63'-linked polyubiquitination in a RIPK2-dependent process (PubMed:22607974, PubMed:17562858, PubMed:29452636, PubMed:30026309). 'Lys-63'-linked polyubiquitin chains attached to RIPK2 serve as docking sites for TAB2 and TAB3 and mediate the recruitment of MAP3K7/TAK1 to IKBKG/NEMO, inducing subsequent activation of IKBKB/IKKB (PubMed:18079694). In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis (PubMed:18079694). The protein kinase activity is dispensable for the NOD1 and NOD2 signaling pathways (PubMed:29452636, PubMed:30026309). Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappa-B activation by NOD2 (PubMed:21887730). Also involved in adaptive immunity: plays a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation (PubMed:14638696). Plays a role in the inactivation of RHOA in response to NGFR signaling (PubMed:26646181).
(Microbial infection) Glycosylated at Tyr-32 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rac and leads to actin disassembly.
Expression down-regulated in quiescent fibroblasts and clearly induced by serum stimulation.
Highest levels in brain, also detected in heart, placenta and pancreas.
Interacts with the GEF protein DOCK7, which promotes the exchange between GDP and GTP, and therefore activates it (PubMed:16982419). Interacts with C1D (PubMed:9852280). Interacts (via C-terminal region) with CIB1; the interaction induces their association with the cytoskeleton upon alpha-IIb/beta3 integrin-mediated adhesion (PubMed:11756406). Interacts with NRBP (PubMed:11956649).
Plasma membrane-associated small GTPase which cycles between an active GTP-bound and inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses, such as cell spreading and the formation of actin-based protusions including lamellipodia and membrane ruffles. Promotes cell adhesion and spreading on fibrinogen in a CIB1 and alpha-IIb/beta3 integrin-mediated manner.
Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. Regulated by the GEF protein DOCK7.
Ubiquitinated at Lys-166 in a FBXL19-mediated manner; leading to proteasomal degradation.
A chromosomal aberration involving DCX is found in lissencephaly. Translocation t(X;2)(q22.3;p25.1).
Highly expressed in neuronal cells of fetal brain (in the majority of cells of the cortical plate, intermediate zone and ventricular zone), but not expressed in other fetal tissues. In the adult, highly expressed in the brain frontal lobe, but very low expression in other regions of brain, and not detected in heart, placenta, lung, liver, skeletal muscles, kidney and pancreas.
Interacts with tubulin (PubMed:27292316). Interacts with USP9X (PubMed:24607389).
Microtubule-associated protein required for initial steps of neuronal dispersion and cortex lamination during cerebral cortex development. May act by competing with the putative neuronal protein kinase DCLK1 in binding to a target protein. May in that way participate in a signaling pathway that is crucial for neuronal interaction before and during migration, possibly as part of a calcium ion-dependent signal transduction pathway. May be part with PAFAH1B1/LIS-1 of overlapping, but distinct, signaling pathways that promote neuronal migration.
Phosphorylation by MARK1, MARK2 and PKA regulates its ability to bind microtubules (By similarity). Phosphorylation at Ser-265 and Ser-297 seems to occur only in neonatal brain, the levels falling precipitously by postnatal day 21 (By similarity).
Ubiquitinated by MDM2, leading to its degradation by the proteasome. Ubiquitinated by MDM2 and subsequent degradation leads to reduce the dendritic spine density of olfactory bulb granule cells.
Down-regulated during breast cancer progression.
Expressed in breast, ovary and prostate.
Has a tumor-suppressor role for NES1 in breast and prostate cancer.
Expressed on cortical thymocytes, dendritic cells, Langerhans cells, on certain T-cell leukemias, and in various other tissues.
Heterodimer with B2M (beta-2-microglobulin). The association with B2M appears to be facilitated by the presence of the propeptide.
Proteolytically cleaved in late endosomes to yield a soluble form.
T-cell surface glycoprotein CD1e, soluble binds diacetylated lipids, including phosphatidyl inositides and diacylated sulfoglycolipids, and is required for the presentation of glycolipid antigens on the cell surface. The membrane-associated form is not active.
Cytokine which is the ligand for CD27. The CD70-CD27 pathway plays an important role in the generation and maintenance of T cell immunity, in particular during antiviral responses. Upon CD27 binding, induces the proliferation of costimulated T-cells and enhances the generation of cytolytic T-cells.
It is uncertain whether Met-1 or Met-13 is the initiator.
Disease susceptibility is associated with variants affecting the gene represented in this entry. A risk haplotype spanning SLC16A11 is associated with a 20% increased risk for T2D. The haplotype includes 5 SLC16A11 variants in strong linkage disequilibrium: variants Ile-113, Gly-127, Ser-340, Thr-443 and a silent variant. This risk haplotype probably derives from H.sapiens neanderthalensis (Neanderthal) introgression and is present at 50% frequency in Native-American samples, 10% in east Asian, while it is rare in European and African samples populations. The risk haplotype contains a cis-eQTL that is responsible for reduced SLC16A11 expression in liver (PubMed:28666119).
Expressed in liver, salivary gland and thyroid.
Proton-linked monocarboxylate transporter. It catalyzes the transport of pyruvate across the plasma membrane (PubMed:28666119). Probably involved in hepatic lipid metabolism: overexpression results in an increase of triacylglycerol(TAG) levels, small increases in intracellular diacylglycerols and decreases in lysophosphatidylcholine, cholesterol ester and sphingomyelin lipids (PubMed:24390345).
Forms physiological amyloids that play a central role in melanosome morphogenesis and pigmentation. The maturation of unpigmented premelanosomes from stage I to II is marked by assembly of processed amyloidogenic fragments into parallel fibrillar sheets, which elongate the vesicle into a striated ellipsoidal shape. In pigmented stage III and IV melanosomes, the amyloid matrix serves as a platform where eumelanin precursors accumulate at high local concentrations for pigment formation. May prevent pigmentation-associated toxicity by sequestering toxic reaction intermediates of eumelanin biosynthesis pathway.
Homodimer; disulfide-linked. Dimerization in the endoplasmic reticulum and early Golgi prevents premature fibril formation. The dimers are resolved to monomers in late- or post-Golgi compartments (PubMed:26694611). Heterooligomer; amyloid-type. Processed amyloidogenic fragments assemble into fibrils that further organize into beta-sheet quaternary amyloid structures (PubMed:28272432, PubMed:30988362). Interacts (via luminal C-terminal fragment) with CD63; this is important for sorting of the luminal fragment in tetraspanin rich microdomains in stage I melanosomes to prevent premature lysosomal degradation (PubMed:21962903). Interacts with APOE; this allows the loading of the luminal fragment on ILVs to induce fibril nucleation (PubMed:26387950). Interacts with MLANA (PubMed:15695812).
N- and O-glycosylated. A small amount of P1/P100 (major form) undergoes glycosylation in ER and Golgi compartments to yield P2/P120 (minor form). The mature P2 form leaves the trans-Golgi network and is mainly targeted to stage I melanosomes via the plasma membrane and clathrin-mediated endocytosis. Stage II melanosomes harbor only Golgi-modified fragments that are derived from M-alpha and that bear sialylated O-linked oligosaccharides. O-glycosylation of the RPT region is a conserved feature likely involved in amyloid sheet separation via electrostatic repulsion.
Normally expressed at low levels in quiescent adult melanocytes but overexpressed by proliferating neonatal melanocytes and during tumor growth. Overexpressed in melanomas. Some expression was found in dysplastic nevi.
Represents a potent melanoma-specific antigen. Among melanoma non-mutated self-peptides, G9-154 (KTWGQYWQV), G9-209 (ITDQVPFSV) and G9-280 (YLEPGPVTA), appear to act as immunodominant common epitopes that stimulate anti-tumor immune response mediated by HLA-A-restricted cytotoxic T cells.
The Kringle-like domain (KLD) contains six highly conserved cysteine residues that are critical for dimer formation.
The core amyloid fragment (CAF) represents the amyloidogenic unit of melanosomal fibrils. It is predicted to form a beta-solenoid structure comprising four coil right-handed beta strands with Tyr-151 and Trp-160 residues pi-stacking against each other to confer stability.
The highly O-glycosylated repeat (RPT) domain drives the generation of the fibrillar amyloid sheet structures within melanosomes. The O-glycosylation sites rather than its primary amino acid sequence are conserved across species.
Undergoes multiple proteolytic processing. In a post-Golgi prelysosomal compartment, P2 is cleaved by a furin-like proprotein convertase (PC) into two disulfide-linked subunits: a large lumenal subunit, M-alpha/ME20-S, and an integral membrane subunit, M-beta. Despite cleavage, only a small fraction of M-alpha is secreted, as most M-alpha and M-beta remain associated with each other intracellularly via a disulfide bond (PubMed:12732614, PubMed:11694580, PubMed:15695812, PubMed:15096515, PubMed:17991747). Once targeted to stage I melanosomes, beta-secretase BACE2 cleaves the M-beta fragment to release the amyloidogenic luminal fragment containing M-alpha and a small portion of M-beta N-terminus (PubMed:23754390). M-alpha is further cleaved by metalloproteinases, likely ADAM10 or ADAM17, and still unknown proteases to yield subfragments that ultimately assemble into amyloid fibrils (PubMed:19047044). The C-terminal fragment of M-beta is processed by the gamma-secretase complex to release a short intracytoplasmic domain (PubMed:19047044).
Interacts with RNF10 (PubMed:16335786). Interacts with TCF15 (By similarity).
Mesodermal transcription factor that plays a key role in somitogenesis and somitogenesis and limb muscle differentiation (By similarity). Required during limb development for normal appendicular muscle formation and for the normal regulation of myogenic genes (By similarity). May have a regulatory role when quiescent vascular smooth muscle cells reenter the cell cycle (By similarity). Also acts as a negative regulator of angiogenesis (PubMed:17074759, PubMed:20516212, PubMed:22206000). Activates expression of CDKN1A and CDKN2A in endothelial cells, acting as a regulator of vascular cell proliferation (PubMed:17074759, PubMed:22206000). While it activates CDKN1A in a DNA-dependent manner, it activates CDKN2A in a DNA-independent manner (PubMed:22206000). Together with TCF15, regulates transcription in heart endothelial cells to regulate fatty acid transport across heart endothelial cells (By similarity).
The poly-His region of MEOX2 is polymorphic and the number of His varies in the population.
The polyhistidine repeat may act as a targeting signal to nuclear speckles.
CRB1 mutations have been found in various retinal dystrophies, chronic and disabling disorders of visual function. They predominantly involve the posterior portion of the ocular fundus, due to degeneration in the sensory layer of the retina, retinal pigment epithelium, Bruch membrane, choroid, or a combination of these tissues. Onset of inherited retinal dystrophies is painless, bilateral and typically progressive. Most people experience gradual peripheral vision loss or tunnel vision, and difficulties with poor illumination and night vision. Central vision is usually unaffected, so the person may still be able to read. However, it can also deteriorate to cause total blindness. Examples of retinal dystrophies are retinitis pigmentosa, Leber congenital amaurosis, cone-rod dystrophy among others.
Component of a complex composed of PALS1, CRB1 and EPB41L5 (PubMed:17920587). Within the complex, interacts (via intracellular domain) with PALS1 and EPB41L5 (via FERM domain) (PubMed:17920587). Forms a complex with MPP4 and PALS1 (PubMed:15914641). Interacts with MPDZ/MUPP1 and MPP4 (By similarity).
Expressed in the retinal layer of the optic vesicle, and weakly expressed in the retinal pigment epithelium at 12.5 dpc.
Plays a role in photoreceptor morphogenesis in the retina (By similarity). May maintain cell polarization and adhesion (By similarity).
Preferential expression in retina, also expressed in brain, testis, fetal brain and fetal eye (PubMed:15914641). Expressed at the outer limiting membrane and apical to adherens junctions in the retina (PubMed:15914641).
Heterotetramer with CBR4; contains two molecules of HSD17B8 and CBR4.
Required for the solubility and assembly of the heterotetramer 3-ketoacyl-[acyl carrier protein] (ACP) reductase functional complex (KAR or KAR1) that forms part of the mitochondrial fatty acid synthase (mtFAS). Alpha-subunit of the KAR complex that acts as a scaffold protein required for the stability of carbonyl reductase type-4 (CBR4, beta-subunit of the KAR complex) and for its 3-ketoacyl-ACP reductase activity, thereby participating in mitochondrial fatty acid biosynthesis. Catalyzes the NAD-dependent conversion of (3R)-3-hydroxyacyl-CoA into 3-ketoacyl-CoA (3-oxoacyl-CoA) with no chain length preference; this enzymatic activity is not needed for the KAR function (PubMed:19571038, PubMed:25203508, PubMed:30508570). Prefers (3R)-3-hydroxyacyl-CoA over (3S)-3-hydroxyacyl-CoA and displays enzymatic activity only in the presence of NAD(+) (PubMed:19571038). Cooperates with enoyl-CoA hydratase 1 in mitochondria, together they constitute an alternative route to the auxiliary enzyme pathways for the breakdown of Z-PUFA (cis polyunsaturated fatty acid) enoyl-esters (Probable) (PubMed:30508570). NAD-dependent 17-beta-hydroxysteroid dehydrogenase with highest activity towards estradiol (17beta-estradiol or E2). Has very low activity towards testosterone and dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one). Primarily an oxidative enzyme, it can switch to a reductive mode determined in the appropriate physiologic milieu and catalyze the reduction of estrone (E1) to form biologically active 17beta-estradiol (PubMed:17978863).
The fatty acyl-CoA dehydrogenase activity is several thousand times higher than the estradiol and testosterone 17beta-hydroxysteroid dehydrogenase conversion.
Widely expressed, particularly abundant in prostate, placenta and kidney (PubMed:17978863). Expressed at protein level in various tissues like brain, cerebellum, heart, lung, kidney, ovary, testis, adrenals and prostate (PubMed:30508570).
Belongs to the RNA polymerase II subunit 5-mediating protein family.
Homodimer. Component of the PAQosome complex which is responsible for the biogenesis of several protein complexes and which consists of R2TP complex members RUVBL1, RUVBL2, RPAP3 and PIH1D1, URI complex members PFDN2, PFDN6, PDRG1, UXT and URI1 as well as ASDURF, POLR2E and DNAAF10/WDR92 (PubMed:31738558). Interacts with POLR2E/RPB5, RUVBL2 and RUVBL1 (PubMed:14615539, PubMed:9819440). Interacts with PFDN2, PFDN4 and STAP1; the interactions are phosphorylation-dependent and occur in a growth-dependent manner in the mitochondrion (PubMed:14615539). Interacts with UXT (PubMed:21730289). Interacts with PPP1CC; the interaction is phosphorylation-dependent and occurs in a growth factor-dependent manner (PubMed:21397856). Interacts (via the middle C-terminal region) with GTF2F1 and GTF2F2 (PubMed:12737519). Interacts with DMAP1 (PubMed:15367675). Interacts with TSC1 and TSC2 (PubMed:28561026). Interacts with PRPF8 and EFTUD2 in a ZNHIT2-dependent manner (PubMed:28561026).
Involved in gene transcription regulation. Acts as a transcriptional repressor in concert with the corepressor UXT to regulate androgen receptor (AR) transcription. May act as a tumor suppressor to repress AR-mediated gene transcription and to inhibit anchorage-independent growth in prostate cancer cells. Required for cell survival in ovarian cancer cells. Together with UXT, associates with chromatin to the NKX3-1 promoter region. Antagonizes transcriptional modulation via hepatitis B virus X protein.
Phosphorylated. Phosphorylation occurs essentially on serine residues. Phosphorylation occurs in response to androgen treatment in prostate cancer cells in a mTOR-dependent manner. Phosphorylated; hyperhosphorylated in mitochondria in a mTORC-dependent signaling pathway. Phosphorylated at Ser-372 by RPS6KB1 in a growth factor- and rapamycin-dependent manner. S6K1-mediated mitochondrial phosphorylation at Ser-372 disrupts the URI1-PPP1CC complex in the mitochondrion, relieves PPP1CC phosphatase inhibition activity and hence engages a negative feedback diminishing RPS6KB1 kinase activity, preventing sustained S6K1-dependent signaling.
Plays a central role in maintaining S6K1 signaling and BAD phosphorylation under normal growth conditions thereby protecting cells from potential deleterious effects of sustained S6K1 signaling. The URI1-PPP1CC complex acts as a central component of a negative feedback mechanism that counteracts excessive S6K1 survival signaling to BAD in response to growth factors. Mediates inhibition of PPP1CC phosphatase activity in mitochondria. Coordinates the regulation of nutrient-sensitive gene expression availability in a mTOR-dependent manner. Seems to be a scaffolding protein able to assemble a prefoldin-like complex that contains PFDs and proteins with roles in transcription and ubiquitination.
Ubiquitous. Expressed in ovarian cancers (at protein level). Expressed strongly in skeletal muscle. Expressed weakly in brain, heart, pancreas and in prostate epithelial cells.
Homooligomer; homooligomerizes to induce formation of the NLRC4 inflammasome (PubMed:25385754, PubMed:33420028). Homooligomerizes following activation by pathogenic proteins (By similarity). Component of the NLRC4 inflammasome, at least composed of NLRC4 and caspase-1 (CASP1) (By similarity). Some NLRC4 inflammasomes contain PYCARD/ASC, while some others directly contact and activate CASP1 (PubMed:25217959). Interacts (via CARD domain) with PYCARD/ASC, pro-caspase-1 (CASP1), NOD2, BCL10 and NALP1 (NAC) by CARD-CARD interaction (PubMed:15107016). Interacts with EIF2AK2/PKR (PubMed:22801494).
In an autoinhibited form the C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. An ADP-mediated interaction between the NBD and the WHD also contributes to the autoinhibition.
Isoform 2 is expressed ubiquitously, although highly expressed in lung and spleen. Isoform 1 is highly expressed in lung, followed by leukocytes especially monocytes, lymph node, colon, brain, prostate, placenta, spleen, bone marrow and fetal liver. Isoform 4 is only detected in brain.
Key component of inflammasomes that indirectly senses specific proteins from pathogenic bacteria and fungi and responds by assembling an inflammasome complex that promotes caspase-1 activation, cytokine production and macrophage pyroptosis (PubMed:15107016). The NLRC4 inflammasome is activated as part of the innate immune response to a range of intracellular bacteria (By similarity).
Phosphorylated at Ser-533 following infection of macrophages with S.typhimurium (Salmonella). Phosphorylation is essential for NLRC4 inflammasome function to promote caspase-1 activation and pyroptosis. PRKCD phosphorylates Ser-533 in vitro.
Expressed predominantly in lymph nodes, spleen, peripheral blood lymphocytes, bone marrow, and fetal liver.
Forms a heteromeric complex with cardiotrophin-like cytokine CRLF1/CLF-1; the CRLF1-CLCF1 complex is a ligand for the ciliary neurotrophic factor receptor/CNTFR (PubMed:26858303). The CRLF1-CLCF1 heterodimer binds SORL1 (via N-terminal ectodomain); within this complex, the interaction is mediated predominantly by the CRLF1 moiety (PubMed:26858303). The tripartite signaling complex formed by CRLF1, CLCF1 and CNTFR also binds SORL1 (PubMed:26858303).
In complex with CRLF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development (Probable). Also stimulates B-cells. Binds to and activates the ILST/gp130 receptor.
Belongs to the protein disulfide isomerase family.
Heterodimer; heterodimerizes with the protein microsomal triglyceride transfer MTTP (PubMed:23475612, PubMed:26224785, PubMed:16478722). Homodimer. Monomers and homotetramers may also occur. Interacts with P4HA2, forming a heterotetramer consisting of 2 alpha subunits (P4HA2) and 2 beta (P4HB), where P4HB plays the role of a structural subunit; this tetramer catalyzes the formation of 4-hydroxyproline in collagen (PubMed:7753822). Also constitutes the structural subunit of the microsomal triacylglycerol transfer protein MTTP in mammalian cells. Stabilizes both enzymes and retain them in the ER without contributing to the catalytic activity (By similarity). Binds UBQLN1 (PubMed:12095988). Interacts with ERO1B (PubMed:11707400). Binds to CD4, and upon HIV-1 binding to the cell membrane, is part of a P4HB/PDI-CD4-CXCR4-gp120 complex. Interacts with ILDR2 (By similarity). Interacts with ERN1/IRE1A (via N-terminus); the interaction is enhanced by phosphorylation of P4HB by FAM20C in response to endoplasmic reticulum stress and results in attenuation of ERN1 activity (PubMed:32149426).
Phosphorylation of Ser-357 by FAM20C is induced by endoplasmic reticulum stress and results in a functional switch from oxidoreductase to molecular chaperone (PubMed:32149426). It also promotes interaction with ERN1 (PubMed:32149426).
Reduces and may activate fusogenic properties of HIV-1 gp120 surface protein, thereby enabling HIV-1 entry into the cell.
This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. May therefore cause structural modifications of exofacial proteins. Inside the cell, seems to form/rearrange disulfide bonds of nascent proteins. At high concentrations and following phosphorylation by FAM20C, functions as a chaperone that inhibits aggregation of misfolded proteins (PubMed:32149426). At low concentrations, facilitates aggregation (anti-chaperone activity). May be involved with other chaperones in the structural modification of the TG precursor in hormone biogenesis. Also acts as a structural subunit of various enzymes such as prolyl 4-hydroxylase and microsomal triacylglycerol transfer protein MTTP. Receptor for LGALS9; the interaction retains P4HB at the cell surface of Th2 T helper cells, increasing disulfide reductase activity at the plasma membrane, altering the plasma membrane redox state and enhancing cell migration (PubMed:21670307).
ADP-ribosylated on Ser-188 in response to DNA damage.
Citrullination at Arg-54 (H1R54ci) by PADI4 takes place within the DNA-binding site of H1 and results in its displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance.
H1 histones are progressively phosphorylated during the cell cycle, becoming maximally phosphorylated during late G2 phase and M phase, and being dephosphorylated sharply thereafter.
Histone H1 protein binds to linker DNA between nucleosomes forming the macromolecular structure known as the chromatin fiber. Histones H1 are necessary for the condensation of nucleosome chains into higher-order structured fibers. Acts also as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing and DNA methylation (By similarity).
Interacts with TSC22D1 isoforms 2 and 5.
The C-terminal domain is required for high-affinity binding to chromatin.
Has E3 ubiquitin-protein ligase activity.
Activated by Ca(2+)/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows autophosphorylation of Thr-287 which turns the kinase in a constitutively active form and confers to the kinase a Ca(2+)-independent activity.
Activity is induced in skeletal muscle during exercise.
Autophosphorylation of Thr-287 following activation by Ca(2+)/calmodulin. Phosphorylation of Thr-287 locks the kinase into an activated state.
CAMK2 is composed of 4 different chains: alpha (CAMK2A), beta (CAMK2B), gamma (CAMK2G), and delta (CAMK2D). The different isoforms assemble into homo- or heteromultimeric holoenzymes composed of 12 subunits with two hexameric rings stacked one on top of the other (PubMed:14722083). Interacts with RRAD and CACNB2 (By similarity).
Calcium/calmodulin-dependent protein kinase involved in the regulation of Ca(2+) homeostatis and excitation-contraction coupling (ECC) in heart by targeting ion channels, transporters and accessory proteins involved in Ca(2+) influx into the myocyte, Ca(2+) release from the sarcoplasmic reticulum (SR), SR Ca(2+) uptake and Na(+) and K(+) channel transport. Targets also transcription factors and signaling molecules to regulate heart function. In its activated form, is involved in the pathogenesis of dilated cardiomyopathy and heart failure. Contributes to cardiac decompensation and heart failure by regulating SR Ca(2+) release via direct phosphorylation of RYR2 Ca(2+) channel on 'Ser-2808'. In the nucleus, phosphorylates the MEF2 repressor HDAC4, promoting its nuclear export and binding to 14-3-3 protein, and expression of MEF2 and genes involved in the hypertrophic program (PubMed:17179159). Is essential for left ventricular remodeling responses to myocardial infarction. In pathological myocardial remodeling acts downstream of the beta adrenergic receptor signaling cascade to regulate key proteins involved in ECC. Regulates Ca(2+) influx to myocytes by binding and phosphorylating the L-type Ca(2+) channel subunit beta-2 CACNB2. In addition to Ca(2+) channels, can target and regulate the cardiac sarcolemmal Na(+) channel Nav1.5/SCN5A and the K+ channel Kv4.3/KCND3, which contribute to arrhythmogenesis in heart failure. Phosphorylates phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2, contributing to the enhancement of SR Ca(2+) uptake that may be important in frequency-dependent acceleration of relaxation (FDAR) and maintenance of contractile function during acidosis (PubMed:16690701). May participate in the modulation of skeletal muscle function in response to exercise, by regulating SR Ca(2+) transport through phosphorylation of PLN/PLB and triadin, a ryanodine receptor-coupling factor. In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of STAT1, stimulating the JAK-STAT signaling pathway (By similarity).
Expressed in cardiac muscle and skeletal muscle. Isoform Delta 3, isoform Delta 2, isoform Delta 8 and isoform Delta 9 are expressed in cardiac muscle. Isoform Delta 11 is expressed in skeletal muscle.
Expression of CAMK2D is significantly increased in patients suffering from dilated cardiomyopathy in PubMed:10189359.
The CAMK2 protein kinases contain a unique C-terminal subunit association domain responsible for oligomerization.
A protein of the expected size has been detected by antibody binding and Western blot in at least one of the analyzed tissues or cells.
Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3. Interacts with CLDN4. Interacts with KLHL3.
Expressed in the epididymis, mainly in the caput segment.
Tight-junction protein required for paracellular chloride transport in the kidney. Mediates recruitment of CLDN4 to tight junction in the kidney. Claudins play a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.
Ubiquitinated by the BCR(KLHL3) E3 ubiquitin ligase complex in the kidney, leading to its degradation.
Expressed in brain, lung, liver, and kidney.
Expressed in prostate, ovary, stomach, pancreas, esophagus, breast, liver, bladder, kidney, thyroid, colon and lung (at protein level). Down-regulated in multiple primary tumors (at protein level). Detected in testis, heart, skeletal muscle, thymus, spleen, small intestine, and peripheral blood leukocytes.
Regulates ciliary localization of the BBSome complex. Together with the BBSome complex, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. May play a role in neurite outgrowth. May have tumor suppressor function.
Self-associates. Interacts with BBS9; the interaction mediates the association of LZTL1 with the BBsome complex and regulates BBSome ciliary trafficking.
The disease is caused by variants affecting the gene represented in this entry. Patients carrying LZTFL1 mutations manifest mesoaxial polydactyly, a clinical feature very uncommon for Bardet-Biedl syndrome (PubMed:22510444, PubMed:23692385). Some patients manifest situs inversus (PubMed:22510444).
Highest expression in heart, placenta, liver, pancreas and colon. Also detected in brain, lung, skeletal muscle, kidney, spleen, prostate, testis, ovary and small intestine. Lowest expression in thymus and leukocytes.
Belongs to the steroid 5-alpha reductase family.
Converts testosterone (T) into 5-alpha-dihydrotestosterone (DHT) and progesterone or corticosterone into their corresponding 5-alpha-3-oxosteroids. It plays a central role in sexual differentiation and androgen physiology.
Expressed in high levels in the prostate and many other androgen-sensitive tissues.
Individuals with Thr-49 have an increased risk of prostate cancer (PubMed:10501358). The enzyme with Thr-49 has a higher in vitro V(max) than the Ala-49 enzyme (PubMed:10501358).
Expressed at high levels in the heart and skeletal muscle. Expressed at low levels in kidney, small intestine, lung and liver.
Interacts with isoform 1 and isoform 3 of BSCL2/seipin to form an oligomeric complex.
Plays an important role in the formation of lipid droplets (LD) which are storage organelles at the center of lipid and energy homeostasis (PubMed:31708432). In association with BSCL2/seipin, defines the sites of LD formation in the endoplasmic reticulum (PubMed:31708432).
Highest expression in adult heart, followed by pancreas, skeletal muscle, brain, testis, retina, liver, kidney, lung and placenta. Present in most primary carcinomas.
Protein kinase that seems to act exclusively upon threonine residues (By similarity). Required for normal entry into proliferative arrest after a limited number of cell divisions, also called replicative senescence. Required for normal cell cycle arrest in response to double-stranded DNA damage.
Expressed in ovarian epithelium (NOE) and breast tissue. Expressed in ovarian cancer; expression is increased relative to NOE cells. Expression in ovarian cancer is stage dependent, with stage III and stage IV showing higher levels than early stage cancers. Expressed in breast cancer; expression is increased relative to normal breast tissue.
Interacts with RAB11FIP1, RAB11FIP2, RAB11FIP3 and RAB11FIP4. Interacts (via the hypervariable C-terminal region) with ITGB1 (via the cytoplasmic region); the interaction is GTP-dependent. Interacts with ITGAV. Associates with the integrin alpha-V/beta-1 heterodimer. Interacts with VPS33B (PubMed:28017832).
Involved in the regulation of cell survival. Promotes invasive migration of cells in which it functions to localize and maintain integrin alpha-V/beta-1 at the tips of extending pseudopodia (PubMed:17925226). Involved in the regulation of epithelial morphogenesis through the control of CLDN4 expression and localization at tight junctions (By similarity). May selectively regulate the apical recycling pathway. Together with MYO5B regulates transcytosis (By similarity).
Essential ion channel and serine/threonine-protein kinase. Crucial for magnesium homeostasis. Has an important role in epithelial magnesium transport and in the active magnesium absorption in the gut and kidney. Isoforms of the type M6-kinase lack the ion channel region.
Forms heterodimers with TRPM7. TRPM6 requires the presence of TRPM7 to be targeted to the cell membrane (in HEK 293 cells). Interacts (via kinase domain) with RACK1.
Highly expressed in kidney and colon. Isoform TRPM6a and isoform TRPM6b, are coexpressed with TRPM7 in kidney, and testis, and are also found in several cell lines of lung origin. Isoform TRPM6c is detected only in testis and in NCI-H510A small cell lung carcinoma cells.
In the C-terminal section; belongs to the protein kinase superfamily. Alpha-type protein kinase family. ALPK subfamily.
In the N-terminal section; belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM6 sub-subfamily.
Elastase that enhances insulin signaling and might have a physiologic role in cellular glucose metabolism. Circulates in plasma and reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity.
Expressed in pancreas. Not detected in keratinocytes (PubMed:10620133). Detected in exocrine secretions of the pancreas (at protein level). Also expressed in a small fraction of cells in pancreatic islets, adrenal cortex, intestinal glands and colonic lymphoid follicles (at protein level) (PubMed:31358993). Detected in plasma (PubMed:31358993).
Interacts with CPA1. Interacts with SERPINA1 (PubMed:31358993).
Interacts with MAPK8 (By similarity). Interacts with ITM2C. Interacts with KIFBP. Interacts (via the N-terminal region) with CIB1 (via C-terminal region); the interaction is direct, occurs in a calcium-dependent manner and attenuates the neurite outgrowth inhibition of STMN2.
Phosphorylated mostly by MAPK8, but also by MAPK9 and MAPK10 in the developing brain cortex.
Regulator of microtubule stability. When phosphorylated by MAPK8, stabilizes microtubules and consequently controls neurite length in cortical neurons. In the developing brain, negatively regulates the rate of exit from multipolar stage and retards radial migration from the ventricular zone (By similarity).
Belongs to the mitochondrial Rho GTPase family.
Interacts with the kinesin-binding proteins TRAK1/OIP106 and TRAK2/GRIF1, forming a link between mitochondria and the trafficking apparatus of the microtubules (PubMed:16630562). Interacts with ARMCX3 (By similarity). Found in a complex with KIF5B, OGT, RHOT1 and TRAK1 (PubMed:24995978).
Mitochondrial GTPase involved in mitochondrial trafficking (PubMed:16630562, PubMed:22396657). Probably involved in control of anterograde transport of mitochondria and their subcellular distribution (PubMed:22396657).
Ubiquitinated by PRKN in a PINK1-dependent manner, leading to its degradation.
Ubiquitously expressed. Highly expressed in heart, liver, skeletal muscle, kidney and pancreas.
Belongs to the UDP-glucose/GDP-mannose dehydrogenase family.
Catalyzes the formation of UDP-alpha-D-glucuronate, a constituent of complex glycosaminoglycans (PubMed:21961565, PubMed:21502315, PubMed:23106432, PubMed:22123821, PubMed:25478983, PubMed:27966912, PubMed:30420606, PubMed:30457329). Required for the biosynthesis of chondroitin sulfate and heparan sulfate. Required for embryonic development via its role in the biosynthesis of glycosaminoglycans (By similarity). Required for proper brain and neuronal development (PubMed:32001716).
Detected in heart, placenta, liver, pancreas, spleen, thymus, prostate, ovary, small intestine and colon (PubMed:9737970). Widely expressed (PubMed:9737970).
The allosteric switch region moves by about 5 Angstroms when UDP-xylose is bound, and occupies part of the UDP-glucose binding site. At the same time it promotes domain movements that disrupt the active hexameric ring structure and lead to the formation of a horseshoe-shaped, inactive hexamer.
The protein goes through several conformation states during the reaction cycle, giving rise to hysteresis. In the initial state, the ligand-free protein is in an inactive conformation (E*). Substrate binding triggers a change to the active conformation (E). UDP-xylose binding triggers the transition to a distinct, inhibited conformation. The presence of an intrinsically disordered C-terminus promotes a more dynamic protein structure and favors a conformation with high affinity for UPD-xylose.
UDP-alpha-D-xylose (UDX) acts as a feedback inhibitor. It binds at the same site as the substrate, but functions as allosteric inhibitor by triggering a conformation change that disrupts the active hexameric ring structure and gives rise to an inactive, horseshoe-shaped hexamer.
Homodimer (By similarity). Forms a heterodimer with PFKFB3 (PubMed:36402789).
In the C-terminal section; belongs to the phosphoglycerate mutase family.
Phosphorylation by AMPK stimulates activity.
Phosphorylation results in the activation of the kinase activity.
Synthesis and degradation of fructose 2,6-bisphosphate.
Belongs to the MINDY deubiquitinase family. FAM188 subfamily.
Hydrolase that can remove 'Lys-48'-linked conjugated ubiquitin from proteins.
Was named CARP for 'CARD domain-containing protein' by PubMed:12054670. However, no CARD domain is detected by any prediction tool.
Widely expressed with high levels in heart, skeletal muscle, and kidney, and low levels in liver and brain (PubMed:12054670). Also expressed in lung (at protein level) (PubMed:21499297).
Interacts with DPPA2 (By similarity). Interacts with PCGF1 (PubMed:26687479).
May be involved in the maintenance of active epigenetic status of target genes. May inhibit differentiation of embryonic cells into a primitive ectoderm lineage.
Glutathione-dependent oxidoreductase that facilitates the maintenance of mitochondrial redox homeostasis upon induction of apoptosis by oxidative stress. Involved in response to hydrogen peroxide and regulation of apoptosis caused by oxidative stress. Acts as a very efficient catalyst of monothiol reactions because of its high affinity for protein glutathione-mixed disulfides. Can receive electrons not only from glutathione (GSH), but also from thioredoxin reductase supporting both monothiol and dithiol reactions. Efficiently catalyzes both glutathionylation and deglutathionylation of mitochondrial complex I, which in turn regulates the superoxide production by the complex. Overexpression decreases the susceptibility to apoptosis and prevents loss of cardiolipin and cytochrome c release.
Monomer; active form. Homodimer; inactive form. The homodimer is probably linked by 1 2Fe-2S cluster.
The 2Fe-2S present in the homodimer leads to inactivation of the enzyme. The 2Fe-2S may serve as a redox sensor: the presence of one-electron oxidants or reductants leading to the loss of the 2Fe-2S cluster, subsequent monomerization and activation of the enzyme. Unlike other glutaredoxins, it is not inhibited by oxidation of structural Cys residues.
The absence of GLRX2 dramatically sensitizes cells to cell death induced by doxorubicin/adriamycin and phenylarsine oxide.
Widely expressed. Expressed in brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta and lung. Not expressed in peripheral blood leukocytes.
Detected in adult testis and pituitary, and in 9-10 week fetal tissue (thorax). Probably expressed in other tissues at low levels.
Expressed in early human development as well as in a limited number of adult tissues.
May have a role in development. May regulate its own transcription. May bind the bicoid consensus sequence TAATCC.
(Microbial infection) AMPylation at Tyr-77 by L.pneumophila DrrA occurs in the switch 2 region and leads to moderate inactivation of the GTPase activity. It appears to prolong the lifetime of the GTP state of RAB1B by restricting access of GTPase effectors to switch 2 and blocking effector-stimulated GTP hydrolysis, thereby rendering RAB1B constitutively active. It is later de-AMPylated by L.pneumophila SidD, releasing RAB1B from bacterial phagosomes.
(Microbial infection) Glycosylated by S.typhimurium protein Ssek3: arginine GlcNAcylation prevents GTPase activity, thereby disrupting vesicular protein transport from the endoplasmic reticulum (ER) to the Golgi compartment.
(Microbial infection) Interacts with L.pneumophila AnkX (PubMed:21822290, PubMed:22307087). Interacts with L.pneumophila Lem3 (PubMed:22158903, PubMed:22307087). Interacts with L.pneumophila SidD (PubMed:21734656, PubMed:21680813). Interacts with L.pneumophila DrrA (PubMed:20064470, PubMed:20651120).
(Microbial infection) Phosphocholinated at Ser-76 by L.pneumophila AnkX, leading to displace GDP dissociation inhibitors (GDI) (PubMed:21822290, PubMed:22307087). Both GDP-bound and GTP-bound forms can be phosphocholinated. Dephosphocholinated by L.pneumophila Lem3, restoring accessibility to L.pneumophila GTPase effector LepB (PubMed:22158903, PubMed:22307087).
Interacts with MICAL1 and MICAL2 (PubMed:15694364, PubMed:27552051). Interacts (in GTP-bound form) with MICALCL, MICAL1 and MILCAL3 (PubMed:15694364, PubMed:27552051). Interacts with GDI1; the interaction requires the GDP-bound state (PubMed:8836150, PubMed:11389151). Interacts with CHM/REP1; the interaction requires the GDP-bound form and is necessary for prenylation by GGTase II (PubMed:9437002, PubMed:11389151). Interacts with RabGAP TBC1D20 (PubMed:23236136). Interacts (in GDP-bound form) with lipid phosphatase MTMR6 (via GRAM domain); the interaction regulates MTMR6 recruitment to the endoplasmic reticulum-Golgi intermediate compartment (PubMed:23188820). Interacts (in GDP-bound form) with lipid phosphatase MTMR7 (By similarity).
Prenylated; by GGTase II, only after interaction of the substrate with Rab escort protein 1 (REP1).
Rab activation is generally mediated by a guanine exchange factor (GEF), while inactivation through hydrolysis of bound GTP is catalyzed by a GTPase activating protein (GAP).
Rab-1B binds GTP and GDP and possesses low intrinsic GTPase activity.
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes (PubMed:20545908, PubMed:9437002). Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (PubMed:9437002). Plays a role in the initial events of the autophagic vacuole development which take place at specialized regions of the endoplasmic reticulum (PubMed:20545908). Regulates vesicular transport between the endoplasmic reticulum and successive Golgi compartments (By similarity). Required to modulate the compacted morphology of the Golgi (PubMed:26209634). Promotes the recruitment of lipid phosphatase MTMR6 to the endoplasmic reticulum-Golgi intermediate compartment (By similarity).
Detected in blood plasma (at protein level) (PubMed:12176993, PubMed:26371182). Predominantly expressed in brain, placenta, ovary, and small intestine. Expressed in a number of carcinomas such as hepatocellular and prostate carcinoma, neuroblastoma and non-small-cell lung cancer. Expressed in body fluids such as plasma, cerebral spinal fluid (CSF), saliva, follicular and amniotic fluids. Not detected in leukocytes. Isoform 1 is more highly expressed in peripheral tissues than in the central nervous system (CNS). Adipocytes only express isoform 1. Isoform 3 is more highly expressed in the brain than in peripheral tissues.
Hydrolyzes lysophospholipids to produce the signaling molecule lysophosphatidic acid (LPA) in extracellular fluids (PubMed:15769751, PubMed:26371182, PubMed:27754931, PubMed:14500380, PubMed:12354767). Major substrate is lysophosphatidylcholine (PubMed:12176993, PubMed:27754931, PubMed:14500380). Can also act on sphingosylphosphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility (PubMed:14500380). Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP (PubMed:15769751, PubMed:12176993). Involved in several motility-related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation (PubMed:11559573). Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein (PubMed:1733949). May have a role in induction of parturition (PubMed:12176993). Possible involvement in cell proliferation and adipose tissue development (Probable). Tumor cell motility-stimulating factor (PubMed:1733949, PubMed:11559573). Required for LPA production in activated platelets, cleaves the sn-1 lysophospholipids to generate sn-1 lysophosphatidic acids containing predominantly 18:2 and 20:4 fatty acids (PubMed:21393252). Shows a preference for the sn-1 to the sn-2 isomer of 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) (PubMed:21393252).
Inhibited by lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). Inhibited by EDTA and EGTA (Probable).
N-glycosylation, but not furin-cleavage, plays a critical role on secretion and on lysoPLD activity.
The interdomain disulfide bond between Cys-414 and Cys-806 is essential for catalytic activity.
Up-regulated in massively obese subjects with glucose intolerance, and during adipogenesis.
(Microbial infection) Interacts with myxoma virus protein M062.
Double-stranded nucleic acid binding that acts as a an antiviral factor by playing an essential role in the formation of cytoplasmic antiviral granules (PubMed:25428864, PubMed:28157624). May play a role in the inflammatory response to tissue injury and the control of extra-osseous calcification, acting as a downstream target of TNF-alpha signaling. Involved in the regulation of EGR1, in coordination with RGL2. May be involved in endosome fusion.
Interacts with RGL2 (PubMed:21160498). Interacts with EEA1 (PubMed:24029230).
The disease is caused by variants affecting the gene represented in this entry. Germline mutations in SAMD9 with a suppressive effect on the cell cycle are associated with somatic loss of the chromosome 7 harboring the mutant allele. This results in the deletion of several genes and predisposes to the development of myelodysplastic syndrome and acute myelogenous leukemia.
Up-regulated by TNF-alpha through p38 MAPKs and NF-kappa-B. Up-regulated by osmotic shock. Induced by IFNG.
Widely expressed. Very low levels are detected in skeletal muscle. Not detected in brain. Down-regulated in aggressive fibromatosis, as well as in breast and colon cancers. Up-regulated in fibroblasts from patients with normophosphatemic tumoral calcinosis (NFTC).
Expression detected in spleen, thymus, testis, ovary, colon, heart, smooth muscle, kidney, brain, lung, liver and white adipose tissue with highest expression in liver and thyroid.
RAP domain is required for FASTKD3 function in mRNA stability and translation.
Required for normal mitochondrial respiration (PubMed:20869947). Increases steady-state levels and half-lives of a subset of mature mitochondrial mRNAs MT-ND2, MT-ND3, MT-CYTB, MT-CO2, and MT-ATP8/6. Promotes MT-CO1 mRNA translation and increases mitochondrial complex IV assembly and activity (PubMed:27789713).
G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling inhibits adenylate cyclase activity.
Strongly expressed in the cerebellum. Expressed at low levels in hippocampus, hypothalamus and thalamus. No expression detected in liver.
Acts as a positive regulator of apoptosis. Also acts as a regulator of cellular reactive oxygen species.
Directly regulated by p53/TP53: induced following cisplatin treatment in a p53/TP53-dependent manner. p53/TP53 activates expression by directly binding to its regulatory regions.
Highly expressed in placenta. Lower levels in heart, lung, skeletal muscle, kidney and pancreas.
Inhibited by thiazolidinedione-type compounds: inhibited by furan- and pyridone- thiazolidinediones.
A positive regulator of the alternate pathway (AP) of complement (PubMed:20382442, PubMed:28264884). It binds to and stabilizes the C3- and C5-convertase enzyme complexes (PubMed:20382442, PubMed:28264884). Inhibits CFI-CFH mediated degradation of Complement C3 beta chain (C3b) (PubMed:31507604).
In plasma, properdin exists as dimers, trimers or tetramers in the relative proportions of 26:54:20 (PubMed:20382442, PubMed:15491616, PubMed:28264884, PubMed:31507604). Interacts with the pro-C3-convertase enzyme complex (C3b-Bb) comprised of Complement C3 beta chain (C3b) and the Complement factor B Bb fragment (Bb), where it binds (via its TSP type-1 5 domain) with C3b and Bb (PubMed:28264884, PubMed:31507604). This interaction stabilizes the complex and allows it to become the active C3-convertase enzyme complex (C3b-Bb-FP) (PubMed:28264884, PubMed:31507604). Interacts with C3b (PubMed:28264884, PubMed:31507604). Interacts with CFB (PubMed:31507604).
TSP type-1 domain 0 binds to TSP type-1 domain 4, and TSP type-1 domain 1 binds to TSP type-1 domain 6 (PubMed:15491616, PubMed:28264884, PubMed:31507604). These interactions mediate multimerization (PubMed:15491616, PubMed:28264884, PubMed:31507604).
Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains.
Belongs to the ribulose-phosphate 3-epimerase family.
Binds 1 divalent metal cation per subunit. Active with Fe(2+), and probably also with Mn(2+), Zn(2+) and Co(2+).
Catalyzes the reversible epimerization of D-ribulose 5-phosphate to D-xylulose 5-phosphate.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PKC subfamily.
Binds 3 Ca(2+) ions per subunit. The ions are bound to the C2 domain.
Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in positive and negative regulation of cell proliferation, apoptosis, differentiation, migration and adhesion, tumorigenesis, cardiac hypertrophy, angiogenesis, platelet function and inflammation, by directly phosphorylating targets such as RAF1, BCL2, CSPG4, TNNT2/CTNT, or activating signaling cascade involving MAPK1/3 (ERK1/2) and RAP1GAP. Involved in cell proliferation and cell growth arrest by positive and negative regulation of the cell cycle. Can promote cell growth by phosphorylating and activating RAF1, which mediates the activation of the MAPK/ERK signaling cascade, and/or by up-regulating CDKN1A, which facilitates active cyclin-dependent kinase (CDK) complex formation in glioma cells. In intestinal cells stimulated by the phorbol ester PMA, can trigger a cell cycle arrest program which is associated with the accumulation of the hyper-phosphorylated growth-suppressive form of RB1 and induction of the CDK inhibitors CDKN1A and CDKN1B. Exhibits anti-apoptotic function in glioma cells and protects them from apoptosis by suppressing the p53/TP53-mediated activation of IGFBP3, and in leukemia cells mediates anti-apoptotic action by phosphorylating BCL2. During macrophage differentiation induced by macrophage colony-stimulating factor (CSF1), is translocated to the nucleus and is associated with macrophage development. After wounding, translocates from focal contacts to lamellipodia and participates in the modulation of desmosomal adhesion. Plays a role in cell motility by phosphorylating CSPG4, which induces association of CSPG4 with extensive lamellipodia at the cell periphery and polarization of the cell accompanied by increases in cell motility. During chemokine-induced CD4(+) T cell migration, phosphorylates CDC42-guanine exchange factor DOCK8 resulting in its dissociation from LRCH1 and the activation of GTPase CDC42 (PubMed:28028151). Is highly expressed in a number of cancer cells where it can act as a tumor promoter and is implicated in malignant phenotypes of several tumors such as gliomas and breast cancers. Negatively regulates myocardial contractility and positively regulates angiogenesis, platelet aggregation and thrombus formation in arteries. Mediates hypertrophic growth of neonatal cardiomyocytes, in part through a MAPK1/3 (ERK1/2)-dependent signaling pathway, and upon PMA treatment, is required to induce cardiomyocyte hypertrophy up to heart failure and death, by increasing protein synthesis, protein-DNA ratio and cell surface area. Regulates cardiomyocyte function by phosphorylating cardiac troponin T (TNNT2/CTNT), which induces significant reduction in actomyosin ATPase activity, myofilament calcium sensitivity and myocardial contractility. In angiogenesis, is required for full endothelial cell migration, adhesion to vitronectin (VTN), and vascular endothelial growth factor A (VEGFA)-dependent regulation of kinase activation and vascular tube formation. Involved in the stabilization of VEGFA mRNA at post-transcriptional level and mediates VEGFA-induced cell proliferation. In the regulation of calcium-induced platelet aggregation, mediates signals from the CD36/GP4 receptor for granule release, and activates the integrin heterodimer ITGA2B-ITGB3 through the RAP1GAP pathway for adhesion. During response to lipopolysaccharides (LPS), may regulate selective LPS-induced macrophage functions involved in host defense and inflammation. But in some inflammatory responses, may negatively regulate NF-kappa-B-induced genes, through IL1A-dependent induction of NF-kappa-B inhibitor alpha (NFKBIA/IKBA). Upon stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA), phosphorylates EIF4G1, which modulates EIF4G1 binding to MKNK1 and may be involved in the regulation of EIF4E phosphorylation. Phosphorylates KIT, leading to inhibition of KIT activity. Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription. Phosphorylates SOCS2 at 'Ser-52' facilitating its ubiquitination and proteasomal degradation (By similarity). Phosphorylates KLHL3 in response to angiotensin II signaling, decreasing the interaction between KLHL3 and WNK4 (PubMed:25313067).
Classical (or conventional) PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. Three specific sites; Thr-497 (activation loop of the kinase domain), Thr-638 (turn motif) and Ser-657 (hydrophobic region), need to be phosphorylated for its full activation.
Recruited in a circadian manner into a nuclear complex which also includes BMAL1 and RACK1 (By similarity). Interacts with ADAP1/CENTA1 (PubMed:12893243). Interacts with CSPG4 (PubMed:15504744). Binds to CAVIN2 in the presence of phosphatidylserine (By similarity). Interacts with PRKCABP/PICK1 (via PDZ domain) (PubMed:15247289). Interacts with TRIM41 (PubMed:17893151). Interacts with PARD3 (PubMed:27925688). Interacts with SOCS2 (By similarity).
Expressed in a variety of tissues. Down-regulated in pancreatic and esophageal cancer.
Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. Plays a role in the regulation of adenylyl cyclase signaling in certain regions of the brain. Plays a role in the formation or stabilzation of a G protein heterotrimer (G(olf) subunit alpha-beta-gamma-7) that is required for adenylyl cyclase activity in the striatum (By similarity).
Part of the core SMN complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP (PubMed:18984161, PubMed:11748230, PubMed:15939020, PubMed:12065586, PubMed:16314521, PubMed:17178713). Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG (PubMed:18984161, PubMed:16314521). Interacts with GEMIN7; the interaction is direct (PubMed:12065586, PubMed:15939020, PubMed:33754639, PubMed:17178713). Interacts with GEMIN8; the interaction is direct (PubMed:33754639). Interacts with SNRPB, SNRPD2, SNRPD3 and SNRPE; the interaction is direct (PubMed:11748230, PubMed:15939020).
Expressed ubiquitously, the highest levels are found in the epididymis followed by testis and trachea.
E3 ubiquitin-protein ligase which mediates 'Lys-48'-linked ubiquitination of STAT2 and induces its proteasomal degradation thereby negatively regulating type-I-interferon signaling. Essential sperm cell-surface protein required for sperm-egg fusion and fertilization (By similarity).
Interacts with STAT2; the interaction results in STAT2 'Lys-48'-linked ubiquitination leading to its proteasomal degradation. Interacts with DCST2 (By similarity).
The RING-type zinc finger domain is responsible for E3 ubiquitin ligase activity.
ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis (PubMed:10419525, PubMed:11092760, PubMed:28389643). Within a catalytic cycle, acquires Cu(+) ion from donor protein on the cytoplasmic side of the membrane and delivers it to acceptor protein on the lumenal side. The transfer of Cu(+) ion across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing to outward-facing state (PubMed:10419525, PubMed:19453293, PubMed:19917612, PubMed:31283225, PubMed:28389643). Under physiological conditions, at low cytosolic copper concentration, it is localized at the trans-Golgi network (TGN) where it transfers Cu(+) ions to cuproenzymes of the secretory pathway (PubMed:28389643, PubMed:11092760). Upon elevated cytosolic copper concentrations, it relocalizes to the plasma membrane where it is responsible for the export of excess Cu(+) ions (PubMed:10419525, PubMed:28389643). May play a dual role in neuron function and survival by regulating cooper efflux and neuronal transmission at the synapse as well as by supplying Cu(+) ions to enzymes such as PAM, TYR and SOD3 (PubMed:28389643) (By similarity). In the melanosomes of pigmented cells, provides copper cofactor to TYR to form an active TYR holoenzyme for melanin biosynthesis (By similarity).
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IB subfamily.
Contains three di-leucine motifs in the C-terminus which are required for recycling from the plasma membrane to the TGN. The di-leucine 1487-Leu-Leu-1488 motif mediates endocytosis at the plasma membrane, whereas the di-leucine 1467-Leu-Leu-1468 motif is a sorting signal for retrograde trafficking to TGN via early endosomes.
Expressed in cerebellum and brain cortex.
Lacks 6 transmembrane regions and 5 heavy-metal-associated (HMA) domains.
Lacks all transmembrane regions and 5 heavy-metal-associated (HMA) domains, but has a putative nuclear localization signal attached at the N-terminus.
Lacks the transmembrane domains 3 and 4. Expressed at a low level in several tissues of normal individuals and is the only isoform found in patients with OHS.
Monomer. Interacts with PDZD11 (PubMed:16051599). Interacts with ATOX1 and COMMD1 (PubMed:21667063, PubMed:19453293, PubMed:31283225). Interacts with TYRP1 (By similarity). Directly interacts with SOD3; this interaction is copper-dependent and is required for SOD3 activity.
The heavy-metal-associated domain (HMA) coordinates a Cu(+) ion via the cysteine residues within the CXXC motif. The transfer of Cu(+) ion from ATOX1 to ATP7A involves the formation of a three-coordinate Cu(+)-bridged heterodimer where the metal is shared between the two metal binding sites of ATOX1 and ATP7A. The Cu(+) ion appears to switch between two coordination modes, forming two links with one protein and one with the other. Cisplatin, a chemotherapeutic drug, can bind the CXXC motif and hinder the release of Cu(+) ion.
The nucleotide-binding domain consists of a twisted six-stranded antiparallel beta-sheet flanked by two pairs of alpha-helices, forming an hydrophobic pocket that interacts with the adenine ring of ATP. The ATP binding site comprises residues located in alpha-1 and alpha-2 helices and beta-2 and beta-3 strands, which are involved in van der Waal's interactions, and Glu-1081 which forms an hydrogen bond with the adenine ring.
Widely expressed including in heart, brain, lung, muscle, kidney, pancreas, and to a lesser extent placenta (PubMed:8490646, PubMed:8490659). Expressed in fibroblasts, aortic smooth muscle cells, aortic endothelial cells and umbilical vein endothelial cells (at protein level) (PubMed:16371425).
Transcriptional regulator that is critical for the regulation of pain perception and processing of noxious stimuli.
Associates with pre-60S ribosomal particles.
Belongs to the ZNF593/BUD20 C2H2-type zinc-finger protein family.
Involved in pre-60S ribosomal particles maturation by promoting the nuclear export of the 60S ribosome (PubMed:32669547). Negatively modulates the DNA binding activity of Oct-2 and therefore its transcriptional regulatory activity (PubMed:9115366).
The protein is largely disordered, with the exception of the zinc finger domain.
Ubiquitous. Detected in spleen, prostate, testis, small intestine, colon and to a minor level in thymus and peripheral blood leukocytes.
A C-terminal internalization signal (YGTL) appears to allow the targeting of plasma membrane proteins to endosomes.
Belongs to the glycosyl hydrolase 33 family.
Catalyzes the removal of sialic acid (N-acetylneuraminic acid) moieties from glycoproteins and glycolipids. To be active, it is strictly dependent on its presence in the multienzyme complex. Appears to have a preference for alpha 2-3 and alpha 2-6 sialyl linkage.
Highly expressed in pancreas, followed by skeletal muscle, kidney, placenta, heart, lung and liver. Weakly expressed in brain.
Interacts with cathepsin A (protective protein), beta-galactosidase and N-acetylgalactosamine-6-sulfate sulfatase in a multienzyme complex.
Phosphorylation of tyrosine within the internalization signal results in inhibition of sialidase internalization and blockage on the plasma membrane.
Belongs to the ATP-dependent AMP-binding enzyme family. Bubblegum subfamily.
Catalyzes the conversion of fatty acids such as long chain and very long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation. Can activate diverse saturated, monosaturated and polyunsaturated fatty acids (PubMed:16371355, PubMed:16762313). Has increased ability to activate oleic and linoleic acid (PubMed:16371355). May play a role in spermatogenesis (PubMed:15685348).
Weakly or not expressed in fetal testis. Highly expressed in adult testis and moderately in elderly testis.
Aberrant O-galactosylation of IgA1 molecules plays a role in the development and progression of IgA nephropathy (IgAN). Genetic interactions of C1GALT1 and ST6GALNAC2 variants influence IgA1 O-glycosylation, disease predisposition, and disease severity, and may contribute to the polygenic nature of IgAN.
Catalyzes the transfer of N-acetylneuraminyl groups onto glycan chains in glycoproteins (PubMed:10742600, PubMed:29251719). Shows a preference for N-acetylgalactosamine (GalNAc) residues already modified by the addition of galactose or galactose followed by sialic acid in alpha-2,3 linkage (PubMed:10742600).
Expressed in skeletal muscle, heart, kidney, placenta, lung and leukocytes.
A chromosomal aberration involving ZMYM3 may be a cause of X-linked intellectual disability in Xq13.1. Translocation t(X;13)(q13.1;?).
May be a component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST, PHF21A/BHC80, ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I.
Most abundant in brain, moderate in muscle and heart, low in other tissues except placenta.
Plays a role in the regulation of cell morphology and cytoskeletal organization.
A chromosomal aberration involving PTHB1 has been found in Wilms tumor. Translocation t(1;7)(q42;p15) with OBSCN.
Part of BBSome complex, that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10. Interacts with LZTL1; the interaction mediates the association of LZTL1 with the BBsome complex and regulates BBSome ciliary trafficking.
The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia. The BBSome complex is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Firstly the BBSome associates with the ciliary membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and promotes docking and fusion of carrier vesicles to the base of the ciliary membrane. Required for proper BBSome complex assembly and its ciliary localization.
Widely expressed. Expressed in adult heart, skeletal muscle, lung, liver, kidney, placenta and brain, and in fetal kidney, lung, liver and brain.
Expressed specifically in hematopoietic cells and tissues.
Hematopoietic modulator for the G1-S cell cycle transition. Modulates the level of phosphorylation of cyclin-dependent kinase 2 (CDK2) through its direct binding to cyclin-dependent kinase inhibitor 3 (CDKN3/KAP).
Interacts with CDKN3. Interacts with CDKN3-CDK2 complexes through its binding to CDKN3; this interaction facilitates dissociation of cyclin A from CDKN3-CDK2 complexes.
The C-terminal region is required for binding to CDKN3-CDK2 complexes and the modulation of CDKN3 activity.
Belongs to the eukaryotic/archaeal RNase P protein component 2 family.
Component of ribonuclease P, a ribonucleoprotein complex that generates mature tRNA molecules by cleaving their 5'-ends.
RNase P consists of a catalytic RNA moiety and about 10 protein subunits; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40 (PubMed:10024167, PubMed:16723659, PubMed:30454648). Within the RNase P complex, POP1, POP7 and RPP25 form the 'finger' subcomplex, POP5, RPP14, RPP40 and homodimeric RPP30 form the 'palm' subcomplex, and RPP21, POP4 and RPP38 form the 'wrist' subcomplex. All subunits of the RNase P complex interact with the catalytic RNA (PubMed:30454648).
This protein is produced by a bicistronic gene which also produces the HTD2 protein from an overlapping reading frame.
DNA-binding transcription factor that can both act as an activator and a repressor.
Interacts (via zinc-fingers) with JARID2. Interacts with NSD1 (By similarity).
The C2H2-type zinc finger 1, also named C2HR, mediates the interaction with NSD1.
Acyltransferase activity is regulated by the binding of GTP and Ca(2+): inactivated by GTP, which stabilizes its closed structure, thereby obstructing the accessibility of substrates to the active sites (PubMed:2903073, PubMed:7592956, PubMed:18092889, PubMed:31991788). In contrast, Ca(2+) acts as a cofactor by inducing conformational change to the active open form (PubMed:2903073, PubMed:18092889, PubMed:31991788). In absence of Ca(2+), Mg(2+) may bind Ca(2+)-binding sites, promoting GTP-binding and subsequent inhibition of the acyltransferase activity (PubMed:31991788). Specifically inhibited by compound VA4 ((S)-Benzyl (6-Acrylamido-1-(4-((5-(dimethylamino)naphthalen-1-yl)sulfonyl)piperazin-1-yl)-1-oxohexan-2-yl)carbamate), which specifically abolishes both the transamidation and GTP-binding activities (PubMed:28858494).
Auto-transglutaminated: Forms covalent cross-links mediated by transglutaminase between Gln-633 and the epsilon-amino group of a lysine residue of itself or HMGB1, forming homopolymers and heteropolymers, respectively.
Calcium-dependent acyltransferase that catalyzes the formation of covalent bonds between peptide-bound glutamine and various primary amines, such as gamma-amino group of peptide-bound lysine, or mono- and polyamines, thereby producing cross-linked or aminated proteins, respectively (PubMed:9252372, PubMed:23941696, PubMed:31991788). Involved in many biological processes, such as bone development, angiogenesis, wound healing, cellular differentiation, chromatin modification and apoptosis (PubMed:1683874, PubMed:7935379, PubMed:9252372, PubMed:27270573). Acts as a protein-glutamine gamma-glutamyltransferase by mediating the cross-linking of proteins, such as ACO2, HSPB6, FN1, HMGB1, RAP1GDS1, SLC25A4/ANT1, SPP1 and WDR54 (PubMed:23941696, PubMed:24349085, PubMed:29618516, PubMed:30458214). Under physiological conditions, the protein cross-linking activity is inhibited by GTP; inhibition is relieved by Ca(2+) in response to various stresses (PubMed:7649299, PubMed:7592956, PubMed:18092889). When secreted, catalyzes cross-linking of proteins of the extracellular matrix, such as FN1 and SPP1 resulting in the formation of scaffolds (PubMed:12506096). Plays a key role during apoptosis, both by (1) promoting the cross-linking of cytoskeletal proteins resulting in condensation of the cytoplasm, and by (2) mediating cross-linking proteins of the extracellular matrix, resulting in the irreversible formation of scaffolds that stabilize the integrity of the dying cells before their clearance by phagocytosis, thereby preventing the leakage of harmful intracellular components (PubMed:7935379, PubMed:9252372). In addition to protein cross-linking, can use different monoamine substrates to catalyze a vast array of protein post-translational modifications: mediates aminylation of serotonin, dopamine, noradrenaline or histamine into glutamine residues of target proteins to generate protein serotonylation, dopaminylation, noradrenalinylation or histaminylation, respectively (PubMed:23797785, PubMed:30867594). Mediates protein serotonylation of small GTPases during activation and aggregation of platelets, leading to constitutive activation of these GTPases (By similarity). Plays a key role in chromatin organization by mediating serotonylation and dopaminylation of histone H3 (PubMed:30867594, PubMed:32273471). Catalyzes serotonylation of 'Gln-5' of histone H3 (H3Q5ser) during serotonergic neuron differentiation, thereby facilitating transcription (PubMed:30867594). Acts as a mediator of neurotransmission-independent role of nuclear dopamine in ventral tegmental area (VTA) neurons: catalyzes dopaminylation of 'Gln-5' of histone H3 (H3Q5dop), thereby regulating relapse-related transcriptional plasticity in the reward system (PubMed:32273471). Regulates vein remodeling by mediating serotonylation and subsequent inactivation of ATP2A2/SERCA2 (By similarity). Also acts as a protein deamidase by mediating the side chain deamidation of specific glutamine residues of proteins to glutamate (PubMed:9623982, PubMed:20547769). Catalyzes specific deamidation of protein gliadin, a component of wheat gluten in the diet (PubMed:9623982). May also act as an isopeptidase cleaving the previously formed cross-links (PubMed:26250429, PubMed:27131890). Also able to participate in signaling pathways independently of its acyltransferase activity: acts as a signal transducer in alpha-1 adrenergic receptor-mediated stimulation of phospholipase C-delta (PLCD) activity and is required for coupling alpha-1 adrenergic agonists to the stimulation of phosphoinositide lipid metabolism (PubMed:8943303).
Disulfide bond formation inactivates the calcium-dependent acyltransferase activity (PubMed:20547769). Cys-370 can form disulfide bonds with both Cys-230 and Cys-371: formation of a disulfide bond between Cys-230 and Cys-370 facilitates formation of the disulfide between Cys-370 and Cys-371, which promotes inactivation of the acyltransferase activity (PubMed:20547769). May also form interchain disulfids between Cys-230 and Cys-370 (PubMed:25192068). Ca(2+) protects against disulfide bond formation and inactivation (PubMed:20547769).
Has cytotoxic activity: is able to induce apoptosis independently of its acyltransferase activity.
Initial enzymatic assays were performed with a protein sequence containing a Gly residue instead of a Val at position 224: such protein displays lower Ca(2+)-binding affinity and reduced transglutaminase activity.
Monomer (PubMed:25192068). Interacts with phospholipase C; promoting alpha-1 adrenergic receptor signaling (PubMed:7592956). Interacts with PLCD1 (By similarity).
S-nitrosylated, leading to inactivation of the acyltransferase activity.
TGM2 constitutes the major autoantigen in celiac disease, a multifactorial chronic disorder of the small intestine caused by intolerance to gluten (PubMed:9212111, PubMed:9623982). Celiac disease is characterized by immune-mediated enteropathy associated with failed intestinal absorption and malnutrition: intestinal inflammation is precipitated by ingestion of the protein gliadin, a component of wheat gluten in the diet (PubMed:9212111, PubMed:9623982). TGM2 is the main target for celiac disease-associated anti-endomysium autoantibodies (PubMed:9212111). It mediates its effect by catalyzing specific deamidation of gliadin; this deamidation creates an epitope that binds efficiently to HLA-DQ2 and is recognized by gut-derived T-cells (PubMed:9623982).
Belongs to the terpene cyclase/mutase family.
Key enzyme in the cholesterol biosynthesis pathway. Catalyzes the cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that forms the sterol nucleus (PubMed:14766201, PubMed:7639730, PubMed:26200341). Through the production of lanosterol may regulate lens protein aggregation and increase transparency (PubMed:26200341).
Widely expressed. Expressed in the hair bulb, the outer root sheath and hair matrix of the hair follicle epithelium. Also detected in dermal papilla, epidermis, sweat glands, sebaceous glands, and blood vessels.
Expressed in the leukocytes, placenta and testis.
Interacts with PD-L1/CD274 (via transmembrane domain); the interaction is direct (PubMed:28813417, PubMed:28813410). Interacts with CMTM4 (PubMed:28813410). Interacts with CD58, ARG1, ENO1 and TMPO (PubMed:28813417).
Master regulator of recycling and plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. Associates with both constitutive and IFNG-induced PD-L1/CD274 at recycling endosomes, where it protects PD-L1/CD274 from being targeted for lysosomal degradation, likely by preventing its STUB1-mediated ubiquitination. May stabilize PD-L1/CD274 expression on antigen presenting cells and potentiates inhibitory signaling by PDCD1/CD279, its receptor on T-cells, ultimately triggering T-cell anergy.
Belongs to the universal ribosomal protein uL23 family.
Component of the large ribosomal subunit (PubMed:23636399, PubMed:32669547). Interacts with LYAR and GNL2 (PubMed:26203195). Interacts with MDM2; this interaction may promote MDM2-mediated p53/TP53 polyubiquitination (PubMed:26203195). Directly interacts (via BIB domain) with IPO5, IPO7, KPNB1 and TNPO1; these interactions are involved in RPL23A nuclear import for the assembly of ribosomal subunits (PubMed:9687515, PubMed:11682607). Interacts with IPO8 (PubMed:11682607).
Component of the large ribosomal subunit (PubMed:23636399, PubMed:32669547). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399, PubMed:32669547). Binds a specific region on the 26S rRNA (PubMed:23636399, PubMed:32669547). May promote p53/TP53 degradation possibly through the stimulation of MDM2-mediated TP53 polyubiquitination (PubMed:26203195).
May be down-regulated by GNL2 (at protein level).
N-terminus is methylated by METTL11A/NTM1.
The N-terminal beta-like import receptor binding (BIB) domain mediates interaction with IPO5, IPO7, KPNB1 and TNPO1.
Belongs to the TRAFAC class translation factor GTPase superfamily. Bms1-like GTPase family. BMS1 subfamily.
Belongs to the glutaminyl-peptide cyclotransferase family.
It is unclear whether this protein requires a metal cofactor for catalysis. It was originally proposed to be a Zn(2+)-dependent metalloenzyme based on structural similarities to bacterial aminopeptidases and the observation that it can bind Zn(2+) ions, typically in a 1:1 stoichiometry (PubMed:21288892). However, a recent study suggests a Zn(2+)-independent catalytic mechanism (By similarity).
Responsible for the biosynthesis of pyroglutamyl peptides.
Belongs to the inositol monophosphatase superfamily.
Can use myo-inositol monophosphates, scylloinositol 1,4-diphosphate, glucose-1-phosphate, beta-glycerophosphate, and 2'-AMP as substrates. Has been implicated as the pharmacological target for lithium Li(+) action in brain.
Inhibited by high Li(+) and restricted Mg(2+) concentrations.
May act as a GTPase-activating protein for Rab family protein(s).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRA5 sub-subfamily.
Generally pentameric. There are five types of GABA(A) receptor subunits: alpha, beta, gamma, delta, and rho.
Ligand-gated chloride channel subunit which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:29961870, PubMed:31056671). May be involved in GABA-A receptor assembly, and GABA-A receptor immobilization and accumulation by gephyrin at the synapse (PubMed:31056671).
Channel that allows the facilitated permeation of water and uncharged molecules, such as hydrogen peroxide and the neutral form of ammonia (NH3), through cellular membranes such as plasma membrane, inner mitochondrial membrane and endoplasmic reticulum membrane of several tissues (PubMed:26972385, PubMed:15948717, PubMed:18948439, PubMed:23541115, PubMed:29732408, PubMed:30579780). The transport of the ammonia neutral form induces a parallel transport of proton, at alkaline pH when the concentration of ammonia is high (By similarity). However, it is unclear whether the transport of proton takes place via the aquaporin or via an endogenous pathway (By similarity). Also, may transport ammonia analogs such as formamide and methylamine, a transport favourited at basic pH due to the increase of unprotonated (neutral) form, which is expected to favor diffusion (PubMed:15948717). Does not transport urea or glycerol (PubMed:15948717). The water transport mechanism is mercury- and copper-sensitive and passive in response to osmotic driving forces (PubMed:15948717). At the canicular plasma membrane, mediates the osmotic transport of water toward the bile canaliculus and facilitates the cAMP-induced bile canalicular water secretion, a process involved in bile formation (PubMed:18948439). In addition, mediates the hydrogen peroxide release from hepatocyte mitochondria that modulates the SREBF2-mediated cholesterol synthesis and facilitates the mitochondrial ammonia uptake which is metabolized into urea, mainly under glucagon stimulation (PubMed:30579780, PubMed:34292591). In B cells, transports the CYBB-generated hydrogen peroxide from the external leaflet of the plasma membrane to the cytosol to promote B cell activation and differentiation for signal amplification (By similarity). In the small intestine and colon system, mediates water transport through mitochondria and apical membrane of epithelial cells (By similarity). May play an important role in the adaptive response of proximal tubule cells to acidosis possibly by facilitating the mitochondrial ammonia transport (PubMed:22622463).
Detected in the sperm midpiece (at protein level) (PubMed:28042826). Expressed only in pancreas and colon.
Persulfidation at Cys-53 is required to gate AQP8 channel; under stress condition, hydrogen peroxide accumulates in the cell leading to CBS activation that produces hydrogen sulfide inducing persulfidation of oxidized Cys-53 (C53-SOH).
Regulated by osmotic stress (PubMed:20144166). Up-regulated in response to metabolic acidosis (PubMed:22622463).
Reversibly gated by a two-step sulfenylation-persulfidation process in cells undergoing diverse stresses.
Sulfenylation at Cys-53(C53-SOH) when hydrogen peroxide flows through the AQP8 channel, making it susceptible to hydrogen sulfide produced by CBS.
Adipokine that modulates insulin action by specifically inhibiting its target protease KLK7 in white adipose tissues.
Glycosylation slightly decreases affinity for heparin, but otherwise has no significant effect on KLK7 inhibitory activity or thermal stability of the protein.
Inhibition of KLK7 is enhanced by heparin.
The reactive center loop (RCL) extends out from the body of the protein and directs binding to the target protease. The protease cleaves the serpin at the reactive site within the RCL, establishing a covalent linkage between the carboxyl group of the serpin reactive site and the serine hydroxyl of the protease. The resulting inactive serpin-protease complex is highly stable.
May bind to RNA via its Arg/Ser-rich domain.
Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 2 complex (dynein-2 complex), a motor protein complex that drives the movement of cargos along microtubules within cilia and flagella in concert with the intraflagellar transport (IFT) system. Required for proper retrograde ciliary transport.
Belongs to the dynein light chain Tctex-type family.
Light chain of the cytoplasmic dynein complex 2, a multisubunit complex composed at least of eleven different proteins (PubMed:25205765, PubMed:26044572). The cytoplasmic dynein 2 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs). Among them, a heavy chain (DYNC2H1), two intermediate chains (DYNC2I2 and DYNC2I1), a light intermediate chain (DYNC2LI1), and a light chain (DYNLT2B) are unique to the dynein-2 complex, but a subset of the light chains are also shared by dynein-1 and dynein-2 complexes (PubMed:25205765, PubMed:26044572). Interacts with DYNC2I1 (PubMed:26044572). The dimer DYNLT2B-DYNLT1/DYNLT3 interacts with DYNC2I1; this interaction is crucial for retrograde trafficking of ciliary proteins (PubMed:29742051, PubMed:26044572).
Associates with NCBP1/CBP80 to form an alternative cap-binding complex (CBC) which plays a key role in mRNA export. NCBP3 serves as adapter protein linking the capped RNAs (m7GpppG-capped RNA) to NCBP1/CBP80. Unlike the conventional CBC with NCBP2 which binds both small nuclear RNA (snRNA) and messenger (mRNA) and is involved in their export from the nucleus, the alternative CBC with NCBP3 does not bind snRNA and associates only with mRNA thereby playing a role in only mRNA export. The alternative CBC is particularly important in cellular stress situations such as virus infections and the NCBP3 activity is critical to inhibit virus growth (PubMed:26382858).
Component of an alternative cap-binding complex (CBC) composed of NCBP1/CBP80 and NCBP3. Interacts with SRRT, KPNA3, THOC5 and EIF4A3.
Belongs to the nuclear hormone receptor family. NR1 subfamily.
Genetic variations in VDR may determine Mycobacterium tuberculosis susceptibility [MIM:607948].
Homodimer in the absence of bound vitamin D3 (PubMed:11980721). Heterodimer with RXRA after vitamin D3 binding (PubMed:15225774, PubMed:11980721, PubMed:10678179). Interacts with MED1, NCOA1, NCOA2, NCOA3 and NCOA6 coactivators, leading to a strong increase of transcription of target genes (PubMed:10866662, PubMed:15728261, PubMed:28698609, PubMed:9267036). Interacts with the corepressor NCOR1 (PubMed:28698609). Interacts with SNW1 (PubMed:9632709). Interacts with IRX4, the interaction does not affect its transactivation activity (PubMed:22323358). Interacts with CRY1 (By similarity). Interacts with CRY2 in a ligand-dependent manner (By similarity).
Nuclear receptor for calcitriol, the active form of vitamin D3 which mediates the action of this vitamin on cells (PubMed:28698609, PubMed:16913708, PubMed:15728261, PubMed:10678179). Enters the nucleus upon vitamin D3 binding where it forms heterodimers with the retinoid X receptor/RXR (PubMed:28698609). The VDR-RXR heterodimers bind to specific response elements on DNA and activate the transcription of vitamin D3-responsive target genes (PubMed:28698609). Plays a central role in calcium homeostasis (By similarity). Also functions as a receptor for the secondary bile acid lithocholic acid (LCA) and its metabolites (PubMed:12016314, PubMed:32354638).
Was thought to be recruited to promoters via its interaction with BAZ1B/WSTF, but this work has later been retracted.
Belongs to the G-protein coupled receptor 1 family. Vasopressin/oxytocin receptor subfamily.
Receptor for oxytocin. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system.
At neuronal promoters, displaces LDB1 from LHX3 LIM domain to form a ternary complex in which ISL1 contacts both LHX3 and LDB1; allosteric structural changes in the DNA binding domain of LHX3, induced by the ISL1:LHX3 interaction, may explain differences in sequence specificity of the different complexes. Interacts with LHX3. Interacts (via C-terminus) with POU4F2 (via C-terminus) isoform 1. Interacts with POU3F2. Interacts with POU4F3. Interacts (via N-terminal domain) with MLIP; the interaction represses ISL1 transactivator activity. Interacts with GCN5/KAT2A. Interactions of ISL1 with MLIP1 or KAT2A may be mutually exclusive (By similarity).
DNA-binding transcriptional activator. Recognizes and binds to the consensus octamer binding site 5'-ATAATTAA-3' in promoter of target genes. Plays a fundamental role in the gene regulatory network essential for retinal ganglion cell (RGC) differentiation. Cooperates with the transcription factor POU4F2 to achieve maximal levels of expression of RGC target genes and RGC fate specification in the developing retina. Involved in the specification of motor neurons in cooperation with LHX3 and LDB1 (By similarity). Binds to insulin gene enhancer sequences (By similarity). Essential for heart development. Marker of one progenitor cell population that give rise to the outflow tract, right ventricle, a subset of left ventricular cells, and a large number of atrial cells as well, its function is required for these progenitors to contribute to the heart. Controls the expression of FGF and BMP growth factors in this cell population and is required for proliferation and survival of cells within pharyngeal foregut endoderm and adjacent splanchnic mesoderm as well as for migration of cardiac progenitors into the heart (By similarity).
Expressed in subsets of neurons of the adrenal medulla and dorsal root ganglion, inner nuclear and ganglion cell layers in the retina, the pineal and some regions of the brain.
Expressed in the forming heart in the stage 9 embryo, in the myocardial trough, and then at stages 10 to 11, in the nondifferentiated mesodermal cells at the venous and arterial poles, as well as cells of the dorsal coelomic wall and ruptured mesocardium (at protein level).
Ubiquitinated probably by WWP1 E3 ubiquitin ligase; ubiquitination is followed by protein degradation.
Catalyzes the synthesis of acetyl-CoA from short-chain fatty acids (PubMed:28003429). Propionate is the preferred substrate (PubMed:28003429). Can utilize acetate and butyrate with a much lower affinity (By similarity).
Belongs to the peptidase S1 family. Tryptase subfamily.
There are two alleles; gamma-I and gamma-II which differ by 5 residues.
(Microbial infection) Interacts with adenovirus E1B 19K protein; plays a role in the suppression of cell apoptosis by the viral protein.
As part of a SNARE complex may be involved in endoplasmic reticulum membranes fusion and be required for the maintenance of endoplasmic reticulum organization (PubMed:15272311). Also plays a role in apoptosis (PubMed:7954800, PubMed:15272311, PubMed:23896122). It is for instance required for endoplasmic reticulum stress-induced apoptosis (PubMed:23896122). As a substrate of RNF185 interacting with SQSTM1, might also be involved in mitochondrial autophagy (Probable).
Component of a SNARE complex consisting of STX18, USE1L, BNIP1/SEC20L and SEC22B (PubMed:15272311). Interacts directly with STX18, RINT1/TIP20L and NAPA (PubMed:15272311). Interacts with ZW10 through RINT1 (PubMed:15272311). Interacts with BCL2 (PubMed:7954800). Interacts with RNF186 (PubMed:23896122). Interacts with RNF185 (PubMed:21931693). Interacts with SQSTM1; increased by 'Lys-63'-linked polyubiquitination of BNIP1 (PubMed:21931693).
Isoform 1 is highly expressed in heart, brain, liver skeletal muscle and pancreas. Isoform 3 is moderately expressed in placenta, lung and kidney. Isoform 4 is highly expressed in testis and small intestine.
Polyubiquitinated (PubMed:21931693, PubMed:23896122). 'Lys-63'-linked polyubiquitination by RNF185 increases the interaction with the autophagy receptor SQSTM1 (PubMed:21931693). Undergoes 'Lys-29'- and 'Lys-63'-linked polyubiquitination by RNF186 that may regulate BNIP1 localization to the mitochondrion (PubMed:23896122).
Widely expressed. Also found in tumors originating from parathyroid gland, colon, stomach, bladder, uterus and prostate.
Glycosyltransferase required for the biosynthesis of heparan-sulfate (HS) (PubMed:11390981). Transfers N-acetyl-alpha-D-glucosamine to the nascent HS chain (GlcNAcT-II activity) (PubMed:11390981). Appears to lack GlcNAcT I and GlcAT-II activities (PubMed:11390981).
Expressed in peripheral retina (at protein level).
Riboflavin-binding protein which might have a role in retinal flavin transport.
tRNA hydroxylase that acts as a component of the wybutosine biosynthesis pathway. Wybutosine is a hyper modified guanosine with a tricyclic base found at the 3'-position adjacent to the anticodon of eukaryotic phenylalanine tRNA. Catalyzes the hydroxylation of 7-(a-amino-a-carboxypropyl)wyosine (yW-72) into undermodified hydroxywybutosine (OHyW*). OHyW* being further transformed into hydroxywybutosine (OHyW) by LCMT2/TYW4. OHyW is a derivative of wybutosine found in higher eukaryotes.
Belongs to the PX domain-containing GAP family.
GTPase-activating protein (GAP) promoting GTP hydrolysis on RHOA, CDC42 and RAC1 small GTPases. May be involved in the differentiation of neuronal cells during the formation of neurite extensions. Involved in NMDA receptor activity-dependent actin reorganization in dendritic spines. May mediate cross-talks between Ras- and Rho-regulated signaling pathways in cell growth regulation. Isoform 2 has higher GAP activity (By similarity).
Interacts with NTRK1 (via cytoplasmic domain); the interaction is independent of the phosphorylation state of NTRK1 (PubMed:12446789). Interacts with SHC3 (via SH2 domain) (PubMed:12446789). Interacts with RASA1 (via SH3 domain); the interaction is necessary for the Ras activation and cell transforming activities of ARHGAP32 (By similarity). Interacts with GAB1 and GAB2 (PubMed:12819203). Interacts with CRK and CRKL (PubMed:12819203, PubMed:12446789). Found in a complex with CRKL and BCAR1; upon EGF stimulation BCAR1 may be replaced by EGFR (PubMed:12446789, PubMed:12819203). Interacts with NCK1 (via SH3 domain); NCK1 recruits phosphorylated BCAR1 to the complex (PubMed:12819203). Isoform 2 interacts with FYN; the interaction appears to be dependent on tyrosine phosphorylation of ARHGAP32 (PubMed:12788081). Interacts with EGFR; the interaction requires EGF stimulation and is increased by SHC3 (PubMed:12446789). Interacts with CDC42; the interaction requires constitutively active CDC42. Interacts with CTNNB1 (PubMed:12531901). Interacts with GRIN2B (PubMed:12857875). Interacts with DLG4 and CDH2 (By similarity). Interacts with GPHN (By similarity).
Isoform 1 and isoform 2 are highly expressed in brain and testis. Isoform 1 is also expressed in other tissues such as lung, liver and spleen.
Isoform 2 is phosphorylated on multiple tyrosine residues by FYN. Phosphorylated tyrosine residues undergo dephosphorylation after stimulation of NMDA receptors (By similarity). Phosphorylated in vitro by CaMK2 in the presence of calmodulin and calcium; which inhibits GAP activity (By similarity).
The N-terminal PX domain interacts specifically with phosphatidylinositides.
The C-terminal domain interacts with the N-terminal domain of RDX.
Belongs to the complex I NDUFB11 subunit family.
Complex I is composed of 45 different subunits (PubMed:12611891, PubMed:27626371). Interacts with BCAP31 (PubMed:31206022).
Endogenous ligand for GPR171. Neuropeptide involved in the regulation of feeding.
Interacts via the C-terminal inhibitory domain with PCSK1 66 kDa form.
May function in the control of the neuroendocrine secretory pathway. Proposed be a specific endogenous inhibitor of PCSK1. ProSAAS and Big PEN-LEN, both containing the C-terminal inhibitory domain, but not the further processed peptides reduce PCSK1 activity in the endoplasmic reticulum and Golgi. It reduces the activity of the 84 kDa form but not the autocatalytically derived 66 kDa form of PCSK1. Subsequent processing of proSAAS may eliminate the inhibition. Slows down convertase-mediated processing of proopiomelanocortin and proenkephalin. May control the intracellular timing of PCSK1 rather than its total level of activity (By similarity).
O-glycosylated with a core 1 or possibly core 8 glycan.
ProSAAS(1-180) increases secretion of enzymatically inactive PCSK1.
The C-terminal inhibitory domain is involved in inhibition of PCSK1. It corresponds to the probable processing intermediate Big PEN-LEN, binds to PCSK1 in vitro and contains the hexapeptide L-L-R-V-K-R, which, as a synthetic peptide, is sufficient for PCSK1 inhibition (By similarity).
The four C-terminal amino acids of Big LEN are sufficient to bind and activate GPR171.
Despite its name, it does not contain a canonical C3H1-type zinc-finger.
Belongs to the N-acylglucosamine 2-epimerase family.
Catalyzes the interconversion of N-acetylglucosamine to N-acetylmannosamine (PubMed:9990133, PubMed:10502668, PubMed:12499362). Involved in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway: although human is not able to catalyze formation of Neu5Gc due to the inactive CMAHP enzyme, Neu5Gc is present in food and must be degraded (PubMed:9990133).
Homodimer (PubMed:1723410, PubMed:9990133). Forms a heterodimer with renin and inhibits its activity (PubMed:1723410, PubMed:9990133).
Inhibited by N-ethylmaleimide, 5,5'-dithiobis-2-nitrobenzoate and iodoacetic acid.
Defects in USH2A has been found in a patient with a form of non-syndromic sensorineural hearing loss.
Interacts with collagen IV and fibronectin via its laminin EGF-like domains. Interaction with collagen may be required for stable integration into the basement membrane (PubMed:14676276, PubMed:16114888). Interacts with NINL (PubMed:18826961). Interacts with USH1C (PubMed:16301216). Component of USH2 complex, composed of ADGRV1, PDZD7, USH2A and WHRN. Interacts with ADGRV1/MASS1 (via N-terminal PDZ domain). Interacts (via the cytoplasmic region) with WHRN (PubMed:16434480). Interacts (via the cytoplasmic region) with PDZD7 (PubMed:20440071). Interacts (via the cytoplasmic region) with VEZT and MYO7A (via MyTH4-FERM domains); the interaction associates VEZT with the USH2 complex at the stereocilia base (By similarity).
Involved in hearing and vision as member of the USH2 complex. In the inner ear, required for the maintenance of the hair bundle ankle formation, which connects growing stereocilia in developing cochlear hair cells. In retina photoreceptors, the USH2 complex is required for the maintenance of periciliary membrane complex that seems to play a role in regulating intracellular protein transport.
Present in the basement membrane of many, but not all tissues. Expressed in retina, cochlea, small and large intestine, pancreas, bladder, prostate, esophagus, trachea, thymus, salivary glands, placenta, ovary, fallopian tube, uterus and testis. Absent in many other tissues such as heart, lung, liver, kidney and brain. In the retina, it is present in the basement membranes in the Bruch's layer choroid capillary basement membranes, where it localizes just beneath the retinal pigment epithelial cells (at protein level). Weakly expressed. Isoform 2 is expressed in fetal eye, cochlea and heart, and at very low level in brain, CNS, intestine, skeleton, tongue, kidney and lung. Isoform 2 is not expressed in stomach and liver. In adult tissues, isoform 2 is expressed in neural retina and testis, and at low level in brain, heart, kidney and liver. Isoform 1 displays a similar pattern of expression but is expressed at very low level in fetal cochlea.
The PDZ-binding motif probably mediates the association with some of the PDZ domains of USH1C and WHRN.
Component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids. Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules (Probable).
Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit and an accessory beta subunit (Probable). Interacts with beta subunits TMEM30A and TMEM30B.
Contaminating sequence. Sequence of unknown origin inserted in the coding sequence.
Ubiquitously expressed at moderate levels.
Gene prediction based on similarity to orthologs.
B regulatory subunit of protein phosphatase 2A (PP2A) that plays a key role in cell cycle by controlling mitosis entry and exit. The activity of PP2A complexes containing PPP2R2D (PR55-delta) fluctuate during the cell cycle: the activity is high in interphase and low in mitosis. During mitosis, activity of PP2A is inhibited via interaction with phosphorylated ENSA and ARPP19 inhibitors. Within the PP2A complexes, the B regulatory subunits modulate substrate selectivity and catalytic activity, and may also direct the localization of the catalytic enzyme to a particular subcellular compartment (By similarity).
PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with ENSA (when phosphorylated at 'Ser-67') and ARPP19 (when phosphorylated at 'Ser-62'), leading to inhibit PP2A activity (By similarity). Interacts with IER5 (PubMed:25816751).
Heterodimer with DUXA2; disulfide-linked (PubMed:25761904). Interacts with CSNK1G2 (PubMed:37099597).
Required for the maturation and the transport from the endoplasmic reticulum to the plasma membrane of functional DUOX2. May play a role in thyroid hormone synthesis.
Specifically expressed in thyroid. Also detected in salivary glands.
A chromosomal aberration involving BRD3 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;9)(q14;q34) with NUTM1 which produces a BRD3-NUTM1 fusion protein.
Chromatin reader that recognizes and binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling and interaction with transcription factors (PubMed:18406326, PubMed:27105114). Regulates transcription by promoting the binding of the transcription factor GATA1 to its targets (By similarity).
Interacts (via bromo domain 1) with GATA1 acetylated at 'Lys-312' and 'Lys-315'. Interacts (via bromo domain 1) with GATA2 acetylated on lysine residues (By similarity). Interacts (via bromo domains) with acetylated lysine residues on the N-terminus of histone H2A, H2B, H3 and H4 (in vitro).
The Bromo domains specifically recognize and bind acetylated histones.
Binds TAF5 and TAF6. Component of TFIID and the TATA-binding protein-free TAF complex (TFTC). TFIID is composed of TATA binding protein (TBP) and a number of TBP-associated factors (TAFs). Binds N-terminal domain of p53/TP53 which is essential for transcription.
Essential for cell viability. TAF9 and TAF9B are involved in transcriptional activation as well as repression of distinct but overlapping sets of genes. May have a role in gene regulation associated with apoptosis. TAFs are components of the transcription factor IID (TFIID) complex, the TBP-free TAFII complex (TFTC), the PCAF histone acetylase complex and the STAGA transcription coactivator-HAT complex. TFIID or TFTC are essential for the regulation of RNA polymerase II-mediated transcription.
Cleaved by caspases at the onset of apoptosis.
Extended rod-like protein with long coiled-coil domains.
Homodimer, may assemble into homohexamers (PubMed:26363069). Homotetramer; forms a parallel homotetramer with a flexible rod-like structure that can give rise to I- and Y-shaped conformations (By similarity). Interacts with GORASP1/GRASP65 (PubMed:16489344, PubMed:18045989, PubMed:26363069). The homooligomer forms a complex with GORASP1 with a 1:1 stoichiometry (By similarity). Interacts with RAB1B that has been activated by GTP-binding (PubMed:11306556). Interacts with p115/USO1; interaction with p115/USO1 inhibits interaction with STX5 and/or RAB1B. Interacts with STX5 (By similarity). Interacts with ZFPL1 (PubMed:18323775). Interacts with AKAP450/AKAP9; leading to recruit AKAP450/AKAP9 to the cis-Golgi (PubMed:19242490).
Methylation by PRMT5 is required for Golgi ribbon formation. While dimethylation at Arg-30 and Arg-35 are confirmed in vivo, it is unclear whether Arg-18 is methylated in vivo.
Peripheral membrane component of the cis-Golgi stack that acts as a membrane skeleton that maintains the structure of the Golgi apparatus, and as a vesicle thether that facilitates vesicle fusion to the Golgi membrane (Probable) (PubMed:16489344). Required for normal protein transport from the endoplasmic reticulum to the Golgi apparatus and the cell membrane (By similarity). Together with p115/USO1 and STX5, involved in vesicle tethering and fusion at the cis-Golgi membrane to maintain the stacked and inter-connected structure of the Golgi apparatus. Plays a central role in mitotic Golgi disassembly: phosphorylation at Ser-37 by CDK1 at the onset of mitosis inhibits the interaction with p115/USO1, preventing tethering of COPI vesicles and thereby inhibiting transport through the Golgi apparatus during mitosis (By similarity). Also plays a key role in spindle pole assembly and centrosome organization (PubMed:26165940). Promotes the mitotic spindle pole assembly by activating the spindle assembly factor TPX2 to nucleate microtubules around the Golgi and capture them to couple mitotic membranes to the spindle: upon phosphorylation at the onset of mitosis, GOLGA2 interacts with importin-alpha via the nuclear localization signal region, leading to recruit importin-alpha to the Golgi membranes and liberate the spindle assembly factor TPX2 from importin-alpha. TPX2 then activates AURKA kinase and stimulates local microtubule nucleation. Upon filament assembly, nascent microtubules are further captured by GOLGA2, thus linking Golgi membranes to the spindle (PubMed:19242490, PubMed:26165940). Regulates the meiotic spindle pole assembly, probably via the same mechanism (By similarity). Also regulates the centrosome organization (PubMed:18045989, PubMed:19109421). Also required for the Golgi ribbon formation and glycosylation of membrane and secretory proteins (PubMed:16489344, PubMed:17314401).
Phosphorylated at Ser-37 by CDK1 at the onset of mitosis, inhibiting the interaction with p115/USO1 and triggering Golgi disassembly (PubMed:20421892, PubMed:26165940). Phosphorylated at Ser-37 in prophase as the Golgi complex starts to break down, and remains phosphorylated during further breakdown and partitioning of the Golgi fragments in metaphase and anaphase. In telophase, GM130 is dephosphorylated by PP2A as the Golgi fragments start to reassemble (By similarity).
Sequence differs from that shown after position 826 due to an internal deletion.
The nuclear localization signal (cNLS) mediates interaction with importin-alpha, recruiting importin-alpha to the Golgi membrane and liberating TPX2.
Detected in the liver and lung (at protein level).
Associates with the phosphatase 2A holoenzyme. Interacts with PPP2CA; the interaction is direct. Interacts with DVL1 (via PDZ domain); the interaction is direct and regulated by oxidative stress (By similarity).
Functions as a redox-dependent negative regulator of the Wnt signaling pathway, possibly by preventing ubiquitination of DVL3 by the BCR(KLHL12) complex. May also function as a transcriptional regulator act as a regulator of protein phosphatase 2A (PP2A) (By similarity).
Activated by autolytic cleavage after Lys-97.
Autoantigen anti-MMP19 are frequent in RA patients.
Endopeptidase that degrades various components of the extracellular matrix, such as aggrecan and cartilage oligomeric matrix protein (comp), during development, haemostasis and pathological conditions (arthritic disease). May also play a role in neovascularization or angiogenesis. Hydrolyzes collagen type IV, laminin, nidogen, nascin-C isoform, fibronectin, and type I gelatin.
Expressed in mammary gland, placenta, lung, pancreas, ovary, small intestine, spleen, thymus, prostate, testis colon, heart and blood vessel walls. Not detected in brain and peripheral blood leukocytes. Also expressed in the synovial fluid of normal and rheumatoid patients (PubMed:8920941).
Strongly inhibited by TIMP-2, TIMP-3 and TIMP-4, while TIMP-1 is less efficient.
Catalyzes the hydrolysis of epoxide-containing fatty acids. Active in vitro against epoxyeicosatrienoic acids (EETs) including 8,9-EET, 9,10-EET, 11,12-EET and 14,15-EET and leukotoxin.
Inhibited by 1-(1-acetylpiperidin-4-yl)-3-(4-(trifl uoromethoxy)phenyl)urea (TPAU), 1-cyclohexyl-3-dodecylurea (CDU), 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), 1-((3S, 5S, 7S)-adamantan-1-yl)-3-(5-(2-(2-ethoxyethoxy) ethoxy)pentyl)urea (AEPU) and to a lesser extent by 8-(3-((3S, 5S, 7S)-adamantan-1-yl)ureido) octanoic acid (AUOA).
Catalyzes the reduction of the C14-unsaturated bond of lanosterol, as part of the metabolic pathway leading to cholesterol biosynthesis.
Expressed in adult heart, brain, pancreas, lung, liver, skeletal muscle, kidney, ovary, prostate, testis and adrenal gland, but not detected in placenta, spleen, thymus, small intestine, colon (mucosal lining), or peripheral blood leukocytes.
Acts as a positive coregulator of ESR1-mediated transcription in breast cancer cells.
E3 ubiquitin-protein ligase. Acts as a negative coregulator for LIM homeodomain transcription factors by mediating the ubiquitination and subsequent degradation of LIM cofactors LDB1 and LDB2 and by mediating the recruitment the SIN3a/histone deacetylase corepressor complex. Ubiquitination and degradation of LIM cofactors LDB1 and LDB2 allows DNA-bound LIM homeodomain transcription factors to interact with other protein partners such as RLIM. Plays a role in telomere length-mediated growth suppression by mediating the ubiquitination and degradation of TERF1. By targeting ZFP42 for degradation, acts as an activator of random inactivation of X chromosome in the embryo, a stochastic process in which one X chromosome is inactivated to minimize sex-related dosage differences of X-encoded genes in somatic cells of female placental mammals.
Interacts with LIM/homeobox factors such as LHX3. Interacts with LDB1, LDB2 and SIN3A (By similarity). Interacts with LIMK1 (By similarity). Interacts (via N-terminus) with TERF1. Interacts (via C-terminus) with ESR1.
Guanine nucleotide exchange factor (GEF).
Available under the names Niastase or Novoseven (Novo Nordisk). Used for the treatment of bleeding episodes in hemophilia A or B patients with antibodies to coagulation factors VIII or IX.
Can be either O-glucosylated or O-xylosylated at Ser-112 by POGLUT1 in vitro.
Heterodimer of a light chain and a heavy chain linked by a disulfide bond.
Initiates the extrinsic pathway of blood coagulation. Serine protease that circulates in the blood in a zymogen form. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis. In the presence of tissue factor and calcium ions, factor VIIa then converts factor X to factor Xa by limited proteolysis. Factor VIIa will also convert factor IX to factor IXa in the presence of tissue factor and calcium.
O- and N-glycosylated. N-glycosylation at Asn-205 occurs cotranslationally and is mediated by STT3A-containing complexes, while glycosylation at Asn-382 is post-translational and is mediated STT3B-containing complexes before folding. O-fucosylated by POFUT1 on a conserved serine or threonine residue found in the consensus sequence C2-X(4,5)-[S/T]-C3 of EGF domains, where C2 and C3 are the second and third conserved cysteines.
The vitamin K-dependent, enzymatic carboxylation of some glutamate residues allows the modified protein to bind calcium.
A chromosomal aberration involving CD74 is found in a non-small cell lung tumor. Results in the formation of a CD74-ROS1 chimeric protein.
Antiviral activity requires delivery of the thyroglobulin domain to the endosomal membrane.
Binds to the peptide-binding site of MHC class II alpha/beta heterodimers forming an alpha-beta-CLIP complex, thereby preventing the loading of antigenic peptides to the MHC class II complex until its release by HLA-DM in the endosome.
Homotrimer. In the endoplasmic reticulum (ER) it forms a heterononameric MHC II-Ii complex: 3 MHC class II molecules (heterodimers of an alpha and a beta subunit) bind to the CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system, the CD74 component undergoes sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide) attached to the MHC class II molecule (alpha-beta-CLIP complex). This processed complex interacts with HLA_DM and HLA_DO heterodimers in order to release CLIP and facilitate the binding of antigenic peptides to the MHC class II molecules. Interacts with CD44; this complex is essential for the MIF-induced signaling cascade that results in B cell survival.
In B cells, represents 10% of total CD74 expression.
In B cells, represents 70% of total CD74 expression.
Interacts with the mature form of CTSL; the complex survive in neutral pH environment.
O-glycosylated with core 1 or possibly core 8 glycans (PubMed:22171320, PubMed:23234360). Contains chondroitin sulfate (PubMed:25326458).
Plays a critical role in MHC class II antigen processing by stabilizing peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis and directing transport of the complex from the endoplasmic reticulum to the endosomal/lysosomal system where the antigen processing and binding of antigenic peptides to MHC class II takes place. Serves as cell surface receptor for the cytokine MIF.
Stabilizes the conformation of mature CTSL by binding to its active site and serving as a chaperone to help maintain a pool of mature enzyme in endocytic compartments and extracellular space of antigen-presenting cells (APCs). Has antiviral activity by stymieing the endosomal entry of Ebola virus and coronaviruses, including SARS-CoV-2 (PubMed:32855215). Disrupts cathepsin-mediated Ebola virus glycoprotein processing, which prevents viral fusion and entry. This antiviral activity is specific to p41 isoform (PubMed:32855215).
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein gM/UL100.
Acts as a regulator of endocytic traffic by participating in membrane delivery. Required for the abcission step in cytokinesis, possibly by acting as an 'address tag' delivering recycling endosome membranes to the cleavage furrow during late cytokinesis. In case of infection by HCMV (human cytomegalovirus), may participate in egress of the virus out of nucleus; this function is independent of ARF6.
Homodimer. Forms a complex with Rab11 (RAB11A or RAB11B) and ARF6. Interacts with RAB11A; the interaction is direct. Forms a heterooligomeric complex with RAB11FIP2, RAB11FIP3 and RAB11FIP5. Interacts with ECPAS.
Present at high level in testis (at protein level). Weakly expressed in other tissues.
The RBD-FIP domain mediates the interaction with Rab11 (RAB11A or RAB11B).
Auto-ubiquitinated upon EGF-mediated cell activation or upon T-cell costimulation by CD28; which promotes proteasomal degradation.
E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome.
E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome. Negatively regulates TCR (T-cell receptor), BCR (B-cell receptor) and FCER1 (high affinity immunoglobulin epsilon receptor) signal transduction pathways. In naive T-cells, inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 ubiquitination, which impairs its recruitment to the TCR and subsequent activation. In activated T-cells, inhibits PLCG1 activation and calcium mobilization upon restimulation and promotes anergy. In B-cells, acts by ubiquitinating SYK and promoting its proteasomal degradation. Slightly promotes SRC ubiquitination. May be involved in EGFR ubiquitination and internalization. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. In association with CBL, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA (By similarity).
Expressed in placenta, heart, lung, kidney, spleen, ovary and testis, as well as fetal brain and liver and hematopoietic cell lines, but not in adult brain, liver, pancreas, salivary gland, or skeletal muscle. Present in lymphocytes (at protein level).
Interacts with SH3 domain-containing proteins LCK, CRK and SORBS1. Interacts with LCP2 and ZAP70. Interacts with CBL (PubMed:29237719). Interacts with SH3 domain-containing proteins VAV1, FYN, FGR, PLCG1, GRB2, CRKL, PIK3R1 and SH3KBP1/CIN85. Identified in heterotrimeric complexes with SH3KBP1/CIN85, CD2AP and ARHGEF7, where one CBLB peptide binds two copies of the other protein. Interacts with poly-ubiquitinated proteins. Dimerization is required for the binding of poly-ubiquitin, but not for the binding of mono-ubiquitin. Interacts with EGFR (phosphorylated). Interacts with IFT20 (PubMed:29237719).
Phosphorylated on tyrosine and serine residues upon TCR or BCR activation, and upon various types of cell stimulation.
The N-terminus is composed of the phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain.
The UBA domain interacts with poly-ubiquitinated proteins.
This protein has one functional calcium-binding site.
Belongs to the WD repeat coronin family.
Expressed in brain, thymus, spleen, bone marrow and lymph node. Low in lung and gut.
May be a crucial component of the cytoskeleton of highly motile cells, functioning both in the invagination of large pieces of plasma membrane, as well as in forming protrusions of the plasma membrane involved in cell locomotion. In mycobacteria-infected cells, its retention on the phagosomal membrane prevents fusion between phagosomes and lysosomes.
Polyubiquitinated by RNF128 with 'Lys-48'-linked chains, leading to proteasomal degradation.
phosphorylation at Thr-412 by PKC strongly down-regulates the association with actin.
Interacts with FGFR1 and FGFR2. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.
Plays an important role in the regulation of cell proliferation and cell differentiation. Required for normal regulation of the hair growth cycle. Functions as an inhibitor of hair elongation by promoting progression from anagen, the growth phase of the hair follicle, into catagen the apoptosis-induced regression phase (By similarity).
Seems to have an antagonistic effect compared to that of the isoform Long.
As part of the MCIA complex, primarily participates in the assembly of the mitochondrial complex I and therefore plays a role in oxidative phosphorylation (PubMed:20816094, PubMed:24158852, PubMed:32320651). This moonlighting protein has also a dehydrogenase activity toward a broad range of substrates with greater specificity for long-chain unsaturated acyl-CoAs (PubMed:12359260, PubMed:16020546, PubMed:21237683, PubMed:24158852). However, in vivo, it does not seem to play a primary role in fatty acid oxidation (PubMed:20816094, PubMed:24158852). In addition, the function in complex I assembly is independent of the dehydrogenase activity of the protein (PubMed:24158852).
Homodimer (PubMed:16020546). Interacts with NDUFAF1 and ECSIT (PubMed:20816094). Part of the mitochondrial complex I assembly/MCIA complex that comprises at least the core subunits TMEM126B, NDUFAF1, ECSIT and ACAD9 and complement subunits such as COA1 and TMEM186 (PubMed:32320651). Interacts with TMEM70 and TMEM242 (PubMed:33753518).
Ubiquitously expressed in most normal human tissues and cancer cell lines with high level of expression in heart, skeletal muscles, brain, kidney and liver (PubMed:12359260). In the cerebellum uniquely expressed in the granular layer (at protein level) (PubMed:21237683).
Ameloblast-specific. Located at the Tomes processes of secretory ameloblasts and in the sheath space between rod-interrod enamel.
Atypical E2F transcription factor that participates in various processes such as angiogenesis and polyploidization of specialized cells. Mainly acts as a transcription repressor that binds DNA independently of DP proteins and specifically recognizes the E2 recognition site 5'-TTTC[CG]CGC-3'. Directly represses transcription of classical E2F transcription factors such as E2F1: component of a feedback loop in S phase by repressing the expression of E2F1, thereby preventing p53/TP53-dependent apoptosis. Plays a key role in polyploidization of cells in placenta and liver by regulating the endocycle, probably by repressing genes promoting cytokinesis and antagonizing action of classical E2F proteins (E2F1, E2F2 and/or E2F3). Required for placental development by promoting polyploidization of trophoblast giant cells. Acts as a promoter of sprouting angiogenesis, possibly by acting as a transcription activator: associates with HIF1A, recognizes and binds the VEGFA promoter, which is different from canonical E2 recognition site, and activates expression of the VEGFA gene.
Following DNA damage (PubMed:18202719). Up-regulation in response to DNA damage is not confirmed by PubMed:22802528.
Homodimer and heterodimer: mainly forms homodimers and, to a lesser extent, heterodimers with E2F8. Dimerization is important for DNA-binding. Interacts with HIF1A.
In contrast to classical members of the E2F transcription factor, atypical members contain 2 DNA-binding domains and regulate transcription in a DP-independent manner. Both DNA-binding domains are required for DNA-binding and are proposed to form an intramolecular structure that is similar to the winged helix structure of the E2F-DP heterodimer (By similarity).
Induced in vascular endothelium by wounding. This effect is potentiated by prior laminar shear stress, which enhances wound closure.
Self-associates. Interacts with CTNND2 (By similarity). Interacts with CTNND1, and this interaction inhibits binding to both methylated and non-methylated DNA. Interacts with NCOR1. Interacts with KPNA2/RCH1, which may mediate nuclear import of this protein. Interacts with CBFA2T3.
Transcriptional regulator with bimodal DNA-binding specificity. Binds to methylated CpG dinucleotides in the consensus sequence 5'-CGCG-3' and also binds to the non-methylated consensus sequence 5'-CTGCNA-3' also known as the consensus kaiso binding site (KBS). Recruits the N-CoR repressor complex to promote histone deacetylation and the formation of repressive chromatin structures in target gene promoters. May contribute to the repression of target genes of the Wnt signaling pathway. May also activate transcription of a subset of target genes by the recruitment of CTNND2. Represses expression of MMP7 in conjunction with transcriptional corepressors CBFA2T3, CBFA2T2 and RUNX1T1 (PubMed:23251453).
Belongs to the methyltransferase superfamily.
Dual methyltransferase that catalyzes methylation of elongation factor 1-alpha (EEF1A1 and EEF1A2) at two different positions, and is therefore involved in the regulation of mRNA translation (PubMed:30612740, PubMed:30143613). Via its C-terminus, methylates EEF1A1 and EEF1A2 at the N-terminal residue 'Gly-2' (PubMed:30143613). Via its N-terminus dimethylates EEF1A1 and EEF1A2 at residue 'Lys-55' (PubMed:30612740, PubMed:30143613). Has no activity towards core histones H2A, H2B, H3 and H4 (PubMed:30612740). Negatively regulates cell proliferation at G1/S transition via transcriptional suppression of cell cycle regulatory genes such as CDK4 and CDK6 (PubMed:26763933).
Forms a tripartite complex containing GAB1, METTL13 and SPRY2 (PubMed:29408807). Within the complex interacts with GAB1 and SPRY2 (PubMed:29408807).
Genetic variants in METTL13 define the deafness modifier locus DFNB26M [MIM:605429]. The DFNB26M phenotype is characterized by normal hearing despite the presence of homozygosity for a causative deafness mutation in the GAB1 gene.
METTL13 unregulation may be involved in tumorigenesis. High METTL13 expression has been observed in pancreatic and lung cancer tissues, correlates with overexpression of dimethylated elongation factor 1-alpha and is associated with poor clinical outcome. The disease mechanism involves dysregulation of mRNA translation and enhanced protein synthesis to sustain growth of malignant cells.
Present in the circulating blood plasma of cancer patients, particularly in ovarian and non-small cell lung cancer patients, may potentially be used as a biomarker (PubMed:27659353). Acts as a tumor suppressor in bladder cancer suppressing cell migration and invasion (PubMed:26763933). Reduced expression is seen in later stages of the disease (PubMed:26763933).
Protein N-terminal methyltransferase activity is inhibited by GTP and GDP.
Binds to the tyrosine-phosphorylated TCR zeta chain via its SH2 domain.
Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
Preferentially expressed by lymphoid cell lines.
Acts as a GTPase activating protein for RAB5. Does not act on RAB4 or RAB11 (By similarity).
Palmitoylation is required for membrane localization and protects TBC1D3 from ubiquitination.
TBC1D3 is encoded by a collection of very similar paralogs with multiple copies of each paralog, some human genomes encoding well over 50 copies depending on ethnic origin of the donor.
Ubiquitinated by a CUL7-based E3 ligase, which leads to proteasomal degradation.
Acetylated. Deacetylation by SIRT3 increases enzyme activity and promotes mitochondrial ceramide accumulation.
Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward stearoyl-CoA (octadecanoyl-CoA; C18:0-CoA) (PubMed:17977534, PubMed:23530041, PubMed:26887952, PubMed:31916624). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively (PubMed:17977534, PubMed:23530041, PubMed:26887952, PubMed:31916624, PubMed:24782409). Plays a predominant role in skeletal muscle in regulating C18 ceramide and dihydroceramide levels with an impact on whole-body glucose metabolism and insulin sensitivity. Protects from diet-induced obesity by suppressing the uptake of glucose in multiple organs in a FGF21-dependent way (By similarity). Generates C18 ceramides in the brain, playing a critical role in cerebellar development and Purkinje cell function (By similarity). In response to cellular stress mediates mitophagy, a known defense mechanism against cell transformation and aging. Upon mitochondria fission, generates C18 ceramides that anchor lipidated MAP1LC3B/LC3B-II autophagolysosomes to outer mitochondrial membranes to eliminate damaged mitochondria (PubMed:22922758).
This protein is produced by a bicistronic gene which also produces the GDF1 protein from a non-overlapping reading frame.
Component of a multisubunit histone acetyltransferase complex (MSL) at least composed of the KAT8/MOF/MYST1, MSL1/hampin, MSL2 and MSL3 (PubMed:16543150, PubMed:23084835). Forms a MSL heterotetrameric core with MSL1 (PubMed:16543150).
Component of histone acetyltransferase complex responsible for the majority of histone H4 acetylation at lysine 16 which is implicated in the formation of higher-order chromatin structure. Acts as an E3 ubiquitin ligase that promotes monoubiquitination of histone H2B at 'Lys-35' (H2BK34Ub), but not that of H2A. This activity is greatly enhanced by heterodimerization with MSL1. H2B ubiquitination in turn stimulates histone H3 methylation at 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) and leads to gene activation, including that of HOXA9 and MEIS1.
Belongs to the Integrator subunit 10 family.
Belongs to the multiprotein complex Integrator, at least composed of INTS1, INTS2, INTS3, INTS4, INTS5, INTS6, INTS7, INTS8, INTS9/RC74, INTS10, INTS11/CPSF3L and INTS12. Interacts with POLR2A.
Component of the Integrator (INT) complex, a complex involved in the small nuclear RNAs (snRNA) U1 and U2 transcription and in their 3'-box-dependent processing. The Integrator complex is associated with the C-terminal domain (CTD) of RNA polymerase II largest subunit (POLR2A) and is recruited to the U1 and U2 snRNAs genes (Probable). May be not involved in the recruitment of cytoplasmic dynein to the nuclear envelope by different components of the INT complex (PubMed:23904267).
Pore-forming subunit of a voltage-gated ion channel.
Although it belongs to the glycosyl hydrolase 1 family, Asp-201 is present instead of the conserved Glu which is an active site residue. It is therefore expected that this protein lacks glycosidase activity.
Plays a role in formation of the lens suture in the eye, which is important for normal optical properties of the lens.
Heterotetramer of 2 alpha/BCKDHA and 2 beta chains/BCKDHB that forms the branched-chain alpha-keto acid decarboxylase (E1) component of the BCKD complex (PubMed:9582350, PubMed:10745006). The branched-chain alpha-ketoacid dehydrogenase is a large complex composed of three major building blocks E1, E2 and E3. It is organized around E2, a 24-meric cubic core composed of DBT, to which are associated 6 to 12 copies of E1, and approximately 6 copies of the dehydrogenase E3, a DLD dimer (PubMed:10745006).
Together with BCKDHA forms the heterotetrameric E1 subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. The BCKD complex catalyzes the multi-step oxidative decarboxylation of alpha-ketoacids derived from the branched-chain amino-acids valine, leucine and isoleucine producing CO2 and acyl-CoA which is subsequently utilized to produce energy. The E1 subunit catalyzes the first step with the decarboxylation of the alpha-ketoacid forming an enzyme-product intermediate. A reductive acylation mediated by the lipoylamide cofactor of E2 extracts the acyl group from the E1 active site for the next step of the reaction.
High-affinity, low capacity permease involved in the transport of the cationic amino acids (arginine, lysine and ornithine) in non-hepatic tissues.
Interacts with TM4SF5; the interaction is negatively regulated by arginine (PubMed:30956113). Forms tissue-specific complexes with ASL, ASS1 and nitric oxide synthase NOS1 or NOS3; the complex regulates cell-autonomous L-arginine synthesis and citrulline recycling while channeling extracellular L-arginine to nitric oxide synthesis pathway (By similarity).
Implicated in nucleolar organization, ribosome biogenesis, protein synthesis and cytoplasmic dsRNA sensing (By similarity) (PubMed:21930779, PubMed:23871209, PubMed:26100019). Stimulates RNA polymerase I transcription of the 47S precursor rRNA. Associates with ribosomal DNA (rDNA) loci where it is involved in POLR1A recruitment (PubMed:21930779). In the cytoplasm, promotes elongation-competent 80S ribosome assembly at the late stage of mRNA translation initiation (PubMed:26100019). Senses cytosolic dsRNA mediating NLRP3 inflammasome formation in macrophages and type I interferon production in myeloid dendritic cells (PubMed:23871209). Required for NLRP3 activation induced by viral dsRNA and bacterial RNA (PubMed:23871209). In dendritic cells, required for induction of type I interferon production induced by cytoplasmic dsRNA via the activation of MAPK and NF-kappa-B signaling pathways (By similarity).
Interacts with UBTF (PubMed:21930779). Interacts with DDX3X, EIF3G and EIF3H; the interaction is independent of RNA (PubMed:26100019). Interacts (via HA2 region and Helicase C-terminal domain) with the components of the large ribosomal subunit RPL3, RPL7, RPL26 and RPL27 (PubMed:26100019). Interacts (via DEAH box) with NLRP3 (via NACHT domain) (PubMed:23871209). Binds to mRNA (PubMed:26100019). Binds to double-stranded RNA (via the helicase C-terminal domain) (PubMed:23871209). Interacts (via the helicase C-terminal domain) with MAVS (By similarity).
Ubiquitinated, leading to its degradation by the proteasome. Deubiquitinated by USP36.
Forms a SNARE complex with STX7, VTI1B and VAMP8 which functions in the homotypic fusion of late endosomes. Part of the SNARE core complex containing STX7, VAMP8 and VTI1B. Interacts with VAMP8 (By similarity). Interacts with HECTD3 (By similarity). Interacts with TPC1 (By similarity).
Highly expressed in heart. Also found in brain, kidney, liver, lung, placenta, skeletal muscle, spleen and pancreas.
Vesicle trafficking protein that functions in the early secretory pathway, possibly by mediating retrograde transport from cis-Golgi membranes to the ER.
(Microbial infection) Interacts with HCV Serine protease/helicase NS3.
(Microbial infection) Interacts with HCV mature core protein; this interaction, which enhances the interaction of Core with 5'-UTR may favor viral replication over translation.
(Microbial infection) Promotes hepatitis C virus (HCV) replication over translation through the inhibition of viral protein expression. Decreases viral translation by linking viral 5'- and 3'-UTRs, blocking 80S ribosome assembly on the viral IRES and enhancing the interaction of the mature core protein and 5'-UTR.
By p53/TP53 following DNA damage (at protein level) (PubMed:24356969). Up-regulated during embryonic stem cell (ESC) differentiation into cardiomyocytes (PubMed:19658189, PubMed:26990106).
Expressed in fetal and adult heart and skeletal muscles (PubMed:22345307, PubMed:25313962).
Interacts with EIF4E; this interaction prevents EIF4E from binding to p53/TP53 mRNA and inhibits the assembly of translation initiation complex (PubMed:29358667).
Multifunctional RNA-binding protein involved in the regulation of pre-mRNA splicing, mRNA stability and mRNA translation important for cell fate decision and differentiation (PubMed:20977548, PubMed:24375645, PubMed:29358667, PubMed:29104163). Plays a major role in pre-mRNA alternative splicing regulation (PubMed:26990106, PubMed:29104163). Mediates preferentially muscle-specific exon inclusion in numerous mRNAs important for striated cardiac and skeletal muscle cell differentiation (PubMed:29104163). Binds to intronic splicing enhancer (ISE) composed of stretches of GU-rich motifs localized in flanking intron of exon that will be included by alternative splicing (By similarity). Involved in embryonic stem cell (ESC) transition to cardiac cell differentiation by promoting pre-mRNA alternative splicing events of several pluripotency and/or differentiation genes (PubMed:26990106). Plays a role in the regulation of mRNA stability (PubMed:20977548, PubMed:24356969, PubMed:24375645, PubMed:29104163). Binds to 3'-untranslated region (UTR) AU-rich elements in target transcripts, such as CDKN1A and MYOG, leading to maintain their stabilities (PubMed:20977548, PubMed:24356969). Involved in myogenic differentiation by regulating MYOG levels (PubMed:20977548). Binds to multiple regions in the mRNA 3'-UTR of TP63 isoform 2, hence inducing its destabilization (PubMed:24375645). Promotes also the destabilization of the CHRM2 mRNA via its binding to a region in the coding sequence (PubMed:29104163). Plays a role in the regulation of mRNA translation (PubMed:29358667). Mediates repression of p53/TP53 mRNA translation through its binding to U-rich element in the 3'-UTR, hence preventing EIF4E from binding to p53/TP53 mRNA and translation initiation (PubMed:29358667). Binds to a huge amount of mRNAs (PubMed:29104163). Required for embryonic heart development, sarcomer and M-band formation in striated muscles (By similarity). Together with RBM20, promotes the expression of short isoforms of PDLIM5/ENH in cardiomyocytes (By similarity).
The RRM domain is necessary for mRNA stability and mRNA translation regulation (PubMed:24356969, PubMed:29358667).
(Microbial infection) Interacts with HHV-8 IRF1, in the nucleus, with HPV-16 E6 and SV40 LT (PubMed:12163600).
Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis (PubMed:27626371). Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (PubMed:27626371). Involved in the interferon/all-trans-retinoic acid (IFN/RA) induced cell death. This apoptotic activity is inhibited by interaction with viral IRF1. Prevents the transactivation of STAT3 target genes. May play a role in CARD15-mediated innate mucosal responses and serve to regulate intestinal epithelial cell responses to microbes (PubMed:15753091).
Belongs to the complex I NDUFA13 subunit family.
By IFNB1/IFN-beta combined with all-trans-retinoic acid (ATRA).
Complex I is composed of 45 different subunits (PubMed:27626371). Interacts with CARD15, but not with CARD4 (PubMed:12611891, PubMed:15753091). Interacts with STAT3, but not with STAT1, STAT2 and STAT5A (PubMed:12628925, PubMed:12867595). Interacts with OLFM4 (PubMed:15059901).
Widely expressed, with highest expression in heart, skeletal muscle, liver, kidney and placenta. In intestinal mucosa, down-regulated in areas involved in Crohn disease and ulcerative colitis.
Binding to PtdIns(3,5)P2 is not required for localization.
Forms a complex with clathrin heavy chain and gamma-adaptin.
Required for normal morphology of late endosomes and/or lysosomes in neurons (By similarity). Binds phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).
The CRAL-TRIO domain is required for targeting to the membrane and for binding PtdIns(3,5)P2.
Homohexamer formed of two homotrimers in a head to head fashion.
Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases. Catalyzes the transformation of 7,8-dihydroneopterin triphosphate into 6-pyruvoyl tetrahydropterin.
Phosphorylation of Ser-19 is required for maximal enzyme activity.
The active site is at the interface between 2 subunits. The proton acceptor Cys is on one subunit, and the charge relay system is on the other subunit.
Expressed predominantly in skeletal muscle, testis, uterus, brain and kidney. Down-regulated in glioblastoma or glioma compared to non-neoplastic brain due to promoter hypermethylation.
Has acyl-CoA thioesterase activity towards medium and long-chain (C14 to C18) fatty acyl-CoA substrates, and probably plays a role in mitochondrial fatty acid metabolism. Plays a role in the apoptotic process, possibly via its regulation of AKT1 activity. According to PubMed:11598301, inhibits AKT1 phosphorylation and activity. According to PubMed:17615157, enhances AKT1 activity by favoring its phosphorylation and translocation to plasma membrane.
Homodimer and homotetramer. Interacts with AKT1 in the cytosol.
Defects in ATXN1 may be a cause of nephronophthisis a chronic tubulo-interstitial nephropathy that leads to anemia, polyuria, polydipsia, isosthenuria and death in uremia.
Expressed in the central nervous system.
Homooligomer (By similarity). Interacts with OGT (By similarity). Interacts with GNB2. Interacts with IQCB1.
Necessary for the survival of cerebellar neurons. Induces neuritogenesis by activating the Ras-MAP kinase pathway. May play a role in the maintenance of a critical intracellular glycosylation level and homeostasis.
Required for primary cilia formation and promotes the localization of the ciliopathy protein BBS4 to both centriolar satellites and cilia.
Detected in saliva and in hypomineralized dental enamel (at protein level).
May be involved in early liver development.
Component of the DNA replication complex, which interacts with two kinases, CDK2 and CDC7, thereby providing a functional and physical link between CDK2 and CDC7 during firing of the origins of replication (PubMed:16082200, PubMed:19889979). Regulates ATR-mediated checkpoint signaling in response to DNA damage (PubMed:19889979). Also involved in the cytoplasmic maturation steps of pre-60S ribosomal particles by promoting the release of shuttling protein RSL24D1/RLP24 from the pre-ribosomal particles (PubMed:35354024). Promotes maturation of pre-60S ribosome together with AFG2A, AFG2B and AIRIM (PubMed:35354024).
Homodimer (PubMed:16082200). Interacts with CDK2 and CDC7 (PubMed:16082200). Interacts with the components of the replication complex, MCM2, MCM3, MCM4, MCM5, MCM6, MCM7 and with ORC2-containing complexes (PubMed:16082200). Interacts with ATRIP (PubMed:19889979). Interacts with CEP152 (PubMed:21131973). Associates with pre-60S ribosomal particles (PubMed:35354024). Interacts with AIRIM (PubMed:35354024).
Not expressed in the pons, thalamus, hypothalamus, hippocampus, caudate, putamen, frontal cortex, basal forebrain, midbrain or liver.
Belongs to the mitochondrial pyruvate carrier (MPC) (TC 2.A.105) family.
Homodimer (PubMed:32403431). Forms heterodimer with MPC2. The heterodimer is the more stable and dominant form (PubMed:26253029, PubMed:32403431).
Mediates the uptake of pyruvate into mitochondria.
Belongs to the F-actin-capping protein beta subunit family.
F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike other capping proteins (such as gelsolin and severin), these proteins do not sever actin filaments.
F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike other capping proteins (such as gelsolin and severin), these proteins do not sever actin filaments. Plays a role in the regulation of cell morphology and cytoskeletal organization. Forms, with CAPZB, the barbed end of the fast growing ends of actin filaments in the dynactin complex and stabilizes dynactin structure. The dynactin multiprotein complex activates the molecular motor dynein for ultra-processive transport along microtubules (By similarity).
Heterodimer of an alpha and a beta subunit.
Heterodimer of an alpha and a beta subunit. Subunit of dynactin, a multiprotein complex part of a tripartite complex with dynein and a adapter, such as BICDL1, BICD2 or HOOK3. The dynactin complex is built around ACTR1A/ACTB filament and consists of an actin-related filament composed of a shoulder domain, a pointed end and a barbed end. Its length is defined by its flexible shoulder domain. The soulder is composed of 2 DCTN1 subunits, 4 DCTN2 and 2 DCTN3. The 4 DCNT2 (via N-terminus) bind the ACTR1A filament and act as molecular rulers to determine the length. The pointed end is important for binding dynein-dynactin cargo adapters. Consists of 4 subunits: ACTR10, DCNT4, DCTN5 and DCTN6. The barbed end is composed of a CAPZA1:CAPZB heterodimers, which binds ACTR1A/ACTB filament and dynactin and stabilizes dynactin (By similarity). Interacts with ARHGAP17 (PubMed:16678097). Interaction with RCSD1/CAPZIP (PubMed:15850461). Component of the WASH complex, composed of F-actin-capping protein subunit alpha (CAPZA1, CAPZA2 or CAPZA3), F-actin-capping protein subunit beta (CAPZB), WASH (WASHC1, WASH2P, WASH3P, WASH4P, WASH5P or WASH6P), WASHC2 (WASHC2A or WASHC2C), WASHC3, WASHC4 and WASHC5 (PubMed:19922875). Interacts with ACTG1 (PubMed:28493397). Directly interacts with CRACD; this interaction decreases binding to actin (PubMed:30361697).
Acts as a transcriptional repressor. May be involved in DNA damage-inducible cell cycle arrests (checkpoints).
Interacts through its C-terminus with the C-terminus of SNW1/SKIP.
Exhibits transcriptional repressor activity (By similarity). Acts as a TGF-beta antagonist in the nervous system.
Expressed in cerebellum, spinal cord and testis. Isoform 2 is present in cerebellum (at protein level).
Activity is increased by EGF, HGF, FGF1 or FGF2 treatments, and slightly decreased by NGF treatment.
Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA (PubMed:10531356, PubMed:11152681, PubMed:11747828, PubMed:12411503, PubMed:15737618, PubMed:17709427, PubMed:20159986, PubMed:20810653, PubMed:21258366, PubMed:21917714, PubMed:22269951, PubMed:21081503). Specifically mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles (PubMed:12411503, PubMed:11747828, PubMed:17709427). Methylates SUPT5H and may regulate its transcriptional elongation properties (PubMed:12718890). May methylate the N-terminal region of MBD2 (PubMed:16428440). Mono- and dimethylates arginine residues of myelin basic protein (MBP) in vitro. May play a role in cytokine-activated transduction pathways. Negatively regulates cyclin E1 promoter activity and cellular proliferation. Methylates histone H2A and H4 'Arg-3' during germ cell development (By similarity). Methylates histone H3 'Arg-8', which may repress transcription (By similarity). Methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage (By similarity). Methylates RPS10. Attenuates EGF signaling through the MAPK1/MAPK3 pathway acting at 2 levels. First, monomethylates EGFR; this enhances EGFR 'Tyr-1197' phosphorylation and PTPN6 recruitment, eventually leading to reduced SOS1 phosphorylation (PubMed:21917714, PubMed:21258366). Second, methylates RAF1 and probably BRAF, hence destabilizing these 2 signaling proteins and reducing their catalytic activity (PubMed:21917714). Required for induction of E-selectin and VCAM-1, on the endothelial cells surface at sites of inflammation. Methylates HOXA9 (PubMed:22269951). Methylates and regulates SRGAP2 which is involved in cell migration and differentiation (PubMed:20810653). Acts as a transcriptional corepressor in CRY1-mediated repression of the core circadian component PER1 by regulating the H4R3 dimethylation at the PER1 promoter (By similarity). Methylates GM130/GOLGA2, regulating Golgi ribbon formation (PubMed:20421892). Methylates H4R3 in genes involved in glioblastomagenesis in a CHTOP- and/or TET1-dependent manner (PubMed:25284789). Symmetrically methylates POLR2A, a modification that allows the recruitment to POLR2A of proteins including SMN1/SMN2 and SETX. This is required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination (PubMed:26700805). Along with LYAR, binds the promoter of gamma-globin HBG1/HBG2 and represses its expression (PubMed:25092918). Symmetrically methylates NCL (PubMed:21081503). Methylates p53/TP53; methylation might possibly affect p53/TP53 target gene specificity (PubMed:19011621). Involved in spliceosome maturation and mRNA splicing in prophase I spermatocytes through the catalysis of the symmetrical arginine dimethylation of SNRPB (small nuclear ribonucleoprotein-associated protein) and the interaction with tudor domain-containing protein TDRD6 (By similarity).
Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA).
Belongs to the class I-like SAM-binding methyltransferase superfamily.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Protein arginine N-methyltransferase family.
Forms, at least, homodimers and homotetramers (PubMed:11152681). Component of the methylosome complex, composed of PRMT5, WDR77 and CLNS1A (PubMed:21081503, PubMed:23071334, PubMed:33376131). Found in a complex composed of PRMT5, WDR77 and RIOK1 (PubMed:21081503). RIOK1 and CLNS1A associate with PRMT5 in a mutually exclusive fashion, which allows the recruitment of distinct methylation substrates, such as nucleolin/NCL and Sm proteins, respectively (PubMed:21081503). Interacts with PRDM1 (By similarity). Identified in a complex composed of methylosome and PRMT1 and ERH (PubMed:25284789). Interacts with EGFR; methylates EGFR and stimulates EGFR-mediated ERK activation. Interacts with HOXA9. Interacts with SRGAP2. Found in a complex with COPRS, RUNX1 and CBFB. Interacts with CHTOP; the interaction symmetrically methylates CHTOP, but seems to require the presence of PRMT1 (PubMed:25284789). Interacts with EPB41L3; this modulates methylation of target proteins. Component of a high molecular weight E2F-pocket protein complex, CERC (cyclin E1 repressor complex). Associates with SWI/SNF remodeling complexes containing SMARCA2 and SMARCA4. Interacts with JAK2, SSTR1, SUPT5H, BRAF and with active RAF1. Interacts with LSM11, PRMT7 and SNRPD3 (PubMed:17709427, PubMed:16087681). Interacts with COPRS; promoting its recruitment on histone H4. Interacts with CLNS1A/pICln (PubMed:21081503, PubMed:9556550). Identified in a complex with CLNS1A/pICln and Sm proteins. Interacts with RPS10 (PubMed:20159986). Interacts with WDR77. Interacts with IWS1. Interacts with CRY1. Interacts with POLR2A (PubMed:26700805). Interacts with SMN1/SMN2 (PubMed:26700805). Interacts with LYAR; this interaction is direct (PubMed:25092918). Interacts with TTC5/STRAP; this interaction is DNA damage-dependent and promotes PRMT5 interaction with p53/TP53 (PubMed:19011621). Interacts with p53/TP53 in response to DNA damage; the interaction is TTC5/STRAP dependent (PubMed:19011621). Interacts with FAM47E; the interaction is direct, promotes PRMT5 localization to chromatin, and does not disrupt its association with WDR77 or STUB1 (PubMed:33376131). Interacts with TDRD6 (By similarity). Interacts with STUB1 (PubMed:33376131). Interacts with MBD2 (PubMed:16428440). Does not interact with MBD3 (PubMed:16428440).
The homeodomain is essential for interaction with OLIG2.
Transcriptional activator involved in the development of insulin-producting beta cells in the endocrine pancreas (By similarity). May also be involved in specifying diencephalic neuromeric boundaries, and in controlling the expression of genes that play a role in axonal guidance. Binds to elements within the NEUROD1 promoter (By similarity).
Belongs to the eIF4E-binding protein family.
Deamidated at Asn-99 and Asn-102 to aspartate (Asp) in brain. Deamidation promotes interaction with RPTOR, subsequent phosphorylation by mTORC1 and increased translation, leading to impair kinetics of excitatory synaptic transmission. Deamidation takes place during postnatal development, when the PI3K-Akt-mTOR signaling is reduced, suggesting it acts as a compensatory mechanism to promote translation despite attenuated PI3K-Akt-mTOR signaling in neuron development. Deamidation converts Asn residues into a mixture of Asp and isoaspartate; interactions with PCMT1 is required to prevent isoaspartate accumulation and convert isoaspartate to Asp.
Hypophosphorylated EIF4EBP2 interacts with EIF4E; phosphorylation of EIF4EBP2 by mTORC1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation (PubMed:7935836, PubMed:24207126, PubMed:21661078, PubMed:25533957). Interacts with RPTOR; promoting phosphorylation by mTORC1 (By similarity). Interacts with PCMT1; required to prevent isoaspartate accumulation and convert isoaspartate to Asp (By similarity).
Intrinsically disordered protein that undergoes folding upon phosphorylation (PubMed:25533957). Hypophosphorylated form interacts strongly with EIF4E using (1) the YXXXXLPhi motif, that undergoes a disorder-to-helix transition upon binding and (2) the secondary EIF4E binding sites (residues 78-82) (PubMed:24207126, PubMed:25533957). Phosphorylation at Thr-37 and Thr-46 induces folding of region encompassing residues from Pro-18 to Arg-62 of into a four-stranded beta-domain that sequesters the helical YXXXXLPhi motif into a buried beta-strand, blocking accessibility to EIF4E. Protein phosphorylated at Thr-37 and Thr-46 is however unstable and subsequent phosphorylation at Ser-65, Thr-70 and Ser-83 is required to stabilize the fold, decreasing affinity for EIF4E by a factor of 4000 (PubMed:24207126, PubMed:25533957).
Phosphorylation at Thr-37, Thr-46, Ser-65, Thr-70 and Ser-83 is mediated by MTOR and corresponds to the hyperphosphorylated form: it abolishes binding to EIF4E by inducing folding of intrinsically disordered regions (PubMed:24207126, PubMed:25533957). First phosphorylated at Thr-37 and Thr-46 by MTOR, inducing folding of region encompassing residues from Pro-18 to Arg-62 of into a four-stranded beta-domain that sequesters the helical YXXXXLPhi motif into a partly buried beta-strand, blocking accessibility to EIF4E. Protein phosphorylated at Thr-37 and Thr-46 is however unstable and subsequent phosphorylation at Ser-65, Thr-70 and Ser-83 is required to stabilize the fold, decreasing affinity for EIF4E by a factor of 4000 (PubMed:24207126, PubMed:25533957). Phosphorylated in response to insulin, EGF and PDGF.
Repressor of translation initiation involved in synaptic plasticity, learning and memory formation (PubMed:30765518). Regulates EIF4E activity by preventing its assembly into the eIF4F complex: hypophosphorylated form of EIF4EBP2 competes with EIF4G1/EIF4G3 and strongly binds to EIF4E, leading to repress translation. In contrast, hyperphosphorylated form dissociates from EIF4E, allowing interaction between EIF4G1/EIF4G3 and EIF4E, leading to initiation of translation (PubMed:30765518, PubMed:25533957). EIF4EBP2 is enriched in brain and acts as a regulator of synapse activity and neuronal stem cell renewal via its ability to repress translation initiation (By similarity). Mediates the regulation of protein translation by hormones, growth factors and other stimuli that signal through the MAP kinase and mTORC1 pathways (By similarity).
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
The lack of 97 nucleotides within coding exon 2 produces a frameshift and results in a truncated protein.
The number of GQ repeats at position 179 is polymorphic.
Transcription factor with important role in somitogenesis. Defines the rostrocaudal patterning of the somite by participating in distinct Notch pathways. Regulates also the FGF signaling pathway. Specifies the rostral half of the somites. Generates rostro-caudal polarity of somites by down-regulating in the presumptive rostral domain DLL1, a Notch ligand. Participates in the segment border formation by activating in the anterior presomitic mesoderm LFNG, a negative regulator of DLL1-Notch signaling. Acts as a strong suppressor of Notch activity. Together with MESP1 is involved in the epithelialization of somitic mesoderm and in the development of cardiac mesoderm.
Acetylated by CLOCK in a circadian manner which negatively regulates its enzyme activity. Deacetylated by histone deacetylases.
Belongs to the argininosuccinate synthase family. Type 1 subfamily.
Homotetramer (PubMed:18323623). Interacts with NMRAL1 (PubMed:17496144). Interacts with CLOCK; in a circadian manner (PubMed:28985504). Forms tissue-specific complexes with ASL, SLC7A1, HSP90AA1 and nitric oxide synthase NOS1, NOS2 or NOS3; the complex regulates cell-autonomous L-arginine synthesis and citrulline recycling while channeling extracellular L-arginine to nitric oxide synthesis pathway.
One of the enzymes of the urea cycle, the metabolic pathway transforming neurotoxic amonia produced by protein catabolism into inocuous urea in the liver of ureotelic animals. Catalyzes the formation of arginosuccinate from aspartate, citrulline and ATP and together with ASL it is responsible for the biosynthesis of arginine in most body tissues.
Adaptor protein complex 2 (AP-2) is a heterotetramer composed of two large adaptins (alpha-type subunit AP2A1 or AP2A2 and beta-type subunit AP2B1), a medium adaptin (mu-type subunit AP2M1) and a small adaptin (sigma-type subunit AP2S1). Interacts with SGIP1 (By similarity). Interacts with HIP1 and RAB11FIP2 (PubMed:11532990, PubMed:12364336). Interacts with SLC12A5 (By similarity). Interacts with clathrin (By similarity). Interacts with RFTN1 (PubMed:27022195). Interacts with KIAA1107 (PubMed:29262337). Interacts with PICALM (PubMed:16262731). Together with AP2B1 and AP2M1, it interacts with ADAM10; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons (PubMed:23676497). Interacts with ABCB11; this interaction regulates cell membrane expression of ABCB11 through its internalization in a clathrin-dependent manner and its subsequent degradation (PubMed:22262466).
Expressed in the brain (at protein level) (PubMed:23676497). Isoform A: Expressed in forebrain, skeletal muscle, spinal cord, cerebellum, salivary gland, heart and colon. Isoform B: Widely expressed in tissues and also in breast cancer and in prostate carcinoma cells.
Component of the nuclear pore complex (NPC)-associated TREX-2 complex (transcription and export complex 2), composed of at least ENY2, the isoform GANP of the MCM3AP gene, PCID2, SEM1, and either centrin CETN2 or CETN3. TREX-2 contains 2 ENY2 chains. The TREX-2 complex also associates with ALYREF/ALY and with the nucleoporin NUP153 (PubMed:23591820, PubMed:22307388). Component of some SAGA transcription coactivator-HAT complexes, at least composed of ATXN7, ATXN7L3, ENY2, GCN5L2, SUPT3H/SPT3, TAF10, TRRAP and USP22 (PubMed:18206972, PubMed:21746879, PubMed:23591820, PubMed:27601583). Within the SAGA complex, ENY2, ATXN7, ATXN7L3, and USP22 form an additional subcomplex of SAGA called the DUB module (deubiquitination module) (PubMed:18206972, PubMed:21746879, PubMed:27601583). Interacts with RNA polymerase II subunit POLR2A (PubMed:22307388). Interacts with ATXN7L3B (PubMed:27601583).
Involved in mRNA export coupled transcription activation by association with both the TREX-2 and the SAGA complexes. The transcription regulatory histone acetylation (HAT) complex SAGA is a multiprotein complex that activates transcription by remodeling chromatin and mediating histone acetylation and deubiquitination. Within the SAGA complex, participates in a subcomplex that specifically deubiquitinates both histones H2A and H2B. The SAGA complex is recruited to specific gene promoters by activators such as MYC, where it is required for transcription. Required for nuclear receptor-mediated transactivation (PubMed:18206972, PubMed:21746879). As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores (PubMed:23591820).
Belongs to the cyclin family. Cyclin Y subfamily.
Found in a complex with CAPRIN2, LRP6 and CDK14 during G2/M stage; CAPRIN2 functions as a scaffold for the complex by binding to CCNY via its N terminus and to CDK14 via its C terminus (PubMed:27821587). Interacts with CDK14 (PubMed:19524571, PubMed:20059949). Interacts with CDK16 (PubMed:22184064). Interacts with LRP6 (PubMed:20059949).
Heavily phosphorylated. Phosphorylation at Ser-71 and Ser-73 by CDK14 is enhanced during the G2 and M cell cycle phases, and creates a phosphodegron triggering SCF-dependent ubiquitination.
Positive regulatory subunit of the cyclin-dependent kinases CDK14/PFTK1 and CDK16. Acts as a cell-cycle regulator of Wnt signaling pathway during G2/M phase by recruiting CDK14/PFTK1 to the plasma membrane and promoting phosphorylation of LRP6, leading to the activation of the Wnt signaling pathway. Recruits CDK16 to the plasma membrane. Isoform 3 might play a role in the activation of MYC-mediated transcription.
Ubiquitinated; leading to its degradation.
It is uncertain whether Met-1 or Met-29 is the initiator.
Implicated in the regulation of circadian rhythms through autocrine and/or paracrine actions.
Activated by forskolin. After forskolin treatment, activity is further increased by calcium/calmodulin. In the absence of forskolin, calcium/calmodulin has little effect on enzyme activity.
Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.
Binds 2 magnesium ions per subunit. Is also active with manganese (in vitro).
Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.
Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling. Participates in signaling cascades triggered by odorant receptors via its function in cAMP biosynthesis. Required for the perception of odorants. Required for normal sperm motility and normal male fertility. Plays a role in regulating insulin levels and body fat accumulation in response to a high fat diet.
Detected in zona glomerulosa and zona fasciculata in the adrenal gland (at protein level) (PubMed:11549699). Expressed in brain, heart, kidney, liver, lung, pancreas islets, placenta, and skeletal muscle (PubMed:9920776). Detected in testis (PubMed:15705663).
Genetic variations at the ADCY3 locus define the body mass index quantitative trait locus 19 (BMIQ19) [MIM:617885]. Variance in body mass index is a susceptibility factor for obesity.
Rapidly phosphorylated after stimulation by odorants or forskolin. Phosphorylation by CaMK2 at Ser-1076 down-regulates enzyme activity.
Sumoylated. Sumoylation is required for targeting ot olfactory cilia.
The protein contains two modules with six transmembrane helices each; both are required for catalytic activity. Isolated N-terminal or C-terminal modules have no catalytic activity, but when they are brought together, enzyme activity is restored. The active site is at the interface of the two modules.
Atypical E3 ubiquitin-protein ligase which specifically mediates ubiquitination of threonine and serine residues on target proteins, instead of ubiquitinating lysine residues (PubMed:29643511). Shows esterification activity towards both threonine and serine, with a preference for threonine, and acts via two essential catalytic cysteine residues that relay ubiquitin to its substrate via thioester intermediates (PubMed:29643511). Interacts with the E2 enzymes UBE2D1, UBE2D3, UBE2E1 and UBE2L3 (PubMed:18308511, PubMed:29643511). Plays a key role in neural development, probably by mediating ubiquitination of threonine residues on target proteins (Probable). Involved in different processes such as regulation of neurite outgrowth, synaptic growth, synaptogenesis and axon degeneration (By similarity). Required for the formation of major central nervous system axon tracts (By similarity). Required for proper axon growth by regulating axon navigation and axon branching: acts by regulating the subcellular location and stability of MAP3K12/DLK (By similarity). Required for proper localization of retinogeniculate projections but not for eye-specific segregation (By similarity). Regulates axon guidance in the olfactory system (By similarity). Involved in Wallerian axon degeneration, an evolutionarily conserved process that drives the loss of damaged axons: acts by promoting destabilization of NMNAT2, probably via ubiquitination of NMNAT2 (By similarity). Catalyzes ubiquitination of threonine and/or serine residues on NMNAT2, consequences of threonine and/or serine ubiquitination are however unknown (PubMed:29643511). Regulates the internalization of TRPV1 in peripheral sensory neurons (By similarity). Mediates ubiquitination and subsequent proteasomal degradation of TSC2/tuberin (PubMed:18308511, PubMed:27278822). Independently of the E3 ubiquitin-protein ligase activity, also acts as a guanosine exchange factor (GEF) for RAN in neurons of dorsal root ganglia (PubMed:26304119). May function as a facilitator or regulator of transcriptional activation by MYC (PubMed:9689053). Acts in concert with HUWE1 to regulate the circadian clock gene expression by promoting the lithium-induced ubiquination and degradation of NR1D1 (PubMed:20534529).
Belongs to the RING-Cys relay (RCR) family.
Expressed in all tissues examined, expression is exceptionally abundant in brain and thymus. Colocalizes with TSC1 and TSC2 along the neurites and in the growth cones. Highly expressed in peripheral and central neurons. Colocalized with TSC1 in one of the filopodial extensions at the tip of a growth cone.
Interacts with MYC (PubMed:9689053). Interacts with TSC2 (tuberin) when TSC2 is in complex with TSC1 (hamartin) (PubMed:14559897). Interacts with FBXO45 (PubMed:19398581). Interacts with RAE1 (PubMed:22357847). Interacts with CPNE1 (via VWFA domain) and CPNE4 (via VWFA domain) (By similarity). Interacts with (sumoylated) RANGAP1; interaction with sumoylated RANGAP1 inhibits E3 ubiquitin-protein ligase activity and promotes MYCBP2 translocation to the nucleus (PubMed:26304119). Interacts with RAN (PubMed:26304119).Interacts with ATP13A2; the interaction inhibits the ubiquitination of TSC2 by MYCBP2 (PubMed:27278822). Interacts with USP11 (PubMed:29293652).
The PHR domains are compact beta-sandwich folds composed of 11 antiparallel strands and decorated with conserved apical loops. They are likely to play a structural role and mediate interactions with substrates or partners (By similarity).
The tandem cysteine domain region confers threonine specificity and contains the two essential catalytic cysteine residues that relay ubiquitin. It binds four zinc ions in a C5HC7HC2 configuration.
Deletions covering the N-terminal regions of COL4A5 and COL4A6, which are localized in a head-to-head manner, are found in the chromosome Xq22.3 centromeric deletion syndrome. This results in a phenotype with features of diffuse leiomyomatosis and Alport syndrome (DL-ATS).
There are six type IV collagen isoforms, alpha 1(IV)-alpha 6(IV), each of which can form a triple helix structure with 2 other chains to generate type IV collagen network.
Interacts with GABARAP; this interaction may be important for GABARAP protein stability (PubMed:36481789). Isoform 1 interacts with LAMP2; this interaction may be important for LAMP2 protein stability (PubMed:36481789).
Plays a role in spermatogenesis, possibly acting in the regulation of the autophagy pathway.
Testis-specific (PubMed:15499386). Expressed in spermatozoa (at protein level) (PubMed:36481789).
Interacts with SMAD1 and CREB-binding protein (CBP). Forms a protein-DNA complex through its association with SMAD1 (By similarity).
Transcriptional coactivator in the bone morphogenetic protein (BMP)-signaling pathway. It positively modulates BMP signaling by interacting with SMAD1 and associating with CBP in the transcription complex. It contributes to the BMP-induced enhancement of cholinergic-neuron-specific gene expression (By similarity).
Highly expressed in testis, fetal lung and heart, followed by pituitary gland, kidney, interventricular septum, pancreas, heart, trachea, thyroid gland and uterus. Weak hybridization signals were observed in the following tissues: amygdala, aorta, esophagus, colon ascending, colon transverse, skeletal muscle, spleen, peripheral blood leukocyte, lymph node, bone marrow, placenta, prostate, liver, salivary gland, mammary gland, some tumor cell lines, fetal brain, fetal liver, fetal spleen and fetal thymus. No signal at all was detectable in RNA from tissues of the nervous system.
Serine/threonine protein kinase which phosphorylates VIME. May play a specific role in the dynamic behavior of the intermediate filament cytoskeleton by phosphorylation of VIME (By similarity). Not essential for the survival of KRAS-dependent AML cell lines.
Plays a role in mitochondrial electron transport and mitochondrial respiration (PubMed:27252383). Through its regulation of the mitochondrial function may play a role in normal postnatal skeletal growth and cartilage homeostasis (PubMed:27252383, PubMed:10471507).
Predominant expression in adult kidney and testis and fetal kidney. Weaker expression found in placenta, ovary, prostate and small intestine (PubMed:9843955, PubMed:10471507). Also expressed in skeletally-derived cells such as synoviocytes and articular cartilage chondrocytes (PubMed:10471507).
Interacts with RARA (PubMed:17455211). Interacts with SMCHD1; leading to recruitment to inactivated chromosome X in females (PubMed:23542155). Interacts (via PxVxL motif) with HP1 (CBX1/HP1-beta, CBX3/HP1-gamma and CBX5/HP1-alpha) (PubMed:23542155).
The Pro-Xaa-Val-Xaa-Leu (PxVxL) motif mediates interaction with HP1 (CBX1/HP1-beta, CBX3/HP1-gamma and CBX5/HP1-alpha).
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The disease is caused by a LRIF1 homozygous variant resulting in loss of isoform 1, in the presence of an haplotype on chromosome 4 permissive for chromatin relaxation of the D4Z4 macrosatellite and inappropriate DUX4 expression. Deregulated expression of DUX4 in skeletal muscle can lead to cell death.
Together with SMCHD1, involved in chromosome X inactivation in females by promoting the compaction of heterochromatin (PubMed:23542155). Also able to repress the ligand-induced transcriptional activity of retinoic acid receptor alpha (RARA), possibly through direct recruitment of histone deacetylases (PubMed:17455211). Also required for silencing of the DUX4 locus in somatic cells (PubMed:32467133).
Widely expressed, with the highest expression levels in heart, liver and placenta.
Interacts with CDKN2A/p14ARF, p53/TP53 and MDM2. Interacts with CHEK2 and MAPK3. Interacts with XRN2 (PubMed:24462208).
Regulates DNA damage response in a dose-dependent manner through a number of signaling pathways involved in cell proliferation, apoptosis and senescence.
Up-regulated during replicative senescence, in response to DNA-damaging drugs, telomere unprotection and oncogenic Ras-induced stress. Induced by proteasomal inhibitor MG132. Up-regulated at G1 and G2 stages of cell cycle.
Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells. May play an important role in normal bladder epithelial physiology, possibly in regulating membrane permeability of superficial umbrella cells or in stabilizing the apical membrane through AUM/cytoskeletal interactions (By similarity).
Heterodimer with uroplakin-3A (UPK3A) or uroplakin-3B (UPK3B).
N-glycosylated with high-mannose oligosaccharides.
(Microbial infection) Interacts with HCV core protein.
Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner (By similarity). Positively regulates phosphorylated protein HSF1 nuclear export to the cytoplasm (PubMed:12917326).
Homodimer (PubMed:17085597). Heterodimerizes with YWHAZ (PubMed:16376338). Interacts with PKA-phosphorylated AANAT (PubMed:11427721). Interacts with ABL1 (phosphorylated form); the interaction retains it in the cytoplasm (PubMed:15696159). Interacts with ARHGEF28 (By similarity). Interacts with BEX3 (By similarity). Weakly interacts with CDKN1B (PubMed:12042314). Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with DENND1A (PubMed:26055712). Interacts with GAB2 (PubMed:19172738). Interacts with phosphorylated GRB10 (PubMed:15722337). Interacts with KSR1 (PubMed:10409742). Interacts with NDEL1 (By similarity). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with the phosphorylated (by AKT1) form of SRPK2 (PubMed:19592491). Interacts with TIAM2. Interacts with the 'Ser-1134' and 'Ser-1161' phosphorylated form of SOS1 (By similarity). Interacts with ZFP36 (via phosphorylated form) (By similarity). Interacts with SLITRK1 (PubMed:19640509). Interacts with HSF1 (via phosphorylated form); this interaction promotes HSF1 sequestration in the cytoplasm in a ERK-dependent manner (PubMed:12917326). Interacts with RIPOR2 isoform 2 (PubMed:25588844). Interacts with KLHL22; required for the nuclear localization of KLHL22 upon amino acid starvation (PubMed:29769719). Interacts with CRTC1 (PubMed:30611118). Interacts with CRTC2 (probably when phosphorylated at 'Ser-171') (PubMed:30611118). Interacts with CRTC3 (probably when phosphorylated at 'Ser-162' and/or 'Ser-273') (PubMed:30611118). Interacts with ATP2B1 and ATP2B3; this interaction inhibits calcium-transporting ATPase activity (PubMed:18029012). Interacts with MEFV (PubMed:27030597).
Expression is cell cycle dependent with the highest levels during G1, S, and M phases, and low level in G2 phase.
Interacts (via N-terminus coiled coil domains) with tubulin and microtubules.
Promotes the assembly and stability of microtubules.
Interacts (via COMM domain) with COMMD1 (via COMM domain). Interacts with NFKB1/p105. Interacts with CCDC22, CCDC93, SCNN1B, CUL3, CUL4A, CUL4B, CUL5.
May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes (PubMed:21778237). May down-regulate activation of NF-kappa-B (PubMed:15799966). Modulates Na(+) transport in epithelial cells by regulation of apical cell surface expression of amiloride-sensitive sodium channel (ENaC) subunits (PubMed:23637203).
Widely expressed with highest expression in thymus.
Expressed in pancreatic ductal adenocarcinoma (PDAC) (at protein level). Strongly expressed in prostate and thyroid. Weakly expressed in lung, heart, liver and kidney.
Involved in the maintenance of mitochondrial membrane potential in pancreatic ductal adenocarcinoma (PDAC) cells. Promotes pancreatic ductal adenocarcinoma (PDAC) cell growth. May play a role as a nucleotide-sugar transporter.
Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6. This inhibits their ability to interact with cyclins D and to phosphorylate the retinoblastoma protein.
Capable of inducing cell cycle arrest in G1 and G2 phases. Acts as a tumor suppressor. Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus. This inhibits the oncogenic action of MDM2 by blocking MDM2-induced degradation of p53 and enhancing p53-dependent transactivation and apoptosis. Also induces G2 arrest and apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes. Binds to BCL6 and down-regulates BCL6-induced transcriptional repression. Binds to E2F1 and MYC and blocks their transcriptional activator activity but has no effect on MYC transcriptional repression. Binds to TOP1/TOPOI and stimulates its activity. This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation. Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, thus inhibiting rRNA processing. Plays a role in inhibiting ribosome biogenesis, perhaps by binding to the nucleolar localization sequence of transcription termination factor TTF1, and thereby preventing nucleolar localization of TTF1 (By similarity). Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination. Interacts with UBE2I/UBC9 and enhances sumoylation of a number of its binding partners including MDM2 and E2F1. Binds to HUWE1 and represses its ubiquitin ligase activity. May play a role in controlling cell proliferation and apoptosis during mammary gland development.
Does not interact with cyclins, CDK1, CDK2, CDK4, CDK5 or CDK6. Binds to BCL6, E2F1, HUWE1, MDM2, MYC, NPM1/B23, TOP1/TOPOI and UBE2I/UBC9. Interacts with TBRG1 and COMMD1. Interacts with CDKN2AIP and E4F1. Interacts with CDK5RAP3 and MDM2; form a ternary complex involved in regulation of p53/TP53 (PubMed:16173922). Interacts with NOP53; the interaction is direct and promotes ARF nucleoplasmic relocalization and ubiquitin-mediated proteasomal degradation (PubMed:27323397). Interacts with TTF1 (via the N-terminal region (NRD) and a C-terminal region); the interaction is direct and inhibits the nucleolar localization of TTF1 (By similarity).
Heterodimer with CDK4 or CDK6. Predominant p16 complexes contained CDK6. Interacts with CDK4 (both 'T-172'-phosphorylated and non-phosphorylated forms); the interaction inhibits cyclin D-CDK4 kinase activity. Interacts with ISCO2.
May be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP.
Phosphorylation seems to increase interaction with CDK4.
The association between cutaneous and uveal melanomas in some families suggests that mutations in CDKN2A may account for a proportion of uveal melanomas. However, CDKN2A mutations are rarely found in uveal melanoma patients.
The proteins described here are encoded by the gene CDKN2A, but are completely unrelated in terms of sequence and function to cyclin-dependent kinase inhibitor 2A (AC P42771) which is encoded by the same gene.
The proteins described here are encoded by the gene CDKN2A, but are completely unrelated in terms of sequence and function to tumor suppressor ARF (AC Q8N726) which is encoded by the same gene.
Ubiquitinated in normal cells by TRIP12 via the ubiquitin fusion degradation (UFD) pathway, a process that mediates ubiquitination at the N-terminus, regardless of the absence of lysine residues. Ubiquitination leads to its proteasomal degradation. In cancer cells, however, TRIP12 is located in a different cell compartment, preventing ubiquitination and degradation.
Widely expressed but not detected in brain or skeletal muscle. Isoform 3 is pancreas-specific.
Interacts with MTX1/metaxin-1. Associates with the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOOL/MIC27, IMMT/MIC60, APOO/MIC23/MIC26 and QIL1/MIC13. This complex was also known under the names MINOS or MitOS complex. The MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1 and MTX2 (together described as components of the mitochondrial outer membrane sorting assembly machinery (SAM) complex) and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9. The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both membranes termed the mitochondrial intermembrane space bridging (MIB) complex.
Involved in transport of proteins into the mitochondrion.
Interacts with TACC2, TACC3, CCDC52, TALPID3.
Plays a role in the microtubule-dependent coupling of the nucleus and the centrosome. Involved in the processes that regulate centrosome-mediated interkinetic nuclear migration (INM) of neural progenitors and for proper positioning of neurons during brain development. Also implicated in the migration and selfrenewal of neural progenitors. Required for centriole duplication and maturation during mitosis and subsequent ciliogenesis (By similarity). Required for the recruitment of CEP295 to the proximal end of new-born centrioles at the centriolar microtubule wall during early S phase in a PLK4-dependent manner (PubMed:27185865).
May form homooligomers and heterooligomers with ADIPOR2 (PubMed:12802337). Interacts with APPL2 (via BAR domain); hinders the accessibility of APPL1 to ADIPOR1; negatively regulates adiponectin signaling; ADIPOQ dissociates this interaction and facilitates the recruitment of APPL1 to ADIPOR1. Interacts with APPL1; ADIPOQ enhances this interaction; inhibites adiponectin-stimulated binding of APPL2 to ADIPOR1 (By similarity).
Receptor for ADIPOQ, an essential hormone secreted by adipocytes that regulates glucose and lipid metabolism (PubMed:25855295, PubMed:12802337). Required for normal glucose and fat homeostasis and for maintaining a normal body weight. ADIPOQ-binding activates a signaling cascade that leads to increased AMPK activity, and ultimately to increased fatty acid oxidation, increased glucose uptake and decreased gluconeogenesis. Has high affinity for globular adiponectin and low affinity for full-length adiponectin (By similarity).
The N-terminus is cytoplasmic and the C-terminus is extracellular, contrary to what is observed for G-protein coupled receptors. Unlike G-protein coupled receptors, transmembrane helices are not kinked or tilted relative to the plane of the membrane.
Widely expressed (PubMed:16044242). Highly expressed in heart and skeletal muscle (PubMed:12802337). Expressed at intermediate level in brain, spleen, kidney, liver, placenta, lung and peripheral blood leukocytes (PubMed:12802337). Weakly expressed in colon, thymus and small intestine (PubMed:12802337).
ADP-ribosyltransferase which, in association with E3 ligase DTX3L, plays a role in DNA damage repair and in immune responses including interferon-mediated antiviral defenses (PubMed:16809771, PubMed:23230272, PubMed:26479788, PubMed:27796300). Within the complex, enhances DTX3L E3 ligase activity which is further enhanced by PARP9 binding to poly(ADP-ribose) (PubMed:28525742). In association with DTX3L and in presence of E1 and E2 enzymes, mediates NAD(+)-dependent mono-ADP-ribosylation of ubiquitin which prevents ubiquitin conjugation to substrates such as histones (PubMed:28525742). During DNA repair, PARP1 recruits PARP9/BAL1-DTX3L complex to DNA damage sites via PARP9 binding to ribosylated PARP1 (PubMed:23230272). Subsequent PARP1-dependent PARP9/BAL1-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites (PubMed:23230272, PubMed:28525742). In response to DNA damage, PARP9-DTX3L complex is required for efficient non-homologous end joining (NHEJ); the complex function is negatively modulated by PARP9 activity (PubMed:28525742). Dispensable for B-cell receptor (BCR) assembly through V(D)J recombination and class switch recombination (CSR) (By similarity). In macrophages, positively regulates pro-inflammatory cytokines production in response to IFNG stimulation by suppressing PARP14-mediated STAT1 ADP-ribosylation and thus promoting STAT1 phosphorylation (PubMed:27796300). Also suppresses PARP14-mediated STAT6 ADP-ribosylation (PubMed:27796300).
Binding to poly(ADP-ribose) does not affect its activity.
Expressed in lymphocyte-rich tissues, spleen, lymph nodes, peripheral blood lymphocytes and colonic mucosa (PubMed:11110709, PubMed:16809771). Expressed in macrophages (PubMed:27796300). Also expressed in nonhematopoietic tissues such as heart and skeletal muscle (PubMed:11110709, PubMed:16809771). Isoform 2 is the predominant form (PubMed:11110709). Most abundantly expressed in lymphomas with a brisk host inflammatory response (PubMed:11110709, PubMed:16809771). In diffuse large B-cell lymphomas tumors, expressed specifically by malignant B-cells (PubMed:11110709, PubMed:16809771).
Forms a stable complex with E3 ligase DTX3L; the interaction is required for PARP9 mediated ADP-ribosylation of ubiquitin (PubMed:12670957, PubMed:28525742). Interacts (via PARP catalytic domain) with DTX3L (via N-terminus) (PubMed:26479788). Forms a complex with STAT1 and DTX3L independently of IFNB1 or IFNG-mediated STAT1 'Tyr-701' phosphorylation (PubMed:26479788). Forms a complex with STAT1, DTX3L and histone H2B H2BC9/H2BJ; the interaction is likely to induce H2BC9/H2BJ ubiquitination (PubMed:26479788). Interacts (via N-terminus) with STAT1 (PubMed:26479788). Interacts with PARP14 in IFNG-stimulated macrophages; the interaction prevents PARP14-mediated STAT1 and STAT6 ADP-riboslylation (PubMed:27796300). Interacts with PARP1 (when poly-ADP-ribosylated) (PubMed:23230272).
Macro domains 1 and 2 may be involved in the binding to poly(ADP-ribose) (PubMed:28525742, PubMed:26479788). Macro domain 2 is required for recruitment to DNA damage sites (PubMed:23230272). Macro domains 1 and 2 are probably dispensable for the interaction with STAT1 and DTX3L and for STAT1 phosphorylation (PubMed:26479788).
Overexpressed at significantly higher levels in fatal high-risk diffuse large B-cell lymphomas (DLB-CL) compared to cured low-risk tumors. Overexpression in B-cell lymphoma transfectants may promote malignant B-cell migration. May therefore be involved in promoting B-cell migration and dissemination of high-risk DLB-CL tumors (PubMed:11110709).
Up-regulated by IFNG in macrophages and in B-cell lymphoma cell lines (PubMed:16809771, PubMed:27796300, PubMed:26479788). Up-regulated by IFNB1 or viral infection (PubMed:26479788). Down-regulated by IL4 in macrophages (PubMed:27796300).
Homodimer (PubMed:31189666, PubMed:34815401, PubMed:34793198). Associates with the RGS7-GNB5 complex, promoting its localization to the cell membrane and regulating its GTPase activator activity (PubMed:31189666, PubMed:34815401, PubMed:34793198). Interacts (via VCPWE motifs) with GNAO1 (PubMed:31189666). Interacts with GPC4 (By similarity). Interacts with EGFLAM (By similarity).
Metabotropic receptor for glycine that controls synapse formation and function in the brain (PubMed:36996198). Acts as an atypical G-protein coupled receptor that recruits and regulates the RGS7-GNB5 complex instead of activating G proteins (PubMed:31189666, PubMed:36996198). In absence of glycine ligand, promotes the GTPase activator activity of RGS7, increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form (PubMed:36996198). Glycine-binding changes the conformation of the intracellular surface, inhibiting the GTPase activator activity of the RGS7-GNB5 complex, promoting G protein alpha subunits into their active GTP-bound form and regulating cAMP levels (PubMed:36996198). Also able to bind taurine, a compound closely related to glycine, but with a two-fold lower affinity (PubMed:36996198). Glycine receptor-dependent regulation of cAMP controls key ion channels, kinases and neurotrophic factors involved in neuronal excitability and synaptic transmission (PubMed:36996198). Plays a pivotal role in regulating mood and cognition via its ability to regulate neuronal excitability in L2/L3 pyramidal neurons of the prefrontal cortex (By similarity). Also involved in spatial learning by regulating hippocampal CA1 neuronal excitability (By similarity). Acts as a synaptic organizer in the hippocampus, required for proper mossy fiber-CA3 neurocircuitry establishment, structure and function: induces presynaptic differentiation in contacting axons via its interaction with GPC4 (By similarity). In addition to glycine, may also act as a receptor for osteocalcin (BGLAP) hormone: osteocalcin-binding initiates a signaling response that prevents neuronal apoptosis in the hippocampus and regulates the synthesis of neurotransmitters (By similarity).
The Cache-like region shares similarity with the Cache domain, a well-known receptor for amino acids (PubMed:34793198). It acts as a ligand-binding module that recognizes and binds glycine and taurine (PubMed:36996198).
Undergoes proteolytic cleavage by furin protease to yield a 60 kDa soluble form that forms a homotrimer and exhibits a low affinity interaction with heparin.
May be involved in cell-cell interactions. No carboxypeptidase activity was found yet (By similarity).
Acts as a ligand for PILRA in neural tissues, where it may be involved in immune regulation.
Mainly expressed in adult brain and cerebellum. Weaker expression in fetal brain and virtually no expression in spleen, heart, kidney, liver and dorsal ganglion relative to brain.
O-glycosylation at Thr-140 is essential for recognition by PILRA.
A hemichannel or connexon is composed of a hexamer of connexins. A functional gap junction is formed by the apposition of two hemichannels. Forms heteromeric channels with GJA3.
Belongs to the connexin family. Alpha-type (group II) subfamily.
Structural component of eye lens gap junctions (PubMed:18006672, PubMed:19756179). Gap junctions are dodecameric channels that connect the cytoplasm of adjoining cells. They are formed by the docking of two hexameric hemichannels, one from each cell membrane (By similarity). Small molecules and ions diffuse from one cell to a neighboring cell via the central pore (PubMed:18006672, PubMed:19756179).
Cell-cycle-specific regulator of classical non-homologous end joining (NHEJ) of DNA double-strand break (DSB) repair, which can act both as an activator or inhibitor of NHEJ, depending on the cell cycle phase (PubMed:24610814, PubMed:28959974). Acts as a regulator of DNA repair pathway choice by specifically inhibiting classical NHEJ during the S and G2 phases, thereby promoting error-free repair by homologous recombination during cell cycle phases when sister chromatids are present (PubMed:28959974). Preferentially protects single-stranded overhangs at break sites by inhibiting classical NHEJ, thereby creating a local environment that favors homologous recombination (PubMed:28959974). Acts via interaction with XRCC5/Ku80 and XRCC6/Ku70 (PubMed:28959974). In contrast, acts as an activator of NHEJ during G1 phase of the cell cycle: promotes classical NHEJ in G1 phase cells via multivalent interactions that increase the affinity of DNA damage response proteins for DSB-associated chromatin. Also involved in immunoglobulin V(D)J recombination (By similarity). May also act as an indirect regulator of proteasome (By similarity).
Does not interact with XRCC5/Ku80 and XRCC6/Ku70 heterodimer (PubMed:24610814).
Interacts (via KBM motif) with XRCC5/Ku80 and XRCC6/Ku70 heterodimer (PubMed:24610814, PubMed:27063109, PubMed:28959974). Interacts (via XLF motif) with TRIM28/KAP1, ATM, MRE11, NBN and RAD50 (By similarity).
Interacts (via KBM motif) with XRCC5/Ku80 and XRCC6/Ku70 heterodimer (PubMed:24610814, PubMed:28959974).
The KBM (Ku-binding motif) mediates interaction with XRCC5/Ku80 and XRCC6/Ku70 and recruitment to DNA damage sites.
The XLM (XLF-like motif) mediates interaction with DNA damage response proteins TRIM28/KAP1, ATM and members of the MRN complex (MRE11, NBN and RAD50).
Carboxyltransferase subunit of the 3-methylcrotonyl-CoA carboxylase, an enzyme that catalyzes the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step for leucine and isovaleric acid catabolism.
Probably a dodecamer composed of six biotin-containing alpha subunits (MCCC1) and six beta (MCCC2) subunits.
Acts as a linker between gene transcription and histone H2B monoubiquitination at 'Lys-120' (H2BK120ub1) (PubMed:21329877). Interacts with the RNA polymerase II transcriptional machinery via its WW domain and with RNF20-RNF40 via its coiled coil region, thereby linking and regulating H2BK120ub1 and gene transcription (PubMed:21329877). Regulates the cell-cycle checkpoint activation in response to DNA damage (PubMed:21329877). Positive regulator of amino acid starvation-induced autophagy (PubMed:22354037). Also acts as a negative regulator of basal autophagy (PubMed:26812014). Positively regulates MTOR activity by promoting, in an energy-dependent manner, the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex. This leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). May negatively regulate the ubiquitin proteasome pathway (PubMed:21329877).
Defects in WAC are the cause of a form of intellectual disability characterized by hypotonia, behavioral problems and distinctive facial dysmorphisms including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin.
Interacts (via coiled coil domain) with RNF20, RNF40 and UBE2A (PubMed:21329877). Interacts (via WW domain) with RNA polymerase II (PubMed:21329877). Interacts with MTOR and other components of the MTOR pathway including RPTOR, RUVBL1, RUVBL2, TTI1 and TTI2 (PubMed:26812014).
Expressed in heart, placenta, lung, liver, skeletal muscle and pancreas (PubMed:12535658). Not expressed in brain (PubMed:12535658). Expressed in epididymis, kidney, testis, spinal cord, and thymus with a strong expression in epididymis and kidney and a weak expression in the spinal cord and thymus (PubMed:20565543).
May be involved in testis development (By similarity). May play a role in hematopoietic differentiation or inflammation (PubMed:12535658). Has immunomodulatory and antimicrobial functions against Francisella tularensis, a Gram-negative bacteria (PubMed:23922243).
Up-regulated by bacterial lipopolysaccharides (LPS), in some cancer cells such as promyelocytic leukemia cells (HL-60) or myelomonocytic leukemia cells (U-937).
Through its association with the EHMT1-EHMT2/G9A and PRC2/EED-EZH2 histone methyltransferase complexes may function in gene silencing, regulating repressive post-translational methylation of histone tails at promoters of target genes.
Belongs to the protein kinase superfamily. Alpha-type protein kinase family. ALPK subfamily.
D-glycero-beta-D-manno-heptose 1,7-bisphosphate (HBP) was initially thought to constitute the bacterial pathogen-associated molecular pattern metabolite (PAMP) triggering the ALPK1-TIFA innate immunune response (PubMed:28877472, PubMed:28222186). It was however shown that ADP-D-glycero-beta-D-manno-heptose (ADP-Heptose) constitutes the main PAMP that activates the kinase activity of ALPK1 (PubMed:30111836).
Highly expressed in liver. Expressed in the optic nerve and retinal pigmented epithelium. Lower expression is observed in the macula and extramacular retina (PubMed:30967659).
Serine/threonine-protein kinase activity is stimulated upon ADP-D-glycero-beta-D-manno-heptose (ADP-Heptose)-binding.
Serine/threonine-protein kinase that detects bacterial pathogen-associated molecular pattern metabolites (PAMPs) and initiates an innate immune response, a critical step for pathogen elimination and engagement of adaptive immunity (PubMed:28877472, PubMed:28222186, PubMed:30111836). Specifically recognizes and binds ADP-D-glycero-beta-D-manno-heptose (ADP-Heptose), a potent PAMP present in all Gram-negative and some Gram-positive bacteria (PubMed:30111836). ADP-Heptose-binding stimulates its kinase activity to phosphorylate and activate TIFA, triggering pro-inflammatory NF-kappa-B signaling (PubMed:30111836). May be involved in monosodium urate monohydrate (MSU)-induced inflammation by mediating phosphorylation of unconventional myosin MYO9A (PubMed:27169898). May also play a role in apical protein transport by mediating phosphorylation of unconventional myosin MYO1A (PubMed:15883161). May play a role in ciliogenesis (PubMed:30967659).
6-mercaptopurine-transport is inhibited by 6-thioguanine, 6-methylmercaptopurine and decynium-22.
Adenine transport is strongly inhibited by decynium-22.
Sodium-independent purine-selective nucleobase transporter which mediates the equilibrative transport of extracellular purine nucleobase adenine (PubMed:30910793). Mediates the influx and efflux of the purine nucleobase analog drug 6-mercaptopurine across the membrane (PubMed:30910793).
Sodium-independent purine-selective nucleobase transporter which mediates the equilibrative transport of extracellular purine nucleobases such as adenine, guanine and hypoxanthine (PubMed:26455426, PubMed:32339528). May regulate fatty acid (FA) transport in adipocytes, acting as a positive regulator of FA efflux and as a negative regulator of FA uptake (By similarity).
Widely expressed with highest levels in the liver and lung, followed by the pancreas (PubMed:26455426). Highly expressed in macrophages (Ref.1).
Belongs to the BPI/LBP/Plunc superfamily. BPI/LBP family.
May have the capacity to recognize and bind specific classes of odorants. May act as a carrier molecule, transporting odorants across the mucus layer to access receptor sites. May serve as a primary defense mechanism by recognizing and removing potentially harmful odorants or pathogenic microorganisms from the mucosa or clearing excess odorant from mucus to enable new odorant stimuli to be received (By similarity).
Expressed in testis. Expressed in many tumors of various histological types at a level that is 100-fold higher than the level observed in normal tissues except testis.
Lys-50 undergoes hypusination, a unique post-translational modification that consists in the addition of a butylamino group from spermidine to lysine side chain, leading to the formation of the unusual amino acid hypusine. eIF-5As are the only known proteins to undergo this modification, which is essential for their function.
Translation factor that promotes translation elongation and termination, particularly upon ribosome stalling at specific amino acid sequence contexts (By similarity). Binds between the exit (E) and peptidyl (P) site of the ribosome and promotes rescue of stalled ribosome: specifically required for efficient translation of polyproline-containing peptides as well as other motifs that stall the ribosome. Acts as ribosome quality control (RQC) cofactor by joining the RQC complex to facilitate peptidyl transfer during CAT tailing step (By similarity). Also involved in actin dynamics and cell cycle progression, mRNA decay and probably in a pathway involved in stress response and maintenance of cell wall integrity (By similarity).
By ER stress-inducing agents such as tunicamycin, thapsigargin, DTT and the calcium ionophore A23187 (at protein level).
Directly interacts with VCP. Interacts with UBQLN1. Forms a complex with VCP and UBQLN1.
Expressed in many tissues, including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Accumulates in Alzheimer disease-afflicted brains (at protein level).
Involved in endoplasmic reticulum-associated protein degradation (ERAD). Acts as a platform to recruit both UBQLN1 and VCP to the ER during ERAD (PubMed:19822669).
The UBX domain is required for interaction with VCP.
The intramembrane domain also contains the signal for ER targeting.
(Microbial infection) Interacts with Japanese encephalitis virus protein NS3.
(Microbial infection) Interacts with enterovirus 71 protein 2B; this interaction relocalizes ILF2 from the nucleus to the cytoplasm.
(Microbial infection) Plays a positive role in HIV-1 virus production by binding to and thereby stabilizing HIV-1 RNA, together with ILF3.
Chromatin-interacting protein that forms a stable heterodimer with interleukin enhancer-binding factor 3/ILF3 and plays a role in several biological processes including transcription, innate immunity or cell growth (PubMed:18458058, PubMed:31212927). Essential for the efficient reshuttling of ILF3 (isoform 1 and isoform 2) into the nucleus. Together with ILF3, forms an RNA-binding complex that is required for mitotic progression and cytokinesis by regulating the expression of a cluster of mitotic genes. Mechanistically, competes with STAU1/STAU2-mediated mRNA decay (PubMed:32433969). Also plays a role in the inhibition of various viruses including Japanese encephalitis virus or enterovirus 71.
Forms heterodimers with ILF3 (PubMed:18458058). ILF2-ILF3 heterodimers may also bind to PRKDC/XRCC7: this may stabilize the interaction of PRKDC/XRCC7 and the heterodimeric complex of G22P1/KU70 and XRCC5/KU80. Forms a complex with ILF3, YLPM1, KHDRBS1, RBMX, NCOA5 and PPP1CA. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with IGF2BP1. Interacts with CRBN; this interaction promotes ubiquitination and subsequent degradation of ILF2 (PubMed:33009960).
Ubiquitinated at Lys-45 by CRBN with polyubiquitin chains by the CUL4-RING E3 ligase (CRL4-CRBN) and then degraded by the proteasome.
Highly expressed in seminiferous tubes in testis. Highly expressed in spermatids, barely detectable in late pachytene spermatocytes, and not detectable in spermatogonia. Detected at intermediate levels in pancreas and lymph nodes, and at much lower levels in spleen, peripheral blood leukocytes, skeletal muscle, liver, lung, placenta, brain and heart.
Maps to a duplicated region on chromosome 15; the gene is present in at least 4 almost identical copies.
Interacts with FGFBP1. Interacts with FGFR2. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.
Plays an important role in the regulation of embryonic development, cell proliferation and cell differentiation. Required for normal branching morphogenesis. Growth factor active on keratinocytes. Possible major paracrine effector of normal epithelial cell proliferation.
Activated by forskolin (PubMed:17916776, PubMed:17110384). Inhibited by calcium ions, already at micromolar concentrations (By similarity). Inhibited by adenosine, AMP and their analogs (By similarity). Activated by GNAS (PubMed:17110384). Is further activated by the complex formed by GNB1 and GNG2 (PubMed:17110384). Phosphorylation by RAF1 results in its activation (By similarity).
Catalyzes the formation of the signaling molecule cAMP downstream of G protein-coupled receptors (PubMed:17916776, PubMed:17110384). Functions in signaling cascades downstream of beta-adrenergic receptors in the heart and in vascular smooth muscle cells (PubMed:17916776). Functions in signaling cascades downstream of the vasopressin receptor in the kidney and has a role in renal water reabsorption. Functions in signaling cascades downstream of PTH1R and plays a role in regulating renal phosphate excretion. Functions in signaling cascades downstream of the VIP and SCT receptors in pancreas and contributes to the regulation of pancreatic amylase and fluid secretion (By similarity). Signaling mediates cAMP-dependent activation of protein kinase PKA. This promotes increased phosphorylation of various proteins, including AKT. Plays a role in regulating cardiac sarcoplasmic reticulum Ca(2+) uptake and storage, and is required for normal heart ventricular contractibility. May contribute to normal heart function (By similarity). Mediates vasodilatation after activation of beta-adrenergic receptors by isoproterenol (PubMed:17916776). Contributes to bone cell responses to mechanical stimuli (By similarity).
Detected in peripheral blood mononuclear leukocytes (at protein level) (PubMed:17916776). Detected in thyroid (PubMed:10978539).
Part of a complex containing AKAP5, ADCY5, PDE4C and PKD2 (By similarity). Interacts with RAF1 (PubMed:15385642). Interacts (via cytoplasmic N-terminus) with GNAS, GNB1 and GNG2 (PubMed:17110384).
Phosphorylation by RAF1 increases enzyme activity. Phosphorylation by PKA at Ser-662 inhibits the GNAS-mediated increase in catalytic activity. Phosphorylation by PKC at Ser-556, Ser-662 and Thr-919 inhibits catalytic activity.
The protein contains two modules with six transmembrane helices each; both are required for catalytic activity. Isolated N-terminal or C-terminal guanylate cyclase domains have no catalytic activity, but when they are brought together, enzyme activity is restored. The active site is at the interface of the two domains. Both contribute substrate-binding residues, but the catalytic metal ions are bound exclusively via the N-terminal guanylate cyclase domain.
Component of the probable ECS(LRR1) E3 ubiquitin-protein ligase complex which contains CUL2, RBX1, Elongin BC complex and LRR1. Interacts with CUL2, RBX1, ELOB and ELOC.
Substrate recognition subunit of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:15601820). ECS(LRR1) ubiquitinates MCM7 and promotes CMG replisome disassembly by VCP and chromatin extraction during S-phase (By similarity). May negatively regulate the 4-1BB-mediated signaling cascades which result in the activation of NK-kappaB and JNK1 (PubMed:11804328).
Ubiquitous. Maximal expression was seen in the heart and skeletal muscle and minimal expression seen in the kidney.
Enhances IgA secretion from B-cells stimulated via CD40.
It is uncertain whether Met-1 or Met-7 is the initiator.
Forms a complex containing RAB11A, ASAP1, RAB3IP, RAP11FIP3 and ARF4; the complex promotes preciliary trafficking; the complex binds to RHO in photoreceptor cells and promotes RHO ciliary transport.
GTP-binding protein that functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP-ribosyltransferase. Involved in protein trafficking; may modulate vesicle budding and uncoating within the Golgi apparatus. Part of the ciliary targeting complex containing Rab11, ASAP1, Rabin8/RAB3IP, RAB11FIP3 and ARF4, which direct preciliary vesicle trafficking to mother centriole and ciliogenesis initiation (PubMed:25673879).
Expressed in testis, kidney and skeletal muscle.
Produced by DMRT2 bicistronic transcripts (AF284223/AF284224) from non-overlapping reading frame, according to PubMed:10729224.
Transcriptional activator that directly regulates early activation of the myogenic determination gene MYF5 by binding in a sequence-specific manner to the early epaxial enhancer element of it. Involved in somitogenesis during embryogenesis and somite development and differentiation into sclerotome and dermomyotome. Required for the initiation and/or maintenance of proper organization of the sclerotome, dermomyotome and myotome (By similarity).
Autophosphorylated (PubMed:7615558). Phosphorylated by TYK2 on tyrosine residues in response to type-I interferon signaling, leading to its activation (PubMed:8232552). Phosphorylated on tyrosine residues in response to interferon gamma signaling (PubMed:7615558). Dephosphorylation of Tyr-1034 and Tyr-1035 by PTPN2 negatively regulates cytokine-mediated signaling (PubMed:11909529).
Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily.
Expressed at higher levels in primary colon tumors than in normal colon tissue. The expression level in metastatic colon tumors is comparable to the expression level in normal colon tissue.
Interacts with IL31RA (PubMed:15194700). Interacts with IFNGR1 (PubMed:7615558). Interacts with JAKMIP1 (PubMed:15277531). Interacts with SHB (PubMed:12200137). Interacts (via N-terminus) with IL2RB and IL10RA (via its cytoplasmic domain) (PubMed:12133952). Interacts with FER (By similarity).
Mn(2+) was used in the in vitro kinase assay but Mg(2+) is likely to be the in vivo cofactor.
The FERM domain mediates interaction with JAKMIP1.
The protein kinase 1 domain is also called the pseudokinase domain and has a regulatory role through the transactivation of other JAK kinases associated with signaling receptors.
The protein kinase 2 domain is the catalytically active domain.
Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway (PubMed:8232552, PubMed:7615558, PubMed:28111307, PubMed:32750333, PubMed:16239216). Kinase partner for the interleukin (IL)-2 receptor (PubMed:11909529) as well as interleukin (IL)-10 receptor (PubMed:12133952). Kinase partner for the type I interferon receptor IFNAR2 (PubMed:8232552, PubMed:7615558, PubMed:28111307, PubMed:32750333, PubMed:16239216). In response to interferon-binding to IFNAR1-IFNAR2 heterodimer, phosphorylates and activates its binding partner IFNAR2, creating docking sites for STAT proteins (PubMed:7759950). Directly phosphorylates STAT proteins but also activates STAT signaling through the transactivation of other JAK kinases associated with signaling receptors (PubMed:8232552, PubMed:16239216, PubMed:32750333).
Ubiquitinated by RNF125; leading to its degradation by the proteasome.
Controls Rho proteins homeostasis. Regulates the GDP/GTP exchange reaction of the Rho proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them. Retains Rho proteins such as CDC42, RAC1 and RHOA in an inactive cytosolic pool, regulating their stability and protecting them from degradation. Actively involved in the recycling and distribution of activated Rho GTPases in the cell, mediates extraction from membranes of both inactive and activated molecules due its exceptionally high affinity for prenylated forms. Through the modulation of Rho proteins, may play a role in cell motility regulation. In glioma cells, inhibits cell migration and invasion by mediating the signals of SEMA5A and PLXNB3 that lead to inactivation of RAC1.
Monomer (By similarity). Interacts with FER (PubMed:21122136). Interacts with PLXNB3 (By similarity). Forms a heterodimer with RAC1 (PubMed:23434736). Interacts with RHOA, the affinity is increased by three orders of magnitude when RHOA is prenylated (PubMed:20628200, PubMed:20400958, PubMed:26646181, PubMed:23434736). Interacts with PSMD10; the interaction increases ARHGDIA association with RHOA, leading to ARHGDIA-mediated inactivation of RHOA and ROCK and prolonged AKT activation (PubMed:20628200). Interacts with KANK2; the interaction is direct and may regulate the interaction of ARHGDIA with RHOA, RAC1 and CDC42 (PubMed:25961457). Interacts with RHOC (PubMed:20400958). Interacts with CDC42 (PubMed:23434736). Interacts with NGFR (via death domain); NGFR binding decreases the affinity for RHOA (PubMed:26646181).
Interacts with PARP1; leading to activate PARP1 in absence of DNA (PubMed:16924674, PubMed:20064938). Interacts with PRKDC (PubMed:16924674). Interacts with XRCC5/Ku80; the interaction is dependent on nucleic acids (PubMed:16924674, PubMed:24598253). Interacts with XRCC6/Ku70; the interaction is dependent on nucleic acids (PubMed:16924674, PubMed:24598253). Interacts with EZH2, HDAC1, HDAC2, SUZ12, YY1, LRIG3 and LIG4 (PubMed:16924674).
Mono-ADP-ribosyltransferase activity of PARP3 is selectively inhibited by ME0328 compound; ME0328 does not inhibit other ARTD/PARP enzymes, such as PARP1 (PubMed:23742272). Mono-ADP-ribosyltransferase is strongly inhibited by KU0058948 compound (PubMed:19354255).
Mono-ADP-ribosyltransferase that mediates mono-ADP-ribosylation of target proteins and plays a key role in the response to DNA damage (PubMed:16924674, PubMed:20064938, PubMed:21211721, PubMed:21270334, PubMed:25043379, PubMed:24598253, PubMed:28447610, PubMed:19354255, PubMed:23742272). Mediates mono-ADP-ribosylation of glutamate, aspartate or lysine residues on target proteins (PubMed:20064938, PubMed:25043379). In contrast to PARP1 and PARP2, it is not able to mediate poly-ADP-ribosylation (PubMed:25043379). Involved in DNA repair by mediating mono-ADP-ribosylation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism, such as histone H2B, XRCC5 and XRCC6 (PubMed:16924674, PubMed:24598253). ADP-ribosylation follows DNA damage and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks (PubMed:16924674, PubMed:21211721, PubMed:21270334). Involved in single-strand break repair by catalyzing mono-ADP-ribosylation of histone H2B on 'Glu-2' (H2BE2ADPr) of nucleosomes containing nicked DNA (PubMed:27530147). Cooperates with the XRCC5-XRCC6 (Ku80-Ku70) heterodimer to limit end-resection thereby promoting accurate NHEJ (PubMed:24598253). Suppresses G-quadruplex (G4) structures in response to DNA damage (PubMed:28447610). Associates with a number of DNA repair factors and is involved in the response to exogenous and endogenous DNA strand breaks (PubMed:16924674, PubMed:21211721, PubMed:21270334). Together with APLF, promotes the retention of the LIG4-XRCC4 complex on chromatin and accelerate DNA ligation during non-homologous end-joining (NHEJ) (PubMed:21211721). May link the DNA damage surveillance network to the mitotic fidelity checkpoint (PubMed:16924674). Acts as a negative regulator of immunoglobulin class switch recombination, probably by controlling the level of AICDA /AID on the chromatin (By similarity). In addition to proteins, also able to ADP-ribosylate DNA: mediates DNA mono-ADP-ribosylation of DNA strand break termini via covalent addition of a single ADP-ribose moiety to a 5'- or 3'-terminal phosphate residues in DNA containing multiple strand breaks (PubMed:29361132, PubMed:29520010).
Widely expressed; the highest levels are in the kidney, skeletal muscle, liver, heart and spleen; also detected in pancreas, lung, placenta, brain, leukocytes, colon, small intestine, ovary, testis, prostate and thymus.
Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.
Higher expression in cell lines established from normal non-tumorigenic tissues compared to cell lines established from highly metastatic invasive carcinomas (at protein level).
Highly expressed in lung, liver, pancreas, kidney, placenta and melanocytes. Weakly expressed in thyroid gland, ovary, brain, heart and skeletal muscle. Also expressed in erythroleukemia cells. But not expressed in colon.
Inactive tyrosine kinase involved in Wnt signaling pathway. Component of both the non-canonical (also known as the Wnt/planar cell polarity signaling) and the canonical Wnt signaling pathway. Functions in cell adhesion, cell migration, cell polarity, proliferation, actin cytoskeleton reorganization and apoptosis. Has a role in embryogenesis, epithelial tissue organization and angiogenesis.
MMP14 cleaves PTK7 between Pro-621 and Leu-622 generating an N-terminal soluble (70 kDa) fragment and a membrane C-terminal (50 kDa) fragment. Proteolysis by MMP14 regulates PTK7 function in non-canonical Wnt signaling pathway.
May regulate voltage-dependent calcium channels.
Belongs to the class-IV pyridoxal-phosphate-dependent aminotransferase family.
Catalyzes the first reaction in the catabolism of the essential branched chain amino acids leucine, isoleucine, and valine (PubMed:8702755, PubMed:25653144, PubMed:17050531). May also function as a transporter of branched chain alpha-keto acids (By similarity).
The disease is caused by variants affecting the gene represented in this entry. A patient with hypervalinemia and hyperleucine-isoleucinemia was identified as compound heterozygote for Gln-170 (inherited from his father) and Lys-264 (inherited from his mother), both variants reduced the catalytic activity of the enzyme. After treatment with vitamin B6, a precursor of pyridoxal 5'-phosphate, a BCAT2 cofactor, the blood levels of branched chain amino acids, especially valine, were decreased and brain lesions were improved.
By IL6/interleukin-6 and IL8//interleukin-8.
Transfers sialic acid from the donor of substrate CMP-sialic acid to galactose containing acceptor substrates. Has alpha-2,6-sialyltransferase activity toward oligosaccharides that have the Gal-beta-1,4-GlcNAc sequence at the non-reducing end of their carbohydrate groups, but it has weak or no activities toward glycoproteins and glycolipids.
Weakly expressed in some tissues, such as small intestine, colon and fetal brain.
Interacts with SCN8A; regulates SCN8A activity (PubMed:15282281, PubMed:21566136, PubMed:33245860). Interacts with SCN1A; may regulate SCN1A activity (PubMed:19406745, PubMed:21566136). Interacts with SCN5A; the interaction is direct and may regulate SNC5A density at membranes and function (PubMed:21817159). May also interact with SCN2A and SCN11A (PubMed:19406745, PubMed:21566136). Interacts with MAPK8IP2; may regulate the MAPK8IP2 scaffolding activity (PubMed:11378392).
Microtubule-binding protein which directly binds tubulin and is involved in both polymerization and stabilization of microtubules (By similarity). Through its action on microtubules, may participate in the refinement of axons by negatively regulating axonal and leading processes branching (By similarity). Plays a crucial role in neuron polarization and migration in the cerebral cortex and the hippocampus (By similarity). Regulates voltage-gated sodium channel transport and function (PubMed:15282281, PubMed:33245860, PubMed:36696443). May also play a role in MAPK signaling (By similarity). Required for the development of axonal initial segment-targeting inhibitory GABAergic synapses made by chandelier neurons (By similarity).
Ubiquitously expressed. Predominantly expressed in the nervous system.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRR2 sub-subfamily.
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. Rho-2 GABA receptor could play a role in retinal neurotransmission.
Isoform 2 could be translated from an upstream initiator ATG located in frame within the first coding exon. The probability of a signal peptide within this isoform is very low.
Converts UTP and GlcNAc-1-P into UDP-GlcNAc, and UTP and GalNAc-1-P into UDP-GalNAc. Isoform AGX1 has 2 to 3 times higher activity towards GalNAc-1-P, while isoform AGX2 has 8 times more activity towards GlcNAc-1-P.
Monomer and homodimer. Isoform AGX1 is a homodimer. Isoform AGX2 is a monomer.
Widely expressed. Isoform AGX1 is more abundant in testis than isoform AGX2, while isoform AGX2 is more abundant than isoform AGX1 in somatic tissue. Expressed at low level in placenta, muscle and liver.
Dysregulation of CDK5 is associated with neurodegenerative disorders such as Alzheimer, Parkinson, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis.
Expressed in the testis, skeletal muscle, colon, bone marrow and ovary.
Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1 (p25) and macromolecular complex composed of at least CDK5, CDK5R1 (p35) and CDK5RAP1 or CDK5RAP2 or CDK5RAP3. Only the heterodimer shows kinase activity. Under neurotoxic stress and neuronal injury conditions, p35 is cleaved by calpain to generate p25 that hyperactivates CDK5, that becomes functionally disabled and often toxic. Found in a trimolecular complex with CABLES1 and ABL1. Interacts with CABLES1 and CABLES2 (By similarity). Interacts with AATK and GSTP1. Binds to HDAC1 when in complex with p25. Interaction with myristoylation p35 promotes CDK5 association with membranes. Both isoforms 1 and 2 interacts with beta-catenin/CTNNB1. Interacts with delta-catenin/CTNND2 and APEX1. Interacts with P53/TP53 in neurons. Interacts with EPHA4; may mediate the activation of NGEF by EPHA4. Interacts with PTK2/FAK1 (By similarity). The complex p35/CDK5 interacts with CLOCK. Interacts with HTR6 (By similarity).
Inhibited by 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine), 1-isopropyl-4-aminobenzyl-6-ether-linked benzimidazoles, resveratrol, AT-7519 and olomoucine. Activated by CDK5R1 (p35) and CDK5R2 (p39) during the development of the nervous system; degradation of CDK5R1 (p35) and CDK5R2 (p39) by proteasome result in down regulation of kinase activity, during this process, CDK5 phosphorylates p35 and induces its ubiquitination and subsequent degradation. Kinase activity is mainly determined by the amount of p35 available and subcellular location; reversible association to plasma membrane inhibits activity. Long-term inactivation as well as CDK5R1 (p25)-mediated hyperactivation of CDK5 triggers cell death. The pro-death activity of hyperactivated CDK5 is suppressed by membrane association of CDK5, via myristoylation of p35. Brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor (NGF), retinoic acid, laminin and neuregulin promote activity. Neurotoxicity enhances nuclear activity, thus leading to MEF2 phosphorylation and inhibition prior to apoptosis of cortical neurons. Repression by GSTP1 via p25/p35 translocation prevents neurodegeneration.
Phosphorylation at Ser-159 is essential for maximal catalytic activity.
Phosphorylation on Tyr-15 by ABL1 and FYN, and on Ser-159 by casein kinase 1 promotes kinase activity. By contrast, phosphorylation at Thr-14 inhibits activity.
Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3-type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Negatively regulates the CACNA1B/CAV2.2 -mediated Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals (By similarity). Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in postmitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Phosphorylates also exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma-dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-BMAL1 heterodimer in association with altered stability and subcellular distribution.
Ubiquitously expressed (PubMed:17009320, PubMed:19693690). Accumulates in cortical neurons (at protein level) (PubMed:17009320).
Accessory component of the DNA polymerase epsilon complex (PubMed:10801849). Participates in DNA repair and in chromosomal DNA replication (By similarity). Forms a complex with CHRAC1 and binds naked DNA, which is then incorporated into chromatin, aided by the nucleosome-remodeling activity of ISWI/SNF2H and ACF1 (PubMed:10801849). Does not enhance nucleosome sliding activity of the ACF-5 ISWI chromatin remodeling complex (PubMed:14759371).
Component of the DNA polymerase epsilon complex consisting of four subunits: the catalytic subunit POLE and the accessory subunits POLE2, POLE3 and POLE4. Interaction with POLE4 is a prerequisite for further binding with POLE and POLE2. Heterodimer with CHRAC1; binds to DNA (PubMed:10880450). Component of the CHRAC ISWI chromatin remodeling complex at least composed of SMARCA5/SNF2H, BAZ1A/ACF1, CHRAC1 and POLE3; the complex preferentially binds DNA through the CHRAC1-POLE3 heterodimer and possesses ATP-dependent nucleosome-remodeling activity (PubMed:10880450). Within the complex, the heterodimer with CHRAC1 interacts with SMARCA5/SNF2H; the interaction is direct and enhances nucleosome sliding activity by the SMARCA5/SNF2H and BAZ1A/ACF1 interaction (PubMed:10880450, PubMed:14759371). Within the complex, the heterodimer with CHRAC1 interacts with BAZ1A/ACF1; the interactions are direct (PubMed:10880450, PubMed:12434153, PubMed:14759371).
Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter FEM1A (PubMed:29779948). Interacts with PTGER4 (PubMed:16424369). Interacts with NFKB1; the interaction is direct (By similarity).
Frequently down-regulated in rhabdomyosarcoma.
Phosphorylated; highly phosphorylated in myoblasts and myotubes. Phosphorylation at Ser-108 promotes PGE2-EP4-mediated inhibition of inflammation. Dephosphorylated by protein phosphatase 2A (PP2A).
Present in macrophages derived from peripheral blood monocytes. Also present in atheromata (at protein level).
Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:33398168, PubMed:33398170). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (PubMed:29779948, PubMed:33398168, PubMed:33398170). The CRL2(FEM1A) complex specifically recognizes proteins with an arginine at the C-terminus: recognizes and binds proteins ending with -Lys/Arg-Xaa-Arg and -Lys/Arg-Xaa-Xaa-Arg C-degrons, such as SIL1 or OR51B2, leading to their ubiquitination and degradation (PubMed:33398168, PubMed:33398170). Promotes ubiquitination and degradation of SLBP (PubMed:28118078). Involved in PGE2-EP4-mediated inhibition of inflammation of macrophages via interaction with NFKB1 and PTGER4 (By similarity). Promotes inflammation in brain microglia through MAP2K4/MKK4-mediated signaling (By similarity).
Adapter protein which regulates several signal transduction cascades by linking activated receptors to downstream signaling components. May play a role in angiogenesis by regulating FGFR1, VEGFR2 and PDGFR signaling. May also play a role in T-cell antigen receptor/TCR signaling, interleukin-2 signaling, apoptosis and neuronal cells differentiation by mediating basic-FGF and NGF-induced signaling cascades. May also regulate IRS1 and IRS2 signaling in insulin-producing cells.
Interacts with PTPN11 (By similarity). Interacts with phosphorylated 'Tyr-720' of the ligand-activated receptor PDGFRA via its SH2 domain. Interacts with the ligand-activated receptors PDGFRB, FGFR1, KDR/VEGFR2, IL2RB and IL2RG. Interacts with EPS8 and V-SRC. Interacts with GRB2 and GRAP. Interacts with CD3Z. Interacts with tyrosine-phosphorylated LAT upon T-cell antigen receptor activation. Interacts with PLCG1. Interacts with ZAP70, LCP2/SLP-76, VAV1 and GRAP2. Interacts with JAK1 and JAK3. Interacts with PTK2/FAK1. Interacts with CRK/CrKII. Interacts with IRS2.
Phosphorylated upon PDGFRA, PDGFRB, TCR, IL2 receptor, FGFR1 or VEGFR2 activation.
The SH2 domain preferentially binds phosphopeptides with the consensus sequence Y-[TVI]-X-L and mediates interaction with PDGFRA, PDGFRB, FGRFR1, IL2RB, IL2RG, CD3Z and CRK/CrKII.
Inactivates MAP kinases. Has a specificity for the ERK family (PubMed:9858808). Plays an important role in alleviating chronic postoperative pain. Necessary for the normal dephosphorylation of the long-lasting phosphorylated forms of spinal MAPK1/3 and MAP kinase p38 induced by peripheral surgery, which drives the resolution of acute postoperative allodynia (By similarity). Also important for dephosphorylation of MAPK1/3 in local wound tissue, which further contributes to resolution of acute pain (By similarity). Promotes cell differentiation by regulating MAPK1/MAPK3 activity and regulating the expression of AP1 transcription factors (PubMed:29043977).
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in DUSP6 also have a heterozygous mutation in another HH-associated gene including FGFR1 and SPRY4 (PubMed:23643382).
Belongs to the archaeal RpoM/eukaryotic RPA12/RPB9/RPC11 RNA polymerase family.
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates (PubMed:12391170). Component of RNA polymerase III which synthesizes small RNAs, such as 5S rRNA and tRNAs (PubMed:12391170, PubMed:30584594). Plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses (PubMed:19631370, PubMed:19609254). Acts as nuclear and cytosolic DNA sensor involved in innate immune response (PubMed:19631370, PubMed:19609254). Can sense non-self dsDNA that serves as template for transcription into dsRNA (PubMed:19631370, PubMed:19609254). The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF-kappa-B through the RIG-I pathway (PubMed:19631370, PubMed:19609254).
(Microbial infection) Proteolytically processed by Staphylococcus aureus seryl, cysteinyl, and metallo-proteases.
Inhibitor of serine proteases. Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin. Irreversibly inhibits trypsin, chymotrypsin and plasminogen activator. The aberrant form inhibits insulin-induced NO synthesis in platelets, decreases coagulation time and has proteolytic activity against insulin and plasmin.
Interacts with CELA2A (PubMed:31358993). Interacts with ERGIC3 and LMAN1/ERGIC53 (PubMed:31142615). Interacts with PRSS1/trypsin (PubMed:11057674). Interacts with PRSS1/Trypsin (PubMed:11057674). The variants S and Z interact with CANX and PDIA3 (PubMed:23826168).
N-glycosylated. Differential glycosylation produces a number of isoforms. N-linked glycan at Asn-107 is alternatively di-antennary, tri-antennary or tetra-antennary. The glycan at Asn-70 is di-antennary with trace amounts of tri-antennary. Glycan at Asn-271 is exclusively di-antennary. Structure of glycans at Asn-70 and Asn-271 is Hex5HexNAc4. The structure of the antennae is Neu5Ac(alpha1-6)Gal(beta1-4)GlcNAc attached to the core structure Man(alpha1-6)[Man(alpha1-3)]Man(beta1-4)GlcNAc(beta1-4)GlcNAc. Some antennae are fucosylated, which forms a Lewis-X determinant.
Proteolytic processing may yield the truncated form that ranges from Asp-30 to Lys-418.
Reversible chymotrypsin inhibitor. It also inhibits elastase, but not trypsin. Its major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human leukocyte elastase (HLE).
The aberrant form is found in the plasma of chronic smokers, and persists after smoking is ceased. It can still be found ten years after smoking has ceased.
The sequence shown is that of the M1V allele which is the most common form of PI (44 to 49%). Other frequent alleles are: M1A 20 to 23%; M2 10 to 11%; M3 14 to 19%.
Ubiquitous. Expressed in leukocytes and plasma.
Probable guanine nucleotide exchange factor (GEF). May promote the exchange of GDP to GTP, converting inactive GDP-bound small GTPases into their active GTP-bound form (Probable). May play a role in neuritogenesis, as well as in neuronal recovery and/or restructuring in the hippocampus following transient cerebral ischemia (By similarity).
Expressed in spermatozoa (at protein level) (PubMed:22495889).
Involved in fertilization. Seems not to play a direct role in sperm-egg binding or gamete fusion.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CK2 subfamily.
Can use both ATP and GTP as phosphoryl donors. Phosphorylation by casein kinase 2 has been estimated to represent up to one quarter of the eukaryotic phosphoproteome. Casein kinase 2 has been found to be increased at protein level and up-regulated at the level of enzyme activity in the majority of cancers. However, elevated levels of casein kinase 2 are present in certain normal organs such as brain and testes.
Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine (PubMed:11239457, PubMed:11704824, PubMed:16193064, PubMed:19188443, PubMed:20625391, PubMed:22406621, PubMed:24962073, PubMed:31439799). Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection (PubMed:12631575, PubMed:19387552, PubMed:19387551). May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response (PubMed:12631575, PubMed:19387552, PubMed:19387551). During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage (PubMed:11704824, PubMed:19188443). Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis (PubMed:11239457). Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3 (PubMed:16193064). Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8 (PubMed:16193064). Phosphorylates YY1, protecting YY1 from cleavage by CASP7 during apoptosis (PubMed:22184066). Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV (PubMed:19387550, PubMed:12631575, PubMed:19387552, PubMed:19387551, PubMed:23123191). Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, ATF4, SRF, MAX, JUN, FOS, MYC and MYB (PubMed:19387550, PubMed:12631575, PubMed:19387552, PubMed:19387551, PubMed:23123191). Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function (PubMed:19387550). Mediates sequential phosphorylation of FNIP1, promoting its gradual interaction with Hsp90, leading to activate both kinase and non-kinase client proteins of Hsp90 (PubMed:30699359). Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1 (PubMed:19387549). Acts as an ectokinase that phosphorylates several extracellular proteins (PubMed:19387550, PubMed:12631575, PubMed:19387552, PubMed:19387551). During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV (PubMed:19387550, PubMed:12631575, PubMed:19387552, PubMed:19387551). Phosphorylates PML at 'Ser-565' and primes it for ubiquitin-mediated degradation (PubMed:20625391, PubMed:22406621). Plays an important role in the circadian clock function by phosphorylating BMAL1 at 'Ser-90' which is pivotal for its interaction with CLOCK and which controls CLOCK nuclear entry (By similarity). Phosphorylates CCAR2 at 'Thr-454' in gastric carcinoma tissue (PubMed:24962073). Phosphorylates FMR1, promoting FMR1-dependent formation of a membraneless compartment (PubMed:30765518, PubMed:31439799).
Constitutively active protein kinase whose activity is not directly affected by phosphorylation. Seems to be regulated by level of expression and localization.
Expressed in gastric carcinoma tissue and the expression gradually increases with the progression of the carcinoma (at protein level).
Heterotetramer composed of two catalytic subunits (alpha chain and/or alpha' chain) and two regulatory subunits (beta chains). The tetramer can exist as a combination of 2 alpha/2 beta, 2 alpha'/2 beta or 1 alpha/1 alpha'/2 beta subunits. Also part of a CK2-SPT16-SSRP1 complex composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B, which forms following UV irradiation. Interacts with RNPS1. Interacts with SNAI1. Interacts with PML (isoform PML-12). Interacts with CCAR2.
Phosphorylated at Thr-344, Thr-360, Ser-362 and Ser-370 by CDK1 in prophase and metaphase and dephosphorylated during anaphase. Phosphorylation does not directly affect casein kinase 2 activity, but may contribute to its regulation by forming binding sites for interacting proteins and/or targeting it to different compartments.
Interacts (via COMM domain) with COMMD1 (via COMM domain). Interacts with RELA, RELB, NFKB1/p105. Interacts with CCDC22, CCDC93, SCNN1B, CUL2, CUL3, CUL4A, CUL5, CUL7.
May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes (PubMed:21778237). Down-regulates activation of NF-kappa-B.
Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2. Predominantly detected as heterodimer with SKP1; the heterodimer with SKP1 is not part of the SCF(FBXO2) complex (By similarity).
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Involved in the endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins by recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation. Prevents formation of cytosolic aggregates of unfolded glycoproteins that have been retrotranslocated into the cytosol. Able to recognize and bind denatured glycoproteins, preferentially those of the high-mannose type (By similarity).
Belongs to the HAD-like hydrolase superfamily. PHOSPHO family.
Expressed at sites of mineralization in bone and cartilage. Highly expressed in osteoblast cell line SaOS-2 which produces a mineralized matrix, but not in MG-63 cell line, which do not mineralize.
Phosphatase that has a high activity toward phosphoethanolamine (PEA) and phosphocholine (PCho) (PubMed:15175005). Involved in the generation of inorganic phosphate for bone mineralization (By similarity). Acts in a non-redundant manner with PHOSPHO1 in skeletal mineralization: while PHOSPHO1 mediates the initiation of hydroxyapatite crystallization in the matrix vesicles (MVs), ALPL/TNAP catalyzes the spread of hydroxyapatite crystallization in the extracellular matrix (By similarity).
Belongs to the C/M/P thioester hydrolase family.
Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels (PubMed:16940157). Functions as a peroxisomal succinyl-coenzyme A thioesterase that can also hydrolyze glutaryl-CoA and long chain saturated acyl-CoAs (PubMed:16940157).
Compared to mouse peroxisomal succinyl-coenzyme A thioesterase/ACOT4, the human enzyme has a broad substrate specificity overlapping the activity of three mouse acyl-coenzyme A thioesterases, providing an explanation for the unexpectedly low number of acyl-coenzyme A thioesterase genes in the human genome.
Strongest expression in liver and kidney and weaker expression in placenta, heart, and muscle.
Adapter protein and signal transducer that links members of the tumor necrosis factor receptor family to different signaling pathways by association with the receptor cytoplasmic domain and kinases. Mediates activation of NF-kappa-B and probably JNK. Seems to be involved in apoptosis. Plays a role in mediating activation of NF-kappa-B by EIF2AK2/PKR.
Belongs to the TNF receptor-associated factor family. A subfamily.
Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon, and peripheral blood.
Homotrimer (Probable). Heteromer with TRAF3. Associates with TNFRSF5/CD40 through interaction with TRAF3. Associates with LTBR/TNFRSF3, TNFRSF4, TNFRSF8/CD30, TNFRSF11A/RANK, TNFRSF13B/TACI, TNFRSF14, TNFRSF17, TNFRSF19/TROY, RIPK2, MAP3K14, MAP3K5, and TRAF and TNF receptor associated protein TDP2. Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain).
Ubiquitinated at Lys-318 by the SCF(FBXL2) complex, leading to its degradation by the proteasome.
Acts as a ligand of the ADGRL1 receptor. Mediates axon guidance and heterophilic cell-cell adhesion.
Belongs to the tenascin family. Teneurin subfamily.
Cytoplasmic proline-rich regions could serve as docking domains for intracellular SH3-containing proteins.
Derives from the membrane form by proteolytic processing.
Derives from the plasma membrane form by proteolytic cleavage and translocates to the nucleus. Homophilic binding of the C-terminal extracellular domain stimulates its proteolytic cleavage and release in the cytoplasmic. Is subjected to rapid degradation by the proteasome pathway (By similarity).
EGF-like domains 2 and 5 which have an odd number of cysteines might enable the formation of intermolecular disulfide bonds.
Highly expressed in heart, followed by brain, liver, kidney and fetal brain and weakly expressed in lung and testis. No expression was detected in skeletal muscle, pancreas, spleen, ovary and fetal liver.
Homodimer; disulfide-linked (Probable). Heterodimer with either TENM1 or TENM3. May also form heterodimer with TENM4 (By similarity). Isoform 2 (C-terminal globular domain) interacts with ADGRL1 isoform 2.
Involved in neural development, regulating the establishment of proper connectivity within the nervous system. Promotes the formation of filopodia and enlarged growth cone in neuronal cells. Induces homophilic cell-cell adhesion (By similarity). May function as a cellular signal transducer.
Belongs to the Mediator complex subunit 4 family.
G proteins are composed of 3 units, alpha, beta and gamma. Forms a complex with GNAO1 and GNB1 (PubMed:34685729). Interacts with SCN8A (PubMed:26900580).
Interacts with the core subunits NDUFAF1, ECSIT and ACAD9 of the MCIA complex (PubMed:33753518). Interacts with ATP5MC3, NDUFC2, TMEM70, MT-ND2 and MT-ND3 (PubMed:33753518).
Scaffold protein that participates in the c-ring assembly of mitochondrial ATP synthase (F(1)F(0) ATP synthase or complex V) by facilitating the membrane insertion and oligomer formation of the subunit c/ATP5MC3 (PubMed:33753518). Participates in the incorporation of the c-ring into vestigial complexes (PubMed:33753518). Additionally influences the incorporation of subunits MT-ATP6, MT-ATP8, ATP5MJ, and ATP5MK in the ATP synthase (PubMed:33753518).
Homodimer. Found in a complex with SYCP1 and SYCE2. Interacts with SYCP1, SYCE2 and SYCE3. Interacts with SIX6OS1.
Major component of the transverse central element of synaptonemal complexes (SCS), formed between homologous chromosomes during meiotic prophase. Requires SYCP1 in order to be incorporated into the central element. May have a role in the synaptonemal complex assembly, stabilization and recombination.
Expressed in brain, heart, kidney, muscle, intestine and stomach. Not expressed in cerebellum, corpus callosum, caudate nucleus, hippocampus, medulla oblongata and putamen. Expressed in all fetal tissues tested.
Phosphorylation at Ser-714 promotes RNA-binding activity. Following growth factor stimulation phosphorylated at Ser-714, promoting binding to the 3'-UTR of CDKN1B/p27 mRNA.
Recruits the CCR4-POP2-NOT deadenylase leading to translational inhibition and mRNA degradation (PubMed:22955276). In case of viral infection, interacts with DHX58 (PubMed:25340845). Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner (PubMed:23125361).
Sequence-specific RNA-binding protein that acts as a post-transcriptional repressor by binding the 3'-UTR of mRNA targets. Binds to an RNA consensus sequence, the Pumilio Response Element (PRE), 5'-UGUANAUA-3', that is related to the Nanos Response Element (NRE) (PubMed:21572425, PubMed:18328718, PubMed:21653694, PubMed:21397187). Mediates post-transcriptional repression of transcripts via different mechanisms: acts via direct recruitment of the CCR4-POP2-NOT deadenylase leading to translational inhibition and mRNA degradation (PubMed:22955276). Also mediates deadenylation-independent repression by promoting accessibility of miRNAs (PubMed:18776931, PubMed:20818387, PubMed:20860814, PubMed:22345517). Following growth factor stimulation, phosphorylated and binds to the 3'-UTR of CDKN1B/p27 mRNA, inducing a local conformational change that exposes miRNA-binding sites, promoting association of miR-221 and miR-222, efficient suppression of CDKN1B/p27 expression, and rapid entry to the cell cycle (PubMed:20818387). Acts as a post-transcriptional repressor of E2F3 mRNAs by binding to its 3'-UTR and facilitating miRNA regulation (PubMed:22345517, PubMed:29474920). Represses a program of genes necessary to maintain genomic stability such as key mitotic, DNA repair and DNA replication factors. Its ability to repress those target mRNAs is regulated by the lncRNA NORAD (non-coding RNA activated by DNA damage) which, due to its high abundance and multitude of PUMILIO binding sites, is able to sequester a significant fraction of PUM1 and PUM2 in the cytoplasm (PubMed:26724866). Involved in neuronal functions by regulating ATXN1 mRNA levels: acts by binding to the 3'-UTR of ATXN1 transcripts, leading to their down-regulation independently of the miRNA machinery (PubMed:25768905, PubMed:29474920). Plays a role in cytoplasmic sensing of viral infection (PubMed:25340845). In testis, acts as a post-transcriptional regulator of spermatogenesis by binding to the 3'-UTR of mRNAs coding for regulators of p53/TP53. Involved in embryonic stem cell renewal by facilitating the exit from the ground state: acts by targeting mRNAs coding for naive pluripotency transcription factors and accelerates their down-regulation at the onset of differentiation (By similarity). Binds specifically to miRNA MIR199A precursor, with PUM2, regulates miRNA MIR199A expression at a postranscriptional level (PubMed:28431233).
Strongly down-regulated in keratinocytes upon UVB irradiation.
The pumilio repeats mediate the association with RNA by packing together to form a right-handed superhelix that approximates a half donut. RNA-binding occurs on the concave side of the surface (PubMed:21397187). PUM1 is composed of 8 pumilio repeats of 36 residues; each repeat binds a single nucleotide in its RNA target. Residues at positions 12 and 16 of the pumilio repeat bind each RNA base via hydrogen bonding or van der Waals contacts with the Watson-Crick edge, while the amino acid at position 13 makes a stacking interaction. The recognition of RNA by pumilio repeats is base specific: cysteine and glutamine at position 12 and 16, respectively, bind adenine; asparagine and glutamine bind uracil; and serine and glutamate bind guanine (PubMed:21572425, PubMed:18328718, PubMed:21653694).
A short soluble form is released from the membrane by proteolysis (PubMed:26876177). The sIL6R is formed mostly by limited proteolysis of membrane-bound receptors, a process referred to as ectodomain shedding, but is also directly secreted from the cells after alternative mRNA splicing (PubMed:26876177, PubMed:28060820). mIL6R is cleaved by the proteases ADAM10 and ADAM17 (PubMed:26876177, PubMed:28060820).
Also interacts with SORL1; this interaction leads to soluble IL6R internalization. May form a trimeric complex with the soluble SORL1 ectodomain and circulating IL6 receptor; this interaction might stabilize circulating IL6, hence promote IL6 'trans-signaling,.
Classic and trans-signaling are both inhibited by tocilizumab, a humanized monoclonal antibody that blocks interleukin IL6R signaling.
Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; first binds to IL6 to associate with the signaling subunit IL6ST (PubMed:12829785, PubMed:28265003). Interacts (via N-terminal ectodomain) with SORL1; this interaction may affect IL6-binding to IL6R, hence decrease IL6 'classic-signaling' (PubMed:28265003).
Expressed in peripheral blood mononuclear cells and weakly found in urine and serum. 1%-20% of the total sIL6R in plasma is generated by alternative splicing (PubMed:28060820).
Genetic variations in IL6R define the IL6 serum level quantitative trait locus [MIM:614752].
Genetic variations in IL6R determine soluble IL6R serum levels [MIM:614689].
Glycosylated. Glycosylation is dispensable for transport, signaling, and cell-surface turnover. Glycosylation at Asn-55 is a protease-regulatory exosite. Glycosylation is required for ADAM17-mediated proteolysis.
Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal (PubMed:28265003). Signal activation necessitate an association with IL6ST. Activation leads to the regulation of the immune response, acute-phase reactions and hematopoiesis (PubMed:30995492, PubMed:31235509). The interaction with membrane-bound IL6R and IL6ST stimulates 'classic signaling', the restricted expression of the IL6R limits classic IL6 signaling to only a few tissues such as the liver and some cells of the immune system. Whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors on neighboring receiver cells (Probable).
Signaling via the membrane-bound IL6R is mostly regenerative and anti-inflammatory (Probable). Drives naive CD4(+) T cells to the Th17 lineage, through 'cluster signaling' by dendritic cells (By similarity).
Soluble form of IL6 receptor (sIL6R) that acts as an agonist of IL6 activity (PubMed:21990364). The IL6:sIL6R complex (hyper-IL6) binds to IL6ST/gp130 on cell surfaces and induces signaling also on cells that do not express membrane-bound IL6R in a process called IL6 'trans-signaling'. sIL6R is causative for the pro-inflammatory properties of IL6 and an important player in the development of chronic inflammatory diseases (PubMed:21990364). In complex with IL6, is required for induction of VEGF production (PubMed:12794819). Plays a protective role during liver injury, being required for maintenance of tissue regeneration (By similarity). 'Trans-signaling' in central nervous system regulates energy and glucose homeostasis (By similarity).
The two fibronectin type-III-like domains, contained in the N-terminal part, form together a cytokine-binding domain.
Belongs to the band 7/mec-2 family. Flotillin subfamily.
Heterooligomeric complex of flotillin-1 and flotillin-2 and caveolin-1 and caveolin-2 (By similarity). Interacts with ECPAS.
Heterooligomeric complex of flotillin-1 and flotillin-2 and caveolin-1 and caveolin-2. Interacts with ECPAS.
In skin, expressed in epidermis and epidermal appendages but not in dermis. Expressed in all layers of the epidermis except the basal layer. In hair follicles, expressed in the suprabasal layer but not the basal layer. Also expressed in melanoma and carcinoma cell lines, fibroblasts and foreskin melanocytes.
May act as a scaffolding protein within caveolar membranes, functionally participating in formation of caveolae or caveolae-like vesicles.
May act as a scaffolding protein within caveolar membranes, functionally participating in formation of caveolae or caveolae-like vesicles. May be involved in epidermal cell adhesion and epidermal structure and function.
ZDHHC5-catalyzed palmitoylation predominantly occurs at Cys-4. ZDHHC5-catalyzed palmitoylation may be required for the formation of higher-order complexes and for neurite outgrowth in cultured neural stem cells.
Belongs to the immunoglobulin superfamily. Contactin family.
In conjunction with another transmembrane protein, CNTNAP2, contributes to the organization of axonal domains at nodes of Ranvier by maintaining voltage-gated potassium channels at the juxtaparanodal region. May be involved in cell adhesion.
Expressed in melanocytes (PubMed:23999003).
Probable calcium-dependent phospholipid-binding protein that may play a role in calcium-mediated intracellular processes (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003).
Belongs to the peptidase M24B family. Eukaryotic-type prolidase subfamily.
Dipeptidase that catalyzes the hydrolysis of dipeptides with a prolyl (Xaa-Pro) or hydroxyprolyl residue in the C-terminal position (PubMed:17081196, PubMed:35165443). The preferred dipeptide substrate is Gly-Pro, but other Xaa-Pro dipeptides, such as Ala-Pro, Met-Pro, Phe-Pro, Val-Pro and Leu-Pro, can be cleaved (PubMed:17081196). Plays an important role in collagen metabolism because the high level of iminoacids in collagen (PubMed:2925654).
Specifically inhibited by the pseudodipeptide CQ31 (PubMed:35165443). Inhibition by CQ31 indirectly activates the CARD8 inflammasome: dipeptide accumulation following PEPD inactivation weaky inhibit dipeptidyl peptidases DDP8 and DPP9, relieving DPP8- and/or DPP9-mediated inhibition of CARD8 (PubMed:35165443).
(Microbial infection) Identified in a complex with IK and influenza A virus RNA polymerase subunits PB1 and PB2; does not directly interact with the viral proteins by itself.
(Microbial infection) Required, together with IK, for normal splicing of influenza A virus NS1 pre-mRNA, which is required for the production of the exportin NS2 and for the production of influenza A virus particles. Not required for the production of VSV virus particles.
Component of the spliceosome B complex (PubMed:22365833, PubMed:28781166). Interacts with IK (PubMed:28781166, PubMed:24945353, PubMed:22365833).
Involved in pre-mRNA splicing as a component of the spliceosome (PubMed:28781166). Regulates alternative splicing of the HSPG2 pre-mRNA (By similarity). Required for normal accumulation of IK (PubMed:24945353). Required for normal mitotic spindle assembly and normal progress through mitosis (By similarity).
The WD repeats assemble into a seven-bladed WD propeller.
Expressed in various brain regions, including cerebellum, corpus callosum, cortex, striatum, brainstem, pons, putamen, spinal cord and substantia nigra. Very low expression in non-neural tissues such as leukocytes, liver, adipose tissue, skeletal muscle and bone marrow.
Interacts with HSPA8/HSC70. Interacts with CLTC. Interacts with AP2A2 (By similarity).
Recruits HSPA8/HSC70 to clathrin-coated vesicles and promotes uncoating of clathrin-coated vesicles. Plays a role in clathrin-mediated endocytosis in neurons (By similarity).
Belongs to the phospholipid scramblase family.
Expression of isoform 1 seems restricted to testis.
Isoform 1 has no prospholipid scramblase activity, due to the lack of a N-terminal proline-rich domain.
May mediate accelerated ATP-independent bidirectional transbilayer migration of phospholipids upon binding calcium ions that results in a loss of phospholipid asymmetry in the plasma membrane. May play a central role in the initiation of fibrin clot formation, in the activation of mast cells and in the recognition of apoptotic and injured cells by the reticuloendothelial system.
The N-terminal proline-rich domain (PRD) is required for phospholipid scramblase activity.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-10/CHRNA10 sub-subfamily.
Expressed in inner-ear tissue, tonsil, immortalized B-cells, cultured T-cells and peripheral blood lymphocytes.
Forms heterooligomeric channels in conjunction with CHRNA9. The native outer hair cell receptor may be composed of CHRNA9-CHRNA10 heterooligomers. Interacts with the conotoxin GeXXA (PubMed:26395518). Interacts with the alpha-conotoxin RgIA (By similarity).
Ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding may induce an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The channel is permeable to a range of divalent cations including calcium, the influx of which may activate a potassium current which hyperpolarizes the cell membrane. In the ear, this may lead to a reduction in basilar membrane motion, altering the activity of auditory nerve fibers and reducing the range of dynamic hearing. This may protect against acoustic trauma.
The heterooligomeric receptor composed of CHRNA9 and CHRNA10 has an atypical pharmacological profile, binding several non-nicotinic ligands including strychnine (a glycine receptor antagonist) and atropine (a muscarinic acetylcholine receptor antagonist).
Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Has a broad spectrum of substrates for peptides such as EA2, Muc5AC, Muc1a, Muc1b. Probably involved in O-linked glycosylation of the immunoglobulin A1 (IgA1) hinge region. Involved in O-linked glycosylation of APOC-III, ANGPTL3 and PLTP. It participates in the regulation of HDL-C metabolism (PubMed:27508872, PubMed:32293671).
Catalyzes the hydrolysis of nucleoside triphosphates and diphosphates in a calcium- or magnesium-dependent manner. Preferentially hydrolyzes nucleoside 5'-triphosphates, with substrate preference for UTP > GTP > CTP. Hydrolyzes ATP and nucleoside diphosphates only to a minor extent.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). CF(0) has three main subunits: a, b and c. Interacts with TMEM70 and TMEM242 (PubMed:33753518).
Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(0) domain. A homomeric c-ring of probably 10 subunits is part of the complex rotary element.
There are three genes which encode the mitochondrial ATP synthase proteolipid and they specify precursors with different import sequences but identical mature proteins. Is the major protein stored in the storage bodies of animals or humans affected with ceroid lipofuscinosis (Batten disease).
Trimethylated by ATPSCKMT at Lys-110. Methylation is required for proper incorporation of the C subunit into the ATP synthase complex and mitochondrial respiration.
Expressed in epithelium of normal cervix and cervical cancer. Overexpressed in early and interim cervical cancer.
Plays a role in somitogenesis. Required for somite segregation and establishment of rostrocaudal polarity in somites (By similarity).
The WRPW motif is required for binding to tle/groucho proteins.
The ripply homology domain is required for transcriptional repression.
Expressed at high levels in colon, kidney, testis, lung and pancreas, and at lower levels in small intestine, liver and skeletal muscle. In immune cells, highly expressed in B-cells, dendritic cells and macrophages. Not detected in T-cells.
Through interaction with TMIGD2, costimulates T-cells in the context of TCR-mediated activation. Enhances T-cell proliferation and cytokine production via an AKT-dependent signaling cascade.
Up-regulated in antigen-presenting cells in response to inflammation. Induced in dendritic cells in response to IFNG, poly(I:C) or heat-killed Listeria monocytogenes (at protein level).
Deubiquitinase which hydrolyzes the isopeptide bond between the ubiquitin C-terminus and the lysine epsilon-amino group of the target protein (PubMed:23827681, PubMed:25944111, PubMed:29395066). May negatively regulate inflammatory and pathogen recognition signaling in innate immune response. Upon phosphorylation at Ser-202 and Ser-204 residues, via IL-1 receptor and Toll-like receptor signaling pathway, specifically deubiquitinates 'Lys-63'-polyubiquitinated MYD88 adapter protein triggering down-regulation of NF-kappa-B-dependent transcription of inflammatory mediators (PubMed:29395066). Independently of the catalytic activity, acts as a scaffold for alternative deubiquitinases to assemble specific deubiquitinase-substrate complexes. Associates with USP7 and USP9X deubiquitinases to stabilize alkylation repair enzyme ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111).
Interacts with MYD88; the interaction is direct (PubMed:29395066). Interacts with ALKBH3; the interaction is direct (PubMed:25944111). Interacts with USP7; the interaction is direct (PubMed:25944111). Interacts with USP9X; the interaction is direct (PubMed:25944111).
Phosphorylated on Ser-202 and Ser-204 likely by CSNK2A1-CSNK2A2 serine/threonine-protein kinase complex. Activates 'Lys-63'-specific deubiquitinase activity.
Phosphorylation on Ser-202 and Ser-204 induces 'Lys-63'-specific deubiquitinase activity.
Predicted from a chimeric transcript isolated from HIV-1-infected cells. The premature stop may be due to intron retention.
Sequence of unknown origin in the N-terminal part.
When expressed in bacteria, recombinant OTUD4 specifically hydrolyzes 'Lys-48'-linked diubiquitin. The physiological relevance of this activity remains unknown (PubMed:23827681, PubMed:25944111, PubMed:29395066). In vivo deubiquitinates 'Lys-63'-linked ubiquitin chains (PubMed:29395066).
By p53/TP53 and p73/TP73. Directly activated by p53/TP53. Significantly down-regulated in tumor cell lines by methylation-dependent transcriptional silencing.
Lysosomal modulator of autophagy that plays a central role in p53/TP53-mediated apoptosis. Not involved in p73/TP73-mediated autophagy.
Belongs to the MsrB Met sulfoxide reductase family.
Methionine-sulfoxide reductase that specifically reduces methionine (R)-sulfoxide back to methionine. While in many cases, methionine oxidation is the result of random oxidation following oxidative stress, methionine oxidation is also a post-translational modification that takes place on specific residue. Acts as a regulator of actin assembly by reducing methionine (R)-sulfoxide mediated by MICALs (MICAL1, MICAL2 or MICAL3) on actin, thereby promoting filament repolymerization. Plays a role in innate immunity by reducing oxidized actin, leading to actin repolymerization in macrophages.
Truncated MSRB1/SEPX1 proteins produced by failed UGA/Sec decoding are ubiquitinated by some Cul2-RING E3 ubiquitin-protein ligase complexes (containing either PRAME, PRAMF6, PRAMF9 or FEM1C as substrate-recognition component).
Defects in LOXL3 are found in a family with an autosomal recessive form of Stickler syndrome, an inherited disorder that associates ocular signs with more or less complete forms of Pierre Robin sequence and sensorineural deafness (PubMed:25663169). Pierre Robin sequence includes an opening in the roof of the mouth (a cleft palate) (PubMed:25663169). The degree of hearing loss varies among affected individuals and may become more severe over time (PubMed:25663169). Syndrome expressivity is variable (PubMed:25663169). Ocular disorders include non-progressive myopia with associated chorioretinal degeneration (PubMed:25663169).
Isoform 1: Predominantly detected in the heart, placenta, lung, and small intestine (PubMed:17018530). Isoform 2: Highly detected in the kidney, pancreas, spleen, and thymus, and is absent in lung (PubMed:17018530). In eye, present in all layers of corneas as well as in the limbus and conjunctiva (at protein level) (PubMed:26218558).
Protein-lysine 6-oxidase that mediates the oxidation of peptidyl lysine residues to allysine in target proteins (PubMed:17018530, PubMed:28065600). Catalyzes the post-translational oxidative deamination of peptidyl lysine residues in precursors of elastin and different types of collagens, a prerequisite in the formation of cross-links between collagens and elastin (PubMed:17018530). Required for somite boundary formation by catalyzing oxidation of fibronectin (FN1), enhancing integrin signaling in myofibers and their adhesion to the myotendinous junction (MTJ) (By similarity). Acts as a regulator of inflammatory response by inhibiting differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): acts by interacting with STAT3 in the nucleus and catalyzing both deacetylation and oxidation of lysine residues on STAT3, leading to disrupt STAT3 dimerization and inhibit STAT3 transcription activity (PubMed:28065600). Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated (PubMed:28065600). Also able to catalyze deacetylation of lysine residues on STAT3 (PubMed:28065600).
Shows protein-lysine 6-oxidase activity toward elastin and different types of collagens, with the highest activity toward collagen type IV (PubMed:17018530).
Shows protein-lysine 6-oxidase activity toward elastin and different types of collagens, with the highest activity toward collagen type VIII (PubMed:17018530).
The lysine tyrosylquinone cross-link (LTQ) is generated by condensation of the epsilon-amino group of a lysine with a topaquinone produced by oxidation of tyrosine.
Acts as an osmosensitive calcium-permeable cation channel (By similarity). Mechanosensitive ion channel that converts mechanical stimuli into a flow of ion (By similarity).
Core replisome component that acts as a replication initiation factor. Binds directly to the CMG complex and functions as a hub to recruit additional proteins to the replication fork.
Trimer (PubMed:32453425, PubMed:34694004). Interacts with the polymerase alpha catalytic subunit POLA1. Interacts with MCM10 (PubMed:17761813). Interacts with DNA2 (PubMed:22570476). Interacts with CDC45 and GINS2 subunit of GINS complex; these interactions associate WDHD1 with the CMG helicase complex (PubMed:32453425, PubMed:34694004).
Binds DNA as a dimer. Can form homodimers or heterodimers with other AP-2 family members (By similarity). Interacts with WWOX. Interacts with CITED4. Interacts with UBE2I. Interacts with KCTD1; this interaction represses transcription activation. Interacts with CITED2 (via C-terminus); the interaction stimulates TFAP2B-transcriptional activity. Interacts with MTA1.
During retinoic acid-mediated differentiation.
Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes. AP-2 factors bind to the consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development. They also suppress a number of genes including MCAM/MUC18, C/EBP alpha and MYC. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer.
Belongs to the ribonucleoside diphosphate reductase large chain family.
Heterodimer of a large and a small subunit. Heterodimer with small subunit RRM2 or RRM2B. The heterodimer with RRM2 has higher catalytic activity than the heterodimer with RRM2B. Interacts with AHCYL1 which inhibits its activity.
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides.
The level of the enzyme activity is closely correlated with the growth rate of a cell and appears to vary with the cell cycle.
Two distinct regulatory sites have been defined: the specificity site, which controls substrate specificity, and the activity site which regulates overall catalytic activity. A substrate-binding catalytic site, located on M1, is formed only in the presence of the second subunit M2.
Under complex allosteric control mediated by deoxynucleoside triphosphates and ATP binding to separate specificity and activation sites on the M1 subunit. The type of nucleotide bound at the specificity site determines substrate preference. It seems probable that ATP makes the enzyme reduce CDP and UDP, dGTP favors ADP reduction and dTTP favors GDP reduction. Stimulated by ATP and inhibited by dATP binding to the activity site, the dATP inhibition is mediated by AHCYL1 which stabilizes dATP in the site.
Interacts with MAD2L2. Interacts with POGZ, CBX1, CBX3 and CBX5.
Phosphorylated by CDK1. Mitotic phosphorylation is required for the attachment of spindle microtubules to the kinetochore.
Required for proper alignment of chromosomes at metaphase and their accurate segregation during mitosis. Involved in the maintenance of spindle microtubules attachment to the kinetochore during sister chromatid biorientation. May recruit CENPE and CENPF to the kinetochore.
Implicated in development of the cochlea.
Interacts (via SIM domains) with SUMO1 and SUMO2.
Component of the outer dense fibers (ODF) of spermatozoa. ODF are filamentous structures located on the outside of the axoneme in the midpiece and principal piece of the mammalian sperm tail and may help to maintain the passive elastic structures and elastic recoil of the sperm tail.
Interacts (via leucine zipper motif) with TCP11 isoform 2 and isoform 3 (PubMed:21597245). Interacts with SPAG4 (By similarity). Interacts with KLC3 (By similarity).
The C-terminal contains many C-X-P repeats.
Belongs to the dienelactone hydrolase family.
Cysteine hydrolase. Can convert the prodrug olmesartan medoxomil into its pharmacologically active metabolite olmerstatan, an angiotensin receptor blocker, in liver and intestine. May also activate beta-lactam antibiotics faropenem medoxomil and lenampicillin.
Strongly inhibited by p-chloromercuribenzoate (PCMB). Partially inhibited by bis-p-nitrophenylphosphate (BNPP). Not inhibited by DFP, PMSF, eserine or EDTA.
Widely expressed, with highest levels in liver, followed by kidney, small intestine and colon. Present in liver and intestine (at protein level).
Acts as a transcriptional activator or repressor (PubMed:27181683). Plays a pivotal role in regulating lineage-specific hematopoiesis by repressing ETS1-mediated transcription of erythroid-specific genes in myeloid cells. Required for monocytic, macrophage, osteoclast, podocyte and islet beta cell differentiation. Involved in renal tubule survival and F4/80 maturation. Activates the insulin and glucagon promoters. Together with PAX6, transactivates weakly the glucagon gene promoter through the G1 element. SUMO modification controls its transcriptional activity and ability to specify macrophage fate. Binds element G1 on the glucagon promoter (By similarity). Involved either as an oncogene or as a tumor suppressor, depending on the cell context. Required for the transcriptional activation of HOXB3 in the rhombomere r5 in the hindbrain (By similarity).
Homodimer or heterodimer with other bHLH-Zip transcription factors. Binds DNA as a homodimer or a heterodimer. Forms homodimers and heterodimers with FOS, FOSB and FOSL2, but not with JUN proteins (JUN, JUNB and JUND). Interacts with PAX6; the interaction is direct. Interacts with ETS1 and LRP1 (By similarity). Interacts with the intracellular cytoplasmic domain of LRP1 (LRPICD); the interaction results in a moderate reduction of MAFB transcriptional potential.
Phosphorylated by GSK3 and MAPK13 on serine and threonine residues.
Sumoylated. Sumoylation on Lys-32 and Lys-297 stimulates its transcriptional repression activity and promotes macrophage differentiation from myeloid progenitors (By similarity).
The leucine-zipper domain is involved in the interaction with LRPICD.
Does not bind to, or colocalize with, filamentous actin.
Protein phosphatase which may play a role in the regulation of actin filament dynamics. Can dephosphorylate and activate the actin binding/depolymerizing factor cofilin, which subsequently binds to actin filaments and stimulates their disassembly (By similarity).
Acetylation at Lys-204 and Lys-701 by KAT5 promotes its transcription activator activity.
Component of a complex, at least composed of APBB1, RASD1/DEXRAS1 and APP (PubMed:18922798, PubMed:18833287, PubMed:18468999). Interacts (via PID domain 2) with APP (with the intracellular domain of the amyloid-beta precursor protein) (PubMed:18833287, PubMed:18468999). Interacts (via PID domain 2) with RASD1/DEXRAS1; impairs the transcription activation activity (PubMed:18922798). Interacts (via PID domain 1) with KAT5/TIP60 (PubMed:33938178). Interacts (via the WW domain) with the proline-rich region of APBB1IP (By similarity). Interacts with TSHZ1 and TSHZ2 (By similarity). Interacts (via the WW domain) with histone H2AX (when phosphorylated on 'Tyr-142') and the proline-rich region of ENAH (PubMed:17686488). Interacts with MAPK8 (PubMed:19234442). Interacts (via PID domain 1) with TSHZ3 (via homeobox domain) (PubMed:19343227). Interacts with SET (PubMed:19343227). Found in a trimeric complex with HDAC1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3 (PubMed:19343227). Interacts (via WWW domain) with NEK6 (PubMed:17512906). Interacts (via WWW domain) with ABL1 (PubMed:15031292). Interacts with RNF157 (PubMed:25342469).
Highly expressed in brain; strongly reduced in post-mortem elderly subjects with Alzheimer disease.
Phosphorylation at Ser-610 by SGK1 promotes its localization to the nucleus (By similarity). Phosphorylated following nuclear translocation (PubMed:15031292, PubMed:18922798). Phosphorylation at Tyr-547 by ABL1 enhances transcriptional activation activity and reduces the affinity for RASD1/DEXRAS1 (PubMed:15031292, PubMed:18922798).
Polyubiquitination by RNF157 leads to degradation by the proteasome (PubMed:25342469).
Transcription coregulator that can have both coactivator and corepressor functions (PubMed:15031292, PubMed:18468999, PubMed:18922798, PubMed:25342469, PubMed:33938178). Adapter protein that forms a transcriptionally active complex with the gamma-secretase-derived amyloid precursor protein (APP) intracellular domain (PubMed:15031292, PubMed:18468999, PubMed:18922798, PubMed:25342469). Plays a central role in the response to DNA damage by translocating to the nucleus and inducing apoptosis (PubMed:15031292, PubMed:18468999, PubMed:18922798, PubMed:25342469). May act by specifically recognizing and binding histone H2AX phosphorylated on 'Tyr-142' (H2AXY142ph) at double-strand breaks (DSBs), recruiting other pro-apoptosis factors such as MAPK8/JNK1 (PubMed:19234442). Required for histone H4 acetylation at double-strand breaks (DSBs) (PubMed:19234442). Its ability to specifically bind modified histones and chromatin modifying enzymes such as KAT5/TIP60, probably explains its transcription activation activity (PubMed:33938178). Functions in association with TSHZ3, SET and HDAC factors as a transcriptional repressor, that inhibits the expression of CASP4 (PubMed:19343227). Associates with chromatin in a region surrounding the CASP4 transcriptional start site(s) (PubMed:19343227). Involved in hippocampal neurite branching and neuromuscular junction formation, as a result plays a role in spatial memory functioning (By similarity). Plays a role in the maintenance of lens transparency (By similarity). May play a role in muscle cell strength (By similarity).
Histone-binding protein required for histone H4 methyltransferase activity of PRMT5. Specifically required for histone H4 'Arg-3' methylation mediated by PRMT5, but not histone H3 'Arg-8' methylation, suggesting that it modulates the substrate specificity of PRMT5. Specifically interacts with the N-terminus of histone H4 but not with histone H3, suggesting that it acts by promoting the association between histone H4 and PRMT5. Involved in CCNE1 promoter repression. Plays a role in muscle cell differentiation by modulating the recruitment of PRMT5 to the promoter of genes involved in the coordination between cell cycle exit and muscle differentiation (By similarity).
Interacts with PRMT5. Interacts with histone H4; specifically interacts with the N-terminus of histone H4 but not with histone H3. Interacts with CBFB (By similarity). Found in a complex with PRMT5, RUNX1 and CBFB (By similarity).
Homodimer (By similarity). May interact with ROPN1.
Sperm surface zona pellucida binding protein. Helps to bind spermatozoa to the zona pellucida with high affinity. Might function in binding zona pellucida and carbohydrates (By similarity).
Sperm surface zona pellucida binding protein. Helps to bind spermatozoa to the zona pellucida with high affinity. Might function in binding zona pellucida and carbohydrates.
Catalyzes the hydrolysis of triacylglycerols to yield free fatty acids, diacylglycerol, monoacylglycerol, and glycerol (PubMed:2243091, PubMed:10358049). Shows a preferential hydrolysis at the sn-3 position of triacylglycerol (PubMed:2243091).
Expressed mainly in the brain and pancreas, including insulin-secreting cells. In the nervous system, more abundantly expressed in the cerebellum, pituitary gland, occipital lobe and the amygdala. Also expressed in fetal brain. Very low levels found in uterus, ovary, prostate, colon, testis, adrenal gland, thyroid gland and salivary gland.
Forms homo- or heterooligomeric complexes. Binds specific components of the JNK signaling pathway namely JNK1, JNK2, JNK3, MAP2K7, MAP3K10, MAP3K11, MAP3K12 and MAPK13. Also binds the proline-rich domain-containing splice variant of apolipoprotein E receptor 2 (ApoER2). Binds the cytoplasmic tails of LRP1 and LRP2 (Megalin). Binds the TPR motif-containing C-terminal of kinesin light chain, Klc1, pre-assembled MAPK8IP1 scaffolding complexes are then transported as a cargo of kinesin, to the required subcellular location (By similarity). Interacts with the cytoplasmic domain of APP (By similarity). Interacts with DCLK2. Interacts with TIAM1 and TIAM2 (By similarity). Interacts with FGF13; enables the interaction with MAPK13 and may regulate the MAPK8IP2 scaffolding activity. Interacts with SH3RF2 (By similarity).
Might be artifactual as it is only predicted from a genomic sequence.
The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. JIP2 inhibits IL1 beta-induced apoptosis in insulin-secreting cells. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity).
Can bind 1 iron ion per dimer. Iron binding seems to decrease LDLR degradation activity.
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of myosin regulatory light chain (MRLC), LDLR, VLDLR and LRP8. Activity depends on E2 enzymes of the UBE2D family. Proteasomal degradation of MRLC leads to inhibit neurite outgrowth in presence of NGF by counteracting the stabilization of MRLC by saposin-like protein (CNPY2/MSAP) and reducing CNPY2-stimulated neurite outgrowth. Acts as a sterol-dependent inhibitor of cellular cholesterol uptake by mediating ubiquitination and subsequent degradation of LDLR.
Expressed in fetal tissues and higher levels were detected in placenta and fetal lung.
Expression is directly activated by NR1H2 and NR1H3. Expression is not dependent of the sterol-response element-binding proteins (SREBPs). Expression is indirectly induced by LDL.
Homodimer. Interacts with the E2 ubiquitin-conjugating enzyme, UBE2D1 (via RING-type zinc finger). Interacts with myosin regulatory light chain (MRLC) and TMEM4.
The FERM domain binds phospholipids and mediates lipoprotein receptors recognition at the plasma membrane through their cytoplasmic tails.
The RING domain mediates ubiquitination and the neurite outgrowth inhibitory activity.
The RING-type zinc finger mediates the interaction with UBE2D E2 enzymes.
Highly expressed in the heart. Weakly expressed in the pancreas and liver.
Interacts with RHOQ and CDC42 in a GTP-dependent manner, and with SEPT7.
Probably involved in the organization of the actin cytoskeleton. May act downstream of CDC42 to induce actin filament assembly leading to cell shape changes. Induces pseudopodia formation in fibroblasts in a CDC42-dependent manner.
The CRIB domain mediates interaction with CDC42.
By AKAP12 and histone deacetylase inhibitors such as sodium butyrate.
Catalyzes the third of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of two carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme catalyzes the dehydration of the 3-hydroxyacyl-CoA intermediate into trans-2,3-enoyl-CoA, within each cycle of fatty acid elongation. Thereby, it participates in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. May be involved in Rac1-signaling pathways leading to the modulation of gene expression. Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571).
Highly expressed in testis, kidney, brain, liver and weakly in skeletal muscle, spleen and heart. No expression detected in leukocytes.
May interact with enzymes of the ELO family (including ELOVL1); with those enzymes that mediate condensation, the first of the four steps of the reaction cycle responsible for fatty acids elongation, may be part of a larger fatty acids elongase complex (PubMed:18554506). Interacts with RAC1 (PubMed:10747961). Associates with internalized insulin receptor/INSR complexes on Golgi/endosomal membranes; HACD3/PTPLAD1 together with ATIC and PRKAA2/AMPK2 is proposed to be part of a signaling network regulating INSR autophosphorylation and endocytosis (PubMed:25687571).
Appears to function as an adapter protein that bridges proteins together or proteins with mRNAs (PubMed:34331014). May function as a ubiquitin ligase-substrate adapter (PubMed:34331014, PubMed:34870550). Additionally, associates with translating cytoplasmic ribosomes and may promote the expression of specific mRNAs (PubMed:34331014, PubMed:34870550).
Monomer (PubMed:16511048). Interacts with PFN1/Profilin-1 (PubMed:34331014). Interacts with ERBB2 (PubMed:32381043). Interacts with ATG12 (PubMed:34870550). Interacts with BECN1 (PubMed:34870550). Interacts with translating ribosomes (PubMed:34331014, PubMed:34870550).
Promotes breast cancer progression by enhancing the interaction between E3 ligase STUB1 and PFN1, thereby promoting proteasomal degradation of PFN1 and subsequent activation of downstream signaling pathways including PI3K/AKT, NF-kB and WNT (PubMed:34331014). Promotes autophagy presumably by stabilizing the ubuiquitin-like protein ATG12 (PubMed:34870550). Enhances mRNA translation of E3 ligase STUB1 and the autophagy-related protein PIK3C3 (PubMed:34331014, PubMed:34870550). Promotes activation and phosphorylation of ERBB2 at 'Tyr-877' and 'Tyr-1196', and prolongs localization of ERBB2 to the cell membrane (PubMed:32381043). Breast cancer patients with SH3BGRL overexpression usually experience frequent relapse and poor prognosis (PubMed:32381043, PubMed:34870550).
The SH3-binding motif is buried in the tertiary structure, and it is therefore unclear whether it directly mediates protein-binding.
Up-regulated during promyelocytic cell differentiation along the monocytic pathway, but not during granulocytic differentiation.
Belongs to the concentrative nucleoside transporter (CNT) (TC 2.A.41) family.
Expressed in heart and skeletal muscle followed by liver, kidney, intestine, pancreas, placenta and brain (PubMed:9435697). Weak expression in lung (PubMed:9435697). In testis, primarily localized to the apicolateral membranes of Sertoli cells and vascular endothelial cells, and weakly expressed in Leydig cells, peritubular myoid cells and germ cells (PubMed:35307651).
Sodium-dependent and purine-selective transporter (PubMed:9435697, PubMed:10087507). Exhibits the transport characteristics of the nucleoside transport system cif or N1 subtype (N1/cif) (selective for purine nucleosides and uridine) (PubMed:9435697, PubMed:10087507, PubMed:21795683). Plays a critical role in specific uptake and salvage of purine nucleosides in kidney and other tissues (PubMed:9435697). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable).
Involved in complement regulation. Can associate with lipoproteins and may play a role in lipid metabolism.
Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance, lamellipodial and filopodial dynamics, platelet activation and cell migration.
Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance, lamellipodial and filopodial dynamics, platelet activation and cell migration. VASP promotes actin filament elongation. It protects the barbed end of growing actin filaments against capping and increases the rate of actin polymerization in the presence of capping protein. VASP stimulates actin filament elongation by promoting the transfer of profilin-bound actin monomers onto the barbed end of growing actin filaments. Plays a role in actin-based mobility of Listeria monocytogenes in host cells. Regulates actin dynamics in platelets and plays an important role in regulating platelet aggregation.
Homotetramer. Interacts with PFN1, PFN2, LPP, ACTN1 and ACTG1. Interacts, via the EVH1 domain, with the Pro-rich regions of ZYX. This interaction is important for targeting to focal adhesions and the formation of actin-rich structures at the apical surface of cells. Interacts, via the EVH1 domain, with the Pro-rich domain of Listeria monocytogenes actA. Interacts with APBB1IP. Interacts, via the Pro-rich domain, with the C-terminal SH3 domain of DNMBP (By similarity). Interacts weakly with MEFV.
Major substrate for cAMP-dependent (PKA) and cGMP-dependent protein kinase (PKG) in platelets. The preferred site for PKA is Ser-157, the preferred site for PKG/PRKG1, Ser-239. In ADP-activated platelets, phosphorylation by PKA or PKG on Ser-157 leads to fibrinogen receptor inhibition. Phosphorylation on Thr-278 requires prior phosphorylation on Ser-157 and Ser-239. In response to phorbol ester (PMA) stimulation, phosphorylated by PKC/PRKCA. In response to thrombin, phosphorylated by both PKC and ROCK1. Phosphorylation at Thr-278 by AMPK does not require prior phosphorylation at Ser-157 or Ser-239. Phosphorylation at Ser-157 by PKA is required for localization to the tight junctions in epithelial cells. Phosphorylation modulates F-actin binding, actin filament elongation and platelet activation. Phosphorylation at Ser-322 by AMPK also alters actin filament binding. Carbon monoxide (CO) promotes phosphorylation at Ser-157, while nitric oxide (NO) promotes phosphorylation at Ser-157, but also at Ser-239. Response to NO and CO is blunted in platelets from diabetic patients, and VASP is not phosphorylated efficiently at Ser-157 and Ser-239.
The EVH2 domain is comprised of 3 regions. Block A is a thymosin-like domain required for G-actin binding. The KLKR motif within this block is essential for the G-actin binding and for actin polymerization. Block B is required for F-actin binding and subcellular location, and Block C for tetramerization.
The WH1 domain mediates interaction with XIRP1.
VASP phosphorylation is used to monitor the effect of so-called antiplatelet drugs that reduce platelet reactivity and are used to prevent stent thrombosis, strokes and heart attacks in patients at risk for these problems.
Binds to the 3' poly(U) terminus of nascent RNA polymerase III transcripts, protecting them from exonuclease digestion and facilitating their folding and maturation (PubMed:3192525, PubMed:2470590). In case of Coxsackievirus B3 infection, binds to the viral internal ribosome entry site (IRES) and stimulates the IRES-mediated translation (PubMed:12384597).
Interacts with DDX15. May interact with RUFY1.
Phosphorylated. The phosphorylation sites are at the C-terminal part of the protein.
Sera from patients with systemic lupus erythematosus (SLE) often contain antibodies that react with the normal cellular La protein as if this antigen was foreign.
Highest expression in retina, skeletal muscle, testis and colon.
Interacts with SYCE1 (By similarity). Interacts with proteasome subunit PSMA8; to participate in meiosis progression during spermatogenesis (By similarity).
Meiotic protein that localizes to the central element of the synaptonemal complex and is required for chromosome synapsis during meiotic recombination. Required for the appropriate processing of intermediate recombination nodules before crossover formation.
(Microbial infection) Interacts with HHV-1 ICP34.5.
(Microbial infection) Interacts with Venezuelan equine encephalitis virus (VEEV) capsid protein; this interaction dephosphorylates the capsid protein, which increases its ability to bind to the viral genome.
(Microbial infection) Necessary for alphaviruses replication.
PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, which is folded into its native form by inhibitor 2 and glycogen synthetase kinase 3, and then complexed to one or several targeting or regulatory subunits. PPP1R12A, PPP1R12B and PPP1R12C mediate binding to myosin. PPP1R3A (in skeletal muscle), PPP1R3B (in liver), PPP1R3C, PPP1R3D and PPP1R3F (in brain) mediate binding to glycogen. Interacts with PPP1R39 (By similarity). Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts with PPP1R9A and PPP1R9B. Part of a complex containing PPP1R15B, PP1 and NCK1/2. Interacts with PHACTR4; which acts as an activator of PP1 activity (By similarity). Interacts with PPP1R15A and PPP1R15B; the interactions mediate binding to EIF2S1 (PubMed:26095357). Interacts with PPP1R7. Interacts with YLPM1. Forms a complex with ILF2, ILF3, YLPM1, KHDRBS1, RBMX and NCOA5. Interacts with NOM1 and PPP1R8. Interacts with PPP1R16B. Interacts with RPSA only in the presence of PPP1R16B. Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1R10/PNUTS and PPP1R8. Interacts with WDR82 in the presence of PPP1R10/PNUTS. Interacts with TRIM28; the interaction dephosphorylates TRIM28 on 'Ser-824' and forms a complex at the p21 promoter site. Interacts with isoform 1 and isoform 4 of NEK2. Interacts with FER; this promotes phosphorylation at Thr-320. Interacts with DAB2; the interaction is mutually exclusive with the AXIN1:PPP1CA interaction. Interacts with FOXP3 (PubMed:23396208). Interacts with CENPA (PubMed:25556658). Interacts with ATG16L1 (PubMed:26083323). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (PubMed:23846654). Interacts with tensin TNS1 (PubMed:19826001). Interacts with SAXO4, PPP1R21, PPP1R26, PPP1R27, PPP1R35, PPP1R36, PPP1R37, SH3RF2, ELFN1 and ELFN2 (PubMed:19389623).
Phosphorylated. Dephosphorylated at Thr-320 in the presence of ionizing radiation.
Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Regulates NEK2 function in terms of kinase activity and centrosome number and splitting, both in the presence and absence of radiation-induced DNA damage. Regulator of neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T-cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Dephosphorylates CENPA (PubMed:25556658). Dephosphorylates the 'Ser-139' residue of ATG16L1 causing dissociation of ATG12-ATG5-ATG16L1 complex, thereby inhibiting autophagy (PubMed:26083323).
The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.
Belongs to the choline/ethanolamine kinase family.
Expressed in kidney, liver, placenta, heart, leukocyte, ovary and testis.
Highly specific for ethanolamine phosphorylation. May be a rate-controlling step in phosphatidylethanolamine biosynthesis.
Cell adhesion leukocyte receptor expressed by mucosal venules, helps to direct lymphocyte traffic into mucosal tissues including the Peyer patches and the intestinal lamina propria. It can bind both integrin alpha-4/beta-7 and L-selectin, regulating both the passage and retention of leukocytes. Isoform 2, lacking the mucin-like domain, may be specialized in supporting integrin alpha-4/beta-7-dependent adhesion strengthening, independent of L-selectin binding.
Highly expressed on high endothelial venules (HEV) and lamina propia venules found in the small intestine, and to a lesser extent in the colon and spleen. Very low levels of expression found in pancreas and brain. Not expressed in the thymus, prostate, ovaries, testis, heart, placenta, lung, liver, skeletal muscle, kidney or peripheral blood leukocytes.
The Ser/Thr-rich mucin-like domain may provide possible sites for O-glycosylation.
The number of repeats in the mucin domain varies between 5 and 8 repeats.
Belongs to the NAD(P)-dependent epimerase/dehydratase family. UDP-glucuronic acid decarboxylase subfamily.
Catalyzes the NAD-dependent decarboxylation of UDP-glucuronic acid to UDP-xylose (PubMed:23656592, PubMed:22810237, PubMed:25521717). Necessary for the biosynthesis of the core tetrasaccharide in glycosaminoglycan biosynthesis (PubMed:23656592, PubMed:22810237, PubMed:25521717).
Homodimer and homotetramer (PubMed:23656592). Interacts with AKT1 (By similarity).
Dimer of alpha and beta chains. A typical microtubule is a hollow water-filled tube with an outer diameter of 25 nm and an inner diameter of 15 nM. Alpha-beta heterodimers associate head-to-tail to form protofilaments running lengthwise along the microtubule wall with the beta-tubulin subunit facing the microtubule plus end conferring a structural polarity. Microtubules usually have 13 protofilaments but different protofilament numbers can be found in some organisms and specialized cells. Interacts with RANBP10.
Hematopoietic cell-specific. Major isotype in leukocytes, where it represents 50% of all beta-tubulins.
May play a role in neurogenesis. May play a role in bone differentiation and matrix mineralization.
Peripherally associated with AMPAR complex. AMPAR complex consists of an inner core made of 4 pore-forming GluA/GRIA proteins (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged in a twofold symmetry. One of the two pairs of distinct binding sites is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR complex is complemented by outer core constituents binding directly to the GluA/GRIA proteins at sites distinct from the interaction sites of the inner core constituents. Outer core constituents include at least PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the inner and outer core serve as a platform for other, more peripherally associated AMPAR constituents, including VWC2L. Alone or in combination, these auxiliary subunits control the gating and pharmacology of the AMPAR complex and profoundly impact their biogenesis and protein processing (By similarity).
Gamma-carboxyglutamate residues are formed by vitamin K dependent carboxylation. These residues are essential for the binding of calcium.
Interacts with NEDD4 (By similarity). Interacts (via cytoplasmic domain) with transcriptional coactivator YAP1 (PubMed:17502622).
Widely expressed with highest levels in kidney (PubMed:23873930). Also highly expressed in the thyroid (PubMed:9256434, PubMed:23873930).
Belongs to the PMP-22/EMP/MP20 family. CACNG subfamily.
Component of a calcium channel complex consisting of a pore-forming alpha subunit (CACNA1S) and the ancillary subunits CACNB1 or CACNB2, CACNG1 and CACNA2D1. The channel complex contains alpha, beta, gamma and delta subunits in a 1:1:1:1 ratio, i.e. it contains either CACNB1 or CACNB2.
Regulatory subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle. Regulates channel inactivation kinetics.
Inhibited by N-ethylmaleimide and high concentrations of zinc chloride.
Monomer and homodimer (By similarity). Interacts with EPB41L3 (via FERM domain); the interaction is direct and inhibits the protein-arginine N-methyltransferase activity of PRMT3 (PubMed:15334060). Interacts with the 40S ribosomal protein RPS2 (PubMed:21059412, PubMed:30530495). Interacts with ALDH1A1; the interaction is direct, inhibits ALDH1A1 aldehyde dehydrogenase activity and is independent of the methyltransferase activity of PRMT3 (PubMed:33495566).
Protein-arginine N-methyltransferase that catalyzes both the monomethylation and asymmetric dimethylation of the guanidino nitrogens of arginine residues in target proteins, and therefore falls into the group of type I methyltransferases (Probable). May regulate retinoic acid synthesis and signaling by inhibiting ALDH1A1 retinal dehydrogenase activity (PubMed:33495566).
The C2H2-type zinc-finger is responsible for substrate specificity.
E3 ubiquitin ligase involved in different processes such as development and immune response (PubMed:22588174, PubMed:30231667). Serves as a negative regulator for innate immune signaling pathways by suppressing RLR-induced activation of IRF3/7 and NF-kappa-B via interaction with adapter ECSIT (PubMed:22588174). Regulates autophagy through modulating both the transcription and the ubiquitination of BECN1 (PubMed:30231667). On the one hand, regulates the transcription of BECN1 through negatively modulating the NF-kappa-B pathway. On the other hand, regulates TRAF6-mediated 'Lys-63'-linked ubiquitination of BECN1, thus affecting the formation of the BECN1-PIK3C3 complex. In addition, mediates 'Lys-48'-linked ubiquitination of TRAF6 and thereby promotes TRAF6 proteasomal degradation (PubMed:30231667). Acts also as a critical regulator for early embryo development from blastocyst stage to gastrula through modulating F-actin assembly and WASH1 'Lys-63'-linked ubiquitination (By similarity).
(Microbial infection) Interacts with human cytomegalovirus protein UL138; this interaction mediates MRP1 degradation via the lysosome.
Lung, testis and peripheral blood mononuclear cells.
MK 571 inhibits sphingosine 1-phosphate and leukotriene C4 export.
Mediates export of organic anions and drugs from the cytoplasm (PubMed:7961706, PubMed:16230346, PubMed:9281595, PubMed:10064732, PubMed:11114332). Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics (PubMed:7961706, PubMed:16230346, PubMed:9281595, PubMed:10064732, PubMed:11114332). Confers resistance to anticancer drugs by decreasing accumulation of drug in cells, and by mediating ATP- and GSH-dependent drug export (PubMed:9281595). Hydrolyzes ATP with low efficiency (PubMed:16230346). Catalyzes the export of sphingosine 1-phosphate from mast cells independently of their degranulation (PubMed:17050692). Participates in inflammatory response by allowing export of leukotriene C4 from leukotriene C4-synthezing cells (By similarity). Mediates ATP-dependent, GSH-independent cyclic GMP-AMP (cGAMP) export (PubMed:36070769). Thus, by limiting intracellular cGAMP concentrations negatively regulates the cGAS-STING pathway (PubMed:36070769).
Enzyme with a broad specificity. Negatively regulates TGF-beta signaling through dephosphorylating SMAD2 and SMAD3, resulting in their dissociation from SMAD4, nuclear export of the SMADs and termination of the TGF-beta-mediated signaling. Dephosphorylates PRKAA1 and PRKAA2. Plays an important role in the termination of TNF-alpha-mediated NF-kappa-B activation through dephosphorylating and inactivating IKBKB/IKKB.
Monomer. Interacts with SMAD2; the interaction dephosphorylates SMAD2 in its C-terminal SXS motif resulting in disruption of the SMAD2/SMAD4 complex, SMAD2 nuclear export and termination of the TGF-beta-mediated signaling. Interacts with SMAD2; the interaction dephosphorylates SMAD2 in its C-terminal SXS motif resulting in disruption of the SMAD2/SMAD4 complex, SMAD2 nuclear export and termination of the TGF-beta-mediated signaling. Interacts with the phosphorylated form of IKBKB/IKKB.
N-myristoylation is essential for the recognition of its substrates for dephosphorylation.
Chromosomal protein that binds to methylated DNA. It can bind specifically to a single methyl-CpG pair. It is not influenced by sequences flanking the methyl-CpGs. Binds both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC)-containing DNA, with a preference for 5-methylcytosine (5mC).
Chromosomal protein that binds to methylated DNA. It can bind specifically to a single methyl-CpG pair. It is not influenced by sequences flanking the methyl-CpGs. Mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A. Binds both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC)-containing DNA, with a preference for 5-methylcytosine (5mC).
Interacts with FNBP3 (By similarity). Interacts with CDKL5 (PubMed:15917271). Interacts with ATRX; MECP2 recruits ATRX to pericentric heterochromatin in neuronal cells (By similarity). Interacts with NCOR2 (By similarity). Interacts with TBL1XR1; bridges interaction between MECP2 and NCOR1 (PubMed:28348241). Interacts with TBL1X; recruits TBL1X to the heterochromatin foci (PubMed:28348241).
Phosphorylated on Ser-423 in brain upon synaptic activity, which attenuates its repressor activity and seems to regulate dendritic growth and spine maturation.
Present in all adult somatic tissues tested.
Ten times higher expression levels than isoform A in brain.
The disease is caused by variants affecting the gene represented in this entry. Increased dosage of MECP2 due to gene duplication appears to be responsible for the intellectual disability phenotype.
The disease is caused by variants affecting the gene represented in this entry. The MECP2 gene is mutated in Rett syndrome, a severe neurodevelopmental disorder that almost always occurs in females. Although it was first thought that MECP2 mutations causing Rett syndrome were lethal in males, later reports identified a severe neonatal encephalopathy in surviving male sibs of patients with Rett syndrome. Additional reports have confirmed a severe phenotype in males with Rett syndrome-associated MECP2 mutations.
Functions as guanine nucleotide exchange factor (GEF) for RAB11A.
Anchoring/scaffolding protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal development and maintenance of cochlear hair cell bundles (By similarity). As part of the intermicrovillar adhesion complex/IMAC plays a role in brush border differentiation, controlling microvilli organization and length. Probably plays a central regulatory role in the assembly of the complex, recruiting CDHR2, CDHR5 and MYO7B to the microvilli tips (PubMed:24725409, PubMed:26812018).
Expressed in small intestine, colon, kidney, eye and weakly in pancreas. Expressed also in vestibule of the inner ear.
Part of the IMAC/intermicrovillar adhesion complex/intermicrovillar tip-link complex composed of ANKS4B, MYO7B, USH1C, CDHR2 and CDHR5 (Probable). Part of a complex composed of USH1C, USH1G and MYO7A (PubMed:21709241). Interacts with F-actin (By similarity). Interacts with USH2A (PubMed:16301216). Interacts with SLC4A7 (PubMed:16301216). Interacts (via PDZ1 domain) with the C-terminus of USHBP1 (PubMed:11311560). Interacts (via N-terminus and PDZ 2 domain) with CDH23 (PubMed:19297620). Interacts with USH1G (PubMed:12588794, PubMed:20142502). Interacts with MYO7B (PubMed:24725409, PubMed:26812017). Interacts with CDHR2 and CDHR5; may mediate their interaction with MYO7B at the microvilli tip (PubMed:24725409, PubMed:26812017). Interacts (via PDZ 1 domain) with ANKS4B (PubMed:26812018, PubMed:26812017). Interacts (via PDZ 1 domain) with DOCK4 (PubMed:16464467).
The N-terminal region constitutes an independently folded domain that has structural similarity with the CCM2 C-terminus, despite very low sequence similarity.
The PDZ 1 domain mediates interaction with ANKS4B, DOCK4, USHBP1, USH1G, SLC4A7.
(Microbial infection) Ubiquitinated by S.flexneri IpaH9.8, leading to its degradation by the proteasome, thereby preventing its ability to promote host defense against bacterial infection.
Interferon (IFN)-inducible GTPase that plays important roles in innate immunity against a diverse range of bacterial, viral and protozoan pathogens, such as bacterial pathogens Listeria monocytogenes and Mycobacterium bovis BCG as well as the protozoan pathogen Toxoplasma gondii (By similarity). Confers protection to several pathogens, including the bacterial pathogens Listeria monocytogenes and Mycobacterium bovis BCG as well as the protozoan pathogen Toxoplasma gondii (By similarity).
Acetylation at Lys-265 and Lys-268 seems to decrease lipid 1-phosphatidylinositol-4-phosphate 5-kinase activity. Deacetylation of these sites by SIRT1 positively regulates the exocytosis of TSH-containing granules from pituitary cells.
Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2/PIP2), a lipid second messenger that regulates several cellular processes such as signal transduction, vesicle trafficking, actin cytoskeleton dynamics, cell adhesion, and cell motility (PubMed:12422219, PubMed:22942276). PtdIns(4,5)P2 can directly act as a second messenger or can be utilized as a precursor to generate other second messengers: inositol 1,4,5-trisphosphate (IP3), diacylglycerol (DAG) or phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3/PIP3) (Probable). PIP5K1A-mediated phosphorylation of PtdIns(4)P is the predominant pathway for PtdIns(4,5)P2 synthesis (By similarity). Together with PIP5K1A, is required for phagocytosis, both enzymes regulating different types of actin remodeling at sequential steps (By similarity). Promotes particle attachment by generating the pool of PtdIns(4,5)P2 that induces controlled actin depolymerization to facilitate Fc-gamma-R clustering. Mediates RAC1-dependent reorganization of actin filaments. Required for synaptic vesicle transport (By similarity). Controls the plasma membrane pool of PtdIns(4,5)P2 implicated in synaptic vesicle endocytosis and exocytosis (PubMed:12847086). Plays a role in endocytosis mediated by clathrin and AP-2 (adaptor protein complex 2) (PubMed:12847086). Required for clathrin-coated pits assembly at the synapse (PubMed:17261850). Participates in cell junction assembly (PubMed:17261850). Modulates adherens junctions formation by facilitating CDH1/cadherin trafficking (PubMed:17261850). Required for focal adhesion dynamics. Modulates the targeting of talins (TLN1 and TLN2) to the plasma membrane and their efficient assembly into focal adhesions (PubMed:12422219). Regulates the interaction between talins (TLN1 and TLN2) and beta-integrins (PubMed:12422219). Required for uropodium formation and retraction of the cell rear during directed migration (By similarity). Has a role in growth factor-stimulated directional cell migration and adhesion (By similarity). Required for talin assembly into nascent adhesions forming at the leading edge toward the direction of the growth factor (PubMed:17635937). Negative regulator of T-cell activation and adhesion (By similarity). Negatively regulates integrin alpha-L/beta-2 (LFA-1) polarization and adhesion induced by T-cell receptor (By similarity). Together with PIP5K1A has a role during embryogenesis and together with PIP5K1B may have a role immediately after birth (By similarity).
Interacts with TLN1 (By similarity). Interacts with TLN2; interaction stimulates 1-phosphatidylinositol-4-phosphate 5-kinase activity (PubMed:12422219). May compete with beta-integrins for the same binding site on TLN1 and TLN2. Interacts with ARF6; interaction stimulates 1-phosphatidylinositol-4-phosphate 5-kinase activity. Interacts with AP2B1. Interacts with AP2M1; phosphorylation of PIP5K1C by CSK disrupts the interaction; clathrin competes with PIP5K1C (By similarity). Interacts with CDH1. Interacts with CSK (By similarity). Interacts with PLCG1; interaction is abolished upon EGF stimulation (By similarity). Interacts with LAPTM4B; promotes SNX5 association with LAPTM4B; kinase activity of PIP5K1C is required; interaction is regulated by phosphatidylinositol 4,5-bisphosphate generated by PIP5K1C (PubMed:25588945).
Isoform 1 is strongly expressed in brain and also detected in heart and lung.
Isoform 2 is strongly expressed in pancreas and liver and in lesser quantities in brain, heart, lung and kidney.
Isoform 3 is detected in large amounts in heart and large intestine, is also present in lung, pancreas and thyroid, and to a lesser extent in brain, stomach and kidney.
Phosphorylation on Ser-650 negatively regulates binding to TLN2 and is strongly stimulated in mitosis. Phosphorylation on Tyr-649 is necessary for targeting to focal adhesions. Phosphorylation on Ser-650 and Tyr-649 are mutually exclusive. Phosphorylated by SYK and CSK (By similarity). Tyrosine phosphorylation is enhanced by PTK2 signaling. Phosphorylated at Tyr-639 upon EGF stimulation. Some studies suggest that phosphorylation on Tyr-649 enhances binding to tailins (TLN1 and TLN2). According to PubMed:15738269 phosphorylation at Tyr-649 does not directly enhance binding to tailins (TLN1 and TLN2) but may act indirectly by inhibiting phosphorylation at Ser-650.
Expressed in several endocrine tissues, mostly in fetal and adult liver, kidney, pancreas, testis, colon, brain and small intestine; not detected in peripheral blood leukocytes, lymphoid organs, and most cell lines.
Interacts with DAZAP2 (PubMed:22070932). Interacts with TRAF3IP2 (PubMed:24120361).
Receptor for the pro-inflammatory cytokines IL17B and IL17E. May play a role in controlling the growth and/or differentiation of hematopoietic cells.
Chemotactic activity for resting CD4, CD8 T-cells and eosinophils. Binds to CCR3 and CCR10 and induces calcium mobilization in a dose-dependent manner.
Preferentially expressed by epithelial cells of diverse tissues including normal and pathological colon, salivary gland, mammary gland, trachea and rectum. Also found in prostate, spleen, thyroid, psoriasis skin and in lower levels in peripheral blood leukocytes, small intestine, Peyer patches, stomach and normal skin.
Binds to BCL9 via the PHD-type zinc finger motif, and thereby becomes part of the nuclear beta-catenin/TCF complex.
Involved in signal transduction through the Wnt pathway.
Component of the outer dynein arm-docking complex (ODA-DC) that mediates outer dynein arms (ODA) binding onto the doublet microtubule. Plays an essential role for the assembly of ODA-DC and for the docking of ODA in ciliary axoneme.
Component of the outer dynein arm-docking complex along with ODAD1, ODAD2 and ODAD3. Interacts with ODAD1; this interaction may facilitate the recruitment and/or attachment of outer dynein arm docking complex proteins, including ODAD1, ODAD3 and ODAD2, to ciliary axonemes (PubMed:27486780). Interacts with components of the IFT complex A, including IFT140, TTC21B/IFT139 and WDR19/IFT144, and the IFT complex B, including IFT46, IFT52 and IFT57 (PubMed:25860617).
Expressed in the nasal mucosa (at protein level).
Amplification of the N-MYC gene is associated with a variety of human tumors, most frequently neuroblastoma, where the level of amplification appears to increase as the tumor progresses.
Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a heterodimer with MAX. Interacts with KDM5A, KDM5B and HUWE1. Interacts with MYCNOS. Interacts with AURKA; interaction is phospho-independent and triggers AURKA activation; AURKA competes with FBXW7 for binding to unphosphorylated MYCN but not for binding to unphosphorylated MYCN (PubMed:27837025). Interacts with FBXW7; FBXW7 competes with AURKA for binding to unphosphorylated MYCN but not for binding to phosphorylated MYCN (PubMed:27837025).
Expressed in the neuronal cells of the cerebrum, neuroblastomas and thyroid tumors (at protein level).
Phosphorylated by GSK3-beta which may promote its degradation (PubMed:24391509). Phosphorylated by AURKA (PubMed:27837025).
Positively regulates the transcription of MYCNOS in neuroblastoma cells.
Activates RhoG GTPase by promoting the exchange of GDP by GTP. Required for the formation of membrane ruffles during macropinocytosis. Required for the formation of cup-like structures during trans-endothelial migration of leukocytes. In case of Salmonella enterica infection, activated by SopB, which induces cytoskeleton rearrangements and promotes bacterial entry.
Certain mRNA species appear to be up-regulated by androgens in prostate cancer cells.
Isoform 1 is broadly expressed, with highest levels in liver (at protein level). Certain mRNA species appear to be specifically expressed in prostate and liver.
(Microbial infection) Interacts with Epstein Barr virus (EBV) lytic switch protein BZLF1; this interaction participates to the activation of early lytic viral genes by BZLF1.
ATPase component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and DNA repair (PubMed:16230350, PubMed:16298340, PubMed:17721549, PubMed:20855601, PubMed:20237820). Binds DNA (PubMed:16298340, PubMed:21303910). As part of the INO80 complex, remodels chromatin by shifting nucleosomes (PubMed:16230350, PubMed:21303910). Regulates transcription upon recruitment by YY1 to YY1-activated genes, where it acts as an essential coactivator (PubMed:17721549). Involved in UV-damage excision DNA repair (PubMed:20855601). The contribution to DNA double-strand break repair appears to be largely indirect through transcriptional regulation (PubMed:20687897). Involved in DNA replication (PubMed:20237820). Required for microtubule assembly during mitosis thereby regulating chromosome segregation cycle (PubMed:20237820).
According to PubMed:10574462, widely expressed. According to PubMed:16298340, specifically expressed in brain, liver and pancreas.
Activated upon binding to double stranded DNA or nucleosomes.
Although the ATP-dependent helicase activity displayed by the INO80 complex requires INO80 ATPase activity, it is likely that the helicase function is carried out by the other components of the complex, RUVBL1 and RUVBL2, and not by INO80 itself.
Component of the chromatin remodeling INO80 complex; three different complex modules assemble on different domains of INO80 (PubMed:16230350, PubMed:18026119, PubMed:18922472, PubMed:21303910). Interacts with DDB1 (PubMed:20855601). Interacts with transcriptional repressor protein YY1; the interaction recruits the INO80 complex to YY1 target genes (PubMed:17721549, PubMed:18026119). Interacts with YY1AP1 (PubMed:27939641). Interacts with tubulin alpha (PubMed:20237820).
The DBINO region is involved in binding to DNA.
Myosin is a hexamer of 2 heavy chains and 4 light chains.
Regulatory light chain of myosin. Does not bind calcium.
Cystine/H(+) symporter that mediates export of cystine, the oxidized dimer of cysteine, from lysosomes (PubMed:11689434, PubMed:18337546, PubMed:22232659, PubMed:29467429, PubMed:33208952, PubMed:15128704). Plays an important role in melanin synthesis by catalyzing cystine export from melanosomes, possibly by inhibiting pheomelanin synthesis (PubMed:22649030). In addition to cystine export, also acts as a positive regulator of mTORC1 signaling in kidney proximal tubular cells, via interactions with components of the v-ATPase and Ragulator complexes (By similarity). Also involved in small GTPase-regulated vesicle trafficking and lysosomal localization of LAMP2A, independently of cystine transporter activity (By similarity).
Interacts with components of the V-ATPase complex. Interacts with components of the Ragulator complex. Interacts with RRAGA/RagA and RRAGC/RagC (By similarity). Interacts with AP-3 complex subunit mu (AP3M1 or AP3M2) (PubMed:25753619).
Represents 5-20 % of CTNS transcripts, with the exception of the testis that expresses both isoforms in equal proportions.
Strongly expressed in pancreas, kidney (adult and fetal), skeletal muscle, melanocytes and keratinocytes (PubMed:22649030). Expressed at lower levels in placenta and heart. Weakly expressed in lung, liver and brain (adult and fetal) (PubMed:22649030).
The lysosomal targeting motif, together with the second PQ-loop mediate targeting to the lysosome.
Belongs to the centaurin gamma-like family.
GTPase activity is stimulated by oxidative stress.
GTPase-activating protein for the ADP ribosylation factor family (Potential). GTPase which may be involved in the degradation of expanded polyglutamine proteins through the ubiquitin-proteasome pathway.
Interacts with PML. Interacts with expanded polyglutamine proteins.
A conserved histidine residue in the third transmembrane domain (His-136) might play an essential role in the pH sensitivity of SLCO2B1/OATP2B1-mediated substrate transport (PubMed:19129463). Transmembrane domain 1 (TM1) may be localized within the substrate binding pocket (PubMed:29871943).
E1S, DHEA-S and PregS transports are regulated by steroid hormones. In the case of testosterone, transport of E1S and DHEA-S was inhibited, whereas progesterone stimulated E1S, DHEA-S and PregS uptake (PubMed:16908597). Progesterone stimulates high-affinity uptake of E1S whereas it inhibits low-affinity uptake of E1S (Ref.24). Progesterone doesn't affect the uptake of PGE2 (Ref.24).
Has estrone 3-sulfate (E1S) transport activity comparable with the full-length isoform 1.
Highest expression in brain. Predominant isoform compared to isoform 3 in small intestine duodenum, kidney, placenta, and skeletal muscle.
Mediates the Na(+)-independent transport of steroid sulfate conjugates and other specific organic anions (PubMed:10873595, PubMed:11159893, PubMed:11932330, PubMed:12724351, PubMed:14610227, PubMed:16908597, PubMed:18501590, PubMed:20507927, PubMed:22201122, PubMed:23531488, PubMed:25132355, PubMed:27576593, PubMed:26383540, PubMed:28408210, PubMed:29871943, PubMed:34628357). Responsible for the transport of estrone 3-sulfate (E1S) through the basal membrane of syncytiotrophoblast, highlighting a potential role in the placental absorption of fetal-derived sulfated steroids including the steroid hormone precursor dehydroepiandrosterone sulfate (DHEA-S) (PubMed:11932330, PubMed:12409283). Also facilitates the uptake of sulfated steroids at the basal/sinusoidal membrane of hepatocytes, therefore accounting for the major part of organic anions clearance of liver (PubMed:11159893). Mediates the intestinal uptake of sulfated steroids (PubMed:12724351, PubMed:28408210). Mediates the uptake of the neurosteroids DHEA-S and pregnenolone sulfate (PregS) into the endothelial cells of the blood-brain barrier as the first step to enter the brain (PubMed:16908597, PubMed:25132355). Also plays a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons (PubMed:25132355). May act as a heme transporter that promotes cellular iron availability via heme oxygenase/HMOX2 and independently of TFRC (PubMed:35714613). Also transports heme by-product coproporphyrin III (CPIII), and may be involved in their hepatic disposition (PubMed:26383540). Mediates the uptake of other substrates such as prostaglandins D2 (PGD2), E1 (PGE1) and E2 (PGE2), taurocholate, L-thyroxine, leukotriene C4 and thromboxane B2 (PubMed:10873595, PubMed:14610227, PubMed:19129463, Ref.24, PubMed:29871943). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable). Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:14610227, PubMed:19129463, PubMed:22201122). The exact transport mechanism has not been yet deciphered but most likely involves an anion exchange, coupling the cellular uptake of organic substrate with the efflux of an anionic compound (PubMed:19129463, PubMed:20507927, PubMed:26277985). Hydrogencarbonate/HCO3(-) acts as a probable counteranion that exchanges for organic anions (PubMed:19129463). Cytoplasmic glutamate may also act as counteranion in the placenta (PubMed:26277985). An inwardly directed proton gradient has also been proposed as the driving force of E1S uptake with a (H(+):E1S) stoichiometry of (1:1) (PubMed:20507927).
Most likely contributes to the oral absorption and the disposition of a wide range of drugs in the intestine and the liver (PubMed:10873595, PubMed:11159893, PubMed:12724351, PubMed:14610227, PubMed:23531488, PubMed:26277985, Ref.24, PubMed:27576593).
Predominant isoform compared to isoform 1 in liver. Also expressed in small intestine duodenum, kidney, brain, placenta, and skeletal muscle.
Strongly expressed in the liver, at the sinusoidal membrane of the hepatocytes (PubMed:10873595, PubMed:11159893, PubMed:23531488). Expressed in the kidney (PubMed:11159893). Expressed in placental trophoblasts and syncytiotrophoblast (PubMed:11159893, PubMed:11932330, PubMed:12409283, PubMed:26277985). Expressed in the small intestine (PubMed:10873595, PubMed:11159893, PubMed:12724351, PubMed:23531488, PubMed:28408210). Expressed in the blood-brain barrier, in endothelial cells of brain capillaries (PubMed:11159893, PubMed:25132355). Expressed in the retina, in the inner nuclear layer and the inner plexiform layer (PubMed:25132355). Expressed in skelettal muscles (PubMed:23531488). In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed within the tubules (PubMed:10873595, PubMed:11159893, PubMed:35307651). Also expressed in pancreas, lung, heart, colon, ovary and spleen (PubMed:10873595, PubMed:11159893). Expressed in fetal brain, heart, kidney, liver, lung, skeletal muscle, spleen and pancreas (PubMed:10873595).
While some reports have shown that E1S transport exhibited single-saturation kinetics (PubMed:11932330, PubMed:14610227), other studies demonstrated a biphasic saturation kinetics (PubMed:22201122, Ref.24, PubMed:11932330, PubMed:14610227). Despite a previous report that demonstrated a pH-dependent substrate uptake and a transport stimulation at low pH (PubMed:14610227), another study did not observe any pH-dependent E1S and taurocholate transport (PubMed:23531488, PubMed:14610227). Was shown to mediate bile acid taurocholate transport at low pH in some studies (PubMed:14610227, PubMed:29871943), but not others (PubMed:23531488, PubMed:11159893, PubMed:29871943). The enterocyte localization of SLCO2B1/OATP2B1 remains uncertain. While some authors found it in the apical membrane (PubMed:12724351), consistent with a function as uptake carrier contributing to the intestinal absorption of drugs, other studies demonstrated a basolateral membrane expression, supporting a physiological role in substrate uptake from the blood flow and intestinal clearance (PubMed:28408210, PubMed:12724351).
Belongs to the TtcA family. CTU1/NCS6/ATPBD3 subfamily.
Component of a complex at least composed of URM1, CTU2/NCS2 and CTU1/ATPBD3. May form a heterodimer with CTU2/NCS2.
Plays a central role in 2-thiolation of mcm(5)S(2)U at tRNA wobble positions of tRNA(Lys), tRNA(Glu) and tRNA(Gln). Directly binds tRNAs and probably acts by catalyzing adenylation of tRNAs, an intermediate required for 2-thiolation. It is unclear whether it acts as a sulfurtransferase that transfers sulfur from thiocarboxylated URM1 onto the uridine of tRNAs at wobble position.
Belongs to the DOK family. Type B subfamily.
DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK5 functions in RET-mediated neurite outgrowth and plays a positive role in activation of the MAP kinase pathway. Putative link with downstream effectors of RET in neuronal differentiation.
Highest expression in skeletal muscle, lower in brain, heart and kidney. Also detected in activated peripheral blood T-lymphocytes.
Interacts with phosphorylated RET. In contrast to other DOK proteins, it does not interact with RASGAP (By similarity).
PTB domain mediates receptor interaction.
Phosphorylated on tyrosine residues in response to insulin, IGF1 and GDNF.
Expressed in gonads, adrenal cortex and kidney.
Plays a key role in steroid hormone synthesis by enhancing the metabolism of cholesterol into pregnenolone. Mediates the transfer of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane where it is cleaved to pregnenolone.
APOD is primarily localized in HDL (60-65%), with most of the remainder in VHDL and only trace amounts in VLDL and LDL.
APOD occurs in the macromolecular complex with lecithin-cholesterol acyltransferase. It is probably involved in the transport and binding of bilin. Appears to be able to transport a variety of ligands in a number of different contexts.
Expressed in liver, intestine, pancreas, kidney, placenta, adrenal, spleen, fetal brain tissue and tears.
Homodimer. In plasma, also exists as a disulfide-linked heterodimer with APOA2.
N-glycosylatd. N-glycan heterogeneity at Asn-65: Hex5HexNAc4 (major) and Hex6HexNAc5 (minor); at Asn-98: Hex5HexNAc4 (minor), dHex1Hex5HexNAc4 (major), dHex1Hex6HexNAc5 (minor) and dHex1Hex7HexNAc6 (minor).
Does not exhibit any ribonuclease activity.
'Ropporin' comes from the Japanese word 'oppo' which means 'tail'.
Homodimer. Interacts with AKAP3 and RHPN1 (By similarity). May interact with SPA17 (PubMed:17551920). Interacts with FSCB; the interaction increases upon spermatozoa capacitation conditions (By similarity).
Important for male fertility. With ROPN1L, involved in fibrous sheath integrity and sperm motility, plays a role in PKA-dependent signaling processes required for spermatozoa capacitation.
Sumoylated, sumoylation decreases upon spermatozoa capacitation conditions.
Testis specific in adult. Overexpressed in hematologic tumor cells.
The RIIa domain mediates interaction with AKAP3.
Converts 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone (PubMed:21173190). Acts on LPA containing saturated or unsaturated fatty acids C16:0-C20:4 at the sn-1 position using C18:1, C20:4 or C18:2-CoA as the acyl donor (PubMed:21173190). Also acts on lysophosphatidylcholine, lysophosphatidylinositol and lysophosphatidylserine using C18:1 or C20:4-CoA (PubMed:21173190). Has a preference for arachidonoyl-CoA as a donor (By similarity). Has also a modest lysophosphatidylinositol acyltransferase (LPIAT) activity, converts lysophosphatidylinositol (LPI) into phosphatidylinositol (By similarity).
Widely expressed with highest levels in testis, pancreas and kidney, followed by spleen, lung, adipose tissue and liver.
Forms a heteromeric complex with ALS2CL. Interacts with ALS2CL.
May act as a GTPase regulator. Controls survival and growth of spinal motoneurons (By similarity).
Belongs to the glycosyltransferase 7 family.
Responsible for the synthesis of complex-type N-linked oligosaccharides in many glycoproteins as well as the carbohydrate moieties of glycolipids (PubMed:9405390). Can produce lactose (PubMed:9405390).
Weakly expressed in various tissues. Highest expression in prostate, testis, ovary, intestine, muscle, and in fetal brain.
A chromosomal aberration involving SRGAP3 is found in a patient with severe idiopathic intellectual disability (PubMed:12195014). Translocation t(X;3)(p11.2;p25) (PubMed:12195014).
GTPase-activating protein for RAC1 and perhaps Cdc42, but not for RhoA small GTPase. May attenuate RAC1 signaling in neurons.
Highly expressed in adult and fetal brain. Expressed at low levels in kidney. Isoform 3 is expressed in the kidney but is absent in the brain.
Homodimer (Probable). Forms a heterooligomer with SRGAP1 and SRGAP2 through its F-BAR domain. Interacts with WASF1. Probably interacts with ROBO1. Interacts with FASLG.
The F-BAR domain mediates oligomerization, binds membranes, and induces plasma membrane protrusions.
Beta-1,3-N-acetylglucosaminyltransferase that plays a role in the elongation of specific branch structures of multiantennary N-glycans. Has strong activity towards tetraantennary N-glycans and 2,6 triantennary glycans.
Highly expressed in small intestine, pancreas, spleen, bone marrow, lung, throat, and ileum, and weakly in fetal brain, cerebellum, heart, liver, tongue, breast, uteri, and testis. Not detected in colon. Differentially expressed in human tumor cell lines.
Interacts with B3GNT2; this interaction greatly increases B3GNT2 catalytic activity, independently of B3GNT8 enzymatic activity.
Expressed in pancreatic islet cells (PubMed:12871971). Expressed in melanocytes (PubMed:23999003).
Interacts with the N-termini of STX1A and/or STX1B1 and DOC2A. Interacts with BSN. Interacts with RIMS1 which recruits UNC13A to the active zone. Forms homodimers via its first C2 domain. Also interacts via this domain with the zinc finger domain of RIMS2. Part of a complex consisting of ERC2, RIMS1 and UNC13A. Also part of a complex consisting of UNC13A, RIMS2 and RAB3A (By similarity). Interacts with FBXO45 (via SRY domain); leading to the degradation of UNC13A by the proteasome (By similarity).
Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. Involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool (RRP). Essential for synaptic vesicle maturation in most excitatory/glutamatergic but not inhibitory/GABA-mediated synapses. Facilitates neuronal dense core vesicles fusion as well as controls the location and efficiency of their synaptic release (By similarity). Also involved in secretory granule priming in insulin secretion. Plays a role in dendrite formation by melanocytes (PubMed:23999003).
The C-terminal region containing both MHD domains and the third C2 domain is required for synaptic vesicle priming activity.
The C2 domains are not involved in calcium-dependent phospholipid binding.
Predominantly expressed in muscle and brain.
RNA-binding protein that regulates alternative splicing events by binding to 5'-UGCAUGU-3' elements. Regulates alternative splicing of tissue-specific exons and of differentially spliced exons during erythropoiesis.
RNA-binding protein that regulates alternative splicing events.
Acts as a transcriptional regulator of muscle creatine kinase (MCK) and so has a role in the establishment of diverse mesodermal muscle types. The protein binds to an A/T-rich element in the muscle creatine enhancer (By similarity).
Expressed specifically in mast cells. Found primarily in lung.
Putative acid-stable proteinase inhibitor.
Contains a thioredoxin domain, but lacks thioredoxin activity.
Required for normal embryonic development.
Ubiquitous. Detected in heart, kidney, muscle, brain, lung, liver and in skin fibroblasts (at protein level).
Belongs to the chloride channel (TC 2.A.49) family. ClC-1/CLCN1 subfamily.
Predominantly expressed in skeletal muscles.
Voltage-gated chloride channel (PubMed:8112288, PubMed:9122265, PubMed:12456816). Plays an important role in membrane repolarization in skeletal muscle cells after muscle contraction. The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons (Probable). The absence of conserved gating glutamate residues is typical for family members that function as channels (Probable).
Plays a key role to hearing function. Required for normal organization and maintenance of the stereocilia bundle and for mechano-electrical transduction.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A7 subfamily.
Brain specific (at protein level) (PubMed:7651355). Highly expressed in hippocampus, corpus striatum and temporal cortex. Also expressed in frontal cortex, occipital cortex and, at lower levels, in cerebellum and parietal cortex (at protein level) (PubMed:7651355).
Brain specific sodium (and chloride)-dependent proline transporter (PubMed:7651355). Terminates the action of proline by its high affinity sodium-dependent reuptake into presynaptic terminals (Probable).
Binds to WNT proteins and inhibits their activities. May be involved in mesoderm segmentation.
Heterodimer with GNB5. Interacts with RGS7BP, leading to regulate the subcellular location of the heterodimer formed with GNB5. Component of the RGS9-1-Gbeta5 complex composed of RGS9 (RGS9-1), Gbeta5 (GNB5) and RGS9BP. Interacts with PDE6G and GNAT1.
Highly expressed in the caudate and putamen, lower levels found in the hypothalamus and nucleus accumbens and very low levels in cerebellum. Not expressed in globus pallidus or cingulate cortex. Isoform 2 is expressed predominantly in pineal gland and retina. Isoform 3 is expressed in retina (abundant in photoreceptors).
In photoreceptor cells the DEP domain is essential for targeting RGS9 to the outer rod segments.
Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Binds to GNAT1. Involved in phototransduction; key element in the recovery phase of visual transduction (By similarity).
Retinal isoform 3 is light-dependent phosphorylated at 'Ser-478'. Phosphorylation is decreased by light exposition (By similarity).
Belongs to the type IA topoisomerase family.
Introduces a single-strand break via transesterification at a target site in duplex DNA. Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(5'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 3'-OH DNA strand.
Isoform 1 is found in testis, heart and skeletal muscle. A 4 kb transcript which probably represents isoform 2 is found in thymus, kidney and pancreas.
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(5'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 3'-OH DNA strand. The free DNA strand than undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 3'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Possesses negatively supercoiled DNA relaxing activity.
Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. Also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines including CCL2, CCL3, CCL3L1, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL17, CCL22, CCL23, CCL24, SCYA2/MCP-1, SCY3/MIP-1-alpha, SCYA5/RANTES and SCYA7/MCP-3. Upon active ligand stimulation, activates a beta-arrestin 1 (ARRB1)-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin (CFL1) through a RAC1-PAK1-LIMK1 signaling pathway. Activation of this pathway results in up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. By scavenging chemokines in tissues, on the surfaces of lymphatic vessels, and in placenta, plays an essential role in the resolution (termination) of the inflammatory response and in the regulation of adaptive immune responses. Plays a major role in the immune silencing of macrophages during the resolution of inflammation. Acts as a regulator of inflammatory leukocyte interactions with lymphatic endothelial cells (LECs) and is required for immature/mature dendritic cells discrimination by LECs.
Found in endothelial cells lining afferent lymphatics in dermis and lymph nodes. Also found in lymph nodes subcapsular and medullary sinuses, tonsillar lymphatic sinuses and lymphatics in mucosa and submucosa of small and large intestine and appendix. Also found in some malignant vascular tumors. Expressed at high levels in Kaposi sarcoma-related pathologies. Expressed on apoptotic neutrophils (at protein level). Expressed primarily in placenta and fetal liver, and found at very low levels in the lung and lymph node.
Phosphorylated on serine residues in the C-terminal cytoplasmic tail.
The C-terminal cytoplasmic tail controls its phosphorylation, stability, intracellular trafficking itinerary, and chemokine scavenging properties.
Increases as cells progress through G1, peaks during S and G2 phases and decreases as cells enter mitosis during G2/M (at protein level).
Interacts with CCP110, CEP97, TALPID3 (PubMed:21620453, PubMed:24421332). Interacts with MPHOSPH9 (PubMed:30375385).
Microtubule-dependent motor protein that acts as a negative regulator of ciliogenesis by mediating recruitment of CCP110 to mother centriole in cycling cells, leading to restrict nucleation of cilia at centrioles. Mediates depolymerization of microtubules of centriolar origin, possibly to suppress aberrant cilia formation (PubMed:21620453). Following activation by NEK2 involved in disassembly of primary cilium during G2/M phase but does not disassemble fully formed ciliary axonemes. As cilium assembly and disassembly is proposed to coexist in a dynamic equilibrium may suppress nascent cilium assembly and, potentially, ciliar re-assembly in cells that have already disassembled their cilia ensuring the completion of cilium removal in the later stages of the cell cycle (PubMed:26290419). Plays an important role in recruiting MPHOSPH9, a negative regulator of cilia formation to the distal end of mother centriole (PubMed:30375385).
Part of the RFX complex that binds to the X-box of MHC II promoters.
The C-terminal domain is necessary for the RFX complex formation.
The RFX heterotetrameric complex consists of 2 molecules of RFX5 and one each of RFXAP and RFX-B/RFXANK; with each subunit representing a separate complementation group. RFX forms cooperative DNA binding complexes with X2BP and CBF/NF-Y. RFX associates with CIITA to form an active transcriptional complex.
Could be created by usage of an unusual splicing donor site.
Expression is regulated by the transcription factor ERG.
Interacts with the CRIB domains of proteins such as Pak1 and Was/Wasp (By similarity). Interacts with GLUL (PubMed:30158707).
Palmitoylated; regulates localization to the plasma membrane and may be mediated by GLUL.
Plasma membrane-associated small GTPase specifically involved in angiogenesis (PubMed:21628409, PubMed:24434213, PubMed:30158707). Required for endothelial cell migration during vascular development via its interaction with GLUL (PubMed:30158707). Elicits the formation of F-actin-rich structures, thereby regulating endothelial cell migration (PubMed:30158707).
Specifically expressed in endothelial cells in different tissues, such as brain, heart, lung and liver.
Class-III neuronal intermediate filament protein (By similarity). May form an independent structural network without the involvement of other neurofilaments or may cooperate with the neuronal intermediate filament proteins NEFL, NEFH, NEFM and INA to form a filamentous network (PubMed:15446584, PubMed:15322088). Assembly of the neuronal intermediate filaments may be regulated by RAB7A (By similarity). Plays a role in the development of unmyelinated sensory neurons (By similarity). May be involved in axon elongation and axon regeneration after injury (By similarity). Inhibits neurite extension in type II spiral ganglion neurons in the cochlea (By similarity).
Expressed in the neurons of the outer hair cells in the organ of Corti and to a lesser extent in type I spiral ganglion cells.
Forms homodimers (in vitro) (By similarity). Homopolymerizes into a filamentous network (in vitro) (PubMed:15446584). Forms heterodimers with NEFL, NEFM or NEFH (in vitro) (By similarity). Interacts with DST (via C-terminus) (By similarity). Interacts with RAB7A; the interaction is direct (PubMed:23179371). Interacts with PRKCE (via phorbol-ester/DAG-type 2 domain) (PubMed:18408015).
Phosphorylated; phosphorylation increases after nerve injury in regenerating neurons.
Activated by ascorbate and magnesium ions.
Detected in colon, small intestine, ovary, testis, prostate, skeletal muscle, heart, liver and urinary bladder.
Dioxygenase that repairs alkylated nucleic acid bases by direct reversal oxidative dealkylation. Can process both double-stranded (ds) and single-stranded (ss) DNA substrates, with a strong preference for dsDNA (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:20714506, PubMed:25797601, PubMed:23972994). Uses molecular oxygen, 2-oxoglutarate and iron as cofactors to oxidize the alkyl groups that are subsequently released as aldehydes, regenerating the undamaged bases. Probes the base pair stability, locates a weakened base pair and flips the damaged base to accommodate the lesion in its active site for efficient catalysis (PubMed:18432238, PubMed:22659876). Repairs monoalkylated bases, specifically N1-methyladenine and N3-methylcytosine, as well as higher order alkyl adducts such as bases modified with exocyclic bridged adducts known as etheno adducts including 1,N6-ethenoadenine, 3,N4-ethenocytosine and 1,N2-ethenoguanine (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:20714506, PubMed:25797601, PubMed:23972994, PubMed:26408825). Acts as a gatekeeper of genomic integrity under alkylation stress. Efficiently repairs alkylated lesions in ribosomal DNA (rDNA). These lesions can cause ss- and dsDNA strand breaks that severely impair rDNA transcription (PubMed:23972994). In a response mechanism to DNA damage, associates with PCNA at replication forks to repair alkylated adducts prior to replication (PubMed:19736315, PubMed:26408825).
Interacts with PCNA homotrimer; this interaction is enhanced during the S-phase of the cell cycle (PubMed:19736315, PubMed:26408825, PubMed:23972994). Interacts with nucleolar proteins NCL, UBTF and NPM1 (PubMed:23972994). Interacts with XRCC5-XRCC6 heterodimer (PubMed:23972994).
The PCNA-binding motif (AlkB homolog 2 PCNA-interacting motif, APIM), mediates the colocalization of ALKBH2 with PCNA at the replication foci, coordinating the repair of alkylated DNA damage with DNA replication.
Interacts with REC114 (PubMed:31704776). Part of the MCD recombinosome complex, at least composed of IHO1, REC114 and MEI4.
Required for DNA double-strand breaks (DSBs) formation in unsynapsed regions during meiotic recombination. Probably acts by forming a complex with IHO1 and REC114, which activates DSBs formation in unsynapsed regions, an essential step to ensure completion of synapsis.
Heterodimer of alpha and beta chains; disulfide-linked. Part of the B-cell antigen receptor complex where the alpha/beta chain heterodimer is non-covalently associated with an antigen-specific membrane-bound surface immunoglobulin of two heavy chains and two light chains. Interacts with LYN (By similarity).
Phosphorylated on tyrosine upon B-cell activation by SRC-type Tyr-kinases such as BLK, LYN and SYK.
Required in cooperation with CD79A for initiation of the signal transduction cascade activated by the B-cell antigen receptor complex (BCR) which leads to internalization of the complex, trafficking to late endosomes and antigen presentation. Enhances phosphorylation of CD79A, possibly by recruiting kinases which phosphorylate CD79A or by recruiting proteins which bind to CD79A and protect it from dephosphorylation.
During assembly of the complex, component of the small nucleolar ribonucleoprotein particles containing H/ACA-type snoRNAs (H/ACA snoRNPs) which contains NOLA2/NHP2, NOLA3/NOP10, NAF1 and DKC1/NOLA4. Interacts directly with DKC1/NOLA4.
RNA-binding protein required for the maturation of box H/ACA snoRNPs complex and ribosome biogenesis. During assembly of the H/ACA snoRNPs complex, it associates with the complex and disappears during maturation of the complex and is replaced by NOLA1/GAR1 to yield mature H/ACA snoRNPs complex. Probably competes with NOLA1/GAR1 for binding with DKC1/NOLA4.
By IFNG/IFN-gamma. The induction is enhanced by TNF in dermal fibroblasts and vein endothelial cells.
Cytokine that affects the growth, movement, or activation state of cells that participate in immune and inflammatory response. Chemotactic for activated T-cells. Binds to CXCR3.
E3 ubiquitin-protein ligase. The BRCA1-BARD1 heterodimer specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Plays a central role in the control of the cell cycle in response to DNA damage. Acts by mediating ubiquitin E3 ligase activity that is required for its tumor suppressor function. Also forms a heterodimer with CSTF1/CSTF-50 to modulate mRNA processing and RNAP II stability by inhibiting pre-mRNA 3' cleavage.
Homo- and heterodimer. Heterodimer (RING-type zinc finger) with BRCA1. Heterodimer (via ANK repeats and BRCT domains) with CSTF1/CSTF-50. Component of the BRCA1-A complex, at least composed of the BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Interacts with UBXN1.
It is uncertain whether Met-1 or Met-26 is the initiator.
Processed during apoptosis. The homodimer is more susceptible to proteolytic cleavage than the BARD1/BRCA1 heterodimer.
ADP-ribosylated (-auto). Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination.
Oligomerizes and associates with TNKS2. Interacts with the cytoplasmic domain of LNPEP/Otase in SLC2A4/GLUT4-vesicles. Binds to the N-terminus of telomeric TERF1 via the ANK repeats. Found in a complex with POT1; TERF1 and TINF2 (PubMed:12768206). Interacts with AXIN1 (PubMed:19759537, PubMed:21478859, PubMed:21799911). Interacts with AXIN2 (PubMed:19759537, PubMed:21478859). Interacts with BLZF1 and CASC3 (PubMed:21478859). Interacts with NUMA1 (PubMed:12080061).
Phosphorylated on serine residues by MAPK kinases upon insulin stimulation. Phosphorylated during mitosis.
Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking (PubMed:10988299, PubMed:11739745, PubMed:16076287, PubMed:19759537, PubMed:21478859, PubMed:22864114, PubMed:23622245, PubMed:25043379). Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation (PubMed:19759537, PubMed:21478859). Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination (PubMed:21478859). Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length (PubMed:11739745). Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI (PubMed:22864114). May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles (PubMed:10988299). May be involved in spindle pole assembly through PARsylation of NUMA1 (PubMed:16076287). Stimulates 26S proteasome activity (PubMed:23622245).
Specifically inhibited by XAV939, a small molecule, leading to inhibit the Wnt signaling pathway by stabilizing AXIN1 and AXIN2 (PubMed:19759537). Inhibited by talazoparib (PubMed:33361107). Not inhibited by olaparib, niraparib and veliparib (PubMed:33361107).
Ubiquitinated by RNF146 when auto-poly-ADP-ribosylated, leading to its degradation.
Expressed in brain; especially in cerebellum, hippocampus, parahippocampal gyrus, superior and middle temporal gyrus. Also expressed in B-cells, colon, eye, and lung. Lower expression was present in bone, brain, cervix, ear, heart, kidney, muscle, nerve, pancreas, prostate, skin, stomach, and testis.
Has probably no intrinsic transporter activity but together with SLC30A5 forms a functional zinc ion:proton antiporter heterodimer, mediating zinc entry into the lumen of organelles along the secretory pathway (PubMed:15994300, PubMed:19366695, PubMed:19759014). As part of that zinc ion:proton antiporter, contributes to zinc ion homeostasis within the early secretory pathway and regulates the activation and folding of enzymes like alkaline phosphatases and enzymes involved in phosphatidylinositol glycan anchor biosynthesis (PubMed:15994300, PubMed:19759014, PubMed:35525268).
Heterodimer with SLC30A5; form a functional zinc ion transmembrane transporter.
Hydrophilic histidine residues that participate to zinc binding in transporters of the family are not conserved in SLC30A6.
Acts as co-chaperone for HSP90. Prevents the stimulation of HSP90AB1 ATPase activity by AHSA1. Positive factor in promoting PGR function in the cell. May be necessary for proper folding of myosin (Potential). Necessary for normal cell proliferation. Necessary for normal myotube formation and myosin accumulation during muscle cell development. May play a role in erythropoiesis in stroma cells in the spleen (By similarity).
Detected in peripheral blood leukocytes, bone marrow, adrenal gland, trachea, spinal cord, thyroid, lymph node and stomach.
Interacts with PGR isoforms A and B as well as with NR3C1 in the absence of ligand, and with HSP90AB1. Binding to HSP90AB1 involves 2 UNC45A monomers per HSP90AB1 dimer.
Interacts with HSP90A, VCP, ATP6V1D, KIAA0665, AMPK, and DMAP1 through its TPR repeat.
Plays a role in the import of cytosolically synthesized preproteins into mitochondria. Binds the mature portion of precursor proteins. Interacts with cellular components, and possesses weak ATPase activity. May be a chaperone-like protein that helps to keep newly synthesized precursors in an unfolded import compatible state.
BMP antagonist which may play a role in neural development. Promotes cell adhesion (By similarity).
Peripherally associated with AMPAR complex. AMPAR complex consists of an inner core made of 4 pore-forming GluA/GRIA proteins (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged in a twofold symmetry. One of the two pairs of distinct binding sites is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR complex is complemented by outer core constituents binding directly to the GluA/GRIA proteins at sites distinct from the interaction sites of the inner core constituents. Outer core constituents include at least PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the inner and outer core serve as a platform for other, more peripherally associated AMPAR constituents, including VWC2. Alone or in combination, these auxiliary subunits control the gating and pharmacology of the AMPAR complex and profoundly impact their biogenesis and protein processing (By similarity).
Detected in the suprabasal layer of the stratified epithelium of the esophagus, exocervix, vagina, mouth and lingual mucosa, and in cells and cell clusters in the mucosa and serous gland ducts of the esophageal submucosa (at protein level). Expressed widely in the exocervix and esophageal epithelium, with lowest levels detected in the basal cell layer.
Heterotetramer of two type I and two type II keratins. Keratin-4 is generally associated with keratin-13.
Three alleles of K4 are known: K4A1, K4A2 and K4B (displayed here).
(Microbial infection) Acts as a receptor for human coronavirus 229E/HCoV-229E. In case of human coronavirus 229E (HCoV-229E) infection, serves as receptor for HCoV-229E spike glycoprotein.
(Microbial infection) Interacts with the S1 domain of human coronavirus 229E/HCoV-229E spike protein.
(Microbial infection) Mediates as well Human cytomegalovirus (HCMV) infection.
Broad specificity aminopeptidase which plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. Also involved in the processing of various peptides including peptide hormones, such as angiotensin III and IV, neuropeptides, and chemokines. May also be involved the cleavage of peptides bound to major histocompatibility complex class II molecules of antigen presenting cells. May have a role in angiogenesis and promote cholesterol crystallization. May have a role in amino acid transport by acting as binding partner of amino acid transporter SLC6A19 and regulating its activity (By similarity).
Estradiol and IL8/interleukin-8 decrease enzymatic activity in vitro in endometrial stromal cells by 40% and 30%, respectively.
Expressed in epithelial cells of the kidney, intestine, and respiratory tract; granulocytes, monocytes, fibroblasts, endothelial cells, cerebral pericytes at the blood-brain barrier, synaptic membranes of cells in the CNS. Also expressed in endometrial stromal cells, but not in the endometrial glandular cells. Found in the vasculature of tissues that undergo angiogenesis and in malignant gliomas and lymph node metastases from multiple tumor types but not in blood vessels of normal tissues. A soluble form has been found in plasma. It is found to be elevated in plasma and effusions of cancer patients.
Found to serve as a receptor for tumor-homing peptides, more specifically NGR peptides. It could serve thus as a target for delivering drugs into tumors. Concentration in human hepatic bile, varies from 17.3 to 57.6 micrograms/ml.
Homodimer. Interacts with SLC6A19 (By similarity).
May undergo proteolysis and give rise to a soluble form.
Expressed in tooth particularly in odontoblast, ameloblast and cementoblast.
May have a dual function during osteoblast differentiation. In the nucleus of undifferentiated osteoblasts, unphosphorylated form acts as a transcriptional component for activation of osteoblast-specific genes like osteocalcin. During the osteoblast to osteocyte transition phase it is phosphorylated and exported into the extracellular matrix, where it regulates nucleation of hydroxyapatite.
Phosphorylated in the cytosol and extracellular matrix and unphosphorylated in the nucleus. Phosphorylation is necessary for nucleocytoplasmic transport and may be catalyzed by a nuclear isoform of CK2 and can be augmented by calcium. Phosphorylated (in vitro) by FAM20C in the extracellular medium at sites within the S-x-E/pS motif.
Contains one proline-rich sequence (Pro-Glu-Ser-Pro-Arg) that is required for transport activity.
Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:10196521, PubMed:10966924, PubMed:12538837, PubMed:17460754, PubMed:20858707). Cation cellular uptake or release is driven by the electrochemical potential, i.e. membrane potential and concentration gradient (PubMed:10966924). Functions as a Na(+)- and Cl(-)-independent, bidirectional uniporter (PubMed:12538837). Implicated in monoamine neurotransmitters uptake such as dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, histamine, serotonin and tyramine, thereby supporting a role in homeostatic regulation of aminergic neurotransmission in the brain (PubMed:10196521, PubMed:16581093, PubMed:20858707). Transports dopaminergic neuromodulators cyclo(his-pro) and salsolinol with low efficiency (PubMed:17460754). May be involved in the uptake and disposition of cationic compounds by renal clearance from the blood flow (PubMed:10966924). May contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier (Probable). Mediates the transport of polyamine spermidine and putrescine (By similarity). Mediates the bidirectional transport of polyamine agmatine (PubMed:12538837). Also transports guanidine (PubMed:10966924). May also mediate intracellular transport of organic cations, thereby playing a role in amine metabolism and intracellular signaling (By similarity).
Expressed in liver (PubMed:10196521, PubMed:9933568). Expressed in intestine (PubMed:16263091, PubMed:20858707). Expressed in kidney in proximal tubular cells (PubMed:10966924). Expressed in placenta (PubMed:9933568, PubMed:10966924). Expressed throughout the brain, including cerebral cortex, cerebrellum, substancia nigra, medulla oblongata, hippocampus, caudate nucleus, nucleus accumbens and pons with low levels of expression detected in nearly all brain regions (PubMed:10196521, PubMed:20858707). In testis, mostly localized to peritubular myoid cells and Leydig cells, and weakly expressed in developing germ cells (PubMed:35307651). Expressed in tracheal and bronchial epithelium of the respiratory tract, where it localizes to the apical membrane of ciliated cells, the entire membrane of basal cells and the basolateral membrane of intermediate cells (PubMed:15817714). Expressed in skeletal muscle, adrenal gland, heart, prostate, aorta, salivary gland, adrenal gland, uterus, lymph node, lung, trachea and spinal cord (PubMed:10196521, PubMed:9933568, PubMed:20858707). Expressed in fetal lung and liver (PubMed:9933568).
Mediates the uptake of clinically used drugs including neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) and platinum-based drug oxaliplatin (PubMed:10196521, PubMed:10966924, PubMed:12538837, PubMed:15817714, PubMed:16263091, PubMed:16914559, PubMed:16581093, PubMed:20858707). Plays a role in the anticancer activity of oxaliplatin and may contribute to antitumor specificity (PubMed:16914559).
Higher expression in the liver. Also found in heart, brain, kidney, pancreas, prostate, testis and ovary.
Kynurenine transaminase activity is competitively inhibited by aminoadipate, asparagine, glutamate, histidine, cysteine, lysine, 3-hydroxy-kynurenine and phenylalanine.
Transaminase with broad substrate specificity. Has transaminase activity towards aminoadipate, kynurenine, methionine and glutamate. Shows activity also towards tryptophan, aspartate and hydroxykynurenine. Accepts a variety of oxo-acids as amino-group acceptors, with a preference for 2-oxoglutarate, 2-oxocaproic acid, phenylpyruvate and alpha-oxo-gamma-methiol butyric acid. Can also use glyoxylate as amino-group acceptor (in vitro).
A chromosomal aberration involving ALK has been identified in a subset of patients with non-small-cell lung carcinoma. This aberration leads to the production of a fusion protein between the N-terminus of EML4 et the C-terminus of ALK. It is unclear whether the fusion protein is caused by a simple inversion within 2p (inv(2)(p21p23)) or whether the chromosome translocation involving 2p is more complex. When tested in a heterologous system, the fusion protein EML4-ALK possesses transforming activity that is dependent on ALK catalytic activity, possibly due to spontaneous dimerization mediated by the EML4 moiety, leading to ALK kinase activation.
A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17.
A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A.
A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas.
A chromosomal aberration involving ALK is found in one subject with colorectal cancer. Translocation t(2;2)(p23.1;p23.3). A 5 million base pair tandem duplication generates an in-frame WDCP-ALK gene fusion.
Activated upon ALKAL2 ligand-binding (PubMed:34646012, PubMed:34819673). ALKAL2-driven activation is coupled with heparin-binding (PubMed:25605972, PubMed:34646012). Following ligand-binding, homodimerizes and autophosphorylates, activating its kinase activity (PubMed:16317043, PubMed:17681947, PubMed:34646012, PubMed:34819673). Inactivated through dephosphorylation by receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) when there is no stimulation by a ligand (PubMed:17681947). Staurosporine, crizotinib and CH5424802 act as inhibitors of ALK kinase activity (PubMed:21575866).
Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells.
Homodimer; homodimerizes following heparin- and ligand-binding (PubMed:16317043, PubMed:25605972, PubMed:34646012, PubMed:34819673). Interacts with CBL, IRS1, PIK3R1 and PLCG1 (PubMed:15226403). Interacts with FRS2 and SHC1 (PubMed:15226403, PubMed:16878150, PubMed:17274988). Interacts with PTN and MDK (PubMed:11278720, PubMed:12122009).
Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system (PubMed:11121404, PubMed:11387242, PubMed:16317043, PubMed:17274988, PubMed:30061385, PubMed:34646012, PubMed:34819673). Also acts as a key thinness protein involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis (By similarity). Following activation by ALKAL2 ligand at the cell surface, transduces an extracellular signal into an intracellular response (PubMed:30061385, PubMed:33411331, PubMed:34646012, PubMed:34819673). In contrast, ALKAL1 is not a potent physiological ligand for ALK (PubMed:34646012). Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway (PubMed:34819673). Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif (PubMed:15226403, PubMed:16878150). Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1 (PubMed:15226403, PubMed:16878150). ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK) (PubMed:11278720, PubMed:11809760, PubMed:12107166, PubMed:12122009). PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation (PubMed:11278720, PubMed:11809760, PubMed:12107166). MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction (PubMed:12122009). Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase (PubMed:15226403, PubMed:16878150). Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK (PubMed:15226403, PubMed:16878150).
Phosphorylated at tyrosine residues by autocatalysis, which activates kinase activity (PubMed:11121404, PubMed:15938644, PubMed:16878150, PubMed:34819673). In cells not stimulated by a ligand, receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) dephosphorylates ALK at the sites in ALK that are undergoing autophosphorylation through autoactivation (PubMed:17681947). Phosphorylation at Tyr-1507 is critical for SHC1 association (PubMed:17274988).
The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.
The EGF-like region drives the cytokine specificity for ALKAL2.
The heparin-binding region binds heparin glycosaminoglycan (PubMed:25605972, PubMed:34646012). Heparin-binding is required for ALKAL2-driven activation (PubMed:34646012).
May play a role in ubiquitination and subsequent proteasomal degradation of target proteins.
Phosphorylated at Ser-281 and Ser-331, dephosphorylation promotes nuclear translocation, most likely due to disruption of the SUGT1-HSP90 complex.
Probably associates with SCF (SKP1-CUL1-F-box protein) complex through interaction with SKP1. Interacts with S100A6. Interacts with HSP90.
The CS domain mediates interaction with HSP90.
Biliary atresia is a chronic and progressive cholestatic liver disease of chilhood characterized by an abnormal villin gene expression and severe malformation of canalicular microvillus structure.
Consists of a large core fragment in the N-terminal portion and a small headpiece (HP) in the C-terminal portion. The core fragment is necessary for both actin-nucleating and -severing activities, whereas the HP binds F-actin strongly in both the presence and absence of calcium and is necessary in actin-bundling activity. The Gelsolin-like 1 repeat is necessary for the actin-capping activity. The entire core fragment is necessary for the actin-severing activity. Two major calcium-sensitive sites are involved in conformational changes and determine separate functional properties: the first site (Glu-25, Asp-44 and Glu-74) regulates the actin-capping and actin-severing activities; while the second site (Asp-61, Asp-86 and Ala-93) regulates only the actin-severing activity.
Epithelial cell-specific Ca(2+)-regulated actin-modifying protein that modulates the reorganization of microvillar actin filaments. Plays a role in the actin nucleation, actin filament bundle assembly, actin filament capping and severing. Binds phosphatidylinositol 4,5-bisphosphate (PIP2) and lysophosphatidic acid (LPA); binds LPA with higher affinity than PIP2. Binding to LPA increases its phosphorylation by SRC and inhibits all actin-modifying activities. Binding to PIP2 inhibits actin-capping and -severing activities but enhances actin-bundling activity. Regulates the intestinal epithelial cell morphology, cell invasion, cell migration and apoptosis. Protects against apoptosis induced by dextran sodium sulfate (DSS) in the gastrointestinal epithelium. Appears to regulate cell death by maintaining mitochondrial integrity. Enhances hepatocyte growth factor (HGF)-induced epithelial cell motility, chemotaxis and wound repair. Upon S.flexneri cell infection, its actin-severing activity enhances actin-based motility of the bacteria and plays a role during the dissemination.
Monomer. Homodimer; homodimerization is necessary for actin-bundling. Associates with F-actin; phosphorylation at tyrosine residues decreases the association with F-actin. Interacts (phosphorylated at C-terminus tyrosine phosphorylation sites) with PLCG1 (via the SH2 domains). Interacts (phosphorylated form) with PLCG1; the interaction is enhanced by hepatocyte growth factor (HGF) (By similarity).
Specifically expressed in epithelial cells. Major component of microvilli of intestinal epithelial cells and kidney proximal tubule cells. Expressed in canalicular microvilli of hepatocytes (at protein level).
Tyrosine phosphorylation is induced by epidermal growth factor (EGF) and stimulates cell migration (By similarity). Phosphorylated on tyrosine residues by SRC. The unphosphorylated form increases the initial rate of actin-nucleating activity, whereas the tyrosine-phosphorylated form inhibits actin-nucleating activity, enhances actin-bundling activity and enhances actin-severing activity by reducing high Ca(2+) requirements. The tyrosine-phosphorylated form does not regulate actin-capping activity. Tyrosine phosphorylation is essential for cell migration: tyrosine phosphorylation sites in the N-terminus half regulate actin reorganization and cell morphology, whereas tyrosine phosphorylation sites in the C-terminus half regulate cell migration via interaction with PLCG1.
Expression is restricted to melanoma and melanocyte cell lines and retina.
Interacts with PMEL. Interacts with GPR143.
Involved in melanosome biogenesis by ensuring the stability of GPR143. Plays a vital role in the expression, stability, trafficking, and processing of melanocyte protein PMEL, which is critical to the formation of stage II melanosomes.
Increased intracellular zinc level, resulting from extracellular zinc supplementation, do not induce any up- or down-regulation of gene expression. Up-regulated by zinc depletion.
Zinc ion transporter mediating zinc entry from the cytosol into the lumen of organelles along the secretory pathway (PubMed:15525635, PubMed:15994300). By contributing to zinc ion homeostasis within the early secretory pathway, regulates the activation and folding of enzymes like alkaline phosphatases (PubMed:15525635, PubMed:15994300).
(Microbial infection) Interacts with Herpes virus saimiri tyrosine kinase interacting protein (Tip).
Autophosphorylated (PubMed:7935444, PubMed:9171348, PubMed:9341198, PubMed:18056483, PubMed:18070987). Phosphorylated on tyrosine residues in response to KIT signaling (PubMed:9341198). Phosphorylation at Tyr-397 is required for optimal activity (PubMed:16920712). Phosphorylation at Tyr-508 inhibits kinase activity (PubMed:9171348). Phosphorylated at Tyr-508 by CSK (PubMed:7935444). Dephosphorylated by PTPRC/CD45 (By similarity). Becomes rapidly phosphorylated upon activation of the B-cell receptor and the immunoglobulin receptor FCGR1A (PubMed:8064233). Phosphorylated in response to ITGB1 in B-cells (PubMed:9020138).
Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily.
Constitutively phosphorylated and activated in cells from a number of chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) patients. Mediates phosphorylation of the BCR-ABL fusion protein. Abnormally elevated expression levels or activation of LYN signaling may play a role in survival and proliferation of some types of cancer cells.
Detected in monocytes (at protein level). Detected in placenta, and in fetal brain, lung, liver and kidney. Widely expressed in a variety of organs, tissues, and cell types such as epidermoid, hematopoietic, and neuronal cells. Expressed in primary neuroblastoma tumors.
Interacts with TEC. Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). Interacts with LIME1 and with CD79A upon activation of the B-cell antigen receptor. Interacts with the B-cell receptor complex. Interacts with phosphorylated THEMIS2. Interacts with EPOR. Interacts with MS4A2/FCER1B. Interaction (via the SH2 and SH3 domains) with MUC1 is stimulated by IL7 and the subsequent phosphorylation increases the binding between MUC1 and CTNNB1/beta-catenin. Interacts with ADAM15. Interacts with NDFIP2 and more weakly with NDFIP1. Interacts with FASLG. Interacts with KIT. Interacts with HCLS1. Interacts with FCGR2B. Interacts with FCGR1A; the interaction may be indirect. Interacts with CD19, CD22, CD79A and CD79B. Interacts (via SH3 domain) with CBLC, PPP1R15A and PDE4A. Interacts with TGFB1I1. Interacts (via SH3 domain) with PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase; this interaction enhances phosphatidylinositol 3-kinase activity. Interacts with CSF2RB, the common subunit of the IL3, IL5 and CSF2 receptors. Interacts with PAG1; identified in a complex with PAG1 and STAT3. Interacts with ABL1. Interacts with PTPN6/SHP-1. Interacts (via SH3 domain) with SCIMP (via proline-rich region) (PubMed:21930792). This interaction facilitates the phosphorylation of SCIMP on 'Tyr-107', which enhances binding of SCIMP to TLR4, and consequently the phosphorylation of TLR4 in response to stimulation by lipopolysaccharide in macrophages (By similarity). Interacts with LPXN (via LD motif 3) and the interaction is induced upon B-cell antigen receptor (BCR) activation. Interacts (via SH3-domain) with ANKRD54 (via ankyrin repeat region) in an activation-independent status of LYN. Forms a multiprotein complex with ANKRD54 and HCLS1. Interacts (via SH2 and SH3 domains) with UNC119; leading to LYN activation. Interacts with CD36. Interacts with LYN (By similarity). Interacts with SKAP1 and FYB1; this interaction promotes the phosphorylation of CLNK (By similarity). Interacts with BCAR1/CAS and NEDD9/HEF1 (PubMed:9020138).
Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Mediates phosphorylation of the BCR-ABL fusion protein. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Phosphorylates SCIMP on 'Tyr-107'; this enhances binding of SCIMP to TLR4, promoting the phosphorylation of TLR4, and a selective cytokine response to lipopolysaccharide in macrophages (By similarity). Phosphorylates CLNK (By similarity). Phosphorylates BCAR1/CAS and NEDD9/HEF1 (PubMed:9020138).
Subject to autoinhibition, mediated by intramolecular interactions between the SH2 domain and the C-terminal phosphotyrosine. Phosphorylation at Tyr-397 is required for optimal activity. Phosphorylated by CSK at Tyr-508; phosphorylation at Tyr-508 inhibits kinase activity. Kinase activity is modulated by dephosphorylation by PTPRC/CD45. Inhibited by Dasatinib, PP2, and SU6656.
The protein kinase domain plays an important role in its localization in the cell membrane.
Ubiquitinated by CBL, leading to its degradation. Ubiquitination is SH3-dependent.
Binds DNA as a monomer or a homodimer (PubMed:17870090). Interacts with NCOA5 coactivator, leading to a strong increase of transcription of target genes (PubMed:11113208). Interacts (via N-terminus) with KAT5 (PubMed:17996965). Interacts (via C-terminus) with HDAC1 (PubMed:17996965). Interacts with ZNHIT1 (PubMed:17892483). Interacts with SIAH2 (PubMed:26392558).
Deacetylated by HDAC1. Acetylation and deacetylation regulate its transcriptional regulatory activity.
Phosphorylated by CSNK1E; phosphorylation enhances its cytoplasmic localization.
The heme-bound form can bind gaseous signaling molecules such as CO and nitric oxide (NO) and NO can reverse its transcriptional repressor activity.
Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components BMAL1 and CLOCK. Also regulates genes involved in metabolic functions, including lipid metabolism and the inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nuclegotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and also negatively regulates the expression of NR1D1. Regulates lipid and energy homeostasis in the skeletal muscle via repression of genes involved in lipid metabolism and myogenesis including: CD36, FABP3, FABP4, UCP3, SCD1 and MSTN. Regulates hepatic lipid metabolism via the repression of APOC3. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). In addition to its activity as a repressor, can also act as a transcriptional activator. Acts as a transcriptional activator of the sterol regulatory element-binding protein 1 (SREBF1) and the inflammatory mediator interleukin-6 (IL6) in the skeletal muscle (By similarity). Plays a role in the regulation of circadian sleep/wake cycle; essential for maintaining wakefulness during the dark phase or active period (By similarity). Key regulator of skeletal muscle mitochondrial function; negatively regulates the skeletal muscle expression of core clock genes and genes involved in mitochondrial biogenesis, fatty acid beta-oxidation and lipid metabolism (By similarity). May play a role in the circadian control of neutrophilic inflammation in the lung (By similarity).
Ubiquitinated by SIAH2; leading to proteasomal degradation.
Under more reducing intracellular redox conditions, Cys-384 is in its heme-bound state, which is optimal for recruitment of the NCOR1/HDAC3 corepressor complex and repression of target genes. When subjected to oxidative stress conditions, Cys-384 undergoes oxidation to form a disulfide bridge with Cys-374, also triggering a ligand switch that results in release of bound heme and derepression of target genes.
Widely expressed. Expressed at high levels in the liver, adipose tissue, skeletal muscle and brain. Expression oscillates diurnally in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as in peripheral tissues.
Activates macrophages and polarizes them into M1-like macrophages through the activation of the MAPK and NF-kappaB signaling pathway. Upon activation, up-regulates the expression of CD80, CD86, CD69 and MHC II on macrophages, and induces the release of pro-inflammatory cytokines such as TNF, IL1B, IL6, CCL2 and nitric oxide (By similarity). May play a role in inhibition of proliferation and migration (PubMed:30456879, PubMed:29131025).
Expressed in renal cells (at protein level) (PubMed:29131025). Expressed in epithelial cells (PubMed:30456879).
Associates with the cytoplasmic domain of a variety of cadherins. The association of catenins to cadherins produces a complex which is linked to the actin filament network, and which seems to be of primary importance for cadherins cell-adhesion properties. Can associate with both E- and N-cadherins. Originally believed to be a stable component of E-cadherin/catenin adhesion complexes and to mediate the linkage of cadherins to the actin cytoskeleton at adherens junctions. In contrast, cortical actin was found to be much more dynamic than E-cadherin/catenin complexes and CTNNA1 was shown not to bind to F-actin when assembled in the complex suggesting a different linkage between actin and adherens junctions components. The homodimeric form may regulate actin filament assembly and inhibit actin branching by competing with the Arp2/3 complex for binding to actin filaments. Involved in the regulation of WWTR1/TAZ, YAP1 and TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation (By similarity). May play a crucial role in cell differentiation.
Expressed at high levels in the nervous system. Lacks the beta-catenin interaction domain.
Expressed ubiquitously in normal tissues.
Germline CTNNA1 truncating mutations have been detected in patients with hereditary diffuse gastric cancer (HDGC) and may play a role in disease susceptibility. Diffuse gastric cancer is a malignant disease characterized by poorly differentiated infiltrating lesions resulting in thickening of the stomach. Malignant tumors start in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body.
Monomer and homodimer; the monomer preferentially binds to CTNNB1 and the homodimer to actin (By similarity). Component of an cadherin:catenin adhesion complex composed of at least of CDH26, beta-catenin/CTNNB1, alpha-catenin/CTNNA1 and p120 catenin/CTNND1 (PubMed:28051089). Possible component of an E-cadherin/ catenin adhesion complex together with E-cadherin/CDH1 and beta-catenin/CTNNB1 or gamma-catenin/JUP; the complex is located to adherens junctions (By similarity). The stable association of CTNNA1 is controversial as CTNNA1 was shown not to bind to F-actin when assembled in the complex (By similarity). Alternatively, the CTNNA1-containing complex may be linked to F-actin by other proteins such as LIMA1 (By similarity). Binds AFDN and F-actin (By similarity). Interacts with ARHGAP21 (PubMed:16184169). Interacts with AJUBA (PubMed:12417594). Interacts with LIMA1 (PubMed:18093941). Interacts with vinculin/VCL (PubMed:26691986). Interacts with TJP2/ZO2 (via N-terminus) (By similarity). Interacts with TJP1/ZO1 (via N-terminus) (By similarity).
Phosphorylation seems to contribute to the strength of cell-cell adhesion rather than to the basic capacity for cell-cell adhesion.
Expressed in skin, followed by lung, small intestine, colon and testis. In skin, it is expressed in the epidermis with strongest staining in suprabasal viable layers. In ATOD patients, it is absent in the most differentiated upper spinous and granular layers (at protein level).
Patients affected by atopic dermatitis display an abnormal distribution of COL29A1 mRNA and protein in skin suggesting that COL29A1 may be involved in the pathogenesis of the disease.
Binds DNA via its HMG boxes. When bound to the mitochondrial light strand promoter, bends DNA into a U-turn shape, each HMG box bending the DNA by 90 degrees.
Binds to the mitochondrial light strand promoter and functions in mitochondrial transcription regulation (PubMed:29445193, PubMed:32183942). Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT that is required for basal transcription of mitochondrial DNA (PubMed:29149603). In this complex, TFAM recruits POLRMT to a specific promoter whereas TFB2M induces structural changes in POLRMT to enable promoter opening and trapping of the DNA non-template strand (PubMed:20410300). Required for accurate and efficient promoter recognition by the mitochondrial RNA polymerase (PubMed:22037172). Promotes transcription initiation from the HSP1 and the light strand promoter by binding immediately upstream of transcriptional start sites (PubMed:22037172). Is able to unwind DNA (PubMed:22037172). Bends the mitochondrial light strand promoter DNA into a U-turn shape via its HMG boxes (PubMed:1737790). Required for maintenance of normal levels of mitochondrial DNA (PubMed:22841477, PubMed:19304746). May play a role in organizing and compacting mitochondrial DNA (PubMed:22037171).
Monomer; binds DNA as a monomer (PubMed:19304746, PubMed:22037171, PubMed:22037172). Homodimer (PubMed:29149603). Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT (PubMed:29149603). In this complex TFAM recruits POLRMT to the promoter whereas TFB2M induces structural changes in POLRMT to enable promoter opening and trapping of the DNA non-template strand (PubMed:29149603). Upon metabolic stress, forms a complex composed of FOXO3, SIRT3, TFAM and POLRMT (PubMed:29445193, PubMed:12897151). Interacts with TFB1M and TFB2M (PubMed:12897151). Interacts with CLPX; this enhances DNA-binding (PubMed:22841477).
Phosphorylation by PKA within the HMG box 1 impairs DNA binding and promotes degradation by the AAA+ Lon protease.
Belongs to the transient receptor (TC 1.A.4) family. STrpC subfamily. TRPC4 sub-subfamily.
Forms a receptor-activated non-selective calcium permeant cation channel. Acts as a cell-cell contact-dependent endothelial calcium entry channel. Probably operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Mediates cation entry, with an enhanced permeability to barium over calcium. May also be activated by intracellular calcium store depletion.
Interacts with TRPC4AP (By similarity). Homotetramer and heterotetramer with TRPC1 and/or TRPC5 (PubMed:12032305). Isoform alpha but not isoform beta interacts with ITPR1, ITPR2 and ITPR3 (PubMed:11163362). Interacts with (via PDZ-binding domain) with NHERF1 (PubMed:12154080). Interacts with MX1 and RNF24 (PubMed:15757897, PubMed:17850865). Interacts (via CIRB domain) with SESTD1 (via spectrin 1 repeat) (PubMed:20164195). Interacts with CDH5 and CTNNB1 (PubMed:19996314). Interacts with SPTAN1 (via C-terminal spectrin repeats) and SPTBN5 (via C-terminus) (PubMed:18048348). Interacts (via protein 4.1-binding domain) with EPB41L2 (PubMed:16254212). Interacts with PLSCR1 (By similarity).
Phosphorylation modulates TRPC channel function by regulating the level of TRPC4 at the cell surface and by increasing the association with NHERF1.
Strongly expressed in placenta. Expressed at lower levels in heart, pancreas, kidney and brain. Expressed in endothelial cells. Isoform alpha was found to be the predominant isoform. Isoform beta was not found in pancreas and brain.
The calmodulin- and inositol 1,4,5-trisphosphate receptor-binding (CIRB) domain (695-724) is sufficient for the interaction with SESTD1.
The cell membrane presentation, the calcium entry function and the interaction with junctional proteins (CTNNB1 and CDH5) are controlled by endothelial cell-cell contacts.
The interaction with spectrin is important in controlling the translocation of TRPC4 channels to the plasma membrane following EGF stimulation.
The protein 4.1-binding domain (654-685) is required for binding to EPB41L2 and channel activation.
The spectrin-binding domain (730-758) is required for binding to SPTAN1 and SPTBN5.
Belongs to the sepiapterin reductase family.
Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.
In vitro phosphorylation of Ser-213 by CaMK2 does not change kinetic parameters.
Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex.
(Microbial infection) Isoform 1 and isoform 3 interact with human papillomavirus (HPV) type-16 E6 oncoprotein.
Binds to the X-box motif of MHC class II genes and represses their expression. May play an important role in regulating the duration of an inflammatory response by limiting the period in which MHC class II molecules are induced by interferon-gamma. Isoform 3 binds to the X-box motif of TERT promoter and represses its expression. Together with PABPC1 or PABPC4, isoform 1 acts as a coactivator for TERT expression. Mediates E2-dependent ubiquitination.
Isoform 1 interacts with PABPC1 and PABPC4.
Isoform 3 is polyubiquitinated in the presence of HPV16 E6 protein; which leads to proteasomal degradation. Isoform 1 is not polyubiquitinated.
The RING-type zinc finger domain interacts with an ubiquitin-conjugating enzyme (E2) and facilitates ubiquitination.
Inhibited by Ni(2+) ions. Fe(2+) ions do not inhibit zinc uptake.
Transporter for the divalent cation Zn(2+). Mediates the influx of Zn(2+) into cells from extracellular space (PubMed:11301334, PubMed:12888280, PubMed:16844077). Functions as the major importer of zinc from circulating blood plasma into prostate cells (PubMed:12888280).
Ubiquitous (PubMed:10610721, PubMed:11301334). Expressed in most adult and fetal tissues including the epidermis.
Belongs to the sulfotransferase 2 family.
Catalyzes the transfer of sulfate to position 4 of the N-acetylgalactosamine (GalNAc) residue of dermatan sulfate. Plays a pivotal role in the formation of 4-0-sulfated IdoA blocks in dermatan sulfate. Transfers sulfate to the C-4 hydroxyl of beta1,4-linked GalNAc that is substituted with an alpha-linked iduronic acid (IdoUA) at the C-3 hydroxyl. Transfers sulfate more efficiently to GalNAc residues in -IdoUA-GalNAc-IdoUA- than in -GlcUA-GalNAc-GlcUA-sequences. Has preference for partially desulfated dermatan sulfate. Addition of sulfate to GalNAc may occur immediately after epimerization of GlcUA to IdoUA. Appears to have an important role in the formation of the cerebellar neural network during postnatal brain development.
Widely expressed. Expressed at high level in pituitary gland, placenta, uterus and thyroid.
Belongs to the PTEN phosphatase protein family.
By high glucose levels in differentiated podocytes (at protein level).
Detected in heart, kidney, brain, thymus, spleen, liver, placenta, lung, skeletal muscle and small intestine.
Interacts with AXL (PubMed:12470648). Interacts with SYK; leading to its phosphorylation (PubMed:22019427). Interacts with SQSTM1 (via PB1 domain); the interaction leads to sequestration of TNS2 in cytoplasmic aggregates with SQSTM1 and promotes TNS2 ubiquitination and proteasomal degradation (PubMed:25101860).
The SH3 domain mediates binding to phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) (PubMed:30092354). It is also required to ensure podocyte integrity while the phosphatase domain is dispensible for podocyte maintenance (By similarity).
Tyrosine-protein phosphatase which regulates cell motility, proliferation and muscle-response to insulin (PubMed:15817639, PubMed:23401856). Phosphatase activity is mediated by binding to phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) via the SH2 domain (PubMed:30092354). In muscles and under catabolic conditions, dephosphorylates IRS1 leading to its degradation and muscle atrophy (PubMed:23401856, PubMed:30092354). Negatively regulates PI3K-AKT pathway activation (PubMed:15817639, PubMed:23401856, PubMed:30092354). Dephosphorylates nephrin NPHS1 in podocytes which regulates activity of the mTORC1 complex (PubMed:28955049). Under normal glucose conditions, NPHS1 outcompetes IRS1 for binding to phosphatidylinositol 3-kinase (PI3K) which balances mTORC1 activity but high glucose conditions lead to up-regulation of TNS2, increased NPHS1 dephosphorylation and activation of mTORC1, contributing to podocyte hypertrophy and proteinuria (PubMed:28955049). Required for correct podocyte morphology, podocyte-glomerular basement membrane interaction and integrity of the glomerular filtration barrier (By similarity). Enhances RHOA activation in the presence of DLC1 (PubMed:26427649). Plays a role in promoting DLC1-dependent remodeling of the extracellular matrix (PubMed:20069572).
Ubiquitinated following sequestration in cytoplasmic aggregates with SQSTM1, leading to proteasomal degradation.
Specifically required during spermatogenesis to promote expression of piRNA precursors. The piRNA metabolic process mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons, which is essential for the germline integrity. Acts by facilitating transcription elongation at piRNA loci during pachytene.
Component of the DRTF1/E2F transcription factor complex. Binds cooperatively with TFDP1/Dp-1 to E2F sites. Interacts with retinoblastoma protein RB1 and related proteins (such as RBL1) that inhibit the E2F transactivation domain. Binds EAPP.
Transcription activator that binds DNA cooperatively with DP proteins through the E2 recognition site, 5'-TTTC[CG]CGC-3' found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication. The DRTF1/E2F complex functions in the control of cell-cycle progression from G1 to S phase. E2F3 binds specifically to RB1 in a cell-cycle dependent manner. Inhibits adipogenesis, probably through the repression of CEBPA binding to its target gene promoters (By similarity).
Heterodimer with P1 at the lateral ribosomal stalk of the large ribosomal subunit.
Associates with the Arp2/3 complex. Interacts with ARPC2; enhanced by activated RAC1. Interacts with ARPC5; the interaction is dependent on RAC1.
Based on a naturally occurring readthrough transcript which produces a C15orf38-AP3S2 fusion protein.
Regulates actin polymerization by inhibiting the actin-nucleating activity of the Arp2/3 complex; the function is competitive with nucleation promoting factors. Participates in an incoherent feedforward loop at the lamellipodium tip where it inhibits the ARP2/2 complex in response to Rac signaling and where Rac also stimulates actin polymerization through the WAVE complex. Involved in steering cell migration by controlling its directional persistence.
The acidic C-terminus is necessary and sufficient to inhibit ARP2/3 complex activity.
Binds 3 Mg(2+) or Mn(2+) ions per subunit.
Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate), PP-InsP4 and [PP]2-InsP4 (bisdiphosphoinositol tetrakisphosphate), suggesting that it may play a role in signal transduction (PubMed:10777568, PubMed:12370170). Can also catalyze the hydrolysis of diadenosine 5',5'''-P1,P6-hexaphosphate (Ap6A) but not diadenosine 5',5'''-P1,P5-pentaphosphate (Ap5A) and the major reaction products are ADP and p4a from Ap6A (PubMed:12370170). Also able to hydrolyze 5-phosphoribose 1-diphosphate (PubMed:12370170). Does not play a role in U8 snoRNA decapping activity (By similarity). Binds U8 snoRNA (By similarity).
Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate), PP-InsP4 and [PP]2-InsP4 (bisdiphosphoinositol tetrakisphosphate), suggesting that it may play a role in signal transduction. Also able to catalyze the hydrolysis of dinucleoside oligophosphate Ap6A, but not Ap5A. The major reaction products are ADP and p4a from Ap6A. Also able to hydrolyze 5-phosphoribose 1-diphosphate. Does not play a role in U8 snoRNA decapping activity. Binds U8 snoRNA.
Expressed in heart and, at lower level in skeletal muscle, pancreas and kidney.
Interacts in its sumoylated form with PIAS2/PIASX which enhances its transcriptional activator activity (PubMed:15920481). Interacts with MAD2L2; the interaction is direct and promotes phosphorylation by the kinases MAPK8 and/or MAPK9 (PubMed:17296730). Interacts with POU1F1 (PubMed:26612202).
On mitogenic stimulation, phosphorylated on C-terminal serine and threonine residues by MAPK1. Ser-383 and Ser-389 are the preferred sites for MAPK1. In vitro, phosphorylation by MAPK1 potentiates ternary complex formation with the serum responses factors, SRE and SRF. Also phosphorylated on Ser-383 by MAPK8 and/or MAKP9. Phosphorylation leads to loss of sumoylation and restores transcriptional activator activity. Phosphorylated and activated by CAMK4, MAPK11, MAPK12 and MAPK14. Upon bFGF stimulus, phosphorylated by PAK1 (By similarity).
Sumoylation represses transcriptional activator activity as it results in recruitment of HDAC2 to target gene promoters which leads to decreased histone acetylation and reduced transactivator activity. It also regulates nuclear retention.
Transcription factor that binds to purine-rich DNA sequences. Forms a ternary complex with SRF and the ETS and SRF motifs of the serum response element (SRE) on the promoter region of immediate early genes such as FOS and IER2. Induces target gene transcription upon JNK-signaling pathway stimulation (By similarity).
Antiporter that transports inorganic anions (sulfate, sulfite, thiosulfate and phosphate) and, to a lesser extent, a variety of dicarboxylates (e.g. malonate, malate and citramalate) and, even more so, aspartate (PubMed:31356773). The sulfate/sulfate exchange is much higher than the phosphate/phosphate and malate/malate exchanges (PubMed:31356773). The transport affinities is higher for sulfate and thiosulfate than for any other substrate (PubMed:31356773). May catalyze the export of sulfite and thiosulfate (the hydrogen sulfide degradation products) from the mitochondria, thereby modulating the level of the hydrogen sulfide (Probable). Also may mediate a very low unidirectional transport of sulfate, phosphate and (S)-malate (PubMed:31356773).
Increased activity at pH 6.0 (PubMed:31356773). sulfate/sulfate exchange activity is inhibited strongly by pyridoxal 5'-phosphate, bathophenanthroline and the organic mercurials mersalyl, p-chloromercuribenzoate and HgCl2 (PubMed:31356773).
Dephosphorylates specifically the 5' and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides, and so protects mitochondrial DNA replication from excess dTTP. Has only marginal activity towards dIMP and dGMP.
Highly expressed in heart, brain and skeletal muscle. Detected at very low levels in kidney and pancreas.
(Microbial infection) Coreceptor for HIV-1.
Belongs to the chemokine-like receptor (CMKLR) family.
Receptor for chemoattractant adipokine chemerin/RARRES2 suggesting a role for this receptor in the regulation of inflammation and energy homesotasis (PubMed:18165312, PubMed:27716822). Signals mainly via beta-arrestin pathway. Binding of RARRES2 activates weakly G proteins, calcium mobilization and MAPK1/MAPK3 (ERK1/2) phosphorylation too (PubMed:27716822). Acts also as a receptor for TAFA1, mediates its effects on neuronal stem-cell proliferation and differentiation via the activation of ROCK/ERK and ROCK/STAT3 signaling pathway (By similarity).
Inhibits the transactivation activity of the Myod family of myogenic factors and represses myogenesis. Acts by associating with Myod family members and retaining them in the cytoplasm by masking their nuclear localization signals. Can also interfere with the DNA-binding activity of Myod family members. Plays an important role in trophoblast and chondrogenic differentiation. Regulates the transcriptional activity of TCF7L1/TCF3 by interacting directly with TCF7L1/TCF3 and preventing it from binding DNA. Binds to the axin complex, resulting in an increase in the level of free beta-catenin. Affects axin regulation of the WNT and JNK signaling pathways (By similarity).
The C-terminus interacts with AXIN1 and LEF1 (By similarity). Interacts with CCNT2 (PubMed:17289077).
Forms homooligomers (PubMed:36481767). Interacts with TRIM3; this interaction reduces TRIM2 activity (PubMed:36481767). Interacts with myosin V; myosin V may not be a substrate for ubiquitination (By similarity). Interacts with NEFL (By similarity). Interacts with phosphorylated BCL2L11. Interacts with SIRPA (By similarity).
RING-type zinc finger-dependent and UBE2D1-dependent autoubiquitination.
The interaction with myosin V is dependent upon its NHL repeats, which form a beta-propeller (NHL) domain containing six blades.
UBE2D1-dependent E3 ubiquitin-protein ligase that mediates the ubiquitination of NEFL and of phosphorylated BCL2L11. Plays a neuroprotective function. May play a role in neuronal rapid ischemic tolerance. Plays a role in antiviral immunity and limits New World arenavirus infection independently of its ubiquitin ligase activity (PubMed:24068738).
Heterotrimer of an A (ELOA, ELOA2 or ELOA3P), ELOB and ELOC subunit.
SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A2 is transcriptionally active but its transcription activity is not enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex).
Belongs to the peroxidase family. XPO subfamily.
Binds 1 heme b (iron(II)-protoporphyrin IX) group covalently per monomer.
Homodimer; disulfide-linked. Each monomer consists of a light and a heavy chain.
Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity (PubMed:9922160). Mediates the proteolytic cleavage of alpha-1-microglobulin to form t-alpha-1-microglobulin, which potently inhibits oxidation of low-density lipoprotein particles and limits vascular damage (PubMed:25698971).
ATP-specific succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of ATP and thus represents the only step of substrate-level phosphorylation in the TCA (PubMed:15877282). The beta subunit provides nucleotide specificity of the enzyme and binds the substrate succinate, while the binding sites for coenzyme A and phosphate are found in the alpha subunit (By similarity).
ATP-specific succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of ATP and thus represents the only step of substrate-level phosphorylation in the TCA. The beta subunit provides nucleotide specificity of the enzyme and binds the substrate succinate, while the binding sites for coenzyme A and phosphate are found in the alpha subunit.
Belongs to the succinate/malate CoA ligase beta subunit family. ATP-specific subunit beta subfamily.
Heterodimer of an alpha and a beta subunit. The beta subunit determines specificity for ATP (By similarity). Interacts with ALAS2 (PubMed:14643893).
Heterodimer of an alpha and a beta subunit. The beta subunit determines specificity for ATP.
Widely expressed. Not expressed in liver and lung.
(Microbial infection) Interacts with human papillomavirus type 6/HPV6 protein E6. Does not interact significantly with E6 proteins from HPV types 11, 16, or 18.
Adhesion plaque protein. Binds alpha-actinin and the CRP protein. Important for targeting TES and ENA/VASP family members to focal adhesions and for the formation of actin-rich structures. May be a component of a signal transduction pathway that mediates adhesion-stimulated changes in gene expression (By similarity).
Interacts with HPV type 6 protein E6. Does not interact significantly with E6 proteins from HPV types 11, 16, or 18. Interacts, via the Pro-rich regions, with the EVH1 domains of ENAH, EVL and VASP. Interacts with the first LIM domain of TES. Interacts with NEBL (isoform 2). Interacts with SYNPO2.
Component of the meiosis-specific cohesin complex, which also contains the SMC1 (SMC1A or SMC1B) and SMC3 heterodimer. Such complex likely contains RAD21, or the meiosis-specific related protein REC8. Interacts with CCDC79/TERB1; recruiting cohesin to telomeres to develop structural rigidity (By similarity).
Meiosis specific component of cohesin complex. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The meiosis-specific cohesin complex probably replaces mitosis specific cohesin complex when it dissociates from chromatin during prophase I.
The disease is caused by variants affecting the gene represented in this entry. A homozygous deletion in STAG3 predicted to result in frameshift and premature truncation, has been shown to be the cause of premature ovarian failure in a large consanguineous family.
Binds the Arp2/3 complex through the C-terminal region and actin through verprolin homology (VPH) domain.
Component of the WAVE1 complex composed of ABI2, CYFIP1 or CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Within the complex, a heterodimer containing NCKAP1 and CYFIP1 interacts with a heterotrimer formed by WAVE1, ABI2 and BRK1. CYFIP2 binds to activated RAC1 which causes the complex to dissociate, releasing activated WASF1. The complex can also be activated by NCK1. Binds actin and the Arp2/3 complex. Interacts with BAIAP2. Interacts with SHANK3; the interaction mediates the association of SHANK3 with the WAVE1 complex. Interacts with ABI1 (via N-terminus). Interacts with SORBS2; this interaction greatly enhances phosphorylation by ABL1 and dephosphorylation by PTPN12 and might mediate partial to focal adhesion sites.
Downstream effector molecule involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. Promotes formation of actin filaments. Part of the WAVE complex that regulates lamellipodia formation (PubMed:29961568). The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex (By similarity). As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes (By similarity). Also involved in the regulation of mitochondrial dynamics (PubMed:29961568).
Highly expressed in brain. Lowly expressed in testis, ovary, colon, kidney, pancreas, thymus, small intestine and peripheral blood.
Phosphorylated on tyrosine residues by ABL1 and dephosphorylated by PTPN12.
Belongs to the eutherian X-chromosome-specific Armcx family.
According to some authors, has impaired kinase activity.
May be a coreceptor along with FZD8 of Wnt proteins, such as WNT1, WNT3, WNT3A and WNT5A. Involved in neuron differentiation, axon guidance, corpus callosum establishment and neurite outgrowth. In response to WNT3 stimulation, receptor C-terminal cleavage occurs in its transmembrane region and allows the C-terminal intracellular product to translocate from the cytoplasm to the nucleus where it plays a crucial role in neuronal development.
Proteolytically cleaved, in part by presenilin, in response to WNT3 stimulation. Cleavage occurs during neuronal differentiation.
The extracellular WIF domain is responsible for Wnt binding.
Expressed specifically in testis. Also expressed in tumors of different origins.
Binds to the phosphorylated receptors CD84, SLAMF1, LY9 and CD244. Does not bind to non-phosphorylated SLAMF1 (PubMed:11689425). Interacts with SLAMF7 (via ITSM phosphorylated on 'Tyr-304'). Interacts with Src kinases HCK, LYN, FYN, FGR and LCK (via kinase domains) (By similarity). Interacts (phosphorylated at Tyr-127) with PLCG1.
Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as CD84, SLAMF1, LY9 and CD244 (PubMed:11689425). In SLAM signaling seems to cooperate with SH2D1A/SAP. Plays a role in regulation of effector functions of natural killer (NK) cells by controlling signal transduction through CD244/2B4 without effecting its tyrosine phosphorylation; downstream signaling involves PLCG1 and ERK activation (PubMed:24687958). Activation of SLAMF7-mediated NK cell function does not effect receptor tyrosine phosphorylation but distal signaling (By similarity). In the context of NK cell-mediated cytotoxicity does not enhance conjugate formation with target cells but stimulates polarization of the microtubule-organizing center and cytotoxic granules toward the NK cell synapse (PubMed:24687958). Negatively regulates CD40-induced cytokine production in dendritic cells downstream of SLAM family receptors probably by inducing activation of the PI3K pathway to inhibit p38 MAPK and JNK activation (By similarity).
Chemotactic factor that attracts monocytes and eosinophils, but not neutrophils. Augments monocyte anti-tumor activity. Also induces the release of gelatinase B. This protein can bind heparin. Binds to CCR1, CCR2 and CCR3.
Monomer. Interacts with TNFAIP6 (via Link domain).
Associated with actin, delta-catenin and alpha and beta tubulins (By similarity). Interacts with OTOF (By similarity). Interacts with PEX5R (By similarity). Interacts with RAB3IP (PubMed:12221131). Interacts with VIM (By similarity). Interacts with CDH1 (By similarity). Interacts with MICALL2 (By similarity). Interacts with GDI1, GDI2, CHML and CHM; phosphorylation at Thr-72 disrupts these interactions (PubMed:29125462). Interacts with MICAL1 (PubMed:32344433).
Phosphorylation of Thr-72 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM, CHML and RAB GDP dissociation inhibitors GDI1 and GDI2.
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. That Rab may be involved in polarized vesicular trafficking and neurotransmitter release. May participate in cell junction dynamics in Sertoli cells (By similarity). May participate in the export of a subset of neosynthesized proteins through a Rab8-Rab10-Rab11-dependent endososomal export route (PubMed:32344433).
Does not seem to have protease activity as it lacks the zinc-binding site.
Heterodimer of PMPCA (alpha) and PMPCB (beta) subunits, forming the mitochondrial processing protease (MPP) in which PMPCA is involved in substrate recognition and binding and PMPCB is the catalytic subunit.
Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.
Ubiquitously expressed with highest expression in fetal tissues and adult brain, cerebellum and cerebellar vermis.
Laminin is a complex glycoprotein, consisting of three different polypeptide chains (alpha, beta, gamma), which are bound to each other by disulfide bonds into a cross-shaped molecule comprising one long and three short arms with globules at each end.
Belongs to the glycosyl hydrolase 22 family.
Expressed in testis, epididymis and spermatozoa (at protein level) (PubMed:16014814, PubMed:28182716). Expressed in late-stage spermatocytes and round spermatids (PubMed:28182716).
May be involved sperm-egg plasma membrane adhesion and fusion during fertilization (PubMed:28182716). Exhibits bacteriolytic activity in vitro against Micrococcus luteus and Staphylococcus aureus (PubMed:28182716, PubMed:24013621). Shows weak bacteriolytic activity against Gram-positive bacteria at physiological pH (PubMed:28182716). Bacteriolytic activity is pH-dependent, with a maximum at around pH 5.6 (PubMed:28182716).
Interacts with SEPTIN2; this interaction impedes tubulin-binding. Interacts with TRAF3IP1 (By similarity). Interacts with KNSTRN (PubMed:29180244).
Non-neuronal microtubule-associated protein. Promotes microtubule assembly.
Phosphorylated at serine residues in K-X-G-S motifs by MAP/microtubule affinity-regulating kinase (MARK1 or MARK2), causing detachment from microtubules, and their disassembly (By similarity). Phosphorylation on Ser-787 negatively regulates MAP4 activity to promote microtubule assembly. Isoform 3 is phosphorylated on Ser-337 and Ser-338.
Binds DNA as a homodimer. Can form a heterodimer with ESR2. Interacts with FOXC2, MAP1S, SLC30A9, UBE1C and NCOA3 coactivator (By similarity). Interacts with PELP1, the interaction is enhanced by 17-beta-estradiol, the interaction increases ESR1 transcriptional activity (PubMed:11481323, PubMed:14963108). Interacts with EP300; the interaction is estrogen-dependent and enhanced by CITED1. Interacts with CITED1; the interaction is estrogen-dependent. Interacts with NCOA5 and NCOA6 coactivators. Interacts with NCOA7; the interaction is a ligand-inducible. Interacts with PHB2, and UBE1C. Interacts with AKAP13. Interacts with CUEDC2. Interacts with KDM5A. Interacts with SMARD1. Interacts with HEXIM1. Interacts with PBXIP1. Interaction with MUC1 is stimulated by 7 beta-estradiol (E2) and enhances ESR1-mediated transcription. Interacts with DNTTIP2, FAM120B and UIMC1. Interacts with isoform 4 of TXNRD1. Interacts with KMT2D/MLL2. Interacts with ATAD2 and this interaction is enhanced by estradiol. Interacts with KIF18A and LDB1. Interacts with RLIM (via C-terminus). Interacts with MACROD1. Interacts with SH2D4A and PLCG. Interaction with SH2D4A blocks binding to PLCG and inhibits estrogen-induced cell proliferation. Interacts with DYNLL1. Interacts with CCDC62 in the presence of estradiol/E2; this interaction seems to enhance the transcription of target genes. Interacts with NR2C1; the interaction prevents homodimerization of ESR1 and suppresses its transcriptional activity and cell growth. Interacts with DNAAF4. Interacts with PRMT2. Interacts with RBFOX2. Interacts with STK3/MST2 only in the presence of SAV1 and vice-versa. Binds to CSNK1D. Interacts with NCOA2; NCOA2 can interact with ESR1 AF-1 and AF-2 domains simultaneously and mediate their transcriptional synergy. Interacts with DDX5 (PubMed:11682626). Interacts with NCOA1; the interaction seems to require a self-association of N-terminal and C-terminal regions. Interacts with ZNF366, DDX17, NFKB1, RELA, SP1 and SP3. Interacts with NRIP1 (By similarity). Interacts with GPER1; the interaction occurs in an estrogen-dependent manner. Interacts with CLOCK and the interaction is stimulated by estrogen. Interacts with BCAS3. Interacts with TRIP4 (ufmylated); estrogen dependent. Interacts with LMTK3; the interaction phosphorylates ESR1 (in vitro) and protects it against proteasomal degradation. Interacts with CCAR2 (via N-terminus) in a ligand-independent manner. Interacts with ZFHX3. Interacts with SFR1 in a ligand-dependent and -independent manner (PubMed:23874500). Interacts with DCAF13, LATS1 and DCAF1; regulates ESR1 ubiquitination and ubiquitin-mediated proteasomal degradation (PubMed:28068668). Interacts (via DNA-binding domain) with POU4F2 (C-terminus); this interaction increases the estrogen receptor ESR1 transcriptional activity in a DNA- and ligand 17-beta-estradiol-independent manner (By similarity). Interacts with ESRRB isoform 1 (PubMed:19755138). Interacts with UBE3A and WBP2 (PubMed:16772533). Interacts with GTF2B (PubMed:1517211). Interacts with RBM39 (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863). Interacts with PI3KR1 or PI3KR2 and PTK2/FAK1 (PubMed:18657504). Interacts with SRC (PubMed:14963108, PubMed:18657504).
Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. The modulating domain, also known as A/B or AF-1 domain has a ligand-independent transactivation function. The C-terminus contains a ligand-dependent transactivation domain, also known as E/F or AF-2 domain which overlaps with the ligand binding domain. AF-1 and AF-2 activate transcription independently and synergistically and act in a promoter- and cell-specific manner. AF-1 seems to provide the major transactivation function in differentiated cells.
Dimethylated by PRMT1 at Arg-260. The methylation may favor cytoplasmic localization (PubMed:18657504, PubMed:24498420). Demethylated by JMJD6 at Arg-260 (PubMed:24498420).
Genetic variations in ESR1 are correlated with bone mineral density (BMD). Low BMD is a risk factor for osteoporotic fracture. Osteoporosis is characterized by reduced bone mineral density, disruption of bone microarchitecture, and the alteration of the amount and variety of non-collagenous proteins in bone. Osteoporotic bones are more at risk of fracture.
Glycosylated; contains N-acetylglucosamine, probably O-linked.
Involved in activation of NOS3 and endothelial nitric oxide production (PubMed:21937726). Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full-length receptor (PubMed:10970861). Binds to ERE and inhibits isoform 1 (PubMed:10970861).
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3 (PubMed:17922032).
Palmitoylated (isoform 3). Not biotinylated (isoform 3).
Palmitoylated by ZDHHC7 and ZDHHC21. Palmitoylation is required for plasma membrane targeting and for rapid intracellular signaling via ERK and AKT kinases and cAMP generation, but not for signaling mediated by the nuclear hormone receptor.
Phosphorylated by cyclin A/CDK2 and CK1. Phosphorylation probably enhances transcriptional activity. Self-association induces phosphorylation. Dephosphorylation at Ser-118 by PPP5C inhibits its transactivation activity. Phosphorylated by LMTK3 in vitro.
Probably homodimerizes or heterodimerizes with isoform 1 and ESR2.
Produced by alternative splicing of isoform 3.
Selective estrogen receptor modulators (SERMs), such as tamoxifen, raloxifene, toremifene, lasofoxifene, clomifene, femarelle and ormeloxifene, have tissue selective agonistic and antagonistic effects on the estrogen receptor (ER). They interfere with the ER association with coactivators or corepressors, mainly involving the AF-2 domain.
The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues.
Ubiquitinated; regulated by LATS1 via DCAF1 it leads to ESR1 proteasomal degradation (PubMed:21602804, PubMed:28068668). Deubiquitinated by OTUB1 (PubMed:19383985).
Was reported to be activated by DDX5. However, this study has been retracted due to concerns of image manipulation.
Widely expressed (PubMed:10970861). Not expressed in the pituitary gland (PubMed:10970861).
Widely expressed, however not expressed in the pituitary gland.
contains an in-frame duplication of exons 6 and 7.
Arginine dimethylation is asymmetric and involves PRMT1 and PRMT3. It does not influence the RNA binding properties (By similarity).
Involved in the 3'-end formation of mRNA precursors (pre-mRNA) by the addition of a poly(A) tail of 200-250 nt to the upstream cleavage product (By similarity). Stimulates poly(A) polymerase (PAPOLA) conferring processivity on the poly(A) tail elongation reaction and controls also the poly(A) tail length (By similarity). Increases the affinity of poly(A) polymerase for RNA (By similarity). Is also present at various stages of mRNA metabolism including nucleocytoplasmic trafficking and nonsense-mediated decay (NMD) of mRNA. Cooperates with SKIP to synergistically activate E-box-mediated transcription through MYOD1 and may regulate the expression of muscle-specific genes (PubMed:11371506). Binds to poly(A) and to poly(G) with high affinity (By similarity). May protect the poly(A) tail from degradation (By similarity). Subunit of the trimeric poly(A) tail exosome targeting (PAXT) complex, a complex that directs a subset of long and polyadenylated poly(A) RNAs for exosomal degradation. The RNA exosome is fundamental for the degradation of RNA in eukaryotic nuclei. Substrate targeting is facilitated by its cofactor MTREX, which links to RNA-binding protein adapters (PubMed:27871484).
May interact with SETX (PubMed:21700224). Monomer and homooligomer. Binds RNA as a monomer and oligomerizes when bound to poly(A). Interacts with PAPOLA, but only in presence of oligo(A) RNA. Interacts with transportin. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Association in a ternary complex with CPSF4 and influenza A virus NS1 blocks pre-mRNAs processing, thereby preventing nuclear export of host cell mRNAs. Associates in a single complex with SKIP and MYOD1 and interacts with SKIP in differentiated myocytes. Interacts with NUDT21/CPSF5. Interacts (via RRM domain and C-terminal arginine-rich region) with ZFP36 (via hypophosphorylated form); this interaction occurs in the nucleus in a RNA-independent manner, decreases in presence of single-stranded poly(A) RNA-oligomer and in a p38-dependent-manner and may down-regulated RNA poly(A) polymerase activity (By similarity). Component of the poly(A) tail exosome targeting (PAXT) complex made of accessory factors, such as PABPN1, ZFC3H1 and MTREX (PubMed:27871484). Interacts with ZFC3H1 in a RNase-insensitive manner (PubMed:27871484). Interacts with FRG1 (PubMed:17103222).
The RRM domain is essential for specific adenine bases recognition in the poly(A) tail but not sufficient for poly(A) binding.
The association of the expanded polyalanine mutations together with the capability to oligomerize may induce intranuclear inclusions and cell death. Expanded polyalanine mutations may either result from unequal crossing over during germ cell homologous recombination or from DNA slippage. The pathogenic mechanisms mediated by polyalanine expansion mutations may be either a general disruption of cellular RNA metabolism due to the trapping by the inclusions of PABPN1, mRNAs and/or nuclear proteins, resulting in the induction of cell death; or may change the normal muscle cell differentiation.
The poly-Ala region of PABPN1 is polymorphic (6-7 repeats) in the population and is expanded to 8-13 repeats in OPMD patients. Compound heterozygotes for (GCG)9 mutation and a (GCG)7 allele result in earlier onset and more severe clinical manifestations of the disease.
Acts as a positive regulator of ciliary hedgehog signaling (By similarity). Involved in ciliogenesis (PubMed:27894351).
Acts as a negative regulator of innate and adaptive immunity by maintaining immune homeostasis (PubMed:27043859). Plays a regulatory role in the Toll-like signaling pathway by determining the strength of LPS-induced signaling and gene expression (PubMed:32188758). Inhibits TCR-mediated T-cell activation and negatively regulate T-cell function to prevent hyperresponsiveness (By similarity). Inhibits also autolysosome formation via negatively modulating MTOR activation by interacting with RAC1 and promoting the disassociation of the RAC1-MTOR complex (PubMed:32460619). Plays an essential role in NK-cell biology by acting as a checkpoint and displaying an expression pattern correlating with NK-cell maturation process and by negatively regulating NK-cell maturation and antitumor immunity (By similarity). Mechanistically, suppresses IL-15-triggered mTOR activity in NK-cells (By similarity).
Belongs to the TNFAIP8 family. TNFAIP8L2 subfamily.
Expressed in T-cells, B-cells, macrophages, neurons in the brain and brainstem, and stratified squamous epithelia of the esophagus, cervix and skin.
May interact with CASP8; however, such result is unclear since PubMed:19079267 could not reproduce the interaction with CASP8. Interacts with RAC1 (PubMed:32460619).
Phosphorylated by TAK1/MAP3K7; this phosphorylation triggers association with BTRC and subsequent ubiquitination and degradation.
The central region was initially thought to constitute a DED (death effector) domain. However, 3D-structure data reveal a previously uncharacterized fold that is different from the predicted fold of a DED (death effector) domain. It consists of a large, hydrophobic central cavity that is poised for cofactor binding.
Ubiquitinated in a BTRC-depdent manner; leading to degradation mediated through the proteasome pathway.
Centrosomal protein involved in regulation of centriole duplication. Required to limit centriole duplication to once per cell cycle by preventing centriole reduplication.
Expressed at low level in G1 and is induced in S and G2 phase, during which point centrioles have already commenced duplication (at protein level).
By TGF-beta (PubMed:1388724, PubMed:8024701).
Gamma-carboxylation is controversial. Gamma-carboxyglutamated; gamma-carboxyglutamate residues are formed by vitamin K dependent carboxylation; these residues may be required for binding to calcium (PubMed:18450759). According to a more recent report, does not contain vitamin K-dependent gamma-carboxyglutamate residues (PubMed:26273833).
Highly expressed in the corneal epithelium (PubMed:27609313, PubMed:8077289). Expressed in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas (PubMed:8077289).
Plays a role in cell adhesion (PubMed:8024701). May play a role in cell-collagen interactions (By similarity).
The EMI domain contains 2 expected intradomain disulfide bridges (Cys-49-Cys85 and Cys-84-Cys-97) and one unusual interdomain disulfide bridge to the second FAS1 domain (Cys-74-Cys-339). This arrangement violates the predicted disulfide bridge pattern of an EMI domain.
Interacts with CCP110; this interaction propmotes CCP110 ubiquitination and degradation via the proteasome pathway. Via its interaction with CCP110, may indirectly interact with CEP97. Interacts with the E3 ubiquitin-protein ligase HERC2 and UBE3A. May interact with MAPK6 and hence mediate MAPK6 interaction with UBE3A. Interaction with UBE3A may be indirect and mediated by HERC2.
Promotes CCP110 ubiquitination and proteasome-dependent degradation. By counteracting accumulation of CP110, maintains normal centriolar homeostasis and preventing formation of ectopic microtubular organizing centers.
The third NHR domain (NHR 3) is required for localization to both mother and daughter centrioles. NHR 1 restricts targeting to daughter centriole (PubMed:22441691). NHR 3 and 4 are required for CCP110/CEP97-binding, but not for HERC2-binding. NHR 5 and 6 are important for HERC2-binding and centrosomal localization (PubMed:22261722).
Ubiquitinated; undergoes HERC2-dependent 'Lys-48' ubiquitination. This ubiquitination leads to proteasomal degradation.
Widely expressed at high levels (including brain).
Acts as a transcriptional activator. Stimulates the promoter of the alpha-glycoprotein gene. Transcriptional regulatory protein involved in the control of cell differentiation in developing lymphoid and neural cell types (By similarity).
Interacts (via LIM domains) with CITED2. Interacts with POU4F2.
LIM domains are necessary for transcription activation.
Transcriptional activator. Binds the consensus DNA sequence 5'-DHWATTGAYTWWD-3' on a variety of gene promoters such as those of HNF3B and TTR (By similarity).
Highest expression in heart, skeletal muscle kidney, liver and peripheral blood leukocytes. Lower expression in all other tissues.
Inhibits calcineurin-dependent transcriptional responses by binding to the catalytic domain of calcineurin A. Could play a role during central nervous system development (By similarity).
Interacts with protein phosphatase PPP3CA/calcineurin A.
Acts in different tissues through interaction to nicotinic acetylcholine receptors (nAChRs) (PubMed:21252236). The proposed role as modulator of nAChR activity seems to be dependent on the nAChR subtype and stoichiometry, and to involve an effect on nAChR trafficking and its cell surface expression, and on single channel properties of the nAChR inserted in the plasma membrane. Modulates functional properties of nicotinic acetylcholine receptors (nAChRs) to prevent excessive excitation, and hence neurodegeneration. Enhances desensitization by increasing both the rate and extent of desensitization of alpha-4:beta-2-containing nAChRs and slowing recovery from desensitization. Promotes large amplitude ACh-evoked currents through alpha-4:beta-2 nAChRs. Is involved in regulation of the nAChR pentameric assembly in the endoplasmic reticulum. Shifts stoichiometry from high sensitivity alpha-4(2):beta-2(3) to low sensitivity alpha-4(3):beta-2(2) nAChR (By similarity). In vitro modulates alpha-3:beta-4-containing nAChRs. Reduces cell surface expression of (alpha-3:beta-4)(2):beta-4 and (alpha-3:beta-4)(2):alpha-5 nAChRs suggesting an interaction with nAChR alpha-3(-):(+)beta-4 subunit interfaces and an allosteric mode. Corresponding single channel effects characterized by decreased unitary conductance, altered burst proportions and enhanced desensitization/inactivation seem to depend on nAChR alpha:alpha subunit interfaces and are greater in (alpha-3:beta-2)(2):alpha-3 when compared to (alpha-3:beta-2)(2):alpha-5 nAChRs (PubMed:28100642). Prevents plasticity in the primary visual cortex late in life (By similarity).
Based on a naturally occurring readthrough transcript which produces a LYNX1-SLURP2 fusion protein.
Interacts with nAChRs containing alpha-4:beta-2 (CHRNA4:CHRNB2) and alpha-7 (CHRNA7) subunits. Interacts with CHRNA4 probably in the endoplasmic reticulum prior to nAChR pentameric assembly (By similarity).
Isoform 1 is considered to be an endogenous 'prototoxin', that shares a N-terminal three-finger structure with snake alpha-neurotoxins.
Mainly expressed in hematopoietic tissues including bone marrow, spleen and fetal liver. Also detected in lung and testis.
Putative adhesion molecule. Sialic acid-binding paired receptor which may activate associated receptors.
Belongs to the nucleoporin NSP1/NUP62 family.
Autoantibodies against DSG4 are found in patients with pemphigus vulgaris. Pemphigus vulgaris is a potentially lethal skin disease in which epidermal blisters occur as the result of the loss of cell-cell adhesion.
Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. Coordinates the transition from proliferation to differentiation in hair follicle keratinocytes (By similarity).
Highly expressed in skin, testis and prostate; less in salivary gland. In scalp follicles, present in the inner root sheath (IRS) and all layers of the matrix and precortex.
(Microbial infection) Interacts (via C-terminal UBX domain) with nipah virus protein V.
Interacts with MAVS; this interaction prevents MAVS oligomerization and thus disrupts the RLR signaling pathway (PubMed:23545497). Interacts with CUL1; this interaction inhibits CUL1-mediated degradation of NF-kappa-B inhibitors (PubMed:28152074). Interacts with BIRC2/c-IAP1; this interaction prevents TNFalpha-stimulated RIP1 ubiquitination and subsequent NF-kappa-B activation (PubMed:25681446). Component of a complex required to couple retrotranslocation, ubiquitination and deglycosylation composed of NGLY1, SAKS1, AMFR, VCP and RAD23B. Interacts with HOMER2 (By similarity). Interacts directly with VCP. Interacts with BRCA1 and BARD1; interaction takes place when BRCA1 is not autoubiquitinated but is strongly enhanced in the presence of autoubiquitinated BRCA1.
The UBA domain specifically recognizes and binds 'Lys-6'-linked polyubiquitin chains.
Ubiquitin-binding protein that plays a role in the modulation of innate immune response. Blocks both the RIG-I-like receptors (RLR) and NF-kappa-B pathways. Following viral infection, UBXN1 is induced and recruited to the RLR component MAVS. In turn, interferes with MAVS oligomerization, and disrupts the MAVS/TRAF3/TRAF6 signalosome. This function probably serves as a brake to prevent excessive RLR signaling (PubMed:23545497). Interferes with the TNFalpha-triggered NF-kappa-B pathway by interacting with cellular inhibitors of apoptosis proteins (cIAPs) and thereby inhibiting their recruitment to TNFR1 (PubMed:25681446). Prevents also the activation of NF-kappa-B by associating with CUL1 and thus inhibiting NF-kappa-B inhibitor alpha/NFKBIA degradation that remains bound to NF-kappa-B (PubMed:28152074). Interacts with the BRCA1-BARD1 heterodimer and regulates its activity. Specifically binds 'Lys-6'-linked polyubiquitin chains. Interaction with autoubiquitinated BRCA1 leads to the inhibition of the E3 ubiquitin-protein ligase activity of the BRCA1-BARD1 heterodimer (PubMed:20351172). Component of a complex required to couple deglycosylation and proteasome-mediated degradation of misfolded proteins in the endoplasmic reticulum that are retrotranslocated in the cytosol.
Interferon-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response (PubMed:34581622). In addition, it may also play a role in other cellular processes such as apoptosis, cell growth, differentiation and gene regulation. Synthesizes higher oligomers of 2'-5'-oligoadenylates (2-5A) from ATP which then bind to the inactive monomeric form of ribonuclease L (RNase L) leading to its dimerization and subsequent activation. Activation of RNase L leads to degradation of cellular as well as viral RNA, resulting in the inhibition of protein synthesis, thus terminating viral replication (PubMed:34581622, PubMed:34145065). Can mediate the antiviral effect via the classical RNase L-dependent pathway or an alternative antiviral pathway independent of RNase L. The secreted form displays antiviral effect against vesicular stomatitis virus (VSV), herpes simplex virus type 2 (HSV-2), and encephalomyocarditis virus (EMCV) and stimulates the alternative antiviral pathway independent of RNase L.
Monomer (PubMed:9407111). Homotetramer (PubMed:9407111, PubMed:23319625).
Not prenylated at C-terminal, is diffusely localized and unable to initiate a detectable block to SARS-CoV-2 replication.
Not prenylated at C-terminal. The non-prenylated form is diffusely localized and unable to initiate a detectable block to SARS-CoV-2 replication.
Polymorphism dbSNP:rs10774671 is associated with protection against severe COVID-19 disease (PubMed:34581622, PubMed:33633408). In humans, the OAS1 protein is expressed as two major forms designated p46 and p42. The longer p46 isoform is generated by alternative splicing to an exon downstream of the terminal exon used by the p42 isoform. Although all human genotypes contain the exon that completes the transcript encoding p46, an intronic SNP (rs10774671) determines OAS1 exon usage. Alleles with a G at this SNP (G alleles) specify expression of the p46 isoform and some p42, whereas alleles with A at this position predominantly encode the p42 isoform and cannot express the p46 isoform (PubMed:34581622). The p42 isoform, which is the most common isoform in humans (~61% of alleles), has no detectable anti-SARS-CoV-2 activity. The p46 isoform has anti-SARS-CoV-2 activity (PubMed:34581622).
Prenylated at C-terminal. C-terminal prenylation is necessary to initiate a block to SARS-CoV-2 and is associated with protection from severe COVID-1. The prenylated form is targeted to perinuclear structures rich in viral dsRNA, whereas the non-prenylated form is diffusely localized and unable to initiate a detectable block to SARS-CoV-2 replication (Probable). C-terminal prenylation is also necessary to initiate a block to cardiovirus EMCV (Probable).
Produced as a latent enzyme which is activated by dsRNA generated during the course of viral infection. The dsRNA activator must be at least 15 nucleotides long, and no modification of the 2'-hydroxyl group is tolerated (PubMed:34581622). ssRNA or dsDNA do not act as activators.
PubMed:1651324 sequence was originally thought to originate from mouse.
When prenylated at C-terminal, acts as a double-stranded RNA (dsRNA) sensor specifically targeted to membranous replicative organelles in SARS coronavirus-2/SARS-CoV-2 infected cells where it binds to dsRNA structures in the SARS-CoV-2 5'-UTR and initiates a potent block to SARS-CoV-2 replication. Recognizes short stretches of dsRNA and activates RNase L. The binding is remarkably specific, with two conserved stem loops in the SARS-CoV-2 5'- untranslated region (UTR) constituting the principal viral target (PubMed:34581622). The same mechanism is necessary to initiate a block to cardiovirus EMCV (PubMed:34581622).
Specifically methylates cytosine 38 in the anticodon loop of tRNA(Asp).
Ubiquitous. Higher expression in testis, ovary and thymus and at much lower levels in spleen, prostate, colon, small intestine, and peripheral blood leukocytes.
Interacts with YIPF6; this interaction may stabilize YIPF1. May also form a ternary complex with YIPF2 and YIPF6.
Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class IV subfamily.
Expressed in kidney and retina. Also at low levels in brain, testis and muscle. Within the retina, expressed in the inner segment of photoreceptors, outer and inner nuclear layers and the ganglion cell layer.
Belongs to the sulfotransferase 1 family.
Exhibits weak sulphating activity and only toward chloro phenols (pentachlorophenol and 3,3',5,5'-tetrachloro-4,4'-biphenyldiol).
Not detectable in any of the tissues tested.
SULT1C3 gene appears to be present only in humans and other primates.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor. Has sulfotransferase activity towards various substrates, such as bile acids, thyroid hormones and toward xenobiotic compounds such as chloro phenols and hydroxypyrenes. Lithocholic acid appears to be the best substrate among the endogenous compounds tested and 3,3',5,5'-tetrachloro-4,4'-biphenyldiol shows the highest specific activity among the xenobiotic compounds.
Olfactory epithelium, brain and fetal lung (PubMed:10359671). Not present in liver (PubMed:10359671).
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:10359671, PubMed:19858781, PubMed:18719240, PubMed:19022937, PubMed:23756265, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:10359671, PubMed:19858781, PubMed:23756265). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (testosterone and epitestosterone) and estrogens (estradiol and epiestriol) (PubMed:18719240, PubMed:19858781, PubMed:19022937, PubMed:23288867). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Shows a high affinity to aliphatic odorants such as citronellol as well as olfactory tissue specificity, and therefore may be involved in olfaction (PubMed:10359671). Shows a potential role in detoxification of toxic waste compounds in the amniotic fluid before birth, and air-born chemical after birth (PubMed:19858781).
UGT2A1 isoform is part of the UGT2A complex locus which displays alternative use of promoters and exons. The locus is defined by 2 alternative promoters giving rise to 2 fonctionally active polypeptides UGT2A1 and UGT2A2. Alternative splicing of exons results in additional isoforms for each protein class.
Belongs to the acetyltransferase family. GNA1 subfamily.
(Microbial infection) Interacts with Epstein-Barr virus (EBV) RK-BARF0.
Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. May regulate branching morphogenesis in the developing vascular system (By similarity).
Heterodimer of a C-terminal fragment N(TM) and a N-terminal fragment N(EC) which are probably linked by disulfide bonds (By similarity). Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH4.
Highly expressed in the heart, moderately in the lung and placenta and at low levels in the liver, skeletal muscle, kidney, pancreas, spleen, lymph node, thymus, bone marrow and fetal liver. No expression was seen in adult brain or peripheral blood leukocytes.
Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane (By similarity).
The poly-Leu region of NOTCH4 (in the signal peptide) is polymorphic and the number of Leu varies in the population (from 6 to 12).
Component of the RNA exosome complex (PubMed:29906447). Specifically part of the catalytically inactive RNA exosome core (Exo-9) complex which is believed to associate with catalytic subunits EXOSC10, and DIS3 or DIS3L in cytoplasmic- and nuclear-specific RNA exosome complex forms (PubMed:11719186, PubMed:20531389, PubMed:26166824). Exo-9 is formed by a hexameric ring of RNase PH domain-containing subunits specifically containing the heterodimers EXOSC4-EXOSC9, EXOSC5-EXOSC8 and EXOSC6-EXOSC7, and peripheral S1 domain-containing components EXOSC1, EXOSC2 and EXOSC3 located on the top of the ring structure (PubMed:11719186, PubMed:20531389). Interacts with DIS3 (PubMed:20531389). Interacts with GTPBP1 (PubMed:21515746). Interacts with ZFP36L1 (via N-terminus) (PubMed:15687258).
Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC2 as peripheral part of the Exo-9 complex stabilizes the hexameric ring of RNase PH-domain subunits through contacts with EXOSC4 and EXOSC7.
After binding to 2-5A (5'-phosphorylated 2',5'-linked oligoadenylates) the homodimerization and subsequent activation occurs. Inhibited by RNASEL inhibitor ABCE1/RLI, a cytoplasmic member of the ATP-binding cassette (ABC) transporter family.
By interferons. Virus replication in higher vertebrates is restrained by IFNs that cause cells to transcribe genes encoding antiviral proteins, such as 2'-5' oligoadenylate synthetases (OASs). oligoadenylate synthetase is stimulated by dsRNA to produce 5'-phosphorylated, 2'-5'-linked oligoadenylates (2-5A), whose function is to activate RNASEL.
Endoribonuclease that functions in the interferon (IFN) antiviral response. In INF treated and virus infected cells, RNASEL probably mediates its antiviral effects through a combination of direct cleavage of single-stranded viral RNAs, inhibition of protein synthesis through the degradation of rRNA, induction of apoptosis, and induction of other antiviral genes. RNASEL mediated apoptosis is the result of a JNK-dependent stress-response pathway leading to cytochrome c release from mitochondria and caspase-dependent apoptosis. Therefore, activation of RNASEL could lead to elimination of virus infected cells under some circumstances. In the crosstalk between autophagy and apoptosis proposed to induce autophagy as an early stress response to small double-stranded RNA and at later stages of prolonged stress to activate caspase-dependent proteolytic cleavage of BECN1 to terminate autophagy and promote apoptosis (PubMed:26263979). Might play a central role in the regulation of mRNA turnover (PubMed:11585831). Cleaves 3' of UpNp dimers, with preference for UU and UA sequences, to sets of discrete products ranging from between 4 and 22 nucleotides in length.
Highly expressed in spleen and thymus followed by prostate, testis, uterus, small intestine, colon and peripheral blood leukocytes.
Manganese or magnesium. Required for optimal RNA cleavage rates.
Monomer (inactive form) or homodimer. Interacts with ABCE1; this interaction inhibits the RNASEL.
The nine ankyrin repeats also called 2-5A sensor constitute the N-terminus 2-5A binding domain.
The protein kinase domain is predicted to be catalytically inactive. It allows the homodimerization.
The ribonuclease domain is located in the C-terminus. A single active nuclease domain in a dimer is sufficient for ribonuclease activity (By similarity).
Metallothioneins have a high content of cysteine residues that bind various heavy metals.
Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids. May be involved in FAM168A anti-apoptotic signaling (PubMed:23251525).
Monomer. Interacts with FAM168A (PubMed:23251525).
Acts as guanine nucleotide exchange factor (GEF) for RHOA, RHOB and RHOC.
Detected in heart, liver, skeletal muscle, kidney and pancreas.
Activated by forskolin. Insensitive to calcium/calmodulin. Stimulated by GNAS and by the G-protein beta and gamma subunit complex.
Detected in the zona glomerulosa and the zona fasciculata in the adrenal gland (at protein level).
Catalyzes the NADPH-dependent reduction of trans-2-enoyl thioesters in mitochondrial fatty acid synthesis (fatty acid synthesis type II). Fatty acid chain elongation in mitochondria uses acyl carrier protein (ACP) as an acyl group carrier, but the enzyme accepts both ACP and CoA thioesters as substrates in vitro. Displays a preference for medium-chain over short- and long-chain substrates (PubMed:18479707, PubMed:12654921, PubMed:27817865). May provide the octanoyl chain used for lipoic acid biosynthesis, regulating protein lipoylation and mitochondrial respiratory activity particularly in Purkinje cells (By similarity).
Highly expressed in skeletal and heart muscle. Expressed at lower level in placenta, liver, kidney and pancreas. Weakly or not expressed in lung.
Homodimer (PubMed:12654921, PubMed:18479707). Isoform 2 interacts with PPARA in the nucleus and increases its activity (By similarity).
Homodimer (By similarity). Forms a heterotetramer composed of 2 DOK7 and 2 MUSK molecules which facilitates MUSK trans-autophosphorylation on tyrosine residue and activation (By similarity). Interacts (via IRS-type PTB domain) with MUSK (via cytoplasmic part); requires MUSK phosphorylation.
Preferentially expressed in skeletal muscle and heart. Present in thigh muscle, diaphragm and heart but not in the liver or spleen (at protein level).
Probable muscle-intrinsic activator of MUSK that plays an essential role in neuromuscular synaptogenesis. Acts in aneural activation of MUSK and subsequent acetylcholine receptor (AchR) clustering in myotubes. Induces autophosphorylation of MUSK.
The PH domain mediated binding to phospholipids with phosphoinositol headgroups. Affinity is highest for phosphatidyl 3,4,5-trisphosphate, followed by phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 4,5-bisphosphate (By similarity).
Interacts with C11orf84/SPINDOC (PubMed:29061846).
Expression levels vary widely in a range of tissues (PubMed:16044242). Expressed in the brain, at high level in the pituitary gland and also in hypothalamus, limbic system, caudate nucleus accumens, pons and olfactory bulb (PubMed:23161870).
Plasma membrane progesterone (P4) receptor coupled to G proteins (PubMed:23763432, PubMed:23161870). Seems to act through a G(s) mediated pathway (PubMed:23161870). May be involved in regulating rapid P4 signaling in the nervous system (PubMed:23763432). Also binds dehydroepiandrosterone (DHEA), pregnanolone, pregnenolone and allopregnanolone (PubMed:23161870).
Acetylated at Lys-373 by CREBBP/CBP, leading to decreased RNA polymerase I transcription (PubMed:24207024). In normal conditions, deacetylated by SIRT7, promoting the association of RNA polymerase I with the rDNA promoter region and coding region (PubMed:24207024). In response to stress, SIRT7 is released from nucleoli leading to hyperacetylation of POLR1E/PAF53 and decreased association of RNA polymerase I with the rDNA promoter region (PubMed:24207024).
Belongs to the eukaryotic RPA49/POLR1E RNA polymerase subunit family.
Component of the RNA polymerase I (Pol I) complex consisting of at least 13 subunits (PubMed:16809778, PubMed:29065309). Interacts with POLR1G (By similarity). Also binds UBTF/UBF (By similarity). Interacts with PWP1 (PubMed:29065309).
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase I which synthesizes ribosomal RNA precursors (PubMed:24207024). Appears to be involved in the formation of the initiation complex at the promoter by mediating the interaction between Pol I and UBTF/UBF (PubMed:24207024).
Dubious isoform produced through intron retention.
Component of Schwann cell signaling pathway(s) that controls axon segregation and myelin formation (By similarity).
Widely expressed, with highest expression in brain.
(Microbial infection) Interacts (via C-terminus) with HTLV-1 TAX (via C-terminus); this interaction inhibits HTLV-1 TAX to transactivate viral long terminal repeat (LTR) promoter (PubMed:14679154).
(Microbial infection) Negatively regulates HTLV-1 TAX-dependent transactivation of viral long terminal repeat (LTR) promoter.
Associates with cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to trigger ARE-containing mRNA deadenylation and decay processes (By similarity). Part of a mRNA decay activation complex at least composed of poly(A)-specific exoribonucleases CNOT6, EXOSC2 and XRN1 and mRNA-decapping enzymes DCP1A and DCP2 (PubMed:15687258). Associates with the RNA exosome complex (PubMed:11719186). Interacts (via phosphorylated form) with 14-3-3 proteins; these interactions promote exclusion of ZFP36 from cytoplasmic stress granules in response to arsenite treatment in a MAPKAPK2-dependent manner and does not prevent CCR4-NOT deadenylase complex recruitment or ZFP36-induced ARE-containing mRNA deadenylation and decay processes (By similarity). Interacts with 14-3-3 proteins; these interactions occur in response to rapamycin in an Akt-dependent manner (PubMed:16702957). Interacts with AGO2 and AGO4 (PubMed:15766526). Interacts (via C-terminus) with CNOT1; this interaction occurs in a RNA-independent manner and induces mRNA deadenylation (PubMed:23644599). Interacts (via N-terminus) with CNOT6 (PubMed:15687258). Interacts with CNOT6L (By similarity). Interacts (via C-terminus) with CNOT7; this interaction occurs in a RNA-independent manner, induces mRNA deadenylation and is inhibited in a phosphorylation MAPKAPK2-dependent manner (PubMed:25106868). Interacts (via unphosphorylated form) with CNOT8; this interaction occurs in a RNA-independent manner and is inhibited in a phosphorylation MAPKAPK2-dependent manner (By similarity). Interacts with DCP1A (PubMed:15687258). Interacts (via N-terminus) with DCP2 (PubMed:15687258, PubMed:16364915). Interacts with EDC3 (PubMed:16364915). Interacts (via N-terminus) with EXOSC2 (PubMed:15687258). Interacts with heat shock 70 kDa proteins (PubMed:20221403). Interacts with KHSRP; this interaction increases upon cytokine-induced treatment (PubMed:16126846). Interacts with MAP3K4; this interaction enhances the association with SH3KBP1/CIN85 (PubMed:20221403). Interacts with MAPKAPK2; this interaction occurs upon skeletal muscle satellite cell activation (By similarity). Interacts with NCL (PubMed:20221403). Interacts with NUP214; this interaction increases upon lipopolysaccharide (LPS) stimulation (PubMed:14766228). Interacts with PABPC1; this interaction occurs in a RNA-dependent manner (PubMed:20221403). Interacts (via hypophosphorylated form) with PABPN1 (via RRM domain and C-terminal arginine-rich region); this interaction occurs in the nucleus in a RNA-independent manner, decreases in presence of single-stranded poly(A) RNA-oligomer and in a p38 MAPK-dependent-manner and inhibits nuclear poly(A) tail synthesis (By similarity). Interacts with PAN2 (By similarity). Interacts (via C3H1-type zinc finger domains) with PKM (PubMed:26926077). Interacts (via C3H1-type zinc finger domains) with nuclear RNA poly(A) polymerase (By similarity). Interacts with PPP2CA; this interaction occurs in LPS-stimulated cells and induces ZFP36 dephosphorylation, and hence may promote ARE-containing mRNAs decay (By similarity). Interacts (via C-terminus) with PRR5L (via C-terminus); this interaction may accelerate ZFP36-mediated mRNA decay during stress (PubMed:21964062). Interacts (via C-terminus) with SFN; this interaction occurs in a phosphorylation-dependent manner (By similarity). Interacts (via extreme C-terminal region) with SH3KBP1/CIN85 (via SH3 domains); this interaction enhances MAP3K4-induced phosphorylation of ZFP36 at Ser-66 and Ser-93 and does not alter neither ZFP36 binding to ARE-containing transcripts nor TNF-alpha mRNA decay (PubMed:20221403). Interacts with XRN1 (PubMed:15687258). Interacts (via C-terminus and Ser-186 phosphorylated form) with YWHAB; this interaction occurs in a p38/MAPKAPK2-dependent manner, increases cytoplasmic localization of ZFP36 and protects ZFP36 from Ser-186 dephosphorylation by serine/threonine phosphatase 2A, and hence may be crucial for stabilizing ARE-containing mRNAs (By similarity). Interacts (via phosphorylated form) with YWHAE (By similarity). Interacts (via C-terminus) with YWHAG; this interaction occurs in a phosphorylation-dependent manner (By similarity). Interacts with YWHAH; this interaction occurs in a phosphorylation-dependent manner (By similarity). Interacts with YWHAQ; this interaction occurs in a phosphorylation-dependent manner (By similarity). Interacts with (via C-terminus) YWHAZ; this interaction occurs in a phosphorylation-dependent manner (By similarity). Interacts (via P-P-P-P-G repeats) with GIGYF2; the interaction is direct (By similarity).
Associates with the cytoplasmic CCR4-NOT deadenylase complex to trigger ARE-containing mRNA deadenylation and decay processes.
Expressed in both basal and suprabasal epidermal layers (PubMed:27182009). Expressed in epidermal keratinocytes (PubMed:27182009). Expressed strongly in mature dendritic cells (PubMed:18367721). Expressed in immature dendritic cells (at protein level) (PubMed:18367721).
Phosphorylated. Phosphorylation at serine and/or threonine residues occurs in a p38 MAPK- and MAPKAPK2-dependent manner (PubMed:16702957). Phosphorylated by MAPKAPK2 at Ser-60 and Ser-186; phosphorylation increases its stability and cytoplasmic localization, promotes binding to 14-3-3 adapter proteins and inhibits the recruitment of cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to the mRNA decay machinery, thereby inhibiting ZFP36-induced ARE-containing mRNA deadenylation and decay processes. Phosphorylation by MAPKAPK2 does not impair ARE-containing RNA-binding. Phosphorylated in a MAPKAPK2- and p38 MAPK-dependent manner upon skeletal muscle satellite cell activation; this phosphorylation inhibits ZFP36-mediated mRNA decay activity, and hence stabilizes MYOD1 mRNA (By similarity). Phosphorylated by MAPK1 upon mitogen stimulation (By similarity). Phosphorylated at Ser-66 and Ser-93; these phosphorylations increase in a SH3KBP1-dependent manner (PubMed:20221403). Phosphorylated at serine and threonine residues in a pyruvate kinase PKM- and p38 MAPK-dependent manner (PubMed:26926077). Phosphorylation at Ser-60 may participate in the PKM-mediated degradation of ZFP36 in a p38 MAPK-dependent manner (PubMed:26926077). Dephosphorylated by serine/threonine phosphatase 2A at Ser-186 (By similarity).
The C3H1-type zinc finger domains are necessary for ARE-binding activity (PubMed:10330172).
Ubiquitinated; pyruvate kinase (PKM)-dependent ubiquitination leads to proteasomal degradation through a p38 MAPK signaling pathway (PubMed:26926077).
Up-regulated by T cell activation (PubMed:15634918). Up-regulated in keratinocytes in response to wounding (PubMed:27182009). Up-regulated by lipopolysaccharide (LPS) in a p38 MAPK- and ERK-dependent manner (at protein level) (PubMed:15187101, PubMed:16508015). Up-regulated strongly during epidermal repair after wounding in keratinocytes (PubMed:20166898). Up-regulated strongly by epidermal growth factor (EGF) and tumor necrosis factor (TNF-alpha) in keratinocytes (PubMed:20166898). Up-regulated moderately by granulocyte macrophage colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF1) in keratinocytes (PubMed:20166898). Up-regulated also by glucocorticoid dexamethasone in keratinocytes (PubMed:20166898). Up-regulated in keratinocytes in response to wounding (PubMed:27182009). Up-regulated by LPS in a p38 MAPK-dependent manner (PubMed:14766228, PubMed:15187101).
Zinc-finger RNA-binding protein that destabilizes several cytoplasmic AU-rich element (ARE)-containing mRNA transcripts by promoting their poly(A) tail removal or deadenylation, and hence provide a mechanism for attenuating protein synthesis (PubMed:9703499, PubMed:10330172, PubMed:10751406, PubMed:11279239, PubMed:12115244, PubMed:12748283, PubMed:15187101, PubMed:15634918, PubMed:17030620, PubMed:16702957, PubMed:20702587, PubMed:20221403, PubMed:21775632, PubMed:27193233, PubMed:23644599, PubMed:25815583, PubMed:31439631). Acts as an 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery (PubMed:15687258, PubMed:23644599). Recruits deadenylase CNOT7 (and probably the CCR4-NOT complex) via association with CNOT1, and hence promotes ARE-mediated mRNA deadenylation (PubMed:23644599). Functions also by recruiting components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs (PubMed:11719186, PubMed:12748283, PubMed:15687258, PubMed:16364915). Self regulates by destabilizing its own mRNA (PubMed:15187101). Binds to 3'-UTR ARE of numerous mRNAs and of its own mRNA (PubMed:10330172, PubMed:10751406, PubMed:12115244, PubMed:15187101, PubMed:15634918, PubMed:17030620, PubMed:16702957, PubMed:19188452, PubMed:20702587, PubMed:20221403, PubMed:21775632, PubMed:25815583). Plays a role in anti-inflammatory responses; suppresses tumor necrosis factor (TNF)-alpha production by stimulating ARE-mediated TNF-alpha mRNA decay and several other inflammatory ARE-containing mRNAs in interferon (IFN)- and/or lipopolysaccharide (LPS)-induced macrophages (By similarity). Also plays a role in the regulation of dendritic cell maturation at the post-transcriptional level, and hence operates as part of a negative feedback loop to limit the inflammatory response (PubMed:18367721). Promotes ARE-mediated mRNA decay of hypoxia-inducible factor HIF1A mRNA during the response of endothelial cells to hypoxia (PubMed:21775632). Positively regulates early adipogenesis of preadipocytes by promoting ARE-mediated mRNA decay of immediate early genes (IEGs) (By similarity). Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA (PubMed:20702587). Plays a role in maintaining skeletal muscle satellite cell quiescence by promoting ARE-mediated mRNA decay of the myogenic determination factor MYOD1 mRNA (By similarity). Associates also with and regulates the expression of non-ARE-containing target mRNAs at the post-transcriptional level, such as MHC class I mRNAs (PubMed:18367721). Participates in association with argonaute RISC catalytic components in the ARE-mediated mRNA decay mechanism; assists microRNA (miRNA) targeting ARE-containing mRNAs (PubMed:15766526). May also play a role in the regulation of cytoplasmic mRNA decapping; enhances decapping of ARE-containing RNAs, in vitro (PubMed:16364915). Involved in the delivery of target ARE-mRNAs to processing bodies (PBs) (PubMed:17369404). In addition to its cytosolic mRNA-decay function, affects nuclear pre-mRNA processing (By similarity). Negatively regulates nuclear poly(A)-binding protein PABPN1-stimulated polyadenylation activity on ARE-containing pre-mRNA during LPS-stimulated macrophages (By similarity). Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion (By similarity). Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis (PubMed:27182009). Plays a role as a tumor suppressor by inhibiting cell proliferation in breast cancer cells (PubMed:26926077).
Zinc-finger RNA-binding protein that destabilizes several cytoplasmic AU-rich element (ARE)-containing mRNA transcripts by promoting their poly(A) tail removal or deadenylation, and hence provide a mechanism for attenuating protein synthesis. Acts as a 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery. Functions by recruiting the CCR4-NOT deadenylase complex and probably other components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs, and hence promotes ARE-mediated mRNA deadenylation and decay processes. Binds to 3'-UTR ARE of numerous mRNAs.
E3 ubiquitin-protein ligase that mediates monoubiquitination of TSG101 at multiple sites, leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors) and exocytic (HIV-1 viral proteins) cargos (PubMed:15256501). Bacterial recognition protein that defends the cytoplasm from invasive pathogens (PubMed:23245322). Localizes to several intracellular bacterial pathogens and generates the bacteria-associated ubiquitin signal leading to autophagy-mediated intracellular bacteria degradation (xenophagy) (PubMed:23245322, PubMed:25484098).
Highly expressed in adult spinal cord motoneurons as well as in fetal spinal cord and muscle tissue.
Interacts with TSG101 (PubMed:17556548). Interacts with PHF23 (PubMed:25484098). Interacts with FUS (PubMed:27615052).
The LRR domain is necessary and sufficient for localization to bacterial targets.
The PTAP motifs mediate the binding to UEV domains.
The RING domain is required for ubiquitination.
The coiled coil domains interact with the SB domain of TSG101.
Ubiquitination promoted by PHF23 leads to proteasomal degradation.
Belongs to the CorA metal ion transporter (MIT) (TC 1.A.35) family.
Has the ability to complement a deletion of MRS2 in S.cerevisiae and partly restore mitochondrial magnesium concentrations.
Magnesium transporter that mediates the influx of magnesium into the mitochondrial matrix (PubMed:11401429, PubMed:18384665). Required for normal expression of the mitochondrial respiratory complex I subunits (PubMed:18384665).
Interacts with RXR and RARA (By similarity). Interacts with importin alpha.
Sumoylated in response to retinoic acid binding, sumoylation is critical for dissociation from ER and subsequent nuclear translocation.
Transports retinoic acid to the nucleus. Regulates the access of retinoic acid to the nuclear retinoic acid receptors.
Belongs to the CTCF zinc-finger protein family.
Interacts with histones, PRMT7 and SETD1A. Interacts (via N-terminus) with BAG6/BAT3.
Is up-regulated in primary spermatocytes (expression overlapping with the genome-wide erasure of methylation) to become silenced on activation of CTCF in post-meiotic germline cells (expression corresponding to DNA remethylation).
Testis specific. Specifically expressed in primary spermatocytes.
Testis-specific DNA binding protein responsible for insulator function, nuclear architecture and transcriptional control, which probably acts by recruiting epigenetic chromatin modifiers. Plays a key role in gene imprinting in male germline, by participating in the establishment of differential methylation at the IGF2/H19 imprinted control region (ICR). Directly binds the unmethylated H19 ICR and recruits the PRMT7 methyltransferase, leading to methylate histone H4 'Arg-3' to form H4R3sme2. This probably leads to recruit de novo DNA methyltransferases at these sites (By similarity). Seems to act as tumor suppressor. In association with DNMT1 and DNMT3B, involved in activation of BAG1 gene expression by binding to its promoter. Required for dimethylation of H3 lysine 4 (H3K4me2) of MYC and BRCA1 promoters.
Acts also as a negative regulator of osteoclast activity (By similarity). Involved in interleukin-4-induced M2 macrophage polarization (By similarity).
Expressed in kidney, heart, brain and placenta.
Interaction with RRAGA; increases RRAGA recruitment to lysosomes (PubMed:31036939). Interacts with MTOR; this interaction is amino acid sensitive (PubMed:31036939).
Lysosomal integral membrane protein that regulates the localization and activity of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids (PubMed:31036939). Interacts with Rag GTPases and increases the lysosomial localization and activity of Rag GTPases and thereby regulates mTORC1 translocation and activity in lysosome (PubMed:31036939). Involved in the regulation of lysosomal morphology and autophagy (PubMed:31036939).
Belongs to the eukaryotic diacylglycerol kinase family.
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:12200442, PubMed:23949095). Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes (Probable). By controlling the levels of diacylglycerol, regulates for instance the PKC and EGF receptor signaling pathways and plays a crucial role during development (By similarity). May also regulate clathrin-dependent endocytosis (PubMed:17880279).
Homooligomer (PubMed:12200442, PubMed:12084710). Monomer (PubMed:12084710). Interacts with AP2A2; regulates clathrin-dependent endocytosis (PubMed:17880279).
Only detected in ovary, and to a lesser extent in spleen.
Phosphorylated (PubMed:12084710). Phosphorylation by PKC induced by phorbol esters prevents homooligomerization and promotes association with membranes (PubMed:12084710).
The PH domain mediates association with membranes.
The SAM domain mediates homooligomerization.
Interacts with FYN, GRB2 and PIK3R1 when phosphorylated. Interacts with LYN.
Phosphorylated on tyrosines by FYN and LYN.
Probable adapter protein involved in signaling pathways. Interacts with the SH2 and SH3 domains of various signaling proteins when it is phosphorylated. May promote FYN activation, possibly by disrupting intramolecular SH3-dependent interactions (By similarity).
Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4. Required for the function of some acidic activation domains, which activate transcription from a distant site (By similarity). Binds double-stranded DNA. Binds dinucleosomes, probably at the linker region between neighboring nucleosomes. Plays a role in chromatin remodeling. May promote TP53/p53 'Lys-321' acetylation, leading to reduced TP53 stability and transcriptional activity (PubMed:22644376). May also promote XRCC6 acetylation thus facilitating cell apoptosis in response to DNA damage (PubMed:22644376).
Expressed in all tissues, but most abundantly in testis.
Interacts with GCN5 and NR3C1. Associated with the P/CAF protein in the PCAF complex. Component of the PCAF complex, at least composed of TADA2L/ADA2, TADA3L/ADA3, TAF5L/PAF65-beta, TAF6L/PAF65-alpha, TAF10/TAFII30, TAF12/TAFII20, TAF9/TAFII31 and TRRAP. Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1. Interacts with CCDC134 (PubMed:22644376).
Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985). Component of the BRCA1-A complex, at least composed of the BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:17525341, PubMed:17525342, PubMed:19261746, PubMed:19261749). In the BRCA1-A complex, interacts directly with ABRAXAS1 (PubMed:17643121, PubMed:17643122, PubMed:19261749, PubMed:19261748, PubMed:18077395). Interacts with UBE2I (PubMed:17698038). Interacts with NR6A1 (PubMed:12080054). Interacts with ESR1 (PubMed:17311814). Interacts with TSP57 (By similarity). Interacts with TRAIP (PubMed:26781088).
Expressed in testis, ovary, thymus and heart. Expressed in germ cells of the testis.
Phosphorylated upon DNA damage by ATM or ATR.
The Abraxas-interacting region (AIR) mediates the interaction with ABRAXAS1.
The tandem UIM domains form a continuous 60 Angstrom-long alpha-helix and mediate binding to 'Lys-63'-linked ubiquitins. UIM1 and UIM2 bind to the proximal and distal ubiquitin moieties and recognize an 'Ile-44'-centered hydrophobic patch. Since UIMs don't interact with the 'Lys-63' isopeptide bond the UIM-linker region between the 2 UIM domains determines the selectivity for 'Lys-63'-linkage, and its length is very important for specificity.
Ubiquitin-binding protein (PubMed:24627472). Specifically recognizes and binds 'Lys-63'-linked ubiquitin (PubMed:19328070, Ref.38). Plays a central role in the BRCA1-A complex by specifically binding 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX. Also weakly binds monoubiquitin but with much less affinity than 'Lys-63'-linked ubiquitin. May interact with monoubiquitinated histones H2A and H2B; the relevance of such results is however unclear in vivo. Does not bind Lys-48'-linked ubiquitin. May indirectly act as a transcriptional repressor by inhibiting the interaction of NR6A1 with the corepressor NCOR1.
Putative antiporter that exchanges dicarboxylates and sulfur oxoanions across the inner membrane of mitochondria.
Heme transporter that regulates intracellular heme availability through the endosomal or lysosomal compartment (PubMed:18418376). In macrophages of the reticuloendothelial system, is the heme transporter for heme-iron recycling. Essential for macrophage iron homeostasis, transports heme from the phagolysosome to the cytoplasm during erythrophagocytosis (EP) (PubMed:23395172).
Highly expressed in the brain, kidney, heart and skeletal muscle. Moderately expressed in the liver, lung, placenta and small intestine. Strongly expressed in macrophages of the reticuloendothelial system (PubMed:23395172).
Induced by iron via heme and non-iron metalloporphyrins in macrophages as well as by erythrophagocytosis (at protein level). Also induced by hemolysis.
Binds to TGF-beta. Could be involved in capturing and retaining TGF-beta for presentation to the signaling receptors (By similarity). In gonadotrope cells, acts as an inhibin A coreceptor and regulates follicle-stimulating hormone (FSH) levels and female fertility (PubMed:34910520).
Extensively modified by glycosaminoglycan groups (GAG).
Heteromer. Composed of TAMALIN, CYTH2 and at least one GRM1. Also interacts with CYTH3, GRM2, GRM3 and GRM5 (By similarity).
Plays a role in intracellular trafficking and contributes to the macromolecular organization of group 1 metabotropic glutamate receptors (mGluRs) at synapses.
Expressed in both differentiating and adult muscles.
Highly expressed in striated muscles. Weakly expressed in thyroid, fetal brain, fetal lung, retina, spinal cord and bone marrow. Not expressed in testis, pancreas, adrenal gland, placenta, liver and kidney.
Homodimer; the filamin repeat 24 and the second hinge domain are important for dimer formation. Interacts with FLNB, INPPL1, ITGB1A, KCND2, MYOT, MYOZ1 and MYOZ3. Interacts with sarcoglycans SGCD and SGCG. Interacts (via filament repeats 17-18, 20-21 and 24) with USP25 (isoform USP25m only). Interacts with FBLIM1. Interacts with XIRP1; this interaction is mediated by filamin 20 repeat. Interacts with KY. Interacts with IGFN1 (By similarity). Interacts with MICALL2 (By similarity). Interacts with ANK3. Interacts with SYNPO2.
Muscle-specific filamin, which plays a central role in sarcomere assembly and organization (PubMed:34405687). Critical for normal myogenesis, it probably functions as a large actin-cross-linking protein with structural functions at the Z lines in muscle cells. May be involved in reorganizing the actin cytoskeleton in response to signaling events (By similarity).
Silenced in MKN28 and MKN74 gastric cancer cell lines due to aberrant methylation of the gene.
Ubiquitinated by FBXL22, leading to proteasomal degradation.
It is uncertain whether Met-1 or Met-37 is the initiator.
Belongs to the universal ribosomal protein uS19 family.
Catalyzes the polycondensation of alpha-2,8-linked sialic acid required for the synthesis of polysialic acid (PSA), which is present on the embryonic neural cell adhesion molecule (N-CAM), necessary for plasticity of neural cells.
Highly expressed in fetal brain, lung and kidney and in adult heart, spleen and thymus. Present to a lesser extent in adult brain, placenta, lung, large and small intestine and peripheral blood leukocytes.
Highest expression of UBASH3A in tissues belonging to the immune system, including spleen, peripheral blood leukocytes, thymus and bone marrow.
Homodimer or homooligomer. Interacts with CBL. Part of a complex containing CBL and activated EGFR. Interacts with ubiquitin and with mono-ubiquitinated proteins. Interacts with dynamin.
Interferes with CBL-mediated down-regulation and degradation of receptor-type tyrosine kinases. Promotes accumulation of activated target receptors, such as T-cell receptors, EGFR and PDGFRB, on the cell surface. Exhibits negligigle protein tyrosine phosphatase activity at neutral pH. May act as a dominant-negative regulator of UBASH3B-dependent dephosphorylation. May inhibit dynamin-dependent endocytic pathways by functionally sequestering dynamin via its SH3 domain.
Hormone involved in the regulation of erythrocyte proliferation and differentiation and the maintenance of a physiological level of circulating erythrocyte mass. Binds to EPOR leading to EPOR dimerization and JAK2 activation thereby activating specific downstream effectors, including STAT1 and STAT3.
Produced by kidney or liver of adult mammals and by liver of fetal or neonatal mammals.
Used for the treatment of anemia. Available under the names Epogen (Amgen), Epogin (Chugai), Epomax (Elanex), Eprex (Janssen-Cilag), NeoRecormon or Recormon (Roche), Dynepo (Shire Pharmaceuticals) and Procrit (Ortho Biotech). Variations in the glycosylation pattern of EPO distinguishes these products. Epogen, Epogin, Eprex and Procrit are generically known as epoetin alfa, NeoRecormon and Recormon as epoetin beta, Dynepo as epoetin delta and Epomax as epoetin omega. Epoetin zeta is the name used for some 'biosimilars' forms of epoetin alfa and is available under the names Silapo (Stada) and Retacrit (Hospira). Darbepoetin alfa is a form created by 5 substitutions (Asn-57, Thr-59, Val-114, Asn-115 and Thr-117) that create 2 new N-glycosylation sites. It has a longer circulating half-life in vivo. It is available under the name Aranesp (Amgen). EPO is being much misused as a performance-enhancing drug in endurance athletes.
Expressed in testis, epididymis and placenta.
(Microbial infection) Interacts with herpes simplex virus 1 protein UL46.
(Microbial infection) Probably interacts with Chlamydia trachomatis protein IncG.
Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negative regulator of osteogenesis. Blocks the nuclear translocation of the phosphorylated form (by AKT1) of SRPK2 and antagonizes its stimulatory effect on cyclin D1 expression resulting in blockage of neuronal apoptosis elicited by SRPK2. Negative regulator of signaling cascades that mediate activation of MAP kinases via AKAP13.
Homodimer (PubMed:17717073). Interacts with SAMSN1 and PRKCE (By similarity). Interacts with AKAP13 (PubMed:21224381). Interacts with SSH1 and TORC2/CRTC2 (PubMed:15454081, PubMed:15159416). Interacts with ABL1; the interaction results in cytoplasmic location of ABL1 and inhibition of cABL-mediated apoptosis (PubMed:15696159). Interacts with ROR2 (dimer); the interaction results in phosphorylation of YWHAB on tyrosine residues (PubMed:17717073). Interacts with GAB2 (PubMed:19172738). Interacts with YAP1 (phosphorylated form) (PubMed:17974916). Interacts with the phosphorylated (by AKT1) form of SRPK2 (PubMed:19592491). Interacts with PKA-phosphorylated AANAT (PubMed:11427721). Interacts with MYO1C (PubMed:24636949). Interacts with SIRT2 (PubMed:18249187). Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with the 'Ser-1134' and 'Ser-1161' phosphorylated form of SOS1 (PubMed:22827337). Interacts (via phosphorylated form) with YWHAB; this interaction occurs in a protein kinase AKT1-dependent manner (PubMed:15538381). Interacts with SLITRK1 (PubMed:19640509). Interacts with SYNPO2 (phosphorylated form); YWHAB competes with ACTN2 for interaction with SYNPO2 (By similarity). Interacts with RIPOR2 (via phosphorylated form) isoform 2; this interaction occurs in a chemokine-dependent manner and does not compete for binding of RIPOR2 with RHOA nor blocks inhibition of RIPOR2-mediated RHOA activity (PubMed:25588844). Interacts with MARK2 and MARK3 (PubMed:16959763). Interacts with TESK1; the interaction is dependent on the phosphorylation of TESK1 'Ser-437' and inhibits TESK1 kinase activity (PubMed:11555644). Interacts with MEFV (PubMed:27030597). Interacts with HDAC4 (PubMed:33537682). Interacts with ADAM22 (via C-terminus) (PubMed:15882968).
The alpha, brain-specific form differs from the beta form in being phosphorylated. Phosphorylated on Ser-60 by protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion.
By ER stress (at protein level). Displays a slow increase with a lag phase of 6 hours but exhibits a dramatic increase after incubation with ER stress agents for more than 12 hours with maximum induction at 24 hours. Also induced by accumulation of misfolded proteins in the ER.
Cleaved by CAPN2/m-calpain in resting macrophages but not in activated macrophages. Macrophage activation up-regulates expression of the calpain inhibitor CAST/calpastatin, resulting in inhibition of CAPN2 activity (By similarity).
Interacts with DERL1, DERL2, DERL3 and SELENOS (PubMed:22016385). The SELENOK-SELENOS complex interacts with VCP (PubMed:22016385). Interacts with ZDHHC6 (PubMed:25368151).
Required for Ca(2+) flux in immune cells and plays a role in T-cell proliferation and in T-cell and neutrophil migration (By similarity). Involved in endoplasmic reticulum-associated degradation (ERAD) of soluble glycosylated proteins (PubMed:22016385). Required for palmitoylation and cell surface expression of CD36 and involved in macrophage uptake of low-density lipoprotein and in foam cell formation (By similarity). Together with ZDHHC6, required for palmitoylation of ITPR1 in immune cells, leading to regulate ITPR1 stability and function (PubMed:25368151). Plays a role in protection of cells from ER stress-induced apoptosis (PubMed:20692228). Protects cells from oxidative stress when overexpressed in cardiomyocytes (PubMed:16962588).
Truncated SELENOK proteins produced by failed UGA/Sec decoding are ubiquitinated by the CRL2(KLHDC2) complex, which recognizes the diglycine (Gly-Gly) at the C-terminus of truncated SELENOK proteins.
Detected in heart, lung, brain, liver, skeletal muscle, pancreas, kidney, spleen, testis and ovary.
Interacts with NEDD4. Interacts with ITCH (via WW domain 2).
Mono- and polyubiquitinated on the CoCUN region (PubMed:31319543). Monoubiquitinated by NEDD4 (By similarity). Polyubiquitinated, leading to its degradation by the proteasome (By similarity). Sumoylated with SUMO1, abrogating polyubiquitination and subsequent degradation (By similarity). Desumoylated by SENP1, leading to accumulation in PML nuclear bodies (By similarity).
Potent suppressor of cytokine production that acts as a regulator of innate immune signaling and inflammation. Acts as a key negative regulator of select cytokine and chemokine responses elicited by TRIF-independent Toll-like receptors (TLRs), thereby limiting inflammatory cytokine responses to minor insults. In response to more threatening pathogens, cleaved by CASP8 downstream of TLR3 or TLR4, leading to its inactivation, thereby allowing production of inflammatory cytokines (By similarity). Acts as a restriction factor against some viruses, such as HIV-1: restricts HIV-1 replication by binding to HIV-1 mRNAs and mediating their degradation via its ribonuclease activity (PubMed:31133753). Also acts as an inhibitor of the E3 ubiquitin-protein ligase ITCH: acts by interacting with the second WW domain of ITCH, leading to compete with ITCH's substrates and impairing ubiquitination of substrates (By similarity).
Proteolytic cleavage by CASP8 or MALT1 leads to its inactivation.
Proteolytically cleaved by CASP8 downstream of TLR3 or TLR4, leading to its inactivation. Mainly cleaved at Asp-490 by CASP8 (By similarity). Cleaved by caspase-like protein MALT1 in T-cells following TCR-mediated activation, leading to its inactivation and subsequent viral reactivation during HIV-1 infection (PubMed:31133753).
The CoCUN region mediates binding to ubiquitin (PubMed:31319543). Does not interact with NEDD8 (PubMed:31319543).
Up-regulated in response to interferon alpha (IFN-alpha) stimulation (at protein level).
Carrier protein. Binds to some hydrophobic molecules and promotes their transfer between the different cellular sites. Binds with high affinity to alpha-tocopherol. Also binds with a weaker affinity to other tocopherols and to tocotrienols. May have a transcriptional activatory activity via its association with alpha-tocopherol. Probably recognizes and binds some squalene structure, suggesting that it may regulate cholesterol biosynthesis by increasing the transfer of squalene to a metabolic active pool in the cell.
Widely expressed. Strong expression in liver, brain and prostate.
Belongs to the Nudix hydrolase family. NudC subfamily.
Homodimer (PubMed:31875550). Homodimerization is essential for its catalytic activity and protein stability (PubMed:31875550). Interacts (via ANK repeats) with BLMH (PubMed:31875550).
mRNA decapping enzyme that specifically removes the nicotinamide adenine dinucleotide (NAD) cap from a subset of mRNAs by hydrolyzing the diphosphate linkage to produce nicotinamide mononucleotide (NMN) and 5' monophosphate mRNA (PubMed:31101919, PubMed:31875550). The NAD-cap is present at the 5'-end of some RNAs; in contrast to the canonical N7 methylguanosine (m7G) cap, the NAD cap promotes mRNA decay (PubMed:31101919). Preferentially acts on NAD-capped transcripts in response to nutrient stress (PubMed:31101919). Also acts on free nicotinamide adenine dinucleotide molecules: hydrolyzes NAD(H) into NMN(H) and AMP, and NADPH into NMNH and 2',5'-ADP (PubMed:12790796). May act to regulate the concentration of peroxisomal nicotinamide nucleotide cofactors required for oxidative metabolism in this organelle (PubMed:12790796). Regulates the levels of circadian clock components PER1, PER2, PER3 and CRY2 in the liver (By similarity).
The LGALS9-like proteins are encoded by a duplicated regions on chromosome 17; there are at least 3 genes coding for galectin-9-like proteins.
E3 ubiquitin-protein ligase that negatively regulates IL3-dependent cellular responses through IL3RA ubiquitination and degradation by the proteasome, having an anti-inflammatory effect.
Expressed in neural and neuroendocrine tissues and cell cultures derived therefrom. Expression of isoform RTN1-C is strongly correlated with neuronal differentiation.
Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity.
Interacts with NDRG1 (PubMed:15922294). Interacts with BACE1 (PubMed:15286784).
Interacts with TMEM33 (PubMed:25612671).
Interacts with UGCG; regulates the ceramide glucosyltransferase activity of UGCG (PubMed:12873973).
Isoforms RTN1-A and RTN1-B are phosphorylated.
Autophosphorylates: phosphorylation promotes ubiquitination by the Cul7-RING(FBXW8) ubiquitin-protein ligase complex, leading to its degradation by the proteasome.
Expressed primarily in hematopoietic organs, including bone marrow, spleen and thymus. Also expressed at very low levels in lung, kidney, mammary glands and small intestine.
Interacts with MAP3K1 (PubMed:8824585). Interacts with FBXW8 (PubMed:24362026). Interacts with CLNK (via its SH2 domain) (By similarity).
Serine/threonine-protein kinase, which may play a role in the response to environmental stress (PubMed:24362026). Appears to act upstream of the JUN N-terminal pathway (PubMed:8824585). May play a role in hematopoietic lineage decisions and growth regulation (PubMed:8824585, PubMed:24362026). Able to autophosphorylate (PubMed:8824585). Together with CLNK, it enhances CD3-triggered activation of T-cells and subsequent IL2 production (By similarity).
Tyrosine-phosphorylated after activation of hemopoietic cells.
Ubiquitinated by the Cul7-RING(FBXW8) ubiquitin-protein ligase complex following autophosphorylation, leading to its degradation by the proteasome.
Involved in cardiomyocyte differentiation.
Can form disulfide-bonded heterodimer with CD94.
Plays a role as a receptor for the recognition of MHC class I HLA-E molecules by NK cells and some cytotoxic T-cells.
Belongs to the glucosamine/galactosamine-6-phosphate isomerase family. 6-phosphogluconolactonase subfamily.
Hydrolysis of 6-phosphogluconolactone to 6-phosphogluconate.
Catalyzes the conversion of fatty acids such as long-chain and very long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:12975357, PubMed:24269233, PubMed:10954726). Can activate diverse saturated, monosaturated and polyunsaturated fatty acids (PubMed:10954726).
Expressed primarily in brain. Expressed at lower level in testis and adrenal gland. Present in all regions of brain except pituitary.
Homodimer (PubMed:25327138). Heterodimer with BCAP31. Binds CASP8 (isoform 9) as a complex containing BCAP31, BCAP29, BCL2 and/or BCL2L1. Interacts with VAMP3, VAMP1 and membrane IgD immunoglobulins. May interact with ACTG1 and non-muscle myosin II (By similarity).
May play a role in anterograde transport of membrane proteins from the endoplasmic reticulum to the Golgi. May be involved in CASP8-mediated apoptosis (By similarity).
Plays a role in the export of secreted proteins in the ER.
Monomer and homodimer. Interacts with CXADR. Interacts presynaptically with the glutamate receptors GRIA2, GRIA3, GRIK3, isoform 3 of GRIA4, isoform A of GRM4, GRM7 and GRM8; with NAPA and NAPB; and with BTG2. The interaction with NAPA and NAPB disrupts the interaction with GRIA2, conducting to the internalization of GRIA2. Interacts with PRKCA; with the amine transporters SLC6A2 and SLC6A3; with the channels ASIC1 and ASIC2; with the GTP-binding proteins ARF1 and ARF3; with the ephrin receptor tyrosine kinases EPHA7, EPHB1 and EPHB2; with ERBB2 and through its PDZ domain with the C-terminal tail of PRLHR. Interacts with UNC5A. Interacts (via AH domain) with NCS1/FREQ; in a calcium-dependent manner. Interacts with F-actin and associates with the ARP2/3 complex. Interacts (via PDZ domain) with ARF1 (activated); the interaction blocks Arp2/3 complex inhibition.
Palmitoylation on Cys-413 is essential for long-term synaptic depression (LTD).
Phosphorylation at Thr-82 appears to inhibit the interaction with AMPA receptors.
Probable adapter protein that bind to and organize the subcellular localization of a variety of membrane proteins containing some PDZ recognition sequence. Involved in the clustering of various receptors, possibly by acting at the receptor internalization level. Plays a role in synaptic plasticity by regulating the trafficking and internalization of AMPA receptors. May be regulated upon PRKCA activation. May regulate ASIC1/ASIC3 channel. Regulates actin polymerization by inhibiting the actin-nucleating activity of the Arp2/3 complex; the function is competitive with nucleation promoting factors and is linked to neuronal morphology regulation and AMPA receptor (AMPAR) endocytosis. Via interaction with the Arp2/3 complex involved in regulation of synaptic plasicity of excitatory synapses and required for spine shrinkage during long-term depression (LTD). Involved in regulation of astrocyte morphology, antagonistic to Arp2/3 complex activator WASL/N-WASP function.
The AH domain mediates binding to F-actin.
The unoccupied PDZ domain is probably involved in allosteric modulation by forming an intramolecular bridge with the AH domain leading to a 'closed' formation. Binding of a PDZ ligand, such as GRIA2, allows enhanced interactions with F-actin and the Arp2/3 complex thus enhanced inhibition of actin polymerization (By similarity).
Although the complete sequence is not known with certainty, sequence shown here appears to be the most probable in accordance with the mouse sequence ortholog.
Heterotetramer of two alpha chains and two delta chains in adult hemoglobin A2 (HbA2). HbA2 represents less than 3.5% of adult hemoglobin.
Involved in oxygen transport from the lung to the various peripheral tissues.
Abundantly expressed in the occipital cortex and weakly expressed in the hippocampus (at protein level).
Expressed in the occipital cortex and hippocampus; higher amounts are observed in the parietal and frontal cortices, putamen, and, particularly, in the temporal neocortex, where it is between 3 and 5 times more abundant than in the hippocampus (at protein level) (PubMed:16787412). Expression is absent in the cerebellum (PubMed:16787412).
Oligomer. Interacts with KCNA1 within a complex containing KCNA1, KCNA4 and KCNAB1. Part of a complex containing ADAM22, DLG4/PSD95 and CACNG2/Stargazin (PubMed:27066583). Can bind to ADAM11 and ADAM23.
Predominantly expressed in neural tissues, especially in brain. Expression is reduced in low-grade brain tumors and significantly reduced or absent in malignant gliomas.
Regulates voltage-gated potassium channels assembled from KCNA1, KCNA4 and KCNAB1. It slows down channel inactivation by precluding channel closure mediated by the KCNAB1 subunit. Ligand for ADAM22 that positively regulates synaptic transmission mediated by AMPA-type glutamate receptors (By similarity). Plays a role in suppressing the production of MMP1/3 through the phosphatidylinositol 3-kinase/ERK pathway. May play a role in the control of neuroblastoma cell survival.
Expressed in brain and spinal cord, and at lower levels in testis, placenta and liver, but no detectable expression observed in any other tissue. When overexpressed in cells, tends to become insoluble and unfolded. Accumulation of the unfolded protein may lead to dopaminergic neuronal death in juvenile Parkinson disease (PDJ).
Forms a complex with PRKN, STUB1 and HSP70. The amount of STUB1 in the complex increases during ER stress. STUB1 promotes the dissociation of HSP70 from PRKN, thus facilitating PRKN-mediated GPR37 ubiquitination. Interacts with PACRG.
Receptor for the neuroprotective and glioprotective factor prosaposin. Ligand binding induces endocytosis, followed by an ERK phosphorylation cascade.
Ubiquitinated by PRKN in the presence of UBE2E1 and UBE2L3 in the endoplasmic reticulum. The unfolded form is specifically ubiquitinated by SYVN1, which promotes its proteasomal degradation and prevents neuronal cell death.
Component of the spliceosomal U1 snRNP, which is essential for recognition of the pre-mRNA 5' splice-site and the subsequent assembly of the spliceosome. U1 snRNP is the first snRNP to interact with pre-mRNA. This interaction is required for the subsequent binding of U2 snRNP and the U4/U6/U5 tri-snRNP. SNRPA binds stem loop II of U1 snRNA. In a snRNP-free form (SF-A) may be involved in coupled pre-mRNA splicing and polyadenylation process. May bind preferentially to the 5'-UGCAC-3' motif on RNAs.
U1 snRNP is composed of the 7 core Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP, and at least three U1 snRNP-specific proteins SNRNP70/U1-70K, SNRPA/U1-A and SNRPC/U1-C. Interacts with SFPQ; component of a snRNP-free complex with SFPQ.
High expression levels in heart, skeletal muscle, brain, testis and ovary; moderate levels in prostate, placenta, liver and colon; and no detectable expression in peripheral leukocytes and thymus.
Thiol protease which is believed to participate in intracellular degradation and turnover of proteins. Has also been implicated in tumor invasion and metastasis.
Brain, placenta, liver, fetal and adult lung.
By phosphorylation (By similarity). Activated by anionic lipid vesicles and by oleic acid or diacylglycerol-containing phosphatidylcholine vesicles (PubMed:7918629, PubMed:8155650).
Monoubiquitinated by the SCF(FBXL2) complex, leading to proteasomal degradation.
The serine residues of the C-terminus are phosphorylated. The inactive soluble form is stabilized by phosphorylation, the active membrane bound form is promoted by anionic lipids or diacylglycerol, and is stabilized by dephosphorylation (By similarity).
Expression detected in spleen, thymus, testis, ovary, colon, heart, smooth muscle, kidney, brain, lung, liver and white adipose tissue with highest expression in heart, smooth muscle and thyroid.
Monomer. Found in a complex with GRSF1, DDX28, DHX30 and FASTKD5. Associates with the 16S mitochondrial rRNA (16S mt-rRNA) (PubMed:25683715). Forms a regulatory protein-RNA complex, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mt-rRNA (PubMed:27667664).
Plays an important role in assembly of the mitochondrial large ribosomal subunit (PubMed:25683715). As a component of a functional protein-RNA module, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mitochondrial ribosomal RNA (16S mt-rRNA), controls 16S mt-rRNA abundance and is required for intra-mitochondrial translation (PubMed:27667664, PubMed:25683715, PubMed:26370583). May play a role in mitochondrial apoptosis.
Interacts with CNEP1R1; the complex dephosphorylates LPIN1 and LPIN2.
Muscle specific with lower expression in other metabolic tissues.
Serine/threonine protein phosphatase forming with CNEP1R1 an active phosphatase complex that dephosphorylates and may activate LPIN1 and LPIN2. LPIN1 and LPIN2 are phosphatidate phosphatases that catalyze the conversion of phosphatidic acid to diacylglycerol and control the metabolism of fatty acids at different levels. May indirectly modulate the lipid composition of nuclear and/or endoplasmic reticulum membranes and be required for proper nuclear membrane morphology and/or dynamics. May also indirectly regulate the production of lipid droplets and triacylglycerol. May antagonize BMP signaling.
Homodimer. Interacts with SYCE1. Interacts with SYCE2. Interacts with proteasome subunit PSMA8; to participate in meiosis progression during spermatogenesis (By similarity). Interacts with SPO16 (By similarity).
Major component of the transverse central element of synaptonemal complexes (SCS), formed between homologous chromosomes during meiotic prophase. Required for chromosome loading of the central element-specific SCS proteins, and for initiating synapsis between homologous chromosomes. Chromosome loading appears to require SYCP1. Required for fertility.
Belongs to the aldo/keto reductase family.
Catalyzes the stereospecific NADPH-dependent reduction of the C4-C5 double bond of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure to yield an A/B cis-ring junction. This cis-configuration is crucial for bile acid biosynthesis and plays important roles in steroid metabolism. Capable of reducing a broad range of delta-(4)-3-ketosteroids from C18 (such as, 17beta-hydroxyestr-4-en-3-one) to C27 (such as, 7alpha-hydroxycholest-4-en-3-one).
Highly expressed in liver. Expressed in testis and weakly in colon.
Subject to inhibition by high substrate concentrations. Inhibited by testosterone concentrations above 10 uM (PubMed:18407998). Inhibited by the primary and secondary bile acids chenodeoxycholic acid and ursodeoxycholic acid (PubMed:21255593).
Highly expressed in spleen, peripheral blood lymphocytes, and germinal centers of lymph nodes. Also expressed in placenta, lung, pancreas and small intestine. Present in B-cells, NK cells and monocytes. Absent from T-cells (at protein level).
Involved in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. May also be involved in BCR (B-cell antigen receptor)-mediated signaling in B-cells and FCGR1 (high affinity immunoglobulin gamma Fc receptor I)-mediated signaling in myeloid cells. Couples activation of these receptors and their associated kinases with distal intracellular events through the recruitment of GRB2.
LAT2 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of LAT2 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.
Phosphorylated on tyrosines following cross-linking of BCR in B-cells, FCGR1 in myeloid cells, or FCER1 in mast cells; which induces the recruitment of GRB2.
When phosphorylated, interacts with GRB2. May also interact with SOS1, GAB1 and CBL.
(Microbial infection) Interacts with HIV-1 Nef and Tat proteins.
(Microbial infection) Interacts with HTLV-1 Tax protein.
A report observed N-glycosylation at Asn-83 (PubMed:19139490). However, as the protein does not localize in an extracellular compartment of the cell, additional evidence is required to confirm this result.
Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.
Non-catalytic component of the proteasome.
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:9344905, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:9344905, PubMed:34711951). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:9344905, PubMed:34711951). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:9344905, PubMed:34711951). Forms a ternary complex with SMAD1 and OAZ1 before PSMB4 is incorporated into the 20S proteasome (PubMed:11571290, PubMed:12097147). Interacts with PRPF19 (PubMed:15660529).
Up-regulated in fibrolamellar carcinomas.
Expressed abundantly in the central nervous system of adult, but not at all in fetal brain. High levels of SCRG1 transcripts are also observed in testis and aorta.
Carboxypeptidase which preferentially cleaves C-terminal acidic residues from peptides and proteins. Can also cleave C-terminal hydrophobic amino acids, with a preference for small residues over large residues.
Strongly inhibited by potato carboxypeptidase inhibitor, and the chelating agents EDTA and 1,10-phenanthroline. Also inhibited by compounds with multiple carboxylic acid groups such as citrate and succinate, and to a lesser exent the amino acids aspartate and glutamate. Not significantly inhibited by benzylsuccinic acid.
C1 is a calcium-dependent trimolecular complex of C1q, C1r and C1s in the molar ration of 1:2:2. C1r is a dimer of identical chains, each of which is activated by cleavage into two chains, A and B, connected by disulfide bonds.
C1r B chain is a serine protease that combines with C1q and C1s to form C1, the first component of the classical pathway of the complement system.
Complement component C1r deficiency [MIM:216950] leads to the failure of the classical complement system activation pathway (C1 deficiency). Individuals with C1 deficiency are highly susceptible to infections by microorganisms and have greater risk in developing autoimmune diseases such as systemic lupus erythematosus (SLE).
Interacts with NEDD4, NEDD4L and TSG101. Interacts with RNF126.
Widely expressed, with highest expression in heart and skeletal muscle.
(Microbial infection) Acts as a receptor for Hendra virus and Nipah virus.
(Microbial infection) Interacts with Hendra virus and Nipah virus G protein (PubMed:16007075, PubMed:16477309, PubMed:17376907, PubMed:15998730).
Cell surface transmembrane ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Binds to receptor tyrosine kinase including EPHA4, EPHA3 and EPHB4. Together with EPHB4 plays a central role in heart morphogenesis and angiogenesis through regulation of cell adhesion and cell migration. EPHB4-mediated forward signaling controls cellular repulsion and segregation from EFNB2-expressing cells. May play a role in constraining the orientation of longitudinally projecting axons.
Inducible phosphorylation of tyrosine residues in the cytoplasmic domain.
Interacts with PDZRN3 (By similarity). Binds to the receptor tyrosine kinases EPHA4, EPHB4 and EPHA3.
Acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate.
Expressed in testis, strongly inhibits cell growth in HeLa cells.
Isoform 3 is expressed in testis, brain and stomach while isoform 4 seems to be testis-specific.
Shows no phosphoinositide phosphatase activity.
Interacts (when phosphorylated at Ser-67) with PPP2R2D (By similarity). Interacts with ABCC8. Interacts with SNCA; interaction is disrupted when phosphorylated at Ser-109.
Phosphorylation at Ser-67 by GWL during mitosis is essential for interaction with PPP2R2D (PR55-delta) and subsequent inactivation of PP2A (By similarity). Phosphorylated by PKA.
Protein phosphatase inhibitor that specifically inhibits protein phosphatase 2A (PP2A) during mitosis. When phosphorylated at Ser-67 during mitosis, specifically interacts with PPP2R2D (PR55-delta) and inhibits its activity, leading to inactivation of PP2A, an essential condition to keep cyclin-B1-CDK1 activity high during M phase (By similarity). Also acts as a stimulator of insulin secretion by interacting with sulfonylurea receptor (ABCC8), thereby preventing sulfonylurea from binding to its receptor and reducing K(ATP) channel currents.
Widely expressed with high levels in skeletal muscle and brain and lower levels in the pancreas.
Interacts (via C-terminus) with IFT20 (PubMed:19889948). Interacts with DYNC1I2 (By similarity).
Required for correct axoneme development in spermatozoa. Important for normal development of the manchette and sperm head morphology. Essential for male fertility. Plays a role in localization of the intraflagellar transport protein IFT20 to the manchette, suggesting function as an adapter for dynein-mediated protein transport during spermatogenesis (PubMed:31278745, PubMed:31151990, PubMed:31048344). Also plays a role in bone growth where it seems to be required for normal osteoblast differentiation (By similarity).
Expressed in many cell types of epithelial, mesenchymal and hematopoietic origins (PubMed:24154973). Expressed in tufs cells (PubMed:35576971).
In the N-terminus possesses a conserved OCA domain for bivalent binding to class II POU domain-containing transcription factors and to an octamer DNA motif (5'-ATGAAAT-3').
Interacts with POU2F3 in a DNA-dependent manner; this interaction increases POU2F3 transactivation activity.
Transcriptional coactivator that specifically associates with POU2F3 (PubMed:35576971). This complex drives the development of tuft cells, a rare a rare chemosensory cells that coordinate immune and neural functions within mucosal epithelial tissues (PubMed:35576971).
Component of the 40S ribosomal subunit (PubMed:23636399). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399).
Component of the small ribosomal subunit (PubMed:23636399). The methylated form interacts with NPM1 (PubMed:20159986).
Methylated by PRMT5. Methylation is necessary for its interaction with NPS1, its localization in the granular component (GC) region of the nucleolus, for the proper assembly of ribosomes, protein synthesis and optimal cell proliferation.
Monoubiquitinated by ZNF598 when a ribosome has stalled during translation of poly(A) sequences, leading to preclude synthesis of a long poly-lysine tail and initiate the ribosome quality control (RQC) pathway to degrade the potentially detrimental aberrant nascent polypeptide (PubMed:28065601, PubMed:28132843, PubMed:28685749, PubMed:32011234, PubMed:36302773). Deubiquitinated by OTUD3 and USP21, antagonizing ZNF598 activity (PubMed:32011234). Deubiquitinated by OTUD1, antagonizing ZNF598 activity and stimulating formation of polysomes: deubiquitination by OTUD1 promotes stability and translation of a subset mRNAs with a high abundance of rare codons can limit the translation rate (PubMed:36445135). Deubiquitinated by USP10 (PubMed:31981475).
By IFNG/IFN-gamma during macrophage activation, and by TNF and IL1B.
Homodimer; homodimerization occurs upon GTP-binding and is required for the association with membranous structures (PubMed:21151871). Heterodimer with other family members, including GBP1, GBP3, GBP4 and GBP5 (PubMed:21151871).
Interferon (IFN)-inducible GTPase that plays important roles in innate immunity against a diverse range of bacterial, viral and protozoan pathogens (PubMed:31091448). Hydrolyzes GTP to GMP in 2 consecutive cleavage reactions, but the major reaction product is GDP (PubMed:8706832). Following infection, recruited to the pathogen-containing vacuoles or vacuole-escaped bacteria and acts as a positive regulator of inflammasome assembly by promoting the release of inflammasome ligands from bacteria (By similarity). Acts by promoting lysis of pathogen-containing vacuoles, releasing pathogens into the cytosol (By similarity). Following pathogen release in the cytosol, promotes recruitment of proteins that mediate bacterial cytolysis: this liberates ligands that are detected by inflammasomes, such as lipopolysaccharide (LPS) that activates the non-canonical CASP4/CASP11 inflammasome or double-stranded DNA (dsDNA) that activates the AIM2 inflammasome (By similarity). Confers protection to the protozoan pathogen Toxoplasma gondii (By similarity). Independently of its GTPase activity, acts as an inhibitor of various viruses infectivity, such as HIV-1, Zika and influenza A viruses, by inhibiting FURIN-mediated maturation of viral envelope proteins (PubMed:31091448).
Belongs to the amidinotransferase family.
Expressed in brain, heart, kidney, liver, lung, salivary gland and skeletal muscle tissue, with the highest expression in kidney. Biallelically expressed in placenta and fetal tissues.
Expression is elevated in the myocardium during heart failure, and decreased in inter-uterine growth restriction (IUGR)-associated placenta.
Homodimer. There is an equilibrium between the monomeric and dimeric forms, shifted towards the side of the monomer.
One chain folds into a compact single domain composed of repeating units, five beta-beta-alpha-beta modules, which surround the central active site.
Transamidinase that catalyzes the transfer of the amidino group of L-arginine onto the amino moiety of acceptor metabolites such as glycine, beta-alanine, gamma-aminobutyric acid (GABA) and taurine yielding the corresponding guanidine derivatives (PubMed:3800397, PubMed:16820567, PubMed:36543883, PubMed:27233232). Catalyzes the rate-limiting step of creatine biosynthesis, namely the transfer of the amidino group from L-arginine to glycine to generate guanidinoacetate, which is then methylated by GAMT to form creatine. Provides creatine as a source for ATP generation in tissues with high energy demands, in particular skeletal muscle, heart and brain (PubMed:3800397, PubMed:36543883, PubMed:9266688, PubMed:27233232) (Probable).
Transamidinase that catalyzes the transfer of the amidino group of L-arginine onto the amino moiety of acceptor metabolites such as glycine, beta-alanine, gamma-aminobutyric acid (GABA) and taurine yielding the corresponding guanidine derivatives. Catalyzes the rate-limiting step of creatine biosynthesis, namely the transfer of the amidino group from L-arginine to glycine to generate guanidinoacetate, which is then methylated by GAMT to form creatine. Provides creatine as a source for ATP generation in tissues with high energy demands, in particular skeletal muscle, heart and brain.
Can degrade casein. Could play a role in tissues homeostasis and repair.
Expressed at high levels in testes and lung. Low levels are detected in kidney, pancreas and skin. Also expressed in fetal lung, brain, skeletal muscle and kidney. Expressed selectively in keratinocytes. Widely expressed in several carcinomas as well. Is up-regulated in response to injury in the skin.
At the begin of fourth week of development detected in cytoplasm of somite cells. Between the sixth and eighth week of development detected in cytoplasm of limb bud cells.
Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5 (PubMed:12500905, PubMed:23435380). Tyrosine phosphatase that dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph) and promotes efficient DNA repair via the recruitment of DNA repair complexes containing MDC1. 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress (PubMed:19351884). Its function as histone phosphatase may contribute to its function in transcription regulation during organogenesis. Plays an important role in hypaxial muscle development together with SIX1 and DACH2; in this it is functionally redundant with EYA1 (PubMed:12500905).
Highest expression in muscle with lower levels in kidney, placenta, pancreas, brain and heart.
Interacts with DACH2 and SIX1, and probably with SIX2, SIX4 and SIX5. Interacts with CAPN8 (By similarity). Interacts with GNAZ and GNAI2; this precludes interaction with SIX1.
A family suffering from Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) was initially clinically diagnosed with Usher syndrome type 3 (PubMed:22938382). Reexamination of one affected member of this family revealed ataxia but not polyneuropathy, demonstrating the phenotypic heterogeneity in PHARC and the need for careful neurological assessments to distinguish this disease from other neuropathic disorders (PubMed:22938382).
Glycosylated; glycosylation is required for optimal activity.
Lysophosphatidylserine (LPS) lipase that mediates the hydrolysis of lysophosphatidylserine, a class of signaling lipids that regulates immunological and neurological processes (PubMed:25290914, PubMed:30237167, PubMed:30420694, PubMed:30720278, PubMed:30643283). Represents a major lysophosphatidylserine lipase in the brain, thereby playing a key role in the central nervous system (By similarity). Also able to hydrolyze oxidized phosphatidylserine; oxidized phosphatidylserine is produced in response to severe inflammatory stress and constitutes a proapoptotic 'eat me' signal (PubMed:30643283). Also has monoacylglycerol (MAG) lipase activity: hydrolyzes 2-arachidonoylglycerol (2-AG), thereby acting as a regulator of endocannabinoid signaling pathways (PubMed:22969151, PubMed:24027063). Has a strong preference for very-long-chain lipid substrates; substrate specificity is likely due to improved catalysis and not improved substrate binding (PubMed:30237167).
Selectively inhibited by DO264 (N-3-pyridyl-N'-(1-[3-chloro-4-{2-chloro-4-(trifluoromethoxy)phenoxy}pyridine-2-yl]piperidin-4-yl)thiourea) (PubMed:30420694, PubMed:30720278). Reversibly inhibited by triterpenoids, but with rather low potency (PubMed:24879289).
Binds calcium via the C2 domains. The calcium-bound C2 domains mediate interactions with phospholipid bilayers (By similarity).
Interacts with RAB3B, RAB3C, RAB3D, RAB8A, RAB27A and RAB27B (By similarity). Interacts with RAB3A; this interaction recruits RPH3A to synaptic vesicules (PubMed:15207266). Interacts (via C2B domain) with SNAP25 (By similarity). Interacts with deubiquitinating enzyme CAND1; this interaction results in the deubiquitination of RPH3A (By similarity). Interacts with GRIN2A and DLG4; this ternary complex regulates NMDA receptor composition at postsynaptic membranes (By similarity). Interacts with SNCA (PubMed:15207266).
Plays an essential role in docking and fusion steps of regulated exocytosis (By similarity). At the presynaptic level, RPH3A is recruited by RAB3A to the synaptic vesicle membrane in a GTP-dependent manner where it modulates synaptic vesicle trafficking and calcium-triggered neurotransmitter release (By similarity). In the post-synaptic compartment, forms a ternary complex with GRIN2A and DLG4 and regulates NMDA receptor stability. Also plays a role in the exocytosis of arginine vasopressin hormone (By similarity).
Ubiquitinated. Deubiquitinated by CAND1 to prevent its degradation.
Cytotoxin and helminthotoxin with low-efficiency ribonuclease activity. Possesses a wide variety of biological activities. Exhibits antibacterial activity, including cytoplasmic membrane depolarization of preferentially Gram-negative, but also Gram-positive strains. Promotes E.coli outer membrane detachment, alteration of the overall cell shape and partial loss of cell content.
Interacts with bacterial lipopolysaccharide (LPS) and lipoteichoic acid (LTA). In vitro interacts with and insert into lipid bilayers composed of dioleoyl phosphatidylcholine and dioleoyl phosphatidylglycerol. In vitro, tends to form amyloid-like aggregates at pH 3, but not at pH 5, nor 7.
All isoforms are expressed in umbilical vein endothelial cells, polynuclear neutrophils, fibroblasts, atrium cardiomyocytes and ventricles. Isoforms A, B and C are also expressed in placenta, lung, heart, adrenal gland and phaeochromocytoma; isoforms A and C in liver, testis and small intestine; isoform B, C and D in endothelial cells and umbilical vein smooth muscle cells; isoforms C and D in saphenous vein cells, and isoform C in kidney.
Converts big endothelin-1 to endothelin-1.
Homodimer; disulfide-linked (PubMed:18992253). Interacts with PPP1R16B (By similarity).
Inhibited by phosphoramidon (PubMed:18992253). Activated by K49-P1-20, a twenty-residue synthetic peptide shortened from the snake B.asper myotoxin II (PubMed:26931059).
Belongs to the proteasome subunit S14 family.
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD8, a base containing 6 ATPases and few additional components. Interacts with DDI2 (PubMed:29290612). Interacts with TASOR (By similarity).
Belongs to the small GTPase superfamily. RGK family.
In vitro, interacts with calmodulin in a calcium-dependent manner.
Most highly expressed in the endothelial lining of the blood vessels in uterus and heart. Lower levels found in spleen, lymph node, kidney and testis. Also found in cells with secretory function such as the islets of Langerhans, lobule/duct epithelium in the breast, bile duct epithelium in the liver, surface epithelium in the endometrial glands of the uterus, colon mucosa and acinar cells in the pancreas and the prostate.
Promotes endothelial cell sprouting and actin cytoskeletal reorganization. May be involved in angiogenesis. May function in Ca(2+) signaling.
Acetylated by a complex containing EP300 and PCAF. The acetylation is essential to activate target genes. Conversely, its deacetylation by SIRT1 inhibits its function (By similarity).
Acts as a transcriptional activator that promotes transcription of muscle-specific target genes and plays a role in muscle differentiation. Together with MYF5 and MYOG, co-occupies muscle-specific gene promoter core region during myogenesis. Induces fibroblasts to differentiate into myoblasts. Interacts with and is inhibited by the twist protein. This interaction probably involves the basic domains of both proteins (By similarity).
Efficient DNA binding requires dimerization with another bHLH protein. Seems to form active heterodimers with ITF-2. Interacts with SUV39H1. Interacts with DDX5. Interacts with CHD2. Interacts with TSC22D3 (By similarity). Interacts with SETD3 (By similarity). Interacts with P-TEFB complex; promotes the transcriptional activity of MYOD1 through its CDK9-mediated phosphorylation (By similarity) (PubMed:12037670). Interacts with CSRP3. Interacts with NUPR1 (By similarity).
Methylation at Lys-104 by EHMT2/G9a inhibits myogenic activity.
Phosphorylated by CDK9. This phosphorylation promotes its function in muscle differentiation.
Ubiquitinated on the N-terminus; which is required for proteasomal degradation.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. IRG family.
Essential component of the mitotic spindle required for normal chromosome segregation and progression into anaphase (PubMed:11724960, PubMed:12356910, PubMed:27462074). Required for chromosome alignment, normal timing of sister chromatid segregation, and maintenance of spindle pole architecture (PubMed:17664331, PubMed:27462074). In complex with SKAP, promotes stable microtubule-kinetochore attachments. May contribute to the regulation of separase activity. May regulate AURKA localization to mitotic spindle, but not to centrosomes and CCNB1 localization to both mitotic spindle and centrosomes (PubMed:18361916, PubMed:21402792). Involved in centriole duplication. Required for CDK5RAP2, CEP152, WDR62 and CEP63 centrosomal localization and promotes the centrosomal localization of CDK2 (PubMed:26297806). In non-mitotic cells, upon stress induction, inhibits mammalian target of rapamycin complex 1 (mTORC1) association and recruits the mTORC1 component RPTOR to stress granules (SGs), thereby preventing mTORC1 hyperactivation-induced apoptosis (PubMed:23953116). May enhance GSK3B-mediated phosphorylation of other substrates, such as MAPT/TAU (PubMed:18055457).
Expression is cell cycle-regulated, with an increase from prophase to cytokinesis and return to basal levels at the next G1 phase.
Highly expressed in testis. Detected at low levels in placenta, liver, pancreas, thymus and colon.
Homodimer, with a globular head domain and a long stalk. Homooligomer; the globular head domains associate, resulting in aster-like structures. Binds to microtubules in the mitotic spindle (PubMed:27462074). Interacts with DCLRE1B/Apollo. Part of an astrin (SPAG5)-kinastrin (SKAP) complex containing KNSTRN, SPAG5, PLK1, DYNLL1 and SGO2. Interacts with KNSTRN. Interacts with RPTOR; this interaction competes with RPTOR binding to MTOR, resulting in decreased mTORC1 formation. Interacts with G3BP1. The complex formed with G3BP1 AND RPTOR is increased by oxidative stress. Interacts with OSBPL8, PCM1 and CDK5RAP2 (PubMed:24424245, PubMed:26297806). Interacts (via C-terminus) with NUMA1 (via C-terminus); this interaction promotes the recruitment of SPAG5 to the microtubules at spindle poles in a dynein-dynactin-dependent manner (PubMed:27462074). Interacts with DYNLL1 (PubMed:22965910).
Highly expressed in pancreas, placenta, and fetal brain.
Plays a role in the control of the actin cytoskeleton via activation of the JNK pathway.
Activates an alternative mTOR signaling through RPS6KB2 activation and EIF4EBP1 repression to regulate cell proliferation and migration (PubMed:29750193). Recruits MTOR at the lysosome, essential for MTOR signaling at the lysosome (PubMed:29750193).
Addition of nutrients and insulin induces its expression (at protein level).
Interacts (via C-terminal domain) with MTOR and MLST8; the interaction with MTOR increases upon nutrient stimulation.
The complex LTO1:YAE1 functions as a target specific adapter that probably recruits apo-ABCE1 to the cytosolic iron-sulfur protein assembly (CIA) complex machinery (PubMed:26182403). May be required for biogenesis of the large ribosomal subunit and initiation of translation (PubMed:26182403).
Is a positive regulator of nascent focal adhesion assembly, involved in the modulation of endothelial cell attachment to the extracellular matrix.
Part of a complex composed of THSD1, PTK2/FAK1, TLN1 and VCL (PubMed:29069646). Interacts with TLN1 (PubMed:27895300, PubMed:29069646).
A chromosomal aberration involving HDAC9 is found in a family with Peters anomaly. Translocation t(1;7)(q41;p21) with TGFB2 resulting in lack of HDAC9 protein.
Broadly expressed, with highest levels in brain, heart, muscle and testis. Isoform 3 is present in human bladder carcinoma cells (at protein level).
Excluded from the nucleus. Does not interact with ETV6.
Homodimer. Interacts with CTBP1. The phosphorylated form interacts with 14-3-3 (By similarity). Interacts with HDAC1 and HDAC3, and probably with HDAC4 and HDAC5. Interacts with MEF2, MAPK10, ETV6, NCOR1 and BCL6. Interacts with FOXP3 in the absence of T-cell stimulation.
Inhibited by Trichostatin A (TSA) and suberoylanilide hydroxamic acid.
Isoform 3 lacks active site residues and therefore is catalytically inactive. Represses MEF2-dependent transcription by recruiting HDAC1 and/or HDAC3. Seems to inhibit skeletal myogenesis and to be involved in heart development. Protects neurons from apoptosis, both by inhibiting JUN phosphorylation by MAPK10 and by repressing JUN transcription via HDAC1 recruitment to JUN promoter.
Major form in most tissues. Inactive due to lack of active site residues.
Phosphorylated on Ser-220 and Ser-450; which promotes 14-3-3-binding, impairs interaction with MEF2, and antagonizes antimyogenic activity. Phosphorylated on Ser-240; which impairs nuclear accumulation (By similarity). Isoform 7 is phosphorylated on Tyr-1010. Phosphorylated by the PKC kinases PKN1 and PKN2, impairing nuclear import.
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Represses MEF2-dependent transcription.
Belongs to the sterol desaturase family. TMEM195 subfamily.
Glyceryl-ether monooxygenase that cleaves the O-alkyl bond of ether lipids. Ether lipids are essential components of brain membranes.
Activity is inhibited by binding to OTUB1, which prevents 'Lys-63'-linked polyubiquitination (PubMed:20725033, PubMed:22325355, PubMed:22367539). Activity is inhibited by GPS2, leading to prevent 'Lys-63'-linked polyubiquitination (By similarity).
Conjugation to ISG15 impairs formation of the thioester bond with ubiquitin but not interaction with UBE2V2.
Heterodimer with UBE2V2 (PubMed:10089880, PubMed:11473255, PubMed:14562038, PubMed:16307917, PubMed:16307917). Interacts (UBE2V2-UBE2N heterodimer) with the E3 ligase STUB1 (via the U-box domain); the complex has a specific 'Lys-63'-linked polyubiquitination activity (PubMed:16307917). Interacts with RNF8 and RNF168 (PubMed:16215985, PubMed:19203578). Interacts with RNF11 (PubMed:18615712). Interacts with the E3 ligases, HLTF and SHPRH; the interactions promote the 'Lys-63'-linked polyubiquitination of PCNA upon genotoxic stress and lead to DNA repair (PubMed:17108083, PubMed:17130289, PubMed:18316726, PubMed:18719106). Interacts with ARIH2 (via RING-type 2) (PubMed:19340006). Interacts with OTUB1; leading to inhibit E2-conjugating activity (PubMed:20725033, PubMed:22325355, PubMed:22367539). Interacts with GPS2; leading to inhibit E2-conjugating activity (By similarity). Interacts with RIGI and RNF135; involved in RIGI ubiquitination and activation (PubMed:28469175). Interacts with ZNRF1 (PubMed:29626159).
The UBE2V1-UBE2N and UBE2V2-UBE2N heterodimers catalyze the synthesis of non-canonical 'Lys-63'-linked polyubiquitin chains. This type of polyubiquitination does not lead to protein degradation by the proteasome. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Acts together with the E3 ligases, HLTF and SHPRH, in the 'Lys-63'-linked poly-ubiquitination of PCNA upon genotoxic stress, which is required for DNA repair. Appears to act together with E3 ligase RNF5 in the 'Lys-63'-linked polyubiquitination of JKAMP thereby regulating JKAMP function by decreasing its association with components of the proteasome and ERAD. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes. Together with RNF135 and UB2V1, catalyzes the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIGI to activate the downstream signaling pathway that leads to interferon beta production (PubMed:28469175, PubMed:31006531). UBE2V1-UBE2N together with TRAF3IP2 E3 ubiquitin ligase mediate 'Lys-63'-linked polyubiquitination of TRAF6, a component of IL17A-mediated signaling pathway.
Belongs to the potassium channel family. G (TC 1.A.1.2) subfamily. Kv6.4/KCNG4 sub-subfamily.
Heterotetramer with KCNB1 (PubMed:19074135).
Highly expressed in brain, and at lower levels in liver, small intestine and colon.
Potassium channel subunit that does not form functional channels by itself. Can form functional heterotetrameric channels with KCNB1; modulates the delayed rectifier voltage-gated potassium channel activation and deactivation rates of KCNB1 (PubMed:19074135).
ATP:ADP antiporter that catalyzes the exchange of ATP and ADP across the endoplasmic reticulum (ER) membrane. Imports ATP from the cytosol to the ER lumen and exports ADP in the opposite direction (PubMed:30154480, PubMed:35041824). Regulates ER energy metabolism and protein biogenesis. Appears to be part of a calcium-dependent ER to cytosol low energy response axis, where calcium efflux from ER to the cytosol triggers ATP import into the ER lumen to maintain sufficient ATP supply. Provides ATP to ER chaperone HSPA5 that drives protein folding and trafficking in the ER (PubMed:30154480, PubMed:35041824). Can transport dATP, UTP or UDP in exchange for ATP, but the physiological relevance of this process remains to be established (PubMed:30154480, PubMed:35041824).
Belongs to the nucleotide-sugar transporter family. SLC35B subfamily.
The di-lysine motif confers endoplasmic reticulum localization for type I membrane proteins.
Has a role in alternative splicing and transcription regulation (PubMed:29522154). Involved in both constitutive and alternative pre-mRNA splicing. May have a role in the recognition of the 3' splice site during the second step of splicing.
Interacts (via Arg/Ser-rich domain) with LUC7L3, RBM39 and RSF1.
Widely expressed. Expressed in brain, spinal cord, cerebellum.
Orphan receptor. May regulate nociceptor function and/or development, including the sensation or modulation of pain (By similarity).
Component of the TSC-TBC complex (also named Rhebulator complex), composed of 2 molecules of TSC1, 2 molecules of TSC2 and 1 molecule of TBC1D7 (PubMed:9809973, PubMed:9580671, PubMed:10585443, PubMed:12172553, PubMed:12906785, PubMed:16464865, PubMed:17658474, PubMed:28215400, PubMed:15963462, PubMed:22795129, PubMed:24529379, PubMed:26893383, PubMed:33436626). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex (PubMed:29127155). Interacts (via C-terminus) with the closed form of HSP90AA1 (via the middle domain and TPR repeat-binding motif) (PubMed:29127155). Interacts with DOCK7 (PubMed:15963462). Interacts with FBXW5 (PubMed:18381890). Interacts with WDR45B (PubMed:28561066). Interacts with RPAP3 and URI1 (PubMed:28561026).
Highly expressed in skeletal muscle, followed by heart, brain, placenta, pancreas, lung, liver and kidney (PubMed:9242607). Also expressed in embryonic kidney cells (PubMed:9242607).
Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth (PubMed:12172553, PubMed:12906785, PubMed:12271141, PubMed:28215400, PubMed:15340059, PubMed:24529379). The TSC-TBC complex acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 (PubMed:12906785, PubMed:15340059, PubMed:24529379). In absence of nutrients, the TSC-TBC complex inhibits mTORC1, thereby preventing phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) by the mTORC1 signaling (PubMed:12271141, PubMed:24529379, PubMed:28215400). The TSC-TBC complex is inactivated in response to nutrients, relieving inhibition of mTORC1 (PubMed:12172553, PubMed:24529379). Within the TSC-TBC complex, TSC1 stabilizes TSC2 and prevents TSC2 self-aggregation (PubMed:10585443, PubMed:28215400). Acts as a tumor suppressor (PubMed:9242607). Involved in microtubule-mediated protein transport via its ability to regulate mTORC1 signaling (By similarity). Also acts as a co-chaperone for HSP90AA1 facilitating HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1 (PubMed:29127155). Increases ATP binding to HSP90AA1 and inhibits HSP90AA1 ATPase activity (PubMed:29127155). Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (PubMed:29127155). Recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and ubiquitin ligase HERC1 (PubMed:16464865, PubMed:29127155).
Phosphorylation at Ser-505 does not affect interaction with TSC2.
The C-terminal putative coiled-coil domain is necessary for interaction with TSC2.
Binds to nucleoporins and the GTP-bound form of Ran.
Highly expressed in testis, moderately in pancreas and weakly in other tissues studied.
May function as a nuclear transport receptor.
(Microbial infection) Acts as a transcriptional repressor of different viruses including influenza virus or papillomavirus. During influenza virus infection, the viral polymerase complex localizes CHD6 to inactive chromatin where it gets degraded in a proteasome independent-manner.
(Microbial infection) Interacts (via N-terminus) with human papillomavirus protein E8^E2C (via C-terminus); this interaction induces transcriptional repression of the viral genome.
(Microbial infection) Interacts with the influenza A polymerase complex composed fo PB1, PB2 and PA.
A chromosomal aberration disrupting CHD6 has been found in a patient with mild to moderate intellectual disability and minor facial anomalies. Translocation t(18;20)(q21.1;q11.2) with TCF4 producing a CHD6-TCF4 fusion transcript (PubMed:18627065).
DNA-dependent ATPase that plays a role in chromatin remodeling. Regulates transcription by disrupting nucleosomes in a largely non-sliding manner which strongly increases the accessibility of chromatin (PubMed:28533432). Activates transcription of specific genes in response to oxidative stress through interaction with NFE2L2.
Interacts with NFE2L2; involved in activation of the transcription.
The sequence differs from position 1528 onward for unknown reasons.
Belongs to the Mediator complex subunit 22 family.
Expression in hepatocytes is induced by LPS stimulus and the induction is mediated by IL6 (PubMed:15124018). Expression is inhibited in presence of TNF (PubMed:15124018).
Has strong antimicrobial activity against E.coli ML35P N.cinerea and weaker against S.epidermidis, S.aureus and group b streptococcus bacteria. Active against the fungus C.albicans. No activity against P.aeruginosa (PubMed:11113131, PubMed:11034317).
Highest expression in liver and to a lesser extent in heart and brain. Low levels in lung, tonsils, salivary gland, trachea, prostate gland, adrenal gland and thyroid gland. Secreted into the urine and blood (PubMed:11034317). Expressed by hepatocytes (PubMed:15124018).
Interacts with SLC40A1; this interaction promotes SLC40A1 rapid ubiquitination.
Liver-produced hormone that constitutes the main circulating regulator of iron absorption and distribution across tissues. Acts by promoting endocytosis and degradation of ferroportin/SLC40A1, leading to the retention of iron in iron-exporting cells and decreased flow of iron into plasma (PubMed:22682227, PubMed:29237594, PubMed:32814342). Controls the major flows of iron into plasma: absorption of dietary iron in the intestine, recycling of iron by macrophages, which phagocytose old erythrocytes and other cells, and mobilization of stored iron from hepatocytes (PubMed:22306005).
Activated by nitric oxide in the presence of magnesium or manganese ions.
Has guanylyl cyclase on binding to the beta-1 subunit.
Heterodimer of an alpha and a beta chain.
Isoform 1 is expressed in fetal brain, liver, colon, endothelium and testis. Isoform 2 is expressed only in liver, colon and endothelium.
Isoform 2 acts as a negative regulator of guanylyl cyclase activity as it forms non-functional heterodimers with the beta subunits.
There are two types of guanylate cyclases: soluble forms and membrane-associated receptor forms.
Expressed in many tumors of several types, such as melanoma, head and neck squamous cell carcinoma, lung carcinoma and breast carcinoma, but not in normal tissues except for testes. Never expressed in kidney tumors, leukemias and lymphomas.
May be involved in transcriptional regulation through interaction with SNW1 and recruiting histone deactelyase HDAC1. May inhibit notch intracellular domain (NICD) transactivation. May play a role in embryonal development and tumor transformation or aspects of tumor progression. Antigen recognized on a melanoma by autologous cytolytic T-lymphocytes.
Expressed in liver, colon and small intestine.
Heterodimer with RXR. Interacts with NCOA1. Interacts (via domain NR LBD) with CRY1 and CRY2 in a ligand-dependent manner (By similarity).
Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.
Belongs to the receptors of complement activation (RCA) family.
Expressed in fetal liver and to a lesser extent in fetal spleen and thymus. Expression appears to be limited to hematopoietic and fetal lymphoid tissue.
Interacts with iC4 (methylamine-treated C4) but not for iC3 (methylamine-treated C3).
Abundantly expressed in heart, pancreas, prostate, kidney, small intestine and peripheral blood leukocytes. Less abundant in placenta, lung, spleen, colon, thymus, testis and ovaries.
Belongs to the potassium channel family. KQT (TC 1.A.1.15) subfamily. Kv7.1/KCNQ1 sub-subfamily.
Deubiquitinated by USP2; counteracts the NEDD4L-specific down-regulation of I(Ks) and restores the membrane localization.
Mutagenesis experiments were carried out by expressing in Xenopus oocytes or COS-7 cells KCNQ1 mutants either individually (homomultimers) or in combination with both wild-type KCNQ1 (mut/wt homomultimers) and minK (heteromultimers).
Non-functional alone but modulatory when coexpressed with the full-length isoform 1.
Phosphorylation at Ser-27 by PKA; increases delayed rectifier potassium channel activity of the KCNQ1-KCNE1 complex through a macromolecular complex that includes PKA, PP1, and the targeting protein AKAP9.
Potassium channel that plays an important role in a number of tissues, including heart, inner ear, stomach and colon (PubMed:10646604, PubMed:25441029). Associates with KCNE beta subunits that modulates current kinetics (PubMed:9312006, PubMed:9108097, PubMed:8900283, PubMed:10646604, PubMed:11101505, PubMed:19687231). Induces a voltage-dependent current by rapidly activating and slowly deactivating potassium-selective outward current (PubMed:9312006, PubMed:9108097, PubMed:8900283, PubMed:10646604, PubMed:11101505, PubMed:25441029). Promotes also a delayed voltage activated potassium current showing outward rectification characteristic (By similarity). During beta-adrenergic receptor stimulation participates in cardiac repolarization by associating with KCNE1 to form the I(Ks) cardiac potassium current that increases the amplitude and slows down the activation kinetics of outward potassium current I(Ks) (By similarity) (PubMed:9312006, PubMed:9108097, PubMed:8900283, PubMed:10646604, PubMed:11101505). Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current (PubMed:10713961). When associated with KCNE3, forms the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions (PubMed:10646604). This interaction with KCNE3 is reduced by 17beta-estradiol, resulting in the reduction of currents (By similarity). During conditions of increased substrate load, maintains the driving force for proximal tubular and intestinal sodium ions absorption, gastric acid secretion, and cAMP-induced jejunal chloride ions secretion (By similarity). Allows the provision of potassium ions to the luminal membrane of the secretory canaliculus in the resting state as well as during stimulated acid secretion (By similarity). When associated with KCNE2, forms a heterooligomer complex leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current (PubMed:11101505). When associated with KCNE4, inhibits voltage-gated potassium channel activity (PubMed:19687231). When associated with KCNE5, this complex only conducts current upon strong and continued depolarization (PubMed:12324418). Also forms a heterotetramer with KCNQ5; has a voltage-gated potassium channel activity (PubMed:24855057). Binds with phosphatidylinositol 4,5-bisphosphate (PubMed:25037568). KCNQ1-KCNE2 channel associates with Na(+)-coupled myo-inositol symporter in the apical membrane of choroid plexus epithelium and regulates the myo-inositol gradient between blood and cerebrospinal fluid with an impact on neuron excitability.
Tetramer (PubMed:18165683, PubMed:19693805, PubMed:25441029). Heterotetramer with KCNE1; targets to the membrane raft (PubMed:25037568, PubMed:19693805, PubMed:20533308). Interacts (via C-terminus) with CALM; forms a heterooctameric structure (with 4:4 KCNQ1:CALM stoichiometry) in a calcium-independent manner (PubMed:18165683, PubMed:25441029). Interacts with AKAP9; targets protein kinase A (PKA) catalytic and regulatory subunits and protein phosphatase 1 (PP1) to the KCNQ1-KCNE1 complex, allowing PKA-mediated phosphorylation and increase of delayed rectifier potassium channel activity (PubMed:11799244, PubMed:25037568). Interacts with KCNE2; forms a heterooligomer complex that targets to the membrane raft and leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current (PubMed:11101505, PubMed:20533308). Interacts with AP2M1; mediates estrogen-induced internalization via clathrin-coated vesicles (PubMed:23529131). Interacts with NEDD4L; promotes internalization and decreases I(Ks) currents (PubMed:23529131, PubMed:22024150). Interacts with USP2; counteracts the NEDD4L-specific down-regulation of I(Ks) and restore plasma membrane localization (PubMed:22024150). Heterotetramer with KCNQ5; has a voltage-gated potassium channel activity (PubMed:24855057). Interacts with KCNE3; alters membrane raft localization (PubMed:20533308). Interacts with KCNE4; impairs KCNQ1 localization in lipid rafts and inhibits voltage-gated potassium channel activity (PubMed:19687231, PubMed:20533308). Interacts with KCNE5; impairs KCNQ1 localization in lipid rafts and only conducts current upon strong and continued depolarization (PubMed:20533308, PubMed:12324418). Interacts with SLC5A3; forms coregulatory channel-transporter complexes that modulate Na(+)-coupled myo-inositol influx through the transporter.
The C-terminal assembly domain promotes self-interactiona; allows functional channel.
The C-terminal coiled-coil domain interacts with a single CALM molecule via the first two membrane-proximal helical regions, with CALM forming a clamp-like structure. Binding of CALM C-terminus to the first helical region is calcium-independent but is essential for assembly of the structure. Binding of CALM N-terminus to the second helical region is calcium-dependent and regulates electrophysiological activity of the channel.
The coiled-coil domain mediates tetramerization.
The segment S6 is involved in the inhibition of voltage-gated potassium channel activity by KCNE4.
Ubiquitinated by NEDD4L; promotes internalization (PubMed:22024150). The ubiquitinylated form is internalized through a clathrin-mediated endocytosis by interacting with AP2M1 and is recycled back to the cell membrane via RAB4A and RAB11A (PubMed:23529131).
Predominantly catalyzes the biosynthesis of ganglioside GD1alpha from GM1b in the brain, by transferring the sialyl group (N-acetyl-alpha-neuraminyl or NeuAc) from CMP-NeuAc to the GalNAc residue on the NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc sequence of GM1b (PubMed:12668675). GD1alpha is a critical molecule in the communication and interaction between neuronal cells and their supportive cells, particularly in brain tissues, and functions as an adhesion molecule in the process of metastasis (By similarity). Also shows activity towards sialyl Lc4Cer (N-acetyl-alpha-neuraminosyl-(2->3)-beta-D-galactosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->3)-beta-D-galactosyl-(1->4)-beta-D-glucosyl-(1<->1')-N-acyl-sphing-4-enine) generating disialyl Lc4Cer, which can lead to the synthesis of disialyl Lewis a (Le(a)), suggested to be a cancer-associated antigen (PubMed:12668675).
Belongs to the CRF-binding protein family.
Binds CRF and inactivates it. May prevent inappropriate pituitary-adrenal stimulation in pregnancy.
Acts as a regulator of the electron transfer flavoprotein by promoting the removal of flavin from the ETF holoenzyme (composed of ETFA and ETFB).
homotetramer (Probable). Interacts with NDUFAB1 (PubMed:27499296). Interacts with ETFA (PubMed:27499296). Interacts with ETFB (PubMed:27499296).
'Ajuba' means 'curiosity' in Urdu, an Indian dialect.
Adapter or scaffold protein which participates in the assembly of numerous protein complexes and is involved in several cellular processes such as cell fate determination, cytoskeletal organization, repression of gene transcription, mitosis, cell-cell adhesion, cell differentiation, proliferation and migration. Contributes to the linking and/or strengthening of epithelia cell-cell junctions in part by linking adhesive receptors to the actin cytoskeleton. May be involved in signal transduction from cell adhesion sites to the nucleus. Plays an important role in regulation of the kinase activity of AURKA for mitotic commitment. Also a component of the IL-1 signaling pathway modulating IL-1-induced NFKB1 activation by influencing the assembly and activity of the PRKCZ-SQSTM1-TRAF6 multiprotein signaling complex. Functions as an HDAC-dependent corepressor for a subset of GFI1 target genes. Acts as a transcriptional corepressor for SNAI1 and SNAI2/SLUG-dependent repression of E-cadherin transcription. Acts as a hypoxic regulator by bridging an association between the prolyl hydroxylases and VHL enabling efficient degradation of HIF1A. Positively regulates microRNA (miRNA)-mediated gene silencing. Negatively regulates the Hippo signaling pathway and antagonizes phosphorylation of YAP1.
Interacts with GRB2, PIP5K1B and SLC1A2 (By similarity). Interacts with AURKA; the interaction occurs during mitosis and both proteins are phosphorylated as they form a complex. Interacts with CTNNA1 and with F-actin. Interacts with LATS2; the interaction occurs during mitosis and the complex regulates organization of the spindle apparatus through recruitment of TUBG to the centrosome. Forms a complex with SQSTM1, PRKCZ and TRAF6. Component of the GFI1-AJUBA-HDAC1 repressor complex. Interacts directly (via the LIM domains) with GFI1; the interaction results in the HDAC-dependent corepression of a subset of GFI1 target genes, and is independent of the GFI1 SNAG domain. Interacts with HDAC1, HDAC2 and HDAC3. Interacts with SNAI2/SLUG (via SNAG domain) and SCRT1 (via SNAG domain) (By similarity). Interacts with EIF4E, AGO1, AGO2, DCP2, DDX6, LATS1, LATS2, SAV1, EGLN2/PHD1 and EGLN3/PHD3. Interacts (via LIM domains) with isoform 1 and isoform 3 of VHL. Interacts (via LIM domains) with SNAI1 (via SNAG domain).
LIM region interacts with CTNNA1. The preLIM region binds directly actin filaments.
LIM-2 and LIM-3 domains mediate the interaction with the N-terminal region of AURKA. The association between LATS2 and AJUBA required the second LIM domain of AJUBA.
Phosphorylated by LATS2 during mitosis. Phosphorylated by AURKA.
Aminooxyacetic acid (AOAA) blocks its activity in both cytoplasm and mitochondria.
By methamphetamine in brain, via dopamine receptor activation (at protein level).
Catalyzes the synthesis of N-acetylaspartate acid (NAA) from L-aspartate and acetyl-CoA (PubMed:19524112, PubMed:19807691, PubMed:20385109). Promotes dopamine uptake by regulating TNF-alpha expression (By similarity). Attenuates methamphetamine-induced inhibition of dopamine uptake (PubMed:20385109).
Expressed in multiple tissues but is absent in brain, lymphoid cells, and platelets.
Interacts with EIF2AK2. Associates with microtubules; it is unsure whether such interaction is direct or indirect.
Involved in spermatogenesis and sperm function. Plays a role in regulation of cell growth. Binds to double-stranded DNA and RNA. Binds most efficiently to poly(I:C) RNA than to poly(dI:dC) DNA. Binds also to single-stranded poly(G) RNA. Binds non-specifically to the mRNA PRM1 3'-UTR and adenovirus VA RNA (By similarity).
Adapter protein, which negatively regulates T-cell receptor (TCR) signaling. Inhibits T-cell antigen-receptor induced activation of nuclear factor of activated T-cells. May act by linking signaling proteins such as ZAP70 with CBL, leading to a CBL dependent degradation of signaling proteins.
Interacts (via SH2 domain) with ZAP70 (phosphorylated) and CD3Z (phosphorylated). Interacts (via SH2 domain) with CSF1R (phosphorylated) (By similarity). Interacts (via its C-terminal domain) with CBL (phosphorylated).
Predominantly expressed in immune system, with highest levels in peripheral blood leukocytes. Expressed in spleen, thymus and lymph nodes. Expressed in T-cells as well as in monocytes, and at low level in B-cells. Also detected in placenta, prostate, skin, retina and colon.
Produced by alternative initiation at Met-28 of isoform 1.
Produced by alternative initiation at Met-28 of isoform 2.
The loss of the C-terminal domain partially abolishes the inhibitory function, but can be partially compensated by higher level of protein expression.
Acts as a molecular chaperone for PCSK2/PC2, preventing its premature activation in the regulated secretory pathway. Binds to inactive PCSK2 in the endoplasmic reticulum and facilitates its transport from there to later compartments of the secretory pathway where it is proteolytically matured and activated. Also required for cleavage of PCSK2 but does not appear to be involved in its folding. Plays a role in regulating pituitary hormone secretion. The C-terminal peptide inhibits PCSK2 in vitro.
Interacts with PCSK2/PC2 early in the secretory pathway. Dissociation occurs at later stages.
Proteolytically cleaved in the Golgi by a furin-like convertase to generate bioactive peptides.
Activity is strongly inhibited by galotannin. Inhibited by P1-(adenosine-5')-P4-(nicotinic-acid-riboside-5')-tetraphosphate (Nap4AD).
Belongs to the eukaryotic NMN adenylyltransferase family.
Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP (PubMed:17402747). Can also use the deamidated form; nicotinic acid mononucleotide (NaMN) as substrate with the same efficiency (PubMed:17402747). Can use triazofurin monophosphate (TrMP) as substrate (PubMed:17402747). Also catalyzes the reverse reaction, i.e. the pyrophosphorolytic cleavage of NAD(+) (PubMed:17402747). For the pyrophosphorolytic activity, prefers NAD(+) and NaAD as substrates and degrades NADH, nicotinic acid adenine dinucleotide phosphate (NHD) and nicotinamide guanine dinucleotide (NGD) less effectively (PubMed:17402747). Involved in the synthesis of ATP in the nucleus, together with PARP1, PARG and NUDT5 (PubMed:27257257). Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming (PubMed:27257257). Also acts as a cofactor for glutamate and aspartate ADP-ribosylation by directing PARP1 catalytic activity to glutamate and aspartate residues on histones (By similarity). Fails to cleave phosphorylated dinucleotides NADP(+), NADPH and NaADP(+) (PubMed:17402747). Protects against axonal degeneration following mechanical or toxic insults (By similarity).
Divalent metal cations. Zn(2+) confers higher activity as compared to Mg(2+).
Homohexamer (PubMed:11751893). Interacts with ADPRT/PARP1 (PubMed:11248244).
Widely expressed with highest levels in skeletal muscle, heart and kidney. Also expressed in the liver pancreas and placenta. Widely expressed throughout the brain.
Expressed in midpiece of spermatozoon (at protein level) (PubMed:27572937). Most abundant in testis and spleen (PubMed:16844083). Highly expressed in CD4 and CD8-positive T-cells as well as CD19-positive B-cells (PubMed:16844083).
Receptor for endocannabinoid N-arachidonyl glycine (NAGly) (PubMed:16844083, PubMed:24762058, PubMed:27572937). However, conflicting results about the role of NAGly as an agonist are reported (PubMed:27018161). Can also be activated by plant-derived and synthetic cannabinoid agonists (PubMed:24762058). The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase (PubMed:16844083). May contribute to regulation of the immune system. Is required for normal homeostasis of CD8+ subsets of intraepithelial lymphocytes (IELs) (CD8alphaalpha and CD8alphabeta IELs)in small intstine by supporting preferential migration of CD8alphaalpha T-cells to intraepithelial compartment over lamina propria compartment, and by mediating their reconstitution into small intestine after bone marrow transplant (By similarity). Plays a role in hypotensive responses, mediating reduction in intraocular and blood pressure (By similarity). Mediates NAGly-induced process of reorganization of actin filaments and induction of acrosomal exocytosis (PubMed:27572937).
Expressed at high level in the testis. Detected also in the pancreas, heart and in the brain.
The BTB/POZ domain seems to direct the protein to discrete regions in the nucleus.
Transcriptional activator of the dopamine transporter (DAT), binding it's promoter at the consensus sequence 5'-CCTGCACAGTTCACGGA-3'. Binds to 5'-d(GCC)(n)-3' trinucleotide repeats in promoter regions and acts as a repressor of the FMR1 gene. Transcriptional repressor of MYC and thymidine kinase promoters.
(Microbial infection) Interacts (via MSP domain) with hepatitis C virus (HCV) non-structural protein 5A (via disordered domain D3) (PubMed:16227268, PubMed:22720086). Interacts with HCV RNA-directed RNA polymerase (PubMed:16227268).
Belongs to the VAMP-associated protein (VAP) (TC 9.B.17) family.
Endoplasmic reticulum-anchored protein that mediates the formation of contact sites between the endoplasmic (ER) and late endosomes via interaction with STARD3 in a FFAT motif phosphorylation dependent manner (PubMed:33124732). Participates in the endoplasmic reticulum unfolded protein response (UPR) by inducing ERN1/IRE1 activity (PubMed:16891305, PubMed:20940299). Involved in cellular calcium homeostasis regulation (PubMed:22131369).
Homodimer, and heterodimer with VAPA (PubMed:20940299). Interacts with VAMP1 and VAMP2 (PubMed:9920726, PubMed:20940299). Interacts (via MSP domain) with ZFYVE27 (PubMed:21976701, PubMed:19289470). Interacts with RMDN3 (PubMed:22131369). Interacts with KIF5A in a ZFYVE27-dependent manner (PubMed:21976701). Interacts (via MSP domain) with STARD3 (via phospho-FFAT motif) (PubMed:24105263, PubMed:33124732). Interacts with STARD3NL (via FFAT motif) (PubMed:24105263). Interacts with CERT1 (PubMed:16895911). Interacts with PLEKHA3 and SACM1L to form a ternary complex (PubMed:30659099). Interacts with VPS13A (via FFAT motif) (PubMed:30741634). Interacts with RB1CC1 (via phosphorylated FFAT motif), MIGA2 (via phosphorylated FFAT motif), RMDN3 (via phosphorylated FFAT motif), OSBPL1A (via FFAT motif), KCNB1 (via phosphorylated FFAT motif) and KCNB2 (via phosphorylated FFAT motif) (PubMed:33124732).
Belongs to the potassium channel family. F (TC 1.A.1.2) subfamily. Kv5.1/KCNF1 sub-subfamily.
Detected in heart, brain, liver, skeletal muscle, kidney and pancreas.
Heteromultimer with KCNG3, KCNG4 and KCNV2. Interacts with DLG1.
Putative voltage-gated potassium channel.
Component of the shieldin complex, consisting of SHLD1, SHLD2, SHLD3 and MAD2L2/REV7 (PubMed:29656893, PubMed:29789392). Within the complex, SHLD2 forms a scaffold which interacts with a SHLD3-MAD2L2 subcomplex via its N-terminus, and with SHLD1 via its C-terminus (PubMed:29656893). Interacts with TP53BP1 (PubMed:29789392). Interacts with RIF1 (PubMed:29789392).
Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs) (PubMed:29656893, PubMed:29789392). During G1 and S phase of the cell cycle, the complex functions downstream of TP53BP1 to promote non-homologous end joining (NHEJ) and suppress DNA end resection (PubMed:29656893, PubMed:29789392). Mediates various NHEJ-dependent processes including immunoglobulin class-switch recombination, and fusion of unprotected telomeres (PubMed:29656893).
In BRCA1-deficient cells, function of the shieldin complex is necessary for sensitivity to camptothecin and the PARP inhibitor olaparib.
Core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (PubMed:11991638, PubMed:10025403, PubMed:19325628, PubMed:21516107, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Most spliceosomal snRNPs contain a common set of Sm proteins, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (PubMed:10025403, PubMed:19325628, PubMed:21516107, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Component of the U1 snRNP (PubMed:19325628, PubMed:25555158). The U1 snRNP is composed of the U1 snRNA and the 7 core Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG, and at least three U1 snRNP-specific proteins SNRNP70/U1-70K, SNRPA/U1-A and SNRPC/U1-C (PubMed:19325628, PubMed:25555158). Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39, plus LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 (PubMed:26912367). Component of the U7 snRNP complex, or U7 Sm protein core complex, that is composed of the U7 snRNA and at least LSM10, LSM11, SNRPB, SNRPD3, SNRPE, SNRPF and SNRPG; the complex does not contain SNRPD1 and SNRPD2 (PubMed:11574479, PubMed:12975319). Component of the minor spliceosome, which splices U12-type introns (PubMed:15146077, PubMed:33509932). Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG; catalyzes core snRNPs assembly (PubMed:12095920, PubMed:18984161, PubMed:16314521). Forms a 6S pICln-Sm complex composed of CLNS1A/pICln, SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG; ring-like structure where CLNS1A/pICln mimics additional Sm proteins and which is unable to assemble into the core snRNP (PubMed:18984161). Identified in a histone pre-mRNA complex, at least composed of ERI1, LSM11, SLBP, SNRPB, SYNCRIP and YBX1 (By similarity). Interacts with TDRD3 and SNUPN (PubMed:12095920, PubMed:15955813). Interacts with PRMT5; interaction leads to its symmetric arginine dimethylation (By similarity). Interacts with TDRD6; interaction promotes association with PRMT5 (By similarity). Interacts with SMN1; the interaction is direct (PubMed:10500148).
Methylated by PRMT5 (By similarity). Arg-108 and Arg-112 are dimethylated, probably to asymmetric dimethylarginine (PubMed:16087681, Ref.10).
Patients with the autoimmune disease systemic lupus erythematosus (SLE) have autoantibodies directed against some of the individual snRNP polypeptides. The most common autoantigen is called Sm. B/b' bear Sm epitopes.
Plays a role in pre-mRNA splicing as a core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (PubMed:11991638, PubMed:18984161, PubMed:19325628, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Component of both the pre-catalytic spliceosome B complex and activated spliceosome C complexes (PubMed:11991638, PubMed:28502770, PubMed:28781166, PubMed:28076346). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (PubMed:15146077). As part of the U7 snRNP it is involved in histone pre-mRNA 3'-end processing (PubMed:12975319).
Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease (By similarity).
Can be proteolytically processed by a furin-like protease.
Expressed in cerebellum, T-cells, esophagus and lung.
The C-terminal cysteine-rich domain mediates interaction with LRP5 and LRP6.
(Microbial infection) Interacts with Epstein-Barr virus EBNA1; this interaction allows the nuclear import of EBNA1.
(Microbial infection) Interacts with HIV-1 Vpr.
(Microbial infection) Interacts with SARS-COV virus ORF6 protein; this interaction blocks the receptor-mediated transport through the nuclear pore.
(Microbial infection) Interacts with SARS-CoV-2 ORF6 protein; this interaction may inhibit IFN-beta production by blocking IRF3 nuclear translocation.
(Microbial infection) Interacts with Zika virus RNA-directed RNA polymerase NS5.
(Microbial infection) Part of a tetrameric complex composed of CRM1, importin alpha/beta dimer and the Venezuelan equine encephalitis virus (VEEV) capsid; this complex blocks the receptor-mediated transport through the nuclear pore.
Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus.
Heterodimer; with KPNB1 (PubMed:17596301). Interacts with ANP32E (By similarity). Component of a complex containing CSE1L, RAN and KPNA2. Interacts directly with CSE1L. Interacts with PLAG1. Interacts with APEX1 (via N-terminus). Interacts with FRG1 (via N-terminus). Interacts with ARL4A, CTNNBL1 and NBN. Interacts with SNAI1 (via zinc fingers) and SNAI2 (via zinc fingers). Interacts with BAG6 (PubMed:29042515). Interacts with AIFM2; this interaction likely mediates the translocation of AIFM2 into the nucleus upon oxidative stress. Interacts with RSL1D1 (PubMed:36647821).
Belongs to the cyclic nucleotide phosphodiesterase family. PDE1 subfamily.
Binds 2 divalent metal cations per subunit. Site 2 has a preference for magnesium ions.
Cyclic nucleotide phosphodiesterase with a dual specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes (PubMed:8855339, PubMed:9419816, PubMed:15260978). Has a preference for cGMP as a substrate (PubMed:9419816).
Type I PDE are activated by the binding of calmodulin in the presence of Ca(2+).
(Microbial infection) Interacts with HIV-1 Vpu.
(Microbial infection) Interacts with vaccinia virus A49; this interaction inhibits NF-kappa-B activation.
Homodimer. Self-associates. Component of the SCF(BTRC) complex formed of CUL1, SKP1, RBX1 and a BTRC dimer (PubMed:10066435, PubMed:9990852, PubMed:22017875, PubMed:22017876, PubMed:22017877, PubMed:36608670). Direct interaction with SKP1 occurs via the F-box domain. Interacts with phosphorylated ubiquitination substrates SMAD3 and SMAD4. Interacts with phosphorylated ubiquitination substrates CTNNB1, NFKBIA, NFKBIB, NFKBIE, NFKB1/nuclear factor NF-kappa-B p105 subunit, ATF4, CDC25A, DLG1, FBXO5 and SNAI1; the interaction requires the phosphorylation of the 2 serine residues in the substrate destruction motif D-S-G-X(2,3,4)-S. Binds UBQLN1. Interacts with CDC34 and UBE2R2. Interacts with FBXW11. Interacts with CUL4A and DDB1. Part of a SCF(BTRC)-like complex lacking CUL1, which is associated with phosphorylated NKBIA and RELA; RELA interacts directly with NFKBIA. Interacts with the phosphorylated form of GLI3. Interacts with CLU. Interacts with PER1 (phosphorylated), PER2 (phosphorylated) and PER3. Interacts with phosphorylated ubiquitination substrate CEP68 (PubMed:25704143, PubMed:25503564). Interacts with ZC3H12A; this interaction occurs when ZC3H12A is phosphorylated in a IKBKB/IKKB-dependent manner (By similarity). Interacts with HSF1; this interaction occurs during mitosis and induces HSF1 ubiquitin-dependent degradation, a process inhibited by CDC20 (PubMed:18794143). Interacts with NFE2L1 (By similarity). Interacts with INAVA (PubMed:29420262). Interacts with IL10RA; this interaction leads to IL10RA ubiquitination and subsequent degradation (PubMed:22087322). Interacts with REST (PubMed:18354482). Interacts with KLF4; this interaction leads to KLF4 ubiquitination and subsequent degradation (By similarity).
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:10066435, PubMed:10497169, PubMed:9990852, PubMed:10644755, PubMed:10835356, PubMed:11238952, PubMed:11359933, PubMed:11158290, PubMed:11994270, PubMed:12791267, PubMed:12902344, PubMed:14603323, PubMed:14681206, PubMed:14988407, PubMed:15448698, PubMed:15917222, PubMed:16371461, PubMed:25503564, PubMed:25704143, PubMed:9859996, PubMed:22017875, PubMed:22017876, PubMed:22017877, PubMed:22087322, PubMed:36608670). Recognizes and binds to phosphorylated target proteins (PubMed:10066435, PubMed:10497169, PubMed:9990852, PubMed:10644755, PubMed:10835356, PubMed:11238952, PubMed:11359933, PubMed:11158290, PubMed:11994270, PubMed:12791267, PubMed:12902344, PubMed:14603323, PubMed:14681206, PubMed:14988407, PubMed:15448698, PubMed:15917222, PubMed:16371461, PubMed:25503564, PubMed:25704143, PubMed:9859996, PubMed:22017875, PubMed:22017876, PubMed:22017877, PubMed:22087322, PubMed:36608670). SCF(BTRC) mediates the ubiquitination of CTNNB1 and participates in Wnt signaling (PubMed:12077367, PubMed:12820959). SCF(BTRC) mediates the ubiquitination of phosphorylated NFKB1, ATF4, CDC25A, DLG1, FBXO5, PER1, SMAD3, SMAD4, SNAI1 and probably NFKB2 (PubMed:10835356, PubMed:11238952, PubMed:14681206, PubMed:14603323). SCF(BTRC) mediates the ubiquitination of NFKBIA, NFKBIB and NFKBIE; the degradation frees the associated NFKB1 to translocate into the nucleus and to activate transcription (PubMed:9859996, PubMed:10066435, PubMed:10497169, PubMed:10644755). Ubiquitination of NFKBIA occurs at 'Lys-21' and 'Lys-22' (PubMed:10066435). The SCF(FBXW11) complex also regulates NF-kappa-B by mediating ubiquitination of phosphorylated NFKB1: specifically ubiquitinates the p105 form of NFKB1, leading to its degradation (PubMed:10835356, PubMed:11158290, PubMed:14673179). SCF(BTRC) mediates the ubiquitination of CEP68; this is required for centriole separation during mitosis (PubMed:25704143, PubMed:25503564). SCF(BTRC) mediates the ubiquitination and subsequent degradation of nuclear NFE2L1 (By similarity). Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and PER2 (PubMed:15917222). May be involved in ubiquitination and subsequent proteasomal degradation through a DBB1-CUL4 E3 ubiquitin-protein ligase. Required for activation of NFKB-mediated transcription by IL1B, MAP3K14, MAP3K1, IKBKB and TNF. Required for proteolytic processing of GLI3 (PubMed:16371461). Mediates ubiquitination of REST, thereby leading to its proteasomal degradation (PubMed:21258371, PubMed:18354482). SCF(BTRC) mediates the ubiquitination and subsequent proteasomal degradation of KLF4; thereby negatively regulating cell pluripotency maintenance and embryogenesis (By similarity). SCF(BTRC) acts as a regulator of mTORC1 signaling pathway by catalyzing ubiquitination and subsequent proteasomal degradation of phosphorylated DEPTOR, TFE3 and MITF (PubMed:22017875, PubMed:22017876, PubMed:22017877, PubMed:33110214, PubMed:36608670).
The N-terminal D domain mediates homodimerization.
Ubiquitinated (PubMed:33110214). Deubiquitinated by OTUD5, promoting its stability (PubMed:33110214).
Involved in sperm capacitation and acrosome reaction.
As apoptosis proceeds, degraded via an proteasome-independent pathway, probably by caspases.
May play a role in apoptosis suppression. May promote melanoma cell invasion in vitro.
Phosphorylated at Ser-641, Ser-646, Ser-692 and Ser-696 by the BRAF/MKK/ERK signaling cascade. In melanoma cells, the C-terminal phosphorylation may prevent targeting to the plasma membrane.
The disease is caused by variants affecting the gene represented in this entry. Disease-causing mutations are located in intron 5 of LMBR1. The mutations do not alter normal LMBR1 expression and function, but disrupt a long-range, cis-regulatory element of SHH expression contained in LMBR1 intron 5, known as ZPA regulatory sequence (ZRS).
The disease is caused by variants affecting the gene represented in this entry. Disease-causing mutations are located in intron 5 of LMBR1. The mutations do not alter normal LMBR1 expression and function, but disrupt a long-range, cis-regulatory element of SHH expression contained in LMBR1 intron 5.
The disease is caused by variants affecting the gene represented in this entry. Disease-causing mutations consists of duplications (16-75 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5. The mutations do not alter normal LMBR1 expression and function, but affect SHH limb expression.
The disease is caused by variants affecting the gene represented in this entry. Disease-causing mutations consists of duplications (89-589 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5. The mutations do not alter normal LMBR1 expression and function, but affect SHH limb expression.
The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH expression.
Widely expressed with strongest expression in heart and pancreas.
Adult brain-derived ZFHX3 is sensitive, but embryonic brain-derived ZFHX3 is resistant to calpain 1-mediated proteolysis.
Genetic variations in ZFHX3 are associated with atrial fibrillation and ischemic stroke in individuals of European ancestry.
Interacts with FNBP3 (By similarity). Interacts with ALKBH4 and PIAS3. Interacts with ESR1. Interacts with RUNX3. Interacts with TRIM25. Interacts with SMAD2 and SMAD3.
Not found in normal gastric mucosa but found in gastric carcinoma cells (at protein level). Expression is higher in ER-positive breast tumors than ER-negative breast tumors (at protein level).
Nuclear localization is essential for its sumoylation.
Phosphorylation decreases its sensitivity to calpain-mediated proteolysis.
The sequence differs from that shown due translation of the 5'-UTR region.
Transcriptional regulator which can act as an activator or a repressor. Inhibits the enhancer element of the AFP gene by binding to its AT-rich core sequence. In concert with SMAD-dependent TGF-beta signaling can repress the transcription of AFP via its interaction with SMAD2/3 (PubMed:25105025). Regulates the circadian locomotor rhythms via transcriptional activation of neuropeptidergic genes which are essential for intercellular synchrony and rhythm amplitude in the suprachiasmatic nucleus (SCN) of the brain (By similarity). Regulator of myoblasts differentiation through the binding to the AT-rich sequence of MYF6 promoter and promoter repression (PubMed:11312261). Down-regulates the MUC5AC promoter in gastric cancer (PubMed:17330845). In association with RUNX3, up-regulates CDKN1A promoter activity following TGF-beta stimulation (PubMed:20599712). Inhibits estrogen receptor (ESR1) function by selectively competing with coactivator NCOA3 for binding to ESR1 in ESR1-positive breast cancer cells (PubMed:20720010).
Ubiquitinated, leading to its proteasomal degradation.
Belongs to the transient receptor (TC 1.A.4) family. Polycystin subfamily. MCOLN1 sub-subfamily.
Channel activity is controlled by multiple regulatory mechanisms in different subcellular compartments. Channel function is transiently modulated by changes in Ca(2+), and inhibited by a reduction of pH; pH changes modify the aggregation state of unitary channels; a negative cooperativity between extracellular/lumenal Ca(2+) and H(+) is suggested (PubMed:12459486, PubMed:28112729). Regulated by phosphoinositides in a compartment-specific manner: in lysosomes activated by PtdIns(3,5)P2 (Phosphatidylinositol 3,5-bisphosphate) and at the plasma membrane inhibited by PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) (PubMed:22733759, PubMed:29019983).
Homotetramer (PubMed:28112729, PubMed:29019983). Homooligomer (PubMed:14749347). Can heterooligomerize with MCOLN2 or MCOLN3; heteromeric assemblies have different channel properties as compared to the respective homooligomers and may be tissue-specific (PubMed:19885840). Interacts with PDCD6 (PubMed:19864416). Interacts with TMEM163 (PubMed:25130899). Interacts with LAPTM4B (PubMed:21224396).
May contribute to cellular lipase activity within the late endosomal pathway or at the cell surface which may be involved in processes of membrane reshaping and vesiculation, especially the growth of tubular structures. However, it is not known, whether it conveys the enzymatic activity directly, or merely facilitates the activity of an associated phospholipase.
Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis (PubMed:11013137, PubMed:12459486, PubMed:15336987, PubMed:14749347, PubMed:29019983, PubMed:27623384). Proposed to play a major role in Ca(2+) release from late endosome and lysosome vesicles to the cytoplasm, which is important for many lysosome-dependent cellular events, including the fusion and trafficking of these organelles, exocytosis and autophagy (PubMed:11013137, PubMed:12459486, PubMed:15336987, PubMed:14749347, PubMed:25720963, PubMed:29019983, PubMed:27623384). Required for efficient uptake of large particles in macrophages in which Ca(2+) release from the lysosomes triggers lysosomal exocytosis. May also play a role in phagosome-lysosome fusion (By similarity). Involved in lactosylceramide trafficking indicative for a role in the regulation of late endocytic membrane fusion/fission events (PubMed:16978393). By mediating lysosomal Ca(2+) release is involved in regulation of mTORC1 signaling and in mTOR/TFEB-dependent lysosomal adaptation to environmental cues such as nutrient levels (PubMed:25720963, PubMed:25733853, PubMed:27787197). Seems to act as lysosomal active oxygen species (ROS) sensor involved in ROS-induced TFEB activation and autophagy (PubMed:27357649). Functions as a Fe(2+) permeable channel in late endosomes and lysosomes (PubMed:18794901). Proposed to play a role in zinc homeostasis probably implicating its association with TMEM163 (PubMed:25130899) In adaptive immunity, TRPML2 and TRPML1 may play redundant roles in the function of the specialized lysosomes of B cells (By similarity).
Palmitoylated; involved in association with membranes.
Phosphorylation by PKA inhibits channel activity. Dephosphorylation increases activity.
Proteolytically cleaved probably involving multiple lysosomal proteases including cathepsin B; inhibits lysosomal channel activity (PubMed:16257972).
The most N-terminal extracellular/lumenal domain (referred to as I-II linker or polycystin-mucolipin domain) contributes to a structure with a four-fold rotational symmetry in a tetrameric assembly; the structure contains a central highly electronegative pore with a 14 A diameter. The pore is critical for Ca(2+) and pH regulation. The protruding structure formed by the I-II linkers may contain all the interaction sites with lipids and proteins in the endolysosomal lumen.
There are conflicting results relative to ion selectivity and permeation. Initially outward rectification has been reported which makes the proposed activity as lysosymal Ca(2+) release channel unlikely. Inward rectification has been decribed in later studies supporting the Ca(2+) release activity.
Widely expressed in adult and fetal tissues.
Expressed constitutively in cells of the myeloid lineage. Found in promyelocyte stage cells as well as in all other stage cells including peripheral blood monocytes and granulocytes. Also appears in myeloblast cells in some cases of acute myeloid Leukemia.
Its N-terminal half (200 amino acids) is sufficient for maximum enhancement of YY1 DNA binding and a portion of this sequence is responsible for binding YY1.
May act as a transcriptional activator/repressor in the myeloid lineage. Plays a role in the granulocyte/monocyte cell-specific response to interferon. Stimulates the DNA binding of the transcriptional repressor protein YY1.
Participates in a ternary complex with YY1 and the YY1 target DNA element. Binds nucleolin and nucleophosmin/NPM/B23.
Strongly induced by alpha interferon which selectively affects expression in late stage cells in the monocytic but not the granulocytic lineage. Induced in vitro by dimethylsulfoxide and 1,25 dihydroxyvitamin D3.
Expressed in heart, muscle, testis, ovary, uterus and prostate.
Expressed in all tissues examined, with most abundant expression in heart and skeletal muscle.
Motor required for the retrograde transport of Golgi vesicles to the endoplasmic reticulum. Has a microtubule plus end-directed motility.
Found at 48 dpc in the anterior cranial base with detection concentrated in the sphenoid precursor. Expression is also detected in the pituitary gland.
Interacts with TCF7L2; in a canonical Wnt signaling independent manner; prevents transcription of differentiation genes in cap mesenchyme. Interacts with OSR1; form a strong repressor complex with TCF7L2, TLE2 and TLE3 to prevent the activation of Wnt/beta-catenin target genes in the cap mesenchyme. Interacts with HOXA11, EYA1 and EYA3.
Strongly expressed in skeletal muscle. Expressed in Wilms' tumor and in the cap mesenchyme of fetal kidney (at protein level).
Transcription factor that plays an important role in the development of several organs, including kidney, skull and stomach. During kidney development, maintains cap mesenchyme multipotent nephron progenitor cells in an undifferentiated state by opposing the inductive signals emanating from the ureteric bud and cooperates with WNT9B to promote renewing progenitor cells proliferation. Acts through its interaction with TCF7L2 and OSR1 in a canonical Wnt signaling independent manner preventing transcription of differentiation genes in cap mesenchyme such as WNT4. Also acts independently of OSR1 to activate expression of many cap mesenchyme genes, including itself, GDNF and OSR1. During craniofacial development plays a role in growth and elongation of the cranial base through regulation of chondrocyte differentiation. During stomach organogenesis, controls pyloric sphincter formation and mucosal growth through regulation of a gene network including NKX2-5, BMPR1B, BMP4, SOX9 and GREM1. During branchial arch development, acts to mediate HOXA2 control over the insulin-like growth factor pathway. May also be involved in limb tendon and ligament development (By similarity). Plays a role in cell proliferation and migration.
Inhibited rather than stimulated by magnesium.
Interacts with ILK. Specific association with ILK is independent of the catalytic activity of either partner.
Protein phosphatase that may play a role in regulation of cell cycle progression via dephosphorylation of its substrates whose appropriate phosphorylation states might be crucial for cell proliferation. Selectively associates with integrin linked kinase (ILK), to modulate cell adhesion and growth factor signaling. Inhibits the ILK-GSK3B signaling axis and may play an important role in inhibiting oncogenic transformation.
Widely expressed. Highest levels expressed in striated muscle. Much lower levels evident in various smooth muscle tissues.
Isoform 1 is widely expressed with a higher level in kidney. Isoform 2 is mainly expressed in endothelial cells.
Phosphorylated by ROCK, leading to activate the RacGAP activity.
Rho GTPase-activating protein involved in cell polarity, cell morphology and cytoskeletal organization. Acts as a GTPase activator for the Rac-type GTPase by converting it to an inactive GDP-bound state. Controls actin remodeling by inactivating Rac downstream of Rho leading to suppress leading edge protrusion and promotes cell retraction to achieve cellular polarity. Able to suppress RAC1 and CDC42 activity in vitro. Overexpression induces cell rounding with partial or complete disruption of actin stress fibers and formation of membrane ruffles, lamellipodia, and filopodia. Isoform 2 is a vascular cell-specific GAP involved in modulation of angiogenesis.
The coiled coil domain mediates the interaction with FLNA leading to its recruitment to lamellae.
Up-regulated during capillary tube formation in umbilical vein endothelial cells.
Highly expressed in the heart, moderately in skeletal muscle and pancreas, and weakly in brain, kidney, liver, testis, thyroid gland and lymphocytes.
Probable E3 ubiquitin protein ligase involved in the proteasome-mediated ubiquitin-dependent degradation of target proteins (PubMed:29374064). Through the degradation of CTNNB1, functions downstream of FOXF2 to negatively regulate the Wnt signaling pathway (PubMed:29374064). Probably plays a role in the development of the central nervous system and in neuronal maintenance (Probable). Also acts as a transcriptional regulator of genes controlling female reproductive function. May play a role in gene transcription by transactivating GNRH1 promoter and repressing PENK promoter (By similarity).
The poly-Gln region is polymorphic; the most frequent allele contained 24 Gln. Stretches of 20-31 Gln are observed in healthy individuals.
Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription.
Component of the general transcription and DNA repair factor IIH (TFIIH) core complex which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA.
Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription.
Highly expressed in hair follicles from scalp. In hair, it is specifically present in the inner root sheath (IRS) of the hair follicle. Present in the IRS Huxley layer, but not in Henle layer or cuticle of the IRS. In the IRS Huxley layer, it is expressed in specialized Huxley cells, termed 'Fluegelzellen, along the area of differentiated Henle cells (at protein level).
(Microbial infection) Up-regulated upon SARS-CoV infection.
Found in a complex, at least composed of BLM, RAD51 and SPIDR; the complex formation is mediated by SPIDR. Interacts (via C-terminal region) with BLM; the interaction is direct. Interacts with RAD51; the interaction is direct. Interacts (via the C-terminal region) with FIGNL1 (via N-terminal one-half region); the interaction is direct.
Plays a role in DNA double-strand break (DBS) repair via homologous recombination (HR). Serves as a scaffolding protein that helps to promote the recruitment of DNA-processing enzymes like the helicase BLM and recombinase RAD51 to site of DNA damage, and hence contributes to maintain genomic integrity.
Up-regulated in vascular endothelial cells treated with IL4.
Belongs to the vasopressin/oxytocin family.
Interacts with oxytocin receptor (Ki=1.5 nM) (PubMed:18174156). Interacts with vasopressin V1aR/AVPR1A (Ki=37 nM), V1bR/AVPR1B (Ki=222 nM) and V2R/AVPR2 receptors (Ki=823 nM) (PubMed:18174156).
Neurophysin 1 specifically binds oxytocin.
Oxytocin causes contraction of the smooth muscle of the uterus and of the mammary gland. Acts by binding to oxytocin receptor (OXTR) (PubMed:18174156).
Oxytocin is available under the names Pitocin (Parke-Davis) and Syntocinon (Sandoz). Used to artificially speed or induce labor.
Acts as component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. Core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built (PubMed:32453425, PubMed:34694004, PubMed:34700328, PubMed:35585232). The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity (PubMed:32453425). Required for the entry in S phase and for cell division (Probable).
Acts as component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity.
Component of the MCM2-7 complex (PubMed:16899510, PubMed:17296731). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (PubMed:16899510, PubMed:17296731, PubMed:34700328, PubMed:34694004, PubMed:32453425). Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex (PubMed:34700328, PubMed:34694004, PubMed:32453425). Associated with the replication-specific DNA polymerase alpha (By similarity). Interacts with MCMBP (PubMed:17296731). Interacts with ANKRD17 (PubMed:23711367). Interacts with MCM3AP isoform MCM3AP; this interaction leads to MCM3 acetylation (PubMed:9712829, PubMed:11258703, PubMed:12226073).
Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. The MCM2-7 hexamer is the proposed physiological active complex.
O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner.
Interacts with CACNA1S, CACNB1 and calsequestrin.
Involved in skeletal muscle excitation/contraction coupling (EC), probably acting as a regulator of the voltage-sensitive calcium channel CACNA1S. EC is a physiological process whereby an electrical signal (depolarization of the plasma membrane) is converted into a chemical signal, a calcium gradient, by the opening of ryanodine receptor calcium release channels. May regulate CACNA1S membrane targeting and activity.
Ubiquitin hydrolase that can remove conjugated ubiquitin from AXIN1 and AXIN2, thereby acting as a regulator of Wnt signaling pathway. Acts as an activator of the Wnt signaling pathway downstream of the beta-catenin destruction complex by deubiquitinating and stabilizing AXIN1 and AXIN2, leading to promote nuclear accumulation of AXIN1 and AXIN2 and positively regulate beta-catenin (CTNBB1)-mediated transcription. Recognizes and hydrolyzes the peptide bond at the C-terminal Gly of ubiquitin. Involved in the processing of poly-ubiquitin precursors as well as that of ubiquitinated proteins.
Contaminating sequence. The C-terminus matches chromosome 8 region.
Ceramide-sensitive subunit of the serine palmitoyltransferase (SPT) complex, which is also composed of SPTLC1, SPTLC2/3 and SPTSSA/B.
Ceramides bind to ORMDL3 N-terminus and stabilize it in a conformation that physically restricts the accessibility of the substrates to their binding sites in the serine palmitoyltransferase (SPT) complex, hence inhibiting SPT catalytic activity. In the absence of ceramides, the N-terminus is flexible and permits substrate binding, thus liberating SPT from inhibition.
Disease susceptibility is associated with variants affecting the gene represented in this entry. SNPs on 17q21 locus that are associated with childhood asthma also show a consistent and strong association with transcript levels of ORMDL3, indicating that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.
Plays an essential role in the homeostatic regulation of sphingolipid de novo biosynthesis by modulating the activity of the serine palmitoyltransferase (SPT) in response to ceramide levels (PubMed:20182505, PubMed:30700557, PubMed:37308477). When complexed to SPT, the binding of ceramides to its N-terminus stabilizes a conformation that block SPT substrate entry, hence preventing SPT catalytic activity. Through this mechanism, maintains ceramide levels at sufficient concentrations for the production of complex sphingolipids, but which prevents the accumulation of ceramides to levels that trigger apoptosis (PubMed:37308477).
When hydroxylated at Pro-137, ubiquitinated via 'Lys-48'-linkage, leading to proteasomal degradation. In endothelial cells, ORMDL3 proteasomal degradation is controlled by the sphingosine 1-phosphate receptor signaling pathway.
Widely expressed. Expressed in adult and fetal heart, brain, lung, liver, skeletal muscle and kidney. Expressed in adult pancreas and placenta and in fetal spleen and thymus.
Acts as a transcriptional activator or repressor. Plays important roles in the early stage of organogenesis of the CNS. Activates the transcription of the serotonin transporter SERT in uncrossed ipsilateral retinal ganglion cells (iRGCs) to refine eye-specific projections in primary visual targets. Its transcriptional activity is repressed by MDFIC. Involved in the formation of the ipsilateral retinal projection at the optic chiasm midline. Drives the expression of EPHB1 on ipsilaterally projecting growth cones. Binds to the minimal GLI-consensus sequence 5'-TGGGTGGTC-3'. Associates to the basal SERT promoter region from ventrotemporal retinal segments of retinal embryos.
Interacts with RNF180. Interacts (via the C2H2-type domains 3, 4 and 5) with MDFIC (via the C2H2-type domains 3, 4 and 5); the interaction reduces its transcriptional activity. Interacts with GLI1 and GLI2 (By similarity). Interacts (via C2H2-type domain 3) with DHX9 (PubMed:17251188).
The poly-His region between amino acids 231-239 of ZIC2 is polymorphic and the number of His can vary from 8 to 12.
Ubiquitinated by RNF180, leading to its degradation.
(Microbial infection) Interacts with Zika virus non-structural protein 1.
Forms a ternary complex with RNF128 and OTUB1. Interacts (via C-terminal UCH catalytic domain) with OTUB1 isoform 1. Interacts with STAM2 (via SH3 domain). Interacts with DNAJB3, EGFR, EPS15, RASGRF1, RNF41, YWHAE, YWHAG and YWHAZ (By similarity). Interacts with NBR1, RASGRF1, RNF41 and IST1. Associates with the ESCRT-0 complex and with microtubules (By similarity). Interacts with BIRC6/bruce and KIF23/MKLP1.
Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation. Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the M phase. Involved in cell proliferation. Required to enter into S phase in response to serum stimulation. May regulate T-cell anergy mediated by RNF128 via the formation of a complex containing RNF128 and OTUB1. Probably regulates the stability of STAM2 and RASGRF1. Regulates endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early endosomes, and maintenance of ESCRT-0 stability. The level of protein ubiquitination on endosomes is essential for maintaining the morphology of the organelle. Deubiquitinates EPS15 and controls tyrosine kinase stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation and downstream MAPK signaling. Involved in acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1. Deubiquitinates BACE1 which inhibits BACE1 lysosomal degradation and modulates BACE-mediated APP cleavage and amyloid-beta formation (PubMed:27302062).
Phosphorylation of Ser-718 is essential for interaction with YWHAE and for cytosol localization. Undergoes dephosphorylation at Ser-718 in the M phase. Tyrosine-phosphorylated in its N-terminal half in an EGFR-dependent manner.
The MIT domain is required for endosomal localization, CHMP1B-binding, maintenance of ESCRT-0 stability and EGFR degradation.
The rhodanese domain is sufficient for RNF41-binding.
Ubiquitinated. Inactive form is mostly monoubiquitinated, but polyubiquitination happens too. Ubiquitination is increased in EGF-stimulated cells. Ubiquitination of active form is undetectable, suggesting a possibility that USP8 deubiquitinates itself, thereby regulating its own function (By similarity).
Upon growth stimulation in starved human fibroblasts. Decreases in response to growth arrest induced by cell-cell contact.
Expressed predominantly in lymphoid organs, including spleen, thymus, lymph node, bone marrow and peripheral blood leukocytes and moderately in the digestive tract, including stomach, duodenum, jejunum, ileum, ileocecum and appendix, as well as in lung and liver. Also expressed in tumors, but at a lower level than in the corresponding normal tissues.
Interacts with integrin-linked protein kinase and actin.
Probably plays a role in the regulation of cell adhesion and cytoskeleton organization.
Interacts (via PTB domain) with MAP3K7IP2 (via C-terminal). Interacts (via C-terminal) with TRAF6 (via TRAF domains). Associates with EPS15 and NOTCH1.
Plays a role in the process of neurogenesis.
Plays a role in the process of neurogenesis. Required throughout embryonic neurogenesis to maintain neural progenitor cells, also called radial glial cells (RGCs), by allowing their daughter cells to choose progenitor over neuronal cell fate. Not required for the proliferation of neural progenitor cells before the onset of embryonic neurogenesis. Also required postnatally in the subventricular zone (SVZ) neurogenesis by regulating SVZ neuroblasts survival and ependymal wall integrity. Negative regulator of NF-kappa-B signaling pathway. The inhibition of NF-kappa-B activation is mediated at least in part, by preventing MAP3K7IP2 to interact with polyubiquitin chains of TRAF6 and RIPK1 and by stimulating the 'Lys-48'-linked polyubiquitination and degradation of TRAF6 in cortical neurons.
The PTB domain is necessary for the inhibition of MAP3K7IP2-mediated activation of NF-kappa-B.
Electroneutral transporter of the plasma membrane mediating the cellular uptake of the divalent metal cations zinc, manganese and iron that are important for tissue homeostasis, metabolism, development and immunity (PubMed:15642354, PubMed:27231142, PubMed:29621230). Functions as an energy-dependent symporter, transporting through the membranes an electroneutral complex composed of a divalent metal cation and two bicarbonate anions (By similarity). Beside these endogenous cellular substrates, can also import cadmium a non-essential metal which is cytotoxic and carcinogenic (By similarity). Controls the cellular uptake by the intestinal epithelium of systemic zinc, which is in turn required to maintain tight junctions and the intestinal permeability (By similarity). Modifies the activity of zinc-dependent phosphodiesterases, thereby indirectly regulating G protein-coupled receptor signaling pathways important for gluconeogenesis and chondrocyte differentiation (By similarity). Regulates insulin receptor signaling, glucose uptake, glycogen synthesis and gluconeogenesis in hepatocytes through the zinc-dependent intracellular catabolism of insulin (PubMed:27703010). Through zinc cellular uptake also plays a role in the adaptation of cells to endoplasmic reticulum stress (By similarity). Major manganese transporter of the basolateral membrane of intestinal epithelial cells, it plays a central role in manganese systemic homeostasis through intestinal manganese uptake (PubMed:31028174). Also involved in manganese extracellular uptake by cells of the blood-brain barrier (PubMed:31699897). May also play a role in manganese and zinc homeostasis participating in their elimination from the blood through the hepatobiliary excretion (By similarity). Also functions in the extracellular uptake of free iron. May also function intracellularly and mediate the transport from endosomes to cytosol of iron endocytosed by transferrin (PubMed:20682781). Plays a role in innate immunity by regulating the expression of cytokines by activated macrophages (PubMed:23052185).
N-glycosylated. N-glycosylation at Asn-102 is required for iron-regulated extraction of the transporter from membranes and subsequent proteasomal degradation.
The disease is caused by variants affecting the gene represented in this entry. Conditional knockin mice overexpressing Arg-438 variant, which is the mouse equivalent of human variant Leu-441, in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients.
Ubiquitinated. Ubiquitination occurs upon iron depletion. The ubiquitinated form undergoes proteasomal degradation.
Ubiquitously expressed, with higher expression in liver, pancreas, fetal liver, thyroid gland, left and right ventricle, right atrium and fetal heart (PubMed:7584044, PubMed:15642354, PubMed:20682781). Weakly expressed in spleen, thymus, and peripheral blood leukocytes (PubMed:7584044). Expressed in liver and in brain by large neurons in the globus pallidus, the insular cortex and the dentate nucleus and to a lower extent in the putamen and the caudate nucleus (at protein level) (PubMed:27231142). Expressed in osteoblasts and giant osteoclast-like cells, but not in osteocytes found osteoblastoma and giant cell tumors (at protein level) (PubMed:29621230). Expressed by microvascular capillary endothelial cells that constitute the blood-brain barrier (at protein level) (PubMed:31699897). Expressed by macrophages (PubMed:23052185).
Up-regulated by iron (at protein level) (PubMed:24927598). Down-regulation upon iron depletion occurs through proteasomal degradation of the intracellular pool (PubMed:24927598). Up-regulated by tunicamycin, a drug inducing endoplasmic reticulum stress (at protein level) (PubMed:28673968). Up-regulated by lipopolysaccharide/LPS (PubMed:23052185).
Widely expressed but not detected in brain, heart, skeletal muscle, placenta and fetal skin.
Autophosphorylated. Phosphorylated (By similarity).
Mainly expressed in skeletal muscle, and weakly in brain and pancreas.
Phosphorylates PPP1C, phosphorylase b and CFTR.
Interacts with EPHA7, EPHB2, KIF5A, KIF5B, KIF5C, GRIA2, GRIA3, GRIPAP1/GRASP1, PPFIA1, PPFIA4, FRAS1, PLCD4, PTPRF and liprins-alpha. Can form homomultimers or heteromultimers with GRIP2. Forms a ternary complex with GRIA2 and CSPG4 (By similarity). Interacts with ATAD1 in an ATP-dependent manner. ATAD1-catalyzed ATP hydrolysis disrupts binding to ATAD1 and to GRIA2 and leads to AMPAR complex disassembly (By similarity). Interacts with EFNB1, EFNB3 and the C-terminal tail of PRLHR. Interacts with SLC30A9 (By similarity). Interacts with BUD23. Forms a complex with NSG1, GRIA2 and STX12; controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting. Interacts with NSG1 (By similarity).
May play a role as a localized scaffold for the assembly of a multiprotein signaling complex and as mediator of the trafficking of its binding partners at specific subcellular location in neurons (PubMed:10197531). Through complex formation with NSG1, GRIA2 and STX12 controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting (By similarity).
PDZ 6 mediates interaction with the PDZ recognition motif of EFNB1 and EPHB2 and with the C-terminus of PPFIA1 and PPFIA4. PDZ 4 and PDZ 5 mediate interaction with the C-terminus of GRIA2 and GRIA3. PDZ 4, PDZ 5 and PDZ 6 mediate homomultimers. PDZ 7 mediates interaction with PDZ domain of GRASP1. PDZ 7 domain binds CSPG4. PDZ 6 mediates interaction with the C-terminus of liprins-alpha. PDZ 1, PDZ 2 and PDZ 3 mediate interaction with the PDZ-binding motif of FRAS1 (By similarity). PDZ 4 and PDZ 5 mediate interaction with PRLHR.
Belongs to the class I-like SAM-binding methyltransferase superfamily. TRM11 methyltransferase family.
Catalytic subunit of an S-adenosyl-L-methionine-dependent tRNA methyltransferase complex that mediates the methylation of the guanosine nucleotide at position 10 (m2G10) in tRNAs.
Belongs to the osteocalcin/matrix Gla protein family.
Bone protein that constitutes 1-2% of the total bone protein, and which acts as a negative regulator of bone formation (PubMed:3019668, PubMed:6967872). Functions to limit bone formation without impairing bone resorption or mineralization (By similarity). It binds strongly to apatite and calcium (PubMed:6967872).
Gamma-carboxyglutamate residues are formed by vitamin K dependent carboxylation by GGCX. These residues are essential for the binding of calcium (By similarity) (PubMed:6967872). Decarboxylation promotes the hormone activity (By similarity).
The uncarboxylated form acts as a hormone secreted by osteoblasts, which regulates different cellular processes, such as energy metabolism, male fertility and brain development. Regulates of energy metabolism by acting as a hormone favoring pancreatic beta-cell proliferation, insulin secretion and sensitivity and energy expenditure. Uncarboxylated osteocalcin hormone also promotes testosterone production in the testes: acts as a ligand for G protein-coupled receptor GPRC6A at the surface of Leydig cells, initiating a signaling response that promotes the expression of enzymes required for testosterone synthesis in a CREB-dependent manner. Also acts as a regulator of brain development: osteocalcin hormone crosses the blood-brain barrier and acts as a ligand for GPR158 on neurons, initiating a signaling response that prevents neuronal apoptosis in the hippocampus, favors the synthesis of all monoamine neurotransmitters and inhibits that of gamma-aminobutyric acid (GABA). Osteocalcin also crosses the placenta during pregnancy and maternal osteocalcin is required for fetal brain development.
Homodimer (PubMed:28052936). Component of the BCR(KLHL3) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL3 and RBX1 (PubMed:14528312, PubMed:23387299, PubMed:23453970, PubMed:23576762, PubMed:23573258). Interacts with CLDN8 (By similarity).
Phosphorylation at Ser-433 by PKA or PKC decreases the interaction with WNK1 and WNK4, leading to inhibit their degradation by the BCR(KLHL3) complex (PubMed:26435498, PubMed:27727489, PubMed:25313067, PubMed:30718414). Phosphorylated at Ser-433 by PKC in response to angiotensin II signaling, decreasing ability to promote degradation of WNK1 and WNK4, leading to activation of Na-Cl cotransporter SLC12A3/NCC (PubMed:25313067). Phosphorylation at Ser-433 is increased by insulin (PubMed:26435498). Dephosphorylated at Ser-433 by calcineurin PPP3CA, promoting degradation of WNK1 and WNK4 (PubMed:30718414).
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron (PubMed:14528312, PubMed:22406640, PubMed:23387299, PubMed:23453970, PubMed:23576762, PubMed:23665031, PubMed:25313067, PubMed:35093948). The BCR(KLHL3) complex acts by mediating ubiquitination and degradation of WNK1 and WNK4, two activators of Na-Cl cotransporter SLC12A3/NCC in distal convoluted tubule cells of kidney, thereby regulating NaCl reabsorption (PubMed:23387299, PubMed:23453970, PubMed:23576762, PubMed:23665031, PubMed:25313067, PubMed:35093948). The BCR(KLHL3) complex also mediates ubiquitination and degradation of WNK3 (PubMed:35179207). The BCR(KLHL3) complex also mediates ubiquitination of CLDN8, a tight-junction protein required for paracellular chloride transport in the kidney, leading to its degradation (By similarity).
The BCR(KLHL3) complex was initially thought to act by mediating ubiquitination of SLC12A3/NCC (PubMed:22406640). However, it was later shown that effects on SLC12A3/NCC are indirect and caused by impaired ubiquitination of WNK4 (PubMed:23387299).
Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter PRAMEF9.
Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex, which mediates ubiquitination of target proteins, leading to their degradation (PubMed:26138980). The CRL2(PRAMEF9) complex mediates ubiquitination and degradation of truncated MSRB1/SEPX1 selenoproteins produced by failed UGA/Sec decoding (PubMed:26138980).
(Microbial infection) Interacts (via N-terminus) with Epstein-Barr virus protein BZLF1 (via C-terminus); this interaction inhibits BZLF1-mediated lytic viral reactivation (PubMed:23678172). Interacts also with EBNA1; this interaction promotes EBNA1-dependent transcription (PubMed:31941781).
(Microbial infection) Plays an essential role in the maintenance of Epstein-Barr virus genome copy number within the host cell by promoting EBNA1/oriP-dependent binding and transcription (PubMed:31941781). Participates also in the inhibition of lytic EBV reactivation by modulating viral BZLF1 activity (PubMed:23678172).
A chromosomal aberration involving PAX5 is a cause of acute lymphoblastic leukemia. Translocation t(9;18)(p13;q11.2) with ZNF521. Translocation t(9;3)(p13;p14.1) with FOXP1. Translocation t(9;12)(p13;p13) with ETV6.
Expressed at early B-cell differentiation, in the developing CNS and in adult testis.
Interacts with ETS1; this interaction alters PAX5 DNA-binding properties (PubMed:11779502). Binds DNA as a monomer (PubMed:11779502). Interacts with TBP; this interaction allows PAX5 to interact with the basal transcription machinery (PubMed:10197586). Interacts with RB1 (PubMed:10197586). Interacts with TLE4 (PubMed:10811620). Interacts with DAXX (By similarity).
Phosphorylated by SYK. This phosphorylation plays an important role in the abolition of BLIMP1 repression by PAX5 in order to trigger plasma cell differentiation.
Transcription factor that plays an essential role in commitment of lymphoid progenitors to the B-lymphocyte lineage (PubMed:10811620, PubMed:27181361). Fulfills a dual role by repressing B-lineage inappropriate genes and simultaneously activating B-lineage-specific genes (PubMed:10811620, PubMed:27181361). In turn, regulates cell adhesion and migration, induces V(H)-to-D(H)J(H) recombination, facilitates pre-B-cell receptor signaling and promotes development to the mature B-cell stage (PubMed:32612238). Repression of the cohesin-release factor WAPL causes global changes of the chromosomal architecture in pro-B cells to facilitate the generation of a diverse antibody repertoire (PubMed:32612238).
Expressed in embryonic brain (PubMed:28264986). Expressed in fetal brain ganglionic eminence, kidney tubules and multinucleate neurons in the temporal cortex (PubMed:28264986). Expressed in adult brain, cerebellum, kidney tubules, intestine and muscles (at protein level) (PubMed:28295209, PubMed:28264986). Widely expressed, mostly in proliferative tissues. Highly expressed in testis. Intermediate levels in adult and fetal thymus, as well as in various cancer cell lines. Low levels in different parts of the digestive tract, bone marrow, lymph nodes, placenta, fetal heart and fetal spleen. Hardly detected in brain.
Homodimer (PubMed:16406728). Interacts (phosphorylated on Ser-425 and Ser-428) with PLK1 (PubMed:16198290). Interacts with AKAP9/CG-NAP; the interaction occurs in interphase and is lost upon mitotic entry (PubMed:16198290). Interacts with PCNT/Kendrin; the interaction occurs in interphase and is lost upon mitotic entry (PubMed:16198290). Directly interacts with PDCD6IP; this interaction is required for PDCD6IP targeting to the midbody; CEP55 binds PDCD6IP in a 2:1 stoichiometry; PDCD6IP competes with TSG101 for the same binding site (PubMed:17853893, PubMed:17556548, PubMed:18641129, PubMed:18948538). Interacts with TSG101; TSG101 competes with PDCD6IP for the same binding site; interaction is required for cytokinesis but not for viral budding (PubMed:17853893, PubMed:17556548, PubMed:18948538). Interacts with MVB12A, VPS37B, VPS37C and VPS28 (PubMed:17853893).
Plays a role in mitotic exit and cytokinesis (PubMed:16198290, PubMed:17853893). Recruits PDCD6IP and TSG101 to midbody during cytokinesis. Required for successful completion of cytokinesis (PubMed:17853893). Not required for microtubule nucleation (PubMed:16198290). Plays a role in the development of the brain and kidney (PubMed:28264986).
There is a hierachy of phosphorylation, where both Ser-425 and Ser-428 are phosphorylated at the onset of mitosis, prior to Ser-436. Phosphorylation at Ser-425 and Ser-428 is required for dissociation from the centrosome at the G2/M boundary. Phosphorylation at the 3 sites, Ser-425, Ser-428 and Ser-436, is required for protein function at the final stages of cell division to complete cytokinesis successfully.
Seems to have a role in zinc absorption and may function as an intracellular zinc transport protein.
Expressed in many tumors of several types, such as melanoma, head and neck squamous cell carcinoma, lung carcinoma and breast carcinoma, but not in normal tissues except for spermatogonia, spermatocytes and placenta.
Not known, though may play a role in embryonal development and tumor transformation or aspects of tumor progression.
A sequential activation is proposed: autophosphorylation at consensus sites is leading to dimerization of the catalytic domain stabilized by phosphorylation at Ser-50 and activation segment exchange (producing an active confirmation of both kinase modules in trans) followed by phosphorylation at Thr-180 in the activation segment and at other regulatory sites (Probable). Phosphorylation at Thr-180, Thr-225 and Thr-265 is essential for activity. Oligomerization is required for full enzymatic activity. Inhibited by pyridone-6 (K00225), a potent, ATP-competitive inhibitor.
Homooligomer in its kinase-active form (homotrimers and homodimers are reported); monomeric in its kinase-inactive form. Homodimerization is required for activation segment autophosphorylation (Probable). Isoform 1 and isoform 2 interact with myosin and PPP1R12A; interaction of isoform 1 with PPP1R12A is inhibited by RhoA dominant negative form. Interacts with NLK, DAXX, STAT3, RHOD (GTP-bound form) and TCP10L. Interacts with PAWR; the interaction is reported conflictingly: according to PubMed:17953487 does not interact with PAWR. Interacts with ULK1; may be a substrate of ULK1.
Serine/threonine kinase which is involved in the regulation of apoptosis, autophagy, transcription, translation and actin cytoskeleton reorganization. Involved in the regulation of smooth muscle contraction. Regulates both type I (caspase-dependent) apoptotic and type II (caspase-independent) autophagic cell deaths signal, depending on the cellular setting. Involved in regulation of starvation-induced autophagy. Regulates myosin phosphorylation in both smooth muscle and non-muscle cells. In smooth muscle, regulates myosin either directly by phosphorylating MYL12B and MYL9 or through inhibition of smooth muscle myosin phosphatase (SMPP1M) via phosphorylation of PPP1R12A; the inhibition of SMPP1M functions to enhance muscle responsiveness to Ca(2+) and promote a contractile state. Phosphorylates MYL12B in non-muscle cells leading to reorganization of actin cytoskeleton. Isoform 2 can phosphorylate myosin, PPP1R12A and MYL12B. Overexpression leads to condensation of actin stress fibers into thick bundles. Involved in actin filament focal adhesion dynamics. The function in both reorganization of actin cytoskeleton and focal adhesion dissolution is modulated by RhoD. Positively regulates canonical Wnt/beta-catenin signaling through interaction with NLK and TCF7L2. Phosphorylates RPL13A on 'Ser-77' upon interferon-gamma activation which is causing RPL13A release from the ribosome, RPL13A association with the GAIT complex and its subsequent involvement in transcript-selective translation inhibition. Enhances transcription from AR-responsive promoters in a hormone- and kinase-dependent manner. Involved in regulation of cell cycle progression and cell proliferation. May be a tumor suppressor.
The internal splice site between exon 8 and the 3' UTR, which yields this truncated isoform, is non-canonical.
The phosphorylation status is critical for kinase activity, oligomerization and intracellular localization. Phosphorylation at Thr-180, Thr-225 and Thr-265 is essential for activity. The phosphorylated form is localized in the cytoplasm promoted by phosphorylation at Thr-299; nuclear translocation or retention is maximal when it is not phosphorylated. Phosphorylation increases the trimeric form, and its dephosphorylation favors a kinase-inactive monomeric form. Both isoform 1 and isoform 2 can undergo autophosphorylation.
Widely expressed. Isoform 1 and isoform 2 are expressed in the bladder smooth muscle.
Another protein KMT2B/MLL4, located on chromosome 19, was first named MLL2 (see AC Q9UMN6). Thus, KMT2B/MLL4 is often referred to as MLL2 and vice versa in the literature.
Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. TRX/MLL subfamily.
Component of the MLL2 complex (also named ASCOM complex), at least composed of catalytic subunit KMT2D/MLL2, ASH2L, RBBP5, WDR5, NCOA6, DPY30, KDM6A, PAXIP1/PTIP, PAGR1 and alpha- and beta-tubulin (PubMed:23508102, PubMed:17500065, PubMed:12482968, PubMed:16603732, PubMed:17021013, PubMed:17761849, PubMed:17851529). Forms a core complex with the evolutionary conserved subcomplex WRAD composed of WDR5, RBBP5, ASH2L/ASH2 and DPY30 subunits; WRAD differentially stimulates the methyltransferase activity (PubMed:25561738). Interacts with ESR1; interaction is direct (PubMed:16603732). Interacts (via WIN motif) with WDR5 (PubMed:22665483, PubMed:22266653).
Expressed in most adult tissues, including a variety of hematoipoietic cells, with the exception of the liver.
Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4) (PubMed:25561738). Part of chromatin remodeling machinery predominantly forms H3K4me1 methylation marks at active chromatin sites where transcription and DNA repair take place (PubMed:25561738, PubMed:17500065). Acts as a coactivator for estrogen receptor by being recruited by ESR1, thereby activating transcription (PubMed:16603732).
LXXLL motifs 5 and 6 are essential for the association with ESR1 nuclear receptor.
This gene mapped to a chromosomal region involved in duplications and translocations associated with cancer.
Activated by autophosphorylation and homodimerization.
Activates the JUN N-terminal pathway through activation of the MAP kinase kinase MAP2K7. Acts synergistically with PRDX3 to regulate the activation of NF-kappa-B in the cytosol. This activation is kinase-dependent and involves activating the IKK complex, the IKBKB-containing complex that phosphorylates inhibitors of NF-kappa-B.
Autophosphorylated on serine and threonine residues.
Expressed in the adult brain, liver, placenta and pancreas, with expression strongest in the pancreas.
Homodimer; forms dimers through the leucine-zipper motif. Interacts with the C-terminus of MAPK8IP1 through the kinase catalytic domain. Binds PRDX3. Associates with the IKK complex through the kinase domain.
Plays a role in fertilization through the acrosome reaction.
Heterotrimer composed of a catalytic subunit and a homodimer of accessory subunits.
Mitochondrial polymerase processivity subunit. It regulates the polymerase and exonuclease activities promoting processive DNA synthesis. Binds to ss-DNA.
Detected in the outer plexiform layer (OPL) of the retina where it localizes to ON-bipolar cells (at protein level).
Plays a role in the synapse formation and synaptic transmission between cone photoreceptor cells and retinal bipolar cells (By similarity). Required for normal transmission of a light-evoked stimulus from the cone photoreceptor cells to the ON-bipolar cells and ON-ganglion cells in the inner retina (PubMed:28334377). Required in retinal ON-bipolar cells for normal localization of the cation channel TRPM1 at dendrite tips (By similarity). Seems to play a specific role in synaptic contacts made by ON-bipolar cells with cone photoreceptor pedicles (By similarity). May also have a role in cone synapse formation (By similarity). Might facilitate FGFR1 exit from the endoplasmic reticulum to the Golgi (PubMed:22673519). Could be a regulator of the FGFRs (PubMed:22673519).
Belongs to the complex I subunit 6 family.
Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits.
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:8644732, PubMed:14595656). Essential for the catalytic activity and assembly of complex I (PubMed:8644732, PubMed:14595656).
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. Essential for the catalytic activity and assembly of complex I.
May play a role in the defense system against pathogens.
A secreted form is produced by caspase-mediated proteolytic cleavage.
Isoform 2 is expressed (at protein level) in prostate and many prostate tumors.
Nitration of Tyr-449 is irreversible and interferes with normal dynein intracellular distribution.
By nerve injury both in dorsal root ganglion neurons and in Schwann cells.
Cleaved by MMP9 protease to generate the Secreted ninjurin-1 form.
Composed of 4 alpha helices: 2 hydrophobic transmembrane regions (alpha3 and alpha4) and 2 alpha helices (alpha1 and alpha2) (PubMed:37198476). Alpha1 and alpha2 feature one hydrophobic side and a hydrophilic side (PubMed:37198476). In normal conditions, NINJ1 is inactivated and alpha1 and alpha2 helices are not inserted into the membrane (PubMed:37198476). Following NINJ1 activation, alpha1 and alpha2 helices insert into the membrane and drive NINJ1 oligomerization via interactions between alpha3 and alpha4 and the hydrophobic face of alpha1 from an adjacent subunit (PubMed:37198476). Such structures disrupt membrane integrity and form a lesion through the introduction of the hydrophilic faces of alpha1 and alpha2 into the hydrophobic membrane (PubMed:37198476).
Effector of necroptotic and pyroptotic programmed cell death that mediates plasma membrane rupture (cytolysis) (PubMed:33472215, PubMed:36468682, PubMed:37196676, PubMed:37198476). Acts downstream of Gasdermin (GSDMA, GSDMB, GSDMC, GSDMD, or GSDME) or MLKL during pyroptosis or necroptosis, respectively: oligomerizes in response to death stimuli and promotes plasma membrane rupture by introducing hydrophilic faces of 2 alpha helices into the hydrophobic membrane, leading to release intracellular molecules named damage-associated molecular patterns (DAMPs) that propagate the inflammatory response (PubMed:33472215, PubMed:36468682, PubMed:37196676, PubMed:37198476). Acts as a regulator of Toll-like receptor 4 (TLR4) signaling triggered by lipopolysaccharide (LPS) during systemic inflammation; directly binds LPS (PubMed:26677008). Involved in leukocyte migration during inflammation by promoting transendothelial migration of macrophages via homotypic binding (By similarity). Promotes the migration of monocytes across the brain endothelium to central nervous system inflammatory lesions (PubMed:22162058). Also acts as a homophilic transmembrane adhesion molecule involved in various processes such as axonal growth, cell chemotaxis and angiogenesis (PubMed:8780658, PubMed:9261151, PubMed:33028854). Promotes cell adhesion by mediating homophilic interactions via its extracellular N-terminal adhesion motif (N-NAM) (PubMed:33028854). Involved in the progression of the inflammatory stress by promoting cell-to-cell interactions between immune cells and endothelial cells (PubMed:22162058, PubMed:26677008, PubMed:32147432). Plays a role in nerve regeneration by promoting maturation of Schwann cells (PubMed:8780658, PubMed:9261151). Acts as a regulator of angiogenesis (PubMed:33028854). Promotes the formation of new vessels by mediating the interaction between capillary pericyte cells and endothelial cells (By similarity). Promotes osteoclasts development by enhancing the survival of prefusion osteoclasts (By similarity). Also involved in striated muscle growth and differentiation (By similarity).
Homooligomer; in response to death stimuli, homooligomerizes into long, highly branched filaments and large, ring-shaped structures in the membrane.
In normal conditions, NINJ1 is inactivated (PubMed:37198476). In response to death stimuli, homooligomerizes and disrupts membrane integrity by introducing the hydrophilic faces of alpha1 and alpha2 helices into the hydrophobic membrane (PubMed:37198476). Homooligomerization and ability to mediate plasma membrane rupture is inhibited by glycine; it is unclear whether glycine directly or indirectly inhibits homooligomerization (PubMed:36468682).
N-linked glycosylation is required for homooligomerization.
Secreted form generated by cleavage, which has chemotactic activity (By similarity). Acts as an anti-inflammatory mediator by promoting monocyte recruitment, thereby ameliorating atherosclerosis (PubMed:32883094).
Widely expressed in both adult and embryonic tissues, primarily those of epithelial origin.
Created from a fragment entry and may await further characterization.
May regulate cilium motility through its role in the assembly of the axonemal radial spokes.
(Microbial infection) Interacts with HIV-1 Vpu protein; this interaction allows Vpu to down-regulate BLM sumoylation.
A chromosomal aberration involving RANBP2 is a cause of chromosome 8p11 myeloproliferative syndrome. Translocation t(2;8)(q12;p11) with FGFR1. Chromosome 8p11 myeloproliferative syndrome is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia.
Despite the presence of a PPIase cyclophilin-type domain, it has probably no peptidyl-prolyl cis-trans isomerase activity.
E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I (PubMed:11792325, PubMed:12032081, PubMed:15378033, PubMed:22194619, PubMed:15931224). Involved in transport factor (Ran-GTP, karyopherin)-mediated protein import via the F-G repeat-containing domain which acts as a docking site for substrates (PubMed:7775481). Binds single-stranded RNA (in vitro) (PubMed:7775481). May bind DNA (PubMed:7775481). Component of the nuclear export pathway (PubMed:10078529). Specific docking site for the nuclear export factor exportin-1 (PubMed:10078529). Inhibits EIF4E-dependent mRNA export (PubMed:22902403). Sumoylates PML at 'Lys-490' which is essential for the proper assembly of PML-NB (PubMed:22155184). Recruits BICD2 to the nuclear envelope and cytoplasmic stacks of nuclear pore complex known as annulate lamellae during G2 phase of cell cycle (PubMed:20386726). Probable inactive PPIase with no peptidyl-prolyl cis-trans isomerase activity (PubMed:20676357, PubMed:23353830).
Part of the nuclear pore complex (PubMed:11839768, PubMed:20386726, PubMed:23353830, PubMed:7603572). Forms a complex with NXT1, NXF1 and RANGAP1 (PubMed:14729961). Forms a tight complex with RANBP1 and UBE2I (PubMed:15388847, PubMed:10078529, PubMed:15826666). Interacts with SUMO1 but not SUMO2 (PubMed:15388847, PubMed:10078529, PubMed:15826666). Interacts with PRKN (PubMed:16332688). Interacts with sumoylated RANGAP1 (PubMed:15378033, PubMed:10078529, PubMed:15826666). Interacts with CDCA8 (PubMed:19413330). Interacts with PML (isoform PML-4) (PubMed:22155184). Interacts with BICD2 (PubMed:20386726). Interacts with MCM3AP isoform GANP (PubMed:20005110). Interacts with COX11 (PubMed:34400285).
Polyubiquitinated by PRKN, which leads to proteasomal degradation.
The PPIase cyclophilin-type domain has high structural similarity with PPIA, but has extremely low and barely detectable proline isomerase activity (in vitro) (PubMed:23353830). Only about half of the residues that surround the PPIA active site cleft are conserved.
The disease is caused by variants affecting the gene represented in this entry. Mutations in the RANBP2 gene predispose to IIAE3, but by themselves are insufficient to make the phenotype fully penetrant; additional genetic and environmental factors are required (PubMed:19118815).
The inner channel of the NPC has a different redox environment from the cytoplasm and allows the formation of interchain disulfide bonds between some nucleoporins, the significant increase of these linkages upon oxidative stress reduces the permeability of the NPC.
Interacts with the GAP domain of NF1 (PubMed:8836031). Interacts (via TPR repeats) with HSP90AA1 and HSPA8 (PubMed:15708368).
(Microbial infection) Cleaved and inactivated by the protease 2A of coxsackievirus B3, poliovirus and enterovirus 71 allowing the virus to disrupt the host type I interferon production.
(Microbial infection) Interacts with Encephalomyocarditis virus protein 2C; this interaction inhibits the induction of the IFN-beta signal pathway.
(Microbial infection) Interacts with SARS-COV-2 virus protein NSP3; the interaction antagonizes ISG15-dependent IFIH1 activation via active de-ISGylation.
(Microbial infection) Interacts with V protein of paramyxoviruses; these interactions prevent IFN-beta induction, and subsequent establishment of an antiviral state.
(Microbial infection) Interacts with herpes simplex virus 1 protein US11; this interaction prevents the interaction of MAVS/IPS1 to IFIH1.
(Microbial infection) Interacts with protease 3C of coxsackievirus A16; this interaction inhibits IFIH1 thereby attenuating type-I IFN production.
Belongs to the helicase family. RLR subfamily.
During apoptosis, processed into 3 cleavage products. The helicase-containing fragment, once liberated from the CARD domains, translocate from the cytoplasm to the nucleus. The processed protein significantly sensitizes cells to DNA degradation.
IFIH1 is the CADM-140 autoantigen, involved in clinically amyopathic dermatomyositis (CADM). This is a chronic inflammatory disorder that shows typical skin manifestations of dermatomyositis but has no or little evidence of clinical myositis. Anti-CADM-140 antibodies appear to be specific to dermatomyositis, especially CADM. Patients with anti-CADM-140 antibodies frequently develop life-threatening acute progressive interstitial lung disease (ILD).
ISGylated by ISG15. ISGylation increases upon infection with dengue (DENV) or Zika (ZIKV) viruses. ISGylation at Lys-23 and Lys-43 is dependent of dephosphorylation at Ser-88, regulates mitochondrial translocation and oligomerization. Essential for IFIH1/MDA5-mediated cytokine responses and restriction of virus replication.
In HIV-1 infected HeLa-CD4 cells, overexpression of IFIH1 results in a great increase in the level of secreted viral p24 protein.
Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and pro-inflammatory cytokines (PubMed:32169843, PubMed:33727702, PubMed:28594402). Its ligands include mRNA lacking 2'-O-methylation at their 5' cap and long-dsRNA (>1 kb in length) (PubMed:22160685). Upon ligand binding it associates with mitochondria antiviral signaling protein (MAVS/IPS1) which activates the IKK-related kinases: TBK1 and IKBKE which phosphorylate interferon regulatory factors: IRF3 and IRF7 which in turn activate transcription of antiviral immunological genes, including interferons (IFNs); IFN-alpha and IFN-beta. Responsible for detecting the Picornaviridae family members such as encephalomyocarditis virus (EMCV), mengo encephalomyocarditis virus (ENMG), and rhinovirus (PubMed:28606988). Detects coronavirus SARS-CoV-2 (PubMed:33440148, PubMed:33514628). Can also detect other viruses such as dengue virus (DENV), west Nile virus (WNV), and reovirus. Also involved in antiviral signaling in response to viruses containing a dsDNA genome, such as vaccinia virus. Plays an important role in amplifying innate immune signaling through recognition of RNA metabolites that are produced during virus infection by ribonuclease L (RNase L). May play an important role in enhancing natural killer cell function and may be involved in growth inhibition and apoptosis in several tumor cell lines.
Monomer in the absence of ligands and homodimerizes in the presence of dsRNA ligands. Can assemble into helical or linear polymeric filaments on long dsRNA (PubMed:33727702). Interacts with MAVS/IPS1. Interacts (via the CARD domains) with TKFC, the interaction is inhibited by viral infection (PubMed:17600090). Interacts with PCBP2. Interacts with NLRC5. Interacts with PIAS2-beta. Interacts with DDX60. Interacts with ANKRD17. Interacts with IKBKE (PubMed:17600090). Interacts with ATG5 and ATG12, either as ATG5 and ATG12 monomers or as ATG12-ATG5 conjugates (PubMed:17709747). Interacts with ZCCHC3; leading to activate IFIH1/MDA5 (PubMed:30193849). Interacts with RNF123 (PubMed:27312109). Interacts with DDX3X (PubMed:20127681). Interacts with NOD1; this interaction promotes transcription of antiviral genes and inhibition of viral replication (PubMed:32169843). Interacts with ECSIT; this interaction bridges IFIH1 to the MAVS complex at the mitochondrion (PubMed:25228397).
Phosphorylated at Ser-88. Dephosphorylated by phsophatases PP1; dephosphorylation precedes and is required for ISGylation.
Sumoylated. Sumoylation positively regulates its role in type I interferon induction and is enhanced by PIAS2-beta.
Ubiquitinated by RNF125, leading to its degradation by the proteasome (PubMed:17460044). USP17/UPS17L2-dependent deubiquitination positively regulates the receptor (PubMed:20368735). Ubiquitinated by TRIM25 via 'Lys-63'-linked ubiquitination, promoting activation of IFIH1/MDA5 (PubMed:30193849). Ubiquitinated by TRIM40 via 'Lys-48'-linked ubiquitination; leading to proteasomal degradation (PubMed:29117565). Ubiquitinated by TRIM65 via 'Lys-63'-linked ubiquitination, promoting activation of IFIH1/MDA5 (PubMed:28594402).
Widely expressed, at a low level. Expression is detected at slightly highest levels in placenta, pancreas and spleen and at barely levels in detectable brain, testis and lung.
Shows a relatively higher expression level in the fetal brain and a lower level in adult. The expression level in liver is highest at 16 weeks of development and declines from 16 to 24 weeks and is lower in adult. Expressed strongly in fetal heart on 18 and 24 weeks, but relatively weakly on the other development stage of embryo, and then reaches a higher level in adult (isoform 3).
Transcriptional repressor which suppresses activation protein 1 (AP-1)- and serum response element (SRE)-mediated transcriptional activity.
Widely expressed in various adult tissues and embryonic developmental stages (isoform 3).
Abundant in spleen, ovary, prostate, testis, and colon mucosa.
Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication.
Expressed until four or five weeks after birth. Detected at very low levels in adults, where it constitutes about 1% of the total hemoglobin. In contrast, the levels of fetal hemoglobin F (two alpha chains and two gamma chains) are increased in children and adults with beta-thalassemia or sickle-cell disease. In cases of homozygous alpha-thalassemia, homotetrameric hemoglobin Bart's is highly expressed and is the predominant form of hemoglobin after 10 weeks of gestation. Its levels increase steadily after 10 weeks of gestation and until birth (at protein level).
Heterotetramer of two alpha chains and two gamma chains in fetal hemoglobin (Hb F). In the case of deletions affecting one or more of the alpha chains, the excess gamma chains form homotetramers that exhibit neither Bohr effect nor heme-heme cooperativity (hemoglobin Bart's).
The modification form of Leu-142 is subject of controversy and could be the artifactual result of sample handling.
Protamines substitute for histones in the chromatin of sperm during the haploid phase of spermatogenesis. They compact sperm DNA into a highly condensed, stable and inactive complex (By similarity).
Expressed at a moderately low level in many tissues. Most abundant in kidney, prostate, ovary, intestine, and spleen.
Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate. Inhibitor of p53-induced apoptosis.
Glycosylated. In testis there are two predominant forms of 77- and 67-kDa and a form of 47-kDa, whereas in epididymal sperm from caput, corpus, and cauda there are two forms of 47- and 43-kDa. Testis forms contain complex carbohydrate residues. Epididymal sperm forms are N-glycosylated. Then undergoes significant glycosylation in the testis and that the majority of these glycoconjugates are removed by the time sperm reach the caput epididymis.
Highly expressed in testis, where it is localized in the acrosome of postmeiotic stages of spermiogenesis (round and elongating spermatids and in ejaculated spermatozoa) (at protein level). Poorly expressed in placenta and fetal lung.
Involved in fertilization ability of sperm.
(Microbial infection) Promotes Dengue virus RNA replication by negatively regulating IFN-beta signaling and mediating 'Lys-48'-linked ubiquitination on IRF3 (PubMed:30157886).
Catalyzes the covalent attachment of ubiquitin to other proteins. Functions in the selective degradation of misfolded membrane proteins from the endoplasmic reticulum (ERAD) and is essential for cells to recover from ER stress (PubMed:28321712). Plays a role in MAPKAPK2-dependent translational control of TNF-alpha synthesis (PubMed:24020373). Acts also as a platform for perinuclear positioning of the endosomal system by mediating ubiquitination of SQSTM1 through interaction with the E3 ubiquitin-protein ligase RNF26 (PubMed:33472082).
Component of the HRD1 complex, which comprises at least SYNV1/HRD1, DERL1/2, FAM8A1, HERPUD1/HERP, OS9, SEL1L and UBE2J1 (PubMed:28827405). Interacts with E3 ligase RNF26 (PubMed:33472082).
Phosphorylated UBE2J1 is rapidly ubiquitinated and subsequently degraded by the proteasome.
Phosphorylated at Ser-184 in a cytosolic stress-dependent manner by MAP kinase p38 MAPKAPK2.
Activated during mitosis by intramolecular autophosphorylation (PubMed:11864968). Activity and autophosphorylation is activated by manganese >> magnesium ions (PubMed:11864968). Sensitive to increasing concentration of detergents (PubMed:11864968). It is not cell-cycle regulated but activity is higher in G0-arrested cells (PubMed:11864968).
Autophosphorylated on serine and threonine residues (PubMed:27153399). When complexed with FACT, exhibits markedly elevated phosphorylation on Thr-210. During mitosis, not phosphorylated on Thr-210. Phosphorylated by CDK1 in vitro (PubMed:14660563).
Dimerizes through its coiled-coil domain.
Expression varied mildly across the cell cycle, with highest expression observed in G1 and stationary-phase cells.
Homodimer; homodimerization is required to activate NEK7 (PubMed:26522158, PubMed:23482567). Binds to Ran GTPase (PubMed:12101123). Has a greater affinity for Ran-GDP over Ran-GTP (PubMed:12101123). Interacts with SSRP1 and SUPT16H, the 2 subunits of the FACT complex (PubMed:14660563). Interacts with DYNLL1; phosphorylation at Ser-944 strongly reduces DYNLL1 binding (PubMed:23482567).
Most abundant in heart, liver, kidney and testis. Also expressed in smooth muscle cells and fibroblasts.
Pleiotropic regulator of mitotic progression, participating in the control of spindle dynamics and chromosome separation (PubMed:12101123, PubMed:12840024, PubMed:14660563, PubMed:19941817). Phosphorylates different histones, myelin basic protein, beta-casein, and BICD2 (PubMed:11864968). Phosphorylates histone H3 on serine and threonine residues and beta-casein on serine residues (PubMed:11864968). Important for G1/S transition and S phase progression (PubMed:12840024, PubMed:14660563, PubMed:19941817). Phosphorylates NEK6 and NEK7 and stimulates their activity by releasing the autoinhibitory functions of Tyr-108 and Tyr-97 respectively (PubMed:12840024, PubMed:14660563, PubMed:19941817, PubMed:26522158).
Dipeptidase that hydrolyzes leukotriene D4 (LTD4) into leukotriene E4 (LTE4) (PubMed:32325220). Hydrolyzes cystinyl-bis-glycine (PubMed:32325220).
Independently of its dipeptidase activity can also modulate macrophage inflammatory response by acting as a regulator of NF-kappaB inflammatory signaling pathway.
ATP- and membrane-binding protein that controls membrane reorganization/tubulation upon ATP hydrolysis (By similarity). Plays a role in membrane trafficking between the plasma membrane and endosomes (PubMed:17233914). Important for the internalization of GLUT4. Required for fusion of myoblasts to skeletal muscle myotubes. Required for normal translocation of FER1L5 to the plasma membrane (By similarity). Regulates the equilibrium between cell surface-associated and cell surface-dissociated caveolae by constraining caveolae at the cell membrane (PubMed:25588833).
Highly expressed in heart and moderately expressed in placenta, lung, and skeletal muscle.
Homodimer and homooligomer. Interacts with EHD1. May also interact with EHD3 and EHD4 (PubMed:17233914). Interacts with MYOF (PubMed:18502764). Interacts with EHBP1. Interacts with FER1L5 (via second C2 domain) (By similarity). Interacts with CAV1 in a cholesterol-dependent manner (PubMed:25588833). Interacts (via EH domain) with PACSIN2 (via NPF motifs); this interaction probably stabilizes the caveolae (PubMed:22323287).
The very low intrinsic ATPase activity is increased upon interaction with liposomes.
Interacts with SH3GL2. Interaction appears to regulate MAP4K3-mediated JNK activation (By similarity).
May play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway.
Ubiquitously expressed in all tissues examined, with high levels in heart, brain, placenta, skeletal muscle, kidney and pancreas and lower levels in lung and liver.
Catalyzes the addition of GlcNAc or GlcUA monosaccharides to the nascent hyaluronan polymer. Therefore, it is essential to hyaluronan synthesis a major component of most extracellular matrices that has a structural role in tissues architectures and regulates cell adhesion, migration and differentiation. This is one of the isozymes catalyzing that reaction. Also able to catalyze the synthesis of chito-oligosaccharide depending on the substrate (By similarity).
Widely expressed. Highly expressed in ovary followed by spleen, thymus, prostate, testes and large intestine. Weakly expressed in small intestine.
Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids, phosphatidylserines (PS) and phosphatidylethanolamines (PE), from the outer to the inner leaflet of the plasma membrane (PubMed:25315773, PubMed:25947375, PubMed:26567335, PubMed:29799007, PubMed:30018401). Does not show flippase activity toward phosphatidylcholine (PC) (PubMed:34403372). Contributes to the maintenance of membrane lipid asymmetry with a specific role in morphogenesis of muscle cells. In myoblasts, mediates PS enrichment at the inner leaflet of plasma membrane, triggering PIEZO1-dependent Ca2+ influx and Rho GTPases signal transduction, subsequently leading to the assembly of cortical actomyosin fibers and myotube formation (PubMed:29799007). May be involved in the uptake of farnesyltransferase inhibitor drugs, such as lonafarnib.
Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit ATP11A and an accessory beta subunit TMEM30A.
Overexpression of ATP11A confers resistance to lonafarnib.
The flippase activity is inactivated by caspase-mediated cleavage in apoptotic cells, allowing for PS exposure on the cell surface and engulfment of apoptotic cells by macrophages. The ATPase activity is up-regulated by aminophospholipids PS and PE and down-regulated by increasing intracellular Ca2+ levels.
Widely expressed (PubMed:26567335). Expressed in myoblasts (PubMed:29799007).
ATM/ATR-mediated phosphorylation at Thr-454 upon DNA damage promotes binding to SIRT1. Phosphorylation at Thr-454 promotes its sumoylation by switching the binding partner of CCAR2 from SENP1 to PIAS3.
Acetylation at Lys-112 and Lys-215 by KAT8 prevents inhibitory binding to SIRT1 and increases its deacetylase activity.
Component of the DBIRD complex (PubMed:22446626). Interacts with ZNF326/ZIRD; the interaction is direct (PubMed:22446626). Interacts (via N-terminus) with SIRT1, which inhibits the deacetylation of substrates (PubMed:18235501, PubMed:18235502, PubMed:21030595, PubMed:22735644, PubMed:23352644, PubMed:24126058, PubMed:25406032). Interacts (via N-terminus) with SUV39H1; this interaction abolishes the interaction with SIRT1 (PubMed:19218236). Component of a nuclear receptor-mediated transcription complex composed of at least ZNF335, CCAR2 and EMSY; the complex stimulates the transcription of nuclear receptor target genes such as SOX9 and HOXA1 (PubMed:19131338). Within the complex interacts with EMSY and interacts with ZNF335 (via C-terminus) (PubMed:19131338). Components of this complex may associate with components of a histone methylation complex to form a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY, MKI67, RBBP5, ASH2L and WDR5 (PubMed:19131338). Within this complex, interacts with ASH2L (PubMed:19131338). Interacts with NR1D1 (PubMed:23398316). Interacts (via N-terminus) with ESR1 and ESR2 (PubMed:20074560). Interacts (via N-terminus) with HDAC3 (via C-terminus) (PubMed:21030595). Interacts with HDAC1 and MED2F (PubMed:21030595). Interacts with MCC (PubMed:24824780). Interacts (via N-terminus) with NR1H2 and NR1H3 in a ligand-independent manner (PubMed:25661920). Interacts with CSNK2A1 (PubMed:24962073). Interacts (via N-terminus) with p53/TP53 (PubMed:25732823). Interacts (via N-terminus) with BRCA1 (via the BRCT domains) (PubMed:20160719). Interacts (via N-terminus) with CHEK2 (via protein kinase domain) (PubMed:25361978). Interacts with PSEM3 (PubMed:25361978). Interacts (via N-terminus) with PSIA3 and SENP1 (PubMed:25406032). The sumoylated form shows a preferential interaction with SIRT1 as compared to its unmodified form (PubMed:25406032).
Core component of the DBIRD complex, a multiprotein complex that acts at the interface between core mRNP particles and RNA polymerase II (RNAPII) and integrates transcript elongation with the regulation of alternative splicing: the DBIRD complex affects local transcript elongation rates and alternative splicing of a large set of exons embedded in (A + T)-rich DNA regions (PubMed:22446626). Inhibits SIRT1 deacetylase activity leading to increasing levels of p53/TP53 acetylation and p53-mediated apoptosis (PubMed:18235501, PubMed:18235502, PubMed:23352644). Inhibits SUV39H1 methyltransferase activity (PubMed:19218236). Mediates ligand-dependent transcriptional activation by nuclear hormone receptors (PubMed:19131338). Plays a critical role in maintaining genomic stability and cellular integrity following UV-induced genotoxic stress (PubMed:23398316). Regulates the circadian expression of the core clock components NR1D1 and BMAL1 (PubMed:23398316). Enhances the transcriptional repressor activity of NR1D1 through stabilization of NR1D1 protein levels by preventing its ubiquitination and subsequent degradation (PubMed:23398316). Represses the ligand-dependent transcriptional activation function of ESR2 (PubMed:20074560). Acts as a regulator of PCK1 expression and gluconeogenesis by a mechanism that involves, at least in part, both NR1D1 and SIRT1 (PubMed:24415752). Negatively regulates the deacetylase activity of HDAC3 and can alter its subcellular localization (PubMed:21030595). Positively regulates the beta-catenin pathway (canonical Wnt signaling pathway) and is required for MCC-mediated repression of the beta-catenin pathway (PubMed:24824780). Represses ligand-dependent transcriptional activation function of NR1H2 and NR1H3 and inhibits the interaction of SIRT1 with NR1H3 (PubMed:25661920). Plays an important role in tumor suppression through p53/TP53 regulation; stabilizes p53/TP53 by affecting its interaction with ubiquitin ligase MDM2 (PubMed:25732823). Represses the transcriptional activator activity of BRCA1 (PubMed:20160719). Inhibits SIRT1 in a CHEK2 and PSEM3-dependent manner and inhibits the activity of CHEK2 in vitro (PubMed:25361978).
Expressed in gastric carcinoma tissue and the expression gradually increases with the progression of the carcinoma (at protein level). Expressed ubiquitously in normal tissues. Expressed in 84 to 100% of neoplastic breast, lung, and colon tissues.
Genotoxic stress induces its sumoylation and sumoylation promotes the SIRT1-CCAR2 interaction which in turn inhibits SIRT1-mediated deacetylation of p53/TP53. Sumoylation leads to transcriptional activation of p53/TP53 by sequestering SIRT1 from p53/TP53. Desumoylated by SENP1.
Regulated at the translational level via an alternative ribosome re-initiation mechanism in response to various stress such as endoplasmic reticulum stress or oxidative stress (PubMed:33384352). In the absence of stress, ribosomes re-initiate translation at an inhibitory upstream open reading frames (uORFs) of the QRICH1 transcript, which preclude QRICH1 translation. In response to stress and subsequent EIF2S1/eIF-2-alpha phosphorylation, ribosomes bypass the inhibitory uORFs and re-initiate translation at the QRICH1 coding sequence (PubMed:33384352). Positive autoregulation at the transcriptional level (PubMed:33384352).
The CARD domain may be involved in the regulation of caspase activity in the context of programmed cell death.
Transcriptional regulator that acts as a mediator of the integrated stress response (ISR) through transcriptional control of protein homeostasis under conditions of ER stress (PubMed:33384352). Controls the outcome of the unfolded protein response (UPR) which is an ER-stress response pathway (PubMed:33384352). ER stress induces QRICH1 translation by a ribosome translation re-initiation mechanism in response to EIF2S1/eIF-2-alpha phosphorylation, and stress-induced QRICH1 regulates a transcriptional program associated with protein translation, protein secretion-mediated proteotoxicity and cell death during the terminal UPR (PubMed:33384352). May cooperate with ATF4 transcription factor signaling to regulate ER homeostasis which is critical for cell viability (PubMed:33384352). Up-regulates CASP3/caspase-3 activity in epithelial cells under ER stress. Central regulator of proteotoxicity associated with ER stress-mediated inflammatory diseases in the intestines and liver (PubMed:33384352). Involved in chondrocyte hypertrophy, a process required for normal longitudinal bone growth (PubMed:30281152).
Expression peaks at S/G2 phases of the cell cycle.
Interacts (phosphorylation-dependent) with CHEK1; regulates CLSPN function in checkpoint for DNA damage and replication (PubMed:12766152, PubMed:15707391, PubMed:16963448). Interacts with ATR and RAD9A and these interactions are slightly reduced during checkpoint activation (PubMed:12766152). Interacts with BRCA1 and this interaction increases during checkpoint activation (PubMed:15096610). Interacts with TIMELESS; the interaction is required for leading-strand replication (PubMed:17141802, PubMed:35585232, PubMed:34700328, PubMed:34694004). Associates with the MCM2-7 complex and other replisome factors (PubMed:34700328, PubMed:34694004, PubMed:27401717). Interacts (via the acidic patch) with CDC7; the interaction is required for phosphorylation of MCM proteins and CLASPIN by CDC7 (PubMed:27401717). Interacts with PCNA (PubMed:27401717). Interacts with FZR1 (PubMed:18662541).
Phosphorylated. Undergoes ATR-dependent phosphorylation by CHEK1 during activation of DNA replication or damage checkpoints. Phosphorylation by CSNK1G1/CK1 promotes CHEK1 binding (PubMed:12766152, PubMed:15096610, PubMed:16963448, PubMed:21680713). Phosphorylated by CDC7 during DNA replication, phosphorylation inhibits interaction between the acidic patch and N-terminal segments leading to increased binding to DNA and PCNA (PubMed:27401717).
Proteolytically cleaved by caspase-7 (CASP7) in response to apoptosis, leading to its inactivation.
Required for checkpoint mediated cell cycle arrest in response to inhibition of DNA replication or to DNA damage induced by both ionizing and UV irradiation (PubMed:12766152, PubMed:15190204, PubMed:15707391, PubMed:16123041). Adapter protein which binds to BRCA1 and the checkpoint kinase CHEK1 and facilitates the ATR-dependent phosphorylation of both proteins (PubMed:12766152, PubMed:15707391, PubMed:15096610, PubMed:16123041). Also required to maintain normal rates of replication fork progression during unperturbed DNA replication. Binds directly to DNA, with particular affinity for branched or forked molecules and interacts with multiple protein components of the replisome such as the MCM2-7 complex and TIMELESS (PubMed:15226314, PubMed:35585232, PubMed:34694004). Important for initiation of DNA replication, recruits kinase CDC7 to phosphorylate MCM2-7 components (PubMed:27401717).
The C-terminus of the protein contains 3 potential CHEK1-binding motifs (CKB motifs). Potential phosphorylation sites within CKB motif 1 and CKB motif 2 are required for interaction with CHEK1.
The acidic patch region is required for normal DNA replication. Interacts with the N-terminal segments and inhibits binding to DNA and PCNA. Mediates the interaction with the kinase CDC7 as well as some replisome factors and DNA polymerases.
Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) during G1 phase, leading to its degradation by the proteasome. Ubiquitination is mediated via its interaction with FZR1/CDH1. Following DNA damage, it is deubiquitinated by USP28 in G2 phase, preventing its degradation.
Acts as an osmosensitive calcium-permeable cation channel (PubMed:30382938, PubMed:31587869). Mechanosensitive ion channel that converts mechanical stimuli into a flow of ion (PubMed:30382938, PubMed:31587869).
Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8 (By similarity). Interacts with CACGN8 (By similarity). Interacts with GRIA1.
Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by regulating their rates of activation, deactivation and desensitization. Blocks CACNG8-mediated resensitization of AMPA receptors.
Contaminating sequence. Potential poly-A sequence starting in position 426.
The cDNA sequence has been translated in the reverse direction.
Amino acid transporter with an apparent selectivity for L-glutamine and L-glutamate. May facilitate glutamine uptake in excitatory neurons. The transport mechanism remains to be elucidated.
Belongs to the immunoglobulin superfamily. FCGR1 family.
High affinity receptor for the Fc region of immunoglobulins gamma. Functions in both innate and adaptive immune responses. Mediates IgG effector functions on monocytes triggering antibody-dependent cellular cytotoxicity (ADCC) of virus-infected cells.
Interacts with IGHG1 (PubMed:11711607). Interacts with FCERG1; forms a functional signaling complex. Interacts with FLNA; prevents FCGR1A degradation. Interacts with EPB41L2, LAT and PPL. Interacts with HCK and LYN.
Binds to target gene promoters, including NKX2-5 and SYCE1, but not GATA4, and may be involved in the maintenance of the active epigenetic status of these genes.
Expressed in embryonic stem cells. No expression is seen in 5 months embryo, mesenchymal stem cells, embryonic fibrocytes and adult tissues.
Expressed in the retina (at protein level). Highly expressed in the retina. Lower amounts are detected in brain, testis, ARPE-19, RPE/choroid and fetal eye. Isoform 5 is retina-specific.
Interacts with MPDZ. May interact with GRIA2 (By similarity). Forms a complex with CRB1 and PALS1. Interacts with FASLG.
May play a role in retinal photoreceptors development.
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Incorporated instead of PSMB5 and PSMB8.
The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Incorporated instead of PSMB5 or PSMB8, this unit reduces the chymotrypsin-like activity of the proteasome (By similarity). Plays a pivotal role in development of CD8-positive T cells (By similarity).
Centrosomal protein involved in centriole biogenesis. Acts as a scaffolding protein during early centriole biogenesis. Required for the targeting of centriole satellite proteins to centrosomes such as of PCM1, SSX2IP and CEP290 and recruitment of WRAP73 to centrioles. Also required for centriole-centriole cohesion during interphase by acting as a platform protein for CEP250 at the centriole. Required for the recruitment of CEP295 to the proximal end of new-born centrioles at the centriolar microtubule wall during early S phase in a PLK4-dependent manner (PubMed:27185865).
Interacts with DCTN2 (By similarity). Interacts with CEP250 (PubMed:18851962).
It has been suggested that DPY19L1 has a related pseudogene DPY19L1P1.
(Microbial infection) Associates with the influenza A viral protein NP in the nucleus of infected cells, promoting viral growth and enhancing the activity of the viral polymerase.
(Microbial infection) Critical for entry of human coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus NL63/HCoV-NL63 (PubMed:33147444). Regulates the expression of the pro-viral genes ACE2 and CTSL through chromatin modulation (PubMed:33147444). Required for SARS-CoV-2 ORF3A-induced reticulophagy which induces endoplasmic reticulum stress and inflammatory responses and facilitates viral infection (PubMed:35239449).
(Microbial infection) Facilitates dengue virus propagation via interaction with the untranslated regions of viral genome. In turn, this interaction with viral RNA may regulate secondary structure of dengue RNA thus facilitating its recognition by the replication complex.
(Microbial infection) Interacts with SARS-CoV-2 ORF3A protein; the interaction promotes association of HMGB1 with BECN1, promoting reticulophagy which induces endoplasmic reticulum stress and inflammatory responses and facilitates viral infection.
(Microbial infection) Interacts with adenovirus protein pVII; this interaction immobilizes HMGB1 on chromatin, thus preventing its release from cell and subsequent inflammation activation.
(Microbial infection) Interacts with influenza A virus protein NP; this interaction promotes viral replication.
(Microbial infection) Promotes Epstein-Barr virus (EBV) latent-to-lytic switch by sustaining the expression of the viral transcription factor BZLF1 that acts as a molecular switch to induce the transition from the latent to the lytic or productive phase of the virus cycle. Mechanistically, participates in EBV reactivation through the NLRP3 inflammasome.
(Microbial infection) Protein levels increase upon infection by human coronavirus SARS-CoV-2.
Acetylated on multiple sites upon stimulation with LPS (PubMed:22801494). Acetylation on lysine residues in the nuclear localization signals (NLS 1 and NLS 2) leads to cytoplasmic localization and subsequent secretion (By similarity). Acetylation on Lys-3 results in preferential binding to DNA ends and impairs DNA bending activity (By similarity).
Forms covalent cross-links mediated by transglutaminase TGM2, between a glutamine and the epsilon-amino group of a lysine residue, forming homopolymers and heteropolymers.
HMG box 2 mediates pro-inflammatory cytokine-stimulating activity and binding to TLR4 (PubMed:12765338, PubMed:20547845). However, not involved in mediating immunogenic activity in the context of apoptosis-induced immune tolerance (PubMed:24474694).
In the cytoplasm proposed to dissociate the BECN1:BCL2 complex via competitive interaction with BECN1 leading to autophagy activation (PubMed:20819940). Involved in oxidative stress-mediated autophagy (PubMed:21395369). Can protect BECN1 and ATG5 from calpain-mediated cleavage and thus proposed to control their proautophagic and proapoptotic functions and to regulate the extent and severity of inflammation-associated cellular injury (By similarity). In myeloid cells has a protective role against endotoxemia and bacterial infection by promoting autophagy (By similarity). Involved in endosomal translocation and activation of TLR9 in response to CpG-DNA in macrophages (By similarity).
In the extracellular compartment (following either active secretion or passive release) involved in regulation of the inflammatory response. Fully reduced HGMB1 (which subsequently gets oxidized after release) in association with CXCL12 mediates the recruitment of inflammatory cells during the initial phase of tissue injury; the CXCL12:HMGB1 complex triggers CXCR4 homodimerization (PubMed:22370717). Induces the migration of monocyte-derived immature dendritic cells and seems to regulate adhesive and migratory functions of neutrophils implicating AGER/RAGE and ITGAM (By similarity). Can bind to various types of DNA and RNA including microbial unmethylated CpG-DNA to enhance the innate immune response to nucleic acids. Proposed to act in promiscuous DNA/RNA sensing which cooperates with subsequent discriminative sensing by specific pattern recognition receptors (By similarity). Promotes extracellular DNA-induced AIM2 inflammasome activation implicating AGER/RAGE (PubMed:24971542). Disulfide HMGB1 binds to transmembrane receptors, such as AGER/RAGE, TLR2, TLR4 and probably TREM1, thus activating their signal transduction pathways. Mediates the release of cytokines/chemokines such as TNF, IL-1, IL-6, IL-8, CCL2, CCL3, CCL4 and CXCL10 (PubMed:12765338, PubMed:18354232, PubMed:19264983, PubMed:20547845, PubMed:24474694). Promotes secretion of interferon-gamma by macrophage-stimulated natural killer (NK) cells in concert with other cytokines like IL-2 or IL-12 (PubMed:15607795). TLR4 is proposed to be the primary receptor promoting macrophage activation and signaling through TLR4 seems to implicate LY96/MD-2 (PubMed:20547845). In bacterial LPS- or LTA-mediated inflammatory responses binds to the endotoxins and transfers them to CD14 for signaling to the respective TLR4:LY96 and TLR2 complexes (PubMed:18354232, PubMed:21660935, PubMed:25660311). Contributes to tumor proliferation by association with ACER/RAGE (By similarity). Can bind to IL1-beta and signals through the IL1R1:IL1RAP receptor complex (PubMed:18250463). Binding to class A CpG activates cytokine production in plasmacytoid dendritic cells implicating TLR9, MYD88 and AGER/RAGE and can activate autoreactive B cells. Via HMGB1-containing chromatin immune complexes may also promote B cell responses to endogenous TLR9 ligands through a B-cell receptor (BCR)-dependent and ACER/RAGE-independent mechanism (By similarity). Inhibits phagocytosis of apoptotic cells by macrophages; the function is dependent on poly-ADP-ribosylation and involves binding to phosphatidylserine on the cell surface of apoptotic cells (By similarity). In adaptive immunity may be involved in enhancing immunity through activation of effector T cells and suppression of regulatory T (TReg) cells (PubMed:15944249, PubMed:22473704). In contrast, without implicating effector or regulatory T-cells, required for tumor infiltration and activation of T-cells expressing the lymphotoxin LTA:LTB heterotrimer thus promoting tumor malignant progression (By similarity). Also reported to limit proliferation of T-cells (By similarity). Released HMGB1:nucleosome complexes formed during apoptosis can signal through TLR2 to induce cytokine production (PubMed:19064698). Involved in induction of immunological tolerance by apoptotic cells; its pro-inflammatory activities when released by apoptotic cells are neutralized by reactive oxygen species (ROS)-dependent oxidation specifically on Cys-106 (PubMed:18631454). During macrophage activation by activated lymphocyte-derived self apoptotic DNA (ALD-DNA) promotes recruitment of ALD-DNA to endosomes (By similarity).
In vitro cleavage by CASP1 is liberating a HMG box 1-containing peptide which may mediate immunogenic activity; the peptide antagonizes apoptosis-induced immune tolerance (PubMed:24474694). Can be proteolytically cleaved by a thrombin:thrombomodulin complex; reduces binding to heparin and pro-inflammatory activities (By similarity).
Inconsistent experimental results may reflect the use of inconsistently defined redox forms. A recombinant fully reduced form has been used in a number of experiments. However, the redox states of HMGB1 administered in vivo, may interconvert among each other. Purified HMGB1 by itself has only weak pro-inflammatory activity.
Interacts (fully reduced HMGB1) with CXCL12; probably in a 1:2 ratio involving two molecules of CXCL12, each interacting with one HMG box of HMGB1; inhibited by glycyrrhizin (PubMed:22370717). Associates with the TLR4:LY96 receptor complex (PubMed:20547845). Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2 (By similarity). Interacts (in cytoplasm upon starvation) with BECN1; inhibits the interaction of BECN1 and BCL2 leading to promotion of autophagy (PubMed:20819940). Interacts with KPNA1; involved in nuclear import (PubMed:17114460). Interacts with SREBF1, TLR2, TLR4, TLR9, PTPRZ1, APEX1, FEN1, POLB, TERT (By similarity). Interacts with IL1B, AGER, MSH2, XPA, XPC, HNF1A, TP53 (PubMed:15014079, PubMed:18250463, PubMed:18160415, PubMed:19446504, PubMed:24474694, PubMed:23063560). Interacts with CD24; the probable CD24:SIGLEC10 complex is proposed to inhibit HGMB1-mediated tissue damage immune response (PubMed:19264983). Interacts with THBD; prevents HGMB1 interaction with ACER/RAGE and inhibits HGMB1 pro-inflammatory activity (PubMed:15841214). Interacts with HAVCR2; impairs HMGB1 binding to B-DNA and likely HMGB1-mediated innate immune response (By similarity). Interacts with XPO1; mediating nuclear export (By similarity). Interacts with HTT (wild-type and mutant HTT with expanded polyglutamine repeat) (PubMed:23303669). Interacts with receptor RAGE/AGER (PubMed:34743181).
Multifunctional redox sensitive protein with various roles in different cellular compartments. In the nucleus is one of the major chromatin-associated non-histone proteins and acts as a DNA chaperone involved in replication, transcription, chromatin remodeling, V(D)J recombination, DNA repair and genome stability (PubMed:33147444). Proposed to be an universal biosensor for nucleic acids. Promotes host inflammatory response to sterile and infectious signals and is involved in the coordination and integration of innate and adaptive immune responses. In the cytoplasm functions as sensor and/or chaperone for immunogenic nucleic acids implicating the activation of TLR9-mediated immune responses, and mediates autophagy. Acts as danger associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury (PubMed:27362237). Released to the extracellular environment can bind DNA, nucleosomes, IL-1 beta, CXCL12, AGER isoform 2/sRAGE, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), and activates cells through engagement of multiple surface receptors (PubMed:34743181). In the extracellular compartment fully reduced HMGB1 (released by necrosis) acts as a chemokine, disulfide HMGB1 (actively secreted) as a cytokine, and sulfonyl HMGB1 (released from apoptotic cells) promotes immunological tolerance (PubMed:23519706, PubMed:23446148, PubMed:23994764, PubMed:25048472). Has proangiogdenic activity (By similarity). May be involved in platelet activation (By similarity). Binds to phosphatidylserine and phosphatidylethanolamide (By similarity). Bound to RAGE mediates signaling for neuronal outgrowth (By similarity). May play a role in accumulation of expanded polyglutamine (polyQ) proteins such as huntingtin (HTT) or TBP (PubMed:23303669, PubMed:25549101).
Nuclear functions are attributed to fully reduced HGMB1. Associates with chromatin and binds DNA with a preference to non-canonical DNA structures such as single-stranded DNA, DNA-containing cruciforms or bent structures, supercoiled DNA and ZDNA. Can bent DNA and enhance DNA flexibility by looping thus providing a mechanism to promote activities on various gene promoters by enhancing transcription factor binding and/or bringing distant regulatory sequences into close proximity (PubMed:20123072). May have an enhancing role in nucleotide excision repair (NER) (By similarity). However, effects in NER using in vitro systems have been reported conflictingly (PubMed:19446504, PubMed:19360789). May be involved in mismatch repair (MMR) and base excision repair (BER) pathways (PubMed:15014079, PubMed:16143102, PubMed:17803946). May be involved in double strand break repair such as non-homologous end joining (NHEJ) (By similarity). Involved in V(D)J recombination by acting as a cofactor of the RAG complex: acts by stimulating cleavage and RAG protein binding at the 23 bp spacer of conserved recombination signal sequences (RSS) (By similarity). In vitro can displace histone H1 from highly bent DNA (By similarity). Can restructure the canonical nucleosome leading to relaxation of structural constraints for transcription factor-binding (By similarity). Enhances binding of sterol regulatory element-binding proteins (SREBPs) such as SREBF1 to their cognate DNA sequences and increases their transcriptional activities (By similarity). Facilitates binding of TP53 to DNA (PubMed:23063560). Proposed to be involved in mitochondrial quality control and autophagy in a transcription-dependent fashion implicating HSPB1; however, this function has been questioned (By similarity). Can modulate the activity of the telomerase complex and may be involved in telomere maintenance (By similarity).
Phosphorylated at serine residues. Phosphorylation in both NLS regions is required for cytoplasmic translocation followed by secretion (PubMed:17114460).
Poly-ADP-ribosylated by PARP1 when secreted following stimulation with LPS (By similarity).
Proposed to contribute to the pathogenesis of various chronic inflammatory and autoimmune diseases, and cancer. High serum levels are found in several inflammatory events including sepsis, rheumatoid arthritis, artherosclerosis chronic kidney disease, systemic lupus erythematosus (SLE). Seems to be implicated in other diseases characterized by cell death and damage, including diabetes and Alzheimer's disease. Its nucleosome-associated release during secondary necrosis may play a role in SLE (PubMed:19064698). During chemotherapy can mediate regrowth and metastasis of remaining cells in a AGER/RAGE-dependent manner (PubMed:23040637). Purified HMG box 1 acts as a specific antagonist to HGMB1 pro-inflammatory activities (PubMed:14695889).
Reduction/oxidation of cysteine residues Cys-23, Cys-45 and Cys-106 and a possible intramolecular disulfide bond involving Cys-23 and Cys-45 give rise to different redox forms with specific functional activities in various cellular compartments: 1- fully reduced HMGB1 (HMGB1C23hC45hC106h), 2- disulfide HMGB1 (HMGB1C23-C45C106h) and 3- sulfonyl HMGB1 (HMGB1C23soC45soC106so).
The acidic C-terminal domain forms a flexible structure which can reversibly interact intramolecularily with the HMG boxes and modulate binding to DNA and other proteins (PubMed:23063560).
Ubiquitous. Expressed in platelets (PubMed:11154118).
Expressed on a subclass of T-lymphocytes known as intra-epithelial lymphocytes which are located between mucosal epithelial cells.
Heterodimer of an alpha and a beta subunit. The alpha subunit is composed of a heavy and a light chains linked by a disulfide bond. Alpha-E associates with beta-7.
Integrin alpha-E/beta-7 is a receptor for E-cadherin. It mediates adhesion of intra-epithelial T-lymphocytes to epithelial cell monolayers.
Integrin alpha-E/beta-7 is induced by TGFB1.
Belongs to the phospholipase B-like family.
In view of the small size of the putative binding pocket, it has been proposed that it may act as an amidase or a peptidase (By similarity). Exhibits a weak phospholipase activity, acting on various phospholipids, including phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine and lysophospholipids.
May form a homodimer, each monomer is composed of a chain A and a chain B.
The maturation cleavages that produces chains A and B are required to open the putative substrate binding pocket. Both chains A and B remain associated in the mature protein.
Anchored to the endoplasmic reticulum membrane by a transmembrane hairpin structure; both N-terminus and C-terminus are cytoplasmic.
Belongs to the extended synaptotagmin family.
Homodimer. Interacts with ESYT1 and ESYT3. Interacts with FGFR1 that has been activated by FGF1 binding. Interacts with the AP-2 complex; identified in a complex with the AP-2 complex and FGFR1.
Tethers the endoplasmic reticulum to the cell membrane and promotes the formation of appositions between the endoplasmic reticulum and the cell membrane. Binds glycerophospholipids in a barrel-like domain and may play a role in cellular lipid transport. Plays a role in FGF signaling via its role in the rapid internalization of FGFR1 that has been activated by FGF1 binding; this occurs most likely via the AP-2 complex. Promotes the localization of SACM1L at endoplasmic reticulum-plasma membrane contact sites (EPCS) (PubMed:27044890).
The C2 domains mediate lipid and calcium binding. The N-terminal C2 domain binds calcium ions and is important for calcium-dependent lipid binding and interaction with membranes. Two calcium ions are bound at a high-affinity site and a third calcium ion is bound with lower affinity. May bind up to four calcium ions. In contrast, the second C2 domain apparently does not bind calcium (PubMed:24373768). The third C2 domain mediates interaction with membranes enriched in phosphatidylinositol 4,5-bisphosphate and is required for location at the cell membrane (PubMed:23791178).
The SMP-LTD domain is a barrel-like domain that binds glycerophospholipids in its interior; can bind two lipid molecules simultaneously. Binds a variety of lipids, including phosphatidylethanolamine, phosphatidylcholine and phosphatidylinositol (PubMed:24847877).
Widely expressed with high level in cerebellum.
Interacts with stathmin and CDKN1B/p27Kip1 (By similarity). Interacts with PAM.
Regulated in a cell-cycle dependent manner, with lowest levels during S phase and highest at G1 phase (at protein level).
Upon serum stimulation, phosphorylates CDKN1B/p27Kip1, thus controlling CDKN1B subcellular location and cell cycle progression in G1 phase. May be involved in trafficking and/or processing of RNA (By similarity).
Widely expressed, with highest levels in skeletal muscle, kidney, placenta and peripheral blood leukocytes.
Acts as a general chaperone in regulated exocytosis (By similarity). Acts as a co-chaperone for the SNARE protein SNAP-25 (By similarity). Involved in the calcium-mediated control of a late stage of exocytosis (By similarity). May have an important role in presynaptic function. May be involved in calcium-dependent neurotransmitter release at nerve endings (By similarity).
Expressed in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain and heart.
Oligomers (PubMed:27452402). Homodimer (By similarity). Interacts with the chaperone complex consisting of HSC70 and SGTA (By similarity). Interacts with ZDHHC13 (via ANK repeats) (By similarity). Interacts with ZDHHC17 (via ANK repeats) (PubMed:28882895). Interacts with SYT1, SYT5 and SYT7, and with SYT9, forming a complex with SNAP25 (By similarity).
Palmitoylated. Could be palmitoylated by DHHC3, DHHC7, DHHC15 and DHHC17. Palmitoylation occurs probably in the cysteine-rich domain and regulates DNAJC5 membrane attachment.
Ser-10 phosphorylation induces an order-to-disorder transition triggering the interaction with Lys-58 (PubMed:27452402). This conformational switch modulates DNAJC5's cellular functions by reducing binding to syntaxin and synaptogamin without altering HSC70 interactions (PubMed:27452402).
Upon phosphorylation, Ser-10 interacts with Lys-58, a highly conserved residue in DnaJ proteins that is also a ubiquitination site in DNAJC5.
Expressed in all tissues examined with higher expression in the heart and brain. No expression was seen in the corpus callosum of the brain.
The poly-Gln tract is polymorphic and the number of Gln varies from 12 to 14 (PubMed:11404004). The size of the poly-Gln region may influence the age at onset of spinocerebellar ataxia type 2 (SCA2) (PubMed:10915763).
Transcriptional regulator of the circadian clock components: CLOCK, BMAL1, BMAL2, PER1/3, CRY1/2, NR1D1/2 and RORA/C. Positively regulates the transcriptional activity of CLOCK a core component of the circadian clock. Regulates transcription through chromatin remodeling by interacting with other proteins in chromatin as well as proteins in the basic transcriptional machinery. May be important for embryonic and postnatal development. May be involved in neuronal differentiation.
Belongs to the fatty acid desaturase type 1 family. DEGS subfamily.
Has sphingolipid-delta-4-desaturase activity. Converts D-erythro-sphinganine to D-erythro-sphingosine (E-sphing-4-enine) (PubMed:11937514, PubMed:30620337, PubMed:30620338). Catalyzes the equilibrium isomerization of retinols (By similarity).
Interacts with RLBP1; the interaction increases synthesis of chromophore-precursors by DEGS1.
Myristoylation can target the enzyme to the mitochondria leading to an increase in ceramide levels.
Isoform 1 is strongly expressed in placenta, spleen, kidney, testis and peripheral blood leukocytes. Expressed in CD4+ and CD8+ T-cells, CD19+ B-cells and CB14+ monocytes. Isoform 3 is strongly expressed in placenta, ovary, tonsil, CD19+ B-cells and CD14+ monocytes.
May be involved in transcriptional regulation. Overexpression causes down-regulation of a number of genes involved in the immune response. Some genes are also up-regulated (By similarity).
Binds to photoactivated, phosphorylated RHO and terminates RHO signaling via G-proteins by competing with G-proteins for the same binding site on RHO (By similarity). May play a role in preventing light-dependent degeneration of retinal photoreceptor cells (PubMed:9565049).
Detected in retina, in the proximal portion of the outer segment of rod photoreceptor cells (at protein level).
Monomer. Homodimer. Homotetramer (PubMed:21288033). Interacts with RHO (via the phosphorylated C-terminus) (PubMed:26200343, PubMed:28753425).
The C-terminus interferes with binding to non-phosphorylated RHO. Interaction with phosphorylated RHO triggers displacement of the C-terminus and leads to a conformation change that mediates high-affinity RHO binding.
As component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is involved in cilia function and/or assembly (PubMed:20889716). Essential for functional IFT-A assembly and ciliary entry of GPCRs (PubMed:20889716). Associates with the BBSome complex to mediate ciliary transport (By similarity).
By androgenic hormones. Expression increased 3-fold in an androgen-stimulated androgen-sensitive prostate adenocarcinoma cell line compared with androgen-deprived cells.
Component of the IFT complex A (IFT-A) complex (PubMed:20889716, PubMed:27932497). IFT-A complex is divided into a core subcomplex composed of IFT122:IFT140:WDR19 which is associated with TULP3 and a peripheral subcomplex composed of IFT43:WDR35:TTC21B (PubMed:27932497, PubMed:29220510). Interacts (via C-terminal region) with IFT122 (via C-terminal region) (PubMed:29220510). Interacts with BBS1 (By similarity). Interacts with TTC25 (PubMed:25860617).
Some isoforms are tissue-specific. Highly expressed in the prostate. Lower expression in the cerebellum, pituitary gland, fetal lung, and pancreas. In normal prostate, expressed in both basal and luminal epithelial cells. No expression detected in fibromuscular stromal cells, endothelial cells, or infiltrating lymphocytes. Uniformed expression in prostate adenocarcinoma cells.
Belongs to the universal ribosomal protein uS10 family.
Belongs to the phosphoglycerate kinase family.
Catalyzes one of the two ATP producing reactions in the glycolytic pathway via the reversible conversion of 1,3-diphosphoglycerate to 3-phosphoglycerate (PubMed:30323285, PubMed:7391028). In addition to its role as a glycolytic enzyme, it seems that PGK-1 acts as a polymerase alpha cofactor protein (primer recognition protein) (PubMed:2324090). May play a role in sperm motility (PubMed:26677959).
Mainly expressed in spermatogonia. Localized on the principle piece in the sperm (at protein level). Expression significantly decreased in the testis of elderly men.
Specifically inhibited by heterocyclic compound CBR-470-0.
Following DNA damage, phosphorylated by HIPK2 which promotes DAZAP2 localization to the nucleus, reduces interaction of DAZAP2 with HIPK2 and SIAH1, and prevents DAZAP2-dependent ubiquitination of HIPK2 by E3 ubiquitin-protein ligase SIAH1 and subsequent HIPK2 proteasomal degradation.
In unstressed cells, promotes SIAH1-mediated polyubiquitination and degradation of the serine/threonine-protein kinase HIPK2, probably by acting as a loading factor that potentiates complex formation between HIPK2 and ubiquitin ligase SIAH1 (PubMed:33591310). In response to DNA damage, localizes to the nucleus following phosphorylation by HIPK2 and modulates the expression of a subset of TP53/p53 target genes by binding to TP53 at target gene promoters (PubMed:33591310). This limits the expression of a number of cell death-mediating TP53 target genes, reducing DNA damage-induced cell death (PubMed:33591310). Enhances the binding of transcription factor TCF7L2/TCF4, a Wnt signaling pathway effector, to the promoters of target genes (By similarity). Plays a role in stress granule formation (PubMed:17984221).
Interacts with SOX6 (By similarity). Interacts with DAZ1 and DAZL (PubMed:10857750). Interacts with IL17RB (PubMed:22070932). May interact with FAM168B (PubMed:22771904). Interacts with INCA1 (PubMed:21750715). Interacts with EIF4G1 and EIF4G2 (PubMed:17984221). Interacts (via PPAY motif) with NEDD4 (via WW domains) (PubMed:11342538). Interacts with transcription factor TCF7L2/TCF4; the interaction results in localization of DAZAP2 to the nucleus (PubMed:19304756). Interacts with transcription factors TCF7 and TCF7L1 (PubMed:19304756). Interacts with transcription factor LEF1 (PubMed:19304756). Interacts with serine/threonine-protein kinase HIPK2; the interaction results in phosphorylation of DAZAP2 which causes localization of DAZAP2 to the nucleus, reduces interaction of DAZAP2 with HIPK2 and prevents DAZAP2-dependent degradation of HIPK2 (PubMed:33591310). Interacts with ubiquitin ligase SIAH1; the interaction is decreased following phosphorylation of DAZAP2 by HIPK2 (PubMed:33591310). Interacts with TP53 at TP53 target gene promoters; the interaction is triggered by DNA damage (PubMed:33591310).
Ubiquitinated (PubMed:11342538, PubMed:21274613, PubMed:22070932). Ubiquitinated by SMURF2, leading to proteasomal degradation (PubMed:22070932). Ubiquitinated by NEDD4, leading to proteasomal degradation (PubMed:11342538).
Widely expressed. Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocytes. Down-regulated in multiple myeloma.
Belongs to the eukaryotic RPB4 RNA polymerase subunit family.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB4 is part of a subcomplex with RPB7 that binds to a pocket formed by RPB1, RPB2 and RPB6 at the base of the clamp element. The RPB4-RPB7 subcomplex seems to lock the clamp via RPB7 in the closed conformation thus preventing double-stranded DNA to enter the active site cleft. The RPB4-RPB7 subcomplex binds single-stranded DNA and RNA (By similarity).
Widely expressed but not detected in skeletal muscle.
Inhibited by both 1-deoxymannojirimycin (dMNJ) and kifunensine.
Involved in glycoprotein quality control targeting of misfolded glycoproteins for degradation. It primarily trims a single alpha-1,2-linked mannose residue from Man(9)GlcNAc(2) to produce Man(8)GlcNAc(2), but at high enzyme concentrations, as found in the ER quality control compartment (ERQC), it further trims the carbohydrates to Man(5-6)GlcNAc(2).
Catalyzes the synthesis of carnosine and homocarnosine. Carnosine is synthesized more efficiently than homocarnosine.
Required for meiosis I progression during spermatogenesis.
Found in a complex with YY1, SIN3A and HDAC1.
Has transcriptional repressor activity, probably as part of a complex with YY1, SIN3A and HDAC1. Required for B cell lymphopoiesis.
Has deubiquitinating activity towards 'Lys-11'-linked polyubiquitin chains.
Increases DNTT terminal deoxynucleotidyltransferase activity (in vitro) (PubMed:11473582). Also acts as a transcriptional regulator, binding to the consensus sequence 5'-GNTGCATG-3' following an AT-tract. Associates with RAB20 promoter and positively regulates its transcription. Binds DNA and nucleosomes; may recruit HDAC1 complexes to nucleosomes or naked DNA.
Monomer and homodimer (PubMed:11473582, PubMed:25653165). A minor proportion may form homotrimers (PubMed:11473582). Interacts with ZNF541 (PubMed:21573134). Interacts with the terminal deoxynucleotidyltransferase DNTT (PubMed:11473582, PubMed:16371131). Interacts with TRERF1 (PubMed:16371131, PubMed:21573134). Identified in a histone deacetylase complex that contains DNTTIP1, HDAC1 and MIDEAS; this complex assembles into a tetramer that contains four copies of each protein chain (PubMed:25653165). Component of a histone deacetylase complex containing DNTTIP1, ZNF541, HDAC1 and HDAC2 (PubMed:21573134). Identified in a complex with KCTD19, HDAC1, HDAC2 and ZNF541 (By similarity).
The C-terminal domain mediates interaction with DNA and nucleosomes (PubMed:11473582, PubMed:25653165). It contains a HTH motif that mediates recognition of the consensus sequence (PubMed:23874396).
The N-terminal domain mediates dimerization.
By tazarotene and by all the retinoic acid receptors tested.
Inhibitor of the cytoplasmic carboxypeptidase AGBL2, may regulate the alpha-tubulin tyrosination cycle.
Not N-glycosylated (PubMed:21303978). O-glycosylated; contains chondroitin sulfate (PubMed:27399812, PubMed:36213313).
Adaptor protein complex 4 (AP-4) is a heterotetramer composed of two large adaptins (epsilon-type subunit AP4E1 and beta-type subunit AP4B1), a medium adaptin (mu-type subunit AP4M1) and a small adaptin (sigma-type AP4S1) (PubMed:10436028, PubMed:10066790, PubMed:11802162). Interacts with tyrosine-based sorting signals on the cytoplasmic tail of cargo proteins such as APP, ATG9A, LAMP2 and NAGPA (PubMed:11139587, PubMed:26544806, PubMed:29180427, PubMed:20230749). Interacts with the C-terminal domain of GRID2 (By similarity). Interacts with GRIA1 and GRIA2; the interaction is indirect via CACNG3 (By similarity). Interacts with CACNG3; CACNG3 associates GRIA1 and GRIA2 with the adaptor protein complex 4 (AP-4) to target them to the somatodendritic compartment of neurons (By similarity). Interacts with HOOK1 and HOOK2; the interactions are direct, mediate the interaction between FTS-Hook-FHIP (FHF) complex and AP-4 and the perinuclear distribution of AP-4 (PubMed:32073997).
Component of the adaptor protein complex 4 (AP-4). Adaptor protein complexes are vesicle coat components involved both in vesicle formation and cargo selection. They control the vesicular transport of proteins in different trafficking pathways (PubMed:10436028, PubMed:11139587, PubMed:10066790, PubMed:11802162, PubMed:20230749). AP-4 forms a non clathrin-associated coat on vesicles departing the trans-Golgi network (TGN) and may be involved in the targeting of proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal system (PubMed:11139587, PubMed:20230749). It is also involved in protein sorting to the basolateral membrane in epithelial cells and the proper asymmetric localization of somatodendritic proteins in neurons (By similarity). Within AP-4, the mu-type subunit AP4M1 is directly involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos (PubMed:10436028, PubMed:11139587, PubMed:26544806, PubMed:20230749). The adaptor protein complex 4 (AP-4) may also recognize other types of sorting signal (By similarity).
Component of the adaptor protein complex 4 (AP-4). Adaptor protein complexes are vesicle coat components involved both in vesicle formation and cargo selection. They control the vesicular transport of proteins in different trafficking pathways. AP-4 forms a non clathrin-associated coat on vesicles departing the trans-Golgi network (TGN) and may be involved in the targeting of proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal system. It is also involved in protein sorting to the basolateral membrane in epithelial cells and the proper asymmetric localization of somatodendritic proteins in neurons. Within AP-4, the mu-type subunit AP4M1 is directly involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos. The adaptor protein complex 4 (AP-4) may also recognize other types of sorting signal.
Ubiquitous. Highly expressed in testis and lowly expressed in brain and lung.
Expression is high in kidney, pancreas, and testis, medium in brain, heart, prostate, small intestine, and spleen, low in liver, placenta, skeletal muscle, colon, ovary, and thymus, and not detectable in lung and peripheral leukocyte. According to PubMed:10945465, highly expressed in most brain areas examined, with the highest levels observed in corpus callosum, caudate nucleus, putamen, substantia nigra, thalamus, hippocampus, and spinal cord as well as in dorsal root ganglia (DRG). In the periphery, expression levels are relatively low, compared to the CNS, with the strongest expression detected in pancreas, testis, uterus, and stomach.
It is uncertain whether Met-1 or Met-9 is the initiator.
Unknown. This retinoic acid-inducible G-protein coupled receptor provide evidence for a possible interaction between retinoid and G-protein signaling pathways.
Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex. The CST complex binds single-stranded DNA with high affinity in a sequence-independent manner, while isolated subunits bind DNA with low affinity by themselves. Initially the CST complex has been proposed to protect telomeres from DNA degradation (PubMed:19854130). However, the CST complex has been shown to be involved in several aspects of telomere replication. The CST complex inhibits telomerase and is involved in telomere length homeostasis; it is proposed to bind to newly telomerase-synthesized 3' overhangs and to terminate telomerase action implicating the association with the ACD:POT1 complex thus interfering with its telomerase stimulation activity. The CST complex is also proposed to be involved in fill-in synthesis of the telomeric C-strand probably implicating recruitment and activation of DNA polymerase alpha (PubMed:22763445). The CST complex facilitates recovery from many forms of exogenous DNA damage; seems to be involved in the re-initiation of DNA replication at repaired forks and/or dormant origins (PubMed:25483097). Involved in telomere maintenance (PubMed:19854131, PubMed:22863775). Involved in genome stability (PubMed:22863775). May be in involved in telomeric C-strand fill-in during late S/G2 phase (By similarity).
Component of the CST complex, composed of TEN1/C17orf106, CTC1/C17orf68 and STN1; in the complex interacts directly with STN1. Interacts with ACD and POT1.
(Microbial infection) In macrophages, induced by SARS-CoV-2 infection.
(Microbial infection) Interacts with M.bovis MPB83.
(Microbial infection) Interacts with M.tuberculosis EsxA.
Cooperates with LY96 to mediate the innate immune response to bacterial lipoproteins and other microbial cell wall components. Cooperates with TLR1 or TLR6 to mediate the innate immune response to bacterial lipoproteins or lipopeptides (PubMed:21078852, PubMed:17889651). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. May also activate immune cells and promote apoptosis in response to the lipid moiety of lipoproteins (PubMed:10426995, PubMed:10426996). Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR6 (PubMed:11441107). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via this receptor, but also partially via TLR4 (PubMed:16622205). MAPK activation in response to bacterial peptidoglycan also occurs via this receptor (PubMed:16622205). Acts as a receptor for M.tuberculosis lipoproteins LprA, LprG, LpqH and PstS1, some lipoproteins are dependent on other coreceptors (TLR1, CD14 and/or CD36); the lipoproteins act as agonists to modulate antigen presenting cell functions in response to the pathogen (PubMed:19362712). M.tuberculosis HSP70 (dnaK) but not HSP65 (groEL-2) acts via this protein to stimulate NF-kappa-B expression (PubMed:15809303). Recognizes M.tuberculosis major T-antigen EsxA (ESAT-6) which inhibits downstream MYD88-dependent signaling (shown in mouse) (By similarity). Forms activation clusters composed of several receptors depending on the ligand, these clusters trigger signaling from the cell surface and subsequently are targeted to the Golgi in a lipid-raft dependent pathway. Forms the cluster TLR2:TLR6:CD14:CD36 in response to diacylated lipopeptides and TLR2:TLR1:CD14 in response to triacylated lipopeptides (PubMed:16880211). Required for normal uptake of M.tuberculosis, a process that is inhibited by M.tuberculosis LppM (By similarity).
Cooperates with LY96 to mediate the innate immune response to bacterial lipoproteins and other microbial cell wall components. Cooperates with TLR1 or TLR6 to mediate the innate immune response to bacterial lipoproteins or lipopeptides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.
Ester-bound lipid substrates are bound through a crevice formed between the LRR 11 and LRR 12.
Genetic variations in TLR2 are associated with susceptibility to leprosy [MIM:246300]. Leprosy is a chronic disease associated with depressed cellular (but not humoral) immunity, the bacterium requires a lower temperature than 37 degrees Celsius and thrives particularly in peripheral Schwann cells and macrophages. The Trp-677 polymorphism in the intracellular domain of TLR2 has a role in susceptibility to lepromatous leprosy. Wild-type TLR2 mediates CD14-enhanced Mycobacterium leprae-dependent activation of NFKB1, but TLR2 containing the Trp-677 polymorphism did not. The impaired function of the Trp-677 polymorphism provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy.
Glycosylation of Asn-442 is critical for secretion of the N-terminal ectodomain of TLR2.
Highly expressed in peripheral blood leukocytes, in particular in monocytes, in bone marrow, lymph node and in spleen. Also detected in lung and in fetal liver. Levels are low in other tissues.
Interacts with LY96, TLR1 and TLR6 (via extracellular domain) (PubMed:17889651). TLR2 seems to exist in heterodimers with either TLR1 or TLR6 before stimulation by the ligand. The heterodimers form bigger oligomers in response to their corresponding ligands as well as further heterotypic associations with other receptors such as CD14 and/or CD36 (PubMed:16880211). Binds MYD88 (via TIR domain). Interacts with TICAM1 (PubMed:12471095). Interacts with CNPY3 (By similarity). Interacts with ATG16L1 (PubMed:23376921). Interacts with PPP1R11 (By similarity). Interacts with TICAM2 (PubMed:25385819). Interacts with TIRAP (PubMed:17322885).
The ATG16L1-binding motif mediates interaction with ATG16L1.
Ubiquitinated at Lys-754 by PPP1R11, leading to its degradation (PubMed:27805901). Deubiquitinated by USP2 (By similarity).
Generally expressed at much higher level than isoform 1.
Interacts with RIOX1; the interaction is direct and inhibits transcription activator activity.
Propionylated. Depropionylation at Lys-371 by SIRT7 activates transcription factor activity and positively regulates bone formation by osteoblasts.
Transcriptional activator essential for osteoblast differentiation (PubMed:23457570). Binds to SP1 and EKLF consensus sequences and to other G/C-rich sequences (By similarity).
Ubiquitination at leads to proteasomal degradation. SP7 is a short-live protein with an endogenous half-life of approximately 12 hours.
Cleaves C-terminal amino acids linked to proline in peptides such as angiotensin II, III and des-Arg9-bradykinin. This cleavage occurs at acidic pH, but enzymatic activity is retained with some substrates at neutral pH.
Highest levels in placenta, lung and liver. Also present in heart, brain, pancreas and kidney.
Proton-conducting pore forming of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment.
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex (PubMed:33065002). The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H (PubMed:33065002). The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR (PubMed:33065002). Interacts with IFITM3 (By similarity).
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex. The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H. The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits.
Belongs to the beta-microseminoprotein family.
Specific receptors for this protein are found on spermatozoa and in the prostate.
Strongly expressed in prostate, liver, kidney, breast and penis. Also expressed in pancreas, esophagus, stomach, deodenum, colon, trachea, lung, salivary glands and fallopian tube. PSP94 is expressed in lung and breast, whereas PSP57 is found in kidney and bladder.
Was originally thought to inhibit the secretion of FSH by pituitary cells.
(Microbial infection) Interacts with HIV-1 Tat.
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:27428775, PubMed:27342858). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC2 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with NDC80/HEC; this interaction is detected only during M phase (PubMed:9295362, PubMed:10409732). Interacts and SQSTM1 (PubMed:15340068). Interacts with PAAF1 (PubMed:15831487). Directly interacts with TRIM5 (PubMed:22078707).
Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.
Expression is not cell cycle-dependent and occurs throughout the cell cycle.
Phosphorylated (PubMed:28539385). Dephosphorylated by UBLCP1 which impairs PSMC2 ATPase activity and disrupts 26S proteasome assembly (PubMed:28539385).
Belongs to the complex I subunit 1 family.
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:1959619). Essential for the catalytic activity and assembly of complex I (PubMed:26929434, PubMed:1959619).
Cleaved by CASP3 and CASP7. The potential C-terminal product released by CASP3 cleavage may inhibit the ERK signaling pathway through MAP2K2.
Functions in the development of neural tissues, particularly the postnatal maturation of the cerebellar cortex. May play a role in neurotransmission through regulation of glutaminase/GLS, an enzyme responsible for the production in neurons of the glutamate neurotransmitter. Alternatively, may regulate the localization of mitochondria within axons and dendrites.
Interacts with KLC1; may link mitochondria to KLC1 and regulate mitochondria localization into neuron projections (By similarity). Interacts with GLS; the interaction is direct and may control GLS localization, negatively regulating its activity. Interacts with PIN1 (via WW domain); upon NGF stimulation. The interaction with PIN1 and GLS is competitive. May interact with MAP2K2.
The CRAL-TRIO domain is known to bind small hydrophobic molecules.
Component of the GPI transamidase complex. Essential for transfer of GPI to proteins, particularly for formation of carbonyl intermediates.
Forms a complex with PIGK/GPI8, PIGT, PIGU and GAA1.
Belongs to the copper/topaquinone oxidase family.
Expressed in many tissues with much higher expression in retina. Isoform 1 and isoform 2 are expressed in adipose tissue, whereas isoform 1 only seems to be present in thymus, and isoform 2 only in testis.
Has a monoamine oxidase activity with substrate specificity for 2-phenylethylamine and tryptamine. May play a role in adipogenesis. May be a critical modulator of signal transmission in retina.
Homodimer; disulfide-linked (By similarity). Forms a heterodimer with AOC3, in vitro.
Topaquinone (TPQ) is generated by copper-dependent autoxidation of a specific tyrosyl residue.
Up-regulated during in vitro adipocyte differentiation.
Acts as a scavenger receptor for acetylated low density lipoprotein. Binds to both Gram-positive and Gram-negative bacteria and may play a role in defense against bacterial infection. When inhibited in endothelial tube formation assays, there is a marked decrease in cell-cell interactions, suggesting a role in angiogenesis. Involved in the delivery of newly synthesized CHID1/SI-CLP from the biosynthetic compartment to the endosomal/lysosomal system.
High levels found in spleen, lymph node, liver and placenta. Also expressed in endothelial cells.
Specific component of the multisubunit TRAPP II complex, which includes at least TRAPPC1, TRAPPC2, TRAPPC3, TRAPPC4, TRAPPC5, TRAPPC6A/B, TRAPPC9, TRAPPC10 and TRAPPC14. TRAPPC9, TRAPPC10 and TRAPPC14 are specific subunits of the TRAPP II complex (PubMed:31467083, PubMed:21525244, PubMed:11805826). Interacts with TRAPPC14 (PubMed:31467083).
Specific subunit of the TRAPP (transport protein particle) II complex, a highly conserved vesicle tethering complex that functions in late Golgi trafficking as a membrane tether.
Inhibitory regulator of the Ras-cyclic AMP pathway. Binds inositol tetrakisphosphate (IP4) with high affinity. Might be a specific IP4 receptor.
Binds to heterochromatin. Does not interact with either methylated or unmethylated DNA (in vitro).
Both MBD and PWWP domains are necessary for chromocentric localization.
Detected in heart, placenta, liver, skeletal muscle, kidney and pancreas.
Deubiquitinating enzyme that specifically hydrolyzes 'Lys-63'-linked polyubiquitin to monoubiquitin (PubMed:23827681). Required for the stability and translation of a subset mRNAs with a high abundance of rare codons by mediating deubiquitination of 40S ribosomal protein RPS10/eS10, thereby antagonizing ZNF598-mediated 40S ubiquitination (PubMed:36445135). The abundance of rare codons in mRNAs can limit the translation rate and can lead to ribosome collisions that trigger activation of ribosome quality control (RQC) pathway by ZNF598 (PubMed:36445135). OTUD1-mediated deubiquitination prevents activation of the RQC and subsequent dissociation of ribosomes and stimulates formation of polysomes and translation (PubMed:36445135).
Specificity is not given by the S1' ubiquitin-binding site within the OTU domain (composed of the Cys-, His- and Variable-loops).
The UIM repeat increases the specificity and efficiency of the enzyme toward 'Lys-63'-linked polyubiquitin.
Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane. Plays a critical role in central nervous system development and function.
Interacts with CAMSAP1 (PubMed:24117850). Interacts with ANK2 (PubMed:15262991, PubMed:34211179). Interacts with CPNE4 (via VWFA domain) (By similarity). Like erythrocyte spectrin, the spectrin-like proteins are capable to form dimers which can further associate to tetramers (By similarity). Can form heterodimers with SPTAN1 (PubMed:34211179). Isoform Short cannot bind to the axonal protein fodaxin.
Isoform 2 is present in brain, lung and kidney (at protein level).
Cyclin-dependent kinase which displays CTD kinase activity and is required for RNA splicing. Has CTD kinase activity by hyperphosphorylating the C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit RPB1, thereby acting as a key regulator of transcription elongation. Required for RNA splicing, probably by phosphorylating SRSF1/SF2. Required during hematopoiesis. In case of infection by HIV-1 virus, interacts with HIV-1 Tat protein acetylated at 'Lys-50' and 'Lys-51', thereby increasing HIV-1 mRNA splicing and promoting the production of the doubly spliced HIV-1 protein Nef.
Expressed in fetal brain, liver, muscle and in adult brain. Also expressed in neuroblastoma and glioblastoma tumors.
Interacts with CCNL1 and CCNL2 (By similarity). Interacts with CCNK. Interacts with C1QBP.
Stabilizes the aggregates of proteoglycan monomers with hyaluronic acid in the extracellular cartilage matrix.
Widely expressed. Weakly expressed in the brain.
Component of the stratum corneum that may contribute to epidermal antimicrobial host defenses.
Expressed in the stratum granulosum, in skin and oral epithelia (at protein level).
Interacts with LCE1B; the interaction is direct (PubMed:36804407). Interacts with LCE2C; the interaction is direct (PubMed:36804407). Interacts with LCE3A; the interaction is direct (PubMed:36804407). Interacts with LCE3C; the interaction is direct (PubMed:36804407). Interacts with LCE4A; the interaction is direct (PubMed:36804407). Interacts with LCE5A; the interaction is direct (PubMed:36804407). Interacts with LCE1C (PubMed:36804407). Interacts with LCE1D (PubMed:36804407). Interacts with LCE1E (PubMed:36804407). Interacts with LCE2A (PubMed:36804407). Interacts with LCE3D (PubMed:36804407). Interacts with LCE3E (PubMed:36804407). Interacts with LCE1A (PubMed:36804407).
Binds to the ATPase domain of HSP70/HSC70 chaperones (PubMed:9873016). Interacts with BCL2 (PubMed:10597216). Interacts with phospholipase C-gamma proteins (PubMed:10980614). Interacts with DNAJB6 (PubMed:22366786). Interacts (via BAG domain) with HSF1; this interaction occurs in normal and heat-shocked cells promoting HSF1 nucleocytoplasmic shuttling (PubMed:26159920). Interacts with HSPA8 (via NBD) (PubMed:27474739, PubMed:24318877). Interacts with HSPA1A (via NBD) and HSPA1B (via NBD) (PubMed:24318877). Interacts (via WW domain 1) with SYNPO2 (via PPPY motif) (PubMed:23434281). Interacts with HSPB8 (PubMed:28144995).
Co-chaperone for HSP70 and HSC70 chaperone proteins. Acts as a nucleotide-exchange factor (NEF) promoting the release of ADP from the HSP70 and HSC70 proteins thereby triggering client/substrate protein release. Nucleotide release is mediated via its binding to the nucleotide-binding domain (NBD) of HSPA8/HSC70 where as the substrate release is mediated via its binding to the substrate-binding domain (SBD) of HSPA8/HSC70 (PubMed:9873016, PubMed:27474739). Has anti-apoptotic activity (PubMed:10597216). Plays a role in the HSF1 nucleocytoplasmic transport (PubMed:26159920).
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv11.2/KCNH6 sub-subfamily.
Expressed in prolactin-secreting adenomas.
Pore-forming (alpha) subunit of voltage-gated potassium channel. Elicits a slowly activating, rectifying current (By similarity). Channel properties may be modulated by cAMP and subunit assembly.
The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming alpha subunits that can associate with modulating beta subunits. Heteromultimers with KCNH2/ERG1 and KCNH7/ERG3 (By similarity).
C2 domains are necessary for calcium-dependent cell membrane association. C2 domains are necessary for neuronal progenitor cell differentiation in a calcium-independent manner (PubMed:25450385).
Calcium-dependent phospholipid-binding protein that plays a role in calcium-mediated intracellular processes (PubMed:14674885). Involved in the TNF-alpha receptor signaling pathway in a calcium-dependent manner (PubMed:14674885). Exhibits calcium-dependent phospholipid binding properties (PubMed:9430674, PubMed:19539605). Plays a role in neuronal progenitor cell differentiation; induces neurite outgrowth via a AKT-dependent signaling cascade and calcium-independent manner (PubMed:23263657, PubMed:25450385). May recruit target proteins to the cell membrane in a calcium-dependent manner (PubMed:12522145). May function in membrane trafficking (PubMed:9430674). Involved in TNF-alpha-induced NF-kappa-B transcriptional repression by inducing endoprotease processing of the transcription factor NF-kappa-B p65/RELA subunit (PubMed:18212740). Also induces endoprotease processing of NF-kappa-B p50/NFKB1, p52/NFKB2, RELB and REL (PubMed:18212740).
Expressed in neutrophils (at protein level) (PubMed:12949241). Widely expressed. Expressed in the brain. Expressed in neutrophil precursors from bone marrow and peripheral blood (PubMed:12949241).
Homodimer; homodimerizes via its C2 domains (PubMed:18212740). Interacts with p65/RELA (via N-terminus); this interaction induces proteolytic cleavage of p65/RELA subunit and inhibition of NF-kappa-B transcriptional activity (PubMed:18212740). Interacts (via VWFA domain) with ACTB, CCDC22, MYCBP2, PPP5C, RDX and UBE2O (PubMed:12522145).
Up-regulated by the inflammatory cytokine TNF-alpha (PubMed:14674885). Up-regulated during neuronal progenitor cell differentiation (PubMed:23263657).
Belongs to the class IV-like SAM-binding methyltransferase superfamily. RNA methyltransferase TrmH family.
Expressed at same level in normal liver and hepatocarcinoma.
S-adenosyl-L-methionine-dependent 2'-O-ribose methyltransferase that catalyzes the formation of 2'-O-methylguanosine at position 1370 (Gm1370) in the 16S mitochondrial large subunit ribosomal RNA (mtLSU rRNA), a conserved modification in the peptidyl transferase domain of the mtLSU rRNA.
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with FUS and SMN. Interacts (via C-terminus) with PRMT1. Forms a complex with ILF2. Can also bind to PRKDC/XRCC7: this may stabilize the interaction of PRKDC/XRCC7 and the heterodimeric complex of XRCC6/KU70 and XRCC5/KU80. Forms a heteromeric complex with ZNF346 and ILF3. Found in a nuclear export complex with XPO5, ILF3, Ran and double-stranded RNA or double-stranded minihelix VA1 RNA. Found in a nuclear export complex with XPO5, RAN, ILF3, ZNF346 and double-stranded RNA. Interacts with XPO5 and ZNF346. Forms a complex with ILF2, YLPM1, KHDRBS1, RBMX, NCOA5 and PPP1CA. Interacts with AGO1 and AGO2. Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:14731398). Interacts with ELAVL1; this interaction occurs in a RNA-dependent manner (PubMed:14731398). Interacts with HAVCR2; this interaction promotes ILF3 ubiquitination and subsequent degradation (PubMed:34110282).
Methylated by protein arginine N-methyltransferase 1.
Phosphorylated at Thr-188 and Thr-315 by PKR in response to certain RNA viruses. This phosphorylation results in the dissociation of ILF2 from the ILF2-ILF3 complex resulting in a cytoplasmic sequestration of ILF3 where it can bind to viral RNAs and impede viral replication.
RNA-binding protein that plays an essential role in the biogenesis of circular RNAs (circRNAs) which are produced by back-splicing circularization of pre-mRNAs. Within the nucleus, promotes circRNAs processing by stabilizing the regulatory elements residing in the flanking introns of the circularized exons. Plays thereby a role in the back-splicing of a subset of circRNAs (PubMed:28625552). As a consequence, participates in a wide range of transcriptional and post-transcriptional processes. Binds to poly-U elements and AU-rich elements (AREs) in the 3'-UTR of target mRNAs (PubMed:14731398). Upon viral infection, ILF3 accumulates in the cytoplasm and participates in the innate antiviral response (PubMed:21123651, PubMed:34110282). Mechanistically, ILF3 becomes phosphorylated and activated by the double-stranded RNA-activated protein kinase/PKR which releases ILF3 from cellular mature circRNAs. In turn, unbound ILF3 molecules are able to interact with and thus inhibit viral mRNAs (PubMed:21123651, PubMed:28625552).
Ubiquitinated at Lys-297 in a TRIM47-dependent manner; this 'Lys-48'-linked ubiquitination promotes ILF3 degradation.
Converts 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone (PubMed:21173190). Acts on LPA containing saturated or unsaturated fatty acids C15:0-C20:4 at the sn-1 position using C18:1-CoA as the acyl donor (PubMed:21173190). Also acts on lysophosphatidylethanolamine using oleoyl-CoA, but not arachidonoyl-CoA, and lysophosphatidylinositol using arachidonoyl-CoA, but not oleoyl-CoA (PubMed:21173190). Activity toward lysophosphatidylglycerol not detectable (PubMed:21173190).
A tripeptide motif (FEE) within disintegrin-like domain could be involved in the binding to egg integrin receptor and thus could mediate sperm/egg binding.
Expressed specifically in spermatogenic cells in the seminiferous cells. Not detected in fetal tissues.
In mammals, exists as a heterodimer composed of an alpha and beta subunits. In human, fertilin subunit alpha is a pseudogene.
Sperm surface membrane protein that may be involved in sperm-egg plasma membrane adhesion and fusion during fertilization. Could have a direct role in sperm-zona binding or migration of sperm from the uterus into the oviduct. Interactions with egg membrane could be mediated via binding between its disintegrin-like domain to one or more integrins receptors on the egg. This is a non catalytic metalloprotease-like protein.
The prodomain and the metalloprotease domain are cleaved during the epididymal maturation of the spermatozoa.
Allosterically activated by fructose 1,6-bisphosphate.
Pyruvate kinase that catalyzes the conversion of phosphoenolpyruvate to pyruvate with the synthesis of ATP, and which plays a key role in glycolysis.
There are 4 isozymes of pyruvate kinase in mammals: L, R, M1 and M2. L type is major isozyme in the liver, R is found in red cells, M1 is the main form in muscle, heart and brain, and M2 is found in early fetal tissues.
Acts as a transcriptional transactivator of ELL and ELL2 elongation activities.
Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3). Interacts with ELL and ELL2.
Strongly expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, prostate, testis, small intestine and colon. Poorly expressed in thymus.
Channel activity inhibited by ATP via ABCB8/MITOSUR subunit.
Isoform 1: Widely expressed (PubMed:31435016). Isoform 2: Expression is barely detectable (PubMed:31435016).
Mitochondrial potassium channel located in the mitochondrial inner membrane (PubMed:31435016). Together with ABCB8/MITOSUR, forms a protein complex localized in the mitochondria that mediates ATP-dependent potassium currents across the inner membrane (that is, mitoK(ATP) channel) (PubMed:31435016). May contribute to the homeostatic control of cellular metabolism under stress conditions by regulating the mitochondrial matrix volume (PubMed:31435016).
The mitochondrial potassium channel (mitoK(ATP)) is composed of 4 subunits of CCDC51/MITOK and 4 subunits of ABCB8/MITOSUR.
(Microbial infection) Plays an important role in Dengue virus entry.
Component of the ESCRT-0 complex composed of STAM or STAM2 and HGS (PubMed:11687594, PubMed:9407053, PubMed:19278655). Probably part of a complex at least composed of HSG, STAM and EPS15 (PubMed:12551915). Found in a complex with HGS and E3 ligase ITCH and DTX3L (PubMed:24790097). Interacts with E3 ligase DTX3L; the interaction brings together STAM and HSG, promotes their recruitment to early endosomes and decreases STAM and HGS ubiquitination by ITCH (PubMed:24790097). Interacts with STAMBP/AMSH (PubMed:10383417). Interacts with PDGFRB (PubMed:20494825). Interacts with LITAF; the interaction is direct (PubMed:23166352). Identified in a complex with HGS and LITAF (PubMed:23166352). Interacts with HAVCR1 (PubMed:29742433).
Involved in intracellular signal transduction mediated by cytokines and growth factors. Upon IL-2 and GM-CSL stimulation, it plays a role in signaling leading to DNA synthesis and MYC induction. May also play a role in T-cell development. Involved in down-regulation of receptor tyrosine kinase via multivesicular body (MVBs) when complexed with HGS (ESCRT-0 complex). The ESCRT-0 complex binds ubiquitin and acts as sorting machinery that recognizes ubiquitinated receptors and transfers them to further sequential lysosomal sorting/trafficking processes.
Phosphorylated on Tyr-198. Phosphorylated in response to IL2, IL3, IL4, IL7, CSF2/GM-CSF, EGF and PDGFB. Phosphorylated by activated PDGFRB.
The VHS domain mediates high-avidity binding to Lys63-linked and Lys48-linked polyubiquitinated cargos.
Component of the 9-1-1 cell-cycle checkpoint response complex that plays a major role in DNA repair. The 9-1-1 complex is recruited to DNA lesion upon damage by the RAD17-replication factor C (RFC) clamp loader complex. Acts then as a sliding clamp platform on DNA for several proteins involved in long-patch base excision repair (LP-BER). The 9-1-1 complex stimulates DNA polymerase beta (POLB) activity by increasing its affinity for the 3'-OH end of the primer-template and stabilizes POLB to those sites where LP-BER proceeds; endonuclease FEN1 cleavage activity on substrates with double, nick, or gap flaps of distinct sequences and lengths; and DNA ligase I (LIG1) on long-patch base excision repair substrates. The 9-1-1 complex is necessary for the recruitment of RHNO1 to sites of double-stranded breaks (DSB) occurring during the S phase.
Component of the toroidal 9-1-1 (RAD9-RAD1-HUS1) complex, composed of RAD9A, RAD1 and HUS1. The 9-1-1 complex associates with LIG1, POLB, FEN1, RAD17, HDAC1, RPA1 and RPA2. The 9-1-1 complex associates with the RAD17-RFC complex. HUS1 interacts with POLB, HDAC1, FEN1, PCNA, RAD1, RAD9A and RAD9B. HUS1 does not interact with RAD17. Interacts with DNAJC7.
Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa.
Factor XII is activated by kallikrein in alpha-factor XIIa, which is further converted by trypsin into beta-factor XIIa. Alpha-factor XIIa is composed of an NH2-terminal heavy chain, called coagulation factor XIIa heavy chain, and a COOH-terminal light chain, called coagulation factor XIIa light chain, connected by a disulfide bond. Beta-factor XIIa is composed of 2 chains linked by a disulfide bond, an N-terminal nonapeptide, called beta-factor XIIa part 1, and coagulation factor XIIa light chain, also known in this context as beta-factor XIIa part 2.
Interacts with HRG; the interaction, which is enhanced in the presence of zinc ions and inhibited by heparin-binding, inhibits factor XII autoactivation and contact-initiated coagulation.
O- and N-glycosylated. The O-linked polysaccharides were not identified, but are probably the mucin type linked to GalNAc.
Detected in blood plasma and in urine (at protein level).
Interacts with TTR (PubMed:5541771, PubMed:7754382, PubMed:10052934, PubMed:19021760). Interaction with TTR prevents its loss by filtration through the kidney glomeruli (Probable). Interacts with STRA6 (PubMed:22665496, PubMed:25910211).
Retinol-binding protein that mediates retinol transport in blood plasma (PubMed:5541771). Delivers retinol from the liver stores to the peripheral tissues (Probable). Transfers the bound all-trans retinol to STRA6, that then facilitates retinol transport across the cell membrane (PubMed:22665496).
Retinol-binding protein that mediates retinol transport in blood plasma.
The disease is caused by variants affecting the gene represented in this entry. Loss of functional RBP4 protein results in serum retinol deficiency. Lack of normal levels of retinol impairs the visual cycle leading to night blindness at early stages; prolonged deficiency may lead to retinal degeneration. Additionally, retinol deficiency may result in dry skin, increased susceptibility to infection and acne (PubMed:23189188).
Belongs to the heme-copper respiratory oxidase family.
Binds 2 heme A groups non-covalently per subunit.
Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). As a newly synthesized protein, rapidly incorporates into a multi-subunit assembly intermediate in the inner membrane, called MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase) complex, whose core components are COA3/MITRAC12 and COX14. Within the MITRAC complex, interacts with COA3 and with SMIM20/MITRAC7; the interaction with SMIM20 stabilizes the newly synthesized MT-CO1 and prevents its premature turnover (PubMed:26321642). Interacts with TMEM177 in a COX20-dependent manner (PubMed:29154948).
MT-CO1 may play a role in the pathogenesis of acquired idiopathic sideroblastic anemia, a disease characterized by inadequate formation of heme and excessive accumulation of iron in mitochondria. Mitochondrial iron overload may be attributable to mutations of mitochondrial DNA because these can cause respiratory chain dysfunction, thereby impairing reduction of ferric iron to ferrous iron. The reduced form of iron is essential to the last step of mitochondrial heme biosynthesis.
Ser-854 is present instead of the conserved Asp which is expected to be an active site residue.
(Microbial infection) Interacts with molluscum contagiosum virus protein MC159L; this interaction is important for the suppression of autophagy.
Expressed in all tissues tested with higher expression in pancreas. Expressed by retinal pigment epithelial cells (at protein level).
Homodimer or homooligomer. Interacts with DNM2, EPS15, clathrin, the adapter protein complex 2/AP-2 and TFRC. Interacts with the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD; the interaction is most probably direct, preferentially occurs with their inactive GDP-bound form and is negatively regulated by amino acids.
May function in transferrin receptor internalization at the plasma membrane through a cargo-specific control of clathrin-mediated endocytosis. Alternatively, may act as a negative regulator of the amino acid-induced TOR signaling by inhibiting the formation of active Rag GTPase complexes. Preferentially binds inactive Rag GTPase complexes and prevents their interaction with the mTORC1 complex inhibiting its relocalization to lysosomes and its activation. Thereby, may indirectly regulate cell growth, proliferation and autophagy.
Overexpression or depletion of SH3BP4 result in a specific decrease of the transferrin receptor endocytosis that can be rescued by DNM2 overexpression.
Phosphorylated upon EGF stimulation. Phosphorylation prevents interaction with DNM2.
The SH3 domain mediates localization to the clathrin-coated pits and vesicles. The SH3 domain mediates interaction with DNM2 and the cytoplasmic part of TFRC with a lower affinity. The SH3 domain also mediates interaction with RRAGB, RRAGC and is required for the negative regulation of mTORC1.
Guanine nucleotide-releasing protein that binds to SH3 domain of CRK and GRB2/ASH. Transduces signals from CRK to activate RAS. Involved in cell branching and adhesion mediated by BCAR1-CRK-RAPGEF1 signaling and activation of RAP1 (PubMed:12432078). Plays a role in the establishment of basal endothelial barrier function. Plays a role in nerve growth factor (NGF)-induced sustained activation of Rap1 and neurite outgrowth.
Interacts with HCK (via SH3-binding sites) (PubMed:14551197). Interacts with CRK (via SH3-binding sites) (PubMed:8662907).
Phosphorylation at Tyr-504 enhances activity as Rap guanine nucleotide exchange factor.
Ubiquitously expressed in adult and fetus. Expression is high in adult skeletal muscle and placenta and in fetal brain and heart. Low levels of expression in adult and fetal liver.
Forms heterodimers with IL17RA; the heterodimer binds IL17C.
Predominantly expressed in mucosal tissues with high levels in keratinocytes and colon epithelial cells. Very low expression in dermal fibroblasts. Expressed in various tumor cell lines.
Specific functional receptor for IL17C. May be signaling through the NF-kappa-B and MAPK pathways. May require TRAF3IP2 /ACT1 for signaling. May be a crucial regulator in innate immunity to bacterial pathogens. Isoform 2 and isoform 4 may be either cytoplasmic inactive or dominant active forms. Isoform 3 and isoform 5 may act as soluble decoy receptors.
Belongs to the TFS-II family. TFA subfamily.
Expressed in all tissues examined. Highly expressed in heart, ovary, prostate and skeletal muscle. Moderately expressed in brain, placenta, testis and small intestine. Weakly expressed in lung, liver and spleen. Expressed in several cancer cell lines.
May be involved in transcriptional regulation. Modulates various viral and cellular promoters in a promoter context-dependent manner. For example, transcription from the FOS promoter is increased, while Rous sarcoma virus (RSV) long terminal repeat (LTR) promoter activity is repressed. Does not bind DNA directly.
Phosphorylation of Ser-38 and Ser-39 is critical for transcriptional repression.
AR is a protein containing cysteines in disulfide linkage(s) that are essential for its biological activity. AR may contain oligosaccharides and/or lipid moieties that are not obligatory for the biological activity.
By phorbol 12-myristate 13-acetate (PMA).
Ligand of the EGF receptor/EGFR. Autocrine growth factor as well as a mitogen for a broad range of target cells including astrocytes, Schwann cells and fibroblasts.
The immature precursor interacts with CNIH.
Bifunctional enzyme that converts glutamate to glutamate 5-semialdehyde, an intermediate in the biosynthesis of proline, ornithine and arginine.
In the C-terminal section; belongs to the gamma-glutamyl phosphate reductase family.
In the N-terminal section; belongs to the glutamate 5-kinase family.
Isoform Short: Inhibited by L-ornithine with a Ki of approximately 0.25 mm. Isoform Long: Insensitive to ornithine inhibition. This is due to the two amino acid insert which abolishes feedback inhibition of P5CS activity by L-ornithine.
Belongs to the flagellar radial spoke RSP9 family.
Component of the axonemal radial spoke 1 (RS1) and 2 (RS2) complexes, at least composed of spoke head proteins RSPH1, RSPH3, RSPH9 and the cilia-specific component RSPH4A or sperm-specific component RSPH6A, spoke stalk proteins RSPH14, DNAJB13, DYDC1, ROPN1L and NME5, and the RS1 complex-specific anchor protein IQUB (By similarity). Interacts with IQUB (By similarity). Interacts with RSPH3B (By similarity). Interacts with RSPH4A (By similarity). Interacts with RSPH6A (By similarity).
Functions as part of axonemal radial spoke complexes that play an important part in the motility of sperm and cilia (PubMed:19200523). Essential for both the radial spoke head assembly and the central pair microtubule stability in ependymal motile cilia (By similarity). Required for motility of olfactory and neural cilia and for the structural integrity of ciliary axonemes in both 9+0 and 9+2 motile cilia (By similarity).
Able to bind zinc in vitro; the binding sites are different from the calcium binding sites. The physiological relevance of zinc binding is unclear. Physiological concentrations of potassium antagonize the binding of both divalent cations, especially affecting the high-affinity calcium-binding sites.
Dimer of either two alpha chains, or two beta chains, or one alpha and one beta chain (PubMed:21296671). Also forms heterodimers with S100P (PubMed:15171681). Interacts with AGER (By similarity). Interacts with CAPZA1 (By similarity). Interacts with FKBP4 (PubMed:20188096). Interacts with RYR1 and RYR2 (PubMed:18650434). Interacts with CACYBP in a calcium-dependent manner (PubMed:12042313). Interacts with PPP5C (via TPR repeats); the interaction is calcium-dependent and modulates PPP5C activity (PubMed:22399290). Interacts with ATP2A2 and PLN in a Ca(2+)-dependent manner (PubMed:12804600). Interacts with mitochondrial F1-ATPase subunits ATP5F1A and ATP5F1B; these interactions increase F1-ATPase activity (By similarity).
Glutathionylated; glutathionylation increases affinity to calcium about 10-fold.
Highly prevalent in heart (PubMed:12804600, PubMed:1384693). Also found in lesser quantities in skeletal muscle and brain (PubMed:1384693).
Small calcium binding protein that plays important roles in several biological processes such as Ca(2+) homeostasis, chondrocyte biology and cardiomyocyte regulation (PubMed:12804600). In response to an increase in intracellular Ca(2+) levels, binds calcium which triggers conformational changes (PubMed:23351007). These changes allow interactions with specific target proteins and modulate their activity (PubMed:22399290). Regulates a network in cardiomyocytes controlling sarcoplasmic reticulum Ca(2+) cycling and mitochondrial function through interaction with the ryanodine receptors RYR1 and RYR2, sarcoplasmic reticulum Ca(2+)-ATPase/ATP2A2 and mitochondrial F1-ATPase (PubMed:12804600). Facilitates diastolic Ca(2+) dissociation and myofilament mechanics in order to improve relaxation during diastole (PubMed:11717446).
Baed on animal models in mouse and zebrafish, it was suggested that KCTD13 is the major factor inducing the macrocephaly phenotype associated with the 16p11.2 deletion (PubMed:22596160). However, a subsequent report showed that KCTD13 does not play a role in brain size.
Homotetramer; forms a two-fold symmetric tetramer in solution (PubMed:28963344). Interacts with CUL3; interaction is direct and forms a 5:5 heterodecamer (PubMed:28963344). Component of the BCR(KCTD13) E3 ubiquitin ligase complex, at least composed of CUL3, KCTD13/BACURD1 and RBX1. Interacts with RHOA; with a preference for RhoA-GDP (PubMed:19782033). Interacts with POLD2 and PCNA (PubMed:11593007). Interacts with SPRTN (PubMed:22902628).
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for synaptic transmission (PubMed:19782033). The BCR(KCTD13) E3 ubiquitin ligase complex mediates the ubiquitination of RHOA, leading to its degradation by the proteasome (PubMed:19782033) Degradation of RHOA regulates the actin cytoskeleton and promotes synaptic transmission (By similarity).
The gene represented in this entry may act as a disease modifier for autism and schizophrenia associated with recurrent deletions and duplications of chromosome 16p11.2 region (PubMed:22596160, PubMed:25695269).
(Microbial infection) Interacts with P.falciparum (strain 3D7) CK1.
Expressed in erythrocytes (at protein level).
May be involved in several stages of intracellular trafficking (By similarity). Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) (PubMed:17400918).
The PX domain mediates specific binding to membranes enriched in phosphatidylinositol 3-phosphate (PtdIns(P3)).
Belongs to the inositol phosphokinase (IPK) family.
Binds two Mg(2+), but the interaction with the protein is mostly indirect.
Inhibited by flavonoids that occupy the ATP-binding pocket. Inhibited by myricetin, quercetin, luteolin, kaempferol, isorhamnetin and diosmetin, and to a lesser degree by rhamnetin and apigenin.
Inositol phosphate kinase with a broad substrate specificity (PubMed:12027805, PubMed:12223481, PubMed:28882892, PubMed:30420721, PubMed:30624931). Phosphorylates inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) first to inositol 1,3,4,5-tetrakisphosphate and then to inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5) (PubMed:12027805, PubMed:12223481, PubMed:28882892, PubMed:30624931). Phosphorylates inositol 1,3,4,6-tetrakisphosphate (Ins(1,3,4,6)P4) (PubMed:12223481). Phosphorylates glycero-3-phospho-1D-myo-inositol 4,5-bisphosphate to glycero-3-phospho-1D-myo-inositol 3,4,5-trisphosphate (PubMed:30420721, PubMed:28882892). Plays an important role in MLKL-mediated necroptosis via its role in the biosynthesis of inositol pentakisphosphate (InsP5) and inositol hexakisphosphate (InsP6). Binding of these highly phosphorylated inositol phosphates to MLKL mediates the release of an N-terminal auto-inhibitory region, leading to activation of the kinase. Essential for activated phospho-MLKL to oligomerize and localize to the cell membrane during necroptosis (PubMed:29883610). Required for normal embryonic development, probably via its role in the biosynthesis of inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5) and inositol hexakisphosphate (InsP6) (By similarity).
Ubiquitous, with the highest expression in skeletal muscle, liver, placenta, lung, peripheral blood leukocytes, kidney, spleen and colon.
Expressed in the striatum and cortex of the brain (at protein level). Highly expressed in testis, fetal kidney and fetal brain. Moderately expressed in pancreas, skeletal muscle, placenta, brain and heart. Weakly expressed in colon, ileum, ovary, prostate, spleen, kidney and fetal lung.
Prenyltransferase that mediates the formation of menaquinone-4 (MK-4) and coenzyme Q10 (PubMed:20953171, PubMed:23374346). MK-4 is a vitamin K2 isoform present at high concentrations in the brain, kidney and pancreas, and is required for endothelial cell development (PubMed:20953171). Mediates the conversion of phylloquinone (PK) into MK-4, probably by cleaving the side chain of phylloquinone (PK) to release 2-methyl-1,4-naphthoquinone (menadione; K3) and then prenylating it with geranylgeranyl pyrophosphate (GGPP) to form MK-4 (PubMed:20953171). Also plays a role in cardiovascular development independently of MK-4 biosynthesis, by acting as a coenzyme Q10 biosynthetic enzyme: coenzyme Q10, also named ubiquinone, plays an important antioxidant role in the cardiovascular system (PubMed:23374346). Mediates biosynthesis of coenzyme Q10 in the Golgi membrane, leading to protect cardiovascular tissues from NOS3/eNOS-dependent oxidative stress (PubMed:23374346).
Strongly down-regulated in transitional cell carcinoma of the bladder and in prostate carcinoma (at protein level) (PubMed:11314041, PubMed:12497587).
Homodimer. May interact with CEBPB (By similarity). Interacts with EXOSC10.
Isomerase activity is increased by sulfhydril compounds. Dithiothreitol (DTT) is most effective, followed by dihydrolipoic acid, glutathione (GSH) and 2-mercaptoethanol.
Isomerase that catalyzes the conversion of PGH2 into the more stable prostaglandin E2 (PGE2) (in vitro) (PubMed:12804604, PubMed:18198127, PubMed:17585783). The biological function and the GSH-dependent property of PTGES2 is still under debate (PubMed:18198127, PubMed:17585783). In vivo, PTGES2 could form a complex with GSH and heme and would not participate in PGE2 synthesis but would catalyze the degradation of prostaglandin E2 H2 (PGH2) to 12(S)-hydroxy-5(Z),8(E),10(E)-heptadecatrienoic acid (HHT) and malondialdehyde (MDA) (PubMed:17585783) (By similarity).
It is not known if heme and GST are required for prostaglandin synthase activity. The protein copurifies with heme and GST when DTT is omitted during the purification procedure. The GSH-heme complex-bound enzyme has been proposed to act as a lyase and catalyze the degradation of prostaglandin E2 H2 (PGH2) to 12(S)-hydroxy-5(Z),8(E),10(E)-heptadecatrienoic acid (HHT) and malondialdehyde (MDA). According to PubMed:18198127, boiling the enzyme leads to loss of prostaglandin synthase activity, but does not eliminate the lyase activity. Besides, free heme can catalyze the formation of 12L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) (PubMed:18198127). A more recent study demonstrates the GSH-dependent property of PTGES2, DTT dissociates the bound heme to produce active PGE2 synthase in vitro (By similarity). PTGES2 can only catalyzes PGE2 synthesis in the free state as an enzyme, while in vivo it forms a complex with heme and does not participate in PGE2 synthesis (By similarity). In agreement with this study, the in vivo evidence from PTGES2 deficient mice do not show that this protein is responsible for the PGE2 production under basal or pathophysiological conditions (By similarity).
Synthesized as a Golgi membrane-associated protein, and the proteolytic removal of the N-terminal hydrophobic domain leads to the formation of a mature cytosolic enzyme.
Widely expressed. Expressed in the heart, including apex, inter-ventricular septum, both atria and ventricles, but not in the aorta. Also expressed in fetal heart. Detected in various regions of the brain: cerebellum; occipital, frontal and parietal lobes. Also expressed in the lymph nodes, skeletal muscle, kidney and trachea, but not in the thymus or lung. Overexpressed in colorectal cancer.
Mutations in UPK3A have been detected in patients with renal adyplasia suggesting a possible involvement of this gene in kidney and urinary tract anomalies.
N-linked glycosylated in complex form containing terminal sialic acid.
Potential role in vesicular protein trafficking, mainly in the early secretory pathway. Appears to play a role in the biosynthesis of secreted cargo including processing and post-translational modifications.
Predominantly monomeric and to lesser extent homodimeric in endoplasmic reticulum, endoplasmic reticulum-Golgi intermediate compartment and cis-Golgi network. Oligomerizes with other members of the EMP24/GP25L family such as TMED2, TMED9 and TMED10. Interacts (via C-terminus) with COPG1; the interaction involves dimeric TMED7.
Down-regulated by cholesterol (at protein level).
Key component of the Ragulator complex, a multiprotein complex involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids (PubMed:20381137, PubMed:22980980, PubMed:29158492). Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator plays a dual role for the small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD): it (1) acts as a guanine nucleotide exchange factor (GEF), activating the small GTPases Rag and (2) mediates recruitment of Rag GTPases to the lysosome membrane (PubMed:22980980, PubMed:30181260, PubMed:31001086, PubMed:32686708, PubMed:36476874, PubMed:29158492, PubMed:28935770). Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated (PubMed:20381137, PubMed:22980980, PubMed:29158492). LAMTOR1 is directly responsible for anchoring the Ragulator complex to the lysosomal membrane (PubMed:31001086, PubMed:32686708). LAMTOR1 wraps around the other subunits of the Ragulator complex to hold them in place and interacts with the Rag GTPases, thereby playing a key role in the recruitment of the mTORC1 complex to lysosomes (PubMed:29285400, PubMed:29107538, PubMed:29123114, PubMed:28935770). Also involved in the control of embryonic stem cells differentiation via non-canonical RagC/RRAGC and RagD/RRAGD activation: together with FLCN, it is necessary to recruit and activate RagC/RRAGC and RagD/RRAGD at the lysosomes, and to induce exit of embryonic stem cells from pluripotency via non-canonical, mTOR-independent TFE3 inactivation (By similarity). Also required for late endosomes/lysosomes biogenesis it may regulate both the recycling of receptors through endosomes and the MAPK signaling pathway through recruitment of some of its components to late endosomes (PubMed:20381137, PubMed:22980980). May be involved in cholesterol homeostasis regulating LDL uptake and cholesterol release from late endosomes/lysosomes (PubMed:20544018). May also play a role in RHOA activation (PubMed:19654316).
N-terminal myristoylation and palmitoylation mediates its recruitment to lysosome membranes, thereby promoting localization of the Ragulator complex to lysosomes (PubMed:31001086). N-myristoylation by NMT1 is required for palmitoylation at Cys-3 and Cys-4 (PubMed:34999170). May be palmitoylated by ZDHHC3 (PubMed:35893977).
Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980, PubMed:29285400, PubMed:29107538, PubMed:29123114, PubMed:29158492, PubMed:28935770, PubMed:31601708, PubMed:32868926, PubMed:35338845, PubMed:36103527, PubMed:36697823). LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:20381137, PubMed:22980980). Interacts with LAMTOR2 and LAMTOR3; the interaction is direct (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and RagD/RRAGD; regulated by amino acid availability (PubMed:20381137, PubMed:22980980, PubMed:32868926). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906, PubMed:22980980). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator (PubMed:31672913, PubMed:31704029). Associates with the lysosomal V-ATPase complex; interaction promotes the guanine nucleotide exchange factor (GEF) of the Ragulator complex (PubMed:36476874). Interacts with MMP14 (PubMed:19654316). Interacts with CDKN1B; prevents the interaction of CDKN1B with RHOA leaving RHOA in a form accessible to activation by ARHGEF2 (PubMed:19654316). Interacts with PIP4P1 (PubMed:29644770).
Ubiquitinated at Lys-60, Lys-103 and Lys-104 by UBE3A, promoting its degradation by the proteasome (PubMed:30020076). Ubiquitination at Lys-20 impairs the association with the lysosomal V-ATPase complex (PubMed:36476874). Deubiquitination at Lys-20 by USP32 promotes the association with the lysosomal V-ATPase complex and subsequent activation of the mTORC1 complex (PubMed:36476874).
Interacts with IKBKE and TBK1 via its coiled coil region. Interaction with TBK1 is disrupted upon viral infection or TLR3 stimulation (PubMed:16281057). Interacts with CDC42BPB (PubMed:25743393).
Physiological suppressor of IKK-epsilon and TBK1 that plays an inhibitory role in virus- and TLR3-triggered IRF3. Inhibits TLR3-mediated activation of interferon-stimulated response elements (ISRE) and the IFN-beta promoter. May act by disrupting the interactions of IKBKE or TBK1 with TICAM1/TRIF, IRF3 and RIGI. Does not inhibit NF-kappa-B activation pathways.
Widely expressed. Expressed in brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung and leukocytes. Present in all cell lines tested (at protein level).
Belongs to the chloride channel (TC 2.A.49) family. ClC-7/CLCN7 subfamily.
Chloride channel 7 are heteromers of alpha (CLCN7) and beta (OSTM1) subunits.
Slowly voltage-gated channel mediating the exchange of chloride ions against protons (PubMed:18449189, PubMed:21527911). Functions as antiporter and contributes to the acidification of the lysosome lumen and may be involved in maintaining lysosomal pH (PubMed:18449189, PubMed:21527911, PubMed:31155284). The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons (By similarity). The presence of conserved gating glutamate residues is typical for family members that function as antiporters (By similarity).
Autophosphorylated on serine and threonine residues. Phosphorylation at Thr-387 by PKB/AKT1, leads to inhibition of its: kinase activity, nuclear translocation and autophosphorylation at Thr-183. It also diminishes its cleavage by caspases and its ability to phosphorylate FOXO3.
Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Ubiquitously expressed.
Homodimer; mediated via the coiled-coil region. Interacts with NORE1, which inhibits autoactivation. Interacts with and stabilizes SAV1. Interacts with RASSF1. Interacts with FOXO3. Interacts with RASSF2 (via SARAH domain). Interacts with AR, PKB/AKT1, TNNI3 and SIRT1. Interacts with DLG5 (via PDZ domain 3). Interacts with MARK3 in the presence of DLG5 (PubMed:28087714). Interacts with SCRIB in the presence of DLG5 (PubMed:28169360).
Inhibited by the C-terminal non-catalytic region. Activated by caspase-cleavage. Full activation also requires homodimerization and autophosphorylation of Thr-183. Activated by RASSF1 which acts by preventing its dephosphorylation.
Proteolytically cleaved by caspase-3 during apoptosis at Asp-326 and Asp-349 resulting in a 37 kDa or a 39 kDa subunit respectively. The 39 kDa subunit is further cleaved into the 37 kDa form. Proteolytic cleavage results in kinase activation and nuclear translocation of the truncated form (MST1/N). It is less likely that cleavage at Asp-349 is a prerequisite for activation as this site is not conserved in the murine ortholog.
Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation (By similarity). Phosphorylates 'Ser-14' of histone H2B (H2BS14ph) during apoptosis. Phosphorylates FOXO3 upon oxidative stress, which results in its nuclear translocation and cell death initiation. Phosphorylates MOBKL1A, MOBKL1B and RASSF2. Phosphorylates TNNI3 (cardiac Tn-I) and alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Phosphorylates FOXO1 on 'Ser-212' and regulates its activation and stimulates transcription of PMAIP1 in a FOXO1-dependent manner. Phosphorylates SIRT1 and inhibits SIRT1-mediated p53/TP53 deacetylation, thereby promoting p53/TP53 dependent transcription and apoptosis upon DNA damage. Acts as an inhibitor of PKB/AKT1. Phosphorylates AR on 'Ser-650' and suppresses its activity by intersecting with PKB/AKT1 signaling and antagonizing formation of AR-chromatin complexes.
Was originally thought to be phosphorylated at Thr-120 (PubMed:19940129). However, this work has been retracted (PubMed:27825096).
Component of a complex composed of CRB3, PALS1 and PATJ (By similarity). Interacts (via C-terminus) with PALS1 (via PDZ domain) (PubMed:12527193, PubMed:12771187). Interacts with PARD6A (PubMed:14718572). Interacts (via intracellular domain) with EPB41L5 (PubMed:17920587).
Involved in the establishment of cell polarity in mammalian epithelial cells (PubMed:12771187, PubMed:14718572). Regulates the morphogenesis of tight junctions (PubMed:12771187, PubMed:14718572). Involved in promoting phosphorylation and cytoplasmic retention of transcriptional coactivators YAP1 and WWTR1/TAZ which leads to suppression of TGFB1-dependent transcription of target genes such as CCN2/CTGF, SERPINE1/PAI1, SNAI1/SNAIL1 and SMAD7 (By similarity).
Preferentially expressed in epithelial tissues (PubMed:14718572). Expressed at high levels in lung, kidney, and colon (PubMed:12527193, PubMed:14718572). Expressed at high levels in retina, colon and mammary glands (PubMed:12527193). Moderately expressed in liver, spleen, pancreas and prostate (PubMed:12527193). Moderately to weakly expressed in the placenta (PubMed:14718572, PubMed:12527193). Weakly expressed in skeletal muscle and small intestine (PubMed:14718572).
The PDZ-binding motif is involved in the interactions with PARD6A and PALS1.
Highly expressed in the placenta (PubMed:10542267). Expressed in trophoblast cells of the villi (PubMed:27917469).
Polyubiquitinated in the presence of UBE2D2 and FBXW2 (in vitro).
Transcription factor involved in the control of expression of placental growth factor (PGF) and other placenta-specific genes (PubMed:10542267, PubMed:18160678). Binds to the trophoblast-specific element 2 (TSE2) of the aromatase gene enhancer (PubMed:10542267). Binds to the SYDE1 promoter (PubMed:27917469). Has a central role in mediating the differentiation of trophoblast cells along both the villous and extravillous pathways in placental development (PubMed:19219068).
Based on a naturally occurring readthrough transcript which produces an EEF1AKMT4-ECE2 fusion protein.
Converts big endothelin-1 to endothelin-1. Also involved in the processing of various neuroendocrine peptides, including neurotensin, angiotensin I, substance P, proenkephalin-derived peptides, and prodynorphin-derived peptides. May play a role in amyloid-beta processing (By similarity).
Converts big endothelin-1 to endothelin-1. May also have methyltransferase activity (By similarity). May play a role in amyloid-beta processing (By similarity).
In the C-terminal section; belongs to the peptidase M13 family.
In the N-terminal section; belongs to the methyltransferase superfamily.
May play a role in developmental myelination of peripheral nerves.
Belongs to the protein-tyrosine phosphatase family. Receptor class 3 subfamily.
Expressed at high levels in the brain, spleen and liver and at lower levels in the heart and stomach. Expressed in pancreatic and colorectal cancer cells, but not in normal pancreas or colon. Expression in hepatocellular carcinoma is related to the differentiation status of the tumor and expression is inversely related to tumor aggressiveness.
Homodimer; disulfide-linked (Probable). Interacts with LCK (PubMed:12837766). Interacts (phosphorylated form) with GRB2 (via SH2 domain) (By similarity). Interacts (phosphorylated form) with FYN (via SH2 domain) (By similarity). Interacts (via extracellular domain) with CEACAM20 (via extracellular domain); the interaction dephosphorylates CEACAM20 (By similarity).
Induced at the early stage of hepatocellular carcinoma and is suppressed at later stages.
Protein phosphatase that may contribute to contact inhibition of cell growth and motility by mediating the dephosphorylation of focal adhesion-associated substrates and thus negatively regulating integrin-promoted signaling processes. Induces apoptotic cell death by at least two distinct mechanisms: inhibition of cell survival signaling mediated by PI 3-kinase, Akt, and ILK and activation of a caspase-dependent proapoptotic pathway. Inhibits the basal activity of LCK and its activation in response to TCR stimulation and TCR-induced activation of MAP kinase and surface expression of CD69. Inhibits TCR-induced tyrosine phosphorylation of LAT and ZAP70. Inhibits both basal activity of DOK1 and its CD2-induced tyrosine phosphorylation. Induces dephosphorylation of BCAR1, focal adhesion kinase and SRC. Reduces migratory activity of activity of Jurkat cells. Reduces tyrosine phosphorylation of CEACAM20 and thereby contributes to suppress the intestinal immune response CEACAM20 (By similarity).
Regulated by reversible dimerization. Dimerization reduces its catalytic activity.
The cytoplasmic domain mediates the interaction with LCK.
The extracellular domain mediates homodimerization. One or more cysteines in the extracellular domain is essential for the formation of dimers probably by forming a disulfide bond.
Mitochondrial serine transporter that mediates transport of serine into mitochondria, an important step of the one-carbon metabolism pathway (PubMed:30442778). Mitochondrial serine is converted to glycine and formate, which then exits to the cytosol where it is used to generate the charged folates that serve as one-carbon donors (PubMed:30442778).
Ubiquitously expressed, with highest levels in heart, liver and pancreas.
Belongs to the TFIIF beta subunit family.
GTF2F2 appears to have ATP-dependent DNA-helicase activity; however this is probably an artifact that happened during the protein purification.
Heterodimer of an alpha and a beta subunit. Interacts with HTATSF1 and GPBP1 (By similarity). Interacts with URI1. Interacts with GTF2B (via N-terminus); this interaction is inhibited in presence of GTF2F1 (PubMed:8504927, PubMed:8662660).
TFIIF is a general transcription initiation factor that binds to RNA polymerase II and helps to recruit it to the initiation complex in collaboration with TFIIB.
May be involved in membrane trafficking between endosomes and plasma membrane.
A chromosomal aberration involving PBX1 is a cause of pre-B-cell acute lymphoblastic leukemia (B-ALL). Translocation t(1;19)(q23;p13.3) with TCF3. TCF3-PBX1 transforms cells by constitutively activating transcription of genes regulated by PBX1 or by other members of the PBX protein family. TCF3-PBX1 binds the DNA sequence 5'-ATCAATCAA-3'.
As part of a PDX1:PBX1b:MEIS2B complex in pancreatic acinar cells, is involved in the transcriptional activation of the ELA1 enhancer; the complex binds to the enhancer B element and cooperates with the transcription factor 1 complex (PTF1) bound to the enhancer A element.
Belongs to the TALE/PBX homeobox family.
Expressed in the kidney. Expressed in the endothelial cells of the glomeruli and interstitium (at protein level) (PubMed:28270404). Expressed in all tissues except in cells of the B and T lineage. Expressed strongly in kidney and brain (PubMed:28270404).
Forms a heterodimer with MEIS1 which binds DNA (PubMed:19799567). The PBX1-MEIS1 heterodimer binds a cAMP-responsive sequence in CYP17 (By similarity). It also binds a consensus region in the SOX3 promoter (PubMed:19799567). PBX1 forms heterotrimers with MEIS1 and a number of HOX proteins including HOXA9, HOXD4, HOXD9 and HOXD10 (By similarity). Forms heterodimers with HOXA1, HOXA5, HOXB7 and HOXB8 which bind the 5'-TGATTGAT-3' consensus sequence (PubMed:9191052). Also forms heterodimers with HOXA5, HOXB7, HOXB8, HOXC8 and HOXD4 which bind the 5'-ATCAATCAA-3' consensus sequence (PubMed:7791786). Interacts with PBXIP1 (PubMed:10825160). Interacts with TLX1 (PubMed:19559479). Interacts with FOXC1 (PubMed:15684392). Interacts with MN1 (PubMed:31839203).
Interacts with MEIS2 isoform 4, SP1, SP3 and KLF4.
Part of a PDX1:PBX1b:MEIS2B complex; PBX1b recruits MEIS2B to the complex.
The homeobox is required for PBX1 nuclear localization and for transcriptional activation of NFIL3.
Transcription factor which binds the DNA sequence 5'-TGATTGAT-3' as part of a heterodimer with HOX proteins such as HOXA1, HOXA5, HOXB7 and HOXB8 (PubMed:9191052). Binds to the DNA sequence 5'-TGATTGAC-3' in complex with a nuclear factor which is not a class I HOX protein (PubMed:9191052). Has also been shown to bind the DNA sequence 5'-ATCAATCAA-3' cooperatively with HOXA5, HOXB7, HOXB8, HOXC8 and HOXD4 (PubMed:8327485, PubMed:7791786). Acts as a transcriptional activator of PF4 in complex with MEIS1 (PubMed:12609849). Also activates transcription of SOX3 in complex with MEIS1 by binding to the 5'-TGATTGAC-3' consensus sequence (By similarity). In natural killer cells, binds to the NFIL3 promoter and acts as a transcriptional activator of NFIL3, promoting natural killer cell development (By similarity). Plays a role in the cAMP-dependent regulation of CYP17A1 gene expression via its cAMP-regulatory sequence (CRS1) (By similarity). Probably in complex with MEIS2, involved in transcriptional regulation by KLF4 (PubMed:21746878). Acts as a transcriptional activator of NKX2-5 and a transcriptional repressor of CDKN2B (By similarity). Together with NKX2-5, required for spleen development through a mechanism that involves CDKN2B repression (By similarity).
Expressed by nucleated hematopoietic cells (at protein level).
Expressed in fetal liver (at protein level). Expressed in embryonic hematopoiesis sites.
Involved in the maintenance of the Golgi structure. May play a role in hematopoiesis.
N-glycosylated in the ER (40 kDa form I), then O-glycosylated in the Golgi apparatus (46 kDa form II), the C-terminal lumenal region is later removed in the Golgi apparatus to produce a 36 kDa form III. O-glycosylated with core 1-like and core 2-like glycans. O-glycan heterogeneity at Thr-346: HexNAc (minor), HexHexNAc (major), Hex1HexNAc2 (minor), Hex2HexNAc2 (minor) and dHex1Hex2HexNAc2 (minor).
Component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin. Interacts with SRF. Forms complexes with SRF and SRF cofactors MYOCD, NKX2-5 and SRFBP1.
Differs from position 1094 onward for unknown reason.
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Required for the stability of the SWI/SNF chromatin remodeling complex SWI/SNF-B (PBAF). May be involved in targeting the complex to different genes. May be involved in regulating transcriptional activation of cardiac genes.
Up-regulated in adult heart (at protein level).
May be not functional as it lacks the poly(A)-binding protein C-terminal (PABC) domain implicated in the mRNA stability and translation regulation.
A chromosomal aberration involving SHROOM4 is a cause of X-linked intellectual disability (XLID). Translocation t(X;19).
A chromosomal aberration involving SHROOM4 is a cause of X-linked intellectual disability (XLID). Translocation t(X;8)(p11.22;p23.3) with FBXO25.
Expressed in all fetal and adult tissues investigated. Expressed in adult heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. In brain regions detected in cerebellum, cerebral cortex, medulla, spinal cord, occipital pole, frontal lobe, temporal lobe and putamen. The expression is strongest in the medulla and weakest in the cerebral cortex.
Probable regulator of cytoskeletal architecture that plays an important role in development. May regulate cellular and cytoskeletal architecture by modulating the spatial distribution of myosin II (By similarity).
Composed of a mini chain and a large chain. The large chain may be split into heavy and light chain. All chains are held together by disulfide bonds.
Important for the overall degradation of proteins in lysosomes.
Exhibits histone deacetylase (HDAC) enhancer properties (PubMed:23460338). May play a role in cell cycle progression and wound repair of bronchial epithelial cells (PubMed:21857995).
Homodimer (PubMed:23460338). Interacts with BRS3 (PubMed:21857995). Interacts (via N-terminus) with SIN3B (PubMed:23460338).
Named amfion, after 'the 4 Amfion heroes in Greek mythology and their deeds in different locations within the mother land.
Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin.
May have an important role in developing neurons by participating in regulation of cell survival, possibly as a neurospecific transcription factor. Belongs to the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity).
Glutamine--tRNA ligase (PubMed:26869582). Plays a critical role in brain development (PubMed:24656866).
Highly expressed in fetal cerebral cortex, particularly in the ventricular zone, inner subventricular zone, outer subventricular zone, and cortical plate.
Monomer (PubMed:26869582). Part of a multisubunit complex that groups tRNA ligases for Arg (RARS1), Asp (DARS1), Gln (QARS1), Ile (IARS1), Leu (LARS1), Lys (KARS1), Met (MARS1) the bifunctional ligase for Glu and Pro (EPRS1) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18 (PubMed:19131329, PubMed:19289464). Interacts with RARS1 (PubMed:24656866). Part of a complex composed of RARS1, QARS1 and AIMP1 (PubMed:25288775).
Catalyzes the dehalogenation of halotyrosines such as 3-bromo-L-tyrosine, 3-chloro-L-tyrosine, 3-iodo-L-tyrosine and 3,5-diiodo-L-tyrosine (PubMed:15289438, PubMed:18434651, PubMed:25395621, PubMed:28157283). During thyroid hormone biosynthesis, facilitates iodide salvage by catalysing the oxidative NADPH-dependent deiodination of the halogenated by-products of thyroid hormone production, monoiodotyrosine (L-MIT) and diiodotyrosine (L-DIT) (PubMed:15289438, PubMed:18434651). The scavanged iodide can then reenter the hormone-producing pathways (PubMed:15289438, PubMed:18434651). Acts more efficiently on 3-iodo-L-tyrosine than 3,5-diiodo-L-tyrosine (PubMed:15289438).
Expressed at a high level in thyroid gland (at protein level). Expressed at a high level in thyroid gland and at lower level in kidney and trachea.
Highly expressed in the heart and weakly in the brain.
Interacts with RHOQ and CDC42, in a GTP-dependent manner, and with SEPT7.
Probably involved in the organization of the actin cytoskeleton. May act downstream of CDC42 to induce actin filament assembly leading to cell shape changes. Induces pseudopodia formation in fibroblasts.
Expressed in brain, kidney, lung and liver.
Part of a SCF (SKP1-cullin-F-box) protein ligase complex (Probable). Interacts with POUF51 (By similarity).
Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation. Likely to be involved in key signaling pathways crucial for normal limb development. May participate in Wnt signaling.
Belongs to the KCNMB (TC 8.A.14.1) family. KCNMB4 subfamily.
Interacts with KCNMA1 tetramer (PubMed:10692449, PubMed:10804197). There are probably 4 molecules of KCMNB4 per KCNMA1 tetramer (PubMed:10692449, PubMed:10804197). Interacts with FMR1 (via N-terminus) (PubMed:25561520).
N-glycosylated. A highly glycosylated form is promoted by KCNMA1. Glycosylation, which is not required for the interaction with KCNMA1 and subcellular location, increases protection against charybdotoxin.
Phosphorylated. Phosphorylation modulates its effect on KCNMA1 activation kinetics.
Predominantly expressed in brain. In brain, it is expressed in the cerebellum, cerebral cortex, medulla, spinal cord, occipital pole, frontal lobe, temporal lobe, putamen, amygdala, caudate nucleus, corpus callosum, hippocampus, substantia nigra and thalamus. Weakly or not expressed in other tissues.
Regulatory subunit of the calcium activated potassium KCNMA1 (maxiK) channel. Modulates the calcium sensitivity and gating kinetics of KCNMA1, thereby contributing to KCNMA1 channel diversity. Decreases the gating kinetics and calcium sensitivity of the KCNMA1 channel, but with fast deactivation kinetics. May decrease KCNMA1 channel openings at low calcium concentrations but increases channel openings at high calcium concentrations. Makes KCNMA1 channel resistant to 100 nM charybdotoxin (CTX) toxin concentrations.
Resistance to charybdotoxin (CTX) toxin is mediated by the extracellular domain.
Treatment with okadaic acid reduces its effect on KCNMA1.
Detected in fibroblasts and urine (at protein level) (PubMed:25326458, PubMed:36213313). Not expressed in blood or lymphatic endothelial cells.
Required for lymphangioblast budding and angiogenic sprouting from venous endothelium during embryogenesis.
Belongs to the AB hydrolase superfamily. AB hydrolase 2 family.
Has depalmitoylating activity toward KCNMA1. Does not exhibit phospholipase nor triacylglycerol lipase activity, able to hydrolyze only short chain substrates due to its shallow active site.
Belongs to the U2 small nuclear ribonucleoprotein A family.
Identified in the spliceosome B complex (PubMed:28781166). Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:28076346). Found in a pre-mRNA splicing complex with SFRS4, SFRS5, SNRNP70, SNRPA1, SRRM1 and SRRM2 (PubMed:9531537). Found in a pre-mRNA exonic splicing enhancer (ESE) complex with SNRNP70, SNRPA1, SRRM1 and TRA2B (PubMed:10339552). Contributes to the binding of stem loop IV of U2 snRNA with SNRPB2 (PubMed:9716128, PubMed:27035939).
Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28502770, PubMed:28781166, PubMed:28076346, PubMed:27035939). Associated with sn-RNP U2, where it contributes to the binding of stem loop IV of U2 snRNA (PubMed:9716128, PubMed:27035939).
Expressed in placenta, fetal and adult brain. Not detected in heart and small intestine, very low levels in fibroblasts. Not expressed in brain of a Prader-Willi patient.
Imprinted, expressed from the paternal chromosome only.
Part of a complex consisting of MAGEL2, TRIM27 and USP7; directly interacts with USP7 (PubMed:26365382). Interacts with TRIM27 (PubMed:23452853). Interacts with VPS35; leading to recruitment at retromer-containing endosomes (PubMed:23452853). Interacts with BMAL1 and PER2 (By similarity).
Probably enhances ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases, possibly through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex. Acts as a regulator of retrograde transport via its interaction with VPS35. Recruited to retromer-containing endosomes and promotes the formation of 'Lys-63'-linked polyubiquitin chains at 'Lys-220' of WASHC1 together with TRIM27, leading to promote endosomal F-actin assembly (PubMed:23452853). Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer. Significantly promotes the cytoplasmic accumulation of CLOCK (By similarity).
The disease is caused by variants affecting the gene represented in this entry. All mutations occurred on the paternal allele.
Belongs to the universal ribosomal protein uS9 family.
Component of the small ribosomal subunit (PubMed:23636399). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Component of the CIA complex (PubMed:22678361, PubMed:22678362, PubMed:23585563). Interacts with CIAO2A and forms a complex with CIAO2B and MMS19; the interactions with CIAO2A and CIAO2B are mutually exclusive (PubMed:22683786, PubMed:23891004, PubMed:23585563). Interacts with CHD1L, ERCC2, IREB2 and POLD1 (PubMed:23891004). Component of the MMXD complex, which includes CIAO1, ERCC2, CIAO2B, MMS19 and SLC25A5 (PubMed:20797633). Interacts with WT1 (PubMed:9556563). Interacts with CIAO3 (PubMed:23585563). Interacts (via LYR motif) with HSC20 (PubMed:29309586).
Key component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into extramitochondrial Fe/S proteins (PubMed:17937914, PubMed:23891004). As a CIA complex component, interacts specifically with CIAO2A or CIAO2B and MMS19 to assist different branches of iron-sulfur protein assembly, depending of its interactors. The complex CIAO1:CIAO2B:MMS19 binds to and facilitates the assembly of most cytosolic-nuclear Fe/S proteins. CIAO1:CIAO2A specifically matures ACO1 and stabilizes IREB2 (PubMed:23891004). Seems to specifically modulate the transactivation activity of WT1 (PubMed:9556563). As part of the mitotic spindle-associated MMXD complex it may play a role in chromosome segregation (PubMed:20797633).
Most abundantly expressed in prostate, testes, pancreas, and heart, with moderate levels in lung and ovary. No detectable expression in brain, placenta, liver, skeletal muscle, kidney, spleen, thymus, small intestine, colon, or peripheral blood leukocytes.
Receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities. May play a role in the development of ovarian cancer. Seems to be coupled to the G(i)/G(o) and G(q) families of heteromeric G proteins.
Fetal lung and kidney, and adult spinal cord. Weak expression in adult adrenal gland, thyroid, trachea and other tissues examined.
Interacts with GREM1 (By similarity). Homodimer. Binds ROBO1 and ROBO2 with high affinity.
The leucine-rich repeat domain is sufficient for guiding both axon projection and neuronal migration, in vitro.
Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors. During neural development involved in axonal navigation at the ventral midline of the neural tube and projection of axons to different regions. SLIT1 and SLIT2 seem to be essential for midline guidance in the forebrain by acting as repulsive signal preventing inappropriate midline crossing by axons projecting from the olfactory bulb. In spinal cord development may play a role in guiding commissural axons once they reached the floor plate by modulating the response to netrin. In vitro, silences the attractive effect of NTN1 but not its growth-stimulatory effect and silencing requires the formation of a ROBO1-DCC complex. May be implicated in spinal cord midline post-crossing axon repulsion. In vitro, only commissural axons that crossed the midline responded to SLIT2. In the developing visual system appears to function as repellent for retinal ganglion axons by providing a repulsion that directs these axons along their appropriate paths prior to, and after passage through, the optic chiasm. In vitro, collapses and repels retinal ganglion cell growth cones. Seems to play a role in branching and arborization of CNS sensory axons, and in neuronal cell migration. In vitro, Slit homolog 2 protein N-product, but not Slit homolog 2 protein C-product, repels olfactory bulb (OB) but not dorsal root ganglia (DRG) axons, induces OB growth cones collapse and induces branching of DRG axons. Seems to be involved in regulating leukocyte migration.
Interacts with EGFR; positively regulates EGFR inducing its autophosphorylation in absence of stimulation by EGF (PubMed:23912460). Interacts with RAF1; displaces 14-3-3 proteins from RAF1 and activates RAF1 within the RAS/MAPK signaling cascade (PubMed:22886302). Interacts with AKT1, PIK3CA and PIK3R1; activates the PI3K/AKT signaling cascade (PubMed:23676467).
Probable proto-oncogene that functions in the epidermal growth factor receptor/EGFR signaling pathway. Activates both the EGFR itself and downstream RAS/MAPK and PI3K/AKT/TOR signaling cascades.
Biotin-attachment subunit of the 3-methylcrotonyl-CoA carboxylase, an enzyme that catalyzes the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step for leucine and isovaleric acid catabolism.
Probably a dodecamer composed of six biotin-containing alpha subunits (MCCC1) and six beta (MCCC2) subunits (PubMed:17360195). Interacts (via the biotin carboxylation domain) with SIRT4 (PubMed:23438705).
Binds to DNA sequences containing the consensus pentanucleotide 5'-CGGA[AT]-3'.
(Microbial infection) Interacts with hepatitis C virus (HCV) NS5A.
(Microbial infection) Interacts with human adenovirus 2 DBP.
Belongs to the SNF2/RAD54 helicase family. SWR1 subfamily.
Catalytic component of the SRCAP complex which mediates the ATP-dependent exchange of histone H2AZ/H2B dimers for nucleosomal H2A/H2B, leading to transcriptional regulation of selected genes by chromatin remodeling. Acts as a coactivator for CREB-mediated transcription, steroid receptor-mediated transcription, and Notch-mediated transcription.
Interacts with CREBBP and EP300. May be part of a complex containing SRCAP, CREBBP, CARM1 and GRIP1. Component of the chromatin-remodeling SRCAP complex composed of at least SRCAP, DMAP1, RUVBL1, RUVBL2, ACTL6A, YEATS4, VPS72, ACTR6 and ZNHIT1. Component of a NuA4-related complex which contains EP400, TRRAP/PAF400, SRCAP, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, actin, ACTL6A/BAF53A, VPS72 and YEATS4/GAS41.
Competitive inhibitor of E2F-mediated transactivation activity. Impairs E2F-mediated cell-cycle progression from G(1) to S phase.
Heterodimer: with E2F family members. TFDP3/E2F heterodimers do not bind DNA and repress E2F-dependent transcriptional activity.
Predominantly expressed in testis. Low level of expression in pancreas. Highly expressed in ovarian and colon cancer cell lines.
The potential DNA-binding domain differs in sequence from that of other DP family members and cannot bind DNA.
Acetylation at Lys-458 lowers transcriptional activation by about two-fold.
Homodimerization is required for HNF4-alpha to bind to its recognition site (PubMed:14982928). Interacts with CLOCK, BMAL1, CRY1, CRY2, PER1 and PER2 (PubMed:30530698). Interacts with NR0B2/SHP; the resulting heterodimer is transcriptionnally inactive (PubMed:28128295). Interacts with DDX3X; this interaction disrupts the interaction between HNF4 and NR0B2 that forms inactive heterodimers and enhances the formation of active HNF4 homodimers (PubMed:28128295).
Phosphorylated on tyrosine residue(s); phosphorylation is important for its DNA-binding activity. Phosphorylation may directly or indirectly play a regulatory role in the subnuclear distribution. Phosphorylation at Ser-313 by AMPK reduces the ability to form homodimers and bind DNA.
Produced by alternative splicing of isoform HNF4-Alpha-1.
Produced by alternative splicing of isoform HNF4-Alpha-7.
Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes (PubMed:30597922). Activates the transcription of CYP2C38 (By similarity). Represses the CLOCK-BMAL1 transcriptional activity and is essential for circadian rhythm maintenance and period regulation in the liver and colon cells (PubMed:30530698).
Absent in patients suffering with peroxisomal disorders such as Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease.
Acetylated, leading to enhanced enzyme activity. Acetylation is enhanced by up to 80% after treatment either with trichostin A (TSA) or with nicotinamide (NAM) with highest increase on Lys-346. Acetylation and enzyme activity increased by about 1.5% on addition of fatty acids.
Enzyme activity enhanced by acetylation.
In the C-terminal section; belongs to the 3-hydroxyacyl-CoA dehydrogenase family.
In the N-terminal section; belongs to the enoyl-CoA hydratase/isomerase family.
Liver and kidney. Strongly expressed in the terminal segments of the proximal tubule. Lower amounts seen in the brain.
Peroxisomal trifunctional enzyme possessing 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and delta 3, delta 2-enoyl-CoA isomerase activities. Catalyzes two of the four reactions of the long chain fatty acids peroxisomal beta-oxidation pathway (By similarity). Can also use branched-chain fatty acids such as 2-methyl-2E-butenoyl-CoA as a substrate, which is hydrated into (2S,3S)-3-hydroxy-2-methylbutanoyl-CoA (By similarity). Optimal isomerase for 2,5 double bonds into 3,5 form isomerization in a range of enoyl-CoA species (Probable). Also able to isomerize both 3-cis and 3-trans double bonds into the 2-trans form in a range of enoyl-CoA species (By similarity). With HSD17B4, catalyzes the hydration of trans-2-enoyl-CoA and the dehydrogenation of 3-hydroxyacyl-CoA, but with opposite chiral specificity (PubMed:15060085). Regulates the amount of medium-chain dicarboxylic fatty acids which are essential regulators of all fatty acid oxidation pathways (By similarity). Also involved in the degradation of long-chain dicarboxylic acids through peroxisomal beta-oxidation (PubMed:15060085).
Negatively regulates the G2-M phase transition, possibly by promoting cyclin B1/CCNB1 and CDK1 proteasomal degradation and thereby preventing their accumulation during interphase.
Phosphorylated by PKC and CDK1 (PubMed:20725088). The antiproliferative effect seems to be positively regulated by PKC phosphorylation and negatively by CDK1 phosphorylation (PubMed:20725088).
The B30.2/SPRY domain is required for the negative regulation of cell proliferation.
Interacts with one or more of the argonaute family proteins AGO1, AGO2, AGO3 and AGO4. Interacts with PABPC1 and EIF4G1. Interacts with CNOT1; the interaction is direct and mediates the association with the CCR4-NOT complex. Interacts with PAN3; the interaction mediates the association with the PAN complex.
Plays a role in RNA-mediated gene silencing by micro-RNAs (miRNAs). Required for miRNA-dependent translational repression of complementary mRNAs by argonaute family proteins. As scaffoldng protein associates with argonaute proteins bound to partially complementary mRNAs and simultaneously can recruit CCR4-NOT and PAN deadenylase complexes.
The silencing domain, also known as C-terminal effector domain (CED), can act in autonomous repression, including both translational inhibition and mRNA degradation.
Transcriptional activator that mediates FGF signaling during neural development (By similarity). Plays a role in the regulation of cell movement (By similarity).
Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle (PubMed:28895244). Calcium ions are bound by clusters of acidic residues at the protein surface, often at the interface between subunits. Can bind around 80 Ca(2+) ions (PubMed:28895244). Regulates the release of lumenal Ca(2+) via the calcium release channel RYR1; this plays an important role in triggering muscle contraction. Negatively regulates store-operated Ca(2+) entry (SOCE) activity (PubMed:27185316).
Expressed in myoblasts (at protein level).
Monomer; increases in response to a depletion of intracellular calcium (PubMed:27185316, PubMed:26136523). Homodimer (PubMed:27185316, PubMed:26136523, PubMed:28895244). Homotetramer and homopolymer. Can form linear homooligomers. Ca(2+) ions promote oligomerization. Interacts (via C-terminal end and preferentially with the monomeric form) with STIM1; this interaction increases in response to a depletion of intracellular calcium, decreases both STIM1 aggregation and clustering, interaction of STIM1 with ORAI1 and store-operated Ca(2+) entry (SOCE) activity (PubMed:27185316). Interacts with ASPH and TRDN (By similarity).
Interacts (via HIT-type zinc finger) with RUVBL2 in the presence of ATP or ADP; shows a stronger interaction in the presence of ADP.
Low expression in most tissues; highly expressed in testis.
May act as a bridging factor mediating the interaction between the R2TP/Prefoldin-like (R2TP/PFDL) complex and U5 small nuclear ribonucleoprotein (U5 snRNP) (PubMed:28561026). Required for the interaction of R2TP complex subunit RPAP3 and prefoldin-like subunit URI1 with U5 snRNP proteins EFTUD2 and PRPF8 (PubMed:28561026). May play a role in regulating the composition of the U5 snRNP complex (PubMed:28561026).
Component of the R2TP complex composed at least of RUVBL1, RUVBL2, RPAP3 and PIHD1 (PubMed:20864032). Component of the PAQosome complex which is responsible for the biogenesis of several protein complexes and which consists of R2TP complex members RUVBL1, RUVBL2, RPAP3 and PIH1D1, URI complex members PFDN2, PFDN6, PDRG1, UXT and URI1 as well as ASDURF, POLR2E and DNAAF10/WDR92 (PubMed:31738558). Interacts with phosphorylated TELO2 and mediates interaction of TELO2 with the R2TP complex (PubMed:20864032, PubMed:24656813). Interacts with phosphorylated ECD, EFTUD2/SNRP116, RPB1 and UBR5 and with RPB1 in a phosphorylation-independent manner (PubMed:24656813). Interacts with the core C/D box snoRNP particle components NOP58 and FBL and with RUVBL1/TIP49 (PubMed:17636026). Interacts with RPAP3 and DNAAF10 (PubMed:21078300). Interacts with histone H4 and with SWI/SNF complex member SMARCB1/SNF5 (PubMed:22368283). Interacts with the mTORC1 complex member RPTOR (PubMed:24036451). Interacts with MSL1 (By similarity).
Expressed at low levels in normal mammary epithelial cells (at protein level) (PubMed:24036451). Highest expression in lung, leukocyte and placenta. Expressed at lower levels in brain, prostate, colon, heart, small intestine, liver, ovary, pancreas, skeletal muscle, spleen, testis and thymus (PubMed:21078300).
Involved in the assembly of C/D box small nucleolar ribonucleoprotein (snoRNP) particles (PubMed:17636026). Recruits the SWI/SNF complex to the core promoter of rRNA genes and enhances pre-rRNA transcription (PubMed:22368283, PubMed:24036451). Mediates interaction of TELO2 with the R2TP complex which is necessary for the stability of MTOR and SMG1 (PubMed:20864032). Positively regulates the assembly and activity of the mTORC1 complex (PubMed:24036451).
The N-terminal region is required for binding to phosphorylated substrates while the C-terminal region binds to the other R2TP complex components.
Belongs to the suppressor of sable family.
RNA-binding protein that suppresses transcription of long non-coding RNAs (lncRNAs) (PubMed:33913806, PubMed:33767452). LncRNAs are defined as transcripts more than 200 nucleotides that are not translated into protein (PubMed:33913806, PubMed:33767452). Together with WDR82, part of a transcription termination checkpoint that promotes transcription termination of lncRNAs and their subsequent degradation by the exosome (PubMed:33913806, PubMed:33767452). The transcription termination checkpoint is activated by the inefficiently spliced first exon of lncRNAs (PubMed:33767452).
Common splicing form, lowest expression in skeletal muscle.
Constitutive activation and subsequent transactivation of target genes may lead to the maintenance of stem-cell characteristics (cycling and longevity) in cells that should normally undergo terminal differentiation and constitute the primary transforming event in colorectal cancer (CRC).
Detected in epithelium from small intestine, with the highest expression at the top of the crypts and a gradient of expression from crypt to villus. Detected in colon epithelium and colon cancer, and in epithelium from mammary gland and carcinomas derived therefrom.
High transcriptional activity. Major isoform in liver.
Highly expressed in crypt regions and barely detectable in villi in epithelium from fetal small intestine at week 16. At week 22 expression in villi had increased strongly.
Interacts with TGFB1I1 (By similarity). Interacts with CTNNB1 (via the armadillo repeat); forms stable transcription complex (PubMed:9065401, PubMed:9916915, PubMed:10080941, PubMed:19816403, PubMed:28829046, PubMed:29739711, PubMed:17052462). Interacts with EP300. Interacts with NLK. Interacts with CCDC85B (probably through the HMG box); prevents interaction with CTNNB1. Interacts with TNIK. Interacts with MAD2L2; prevents TCF7L2/TCF4 binding to promZIPK/DAPK3oters, negatively modulating its transcriptional activity. Interacts with ZIPK/DAPK3. Interacts with XIAP/BIRC4 and TLE3. Interacts with DDIT3/CHOP. The CTNNB1 and TCF7L2/TCF4 complex interacts with PML (isoform PML-4). Identified in a complex with CTNNB1 and FERMT2. Interacts with SPIN1 (PubMed:22258766, PubMed:24589551, PubMed:29061846). Interacts with C11orf84/SPINDOC in a SPIN1-dependent manner (PubMed:29061846). Interacts with DAZAP2; the interaction results in localization of DAZAP2 to the nucleus (PubMed:19304756).
Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner. Acts as repressor in the absence of CTNNB1, and as activator in its presence. Activates transcription from promoters with several copies of the Tcf motif 5'-CCTTTGATC-3' in the presence of CTNNB1. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by TCF7L2/TCF4 and CTNNB1. Expression of dominant-negative mutants results in cell-cycle arrest in G1. Necessary for the maintenance of the epithelial stem-cell compartment of the small intestine.
Phosphorylated at Thr-201 and/or Thr-212 by NLK. Phosphorylation by NLK at these sites inhibits DNA-binding by TCF7L2/TCF4, thereby preventing transcriptional activation of target genes of the canonical Wnt/beta-catenin signaling pathway.
Polysumoylated. Sumoylation is enhanced by PIAS family members and desumoylation is enhanced by SENP2. Sumoylation/desumoylation regulates TCF7L2/TCF4 transcription activity in the Wnt/beta-catenin signaling pathway without altering interaction with CTNNB1 nor binding to DNA.
The promoter-specific activation domain interacts with the transcriptional coactivator EP300.
Interacts with PSRC1 (By similarity). Interacts with APC (PubMed:11691822). Interacts with CTNNB1 (PubMed:9823329). Interacts with MAPRE1 and MAPRE3 (PubMed:10644998). Interacts with TP53BP (PubMed:10646860). Interacts possibly with AXIN2 (PubMed:10021369).
Stabilizes microtubules and may regulate actin fiber dynamics through the activation of Rho family GTPases (PubMed:25753423). May also function in Wnt signaling by promoting the rapid degradation of CTNNB1 (PubMed:10021369, PubMed:11691822, PubMed:9823329).
Widely expressed (at protein level). Specifically expressed in the CNS.
Expressed exclusively in heart and skeletal muscle.
Probable C to U editing enzyme whose physiological substrate is not yet known. Does not display detectable apoB mRNA editing. Has a low intrinsic cytidine deaminase activity. May play a role in the epigenetic regulation of gene expression through the process of active DNA demethylation.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ5 subfamily.
Islets, exocrine pancreas and heart. Expressed in the adrenal cortex, particularly the zona glomerulosa.
May associate with GIRK1 and GIRK2 to form a G-protein-activated heteromultimer pore-forming unit. The resulting inward current is much larger.
Mutations in KCNJ5 are involved in the pathogenesis of hypertension without primary aldosteronism but with increased aldosterone response to ACTH stimulation.
Somatic mutations in KCNJ5 have been found in aldosterone-producing adrenal adenomas and can be responsible for aldosteronism associated with cell autonomous proliferation. APAs are typically solitary, well circumscribed tumors diagnosed between ages 30 and 70. They come to medical attention due to new or worsening hypertension, often with hypokalemia. The precise role of KCNJ5 mutations in APA is under debate. They produce increased sodium conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium entry, the signal for aldosterone production and cell proliferation. However, they may not be causative of APA development but may be a consequence of tumorigenesis, playing only a contributory role toward aldosterone overproduction and tumor growth (PubMed:22275527). Somatic mutations in KCNJ5 have not been found in non-aldosterone secreting adrenal adenomas suggesting that they are specifically associated with APA (PubMed:22275527, PubMed:22848660).
This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by external barium.
Histone chaperone involved in single-strand and double-strand DNA break repair (PubMed:17353262, PubMed:17396150, PubMed:21211721, PubMed:21211722, PubMed:30104678, PubMed:29905837). Recruited to sites of DNA damage through interaction with branched poly-ADP-ribose chains, a polymeric post-translational modification synthesized transiently at sites of chromosomal damage to accelerate DNA strand break repair reactions (PubMed:17353262, PubMed:17396150, PubMed:21211721, PubMed:30104678). Following recruitment to DNA damage sites, acts as a histone chaperone that mediates histone eviction during DNA repair and promotes recruitment of histone variant MACROH2A1 (PubMed:21211722, PubMed:30104678, PubMed:29905837). Also has a nuclease activity: displays apurinic-apyrimidinic (AP) endonuclease and 3'-5' exonuclease activities in vitro (PubMed:17353262, PubMed:17396150). Also able to introduce nicks at hydroxyuracil and other types of pyrimidine base damage (PubMed:17353262, PubMed:17396150). Together with PARP3, promotes the retention of the LIG4-XRCC4 complex on chromatin and accelerate DNA ligation during non-homologous end-joining (NHEJ) (PubMed:21211721, PubMed:23689425). Also acts as a negative regulator of cell pluripotency by promoting histone exchange (By similarity). Required for the embryo implantation during the epithelial to mesenchymal transition in females (By similarity).
Interacts with LIG4 (PubMed:17396150). Interacts with PARP1 (PubMed:17396150, PubMed:17353262). Interacts with XRCC4 (PubMed:17396150, PubMed:17353262, PubMed:18077224). Interacts (via KBM motif) with XRCC5 and XRCC6; promoting recruitment to DNA damage sites (PubMed:23689425). Interacts with XRCC1 (PubMed:17507382, PubMed:17353262). Interacts (via C-terminal disordered region) with histones; interacts with histone H2A, H2B and H3-H4 (PubMed:21211722, PubMed:29905837).
Phosphorylated in an ATM-dependent manner upon double-strand DNA break.
Poly-ADP-ribosylated. In addition to binding non covalently poly-ADP-ribose via its PBZ-type zinc fingers, the protein is also covalently poly-ADP-ribosylated by PARP1.
The FHA-like domain mediates interaction with XRCC1 and XRCC4.
The PBZ-type zinc fingers (also named CYR) mediate non-covalent poly-ADP-ribose-binding (PubMed:18474613, PubMed:18172500, PubMed:30104678). Specifically recognizes branched poly-ADP-ribose chains generated by PARP2 (PubMed:30104678). Poly-ADP-ribose-binding is dependent on the presence of zinc and promotes its recruitment to DNA damage sites (PubMed:18474613, PubMed:18172500).
Forms a homo/heterooligomeric complex with EXT2. Interacts with NDST1.
Glycosyltransferase required for the biosynthesis of heparan-sulfate. The EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone. Appears to be a tumor suppressor. Required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413).
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration resulting in the loss of functional copies of TRPS1 and EXT1 has been found in TRPS2 patients.
A chromosomal aberration involving POU2AF1/OBF1 may be a cause of a form of B-cell leukemia. Translocation t(3;11)(q27;q23) with BCL6.
B-cell specific (PubMed:7779176, PubMed:7859290). Detected in mainly in spleen, but also in thymus, periphral blood leukocyte and small intestine (PubMed:7779176, PubMed:7859290).
In the N-terminus possesses a conserved OCA domain for bivalent binding to class II POU domain-containing transcription factors and to an octamer DNA motif.
Interacts with POU2F1/OCT1 and POU2F2/OCT2; the interaction increases POU2F1 and POU2F2 transactivation activity.
Transcriptional coactivator that specifically associates with either POU2F1/OCT1 or POU2F2/OCT2 (PubMed:7859290). It boosts the POU2F1/OCT1 mediated promoter activity and to a lesser extent, that of POU2F2/OCT2 (PubMed:7779176). It recognizes the POU domains of POU2F1/OCT1 and POU2F2/OCT2 (PubMed:7779176). It is essential for the response of B-cells to antigens and required for the formation of germinal centers (PubMed:7623806, PubMed:7859290). Regulates IL6 expression in B cells as POU2F2/OCT2 coactivator (By similarity).
Expressed at moderate levels in monocytes, myeloid blood dendritic cells and granulocytes and at low levels in plasmacytoid blood dendritic cells, monocyte-derived ma crophages and monocyte-derived dendritic cells, with no expression detected in T-lymphocytes, B-lymphocytes and natural killer cells (at protein level). Expressed widely in different tissues, with highest expression levels in liver, lung, peripheral blood leukocytes and spleen, and lowest levels in neuronal tissues, skeletal muscle and ovary. Isoform 2 and isoform 3 are expressed in malignant Hodgkin lymphoma cells called Hodgkin and Reed-Sternberg (HRS) cells.
Expressed at relatively high levels in fetal lung, liver, spleen and kidney with lower expression levels detected in heart, thymus and brain.
Isoform 2 and isoform 3 are produced in HRS cells by a transcriptional control mechanism which cotranscribe an mRNA containing LY75 and CD302 prior to generating the intergenically spliced mRNA to produce LY75/CD302 fusion proteins.
May be heterogeneously N-glycosylated in some cell types.
Potential multifunctional C-type lectin receptor that may play roles in endocytosis and phagocytosis as well as in cell adhesion and migration.
Produced by intergenic splicing of LY75 and CD302.
Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Binds to both G(i)-alpha and G(q)-alpha (By similarity).
Belongs to the actin family. ARP1 subfamily.
Component of a multi-subunit complex involved in microtubule based vesicle motility. It is associated with the centrosome.
Monomer (PubMed:34862464). Interacts with SARS1/SerRS; interaction is mediated via tRNA(Ser) and is required for N(3)-methylcytidine methylation (PubMed:28655767, PubMed:34268557).
S-adenosyl-L-methionine-dependent methyltransferase that mediates N(3)-methylcytidine modification of residue 32 of the tRNA anticodon loop of tRNA(Ser), including tRNA(Ser)(UGA) and tRNA(Ser)(GCU) (PubMed:32923617, PubMed:34922197, PubMed:34268557, PubMed:34862464). Interaction with SARS1/SerRS is required for N(3)-methylcytidine methylation (PubMed:34268557).
Has been found to be frequently mutated in melanoma. ADAM7 mutations may play a role in melanoma progression and metastasis.
May be involved in spermatogenesis and fertilization. Seems to be a non catalytic metalloprotease-like protein.
Arises by species-specific retrovirus-mediated alternative splice mimicry.
Expressed in various tissues with high expression in liver and skeletal muscle. Isoform 4 is predominantly expressed in kidney, bladder, adrenal gland and brain stem. Isoform 1 expression in placenta is predominant in chorion and decidua. Isoform 4 is highly expressed in placental villi. Isoform 2 is expressed in lung, stomach and muscle. Low levels in liver.
Genetic variation in GHR may act as phenotype modifier in familial hypercholesterolemia [MIM:143890] patients carrying a mutation in the LDLR gene.
Isoform 2 up-regulates the production of GHBP and acts as a negative inhibitor of GH signaling.
On GH binding, phosphorylated on tyrosine residues in the cytoplasmic domain by JAK2.
On growth hormone (GH) binding, forms homodimers and binds JAK2 via a box 1-containing domain. Binding to SOCS3 inhibits JAK2 activation, binding to CIS and SOCS2 inhibits STAT5 activation. Interacts with ADAM17.
On ligand binding, ubiquitinated on lysine residues in the cytoplasmic domain. This ubiquitination is not sufficient for GHR internalization (By similarity).
Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway (By similarity).
The extracellular domain is the ligand-binding domain representing the growth hormone-binding protein (GHBP).
The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling.
The soluble form (GHBP) is produced by phorbol ester-promoted proteolytic cleavage at the cell surface (shedding) by ADAM17/TACE. Shedding is inhibited by growth hormone (GH) binding to the receptor probably due to a conformational change in GHR rendering the receptor inaccessible to ADAM17 (By similarity).
The ubiquitination-dependent endocytosis motif (UbE) is required for recruitment of the ubiquitin conjugation system on to the receptor and for its internalization.
(Microbial infection) Cleaved by S.pyogenes SpeB protease; leading to its degradation (PubMed:24331465). Degradation by SpeB prevents autophagy, promoting to S.pyogenes intracellular replication (PubMed:24331465).
(Microbial infection) Interacts with Influenza A virus protein PB1; this interaction promotes NBR1-mediated selective autophagic degradation of MAVS.
Homooligomer and heterooligomer. Interacts with TRIM55 (By similarity). Interacts with titin/TTN (By similarity). Interacts with RNF29, USP8, MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAP, GABARAPL1 and GABARAPL2 (PubMed:19250911). Binds to ubiquitin and ubiquitinated proteins (PubMed:24692539). Interacts with SQSTM1 (PubMed:19250911). Interacts with TAX1BP1 (PubMed:33226137, PubMed:34471133). Interacts with IRF3; this interaction mediates autophagic degradation of IRF3 (PubMed:35914352). Interacts with IL12A and IL12B (By similarity).
Phosphorylated by GSK3A; this phosphorylation inhibits NBR1 involvement in the formation of ubiquitinated protein aggregates.
The PB1 domain mediates interaction with SQSTM1.
Ubiquitin-binding autophagy adapter that participates in different processes including host defense or intracellular homeostasis (PubMed:33577621, PubMed:24692539). Possesses a double function during the selective autophagy by acting as a shuttle bringing ubiquitinated proteins to autophagosomes and also by participating in the formation of protein aggregates (PubMed:24879152, PubMed:34471133). Plays a role in the regulation of the innate immune response by modulating type I interferon production and targeting ubiquitinated IRF3 for autophagic degradation (PubMed:35914352). In response to oxidative stress, promotes an increase in SQSTM1 levels, phosphorylation, and body formation by preventing its autophagic degradation (By similarity). In turn, activates the KEAP1-NRF2/NFE2L2 antioxidant pathway (By similarity). Plays also non-autophagy role by mediating the shuttle of IL-12 to late endosome for subsequent secretion (By similarity).
Was originally thought to be the ovarian carcinoma antigen CA125.
Component of the oligosaccharyltransferase (OST) complex. OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits (PubMed:22266900). STT3A complex assembly occurs through the formation of 3 subcomplexes. Subcomplex 1 contains RPN1 and TMEM258, subcomplex 2 contains the STT3A-specific subunits STT3A, DC2/OSTC, and KCP2 as well as the core subunit OST4, and subcomplex 3 contains RPN2, DAD1, and OST48. The STT3A complex can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes (By similarity). Interacts with PSEN1 and NCSTN; indicative for an association with the gamma-secretase complex (PubMed:21768116).
Expressed in skin, heart, placental, liver, skeletal muscle, kidney, pancreas, keratinocytes and dermal fibroblasts.
Produced at low levels due to suboptimal Kozak context.
Subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation. N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity (PubMed:22467853). May be involved in N-glycosylation of APP (amyloid-beta precursor protein). Can modulate gamma-secretase cleavage of APP by enhancing endoprotelysis of PSEN1 (PubMed:21768116).
Acts as a guanine nucleotide exchange factor (GEF) for Rab5 GTPase. Regulates the ALS2-mediated endosome dynamics.
Homodimer. Forms a heteromeric complex with ALS2 (By similarity). Interacts with ALS2 and RAB5A.
Component of the KPC complex composed of RNF123/KPC1 and UBAC1/KPC2 (PubMed:15531880, PubMed:15746103, PubMed:16227581). Interacts (via ubiquitin-like domain) with RNF123 (PubMed:15746103, PubMed:16227581). Interacts (via ubiquitin-like and UBA domains) with the proteasome via its N-terminal domain (PubMed:15746103, PubMed:16227581).
Non-catalytic component of the KPC complex, a E3 ubiquitin-protein ligase complex that mediates polyubiquitination of target proteins, such as CDKN1B and NFKB1 (PubMed:15531880, PubMed:15746103, PubMed:16227581, PubMed:25860612). The KPC complex catalyzes polyubiquitination and proteasome-mediated degradation of CDKN1B during G1 phase of the cell cycle (PubMed:15531880, PubMed:15746103). The KPC complex also acts as a key regulator of the NF-kappa-B signaling by promoting maturation of the NFKB1 component of NF-kappa-B by catalyzing ubiquitination of the NFKB1 p105 precursor (PubMed:25860612). Within the KPC complex, UBAC1 acts as an adapter that promotes the transfer of target proteins that have been polyubiquitinated by RNF123/KPC1 to the 26S proteasome (PubMed:16227581).
The UBA domains recognize and bind polyubiquitinated proteins.
(Microbial infection) Interacts with encephalomyocarditis virus (EMCV) C3 protease; the interaction results in C3 protease 'Lys-48'-linked ubiquitination.
(Microbial infection) Interacts with human rhinovirus (HRV) C3 protease; the interaction results in C3 protease 'Lys-48'-linked ubiquitination.
Binding to PARP9 enhances DTX3L catalytic activity.
E3 ubiquitin-protein ligase which, in association with ADP-ribosyltransferase PARP9, plays a role in DNA damage repair and in interferon-mediated antiviral responses (PubMed:12670957, PubMed:19818714, PubMed:26479788, PubMed:23230272). Monoubiquitinates several histones, including histone H2A, H2B, H3 and H4 (PubMed:28525742). In response to DNA damage, mediates monoubiquitination of 'Lys-91' of histone H4 (H4K91ub1) (PubMed:19818714). The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 'Lys-20' methylation (H4K20me) (PubMed:19818714). PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites (PubMed:23230272). By monoubiquitinating histone H2B H2BC9/H2BJ and thereby promoting chromatin remodeling, positively regulates STAT1-dependent interferon-stimulated gene transcription and thus STAT1-mediated control of viral replication (PubMed:26479788). Independently of its catalytic activity, promotes the sorting of chemokine receptor CXCR4 from early endosome to lysosome following CXCL12 stimulation by reducing E3 ligase ITCH activity and thus ITCH-mediated ubiquitination of endosomal sorting complex required for transport ESCRT-0 components HGS and STAM (PubMed:24790097). In addition, required for the recruitment of HGS and STAM to early endosomes (PubMed:24790097). In association with PARP9, plays a role in antiviral responses by mediating 'Lys-48'-linked ubiquitination of encephalomyocarditis virus (EMCV) and human rhinovirus (HRV) C3 proteases and thus promoting their proteasomal-mediated degradation (PubMed:26479788).
Homodimer and heterodimer (PubMed:12670957, PubMed:28525742). Can heterodimerize with DTX1, enhancing its ubiquitin ligase activity in vitro (PubMed:12670957). Interacts (via N-terminus) with ADP ribosyltransferase PARP9/BAL1 (via PARP catalytic domain) forming a stable complex; the interaction is required to activate PARP9 but is dispensable for DTX3L catalytic activity (PubMed:12670957, PubMed:23230272, PubMed:26479788, PubMed:28525742). Forms a complex with STAT1 and PARP9 independently of IFNB1 or IFNG-mediated STAT1 'Tyr-701' phosphorylation (PubMed:26479788). Found in a complex with PARP9, STAT1 and H2BC9 (PubMed:26479788). Found in a complex with E3 ligase ITCH and ESCRT-0 components HGS and STAM (PubMed:24790097). Interacts (via C-terminus) with ITCH; the interaction is increased upon CXCL12 stimulation and inhibits ITCH catalytic activity; the interaction is direct (PubMed:24790097). Interacts with HGS and STAM; the interaction brings together HGS and STAM and promotes their recruitment to early endosomes (PubMed:24790097).
Induced by IFNG (PubMed:16809771, PubMed:26479788). Induced by IFNB1 (PubMed:26479788).
Part of the multisubunit axonemal dynein complex formed at least of two heavy chains and a number of intermediate and light chains. Interacts with tubulin. Associates with microtubule.
Ubiquitinated. Ubiquitination leads to its degradation through the 26S proteasome. Ubiquitin-proteasome-mediated DNAI7 degradation occurs in mitosis.
Via its association with the multisubunit axonemal dynein complex, is potentially involved in the regulation of cilia function. May also act as a cell cycle regulator.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Glycine receptor (TC 1.A.9.3) subfamily. GLRB sub-subfamily.
Glycine receptors are ligand-gated chloride channels. GLRB does not form ligand-gated ion channels by itself, but is part of heteromeric ligand-gated chloride channels. Channel opening is triggered by extracellular glycine (PubMed:8717357, PubMed:15302677, PubMed:16144831, PubMed:22715885, PubMed:25445488, PubMed:11929858, PubMed:23238346, PubMed:34473954). Heteropentameric channels composed of GLRB and GLRA1 are activated by lower glycine levels than homopentameric GLRA1 (PubMed:8717357). Plays an important role in the down-regulation of neuronal excitability (PubMed:11929858, PubMed:23238346). Contributes to the generation of inhibitory postsynaptic currents (PubMed:25445488).
Heteropentamer composed of GLRB and GLRA1 (PubMed:8717357, PubMed:14551753, PubMed:22973015, PubMed:22715885, PubMed:25445488, PubMed:11929858, PubMed:23238346). Heteropentamer composed of GLRB and GLRA2 (PubMed:15302677, PubMed:16144831, PubMed:25445488, PubMed:34473954). Heteropentamer composed of GLRB and GLRA3 (PubMed:25445488). Heteropentamer composed of two GLRA1 and three GLRB subunits (PubMed:22715885). Heteropentamer composed of three GLRA1 and two GLRB subunits (PubMed:22973015). Interacts with GLRA1 (PubMed:35526563). Interacts with GPHN (PubMed:12684523, PubMed:26613940).
Abundant in a subset of astrocytes in the normal human brain, but greatly reduced in the Alzheimer disease (AD) brain.
Binds heavy metals. Contains three zinc and three copper atoms per polypeptide chain and only a negligible amount of cadmium. Inhibits survival and neurite formation of cortical neurons in vitro.
Abundant in heart, followed in order by brain, kidney, skeletal muscle, and lung, whereas in liver it is undetectable. Expressed (at protein level) in all tissues (except in liver), most abundant in myocardium, then brain, kidney, adrenal glands, skeletal muscle and lung; also detectable in leukocytes and fibroblasts.
Belongs to the 3-oxoacid CoA-transferase family.
Homodimer (PubMed:10964512, PubMed:23420214). Only one subunit is competent to transfer the CoA moiety to the acceptor carboxylate (3-oxo acid) (By similarity).
Key enzyme for ketone body catabolism. Catalyzes the first, rate-limiting step of ketone body utilization in extrahepatic tissues, by transferring coenzyme A (CoA) from a donor thiolester species (succinyl-CoA) to an acceptor carboxylate (acetoacetate), and produces acetoacetyl-CoA. Acetoacetyl-CoA is further metabolized by acetoacetyl-CoA thiolase into two acetyl-CoA molecules which enter the citric acid cycle for energy production (PubMed:10964512). Forms a dimeric enzyme where both of the subunits are able to form enzyme-CoA thiolester intermediates, but only one subunit is competent to transfer the CoA moiety to the acceptor carboxylate (3-oxo acid) and produce a new acyl-CoA. Formation of the enzyme-CoA intermediate proceeds via an unstable anhydride species formed between the carboxylate groups of the enzyme and substrate (By similarity).
Key enzyme for ketone body catabolism. Transfers the CoA moiety from succinate to acetoacetate. Formation of the enzyme-CoA intermediate proceeds via an unstable anhydride species formed between the carboxylate groups of the enzyme and substrate.
Acylation at both Gly-2 and Cys-4 is required for proper localization to the endosomes.
Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, ITCH and TAX1BP1, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of TNFAIP3 to RIPK1 after TNF stimulation. TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NF-kappa-B. Recruits STAMBP to the E3 ubiquitin-ligase SMURF2 for ubiquitination, leading to its degradation by the 26S proteasome.
Expressed at low levels in the lung, liver, kidney, pancreas, spleen, prostate, thymus, ovary, small intestine, colon, and peripheral blood lymphocytes, and, at intermediate levels, in the testis, heart, brain and placenta. Highest expression in the skeletal muscle. In the brain, expressed at different levels in several regions: high levels in the amygdala, moderate in the hippocampus and thalamus, low in the caudate and extremely low levels in the corpus callosum (at protein level). Restricted to neurons, enriched in somatodendritic compartments and excluded from white matter (at protein level). In substantia nigra, present in cell bodies and processes of dopaminergic and nondopaminergic cells (at protein level). In Parkinson disease, sequestered in Lewy bodies and neurites. Overexpressed in breast cancer cells, but not detected in the surrounding stroma and weakly, if at all, in normal breast epithelial cells (at protein level). Also expressed in several tumor cell lines.
Interacts (when phosphorylated) with 14-3-3. Interacts with the E3 ubiquitin-ligases NEDD4, ITCH, SMURF2 and WWP1 (By similarity). Also interacts with the E2 ubiquitin-conjugating enzymes UBE2D1 and UBE2N, but neither with CDC34, nor with UBE2L3. Interacts with ZNF350, EPS15 and STAMBP. After TNF stimulation, interacts with TAX1BP1, TNFAIP3 and RIPK1; these interactions are transient and they are lost after 1 hour of stimulation with TNF (By similarity). Interacts with GGA1.
Phosphorylation by PKB/AKT1 may accelerate degradation by the proteasome.
The PPxY motif mediates interaction with NEDD4.
Ubiquitinated in the presence of ITCH, or SMURF2, and UBE2D1, as well as WWP1.
Cysteine protease. May have an important role in corneal physiology.
Predominantly expressed in the thymus and testis. Also expressed in corneal epithelium, and to a lesser extent in conjunctival epithelium and skin.
Involved in transport of proteins from the cis/medial-Golgi to the trans-Golgi network.
Part of a unique SNARE complex composed of the Golgi SNAREs GOSR1, STX5 and YKT6 (By similarity). Interacts (via IxM motif) with SEC24C and SEC24D; mediates GOSR2 packaging into COPII-coated vesicles (PubMed:18843296).
Activated by cytosolic calcium, which is necessary for binding to membrane lipids (PubMed:12672805). Activated by phosphorylation in response to mitogenic stimuli (PubMed:8381049). Activated by ceramide-1-phosphate. Binding (via C2 domain) to ceramide-1-phosphate increases the affinity for membrane lipids (PubMed:17472963). Can be activated by phosphoinositides in the absence of calcium (PubMed:12672805). Inhibited by ANXA5 in a calcium- and substrate-dependent way (PubMed:9425121).
Expressed in various cells and tissues such as macrophages, neutrophils, fibroblasts and lung endothelium. Expressed in platelets (at protein level) (PubMed:25102815).
Has primarily calcium-dependent phospholipase and lysophospholipase activities, with a major role in membrane lipid remodeling and biosynthesis of lipid mediators of the inflammatory response (PubMed:7794891, PubMed:8619991, PubMed:8702602, PubMed:9425121, PubMed:10358058, PubMed:14709560, PubMed:16617059, PubMed:17472963, PubMed:27642067, PubMed:18451993). Plays an important role in embryo implantation and parturition through its ability to trigger prostanoid production (By similarity). Preferentially hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) (PubMed:7794891, PubMed:8619991, PubMed:9425121, PubMed:10358058, PubMed:17472963, PubMed:18451993). Selectively hydrolyzes sn-2 arachidonoyl group from membrane phospholipids, providing the precursor for eicosanoid biosynthesis via the cyclooxygenase pathway (PubMed:18451993, PubMed:7794891, PubMed:9425121, PubMed:10358058, PubMed:17472963). In an alternative pathway of eicosanoid biosynthesis, hydrolyzes sn-2 fatty acyl chain of eicosanoid lysophopholipids to release free bioactive eicosanoids (PubMed:27642067). Hydrolyzes the ester bond of the fatty acyl group attached at sn-1 position of phospholipids (phospholipase A1 activity) only if an ether linkage rather than an ester linkage is present at the sn-2 position. This hydrolysis is not stereospecific (PubMed:7794891). Has calcium-independent phospholipase A2 and lysophospholipase activities in the presence of phosphoinositides (PubMed:12672805). Has O-acyltransferase activity. Catalyzes the transfer of fatty acyl chains from phospholipids to a primary hydroxyl group of glycerol (sn-1 or sn-3), potentially contributing to monoacylglycerol synthesis (PubMed:7794891).
Phosphorylated at both Ser-505 and Ser-727 in response to mitogenic stimuli.
The N-terminal C2 domain associates with lipid membranes upon calcium binding.
The N-terminal C2 domain associates with lipid membranes upon calcium binding. It modulates enzyme activity by presenting the active site to its substrate in response to elevations of cytosolic calcium (PubMed:9430701, PubMed:9665851, PubMed:11375391). In the presence of phosphoinositides, regulates phospholipase A2 and lysophospholipase activities in a calcium-independent way (PubMed:12672805).
Interacts (via COMM domain) with COMMD1 (via COMM domain) (PubMed:15799966). Interacts with RELA, RELB, NFKB1/p105. Interacts with CCDC22, CCDC93, SCNN1B, CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5 (PubMed:15799966, PubMed:21778237, PubMed:23563313, PubMed:23637203, PubMed:25355947, PubMed:28892079).
Widely expressed with highest expression in thyroid.
Homodimer; dityrosine-linked. Homodimerization seems specific of the human protein and enhances the zinc transport efficiency. Interacts with TMEM163 (PubMed:36204728).
Homodimerization through dityrosine bonds is stimulated by oxidative stress.
Probable proton-coupled zinc ion antiporter mediating the import of zinc from cytoplasm into synaptic vesicles and participating to cellular zinc ion homeostasis in the brain.
A chromosomal aberration involving TAL2 may be a cause of some T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(7;9)(q34;q32) with TCRB.
Exoribonuclease that is part of the telomerase RNA 3' end processing complex and which has the ability to all four unpaired RNA nucleotides from 5' end or 3' end with higher efficiency for purine bases (PubMed:28322335).
Part of the telomerase RNA 3' end complex which contains about 488 proteins (PubMed:28322335).
The C-terminus contains a key domain which is responsible for the RNA digestion activity (PubMed:28322335).
Zn(2+) inhibits the RNase activity while Mg(2+), Ca(2+), Mn(2+), K(+), Na(+), EDTA and EGTA show little effect on the exoribonuclease activity (PubMed:28322335).
Interacts (via ANK repeats) with CLIP3 (PubMed:26198635). Interacts (via ANK repeats) with DNAJC5 (via C-terminus) (By similarity). Interacts (via ANK repeats) with HTT (PubMed:26198635). Interacts (via ANK repeats) with MAP6 (PubMed:26198635). Interacts (via ANK repeats) with SNAP23. Interacts (via ANK repeats) with SNAP25. May interact (via ANK repeats) with SPRED2 (By similarity).
Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates (By similarity). Palmitoyltransferase for HTT and GAD2. May play a role in Mg(2+) transport.
Homodimer. Interacts with FGFR2 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.
It is uncertain whether variants in this gene are associated with Parkinson disease. Some authors mention association with the disease (PubMed:18252210). In contrast, some others do not observe any association (PubMed:19133659).
Neurotrophic factor that regulates central nervous development and function.
Predominantly expressed in the cerebellum.
Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5. Associates with polysomes (By similarity). Interacts with HNRNPH1; the interaction in RNA-dependent. Interacts with PARN.
Phosphorylated. Its phosphorylation status increases in senescent cells.
RNA-binding protein implicated in the regulation of several post-transcriptional events. Involved in pre-mRNA alternative splicing, mRNA translation and stability. Mediates exon inclusion and/or exclusion in pre-mRNA that are subject to tissue-specific and developmentally regulated alternative splicing. Specifically activates exon 5 inclusion of cardiac isoforms of TNNT2 during heart remodeling at the juvenile to adult transition. Acts as both an activator and repressor of a pair of coregulated exons: promotes inclusion of the smooth muscle (SM) exon but exclusion of the non-muscle (NM) exon in actinin pre-mRNAs. Activates SM exon 5 inclusion by antagonizing the repressive effect of PTB. Promotes exclusion of exon 11 of the INSR pre-mRNA. Inhibits, together with HNRNPH1, insulin receptor (IR) pre-mRNA exon 11 inclusion in myoblast. Increases translation and controls the choice of translation initiation codon of CEBPB mRNA. Increases mRNA translation of CEBPB in aging liver (By similarity). Increases translation of CDKN1A mRNA by antagonizing the repressive effect of CALR3. Mediates rapid cytoplasmic mRNA deadenylation. Recruits the deadenylase PARN to the poly(A) tail of EDEN-containing mRNAs to promote their deadenylation. Required for completion of spermatogenesis (By similarity). Binds to (CUG)n triplet repeats in the 3'-UTR of transcripts such as DMPK and to Bruno response elements (BREs). Binds to muscle-specific splicing enhancer (MSE) intronic sites flanking the alternative exon 5 of TNNT2 pre-mRNA. Binds to AU-rich sequences (AREs or EDEN-like) localized in the 3'-UTR of JUN and FOS mRNAs. Binds to the IR RNA. Binds to the 5'-region of CDKN1A and CEBPB mRNAs. Binds with the 5'-region of CEBPB mRNA in aging liver. May be a specific regulator of miRNA biogenesis. Binds to primary microRNA pri-MIR140 and, with CELF2, negatively regulates the processing to mature miRNA (PubMed:28431233).
RRM1 and RRM2 domains preferentially target UGU(U/G)-rich mRNA elements.
Up-regulated in myotonic dystrophy pathophysiology (DM).
Involved in trafficking and recycling of synaptic vesicles.
The gene represented in this entry may be involved in disease pathogenesis. Genetic variants in TMEM230 and DNAJC13 have been found in the same large multigenerational family with adult-onset Parkinson disease. The pathological role of each gene and therefore the exact molecular basis of the disease is unclear.
Belongs to the complex I LYR family. LYRM9 subfamily.
Expressed in placenta, kidney, pancreas, prostate, testis, thymus, and trachea.
Inhibitor of HGFAC (PubMed:9346890). Also inhibits plasmin, and plasma and tissue kallikrein (PubMed:9115294). Inhibits serine protease activity of TMPRSS13 (PubMed:20977675, PubMed:28710277). Inhibits serine protease activity of ST14/matriptase in vitro (PubMed:28710277).
Interacts with TMPRSS13; the interaction promotes the phosphorylation and cell membrane localization of TMPRSS13.
This inhibitor contains two inhibitory domains.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins (PubMed:8132613, PubMed:17588522, PubMed:20061386). E2 ubiquitin conjugating enzyme that transfers ubiquitin to MAEA, a core component of the CTLH E3 ubiquitin-protein ligase complex (PubMed:29911972). In vitro catalyzes 'Lys-11'- and 'Lys-48'-linked polyubiquitination (PubMed:20061386). Capable, in vitro, to ubiquitinate histone H2A (PubMed:8132613).
Autoubiquitinated in vitro in the presence of NEDD4L.
Interacts with MAEA and WDR26, components of the CTLH complex that contains GID4, RANBP9 and/or RANBP10, MKLN1, MAEA, RMND5A (or alternatively its paralog RMND5B), GID8, ARMC8, WDR26 and YPEL5.
Binds actin (By similarity). Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2.
Expressed in adult and fetal brain with enrichment in the cerebellum. Detected in testis.
Interacts with PLEKHG6. Interacts with ARMC9, TOGARAM1, CCDC66, CEP104 and CEP290 (PubMed:32453716).
Isoform 1 expression increases throughout the cell cycle and peaks in G2/M phase. Isoform 2 expression is highest in G1 phase and decreases thereafter.
May play a role in cell-cycle-dependent microtubule organization.
Phosphorylated. Phosphorylation increases in colcemide-treated cells.
EGF stimulates phosphorylation on Tyr-residues.
Homodimer (Potential). Interacts with RAB11FIP2. Interacts with RALBP1, CRK and GRB2. Binding to RALBP1 does not affect its Ral-binding activity. Forms a complex with the SH3 domains of CRK and GRB2 which may link it to an EGF-responsive tyrosine kinase (By similarity). Interacts with AMPH, ITSN1 (via SH3 domains) and SGIP1; may be involved in clathrin-mediated endocytosis.
May coordinate the cellular actions of activated EGF receptors and Ral-GTPases.
Widely expressed with highest levels in heart and testis.
Belongs to the methyltransferase superfamily. HEN1 family.
Methyltransferase that adds a 2'-O-methyl group at the 3'-end of piRNAs, a class of 24 to 30 nucleotide RNAs that are generated by a Dicer-independent mechanism and are primarily derived from transposons and other repeated sequence elements. This probably protects the 3'-end of piRNAs from uridylation activity and subsequent degradation. Stabilization of piRNAs is essential for gametogenesis.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia and flagellar axoneme. Forms filamentous polymers in the walls of ciliary and flagellar microtubules.
Predominantly expressed in testis. Expressed in airway epithelial cells (PubMed:36191189).
Contains two sets of 2 zinc-fingers, which are widely separated and recognize the same DNA sequence. There is a fifth zinc-finger in-between.
This protein specifically binds to the DNA sequence 5'-GGGACTTTCC-3' which is found in the enhancer elements of numerous viral promoters such as those of SV40, CMV, or HIV-1. In addition, related sequences are found in the enhancer elements of a number of cellular promoters, including those of the class I MHC, interleukin-2 receptor, and interferon-beta genes. It may act in T-cell activation. Involved in activating HIV-1 gene expression. Isoform 2 and isoform 3 also bind to the IPCS (IRF1 and p53 common sequence) DNA sequence in the promoter region of interferon regulatory factor 1 and p53 genes and are involved in transcription regulation of these genes. Isoform 2 does not activate HIV-1 gene expression. Isoform 2 and isoform 3 may be involved in apoptosis.
Belongs to the connexin family. Beta-type (group I) subfamily.
(Microbial infection) Interacts with Epstein-Barr virus protein BALF1.
(Microbial infection) Interacts with adenovirus protein E1B 19K.
(Microbial infection) Interacts with myxoma virus protein M11L.
(Microbial infection) Interacts with vaccinia virus protein F1.
Expressed in a wide variety of tissues, with highest levels in the heart and skeletal muscle.
Homodimer. Formation of the homodimer is zinc-dependent (PubMed:17157251). Forms heterodimers with BCL2 and BCL2L1 isoform Bcl-X(L) (PubMed:9020082). Forms heterooligomers with BAX (PubMed:29531808). Interacts with BCL2A1 (By similarity). Interacts with RTL10/BOP (PubMed:23055042). Interacts with VDAC1 (PubMed:25296756). Interacts with GIMAP3/IAN4 and GIMAP5/IAN5 (PubMed:16509771).
Intact BH3 motif is required by BIK, BID, BAK, BAD and BAX for their pro-apoptotic activity and for their interaction with anti-apoptotic members of the Bcl-2 family.
Plays a role in the mitochondrial apoptotic process. Upon arrival of cell death signals, promotes mitochondrial outer membrane (MOM) permeabilization by oligomerizing to form pores within the MOM. This releases apoptogenic factors into the cytosol, including cytochrome c, promoting the activation of caspase 9 which in turn processes and activates the effector caspases.
Cleaved by enterovirus protease 3C to promote apoptosis.
Interacts with MCRS1, TERT, TERF1, NCL/nucleolin, and the telomerase RNA.
Microtubule-binding protein essential for faithful chromosome segregation. Mediates TRF1 and TERT accumulation in nucleolus and enhances TRF1 binding to telomeres. Inhibits telomerase activity. May inhibit cell proliferation and act as tumor suppressor.
The TBM domain mediates interaction with TERF1.
The TID (telomerase inhibiting domain) domain is sufficient to bind TERT and inhibit its activity.
Ubiquitous; expressed at low levels. Not detectable in a number of hepatocarcinoma cell lines.
Cytoplasmic protein involved in the delivery of the dynein machinery to the motile cilium. It is required for the assembly of the axonemal dynein inner and outer arms, two structures attached to the peripheral outer doublet A microtubule of the axoneme, that play a crucial role in cilium motility.
Expressed by immature cells in the process of extending cilia.
Expressed in nasal epithelium and lung epithelium by ciliated cells (at protein level).
Interacts with DNAI2; probably involved in outer arm dynein assembly.
ATP-binding RNA helicase that plays a role in maturation of the small ribosomal subunit in ribosome biogenesis (PubMed:30582406). Required for the release of the U3 snoRNP from pre-ribosomal particles (PubMed:30582406). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797). Plays a role in early testis development (PubMed:31287541, PubMed:31337883). Probably also plays a role in brain development (PubMed:31256877).
Expressed in the fallopian tube, ovary, uterus and testis. Also expressed in the brain.
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Interacts with UTP14A (PubMed:30582406).
Acts as a repressor in the regulation of translation initiation of poly(A)-containing mRNAs. Its inhibitory activity on translation is mediated via its action on PABPC1. Displaces the interaction of PABPC1 with poly(A) RNA and competes with PAIP1 for binding to PABPC1. Its association with PABPC1 results in disruption of the cytoplasmic poly(A) RNP structure organization.
Expressed at highest level in testis, but also abundant in brain, cervix, lung, ovary, placenta, adipose tissue, thymus and thyroid.
Interacts with the second and third RRM domains and C-terminus regions of PABPC1 in a 2:1 stoichiometry.
Only the PABPC1-interacting motif-1 (PAM1) interferes with the binding of PABPC1 to poly(A) RNA and translation initiation.
Probably contributes to terminal cornification.
Synthesized during maturation of epidermal keratinocytes.
May regulate cell proliferation and coordinate apoptosis and cell cycle progression via a novel mechanism independent of both p53/TP53 and NF-kappa-B.
Partially edited. Decreased editing levels seen in astrocytomas, bladder cancer and colorectal cancer as compared to the related normal tissues.
Ubiquitous. Expressed in cervical tissues. Down-regulated in bladder invasive carcinoma, renal cell carcinoma and in primary cervical carcinoma.
Expressed in placenta, including the invasive extravillus trophoblast cells.
Involved in cell cycle regulation by binding to the CCNB1 promoter, up-regulating its expression and promoting mitotic entry (PubMed:22253775). Induces phosphorylation of MAPT/tau (PubMed:22995177).
Involved in regulating the levels of reactive oxidative species and reactive nitrogen species and in mitochondrial homeostasis in the placenta (PubMed:24738702). Required for regulation of inner ear epithelial cell proliferation via the AKT signaling pathway (By similarity).
Allosterically inhibited by the N-terminal domain (PubMed:36177733). Inhibited by phloretin (PubMed:36177733, PubMed:18000046).
Electroneutral Na(+) Li(+)/H(+) antiporter that extrudes Na(+) or Li(+) in exchange for external protons across the membrane (PubMed:18000046, PubMed:28154142, PubMed:22948142, PubMed:18508966, PubMed:36177733). Uses the proton gradient/membrane potential to extrude sodium (PubMed:22948142). Contributes to the regulation of intracellular pH and sodium homeostasis (By similarity). Also able to mediate Na(+)/Li(+) antiporter activity in kidney (PubMed:22948142). May play a physiological role in renal tubular function and blood pressure homeostasis (By similarity). Plays an important role for insulin secretion and clathrin-mediated endocytosis in beta-cells (By similarity). Involved in sperm motility and fertility (By similarity). It is controversial whether SLC9B2 plays a role in osteoclast differentiation or not (By similarity).
Homodimer (PubMed:28071645). Dimerization is essential for SLC9B2 activity (By similarity). Lipids seem to play a role in the stabilization of the dimerization subdomain (By similarity).
The subcellular localization of SLC9B2 remains controversial. Was initially thought to partially localize to mitochondria (By similarity). However SLC9B2 does not seem to contain a mitochondrial targeting sequence. It was later established that its localizes predominantly in plasma membrane or intracellularly to endosomes and lysosomes (By similarity). In another recent study, endogenous SLC9B2 in the distal tubular cell line mpkDCT4 is detected in recycling endosomes but absent in plasma membrane (By similarity).
Widely expressed (PubMed:18508966). High levels detected in the distal tubules of the kidney nephron (PubMed:18508966). Detected in red blood cells (at protein level) (PubMed:18000046, PubMed:18508966).
Found in a post-splicing messenger ribonucleoprotein (mRNP) complex. Associates with the exon junction complex (EJC). Interacts with UPF2 and RBM8A. Interacts with DHX34; the interaction is RNA-independent (PubMed:25220460).
Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by associating with the nuclear exon junction complex (EJC) and serving as link between the EJC core and NMD machinery. Recruits UPF2 at the cytoplasmic side of the nuclear envelope and the subsequent formation of an UPF1-UPF2-UPF3 surveillance complex (including UPF1 bound to release factors at the stalled ribosome) is believed to activate NMD. However, UPF3A is shown to be only marginally active in NMD as compared to UPF3B. Binds spliced mRNA upstream of exon-exon junctions. In vitro, weakly stimulates translation.
Isoform 1 is strongly expressed in testis, uterus, muscle, fetal brain and spinal cord. Isoform 2 is strongly expressed in fetal brain and spinal cord.
Orphan receptor involved in normal circadian rhythm behavior. Acts through the G-protein subclass G(z)-alpha and has an agonist-independent basal activity to repress cAMP production.
CRYAB mutations may be involved in restrictive cardiomyopathy (RCM), a rare non-ischemic myocardial disease. RCM is characterized by restrictive ventricular-filling physiology in the presence of normal or reduced diastolic and/or systolic volumes (of 1 or both ventricles), biatrial enlargement, and normal ventricular wall thickness.
Heteromer composed of three CRYAA and one CRYAB subunits (PubMed:20836128). Aggregates with homologous proteins, including the small heat shock protein HSPB1, to form large heteromeric complexes (PubMed:10751411). Inter-subunit bridging via zinc ions enhances stability, which is crucial as there is no protein turn over in the lens (PubMed:22890888). Interacts with HSPBAP1 and TTN/titin (PubMed:14676215). Interacts with TMEM109; in the cellular response to DNA damage (PubMed:23542032). Interacts with DES; binds rapidly during early stages of DES filament assembly and a reduced binding seen in the later stages (PubMed:28470624). Interacts with TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion (PubMed:32272059). Interacts with ATP6V1A and with MTOR, forming a ternary complex (PubMed:31786107).
Lens as well as other tissues (PubMed:838078, PubMed:2387586). Expressed in myocardial tissue (PubMed:28493373).
May contribute to the transparency and refractive index of the lens. Has chaperone-like activity, preventing aggregation of various proteins under a wide range of stress conditions.
May contribute to the transparency and refractive index of the lens. Has chaperone-like activity, preventing aggregation of various proteins under a wide range of stress conditions. In lens epithelial cells, stabilizes the ATP6V1A protein, preventing its degradation by the proteasome (By similarity).
By nitric oxide and DMSO in HL-60 cells, an acute myeloid leukemia cell line.
Detected only in peripheral blood leukocytes, predominantly in eosinophils and granulocytes, and at lower levels in monocytes.
Interacts (via pyrin domain) with ASC. Interacts (via pyrin domain) with FAF1 (via UBA domain) (PubMed:21978668). Interacts with MAP3K14; this interaction promotes proteasomal degradation of MAP3K14 (PubMed:17237370). Interacts with NOD2; this interaction promotes degradation of NOD2 through the ubiquitin-proteasome pathway (PubMed:30559449). Interacts with HSPA1A and HSPA8 (PubMed:17947705). Interacts with HSP90AA1 (PubMed:17947705, PubMed:30559449). Interacts with TRIM25; this interaction inhibits RIGI-mediated signaling pathway (PubMed:30902577).
Plays an essential role as an potent mitigator of inflammation (PubMed:30559449). Primarily expressed in dendritic cells and macrophages, inhibits both canonical and non-canonical NF-kappa-B and ERK activation pathways (PubMed:15489334, PubMed:17947705). Functions as a negative regulator of NOD2 by targeting it to degradation via the proteasome pathway (PubMed:30559449). In turn, promotes bacterial tolerance (PubMed:30559449). Inhibits also the RIGI-mediated immune signaling against RNA viruses by reducing the E3 ubiquitin ligase TRIM25-mediated 'Lys-63'-linked RIGI activation but enhancing the E3 ubiquitin ligase RNF125-mediated 'Lys-48'-linked RIGI degradation (PubMed:30902577). Acts also as a negative regulator of inflammatory response to mitigate obesity and obesity-associated diseases in adipose tissue (By similarity).
(Microbial infection) Acts as a coreceptor (CD4 being the primary receptor) for human immunodeficiency virus-1/HIV-1 X4 isolates and as a primary receptor for some HIV-2 isolates. Promotes Env-mediated fusion of the virus (PubMed:8849450, PubMed:8929542, PubMed:9427609, PubMed:10074122, PubMed:10756055).
(Microbial infection) Interacts with HHV-8 protein ORF K4 (PubMed:25612609).
(Microbial infection) Interacts with HIV-1 surface protein gp120 and Tat.
(Microbial infection) Interacts with Staphylococcus aureus protein SSL10.
(Microbial infection) May be down-regulated by HIV-1 tat.
(Microbial infection) May be down-regulated by Human cytomegalovirus/HHV-5.
(Microbial infection) May interact with human cytomegalovirus/HHV-5 protein UL78.
CXCR4 mutations play a role in the pathogenesis of Waldenstroem macroglobulinemia (WM) and influence disease presentation and outcome, as well as response to therapy. WM is a B-cell lymphoma characterized by accumulation of malignant lymphoplasmacytic cells in the bone marrow, lymph nodes and spleen, and hypersecretion of monoclonal immunoglobulin M (IgM). Excess IgM production results in serum hyperviscosity, tissue infiltration, and autoimmune-related pathology.
Expressed in numerous tissues, such as peripheral blood leukocytes, spleen, thymus, spinal cord, heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, cerebellum, cerebral cortex and medulla (in microglia as well as in astrocytes), brain microvascular, coronary artery and umbilical cord endothelial cells. Isoform 1 is predominant in all tissues tested.
Monomer. Can form homodimers (PubMed:20929726). Interacts with CD164 (PubMed:17077324). Interacts with ARRB2; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and allows activation of MAPK1 and MAPK3. Interacts with ARR3; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and modulates calcium mobilization (PubMed:20048153). Interacts with RNF113A; the interaction, enhanced by CXCL12, promotes CXCR4 ubiquitination and subsequent degradation (PubMed:28978524). Interacts (via the cytoplasmic C-terminal) with ITCH (via the WW domains I and II); the interaction, enhanced by CXCL12, promotes CXCR4 ubiquitination and leads to its degradation. Interacts with extracellular ubiquitin. Interacts with DBN1; this interaction is enhanced by antigenic stimulation. Following LPS binding, may form a complex with GDF5, HSP90AA1 and HSPA8.
O- and N-glycosylated. Asn-11 is the principal site of N-glycosylation. There appears to be very little or no glycosylation on Asn-176. N-glycosylation masks coreceptor function in both X4 and R5 laboratory-adapted and primary HIV-1 strains through inhibiting interaction with their Env glycoproteins. The O-glycosylation chondroitin sulfate attachment does not affect interaction with CXCL12/SDF-1alpha nor its coreceptor activity.
Phosphorylated on agonist stimulation. Rapidly phosphorylated on serine and threonine residues in the C-terminal. Phosphorylation at Ser-324 and Ser-325 leads to recruitment of ITCH, ubiquitination and protein degradation.
Plerixafor (AMD3100), an antagonist of CXCR4 activity, blocks HIV-1 entry, interaction with CXCL12 and subsequent CXCR4 signaling.
Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation (PubMed:10452968, PubMed:28978524, PubMed:18799424, PubMed:24912431). Involved in the AKT signaling cascade (PubMed:24912431). Plays a role in regulation of cell migration, e.g. during wound healing (PubMed:28978524). Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels (PubMed:20228059). Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205). Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival (By similarity).
Sulfation on Tyr-21 is required for efficient binding of CXCL12/SDF-1alpha and promotes its dimerization. Tyr-7 and Tyr-12 are sulfated in a sequential manner after Tyr-21 is almost fully sulfated, with the binding affinity for CXCL12/SDF-1alpha increasing with the number of sulfotyrosines present. Sulfotyrosines Tyr-7 and Tyr-12 occupy clefts on opposing CXCL12 subunits, thus bridging the CXCL12 dimer interface and promoting CXCL12 dimerization.
The amino-terminus is critical for ligand binding. Residues in all four extracellular regions contribute to HIV-1 coreceptor activity.
Ubiquitinated after ligand binding, leading to its degradation (PubMed:28978524). Ubiquitinated by ITCH at the cell membrane on agonist stimulation (PubMed:14602072, PubMed:34927784). The ubiquitin-dependent mechanism, endosomal sorting complex required for transport (ESCRT), then targets CXCR4 for lysosomal degradation. This process is dependent also on prior Ser-/Thr-phosphorylation in the C-terminal of CXCR4. Also binding of ARRB1 to STAM negatively regulates CXCR4 sorting to lysosomes though modulating ubiquitination of SFR5S.
Was originally thought to be a receptor for neuropeptide Y type 3 (NPY3R) (NPY3-R) (PubMed:8329116, PubMed:8234909). Later reports showed that it acts as a receptor for the C-X-C chemokine CXCL12/SDF-1 (PubMed:9427609, PubMed:10825158, PubMed:12034737).
Acts as a transcriptional repressor of the GATA3 promoter. Sequence-specific DNA-binding factor that binds to the 5'-AGGTCTC-3' sequence within the negative cis-acting element intronic regulatory region (IRR) of the GATA3 gene (By similarity). Component of the little elongation complex (LEC), a complex required to regulate small nuclear RNA (snRNA) gene transcription by RNA polymerase II and III (PubMed:23932780). Induces thymocyte apoptosis when overexpressed, which may indicate a role in regulation of thymocyte homeostasis.
Component of the little elongation complex (LEC), at least composed of ELL (ELL, ELL2 or ELL3), ZC3H8, ICE1 and ICE2. Interacts with ICE1 (via C-terminus domain).
The N-terminal region and all three C3H1-type zinc fingers are necessary to induce transcriptional repression.
Does not exhibit calcium-activated chloride channel (CaCC) activity.
Expressed in embryonic stem cells, fetal brain and neural tissues.
The term 'anoctamin' was coined because these channels are anion selective and have eight (OCT) transmembrane segments. There is some dissatisfaction in the field with the Ano nomenclature because it is not certain that all the members of this family are anion channels or have the 8-transmembrane topology.
Hydrolyzes the ester bond of the acyl group attached at the sn-1 position of phosphatidylserines (phospholipase A1 activity) and 1-acyl-2-lysophosphatidylserines (lysophospholipase activity) in the pathway of phosphatidylserines acyl chain remodeling (PubMed:10196188). Cleaves phosphatidylserines exposed on the outer leaflet of the plasma membrane of apoptotic cells producing 2-acyl-1-lysophosphatidylserines, which in turn enhance mast cell activation and histamine production (By similarity). Has no activity toward other glycerophospholipids including phosphatidylcholines, phosphatidylethanolamines, phosphatidic acids or phosphatidylinositols, or glycerolipids such as triolein (By similarity).
Widely expressed. Expressed in placenta, prostate and liver. Weakly or not expressed in skin, leukocytes, platelets, colon, spleen, lung, muscle and kidney.
Although only weakly related to the S.cerevisiae SEN15 protein, it probably displays the same function within the tRNA splicing endonuclease complex.
Homodimer (PubMed:17166513). tRNA splicing endonuclease is a heterotetramer composed of TSEN2, TSEN15, TSEN34/LENG5 and TSEN54. tRNA splicing endonuclease complex also contains proteins of the Pre-mRNA 3' end processing machinery, such as CLP1, CPSF1, CPSF4 and CSTF2.
Non-catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA. It cleaves pre-tRNA at the 5' and 3' splice sites to release the intron. The products are an intron and two tRNA half-molecules bearing 2',3' cyclic phosphate and 5'-OH termini (PubMed:15109492, PubMed:27392077). There are no conserved sequences at the splice sites, but the intron is invariably located at the same site in the gene, placing the splice sites an invariant distance from the constant structural features of the tRNA body. The tRNA splicing endonuclease is also involved in mRNA processing via its association with pre-mRNA 3'-end processing factors, establishing a link between pre-tRNA splicing and pre-mRNA 3'-end formation, suggesting that the endonuclease subunits function in multiple RNA-processing events (PubMed:15109492).
Widely expressed. Highly expressed in testis and uterus.
May be involved in acrosome formation of spermatids.
(Microbial infection) Interacts with Staphylococcus aureus HIgB; this interaction regulates AMFR-mediated inflammation by promoting TAB3 ubiquitination to promote TAB3-TAK1 complex formation.
E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins, such as CD3D, CYP3A4, CFTR, INSIG1, SOAT2/ACAT2 and APOB for proteasomal degradation (PubMed:10456327, PubMed:11724934, PubMed:12670940, PubMed:19103148, PubMed:24424410, PubMed:28604676). Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of endoplasmic reticulum-associated degradation (ERAD) (PubMed:10456327, PubMed:11724934, PubMed:19103148, PubMed:24424410). The VCP/p97-AMFR/gp78 complex is involved in the sterol-accelerated ERAD degradation of HMGCR through binding to the HMGCR-INSIG1 complex at the ER membrane (PubMed:16168377, PubMed:22143767). In addition, interaction of AMFR with AUP1 facilitates interaction of AMFR with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase RNF139, leading to sterol-induced HMGCR ubiquitination (PubMed:23223569). The ubiquitinated HMGCR is then released from the ER into the cytosol for subsequent destruction (PubMed:16168377, PubMed:22143767, PubMed:23223569). In addition to ubiquitination on lysine residues, catalyzes ubiquitination on cysteine residues: together with INSIG1, mediates polyubiquitination of SOAT2/ACAT2 at 'Cys-277', leading to its degradation when the lipid levels are low (PubMed:28604676). Catalyzes ubiquitination and subsequent degradation of INSIG1 when cells are depleted of sterols (PubMed:17043353). Mediates polyubiquitination of INSIG2 at 'Cys-215' in some tissues, leading to its degradation (PubMed:31953408). Also regulates ERAD through the ubiquitination of UBL4A a component of the BAG6/BAT3 complex (PubMed:21636303). Also acts as a scaffold protein to assemble a complex that couples ubiquitination, retranslocation and deglycosylation (PubMed:21636303). Mediates tumor invasion and metastasis as a receptor for the GPI/autocrine motility factor (PubMed:10456327). In association with LMBR1L and UBAC2, negatively regulates the canonical Wnt signaling pathway in the lymphocytes by promoting the ubiquitin-mediated degradation of CTNNB1 and Wnt receptors FZD6 and LRP6 (PubMed:31073040). Regulates NF-kappa-B and MAPK signaling pathways by mediating 'Lys-27'-linked polyubiquitination of TAB3 and promoting subsequent TAK1/MAP3K7 activation (PubMed:36593296).
Interacts with RNF5 (By similarity). Also forms an ERAD complex containing VCP/p97, NGLY1; PSMC1; SAKS1 and RAD23B required for coupling retrotranslocation, ubiquitination and deglycosylation (By similarity). Interacts with DERL1 (PubMed:16186510). Interacts (through a region distinct from the RING finger) with UBE2G2/UBC7 (PubMed:11724934). Component of the VCP/p97-AMFR/gp78 complex that enhances VCP/p97 binding to polyubiquitinated proteins for their degradation by the endoplasmic reticulum-associated degradation (ERAD) pathway (By similarity). Interacts (via the VIM) with VCP/p97 (PubMed:16168377, PubMed:16186510). Interacts (via its membrane domain) with INSIG1; the interaction initiates the sterol-mediated ubiquitination and degradation of HMGCR by the ERAD pathway (PubMed:16168377, PubMed:22143767). Interacts with AUP1, UBE2G2 and RNF139/TRC8; interaction with AUP1 facilitates interaction of AMFR with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase RNF139, leading to sterol-induced ubiquitination of HMGCR and its subsequent proteasomal degradation (PubMed:23223569). Interacts with BAG6 (PubMed:21636303). Interacts with USP13 (via UBA 2 domain); the interaction is direct (PubMed:24424410). Interacts with LMBR1L (PubMed:31073040). Interacts with UBAC2 and CTNNB1 (By similarity). Interacts with C18orf32 (PubMed:29275994).
Palmitoylation of the RING-type zing finger by ZDHHC6 promotes localization to the peripheral endoplasmic reticulum.
The CUE domain is required for recognition of misfolded proteins such as mutant CFTR.
The VCP/p97-interacting motif (VIM) is sufficient for binding VCP/p97 to form a complex capable of transferring VCP/p97 from the cytosol to microsomes.
Antagonists for this receptor have proven to be effective therapy for acid peptic disorders of the gastrointestinal tract. Certain antagonists are used in the treatment of neuropsychiatric and neurological diseases such as schizophrenia, Alzheimer disease and Parkinson disease.
The H2 subclass of histamine receptors mediates gastric acid secretion. Also appears to regulate gastrointestinal motility and intestinal secretion. Possible role in regulating cell growth and differentiation. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and, through a separate G protein-dependent mechanism, the phosphoinositide/protein kinase (PKC) signaling pathway (By similarity).
Expressed only in the gastrointestinal tract, particularly the colon.
A previous study reported that GSH and oxidized glutathione (GSSG) are not substrates for murine GGT5 (By similarity). However, this result contrasts with two studies reported that GSH is indeed a substrate for GGT5 (PubMed:21447318, PubMed:1676842).
Cleaved by autocatalysis into a large and a small subunit.
Cleaves the gamma-glutamyl peptide bond of glutathione and glutathione-S-conjugate such as leukotriene C4 (PubMed:21447318). Does not cleaves gamma-glutamyl compounds such as gamma-glutamyl leucine (PubMed:21447318). May also catalyze a transpeptidation reaction in addition to the hydrolysis reaction, transferring the gamma-glutamyl moiety to an acceptor amino acid to form a new gamma-glutamyl compound (PubMed:21447318). Acts as a negative regulator of geranylgeranyl glutathione bioactivity by cleaving off its gamma-glutamyl group, playing a role in adaptive immune responses (PubMed:30842656).
Expressed predominantly in adult liver (PubMed:11896456, PubMed:17693185). Expressed in testis (PubMed:16720576, PubMed:17693185). Also expressed in kidney, lung and fetal liver (PubMed:17693185). Low levels in heart, thyroid, adrenal gland, pancreas, ovary, prostate, skin, plasma leukocytes, bone marrow and fetal brain (PubMed:17693185). Not detected in brain, spleen, colon, small intestine, skeletal muscle, stomach, placenta, salivary gland and uterus (PubMed:17693185).
Promotes functional cell surface expression of the bitter taste receptors TAS2R16 and TAS2R43.
Belongs to the SLC35G solute transporter family.
This gene appears to be the source locus of an SVA-mediated retrotransposition event that gave rise to SLC35G3, SLC35G4 and SLC35G5 genes.
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO38) composed of CUL1, SKP1, RBX1 and FBXO38 (Probable). Interacts with KLF7 (By similarity). Interacts with PDCD1/PD-1 (PubMed:30487606).
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of PDCD1/PD-1, thereby regulating T-cells-mediated immunity (PubMed:30487606). Required for anti-tumor activity of T-cells by promoting the degradation of PDCD1/PD-1; the PDCD1-mediated inhibitory pathway being exploited by tumors to attenuate anti-tumor immunity and facilitate tumor survival (PubMed:30487606). May indirectly stimulate the activity of transcription factor KLF7, a regulator of neuronal differentiation, without promoting KLF7 ubiquitination (By similarity).
Up-regulated by IL2 (PubMed:30487606). Down-regulated in tumor-infiltrating T-cells (PubMed:30487606).
Interacts with DDB1, CUL4A or CUL4B (PubMed:29691401). Interacts with L3MBTL3 (PubMed:29691401). Interacts with DNMT1 (PubMed:29691401). Interacts with E2F1 (PubMed:29691401). Interacts with SOX2 (By similarity).
Is a substrate receptor for the CUL4-DDB1 E3 ubiquitin-protein ligase complex (CRL4) (PubMed:29691401, PubMed:30442713). The complex CRL4-DCAF5 is involved in the ubiquitination of a set of methylated non-histone proteins, including SOX2, DNMT1 and E2F1 (PubMed:29691401, PubMed:30442713).
Cardiac muscle Tn-C can bind 3 calcium ions per molecule. Domain I does not bind calcium.
Troponin is the central regulatory protein of striated muscle contraction. Tn consists of three components: Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin and Tn-C. The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments.
Component of the conserved oligomeric Golgi complex which is composed of eight different subunits and is required for normal Golgi morphology and localization.
Required for normal Golgi morphology and function.
Highly expressed in kidney, small intestine, stomach, colon, jejunum and duodenum.
Homodimer; homodimerization is mediated by the transmembrane domain.
Selective transporter that mediates the uptake of Zn(2+) (PubMed:17202136, PubMed:22242765, PubMed:27321477, PubMed:28875161, PubMed:31164399, PubMed:31914589, PubMed:31979155, PubMed:33837739, PubMed:36473915). Plays an essential role for dietary zinc uptake from small intestine (By similarity). The Zn(2+) uniporter activity is regulated by zinc availability (PubMed:32348750, PubMed:17202136). Exhibits also polyspecific binding and transport of Cu(2+), Cd(2+) and possibly Ni(2+) but at higher concentrations (PubMed:22242765, PubMed:31914589).
The N-terminal extracellular domain is required for high efficient zinc transport.
The Zn(2+) uniporter activity is regulated by zinc availability (PubMed:32348750, PubMed:17202136). Extracellular acidification stimulated SLC39A4-dependent Zn(2+) uptake (PubMed:31979155).
The extracellular N-terminal ectodomain is cleaved when cells are Zn(2+) deficient, N-terminally cleaved SLC39A4 is internalized at a faster rate.
The two metal binding sites M1 and M2 that are halfway through the membrane form a binuclear metal center. M1 is essential to Zn(2+) transport, while the other, M2 appears to have an auxiliary role presumably by acting as an additional transport site that can modulate the properties of the primary transport site (PubMed:28875161, PubMed:31914589). The binuclear metal center plays a key role in Zn(2+) sensing (PubMed:32348750).
Under excess Zn(2+) conditions, SLC39A4 on the cell surface is rapidly endocytosed, ubiquitinated and degraded.
Defects in PPM1F may be a cause of sclerosing cholangitis, short stature, hypothyroidism, and abnormal tongue pigmentation.
Dephosphorylates and concomitantly deactivates CaM-kinase II activated upon autophosphorylation, and CaM-kinases IV and I activated upon phosphorylation by CaM-kinase kinase. Promotes apoptosis.
Highly expressed in brain and testis. Lower levels in small intestine, placenta and spleen. In brain regions, detected in all regions tested, but somewhat lower levels in the corpus callosum, medulla and spinal cord.
C2 domain 1 is involved in binding calcium and phospholipids.
Calcium sensor which most probably regulates fusion of vesicles with membranes. Binds calcium and phospholipids. May be involved in calcium dependent neurotransmitter release through the interaction with UNC13A. May be involved in calcium-dependent spontaneous release of neurotransmitter in absence of action potentials in neuronal cells. Regulates Ca(2+)-dependent secretory lysosome exocytosis in mast cells.
Interacts (via N-terminus) with UNC13A. Interacts with cytoplasmic dynein light chain DYNLT1. Interacts with UNC13D.
Predominantly expressed in brain. Also expressed in testis.
Binds single-stranded RNA. Involved in the process of mRNA degradation and in the positive regulation of mRNA decapping. May play a role in spermiogenesis and oogenesis.
Expressed in theca and granulosa cells in ovary, and in spermatids of the meiotic division part II and apical membrane of Sertoli cells in testis (at protein level). Also expressed in brain and mammary gland.
Homodimer (via YjeF N-terminal domain). Forms a complex with DCP1A, DCP2, DDX6 and EDC4/HEDLS, within this complex directly interacts with DCP1A and DDX6 (PubMed:16364915, PubMed:31422817, PubMed:19285948, PubMed:31439631). Interacts with ZFP36.
The DFDF domain is unstructured by itself. It assumes a helical fold upon interaction with DDX6.
Binds EFNB1 and EFNB2 (By similarity). Binds the GNB1-GNG2 heterodimer.
Down-regulates signaling from heterotrimeric G-proteins by increasing the GTPase activity of the alpha subunits, thereby driving them into their inactive GDP-bound form. Down-regulates G-protein-mediated release of inositol phosphates and activation of MAP kinases.
Phosphorylated by cyclic GMP-dependent protein kinase.
B-cells. Expressed in a number of B-cell lines including P32/ISH and Namalwa. Expressed in erythroleukemia cell and small cell lung carcinoma cell lines. Also expressed on the surface of T-cells.
Expression is lost when primary B-cells are induced to differentiate in antibody-forming cells.
Interacts with LYN and FGR in a cell-type specific manner. Binds FRG in a small cell cancer line, LYN in the erythroleukemia cell line K-562 and in Burkitt's lymphoma.
May have a pivotal role in cell differentiation of different cell types. Signaling could be triggered by the binding of a lectin-like ligand to the CD24 carbohydrates, and transduced by the release of second messengers derived from the GPI-anchor. Modulates B-cell activation responses. Promotes AG-dependent proliferation of B-cells, and prevents their terminal differentiation into antibody-forming cells (PubMed:11313396). In association with SIGLEC10 may be involved in the selective suppression of the immune response to danger-associated molecular patterns (DAMPs) such as HMGB1, HSP70 and HSP90. Plays a role in the control of autoimmunity (By similarity).
RTL8C is one of at least 11 genes called Mar or Mart related to long terminal repeat retrotransposons. They do not correspond to functional retrotransposons, but rather to neofunctionalized retrotransposons genes.
There seem to be two proteins that can be transcribed from FAM127A, one with a C-terminal CAAX box (AC O15255) and a smaller protein (the sequence shown here) that seems to be encoded by a multicopy gene originating from a retrotransposon.
Specifically expressed in testis. Expressed at 5.6-fold higher levels in adult testis than in fetal testis.
Component of the MCM8-MCM9 complex, a complex involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR) (PubMed:23401855). Required for DNA resection by the MRE11-RAD50-NBN/NBS1 (MRN) complex by recruiting the MRN complex to the repair site and by promoting the complex nuclease activity (PubMed:26215093). Probably by regulating the localization of the MNR complex, indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs (PubMed:23401855). The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression (PubMed:23401855). However, may play a non-essential for DNA replication: may be involved in the activation of the prereplicative complex (pre-RC) during G(1) phase by recruiting CDC6 to the origin recognition complex (ORC) (PubMed:15684404). Probably by regulating HR, plays a key role during gametogenesis (By similarity). Stabilizes MCM9 protein (PubMed:23401855, PubMed:26215093).
Component of the MCM8-MCM9 complex, which forms a hexamer composed of MCM8 and MCM9 (PubMed:23401855, PubMed:26300262). Interacts with the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1 (PubMed:26300262). Interacts with RAD51; the interaction recruits RAD51 to DNA damage sites (PubMed:23401855). Interacts with the MRN complex composed of MRE11, RAD50 and NBN/NBS1 (PubMed:26215093). Interacts with CDC6 and ORC2 (PubMed:15684404). Interacts with HROB; the interaction recruits the MCM8-MCM9 complex to DNA damage sites (PubMed:31467087).
Highest levels in placenta, lung and pancreas. Low levels in skeletal muscle and kidney. Expressed in various tumors with highest levels in colon and lung cancers.
No experimental confirmation available. According to PubMed:12771218, this isoform could be derived from an aberrant mRNA form found in placental choriocarcinoma.
Was initially thought to play a role in DNA replication (PubMed:15684404). However, it was later shown that it is mainly involved in homologous recombination repair (PubMed:23401855).
(Microbial infection) Binds to HIV-1 Rev.
(Microbial infection) In case of HIV-1 infection, binds and mediates the nuclear import of HIV-1 Rev.
Belongs to the importin beta family. Importin beta-2 subfamily.
Functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates (PubMed:24753571). May mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus (By similarity). Involved in nuclear import of M9-containing proteins. In vitro, binds directly to the M9 region of the heterogeneous nuclear ribonucleoproteins (hnRNP), A1 and A2 and mediates their nuclear import. Involved in hnRNP A1/A2 nuclear export. Mediates the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5 (PubMed:11682607). In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones (By similarity). In vitro, mediates nuclear import of SRP19 (PubMed:11682607). Mediates nuclear import of ADAR/ADAR1 isoform 1 and isoform 5 in a RanGTP-dependent manner (PubMed:19124606, PubMed:24753571).
Identified in a complex that contains TNPO1, RAN and RANBP1 (PubMed:9428644). Binds HNRPA1, HNRPA2, HNRNPDL, RPS7, RPL5 and RAN. Interacts with H2A, H2B, H3 and H4 histones (By similarity). Interacts with isoform 1 and isoform 5 of ADAR/ADAR1 (via DRBM 3 domain) (PubMed:19124606, PubMed:24753571). Interacts with SNAI1 (via zinc fingers); the interaction mediates SNAI1 nuclear import (PubMed:19386897). Interacts with SNAI2 (via zinc fingers) (PubMed:19386897). Interacts with RPL23A (via BIB domain) and SRP19; this interaction is involved in RPL23A and SRP19 import into the nucleus (PubMed:11682607).
(Microbial infection) Interacts with hepatitis C virus (HCV) non-structural protein 5A; this interaction allows the modulation by the virus of JNK, p38 MAPK, STAT3, and Akt signaling pathways in a DR6-dependent manner.
Associates with TRADD (PubMed:9714541). Interacts with NGFR (PubMed:23559013). Interacts with CASP8 (PubMed:34012073). Interacts with N-APP (By similarity).
Detected in fetal spinal cord and in brain neurons, with higher levels in brain from Alzheimer disease patients (at protein level). Highly expressed in heart, brain, placenta, pancreas, lymph node, thymus and prostate. Detected at lower levels in lung, skeletal muscle, kidney, testis, uterus, small intestine, colon, spleen, bone marrow and fetal liver. Very low levels were found in adult liver and peripheral blood leukocytes.
Oxidized in response to reactive oxygen species (ROS), leading to endocytosis.
Promotes apoptosis, possibly via a pathway that involves the activation of NF-kappa-B. Can also promote apoptosis mediated by BAX and by the release of cytochrome c from the mitochondria into the cytoplasm. Plays a role in neuronal apoptosis, including apoptosis in response to amyloid peptides derived from APP, and is required for both normal cell body death and axonal pruning. Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP). N-APP binds TNFRSF21; this triggers caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6). Negatively regulates oligodendrocyte survival, maturation and myelination. Plays a role in signaling cascades triggered by stimulation of T-cell receptors, in the adaptive immune response and in the regulation of T-cell differentiation and proliferation. Negatively regulates T-cell responses and the release of cytokines such as IL4, IL5, IL10, IL13 and IFNG by Th2 cells. Negatively regulates the production of IgG, IgM and IgM in response to antigens. May inhibit the activation of JNK in response to T-cell stimulation. Also acts as a regulator of pyroptosis: recruits CASP8 in response to reactive oxygen species (ROS) and subsequent oxidation, leading to activation of GSDMC (PubMed:34012073).
Expressed in spleen, lung, heart, liver, kidney, pancreas, thymus, gonads and leukocytes.
Orphan receptor; could be a chemoattractant receptor.
The sequence shown in this entry differs from the translation of the reference genome assembly (GRCh38/hg38) due to a nonsense variant creating stop codon at position 140 in the reference genome.
The sequence shown in this entry differs from the translation of the reference genome assembly (GRCh38/hg38) due to a nonsense variant creating stop codon at position 140 in the reference genome. The sequence shown in this entry is that of variant p.Ter140Arg. This variant has a frequency of about 1% in the human population according to the Genome Aggregation Database (gnomAD v3.1.2). Polymorphic GPR33 gene inactivation has been observed in hominoids, including chimpanzees, as well as in some rodents, such as rat, but not in other mammals. A likely cause of GPR33 inactivation by selection is its interplay with an exogenous factor, such as a rodent-hominoidotopic pathogen.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. DMPK subfamily.
Expressed in all tissues examined, with high levels in heart, brain, placenta and lung.
Homodimer and homotetramer via the coiled coil regions (PubMed:21949762). Interacts tightly with GTP-bound but not GDP-bound CDC42. Interacts with TJP1, when in the presence of catalytically active CDC42 (By similarity). Forms a tripartite complex with MYO18A and LURAP1 with the latter acting as an adapter connecting CDC42BPB and MYO18A. LURAP1 binding results in activation of CDC42BPB by abolition of its negative autoregulation (PubMed:18854160). Interacts with STRIP1, STRN3 and SIKE1 (PubMed:25743393). Interacts with CPNE4 (via VWFA domain). Interacts with LURAP1. Interacts (via AGC-kinase C-terminal domain) with FAM89B/LRAP25 (via LRR repeat). Forms a tripartite complex with FAM89B/LRAP25 and LIMK1 (By similarity).
Maintained in an inactive, closed conformation by an interaction between the kinase domain and the negative autoregulatory C-terminal coiled-coil region. Agonist binding to the phorbol ester binding site disrupts this, releasing the kinase domain to allow N-terminus-mediated dimerization and kinase activation by transautophosphorylation (By similarity). Inhibited by chelerythrine chloride.
Proteolytically cleaved by caspases upon apoptosis induction.
Serine/threonine-protein kinase which is an important downstream effector of CDC42 and plays a role in the regulation of cytoskeleton reorganization and cell migration. Regulates actin cytoskeletal reorganization via phosphorylation of PPP1R12C and MYL9/MLC2 (PubMed:21457715, PubMed:21949762). In concert with MYO18A and LURAP1, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration (PubMed:18854160). Phosphorylates PPP1R12A (PubMed:21457715). In concert with FAM89B/LRAP25 mediates the targeting of LIMK1 to the lamellipodium resulting in its activation and subsequent phosphorylation of CFL1 which is important for lamellipodial F-actin regulation (By similarity).
Component of the chaperonin-containing T-complex (TRiC), a heterooligomeric complex of about 850 to 900 kDa that forms two stacked rings, 12 to 16 nm in diameter (PubMed:20080638, PubMed:25467444). Interacts with PACRG (PubMed:14532270). Interacts with FLCN (PubMed:27353360). Interacts with DLEC1 (PubMed:33144677).
Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of proteins upon ATP hydrolysis (PubMed:25467444). The TRiC complex mediates the folding of WRAP53/TCAB1, thereby regulating telomere maintenance (PubMed:25467444). As part of the TRiC complex may play a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia (PubMed:20080638). The TRiC complex plays a role in the folding of actin and tubulin (Probable).
Isoform 1 and isoform 2 are expressed at high levels in the lung, brain, whole eye and retina. Isoform 1 shows a weaker expression in the heart, kidney and skeletal muscle. Isoform 2 shows a weaker expression in the kidney, bone marrow and skeletal muscle. Isoform 1 and isoform 2 are expressed at high levels in the fetal heart, kidney, and whole eye, whereas a weak expression is seen in the fetal liver.
Interacts with ACTN2 (By similarity). Interacts with F-actin.
Protects actin filaments from depolymerization.
Antibodies against KIAA1671 are present in sera from patients with breast cancer who developed several autoantibodies.
Detected in urine (at protein level) (PubMed:25326458, PubMed:36213313). Constitutively expressed in eccrine sweat gland cells (at protein level). Secreted into the sweat at a concentration of 1-10 micrograms/ml.
Found in sweat, has an antimicrobial activity during early bacterial colonization (PubMed:11694882, PubMed:23426625). The secreted peptide assembles into homohexameric complexes that can associate with and also insert into pathogen membranes (PubMed:23426625). Once inserted in bacteria membranes forms anion channels probably altering the transmembrane potential essential for bacterial survival (PubMed:23426625). Highly effective against E.coli, E.faecalis, S.aureus and C.albicans (PubMed:11694882). Optimal pH and salt concentration resemble the conditions in sweat (PubMed:11694882). Also exhibits proteolytic activity, cleaving on the C-terminal side of Arg and, to a lesser extent, Lys residues (PubMed:17448443).
Promotes survival of neurons and displays phosphatase activity (PubMed:9736629). It may bind IgG (PubMed:9736629).
May play a role in spermatogenesis. May be involved in synaptic processes (By similarity).
Homodimer (PubMed:34731008). Part of the tectonic-like complex (also named B9 complex) (By similarity). Interacts with DNAJB9, DNAJC10 and mutated SFTPC. Interacts with SYNE2 during the early establishment of cell polarity. Interacts (via C-terminus) with FLNA. Interacts with TMEM218 (PubMed:35137054). Interacts with WNT5A (PubMed:34731008, PubMed:26035863). Interacts with ROR2 (PubMed:26035863).
Required for ciliary structure and function. Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition (By similarity). Involved in centrosome migration to the apical cell surface during early ciliogenesis. Involved in the regulation of cilia length and appropriate number through the control of centrosome duplication. Is a key regulator of stereociliary bundle orientation (By similarity). Required for epithelial cell branching morphology. Essential for endoplasmic reticulum-associated degradation (ERAD) of surfactant protein C (SFTPC). Involved in the negative regulation of canonical Wnt signaling, and activation of the non-canonical cascade stimulated by WNT5A (PubMed:26035863). In non-canonical Wnt signaling, it may act as ROR2 coreceptor (By similarity).
TMEM67 mutations result in ciliary dysfunction leading to a broad spectrum of disorders, collectively termed ciliopathies. Overlapping clinical features include retinal degeneration, renal cystic disease, skeletal abnormalities, fibrosis of various organ, and a complex range of anatomical and functional defects of the central and peripheral nervous system. The ciliopathy range of diseases includes Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, and nephronophtisis among others. Single-locus allelism is insufficient to explain the variable penetrance and expressivity of such disorders, leading to the suggestion that variations across multiple sites of the ciliary proteome influence the clinical outcome.
The gene represented in this entry may act as a disease modifier. TMEM67 variations may influence the expression of Bardet-Biedl syndrome in patients who have causative mutations in other genes. Heterozygosity for a complex mutation in the TMEM67 gene coding for a protein with 2 in cis changes, and homozygosity for a truncating mutation of the CEP290 gene has been found in a patient with Bardet-Biedl syndrome 14.
Widely expressed in adult and fetal tissues. Expressed at higher level in spinal cord.
Belongs to the helicase family. SKI2 subfamily.
Preferentially expressed in testis and ovary.
Required for crossover formation and complete synapsis of homologous chromosomes during meiosis.
A WASHC2C construct with WASHC2A-specific sequence insertions has been used in a number of experiments; the results are included in the WASHC2C entry.
Acts at least in part as component of the WASH core complex whose assembly at the surface of endosomes inhibits WASH nucleation-promoting factor (NPF) activity in recruiting and activating the Arp2/3 complex to induce actin polymerization and is involved in the fission of tubules that serve as transport intermediates during endosome sorting. Mediates the recruitment of the WASH core complex to endosome membranes via binding to phospholipids and VPS35 of the retromer CSC. Mediates the recruitment of the F-actin-capping protein dimer to the WASH core complex probably promoting localized F-actin polymerization needed for vesicle scission. Via its C-terminus binds various phospholipids, most strongly phosphatidylinositol 4-phosphate (PtdIns-(4)P), phosphatidylinositol 5-phosphate (PtdIns-(5)P) and phosphatidylinositol 3,5-bisphosphate (PtdIns-(3,5)P2). Involved in the endosome-to-plasma membrane trafficking and recycling of SNX27-retromer-dependent cargo proteins, such as GLUT1. Required for the association of DNAJC13, ENTR1, ANKRD50 with retromer CSC subunit VPS35. Required for the endosomal recruitment of CCC complex subunits COMMD1 and CCDC93 as well as the retriever complex subunit VPS35L.
Component of the WASH core complex also described as WASH regulatory complex (SHRC) composed of WASH (WASHC1, WASH2P or WASH3P), WASHC2 (WASHC2A or WASHC2C), WASHC3, WASHC4 and WASHC5; in the complex interacts (via N-terminus) directly with WASHC1. The WASH core complex associates with the F-actin-capping protein dimer (formed by CAPZA1, CAPZA2 or CAPZA3 and CAPZB) in a transient or substoichiometric manner which was initially described as WASH complex. Interacts with VPS35; mediates the association with the retromer CSC complex. Interacts with FKBP15. Interacts with CCDC93, CCDC22, VPS35L; indicative for an association of the WASH core complex with the CCC and retriever complexes (PubMed:25355947). Directly interacts with TBC1D23 (PubMed:29084197).
In human, WASHC2 has undergone evolutionary duplication, with 2 highly homologous family members WASHC2A and WASHC2C.
The LFa (leucine-phenylalanine-acidic) motif bind directly to VPS35 of retromer CSC; adjacent motifs can act cooperatively to bind multiple CSCs, although there is significant variability in the affinities of different motifs for retromer.
Component of the lateral elements of synaptonemal complexes. Heterodimer with SYCP3 (By similarity). Interacts with SMC1A and SMC3 (By similarity). Interacts with TEX11 (By similarity).
Major component of the axial/lateral elements of synaptonemal complexes (SCS) during meiotic prophase. Plays a role in the assembly of synaptonemal complexes. Required for normal meiotic chromosome synapsis during oocyte and spermatocyte development and for normal male and female fertility. Required for insertion of SYCP3 into synaptonemal complexes. May be involved in the organization of chromatin by temporarily binding to DNA scaffold attachment regions. Requires SYCP3, but not SYCP1, in order to be incorporated into the axial/lateral elements.
Adapter protein that plays essential roles in both innate and adaptive immunity. Plays a crucial role in the regulation of thymocyte development (PubMed:26195727). Mechanistically, mediates TCR-stimulated activation through recruiting MAP2K1/MEK1 to the Golgi and, thereby, facilitating the interaction of MAP2K1/MEK1 with its activator BRAF (PubMed:26195727). Also plays an essential role in regulatory T-cell stability and function by recruiting the serine-threonine phosphatase catalytic subunit (PPP2CA) to the lysosome, thereby facilitating the interaction of PP2Ac with the mTORC1 component RPTOR and restricting glycolytic metabolism (PubMed:30115741). Positively regulates TLR4 signaling activity in macrophage-mediated inflammation by acting as a molecular clamp to facilitate LPS-induced translocation of TLR4 to lipid rafts (PubMed:30573680). In response to viral infection, facilitates the recruitment of TRAF3 to MAVS within mitochondria leading to IRF3 activation and interferon production (PubMed:31390091). However, participates in the maintenance of immune homeostasis and the prevention of overzealous innate immunity by promoting 'Lys-48'-dependent ubiquitination of TBK1 (PubMed:32366851).
Interacts (via its coiled-coil domain) with TRAF3 (via isoleucine zipper) (PubMed:31390091, PubMed:32366851). Interacts with MAP2K1 (PubMed:26195727). Interacts with PPP2CA; this interaction targets PPP2CA to the lysosomes (PubMed:30115741). Interacts with TLR4 (PubMed:30573680). Interacts with MAVS (PubMed:31390091). Interacts with TBK1 (PubMed:32366851).
Belongs to the paired homeobox family. Unc-4 subfamily.
Transcription factor involved in somitogenesis and neurogenesis. Required for the maintenance and differentiation of particular elements of the axial skeleton. May act upstream of PAX9. Plays a role in controlling the development of connections of hypothalamic neurons to pituitary elements, allowing central neurons to reach the peripheral blood circulation and to deliver hormones for control of peripheral functions (By similarity).
Acetylation of Lys-50 leads to loss of DNA nicking activity. Acetylation of Lys-154 has no effect.
Detected in testis, skeletal muscle, heart, brain, placenta, lung, pancreas, kidney and liver.
Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Has DNA glycosylase activity towards 5-hydroxyuracil and other oxidized derivatives of cytosine with a preference for mismatched double-stranded DNA (DNA bubbles). Has low or no DNA glycosylase activity towards thymine glycol, 2-hydroxyadenine, hypoxanthine and 8-oxoguanine. Has AP (apurinic/apyrimidinic) lyase activity and introduces nicks in the DNA strand. Cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates.
The zinc-finger domain is important for DNA binding.
Both the RRM domain and the arginine, glycine (RGG) rich domain are necessary for binding to the TXN 3'-untranslated region. Both the RRM domain and the arginine, glycine (RGG) rich domain (RGG repeats) are necessary for optimal recruitment into SGs upon cellular stress. The C-terminal domain containing RGG repeats is necessary for translational repression (By similarity).
By cold stress in response to DNA damage induced by UV irradiation or UV mimetic agents. Up-regulated by hypoxia.
Cold-inducible mRNA binding protein that plays a protective role in the genotoxic stress response by stabilizing transcripts of genes involved in cell survival. Acts as a translational activator. Seems to play an essential role in cold-induced suppression of cell proliferation. Binds specifically to the 3'-untranslated regions (3'-UTRs) of stress-responsive transcripts RPA2 and TXN. Acts as a translational repressor (By similarity). Promotes assembly of stress granules (SGs), when overexpressed.
Interacts with EIF4G1. Associates with ribosomes.
Methylated on arginine residues. Methylation of the RGG motifs is a prerequisite for recruitment into SGs (By similarity).
Phosphorylated by CK2, GSK3A and GSK3B. Phosphorylation by GSK3B increases RNA-binding activity to the TXN 3'-UTR transcript upon exposure to UV radiation.
Interacts with EHD1 (By similarity). Interacts with EHD2. Interacts with RAB8A, RAB10, RAB13 and RAB15 (in their GTP-bound forms); at least in case of RAB8A may bind 2 molecules of RAB8A simultaneously through a high and a low affinity binding site, respectively.
May play a role in actin reorganization. Links clathrin-mediated endocytosis to the actin cytoskeleton. May act as Rab effector protein and play a role in vesicle trafficking (PubMed:14676205, PubMed:27552051). Required for perinuclear sorting and insulin-regulated recycling of SLC2A4/GLUT4 in adipocytes (By similarity).
Prenylated (Probable). Farnelysation (predominant) and geranylgeranylation has been observed in vitro.
The CAAX motif is a signal for prenylation and required for endosomal colocalization with Rab8 and Rab10.
The bivalent Mical/EHBP Rab binding (bMERB) domain, mediates binding to Rab8, Rab10, Rab10, Rab13 and Rab15 (in their GTP-bound forms).
Belongs to the KIF-binding protein family.
Highly expressed in heart, brain, ovary, testis, spinal cord and all specific brain regions examined. Moderate expressed at intermediate level in all other adult tissues examined, as well as in fetal liver and brain. Not expressed in blood leukocytes.
Interacts with KIF1B (PubMed:16225668). Interacts with STMN2 (PubMed:20621975).
Required for organization of axonal microtubules, and axonal outgrowth and maintenance during peripheral and central nervous system development.
Was originally shown to localize in the mitochondrion and to play a role in mitochondrial transport (PubMed:16225668). Recent articles, however, have shown that it does not localize to mitochondria, it interacts with the cytoskeleton and does not have a role in mitochondrial function (PubMed:20621975, PubMed:23427148).
According to a report, N6-methylation of MAT2A affects MAT2A mRNA stability instead of preventing splicing (By similarity). However, it was later shown that N6-methylation of MAT2A transcripts prevents recognition of their 3'-splice site by U2AF1/U2AF35, thereby inhibiting splicing and protein production (PubMed:33930289).
Belongs to the methyltransferase superfamily. METTL16/RlmF family.
Interacts with MEPCE (PubMed:29051200). Interacts with LARP7 (PubMed:29051200).
Methyltransferase activity is autoinhibited by the K-loop region that blocks S-adenosyl-L-methionine-binding (PubMed:30197297). Upon activation, K-loop changes conformation, allowing S-adenosyl-L-methionine-binding and subsequent methyltransferase activity (PubMed:30197297). mRNA N6-adenosine-methyltransferase activity is inhibited by zinc (PubMed:33428944).
RNA N6-methyltransferase that methylates adenosine residues at the N(6) position of a subset of RNAs and is involved in S-adenosyl-L-methionine homeostasis by regulating expression of MAT2A transcripts (PubMed:28525753, PubMed:30197299, PubMed:30197297, PubMed:33428944, PubMed:33930289). Able to N6-methylate a subset of mRNAs and U6 small nuclear RNAs (U6 snRNAs) (PubMed:28525753). In contrast to the METTL3-METTL14 heterodimer, only able to methylate a limited number of RNAs: requires both a 5'UACAGAGAA-3' nonamer sequence and a specific RNA structure (PubMed:28525753, PubMed:30197299, PubMed:30197297). Plays a key role in S-adenosyl-L-methionine homeostasis by mediating N6-methylation of MAT2A mRNAs, altering splicing of MAT2A transcripts: in presence of S-adenosyl-L-methionine, binds the 3'-UTR region of MAT2A mRNA and specifically N6-methylates the first hairpin of MAT2A mRNA, preventing recognition of their 3'-splice site by U2AF1/U2AF35, thereby inhibiting splicing and protein production of S-adenosylmethionine synthase (PubMed:28525753, PubMed:33930289). In S-adenosyl-L-methionine-limiting conditions, binds the 3'-UTR region of MAT2A mRNA but stalls due to the lack of a methyl donor, preventing N6-methylation and promoting expression of MAT2A (PubMed:28525753). In addition to mRNAs, also able to mediate N6-methylation of U6 small nuclear RNA (U6 snRNA): specifically N6-methylates adenine in position 43 of U6 snRNAs (PubMed:28525753, PubMed:29051200, PubMed:32266935). Also able to bind various lncRNAs, such as 7SK snRNA (7SK RNA) or 7SL RNA (PubMed:29051200). Specifically binds the 3'-end of the MALAT1 long non-coding RNA (PubMed:27872311).
Stoichiometry of the protein is unclear. According to two reports, the methyltransferase acts as a monomer (PubMed:30197299, PubMed:30197297). According to a another paper, it acts as a homodimer (PubMed:29593291).
The K-loop region occludes the S-adenosyl-L-methionine-binding pocket (PubMed:30197297). Upon activation, conformation of the K-loop changes, allowing S-adenosyl-L-methionine-binding (PubMed:30197297).
The VCR (vertebrate conserved) regions bind the first hairpin of MAT2A mRNAs (PubMed:28525753). The VCR regions interact with the internal stem-loop within U6 snRNAs, inducing the conformational rearrangement of the A43-containing region of U6 snRNA, thereby modifying the RNA structure to become suitable for productive catalysis by the methyltransferase region (PubMed:32266935).
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD7, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD7 interacts with subunit PSMD4 through their respective MPN domain. Interacts with TRIM5 (PubMed:22078707).
(Microbial infection) Regulates the duration of C.botulinum neurotoxin type A (BoNT/A) intoxication by catalyzing deubiquitination of Botulinum neurotoxin A light chain (LC), thereby preventing LC degradation by the proteasome, and accelerating botulinum neurotoxin intoxication in patients.
Binds VCP and the ternary complex containing STX5A, NSFL1C and VCP.
Deubiquitinating enzyme involved in DNA repair and reassembly of the Golgi apparatus and the endoplasmic reticulum following mitosis (PubMed:32649882). Necessary for VCP-mediated reassembly of Golgi stacks after mitosis (By similarity). Plays a role in VCP-mediated formation of transitional endoplasmic reticulum (tER) (By similarity). Mediates dissociation of the ternary complex containing STX5A, NSFL1C and VCP (By similarity). Also involved in DNA repair following phosphorylation by ATM or ATR: acts by catalyzing deubiquitination of SPRTN, thereby promoting SPRTN recruitment to chromatin and subsequent proteolytic cleavage of covalent DNA-protein cross-links (DPCs) (PubMed:32649882). Hydrolyzes 'Lys-11'- and 'Lys-48'-linked polyubiquitin chains (PubMed:23827681).
Phosphorylated at Ser-1207 by ATM or ATR following induction of covalent DNA-protein cross-links (DPCs).
A chromosomal aberration involving MRTFB is found in 3 chondroid lipomas. Translocation t(11;16)(q13;p13) with MRTFB produces a ZFTA-MRTFB fusion protein (PubMed:20607705).
A chromosomal aberration involving RELA is found in more than two-thirds of supratentorial ependymomas. Translocation with RELA produces a ZFTA-RELA fusion protein. ZFTA-RELA translocations are potent oncogenes that probably transform neural stem cells by driving an aberrant NF-kappa-B transcription program (PubMed:24553141).
Belongs to the sarcoglycan beta/delta/gamma/zeta family.
Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix. May play a role in the maintenance of striated muscle membrane stability (By similarity).
Acyltransferase that regulates cellular triglyceride (TG) content and glycerolipid composition via the monoglyceride pathway. Primarily acyl-CoA:monoacylglycerol acyltransferase (MGAT), but can also exhibit acyl-CoA:diacylglycerol acyltransferase (DGAT) activity. By regulating the synthesis of diglyceride precursors, it may affect the levels of glycerophospholipids such as phosphatidylcholine, phosphatidylinositol and phosphatidylethanolamine. Plays a role in lipogenesis by inducing the expression of some key regulators such as diglyceride acyltransferases (DGATs) and enzymes of de novo fatty acid synthesis.
Belongs to the diacylglycerol acyltransferase family. Highly divergent.
Adaptins are components of the adapter complexes which link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. Binding of AP180 to clathrin triskelia induces their assembly into 60-70 nm coats (By similarity).
Binds AP2A2. Interacts with AP2B1; clathrin competes with SNAP91 (By similarity).
Possesses a three domain structure: the N-terminal 300 residues harbor a clathrin binding site, an acidic middle domain 450 residues, interrupted by an Ala-rich segment, and the C-terminal domain (166 residues).
Thr-310 can be modified by the addition of N-acetylglucosamine which can be further phosphorylated. There is no evidence for direct Thr-310 phosphorylation (By similarity).
Activated by phosphorylation on Thr-221.
Binds to and is activated by YWHAZ when phosphorylated on Thr-221 (PubMed:16306228). Interacts with 14-3-3 proteins (PubMed:29211348). Interacts with HDAC4; this interaction leads to HDAC4 retention in the cytoplasm (By similarity). Interacts with DEPTOR, MLST8/GbetaL, RICTOR and RPTOR (PubMed:30232230).
Phosphorylated at Thr-221 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39 (PubMed:14976552). Phosphorylation at Thr-221 is inhibited in response to PTHLH/PTHrP (PubMed:30232230). Phosphorylated at Thr-469 and Ser-551 in response to cAMP signaling (Probable).
Positive regulator of mTOR signaling that functions by triggering the degradation of DEPTOR, an mTOR inhibitor. Involved in the dynamic regulation of mTOR signaling in chondrocyte differentiation during skeletogenesis (PubMed:30232230). Negatively regulates cAMP signaling pathway possibly by acting on CRTC2/TORC2 and CRTC3/TORC3 (Probable). Prevents HDAC4 translocation to the nucleus (By similarity).
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family. SerC subfamily.
Binds 1 pyridoxal phosphate per subunit.
Catalyzes the reversible conversion of 3-phosphohydroxypyruvate to phosphoserine and of 3-hydroxy-2-oxo-4-phosphonooxybutanoate to phosphohydroxythreonine.
Expressed at high levels in the brain, liver, kidney and pancreas, and very weakly expressed in the thymus, prostate, testis and colon.
Expressed in bone marrow (at protein level).
May be involved in early DNA damage response.
Plays a role in the regulation of neuronal activity.
AK6 and TAF9 were initially considered as products of the same gene since they share two exons. However, they are translated from different initiation codons and reading frames and encode unrelated proteins. This arrangement is conserved in some mammalian species.
Component of the TFIID basal transcription factor complex, composed of TATA-box-binding protein TBP, and a number of TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473). Component of the TATA-binding protein-free TAF complex (TFTC), the PCAF histone acetylase complex and the STAGA transcription coactivator-HAT complex (PubMed:11564863, PubMed:9885574). The PCAF complex consists at least of TADA2L/ADA2, SUPT3H/SPT3, TADA3L/ADA3, TAF5L/PAF65-beta, TAF6L/PAF65-alpha, TAF10/TAFII30, TAF12/TAFII20, TAF9/TAFII31 and TRRAP (PubMed:9885574, PubMed:9674425). The STAGA transcription coactivator-HAT complex consists at least of SUPT3H, GCN5L2, SUPT7L, TAF5L, TAF6L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9 (PubMed:11564863). Binds N-terminal domain of p53/TP53 which is essential for transcription (PubMed:7761466). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975). Binds TFIIB and the Herpes simplex virus activator VP16 (PubMed:7761466). Forms a heterodimer with TAF6 in a complex with the TAF4B-TAF12 heterodimer (PubMed:7597030, PubMed:15601843). Also interacts with TAF5 (PubMed:15899866). Binds directly DNA (PubMed:15601843). Increased DNA binding when complexed with TAF6 (PubMed:15601843).
The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription (PubMed:33795473). TFIID recognizes and binds promoters with or without a TATA box via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC) (PubMed:33795473). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473). TAF9 is also a component of the TBP-free TAFII complex (TFTC), the PCAF histone acetylase complex and the STAGA transcription coactivator-HAT complex (PubMed:15899866). TAF9 and its paralog TAF9B are involved in transcriptional activation as well as repression of distinct but overlapping sets of genes (PubMed:15899866). Essential for cell viability (PubMed:15899866). May have a role in gene regulation associated with apoptosis (PubMed:15899866).
Expressed in umbilical vein endothelial cells and platelets (at protein level). Expressed in heart, kidney, skeletal muscle, pancreas, ovary, breast, lung, brain cortex, hypothalamus, spinal cord, dorsal root ganglion, endothelial cells of umbilical cord artery and vein, megakaryocytes, osteoblasts, coronary muscle and erythroid cells. Weakly expressed in peripheral blood leukocytes and macrophages.
Interacts with SHC2 upon its aggregation-induced tyrosine phosphorylation.
Phosphorylated in the intracellular domain on tyrosine residues (By similarity). Phosphorylated on tyrosine residues by SRC. Tyrosine phosphorylation is detected upon platelet aggregation stimulated by collagen, TRAP and thrombin and platelet-platelet contacts but not after platelet activation. Tyrosine phosphorylation enhanced its association with SHC1 and SHC2.
When overexpressed, reduces the number of both early and late non-adherent myeloid progenitor cells.
Component of the DNA damage/stress response pathway that functions downstream of p53/TP53 and can either promote cell survival or apoptosis (PubMed:10973264, PubMed:15073321, PubMed:16360037, PubMed:17159900). Associated with CRADD and the CASP2 caspase, it forms the PIDDosome a complex that activates CASP2 and triggers apoptosis (PubMed:15073321, PubMed:17159900). Associated with IKBKG and RIPK1, it enhances sumoylation and ubiquitination of IKBKG which is important for activation of the transcription factor NF-kappa-B (PubMed:16360037, PubMed:17159900).
Forms a complex named the PIDDosome with CASP2 and CRADD (PubMed:15073321, PubMed:16652156, PubMed:17159900, PubMed:17289572, PubMed:33414379). Forms a complex with IKBKG and RIPK1 (PubMed:16360037). Interacts with FADD and MADD (PubMed:10825539).
The Death domain mediates the interaction with CRADD and the formation of a complex composed of 5 PIDD1 and 7 CRADD proteins which in turn recruit 7 CASP2 to form the PIDDosome.
The LRR repeat-containing domain has a regulatory activity, being autoinhibitory for the activation of NF-kappa-B.
Undergoes autoproteolytic processing whose extent either directs cells towards survival or apoptotic pathways (PubMed:17159900). Autoproteolytically cleaved into two main fragments PIDD-N and PIDD-C (PubMed:17159900). PIDD-C can be further processed into PIDD-CC, a processing which is enhanced by DNA damage (PubMed:17159900). The cleavage producing PIDD-C is required for translocation of PIDD1 to the nucleus upon DNA damage and activation of NF-kappa-B (PubMed:17159900). PIDD-CC mediates the interaction with CRADD and the cleavage producing PIDD-CC is required for the activation of CASP2 (PubMed:17159900). PIDD-N remains associated with PIDD-C and PIDD-CC after cleavage (PubMed:17159900).
Proton-sensing G-protein coupled receptor.
Expressed in submandibular and sublingual saliva but not in parotid saliva (at protein level). Expressed in saliva, tears, urine and seminal fluid.
Phosphorylated at both its N- and C-terminal regions.
This protein strongly inhibits papain and ficin, partially inhibits stem bromelain and bovine cathepsin C, but does not inhibit porcine cathepsin B or clostripain. Papain is inhibited non-competitively.
A CDS in the 3'-UTR of SPG7 mRNA had been erroneously identified as a cell matrix adhesion regulator and originally thought to be encoded by the CMAR gene. There is no experimental evidence for the production of endogenous CMAR protein.
ATP-dependent zinc metalloprotease. Plays a role in the formation and regulation of the mitochondrial permeability transition pore (mPTP) and its proteolytic activity is dispensable for this function (PubMed:26387735).
Defects in SPG7 may cause autosomal recessive osteogenesis imperfecta (OI). Osteogenesis imperfecta defines a group of connective tissue disorders characterized by bone fragility and low bone mass. Clinical features of SPG7-related osteogenesis imperfecta include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing and white sclera.
Forms heterooligomers with AFG3L1 and AFG3L2 (By similarity). Component of the mitochondrial permeability transition pore complex (mPTPC), at least composed of SPG7, VDAC1 and PPIF (PubMed:26387735). Interacts with AFG3L2; the interaction is required for the efficient assembly of mitochondrial complex I (PubMed:14623864, PubMed:26387735). Interacts with AFG3L1 (By similarity). Interacts with MAIP1 (PubMed:27499296). Interacts with VDAC1 and PPIF (PubMed:26387735).
In the C-terminal section; belongs to the peptidase M41 family.
In the N-terminal section; belongs to the AAA ATPase family.
Upon import into the mitochondrion, the N-terminal transit peptide is cleaved by the mitochondrial-processing peptidase (MPP) to generate an intermediate form which undergoes a second proteolytic cleavage mediated by proteases AFG3L1 and/or AFG3L2 removing an additional N-terminal fragment to generate the proteolytically active mature form.
Belongs to the class I-like SAM-binding methyltransferase superfamily. TPMT family.
Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (also called mercaptopurine, 6-MP or its brand name Purinethol) and 6-thioguanine (also called tioguanine or 6-TG) using S-adenosyl-L-methionine as the methyl donor (PubMed:657528, PubMed:18484748). TPMT activity modulates the cytotoxic effects of thiopurine prodrugs. A natural substrate for this enzyme has yet to be identified.
Inhibited by S-adenosyl-L-homocysteine (SAH).
Polymorphic variations define TPMT activity levels that are variable among ethnic groups. 90% of Caucasians have high TPMT activity, 10% have intermediate activity, and 1 in 300 individuals has low activity (PubMed:10208641). These differences influence the clinical use and therapeutic efficacy of thiopurine drugs, generally used as immunosuppressants or cytotoxic drugs in conditions including leukemia, autoimmune disease and organ transplantation. Intermediate or low TPMT activity is associated with thiopurine intolerance and patients are at risk of toxicity after receiving standard doses of thiopurine drugs [MIM:610460] (PubMed:10751626, PubMed:15819814, PubMed:16220112, PubMed:16476125, PubMed:16789994, PubMed:7862671, PubMed:8561894, PubMed:8644731, PubMed:9246020, PubMed:9336428, PubMed:9711875, PubMed:9931345, PubMed:9931346). The most prevalent TPMT alleles associated with TPMT deficiency are TPMT*2 and TPMT*3A. The proteins encoded by TPMT*2 and TPMT*3A mutant are degraded more rapidly by an ATP-dependent proteasome-mediated pathway (PubMed:9177237, PubMed:8644731).
TPMT*3A is the most common allele in the Caucasians and American Caucasians; it is the only mutant allele found in the South West Asians; it is not found in the Chinese. TPMT*3C is common in African-Americans and is the only allele in Chinese, Japanese and Taiwanese individuals. This allele is found at a low frequency in the Caucasians. This suggests that TPMT*3C is the oldest mutation, with TPMT*3B being acquired later to form the TPMT*3A allele in the Caucasian and South West Asian populations. TPMT*2 appears to be a more recent allele, which has only been detected in Caucasians to date.
Binds to extracellular matrix proteins. Binds to pathogen-associated molecular patterns (PAMPs) present on the cell walls of Gram-positive and Gram-negative bacteria and fungi, behaving as a pattern recognition receptor (PRR). Induces bacterial and fungal aggregation and subsequent inhibition of PAMP-induced cytokine release. Does not possess intrinsic bactericidal activity. May play a role in the innate defense and homeostasis of certain epithelial surfaces (By similarity).
Highly expressed in monocytes/macrophages and T-lymphocytes. Highly expressed in placenta and spleen, and also detected at lower levels in colon, and more weakly in lung, heart and kidney.
Belongs to the eukaryotic release factor 1 family.
Component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons (PubMed:7990965, PubMed:10676813, PubMed:16777602, PubMed:24486019, PubMed:26245381, PubMed:27863242, PubMed:36638793). The eRF1-eRF3-GTP complex binds to a stop codon in the ribosomal A-site (PubMed:26245381, PubMed:27863242, PubMed:36638793). ETF1/ERF1 is responsible for stop codon recognition and inducing hydrolysis of peptidyl-tRNA (PubMed:26245381, PubMed:27863242, PubMed:36638793). Following GTP hydrolysis, eRF3 (GSPT1/ERF3A or GSPT2/ERF3B) dissociates, permitting ETF1/eRF1 to accommodate fully in the A-site and mediate hydrolysis of peptidyl-tRNA (PubMed:10676813, PubMed:16777602, PubMed:26245381, PubMed:27863242). Component of the transient SURF complex which recruits UPF1 to stalled ribosomes in the context of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons (PubMed:19417104). Required for SHFL-mediated translation termination which inhibits programmed ribosomal frameshifting (-1PRF) of mRNA from viruses and cellular genes (PubMed:30682371).
Component of the eRF1-eRF3-GTP ternary complex, composed of ETF1/ERF1 and eRF3 (GSPT1/ERF3A or GSPT2/ERF3B) and GTP (PubMed:19417105, PubMed:27863242). Component of the transient SURF (SMG1-UPF1-eRF1-eRF3) complex (PubMed:19417104). Interacts with JMJD4 (PubMed:24486019). The ETF1-GSPT1 complex interacts with JMJD4 (PubMed:24486019).
Hydroxylation at Lys-63 by JMJD4 promotes its translational termination efficiency.
Ubiquitinated via 'Lys-6'-linked polyubiquitin chains by RNF14 and RNF25 in response to ribosome collisions (ribosome stalling), leading to its degradation by the proteasome and rescue of stalled ribosomes.
Belongs to the metallo-dependent hydrolases superfamily. HutI family.
Amidation of Leu-98 is essential for obestatin activity.
Ghrelin is the ligand for growth hormone secretagogue receptor type 1 (GHSR) (PubMed:10604470). Induces the release of growth hormone from the pituitary (PubMed:10604470). Has an appetite-stimulating effect, induces adiposity and stimulates gastric acid secretion. Involved in growth regulation.
Highest level in stomach. All forms are found in serum as well. Other tissues compensate for the loss of ghrelin synthesis in the stomach following gastrectomy.
May be the ligand for GPR39. May have an appetite-reducing effect resulting in decreased food intake. May reduce gastric emptying activity and jejunal motility (By similarity).
O-octanoylated by GOAT/MBOAT4 (PubMed:18443287). O-octanoylation or O-decanoylation is essential for ghrelin activity (PubMed:10604470). The O-decanoylated forms Ghrelin-27-C10 and Ghrelin-28-C10 differ in the length of the carbon backbone of the carboxylic acid bound to Ser-26 (PubMed:10604470). A small fraction of ghrelin, ghrelin-28-C10:1, may be modified with a singly unsaturated carboxylic acid (PubMed:10604470). Also O-acetylated and O-butyrylated on Ser-26 to minor levels (PubMed:18443287).
Belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family.
Component of the serine palmitoyltransferase (SPT) complex, which is composed of SPTLC1, SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. The heterodimer consisting of SPTLC1 and SPTLC2/SPTLC3 forms the catalytic core of the enzyme, while SPTSSA or SPTSSB subunits determine substrate specificity (PubMed:19416851). SPT also interacts with ORMDL proteins, especially ORMDL3, which negatively regulate SPT activity in the presence of ceramides (By similarity).
Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-chain bases (PubMed:19648650, PubMed:19416851). The SPT complex is composed of SPTLC1, SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this complex, the heterodimer consisting of SPTLC1 and SPTLC2/SPTLC3 forms the catalytic core. The composition of the serine palmitoyltransferase (SPT) complex determines the substrate preference (PubMed:19416851). The SPTLC1-SPTLC2-SPTSSA complex shows a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as substrates, with a slight preference for C14-CoA. The SPTLC1-SPTLC2-SPTSSB complex shows a strong preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB isozyme displays an ability to use a broader range of acyl-CoAs, without apparent preference (PubMed:19648650, PubMed:19416851).
Expressed in most tissues, except peripheral blood cells and bone marrow, with highest levels in heart, kidney, liver, uterus and skin.
SPT complex catalytic activity is negatively regulated by ORMDL proteins, including ORMDL3, in the presence of ceramides (By similarity). This mechanism allows to maintain ceramide levels at sufficient concentrations for the production of complex sphingolipids, but which prevents the accumulation of ceramides to levels that trigger apoptosis (Probable).
Directly interacts with actin-capping proteins CAPZA1, CAPZA2 and CAPZB; this interaction decreases the binding of capping proteins to actin.
Expressed in intestinal epithelial cells (at protein level).
In colorectal cancers, CRACD gene is observed to be often the target of inactivating mutations. In the absence of genetic mutations, expression levels tend to be down-regulated.
Involved in epithelial cell integrity by acting on the maintenance of the actin cytoskeleton. Positively regulates the actin polymerization, by inhibiting the interaction of actin-capping proteins with actin.
AcSDKP is inactivated by ACE, which removes the dipeptide Lys-Pro from its C-terminus.
By alpha interferons. Decreased levels in THP-1 cells after treatment with recombinant interferon-lambda.
Expressed in several hemopoietic cell lines and lymphoid malignant cells. Decreased levels in myeloma cells.
Identified in a complex composed of ACTA1, COBL, GSN AND TMSB4X (PubMed:23009842). Interacts with SERPINB1 (By similarity).
Plays an important role in the organization of the cytoskeleton (PubMed:1999398, PubMed:10848969). Binds to and sequesters actin monomers (G actin) and therefore inhibits actin polymerization (PubMed:1999398, PubMed:10848969).
Plays an important role in the organization of the cytoskeleton. Binds to and sequesters actin monomers (G actin) and therefore inhibits actin polymerization.
Potent inhibitor of bone marrow derived stem cell differentiation (PubMed:7694679). Acts by inhibits the entry of hematopoietic pluripotent stem cells into the S-phase (By similarity).
Acts as a E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins (PubMed:29507230). Triggers apoptosis in response to prolonged ER stress by mediating the polyubiquitination and subsequent proteasomal degradation of BCL2L1 (PubMed:29507230). May collaborate with FATE1 to restrain BIK protein levels thus regulating apoptotic signaling (PubMed:26567849).
Interacts with FATE1 (PubMed:26567849). Interacts with SEC16A (By similarity). Interacts with BCL2L1 (PubMed:29507230).
Up-regulated by ER stress in an ERN1-dependent manner.
Activated by phosphorylation by specific MAP kinase kinase kinases such as MAP3K1/MEKK1, MAP3K3/MEKK3, MAP3K11/MLK3 and MAP3K12/DLK.
Activated by phosphorylation on Ser-271 and Thr-275 by MAP kinase kinase kinases (MAP3Ks).
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K4/MKK4, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4/MKK4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The monophosphorylation of JNKs on the Thr residue is sufficient to increase JNK activity indicating that MAP2K7/MKK7 is important to trigger JNK activity, while the additional phosphorylation of the Tyr residue by MAP2K4/MKK4 ensures optimal JNK activation. Has a specific role in JNK signal transduction pathway activated by pro-inflammatory cytokines. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Part of a non-canonical MAPK signaling pathway, composed of the upstream MAP3K12 kinase and downstream MAP kinases MAPK1/ERK2 and MAPK3/ERK1, that enhances the AP-1-mediated transcription of APP in response to APOE (PubMed:28111074).
Interacts with isoform 1 of VRK2. Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3 (By similarity). Interacts (via its DVD domain) with MAP3Ks activators like MAP3K5/ASK1 and MAP3K1/MEKK1 (By similarity). Interacts with MAPK8IP1/JIP1, MAPK8IP2/JIP2 and MAPK8IP3/JIP3 scaffold proteins. Interacts with RASSF7, the interaction promotes phosphorylation. Found in a complex with SH3RF1, RAC1, MAP3K11/MLK3, MAPK8IP1/JIP1 and MAPK8/JNK1. Found in a complex with SH3RF1, RAC2, MAP3K7/TAK1, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (By similarity).
The D domain (residues 37-57) contains a conserved docking site and is required for the binding to MAPK substrates.
The DVD domain (residues 377-400) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation.
Ubiquitous; with highest level of expression in skeletal muscle. Isoform 3 is found at low levels in placenta, fetal liver, and skeletal muscle.
Interacts with RABIF (PubMed:21194374). Interacts with OPTN (By similarity). Interacts with LRRK2; interaction facilitates phosphorylation of Ser-106 (PubMed:26824392). Interacts with GDI1, GDI2, CHM and CHML; these interactions are disrupted by phosphorylation on Ser-106 (PubMed:26824392, PubMed:29125462). Interacts with RILPL1 and RILPL2; these interactions are dependent on phosphorylation of Ser-106 (PubMed:26824392, PubMed:29125462).
Phosphorylation of Ser-106 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM, CHML and RAB GDP dissociation inhibitors GDI1 and GDI2.
Rab activation is generally mediated by a guanine exchange factor (GEF), while inactivation through hydrolysis of bound GTP is catalyzed by a GTPase activating protein (GAP) (By similarity). That Rab is activated by DENND3, a guanine exchange factor.
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. That Rab may play a role in protein transport from recycling endosomes to lysosomes regulating, for instance, the degradation of the transferrin receptor. Involved in autophagy (By similarity).
Expressed almost exclusively in testis. Also expressed in several cancers.
Interacts with NXT1, NXT2, E1B-AP5, the REF proteins and with nucleoporins, Nup62, Nup153 and Nup214. Interacts with LUZP4.
Involved in the export of mRNA from the nucleus to the cytoplasm.
The C-terminal fragment, containing the TAP domain (also called UBA-like domain) and part of the NTF2-like domain, named the NPC-binding domain, mediates direct interactions with nucleoporin-FG-repeats and is necessary and sufficient for localization of NXF2 to the nuclear rim.
The NTF2 domain heterodimerizes with NXT1 and NXT2. The formation of NXF1/NXT1 heterodimers is required for NXF2-mediated nuclear mRNA export.
The RNA-binding domain is a non-canonical RNP-type domain.
The leucine-rich repeats and the NTF2-domain are essential for the export of mRNA from the nucleus.
The sequence differs from that shown due to either intron retention or a splicing event.
Forms heterodimers with NEFL; which can further hetero-oligomerize (in vitro) (By similarity). Forms heterodimers with INA (in vitro) (By similarity).
Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber. NEFH has an important function in mature axons that is not subserved by the two smaller NF proteins. May additionally cooperate with the neuronal intermediate filament proteins PRPH and INA to form neuronal filamentous networks (By similarity).
Phosphorylated in the head and rod regions by the PKC kinase PKN1, leading to the inhibition of polymerization.
Phosphorylation seems to play a major role in the functioning of the larger neurofilament polypeptides (NF-M and NF-H), the levels of phosphorylation being altered developmentally and coincidentally with a change in the neurofilament function.
The number of repeats is shown to vary between 29 and 30.
There are a number of repeats of the tripeptide K-S-P, NFH is phosphorylated on a number of the serines in this motif. It is thought that phosphorylation of NFH results in the formation of interfilament cross bridges that are important in the maintenance of axonal caliber.
Interacts with VPS33B (PubMed:19109425, PubMed:23901104, PubMed:28017832). Associates with the homotypic fusion and vacuole protein sorting (HOPS) complex; impaired by VPS33B (PubMed:19109425, PubMed:23918659, PubMed:22753090). A possible interaction with VPS33A is reported conflictingly (PubMed:19109425, PubMed:23901104). Interacts with RAB11A (PubMed:20190753).
Proposed to be involved in endosomal maturation implicating in part VPS33B. In epithelial cells, the VPS33B:VIPAS39 complex may play a role in the apical RAB11A-dependent recycling pathway and in the maintenance of the apical-basolateral polarity (PubMed:20190753). May play a role in lysosomal trafficking, probably via association with the core HOPS complex in a discrete population of endosomes; the functions seems to be independent of VPS33B (PubMed:19109425). May play a role in vesicular trafficking during spermatogenesis (By similarity). May be involved in direct or indirect transcriptional regulation of E-cadherin (By similarity).
The disease is caused by variants affecting the gene represented in this entry. In liver, CEACAM5 and ABCB11 are mislocalized and E-cadherin expression is decreased.
Belongs to the G-protein coupled receptor 1 family. Endothelin receptor subfamily. EDNRA sub-subfamily.
Isoform 1, isoform 3 and isoform 4 are expressed in a variety of tissues, with highest levels in the aorta and cerebellum, followed by lung, atrium and cerebral cortex, lower levels in the placenta, kidney, adrenal gland, duodenum, colon, ventricle and liver but no expression in umbilical vein endothelial cells. Within the placenta, isoform 1, isoform 2, isoform 3 and isoform 4 are expressed in the villi and stem villi vessels.
Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of binding affinities for ET-A is: ET1 > ET2 >> ET3.
Belongs to the STXBP/unc-18/SEC1 family.
Interacts with STX17. Interacts with STX5A. Interacts with the COG complex via COG4 (By similarity).
Plays a role in SNARE-pin assembly and Golgi-to-ER retrograde transport via its interaction with COG4. Involved in vesicular transport between the endoplasmic reticulum and the Golgi (By similarity).
Expressed in perivascular macrophages. Expressed in plaques-surrounding reactive astrocytes and in perivascular astrocytes associated with cerebral amyloid angiopathy (CAA) in the temporal cortex of Alzheimer patient (at protein level). Strongly expressed in placenta. Moderately expressed in heart, skeletal muscle, small intestine and lung. Weakly expressed in brain, colon, thymus and kidney. Expressed in nurse-like cells. Expressed in reactive astrocytes and vascular/perivascular cells in the brain of Alzheimer patient.
Scavenger receptor that displays several functions associated with host defense. Promotes binding and phagocytosis of Gram-positive, Gram-negative bacteria and yeast. Mediates the recognition, internalization and degradation of oxidatively modified low density lipoprotein (oxLDL) by vascular endothelial cells. Binds to several carbohydrates including Gal-type ligands, D-galactose, L- and D-fucose, GalNAc, T and Tn antigens in a calcium-dependent manner and internalizes specifically GalNAc in nurse-like cells. Binds also to sialyl Lewis X or a trisaccharide and asialo-orosomucoid (ASOR). May also play a role in the clearance of amyloid-beta in Alzheimer disease.
The extracellular domain forms a stable trimer. The extracellular domain interacts with fibrillar amyloid-beta peptide.
Acts as a critical modulator of FOXO3-induced autophagy via increased cellular ROS.
By progesterone, testosterone and, to a much lower extent, estrogen. Induced by oxidative stress via FOXO3 activation (PubMed:28545464). Up-regulated by hypoxia (at protein level).
Expressed in various tissues, including pancreas, placenta, ovary, testis and kidney.
High levels in first trimester deciduas. Higher levels in the endometria during secretory phase than the proliferative phase, especially after the mid-secretory phase.
Activated following N-terminal proteolytic cleavage by thrombin and/or proteases.
Highly expressed in brain and small intestine, and moderately expressed in colon, heart, prostate, and testis. Very low levels were detected in kidney, liver, ovary, placenta, spleen, and thymus.
Belongs to the protein kinase superfamily. Tyr protein kinase family. ABL subfamily.
Contains two distinct classes of F-actin-binding domains. Although both can bind F-actin, the 2 are required to bundle actin filaments (By similarity).
Interacts with PSMA7. Interacts with CTTN. Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases.
Non-receptor tyrosine-protein kinase that plays an ABL1-overlapping role in key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion and receptor endocytosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like MYH10 (involved in movement); CTTN (involved in signaling); or TUBA1 and TUBB (microtubule subunits). Binds directly F-actin and regulates actin cytoskeletal structure through its F-actin-bundling activity. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as CRK, CRKL, DOK1 or ARHGAP35. Adhesion-dependent phosphorylation of ARHGAP35 promotes its association with RASA1, resulting in recruitment of ARHGAP35 to the cell periphery where it inhibits RHO. Phosphorylates multiple receptor tyrosine kinases like PDGFRB and other substrates which are involved in endocytosis regulation such as RIN1. In brain, may regulate neurotransmission by phosphorylating proteins at the synapse. ABL2 acts also as a regulator of multiple pathological signaling cascades during infection. Pathogens can highjack ABL2 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. Positively regulates chemokine-mediated T-cell migration, polarization, and homing to lymph nodes and immune-challenged tissues, potentially via activation of NEDD9/HEF1 and RAP1 (By similarity).
Phosphorylated at Tyr-261 by ABL1 in response to oxidative stress. Phosphorylated by PDGFRB (By similarity).
Polyubiquitinated. Polyubiquitination of ABL2 leads to degradation.
Stabilized in the inactive form by an association between the SH3 domain and the SH2-TK linker region, interactions of the N-terminal cap, and contributions from an N-terminal myristoyl group and phospholipids. Activated by autophosphorylation as well as by SRC-family kinase-mediated phosphorylation. Activated by RIN1 binding to the SH2 and SH3 domains. Inhibited by imatinib mesylate (Gleevec) which is used for the treatment of chronic myeloid leukemia (CML). Phosphatidylinositol 4,5-bisphosphate (PIP2), a highly abundant phosphoinositide known to regulate cytoskeletal and membrane proteins, inhibits the tyrosine kinase activity (By similarity).
Belongs to the EGR C2H2-type zinc-finger protein family.
It is uncertain whether Met-1 or Met-104 is the initiator. Some orthologous sequences cannot be extended.
Transcriptional regulator. Recognizes and binds to the DNA sequence 5'-GCGGGGGCG-3' (GSG). Activates the transcription of target genes whose products are required for mitogenesis and differentiation (By similarity).
Expressed exclusively in testis. Expressed in ejaculated spermatozoa of germ cell. Expressed in the nuclei of spermatogonia, spermatocytes, and round spermatids, except elongated spermatids (at protein level).
Interacts with MAP1S. Interacts with UBE3A (via HECT domain).
Esterifies acyl-group from acyl-ACP to the sn-1 position of glycerol-3-phosphate, an essential step in glycerolipids biosynthesis such as triglycerides, phosphatidic acids and lysophosphatidic acids.
Could be a T-cell-specific adapter protein involved in the control of T-cell activation. May play a role in the CD4-p56-LCK-dependent signal transduction pathway. Could also play an important role in normal and pathological angiogenesis. Could be an adapter protein that facilitates and regulates interaction of KDR with effector proteins important to endothelial cell survival and proliferation.
Expression limited to tissues of the immune system and, in particular, activated T-cells. Expressed in peripheral blood leukocytes, thymus and spleen. Much lower expression or undetectable, in brain, placenta, skeletal muscle, prostate, testis, ovary, small intestine, and colon. Expressed at low levels in unstimulated T-cells, but not expressed in normal resting or activated B-cells. According to PubMed:10692392, expression is not restricted to activated T-cells, but strongly expressed in blood cell lineages, the endothelium and other cell and tissue types, such as heart, lung, and liver.
Interacts with KDR. Interacts with TXK and ITK (By similarity).
Rapidly induced after activation of T-cells. However, the gene continues to be expressed in long-term cultures of activated T-cells.
Activates E box-dependent transcription in collaboration with TCF3/E47. May be a trans-acting factor involved in the development and maintenance of the mammalian nervous system. Transactivates the promoter of its own gene (By similarity).
(Microbial infection) Acts as a receptor for Coxsackievirus A21, coxsackieviruses B1, B3 and B5.
(Microbial infection) Acts as a receptor for Human echoviruses 6, 7, 11, 12, 20 and 21.
(Microbial infection) Acts as a receptor for Human enterovirus 70 and D68 (Probable).
(Microbial infection) Interacts with coxsackievirus A21, coxsackieviruses B1, B3 and B5 capsid proteins.
(Microbial infection) Interacts with human echoviruses 6, 7, 11, 12, 20 and 21 capsid proteins.
(Microbial infection) Interacts with human enterovirus 70 and D68 capsid proteins (Probable).
Expressed on the plasma membranes of all cell types that are in intimate contact with plasma complement proteins. It is also found on the surfaces of epithelial cells lining extracellular compartments, and variants of the molecule are present in body fluids and in extracellular matrix.
Includes partial sequence of the intron 7.
Monomer (major form) and non-disulfide-linked, covalent homodimer (minor form). Interacts with ADGRE5 (PubMed:11297558).
Responsible for the Cromer blood group system (CROM) [MIM:613793]. It consists of at least 8 high-incidence (Cr(a), Tc(a), Dr(a), Es(a), WES(b), UMC, IFC and GUTI) and three low-incidence (Tc(b), Tc(c) and WES(a)) antigens that reside on DAF. In the Cromer phenotypes Dr(a-) and Inab there is reduced or absent expression of DAF, respectively. In the case of the Dr(a-) phenotype, a single nucleotide substitution within exon 5 accounts for two changes: a simple amino acid substitution, Leu-199 that is the basis of the antigenic variation, and an alternative splicing event that underlies the decreased expression of DAF in this phenotype. The Inab phenotype is a very rare one in which the red blood cells lack all Cromer system antigens. The red blood cells of individuals with Inab phenotype have a deficiency of DAF, but these individuals are not known to have any associated hematologic or other abnormalities (PubMed:12675719).
The Ser/Thr-rich domain is heavily O-glycosylated.
The disease is caused by variants affecting the gene represented in this entry. CHAPLE is caused by biallelic mutations in the CD55 gene.
The first Sushi domain (SCR1) is not necessary for function. SCR2 and SCR4 provide the proper conformation for the active site on SCR3 (By similarity).
This protein recognizes C4b and C3b fragments that condense with cell-surface hydroxyl or amino groups when nascent C4b and C3b are locally generated during C4 and c3 activation. Interaction of daf with cell-associated C4b and C3b polypeptides interferes with their ability to catalyze the conversion of C2 and factor B to enzymatically active C2a and Bb and thereby prevents the formation of C4b2a and C3bBb, the amplification convertases of the complement cascade (PubMed:7525274). Inhibits complement activation by destabilizing and preventing the formation of C3 and C5 convertases, which prevents complement damage (PubMed:28657829).
Activation of PRKCA induces phosphorylation of TRPC1 and subsequent Ca2+ entry into cells.
Belongs to the transient receptor (TC 1.A.4) family. STrpC subfamily. TRPC1 sub-subfamily.
Interacts with TRPC4AP (By similarity). Homotetramer and heterotetramer with TRPC4 and/or TRPC5 (PubMed:12032305). Interacts with TRPC4 and TRPC5 (By similarity). Interacts with ITPR3 (PubMed:10766822). Interacts with MX1 and RNF24 (PubMed:15757897, PubMed:17850865). Interacts with FKBP4 (PubMed:19945390). Interacts with PLSCR1 (By similarity).
Thought to form a receptor-activated non-selective calcium permeant cation channel. Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Seems to be also activated by intracellular calcium store depletion.
This is a receptor for the tachykinin neuropeptide substance K (neurokinin A). It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: substance K > neuromedin-K > substance P.
Expressed in all tissues, but most abundantly in heart, placenta, kidney, and liver.
Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. When expressed in rat HTC4 hepatoma cells, is capable of mediating S1P-induced cell proliferation and suppression of apoptosis.
Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including cartilage and bone formation or neurogenesis (PubMed:11580864, PubMed:29321139). Initiates the canonical BMP signaling cascade by associating with type I receptor BMPR1A and type II receptor BMPR2 (PubMed:11580864). In turn, BMPR1A propagates signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act as activators and repressors of transcription of target genes (PubMed:29321139, PubMed:11580864). Can also signal through non-canonical pathway such as MAPK p38 signaling cascade to promote chondrogenic differentiation (PubMed:20402566). Promotes the expression of HAMP, this is repressed by its interaction with ERFE (PubMed:30097509).
Interacts with ERFE; the interaction inhibits BMP-induced transcription of HAMP.
Expressed in placenta, testis and pituitary.
Expressed in heart, brain, liver, skeletal muscle, kidney and pancreas (PubMed:30312582). In brain, expressed by glia, pyramidal neurons and astrocytes (at protein level) (PubMed:30312582). Highly expressed in placental trophoblasts (PubMed:30312582).
Involved in the regulation of the cytoskeletal dynamics, plays a role in actin stress fiber formation.
Interacts with CTNNB1 (PubMed:11590244). Interacts with PKP2 (PubMed:17535849).
May be involved in formation of stretch-resistant cell-cell adhesion complexes.
Predominantly expressed in heart and testis. Expressed at lower levels in brain, kidney, liver and skeletal muscle.
Dubious isoform. Probable cloning artifact.
Highly expressed in kidney, moderately in placenta, lung, prostate, liver, and digestive system. In the kidney, localized in the proximal tubules but not in the glomerulus or distal tubules. Detected in most of the male urogenital tract epithelia, with the exception of epididymis.
Interacts with MET; oligomerization increases affinity for MET.
May regulate MET signaling cascade. Seems to decrease hepatocyte growth factor (HGF)-induced transient MAPK activation. Blocks GRB2 recruitment to MET thus suppressing the GRB2-RAS pathway. Inhibits HGF-induced proliferation of MMP1 and MMP9 expression.
The region encoding the tandem repeats is highly polymorphic. Divergence of the number of tandem repeats was seen in different cDNA libraries.
Interacts with Protein phosphatase 1 (PP1).
Isoform 4 is predominantly expressed in leukocytes and spleen.
May target protein phosphatase 1 to F-actin cytoskeleton.
Centriole-enriched microtubule-binding protein involved in centriole biogenesis (PubMed:20844083, PubMed:25131205, PubMed:27185865). Essential for the generation of the distal portion of new-born centrioles in a CENPJ- and CEP120-mediated elongation dependent manner during the cell cycle S/G2 phase after formation of the initiating cartwheel structure (PubMed:27185865). Required for the recruitment of centriolar proteins, such as POC1B, POC5 and CEP135, into the distal portion of centrioles (PubMed:27185865). Also required for centriole-to-centrosome conversion during mitotic progression, but is dispensable for cartwheel removal or centriole disengagement (PubMed:25131205). Binds to and stabilizes centriolar microtubule (PubMed:27185865).
Interacts (via ALMS motif) with microtubules; this interaction is direct.
The N-terminal and the ALMS motif-containing C-terminal regions are essential for CEP295-mediated centriole elongation.
ADP-ribosylhydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1'' position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine and threonine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose (PubMed:21498885, PubMed:30830864, PubMed:33769608, PubMed:30045870, PubMed:29907568, PubMed:34321462, PubMed:30401461, PubMed:33186521, PubMed:34019811, PubMed:33894202, PubMed:34479984, PubMed:34625544). Specifically acts as a serine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to serine residues on proteins, thereby playing a key role in DNA damage response (PubMed:28650317, PubMed:29234005, PubMed:33186521, PubMed:34625544, PubMed:30045870, PubMed:34019811). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802, PubMed:33186521, PubMed:34625544). Does not hydrolyze ADP-ribosyl-arginine, -cysteine, -diphthamide, or -asparagine bonds (PubMed:16278211, PubMed:33769608). Also able to degrade protein free poly(ADP-ribose), which is synthesized in response to DNA damage: free poly(ADP-ribose) acts as a potent cell death signal and its degradation by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a process named parthanatos (PubMed:16278211). Also hydrolyzes free poly(ADP-ribose) in mitochondria (PubMed:22433848). Specifically digests O-acetyl-ADP-D-ribose, a product of deacetylation reactions catalyzed by sirtuins (PubMed:17075046, PubMed:21498885). Specifically degrades 1''-O-acetyl-ADP-D-ribose isomer, rather than 2''-O-acetyl-ADP-D-ribose or 3''-O-acetyl-ADP-D-ribose isomers (PubMed:21498885).
The protein undergoes a dramatic conformational switch from closed to open states upon substrate-binding, which enables specific substrate recognition for the 1''-O-linkage (PubMed:29907568, PubMed:34321462). The glutamate flap (Glu-41) blocks substrate entrance to Mg(2+) in the unliganded closed state (PubMed:30045870, PubMed:29907568, PubMed:34321462). In presence of substrate, Glu-41 is ejected from the active site: this closed-to-open transition significantly widens the substrate-binding channel and precisely positions the scissile 1''-O-linkage for cleavage while securing tightly 2'- and 3'-hydroxyls of ADP-ribose (PubMed:30045870, PubMed:29907568, PubMed:34321462).
Ubiquitous (PubMed:16278211). Expressed in skin fibroblasts (PubMed:30830864).
Belongs to the mitochondrion-specific ribosomal protein mL54 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:25838379, PubMed:28892042). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins.
Detected in intestine and pancreas. Lower expression is also detected in liver and kidney.
(Microbial infection) Interacts with Herpes simplex virus ICP22.
Cell-cycle regulated: levels are highest early in S phase; not detectable in G2.
Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the N-terminus of INO80 (PubMed:16230350, PubMed:18922472, PubMed:21303910). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975). Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1 (PubMed:20018852). Interacts with NOP2 (PubMed:9654073). Interacts with PINX1 (PubMed:15044100). Interacts with TERT (PubMed:15044100). Interacts with CCDC85B (PubMed:17014843). Interacts with DAXX (PubMed:11948183). Interacts (via N-terminus) with FMR1 (via phosphorylated form) (PubMed:16571602). Interacts with FXR1 and FXR2 (PubMed:16571602).
Detected in testis, and at lower levels in spleen, thymus, prostate, uterus, small intestine, colon and leukocytes.
Modulates the transcription repressor activity of DAXX by recruiting it to the nucleolus (PubMed:11948183). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852). Putative regulatory component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair. May also be an inhibitor of TERT telomerase activity (PubMed:15044100). Binds to G-quadruplex structures in mRNA (PubMed:16571602). Binds to RNA homomer poly(G) and poly(U) (PubMed:16571602).
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL17) composed of CUL1, SKP1, RBX1 and FBXL17 (PubMed:24035498). Interacts with BTB domain-containing proteins such as KLHL12, BCL6 and BACH1; specifically recognizes and binds a conserved degron of non-consecutive residues present at the interface of BTB dimers of aberrant composition (PubMed:30190310). Interacts with SUFU (PubMed:27234298). Interacts with PRMT1 (By similarity).
Substrate-recognition component of the SCF(FBXL17) E3 ubiquitin ligase complex, a key component of a quality control pathway required to ensure functional dimerization of BTB domain-containing proteins (dimerization quality control, DQC) (PubMed:30190310). FBXL17 specifically recognizes and binds a conserved degron of non-consecutive residues present at the interface of BTB dimers of aberrant composition: aberrant BTB dimer are then ubiquitinated by the SCF(FBXL17) complex and degraded by the proteasome (PubMed:30190310). The ability of the SCF(FBXL17) complex to eliminate compromised BTB dimers is required for the differentiation and survival of neural crest and neuronal cells (By similarity). The SCF(FBXL17) complex mediates ubiquitination and degradation of BACH1 (PubMed:24035498, PubMed:30190310). The SCF(FBXL17) complex is also involved in the regulation of the hedgehog/smoothened (Hh) signaling pathway by mediating the ubiquitination and degradation of SUFU, allowing the release of GLI1 from SUFU for proper Hh signal transduction (PubMed:27234298). The SCF(FBXL17) complex mediates ubiquitination and degradation of PRMT1 (By similarity).
Detected in adult brain cortex and fetal frontal lobe (at protein level). Highly expressed in brain cortex, putamen, amygdala, hippocampus and cerebellum.
Expressed in the developing cerebral neocortex and glanglionic eminence in 57 days post-fertilization fetal brain.
Homodimer. Interacts with AP2M1; required for clathrin-mediated endocytosis.
Involved in neuronal migration during development of the cerebral neocortex. May function in a cell autonomous and a non-cell autonomous manner and play a role in appropriate adhesion between migrating neurons and radial glial fibers. May also regulate growth and differentiation of dendrites.
Shedding of the extracellular domain and intramembrane cleavage produce several proteolytic products. The intramembrane cleavage releases a soluble cytoplasmic polypeptide that translocates to the nucleolus.
Transfers the sialyl group (N-acetyl-alpha-neuraminyl or NeuAc) from CMP-NeuAc to the GalNAc residue on the NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc sequence of glycoproteins and glycolipids forming an alpha-2,6-linkage. Produces branched type disialyl structures by transfer of a sialyl group onto a GalNAc residue inside the backbone core chains. Prefers O-glycans to glycoproteins or glycolipids.
Interacts with NAPA and SNAP23. Identified in a complex containing STX6, STX12, VAMP4 and VTI1A (By similarity). Associates with the BLOC-1 complex (PubMed:19546860). Interacts with BLOC1S6 (PubMed:19546860). Interacts with GRIPAP1 (By similarity). Forms a complex with GRIP1, GRIA2 and NSG1; controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting. Interacts with NSG1 (By similarity). Interacts with TPC1 (By similarity). Interacts (via N-terminus) with VPS13B (By similarity).
SNARE promoting fusion of transport vesicles with target membranes. Together with SNARE STX6, promotes movement of vesicles from endosomes to the cell membrane, and may therefore function in the endocytic recycling pathway. Through complex formation with GRIP1, GRIA2 and NSG1 controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting.
Homotetramer, and heterotetramer with other DPYS-like proteins. Interacts with DPYSL2, DPYSL3 and DPYSL4 (By similarity). Interacts with MAP2 and TUBB3 (PubMed:33894126).
Involved in the negative regulation of dendrite outgrowth.
Lacks most of the conserved residues that are essential for binding the metal cofactor and hence for dihydropyrimidinase activity. Its enzyme activity is therefore unsure.
(Microbial infection) Interacts with HTLV-1 protein Tax; this interaction enhances tax transcriptional activity.
Binding, as a tetramer, through its N-terminal region, with the bZIP domain of CREB1 enhances recruitment of TAF4 to the promoter (PubMed:14506290). 'Arg-314' in the bZIP domain of CREB1 is essential for this interaction (PubMed:14506290). Interacts (when phosphorylated at Ser-162 and Se-273) with 14-3-3 proteins (PubMed:30611118). Interacts with YWHAE (PubMed:30611118). Interacts (when phosphorylated at Ser-391) with phosphatase PP2A catalytic subunit PPP2CA and regulatory subunits PPP2R1A and PPP2R2A (PubMed:30611118). Interacts, via the N-terminal with the ankyrin repeats of BCL3, to form a complex with CREB1 on CRE and TxRE responsive elements and represses HTLV-1 LTR-mediated transcription (PubMed:17644518).
Phosphorylation/dephosphorylation states of Ser-273 are required for regulating transduction of CREB activity (By similarity). CRTCs/TORCs are inactive when phosphorylated, and active when dephosphorylated at this site (By similarity). May be phosphorylated at Ser-391 by MAPK3/ERK1 and/or MAPK1/ERK2 or by some cyclin-dependent kinases such as CDK1,CDK2 or CDK5 (PubMed:30611118). Following adenylyl cyclase activation, dephosphorylated at Ser-162 and Ser-273 resulting in its dissociation from 14-3-3 proteins probably promoting CRTC3 translocation into the nucleus (PubMed:30611118).
Predominantly expressed in B and T lymphocytes. Highest levels in lung. Also expressed in brain, colon, heart, kidney, ovary, and prostate. Weak expression in liver, pancreas, muscle, small intestine, spleen and stomach.
Transcriptional coactivator for CREB1 which activates transcription through both consensus and variant cAMP response element (CRE) sites. Acts as a coactivator, in the SIK/TORC signaling pathway, being active when dephosphorylated and acts independently of CREB1 'Ser-133' phosphorylation. Enhances the interaction of CREB1 with TAF4. Regulates the expression of specific CREB-activated genes such as the steroidogenic gene, StAR. Potent coactivator of PPARGC1A and inducer of mitochondrial biogenesis in muscle cells. Also coactivator for TAX activation of the human T-cell leukemia virus type 1 (HTLV-1) long terminal repeats (LTR).
Dual specificity phosphatase; can dephosphorylate both phosphotyrosine and phosphoserine or phosphothreonine residues. Can dephosphorylate glucokinase (in vitro) (By similarity). Has phosphatase activity with the synthetic substrate 6,8-difluoro-4-methylumbelliferyl phosphate and other in vitro substrates (PubMed:10446167, PubMed:24531476).
Ubiquitous, highest expression in spleen, testis, ovary, and peripheral blood leukocytes and lower expression in liver and lung.
Protein phosphatase 6 (PP6) holoenzyme is proposed to be a heterotrimeric complex formed by the catalytic subunit, a SAPS domain-containing subunit (PP6R) and an ankyrin repeat-domain containing regulatory subunit (ARS). Interacts with PPP6C and NFKBIE. Interacts with ANKRD28.
Regulatory subunit of protein phosphatase 6 (PP6). May function as a scaffolding PP6 subunit. Involved in the PP6-mediated dephosphorylation of NFKBIE opposing its degradation in response to TNF-alpha.
Ubiquitously expressed with strongest expression in the testis followed by liver, heart, kidney, brain and placenta.
Belongs to the cyclic nucleotide phosphodiesterase family. PDE3 subfamily.
Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological process (PubMed:14592490, PubMed:21393242). Regulates angiogenesis by inhibiting the cAMP-dependent guanine nucleotide exchange factor RAPGEF3 and downstream phosphatidylinositol 3-kinase gamma-mediated signaling (PubMed:21393242). Controls cardiac contractility by reducing cAMP concentration in cardiocytes (By similarity).
Homodimer (PubMed:15147193). Interacts with PIK3CG; regulates PDE3B activity and thereby cAMP levels in cells (By similarity). Interacts with RAPGEF3 and PIK3R6; form a signaling complex that regulates phosphatidylinositol 3-kinase gamma in angiogenesis (PubMed:21393242). Interacts with ABHD15; this interaction regulates PDE3B's stability and expression and, thereby, impacts the antilipolytic action of insulin (By similarity).
Phosphorylation at Ser-295 mediates insulin-induced activation of PDE3B.
As part of the BORC complex may play a role in lysosomes movement and localization at the cell periphery. Associated with the cytosolic face of lysosomes, the BORC complex may recruit ARL8B and couple lysosomes to microtubule plus-end-directed kinesin motor (PubMed:25898167). May be involved in the biogenesis of lysosome-related organelles such as melanosomes (By similarity).
Component of the BLOC-one-related complex (BORC) which is composed of BLOC1S1, BLOC1S2, BORCS5, BORCS6, BORCS7, BORCS8, KXD1 and SNAPIN (PubMed:25898167). Associates with the BLOC-1 complex. Interacts with BLOC1S1. Interacts with DTNBP1/BLOC1S7 (via coiled-coil domain) (By similarity).
Highest levels of expression are detected in muscle and adipose tissue small, intermediate levels in small intestine, and barely detectable in liver (PubMed:10873384, PubMed:21395585). Expressed in brain gray matter (PubMed:21395585).
Mediates the import of long-chain fatty acids (LCFA) into the cell by facilitating their transport at the plasma membrane (PubMed:12556534, PubMed:20530735, PubMed:21395585, PubMed:28178239). Also functions as an acyl-CoA ligase catalyzing the ATP-dependent formation of fatty acyl-CoA using LCFA and very-long-chain fatty acids (VLCFA) as substrates, which prevents fatty acid efflux from cells and might drive more fatty acid uptake. May act directly as a bona fide transporter, or alternatively, in a cytoplasmic or membrane-associated multimeric protein complex to trap and draw fatty acids towards accumulation. Plays a pivotal role in regulating available LCFA substrates from exogenous sources in tissues undergoing high levels of beta-oxidation or triglyceride synthesis. May be involved in regulation of cholesterol metabolism (By similarity). Probably involved in fatty acid transport across the blood barrier (PubMed:21395585).
Self-associates. May function as a homodimer (By similarity). Interacts with EPRS1; mediates the translocation of SLC27A1 from the cytoplasm to the plasma membrane thereby increasing the uptake of long-chain fatty acids (PubMed:28178239). Interacts with DGAT2 and this interaction is enhanced in the presence of ZFYVE1 (PubMed:28178239).
Plays a role in promoting axonal degeneration following neuronal injury by toxic insult or trauma.
Down-regulated in multiple cancers including colorectal, breast, ovary, uterus, stomach, lung, or kidney cancers.
Homodimer and homooligomer. Interacts with the cytoplasmic part of DCC. Interacts with MAGED1. Interacts with PRKCABP, possibly mediating some interaction with PKC (By similarity). Interacts (via extracellular domain) with FLRT2 (via extracellular domain) (PubMed:25374360). Interacts (via extracellular domain) with FLRT3 (via extracellular domain) (By similarity).
Phosphorylated on cytoplasmic tyrosine residues (By similarity). Phosphorylated by PKC in vitro (By similarity).
Proteolytically cleaved by caspases during apoptosis. The cleavage does not take place when the receptor is associated with netrin ligand. Its cleavage by caspases is required to induce apoptosis.
Receptor for netrin required for axon guidance. Functions in the netrin signaling pathway and promotes neurite outgrowth in response to NTN1. Mediates axon repulsion of neuronal growth cones in the developing nervous system in response to netrin. Axon repulsion in growth cones may be mediated by its association with DCC that may trigger signaling for repulsion. It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand.
Receptor for netrin required for axon guidance. Mediates axon repulsion of neuronal growth cones in the developing nervous system upon ligand binding.
The ZU5 domain mediates the interaction with MAGED1, which participates in the induction of apoptosis.
Highest expression in thymus, kidney and placenta. Also detected in colon, small intestine and lung. Tends to be down-regulated in 30-60% of tumors derived from breast, colon, kidney liver, rectum, pancreas, stomach and the thyroid gland compared to the normal counterpart.
Interacts with MOAP1 (By similarity). Interaction with activated KRAS is still a matter of debate: interaction has been shown in the mouse (PubMed:17404571), but not in human (PubMed:17367779). Lack of interaction with MRAS, NRAS nor RRAS2 has also been reported (PubMed:17367779).
Involved in the induction of apoptosis, through both caspase-dependent and caspase-independent pathways. May act as a Ras effector protein. May suppress the serum-induced basal levels of NF-kappa-B (By similarity).
Highly expressed in testis. Also expressed in breast carcinoma cell lines.
Transcriptional repressor that binds to elements found predominantly in genes that participate in lipid metabolism. Among its targets are structural components of lipoprotein particles (apolipoproteins AIV, CIII, and E), enzymes involved in lipid processing (lipoprotein lipase, lecithin cholesteryl ester transferase), transporters involved in lipid homeostasis (ABCA1, ABCG1), and several genes involved in processes related to energy metabolism and vascular disease.
Expressed in heart, brain, placenta, lung, skeletal muscle, prostate, testis, ovary and small intestine. Also expressed in fetal brain, lung and kidney.
Interaction with the co-SMAD SMAD4. Interacts with PEBP2-alpha subunit. Interacts with RANBP3L (PubMed:25755279).
Phosphorylated on serine by BMP (bone morphogenetic proteins) type 1 receptor kinase.
Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD9 is a receptor-regulated SMAD (R-SMAD).
Belongs to the cytokine receptor-like factor 3 family.
Expressed in several embryonic and adult tissues, including adult and fetal brain, liver, spleen and pancreas. Expressed in adult, but not fetal kidney. Expressed in skin and squamous cell carcinoma (SCC) and in several other cancer types. Also detected in lesion actinic keratosis (AK).
May play a role in the negative regulation of cell cycle progression.
Essential for normal spermatogenesis and male fertility (By similarity). Required for the completion of meiosis in male germ cells (By similarity).
Heterotetramer of TRAP-alpha, TRAP-beta, TRAP-delta and TRAP-gamma. Interacts with palmitoylated calnexin (CALX), the interaction is required for efficient folding of glycosylated proteins.
Shows a remarkable charge distribution with the N-terminus being highly negatively charged, and the cytoplasmic C-terminus positively charged.
TRAP proteins are part of a complex whose function is to bind calcium to the ER membrane and thereby regulate the retention of ER resident proteins. May be involved in the recycling of the translocation apparatus after completion of the translocation process or may function as a membrane-bound chaperone facilitating folding of translocated proteins.
Plays a role in the regulation of imprinted gene expression, regulates repressive epigenetic modifications associated with SETDB1. Required for the recruitment or accumulation of SETDB1 to the endogenous retroviruses (ERVs) and maintenance of repressive chromatin configuration, contributing to a subset of the SETDB1-dependent ERV silencing in embryonic stem cells.
Belongs to the gamma-glutamylcyclotransferase family.
Contributes to degradation of proteins cross-linked by transglutaminases by degrading the cross-link between a lysine and a glutamic acid residue. Catalyzes the formation of 5-oxo-L-proline from L-gamma-glutamyl-L-epsilon-lysine. Inactive with L-gamma-glutamyl-alpha-amino acid substrates such as L-gamma-glutamyl-L-alpha-cysteine and L-gamma-glutamyl-L-alpha-alanine.
Encoded by one of the numerous copies of NBPF genes clustered in the p36, p12 and q21 region of the chromosome 1.
(Microbial infection) Interacts with herpes simplex virus 1/HHV-1 protein CVC2/UL25.
(Microbial infection) Promotes human herpes simplex virus 1/HHV-1 proliferation.
May play a role in cell proliferation by promoting progression into S phase.
Contains one Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif that mediates interaction with nuclear receptors.
Does not colocalize with actin cytoskeleton structures.
F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein (Probable). Probably involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation (PubMed:15772161). Involved in tight junction assembly in epithelial cells probably through interaction with MICALL2. Links MICALL2 to the actin cytoskeleton and recruits it to the tight junctions (By similarity). May also function as a transcriptional coactivator, stimulating transcription mediated by the nuclear hormone receptors PPARG and RARA (PubMed:22351778).
Homodimer; antiparallel. Binds TRIM3 at the N-terminus (PubMed:15772161). Interacts with MICALL2 (preferentially in opened conformation); stimulated by RAB13 activation (By similarity). Identified in a complex with CASK, IQGAP1, MAGI2, NPHS1, SPTAN1 and SPTBN1 (By similarity). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3 (PubMed:15772161). Interacts with MAGI1 (PubMed:12042308). Interacts with PDLIM2 (By similarity). Interacts with PPARG and RARA (PubMed:22351778). Binds to VCL; this interaction triggers VCL conformational changes (PubMed:15988023). Interacts with SEPTIN14 (PubMed:33228246).
A chromosomal aberration involving BCL9 is found in a patient with precursor B-cell acute lymphoblastic leukemia (ALL). Translocation t(1;14)(q21;q32). This translocation leaves the coding region intact, but may have pathogenic effects due to alterations in the expression level of BCL9. Several cases of translocations within the 3'-UTR of BCL9 have been found in B-cell malignancies.
Binds to beta-catenin (CTNNB1), PYGO1 and PYGO2; the interaction with PYGO1 increases PYGO1 affinity to histone H3 methylated at 'Lys 4'.
Detected at low levels in thymus, prostate, testis, ovary and small intestine, and at lower levels in spleen, colon and blood.
Involved in signal transduction through the Wnt pathway. Promotes beta-catenin's transcriptional activity (By similarity).
Mono-ADP-ribosyltransferase that mediates mono-ADP-ribosylation of target proteins.
Interacts with RAB14 (By similarity). Interacts with PTPN21.
Plus end-directed microtubule-dependent motor protein involved in endosome transport and receptor recycling and degradation. Regulates the plus end motility of early endosomes and the balance between recycling and degradation of receptors such as EGF receptor (EGFR) and FGF receptor (FGFR). Regulates the Golgi to endosome transport of FGFR-containing vesicles during early development, a key process for developing basement membrane and epiblast and primitive endoderm lineages during early postimplantation development.
Primarily expressed in brain. Also present in kidney, liver, intestine, placenta, leukocytes, heart and skeletal muscle (at protein level).
The PX domain mediates binding to phosphatidylinositol 3-phosphate (PtdIns(3)P), phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2), phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). Does not bind phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2).
Acts as both a repressor and activator of transcription. Binds to the consensus sequence 5'-GACCACCCAC-3' (By similarity).
In the adult, expressed at high levels in the kidney and at lower levels in the brain, skeletal muscle, pancreas, liver, lung, thymus and ovary.
Guanine-nucleotide-releasing protein that acts on members of the SEC4/YPT1/RAB subfamily. Stimulates GDP release from both YPT1, RAB3A and RAB10, but is less active on these proteins than on the SEC4 protein (PubMed:31540829). Might play a general role in vesicular transport.
Expressed in heart, brain, liver and skeletal muscle.
(Microbial infection) Isoform 3 interacts with HCV core protein.
By IFNG/IFN-gamma and all-trans retinoic acid (ATRA).
Highly expressed in peripheral blood leukocytes and spleen. Detected at intermediate levels in thymus, prostate, testis, ovary, small intestine and colon, and at low levels in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Transcription factor. May be a nuclear hormone receptor coactivator. Enhances transcription of genes with retinoic acid response elements (RARE).
Interacts with MRAP; increasing ligand-sensitivity and generation of cAMP. Interacts with MRAP2; competing with MRAP for binding to MC2R and impairing the binding of corticotropin (ACTH).
Receptor for corticotropin (ACTH). This receptor is mediated by G proteins (G(s)) which activate adenylate cyclase (cAMP).
A soluble form (sIL-15RA) arises from proteolytic shedding of the membrane-anchored receptor (PubMed:15265897). It also binds IL-15 and thus interferes with IL-15 binding to the membrane receptor (PubMed:15265897).
Expressed in neutrophils (at protein level) (PubMed:15123770). Expressed in fetal brain with higher expression in the hippocampus and cerebellum than in cortex and thalamus (PubMed:12114302). Higher levels of soluble sIL-15RA form in comparison with membrane-bound forms is present in all brain structures (PubMed:12114302). Isoforms 1, 3, 4, 5, 6, 7, 8 and 9: Widely expressed (PubMed:10480910, PubMed:8530383).
High-affinity receptor for interleukin-15 (PubMed:8530383). Can signal both in cis and trans where IL15R from one subset of cells presents IL15 to neighboring IL2RG-expressing cells (By similarity). In neutrophils, binds and activates kinase SYK in response to IL15 stimulation (PubMed:15123770). In neutrophils, required for IL15-induced phagocytosis in a SYK-dependent manner (PubMed:15123770). Expression of different isoforms may alter or interfere with signal transduction (PubMed:10480910).
The interleukin-15 receptor IL15R is a heterotrimer of IL15RA, IL2RB and IL2RG. IL15RA also self-associates (PubMed:17643103). Interacts with SYK (PubMed:15123770).
Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation. Thr-312 is likely to be the main autophosphorylation site. Autophosphorylation also occurs on Thr-304 and Ser-308.
Expressed in epithelial tumor cell lines of colonic, breast and esophageal origin.
Homodimerization via the leucine zipper domains is required for autophosphorylation of multiple sites in the activation loop and subsequent activation. Autophosphorylation at Thr-312 is the key step in activation of MAP3K9/MLK1 and is required for full phosphorylation. Autophosphorylation at Thr-304 and Ser-308 have been shown to be of secondary importance in the activation of MAP3K9/MLK1. CEP-1347 and many indolocarbazole analogs have been shown to act as inhibitors of MAP3K9/MLK1 activity.
Homodimerization via the leucine zipper domains is required for autophosphorylation.
May play a role in esophageal cancer susceptibility and/or development.
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade through the phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7 which in turn activate the JNKs. The MKK/JNK signaling pathway regulates stress response via activator protein-1 (JUN) and GATA4 transcription factors. Also plays a role in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis.
Efficient DNA binding requires dimerization with another bHLH protein. Forms homo- or heterooligomers with myogenin, E12 and ITF2 proteins. Interacts with PTF1A. Interacts with NEUROD2 (By similarity). Interacts with RUNX1T1. Interacts with AML1-MTG8/ETO (via nervy homology region 2 in oligomerized form) (PubMed:23812588). Interacts with BHLHA9 (PubMed:25466284).
Expressed in several tissues and cell types including skeletal muscle, thymus, and a B-cell line.
Transcriptional regulator. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3') (By similarity). May be involved in the functional network that regulates the development of the GnRH axis (PubMed:32620954).
Could be an important component in vesicular trafficking cycling between the Golgi complex and the apical plasma membrane. Could be involved in myelin biogenesis and/or myelin function.
Expressed in the intermediate and late stages of T-cell differentiation.
Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals. The BLOC-1 complex, in association with SNARE proteins, is also proposed to be involved in neurite extension. Associates with the BLOC-2 complex to facilitate the transport of TYRP1 independent of AP-3 function. Plays a role in synaptic vesicle trafficking and in neurotransmitter release. Plays a role in the regulation of cell surface exposure of DRD2. May play a role in actin cytoskeleton reorganization and neurite outgrowth. May modulate MAPK8 phosphorylation. Appears to promote neuronal transmission and viability through regulating the expression of SNAP25 and SYN1, modulating PI3-kinase-Akt signaling and influencing glutamatergic release. Regulates the expression of SYN1 through binding to its promoter. Modulates prefrontal cortical activity via the dopamine/D2 pathway.
Defects in DTNBP1 are associated with susceptibility to schizophrenia, a mental disorder characterized by a breakdown of thought processes and by poor emotional responsiveness. Genetic mutations lead to alterations in the glutamatergic transmission in the brain and modified Akt signaling (PubMed:15345706). Protein levels and expression are reduced in nerve terminals of the hippocampus and there is an increased release of glutamate in schizophrenic patients (PubMed:15124027). Levels of isoform 1 are reduced in the pSTG, but not in HF, by about 48% in 92% of schizophrenic patients. In the HF, there is an average of 33% reduction in synaptic expression of isoform 2 in 67% of cases, and of isoform 3, an average reduction of 35% in 80% of cases. In the dorsolateral prefrontal cortex (DLPFC), significant reductions in levels of isoform 3 are observed about 71% of schizophrenic patients showed an average reduction of this isoform of about 60% (PubMed:19617633).
Detected in brain, in neurons and in neuropil. Isoform 1 is expressed in the cerebral cortex, and hippocampal frontal (HF). Specific expression in the posterior half of the superior temporal gyrus (pSTG). Higher expression of isoform 2 and 3 in the HF than in the pSTG while isoform 1 shows no difference in expression in these areas. In the HF, detected in dentate gyrus (DG) and in pyramidal cells of hippocampus CA2 and CA3 (at protein level). Expressed in all principal neuronal populations of the HF, namely pyramidal neurons in the subiculum and CA1-3, granule cells in the dense cell layer of the DG (DGg), and polymorph cells in the hilus of the DG (DGh). Maximal levels in CA2, CA3, and DGh. Isoform 2 not expressed in the cerebral cortex.
Interacts (via its coiled coil domain) with KXD1. Interacts with CMYA5, PI4K2 and RNF151 (By similarity). Component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) composed of at least BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. Interacts directly in the complex with BLOC1S5, BLOC1S6 and SNAPIN/BLOC1S8. The BLOC-1 complex associates with the AP-3 protein complex and membrane protein cargos. This BLOC-1 complex also associates with the BLOC-2 complex in endosomes. Binds to DTNA and DTNB but may not be a physiological binding partner (PubMed:16980328). Interacts (isoform 1 and isoform 2 only) with the DNA-dependent protein kinase complex DNA-PK; the interaction phosphorylates DTNBP1 in vitro. Interacts directly in this complex with XRCC5 and XRCC6. Interacts with AP3M1, AP3B2 and TRIM32. Interacts with XPO1; the interaction exports DTNBP1 out of the nucleus.
Isoforms 1 and 2 highly phosphorylated by PRKDC in vitro. Isoform 3 only weakly phosphorylated by PRKDC in vitro.
Ubiquitinated by TRIM32. Ubiquitination leads to DTNBP1 degradation.
(Microbial infection) Preferentially ubiquitinated with 'Lys-48' and 'Lys-11'-linked ubiquitin chains by Salmonella effector SopA leading to proteasomal targeting and degradation.
E3 ubiquitin-protein ligase that plays a key role in innate antiviral immunity by mediating ubiquitination of CGAS and STING1 (PubMed:21289118, PubMed:29426904). In response to pathogen- and host-derived double-stranded DNA (dsDNA), targets STING1 to 'Lys-63'-linked ubiquitination, thereby promoting its homodimerization, a step required for the production of type I interferon IFN-beta (By similarity). Also mediate monoubiquitination of CGAS, thereby promoting CGAS oligomerization and subsequent activation (PubMed:29426904). Promotes also TNFalpha-induced NF-kappa-B signaling by mediating 'Lys-63'-linked ubiquitination TAK1, leading to enhanced interaction between TAK1 and CHUK/IKKalpha (PubMed:35952808). Independently of its E3 ubiquitin ligase activity, positive regulator of TLR3 signaling. Potentiates extracellular double stranded RNA (dsRNA)-induced expression of IFNB1 and interferon-stimulated genes ISG15, IFIT1/ISG56, CXCL10, OASL and CCL5/RANTES (PubMed:22948160). Promotes establishment of an antiviral state by TLR3 ligand and TLR3-mediated chemokine induction following infection by hepatitis C virus (PubMed:22948160). Acts as restriction factor of Zika virus through direct interaction with the viral RNA via its C-terminal region (PubMed:31251739).
Homooligomer. Interacts with STING1 (By similarity). Interacts with TICAM1 (PubMed:22948160).
Acetylated by histone acetyltransferase p300, deacetylated by HDACs. Acetylation/deacetylation states regulate transcriptional activity. Acetylation appears to activate transcription. Alternate sumoylation and acetylation at Lys-551 also control transcriptional activity. Ceramides can also regulate acetylation/deacetylation events through altering the interaction of HDAC with SP3. In vitro, C(18)-ceramides, but not C(16)-ceramides, increase the interaction of HDAC1 with SP3 and enhance the deacetylation of SP3 and the subsequent repression of the TERT promoter.
Interacts with HLTF; the interaction may be required for basal transcriptional activity of HLTF. Interacts with HDAC1; the interaction deacetylates SP3 and regulates its transcriptional activity. Interacts with HDAC2 (preferably the CK2-phosphorylated form); the interaction deacetylates SP3 and regulates its transcriptional activity. Interacts with MEIS2 isoform 4 and PBX1 isoform PBX1a.
Produced by alternative initiation at Met-13 of isoform 1.
Produced by alternative initiation at Met-286 of isoform 1.
Produced by alternative initiation at Met-303 of isoform 1.
Produced by alternative splicing. An AUA codon is translated into Met and used as a translation initiation site (in vitro).
Sumoylated on all isoforms. Sumoylated on 2 sites in longer isoforms with Lys-551 being the major site. Sumoylation at this site promotes nuclear localization to the nuclear periphery, nuclear dots and PML nuclear bodies. Sumoylation on Lys-551 represses the transactivation activity, except for the largest isoform, L-Sp3, which has little effect on transactivation. Alternate sumoylation and acetylation at Lys-551 also control transcriptional activity.
Transcriptional factor that can act as an activator or repressor depending on isoform and/or post-translational modifications. Binds to GT and GC boxes promoter elements. Competes with SP1 for the GC-box promoters. Weak activator of transcription but can activate a number of genes involved in different processes such as cell-cycle regulation, hormone-induction and house-keeping.
As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway.
As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway (PubMed:23723238, PubMed:29590090, PubMed:35338845). In response to amino acid depletion, the GATOR1 complex has GTPase activating protein (GAP) activity and strongly increases GTP hydrolysis by RagA/RRAGA (or RagB/RRAGB) within heterodimeric Rag complexes, thereby turning them into their inactive GDP-bound form, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling (PubMed:23723238, PubMed:29590090, PubMed:35338845). In the presence of abundant amino acids, the GATOR1 complex is negatively regulated by GATOR2, the other GATOR subcomplex, in this amino acid-sensing branch of the TORC1 pathway (PubMed:23723238).
Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins are detected in glioblastoma and ovarian tumors and are associated with loss of heterozygosity events. Inactivation of GATOR1 proteins promotes constitutive localization of mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation following amino acid withdrawal (PubMed:23723238).
Ser-489 is missing in the human genome assembly but is present in all available mRNAs and ESTs.
Widely expressed. Expressed in the frontal lobe cortex as well as in the temporal, parietal, and occipital lobes (PubMed:27173016, PubMed:26505888).
Within the GATOR complex, component of the GATOR1 subcomplex, made of DEPDC5, NPRL2 and NPRL3 (PubMed:23723238, PubMed:29590090, PubMed:35338845). GATOR1 mediates the strong interaction of the GATOR complex with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD) heterodimers (PubMed:23723238). GATOR1 interacts with GPR155/LYCHOS; interaction takes place in presence of cholesterol and prevents interaction between GATOR1 and KICSTOR (PubMed:36007018).
Atypical member of the structural maintenance of chromosomes (SMC) protein family. Like other members of the SMC family, has ATPase activity, which is probably necessary for its engagement with chromatin, and a SMC hinge domain. However, the SMC hinge domain adopts an unconventional homodimeric arrangement augmented by an intermolecular coiled coil formed between the two monomers. This suggests that protein may assemble as a head-to-head parallel dimer without adopting a hairpin shape at the hinge domain, unlike the dimeric arrangement conventionally found in other members of the SMC protein family. The SMC hinge domain binds DNA and RNA.
Belongs to the SMC family. Highly divergent.
Homodimer; homodimerizes via its SMC hinge domain (By similarity). Interacts with LRIF1 (PubMed:23542155).
Non-canonical member of the structural maintenance of chromosomes (SMC) protein family that plays a key role in epigenetic silencing by regulating chromatin architecture (By similarity). Promotes heterochromatin formation in both autosomes and chromosome X, probably by mediating the merge of chromatin compartments (By similarity). Plays a key role in chromosome X inactivation in females by promoting the spreading of heterochromatin (PubMed:23542155). Recruited to inactivated chromosome X by Xist RNA and acts by mediating the merge of chromatin compartments: promotes random chromatin interactions that span the boundaries of existing structures, leading to create a compartment-less architecture typical of inactivated chromosome X (By similarity). Required to facilitate Xist RNA spreading (By similarity). Also required for silencing of a subset of clustered autosomal loci in somatic cells, such as the DUX4 locus (PubMed:23143600). Has ATPase activity; may participate in structural manipulation of chromatin in an ATP-dependent manner as part of its role in gene expression regulation (PubMed:29748383). Also plays a role in DNA repair: localizes to sites of DNA double-strand breaks in response to DNA damage to promote the repair of DNA double-strand breaks (PubMed:25294876, PubMed:24790221). Acts by promoting non-homologous end joining (NHEJ) and inhibiting homologous recombination (HR) repair (PubMed:25294876).
The disease is caused by variants affecting the gene represented in this entry. SMCHD1 mutations lead to DUX4 expression in somatic tissues, including muscle cells, when an haplotype on chromosome 4 is permissive for DUX4 expression (PubMed:23143600). Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death (PubMed:23143600). FSHD2 and FSHD1 share a common pathophysiological pathway in which the FSHD2 gene SMCHD1 can act as a modifier for disease severity in families affected by FSHD1 (PubMed:24075187, PubMed:25370034).
Fetal ovary and fetal testis. Present in all germ cells of seminiferous tubules of the 24-week fetus (at protein level).
Interacts with CNOT1, CNOT3, CNOT6L, CNOT7 and CNOT9.
Plays a key role in the sexual differentiation of germ cells by promoting the male fate but suppressing the female fate. Represses the female fate pathways by suppressing meiosis, which in turn results in the promotion of the male fate. Maintains the suppression of meiosis by preventing STRA8 expression, which is required for premeiotic DNA replication, after CYP26B1 is decreased. Regulates the localization of the CCR4-NOT deadenylation complex to P-bodies and plays a role in recruiting the complex to trigger the degradation of mRNAs involved in meiosis. Required for the maintenance of the spermatogonial stem cell population. Not essential for the assembly of P-bodies but is required for the maintenance of their normal state (By similarity).
Testis and ovary. Expression found in several spermatogenic stages: in cells on the periphery of the tubules which could correspond to spermatogonia, in spermatocytes and in round spermatids (at protein level).
The Nanos-type zinc finger is composed of two C2HC motifs, each motif binding one molecule of zinc. It is essential for the translation repression activity of the protein.
Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class I subfamily.
Binds to type I and type II collagen, fibronectin and TGF-beta. Forms a ternary complex with MFAP2 and ELN.
Binds to type I and type II collagen, fibronectin and TGF-beta. Forms a ternary complex with MFAP2 and ELN. Interacts with DPT (By similarity).
Detected in placenta (at protein level) (PubMed:32337544). Detected in cerebrospinal fluid, fibroblasts and urine (at protein level) (PubMed:25326458, PubMed:36213313).
May affect the rate of fibrils formation.
The attached glycosaminoglycan chain can be either chondroitin sulfate or dermatan sulfate depending upon the tissue of origin.
Plays a role in endosomal trafficking of the epidermal growth factor receptor (EGFR).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Delta/CHRND sub-subfamily.
Expressed in oocytes and testicular germ cells in the stage of spermatogonia to spermatocyte. Also observed placental trophoblasts, as well as in vascular smooth muscle cells in the pulmonary artery, myocardium, and skeletal muscle. Undetectable in epithelial cells in respiratory, gastrointestinal, and urogenital tracts. Up-regulated in various carcinomas and germ cell tumors (at protein level).
Found in a mRNP complex with PABPC1 and YBX3. Found in a mRNP complex with ZAR1 and ZAR1L.
Major constituent of messenger ribonucleoprotein particles (mRNPs). Involved in the regulation of the stability and/or translation of germ cell mRNAs. Binds to Y-box consensus promoter element. Binds to full-length mRNA with high affinity in a sequence-independent manner. Binds to short RNA sequences containing the consensus site 5'-UCCAUCA-3' with low affinity and limited sequence specificity. Its binding with maternal mRNAs is necessary for its cytoplasmic retention. May mark specific mRNAs (those transcribed from Y-box promoters) in the nucleus for cytoplasmic storage, thereby linking transcription and mRNA storage/translational delay (By similarity).
Phosphorylated during oocyte maturation and dephosphorylated following egg activation. Phosphorylated in vitro by a kinase activity associated with testicular mRNPs. Dephosphorylation leads to a decrease in its affinity to bind RNA in vitro (By similarity).
Belongs to the liprin family. Liprin-alpha subfamily.
Expressed only in the heart, brain, and skeletal muscle.
Forms homodimers and heterodimers with liprins-alpha and liprins-beta. Interacts with the second PTPase domain of PTPRD, PTPRF and PTPRS. Interacts with RIMS1 and RIMS2 (By similarity). Interacts with GIT1 and GIT2 (By similarity). Interacts with GRIP1 (By similarity). Interacts with KIF1A (By similarity).
May regulate the disassembly of focal adhesions. May localize receptor-like tyrosine phosphatases type 2A at specific sites on the plasma membrane, possibly regulating their interaction with the extracellular environment and their association with substrates (By similarity).
The N-terminal coiled coil regions mediate homodimerization preferentially and heterodimerization type alpha/alpha. The C-terminal, non-coiled coil regions mediate heterodimerization type alpha/beta and interaction with PTPRD, PTPRF and PTPRS (By similarity).
(Microbial infection) In CMV-infected cells, interacts with the viral glycoprotein UL16; this interaction causes ULBP1 retention in the endoplasmic reticulum and cis-Golgi and prevents binding to and activation of KLRK1/NKG2D, providing CMV with an immune evasion mechanism.
Binds and activates the KLRK1/NKG2D receptor, mediating natural killer cell cytotoxicity.
Expressed in T-cells, B-cells, erythroleukemia cell lines and in a wide range of tissues including heart, brain, lung, liver, testis, lymph node, thymus, tonsil and bone marrow. Also found in fetal heart, brain, lung and liver.
Interacts with KLRK1/NKG2D (PubMed:11777960). Does not bind to beta2-microglobulin (PubMed:12782710).
UL16-binding proteins (ULBPs) are unusual members of the extended MHC class I superfamily. They do not contain the alpha 3 domain and lack a transmembrane domain.
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types (By similarity).
Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter KLHDC2 (PubMed:29779948, PubMed:29775578, PubMed:30526872). Interacts with CREB3; interaction is direct and specific as it does not interact with CREB1, ATF4, ATF6, JUN, FOS, CEBPA or herpes simplex virus transactivator VP16 (PubMed:11384994).
Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:29775578, PubMed:30526872). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (PubMed:29779948, PubMed:29775578, PubMed:30526872). The CRL2(KLHDC2) complex specifically recognizes proteins with a diglycine (Gly-Gly) at the C-terminus, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:29775578, PubMed:30526872). The CRL2(KLHDC2) complex mediates ubiquitination and degradation of truncated SELENOK and SELENOS selenoproteins produced by failed UGA/Sec decoding, which end with a diglycine (PubMed:26138980, PubMed:30526872). The CRL2(KLHDC2) complex also recognizes proteolytically cleaved proteins ending with Gly-Gly, such as the N-terminal fragment of USP1, leading to their degradation (PubMed:29775578, PubMed:30526872). May also act as an indirect repressor of CREB3-mediated transcription by interfering with CREB3-DNA-binding (PubMed:11384994).
Widely expressed, with high levels in skeletal muscle, heart, pancreas and liver (PubMed:11384994, PubMed:16964437). Undetectable in peripheral blood leukocytes (PubMed:16964437).
Belongs to the type II cytokine receptor family.
Genetic variations in IFNAR2 influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424].
Heterodimer with IFNAR1; forming the receptor for type I interferon (PubMed:8181059, PubMed:7665574, PubMed:10049744, PubMed:24075985, PubMed:21854986). Interacts with JAK1 (PubMed:8181059, PubMed:7759950). Interacts with the transcriptional factors STAT1 and STAT2 (PubMed:9121453, PubMed:28165510). Interacts with USP18; indirectly via STAT2, it negatively regulates the assembly of the ternary interferon-IFNAR1-IFNAR2 complex and therefore type I interferon signaling (PubMed:28165510).
Isoform 3 is detected in the urine (at protein level) (PubMed:8181059, PubMed:7759950). Expressed in blood cells. Expressed in lymphoblastoid and fibrosarcoma cell lines.
Phosphorylated on tyrosine residues upon interferon binding. Phosphorylation at Tyr-337 or Tyr-512 are sufficient to mediate interferon dependent activation of STAT1, STAT2 and STAT3 leading to antiproliferative effects on many different cell types.
Potent inhibitor of type I IFN receptor activity.
Together with IFNAR1, forms the heterodimeric receptor for type I interferons (including interferons alpha, beta, epsilon, omega and kappa) (PubMed:8181059, PubMed:7665574, PubMed:7759950, PubMed:8798579, PubMed:8969169, PubMed:10049744, PubMed:10556041, PubMed:21854986, PubMed:26424569, PubMed:28165510, PubMed:32972995). Type I interferon binding activates the JAK-STAT signaling cascade, resulting in transcriptional activation or repression of interferon-regulated genes that encode the effectors of the interferon response (PubMed:8181059, PubMed:7665574, PubMed:7759950, PubMed:8798579, PubMed:8969169, PubMed:10049744, PubMed:17517919, PubMed:21854986, PubMed:26424569, PubMed:28165510, PubMed:32972995). Mechanistically, type I interferon-binding brings the IFNAR1 and IFNAR2 subunits into close proximity with one another, driving their associated Janus kinases (JAKs) (TYK2 bound to IFNAR1 and JAK1 bound to IFNAR2) to cross-phosphorylate one another (PubMed:10556041, PubMed:11682488, PubMed:12105218, PubMed:21854986, PubMed:32972995). The activated kinases phosphorylate specific tyrosine residues on the intracellular domains of IFNAR1 and IFNAR2, forming docking sites for the STAT transcription factors (STAT1, STAT2 and STAT) (PubMed:11682488, PubMed:12105218, PubMed:21854986, PubMed:32972995). STAT proteins are then phosphorylated by the JAKs, promoting their translocation into the nucleus to regulate expression of interferon-regulated genes (PubMed:9121453, PubMed:12105218, PubMed:28165510).
Associates with SKI complex; the interaction with SKIC2 is direct (PubMed:28204585). Associates with the exosome complex; the interaction with EXOSC3 is direct (PubMed:28204585).
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family.
Component of the Pelota-HBS1L complex, also named Dom34-Hbs1 complex, composed of PELO and HBS1L (PubMed:27863242). Interacts with the SKI complex (PubMed:23667253, PubMed:28204585).
Defects in HBS1L have been found in one patient with a developmental disorder characterized by growth restriction, facial dysmorphism and developmental delay (PubMed:24288412, PubMed:30707697). Additional pleiotropic features include sparse hair and eyebrows, deep-set eyes with blue sclerae, bifid uvula with a submucous cleft palate, velopharyngeal insufficiency, C2-C3 vertebral fusion, scoliosis, vesicoureteral reflux with a bladder diverticulum and significant hypotonia (PubMed:24288412, PubMed:30707697). Deficiency is caused by the complete absence of isoform 1 and isoform 3, while isoform 2 is relatively unaffected in this patient (PubMed:30707697).
Detected in heart, brain, placenta, liver, muscle, kidney and pancreas.
GTPase component of the Pelota-HBS1L complex, a complex that recognizes stalled ribosomes and triggers the No-Go Decay (NGD) pathway (PubMed:21448132, PubMed:23667253, PubMed:27863242). The Pelota-HBS1L complex recognizes ribosomes stalled at the 3' end of an mRNA and engages stalled ribosomes by destabilizing mRNA in the mRNA channel (PubMed:27863242). Following mRNA extraction from stalled ribosomes by the SKI complex, the Pelota-HBS1L complex promotes recruitment of ABCE1, which drives the disassembly of stalled ribosomes, followed by degradation of damaged mRNAs as part of the NGD pathway (PubMed:21448132, PubMed:32006463).
Functions as a guanine nucleotide exchange factor (GEF) activating either RalA or RalB GTPases and plays an important role in intracellular transport. Interacts and acts as an effector molecule for R-Ras, H-Ras, K-Ras, and Rap (By similarity). During bacterial clearance, recognizes 'Lys-33'-linked polyubiquitinated TRAF3 and subsequently mediates assembly of the exocyst complex (PubMed:27438768).
Interacts with RIT1 and RIT2 (By similarity). Interacts with OOG1 (By similarity). Interacts with TRAF3 (PubMed:27438768). Interacts with HRAS (By similarity).
Phosphorylation of Tyr-814 by MET blocks HRAS binding.
The Ras-associating domain interacts with Ras.
Detected in epidermal keratinocytes (at protein level). Epidermis, prostate, testis, placenta, spleen and thymus.
Acid protease active in intracellular protein breakdown. Plays a role in APP processing following cleavage and activation by ADAM30 which leads to APP degradation (PubMed:27333034). Involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer disease.
As well as the major heavy chain which starts at Leu-169, 2 minor forms starting at Gly-170 and Gly-171 have been identified (PubMed:1426530). An additional form starting at Ala-168 has also been identified (PubMed:27333034).
Consists of a light chain and a heavy chain (PubMed:8393577, PubMed:1426530). Interacts with ADAM30; this leads to activation of CTSD (PubMed:27333034). Interacts with GRN; stabilizes CTSD; increases its proteolytic activity (By similarity).
Expressed in the aorta extracellular space (at protein level) (PubMed:20551380). Expressed in liver (at protein level) (PubMed:1426530).
The Val-58 allele is significantly overrepresented in demented patients (11.8%) compared with non-demented controls (4.9%). Carriers of the Val-58 allele have a 3.1-fold increased risk for developing AD than non-carriers.
Undergoes proteolytic cleavage and activation by ADAM30.
Belongs to the mitochondrion-specific ribosomal protein mL65 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379, PubMed:25278503). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. mL65 forms a heterodimer with mL37.
Heart, skeletal muscle, kidney and liver. Lower expression in placenta and peripheral blood leukocytes.
By carcinogenic agents and by UV light. During squamous differentiation of epidermal keratinocytes.
Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane. Can function as both amine donor and acceptor in transglutaminase-mediated cross-linkage.
Binds to and stabilizes microtubules. Interacts with MAPK8IP1/JIP-1, MAPK8IP2/JIP-2, MAPK9/JNK2, PPP1R9B/NEURABIN-2 and actin.
Expressed in fetal brain, and, to a lower extent, in fetal kidney.
Protein kinase with a significantly reduced C(a2+)/CAM affinity and dependence compared to other members of the CaMK family. May play a role in the down-regulation of CRE-dependent gene activation probably by phosphorylation of the CREB coactivator CRTC2/TORC2 and the resulting retention of TORC2 in the cytoplasm (By similarity).
The doublecortin domains are involved in the colocalization with microtubules.
A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation.
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. RAF subfamily.
Defects in BRAF are found in a wide range of cancers.
In quiescent cells, maintained in an inactive state via an intramolecular interaction between the protein kinase and N-terminal domains. Following mitogen-mediated cell activation, binds via its RGB domain to active HRAS (GTP-bound) which releases the inhibitory intramolecular interaction between the two domains. This allows the MAP2K1-mediated dimerization of KSR1 or KSR2, and BRAF which activates BRAF.
Methylation at Arg-671 decreases stability and kinase activity.
Monomer (PubMed:19710016). Homodimer (PubMed:19710016, PubMed:36402789). Heterodimerizes with RAF1, and the heterodimer possesses a highly increased kinase activity compared to the respective homodimers or monomers (PubMed:19710016). Heterodimerization is mitogen-regulated and enhanced by 14-3-3 proteins. MAPK1/ERK2 activation can induce a negative feedback that promotes the dissociation of the heterodimer by phosphorylating BRAF at Thr-753. Heterodimerizes (via N-terminus) with KSR1 (via N-terminus) or KSR2 (via N-terminus) in a MAP2K1-dependent manner (PubMed:29433126). Interacts with MAP2K1 and MAP2K2 (PubMed:29433126). Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3 and RGS14. Interacts with RIT1. Interacts (via N-terminus) with RGS14 (via RBD domains); the interaction mediates the formation of a ternary complex with RAF1, a ternary complex inhibited by GNAI1 (By similarity). Interacts with DGKH (PubMed:19710016). Interacts with PRMT5 (PubMed:21917714). Interacts with KSR2 (PubMed:21441910). Interacts with AKAP13, MAP2K1 and KSR1. Identified in a complex with AKAP13, MAP2K1 and KSR1 (PubMed:21102438). Interacts with FNIP1 and FNIP2 (PubMed:27353360).
Phosphorylation at Ser-365 by SGK1 inhibits its activity.
Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus (Probable). Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway (PubMed:21441910, PubMed:29433126). Phosphorylates PFKFB2 (PubMed:36402789). May play a role in the postsynaptic responses of hippocampal neurons (PubMed:1508179).
Ubiquitinated by RNF149; which leads to proteasomal degradation. Polyubiquitinated at Lys-578 in response to EGF.
Interacts with BRCA1 and ATM. Interacts with MTOR and RPTOR. Interacts with NDFIP1. Interacts with SMC1A and PRKDC.
Involved in DNA damage response; activates kinases ATM, SMC1A and PRKDC by modulating their phosphorylation status following ionizing radiation (IR) stress (PubMed:16452482, PubMed:22977523). Plays a role in regulating mitochondrial function and cell proliferation (PubMed:25070371). Required for protein stability of MTOR and MTOR-related proteins, and cell cycle progress by growth factors (PubMed:25657994).
Ubiquitinated by NEDD4, NEDD4L and ITCH; mono- and polyubiquitinated forms are detected.
Chemoattractant for eosinophils and basophils (PubMed:10415065, PubMed:10488147). Acts as a ligand for C-C chemokine receptor CCR3 which triggers Ca(2+) mobilization in eosinophils (PubMed:10415065, PubMed:10488147, PubMed:11425309). Also acts as a ligand for CX3C chemokine receptor CX3CR1, inducing cell chemotaxis (PubMed:20974991).
Ubiquitously expressed at low levels in various tissues including heart and ovary.
Component of the little elongation complex (LEC), a complex required to regulate small nuclear RNA (snRNA) gene transcription by RNA polymerase II and III.
Component of the little elongation complex (LEC), at least composed of ELL (ELL, ELL2 or ELL3), ZC3H8, ICE1 and ICE2. Interacts with ICE1 (via C-terminus domain). Interacts with ELL.
Expressed at low levels in lung and testis.
Expressed in fetal brain, kidney, liver and lung.
Banana-shaped homodimer laterally assembling into tetramers, the tetramers further pack helically onto the membrane. Interacts with GTP-bound ARF6. Interacts with third cytoplasmic loop of SLC2A4/GLUT4. Interacts with CLTC. Interacts with GULP1. Forms a complex with GDP-bound ARF6 and GULP1. Interacts with ITGB1; required for ITGB1 recycling.
Cells overexpressing ACAP1 show an accumulation of ITGB1 in recycling endosomes and inhibition of stimulation-dependent cell migration. Cells with reduced levels of ACAP1 or AKT1 and AKT2 show inhibition of stimulation-dependent cell migration. Cells overexpressing ACAP1 and PIP5K1C show formation of tubular structures derived from endosomal membranes.
GAP activity stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid.
GTPase-activating protein (GAP) for ADP ribosylation factor 6 (ARF6) required for clathrin-dependent export of proteins from recycling endosomes to trans-Golgi network and cell surface. Required for regulated export of ITGB1 from recycling endosomes to the cell surface and ITGB1-dependent cell migration.
Highest level in lung and spleen. Low level in heart, kidney, liver and pancreas.
PH domain binds phospholipids including phosphatidic acid, phosphatidylinositol 3-phosphate, phosphatidylinositol 3,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). May mediate ACAP1-binding to PIP2 or PIP3 containing membranes. Only one PH domain of one ACAP1 dimer inserts into the membrane, while the other PH domain acts primaryly to interact with adjacent ACAP1 dimers.
Phosphorylation at Ser-554 by PKB is required for interaction with ITGB1, export of ITGB1 from recycling endosomes to the cell surface and ITGB1-dependent cell migration.
The BAR domain mediates homodimerization, it can neither bind membrane nor impart curvature, but instead requires the neighboring PH domain to achieve these functions.
Constitutively phosphorylated. This increases during mitosis when the cytoplasmic intermediate filament network is reorganized (By similarity).
Forms homodimers and homotetramers in vitro. In mixtures with other intermediate filament proteins such as vimentin and alpha-internexin, tis protein preferentially forms heterodimers which can assemble to form intermediate filaments if nestin does not exceed 25%. Interacts with FHOD3 (By similarity).
Required for brain and eye development. Promotes the disassembly of phosphorylated vimentin intermediate filaments (IF) during mitosis and may play a role in the trafficking and distribution of IF proteins and other cellular factors to daughter cells during progenitor cell division. Required for survival, renewal and mitogen-stimulated proliferation of neural progenitor cells (By similarity).
Upon terminal neural differentiation, nestin is down-regulated and replaced by neurofilaments.
A head-to-tail association, of the N-terminal and C-terminal halves results in a closed conformation (inactive form) which is incapable of actin or membrane-binding.
Expressed in cerebral cortex, basal ganglia, hippocampus, hypophysis, and optic nerve. Weakly expressed in brain stem and diencephalon. Stronger expression was detected in gray matter of frontal lobe compared to white matter (at protein level). Component of the microvilli of intestinal epithelial cells. Preferentially expressed in astrocytes of hippocampus, frontal cortex, thalamus, parahippocampal cortex, amygdala, insula, and corpus callosum. Not detected in neurons in most tissues studied.
Has three main structural domains: an N-terminal FERM domain, a central alpha-helical domain and a C-terminal actin-binding domain.
Monomer. Homodimer (PubMed:27364155). Interacts with PALS1 and NHERF2. Found in a complex with EZR, PODXL and NHERF2 (By similarity). Interacts with MCC, PLEKHG6, PODXL, SCYL3/PACE1, NHERF1 and TMEM8B (PubMed:9314537, PubMed:12651155, PubMed:15498789, PubMed:17616675, PubMed:17881735, PubMed:19555689). Interacts (when phosphorylated) with FES/FPS (PubMed:18046454). Interacts with dimeric S100P, the interaction may be activating through unmasking of F-actin binding sites (PubMed:12808036, PubMed:19111582). Identified in complexes that contain VIM, EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, PRX and spectrin (By similarity). Detected in a complex composed of at least EZR, AHNAK, PPL and PRX (By similarity). Interacts with PDPN (via cytoplasmic domain); activates RHOA and promotes epithelial-mesenchymal transition (PubMed:17046996). Interacts with SPN/CD43 cytoplasmic tail, CD44 and ICAM2 (By similarity). Interacts with SLC9A3; interaction targets SLC9A3 to the apical membrane (By similarity). Interacts with SLC9A1; regulates interactions of SLC9A1 with cytoskeletal and promotes stress fiber formation (By similarity).
Phosphorylated by tyrosine-protein kinases. Phosphorylation by ROCK2 suppresses the head-to-tail association of the N-terminal and C-terminal halves resulting in an opened conformation which is capable of actin and membrane-binding (By similarity).
Probably involved in connections of major cytoskeletal structures to the plasma membrane. In epithelial cells, required for the formation of microvilli and membrane ruffles on the apical pole. Along with PLEKHG6, required for normal macropinocytosis.
S-nitrosylation is induced by interferon-gamma and oxidatively-modified low-densitity lipoprotein (LDL(ox)) possibly implicating the iNOS-S100A8/9 transnitrosylase complex.
The FERM domain is organized in a clover-shaped structure that comprises three subdomains identified as F1 (residues 2-82), F2 (residues 96-198), and F3 (residues 204-296). In the active form, the subdomain F3 adopts two mutually exclusive conformational isomers where a row of four phenylalanine side chains (Phe250, Phe255, Phe267 and Phe269) must point in the same direction. In the autoinhibited form, the F3 subdomain interacts with the C-terminal domain (residues 516-586) and stabilizes the structure, selecting only one possible arrangement of phenylalanine side chains. The FERM domain mediates binding to membrane lipids and signaling molecules.
The [IL]-x-C-x-x-[DE] motif is a proposed target motif for cysteine S-nitrosylation mediated by the iNOS-S100A8/A9 transnitrosylase complex.
The central alpha-helical domain is composed of two alpha helices (residues 326-406 and 417-466) connected by a linker. It protrudes from the FERM domain forming a coiled coil structure where the linker can have either a loop or a helix conformation. The monomer is predicted to form an intra-molecular helix-loop-helix coiled coil structure. Whereas the dimer adopts an elongated dumbbell-shaped configuration where continuous alpha helices from each protomer are organized in a antiparallel coiled coil structure that connect FERM:C-terminal domain swapped complex at each end. The dimer is predicted to link actin filaments parallel to the plasma membrane.
Very strong staining is detected in the Purkinje cell layer and in part of the molecular layer of the infant brain compared to adult brain.
Binds DNA as a multimer, probably a dimer (PubMed:7637780). Interacts with MRTFA, forming the SRF-MRTFA nuclear complex which binds the 5'-CArG-3' consensus motif (CArG box) on DNA via SRF (PubMed:14565952, PubMed:19350017). Forms a nuclear ternary complex with MRTFA and SCAI (PubMed:19350017). Interacts with MRTFB (PubMed:14565952). Interacts with MLLT7/FOXO4, NKX3A and SSRP1 (PubMed:16054032). Interacts with ARID2 (By similarity). Interacts with SRFBP1 (By similarity). Interacts with FOXK1 (PubMed:17670796). Interacts with LPXN (PubMed:18497331). Interacts with OLFM2; the interaction promotes dissociation of SRF from the transcriptional repressor HEY2, facilitates binding of SRF to target genes and promotes smooth muscle differentiation (PubMed:25298399). Interacts with NKX3-1 (By similarity). Interacts with KAT5 (By similarity).
SRF is a transcription factor that binds to the serum response element (SRE), a short sequence of dyad symmetry located 300 bp to the 5' of the site of transcription initiation of some genes (such as FOS). Together with MRTFA transcription coactivator, controls expression of genes regulating the cytoskeleton during development, morphogenesis and cell migration. The SRF-MRTFA complex activity responds to Rho GTPase-induced changes in cellular globular actin (G-actin) concentration, thereby coupling cytoskeletal gene expression to cytoskeletal dynamics. Required for cardiac differentiation and maturation.
Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity (PubMed:15286784). Enhances trafficking of the glutamate transporter SLC1A1/EAAC1 from the endoplasmic reticulum to the cell surface (By similarity). Plays a role in the translocation of SLC2A4/GLUT4 from intracellular membranes to the cell membrane which facilitates the uptake of glucose into the cell (By similarity).
Interacts with isoform 1 but not isoform 3 of SPAST (PubMed:22232211). Interacts with BACE1 (PubMed:15286784). Interacts (via first transmembrane domain) with ARL6IP5/GTRAP3-18 (By similarity). Interacts (via N-terminus) with SLC1A1/EAAC1; the interaction promotes cell surface expression of SLC1A1 (By similarity).
Produced by alternative initiation at Met-341 of isoform RTN2-A.
Acts as a cytosolic iron-sulfur (Fe-S) cluster assembly factor that facilitates [2Fe-2S] cluster insertion into a subset of cytosolic proteins (PubMed:26613676, PubMed:27519415). Acts together with the monothiol glutaredoxin GLRX3 (PubMed:26613676, PubMed:27519415).
Interacts with GLRX3; forms a heterotrimeric complex composed by two BOLA2 molecules and one GLRX3 molecule; linked by [2Fe-2S] clusters (PubMed:22309771, PubMed:26613676, PubMed:27519415).
Different forms varying in molecular weight have been observed. Such forms are possibly due to different levels of glycosylation and protein cleavage (By similarity).
Highly expressed in synovial tissue, cartilage and liver and weakly in heart and lung. Isoform B is expressed in kidney, lung, liver, heart and brain. Isoform C and isoform D are widely expressed.
Isoform F plays a role as a growth factor acting on the primitive cells of both hematopoietic and endothelial cell lineages.
O-glycosylated; contains glycosaminoglycan chondroitin sulfate and keratan sulfate. O-glycosylated with sialylated oligosaccharides which are predominantly represented by the monosialylated core type I structure, NeuNAcalpha2-3Galbeta1-3GalNAc, with smaller amounts of disialylated O-glycans (PubMed:25187573).
Plays a role in boundary lubrication within articulating joints. Prevents protein deposition onto cartilage from synovial fluid by controlling adhesion-dependent synovial growth and inhibiting the adhesion of synovial cells to the cartilage surface.
Proteolytically cleaved by cathepsin CTSG.
The disulfide bond between Cys-1146 and Cys-1403 is essential for protein cleavage.
Arginine hydroxylase involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) at early stages (PubMed:18940309, PubMed:27226634). Acts by mediating hydroxylation of 'Arg-111' of NDUFS7 (PubMed:27226634). May also have methyltransferase activity (Probable).
Interacts with NDUFAF8, leading to stabilize NDUFAF5 (PubMed:27499296). Interacts with NDUFS7 (PubMed:27226634). Interacts with PYURF (via TRM112 domain); the interaction is direct and stabilizes NDUFAF5 protein (PubMed:35614220).
Belongs to the eukaryotic ribosomal protein eL15 family.
Component of the large ribosomal subunit (PubMed:23636399, PubMed:32669547). Interacts with IFIT1 (via TPR repeats 1-4) (PubMed:21612406).
Belongs to the glycosyltransferase 31 family. Beta3-Gal-T subfamily.
Glycosyltransferase that generates the core 1 O-glycan Gal-beta1-3GalNAc-alpha1-Ser/Thr (T antigen), which is a precursor for many extended O-glycans in glycoproteins. Plays a central role in many processes, such as angiogenesis, thrombopoiesis and kidney homeostasis development.
Homodimer; disulfide-linked (By similarity). Interacts with the C1GALT1C1 chaperone; required for galactosyltransferase activity.
Widely expressed. Highly expressed in kidney, heart, placenta and liver.
Interacts (via cytoplasmic region) with ILK.
Transmembrane receptor that senses neutrophil extracellular traps (NETs) and triggers the ILK-PARVB pathway to enhance cell motility (PubMed:32528174). NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation (PubMed:32528174). Formation of NETs is also associated with cancer metastasis, NET-DNA acting as a chemotactic factor to attract cancer cells (PubMed:32528174). Specifically binds NETs on its extracellular region, in particular the 8-OHdG-enriched DNA present in NETs, and recruits ILK, initiating the ILK-PARVB cascade to induce cytoskeleton rearrangement and directional migration of cells (PubMed:32528174). In the context of cancer, promotes cancer metastasis by sensing NETs and promoting migration of tumor cells (PubMed:32528174).
Activates RB1 transcription most probably by antagonizing ZBTB17 repression of RB1. Does not bind directly RB1 promoter.
Binds CDKN1A promoter and activates its transcription; this activity is further potentiated in the presence of EP300 (synergistic) and ZBTB17/Miz-1 (additive).
Highly expressed in normal epidermis and in other epithelial tissues, including in colon and lung. Tends to be down-regulated in colon, lung and skin cancer tissues.
Induced by the DNA-damaging agent etoposide. This induction is mediated by TP53 at the transcriptional level.
Isoform 1 interacts with EP300 and KAT5/Tip60. The interaction with EP300 is direct and leads to synergistic induction of CDKN1A. On the CDKN1A promoter, forms a complex with ZBTB17/Miz-1; this interaction leads to additive CDKN1A transactivation. Isoform 3 also interacts with ZBTB17; this interaction may block ZBTB17 repressor activity.
Transcription factor. Inhibits cell proliferation by activating either CDKN1A/p21 transcription or RB1 transcription.
(Microbial infection) Interacts with HCV core protein (PubMed:9651361).
Arg-296 and Arg-299 are dimethylated, probably to asymmetric dimethylarginine.
By DNA damage, including ionizing radiations and phleomycin treatment or UV irradiation. This induction requires ATM kinase activity (ionizing radiations and phleomycin) or ATR activity (UV irradiation). Up-regulation is due to protein stabilization. Constitutive protein levels are controlled by MDM2-mediated ubiquitination and degradation via the proteasome pathway.
Interacts with RBM42 and ZIK1 (By similarity). Interacts with BRDT (By similarity). Identified in the spliceosome C complex (PubMed:11991638). Interacts with ANKRD28 (PubMed:16564677). Interacts with ASFV p30 protein (PubMed:18775702). Interacts with DDX1 (PubMed:12183465). Interacts with MDM2; this interaction leads to ubiquitination and proteasomal degradation (PubMed:16360036). Interacts with p53/TP53 (PubMed:16360036). Interacts with IVNS1ABP (PubMed:23825951). Interacts with PPIA/CYPA (PubMed:25678563). Part of a transcription inhibitory ribonucleoprotein complex composed at least of the circular RNA circZNF827, ZNF827 and HNRNPL (PubMed:33174841).
One of the major pre-mRNA-binding proteins. Binds tenaciously to poly(C) sequences. Likely to play a role in the nuclear metabolism of hnRNAs, particularly for pre-mRNAs that contain cytidine-rich sequences. Can also bind poly(C) single-stranded DNA. Plays an important role in p53/TP53 response to DNA damage, acting at the level of both transcription activation and repression. When sumoylated, acts as a transcriptional coactivator of p53/TP53, playing a role in p21/CDKN1A and 14-3-3 sigma/SFN induction (By similarity). As far as transcription repression is concerned, acts by interacting with long intergenic RNA p21 (lincRNA-p21), a non-coding RNA induced by p53/TP53. This interaction is necessary for the induction of apoptosis, but not cell cycle arrest. As part of a ribonucleoprotein complex composed at least of ZNF827, HNRNPL and the circular RNA circZNF827 that nucleates the complex on chromatin, may negatively regulate the transcription of genes involved in neuronal differentiation (PubMed:33174841).
Sumoylated by CBX4. Sumoylation is increased upon DNA damage, such as that produced by doxorubicin, etoposide, UV light and camptothecin, due to enhanced CBX4 phosphorylation by HIPK2 under these conditions.
Ubiquitinated by MDM2. Doxorubicin treatment does not affect monoubiquitination, but slightly decreases HNRNPK poly-ubiquitination.
Acts as a transcriptional coactivator of ATF2.
Binds to the N-terminal region of ATF2. Associates with the TFIID complex through interaction with TBP.
The leucine-zipper domain is required for coactivation activity. When this domain is deleted, the protein is able to stimulate transcription from a number of gene promoters (By similarity).
(Microbial infection) Functions as a retroviral receptor and confers human cells susceptibility to infection to amphotropic murine leukemia virus (A-MuLV), 10A1 murine leukemia virus (10A1 MLV) and some feline leukemia virus subgroup B (FeLV-B) variants.
Belongs to the inorganic phosphate transporter (PiT) (TC 2.A.20) family.
Increased by phosphate depletion in osteosarcoma cell lines.
Sodium-phosphate symporter which preferentially transports the monovalent form of phosphate with a stoichiometry of two sodium ions per phosphate ion (PubMed:12205090, PubMed:15955065, PubMed:16790504, PubMed:17494632, PubMed:22327515, PubMed:28722801, PubMed:30704756). Plays a critical role in the determination of bone quality and strength by providing phosphate for bone mineralization (By similarity). Required to maintain normal cerebrospinal fluid phosphate levels (By similarity). Mediates phosphate-induced calcification of vascular smooth muscle cells (VCMCs) and can functionally compensate for loss of SLC20A1 in VCMCs (By similarity).
Probably acts as a transcriptional activator. Mediates neuronal differentiation. Required for the regulation of amacrine cell fate specification in the retina (By similarity).
Serine or threonine phosphorylation within the basic region may regulate neurogenic activity.
Deubiquitinated by USP13; leading to TOPBP1 stabilizion and activation of the ATR-TOPBP1 axis pathway.
Highly expressed in heart, brain, placenta, lung and kidney.
Interacts with POLE (PubMed:11395493). Interacts with RAD9A (PubMed:11395493). Interacts with UBR5 (PubMed:11714696). Interacts with E2F1 (PubMed:12697828, PubMed:15075294). Interacts with PML (PubMed:12773567). Interacts with SMARCA2 (PubMed:15075294). Interacts with SMARCA4 (PubMed:15075294). Interacts with RHNO1 (PubMed:21659603). May interact with TOP2B (PubMed:9461304). Interacts with TICRR (PubMed:20080954). Interacts with HELB (PubMed:25933514).
Phosphorylated on serine and threonine residues in response to X-ray irradiation.
Required for DNA replication. Plays a role in the rescue of stalled replication forks and checkpoint control (PubMed:33592542). Binds double-stranded DNA breaks and nicks as well as single-stranded DNA. Recruits the SWI/SNF chromatin remodeling complex to E2F1-responsive promoters. Down-regulates E2F1 activity and inhibits E2F1-dependent apoptosis during G1/S transition and after DNA damage. Induces a large increase in the kinase activity of ATR (PubMed:16530042).
Ubiquitinated and degraded by the proteasome. X-ray irradiation reduces ubiquitination.
Up-regulated during the S phase of the cell cycle. Up-regulated by E2F1 and interferon.
Has been found to be frequently mutated in melanoma (PubMed:21618342). ADAM7 mutations may play a role in melanoma progression and metastasis (PubMed:21618342). Expressed in melanoma cells but not in healthy melanocytes (PubMed:21618342).
Interacts with ITM2B in sperm; the interaction increases following capacitation (By similarity). Interacts with HSPA5 and CANX (By similarity).
Required for normal male fertility via maintenance of epithelial cell morphology in the caput epididymis and subsequently correct epididymis lumen structure required for sperm development (By similarity). Plays a role in sperm motility, flagella morphology and tyrosine phosphorylation during sperm capacitance (By similarity). Plays a role in normal expression levels of HSPA5, ITM2B and ADAM2 in sperm both prior to and post-capacitation (By similarity). This is a non catalytic metalloprotease-like protein (By similarity).
Belongs to the eukaryotic RPC4/POLR3D RNA polymerase subunit family.
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits (By similarity). Interacts with POLR3E/RPC5.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Specific peripheric component of RNA polymerase III which synthesizes small RNAs, such as 5S rRNA and tRNAs. Plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF- Kappa-B through the RIG-I pathway (By similarity).
A cytochrome P450 monooxygenase involved in the metabolism of retinoates (RAs), the active metabolites of vitamin A, and critical signaling molecules in animals (PubMed:22020119, PubMed:9228017, PubMed:9716180). RAs exist as at least four different isomers: all-trans-RA (atRA), 9-cis-RA, 13-cis-RA, and 9,13-dicis-RA, where atRA is considered to be the biologically active isomer, although 9-cis-RA and 13-cis-RA also have activity (Probable). Catalyzes the hydroxylation of atRA primarily at C-4 and C-18, thereby contributing to the regulation of atRA homeostasis and signaling (PubMed:22020119, PubMed:9228017, PubMed:9716180). Hydroxylation of atRA limits its biological activity and initiates a degradative process leading to its eventual elimination (Probable). Involved in the convertion of atRA to all-trans-4-oxo-RA. Able to metabolize other RAs such as 9-cis, 13-cis and 9,13-di-cis RA (By similarity) (PubMed:9228017). Can oxidize all-trans-13,14-dihydroretinoate (DRA) to metabolites which could include all-trans-4-oxo-DRA, all-trans-4-hydroxy-DRA, all-trans-5,8-epoxy-DRA, and all-trans-18-hydroxy-DRA (By similarity). May play a role in the oxidative metabolism of xenobiotics such as tazarotenic acid (PubMed:26937021).
Expressed in most fetal and adult tissues with highest levels in adult liver, heart, pituitary gland, adrenal gland, placenta and regions of the brain (PubMed:9826557). Expressed at high levels in lung, pancreas, skin and uterus (at protein level) (PubMed:22020119). Lower expression level is detected in spleen, kidney, intestine and adipose tissue (at protein level) (PubMed:22020119).
Belongs to the G-protein coupled receptor OA family.
Expressed at high levels in the retina, including the retinal pigment epithelium (RPE), and in melanocytes. Weak expression is observed in brain and adrenal gland.
Interacts with heterotrimeric G(i) proteins. Interacts with ARRB1 and ARRB2. Interacts with MLANA.
Receptor for tyrosine, L-DOPA and dopamine. After binding to L-DOPA, stimulates Ca(2+) influx into the cytoplasm, increases secretion of the neurotrophic factor SERPINF1 and relocalizes beta arrestin at the plasma membrane; this ligand-dependent signaling occurs through a G(q)-mediated pathway in melanocytic cells. Its activity is mediated by G proteins which activate the phosphoinositide signaling pathway. Also plays a role as an intracellular G protein-coupled receptor involved in melanosome biogenesis, organization and transport.
The cytoplasmic domain 3 and the C-terminus tail domain contain the lysosomal sorting signals and are necessary and sufficient for intracellular retention and delivery to lysosomal and melanosomal, respectively in melanocytic and non-melanocytic cells.
Abundant in testis, thymus, and in tumor derived cell lines, while barely detectable in liver, prostate, and kidney.
Associates with alpha- and beta-tubulins.
Possesses microtubule stabilizing properties. Involved in regulating aneuploidy, cell cycling, and cell death in a p53/TP53-dependent manner (By similarity).
Present at the G1/S boundary. Accumulates as cells progress from S to G2 into mitosis. Rapidly degraded during mitosis exit by CDH1-activated anaphase promoting complex/cyclosome (APC/C).
Up-regulated in primary human gastric cancers.
CDS lacks C-terminal region which is nevertheless present in the underlying cDNA.
Interacts with RHBG and SPTBN1 (PubMed:15262991, PubMed:15611082). Colocalizes with Na/K ATPase, Na/Ca exchanger and SPTBN1 (PubMed:19007774). Directly interacts with DMD; this interaction is necessary for DMD localization at the sarcolemma. Interacts with DCTN4; this interaction is required for DCTN4 retention at costameres. Identified in complexes that contain VIM, EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, PRX and spectrin (By similarity). Interacts (via death domain) with RABGAP1L (via Rab-GAP TBC domain) (PubMed:27718357).
Phosphorylated at multiple sites by different protein kinases and each phosphorylation event regulates the protein's structure and function.
Plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in several cell types, including cardiomyocytes, as well as in striated muscle cells. In skeletal muscle, required for proper localization of DMD and DCTN4 and for the formation and/or stability of a special subset of microtubules associated with costameres and neuromuscular junctions. In cardiomyocytes, required for coordinate assembly of Na/Ca exchanger, SLC8A1/NCX1, Na/K ATPases ATP1A1 and ATP1A2 and inositol 1,4,5-trisphosphate (InsP3) receptors at sarcoplasmic reticulum/sarcolemma sites. Required for expression and targeting of SPTBN1 in neonatal cardiomyocytes and for the regulation of neonatal cardiomyocyte contraction rate (PubMed:12571597). In the inner segment of rod photoreceptors, required for the coordinated expression of the Na/K ATPase, Na/Ca exchanger and beta-2-spectrin (SPTBN1) (By similarity). Plays a role in endocytosis and intracellular protein transport. Associates with phosphatidylinositol 3-phosphate (PI3P)-positive organelles and binds dynactin to promote long-range motility of cells. Recruits RABGAP1L to (PI3P)-positive early endosomes, where RABGAP1L inactivates RAB22A, and promotes polarized trafficking to the leading edge of the migrating cells. Part of the ANK2/RABGAP1L complex which is required for the polarized recycling of fibronectin receptor ITGA5 ITGB1 to the plasma membrane that enables continuous directional cell migration (By similarity).
Present in plasma membrane of neurons as well as glial cells throughout the brain. Expressed in fetal brain and in temporal cortex of adult brain. Also expressed in the inner segments of rod photoreceptors in retina.
The tandem configuration of the two ZU5 and the UPA domains forms a structural supramodule termed ZZU. ZU5-1 mediates interaction with beta-spectrin, and the ZU5-1/UPA interface is required for ankyrin's function other than binding to spectrin.
Abundant in testes, skeletal muscle and heart.
Associates with mitochondrial leucine tRNAs. Interacts with ELAC2.
Mitochondrial protein implicated in negative regulation of leucine tRNA levels, as well as negative regulation of mitochondria-encoded proteins and COX activity. Affects also the 3'-processing of mitochondrial tRNAs.
Heterodimer of a B chain and an A chain linked by two disulfide bonds.
Highly expressed in rectum with lower levels in uterus and ascending and descending colon.
May have a role in gut contractility or in thymic development and regulation. Activates RXFP4 with high potency and appears to be the endogenous ligand for this receptor.
Detected in fibroblasts (at protein level).
Extracellular matrix protein implicated in guidance of migrating neurons as well as axons during development, synaptic plasticity as well as neuronal regeneration. Promotes neurite outgrowth from cortical neurons grown on a monolayer of astrocytes. Ligand for integrins alpha-8/beta-1, alpha-9/beta-1, alpha-V/beta-3 and alpha-V/beta-6. In tumors, stimulates angiogenesis by elongation, migration and sprouting of endothelial cells (PubMed:19884327).
Homohexamer; disulfide-linked. A homotrimer may be formed in the triple coiled-coil region and may be stabilized by disulfide rings at both ends. Two of such half-hexabrachions may be disulfide linked within the central globule. Interacts with CSPG4.
May regulate some ion channels' activity and therebye regulate calcium fluxes during sperm capacitation.
(Microbial infection) Methylated at Cys-673 by enteropathogenic E.coli protein NleE or S.flexneri protein OspZ: methylation disrupts zinc-binding and ability to bind 'Lys-63'-linked ubiquitin, leading to NF-kappa-B inactivation.
Adapter required to activate the JNK and NF-kappa-B signaling pathways through the specific recognition of 'Lys-63'-linked polyubiquitin chains by its RanBP2-type zinc finger (NZF) (PubMed:10882101, PubMed:11460167, PubMed:15327770, PubMed:22158122, PubMed:33184450, PubMed:36681779). Acts as an adapter linking MAP3K7/TAK1 and TRAF6 to 'Lys-63'-linked polyubiquitin chains (PubMed:10882101, PubMed:11460167, PubMed:15327770, PubMed:22158122). The RanBP2-type zinc finger (NZF) specifically recognizes Lys-63'-linked polyubiquitin chains unanchored or anchored to the substrate proteins such as RIPK1/RIP1 and RIPK2: this acts as a scaffold to organize a large signaling complex to promote autophosphorylation of MAP3K7/TAK1, and subsequent activation of I-kappa-B-kinase (IKK) core complex by MAP3K7/TAK1 (PubMed:15327770, PubMed:18079694, PubMed:22158122). Regulates the IL1-mediated translocation of NCOR1 out of the nucleus (By similarity). Involved in heart development (PubMed:20493459).
Degraded in a lysosome-dependent manner following interaction with TRIM38.
Interacts with MAP3K7 and TRAF6 (PubMed:10882101). Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2 (PubMed:11460167). Binds 'Lys-63'-linked polyubiquitin chains (PubMed:19675569, PubMed:19935683). Interacts with NCOR1 and HDAC3 to form a ternary complex (By similarity). Interacts (via C-terminal) with NUMBL (via PTB domain) (PubMed:18299187). Interacts (via the C-terminus) with DYNC2I2 (via WD domains) (PubMed:19521662). Interacts with RBCK1 (PubMed:17449468). Interacts with TRIM5 (PubMed:21512573). Interacts with TRIM38 (via B30.2/SPRY domain), leading to its translocation to lysosomes and degradation (PubMed:24434549).
SUMOylated by TRIM60; leading to inhibition of MAPK/NF-kappaB activation and the innate immune response.
The RanBP2-type zinc finger (NZF) mediates binding to two consecutive 'Lys-63'-linked ubiquitins.
The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving TAB2 has been found in a family with congenital heart disease. Translocation t(2;6)(q21;q25).
Ubiquitinated; following IL1 stimulation or TRAF6 overexpression. Ubiquitination involves RBCK1 leading to proteasomal degradation. Ubiquitinated at Lys-611 by TRIM45 leading to proteasomal degradation (PubMed:36681779).
Widely expressed. In the embryo, expressed in the ventricular trabeculae, endothelial cells of the conotruncal cushions of the outflow tract and in the endothelial cells lining the developing aortic valves.
Acts as component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. Core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built (PubMed:32453425, PubMed:34694004, PubMed:34700328, PubMed:35585232, PubMed:25661590, PubMed:9305914). The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity (PubMed:32453425). Required for S-phase checkpoint activation upon UV-induced damage.
Component of the MCM2-7 complex (PubMed:9305914, PubMed:16899510, PubMed:17296731). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (PubMed:9305914, PubMed:16899510, PubMed:17296731, PubMed:32453425). Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex (PubMed:34700328, PubMed:34694004, PubMed:32453425). Interacts with the ATR-ATRIP complex and with RAD17 (PubMed:15210935, PubMed:15538388). Interacts with TIPIN (PubMed:17116885). Interacts with MCMBP (PubMed:17296731). Interacts with ANKRD17 (PubMed:23711367). Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR (PubMed:28191891).
Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. Specifically a MCM467 subcomplex is shown to have in vitro helicase activity which is inhibited by the MCM2 subunit. The MCM2-7 hexamer is the proposed physiological active complex.
Ubiquitinated by ECS(LRR1) E3 ubiquitin-protein ligase complex when forks converge following formation of DNA interstrand cross-links. During mitosis, ubiquitinated by TRAIP when forks converge following formation of DNA interstrand cross-links (By similarity). Short ubiquitin chains on MCM7 promote recruitment of DNA glycosylase NEIL3 (By similarity). If the interstrand cross-link cannot be cleaved by NEIL3, the ubiquitin chains continue to grow on MCM7, promoting the unloading of the CMG helicase complex by the VCP/p97 ATPase (By similarity).
Belongs to the DNA polymerase type-Y family.
Deoxycytidyl transferase involved in DNA repair. Transfers a dCMP residue from dCTP to the 3'-end of a DNA primer in a template-dependent reaction. May assist in the first step in the bypass of abasic lesions by the insertion of a nucleotide opposite the lesion. Required for normal induction of mutations by physical and chemical agents.
Monomer. Interacts with the DNA polymerase zeta which is composed of REV3L and MAD2L2; the interaction with MAD2L2 is direct and requires that REV3L is in its closed conformation. Interacts with POLH, POLI and POLK. May bind ITGA3. Interacts with FAAP20/C1orf86.
The C-terminal domain is necessary for protein interactions.
Expressed in hair root but not in skin. Expressed also in brain and skeletal muscle.
Myoblast-specific protein that mediates myoblast fusion, an essential step for the formation of multi-nucleated muscle fibers (PubMed:28681861). Actively participates in the membrane fusion reaction by mediating the mixing of cell membrane lipids (hemifusion) upstream of MYMX. Acts independently of MYMX (By similarity). Involved in skeletal muscle regeneration in response to injury by mediating the fusion of satellite cells, a population of muscle stem cells, with injured myofibers (By similarity). Also involved in skeletal muscle hypertrophy, probably by mediating the fusion of satellite cells with myofibers (By similarity).
Palmitoylated at the C-terminus; palmitoylation promotes localization to the Golgi apparatus.
Associates with EBI3 to form the IL-27 interleukin, a heterodimeric cytokine which functions in innate immunity. IL-27 has pro- and anti-inflammatory properties, that can regulate T-helper cell development, suppress T-cell proliferation, stimulate cytotoxic T-cell activity, induce isotype switching in B-cells, and that has diverse effects on innate immune cells. Among its target cells are CD4 T-helper cells which can differentiate in type 1 effector cells (TH1), type 2 effector cells (TH2) and IL17 producing helper T-cells (TH17). It drives rapid clonal expansion of naive but not memory CD4 T-cells. It also strongly synergizes with IL-12 to trigger interferon-gamma/IFN-gamma production of naive CD4 T-cells, binds to the cytokine receptor WSX-1/TCCR which appears to be required but not sufficient for IL-27-mediated signal transduction. IL-27 potentiate the early phase of TH1 response and suppress TH2 and TH17 differentiation. It induces the differentiation of TH1 cells via two distinct pathways, p38 MAPK/TBX21- and ICAM1/ITGAL/ERK-dependent pathways. It also induces STAT1, STAT3, STAT4 and STAT5 phosphorylation and activates TBX21/T-Bet via STAT1 with resulting IL12RB2 up-regulation, an event crucial to TH1 cell commitment. It suppresses the expression of GATA3, the inhibitor TH1 cells development. In CD8 T-cells, it activates STATs as well as GZMB. IL-27 reveals to be a potent inhibitor of TH17 cell development and of IL-17 production. Indeed IL27 alone is also able to inhibit the production of IL17 by CD4 and CD8 T-cells. While IL-27 suppressed the development of pro-inflammatory Th17 cells via STAT1, it inhibits the development of anti-inflammatory inducible regulatory T-cells, iTreg, independently of STAT1. IL-27 has also an effect on cytokine production, it suppresses pro-inflammatory cytokine production such as IL2, IL4, IL5 and IL6 and activates suppressors of cytokine signaling such as SOCS1 and SOCS3. Apart from suppression of cytokine production, IL-27 also antagonizes the effects of some cytokines such as IL6 through direct effects on T-cells. Another important role of IL-27 is its antitumor activity as well as its antiangiogenic activity with activation of production of antiangiogenic chemokines such as IP-10/CXCL10 and MIG/CXCL9. In vein endothelial cells, it induces IRF1/interferon regulatory factor 1 and increase the expression of MHC class II transactivator/CIITA with resulting up-regulation of major histocompatibility complex class II. IL-27 also demonstrates antiviral activity with inhibitory properties on HIV-1 replication.
Heterodimer with EBI3; not disulfide-linked. This heterodimer is known as interleukin IL-27.
Transiently induced by bacterial lipopolysaccharides (LPS) stimulation in monocytes.
During maturation of dendritic cells, expression is down-regulated and stabilizes MHC class II proteins accumulate at the plasma membrane.
E3 ubiquitin-protein ligase that mediates ubiquitination of TFRC, CD86, FAS and MHC class II proteins, such as HLA-DR alpha and beta, and promotes their subsequent endocytosis and sorting to lysosomes via multivesicular bodies. By constitutively ubiquitinating MHC class II proteins in immature dendritic cells, down-regulates their cell surface localization thus sequestering them in the intracellular endosomal system.
Expressed in antigen presenting cells, APCs, located in lymph nodes and spleen. Also expressed in lung. Expression is high in follicular B-cells, moderate in dendritic cells and low in splenic T-cells.
Has a short half-life. Instability/short half-life permits rapid changes that allow efficient induction of antigen presentation once antigen presenting cells, APCs, receive maturation signals. Small changes in protein levels significantly alter the cell surface display of MHC class II proteins (By similarity).
Defects in RASGRP2 were initially thought (PubMed:17576779) to be the cause of leukocyte adhesion deficiency type 3 (LAD3), a syndrome characterized by recurrent bacterial infections and major bleeding disorders. However, it was later shown (PubMed:19064721, PubMed:19234463, PubMed:19234460) that it is not the case and that LAD3 is caused by defects in FERMT3 gene.
Detected in platelets, neutrophils and T lymphocytes (at protein level). Expressed in brain where it is enriched in the striatum. Also expressed in the hematopoietic system. Detected in heart, brain, lung, placenta, liver, skeletal muscle and kidney.
Forms a signaling complex with RAP1 and BRAF (By similarity). Interacts with RAP1. Interacts with F-actin.
Functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP. May also activate other GTPases such as RRAS, RRAS2, NRAS, KRAS but not HRAS. Functions in aggregation of platelets and adhesion of T-lymphocytes and neutrophils probably through inside-out integrin activation. May function in the muscarinic acetylcholine receptor M1/CHRM1 signaling pathway.
Isoform 1 and isoform 2 are differently regulated by calcium and DAG.
Isoform 2 is palmitoylated and myristoylated.
The N-terminal Ras-GEF domain mediates association with F-actin.
The corresponding protein is not undetectable.
Expressed in malignantly transformed cells but not detected in normal tissues.
Functions as an integral cofactor in cell pH regulation by controlling plasma membrane-type Na(+)/H(+) exchange activity. Binds to and activates SLC9A1/NHE1 in a serum-independent manner, thus increasing pH and protecting cells from serum deprivation-induced death. Also plays a role in the regulation of cell proliferation and tumor growth by increasing the phosphatase activity of PPP3CA in a calcium-dependent manner. Activator of the calcineurin/NFAT signaling pathway. Involved in the cytoplasmic translocation of the transcription factor NFATC3 to the nucleus.
Interacts with PPP3CA. Interacts with SLC9A1/NHE1; the interaction occurs in a calcium-dependent manner.
Essential for the proper localization of brevican (BCAN), mainly as a perineuronal nets (PNNs)-type deposition in the brainstem and cerebellum thereby playing a key role in the formation and structural organization of PNNs (By similarity). Contributes to the formation and transmission of inhibitory GABAergic synapses between Purkinje cells and deep cerebellar nuclei neurons (By similarity).
Contrarily to other members of the family that can bind several FGF receptors FGF19 is specific for FGFR4.
Expressed in fetal brain, cartilage, retina, and adult gall bladder.
Induced by the bile acids receptor NR1H4 that binds and activates a NR1H4-responsive element within intron 2.
Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by KL, KLB and heparan sulfate glycosaminoglycans that function as coreceptors. Interacts with KL; this interaction is direct. Interacts with KLB; this interaction is direct. Interacts with FGFR4 in the presence of heparin, KL or KLB. Interacts with MALRD1 (PubMed:23747249).
Involved in the suppression of bile acid biosynthesis through down-regulation of CYP7A1 expression, following positive regulation of the JNK and ERK1/2 cascades. Stimulates glucose uptake in adipocytes. Activity requires the presence of KLB and FGFR4.
Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini. Is a component of the double-stranded telomeric DNA-binding TRF1 complex which is involved in the regulation of telomere length by cis-inhibition of telomerase. Also acts as a single-stranded telomeric DNA-binding protein and thus may act as a downstream effector of the TRF1 complex and may transduce information about telomere maintenance and/or length to the telomere terminus. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Binds to two or more telomeric single-stranded 5'-TTAGGG-3' repeats (G-strand) and with high specificity to a minimal telomeric single-stranded 5'-TAGGGTTAG-3' sequence. Binds telomeric single-stranded sequences internally or at proximity of a 3'-end. Its activity is TERT dependent but it does not increase TERT activity by itself. In contrast, the ACD-POT1 heterodimer enhances telomere elongation by increasing telomerase processivity.
Homodimer or homooligomer (PubMed:17237768). Component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP, ACD and POT1 (PubMed:15316005, PubMed:15383534). Binds single-stranded telomeric DNA as a monomer (PubMed:15558049). Associated component of the telomerase holoenzyme complex (PubMed:19179534). Found in a complex with TERF1, TINF2 and TNKS1 (PubMed:12768206). Interacts with TNKS1. Forms heterodimers with ACD (PubMed:15231715). Identified in a complex with ACD and single-stranded telomeric DNA (PubMed:17237768).
Component of the dolichol-phosphate mannose (DPM) synthase complex composed of DPM1, DPM2 and DPM3; within the complex, associates with DPM1 via its C-terminal domain and with DPM2 via its N-terminal portion (PubMed:10835346, PubMed:19576565). This interaction stabilizes DPM1 protein (PubMed:19576565).
Component of the dolichol-phosphate mannose (DPM) synthase complex.
Stabilizer subunit of the dolichol-phosphate mannose (DPM) synthase complex; tethers catalytic subunit DPM1 to the endoplasmic reticulum.
Stabilizer subunit of the dolichol-phosphate mannose (DPM) synthase complex; tethers catalytic subunit to the ER.
Controls cell shape changes in the neuroepithelium during neural tube closure. Induces apical constriction in epithelial cells by promoting the apical accumulation of F-actin and myosin II, and probably by bundling stress fibers (By similarity). Induces apicobasal cell elongation by redistributing gamma-tubulin and directing the assembly of robust apicobasal microtubule arrays (By similarity).
Interacts with F-actin (By similarity). Interacts with ROCK1 (PubMed:22493320).
It is uncertain whether Met-1 or Met-2 is the initiator. Met-2 is more conserved than Met-1 among the orthologs.
The ASD1 domain mediates F-actin binding.
The ASD2 domain mediates the interaction with ROCK1 and is required for apical constriction induction.
Catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) to phosphatidylinositol-4-phosphate (PtdIns-4-P) (PubMed:16365287). Does not hydrolyze phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-bisphosphate, inositol 3,5-bisphosphate, inositol 3,4-bisphosphate, phosphatidylinositol 5-monophosphate, phosphatidylinositol 4-monophosphate and phosphatidylinositol 3-monophosphate (PubMed:16365287). Negatively regulates the phagocytosis of large particles by reducing phagosomal phosphatidylinositol 4,5-bisphosphate accumulation during cup formation (By similarity).
Low level in normal B and T-cells, high level in activated lymphocytes and monocytes. Also found in thymus, tonsil, bone marrow, developing vessels, and fetal brain.
Transcription factor required for TBX21/T-bet-dependent maturation of Th1 cells as well as maintenance of Th1-specific gene expression. Involved in embryogenesis and hematopoiesis (By similarity).
Calcium/calmodulin-dependent cyclic nucleotide phosphodiesterase with a dual specificity for the second messengers cGMP and cAMP, which are key regulators of many important physiological processes. Has a higher efficiency with cGMP compared to cAMP.
Homodimer (By similarity). Interacts with YWHAZ (PubMed:16959763).
Several tissues, including brain, kidney, testes and heart.
Catalyzes the attachment of leucine to its cognate tRNA.
Ubiquitously expressed, but highest expression in tissues with high metabolic rates, such as skeletal muscle, heart, and kidney.
Belongs to the Nudix hydrolase family. PCD1 subfamily.
Expressed in liver, kidney, pancreas, pituitary, small intestine, spleen, heart and placenta. Weakly expressed in brain.
Fatty acyl-coenzyme A (CoA) diphosphatase that hydrolyzes fatty acyl-CoA to yield acyl-4'-phosphopantetheine and adenosine 3',5'-bisphosphate (By similarity). Cleaves CoA, CoA esters and oxidized CoA with similar efficiencies (By similarity). Preferentially hydrolyzes medium-chain acyl-CoAs and bile acid-CoAs (By similarity). Has no activity toward NDP-sugars, CDP-alcohols, (deoxy)nucleoside 5'-triphosphates, nucleoside 5'-di or monophosphates, diadenosine polyphosphates, NAD, NADH, NADP, NADPH or thymidine-5'-monophospho-p-nitrophenyl ester (By similarity). May be required to eliminate oxidized CoA from peroxisomes, or regulate CoA and acyl-CoA levels in this organelle in response to metabolic demand (By similarity). Does not play a role in U8 snoRNA decapping activity (By similarity). Binds U8 snoRNA (By similarity). Exhibits decapping activity towards dpCoA-capped RNAs in vitro (By similarity).
Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape and migration. Required for developmental angiogenesis (By similarity). In this process, required for microtubule reorganization and for efficient endothelial cell elongation. In quiescent endothelial cells, triggers rearrangement of the actin cytoskeleton, but does not alter microtubule alignement.
Pancreas. Not detectable in keratinocytes.
Was originally thought to be elastase 1.
Contains a protease-associated domain (PA) of unknown function.
Involved in endoplasmic reticulum-associated degradation (ERAD). Accelerates the glycoprotein ERAD by proteasomes, by catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans (PubMed:25092655). May also participate in mannose trimming from all glycoproteins and not just misfolded ones targeted to ERAD (PubMed:34143952). May have alpha 1,2-mannosidase activity (By similarity).
A pair of annexin repeats may form one binding site for calcium and phospholipid.
Inhibitor of phospholipase A2, also possesses anti-coagulant properties. Also cleaves the cyclic bond of inositol 1,2-cyclic phosphate to form inositol 1-phosphate.
Auxiliary enzyme of beta-oxidation. It participates in the metabolism of unsaturated fatty enoyl-CoA esters having double bonds in both even- and odd-numbered positions in mitochondria. Catalyzes the NADP-dependent reduction of 2,4-dienoyl-CoA to yield trans-3-enoyl-CoA.
Heart = liver = pancreas > kidney >> skeletal muscle = lung.
The protein represented in this entry is involved in disease pathogenesis. A selective decrease in mitochondrial NADP(H) levels due to NADK2 mutations causes a deficiency of NADPH-dependent mitochondrial enzymes, such as DECR1 and AASS.
Postsynaptic density scaffolding protein. Binds and cross-links cytoplasmic regions of GRM1, GRM5, ITPR1, DNM3, RYR1, RYR2, SHANK1 and SHANK3. By physically linking GRM1 and GRM5 with ER-associated ITPR1 receptors, it aids the coupling of surface receptors to intracellular calcium release. Isoforms can be differently regulated and may play an important role in maintaining the plasticity at glutamatergic synapses. Negatively regulates T cell activation by inhibiting the calcineurin-NFAT pathway. Acts by competing with calcineurin/PPP3CA for NFAT protein binding, hence preventing NFAT activation by PPP3CA (PubMed:18218901).
Tetramer (PubMed:19345194). Isoform 1 and isoform 2 encode coiled-coil structures that mediate homo- and heteromultimerization. Interacts with NFATC2; interaction is calcium independent; interaction competes with PPP3CA for NFATC2 binding; interaction is reduced by AKT activation (PubMed:18218901). Interacts with NFATC1 and NFATC4 (PubMed:18218901). Interacts with SHANK1; forms a high-order complex at least composed of SHANK1 and HOMER3; the complex formation is regulated by CAMK2A-mediated phosphorylation (PubMed:19345194).
The WH1 domain interacts with the PPXXF motif in GRM1, GRM5, RYR1, RYR2, ITPR1, SHANK 1 and SHANK3.
Induces cartilage and bone formation. May be the osteoinductive factor responsible for the phenomenon of epithelial osteogenesis. Plays a role in calcium regulation and bone homeostasis (By similarity).
By hydrogen peroxide and UV irradiation (PubMed:14749723, PubMed:15976810). In pancreatic islets, expression increases under hyperglycemic conditions (PubMed:22611253). Expression is also induced by sulforaphane, an isothiocyanate obtained from cruciferous vegetables (PubMed:26995087).
Cys-106 is easily oxidized to sulfinic acid.
Deglycase activity does not require glutathione as a cofactor, however, glycated glutathione constitutes a PARK7 substrate.
Glyoxalase activity has been reported (PubMed:22523093, PubMed:31653696). It may however reflect its deglycase activity (PubMed:25416785).
Highly expressed in pancreas, kidney, skeletal muscle, liver, testis and heart. Detected at slightly lower levels in placenta and brain (at protein level). Detected in astrocytes, Sertoli cells, spermatogonia, spermatids and spermatozoa. Expressed by pancreatic islets at higher levels than surrounding exocrine tissues (PubMed:22611253).
Homodimer (PubMed:12851414, PubMed:12796482, PubMed:12855764, PubMed:31653696). Binds EFCAB6/DJBP and PIAS2 (PubMed:11477070, PubMed:12851414, PubMed:12612053). Part of a ternary complex containing PARK7, EFCAB6/DJBP and AR (PubMed:12612053). Interacts (via N-terminus) with OTUD7B (PubMed:21097510). Interacts with BBS1, HIPK1, CLCF1 and MTERF (PubMed:16390825, PubMed:21097510). Forms a complex with PINK1 and PRKN (PubMed:19229105). Interacts (via C-terminus) with NCF1; the interaction is enhanced by LPS and modulates NCF1 phosphorylation and membrane translocation (By similarity). Interacts with NENF (PubMed:31536960).
In pancreatic islets, expression increases during aging.
Multifunctional protein with controversial molecular function which plays an important role in cell protection against oxidative stress and cell death acting as oxidative stress sensor and redox-sensitive chaperone and protease (PubMed:17015834, PubMed:20304780, PubMed:18711745, PubMed:12796482, PubMed:19229105, PubMed:25416785, PubMed:26995087, PubMed:28993701). It is involved in neuroprotective mechanisms like the stabilization of NFE2L2 and PINK1 proteins, male fertility as a positive regulator of androgen signaling pathway as well as cell growth and transformation through, for instance, the modulation of NF-kappa-B signaling pathway (PubMed:12612053, PubMed:15502874, PubMed:14749723, PubMed:17015834, PubMed:21097510, PubMed:18711745). Has been described as a protein and nucleotide deglycase that catalyzes the deglycation of the Maillard adducts formed between amino groups of proteins or nucleotides and reactive carbonyl groups of glyoxals (PubMed:25416785, PubMed:28596309). But this function is rebuted by other works (PubMed:27903648, PubMed:31653696). As a protein deglycase, repairs methylglyoxal- and glyoxal-glycated proteins, and releases repaired proteins and lactate or glycolate, respectively. Deglycates cysteine, arginine and lysine residues in proteins, and thus reactivates these proteins by reversing glycation by glyoxals. Acts on early glycation intermediates (hemithioacetals and aminocarbinols), preventing the formation of advanced glycation endproducts (AGE) that cause irreversible damage (PubMed:25416785, PubMed:28013050, PubMed:26995087). Also functions as a nucleotide deglycase able to repair glycated guanine in the free nucleotide pool (GTP, GDP, GMP, dGTP) and in DNA and RNA. Is thus involved in a major nucleotide repair system named guanine glycation repair (GG repair), dedicated to reversing methylglyoxal and glyoxal damage via nucleotide sanitization and direct nucleic acid repair (PubMed:28596309). Protects histones from adduction by methylglyoxal, controls the levels of methylglyoxal-derived argininine modifications on chromatin (PubMed:30150385). Able to remove the glycations and restore histone 3, histone glycation disrupts both local and global chromatin architecture by altering histone-DNA interactions as well as histone acetylation and ubiquitination levels (PubMed:30150385, PubMed:30894531). Displays a very low glyoxalase activity that may reflect its deglycase activity (PubMed:22523093, PubMed:31653696, PubMed:28993701). Eliminates hydrogen peroxide and protects cells against hydrogen peroxide-induced cell death (PubMed:16390825). Required for correct mitochondrial morphology and function as well as for autophagy of dysfunctional mitochondria (PubMed:19229105, PubMed:16632486). Plays a role in regulating expression or stability of the mitochondrial uncoupling proteins SLC25A14 and SLC25A27 in dopaminergic neurons of the substantia nigra pars compacta and attenuates the oxidative stress induced by calcium entry into the neurons via L-type channels during pacemaking (PubMed:18711745). Regulates astrocyte inflammatory responses, may modulate lipid rafts-dependent endocytosis in astrocytes and neuronal cells (PubMed:23847046). In pancreatic islets, involved in the maintenance of mitochondrial reactive oxygen species (ROS) levels and glucose homeostasis in an age- and diet dependent manner. Protects pancreatic beta cells from cell death induced by inflammatory and cytotoxic setting (By similarity). Binds to a number of mRNAs containing multiple copies of GG or CC motifs and partially inhibits their translation but dissociates following oxidative stress (PubMed:18626009). Metal-binding protein able to bind copper as well as toxic mercury ions, enhances the cell protection mechanism against induced metal toxicity (PubMed:23792957). In macrophages, interacts with the NADPH oxidase subunit NCF1 to direct NADPH oxidase-dependent ROS production, and protects against sepsis (By similarity).
Sumoylated on Lys-130 by PIAS2 or PIAS4; which is enhanced after ultraviolet irradiation and essential for cell-growth promoting activity and transforming activity.
The protein deglycation activity is controversial. It has been ascribed to a TRIS buffer artifact by a publication (PubMed:27903648) and as a result of the removal of methylglyoxal by glyoxalase activity that leads to a subsequent decomposition of hemithioacetals and hemianimals due to the shift in equilibrium position by another one (PubMed:31653696). However, biochemical experiments showing that PARK7 is a bona fide deglycase have been performed (PubMed:25416785, PubMed:28013050, PubMed:28596309).
Undergoes cleavage of a C-terminal peptide and subsequent activation of protease activity in response to oxidative stress.
Expressed in retina pigment epithelial cells (at protein level). Widely expressed.
Found in a complex with ARL2BP, ARL2 and SLC25A6. Found in a complex with ARL2, ARL2BP and SLC25A4. Interacts with STAT2, STAT3 and STAT4. Interacts with GTP-bound ARL2 and ARL3; the complex ARL2-ARL2BP as well as ARL2BP alone, binds to SLC25A4. Interaction with ARL2 may be required for targeting to cilia basal body. Interacts with STAT3; interaction is enhanced with ARL2.
Together with ARL2, plays a role in the nuclear translocation, retention and transcriptional activity of STAT3. May play a role as an effector of ARL2.
Belongs to the sodium channel auxiliary subunit SCN2B (TC 8.A.17) family.
Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-2 causes an increase in the plasma membrane surface area and in its folding into microvilli. Interacts with TNR may play a crucial role in clustering and regulation of activity of sodium channels at nodes of Ranvier (By similarity).
Genetic variations in SCN2B may be involved in Brugada syndrome (PubMed:23559163). This tachyarrhythmia is characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset.
The voltage-sensitive sodium channel consists of an ion-conducting pore-forming alpha subunit (such as SCN2A or SCN8A) regulated by one or more beta subunits (SCN1B, SCN2B, SCN3B and SCN4B). SCN1B and SCN3B are non-covalently associated with the alpha subunit. SCN2B and SCN4B are disulfide-linked to the alpha subunit.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRP sub-subfamily.
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. In the uterus, the function of the receptor appears to be related to tissue contractility. The binding of this pI subunit with other GABA(A) receptor subunits alters the sensitivity of recombinant receptors to modulatory agents such as pregnanolone.
Generally pentameric. There are five types of GABA(A) receptor chains: alpha, beta, gamma, delta, and epsilon. A sixth class of subunit: Rho form homomeric GABA receptors that do not appear to coexist with GABA(A) receptor subunits but with GABA(C) receptor subunits. Subunit Pi can also bind this complex.
Most abundant in the uterus, also expressed in lung, thymus and prostate.
Interacts with DNTTIP1 (PubMed:21573134). Identified in a complex with KCDT19, HDAC1 and HSPA2 (By similarity). Component of a histone deacetylase complex containing DNTTIP1, ZNF541, HDAC1 and HDAC2 (PubMed:21573134). Identified in a complex with HDAC1, HDAC2, DNTTIP1 and KCTD19 (By similarity).
Transcription regulator which is essential for male fertility and for the completion of meiotic prophase in spermatocytes. Regulates progression of the pachytene stage of meiotic prophase by activating the expression of genes involved in meiosis during spermatogenesis. Maintains the repression of pre-pachytene transcriptional programs, including meiotic double-strand breaks (DSB) formation genes in pachytene spermatocytes and suppresses aberrant DSB formation after mid-pachytene, thus ensuring meiosis progression.
Overlaps in opposite strand with ZNF428.
A chromosomal aberration involving NUTM1 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with BRD4 which produces a BRD4-NUTM1 fusion protein.
A chromosomal aberration involving NUTM1 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;9)(q14;q34) with BRD3 which produces a BRD3-NUTM1 fusion protein.
Phosphorylation on Ser-1026, Ser-1029 or Ser-1031 is important for cytoplasmic export.
Plays a role in the regulation of proliferation. Regulates TERT expression by modulating SP1 binding to TERT promoter binding sites.
Expressed in brain (at protein level). Expressed in spinal cord. Isoform 2 expression is up-regulated in the prefrontal cortex (Brodmann's area 46) of patients with schizophrenia (postmortem brain study).
Interacts with calmodulin (via C-terminus); the interaction is dependent on Ca(2+) (By similarity). Interacts (via C-terminus) with TMEM106B (via N-terminus) (PubMed:24357581). Interacts with ZDHHC17 (via ANK repeats) (PubMed:26198635). Interacts with ZDHHC13 (via ANK repeats) (PubMed:26198635).
Involved in microtubule stabilization in many cell types, including neuronal cells (By similarity). Specifically has microtubule cold stabilizing activity (By similarity). Involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking via its interaction with TMEM106B (PubMed:24357581). Regulates KIF5A-mediated axonal cargo transport (By similarity). Regulates axonal growth during neuron polarization (By similarity).
Palmitoylated. Probably depalmitoylated by ABHD17A, ABHD17B and ABHD17C. During neuronal polarization, palmitoylation and depalmitoylation cycles regulate MAP6 shuttling between secretory vesicles and microtubules, and its polarized distribution in the axon.
Contains two homologous but distinct carbohydrate-binding domains.
Galectin that binds lactose and a related range of sugars. May be involved in the assembly of adherens junctions.
Glutathionylated (By similarity). N-glycosylated (By similarity).
Involved in cell adhesion and establishing epithelial cell polarity.
The sodium/potassium-transporting ATPase is composed of a catalytic alpha subunit, an auxiliary non-catalytic beta subunit and an additional regulatory subunit. Interacts with catalytic subunit ATP12A (By similarity). Interacts with regulatory subunit FXYD1 (By similarity). Interacts with regulatory subunit FXYD3 (By similarity). Interacts with NKAIN1, NKAIN2 and NKAIN4 (By similarity). Interacts with MLC1 (PubMed:22328087). Part of a complex containing MLC1, TRPV4, AQP4 and HEPACAM (PubMed:22328087). Interacts with KIRREL3 (PubMed:25902260). Interacts with OBSCN (via protein kinase domain 1) (By similarity). Interacts with TRAF3 and TRAF6 (PubMed:34011520).
This is the non-catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of Na(+) and K(+) ions across the plasma membrane.
This is the non-catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of Na(+) and K(+) ions across the plasma membrane. The beta subunit regulates, through assembly of alpha/beta heterodimers, the number of sodium pumps transported to the plasma membrane (PubMed:19694409). Plays a role in innate immunity by enhancing virus-triggered induction of interferons (IFNs) and interferon stimulated genes (ISGs). Mechanistically, enhances the ubiquitination of TRAF3 and TRAF6 as well as the phosphorylation of TAK1 and TBK1 (PubMed:34011520).
Belongs to the CMP-NeuNAc synthase family.
Catalyzes the activation of N-acetylneuraminic acid (NeuNAc) to cytidine 5'-monophosphate N-acetylneuraminic acid (CMP-NeuNAc), a substrate required for the addition of sialic acid. Has some activity toward NeuNAc, N-glycolylneuraminic acid (Neu5Gc) or 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (KDN).
Homotetramer; the active enzyme is formed by a dimer of dimers.
The BC2 (basic cluster 2) motif is necessary and sufficient for the nuclear localization and contains the catalytic active site. The localization in the nucleus is however not required for the enzyme activity (By similarity).
Ubiquitously expressed. Expressed in pancreas, kidney, liver, skeletal muscle, lung, placenta, brain, heart, colon, PBL, small intestine, ovary, testis, prostate, thymus and spleen.
Encoded by an exapted DNA transposon located in an intron of the ZC3H11A gene.
Expressed in pancreatic islet cells (at protein level).
Transcriptional repressor which binds to the consensus sequence 5'-GCTCGC-3', transcription regulation may be tissue-specific (By similarity). Regulates the expression of target genes such as: IGF2, PGAP6/TMEM8, ENHO, and PIANP (By similarity). Acts as a transcriptional repressor of growth factor IGF2, thereby negatively regulating postnatal growth of muscles and internal organs, especially in females (By similarity). Negatively regulates myoblast differentiation and myoblast mitochondrial activity via its regulation of IGF2 transcription (By similarity). Negatively regulates the cell cycle of myoblasts, potentially via transcriptional regulation of the E2F family of transcription factors such as: E2F1 and E2F2 (By similarity). Positively regulates the cell cycle and survival of pancreatic beta cells (PubMed:24043816). Binds to the CDH2 gene and may directly repress CDH2 transcription (By similarity). Probably by controlling CDH2 expression, regulates pancreatic beta cell adhesion, and formation of cell-to-cell junctions between pancreatic beta cells and neural crest stem cells (By similarity). May also play a role in embryonic beta cell differentiation (By similarity). May play a role in insulin sensitivity and glucose clearance (By similarity).
Interacts with ELAVL1; the interaction is indirect, mRNA-dependent and may regulate p53/TP53 expression (By similarity). Interacts with p53/TP53; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest.
RNA-binding protein that affects the localization and the translation of a subset of mRNA. May play a role in adipogenesis through binding to the 3'-UTR of CEBPA mRNA and regulation of its translation. Targets ITPR1 mRNA to dendrites in Purkinje cells, and may regulate its activity-dependent translation. With ELAVL1, binds the 3'-UTR of p53/TP53 mRNAs to control their nuclear export induced by CDKN2A. Hence, may regulate p53/TP53 expression and mediate in part the CDKN2A anti-proliferative activity. May also bind CCNB1 mRNA. Alternatively, may also regulate p53/TP53 activity through direct protein-protein interaction. Interacts with p53/TP53 and promotes cell-cycle arrest over apoptosis enhancing preferentially the DNA binding and transactivation of p53/TP53 on cell-cycle arrest target genes over proapoptotic target genes. May also regulate the ubiquitination and stability of CDKN1A promoting DNA damage-induced cell cycle arrest. Also plays a role in megakaryocytes differentiation.
Ubiquitinated upon prolonged exposure to genotoxic stress, which leads to proteasomal degradation of ZNF385A and releases p53/TP53 from cell-cycle arrest target gene promoters.
Up-regulated by p53/TP53 in response to DNA damage and oxidative stress.
Essential for mesoderm formation and axial patterning during embryonic development.
Catalyzes the transfer of sulfate to position 4 of the N-acetylgalactosamine (GalNAc) residue of chondroitin and desulfated dermatan sulfate. Chondroitin sulfate constitutes the predominant proteoglycan present in cartilage and is distributed on the surfaces of many cells and extracellular matrices. Activity toward partially desulfated dermatan sulfate is however lower. Does not form 4, 6-di-O-sulfated GalNAc when chondroitin sulfate C is used as an acceptor.
Widely expressed. Expressed a high level in spinal chord, heart, spleen, thyroid, pituitary gland, adrenal gland, peripheral blood leukocytes, thymus, lung, small intestine, fetal kidney, fetal spleen and fetal lung.
Belongs to the SMC family. SMC2 subfamily.
Central component of the condensin complex, a complex required for conversion of interphase chromatin into mitotic-like condense chromosomes. The condensin complex probably introduces positive supercoils into relaxed DNA in the presence of type I topoisomerases and converts nicked DNA into positive knotted forms in the presence of type II topoisomerases.
Forms a heterodimer with SMC4. Component of the condensin complex, which contains the SMC2 and SMC4 heterodimer, and three non SMC subunits that probably regulate the complex: BRRN1/CAPH, CNAP1/CAPD2 and CAPG. Interacts with BRD4 (isoform B), leading to insulate chromatin from DNA damage response pathway.
The SMC hinge domain, which separates the large intramolecular coiled coil regions, allows the heterodimerization with SMC4, forming a V-shaped heterodimer.
Cell surface transmembrane ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development (PubMed:8070404, PubMed:7973638). Binding to Eph receptors residing on adjacent cells leads to contact-dependent bidirectional signaling into neighboring cells (PubMed:8070404, PubMed:7973638). Shows high affinity for the receptor tyrosine kinase EPHB1/ELK (PubMed:8070404, PubMed:7973638). Can also bind EPHB2 and EPHB3 (PubMed:8070404). Binds to, and induces collapse of, commissural axons/growth cones in vitro (By similarity). May play a role in constraining the orientation of longitudinally projecting axons (By similarity).
Interacts (via PDZ-binding motif) with GRIP1 and GRIP2 (via PDZ domain 6) (PubMed:10197531). Interacts with TLE1 (PubMed:21429299). The intracellular domain peptide interacts with ZHX2; the interaction enhances ZHX2 transcriptional repression activity (By similarity).
Proteolytically processed. The ectodomain is cleaved, probably by a metalloprotease, to produce a membrane-tethered C-terminal fragment. This fragment is then further processed by the gamma-secretase complex to yield a soluble intracellular domain peptide which can translocate to the nucleus. The intracellular domain peptide is highly labile suggesting that it is targeted for degradation by the proteasome.
Widely expressed (PubMed:8070404, PubMed:7973638). Detected in both neuronal and non-neuronal tissues (PubMed:8070404, PubMed:7973638). Seems to have particularly strong expression in retina, sciatic nerve, heart and spinal cord (PubMed:7973638).
Cleaved by caspases downstream of the polyglutamine stretch (PubMed:8696339, PubMed:9535906, PubMed:10770929, PubMed:29802276). The resulting N-terminal fragments are cytotoxic and provokes apoptosis (PubMed:10770929).
Expressed in the brain cortex (at protein level). Widely expressed with the highest level of expression in the brain (nerve fibers, varicosities, and nerve endings). In the brain, the regions where it can be mainly found are the cerebellar cortex, the neocortex, the striatum, and the hippocampal formation.
Forms with expanded polyglutamine expansion are specifically ubiquitinated by SYVN1, which promotes their proteasomal degradation.
Interacts with PFN1 (PubMed:18573880). Interacts through its N-terminus with PRPF40A (PubMed:9700202). Interacts with PQBP1 (PubMed:10332029). Interacts with SETD2 (PubMed:9700202, PubMed:10958656, PubMed:11461154). Interacts with SH3GLB1 (By similarity). Interacts with SYVN (PubMed:17141218). Interacts with TPR; the interaction is inhibited by forms of Huntingtin with expanded polyglutamine stretch (PubMed:15654337). Interacts with ZDHHC13 (via ANK repeats) (PubMed:26198635). Interacts with ZDHHC17 (via ANK repeats) (PubMed:26198635, PubMed:28882895, PubMed:28757145). Interacts with F8A1/F8A2/F8A3 (PubMed:29466333, PubMed:16476778). Found in a complex with F8A1/F8A2/F8A3, HTT and RAB5A; mediates the recruitment of HTT by RAB5A (PubMed:16476778).
May play a role in microtubule-mediated transport or vesicle function.
Myristoylated at Gly-551, following proteolytic cleavage at Asp-550.
Phosphorylation at Ser-1179 and Ser-1199 by CDK5 in response to DNA damage in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity.
Promotes the formation of autophagic vesicles.
The N-terminal Gln-rich and Pro-rich domain has great conformational flexibility and is likely to exist in a fluctuating equilibrium of alpha-helical, random coil, and extended conformations.
The poly-Gln region of HTT is highly polymorphic (10 to 35 repeats) in the normal population and is expanded to about 36-120 repeats in Huntington disease patients. The repeat length usually increases in successive generations, but contracts also on occasion. The adjacent poly-Pro region is also polymorphic and varies between 7-12 residues. Polyglutamine expansion leads to elevated susceptibility to apopain cleavage and likely result in accelerated neuronal apoptosis (PubMed:8696339).
Acetylation at Lys-225, Lys-257 and Lys-264 by NAT8 and NAT8B may control PROM1 protein expression and its function in cell apoptosis.
Interacts with CDHR1 and with actin filaments. Interacts with NAT8 and NAT8B.
Is used as marker for hematopoietic stem and progenitor cells (HSPC) for somatic stem cell isolation.
Isoform 1 and isoform 2 are glycosylated.
Isoform 1 is selectively expressed on CD34 hematopoietic stem and progenitor cells in adult and fetal bone marrow, fetal liver, cord blood and adult peripheral blood. Isoform 1 is not detected on other blood cells. Isoform 1 is also expressed in a number of non-lymphoid tissues including retina, pancreas, placenta, kidney, liver, lung, brain and heart. Found in saliva within small membrane particles. Isoform 2 is predominantly expressed in fetal liver, skeletal muscle, kidney, and heart as well as adult pancreas, kidney, liver, lung, and placenta. Isoform 2 is highly expressed in fetal liver, low in bone marrow, and barely detectable in peripheral blood. Isoform 2 is expressed on hematopoietic stem cells and in epidermal basal cells (at protein level). Expressed in adult retina by rod and cone photoreceptor cells (at protein level).
May play a role in cell differentiation, proliferation and apoptosis (PubMed:24556617). Binds cholesterol in cholesterol-containing plasma membrane microdomains and may play a role in the organization of the apical plasma membrane in epithelial cells. During early retinal development acts as a key regulator of disk morphogenesis. Involved in regulation of MAPK and Akt signaling pathways. In neuroblastoma cells suppresses cell differentiation such as neurite outgrowth in a RET-dependent manner (PubMed:20818439).
Heterodimerizes (via N-terminus) with BRAF (via N-terminus) in a MAP2K1/MEK1-dependent manner (PubMed:29433126). Interacts with BRAF; this increases the low intrinsic protein kinase activity of KSR2 (PubMed:21441910). Interacts with MAP2K1, forming a heterodimer that can dimerize to form a heterotetramer (PubMed:29433126, PubMed:21441910, PubMed:12975377). Interacts with MAP3K8, MAPK, RAS and RAF (PubMed:12975377).
KSR2 binds ATP and has very low in vitro protein kinase activity; the physiological relevance of this activity is unknown. KSR2 is proposed to be in an inactive conformation by itself or in complex with MAP2K1. Interaction with BRAF is proposed to induce a conformation change that increases the low intrinsic kinase activity (PubMed:21441910).
Location-regulated scaffold connecting MEK to RAF. Has very low protein kinase activity and can phosphorylate MAP2K1 at several Ser and Thr residues with very low efficiency (in vitro). Acts as MAP2K1/MEK1-dependent allosteric activator of BRAF; upon binding to MAP2K1/MEK1, dimerizes with BRAF and promotes BRAF-mediated phosphorylation of MAP2K1/MEK1 (PubMed:29433126). Interaction with BRAF enhances KSR2-mediated phosphorylation of MAP2K1 (in vitro). Blocks MAP3K8 kinase activity and MAP3K8-mediated signaling. Acts as a negative regulator of MAP3K3-mediated activation of ERK, JNK and NF-kappa-B pathways, inhibiting MAP3K3-mediated interleukin-8 production.
The protein kinase domain is predicted to be catalytically inactive and seems to have very low intrinsic kinase activity. This low kinase activity can be increased by interaction with BRAF.
Detected in the basal layer of the epidermis from inflammatory skin from psoriasis patients, but not in normal skin.
Interacts with PTH1R (via N-terminal extracellular domain).
PTH elevates calcium level by dissolving the salts in bone and preventing their renal excretion. Stimulates [1-14C]-2-deoxy-D-glucose (2DG) transport and glycogen synthesis in osteoblastic cells.
Expressed in the developing eye and weakly expressed in the adult retina.
Plays a critical role in eye formation by regulating the initial specification of retinal cells and/or their subsequent proliferation. Binds to the photoreceptor conserved element-I (PCE-1/Ret 1) in the photoreceptor cell-specific arrestin promoter.
(Microbial infection) Acts as a positive regulator of influenza A virus (IAV) replication. Required for the assembly and nuclear export of the viral ribonucleoprotein (vRNP) components.
(Microbial infection) Interacts (via KH 2 domain) with influenza A nucleoprotein (NP); this interaction occurs in a RNA-dependent manner and stimulates viral ribonucleoprotein (vRNP) assembly and subsequent RNA synthesis.
(Microbial infection) Interacts with Sindbis virus non-structural protein 3 (via C-terminus); this interaction inhibits the formation of host stress granules on viral mRNAs and the nsp3-FMR1 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes.
(Microbial infection) Up-regulated in response to infection by influenza A virus.
Binds to RNA homomer; preferentially on poly(G) and to a lesser extent on poly(U), but not on poly(A) or poly(C) (PubMed:24204304). May bind to RNA in Cajal bodies (PubMed:24204304).
Expressed in the brain, cerebellum and testis (PubMed:8401578, PubMed:9259278). Also expressed in epithelial tissues (PubMed:8401578). Expressed in mature oligodendrocytes (OLGs) (PubMed:23891804). Expressed in fibroblast (PubMed:24204304). Expressed in neurons, Purkinje cells and spermatogonias (at protein level) (PubMed:8401578, PubMed:9259278). Expressed in brain, testis and placenta (PubMed:8504300, PubMed:9259278). Expressed in neurons and lymphocytes (PubMed:8504300).
Homodimer (PubMed:7489725, PubMed:12950170, PubMed:16636078). Forms heterodimer with FXR1; heterodimerization occurs in a methylation-dependent manner (PubMed:7489725, PubMed:11157796, PubMed:16636078). Forms heterodimer with FXR2 (PubMed:7489725, PubMed:11157796). Homooligomer (PubMed:11157796, PubMed:18664458). Component of the CYFIP1-EIF4E-FMR1 complex at least composed of CYFIP, EIF4E and FMR1; this mRNA cap binding complex formation increases in presence of the brain cytoplasmic RNA BC1 and is dynamically regulated in an activity-dependent manner to repress and then possibly release dendritic mRNAs for translation in response to mGluR stimulation (By similarity). Associates with the SMN core complex that contains SMN, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP (PubMed:18093976). Part of a ribonucleoprotein complex with AGO2/EIF2C2 and miRNAs (PubMed:14703574). Interacts with AGO2/EIF2C2 (PubMed:14703574). Interacts (via C-terminus) with CACNA1B; this interaction induces a decrease in the number of presynaptic functional CACNA1B channels at the cell surface (By similarity). Interacts with CYFIP1; this interaction recruits CYFIP1 to capped mRNA (By similarity). Interacts with CYFIP2 (By similarity). Interacts with EIF5; this interaction occurs in a RNA-dependent manner (By similarity). Interacts with dynein (By similarity). Interacts with FXR1 and FXR2 (PubMed:8668200, PubMed:14532325, PubMed:15380484). Interacts with methylated histone H3 (PubMed:24813610). Interacts with IGF2BP1; this interaction allows to recruit IGF2BP1 to mRNA in a FMR1-dependent manner (PubMed:15282548). Interacts (via N-terminus) with KCNMB4 (PubMed:25561520). Interacts with KCNT1 (via C-terminus); this interaction alters gating properties of KCNT1 (PubMed:20512134). Interacts (via phosphorylated form) with MCRS1 (via N-terminus) (PubMed:16571602). Interacts with MOV10; this interaction is direct, occurs in an RNA-dependent manner on polysomes and induces association of MOV10 with RNAs (PubMed:25464849). Interacts with MYO5A and PURA; these interactions occur in association with polyribosome (By similarity). Interacts with NCL (By similarity). Interacts with NUFIP1 (PubMed:10556305). Interacts (via N-terminus) with NUFIP2 (PubMed:12837692, PubMed:16407062). Interacts with NXF1; this interaction occurs in a mRNA-dependent and polyribosome-independent manner in the nucleus (PubMed:18936162). Interacts with NXF2 (via N-terminus); this interaction is direct and occurs in a NXF1 mRNA-containing mRNP complexes (By similarity). Interacts with RANBP9 (via C-terminus); this interaction is direct and inhibits binding of FMR1 to RNA homomer (PubMed:15381419). Interacts with RPLP0 (PubMed:15380484). Interacts (via C-terminus) with SMN (via C-terminus); this interaction is direct and occurs in a RNA-independent manner (PubMed:18093976). Interacts with TDRD3 (via C-terminus); this interaction is direct (PubMed:18632687, PubMed:18664458). Interacts with YBX1; this interaction occurs in association with polyribosome (By similarity). Interacts with nucleosome (PubMed:24813610). Associates with polyribosome; this association occurs in a mRNA-dependent manner (PubMed:9659908, PubMed:11719188, PubMed:12594214, PubMed:19097999, PubMed:24448548). Associates with cytoplasmic messenger ribonucleoprotein particles (mRNPs) (PubMed:7692601, PubMed:9659908, PubMed:12575950, PubMed:19097999). Associates with microtubules in a kinesin- and dynein-dependent manner (By similarity). Isoform 6 interacts (via N-terminus) with NCL (via C-terminus) (PubMed:24658146). Isoform 6 interacts with CYFIP2; this interaction occurs in a RNA-dependent manner (PubMed:24658146). Isoform 6 interacts with EIF5; this interaction occurs in a RNA-dependent manner (PubMed:24658146). Isoform 6 interacts with RPLP0 (PubMed:24658146). Interacts with HABP4 (PubMed:21771594). Interacts with SND1 (PubMed:14508492). Interacts (when phosphorylated by CK2) with CAPRIN1; interaction with CAPRIN1 promotes formation of a membraneless compartment (PubMed:31439799).
Monomethylated and asymmetrically dimethylated by PRMT1, PRMT3 and PRMT4 at four arginine residues of the arginine-glycine-glycine box (PubMed:16922515, PubMed:30765518). Methylation decreases ability to undergo liquid-liquid phase separation (LLPS) for the formation of a membraneless compartment (PubMed:30765518). Methylation does not affect mRNA-binding (PubMed:30765518). Methylation is necessary for heterodimerization with FXR1, association with polyribosomes, recruitment into stress granules and translation of FMR1 target mRNAs (PubMed:16636078).
Monoubiquitinated. Polyubiquitinated. Ubiquitinated and targeted for proteasomal degradation after activation of metabotropic glutamate receptor (mGluR).
Multifunctional polyribosome-associated RNA-binding protein that plays a central role in neuronal development and synaptic plasticity through the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsynaptic local protein synthesis of target mRNAs (PubMed:12417522, PubMed:16631377, PubMed:18653529, PubMed:19166269, PubMed:23235829, PubMed:25464849). Acts as an mRNA regulator by mediating formation of some phase-separated membraneless compartment: undergoes liquid-liquid phase separation upon binding to target mRNAs, leading to assemble mRNAs into cytoplasmic ribonucleoprotein granules that concentrate mRNAs with associated regulatory factors (PubMed:12417522, PubMed:30765518, PubMed:31439799). Plays a role in the alternative splicing of its own mRNA (PubMed:18653529). Stabilizes the scaffolding postsynaptic density protein DLG4/PSD-95 and the myelin basic protein (MBP) mRNAs in hippocampal neurons and glial cells, respectively; this stabilization is further increased in response to metabotropic glutamate receptor (mGluR) stimulation (By similarity). Plays a role in selective delivery of a subset of dendritic mRNAs to synaptic sites in response to mGluR activation in a kinesin-dependent manner (By similarity). Undergoes liquid-liquid phase separation following phosphorylation and interaction with CAPRIN1, promoting formation of cytoplasmic ribonucleoprotein granules that concentrate mRNAs with factors that inhibit translation and mediate deadenylation of target mRNAs (PubMed:31439799). Acts as a repressor of mRNA translation in synaptic regions by mediating formation of neuronal ribonucleoprotein granules and promoting recruitmtent of EIF4EBP2 (PubMed:30765518). Plays a role as a repressor of mRNA translation during the transport of dendritic mRNAs to postsynaptic dendritic spines (PubMed:11532944, PubMed:11157796, PubMed:12594214, PubMed:23235829). Component of the CYFIP1-EIF4E-FMR1 complex which blocks cap-dependent mRNA translation initiation (By similarity). Represses mRNA translation by stalling ribosomal translocation during elongation (By similarity). Reports are contradictory with regards to its ability to mediate translation inhibition of MBP mRNA in oligodendrocytes (PubMed:23891804). Also involved in the recruitment of the RNA helicase MOV10 to a subset of mRNAs and hence regulates microRNA (miRNA)-mediated translational repression by AGO2 (PubMed:14703574, PubMed:17057366, PubMed:25464849). Facilitates the assembly of miRNAs on specific target mRNAs (PubMed:17057366). Also plays a role as an activator of mRNA translation of a subset of dendritic mRNAs at synapses (PubMed:19097999, PubMed:19166269). In response to mGluR stimulation, FMR1-target mRNAs are rapidly derepressed, allowing for local translation at synapses (By similarity). Binds to a large subset of dendritic mRNAs that encode a myriad of proteins involved in pre- and postsynaptic functions (PubMed:7692601, PubMed:11719189, PubMed:11157796, PubMed:12594214, PubMed:17417632, PubMed:23235829, PubMed:24448548). Binds to 5'-ACU[GU]-3' and/or 5'-[AU]GGA-3' RNA consensus sequences within mRNA targets, mainly at coding sequence (CDS) and 3'-untranslated region (UTR) and less frequently at 5'-UTR (PubMed:23235829). Binds to intramolecular G-quadruplex structures in the 5'- or 3'-UTRs of mRNA targets (PubMed:11719189, PubMed:18579868, PubMed:25464849, PubMed:25692235). Binds to G-quadruplex structures in the 3'-UTR of its own mRNA (PubMed:7692601, PubMed:11532944, PubMed:12594214, PubMed:15282548, PubMed:18653529). Binds also to RNA ligands harboring a kissing complex (kc) structure; this binding may mediate the association of FMR1 with polyribosomes (PubMed:15805463). Binds mRNAs containing U-rich target sequences (PubMed:12927206). Binds to a triple stem-loop RNA structure, called Sod1 stem loop interacting with FMRP (SoSLIP), in the 5'-UTR region of superoxide dismutase SOD1 mRNA (PubMed:19166269). Binds to the dendritic, small non-coding brain cytoplasmic RNA 1 (BC1); which may increase the association of the CYFIP1-EIF4E-FMR1 complex to FMR1 target mRNAs at synapses (By similarity). Plays a role in mRNA nuclear export (PubMed:31753916). Specifically recognizes and binds a subset of N6-methyladenosine (m6A)-containing mRNAs, promoting their nuclear export in a XPO1/CRM1-dependent manner (PubMed:31753916). Together with export factor NXF2, is involved in the regulation of the NXF1 mRNA stability in neurons (By similarity). Associates with export factor NXF1 mRNA-containing ribonucleoprotein particles (mRNPs) in a NXF2-dependent manner (By similarity). Binds to a subset of miRNAs in the brain (PubMed:14703574, PubMed:17057366). May associate with nascent transcripts in a nuclear protein NXF1-dependent manner (PubMed:18936162). In vitro, binds to RNA homomer; preferentially on poly(G) and to a lesser extent on poly(U), but not on poly(A) or poly(C) (PubMed:7688265, PubMed:7781595, PubMed:12950170, PubMed:15381419, PubMed:8156595). Moreover, plays a role in the modulation of the sodium-activated potassium channel KCNT1 gating activity (PubMed:20512134). Negatively regulates the voltage-dependent calcium channel current density in soma and presynaptic terminals of dorsal root ganglion (DRG) neurons, and hence regulates synaptic vesicle exocytosis (By similarity). Modulates the voltage-dependent calcium channel CACNA1B expression at the plasma membrane by targeting the channels for proteasomal degradation (By similarity). Plays a role in regulation of MAP1B-dependent microtubule dynamics during neuronal development (By similarity). Recently, has been shown to play a translation-independent role in the modulation of presynaptic action potential (AP) duration and neurotransmitter release via large-conductance calcium-activated potassium (BK) channels in hippocampal and cortical excitatory neurons (PubMed:25561520). Finally, FMR1 may be involved in the control of DNA damage response (DDR) mechanisms through the regulation of ATR-dependent signaling pathways such as histone H2AX/H2A.x and BRCA1 phosphorylations (PubMed:24813610).
Phosphorylated on several serine residues (PubMed:14532325). Phosphorylation by casein kinase II (CK2) promotes interaction with CAPRIN1 and liquid-liquid phase separation (LLPS) for the formation of a membraneless compartment that concentrates mRNAs with associated regulatory factors (PubMed:30765518, PubMed:31439799). Phosphorylation at Ser-500 by CK2 promotes secondary phosphorylation of other nearby serine residues (By similarity). Phosphorylation has no effect on the binding of individual mRNA species (By similarity). Unphosphorylated FMR1 is associated with actively translating polyribosome, whereas a fraction of phosphorylated FMR1 is associated with apparently stalled polyribosome (By similarity). Dephosphorylation by an activated phosphatase may release the FMR1-mediated translational repression and allow synthesis of a locally required protein at synapses (By similarity).
The C-terminal disordered region undergoes liquid-liquid phase separation (LLPS) for the formation of a membraneless compartment that concentrates mRNAs with associated regulatory factors.
The C-terminal region contains a Cajal body localization signal at positions 490 through 506 (PubMed:24204304).
The N-terminal 134 amino acids are necessary for homodimerization and RNA-binding (PubMed:12950170). The N-terminal 298 amino acids are sufficient to interact with KCNMB4 and to regulate presynaptic action potential (AP) duration in neurons (PubMed:25561520). The two agenet-like domains are necessary for binding to histone H3 in a methylation-dependent manner (PubMed:24813610). The KH domains are necessary for mediating miRNA annealing to specific RNA targets (PubMed:17057366). The KH 2 domain is necessary for binding to kissing complex (kc) RNA ligands (PubMed:15805463). The RGG box domain is necessary for binding to mRNA targets that contain G-quadruplex structures (PubMed:11719189, PubMed:18579868, PubMed:25692235). The RGG-box domain is necessary for binding to a triple stem-loop RNA structure, called Sod1 stem loop interacting with FMRP (SoSLIP), in the superoxide dismutase SOD1 mRNA (PubMed:19166269). The RGG box domain is necessary for binding to its own mRNA (PubMed:11532944). The RGG-box domain is necessary for binding to homomer poly(G) (PubMed:14532325).
The mechanism of the severe phenotype in the Asn-304 patient lies in the sequestration of bound mRNAs in nontranslatable mRNP particles. In the absence of FMRP, these same mRNAs may be partially translated via alternate mRNPs, although perhaps abnormally localized or regulated, resulting in typical fragile X syndrome. Asn-304 mutation maps to a position within the second KH domain of FMRP that is critical for stabilizing sequence-specific RNA-protein interactions. Asn-304 mutation abrogates the association of the FMRP KH 2 domain with its target, kissing complex RNA.
Undergoes proteolytic cleavage; may be specifically cleaved by calpain-1/CAPN1 in cajal bodies (PubMed:24204304).
In an ex vivo erythroid culture system, highly expressed from early (preproerythroblasts) to mid (basophilic normoblasts) maturation. Markedly reduced in more mature erythroblasts (at protein level). The decrease in LYAR protein correlates with the rise of beta-globin (HBB) mRNA levels during erythroid cell differentiation.
Induced by MYCN (PubMed:28686580). Induced by interferon-beta (PubMed:31413131).
Interacts with PRMT5; this interaction is direct (PubMed:25092918). Interacts with GNL2 and RPL23A (PubMed:26203195). Interacts with nucleolin/NCL; this interaction is direct (By similarity). Interacts with phosphorylated IRF3; this interaction impairs IRF3 DNA-binding activity (PubMed:31413131).
Plays a role in the maintenance of the appropriate processing of 47S/45S pre-rRNA to 32S/30S pre-rRNAs and their subsequent processing to produce 18S and 28S rRNAs (PubMed:24495227). Also acts at the level of transcription regulation. Along with PRMT5, binds the gamma-globin (HBG1/HBG2) promoter and represses its expression (PubMed:25092918). In neuroblastoma cells, may also repress the expression of oxidative stress genes, including CHAC1, HMOX1, SLC7A11, ULBP1 and SNORD41 that encodes a small nucleolar RNA (PubMed:28686580). Preferentially binds to a DNA motif containing 5'-GGTTAT-3' (PubMed:25092918). Negatively regulates the antiviral innate immune response by targeting IRF3 and impairing its DNA-binding activity (PubMed:31413131). In addition, inhibits NF-kappa-B-mediated expression of pro-inflammatory cytokines (PubMed:31413131). Stimulates phagocytosis of photoreceptor outer segments by retinal pigment epithelial cells (By similarity). Prevents nucleolin/NCL self-cleavage, maintaining a normal steady-state level of NCL protein in undifferentiated embryonic stem cells (ESCs), which in turn is essential for ESC self-renewal (By similarity).
The N-terminal zinc-finger domains are required for the appropriate production of 28S rRNA and the formation of pre-60S particles.
(Microbial infection) Acetylation of Ser-222 and Ser-226 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity). Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation (PubMed:29433126).
Interacts with MORG1 (By similarity). Interacts with SGK1 (PubMed:19447520). Interacts with KSR1 (PubMed:10409742). Interacts with KSR1 and BRAF; the interaction with KSR1 mediates KSR1-BRAF dimerization (PubMed:29433126). Interacts with GLS (PubMed:22538822).
MAPKK is itself dependent on Ser/Thr phosphorylation for activity catalyzed by MAP kinase kinase kinases (RAF or MEKK1). Phosphorylated by MAP2K1/MEK1 (By similarity).
Lacks critical consensus sites important for cysteine protease inhibition.
CLIP2 is located in the Williams-Beuren syndrome (WBS) critical region (PubMed:9799601). WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of CLIP2 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease. However, it has been demonstrated that haploinsufficiency of this gene alone is not sufficient to cause any of the cognitive or facial features of WBS (PubMed:22608712).
Interacts with CLASP1 and CLASP2 (PubMed:11290329). Binds preferentially to tyrosinated microtubules, and only marginally to detyrosinated microtubules (By similarity).
Seems to link microtubules to dendritic lamellar body (DLB), a membranous organelle predominantly present in bulbous dendritic appendages of neurons linked by dendrodendritic gap junctions. May operate in the control of brain-specific organelle translocations (By similarity).
May participate in the regulation of neuronal exocytosis.
Widely expressed, with highest levels in brain and lung.
Component of the ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, a VPS37 protein (VPS37A to -D) and MVB12A or MVB12B in a 1:1:1:1 stoichiometry. Interacts with TSG101, VPS28, MVB12A and MVB12B. Component of the ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, a VPS37 protein (VPS37A to -D) and UBAP1 in a 1:1:1:1 stoichiometry. Interacts with CEP55. Interacts with IST1.
Component of the ESCRT-I complex, a regulator of vesicular trafficking process. Required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies. May be involved in cell growth and differentiation.
Widely expressed. Expressed in macrophages and lymphocytes.
(Microbial infection) Interacts with mumps virus protein F; this interaction promotes protein F cleavage by FURIN.
(Microbial infection) Plays a positive role in post-entry steps of influenza A virus replication, either virus uncoating, cytosolic transport, or nuclear import of viral components, and promotes nuclear accumulation of influenza nucleoprotein/NP at early stages of viral infection.
(Microbial infection) Promotes the intracellular proliferation of Salmonella typhimuium.
(Microbial infection) Supports the FURIN-mediated cleavage of mumps virus fusion protein F by interacting with both FURIN and the unprocessed form but not the processed form of the viral protein F.
(Microbial infection) Upon Salmonella typhimurium infection, at both transcriptional and translational levels.
By UPR transcription factor ATF4 signaling.
Detected in tonsil interdigitating dendritic cells, in spleen, lymph node, Peyer's patches in the small instestine, in thymus medulla and in B-cells (at protein level). Expressed in lymphoid organs and dendritic cells. Expressed in lung. Up-regulated in carcinomas of the esophagus, colon, rectum, ureter, stomach, breast, fallopian tube, thyroid and parotid tissues.
Lysosomal membrane glycoprotein which plays a role in the unfolded protein response (UPR) that contributes to protein degradation and cell survival during proteasomal dysfunction (PubMed:25681212). Plays a role in the process of fusion of the lysosome with the autophagosome, thereby modulating the autophagic process (PubMed:24434718). Promotes hepatocellular lipogenesis through activation of the PI3K/Akt pathway (PubMed:29056532). May also play a role in dendritic cell function and in adaptive immunity (PubMed:9768752).
Monomer (PubMed:22809326). Interacts with FURIN (PubMed:32295904).
Up-regulated during dendritic cell maturation.
Functions as a component of the nuclear pore complex (NPC). NPC components, collectively referred to as nucleoporins (NUPs), can play the role of both NPC structural components and of docking or interaction partners for transiently associated nuclear transport factors. May play a role in the association of MAD1 with the NPC.
Interacts with TMEM48/NDC1. Forms a complex with NUP93, NUP155, NUP205 and lamin B; the interaction with NUP93 is direct.
Citrullination at Arg-62 (H1R54ci) by PADI4 takes place within the DNA-binding site of H1 and results in its displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance.
Histones H1 are necessary for the condensation of nucleosome chains into higher-order structures.
(Microbial infection) Interacts with HIV-1 Nef through its SH3 domain.
Activated by threonine and tyrosine phosphorylation.
Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. MAP kinase subfamily.
Binds both upstream activators and downstream substrates in multimolecular complexes. This interaction inhibits its tyrosine-kinase activity. Interacts with ADAM15, ARHGEF2, ARRB2, DAPK1 (via death domain), HSF4, IER3, IPO7, NISCH, SGK1, and isoform 1 of NEK2. Interacts (via phosphorylated form) with TPR (via C-terminal region and phosphorylated form); the interaction requires dimerization of MAPK1/ERK2 and increases following EGF stimulation (PubMed:18794356). Interacts with MAP2K1 (PubMed:32721402). Interacts with DUSP6 (PubMed:9596579, PubMed:32721402). Interacts (phosphorylated form) with CAV2 ('Tyr-19'-phosphorylated form); the interaction, promoted by insulin, leads to nuclear location and MAPK1 activation. Interacts with MORG1, PEA15 and MKNK2 (By similarity). MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation (By similarity). Interacts with DCC (By similarity). The phosphorylated form interacts with PML (isoform PML-4). Interacts with STYX. Interacts with CDK2AP2. Interacts with CAVIN4 (By similarity). Interacts with DUSP7; the interaction enhances DUSP7 phosphatase activity (PubMed:9788880). Interacts with GIT1; this interaction is necessary for MAPK1 localization to focal adhesions (By similarity). Interacts with ZNF263 (PubMed:32051553).
Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-185 and Tyr-187 in response to external stimuli like insulin or NGF. Both phosphorylations are required for activity. This phosphorylation causes dramatic conformational changes, which enable full activation and interaction of MAPK1/ERK2 with its substrates. Phosphorylation on Ser-29 by SGK1 results in its activation by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. Dephosphorylated and inactivated by DUSP1, DUSP3, DUSP6 and DUSP9. Inactivated by pyrimidylpyrrole inhibitors.
Phosphorylated upon KIT and FLT3 signaling (By similarity). Dually phosphorylated on Thr-185 and Tyr-187, which activates the enzyme. Undergoes regulatory phosphorylation on additional residues such as Ser-246 and Ser-248 in the kinase insert domain (KID) These phosphorylations, which are probably mediated by more than one kinase, are important for binding of MAPK1/ERK2 to importin-7 (IPO7) and its nuclear translocation. In addition, autophosphorylation of Thr-190 was shown to affect the subcellular localization of MAPK1/ERK2 as well. Ligand-activated ALK induces tyrosine phosphorylation. Dephosphorylated by PTPRJ at Tyr-187. Phosphorylation on Ser-29 by SGK1 results in its activation by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. DUSP3 and DUSP6 dephosphorylate specifically MAPK1/ERK2 and MAPK3/ERK1 whereas DUSP9 dephosphorylates a broader range of MAPKs. Dephosphorylated by DUSP1 and DUSP2 at Thr-185 and Tyr-187 (By similarity) (PubMed:16288922).
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade also plays a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1 and FXR1) and a variety of other signaling-related molecules (like ARHGEF2, DCC, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. Mediates phosphorylation of TPR in response to EGF stimulation. May play a role in the spindle assembly checkpoint. Phosphorylates PML and promotes its interaction with PIN1, leading to PML degradation. Phosphorylates CDK2AP2 (By similarity).
Ubiquitinated by TRIM15 via 'Lys-63'-linked ubiquitination; leading to activation. Deubiquitinated by CYLD.
Binding to its receptor activates G proteins and stimulates adenylate cyclase in pituitary cells. Promotes neuron projection development through the RAPGEF2/Rap1/B-Raf/ERK pathway. In chromaffin cells, induces long-lasting increase of intracellular calcium concentrations and neuroendocrine secretion (By similarity). Involved in the control of glucose homeostasis, induces insulin secretion by pancreatic beta cells (By similarity).
Interacts with ADCYAP1R1 (via N-terminal extracellular domain).
Component of the SOSS complex, a multiprotein complex that functions downstream of the MRN complex to promote DNA repair and G2/M checkpoint. The SOSS complex associates with single-stranded DNA at DNA lesions and influences diverse endpoints in the cellular DNA damage response including cell-cycle checkpoint activation, recombinational repair and maintenance of genomic stability. Required for efficient homologous recombination-dependent repair of double-strand breaks (DSBs) and ATM-dependent signaling pathways.
Component of the SOSS complex, a multiprotein complex that functions downstream of the MRN complex to promote DNA repair and G2/M checkpoint. The SOSS complex associates with single-stranded DNA at DNA lesions and influences diverse endpoints in the cellular DNA damage response including cell-cycle checkpoint activation, recombinational repair and maintenance of genomic stability. Required for efficient homologous recombination-dependent repair of double-strand breaks (DSBs).
Component of the SOSS complex, composed of SOSS-B (SOSS-B1/NABP2 or SOSS-B2/NABP1), SOSS-A/INTS3 and SOSS-C/INIP. SOSS complexes containing SOSS-B1/NABP2 are more abundant than complexes containing SOSS-B2/NABP1. Interacts with INTS3; the interaction is direct.
Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER) (By similarity). SRP9 together with SRP14 and the Alu portion of the SRP RNA, constitutes the elongation arrest domain of SRP (PubMed:11089964). The complex of SRP9 and SRP14 is required for SRP RNA binding (By similarity).
Heterodimer with SRP14; binds RNA as heterodimer (By similarity). Component of a signal recognition particle complex that consists of a 7SL RNA molecule of 300 nucleotides and six protein subunits: SRP72, SRP68, SRP54, SRP19, SRP14 and SRP9 (PubMed:11089964).
Belongs to the eukaryotic ribosomal protein eL34 family.
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25957688, PubMed:25901680, PubMed:32669547).
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25957688, PubMed:25901680, PubMed:32669547). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:12962325, PubMed:23636399, PubMed:25957688, PubMed:25901680, PubMed:32669547).
Cap-specific adenosine methyltransferase activity is inhibited by zinc.
Cap-specific adenosine methyltransferase that catalyzes formation of N(6),2'-O-dimethyladenosine cap (m6A(m)) by methylating the adenosine at the second transcribed position of capped mRNAs (PubMed:30467178, PubMed:30487554, PubMed:31279658, PubMed:31279659, PubMed:33428944). Recruited to the early elongation complex of RNA polymerase II (RNAPII) via interaction with POLR2A and mediates formation of m6A(m) co-transcriptionally (PubMed:30467178).
Interacts with POLR2A; interacts with the phosphorylated C-terminal domain (CTD) of POLR2A.
The WW domain is sufficient for direct and specific interaction with the phosphorylated CTD of RNAPII largest subunit.
The role of N(6),2'-O-dimethyladenosine cap (m6A(m)) on transcripts is unclear and subject to discussion (PubMed:31279658, PubMed:31279659, PubMed:30467178). According to a report, m6A(m) promotes translation of capped mRNAs (PubMed:30467178). In contrast, another study did not observe a clear effect on mRNA translation, but reported an increased stability of a subset of m6A(m) transcripts (PubMed:31279658). According to a third report, m6A(m) inhibits mRNA translation without affecting mRNA stability (PubMed:31279659).
Catalyzes the transfer of adenosine 5'-monophosphate (AMP) to Ser, Thr and Tyr residues of target proteins (AMPylation) (PubMed:30270044). May be a redox-active mitochondrial selenoprotein which interacts with a redox target protein (PubMed:24751718).
A 24 bp duplication in exon 10 leads to the activation of an alternative splice site and the production of an inactive protein resulting in chitotriosidase deficiency [MIM:614122]. About 6% of the population are deficient for CHIT1 activity, while 35% are carriers and show reduced enzyme levels. People with CHIT1 deficiency appear perfectly healthy.
Degrades chitin, chitotriose and chitobiose. May participate in the defense against nematodes and other pathogens. Isoform 3 has no enzymatic activity.
Detected in spleen. Secreted by cultured macrophages.
Duplication of 24 bp in exon 10 leads to the use of a cryptic splice site. The normal splice site is still present but not used.
Very high plasma levels of CHIT1 are found in patients with Gaucher disease type 1 (GD I). Can be used as diagnostic aid and to evaluate the success of treatment that brings levels back to normal.
Belongs to the multicopper oxidase family.
Detected in breast, colon, bone trabecular cells and fibroblasts.
May function as a ferroxidase for ferrous (II) to ferric ion (III) conversion and may be involved in copper transport and homeostasis. Implicated in iron homeostasis and may mediate iron efflux associated to ferroportin 1.
(Microbial infection) In case of infection by HIV-1 virus, it is recruited by HIV-1 Vpr in order to hijack the CUL4A-RBX1-DDB1-DCAF1/VPRBP function leading to arrest the cell cycle in G2 phase, and also to protect the viral protein from proteasomal degradation by another E3 ubiquitin ligase. The HIV-1 Vpr protein hijacks the CUL4A-RBX1-DDB1-DCAF1/VPRBP complex to promote ubiquitination and degradation of proteins such as TERT and ZIP/ZGPAT.
(Microbial infection) In case of infection by HIV-2 virus, it is recruited by HIV-2 Vpx in order to hijack the CUL4A-RBX1-DDB1-DCAF1/VPRBP function leading to enhanced efficiency of macrophage infection and promotion of the replication of cognate primate lentiviruses in cells of monocyte/macrophage lineage.
(Microbial infection) Interacts (via C-terminus) with human cytomegalovirus protein UL35; this interaction induces the accumulation of cells in the G2 phase of the cell cycle.
(Microbial infection) Interacts with HIV-1 virus Vpr protein; the interaction is direct.
(Microbial infection) Interacts with HIV-2 virus Vpx protein; the interaction is direct and the complex recruits SAMHD1 to promote its ubiquitin-dependent proteasomal degradation.
Acts both as a substrate recognition component of E3 ubiquitin-protein ligase complexes and as an atypical serine/threonine-protein kinase, playing key roles in various processes such as cell cycle, telomerase regulation and histone modification. Probable substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, named CUL4A-RBX1-DDB1-DCAF1/VPRBP complex, which mediates ubiquitination and proteasome-dependent degradation of proteins such as NF2. Involved in the turnover of methylated proteins: recognizes and binds methylated proteins via its chromo domain, leading to ubiquitination of target proteins by the RBX1-DDB1-DCAF1/VPRBP complex (PubMed:23063525). The CUL4A-RBX1-DDB1-DCAF1/VPRBP complex is also involved in B-cell development: DCAF1 is recruited by RAG1 to ubiquitinate proteins, leading to limit error-prone repair during V(D)J recombination. Also part of the EDVP complex, an E3 ligase complex that mediates ubiquitination of proteins such as TERT, leading to TERT degradation and telomerase inhibition (PubMed:23362280). Also acts as an atypical serine/threonine-protein kinase that specifically mediates phosphorylation of 'Thr-120' of histone H2A (H2AT120ph) in a nucleosomal context, thereby repressing transcription. H2AT120ph is present in the regulatory region of many tumor suppresor genes, down-regulates their transcription and is present at high level in a number of tumors (PubMed:24140421). Involved in JNK-mediated apoptosis during cell competition process via its interaction with LLGL1 and LLGL2 (PubMed:20644714). By acting on TET dioxygenses, essential for oocyte maintenance at the primordial follicle stage, hence essential for female fertility (By similarity).
Component of the DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, named CUL4A-RBX1-DDB1-DCAF1/VPRBP complex. Interacts with DDB1; the interaction is direct. Also forms a ternary complex with DDA1 and DDB1. Interacts with NF2 (via FERM domain). Component of the EDVP complex, a E3 ligase complex containing DYRK2, EDD/UBR5, DDB1 and DCAF1 (PubMed:24357321). Interacts with DYRK2; the interaction is direct. Interacts with RAG1; the interaction is direct. Interacts with LLGL1 and LLGL2. Interacts with histone H3. Interacts with ESR1 and LATS1; probably recruited by LATS1 to promote ESR1 ubiquitination and ubiquitin-mediated proteasomal degradation (PubMed:28068668). Directly interacts with TET1, TET2 and TET3 (via C-terminus) (PubMed:24357321, PubMed:25557551).
The DWD boxes are required for interaction with DDB1.
The chromo domain with a restricted pocket directly recognizes monomethylated substrates.
The protein kinase-like region mediates the threonine-protein kinase activity.
Up-regulated in a number of cancer cell lines (at protein level).
Binds to activated CDC42 and RAC1 but does not seem to stimulate their GTPase activity. Associates with calmodulin.
Isoform 2 expression is enhanced in testis.
Homodimer (via BAR-like domain) (PubMed:27528616). Heterodimer (via BAR-like domain) with FAM92A (PubMed:27528616). Interacts with CBY1 (PubMed:27528616).
May play a role in ciliogenesis (By similarity). In cooperation with CBY1 may facilitate ciliogenesis likely by the recruitment and fusion of endosomal vesicles at distal appendages during early stages of ciliogenesis (PubMed:27528616).
Restricted to certain tissues, most prominently expressed in multicilaited tissues.
The BAR-like domain displays limited similarity to other BAR domains.
Binds to the intracellular domain of tumor necrosis factor type 1 receptor. Binds to RB1. Interacts with SRC. Interacts with SDHA.
Chaperone that expresses an ATPase activity. Involved in maintaining mitochondrial function and polarization, downstream of PINK1 and mitochondrial complex I. Is a negative regulator of mitochondrial respiration able to modulate the balance between oxidative phosphorylation and aerobic glycolysis. The impact of TRAP1 on mitochondrial respiration is probably mediated by modulation of mitochondrial SRC and inhibition of SDHA.
Found in skeletal muscle, liver, heart, brain, kidney, pancreas, lung, placenta and bladder. Expression is highly reduced in bladder cancer and renal cell carcinoma specimens compared to healthy tissues, but it is increased in other type of tumors.
Detected in brain, liver, kidney and pancreas, and at low levels in skeletal muscle.
Hydrolyzes N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA) which act as inhibitors of NOS. Has therefore a role in the regulation of nitric oxide generation.
Inhibited by zinc ions (By similarity). Enzyme purified in the absence of 1,10-phenanthroline contains on average 0.4 zinc atoms per subunit. Inhibited by 4-hydroxy-nonenal through the formation of a covalent adduct with His-173. Competitively inhibited by N(5)-iminopropyl-ornithine.
A chromosomal aberration involving EML4 has been identified in a subset of patients with non-small-cell lung carcinoma. This aberration leads to the production of a fusion protein between the N-terminus of EML4 and the C-terminus of ALK. It is unclear whether the fusion protein is caused by a simple inversion within 2p (inv(2)(p21p23)) or whether the chromosome translocation involving 2p is more complex. When tested in a heterologous system, the fusion protein EML4-ALK possesses transforming activity that is dependent on ALK catalytic activity, possibly due to spontaneous dimerization mediated by the EML4 moiety, leading to ALK kinase activation.
Essential for the formation and stability of microtubules (MTs) (PubMed:16890222, PubMed:31409757). Required for the organization of the mitotic spindle and for the proper attachment of kinetochores to MTs (PubMed:25789526). Promotes the recruitment of NUDC to the mitotic spindle for mitotic progression (PubMed:25789526).
Homotrimer; self-association is mediated by the N-terminal coiled coil (PubMed:25740311). Interacts (via WD repeats) with NUDC (PubMed:25789526). Interacts with alpha- and beta-tubulin during mitosis (PubMed:31409757).
Phosphorylated during mitosis (PubMed:16890222). Phosphorylation at Ser-144 and Ser-146 promotes its dissociation from microtubules during mitosis which is required for efficient chromosome congression (PubMed:31409757).
Autophosphorylation at His-118 increases serine/threonine protein kinase activity of the enzyme. Interaction with the SET complex inhibits the endonuclease activity.
Hexamer of two different chains: A and B (A6, A5B, A4B2, A3B3, A2B4, AB5, B6). Interacts with PRUNE1. Component of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and TREX1. Within this complex, interacts directly with SET. Also interacts with TREX1, but only following translocation to the nucleus.
Isoform 1 is expressed in heart, brain, placenta, lung, liver, skeletal muscle, pancreas, spleen and thymus. Expressed in lung carcinoma cell lines but not in normal lung tissues. Isoform 2 is ubiquitously expressed and its expression is also related to tumor differentiation.
Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate. Possesses nucleoside-diphosphate kinase, serine/threonine-specific protein kinase, geranyl and farnesyl pyrophosphate kinase, histidine protein kinase and 3'-5' exonuclease activities. Involved in cell proliferation, differentiation and development, signal transduction, G protein-coupled receptor endocytosis, and gene expression. Required for neural development including neural patterning and cell fate determination. During GZMA-mediated cell death, works in concert with TREX1. NME1 nicks one strand of DNA and TREX1 removes bases from the free 3' end to enhance DNA damage and prevent DNA end reannealing and rapid repair.
The role of this protein in tumor development and progression is uncertain. This protein is found in reduced amount in some tumor cells of high metastatic potential. However, increased NME1 levels correlate with aggressive tumor features in neuroblastoma. May have distinct if not opposite roles in different tumors.
Binds NEDD4 (PubMed:11717310). Interacts with 14-3-3 proteins (PubMed:15324660). Interacts with MAVS (PubMed:34880843).
Plays a positive role in the antiviral innate immune signaling pathway. Mechanistically, interacts with MAVS and functions as a positive regulator to promote 'Lys-63'-linked polyubiquitination of MAVS and thus strengthens the interaction between MAVS and TRAF2 (PubMed:34880843). Also plays a role in axon and dendrite arborization during cranial nerve development. May also be important for neural crest migration and early development of other anterior structures including eye, brain and cranial cartilage (By similarity).
Activated by the ototoxic drug cisplatin (By similarity). Activated by NOXO1. Cooperatively activated by NCF1 and NCF2 or NOXA1 in a phorbol 12-myristate 13-acetate (PMA)-dependent manner. Inhibited by diphenyleneiodonium chloride.
Expressed in fetal kidney and to a lower extent in liver, lung and spleen.
Interacts with and stabilizes CYBA/p22phox.
NADPH oxidase which constitutively produces superoxide upon formation of a complex with CYBA/p22phox. Plays a role in the biogenesis of otoconia/otolith, which are crystalline structures of the inner ear involved in the perception of gravity.
Belongs to the SOS response-associated peptidase family.
Expressed at higher level in S-phase than in quiescent cells.
Glu-127 is involved in sensing abasic sites in single-stranded DNA (ssDNA). His-210 stabilizes the abasic sites by forming a hydrogen bond with the O4' hydroxyl group.
Interacts (via PIP-box motif) with PCNA.
Sensor of abasic sites in single-stranded DNA (ssDNA) required to preserve genome integrity by promoting error-free repair of abasic sites (PubMed:30554877, PubMed:31235915, PubMed:31235913). Acts as an enzyme that recognizes and binds abasic sites in ssDNA at replication forks and chemically modifies the lesion by forming a covalent cross-link with DNA: forms a stable thiazolidine linkage between a ring-opened abasic site and the alpha-amino and sulfhydryl substituents of its N-terminal catalytic cysteine residue (PubMed:30554877, PubMed:31235913). The HMCES DNA-protein cross-link is then degraded by the proteasome (PubMed:30554877). Promotes error-free repair of abasic sites by acting as a 'suicide' enzyme that is degraded, thereby protecting abasic sites from translesion synthesis (TLS) polymerases and endonucleases that are error-prone and would generate mutations and double-strand breaks (PubMed:30554877). Has preference for ssDNA, but can also accommodate double-stranded DNA with 3' or 5' overhang (dsDNA), and dsDNA-ssDNA 3' junction (PubMed:31235915, PubMed:31806351). Also involved in class switch recombination (CSR) in B-cells independently of the formation of a DNA-protein cross-link: acts by binding and protecting ssDNA overhangs to promote DNA double-strand break repair through the microhomology-mediated alternative-end-joining (Alt-EJ) pathway (By similarity). Acts as a protease: mediates autocatalytic processing of its N-terminal methionine in order to expose the catalytic cysteine (By similarity).
Ubiquitinated; the covalent HMCES DNA-protein cross-link is ubiquitinated, leading to its degradation by the proteasome.
Was initially reported to specifically bind 5-hydroxymethylcytosine (5hmC)-containing DNA in stem cells (By similarity). It was later suggested to act as an endonuclease that specifically cleaves 5hmC-containing DNA (By similarity). However, the endonuclease activity on 5hmC-containing DNA could not be confirmed by another report (PubMed:30554877).
Binds to activated (phosphorylated) protein-tyrosine kinases through its SH2 domain and regulates their kinase activity. During insulin stimulation, it also binds to IRS-1.
Heterodimer of a regulatory subunit PIK3R3 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts with AXL.
Highest levels in brain and testis. Lower levels in adipose tissue, kidney, heart, lung and skeletal muscle.
Expressed in embryonal stem cells and in the developing brain.
Transcription factor that binds to the octamer motif (5'-ATTTGCAT-3') (By similarity). Acts as a transcriptional activator when binding cooperatively with SOX4, SOX11, or SOX12 to gene promoters (By similarity). Acts as a transcriptional repressor of myelin-specific genes (By similarity).
Acetylated. Deacetylated at Lys-66 by SIRT2; deacetylation enhances the interaction of CDC20 with CDC27, leading to activation of anaphase promoting complex/cyclosome (APC/C).
Belongs to the WD repeat CDC20/Fizzy family.
Component of a complex with CDC20, CDC27, SPATC1 and TUBG1 (By similarity). Interacts with NEUROD2 (By similarity). Interacts with dimeric MAD2L1 in its closed conformation form (PubMed:9811605, PubMed:9637688, PubMed:15525512, PubMed:19098431, PubMed:29162720). Interacts with BUB1B (PubMed:15525512, PubMed:18997788, PubMed:19098431, PubMed:33094908). The phosphorylated form interacts with APC/C (PubMed:9811605, PubMed:9734353, PubMed:9637688). Interacts with NINL (PubMed:17403670). May interact with MAD2L2 (PubMed:11459826). Interacts with CDK5RAP2 (PubMed:19282672). Interacts with SIRT2 (PubMed:22014574). Interacts with isoform 1 of NEK2 (PubMed:20034488). Interacts with HSF1 (via phosphorylated form); this interaction occurs in mitosis in a MAD2L1-dependent manner and prevents PLK1-stimulated degradation of HSF1 by blocking the recruitment of the SCF(BTRC) ubiquitin ligase complex (PubMed:18794143). Interacts (via the N-terminal substrate-binding domain) with FBXO5 (By similarity). Interacts with CCNF (PubMed:27653696).
Involved in the metaphase/anaphase transition of cell cycle (PubMed:32666501). Required for full ubiquitin ligase activity of the anaphase promoting complex/cyclosome (APC/C) and may confer substrate specificity upon the complex. Is regulated by MAD2L1: in metaphase the MAD2L1-CDC20-APC/C ternary complex is inactive and in anaphase the CDC20-APC/C binary complex is active in degrading substrates. The CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. CDC20-APC/C-induced degradation of NEUROD2 induces presynaptic differentiation. The CDC20-APC/C complex promotes proper dilation formation and radial migration by degrading CCDC41 (By similarity).
Originally thought to be phosphorylated by MPF during mitosis. However this paper was retracted due to falsification of data.
Phosphorylated during mitosis (PubMed:14657031). Phosphorylated by BUB1 at Ser-41; Ser-72; Ser-92; Ser-153; Thr-157 and Ser-161 (PubMed:15525512). Phosphorylated by NEK2 (PubMed:20034488).
Synthesis is initiated at G1/S, protein level peaks in M phase and protein is abruptly degraded at M/G1 transition.
Ubiquitinated and degraded by the proteasome during spindle assembly checkpoint. Deubiquitinated by USP44, leading to stabilize the MAD2L1-CDC20-APC/C ternary complex, thereby preventing premature activation of the APC/C. Ubiquitinated at Lys-490 during prometaphase. Ubiquitination at Lys-485 and Lys-490 has no effect on its ability to bind the APC/C complex.
Adapter protein involved in asymmetrical cell division and cell polarization processes. May play a role in the formation of epithelial tight junctions. The PARD6-PARD3 complex links GTP-bound Rho small GTPases to atypical protein kinase C proteins (By similarity).
Interacts with PARD3 (Probable). Interacts with GTP-bound forms of CDC42, RHOQ/TC10 and RAC1. Interacts with the N-terminal part of PRKCI and PRKCZ.
The pseudo-CRIB domain together with the PDZ domain is required for the interaction with Rho small GTPases.
Widely expressed, with a higher expression in fetal and adult kidney.
Belongs to the DEAD box helicase family. DDX31/DBP7 subfamily.
Interacts with NPM1; this interaction prevents interaction between NPM1 and HDM2.
Probable ATP-dependent RNA helicase (By similarity). Plays a role in ribosome biogenesis and TP53/p53 regulation through its interaction with NPM1 (PubMed:23019224).
Weakly or undetectably expressed in normal organs. Up-regulated in renal cell carcinoma.
Dual regulator of transcription and autophagy. Positively regulates autophagy and is required for autophagosome formation and processing. May act as a scaffold protein that recruits MAP1LC3A, GABARAP and GABARAPL2 and brings them to the autophagosome membrane by interacting with VMP1 where, in cooperation with the BECN1-PI3-kinase class III complex, they trigger autophagosome development. Acts as a transcriptional activator of THRA.
Interacts with VMP1, GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B, MAP1LC3C and THRA.
The LC3 interacting region (LIR) motif mediates interaction with GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B and MAP1LC3C.
Corresponds to the light chain of other gamma-glutamyltransferase family members. Has no catalytic activity.
Activity is increased at acidic pH (6.5) (PubMed:29791142). Inhibited in the presence of high extracellular K(+) (PubMed:29791142, PubMed:30914478).
Expressed only in prostate and uterine epithelial cells.
It was previously proposed that SLC39A2 operates as a Zn2(+)/HCO3(-) symport mechanism (PubMed:10681536). However in more recent studies, SLC39A2-mediated transport is independent of both HCO3(-) and H(+)-driving forces, but modulated by extracellular pH and voltage (PubMed:29791142, PubMed:30914478).
Shows a dramatic induction in normal epithelial cells contact inhibition.
Transporter for the divalent cation Zn(2+) (PubMed:10681536, PubMed:29791142, PubMed:30914478). Mediates the influx of Zn(2+) into cells from extracellular space. The Zn(2+) uniporter activity is independent of H(+)-driving force, but is modulated by extracellular pH and membrane potential. Transports also other divalent cations Zn(2+), Cd2(+), Cu2(+), Co2(+) in the order of decreasing affinity, respectively (PubMed:29791142, PubMed:30914478). In the skin, aids in the differentiation of keratinocytes in the epidermis (By similarity).
Adapter protein which modulates coupling of a number of cell surface receptor kinases with specific signaling pathways. Binds to, and suppress signals from, activated receptors tyrosine kinases, including the insulin (INSR) and insulin-like growth factor (IGF1R) receptors. The inhibitory effect can be achieved by 2 mechanisms: interference with the signaling pathway and increased receptor degradation. Delays and reduces AKT1 phosphorylation in response to insulin stimulation. Blocks association between INSR and IRS1 and IRS2 and prevents insulin-stimulated IRS1 and IRS2 tyrosine phosphorylation. Recruits NEDD4 to IGF1R, leading to IGF1R ubiquitination, increased internalization and degradation by both the proteasomal and lysosomal pathways. May play a role in mediating insulin-stimulated ubiquitination of INSR, leading to proteasomal degradation. Negatively regulates Wnt signaling by interacting with LRP6 intracellular portion and interfering with the binding of AXIN1 to LRP6. Positive regulator of the KDR/VEGFR-2 signaling pathway. May inhibit NEDD4-mediated degradation of KDR/VEGFR-2.
GRB10 is unlikely to be responsible for Silver-Russell syndrome (SRS).
Interacts with ligand-activated tyrosine kinase receptors, including FGFR1, INSR, IGF1R, MET and PDGFRB in a phosphotyrosine-dependent manner through the SH2 domain (By similarity). Poorly binds to the EGFR (By similarity). Directly interacts with MAP3K14/NIK and is recruited to the EGFR-ERBB2 complex. Interacts with GIGYF1/PERQ1 and GIGYF2/TNRC15 (By similarity). When unphosphorylated, interacts with AKT1 and when phosphorylated with YWHAE/14-3-3 epsilon. Interacts with NEDD4. Interacts with LRP6, thus interfering with the binding of AXIN1 to LRP6 (By similarity). Binds to activated NRAS.
Phosphorylated on serine residues upon EGF, FGF and PDGF stimulation (By similarity). Phosphorylated at Tyr-67 by TEC.
Phosphorylation by mTORC1 stabilizes and activates GRB10 constituting a feedback pathway by which mTORC1 inhibits INSR-dependent signaling.
The GRB10 locus is imprinted. During embryonic development, the expression in the brain and spinal cord is from the paternal allele, while in placental villous trophoblasts and skeletal muscle, it is from the maternal one. Expression is biallelic in most other tissues. Paternal expression in the brain is maintained throughout adulthood. Imprinting often is isoform-specific.
The PH domain binds relatively non-specifically to several phosphoinositides, including PI(5)P, PI(4,5)P2, PI(3,4)P2 and PI(3,4,5)P3, with modest affinities.
Widely expressed in fetal and adult tissues, including fetal and postnatal liver, lung, kidney, skeletal muscle, heart, spleen, skin and brain.
Expressed exclusively in the testis and ovary and at higher levels in the adult testis compared with the adult ovary.
Interacts with DDX4, PIWIL1, RANBP9 and TDRD1.
Plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. Its association with pi-bodies suggests a participation in the primary piRNAs metabolic process. Required prior to the pachytene stage to facilitate the production of multiple types of piRNAs, including those associated with repeats involved in the regulation of retrotransposons. May act by mediating protein-protein interactions during germ cell maturation (By similarity).
Contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. Upon phosphorylation of ITIM motif KLRG1 associates with the two phosphatases PTPN11 and INPP5D (By similarity).
Expressed specifically on natural killer (NK) cells and T-cells, mainly CD8 T-cells.
Forms a monomer and homodimer; disulfide-linked. Interacts (via ITIM motif) with PTPN11 and INPP5D.
Plays an inhibitory role on natural killer (NK) cells and T-cell functions upon binding to their non-MHC ligands. May mediate missing self recognition by binding to a highly conserved site on classical cadherins, enabling it to monitor expression of E-cadherin/CDH1, N-cadherin/CDH2 and R-cadherin/CDH4 on target cells.
Activated by 5 mM Ca(2+) and inhibited by 5 mM Zn(2+).
Belongs to the alkaline ceramidase family.
Endoplasmic reticulum and Golgi ceramidase that catalyzes the hydrolysis of unsaturated long-chain C18:1-, C20:1- and C20:4-ceramides, dihydroceramides and phytoceramides into sphingoid bases like sphingosine and free fatty acids at alkaline pH (PubMed:20068046, PubMed:26792856, PubMed:20207939, PubMed:11356846, PubMed:30575723). Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation (PubMed:20068046). Controls the generation of sphingosine in erythrocytes, and thereby sphingosine-1-phosphate in plasma (PubMed:20207939). Through the regulation of ceramides and sphingosine-1-phosphate homeostasis in the brain may play a role in neurons survival and function (By similarity). By regulating the levels of pro-inflammatory ceramides in immune cells and tissues, may modulate the inflammatory response (By similarity).
Hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid.
Ubiquitously expressed. Highly expressed in placenta (PubMed:11356846). Expressed in erythrocytes (PubMed:20207939).
Isoform 1 is testis-specific. Isoform 2 is expressed in heart, brain, skeletal muscle, kidney and pancreas. Isoform 1 is not expressed in fetus or in azoospermic patients.
Causes an allergic reaction in human. Binds to IgE from atopic dermatitis (AD) patients. Identified as an IgE autoantigen in atopic dermatitis (AD) patients with severe skin manifestations.
Identified in the spliceosome C complex. Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39. Interacts with UBL5 (PubMed:25092792).
Plays a role in mRNA splicing as a component of the U4/U6-U5 tri-snRNP, one of the building blocks of the spliceosome. May also bind to DNA.
(Microbial infection) Deamidated at Gln-204 by Photorhabdus asymbiotica toxin PAU_02230, blocking GTP hydrolysis of heterotrimeric GNAQ or GNA11 and G-alphai (GNAI1, GNAI2 or GNAI3) proteins, thereby activating RhoA.
(Microbial infection) Interacts with human cytomegalovirus (HHV-5) US27; this interaction this interaction does not lead to the catalytic activation of Gi complex and probably interferes with the chemokine-Gi signaling.
(Microbial infection) Interacts with human cytomegalovirus (HHV-5) US28; this interaction does not lead to the catalytic activation of Gi complex and probably interferes with the chemokine-Gi signaling.
Belongs to the G-alpha family. G(i/o/t/z) subfamily.
Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal. Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins (PubMed:8774883, PubMed:18434541). Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels (By similarity). The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. Required for normal cytokinesis during mitosis (PubMed:17635935). Required for cortical dynein-dynactin complex recruitment during metaphase (PubMed:22327364).
Heterotrimeric G proteins are composed of 3 units; alpha, beta and gamma. Part of a spindle orientation complex at least composed of GNAI1, GPSM2 and NUMA1 (PubMed:26766442). The alpha chain contains the guanine nucleotide binding site. Identified in complex with the beta subunit GNB1 and the gamma subunit GNG1 (PubMed:22383884). Identified in complex with the beta subunit GNB1 and the gamma subunit GNG2 (PubMed:18434541). GTP binding causes dissociation of the heterotrimer, liberating the individual subunits so that they can interact with downstream effector proteins (PubMed:22383884). Interacts (GDP-bound form) with GPSM1; this inhibits guanine nucleotide exchange and GTP binding (By similarity). Interacts (GDP-bound form) with GPSM2 (via GoLoco domains); this inhibits guanine nucleotide exchange (PubMed:22952234). Interacts with RGS10; this strongly enhances GTP hydrolysis (PubMed:8774883, PubMed:18434541). Interacts with RGS1 and RGS16; this strongly enhances GTPase activity (PubMed:18434541). Interacts with RGS4 (PubMed:18434541). Interacts with RGS12 (PubMed:18434541). Interacts (via active GTP- or inactive GDP-bound forms) with RGS14 (via RGS and GoLoco domains) (PubMed:11976690, PubMed:18434541, PubMed:21115486, PubMed:22383884). Interacts with RGS3, RGS6, RGS7, RGS8, RGS17, RGS18 and RGS20 (in vitro) (PubMed:18434541). Interacts (GDP-bound form) with RIC8A (via C-terminus) (By similarity). Interacts (inactive GDP-bound form) with NUCB1 (via GBA motif); the interaction leads to activation of GNAI1 (By similarity). Interacts (inactive GDP-bound form) with CCDC88C/DAPLE (via GBA motif); the interaction leads to activation of GNAI1 (PubMed:26126266). Interacts (inactive GDP-bound form) with CCDC8A/GIV (via GBA motif) (PubMed:19211784).
Myristoylation at Gly-2 is required for membrane anchoring before palmitoylation.
Palmitoylation at Cys-3 varies with membrane lipid composition.
A chromosomal aberration involving JAZF1 may be a cause of endometrial stromal tumors. Translocation t(7;17)(p15;q21) with SUZ12. The translocation generates the JAZF1-SUZ12 oncogene consisting of the N-terminus part of JAZF1 and the C-terminus part of SUZ12. It is frequently found in all cases of endometrial stromal tumors, except in endometrial stromal sarcomas, where it is rarer. Translocation t(6;7)(p21;p22) with PHF1.
Acts as a transcriptional corepressor of orphan nuclear receptor NR2C2 (PubMed:15302918). Inhibits expression of the gluconeogenesis enzyme PCK2 through inhibition of NR2C2 activity (By similarity). Also involved in transcriptional activation of NAMPT by promoting expression of PPARA and PPARD (By similarity). Plays a role in lipid metabolism by suppressing lipogenesis, increasing lipolysis and decreasing lipid accumulation in adipose tissue (By similarity). Plays a role in glucose homeostasis by improving glucose metabolism and insulin sensitivity (By similarity).
Highest expression in testis with moderate levels in colon, placenta, prostate and ovary and low levels in brain, spleen, liver and small intestine.
Interacts with NR2C2 (via ligand-binding region).
Under hypoxic conditions, the precursor SUZ12 RNA undergoes regulated trans-splicing with the JAZF1 RNA, resulting in a chimeric isoform which may be protective against apoptosis. The chimeric transcript is characterized by JAZF1 exons 1-3 joined to SUZ12 exon 2-16. The chimeric transcript is expressed primarily in the endometrium from late secretory and early proliferative phases of the menstrual cycle, but not in normal myometrium at any phase of the cycle. Its expression is slightly induced by low levels of progesterone, but suppressed by both estrogen and high levels of progesterone (PubMed:18772439).
May be involved in several stages of intracellular trafficking. May play a role in endosome homeostasis (By similarity). Acts as a GAP for Galphas.
Involved in retrograde transport of recycling endosomes.
The PH domain specifically binds phosphatidylserine, which is enriched in recycling endosome membranes, it doesn't recognize PIPs.
Interacts with TJP1 (PubMed:17186462). Interacts with the ubiquitin ligase ITCH (PubMed:28436082). Interacts (via C-terminal cytoplasmic domain) with LSR (via the cytoplasmic domain), ILDR1 and ILDR2; the interaction is required to recruit MARVELD2 to tricellular contacts (By similarity).
Plays a role in the formation of tricellular tight junctions and of epithelial barriers (By similarity). Required for normal hearing via its role in the separation of the endolymphatic and perilymphatic spaces of the organ of Corti in the inner ear, and for normal survival of hair cells in the organ of Corti (PubMed:17186462).
Ubiquitinated by ITCH; but this ubiquitination does not lead to proteasomal degradation.
Almost testis-specific (PubMed:12490704, PubMed:19333399, PubMed:28502657). Also expressed in pre- and postmenopausal ovary (PubMed:19333399).
Component of a male germ cell-specific 60S large ribosomal subunit (LSU), which contains RPL10L and RPL39L, instead of RPL10 and RPL39 paralogs (PubMed:23636399, PubMed:25901680, PubMed:32669547). The composition of the rest of the complex is similar to classical ribosomes (By similarity).
Testis-specific component of the ribosome, which is required for the transition from prophase to metaphase in male meiosis I (By similarity). Compensates for the inactivated X-linked RPL10 paralog during spermatogenesis (PubMed:12490704). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399, PubMed:25901680, PubMed:32669547). The male germ cell-specific ribosome displays a ribosomal polypeptide exit tunnel of distinct size and charge states compared with the classical ribosome (By similarity). It is responsible for regulating the biosynthesis and folding of a subset of male germ-cell-specific proteins that are essential for the formation of sperm (By similarity).
This gene has no introns in its coding regions, and therefore was most likely produced by retrotransposition of the original X-linked gene during evolution.
Detected in cerebrospinal fluid and urine (at protein level) (PubMed:25326458, PubMed:36213313). Detected at high levels in the substantia nigra, fetal kidney and trachea; at lower levels in testis, uterus, ovary and placenta. Not detectable in many regions of the central nervous system. Also detected at high levels in lymphoblastic leukemia and colorectal adenocarcinoma.
Plays a regulatory role in the organization of neuroendocrine signals accessing the anterior pituitary gland. Stimulates water drinking and food intake. May play a role in the hypothalamic response to stress (By similarity). NPW23 activates GPR7 and GPR8 more efficiently than NPW30.
Belongs to the aldo/keto reductase family. Glutamate--cysteine ligase light chain subfamily.
Heterodimer of a catalytic heavy chain and a regulatory light chain.
In all tissues examined. Highest levels in skeletal muscle.
Can bind and activate Notch-1 or another Notch receptor.
Inhibits primary neurogenesis. May be required to divert neurons along a specific differentiation pathway. Plays a role in the formation of somite boundaries during segmentation of the paraxial mesoderm (By similarity).
The DSL domain is required for binding to the Notch receptor.
Ubiquitinated by MIB (MIB1 or MIB2), leading to its endocytosis and subsequent degradation.
Divalent metal cations; Mg(2+) or Mn(2+) (PubMed:31127291). Acts as a 3'-5' exoribonuclease in presence of Mg(2+), while it has no 3'-5' exodeoxyribonuclease activity (PubMed:29335528, PubMed:31127291). Has both as a 3'-5' exoribonuclease and exodeoxyribonuclease activities in presence of Mn(2+) (PubMed:31127291).
Exonuclease that has both 3'-5' exoribonuclease and exodeoxyribonuclease activities, depending on the divalent metal cation used as cofactor (PubMed:29335528, PubMed:31127291). In presence of Mg(2+), only shows 3'-5' exoribonuclease activity, while it shows both exoribonuclease and exodeoxyribonuclease activities in presence of Mn(2+) (PubMed:29335528, PubMed:31127291). Acts as an exoribonuclease in mitochondrion, possibly by regulating ATP production and mitochondrial translation (PubMed:29335528). Also involved in the response to DNA damage (PubMed:26807646, PubMed:31255466). Acts as 3'-5' exodeoxyribonuclease for double-strand breaks resection and efficient homologous recombination (PubMed:20603073, PubMed:26807646). Plays a key role in controlling the initial steps of chromosomal break repair, it is recruited to chromatin in a damage-dependent manner and functionally interacts with the MRN complex to accelerate resection through its 3'-5' exonuclease activity, which efficiently processes double-stranded DNA substrates containing nicks (PubMed:26807646). Also involved in response to replicative stress: recruited to stalled forks and is required to stabilize and restart stalled replication forks by restraining excessive fork regression, thereby suppressing their degradation (PubMed:31255466).
Homodimer (PubMed:31127291). Interacts with RBBP8, MRE11 and BRCA1 (PubMed:26807646).
Subcellular location is subject to discussion. Different publications report a mitochondrial localization (PubMed:29335528, PubMed:29599527, PubMed:31127291). According to some reports, tranlocates to the nucleus in response of DNA damage (PubMed:26807646, PubMed:31255466). However, according to another publication, DNA damage does not result in nuclear translocation (PubMed:31127291). Its precise localization in mitochondrion is also controversial (PubMed:29335528, PubMed:29599527, PubMed:31127291). Two different groups report a localization to the mitochondrial outer membrane, which is consistent with the presence of a N-terminal transmembrane region (PubMed:29599527, PubMed:31127291). In contrast, a publication reports localization to the mitochondrial matrix; protease accessibility used in this assay can however lead to misinterpretation if the target protein is unexpectedly resistant to proteases (PubMed:29335528). Mechanisms that explain its dual role in mitochondrion and nuclear DNA repair are unknown and additional evidences are needed to reconciliate these two apparently incompatible functions.
Cilium-specific protein required for the stability of the ciliary architecture. Plays a role in cytoplasmic preassembly of dynein arms. Involved in regulation of microtubule-based cilia and actin-based brush border microvilli.
Allosterically activated by ADP, AMP, or fructose 2,6-bisphosphate, and allosterically inhibited by ATP or citrate. GlcNAcylation by OGT overcomes allosteric regulation.
Belongs to the phosphofructokinase type A (PFKA) family. ATP-dependent PFK group I subfamily. Eukaryotic two domain clade 'E' sub-subfamily.
Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis (PubMed:22923583). Negatively regulates the phagocyte oxidative burst in response to bacterial infection by controlling cellular NADPH biosynthesis and NADPH oxidase-derived reactive oxygen species. Upon macrophage activation, drives the metabolic switch toward glycolysis, thus preventing glucose turnover that produces NADPH via pentose phosphate pathway (By similarity).
GlcNAcylation at Ser-529 by OGT decreases enzyme activity, leading to redirect glucose flux through the oxidative pentose phosphate pathway. Glycosylation is stimulated by both hypoxia and glucose deprivation.
Glycosylation may play a role in cancer cell proliferation: inhibition of 6-phosphofructokinase activity and subsequent redirection of the glucose flux through the oxidative pentose phosphate pathway confers a selective growth advantage on cancer cells. Moreover GlcNAcylation is observed in multiple cancer cell lines and tissue samples and GlcNAcylation leads to larger xenografts tunors in mice (PubMed:22923583).
Homo- and heterotetramers (By similarity). Phosphofructokinase (PFK) enzyme functions as a tetramer composed of different combinations of 3 types of subunits, called PFKM (where M stands for Muscle), PFKL (Liver) and PFKP (Platelet). The composition of the PFK tetramer differs according to the tissue type it is present in. In muscles, it is composed of 4 PFKM subunits (also called M4). In the liver, the predominant form is a tetramer of PFKL subunits (L4). In erythrocytes, both PFKM and PFKL subunits randomly tetramerize to form M4, L4 and other combinations (ML3, M2L2, M3L). The kinetic and regulatory properties of the tetrameric enzyme are dependent on the subunit composition, hence can vary across tissues (Probable).
In human PFK exists as a system of 3 types of subunits, PFKM (muscle), PFKL (liver) and PFKP (platelet) isoenzymes.
Cells overexpressing TELO2 are hypersensitive to hydroxyurea (HU) and undergo apoptotic death in response to treatment with HU.
Component of the TTT complex composed of TELO2, TTI1 and TTI2. Interacts with ATM, ATR, MTOR, PRKDC, RUVBL2, TTI1, TTI2, SMG1 and TRRAP. Component of the mTORC1 and mTORC2 complexes. Interacts (phosphorylated form) with PIH1D1 which mediates interaction of TELO2 with the R2TP complex composed of RUVBL1, RUVBL2, PIH1D1, and RPAP3 (PubMed:20864032, PubMed:24656813).
Hydroxylation by PHD3 is required for a proper interaction with ATR, and activation of the ATR/CHK1/p53 pathway following DNA damage.
Phosphorylated at Ser-485 by CK2 following growth factor deprivation, leading to its subsequent ubiquitination by the SCF(FBXO9) complex. Phosphorylation by CK2 only takes place when TELO2 is bound to mTORC1, not mTORC2; leading to selective ubiquitination of mTORC1-associated protein.
Regulator of the DNA damage response (DDR). Part of the TTT complex that is required to stabilize protein levels of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins. The TTT complex is involved in the cellular resistance to DNA damage stresses, like ionizing radiation (IR), ultraviolet (UV) and mitomycin C (MMC). Together with the TTT complex and HSP90 may participate in the proper folding of newly synthesized PIKKs. Promotes assembly, stabilizes and maintains the activity of mTORC1 and mTORC2 complexes, which regulate cell growth and survival in response to nutrient and hormonal signals. May be involved in telomere length regulation.
Ubiquitinated by the SCF(FBXO9) complex following phosphorylation by CK2 in response to growth factor deprivation, leading to its degradation by the proteasome. Only mTORC1-associated protein is ubiquitinated and degraded, leading to selective inactivation of mTORC1 to restrain cell growth and protein translation, while mTORC2 is activated due to the relief of feedback inhibition by mTORC1.
Component of the PAT complex, composed of WDR83OS/Asterix and CCDC47 (PubMed:32814900, PubMed:36261522). The PAT complex is part of the multi-pass translocon (MPT) complex, composed of three subcomplexes, the GEL complex (composed of RAB5IF/OPTI and TMCO1), the BOS complex (composed of NCLN/Nicalin, NOMO and TMEM147) and the PAT complex (composed of WDR83OS/Asterix and CCDC47) (PubMed:36261522). The MPT complex associates with the SEC61 complex (PubMed:32814900, PubMed:36261522).
Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes (PubMed:12475939, PubMed:32814900, PubMed:36261522). The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions (PubMed:32814900, PubMed:36261522). Within the MPT complex, the PAT subcomplex sequesters any highly polar regions in the transmembrane domains away from the non-polar membrane environment until they can be buried in the interior of the fully assembled protein (By similarity). Within the PAT subcomplex, WDR83OS/Asterix binds to and redirects the substrate to a location behind the SEC61 complex (By similarity).
Binds to the plasma membrane and may be internalized by a receptor- and caveolae-mediated endocytosis manner to reach cytosolic compartments in a dynamin-dependent manner.
Derives from the plasma membrane form by proteolytic processing. Further proteolytic cleavage may be generated (By similarity).
Homodimer; disulfide-linked. Heterodimer with either TENM2 or TENM3. May also form heterodimer with TENM4. Ten-1 ICD interacts with SORBS1 (via third SH3 domain). Interacts with MBD1 (By similarity). Ten-1 ICD interacts with HINT1 (By similarity).
Involved in neural development, regulating the establishment of proper connectivity within the nervous system. May function as a cellular signal transducer (By similarity).
Plays a role in the regulation of neuroplasticity in the limbic system. Mediates a rapid reorganization of actin- and tubulin-based cytoskeleton elements with an increase in dendritic arborization and spine density formation of neurons in the hippocampus and amygdala. Induces BDNF transcription inhibition in neurons. Activates the mitogen-activated protein (MAP) kinase 2 (MEK2) and extracellular signal-regulated kinase (ERK) cascade. Acts also as a bioactive neuroprotective peptide on limbic neurons of the brain and regulates stress-induced behavior: attenuates alkalosis-associated necrotic cell death and the effects of corticotropin-releasing factor (CRF) on c-fos/FOS induction and on the reinstatement of cocaine seeking (By similarity).
Involved in double-stranded break repair. Plays a central role in genetic recombination and DNA repair by promoting the annealing of complementary single-stranded DNA and by stimulation of the RAD51 recombinase.
Phosphorylated upon DNA damage by ABL1, and probably by ATM or ATR.
The full-length protein forms heptameric rings (PubMed:12191481). Interacts with ABL1 (PubMed:12379650). Interacts with RPA2; the interaction is direct and associates RAD52 with the RPA complex (PubMed:8702565). Interacts with RAD51AP1 (PubMed:31400850).
Unable to interact with isoform alpha, may act as dominant negative.
Catalyzes the epimerization of the S- and R-forms of NAD(P)HX, a damaged form of NAD(P)H that is a result of enzymatic or heat-dependent hydration. This is a prerequisite for the S-specific NAD(P)H-hydrate dehydratase to allow the repair of both epimers of NAD(P)HX. Accelerates cholesterol efflux from endothelial cells to high-density lipoprotein (HDL) and thereby regulates angiogenesis (PubMed:23719382).
Homodimer (By similarity). Interacts with APOA1 and APOA2.
Ubiquitously expressed, with highest levels in kidney, heart and liver. Present in cerebrospinal fluid and urine but not in serum from healthy patients. Present in serum of sepsis patients (at protein level).
Undergoes physiological phosphorylation during sperm capacitation, downstream to PKA activation.
Activated by CHAPS (PubMed:9490062). Inhibited by chlorpyrifos oxon (IC(50)=0.21 nM), paraoxon (IC(50)=0.29 nM), or methyl paraoxon (IC(50)=49 nM) (PubMed:18762277).
Cleavage of the signal sequence can occur at 2 positions, either between Trp-17 and Gly-18 or between Gly-18 and His-19.
Expressed predominantly in liver with lower levels in heart and lung (PubMed:10562416). Expressed in macrophages (PubMed:11015575, PubMed:21049984, PubMed:18762277).
Genetic variants in CES1 are associated with clinically significant alterations in pharmacokinetics and drug response of carboxylesterase 1 substrates [MIM:618057].
Homotrimer and homohexamer. Binds to beta-glucuronidase.
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs (PubMed:7980644, PubMed:9169443, PubMed:9490062, PubMed:18762277). Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl-CoA ester (PubMed:7980644, PubMed:9169443, PubMed:9490062, PubMed:18762277). Hydrolyzes the methyl ester group of cocaine to form benzoylecgonine (PubMed:7980644). Catalyzes the transesterification of cocaine to form cocaethylene (PubMed:7980644). Displays fatty acid ethyl ester synthase activity, catalyzing the ethyl esterification of oleic acid to ethyloleate (PubMed:7980644). Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes of 2-arachidonoylglycerol and prostaglandins (PubMed:21049984). Hydrolyzes cellular cholesteryl esters to free cholesterols and promotes reverse cholesterol transport (RCT) by facilitating both the initial and final steps in the process (PubMed:18762277, PubMed:16024911, PubMed:11015575, PubMed:16971496). First of all, allows free cholesterol efflux from macrophages to extracellular cholesterol acceptors and secondly, releases free cholesterol from lipoprotein-delivered cholesteryl esters in the liver for bile acid synthesis or direct secretion into the bile (PubMed:18762277, PubMed:18599737, PubMed:16971496).
Interacts with IGF2; this interaction is required for IGF2 secretion.
Putative glycosidase. Promotes myogenesis by activating AKT signaling through the maturation and secretion of IGF2.
The requirement of the predicted catalytic residue Asp-463 to support myogenic function strongly suggests that MYORG is an enzymatically active glycosidase in vivo, even if concrete experimental proof for enzymatic activity is still missing.
A cytochrome P450 monooxygenase involved in the metabolism of retinoids and eicosanoids (PubMed:12711469, PubMed:21068195). In epidermis, may contribute to the oxidative metabolism of all-trans-retinoic acid. For this activity, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12711469). Additionally, displays peroxidase and isomerase activities toward various oxygenated eicosanoids such as prostaglandin H2 (PGH2) and hydroperoxyeicosatetraenoates (HPETEs) (PubMed:21068195). Independently of cytochrome P450 reductase, NADPH, and O2, catalyzes the breakdown of PGH2 to hydroxyheptadecatrienoic acid (HHT) and malondialdehyde (MDA), which is known to act as a mediator of DNA damage (PubMed:21068195).
Expressed at higher levels in extrahepatic tissues including trachea, lung, stomach, small intestine, colon, kidney, breast, placenta and spleen (PubMed:11181079, PubMed:12711469). Expressed in peripheral blood leukocytes (PubMed:11181079). Constitutively expressed in skin (at protein level) (PubMed:12711469).
Up-regulated in skin upon exposure to ultraviolet radiation or treatment with all-trans retinoic acid (substrate-inducible).
Belongs to the ABC transporter superfamily. ABCB family. Multidrug resistance exporter (TC 3.A.1.201) subfamily.
Expressed in small intestine (PubMed:28408210). Expressed in liver, kidney and brain.
Genetic variation in ABCB1 may play a role in patients who do not respond to drug treatment.
Interacts with PSMB5. Finds in a complex with ABCB1, TFPI2 and PPP2R3C; leading to the dephosphorylation of ABCB1.
Translocase activity is inhibited by verapamil and is sensitive to energy depletion (PubMed:8898203). C1orf115 regulates drug efflux through modulation of ABCB1 localization and activity (PubMed:35970996).
Translocates drugs and phospholipids across the membrane (PubMed:8898203, PubMed:2897240, PubMed:9038218, PubMed:35970996). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:9038218, PubMed:35970996).
Function as phospholipase selective for phosphatidylcholine (PubMed:9582313). May have a role in signal-induced cytoskeletal regulation and/or endocytosis (By similarity).
Interacts with PIP5K1B (PubMed:11032811). Interacts with EGFR (By similarity).
Stimulated by phosphatidylinositol 4,5-bisphosphate and slightly activated by the ADP-ribosylation factor-1 (ARF-1).
(Microbial infection) Deamidated at Gln-209 by Photorhabdus asymbiotica toxin PAU_02230, blocking GTP hydrolysis of heterotrimeric GNAQ or GNA11 and G-alphai (GNAI1, GNAI2 or GNAI3) proteins, thereby activating RhoA.
(Microbial infection) Interacts with human cytomegalovirus (HHV-5) US28.
Belongs to the G-alpha family. G(q) subfamily.
G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site (PubMed:35061538). Interacts with RGS22 (PubMed:18703424). Interacts with NTSR1 (PubMed:21725197).
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems (PubMed:31073061). Acts as an activator of phospholipase C (PubMed:31073061). Transduces FFAR4 signaling in response to long-chain fatty acids (LCFAs) (PubMed:27852822). Together with GNAQ, required for heart development (By similarity).
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL15) composed of CUL1, SKP1, RBX1 and FBXL15.
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of SMURF1, thereby acting as a positive regulator of the BMP signaling pathway. Required for dorsal/ventral pattern formation and bone mass maintenance. Also mediates ubiquitination of SMURF2 and WWP2.
Expressed in liver, kidney and colon. Not expressed in esophagus and small intestine.
Homodimer (PubMed:17179145). Homooligomer (Probable). Interacts with UGT1A1, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 to form heterodimers (PubMed:17179145). Isoform 1 interacts with isoform 2/i2 suggesting that oligomerization is involved in negative regulation of transferase activity by isoform 2. Isoform 1 also interacts with respective i2 isoforms of UGT1A1, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 (PubMed:20610558).
Lacks UDP-glucuronosyltransferase (UGT) activity but acts as a negative regulator of isoform 1.
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:15472229, PubMed:18674515, PubMed:18719240, PubMed:23756265, PubMed:23288867, PubMed:24641623). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:23756265). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229, PubMed:18719240, PubMed:23288867). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Involved in the glucuronidation of calcidiol, which is the major circulating form of vitamin D3, essential for the regulation of calcium and phosphate homeostasis (PubMed:24641623). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonists losartan, candesartan and zolarsartan, which can inhibit the effect of angiotensin II (PubMed:18674515).
UGT1A3 isoform is part of the UGT1A complex locus which displays alternative use of promoters, first exons and terminal exons. The locus is defined by 13 first exons, which are alternatively spliced to 3 other common exons and 2 alternative terminal exons 5. From the 27 possible mRNA isoforms, 9 produce functionally active polypeptides (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9 and 1A10) called isoforms 1 (i1). Use of an alternative exon 5 (5b) as terminal exon is leading to 9 additional alternatively spliced products termed isoforms i2 and which lack transferase activity.
Binds to GC box promoters elements and selectively activates mRNA synthesis from genes that contain functional recognition sites.
The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. In SP2, the motif is inactive.
May play a role in vesicular transport during the biogenesis of melanosomes.
Part of the multisubunit transport protein particle (TRAPP) complex. Heterodimer with TRAPPC3 (PubMed:16828797, PubMed:16262728). The heterodimer TRAPPC3-TRAPPC6A interacts with TRAPPC2L. Interacts with TRAPPC2L (PubMed:19416478).
Component of the dolichol-phosphate mannose (DPM) synthase complex composed of DPM1, DPM2 and DPM3; in the complex interacts directly with DPM3 (PubMed:10835346). Component of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex composed at least by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2 (PubMed:16162815). Interacts with PIGA, PIGC and PIGQ (PubMed:10944123).
Regulates the biosynthesis of dolichol phosphate-mannose (PubMed:10835346). Regulatory subunit of the dolichol-phosphate mannose (DPM) synthase complex; essential for the ER localization and stable expression of DPM1 (PubMed:10835346). Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis (PubMed:16162815). May act by regulating the GPI-GNT complex (PubMed:10944123).
Component of the biogenesis of lysosome-related organelles complex-2 (or BLOC2) composed of HPS3, HPS5 and HPS6. Interacts with HPS6 (PubMed:15030569, PubMed:25189619). Interacts with HPS3 (PubMed:15030569). May interact with all alpha-integrin chains that have an aromatic residue before the first lysine of the conserved KXGFFKR motif, including ITGA2, ITGA3, ITGA5 and ITGA6 (PubMed:10094488).
May regulate the synthesis and function of lysosomes and of highly specialized organelles, such as melanosomes and platelet dense granules. Regulates intracellular vesicular trafficking in fibroblasts. May be involved in the regulation of general functions of integrins.
Widely expressed. Isoform 1:Highly expressed in lungs and testis. Isoform 2:Highly expressed in placenta, kidney, testis ovary, lung and thymus.
Mitochondrial RNA-binding protein involved in mitochondrial transcription regulation. Functions as a protective factor to maintain proper mitochondrial RNA level during stress. Acts at the transcription level and its protective function depends on its RNA binding ability (PubMed:31226201). Part of a mitoribosome-associated quality control pathway that prevents aberrant translation by responding to interruptions during elongation (PubMed:33243891, PubMed:31396629). As heterodimer with MTRF, ejects the unfinished nascent chain and peptidyl transfer RNA (tRNA), respectively, from stalled ribosomes. Recruitment of mitoribosome biogenesis factors to these quality control intermediates suggests additional roles for MTRES1 and MTRF during mitoribosome rescue (PubMed:33243891).
Monomer (PubMed:31226201). Interacts with POLRMT (PubMed:31226201). Interacts (via S4 domain) with MTRFR (via C-terminus) (PubMed:33243891, PubMed:31396629). Associates with mitoribosomal S39 large subunit, peptidyl tRNA and nascent chain (PubMed:33243891, PubMed:31396629).
Up-regulated upon depletion of mitochondrial nucleic acids.
Expressed constitutively in several normal tissues: spleen, liver, skeletal and heart muscle, gut, and bone marrow, present at high concentrations (1-80 nM) in plasma.
HCC-1(1-74), but not HCC-1(3-74) and HCC-1(4-74), is partially O-glycosylated; the O-linked glycan consists of one Gal-GalNAc disaccharide, further modified by two N-acetylneuraminic acids.
Has weak activities on human monocytes and acts via receptors that also recognize MIP-1 alpha. It induces intracellular Ca(2+) changes and enzyme release, but no chemotaxis, at concentrations of 100-1,000 nM, and is inactive on T-lymphocytes, neutrophils, and eosinophil leukocytes. Enhances the proliferation of CD34 myeloid progenitor cells. The processed form HCC-1(9-74) is a chemotactic factor that attracts monocytes, eosinophils, and T-cells and is a ligand for CCR1, CCR3 and CCR5.
The N-terminal processed forms HCC-1(3-74), HCC-1(4-74) and HCC-1(9-74) are produced in small amounts by proteolytic cleavage after secretion in blood.
'Ana-mors-in' means 'anti-death molecule' in Latin.
Component of the cytosolic iron-sulfur (Fe-S) protein assembly (CIA) machinery required for the maturation of extramitochondrial Fe-S proteins. Part of an electron transfer chain functioning in an early step of cytosolic Fe-S biogenesis, facilitating the de novo assembly of a [4Fe-4S] cluster on the scaffold complex NUBP1-NUBP2. Electrons are transferred to CIAPIN1 from NADPH via the FAD- and FMN-containing protein NDOR1 (PubMed:23596212). NDOR1-CIAPIN1 are also required for the assembly of the diferric tyrosyl radical cofactor of ribonucleotide reductase (RNR), probably by providing electrons for reduction during radical cofactor maturation in the catalytic small subunit (By similarity). Has anti-apoptotic effects in the cell. Involved in negative control of cell death upon cytokine withdrawal. Promotes development of hematopoietic cells (By similarity).
In the presence of oxygen, the A site-bound [2Fe-2S] cluster is labile and the B site-bound [4Fe-4S] cluster is readily converted into a [2Fe-2S] cluster, a reason why recombinant protein is often isolated with a single [2Fe-2S] cluster.
Monomer. Interacts with NDOR1; its oxidized form can be reduced by NDOR1. Interacts with CHCHD4 and may be a substrate for CHCHD4 chaperone activity.
The C-terminal domain binds 2 Fe-S clusters but is otherwise mostly in an intrinsically disordered conformation.
The N-terminal domain has structural similarity with S-adenosyl-L-methionine-dependent methyltransferases, but does not bind S-adenosyl-L-methionine. It is required for correct assembly of the 2 Fe-S clusters.
The twin Cx2C motifs are involved in the recognition by the mitochondrial CHCHD4/MIA40-GFER/ERV1 disulfide relay system. The formation of 2 disulfide bonds in the Cx2C motifs through dithiol/disulfide exchange reactions effectively traps the protein in the mitochondrial intermembrane space.
Ubiquitously expressed. Highly expressed in heart, liver and pancreas.
Homodimer. Interacts with SNX1, SNX2 and SNX4.
May be involved in several stages of intracellular trafficking. Overexpression of SNX15 disrupts the normal trafficking of proteins from the plasma membrane to recycling endosomes or the TGN.
(Microbial infection) Binds to human adenovirus gene promoters and contributes to transcriptional repression and virus growth inhibition during early stages of infection.
(Microbial infection) Interacts (via C-terminus) with human adenovirus early E1A protein (via C-terminus); the interaction is direct.
Autosumoylated with SUMO1, SUMO2, and SUMO3.
Expression is linked to the cell cycle: low in serum-starved fibroblasts, increasing during the G1/S phase, highest during the S/G2 phase and then decreasing again.
Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase which sumoylates CHD3/Mi2-alpha, causing its release from DNA (PubMed:27068747). This results in suppression of CHD3/Mi2-alpha transcription repression, increased recruitment of RNA polymerase II to gene promoters and positive regulation of transcription including H1-5 and ribosomal proteins such as: RPS6, RPL10A, and RPL12 (PubMed:12663651, PubMed:17209048, PubMed:17220279, PubMed:27068747). The resulting increased transcriptional activity drives cell proliferation (PubMed:12663651, PubMed:17220279). Binds to 5'-TGTCG[CT]GA[CT]A-3' consensus sequences in gene promoters of ribosomal proteins (PubMed:12663651, PubMed:17209048, PubMed:17220279, PubMed:27068747).
Homodimer and homomultimer (PubMed:17209048). Homodimerization is necessary for protein nuclear localization and DNA binding (PubMed:17209048). Interacts with KPNB1; required for nuclear import of ZBED1/hDREF (PubMed:17209048). Interacts with CHD3/Mi2-alpha (PubMed:27068747). Interacts with SUMO1 (PubMed:27068747). Interacts with UBE2I/UBC9 (PubMed:27068747).
Ubiquitously expressed at low levels (PubMed:9887332). Expression is highest in skeletal muscle, heart, spleen and placenta (PubMed:9887332).
Was first identified as gene weakly similar to Ac transposable elements, but does not code for any transposase activity.
Cytokine secreted primarily by mast cells, T-cells, eosinophils, and basophils that plays a role in regulating antibody production, hematopoiesis and inflammation, and the development of effector T-cell responses (PubMed:3016727, PubMed:1993171). Induces the expression of class II MHC molecules on resting B-cells. Enhances both secretion and cell surface expression of IgE and IgG1 (PubMed:1993171). Regulates also the expression of the low affinity Fc receptor for IgE (CD23) on both lymphocytes and monocytes (PubMed:2521231). Positively regulates IL31RA expression in macrophages. Stimulates autophagy in dendritic cells by interfering with mTORC1 signaling and through the induction of RUFY4. In addition, plays a critical role in higher functions of the normal brain, such as memory and learning (By similarity). Upon binding to IL4, IL4R receptor dimerizes either with the common IL2R gamma chain/IL2RG to produce the type 1 signaling complex, located mainly on hematopoietic cells, or with the IL13RA1 to produce the type 2 complex, which is expressed also on nonhematopoietic cells (PubMed:10219247, PubMed:11526337, PubMed:18243101). Engagement of both types of receptors initiates JAK3 and to a lower extend JAK1 phosphorylation leading to activation of the signal transducer and activator of transcription 6/STAT6 (PubMed:7721895).
Interacts with IL4R (PubMed:10219247, PubMed:11526337). Interacts with IL13RA1 (PubMed:18243101).
Participates in at least several B-cell activation processes as well as of other cell types. It is a costimulator of DNA-synthesis. It induces the expression of class II MHC molecules on resting B-cells. It enhances both secretion and cell surface expression of IgE and IgG1. It also regulates the expression of the low affinity Fc receptor for IgE (CD23) on both lymphocytes and monocytes.
A genetic variation in NCR3 is associated with mild malaria susceptibility [MIM:609148].
Belongs to the natural cytotoxicity receptor (NCR) family.
Cell membrane receptor of natural killer/NK cells that is activated by binding of extracellular ligands including BAG6 and NCR3LG1. Stimulates NK cells cytotoxicity toward neighboring cells producing these ligands. It controls, for instance, NK cells cytotoxicity against tumor cells. Engagement of NCR3 by BAG6 also promotes myeloid dendritic cells (DC) maturation, both through killing DCs that did not acquire a mature phenotype, and inducing the release by NK cells of TNFA and IFNG which promote DC maturation.
Homodimer in the unliganted form. Interacts with CD3Z. Interacts with and is activated by binding to NCR3LG1. Interacts with and is activated by binding to BAG6.
Selectively expressed by all resting and activated NK cells and weakly expressed in spleen.
(Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins.
(Microbial infection) Interacts with Epstein-Barr virus/HHV-4 glycoprotein L/gL and glycoprotein H/gH heterodimer; this interaction facilitates virus internalization and fusion.
(Microbial infection) Interacts with human cytomegalovirus (HCMV) glycoprotein L/gL and glycoprotein H/gH heterodimer.
(Microbial infection) Interacts with human herpes virus 8/HHV-8 glycoprotein L/gL and glycoprotein H/gH heterodimer; this interaction triggers EPHA2 phosphorylation and endocytosis, allowing virus entry.
Acts as a receptor for human cytomegalovirus (HCMV) to mediate viral entry and fusion in glioblastoma cells.
Autophosphorylates. Phosphorylated on tyrosine upon binding and activation by EFNA1. Phosphorylated residues Tyr-588 and Tyr-594 are required for binding VAV2 and VAV3 while phosphorylated residues Tyr-735 and Tyr-930 are required for binding PI3-kinase p85 subunit (PIK3R1, PIK3R2 or PIK3R3). These phosphorylated residues are critical for recruitment of VAV2 and VAV3 and PI3-kinase p85 subunit which transduce downstream signaling to activate RAC1 GTPase and cell migration. Dephosphorylation of Tyr-930 by PTPRF prevents the interaction of EPHA2 with NCK1. Phosphorylated at Ser-897 by PKB; serum-induced phosphorylation which targets EPHA2 to the cell leading edge and stimulates cell migration. Phosphorylation by PKB is inhibited by EFNA1-activated EPHA2 which regulates PKB activity via a reciprocal regulatory loop. Phosphorylated at Ser-897 in response to TNF by RPS6KA1 and RPS6KA3; RPS6KA-EPHA2 signaling pathway controls cell migration (PubMed:26158630). Phosphorylated at Ser-897 by PKA; blocks cell retraction induced by EPHA2 kinase activity (PubMed:27385333). Dephosphorylated by ACP1.
Expressed in brain and glioma tissue and glioma cell lines (at protein level). Expressed most highly in tissues that contain a high proportion of epithelial cells, e.g. skin, intestine, lung, and ovary.
Homodimer. Interacts with SLA. Interacts (phosphorylated form) with VAV2, VAV3 and PI3-kinase p85 subunit (PIK3R1, PIK3R2 or PIK3R3); critical for the EFNA1-induced activation of RAC1 which stimulates cell migration (By similarity). Interacts with INPPL1; regulates activated EPHA2 endocytosis and degradation. Interacts (inactivated form) with PTK2/FAK1 and interacts (EFNA1 ligand-activated form) with PTPN11; regulates integrin-mediated adhesion. Interacts with ARHGEF16, DOCK4 and ELMO2; mediates ligand-independent activation of RAC1 which stimulates cell migration. Interacts with CLDN4; phosphorylates CLDN4 and may regulate tight junctions. Interacts with ACP1. Interacts (via SAM domain) with ANKS1A (via SAM domain). Interacts with CEMIP. Interacts with NCK1; may regulate EPHA2 activity in cell migration and adhesion. Interacts with TIMD4 (PubMed:34067457).
Overexpressed in several cancer types and promotes malignancy.
Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand-independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis.
Ubiquitinated by CHIP/STUB1. Ubiquitination is regulated by the HSP90 chaperone and regulates the receptor stability and activity through proteasomal degradation. ANKS1A prevents ubiquitination and degradation (By similarity).
Up-regulated by UV irradiation via a TP53-independent, MAPK-dependent mechanism.
All O-linked glycans consist of Gal-GlcNAc-Gal-GalNAc tetrasaccharide core and get elongated (microheterogeneity).
Might act as an inhibitor of spontaneous calcium carbonate precipitation. May be associated with neuronal sprouting in brain, and with brain and pancreas regeneration.
While belonging to the GST superfamily, it probably lacks glutathione transferase activity.
As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway. Recruits, in an amino acid-independent manner, the GATOR1 complex to the lysosomal membranes and allows its interaction with GATOR2 and the RAG GTPases. Functions upstream of the RAG GTPases and is required to negatively regulate mTORC1 signaling in absence of amino acids. In absence of the KICSTOR complex mTORC1 is constitutively localized to the lysosome and activated. The KICSTOR complex is also probably involved in the regulation of mTORC1 by glucose.
Part of the KICSTOR complex composed of KPTN, ITFG2, KICS2 and SZT2. SZT2 probably serves as a link between the other three proteins in the KICSTOR complex and mediates the direct interaction with the GATOR1 complex (PubMed:28199306). May associate with F-actin filaments (PubMed:10099934).
GTPase that recruits MYO1E to MHC class II-containing vesicles via the effector protein ARL14EP and hence controls the movement of these vesicles along the actin cytoskeleton in dendritic cells.
A chromosomal aberration involving ZFTA is found in 3 chondroid lipomas. Translocation t(11;16)(q13;p13) with ZFTA produces a ZFTA-MRTFB fusion protein (PubMed:20607705).
Acts as a transcriptional coactivator of serum response factor (SRF). Required for skeletal myogenic differentiation.
The N-terminal region is required for nuclear localization and the C-terminal region mediates transcriptional activity.
Component of the spliceosome A complex (also known as the prespliceosome). Appears to dissociate from the spliceosome upon formation of the spliceosome B complex (also known as the precatalytic spliceosome), in which the heterotrimeric U4/U6.U5 snRNPs are bound. Interacts with U2AF2; this interaction is direct. Also interacts with ACIN1, PRPF8, SFRS3, SNRPB, SNRPN, SNRNP70 and SNRNP200; these interactions may be indirect.
Component of the spliceosome A complex. Regulates alternative splicing of a number of mRNAs. May modulate splice site pairing after recruitment of the U1 and U2 snRNPs to the 5' and 3' splice sites of the intron. May both positively and negatively regulate apoptosis by regulating the alternative splicing of several genes involved in this process, including FAS and CASP2/caspase-2. In the case of FAS, promotes exclusion of exon 6 thereby producing a soluble form of FAS that inhibits apoptosis. In the case of CASP2/caspase-2, promotes exclusion of exon 9 thereby producing a catalytically active form of CASP2/Caspase-2 that induces apoptosis.
Isoform 5 is widely expressed in normal tissues and is expressed at increased levels in T-leukemic cell lines.
Electrogenic Na(+)-coupled sugar symporter that may play a primary role in D-mannose and possibly D-fructose and D-glucose transport at the plasma membrane. Transporter activity is driven by a transmembrane Na(+) electrochemical gradient set by the Na(+)/K(+) pump. Exclusively recognizes sugar substrates having a pyranose ring with an axial hydroxyl group on carbon 2.
Expressed in the small intestine, kidney and liver.
Composed of two functionally independent domains. The N-terminal domain forms a hydrophobic cleft involved in microtubule binding and the C-terminal is involved in the formation of mutually exclusive complexes with APC and DCTN1.
Expressed in different tumor cell lines. Up-regulated in activated B- and T-lymphocytes.
Interacts with DCTN1 (PubMed:14514668). Interacts with APC (via C-terminal) (PubMed:9233623, PubMed:14514668). Interacts with monomeric and polymerized tubulin (PubMed:10188731, PubMed:14514668, PubMed:26637975). Interacts with SLAIN1 (PubMed:21646404). Interacts (via the N-terminal region) with BAG1 (PubMed:15986447).
May be involved in microtubule polymerization, and spindle function by stabilizing microtubules and anchoring them at centrosomes. May play a role in cell migration (By similarity).
A chromosomal aberration involving UVRAG has been observed in a patient with heterotaxy (left-right axis malformation). Inversion Inv(11)(q13.5;q25).
Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex II (PI3KC3-C2) in which the core composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 is associated with UVRAG; in the complex interacts directly with BECN1. PI3KC3-C2 can associate with further regulatory subunits such as RUBCN and probably SH3GLB1/Bif-1 (PubMed:16799551, PubMed:18843052, PubMed:19050071, PubMed:19270696, PubMed:20643123, PubMed:23878393, PubMed:24056303). Interacts with SH3GLB1; UVRAG bridges the interaction to BECN1 indicative for an association with the PI3K complex PI3KC3-C2 (PubMed:17891140). Interacts with RINT1. Associates with the NRZ complex under basal conditions and dissociates from it under autophagy conditions to associate with the PI3K complex; these complex associations seem to be mutually exclusive (PubMed:24056303). Interacts with VPS16; VPS11; VPS18; VPS33 (VPS33A or VPS33B) and VPS39; indicative for an association with a class C Vps tethering complex (possibly the HOPS complex) (PubMed:18552835, PubMed:25533187). Interacts with RAB7A; RAB7A competes with UVRAG for RUBCN binding (PubMed:25533187, PubMed:20974968). Interacts with STX7, VTI1B, STX8 (PubMed:24550300). Interacts with PRKDC, XRCC6 and XRCC5; indicative for an association with the DNA-dependent protein kinase complex DNA-PK. Interacts with CEP63 (PubMed:22542840). Directly interacts with FEZ1 and SCOC; the interaction with SCOC is reduced by amino acid starvation, but the complex is stabilized in the presence of FEZ1 (PubMed:22354037). Interacts with BECN1P1/BECN2 (PubMed:23954414). Interacts with SLAMF1 (PubMed:22493499). Interacts with RUBCNL/PACER; promoting targeting of UVRAG to autophagosome (PubMed:28306502). Interacts with WNK1 (PubMed:27911840).
Highly expressed in brain, lung, kidney and liver.
Involved in maintaining chromosomal stability. Promotes DNA double-strand break (DSB) repair by association with DNA-dependent protein kinase complex DNA-PK and activating it in non-homologous end joining (NHEJ) (PubMed:22542840). Required for centrosome stability and proper chromosome segregation (PubMed:22542840).
Phosphorylated at Ser-498 by MTOR under basal conditions; increases the interaction with RUBCN implicated in inhibitory effect of RUBCN on PI3KC3 and decreases interaction with RAB7,A and VPS16 and VPS39 (indicative for a class C Vps complex, possibly the HOPS complex) (PubMed:25533187).
Versatile protein that is involved in regulation of different cellular pathways implicated in membrane trafficking. Involved in regulation of the COPI-dependent retrograde transport from Golgi and the endoplasmic reticulum by associating with the NRZ complex; the function is dependent on its binding to phosphatidylinositol 3-phosphate (PtdIns(3)P) (PubMed:16799551, PubMed:18552835, PubMed:20643123, PubMed:24056303, PubMed:28306502). During autophagy acts as regulatory subunit of the alternative PI3K complex II (PI3KC3-C2) that mediates formation of phosphatidylinositol 3-phosphate and is believed to be involved in maturation of autophagosomes and endocytosis. Activates lipid kinase activity of PIK3C3 (PubMed:16799551, PubMed:20643123, PubMed:24056303, PubMed:28306502). Involved in the regulation of degradative endocytic trafficking and cytokinesis, and in regulation of ATG9A transport from the Golgi to the autophagosome; the functions seems to implicate its association with PI3KC3-C2 (PubMed:16799551, PubMed:20643123, PubMed:24056303). Involved in maturation of autophagosomes and degradative endocytic trafficking independently of BECN1 but depending on its association with a class C Vps complex (possibly the HOPS complex); the association is also proposed to promote autophagosome recruitment and activation of Rab7 and endosome-endosome fusion events (PubMed:18552835, PubMed:28306502). Enhances class C Vps complex (possibly HOPS complex) association with a SNARE complex and promotes fusogenic SNARE complex formation during late endocytic membrane fusion (PubMed:24550300). In case of negative-strand RNA virus infection is required for efficient virus entry, promotes endocytic transport of virions and is implicated in a VAMP8-specific fusogenic SNARE complex assembly (PubMed:24550300).
Expressed in skeletal muscle, placenta, heart, pancreas, testis, brain, lung, liver, kidney, spleen, thymus, prostate, small intestine, colon and leukocytes.
Protein phosphatase 6 (PP6) holoenzyme is proposed to be a heterotrimeric complex formed by the catalytic subunit, a SAPS domain-containing subunit (PP6R) and an ankyrin repeat-domain containing regulatory subunit (ARS). Interacts with PPP6C and ANKRD28.
Regulatory subunit of protein phosphatase 6 (PP6). May function as a scaffolding PP6 subunit. May have an important role in maintaining immune self-tolerance.
Encoded by one of the numerous copies of centaurin gamma-like genes clustered in the q11 region of chromosome 10.
Isoform 2 is widely expressed. Isoform 3 is highly expressed in heart, brain and lung, lower expressed in thymus and much lower expressed in peripheral blood leukocytes.
Orthologs of U2AF1L4 do not appear to exist in lower eukaryotes, Drosophila, C. elegans, plants, or vertebrates such as Xenopus or zebrafish. Existence of circadian and light-inducible alternative splicing of U2AF1L4 similar to the mouse in human and rat is not yet proven.
RNA-binding protein that function as a pre-mRNA splicing factor. Plays a critical role in both constitutive and enhancer-dependent splicing by mediating protein-protein interactions and protein-RNA interactions required for accurate 3'-splice site selection. Acts by enhancing the binding of U2AF2 to weak pyrimidine tracts. Also participates in the regulation of alternative pre-mRNA splicing. Activates exon 5 skipping of PTPRC during T-cell activation; an event reversed by GFI1. Binds to RNA at the AG dinucleotide at the 3'-splice site (By similarity). Shows a preference for AGC or AGA (By similarity).
The region 162-220 is essential for the nuclear import of the protein in spite of the absence of a nuclear localization signal (NLS). This region is essential for the interaction with C1QBP, interaction which is required for the nuclear translocation. This region may be involved in the localization in nuclear dot-like structures and it also confers the ability of nucleo-cytoplasmic shuttling.
The second zinc finger in necessary for interaction with GFI1 and for alternative pre-mRNA splicing events.
A chromosomal aberration involving CPA6 was found in a patient with Duane retraction syndrome. Translocation t(6;8)(q26;q13).
Expressed in the hippocampus, nucleus raphe, and cortex.
May be involved in the proteolytic inactivation of enkephalins and neurotensin in some brain areas. May convert inactive angiotensin I into the biologically active angiotensin II (PubMed:18178555). Releases a C-terminal amino acid, with preference for large hydrophobic C-terminal amino acids and shows only very weak activity toward small amino acids and histidine (PubMed:20855895).
By phorbol ester (PMA) and bacterial lipopolysaccharides (LPS) treatment in macrophage cell line. By Aspergillus fumigatus conidia in peripheral blood mnonocytes.
Inhibits the activity of interleukin-36 (IL36A,IL36B and IL36G) by binding to receptor IL1RL2 and preventing its association with the coreceptor IL1RAP for signaling. Part of the IL-36 signaling system that is thought to be present in epithelial barriers and to take part in local inflammatory response; similar to the IL-1 system with which it shares the coreceptor. Proposed to play a role in skin inflammation. May be involved in the innate immune response to fungal pathogens, such as Aspergillus fumigatus. May activate an anti-inflammatory signaling pathway by recruiting SIGIRR.
Interacts with cargo receptor TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion.
Predominantly expressed in skin keratinocytes but not in fibroblasts, endothelial cells or melanocytes. Detected also in the spleen, brain leukocyte and macrophage cell types. Increased in lesional psoriasis skin.
May activate NF-kappa-B signaling pathways.
Belongs to the acetyltransferase family. GNAT subfamily.
Component of the N-terminal acetyltransferase E (NatE) complex at least composed of NAA10, NAA15 and NAA50 (PubMed:16507339, PubMed:29754825, PubMed:32042062). Interacts with NAA10 (PubMed:16507339, PubMed:32042062). Interacts with NAA15 (PubMed:16507339, PubMed:29754825, PubMed:32042062). Predominantly interacts with NAA15 in the N-terminal acetyltransferase A complex (NatA complex); the interactions reduce the acetylation activity of the NatA complex (PubMed:16507339, PubMed:32042062). Component of the N-terminal acetyltransferase E (NatE)/HYPK complex at least composed of NAA10, NAA15, NAA50 and HYPK (PubMed:32042062). Within the complex interacts with NAA15 (PubMed:32042062). Its capacity to interact with the NatA complex is reduced by HYPK (PubMed:32042062). Interacts with NAA35 (By similarity).
N-alpha-acetyltransferase that acetylates the N-terminus of proteins that retain their initiating methionine (PubMed:19744929, PubMed:22311970, PubMed:21900231, PubMed:27484799). Has a broad substrate specificity: able to acetylate the initiator methionine of most peptides, except for those with a proline in second position (PubMed:27484799). Also displays N-epsilon-acetyltransferase activity by mediating acetylation of the side chain of specific lysines on proteins (PubMed:19744929). Autoacetylates in vivo (PubMed:19744929). The relevance of N-epsilon-acetyltransferase activity is however unclear: able to acetylate H4 in vitro, but this result has not been confirmed in vivo (PubMed:19744929). Component of N-alpha-acetyltransferase complexes containing NAA10 and NAA15, which has N-alpha-acetyltransferase activity (PubMed:16507339, PubMed:29754825, PubMed:27484799, PubMed:32042062). Does not influence the acetyltransferase activity of NAA10 (PubMed:16507339, PubMed:27484799). However, it negatively regulates the N-alpha-acetyltransferase activity of the N-terminal acetyltransferase A complex (also called the NatA complex) (PubMed:32042062). The multiprotein complexes probably constitute the major contributor for N-terminal acetylation at the ribosome exit tunnel, with NAA10 acetylating all amino termini that are devoid of methionine and NAA50 acetylating other peptides (PubMed:16507339, PubMed:27484799). Required for sister chromatid cohesion during mitosis by promoting binding of CDCA5/sororin to cohesin: may act by counteracting the function of NAA10 (PubMed:17502424, PubMed:27422821).
Can be activated without removal of the activation peptide.
Cleaves collagens of types I, II, and III at one site in the helical domain. Also cleaves collagens of types VII and X (PubMed:2557822, PubMed:2153297, PubMed:1645757). In case of HIV infection, interacts and cleaves the secreted viral Tat protein, leading to a decrease in neuronal Tat's mediated neurotoxicity (PubMed:16807369).
There are two distinct domains in this protein; the catalytic N-terminal, and the C-terminal which is involved in substrate specificity and in binding TIMP (tissue inhibitor of metalloproteinases).
Tyrosine phosphorylated in platelets by PKDCC/VLK.
Undergoes autolytic cleavage to two major forms (22 kDa and 27 kDa). A minor form (25 kDa) is the glycosylated form of the 22 kDa form. The 27 kDa form has no activity while the 22/25 kDa form can act as activator for collagenase.
Death-promoting transcriptional repressor. May be involved in cyclin-D1/CCND1 mRNA stability through the SNARP complex which associates with both the 3'end of the CCND1 gene and its mRNA.
Interacts with Bcl-2 related proteins, EMD, with the adenovirus E1B 19 kDa protein and with DNA. Component of the SNARP complex which consists at least of SNIP1, SNW1, THRAP3, BCLAF1 and PNN. Component of a MACOM-like complex, named WTAP complex, composed of WTAP, ZC3H13, CBLL1, KIAA1429, RBM15, BCLAF1 and THRAP3.
Dioxygenase that mediates demethylation of DNA and RNA containing 1-methyladenosine (m1A) (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:26863196, PubMed:26863410). Repairs alkylated DNA containing 1-methyladenosine (m1A) and 3-methylcytosine (m3C) by oxidative demethylation (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:25944111). Has a strong preference for single-stranded DNA (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:20714506). Able to process alkylated m3C within double-stranded regions via its interaction with ASCC3, which promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3 (PubMed:22055184). Can repair exocyclic 3,N4-ethenocytosine adducs in single-stranded DNA (PubMed:25797601). Also acts on RNA (PubMed:12594517, PubMed:16174769, PubMed:26863196, PubMed:26863410, PubMed:16858410). Demethylates N(1)-methyladenosine (m1A) RNA, an epigenetic internal modification of messenger RNAs (mRNAs) highly enriched within 5'-untranslated regions (UTRs) and in the vicinity of start codons (PubMed:26863196, PubMed:26863410). Requires molecular oxygen, alpha-ketoglutarate and iron (PubMed:22055184, PubMed:16858410).
Interacts with the ASCC complex composed of ASCC1, ASCC2 and ASCC3 (PubMed:29144457, PubMed:22055184). Interacts directly with ASCC3, and is thereby recruited to the ASCC complex (PubMed:22055184, PubMed:29144457). Interacts with OTUD4; the interaction is direct (PubMed:25944111). Interacts with USP7 and USP9X (PubMed:25944111).
Ubiquitinated; undergoes 'Lys-48'-linked polyubiquitination. OTUD4 promotes USP7 and USP9X-dependent deubiquitination of 'Lys-48'-polyubiquitinated ALKBH3 promoting the repair of alkylated DNA lesions.
Ubiquitous. Detected in heart, pancreas, skeletal muscle, thymus, testis, ovary, spleen, prostate, small intestine, peripheral blood leukocytes, urinary bladder and colon.
Involved in lipid remodeling during GPI-anchor maturation.
Barely detectable in normal blood leukocytes. Weaker expression was seen in heart, kidney and lung. Not detected in brain.
Down-regulated during granulocytic regulation.
Probable receptor for purines coupled to G-proteins.
Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation. Sperm cell hyperactivation is needed for sperm motility which is essential late in the preparation of sperm for fertilization.
Component of the CatSper complex or CatSpermasome composed of the core pore-forming members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 as well as auxiliary members CATSPERB, CATSPERG, CATSPERD, CATSPERE, CATSPERZ, C2CD6/CATSPERT, TMEM249, TMEM262 and EFCAB9. HSPA1 may be an additional auxiliary complex member. The core complex members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 form a heterotetrameric channel. The auxiliary CATSPERB, CATSPERG, CATSPERD and CATSPERE subunits form a pavilion-like structure over the pore which stabilizes the complex through interactions with CATSPER4, CATSPER3, CATSPER1 and CATSPER2 respectively. TMEM262/CATSPERH interacts with CATSPERB, further stabilizing the complex. C2CD6/CATSPERT interacts at least with CATSPERD and is required for targeting the CatSper complex in the flagellar membrane.
Exhibits both acyltransferase and acetyltransferase activities (PubMed:17182612, PubMed:20363836, PubMed:21498505). Catalyzes the conversion of lysophosphatidylcholine (1-acyl-sn-glycero-3-phosphocholine or LPC) into phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine or PC) (PubMed:21498505). Catalyzes the conversion 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone (PubMed:20363836). Involved in platelet-activating factor (PAF) biosynthesis by catalyzing the conversion of the PAF precursor, 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) into 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) (PubMed:17182612). Also converts lyso-PAF to 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine (PC), a major component of cell membranes and a PAF precursor (By similarity). Under resting conditions, acyltransferase activity is preferred (By similarity). Upon acute inflammatory stimulus, acetyltransferase activity is enhanced and PAF synthesis increases (By similarity). Involved in the regulation of lipid droplet number and size (PubMed:25491198).
The HXXXXD motif is essential for acyltransferase activity.
Cell surface glycoprotein that plays a role in cell adhesion in a calcium-independent manner (PubMed:8776764, PubMed:2022629, PubMed:11590190). Mediates heterophilic cell adhesion with other carcinoembryonic antigen-related cell adhesion molecules, such as CEACAM6 (PubMed:8776764, PubMed:2022629, PubMed:11590190). Heterophilic interaction with CEACAM8 occurs in activated neutrophils (PubMed:8776764).
Expressed in leukocytes of chronic myeloid Leukemia patients and bone marrow.
Monomer. Heterodimer with CEACAM6; heterodimerizes via its Ig-like V-type domain.
The N-terminus Ig-like V-type domain is necessary for heterophilic intercellular adhesion.
Cell membrane-cytoskeleton-associated protein that plays a role in the regulation of actin polymerization at the barbed end of actin filaments. Prevents F-actin heterodimeric capping protein (CP) activity at the leading edges of migrating cells, and hence generates uncapped barbed ends and enhances actin polymerization (PubMed:26466680). Plays a role in cell protrusion formations; involved in cell polarity, lamellipodial assembly, membrane ruffling and macropinosome formations (PubMed:19846667, PubMed:26578515, PubMed:26466680). Involved as well in cell migration and invadopodia formation during wound healing (PubMed:19846667, PubMed:26578515, PubMed:26466680). Required for CD28-mediated stimulation of NF-kappa-B signaling, involved in naive T cells activation, maturation into T memory cells, and differentiation into T helper and T regulatory cells (PubMed:27647349, PubMed:27647348, PubMed:28112205).
Expressed in all tissues tested, including thymus, spleen, colon, leukocytes, peripheral blood, skin, skin keratinocytes and skin fibroblasts. Strong expression is detected in naive and memory CD4+ and CD8+ T cells, naive and memory B cells, regulatory T cells and NK cells, whereas it is poorly expressed in monocytes (PubMed:27647349).
Forms homodimers (PubMed:27647349, PubMed:27647348). Interacts (via C-terminus) with heterodimeric capping protein (CP); the interaction inhibits CP activity and hence promotes actin polymerization at the barbed end of actin filaments (PubMed:26466680).
The N-terminal leucine-rich repeat (LRR) domain is necessary for localization to vimentin filaments (PubMed:26466680). The C-terminus is necessary for localization to the cell membrane (PubMed:26578515).
Belongs to the GST superfamily. Theta family.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles (PubMed:1417752). Has a sulfatase activity (PubMed:1417752).
Expressed at low levels in liver. In lung, expressed at low levels in ciliated bronchiolar cells, alveolar macrophages and alveolar type II cells.
Belongs to the major facilitator superfamily. Sugar transporter (TC 2.A.1.1) family.
D-glucose and maltose competitively inhibit fructose transport (PubMed:8457197). D-glucose, D-fructose and maltose inhibit deoxyglucose transport (PubMed:8457197). Glucose and fructose transport are inhibited by flavonoids such as epigallocatechin gallate, apigenin and quercetin (PubMed:29548810).
Facilitative hexose transporter that mediates the transport of glucose, fructose and galactose (PubMed:8027028, PubMed:16186102, PubMed:23396969, PubMed:28083649, PubMed:8457197). Likely mediates the bidirectional transfer of glucose across the plasma membrane of hepatocytes and is responsible for uptake of glucose by the beta cells; may comprise part of the glucose-sensing mechanism of the beta cell (PubMed:8027028). May also participate with the Na(+)/glucose cotransporter in the transcellular transport of glucose in the small intestine and kidney (PubMed:3399500). Also able to mediate the transport of dehydroascorbate (PubMed:23396969).
Liver, insulin-producing beta cell, small intestine and kidney.
N-glycosylated; required for stability and retention at the cell surface of pancreatic beta cells.
Functions as a transcriptional repressor. Seems to function as a transcriptional corepressor in neuronal cells through recruitment of HDAC3 and HDAC4. Contributes to tumor progression, and tumor cell proliferation and survival. This may be mediated at least in part through repressing transcriptional activity of GADD45GIP1. Required for recruiting the proteasome from the nucleus to the cytoplasm and dendritic spines.
Homooligomer; mediated by the BTB domain. Interacts with HDAC3 and HDAC4. Interacts (via BTB domain) with CUL3, PSMD7 and RCOR1.
Overexpressed in several types of carcinomas including ovarian serous carcinomas. Expression levels positively correlate with tumor recurrence in ovarian serous carcinomas, and intense immunoreactivity in primary ovarian tumors predicts early recurrence. Up-regulated in ovarian carcinomas after chemotherapy, suggesting a role in development of chemotherapy resistance in ovarian cancer.
Component of the BLOC-3 complex, a complex that acts as a guanine exchange factor (GEF) for RAB32 and RAB38, promotes the exchange of GDP to GTP, converting them from an inactive GDP-bound form into an active GTP-bound form. The BLOC-3 complex plays an important role in the control of melanin production and melanosome biogenesis and promotes the membrane localization of RAB32 and RAB38 (PubMed:23084991).
Component of the biogenesis of lysosome-related organelles complex-3 (or BLOC-3), a heterodimer of HPS1 and HPS4 (PubMed:20048159, PubMed:23084991). HPS1 cannot but BLOC-3 complex (heterodimer of HPS1 and HPS4) can interact with the GTP-bound form of RAB9A and RAB9B. HPS1 and BLOC-3 complex do not interact with the GDP-bound form of RAB9A and RAB9B (PubMed:20048159).
Axonemal protein which is implicated in axonemal and/or peri-axonemal structures assembly and regulates flagella assembly and beating and therefore sperm motility.
Expressed in spermatozoa (at protein level).
The TPR repeats are required for proper localization into the axoneme and proper function in flagella beating and motility.
Heteromultimers composed of alpha-s1 casein and kappa casein linked by disulfide bonds.
Kappa-casein stabilizes micelle formation, preventing casein precipitation in milk.
Mammary gland specific. Secreted in milk.
Can cross-link actin filaments into both network and bundle structures (By similarity). May modulate changes in actin filament integrity and induce lamellipodia formation. May function as an adapter molecule that links other proteins, such as SRC and PKC to the actin cytoskeleton. Seems to play a role in the development and progression of prostate adenocarcinoma by regulating cell-matrix adhesions and migration in the cancer cells.
Knockdown in MDA-MB-231 cells resulted in loss of actin stress fibers, decreased adhesion and spreading on fibronectin.
Low expression in normal breast epithelial cell line MCF-10A and in tumorigenic breast cancer cell lines MCF-7, T-47D and ZR-75-1. Highly expressed in the invasive breast cancer cell lines MDA-MB-231 and MDA-MB-435. Overexpressed in prostate carcinoma.
Monomer and homomultimer. Interacts via its C-terminus with F-actin; probably involving AFAP1 multimers (By similarity). Interacts with activated SRC SH3-SH2 domains. Interacts via its PH 1 domain with PRKCA, PRKCB and PRKCI (By similarity).
Phosphorylated on tyrosine residues by SRC.
Expressed in many areas of the brain, especially in the cerebral cortex, hippocampus, and cerebellum. Expression of GRM7 isoforms in non-neuronal tissues appears to be restricted to isoform 3 and isoform 4.
G-protein coupled receptor activated by glutamate that regulates axon outgrowth through the MAPK-cAMP-PKA signaling pathway during neuronal development (PubMed:33500274). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase that it inhibits (PubMed:9473604).
Homodimer (PubMed:33476302, PubMed:33500274). Interacts with PICK1.
Component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin. Interacts with PHF10/BAF45A (By similarity). Interacts with acetylated 'Lys-14' of histone H3 (H3K14ac), and may also interact with other acetylated or methylated Lys residues on histone H3.
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Required for the stability of the SWI/SNF chromatin remodeling complex SWI/SNF-B (PBAF). Acts as a negative regulator of cell proliferation.
Expressed in all tissues examined including brain, heart, lung, liver, skeletal muscle, kidney, placenta, pancreas, spleen, thymus and testis. Highest levels of expression in placenta, pancreas, thymus and testis.
Monomer (PubMed:28334766). Homodimer or homomultimer (By similarity). Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSKN1D and/or CSNK1E, TIMELESS, and the PER proteins (PubMed:9856465). Interacts with PER2 (PubMed:31138685). The interaction with PER2 is direct and via its second PAS domain (By similarity). Interacts directly with PER1 and PER3 (By similarity). Interacts with CRY2, CHEK1, ATR and ATRIP (PubMed:15798197, PubMed:31138685). Interacts with CRY1 (By similarity) (PubMed:15798197). Interacts with CLSPN; the interaction is required for leading-strand replication (PubMed:23359676, PubMed:17141802, PubMed:35585232, PubMed:34694004, PubMed:34700328). Interacts (via N-terminus) with TIPIN (PubMed:17102137, PubMed:17116885, PubMed:17296725, PubMed:34694004, PubMed:34700328, PubMed:28334766). The TIMELESS-TIPIN heterodimer binds preferably to guanine-rich quadruplex-forming (G4) DNA structures (PubMed:32705708). Associates with the MCM2-7 complex (PubMed:34700328, PubMed:34694004, PubMed:23359676). Interacts with DNA polymerases alpha, delta and epsilon (PubMed:23359676). Interacts with DDX11; this interaction increases recruitment of both proteins onto chromatin in response to replication stress induction by hydroxyurea (PubMed:20124417, PubMed:26503245, PubMed:32705708). Interacts with PARP1; interaction is direct and independent of poly-ADP-ribose (PubMed:26344098, PubMed:30356214).
Plays an important role in the control of DNA replication, maintenance of replication fork stability, maintenance of genome stability throughout normal DNA replication, DNA repair and in the regulation of the circadian clock (PubMed:9856465, PubMed:17141802, PubMed:17296725, PubMed:23418588, PubMed:26344098, PubMed:23359676, PubMed:35585232, PubMed:31138685, PubMed:32705708). Required to stabilize replication forks during DNA replication by forming a complex with TIPIN: this complex regulates DNA replication processes under both normal and stress conditions, stabilizes replication forks and influences both CHEK1 phosphorylation and the intra-S phase checkpoint in response to genotoxic stress (PubMed:17141802, PubMed:17296725, PubMed:23359676, PubMed:35585232). During DNA replication, inhibits the CMG complex ATPase activity and activates DNA polymerases catalytic activities, coupling DNA unwinding and DNA synthesis (PubMed:23359676). TIMELESS promotes TIPIN nuclear localization (PubMed:17141802, PubMed:17296725). Plays a role in maintaining processive DNA replication past genomic guanine-rich DNA sequences that form G-quadruplex (G4) structures, possibly together with DDX1 (PubMed:32705708). Involved in cell survival after DNA damage or replication stress by promoting DNA repair (PubMed:17141802, PubMed:17296725, PubMed:26344098, PubMed:30356214). In response to double-strand breaks (DSBs), accumulates at DNA damage sites and promotes homologous recombination repair via its interaction with PARP1 (PubMed:26344098, PubMed:30356214, PubMed:31138685). May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light (PubMed:15798197). Involved in the determination of period length and in the DNA damage-dependent phase advancing of the circadian clock (PubMed:23418588, PubMed:31138685). Negatively regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus (PubMed:9856465, PubMed:31138685). May play a role as destabilizer of the PER2-CRY2 complex (PubMed:31138685). May also play an important role in epithelial cell morphogenesis and formation of branching tubules (By similarity).
Regulated by the cell cycle. High levels in S, G(2) and M phases, with highest level in S phase. Low expression in G(0) and G(1) phases.
Residues 1182-1199 comprise a putative nuclear localization signal; nuclear localization is required for the regulation of period length of the circadian clock.
The C-terminal domain, comprising the DNA-binding domain and the PARP1-binding region, is required for the replication past genomic guanine-rich DNA sequences that form G-quadruplex (G4) structures.
The DNA-binding domain (residues 816-954) binds to both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), and has high affinity for DNA sequences rich in guanine that form G-quadruplex (G4) structures.
B3GALNT1 activity is responsible for the globoside blood group system (GLOB), which is defined by the P antigen [MIM:615021].
Genetic variation in B3GALNT1 is responsible for the blood group P1PK system [MIM:111400]. Different combinations or absence of the P1PK antigens define 5 different phenotypes: P1, P2, P1(k), P2(k), and P. The P1(k) and P2(k) phenotypes are rare and characterized by lack of the P antigen.
Higher expression in heart and brain, and to a lesser extent in lung, placenta, kidney and testis. Lower expression in liver, spleen and stomach. No expression in skeletal muscle.
Transfers N-acetylgalactosamine onto globotriaosylceramide (PubMed:10993897). Plays a critical role in preimplantation stage embryonic development (By similarity).
Expressed in brain, aorta and lung at low levels.
May recognize and hydrolyze the peptide bond at the C-terminal Gly of ubiquitin. Involved in the processing of poly-ubiquitin precursors as well as that of ubiquitinated proteins (By similarity).
Protein phosphatase 6 (PP6) holoenzyme is proposed to be a heterotrimeric complex formed by the catalytic subunit, a SAPS domain-containing subunit (PP6R) and an ankyrin repeat-domain containing regulatory subunit (ARS). Interacts with PPP6R1.
Putative regulatory subunit of protein phosphatase 6 (PP6) that may be involved in the recognition of phosphoprotein substrates.
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is composed of 13 subunits: EIF3A, EIF3B, EIF3C, EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L and EIF3M. The eIF-3 complex appears to include 3 stable modules: module A is composed of EIF3A, EIF3B, EIF3G and EIF3I; module B is composed of EIF3F, EIF3H, and EIF3M; and module C is composed of EIF3C, EIF3D, EIF3E, EIF3K and EIF3L. EIF3C of module C binds EIF3B of module A and EIF3H of module B, thereby linking the three modules. EIF3J is a labile subunit that binds to the eIF-3 complex via EIF3B. The eIF-3 complex interacts with RPS6KB1 under conditions of nutrient depletion. Mitogenic stimulation leads to binding and activation of a complex composed of MTOR and RPTOR, leading to phosphorylation and release of RPS6KB1 and binding of EIF4B to eIF-3.
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:17581632, PubMed:25849773, PubMed:27462815). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation (PubMed:17581632). The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression (PubMed:25849773).
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis. The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation. The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression.
Phosphorylated by TGF-beta type II receptor.
Seems to be involved in pore-forming activity and may contribute to the unspecific permeability of the peroxisomal membrane.
Belongs to the archaeal Rpo10/eukaryotic RPB10 RNA polymerase subunit family.
Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and a small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2L/RBP10 is part of the core element with the central large cleft (By similarity).
Although it contains a PPIase FKBP-type domain, does not show peptidyl-prolyl cis-trans isomerase activity.
Detected in all tissues examined, with higher expression in testis, heart, skeletal muscle, liver, and kidney.
FKBP6 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of FKBP6 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease (PubMed:9782077). A father and son with Williams-Beuren syndrome appear to have a common heterozygous deletion that includes FKBP6 gene. However, the haploinsufficiency for FKBP6 does not appear to preclude male fertility (PubMed:15770126).
Has an essential role in spermatogenesis (PubMed:36150389). It is required to repress transposable elements and prevent their mobilization, which is essential for the germline integrity (By similarity). Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons (By similarity). Acts as a co-chaperone via its interaction with HSP90 and is required for the piRNA amplification process, the secondary piRNA biogenesis (By similarity). May be required together with HSP90 in removal of 16 nucleotide ping-pong by-products from Piwi complexes, possibly facilitating turnover of Piwi complexes (By similarity).
Interacts (via TPR repeats) with HSP90 (By similarity). Interacts with HSP72/HSPA2 and CLTC. Interacts with GAPDH; leading to inhibit GAPDH catalytic activity.
The first GAGE nomenclature was based on identified mRNA sequences, but the high identity of the GAGE members made impossible to separate products of paralogous genes from polymorph products. PubMed:18179644 presented a new GAGE gene nomenclature based on the identified genes and their products.
This gene belongs to a multigene family expressed in a large variety of tumors whereas in normal tissues, expression is restricted to germ cells. These genes organized in clustered repeats, have a high degree of predicted sequence identity, but differ by scattered single nucleotide substitution. Their sequences contain either the antigenic peptide YYWPRPRRY or YRPRPRRY which is recognized by cytotoxic T-cells.
Highly expressed in the brain and in some high-grade but not low-grade gliomas. Detected slightly or not at all in other tissues.
Interacts with LGI1 (PubMed:27066583). Interacts with DLG4/PSD95 (PubMed:27066583). Also binds LGI4 (By similarity). Interacts with KCNA2 and DLG2 (By similarity). Interacts with ADAM11 (By similarity). Interacts (via C-terminus) with YWHAB/14-3-3 beta (PubMed:15882968). Interacts (via C-terminus) with YWHAZ/14-3-3 zeta (PubMed:12589811).
Probable ligand for integrin in the brain. This is a non catalytic metalloprotease-like protein (PubMed:19692335). Involved in regulation of cell adhesion and spreading and in inhibition of cell proliferation. Neuronal receptor for LGI1.
Bidirectional proton-coupled monocarboxylate transporter (PubMed:12946269, PubMed:33333023, PubMed:32946811). Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, acetate and the ketone bodies acetoacetate and beta-hydroxybutyrate, and thus contributes to the maintenance of intracellular pH (PubMed:12946269, PubMed:33333023). The transport direction is determined by the proton motive force and the concentration gradient of the substrate monocarboxylate. MCT1 is a major lactate exporter (By similarity). Plays a role in cellular responses to a high-fat diet by modulating the cellular levels of lactate and pyruvate that contribute to the regulation of central metabolic pathways and insulin secretion, with concomitant effects on plasma insulin levels and blood glucose homeostasis (By similarity). Facilitates the protonated monocarboxylate form of succinate export, that its transient protonation upon muscle cell acidification in exercising muscle and ischemic heart (PubMed:32946811). Functions via alternate outward- and inward-open conformation states. Protonation and deprotonation of 309-Asp is essential for the conformational transition (PubMed:33333023).
Interacts with EMB; interaction mediates SLC16A1 targeting to the plasma membrane (By similarity). Interacts with isoform 2 of BSG; interaction mediates SLC16A1 targeting to the plasma membrane (PubMed:17127621, PubMed:25957687, PubMed:33333023).
Overexpression in pancreatic beta-cells triggers insulin secretion in response to pyruvate, causing hyperinsulemia and hypoglycemia during strenuous exercise.
Selectively inhibited by AZD3965, that acts as a competitive inhibitor binding to the central channel in the outward open conformation.
Widely expressed (PubMed:15901598, PubMed:15505343, PubMed:12115955). Detected in heart and in blood lymphocytes and monocytes (at protein level) (PubMed:15505343).
Expressed in whole embryos and fetuses at 5-9 weeks from conception.
Belongs to the major facilitator superfamily. Feline leukemia virus subgroup C receptor (TC 2.A.1.28.1) family.
Expressed in follicular cells of the developing thyroid at 18 dpc (at protein level).
Expressed in non-hematopoietic tissues, with relative abundant expression in brain, placenta, lung, liver and kidney (PubMed:20823265). Also expressed in hematopoietic tissues (fetal liver, spleen, lymph node, thymus, leukocytes and bone marrow) (PubMed:20823265). Found in acidophil cells of the pituitary that secrete growth hormone and prolactin (at protein level) (PubMed:14729055).
Interacts with components of electron transfer chain complexes III, IV and V including CYC1, NDUFA4, COX4I1, ATP5PD and ATP5F1C; these interactions occur in the absence of heme and are disrupted upon heme binding (By similarity). Interacts with ATP2A2; this interaction occurs in the absence of heme and promotes ATP2A2 proteasomal degradation; the complex is dissociated upon heme binding (By similarity). Interacts with HMOX1; this interaction is potentiated in the presence of heme (By similarity).
Putative heme b importer/sensor involved in heme homeostasis in response to the metabolic state of the cell and to diet. May act as a sensor of cytosolic and/or mitochondrial heme levels to regulate mitochondrial respiration processes, ATP synthesis and thermogenesis. At low heme levels, interacts with components of electron transfer chain (ETC) complexes and ATP2A2, leading to ubiquitin-mediated degradation of ATP2A2 and inhibition of thermogenesis. Upon heme binding, dissociates from ETC complexes to allow switching from mitochondrial ATP synthesis to thermogenesis. Alternatively, in coordination with ATP2A2 may mediate calcium transport and signaling in response to heme.
The N-terminus contains histidine-proline motifs involved in heme binding. Can bind 2 to 3 heme molecules.
Favors the reduction of estrogens and androgens. Converts estrone (E1) to a more potent estrogen, 17beta-estradiol (E2) (PubMed:8994190). Also has 20-alpha-HSD activity. Uses preferentially NADH.
Favors the reduction of estrogens and androgens. Uses preferentially NADH.
Homodimer. Exists predominantly as an homodimer but also exits as monomer.
Isoform 1 is abundant in placenta. Relatively highly expressed in thymus, testis, and small intestine. Expressed at low levels in several tissues including spleen, prostate, brain, heart, ovary, colon, kidney, lung, liver and pancreas and not expressed in skeletal muscle and leukocytes. Isoform 2 expression is highest in placenta (but at relatively low level compared to isoform 1). Very low level of expression in numerous tissues including adipose tissue and many brain regions. Isoform 3 is expressed in brain and heart and, at lower levels, in kidney, liver, lung and pancreas.
Receptor for NPAF (A-18-F-amide) and NPFF (F-8-F-amide) neuropeptides, also known as morphine-modulating peptides. Can also be activated by a variety of naturally occurring or synthetic FMRF-amide like ligands. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
High expression level is found in brain, testis, liver and kidney. Weak expression in spleen, leukocytes, small intestine and colon.
Part of the neuronal tubulin polyglutamylase complex which contains TPGS1, TPGS2, TTLL1, LRRC49 and NICN1.
(Microbial infection) Dephosphorylated by M.tuberculosis PtpA, which induces the reduction of host phagolysosome fusion in M.tuberculosis-infected macrophages.
(Microbial infection) Interacts with M.tuberculosis PtpA.
According to PubMed:18474358, it is autophosphorylated. However, it is not related with protein kinases, suggesting it is phosphorylated by another protein.
Interacts with RAB11A and VIPAS39 (PubMed:28017832). Interacts with RAB25 (PubMed:28017832). Associates with adapter protein complex 3 (AP-3), clathrin:AP-3 and clathrin:HGS complexes (PubMed:21411634).
May play a role in vesicle-mediated protein trafficking to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes. Required for proper trafficking and targeting of the collagen-modifying enzyme lysyl hydroxylase 3 (LH3) to intracellular collagen (PubMed:28017832). Mediates phagolysosomal fusion in macrophages (PubMed:18474358). Proposed to be involved in endosomal maturation implicating VIPAS39. In epithelial cells, the VPS33B:VIPAS39 complex may play a role in the apical recycling pathway and in the maintenance of the apical-basolateral polarity (PubMed:20190753). Seems to be involved in the sorting of specific cargos from the trans-Golgi network to alpha-granule-destined multivesicular bodies (MVBs) promoting MVBs maturation in megakaryocytes (By similarity).
Ubiquitous; highly expressed in testis and low expression in the lung.
A tripeptide motif (VGE) within disintegrin-like domain could be involved in the binding to egg integrin receptor and thus could mediate sperm/egg binding.
Has no obvious cleavage site for furin endopeptidase, suggesting that the proteolytic processing is regulated.
May be involved in sperm maturation and/or fertilization. May also be involved in epithelia functions associated with establishing and maintaining gradients of ions or nutrients.
May be the functional equivalent of ADAM 1/fertilin alpha which is a pseudogene in human.
The cysteine-rich domain encodes putative cell-fusion peptides, which could be involved in sperm-egg fusion.
Apparently an obligate constituent of all desmosomes.
Expressed in oral mucosa (at protein level) (PubMed:30479852). Expressed in arrector pili muscle (at protein level) (PubMed:29034528).
Homodimer. Interacts with COL17A1 (via cytoplasmic region) (PubMed:12482924). Interacts with DSC2 (PubMed:21062920). Interacts with PKP2 (PubMed:11790773, PubMed:22781308). Interacts with PKP1 (PubMed:11790773, PubMed:10852826). Interacts weakly with TMEM65.
Major high molecular weight protein of desmosomes. Regulates profibrotic gene expression in cardiomyocytes via activation of the MAPK14/p38 MAPK signaling cascade and increase in TGFB1 protein abundance (By similarity).
Resides predominantly in tissues and cells of stratified origin.
The N-terminal region is required for localization to the desmosomal plaque and interacts with the N-terminal region of PKP1.
Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates (PubMed:12297501, PubMed:17696782, PubMed:23625928, PubMed:28445460, PubMed:33157014, PubMed:16118278). Binds long polyubiquitin chains and trims them, while it has weak or no activity against chains of 4 or less ubiquitins (PubMed:17696782). Involved in degradation of misfolded chaperone substrates via its interaction with STUB1/CHIP: recruited to monoubiquitinated STUB1/CHIP, and restricts the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension (By similarity). Interacts with key regulators of transcription and represses transcription: acts as a histone-binding protein that regulates transcription (PubMed:12297501). Acts as a negative regulator of mTORC1 signaling in response to amino acid deprivation by mediating deubiquitination of RHEB, thereby promoting RHEB inactivation by the TSC-TBC complex (PubMed:33157014). Regulates autophagy via the deubiquitination of 'Lys-402' of BECN1 leading to the stabilization of BECN1 (PubMed:28445460).
Interacts with STUB1/CHIP (when monoubiquitinated) (By similarity). Interacts with DNA repair proteins RAD23A and RAD23B (PubMed:16020535, PubMed:30455355). Interacts with BECN1 (via its poly-Gln domain) (PubMed:28445460). Interacts with PRKN, UBR2, VCP and tubulin. Short isoform 1 interacts with CASP7 (PubMed:30455355).
Monoubiquitinated N-terminally by UBE2W, possibly leading to activate the deubiquitinating enzyme activity (PubMed:23696636).
The UIM domains bind ubiquitin and interact with various E3 ubiquitin-protein ligase, such as STUB1/CHIP. They are essential to limit the length of ubiquitin chains (By similarity).
The poly-Gln domain is involved in the interaction with BECN1 and subsequent starvation-induced autophagy (PubMed:28445460).
The poly-Gln region of ATXN3 is highly polymorphic (14 to 41 repeats) in the normal population and is expanded to about 55-82 repeats in spinocerebellar ataxia 3 (SCA3) patients (PubMed:7874163, PubMed:9274833).
'Lys-48'-linked polyubiquitination and subsequent proteasomal degradation is NMI-dependent in response to Sendai virus infection.
'Lys-63'-linked ubiquitination by NEURL3 promotes IRF7 activation.
(Microbial infection) Cleaved and inactivated by the protease 3C of enterovirus 71 allowing the virus to disrupt the host type I interferon production.
(Microbial infection) Cleaved and inactivated by the protease 3C of human enterovirus 68D (EV68) allowing the virus to disrupt the host type I interferon production.
(Microbial infection) Interacts with Epstein-Barr virus LF2 and LMP1.
(Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction is involved in the suppression of IRF7 expression and phosphorylation by the virus.
(Microbial infection) Interacts with ebolavirus VP35; this interaction mediates the sumoylation of IRF7 and contributes to the viral inhibition of IFN-type I production.
(Microbial infection) Interacts with herpes virus 8/HHV-8 protein vIRF-4; this interaction prevents IRF7 dimerization and subsequent activation (PubMed:28342865).
(Microbial infection) Interacts with human herpes virus 8/HHV-8 proteins ORF45 and vIRF-1.
(Microbial infection) Interacts with human metapneumovirus protein M2-2; this interaction prevents IRF7 phosphorlyation and subsequent TLR7/9-dependent IFN-alpha induction.
(Microbial infection) Interacts with rotavirus A NSP1; this interaction leads to the proteasome-dependent degradation of IRF7.
(Microbial infection) Interacts with severe fever with thrombocytopenia syndrome virus (SFTSV) NSs; this interaction sequesters IRF7 in NSs-induced cytoplasmic inclusion bodies.
Acetylation inhibits its DNA-binding ability and activity.
Expressed predominantly in spleen, thymus and peripheral blood leukocytes.
In response to a viral infection, phosphorylated on Ser-477 and Ser-479 by TBK1 and IKBKE1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein E3. In TLR7- and TLR9-mediated signaling pathway, phosphorylated by IRAK1.
In the absence of viral infection, maintained as a monomer in an autoinhibited state and phosphorylation disrupts this autoinhibition leading to the liberation of the DNA-binding and dimerization activities and its nuclear localization where it can activate type I IFN and ISG genes.
Key transcriptional regulator of type I interferon (IFN)-dependent immune responses and plays a critical role in the innate immune response against DNA and RNA viruses (PubMed:28342865, PubMed:28768858). Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters (PubMed:17574024, PubMed:32972995). Can efficiently activate both the IFN-beta (IFNB) and the IFN-alpha (IFNA) genes and mediate their induction via both the virus-activated, MyD88-independent pathway and the TLR-activated, MyD88-dependent pathway. Induces transcription of ubiquitin hydrolase USP25 mRNA in response to lipopolysaccharide (LPS) or viral infection in a type I IFN-dependent manner (By similarity). Required during both the early and late phases of the IFN gene induction but is more critical for the late than for the early phase. Exists in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, becomes phosphorylated by IKBKE and TBK1 kinases. This induces a conformational change, leading to its dimerization and nuclear localization where along with other coactivators it can activate transcription of the type I IFN and ISG genes. Can also play a role in regulating adaptive immune responses by inducing PSMB9/LMP2 expression, either directly or through induction of IRF1. Binds to the Q promoter (Qp) of EBV nuclear antigen 1 a (EBNA1) and may play a role in the regulation of EBV latency. Can activate distinct gene expression programs in macrophages and regulate the anti-tumor properties of primary macrophages (By similarity) (PubMed:11073981, PubMed:12374802, PubMed:15361868, PubMed:17404045).
Monomer. Homodimer; phosphorylation-induced. Heterodimer with IRF3 (PubMed:17574024). Interacts with TICAM1 and TICAM2. Interacts with MYD88 and TRAF6. Interacts with TRIM35 (PubMed:25907537, PubMed:11073981, PubMed:11314014, PubMed:14517278, PubMed:14739303, PubMed:15361868, PubMed:15492225). Interacts with NMI; the interaction is direct and leads to the inhibition of IRF7-mediated type I IFN production (By similarity). Interacts with GBP4; preventing interaction between TRAF6 and IRF7, resulting in impaired TRAF6-mediated IRF7 ubiquitination (By similarity).
Sumoylated by TRIM28, which inhibits its transactivation activity.
TRAF6-mediated ubiquitination is required for IRF7 activation (By similarity). TRIM35 mediates IRF7 'Lys-48'-linked polyubiquitination and subsequent proteasomal degradation (PubMed:25907537). Ubiquitinated by UBE3C, leading to its degradation (PubMed:21167755).
Although found in NIDDM patients, genetic variations of HK2 do not contribute to the disease (PubMed:7883122, PubMed:7883123).
Catalyzes the phosphorylation of hexose, such as D-glucose and D-fructose, to hexose 6-phosphate (D-glucose 6-phosphate and D-fructose 6-phosphate, respectively) (PubMed:23185017, PubMed:26985301, PubMed:29298880). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (PubMed:29298880). Plays a key role in maintaining the integrity of the outer mitochondrial membrane by preventing the release of apoptogenic molecules from the intermembrane space and subsequent apoptosis (PubMed:18350175).
Hexokinase activity is specifically inhibited by 2,6-disubstituted glucosamines.
Hexokinase is known to act as a monomer in normal conditions (By similarity). It however homodimerizes at elevated protein concentrations used for crystallizations (PubMed:26985301, PubMed:29298880).
Monomer (By similarity). Interacts with TIGAR; the interaction increases hexokinase activity in a hypoxia- and HIF1A-dependent manner (PubMed:23185017).
Predominant hexokinase isozyme expressed in insulin-responsive tissues such as skeletal muscle.
The N- and C-terminal halves of the protein contain a hexokinase domain (PubMed:29298880). In contrast to hexokinase-1 and -3 (HK1 and HK3, respectively), both hexokinase domains display catalytic activity (PubMed:29298880). The region connecting the two hexokinase domains is required for the catalytic activity of the N-terminal hexokinase domain (PubMed:29298880). The N-terminal half regulates stability of the whole enzyme (PubMed:29298880).
Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates and thus, functions to process newly synthesized Ubiquitin, to recycle ubiquitin molecules or to edit polyubiquitin chains and prevents proteasomal degradation of substrates. Hydrolyzes both 'Lys-48'- and 'Lys-63'-linked tetraubiquitin chains.
Homodimer or oligomer. Interacts with ACTA1 (via its C-terminus); the interaction occurs for all isoforms but is strongest for isoform USP25m in muscle differentiating cells. Interacts (isoform USP25m only) with MYBPC1; the interaction prevents proteasomal degradation of MYBPC1. Interacts (isoform USP25m only) with FLNC (via filament repeats 17-18, 20-21 and 24). Interacts with GAPDH. Interacts with SUMO3; the interaction sumoylates efficiently USP25. Interacts with SUMO2; the interaction sumoylates efficiently USP25. Interacts with SUMO1; the interaction only weakly sumoylates USP25. Interacts with SYK; phosphorylates USP25 and regulates USP25 intracellular levels.
Isoform USP25a is found in most adult and fetal tissues; expression is moderately high in testis, pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, but very low in peripheral blood, colon, small intestine, ovary, prostate, thymus and spleen. Isoform USP25b is found in all tissues except heart and skeletal muscle. Isoform USP25m is heart and skeletal muscle specific.
Phosphorylation in the C-terminal by SYK regulates USP25 cellular levels.
Preferentially monoubiquitinated but can also be polyubiquitinated. Autodeubiquitinated. Ubiquitination activates the enzymatic activity either by preventing sumoylation or by allowing novel interactions.
Sumoylation impairs binding to and hydrolysis of ubiquitin chains. Sumoylated preferentially with SUMO2 or SUMO3. Desumoylated by SENP1. Regulated by ubiquitination on the same residue.
The muscle-specific isoform (USP25m) is up-regulated during myocyte differentiation. Levels increase up to 100-fold towards completion of differentiation.
The muscle-specific isoform (USP25m) may have a role in the regulation of muscular differentiation and function.
Highly expressed in retina. Specifically localized to the developing photoreceptor layer and within the photoreceptors of the adult retina.
May be important in protein trafficking and/or protein folding and stabilization.
GTP-binding protein that functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP-ribosyltransferase. Involved in protein trafficking; may modulate vesicle budding and uncoating within the Golgi apparatus (By similarity).
Acetylated at Ala-42 following proteolytic cleavage at Leu-41.
Expressed in the cortex and nucleus of the retina lens (at protein level).
Myristoylated at Gly-434 following proteolytic cleavage at Asp-433.
Part of a complex required for lens intermediate filament formation composed of BFSP1, BFSP2 and CRYAA (PubMed:28935373). Identified in a complex that contains VIM, EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, PRX and spectrin (By similarity). Found in a complex composed of PPL (via C-terminal linker domain), BFSP1 and BFSP2 in the retinal lens (By similarity). Within the complex interacts with BFSP2 (By similarity). Interacts (via C-terminus) with MIP (via C-terminus) in aged lens fiber cells (By similarity).
Proteolytically cleaved during lens cell fiber differentiation with increased fragmentation as fiber cell age increases.
Required for the correct formation of lens intermediate filaments as part of a complex composed of BFSP1, BFSP2 and CRYAA (PubMed:28935373). Involved in altering the calcium regulation of MIP water permeability (PubMed:30790544).
Based on a naturally occurring readthrough transcript which produces a MYZAP-POLR2M fusion protein.
Detected in heart, liver, skeletal muscle, placenta, small intestine, lung, prostate and testis. Expressed in arrector pili muscle (at protein level) (PubMed:29034528).
Interacts with DSP, MPRIP and TJP1/ZO1. Interaction with MPRIP inhibits the activation of transcription factor SRF (By similarity). Interacts with GRIN1. Interacts with DYNLL1.
Plays a role in cellular signaling via Rho-related GTP-binding proteins and subsequent activation of transcription factor SRF (By similarity). Targets TJP1 to cell junctions. In cortical neurons, may play a role in glutaminergic signal transduction through interaction with the NMDA receptor subunit GRIN1 (By similarity).
The adjacent MYZAP and POLR2M genes are part of a complex transcription unit. The respective transcripts derive from different promoters and are alternatively spliced. In human, some transcripts of the upstream promoter of MYZAP use exons of the downstream POLR2M gene.
Interacts with the Salmonella typhimurium virulence protein spiC.
Ubiquitous. Highly expressed in liver, kidney and muscle. Expressed at intermediate level in brain, heart, colon, thymus, kidney, small intestine, placenta, lung, leukocytes and spleen.
Belongs to the aggrecan/versican proteoglycan family.
Expressed between 6 and 19 weeks post-conception (WPC) in the outer neuroblastic zone, inner neuroblastic zone, and inner plexiform layer of the retina (at protein level) (PubMed:29777959). Expressed at the surface ectoderm at 6 WPC and the neural retinal at 6 to 8 WPC (at protein level) (PubMed:29777959). Expressed in the interphotoreceptor matrix and abundantly in developing photoreceptors between 12 and 19 WPC (at protein level) (PubMed:29777959). Isoform 1: Highly expressed from birth through 8 years of age and is down-regulated by 20 years of age to low levels that are maintained in the normal adult cortex (PubMed:11054543). Isoform 2: Expressed at uniformly low levels throughout development (PubMed:11054543).
Expressed in the retina, specifically in the inner nuclear layer, inner plexiform layer and ganglion cell layer (at protein level) (PubMed:29777959). Detected in cerebrospinal fluid (at protein level) (PubMed:25326458).
May play a role in the terminally differentiating and the adult nervous system during postnatal development. Could stabilize interactions between hyaluronan (HA) and brain proteoglycans.
O-glycosylated; contains chondroitin sulfate (PubMed:25326458). O-glycosylated with a core 1 or possibly core 8 glycan (PubMed:19838169).
Plays a crucial role in the structural integrity of mitotic centrosomes and in the maintenance of spindle bipolarity by promoting PLK1 activity at the spindle poles in early mitosis. May function as a scaffold promoting the interaction between AURKA and PLK1, thereby enhancing AURKA-mediated PLK1 phosphorylation.
When phosphorylated by CDK1, interacts with PLK1; this interaction occurs in mitotic cells, but not in interphase cells, and leads to further phosphorylation by PLK1. Interacts with AURKA.
Expressed in testis, uterus, prostate, heart, muscle, brain, spinal cord and placenta.
Found in a post-splicing messenger ribonucleoprotein (mRNP) complex. Core component of the mRNA splicing-dependent exon junction complex (EJC); the core complex contains CASC3, EIF4A3, MAGOH or MAGOHB, and RBM8A. The EJC core components EIF4A3 and the MAGOH-RBM8A dimer form a composite binding site for UPF3B which overlaps with the EJC binding site for WIBG (PubMed:16601204, PubMed:18066079, PubMed:23917022, PubMed:20479275). Interacts with EST1A, UPF2 and RBM8A (PubMed:12554878, PubMed:18066079, PubMed:15004547). Interacts with CPSF6 (PubMed:19864460). Interacts with DHX34; the interaction is RNA-independent.
Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by associating with the nuclear exon junction complex (EJC) and serving as link between the EJC core and NMD machinery. Recruits UPF2 at the cytoplasmic side of the nuclear envelope and the subsequent formation of an UPF1-UPF2-UPF3 surveillance complex (including UPF1 bound to release factors at the stalled ribosome) is believed to activate NMD. In cooperation with UPF2 stimulates both ATPase and RNA helicase activities of UPF1. Binds spliced mRNA upstream of exon-exon junctions. In vitro, stimulates translation; the function is independent of association with UPF2 and components of the EJC core.
Cleavage by CASP8 relieves autoinhibition by releasing the N-terminal moiety (Gasdermin-C, N-terminal) that initiates pyroptosis (PubMed:32929201, PubMed:34012073). The cleavage site is unclear (PubMed:32929201, PubMed:34012073). According to a publication, it takes place after Asp-240 in response to alpha-ketoglutarate (PubMed:34012073). Another paper reports cleavage by CASP8 after Asp-365 (PubMed:32929201).
Expressed mainly in trachea and spleen (PubMed:11223543). In the esophagus, expressed in differentiating cells and probably in differentiated cells. Also detected in gastric epithelium (PubMed:19051310).
Expression in induced by STAT3 and CD274/PD-L1 in response to hypoxia.
Homooligomer; homooligomeric ring-shaped pore complex containing 27-28 subunits when inserted in the membrane.
Intramolecular interactions between N- and C-terminal domains are important for autoinhibition in the absence of activation signal (By similarity). The intrinsic pyroptosis-inducing activity is carried by the N-terminal domain (By similarity).
Pore-forming protein that causes membrane permeabilization and pyroptosis (PubMed:27281216, PubMed:32929201, PubMed:34012073). Produced by the cleavage of gasdermin-D by caspase CASP8 in response to death signals (PubMed:32929201, PubMed:34012073). After cleavage, moves to the plasma membrane where it strongly binds to membrane inner leaflet lipids (PubMed:32929201, PubMed:34012073). Homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:32929201, PubMed:34012073).
The full-length protein before cleavage is inactive: intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of activation signal (PubMed:32929201, PubMed:34012073). The intrinsic pyroptosis-inducing activity is carried by the released N-terminal moiety (Gasdermin-C, N-terminal) following cleavage by caspase CASP8 (PubMed:32929201, PubMed:34012073).
This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-C, N-terminal) binds to membranes and forms pores, triggering pyroptosis.
Complexin that regulates SNARE protein complex-mediated synaptic vesicle fusion (By similarity). Required for the maintenance of synaptic ultrastructure in the adult retina (By similarity). Positively regulates synaptic transmission through synaptic vesicle availability and exocytosis of neurotransmitters at photoreceptor ribbon synapses in the retina (By similarity). Suppresses tonic photoreceptor activity and baseline 'noise' by suppression of Ca(2+) vesicle tonic release and the facilitation of evoked synchronous and asynchronous Ca(2+) vesicle release (By similarity).
Farnesylation mediates presynaptic targeting.
Belongs to the methyltransferase superfamily. METTL23 family.
Histone methyltransferase that dimethylates histone H3 at 'Arg-17', forming asymmetric dimethylarginine (H3R17me2a), leading to activate transcription via chromatin remodeling (By similarity). Maternal factor involved in epigenetic chromatin reprogramming of the paternal genome in the zygote: mediates H3R17me2a, promoting histone H3.3 incorporation in the male pronucleus, leading to TET3 recruitment and subsequent DNA demethylation (By similarity).
Interacts with HSPA5, HSP90B1, TUBULIN, UGGT1 and UGGT2 (PubMed:23349634). Interacts with TET3 (By similarity). Interacts with STPG4 (By similarity).
Antigen-presenting protein that binds self and non-self lipid and glycolipid antigens and presents them to T-cell receptors on natural killer T-cells.
During protein synthesis and maturation, CD1 family members bind endogenous lipids that are replaced by lipid or glycolipid antigens when the proteins are internalized and pass through endosomes or lysosomes, before trafficking back to the cell surface. Interaction with saposin C is required for the loading of bacterial lipid antigens onto CD1B in the lysosome.
Expressed on cortical thymocytes, on certain T-cell leukemias, and in various other tissues.
Heterodimer with B2M (beta-2-microglobulin). Interacts with saposin C.
Found in a complex with ARL2, ARL2BP and SLC25A6 (PubMed:30945270). Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD. Found in a complex with ARL2, ARL2BP and SLC25A4. The GTP-bound form interacts with PDE6D. Interacts with ELMOD2. The GTP-bound form interacts with ARL2BP. Interacts, preferentially in its GDP-bound state, with TBCD (PubMed:10488091, PubMed:10831612, PubMed:11303027, PubMed:11847227, PubMed:17452337, PubMed:18234692, PubMed:18981177, PubMed:19368893, PubMed:27666374). Interacts with UNC119.
Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). GTP-binding protein that does not act as an allosteric activator of the cholera toxin catalytic subunit. Regulates formation of new microtubules and centrosome integrity. Prevents the TBCD-induced microtubule destruction. Participates in association with TBCD, in the disassembly of the apical junction complexes. Antagonizes the effect of TBCD on epithelial cell detachment and tight and adherens junctions disassembly. Together with ARL2, plays a role in the nuclear translocation, retention and transcriptional activity of STAT3. Component of a regulated secretory pathway involved in Ca(2+)-dependent release of acetylcholine. Required for normal progress through the cell cycle (PubMed:10831612, PubMed:16525022, PubMed:18234692, PubMed:18588884, PubMed:20740604). Also regulates mitochondrial integrity and function (PubMed:30945270).
(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) matrix protein; this interaction probably facilitates viral release.
(Microbial infection) Bradykinin is generated upon proteolytic cleavage by S.pyogenes SpeB to produce hypotension during septic shock.
Bradykinin is inactivated by ACE, which removes the dipeptide Arg-Phe from its C-terminus.
Bradykinin is released from kininogen by plasma kallikrein.
Hydroxylation of Pro-383 occurs prior to the release of bradykinin.
Kininogens are inhibitors of thiol proteases. HMW-kininogen plays an important role in blood coagulation by helping to position optimally prekallikrein and factor XI next to factor XII; HMW-kininogen inhibits the thrombin- and plasmin-induced aggregation of thrombocytes. LMW-kininogen inhibits the aggregation of thrombocytes. LMW-kininogen is in contrast to HMW-kininogen not involved in blood clotting.
N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans.
Secreted in plasma. T-kinin is detected in malignant ovarian, colon and breast carcinomas, but not in benign tumors.
The T-kinin peptide is missing residues 378 to 380, probably as a result of a naturally occurring variant. The complete sequence of the T-kinin peptide is therefore ISRPPGFSPFR. This peptide is associated with malignant tumors but not with benign ones.
The active peptide bradykinin is a potent vasodilatator that is released from HMW-kininogen shows a variety of physiological effects: (A) influence in smooth muscle contraction, (B) induction of hypotension, (C) natriuresis and diuresis, (D) decrease in blood glucose level, (E) it is a mediator of inflammation and causes (E1) increase in vascular permeability, (E2) stimulation of nociceptors (4E3) release of other mediators of inflammation (e.g. prostaglandins), (F) it has a cardioprotective effect (directly via bradykinin action, indirectly via endothelium-derived relaxing factor action).
Interacts with TGFB1; associates via disulfide bonds with the Latency-associated peptide chain (LAP) regulatory chain of TGFB1, leading to regulate activation of TGF-beta-1 (PubMed:29909984). Interacts (via LRR repeats) with TLR2, TLR3, TLR4, TLR9 and probably other Toll-like receptors (PubMed:23545260). Interacts with CYBB/NOX2; the interaction is direct (By similarity).
Key regulator of transforming growth factor beta-1 (TGFB1) specifically required for microglia function in the nervous system (By similarity). Required for activation of latent TGF-beta-1 in macrophages and microglia: associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGFB1, and regulates integrin-dependent activation of TGF-beta-1 (By similarity). TGF-beta-1 activation mediated by LRRC33/NRROS is highly localized: there is little spreading of TGF-beta-1 activated from one microglial cell to neighboring microglia, suggesting the existence of localized and selective activation of TGF-beta-1 by LRRC33/NRROS (By similarity). Indirectly plays a role in Toll-like receptor (TLR) signaling: ability to inhibit TLR-mediated NF-kappa-B activation and cytokine production is probably a consequence of its role in TGF-beta-1 signaling (PubMed:23545260).
Mainly expressed in cells of hematopoietic origin (PubMed:29909984). Highly expressed in bone marrow, thymus, liver, lung, intestine and spleen (PubMed:23545260). In the brain, highly expressed in microglia (PubMed:32100099).
Despite its name, it is related to the unc-93 family and not to the major facilitator superfamily.
Required for spermatogenesis and is involved in the suppression of retrotransposon transcription in male germ cells.
Muscle-specific expression is increased by endurance exercise.
Regulates the expression of selective PPARGC1A/B and ESRRA/B/G target genes with roles in glucose and lipid metabolism, energy transfer, contractile function, muscle mitochondrial biogenesis and oxidative capacity. Required for the efficient induction of MT-CO2, MT-CO3, COX4I1, TFB1M, TFB2M, POLRMT and SIRT3 by PPARGC1A. Positively regulates the PPARGC1A/ESRRG-induced expression of CKMT2, TNNI3 and SLC2A4 and negatively regulates the PPARGC1A/ESRRG-induced expression of PDK4.
Associates with components of the U1 and U2 U1 small nuclear ribonucleoprotein complexes.
Left ventricular non-compaction (LVNCX): A form of left ventricular non-compaction, a cardiomyopathy due to myocardial morphogenesis arrest and characterized by a hypertrophic left ventricle, a severely thickened 2-layered myocardium, numerous prominent trabeculations, deep intertrabecular recesses, and poor systolic function. Clinical manifestations are variable. Some affected individuals experience no symptoms at all, others develop heart failure. In some cases, left ventricular non-compaction is associated with other congenital heart anomalies. The disease is caused by variants affecting the gene represented in this entry.
Mainly expressed in the heart (PubMed:19712804, PubMed:23886709). Also expressed in skeletal muscle tissues, ovary, small intestine and colon (PubMed:23886709).
Phosphorylation regulates the subcellular localization (PubMed:35427468). Phosphorylation of Ser-635 and Ser-637 in the RS (arginine/serine-rich) region promotes nuclear localization of the protein (PubMed:35427468). In contrast, phosphorylation of the C-terminal disordered region promotes localization to cytoplasmic ribonucleoprotein granules (PubMed:35427468).
RNA-binding protein that acts as a regulator of mRNA splicing of a subset of genes encoding key structural proteins involved in cardiac development, such as TTN (Titin), CACNA1C, CAMK2D or PDLIM5/ENH (PubMed:22466703, PubMed:24960161, PubMed:27531932, PubMed:27496873, PubMed:26604136, PubMed:29895960, PubMed:30948719, PubMed:32840935, PubMed:35427468, PubMed:34732726). Acts as a repressor of mRNA splicing: specifically binds the 5'UCUU-3' motif that is predominantly found within intronic sequences of pre-mRNAs, leading to the exclusion of specific exons in target transcripts (PubMed:24960161, PubMed:30948719, PubMed:34732726). RBM20-mediated exon skipping is hormone-dependent and is essential for TTN isoform transition in both cardiac and skeletal muscles (PubMed:27531932, PubMed:30948719). RBM20-mediated exon skipping of TTN provides substrates for the formation of circular RNA (circRNAs) from the TTN transcripts (PubMed:27531932, PubMed:34732726). Together with RBM24, promotes the expression of short isoforms of PDLIM5/ENH in cardiomyocytes (By similarity).
Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylcholine and galactosylceramide (By similarity). Seems to act as potassium channel regulator and may inhibit pain signaling; can facilitate KCNT1/Slack channel activity by promoting its full single-channel conductance at very low sodium concentrations and by increasing its sodium sensitivity (By similarity). Does not exhibit calcium-activated chloride channel (CaCC) activity (PubMed:21984732).
Highly expressed in the forebrain striatum.
Interacts with CREM (via the third LIM domain). Interacts (via second LIM domain) with SPAG8.
May be involved in the regulation of spermatogenesis. Stimulates CREM transcriptional activity in a phosphorylation-independent manner.
Dysfunction of LGN is associated with the phenotype of multiple micronuclei due to chromosomal mis-segregation and defect in cell division through mis-localization of mitotic spindle regulator protein NUMA1.
Interacts with the dynein-dynactin complex; this interaction is inhibited in a PLK1-dependent manner (PubMed:22327364). Part of a spindle orientation complex at least composed of GNAI1, GPSM2 and NUMA1 (PubMed:26766442). Interacts with LLGL2 (PubMed:15632202). Interacts (via TPR repeat region) with INSC/inscuteable (PubMed:16458856, PubMed:22074847). Interacts (via TPR repeat region) with NUMA1 (via C-terminus); this interaction is direct, inhibited in a PLK1-dependent manner, prevents the binding of NUMA1 with SPAG5 and promotes spindle pole organization (PubMed:11781568, PubMed:22327364, PubMed:27462074). INSC and NUMA1 compete for the same binding site, but INSC has higher affinity and can displace NUMA1 (in vitro) (PubMed:22074847). Interacts with GNAI2 (PubMed:8973305). Interacts (via GoLoco domains) with the GDP-bound form of GNAI1 and GNAI3; has much lower affinity for the GTP-bound form. Interaction with GDP-bound GNAI3 strongly enhances the affinity for NUMA1 (By similarity). Interacts (via TPR repeat region) with FRMPD1 (PubMed:22074847). INSC and FRMPD1 compete for the same binding site, but INSC has higher affinity and can displace FRMPD1 (in vitro) (By similarity). Interacts (via TPR repeat region) with FRMPD4 (PubMed:22074847, PubMed:25664792). Identified in a complex with INSC and F2RL2/Par3 (PubMed:16458856). Interacts with TASOR (By similarity).
It is uncertain whether Met-1 or Met-8 is the initiator.
Mutations in GPSM2 have been identified in people with profound congenital non-syndromic deafness designated as DFNB82 (PubMed:20602914). Subsequent brain imaging of these individuals has revealed frontal polymicrogyria, abnormal corpus callosum, and gray matter heterotopia, consistent with a diagnosis of Chudley-McCullough syndrome (PubMed:22578326).
Plays an important role in mitotic spindle pole organization via its interaction with NUMA1 (PubMed:11781568, PubMed:15632202, PubMed:21816348). Required for cortical dynein-dynactin complex recruitment during metaphase (PubMed:22327364). Plays a role in metaphase spindle orientation (PubMed:22327364). Also plays an important role in asymmetric cell divisions (PubMed:21816348). Has guanine nucleotide dissociation inhibitor (GDI) activity towards G(i) alpha proteins, such as GNAI1 and GNAI3, and thereby regulates their activity (By similarity).
Belongs to the cytochrome c oxidase subunit 6B family.
Accessory component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids. Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules. The beta subunit may assist in binding of the phospholipid substrate. Required for the proper folding, assembly and ER to Golgi exit of the ATP8A2:TMEM30A flippase complex. ATP8A2:TMEM30A may be involved in regulation of neurite outgrowth, and, reconstituted to liposomes, predomiminantly transports phosphatidylserine (PS) and to a lesser extent phosphatidylethanolamine (PE). The ATP8A1:TMEM30A flippase complex seems to play a role in regulation of cell migration probably involving flippase-mediated translocation of phosphatidylethanolamine (PE) at the plasma membrane. Required for the formation of the ATP8A2, ATP8B1 and ATP8B2 P-type ATPAse intermediate phosphoenzymes. Involved in uptake of platelet-activating factor (PAF), synthetic drug alkylphospholipid edelfosine, and, probably in association with ATP8B1, of perifosine. Also mediates the export of alpha subunits ATP8A1, ATP8B1, ATP8B2, ATP8B4, ATP10A, ATP10B, ATP10D, ATP11A, ATP11B and ATP11C from the ER to other membrane localizations.
Component of various P4-ATPase flippase complexes which consists of a catalytic alpha subunit and an accessory beta subunit (PubMed:31416931). Interacts with ATP8A1 to form a flippase complex; this complex forms an intermediate phosphoenzyme (PubMed:31416931). The ATP8A2:TMEM30A flippase complex has been purified, and ATP8B1:TMEM30A and ATP8B2:TMEM30A flippase complexes have been shown to form intermediate phosphoenzymes in vitro. Interacts with alpha subunits ATP8A1, ATP8B1, ATP8B2, ATP8B4, ATP10A, ATP10B, ATP10D, ATP11A, ATP11B and ATP11C.
N-glycosylated. Contains high mannose-type oligosaccharides (By similarity).
The N-terminal domain seems to play a role in the reaction cycle of the catalytic subunit such as ATP8A2.
Interacts with CHCHD4/MIA40 forming transient intermolecular disulfide bridges.
Required for the transduction of an SCO1-dependent redox signal from the mitochondrion to ATP7A to regulate cellular copper homeostasis (PubMed:23345593). May be required for the assembly of mitochondrial cytochrome c oxidase (By similarity).
Ubiquitously expressed. Highly expressed in skeletal muscle.
Detected in cytoplasm of somite cells at the beginning of fourth week of development. Detected in cytoplasm of limb bud cell between the sixth and eighth week of development.
Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5 (By similarity). Tyrosine phosphatase that dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph) and promotes efficient DNA repair via the recruitment of DNA repair complexes containing MDC1. 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress (PubMed:19234442). Its function as histone phosphatase may contribute to its function in transcription regulation during organogenesis (By similarity). Has also phosphatase activity with proteins phosphorylated on Ser and Thr residues (in vitro) (By similarity). Required for normal embryonic development of the craniofacial and trunk skeleton, kidneys and ears (By similarity). Together with SIX1, it plays an important role in hypaxial muscle development; in this it is functionally redundant with EYA2 (By similarity).
In the embryo, highly expressed in kidney with lower levels in brain. Weakly expressed in lung. In the adult, highly expressed in heart and skeletal muscle. Weakly expressed in brain and liver. No expression in eye or kidney.
Probably interacts with SIX2, SIX4 and SIX5. Interacts with H2AX in response to DNA damage. Interacts with SIX3; promotes EYA1 translocation to the nucleus.
(Microbial infection) Interacts with Zika virus capsid protein C; this interaction is probably linked to the inhibition of stress granules formation by the virus.
Ability to mediate liquid-liquid phase separation is regulated by ATP: moderate concentrations of ATP enhance phase separation, whereas high concentrations of ATP lead to inhibition of phase separation.
May form homomultimers (PubMed:14764709). Interacts with G3BP1; interaction is direct and promotes stress granule formation (PubMed:17210633, PubMed:27022092, PubMed:32302570, PubMed:32302571, PubMed:32302572, PubMed:36183834, PubMed:36279435). Interacts with G3BP2; interaction is direct and promotes stress granule formation (PubMed:27022092). Interacts with PQBP1 (PubMed:21933836). Interacts with DDX3X (PubMed:28733330). Interacts (when phosphorylated by EPHA4) with FMR1; interaction with FMR1 promotes formation of a membraneless compartment (PubMed:31439799).
O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner (PubMed:22967762). O-glycosylation by OGT inhibit ability to undergo liquid-liquid phase separation (LLPS) (PubMed:34074792).
The C-terminal disordered region undergoes liquid-liquid phase separation (LLPS) for the formation of a membraneless compartment that concentrates mRNAs with associated regulatory factors (PubMed:31439799, PubMed:34074792, PubMed:36040869). CAPRIN1 molecules in the condensed phase are neutral (PubMed:36040869). mRNA-binding promotes phase separation (PubMed:31439799). Moderate concentrations of ATP enhance phase separation by reducing the electrostatic potential of CAPRIN1, thereby promoting intermolecular interactions (PubMed:34074792, PubMed:36040869). In contrast, high concentrations of ATP invert the electrostatic potential of CAPRIN1, so that CAPRIN1 molecules become negatively charged, lead to inhibition of phase separation (PubMed:36040869).
Tyrosine phosphorylation by EPHA4 promotes interaction with FMR1 and liquid-liquid phase separation (LLPS) for the formation of a membraneless compartment that concentrates mRNAs with associated regulatory factors.
Was originally thought to be a GPI-anchored membrane protein.
mRNA-binding protein that acts as a regulator of mRNAs transport, translation and/or stability, and which is involved in synaptic plasticity in neurons and cell proliferation and migration in multiple cell types (PubMed:17210633, PubMed:31439799). Acts as an mRNA regulator by mediating formation of some phase-separated membraneless compartment: undergoes liquid-liquid phase separation upon binding to target mRNAs, leading to assemble mRNAs into cytoplasmic ribonucleoprotein granules that concentrate mRNAs with associated regulatory factors (PubMed:31439799, PubMed:32302570, PubMed:32302571, PubMed:32302572, PubMed:34074792, PubMed:36040869, PubMed:36279435). Undergoes liquid-liquid phase separation following phosphorylation and interaction with FMR1, promoting formation of cytoplasmic ribonucleoprotein granules that concentrate mRNAs with factors that inhibit translation and mediate deadenylation of target mRNAs (PubMed:31439799). In these cytoplasmic ribonucleoprotein granules, CAPRIN1 mediates recruitment of CNOT7 deadenylase, leading to mRNA deadenylation and degradation (PubMed:31439799). Binds directly and selectively to MYC and CCND2 mRNAs (PubMed:17210633). In neuronal cells, directly binds to several mRNAs associated with RNA granules, including BDNF, CAMK2A, CREB1, MAP2, NTRK2 mRNAs, as well as to GRIN1 and KPNB1 mRNAs, but not to rRNAs (PubMed:17210633).
Transcriptional regulator that has an essential role in the organogenesis of lungs, pelvis, and hindlimbs.
During epidermal differentiation: expression is activated by p63/TP63.
Expressed in the skin, prostate, lung, placenta and thymus, and at low level in T-cells. Not expressed in peripheral blood leukocytes, pancreas and brain. Clearly expressed in primary keratinocytes but not in fibroblasts.
Transcription factor involved in epidermis differentiation. Required for terminal epidermal differentiation: acts downstream of p63/TP63 and activates expression of late epidermal differentiation genes. Specifically binds to the promoter of KLF4 and promotes its expression.
(Microbial infection) Interacts transiently interacts with hepatitis C virus (HCV) protein NS5B during HCV infection.
(Microbial infection) Interacts with S.flexneri IcsA; bacterial IcsB inhibits this interaction.
(Microbial infection) May act as a proviral factor. In association with ATG12, negatively regulates the innate antiviral immune response by impairing the type I IFN production pathway upon vesicular stomatitis virus (VSV) infection (PubMed:17709747). Required for the translation of incoming hepatitis C virus (HCV) RNA and, thereby, for initiation of HCV replication, but not required once infection is established (PubMed:19666601).
Conjugated to ATG12; which is essential for autophagy, but is not required for association with isolation membrane.
Forms a conjugate with ATG12 (PubMed:12207896, PubMed:11825910, PubMed:17709747, PubMed:26812546). The ATG5-ATG12 conjugate forms a complex with several units of ATG16L1. Forms an 800-kDa complex composed of ATG12-ATG5 and ATG16L2 (By similarity). Interacts with TECPR1; the interaction is direct and does not take place when ATG16L1 is associated with the ATG5-ATG12 conjugate (PubMed:21575909, PubMed:22342342). Interacts with DHX58/RIG-1, IFIH1/MDA5 and MAVS/IPS-1 in monomeric form as well as in ATG12-ATG5 conjugate form. The interaction with MAVS is further enhanced upon vesicular stomatitis virus (VSV) infection (PubMed:17709747). Interacts with ATG3 (PubMed:12207896, PubMed:11825910). Interacts with ATG7 and ATG10 (By similarity). Interacts with FADD (PubMed:15778222). Interacts with Bassoon/BSN; this interaction is important for the regulation of presynaptic autophagy (By similarity). Interacts with ATG16L2 (By similarity).
Involved in autophagic vesicle formation. Conjugation with ATG12, through a ubiquitin-like conjugating system involving ATG7 as an E1-like activating enzyme and ATG10 as an E2-like conjugating enzyme, is essential for its function. The ATG12-ATG5 conjugate acts as an E3-like enzyme which is required for lipidation of ATG8 family proteins and their association to the vesicle membranes. Involved in mitochondrial quality control after oxidative damage, and in subsequent cellular longevity. Plays a critical role in multiple aspects of lymphocyte development and is essential for both B and T lymphocyte survival and proliferation. Required for optimal processing and presentation of antigens for MHC II. Involved in the maintenance of axon morphology and membrane structures, as well as in normal adipocyte differentiation. Promotes primary ciliogenesis through removal of OFD1 from centriolar satellites and degradation of IFT20 via the autophagic pathway.
May play an important role in the apoptotic process, possibly within the modified cytoskeleton. Its expression is a relatively late event in the apoptotic process, occurring downstream of caspase activity. Plays a crucial role in IFN-gamma-induced autophagic cell death by interacting with FADD.
Ubiquitous. The mRNA is present at similar levels in viable and apoptotic cells, whereas the protein is dramatically highly expressed in apoptotic cells.
Involved in the regulation of glucose homeostasis and lipid metabolism.
Activity is divalent cation-dependent. It is stimulated by manganese, magnesium or calcium ions and reversibly inhibited by zinc, cobalt and iron (By similarity).
Cleaves proteins, imported into the mitochondrion, to their mature size.
Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2/PIP2), a lipid second messenger that regulates several cellular processes such as signal transduction, vesicle trafficking, actin cytoskeleton dynamics, cell adhesion, and cell motility (By similarity). PtdIns(4,5)P2 can directly act as a second messenger or can be utilized as a precursor to generate other second messengers: inositol 1,4,5-trisphosphate (IP3), diacylglycerol (DAG) or phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3/PIP3) (By similarity). Mediates RAC1-dependent reorganization of actin filaments. Contributes to the activation of phospholipase PLD2. Together with PIP5K1A, is required, after stimulation by G-protein coupled receptors, for the synthesis of IP3 that will induce stable platelet adhesion (By similarity).
Detected in heart, pancreas, brain, kidney, skeletal muscle and lung.
Interacts with RAC1, AJUBA, PLD1, PLD2 and ARF1.
There is confusion in the literature with phosphatidylinositol 4-phosphate 5-kinase type I nomenclature due to the fact that frequently mouse PIP5K1B is named Phosphatidylinositol 4-phosphate 5-kinase type I alpha.
Expressed at high levels in brain and immune system.
Functional P2XRs are organized as homomeric and heteromeric trimers.
Receptor for ATP that acts as a ligand-gated ion channel.
Contains a 27 bp insertion which does not match the genome.
Heterotrimer. Interacts with PAX1 and ARHGEF6 (or ARHGEF7).
Protein phosphatase that inactivates multifunctional CaM kinases such as CAMK4 and CAMK2 (By similarity). Dephosphorylates and inactivates PAK. May play a role in the inhibition of actin fiber stress breakdown and in morphological changes driven by TNK2/CDC42. Dephosphorylates PRKAA2 (By similarity).
The poly-Pro-Glu stretch is polymorphic.
In adult liver the amount of HPR mRNA is at the lower limit of detection, therefore the extent of its expression is at most less than 1000-fold that of the HP1F gene. No HPR mRNA can be detected in fetal liver. Expressed in Hep-G2 and leukemia MOLT-4 cell lines.
Primate-specific plasma protein associated with apolipoprotein L-I (apoL-I)-containing high-density lipoprotein (HDL). This HDL particle, termed trypanosome lytic factor-1 (TLF-1), mediates human innate immune protection against many species of African trypanosomes. Binds hemoglobin with high affinity and may contribute to the clearance of cell-free hemoglobin to allow hepatic recycling of heme iron.
The uncleaved signal sequence interacts with HDL fluid lipids and mediates incorporation into the HDL particle.
Belongs to the FAD-dependent oxidoreductase family.
Expressed in all tested tissues (PubMed:16644725). Detected in muscle and skin fibroblasts (at protein level) (PubMed:23217327). Expressed in osteoblasts (at protein level) (PubMed:28842795).
Expressed in all tested tissues except brain.
Functions both as NADH oxidoreductase and as regulator of apoptosis (PubMed:20362274, PubMed:23217327, PubMed:17094969, PubMed:33168626). In response to apoptotic stimuli, it is released from the mitochondrion intermembrane space into the cytosol and to the nucleus, where it functions as a proapoptotic factor in a caspase-independent pathway (PubMed:20362274). Release into the cytoplasm is mediated upon binding to poly-ADP-ribose chains (By similarity). The soluble form (AIFsol) found in the nucleus induces 'parthanatos' i.e. caspase-independent fragmentation of chromosomal DNA (PubMed:20362274). Binds to DNA in a sequence-independent manner (PubMed:27178839). Interacts with EIF3G, and thereby inhibits the EIF3 machinery and protein synthesis, and activates caspase-7 to amplify apoptosis (PubMed:17094969). Plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells (PubMed:19418225). In contrast, participates in normal mitochondrial metabolism. Plays an important role in the regulation of respiratory chain biogenesis by interacting with CHCHD4 and controlling CHCHD4 mitochondrial import (PubMed:26004228).
Has NADH oxidoreductase activity. Does not induce nuclear apoptosis.
Isoform 5 is frequently down-regulated in human cancers.
Monomer (oxidized form). Homodimer (reduced form). Upon reduction with NADH, undergoes dimerization and forms tight, long-lived FADH2-NAD charge transfer complexes (CTC) resistant to oxidation (PubMed:24914854, PubMed:20111043, PubMed:23217327, PubMed:27818101). Also dimerizes with isoform 3 preventing its release from mitochondria (PubMed:20111043). Interacts with XIAP/BIRC4 (PubMed:17967870). Interacts (via N-terminus) with EIF3G (via C-terminus) (PubMed:17094969). Interacts with PRELID1 (PubMed:21364629). Interacts with CHCHD4; the interaction increases in presence of NADH (PubMed:26004228). Interacts with processed form of PARP1 (Poly [ADP-ribose] polymerase 1, processed C-terminus); interaction is mediated with poly-ADP-ribose chains attached to PARP1, promoting translocation into the nucleus (PubMed:33168626).
Strongly down-regulated in many tumor cells, up-regulated by gamma-irradiation.
Ubiquitination by XIAP/BIRC4 does not lead to proteasomal degradation. Ubiquitination at Lys-255 by XIAP/BIRC4 blocks its ability to bind DNA and induce chromatin degradation, thereby inhibiting its ability to induce cell death.
Under normal conditions, a 54-residue N-terminal segment is first proteolytically removed during or just after translocation into the mitochondrial intermembrane space (IMS) by the mitochondrial processing peptidase (MPP) to form the inner-membrane-anchored mature form (AIFmit). During apoptosis, it is further proteolytically processed at amino-acid position 101 leading to the generation of the mature form, which is confined to the mitochondrial IMS in a soluble form (AIFsol). AIFsol is released to the cytoplasm in response to specific death signals, and translocated to the nucleus, where it induces nuclear apoptosis in a caspase-independent manner.
Catalyzes the transfer of Gal to GlcNAc-based acceptors with a preference for the core3 O-linked glycan GlcNAc(beta1,3)GalNAc structure. Can use glycolipid LC3Cer as an efficient acceptor.
Expressed in stomach, jejunum, colon, pancreas, small intestine, testis and gastrointestinal and pancreatic cancer cell lines. Hardly detected in lung, liver, adrenal gland and peripheral blood leukocytes.
Found in a complex with CABLES1, CCNA1 and CCNE1. Interacts with CABLES1 (By similarity). Interacts with UHRF2. Part of a complex consisting of UHRF2, CDK2 and CCNE1. Interacts with the Speedy/Ringo proteins SPDYA and SPDYC (PubMed:15611625). Interaction with SPDYA promotes kinase activation via a conformation change that alleviates obstruction of the substrate-binding cleft by the T-loop (PubMed:28666995). Found in a complex with both SPDYA and CDKN1B/KIP1 (PubMed:12972555, PubMed:28666995). Binds to RB1 and CDK7. Binding to CDKN1A (p21) leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair. Associated with PTPN6 and beta-catenin/CTNNB1. Interacts with CACUL1. May interact with CEP63. Interacts with ANKRD17. Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Forms a ternary complex with CCNA2 and CDKN1B; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements (PubMed:8684460). Interacts with cyclins A, B1, B3, D, or E (PubMed:10499802, PubMed:10884347, PubMed:12185076, PubMed:23781148). Interacts with CDK2AP2 (PubMed:23781148).
Induced transiently by TGFB1 at an early phase of TGFB1-mediated apoptosis.
Nitrosylated after treatment with nitric oxide (DETA-NO).
Phosphorylated at Thr-160 by CDK7 in a CAK complex (PubMed:28666995). Phosphorylation at Thr-160 promotes kinase activity, whereas phosphorylation at Tyr-15 by WEE1 reduces slightly kinase activity. Phosphorylated on Thr-14 and Tyr-15 during S and G2 phases before being dephosphorylated by CDC25A.
Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-160 activates it (PubMed:1396589). Inhibited by 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)), AG-024322, N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), R547 (Ro-4584820), purine, pyrimidine and pyridine derivatives, 2-aminopyrimidines, paullones, thiazo derivatives, macrocyclic quinoxalin-2-one, pyrazolo[1,5-a]-1,3,5-triazine, pyrazolo[1,5-a]pyrimidine, 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine, seliciclib and CYC202), SNS-032 (BMS-387032), triazolo[1,5-a]pyrimidines, staurosporine and olomoucine. Stimulated by MYC. Inactivated by CDKN1A (p21).
Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability (By similarity). Phosphorylates CDK2AP2 (PubMed:12944431). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878).
Involved in hearing. Required for normal function of hair cells in the inner ear (By similarity).
May play a role in transcription or may interact with other nuclear matrix proteins to form the internal fibrogranular network. In association with the SFPQ-NONO heteromer may play a role in nuclear retention of defective RNAs. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728). Binds to N6-methyladenosine (m6A)-containing mRNAs and contributes to MYC stability by binding to m6A-containing MYC mRNAs (PubMed:32245947). May bind to specific miRNA hairpins (PubMed:28431233).
Part of a complex consisting of SFPQ, NONO and MATR3. Interacts with AGO1 and AGO2. Part of a complex composed at least of ASH2L, EMSY, HCFC1, HSPA8, CCAR2, MATR3, MKI67, RBBP5, TUBB2A, WDR5 and ZNF335; this complex may have a histone H3-specific methyltransferase activity. Interacts with TARDBP. Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA (PubMed:28712728). Interacts with FUS. Interacts with IGF2BP1; the interaction is enhanced by SEPIN14P20 peptide RBPR (PubMed:32245947, PubMed:29476152). Interacts with IGF2BP2 and IGF2BP3 (PubMed:29476152).
A chromosomal aberration involving SLC9A9 has been found in a family with early-onset behavioral/developmental disorder with features of attention deficit-hyperactivity disorder and intellectual disability. Inversion inv(3)(p14:q21). The inversion disrupts DOCK3 and SLC9A9.
Conditioned medium from iron-depleted astrocytes increases SLC9A9 levels in human blood-brain barrier endothelial cells (hBMVECs).
Endosomal Na(+), K(+)/H(+) antiporter. Mediates the electroneutral exchange of endosomal luminal H(+) for a cytosolic Na(+) or K(+) (Probable). By facilitating proton efflux, SLC9A9 counteracts the acidity generated by vacuolar (V)-ATPase, thereby limiting luminal acidification. Regulates organellar pH and consequently, e.g., endosome maturation and endocytic trafficking of plasma membrane receptors and neurotransporters (PubMed:28130443, PubMed:15522866, PubMed:24065030). Promotes the recycling of transferrin receptors back to the cell surface to facilitate additional iron uptake in the brain (PubMed:28130443). Regulates synaptic transmission by regulating the luminal pH of axonal endosomes (By similarity). Regulates phagosome lumenal pH, thus affecting phagosome maturation, and consequently, microbicidal activity in macrophages (By similarity). Can also be active at the cell surface of specialized cells, e.g., in the inner ear hair bundles uses the high K(+) of the endolymph to regulate intracelular pH (By similarity).
Homodimer; phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) could be involved in the dimer stabilization (By similarity). Interacts (via the C-terminus) with RACK1 (PubMed:18057008). Interacts with CHP1 (By similarity).
Ubiquitously expressed in all tissues tested. Expressed at highest levels in heart and skeletal muscle, followed by placenta, kidney, and liver. Expressed in the brain, in the medulla and spinal cord.
(Microbial infection) Acts as a receptor for Coxsackievirus B1 to B6.
(Microbial infection) Acts as a receptor for adenovirus type C.
(Microbial infection) Interacts with adenovirus subgroups A, C, D, E and F fiber proteins as well as coxsackievirus B1, B2, B3, B4, B5 and B6 capsid proteins (PubMed:14978041, PubMed:9733828, PubMed:10666333, PubMed:10814575, PubMed:12297051, PubMed:10567268).
Component of the epithelial apical junction complex that may function as a homophilic cell adhesion molecule and is essential for tight junction integrity. Also involved in transepithelial migration of leukocytes through adhesive interactions with JAML a transmembrane protein of the plasma membrane of leukocytes. The interaction between both receptors also mediates the activation of gamma-delta T-cells, a subpopulation of T-cells residing in epithelia and involved in tissue homeostasis and repair. Upon epithelial CXADR-binding, JAML induces downstream cell signaling events in gamma-delta T-cells through PI3-kinase and MAP kinases. It results in proliferation and production of cytokines and growth factors by T-cells that in turn stimulate epithelial tissues repair.
Expressed in pancreas, brain, heart, small intestine, testis, prostate and at a lower level in liver and lung. Isoform 5 is ubiquitously expressed. Isoform 3 is expressed in heart, lung and pancreas. In skeletal muscle, isoform 1 is found at the neuromuscular junction and isoform 2 is found in blood vessels. In cardiac muscle, isoform 1 and isoform 2 are found at intercalated disks. In heart expressed in subendothelial layers of the vessel wall but not in the luminal endothelial surface. Expression is elevated in hearts with dilated cardiomyopathy.
Monomer. May form homodimer. Interacts with LNX, MAGI1, DLG4, PRKCABP, TJP1 and CTNNB1. Interacts with MPDZ; recruits MPDZ to intercellular contact sites. Interacts with JAML (homodimeric form). Secreted isoform 3, isoform 4 and isoform 5 can interact with the extracellular domain of the receptor.
Palmitoylated on Cys-259 and/or Cys-260; required for proper localization to the plasma membrane.
The Ig-like C2-type 1 domain mediates homodimerization and interaction with JAML.
The PDZ-binding motif mediates interaction with MPDZ and MAGI1.
(Microbial infection) Interacts with herpes virus 8 protein K15.
Adapter protein that may provide indirect link between the endocytic membrane traffic and the actin assembly machinery. May regulate the formation of clathrin-coated vesicles (CCPs). Seems to be involved in CCPs maturation including invagination or budding. Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR). Plays a role in dendrite formation by melanocytes (PubMed:23999003).
Belongs to a complex that may contain multimers of ITSN1, ITSN2 and EPS15, and different partners according to the step in the endocytic process. Interacts with ADAM15. Interacts with FASLG. Interacts with ANKRD54 (By similarity). Interacts with FCHO2.
Expressed in melanocytes (PubMed:23999003). Ubiquitous. Isoform 1 is primarily expressed in adult heart and liver.
Overexpression results in the inhibition of the transferrin uptake and the blockage of the clathrin-mediated endocytosis.
Studies in clathrin-mediated endocytosis of ITGB1 and TFR used a siRNA mixture of ISTN1 and ISTN2 suggesting a partially overlapping role of the EH domain-containing proteins.
E3 ubiquitin-protein ligase which catalyzes the formation of 'Lys-48'-polyubiquitin chains (PubMed:20059950, PubMed:30696809). Mediates the ubiquitination and subsequent degradation of phosphorylated Akt (AKT1, AKT2 and AKT3) in the nucleus (PubMed:20059950). Acts as a terminal regulator of Akt signaling after activation; its phosphorylation by Akt, which is a prerequisite for ubiquitin ligase activity, suggests the existence of a regulation mechanism required to control Akt levels after activation (PubMed:20059950). Positively regulates TGFB1-induced epithelial-mesenchymal transition and myofibroblast differentiation by mediating the ubiquitination and subsequent degradation of SMURF2 (PubMed:30696809). Regulates neuronal differentiation by regulating actin remodeling and Golgi organization via a signaling cascade involving RHOA, CIT and ROCK (PubMed:17488780, PubMed:24695496). Inhibits cell proliferation (PubMed:30203323).
Interacts (when phosphorylated on Ser-378) with AKT1, AKT2 and AKT3 (when phosphorylated) (PubMed:20059950). Interacts with CIT (PubMed:17488780). Interacts with POLG (PubMed:29290964). Interacts with HSP70 (PubMed:29290964). Interacts with SMURF2 (PubMed:30696809).
Phosphorylation on Ser-378 by Akt is required for ubiquitin ligase activity.
Proteolytically cleaved into differently sized N- and C-terminal fragments.
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:20972997, PubMed:11555828, PubMed:12865317, PubMed:10681376, PubMed:15258110). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:20972997, PubMed:11555828, PubMed:12865317, PubMed:10681376, PubMed:15258110). Exhibits catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2- and 4-hydroxy E1 and E2. Displays a predominant hydroxylase activity toward E2 at the C-4 position (PubMed:11555828, PubMed:12865317). Metabolizes testosterone and progesterone to B or D ring hydroxylated metabolites (PubMed:10426814). May act as a major enzyme for all-trans retinoic acid biosynthesis in extrahepatic tissues. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376, PubMed:15258110). Catalyzes the epoxidation of double bonds of certain PUFA. Converts arachidonic acid toward epoxyeicosatrienoic acid (EpETrE) regioisomers, 8,9-, 11,12-, and 14,15- EpETrE, that function as lipid mediators in the vascular system (PubMed:20972997). Additionally, displays dehydratase activity toward oxygenated eicosanoids hydroperoxyeicosatetraenoates (HpETEs). This activity is independent of cytochrome P450 reductase, NADPH, and O2 (PubMed:21068195). Also involved in the oxidative metabolism of xenobiotics, particularly converting polycyclic aromatic hydrocarbons and heterocyclic aryl amines procarcinogens to DNA-damaging products (PubMed:10426814). Plays an important role in retinal vascular development. Under hyperoxic O2 conditions, promotes retinal angiogenesis and capillary morphogenesis, likely by metabolizing the oxygenated products generated during the oxidative stress. Also, contributes to oxidative homeostasis and ultrastructural organization and function of trabecular meshwork tissue through modulation of POSTN expression (By similarity).
By polycyclic aromatic hydrocarbons (PAH) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
Enzyme activity is increased by liposomes containing anionic phospholipids, phosphatidic acid and cardiolipin. Inhibited by naringenin with an IC(50) of 5 uM (PubMed:22888116, PubMed:22935222). Enzyme activity is increased by cytochrome b5.
Expressed in heart, brain, lung, skeletal muscle, kidney, spleen, thymus, prostate, testis, ovary, small intestine, colon, and peripheral blood leukocytes (PubMed:8175734). Expressed in retinal endothelial cells and umbilical vein endothelial cells (at protein level) (PubMed:19005183).
The gene represented in this entry acts as a disease modifier. Digenic mutations in CYP1B1 and MYOC have been found in a family segregating both primary adult-onset and juvenile forms of open angle glaucoma (PubMed:11774072). All affected family members with mutations in both MYOC and CYP1B1 had juvenile glaucoma, whereas those with only the MYOC mutation had the adult-onset form (PubMed:11774072).
Various CYP1B1 alleles are known. The sequence shown is that of allele CYP1B1*1.
Negatively regulates growth hormone (GH) receptor cell surface expression in liver. May play a role in liver resistance to GH during periods of reduced nutrient availability.
Widely expressed, with highest expression in heart, testis, adrenal gland, thymus, and spleen, and lowest expression in lung and skeletal muscle.
Contains a short sequence motif (Phe-Xaa-Xaa-Phe-Tyr) that can bind to AR and may modulate AR activity.
Detected in epithelial and stromal cells in benign prostate hyperplasia tissue (at protein level).
Identified in the spliceosome C complex (PubMed:28502770, PubMed:28076346). May interact with AR (PubMed:25091737).
Involved in the pre-mRNA splicing process (PubMed:28502770, PubMed:28076346). May play a role as regulator of AR transcriptional activity; may increase AR transcriptional activity (PubMed:25091737).
Detected in brain neocortex and caudate nucleus (at protein level).
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Regulates the release of 5-hydroxytryptamine in the brain, and thereby affects neural activity. May also play a role in regulating the release of other neurotransmitters. May play a role in vasoconstriction.
Auxillary component of the N-terminal acetyltransferase C (NatC) complex which catalyzes acetylation of N-terminal methionine residues.
Component of the N-terminal acetyltransferase C (NatC) complex, which is composed of NAA35, NAA38 and NAA30.
Co-chaperone for Hsp70 protein HSPA5/BiP that acts as a key repressor of the ERN1/IRE1-mediated unfolded protein response (UPR) (By similarity). J domain-containing co-chaperones stimulate the ATPase activity of Hsp70 proteins and are required for efficient substrate recognition by Hsp70 proteins (PubMed:18400946). In the unstressed endoplasmic reticulum, interacts with the luminal region of ERN1/IRE1 and selectively recruits HSPA5/BiP: HSPA5/BiP disrupts the dimerization of the active ERN1/IRE1 luminal region, thereby inactivating ERN1/IRE1 (By similarity). Also involved in endoplasmic reticulum-associated degradation (ERAD) of misfolded proteins. Required for survival of B-cell progenitors and normal antibody production (By similarity).
Interacts with HSPA5/BiP; interaction is direct (By similarity). Interacts with ERN1/IRE1 (via the luminal region) (By similarity). Interacts with DERL1 (By similarity).
The J domain stimulates the ATPase activity of HSPA5/BiP, while the divergent targeting domain is required for efficient substrate recognition by HSPA5/BiP. The divergent targeting domain specifically recognizes and binds to aggregation-prone sequences.
Widely expressed. Expressed at highest level in the liver, placenta and kidney (PubMed:11836248).
Autoubiquitinated in vitro in the presence of E2 enzyme UBE2D1/UBCH5A.
E3 ubiquitin-protein ligase that catalyzes 'Lys-11'- or 'Lys-33'-linked polyubiquitin chains, with some preference for 'Lys-33' linkages (PubMed:25752577). E3 ubiquitin-protein ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:23479728, PubMed:31578312). Ubiquitinates SEPTIN4, DIABLO/SMAC and HTRA2 in vitro (PubMed:23479728). Modulates pulmonary inflammation by targeting SOCS2 for ubiquitination and subsequent degradation by the proteasome (PubMed:31578312).
Interacts with SOCS2 (PubMed:31578312). Interacts (via HECT domain) with HTRA2, DIABLO/SMAC and SEPTIN4; in the cytoplasm following induction of apoptosis (PubMed:23479728).
Downstream effector of Notch signaling which may be required for cardiovascular development. Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGTG-3'. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6.
May self-associate (By similarity). Interacts with GATA4, HES1 and HEYL (By similarity). Interacts with HDAC1, NCOR1 and SIN3A (By similarity). Interacts with ARNT and GATA6.
Aminocarboxypropyltransferase that catalyzes the aminocarboxypropyl transfer on pseudouridine at position 1248 (Psi1248) in 18S rRNA (Probable). It constitutes the last step in biosynthesis of the hypermodified N1-methyl-N3-(3-amino-3-carboxypropyl) pseudouridine (m1acp3-Psi) conserved in eukaryotic 18S rRNA (Probable).
Belongs to the TDD superfamily. TSR3 family.
Belongs to the HAD-like hydrolase superfamily. NANP family.
It seems to be derived from genomic DNA and not from cDNA.
Because S100A10 induces the dimerization of ANXA2/p36, it may function as a regulator of protein phosphorylation in that the ANXA2 monomer is the preferred target (in vitro) of tyrosine-specific kinase.
Does not appear to bind calcium. Contains 2 ancestral calcium site related to EF-hand domains that have lost their ability to bind calcium.
Heterotetramer containing 2 light chains of S100A10/p11 and 2 heavy chains of ANXA2/p36 (PubMed:9886297). Interacts with SCN10A (By similarity). Interacts with TASOR (By similarity).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIK2 subfamily.
Cold receptor activity activated by temperatures between 10-19 degrees Celsius.
Expression is higher in cerebellum than in cerebral cortex.
Homotetramer or heterotetramer of pore-forming glutamate receptor subunits. Tetramers may be formed by the dimerization of dimers (Probable). Assembles into a kainate-gated homomeric channel that does not bind AMPA. GRIK2 associated to GRIK5 forms functional channels that can be gated by AMPA (By similarity). Interacts with DLG4. Interacts with NETO2 (By similarity). Interacts (via C-terminus) with KLHL17 (via kelch repeats); the interaction targets GRIK2 for degradation via ubiquitin-proteasome pathway (By similarity).
Independent of its ionotropic glutamate receptor activity, acts as a thermoreceptor conferring sensitivity to cold temperatures (PubMed:31474366). Functions in dorsal root ganglion neurons (By similarity).
Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist (PubMed:28180184). Modulates cell surface expression of NETO2 (By similarity).
Partially edited. The presence of Gln at position 621 (non-edited) determines channels with low calcium permeability, whereas Arg (edited) determines a higher calcium permeability especially if the preceding sites are fully edited. This receptor is nearly completely edited in all gray matter structures (90% of the receptors), whereas much less edited in the white matter (10% of the receptors).
Phosphorylated by PKC at Ser-868 upon agonist activation, this directly enhance sumoylation.
Seems to be specific for non-neuronal cells. May not function as active channel.
Sumoylation mediates kainate receptor-mediated endocytosis and regulates synaptic transmission. Sumoylation is enhanced by PIAS3 and desumoylated by SENP1 (By similarity).
The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds domoate > kainate > quisqualate > 6-cyano-7-nitroquinoxaline-2,3-dione > L-glutamate = 6,7-dinitroquinoxaline-2,3-dione > dihydrokainate.
Ubiquitinated. Ubiquitination regulates the GRIK2 levels at the synapse by leading kainate receptor degradation through proteasome (By similarity).
Belongs to the V-ATPase e1/e2 subunit family.
Isoform 1 is expressed at high levels in heart, brain and kidney and also detected in inner ear epithelium, vestibule, testis, epididymis and bladder. Isoform 2 is expressed in heart, kidney, placenta and pancreas. Isoform 2 is not detected in frontal cortex, but is prevalent in all other brain areas.
Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (By similarity). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (By similarity).
Atypical kinesin that plays a key role in enteric neuron development. Acts by repressing a cell growth signaling pathway in the enteric nervous system development, possibly via its interaction with GRB2 that prevents GRB2-binding to SHC, thereby attenating the GDNF-Ret signaling (By similarity). Binds to microtubules but lacks microtubule-based motility due to the absence of ATPase activity (By similarity). Plays a critical role in cerebral cortical development. It probably acts as a microtubule stabilizer that regulates neurite growth and radial migration of cortical excitatory neurons (PubMed:36228617).
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. KIF26 subfamily.
Expressed in the cortical plate, subplate, and intermediate zone of the mid-gestation fetal cortex.
In contrast to other kinesin-like proteins, residues required for ATPase activity are missing.
In the developing cerebral cortex, preferentially expressed by migrating excitatory neurons.
Cell adhesion molecule that mediates both heterotypic cell-cell contacts via its interaction with CD6, as well as homotypic cell-cell contacts (PubMed:7760007, PubMed:15496415, PubMed:15048703, PubMed:16352806, PubMed:23169771, PubMed:24945728). Promotes T-cell activation and proliferation via its interactions with CD6 (PubMed:15048703, PubMed:16352806, PubMed:24945728). Contributes to the formation and maturation of the immunological synapse via its interactions with CD6 (PubMed:15294938, PubMed:16352806). Mediates homotypic interactions with cells that express ALCAM (PubMed:15496415, PubMed:16352806). Acts as a ligand for the LILRB4 receptor, enhancing LILRB4-mediated inhibition of T cell proliferation (PubMed:29263213). Required for normal hematopoietic stem cell engraftment in the bone marrow (PubMed:24740813). Mediates attachment of dendritic cells onto endothelial cells via homotypic interaction (PubMed:23169771). Inhibits endothelial cell migration and promotes endothelial tube formation via homotypic interactions (PubMed:15496415, PubMed:23169771). Required for normal organization of the lymph vessel network. Required for normal hematopoietic stem cell engraftment in the bone marrow. Plays a role in hematopoiesis; required for normal numbers of hematopoietic stem cells in bone marrow. Promotes in vitro osteoblast proliferation and differentiation (By similarity). Promotes neurite extension, axon growth and axon guidance; axons grow preferentially on surfaces that contain ALCAM. Mediates outgrowth and pathfinding for retinal ganglion cell axons (By similarity).
Detected on hematopoietic stem cells derived from umbilical cord blood (PubMed:24740813). Detected on lymph vessel endothelial cells, skin and tonsil (PubMed:23169771). Detected on peripheral blood monocytes (PubMed:15048703). Detected on monocyte-derived dendritic cells (at protein level) (PubMed:16352806). Detected at low levels in spleen, placenta, liver (PubMed:9502422). Expressed by activated T-cells, B-cells, monocytes and thymic epithelial cells (PubMed:7760007). Isoform 1 and isoform 3 are detected in vein and artery endothelial cells, astrocytes, keratinocytes and artery smooth muscle cells (PubMed:15496415). Expressed by neurons in the brain. Restricted expression in tumor cell lines. Detected in highly metastasizing melanoma cell lines (PubMed:9502422).
Homodimer (PubMed:7760007, PubMed:16352806, PubMed:15048703, PubMed:26146185). Interacts (via extracellular domain) with CD6 (via extracellular domain) (PubMed:7760007, PubMed:8823162, PubMed:15048703, PubMed:16914752, PubMed:24945728, PubMed:26146185). Homodimerization and interaction with CD6 involve the same region and cannot occur simultaneously. The affinity for CD6 is much higher than the affinity for self-association (PubMed:15048703). Interacts (via glycosylated extracellular domain) with LGALS1 and LGALS3 (PubMed:24945728). Interaction with LGALS1 or LGALS3 inhibits interaction with CD6 (PubMed:24945728).
Inhibits activities of membrane-bound isoforms by competing for the same interaction partners. Inhibits cell attachment via homotypic interactions. Promotes endothelial cell migration. Inhibits endothelial cell tube formation.
Secreted form, inhibits isoform 1 homophilic interaction.
The CD6 binding site is located in the N-terminal Ig-like domain.
Up-regulated by TNF and IFNG (at protein level).
Highly expressed in normal germinal center (GC) B-cells and GC B-cell-derived malignancies.
Protease inhibitor that inhibits trypsin and trypsin-like serine proteases (in vitro). Inhibits plasmin and thrombin with lower efficiency (in vitro).
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB5. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Directly interacts with POMP. Interacts with TAP1.
The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB5 by PSMB8 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues. Involved in the generation of spliced peptides resulting from the ligation of two separate proteasomal cleavage products that are not contiguous in the parental protein (PubMed:27049119). Acts as a major component of interferon gamma-induced sensitivity. Plays a key role in apoptosis via the degradation of the apoptotic inhibitor MCL1. May be involved in the inflammatory response pathway. In cancer cells, substitution of isoform 1 (E2) by isoform 2 (E1) results in immunoproteasome deficiency. Required for the differentiation of preadipocytes into adipocytes.
Up-regulated by IFNG/IFN-gamma and IRF1 (at protein level). Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Down-regulated by the selective inhibitor PR-957. Down-regulated in mature dendritic cells by HSV-1 infection. Up-regulated by heat shock treatment.
Stimulates the proliferation of early hematopoietic cells by activating FLT3. Synergizes well with a number of other colony stimulating factors and interleukins.
In the eye, expressed in trabecular meshwork and neural retina; in non-ocular tissues, expressed in brain and lung.
Peripherally associated with AMPAR complex. AMPAR complex consists of an inner core made of 4 pore-forming GluA/GRIA proteins (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged in a twofold symmetry. One of the two pairs of distinct binding sites is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR complex is complemented by outer core constituents binding directly to the GluA/GRIA proteins at sites distinct from the interaction sites of the inner core constituents. Outer core constituents include at least PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the inner and outer core serve as a platform for other, more peripherally associated AMPAR constituents, including OLFM3. Alone or in combination, these auxiliary subunits control the gating and pharmacology of the AMPAR complex and profoundly impact their biogenesis and protein processing. Homodimer. Interacts with MYOC (By similarity). Interacts with OLFM2 (PubMed:21228389).
Abundantly expressed in cardiac muscle, but not in skeletal or smooth muscle. Localized to Z-lines in cardiac cells and to dense bodies in nonmuscle cells. Isoform 2 is expressed in non-muscle cells such as in fibroblasts.
Binds to actin and plays an important role in the assembly of the Z-disk. May functionally link sarcomeric actin to the desmin intermediate filaments in the heart muscle sarcomeres (PubMed:27733623). Isoform 2 might play a role in the assembly of focal adhesion (PubMed:15004028).
Expressed in non-muscle cells. May be transcribed from an upstream promoter active in non-muscle cells.
Isoform 2 interacts with ZYX (Zyxin) (PubMed:15004028). Interacts (via nebulin repeats 1-5) with DESM (via rod region) (PubMed:27733623).
Interacts with the basal transcription factor GTF2B. Interacts with REXO1.
Necessary for efficient RNA polymerase II transcription elongation past template-encoded arresting sites. The arresting sites in DNA have the property of trapping a certain fraction of elongating RNA polymerases that pass through, resulting in locked ternary complexes. Cleavage of the nascent transcript by S-II allows the resumption of elongation from the new 3'-terminus.
Association with EPOR may target the protein for proteolysis by the ubiquitin-dependent proteasome pathway. CIS is mainly monubiquitinated (37 kDa form) but may also exist in a polyubiquitinated form (45 kDa).
By a subset of cytokines including EPO/erythropoietin.
CISH polymorphisms are involved in susceptibility to malaria [MIM:611162].
Expressed in various epithelial tissues. Abundantly expressed in liver and kidney, and to a lesser extent in lung. The tissue distribution of isoforms 1 and 1B is distinct.
Genetic variations in CISH are associated with susceptibility to bacterial invasion of the blood and define the bacteremia susceptibility locus 2 (BACTS2) [MIM:614383].
Genetic variations in CISH are involved in susceptibility to tuberculosis [MIM:607948].
SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. CIS is involved in the negative regulation of cytokines that signal through the JAK-STAT5 pathway such as erythropoietin, prolactin and interleukin 3 (IL3) receptor. Inhibits STAT5 trans-activation by suppressing its tyrosine phosphorylation. May be a substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (By similarity).
Stably associated with the tyrosine-phosphorylated IL3 receptor beta chain and tyrosine-phosphorylated EPO receptor (EPOR).
Activated by Ca(2+), Mg(2+) and Na(+) cations (PubMed:12764132). Inhibited by Zn(2+) (PubMed:12764132). Phosphatidylserine and phosphatidic acid stimulate while cardiolipin, phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and sphingomyelin inhibit the reverse ceramide synthase activity (PubMed:12764132). Phosphatidic acid, phosphatidylinositol and C16-ceramide inhibit the ceramidase/hydrolase activity (PubMed:12764132).
Broadly expressed with higher expression in heart.
Heterodimer; disulfide-linked (PubMed:7744740, PubMed:11451951, PubMed:30525581, PubMed:29692406). The heterodimer is composed of the disulfide-linked alpha and beta chains produced by autocatalytic cleavage of the precursor (PubMed:7744740, PubMed:11451951, PubMed:30525581, PubMed:29692406). Isoform 2: May interact with NR5A1 in the nucleus; the direct interaction would negatively regulate NR5A1 transcriptional activity (Probable).
Lysosomal ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at acidic pH (PubMed:10610716, PubMed:7744740, PubMed:15655246, PubMed:11451951). Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation (PubMed:10610716). Has a higher catalytic efficiency towards C12-ceramides versus other ceramides (PubMed:7744740, PubMed:15655246). Also catalyzes the reverse reaction allowing the synthesis of ceramides from fatty acids and sphingosine (PubMed:12764132, PubMed:12815059). For the reverse synthetic reaction, the natural sphingosine D-erythro isomer is more efficiently utilized as a substrate compared to D-erythro-dihydrosphingosine and D-erythro-phytosphingosine, while the fatty acids with chain lengths of 12 or 14 carbons are the most efficiently used (PubMed:12764132). Has also an N-acylethanolamine hydrolase activity (PubMed:15655246). By regulating the levels of ceramides, sphingosine and sphingosine-1-phosphate in the epidermis, mediates the calcium-induced differentiation of epidermal keratinocytes (PubMed:17713573). Also indirectly regulates tumor necrosis factor/TNF-induced apoptosis (By similarity). By regulating the intracellular balance between ceramides and sphingosine, in adrenocortical cells, probably also acts as a regulator of steroidogenesis (PubMed:22261821).
May directly regulate steroidogenesis by binding the nuclear receptor NR5A1 and negatively regulating its transcriptional activity.
Mutagenesis in position: 25:L->A (Loss of interaction with NR5A1).
Proteolytically cleaved into two chains alpha and beta that remain associated via a disulfide bond (PubMed:7744740, PubMed:11451951, PubMed:30525581, PubMed:29692406). Cleavage gives rise to a conformation change that activates the enzyme. The same catalytic Cys residue mediates the autoproteolytic cleavage and subsequent hydrolysis of lipid substrates (PubMed:30525581, PubMed:29692406). The beta chain may undergo an additional C-terminal processing (PubMed:12815059).
May be involved in transcriptional regulation. May play a role during osteoclast differentiation by modulating TRAF6 signaling activity.
Component of the TFIID basal transcription factor complex, composed of TATA-box-binding protein TBP, and a number of TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473, PubMed:8262073). Interacts directly with TBP, TAF1/TAFII250, TAF9/TAFII31 and TAF12/TAFII20 (PubMed:7667268). The TAF6/TAFII70-TAF9/TAFII31 heterodimer forms an octamer complex with the TAF4B/TFII105-TAF12/TFIID20 heterodimer (PubMed:15601843). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975). Also interacts with the GTFs, TFIIEalpha/GTF2E1 and TFIIFalpha/GTF2F1 (PubMed:7667268). Component of the TBP-free TAFII-histone acetylase complex (TFTC-HAT) (PubMed:12601814).
In cells undergoing apoptosis, cleaved in a caspase-dependent manner to produce a 40 kDa product.
Not part of the TBP-free TAFII-histone acetylase complex (TFTC-HAT) (PubMed:11583621). Part of a TFIID-like complex which lacks TAF9 (PubMed:11583621). Interacts with TP53/p53 (PubMed:20096117).
The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription (PubMed:33795473). TFIID recognizes and binds promoters with or without a TATA box via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC) (PubMed:33795473). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473). The TFIID complex structure can be divided into 3 modules TFIID-A, TFIID-B, and TFIID-C (PubMed:33795473). TAF6 homodimer connects TFIID modules, forming a rigid core (PubMed:33795473).
Transcriptional regulator which acts primarily as a positive regulator of transcription (PubMed:20096117, PubMed:29358700). Recruited to the promoters of a number of genes including GADD45A and CDKN1A/p21, leading to transcriptional up-regulation and subsequent induction of apoptosis (PubMed:11583621). Also up-regulates expression of other genes including GCNA/ACRC, HES1 and IFFO1 (PubMed:18628956). In contrast, down-regulates transcription of MDM2 (PubMed:11583621). Acts as a transcriptional coactivator to enhance transcription of TP53/p53-responsive genes such as DUSP1 (PubMed:20096117). Can also activate transcription and apoptosis independently of TP53 (PubMed:18628956). Drives apoptosis via the intrinsic apoptotic pathway by up-regulating apoptosis effectors such as BCL2L11/BIM and PMAIP1/NOXA (PubMed:29358700).
Plays a role in spermiogenesis. Involved in the elongation of flagella and the formation of sperm heads.
Interacts with ATP2B1, ATP2B2, ATP2B3, ATP2B4 and ATP7A (PubMed:12763866, PubMed:16051599). Interacts with PLEKHA7 (via WW domains) at zonula adherens; this interaction is essential for the interaction between PLEKHA7 and the ADAM10-binding protein TSPAN33 (PubMed:30463011). Interacts with SLC5A6 (PubMed:21183659).
Mediates docking of ADAM10 to zonula adherens by interacting with PLEKHA7 which is required for PLEKHA7 to interact with the ADAM10-binding protein TSPAN33.
4Fe-4S iron-sulfur-binding is required for helicase activity.
Acetylation at Lys-1249 facilitates DNA end processing required for repair and checkpoint signaling.
Binds directly to the BRCT domains of BRCA1 (PubMed:15125843). Interacts with the CIA complex components CIAO1, CIAO2B and MMS19 (PubMed:23585563).
DNA-dependent ATPase and 5' to 3' DNA helicase required for the maintenance of chromosomal stability. Acts late in the Fanconi anemia pathway, after FANCD2 ubiquitination. Involved in the repair of DNA double-strand breaks by homologous recombination in a manner that depends on its association with BRCA1.
Phosphorylated. Phosphorylation is necessary for interaction with BRCA1, and is cell-cycle regulated.
Ubiquitously expressed, with highest levels in testis.
Expressed in brain, but not in lung, nor chondrocytes.
Palmitoylated by ZDHHC5. Palmitoylation is required for the maintenance of ZDHHC5 at the plasma membrane.
Play a role in cell adhesion by regulating the plasma membrane localization of the palmitoyltransferase ZDHHC5 (PubMed:31402609). May be involved in protein transport from Golgi to cell surface.
Shares an exon with the neighboring tail-to-tail oriented gene CRTAC1.
Belongs to the CDP-alcohol phosphatidyltransferase class-I family.
Ethanolaminephosphotransferase that catalyzes the transfer of phosphoethanolamine/PE from CDP-ethanolamine to lipid acceptors, the final step in the synthesis of PE via the 'Kennedy' pathway (PubMed:17132865, PubMed:28052917, PubMed:29500230). PE is the second most abundant phospholipid of membranes in mammals and is involved in various membrane-related cellular processes (PubMed:17132865). The enzyme is critical for the synthesis of several PE species and could also catalyze the synthesis of ether-linked phospholipids like plasmanyl- and plasmenyl-PE which could explain it is required for proper myelination and neurodevelopment (PubMed:29500230).
Widely expressed. Abundant in brain, placenta, liver and pancreas, followed by heart, skeletal muscle, lung and kidney. In brain it is strongly expressed in cerebellum, followed by the occipital pole and the frontal lobe.
Belongs to the eukaryotic ribosomal protein eS4 family.
A N-terminal fragment of KCTD11 isoform 2 (comprising residues 15 - 115) has been used for some KCTD11:CUL3 interaction studies.
Haploinsufficiency of KCTD11 may be a cause of development of medulloblastoma (MDB). MDB is a malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children. An allelic deletion involving genes from chromosome region 17p11.2-pter, sometimes restricted to 17p13.2-13.3, occurs in up to 50% of MDB.
Higher expression in cerebellum than in whole brain and lower expression in medulloblastoma.
Homopentamer. Interacts with KCTD6 and KCTD21; KCTD11 and KCTD6 or KCTD21 may associate in pentameric assemblies. Component of the BCR(KCTD11) E3 ubiquitin ligase complex, at least composed of CUL3 and KCTD11 and RBX1. Interacts (via BTB domain) with CUL3; initially a 4:4 stoichiometry has been reported, however, electron microscopy revealed pentameric states of the BTB domain.
Plays a role as a marker and a regulator of neuronal differentiation; Up-regulated by a variety of neurogenic signals, such as retinoic acid, epidermal growth factor/EGF and NGFB/nerve growth factor. Induces apoptosis, growth arrest and the expression of cyclin-dependent kinase inhibitor CDKN1B. Plays a role as a tumor repressor and inhibits cell growth and tumorigenicity of medulloblastoma (MDB). Acts as probable substrate-specific adapter for a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex towards HDAC1. Functions as antagonist of the Hedgehog pathway on cell proliferation and differentiation by affecting the nuclear transfer of transcription factor GLI1, thus maintaining cerebellar granule cells in undifferentiated state, this effect probably occurs via HDAC1 down-regulation, keeping GLI1 acetylated and inactive. When knock-down, Hedgehog antagonism is impaired and proliferation of granule cells is sustained. Activates the caspase cascade.
The BTB domain is required for growth-suppressing properties.
ATP- and membrane-binding protein that controls membrane reorganization/tubulation upon ATP hydrolysis (PubMed:25686250). In vitro causes tubulation of endocytic membranes (PubMed:24019528). Binding to phosphatidic acid induces its membrane tubulation activity (By similarity). Plays a role in endocytic transport. Involved in early endosome to recycling endosome compartment (ERC), retrograde early endosome to Golgi, and endosome to plasma membrane (rapid recycling) protein transport. Involved in the regulation of Golgi maintenance and morphology (PubMed:16251358, PubMed:17233914, PubMed:19139087, PubMed:23781025). Involved in the recycling of internalized D1 dopamine receptor (PubMed:21791287). Plays a role in cardiac protein trafficking probably implicating ANK2 (PubMed:20489164). Involved in the ventricular membrane targeting of SLC8A1 and CACNA1C and probably the atrial membrane localization of CACNA1GG and CACNA1H implicated in the regulation of atrial myocyte excitability and cardiac conduction (By similarity). In conjunction with EHD4 may be involved in endocytic trafficking of KDR/VEGFR2 implicated in control of glomerular function (By similarity). Involved in the rapid recycling of integrin beta-3 implicated in cell adhesion maintenance (PubMed:23781025). Involved in the unidirectional retrograde dendritic transport of endocytosed BACE1 and in efficient sorting of BACE1 to axons implicating a function in neuronal APP processing (By similarity). Plays a role in the formation of the ciliary vesicle, an early step in cilium biogenesis; possibly sharing redundant functions with EHD1 (PubMed:25686250).
Highly expressed in heart and brain and moderately expressed in kidney, liver, and placenta.
Homooligomer, and heterooligomer with EHD1, EHD2 and EHD4, ATP-binding is required for heterooligomerization (PubMed:16251358, PubMed:17233914). Interacts with PACSIN1 (By similarity). Interacts with PACSIN2 (By similarity). Interacts (via EH domain) with MICALL1 (PubMed:19864458). Interacts (via EH domain) with RAB11FIP2 (PubMed:16251358). Interacts with ANK2 (PubMed:20489164).
Central scaffolding component of the centrioles ensuring their 9-fold symmetry. Required for centrosome biogenesis and duplication: required both for mother-centriole-dependent centriole duplication and deuterosome-dependent centriole amplification in multiciliated cells. Overexpression results in excess foci-bearing centriolar markers. Required for the recruitment of STIL to the procentriole and for STIL-mediated centriole amplification (PubMed:22020124).
Nine homodimers form a cartwheel structure with an internal diameter of 23 nM and radial spokes connecting to the microtubule triplets (By similarity). Interacts with FBXW5 (PubMed:21725316). Forms a complex with CENPJ and STIL (PubMed:22020124). Interacts with NUP62 and TUBG1 at the centrosome (PubMed:24107630). Interacts with CENATAC; the interaction increases with CENATAC acetylation (PubMed:31722219). Interacts with FZR1; the interaction is regulated by CENATAC and leads to SASS6 proteasomal degradation (PubMed:31722219).
The 35 nM long coiled-coil domain mediates homodimerization while the globular N-terminus links the dimers at an angle of 40 degrees to form the inner ring.
Ubiquitinated by the SCF(FBXW5) E3 ubiquitin-protein ligase complex during S phase, leading to its degradation and preventing centriole reduplication. Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin-protein ligase complex, leading to its degradation and preventing centriole reduplication (PubMed:31722219).
Belongs to the BPI/LBP/Plunc superfamily. Plunc family.
Accessory component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids. Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules. The beta subunit may assist in binding of the phospholipid substrate (Probable). Can mediate the export of alpha subunits ATP8A1, ATP8B1, ATP8B2 and ATP8B4 from the ER to the plasma membrane.
Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit and an accessory beta subunit (Probable). Interacts with alpha subunits ATP8A1, ATP8B1, ATP8B2 and ATP8B4.
(Microbial infection) Acts as a receptor for nipah virus and hendra virus.
(Microbial infection) Interacts with nipah virus and hendra virus glycoprotein (PubMed:16477309, PubMed:17376907).
Cell surface transmembrane ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. May play a pivotal role in forebrain function. Binds to, and induce the collapse of, commissural axons/growth cones in vitro. May play a role in constraining the orientation of longitudinally projecting axons (By similarity).
Highly expressed in brain; expressed in embryonic floor plate, roof plate and hindbrain segments.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to an N-unsubstituted glucosamine linked to a 2-O-sulfo iduronic acid unit on heparan sulfate (PubMed:10520990, PubMed:9988768). Catalyzes the O-sulfation of glucosamine in IdoUA2S-GlcNS and also in IdoUA2S-GlcNH2 (PubMed:10520990, PubMed:9988768). The substrate-specific O-sulfation generates an enzyme-modified heparan sulfate which acts as a binding receptor to Herpes simplex virus-1 (HSV-1) and permits its entry (PubMed:10520990). Unlike HS3ST1/3-OST-1, does not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate (PubMed:9988768).
Ubiquitous. Most abundant in liver and placenta, followed by heart and kidney.
A stop codon at position Arg-236 in the gene coding for this protein is responsible for functional diversity thus producing a pseudogene.
Component of the cornified envelope of keratinocytes. May link the cornified envelope to desmosomes and intermediate filaments. May act as a localization signal in PKB/AKT-mediated signaling.
During differentiation of epidermal keratinocytes.
Expressed in stratified squamous epithelia and in some other epithelia.
Expressed in the epidermis, nuclei of dermal fibroblasts, cell periphery of flattened keratinocytes, and dermal and epithelial cells lining the excretory ducts of the sweat glands in neonatal foreskin.
Homodimer or a heterodimer with EVPL (PubMed:9412476). Found in a complex composed of PPL (via C-terminal linker domain), BFSP1 and BFSP2 in the retinal lens (By similarity). Within the complex interacts (via C-terminal linker domain) with BFSP2 (By similarity). Interacts with VIM (By similarity). Binds to the PH domain of AKT1 (PubMed:12244133). Interacts with FCGR1A (PubMed:15229321). May interact with PPHLN1 (PubMed:12853457).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Glycine receptor (TC 1.A.9.3) subfamily. GLRA3 sub-subfamily.
Glycine receptors are ligand-gated chloride channels. Channel opening is triggered by extracellular glycine (PubMed:9677400, PubMed:26416729). Channel characteristics depend on the subunit composition; heteropentameric channels display faster channel closure (By similarity). Plays an important role in the down-regulation of neuronal excitability (By similarity). Contributes to the generation of inhibitory postsynaptic currents (By similarity). Contributes to increased pain perception in response to increased prostaglandin E2 levels (By similarity). Plays a role in cellular responses to ethanol (By similarity).
Homopentamer (in vitro) (PubMed:26416729). Heteropentamer composed of GLRA3 and GLRB. Both homopentamers and heteropentamers form functional ion channels, but their characteristics are subtly different (By similarity).
Phosphorylated by PKA; this causes down-regulation of channel activity.
The N-terminal domain carries structural determinants essential for agonist and antagonist binding. The channel pore is formed by pentameric assembly of the second transmembrane domain from all five subunits (PubMed:26416729). The cytoplasmic loop is an important determinant of channel inactivation kinetics.
Widely distributed throughout the central nervous system.
Synthesis begins slightly higher in the hair shaft than HB1 and HB3 and continues much farther up, ending in the keratogeneous zone.
Catalyzes the transport of 2-oxoglutarate (alpha-oxoglutarate) across the inner mitochondrial membrane in an electroneutral exchange for malate. Can also exchange 2-oxoglutarate for other dicarboxylic acids such as malonate, succinate, maleate and oxaloacetate, although with lower affinity. Contributes to several metabolic processes, including the malate-aspartate shuttle, the oxoglutarate/isocitrate shuttle, in gluconeogenesis from lactate, and in nitrogen metabolism (By similarity). Maintains mitochondrial fusion and fission events, and the organization and morphology of cristae (PubMed:21448454). Involved in the regulation of apoptosis (By similarity). Helps protect from cytotoxic-induced apoptosis by modulating glutathione levels in mitochondria (By similarity).
GTF2IRD2 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region (PubMed:16532385).
Belongs to the LAPTM4/LAPTM5 transporter family.
May function in the transport of nucleosides and/or nucleoside derivatives between the cytosol and the lumen of an intracellular membrane-bound compartment.
The C-terminal domain is necessary for retention within intracellular membranes.
Interacts with C1QBP (PubMed:21536856). Interacts with RRP1B (PubMed:20926688).
Plays a critical role in the generation of 28S rRNA.
Ubiquitously expressed in fetal and adult tissues.
Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA). Specifically mediates the symmetrical dimethylation of SF3B2. Involved in the regulation of alternative splicing of pre-mRNA (PubMed:25737013, PubMed:25979344).
Found in a complex with PRMT9, SF3B2 and SF3B4 (PubMed:25737013). Interacts with SF3B2 (PubMed:25737013).
This protein should not be confused with FBXO11 (AC Q86XK2) that was initially erroneously named PRMT9.
Interacts with FKBP4 and FKBP1A (PubMed:8955134, PubMed:12604780, PubMed:11164950). Isoform 1: Interacts with RBX1 (via RING domain) (PubMed:22405651, PubMed:22748924). Identified in complexes that contain RBX1 plus one of the cullins CUL1, CUL2, CUL3, and CUL4A (PubMed:22405651, PubMed:22748924). Identified in a SCF complex composed of CUL1, RBX1, SKP1, FBXW7 and GLMN (PubMed:22405651). Component of a SCF-like complex consisting of CUL7, RBX1, SKP1, FBXW8 and GLMN (PubMed:12904573). Interacts with unphosphorylated MET and is released upon MET phosphorylation (PubMed:11571281).
Regulatory component of cullin-RING-based SCF (SKP1-Cullin-F-box protein) E3 ubiquitin-protein ligase complexes (PubMed:22405651, PubMed:22748924). Inhibits E3 ubiquitin ligase activity by binding to RBX1 (via RING domain) and inhibiting its interaction with the E2 ubiquitin-conjugating enzyme CDC34 (PubMed:22405651, PubMed:22748924). Inhibits RBX1-mediated neddylation of CUL1 (PubMed:22405651). Required for normal stability and normal cellular levels of key components of SCF ubiquitin ligase complexes, including FBXW7, RBX1, CUL1, CUL2, CUL3, CUL4A, and thereby contributes to the regulation of CCNE1 and MYC levels (By similarity). Essential for normal development of the vasculature (PubMed:11845407). Contributes to the regulation of RPS6KB1 phosphorylation (PubMed:11571281).
The C-terminal half of the protein is important for interaction with RBX1.
By EGF, TGFB1, retinoic acid- and 1,25-dihydroxyvitamin D(3).
Interacts with PTPN2. Interacts with microtubules. Interacts with VAPB. Interacts (via FFAT motif) with MOSPD2 (via MSP domain) (PubMed:29858488). Interacts (via phosphorylated FFAT motif) with MOSPD2, VAPA and VAPB (PubMed:33124732).
Involved in cellular calcium homeostasis regulation. May participate in differentiation and apoptosis of keratinocytes. Overexpression induces apoptosis.
Phosphorylation at Thr-160 of the FFAT motif activates interaction with MOSPD2, VAPA and VAPB.
Present at high level in epidermis and seminiferous epithelium: while basal cells in the epidermis and spermatogonia show no perceptible amount, keratinocytes of suprabasal layers and differentiating first-order spermatocytes up to spermatids exhibit high expression. In skeletal muscle, its presence is restricted to fibers of the fast twitch type. In surface epithelia containing ciliated cells, it is associated with the microtubular structures responsible for ciliary movement. Also present in specific structures of the central nervous system such as neurons of the hippocampal region, ganglion cells of the autonomic nervous system, and axons of the peripheral nervous system (at protein level). Widely expressed.
The FFAT motif is required for interaction with MOSPD2 (PubMed:29858488). The FFAT motif is involved in the interaction with VAPA and VAPB and its phosphorylation regulates these interactions (PubMed:33124732).
The transmembrane region is required for mitochondrial localization.
Expressed in normal prostate epithelial cells, and androgen-sensitive prostate adenocarcinoma cells. Not expressed in androgen-insensitive prostate adenocarcinoma cells.
Hypermethylation-mediated silencing of PXMP4 may be involved in prostate carcinogenesis. PXMP4 undergoes hypermethylation and silencing during the transition of prostate adenocarcinoma cells from androgen dependence to androgen independence.
Acts as a ligand for integrins, specifically ITGA5:ITGB1 and ITGAV:ITGB3; both integrins and the CD40 receptor are required for activation of CD40-CD40LG signaling, which have cell-type dependent effects, such as B-cell activation, NF-kappa-B signaling and anti-apoptotic signaling.
Cytokine that acts as a ligand to CD40/TNFRSF5 (PubMed:1280226, PubMed:31331973). Costimulates T-cell proliferation and cytokine production (PubMed:8617933). Its cross-linking on T-cells generates a costimulatory signal which enhances the production of IL4 and IL10 in conjunction with the TCR/CD3 ligation and CD28 costimulation (PubMed:8617933). Induces the activation of NF-kappa-B (PubMed:15067037, PubMed:31331973). Induces the activation of kinases MAPK8 and PAK2 in T-cells (PubMed:15067037). Induces tyrosine phosphorylation of isoform 3 of CD28 (PubMed:15067037). Mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL4 (By similarity). Involved in immunoglobulin class switching (By similarity).
Homotrimer (PubMed:8626375, PubMed:11676606, PubMed:8589998). Interacts with isoform 3 of CD28 (PubMed:15067037). CD40 ligand, soluble form: Exists as either a monomer or a homotrimer (PubMed:8626375, PubMed:31331973). Forms a ternary complex between CD40 and integrins for CD40-CD40LG signaling (PubMed:31331973).
N-linked glycan is a mixture of high mannose and complex type. Glycan structure does not influence binding affinity to CD40.
Specifically expressed on activated CD4+ T-lymphocytes.
Belongs to the transient receptor (TC 1.A.4) family. STrpC subfamily. TRPC7 sub-subfamily.
Interacts with MX1 and RNF24. Interacts (via ANK-repeat domains) with PRKG1.
Phosphorylation by PRKG1 at Thr-15 negatively regulates TRPC7 activity.
Thought to form a receptor-activated non-selective calcium permeant cation channel. Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Activated by diacylglycerol (DAG) (By similarity). May also be activated by intracellular calcium store depletion.
Inhibited by pyridoxal 5'-phosphate and bathophenanthroline.
Interacts (via N- and C-terminus peroxisomal targeting regions) with PEX19; the interaction occurs with the newly synthesized SLC25A17 in the cytosol.
Peroxisomal transporter for multiple cofactors like coenzyme A (CoA), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) and nucleotide adenosine monophosphate (AMP), and to a lesser extent for nicotinamide adenine dinucleotide (NAD(+)), adenosine diphosphate (ADP) and adenosine 3',5'-diphosphate (PAP). May catalyze the transport of free CoA, FAD and NAD(+) from the cytosol into the peroxisomal matrix by a counter-exchange mechanism.
The N- and C-terminal portions are exposed to the cytoplasm. Lacks a typical peroxisomal sorting signal. A region between helical transmembrane domains (TM) 4 and 5 and TM1-TM3 or TM4-TM6 are necessary for the peroxisome-targeting activity.
Was first identified as a peroxisomal ATP transporter (PubMed:12445829). However, later experiments showed that it acts as a peroxisomal transporter for multiple cofactors (PubMed:22185573).
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL7) composed of CUL1, SKP1, RBX1 and FBXL7 (By similarity). Interacts with AURKA; interaction takes place during mitosis but not in interphase (By similarity). Interacts with BIRC5; this interaction allows BIRC5 to be polyubiquitinated by the SCF(FBXL7) E3 ubiquitin-protein ligase complex (PubMed:28218735).
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex (PubMed:25778398). During mitosis, it mediates the ubiquitination and subsequent proteasomal degradation of AURKA, causing mitotic arrest (By similarity). It also regulates mitochondrial function by mediating the ubiquitination and proteasomal degradation of the apoptosis inhibitor BIRC5 (PubMed:25778398, PubMed:28218735).
On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for activin A, activin B and inhibin A (PubMed:17911401). Mediates induction of adipogenesis by GDF6 (By similarity).
Part of a complex consisting of MAGI2/ARIP1, ACVR2A, ACVR1B and SMAD3 (By similarity). Interacts with MAGI2/ARIP1 (By similarity). Interacts with type I receptor ACVR1 (PubMed:17911401). Interacts with BMP7 (PubMed:12667445). Interacts with TSC22D1/TSC-22 (PubMed:21791611).
Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B) and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific (Probable). Component of the BAF complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM, SMARCA4/BRG1, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C. In muscle cells, the BAF complex also contains DPF3 (PubMed:18765789). Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin (By similarity). Component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin (PubMed:22952240, PubMed:26601204). Component of SWI/SNF (GBAF) subcomplex, which includes at least BICRA or BICRAL (mutually exclusive), BRD9, SS18, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, SMARCC1/BAF155, and SMARCD1/BAF60A (PubMed:29374058). May also interact with the SIN3A histone deacetylase transcription repressor complex in conjunction with SMARCA2 and SMARCA4 (PubMed:11238380). The minimal complex composed of SMARCC1 and SMARCA4 seems to be able to associate with cyclin such as CCNE1 or transcription factors such as KLF1 or GATA1 (PubMed:9891079). Interacts with NR3C1 and SMARD1 (PubMed:12917342). Interacts with TRIP12; leading to disrupt interaction between TRIP12 and SMARCE1 and prevent SMARCE1 ubiquitination (PubMed:20111005). Interacts with CEBPB (when not methylated) (PubMed:20829358). Interacts with KDM6B (By similarity). Interacts with MKKS; the interaction takes place predominantly in the cytoplasm and may modulate SMARCC1 location (PubMed:28753627). Interacts with DPF2 (PubMed:28533407). Interacts with PRDM1/BLIMP1 (PubMed:32417234). Interacts with DPF3a (isoform 2 of DPF3/BAF45C) and with HDGFL2 in a DPF3a-dependent manner (PubMed:32459350).
Expressed in brain, heart, muscle, placenta, lung, liver, muscle, kidney and pancreas.
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. May stimulate the ATPase activity of the catalytic subunit of the complex (PubMed:10078207, PubMed:29374058). Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity).
Phosphorylated on undefined residues at the G2/M transition by ERK1 and other kinases. This may contribute to cell cycle specific inactivation of remodeling complexes containing the phosphorylated protein.
Does not contain a CXXC active site motif indicating that it is a catalytically redox-inactive member of the protein disulfide isomerase family.
Specifically binds unfolded proteins and may recruit protein disulfide isomerase PDIA3 to unfolded substrates (PubMed:16940051, PubMed:23192347). Binds protein substrates via a hydrophobic pocket in the C-terminal domain (PubMed:16940051, PubMed:23192347). May play a role in the unfolded stress response (PubMed:23192347).
Activated by an increase in cytosolic calcium levels that induce a conformational change of the N-terminal regulatory domain, uncapping the channel and allowing transport.
Electroneutral antiporter that most probably mediates the transport of adenyl nucleotides through the inner mitochondrial membrane. Originally identified as an ATP-magnesium/inorganic phosphate antiporter, it could have a broader specificity for adenyl nucleotides. By regulating the mitochondrial matrix adenyl nucleotide pool could adapt to changing cellular energetic demands and indirectly regulate adenyl nucleotide-dependent metabolic pathways.
Expression is restricted to kidney and lung.
Linker region/H9 could directly block the transport of substrates across the transporter.
The C-terminal mitochondrial carrier domain/transmembrane domain/TMD bears the transmembrane transporter activity.
The regulatory N-terminal domain/NTD, binds calcium in the mitochondrial intermembrane space and regulates the antiporter activity of the transmembrane domain/TMD. In absence of calcium, the apo form of the N-terminal domain is intrinsically disordered and binds to the transmembrane domain, inhibiting the transporter activity. Binding of calcium leads to a major conformational change and abolishes the interaction with the transmembrane domain and the inhibition of the transporter activity.
Widely expressed. Expressed in fetal and adult liver, skeletal muscle, testis, ovary, hippocampus and caudate nucleus.
Detected in liver, kidney, pancreas, prostate, spleen, small intestine and placenta, in particular in the syncytiotrophoblast.
Homodimer, and heterodimer with NHERF2. Binds the N-termini of EZR, RDX and MSN. Binds the C-termini of PDGFRA, PDGFRB, ADRB2, NOS2 and CFTR. Binds ARHGAP17, EPI64, RACK1, OPRK1, GNAQ, CTNNB1 and PLCB3. Binds PDZK1 (By similarity). Interacts with CLCN3. Binds the C-terminus of PAG1. In resting T-cells, part of a PAG1-NHERF1-MSN complex which is disrupted upon TCR activation. Forms a complex with CFTR and SLC4A7. Forms a complex with SLC4A7 and ATP6V1B1. Interacts with TRPC4 (via the PDZ-binding domain). Directly interacts with HTR4 (By similarity). Interacts (via the PDZ 1 domain) with PODXL (via the C-terminal PDZ-binding motif DTHL); interaction is not detected in glomerular epithelium cells. Interacts (via the PDZ 1 domain) with PODXL (via the C-terminal PDZ-binding motif DTHL); the interaction take place early in the secretory pathway and is necessary for its apical membrane sorting (By similarity). Interacts with SLC26A3 (By similarity). Interacts with MCC. Interacts with SLC34A1. Interacts (via the PDZ domains) with SLC26A6 isoform 4 and isoform 5. Interacts (via PDZ domains) with ACE2 (via PDZ-binding motif); the interaction may enhance ACE2 membrane residence (PubMed:34189428).
Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for recycling of internalized ADRB2. Was first known to play a role in the regulation of the activity and subcellular location of SLC9A3. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May enhance Wnt signaling. May participate in HTR4 targeting to microvilli (By similarity). Involved in the regulation of phosphate reabsorption in the renal proximal tubules. Involved in sperm capacitation. May participate in the regulation of the chloride and bicarbonate homeostasis in spermatozoa.
5'->3' double-stranded DNA exonuclease which may also possess a cryptic 3'->5' double-stranded DNA exonuclease activity. Functions in DNA mismatch repair (MMR) to excise mismatch-containing DNA tracts directed by strand breaks located either 5' or 3' to the mismatch. Also exhibits endonuclease activity against 5'-overhanging flap structures similar to those generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. Required for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes. Essential for male and female meiosis.
5'->3' double-stranded DNA exonuclease which may also possess a cryptic 3'->5' double-stranded DNA exonuclease activity. Functions in DNA mismatch repair.
Belongs to the XPG/RAD2 endonuclease family. EXO1 subfamily.
Highly expressed in bone marrow, testis and thymus. Expressed at lower levels in colon, lymph nodes, ovary, placenta, prostate, small intestine, spleen and stomach.
Highly expressed in fetal liver and at lower levels in fetal brain, heart, kidney, spleen and thymus.
Interacts with the MLH1-PMS2 heterodimer via MLH1. Interacts with MSH3. Interacts with the MSH2-MSH6 heterodimer via MSH2, and this interaction may increase the processivity of the 5'->3' exonuclease activity. Interacts with PCNA, and this interaction may both stimulate the cryptic 3'->5' exonuclease activity and suppress the 5'->3' exonuclease activity. Interacts with WRN, and this interaction stimulates both the 5'->3' exonuclease activity and cleavage of 5'-overhanging flap structures. Interacts with RECQL/RECQ1, and this interaction stimulates cleavage of 5'-overhanging flap structures.
Most naturally occurring variants in this protein are not associated with familial disposition to hereditary non-polyposis colorectal cancer (HNPCC) (PubMed:12517792). Furthermore, germline deletions involving this locus are not associated with clinically manifested colorectal tumors (PubMed:14623461).
Phosphorylated upon DNA damage and in response to agents stalling DNA replication, probably by ATM or ATR. Phosphorylation at Ser-454, Thr-621 and Ser-714 is induced upon DNA-damage caused by treatment with hydroxyurea (HU) but not upon IR treatment. The HU-induced EXO1 triple phosphorylation facilitates destabilization/degradation of the protein.
AMP deaminase plays a critical role in energy metabolism.
Belongs to the metallo-dependent hydrolases superfamily. Adenosine and AMP deaminases family.
A conformation change in the N-terminal region spanning the first 42 residues plays an important role in the regulation of enzyme activity by malonyl-CoA.
Belongs to the carnitine/choline acetyltransferase family.
Catalyzes the transfer of the acyl group of long-chain fatty acid-CoA conjugates onto carnitine, an essential step for the mitochondrial uptake of long-chain fatty acids and their subsequent beta-oxidation in the mitochondrion (PubMed:9691089, PubMed:11350182, PubMed:14517221). Plays an important role in hepatic triglyceride metabolism (By similarity).
Homohexamer and homotrimer (By similarity). Identified in a complex that contains at least CPT1A, ACSL1 and VDAC1 (By similarity). Also identified in complexes with ACSL1 and VDAC2 and VDAC3 (By similarity).
Strong expression in kidney and heart, and lower in liver and skeletal muscle.
Catalyzes uridine to pseudouridine isomerization (pseudouridylation) of different mitochondrial RNA substrates (PubMed:27974379, PubMed:28082677). Acts on position 1397 in 16S mitochondrial ribosomal RNA (16S mt-rRNA) (PubMed:27974379). This modification is required for the assembly of 16S mt-rRNA into a functional mitochondrial ribosome (PubMed:27974379). As a component of a functional protein-RNA module, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mt-rRNA, controls 16S mt-rRNA abundance and is required for intra-mitochondrial translation (PubMed:27667664). Acts on position 39 in mitochondrial tRNA(Phe) (PubMed:28082677). Also catalyzes pseudouridylation of mRNAs in nucleus: acts as a regulator of pre-mRNA splicing by mediating pseudouridylation of pre-mRNAs at locations associated with alternatively spliced regions (PubMed:35051350). Pseudouridylation of pre-mRNAs near splice sites directly regulates mRNA splicing and mRNA 3'-end processing (PubMed:35051350).
Interacts with 16S mt-rRNA, mt-tRNA(Phe) and mt-tRNA(Met) (PubMed:28082677). Forms a regulatory protein-RNA complex, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mt-rRNA (PubMed:27667664).
Acetylation at Lys-250 regulates its degradation and timing in anaphase entry.
Autophosphorylated in vitro. Intramolecular autophosphorylation is stimulated by CENPE. Phosphorylated during mitosis and hyperphosphorylated in mitotically arrested cells. Phosphorylation at Ser-670 and Ser-1043 occurs at kinetochores upon mitotic entry with dephosphorylation at the onset of anaphase.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. BUB1 subfamily.
Defects in BUB1B are associated with tumor formation.
Essential component of the mitotic checkpoint. Required for normal mitosis progression. The mitotic checkpoint delays anaphase until all chromosomes are properly attached to the mitotic spindle. One of its checkpoint functions is to inhibit the activity of the anaphase-promoting complex/cyclosome (APC/C) by blocking the binding of CDC20 to APC/C, independently of its kinase activity. The other is to monitor kinetochore activities that depend on the kinetochore motor CENPE. Required for kinetochore localization of CENPE. Negatively regulates PLK1 activity in interphase cells and suppresses centrosome amplification. Also implicated in triggering apoptosis in polyploid cells that exit aberrantly from mitotic arrest. May play a role for tumor suppression.
Highly expressed in thymus followed by spleen. Preferentially expressed in tissues with a high mitotic index.
Interacts with CENPE (PubMed:12925705, PubMed:19625775). Interacts with PLK1 (PubMed:16760428, PubMed:17785528, PubMed:17376779, PubMed:19503101). Part of a complex containing BUB3, CDC20 and BUB1B (PubMed:11702782). Interacts with anaphase-promoting complex/cyclosome (APC/C) (PubMed:10477750). Interacts with KNL1 (PubMed:17981135). Interacts with KAT2B (PubMed:19407811). Interacts with RIPK3 (PubMed:29883609). Interacts with the closed conformation form of MAD2L1 (PubMed:29162720).
Proteolytically cleaved by caspase-3 in a cell cycle specific manner. The cleavage might be involved in the durability of the cell cycle delay. Caspase-3 cleavage is associated with abrogation of the mitotic checkpoint. The major site of cleavage is at Asp-610.
Sumoylated with SUMO2 and SUMO3. The sumoylation mediates the association with CENPE at the kinetochore.
The BUB1 N-terminal domain directs kinetochore localization and binding to BUB3.
The D-box targets the protein for rapid degradation by ubiquitin-dependent proteolysis during the transition from mitosis to interphase.
The disease is caused by variants affecting the gene represented in this entry. MVA1 is caused by biallelic mutations in the BUB1B gene.
Ubiquitinated. Degraded by the proteasome.
Cleavage of the N-terminal propeptide which is composed of 7 amino acids occurs in two steps. The initial cleavage of 5 amino acids is followed by the cleavage of a dipeptide to produce the mature form.
This is a neutrophil granule-derived antibacterial and monocyte- and fibroblast-specific chemotactic glycoprotein. Binds heparin. The cytotoxic action is limited to many species of Gram-negative bacteria; this specificity may be explained by a strong affinity of the very basic N-terminal half for the negatively charged lipopolysaccharides that are unique to the Gram-negative bacterial outer envelope. It may play a role in mediating recruitment of monocytes in the second wave of inflammation. Has antibacterial activity against the Gram-negative bacterium P.aeruginosa, this activity is inhibited by LPS from P.aeruginosa. Acting alone, it does not have antimicrobial activity against the Gram-negative bacteria A.actinomycetemcomitans ATCC 29532, A.actinomycetemcomitans NCTC 9709, A.actinomycetemcomitans FDC-Y4, H.aphrophilus ATCC 13252, E.corrodens ATCC 23834, C.sputigena ATCC 33123, Capnocytophaga sp ATCC 33124, Capnocytophaga sp ATCC 27872 or E.coli ML-35. Has antibacterial activity against C.sputigena ATCC 33123 when acting synergistically with either elastase or cathepsin G.
Fast twitching myosin mediating the high-velocity and low-tension contractions of specific striated muscles.
Specifically expressed in extraocular and laryngeal muscles.
The head-like domain S1 exhibits a much faster ATP-induced detachment from actin, and ADP affinity is more than 3-fold weaker than other myosins.
Promotes meiotic crossing over formation through its interaction with CNTD1 by participating in the crossover differentiation step of crossover-specific recombination intermediates.
Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family.
Expressed in skeletal muscles and testis. Overexpressed in a majority of colorectal and hepatocellular carcinomas.
Histone methyltransferase activity strongly stimulated by HSPCA.
Histone methyltransferase. Specifically methylates 'Lys-4' of histone H3, inducing di- and tri-methylation, but not monomethylation (PubMed:15235609, PubMed:22419068). Also methylates 'Lys-5' of histone H4 (PubMed:22419068). Plays an important role in transcriptional activation as a member of an RNA polymerase complex (PubMed:15235609). Binds DNA containing 5'-CCCTCC-3' or 5'-GAGGGG-3' sequences (PubMed:15235609).
Interacts with HSPCA (PubMed:15235609). Interacts with HELZ (PubMed:15235609). Interacts with POLR2A; the interaction may be indirect and may be mediated by HELZ (PubMed:15235609). Interacts with HSP90AA1; this interaction enhances SMYD3 histone-lysine N-methyltransferase (PubMed:25738358).
Multifunctional protein with various roles in different cellular compartments. May act in a redox sensitive manner. Associates with chromatin and binds DNA with a preference for non-canonical DNA structures such as single-stranded DNA. Can bend DNA and enhance DNA flexibility by looping thus providing a mechanism to promote activities on various gene promoters (By similarity). Proposed to be involved in the innate immune response to nucleic acids by acting as a cytoplasmic promiscuous immunogenic DNA/RNA sensor (By similarity). Negatively regulates B-cell and myeloid cell differentiation. In hematopoietic stem cells may regulate the balance between self-renewal and differentiation. Involved in negative regulation of canonical Wnt signaling (By similarity).
Reduction/oxidation of cysteine residues Cys-23, Cys-45 and Cys-104 and a possible intramolecular disulfide bond involving Cys-23 and Cys-45 give rise to different redox forms with specific functional activities in various cellular compartments: 1- fully reduced HMGB3 (HMGB3C23hC45hC104h), 2- disulfide HMGB3 (HMGB3C23-C45C104h) and 3- sulfonyl HMGB3 (HMGB3C23soC45soC104so).
Belongs to the protein-tyrosine phosphatase family. Receptor class 4 subfamily.
Integrin binding to extracellular matrix induces phosphorylation at Tyr-798 which induces PTPRA localization and recruitment of BCAR3, BCAR1 and CRK to focal adhesions.
Part of a complex comprised of PTPRA, BCAR1, BCAR3 (via SH2 domain), and SRC (PubMed:22801373). Within the complex, interacts (when phosphorylated on Tyr-798) with BCAR3 (via SH2 domain) (PubMed:22801373). Interacts with GRB2 (PubMed:22801373).
Tyrosine protein phosphatase which is involved in integrin-mediated focal adhesion formation (By similarity). Following integrin engagement, specifically recruits BCAR3, BCAR1 and CRK to focal adhesions thereby promoting SRC-mediated phosphorylation of BRAC1 and the subsequent activation of PAK and small GTPase RAC1 and CDC42 (By similarity).
Both N- and C-terminal domains are required for transcriptional activation.
Component of the NF-kappa-B RelB-p50 complex. Component of the NF-kappa-B RelB-p52 complex. Self-associates; the interaction seems to be transient and may prevent degradation allowing for heterodimer formation with p50 or p52. Interacts with NFKB1/p50, NFKB2/p52 and NFKB2/p100. Interacts with NFKBID. Interacts with BMAL1 and the interaction is enhanced in the presence of CLOCK (By similarity).
NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric RelB-p50 and RelB-p52 complexes are transcriptional activators. RELB neither associates with DNA nor with RELA/p65 or REL. Stimulates promoter activity in the presence of NFKB2/p49. As a member of the NUPR1/RELB/IER3 survival pathway, may provide pancreatic ductal adenocarcinoma with remarkable resistance to cell stress, such as starvation or gemcitabine treatment. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer in a CRY1/CRY2 independent manner. Increased repression of the heterodimer is seen in the presence of NFKB2/p52. Is required for both T and B lymphocyte maturation and function (PubMed:26385063).
Phosphorylation at 'Thr-103' and 'Ser-573' is followed by proteasomal degradation.
Was originally thought to inhibit the transcriptional activity of nuclear factor NF-kappa-B.
5-fluoro-1,3-dihydro-1-hydroxy-1,2-benzoxaborole inhibits LARS1 by forming a covalent adduct with the 3' adenosine of tRNA(Leu) at the editing site, thus locking the enzyme in an inactive conformation.
Catalyzes the specific attachment of an amino acid to its cognate tRNA in a two step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. Exhibits a post-transfer editing activity to hydrolyze mischarged tRNAs.
Cell surface receptor for PLXNB2. May play a role in axon guidance (By similarity).
Associates with SLC3A2 to form a functional heterodimeric complex that translocates small and large neutral amino acids with broad specificity and a stoichiometry of 1:1. Functions as amino acid antiporter mediating the influx of extracellular essential amino acids mainly in exchange with the efflux of highly concentrated intracellular amino acids (PubMed:10391915, PubMed:15918515, PubMed:11311135, PubMed:11847106, PubMed:12716892, PubMed:15081149, PubMed:29355479, PubMed:33298890, PubMed:34848541). Has relatively symmetrical selectivities but strongly asymmetrical substrate affinities at both the intracellular and extracellular sides of the transporter (PubMed:11847106). This asymmetry allows SLC7A8 to regulate intracellular amino acid pools (mM concentrations) by exchange with external amino acids (uM concentration range), equilibrating the relative concentrations of different amino acids across the plasma membrane instead of mediating their net uptake (PubMed:11847106, PubMed:10391915). May play an essential role in the reabsorption of neutral amino acids from the epithelial cells to the bloodstream in the kidney (PubMed:12716892). Involved in the uptake of methylmercury (MeHg) when administered as the L-cysteine or D,L-homocysteine complexes, and hence plays a role in metal ion homeostasis and toxicity (PubMed:12117417). Involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the transmembrane (PubMed:15769744). Imports the thyroid hormone diiodothyronine (T2) and to a smaller extent triiodothyronine (T3) but not rT 3 or thyroxine (T4) (By similarity). Mediates the uptake of L-DOPA (By similarity). May participate in auditory function (By similarity).
Belongs to the amino acid-polyamine-organocation (APC) superfamily. L-type amino acid transporter (LAT) (TC 2.A.3.8) family.
Disulfide-linked heterodimer composed of the catalytic light chain subunit SLC7A8 and the heavy chain subunit SLC3A2. SLC3A2 acts as chaperones for correct plasma membrane trafficking and stabilization of SLC7A8 and modulates the substrate affinity and specificity of SLC7A8 (PubMed:10391915, PubMed:10574970, PubMed:15918515, PubMed:11311135, PubMed:15769744, PubMed:33066406, PubMed:33298890, PubMed:34848541). ICAM-1 associates with the heterodimer SLC3A2/SLC7A8; this interaction regulates SLC7A8 activity (PubMed:12716892).
Inhibited by the L-type inhibitor 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH).
Strongest expression is observed in kidney and moderate expression in placenta and brain, followed by liver, prostate, testis, ovary, lymph node, thymus, spleen, skeletal muscle and heart. Also expressed in fetal liver as well as in the retinal pigment epithelial cell line ARPE-19 and the intestinal epithelial cell line Caco-2.
Expressed in adipocytes (PubMed:31010960). Expressed in blood cells, with higher expression in patients with low coronary lesions (PubMed:27586541).
May play a role in fatty acid biosynthesis and insulin sensitivity.
Acts as a mediator between the cap-binding complex (CBC) and the primary microRNAs (miRNAs) processing machinery during cell proliferation. Contributes to the stability and delivery of capped primary miRNA transcripts to the primary miRNA processing complex containing DGCR8 and DROSHA, thereby playing a role in RNA-mediated gene silencing (RNAi) by miRNAs. Binds capped RNAs (m7GpppG-capped RNA); however interaction is probably mediated via its interaction with NCBP1/CBP80 component of the CBC complex. Involved in cell cycle progression at S phase. Does not directly confer arsenite resistance but rather modulates arsenic sensitivity. Independently of its activity on miRNAs, necessary and sufficient to promote neural stem cell self-renewal. Does so by directly binding SOX2 promoter and positively regulating its transcription (By similarity).
Interacts with NCBP1 and DROSHA (By similarity). Interacts with CASP8AP2 and ERBB4. Interacts with LUZP4. Interacts with NCBP2/CBP20 and NCBP3 (PubMed:26382858). Interacts with MTREX (PubMed:30842217).
(Microbial infection) Acts as a host factor for picornaviruses: required during early infection to promote viral genome release into the cytoplasm (PubMed:28077878). May act as a cellular sensor of membrane damage at sites of virus entry, which relocalizes to sites of membrane rupture upon virus unfection (PubMed:28077878). Facilitates safe passage of the RNA away from LGALS8, enabling viral genome translation by host ribosome (PubMed:28077878). May also be involved in initiating pore formation, increasing pore size or in maintaining pores for genome delivery (PubMed:28077878). The lipid-modifying enzyme activity is required for this process (PubMed:28077878).
Exhibits both phospholipase A1/2 and acyltransferase activities (PubMed:19615464, PubMed:19047760, PubMed:22825852, PubMed:22605381, PubMed:26503625). Shows phospholipase A1 (PLA1) and A2 (PLA2) activity, catalyzing the calcium-independent release of fatty acids from the sn-1 or sn-2 position of glycerophospholipids (PubMed:19615464, PubMed:19047760, PubMed:22825852, PubMed:22605381, PubMed:22923616). For most substrates, PLA1 activity is much higher than PLA2 activity (PubMed:19615464). Shows O-acyltransferase activity,catalyzing the transfer of a fatty acyl group from glycerophospholipid to the hydroxyl group of lysophospholipid (PubMed:19615464). Shows N-acyltransferase activity, catalyzing the calcium-independent transfer of a fatty acyl group at the sn-1 position of phosphatidylcholine (PC) and other glycerophospholipids to the primary amine of phosphatidylethanolamine (PE), forming N-acylphosphatidylethanolamine (NAPE), which serves as precursor for N-acylethanolamines (NAEs) (PubMed:19615464, PubMed:19047760, PubMed:22825852, PubMed:22605381). Exhibits high N-acyltransferase activity and low phospholipase A1/2 activity (PubMed:22825852). Required for complete organelle rupture and degradation that occur during eye lens terminal differentiation, when fiber cells that compose the lens degrade all membrane-bound organelles in order to provide lens with transparency to allow the passage of light. Organelle membrane degradation is probably catalyzed by the phospholipase activity (By similarity).
Interacts with PPP2R1A; this interaction might decrease PP2A activity.
The C-terminal transmembrane domain is required for the targeting of the protein to damaged organelles.
Widely expressed. low expression, if any, in hematopoietic cells and thymus. In testis, confined to round spermatids. Expressed in normal ovarian epithelial cells. Down-regulated in some ovarian carcinomas and testicular germ cell tumors. Highly expressed in white adipose tissue (PubMed:19136964).
Belongs to the bacterial ribosomal protein bL19 family.
Interacts (via PxIxIT motif, when phosphorylated on Thr-44) with PPP3CA.
May act as a prognostic marker of median survival time in pancreatic cancer patients.
Not expressed in pancreatic duct cells (at protein level). Abundantly expressed in the lymph node and weakly expressed in the stomach, trachea and bone marrow.
Not expressed in pancreatic duct cells (at protein level). Abundantly expressed in the pancreas and weakly expressed in the thyroid.
Belongs to the HMG-CoA reductase family.
Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis (PubMed:2991281, PubMed:21357570, PubMed:6995544). HMGCR is the main target of statins, a class of cholesterol-lowering drugs (PubMed:11349148, PubMed:18540668).
Detected in the cerebellum, fetal brain, testis and adrenal gland.
Homotetramer (PubMed:10698924). Homodimer (PubMed:10698924). Interacts (via its SSD) with INSIG1; the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway (PubMed:12535518, PubMed:19458199). Interacts with UBIAD1 (PubMed:23169578).
Low abundance except in skin, esophagus, and uterine cervix.
N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner.
Phosphorylated. Phosphorylation at Ser-872 reduces the catalytic activity.
Regulated by a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate (PubMed:6995544). Phosphorylation at Ser-872 down-regulates the catalytic activity (By similarity). Inhibited by statins, a class of hypolipidemic agents used as pharmaceuticals to lower cholesterol levels in individuals at risk from cardiovascular disease due to hypercholesterolemia (PubMed:11349148, PubMed:18540668). Inhibition of HMGCR in the liver stimulates the LDL-receptors, which results in an increased clearance of LDL from the bloodstream and a decrease in blood cholesterol levels (PubMed:11349148, PubMed:18540668). The first results can be seen after one week of statin use and the effect is maximal after four to six weeks (PubMed:11349148, PubMed:18540668).
Ubiquitously expressed with the highest levels in the cerebellum, fetal brain, testis, skin and adrenal gland.
Undergoes sterol-mediated ubiquitination and ER-associated degradation (ERAD) (PubMed:12535518, PubMed:19458199, PubMed:21778231). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1 or INSIG2 (PubMed:12535518, PubMed:19458199, PubMed:21778231, PubMed:22143767). The INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, RNF139 or RNF145, initiating ubiquitination of the reductase (PubMed:12535518, PubMed:19458199, PubMed:21778231). The ubiquitinated reductase is then extracted from the ER membrane and delivered to cytosolic 26S proteosomes by a mechanism probably mediated by the ATPase Valosin-containing protein VCP/p97 (PubMed:12535518, PubMed:19458199, PubMed:21778231). The INSIG2-binding leads to the recruitment of the ubiquitin ligase RNF139, initiating ubiquitination of the reductase (PubMed:22143767). Lys-248 is the main site of ubiquitination (PubMed:19458199). Ubiquitination is enhanced by the presence of a geranylgeranylated protein (PubMed:21778231).
(Microbial infection) Cleaves Neisseria meningitidis NHBA in saliva; Neisseria is an obligate commensal of the nasopharyngeal mucosa.
Genetic variations in KLK1 are the cause of a decreased in urinary kallikrein activity [MIM:615953]. The His-77 mutation dramatically reduces the activity of the enzyme in the urine. There is a 50 to 60% reduction in urinary kallikrein activity in His-77 individuals, but renal and hormonal adaptation to dietary changes in sodium and potassium are unaffected. However, in studies of brachial artery function, His-77 individuals consistently exhibited an increase in wall shear stress and a paradoxical reduction in artery diameter and lumen compared to Arg-77 individuals. This partial genetic deficiency in kallikrein activity is associated with a form of arterial dysfunction involving inappropriate inward remodeling of the brachial artery despite a chronic increase in shear stress.
Isoform 2 is expressed in pancreas, salivary glands, kidney, colon, prostate gland, testis, spleen and the colon adenocarcinoma cell line T84.
The O-linked polysaccharides on Ser-93, Ser-104 and Ser-167 are probably the mucin type linked to GalNAc. In PubMed:3163150, GalNAc was detected with the corresponding peptides but not located.
Belongs to the class-II aminoacyl-tRNA synthetase family. Type 2 subfamily.
Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.
Expression in the developing and adult brain shows similar patterns. Highly expressed in the ventricular and subventricular zones, including hippocampal subfields, the midlateral temporal cortex and the frontal polar cortex. The cerebellum, cerebral cortex, hippocampus, and lateral ventricle show preferential neuronal expression. Expression in the peripheral neurons is evident in the colon.
Homodimer (PubMed:23609930). Part of a multisubunit complex that groups tRNA ligases for Arg (RARS1), Asp (DARS1), Gln (QARS1), Ile (IARS1), Leu (LARS1), Lys (KARS1), Met (MARS1) the bifunctional ligase for Glu and Pro (EPRS1) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18 (PubMed:19131329, PubMed:19289464).
(Microbial infection) Interacts with Human herpesvirus 8 protein ORF16; may sequester ORF16 in host nucleolus and reduce its antiapoptotic activity.
(Microbial infection) Interacts with herpes simplex virus 1 early proteins ICP22 and ICP0.
Down-regulated by nucleolar stress through ubiquitin-independent proteasomal degradation (at protein level) (PubMed:24923447). Up-regulated upon mitochondrial stress (at protein level) (PubMed:24556985). Expression of the protein might be regulated by DNA damage but results are not consistent (PubMed:21741933, PubMed:27829214).
Expressed at high levels in heart and pancreas, moderate levels in placenta, liver, skeletal muscle, and kidney, and low levels in brain and lung.
Homooligomer (PubMed:24735870, PubMed:26903295). Interacts with PTEN; regulates PTEN phosphorylation and increases its stability (PubMed:15355975). Interacts with RPL11; retains RPL11 into the nucleolus (PubMed:24556985, PubMed:27829214). Interacts with CDKN2A/isoform tumor suppressor ARF; the interaction is direct and promotes ARF nucleoplasmic relocalization and ubiquitin-mediated proteasomal degradation (PubMed:27323397). Interacts with NPM1; the interaction is direct and competitive with MYC (PubMed:25956029). Interacts with NF2 (via FERM domain); the interaction is direct (PubMed:21167305). Interacts with p53/TP53 (via the oligomerization region); the interaction is direct and may prevent the MDM2-mediated proteasomal degradation of p53/TP53 (PubMed:22522597). Interacts with RIGI; may regulate RIGI through USP15-mediated 'Lys-63'-linked deubiquitination (PubMed:27824081). Interacts with UBTF (PubMed:27729611).
Nucleolar protein which is involved in the integration of the 5S RNP into the ribosomal large subunit during ribosome biogenesis (PubMed:24120868). In ribosome biogenesis, may also play a role in rRNA transcription (PubMed:27729611). Also functions as a nucleolar sensor that regulates the activation of p53/TP53 in response to ribosome biogenesis perturbation, DNA damage and other stress conditions (PubMed:21741933, PubMed:24120868, PubMed:27829214). DNA damage or perturbation of ribosome biogenesis disrupt the interaction between NOP53 and RPL11 allowing RPL11 transport to the nucleoplasm where it can inhibit MDM2 and allow p53/TP53 activation (PubMed:24120868, PubMed:27829214). It may also positively regulate the function of p53/TP53 in cell cycle arrest and apoptosis through direct interaction, preventing its MDM2-dependent ubiquitin-mediated proteasomal degradation (PubMed:22522597). Originally identified as a tumor suppressor, it may also play a role in cell proliferation and apoptosis by positively regulating the stability of PTEN, thereby antagonizing the PI3K-AKT/PKB signaling pathway (PubMed:15355975, PubMed:16971513, PubMed:27729611). May also inhibit cell proliferation and increase apoptosis through its interaction with NF2 (PubMed:21167305). May negatively regulate NPM1 by regulating its nucleoplasmic localization, oligomerization and ubiquitin-mediated proteasomal degradation (PubMed:25818168). Thereby, may prevent NPM1 interaction with MYC and negatively regulate transcription mediated by the MYC-NPM1 complex (PubMed:25956029). May also regulate cellular aerobic respiration (PubMed:24556985). In the cellular response to viral infection, may play a role in the attenuation of interferon-beta through the inhibition of RIGI (PubMed:27824081).
Phosphorylated upon DNA damage probably by ATM and DNA-PK; may regulate NOP53 degradation.
Ubiquitin-mediated proteasomal degradation is regulated by c-JUN. It is associated with relocalization to the nucleoplasm and decreased homooligomerization.
Despite its name, the presence of HEAT repeat is unsure and is not confirmed by repeat-detection programs.
Belongs to the DEAD box helicase family. DDX55/SPB4 subfamily.
The Q motif is unique to and characteristic of the DEAD box family of RNA helicases and controls ATP binding and hydrolysis.
Coreceptor for SEMA3A. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance in the developing nervous system. Class 3 semaphorins bind to a complex composed of a neuropilin and a plexin. The plexin modulates the affinity of the complex for specific semaphorins, and its cytoplasmic domain is required for the activation of down-stream signaling events in the cytoplasm (By similarity).
F-box-like protein which is required for entry into mitosis. Acts by participating in E3 ligase complexes that mediate the ubiquitination and degradation of WEE1 kinase at G2/M phase (By similarity).
Interacts with SKP1. Part of a SCF (SKP1-cullin-F-box) protein ligase complex (By similarity).
The KEN box is required for the association with the APC/C-Cdh1 complex.
Ubiquitinated and degraded by the APC/C-Cdh1 complex.
Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively) (PubMed:7742312, PubMed:11916951, PubMed:15277402, PubMed:17082186, PubMed:18322640, PubMed:19146401, PubMed:25015100, PubMed:8325892). Compared to other hexokinases, has a weak affinity for D-glucose, and is effective only when glucose is abundant (By similarity). Mainly expressed in pancreatic beta cells and the liver and constitutes a rate-limiting step in glucose metabolism in these tissues (PubMed:18322640, PubMed:25015100, PubMed:8325892, PubMed:11916951, PubMed:15277402). Since insulin secretion parallels glucose metabolism and the low glucose affinity of GCK ensures that it can change its enzymatic activity within the physiological range of glucose concentrations, GCK acts as a glucose sensor in the pancreatic beta cell (By similarity). In pancreas, plays an important role in modulating insulin secretion (By similarity). In liver, helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage (By similarity). Required to provide D-glucose 6-phosphate for the synthesis of glycogen (PubMed:8878425). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (PubMed:7742312).
Monomer (PubMed:15016359, PubMed:19362831, PubMed:23957911). Interacts with MIDN; the interaction occurs preferentially at low glucose levels and results in inhibition of hexokinase activity (PubMed:24187134). Interacts with GCKR; leading to sequestration in the nucleus (PubMed:10456334).
Subject to allosteric regulation (PubMed:15016359). Low glucose and high fructose-6-phosphate triggers association with the inhibitor GCKR followed by sequestration in the nucleus (PubMed:10456334).
Homodimer. Interacts with HOOK1. Interacts with HOOK2. Interacts with HOOK3.
Microtubule-binding protein that localizes to the microtubular manchette of elongating spermatids.
Autophosphorylated on Tyr-713. Phosphorylated by LYN in response to FCER1 activation. Phosphorylated by HCK.
Belongs to the protein kinase superfamily. Tyr protein kinase family. Fes/fps subfamily.
Cellular homolog of retroviral oncogenes. In contrast to the viral oncoproteins, the kinase activity of cellular FSP/FES is tightly regulated, and the kinase is inactive in normal cells in the absence of activating stimuli (PubMed:15485904).
Has been shown to act as proto-oncogene in some types of cancer, possibly due to abnormal activation of the kinase. Has been shown to act as tumor suppressor in other types of cancer. Expressed and present as activated kinase in a subset of acute myeloid leukemia patients; promotes survival of leukemia cells (PubMed:20111072). Expression is absent in K562 leukemia cells; ectopic expression of FSP/FES restores myeloid differentiation (PubMed:2656706). May function as tumor suppressor in colorectal cancer; expression is reduced or absent in samples from some colon cancer patients (PubMed:16455651). May function as tumor suppressor in melanoma by preventing melanoma cell proliferation; expression is reduced or absent in samples from some melanoma patients (PubMed:28463229). Ectopic expression of FSP/FES suppresses anchorage-independent growth in colon cancer cell lines (PubMed:16455651). Up-regulated in prostate cancer, and might be a predictor of recurrence after radical surgery (PubMed:16455651). May promote growth of renal carcinoma cells (PubMed:19082481).
Homooligomer. Interacts with BCR. Interacts (when activated, via coiled coil domain) with TRIM28. Interacts (via SH2 domain) with phosphorylated EZR, MS4A2/FCER1B and HCLS1/HS1. Interacts with phosphorylated KIT. Interacts with FLT3. Interacts (via F-BAR domain) with soluble tubulin. Interacts (via SH2 domain) with microtubules.
Kinase activity is tightly regulated. Activated in response to signaling from a cell surface receptor. Activation probably requires binding of a substrate via the SH2 domain, plus autophosphorylation at Tyr-713. Present in an inactive form in the absence of activating stimuli.
The N-terminal region including the first coiled coil domain mediates interaction with phosphoinositide-containing membranes.
The coiled coil domains are important for regulating the kinase activity. They mediate homooligomerization and probably also interaction with other proteins.
Tyrosine-protein kinase that acts downstream of cell surface receptors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, cell attachment and cell spreading. Plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Acts down-stream of the activated FCER1 receptor and the mast/stem cell growth factor receptor KIT. Plays a role in the regulation of mast cell degranulation. Plays a role in the regulation of cell differentiation and promotes neurite outgrowth in response to NGF signaling. Plays a role in cell scattering and cell migration in response to HGF-induced activation of EZR. Phosphorylates BCR and down-regulates BCR kinase activity. Phosphorylates HCLS1/HS1, PECAM1, STAT3 and TRIM28.
Widely expressed. Detected in adult colon epithelium (at protein level) (PubMed:16455651, PubMed:19051325). Expressed in melanocytes (at protein level) (PubMed:28463229).
Belongs to the autoinducer-2 exporter (AI-2E) (TC 2.A.86) family.
Endoplasmic reticulum 2-OH acyl-CoA lyase involved in the cleavage (C1 removal) reaction in the fatty acid alpha-oxydation in a thiamine pyrophosphate (TPP)-dependent manner. Involved in the phytosphingosine degradation pathway.
Expressed in all tissues tested, with highest expression in heart, pancreas and placenta.
Sequence of unknown origin at the C-terminus.
Can bind at least three actin monomers and thereby provides a nucleus for actin filament formation (PubMed:18403713, PubMed:26417072). Interacts (via N-terminus) with tropomyosin alpha (TPM1) (via N-terminus) (PubMed:25250574, PubMed:26873245). May also interact with TPM2 (via N-terminus) (PubMed:25250574).
Mediates nucleation of actin filaments and thereby promotes actin polymerization (PubMed:18403713, PubMed:26370058, PubMed:25250574, PubMed:26417072). Plays a role in the regulation of actin filament length (By similarity). Required for normal sarcomere organization in the heart, and for normal heart function (PubMed:18403713).
Specifically expressed in heart and skeletal muscles, with higher levels in heart (at protein level). Not expressed in other tissues.
Found in various tissues. Highest expression in placenta, prostate, testis, ovary, intestine and muscle, and in fetal brain.
Responsible for the synthesis of complex-type N-linked oligosaccharides in many glycoproteins as well as the carbohydrate moieties of glycolipids.
High expression restricted to ureteric urothelium (most superficial cells); low expression in prostate. Expression in normal urothelial cells is lost in culture. Some expression in tumor cell lines derived from urothelial malignancies.
Homodimer; disulfide-linked. Interacts with uroplakin-2 (UPK2) (By similarity).
Contributes to normal sperm motility, but not essential for male fertility.
Expressed in spermatogenic cells, especially in spermatocytes (at protein level).
The poly-Ala region seems to be polymorphic and the number of Ala varies between 4 and 6.
Autocatalytically cleaved at low pH; the two chains remain linked via two disulfide bonds.
Belongs to the repulsive guidance molecule (RGM) family.
Homooligomer (By similarity). Interacts with DRGX (By similarity). Interacts with BMP2 and BMP4 (By similarity). Interacts with the BMP type I receptors ACVR1, BMPR1A and BMPR1B and with the BMP type II receptor ACVR2B (By similarity). The functional complex with its receptor NEO1/neogenin appears to be a heterotetramer with a 2:2 stoichiometry, RGM molecules acting as staples that bring two NEO1 receptors together without interacting themselves, this arrangement leads to activation of downstream signaling via RhoA.
Member of the repulsive guidance molecule (RGM) family that contributes to the patterning of the developing nervous system (By similarity). Acts as a bone morphogenetic protein (BMP) coreceptor that potentiates BMP signaling (By similarity). Promotes neuronal adhesion (By similarity). May inhibit neurite outgrowth.
Component of the precatalytic spliceosome (spliceosome B complex) (PubMed:28781166). Component of the U4/U6-U5 tri-snRNP complex, a building block of the precatalytic spliceosome (spliceosome B complex) (PubMed:9257651, PubMed:9404889, PubMed:9328476, PubMed:28781166, PubMed:26912367). The U4/U6-U5 tri-snRNP complex is composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39, plus LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 (PubMed:16723661, PubMed:26912367). Interacts directly with PRPF18, PPIH and PRPF3 (PubMed:9404889, PubMed:9328476, PubMed:9000057, PubMed:12875835, PubMed:25383878). Part of a heteromeric complex containing PPIH, PRPF3 and PRPF4 that is stable in the absence of RNA (PubMed:9404889). Interacts with ERCC6 (PubMed:26030138).
Plays a role in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex that is involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex).
Coordinated expression with SEPTIN6 and SEPTIN7.
Filament-forming cytoskeletal GTPase. Forms a filamentous structure with SEPTIN12, SEPTIN6, SEPTIN2 and probably SEPTIN4 at the sperm annulus which is required for the structural integrity and motility of the sperm tail during postmeiotic differentiation (PubMed:25588830). Required for normal organization of the actin cytoskeleton. Plays a role in the biogenesis of polarized columnar-shaped epithelium by maintaining polyglutamylated microtubules, thus facilitating efficient vesicle transport, and by impeding MAP4 binding to tubulin. Required for the progression through mitosis. Forms a scaffold at the midplane of the mitotic splindle required to maintain CENPE localization at kinetochores and consequently chromosome congression. During anaphase, may be required for chromosome segregation and spindle elongation. Plays a role in ciliogenesis and collective cell movements. In cilia, required for the integrity of the diffusion barrier at the base of the primary cilium that prevents diffusion of transmembrane proteins between the cilia and plasma membranes: probably acts by regulating the assembly of the tectonic-like complex (also named B9 complex) by localizing TMEM231 protein. May play a role in the internalization of 2 intracellular microbial pathogens, Listeria monocytogenes and Shigella flexneri.
Septins polymerize into heterooligomeric protein complexes that form filaments, and associate with cellular membranes, actin filaments and microtubules (PubMed:17637674, PubMed:25588830, Ref.36). GTPase activity is required for filament formation. Filaments are assembled from asymmetrical heterotrimers, composed of SEPTIN2, SEPTIN6 and SEPTIN7 that associate head-to-head to form a hexameric unit (PubMed:16093351, PubMed:16914550). Interaction between SEPTIN2 and SEPTIN7 seems indirect. Interacts with SEPTIN5 (By similarity). Interaction with SEPTIN4 not detected (By similarity). Interacts with SEPTIN9 (PubMed:19145258). Component of a septin core octameric complex consisting of SEPTIN12, SEPTIN7, SEPTIN6 and SEPTIN2 or SEPTIN4 in the order 12-7-6-2-2-6-7-12 or 12-7-6-4-4-6-7-12 and located in the sperm annulus (PubMed:16093351, PubMed:16914550). Interacts with MAP4. Interacts with DZIP1L (PubMed:28530676).
Widely expressed. Up-regulated in liver cancer.
Although ZNF674 has been reported to be involved in X-linked intellectual disability (PubMed:16385466), its pathological role is questionable (PubMed:23871722).
(Microbial infection) Through a sequential action with ZDHHC20, rapidly and efficiently palmitoylates SARS coronavirus-2/SARS-CoV-2 spike protein following its synthesis in the endoplasmic reticulum (ER). In the infected cell, promotes spike biogenesis by protecting it from premature ER degradation, increases half-life and controls the lipid organization of its immediate membrane environment. Once the virus has formed, spike palmitoylation controls fusion with the target cell.
Belongs to the DHHC palmitoyltransferase family. ERF2/ZDHHC9 subfamily.
Highly expressed in kidney, skeletal muscle, brain, lung and liver. Absent in thymus, spleen and leukocytes.
Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates (Probable). The ZDHHC9-GOLGA7 complex is a palmitoyltransferase specific for HRAS and NRAS (PubMed:16000296). May have a palmitoyltransferase activity toward the beta-2 adrenergic receptor/ADRB2 and therefore regulate G protein-coupled receptor signaling (PubMed:27481942).
Probable hydrophobic ligand-binding protein; may play a role in the transport of hydrophobic ligands like tocopherol, squalene and phospholipids.
Acts as a bone morphogenetic protein (BMP) coreceptor (PubMed:18976966). Through enhancement of BMP signaling regulates hepcidin (HAMP) expression and regulates iron homeostasis (PubMed:18976966).
Adult and fetal liver, heart, and skeletal muscle.
Autocatalytically cleaved at low pH; the two chains remain linked via two disulfide bonds (PubMed:25156943). Also proteolytically processed by TMPRSS6, several fragments being released in the extracellular space; regulates HJV activity in BMP signaling and thefore iron homeostasis (PubMed:18976966, PubMed:25156943).
Interacts with BMP2 and BMP4 (By similarity). Interacts with BMP6 (By similarity). Interacts with BMPR1B (PubMed:16604073). Interacts with TMPRSS6 (PubMed:18976966, PubMed:19357398).
Component of the eRF1-eRF3-GTP ternary complex, composed of ETF1/ERF1 and ERF3 (GSPT1/ERF3A or GSPT2/ERF3B) and GTP (PubMed:15987998). Component of the transient SURF (SMG1-UPF1-eRF1-eRF3) complex (PubMed:19417104). Interacts with UPF1 and PABPC1 (PubMed:18447585).
GTPase component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons UAA, UAG and UGA (PubMed:15987998, PubMed:11524954, PubMed:17562865). GSPT2/ERF3B mediates ETF1/ERF1 delivery to stop codons: The eRF1-eRF3-GTP complex binds to a stop codon in the ribosomal A-site (PubMed:15987998). GTP hydrolysis by GSPT2/ERF3B induces a conformational change that leads to its dissociation, permitting ETF1/ERF1 to accommodate fully in the A-site (PubMed:15987998). Component of the transient SURF complex which recruits UPF1 to stalled ribosomes in the context of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons (PubMed:19417104).
Highly expressed in IUCC stage II colorectal cancer (CRC).
May have metallophosphoesterase activity (in vitro).
Although it belongs to the protein kinase superfamily, the ATP-binding motif VAIK has an arginine instead of a lysine residue suggesting that KSR1 cannot bind ATP and therefore lacks protein kinase activity. However, KSR1 is capable of binding ATP (PubMed:29433126). Has protein kinase activity towards MAP2K1 in the presence of RAF1/c-RAF in vitro (By similarity).
Homodimer (PubMed:29433126). Heterodimerizes (via N-terminus) with BRAF (via N-terminus) in a MAP2K1/MEK1 or MAP2K2/MEK2-dependent manner (PubMed:29433126). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2 (PubMed:10409742, PubMed:29433126). Binding to MAP2K1/MEK1 releases the intramolecular inhibitory interaction between KSR1 N-terminus and kinase domains which is required for the subsequent RSK1 dimerization with BRAF (PubMed:29433126). Identified in a complex with AKAP13, MAP2K1 and BRAF (By similarity). Interacts with AKAP13 and BRAF (PubMed:21102438). Interacts with RAF and MAPK/ERK, in a Ras-dependent manner (By similarity). Interacts with 14-3-3 proteins including YWHAB (By similarity). Interacts with HSP90AA1/HSP90, YWHAE/14-3-3 and CDC37 (PubMed:10409742, PubMed:29433126). The binding of 14-3-3 proteins to phosphorylated KSR1 prevents the membrane localization (By similarity). Interacts with MARK3/C-TAK1 (PubMed:12941695). Interacts with PPP2R1A and PPP2CA (By similarity). Interacts with isoform 1 of VRK2 (PubMed:20679487).
Part of a multiprotein signaling complex which promotes phosphorylation of Raf family members and activation of downstream MAP kinases (By similarity). Independently of its kinase activity, acts as MAP2K1/MEK1 and MAP2K2/MEK2-dependent allosteric activator of BRAF; upon binding to MAP2K1/MEK1 or MAP2K2/MEK2, dimerizes with BRAF and promotes BRAF-mediated phosphorylation of MAP2K1/MEK1 and/or MAP2K2/MEK2 (PubMed:29433126). Promotes activation of MAPK1 and/or MAPK3, both in response to EGF and to cAMP (By similarity). Its kinase activity is unsure (By similarity). Some protein kinase activity has been detected in vitro, however the physiological relevance of this activity is unknown (By similarity).
Phosphorylated on Ser-311 and, to a higher extent, on Ser-406 by MARK3. Dephosphorylated on Ser-406 by PPP2CA. In resting cells, phosphorylated KSR1 is cytoplasmic and in stimulated cells, dephosphorylated KSR1 is membrane-associated. Phosphorylated by PKA at Ser-888. Phosphorylation at Ser-888 is required for cAMP-dependent activation of MAPK1 and/or MAPK3 (By similarity).
The N-terminal region mediates interaction with BRAF (PubMed:29433126). Also mediates membrane localization (By similarity).
The protein kinase domain is predicted to be catalytically inactive. The domain is sufficient for KSR1 and KSR1-mediated MAP2K1 and MAP2K2 membrane localization. The domain is required but not sufficient for MAP kinase-mediated inhibition of ELK1 phosphorylation (PubMed:10409742).
Acts as a positive regulator of T-cell maturation and inflammatory function. Required for several functions of T-cells, in both the CD4(+) and the CD8(+) compartments and this includes expression of cell surface markers of activation, proliferation, and cytokine production in response to specific or non-specific stimulation (By similarity). Enhances NK cell cytotoxicity by positively regulating polarization of microtubule-organizing center (MTOC) to cytotoxic synapse, lytic granule transport along microtubules, and dynein-mediated clustering to MTOC (PubMed:25762780). Interacts with HSPA5 and stabilizes the interaction between HSPA5 and ERN1, leading to suppression of ERN1-induced JNK activation and endoplasmic reticulum stress-induced apoptosis (PubMed:21289099).
Expressed in endothelium (at protein level) (PubMed:21289099). Expressed in NK cells (at protein level) (PubMed:25762780).
Homodimer (PubMed:25762780). Interacts with DOCK8 (PubMed:25762780). Interacts (via C-terminus) with intact microtubules (PubMed:25762780). Interacts with dynein-dynactin motor complex (PubMed:25762780). Interacts (via C-terminus) with HSPA5 (PubMed:21289099).
Binds polysaccharidesin a Ca(2+)-independent manner with a preferentially binding to fucoidan, beta-glucans and galactans.
May play a role in the structure and strength of both muscle and bone.
Contains a potential peptide which could stimulate a broad spectrum of phagocytotic cells.
Heavy chains are linked to bikunin via chondroitin 4-sulfate esterified to the alpha-carboxyl of the C-terminal aspartate after propeptide cleavage.
I-alpha-I plasma protease inhibitors are assembled from one or two heavy chains (HC) and one light chain, bikunin. Inter-alpha-inhibitor (I-alpha-I) is composed of ITIH1/HC1, ITIH2/HC2 and bikunin (PubMed:2476436). Interacts with TNFAIP6 (via Link and CUB domains) (PubMed:26468290).
May act as a carrier of hyaluronan in serum or as a binding protein between hyaluronan and other matrix protein, including those on cell surfaces in tissues to regulate the localization, synthesis and degradation of hyaluronan which are essential to cells undergoing biological processes.
The S-linked glycan is composed of two 6-carbon sugars, possibly Glc or Gal.
There are 3 common alleles; ITIH1*1 with Glu-585/Gln-595, ITIH1*2 with Val-585/Arg-595 and ITIH1*3 with Glu-585/Arg-595.
CSH1 sequence only differs from CSH2 sequence in 1 aa.
CSH2 sequence only differs from CSH1 sequence in 1 aa.
Can be found in a monomeric as well as dimeric form.
Produced only during pregnancy and is involved in stimulating lactation, fetal growth and metabolism. Does not interact with GHR but only activates PRLR through zinc-induced dimerization.
Highly expressed in placenta, skeletal muscle, spleen, thymus, testis and peripheral leukocyte and is expressed weakly in the heart, liver and fetal brain.
Restriction factor required to restrict infectivity of lentiviruses, such as HIV-1: acts by inhibiting an early step of viral infection. Impairs the penetration of the viral particle into the cytoplasm (PubMed:26416733, PubMed:26416734). Enhances the incorporation of serine into phosphatidylserine and sphingolipids. May play a role in providing serine molecules for the formation of myelin glycosphingolipids in oligodendrocytes (By similarity).
Although at least one in vitro system can process and methylate the prenylated C-terminal, in an in vitro system that normally express Rab-38 and in vivo the prenylated C-terminal is not proteolytically processed and not methylated.
Interacts with ANKRD27 (PubMed:19403694).
May be involved in melanosomal transport and docking. Involved in the proper sorting of TYRP1. Involved in peripheral melanosomal distribution of TYRP1 in melanocytes; the function, which probably is implicating vesicle-trafficking, includes cooperation with ANKRD27 and VAMP7 (By similarity). Plays a role in the maturation of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis (PubMed:21255211). Plays an important role in the control of melanin production and melanosome biogenesis (PubMed:23084991). In concert with RAB32, regulates the proper trafficking of melanogenic enzymes TYR, TYRP1 and DCT/TYRP2 to melanosomes in melanocytes (By similarity).
Regulated by a guanine nucleotide-exchange factor (GEF) and a GTPase-activating protein (GAP) and alternates between an inactive GDP-bound and an active GTP-bound form. The BLOC-3 complex composed of HPS1 and HPS4 acts as its GEF, promotes the exchange of GDP to GTP, converting it from an inactive GDP-bound form into an active GTP-bound form. SGSM2 acts as its GAP and inactivates it by stimulating its GTPase activity.
Detected in blood plasma (at protein level) (PubMed:10092508, PubMed:20410020). Ubiquitous. Highly expressed in heart, placenta, skeletal muscle, kidney and pancreas. Detected at lower levels in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes (PubMed:10092508).
Has dual calcium-independent phospholipase and O-acyltransferase activities with a potential role in glycerophospholipid homeostasis and remodeling of acyl groups of lipophilic alcohols present in acidic cellular compartments (PubMed:10092508, PubMed:11790796, PubMed:20410020, PubMed:23958596, PubMed:29724779, PubMed:25727495). Catalyzes hydrolysis of the ester bond of the fatty acyl group attached at sn-1 or sn-2 position of phospholipids (phospholipase A1 or A2 activity) and transfer it to the hydroxyl group at the first carbon of lipophilic alcohols (O-acyltransferase activity) (PubMed:10092508, PubMed:11790796, PubMed:20410020, PubMed:23958596, PubMed:29724779, PubMed:25727495). Among preferred fatty acyl donors are phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols and phosphatidylserines (PubMed:29724779). Favors sn-2 over sn-1 deacylation of unsaturated fatty acyl groups of phosphatidylcholines and phosphatidylethanolamines (By similarity). Among preferred fatty acyl acceptors are natural lipophilic alcohols including short-chain ceramide N-acetyl-sphingosine (C2 ceramide), alkylacylglycerols, monoacylglycerols, and acylethanolamides such as anandamide and oleoylethanolamide (PubMed:29724779). Selectively hydrolyzes the sn-1 fatty acyl group of truncated oxidized phospholipids and may play a role in detoxification of reactive oxidized phospholipids during oxidative stress (PubMed:30830753). Required for normal phospholipid degradation in alveolar macrophages with potential implications in pulmonary surfactant clearance (By similarity). At neutral pH, hydrolyzes the sn-1 fatty acyl group of the lysophosphatidylcholines (PubMed:10092508).
Inhibited by zinc ions at neutral pH. Zinc ions in plasma may keep the enzyme from hydrolyzing inappropriate substrates.
N-glycosylated (PubMed:11790796, PubMed:23958596). N-glycosylation is important for maturation of the enzyme and normal subcellular location (PubMed:23958596).
By liver X-receptor/retinoid X receptor agonists or cholesterol loading.
Expressed in several tumor cell lines (at protein level). Expressed in lung, brain, leukocytes and placenta.
Interacts with CYTH2. Interacts with alpha tubulin; interaction is independent on the ARL4C GTP or GDP binding status.
Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). GTP-binding protein that does not act as an allosteric activator of the cholera toxin catalytic subunit. May be involved in transport between a perinuclear compartment and the plasma membrane, apparently linked to the ABCA1-mediated cholesterol secretion pathway. Recruits CYTH1, CYTH2, CYTH3 and CYTH4 to the plasma membrane in the GDP-bound form. Regulates the microtubule-dependent intracellular vesicular transport from early endosome to recycling endosome process.
May be involved in fusion of ER-derived transport vesicles with the Golgi complex.
Widely expressed. Tends to be up-regulated in seminomas compared to normal testis.
Belongs to the DNA polymerase type-B family.
Catalytic subunit of the DNA polymerase zeta complex, an error-prone polymerase specialized in translesion DNA synthesis (TLS). Lacks an intrinsic 3'-5' exonuclease activity and thus has no proofreading function.
Heterodimer with MAD2L2. This dimer forms the minimal DNA polymerase zeta complex (Pol-zeta2), with REV3L bearing DNA polymerase catalytic activity, although its activity is very low in this context. Component of the tetrameric Pol-zeta complex (Pol-zeta4), which consists of REV3L, MAD2L2, POLD2 and POLD3; Pol-zeta4 is the fully active form of DNA polymerase zeta.
Its C-terminal part could serve as the catalytic domain during nucleotide polymerization, while its N-terminal part could provide sites for protein-protein interactions with other factors during translesion DNA synthesis.
The CysB motif binds 1 4Fe-4S cluster and is required for the formation of polymerase complexes.
May form a heteromeric complex composed of ERGIC1, ERGIC2 and ERGIC3 (PubMed:31142615). Within the complex, the interaction with ERGIC3 is direct (PubMed:31142615). Interacts with ERGIC3/ERV46 (PubMed:15308636).
Possible role in transport between endoplasmic reticulum and Golgi.
Acts as a glycogen-targeting subunit for phosphatase PP1. Facilitates interaction of the PP1 with enzymes of the glycogen metabolism and regulates its activity. Suppresses the rate at which PP1 dephosphorylates (inactivates) glycogen phosphorylase and enhances the rate at which it activates glycogen synthase and therefore limits glycogen breakdown. Its activity is inhibited by PYGL, resulting in inhibition of the glycogen synthase and glycogen phosphorylase phosphatase activities of PP1. Dramatically increases basal and insulin-stimulated glycogen synthesis upon overexpression in hepatocytes (By similarity).
Highly expressed in the liver and, at lower levels, in skeletal muscle, including in vastus lateralis, gastrocnemius and soleus (at protein level). Highest mRNA levels are observed in skeletal muscle, and only moderate levels in liver and heart. Weak expression in placenta and lung.
Interacts with glycogen, PPP1CC catalytic subunit of PP1 and PYGL. Associates with glycogen particles. Forms complexes with debranching enzyme, glycogen phosphorylase, glycogen synthase and phosphorylase kinase which is necessary for its regulation of PP1 activity (By similarity).
The N-terminal region is required for binding to PP1, the central region is required for binding to glycogen and the C-terminal region is required for binding to PYGL.
Involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors. Known substrate: EFNB3.
Proteolytic processing of the proenzyme produces a N-terminal fragment (NTF) and a C-terminal fragment (CTF). The processing is required for activation of the protease.
Belongs to the gastrin/cholecystokinin family.
Gastrin stimulates the stomach mucosa to produce and secrete hydrochloric acid and the pancreas to secrete its digestive enzymes. It also stimulates smooth muscle contraction and increases blood circulation and water secretion in the stomach and intestine.
Sulfation enhances proteolytic processing, and blocks peptide degradation. Levels of sulfation differ between proteolytically-cleaved gastrins. Thus, gastrin-6 is almost 73% sulfated, whereas the larger gastrins are less than 50% sulfated. Sulfation levels are also tissue-specific.
Two different processing pathways probably exist in antral G-cells. In the dominant pathway progastrin is cleaved at three sites resulting in two major bioactive gastrins, gastrin-34 and gastrin-17. In the putative alternative pathway, progastrin may be processed only at the most C-terminal dibasic site resulting in the synthesis of gastrin-71.
Expressed in testis, skeletal muscle, thymus, prostate, colon, peripheral blood cells, brain and placenta.
Induced by EGF growth factor at mRNA and protein levels (PubMed:21323578). Induced by androgens (PubMed:22155408). Negatively regulated by the microRNA miR-132 (PubMed:25450365).
Interacts with the complex composed, at least, of APC, CTNNB1 and GSK3B; the interaction takes place with the inactive form of GSK3B (phosphorylated at 'Ser-9').
Modulates negatively AKT-mediated GSK3B signaling (PubMed:21323578, PubMed:22155408). Induces CTNNB1 'Ser-33' phosphorylation and degradation through the suppression of the inhibitory 'Ser-9' phosphorylation of GSK3B, which represses the function of the APC:CTNNB1:GSK3B complex and the interaction with CDH1/E-cadherin in adherent junctions (PubMed:25169422). Plays a role in the regulation of cell cycle and cell adhesion (PubMed:25169422, PubMed:25450365). Has an inhibitory role on AR-signaling pathway through the induction of receptor proteasomal degradation (PubMed:22155408).
In the retina, it is expressed in cone and rod photoreceptor cells.
Stimulates two retinal guanylyl cyclases (GCs) GUCY2D and GUCY2F when free calcium ions concentration is low, and inhibits GUCY2D and GUCY2F when free calcium ions concentration is elevated (By similarity). This Ca(2+)-sensitive regulation of GCs is a key event in recovery of the dark state of rod photoreceptors following light exposure (By similarity). May be involved in cone photoreceptor response and recovery of response in bright light (By similarity).
Homodimer when bound to RAB5A (PubMed:15378032). Heterodimer with RABGEF1 (PubMed:11452015, PubMed:9323142). The heterodimer binds RAB4A and RAB5A that have been activated by GTP-binding (PubMed:10698684, PubMed:8521472, PubMed:20098723, PubMed:12773381). Interacts with TSC2 (PubMed:9045618). Interacts with GGA1 (via GAE domain), GGA2 (via GAE domain) and GGA3 (via GAE domain) (PubMed:12505986, PubMed:14665628). Interacts with AP1G1 (via GAE domain) (PubMed:12505986, PubMed:12773381, PubMed:14665628). Interacts with AP1G2 (via GAE domain) (PubMed:12505986, PubMed:14665628). Interacts with ECPAS (PubMed:20682791). Interacts with KCNH1 (By similarity). Interacts with PKD1 (via C-terminal domain) and GGA1; the interactions recruit PKD1:PKD2 complex to GGA1 and ARL3 at trans-Golgi network (By similarity). Interacts with KCNH1 (By similarity).
Proteolytic cleavage by caspases in apoptotic cells causes loss of endosome fusion activity.
Rab effector protein acting as linker between gamma-adaptin, RAB4A and RAB5A. Involved in endocytic membrane fusion and membrane trafficking of recycling endosomes. Involved in KCNH1 channels trafficking to and from the cell membrane (PubMed:22841712). Stimulates RABGEF1 mediated nucleotide exchange on RAB5A. Mediates the traffic of PKD1:PKD2 complex from the endoplasmic reticulum through the Golgi to the cilium (By similarity).
Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B), and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific (PubMed:12672490, PubMed:22952240, PubMed:26601204). Component of the BAF complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C. In muscle cells, the BAF complex also contains DPF3 (PubMed:18765789). Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin. May be a component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin (ACTB) (PubMed:22952240, PubMed:26601204). Interacts with BRDT (By similarity). Also binds to the SRC/p160 family of histone acetyltransferases (HATs) composed of NCOA1, NCOA2, and NCOA3. Interacts with RCOR1/CoREST, NR3C1 and ZMIM2/ZIMP7 (PubMed:12192000, PubMed:12917342, PubMed:16051670).
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Required for the coactivation of estrogen responsive promoters by SWI/SNF complexes and the SRC/p160 family of histone acetyltransferases (HATs). Also specifically interacts with the CoREST corepressor resulting in repression of neuronal specific gene promoters in non-neuronal cells.
The HMG domain is essential for CD4 silencing and CD8 activation; mutation of this domain blocks thymus development.
Ubiquitinated by TRIP12, leading to its degradation by the proteasome. Ubiquitination is prevented upon interaction between TRIP12 and SMARCC1.
Differentially targeted protein that binds to type I and II regulatory subunits of protein kinase A and anchors them to the mitochondria or the plasma membrane. Although the physiological relevance between PKA and AKAPS with mitochondria is not fully understood, one idea is that BAD, a proapoptotic member, is phosphorylated and inactivated by mitochondria-anchored PKA. It cannot be excluded too that it may facilitate PKA as well as G protein signal transduction, by acting as an adapter for assembling multiprotein complexes. With its RGS domain, it could lead to the interaction to G-alpha proteins, providing a link between the signaling machinery and the downstream kinase (By similarity).
Protein transport. Probably involved in vesicular traffic (By similarity).
Ubiquitously present in all tissues examined.
Although strongly related to other members of the family, lacks the kinase activity. A conserved Asp/Glu residue present in other members of the family, which coordinates the Mn(2+) ion and the ion-pair Lys and is indispensable for kinase activity, is replaced by a Gln in position 258.
Highly expressed in lung and liver. Intermediate levels in thymus and ovary.
Interacts with FAM20C; probably forming a heterotetramer of 2 subunits of FAM20A and 2 subunits of FAM20C.
Pseudokinase that acts as an allosteric activator of the Golgi serine/threonine protein kinase FAM20C and is involved in biomineralization of teeth. Forms a complex with FAM20C and increases the ability of FAM20C to phosphorylate the proteins that form the 'matrix' that guides the deposition of the enamel minerals.
Autoantibodies against RPP30 are found in sera from scleroderma patients.
Belongs to the eukaryotic/archaeal RNase P protein component 3 family.
Component of nuclear RNase P and RNase MRP ribonucleoproteins (PubMed:9037013, PubMed:9630247, PubMed:16723659, PubMed:30454648). RNase P consists of a catalytic RNA moiety and about 10 protein subunits; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40 (PubMed:9037013, PubMed:9630247, PubMed:16723659, PubMed:30454648). Within the RNase P complex, POP1, POP7 and RPP25 form the 'finger' subcomplex, POP5, RPP14, RPP40 and homodimeric RPP30 form the 'palm' subcomplex, and RPP21, POP4 and RPP38 form the 'wrist' subcomplex. All subunits of the RNase P complex interact with the catalytic RNA (PubMed:30454648). Several subunits of RNase P are also part of the RNase MRP complex. RNase MRP consists of a catalytic RNA moiety and about 8 protein subunits; POP1, POP7, RPP25, RPP30, RPP38, RPP40 and possibly also POP4 and POP5 (PubMed:16723659, PubMed:28115465).
Component of ribonuclease P, a ribonucleoprotein complex that generates mature tRNA molecules by cleaving their 5'-ends (PubMed:9037013, PubMed:9630247, PubMed:30454648). Also a component of the MRP ribonuclease complex, which cleaves pre-rRNA sequences (PubMed:28115465).
Interacts with DAZ1 (PubMed:12511597, PubMed:15081113). Interacts with the BBSome; recruits the BBSome to centriolar satellites of the cilium (PubMed:27979967). Interacts with PCM1; localizes DZIP1 and the associated BBSome to centriolar satellites (PubMed:27979967). Interacts with RAB8A (GDP-bound inactive form); recruits RAB8A to the basal body of the cilium and prevents its inhibition by GDI2 (PubMed:25860027). Interacts with GDI2; negatively regulates the interaction of GDI2 with GDP-bound RAB8A (PubMed:25860027). Interacts with GLI3; retains GLI3 within the cytoplasm (PubMed:23955340). Interacts with CEP164 (By similarity). Interacts with IFT88 (By similarity).
Molecular adapter that recruits protein complexes required for cilium assembly and function to the cilium basal body (PubMed:19852954, PubMed:23955340, PubMed:27979967, PubMed:32051257). At the exit of mitosis, localizes to the basal body and ciliary base of the forming primary cilium where it recruits and activates RAB8A to direct vesicle-mediated transport of proteins to the cilium (By similarity). Also recruits the BBSome, a complex involved in cilium biogenesis, by bridging it to PCM1 at the centriolar satellites of the cilium (PubMed:27979967). It is also required for the recruitment to the cilium basal body of the intraflagellar transport (IFT) machinery as well as the ciliary appendage proteins CEP164 and NINEIN (By similarity). Functions as a regulator of Hedgehog signaling both through its role in cilium assembly but also probably through its ability to retain GLI3 within the cytoplasm (By similarity). It is involved in spermatogenesis through its role in organization of the basal body and assembly of the sperm flagellum (PubMed:32051257). Also indirectly involved in heart development through its function in ciliogenesis (PubMed:31118289).
Phosphorylation at Ser-226 by PLK1 before mitosis prevents interaction with PCM1 and localization to centriolar satellites. Thereby, it negatively regulates the localization of the BBSome to centriolar satellites.
Predominantly expressed in testis (at protein level) (PubMed:15081113, PubMed:32051257). Also expressed in fetal brain, adult oocytes and ovary (PubMed:15081113). Expressed in undifferentiated ES cells (PubMed:15081113). In testis, it is specifically expressed in germ cells (at protein level) (PubMed:15081113, PubMed:32051257). Expressed in mature germ cells and secondary spermatocytes, while it is weakly or not expressed in primary spermatocytes (PubMed:15081113).
Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1 (PubMed:19240031, PubMed:17502376). Promotes sterol-accelerated ERAD of HMGCR probably implicating an AMFR/gp78-containing ubiquitin ligase complex (PubMed:21343306). Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway. May promote ER retention of the SCAP-SREBF complex (PubMed:24217618).
Forms a heteromeric complex with ERLIN1. In complex with ERLIN1, interacts with RNF170 (PubMed:19240031, PubMed:21610068). Interacts with activated ITPR1, independently of the degree of ITPR1 polyubiquitination (By similarity). Interacts with SCAP, INSIG1, SREBF1 and SREBF2 under cholesterol sufficiency conditions; indicative for an association with the SCAP-SREBP-INSIG complex (PubMed:24217618). Probably part of an AMFR/gp78 and INSIG1-containing ubiquitin ligase complex involved in ERAD of HMGCR. Interacts with TMUB1; TMUB1 bridges the association with AMFR. Interacts with SYVN1 and RNF139 (PubMed:21343306). Interacts with TMEM259 (By similarity). Interacts with TMEM41B (PubMed:30352685).
Mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs). Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway.
By interferons and bacterial lipopolysaccharides (LPS).
Erroneous prediction of the initiator methionine.
Expressed at high levels in lung, placenta and thymus and at lower levels in ovary, intestine and brain (PubMed:15456791). Highly abundant in oocytes and early embryos, however poorly expressed in somatic tissues such as brain, kidney, liver and spinal cord (PubMed:30877238).
Interacts with CHUK (PubMed:15456791). Interacts with IKBKB (PubMed:15456791). Interacts with IKBKG (PubMed:15456791). Interacts with MEFV (PubMed:17431422). Interacts with PYCARD (PubMed:15030775, PubMed:15456791). Interacts (via pyrin domain) with PYDC2 (PubMed:17178784). Interacts with CARD8 (PubMed:15030775).
Suppresses TNF- and CD40-induced NFKB1 activity at the level of the IKK complex, by inhibiting NFKBIA degradation induced by TNF. When associated with PYCARD, activates CASP1, leading to the secretion of mature pro-inflammatory cytokine IL1B. May be a component of the inflammasome, a protein complex which also includes PYCARD, CARD8 and CASP1 and whose function would be the activation of pro-inflammatory caspases.
The pyrin domain is necessary and sufficient for suppression of NFKB1 activation induced by TNF and for inducing IL1B secretion in collaboration with caspase-1. It is involved in interaction with PYCARD.
When isolated, the NACHT domain is involved in interaction with CARD8. This interaction is not detected for the full-length protein, maybe due to autoinhibition, this inhibition might by relieved by an inducible change in protein folding.
Expressed in hypophyseal pars tuberalis and hypothalamic suprachiasmatic nuclei (SCN). Hippocampus.
High affinity receptor for melatonin. Likely to mediate the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity.
In NK cells and an NK-like cell line but not in resting T-cells or in other tissues. The S-form is more commonly seen in hematopoietic lines, whereas the B-form is detected in cells both of hematopoietic and epithelial origins.
Interacts with STAM2 and MYO18A (By similarity). Interacts with SHB.
May be inactive as it lacks some part of the kinase domain.
Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A and STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.
Possesses two phosphotransferase domains. The second one probably contains the catalytic domain (By similarity), while the presence of slight differences suggest a different role for domain 1.
Tyrosine phosphorylated in response to IL-2 and IL-4. Dephosphorylation of Tyr-980 and Tyr-981 by PTPN2 negatively regulates cytokine-mediated signaling (Probable).
Wrong choice of CDS. Was erroneously described as an isoform JAK3M while it is a fragmentary mRNA of INSL3.
A chromosomal aberration involving MYC may be a cause of a form of B-cell chronic lymphocytic leukemia. Translocation t(8;12)(q24;q22) with BTG1.
Alternative translation initiation from an upstream, in-frame non-ATG (CTG) codon or a downstream ATG start site results in the production of 2 isoforms with distinct N-termini, shown in this entry as isoforms 2/3 and isoform 1, respectively.
Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a heterodimer with MAX (PubMed:9680483). Interacts with TAF1C and SPAG9. Interacts with PARP10. Interacts with KDM5A and KDM5B. Interacts (when phosphorylated at Thr-73 and Ser-77) with FBXW7(PubMed:25775507, PubMed:17558397). Interacts with PIM2. Interacts with RIOX1. The heterodimer MYC:MAX interacts with ABI1; the interaction may enhance MYC:MAX transcriptional activity. Interacts with TRIM6 (By similarity). Interacts with NPM1; the binary complex is recruited to the promoter of MYC target genes and enhances their transcription (PubMed:25956029). Interacts with CIP2A; leading to the stabilization of MYC (PubMed:17632056).
Phosphorylated by PRKDC (PubMed:1597196). Phosphorylation at Ser-344 by PIM2 leads to the stabilization of MYC (By similarity). Phosphorylation at Ser-77 by CDK2 prevents Ras-induced senescence (PubMed:19966300, PubMed:20713526). Phosphorylated at Ser-77 by DYRK2; this primes the protein for subsequent phosphorylation by GSK3B at Thr-73 (PubMed:22307329). Phosphorylation at Thr-73 and Ser-77 by GSK3 is required for ubiquitination and degradation by the proteasome (PubMed:15103331, PubMed:17558397, PubMed:8386367). Dephosphorylation at Ser-77 by protein phosphatase 2A (PPP2CA) promotes its degradation; interaction with PPP2CA is enhanced by AMBRA1 (PubMed:25803737, PubMed:25438055).
Produced by alternative translation initiation from a CTG codon, which is translated as Met, and alternative splicing.
Produced by alternative translation initiation from a CTG codon, which is translated as Met.
The gene represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving MYC are usually found in Burkitt lymphoma. Translocations t(8;14), t(8;22) or t(2;8) which juxtapose MYC to one of the heavy or light chain immunoglobulin gene loci.
Transcription factor that binds DNA in a non-specific manner, yet also specifically recognizes the core sequence 5'-CAC[GA]TG-3' (PubMed:24940000, PubMed:25956029). Activates the transcription of growth-related genes (PubMed:24940000, PubMed:25956029). Binds to the VEGFA promoter, promoting VEGFA production and subsequent sprouting angiogenesis (PubMed:24940000, PubMed:25956029). Regulator of somatic reprogramming, controls self-renewal of embryonic stem cells (By similarity). Functions with TAF6L to activate target gene expression through RNA polymerase II pause release (By similarity). Positively regulates transcription of HNRNPA1, HNRNPA2 and PTBP1 which in turn regulate splicing of pyruvate kinase PKM by binding repressively to sequences flanking PKM exon 9, inhibiting exon 9 inclusion and resulting in exon 10 inclusion and production of the PKM M2 isoform (PubMed:20010808).
Ubiquitinated by the SCF(FBXW7) complex when phosphorylated at Thr-73 and Ser-77, leading to its degradation by the proteasome (PubMed:15103331, PubMed:17558397, PubMed:25775507). In the nucleoplasm, ubiquitination is counteracted by USP28, which interacts with isoform 1 of FBXW7 (FBW7alpha), leading to its deubiquitination and preventing degradation (PubMed:17873522, PubMed:17558397). In the nucleolus, however, ubiquitination is not counteracted by USP28 but by USP36, due to the lack of interaction between isoform 3 of FBXW7 (FBW7gamma) and USP28, explaining the selective MYC degradation in the nucleolus (PubMed:17558397, PubMed:25775507). Also polyubiquitinated by the DCX(TRPC4AP) complex (PubMed:20551172, PubMed:29779948). Ubiquitinated by TRIM6 in a phosphorylation-independent manner (By similarity).
Mostly monomeric (By similarity). Interacts with collagen type II.
Promotes attachment of chondrocytes, fibroblasts, and osteoblasts. This binding is mediated (at least for chondrocytes and fibroblasts) by the integrin alpha(2)beta(1). May play an important role in the regulation of chondrocyte growth and proliferation (By similarity).
Expressed in the aorta (at protein level) (PubMed:17293099). Isoform Long: Expressed in fibroblasts (PubMed:17293099).
Interacts with TGFB1; associates via disulfide bonds with the Latency-associated peptide chain (LAP) regulatory chain of TGFB1, leading to regulate activation of TGF-beta-1 (PubMed:10930463, PubMed:2022183, PubMed:8617200, PubMed:15567420, PubMed:8939931, PubMed:22278742). LTBP1 does not bind directly to TGF-beta-1, the active chain of TGFB1 (PubMed:10930463). Interacts (via C-terminal domain) with FBN1 (via N-terminal domain) (PubMed:12429738, PubMed:17293099, PubMed:33991472). Interacts with FBN2 (PubMed:12429738, PubMed:33991472). Interacts with ADAMTSL2 (PubMed:18677313). Interacts with EFEMP2 (PubMed:27339457).
Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space (PubMed:2022183, PubMed:8617200, PubMed:8939931). Associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGF-beta, and regulates integrin-dependent activation of TGF-beta (PubMed:8617200, PubMed:8939931, PubMed:15184403). Outcompeted by LRRC32/GARP for binding to LAP regulatory chain of TGF-beta (PubMed:22278742).
O-glycosylated on serine residues by POGLUT2 and POGLUT3.
The 8-Cys3 region in the third TB domain mediates the interchain disulfide bond interaction with the Latency-associated peptide chain (LAP) regulatory chain of TGFB1.
Could be a regulatory protein, possibly participating in receptor-mediated signal transduction at the plasma membrane. Has guanine nucleotide-binding activity but undetectable intrinsic GTPase activity.
Interacts with calmodulin in a Ca(2+)-dependent manner. Binds ROCK1.
Most abundant in thymus, spleen, kidney, lung, and testis. Less abundant in heart, brain, liver and skeletal muscle.
May positively contribute to the induction of apoptosis triggered by O(6)-methylguanine.
Expressed in natural killer (NK) cells, CD8(+) alpha-beta and gamma-delta T-cells. Expressed on essentially all CD56+CD3- NK cells from freshly isolated PBMC. Expressed in interferon-producing killer dendritic cells (IKDCs).
Functions as an activating and costimulatory receptor involved in immunosurveillance upon binding to various cellular stress-inducible ligands displayed at the surface of autologous tumor cells and virus-infected cells. Provides both stimulatory and costimulatory innate immune responses on activated killer (NK) cells, leading to cytotoxic activity. Acts as a costimulatory receptor for T-cell receptor (TCR) in CD8(+) T-cell-mediated adaptive immune responses by amplifying T-cell activation. Stimulates perforin-mediated elimination of ligand-expressing tumor cells. Signaling involves calcium influx, culminating in the expression of TNF-alpha. Participates in NK cell-mediated bone marrow graft rejection. May play a regulatory role in differentiation and survival of NK cells. Binds to ligands belonging to various subfamilies of MHC class I-related glycoproteins including MICA, MICB, RAET1E, RAET1G, RAET1L/ULBP6, ULBP1, ULBP2, ULBP3 (ULBP2>ULBP1>ULBP3) and ULBP4.
Homodimer; disulfide-linked. Heterohexamer composed of two subunits of KLRK1 and four subunits of HCST/DAP10. Interacts (via transmembrane domain) with HCST/DAP10 (via transmembrane domain); the interaction is required for KLRK1 NK cell surface and induces NK cell-mediated cytotoxicity. Does not interact with TYROBP. Interacts with CEACAM1; recruits PTPN6 that dephosphorylates VAV1 (PubMed:23696226).
Is not capable of signal transduction by itself, but operates through the adapter protein HCST (PubMed:10426994, PubMed:15894612). Some families of ligands for human and mouse KLRK1 receptors have been characterized being very similar in structure and highly likely to be orthologs. In humans, an additional distinct subfamily of ligands (MICA and MICB) differs structurally, having an extra MHC alpha 3-like domain (PubMed:23298206).
Up-regulated by interleukin IL15 in primary NK cells.
CRYBB1 mutations may be a cause of congenital cataract and microcornea syndrome, a disease characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Clinical findings include a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye, and an inherited cataract, which is most often bilateral posterior polar with opacification in the lens periphery. The cataract progresses to form a total cataract after visual maturity has been achieved, requiring cataract extraction in the first to third decade of life (PubMed:16110300, PubMed:21972112).
Homo/heterodimer, or complexes of higher-order. The structure of beta-crystallin oligomers seems to be stabilized through interactions between the N-terminal arms.
Specific cleavages in the N-terminal arm occur during lens maturation and give rise to truncated forms, leading to impaired oligomerization and protein insolubilization.
Highly expressed in the skeletal muscle, in subcutaneous adipose tissue, epididymal white adipose tissue depots and heart. Also expressed in brown adipose tissues and kidney.
Hormone induced following exercise or cold exposure that promotes energy expenditure. Induced either in the skeletal muscle after exercise or in adipose tissue following cold exposure and is present in the circulation. Able to stimulate energy expenditure associated with the browning of the white fat depots and improves glucose tolerance. Does not promote an increase in a thermogenic gene program via direct action on adipocytes, but acts by stimulating several immune cell subtypes to enter the adipose tissue and activate their prothermogenic actions. Stimulates an eosinophil-dependent increase in IL4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Required for some cold-induced thermogenic responses, suggesting a role in metabolic adaptations to cold temperatures (By similarity).
Belongs to the selenium-binding protein family.
Catalyzes the oxidation of methanethiol, an organosulfur compound known to be produced in substantial amounts by gut bacteria (PubMed:29255262). Selenium-binding protein which may be involved in the sensing of reactive xenobiotics in the cytoplasm. May be involved in intra-Golgi protein transport (By similarity).
Catalyzes the oxidation of methanethiol, an organosulfur compound known to be produced in substantial amounts by gut bacteria. Selenium-binding protein which may be involved in the sensing of reactive xenobiotics in the cytoplasm. May be involved in intra-Golgi protein transport.
Down-regulated by androgen in prostate cancer cells.
Widely expressed. Highly expressed in liver, lung, colon, prostate, kidney and pancreas. In brain, present both in neurons and glia (at protein level). Down-regulated in lung adenocarcinoma, colorectal carcinoma and ovarian cancer. Two-fold up-regulated in brain and blood from schizophrenia patients.
Acetylated by CLOCK in a circadian manner (PubMed:28985504).
Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth (PubMed:7903306, PubMed:7763314). Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism (PubMed:14766016). It may also have a role in the development of malignancy and the growth progression of some tumors.
Genetic variants in the IMPDH2 gene are responsible for the large inter-individual variability in enzyme activity and may influence immunosuppressive efficacy and side effects in transplant recipients receiving mycophenolic acid [MIM:617995].
Homotetramer (PubMed:7903306, Ref.28, Ref.29). Interacts with CLOCK; in a circadian manner (PubMed:28985504). Interacts with ANKRD9; leading to its ubiquitination and degradation by the proteasome (PubMed:30293565).
IMPDH1 is the main species in normal leukocytes and IMPDH2 predominates over IMPDH1 in the tumor.
Mycophenolic acid (MPA) is a non-competitive inhibitor that prevents formation of the closed enzyme conformation by binding to the same site as the amobile flap. In contrast, mizoribine monophosphate (MZP) is a competitive inhibitor that induces the closed conformation. MPA is a potent inhibitor of mammalian IMPDHs but a poor inhibitor of the bacterial enzymes. MZP is a more potent inhibitor of bacterial IMPDH. Subject to product inhibition by XMP and NADH (PubMed:7903306). Also inhibited by ADP.
Selectively up-regulated in neoplastic and replicating cells.
Ubiquitinated leading to its degradation by the proteasome.
FK506- and rapamycin-binding proteins (FKBPs) constitute a family of receptors for the two immunosuppressants which inhibit T-cell proliferation by arresting two distinct cytoplasmic signal transmission pathways. PPIases accelerate the folding of proteins.
Inhibited preferentially by rapamycin over FK506.
A chromosomal aberration involving TPM3 is found in papillary thyroid carcinomas (PTCs). A rearrangement with NTRK1 generates the TRK fusion transcript by fusing the amino end of isoform 2 of TPM3 to the 3'-end of NTRK1.
Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments.
Homodimer. Heterodimer of an alpha (TPM1, TPM3 or TPM4) and a beta (TPM2) chain (By similarity). Interacts with TMOD1 (PubMed:8002995).
Peptides 2-27, 41-55, 132-153 and 163-169 have been identified and sequenced by MS.
Peptides 2-27, 41-55, 132-153, 163-169, 216-225 and 237-248 have been identified and sequenced by MS. PubMed:16201836 (ABC40673) sequence corresponds to a TPM3 retrocopy (rcTPM3) on chromosome 16 that is generated by retroposition of reversed transcribed mRNA back to the genome. rcTPM3 functionality is uncertain. It has been detected by MS in primary breast cancer tissues.
Belongs to the protein prenyltransferase subunit beta family.
Catalyzes the transfer of a geranyl-geranyl moiety from geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. Known substrates include RAC1, RAC2, RAP1A and RAP1B.
Heterodimer of FNTA and PGGT1B. PGGT1B mediates interaction with substrate peptides.
Cell surface glycoprotein that plays a role in cell adhesion and tumor progression (PubMed:2803308, PubMed:2022629, PubMed:1378450, PubMed:8776764, PubMed:11590190, PubMed:10910050, PubMed:14724575, PubMed:16204051). Intercellular adhesion occurs in a calcium- and fibronectin-independent manner (PubMed:2022629, PubMed:16204051). Mediates homophilic and heterophilic cell adhesion with other carcinoembryonic antigen-related cell adhesion molecules, such as CEACAM5 and CEACAM8 (PubMed:2803308, PubMed:2022629, PubMed:8776764, PubMed:11590190, PubMed:16204051). Heterophilic interaction with CEACAM8 occurs in activated neutrophils (PubMed:8776764). Plays a role in neutrophil adhesion to cytokine-activated endothelial cells (PubMed:1378450). Plays a role as an oncogene by promoting tumor progression; positively regulates cell migration, cell adhesion to endothelial cells and cell invasion (PubMed:16204051). Also involved in the metastatic cascade process by inducing gain resistance to anoikis of pancreatic adenocarcinoma and colorectal carcinoma cells (PubMed:10910050, PubMed:14724575).
Expressed in neutrophils (PubMed:1378450). Expressed in columnar epithelial and goblet cells of the colon (PubMed:10436421). Expressed in numerous tumor cell lines (at protein level) (PubMed:16204051).
Homodimer; homodimerizes via its Ig-like V-type domain. Heterodimer with CEACAM8; heterodimerizes via its Ig-like V-type domain.
The extracellular N-terminus Ig-like V-type domain is necessary for homophilic and heterophilic intercellular adhesion.
Up-regulated in anoikis-resistant pancreatic adenocarcinoma cells (at protein level).
Catalyzes the addition of GlcNAc or GlcUA monosaccharides to the nascent hyaluronan polymer. Therefore, it is essential to hyaluronan synthesis a major component of most extracellular matrices that has a structural role in tissues architectures and regulates cell adhesion, migration and differentiation. This is one of three isoenzymes responsible for cellular hyaluronan synthesis.
Homodimers (PubMed:25795779). Forms heterodimers with HAS2 and HAS1 (PubMed:25795779).
O-GlcNAcylation increases the hyaluronan synthase activity, HAS3 stability and its plasma membrane residence. The concentration of UDP-GlcNAc controls the level of O-GlcNAc modification.
The enzymatic activity depends on the availability of cytosolic levels of UDP-GlcUA and UDP-GlcNAc.
(Microbial infection) In case of hepatitis C virus/HCV infection, the complex formed by SLC3A2 and SLC7A5/LAT1 plays a role in HCV propagation by facilitating viral entry into host cell and increasing L-leucine uptake-mediated mTORC1 signaling activation, thereby contributing to HCV-mediated pathogenesis.
(Microbial infection) Up-regulation of the complex formed by SLC3A2 and SLC7A5/LAT1 upon hepatitis C virus/HCV infection.
Detected in placenta, in the syncytiotrophoblast layer (at protein level) (PubMed:11389679). Expressed abundantly in adult lung, liver, brain, skeletal muscle, placenta, bone marrow, testis, resting lymphocytes and monocytes, and in fetal liver. Weaker expression in thymus, cornea, retina, peripheral leukocytes, spleen, kidney, colon and lymph node. During gestation, expression in the placenta was significantly stronger at full-term than at the mid-trimester stage. Also expressed in all human tumor cell lines tested and in the astrocytic process of primary astrocytic gliomas. Expressed in retinal endothelial cells and in the intestinal epithelial cell line Caco-2.
Disulfide-linked heterodimer with the amino acid transport protein SLC3A2/4F2hc (PubMed:10049700, PubMed:10574970, PubMed:11389679, PubMed:11557028, PubMed:11564694, PubMed:12117417, PubMed:12225859, PubMed:15769744, PubMed:9751058, PubMed:25998567, PubMed:30867591). Interacts with LAPTM4B; this recruits the heterodimer formed by SLC3A2/4F2hc and SLC7A5 to lysosomes to promote leucine uptake into these organelles and is required for mTORC1 activation (PubMed:25998567).
Expression induced in quiescent peripheral blood lymphocytes after treatment with phorbol myristate acetate (PMA) and phytohemagglutinin (PHA). Expression and the uptake of leucine is stimulated in mononuclear, cytotrophoblast-like choriocarcinoma cells by combined treatment with PMA and calcium ionophore.
The heterodimer with SLC3A2 functions as sodium-independent, high-affinity transporter that mediates uptake of large neutral amino acids such as phenylalanine, tyrosine, leucine, histidine, methionine, tryptophan, valine, isoleucine and alanine (PubMed:9751058, PubMed:10049700, PubMed:11557028, PubMed:10574970, PubMed:11564694, PubMed:12117417, PubMed:12225859, PubMed:25998567, PubMed:30867591, PubMed:18262359, PubMed:15769744). The heterodimer with SLC3A2 mediates the uptake of L-DOPA (By similarity). Functions as an amino acid exchanger (PubMed:11557028, PubMed:12117417, PubMed:12225859, PubMed:30867591). May play a role in the transport of L-DOPA across the blood-brain barrier (By similarity). May act as the major transporter of tyrosine in fibroblasts (Probable). May mediate blood-to-retina L-leucine transport across the inner blood-retinal barrier (By similarity).Can mediate the transport of thyroid hormones diiodothyronine (T2), triiodothyronine (T3) and thyroxine (T4) across the cell membrane (PubMed:11564694). When associated with LAPTM4B, the heterodimer formed by SLC3A2 and SLC7A5 is recruited to lysosomes to promote leucine uptake into these organelles, and thereby mediates mTORC1 activation (PubMed:25998567). Involved in the uptake of toxic methylmercury (MeHg) when administered as the L-cysteine or D,L-homocysteine complexes (PubMed:12117417). Involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the membrane (PubMed:15769744).
The uptake of leucine, tyrosine and tryptophan is inhibited by the different iodothyronines, in particular T3 (PubMed:11564694). The uptake of T3 is almost completely blocked by coincubation with leucine, tryptophan, tyrosine, and phenylalanine, or 2-amino-bicyclo-(2,2,1)-heptane-2-carboxylate (BCH) (PubMed:11564694). Methionine uptake was inhibited by the L-system substrates L-leucine, BCH, L-cysteine and by the MeHg-L-cysteine complex and structurally related S-ethyl-L-cysteine (PubMed:12117417). MeHg-L-cysteine uptake is inhibited by L-methionine, L-leucine, BCH and S-ethyl-L-cysteine (PubMed:12117417). L-leucine transport is inhibited by phenylalanine, tyrosine, L-dopa, 3-O-methyldopa, a-methyltyrosine, a-methyldopa, gabapentin, triiodothyronine, thyroxine, melphalan and BCH (PubMed:12225859). L-leucine uptake was inhibited by L-CNSO (PubMed:15769744). Tyrosine uptake in fibroblasts was inhibited by D-methionine, and methyl-aminoisobutyric acid (MeAIB) (PubMed:18262359).
(Microbial infection) Specifically inhibited by the cowpox virus Crma protein.
Can form a heterodimer with Caspase-1 subunit p20 which then has an inhibitory effect.
Cleavage in the interdomain linker region is required to induce pyroptosis.
Expressed in larger amounts in spleen and lung. Detected in liver, heart, small intestine, colon, thymus, prostate, skeletal muscle, peripheral blood leukocytes, kidney and testis. No expression in the brain.
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-1 subunit p20) and a 10 kDa (Caspase-1 subunit p10) subunit (PubMed:8044845, PubMed:32109412, PubMed:32553275). Can form a heterodimer with isoform epsilon which then has an inhibitory effect (PubMed:7876192).
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-1 subunit p20) and a 10 kDa (Caspase-1 subunit p10) subunit (PubMed:8044845, PubMed:9987822, PubMed:32109412, PubMed:32553275). May be a component of the inflammasome, a protein complex which also includes PYCARD, CARD8 and NLRP2 and whose function would be the activation of pro-inflammatory caspases (PubMed:15030775, PubMed:33420033). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity). Interacts with CARD8; interacts with the released C-terminus of CARD8 which forms an inflammasome and directly activates CASP1 to promote pyroptosis (PubMed:32051255). Both the p10 and p20 subunits interact with MEFV (PubMed:16785446). Interacts with CARD17P/INCA and CARD18 (PubMed:15383541, PubMed:11051551). Interacts with SERPINB1; this interaction regulates CASP1 activity (PubMed:30692621).
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-1 subunit p20) and a 10 kDa (Caspase-1 subunit p10) subunit.
The two subunits are derived from the precursor sequence by an autocatalytic mechanism.
Thiol protease involved in a variety of inflammatory processes by proteolytically cleaving other proteins, such as the precursors of the inflammatory cytokines interleukin-1 beta (IL1B) and interleukin 18 (IL18) as well as the pyroptosis inducer Gasdermin-D (GSDMD), into active mature peptides (PubMed:15326478, PubMed:1574116, PubMed:7876192, PubMed:15498465, PubMed:26375003, PubMed:32051255). Plays a key role in cell immunity as an inflammatory response initiator: once activated through formation of an inflammasome complex, it initiates a pro-inflammatory response through the cleavage of the two inflammatory cytokines IL1B and IL18, releasing the mature cytokines which are involved in a variety of inflammatory processes (PubMed:1574116, PubMed:7876192, PubMed:15498465, PubMed:15326478, PubMed:32051255). Cleaves a tetrapeptide after an Asp residue at position P1 (PubMed:1574116, PubMed:7876192, PubMed:15498465). Also initiates pyroptosis, a programmed lytic cell death pathway, through cleavage of GSDMD (PubMed:26375003). In contrast to cleavage of interleukins IL1B and IL1B, recognition and cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP1 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32051255, PubMed:32109412, PubMed:32553275). Cleaves and activates CASP7 in response to bacterial infection, promoting plasma membrane repair (PubMed:22464733). Upon inflammasome activation, during DNA virus infection but not RNA virus challenge, controls antiviral immunity through the cleavage of CGAS, rendering it inactive (PubMed:28314590). In apoptotic cells, cleaves SPHK2 which is released from cells and remains enzymatically active extracellularly (PubMed:20197547).
Transcription and translation induced by M.tuberculosis and a number of different M.tuberculosis components; EsxA is the most potent activator tested (at protein level) (PubMed:20148899).
Ubiquitinated via 'Lys-11'-linked polyubiquitination. Deubiquitinated by USP8.
Interacts (via KRAB domain) with NR3C1/GR (via NR LBD domain); the interaction regulates transcription factor activity of NR3C1 by directing its actions toward certain biologic pathways.
The KRAB domain and the zinc finger domain are both necessary for the regulation of NR3C1/GR transcriptional activity.
Zinc finger protein that functions as a cofactor for steroid hormone receptors, such as NR3C1/GR (PubMed:28139699). Directs NR3C1/GR transcriptional activity toward specific biologic pathways by changing NR3C1/GR binding and transcriptional activity on the glucocorticoid-responsive genes (PubMed:28139699).
(Microbial infection) During Ebola virus (EBOV) infection, controls the movement of endosomes containing virus particles and is required by EBOV to escape from the endosomal network into the cell cytoplasm.
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. Two pore calcium channel subfamily.
Dimer. Interacts with MTOR; the interaction is required for TPCN1 ATP sensitivity (PubMed:23394946). Interacts with STX7, STX8 and STX12 (By similarity). Interacts with JPT2 (PubMed:33758061). Found in a complex with LSM12, TPCN1 and TPCN2 (PubMed:34362892).
Each of the two internal repeats contains five hydrophobic transmembrane segments (S1, S2, S3, S5, S6) and one positively charged transmembrane segment (S4). S4 segments represent the voltage-sensor and are characterized by a series of positively charged amino acids at every third position.
Highest expression found in the heart and kidney, and lowest expression found in the spleen.
Intracellular channel initially characterized as a non-selective Ca(2+)-permeable channel activated by NAADP (nicotinic acid adenine dinucleotide phosphate), it is also a voltage-gated highly-selective Na(+) channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate) that senses pH changes and confers electrical excitability to organelles (PubMed:19620632, PubMed:23063126, PubMed:24776928, PubMed:23394946). Localizes to the early and recycling endosomes membranes where it plays a role in the uptake and processing of proteins and regulates organellar membrane excitability, membrane trafficking and pH homeostasis (PubMed:23394946) (Probable). Ion selectivity is not fixed but rather agonist-dependent and under defined ionic conditions, can be readily activated by both NAADP and PI(3,5)P2 (Probable). Required for mTOR-dependent nutrient sensing (PubMed:23394946) (Probable).
Na(+) current is inhibited by ATP in a MTORC-dependent manner. ATP sensitivity is independent of PI(3,5)P2 (PubMed:23394946). Probably regulated by Mg(2+) ions, cytosolic Mg(2+) selectively inhibits outward current while lysosomal Mg(2+) modestly inhibits both the outward and inward currents. In the absence of Mg(2+), NAADP readily activates TPCN2, with properties similar to PI(3,5)P2 (By similarity). Both current elicited by PI(3,5)P2 as well as NAADP are inhibited by tetrandrine.
Lipid phosphatase that has high specificity for phosphatidylinositol 3-phosphate and has no activity with phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate (PubMed:11733541, PubMed:27018598). Activity with phosphatidylinositol (3,5)-bisphosphate is controversial; it has been shown by PubMed:27018598, while PubMed:11733541 find no activity with this substrate.
The C-terminal region is required for dimerization.
Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 2 complex (dynein-2 complex), a motor protein complex that drives the movement of cargos along microtubules within cilia and flagella in concert with the intraflagellar transport (IFT) system (PubMed:23910462, PubMed:25205765, PubMed:31451806, PubMed:29742051). DYNC2I1 plays a major role in retrograde ciliary protein trafficking in cilia and flagella (PubMed:29742051, PubMed:30320547, PubMed:30649997). Requires also to maintain a functional transition zone (PubMed:30320547).
Expressed in chondrocytes (at protein level).
Intermediate chain of the cytoplasmic dynein complex 2, a multisubunit complex, composed at least of eleven different proteins (PubMed:31451806, PubMed:25205765). The cytoplasmic dynein 2 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs). Among them, a heavy chain (DYNC2H1), two intermediate chains (DYNC2I2 and DYNC2I1), a light intermediate chain (DYNC2LI1), and a light chain (DYNLT2B) are unique to the cytoplasmic dynein complex 2, but a subset of the light chains are also shared by dynein-1 and dynein-2 complexes (PubMed:25205765, PubMed:31451806). Interacts with DYNC2I2; their C-terminal domains each bind a copy of the heavy chain, and their extended N-terminal regions are held together by an array of light chain dimers (PubMed:29742051, PubMed:31451806, PubMed:30320547). Interacts with DYNLT2B (PubMed:26044572). Interacts (via the N-terminal half) with DYNLT2B-DYNLT1 dimer or with DYNLT2B-DYNLT3 dimer; this interaction is crucial for retrograde trafficking of ciliary proteins (PubMed:29742051).
The disease is caused by variants affecting the gene represented in this entry. Fibroblasts from affected individuals exhibit a defect in ciliogenesis and aberrant accumulation of the GLI2 transcription factor at the centrosome or basal body in the absence of an obvious axoneme.
Expressed in retina and at low levels in brain, lung and placenta (PubMed:11779638). High expression in fetal tissues (PubMed:11867212).
Has aminoprocollagen type I processing activity in the absence of ADAMTS2 (PubMed:11741898). Seems to be synthesized as a latent enzyme that requires activation to display aminoprocollagen peptidase activity (PubMed:11741898). Cleaves lysyl oxidase LOX at a site downstream of its propeptide cleavage site to produce a short LOX form (PubMed:31152061).
Produced by alternative splicing of isoform A.
Anti-inflammatory antagonist of interleukin-1 family of proinflammatory cytokines such as interleukin-1beta/IL1B and interleukin-1alpha/IL1A. Protects from immune dysregulation and uncontrolled systemic inflammation triggered by IL1 for a range of innate stimulatory agents such as pathogens.
Available under the name Kineret (Amgen). Used for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis.
The intracellular form of IL1RN is predominantly expressed in epithelial cells.
Hydrolyzes the phosphodiester bond of glycerophosphodiesters such as glycerophosphoinositol (GroPIns) and glycerophosphoethanolamine (GroPEth), to yield a glycerol phosphate and an alcohol (By similarity). Hydrolyzes glycerophospho-N-acylethanolamines to N-acylethanolamines in the brain and participates in bioactive N-acylethanolamine biosynthesis such as anandamide (an endocannabinoid), N-palmitoylethanolamine (an anti-inflammatory), and N-oleoylethanolamine (an anorexic). In addition, has a lysophospholipase D activity by hydrolyzing N-acyl-lysoplasmenylethanolamine (N-acyl-lysoPlsEt) to N-acylethanolamine. However lysophospholipase D activity is lower than glycerophosphodiester phosphodiesterase activity (By similarity). Has little or no activity towards glycerophosphocholine (By similarity).
Inhibited by EDTA, calcium chloride, and zinc chloride. Enhanced by magnesium chloride (By similarity). Glycerophosphodiester phosphodiesterase activity can be modulated by G-protein signaling pathways (By similarity).
Interacts with PRAF2 (PubMed:16472945). Interacts with RGS16 (By similarity).
Expressed in fetal skeletal muscle and retina.
A short peptide sequence (termed the Stachel sequence) in the C-terminal part of the extra-cellular domain (ECD) functions as a tethered agonist. Upon structural changes within the ECD, e.g. due to extracellular ligand binding or mechanical movements, this intramolecular agonist is exposed to the 7TM domain, triggering G-protein activation.
Expressed in placenta and to a lower extent in pancreas and liver. Detected in aortic endothelial cells but not in skin microvascular endothelial cells.
G-protein coupled receptor which is activated by type IV collagen, a major constituent of the basement membrane (By similarity). Couples to G(i)-proteins as well as G(s)-proteins (PubMed:24227709). Essential for normal differentiation of promyelinating Schwann cells and for normal myelination of axons (PubMed:24227709). Regulates neural, cardiac and ear development via G-protein- and/or N-terminus-dependent signaling (By similarity). May act as a receptor for PRNP which may promote myelin homeostasis (By similarity).
Genetic variations in ADGRG6 influences stature as a quantitative trait (STQTL) [MIM:606255]. Adult height is an easily observable and highly heritable complex continuous trait. Because of this, it is a model trait for studying genetic influence on quantitative traits.
Interacts with Laminin-2; this interaction stabilizes the receptor in an inactive state. Laminin-2 polymerization could facilitate ADGRG6-NTF removal, thereby exposing the tethered agonist to drive myelination. Interacts with PRNP.
Proteolytically cleaved into 2 conserved sites: one in the GPS domain (S1 site) and the other in the middle of the extracellular domain (S2 site). The proteolytic cleavage at S1 site generates an extracellular subunit and a seven-transmembrane subunit. Furin is involved in the cleavage of the S2 site generating a soluble fragment. Processing at the GPS domain occurred independent of and probably prior to the cleavage at the S2 site. Proteolytic cleavage is required for activation of the receptor.
Up-regulated by bacterial lipopolysaccharides (LPS) and thrombin, but not by other inflammatory stimuli in primary umbilical veins.
Interacts with the MON1A-CCZ1B complex (PubMed:34432599). Interacts with GDP-bound RAB7A and promotes its interaction with the MON1A-CCZ1B complex (PubMed:34432599).
Plays an important role in the removal of damaged mitochondria via mitophagy by controlling the stability and localization of RAB7A. Required for the recruitment of RAB7A and ATG9A vesicles to damaged mitochondria and promotes the stability of RAB7A by inhibiting its proteasomal degradation during mitophagy.
Catalyzes the conversion of prostaglandin H2 (PGH2) to thromboxane A2 (TXA2), a potent inducer of blood vessel constriction and platelet aggregation (PubMed:8436233, PubMed:11297515, PubMed:9873013, PubMed:11097184, PubMed:24009185, PubMed:22735388). Cleaves also PGH2 to 12-hydroxy-heptadecatrienoicacid (12-HHT) and malondialdehyde, which is known to act as a mediator of DNA damage. 12-HHT and malondialdehyde are formed stoichiometrically in the same amounts as TXA2 (PubMed:11297515, PubMed:9873013, PubMed:22735388). Additionally, displays dehydratase activity, toward (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (15(S)-HPETE) producing 15-KETE and 15-HETE (PubMed:17459323).
It is uncertain whether Met-1 is the initiator. An alternative upstream Met is found in primates, but not in other mammals.
Platelets, lung, kidney, spleen, macrophages and lung fibroblasts.
Thromboxane synthetase deficiency has been detected in some patients with a bleeding disorder due to platelet dysfunction.
GTPase activating protein (GAP) which specifically converts GTP-bound Rho-type GTPases including RAC1 and CDC42 in their inactive GDP-bound form. By specifically inactivating RAC1 at the leading edge of migrating cells, it regulates the spatiotemporal organization of cell protrusions which is important for proper cell migration (PubMed:21658605). Also negatively regulates CDC42 in the process of actin remodeling and the formation of epithelial cell junctions (PubMed:22891260). Through its GAP activity toward RAC1 and/or CDC42 plays a specific role in phagocytosis of large particles. Specifically recruited by a PI3 kinase/PI3K-dependent mechanism to sites of large particles engagement, inactivates RAC1 and/or CDC42 allowing the reorganization of the underlying actin cytoskeleton required for engulfment (PubMed:26465210). It also plays a role in angiogenesis and the process of repulsive guidance as part of a semaphorin-plexin signaling pathway. Following the binding of PLXND1 to extracellular SEMA3E it dissociates from PLXND1 and inactivates RAC1, inducing the intracellular reorganization of the actin cytoskeleton and the collapse of cells (PubMed:24841563).
Interacts with RAC1 (By similarity). Interacts with the exocyst via EXOC4 and EXOC8; required for the localization of both SH3BP1 and the exocyst to the leading edge of migrating cells (PubMed:21658605). Interacts with CD2AP and CGNL1; probably part of a complex at cell junctions (PubMed:22891260). Interacts with CAPZA1; recruits CAPZA1 to forming cell junctions (PubMed:22891260). May interact with AFDN (PubMed:22891260). Interacts with PLXND1; they dissociate upon SEMA3E binding to PLXND1 allowing SH3BP1 to transduce downstream signal through RAC1 inactivation (PubMed:24841563). Interacts with ABL1, GRB2 and SRC (via SH3 domain) (By similarity).
The BAR domain mediates interaction with the exocyst components EXOC4 and EXOC8 and is required for the function in cell migration (PubMed:21658605). It also mediates the interaction with PLXND1 (PubMed:24841563).
Maximal expression during the erythroblast terminal differentiation.
A connexon is composed of a hexamer of connexins. Interacts with CNST (By similarity).
(Microbial infection) Interacts (via C-terminus) with HIV-1 Tat and Rev.
Expressed in lymphatic tissues. Detected in the spleen, thymus, peripheral blood leukocytes as well as prostate, uterus and small intestine. Expressed in lymphatic endothelial cells (PubMed:35235341).
Interacts with HAND1; leading to sequester HAND1 into the nucleolus and prevent its activity. The C-terminus interacts with ZIC2 (By similarity). The C-terminus interacts with AXIN1, the histidine-rich region of CCNT1/cyclin-T and weakly with LEF1 (PubMed:12192039). Interacts with CCNT2 (PubMed:17289077). Interacts with GATA2 (By similarity).
Minor isoform. Initiates from a GTG codon. Contains a Nucleolar localization signal at positions 45-63.
Required to control the activity of various transcription factors through their sequestration in the cytoplasm. Retains nuclear Zic proteins ZIC1, ZIC2 and ZIC3 in the cytoplasm and inhibits their transcriptional activation (By similarity). Modulates the expression from both cellular and viral promoters. Down-regulates Tat-dependent transcription of the human immunodeficiency virus type 1 (HIV-1) LTR by interacting with HIV-1 Tat and Rev and impairing their nuclear import, probably by rendering the NLS domains inaccessible to importin-beta (PubMed:16260749, PubMed:12944466, Ref.6). Also stimulates activation of human T-cell leukemia virus type I (HTLV-I) LTR (PubMed:10671520). Binds to the axin complex, resulting in an increase in the level of free beta-catenin (PubMed:12192039). Affects axin regulation of the WNT and JNK signaling pathways (PubMed:12192039). Has a role in the development of lymphatic vessel valves. It is required to promote lymphatic endothelial cell migration, in a process that involves down-regulation of integrin beta 1 activation and control of cell adhesion to the extracellular matrix (PubMed:35235341) (By similarity).
The cysteine-rich C-terminus is involved in its granular distribution in the cytoplasm. The cysteine-rich C-terminus mediates protein-protein interactions, including interaction with HIV-1 Tat, transcription factors, AXIN1, CCNT1 (PubMed:16260749, PubMed:12192039, PubMed:12944466).
Belongs to the gamma type-C retroviral envelope protein family. HERV class-I FRD env subfamily.
CKS-17 sequence does not match the minimal active consensus.
Contains the CKS-17 immunosuppressive domain present in many retroviral envelope proteins. As a synthetic peptide, it inhibits immune function in vitro and in vivo (By similarity).
Endogenous envelope proteins may have kept, lost or modified their original function during evolution but this one can still make pseudotypes with MLV, HIV-1 or SIV-1 virions and confer infectivity. Retroviral envelope proteins mediate receptor recognition and membrane fusion during early infection. The surface protein mediates receptor recognition, while the transmembrane protein anchors the envelope heterodimer to the viral membrane through one transmembrane domain. The other hydrophobic domain, called fusion peptide, mediates fusion of the viral membrane with the target cell membrane (PubMed:14694139).
Expressed at higher level in placenta. Expressed at lower level in adrenal, bone marrow, brain, breast, colon, kidney, lung, ovary, peripheral blood lymphocytes, prostate, skin, spleen, testis, thymus, thyroid, trachea.
HERV-FRD subgenomic RNA has been observed.
Ortholog in old-world and new-world monkeys, but not in prosimians.
Specific enzymatic cleavages in vivo yield the mature SU and TM proteins.
The CXXC motif is highly conserved across a broad range of retroviral envelope proteins. It is thought to participate in the formation of a labile disulfide bond possibly with the CX6CC motif present in the transmembrane protein. Isomerization of the intersubunit disulfide bond to an SU intrachain disulfide bond is thought to occur upon receptor recognition in order to allow membrane fusion (By similarity).
The human genome contains a high percentage of proviral-like elements, also called endogenous retroviruses (ERVs) that are the genomic traces of ancient infections of the germline by exogenous retroviruses. Although most of these elements are defective, some have conserved a functional envelope (env) gene, most probably diverted by the host for its benefit.
The surface and transmembrane proteins form a heterodimer. They are attached by non-covalent interactions or by a labile interchain disulfide bond (By similarity). Interacts with MFSD2A.
This endogenous retroviral envelope protein has retained its original fusogenic properties and participates in trophoblast fusion and the formation of a syncytium during placenta morphogenesis. The interaction with MFSD2A is apparently important for this process (PubMed:18988732).
Belongs to the HAD-like hydrolase superfamily.
Inactive serine/threonine-protein kinase (PubMed:32531246, PubMed:32531245) (Probable). May control NRAS activity via an associated kinase (PubMed:32531246) (Probable).
Inactive serine/threonine-protein kinase.
Increased by ultraviolet radiation in melanocyte.
Monocytes, hepatocytes, epithelial cells, T- and B-lymphocytes.
Originally found as a serine/threonine-protein kinase that phosphorylates CSN1S1/alpha-casein at serine/threonine residues, histones at serine residues (PubMed:9812991) and NRAS at serine residues (PubMed:30712867, PubMed:9812991). According to a recent study, it is inactive (PubMed:32531246, PubMed:32531245).
There is a discrepancy about the expression of this isoform (PubMed:32531245, PubMed:30712867). At protein level, Rodriguez-Martinez et al. shows that isoform 1 is not expressed in melanocyte cells lines and two commonly used human cell lines (HEK293 and HeLa) (PubMed:32531245). According to Yin et al. isoform 1 is expressed, at very low level, in melanocyte cells lines and human primary melanocytes (PubMed:30712867).
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3. Interacts with RPS19; the interaction is direct and mediates the integration of RPS19 in state post-A1 (PubMed:34516797). Interacts with SIRT1 (PubMed:17964266).
Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. Acts as a chaperone that specifically mediates the integration of RPS19 in state post-A1 (PubMed:34516797). Direct regulator of SIRT1. Enhances SIRT1-mediated deacetylation of p53/TP53, thereby participating in inhibition of p53/TP53-mediated transcriptional activity (PubMed:17964266).
Predominantly expressed in adult atrial muscle.
Expressed in sperm and airway epithelial cells (at protein level).
In the C-terminal section; belongs to the dpy-30 family.
In the central section; belongs to the adenylate kinase family.
Nucleoside monophosphate (NMP) kinase that catalyzes the reversible transfer of the terminal phosphate group between nucleoside triphosphates and monophosphates. Has highest activity toward AMP, and weaker activity toward dAMP, CMP and dCMP. Also displays broad nucleoside diphosphate kinase activity. Involved in maintaining ciliary structure and function.
Abundant in the heart, brain, skeletal muscle, kidney, and pancreas, with little or no expression in the lung and liver.
Homodimer and homotetramer via the coiled coil regions (PubMed:11283256). Interacts tightly with GTP-bound but not GDP-bound CDC42 (PubMed:9418861). Forms a tripartite complex with MYO18A and LURAP1 with the latter acting as an adapter connecting CDC42BPA and MYO18A. LURAP1 binding results in activation of CDC42BPA by abolition of its negative autoregulation (PubMed:18854160). Interacts with LURAP1. Interacts (via AGC-kinase C-terminal domain) with FAM89B/LRAP25 (via LRR repeat). Forms a tripartite complex with FAM89B/LRAP25 and LIMK1 (By similarity).
Maintained in an inactive, closed conformation by an interaction between the kinase domain and the negative autoregulatory C-terminal coiled-coil region. Agonist binding to the phorbol ester binding site disrupts this, releasing the kinase domain to allow N-terminus-mediated dimerization and kinase activation by transautophosphorylation. Inhibited by chelerythrine chloride.
Proteolytically cleaved by caspases upon apoptosis induction. The cleavage at Asp-478 by CASP3 increases its kinase activity (in vitro).
Serine/threonine-protein kinase which is an important downstream effector of CDC42 and plays a role in the regulation of cytoskeleton reorganization and cell migration (PubMed:15723050, PubMed:9418861, PubMed:9092543). Regulates actin cytoskeletal reorganization via phosphorylation of PPP1R12C and MYL9/MLC2 (PubMed:21457715). In concert with MYO18A and LURAP1, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration (PubMed:18854160). Phosphorylates: PPP1R12A, LIMK1 and LIMK2 (PubMed:11340065, PubMed:11399775). May play a role in TFRC-mediated iron uptake (PubMed:20188707). In concert with FAM89B/LRAP25 mediates the targeting of LIMK1 to the lamellipodium resulting in its activation and subsequent phosphorylation of CFL1 which is important for lamellipodial F-actin regulation (By similarity). Triggers the formation of an extrusion apical actin ring required for epithelial extrusion of apoptotic cells (PubMed:29162624).
Functions as thioether S-methyltransferase and is active with a variety of thioethers and the corresponding selenium and tellurium compounds, including 3-methylthiopropionaldehyde, dimethyl selenide, dimethyl telluride, 2-methylthioethylamine, 2-methylthioethanol, methyl-n-propyl sulfide and diethyl sulfide. Plays an important role in the detoxification of selenium compounds (By similarity). Catalyzes the N-methylation of tryptamine and structurally related compounds.
Widely expressed. The highest levels were in thyroid, adrenal gland, adult and fetal lung. Intermediate levels in heart, placenta, skeletal muscle, testis, small intestine, pancreas, stomach, spinal cord, lymph node and trachea. Very low levels in adult and fetal kidney and liver, in adult spleen, thymus, ovary, colon and bone marrow. Not expressed in peripheral blood leukocytes and brain.
FABPs are thought to play a role in the intracellular transport of long-chain fatty acids and their acyl-CoA esters.
Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2. The complex exists in quiescent cells where it represses cell cycle-dependent genes. It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2.
Component of the DREAM complex, a multiprotein complex that can both act as a transcription activator or repressor depending on the context (PubMed:17671431, PubMed:17531812). In G0 phase, the complex binds to more than 800 promoters and is required for repression of E2F target genes (PubMed:17671431, PubMed:17531812). In S phase, the complex selectively binds to the promoters of G2/M genes whose products are required for mitosis and participates in their cell cycle dependent activation (PubMed:17671431, PubMed:17531812). In the complex, acts as a DNA-binding protein that binds the promoter of CDK1 in a sequence-specific manner (PubMed:19725879). Specifically recognizes the consensus motif 5'-TTYRAA-3' in target DNA (PubMed:27465258).
The CRC domain mediates DNA-binding (PubMed:19725879, PubMed:27465258). It contains two CXC subdomains (joined by a flexible linker) which are both required for efficient association with target DNA (PubMed:27465258). Each CXC subdomain coordinates three Zn(2+) ions (PubMed:27465258).
Homodimer. Found in a complex with SYCP1 and SYCE1. Interacts with SYCP1, SYCE1 and SYCE3 (By similarity). Interacts with TEX12 (By similarity).
Major component of the transverse central element of synaptonemal complexes (SCS), formed between homologous chromosomes during meiotic prophase. Requires SYCP1 in order to be incorporated into the central element. May have a role in the synaptonemal complex assembly, stabilization and recombination (By similarity).
Bone marrow cells. Neutrophil (PubMed:10947984).
Serine protease that modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis (PubMed:15140022). Promotes cleavage of GSDMB, thereby inhibiting pyroptosis (PubMed:36899106). Capable of killing E.coli but not S.aureus in vitro; digests outer membrane protein A (ompA) in E.coli and K.pneumoniae (PubMed:10947984).
Deubiquitinating enzyme that hydrolyzes 'Lys-27'-, 'Lys-29'- and 'Lys-33'-linked polyubiquitin chains. Also able to hydrolyze 'Lys-11'-linked ubiquitin chains.
Expressed in bronchial and nasal epithelial cells (at protein level) (PubMed:30665704). Expressed in brain, kidney, lung, testis, fallopian tubes, and skeletal muscle (PubMed:12584248, PubMed:30665704). Expressed at low levels in stomach and colon (PubMed:30665704).
Interacts with ADORA2A (via its cytoplasmic C-terminal domain) (By similarity). Interacts with GNAS, GNAL, GNAQ, and GNA13 (PubMed:23994616). Interacts with MAPRE1 (PubMed:24706950).
Involved in the cross-linking of microtubules and microfilaments (PubMed:12584248, PubMed:24706950). Regulates microtubule dynamics and stability by interacting with microtubule plus-end tracking proteins, such as MAPRE1, to regulate microtubule growth along actin stress fibers (PubMed:24706950). Enhances ADORA2-mediated adenylyl cyclase activation by acting as a scaffold to recruit trimeric G-protein complexes to ADORA2A (By similarity). Regulates ciliary orientation and performance in cells located in the airway (PubMed:30665704).
The disease is caused by variants affecting the gene represented in this entry. Absence of GAS2L2 results in ciliary orientation defect and affects performance of cilia.
Belongs to the ABC transporter superfamily. ABCG family. Eye pigment precursor importer (TC 3.A.1.204) subfamily.
Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity).
Genetic variations in ABCG2 define the blood group Junior system (JR) [MIM:614490]. Individuals with Jr(a-) blood group lack the Jr(a) antigen on their red blood cells. These individuals may have anti-Jr(a) antibodies in their serum, which can cause transfusion reactions or hemolytic disease of the fetus or newborn. Although the clinical significance of the Jr(a-) blood group has been controversial, severe fatal hemolytic disease of the newborn has been reported. The Jr(a-) phenotype has a higher frequency in individuals of Asian descent, compared to those of European descent. The Jr(a-) phenotype is inherited as an autosomal recessive trait.
Genetic variations in ABCG2 influence the variance in serum uric acid concentrations and define the serum uric acid concentration quantitative trait locus 1 (UAQTL1) [MIM:138900]. Excess serum accumulation of uric acid can lead to the development of gout, a common disorder characterized by tissue deposition of monosodium urate crystals as a consequence of hyperuricemia (PubMed:18834626, PubMed:19506252, PubMed:20368174).
Highly expressed in placenta (PubMed:9850061). Low expression in small intestine, liver and colon (PubMed:9861027). Expressed in brain (at protein level) (PubMed:12958161).
Homodimer; disulfide-linked (PubMed:15001581, PubMed:17686774, PubMed:18056989, PubMed:28554189). The minimal functional unit is a homodimer, but the major oligomeric form in plasma membrane is a homotetramer with possibility of higher order oligomerization up to homododecamers (PubMed:15001581).
N-glycosylated (PubMed:15807535, PubMed:23189181). Glycosylation-deficient ABCG2 is normally expressed and functional.
Phosphorylated. Phosphorylation at Thr-362 by PIM1 is induced by drugs like mitoxantrone and is associated with cells increased drug resistance. It regulates the localization to the plasma membrane, the homooligomerization and therefore, the activity of the transporter.
Specifically inhibited by the fungal toxin fumitremorgin C and Ko143.
The extracellular loop 3 (ECL3) is involved in binding porphyrins and transfer them to other carriers, probably albumin.
Was originally proposed to function as a glutathione transporter (PubMed:20332504). However, some evidences suggest it is not the case (PubMed:24312054).
Probable component of the NALCN channel complex, a channel that regulates the resting membrane potential and controls neuronal excitability.
Belongs to the aldo/keto reductase family. Aldo/keto reductase 2 subfamily.
Can reduce the dialdehyde protein-binding form of aflatoxin B1 (AFB1) to the non-binding AFB1 dialcohol. May be involved in protection of liver against the toxic and carcinogenic effects of AFB1, a potent hepatocarcinogen.
Expressed in colon, kidney, liver, pancreas, adenocarcinoma and endometrium.
Does not bind diphenhydramine, loratadine, ranitidine, cimetidine and chlorpheniramine. Shows modest affinity for dimaprit, impromidine, clobenpropit, thioperamide, burimamide clozapine, immepip and imetit. The order of inhibitory activity was imetit > clobenpropit > burimamide > thioperamide. Clobenpropit behaves as a partial agonist, dimaprit and impromidine show some agonist activity while clozapine behaves as a full agonist. Thioperamide shows inverse agonism (enhances cAMP activity). The order of inhibitory activity of histamine derivatives was Histamine > N-alpha-methylhistamine > R(-)-alpha-methylhistamine > S(+)-alpha-methylhistamine. Both N-alpha-methylhistamine > R(-)-alpha-methylhistamine behave as full agonists.
Expressed primarily in the bone marrow and eosinophils. Shows preferential distribution in cells of immunological relevance such as T-cells, dendritic cells, monocytes, mast cells, neutrophils. Also expressed in a wide variety of peripheral tissues, including the heart, kidney, liver, lung, pancreas, skeletal muscle, prostate, small intestine, spleen, testis, colon, fetal liver and lymph node.
Expression is either up-regulated or down-regulated upon activation of the lymphoid tissues and this regulation may depend on the presence of IL10/interleukin-10 or IL13/interleukin-13.
The H4 subclass of histamine receptors could mediate the histamine signals in peripheral tissues. Displays a significant level of constitutive activity (spontaneous activity in the absence of agonist).
(Microbial infection) Interacts with hepatitis virus C/HCV core protein.
Has been sometimes referred to as a collectin receptor.
Highly expressed in endothelial cells, platelets, cells of myeloid origin, such as monocytes and neutrophils. Not expressed in cells of lymphoid origin.
Interacts with C1QBP; the association may represent a cell surface C1q receptor.
PubMed:11994479 reported that C1q is not a ligand for C1QR1.
Receptor (or element of a larger receptor complex) for C1q, mannose-binding lectin (MBL2) and pulmonary surfactant protein A (SPA). May mediate the enhancement of phagocytosis in monocytes and macrophages upon interaction with soluble defense collagens. May play a role in intercellular adhesion.
(Microbial infection) Confers susceptibility to feline leukemia virus subgroup C (FeLV-C) infection in vitro.
Defects in FLVCR1 are a cause of a sensory neuropathy resulting in pain insensitivity. Patients have decreased sensing of pain, temperature and touch. Self-injury, ulcers and amputations are commonly observed in affected individuals.
Down-regulated in haemopoietic progenitor cells undergoing differentiation and hemoglobinization. Abundant in fetal liver.
Found all hematopoietic tissues including peripheral blood lymphocytes. Some expression is found in pancreas and kidney.
Has a probable mitochondrial transit peptide at positions 1-38.
Heme b transporter that mediates heme efflux from the cytoplasm to the extracellular compartment. Heme export depends on the presence of HPX and is required to maintain intracellular free heme balance, protecting cells from heme toxicity. Heme export provides protection from heme or ferrous iron toxicities in liver, brain, sensory neurons and during erythropoiesis, a process in which heme synthesis intensifies. Possibly export coproporphyrin and protoporphyrin IX, which are both intermediate products in the heme biosynthetic pathway. Does not export bilirubin. The molecular mechanism of heme transport, whether electrogenic, electroneutral or coupled to other ions, remains to be elucidated.
Heme b transporter that promotes heme efflux from the mitochondrion to the cytoplasm. Essential for erythroid differentiation.
The disease is caused by variants affecting the gene represented in this entry. Defective neuronal heme transmembrane export due to FLVCR1 mutations may abrogate the neuroprotective effects of neuroglobin and initiate an apoptotic cascade that results in the selective degeneration of photoreceptors in the neurosensory retina and sensory neurons in the posterior spinal cord.
Belongs to the Antp homeobox family. Labial subfamily.
Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. Acts on the anterior body structures.
A stop codon in the gene coding for this protein at position Tyr-259 is responsible for functional diversity thus producing thus a pseudogene.
Expressed at high levels in spleen, thymus and leukocytes. Also expressed in lung and placenta, and at very low levels in brain, heart, skeletal muscle and kidney. Expressed in cytotoxic T-lymphocytes (CTL) and mast cells.
Interacts with DOC2A (By similarity). Interacts with RAB27A (PubMed:15548590, PubMed:17237785). Interacts with RHOG; the interaction increases RhoG affinity to the membrane lipids, targets UNC13D to membrane lipids and facilitates cytotoxic granule (CG) docking to the plasma membrane (PubMed:33513601).
Plays a role in cytotoxic granule exocytosis in lymphocytes. Required for both granule maturation and granule docking and priming at the immunologic synapse. Regulates assembly of recycling and late endosomal structures, leading to the formation of an endosomal exocytic compartment that fuses with perforin-containing granules at the immunologic synapse and licences them for exocytosis. Regulates Ca(2+)-dependent secretory lysosome exocytosis in mast cells.
The MHD1 and MHD2 domains mediate localization on recycling endosomes and lysosome.
Highly variable expression among individuals is associated with differential sensitivity to the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), decreased expression being associated with increased sensitivity.
(Microbial infection) Interacts with Yersinia YopJ.
(Microbial infection) Yersinia YopJ may acetylate Ser/Thr residues, preventing phosphorylation and activation, thus blocking the MAPK signaling pathway.
Abundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues.
Activated by dual phosphorylation on Ser-218 and Thr-222.
Autophosphorylated. Phosphorylation on Ser-218 and Thr-222 by MAP kinase kinase kinases regulates positively the kinase activity (PubMed:8622669). Phosphorylated by TAOK2 (PubMed:11279118).
Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK (PubMed:21224381). Binds to DYRK1B/MIRK and increases its kinase activity (PubMed:11980910). Part of a complex with MAP3K3, RAC1 and CCM2 (By similarity). Interacts with ARRB1 (PubMed:16709866).
Defects in MAP2K3 may be involved in colon cancer.
Dual specificity kinase. Is activated by cytokines and environmental stress in vivo. Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinase p38. Part of a signaling cascade that begins with the activation of the adrenergic receptor ADRA1B and leads to the activation of MAPK14.
Activated by autocatalytic cleavage (PubMed:23682772). Inhibited by serine-borate (PubMed:21447318).
Chloride ions bound in the active site cavity may contribute to stabilize the protein fold.
Cleaves the gamma-glutamyl bond of extracellular glutathione (gamma-Glu-Cys-Gly), glutathione conjugates (such as maresin conjugate (13R)-S-glutathionyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate, MCTR1) and other gamma-glutamyl compounds (such as leukotriene C4, LTC4) (PubMed:17924658, PubMed:21447318, PubMed:27791009). The metabolism of glutathione by GGT1 releases free glutamate and the dipeptide cysteinyl-glycine, which is hydrolyzed to cysteine and glycine by dipeptidases (PubMed:27791009). In the presence of high concentrations of dipeptides and some amino acids, can also catalyze a transpeptidation reaction, transferring the gamma-glutamyl moiety to an acceptor amino acid to form a new gamma-glutamyl compound (PubMed:17924658, PubMed:7673200, PubMed:7759490, PubMed:8095045, PubMed:8827453, PubMed:21447318). Contributes to cysteine homeostasis, glutathione homeostasis and in the conversion of the leukotriene LTC4 to LTD4.
Cleaves the gamma-glutamyl peptide bond of glutathione and glutathione conjugates.
Cys-454 was thought to bind the gamma-glutamyl moiety, but mutagenesis of this residue had no effect on activity.
Detected in fetal and adult kidney and liver, adult pancreas, stomach, intestine, placenta and lung. There are several other tissue-specific forms that arise from alternative promoter usage but that produce the same protein.
N-glycosylated on both chains. Contains hexoses, hexosamines and sialic acid residues. Glycosylation profiles tested in kidney and liver tissues reveal the presence of tissue-specific and site-specific glycan composition, despite the overlap in composition among the N-glycans. A total of 36 glycan compositions, with 40 unique structures are observed. Up to 15 different glycans are observed at a single site, with site-specific variation in glycan composition. The difference in glycosylation profiles in the 2 tissues do not affect the enzyme activity.
The disease is caused by variants affecting the gene represented in this entry. A large homozygous deletion that removes several exons of all isoforms of GGT1 has been found in one family affected by glutathionuria.
(Microbial infection) The NELF complex is involved in HIV-1 latency possibly involving recruitment of PCF11 to paused RNA polymerase II (PubMed:23884411). In vitro, binds weakly to the HIV-1 TAR RNA which is located in the long terminal repeat (LTR) of HIV-1 (PubMed:23884411).
Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II (PubMed:12612062). The NELF complex, which acts via an association with the DSIF complex and causes transcriptional pausing, is counteracted by the P-TEFb kinase complex (PubMed:10199401). May be able to induce chromatin unfolding (PubMed:11739404). Essential for early embryogenesis; plays an important role in maintaining the undifferentiated state of embryonic stem cells (ESCs) by preventing unscheduled expression of developmental genes (By similarity). Plays a key role in establishing the responsiveness of stem cells to developmental cues; facilitates plasticity and cell fate commitment in ESCs by establishing the appropriate expression level of signaling molecules (By similarity). Supports the transcription of genes involved in energy metabolism in cardiomyocytes; facilitates the association of transcription initiation factors with the promoters of the metabolism-related genes (By similarity).
Produced by alternative initiation at a CTG start codon.
The NELF complex is composed of NELFA, NELFB, NELFCD (isoform NELF-C or isoform NELF-D) and NELFE; the N-terminus of NELFB binds to the NELFA:NELFCD subcomplex (PubMed:12612062). Binds RNA which may help to stabilize the NELF complex on nucleic acid (PubMed:27282391). Interacts with the first BRCT repeat of BRCA1 (PubMed:11739404). Interacts with KIAA1191 (PubMed:21153684). Interacts with NELFE (By similarity).
Binds GTP but lacks intrinsic GTPase activity and is resistant to Rho-specific GTPase-activating proteins.
Binds ROCK1 (By similarity). Interacts with UBXD5.
Associates with the V0 complex of the vacuolar ATPase (V-ATPase) (PubMed:29127204). Interacts with ATP6AP2 (PubMed:29127204).
Protein characterization data are from PubMed:19379691. Due to a number of errors in the figure panels, the article has been retracted but the authors stand by the validity of the main results and conclusions (PubMed:20873370).
Required for the assembly of the V0 complex of the vacuolar ATPase (V-ATPase) in the endoplasmic reticulum.
The disease is caused by variants affecting the gene represented in this entry. VMA21 deficiency results in an increase of lysosomal pH from 4.7 to 5.2, which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids, which up-regulates the mTOR pathway and mTOR-dependent macroautophagy, resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge together, and vacuolate the cell.
Anti-apoptotic protein which can inhibit apoptosis induced by intrinsic and extrinsic apoptotic stimuli. Can modulate both capacitative Ca2+ entry and inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release.
Belongs to the BI1 family. LFG subfamily.
Homotrimer. Binds to PKC beta-1 (By similarity).
Required for neuron survival through the modulation of MAPK pathways (By similarity). Involved in the regulation of hypothalamic GNRH secretion and the control of puberty (By similarity).
Frequently deleted, mutated, and hypermethylated in lung cancers.
Homodimer. May interact with F actin through the GPA motif (Gly/Pro/Ala-rich).
May be involved in intracellular trafficking of the muscle cell when in the cytoplasm, whereas entering the nucleus, may be involved in the regulation of muscle specific genes. May play a role in the control of tumor development and progression; restored MYO18B expression in lung cancer cells suppresses anchorage-independent growth.
Reaches an expression peak in the third day after induction and remains at similar level during successive myotubule maturation.
Selectively expressed in cardiac and skeletal muscles. Weakly expressed in testis, pancreas, placenta, prostate, lung and thymus.
Gln-345 is the main determinant for regioselectivity, which segregates between initiases and elongases in all tubulin--tyrosine ligase family. A glutamine residue at this position is found in elongases TTLL6, TTLL9, TTLL11, TTLL13, TTLL10 and favors glutamate-chain elongation, whereas an arginine residue is found in initiases TTLL2, TTLL4, TTLL5, TTLL3, TTLL8 and favors initiation.
Polyglutamylase which modifies tubulin, generating polyglutamate side chains of variable lengths on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of tubulin. Preferentially mediates ATP-dependent polyglutamate long side-chain elongation over the initiation step of the polyglutamylation reaction. Preferentially modifies the alpha-tubulin tail over a beta-tail (By similarity). Required for CCSAP localization to both spindle and cilia microtubules (PubMed:22493317). Promotes tubulin polyglutamylation which stimulates spastin/SPAST-mediated microtubule severing, thereby regulating microtubule functions (By similarity).
Four distinct glycoforms A, C, F and S arise from different N-linked oligosaccharide chains at amino acid residues Asn-46 and Asn-81. Glycodelin-A and -F are taken up by the cumulus cells in which partial deglycosylation takes place to produce glycodelin-C.
Glycoprotein that regulates critical steps during fertilization and also has immunomonomodulatory effects. Four glycoforms, namely glycodelin-S, -A, -F and -C have been identified in reproductive tissues that differ in glycosylation and biological activity. Glycodelin-A has contraceptive and immunosuppressive activities (PubMed:9918684, PubMed:7531163). Glycodelin-C stimulates binding of spermatozoa to the zona pellucida (PubMed:17192260). Glycodelin-F inhibits spermatozoa-zona pellucida binding and significantly suppresses progesterone-induced acrosome reaction of spermatozoa (PubMed:12672671). Glycodelin-S in seminal plasma maintains the uncapacitated state of human spermatozoa (PubMed:15883155).
Homodimer (PubMed:25422905, PubMed:9239694).
This protein is, the main protein synthesized and secreted in the endometrium from mid-luteal phase of the menstrual cycle and during the first semester of pregnancy (PubMed:3667877). Glycodelin-A is expressed in amniotic fluid, endometrium/decidua and maternal serum (at protein level) (PubMed:3194393). Glycodelin-F is expressed in follicular fluid, luteinized granulosa cells and the oviduct (at protein level) (PubMed:12672671). Glycodelin-S is expressed in seminal plasma and seminal vesicles (at protein level) (PubMed:9239694). Glycodelin-C is detected in cumulus cells (at protein level), but cumulus cells do not synthesize Glycodelin-C but take up and convert glycodelin-A and -F vis glycan remodeling (PubMed:17192260).
Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases. Could also be a critical factor in the exacerbation of neurodegeneration in Alzheimer disease. Cleaves aggrecan at the '392-Glu-|-Ala-393' site.
Expressed in brain, lung and heart (PubMed:23897278). Expressed at very low level in placenta and skeletal muscles (PubMed:23897278). Isoform 2: Detected in osteoarthritic synovium (PubMed:16723216, PubMed:23897278).
Has sometimes been referred to as ADAMTS2.
Has a major role in enamel formation (PubMed:15235027). Required during the maturation stage of tooth development for clearance of enamel proteins and normal structural patterning of the crystalline matrix (By similarity).
N-glycosylated. The N-glycan structures are of complex diantennary or triantennary type, which may be further modified with up to 2 sialic acid residues.
May act as a GTPase-activating protein for RAB2A, RAB8A, RAB10 and RAB14. Isoform 2 promotes insulin-induced glucose transporter SLC2A4/GLUT4 translocation at the plasma membrane, thus increasing glucose uptake.
Phosphorylated by AKT1; insulin-induced. Also phosphorylated by AMPK in response to insulin. Insulin-stimulated phosphorylation is required for SLC2A4/GLUT4 translocation. Has no effect on SLC2A4/GLUT4 internalization. Physiological hyperinsulinemia increases phosphorylation in skeletal muscle. Insulin-stimulated phosphorylation is reduced by 39% in type 2 diabetic patients.
Widely expressed. Isoform 2 is the highest overexpressed in most tissues. Isoform 1 is highly expressed in skeletal muscle and heart, but was not detectable in the liver nor in adipose tissue. Isoform 2 is strongly expressed in adrenal and thyroid gland, and also in lung, kidney, colon, brain and adipose tissue. Isoform 2 is moderately expressed in skeletal muscle. Expressed in pancreatic Langerhans islets, including beta cells (at protein level). Expression is decreased by twofold in pancreatic islets in type 2 diabetes patients compared to control subjects. Up-regulated in T-cells from patients with atopic dermatitis.
Binds and promotes bundling of vimentin filaments originating from the Golgi.
Folate-dependent enzyme, that displays both transferase and deaminase activity. Serves to channel one-carbon units from formiminoglutamate to the folate pool.
Homooctamer, including four polyglutamate binding sites. The subunits are arranged as a tetramer of dimers, and form a planar ring-shaped structure.
In the C-terminal section; belongs to the cyclodeaminase/cyclohydrolase family.
In the N-terminal section; belongs to the formiminotransferase family.
Cholesterol transporter that mediates non-vesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER) (By similarity). Contains unique domains for binding cholesterol and the PM, thereby serving as a molecular bridge for the transfer of cholesterol from the PM to the ER (By similarity). Plays a crucial role in cholesterol homeostasis in the adrenal gland and has the unique ability to localize to the PM based on the level of membrane cholesterol (By similarity). In lipid-poor conditions localizes to the ER membrane and in response to excess cholesterol in the PM is recruited to the endoplasmic reticulum-plasma membrane contact sites (EPCS) which is mediated by the GRAM domain (By similarity). At the EPCS, the sterol-binding VASt/ASTER domain binds to the cholesterol in the PM and facilitates its transfer from the PM to ER (By similarity).
May modify the assembly dynamics of microtubules, such that microtubules are slightly longer, but more dynamic.
The sequence differs from that shown in N-terminus because it seems to be derived from a pre-mRNA.
Component of the IFT complex B required for sonic hedgehog/SHH signaling. May mediate transport of SHH components: required for the export of SMO and PTCH1 receptors out of the cilium and the accumulation of GLI2 at the ciliary tip in response to activation of the SHH pathway, suggesting it is involved in the dynamic transport of SHH signaling molecules within the cilium. Not required for ciliary assembly. Its role in intraflagellar transport is mainly seen in tissues rich in ciliated cells such as kidney and testis. Essential for male fertility, spermiogenesis and sperm flagella formation. Plays a role in the early development of the kidney. May be involved in the regulation of ureteric bud initiation (By similarity).
Component of the IFT complex B, at least composed of IFT20, IFT22, IFT25, IFT27, IFT46, IFT52, TRAF3IP1/IFT54, IFT57, IFT74, IFT80, IFT81, and IFT88. Interacts with IFT27. Interacts with IFT88 (By similarity).
Was initially classified as a member of the small heat shock family protein. However, it was later shown that it is not the case (PubMed:19921466).
Cellular negative regulator of the hepatitis B virus (HBV) X protein.
Interacts with RET in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex.
May play a positive role in AHR-mediated (aromatic hydrocarbon receptor) signaling, possibly by influencing its receptivity for ligand and/or its nuclear targeting.
Widely expressed. Higher levels seen in the heart, placenta and skeletal muscle. Not expressed in the liver.
DNA helicase that may play a role in the repair of DNA that is damaged by ultraviolet light or other mutagens. Exhibits a magnesium-dependent ATP-dependent DNA-helicase activity that unwinds single- and double-stranded DNA in a 3'-5' direction.
High expression in heart, lung, skeletal muscle and kidney, low expression in brain.
Interacts with EXO1 (PubMed:15886194). Interacts with MLH1.
Required for the function of coenzyme Q in the respiratory chain. May serve as a chaperone or may be involved in the transport of Q6 from its site of synthesis to the catalytic sites of the respiratory complexes (Probable).
Ubiquitously expressed with a higher expression observed in breast and liver. Also expressed in neuroblastoma cell line.
Highly expressed in fetal kidney, and at slightly lower levels in fetal brain, lung and liver.
Monomer, and heterodimer with PLXNB2 after proteolytic processing (PubMed:12533544, PubMed:17916560, PubMed:18411422, PubMed:18275816, PubMed:19843518, PubMed:20877282, PubMed:21912513). Binds RAC1 that has been activated by GTP binding (PubMed:11035813, PubMed:17916560, PubMed:18275816, PubMed:19843518). Interaction with SEMA4D promotes binding of cytoplasmic ligands (PubMed:10520995, PubMed:12198496, PubMed:19843518). Interacts with PLXNA1 (By similarity). Interacts with ARHGEF11 and ARHGEF12 (PubMed:12196628). Interacts with ERBB2 (PubMed:15210733). Interacts with MET (PubMed:12198496, PubMed:15184888). Interacts with MST1R (PubMed:15184888). Interacts with RRAS (PubMed:19843518). Interacts with RHOD (PubMed:17916560). Interacts with RND1 (PubMed:12730235, PubMed:17916560, PubMed:18275816, PubMed:19843518). Interacts with NRP1 and NRP2 (PubMed:10520995).
Phosphorylated on tyrosine residues by ERBB2 and MET upon SEMA4D binding.
Proteolytic processing favors heterodimerization with PLXNB2 and SEMA4D binding.
Receptor for SEMA4D (PubMed:19843518, PubMed:20877282, PubMed:21912513). Plays a role in GABAergic synapse development (By similarity). Mediates SEMA4A- and SEMA4D-dependent inhibitory synapse development (By similarity). Plays a role in RHOA activation and subsequent changes of the actin cytoskeleton (PubMed:12196628, PubMed:15210733). Plays a role in axon guidance, invasive growth and cell migration (PubMed:12198496).
Belongs to the succinate dehydrogenase/fumarate reductase iron-sulfur protein family.
Component of complex II composed of four subunits: the flavoprotein (FP) SDHA, iron-sulfur protein (IP) SDHB, and a cytochrome b560 composed of SDHC and SDHD (By similarity). Interacts with SDHAF1; the interaction is required for iron-sulfur cluster incorporation into SDHB (PubMed:26749241).
Iron-sulfur protein (IP) subunit of the succinate dehydrogenase complex (mitochondrial respiratory chain complex II), responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
Belongs to the ribose 5-phosphate isomerase family.
Catalyzes the reversible conversion of ribose-5-phosphate to ribulose 5-phosphate and participates in the first step of the non-oxidative branch of the pentose phosphate pathway.
(Microbial infection) Interacts with Sin nombre virus nucleoprotein (via N-terminus); this interaction probably mediates the loading of the 40S ribosomal subunit on viral capped mRNA during N-mediated translation initiation.
Belongs to the eukaryotic ribosomal protein eS19 family.
Component of the small ribosomal subunit (PubMed:23636399). Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3. Interacts with RPS19BP1; the interaction is direct and mediates the integration of RPS19 in state post-A1 (PubMed:34516797). Interacts with RPS19BP1 (By similarity).
Component of the small ribosomal subunit (PubMed:23636399). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399). Required for pre-rRNA processing and maturation of 40S ribosomal subunits (PubMed:16990592). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Higher level expression is seen in the colon carcinoma tissue than normal colon tissue.
May be involved in signal-transduction pathways related to the control of brain development.
Required for efficient formation of stress granules.
Expressed specifically in skeletal muscle. Not detected in heart.
Interacts with ACTN2, LDB3, FLNC, PPP3CA and TCAP.
Myozenins may serve as intracellular binding proteins involved in linking Z line proteins such as alpha-actinin, gamma-filamin, TCAP/telethonin, LDB3/ZASP and localizing calcineurin signaling to the sarcomere. Plays an important role in the modulation of calcineurin signaling. May play a role in myofibrillogenesis.
APOA1 is the most potent activator in plasma (PubMed:19065001, PubMed:8016111). Also activated by APOE, APOC1 and APOA4 (PubMed:19065001, PubMed:8016111). Inhibited by haptoglobin and 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) (PubMed:8016111, PubMed:24620755).
Central enzyme in the extracellular metabolism of plasma lipoproteins. Synthesized mainly in the liver and secreted into plasma where it converts cholesterol and phosphatidylcholines (lecithins) to cholesteryl esters and lysophosphatidylcholines on the surface of high and low density lipoproteins (HDLs and LDLs) (PubMed:10329423, PubMed:19065001, PubMed:26195816). The cholesterol ester is then transported back to the liver. Has a preference for plasma 16:0-18:2 or 18:O-18:2 phosphatidylcholines (PubMed:8820107). Also produced in the brain by primary astrocytes, and esterifies free cholesterol on nascent APOE-containing lipoproteins secreted from glia and influences cerebral spinal fluid (CSF) APOE- and APOA1 levels. Together with APOE and the cholesterol transporter ABCA1, plays a key role in the maturation of glial-derived, nascent lipoproteins. Required for remodeling high-density lipoprotein particles into their spherical forms (PubMed:10722751). Catalyzes the hydrolysis of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelet-activating factor or PAF) to 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) (PubMed:8016111). Also catalyzes the transfer of the acetate group from PAF to 1-hexadecanoyl-sn-glycero-3-phosphocholine forming lyso-PAF (PubMed:8016111). Catalyzes the esterification of (24S)-hydroxycholesterol (24(S)OH-C), also known as cerebrosterol to produce 24(S)OH-C monoesters (PubMed:24620755).
Detected in blood plasma (PubMed:3458198, PubMed:8820107, PubMed:10222237). Detected in cerebral spinal fluid (at protein level) (PubMed:10222237). Detected in liver (PubMed:3797244, PubMed:3458198). Expressed mainly in brain, liver and testes.
Levels of LCAT activity correlates inversely with leptin levels as well as with obesity for a wide range of BMI values.
O- and N-glycosylated. O-glycosylation on Thr-431 and Ser-433 consists of sialylated galactose beta 1-->3N-acetylgalactosamine structures. N-glycosylated sites contain sialylated triantennary and/or biantennary complex structures.
Among the many cysteines in the lumenal domain, most are probably involved in disulfide bonds.
Homodimer (PubMed:17179145). Homooligomer (Probable). Interacts with UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8 and UGT1A9 to form heterodimers (PubMed:17179145). Isoform 1 interacts with isoform 2/i2 suggesting that oligomerization is involved in negative regulation of transferase activity by isoform 2. Isoform 1 also interacts with respective i2 isoforms of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8 and UGT1A9 (PubMed:20610558).
Liver and colon (PubMed:9271343). Isoform 1 and isoform 2 are expressed in colon, esophagus and small intestine; isoform 2 but not isoform 1 is expressed in liver or kidney (PubMed:18004212).
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:18719240, PubMed:19545173, PubMed:23288867, PubMed:26220143). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:18719240, PubMed:23288867, PubMed:26220143). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, caderastan and zolarsatan, drugs which can inhibit the effect of angiotensin II (PubMed:18674515).
UGT1A10 isoform is part of the UGT1A complex locus which displays alternative use of promoters, first exons and terminal exons. The locus is defined by 13 first exons, which are alternatively spliced to 3 other common exons and 2 alternative terminal exons 5. From the 27 possible mRNA isoforms, 9 produce functionally active polypeptides (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9 and 1A10) called isoforms 1 (i1). Use of an alternative exon 5 (5b) as terminal exon is leading to 9 additional alternatively spliced products termed isoforms i2 and which lack transferase activity.
Associates with the RNA polymerase II complex.
Interacts with phosphorylated C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit POLR2A, and participates in dephosphorylation of the CTD by RPAP2. May act as a negative regulator of cyclin-D1 (CCND1) and cyclin-E (CCNE1) in the cell cycle.
May form a heterodimer with RPRD1B (PubMed:24997600). Associates with the RNA polymerase II subunit POLR2A (via CTD phosphorylated at 'Ser-2' and 'Ser-7' of the heptad repeats) (PubMed:22231121, PubMed:24997600, PubMed:24399136).
Up-regulated in cells overexpressing CDKN2B.
Activated by dimerization and subsequent intermolecular autophosphorylation on Thr-298 (By similarity). Activated by the non-canonical Wnt signaling pathway, in which WNT5A treatment leads to activation of MAP3K7/TAK1 and HIPK2, which subsequently phosphorylates and activates this protein. Other cytokines such as IL6 may also activate this regulatory circuit.
Contains a TQE activation loop motif in which autophosphorylation of the threonine residue (Thr-298) is sufficient for kinase activation. This mode of activation contrasts with that of classical MAP kinases, which contain a TXY activation loop motif in which phosphorylation of both the threonine and tyrosine residues is required for kinase activation.
Homodimer. Homodimerization is required for intermolecular autophosphorylation, kinase activation and nuclear localization (By similarity). May interact with components of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes (By similarity). Interacts with LEF1, MEF2A, MYBL1 and MYBL2 (By similarity). Interacts with the upstream activating kinases HIPK2 and MAP3K7/TAK1. Interaction with MAP3K7/TAK1 seems to be indirect, and may be mediated by other proteins such as STAT3, TAB1 and TAB2. Interacts with and phosphorylates a number of transcription factors including FOXO1, FOXO3, FOXO4, MYB, NOTCH1 and TCF7L2/TCF4. Interacts with DAPK3/ZIPK, and this interaction may disrupt interaction with transcription factors such as TCF7L2/TCF4. Interacts with RNF138/NARF. Interacts with ATF5; the interaction stabilizes ATF5 at the protein level in a kinase-independent manner (PubMed:25512613).
Phosphorylated on Thr-298. Intermolecular autophosphorylation on Thr-298 activates the enzyme.
Serine/threonine-protein kinase that regulates a number of transcription factors with key roles in cell fate determination (PubMed:14960582, PubMed:12482967, PubMed:15004007, PubMed:15764709, PubMed:20061393, PubMed:20874444, PubMed:21454679). Positive effector of the non-canonical Wnt signaling pathway, acting downstream of WNT5A, MAP3K7/TAK1 and HIPK2 (PubMed:15004007, PubMed:15764709). Negative regulator of the canonical Wnt/beta-catenin signaling pathway (PubMed:12482967). Binds to and phosphorylates TCF7L2/TCF4 and LEF1, promoting the dissociation of the TCF7L2/LEF1/beta-catenin complex from DNA, as well as the ubiquitination and subsequent proteolysis of LEF1 (PubMed:21454679). Together these effects inhibit the transcriptional activation of canonical Wnt/beta-catenin target genes (PubMed:12482967, PubMed:21454679). Negative regulator of the Notch signaling pathway (PubMed:20118921). Binds to and phosphorylates NOTCH1, thereby preventing the formation of a transcriptionally active ternary complex of NOTCH1, RBPJ/RBPSUH and MAML1 (PubMed:20118921). Negative regulator of the MYB family of transcription factors (PubMed:15082531). Phosphorylation of MYB leads to its subsequent proteolysis while phosphorylation of MYBL1 and MYBL2 inhibits their interaction with the coactivator CREBBP (PubMed:15082531). Other transcription factors may also be inhibited by direct phosphorylation of CREBBP itself (PubMed:15082531). Acts downstream of IL6 and MAP3K7/TAK1 to phosphorylate STAT3, which is in turn required for activation of NLK by MAP3K7/TAK1 (PubMed:15004007, PubMed:15764709). Upon IL1B stimulus, cooperates with ATF5 to activate the transactivation activity of C/EBP subfamily members (PubMed:25512613). Phosphorylates ATF5 but also stabilizes ATF5 protein levels in a kinase-independent manner (PubMed:25512613). Acts as an inhibitor of the mTORC1 complex in response to osmotic stress by mediating phosphorylation of RPTOR, thereby preventing recruitment of the mTORC1 complex to lysosomes (PubMed:26588989).
Was reported to form a transcriptional repressor complex with CHD7 and SETDB1 involved in PPARG repression (PubMed:17952062). However, this work was later retracted (PubMed:25358353).
Belongs to the major facilitator superfamily. Sodium/anion cotransporter family.
Expressed in the liver and kidney (PubMed:9149941, PubMed:20810651). It is detected in proximal tubules in renal cortex as well as some tubules and glomeruli, with highest expression at the apical side of proximal tubules (at protein level) (PubMed:20810651).
Genetic variations in SLC17A3 influence the variance in serum uric acid concentrations and define the serum uric acid concentration quantitative trait locus 4 (UAQTL4) [MIM:612671]. Excess serum accumulation of uric acid can lead to the development of gout, a common disorder characterized by tissue deposition of monosodium urate crystals as a consequence of hyperuricemia.
Transports organic anions in a voltage-driven, multispecific, manner, on the apical side of renal proximal tubule (PubMed:20810651). In particular, participates in the secretion of urate from the cell into the lumen (PubMed:20810651). Urate is the end product of purine metabolism (PubMed:20810651). May have roles in the metabolism and secretion of estrone sulfate, estradiol-17-beta-glucuronide, ochratoxin A, as wells as drugs such as bumetanide (PubMed:20810651).
Expressed in skin, lung and colon (at protein level).
O-glycosylated with core 1 or possibly core 8 glycans.
Proteolytically cleaved. Cleaved at Arg-120 and Arg-437 leading to a processed mature product of 35 kDa. The cleavage takes place in the Golgi apparatus.
Expressed in umbilical vein endothelial cells (HUVEC), and at lower levels in aortic smooth muscle cells (HASMC).
Negatively regulates TNF-alpha-induced pro-inflammatory response in endothelial cells (ECs) via inhibition of TNF-alpha-induced NF-kappaB activation in ECs (PubMed:25193116). Positively regulates lipid accumulation in adipose cells (By similarity).
Up-regulated by pioglitazone and down-regulated by TNF in HUVEC.
Acts both as a nuclear p53/TP53-cofactor and a cytoplasmic regulator of actin dynamics depending on conditions (PubMed:30420355). In nucleus, acts as a cofactor that increases p53/TP53 response via its interaction with p300/EP300. Increases p53/TP53-dependent transcription and apoptosis, suggesting an important role in p53/TP53 stress response such as DNA damage. In cytoplasm, acts as a nucleation-promoting factor for both branched and unbranched actin filaments (PubMed:30420355). Activates the Arp2/3 complex to induce branched actin filament networks. Also catalyzes actin polymerization in the absence of Arp2/3, creating unbranched filaments (PubMed:30420355). Contributes to cell motility by controlling actin dynamics. May promote the rapid formation of a branched actin network by first nucleating new mother filaments and then activating Arp2/3 to branch off these filaments. Upon nutrient stress, directly recruited by MAP1LC3B to the phagophore membrane surfaces to promote actin assembly during autophagy (PubMed:30420355). The p53/TP53-cofactor and actin activator activities are regulated via its subcellular location (By similarity).
Interacts with p300/EP300, the complex activates p53/TP53 transcriptional activity. Interacts with TTC5; the interaction facilitates the association between JMY and p300/EP300 (By similarity). Interacts with MAP1LC3B; the interaction results in the activation of JYM's nucleation activity in the cytoplasm (PubMed:30420355). Interacts with TTC5/STRAP; the interaction results in the inhibition of JYM's nucleation activity in the cytoplasm due to competition with MAP1LC3B binding (PubMed:30420355).
The N-terminal region is involved in actin binding and actin nucleation activity.
Ubiquitinated by MDM2, leading to its subsequent degradation by the proteasome. In case of DNA damage, the interaction with MDM2 is altered, preventing degradation and allowing interaction with p300/EP300 and its function in p53/TP53 stress response (By similarity).
Genetically increasing or decreasing the expression of PM20D1 reduces and aggravates Alzheimer's disease (AD) related pathologies, respectively. These findings suggest that in a particular genetic background, PM20D1 contributes to neuroprotection against AD.
Lipoproteins are powerful coactivators of PM20D1 activity in vitro and NAA biosynthesis in vivo.
Secreted enzyme that regulates the endogenous N-fatty acyl amino acid (NAAs) tissue and circulating levels by functioning as a bidirectional NAA synthase/hydrolase (PubMed:27374330). It condenses free fatty acids and free amino acids to generate NAAs and bidirectionally catalyzes the reverse hydrolysis reaction (PubMed:27374330). Some of these NAAs stimulate oxidative metabolism via mitochondrial uncoupling, increasing energy expenditure in a UPC1-independent manner. Thereby, this secreted protein may indirectly regulate whole body energy expenditure. PM20D1 circulates in tight association with both low- and high-density (LDL and HDL,respectively) lipoprotein particles (By similarity).
Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:17681178, PubMed:24269233, PubMed:22633490). ACSL5 may activate fatty acids from exogenous sources for the synthesis of triacylglycerol destined for intracellular storage (By similarity). Utilizes a wide range of saturated fatty acids with a preference for C16-C18 unsaturated fatty acids (By similarity). It was suggested that it may also stimulate fatty acid oxidation (By similarity). At the villus tip of the crypt-villus axis of the small intestine may sensitize epithelial cells to apoptosis specifically triggered by the death ligand TRAIL. May have a role in the survival of glioma cells.
Localize in mitochondrion and endoplasmic reticulum.
An alternative upstream Met is found in primates and translation may initiate from the upstream Met which would give rise to a 680-residue protein. However, the upstream codon has a weak Kozak signal while the codon used for translation of the shorter 677-residue sequence has a strong Kozak signal and is widely conserved. In addition, protein sequencing indicates that this is the preferred start codon in vivo.
Belongs to the NADPH--cytochrome P450 reductase family.
In the C-terminal section; belongs to the flavoprotein pyridine nucleotide cytochrome reductase family.
In the N-terminal section; belongs to the flavodoxin family.
This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes. It can also provide electron transfer to heme oxygenase and cytochrome B5.
Putative taste receptor. TAS1R2/TAS1R3 recognizes diverse natural and synthetic sweeteners.
Major component of the vertebrate myofibrillar M band. Binds myosin, titin, and light meromyosin. This binding is dose dependent.
Binds PtdIns3P in vitro with high specificity over other phosphoinositides. Interacts (via WD repeat 2) with tyrosine-phosphorylated TLR3 (via TIR domain) in response to poly(I:C) (PubMed:25736436). Interacts with TICAM1 in response to poly(I:C) (By similarity). Interacts with TLR4 in response to LPS (By similarity).
Positively regulates TLR3- and TLR4-mediated signaling pathways by bridging the interaction between TLR3 or TLR4 and TICAM1. Promotes TLR3/4 ligand-induced activation of transcription factors IRF3 and NF-kappa-B, as well as the production of IFN-beta and inflammatory cytokines (PubMed:25736436).
The FYVE-type zinc finger domain mediates interactions with phosphatidylinositol 3-phosphate in membranes of early endosomes and penetrates bilayers. The FYVE domain insertion into PtdIns(3)P-enriched membranes is substantially increased in acidic conditions. The FYVE domain is required for its function in regulating TLR3 signaling (PubMed:25736436).
Plays a major role in formation of tooth enamel (PubMed:19853237, PubMed:25008349). Specifically required during the maturation phase of amelogenesis for normal formation of the enamel matrix and clearance of enamel proteins. May be involved in localization of the calcium transporter SLC24A4 to the ameloblast cell membrane.
Brain, lymph node, prostate, stomach, thyroid, tongue, trachea, uterus, skeletal muscle, spleen, kidney, liver and small intestine.
By interferon (IFN). Up-regulated during vesicular stomatitis virus (VSV), or poliovirus (PV) infection.
Interacts with EXOSC1, EXOSC4, RIGI, IFIH1/MDA5 and DHX58/LGP2.
Positively regulates RIGI- and IFIH1/MDA5-dependent type I interferon and interferon inducible gene expression in response to viral infection. Binds ssRNA, dsRNA and dsDNA and can promote the binding of RIGI to dsRNA. Exhibits antiviral activity against hepatitis C virus and vesicular stomatitis virus (VSV).
Belongs to the bZIP family. Jun subfamily.
Binds DNA as a homodimer or as a heterodimer with another member of the Jun/Fos family. Component of an AP-1 transcription factor complex composed of JUN-FOS heterodimers composed of JUN-FOS heterodimers (By similarity). As part of the AP-1 transcription factor complex, forms heterodimers with FOSB, thereby binding to the AP-1 consensus sequence and stimulating transcription (By similarity). Interacts with ITCH (via its WW domains).
Transcription factor involved in regulating gene activity following the primary growth factor response. Binds to the DNA sequence 5'-TGA[GC]TCA-3'. Heterodimerizes with proteins of the FOS family to form an AP-1 transcription complex, thereby enhancing its DNA binding activity to an AP-1 consensus sequence and its transcriptional activity (By similarity).
Ubiquitinated by ITCH, leading to its degradation.
Interacts with RALA through the TIG domain.
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts with EXOC3L1 (By similarity). Interacts with GNEFR/DELGEF; this interaction occurs only in the presence of magnesium or manganese and is stimulated by dCTP or GTP (PubMed:12459492). Interacts with RALA and RALB (PubMed:18756269, PubMed:19166349, PubMed:12459492) (By similarity). Interacts with ARL13B; regulates ARL13B localization to the cilium membrane.
Widely expressed with highest levels in brain and placenta.
Strongly expressed in brain and spinal cord. Expressed at equal level in spinal cord and sciatic nerve. Weakly expressed in striated muscle.
Belongs to the transient receptor (TC 1.A.4) family. STrpC subfamily. TRPC6 sub-subfamily.
Expressed primarily in placenta, lung, spleen, ovary and small intestine. Expressed in podocytes and is a component of the glomerular slit diaphragm.
Homodimer; forms channel complex (PubMed:26892346). Interacts with MX1 and RNF24 (PubMed:15757897, PubMed:17850865).
Phosphorylated by FYN, leading to an increase of TRPC6 channel activity.
Thought to form a receptor-activated non-selective calcium permeant cation channel (PubMed:19936226, PubMed:23291369). Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C (PubMed:26892346). Seems not to be activated by intracellular calcium store depletion.
Activated by phosphorylation on threonine and tyrosine by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6. MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 induced by environmental stress. HDAC3 interacts directly and selectively with MAPK11 to repress ATF2 transcriptional activity, and regulate TNF gene expression in LPS-stimulated cells. Inhibited by SB203580 and pyridinyl-imidazole related compounds.
Dually phosphorylated on Thr-180 and Tyr-182 by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6, which activates the enzyme.
Highest levels in the brain and heart. Also expressed in the placenta, lung, liver, skeletal muscle, kidney and pancreas.
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway (PubMed:12452429, PubMed:20626350, PubMed:35857590). MAPK11 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as pro-inflammatory cytokines or physical stress leading to direct activation of transcription factors (PubMed:12452429, PubMed:20626350, PubMed:35857590). Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each (PubMed:12452429, PubMed:20626350, PubMed:35857590). MAPK11 functions are mostly redundant with those of MAPK14 (PubMed:12452429, PubMed:20626350, PubMed:35857590). Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets (PubMed:12452429, PubMed:20626350). RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1 (PubMed:9687510). RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2 (PubMed:11154262). In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Additional examples of p38 MAPK substrates are the FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A (PubMed:9430721, PubMed:10330143, PubMed:15356147). The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers (PubMed:9430721, PubMed:10330143, PubMed:15356147). The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates NLRP1 downstream of MAP3K20/ZAK in response to UV-B irradiation and ribosome collisions, promoting activation of the NLRP1 inflammasome and pyroptosis (PubMed:35857590).
Interacts with the nucleosomes, in particular nucleosomes bearing histone H3 crotonylated at 'Lys-14' (H3K14cr) for which DPF2 has high affinity (PubMed:27775714). Also interacts (via PHD-type zinc finger domains) with histone H3 butyrylated at 'Lys-14' (H3K14bu), histone H3 propionylated at 'Lys-14' (H3K14pr), and histone H3 acetylated at 'Lys-14' (H3K14ac) (PubMed:29429572, PubMed:28533407, PubMed:27775714). Interacts with histone H3 acetylated at 'Lys-9' (H3K9ac), histone H3 di-methylated at 'Lys-9' (H3K9me2), and histone H3 tri-methylated at 'Lys-9' (H3K9me3) (PubMed:29429572). Interacts with histone H4 acetylated at 'Lys-12' (H4K12ac) (PubMed:29429572). Interacts with histone H4 acetylated at 'Lys-16' (H4K16ac) (PubMed:28533407). Interacts with SWI/SNF complex components (PubMed:20460684, PubMed:28533407). Interacts with SMARCA2, SMARCA4, SMARCB1 and SMARCD1 (PubMed:20460684). Interacts with SMARCC1, SMARCC2 and ACTL6A (PubMed:28533407). Interacts with RUNX1 (PubMed:28533407).
Plays an active role in transcriptional regulation by binding modified histones H3 and H4 (PubMed:28533407, PubMed:27775714). Is a negative regulator of myeloid differentiation of hematopoietic progenitor cells (PubMed:28533407). Might also have a role in the development and maturation of lymphoid cells (By similarity). Involved in the regulation of non-canonical NF-kappa-B pathway (PubMed:20460684).
Belongs to the bacterial ribosomal protein bS18 family.
Component of the mitochondrial small ribosomal subunit (mt-SSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. bS18m has a zinc binding site.
There are 3 mitochondrial isoforms of bS18 in mammalia, localizing to 3 distinct sites in the mitoribosome. bS18m (bs18c, this protein) binds to the same site as bacterial bS18, mS40 (bS18b) binds to a novel location of the 28S small subunit, and mL66 (bS18a) binds to the 39S large subunit.
Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin. Facilitates the interaction between dynein and dynactin and activates dynein processivity (the ability to move along a microtubule for a long distance without falling off the track). Predominantly recruits 2 dyneins, which increases both the force and speed of the microtubule motor. Component of secretory vesicle machinery in developing neurons that acts as a regulator of neurite outgrowth. Regulates the secretory vesicle transport by controlling the accumulation of Rab6-containing secretory vesicles in the pericentrosomal region restricting anterograde secretory transport during the early phase of neuronal differentiation, thereby inhibiting neuritogenesis.
Part of a tripartite complex with dynein and dynactin, acts an adapter linking the dynein motor complex and dynactin. Interacts with KIF1C. Interacts with RAB6A and RAB6B; interaction is specific to Rab6.
Functions as 15-oxo-prostaglandin 13-reductase and acts on 15-keto-PGE1, 15-keto-PGE2, 15-keto-PGE1-alpha and 15-keto-PGE2-alpha with highest efficiency towards 15-keto-PGE2-alpha. Overexpression represses transcriptional activity of PPARG and inhibits adipocyte differentiation.
Expressed in proliferating embryonic stem cells and down-regulated during differentiation.
Forms heterooligomers with ATAD3A. Interacts with components of the mitochondrial ribosome, including MRPL11 and MRPS18B, and with other proteins involved in mitochondrial RNA metabolism, possibly via interaction with ATAD3A. Interacts with GADD45GIP1.
May play a role in a mitochondrial network organization typical for stem cells, characterized by reduced mitochondrial metabolism, low mtDNA copies and fragmentated mitochondrial network. may act by suppressing ATAD3A function, interfering with ATAD3A interaction with matrix nucleoid complexes.
Tends to be down-regulated in differentiated cells and re-expressed in pluripotent stem cells or cancer cells (at protein level).
Composed of a heavy chain (beta) and a light chain (alpha). Component of an NADPH oxidase complex composed of a heterodimer formed by the membrane proteins CYBA and CYBB and the cytosolic subunits NCF1, NCF2 and NCF4. Interacts with NCF1. Interacts with calprotectin (S100A8/9). Interacts with NRROS; the interaction is direct and impairs formation of a stable NADPH oxidase complex (PubMed:19028840, PubMed:3600769, PubMed:9224653). Interacts with CYBC1; CYBC1 may act as a chaperone stabilizing Cytochrome b-245 heterodimer (PubMed:28351984). Interacts with NCF2; the interaction is enhanced in the presence of GBP7 (By similarity). The CYBA-CYBB complex interacts with GBP7 (By similarity).
Critical component of the membrane-bound oxidase of phagocytes that generates superoxide. It is the terminal component of a respiratory chain that transfers single electrons from cytoplasmic NADPH across the plasma membrane to molecular oxygen on the exterior. Also functions as a voltage-gated proton channel that mediates the H(+) currents of resting phagocytes. It participates in the regulation of cellular pH and is blocked by zinc.
Detected in neutrophils (at protein level).
Undergoes 'Lys-48'-linked polyubiquitination, likely by RNF145, triggering endoplasmic reticulum-associated degradation.
Chromosomal aberrations involving NTRK1 are found in papillary thyroid carcinomas (PTCs) (PubMed:2869410, PubMed:7565764, PubMed:1532241). Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1 (PubMed:7565764). A rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1 (PubMed:2869410). An intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein (PubMed:1532241).
Constitutively active. Does not bind NGF and does not interact with GRB2 and FRS2.
Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures. Homodimerization is induced by binding of a NGF dimer (PubMed:1281417, PubMed:10490030, PubMed:17196528). Interacts with SQSTM1; bridges NTRK1 to NGFR (PubMed:11244088). Forms a ternary complex with NGFR and KIDINS220; this complex is affected by the expression levels of KIDINS220 and an increase in KIDINS220 expression leads to a decreased association of NGFR and NTRK1 (By similarity). Interacts with SH2D1A; regulates NTRK1 (By similarity). Interacts (phosphorylated upon activation by NGF) with SHC1; mediates SHC1 phosphorylation and activation (PubMed:8155326, PubMed:15488758). Interacts (phosphorylated upon activation by NGF) with PLCG1; mediates PLCG1 phosphorylation and activation (PubMed:7510697, PubMed:15488758). Interacts (phosphorylated) with SH2B1 and SH2B2 (By similarity). Interacts with GRB2 (PubMed:15488758). Interacts with PIK3R1 (PubMed:15488758). Interacts with FRS2 (PubMed:15488758). Interacts with SORT1; may regulate NTRK1 anterograde axonal transport (PubMed:21102451). Interacts with RAB7A (By similarity). Found in a complex, at least composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; the complex is mainly formed at late endosomes in a nerve growth factor (NGF)-dependent manner (By similarity). Interacts with RAPGEF2; the interaction is strengthened after NGF stimulation (By similarity). Interacts with PTPRS (By similarity). Interacts with USP36; USP36 does not deubiquitinate NTRK1 (PubMed:27445338). Interacts with GGA3 (PubMed:26446845).
Has enhanced responsiveness to NTF3 neurotrophin.
Isoform TrkA-I is found in most non-neuronal tissues. Isoform TrkA-II is primarily expressed in neuronal cells. TrkA-III is specifically expressed by pluripotent neural stem and neural crest progenitors.
Isoform TrkA-III is up-regulated upon hypoxia in cells normally expressing it.
Ligand-mediated autophosphorylation (PubMed:2927393, PubMed:1281417, PubMed:15488758, PubMed:7510697, PubMed:8155326, PubMed:8325889, PubMed:27676246, PubMed:28177573). Interaction with SQSTM1 is phosphotyrosine-dependent. Autophosphorylation at Tyr-496 mediates interaction and phosphorylation of SHC1 (PubMed:15488758, PubMed:7510697, PubMed:8155326, PubMed:8325889).
N-glycosylated (PubMed:2927393). Isoform TrkA-I and isoform TrkA-II are N-glycosylated.
Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand (PubMed:1850821, PubMed:1849459, PubMed:1281417, PubMed:8325889, PubMed:15488758, PubMed:22649032, PubMed:17196528, PubMed:27445338). Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival (By similarity). Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation (PubMed:1281417). Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors.
Resistant to NGF, it constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.
The extracellular domain mediates interaction with NGFR.
The pro-survival signaling effect of NTRK1 in neurons requires its endocytosis into signaling early endosomes and its retrograde axonal transport. This is regulated by different proteins including CFL1, RAC1 and SORT1. NTF3 is unable to induce this signaling probably due to the lability of the NTF3-NTRK1 complex in endosomes. SH2D1A inhibits the autophosphorylation of the receptor, and alters the recruitment and activation of downstream effectors and signaling cascades (By similarity). Regulated by NGFR (By similarity).
The transmembrane domain mediates interaction with KIDINS220.
Trk also stands for tropomyosin-related kinase since it was first isolated as an oncogenic protein which was the result of a fusion between the tropomyosin gene TPM3 and NTRK1.
Ubiquitinated (PubMed:27445338). Undergoes polyubiquitination upon activation; regulated by NGFR (PubMed:27445338). Ubiquitination by NEDD4L leads to degradation (PubMed:27445338). Ubiquitination regulates the internalization of the receptor (By similarity).
Activated by calcium and magnesium and inhibited by other bivalent cations.
Belongs to the CDP-alcohol phosphatidyltransferase class-II family.
Functions in the biosynthesis of the anionic phospholipids phosphatidylglycerol and cardiolipin.
Component of the SKA1 complex, a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation (PubMed:19289083, PubMed:19360002, PubMed:23085020). The SKA1 complex is a direct component of the kinetochore-microtubule interface and directly associates with microtubules as oligomeric assemblies (PubMed:19289083, PubMed:19360002). The complex facilitates the processive movement of microspheres along a microtubule in a depolymerization-coupled manner (PubMed:19289083). In the complex, it mediates the microtubule-stimulated oligomerization (PubMed:19289083). Affinity for microtubules is synergistically enhanced in the presence of the ndc-80 complex and may allow the ndc-80 complex to track depolymerizing microtubules (PubMed:23085020).
Component of the SKA1 complex, composed of SKA1, SKA2 and SKA3 (PubMed:19289083, PubMed:19360002). The core SKA1 complex is composed of 2 SKA1-SKA2 heterodimers, each heterodimer interacting with a molecule of the SKA3 homodimer (PubMed:19289083, PubMed:19360002). The core SKA1 complex associates with microtubules and forms oligomeric assemblies (PubMed:19289083, PubMed:19360002, PubMed:23085020). Interacts with SKA1; the interaction is direct (PubMed:19289083, PubMed:23085020).
Anti-angiogenic and anti-tumor peptide that inhibits endothelial cell migration, collagen-induced endothelial tube morphogenesis and blood vessel growth in the chorioallantoic membrane. Blocks endothelial cell adhesion to fibronectin and type I collagen. Anti-tumor agent in neovascularization. Interaction with its ligand, integrin alpha2/beta1, is required for the anti-angiogenic properties. Evokes a reduction in phosphorylation of receptor tyrosine kinases via alpha2/beta1 integrin-mediated activation of the tyrosine phosphatase, PTPN6.
Detected in cerebrospinal fluid, fibroblasts and urine (at protein level).
Has a strong tendency to aggregate in dimers or stellate structures. Interacts with other basement membrane components such as laminin, prolargin and collagen type IV. Interacts with COL13A1, FGFBP1 and VWA1. Interacts (via C-terminus) with ECM1 (via C-terminus).
Has anti-angiogenic properties that require binding of calcium ions for full activity.
Has been found in the urine of patients with end-stage renal disease and in the amniotic fluid of pregnant women with premature rupture of fetal membranes.
Integral component of basement membranes. Component of the glomerular basement membrane (GBM), responsible for the fixed negative electrostatic membrane charge, and which provides a barrier which is both size- and charge-selective. It serves as an attachment substrate for cells. Plays essential roles in vascularization. Critical for normal heart development and for regulating the vascular response to injury. Also required for avascular cartilage development.
O-glycosylated with core 1 or possibly core 8 glycans. Contains three heparan sulfate chains. Also contains chondroitin sulfate.
Proteolytic processing produces the C-terminal angiogenic peptide, endorepellin. This peptide can be further processed to produce the LG3 peptide.
Basal body protein required in multiciliate cells to align and maintain cilia orientation in response to flow. May act by mediating a maturation step that stabilizes and aligns cilia orientation. Not required to respond to planar cell polarity (PCP) or flow-based orientation cues (By similarity).
Homohexamer. Interacts with GABARAP and GABARAPL2. Interacts with GRIA2. Interacts with PLK2, leading to disrupt the interaction with GRIA2. Interacts with MUSK; may regulate MUSK endocytosis and activity (By similarity). Interacts with CDK16 (By similarity).
Phosphorylation at Ser-569 interferes with homohexamerization.
Required for vesicle-mediated transport. Catalyzes the fusion of transport vesicles within the Golgi cisternae. Is also required for transport from the endoplasmic reticulum to the Golgi stack. Seems to function as a fusion protein required for the delivery of cargo proteins to all compartments of the Golgi stack independent of vesicle origin.
Required for vesicle-mediated transport. Catalyzes the fusion of transport vesicles within the Golgi cisternae. Is also required for transport from the endoplasmic reticulum to the Golgi stack. Seems to function as a fusion protein required for the delivery of cargo proteins to all compartments of the Golgi stack independent of vesicle origin. Interaction with AMPAR subunit GRIA2 leads to influence GRIA2 membrane cycling (By similarity).
ATP-dependent RNA helicase involved in mRNA export from the nucleus. Rather than unwinding RNA duplexes, DDX19 functions as a remodeler of ribonucleoprotein particles, whereby proteins bound to nuclear mRNA are dissociated and replaced by cytoplasmic mRNA binding proteins.
Belongs to the DEAD box helicase family. DDX19/DBP5 subfamily.
The N-terminal extension helix acts as an autoinhibitory domain, preventing ATP hydrolysis, unless the N-terminus of the protein is displaced by RNA binding, allowing cleft closure to bring key side chains into position for catalysis.
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC4 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with NR1I3. Interacts with PAAF1 (PubMed:15831487). Interacts with TRIM5 (PubMed:22078707). Interacts with ZFAND1 (PubMed:29804830).
Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC4 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.
Belongs to the Integrator subunit 5 family.
Component of the Integrator (INT) complex, a complex involved in the small nuclear RNAs (snRNA) U1 and U2 transcription and in their 3'-box-dependent processing. The Integrator complex is associated with the C-terminal domain (CTD) of RNA polymerase II largest subunit (POLR2A) and is recruited to the U1 and U2 snRNAs genes (Probable). Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the INT complex (PubMed:23904267).
Expressed at high levels in heart, mammary gland, adrenal gland, stomach, smooth muscle and skeletal muscle, and at lower levels in brain and lung. Strongly down-regulated in lung cancer tissues, due to hypermethylation of the corresponding locus (PubMed:12660825). Expressed in adipose tissue (PubMed:26629404).
Interacts with SLC2A4; the interaction is required for proper SLC2A4 reacycling after insulin stimulation.
Regulates insulin-mediated adipose tissue glucose uptake and transport by modulation of SLC2A4 recycling. Not required for SLC2A4 membrane fusion upon an initial stimulus, but rather is necessary for proper protein recycling during prolonged insulin stimulation.
Belongs to the complex I NDUFA4 subunit family.
(Microbial infection) Acts as a coreceptor (CD4 being the primary receptor) of human immunodeficiency virus-1/HIV-1.
(Microbial infection) Interacts with HIV-1 surface protein gp120.
(Microbial infection) May be down-regulated by human cytomegalovirus/HHV-5 protein UL78.
Highly expressed in spleen, thymus, in the myeloid cell line THP-1, in the promyeloblastic cell line KG-1a and on CD4+ and CD8+ T-cells. Medium levels in peripheral blood leukocytes and in small intestine. Low levels in ovary and lung.
Interacts with PRAF2 (PubMed:15757671). Efficient ligand binding to CCL3/MIP-1alpha and CCL4/MIP-1beta requires sulfation, O-glycosylation and sialic acid modifications. Glycosylation on Ser-6 is required for efficient binding of CCL4 (PubMed:11733580, PubMed:8663314, PubMed:8699119, PubMed:10383387). Interacts with GRK2 (PubMed:10085131). Interacts with ARRB1 and ARRB2 (PubMed:11448957, PubMed:16144840). Interacts with CNIH4 (PubMed:24405750). Interacts with S100A4; this interaction stimulates T-lymphocyte chemotaxis (PubMed:30713770).
O-glycosylated, but not N-glycosylated. Ser-6 appears to be the major site even if Ser-7 may be also O-glycosylated. Also sialylated glycans present which contribute to chemokine binding. Thr-16 and Ser-17 may also be glycosylated and, if so, with small moieties such as a T-antigen.
Palmitoylation in the C-terminal is important for cell surface expression, and to a lesser extent, for HIV entry.
Phosphorylation on serine residues in the C-terminal is stimulated by binding CC chemokines especially by APO-RANTES.
Receptor for a number of inflammatory CC-chemokines including CCL3/MIP-1-alpha, CCL4/MIP-1-beta and RANTES and subsequently transduces a signal by increasing the intracellular calcium ion level. May play a role in the control of granulocytic lineage proliferation or differentiation. Participates in T-lymphocyte migration to the infection site by acting as a chemotactic receptor (PubMed:30713770).
Sulfated on at least 2 of the N-terminal tyrosines. Sulfation contributes to the efficiency of HIV-1 entry and is required for efficient binding of the chemokines, CCL3 and CCL4.
Variations in CCR5 are associated with resistance or susceptibility to immunodeficiency virus type 1 (resistance or susceptibility to HIV-1) [MIM:609423]. Variations in CCR5 gene also influence the rate of progression to AIDS after infection.
Variations in CCR5 are associated with susceptibility to West Nile virus (WNV) infection [MIM:610379].
In the PI-PLC X-box Thr-486 is present instead of the conserved His which is one of the active site residues. It is therefore expected that this protein lacks catalytic activity.
May play an role in the regulation of Ins(1,4,5)P3 around the endoplasmic reticulum.
As opposed to other villin-type headpiece domains, supervillin HP (SVHP) doesn't bind F-actin due to the absence of a conformationally flexible region (V-loop).
Associates with F-actin (PubMed:9867483). Interacts with NEB (PubMed:18639526). Interacts with MYH9 (By similarity). Interacts with MYLK (By similarity). Interacts with TASOR (By similarity).
Expressed in many tissues. Most abundant in muscle, bone marrow, thyroid gland and salivary gland. Isoform 1 (archvillin) is muscle specific.
Forms a high-affinity link between the actin cytoskeleton and the membrane. Is among the first costameric proteins to assemble during myogenesis and it contributes to myogenic membrane structure and differentiation (PubMed:12711699). Appears to be involved in myosin II assembly. May modulate myosin II regulation through MLCK during cell spreading, an initial step in cell migration. May play a role in invadopodial function (PubMed:19109420).
Interacts with TRIP6 (By similarity). Interacts with DYNLT1 (By similarity). Interacts with KIF14; at midbody during cytokinesis (By similarity).
May be involved in modulation of focal adhesions. Supervillin-mediated down-regulation of focal adhesions involves binding to TRIP6. Plays a role in cytokinesis through KIF14 interaction (By similarity).
(Microbial infection) Mono-ADP-ribosylated at Thr-66 by the C.violaceum CteC virulence factor. ADP-ribosylation causes the shutdown of polyubiquitin synthesis and disrupts the recognition and reversal of polyubiquitin.
Exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in proteotoxic stress response and cell cycle; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.
For a better understanding, features related to ubiquitin are only indicated for the first chain.
Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.
Mono-ADP-ribosylated at the C-terminus by PARP9, a component of the PPAR9-DTX3L complex. ADP-ribosylation requires processing by E1 and E2 enzymes and prevents ubiquitin conjugation to substrates such as histones.
Phosphorylated at Ser-65 by PINK1 during mitophagy (PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25527291, PubMed:26161729). Phosphorylated ubiquitin specifically binds and activates parkin (PRKN), triggering mitophagy (PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25527291, PubMed:26161729). Phosphorylation does not affect E1-mediated E2 charging of ubiquitin but affects discharging of E2 enzymes to form polyubiquitin chains. It also affects deubiquitination by deubiquitinase enzymes such as USP30 (PubMed:25527291).
The mRNA encoding variant UBB(+1) is produced by an unknown mechanism involving the deletion of a GT dinucleotide in the close proximity of a GAGAG motif (PubMed:9422699). This variant mRNA is found in normal brain, but the encoded protein accumulates only in brain neurofibrillary tangles and neuritic plaques in Alzheimer disease and other tauopathies, as well as polyglutaminopathies (PubMed:14597671). UBB(+1) variant cannot be used for polyubiquitination, is not effectively degraded by the proteasome when ubiquitinated and ubiquitinated UBB(+1) is refractory to disassembly by deubiquitinating enzymes (DUBs). In healthy brain, UBB(+1) C-terminus can be cleaved by UCHL3 (PubMed:21762696).
Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins eL40 and eS31, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.
Catalyzes the post-translational addition of a tyrosine to the C-terminal end of detyrosinated alpha-tubulin.
Belongs to the bZIP family. Fos subfamily.
Constitutively sumoylated with SUMO1, SUMO2 and SUMO3. Desumoylated by SENP2. Sumoylation requires heterodimerization with JUN and is enhanced by mitogen stimulation. Sumoylation inhibits the AP-1 transcriptional activity and is, itself, inhibited by Ras-activated phosphorylation on Thr-232.
Expressed at very low levels in quiescent cells. When cells are stimulated to reenter growth, they undergo 2 waves of expression, the first one peaks 7.5 minutes following FBS induction. At this stage, the protein is localized endoplasmic reticulum. The second wave of expression occurs at about 20 minutes after induction and peaks at 1 hour. At this stage, the protein becomes nuclear.
Heterodimer; with JUN (By similarity). Component of the SMAD3/SMAD4/JUN/FOS complex required for synergistic TGF-beta-mediated transcription at the AP1 promoter site (PubMed:9732876). Interacts with SMAD3; the interaction is weak even on TGF-beta activation (PubMed:9732876). Interacts with MAFB (By similarity). Interacts with TSC22D3 (via N-terminus); this interaction inhibits the binding of active AP1 to its target DNA (By similarity). Interacts with CDS1 and PI4K2A (By similarity). Interacts (via bZIP domain and leucine-zipper region) with the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF) subunits SMARCB1, SMARCC2 and SMARCD1 (By similarity). Interacts (via bZIP domain and leucine-zipper region) with ARID1A (By similarity).
In quiescent cells, the small amount of FOS present is phosphorylated at Tyr-10 and Tyr-30 by SRC. This Tyr-phosphorylated form is cytosolic. In growing cells, dephosphorylated by PTPN2. Dephosphorylation leads to the association with endoplasmic reticulum membranes and activation of phospholipid synthesis.
Nuclear phosphoprotein which forms a tight but non-covalently linked complex with the JUN/AP-1 transcription factor. In the heterodimer, FOS and JUN/AP-1 basic regions each seems to interact with symmetrical DNA half sites. On TGF-beta activation, forms a multimeric SMAD3/SMAD4/JUN/FOS complex at the AP1/SMAD-binding site to regulate TGF-beta-mediated signaling. Has a critical function in regulating the development of cells destined to form and maintain the skeleton. It is thought to have an important role in signal transduction, cell proliferation and differentiation. In growing cells, activates phospholipid synthesis, possibly by activating CDS1 and PI4K2A. This activity requires Tyr-dephosphorylation and association with the endoplasmic reticulum.
Phosphorylated in the C-terminal upon stimulation by nerve growth factor (NGF) and epidermal growth factor (EGF). Phosphorylated, in vitro, by MAPK and RSK1. Phosphorylation on both Ser-362 and Ser-374 by MAPK1/2 and RSK1/2 leads to protein stabilization with phosphorylation on Ser-374 being the major site for protein stabilization on NGF stimulation. Phosphorylation on Ser-362 and Ser-374 primes further phosphorylations on Thr-325 and Thr-331 through promoting docking of MAPK to the DEF domain. Phosphorylation on Thr-232, induced by HA-RAS, activates the transcriptional activity and antagonizes sumoylation. Phosphorylation on Ser-362 by RSK2 in osteoblasts contributes to osteoblast transformation (By similarity).
Positive regulator of amyloid protein aggregation and proteotoxicity (PubMed:20723760). Induces conformational changes in amyloid proteins, such as HTT, driving them into compact formations preceding the formation of aggregates (PubMed:20723760).
Strong expression in fetal heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Weak expression in adult pancreas, spleen, thymus, and ovary.
Expressed in all tissues tested, including brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung and peripheral blood lymphocytes.
Isoform 1 may function as a nuclear receptor coactivator, enhancing transcription through other coactivators such as NCOA6 and CITED1. Isoform 2, functions as a transcriptional repressor, modulating transcriptional activities of coactivators including isoform 1, NCOA6 and CITED1 (PubMed:11443112). Regulates centriole biogenesis by suppressing the formation of aberrant centriolar protein complexes in the cytoplasm and thus preserving mitotic spindle integrity. Prevents the formation of the STIL-CENPJ complex (which can induce the formation of aberrant centriolar protein complexes) by interfering with the interaction of STIL with CENPJ (PubMed:25385835). Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728).
Isoform 1: Interacts with NCOA6, CITED1 and XRCC5/KU86 (PubMed:11443112). Isoform 1: Interacts with SS18 isoform 1 (PubMed:15919756). Isoform 1: Interacts with SS18 isoform 2 (PubMed:15919756). Interacts with STIL and interferes with its interaction with CENPJ. Interacts with gamma-tubulin (PubMed:25385835).Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA.
Endothelial receptor which functions together with RECK to enable brain endothelial cells to selectively respond to Wnt7 signals (WNT7A or WNT7B) (PubMed:28289266, PubMed:30026314). Plays a key role in Wnt7-specific responses, such as endothelial cell sprouting and migration in the forebrain and neural tube, and establishment of the blood-brain barrier (By similarity). Acts as a Wnt7-specific coactivator of canonical Wnt signaling: required to deliver RECK-bound Wnt7 to frizzled by assembling a higher-order RECK-ADGRA2-Fzd-LRP5-LRP6 complex (PubMed:30026314). ADGRA2-tethering function does not rely on its G-protein coupled receptor (GPCR) structure but instead on its combined capacity to interact with RECK extracellularly and recruit the Dishevelled scaffolding protein intracellularly (PubMed:30026314). Binds to the glycosaminoglycans heparin, heparin sulfate, chondroitin sulfate and dermatan sulfate (PubMed:16982628).
Expressed in endothelial cells (at protein level) (PubMed:15021905, PubMed:16982628). Abundantly expressed in heart, placenta, ovary, small intestine, and colon (PubMed:15021905).
Interacts with RECK; the interaction is direct (By similarity). Interacts (via PDZ-binding motif) with DLG1 (via PDZ domains) (PubMed:15021905). The cleaved extracellular subunit interacts with the integrin heterodimer ITGAV:ITGB3 (PubMed:16982628).
Proteolytically cleaved into two subunits, an extracellular subunit and a seven-transmembrane subunit (PubMed:22013897, PubMed:16982628). Cleaved by thrombin (F2) and MMP1 (PubMed:22013897). Also cleaved by MMP9, with lower efficiency (PubMed:22013897, PubMed:16982628). Presence of the protein disulfide-isomerase P4HB at the cell surface is additionally required for shedding of the extracellular subunit, suggesting that the subunits are linked by disulfide bonds (PubMed:22013897). Shedding is enhanced by the growth factor FGF2 and may promote cell survival during angiogenesis (PubMed:16982628).
The RGD motif is involved in integrin ITGAV:ITGB3 binding.
The leucine-rich repeats (LRRs) are important for potentiation of Wnt7 signaling.
Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX. Component of a complex containing at least CRELD2, MANF, MATN3 and PDIA4 (By similarity).
Part of a large chaperone multiprotein complex.
Was originally thought to be a deoxycytidine kinase.
Hydrolase that can remove conjugated ubiquitin from proteins in vitro and may therefore play an important regulatory role at the level of protein turnover by preventing degradation. Mediates deubiquitination of 'Lys-11'-,'Lys-48'- and 'Lys-63'-linked polyubiquitin chains, with a preference for 'Lys-63'-linked polyubiquitin chains.
In the structure described by PubMed:15258613, the Asp-48 active site of the catalytic triad is located too far to interact directly with the active site His-224. A possible explanation is that OTUB2 is in inactive conformation in absence of ubiquitin and a conformation change may move Asp-48 in the proximity of His-224 in presence of ubiquitin substrate.
Widely expressed. Expressed at higher level in brain.
Component of some HBO1 complex composed of KAT7/HBO1, MEAF6, ING4 or ING5, and BRPF3 (PubMed:26620551). Component of the MOZ/MORF complex composed at least of ING5, KAT6A, KAT6B, MEAF6 and one of BRPF1, BRD1/BRPF2 and BRPF3 (PubMed:16387653, PubMed:18794358). Interacts with KAT7/HBO1; the interaction is direct (PubMed:26677226).
Scaffold subunit of various histone acetyltransferase (HAT) complexes, such as the MOZ/MORF and HBO1 complexes, which have a histone H3 acetyltransferase activity (PubMed:16387653, PubMed:26620551, PubMed:26677226). Plays a role in DNA replication initiation by directing KAT7/HBO1 specificity towards histone H3 'Lys-14' acetylation (H3K14ac), thereby facilitating the activation of replication origins (PubMed:26620551). Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity (PubMed:16387653).
Directly interacts (via CARD) with TMEM173/STING; this interaction reduces TMEM173 trafficking to the perinuclear region in response to interferon stimulatory DNA. Also interacts, but to a lesser extent, with TBK1 (PubMed:24560620). Interacts with TRAF6; this interaction results in decreased TRAF6 'Lys-63'-linked polyubiquitination, but leaves 'Lys-48'-linked chains unchanged, promoting TRAF6 protein degradation (PubMed:22863753). Interacts with PIK3R1/PIK3R2; this interaction disrupts the association between PIK3R1/PIK3R2 and the p110 catalytic subunit PIK3CA/PIK3CB/PIK3CD and reduces PIK3R1/PIK3R2 activation (By similarity). Weakly interacts with PYCARD/ASC. Interacts with CASP1 and CASP5 (PubMed:25277106).
In primary T-cells, down-regulated upon T-cell receptor activation (PubMed:15705585). Down-regulated in peritoneal macrophages soon after the beginning of LPS stimulation. Levels start increasing again after 3 days of LPS treatment (PubMed:22863753).
Negative regulator of the innate immune response (PubMed:15705585, PubMed:22863753, PubMed:25277106). Attenuates signaling pathways activated by Toll-like receptors (TLRs) and the DNA sensor STING/TMEM173 in response to pathogen-associated molecular patterns, such as intracellular poly(dA:dT), but not poly(I:C), or in response to DNA virus infection, including that of Herpes simplex virus 1 (HSV1) (By similarity) (PubMed:22863753). May affect TLR4 signaling by acting at the level of TRAF6 ubiquitination, decreasing the activating 'Lys-63'-linked ubiquitination and leaving unchanged the degradative 'Lys-48'-linked ubiquitination (PubMed:22863753). Inhibits the PI3K-AKT-mTOR pathway possibly by directly interacting with the posphatidylinositol 3-kinase regulatory subunit p85 (PIK3R1/PIK3R2) and disrupting the association between PIK3R1/PIK3R2 and the catalytic subunit p110 (PIK3CA/PIK3CB/PIK3CD) and reducing PIK3R1/PIK3R2 activation. Via its regulation of the PI3K-AKT-mTOR pathway, controls cell proliferation, predominantly in intestinal epithelial cells (By similarity). May also affect NOD1- or NOD2-mediated NF-kappa-B activation (PubMed:25277106). Might also affect the inflammatory response by preventing NLRP3 inflammasome formation, CASP1 cleavage and IL1B maturation (PubMed:25277106).
The leucine-rich repeat domain may reduce the interaction with TMEM173/STING.
May form homodimers (PubMed:10564661). Part of a DNA-bound corepressor complex containing SAP18, GLI1 and SIN3 (By similarity). Part of a complex containing CTNNB1 (By similarity). Binds BTRC, GLI2, GLI3, SAP18 and STK36 (PubMed:10564661, PubMed:10806483). Binds both free and DNA-bound GLI1 (PubMed:10559945, PubMed:15367681, PubMed:24217340, PubMed:24311597, PubMed:28965847). Interacts with KIF7 (By similarity). Interacts with GLI3FL and this interaction regulates the formation of either repressor or activator forms of GLI3 (PubMed:24311597, PubMed:28965847). Its association with GLI3FL is regulated by Hh signaling and dissociation of the SUFU-GLI3 interaction requires the presence of the ciliary motor KIF3A (PubMed:24311597, PubMed:28965847). Interacts with ULK3; inactivating the protein kinase activity of ULK3 (PubMed:20643644). Interacts with RAB23 (PubMed:22365972).
Negative regulator in the hedgehog signaling pathway. Down-regulates GLI1-mediated transactivation of target genes. Part of a corepressor complex that acts on DNA-bound GLI1. May also act by linking GLI1 to BTRC and thereby targeting GLI1 to degradation by the proteasome. Sequesters GLI1, GLI2 and GLI3 in the cytoplasm, this effect is overcome by binding of STK36 to both SUFU and a GLI protein. Negative regulator of beta-catenin signaling. Regulates the formation of either the repressor form (GLI3R) or the activator form (GLI3A) of the full-length form of GLI3 (GLI3FL). GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state. Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R. When Hh signaling is initiated, SUFU dissociates from GLI3FL and the latter translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A).
Negative regulator in the hedgehog/smoothened signaling pathway (PubMed:10559945, PubMed:10564661, PubMed:10806483, PubMed:12068298, PubMed:12975309, PubMed:27234298, PubMed:15367681, PubMed:22365972, PubMed:24217340, PubMed:24311597, PubMed:28965847). Down-regulates GLI1-mediated transactivation of target genes (PubMed:15367681, PubMed:24217340, PubMed:24311597). Down-regulates GLI2-mediated transactivation of target genes (PubMed:24311597, PubMed:24217340). Part of a corepressor complex that acts on DNA-bound GLI1. May also act by linking GLI1 to BTRC and thereby targeting GLI1 to degradation by the proteasome (PubMed:10559945, PubMed:10564661, PubMed:10806483, PubMed:24217340). Sequesters GLI1, GLI2 and GLI3 in the cytoplasm, this effect is overcome by binding of STK36 to both SUFU and a GLI protein (PubMed:10559945, PubMed:10564661, PubMed:10806483, PubMed:24217340). Negative regulator of beta-catenin signaling (By similarity). Regulates the formation of either the repressor form (GLI3R) or the activator form (GLI3A) of the full-length form of GLI3 (GLI3FL) (PubMed:24311597, PubMed:28965847). GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state (PubMed:24311597, PubMed:28965847). Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R (PubMed:24311597, PubMed:28965847). When Hh signaling is initiated, SUFU dissociates from GLI3FL and the latter translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A) (PubMed:24311597, PubMed:28965847). Required for normal embryonic development (By similarity). Required for the proper formation of hair follicles and the control of epidermal differentiation (By similarity).
Phosphorylation at Ser-342, Ser-346, Ser-352 and Thr-353 prevents ubiquitination by the SCF(FBXL17) complex.
Polyubiquitinated at Lys-257 by the SCF(FBXL17) complex, leading to its subsequent degradation and allowing the release of GLI1 for proper hedgehog/smoothened signal transduction (PubMed:27234298). Ubiquitination is impaired by phosphorylation at Ser-342, Ser-346, Ser-352 and Thr-353 (PubMed:27234298).
Ubiquitous in adult tissues. Detected in osteoblasts of the perichondrium in the developing limb of 12-week old embryos. Isoform 1 is detected in fetal brain, lung, kidney and testis. Isoform 2 is detected in fetal testis, and at much lower levels in fetal brain, lung and kidney.
Belongs to the prefoldin subunit beta family.
Binds specifically to cytosolic chaperonin (c-CPN) and transfers target proteins to it. Binds to nascent polypeptide chain and promotes folding in an environment in which there are many competing pathways for nonnative proteins.
Heterohexamer of two PFD-alpha type and four PFD-beta type subunits (By similarity). Component of the PAQosome complex which is responsible for the biogenesis of several protein complexes and which consists of R2TP complex members RUVBL1, RUVBL2, RPAP3 and PIH1D1, URI complex members PFDN2, PFDN6, PDRG1, UXT and URI1 as well as ASDURF, POLR2E and DNAAF10/WDR92 (PubMed:31738558). Interacts with URI1; the interaction is phosphorylation-dependent and occurs in a growth-dependent manner (PubMed:17936702).
Expressed throughout the cell cycle independently of DNA synthesis.
H3F3A and H3F3B mutations affecting residues involved in post-translational modifications of histone H3.3 are implicated in the pathogenesis of some bone and cartilage neoplasms. Mutations have been found with high prevalence in chondroblastoma and giant cell tumors of bone, and with low frequency in osteosarcoma, conventional chondrosarcoma and clear cell chondrosarcoma. Chondroblastoma samples frequently carry a H3F3B mutation affecting residue Lys-37 (H3K36), although H3F3A is mutated in some cases. Most giant cell tumors of bone harbor H3F3A mutations affecting residue Gly-35 (H3G34).
Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 or isoform M2 of PKM (PKM2) is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin. Phosphorylation on Ser-32 (H3S31ph) is specific to regions bordering centromeres in metaphase chromosomes.
Serine ADP-ribosylation by PARP1 or PARP2 constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802, PubMed:34874266). Serine ADP-ribosylation at Ser-11 (H3S10ADPr) promotes recruitment of CHD1L (PubMed:34874266). H3S10ADPr is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac) (PubMed:30257210).
Specific interaction of trimethylated form at 'Lys-36' (H3.3K36me3) with ZMYND11 is mediated by the encapsulation of Ser-32 residue with a composite pocket formed by the tandem bromo-PWWP domains.
Specifically enriched in modifications associated with active chromatin such as methylation at Lys-5 (H3K4me), Lys-37 and Lys-80. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me), which are linked to gene repression, are underrepresented. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication.
The disease is caused by variants affecting the gene represented in this entry. BRYLIB1 is caused by variants in H3-3A.
The disease is caused by variants affecting the gene represented in this entry. BRYLIB2 is caused by variants in H3-3B.
The gene represented in this entry is involved in disease pathogenesis. H3F3A mutations affecting residues involved in post-translational modifications of histone H3.3 are recurrent in malignant, aggressive gliomas including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) (PubMed:22286061, PubMed:22286216). The mechanism through which mutations lead to tumorigenesis involves altered histones methylation, impaired regulation of Polycomb repressive complex 2 (PRC2) activity, and aberrant epigenetic regulation of gene expression (PubMed:23539269, PubMed:23539183, PubMed:23603901).
The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Interacts with HIRA, a chaperone required for its incorporation into nucleosomes. Interacts with ZMYND11; when trimethylated at 'Lys-36' (H3.3K36me3). Found in a co-chaperone complex with DNJC9, MCM2 and histone H3.3-H4 dimers (PubMed:33857403). Within the complex, interacts with DNJC9 (via C-terminus); the interaction is direct (PubMed:33857403). Interacts with ASF1A, MCM2, NASP and SPT2 (PubMed:33857403). Interacts with DAXX; the interaction is direct (PubMed:20504901, PubMed:34876591).
Ubiquitinated. Monoubiquitinated by RAG1 in lymphoid cells, monoubiquitination is required for V(D)J recombination (By similarity).
Variant histone H3 which replaces conventional H3 in a wide range of nucleosomes in active genes. Constitutes the predominant form of histone H3 in non-dividing cells and is incorporated into chromatin independently of DNA synthesis. Deposited at sites of nucleosomal displacement throughout transcribed genes, suggesting that it represents an epigenetic imprint of transcriptionally active chromatin. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.
(Microbial infection) Interacts (via RNA-binding domain) with Ebolavirus nucleoprotein; this interaction recruits NXF1 to the inclusion bodies were viral replication takes place, probably to export viral mRNA-NXF1 complexes from these sites.
(Microbial infection) Interacts with Epstein Barr virus (EBV) mRNA export factor ICP27 homolog; this interaction plays a role in mRNA export.
(Microbial infection) Interacts with Saimiriine herpesvirus 2 TIP protein.
(Microbial infection) Interacts with human herpes virus 1 (HHV-1) ICP27 protein; this interaction allows efficient export of HHV-1 early and late transcripts.
Heterodimer (via NTF2 domain) with NXT1 (PubMed:11583626). The formation of NXF1-NXT1 heterodimers is required for the NXF1-mediated nuclear mRNA export (PubMed:11583626). Forms a complex with RANBP2/NUP358, NXT1 and RANGAP1 (PubMed:14729961). Associates with the exon junction complex (EJC) and with the transcription/export (TREX) complex (PubMed:11707413, PubMed:22893130). Found in a mRNA complex with UPF3A and UPF3B (PubMed:11546873). Found in a post-splicing complex with RBM8A, UPF1, UPF2, UPF3A, UPF3B and RNPS1 (PubMed:11546874). Interacts (via N-terminus) with DHX9 (via N-terminus); this interaction is direct and negatively regulates NXF1-mediated nuclear export of constitutive transport element (CTE)-containing cellular mRNAs (PubMed:10924507). Interacts with ALYREF/THOC4 (PubMed:11707413, PubMed:14730019, PubMed:19165146, PubMed:23299939). Interacts with FYTTD1/UIF (PubMed:19836239). Interacts with EIF4A3 (PubMed:14730019). Interacts with NUP42 (PubMed:10228171). Interacts with THOC5 (PubMed:19165146, PubMed:23299939). Interacts with CHTOP (PubMed:23299939, PubMed:23826332). Interacts with FRG1 (via N-terminus) (PubMed:21699900). Interacts with LUZP4 (PubMed:25662211). Interacts with FMR1; the interaction occurs in a mRNA-dependent and polyribosomes-independent manner in the nucleus (PubMed:18936162). Interacts with CPSF6 (via N-terminus); this interaction is direct (PubMed:19864460). Interacts with RBM15 (PubMed:17001072). Interacts with RBM15B (PubMed:19586903). Interacts with MCM3AP isoform GANP; this interaction is not mediated by RNA (PubMed:20005110). Interacts with DDX3X (via C-terminus); this interaction may be partly involved in DDX3X nuclear export and in NXF1 localization to stress granules (PubMed:18596238). Interacts with PABPC1/PABP1 (PubMed:18596238).
Involved in the nuclear export of mRNA species bearing retroviral constitutive transport elements (CTE) and in the export of mRNA from the nucleus to the cytoplasm (TAP/NFX1 pathway) (PubMed:10924507). The NXF1-NXT1 heterodimer is involved in the export of HSP70 mRNA in conjunction with ALYREF/THOC4 and THOC5 components of the TREX complex (PubMed:18364396, PubMed:19165146, PubMed:9660949). ALYREF/THOC4-bound mRNA is thought to be transferred to the NXF1-NXT1 heterodimer for export (PubMed:18364396, PubMed:19165146, PubMed:9660949). Also involved in nuclear export of m6A-containing mRNAs: interaction between SRSF3 and YTHDC1 facilitates m6A-containing mRNA-binding to both SRSF3 and NXF1, promoting mRNA nuclear export (PubMed:28984244).
The NTF2 domain is functional only in the presence of NXT1 and is essential for the export of mRNA from the nucleus. It inhibits RNA binding activity through an intramolecular interaction with the N-terminal RNA binding domain (RBD); the inhibition is removed by an association with the TREX complex, specifically involving ALYREF/THOC4 and THOC5.
The TAP-C domain mediates direct interactions with nucleoporin-FG-repeats and is necessary and sufficient for localization of NXF1 to the nuclear rim. The conserved loop 594-NWD-596 of the TAP-C domain has a critical role in the interaction with nucleoporins.
The leucine-rich repeats are essential for the export of mRNA from the nucleus.
The minimal CTE binding domain consists of an RNP-type RNA binding domain (RBD) and leucine-rich repeats.
The nucleoporin binding domain consists of a NTF2 domain (also called NTF2-like domain) and a TAP-C domain (also called UBA-like domain). It has 2 nucleoporin-FG-repeats binding sites (one in the NTF2 and the other in the TAP-C domain) which contribute to nucleoporin association and act synergistically to export cellular mRNAs.
Binding partner of the GTPase-activating protein FLCN: involved in the cellular response to amino acid availability by regulating the non-canonical mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:17028174, PubMed:18663353, PubMed:24081491, PubMed:37079666). Required to promote FLCN recruitment to lysosomes and interaction with Rag GTPases, leading to activation of the non-canonical mTORC1 signaling (PubMed:24081491). In low-amino acid conditions, component of the lysosomal folliculin complex (LFC) on the membrane of lysosomes, which inhibits the GTPase-activating activity of FLCN, thereby inactivating mTORC1 and promoting nuclear translocation of TFEB and TFE3 (By similarity). Upon amino acid restimulation, disassembly of the LFC complex liberates the GTPase-activating activity of FLCN, leading to activation of mTORC1 and subsequent inactivation of TFEB and TFE3 (PubMed:37079666). Together with FLCN, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy (PubMed:25126726). In addition to its role in mTORC1 signaling, also acts as a co-chaperone of HSP90AA1/Hsp90: following gradual phosphorylation by CK2, inhibits the ATPase activity of HSP90AA1/Hsp90, leading to activate both kinase and non-kinase client proteins of HSP90AA1/Hsp90 (PubMed:27353360, PubMed:30699359). Acts as a scaffold to load client protein FLCN onto HSP90AA1/Hsp90 (PubMed:27353360). Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (PubMed:27353360). Also acts as a core component of the reductive stress response by inhibiting activation of mitochondria in normal conditions: in response to reductive stress, the conserved Cys degron is reduced, leading to recognition and polyubiquitylation by the CRL2(FEM1B) complex, followed by proteasomal (By similarity). Required for B-cell development (PubMed:32905580).
GlcNAcylation at Ser-938 by OGT following dephosphorylation by protein phosphatase 5 (PP5) promotes ubiquitination and degradation by the proteasome.
Homodimer and homomultimer (PubMed:18403135, PubMed:27353360). Heterodimer and heteromultimer with FNIP2 (PubMed:18403135, PubMed:27353360). Interacts with FLCN (via C-terminus) (PubMed:17028174, PubMed:27353360). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator (By similarity). Interacts with HSPCA and with the PRKAA1, PRKAB1 and PRKAG1 subunits of 5'-AMP-activated protein kinase (AMPK) (PubMed:17028174). Phosphorylated FLCN and AMPK are preferentially bound (PubMed:17028174). Interacts with HSP70, STIP1, PTGES3, CDC37, BRAF, GCR and CDK4 (PubMed:27353360). Interacts with HSP90AA1; the interaction inhibits HSP90AA1 ATPase activity (PubMed:27353360, PubMed:30699359). Interacts with ATP2A2 (By similarity).
Oxidation of the Cys degron in normal conditions promotes its stabilization by preventing recognition and ubiquitination by the CRL2(FEM1B) complex.
Phosphorylated by AMPK in response to energetic stress (PubMed:17028174, PubMed:37079666). Phosphorylation by AMPK in response to mitochondrial damage promotes inactivation of the non-canonical mTORC1 signaling, nuclear translocation of TFEB and TFE3, inducing transcription of lysosomal or autophagy genes (PubMed:37079666). Sequential phosphorylation by CK2 promotes its gradual interaction with HSP90AA1/Hsp90 (PubMed:30699359). Priming phosphorylation at Ser-938 is followed by relay phosphorylation at Ser-939, Ser-941, Ser-946 and Ser-948, promoting its gradual interaction with HSP90AA1/Hsp90 (PubMed:30699359). This leads to incremental inhibition of HSP90AA1/Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients (PubMed:30699359). Dephosphorylated by protein phosphatase 5 (PP5), promoting glycosylation by OGT (PubMed:30699359).
Strong expression is found in the heart, liver placenta, muscle, nasal mucosa, salivary gland and uvula and moderate expression in kidney and lung. Higher levels detected in clear cell renal cell carcinoma (RCC) and chromophobe RCC than in normal kidney tissue. Expressed in peripheral blood mononuclear cells (PubMed:32181500).
The KY-finger orients the Cys degron for ubiquitination by the CRL2(FEM1B) complex.
Ubiquitinated through 'Lys-11' linkage of ubiquitin moieties at Lys-1119 following glycosylation by OGT, leading to its degradation by the proteasome (PubMed:30699359). Ubiquitinated by the CRL2(FEM1B) complex in response to reductive stress: reductive stress causes reduction of the conserved Cys degron in FNIP1, followed by zinc-binding, zinc acting as a molecular glue for recognition by the CRL2(FEM1B) complex (By similarity). Ubiquitination leads to FNIP1 degradation, and activation of mitochondria to recalibrate reactive oxygen species (ROS) (By similarity).
Chromosomal aberrations involving BCL11A are associated with B-cell malignancies. Translocation t(2;14)(p13;q32.3) causes BCL11A deregulation and overexpression.
Expressed at high levels in brain, spleen thymus, bone marrow and testis. Expressed in CD34-positive myeloid precursor cells, B-cells, monocytes and megakaryocytes. Expression is tightly regulated during B-cell development.
Expressed in fetal and adult brain, and in the plasmacytoid dendritic cell.
Genetic variation in BCL11A underlies the fetal hemoglobin quantitative trait locus 5 [MIM:142335]. It is associated with quantitative variation in the production of F cells, that is erythrocytes containing measurable amounts of fetal hemoglobin (HbF). In healthy adults, HbF is present at residual levels (less than 0.6% of total hemoglobin) with over twenty-fold variation. Ten to fifteen percent of adults in the upper tail of the distribution have HbF levels between 0.8% and 5.0%, a condition referred to as heterocellular hereditary persistence of fetal hemoglobin (hHPFH). Although these HbF levels are modest in otherwise healthy individuals, interaction of hHPFH with beta thalassemia or sickle cell disease can increase HbF output in these individuals to levels that are clinically beneficial.
Interacts with NR2F1, PIAS3, NR2F2 and NR2F6 (By similarity). Isoform 1, isoform 2 and isoform 3 form homodimers and heterodimers (PubMed:27453576). Isoform 2 interacts with TBR1 (PubMed:30250039).
The C-terminus of isoform 2 is necessary for isoform 2 interaction with TBR1.
The N-terminus is involved in protein dimerization and in transactivation of transcription.
Transcription factor (PubMed:16704730, PubMed:29606353). Associated with the BAF SWI/SNF chromatin remodeling complex (PubMed:23644491). Binds to the 5'-TGACCA-3' sequence motif in regulatory regions of target genes, including a distal promoter of the HBG1 hemoglobin subunit gamma-1 gene (PubMed:29606353). Involved in regulation of the developmental switch from gamma- to beta-globin, probably via direct repression of HBG1; hence indirectly repressing fetal hemoglobin (HbF) level (PubMed:29606353, PubMed:26375765). Involved in brain development (PubMed:27453576). May play a role in hematopoiesis (By similarity). Essential factor in lymphopoiesis required for B-cell formation in fetal liver (By similarity). May function as a modulator of the transcriptional repression activity of NR2F2 (By similarity).
Zinc finger domains are necessary for sequence-specific binding to DNA.
Automethylated; Lys-39 and Lys-179 serve as the major automethylation sites.
Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. SETD6 subfamily.
Monomer, homodimer and homotrimer; these structures are stabilized in the presence of S-adenosyl-L-methionine (SAM).
Protein-lysine N-methyltransferase. Monomethylates 'Lys-310' of the RELA subunit of NF-kappa-B complex, leading to down-regulation of NF-kappa-B transcription factor activity (PubMed:21131967, PubMed:30189201, PubMed:21515635). Monomethylates 'Lys-8' of H2AZ (H2AZK8me1) (PubMed:23324626). Required for the maintenance of embryonic stem cell self-renewal (By similarity). Methylates PAK4.
Involved in plasma membrane dynamics and cell process formation. Isoform 1 and isoform 2 are necessary for axonal and dendritic filopodia induction, for dendritic spine maturation and synapse formation in a palmitoylation-dependent manner.
Widely expressed with highest expression in brain and testis and intermediate expression in heart and adrenal gland.
Binds DNA as a monomer (By similarity). Interacts with FOXA2. Interacts with NKX2-1. Interacts with HDAC7. Interacts with the histone H3-H4 heterodimer. Associates with nucleosomes containing histone H2A. Interacts with AR. Interacts with NR0B2 (By similarity).
Highly expressed in prostate and ESR1-positive breast tumors. Overexpressed in esophageal and lung adenocarcinomas.
Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues. Is thought to act as a 'pioneer' factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites. Binds DNA with the consensus sequence 5'-[AC]A[AT]T[AG]TT[GT][AG][CT]T[CT]-3' (By similarity). Proposed to play a role in translating the epigenetic signatures into cell type-specific enhancer-driven transcriptional programs. Its differential recruitment to chromatin is dependent on distribution of histone H3 methylated at 'Lys-5' (H3K4me2) in estrogen-regulated genes. Involved in the development of multiple endoderm-derived organ systems such as liver, pancreas, lung and prostate; FOXA1 and FOXA2 seem to have at least in part redundant roles (By similarity). Modulates the transcriptional activity of nuclear hormone receptors. Is involved in ESR1-mediated transcription; required for ESR1 binding to the NKX2-1 promoter in breast cancer cells; binds to the RPRM promoter and is required for the estrogen-induced repression of RPRM. Involved in regulation of apoptosis by inhibiting the expression of BCL2. Involved in cell cycle regulation by activating expression of CDKN1B, alone or in conjunction with BRCA1. Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis.
Forms homo- and heterooligomers with DERL2 and, to a lesser extent, with DERL1 (PubMed:16449189). Interacts with VCP and EDEM1 (PubMed:16449189). Interacts with SELENOK and SELENOS (PubMed:22016385). Interacts with the signal recognition particle/SRP and the SRP receptor; in the process of endoplasmic reticulum stress-induced pre-emptive quality control (PubMed:26565908).
Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal glycoproteins, but not that of misfolded nonglycoproteins. May act by forming a channel that allows the retrotranslocation of misfolded glycoproteins into the cytosol where they are ubiquitinated and degraded by the proteasome. May mediate the interaction between VCP and the misfolded glycoproteins (PubMed:16449189, PubMed:22607976). May be involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation (PubMed:26565908).
Unlike DERL1 and DERL2, restricted to several tissues. Expressed at high levels in placenta, pancreas, spleen and small intestine.
Identified in the ASCC complex that contains ASCC1, ASCC2 and ASCC3 (PubMed:29144457, PubMed:29997253). Interacts directly with ASCC3 (PubMed:29997253). The ASCC complex interacts with ALKBH3 (PubMed:29144457, PubMed:22055184). Part of the ASC-1 complex, that contains TRIP4, ASCC1, ASCC2 and ASCC3 (PubMed:12077347). Interacts with CSRP1 (PubMed:26924529). Interacts with ZCCHC4 (PubMed:31799605).
Plays a role in DNA damage repair as component of the ASCC complex (PubMed:29997253). Part of the ASC-1 complex that enhances NF-kappa-B, SRF and AP1 transactivation (PubMed:12077347). In cells responding to gastrin-activated paracrine signals, it is involved in the induction of SERPINB2 expression by gastrin. May also play a role in the development of neuromuscular junction.
(Microbial infection) Acetylation by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation (PubMed:29433126). Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis.
Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3/ERK1 and RGS14 (By similarity). Forms a heterodimer with MAP2K2/MEK2 (By similarity). Forms heterodimers with KSR2 which further dimerize to form tetramers (By similarity). Interacts with KSR1 or KSR2 and BRAF; the interaction with KSR1 or KSR2 mediates KSR1-BRAF or KSR2-BRAF dimerization (PubMed:10409742, PubMed:29433126). Interacts with ARBB2, LAMTOR3 and RAF1 (By similarity). Interacts with MAPK1/ERK2 (PubMed:32721402). Interacts with MORG1 (By similarity). Interacts with PPARG (PubMed:17101779). Interacts with isoform 1 of VRK2 (PubMed:20679487). Interacts with SGK1 (PubMed:19447520). Interacts with BIRC6/bruce (PubMed:18329369). Interacts with KAT7; the interaction promotes KAT7 phosphorylation (By similarity). Interacts with RAF1 and NEK10; the interaction is required for ERK1/2-signaling pathway activation in response to UV irradiation (PubMed:20956560). Interacts with TRAF3IP3 (PubMed:26195727).
Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase kinases (BRAF or MEKK1) positively regulates kinase activity (PubMed:29433126, PubMed:8131746). Also phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-298 by PAK (PubMed:16129686). MAPK1/ERK2 phosphorylation of Thr-292 occurs in response to cellular adhesion and leads to inhibition of Ser-298 phosphorylation by PAK (PubMed:16129686). Autophosphorylated at Ser-218 and Ser-222, autophosphosphorylation is promoted by NEK10 following UV irradiation (PubMed:20956560).
Ras proteins such as HRAS mediate the activation of RAF proteins such as RAF1 or BRAF which in turn activate extracellular signal-regulated kinases (ERK) through MAPK (mitogen-activated protein kinases) and ERK kinases MAP2K1/MEK1 and MAP2K2/MEK2 (PubMed:29433126). Activation occurs through phosphorylation of Ser-218 and Ser-222 (By similarity). MAP2K1/MEK1 binds KSR1 or KSR2 releasing the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains (PubMed:29433126). This allows KSR1 or KSR2 dimerization with BRAF leading to BRAF activation and phosphorylation of MAP2K1 (PubMed:29433126). MAP2K1/MEK1 is also the target of negative feed-back regulation by its substrate kinases, such as MAPK1/ERK2. These phosphorylate MAP2K1/MEK1 on Thr-292, thereby facilitating dephosphorylation of the activating residues Ser-218 and Ser-222. Inhibited by serine/threonine phosphatase 2A (By similarity). Many inhibitors have been identified including pyrrole derivatives, TAK-733 (one of a series of 8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione derivatives), CH4987655 and RDEA119/BAY 869766 (PubMed:21310613, PubMed:20621728, PubMed:19706763, PubMed:19019675, PubMed:19161339, PubMed:18951019, PubMed:17880056, PubMed:15543157).
The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1.
Widely expressed, with extremely low levels in brain.
Belongs to the eIF-2B alpha/beta/delta subunits family.
Complex of five different subunits; alpha, beta, gamma, delta and epsilon.
Cytokine that binds to TNFRSF9. Induces the proliferation of activated peripheral blood T-cells. May have a role in activation-induced cell death (AICD). May play a role in cognate interactions between T-cells and B-cells/macrophages.
Expressed in brain, placenta, lung, skeletal muscle and kidney.
Expressed in the cerebellum. Expressed in neurons and glial cells, including layers II neurons in the frontal cortex and CA1 pyramidal neurons in the hippocampus. Expressed in heart, liver, pancreas, skeletal muscle, placenta, primary fibroblasts and peripheral blood monocytes (at protein level). Ubiquitously expressed. Highly expressed in heart, placenta and skeletal muscle. Weakly expressed in pancreas, kidney, liver, lung and brain.
Found to be expressed in fetal brain. Down-regulated in fetal Down syndrome (DS) brain.
Interacts with TNPO3; the interaction mediates nuclear import of the protein and is disrupted by nuclear Ran bound to GTP. Interacts with EIF4G1 and WT1. Interacts with EIF4A1; the interaction is modulated under stress-induced conditions. Interacts with AGO1. Interacts with AGO2; the interaction occurs under both cell proliferation and differentiation conditions and in an RNA- and phosphorylation-independent manner. Interacts with DDX5; the interaction occurs in an RNA-independent manner.
Phosphorylation on Ser-309 is induced upon cell muscle differentiation (By similarity). Phosphorylated. Phosphorylated in vitro on Ser-309 by SRPK1. Phosphorylation on Ser-309 is induced upon cell stress signaling, which alters its subcellular localization and may modulate its activity on IRES-mediated mRNA translation.
RNA-binding factor involved in multiple aspects of cellular processes like alternative splicing of pre-mRNA and translation regulation. Modulates alternative 5'-splice site and exon selection. Acts as a muscle cell differentiation-promoting factor. Activates exon skipping of the PTB pre-mRNA during muscle cell differentiation. Antagonizes the activity of the splicing factor PTBP1 to modulate muscle cell-specific exon selection of alpha tropomyosin. Binds to intronic pyrimidine-rich sequence of the TPM1 and MAPT pre-mRNAs. Required for the translational activation of PER1 mRNA in response to circadian clock. Binds directly to the 3'-UTR of the PER1 mRNA. Exerts a suppressive activity on Cap-dependent translation via binding to CU-rich responsive elements within the 3'UTR of mRNAs, a process increased under stress conditions or during myocytes differentiation. Recruits EIF4A1 to stimulate IRES-dependent translation initiation in respons to cellular stress. Associates to internal ribosome entry segment (IRES) in target mRNA species under stress conditions. Plays a role for miRNA-guided RNA cleavage and translation suppression by promoting association of AGO2-containing miRNPs with their cognate target mRNAs. Associates with miRNAs during muscle cell differentiation. Binds preferentially to 5'-CGCGCG[GCA]-3' motif in vitro.
Found in prostate, liver, salivary gland, kidney, lung, pancreas, colon, bronchus and renal proximal tubular cells. In the prostate gland it may be synthesized in epithelial cells, secreted into the ducts, and excreted into the seminal fluid.
Heterodimer of two chains, light and heavy, held by a disulfide bond.
Possesses a trypsin-like cleavage specificity with a preference for poly-basic substrates. Stimulates epithelial sodium channel (ENaC) activity through activating cleavage of the gamma subunits (SCNN1G).
Stimulates transcription from the HSP70 promoter.
Dysidenin and perchlorate inhibit iodide transport activity.
Expression is primarily in thyroid tissue, but also to a lower extent in mammary gland and ovary. Expression is reduced in tumors.
Sodium:iodide symporter that mediates the transport of iodide into the thyroid gland (PubMed:8806637, PubMed:9329364, PubMed:20797386, PubMed:12488351, PubMed:18372236, PubMed:18708479, PubMed:31310151, PubMed:32084174). Can also mediate the transport of chlorate, thiocynate, nitrate and selenocynate (PubMed:12488351).
Up-regulated by forskolin and thyrotropin (at protein level).
Binds to its receptors; DCC, UNC5A, UNC5B, UNC5C and probably UNC5D (PubMed:9950216). Binds to its receptor; DSCAM (PubMed:19196994). Interacts with APP (By similarity).
Netrins control guidance of CNS commissural axons and peripheral motor axons. Its association with either DCC or some UNC5 receptors will lead to axon attraction or repulsion, respectively. Binding to UNC5C might cause dissociation of UNC5C from polymerized TUBB3 in microtubules and thereby lead to increased microtubule dynamics and axon repulsion (PubMed:28483977). Involved in dorsal root ganglion axon projection towards the spinal cord (PubMed:28483977). It also serves as a survival factor via its association with its receptors which prevent the initiation of apoptosis. Involved in tumorigenesis by regulating apoptosis (PubMed:15343335).
Widely expressed in normal adult tissues with highest levels in heart, small intestine, colon, liver and prostate. Reduced expression in brain tumors and neuroblastomas. Expressed in epididymis (at protein level).
Expressed in some prostate cancer tissues but not in normal prostate tissue.
The first GAGE nomenclature was based on identified mRNA sequences, but the high identity of the GAGE members made impossible to separate products of paralogous genes from polymorph products. PubMed:18179644 presented a new GAGE gene nomenclature based on the identified genes and their products. GAGE12B is present as fragment in GRCh37 reference genome assembly due to an unsequenced gap between two clusters in the GAGE locus.
This gene belongs to a family of genes organized in clustered repeats. They have a high degree of predicted sequence identity, but differ by scattered single nucleotide substitution. Their sequences contain either the antigenic peptide YYWPRPRRY or YRPRPRRY which is recognized by cytotoxic T-cells.
Belongs to the archaeal Rpo6/eukaryotic RPB6 RNA polymerase subunit family.
DNA-dependent RNA polymerases catalyze the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II, and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2F/RPB6 is part of the clamp element and together with parts of RPB1 and RPB2 forms a pocket to which the RPB4-RPB7 subcomplex binds (By similarity).
Acts as a carrier protein that release fibroblast-binding factors (FGFs) from the extracellular matrix (EM) storage and thus enhance the mitogenic activity of FGFs. Enhances FGF2 signaling during tissue repair, angiogenesis and in tumor growth.
Belongs to the fibroblast growth factor-binding protein family.
Expressed in the suprabasal region of the epidermis, in hair follicles, the basement membrane at the dermo-epidermal junction (occasionally extending into the basement membrane of dermal blood vessels), wounded skin and several invasive squamous cell carcinomas (at protein level). Expressed in normal and wounded skin and various squamous cell carcinomas.
Expression is significantly up-regulated in carcinogen-induced skin tumors, various squamous cell carcinomas, some colon cancer cell lines and tumors.
Found in a complex with FGFBP1, FGF1 and FGF2. Interacts with FGF1, FGF2, FGF7, FGF10, FGF22 and HSPG2.
Up-regulated in epithelial cells after skin injury. Keratinocyte mitogens.
Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class II subfamily.
Binds the basement membrane heparan sulfate proteoglycan perlecan and triple helical collagens type I and type II.
May anchor basement membranes to the underlying connective tissue.
The basic N-terminal Arg/Pro-rich region binds heparin and heparan sulfate (PubMed:11007795). Binds collagens type I and type II through its leucine-rich repeat domain (By similarity).
Deletion of exon 3 in GYPC results in resistance to Plasmodium falciparum invasion and protection against severe malaria [MIM:611162].
GYPC is responsible for the Gerbich blood group system (Ge) [MIM:616089]. Ge negative individuals carry a deletion of GYPC exon 3.
Glycophorin-C is expressed in erythrocytes. Glycophorin-D and IsoGPC are ubiquitously expressed.
This protein is a minor sialoglycoprotein in human erythrocyte membranes. The blood group Gerbich antigens and receptors for Plasmodium falciparum merozoites are most likely located within the extracellular domain. Glycophorin-C plays an important role in regulating the stability of red cells.
Disordered region at the N-terminus undergoes liquid-liquid phase separation (LLPS) for the formation of membraneless compartments that store maternal mRNAs in oocytes.
The 3CxxC-type mediates binding to the 3'-UTR of mRNAs.
mRNA-binding protein required for maternal mRNA storage, translation and degradation during oocyte maturation (By similarity). Probably promotes formation of some phase-separated membraneless compartment that stores maternal mRNAs in oocytes: acts by undergoing liquid-liquid phase separation upon binding to maternal mRNAs (By similarity). Binds to the 3'-UTR of maternal mRNAs, inhibiting their translation (By similarity).
Homodimer (PubMed:32403431). Homooligomer (PubMed:29472561). Forms heterodimers with MPC1 and MPC1L. The heterodimer is the more stable and dominant form (PubMed:26253029, PubMed:32403431).
Adaptor protein complex 2 (AP-2) is a heterotetramer composed of two large adaptins (alpha-type subunit AP2A1 or AP2A2 and beta-type subunit AP2B1), a medium adaptin (mu-type subunit AP2M1) and a small adaptin (sigma-type subunit AP2S1). Interacts with CCDC32; the interaction is direct and mediates association of CCDC32 with adaptor protein complex 2 (AP-2) (PubMed:33859415).
Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. The AP-2 alpha and AP-2 sigma subunits are thought to contribute to the recognition of the [ED]-X-X-X-L-[LI] motif (By similarity). May also play a role in extracellular calcium homeostasis.
Component of the GPI transamidase complex, necessary for transfer of GPI to proteins (PubMed:34576938). May be involved in the recognition of either the GPI attachment signal or the lipid portion of GPI.
Forms a complex with PIGK/GPI8, PIGS, PIGT and GPAA1/GAA1.
May play a significant role in AAUAAA-independent mRNA polyadenylation in germ cells. Directly involved in the binding to pre-mRNAs (By similarity).
Interacts with HDAC1, HDAC2, HDAC3, CBX1 and EP300.
Putative histone methyltransferase that acts as a transcriptional repressor of smooth muscle gene expression. Promotes the transition from differentiated to proliferative smooth muscle by suppressing differentiation and maintaining the proliferative potential of vascular smooth muscle cells. Also plays a role in endothelial cells by inhibiting endothelial cell proliferation, survival and differentiation. It is unclear whether it has histone methyltransferase activity in vivo. According to some authors, it does not act as a histone methyltransferase by itself and represses transcription by recruiting EHMT2/G9a. According to others, it possesses histone methyltransferase activity when associated with other proteins and specifically methylates 'Lys-20' of histone H4 in vitro. 'Lys-20' methylation represents a specific tag for epigenetic transcriptional repression.
Expressed in peripheral blood cells and monocytes. Expressed in adrenal medulla.
Receptor for plasminogen. Regulates urokinase plasminogen activator-dependent and stimulates tissue-type plasminogen activator-dependent cell surface plasminogen activation. Proposed to be part of a local catecholaminergic cell plasminogen activation system that regulates neuroendocrine prohormone processing. Involved in regulation of inflammatory response; regulates monocyte chemotactic migration and matrix metalloproteinase activation, such as of MMP2 and MMP9.
GTPase-activating protein for RHOA and CDC42.
Interacts with NYAP1, NYAP2 and MYO16 (By similarity). Binds to the C-terminus of PTK2/FAK1.
The gene represented in this entry is involved in disease pathogenesis. A chromosomal translocation t(5;11)(q31;q23) with KMT2A/MLL1 has been found in leukemic cells from JMML patients, also carrying inactivating mutations on the second allele (PubMed:10908648).
May play a role in nucleosome assembly by neutralizing basic proteins such as A and B core hnRNPs.
Testis. Detected in germ cells at all stages of the seminiferous epithelium, strong expression in elongating spermatids (at protein level) (PubMed:26168773).
Belongs to the universal ribosomal protein uL3 family.
Component of the large ribosomal subunit in striated muscle cells.
Heart- and skeletal muscle-specific component of the ribosome, which regulates muscle function. Component of the large ribosomal subunit in striated muscle cells: replaces the RPL3 paralog in the ribosome in these cells. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. Inhibits myotube growth and muscle function.
Acts as transcription regulator that binds target promoter DNA and bends the DNA. Binds to the sequences 5'-AACAAT-'3 or 5'-AACAAAG-3'. Modulates transcriptional regulation via WNT3A. Inhibits Wnt signaling. Promotes degradation of activated CTNNB1. Plays a key role in the regulation of embryonic development. Required for normal development of the definitive gut endoderm. Required for normal looping of the embryonic heart tube. Plays an important role in embryonic and postnatal vascular development, including development of arteries. Plays an important role in postnatal angiogenesis, where it is functionally redundant with SOX18. Required for the generation and maintenance of fetal hematopoietic stem cells, and for fetal hematopoiesis. Probable transcriptional activator in the premeiotic germ cells.
Expressed in adult heart, lung, spleen, testis, ovary, placenta, fetal lung, and kidney. In normal gastrointestinal tract, it is preferentially expressed in esophagus, stomach and small intestine than in colon and rectum.
Homohexamer. Associates with heptad repeats of HSF1 trimers and probably also HSF1 monomers, and with HSP70. Association with HSF1 trimers and HSP70 coincides with attenuation of heat shock response and the conversion of HSF1 trimer to monomer.
Negative regulator of the heat shock response. Negatively affects HSF1 DNA-binding activity. May have a role in the suppression of the activation of the stress response during the aging process.
Belongs to the DOK family. Type A subfamily.
Constitutively tyrosine-phosphorylated. Phosphorylated by TEC (By similarity). Phosphorylated by LYN (By similarity). Phosphorylated on tyrosine residues by the insulin receptor kinase. Results in the negative regulation of the insulin signaling pathway. Phosphorylated on tyrosine residues by SRMS.
DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK1 appears to be a negative regulator of the insulin signaling pathway. Modulates integrin activation by competing with talin for the same binding site on ITGB3.
Expressed in pancreas, heart, leukocyte and spleen. Expressed in both resting and activated peripheral blood T-cells. Expressed in breast cancer.
Interacts with ABL1 (By similarity). Interacts with RasGAP and INPP5D/SHIP1. Interacts directly with phosphorylated ITGB3. Interacts with SRMS (via the SH2 and SH3 domains).
Produced by alternative initiation at Met-140 of isoform 1.
The PTB domain mediates receptor interaction.
Identified in the spliceosome B complex (PubMed:28781166). Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39 (PubMed:11867543, PubMed:16723661, PubMed:26912367). Interacts with a complex formed by SNU13 and U4 snRNA, but not with SNU13 or U4 snRNA alone (PubMed:17412961, PubMed:21784869). The complex formed by SNU13 and PRPF31 binds also U4atac snRNA, a characteristic component of specific, less abundant spliceosomal complexes (PubMed:21784869). Interacts with PRPF6/U5 snRNP-associated 102 kDa protein (PubMed:11867543, PubMed:17412961, PubMed:26912367). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975). Interacts (via its NLS) with CTNNBL1 (PubMed:21385873). Interacts with USH1G (PubMed:34023904).
Interacts with the snRNP via the Nop domain.
Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11867543, PubMed:28781166). Required for the assembly of the U4/U5/U6 tri-snRNP complex, one of the building blocks of the spliceosome (PubMed:11867543).
The coiled coil domain is formed by two non-contiguous helices.
Belongs to the secretoglobin family. Lipophilin subfamily.
Highest expression was found in skeletal muscle. Expressed as well in thymus, trachea, kidney, steroid responsive tissues (prostate, testis, uterus, breast and ovary) and salivary gland.
May bind androgens and other steroids, may also bind estramustine, a chemotherapeutic agent used for prostate cancer. May be under transcriptional regulation of steroid hormones.
By spinal cord injury. This effect is particularly prominent in macrophages, microglia and reactive astrocytes.
In fluids, highest levels found in milk of lactating women followed by cerebrospinal fluid, nipple aspirate fluid and breast cyst fluid. Also found in serum, seminal plasma and some amniotic fluids and breast tumor cytosolic extracts. Not detected in urine. At the tissue level, highest concentrations found in glandular tissues such as salivary glands followed by lung, colon, fallopian tube, placenta, breast, pituitary and kidney. Not detected in skin, spleen, bone, thyroid, heart, ureter, liver, muscle, endometrium, testis, pancreas, seminal vesicle, ovary, adrenals and prostate. In brain, detected in gray matter neurons (at protein level). Colocalizes with pathological inclusions such as Lewy bodies and glial cytoplasmic inclusions. Overexpressed in primary breast tumors but not expressed in metastatic tumors.
Inactivated by autolytic cleavage after Arg-80.
Inhibited by a range of serine protease inhibitors including soybean trypsin inhibitor, benzamidine and serpins. Activated by a range of glycosaminoglycans including chondroitin sulfate, dermatan sulfate, heparan sulfate and heparin.
Serine protease which exhibits a preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position. Shows activity against amyloid precursor protein, myelin basic protein, gelatin, casein and extracellular matrix proteins such as fibronectin, laminin, vitronectin and collagen. Degrades alpha-synuclein and prevents its polymerization, indicating that it may be involved in the pathogenesis of Parkinson disease and other synucleinopathies. May be involved in regulation of axon outgrowth following spinal cord injury. Tumor cells treated with a neutralizing KLK6 antibody migrate less than control cells, suggesting a role in invasion and metastasis.
Catalyzes preferentially the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to the N-acetyl-beta-D-glucosamine (GlcNAc) of an N-acetyllactosamine unit (type 2 chain) of an oligosaccharide, or a glycoprotein- and a glycolipid-linked N-acetyllactosamine unit via an alpha (1,3) linkage and participates in the surface expression of VIM-2, Lewis X/SSEA-1 and sialyl Lewis X antigens (PubMed:14718375, PubMed:1740457, PubMed:7721776, PubMed:9737988, PubMed:17604274, PubMed:9737989, PubMed:29593094). Preferentially transfers fucose to the GlcNAc of an internal N-acetyllactosamine unit of a poly-N-acetyllactosamine chain acceptor substrate (PubMed:7721776, PubMed:17604274). Also catalyzes to a lesser extend the transfer of L-fucose to the GlcNAc of a type 1 (beta-D-galactosyl-(1->3)-N-acetyl-beta-D-glucosaminyl) or H-type 1 (alpha-L-Fuc-(1->2)-beta-D-Gal-(1->3)-D-GlcNAc) chain oligosaccharide via an alpha (1,4) linkage (PubMed:14718375, PubMed:1740457, PubMed:7721776, PubMed:9737988, PubMed:17604274). Preferentially catalyzes sialylated type 2 oligosaccharide acceptors over neutral type 2 or H type 2 (alpha-L-Fuc-(1->2)-beta-D-Gal-(1->4)-D-GlcNAc) oligosaccharide acceptors (PubMed:1740457, PubMed:9737989). Lactose-based structures are also acceptor substrates (PubMed:1740457, PubMed:7721776).
Liver, colon and testis and trace amounts in T-cells and brain.
Receptor for neuromedin-B (PubMed:1655761). Contributes to the maintenance of basal sigh rate through signaling in the pre-Botzinger complex, a cluster of several thousand neurons in the ventrolateral medulla responsible for inspiration during respiratory activity (By similarity). Contributes to the induction of sneezing following exposure to chemical irritants or allergens which causes release of NMB by nasal sensory neurons and activation of NMBR-expressing neurons in the sneeze-evoking region of the brainstem (By similarity). These in turn activate neurons of the caudal ventral respiratory group, giving rise to the sneezing response (By similarity). Contributes to induction of acute itch, possibly through its activation on dorsal root ganglion neurons by the NMB peptide (By similarity). Plays a role in the innate immune response to influenza A virus infection by enhancing interferon alpha expression and reducing expression of IL6 (PubMed:31601264). Plays a role in CSF1-induced proliferation of osteoclast precursors by contributing to the positive regulation of the expression of the CSF1 receptor CSF1R (By similarity).
Up-regulated in response to infection with influenza A virus.
Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB5 displays a chymotrypsin-like activity.
Down-regulated by IFNG/IFN-gamma (at protein level). Induced in breast cancer tissue. Up-regulated by sulforaphane in breast cancer cells.
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:8163024, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:8163024, PubMed:34711951). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:8163024, PubMed:34711951). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:8163024, PubMed:34711951). Directly interacts with POMP (PubMed:15944226). Interacts with ABCB1 and TAP1 (PubMed:15488952).
Abundantly expressed in kidney but has a ubiquitously low expression pattern in other adult tissues.
Belongs to the cyclophilin-type PPIase family. PPIL4 subfamily.
PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides (By similarity).
Belongs to the gamma type-C retroviral envelope protein family. HERV class-I W env subfamily.
Endogenous envelope proteins may have kept, lost or modified their original function during evolution. Retroviral envelope proteins mediate receptor recognition and membrane fusion during early infection. The surface protein (SU) mediates receptor recognition, while the transmembrane protein (TM) acts as a class I viral fusion protein. The protein may have at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of membranes.
Expressed at higher level in placental syncytiotrophoblast. Expressed at intermediate level in testis. Seems also to be found at low level in adrenal tissue, bone marrow, breast, colon, kidney, ovary, prostate, skin, spleen, thymus, thyroid, brain and trachea. Both mRNA and protein levels are significantly increased in the brain of individuals with multiple sclerosis, particularly in astrocytes and microglia.
HERV-W family subgenomic RNAs have been observed.
In placenta, detected at higher level during early pregnancy and at lower level during late pregnancy.
It can make pseudotypes with HIV-1 virions and confer infectivity. Can also induce cellular resistance to spleen necrosis virus in vitro.
Orthologs in P.troglodytes, G.gorilla, P.pygmaeus and H.moloch.
Probably involved in the development of multiple sclerosis (MS). MS is a neurodegenerative disease characterized by the gradual accumulation of focal plaques of demyelination particularly in the periventricular areas of the brain. It leads to physical and cognitive disabilities. Viral particles or intracellular RNA of HERV-W family members have been detected in tissue from patients with multiple sclerosis or schizophrenia.
Specific enzymatic cleavages in vivo yield mature proteins. Envelope glycoproteins are synthesized as an inactive precursor that is heavily N-glycosylated and processed likely by furin in the Golgi to yield the mature SU and TM proteins. The cleavage site between SU and TM requires the minimal sequence [KR]-X-[KR]-R. The intracytoplasmic tail cleavage by the viral protease that is required for the fusiogenic activity of some retroviruses envelope proteins seems to have been lost during evolution.
The 17 amino acids long immunosuppressive region is present in many retroviral envelope proteins. Synthetic peptides derived from this relatively conserved sequence inhibit immune function in vitro and in vivo (By similarity).
The CXXC motif is highly conserved across a broad range of retroviral envelope proteins. It is thought to participate in the formation of a labile disulfide bond possibly with the CX6CC motif present in the transmembrane protein. Isomerization of the intersubunit disulfide bond to an SU intrachain disulfide bond is thought to occur upon receptor recognition in order to allow membrane fusion.
The cytoplasmic region is essential for the fusiogenic function.
The mature envelope protein (Env) consists of a trimer of SU-TM heterodimers attached probably by a labile interchain disulfide bond. Interacts with the C-type lectin CD209/DC-SIGN.
This endogenous retroviral envelope protein has retained its original fusogenic properties and participates in trophoblast fusion and the formation of a syncytium during placenta morphogenesis. May induce fusion through binding of SLC1A4 and SLC1A5 (PubMed:10708449, PubMed:12050356, PubMed:23492904).
This provirus is intergenic, the closest flanking genes being ODAG and PEX1.
Displays enhanced splicing regulatory activity compared with TIA isoform Long.
Expressed in heart, small intestine, kidney, liver, lung, skeletal muscle, testes, pancreas, and ovary (at protein level).
Homooligomer; homooligomerization is induced by Zn(2+) (By similarity). Interacts with FASTK; the interactions leads to its phosphorylation (PubMed:7544399, PubMed:17135269). Interacts (via RRM1 and the C-terminal glutamine-rich (Q) sequence) with SNRPC/U1-C (via N-terminus); thereby facilitating spliceosomal U1 snRNP recruitment to 5' splice sites (PubMed:12486009).
Phosphorylated by FASTK; phosphorylation occurs after FAS ligation in FAS-mediated apoptosis and before DNA fragmentation.
RNA-binding protein involved in the regulation of alternative pre-RNA splicing and mRNA translation by binding to uridine-rich (U-rich) RNA sequences (PubMed:8576255, PubMed:11106748, PubMed:12486009, PubMed:17488725). Binds to U-rich sequences immediately downstream from a 5' splice sites in a uridine-rich small nuclear ribonucleoprotein (U snRNP)-dependent fashion, thereby modulating alternative pre-RNA splicing (PubMed:11106748, PubMed:8576255). Preferably binds to the U-rich IAS1 sequence in a U1 snRNP-dependent manner; this binding is optimal if a 5' splice site is adjacent to IAS1 (By similarity). Activates the use of heterologous 5' splice sites; the activation depends on the intron sequence downstream from the 5' splice site, with a preference for a downstream U-rich sequence (PubMed:11106748). By interacting with SNRPC/U1-C, promotes recruitment and binding of spliceosomal U1 snRNP to 5' splice sites followed by U-rich sequences, thereby facilitating atypical 5' splice site recognition by U1 snRNP (PubMed:11106748, PubMed:12486009, PubMed:17488725). Activates splicing of alternative exons with weak 5' splice sites followed by a U-rich stretch on its own pre-mRNA and on TIAR mRNA (By similarity). Acts as a modulator of alternative splicing for the apoptotic FAS receptor, thereby promoting apoptosis (PubMed:11106748, PubMed:1934064, PubMed:17488725). Binds to the 5' splice site region of FAS intron 5 to promote accumulation of transcripts that include exon 6 at the expense of transcripts in which exon 6 is skipped, thereby leading to the transcription of a membrane-bound apoptotic FAS receptor, which promotes apoptosis (PubMed:11106748, PubMed:1934064, PubMed:17488725). Binds to a conserved AU-rich cis element in COL2A1 intron 2 and modulates alternative splicing of COL2A1 exon 2 (PubMed:17580305). Also binds to the equivalent AT-rich element in COL2A1 genomic DNA, and may thereby be involved in the regulation of transcription (PubMed:17580305). Binds specifically to a polypyrimidine-rich controlling element (PCE) located between the weak 5' splice site and the intronic splicing silencer of CFTR mRNA to promote exon 9 inclusion, thereby antagonizing PTB1 and its role in exon skipping of CFTR exon 9 (PubMed:14966131). Involved in the repression of mRNA translation by binding to AU-rich elements (AREs) located in mRNA 3' untranslated regions (3' UTRs), including target ARE-bearing mRNAs encoding TNF and PTGS2 (By similarity). Also participates in the cellular response to environmental stress, by acting downstream of the stress-induced phosphorylation of EIF2S1/EIF2A to promote the recruitment of untranslated mRNAs to cytoplasmic stress granules (SGs), leading to stress-induced translational arrest (PubMed:10613902). Formation and recruitment to SGs is regulated by Zn(2+) (By similarity). Possesses nucleolytic activity against cytotoxic lymphocyte target cells (PubMed:1934064).
The C-terminal glutamine-rich (Q) sequence in combination with the RRM 1 domain is required for the interaction with SNRPC/U1-C and to facilitate recruitment of spliceosomal U1 snRNP to 5' splice sites.
The RNA recognition motif domains RRM 2 and RRM 3 are necessary and sufficient for binding to uridine-rich target pre-mRNA.
The RRM 1 and RRM 2 domains are required for the localization to stress granules (SGs) and for the recruitment of TIAR1 and poly(A) RNA to SGs in response to stress.
The RRM2 domain and the C-terminal residues 287-340 contribute to nuclear localization.
The RRM3 domain mediates nuclear export.
(Microbial infection) Proteolytically cleaved by Staphylococcus aureus staphopain A/SspP. This cleavage inhibits CXCR2-dependent neutrophil activation and chemotaxis.
Interacts with IL8 (PubMed:1891716). Interacts with GNAI2 (PubMed:8662698).
Phosphorylated upon ligand binding; which is required for desensitization.
Receptor for interleukin-8 which is a powerful neutrophil chemotactic factor (PubMed:1891716). Binding of IL-8 to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system (PubMed:8662698). Binds to IL-8 with high affinity. Also binds with high affinity to CXCL3, GRO/MGSA and NAP-2.
Heterodimer with PDIA3; disulfide-linked. Obligatory mediator for the interaction between newly assembled MHC class I molecules, calreticulin, PDIA3 and TAP. Up to 4 MHC class I/tapasin complexes bind to 1 TAP (PubMed:19119025, PubMed:21263072, PubMed:26611325). Interacts with HLA-G-B2M complex; this interaction is required for loading of high affinity peptides.
Involved in the association of MHC class I with transporter associated with antigen processing (TAP) and in the assembly of MHC class I with peptide (peptide loading).
Neutrophils, mostly in fully differentiated cells.
The 2 alleles of TAPBP; TAPBP*01 (Tapasin*01) (shown here) and TAPBP*02 (Tapasin*02); are in linkage disequilibria with the HLA-DRB1 locus in a Japanese population.
The N-terminus is required for efficient association with MHC class I molecule and for a stable interaction between MHC I and calreticulin. Binding to TAP is mediated by the C-terminal region.
May act as receptor for class I MHC antigens.
Component of the TIM22 complex, a complex that mediates the import and insertion of multi-pass transmembrane proteins into the mitochondrial inner membrane. The TIM22 complex forms a twin-pore translocase that uses the membrane potential as the external driving force. In the TIM22 complex, it may act as a docking point for the soluble 70 kDa complex that guides the target proteins in transit through the aqueous mitochondrial intermembrane space.
Component of the TIM22 complex, which core is composed of TIMM22, associated with TIMM10 (TIMM10A and/or TIMM10B), TIMM9, AGK and TIMM29 (PubMed:28712724).
Mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane. Also required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. Acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space.
The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space.
The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space. However, during the transit of TIMM10B from cytoplasm into mitochondrion, the Cys residues probably coordinate zinc, thereby preventing folding and allowing its transfer across mitochondrial outer membrane.
Ubiquitous, with highest expression in heart, kidney, liver and skeletal muscle.
As part of the spliceosome, plays a role in pre-mRNA splicing (PubMed:29360106). Probable inactive PPIase with no peptidyl-prolyl cis-trans isomerase activity (PubMed:20676357). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
Belongs to the cyclophilin-type PPIase family.
Despite the fact that it belongs to the cyclophilin-type PPIase family, a report has shown that it has probably no peptidyl-prolyl cis-trans isomerase activity.
Part of the activated spliceosome B/catalytic step 1 spliceosome, one of the forms of the spliceosome which has a well-formed active site but still cannot catalyze the branching reaction and is composed at least of 52 proteins, the U2, U5 and U6 snRNAs and the pre-mRNA. Recruited during early steps of activated spliceosome B maturation, it is probably one of the first proteins released from this complex as he matures to the spliceosome C complex. Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932).
Highly expressed in macrophage and in monocyte-derived dendritic cells, and thymus. Also found in lymph node, appendix, activated monocytes, resting and activated macrophages. Lower expression in lung and spleen. Very weak expression in small intestine. In lymph node expressed in a mature subset of Langerhans' cells (CD1a+ and CD83+). Expressed in Langerhans' cell histiocytosis but not in dermatopathic lymphadenopathy. Expressed in atopic dermatitis, allergic contact dermatitis skin, and psoriasis, in both the epidermis and dermis.
May play a role in the trafficking of activated/effector T-lymphocytes to inflammatory sites and other aspects of activated T-lymphocyte physiology. Chemotactic for monocytes, dendritic cells and natural killer cells. Mild chemoattractant for primary activated T-lymphocytes and a potent chemoattractant for chronically activated T-lymphocytes but has no chemoattractant activity for neutrophils, eosinophils, and resting T-lymphocytes. Binds to CCR4. Processed forms MDC(3-69), MDC(5-69) and MDC(7-69) seem not be active.
The N-terminal processed forms MDC(3-69), MDC(5-69) and MDC(7-69) are produced by proteolytic cleavage after secretion from monocyte derived dendrocytes.
Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. Involved in the organization of the laminar architecture of cerebral cortex. It is probably required for the integrity of the basement membrane/glia limitans that serves as an anchor point for the endfeet of radial glial cells and as a physical barrier to migrating neurons. Radial glial cells play a central role in cerebral cortical development, where they act both as the proliferative unit of the cerebral cortex and a scaffold for neurons migrating toward the pial surface.
Laminin is a complex glycoprotein, consisting of three different polypeptide chains (alpha, beta, gamma), which are bound to each other by disulfide bonds into a cross-shaped molecule comprising one long and three short arms with globules at each end. Beta-1 is a subunit of laminin-1 (laminin-111 or EHS laminin), laminin-2 (laminin-211 or merosin), laminin-6 (laminin-311 or K-laminin), laminin-8 (laminin-411), laminin-10 (laminin-511) and laminin-12 (laminin-213). Interacts with ITGB1 (By similarity).
Belongs to the potassium channel family. G (TC 1.A.1.2) subfamily. Kv6.1/KCNG1 sub-subfamily.
Expressed in brain and placenta, and at much lower levels in kidney and pancreas (PubMed:9434767).
Associated component of the adapter-like complex 4 (AP-4) (PubMed:30262884). Interacts with IKBKG and TRAF6 (PubMed:19365808). Interacts with F-actin, acetylated actin, TUBB3, STX1A, KIF5B and KLC1 (By similarity).
Associates with the adapter-like complex 4 (AP-4) and may therefore play a role in vesicular trafficking of proteins at the trans-Golgi network (PubMed:30262884). Signaling adapter which plays a role in neuronal differentiation (PubMed:15024033). Involved in regulation of NGF-dependent neurite outgrowth (PubMed:15024033). May play a role in neuronal vesicular trafficking, specifically involving pre-synaptic membrane proteins (By similarity). Seems to be involved in signaling pathways that are regulated by the prolonged activation of MAPK (PubMed:15024033). Can regulate the polyubiquitination of IKBKG and thus may be involved in regulation of the NF-kappa-B pathway (PubMed:19365808).
Phosphorylated on serine residues following nuclear translocation.
Polyubiquitinated; polyubiquitination involves TRAF6.
The RUN domain is necessary for NGF induced nuclear redistribution.
Part of the secretory IgA (sIgA) complex that consists of two, four or five IgA monomers, and two additional non-Ig polypeptides, namely the JCHAIN and the secretory component (the proteolytic product of PIGR).
Serves to link two monomer units of either IgM or IgA. In the case of IgM, the J chain-joined dimer is a nucleating unit for the IgM pentamer, and in the case of IgA it induces dimers and/or larger polymers. It also helps to bind these immunoglobulins to secretory component.
Brain specific; expressed in oligodendrocytes (PubMed:11814680, PubMed:30837646). Expressed in oligodendrocytes in remyelinating multiple sclerosis plaques (PubMed:30837646).
Central nervous system-specific myelin protein that increase myelin genes expression during oligodendrocyte differentiation. Promotes oligodendrocyte terminal differentiation.
According to a report, the gene is imprinted in placenta, where it is predominantly expressed from the maternal allele only. Not imprinted in other tissues (PubMed:12504849). According to another report, it is not imprinted in trophoblast stem cells (PubMed:20644730).
Lipid transporter involved in lipid countertransport between the endoplasmic reticulum and the plasma membrane: specifically exchanges phosphatidylserine with phosphatidylinositol 4-phosphate (PI4P), delivering phosphatidylserine to the plasma membrane in exchange for PI4P, which is degraded by the SAC1/SACM1L phosphatase in the endoplasmic reticulum. Binds phosphatidylserine and PI4P in a mutually exclusive manner (PubMed:23934110, PubMed:26206935). May cooperate with NPC1 to mediate the exit of cholesterol from endosomes/lysosomes (PubMed:21220512). Binds 25-hydroxycholesterol and cholesterol (PubMed:17428193).
Highly expressed in breast cancer, but shows a restricted expression pattern in normal tissues such as adipose, adrenal gland, kidney, lung, mammary gland, placenta, thyroid, trachea, and uterus (PubMed:23131994). Also expressed in colon; down-regulated in colon cancer tissues (PubMed:25351403).
Interacts with LGALS1; leads to an increased amount of LGALS1 on the cell surface (PubMed:23131994). Interacts with GPR15LG; the interaction is direct (PubMed:25351403).
May be a cytokine receptor for GPR15LG. May be a tumor suppressor; together with GPR15LG has a growth inhibitory effect on colon cancer cells which includes G1 cell cycle arrest (PubMed:25351403). May play a role in breast tumorigenesis (PubMed:23131994).
Cadherin 1 to cadherin 4 domains mediate homophilic trans-interaction, the interaction with an identical protocadherin expressed by a neighboring cell. This is a head-to-tail interaction, the cadherin 1 domain interacting with the cadherin 4 domain and the cadherin 2 domain interacting the cadherin 3 domain of the other protocadherin. The cadherin 6 domain mediates promiscuous interactions with protocadherins on the same cell membrane. Each cadherin domain binds three calcium ions.
Calcium-dependent cell-adhesion protein involved in cells self-recognition and non-self discrimination. Thereby, it is involved in the establishment and maintenance of specific neuronal connections in the brain.
Forms homodimers in trans (molecules expressed by two different cells). Forms promiscuous heterodimers in cis (at the plasma membrane of the same cell) with other protocadherins. Interacts with FYN.
Expressed in fetal human tissues, such as kidney, liver, lung and brain, and in a variety of tumor cell lines. Weakly expressed in adult tissues including skeletal muscle, liver, placenta and heart.
Inhibited by serine protease inhibitors PMSF and 4-(2-aminoethyl)benzenesulfonyl fluoride, but not by EDTA.
Proteolytically cleaved to generate 3 independent serine protease chains. The cleaved chains may remain attached to the membrane thanks to disulfide bonds. It is unclear whether cleavage always takes place.
Serase-1 and serase-2 are serine proteases that hydrolyze the peptides N-t-Boc-Gln-Ala-Arg-AMC and N-t-Boc-Gln-Gly-Arg-AMC. In contrast, N-t-Boc-Ala-Phe-Lys-AMC and N-t-Boc-Ala-Pro-Ala-AMC are not significantly hydrolyzed.
The serine protease 1 and 2 domains are catalytically active, whereas the serine protease 3 domain lacks the essential Ser residue of the catalytic triad at position 1009 and is predicted to be inactive.
Component of the oligosaccharyltransferase (OST) complex (PubMed:31831667). OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits (PubMed:23606741, PubMed:25135935, PubMed:31831667). STT3A complex assembly occurs through the formation of 3 subcomplexes. Subcomplex 1 contains RPN1 and TMEM258, subcomplex 2 contains the STT3A-specific subunits STT3A, DC2/OSTC, and KCP2 as well as the core subunit OST4, and subcomplex 3 contains RPN2, DAD1, and OST48. The STT3A complex can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes (By similarity). Interacts with DDI2 (PubMed:29290612). Interacts with TMEM35A/NACHO (By similarity).
Subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation (PubMed:31831667). N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity.
Monomer (PubMed:34268557). Interacts with DALRD3 (PubMed:32427860).
S-adenosyl-L-methionine-dependent methyltransferase that mediates N(3)-methylcytidine modification of residue 32 of the tRNA anticodon loop of tRNA(Thr)(UGU) and tRNA(Arg)(CCU) (PubMed:28655767, PubMed:34268557). N(3)-methylcytidine methylation by METTL2A requires the N6-threonylcarbamoylation of tRNA (t6A37) by the EKC/KEOPS complex as prerequisite (PubMed:34268557).
By extensive retinoic acid treatment, in Ntera-2 teratoma cell line induced to differentiate into post-mitotic neurons (NTN2) (at protein level).
Isoprenylation is inefficient compared to other Rab family members.
May be involved in autophagy-related processes.
The unusual Ser-67, instead of a conserved Gln in other family members, is the cause of low GTPase activity. As a result, the predominant nucleotide associated with the protein is GTP (By similarity).
Unlike other Rab family members, does not interact with GDP dissociation inhibitors (GDIs), including ARHGDIA and ARHGDIB. Interacts with ZFYVE20.
Highly expressed in placenta, brain and kidney. Lower expression in lung, liver and heart.
May be an inhibitor of SLC12A1. Seems to correspond to a subunit of a multimeric transport system and thus, additional subunits may be required for its function.
GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state. Could regulate the interactions of signaling molecules with the actin cytoskeleton. Promotes continuous elongation of cytoplasmic processes during cell motility and simultaneous retraction of the cell body changing the cell morphology.
Highly expressed in kidney, heart and skeletal muscle followed by retina, lymphoblast, placenta, lung, brain, pancreas and liver.
Bifunctional enzyme that catalyzes the fourth and fifth sequential steps of CoA biosynthetic pathway. The fourth reaction is catalyzed by the phosphopantetheine adenylyltransferase, coded by the coaD domain; the fifth reaction is catalyzed by the dephospho-CoA kinase, coded by the coaE domain. May act as a point of CoA biosynthesis regulation.
Expressed in all tissues examined including brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung and peripheral blood leukocyte. Lowest expression in peripheral blood leukocytes and highest in kidney and liver. Isoform 2 is expressed mainly in the brain.
In the central section; belongs to the eukaryotic CoaD family.
Expressed only in brain and ovary among normal tissues. Isoform 1 and isoform 2 are specifically expressed in glioma cells among cancer cells. Detected in some renal cell carcinoma samples.
May enhance ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex.
May function as a negative regulator of endoplasmic reticulum-stress induced autophagy.
Homodimer. Interacts with TNIP1, TAX1BP1 and TRAF2. Interacts with RNF11, ITCH and TAX1BP1 only after TNF stimulation; these interaction are transient and they are lost after 1 hour of stimulation with TNF (By similarity). Interacts with YWHAZ and YWHAH. Interacts with IKBKG; the interaction is induced by TNF stimulation and by polyubiquitin. Interacts with RIPK1. Interacts with UBE2N; the interaction requires TAX1BP1. Interacts with TRAF6; the interaction is inhibited by HTLV-1 protein Tax.
Proteolytically cleaved by MALT1 upon TCR stimulation; disrupts NF-kappa-B inhibitory function and results in increased IL-2 production. It is proposed that only a fraction of TNFAIP3 colocalized with TCR and CBM complex is cleaved, leaving the main TNFAIP3 pool intact.
The A20-type zinc fingers mediate the ubiquitin ligase activity. The A20-type zinc finger 4 selectively recognizes 'Lys-63'-linked polyubiquitin. The A20-type zinc finger 4-7 are sufficient to bind polyubiquitin.
The OTU domain mediates the deubiquitinase activity.
Ubiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities. Involved in immune and inflammatory responses signaled by cytokines, such as TNF-alpha and IL-1 beta, or pathogens via Toll-like receptors (TLRs) through terminating NF-kappa-B activity. Essential component of a ubiquitin-editing protein complex, comprising also RNF11, ITCH and TAX1BP1, that ensures the transient nature of inflammatory signaling pathways. In cooperation with TAX1BP1 promotes disassembly of E2-E3 ubiquitin protein ligase complexes in IL-1R and TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2 and BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. In cooperation with TAX1BP1 promotes ubiquitination of UBE2N and proteasomal degradation of UBE2N and UBE2D3. Upon TNF stimulation, deubiquitinates 'Lys-63'-polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NF-kappa-B. Deubiquitinates TRAF6 probably acting on 'Lys-63'-linked polyubiquitin. Upon T-cell receptor (TCR)-mediated T-cell activation, deubiquitinates 'Lys-63'-polyubiquitin chains on MALT1 thereby mediating disassociation of the CBM (CARD11:BCL10:MALT1) and IKK complexes and preventing sustained IKK activation. Deubiquitinates NEMO/IKBKG; the function is facilitated by TNIP1 and leads to inhibition of NF-kappa-B activation. Upon stimulation by bacterial peptidoglycans, probably deubiquitinates RIPK2. Can also inhibit I-kappa-B-kinase (IKK) through a non-catalytic mechanism which involves polyubiquitin; polyubiquitin promotes association with IKBKG and prevents IKK MAP3K7-mediated phosphorylation. Targets TRAF2 for lysosomal degradation. In vitro able to deubiquitinate 'Lys-11'-, 'Lys-48'- and 'Lys-63' polyubiquitin chains. Inhibitor of programmed cell death. Has a role in the function of the lymphoid system. Required for LPS-induced production of pro-inflammatory cytokines and IFN beta in LPS-tolerized macrophages.
Belongs to the acetyltransferase family. ARD1 subfamily.
Component of the N-terminal acetyltransferase A (NatA) complex composed of NAA11 and NAA15 (Probable). Interacts with HIF1A.
Displays alpha (N-terminal) acetyltransferase activity. Proposed alternative catalytic subunit of the N-terminal acetyltransferase A (NatA) complex.
Present in several cell lines, with highest levels in MCF-7 cells (at protein level).
FAD-dependent sulfhydryl oxidase that regenerates the redox-active disulfide bonds in CHCHD4/MIA40, a chaperone essential for disulfide bond formation and protein folding in the mitochondrial intermembrane space. The reduced form of CHCHD4/MIA40 forms a transient intermolecular disulfide bridge with GFER/ERV1, resulting in regeneration of the essential disulfide bonds in CHCHD4/MIA40, while GFER/ERV1 becomes re-oxidized by donating electrons to cytochrome c or molecular oxygen.
Homodimer; disulfide-linked. May form heterodimers of isoform 1 and isoform 2 (PubMed:12180965, PubMed:20593814, PubMed:21383138, PubMed:22224850). Interacts with CHCHD4/MIA40 (PubMed:23676665, PubMed:21383138).
May act as an autocrine hepatotrophic growth factor promoting liver regeneration.
Ubiquitously expressed. Highest expression in the testis and liver and low expression in the muscle.
Belongs to the flavoprotein pyridine nucleotide cytochrome reductase family.
NADH-cytochrome b5 reductases are involved in desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction (By similarity). Responsible for NADH-dependent lucigenin chemiluminescence in spermatozoa by reducing both lucigenin and 2-[4-iodophenyl]-3-[4-nitrophenyl]-5-[2,4-disulfophenyl]-2H tetrazolium monosodium salt (WST-1).
Bifunctional enzyme with both ATP sulfurylase and APS kinase activity, which mediates two steps in the sulfate activation pathway. The first step is the transfer of a sulfate group to ATP to yield adenosine 5'-phosphosulfate (APS), and the second step is the transfer of a phosphate group from ATP to APS yielding 3'-phosphoadenylylsulfate/PAPS, the activated sulfate donor used by sulfotransferases (PubMed:19474428, PubMed:11773860, PubMed:23824674, PubMed:25594860). In mammals, PAPS is the sole source of sulfate while APS appears to only be an intermediate in the sulfate-activation pathway (PubMed:19474428, PubMed:11773860, PubMed:23824674, PubMed:25594860). Plays indirectly an important role in skeletogenesis during postnatal growth (PubMed:9771708).
Expressed in cartilage and adrenal gland.
In the C-terminal section; belongs to the sulfate adenylyltransferase family.
In the N-terminal section; belongs to the APS kinase family.
Expressed abundantly in the brain with moderate expression also present in spinal cord and thyroid.
Expressed in a variety of tissues including muscle, heart, pancreas, kidney, spleen, prostate, small intestine, colon and peripheral blood leukocytes.
Has an anti-hypocalcemic action on calcium and phosphate homeostasis.
Binds 1 Mo-molybdopterin (Mo-MPT) cofactor per subunit.
Catalyzes the reduction of N-oxygenated molecules, acting as a counterpart of cytochrome P450 and flavin-containing monooxygenases in metabolic cycles (PubMed:19053771, PubMed:21029045, PubMed:30397129). As a component of prodrug-converting system, reduces a multitude of N-hydroxylated prodrugs particularly amidoximes, leading to increased drug bioavailability (PubMed:19053771). May be involved in mitochondrial N(omega)-hydroxy-L-arginine (NOHA) reduction, regulating endogenous nitric oxide levels and biosynthesis (PubMed:21029045). Postulated to cleave the N-OH bond of N-hydroxylated substrates in concert with electron transfer from NADH to cytochrome b5 reductase then to cytochrome b5, the ultimate electron donor that primes the active site for substrate reduction (PubMed:21029045, PubMed:19053771).
Component of a complex composed of cytochrome b5, NADH-cytochrome b5 reductase and MTARC1.
Comprises two structural domains, the molybdenum cofactor/Moco sulfurase C-terminal (MOSC) domain and the MOSC N-terminal region, forming a cleft that accommodates Moco. The MOSC domain, which contains a large seven-stranded mostly antiparallel beta-barrel, engages multiple interactions with Moco both pterin ring and phosphate group, allowing for a tight coordination of Moco within the core of the enzyme.
Heterodimer of a catalytic alpha subunit (GANAB) and a beta subunit (PRKCSH) (PubMed:10929008). Binds glycosylated PTPRC (By similarity).
Regulatory subunit of glucosidase II that cleaves sequentially the 2 innermost alpha-1,3-linked glucose residues from the Glc(2)Man(9)GlcNAc(2) oligosaccharide precursor of immature glycoproteins (PubMed:10929008). Required for efficient PKD1/Polycystin-1 biogenesis and trafficking to the plasma membrane of the primary cilia (By similarity).
Binds pre-mRNA and nucleates the assembly of 40S hnRNP particles (PubMed:8264621). Interacts with poly-U tracts in the 3'-UTR or 5'-UTR of mRNA and modulates the stability and the level of translation of bound mRNA molecules (PubMed:12509468, PubMed:16010978, PubMed:7567451, PubMed:8264621). Single HNRNPC tetramers bind 230-240 nucleotides. Trimers of HNRNPC tetramers bind 700 nucleotides (PubMed:8264621). May play a role in the early steps of spliceosome assembly and pre-mRNA splicing. N6-methyladenosine (m6A) has been shown to alter the local structure in mRNAs and long non-coding RNAs (lncRNAs) via a mechanism named 'm(6)A-switch', facilitating binding of HNRNPC, leading to regulation of mRNA splicing (PubMed:25719671).
Phosphorylated on Ser-260 and Ser-299 in resting cells. Phosphorylated on Ser-253 and on 1 serine residue in the poly-Ser stretch at position 238 in response to hydrogen peroxide.
Sumoylated. Sumoylation reduces affinity for mRNA.
Tetramer composed of 3 copies of isoform C1 and 1 copy of isoform C2. Assembly of 3 tetramers with bound pre-mRNA gives rise to a 19S complex that interacts with HNRNPA2B1 tetramers. Component of the 40S hnRNP particle. Identified in the spliceosome C complex. Interacts with IGF2BP1. Interacts with DHX9; this interaction is direct, enhanced probably by their concomitant binding to RNA and mediates the attachment to actin filaments (PubMed:11687588). Interacts with PPIA/CYPA (PubMed:25678563).
Binds PTPN6 when phosphorylated. Binds FCGR1A. Interacts with peptide-bound HLA-G-B2M; this interaction is direct (PubMed:16455647). Interacts with peptide-bound HLA-F-B2M; this interaction is direct (PubMed:11169396).
Contains 3 copies of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases.
Expressed in monocytes and at lower levels in myeloid and plasmacytoid dendritic cells. Expressed in tolerogenic IL10-producing dendritic cells (PubMed:20448110). Expressed in myeloid-derived suppressor cells during pregnancy (PubMed:27859042). Detected at low levels in natural killer (NK) cells. Expressed in B cells.
Induced on monocyte-derived macrophages by S.typhimurium infection.
Receptor for class I MHC antigens. Recognizes a broad spectrum of HLA-A, HLA-B, HLA-C, HLA-G and HLA-F alleles (PubMed:11169396, PubMed:12853576, PubMed:16455647, PubMed:20448110, PubMed:27859042). Involved in the down-regulation of the immune response and the development of tolerance. Recognizes HLA-G in complex with B2M/beta-2 microglobulin and a nonamer self-peptide (peptide-bound HLA-G-B2M) triggering differentiation of type 1 regulatory T cells and myeloid-derived suppressor cells, both of which actively maintain maternal-fetal tolerance (PubMed:20448110, PubMed:27859042, PubMed:16455647). Competes with CD8A for binding to class I MHC antigens. Inhibits FCGR1A-mediated phosphorylation of cellular proteins and mobilization of intracellular calcium ions (PubMed:11875462, PubMed:12853576, PubMed:9548455, PubMed:9842885).
Anticoagulant plasma protein; it is a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa. It helps to prevent coagulation and stimulating fibrinolysis.
(Microbial infection) Contributes to hepatitis B virus (HBV) replication by acetylating histone H4 at the sites of 'Lys-5' and 'Lys-12' on the covalently closed circular DNA (cccDNA) minichromosome leading to its accumulation within the host cell.
By viruses and interferons (PubMed:31812350). Up-regulated also by estrogen (PubMed:12841681).
Catalytic subunit of the type B histone acetyltransferase (HAT) complex, composed of RBBP7 and HAT1. Interacts with histones H4 and H2A. The interaction is dependent of the ability of RBBP7 to bind to the N-terminus of histones. Component of the histone H3.1 and H3.3 complexes.
Highly expressed in mitotic cells (at protein level).
Histone acetyltransferase that plays a role in different biological processes including cell cycle progression, glucose metabolism, histone production or DNA damage repair (PubMed:31278053, PubMed:20953179, PubMed:23653357, PubMed:32081014). Coordinates histone production and acetylation via H4 promoter binding (PubMed:31278053). Acetylates histone H4 at 'Lys-5' (H4K5ac) and 'Lys-12' (H4K12ac) and, to a lesser extent, histone H2A at 'Lys-5' (H2AK5ac) (PubMed:22615379, PubMed:11585814). Drives H4 production by chromatin binding to support chromatin replication and acetylation. Since transcription of H4 genes is tightly coupled to S-phase, plays an important role in S-phase entry and progression (PubMed:31278053). Promotes homologous recombination in DNA repair by facilitating histone turnover and incorporation of acetylated H3.3 at sites of double-strand breaks (PubMed:23653357). In addition, acetylates other substrates such as chromatin-related proteins (PubMed:32081014). Acetylates also RSAD2 which mediates the interaction of ubiquitin ligase UBE4A with RSAD2 leading to RSAD2 ubiquitination and subsequent degradation (PubMed:31812350).
Phosphorylated by AMPK at Ser-190; phosphorylation increases HAT1 activity.
Component of the TFIID basal transcription factor complex, composed of TATA-box-binding protein TBP, and a number of TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:10438527, PubMed:27007846, PubMed:33795473). Part of a TFIID-containing RNA polymerase II pre-initiation complex that is composed of TBP and at least GTF2A1, GTF2A2, GTF2E1, GTF2E2, GTF2F1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2B, TCEA1, ERCC2, ERCC3, TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:27007846, PubMed:33795473). Interacts with TAF1; the interaction is direct (PubMed:25412659). Interacts with TAF1, TAF5, TAF11, TAF12, and TAF13, but not with TAF10 or TBP (PubMed:10438527, PubMed:8702684). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975). Interacts with CIITA and TAF1 and inhibits their acetyltransferase activity, and behaving as a repressor of CIITA- and TAF1-regulated promoters (PubMed:20937824, PubMed:11592977).
Overexpression of TAF7 in HeLa cells inhibits cyclin D1 and cyclin A gene transcription and causes the cells to accumulate in early S phase. In contrast, depletion of TAF7 from TFIID complexes by siRNAs increases histone H3 acetylation at both cyclin promoters and stimulates cyclins CCND1 and CCNA gene transcription.
Phosphorylated by CIITA. Phosphorylation at Ser-264 by TAF1 in early G1 phase disrupts binding to TAF1.
The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription (PubMed:33795473). TFIID recognizes and binds promoters with or without a TATA box via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC) (PubMed:33795473). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473, PubMed:10438527). TAF7 forms a promoter DNA binding subcomplex of TFIID, together with TAF1 and TAF2 (PubMed:33795473). Part of a TFIID complex containing TAF10 (TFIID alpha) and a TFIID complex lacking TAF10 (TFIID beta) (PubMed:10438527).
The [KR]-[STA]-K motif is specifically recognized by the SETD7 methyltransferase, which methylates Lys-5 in vitro.
Belongs to the universal ribosomal protein uS2 family.
Required for mitoribosome formation and stability, and mitochondrial translation.
Antibodies against CEP290 are present in sera from patients with cutaneous T-cell lymphomas, but not in the healthy control population.
Involved in early and late steps in cilia formation. Its association with CCP110 is required for inhibition of primary cilia formation by CCP110 (PubMed:18694559). May play a role in early ciliogenesis in the disappearance of centriolar satellites and in the transition of primary ciliar vesicles (PCVs) to capped ciliary vesicles (CCVs). Required for the centrosomal recruitment of RAB8A and for the targeting of centriole satellite proteins to centrosomes such as of PCM1 (PubMed:24421332). Required for the correct localization of ciliary and phototransduction proteins in retinal photoreceptor cells; may play a role in ciliary transport processes (By similarity). Required for efficient recruitment of RAB8A to primary cilium (PubMed:17705300). In the ciliary transition zone is part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition (By similarity). Involved in regulation of the BBSome complex integrity, specifically for presence of BBS2, BBS5 and BBS8/TTC8 in the complex, and in ciliary targeting of selected BBSome cargos. May play a role in controlling entry of the BBSome complex to cilia possibly implicating IQCB1/NPHP5 (PubMed:25552655). Activates ATF4-mediated transcription (PubMed:16682973).
Part of the tectonic-like complex (also named B9 complex) (By similarity). Interacts with ATF4 via its N-terminal region (PubMed:16682973). Associates with the BBSome complex (PubMed:25552655, PubMed:23943788), interacting (via N-terminus) with BBS4 (PubMed:23943788). Interacts with IQCB1/NPHP5; IQCB1 and CEP290/NPHP6 are proposed to form a functional NPHP5-6 module localized to the centrosome. Interacts with NPHP4; the interaction likely requires additional interactors. Interacts with ZNF423, FAM161A, CEP162, CEP162, CEP131, TALPID3, CCDC13, CC2D2A, RPGRIP1 (PubMed:18950740, PubMed:18723859, PubMed:21565611, PubMed:22863007, PubMed:22940612, PubMed:22797915, PubMed:23446637, PubMed:23644468, PubMed:24421332, PubMed:24816561, PubMed:20200501). Can self-associate (homo- or heteromeric) (PubMed:18723859). Interacts with CCP110; required for suppressing cilia formation (PubMed:18694559). Interacts with RPGR (By similarity). Associates (via C-terminus) with microtubules (PubMed:24121310, PubMed:24051377); association to microtubule is reduced in response to cellular stress, such as ultraviolet light (UV) radiation or heat shock, in a process that requires p38 MAP kinase signaling (PubMed:24121310). Interacts with FAM161A (By similarity). Interacts with PCM1 (By similarity). Interacts with CCDC66 (PubMed:28235840). Interacts with ARMC9 and CSPP1 (PubMed:32453716).
Ubiquitinated. May undergo monoubiquitination; monoubiquitination is inhibited in response to cellular stress, such as ultraviolet light (UV) radiation or heat shock, but does not cause its displacement from centriolar satellites.
Ubiquitous. Expressed strongly in placenta and weakly in brain.
ADP-ribosylated on Ser-150 in response to DNA damage.
Acetylated at Lys-26. Deacetylated at Lys-26 by SIRT1.
This variant accounts for 60% of histone H1.
Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine (PubMed:27903914, PubMed:31481669). The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37 (PubMed:27903914, PubMed:31481669). GON7 plays a supporting role to the catalytic subunit OSGEP in the complex (PubMed:27903914, PubMed:31481669).
Receptor for the C-terminal sequence motif K-D-E-L that is present on endoplasmic reticulum resident proteins and that mediates their recycling from the Golgi back to the endoplasmic reticulum.
Highly expressed in ileocecal tissue and endometrium.
Secreted protein may play a role in transcription regulation via the MAPK3/MAPK1 pathway through an unidentified receptor on the plasma membrane.
Expressed in fetal lung (PubMed:9070861, PubMed:9077527). Expressed in fetal calvaria and to a lesser extent in fetal kidney and skeletal muscles (PubMed:9593714, PubMed:9077527).
Interacts with MEPE; the interaction is zinc-dependent (via ASARM motif).
Peptidase that cleaves SIBLING (small integrin-binding ligand, N-linked glycoprotein)-derived ASARM peptides, thus regulating their biological activity (PubMed:9593714, PubMed:15664000, PubMed:18162525, PubMed:18597632). Cleaves ASARM peptides between Ser and Glu or Asp residues (PubMed:18597632). Regulates osteogenic cell differentiation and bone mineralization through the cleavage of the MEPE-derived ASARM peptide (PubMed:18597632). Promotes dentin mineralization and renal phosphate reabsorption by cleaving DMP1- and MEPE-derived ASARM peptides (PubMed:18597632, PubMed:18162525). Inhibits the cleavage of MEPE by CTSB/cathepsin B thus preventing MEPE degradation (PubMed:12220505).
Specifically expressed in ovary (PubMed:9070861). Expressed at low levels in kidney (PubMed:9070861).
Activated by EGF, NRG1 and IGF1. Inhibited by SOCS3 to phosphorylate STAT3. Stabilized in the inactive form by an association between the SH3 domain and the SH2-TK linker region. Interaction between Trp-184 within SH2-TK linker region and the catalytic domain appears essential for positive regulation of kinase activity.
Autophosphorylated. Autophosphorylation of Tyr-342 leads to an increase of kinase activity. Tyr-447 binds to the SH2 domain when phosphorylated and negatively regulates kinase activity.
Belongs to the protein kinase superfamily. Tyr protein kinase family. BRK/PTK6/SIK subfamily.
Epithelia-specific. Very high level in colon and high levels in small intestine and prostate, and low levels in some fetal tissues. Not expressed in breast or ovarian tissue but expressed in high percentage of breast and ovarian cancers. Also overexpressed in some metastatic melanomas, lymphomas, colon cancers, squamous cell carcinomas and prostate cancers. Also found in melanocytes. Not expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform 2 is present in prostate epithelial cell lines derived from normal prostate and prostate adenocarcinomas, as well as in a variety of cell lines.
Interacts with GAP-A.p65 (By similarity). Interacts (via SH3 and SH2 domains) with KHDRBS1. Interacts (via SH3 and SH2 domains) with phosphorylated IRS4. Interacts with ADAM15. Interacts (via SH3 domain) with SFPQ. Interacts with EGFR and ERBB2. Interacts with STAP2. Interacts with PNX. Interacts with SFPQ. Interacts with PTK/ATK. Interacts with CTNNB1.
Isoform 2 inhibits PTK6 phosphorylation and PTK6 association with other tyrosine-phosphorylated proteins.
Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B and a variety of signaling molecules: ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Associates also with a variety of proteins that are likely upstream of PTK6 in various signaling pathways, or for which PTK6 may play an adapter-like role. These proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 promotes cellular differentiation and apoptosis. In tumors PTK6 contributes to cancer progression by sensitizing cells to mitogenic signals and enhancing proliferation, anchorage-independent survival and migration/invasion. Association with EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and growth through enhancement of EGF-induced signaling via BTK/AKT and PI3 kinase. Contributes to migration and proliferation by contributing to EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes association with RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation. Nuclear PTK6 may be important for regulating growth in normal epithelia, while cytoplasmic PTK6 might activate oncogenic signaling pathways.
The SH3 domain plays a major role in substrate interactions. The SH2 domain of PTK6 plays a role in protein-protein interactions, but is likely more important for the regulation of catalytic activity.
The inhibitors bind to the ATP-binding pocket.
Highly expressed in liver, skeletal muscle, and kidney. Expressed in cardiomyocytes. Expression is highly reduced in cardiac tissue of patients with non-ischemic cardiomyopathy and aortic aneurysm, and in glomerular disease. Not expressed in bone marrow or lymphoid tissues.
In podocytes, up-regulated by retinoic acid.
KLF15 deficiency results in loss of rhythmic QT variation and abnormal heart repolarization (PubMed:22367544). It may play a role in susceptibility to ventricular arrhythmias (PubMed:22367544), and development of pathological cardiac hypertrophy leading to heart failure (PubMed:20375365).
Transcriptional regulator that binds to the GA element of the CLCNKA promoter. Binds to the KCNIP2 promoter and regulates KCNIP2 circadian expression in the heart (By similarity). Is a repressor of CCN2 expression, involved in the control of cardiac fibrosis. It is also involved in the control of cardiac hypertrophy acting through the inhibition of MEF2A and GATA4 (By similarity). Involved in podocyte differentiation (By similarity). Inhibits MYOCD activity. Is a negative regulator of TP53 acetylation. Inhibits NF-kappa-B activation through repression of EP300-dependent RELA acetylation.
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.7/KCNA7 sub-subfamily.
Heterotetramer of potassium channel proteins.
Highly expressed in skeletal muscle, heart and kidney.
Mediates the voltage-dependent potassium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a potassium-selective channel through which potassium ions may pass in accordance with their electrochemical gradient (By similarity).
The N-terminus may be important in determining the rate of inactivation of the channel while the tail may play a role in modulation of channel activity and/or targeting of the channel to specific subcellular compartments.
Catalyzes the efflux of phospholipids such as sphingomyelin, cholesterol and its oxygenated derivatives like 7beta-hydroxycholesterol and this transport is coupled to hydrolysis of ATP (PubMed:17408620, PubMed:24576892). The lipid efflux is ALB-dependent (PubMed:16702602). Is an active component of the macrophage lipid export complex. Could also be involved in intracellular lipid transport processes. The role in cellular lipid homeostasis may not be limited to macrophages. Prevents cell death by transporting cytotoxic 7beta-hydroxycholesterol (PubMed:17408620).
Expressed in several tissues. Expressed in macrophages; expression is increased in macrophages from patients with Tangier disease.
Homodimer; disulfide-linked (PubMed:16702602). Homooligomer (PubMed:16702602). May form heterodimers with several heterologous partners of the ABCG subfamily. Forms heterodimers with ABCG4 (PubMed:27228027). Interacts with CAV1; this interaction regulates ABCG1-mediated cholesterol efflux (PubMed:24576892).
Palmitoylation at Cys-315 seems important for trafficking from the endoplasmic reticulum.
Strongly induced in monocyte-derived macrophages during cholesterol influx. Conversely, mRNA and protein expression are suppressed by lipid efflux. Induction is mediated by the liver X receptor/retinoid X receptor (LXR/RXR) pathway. Not induced by bacterial lipopolysaccharides (LPS). Repressed by ZNF202.
The cholesterol efflux is enhanced by APOA1.
Expressed in heart, with higher expression in the atria.
Expressed in left atrium and ventricle, arteria mammaria interna and skeletal muscle.
Expressed specifically en the left atrium.
Myosin-binding protein which plays a role in cardiac function (PubMed:28778945). Seems to regulate conduction in the atria and ventricular conduction systems (PubMed:28778945).
A chromosomal aberration involving ATP13A4 is found in 2 patients with specific language impairment (SLI) disorders. Paracentric inversion inv(3)(q25;q29). The inversion produces a disruption of the protein.
Decreased by half in the SLI patient lymphoblasts.
Dubious isoform lacking mature mRNA evidence.
Expressed in heart, placenta, liver, skeletal muscles, and pancreas. Lower levels of expression are also detected in brain, lung and kidney. Weakly expressed in the adult brain. Expression in fetal brain is higher than in adult brain, with levels similar to several other fetal tissues including spleen and skeletal muscle. In adult brain expressed at low levels in all tissues examined, including the temporal lobe and putamen (PubMed:15925480). Highly expressed in the respiratory and integumentary systems (PubMed:29505581).
Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. MITRAC complexes regulate both translation of mitochondrial encoded components and assembly of nuclear-encoded components imported in mitochondrion. Required for assembly of mitochondrial respiratory chain complex I and complex IV (PubMed:23260140). As part of the MCIA complex, required for efficient assembly of the mitochondrial complex I (PubMed:32320651).
Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, the core components of this complex being COA3/MITRAC12 and COX14. Interacts with COX17 and COA6. Part of the mitochondrial complex I assembly/MCIA complex that comprises at least the core subunits TMEM126B, NDUFAF1, ECSIT and ACAD9 and complement subunits such as COA1 and TMEM186 (PubMed:32320651).
Exclusively expressed in the epidermis within the granular keratinocytes.
Plays a highly specific role in the last step of keratinocyte differentiation. May have an essential function in lipid metabolism of the most differentiated epidermal layers.
According to a report, interaction with FOXK2 is not dependent on phosphorylation of BAP1 (PubMed:24748658). However, it was later shown that phosphorylation at Thr-493 promotes interaction with FOXK2 (PubMed:25451922).
Belongs to the peptidase C12 family. BAP1 subfamily.
Component of the PR-DUB complex, at least composed of BAP1 and ASXL1 (PubMed:20436459). Interacts with BRCA1 (via the RING finger) (PubMed:19117993, PubMed:9528852). Interacts (via HBM-like motif) with HCFC1 (PubMed:19188440, PubMed:19815555). Interacts (when phosphorylated at Thr-493) with FOXK1 (PubMed:25451922). Interacts (when phosphorylated at Thr-493) with FOXK2; leading to recruit the PR-DUB complex and repress FOXK2 target genes (PubMed:24748658, PubMed:25451922).
Deubiquitinating enzyme that plays a key role in chromatin by mediating deubiquitination of histone H2A and HCFC1 (PubMed:12485996, PubMed:18757409, PubMed:20436459, PubMed:25451922, PubMed:35051358). Catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-119' (H2AK119ub1) (PubMed:20436459, PubMed:25451922, PubMed:35051358). Does not deubiquitinate monoubiquitinated histone H2B (PubMed:20436459). Acts as a regulator of cell growth by mediating deubiquitination of HCFC1 N-terminal and C-terminal chains, with some specificity toward 'Lys-48'-linked polyubiquitin chains compared to 'Lys-63'-linked polyubiquitin chains (PubMed:19188440, PubMed:19815555). Deubiquitination of HCFC1 does not lead to increase stability of HCFC1 (PubMed:19188440, PubMed:19815555). Interferes with the BRCA1 and BARD1 heterodimer activity by inhibiting their ability to mediate ubiquitination and autoubiquitination (PubMed:19117993). It however does not mediate deubiquitination of BRCA1 and BARD1 (PubMed:19117993). Able to mediate autodeubiquitination via intramolecular interactions to couteract monoubiquitination at the nuclear localization signal (NLS), thereby protecting it from cytoplasmic sequestration (PubMed:24703950). Acts as a tumor suppressor (PubMed:9528852).
Highly expressed in testis, placenta and ovary. Expressed in breast.
Ubiquitinated: monoubiquitinated at multiple site of its nuclear localization signal (NLS) BY UBE2O, leading to cytoplasmic retention. Able to mediate autodeubiquitination via intramolecular interactions to couteract cytoplasmic retention.
Increased expression levels in glioblastoma multiforme biopsy samples correlate with poor patient survival prognosis (PubMed:16609006). Has been proposed as a potential target for antibodies coupled to cytotoxic drugs in the context of cancer immunotherapy, including that of melanoma (PubMed:16489096).
Up-regulated by G-CSF/CSF3 and M-CSF/CSF1 in bone marrow mononuclear cells, hence up-regulation may be linked to differentiation.
Widely expressed, but very low expression, if any, in the brain (PubMed:12609765, PubMed:16609006). Expressed in the epidermis with higher levels in melanocytes compared with keratinocytes and Langerhans cells (at protein level) (PubMed:29336782). Expressed in peripheral blood, but not bone marrow mononuclear cells (PubMed:12609765). Expressed in tissue macrophages, including liver Kuppfer cells and lung alveolar macrophages, in podocytes and in some cells of the ciliary body of the eye (at protein level) (PubMed:16489096). May be overexpressed in various cancers, including melanoma and glioblastoma multiforme (PubMed:7814155, PubMed:16489096, PubMed:16609006).
BUD23 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of BUD23 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.
Belongs to the class I-like SAM-binding methyltransferase superfamily. BUD23/WBSCR22 family.
Heterodimer with TRMT112; this heterodimerization is necessary for the metabolic stability and activity of the catalytic subunit BUD23 (PubMed:25851604, PubMed:34948388). Interacts with GRIP1 (PubMed:24488492).
May be ubiquitinated and targeted to degradation in response to pro-inflammatory cytokine signaling.
S-adenosyl-L-methionine-dependent methyltransferase that specifically methylates the N(7) position of a guanine in 18S rRNA (PubMed:25851604). Requires the methyltransferase adapter protein TRM112 for full rRNA methyltransferase activity (PubMed:25851604). Involved in the pre-rRNA processing steps leading to small-subunit rRNA production independently of its RNA-modifying catalytic activity (PubMed:25851604). Important for biogenesis end export of the 40S ribosomal subunit independent on its methyltransferase activity (PubMed:24086612). Locus-specific steroid receptor coactivator. Potentiates transactivation by glucocorticoid (NR3C1), mineralocorticoid (NR3C2), androgen (AR) and progesterone (PGR) receptors (PubMed:24488492). Required for the maintenance of open chromatin at the TSC22D3/GILZ locus to facilitate NR3C1 loading on the response elements (PubMed:24488492). Required for maintenance of dimethylation on histone H3 'Lys-79' (H3K79me2), although direct histone methyltransferase activity is not observed in vitro (PubMed:24488492).
Up-regulated in CD8+ T lymphocytes by treatment with anti-CD3 and in B lymphocytes by treatment with CD40 ligand and anti-B cell receptor antibody. In macrophages, no induction following LPS treatment. Down-regulated by a combined treatment with TNF and IFNG (at protein level).
Widely expressed, with high levels in heart, skeletal muscle and kidney. Detected at high levels in bronchial brushings and in normal lung (at protein level). In fetal lung tissue, expressed in the developing bronchial lumen lining cells (at protein level). Tends to be down-regulated in lungs affected by inflammatory diseases or neoplasia (at protein level). Expressed in immune cells, including B and T lymphocytes and macrophages.
As part of a cytosolic protein quality control complex, the BAG6/BAT3 complex, maintains misfolded and hydrophobic patches-containing proteins in a soluble state and participates in their proper delivery to the endoplasmic reticulum or alternatively can promote their sorting to the proteasome where they undergo degradation (PubMed:20676083, PubMed:21636303, PubMed:21743475, PubMed:28104892). The BAG6/BAT3 complex is involved in the post-translational delivery of tail-anchored/type II transmembrane proteins to the endoplasmic reticulum membrane. Recruited to ribosomes, it interacts with the transmembrane region of newly synthesized tail-anchored proteins and together with SGTA and ASNA1 mediates their delivery to the endoplasmic reticulum (PubMed:20676083, PubMed:28104892, PubMed:25535373). Client proteins that cannot be properly delivered to the endoplasmic reticulum are ubiquitinated and sorted to the proteasome (PubMed:28104892). Similarly, the BAG6/BAT3 complex also functions as a sorting platform for proteins of the secretory pathway that are mislocalized to the cytosol either delivering them to the proteasome for degradation or to the endoplasmic reticulum (PubMed:21743475). The BAG6/BAT3 complex also plays a role in the endoplasmic reticulum-associated degradation (ERAD), a quality control mechanism that eliminates unwanted proteins of the endoplasmic reticulum through their retrotranslocation to the cytosol and their targeting to the proteasome. It maintains these retrotranslocated proteins in an unfolded yet soluble state condition in the cytosol to ensure their proper delivery to the proteasome (PubMed:21636303).
Component of the BAG6/BAT3 complex, at least composed of BAG6, UBL4A and GET4/TRC35 (PubMed:20676083, PubMed:25535373). Interacts with BAG6; the interaction is direct and required for UBL4A protein stability (PubMed:25713138, PubMed:25535373). Interacts with USP13; may be indirect via BAG6 (PubMed:24424410).
Polyubiquitinated. Ubiquitination by AMFR and deubiquitination by USP13 may regulate the interaction between the BAG6/BAT3 complex and SGTA and therefore may regulate client proteins fate.
(Microbial infection) In gut epithelial cells, facilitates human coronavirus SARS-CoV-2 infection through, at least, the cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry.
High levels in pancreatic, gastric, colorectal and ampullary cancer. Very weak expression in normal gastrointestinal and urogenital tract (PubMed:10825129). Coexpressed with ACE2 within mature enterocytes (PubMed:32404436).
Plasma membrane-anchored serine protease that directly induces processing of pro-uPA/PLAU into the active form through proteolytic activity (PubMed:24434139). Seems to be capable of activating ENaC (By similarity).
Proteolytically processed; probably by an autocatalytic mechanism.
A flexible loop interacts with the SHH zinc binding site and contributes to zinc binding.
Genetic variations in HHIP define the stature quantitative trait locus 12 (STQTL12) [MIM:612224]. Adult height is an easily observable and highly heritable complex continuous trait. Because of this, it is a model trait for studying genetic influence on quantitative traits.
Interacts with all three hedgehog family members, SHH, IHH and DHH.
Modulates hedgehog signaling in several cell types including brain and lung through direct interaction with members of the hedgehog family.
Widely expressed in fetal and adult tissues. Highest expression in adult heart, liver and pancreas, and in fetal kidney.
Autophosphorylated and phosphorylated during M-phase and the G1/S-phase of the cell cycle. Phosphorylated and activated by STK3/MST2. Phosphorylation by NUAK2 may regulate its activity in phosphorylation and inactivation YAP1 (PubMed:32845958).
Expressed at high levels in heart and skeletal muscle and at lower levels in all other tissues examined.
Interacts with and is phosphorylated by AURKA. Binds to AR. Interacts with AJUBA during mitosis and this complex regulates organization of the spindle apparatus through recruitment of gamma-tubulin to the centrosome. Interacts (via PPxY motif) with YAP1 (via WW domains). Interacts with MOB1A and MOB1B. Interacts with LIMD1, WTIP and AJUBA. Interacts with SNAI1.
Negative regulator of YAP1 in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. Acts as a tumor suppressor which plays a critical role in centrosome duplication, maintenance of mitotic fidelity and genomic stability. Negatively regulates G1/S transition by down-regulating cyclin E/CDK2 kinase activity. Negative regulator of the androgen receptor. Phosphorylates SNAI1 in the nucleus leading to its nuclear retention and stabilization, which enhances its epithelial-mesenchymal transition and tumor cell invasion/migration activities. This tumor-promoting activity is independent of its effects upon YAP1 or WWTR1/TAZ.
Glycosyltransferase that catalyzes the transfer of GlcNAc from UDP-GlcNAc to the GlcNAcbeta1-2Manalpha1-3 arm of the core structure of N-linked glycans through a beta1-4 linkage and participates in the production of tri- and tetra-antennary N-linked sugar chains (PubMed:17006639, PubMed:10372966). Prefers complex-type N-glycans over hybrid-types (PubMed:17006639). Has lower affinities for donors or acceptors than MGAT4A, suggesting that, under physiological conditions, it is not the main contributor in N-glycan biosynthesis (PubMed:17006639).
Widely expressed. Strongly overexpressed in pancreatic cancer.
Probable component of the PAM complex at least composed of a mitochondrial HSP70 protein, GRPEL1 or GRPEL2, TIMM44, TIMM16/PAM16 and TIMM14/DNAJC19 (By similarity). Interacts with DNAJC19. Directly interacts with DNAJC15; this interaction counteracts DNAJC15-dependent stimulation of HSPA9 ATPase activity. Associates with the TIM23 complex. Associates with the TIM23 complex (By similarity).
Regulates ATP-dependent protein translocation into the mitochondrial matrix. Inhibits DNAJC19 stimulation of HSPA9/Mortalin ATPase activity.
The J-like region, although related to the J domain does not have co-chaperone activity.
ADP-ribosylation at Arg-125 is necessary and sufficient to activate P2RX7 and gate the channel.
Functional P2XRs are organized as homomeric and heteromeric trimers. Interacts with LAMA3, ITGB2, ACTB, ACTN4, SVIL, MPP3, HSPA1, HSPCB, HSPA8, PIK230 and PTPRB. Interacts (via C-terminus) with EMP2 (PubMed:12107182).
Palmitoylation of several cysteines in the C-terminal cytoplasmic tail is required for efficient localization to cell surface.
Phosphorylation results in its inactivation.
Receptor for ATP that acts as a ligand-gated ion channel. Responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to large molecules. Could function in both fast synaptic transmission and the ATP-mediated lysis of antigen-presenting cells. In the absence of its natural ligand, ATP, functions as a scavenger receptor in the recognition and engulfment of apoptotic cells (PubMed:21821797, PubMed:23303206).
Widely expressed with highest levels in brain and immune tissues.
BRCT domain 1 is required to prevent abnormal chromosome condensation. It binds directly to the SWI-SNF chromatin remodeling complex (PubMed:19925808).
BRCT domains 2 and 3 recognize phosphoserine/phosphothreonine marks on proteins with high selectivity, and mediate interaction with phosphorylated CDC27. They also mediate the dual recognition of phosphoserine and phosphotyrosine in the C-terminal tail of histone H2AX (PubMed:22139841, PubMed:22908299, PubMed:22908299).
Expressed in fetal brain, liver and kidney.
Implicated in chromosome condensation and DNA damage induced cellular responses. May play a role in neurogenesis and regulation of the size of the cerebral cortex.
Interacts with CDC27 and maybe other components of the APC/C complex. Interacts with histone variant H2AX under DNA damage conditions.
MCPH1 deficient cells exhibit a delay in post-mitotic chromosome decondensation.
Component of the protein machinery at the inhibitory synapses, probably acting as a scaffold. Inhibitory synapses dampen neuronal activity through postsynaptic hyperpolarization. This synaptic inhibition is fundamental for the functioning of the central nervous system, shaping and orchestrating the flow of information through neuronal networks to generate a precise neural code.
Expressed predominantly in fetal brain, adult brain and testis.
Extensively phosphorylated on serine residues in the RS domain.
Found in a pre-mRNA splicing complex with SRSF4/SFRS4, SRSF5/SFRS5, SNRNP70, SNRPA1, SRRM1 and SRRM2. Interacts with PNN.
Plays a role in alternative splice site selection during pre-mRNA splicing. Represses the splicing of MAPT/Tau exon 10.
Autoantibodies against IGF2BP2 are detected in sera from some patients with hepatocellular carcinoma.
Can form homooligomers and heterooligomers with IGF2BP1 and IGF2BP3 in an RNA-dependent manner (PubMed:23640942). Interacts with HNRPD (PubMed:12674497). Interacts with IGF2BP1 (PubMed:17289661). Interacts with ELAVL1, DHX9, HNRNPU, MATR3 and PABPC1 (PubMed:23640942, PubMed:29476152). Interacts with the HOXB-AS3 peptide; the interaction increases MYC stability (PubMed:34457052).
Domains KH3 and KH4 are the major RNA-binding modules, although KH1 and KH2 may also contribute (PubMed:29476152). The contribution to RNA-binding of individual KH domains may be target-specific. KH1 and KH2, and possibly KH3 and KH4, promote the formation of higher ordered protein-RNA complexes, which may be essential for IGF2BP1 cytoplasmic retention. KH domains are required for RNA-dependent homo- and heterooligomerization and for localization to stress granules.
Expressed in oocytes, granulosa cells of small and growing follicles, Leydig cells, spermatogonia and semen (at protein level). Expressed in testicular cancer (at protein level). Expressed weakly in heart, placenta, skeletal muscle, bone marrow, colon, kidney, salivary glands, testis and pancreas. Detected in fetal liver, fetal ovary, gonocytes and interstitial cells of the testis.
Generated by alternative initiation at Met-69.
RNA-binding factor that recruits target transcripts to cytoplasmic protein-RNA complexes (mRNPs). This transcript 'caging' into mRNPs allows mRNA transport and transient storage. It also modulates the rate and location at which target transcripts encounter the translational apparatus and shields them from endonuclease attacks or microRNA-mediated degradation (By similarity). Preferentially binds to N6-methyladenosine (m6A)-containing mRNAs and increases their stability (PubMed:29476152). Binds to the 5'-UTR of the insulin-like growth factor 2 (IGF2) mRNAs (PubMed:9891060). Binding is isoform-specific. Binds to beta-actin/ACTB and MYC transcripts. Increases MYC mRNA stability by binding to the coding region instability determinant (CRD) and binding is enhanced by m6A-modification of the CRD (PubMed:29476152).
Expressed in frontal cortex. Isoform 1 is expressed in brain and lung. Isoform 2 is expressed in heart, brain, placenta, lung, liver, kidney, skeletal muscle and pancreas. Isoform 4 is expressed in heart, lung, skeletal muscle, kidney and pancreas.
Isoform 1 is expressed in fetal brain. Isoform 2 is expressed in fetal heart, brain, thymus, lung, liver, skeletal muscle, kidney and spleen. Isoform 4 is expressed in fetal heart, brain, thymus, lung and skeletal muscle.
RNA-binding protein implicated in the regulation of several post-transcriptional events. Involved in pre-mRNA alternative splicing, mRNA translation and stability. Mediates exon inclusion and/or exclusion in pre-mRNA that are subject to tissue-specific and developmentally regulated alternative splicing. Specifically activates exon 5 inclusion of TNNT2 in embryonic, but not adult, skeletal muscle. Activates TNNT2 exon 5 inclusion by antagonizing the repressive effect of PTB. Acts as both an activator and repressor of a pair of coregulated exons: promotes inclusion of the smooth muscle (SM) exon but exclusion of the non-muscle (NM) exon in actinin pre-mRNAs. Promotes inclusion of exonS 21 and exclusion of exon 5 of the NMDA receptor R1 pre-mRNA. Involved in the apoB RNA editing activity. Increases COX2 mRNA stability and inhibits COX2 mRNA translation in epithelial cells after radiation injury (By similarity). Modulates the cellular apoptosis program by regulating COX2-mediated prostaglandin E2 (PGE2) expression (By similarity). Binds to (CUG)n triplet repeats in the 3'-UTR of transcripts such as DMPK. Binds to the muscle-specific splicing enhancer (MSE) intronic sites flanking the TNNT2 alternative exon 5. Binds preferentially to UG-rich sequences, in particular UG repeat and UGUU motifs. Binds to apoB mRNA, specifically to AU-rich sequences located immediately upstream of the edited cytidine. Binds AU-rich sequences in the 3'-UTR of COX2 mRNA (By similarity). Binds to an intronic RNA element responsible for the silencing of exon 21 splicing (By similarity). Binds to (CUG)n repeats (By similarity). May be a specific regulator of miRNA biogenesis. Binds to primary microRNA pri-MIR140 and, with CELF1, negatively regulates the processing to mature miRNA (PubMed:28431233).
During differentiation of the hair, it is one of the last keratins expressed.
Expressed in skin and scalp. In the hair follicle, it is present in the upper hair cuticle and the upper cortex. Also present in the in the upper portion of beard hairs (at protein level).
May play a role in late hair differentiation.
Interacts (via its WW domains) with DRPLA (PubMed:9647693). Interacts (via its second PDZ domain) with PTEN (via unphosphorylated C-terminus); this interaction diminishes the degradation rate of PTEN (PubMed:10760291, PubMed:11707428). Interacts (via guanylate kinase domain) with DLGAP1 (By similarity). Interacts (via the PDZ domains) with GRIN2A, GRID2 and NLGN1 (By similarity). Interacts with CTNND2, CTNNB1, MAGUIN-1, ACVR2A, SMAD2 and SMAD3 (By similarity). Part of a complex consisting of MAGI2/ARIP1, ACVR2A, ACVR1B and SMAD3 (By similarity). May interact with HTR2A (By similarity). Interacts with IGSF9, RAPGEF2 and HTR4 (By similarity). Identified in a complex with ACTN4, CASK, IQGAP1, NPHS1, SPTAN1 and SPTBN1 (By similarity). Found in a complex, at least composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; the complex is mainly formed at late endosomes in a NGF-dependent manner (By similarity). Interacts with RAPGEF2; the interaction occurs before or after nerve growth factor (NGF) stimulation (By similarity). Interacts (via PDZ domain) with KIDINS220 (via C-terminal domain) (By similarity). Interacts with DDN (PubMed:16464232). Interacts with DLL1 (By similarity). Found in a complex with IGSF9B and NLGN2; the interaction with IGSF9B is mediated via the PDZ 5 and PDZ 6 domains, while the interaction with NLGN2 is mediated via the WW1, WW2 and PDZ2 domains (PubMed:23751499). Interacts (via PDZ 6 domain) with USH1G (via SAM domain); the interaction is triggered by phosphorylation of USH1G by CK2 and negatively regulates MAGI2-mediated endocytosis (PubMed:24608321).
Seems to act as a scaffold molecule at synaptic junctions by assembling neurotransmitter receptors and cell adhesion proteins (By similarity). Plays a role in nerve growth factor (NGF)-induced recruitment of RAPGEF2 to late endosomes and neurite outgrowth (By similarity). May play a role in regulating activin-mediated signaling in neuronal cells (By similarity). Enhances the ability of PTEN to suppress AKT1 activation (PubMed:10760291). Plays a role in receptor-mediated clathrin-dependent endocytosis which is required for ciliogenesis (By similarity).
Belongs to the carnosine N-methyltransferase family.
Expressed at higher level in kidney. Expressed at lower level in brain and skeletal muscle.
Homodimer. Each monomer accommodates one molecule of carnosine in its active pocket (residues 313-398), precisely anchoring the histidine imidazole ring such that only N1 is exposed and deprotonated for methylation.
N-methyltransferase that catalyzes the formation of anserine (beta-alanyl-N(Pi)-methyl-L-histidine) from carnosine. Anserine, a methylated derivative of carnosine (beta-alanyl-L-histidine), is an abundant constituent of vertebrate skeletal muscles. Also methylates other L-histidine-containing di- and tripeptides such as Gly-Gly-His, Gly-His and homocarnosine (GABA-His).
The Gly-Xaa-Gly-Xaa-Gly (GXGXG) motif binds the adenosyl part of S-adenosyl-L-methionine.
The carnosine-binding region forms hydrophobic and hydrogen bonds with carnosine, defining a flipping orientation of the imidazole ring so that N1 is present next to S-adenosyl-L-methionine for methylation.
Associates with OSMR to form the interleukin-31 receptor which activates STAT3 and to a lower extent STAT1 and STAT5 (PubMed:11877449, PubMed:14504285, PubMed:15627637, PubMed:15194700). May function in skin immunity (PubMed:15184896). Mediates IL31-induced itch, probably in a manner dependent on cation channels TRPA1 and TRPV1 (By similarity). Positively regulates numbers and cycling status of immature subsets of myeloid progenitor cells in bone marrow in vivo and enhances myeloid progenitor cell survival in vitro (By similarity).
Belongs to the type I cytokine receptor family. Type 2 subfamily.
Expressed in CD14- and CD56-positive blood cells (PubMed:11877449). Expressed in macrophages (PubMed:16461143, PubMed:18439099). Expressed in keratinocytes (PubMed:21261663). Expressed in a subset of dorsal root ganglia neurons (at protein level) (PubMed:24373353). Expressed at low levels in testis, ovary, brain, prostate, placenta, thymus, bone marrow, trachea and skin (PubMed:15184896, PubMed:11877449, PubMed:14504285). Expressed in bronchial and alveolar epithelial cells and pulmonary fibroblasts (PubMed:18439099). Detected in all of the myelomonocytic lineage (PubMed:14504285). Isoform 6: Expressed at higher levels in lesional skin compared to healthy skin of atopic dermatitis patients (PubMed:24373353).
Heterodimer with OSMR. Interacts with JAK1 and STAT3.
Major isoform. Dominant negative IL31 receptor.
Major isoform. Functional IL31 receptor.
Up-regulated in lesional keratinocytes of patients with atopic dermatitis (PubMed:16461143). Up-regulated by IFNG/IFN-gamma (PubMed:11877449, PubMed:14504285, PubMed:15184896, PubMed:21261663, PubMed:18439099). Up-regulated by bacterial lipopolysaccharides (LPS) (PubMed:11877449, PubMed:15184896, PubMed:14504285). Up-regulated by triacylated lipoprotein (Pam3Cys) (PubMed:21261663). Up-regulated by TGFB1/TGF-beta (PubMed:18439099).
Expressed not only by natural killer (NK) cells but also by T-cell subsets, B-cells, dendritic cells, mast cells, granulocytes and monocytes.
Inhibitory receptor which may contribute to the down-regulation of cytolytic activity in natural killer (NK) cells, and to the down-regulation of mast cell degranulation (PubMed:10746781, PubMed:16339535, PubMed:9701027). Negatively regulates the Toll-like receptor (TLR) signaling mediated by MYD88 but not TRIF through activation of PTPN6 (PubMed:22043923).
Upon tyrosine-phosphorylation, interacts with PTN6/SHP-1 and PTPN11/SHP-2 and INPP5D.
Associates with IL27 to form the IL-27 interleukin, a heterodimeric cytokine which functions in innate immunity. IL-27 has pro- and anti-inflammatory properties, that can regulate T-helper cell development, suppress T-cell proliferation, stimulate cytotoxic T-cell activity, induce isotype switching in B-cells, and that has diverse effects on innate immune cells. Among its target cells are CD4 T-helper cells which can differentiate in type 1 effector cells (TH1), type 2 effector cells (TH2) and IL17 producing helper T-cells (TH17). It drives rapid clonal expansion of naive but not memory CD4 T-cells. It also strongly synergizes with IL-12 to trigger interferon-gamma/IFN-gamma production of naive CD4 T-cells, binds to the cytokine receptor WSX-1/TCCR. Another important role of IL-27 is its antitumor activity as well as its antiangiogenic activity with activation of production of antiangiogenic chemokines.
Heterodimer with IL27/IL27A; not disulfide-linked (PubMed:12121660). This heterodimer is known as interleukin IL-27 (PubMed:12121660). Heterodimer with IL12A; not disulfide-linked (PubMed:9342359). This heterodimer is known as interleukin IL-35 (PubMed:9342359). Interacts with SQSTM1 (PubMed:8551575).
CAMK2 is composed of 4 different chains: alpha (CAMK2A), beta (CAMK2B), gamma (CAMK2G), and delta (CAMK2D). The different isoforms assemble into homo- or heteromultimeric holoenzymes composed of 12 subunits with two hexameric rings stacked one on top of the other.
Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in sarcoplasmic reticulum Ca(2+) transport in skeletal muscle and may function in dendritic spine and synapse formation and neuronal plasticity (PubMed:16690701). In slow-twitch muscles, is involved in regulation of sarcoplasmic reticulum (SR) Ca(2+) transport and in fast-twitch muscle participates in the control of Ca(2+) release from the SR through phosphorylation of the ryanodine receptor-coupling factor triadin (PubMed:16690701). In the central nervous system, it is involved in the regulation of neurite formation and arborization (PubMed:30184290). It may participate in the promotion of dendritic spine and synapse formation and maintenance of synaptic plasticity which enables long-term potentiation (LTP) and hippocampus-dependent learning. In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of STAT1, stimulating the JAK-STAT signaling pathway (By similarity).
Expressed at high levels in skeletal muscle and heart; in moderate levels in brain, kidney, and liver; and at low levels in colon, thymus, spleen, small intestine, placenta, lung and peripheral blood leukocyte.
The RING-type zinc finger domain coordinates an additional third zinc ion.
The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:10922056, PubMed:25043029). Interacts with the cullin domain of ANAPC2 (PubMed:11739784). Interacts with UBE2D2 (PubMed:11739784).
Together with the cullin protein ANAPC2, constitutes the catalytic component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. May recruit the E2 ubiquitin-conjugating enzymes to the complex.
Detected in peripheral blood leukocytes, osteoblasts, lymph node, thymus and spleen. Isoform 1, isoform 2 and isoform 4 are expressed in T- and B-lymphocytes, and at lower levels in NK cells. They are also expressed in B-cell lines and LPS-matured monocyte-derived dendritic cells.
Receptor for KLRB1 that protects target cells against natural killer cell-mediated lysis (PubMed:20843815, PubMed:16339513). Inhibits osteoclast formation (PubMed:14753741, PubMed:15123656). Inhibits bone resorption (PubMed:14753741). Modulates the release of interferon-gamma (PubMed:15104121). Binds high molecular weight sulfated glycosaminoglycans (PubMed:15123656).
Up-regulated by IL1A/interleukin-1 alpha and prostaglandin E2 in cultured osteogenic sarcoma cells.
Interacts with KNOP1. Interacts with TARDBP and NUP107. Interacts (via N-terminus) with RBM39. Interacts with the SH3 domains of FYN and GRB2.
RNA-binding protein. Specifically binds to 5'-GGGGCC-3' sequence repeats in RNA. Essential for maintenance of peripheral motor neuron and skeletal muscle function. Required for normal expression and/or alternative splicing of a number of genes in spinal cord and skeletal muscle, including the neurite outgrowth inhibitor RTN4. Also contributes to normal mitochondrial respiratory function in motor neurons, via an unknown mechanism.
Expressed at basal lvels in the adult normal prostate gland but is highly up-regulated in the fetal prostate and prostate cancer cells (PubMed:12489849, PubMed:25374899, PubMed:24559171, PubMed:24263171). Preferentially expressed in normal male and female reproductive tissues, testis, fallopian tube, uterus, and placenta, as well as in testicular cancer, uterine cancer, cervical cancer and kidney cancer (PubMed:9724777, PubMed:12489849).
HIPK1-mediated phosphorylation at Thr-51 leads to the compaction of its intrinsically disordered conformation and is critical for its ability to potentiate the transcriptional activator activity of JUN inspite of a reduced interaction with JUN (PubMed:24559171, PubMed:26242913). CLK2-mediated phosphorylation at multiple Ser and Thr residues attenuates its ability to potentiate JUN transcriptional activator activity (PubMed:28289210).
Highly expressed in the earlier stages of fetal development, expression decreases dramatically by the time the pre-pubertal prostate buds are developed (36 weeks).
Intrinsically disordered protein that potentiates the transcriptional activator activity of JUN (PubMed:24263171, PubMed:28289210). Protects cells from stress-induced apoptosis by inhibiting reactive oxygen species (ROS) production and via regulation of the MAPK signaling pathway (PubMed:21357425, PubMed:25374899, PubMed:30658679).
Up-regulated in response to a variety of stress factors.
Beta-1,3-N-acetylglucosaminyltransferase involved in the synthesis of poly-N-acetyllactosamine. Has activity for type 2 oligosaccharides.
Mainly expressed in brain tissues such as whole brain, hippocampus, amygdala, cerebellum and caudate nucleus. Also expressed in colon, esophagus and kidney.
Contains a novel CRM1-dependent nuclear export signal that compensates in cis for the loss of the nuclear pore targeting domain.
Expressed at high level in testis and at low level in a small number of tissues.
Interacts with NXT1, NXT2, E1B-AP5 and CRM1 nuclear export factor.
Lacks C-terminal domain that mediates direct interactions with nucleoporins.
May function as a tissue-specific nuclear mRNA export factor.
Acetylated. Could occur at proximity of the cofactor-binding sites and reduce the catalytic activity. Could be deacetylated by SIRT3.
Homotetramer (PubMed:8823176, Ref.23). Interacts with the heterodimeric electron transfer flavoprotein ETF.
Medium-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation, an aerobic process breaking down fatty acids into acetyl-CoA and allowing the production of energy from fats (PubMed:1970566, PubMed:8823175, PubMed:21237683, PubMed:2251268). The first step of fatty acid beta-oxidation consists in the removal of one hydrogen from C-2 and C-3 of the straight-chain fatty acyl-CoA thioester, resulting in the formation of trans-2-enoyl-CoA (PubMed:2251268). Electron transfer flavoprotein (ETF) is the electron acceptor that transfers electrons to the main mitochondrial respiratory chain via ETF-ubiquinone oxidoreductase (ETF dehydrogenase) (PubMed:25416781, PubMed:15159392). Among the different mitochondrial acyl-CoA dehydrogenases, medium-chain specific acyl-CoA dehydrogenase acts specifically on acyl-CoAs with saturated 6 to 12 carbons long primary chains (PubMed:1970566, PubMed:8823175, PubMed:21237683, PubMed:2251268).
Expressed in the epithelial cells of renal proximal tubules and stomach as well as hematopoietic cells in the bone marrow and spleen in the fetal tissues. In adult, expressed in epithelial cells of the renal proximal tubules and present in keratinocytes in the basal epidermal layer of epidermis.
Interacts with YAP1 and CSF1R (By similarity). Interacts with CTNND1; this interaction allows YES1-mediated activation of FYN and FER and subsequent phosphorylation of CTNND1 (By similarity). Interacts with FASLG. Interacts with IL6ST/gp130 (PubMed:25731159).
Non-receptor protein tyrosine kinase that is involved in the regulation of cell growth and survival, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. Stimulation by receptor tyrosine kinases (RTKs) including EGFR, PDGFR, CSF1R and FGFR leads to recruitment of YES1 to the phosphorylated receptor, and activation and phosphorylation of downstream substrates. Upon EGFR activation, promotes the phosphorylation of PARD3 to favor epithelial tight junction assembly. Participates in the phosphorylation of specific junctional components such as CTNND1 by stimulating the FYN and FER tyrosine kinases at cell-cell contacts. Upon T-cell stimulation by CXCL12, phosphorylates collapsin response mediator protein 2/DPYSL2 and induces T-cell migration. Participates in CD95L/FASLG signaling pathway and mediates AKT-mediated cell migration. Plays a role in cell cycle progression by phosphorylating the cyclin-dependent kinase 4/CDK4 thus regulating the G1 phase. Also involved in G2/M progression and cytokinesis. Catalyzes phosphorylation of organic cation transporter OCT2 which induces its transport activity (PubMed:26979622).
Palmitoylation at Cys-3 promotes membrane localization.
Phosphorylation by CSK on the C-terminal tail maintains the enzyme in an inactive state. Autophosphorylation at Tyr-426 maintains enzyme activity by blocking CSK-mediated inhibition.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Beta-4/CHRNB4 sub-subfamily.
Neuronal AChR is composed of two different types of subunits: alpha and beta. Beta-4 subunit can be combined to alpha-2, alpha-3 or alpha-4 to give rise to functional receptors. Interacts with RIC3; which is required for proper folding and assembly (PubMed:16120769). Interacts with LYPD6 (PubMed:27344019). The pentamer alpha3-beta-4 interacts with the conotoxin BuIA (By similarity). The heteropentamer composed of alpha-3 and beta-4 subunits interacts with the alpha-conotoxin ImI (PubMed:15609996).
Highly expressed in brain and in malignant T-cell lines derived from patients with adult T-cell leukemia/lymphoma.
Interacts with TFCOUP1, SIRT1, ARP1 and EAR2 (By similarity). Interacts with EP300; the interaction is detected in activated T-lymphocytes, but not under resting conditions (PubMed:27959755).
Key regulator of both differentiation and survival of T-lymphocytes during thymocyte development in mammals. Essential in controlling the responsiveness of hematopoietic stem cells to chemotactic signals by modulating the expression of the receptors CCR7 and CCR9, which direct the movement of progenitor cells from the bone marrow to the thymus (PubMed:27959755). Is a regulator of IL2 promoter and enhances IL2 expression in activated CD4(+) T-lymphocytes (PubMed:16809611). Tumor-suppressor that represses transcription through direct, TFCOUP2-independent binding to a GC-rich response element (By similarity). May also function in the P53-signaling pathway (By similarity).
Binds to CCK-A receptors in the pancreas and CCK-B receptors in the brain.
Detected in cerebrospinal fluid and urine (at protein level).
The precursor is cleaved by ACE, which removes the Gly-Arg-Arg peptide at the C-terminus, leading to mature hormone.
The precursor is cleaved by proteases to produce a number of active cholecystokinins.
This peptide hormone induces gall bladder contraction and the release of pancreatic enzymes in the gut. Its function in the brain is not clear. Binding to CCK-A receptors stimulates amylase release from the pancreas, binding to CCK-B receptors stimulates gastric acid secretion.
(Microbial infection) Acts as a receptor for herpes simplex virus 1 (HHV-1) mutant Rid1, herpes simplex virus 1 (HHV-2) and pseudorabies virus (PRV).
(Microbial infection) Interacts with herpes simplex virus 1 (HHV-1) mutant Rid1, herpes simplex virus 1 (HHV-2) and pseudorabies virus (PRV) envelope glycoprotein D (PubMed:11602758, PubMed:9657005).
Can form trans-heterodimers with NECTIN3 (By similarity). Interacts with CD226 or with PVRIG; these interactions are competitive and have a differential functional outcome on T-cell activation, either positive or negative, respectively. Binds with low affinity to TIGIT.
Modulator of T-cell signaling. Can be either a costimulator of T-cell function, or a coinhibitor, depending on the receptor it binds to. Upon binding to CD226, stimulates T-cell proliferation and cytokine production, including that of IL2, IL5, IL10, IL13, and IFNG. Upon interaction with PVRIG, inhibits T-cell proliferation. These interactions are competitive (PubMed:26755705). Probable cell adhesion protein (PubMed:9657005).
(Microbial infection) Acetylation of Thr-180 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B pathway.
(Microbial infection) Interacts with vaccinia virus protein B14.
(Microbial infection) Monoubiquitination by TRIM21 is disrupted by Yersinia YopJ.
Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits (PubMed:32935379). The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (PubMed:17287217). Interacts with SQSTM1 through PRKCZ or PRKCI (PubMed:10356400). Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6 (By similarity). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with NALP2 (PubMed:15456791). Interacts with TICAM1 (PubMed:14739303). Interacts with FAF1; the interaction disrupts the IKK complex formation (PubMed:17684021). Interacts with ATM (PubMed:16497931). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833). Interacts with NIBP; the interaction is direct (PubMed:15951441). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with TRIM21 (PubMed:19675099). Interacts with NLRC5; prevents IKBKB phosphorylation and kinase activity (PubMed:20434986). Interacts with PDPK1 (PubMed:16207722). Interacts with EIF2AK2/PKR (PubMed:10848580). The phosphorylated form interacts with PPM1A and PPM1B (PubMed:18930133). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with IKBKE (PubMed:23453969). Interacts with AKAP13 (PubMed:23090968). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14; disrupts IKBKB-IKBKG interaction preventing I-kappa-B-kinase (IKK) core complex formation and leading to a decrease of IKBKB phosphorylation and NF-kappaB activation (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Interacts with ARFIP2 (PubMed:26296658). Interacts with FKBP5 (PubMed:31434731, PubMed:26101251).
Highly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood.
Hydroxylated by PHD1/EGLN2, loss of hydroxylation under hypoxic conditions results in activation of NF-kappa-B.
Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:20434986, PubMed:20797629, PubMed:21138416, PubMed:9346484, PubMed:30337470). Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation (PubMed:9346484). Phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues (PubMed:9346484, PubMed:20434986, PubMed:20797629, PubMed:21138416). These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome (PubMed:9346484, PubMed:20434986, PubMed:20797629, PubMed:21138416). In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis (PubMed:9346484, PubMed:20434986, PubMed:20797629, PubMed:21138416). In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE (PubMed:11297557, PubMed:14673179, PubMed:20410276, PubMed:21138416). IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs (PubMed:11297557, PubMed:20410276, PubMed:21138416). Phosphorylates FOXO3, mediating the TNF-dependent inactivation of this pro-apoptotic transcription factor (PubMed:15084260). Also phosphorylates other substrates including NAA10, NCOA3, BCL10 and IRS1 (PubMed:19716809, PubMed:17213322). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates the C-terminus of IRF5, stimulating IRF5 homodimerization and translocation into the nucleus (PubMed:25326418).
The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG.
Ubiquitinated. Monoubiquitination involves TRIM21 that leads to inhibition of Tax-induced NF-kappa-B signaling. According to PubMed:19675099, 'Ser-163' does not serve as a monoubiquitination site. According to PubMed:16267042, ubiquitination on 'Ser-163' modulates phosphorylation on C-terminal serine residues.
Upon cytokine stimulation, phosphorylated on Ser-177 and Ser-181 by MEKK1 and/or MAP3K14/NIK as well as TBK1 and PRKCZ; which enhances activity (PubMed:10022904, PubMed:16207722). Phosphorylated by MAP3K7/TAK1 in response to NOD1 and NOD2 signaling, promoting activation and phosphorylation of NF-kappa-B inhibitors, leading to NF-kappa-B activation (PubMed:11460167). Once activated, autophosphorylates on the C-terminal serine cluster; which decreases activity and prevents prolonged activation of the inflammatory response (PubMed:10195894). Phosphorylated by the IKK-related kinases TBK1 and IKBKE, which is associated with reduced CHUK/IKKA and IKBKB activity and NF-kappa-B-dependent gene transcription (PubMed:10783893). Dephosphorylated at Ser-177 and Ser-181 by PPM1A and PPM1B (PubMed:18930133).
Detected in liver, lung, placenta, endothelial cells and spleen.
Interacts with UPF2 (Probable). Component of the small ribosomal subunit, ribosomal RNA processing complex (SSU RRP complex) (PubMed:15231747).
May play a role in mRNA degradation (Probable). Endonuclease required for processing of 20S pre-rRNA precursor and biogenesis of 40S ribosomal subunits (By similarity).
(Microbial infection) Acts as a receptor for human herpesvirus 6B/HHV-6B.
(Microbial infection) Interacts with Human herpesvirus 6B/HHV-6B gQ1:gQ2 proteins.
Receptor for TNFSF4/OX40L/GP34. Is a costimulatory molecule implicated in long-term T-cell immunity.
Catalyzes the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to the N-acetyl glucosamine (GlcNAc) of a distal lactosamine unit of a glycoprotein or a glycolipid-linked polylactosamine chains through an alpha-1,3 glycosidic linkage and participates in particular to the Lewis x (Lex)/CD15 epitope biosynthesis in neurons which allows cell differentiation, cell adhesion, and initiation of neurite outgrowth (PubMed:23263199, PubMed:23192350, PubMed:10386598, PubMed:17335083, PubMed:23000574, PubMed:11278338, PubMed:10622713, PubMed:18395013, PubMed:12107078, PubMed:16282604, PubMed:29593094). Also fucosylates di-, tri- and tetraantennary N-glycans linked to glycoproteins and the inner lactosamine unit of the alpha2,3-sialylated polylactosamine resulting in sLex (CD15s) epitope synthesis (PubMed:12107078, PubMed:18395013). Furthermore, it is capable of synthesizing Lewis a (Lea), although to a lesser extent than Lex and Lewis y (Ley) and to confer SELE-dependent, but not SELL- and SELP-selectin-dependent, cell rolling and adhesion by enhancing Lex and sLex synthesis (PubMed:18395013, PubMed:23192350). May also fucosylate the internal LacNAc unit of the polylactosamine chain to form VIM-2 antigen that serves as recognition epitope for SELE.
N-glycosylated with complex-type N-glycans.
Strongly expressed in forebrain and stomach, lower expression in spleen and peripheral blood leukocytes, and no expression in small intestine, colon, liver, lung, kidney, adrenal cortex or uterus (PubMed:10386598). Highly expressed in granulocytes. Not expressed in monocytes (PubMed:11278338).
Could be involved in signal transduction.
Binds both 2-arachidonoylglycerol (2-AG) and anandamide.
Dubious isoform. A putative downstream initiation AUG is used to produce isoform 2 (PubMed:1718258). The use of the first AUG (same as isoform 1) gives a truncated protein of 36 AA.
Dysfunction of the endogenous cannabinoid system including CNR1 has been implicated in the pathogenesis of a number of central nervous system disorders, including Huntington disease, Parkinson disease, and Alzheimer disease (PubMed:32549916). In post-mortem brains from Huntington disease patients, a progressive CNR1 loss has been observed in the caudate nucleus, putamen, and substantia nigra pars reticulata, and altered expression and abnormal endocannabinoid levels precede motor symptoms in a disease mouse model (PubMed:8255419, PubMed:10828533, PubMed:19524019). In Parkinson disease, low CNR1 expression in mid-superior frontal gyrus and mid-cingulate cortex has been associated with poor mind, poor executive functioning and poor episode memory, while patients with more severe visuospatial dysfunction showed decreased receptor availability in the precuneus, mid-cingulate, supplementary motor cortex, inferior orbitofrontal gyrus and thalamus (PubMed:31342135). In an animal model for Alzheimer disease, CNR1 heterozygous deletion has been associated with decreased levels of postsynaptic density protein 95 (DLG4/PSD95) and accelerated memory impairment, suggesting synaptic dysfunction and a crucial role for CNR1 in the progression of disease symptoms (PubMed:30096288, PubMed:8255419, PubMed:10828533, PubMed:19524019, PubMed:31342135).
G-protein coupled receptor for cannabinoids, including endocannabinoids (eCBs), such as N-arachidonoylethanolamide (also called anandamide or AEA) and 2-arachidonoylglycerol (2-AG). Signaling typically involves reduction in cyclic AMP.
G-protein coupled receptor for endogenous cannabinoids (eCBs), including N-arachidonoylethanolamide (also called anandamide or AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids, such as delta(9)-tetrahydrocannabinol (THC) (PubMed:15620723, PubMed:27768894, PubMed:27851727). Mediates many cannabinoid-induced effects, acting, among others, on food intake, memory loss, gastrointestinal motility, catalepsy, ambulatory activity, anxiety, chronic pain. Signaling typically involves reduction in cyclic AMP (PubMed:1718258, PubMed:21895628, PubMed:27768894). In the hypothalamus, may have a dual effect on mitochondrial respiration depending upon the agonist dose and possibly upon the cell type. Increases respiration at low doses, while decreases respiration at high doses. At high doses, CNR1 signal transduction involves G-protein alpha-i protein activation and subsequent inhibition of mitochondrial soluble adenylate cyclase, decrease in cyclic AMP concentration, inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system, including NDUFS2. In the hypothalamus, inhibits leptin-induced reactive oxygen species (ROS) formation and mediates cannabinoid-induced increase in SREBF1 and FASN gene expression. In response to cannabinoids, drives the release of orexigenic beta-endorphin, but not that of melanocyte-stimulating hormone alpha/alpha-MSH, from hypothalamic POMC neurons, hence promoting food intake. In the hippocampus, regulates cellular respiration and energy production in response to cannabinoids. Involved in cannabinoid-dependent depolarization-induced suppression of inhibition (DSI), a process in which depolarization of CA1 postsynaptic pyramidal neurons mobilizes eCBs, which retrogradely activate presynaptic CB1 receptors, transiently decreasing GABAergic inhibitory neurotransmission. Also reduces excitatory synaptic transmission (By similarity). In superior cervical ganglions and cerebral vascular smooth muscle cells, inhibits voltage-gated Ca(2+) channels in a constitutive, as well as agonist-dependent manner (PubMed:17895407). In cerebral vascular smooth muscle cells, cannabinoid-induced inhibition of voltage-gated Ca(2+) channels leads to vasodilation and decreased vascular tone (By similarity). Induces leptin production in adipocytes and reduces LRP2-mediated leptin clearance in the kidney, hence participating in hyperleptinemia. In adipose tissue, CNR1 signaling leads to increased expression of SREBF1, ACACA and FASN genes (By similarity). In the liver, activation by endocannabinoids leads to increased de novo lipogenesis and reduced fatty acid catabolism, associated with increased expression of SREBF1/SREBP-1, GCK, ACACA, ACACB and FASN genes. May also affect de novo cholesterol synthesis and HDL-cholesteryl ether uptake. Peripherally modulates energy metabolism (By similarity). In high carbohydrate diet-induced obesity, may decrease the expression of mitochondrial dihydrolipoyl dehydrogenase/DLD in striated muscles, as well as that of selected glucose/ pyruvate metabolic enzymes, hence affecting energy expenditure through mitochondrial metabolism (By similarity). In response to cannabinoid anandamide, elicits a pro-inflammatory response in macrophages, which involves NLRP3 inflammasome activation and IL1B and IL18 secretion (By similarity). In macrophages infiltrating pancreatic islets, this process may participate in the progression of type-2 diabetes and associated loss of pancreatic beta-cells (PubMed:23955712).
Hemopressin, a peptide derived from hemoglobin subunit alpha (HBA1 and/or HBA2), acts as an antagonist peptide: hemopressin-binding efficiently blocks cannabinoid receptor CNR1 and subsequent signaling.
High-fat diet also increases the hepatic levels of CNR1 ligand anandamide, but not that of 2-arachidonoylglycerol.
Interacts (via C-terminus) with CNRIP1; this interaction attenuates constitutive, but not agonist-dependent, inhibition of voltage-gated Ca(2+) channels in neurons (PubMed:17895407). Associates with G protein alpha subunits, including G(i) alpha-1/GNAI1, G(i) alpha-3/GNAI3 and G(o)-alpha/GNAO1; palmitoylation is important for interaction with GNAI3 and GNAO1 (PubMed:12237474).
Only binds 2-arachidonoylglycerol (2-AG) with high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an inverse agonist on isoform 2 in assays measuring GTP binding to membranes.
Only binds 2-arachidonoylglycerol (2-AG) with high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an inverse agonist on isoform 3 in assays measuring GTP binding to membranes.
Palmitoylation at Cys-415 is important for recruitment at plasma membrane and lipid rafts and association with G protein alpha subunits.
The protein represented in this entry may be involved in disease pathogenesis. May contribute to the development of diet-induced obesity and several obesity-associated features, such as dyslipidemia and liver steatosis, regulating peripheral lipogenesis, energy expenditure and feeding behavior. CNR1 inverse agonists have been shown to reduce body weight and improve metabolic abnormalities in obese subjects, although adverse neuropsychiatric effects, including anxiety, irritability, and depressed mood, halted their therapeutic development (PubMed:18177726). In obese mice, peripherally restricted CNR1 inverse agonists have been shown to normalize metabolic abnormalities, including insulin resistance and fatty liver, and to reverse leptin resistance.
Up-regulated by endocannabinoid anandamide.
Widely expressed, with highest levels in fetal and adult brain. Expression levels of isoform 2 and isoform 3 are much lower than those of isoform 1.
Forms linear homooligomers, giving rise to a RAD51 nucleoprotein filament, which is essential for strand-pairing reactions during DNA recombination. Interacts with BRCA1 and either directly or indirectly with p53. Interacts with XRCC3, RAD54L and RAD54B. Interacts with the BCDX2 subcomplex RAD51C:RAD51B. Component of the homologous recombination repair (HR) complex composed of ERCC5/XPG, BRCA2, PALB2, DSS1 and RAD51 (PubMed:26833090). Interacts directly with PALB2 which may serve as a scaffold for a HR complex containing PALB2, BRCA2, RAD51C, RAD51 and XRCC3. Interacts with RAD51AP1 and RAD51AP2. Interacts with CHEK1, and this may require prior phosphorylation of CHEK1. Interacts with the MND1-PSMC3IP heterodimer. Found in a complex, at least composed of BLM, RAD51 and SPIDR; the complex formation is mediated by SPIDR. Interacts with SPIDR; the interaction is direct and recruits RAD51 to DNA damage sites. Interacts with FIGNL1 (via N-terminal one-half region); the interaction is direct. Interacts with RAD51AP1 (via C-terminal region); the interaction is direct. Interacts with NABP2, RPA1, PALB2 and RAD51. Interacts with SWI5/C9orf119, and at lower level with SFR1/MEIR5. Interacts with hyperphosphorylated RPA2; this interaction is necessary for efficient recruitment to chromatin in response to DNA damage. Interacts with SWSAP1; involved in homologous recombination repair. Interacts with PARPBP, BRCA2 and RECQL5; these interactions interfere with the formation of the RAD51-DNA homologous recombination structure. Interacts with POLQ; POLQ acts as an inhibitor of homology-recombination repair (HR) pathway by limiting RAD51 accumulation at resected ends (PubMed:25642963). Interacts with FBH1 (PubMed:23393192). Interacts with POLN (PubMed:19995904). Interacts with RFWD3 (PubMed:28575658). Interacts with the MCM8-MCM9 complex; the interaction recruits RAD51 to DNA damage sites (PubMed:23401855). Component of a multiprotein complex with MEIOB and SPATA22. Interacts with the complex BRME1:HSF2BP:BRCA2 (By similarity). Interacts with HELQ; stimulating HELQ DNA helicase activity and ability to unwing DNA (PubMed:34937945). Interacts with MMS22L; the interaction is direct and promotes recruitment of RAD51 to sites of DNA damage (PubMed:27797818). Interacts with the ATAD5 RFC-like complex (PubMed:31844045). Within the ATAD5 RFC-like complex, interacts with ATAD5 (via N-terminus); the interaction is direct and enhanced under replication stress (PubMed:31844045). Interacts with WDR48; the interaction is enhanced under replication stress (PubMed:31844045).
Highly expressed in testis and thymus, followed by small intestine, placenta, colon, pancreas and ovary. Weakly expressed in breast.
Mutagenesis of Arg-264 to Ala inhibits nuclear localization. Mutagenesis of Lys-264 to Gln inhibits nuclear localization. Deletion of 254-Arg-Lys-255 inhibits nuclear localization.
Phosphorylated. Phosphorylation of Thr-309 by CHEK1 may enhance association with chromatin at sites of DNA damage and promote DNA repair by homologous recombination. Phosphorylation by ABL1 inhibits function.
Plays an important role in homologous strand exchange, a key step in DNA repair through homologous recombination (HR) (PubMed:18417535, PubMed:20348101, PubMed:12205100, PubMed:20231364, PubMed:23754376, PubMed:23509288, PubMed:28575658, PubMed:26681308). Binds to single-stranded DNA in an ATP-dependent manner to form nucleoprotein filaments which are essential for the homology search and strand exchange (PubMed:18417535, PubMed:20348101, PubMed:12205100, PubMed:20231364, PubMed:23754376, PubMed:23509288, PubMed:28575658, PubMed:26681308). Catalyzes the recognition of homology and strand exchange between homologous DNA partners to form a joint molecule between a processed DNA break and the repair template (PubMed:18417535, PubMed:20348101, PubMed:12205100, PubMed:20231364, PubMed:23754376, PubMed:23509288, PubMed:28575658, PubMed:26681308). Recruited to resolve stalled replication forks during replication stress (PubMed:27797818, PubMed:31844045). Part of a PALB2-scaffolded HR complex containing BRCA2 and RAD51C and which is thought to play a role in DNA repair by HR (PubMed:24141787, PubMed:12442171). Plays a role in regulating mitochondrial DNA copy number under conditions of oxidative stress in the presence of RAD51C and XRCC3 (PubMed:20413593). Also involved in interstrand cross-link repair (PubMed:26253028).
The nuclear localization may reside in the C-terminus (between 259 and 339 AA).
Ubiquitinated by the SCF(FBH1) E3 ubiquitin ligase complex, regulating RAD51 subcellular location and preventing its association with DNA. Ubiquitinated by RFWD3 in response to DNA damage: ubiquitination leads to degradation by the proteasome, promoting homologous recombination (PubMed:28575658).
Activated by proteolytic processing. In vitro activation is commonly achieved by cleavage with dispase, a neutral bacterial protease. Dispase cleavage site was proposed to lie between Ser-470 and Ser-471 (PubMed:8099584) or between Pro-465 and Phe-466 (PubMed:16565075). Physiological activation may be catalyzed by CTSL and, to a lesser extent, by CTSS, but not by CTSB, CTSD nor CTSV (PubMed:16565075).
Binds 3 Ca(2+) cations per subunit. Binds 1 Ca(2+) as a zymogen, and binds 2 more Ca(2+) cations, or other divalent metal cations, after proteolytic processing.
Catalyzes the calcium-dependent formation of isopeptide cross-links between glutamine and lysine residues in various proteins, as well as the conjugation of polyamines to proteins. Involved in the formation of the cornified envelope (CE), a specialized component consisting of covalent cross-links of proteins beneath the plasma membrane of terminally differentiated keratinocytes. Catalyzes small proline-rich proteins (SPRR1 and SPRR2) and LOR cross-linking to form small interchain oligomers, which are further cross-linked by TGM1 onto the growing CE scaffold (By similarity). In hair follicles, involved in cross-linking structural proteins to hardening the inner root sheath.
Consists of two polypeptide chains, which are synthesized as a precursor form of a single polypeptide.
Plays a critical role for male fertility and sperm motility by regulating sperm cytoplasm removal and maintaining axoneme integrity.
Has some calmodulin-like activity with respect to enzyme activation and growth regulation. Binds two calcium ions.
Expressed in 32-52 days embryos in the distal cardiac outflow tract and pulmonary artery, major arteries, portal vein, optic vesicle, otocyst, branchial arches, metanephros, pancreas, mesocardium, around the major bronchial branches, and in the neural tube.
Interacts with NOTCH2 and NOTCH3 (By similarity). Interacts with NOTCH1 (in the presence of calcium ions) (PubMed:18660822).
Ligand for multiple Notch receptors and involved in the mediation of Notch signaling (PubMed:18660822, PubMed:20437614). May be involved in cell-fate decisions during hematopoiesis (PubMed:9462510). Seems to be involved in early and late stages of mammalian cardiovascular development. Inhibits myoblast differentiation (By similarity). Enhances fibroblast growth factor-induced angiogenesis (in vitro).
Widely expressed in adult and fetal tissues. In cervix epithelium expressed in undifferentiated subcolumnar reserve cells and squamous metaplasia. Expression is up-regulated in cervical squamous cell carcinoma. Expressed in bone marrow cell line HS-27a which supports the long-term maintenance of immature progenitor cells.
Defects in YARS1 may be the cause of proximal-predominant motor neuropathy. Affected individuals may develop tremors, cramping of hands, asymmetric weakness in the upper and lower extremities, and present with elevated creatine kinase levels.
Homodimer (PubMed:12427973, PubMed:14671330, PubMed:30304524). Interacts (when binding to resveratrol) with PARP1; interaction stimulates the poly-ADP-ribosyltransferase activity of PARP1 (PubMed:25533949).
Resveratrol strongly inhibits the tyrosine--tRNA ligase activity.
The nuclear localization signal, which mediates localization to the nucleus, is also important for interacting with tRNA(Tyr), suggesting that it is sterically blocked when tRNA(Tyr) is bound.
Tyrosine--tRNA ligase that catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr) (Probable) (PubMed:25533949). Also acts as a positive regulator of poly-ADP-ribosylation in the nucleus, independently of its tyrosine--tRNA ligase activity (PubMed:25533949). Activity is switched upon resveratrol-binding: resveratrol strongly inhibits the tyrosine--tRNA ligase activity and promotes relocalization to the nucleus, where YARS1 specifically stimulates the poly-ADP-ribosyltransferase activity of PARP1 (PubMed:25533949).
According to PubMed:8812458; testis-specific. According to PubMed:11306702, placenta-specific.
Phosphorylates uridine and cytidine to uridine monophosphate and cytidine monophosphate (PubMed:11306702, PubMed:11494055). Does not phosphorylate deoxyribonucleosides or purine ribonucleosides (PubMed:11306702). Can use ATP or GTP as a phosphate donor (PubMed:11306702). Can also phosphorylate cytidine and uridine nucleoside analogs such as 6-azauridine, 5-fluorouridine, 4-thiouridine, 5-bromouridine, N(4)-acetylcytidine, N(4)-benzoylcytidine, 5-fluorocytidine, 2-thiocytidine, 5-methylcytidine, and N(4)-anisoylcytidine (PubMed:11306702).
E3 ubiquitin ligase responsible for the post-transcriptional regulation of common HLA-A allotypes. Binds to the 3' UTR of HLA-A2 mRNA, and regulates its levels by promoting mRNA decay. RNA binding is sufficient to prevent translation, but ubiquitin ligase activity is required for mRNA degradation.
Genetic variations in MEX3C may be associated with susceptibility to essential hypertension.
Highest levels found in fetal brain and testis. Also expressed in thymus, salivary gland and uterus. Highly expressed in cells of the innate immune system, in particular activated NK cells. Week expression in the intestine.
Interacts with USP7, which antagonizes the ability to degrade mRNA.
Facilitates flavin adenine dinucleotide (FAD) translocation across the mitochondrial inner membrane into the mitochondrial matrix where it acts as a redox cofactor to assist flavoenzyme activities in fundamental metabolic processes including fatty acid beta-oxidation, amino acid and choline metabolism as well as mitochondrial electron transportation. In particular, provides FAD to DLD dehydrogenase of the glycine cleavage system, part of mitochondrial one-carbon metabolic pathway involved in neural tube closure in early embryogenesis.
Initially postulated to transport folate based on complementation evidence, but it was latter shown to rather function as a FAD transporter indirectly affecting folate levels and folate-mediated one-carbon metabolism in mitochondria.
Highly expressed in keratinocytes, placenta, colon and spleen. Expressed at lower level in thymus and testis.
Up-regulated in the mucosa of patients suffering of colorectal cancer.
Acts as a transcriptional corepressor. Negative regulator of the transcriptional activity of TBX1. Plays a role in the development of the pharyngeal apparatus and derivatives (By similarity).
Expressed at a low level in fetal kidney and fetal brain.
The Ripply homology domain and the WRPW motif are both necessary for its transcriptional corepressor activity on the transcription activator TBX1.
Belongs to the peptidase M28 family. M28B subfamily.
Binds 2 Zn(2+) ions per subunit. Required for NAALADase activity.
Has N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. Also exhibits a dipeptidyl-peptidase IV type activity. Inactivates the peptide neurotransmitter N-acetylaspartylglutamate.
Highest expression in the testis. Also found in ovary and spleen. Weak expression in prostate, heart and placenta. In brain, expressed in striatum, parietal cortex and ventral striatum with lower levels in hippocampus, brain stem, putamen and superior colliculus.
The NAALADase activity is found in the central region, the dipeptidyl peptidase IV type activity in the C-terminal.
Expressed in adult brain, heart, skeletal muscle, kidney and liver. Also detected in fetal brain and kidney, and at lower levels in fetal lung and liver.
Transcriptional repressor that binds the GZF1 responsive element (GRE) (consensus: 5'-TGCGCN[TG][CA]TATA-3'). May be regulating VSX2/HOX10 expression.
Catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) to alpha-ketoglutarate (PubMed:15070399, PubMed:15609246, PubMed:16037974, PubMed:20020533, PubMed:33431826). Also catalyzes the oxidation of other D-2-hydroxyacids, such as D-malate (D-MAL) and D-lactate (D-LAC) (PubMed:33431826). Exhibits high activities towards D-2-HG and D-MAL but a very weak activity towards D-LAC (PubMed:33431826).
Phosphorylated at Ser-422 by RPS6KA1 and RPS6KB1; phosphorylation enhances the affinity of EIF4B for the EIF3 complex. In response to mTORC1 activation, RPS6KA1-mediated phosphorylation at 'Ser-406' and 'Ser-422' stimulates bicarbonate cotransporter SLC4A7 mRNA translation, increasing SLC4A7 protein abundance and function.
Required for the binding of mRNA to ribosomes. Functions in close association with EIF4-F and EIF4-A. Binds near the 5'-terminal cap of mRNA in presence of EIF-4F and ATP. Promotes the ATPase activity and the ATP-dependent RNA unwinding activity of both EIF4-A and EIF4-F.
Self-associates and interacts with EIF3 p170 subunit.
Catalyzes the oxidative cleavage of heme at the alpha-methene bridge carbon, released as carbon monoxide (CO), to generate biliverdin IXalpha, while releasing the central heme iron chelate as ferrous iron.
Inhibited by metalloporphyrins such as Sn- and Zn-protoporphyrins.
A previous study found the localization of TMEM174 in the endoplasmic reticulum (PubMed:20331980). A more recent study detected TMEM174 in cell membrane (PubMed:35459732). The difference between these two studies could be due to the use of different cell lines.
Interacts with SLC34A1; regulates SLC34A1 internalization by PTH and FGF23.
Predominantly expressed in kidney (PubMed:20331980). Selectively localized in the apical membrane of renal proximal tubule epithelial cells (PubMed:35459732).
Regulator of plasma phosphate homeostasis. Decreases serum inorganic phosphate (Pi) uptake by regulating the sodium-phosphate cotransporter SLC34A1 trafficking by PTH and FGF23 in the kidney.
Acetylation at Lys-518 down-regulates transcriptional activity. Deacetylated by HDAC1.
Acts as a transcriptional activator (PubMed:19706761, PubMed:10806483, PubMed:19878745, PubMed:24076122, PubMed:24311597, PubMed:24217340). Binds to the DNA consensus sequence 5'-GACCACCCA-3' (PubMed:2105456, PubMed:8378770, PubMed:24217340). Regulates the transcription of specific genes during normal development (PubMed:19706761). Plays a role in craniofacial development and digital development, as well as development of the central nervous system and gastrointestinal tract. Mediates SHH signaling (PubMed:19706761, PubMed:28973407). Plays a role in cell proliferation and differentiation via its role in SHH signaling (PubMed:11238441, PubMed:28973407).
Acts as a transcriptional activator, but activates a different set of genes than isoform 1. Activates expression of CD24, unlike isoform 1. Mediates SHH signaling. Promotes cancer cell migration.
Detected in testis (at protein level) (PubMed:2105456). Testis, myometrium and fallopian tube. Also expressed in the brain with highest expression in the cerebellum, optic nerve and olfactory tract (PubMed:19878745). Isoform 1 is detected in brain, spleen, pancreas, liver, kidney and placenta; isoform 2 is not detectable in these tissues (PubMed:19706761).
Interacts with KIF7 (By similarity). Interacts with STK36 (PubMed:10806483). Interacts with ZIC1; the interaction enhances transcription activation (PubMed:11238441). Interacts with SUFU; this inhibits transcriptional activation by GLI1 (PubMed:10806483, PubMed:24311597, PubMed:24217340, PubMed:28965847).
Isoform 1 and isoform 2 are amplified in glioblastoma cells.
Ubiquitinated by the CRL2(FEM1B) complex, suppressing GLI1 transcriptional activator activity.
Undetectable in normal cells but highly expressed in cancer cells.
Interacts with RAB11FIP5 (PubMed:11278501). Interacts with VTI1A (By similarity).
Required for vesicular transport between the endoplasmic reticulum and the Golgi apparatus.
Based on a naturally occurring readthrough transcript which produces an NME1-NME2 fusion protein.
Hexamer of two different chains: A and B (A6, A5B, A4B2, A3B3, A2B4, AB5, B6) (PubMed:1851158). Interacts with CAPN8 (By similarity). Interacts with AKAP13 (PubMed:15249197). Interacts with ITGB1BP1 (via C-terminal domain region) (PubMed:11919189). Interacts with BCL2L10 (PubMed:17532299).
Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate (By similarity). Negatively regulates Rho activity by interacting with AKAP13/LBC (PubMed:15249197). Acts as a transcriptional activator of the MYC gene; binds DNA non-specifically (PubMed:8392752, PubMed:19435876). Binds to both single-stranded guanine- and cytosine-rich strands within the nuclease hypersensitive element (NHE) III(1) region of the MYC gene promoter. Does not bind to duplex NHE III(1) (PubMed:19435876). Has G-quadruplex (G4) DNA-binding activity, which is independent of its nucleotide-binding and kinase activity. Binds both folded and unfolded G4 with similar low nanomolar affinities. Stabilizes folded G4s regardless of whether they are prefolded or not (PubMed:25679041). Exhibits histidine protein kinase activity (PubMed:20946858).
(Microbial infection) Glucosylated at Thr-37 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:24905543).
(Microbial infection) Glycosylated at Tyr-34 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rho and leads to actin disassembly.
Interacts with RTKN (By similarity). Interacts with AKAP13 (PubMed:11546812). Interacts with DIAPH1 (PubMed:15864301). Interacts with PKN2 (PubMed:20974804). Interacts with ROCK1 and ROCK2 (PubMed:8816443). Interacts with ARHGDIA (PubMed:20400958). Interacts with RIPOR1 (PubMed:27807006).
Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Serves as a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Regulates apical junction formation in bronchial epithelial cells.
Transcription factor expressed by neural progenitor cells in specific regions of the embryonic neuroepithelium. Essential for the mammillary nuclei maintenance. Negatively regulates the proliferation of oligodendrocyte progenitors and promotes oligodendrocyte maturation. Also expressed in mammary glands, plays a role in lactation, controls development of mammary glands and the inferior colliculi of the midbrain in the central nervous system that regulates the milk-ejection reflex.
Belongs to the aldolase class II family. Adducin subfamily.
Each subunit is comprised of three regions: a NH2-terminal protease-resistant globular head region, a short connecting subdomain, and a protease-sensitive tail region.
Expressed in all tissues. Found in much higher levels in reticulocytes than the beta subunit.
Heterodimer of an alpha and a beta subunit or an alpha and a gamma subunit.
Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network. Binds to calmodulin.
Homotrimer; The trimer binds only one molecule of glutathione.
Expressed in germinal center B-cells, placenta, stomach as well as in colon tumor.
Binding to MYC is dependent on a Myc domain essential for oncogenic activity.
Forms homohexameric rings (PubMed:33205750). Can form a dodecamer with RUVBL2 made of two stacked hexameric rings; however, even though RUVBL1 and RUVBL2 are present in equimolar ratio, the oligomeric status of each hexamer is not known (PubMed:33205750). Oligomerization may regulate binding to nucleic acids and conversely, binding to nucleic acids may affect the dodecameric assembly. Interaction of the complex with DHX34 results in conformational changes of the N-terminus of the RUVBL2 subunits, resulting in loss of nucleotide binding ability and ATP hydrolysis of the complex (PubMed:33205750). Interacts with the transcriptional activation domain of MYC. Component of the RNA polymerase II holoenzyme complex. May also act to bridge the LEF1/TCF1-CTNNB1 complex and TBP. Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6. The NuA4 complex interacts with MYC and the adenovirus E1A protein. RUVBL1 interacts with EP400. Component of a NuA4-related complex which contains EP400, TRRAP/PAF400, SRCAP, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, actin, ACTL6A/BAF53A, VPS72 and YEATS4/GAS41. Component of the BAF53 complex, at least composed of ACTL6A/BAF53A, RUVBL1/TIP49, SMARCA2/BRM, and TRRAP/PAF400. Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Associates with alpha and gamma tubulins, particularly during metaphase and early anaphase. Interacts with NPAT. Component of the chromatin-remodeling INO80 complex; specifically part of a complex module associated with the helicase ATP-binding and the helicase C-terminal domain of INO80. Interacts with IGHMBP2. Interacts with OFD1. Interacts with HINT1. Component of a complex with USP49 and PSMC5. Component of a SWR1-like complex. Component of the R2TP complex composed at least of RUVBL1, RUVBL2, RPAP3 and PIHD1 (PubMed:20864032). Component of the PAQosome complex which is responsible for the biogenesis of several protein complexes and which consists of R2TP complex members RUVBL1, RUVBL2, RPAP3 and PIH1D1, URI complex members PFDN2, PFDN6, PDRG1, UXT and URI1 as well as ASDURF, POLR2E and DNAAF10/WDR92 (PubMed:31738558). Interacts with PIH1D1 (PubMed:17636026). Interacts with ITFG1 (PubMed:25437307). Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). The RUVBL1/RUVBL2 complex interacts with ZNHIT1 (via HIT-type zinc finger), ZNHIT3 (via HIT-type zinc finger), ZNHIT6 (via HIT-type zinc finger) and DDX59/ZNHIT5 (via HIT-type zinc finger) in the presence of ADP (PubMed:28561026). Interacts with NOPCHAP1; the interaction is direct and disrupted upon ATP binding (PubMed:33367824). Interacts with SMG1 (PubMed:33205750).
High level of autoantibodies against RUVBL1 are detected in sera of patients with autoimmune diseases such as polymyositis/dermatomyosistis and autoimmune hepatitis.
Possesses single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (3' to 5') activity; hexamerization is thought to be critical for ATP hydrolysis and adjacent subunits in the ring-like structure contribute to the ATPase activity (PubMed:17157868, PubMed:33205750). Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A (PubMed:14966270). This modification may both alter nucleosome-DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription (PubMed:14966270). This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair (PubMed:14966270). The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage (PubMed:14966270). Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome (PubMed:24463511). Proposed core component of the chromatin remodeling INO80 complex which exhibits DNA- and nucleosome-activated ATPase activity and catalyzes ATP-dependent nucleosome sliding (PubMed:16230350, PubMed:21303910). Plays an essential role in oncogenic transformation by MYC and also modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex (PubMed:10882073, PubMed:16014379). Essential for cell proliferation (PubMed:14506706). May be able to bind plasminogen at cell surface and enhance plasminogen activation (PubMed:11027681).
Proposed core component of the chromatin remodeling Ino80 complex which exhibits DNA- and nucleosome-activated ATPase activity and catalyzes ATP-dependent nucleosome sliding.
Ubiquitously expressed with high expression in heart, skeletal muscle and testis.
Component of the spliceosome (PubMed:35241646). Interacts with SNRNP200; the interaction is direct (PubMed:35241646). Interacts with PRPF8 (PubMed:35167828, PubMed:35241646).
Plays a role in pre-mRNA splicing by promoting usage of the upstream 3'-splice site at alternative NAGNAG splice sites; these are sites featuring alternative acceptor motifs separated by only a few nucleotides (PubMed:35241646). May also modulate exon inclusion events (PubMed:35241646). Plays a role in spliceosomal remodeling by displacing WBP4 from SNRNP200 and may act to inhibit SNRNP200 helicase activity (PubMed:35241646). Binds U5 snRNA (PubMed:35241646). Required for proper chromosome segregation (PubMed:35167828). Not required for splicing of shelterin components (PubMed:35167828).
Homodimer. The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:25043029). Interacts with RB. Interacts with FAM168B/MANI (By similarity). Interacts with MCPH1 (PubMed:22139841).
May be due to competing acceptor splice site.
Phosphorylated. Phosphorylation on Ser-426 and Thr-446 occurs specifically during mitosis.
Belongs to the dihydroorotate dehydrogenase family. Type 2 subfamily.
Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Required for UMP biosynthesis via de novo pathway.
The identification of DHODH defects as the cause of postaxial acrofacial dysostosis (POADS) was obtained via exome sequencing (PubMed:19915526), demonstrating that this method is a powerful tool for identifying genes underlying rare Mendelian disorders. Exome sequencing consists of targeted resequencing of all protein-coding subsequences, which requires around 5% as much sequencing as a whole human genome.
The uncleaved transit peptide is required for mitochondrial targeting and proper membrane integration.
Enzyme that can either act as an ADP-sugar pyrophosphatase in absence of diphosphate or catalyze the synthesis of ATP in presence of diphosphate (PubMed:27257257). In absence of diphosphate, hydrolyzes with similar activities various modified nucleoside diphosphates such as ADP-ribose, ADP-mannose, ADP-glucose, 8-oxo-GDP and 8-oxo-dGDP (PubMed:10567213, PubMed:10722730, PubMed:19699693, PubMed:21389046, PubMed:17052728). Can also hydrolyze other nucleotide sugars with low activity (PubMed:19699693, PubMed:21389046). In presence of diphosphate, mediates the synthesis of ATP in the nucleus by catalyzing the conversion of ADP-ribose to ATP and ribose 5-phosphate. Nuclear ATP synthesis takes place when dephosphorylated at Thr-45 (PubMed:27257257). Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming (PubMed:27257257). Does not play a role in U8 snoRNA decapping activity (By similarity). Binds U8 snoRNA (By similarity).
Homodimer (PubMed:27257257, PubMed:17052728, PubMed:18462755, PubMed:21768126). Interacts with PARG (PubMed:27257257).
Overexpressed in cancer patients with a poor outcome.
Phosphorylation at Thr-45 is required for homodimer stability; dephosphorylation results in destabilization of the homodimer. Dephosphorylation at Thr-45 promotes the ATP-synthesis activity.
Widely expressed. Most abundant in liver.
Interacts with GLDC (By similarity). The glycine cleavage system is composed of four proteins: P (GLDC), T (GCST), L (DLD) and H (GCSH).
The glycine cleavage system catalyzes the degradation of glycine. The H protein (GCSH) shuttles the methylamine group of glycine from the P protein (GLDC) to the T protein (GCST).
Expressed in multiple tissues including brain.
Interacts with APBA1 (via PDZ 1 and 2 domains).
Intragenic, in the second intron of RAB54B gene.
Transcriptional repressor that down-regulates the expression of the fibrinogen gamma chain. Represses transcription of GSK3B gene promoter via its interaction with APBA1.
Interacts with CCDC68 and CCDC120; leading to recruitment to centrosomes (PubMed:28422092). Interacts with PLK1 (PubMed:15616186). Interacts with NIN (By similarity). Interacts with FHDC1 (By similarity). Interacts with CCDC61 (PubMed:30354798, PubMed:31789463). Interacts with TBK1; efficient complex formation may be dependent on the presence of CCDC61 (PubMed:30354798).
Plays a role in microtubule organization (PubMed:15616186). Required for centriole subdistal appendage assembly (PubMed:28422092).
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Chromokinesin subfamily.
Binds 1 [4Fe-4S] cluster (By similarity). In the presence of oxygen, the [4Fe-4S] cluster may be converted to [2Fe-2S] (By similarity).
Iron-sulfur (Fe-S) cluster binding motor protein that has a role in chromosome segregation during mitosis (By similarity). Translocates PRC1 to the plus ends of interdigitating spindle microtubules during the metaphase to anaphase transition, an essential step for the formation of an organized central spindle midzone and midbody and for successful cytokinesis (By similarity). May play a role in mitotic chromosomal positioning and bipolar spindle stabilization (By similarity).
May be involved in the control of cytoskeleton formation by regulating actin polymerization.
Strongly expressed in breast, liver, lung, skeletal muscle and kidney.
Each subunit of the homodimer independently transports zinc ions in a pH-dependent manner. The cytosolic pH promotes binding of zinc ions to the transporter binding site. Upon change into the organelle-facing conformation, the two histidines of the zinc-binding site get protonated at lumenal lower pH, triggering zinc release into the organelle. The transporter then moves back to the cytosolic-facing conformation where the two histidines get deprotonated at higher pH, resulting in a net antiport of 2 protons.
In the endocrine pancreas, expressed in insulin-producing beta cells. Expressed at relatively high levels in subcutaneous fat tissue from lean persons; much lower levels in visceral fat, whether from lean or obese individuals, and in subcutaneous fat tissue from obese individuals. Expressed in peripheral blood mononuclear cells, including T-cells and B-cells, with great variation among individuals ranging from negative to strongly positive.
Proton-coupled zinc ion antiporter mediating the entry of zinc into the lumen of pancreatic beta cell secretory granules, thereby regulating insulin secretion.
Variant Trp-325 is a risk factor that confers susceptibility to type 2 diabetes mellitus (T2D) [MIM:125853].
(Microbial infection) Proteolytically cleaves the N protein of coronoviruses such as MERS-CoV and SARS-CoV (PubMed:35922005, PubMed:18155731). The cleavage of MERS-CoV N-protein leads to two fragments and modulates coronavirus replication by regulating IFN signaling. The two fragments produced by the cleavage interact with IRF3 inhibiting its nuclear translocation after activation and reduce the expression of IFNB and IFN-stimulated genes (PubMed:35922005). The same mechanism seems to be used by other coronaviruses such as SARS-CoV and SARS-CoV-2 to enhance their replication (PubMed:35922005).
Can be cleaved and activated by different caspases, depending on the context (PubMed:19133298, PubMed:28864531). Cleaved and activated by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3) (PubMed:9463409). Can also undergo autoactivation by mediating autocleavage at Asp-179 and Asp-193, while it is not able to cleave its N-terminal disordered prodomain (PubMed:19133298, PubMed:28864531). Cleaved and activated by CASP1, possibly in the context of inflammation (PubMed:16123779).
Cysteine protease that plays essential roles in programmed cell death, axonal degeneration, development and innate immunity (PubMed:8663580, PubMed:19133298, PubMed:22858542, PubMed:27032039, PubMed:28864531, PubMed:30420425, PubMed:32298652). Acts as a non-canonical executioner caspase during apoptosis: localizes in the nucleus and cleaves the nuclear structural protein NUMA1 and lamin A/LMNA thereby inducing nuclear shrinkage and fragmentation (PubMed:8663580, PubMed:9463409, PubMed:11953316, PubMed:17401638). Lamin-A/LMNA cleavage is required for chromatin condensation and nuclear disassembly during apoptotic execution (PubMed:11953316). Acts as a regulator of liver damage by promoting hepatocyte apoptosis: in absence of phosphorylation by AMP-activated protein kinase (AMPK), catalyzes cleavage of BID, leading to cytochrome c release, thereby participating in nonalcoholic steatohepatitis (PubMed:32029622). Cleaves PARK7/DJ-1 in cells undergoing apoptosis (By similarity). Involved in intrinsic apoptosis by mediating cleavage of RIPK1 (PubMed:22858542). Furthermore, cleaves many transcription factors such as NF-kappa-B and cAMP response element-binding protein/CREBBP (PubMed:10559921, PubMed:14657026). Cleaves phospholipid scramblase proteins XKR4 and XKR9 (By similarity). In addition to apoptosis, involved in different forms of programmed cell death (PubMed:32298652). Plays an essential role in defense against viruses by acting as a central mediator of the ZBP1-mediated pyroptosis, apoptosis, and necroptosis (PANoptosis), independently of its cysteine protease activity (PubMed:32298652). PANoptosis is a unique inflammatory programmed cell death, which provides a molecular scaffold that allows the interactions and activation of machinery required for inflammasome/pyroptosis, apoptosis and necroptosis (PubMed:32298652). Mechanistically, interacts with RIPK3 and enhances the interaction between RIPK3 and ZBP1, leading to ZBP1-mediated inflammasome activation and cell death (PubMed:32298652). Plays an essential role in axon degeneration during axon pruning which is the remodeling of axons during neurogenesis but not apoptosis (By similarity). Regulates B-cell programs both during early development and after antigen stimulation (By similarity).
During activation, the N-terminal disordered prodomain is removed by cleavage (PubMed:8900201, PubMed:8663580, PubMed:19133298, PubMed:28864531). Concomitantly, double cleavage gives rise to a large 18-kDa and a small 11-kDa subunit (PubMed:8663580, PubMed:19133298). The two large and two small subunits then assemble to form the active CASP6 complex (PubMed:8663580). Can be cleaved and activated by different caspases, depending on the context (PubMed:9463409, PubMed:19133298). Cleaved and activated by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3) (PubMed:9463409). Can also undergo autoactivation by mediating autocleavage at Asp-179 and Asp-193, while it is not able to cleave its N-terminal disordered prodomain (PubMed:19133298, PubMed:28864531). Intramolecular cleavage at Asp-193 is a prerequisite for CASP6 self-activation (PubMed:20890311, PubMed:28864531). Cleaved and activated by CASP1 in neurons, possibly in the context of inflammation (PubMed:16123779). Phosphorylation at Ser-257 inhibits autocleavage, preventing caspase activation (PubMed:15273717, PubMed:32029622, PubMed:22433863, PubMed:22483120). Specifically inhibited by compound 3 (benzyloxycarbonyl (Z)-VEID-tetrafluorophenoxymethyl ketone) (PubMed:23227217).
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit.
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 11 kDa (p11) subunits (PubMed:19133298, PubMed:19694615, PubMed:20890311). Interacts with BIRC6/bruce (PubMed:15200957). Interacts with RIPK3 (PubMed:32298652).
Palmitoylation by ZDHHC17 blocks dimerization and subsequent activation, leading to inhibit the cysteine protease activity.
Phosphorylated by NUAK1; phosphorylation inhibits self-activation (PubMed:15273717, PubMed:22483120). Phosphorylation at Ser-257 by AMP-activated protein kinase (PRKAA1 or PRKAA2) inhibits autocleavage, preventing caspase activation, thereby preventing hepatocyte apoptosis (PubMed:32029622).
The N-terminal disordered prodomain is required to prevent self-activation.
The Tri-arginine exosite is required to recruit substrates for hydrolysis.
Undergoes helix-strand structural transitions upon substrate-binding: the 130's region interconverts between an inactive helical state and the canonically active strand state (PubMed:28154009). Other caspases rest constitutively in the strand conformation before and after substrate-binding (PubMed:28154009).
Homodimer, and heterodimer with MIS18A (PubMed:17199038, PubMed:26921242). Identified in a complex containing MIS18A, OIP5/MIS18B, MIS18BP1, RBBP7 and RBBP4 (PubMed:17199038). Binds outer membrane protein OpaP from Neisseria gonorrhoeae (in vitro) (PubMed:9466265).
Although it belongs to the alpha-carbonic anhydrase family, Arg-116 is present instead of the conserved His which is a zinc-binding residue. It is therefore expected that this protein lacks carbonic anhydrase activity.
Does not have a carbonic anhydrase catalytic activity.
PHM and PHV also cause vasodilation. PHM-27 is a potent agonist of the calcitonin receptor CALCR, with similar efficacy as calcitonin.
VIP causes vasodilation, lowers arterial blood pressure, stimulates myocardial contractility, increases glycogenolysis and relaxes the smooth muscle of trachea, stomach and gall bladder.
Binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit to form the 80S initiation complex in the cytoplasm (PubMed:10085284, PubMed:14654845, PubMed:21536732, PubMed:32669547). Behaves as a stimulatory translation initiation factor downstream insulin/growth factors. Is also involved in ribosome biogenesis. Associates with pre-60S subunits in the nucleus and is involved in its nuclear export. Cytoplasmic release of TIF6 from 60S subunits and nuclear relocalization is promoted by a RACK1 (RACK1)-dependent protein kinase C activity (PubMed:10085284, PubMed:14654845, PubMed:21536732). In tissues responsive to insulin, controls fatty acid synthesis and glycolysis by exerting translational control of adipogenic transcription factors such as CEBPB, CEBPD and ATF4 that have G/C rich or uORF in their 5'UTR. Required for ROS-dependent megakaryocyte maturation and platelets formation, controls the expression of mitochondrial respiratory chain genes involved in reactive oxygen species (ROS) synthesis (By similarity). Involved in miRNA-mediated gene silencing by the RNA-induced silencing complex (RISC). Required for both miRNA-mediated translational repression and miRNA-mediated cleavage of complementary mRNAs by RISC (PubMed:17507929). Modulates cell cycle progression and global translation of pre-B cells, its activation seems to be rate-limiting in tumorigenesis and tumor growth (By similarity).
Expressed at very high levels in colon carcinoma with lower levels in normal colon and ileum and lowest levels in kidney and muscle (at protein level).
Monomer. Associates with the 60S ribosomal subunit. Interacts with RACK1. Interacts with DICER1, AGO2, TARBP2, MOV10 and RPL7A; they form a large RNA-induced silencing complex (RISC) (PubMed:17507929).
Phosphorylation at Ser-174 and Ser-175 by CSNK1D/CK1 promotes nuclear export.
Can influence paracellular permeability. Appears to be involved in cell-cell interactions through adherens.
Highly expressed in lung, heart, kidney and placenta. Lower expression in thymus, spleen, liver, testis and ovary. Expressed in endothelial and restricted epithelial cell populations.
RNA-binding protein that initiates the antiviral response and is required to restrict the replication of RNA viruses (PubMed:33872655). Acts as a double-stranded RNA (dsRNA) sensor that recognizes viral RNA and then interacts with MAVS to initiate the type I interferon response (By similarity). Also required for immunity against some bacteria, such as mycobacteria (PubMed:33876776).
Expression can only be detected in tissues derived from the head and neck, and in skin, prostate and testis.
Forms a heterodimer with SERPINA5 and SERPINE1.
Serine protease which possesses both gelatinolytic and caseinolytic activities. Shows a preference for Arg in the P1 position.
Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4.
Found in a complex with COX20, COA6, MT-CO2/COX2, COX18, SCO1 and SCO2. Interacts with COX20. Interacts with COX1, MT-CO2/COX2, SCO1 and SCO2 in a COX20-dependent manner.
Plays a role in the early steps of cytochrome c oxidase subunit II (MT-CO2/COX2) maturation and is required for the stabilization of COX20 and the newly synthesized MT-CO2/COX2 protein.
In fetal and adult fast skeletal muscles, with a higher level expression in fetal than in adult muscle.
Minor isoform detected in approximately 1% of cDNA clones.
Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
Binding to dsRNA, but not CDE RNA, crosstalks with the E3 ubiquitin ligase activity and may inhibit ubiquitination.
Expressed in spleen, testis, ovary and small intestine.
HEPN (higher eukaryotes and prokaryotes nucleotide-binding) are observed in both N- and C-terminal sides of ROQ domain with 3D structure even if they are poredcted on the basis of sequence.
Interacts with EDC4. Interacts with CCR4-NOT deadenylase complex (By similarity). Interacts with MAP3K5; the interaction is probably stimulus-dependent (PubMed:24448648).
Post-transcriptional repressor of mRNAs containing a conserved stem loop motif, called constitutive decay element (CDE), which is often located in the 3'-UTR, as in HMGXB3, ICOS, IER3, NFKBID, NFKBIZ, PPP1R10, TNF and in many more mRNAs. Binds to CDE and promotes mRNA deadenylation and degradation. This process does not involve miRNAs. In follicular helper T (Tfh) cells, represses of ICOS and TNFRSF4 expression, thus preventing spontaneous Tfh cell differentiation, germinal center B-cell differentiation in the absence of immunization and autoimmunity. In resting or LPS-stimulated macrophages, controls inflammation by suppressing TNF expression. Also recognizes CDE in its own mRNA and in that of paralogous RC3H1, possibly leading to feedback loop regulation (By similarity). miRNA-binding protein that regulates microRNA homeostasis. Enhances DICER-mediated processing of pre-MIR146a but reduces mature MIR146a levels through an increase of 3' end uridylation. Both inhibits ICOS mRNA expression and they may act together to exert the suppression (PubMed:25697406). Acts as a ubiquitin E3 ligase. Pairs with E2 enzymes UBE2B, UBE2D2, UBE2E2, UBE2E3, UBE2G2, UBE2K and UBE2Q2 and produces polyubiquitin chains (PubMed:26489670). Shows the strongest activity when paired with UBE2N:UBE2V1 or UBE2N:UBE2V2 E2 complexes and generate both short and long polyubiquitin chains (PubMed:26489670). Involved in the ubiquitination of MAP3K5 (PubMed:24448648, PubMed:26489670, PubMed:29186683). Able to interact with double-stranded RNA (dsRNA) (PubMed:26489670).
Proteolytically cleaved after Arg-509 and Arg-585 by MALT1 in activated CD4(+) T cells; cleavage at Arg-509 and Arg-585 is critical for promoting RC3H1 degradation in response to T-cell receptor (TCR) stimulation, and hence is necessary for prolonging the stability of a set of mRNAs controlling Th17 cell differentiation.
The RING-type zinc finger is required for proper localization to stress granules, but not to P-bodies.
The ROQ region is required for CDE RNA-binding. Has 2 separate RNA-binding sites, one for CDE RNA and the other for dsRNA (PubMed:26249698). It may also be involved in localization to stress granules (By similarity).
Detected in migrating keratinocytes from wounded skin, but not in differentiating keratinocytes or in normal skin. Detected in chronic wounds, basal cell carcinoma and ulcerative colitis.
In keratinocytes, by wounding or contact with collagen.
May be a transcriptional activator. May be involved in chromatin remodeling (By similarity). Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape.
Catalyzes the transfer of a phosphate from ATP to alpha-D-galactose and participates in the first committed step in the catabolism of galactose.
Association with calcitriol does not affect its enzymatic activity.
Detected in the flagellum and head region of spermatozoa (at protein level) (PubMed:20400973). Expressed in liver, stomach and colon (at protein level). Expressed in gastric parietal cells and chief cells (at protein level) (PubMed:24188822).
Part of the major histocompatibility complex class I (MHC I) peptide loading complex composed of TAP1, TAP2, B2M, MHC heavy chain, TAPBP, PDIA3, and CALR (PubMed:19119025, PubMed:35948544, PubMed:36104323). Interacts with ERP27 and CANX (PubMed:16940051, PubMed:16905107). Interacts with SERPINA2 and with the S and Z variants of SERPINA1 (PubMed:23826168). Interacts with ATP2A2 (By similarity).
Protein disulfide isomerase that catalyzes the formation, isomerization, and reduction or oxidation of disulfide bonds in client proteins and functions as a protein folding chaperone (PubMed:7487104, PubMed:11825568, PubMed:16193070, PubMed:27897272, PubMed:36104323). Core component of the major histocompatibility complex class I (MHC I) peptide loading complex where it functions as an essential folding chaperone for TAPBP. Through TAPBP, assists the dynamic assembly of the MHC I complex with high affinity antigens in the endoplasmic reticulum. Therefore, plays a crucial role in the presentation of antigens to cytotoxic T cells in adaptive immunity (PubMed:35948544, PubMed:36104323).
Was originally thought to be a phosphatidylinositol 4,5-bisphosphate phosphodiesterase type I (phospholipase C-alpha).
Within the major histocompatibility complex class I (MHC I) peptide loading complex forms reversible disulfide-linked heterodimers with TAPBP as part of its protein folding chaperone activity. This is essential to assist the dynamic assembly of the MHC I complex with high affinity antigens in the endoplasmic reticulum.
Rho GTPase activating protein that suppresses F-actin polymerization by inhibiting Rho. Rho GTPase activating proteins act by converting Rho-type GTPases to an inactive GDP-bound state (PubMed:21865595). Plays a key role in tissue tension and 3D tissue shape by regulating cortical actomyosin network formation. Acts downstream of YAP1 and inhibits actin polymerization, which in turn reduces nuclear localization of YAP1 (PubMed:25778702). Regulates cell shape, spreading, and migration (PubMed:21865595).
Guanine nucleotide dissociation inhibitor (GDI) which functions as a receptor-independent activator of heterotrimeric G-protein signaling. Keeps G(i/o) alpha subunit in its GDP-bound form thus uncoupling heterotrimeric G-proteins signaling from G protein-coupled receptors. Controls spindle orientation and asymmetric cell fate of cerebral cortical progenitors. May also be involved in macroautophagy in intestinal cells. May play a role in drug addiction.
Interacts with GNAI1, GNAI2 and GNAI3 preferentially in their GDP-bound state. May also interact with GNAO1. Interacts with STK11/LKB1 and MACF1 (By similarity). Interacts with INSC/inscuteable and FRMPD1.
Phosphorylation regulates interaction with G(i/o) alpha.
The GoLoco domains mediate interaction with G(i/o) alpha (By similarity). The GoLoco domains are essential for the GDI activity toward G(i/o) alpha.
Interacts with HDAC1; the interaction prevents binding of HDAC1 to CDKN1A/p21 and facilitates the acetylation and stabilization of CDKN1A/p21. Interacts with p53/TP53; the interaction inhibits binding of p53/TP53 and MDM2.
Tumor suppressor that is required to sustain G2/M checkpoint after DNA damage. Acts as a p53/TP53 activator by inhibiting MDM2 binding to p53/TP53 and stimulating non-proteolytic polyubiquitination of p53/TP53. Exhibits ubiquitin ligase (E3) activity and assemble ubiquitin polymers through 'Lys-11'- (K11-), 'Lys-29'- (K29-) and 'Lys-63'- (K63)-linkages, independently of the ubiquitin-conjugating enzyme (E2). Promotes p53/TP53-dependent transcription of CDKN1A/p21, leading to robust checkpoint response. Mediates CDKN1A/p21 protein stability in a ubiquitin-independent manner. Interacts with HDAC1 and prevents binding of HDAC1 to CDKN1A/p21 and facilitates the acetylation and stabilization of CDKN1A/p21 (By similarity). May have a role in the assembly of primary cilia (Probable).
Plays an essential role in the homeostatic regulation of sphingolipid de novo biosynthesis by modulating the activity of the serine palmitoyltransferase (SPT) in response to ceramide levels (PubMed:20182505). When complexed to SPT, the binding of ceramides to its N-terminus stabilizes a conformation that block SPT substrate entry, hence preventing SPT catalytic activity. Through this mechanism, maintains ceramide levels at sufficient concentrations for the production of complex sphingolipids, but which prevents the accumulation of ceramides to levels that trigger apoptosis (By similarity).
Widely expressed. Expressed in adult and fetal heart, brain, lung, liver, skeletal muscle and kidney. Expressed in adult pancreas and placenta and in fetal spleen abd thymus.
Mitotic kinesin required for chromosome passenger complex (CPC)-mediated cytokinesis. Following phosphorylation by PLK1, involved in recruitment of PLK1 to the central spindle. Interacts with guanosine triphosphate (GTP)-bound forms of RAB6A and RAB6B. May act as a motor required for the retrograde RAB6 regulated transport of Golgi membranes and associated vesicles along microtubules. Has a microtubule plus end-directed motility.
Phosphorylated by PLK1 at Ser-528 during mitosis, creating a docking site for PLK1 and recruiting PLK1 at central spindle.
Overexpression suppresses cell proliferation by inducing G2/M arrest.
Expressed in nonneural tissues, such as heart, lung, spleen, muscle, testis, placenta and melanocytes.
Homodimer; disulfide-linked. May form heterodimers with FEZ1. Interacts with synaptotagmin.
Involved in axonal outgrowth and fasciculation.
(Microbial infection) Interacts with the S.typhimurium sifA protein; required for S.typhimurium infection.
Interacts with KLC2 (via TPR repeats) (Probable). Interacts with KIF5B (PubMed:15905402). Interacts with BORCS5 (PubMed:25898167). Interacts (via RUN domain) with ARL8B (GTP-bound form); PLEKHM1 and PLEKHM2 compete for interaction with ARL8B (PubMed:28325809, PubMed:22172677). Interacts with ARL8A (PubMed:28325809).
Plays a role in lysosomes movement and localization at the cell periphery acting as an effector of ARL8B. Required for ARL8B to exert its effects on lysosome location, recruits kinesin-1 to lysosomes and hence direct their movement toward microtubule plus ends. Binding to ARL8B provides a link from lysosomal membranes to plus-end-directed motility (PubMed:28325809, PubMed:22172677, PubMed:25898167, PubMed:24088571). Critical factor involved in NK cell-mediated cytotoxicity. Drives the polarization of cytolytic granules and microtubule-organizing centers (MTOCs) toward the immune synapse between effector NK lymphocytes and target cells (PubMed:24088571). Required for maintenance of the Golgi apparatus organization (PubMed:22172677). May play a role in membrane tubulation (PubMed:15905402).
Interacts with FBN1; this interaction promotes microfibrils assembly.
Metalloprotease that participate in microfibrils assembly. Microfibrils are extracellular matrix components occurring independently or along with elastin in the formation of elastic tissues.
Belongs to the glycosyl hydrolase 2 family.
N-linked glycosylated with 3 to 4 oligosaccharide chains.
Plays an important role in the degradation of dermatan and keratan sulfates.
Homodimer (PubMed:18186464). Interacts with ACBD3 and ARFGEF1. Interacts with YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ and YWHAZ (PubMed:23572552).
Expressed in fetal and adult brain. Also detected in fetal liver and skeletal muscle, but not in their adult counterparts.
Interacts with CHEK1 and CHEK2; dephosphorylates them. Interacts with MAPK14 (PubMed:21283629).
Involved in the negative regulation of p53 expression (PubMed:23242139). Required for the relief of p53-dependent checkpoint mediated cell cycle arrest. Binds to and dephosphorylates 'Ser-15' of TP53 and 'Ser-345' of CHEK1 which contributes to the functional inactivation of these proteins (PubMed:15870257, PubMed:16311512). Mediates MAPK14 dephosphorylation and inactivation (PubMed:21283629). Is also an important regulator of global heterochromatin silencing and critical in maintaining genome integrity (By similarity).
Plays a major role in early metanephros and genital development.
Probable cloning artifact. Spurious priming from an intronic poly-A tract.
Widely expressed, with prominent expression in the cochlea (PubMed:29955957). Expressed at high levels in fetal kidney (PubMed:29100091). In adult tissues, highest levels in vagina, cervix and epididymis (PubMed:29100091).
Catalyzes the phosphorylation of thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), the immediate precursor for the DNA building block dTTP, with ATP as the preferred phosphoryl donor in the presence of Mg(2+).
The levels of dTMP kinase mRNA and its enzymatic activity fluctuate during the cell cycle, peaking at the S phase.
Acetyltransferase activity increases in presence of the kinase substrate, sphingosine (By similarity). In Purkinje cells, kinase activity on sphingosine increases in presence of VEGFA (PubMed:25417698). In neurons, kinase activity increases during the first 24h in presence of Amyloid-beta protein 42 to decrease after 96h (By similarity).
Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol (PubMed:20577214, PubMed:23602659, PubMed:29662056, PubMed:24929359, PubMed:11923095). In contrast to proapoptotic SPHK2, has a negative effect on intracellular ceramide levels, enhances cell growth and inhibits apoptosis (PubMed:16118219). Involved in the regulation of inflammatory response and neuroinflammation. Via the product sphingosine 1-phosphate, stimulates TRAF2 E3 ubiquitin ligase activity, and promotes activation of NF-kappa-B in response to TNF signaling leading to IL17 secretion (PubMed:20577214). In response to TNF and in parallel to NF-kappa-B activation, negatively regulates RANTES induction through p38 MAPK signaling pathway (PubMed:23935096). Involved in endocytic membrane trafficking induced by sphingosine, recruited to dilate endosomes, also plays a role on later stages of endosomal maturation and membrane fusion independently of its kinase activity (PubMed:28049734, PubMed:24929359). In Purkinje cells, seems to be also involved in the regulation of autophagosome-lysosome fusion upon VEGFA (PubMed:25417698).
Has serine acetyltransferase activity on PTGS2/COX2 in an acetyl-CoA dependent manner. The acetyltransferase activity increases in presence of the kinase substrate, sphingosine. During neuroinflammation, through PTGS2 acetylation, promotes neuronal secretion of specialized preresolving mediators (SPMs), especially 15-R-lipoxin A4, which results in an increase of phagocytic microglia.
Interacts with ACY1 (By similarity). Binds to calmodulin. Interacts with SPHKAP (PubMed:12080051). Interacts with CIB1, the interaction occurs in a calcium-dependent manner (PubMed:19854831). Interacts with TRAF2 (PubMed:20577214). Interacts with EEF1A1; the interaction enhances SPHK1 kinase activity (PubMed:18263879).
Widely expressed with highest levels in adult liver, kidney, heart and skeletal muscle. Expressed in brain cortex (at protein level) (PubMed:29662056).
Belongs to the major facilitator superfamily. SLC46A family.
Lysosomal proton-coupled steroid conjugate and bile acid transporter. Preferentially recognizes lipophilic steroid conjugates or bile acis as endogenous substrates and seems to mediate escape from lysosomes to the cytoplasm (PubMed:36741448). Modulates hepatic cytosolic copper homeostasis, maybe acting as a lysosomal copper transporter and sequestering copper ions in the lysosome (By similarity). Transports catabolites of non-cleavable antibody-drug conjugates from the lysosome to the cytoplasm (PubMed:26631267, PubMed:30131388, PubMed:36741448). Delivers pathogen-associated molecular patterns to cytosolic pattern recognition receptors as part of the innate immune response to microbes. Selectively transports bacterial muramyl dipeptide (MDP) into the cytosol for recognition by NOD2, triggering inflammatory responses (By similarity). Likely acts as a redundant importer of cyclic GMP-AMP dinucleotides (cGAMPs) in monocyte and macrophage cell lineages (PubMed:34235268). The transport mechanism, its electrogenicity and stoichiometry remain to be elucidated (Probable).
Catalyzes the fifth step in the leucine degradation pathway, the reversible hydration of 3-methylglutaconyl-CoA (3-MG-CoA) to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) (PubMed:12434311, PubMed:16640564, PubMed:11738050, PubMed:12655555). Can catalyze the reverse reaction but at a much lower rate in vitro (PubMed:16640564). HMG-CoA is then quickly degraded by another enzyme (such as HMG-CoA lyase) to give acetyl-CoA and acetoacetate (PubMed:16640564). Uses other substrates such as (2E)-glutaconyl-CoA efficiently in vitro, and to a lesser extent 3-methylcrotonyl-CoA (3-methyl-(2E)-butenoyl-CoA), crotonyl-CoA ((2E)-butenoyl-CoA) and 3-hydroxybutanoyl-CoA (the missing carboxylate reduces affinity to the active site) (PubMed:16640564). Originally it was identified as an RNA-binding protein as it binds to AU-rich elements (AREs) in vitro (PubMed:7892223). AREs direct rapid RNA degradation and mRNA deadenylation (PubMed:7892223). Might have itaconyl-CoA hydratase activity, converting itaconyl-CoA into citramalyl-CoA in the C5-dicarboxylate catabolism pathway (PubMed:29056341). The C5-dicarboxylate catabolism pathway is required to detoxify itaconate, an antimicrobial metabolite and immunomodulator produced by macrophages during certain infections, that can act as a vitamin B12-poisoning metabolite (PubMed:29056341).
Belongs to the PNP/UDP phosphorylase family.
By vitamin D3 and a mixture of inflammatory cytokines: TNF, IL1/interleukin-1 and IFNG/IFN-gamma.
Catalyzes the reversible phosphorylytic cleavage of uridine and deoxyuridine to uracil and ribose- or deoxyribose-1-phosphate (PubMed:7488099). The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis.
Highest expression in placenta, muscle, fetal brain, and adult brain, with lower expression in heart, kidney, stomach, testis, and adrenal gland. In the central nervous system, highest expression is in temporal lobe, hypothalamus, medulla and spinal cord, with lower expression in other brain regions.
The Arg-7 polymorphism may be associated with progressive supranuclear palsy.
Was called 'saitohin' in honor of the late Tsuanao Saitoh and his laboratory.
Catalyzes the oxidative metabolism of numerous xenobiotics, including mainly therapeutic drugs and insecticides that contain a soft nucleophile, most commonly nitrogen and sulfur and participates to their bioactivation (PubMed:9804831, PubMed:15294458, PubMed:15144220, PubMed:18948378, PubMed:18930751). Specifically catalyzes S-oxygenation of sulfur derived compounds such as thioureas-derived compounds, thioetherorganophosphates to their sulfenic acid (PubMed:9804831, PubMed:15144220). In vitro, catalyzes S-oxygenation of the second-line antitubercular drugs thiacetazone (TAZ) and ethionamide (ETA), forming a sulfinic acid and a carbodiimide via a postulated sulfenic acid intermediate (PubMed:18948378, PubMed:18930751). Also catalyzes S-oxygenation of the thioether-containing organophosphate insecticides, phorate and disulfoton (PubMed:15294458).
Expressed in lung (at protein level). Expressed predominantly in lung, and at a much lesser extent in kidney. Also expressed in fetal lung, but not in liver, kidney and brain.
The sequence shown is that of the allele FMO2*1. FMO2*2A is the major allele in the human population, however it encodes a truncated and catalytically inactive protein (PubMed:9804831). FMO2*2A occurs in essentially 100% of Caucasians and Asians (PubMed:9804831). FMO2*1 is present at a frequency of approximately 4% to 13% in the sample of population of African descent (PubMed:9804831, PubMed:11042094, PubMed:18794725).
Contains N-linked glycan resistant to endoglycosydase H.
Exhibits 3'-nucleotidase activity toward adenosine 3',5'-bisphosphate (PAP), namely hydrolyzes adenosine 3',5'-bisphosphate into adenosine 5'-monophosphate (AMP) and a phosphate. May play a role in the formation of skeletal elements derived through endochondral ossification, possibly by clearing adenosine 3',5'-bisphosphate produced by Golgi sulfotransferases during glycosaminoglycan sulfation. Has no activity toward 3'-phosphoadenosine 5'-phosphosulfate (PAPS) or inositol phosphate (IP) substrates including I(1)P, I(1,4)P2, I(1,3,4)P3, I(1,4,5)P3 and I(1,3,4,5)P4.
Phosphorylated. Phosphorylation on Ser-355 occurs specifically during mitosis.
Belongs to the G-alpha family. G(12) subfamily.
G proteins are composed of 3 units; alpha, beta and gamma (PubMed:10026210). The alpha chain contains the guanine nucleotide binding site (By similarity). Interacts with UBXD5 (PubMed:16202387). Interacts (in GTP-bound form) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane. Interacts with RGS22 (PubMed:18703424). Interacts (via N-terminus) with NAPA; the interaction promotes CDH5 localization to plasma membrane (PubMed:15980433). Interacts with CTNND1 (via N-terminus); the interaction regulates CDH1-mediated cell-cell adhesion (PubMed:15240885). Interacts with PPP2R1A; the interaction promotes protein phosphatase 2A activation causing dephosphorylation of MAPT (PubMed:15525651). Interacts (in GTP-bound form) with ARHGEF1 (By similarity). Interacts (in GTP-bound form) with ARHGEF11 (via RGS domain) (PubMed:10026210). Interacts (in GTP-bound form) with ARHGEF12 (via RGS domain) (PubMed:11094164).
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems (PubMed:22609986, PubMed:15525651, PubMed:15240885, PubMed:17565996, PubMed:12515866, PubMed:16787920, PubMed:16705036, PubMed:23762476, PubMed:27084452). Activates effector molecule RhoA by binding and activating RhoGEFs (ARHGEF12/LARG) (PubMed:15240885, PubMed:12515866, PubMed:16202387). GNA12-dependent Rho signaling subsequently regulates transcription factor AP-1 (activating protein-1) (By similarity). GNA12-dependent Rho signaling also regulates protein phosphatese 2A activation causing dephosphorylation of its target proteins (PubMed:15525651, PubMed:17565996). Promotes tumor cell invasion and metastasis by activating RhoA/ROCK signaling pathway and up-regulating pro-inflammatory cytokine production (PubMed:23762476, PubMed:16787920, PubMed:16705036, PubMed:27084452). Inhibits CDH1-mediated cell adhesion in process independent from Rho activation (PubMed:11976333, PubMed:16787920). Together with NAPA promotes CDH5 localization to plasma membrane (PubMed:15980433). May play a role in the control of cell migration through the TOR signaling cascade (PubMed:22609986).
Componement of the stereocilia rootlet in hair cells of inner ear. Bridges the apical plasma membrane with the lower rootlet and maintains normal distribution of TRIOBP, thereby reinforcing stereocilia insertion points and organizing rootlets for hearing with long-term resilience.
Homodimer. Interacts (via C-terminal domain) with TRIOBP (via C-terminal domain) isoform 4; recruits TRIOBP isoform 4 to stereocilia rootlets.
Cleaved, during apoptosis, on a specific aspartic residue by caspases.
May play a role in apoptosis by acting as a cell death substrate for caspases. Is cleaved during apoptosis and the cleaved form induces dramatic rearrangements of the actin cytoskeleton and potent changes in the shape of the affected cells. May be involved in the membrane ruffling process (By similarity).
Phosphorylated on serine residues during the G0-G1 transition phase.
Specifically expressed at growth arrest.
Ubiquitously expressed with highest levels in liver, lung, and kidney. Not found in spleen.
Ectopic expression of TMED2 alone does not result in its proper cis-Golgi network localization. Coexpression of TMED10 is necessary, and coexpression of TMED3 and/or TMED9 is facilitating localization. Down-regulation of TMED10 expression reduces TMED2 protein level.
Involved in vesicular protein trafficking. Mainly functions in the early secretory pathway but also in post-Golgi membranes. Thought to act as cargo receptor at the lumenal side for incorporation of secretory cargo molecules into transport vesicles and to be involved in vesicle coat formation at the cytoplasmic side. In COPII vesicle-mediated anterograde transport involved in the transport of GPI-anchored proteins and proposed to act together with TMED10 as their cargo receptor; the function specifically implies SEC24C and SEC24D of the COPII vesicle coat and lipid raft-like microdomains of the ER. Recognizes GPI anchors structural remodeled in the ER by PGAP1 and MPPE1. In COPI vesicle-mediated retrograde transport inhibits the GTPase-activating activity of ARFGAP1 towards ARF1 thus preventing immature uncoating and allowing cargo selection to take place. Involved in trafficking of G protein-coupled receptors (GPCRs). Regulates F2RL1, OPRM1 and P2RY4 exocytic trafficking from the Golgi to the plasma membrane thus contributing to receptor resensitization. Facilitates CASR maturation and stabilization in the early secretory pathway and increases CASR plasma membrane targeting. Proposed to be involved in organization of intracellular membranes such as the maintenance of the Golgi apparatus. May also play a role in the biosynthesis of secreted cargo such as eventual processing.
Monomer and homodimer in the endoplasmic reticulum, endoplasmic reticulum-Golgi intermediate compartment and Golgi. Probably oligomerizes with other members of the EMP24/GP25L family such as TMED7, TMED9 and TMED10. Interacts (via GOLD domain) with TMED10 (via GOLD domain). Associates with the COPI vesicle coat (coatomer); TMED10:TMED2 heterotetramers are proposed to be involved in coatomer association. Interacts (via C-terminus) with COPG1; the interaction involves dimeric TMED2. Interacts with SEC23A; indicative for an association of TMED2 with the COPII vesicle coat. Interacts with ARF1 and ARFGAP1 (By similarity). Interacts with CD59, SEC24A, SEC24B, SEC24C, SEC24D and ATL1. Interacts with KDELR1; the interaction is decreased by KDEL ligand (By similarity). Interacts with F2RL1; the interaction occurs at the Golgi apparatus. Interacts with CASR (immaturely glycosylated form); the interaction occurs in the endoplasmic reticulum-Golgi intermediate compartment or cis-Golgi. Interacts with F2RL1; the interaction occurs at the Golgi apparatus. Interacts with GORASP1 and GORASP2 (By similarity). Found in a complex composed at least of SURF4, TMED2 and TMED10.
G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. Forms a complex with GNB1 and GNG3 (PubMed:34685729). Interacts with RGS14 (By similarity). Interacts with RGS19 (PubMed:34685729).
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(o) protein function is not clear. Stimulated by RGS14.
Histaminylated at Gln-205 residues by TGM2.
Interacts with RNA polymerase II and HELZ. Interacts with SIN3A and HDAC1 (By similarity). Interacts (via MYND-type zinc finger) with EPB41L3. Interacts (via SET domain) with p53/TP53. Interacts with RB1 and HSP90AA1.
Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1. Specifically trimethylates histone H3 'Lys-4' (H3K4me3) in vivo. The activity requires interaction with HSP90alpha. Shows even higher methyltransferase activity on p53/TP53. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates RB1 at 'Lys-860'.
Adapter protein that links membrane-bound small G-proteins to cytoplasmic effector proteins. Necessary for CDC42-mediated reorganization of the actin cytoskeleton and for RAC1-mediated membrane ruffling. Involved in the regulation of the actin cytoskeleton by WASF family members and the Arp2/3 complex. Plays a role in neurite growth. Acts syngeristically with ENAH to promote filipodia formation. Plays a role in the reorganization of the actin cytoskeleton in response to bacterial infection. Participates in actin bundling when associated with EPS8, promoting filopodial protrusions.
Homodimer. Interacts with CDC42 and RAC1 that have been activated by GTP binding. Interacts with ATN1, ADGRB1, EPS8, SHANK1, SHANK2, SHANK3, WASF1 and WASF2. Interacts with ENAH after recruitment of CDC42. Interacts with TIAM1 and DIAPH1 (By similarity). Interacts (via SH3 domain) with E.coli effector protein EspF(U) (via PXXP motifs). Interacts with E.coli intimin receptor Tir.
Isoform 1 and isoform 4 are expressed almost exclusively in brain. Isoform 4 is barely detectable in placenta, prostate and testis. A short isoform is ubiquitous, with the highest expression in liver, prostate, testis and placenta.
It is uncertain whether Met-1 or Met-59 is the initiator.
Phosphorylated on tyrosine residues by INSR in response to insulin treatment.
The IMD domain forms a coiled coil. The isolated domain can induce actin bundling and filopodia formation. In the absence of G-proteins intramolecular interaction between the IMD and the SH3 domain gives rise to an auto-inhibited state of the protein. Interaction of the IMD with RAC1 or CDC42 leads to activation.
The SH3 domain interacts with ATN1, ADGRB1, WASF1, WASF2, SHANK1, DIAPH1 and ENAH.
Expressed in all of the transcriptionally active stages of germ cell development from spermatogonia through spermatocytes to round spermatids.
Interacts with splicing factor proteins SFRS3/SRP20, TRA2B/SFRS10, KHDRBS1/SAM68 and KHDRBS3.
RNA-binding protein which may be involved in spermatogenesis. Required for sperm development, possibly by participating in pre-mRNA splicing in the testis.
The RBMY1 proteins are encoded by repeated regions of the Y chromosome, mostly within the AZFb region. The exact number of functional copies is unclear and may vary between individuals, and some of them may represent pseudogenes. The proteins are very similar, which makes the characterization of each protein difficult. Thus, most experiments do not discriminate between the different members. One can therefore suppose that reported interactions with a RBMY1 protein involve all the proteins.
Belongs to the opioid growth factor receptor family.
Highly expressed in the heart and liver, moderately in skeletal muscle and kidney and to a lesser extent in brain and pancreas. Expressed in fetal tissues including liver and kidney.
Receptor for opioid growth factor (OGF), also known as Met-enkephalin. Seems to be involved in growth regulation.
Involved in the 5-carboxymethylaminomethyl modification (mnm(5)s(2)U34) of the wobble uridine base in mitochondrial tRNAs.
Ubiquitously expressed in various tissues, but with a markedly elevated expression in tissues of high metabolic rates including cochlea.
High level of expression in placenta. Expressed throughout the brain at low level. No expression detected in skeletal muscle, lung, heart, liver, pancreas, or kidney.
Orphan receptor. Displays a significant level of constitutive activity. Its effect is mediated by G(s)-alpha protein that stimulate adenylate cyclase, resulting in an elevation of intracellular cAMP.
Copper metallochaperone essential for the maturation of cytochrome c oxidase subunit II (MT-CO2/COX2). Not required for the synthesis of MT-CO2/COX2 but plays a crucial role in stabilizing MT-CO2/COX2 during its subsequent maturation. Involved in transporting copper to the Cu(A) site on MT-CO2/COX2 (PubMed:15659396, PubMed:16735468, PubMed:17189203, PubMed:19336478, PubMed:15229189). Plays an important role in the regulation of copper homeostasis by controlling the abundance and cell membrane localization of copper transporter CTR1 (By similarity).
Homodimer (PubMed:16735468, PubMed:15229189). Interacts with COA6 (PubMed:26160915). Found in a complex with TMEM177, COX20, COA6, MT-CO2/COX2, COX18 and SCO2 (PubMed:29154948). Interacts with TMEM177 in a COX20-dependent manner (PubMed:29154948). Interacts with COX20 in a MT-CO2/COX2- and COX18-dependent manner (PubMed:29154948, PubMed:24403053, PubMed:28330871). Interacts with COX16 (PubMed:29381136).
Predominantly expressed in tissues characterized by high rates of oxidative phosphorylation (OxPhos), including muscle, heart, and brain.
Broadly expressed, with high levels in muscle, brain, heart, pancreas and testis. In the central nervous system, highest levels are detected in the cerebellum and pituitary gland. Over-expressed in brains from patients with bipolar disease or schizophrenia. Isoform 5 is predominantly expressed in the brain.
Molecular chaperone which facilitates proper subunit assembly and surface trafficking of alpha-7 (CHRNA7) and alpha-8 (CHRNA8) nicotinic acetylcholine receptors (PubMed:12821669, PubMed:15504725, PubMed:16120769, PubMed:18691158, PubMed:32204458). May also promote functional expression of homomeric serotoninergic 5-HT3 receptors, and of heteromeric acetylcholine receptors alpha-3/beta-2, alpha-3/beta-4, alpha-4/beta-2 and alpha-4/beta-4.
Monomer and homodimer. Interacts with CHRNA7, CHRNA3, CHRNA4, CHRNB2, CHRNB4 and HTR3A.
The coiled-coil domain mediates transient homodimerization with other acetylcholine receptor-bound RIC3 molecules, promoting stepwise ACHR homomeric assembly at the membrane.
Expressed in skin. Also expressed in heart and skeletal muscle.
Expressed by cementoblasts, a subpopulation of periodontal ligament cells and cells located around vessels in periodontium (at protein level).
May play a role in development of the periodontium which surrounds and supports the teeth by promoting the differentiation of multi-potent cells from the periodontal ligament into cementoblasts to form the cementum (PubMed:21929512, PubMed:17509525, PubMed:21465469). Binds hydroxyapatite and may promote the biomineralization of the cementum (PubMed:19393626). Also promotes cell proliferation (PubMed:17509525, PubMed:21929512, PubMed:26011628).
Up-regulated by hypoxia (at protein level).
Arginine methylation by PRMT5 is required for the interaction with Tudor domain-containing protein (TDRD1, TDRKH/TDRD2, RNF17/TDRD4, TDRD6, TDRD7 and TDRD9) and subsequent localization to the meiotic nuage, also named P granule.
Belongs to the argonaute family. Piwi subfamily.
Defects in PIWIL1 may be a cause of a disorder resulting in the absence of sperm (azoospermia) in the semen, leading to male infertility. Male sterility can be caused by defects in ubiquitination and degradation during late spermatogenesis.
Down-regulated in CD34(+) hematopoietic cells during differentiation.
Endoribonuclease that plays a central role in postnatal germ cells by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. Directly binds methylated piRNAs, a class of 24 to 30 nucleotide RNAs that are generated by a Dicer-independent mechanism and are primarily derived from transposons and other repeated sequence elements. Strongly prefers a uridine in the first position of their guide (g1U preference, also named 1U-bias). Not involved in the piRNA amplification loop, also named ping-pong amplification cycle. Acts as an endoribonuclease that cleaves transposon messenger RNAs. Besides their function in transposable elements repression, piRNAs are probably involved in other processes during meiosis such as translation regulation. Probable component of some RISC complex, which mediates RNA cleavage and translational silencing. Also plays a role in the formation of chromatoid bodies and is required for some miRNAs stability. Required to sequester RNF8 in the cytoplasm until late spermatogenesis; RNF8 being released upon ubiquitination and degradation of PIWIL1.
Expressed in spermatocytes and spermatids. Also detected in prostate cancer (at protein level). Detected in most fetal and adult tissues. Expressed in testes, specifically in germline cells; detected in spermatocytes and spermatids during spermatogenesis. Increased expression in testicular tumors originating from embryonic germ cells with retention of germ cells phenotype. No expression in testicular tumors of somatic origin, such as Sertoli cell and Leydig cell tumors. Overexpressed in gastric cancer cells. Isoform 3: Ubiquitously expressed, and specifically in CD34(+) hematopoietic progenitor cells but not in more differentiated cells.
Interacts (via Piwi domain) with DICER1, suggesting that it forms ribonucleoprotein RISC complexes; this interaction is regulated by HSP90AB1 activity. Interacts with MAEL, KIF17, PABPC1, PRMT5 and WDR77. Interacts (when methylated on arginine residues) with TDRD1, TDRKH/TDRD2, RNF17/TDRD4, TDRD6, TDRD7 and TDRD9. Interacts with CLOCK. Interacts with MOV10L1. Interacts with ANAPC10; interaction oly takes place following piRNA-binding. Interacts with RNF8; leading to sequester RNF8 in the cytoplasm. Interacts with TEX19 (By similarity).
May be a negative developmental regulator (PubMed:12037681, PubMed:16287078).
The D-box (destruction box) acts as a recognition signal for association with the APC/C complex, ubiquitination and degradation.
The PAZ domain specifically recognizes binds the 2'-O-methylated 3'-end of piRNAs (PubMed:21193640, PubMed:21465557). The MID region is required for recognition of uridine in the first position of piRNAs (g1U preference, also named 1U-bias) (By similarity).
Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) in late spermatids, leading to its degradation (PubMed:28552346). Ubiquitination only takes place following piRNA-binding in adult testis (By similarity). Ubiquitination and degradation in late spermatogenesis by APC/C is probably required to release RNF8 from the cytoplasm and promote histone to protamine exchange by RNF8 (By similarity).
Belongs to the JHDM3 histone demethylase family.
Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27', H3 'Lys-36' nor H4 'Lys-20'. Only able to demethylate trimethylated H3 'Lys-9', with a weaker activity than KDM4A, KDM4C and KDM4D. Demethylation of Lys residue generates formaldehyde and succinate (PubMed:16603238, PubMed:28262558). Plays a critical role in the development of the central nervous system (CNS).
The 2 Tudor domains recognize and bind methylated histones. Double Tudor domain has an interdigitated structure and the unusual fold is required for its ability to bind methylated histone tails (By similarity).
May be a substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. Probably mediates ubiquitination and subsequent proteasomal degradation of DAPK1, thereby antagonizing anti-apoptotic effects of DAPK1 to promote TNF-induced apoptosis (By similarity). Involved in ubiquitination of centriolar satellite CEP131, CEP290 and PCM1 proteins and hence inhibits primary cilium formation in proliferating cells. Mediates 'Lys-63'-linked polyubiquitination of TBK1, which probably participates in kinase activation.
In epilepsy brain tissue, levels of expression are increased in the cytoplasm and microsomal fractions (endoplasmic reticulum).
Ubiquitinated; possibly via autoubiquitination (By similarity). Ubiquitinated; this modification is inhibited in response to cellular stress, such as ultraviolet light (UV) radiation or heat shock.
Widely expressed at low level. Expressed at higher level in spinal cord, ovary, whole brain, and all specific brain regions examined.
Belongs to the universal ribosomal protein uL30 family.
Activity is inhibited by D-1MT (1-methyl-D-tryptophan) and MTH-trp (methylthiohydantoin-DL-tryptophan) but not L-1MT (1-methyl-L-tryptophan).
Belongs to the indoleamine 2,3-dioxygenase family.
Catalyzes the first and rate limiting step of the catabolism of the essential amino acid tryptophan along the kynurenine pathway (PubMed:17671174). Involved in immune regulation. May not play a significant role in tryptophan-related tumoral resistance (PubMed:25691885).
Detected in liver, small intestine, spleen, placenta, thymus, lung, brain, kidney, and colon (PubMed:17671174). Also expressed at low level in testis and thyroid. Not expressed in the majority of human tumor samples (>99%) (PubMed:25691885).
IDO1 and IDO2 are 2 distinct enzymes which catalyze the same reaction. IDO2 affinity for tryptophan is much lower than that of IDO1. 50 % of Caucasians harbor polymorphisms which abolish IDO2 enzymatic activity. IDO2 is expressed in human tumors in an inactive form: tryptophan degradation is entirely provided by IDO1 in these cells (PubMed:18418598). IDO2 may play a role as a negative regulator of IDO1 by competing for heme-binding with IDO1 (PubMed:25394548). Low efficiency IDO2 enzymes have been conserved throughout vertebrate evolution, whereas higher efficiency IDO1 enzymes are dispensable in many lower vertebrate lineages (PubMed:25950090). IDO1 may have arisen by gene duplication of a more ancient proto-IDO gene before the divergence of marsupial and eutherian (placental) mammals.
The variant Trp-248 (p.R248W) drastically reduces the enzymatic activity (PubMed:17671174, PubMed:18418598). The Del359-420 variant (p.Y359X) generates a truncated, enzymatically inactive protein (PubMed:17671174). The high prevalence of these polymorphic alleles results in a non-functional IDO2 enzyme in up to 50% of Caucasians (PubMed:18418598).
Contains a C-terminal domain similar to that of the C-terminal section of MAP3K7.
Detected in lung and peripheral blood leukocytes. Expressed predominantly in peripheral blood leukocytes and ubiquitously in adult and fetal tissues. Also expressed strongly in breast carcinoma GI-101, colon adenocarcinoma GI-112, and prostatic adenocarcinoma PC3.
Expressed in brain, kidney, testis, liver and placenta with moderate expression in all other tissues. Detected on a majority of B-cells, T-cells, and natural killer cells but not on monocytes, polynuclear cells and platelets.
Interacts directly with CD82, CD81/tetraspanin-28 and CD9/tetraspanin-29. Also interacts with integrin alpha-3/beta-1 and integrin alpha-4/beta-1.
May play a key role in diverse functions ascribed to CD81 and CD9 such as oocytes fertilization or hepatitis C virus function. May regulate proliferation and differentiation of keratinocytes. May be a negative regulator of cell motility: suppresses T-cell mobility coordinately with CD81, associates with CD82 to suppress prostate cancer cell migration, regulates epidermoid cell reaggregation and motility on laminin-5 with CD9 and CD81 as key linkers. May also play a role on integrin-dependent morphology and motility functions. May participate in the regulation of neurite outgrowth and maintenance of the neural network in the adult brain.
The Ig-like C2-type domains 3 and 4 are required for interaction with CD81.
The short cytoplasmic domain is very basic, interacts with membrane PIPs, and mediates plasma membrane localization.
Downstream effector of Rap required for cell adhesion and migration of neural crest precursors during development.
Interacts with RAP1A; in a GTP-dependent manner. Does not interact with members of the Ras family (PubMed:17704304). Interacts (via PDZ domain) with KIF14; is recruited to the microtubule network restricting its interaction with activated RAP1A (PubMed:23209302).
Highly expressed in most normal human tissues, with an exception of in testis, small intestine, colon and peripheral blood leukocyte.
Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Up-regulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:22517918, PubMed:16829952, PubMed:23396208). Induces insulin resistance in adipocytes via inhibition of insulin-induced IRS1 tyrosine phosphorylation and insulin-induced glucose uptake. Induces GKAP42 protein degradation in adipocytes which is partially responsible for TNF-induced insulin resistance (By similarity). Plays a role in angiogenesis by inducing VEGF production synergistically with IL1B and IL6 (PubMed:12794819). Promotes osteoclastogenesis and therefore mediates bone resorption (By similarity).
Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Induces insulin resistance in adipocytes via inhibition of insulin-induced IRS1 tyrosine phosphorylation and insulin-induced glucose uptake. Induces GKAP42 protein degradation in adipocytes which is partially responsible for TNF-induced insulin resistance. Plays a role in angiogenesis by inducing VEGF production synergistically with IL1B and IL6.
Genetic variations in TNF are involved in susceptibility to malaria [MIM:611162].
Genetic variations in TNF influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424].
O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid.
The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.
The membrane form, but not the soluble form, is phosphorylated on serine residues. Dephosphorylation of the membrane form occurs by binding to soluble TNFRSF1A/TNFR1.
The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form is further proteolytically processed by SPPL2A or SPPL2B through regulated intramembrane proteolysis producing TNF intracellular domains (ICD1 and ICD2) released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into the extracellular space.
The soluble form is demyristoylated at Lys-19 and Lys-20 by SIRT6, promoting its secretion.
A chromosomal aberration involving LMO2 may be a cause of a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(11,14)(p13;q11) with TCRD.
Acts with TAL1/SCL to regulate red blood cell development. Also acts with LDB1 to maintain erythroid precursors in an immature state.
Interacts via its LIM domains with ELF2 and LDB1. Also interacts with basic helix-loop-helix protein TAL1/SCL and can assemble in a complex with LMO2 and TAL1/SCL (By similarity). Interacts with BEX2 and KDM5A.
The second LIM zinc-binding domain interacts with KDM5A.
Down-regulated in CD40-activated monocyte-derived dendritic cells.
Expressed in plasmacytoid dendritic cells (PDC), monocyte-derived dendritic cells (MDDC), granulocytes, monocytes, B-lymphocytes, peripheral blood leukocytes, spleen, bone marrow, and, to a lesser extent, lymph nodes, fetal liver, and appendix but not in thymus.
Interacts with RIGI (PubMed:29288164). Interacts with SQSTM1 (PubMed:29288164). Interacts with p65/RELA; this interaction promotes the degradation of RELA through autophagy (PubMed:29044191).
Plays a role in the inhibition of RLR-mediated type I interferon signaling pathway by targeting RIGI for autophagic degradation. Interacts specifically with ISG15-associated RIGI to promote interaction between RIGI and the autophagic cargo receptor p62/SQSTM1 to mediate RIGI degradation via selective autophagy (PubMed:29288164). Also plays a role in the inhibition of NF-kappa-B signaling pathway and inflammatory response by promoting the degradation of p65/RELA.
May be involved in 20S pre-rRNA processing.
(Microbial infection) Involved in Vpr-dependent replication of HIV-1 in non-proliferating cells and primary macrophages. Required for the association of HIV-1 Vpr with the host proteasome.
Interacts with XPC; the interaction is suggesting the existence of a functional equivalent variant XPC complex. Interacts with PSMD4 and PSMC5. Interacts with ATXN3 (PubMed:30455355). Interacts with UBQLN2.
Involved in nucleotide excision repair and is thought to be functional equivalent for RAD23B in global genome nucleotide excision repair (GG-NER) by association with XPC. In vitro, the XPC:RAD23A dimer has NER activity. Can stabilize XPC.
Multiubiquitin chain receptor involved in modulation of proteasomal degradation. Binds to 'Lys-48'-linked polyubiquitin chains in a length-dependent manner and with a lower affinity to 'Lys-63'-linked polyubiquitin chains. Proposed to be capable to bind simultaneously to the 26S proteasome and to polyubiquitinated substrates and to deliver ubiquitinated proteins to the proteasome.
Multiubiquitin chain receptor involved in modulation of proteasomal degradation. Involved in nucleotide excision repair.
The ubiquitin-like (UBL) and the UBA (ubiquitin-associated) domains interact intramolecularly in a highly dynamic manner, as each UBA domain competes for an overlapping UBL domain surface. Binding of ubiquitin or proteasome subunit PSMD4 disrupt the UBL-UBA domain interactions and drive RAD23A in to an open conformation.
The ubiquitin-like domain mediates interaction with ATXN3.
Abundant in heart and present at low levels in many other tissues.
Belongs to the protease inhibitor I35 (TIMP) family.
Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. Known to act on MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9.
Expressed in acute lymphoblastic leukemia B-cells and Epstein-Barr virus-transformed B-cells.
HB-1 forms a complex with MHC class I HLA-B44.
Precursor of the histocomplatibility antigen HB-1. More generally, minor histocomplatibility antigens (mHags) refer to immunogenic peptide which, when complexed with MHC, can generate an immune response after recognition by specific T-cells. The peptides are derived from polymorphic intracellular proteins, which are cleaved by normal pathways of antigen processing. The binding of these peptides to MHC class I or class II molecules and its expression on the cell surface can stimulate T-cell responses and thereby trigger graft rejection or graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation from HLA-identical sibling donor. GVHD is a frequent complication after bone marrow transplantation (BMT), due to mismatch of minor histocomplatibility antigen in HLA-matched sibling marrow transplants. HB-1 is presented on the cell surface by MHC class I HLA-B44. This complex specifically elicits donor-cytotoxic T lymphocyte (CTL) reactivity in B-cell acute lymphoblastic leukemia (B-ALL) after treatment by HLA-identical allogenic bone marrow transplantation (BMT). It induces cell recognition and lysis by CTL. However, HB-1 restricted expression in B-ALL cells and not in normal tissues may allow a specific CTL reactivity against B-ALL without the risk of evoking graft-versus-host disease.
PubMed:9892612 postulated that the initiator methionine is coded by a non-canonical CTG leucine codon.
This sequence containing mHag HB-1 may not represent the full-length protein, because functional domains are absent in this short gene product.
During fetal neocortex development, may be essential to maintain the full number of basal radial glia (bRG). bRG are neural progenitor cells that undergo asymmetric divisions, generating a bRG (self-renewal) and a neuron, in contrast to basal intermediate progenitors (bIPs), which typically divide once to give rise to 2 neurons. bRG generate more cortical neurons over time than bIPs.
Expressed in fetal neocortex, with highest expression in the developing frontal lobe. Expression increases with development from 9 to at least 17 postconception weeks (PCW). At 11 PCW, expression in frontal lobe is detectable in the ventricular zone and subventricular zone. At PCW 17, highly expressed in the frontal lobe of fetal neocortex, but not in the occipital lobe.
Variant Lys-317 is typically present in extinct archaic humans, Neanderthals and Denisovans, as well as in other primates. It is rare in modern human population with a frequency of 0.03%. No homozygote is reported in the Genome Aggregation Database (gnomAD v2.1.1). The modern human variant Arg-317 is thought to lead to a greater neocortical neurogenesis compared to archaic human Lys-317, in particular in the frontal lobe. It is currently unknown if the presence of variant Lys-317 in modern humans is associated with a disease or has any effect on cognitive skills.
Widely expressed (PubMed:8838793). Expressed in endothelial cells and in peripheral neurons (at protein level) (PubMed:15991799).
Inhibited by vanadate and zinc, and slightly by calcium.
Magnesium-dependent phosphatase which may act as a tyrosine phosphatase.
Probable retinal pigment epithelium (RPE)-specific proton-coupled L-lactate transporter (By similarity). May facilitate transport of lactate and H(+) out of the retina and could therefore play a role in pH and ion homeostasis of the outer retina (By similarity).
The two basolateral sorting signals (BSS) are required to direct SLC16A8 to the basolateral membrane.
Binds APS. Identified in a complex with ELOB and ELOC (By similarity). Interacts with CUL5 and RNF7.
Probable substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
Peptide Lv enhances L-type voltage-gated calcium channel (L-VGCC) currents in retinal photoreceptors.
Proteolytically cleaved to generate a bioactive peptide.
Belongs to the galactose-3-O-sulfotransferase family.
Catalyzes the transfer of sulfate to beta-1,3-linked galactose residues in O-linked glycoproteins. Good substrates include asialofetuin, Gal-beta-1,3-GalNAc and Gal-beta-1,3 (GlcNAc-beta-1,6)GalNAc.
Expressed mainly in placenta, thymus, testis, ovary, spinal cord, trachea and adrenal gland and at low levels in brain, lung, spleen, prostate, small intestine, colon, stomach thyroid and lymph node.
Acts in concert with MON1A, as a guanine exchange factor (GEF) for RAB7, promotes the exchange of GDP to GTP, converting it from an inactive GDP-bound form into an active GTP-bound form (PubMed:23084991).
Interacts with MON1A (PubMed:23084991). Found in a complex with RMC1, CCZ1, MON1A and MON1B (PubMed:29038162).
The MON1A-CCZ1B complex interacts with RIMOC1 (PubMed:34432599). The MON1A-CCZ1B complex interacts with RAB7A and this interaction is enhanced in the presence of RIMOC1 (PubMed:34432599).
Acts as an inhibitor of BTK tyrosine kinase activity, thereby playing a role in B-cell development. Down-regulates BTK kinase activity, leading to interference with BTK-mediated calcium mobilization and NF-kappa-B-driven transcription.
Expressed in DeFew, HEK293T, HeLa and in Jurkat, MC3 and NB4 lymphoid cells (at protein level). Isoform 1 is the predominant isoform expressed in all examined tissues and cell lines. Highly expressed in hemopoietic tissues (fetal liver, spleen, lymph node, thymus, peripheral blood leukocytes and bone marrow). Weakly or not expressed in other tissues.
Interacts with the PH domain of BTK. Isoform 2 does not interact with BTK.
Dynein heavy chains probably consist of an N-terminal stem (which binds cargo and interacts with other dynein components), and the head or motor domain. The motor contains six tandemly-linked AAA domains in the head, which form a ring. A stalk-like structure (formed by two of the coiled coil domains) protrudes between AAA 4 and AAA 5 and terminates in a microtubule-binding site. A seventh domain may also contribute to this ring; it is not clear whether the N-terminus or the C-terminus forms this extra domain. There are four well-conserved and two non-conserved ATPase sites, one per AAA domain. Probably only one of these (within AAA 1) actually hydrolyzes ATP, the others may serve a regulatory function.
Expressed in spermatozoa (at protein level). Not detected in airway epithelial cells (at protein level).
Expression is detected in the germ cells from the early spermatocyte to late spermatid stages but not in the somatic cells (Leydig, Sertoli cells).
Force generating protein component of the outer dynein arms (ODAs) in the sperm flagellum. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Involved in sperm motility; implicated in sperm flagellar assembly.
Induced by the interleukin IL1B (PubMed:10377395, PubMed:10760517). Induced By p53/TP53 (PubMed:9305847).
Terminal enzyme of the cyclooxygenase (COX)-2-mediated prostaglandin E2 (PGE2) biosynthetic pathway. Catalyzes the glutathione-dependent oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2) in response to inflammatory stimuli (PubMed:18682561, PubMed:10377395, PubMed:12672824, PubMed:12460774, PubMed:10869354, PubMed:12244105). Plays a key role in inflammation response, fever and pain (By similarity). Catalyzes also the oxidoreduction of endocannabinoids into prostaglandin glycerol esters and PGG2 into 15-hydroperoxy-PGE2 (PubMed:12244105, PubMed:12672824). In addition, displays low glutathione transferase and glutathione-dependent peroxidase activities, toward 1-chloro-2,4-dinitrobenzene and 5-hydroperoxyicosatetraenoic acid (5-HPETE), respectively (PubMed:12672824).
Expressed in ES cells, primitive neuroectoderm, fetal brain, infant brain, adult neural tissues and prostate.
May play a role in the interactions between neurites derived from specific subsets of neurons during development.
May contribute to the regulation of sleep duration. An intronic variant of this gene may account for about 5% of the variation of sleep duration between individuals (PubMed:22105623). Sleep duration is influenced both by environmental and genetic factors, with an estimated heritability of about 40%. Numerous genes are expected to contribute to the regulation of sleep duration.
Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with KCNJ11. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation.
Inhibited by propranolol (PubMed:18930839). Not inhibited by N-ethylmaleimide or bromoenolactome (PubMed:18930839).
Magnesium-independent polyisoprenoid diphosphatase that catalyzes the sequential dephosphorylation of presqualene, farnesyl, geranyl and geranylgeranyl diphosphates (PubMed:16464866, PubMed:19220020, PubMed:20110354). Functions in the innate immune response through the dephosphorylation of presqualene diphosphate which acts as a potent inhibitor of the signaling pathways contributing to polymorphonuclear neutrophils activation (PubMed:16464866, PubMed:23568778). May regulate the biosynthesis of cholesterol and related sterols by dephosphorylating presqualene and farnesyl diphosphate, two key intermediates in this biosynthetic pathway (PubMed:20110354). May also play a role in protein prenylation by acting on farnesyl diphosphate and its derivative geranylgeranyl diphosphate, two precursors for the addition of isoprenoid anchors to membrane proteins (PubMed:20110354). Has a lower activity towards phosphatidic acid (PA), but through phosphatidic acid dephosphorylation may participate in the biosynthesis of phospholipids and triacylglycerols (PubMed:18930839). May also act on ceramide-1-P, lysophosphatidic acid (LPA) and sphing-4-enine 1-phosphate/sphingosine-1-phosphate (PubMed:18930839, PubMed:20110354).
Phosphorylation by PKC activates the phosphatase activity towards presqualene diphosphate.
Widely expressed. Expressed in most organs, in particular gastrointestinal organs, spleen, placenta, kidney, thymus and brain.
A chromosomal aberration involving KDSR is a cause of follicular lymphoma; also known as type II chronic lymphatic leukemia. Translocation t(2;18)(p11;q21) with a Ig J kappa chain region (PubMed:8417785).
Catalyzes the reduction of 3-ketodihydrosphingosine (KDS) to dihydrosphingosine (DHS).
Expressed in all tissues examined. Highest expression in placenta. High expression in lung, kidney, stomach and small intestine, low expression in heart, spleen and skeletal muscle. Weakly expressed in normal hematopoietic tissues. Higher expression in some T-cell malignancies and PHA-stimulated lymphocytes.
Expressed in many brain regions, including cerebellum, thalamus and occipital, parietal and temporal lobes (at protein level). Also expressed in the spinal cord (at protein level).
The disease is caused by variants affecting the gene represented in this entry. A disease-causing mutation has been reported that affects an intronic splice donor site and causes exon 9 skipping, this leads to an out-of-frame stop codon after 60 aberrant amino acids. Patients carrying this mutation exhibit much lower mRNA and protein levels compared to unaffected controls, probably due to mRNA nonsense-mediated decay (PubMed:25361784).
Interacts with FLT3 cytoplasmic catalytic domain, following receptor stimulation, in a kinase-independent manner. Does not interact with other structurally related receptor tyrosine kinases, including KIT, CSF1R and PDGFR. Interacts with NRL (By similarity).
May be a transcriptional repressor of NRL function in photoreceptors. Does not repress CRX-mediated transactivation (By similarity).
Exhibits arylsulfatase activity towards the artificial substrate 4-methylumbelliferyl sulfate.
Autoantigen found in infectious mononucleosis caused by Epstein-Barr virus. An epitope recognized by B-cells, which cross-react with the BKRF1 protein (EBNA-1 nuclear protein) of Epstein-Barr virus has been identified.
Expressed in heart, brain, lung, liver, skeletal muscle, kidney and pancreas. Weakly expressed in placenta.
Identified in the spliceosome C complex (PubMed:11991638). Interacts (through its RNA-binding domain) with FUS (through its RNA-binding domain); both are components of the same RNPs (PubMed:30354839).
RNA-binding protein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the liver. Binds the lipid-responsive non-coding RNA LeXis and is required for LeXis-mediated effect on cholesterogenesis (By similarity). May be a heterogeneous nuclear ribonucleoprotein (hnRNP) (PubMed:9376072).
Component of the cleavage and polyadenylation specificity factor (CPSF) complex that plays a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. This subunit is involved in the RNA recognition step of the polyadenylation reaction (PubMed:14749727). May play a role in eye morphogenesis and the development of retinal ganglion cell projections to the midbrain (By similarity).
Component of the cleavage and polyadenylation specificity factor (CPSF) complex, composed of CPSF1, CPSF2, CPSF3, CPSF4 and FIP1L1. Found in a complex with CPSF1, FIP1L1 and PAPOLA. Interacts with FIP1L1, TENT2/GLD2 and SRRM1. Interacts with TUT1; the interaction is direct and mediates the recruitment of the CPSF complex on the 3'UTR of selected pre-mRNAs.
Widely expressed, with high expression in the retina.
Expressed in umbilical vein endothelial cells, epithelial cells, and fibroblasts cells (at protein level). Highly expressed in thyroid, kidney and placenta. Low expression in heart, skeletal muscle, spleen, liver, and lung. Expressed at higher levels in tonsil-derived mesenchymal stem cells (MSCs) than in adipose tissue-derived MSCs or bone marrow-derived MSCs (PubMed:31905841). Expressed in tumor endothelial cells. Expression seems to be down-regulated in thyroid tumor tissues and in anaplastic carcinomas.
Interacts with EGFR; EGF promotes the interaction with EGFR (PubMed:15140944). Interacts with PTK2/FAK1 and BCAR1 (PubMed:15140944). Tyrosine phosphorylation is critical for these interactions (PubMed:15140944). Interacts with Rho GTPase-activating protein DLC1 and with the regulatory p85 subunit of the PI3K kinase complex; in resting cells, interacts (via C2 tensin-type domain) with DLC1 but, following growth factor stimulation, TNS3 is phosphorylated which leads to weakened interaction with DLC1 and enhanced interaction (via C2 tensin-type domain) with p85 while DLC1 interaction with PTEN increases (PubMed:26166433). Interacts (when phosphorylated on the SH2 domain) with integrins ITGB1, ITGB3 and ITGB5 and with scaffolding protein PEAK1 (phosphorylated on 'Tyr-635'); mediates the association of PEAK1 with ITGB1, ITGB3 and ITGB5 (PubMed:35687021). Interacts (via N-terminus) with DOCK5 (via N-terminus); the interaction increases DOCK5 guanine nucleotide exchange activity towards Rac (By similarity). Interacts with receptor tyrosine kinase MET (PubMed:24814316).
May act as a protein phosphatase and/or a lipid phosphatase (Probable). Involved in the dissociation of the integrin-tensin-actin complex (PubMed:17643115). EGF activates TNS4 and down-regulates TNS3 which results in capping the tail of ITGB1 (PubMed:17643115). Increases DOCK5 guanine nucleotide exchange activity towards Rac and plays a role in osteoclast podosome organization (By similarity). Enhances RHOA activation in the presence of DLC1 (PubMed:26427649). Required for growth factor-induced epithelial cell migration; growth factor stimulation induces TNS3 phosphorylation which changes its binding preference from DLC1 to the p85 regulatory subunit of the PI3K kinase complex, displacing PI3K inhibitor PTEN and resulting in translocation of the TNS3-p85 complex to the leading edge of migrating cells to promote RAC1 activation (PubMed:26166433). Meanwhile, PTEN switches binding preference from p85 to DLC1 and the PTEN-DLC1 complex translocates to the posterior of migrating cells to activate RHOA (PubMed:26166433). Acts as an adapter protein by bridging the association of scaffolding protein PEAK1 with integrins ITGB1, ITGB3 and ITGB5 which contributes to the promotion of cell migration (PubMed:35687021). Controls tonsil-derived mesenchymal stem cell proliferation and differentiation by regulating the activity of integrin ITGB1 (PubMed:31905841).
Phosphorylated on Ser/Thr and Tyr residues (PubMed:26166433). Phosphorylated on Thr-323 in the C2-type tensin domain following EGF stimulation which changes its binding preference from DLC1 to the p85 regulatory subunit of the PI3K kinase complex (PubMed:26166433). EGF induces tyrosine phosphorylation in a time- and dose-dependent manner (PubMed:15140944). Phosphorylation of the SH2 domain enhances interaction with PEAK1 (PubMed:35687021).
Controls cell proliferation in a tissue-specific manner and is involved in morphogenesis. During embryonic development, exerts a role in the expansion of muscle progenitors. May play a role in the proper localization of asymmetric organs such as the heart and stomach. Isoform PTX2C is involved in left-right asymmetry the developing embryo (By similarity).
Phosphorylation at Thr-90 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1.
Interacts with high affinity with GDF5; positively regulates chondrocyte differentiation (PubMed:24098149). Interacts with SCUBE3 (PubMed:33308444). Interacts with TSC22D1/TSC-22 (PubMed:21791611).
On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP7/OP-1 and GDF5. Positively regulates chondrocyte differentiation through GDF5 interaction.
Functions in exocytosis in pancreatic acinar cells regulating the fusion of zymogen granules with each other. May have a pore-forming activity on membranes and regulate exocytosis in other exocrine tissues (By similarity).
Monomer and homooligomer; most probably hexameric. Interacts with GP2 (By similarity).
Expressed in cartilage, spleen, intestine, lung, and to a lesser extent in heart, brain, liver, muscle and stomach.
Homodimer. Heterodimer with BHLHE41/DEC2. Interacts with TCF3/E47. Interacts with ubiquitin-conjugating enzyme UBE2I/UBC9. Interacts with HDAC1, SUMO1, RXRA and BMAL1.
Sumoylation inhibits its ubiquitination and promotes its negative regulation of the CLOCK-BMAL1 heterodimer transcriptional activator activity.
Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes (PubMed:12397359, PubMed:18411297). Acts as the negative limb of a novel autoregulatory feedback loop (DEC loop) which differs from the one formed by the PER and CRY transcriptional repressors (PER/CRY loop) (PubMed:14672706). Both these loops are interlocked as it represses the expression of PER1/2 and in turn is repressed by PER1/2 and CRY1/2 (PubMed:15193144). Represses the activity of the circadian transcriptional activator: CLOCK-BMAL1|BMAL2 heterodimer by competing for the binding to E-box elements (5'-CACGTG-3') found within the promoters of its target genes (PubMed:15560782). Negatively regulates its own expression and the expression of DBP and BHLHE41/DEC2 (PubMed:14672706). Acts as a corepressor of RXR and the RXR-LXR heterodimers and represses the ligand-induced RXRA and NR1H3/LXRA transactivation activity (PubMed:19786558). May be involved in the regulation of chondrocyte differentiation via the cAMP pathway (PubMed:19786558). Represses the transcription of NR0B2 and attentuates the transactivation of NR0B2 by the CLOCK-BMAL1 complex (PubMed:28797635). Drives the circadian rhythm of blood pressure through transcriptional repression of ATP1B1 in the cardiovascular system (PubMed:30012868).
Ubiquitinated; which may lead to proteasomal degradation.
Associates with TRAF1, TRAF2, TRAF3 and TRAF5. Interacts with LINGO1.
Can mediate activation of JNK and NF-kappa-B. May promote caspase-independent cell death.
Highly expressed in prostate. Detected at lower levels in thymus, spleen, testis, uterus, small intestine, colon and peripheral blood leukocytes.
Genetic variations in ALOX5AP may be associated with susceptibility to myocardial infarction. Involvement in myocardial infarction is however unclear: according to some authors (PubMed:14770184), a 4-SNP haplotype in ALOX5AP confers risk of myocardial infarction, while according to other (PubMed:17304054) ALOX5AP is not implicated in this condition.
Homotrimer. Interacts with LTC4S and ALOX5.
Required for leukotriene biosynthesis by ALOX5 (5-lipoxygenase). Anchors ALOX5 to the membrane. Binds arachidonic acid, and could play an essential role in the transfer of arachidonic acid to ALOX5. Binds to MK-886, a compound that blocks the biosynthesis of leukotrienes.
The C-terminal part after residue 140 is mostly unstructured.
Guanyl-nucleotide exchange factor of the RHOG GTPase stimulating the exchange of RHOG-associated GDP for GTP. May play a role in chemotactic cell migration by mediating the activation of RAC1 by EPHA2. May also activate CDC42 and mediate activation of CDC42 by the viral protein HPV16 E6.
Interacts with ELMO2, EPHA2, RAC1 and RHOG; mediates activation of RAC1 by EPHA2. Interacts with TAX1BP3 (via PDZ domain). May interact with CDC42; stimulated by HPV16 E6.
The PDZ-binding motif mediates interaction with TAX1BP3.
Up-regulated by HPV16 E6 (at protein level).
Belongs to the bombesin/neuromedin-B/ranatensin family.
Induces an itch response through activation of receptors present on mast cells, triggering mast cell degranulation.
Stimulates the release of gastrin and other gastrointestinal hormones (By similarity). Contributes to the perception of prurient stimuli and to the transmission of itch signals in the spinal cord that promote scratching behavior (By similarity). Contributes primarily to nonhistaminergic itch sensation (By similarity). In one study, shown to act in the amygdala as part of an inhibitory network which inhibits memory specifically related to learned fear (By similarity). In another study, shown to act on vasoactive intestinal peptide (VIP)-expressing cells in the auditory cortex, most likely via extrasynaptic diffusion from local and long-range sources, to mediate disinhibition of glutamatergic cells via VIP cell-specific GRPR signaling which leads to enhanced auditory fear memories (By similarity). Contributes to the regulation of food intake (By similarity). Inhibits voltage-gated sodium channels but enhances voltage-gated potassium channels in hippocampal neurons (By similarity). Induces sighing by acting directly on the pre-Botzinger complex, a cluster of several thousand neurons in the ventrolateral medulla responsible for inspiration during respiratory activity (By similarity).
Enzyme with a broad specificity. Dephosphorylates CDK2 and CDK6 in vitro. Dephosphorylates PRKAA1 and PRKAA2. Inhibits TBK1-mediated antiviral signaling by dephosphorylating it at 'Ser-172'. Plays an important role in the termination of TNF-alpha-mediated NF-kappa-B activation through dephosphorylating and inactivating IKBKB/IKKB.
Isgylation negatively regulates its activity.
Monomer (By similarity). Interacts with PAK6. Interacts with the phosphorylated form of IKBKB/IKKB.
Enhances the promotion of guanine-nucleotide exchange by PSCD2 on ARF6 in a concentration-dependent manner.
Interacts with guanine-nucleotide exchange factors PSCD1, PSCD2, PSCD3 and PSCD4 (By similarity). Interacts (via C-terminus) with cytohesin-2 CYTH2 (PubMed:22085542).
Detected in fibroblasts (at protein level) (PubMed:23959653). Detected in spleen, prostate, testis, ovary, colon, pancreas, kidney, placenta and heart (PubMed:10952778).
Interacts with PLOD1, P3H3 and PPIB. Identified in a complex with PLOD1 and P3H3.
Part of a complex composed of PLOD1, P3H3 and P3H4 that catalyzes hydroxylation of lysine residues in collagen alpha chains and is required for normal assembly and cross-linking of collagen fibrils. Required for normal bone density and normal skin stability via its role in hydroxylation of lysine residues in collagen alpha chains and in collagen fibril assembly.
Was originally identified in the nucleolus (PubMed:8862517). A recent publication found it only in the endoplasmic reticulum, which agrees with its biological function and the predicted signal sequence (PubMed:23959653).
Testis-specific (PubMed:17091336, PubMed:26168773). Detected in the germ cell lineage at all stages (PubMed:26168773).
Expressed in a wide array of tissues, highest expression is found in liver followed by brain, lung, heart, and retina. A lower level is found in breast tumor when compared with normal tissues; lowest levels were found in patients with poor prognostic index.
Involved in the biosynthesis of highly unsaturated fatty acids (HUFA) from the essential polyunsaturated fatty acids (PUFA) linoleic acid (LA) (18:2n-6) and alpha-linolenic acid (ALA) (18:3n-3) precursors, acting as a fatty acyl-coenzyme A (CoA) desaturase that introduces a cis double bond at carbon 6 of the fatty acyl chain. Catalyzes the first and rate limiting step in this pathway which is the desaturation of LA (18:2n-6) and ALA (18:3n-3) into gamma-linoleate (GLA) (18:3n-6) and stearidonate (18:4n-3), respectively (PubMed:12713571). Subsequently, in the biosynthetic pathway of HUFA n-3 series, it desaturates tetracosapentaenoate (24:5n-3) to tetracosahexaenoate (24:6n-3), which is then converted to docosahexaenoate (DHA)(22:6n-3), an important lipid for nervous system function (By similarity). Desaturates hexadecanate (palmitate) to produce 6Z-hexadecenoate (sapienate), a fatty acid unique to humans and major component of human sebum, that has been implicated in the development of acne and may have potent antibacterial activity (PubMed:12713571). It can also desaturate (11E)-octadecenoate (trans-vaccenoate, the predominant trans fatty acid in human milk) at carbon 6 generating (6Z,11E)-octadecadienoate (By similarity). In addition to Delta-6 activity, this enzyme exhibits Delta-8 activity with slight biases toward n-3 fatty acyl-CoA substrates (By similarity).
Repressed by dietary highly unsaturated fatty acids.
The protein sequence includes a number of characteristic features of microsomal fatty acid desaturases including the three histidine boxes HXXXH, HXXHH, and QXXHH (these domains may contain the active site and/or be involved in metal ion binding), and the N-terminal cytochrome b5 domain containing the heme-binding motif, HPGG, similar to that of other fatty acid desaturases.
E3 ubiquitin-protein ligase involved in DNA repair. Upon genotoxic stress, accepts ubiquitin from the UBE2N-UBE2V2 E2 complex and transfers it to 'Lys-164' of PCNA which had been monoubiquitinated by UBE2A/B-RAD18, promoting the formation of non-canonical poly-ubiquitin chains linked through 'Lys-63'.
Homodimer. Interacts with HLTF, PCNA, UBE2N and RAD18.
The RING finger mediates E3 ubiquitin ligase activity.
Binds cholesterol and may regulate the distribution and homeostasis of cholesterol in hair cells (PubMed:36317962). May play a role in angiogenesis (PubMed:35727972).
Highly expressed in the auditory hair cells.
Detected in all tissues examined with high expression found in placenta lung and kidney and low expression, in liver, pancreas and skeletal muscle.
Exists as both a monomer and homodimer (By similarity). Component of a PRC1-like complex (PubMed:19636380, PubMed:21282530, PubMed:26151332). Interacts with CBX8, RING1 and RNF2 (PubMed:19636380). Interacts with CBX7 (By similarity). Interacts with PHC2 (By similarity).
Phosphorylated. Homodimer formation is regulated by phosphorylation with only unphosphorylated proteins forming homodimers.
Transcriptional repressor. Binds specifically to the DNA sequence 5'-GACTNGACT-3'. Has tumor suppressor activity. May play a role in control of cell proliferation and/or neural cell development. Regulates proliferation of early T progenitor cells by maintaining expression of HES1. Also plays a role in antero-posterior specification of the axial skeleton and negative regulation of the self-renewal activity of hematopoietic stem cells (By similarity). Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:26151332). Within the PRC1-like complex, regulates RNF2 ubiquitin ligase activity (PubMed:26151332).
(Microbial infection) Interacts with herpes simplex virus 1 protein UL12 (PubMed:20943970).
Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:10839544, PubMed:26215093). As part of the MRN complex, interacts with MCM9; the interaction recruits the complex to DNA repair sites (PubMed:26215093). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (PubMed:10783165). Found in a complex with TERF2 (PubMed:10888888). Interacts with DCLRE1C/Artemis and DCLRE1B/Apollo (PubMed:15456891, PubMed:15723659, PubMed:18469862). Interacts with ATF2 (PubMed:15916964). Interacts with EXD2 (PubMed:26807646). Interacts with MRNIP (PubMed:27568553). Interacts with SAMHD1; leading to stimulate 3'-5' exonuclease activity (PubMed:28834754, PubMed:29670289). Interacts (when ubiquitinated) with UBQLN4 (via its UBA domain) (PubMed:30612738). Interacts with CYREN (via XLF motif) (By similarity).
Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11 (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). RAD50 may be required to bind DNA ends and hold them in close proximity (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11 to prevent nucleolytic degradation past a given point (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289, PubMed:30612738). The complex may also be required for DNA damage signaling via activation of the ATM kinase (PubMed:15064416). In telomeres the MRN complex may modulate t-loop formation (PubMed:10888888).
Defects in MRE11 can be a cause of nephronophthisis-related ciliopathies (NPHP-RC), a group of recessive diseases that affect kidney, retina and brain. A homozygous truncating mutation MRE11 has been found in patients with cerebellar vermis hypoplasia, ataxia and dysarthria.
In case of infection by adenovirus E4, the MRN complex is inactivated and degraded by viral oncoproteins, thereby preventing concatenation of viral genomes in infected cells.
Interaction with SAMHD1 stimulates the double-strand-specific 3'-5' exonuclease activity.
Involved in DNA double-strand break repair (DSBR). Possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity. Also involved in meiotic DSB processing.
Ubiquitinated following DNA damage. Ubiquitination triggers interaction with UBQLN4, leading to MRE11 removal from chromatin and degradation by the proteasome.
Regulates UHRF2 function as a specific 5-hydroxymethylcytosine (5hmC) reader by regulating its chromatin localization.
Belongs to the WD repeat RBAP46/RBAP48/MSI1 family.
Binds directly to helix 1 of the histone fold of histone H4, a region that is not accessible when H4 is in chromatin (PubMed:8858152, PubMed:9427644, PubMed:24920672). Subunit of the chromatin assembly factor 1 (CAF-1) complex, which is composed of RBBP4, CHAF1B and CHAF1A (PubMed:8858152). Subunit of the core histone deacetylase (HDAC) complex, which is composed of HDAC1, HDAC2, RBBP4 and RBBP7 (PubMed:9150135). The core HDAC complex associates with SIN3A, ARID4B/SAP180, SAP18, SAP30, SAP130, SUDS3/SAP45 and possibly ARID4A/RBP1 and ING1 to form the SIN3 HDAC complex (PubMed:9150135, PubMed:9651585, PubMed:11118440, PubMed:11784859). Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5 (PubMed:33283408, PubMed:9790534, PubMed:10444591, PubMed:11102443, PubMed:28977666, PubMed:16428440). The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes (PubMed:33283408, PubMed:16428440, PubMed:28977666). The NuRD complex may also interact with MBD3L1 and MBD3L2 (PubMed:15456747, PubMed:15701600). Component of the PRC2 complex, which consists of the core subunits EED, EZH1 or EZH2, SUZ12, and RBBP4, and various combinations of accessory subunits including AEBP2, JARID2, PHF19, MTF2 and EPOP (PubMed:12435631, PubMed:12351676, PubMed:29499137, PubMed:31959557). Forms a monomeric PRC2.2 (class 2) complex consisting of at least SUZ12, RBBP4, AEBP2 and JARID2 (PubMed:29499137). Forms a dimeric PRC2.1 (class 1, PRC-PCL) complex consisting of at least SUZ12, RBBP4, and PHF19; PHF19 stabilizes the dimeric structure which enhances PRC2 interaction with chromatin (PubMed:31959557). Component of the NURF-1 ISWI chromatin remodeling complex (also called the nucleosome-remodeling factor (NURF) complex) at least composed of SMARCA1 (isoform 2), BPTF, RBBP4 and RBBP7 (PubMed:14609955, PubMed:15310751). Within the complex interacts with isoform 2 of SMARCA1 (PubMed:14609955, PubMed:15310751). Component of the BPFT-SMARCA1 complex at least composed of SMARCA1 (isoform 1), BPFT, RBBP4 and RBBP7; the complex is catalytically inactive and does not remodel chromatin (PubMed:15310751). Within the complex interacts with isoform 1 of SMARCA1 (PubMed:15310751). Interacts with the ISWI chromatin remodeling complex component SMARCA5; the interaction is direct (PubMed:12198550). Interacts with the viral protein-binding domain of the retinoblastoma protein (RB1) (PubMed:7503932, PubMed:10734134). Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2 (PubMed:17671431, PubMed:17531812). The complex exists in quiescent cells where it represses cell cycle-dependent genes (PubMed:17671431, PubMed:17531812). It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2 (PubMed:17671431, PubMed:17531812). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (By similarity). Interacts with ZNF827; the interaction is direct and recruits RBBP4 to telomeres (PubMed:30045876). Interacts with MTA1; the interaction is direct and mutually exclusive with binding histone H4 (PubMed:12920132, PubMed:24920672). Interacts with ARMC12 (via ARM domains) (PubMed:30026490). Interacts with BRCA1 (PubMed:10220405). Interacts with CDK2AP1 (PubMed:20523938). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP (PubMed:10866654). Interacts with ERCC6 (PubMed:26030138). Interacts with HDAC7 (By similarity). Interacts with PHF6 (PubMed:24554700). Interacts with PWWP2B (By similarity). Interacts with SPEN/MINT (PubMed:11331609). Interacts with SUV39H1 (By similarity).
Core histone-binding subunit that may target chromatin assembly factors, chromatin remodeling factors and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the chromatin assembly factor 1 (CAF-1) complex, which is required for chromatin assembly following DNA replication and DNA repair; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; the PRC2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex.
Expressed in spleen, lymph node, thymus, bone marrow, and fetal liver, but not in non-lymphoid tissues.
Interacts with FASN; the interaction is direct (By similarity). Interacts with IgM; protecting CD5L from renal excretion and leading to increased CD5L levels in circulating blood (PubMed:8034987, PubMed:24804991).
Not N-glycosylated (PubMed:23236605). Probably not O-glycosylated (PubMed:23236605).
Secreted protein that acts as a key regulator of lipid synthesis: mainly expressed by macrophages in lymphoid and inflamed tissues and regulates mechanisms in inflammatory responses, such as infection or atherosclerosis. Able to inhibit lipid droplet size in adipocytes. Following incorporation into mature adipocytes via CD36-mediated endocytosis, associates with cytosolic FASN, inhibiting fatty acid synthase activity and leading to lipolysis, the degradation of triacylglycerols into glycerol and free fatty acids (FFA). CD5L-induced lipolysis occurs with progression of obesity: participates in obesity-associated inflammation following recruitment of inflammatory macrophages into adipose tissues, a cause of insulin resistance and obesity-related metabolic disease. Regulation of intracellular lipids mediated by CD5L has a direct effect on transcription regulation mediated by nuclear receptors ROR-gamma (RORC). Acts as a key regulator of metabolic switch in T-helper Th17 cells. Regulates the expression of pro-inflammatory genes in Th17 cells by altering the lipid content and limiting synthesis of cholesterol ligand of RORC, the master transcription factor of Th17-cell differentiation. CD5L is mainly present in non-pathogenic Th17 cells, where it decreases the content of polyunsaturated fatty acyls (PUFA), affecting two metabolic proteins MSMO1 and CYP51A1, which synthesize ligands of RORC, limiting RORC activity and expression of pro-inflammatory genes. Participates in obesity-associated autoimmunity via its association with IgM, interfering with the binding of IgM to Fcalpha/mu receptor and enhancing the development of long-lived plasma cells that produce high-affinity IgG autoantibodies (By similarity). Also acts as an inhibitor of apoptosis in macrophages: promotes macrophage survival from the apoptotic effects of oxidized lipids in case of atherosclerosis (PubMed:24295828). Involved in early response to microbial infection against various pathogens by acting as a pattern recognition receptor and by promoting autophagy (PubMed:16030018, PubMed:24223991, PubMed:24583716, PubMed:25713983).
Phosphorylated on Tyr residues after EGF stimulation.
Present in most normal tissues. Higher expression observed in epithelial cells with secretory and excretory functions, as well as in cells chronically exposed to xenobiotics, such as bronchial cells and cells lining the intestine. Overexpressed in many multidrug-resistant cancer cells.
Required for normal vault structure. Vaults are multi-subunit structures that may act as scaffolds for proteins involved in signal transduction. Vaults may also play a role in nucleo-cytoplasmic transport. Down-regulates IFNG-mediated STAT1 signaling and subsequent activation of JAK. Down-regulates SRC activity and signaling through MAP kinases.
The vault ribonucleoprotein particle is a huge (400 A x 670 A) cage structure of 12.9 MDa. It consists of a dimer of half-vaults, with each half-vault comprising 39 identical major vault protein (MVP) chains, PARP4 and one or more vault RNAs (vRNAs). Interacts with TEP1. Interacts with PTEN and activated MAPK1. The phosphorylated protein interacts with the SH2 domains of PTPN11 and SRC. Interacts with APEX1. May interact with ZNF540.
Absent or down-regulated in many advanced cases of ovarian adenocarcinoma, due to hypermethylation and allelic loss. Loss of expression correlates with increased resistance to antineoplastic drugs, such as cisplatin.
Expressed at highest levels in heart, followed by liver and kidney.
Interacts with the TIM23 complex. Directly interacts with PAM16/MAGMAS; this interaction counteracts DNAJC15-dependent stimulation of HSPA9 ATPase activity. Associates with complex I of the mitochondrial electron transfer chain; this interaction may interfere with the formation of supercomplexes that facilitate the transfer of electrons between complexes (By similarity).
Negative regulator of the mitochondrial respiratory chain. Prevents mitochondrial hyperpolarization state and restricts mitochondrial generation of ATP (By similarity). Acts as an import component of the TIM23 translocase complex. Stimulates the ATPase activity of HSPA9.
Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
Expression is significantly down-regulated in hepatocellular carcinoma (HCC) patients.
High expression in heart, brain, placenta, skeletal muscle, prostate and small intestine; moderate in kidney, pancreas, spleen, testis, ovary and colon; low in lung, liver, thymus and leukocyte.
Homodimer (Probable). The cytoplasmic dynein 1 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs); the composition seems to vary in respect to the IC, LIC and LC composition. The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits. The ICs and LICs bind directly to the HC dimer and the LCs assemble on the IC dimer. Interacts with DYNC1I1 and DYNC1I2. Self-associates. Interacts with DYNLRB1.
Homodimer. The cytoplasmic dynein 1 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs); the composition seems to vary in respect to the IC, LIC and LC composition. The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits. The ICs and LICs bind directly to the HC dimer and the LCs assemble on the IC dimer.
Induced by homocysteine and other endoplasmic reticulum stress-inducing reagents. Induced by phorbol ester (TPA)/ionomycin, and stimulation of the T-cell receptor (TCR) complex in T-cells.
Interacts with RPL14, EIF3S7 and PABPC4.
Seems to be involved in regulation of apoptosis. May be involved in detachment-mediated programmed cell death. May mediate apoptosis during neuronal development. May be involved in regulation of anti-apoptotic effects of IGF1. May be involved in translational regulation.
Widely expressed with highest levels in pancreas. Strongly expressed by benign melanocytic nevi, and progressively reduced expressed in primary and metastatic melanomas (at protein level).
May have arisen from retrotransposition of the X-linked UBL4A gene during mammalian evolution.
By IL4/interleukin-4 in dendritic cells.
Positively regulates macroautophagy in primary dendritic cells. Increases autophagic flux, probably by stimulating both autophagosome formation and facilitating tethering with lysosomes. Binds to phosphatidylinositol 3-phosphate (PtdIns3P) through its FYVE-type zinc finger.
The RUN domain and the FYVE-type zinc finger are essential for its function in the positive regulation of macroautophagy.
Glycosylation at Asn-475 is required for catalytic activity.
Higher levels of expression compared to isoform 1 when expressed in HeLa cells. Exhibits similar intracellular GlcNAc-6-O-sulfation activity.
Homodimer; disulfide-linked. Homodimerization is not essential for enzyme activity.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues within keratan-like structures on N-linked glycans and within mucin-associated glycans that can ultimately serve as SELL ligands. SELL ligands are present in high endothelial cells (HEVs) and play a central role in lymphocyte homing at sites of inflammation. Participates in biosynthesis of the SELL ligand sialyl 6-sulfo Lewis X and in lymphocyte homing to Peyer patches. Has no activity toward O-linked sugars. Its substrate specificity may be influenced by its subcellular location. Sulfates GlcNAc residues at terminal, non-reducing ends of oligosaccharide chains.
Widely expressed. Highly expressed in bone marrow, peripheral blood leukocytes, spleen, brain, spinal cord, ovary and placenta. Expressed by high endothelial cells (HEVs) and leukocytes.
Belongs to the distal-less homeobox family.
Expressed in leukemia cells and placenta. Also expressed in kidney and fetal liver.
May play a role in determining the production of hemoglobin S. May act as a repressor. During embryonic development, plays a role in palatogenesis.
Belongs to the universal ribosomal protein uL2 family.
Transcriptional repressor. Plays a role in oligodendrocyte differentiation, together with OLIG2. Mediates Notch signaling-activated formation of oligodendrocyte precursors. Promotes differentiation of adult neural stem progenitor cells (NSPCs) into mature oligodendrocytes and contributes to remyelination following nerve injury.
Belongs to the universal ribosomal protein uL4 family.
Component of the large ribosomal subunit (PubMed:23636399, PubMed:32669547). May bind IPO9 with low affinity (PubMed:11823430). Interacts with RBM3 (By similarity).
A chromosomal aberration involving CHCHD7 is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(6;8)(p21.3-22;q13) with PLAG1.
Component of the oligosaccharyltransferase (OST) complex (PubMed:31831667). OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits (PubMed:26472760, PubMed:27974209, PubMed:31831667). STT3A complex assembly occurs through the formation of 3 subcomplexes. Subcomplex 1 contains RPN1 and TMEM258, subcomplex 2 contains the STT3A-specific subunits STT3A, DC2/OSTC, and KCP2 as well as the core subunit OST4, and subcomplex 3 contains RPN2, DAD1, and OST48. The STT3A complex can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes (By similarity). Interacts with SYNE1 (via KASH domain), SYNE2 (via KASH domain) and SUN1 (PubMed:28716842).
Subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation (PubMed:31831667). N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity (PubMed:26472760, PubMed:27974209). Involved in ER homeostasis in the colonic epithelium (By similarity).
(Microbial infection) Interacts with hepatitis B virus X protein (HBX).
Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Inhibits the transactivation function of HIF-1A under both normoxic and hypoxia-mimicking conditions. The interaction with EMAP2 increases the proteasome-mediated HIF-1A degradation under the hypoxic conditions. Plays a role in hepatitis C virus internal ribosome entry site-mediated translation. Mediates nuclear translocation of the androgen receptor (AR) and thereby enhances androgen-mediated transactivation. Promotes MAVS degradation and thereby negatively regulates MAVS-mediated innate immune response.
Down-regulated by the ribozyme Rz3'X. Up-regulated in colorectal cancer tissues.
Phosphorylation by ABL1 or ABL2 leads to an inhibition of proteasomal activity and cell cycle transition blocks.
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). PSMA7 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (PubMed:16251969). Interacts with HIF1A (PubMed:11389899). Interacts with RAB7A (PubMed:14998988). Interacts with PRKN (PubMed:15987638). Interacts with ABL1 and ABL2 (PubMed:16678104). Interacts with EMAP2 (PubMed:19362550). Interacts with MAVS (PubMed:19734229).
Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4.
Probable core component of the endosomal sorting required for transport complex III (ESCRT-III). ESCRT-III components are thought to multimerize to form a flat lattice on the perimeter membrane of the endosome. Several assembly forms of ESCRT-III may exist that interact and act sequentially. Interacts with CHMP2A. Interacts with VPS4A. Interacts with VPS4B; the interaction is direct.
The acidic C-terminus and the basic N-termminus are thought to render the protein in a closed, soluble and inactive conformation through an autoinhibitory intramolecular interaction. The open and active conformation, which enables membrane binding and oligomerization, is achieved by interaction with other cellular binding partners, probably including other ESCRT components (By similarity).
Widely expressed. Expressed in brain, heart, skeletal muscle, spleen, kidney, liver, small intestine, pancreas, lung, placenta and leukocytes. In brain, it is expressed in cerebellum, cerebral cortex, medulla, spinal chord, occipital lobe, frontal lobe, temporal lobe and putamen.
Chaperone protein which promotes assembly of the 20S proteasome.
Interacts with PSMG3. Associates with alpha subunits of the 20S proteasome.
Cell-cycle regulated, maximal activity in S-phase. Inactivated by phosphorylation at Ser-743, potentially by CHEK1.
Rapidly and transiently inhibited by phosphorylation following the generation of DNA double-stranded breaks during S-phase. This is cell cycle checkpoint and ATM-pathway dependent and appears to regulate processes involved in chromatin assembly. Isoform 3 phosphorylates and enhances the stability of the t-SNARE SNAP23, augmenting its assembly with syntaxin. Isoform 3 protects the cells from the ionizing radiation by facilitating the repair of DSBs. In vitro, phosphorylates histone H3 at 'Ser-10'.
Widely expressed. Present in fetal placenta, liver, kidney and pancreas but not heart or skeletal muscle. Also found in adult cell lines. Isoform 3 is ubiquitously expressed in all tissues examined.
Belongs to the acetyltransferase family. MAK3 subfamily.
Catalytic subunit of the N-terminal acetyltransferase C (NatC) complex. Catalyzes acetylation of the N-terminal methionine residues of peptides beginning with Met-Leu-Ala and Met-Leu-Gly. Necessary for the lysosomal localization and function of ARL8B sugeesting that ARL8B is a NatC substrate.
Acetylation at Lys-150 is predominantly observed in the nuclear fraction, and may regulate nucleocytoplasmic transport.
Mainly expressed in testis. Expressed to a lower level in thymus. Weakly or not expressed in heart, liver, brain, placenta, lung, skeletal muscle, kidney and pancreas.
RNA-binding protein, which may be required during spermatogenesis.
Belongs to the S100-fused protein family.
Can be divided into a N-terminal domain with significant homology to S100-like calcium-binding proteins, a central domain containing a series of short tandem repeats, and two flanking segments with low homology to the consensus sequences of the central repeats.
Expression is scattered in the normal epidermis but strong in the acrosyringium, the inner hair root sheath and in the filiform papilli of the tongue.
Involved in the cornified cell envelope formation. Multifunctional epidermal matrix protein. Reversibly binds calcium.
Potential substrate of transglutaminase. Some arginines are probably converted to citrullines by peptidylarginine deimidase.
Isoform 1 is O-glycosylated, while other isoforms are not.
May enhance cellular proliferation. May reduce growth inhibitory activity of CDKN2A.
Predominant isoform. Overexpressed in about 67% of primary breast tumors.
(Microbial infection) A higher molecular weight form is also seen in M.bovis infected cells.
(Microbial infection) Interacts with HTLV-1 Tax protein, leading to abrogate Tax transactivation of HTLV-1 LTR.
(Microbial infection) Plays a role in defense against mycobacterial infections. Methylates M.tuberculosis HupB on 'Lys-140', probably methylates HupB of M.bovis also. Methylation has an inhibitory effect on mycobacterial growth in the host. Macrophages expressing about 60% SUV39H1 are slightly more susceptible to M.bovis or M.tuberculosis infection. Chaetocin (an inhibitor of this enzyme) increases macrophage survival of M.tuberculosis. This protein inhibits biofilm formation by M.tuberculosis via 'Lys-140' trimethylation.
(Microbial infection) Rapidly induced in macrophages upon infection by Mycobacterium bovis, M.smegmatis and M.tuberculosis but not E.coli or Candida glabrata (at protein level).
Accumulates during mitosis at centromeres during prometaphase, but dissociates from the centromere at the meta- to anaphase transition.
Acetylated at Lys-266, leading to inhibition of enzyme activity. SIRT1-mediated deacetylation relieves this inhibition.
Although the SET domain contains the active site of enzymatic activity, both pre-SET and post-SET domains are required for methyltransferase activity. The SET domain also participates in stable binding to heterochromatin.
Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. Suvar3-9 subfamily.
Histone methyltransferase that specifically trimethylates 'Lys-9' of histone H3 using monomethylated H3 'Lys-9' as substrate. Also weakly methylates histone H1 (in vitro). H3 'Lys-9' trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. Mainly functions in heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin at pericentric and telomere regions. H3 'Lys-9' trimethylation is also required to direct DNA methylation at pericentric repeats. SUV39H1 is targeted to histone H3 via its interaction with RB1 and is involved in many processes, such as repression of MYOD1-stimulated differentiation, regulation of the control switch for exiting the cell cycle and entering differentiation, repression by the PML-RARA fusion protein, BMP-induced repression, repression of switch recombination to IgA and regulation of telomere length. Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. Recruited by the large PER complex to the E-box elements of the circadian target genes such as PER2 itself or PER1, contributes to the conversion of local chromatin to a heterochromatin-like repressive state through H3 'Lys-9' trimethylation.
In the pre-SET domain, Cys residues bind 3 zinc ions that are arranged in a triangular cluster; some of these Cys residues contribute to the binding of two zinc ions within the cluster.
Inhibited by S-adenosyl-L-homocysteine. Negatively regulated by CCAR2.
Interacts with H3 and H4 histones. Interacts with GFI1B, DNMT3B, CBX1, CBX4, CCAR2, MBD1, RUNX1, RUNX3, MYOD1, SMAD5 and RB1. Interacts with SBF1 through the SET domain. Interacts with HDAC1 and HDAC2 through the N-terminus and associates with the core histone deacetylase complex composed of HDAC1, HDAC2, RBBP4 and RBBP7. Component of the eNoSC complex, composed of SIRT1, SUV39H1 and RRP8. Interacts (via SET domain) with MECOM; enhances MECOM transcriptional repression activity. Interacts with LMNA; the interaction increases stability of SUV39H1. The large PER complex involved in the histone methylation is composed of at least PER2, CBX3, TRIM28, SUV39H1 and/or SUV39H2; CBX3 mediates the formation of the complex.
Phosphorylated on serine residues, and to a lesser degree, on threonine residues. The phosphorylated form is stabilized by SBF1 and is less active in its transcriptional repressor function.
Ubiquitinated by the DCX(DCAF13) E3 ubiquitin ligase complex, leading to its degradation.
A chromosomal aberration involving CBFA2T2 is found in acute myeloid leukemia. Translocation t(20;21)(q11;q22) with RUNX1/AML1.
A chromosomal aberration involving CBFA2T2 is found in childhood precursor B-cell acute lymphoblastic leukemia (pre-B ALL). Translocation t(9;20)(p13;q11) with PAX5.
Homooligomer. Homotetramerization is mediated by nervy homology region 2 (By similarity). Can interact with RUNX1T1/CBFA2T1 and CBFA2T3/MTG16; heterotetramerization between members of the CBFA2T family is proposed (PubMed:12242670, PubMed:14703694, PubMed:16616331). Forms a heterooligomer with the AML1-MTG8/ETO fusion protein (PubMed:9447981). Interacts with PRDM14 (PubMed:27281218). Interacts with RBPJ, GFI1, TCF4. Interacts with TAL1 and CBFA2T3/MTG16; the heteromer with CBFA2T3/MTG16 may function in repression of TAL1 (By similarity).
Nervy homology region 2 (NHR2) mediates homo- and possibly heterotypic oligomerization by forming a four-helix bundle tetrameric structure.
Transcriptional corepressor which facilitates transcriptional repression via its association with DNA-binding transcription factors and recruitment of other corepressors and histone-modifying enzymes (PubMed:12559562, PubMed:15203199). Via association with PRDM14 is involved in regulation of embryonic stem cell (ESC) pluripotency (PubMed:27281218). Involved in primordial germ cell (PCG) formation. Stabilizes PRDM14 and OCT4 on chromatin in a homooligomerization-dependent manner (By similarity). Can repress the expression of MMP7 in a ZBTB33-dependent manner (PubMed:23251453). May function as a complex with the chimeric protein RUNX1/AML1-CBFA2T1/MTG8 (AML1-MTG8/ETO fusion protein) which is produced in acute myeloid leukemia with the chromosomal translocation t(8;21). May thus be involved in the repression of AML1-dependent transcription and the induction of G-CSF/CSF3-dependent cell growth. May be a tumor suppressor gene candidate involved in myeloid tumors with the deletion of the 20q11 region. Through heteromerization with CBFA2T3/MTG16 may be involved in regulation of the proliferation and the differentiation of erythroid progenitors by repressing the expression of TAL1 target genes (By similarity). Required for the maintenance of the secretory cell lineage in the small intestine. Can inhibit Notch signaling probably by association with RBPJ and may be involved in GFI1-mediated Paneth cell differentiation (By similarity).
Ubiquitously expressed in fetal and adult tissues. Highly expressed in adult brain, heart, lung, kidney, lymph node, appendix, thymus, testis, uterus, small intestine, prostate and thymus.
(Microbial infection) Interacts with HTLV-1 protein Tax.
Auto-methylated on Arg-550. Methylation enhances transcription coactivator activity. Methylation is required for its role in the regulation of pre-mRNA alternative splicing (By similarity).
Homodimer (By similarity). Interacts with NR1H4 (PubMed:15471871). Interacts with SNRPC (By similarity). Interacts with the C-terminus of NCOA2/GRIP1, NCO3/ACTR and NCOA1/SRC1 (By similarity). Part of a complex consisting of CARM1, EP300/P300 and NCOA2/GRIP1 (By similarity). Interacts with FLII, TP53, myogenic factor MEF2, EP300/P300, TRIM24, CREBBP and CTNNB1 (By similarity). Interacts with RELA (PubMed:16497732). Identified in a complex containing CARM1, TRIM24 and NCOA2/GRIP1 (By similarity). Interacts with NCOA3/SRC3 (By similarity). Interacts with SKP2 (By similarity). Interacts (via PH domain-like fold) with C9orf72 (By similarity). Interacts with PARP1; promoting PARP1 recruimtent to replication forks (PubMed:33412112).
Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability (PubMed:12237300, PubMed:16497732, PubMed:19405910). Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activates transcription via chromatin remodeling (PubMed:12237300, PubMed:16497732, PubMed:19405910). During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription (By similarity). During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C (By similarity). During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B (By similarity). Acts as coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue (By similarity). Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors (By similarity). Also seems to be involved in p53/TP53 transcriptional activation (By similarity). Methylates EP300/P300, both at 'Arg-2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation (PubMed:15731352). Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA-stabilizing properties and the half-life of their target mRNAs (By similarity). Acts as a transcriptional coactivator of ACACA/acetyl-CoA carboxylase by enriching H3R17 methylation at its promoter, thereby positively regulating fatty acid synthesis (By similarity). Independently of its methyltransferase activity, involved in replication fork progression: promotes PARP1 recruitment to replication forks, leading to poly-ADP-ribosylation of chromatin at replication forks and reduced fork speed (PubMed:33412112).
Methylation of H3R17 (H3R17me) by CARM1 is stimulated by preacetylation of H3 'Lys-18' (H3K18ac) H3 'Lys-23' (H3K23ac) by EP300 and blocked by citrullination of H3 'Arg-17' (H3R17ci) by PADI4.
Overexpressed in prostate adenocarcinomas and high-grade prostatic intraepithelial neoplasia.
Phosphorylation at Ser-216 is strongly increased during mitosis, and decreases rapidly to a very low, basal level after entry into the G1 phase of the cell cycle (PubMed:19843527). Phosphorylation at Ser-216 may promote location in the cytosol. Phosphorylation at Ser-216 interferes with S-adenosyl-L-methionine binding and strongly reduces methyltransferase activity (By similarity).
Ubiquitinated by E3 ubiquitin-protein ligase complex containing FBXO9 at Lys-227; leading to proteasomal degradation.
Expressed in many tissues with a relatively high level in skeletal muscle.
MTCP1 and MTCP1NB are transcribed from the same promoter and could be considered the same gene.
Overexpressed in T-cell leukemia bearing a t(X;14) translocation.
Shares a non-coding 5' exon with isoform 2 which is spliced to a different set of 3' exons encoding an unrelated protein.
The twin Cx9C motifs are involved in the recognition by the mitochondrial disulfide relay system.
Although PubMed:11174199 reported this as a pseudogene, PubMed:12391231 showed it is expressed and has proteolytic activity when expressed in bacterial cells.
Expressed in colon, lung, heart and synovial tissue. May be specific to mast cells.
Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type.
May play a role in Cajal bodies formation.
Overexpression changes the morphology of Cajal bodies, while depletion disrupts the localization of components of Cajal bodies, reduces splicing capacity and inhibits cell proliferation.
May regulate the LIS1/dynein pathway by stabilizing LIS1 with Hsp90 chaperone.
Part of the CSA complex (DCX(ERCC8) complex), a DCX E3 ubiquitin-protein ligase complex containing ERCC8, RBX1, DDB1 and CUL4A; the CSA complex interacts with RNA polymerase II; upon UV irradiation it interacts with the COP9 signalosome and preferentially with the hyperphosphorylated form of RNA polymerase II. Interacts with ERCC6 and KIAA1530/UVSSA. Interacts with a subunit of RNA polymerase II TFIIH. Interacts directly with DDB1 (PubMed:22118460).
Substrate-recognition component of the CSA complex, a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, involved in transcription-coupled nucleotide excision repair. The CSA complex (DCX(ERCC8) complex) promotes the ubiquitination and subsequent proteasomal degradation of ERCC6 in a UV-dependent manner; ERCC6 degradation is essential for the recovery of RNA synthesis after transcription-coupled repair. It is required for the recruitment of XAB2, HMGN1 and TCEA1/TFIIS to a transcription-coupled repair complex which removes RNA polymerase II-blocking lesions from the transcribed strand of active genes. Plays a role in DNA single-strand and double-strand breaks (DSSBs) repair; involved in repair of DSSBs by non-homologous end joining (NHEJ) (PubMed:29545921).
Involved in the regulation of the perinuclear actin network and nuclear shape through interaction with filamins. Plays an essential role in actin cytoskeleton formation in developing cartilaginous cells.
Expressed in the pyramidal cells of the prefrontal cortex, in hypothalamus and in caudate nucleus. No expression in spleen. Up-regulated in the prefrontal cortex of schizophrenic patients with nearly twice the levels of non-schizophrenics.
In cerebrospinal fluid (CSF), found to be O-glycosylated in the predicted intracellular region at Thr-180 and Thr-189 (PubMed:19838169). This glycosylation has been confirmed by a separate mass spectrometry (MS) method (PubMed:23234360). Glycosylation in this region of the protein is unexplained as yet.
Interacts with clathrin light chain A and stimulates clathrin self-assembly and clathrin-mediated endocytosis.
Was originally thought to interact with the D1 dopamine receptor (DRD1) and to play a role in potentiating calcium ion-dependent signaling but this work was later retracted.
Belongs to the class-III pyridoxal-phosphate-dependent aminotransferase family.
Can metabolize asymmetric dimethylarginine (ADMA) via transamination to alpha-keto-delta-(NN-dimethylguanidino) valeric acid (DMGV). ADMA is a potent inhibitor of nitric-oxide (NO) synthase, and this activity provides mechanism through which the kidney regulates blood pressure.
Genetic variants in AGXT2 are association with beta-aminoisobutyric aciduria (BAIBA)[MIM:210100]. Excretion of beta-aminoisobutyric acid in urine is a common, benign, metabolic trait.
Essential for the normal assembly and function of sperm flagella axonemes.
Core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (PubMed:11991638, PubMed:19325628, PubMed:21516107, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Most spliceosomal snRNPs contain a common set of Sm proteins, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (PubMed:19325628, PubMed:21516107, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Component of the U1 snRNP (PubMed:19325628, PubMed:25555158). The U1 snRNP is composed of the U1 snRNA and the 7 core Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG, and at least three U1 snRNP-specific proteins SNRNP70/U1-70K, SNRPA/U1-A and SNRPC/U1-C (PubMed:19325628, PubMed:25555158). Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39, plus LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 (PubMed:26912367). Component of the U7 snRNP complex, or U7 Sm protein core complex, that is composed of the U7 snRNA and at least LSM10, LSM11, SNRPB, SNRPD3, SNRPE, SNRPF and SNRPG; the complex does not contain SNRPD1 and SNRPD2 (PubMed:11574479, PubMed:12975319). Component of the minor spliceosome, which splices U12-type introns (PubMed:15146077, PubMed:33509932). Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG; catalyzes core snRNPs assembly (PubMed:18984161, PubMed:16314521). Forms a 6S pICln-Sm complex composed of CLNS1A/pICln, SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG; ring-like structure where CLNS1A/pICln mimics additional Sm proteins and which is unable to assemble into the core snRNP (PubMed:18984161, PubMed:23333303). Interacts with GEMIN2 (via N-terminus); the interaction is direct (PubMed:21816274). Interacts with SNRPE; the interaction is direct (PubMed:21816274, PubMed:31799625).
Plays a role in pre-mRNA splicing as a core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (PubMed:11991638, PubMed:18984161, PubMed:19325628, PubMed:23333303, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Component of both the pre-catalytic spliceosome B complex and activated spliceosome C complexes (PubMed:11991638, PubMed:28502770, PubMed:28781166, PubMed:28076346). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (PubMed:15146077). As part of the U7 snRNP it is involved in histone 3'-end processing (PubMed:12975319).
Plays role in pre-mRNA splicing as core component of the SMN-Sm complex that mediates spliceosomal snRNP assembly and as component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. Component of both the pre-catalytic spliceosome B complex and activated spliceosome C complexes. Is also a component of the minor U12 spliceosome. As part of the U7 snRNP it is involved in histone 3'-end processing.
(Microbial infection) Acts as a coreceptor for hepatitis C virus (HCV) in hepatocytes.
(Microbial infection) Cleaved by S.pyogenes SpeB protease; leading to its degradation (PubMed:23532847). Degradation by SpeB promotes bacterial translocation across the host epithelial barrier (PubMed:23532847).
Dephosphorylated by PTPRJ. The tyrosine phosphorylation on Tyr-398 and Tyr-402 reduces its ability to interact with TJP1. Phosphorylation at Ser-490 also attenuates the interaction with TJP1.
Interacts with TJP1/ZO1 (PubMed:19017651). Interacts with VAPA (PubMed:10523508). Interacts with CLDN1, CLDN6, CLDN9, CLDN11, CLDN12 and CLDN17 (PubMed:20375010). Interacts with PLSCR1 (PubMed:21806988). Interacts with LSR, ILDR1 and ILDR2 (PubMed:23239027). Interacts with TJP2/ZO2 (By similarity).
Localized at tight junctions of both epithelial and endothelial cells. Highly expressed in kidney. Not detected in testis.
May play a role in the formation and regulation of the tight junction (TJ) paracellular permeability barrier.
May play a role in the formation and regulation of the tight junction (TJ) paracellular permeability barrier. It is able to induce adhesion when expressed in cells lacking tight junctions.
The C-terminal is cytoplasmic and is important for interaction with ZO-1. Sufficient for the tight junction localization. Involved in the regulation of the permeability barrier function of the tight junction (By similarity). The first extracellular loop participates in an adhesive interaction.
A report has suggested that the protein is expressed at the cell surface, associated with the cell membrane via its N-terminus. However, there is no direct evidence for that localization and the properties of the protein argue against it.
PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding (PubMed:20676357). Component of a putative tumor-recognition complex involved in the function of NK cells (PubMed:8421688).
Found in large molecular weight complexes containing CCNL1 and the p110 isoforms of either CDC2L1 or CDC2L2 (PubMed:12501247, PubMed:14684736). Interacts with CCNL2 and CPSF6 (PubMed:15169763, PubMed:12501247). Interacts with NXF1 (PubMed:12667464, PubMed:17036044). Interacts with YTHDC1 (By similarity).
Required for pre-mRNA splicing. Can also modulate alternative splicing in vitro. Represses the splicing of MAPT/Tau exon 10. May function as export adapter involved in mRNA nuclear export such as of histone H2A. Binds mRNA which is thought to be transferred to the NXF1-NXT1 heterodimer for export (TAP/NXF1 pathway); enhances NXF1-NXT1 RNA-binding activity. RNA-binding is semi-sequence specific.
Belongs to the NAD(P)-dependent epimerase/dehydratase family. GDP-mannose 4,6-dehydratase subfamily.
Catalyzes the conversion of GDP-D-mannose to GDP-4-dehydro-6-deoxy-D-mannose.
Highly expressed in pancreas and small intestine. Expressed in thymus, protstate, colon, heart, placenta, liver and kidney. Expressed at low levels in spleen, testis, brain and lung.
As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates that form during DNA replication or upon DNA stress. It prevents their reannealing and in parallel, recruits and activates different proteins and complexes involved in DNA metabolism. Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage (PubMed:9430682). In the cellular response to DNA damage, the RPA complex controls DNA repair and DNA damage checkpoint activation. Through recruitment of ATRIP activates the ATR kinase a master regulator of the DNA damage response (PubMed:24332808). It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin, in response to DNA damage. Also recruits to sites of DNA damage proteins like XPA and XPG that are involved in nucleotide excision repair and is required for this mechanism of DNA repair (PubMed:7697716). Also plays a role in base excision repair (BER), probably through interaction with UNG (PubMed:9765279). Also recruits SMARCAL1/HARP, which is involved in replication fork restart, to sites of DNA damage. May also play a role in telomere maintenance. RPA3 has its own single-stranded DNA-binding activity and may be responsible for polarity of the binding of the complex to DNA (PubMed:19010961). As part of the alternative replication protein A complex, aRPA, binds single-stranded DNA and probably plays a role in DNA repair. Compared to the RPA2-containing, canonical RPA complex, may not support chromosomal DNA replication and cell cycle progression through S-phase. The aRPA may not promote efficient priming by DNA polymerase alpha but could support DNA synthesis by polymerase delta in presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange (PubMed:19996105).
Belongs to the replication factor A protein 3 family.
Component of the canonical replication protein A complex (RPA), a heterotrimer composed of RPA1, RPA2 and RPA3. Also a component of the aRPA, the alternative replication protein A complex, a trimeric complex similar to the replication protein A complex/RPA but where RPA1 and RPA3 are associated with RPA4 instead of RPA2.
Ubiquitinated by RFWD3 at stalled replication forks in response to DNA damage: ubiquitination by RFWD3 does not lead to degradation by the proteasome and promotes removal of the RPA complex from stalled replication forks, promoting homologous recombination (PubMed:26474068).
Belongs to the L-aspartate dehydrogenase family.
Component of the N-terminal acetyltransferase B (NatB) complex which is composed of NAA20 and NAA25.
Non-catalytic subunit of the NatB complex which catalyzes acetylation of the N-terminal methionine residues of peptides beginning with Met-Asp, Met-Glu, Met-Asn and Met-Gln. May play a role in normal cell-cycle progression.
Deubiquitination by USP17L2/USP17 negatively regulates the proteolytic activity toward Ras GTPases.
Proteolytically removes the C-terminal three residues of farnesylated and geranylated proteins. Seems to be able to process K-Ras, N-Ras, H-Ras, RAP1B and G-gamma-1 (PubMed:10085068).
Ubiquitinated. Undergoes 'Lys-48'- and 'Lys-63'-linked ubiquitination. 'Lys-48' ubiquitination induces its degradation. Deubiquitinated by USP17L2/USP17 that cleaves 'Lys-63'-linked ubiquitin chains.
Catalyzes the oxygenation of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) to 5-hydroperoxyeicosatetraenoate (5-HPETE) followed by the dehydration to 5,6- epoxyeicosatetraenoate (Leukotriene A4/LTA4), the first two steps in the biosynthesis of leukotrienes, which are potent mediators of inflammation (PubMed:8631361, PubMed:21233389, PubMed:22516296, PubMed:24282679, PubMed:19022417, PubMed:23246375, PubMed:8615788, PubMed:24893149, PubMed:31664810). Also catalyzes the oxygenation of arachidonate into 8-hydroperoxyicosatetraenoate (8-HPETE) and 12-hydroperoxyicosatetraenoate (12-HPETE) (PubMed:23246375). Displays lipoxin synthase activity being able to convert (15S)-HETE into a conjugate tetraene (PubMed:31664810). Although arachidonate is the preferred substrate, this enzyme can also metabolize oxidized fatty acids derived from arachidonate such as (15S)-HETE, eicosapentaenoate (EPA) such as (18R)- and (18S)-HEPE or docosahexaenoate (DHA) which lead to the formation of specialized pro-resolving mediators (SPM) lipoxin and resolvins E and D respectively, therefore it participates in anti-inflammatory responses (PubMed:21206090, PubMed:31664810, PubMed:8615788, PubMed:17114001, PubMed:32404334). Oxidation of DHA directly inhibits endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor gamma (PPARgamma) (By similarity). It does not catalyze the oxygenation of linoleic acid and does not convert (5S)-HETE to lipoxin isomers (PubMed:31664810). In addition to inflammatory processes, it participates in dendritic cell migration, wound healing through an antioxidant mechanism based on heme oxygenase-1 (HO-1) regulation expression, monocyte adhesion to the endothelium via ITGAM expression on monocytes (By similarity). Moreover, it helps establish an adaptive humoral immunity by regulating primary resting B cells and follicular helper T cells and participates in the CD40-induced production of reactive oxygen species (ROS) after CD40 ligation in B cells through interaction with PIK3R1 that bridges ALOX5 with CD40 (PubMed:21200133). May also play a role in glucose homeostasis, regulation of insulin secretion and palmitic acid-induced insulin resistance via AMPK (By similarity). Can regulate bone mineralization and fat cell differentiation increases in induced pluripotent stem cells (By similarity).
Homodimer (PubMed:22516296, PubMed:21233389). Interacts with ALOX5AP and LTC4S (PubMed:19233132). Interacts with COTL1, the interaction is required for stability and efficient catalytic activity (PubMed:19807693). Interacts with PIK3R1; this interaction bridges ALOX5 with CD40 after CD40 ligation in B cells and leads to the production of reactive oxygen species (ROS) (PubMed:21200133). Interacts (via PLAT domain) with DICER1 (via Dicer dsRNA-binding fold domain); this interaction enhances arachidonate 5-lipoxygenase activity and modifies the miRNA precursor processing activity of DICER1 (PubMed:19022417).
Serine phosphorylation by MAPKAPK2 is stimulated by arachidonic acid (PubMed:11844797, PubMed:18978352). Phosphorylation on Ser-524 by PKA has an inhibitory effect (PubMed:15280375). Phosphorylation on Ser-272 prevents export from the nucleus (PubMed:11844797, PubMed:18978352). Phosphorylation at Ser-524 is stimulated by 8-bromo-3',5'-cyclic AMP or prostaglandin E2 (PubMed:26210919).
Undergoes a sequential loss of the oxygenase and pseudoperoxidase activities which is dependent on the structural characteristics of the substrate for the reaction, on oxygen concentration and on exposure to phospholipids and calcium (PubMed:8631361). 15-HETE and other 15-mono-hydroxyeicosanoids exhibit the highest inhibitory potencies in their capability of suppressing 5-lipoxygenation of arachidonic acid, whereas the other HETEs, (5S,15S)-dihydroxy-(6E,8Z,11Z,13E)-eicosatetraenoic acid (5,15-diHETE) as well as octadecanoids, are modest or poor inhibitors (PubMed:8615788). The formation of (5S)-hydroperoxy-(15S)-hydroxy-(6E,8Z,11Z,13E)-eicosatetraenoate is strongly stimulated by either hydroperoxypolyenoic fatty acids or arachidonic acid (PubMed:8615788). Arachidonate 5-lipoxygenase and leukotriene A4 synthase activities are allosterically increased by ATP (PubMed:24893149).
May function as RNase and regulate the levels of target RNA species.
Transcription factor with repressor activity involved in the regulation of axon-glial interactions at myelin paranodes in oligodendrocytes. Binds to the consensus DNA sequence 5'-(A/T)TTAATGA-3'. In oligodendrocytes, binds to MBP and PLP1 promoter regions.
Belongs to the activator 1 small subunits family.
Despite of the presence of a putative ATP-binding motif, this protein does not bind ATP.
Heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 that can form a complex either with RFC1 or with RAD17. The former interacts with PCNA in the presence of ATP, while the latter has ATPase activity but is not stimulated by PCNA. Interacts with CNTD1; this interaction facilitates crossover formation (By similarity).
The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1. This subunit may be involved in the elongation of the multiprimed DNA template.
Intron-exon boundaries of the last intron are not canonical, they have a CT-AG boundary.
Belongs to the krueppel C2H2-type zinc-finger protein family. ZBTB18 subfamily.
Transcriptional repressor. Specifically binds DNA and probably acts by recruiting chromatin remodeling multiprotein complexes.
While the gene symbol and protein names are indicative of the presence of LRR repeats, such repeats are not present in this protein.
Catalytic subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation (PubMed:31831667). N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity. This subunit contains the active site and the acceptor peptide and donor lipid-linked oligosaccharide (LLO) binding pockets (By similarity). STT3B is present in a small subset of OST complexes and mediates both cotranslational and post-translational N-glycosylation of target proteins: STT3B-containing complexes are required for efficient post-translational glycosylation and while they are less competent than STT3A-containing complexes for cotranslational glycosylation, they have the ability to mediate glycosylation of some nascent sites that are not accessible for STT3A. STT3B-containing complexes also act post-translationally and mediate modification of skipped glycosylation sites in unfolded proteins. Plays a role in ER-associated degradation (ERAD) pathway that mediates ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins by mediating N-glycosylation of unfolded proteins, which are then recognized by the ERAD pathway and targeted for degradation. Mediates glycosylation of the disease variant AMYL-TTR 'Asp-38' of TTR at 'Asn-118', leading to its degradation (PubMed:19167329, PubMed:22607976).
Component of the oligosaccharyltransferase (OST) complex (PubMed:31831667). OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits (PubMed:31831667). OST can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes (By similarity).
Expressed in heart, brain, placenta, lung, liver, muscle, kidney and pancreas. Expressed in skin fibroblasts (at protein level).
Homodimer (PubMed:20826455). Heterodimer with PEX11G (PubMed:20826455). Interacts with PEX19 (PubMed:10704444). Interacts with FIS1 (PubMed:20826455).
Involved in peroxisomal proliferation (PubMed:9792670). May regulate peroxisome division by recruiting the dynamin-related GTPase DNM1L to the peroxisomal membrane (PubMed:12618434). Promotes membrane protrusion and elongation on the peroxisomal surface (PubMed:20826455).
PubMed:9792670 states that both the N- and the C-terminus are located in the cytoplasm.
Belongs to the SLC34A transporter family.
Interacts via its C-terminal region with NHERF4 (By similarity). Interacts with NHERF1 (PubMed:22506049). Interacts with TMEM174; regulates SLC34A1 internalization by PTH and FGF23 (By similarity).
Involved in actively transporting phosphate into cells via Na(+) cotransport in the renal brush border membrane (PubMed:26047794, PubMed:8327470, PubMed:12324554, PubMed:20335586). The cotransport has a Na(+):Pi stoichiometry of 3:1 and is electrogenic (By similarity).
Exhibits phosphohistidine phosphatase activity.
Expressed abundantly in heart and skeletal muscle.
Belongs to the methyltransferase superfamily. ETFBKMT family.
Interacts with HSPD1; this protein may possibly be a methylation substrate.
Protein-lysine methyltransferase that selectively trimethylates the flavoprotein ETFB in mitochondria (PubMed:25023281, PubMed:25416781). Thereby, may negatively regulate the function of ETFB in electron transfer from Acyl-CoA dehydrogenases to the main respiratory chain (PubMed:25416781).
Binds 3 Mg(2+) or Mn(2+) ions per subunit. Mn(2+) may be the true cofactor in vivo.
Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate), suggesting that it may play a role in signal transduction. Also able to catalyze the hydrolysis of dinucleoside oligophosphates, with Ap6A and Ap5A being the preferred substrates. The major reaction products are ADP and p4a from Ap6A and ADP and ATP from Ap5A. Also able to hydrolyze 5-phosphoribose 1-diphosphate.
Mainly expressed in testis and, at lower level in brain. According to PubMed:12121577, it is also expressed in pancreas and weakly expressed in thymus, prostate, ovary, lung, small intestine and heart.
Acts as a negative regulator of the endoplasmic reticulum stress response or unfolded protein response (UPR). Represses the transcriptional activity of CREB3 during the UPR. Recruits CREB3 into nuclear foci.
Belongs to the bZIP family. CREBRF subfamily.
Interacts (via leucine-zipper domain) with CREB3 (via leucine-zipper domain); the interaction promotes CREB3 degradation.
Up-regulated by endoplasmic reticulum stress.
Contaminating sequence. Vector contamination at the C-terminus.
May be involved in transcriptional repression (PubMed:31856708). Inhibits cell proliferation through CDKN1A/p21 induction by down-regulation of NIBAN1/FAM129A at low cell density (PubMed:25560148).
Expressed in heart, brain, placenta, lung, liver, kidney, pancreas, spleen, thymus, prostate, testis, uterus, small intestine and colon. Not detected in peripheral blood lymphocytes.
May mediate accelerated ATP-independent bidirectional transbilayer migration of phospholipids upon binding calcium ions that results in a loss of phospholipid asymmetry in the plasma membrane.
Binds DNA and functions as a transcriptional activator (PubMed:12270922). Binds to two G/A-rich sites, ME1a1 and ME1a2, within the MYC promoter having greater affinity for the former (PubMed:1502157). Also binds to multiple G/C-rich sites within the promoter of the Sp1 family of transcription factors (PubMed:1502157).
Binds DNA and functions as a transcriptional activator (PubMed:12270922). Inhibits MAZ isoform 1-mediated transcription (PubMed:12270922).
Binds DNA and functions as a transcriptional activator.
Expressed in the heart, brain, placenta, lung, liver, skeletal muscle and weakly expressed in the kidney (PubMed:1502157). Expressed in the joint synovium (PubMed:19583771).
Forms a heterodimer with MAZ isoform 1; the interaction inhibits MAZ isoform 1-mediated transcription activation.
Forms a heterodimer with MAZ isoform 2; the interaction inhibits MAZ isoform 1-mediated transcription activation.
Induced by cytokine and growth factor stimulation.
May act as a dominant negative of isoform 1. Reduced expression during inflammatory conditions.
Present in kidney, liver and brain. In the brain, highest levels are found in motor cortex and midfrontal cortex (at protein level).
The transactivation potential of isoform 3 is much greater than that of the predominantly expressed isoform 1.
Transcriptional regulator, potentially with dual roles in transcription initiation and termination.
Belongs to the cyclic nucleotide phosphodiesterase family. PDE7 subfamily.
Binds 2 divalent metal cations per subunit (PubMed:19350606). Site 1 may preferentially bind zinc ions, while site 2 has a preference for magnesium and/or manganese ions (PubMed:19350606).
Developmentally regulated (PubMed:9195912). PDE7A1 and PDE7A2 are found in several fetal tissues, expression is reduced throughout development (PubMed:9195912). It persists strongly only in adult skeletal muscle (PubMed:9195912).
Found abundantly in skeletal muscle and at low levels in heart.
Found at high levels in skeletal muscle and at low levels in a variety of tissues including brain and heart (PubMed:9195912). It is expressed as well in two T-cell lines (PubMed:9195912).
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes (PubMed:8389765, PubMed:9195912, PubMed:19350606). May have a role in muscle signal transduction (PubMed:9195912).
Insensitive to all selective PDE inhibitors.
Homodimer (By similarity). Interacts with POLDIP3. Component of the methylosome, a 20S complex containing at least CLNS1A/pICln, PRMT5/SKB1, WDR77/MEP50, PRMT1 and ERH (PubMed:25284789). Interacts with CHTOP (PubMed:25284789).
Hydrolyzes the non-reducing end N-acetyl-D-hexosamine and/or sulfated N-acetyl-D-hexosamine of glycoconjugates, such as the oligosaccharide moieties from proteins and neutral glycolipids, or from certain mucopolysaccharides (PubMed:11707436, PubMed:9694901, PubMed:8672428, PubMed:8123671). The isozyme S is as active as the isozyme A on the anionic bis-sulfated glycans, the chondroitin-6-sulfate trisaccharide (C6S-3), and the dermatan sulfate pentasaccharide, and the sulfated glycosphingolipid SM2 (PubMed:11707436). The isozyme B does not hydrolyze each of these substrates, however hydrolyzes efficiently neutral oligosaccharide (PubMed:11707436). Only the isozyme A is responsible for the degradation of GM2 gangliosides in the presence of GM2A (PubMed:9694901, PubMed:8672428, PubMed:8123671).
N-linked glycan at Asn-115 consists of Man(3)-GlcNAc(2) (PubMed:1533633, PubMed:16698036, PubMed:19159218) (Probable). N-linked glycan at Asn-157 consists of either GlcNAc or GlcNAc(2)-Man(7-9). N-linked glycan at Asn-295 consists of either GlcNAc, GlcNAc-Fuc, or GlcNAc(2)-Man(4) (Probable).
There are 3 beta-hexosaminidase isozymes: isozyme A (hexosaminidase A) is an heterodimer composed of one subunit alpha and one subunit beta (chain A and B); isozyme B (hexosaminidase B) is an homodimer of two beta subunits (two chains A and B); isozyme S (hexosaminidase S) is a homodimer of two alpha subunits (PubMed:16698036). The composition of the dimer (isozyme A versus isozyme S) has a significant effect on the substrate specificity of the alpha subunit active site (PubMed:8672428).
Component of the U11/U12 snRNPs that are part of the U12-type spliceosome. Interacts (via RS domain) with SRSF1 and SRSF2. Interacts with U2AF2/U2AF65.
Phosphorylated in the RS domain by SRPK1.
Pre-mRNA-binding protein required for splicing of both U2- and U12-type introns. Selectively interacts with the 3'-splice site of U2- and U12-type pre-mRNAs and promotes different steps in U2 and U12 intron splicing. Recruited to U12 pre-mRNAs in an ATP-dependent manner and is required for assembly of the prespliceosome, a precursor to other spliceosomal complexes. For U2-type introns, it is selectively and specifically required for the second step of splicing.
May act as a guanine-nucleotide releasing factor.
Homodimer. Interacts with IGF2R; the interaction is dependent on glycosylation.
May contribute to the transcriptional control of cell growth and differentiation. Antagonizes transcriptional activation and cellular transformation by the adenovirus E1A protein. The transcriptional control activity of cell growth requires interaction with IGF2R.
Alpha1 catalytic subunit of the cytosolic type I platelet-activating factor (PAF) acetylhydrolase (PAF-AH (I)) heterotetrameric enzyme that catalyzes the hydrolyze of the acetyl group at the sn-2 position of PAF and its analogs and modulates the action of PAF. The activity and substrate specificity of PAF-AH (I) are affected by its subunit composition. Both alpha1/alpha1 homodimer (PAFAH1B3/PAFAH1B3 homodimer) and alpha1/alpha2 heterodimer(PAFAH1B3/PAFAH1B2 heterodimer) hydrolyze 1-O-alkyl-2-acetyl-sn-glycero-3-phosphoric acid (AAGPA) more efficiently than PAF, but they have little hydrolytic activity towards 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylethanolamine (AAGPE). Plays an important role during the development of brain.
Belongs to the 'GDSL' lipolytic enzyme family. Platelet-activating factor acetylhydrolase IB beta/gamma subunits subfamily.
Beta subunit (PAFAH1B1) inhibits the acetylhydrolase activity of the alpha1/alpha1 catalytic homodimer.
Forms a catalytic dimer which is either homodimer (alpha1/alpha1 homodimer) or heterodimer with PAFAH1B2 (alpha1/alpha2 heterodimer). Component of the cytosolic (PAF-AH (I)) heterotetrameric enzyme, which is composed of PAFAH1B1 (beta), PAFAH1B2 (alpha2) and PAFAH1B3 (alpha1) subunits. The catalytic activity of the enzyme resides in the alpha1 (PAFAH1B3) and alpha2 (PAFAH1B2) subunits, whereas the beta subunit (PAFAH1B1) has regulatory activity. Trimer formation is not essential for the catalytic activity (By similarity). Interacts with VLDLR; this interaction may modulate the Reelin pathway (By similarity).
In the adult, expressed in brain, skeletal muscle, kidney, thymus, spleen, colon, testis, ovary and peripheral blood leukocytes. In the fetus, highest expression occurs in brain.
Originally the subunits of the type I platelet-activating factor (PAF) acetylhydrolase was named alpha (PAFAH1B1), beta (PAFAH1B2) and gamma (PAFAH1B3) (PubMed:7669037) (By similarity). Now these subunits have been renamed beta (PAFAH1B1), alpha2 (PAFAH1B2) and alpha1 (PAFAH1B3) respectively (By similarity).
Expressed in all tissues examined. Highest levels in placenta, skeletal muscle, heart, ovary, kidney, small intestine and spleen.
Forms heterodimers with DP family members TFDP1 or TFDP2 (PubMed:9704927). Component of the DRTF1/E2F transcription factor complex (PubMed:12004135). Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EUHMTASE1, RING1, RNF2, MBLR, L3MBTL2 and YAF2 (PubMed:12004135). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975).
Inhibitor of E2F-dependent transcription (PubMed:9689056, PubMed:9704927, PubMed:9501179). Binds DNA cooperatively with DP proteins through the E2 recognition site, 5'-TTTC[CG]CGC-3' (PubMed:9501179). Has a preference for the 5'-TTTCCCGC-3' E2F recognition site (PubMed:9501179). E2F6 lacks the transcriptional activation and pocket protein binding domains (PubMed:9704927, PubMed:9501179). Appears to regulate a subset of E2F-dependent genes whose products are required for entry into the cell cycle but not for normal cell cycle progression (PubMed:9689056, PubMed:9501179). Represses expression of some meiosis-specific genes, including SLC25A31/ANT4 (By similarity). May silence expression via the recruitment of a chromatin remodeling complex containing histone H3-K9 methyltransferase activity. Overexpression delays the exit of cells from the S-phase (PubMed:9501179).
ATPase activity is stimulated by microtubules, which promote homooligomerization. ATP-dependent microtubule severing is stimulated by interaction with KATNB1.
Belongs to the AAA ATPase family. Katanin p60 subunit A1 subfamily. A-like 1 sub-subfamily.
Can homooligomerize into hexameric rings, which may be promoted by interaction with microtubules. Interacts with KATNB1, which may serve as a targeting subunit. Interacts with ASPM; the katanin complex formation KATNA1:KATNB1 is required for the association of ASPM. Interacts with dynein and NDEL1. Associates with the E3 ligase complex containing DYRK2, EDD/UBR5, DDB1 and DCAF1 proteins (EDVP complex). Interacts with KLHL42 (via the kelch domains). Interacts with CUL3; the interaction is enhanced by KLHL42. Interacts with KATNB1 and KATNBL1. Interacts with CAMSAP2 and CAMSAP3; leading to regulate the length of CAMSAP-decorated microtubule stretches.
Catalytic subunit of a complex which severs microtubules in an ATP-dependent manner. Microtubule severing may promote rapid reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. Microtubule release from the mitotic spindle poles may allow depolymerization of the microtubule end proximal to the spindle pole, leading to poleward microtubule flux and poleward motion of chromosome. Microtubule release within the cell body of neurons may be required for their transport into neuronal processes by microtubule-dependent motor proteins. This transport is required for axonal growth.
Expressed in testis, restricted to Sertoli cells (at protein level).
Phosphorylation by DYRK2 triggers ubiquitination and subsequent degradation.
Regulates microtubule dynamics in Sertoli cells, a process that is essential for spermiogenesis and male fertility. Severs microtubules in an ATP-dependent manner, promoting rapid reorganization of cellular microtubule arrays (By similarity). Has microtubule-severing activity in vitro (PubMed:26929214).
Regulates microtubule dynamics in Sertoli cells, a process that is essential for spermiogenesis and male fertility. Severs microtubules in an ATP-dependent manner, promoting rapid reorganization of cellular microtubule arrays.
The N-terminus is sufficient for interaction with microtubules, although high affinity binding to microtubules also requires an intact C-terminal domain and ATP, which promotes oligomerization.
Ubiquitinated by the BCR(KLHL42) E3 ubiquitin ligase complex, leading to its proteasomal degradation. Ubiquitinated by the EDVP E3 ligase complex and subsequently targeted for proteasomal degradation.
Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta. Expression is observed in the fibroblasts.
(Microbial infection) Interacts (via PAIP1M) with human SARS coronaviruses SARS-COV and SARS-COV-2 NSP3 protein (via SARS-unique domain); the interaction increases binding affinity with PABPC1.
(Microbial infection) Upon interaction with SARS coronavirus SARS-CoV NSP3 protein, plays an important role in viral protein synthesis.
Acts as a coactivator in the regulation of translation initiation of poly(A)-containing mRNAs. Its stimulatory activity on translation is mediated via its action on PABPC1. Competes with PAIP2 for binding to PABPC1. Its association with EIF4A and PABPC1 may potentiate contacts between mRNA termini. May also be involved in translationally coupled mRNA turnover. Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain.
Interacts with the RRM1-RRM2 and C-terminus regions of PABPC1 in a 1:1 stoichiometry. Interacts with EIF4A.
Only the PABPC1-interacting motif-1 (PAM1) stimulates translation initiation.
Transcription factor required in complex with TAF3 for the differentiation of myoblasts into myocytes. The complex replaces TFIID at specific promoters at an early stage in the differentiation process (By similarity).
Ubiquitously expressed in all tissues examined with highest levels in heart, lung, ovary, spleen and testes.
Activates erythroid-specific, globin gene expression.
Heterodimer with MAFG, MAFK and other small MAF proteins that binds to the MAF recognition elements (MARE).
Highly expressed in human placenta and also in B-cell and monocyte cell lines. Low expression in heart, brain, lung, skeletal muscle, kidney and pancreas.
(Microbial infection) Interacts with human adenovirus 5 E1A protein; this interaction seems to potentiate viral replication.
Belongs to the D-isomer specific 2-hydroxyacid dehydrogenase family.
Can form homodimers or heterodimers of CTBP1 and CTBP2. Interacts with HIPK2 and ZNF217. Interacts with PRDM16; represses white adipose tissue (WAT)-specific genes expression (By similarity). Interacts with PNN, NRIP1 and WIZ. Interacts with MCRIP1 (PubMed:25728771).
Corepressor targeting diverse transcription regulators. Functions in brown adipose tissue (BAT) differentiation (By similarity).
Isoform 2 probably acts as a scaffold for specialized synapses.
Ubiquitous. Highest levels in heart, skeletal muscle, and pancreas.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class 3 subfamily.
Protein-tyrosine phosphatase that could participate in the transfer of hydrophobic ligands or in functions of the Golgi apparatus.
Catalyzes the demethylation of N,N-dimethylglycine to sarcosine. Also has activity with sarcosine in vitro.
Belongs to the histone deacetylase family.
Its activity is inhibited by trapoxin, a known histone deacetylase inhibitor.
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes.
Weakly expressed in most tissues. Strongly expressed in brain, heart, skeletal muscle, kidney and testis.
Essential subunit of the farnesyltransferase complex. Catalyzes the transfer of a farnesyl moiety from farnesyl diphosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X.
Inhibited by divalent copper and zinc ions, but not by nickel or cobalt (PubMed:10644685). Inhibited by its prosegment, but not smaller fragments (PubMed:10644685). Inhibited by 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), a serine protease inhibitor (PubMed:12782636).
Interacts with LYSET; this interaction bridges GNPTAB to MBTPS1.
Serine protease that cleaves after hydrophobic or small residues, provided that Arg or Lys is in position P4: known substrates include SREBF1/SREBP1, SREBF2/SREBP2, BDNF, GNPTAB, ATF6, ATF6B and FAM20C (PubMed:10644685, PubMed:12782636, PubMed:21719679, PubMed:34349020). Cleaves substrates after Arg-Ser-Val-Leu (SREBP2), Arg-His-Leu-Leu (ATF6), Arg-Gly-Leu-Thr (BDNF) and its own propeptide after Arg-Arg-Leu-Leu (PubMed:10644685, PubMed:21719679). Catalyzes the first step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:12782636). Also mediates the first step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6 and ATF6B) (PubMed:12782636). Mediates the protein cleavage of GNPTAB into subunit alpha and beta, thereby participating in biogenesis of lysosomes (PubMed:21719679). Cleaves the propeptide from FAM20C which is required for FAM20C secretion from the Golgi apparatus membrane and for enhancement of FAM20C kinase activity, promoting osteoblast differentiation and biomineralization (PubMed:34349020). Involved in the regulation of M6P-dependent Golgi-to-lysosome trafficking of lysosomal enzymes (PubMed:21719679, PubMed:30046013). It is required for the activation of CREB3L2/BBF2H7, a transcriptional activator of MIA3/TANGO and other genes controlling mega vesicle formation (PubMed:30046013). Therefore, it plays a key role in the regulation of mega vesicle-mediated collagen trafficking (PubMed:30046013). In astrocytes and osteoblasts, upon DNA damage and ER stress, mediates the first step of the regulated intramembrane proteolytic activation of the transcription factor CREB3L1, leading to the inhibition of cell-cycle progression (PubMed:16417584).
The 148 kDa zymogen is processed progressively into two membrane-bound 120 and 106 kDa forms in the endoplasmic reticulum, and late into a secreted 98 kDa form (PubMed:10644685). The propeptide is autocatalytically removed through an intramolecular cleavage after Leu-186. Further cleavage generates 14, 10, and 8 kDa intermediates (PubMed:10644685).
Although it belongs to the SDR family, Phe-218 is present instead of the conserved Tyr which is an active site residue. It is therefore expected that this protein lacks oxidoreductase activity.
Belongs to the short-chain dehydrogenases/reductases (SDR) family. 17-beta-HSD 3 subfamily.
Highly expressed in testis and ovary. Also detected in thyroid, spinal cord, adrenal gland, heart, placenta, skeletal muscle, small intestine, colon, spleen, prostate and pancreas.
Component of the FTS/Hook/FHIP complex (FHF complex), composed of AKTIP/FTS, FHIP1B, and one or more members of the Hook family of proteins HOOK1, HOOK2, and HOOK3 (PubMed:32073997). The FHF complex associates with the homotypic vesicular sorting complex (the HOPS complex).
Component of the FTS/Hook/FHIP complex (FHF complex). The FHF complex may function to promote vesicle trafficking and/or fusion via the homotypic vesicular protein sorting complex (the HOPS complex). FHF complex promotes the distribution of AP-4 complex to the perinuclear area of the cell (PubMed:32073997).
Product of a dubious gene prediction. The corresponding gene is on a region of chromosome 21 that is known to be an artifactual duplication of another chromosome 21 region in the GRCh38 assembly. This entry may represent an artifactual copy of AC P0DPI2.
Acts as a translational repressor of SRE-containing messengers.
Although its dehydrogenase activity is NAD-specific, it can also utilize NADP at a reduced efficiency.
Belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.
Expressed only in developing normal tissues.
This NAD-dependent bifunctional enzyme has very different kinetic properties than the larger NADP-dependent trifunctional enzyme and is unique in that it requires formation of an enzyme-magnesium complex to allow binding of NAD.
Adds the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP-Man(7)GlcNAc(2)) required for protein glycosylation.
Belongs to the glycosyltransferase 22 family.
Heterotetramer of 2 alpha/BCKDHA and 2 beta chains/BCKDHB that forms the branched-chain alpha-keto acid decarboxylase (E1) component of the BCKD complex (PubMed:10745006, PubMed:9582350). The branched-chain alpha-ketoacid dehydrogenase is a large complex composed of three major building blocks E1, E2 and E3. It is organized around E2, a 24-meric cubic core composed of DBT, to which are associated 6 to 12 copies of E1, and approximately 6 copies of the dehydrogenase E3, a DLD dimer (PubMed:10745006).
Together with BCKDHB forms the heterotetrameric E1 subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. The BCKD complex catalyzes the multi-step oxidative decarboxylation of alpha-ketoacids derived from the branched-chain amino-acids valine, leucine and isoleucine producing CO2 and acyl-CoA which is subsequently utilized to produce energy. The E1 subunit catalyzes the first step with the decarboxylation of the alpha-ketoacid forming an enzyme-product intermediate. A reductive acylation mediated by the lipoylamide cofactor of E2 extracts the acyl group from the E1 active site for the next step of the reaction.
Belongs to the sodium channel auxiliary subunit SCN1B (TC 8.A.17) family.
Cell adhesion molecule that plays a critical role in neuronal migration and pathfinding during brain development. Stimulates neurite outgrowth (PubMed:21994374). Has no regulatory function on the SCN2A sodium channel complex (PubMed:14622265).
Component of a voltage-sensitive sodium channel complex that consists of a pore-forming alpha subunit and one or more regulatory beta subunits (PubMed:15525788, PubMed:21994374, PubMed:30190309, PubMed:36823201, PubMed:36696443). Interacts with SCN4A (PubMed:8125980). Interacts with NFASC. Interacts with SCN10A (By similarity). Interacts with SCN1A (PubMed:15525788, PubMed:21994374, PubMed:17928445). Interacts with SCN3A (PubMed:21994374). Interacts with SCN5A (PubMed:21994374). Interacts with SCN8A (PubMed:26900580, PubMed:36823201, PubMed:36696443).
Regulatory subunit of multiple voltage-gated sodium channel complexes that play important roles in excitable membranes in brain, heart and skeletal muscle. Enhances the presence of the pore-forming alpha subunit at the cell surface and modulates channel gating characteristics and the rate of channel inactivation. Modulates the activity of multiple pore-forming alpha subunits, such as SCN1A, SCN2A, SCN3A, SCN4A, SCN5A and SCN10A.
The overall expression of isoform 1 and isoform 2 is very similar. Isoform 1 is abundantly expressed in skeletal muscle, heart and brain. Isoform 2 is highly expressed in brain and skeletal muscle and present at a very low level in heart, placenta, lung, liver, kidney and pancreas. In brain, isoform 2 is most abundant in the cerebellum, followed by the cerebral cortex and occipital lobe, while isoform 1 levels are higher in the cortex compared to the cerebellum. Isoform 2 is expressed in many regions of the brain, including cerebellar Purkinje cells, cortex pyramidal neurons and many of the neuronal fibers throughout the brain (at protein level). Also detected in dorsal root ganglion, in fibers of the spinal nerve and in cortical neurons and their processes (at protein level).
Expressed in olfactory epithelium and embryos.
Activated by lysophosphatidylcholine (lysoPC).
Anchoring protein that mediates the subcellular compartmentation of protein kinase A (PKA) and protein kinase C (PKC).
Antibodies against the C-terminal of gravin can be produced by patients with myasthenia gravis (MG).
Binds to dimeric RII-alpha regulatory subunit of PKC.
Expressed in endothelial cells, cultured fibroblasts and osteosarcoma, but not in platelets, leukocytes, monocytic cell lines or peripherical blood cells.
Polybasic regions located between residues 266 and 557 are involved in binding PKC.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class CDC14 subfamily.
Composed of two structurally equivalent A and B domains that adopt a dual specificity protein phosphatase (DSP) fold.
Dual-specificity phosphatase involved in DNA damage response. Essential regulator of the G2 DNA damage checkpoint: following DNA damage, translocates to the nucleus and dephosphorylates FZR1/CDH1, a key activator of the anaphase promoting complex/cyclosome (APC/C). Dephosphorylates SIRT2 around early anaphase. Dephosphorylation of FZR1/CDH1 activates the APC/C, leading to the ubiquitination of PLK1, preventing entry into mitosis. Preferentially dephosphorylates proteins modified by proline-directed kinases.
Detected in skeletal muscle, adipocyte, brain, lung, colon and mammary gland.
Homodimer, and heterodimer with SH3GLB1.
ADP-ribosyltransferase activity is inhibited by PJ34; inhibition is however not specific to TIPARP and other PARP-domain containing proteins are also inhibited by PJ34 (PubMed:30373764). Partially inhibited by KU0058948 (PubMed:30373764).
ADP-ribosyltransferase that mediates mono-ADP-ribosylation of glutamate, aspartate and cysteine residues on target proteins (PubMed:23275542, PubMed:25043379, PubMed:30373764). Acts as a negative regulator of AHR by mediating mono-ADP-ribosylation of AHR, leading to inhibit transcription activator activity of AHR (PubMed:23275542, PubMed:30373764).
A soluble form may be derived from the membrane form by proteolytic processing.
Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules. Modulates NOTCH1 activity by modifying O-fucose residues at specific EGF-like domains resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1 (By similarity). Decreases the binding of JAG1 to NOTCH2 but not that of DLL1 (PubMed:11346656). Essential mediator of somite segmentation and patterning (By similarity).
Able to inhibit growth in several cell lines.
Ubiquitously expressed with high expression in testis and the cerebellum.
Adapter protein linking the transcription factors PAX3 and PAX7 to the histone methylation machinery and involved in myogenesis. Associates with a histone methyltransferase complex that specifically mediates dimethylation and trimethylation of 'Lys-4' of histone H3. Mediates the recruitment of that complex to the transcription factors PAX3 and PAX7 on chromatin to regulate the expression of genes involved in muscle progenitor cells proliferation including ID3 and CDC20 (By similarity).
Interacts with PAX3 and PAX7. Interacts with WDR5; associates with a histone methyltransferase (HMT) complex composed at least of RBBP5, ASH2L, SET1, SET2 and KMT2A/MLL1, KMT2D/MLL2, KMT2C/MLL3 and KMT2B/MLL4 through direct interaction with WDR5 (By similarity).
Most abundantly expressed isoform, at mRNA level according to PubMed:11707072, despite the presence of a premature stop codon in the mRNA that may lead to nonsense-mediated mRNA decay.
Interacts with the CDC2 protein kinase to form a serine/threonine kinase holoenzyme complex also known as maturation promoting factor (MPF). The cyclin subunit imparts substrate specificity to the complex. Binds HEI10. Interacts with catalytically active RALBP1 and CDC2 during mitosis to form an endocytotic complex during interphase. Interacts with CCNF; interaction is required for nuclear localization. Interacts with CDK5RAP3 (PubMed:15790566). Interacts with RFPL4A and UBE2A (By similarity). Interacts with INCA1 (PubMed:21540187).
Phosphorylated by PLK1 at Ser-133 on centrosomes during prophase: phosphorylation by PLK1 does not cause nuclear import. Phosphorylation at Ser-147 was also reported to be mediated by PLK1 but Ser-133 seems to be the primary phosphorylation site.
Ubiquitinated by the SCF(NIPA) complex during interphase, leading to its destruction. Not ubiquitinated during G2/M phases.
Expressed in adult and fetal brain, slightly lower levels in testis and ovary, and intermediate levels in all other peripheral tissues examined. Not expressed in spleen or liver. Expression was high in brain, with highest levels in amygdala and caudate nucleus, followed by thalamus and subthalamic nucleus.
Homodimer; disulfide-linked; to mediate homophilic cell adhesion. Heterodimer with either TENM1 or TENM2. May also form heterodimer with TENM4.
Involved in neural development by regulating the establishment of proper connectivity within the nervous system. Acts in both pre- and postsynaptic neurons in the hippocampus to control the assembly of a precise topographic projection: required in both CA1 and subicular neurons for the precise targeting of proximal CA1 axons to distal subiculum, probably by promoting homophilic cell adhesion. Required for proper dendrite morphogenesis and axon targeting in the vertebrate visual system, thereby playing a key role in the development of the visual pathway. Regulates the formation in ipsilateral retinal mapping to both the dorsal lateral geniculate nucleus (dLGN) and the superior colliculus (SC). May also be involved in the differentiation of the fibroblast-like cells in the superficial layer of mandibular condylar cartilage into chondrocytes.
Binds target DNA via the HMG box domain.
Detected in heart, lung, placenta, skeletal muscle, liver, kidney, spleen, prostate, ovary, msosmall intestine and colon.
Interacts (via C-terminus) with MEF2C (via MADS box).
Transcriptional activator that binds to the consensus sequence 5'-AACAAAG-3' in the promoter of target genes and plays an essential role in embryonic cardiovascular development and lymphangiogenesis. Activates transcription of PROX1 and other genes coding for lymphatic endothelial markers. Plays an essential role in triggering the differentiation of lymph vessels, but is not required for the maintenance of differentiated lymphatic endothelial cells. Plays an important role in postnatal angiogenesis, where it is functionally redundant with SOX17. Interaction with MEF2C enhances transcriptional activation. Besides, required for normal hair development.
Plays a role in somitogenesis. Essential for transcriptional repression of the segmental patterning genes, thus terminating the segmentation program in the presomitic mesoderm, and also required for the maintenance of rostrocaudal polarity in somites (By similarity).
Has antibacterial activity (Probable). Upon stimulation with lipoteichoic acid, promotes cytokines and chemokines production and secretion (PubMed:26649771).
Highly expressed in testis. Is moderately expressed in the prostate and small intestine.
Up-regulated upon stimulation with lipoteichoic acid.
Expressed in most tissues with highest levels in the pancreas, followed by placenta, kidney and lung. Isoform 2 is strongly expressed in brain and pancreas, weaker in heart, placenta, lung, liver and skeletal muscle.
Homodimer; disulfide-linked. Forms a trimeric complex with FBXW7 and NOTCH1. Interacts with MAPK3/ERK1, MAPK1/ERK2, MAP2K1/MEK1, MAP2K2/MEK2, NEDD4, NEDD4L, MAPT/TAU, MAPK7, CREB1, SLC9A3R2/NHERF2 and KCNJ1/ROMK1. Associates with the mammalian target of rapamycin complex 2 (mTORC2) via an interaction with MAPKAP1/SIN1.
Induced by a very large spectrum of stimuli distinct from glucocorticoids and serum. These include aldosterone, cell shrinkage, cell swelling, TGF-beta, ischemic injury of the brain, neuronal excitotoxicity memory consolidation, chronic viral hepatitis, DNA-damaging agents, vitamin D3 psychophysiological stress, iron, glucose, EDN1, CSF2, fibroblast growth factor, platelet-derived growth factor, phorbolesters, follicle-stimulating hormone, sorbitol, heat shock, oxidative stress, UV irradiation, and p53/TP53. Many of these stimuli are highly cell-specific, as is the case, for example for aldosterone, which has been found to stimulate its expression only in cells derived from aldosterone-responsive epithelia. Isoform 2 is not induced by glucocorticoids but by excessive extracellular glucose and by TGFB1, in cultured cells.
Isoform 2 subcellular localization at the cell membrane and resistance to proteasomal degradation is mediated by the sequences within the first 120 amino acids.
Regulated by phosphorylation (PubMed:10191262, PubMed:11096081, PubMed:18925875, PubMed:20338997, PubMed:36373794). Activated by phosphorylation on Ser-422 by mTORC2, transforming it into a substrate for PDPK1 which phosphorylates it on Thr-256 (PubMed:10191262, PubMed:18925875, PubMed:20338997, PubMed:36373794). Phosphorylation on Ser-397 and Ser-401 are also essential for its activity (PubMed:19068477). Phosphorylation on Ser-78 by MAPK7 is required for growth factor-induced cell cycle progression (PubMed:11254654).
Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cellular enzymes, transcription factors, neuronal excitability, cell growth, proliferation, survival, migration and apoptosis. Plays an important role in cellular stress response. Contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Up-regulates Na(+) channels: SCNN1A/ENAC, SCN5A and ASIC1/ACCN2, K(+) channels: KCNJ1/ROMK1, KCNA1-5, KCNQ1-5 and KCNE1, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channels: BSND, CLCN2 and CFTR, glutamate transporters: SLC1A3/EAAT1, SLC1A2 /EAAT2, SLC1A1/EAAT3, SLC1A6/EAAT4 and SLC1A7/EAAT5, amino acid transporters: SLC1A5/ASCT2, SLC38A1/SN1 and SLC6A19, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, glutamate receptor: GRIK2/GLUR6. Up-regulates carriers: SLC9A3/NHE3, SLC12A1/NKCC2, SLC12A3/NCC, SLC5A3/SMIT, SLC2A1/GLUT1, SLC5A1/SGLT1 and SLC15A2/PEPT2. Regulates enzymes: GSK3A/B, PMM2 and Na(+)/K(+) ATPase, and transcription factors: CTNNB1 and nuclear factor NF-kappa-B. Stimulates sodium transport into epithelial cells by enhancing the stability and expression of SCNN1A/ENAC. This is achieved by phosphorylating the NEDD4L ubiquitin E3 ligase, promoting its interaction with 14-3-3 proteins, thereby preventing it from binding to SCNN1A/ENAC and targeting it for degradation. Regulates store-operated Ca(+2) entry (SOCE) by stimulating ORAI1 and STIM1. Regulates KCNJ1/ROMK1 directly via its phosphorylation or indirectly via increased interaction with SLC9A3R2/NHERF2. Phosphorylates MDM2 and activates MDM2-dependent ubiquitination of p53/TP53. Phosphorylates MAPT/TAU and mediates microtubule depolymerization and neurite formation in hippocampal neurons. Phosphorylates SLC2A4/GLUT4 and up-regulates its activity. Phosphorylates APBB1/FE65 and promotes its localization to the nucleus. Phosphorylates MAPK1/ERK2 and activates it by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. Phosphorylates FBXW7 and plays an inhibitory role in the NOTCH1 signaling. Phosphorylates FOXO1 resulting in its relocalization from the nucleus to the cytoplasm. Phosphorylates FOXO3, promoting its exit from the nucleus and interference with FOXO3-dependent transcription. Phosphorylates BRAF and MAP3K3/MEKK3 and inhibits their activity. Phosphorylates SLC9A3/NHE3 in response to dexamethasone, resulting in its activation and increased localization at the cell membrane. Phosphorylates CREB1. Necessary for vascular remodeling during angiogenesis. Sustained high levels and activity may contribute to conditions such as hypertension and diabetic nephropathy. Isoform 2 exhibited a greater effect on cell plasma membrane expression of SCNN1A/ENAC and Na(+) transport than isoform 1.
Two specific sites, one in the kinase domain (Thr-256) and the other in the C-terminal regulatory region (Ser-422), need to be phosphorylated for its full activation (PubMed:10191262). Phosphorylation at Ser-397 and Ser-401 are also essential for its activity (PubMed:19068477). Activated by WNK1, WNK2, WNK3 and WNK4; which promote phosphorylation by mTORC2 (PubMed:36373794).
Ubiquitinated by NEDD4L; which promotes proteasomal degradation. Ubiquitinated by SYVN1 at the endoplasmic reticulum; which promotes rapid proteasomal degradation and maintains a high turnover rate in resting cells. Isoform 2 shows enhanced stability.
Probably mediates the hydrolysis of some nucleoside diphosphate derivatives.
Activation requires autophosphorylation of Ser-356 and, to a lower extent, Ser-352 (By similarity).
Autophosphorylated (PubMed:18593598, PubMed:21733846). Autophosphorylation at Ser-352 and Ser-356 promotes its activity (By similarity).
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WNK subfamily.
Expressed in various cancer cell lines (at protein level). Predominantly expressed in heart, brain, skeletal muscle and colon.
Forms a complex with the phosphorylated form of STK39.
Serine/threonine-protein kinase component of the WNK2-SPAK/OSR1 kinase cascade, which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival, and proliferation (PubMed:17667937, PubMed:18593598, PubMed:21733846). The WNK2-SPAK/OSR1 kinase cascade is composed of WNK2, which mediates phosphorylation and activation of downstream kinases OXSR1/OSR1 and STK39/SPAK (By similarity). Following activation, OXSR1/OSR1 and STK39/SPAK catalyze phosphorylation of ion cotransporters, regulating their activity (By similarity). Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively (PubMed:21733846). Activates SLC12A2, SCNN1A, SCNN1B, SCNN1D and SGK1 and inhibits SLC12A5 (PubMed:21733846). Negatively regulates the EGF-induced activation of the ERK/MAPK-pathway and the downstream cell cycle progression (PubMed:17667937, PubMed:18593598). Affects MAPK3/MAPK1 activity by modulating the activity of MAP2K1 and this modulation depends on phosphorylation of MAP2K1 by PAK1 (PubMed:17667937, PubMed:18593598). WNK2 acts by interfering with the activity of PAK1 by controlling the balance of the activity of upstream regulators of PAK1 activity, RHOA and RAC1, which display reciprocal activity (PubMed:17667937, PubMed:18593598).
Was named WNK/'with no lysine(K)' because key residues for catalysis, including the lysine involved in ATP binding, are either not conserved or differ compared to the residues described in other kinase family proteins.
Antigen-presenting protein that binds self and non-self glycolipids and presents them to T-cell receptors on natural killer T-cells.
During protein synthesis and maturation, CD1 family members bind endogenous lipids that are replaced by lipid or glycolipid antigens when the proteins are internalized and pass through endosomes, before trafficking back to the cell surface.
Heterodimer with B2M (beta-2-microglobulin). Interacts with MHC II.
Core component of the 7SK RNP complex, at least composed of 7SK RNA, LARP7, MEPCE, HEXIM1 (or HEXIM2) and P-TEFb (composed of CDK9 and CCNT1/cyclin-T1) (PubMed:17643375, PubMed:19906723). Interacts with METTL16 (PubMed:29051200). Interacts with RBM7; upon genotoxic stress this interaction is enhanced, triggering the release of inactive P-TEFb complex from the core, yielding to P-TEFb complex activation (PubMed:30824372).
Expressed in chronic myeloid leukemia cells, adrenal gland, brain, cerebellum, kidney, lung, mammary gland and testis (PubMed:12358911). Weakly or not expressed in other tissues (PubMed:12358911).
S-adenosyl-L-methionine-dependent methyltransferase that adds a methylphosphate cap at the 5'-end of 7SK snRNA (7SK RNA), leading to stabilize it (PubMed:17643375, PubMed:19906723, PubMed:30559425). Also has a non-enzymatic function as part of the 7SK RNP complex: the 7SK RNP complex sequesters the positive transcription elongation factor b (P-TEFb) in a large inactive 7SK RNP complex preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation (PubMed:17643375). The 7SK RNP complex also promotes snRNA gene transcription by RNA polymerase II via interaction with the little elongation complex (LEC) (PubMed:28254838). In the 7SK RNP complex, MEPCE is required to stabilize 7SK RNA and facilitate the assembly of 7SK RNP complex (PubMed:19906723). MEPCE has a non-enzymatic function in the 7SK RNP complex; interaction with LARP7 within the 7SK RNP complex occluding its catalytic center (PubMed:19906723).
Expressed preferentially in lymphoid tissues, and in most hematopoietic cell types.
Catalyzes the transmethylation of nonepinephrine (noradrenaline) to form epinephrine (adrenaline), using S-adenosyl-L-methionine as the methyl donor (PubMed:20496117). Other substrates include phenylethanolamine and octopamine (PubMed:8812853, PubMed:16363801, PubMed:16277617). Also methylates normetanephrine (By similarity).
Inhibited by methyl methanethiosulfonate, phenylglyoxal, tetranitromethane and diethyl pyrocarbonate (PubMed:8812853). Inhibited by 4-oxo-1,4-dihydro-quinoline-3,7-dicarboxylic acid, 4-(benzo[d][1,3]dioxol-5-ylamino)-4-oxobutanoic acid and 1,4-diaminonaphthalene-2,6-disulfonic acid (PubMed:20496117).
(Microbial infection) Interacts with Hantaan hantavirus nucleoprotein.
(Microbial infection) Interacts with Seoul hantavirus nucleoprotein.
Autophosphorylation at Tyr-361 in the activation loop activates the kinase and promotes nuclear localization.
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. HIPK subfamily.
Cleaved at Asp-923 and Asp-984 by CASP6 in a p53/TP53-dependent manner. The cleaved form lacks the autoinhibitory C-terminal domain (AID), resulting in a hyperactive kinase, which potentiates p53/TP53 Ser-46 phosphorylation and subsequent activation of the cell death machinery.
Highly expressed in heart, muscle and kidney. Weakly expressed in a ubiquitous way. Down-regulated in several thyroid and breast tumors.
Interacts with CREB1, SIAH1, WSB1, CBX4, TRADD, p53/TP53, TP73, TP63, CREBBP, DAXX, P53DINP1, SKI, SMAD1, SMAD2 and SMAD3, but not SMAD4. Interacts with ATF1, PML, RUNX1, EP300, NKX1-2, NKX2-5, UBE2I, HMGA1, CTBP1, AXIN1, NLK, MYB, POU4F1, POU4F2, POU4F3, UBE2I, UBL1 and ZBTB4. Probably part of a complex consisting of p53/TP53, HIPK2 and AXIN1. Interacts with SP100; positively regulates TP53-dependent transcription. Interacts with SUMO1P1/SUMO5 (PubMed:27211601). Interacts with DAZAP2; the interaction results in phosphorylation of DAZAP2 which causes localization of DAZAP2 to the nucleus, reduces interaction of DAZAP2 with HIPK2 and prevents DAZAP2-dependent degradation of HIPK2 (PubMed:33591310). Interacts with SIAH1; the interaction is promoted by DAZAP2 and results in SIAH1-mediated ubiquitination and subsequent proteasomal degradation of HIPK2 (PubMed:33591310).
Interesting targets for cancer therapy. HIPK2 deregulation would end up in a multifactorial response leading to tumor chemoresistance by affecting p53/TP53 activity on one hand and to angiogenesis and cell proliferation by affecting HIF1A activity on the other hand. May provide important insights in the process of tumor progression, and may also serve as the crucial point in the diagnostic and therapeutical aspects of cancer. Tumor treatment may potential be improved by zinc supplementation in combination with chemotherapy to address hypoxia (PubMed:20514025).
Serine/threonine-protein kinase involved in transcription regulation, p53/TP53-mediated cellular apoptosis and regulation of the cell cycle. Acts as a corepressor of several transcription factors, including SMAD1 and POU4F1/Brn3a and probably NK homeodomain transcription factors. Phosphorylates PDX1, ATF1, PML, p53/TP53, CREB1, CTBP1, CBX4, RUNX1, EP300, CTNNB1, HMGA1, ZBTB4 and DAZAP2. Inhibits cell growth and promotes apoptosis through the activation of p53/TP53 both at the transcription level and at the protein level (by phosphorylation and indirect acetylation). The phosphorylation of p53/TP53 may be mediated by a p53/TP53-HIPK2-AXIN1 complex. Involved in the response to hypoxia by acting as a transcriptional co-suppressor of HIF1A. Mediates transcriptional activation of TP73. In response to TGFB, cooperates with DAXX to activate JNK. Negative regulator through phosphorylation and subsequent proteasomal degradation of CTNNB1 and the antiapoptotic factor CTBP1. In the Wnt/beta-catenin signaling pathway acts as an intermediate kinase between MAP3K7/TAK1 and NLK to promote the proteasomal degradation of MYB. Phosphorylates CBX4 upon DNA damage and promotes its E3 SUMO-protein ligase activity. Activates CREB1 and ATF1 transcription factors by phosphorylation in response to genotoxic stress. In response to DNA damage, stabilizes PML by phosphorylation. PML, HIPK2 and FBXO3 may act synergically to activate p53/TP53-dependent transactivation. Promotes angiogenesis, and is involved in erythroid differentiation, especially during fetal liver erythropoiesis. Phosphorylation of RUNX1 and EP300 stimulates EP300 transcription regulation activity. Triggers ZBTB4 protein degradation in response to DNA damage. In response to DNA damage, phosphorylates DAZAP2 which localizes DAZAP2 to the nucleus, reduces interaction of DAZAP2 with HIPK2 and prevents DAZAP2-dependent ubiquitination of HIPK2 by E3 ubiquitin-protein ligase SIAH1 and subsequent proteasomal degradation (PubMed:33591310). Modulates HMGA1 DNA-binding affinity. In response to high glucose, triggers phosphorylation-mediated subnuclear localization shifting of PDX1. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis.
Sumoylated. When conjugated it is directed to nuclear speckles. Desumoylated by SENP1 (By similarity). Sumoylation on Lys-32 is promoted by the E3 SUMO-protein ligase CBX4.
Ubiquitinated by FBXO3, WSB1 and SIAH1, leading to rapid proteasome-dependent degradation. The degradation mediated by FBXO3, but not ubiquitination, is prevented in the presence of PML. The degradation mediated by WSB1 and SIAH1 is reversibly reduced upon DNA damage.
Unstable in unstressed cells but stabilized upon DNA damage. Induced by UV irradiation and other genotoxic agents (adriamycin ADR, cisplatin CDDP, etoposide, IR, roscovitin), thus triggering p53/TP53 apoptotic response. Consistutively negatively regulated by SIAH1 and WSB1 through proteasomal degradation. This negative regulation is impaired upon genotoxic stress. Repressed upon hypoxia (often associated with tumors), through MDM2- (an E3 ubiquitin ligases) mediated proteasomal degradation, thus inactivating p53/TP53 apoptotic response. This hypoxia repression is reversed by zinc. The stabilization mediated by DNA damage requires the damage checkpoint kinases ATM and ATR.
Acts as a transcriptional corepressor in a IRF2-dependent manner; this repression is not mediated by histone deacetylase activities. May act as an E3 ligase towards JDP2, enhancing its polyubiquitination. Represses ATF2-dependent transcriptional activation.
Interacts with IRF2. Part of a corepressor complex containing IRF2 and IRF2BP2. Interacts with JDP2.
Adapter protein which non-covalently associates with activating receptors found on the surface of a variety of immune cells to mediate signaling and cell activation following ligand binding by the receptors (PubMed:9490415, PubMed:9655483, PubMed:10604985). TYROBP is tyrosine-phosphorylated in the ITAM domain following ligand binding by the associated receptors which leads to activation of additional tyrosine kinases and subsequent cell activation (PubMed:9490415). Also has an inhibitory role in some cells (PubMed:21727189). Non-covalently associates with activating receptors of the CD300 family to mediate cell activation (PubMed:15557162, PubMed:16920917, PubMed:17928527, PubMed:26221034). Also mediates cell activation through association with activating receptors of the CD200R family (By similarity). Required for neutrophil activation mediated by integrin (By similarity). Required for the activation of myeloid cells mediated by the CLEC5A/MDL1 receptor (PubMed:10449773). Associates with natural killer (NK) cell receptors such as KIR2DS2 and the KLRD1/KLRC2 heterodimer to mediate NK cell activation (PubMed:9490415, PubMed:9655483, PubMed:23715743). Also enhances trafficking and cell surface expression of NK cell receptors KIR2DS1, KIR2DS2 and KIR2DS4 and ensures their stability at the cell surface (PubMed:23715743). Associates with SIRPB1 to mediate activation of myeloid cells such as monocytes and dendritic cells (PubMed:10604985). Associates with TREM1 to mediate activation of neutrophils and monocytes (PubMed:10799849). Associates with TREM2 on monocyte-derived dendritic cells to mediate up-regulation of chemokine receptor CCR7 and dendritic cell maturation and survival (PubMed:11602640). Association with TREM2 mediates cytokine-induced formation of multinucleated giant cells which are formed by the fusion of macrophages (PubMed:18957693). Stabilizes the TREM2 C-terminal fragment (TREM2-CTF) produced by TREM2 ectodomain shedding which suppresses the release of pro-inflammatory cytokines (PubMed:25957402). In microglia, required with TREM2 for phagocytosis of apoptotic neurons (By similarity). Required with ITGAM/CD11B in microglia to control production of microglial superoxide ions which promote the neuronal apoptosis that occurs during brain development (By similarity). Promotes pro-inflammatory responses in microglia following nerve injury which accelerates degeneration of injured neurons (By similarity). Positively regulates the expression of the IRAK3/IRAK-M kinase and IL10 production by liver dendritic cells and inhibits their T cell allostimulatory ability (By similarity). Negatively regulates B cell proliferation (PubMed:21727189). Required for CSF1-mediated osteoclast cytoskeletal organization (By similarity). Positively regulates multinucleation during osteoclast development (By similarity).
Expressed at low levels in the early development of the hematopoietic system and in the promonocytic stage and at high levels in mature monocytes. Expressed in hematological cells and tissues such as peripheral blood leukocytes and spleen. Also found in bone marrow, lymph nodes, placenta, lung and liver. Expressed at lower levels in different parts of the brain especially in the basal ganglia and corpus callosum.
Following ligand binding by associated receptors, tyrosine phosphorylated in the ITAM domain which leads to activation of additional tyrosine kinases and subsequent cell activation.
Homodimer; disulfide-linked (PubMed:20890284). Homotrimer; disulfide-linked (PubMed:25981043). Homotetramer; disulfide-linked (PubMed:25981043). Homotrimers and homotetramers form when low levels of partner receptors are available and are competitive with assembly with interacting receptors (PubMed:25981043). They may represent alternative oligomerization states or may be intermediates in the receptor assembly process (PubMed:25981043). Binding of a metal cation aids in homooligomerization through coordination of the metal ion by the subunits of the oligomer (PubMed:25981043). Interacts with TREM1 (PubMed:10799849). Interacts with TREM2 (PubMed:11602640, PubMed:25957402). Interacts with SIRPB1 (PubMed:10604985). Interacts with CLECSF5 (PubMed:10449773). Interacts with SIGLEC14 (PubMed:17012248). Interacts with CD300LB and CD300E (PubMed:15557162, PubMed:16920917, PubMed:17928527). Interacts with CD300C2 (By similarity). Interacts (via ITAM domain) with SYK (via SH2 domains); activates SYK mediating neutrophil and macrophage integrin-mediated activation (By similarity). Interacts with KLRC2, KIR2DS3 and KIR2DS5 (PubMed:18624290, PubMed:20890284). Interacts with CD300H (PubMed:26221034). Interacts with KIR2DS1 (PubMed:23715743). Interacts with KLRD1 (PubMed:9655483, PubMed:15940674). Interacts with SIGLEC1 (PubMed:26358190).
Adipose tissue. Expression is higher in subcutaneous adipose tissue as compared to visceral adipose tissue.
Binds 2 magnesium ions, but the ions are only loosely bound to the protein.
Phosphatase which catalyzes the conversion of NADP(+) to NAD(+) and of NADPH to NADH (PubMed:31147539). Shows a small preference for NADPH over NADP(+) (PubMed:31147539). Represses translation and promotes degradation of target mRNA molecules (PubMed:29860338). Plays an important role in post-transcriptional regulation of metabolic genes under circadian control (By similarity). Exerts a rhythmic post-transcriptional control of genes necessary for metabolic functions including nutrient absorption, glucose/insulin sensitivity, lipid metabolism, adipogenesis, inflammation and osteogenesis (By similarity). Plays an important role in favoring adipogenesis over osteoblastogenesis and acts as a key regulator of the adipogenesis/osteogenesis balance (By similarity). Promotes adipogenesis by facilitating PPARG nuclear translocation which activates its transcriptional activity (By similarity). Regulates circadian expression of NOS2 in the liver and negatively regulates the circadian expression of IGF1 in the bone (By similarity). Critical for proper development of early embryos (By similarity).
Was initially shown to have low deadenylase activity that was lost when the metal-binding Glu was mutated (By similarity). Later studies showed that the purified protein lacked deadenylase activity (PubMed:29860338, PubMed:30389976). Was subsequently shown to act as a phosphatase (PubMed:31147539).
Expressed in heart, spleen, liver, stomach, muscle, lung, testis, skin, PBL and bone marrow.
Calcium-dependent cell-adhesion protein. Mediates functions in neuroprogenitor cell proliferation and differentiation. In the heart, has a critical role for proper morphogenesis of the mitral valve, acting in the regulation of cell migration involved in valve formation (PubMed:26258302).
Expressed in fibroblasts but not in melanocytes or keratinocytes.
Heterophilic interaction with FAT4; this interaction affects their respective protein levels.
Homodimer (PubMed:31649201). Heteromultimer with other K-Cl cotransporters (PubMed:11551954).
Mediates electroneutral potassium-chloride cotransport when activated by cell swelling. May contribute to cell volume homeostasis in single cells (PubMed:10913127, PubMed:34031912). May be involved in the regulation of basolateral Cl(-) exit in NaCl absorbing epithelia (By similarity).
Not detected in circulating reticulocytes.
Phosphorylated, phosphorylation may regulate transporter activity.
Ubiquitous (PubMed:8663127, PubMed:9516379). Levels are much higher in erythrocytes from patients with Hb SC and Hb SS compared to normal AA erythrocytes (PubMed:9516379). This may contribute to red blood cell dehydration and to the manifestation of sickle cell disease by increasing the intracellular concentration of HbS (PubMed:9516379).
May act as a guanine nucleotide exchange factor (GEF).
(Microbial infection) In case of infection by HIV-1, the EDVP complex is hijacked by HIV-1 via interaction between HIV-1 Vpr and DCAF1/VPRBP, leading to ubiquitination and degradation.
Activated by cytotoxic events and down-regulated during aging. In peripheral T-lymphocytes, induced By CD3 and by PMA/ionomycin. Inhibited by herbimycin B.
Activation of telomerase has been implicated in cell immortalization and cancer cell pathogenesis.
Belongs to the reverse transcriptase family. Telomerase subfamily.
Catalytic component of the telomerase holoenzyme complex composed of one molecule of TERT, one molecule of WRAP53/TCAB1, two molecules of H/ACA ribonucleoprotein complex subunits DKC1, NOP10, NHP2 and GAR1, and a telomerase RNA template component (TERC) (PubMed:19179534, PubMed:20351177, PubMed:29695869). The telomerase holoenzyme complex is associated with TEP1, SMG6/EST1A and POT1 (PubMed:19179534). The molecular chaperone HSP90/P23 complex is required for correct assembly and stabilization of the active telomerase (PubMed:11274138). Interacts directly with HSP90A and PTGES3 (PubMed:11274138). Interacts with HSPA1A; the interaction occurs in the absence of TERC and dissociates once the complex has formed (PubMed:11274138). Interacts with RAN; the interaction promotes nuclear export of TERT (PubMed:12808100). Interacts with XPO1 (PubMed:12808100). Interacts with PTPN11; the interaction retains TERT in the nucleus (PubMed:18829466). Interacts with NCL (via RRM1 and C-terminal RRM4/Arg/Gly-rich domains); the interaction is important for nucleolar localization of TERT (PubMed:15371412). Interacts with SMARCA4 (via the bromodomain); the interaction regulates Wnt-mediated signaling (By similarity). Interacts with MCRS1 (isoform MCRS2); the interaction inhibits in vitro telomerase activity (PubMed:15044100). Interacts with PIF1; the interaction has no effect on the elongation activity of TERT (By similarity). Interacts with PML; the interaction recruits TERT to PML bodies and inhibits telomerase activity (PubMed:19567472). Interacts with GNL3L (By similarity). Interacts with isoform 1 and isoform 2 of NVL (PubMed:22226966). Interacts with DHX36 (PubMed:21846770). Interacts with ATF7 (PubMed:29490055).
Expressed at a high level in thymocyte subpopulations, at an intermediate level in tonsil T-lymphocytes, and at a low to undetectable level in peripheral blood T-lymphocytes.
Genetic variations in TERT are associated with coronary artery disease (CAD).
Phosphorylation at Tyr-707 under oxidative stress leads to translocation of TERT to the cytoplasm and reduces its antiapoptotic activity. Dephosphorylated by SHP2/PTPN11 leading to nuclear retention. Phosphorylation at Ser-227 by the AKT pathway promotes nuclear location. Phosphorylation at the G2/M phase at Ser-457 by DYRK2 promotes ubiquitination by the EDVP complex and degradation.
Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Active in progenitor and cancer cells. Inactive, or very low activity, in normal somatic cells. Catalytic component of the teleromerase holoenzyme complex whose main activity is the elongation of telomeres by acting as a reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. Catalyzes the RNA-dependent extension of 3'-chromosomal termini with the 6-nucleotide telomeric repeat unit, 5'-TTAGGG-3'. The catalytic cycle involves primer binding, primer extension and release of product once the template boundary has been reached or nascent product translocation followed by further extension. More active on substrates containing 2 or 3 telomeric repeats. Telomerase activity is regulated by a number of factors including telomerase complex-associated proteins, chaperones and polypeptide modifiers. Modulates Wnt signaling. Plays important roles in aging and antiapoptosis.
The RNA-interacting domain 1 (RD1)/N-terminal extension (NTE) is required for interaction with the pseudoknot-template domain of each of TERC dimers. It contains anchor sites that bind primer nucleotides upstream of the RNA-DNA hybrid and is thus an essential determinant of repeat addition processivity.
The RNA-interacting domain 2 (RD2) is essential for both interaction with the CR4-CR5 domain of TERC and for DNA synthesis.
The primer grip sequence in the RT domain is required for telomerase activity and for stable association with short telomeric primers.
Ubiquitinated by the EDVP complex, a E3 ligase complex following phosphorylation at Ser-457 by DYRK2. Ubiquitinated leads to proteasomal degradation.
Allosterically activated by ADP, AMP, or fructose 2,6-bisphosphate, and allosterically inhibited by ATP or citrate.
Belongs to the phosphofructokinase type A (PFKA) family. ATP-dependent PFK group I subfamily. Eukaryotic two domain clade "E" sub-subfamily.
Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis.
GlcNAcylation decreases enzyme activity.
Homo- and heterotetramers (By similarity). Phosphofructokinase (PFK) enzyme functions as a tetramer composed of different combinations of 3 types of subunits, called PFKM (where M stands for Muscle), PFKL (Liver) and PFKP (Platelet). The composition of the PFK tetramer differs according to the tissue type it is present in. In muscles, it is composed of 4 PFKM subunits (also called M4). In the liver, the predominant form is a tetramer of PFKL subunits (L4). In erythrocytes, both PFKM and PFKL subunits randomly tetramerize to form M4, L4 and other combinations (ML3, M2L2, M3L). In platelets, brain and fibroblasts, PFK contains a higher proportion of PFKP subunits. The kinetic and regulatory properties of the tetrameric enzyme are dependent on the subunit composition, hence can vary across tissues (Probable). Interacts with ATG4B; promoting phosphorylation of ATG4B (PubMed:33607258).
Phosphorylation at Ser-386 promotes interaction with ATG4B.
Highly induced by bacterial lipopolysaccharides (LPS) and TGFB1, more moderately by IFNG, IL18, IL1B, TNF and the dinucleotide CpG (at protein level). Constitutive expression in bone marrow macrophages is down-regulated in the presence of IL4 and CSF2. Induced by phorbol myristate acetate (PMA) in different cell lines.
Immune regulatory cytokine that acts as a suppressor of innate inflammatory and immune responses involved in curbing excessive inflammation. Signaling can occur via two mechanisms, intracellularly through nuclear translocation with SMAD3 and extracellularly after secretion and binding to its receptor composed of IL18R1 and IL18RAP. Suppresses, or reduces, pro-inflammatory cytokine production, including IL1A and IL6, as well as CCL12, CSF1, CSF2, CXCL13, IL1B, IL23A and IL1RN, but spares anti-inflammatory cytokines. Inhibits dendritic cell activation.
In general, low constitutive expression, if any, in healthy tissues; high expression in inflammatory counterparts, including in synovial tissues from individuals with active rheumatoid arthritis. Isoform A, isoform B and isoform C are expressed in testis, colon, placenta, lung and lymph node. Isoform D and isoform E were found only in testis and bone marrow. Whereas only isoform A is found in brain, only isoform B in kidney and only isoform C in heart.
Interacts with SMAD3. Binds IL18R1, but not to IL1R1, with lower affinity than IL18, and does not seem to act as a receptor antagonist for IL18. Interacts with cargo receptor TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion (PubMed:32272059).
Proteolytically converted to the mature form by CASP1.
The name IL-HL refers to isoform B containing polymorphisms Val-31 and Ala-42.
Interacts with YWHAQ; the interaction requires KANK1 phosphorylation at Ser-325 and is enhanced by growth factor stimulation (PubMed:18458160). Interacts with YWHAB, YWHAG, YWHAE, YWHAH, YWHAZ and SFN; the interaction requires KANK1 phosphorylation at Ser-325 (PubMed:18458160). Interacts with ARFGEF1; however, colocalization cannot be experimentally confirmed (PubMed:22084092). Interacts with BAIAP2 (PubMed:19171758). Interacts (via ANK repeats 1-5) with KIF21A (via residues 1146-1167); KIF21A enhances translocation of KANK1 to the plasma membrane (PubMed:19559006, PubMed:29183992). Interacts with CTNNB1 (PubMed:16968744).
Involved in the control of cytoskeleton formation by regulating actin polymerization. Inhibits actin fiber formation and cell migration (PubMed:25961457). Inhibits RhoA activity; the function involves phosphorylation through PI3K/Akt signaling and may depend on the competitive interaction with 14-3-3 adapter proteins to sequester them from active complexes (PubMed:25961457). Inhibits the formation of lamellipodia but not of filopodia; the function may depend on the competitive interaction with BAIAP2 to block its association with activated RAC1 (PubMed:25961457). Inhibits fibronectin-mediated cell spreading; the function is partially mediated by BAIAP2. Inhibits neurite outgrowth. Involved in the establishment and persistence of cell polarity during directed cell movement in wound healing. In the nucleus, is involved in beta-catenin-dependent activation of transcription. Potential tumor suppressor for renal cell carcinoma. Regulates Rac signaling pathways (PubMed:25961457).
Widely expressed. Isoform 1 is predominantly expressed in heart and kidney. Isoform 2 probably is widely expressed at basic levels.
Available under the names Roferon-A (Roche) or Intron-A (Schering-Plough). Used as an anticancer drug for its antiproliferative activity.
Produced by macrophages, IFN-alpha have antiviral activities.
Three alleles exist; alpha-2A, alpha-2B (shown here) and alpha-2C (PubMed:7627809). Allele alpha-2B is the predominant allele while allele alpha-2A is less predominant and alpha-2C only a minor allelic variant.
Interacts with PAK1 (PubMed:25766321). Interacts (via C-terminus) with Ras-related Rab-5 proteins (PubMed:20376209). Interacts (via C-terminus) with Ras-related Rap-2 proteins (PubMed:20376209). Interacts with PIK3CA and PIK3R1 (By similarity). Interacts (via N-terminus) with FSCN1; this interaction induces neuron axon development (By similarity). Interacts with DBN1 (By similarity).
Overexpressed in gastric cancer cells and tissues (at protein level) (PubMed:25766321).
Phosphorylated by PAK1 (PubMed:25766321). Isoform 1 is partially phosphorylated (By similarity).
Plays a role in the generation of neuronal polarity formation and axon growth (By similarity). Implicated in the formation of a single axon by developing neurons (By similarity). May inhibit the formation of additional axons by inhibition of PI3K in minor neuronal processes (By similarity). Plays a role in the formation of F-actin-enriched protrusive structures at the cell periphery (PubMed:25766321). Plays a role in cytoskeletal organization by regulating the subcellular localization of FSCN1 and DBN1 at axonal growth cones (By similarity). Promotes gastric cancer cell migration and invasion in a PAK1-dependent manner (PubMed:25766321).
(Microbial infection) Interacts with Epstein-Barr virus (EBV) tegument protein BGLF2; this interaction participates in the regulation of cellular miRNA by the virus, leading to enhanced SUMOylation.
(Microbial infection) Upon Sars-CoV-2 infection, associates with viral miRNA-like small RNA, CoV2-miR-O7a, and may repress mRNAs, such as BATF2, to evade the IFN response.
Belongs to the argonaute family. Ago subfamily.
Hydroxylated. 4-hydroxylation appears to enhance protein stability but is not required for miRNA-binding or endonuclease activity.
Interacts with DICER1 through its Piwi domain and with TARBP2 during assembly of the RNA-induced silencing complex (RISC)(PubMed:14749716, PubMed:16271387, PubMed:16289642, PubMed:16357216, PubMed:15973356, PubMed:17507929, PubMed:18690212, PubMed:18178619, PubMed:33199684). Together, DICER1, AGO2 and TARBP2 constitute the trimeric RISC loading complex (RLC), or micro-RNA (miRNA) loading complex (miRLC). Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto AGO2. AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. Note however that the term RISC has also been used to describe the trimeric RLC/miRLC. The formation of RISC complexes containing siRNAs rather than miRNAs appears to occur independently of DICER1. Interacts with AGO1. Also interacts with DDB1, DDX5, DDX6, DDX20, DHX30, DHX36, DDX47, DHX9, ELAVL, FXR1, GEMIN4, HNRNPF, IGF2BP1, ILF3, IMP8, MATR3, PABPC1, PRMT5, P4HA1, P4HB, RBM4, SART3, TNRC6A, TNRC6B, UPF1 and YBX1. Interacts with the P-body components DCP1A and XRN1. Associates with polysomes and messenger ribonucleoproteins (mNRPs). Interacts with RBM4; the interaction is modulated under stress-induced conditions, occurs under both cell proliferation and differentiation conditions and in an RNA- and phosphorylation-independent manner. Interacts with LIMD1, WTIP and AJUBA. Interacts with TRIM71; the interaction increases in presence of RNA (PubMed:23125361). Interacts with APOBEC3G in an RNA-dependent manner. Interacts with APOBEC3A, APOBEC3C, APOBEC3F and APOBEC3H. Interacts with DICER1, TARBP2, EIF6, MOV10 and RPL7A (60S ribosome subunit); they form a large RNA-induced silencing complex (RISC) (PubMed:17507929, PubMed:24726324). Interacts with FMR1 (PubMed:14703574). Interacts with ZFP36 (PubMed:15766526). Found in a complex, composed of AGO2, CHD7 and FAM172A (By similarity). Interacts with RC3H1; the interaction is RNA independent (PubMed:25697406). Interacts with SND1 (PubMed:14508492, PubMed:28546213). Interacts with SYT11 (By similarity). Interacts with CLNK (PubMed:26009488). Interacts with GARRE1 (PubMed:29395067).
Phosphorylated. A phosphorylation cycle of C-terminal serine cluster (Ser-824-Ser-834) regulates the release of target mRNAs. Target-binding leads to phosphorylation of these residues by CSNK1A1, which reduces the affinity of AGO2 for mRNA and enables target release. The ANKRD52-PPP6C phosphatase complex dephosphorylates the residues, which primes AGO2 for binding a new target.
Phosphorylation at Ser-387 by AKT3; leads to up-regulate translational repression of microRNA target and down-regulate endonucleolytic cleavage.
Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC). The 'minimal RISC' appears to include AGO2 bound to a short guide RNA such as a microRNA (miRNA) or short interfering RNA (siRNA). These guide RNAs direct RISC to complementary mRNAs that are targets for RISC-mediated gene silencing. The precise mechanism of gene silencing depends on the degree of complementarity between the miRNA or siRNA and its target. Binding of RISC to a perfectly complementary mRNA generally results in silencing due to endonucleolytic cleavage of the mRNA specifically by AGO2. Binding of RISC to a partially complementary mRNA results in silencing through inhibition of translation, and this is independent of endonuclease activity. May inhibit translation initiation by binding to the 7-methylguanosine cap, thereby preventing the recruitment of the translation initiation factor eIF4-E. May also inhibit translation initiation via interaction with EIF6, which itself binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. The inhibition of translational initiation leads to the accumulation of the affected mRNA in cytoplasmic processing bodies (P-bodies), where mRNA degradation may subsequently occur. In some cases RISC-mediated translational repression is also observed for miRNAs that perfectly match the 3' untranslated region (3'-UTR). Can also up-regulate the translation of specific mRNAs under certain growth conditions. Binds to the AU element of the 3'-UTR of the TNF (TNF-alpha) mRNA and up-regulates translation under conditions of serum starvation. Also required for transcriptional gene silencing (TGS), in which short RNAs known as antigene RNAs or agRNAs direct the transcriptional repression of complementary promoter regions.
The Piwi domain may perform RNA cleavage by a mechanism similar to that of RNase H. However, while RNase H utilizes a triad of Asp-Asp-Glu (DDE) for metal ion coordination, this protein appears to utilize a triad of Asp-Asp-His (DDH).
Ubiquitinated on surface-exposed lysines by a SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 during target-directed microRNA degradation (TDMD), a process that mediates degradation of microRNAs (miRNAs) (PubMed:33184234, PubMed:33184237). Ubiquitination by the SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 leads to its subsequent degradation, thereby exposing miRNAs for degradation (PubMed:33184234, PubMed:33184237). ZSWIM8 recognizes and binds AGO2 when it is engaged with a TDMD target (PubMed:33184237).
cDNA contains a duplication of an internal sequence at the 5' end.
Zinc-dependent transcriptional regulator of cellular adaption to conditions of exposure to heavy metals (PubMed:8065932). Binds to metal responsive elements (MRE) in promoters and activates the transcription of metallothionein genes like metallothionein-2/MT2A (PubMed:8065932). Also regulates the expression of metalloproteases in response to intracellular zinc and functions as a catabolic regulator of cartilages (By similarity).
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol.
Belongs to the G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRA2A sub-subfamily.
Interacts (via C-terminal cytoplasmic tail) with PI4KA.
Regulates localization of phosphatidylinositol 4-kinase (PI4K) to the plasma membrane, possibly by reducing the association of TTC7 (TTC7A or TTC7B) with the PI4K complex (PubMed:25608530). Acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (PubMed:25608530). May also play a role in fasting-induced catabolism (By similarity).
May be involved in cell cycle regulation.
N-terminally acetylated in a HYPK-dependent manner by the NatA acetyltransferase complex which is composed of NAA10 and NAA15.
Ubiquitinated; mediated by UHRF2 and leading to its subsequent proteasomal degradation.
Controls vesicular trafficking from endosomes to the trans-Golgi network (TGN). Acts as a negative regulator of TLR9 signaling and can suppress TLR9-triggered TNFA, IL6, and IFNB production in macrophages by promoting TLR9 lysosomal degradation. Also negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4. Promotes megakaryocytic differentiation by increasing NF-kappa-B-dependent IL6 production and subsequently enhancing the association of STAT3 with GATA1. Not involved in the regulation of the EGF- and EGFR degradation pathway.
Expressed in heart, placenta, lung, skeletal muscle and peripheral blood leukocyte.
Detected in all of the tissues except brain, testis and small intestine, expression level is higher in placenta, heart, lung, skeletal muscle, spleen and leukocyte. Up-regulated in various pancreatic ductal adenocarcinomas and pancreatic intraepithelial neoplasias.
Homodimer and heterodimer with S100A1. Interacts with S100PBP and S100Z. Interacts with CACYBP in a calcium-dependent manner. Dimeric form binds to and activates EZR/Ezrin by unmasking its F-actin binding sites. Interacts with PPP5C (via TPR repeats); the interaction is calcium-dependent and modulates PPP5C activity.
May function as calcium sensor and contribute to cellular calcium signaling. In a calcium-dependent manner, functions by interacting with other proteins, such as EZR and PPP5C, and indirectly plays a role in physiological processes like the formation of microvilli in epithelial cells. May stimulate cell proliferation in an autocrine manner via activation of the receptor for activated glycation end products (RAGE).
In skeletal muscle, isoform 1 is more abundant than isoform 2.
Methylated at Arg-563 in response to EGF treatment. This modification leads to destabilization of the protein, possibly through proteasomal degradation.
Monomer. Homodimer. Heterodimerizes with BRAF and this heterodimer possesses a highly increased kinase activity compared to the respective homodimers or monomers (PubMed:16508002). Heterodimerization is mitogen-regulated and enhanced by 14-3-3 proteins (PubMed:16508002). MAPK1/ERK2 activation can induce a negative feedback that promotes the dissociation of the heterodimer (PubMed:16508002). Forms a multiprotein complex with Ras (M-Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC) (PubMed:16630891). Interacts with LZTR1 (PubMed:30368668). Interacts with Ras proteins; the interaction is antagonized by RIN1 (PubMed:11784866). Weakly interacts with RIT1. Interacts (via N-terminus) with RGS14 (via RBD domains); the interaction mediates the formation of a ternary complex with BRAF, a ternary complex inhibited by GNAI1 (By similarity). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Interacts with STK3/MST2; the interaction inhibits its pro-apoptotic activity (PubMed:15618521). Interacts (when phosphorylated at Ser-259) with YWHAZ (unphosphorylated at 'Thr-232') (PubMed:9360956, PubMed:31024343). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2 (By similarity). Interacts with MAP3K5/ASF1 (via N-terminus) and this interaction inhibits the proapoptotic function of MAP3K5/ASK1 (PubMed:11427728). Interacts with PAK1 (via kinase domain) (PubMed:11733498). The phosphorylated form interacts with PIN1 (By similarity). The Ser-338 and Ser-339 phosphorylated form (by PAK1) interacts with BCL2 (PubMed:15849194). Interacts with PEBP1/RKIP and this interaction is enhanced if RAF1 is phosphorylated on residues Ser-338, Ser-339, Tyr-340 and Tyr-341 (PubMed:18294816). Interacts with ADCY2, ADCY5, ADCY6, DGKH, RCAN1/DSCR1, PPP1R12A, PKB/AKT1, PPP2CA, PPP2R1B, SPRY2, SPRY4, CNKSR1/CNK1, KSR2 and PHB/prohibitin (PubMed:10801873, PubMed:11719507, PubMed:12717443, PubMed:15385642, PubMed:15935327, PubMed:19710016, PubMed:10576742). Interacts with ROCK2 (By similarity). In its active form, interacts with PRMT5 (PubMed:21917714). Interacts with FAM83B; displaces 14-3-3 proteins from RAF1 and activates RAF1 (PubMed:22886302). Interacts with PDE8A; the interaction promotes RAF1 activity (PubMed:23509299). Interacts with MFHAS1 (PubMed:23327923). Interacts with GLS (PubMed:22538822). Interacts with NEK10 and MAP2K1; the interaction is direct with NEK10 and required for ERK1/2-signaling pathway activation in response to UV irradiation (PubMed:20956560).
Phosphorylation at Thr-269, Ser-338, Tyr-341, Thr-491 and Ser-494 results in its activation. Phosphorylation at Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2 results in its inactivation. Phosphorylation at Ser-259 induces the interaction with YWHAZ and inactivates kinase activity. Dephosphorylation of Ser-259 by the complex containing protein phosphatase 1, SHOC2 and M-Ras/MRAS relieves inactivation, leading to stimulate RAF1 activity. Phosphorylation at Ser-338 by PAK1 and PAK5 and Ser-339 by PAK1 is required for its mitochondrial localization. Phosphorylation at Ser-621 in response to growth factor treatment stabilizes the protein, possibly by preventing proteasomal degradation. Phosphorylation at Ser-289, Ser-296, Ser-301, Ser-338 and Ser-621 are somehow linked to the methylation potential of cells. Treatment of cells with HGF in the presence of the methylation inhibitor 5'-methylthioadenosine (MTA) results in increased phosphorylation at Ser-338 and Ser-621 and decreased phosphorylation at Ser-296, Ser-301 and Ser-338. Dephosphorylation at Ser-338 by PPP5C results in an activity decrease.
Regulation is a highly complex process involving membrane recruitment, protein-protein interactions, dimerization, and phosphorylation/dephosphorylation events. Ras-GTP recruits RAF1 to the membrane, thereby promoting its activation. The inactive conformation of RAF1 is maintained by autoinhibitory interactions occurring between the N-terminal regulatory and the C-terminal catalytic domains and by the binding of a 14-3-3 protein that contacts two phosphorylation sites, Ser-259 and Ser-621. Upon mitogenic stimulation, Ras and PPP2R1A cooperate to release autoinhibition and the subsequent phosphorylation of activating sites: Ser-338, Tyr-341, Thr-491, and Ser-494, yields a fully active kinase. Through a negative feedback mechanism involving MAPK1/ERK2, RAF1 is phosphorylated on Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2, which yields an inactive, desensitized kinase. The signaling-competent conformation of RAF1 is finally re-established by the coordinated action of PIN1, a prolyl isomerase that converts pSer and pThr residues from the cis to the trans conformation, which is preferentially recognized and dephosphorylated by PPP2R1A. Activated by homodimerization and heterodimerization (with BRAF). Also regulated through association with other proteins such as KSR2, CNKSR1/CNK1, PEBP1/RKIP, PHB/prohibitin and SPRY4. PEBP1/RKIP acts by dissociating RAF1 from its substrates MAP2K1/MEK1 and MAP2K2/MEK2. PHB/prohibitin facilitates the displacement of 14-3-3 from RAF1 by activated Ras, thereby promoting cell membrane localization and phosphorylation of RAF1 at the activating Ser-338. SPRY4 inhibits Ras-independent, but not Ras-dependent, activation of RAF1. CNKSR1/CNK1 regulates Src-mediated RAF1 activation.
Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation.
By 12-O-tetradecanoylphorbol-13-acetate (TPA) in promyelocytic HL-60 cells.
GTPase activator for the nuclear Ras-related regulatory protein RAP-1A (KREV-1), converting it to the putatively inactive GDP-bound state.
Significant expression seen in the brain, kidney and pancreas. Abundant in the cerebral cortex and expressed at much lower levels in the spinal cord. Not detected in the lymphoid tissues.
Detected in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas, and at very low levels in brain.
Binds 1 divalent metal cation per subunit. Most active with Zn(2+) and Mn(2+) ions. The physiological cofactor is most likely Ca(2+) or Mg(2+).
Gluconolactonase catalyzes a key step in ascorbic acid (vitamin C) biosynthesis, but primates lack the last enzyme in the pathway and are unable to synthesize vitamin C.
Gluconolactonase with low activity towards other sugar lactones, including gulonolactone and galactonolactone. Can also hydrolyze diisopropyl phosphorofluoridate and phenylacetate (in vitro). Calcium-binding protein. Modulates Ca(2+) signaling, and Ca(2+)-dependent cellular processes and enzyme activities (By similarity).
The PH domain mediates the binding to phosphoinositides.
Expressed in testis, in germ cells in seminiferous tubules (at protein level) (PubMed:15591451, PubMed:19419568). Prominently expressed in pachytene/diplotene stage spematocytes (PubMed:33438010).
Involved in male fertility. Required for manchette development and acrosome biogenesis during spermiogenesis (By similarity). Binds in vitro to phospholipids, including phosphatidylinositol 3-phosphate (PtdIns(3)P), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), phosphatidylinositol 4-phosphate (PtdIns(4)P) and phosphatidic acid (PA) (PubMed:19419568). Contrary to other profilin family members, does not bind to actin in vitro (PubMed:19419568).
Belongs to the sarcoglycan alpha/epsilon family.
Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.
Interacts with the syntrophin SNTA1. Cross-link to form 2 major subcomplexes: one consisting of SGCB, SGCD and SGCG and the other consisting of SGCB and SGCD. The association between SGCB and SGCG is particularly strong while SGCA is loosely associated with the other sarcoglycans (By similarity).
Most strongly expressed in skeletal muscle. Also expressed in cardiac muscle and, at much lower levels, in lung. In the fetus, most abundant in cardiac muscle and, at lower levels, in lung. Also detected in liver and kidney. Not expressed in brain.
Interacts directly with activated HRAS; a RASSF5-STK4/MST1 complex probably associates with activated HRAS (By similarity). Interacts with KRAS (By similarity). Probably interacts with Ras-like GTPases RRAS, MRAS, RAP1B, RAP2A and RALA (By similarity). Interacts with RRAS2 (PubMed:31130282). Can self-associate (By similarity). Interacts with RSSF1 isoform A (By similarity). The RSSF1 isoform A-RSSF5 heterodimer probably mediates the association of RSSF1 with HRAS (By similarity). Isoform 2 interacts with activated RAP1A and ITGAL/LFA-1 (PubMed:12845325, PubMed:15569673). Binds STK4/MST1, inhibiting STK4/MST1 autoactivation (PubMed:15109305).
Potential tumor suppressor. Seems to be involved in lymphocyte adhesion by linking RAP1A activation upon T-cell receptor or chemokine stimulation to integrin activation. Isoform 2 stimulates lymphocyte polarization and the patch-like distribution of ITGAL/LFA-1, resulting in an enhanced adhesion to ICAM1. Together with RAP1A may participate in regulation of microtubule growth. The association of isoform 2 with activated RAP1A is required for directional movement of endothelial cells during wound healing. May be involved in regulation of Ras apoptotic function. The RASSF5-STK4/MST1 complex may mediate HRAS and KRAS induced apoptosis.
Widely expressed. Frequently down-regulated in lung tumor cell lines and primary lung tumors.
Cell surface proteoglycan (PubMed:14610063). Negatively regulates the hedgehog signaling pathway when attached via the GPI-anchor to the cell surface by competing with the hedgehog receptor PTC1 for binding to hedgehog proteins (By similarity). Binding to the hedgehog protein SHH triggers internalization of the complex by endocytosis and its subsequent lysosomal degradation (By similarity). Positively regulates the canonical Wnt signaling pathway by binding to the Wnt receptor Frizzled and stimulating the binding of the Frizzled receptor to Wnt ligands (PubMed:16227623, PubMed:24496449). Positively regulates the non-canonical Wnt signaling pathway (By similarity). Binds to CD81 which decreases the availability of free CD81 for binding to the transcriptional repressor HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (By similarity). Inhibits the dipeptidyl peptidase activity of DPP4 (PubMed:17549790). Plays a role in limb patterning and skeletal development by controlling the cellular response to BMP4 (By similarity). Modulates the effects of growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis (By similarity). Required for coronary vascular development (By similarity). Plays a role in regulating cell movements during gastrulation (By similarity).
Cleaved intracellularly by a furin-like convertase to generate 2 subunits, alpha and beta, which remain associated through disulfide bonds and are associated with the cell surface via the GPI-anchor (PubMed:14610063). This processing is essential for its role in inhibition of hedgehog signaling (PubMed:25653284). A second proteolytic event may result in cleavage of the protein on the cell surface, separating it from the GPI-anchor and leading to its shedding from the cell surface (PubMed:14610063).
Detected in placenta (at protein level) (PubMed:32337544). Highly expressed in lung, liver and kidney.
Heterodimer; disulfide-linked (PubMed:14610063). Cleavage by a furin-like convertase results in production of alpha and beta chains which form a disulfide-linked heterodimer (PubMed:14610063). Interacts with DPP4 (PubMed:17549790). Interacts with FGF2 (By similarity). Interacts with WNT5A (PubMed:14610063). Also interacts with WNT3A and WNT7B (PubMed:16227623). Interacts with hedgehog protein SHH; the heparan sulfate chains are not required for the interaction (By similarity). Also interacts with hedgehog protein IHH (By similarity). Interacts with CD81 (By similarity). Interacts with Wnt receptors FZD4, FZD7 and FZD8; the heparan sulfate chains are required for the interaction (PubMed:24496449).
O-glycosylated; contains heparan sulfate and/or chondroitin sulfate.
Used as a marker for hepatocellular carcinoma (HCC) as it is expressed in HCC but is not detectable in hepatocytes from normal or benign liver diseases (PubMed:12851874). When attached to the cell surface, stimulates the growth of HCC cells by increasing canonical Wnt signaling (PubMed:16024626). Cleavage is not required for stimulation of Wnt signaling or HCC growth (PubMed:16227623).
Detected in fibroblasts (at protein level) (PubMed:36213313). Retina and heart; less in placenta, pancreas, lung, liver, skeletal muscle, kidney and brain.
May be involved in phagocytosis during disk shedding, cell adhesion to cells other than the pigment epithelium or signal transduction.
Cyclins are positive regulatory subunits of the cyclin-dependent kinases (CDKs), and thereby play an essential role in the control of the cell cycle, notably via their destruction during cell division. Its tissue specificity suggest that it may be required during early meiotic prophase I.
Testis specific. In testis, it is expressed in developing germ cells, but not in Leydig cells. Weakly or not expressed in other tissues.
The N-terminal destruction box (D-box) probably acts as a recognition signal for degradation via the ubiquitin-proteasome pathway.
Ubiquitinated (Probable). Ubiquitination leads to its degradation during anaphase entry, after degradation of CCNB1.
(Microbial infection) Interacts with human cytomegalovirus protein UL37 isoform vMIA; this interaction rewires mitochondria by engaging the conserved MICOS complex.
Belongs to the MICOS complex subunit Mic19 family. Metazoan Mic25 subfamily.
Component of the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOOL/MIC27, IMMT/MIC60, APOO/MIC23/MIC26 and MICOS13/MIC13. This complex was also known under the names MINOS or MitOS complex. The MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1 and MTX2 (together described as components of the mitochondrial outer membrane sorting assembly machinery (SAM) complex) and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9 (PubMed:17624330, PubMed:22228767, PubMed:25781180, PubMed:25997101). The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both membranes termed the mitochondrial intermembrane space bridging (MIB) complex. Interacts with DISC1 (PubMed:22228767). Interacts with DISC1 (PubMed:22228767). Interacts with IMMT/MIC60 (PubMed:22228767, PubMed:25997101).
Down-regulated following genotoxic stress.
Homodimer. May also form higher oligomers. Interacts with FLII. Interacts with MYD88. Competes with FLII for MyD88-binding, even in the absence of LPS.
The DNA-binding domain is intrinsically unstructured.
Transcriptional repressor which preferentially binds to the GC-rich consensus sequence (5'-AGCCCCCGGCG-3') and may regulate expression of TNF, EGFR and PDGFA. May control smooth muscle cells proliferation following artery injury through PDGFA repression. May also bind double-stranded RNA. Positively regulates Toll-like receptor (TLR) signaling in response to agonist probably by competing with the negative FLII regulator for MYD88-binding.
Cytokine that acts as a physiological ligand for receptor tyrosine kinase LTK, leading to its activation (PubMed:25331893, PubMed:26418745, PubMed:26630010, PubMed:34646012, PubMed:34819673). Monomeric ALKAL1 binds to LTK, leading to LTK homodimerization and activation (PubMed:34646012, PubMed:34819673). In contrast to ALKAL2, does not act as a potent physiological ligand for ALK (PubMed:26418745, PubMed:34646012).
Widely expressed with highest levels in thyroid and moderate levels in stomach, trachea, small intestine, prostate and brain.
Interacts with NRAP. Interacts with LASP1. Part of a complex that contains CUL3, RBX1 and KLHL41.
Involved in skeletal muscle development and differentiation. Regulates proliferation and differentiation of myoblasts and plays a role in myofibril assembly by promoting lateral fusion of adjacent thin fibrils into mature, wide myofibrils. Required for pseudopod elongation in transformed cells.
Ubiquitinated by E3 ubiquitin ligase complex formed by CUL3 and RBX1 and probably targeted for proteasome-independent degradation. Quinone-induced oxidative stress increases its ubiquitination.
Belongs to the HIBADH-related family. NP60 subfamily.
Cytokine-like nuclear factor with chromatin gene reader activity involved in chromatin modification and regulation of gene expression (PubMed:23260659, PubMed:30970244). Acts as a nucleosome-destabilizing factor that is recruited to genes during transcriptional activation (PubMed:30970244, PubMed:29759984). Recognizes and binds histone H3 without a preference for specific epigenetic markers and also binds DNA (PubMed:20850016, PubMed:30970244). Interacts with KDM1B and promotes its histone demethylase activity by facilitating the capture of H3 tails, they form a multifunctional enzyme complex that modifies transcribed chromatin and facilitates Pol II transcription through nucleosomes (PubMed:23260659, PubMed:30970244, PubMed:29759984). Stimulates the acetylation of 'Lys-56' of nucleosomal histone H3 (H3K56ac) by EP300 (PubMed:29759984). With GATA4, co-binds a defined set of heart development genes and coregulates their expression during cardiomyocyte differentiation (PubMed:35182466). Regulates p38 MAP kinase activity by mediating stress activation of MAPK14/p38alpha and specifically regulating MAPK14 signaling (PubMed:16352664). Indirectly promotes phosphorylation of MAPK14 and activation of ATF2 (PubMed:16352664). The phosphorylation of MAPK14 requires upstream activity of MAP2K4 and MAP2K6 (PubMed:16352664).
Homotetramere (PubMed:31408337, PubMed:30970244). Interacts with MAPK14 (PubMed:16352664). Interacts with KDM1B at nucleosomes; this interaction stimulates H3K4me1 and H3K4me2 demethylation (PubMed:23260659). Binds to mononucleosomes (PubMed:29759984). Interacts with GATA4; the interaction is required for a synergistic activation of GATA4 target genes transcription (PubMed:35182466).
In the dehydrogenase domain, the conserved NAD(P)H-binding sites and sequence similarity to plant dehydrogenases suggest that this protein may have oxidoreductase activity (PubMed:23260659, PubMed:30970244). However, since the active site is not conserved, the dehydrogenase domain seems to serve as a catalytically inert oligomerization module (PubMed:30970244).
The A.T hook DNA-binding domain is required for the interaction with MAPK14.
The PWWP domain is a H3 reader and strongly binds DNA.
Widely expressed. Expressed in adult and fetal liver, kidney and lung. Expressed in fetal brain. Weakly expressed in fetal spleen.
(Microbial infection) Interacts with HIV-1 Vif.
(Microbial infection) Interacts with HIV-1 reverse transcriptase/ribonuclease H.
(Microbial infection) Interacts with hepatitis B virus capsid protein.
Accumulation of APOBEC3G induced non-lethal hypermutation could contribute to the genetic variation of primate lentiviral populations.
Assembly into ribonucleoprotein complexes of high-molecular-mass (HMM) inhibits its enzymatic activity. Antiviral activity is neutralized by the HIV-1 virion infectivity factor (Vif), that prevents its incorporation into progeny HIV-1 virions by both inhibiting its translation and/or by inducing its ubiquitination and subsequent degradation by the 26S proteasome. Can also be neutralized by simian immunodeficiency virus sooty mangabey monkey virus (SIV-sm) and chimpanzee immunodeficiency virus (SIV-cpz) Vif.
DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. Exhibits potent antiviral activity against Vif-deficient HIV-1. After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA. The resultant detrimental levels of mutations in the proviral genome, along with a deamination-independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells. Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single- or double-stranded RNA. Exhibits antiviral activity also against simian immunodeficiency viruses (SIVs), hepatitis B virus (HBV), equine infectious anemia virus (EIAV), xenotropic MuLV-related virus (XMRV) and simian foamy virus (SFV). May inhibit the mobility of LTR and non-LTR retrotransposons.
Expressed in spleen, testes, ovary and peripheral blood leukocytes and CD4+ lymphocytes. Also expressed in non-permissive peripheral blood mononuclear cells, and several tumor cell lines; no expression detected in permissive lymphoid and non-lymphoid cell lines. Exists only in the LMM form in peripheral blood-derived resting CD4 T-cells and monocytes, both of which are refractory to HIV-1 infection. LMM is converted to a HMM complex when resting CD4 T-cells are activated or when monocytes are induced to differentiate into macrophages. This change correlates with increased susceptibility of these cells to HIV-1 infection.
Homodimer. Homooligomer. Can bind RNA to form ribonucleoprotein complexes of high-molecular-mass (HMM) or low-molecular-mass (LMM). HMM is inactive and heterogeneous in protein composition because of binding nonselectively to cellular RNAs, which in turn are associated with variety of cellular proteins. The LMM form which is enzymatically active has few or no RNAs associated. Its ability to form homooligomer is distinct from its ability to assemble into HMM. Interacts with APOBEC3B, APOBEC3F, MOV10, AGO2, EIF4E, EIF4ENIF1, DCP2 and DDX6 in an RNA-dependent manner. Interacts with AGO1, AGO3 and PKA/PRKACA.
It is one of seven related genes or pseudogenes found in a cluster, thought to result from gene duplication, on chromosome 22.
Phosphorylation at Thr-32 reduces its binding to HIV-1 Vif and subsequent ubiquitination and degradation thus promoting its antiviral activity.
The CMP/dCMP deaminase domain 1 mediates RNA binding, RNA-dependent oligomerization and virion incorporation whereas the CMP/dCMP deaminase domain 2 confers deoxycytidine deaminase activity and substrate sequence specificity.
Ubiquitinated in the presence of HIV-1 Vif. Association with Vif targets the protein for proteolysis by the ubiquitin-dependent proteasome pathway.
Expression is restricted to non-neuronal tissues.
Interacts with REST (By similarity). Monomer.
Recruited by REST to neuronal genes that contain RE-1 elements, leading to neuronal gene silencing in non-neuronal cells (By similarity). Preferentially catalyzes the dephosphorylation of 'Ser-5' within the tandem 7 residue repeats in the C-terminal domain (CTD) of the largest RNA polymerase II subunit POLR2A. Negatively regulates RNA polymerase II transcription, possibly by controlling the transition from initiation/capping to processive transcript elongation.
Catalyzes the demethylation of diphthine methyl ester to form diphthine, an intermediate diphthamide biosynthesis, a post-translational modification of histidine which occurs in translation elongation factor 2 (EEF2) which can be ADP-ribosylated by diphtheria toxin and by Pseudomonas exotoxin A (Eta).
Expressed in testis. Not expressed in other normal tissues, but is expressed in tumors of different histological origins.
Expressed strongly in testis and pancreas. Also detected in brain, colon, liver, lung, ovary, placenta, prostate, small intestine, spleen and thymus. Not detected in heart, kidney and skeletal muscle.
In contrast to BANF1, it does not seem to bind DNA.
May play a role in BANF1 regulation and influence tissue-specific roles of BANF1.
Interacts with members of the heat shock protein 70 and 90 families and of the TCP-1 chaperonin family, as well as with HSPD1, STIP1 and tubulin; at least some of these proteins may be methylation substrates.
Protein-lysine methyltransferase that selectively mono-, di- and trimethylates 'Lys-165' of the translation elongation factors EEF1A1 and EEF1A2 in an aminoacyl-tRNA and GTP-dependent manner. EEF1A1 methylation by EEF1AKMT3 is dynamic as well as inducible by stress conditions, such as ER-stress, and plays a regulatory role on mRNA translation.
Binds EGFR, the EGF receptor, inducing EGFR autophosphorylation and the activation of downstream signaling pathways. May play a role in cell adhesion and migration. May function as a negative regulator of chondrocyte differentiation. In the olfactory epithelium, it may regulate glial cell migration, differentiation and the ability of glial cells to support neuronal neurite outgrowth.
In the eye, associated with photoreceptor outer and inner segment regions, the nerve fiber layer, outer nuclear layer and inner and outer plexiform layers of the retina.
Interacts with ECM1. Interacts with TIMP3.
Up-regulated in malignant gliomas. May increase glioma cell adhesiveness and invasive properties.
May play an important role in hippocampus-dependent long-lasting memory.
Contains inter- or intramolecular disulfide-bonds.
Major keratinocyte cell envelope protein.
Substrate of transglutaminases. Some glutamines and lysines are cross-linked to other loricrin molecules and to SPRRs proteins.
Acts as a plasma-membrane magnesium transporter (PubMed:16984228). Can also mediate the transport of other divalent metal cations in an order of Ba(2+) > Ni(2+) > Co(2+) > Fe(2+) > Mn(2+) (By similarity).
Belongs to the SLC41A transporter family.
Expressed early in fetal white adipose tissues from 17 to 21 weeks of gestation (at protein level).
N-glycosylated. N-linked glycosylation is critical for secretion but not for preadipocyte cell differentiation activity.
Plays a role in the regulation of the early stage of white and brown preadipocyte cell differentiation. Promotes adipogenic commitment of preadipocytes by increasing gene expression of the transcription factor PPARG in a BMP4-dependent signaling pathway.
Catalyzes the NADPH-dependent reduction of several pentoses, tetroses, trioses, alpha-dicarbonyl compounds and L-xylulose. Participates in the uronate cycle of glucose metabolism. May play a role in the water absorption and cellular osmoregulation in the proximal renal tubules by producing xylitol, an osmolyte, thereby preventing osmolytic stress from occurring in the renal tubules.
Highly expressed in kidney, liver and epididymis. In the epididymis, it is mainly expressed in the proximal and distal sections of the corpus region. Weakly or not expressed in brain, lung, heart, spleen and testis.
Belongs to the carotenoid/retinoid oxidoreductase family. CrtISO subfamily.
Catalyzes the saturation of all-trans-retinol to all-trans-13,14-dihydroretinol. Does not exhibit any activity toward all-trans-retinoic acid, nor 9-cis, 11-cis or 13-cis-retinol isomers. May play a role in the metabolism of vitamin A. Independently of retinol conversion, may regulate liver metabolism upstream of MLXIPL/ChREBP. May play a role in adipocyte differentiation.
Expressed in liver; expression positively correlates with obesity and liver steatosis (PubMed:28855500). Expressed in adipose tissue; expression tends to be decreased in obese versus lean individuals (PubMed:19139408).
Transcription factor that regulates gene expression in intestine. May participate in vitamin A metabolism most likely by regulating BCO1 expression in the intestine (By similarity).
Belongs to the MIP/aquaporin (TC 1.A.8) family. AQP11/AQP12 subfamily.
Channel protein that facilitates the transport of water, glycerol and hydrogen peroxide across membrane of cell or organelles guaranteeing intracellular homeostasis in several organes like liver, kidney and brain (PubMed:24845055, PubMed:24918044, PubMed:31546170). In situation of stress, participates in endoplasmic reticulum (ER) homeostasis by regulating redox homeostasis through the transport of hydrogen peroxide across the endoplasmic reticulum membrane thereby regulating the oxidative stress through the NADPH oxidase 2 pathway (PubMed:31546170). Plays a role by maintaining an environment suitable for translation or protein foldings in the ER lumen namely by participating in the PKD1 glycosylation processing resulting in regulation of PKD1 membrane trafficking thereby preventing the accumulation of unfolding protein in ER (By similarity). Plays a role in the proximal tubule function by regulating its endosomal acidification (By similarity). May play a role in postnatal kidney development (By similarity).
Detected in the sperm head and tail (at protein level) (PubMed:28042826). Expressed in subcutaneous adipocytes (PubMed:24845055). Expressed in testis, kidney and ejaculated spermatozoa (PubMed:19812234).
Homodimer; disulfide-linked (By similarity). Can also form homomultimer (PubMed:24918044, PubMed:31546170).
The NPC motif is essential for oligomerization and water permeability function.
ATPase which is preferentially stimulated by single-stranded DNA and is involved in homologous recombination repair (HRR). Has a DNA-binding activity which is independent of its ATPase activity.
Interacts with ZSWIM7; they form a functional complex involved in homologous recombination repair and stabilize each other. Interacts with RAD51, RAD51B, RAD51C, RAD51D and XRCC3; involved in homologous recombination repair.
Associated component of the WMM complex, a complex that mediates N6-methyladenosine (m6A) methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing (PubMed:29507755). Acts as a key regulator of m6A methylation by promoting m6A methylation of mRNAs at the 3'-UTR (By similarity). Controls embryonic stem cells (ESCs) pluripotency via its role in m6A methylation (By similarity). In the WMM complex, anchors component of the MACOM subcomplex in the nucleus (By similarity). Also required for bridging WTAP to the RNA-binding component RBM15 (RBM15 or RBM15B) (By similarity).
Component of the WMM complex, a N6-methyltransferase complex composed of a catalytic subcomplex, named MAC, and of an associated subcomplex, named MACOM (PubMed:29507755). The MAC subcomplex is composed of METTL3 and METTL14. The MACOM subcomplex is composed of WTAP, ZC3H13, CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B) (PubMed:29507755). Also a component of a MACOM-like complex, named WTAP complex, composed of WTAP, ZC3H13, CBLL1/HAKAI, VIRMA, RBM15, BCLAF1 and THRAP3 (PubMed:24100041).
Heart, placenta and less abundantly, in lung. Detected in the outer and inner plexiform layers of the retina (at protein level) (PubMed:22137173). Expressed in monocytes and macrophages (PubMed:25725101).
Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids (PubMed:8300559). Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity), preferentially releasing fatty acyl groups with a low degree of unsaturation such as oleoyl (C18:1) and linoleoyl (C18:2) groups (PubMed:8300559, PubMed:14998370, PubMed:23533611). Hydrolyzes low-density lipoprotein (LDL) phospholipids releasing unsaturated fatty acids that drive macrophage polarization toward an M2 phenotype (By similarity). May act in an autocrine and paracrine manner. Contributes to lipid remodeling of cellular membranes at different subcellular locations and generation of lipid mediators involved in pathogen clearance. Cleaves sn-2 fatty acyl chains of cardiolipin, a major component of the inner membrane of mitochondria and bacterial membranes (PubMed:23533611). Promotes phagocytosis of bacteria in macrophages through production of lysophosphatidylethanolamines (PubMed:25725101). Displays bactericidal activity against Gram-positive bacteria by directly hydrolyzing phospholipids of the bacterial membrane (PubMed:11694541). Promotes phagocytosis and killing of ingested fungi likely through controlling phagosome-lysosome fusion and phagosome maturation (By similarity). Plays a role in biosynthesis of cysteinyl leukotrienes (CysLTs) in myeloid cells (PubMed:12124392, PubMed:12796497). In eosinophils, triggers perinuclear arachidonate release and LTC4 synthesis in a PLA2G4A-independent way (PubMed:12796497). In neutrophils, amplifies CysLTs biosynthesis initiated by PLA2G4A (PubMed:12124392). Promotes immune complex clearance in macrophages via stimulating synthesis of CysLTs, which act through CYSLTR1 to trigger phagocytosis (By similarity). May regulate antigen processing in antigen-presenting cells (By similarity). In pulmonary macrophages regulates IL33 production required for activation of group 2 innate lymphoid cells (By similarity). May play a role in the biosynthesis of N-acyl ethanolamines that regulate energy metabolism. Hydrolyzes N-acyl phosphatidylethanolamines to N-acyl lysophosphatidylethanolamines, which are further cleaved by a lysophospholipase D to release N-acyl ethanolamines (PubMed:14998370).
This enzyme lacks one of the seven disulfide bonds found in similar PLA2 proteins.
Up-regulated upon M2 macrophage polarization in response to IL4, CSF1 or IL10.
(Microbial infection) Interacts with herpes simplex virus 1 (HHV-1) protein ICP34.5; this interaction antagonizes the host autophagy response.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein TRS1.
(Microbial infection) Interacts with murine gammaherpesvirus 68 M11.
A homodimeric form is proposed to exist; this metastable form readily transits to ATG14- or UVRAG-containing complexes with BECN1:UVRAG being more stable than BECN1:ATG14 (By similarity). Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex the core of which is composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 associating with additional regulatory/auxilliary subunits to form alternative complex forms. Alternative complex forms containing a forth regulatory subunit in a mutually exclusive manner are PI3K complex I (PI3KC3-C1) containing ATG14, and PI3K complex II (PI3KC3-C2) containing UVRAG. PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex (PubMed:18843052, PubMed:19050071, PubMed:19270696, PubMed:23878393, PubMed:25490155). Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits, such as RUBCN, SH3GLB1/Bif-1 and AMBRA1 (PubMed:20643123, PubMed:19270696). PI3KC3-C1 probably associates with PIK3CB (By similarity). Interacts with AMBRA1, GOPC, GRID2 (PubMed:21358617). Forms a complex with PPP2CA and AMBRA1; AMBRA1 and BECN1 components of the complex regulate MYC stability via different pathways (PubMed:25803737). Interacts with BCL2 and BCL2L1 isoform Bcl-X(L); the interaction inhibits BECN1 function in promoting autophagy by interfering with the formation of the PI3K complex (PubMed:9765397, PubMed:16179260, PubMed:17446862, PubMed:18570871, PubMed:21358617, PubMed:22498477, PubMed:17337444, PubMed:17659302). Interacts with cytosolic HMGB1; inhibits the interaction of BECN1 and BCL2 leading to promotion of autophagy (PubMed:20819940). Interacts with USP10, USP13, VMP1, DAPK1, RAB39A (PubMed:19180116, PubMed:17724469, PubMed:17337444, PubMed:21962518, PubMed:24349490). Interacts with the poly-Gln domain of ATXN3; the interaction causes deubiquitination at Lys-402 and stabilizes BECN1 (PubMed:28445460). Interacts with SLAMF1 (PubMed:22493499). Interacts with TRIM5; the interaction causes activation of BECN1 by causing its dissociation from its inhibitors BCL2 and TAB2 (PubMed:25127057). Interacts with active ULK1 (phosphorylated on 'Ser-317') and MEFV simultaneously (PubMed:26347139). Interacts with WDR81 and WDR91; negatively regulates the PI3 kinase/PI3K activity associated with endosomal membranes (PubMed:26783301). Interacts with LAPTM4B; competes with EGFR for LAPTM4B binding; regulates EGFR activity (PubMed:28479384). Interacts with TRIM50 (PubMed:29604308). Interacts with TRIM16. Interacts with ATG14; this interaction is increased in the absence of TMEM39A (PubMed:31806350). Interacts with WASHC1; preventing interaction with AMBRA1 and the DCX(AMBRA1) complex and subsequent ubiquitination (PubMed:23974797). Interacts with TRIM17 (PubMed:27562068). Interacts with BCL2L10/BCL-B (via BH1 domain) (PubMed:22498477). Interacts with SH3BGRL (PubMed:34870550). Interacts with IRGM; enhancing BECN1-interacting partners and influencing the composition of the BECN1 complex (PubMed:25891078).
Beclin-1-C 35 kDa localized to mitochondria can promote apoptosis; it induces the mitochondrial translocation of BAX and the release of proapoptotic factors.
Expanded poly-Gln tracts inhibit ATXN3-BECN1 interaction, decrease BECN1 levels and impair starvation-induced autophagy (PubMed:28445460).
Phosphorylation at Thr-119 by DAPK1 reduces its interaction with BCL2 and BCL2L1 and promotes induction of autophagy (PubMed:19180116). In response to autophagic stimuli, phosphorylated at serine residues by AMPK in an ATG14-dependent manner, and this phosphorylation is critical for maximally efficient autophagy (PubMed:23878393, PubMed:25891078).
Plays a central role in autophagy (PubMed:18570871, PubMed:21358617, PubMed:23184933, PubMed:23974797, PubMed:28445460, PubMed:25484083). Acts as core subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and required for the abcission step in cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20643123, PubMed:20208530, PubMed:23974797, PubMed:26783301). Essential for the formation of PI3KC3-C2 but not PI3KC3-C1 PI3K complex forms. Involved in endocytosis (PubMed:25275521). Protects against infection by a neurovirulent strain of Sindbis virus (PubMed:9765397). May play a role in antiviral host defense.
Polyubiquitinated by NEDD4, both with 'Lys-11'- and 'Lys-63'-linkages (PubMed:21936852). 'Lys-11'-linked polyubiquitination leads to degradation and is enhanced when the stabilizing interaction partner VPS34 is depleted (PubMed:21936852). Deubiquitinated by USP10 and USP13, leading to stabilize the PIK3C3/VPS34-containing complexes (PubMed:21962518). Polyubiquitinated at Lys-402 with 'Lys-48'-linkages (PubMed:28445460). 'Lys-48'-linked polyubiquitination of Lys-402 leads to degradation (PubMed:28445460). Deubiquitinated by ATXN3, leading to stabilization (PubMed:28445460). Ubiquitinated at Lys-437 via 'Lys-63'-linkage by the DCX(AMBRA1) complex, thereby increasing the association between BECN1 and PIK3C3 to promote PIK3C3 activity (PubMed:23974797). 'Lys-48'-linked ubiquitination by RNF216 leads to proteasomal degradation and autophagy inhibition (PubMed:25484083).
Proteolytically processed by caspases including CASP8 and CASP3; the C-terminal fragments lack autophagy-inducing capacity and are proposed to induce apoptosis. Thus the cleavage is proposed to be an determinant to switch from autophagy to apoptosis pathways affecting cellular homeostasis including viral infections and survival of tumor cells.
The C-terminal evolutionary conserved domain (ECD) contains poly-Gln-binding domains such as the ATXN3 poly-Gln motif, consistent with structural docking models revealing two highly scored poly-Gln-binding pockets in the ECD (PubMed:28445460). As some binding is observed with BECN1 lacking the ECD, other domains of BECN1 may also interact with ATXN3 (PubMed:28445460).
The coiled coil domain can form antiparallel homodimers and mediates dimerization with the coiled coil domains of ATG14 or UVRAG involved in the formation of PI3K complexes.
(Microbial infection) Interacts with herpes virus 8 virus protein LANA1.
(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein NS1.
(Microbial infection) Interacts with molluscum contagiosum virus MC132.
(Microbial infection) Substrate adapter protein can be a viral protein such as HIV Vif.
Core component of multiple cullin-RING-based ECS (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of target proteins (PubMed:10205047, PubMed:12004076, PubMed:12050673, PubMed:15590694, PubMed:26138980, PubMed:29779948, PubMed:30166453, PubMed:29775578). This includes the von Hippel-Lindau ubiquitination complex CBC(VHL) (PubMed:10205047, PubMed:12004076, PubMed:12050673, PubMed:15590694). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes (PubMed:10205047, PubMed:12004076, PubMed:12050673, PubMed:15590694). As part of a multisubunit ubiquitin ligase complex composed of elongin BC complex (ELOB and ELOC), elongin A/ELOA, RBX1 and CUL5; polyubiquitinates monoubiquitinated POLR2A (PubMed:19920177). A number of ECS complexes (containing either KLHDC2, KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B or FEM1C as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:26138980, PubMed:29779948, PubMed:29775578). ECS(LRR1) ubiquitinates MCM7 and promotes CMG replisome disassembly by VCP and chromatin extraction during S-phase (By similarity).
Heterotrimer of an A (ELOA, ELOA2 or ELOA3P), ELOB and ELOC subunit (PubMed:17997974). The elongin BC complex interacts with EPOP; leading to recruit the elongin BC complex to Polycomb group (PcG) target genes, thereby restricting excessive activity of the PRC2/EED-EZH2 complex (By similarity). Part of E3 ubiquitin ligase complexes with CUL5 or CUL2, RBX1 and a substrate adapter protein that can be either ASB2, KLHDC2, KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B, FEM1C, LRR1, SOCS1, SOCS5, ELOA, VHL or WSB1 (PubMed:15590694, PubMed:21119685, PubMed:26138980, PubMed:29779948, PubMed:29775578, PubMed:34700328, PubMed:19920177). The elongin BC complex is part of a complex with VHL and hydroxylated HIF1A (PubMed:12050673, PubMed:12004076). Part of an E3 ubiquitin-protein ligase complex including ZYG11B, CUL2 and Elongin BC. Part of an E3 ubiquitin-protein ligase complex including ZER1, CUL2 and Elongin BC (PubMed:17304241). Interacts with VHL (PubMed:10205047, PubMed:12050673, PubMed:11006129). Interacts with TMF1 (PubMed:15467733). Interacts with SPSB1 (PubMed:17189197). Interacts with SPSB1. Interacts with KLHDC10; which may be an E3 ubiquitin ligase complex substrate recognition component (PubMed:23102700). Interacts with NOS2 in the presence of SPSB1 or SPSB2 or SPSB4 (PubMed:21199876). As part of the Elongin BC E3 ubiquitin ligase complex; interacts with NRBP1 (PubMed:22510880). Component of the ECS(PCMTD1) complex with the substrate recognition subunit PCMTD1 (PubMed:35486881). Interacts with PCMTD1 (via the BC-box); the interaction is direct and stabilizes PCMTD1 (PubMed:35486881).
Overexpressed in prostate cancer cell line PC-3 and breast cancer cell line SK-BR-3.
SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex) (PubMed:7821821). In embryonic stem cells, the elongin BC complex is recruited by EPOP to Polycomb group (PcG) target genes in order generate genomic region that display both active and repressive chromatin properties, an important feature of pluripotent stem cells (By similarity).
Ubiquitinated by the DCX(AMBRA1) complex, leading to its degradation by the proteasome.
Appears to mediate interactions between cells and the extracellular matrix. Substrate-adhesion molecule that appears to inhibit cell migration. Accelerates collagen fibril formation. May play a role in supporting the growth of epithelial tumors.
Expression levels are lower in adults than in children.
Highly expressed in fetal adrenal, in fetal testis, fetal smooth, striated and cardiac muscle. Isoform XB-short is only expressed in the adrenal gland.
Homotrimer. Interacts with type I, III and V collagens and tropoelastin via its 29th fibronectin type-III domain.
May be due to competing acceptor splice site in exon 24.
May be due to competing donor splice site in exon 1.
There are two genes for TN-X: TNXA and TNXB. TNXA can sometimes recombine with TNXB.
Expressed in brain and heart. Expressed in brain at protein level. Expressed in prefontal and visual cortex. Isoform 4 and isoform 5 are expressed ubiquitously. Isoform 1, isoform 2 and isoform 3 are not expressed in the cerebellum.
Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Activity on G(z)-alpha is inhibited by phosphorylation of the G-protein. Activity on G(z)-alpha and G(i)-alpha-1 is inhibited by palmitoylation of the G-protein.
Allosterically activated by intracellular ATP.
Despite a previous report demonstrating SLC22A4/OCTN1-mediated transport of nucleosides such as the endogenous 2'deoxycytidine or the anticancer drug cytarabine, another study was unable to verify these findings.
Mediates the Na(+)-independent and pH-dependent bidirectional transport of exogenous prototype organic cation tetraethylammonium (TEA).
Transporter that mediates the transport of endogenous and microbial zwitterions and organic cations (PubMed:15795384, PubMed:10215651, PubMed:16729965, PubMed:20601551, PubMed:22569296, PubMed:29530864, PubMed:15107849, PubMed:22206629). Functions as a Na(+)-dependent and pH-dependent high affinity microbial symporter of potent food-derived antioxidant ergothioeine (PubMed:15795384, PubMed:29530864, PubMed:33124720). Transports one sodium ion with one ergothioeine molecule (By similarity). Involved in the absorption of ergothioneine from the luminal/apical side of the small intestine and renal tubular cells, and into non-parenchymal liver cells, thereby contributing to maintain steady-state ergothioneine level in the body (PubMed:20601551). Also mediates the bidirectional transport of acetycholine, although the exact transport mechanism has not been fully identified yet (PubMed:22206629). Most likely exports anti-inflammatory acetylcholine in non-neuronal tissues, thereby contributing to the non-neuronal cholinergic system (PubMed:22569296, PubMed:22206629). Displays a general physiological role linked to better survival by controlling inflammation and oxidative stress, which may be related to ergothioneine and acetycholine transports (PubMed:15795384, PubMed:22206629). May also function as a low-affinity Na(+)-dependent transporter of L-carnitine through the mitochondrial membrane, thereby maintaining intracellular carnitine homeostasis (PubMed:10215651, PubMed:16729965, PubMed:15107849). May contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier (PubMed:35307651).
Widely expressed (PubMed:9426230). Highly expressed in kidney, trachea, ileum, bone marrow and whole blood (PubMed:9426230, PubMed:15795384). Expressed in small intestines (PubMed:20601551). Weakly expressed in skeletal muscle, prostate, lung, pancreas, placenta, heart, uterus, spleen and spinal cord (PubMed:9426230, PubMed:15795384, PubMed:16729965). Expressed in testis, primarily to the basal membrane of Sertoli cells (PubMed:35307651, PubMed:16729965). Expressed in brain (PubMed:16729965). Expressed in liver (PubMed:16729965). Highly expressed in intestinal cell types affected by Crohn disease, including epithelial cells. Expressed in CD68 macrophage and CD43 T-cells but not in CD20 B-cells (PubMed:15107849). Predominantly expressed in CD14 cells in peripheral blood mononuclear cells (PubMed:14608356). Expressed in fetal liver, kidney and lung (PubMed:9426230, PubMed:15795384).
(Microbial infection) Interacts with Epstein-Barr virus BHRF1.
(Microbial infection) Interacts with adenovirus E1B 19 kDa protein.
Apoptosis-inducing protein that can overcome BCL2 suppression. May play a role in repartitioning calcium between the two major intracellular calcium stores in association with BCL2. Involved in mitochondrial quality control via its interaction with SPATA18/MIEAP: in response to mitochondrial damage, participates in mitochondrial protein catabolic process (also named MALM) leading to the degradation of damaged proteins inside mitochondria. The physical interaction of SPATA18/MIEAP, BNIP3 and BNIP3L/NIX at the mitochondrial outer membrane regulates the opening of a pore in the mitochondrial double membrane in order to mediate the translocation of lysosomal proteins from the cytoplasm to the mitochondrial matrix. Plays an important role in the calprotectin (S100A8/A9)-induced cell death pathway.
Homodimer. Binds to BCL2. Interacts with BNIP3L and ACAA2. Interacts (via BH3 domain) with SPATA18 (via coiled-coil domains). Interacts with BOK; promotes BOK oligomerization (PubMed:15868100).
In human, WASHC2 has undergone evolutionary duplication giving rise to highly homologous family members. A WASHC2C construct with WASHC2A-specific sequence insertions (of 2 aa and 21 aa length resulting in a construct length of 1341 aa similar to WASHC2A length) has been used to demonstrate the interaction with WASHC2 (PubMed:24643499).
Interacts with WASHC2C; mediates the association with the WASH complex (PubMed:24643499).
Involved in membrane trafficking through early endosomes, such as the early endosome to recycling endosome transport implicated in the recycling of transferrin and the early endosome to late endosome transport implicated in degradation of EGF and EGFR (PubMed:18256511, PubMed:18307993). Involved in the regulation of endosomal membrane tubulation and regulates the dynamics of SNX1 on the endosomal membrane; via association with WASHC2 may link the WASH complex to the retromer SNX-BAR subcomplex (PubMed:24643499).
The gene represented in this entry may be involved in disease pathogenesis. Genetic variants in DNAJC13 (PubMed:24218364, PubMed:25393719) and TMEM230 (PubMed:27270108) have been found in the same large multigenerational family with adult-onset Parkinson disease. The pathological role of each gene and therefore the exact molecular basis of the disease is unclear.
Calmodulin-dependent cyclic nucleotide phosphodiesterase with a dual specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes (PubMed:8557689, PubMed:29860631). Has a high affinity for both cAMP and cGMP (PubMed:8557689). Modulates the amplitude and duration of the cAMP signal in sensory cilia in response to odorant stimulation, hence contributing to the generation of action potentials. Regulates smooth muscle cell proliferation. Regulates the stability of growth factor receptors, including PDGFRB (Probable).
Isoform PDE1C2 is present in the heart and brain and, at lower levels in the lung, liver, kidney and skeletal muscle (PubMed:8557689). Isoform PDE1C1 is expressed in the heart and brain and, at lower levels in lung (PubMed:8557689). Also expressed at low levels in uterus and testis (PubMed:8557689).
Expressed in the upper spinous and granular suprabasal layers of normal adult epidermal tissues from most body sites including thigh, breast nipple, foot sole, penile shaft and axilla. Not present in foreskin, squamous metaplasias and carcinomas. Expression in hypertrophic and keloid scars begins in the deepest suprabasal layer. Weakly expressed in normal gingiva and tongue, however expression is induced in benign keratoses of lingual mucosa and in mild-to-moderate oral dysplasia with orthokeratinization.
Heterotetramer of two type I and two type II keratins. Associates with KRT10.
Induced in keratinocytes by all-trans retinoic acid (ATRA), via increase in mRNA stability.
Probably contributes to terminal cornification (PubMed:1380918). Associated with keratinocyte activation, proliferation and keratinization (PubMed:12598329). Required for maintenance of corneocytes and keratin filaments in suprabasal keratinocytes in the epidermis of the ear, potentially via moderation of expression and localization of keratins and their partner proteins (By similarity). Plays a role in the establishment of the epidermal barrier on plantar skin (By similarity).
Synthesized during maturation of epidermal keratinocytes and localized in the upper intermediate cells of fetal skin. Earliest expression is at 10 weeks in the developing embryo in the presumptive nail bed of developing digits, shifting to the proximal nail fold by 13.5 weeks. At 12.5 weeks, detected in scattered cells of the intermediate layer of trunk skin. At 19.3 weeks, regional expression patterns were observed in upper intermediate keratinocytes of cheek, trunk, dorsal and ventral knee, elbow and dorsal hand. Distal areas around the periumbilical region showed increased number of positive cells and by 15 weeks is expressed in small groups of cells in the fetal hair follicles.
Self-associates. Interacts with ZXDC and CIITA (By similarity).
Expressed in endometrium during the mid-secretory phase (LH + 7) (at protein level).
Regulator of microtubule dynamic that has microtubule bundling activity (PubMed:17105200, PubMed:19633818). Required for embryo implantation; possibly by regulating beta-catenin (By similarity). Also required for decidualization via regulation of beta-catenin (PubMed:30667362).
Although it belongs to the non-receptor class myotubularin subfamily, lacks the conserved active site cysteine residue at position 1410 in the dsPTPase catalytic loop, suggesting that it has no phosphatase activity.
Guanine nucleotide exchange factor (GEF) which activates RAB21 and possibly RAB28 (PubMed:20937701, PubMed:25648148). Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form (PubMed:20937701, PubMed:25648148). In response to starvation-induced autophagy, activates RAB21 which in turn binds to and regulates SNARE protein VAMP8 endolysosomal transport required for SNARE-mediated autophagosome-lysosome fusion (PubMed:25648148). Acts as an adapter for the phosphatase MTMR2 (By similarity). Increases MTMR2 catalytic activity towards phosphatidylinositol 3,5-bisphosphate and to a lesser extent towards phosphatidylinositol 3-phosphate (By similarity).
Homodimer (By similarity). Heterotetramer consisting of one MTMR2 dimer and one SBF2/MTMR13 dimer (PubMed:15998640). Interacts with class II PI3-kinase PIK3C2A (By similarity). Interacts (via DENN domain) with RAB21 (in GDP-bound form) in response to starvation; the interaction activates RAB21 (PubMed:25648148). Interacts with VAMP8 in response to starvation (PubMed:25648148).
The C-terminal domain mediates homodimerization (By similarity). By mediating SBF2/MTMR13 homodimerization, indirectly involved in SBF2/MTMR13 and MTMR2 heterotetramerization (By similarity).
The GRAM domain mediates binding to phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol 3,5-biphosphate and phosphatidylinositol 3,4,5-trisphosphate.
The PH domain binds preferentially phosphatidylinositol 3,4,5-trisphosphate (By similarity). Appears to be dispensable for localization to membranes (By similarity).
Widely expressed. Expressed in spinal cord.
ATP-dependent helicase that binds and distorts nucleosomal DNA (PubMed:28977666). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:9804427, PubMed:30397230, PubMed:16428440, PubMed:28977666). Involved in transcriptional repression as part of the NuRD complex (PubMed:27068747). Required for anchoring centrosomal pericentrin in both interphase and mitosis, for spindle organization and centrosome integrity (PubMed:17626165).
Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5 (PubMed:33283408, PubMed:9804427, PubMed:27068747, PubMed:28977666, PubMed:16428440). The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes (PubMed:28977666, PubMed:16428440, PubMed:33283408). Interacts with CBX1 (PubMed:28977666). Interacts with CBX3 (PubMed:28977666). Interacts with CBX5 (PubMed:28977666). Interacts (via its C-terminal) with HABP4 (PubMed:12505151). Interacts with HDAC1 (PubMed:28977666). Interacts with MTA1 (PubMed:28977666). Interacts with PCNT; the interaction regulates centrosome integrity (PubMed:17626165). Interacts with RBBP7 (PubMed:28977666). Interacts with SERBP1 (PubMed:12505151). Interacts with TRIM28 (PubMed:11230151). Interacts with ZBED1/hDREF (PubMed:27068747).
Differs from position 1967 onward for unknown reasons.
One of the main antigens reacting with anti-MI-2 positive sera of dermatomyositis.
Sumoylation at Lys-1971 results in dissociation from chromatin and suppression of transcriptional repression.
CLDN3 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region.
Can form homo- and heteropolymers with other CLDN. Homopolymers interact with CLDN1 and CLDN2 homopolymers. Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3 (By similarity).
Can form homo- and heteropolymers with other CLDN. Homopolymers interact with CLDN1 and CLDN2 homopolymers. Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3.
Acts as an adapter for the myotubularin-related phosphatases (PubMed:11504939, PubMed:12847286, PubMed:23818870). Regulates phosphatase MTM1 protein stability and possibly its intracellular location (PubMed:23818870). By stabilizing MTM1 protein levels, required for skeletal muscle maintenance but not for myogenesis (By similarity).
Although it belongs to the non-receptor class myotubularin subfamily, lacks the conserved active site cysteine residue at position 391 in the dsPTPase catalytic loop and does not have phosphatase activity.
Expressed in skeletal muscles (at protein level) (PubMed:23818870). Ubiquitous with prominent expression in brain, heart, kidney, placenta, and lung (PubMed:11504939).
Heterodimer with lipid phosphatase MTM1 (PubMed:12847286, PubMed:23818870). Heterodimer with lipid phosphatase MTMR2 (PubMed:12847286).
Able to act as transcription factor, cannot regulate the expression of the same subset of genes than isoform 1. Does not have antiapoptotic effect on neuronal cells.
Expressed in the brain and the retina. Present in the developing brain, spinal cord and eye.
Expression peaks early in embryogenesis (day 13.5) and is undetectable 14 days after birth.
Interacts (via N-terminus) with RIT2; the interaction controls POU4F1 transactivation activity on some neuronal target genes. Isoform 1 interacts with POU4F2; this interaction inhibits both POU4F1 DNA-binding and transcriptional activities. Isoform 1 interacts (C-terminus) with ESR1 (via DNA-binding domain); this interaction decreases the estrogen receptor ESR1 transcriptional activity in a DNA- and ligand 17-beta-estradiol-independent manner.
Multifunctional transcription factor with different regions mediating its different effects. Acts by binding (via its C-terminal domain) to sequences related to the consensus octamer motif 5'-ATGCAAAT-3' in the regulatory regions of its target genes. Regulates the expression of specific genes involved in differentiation and survival within a subset of neuronal lineages. It has been shown that activation of some of these genes requires its N-terminal domain, maybe through a neuronal-specific cofactor. Ativates BCL2 expression and protects neuronal cells from apoptosis (via the N-terminal domain). Induces neuronal process outgrowth and the coordinate expression of genes encoding synaptic proteins. Exerts its major developmental effects in somatosensory neurons and in brainstem nuclei involved in motor control. Stimulates the binding affinity of the nuclear estrogene receptor ESR1 to DNA estrogen response element (ERE), and hence modulates ESR1-induced transcriptional activity. May positively regulate POU4F2 and POU4F3. Regulates dorsal root ganglion sensory neuron specification and axonal projection into the spinal cord. Plays a role in TNFSF11-mediated terminal osteoclast differentiation. Negatively regulates its own expression interacting directly with a highly conserved autoregulatory domain surrounding the transcription initiation site.
The C-terminal domain is able to act as both DNA-binding domain and a transcriptional activator. The N-terminal domain is also required for transactivation activity on some target genes acting as a discrete activation domain. Neurite outgrowth and expression of genes required for synapse formation are primarily dependent on the C-terminal domain, however the N-terminal domain is required for maximal induction.
Forms both hetero- and homodimers with SOHLH1.
It is uncertain whether Met-1 or Met-10 is the initiator.
Can form homooligomers (monomers as predominant form and dimers).
Disease susceptibility is associated with variants affecting the gene represented in this entry. CPS1 variants influence the availability of precursors for nitric oxide (NO) synthesis and play a role in clinical situations where endogenous NO production is critically important, such as neonatal pulmonary hypertension, increased pulmonary artery pressure following surgical repair of congenital heart defects or hepatovenocclusive disease following bone marrow transplantation. Infants with neonatal pulmonary hypertension homozygous for Thr-1406 have lower L-arginine concentrations than neonates homozygous for Asn-1406 (PubMed:11407344).
Glutarylated. Glutarylation levels increase during fasting. Deglutarylated by SIRT5 at Lys-55, Lys-219, Lys-412, Lys-889, Lys-892, Lys-915, Lys-1360 and Lys-1486, leading to activation.
Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.
Primarily in the liver and small intestine.
Requires N-acetyl-L-glutamate (NAG) as an allosteric activator. Activated by glycerol in the absence of NAG, whereas in the presence of NAG it is inhibited by increasing concentrations of glycerol.
Succinylated at Lys-287 and Lys-1291. Desuccinylated at Lys-1291 by SIRT5, leading to activation (By similarity).
The type-1 glutamine amidotransferase domain is defective.
Undergoes proteolytic cleavage in the C-terminal region corresponding to the loss of approximately 12 AA residues from the C-terminus.
Belongs to the prenylcysteine oxidase family.
Trans-Golgi-associated GTPase that regulates protein sorting. Controls the targeting of ARL1 and its effector to the trans-Golgi. Required for the lipidation of chylomicrons in the intestine and required for VLDL lipidation in the liver.
Belongs to the universal ribosomal protein uL14 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:25278503, PubMed:25838379, PubMed:28892042). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (PubMed:25278503, PubMed:25838379). Interacts with MALSU1 (PubMed:22829778).
Forms part of 2 intersubunit bridges in the assembled ribosome. Upon binding to MALSU1 intersubunit bridge formation is blocked, preventing ribosome formation and repressing translation (Probable).
(Microbial infection) Interacts with influenza A virus PB1-F2 protein.
ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell (By similarity). Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane (By similarity). In addition to its ADP:ATP antiporter activity, also involved in mitochondrial uncoupling and mitochondrial permeability transition pore (mPTP) activity (PubMed:15033708). Plays a role in mitochondrial uncoupling by acting as a proton transporter: proton transport uncouples the proton flows via the electron transport chain and ATP synthase to reduce the efficiency of ATP production and cause mitochondrial thermogenesis (By similarity). Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A6/ANT3 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity) (By similarity). Proton transporter activity requires free fatty acids as cofactor, but does not transport it (By similarity). Also plays a key role in mPTP opening, a non-specific pore that enables free passage of the mitochondrial membranes to solutes of up to 1.5 kDa, and which contributes to cell death (PubMed:15033708). It is however unclear if SLC25A6/ANT3 constitutes a pore-forming component of mPTP or regulates it (By similarity).
Catalyzes the exchange of ADP and ATP across the membrane.
Monomer (By similarity). Found in a complex with ARL2, ARL2BP and SLC25A6/ANT3 (By similarity).
The gene coding for this protein is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes and escapes X-inactivation.
Broadly expressed, with highest levels in skeletal muscle, kidney and pancreas. Present in acinar cells of the pancreas (at protein level).
E3 ubiquitin-protein ligase which is a component of the N-end rule pathway (PubMed:15548684, PubMed:20835242). Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation (By similarity). Plays a critical role in chromatin inactivation and chromosome-wide transcriptional silencing during meiosis via ubiquitination of histone H2A (By similarity). Binds leucine and is a negative regulator of the leucine-mTOR signaling pathway, thereby controlling cell growth (PubMed:20298436). Required for spermatogenesis, promotes, with Tex19.1, SPO11-dependent recombination foci to accumulate and drive robust homologous chromosome synapsis (By similarity). Polyubiquitinates LINE-1 retrotransposon encoded, LIRE1, which induces degradation, inhibiting LINE-1 retrotransposon mobilization (By similarity). Catalyzes ubiquitination and degradation of the N-terminal part of NLRP1 following NLRP1 activation by pathogens and other damage-associated signals: ubiquitination promotes degradation of the N-terminal part and subsequent release of the cleaved C-terminal part of NLRP1, which polymerizes and forms the NLRP1 inflammasome followed by host cell pyroptosis (By similarity).
Interacts with UBE2B; promotes the UBE2B-H2A interaction and the ubiquitination of histone H2A by UBE2B and UBR2 (By similarity). Interacts with RECQL4 (PubMed:15317757, PubMed:20835242). Interacts with TEX19; does not lead to TEX19 degradation and stabilizes it (By similarity). Interacts with CASP8 (PubMed:28602583). Interacts with ATXN3 (PubMed:30455355). Interacts with UBE2O (By similarity).
The RING-H2 zinc finger is an atypical RING finger with a His ligand in place of the fourth Cys of the classical motif.
The UBR-type zinc finger forms a pocket that mediates recognition of type 1 N-degrons. It exhibits preference for Arginine in first position, has poor affinity for histidine, and doesn't bind acetylated peptides.
Ubiquitin ligase protein which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation.
Essential component of the high affinity receptor for the general membrane fusion machinery and an important regulator of transport vesicle docking and fusion.
Homotetramer (via coiled-coil domain), also forms heterotetramers with STX4 and VAMP3 (PubMed:12556468). Found in a complex with VAMP8 and STX1A (PubMed:12130530). Found in a complex with VAMP8 and STX4 in pancreas (By similarity). Interacts simultaneously with SNAPIN and SYN4 (By similarity). Interacts with STX1A (By similarity). Interacts with STX12 (By similarity). Interacts tightly to multiple syntaxins and synaptobrevins/VAMPs (By similarity). Interacts with ZDHHC13 (via ANK repeats) (By similarity). Interacts with ZDHHC17 (via ANK repeats) (PubMed:28882895).
Ubiquitous. Highest levels where found in placenta.
(Microbial infection) May interact with Dengue virus DENV2 16681 non-structural protein 4A/NS4A.
(Microbial infection) May interact with Zika virus strain Mr-766 non-structural protein 4A/NS4A (PubMed:30550790). May interact with Zika virus French Polynesia 10087PF/2013 non-structural protein 4A/NS4A (PubMed:30550790).
Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER) (By similarity). Forms a ribosome receptor and a gated pore in the ER membrane, both functions required for cotranslational translocation of nascent polypeptides (By similarity). The SEC61 channel is also involved in ER membrane insertion of transmembrane proteins: it mediates membrane insertion of the first few transmembrane segments of proteins, while insertion of subsequent transmembrane regions of multi-pass membrane proteins is mediated by the multi-pass translocon (MPT) complex (PubMed:32820719, PubMed:36261522). The SEC61 channel cooperates with the translocating protein TRAM1 to import nascent proteins into the ER (By similarity).
The SEC61 channel-forming translocon complex consists of channel-forming core components SEC61A1, SEC61B and SEC61G and different auxiliary components such as SEC62 and SEC63 (By similarity). The SEC61 channel associates with the multi-pass translocon (MPT) complex (PubMed:32820719, PubMed:36261522).
Expressed in spleen, thymus, and peripheral blood leukocytes. Expressed in several B-, T-, NK and monocyte cell lines.
Negatively regulates TCR (T-cell antigen receptor)-mediated signaling in T-cells and BCR (B-cell antigen receptor)-mediated signaling in B-cells.
Phosphorylated on tyrosines by Syk, Lck or ZAP70 upon TCR or BCR activation; which leads to the recruitment of GRB2, PIK3R1 and GRAP2.
Up-regulated in T-cells following TCR engagement.
When phosphorylated, interacts with GRB2, PIK3R1 and GRAP2.
Interacts with distinct SNARE complexes that contain either STX5 or STX6. Interacts with NAPA and, to a lesser extent, with NAPG. Identified in a complex containing STX6, STX12, VAMP4 and VTI1A.
V-SNARE that mediates vesicle transport pathways through interactions with t-SNAREs on the target membrane. These interactions are proposed to mediate aspects of the specificity of vesicle trafficking and to promote fusion of the lipid bilayers. Involved in vesicular transport from the late endosomes to the trans-Golgi network. Along with VAMP7, involved in an non-conventional RAB1-dependent traffic route to the cell surface used by KCNIP1 and KCND2. May be involved in increased cytokine secretion associated with cellular senescence.
Expressed in brain and testis and detected in heart and placenta.
Probable E3 ubiquitin-protein ligase involved in either protein trafficking or in the distribution of cellular structures. Required for spermatozoon maturation and fertility, and for the removal of the cytoplasmic droplet of the spermatozoon. E3 ubiquitin-protein ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer it to targeted substrates.
Contains three transmembrane domains, including a tandem transmembrane domain insertion into its glycosyltransferase-A fold (PubMed:29374258). Transmembrane domain 1 functions as a signal for Golgi targeting (PubMed:29374258).
Golgi-resident glycosylphosphatidylinositol (GPI)-N-acetylgalactosamine transferase involved in the lipid remodeling steps of GPI-anchor maturation. Lipid remodeling steps consist in the generation of 2 saturated fatty chains at the sn-2 position of GPI-anchors proteins (PubMed:29374258). Required for the initial step of GPI-GalNAc biosynthesis, transfers GalNAc to GPI in the Golgi after fatty acid remodeling by PGAP2 (PubMed:29374258).
Genetic variations in MARK1 may be associated with susceptibility to autism. MARK1 is overexpressed in the prefrontal cortex of patients with autism and causes changes in the function of cortical dendrites.
Highly expressed in heart, skeletal muscle, brain, fetal brain and fetal kidney.
Inhibited by phosphorylation at Ser-219 (By similarity). Activated by phosphorylation on Thr-215.
Phosphorylation at Thr-613 by PRKCZ/aPKC in polarized epithelial cells inhibits the kinase activity (By similarity). Phosphorylated at Thr-215 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Phosphorylation at Thr-215 by TAOK1 activates the kinase activity, leading to phosphorylation and detachment of MAPT/TAU from microtubules. Phosphorylation at Ser-219 by GSK3-beta (GSK3B) inhibits the kinase activity.
Phosphorylation of MAPT/tau by MARK1 could play a role in early steps of Alzheimer disease. Pathological aggregation of MAPT/tau to neurofibrillary tangles, filamentous structures consisting of paired helical filaments (PHFs), is one of the hallmarks of Alzheimer disease. Hyperphosphorylation by MARK1 could be the initial step for this abnormal aggregation of tau in Alzheimer disease and animal models of tauopathy (PubMed:11089574).
Serine/threonine-protein kinase (PubMed:23666762). Involved in cell polarity and microtubule dynamics regulation. Phosphorylates DCX, MAP2 and MAP4. Phosphorylates the microtubule-associated protein MAPT/TAU (PubMed:23666762). Involved in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3).
The KA1 domain mediates binding to phospholipids and targeting to membranes. Binds phosphatidic acid (PA), phosphatidylserine (PtdSer) and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2).
The UBA domain does not seem to bind ubiquitin and ubiquitin-like and might play a role in regulating the enzyme conformation and localization. Activation of the kinase activity following phosphorylation at Thr-208 is accompanied by a conformational change that alters the orientation of the UBA domain with respect to the catalytic domain (By similarity).
For practical reasons, PLN activity is most often studied with ATP2A1 instead of ATP2A2.
Homopentamer (PubMed:16043693, PubMed:16897780). Interacts with HAX1 (PubMed:17241641). Interact with ATP2A2; the inhibition decreases ATP2A2 Ca(2+) affinity (PubMed:28890335). Interacts with VMP1; VMP1 competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2 (PubMed:28890335). Interacts with S100A1 in a Ca(2+)-dependent manner (PubMed:12804600).
In elongated spermatids, proteolytically cleaved by SPPL2C which modulates intracellular Ca(2+) homeostasis.
Palmitoylated by ZDHHC16, promoting formation of the homopentamer.
Phosphorylation by PKA abolishes the inhibition of ATP2A2-mediated calcium uptake. Phosphorylated at Thr-17 by CaMK2, and in response to beta-adrenergic stimulation. Phosphorylation by DMPK may stimulate sarcoplasmic reticulum calcium uptake in cardiomyocytes.
Reversibly inhibits the activity of ATP2A2 in cardiac sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+) (PubMed:28890335). Modulates the contractility of the heart muscle in response to physiological stimuli via its effects on ATP2A2. Modulates calcium re-uptake during muscle relaxation and plays an important role in calcium homeostasis in the heart muscle. The degree of ATP2A2 inhibition depends on the oligomeric state of PLN. ATP2A2 inhibition is alleviated by PLN phosphorylation. Controls intracellular Ca(2+) levels in elongated spermatids. May play a role in germ cell differentiation (By similarity).
Reversibly inhibits the activity of ATP2A2 in cardiac sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+). Modulates the contractility of the heart muscle in response to physiological stimuli via its effects on ATP2A2. Modulates calcium re-uptake during muscle relaxation and plays an important role in calcium homeostasis in the heart muscle. The degree of ATP2A2 inhibition depends on the oligomeric state of PLN.
Interacts with methylated DNMT1 (DNMT1K142me1) (PubMed:24492612). Interacts with SOX2 (PubMed:29358331).
Is a negative regulator of proteasomal degradation of a set of methylated proteins, including DNMT1 and SOX2 (PubMed:24492612, PubMed:29358331). Involved in the maintainance of embryonic stem cells pluripotency, through the regulation of SOX2 levels (By similarity).
Component of a SNARE complex consisting of STX18, USE1L, BNIP1/SEC20L, and SEC22B. RINT1/TIP20L and ZW10 are associated with the complex through interaction with BNIP1/SEC20L. Interacts directly with USE1L and BNIP1/SEC20L.
Syntaxin that may be involved in targeting and fusion of Golgi-derived retrograde transport vesicles with the ER.
Interacts with MYLK (By similarity). Interacts with TCF4 (PubMed:24094747).
Unlikely isoform. Probable cloning artifact.
A chromosomal aberration involving LNP1 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(3;11)(q12.2;p15.4) with NUP98.
Although strongly related to the nudix NUDT16 protein, lacks the Nudix box and is therefore not related to the rest of the family (PubMed:18820299, PubMed:21070968). Gene organization and evolutionary distribution suggest that syndesmos NUDT16L1 probably originated as a gene duplication event of the more ancient U8 snoRNA-decapping enzyme NUDT16 (PubMed:18820299). Although similar to U8 snoRNA-decapping enzyme NUDT16, lacks a number of residues which are necessary for hydrolase activity and does not play a role in U8 snoRNA decapping activity (PubMed:21070968).
Belongs to the Nudix hydrolase family. TIRR subfamily.
Homodimer (PubMed:28241136). Interacts with TP53BP1 (via the Tudor-like domain); interaction is abolished following DNA damage and TP53BP1 phosphorylation by ATM (PubMed:28241136). Interacts (via the cytoplasmic part) with SDC4 (By similarity). Interacts with TGFB1I1 and PXN (By similarity).
Key regulator of TP53BP1 required to stabilize TP53BP1 and regulate its recruitment to chromatin (PubMed:28241136). In absence of DNA damage, interacts with the tandem Tudor-like domain of TP53BP1, masking the region that binds histone H4 dimethylated at 'Lys-20' (H4K20me2), thereby preventing TP53BP1 recruitment to chromatin and maintaining TP53BP1 localization to the nucleus (PubMed:28241136). Following DNA damage, ATM-induced phosphorylation of TP53BP1 and subsequent recruitment of RIF1 leads to dissociate NUDT16L1/TIRR from TP53BP1, unmasking the tandem Tudor-like domain and allowing recruitment of TP53BP1 to DNA double strand breaks (DSBs) (PubMed:28241136). Binds U8 snoRNA (PubMed:18820299).
Cytokine that binds to and signals through the IL1RL2/IL-36R receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells linked to a pro-inflammatory response. Part of the IL-36 signaling system that is thought to be present in epithelial barriers and to take part in local inflammatory response; similar to the IL-1 system with which it shares the coreceptor IL1RAP. Seems to be involved in skin inflammatory response by acting on keratinocytes, dendritic cells and indirectly on T-cells to drive tissue infiltration, cell maturation and cell proliferation. In cultured keratinocytes induces the expression of macrophage, T-cell, and neutrophil chemokines, such as CCL3, CCL4, CCL5, CCL2, CCL17, CCL22, CL20, CCL5, CCL2, CCL17, CCL22, CXCL8, CCL20 and CXCL1, and the production of pro-inflammatory cytokines such as TNF-alpha, IL-8 and IL-6. In cultured monocytes up-regulates expression of IL-1A, IL-1B and IL-6. In myeloid dendritic cells involved in cell maturation by up-regulating surface expression of CD83, CD86 and HLA-DR. In monocyte-derived dendritic cells facilitates dendritic cell maturation and drives T-cell proliferation. May play a role in pro-inflammatory effects in the lung.
Expressed in immune system and fetal brain, but not in other tissues tested or in multiple hematopoietic cell lines. Predominantly expressed in skin keratinocytes but not in fibroblasts, endothelial cells or melanocytes. Increased in lesional psoriasis skin.
Initial experiments using non-processed full-length protein found in vitro activity only in the ug range.
Interacts with TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion.
N-terminal truncation leads to a dramatic enhancement of its activity (>1000-fold).
Interacts with RAF1 and MAP2K1; the interaction is direct with RAF1 and required for ERK1/2-signaling pathway activation in response to UV irradiation.
Plays a role in the cellular response to UV irradiation. Mediates G2/M cell cycle arrest, MEK autoactivation and ERK1/2-signaling pathway activation in response to UV irradiation. In ciliated cells of airways, it is involved in the regulation of mucociliary transport (PubMed:31959991).
Ca(2+) release-activated Ca(2+)-like (CRAC-like) channel subunit which mediates Ca(2+) influx and increase in Ca(2+)-selective current by synergy with the Ca(2+) sensor, STIM1.
Expressed in both naive and effector T helper cells with higher levels in effector cells.
Component of the BCR(KLHL22) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL22 and RBX1 (PubMed:19995937). Interacts with PLK1 (PubMed:24067371, PubMed:23455478). Interacts with DEPDC5 (via DEP domain); the interaction depends on amino acid availability (PubMed:29769719). Interacts with YWHAE; required for the nuclear localization of KLHL22 upon amino acid starvation (PubMed:29769719).
Defects in KLHL22 has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea.
Potential oncogene that is up-regulated in breast cancer cells and promotes tumor growth.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex required for chromosome alignment and localization of PLK1 at kinetochores. The BCR(KLHL22) ubiquitin ligase complex mediates monoubiquitination of PLK1, leading to PLK1 dissociation from phosphoreceptor proteins and subsequent removal from kinetochores, allowing silencing of the spindle assembly checkpoint (SAC) and chromosome segregation. Monoubiquitination of PLK1 does not lead to PLK1 degradation (PubMed:19995937, PubMed:23455478). The BCR(KLHL22) ubiquitin ligase complex is also responsible for the amino acid-stimulated 'Lys-48' polyubiquitination and proteasomal degradation of DEPDC5. Through the degradation of DEPDC5, releases the GATOR1 complex-mediated inhibition of the TORC1 pathway. It is therefore an amino acid-dependent activator within the amino acid-sensing branch of the TORC1 pathway, indirectly regulating different cellular processes including cell growth and autophagy (PubMed:29769719).
Catalyzes the reduction of the delta-24 double bond of sterol intermediates during cholesterol biosynthesis (PubMed:11519011, PubMed:21671375, PubMed:25637936, PubMed:22178193). In addition to its cholesterol-synthesizing activity, can protect cells from oxidative stress by reducing caspase 3 activity during apoptosis induced by oxidative stress (PubMed:11007892, PubMed:22010141). Also protects against amyloid-beta peptide-induced apoptosis (PubMed:11007892).
Highly expressed in brain and adrenal gland with moderate expression in liver, lung, spleen, prostate and spinal cord. Low expression in heart, uterus and prostate. Undetectable in blood cells. In the brain, strongly expressed in cortical regions, substantia nigra, caudate nucleus, hippocampus, medulla oblongata and pons. In brains affected by Alzheimer disease, expression in the inferior temporal lobe is substantially lower than in the frontal cortex.
Interacts with DHCR7; this interaction regulates DHCR7 activity.
Has no glucosyltransferase activity. Concerning beta-galactosyltransferase activity, the level of CERCAM could be too low to detect any activity when tested in transfected insect cells.
Probable cell adhesion protein involved in leukocyte transmigration across the blood-brain barrier. Does not express any beta-galactosyltransferase activity in vitro.
Ubiquitous. Highly expressed in secretory and nervous tissues.
Inhibits TIFA-mediated TRAF6 activation possibly by inducing a conformational change in TIFA.
Phosphorylated by CK2 (casein kinase II) in vitro.
Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids. Acts as a NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductase on the steroid nucleus and side chain and regulates the metabolism of androgens, estrogens and progesterone (PubMed:10622721, PubMed:11165022, PubMed:7650035, PubMed:9415401, PubMed:9927279). Displays the ability to catalyze both oxidation and reduction in vitro, but most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentration of NADPH (PubMed:14672942, PubMed:11165022). Acts preferentially as a 17-ketosteroid reductase and has the highest catalytic efficiency of the AKR1C enzyme for the reduction of delta4-androstenedione to form testosterone (PubMed:20036328). Reduces prostaglandin (PG) D2 to 11beta-prostaglandin F2, progesterone to 20alpha-hydroxyprogesterone and estrone to 17beta-estradiol (PubMed:15047184, PubMed:20036328, PubMed:10622721, PubMed:11165022, PubMed:10998348, PubMed:19010934). Catalyzes the transformation of the potent androgen dihydrotestosterone (DHT) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol) (PubMed:10998348, PubMed:14672942, PubMed:11165022, PubMed:7650035, PubMed:9415401, PubMed:10557352). Also displays retinaldehyde reductase activity toward 9-cis-retinal (PubMed:21851338).
Expressed in many tissues including adrenal gland, brain, kidney, liver, lung, mammary gland, placenta, small intestine, colon, spleen, prostate and testis. High expression in prostate and mammary gland. In the prostate, higher levels in epithelial cells than in stromal cells. In the brain, expressed in medulla, spinal cord, frontotemporal lobes, thalamus, subthalamic nuclei and amygdala. Weaker expression in the hippocampus, substantia nigra and caudate.
Strongly inhibited by nonsteroidal anti-inflammatory drugs (NSAID) including flufenamic acid and indomethacin. Also inhibited by the flavinoid, rutin, and by selective serotonin inhibitors (SSRIs) (PubMed:14979715, PubMed:14996743, PubMed:10557352). The oxidation reaction is inhibited by low micromolar concentrations of NADPH (PubMed:14672942).
Mainly expressed in liver and kidney. Lower levels are also detected in many other tissues.
Expressed in heart, liver, skeletal muscle, kidney and pancreas, and, to a lesser extent, in brain, lung and spleen. In the pancreas, expressed in islet cells, including insulin- and glucagon-producing alpha- and beta-cells, but not in acinar cells (at protein level). Detected in adrenal glands, particularly in the deeper layer of the cortex (at protein level).
Expressed in the islet-like cells of the developing pancreas and epithelial cells of the duodenum from gestational weeks 8 to 20 (at protein level).
May function as a growth suppressor or tumor suppressor in liver cells and in certain neurons.
Consists of at least two heavy chains and a number of intermediate and light chains. Interacts with CFAP45 (PubMed:33139725).
Expressed in airway ciliated epithelial cells (at protein level) (PubMed:31178125, PubMed:33139725). Not detected in spermatozoa (at protein level) (PubMed:31178125).
Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP.
Catalyzes the activation of fatty acids by CoA to produce an acyl-CoA, the first step in fatty acid metabolism (By similarity). Capable of activating medium-chain fatty acids (e.g. butyric (C4) to decanoic (C10) acids), and certain carboxylate-containing xenobiotics, e.g. benzoate (By similarity).
Binds to CD48 with a sronger affinity than isoform 1, and interactions induces greater cytotoxicity and intracellular calcium release.
Expressed in spleen, PBL, followed by lung, liver, testis and small intestine. Expressed in all natural killer (NK) cells, monocytes and basophils, TCR-gamma/delta+ T-cells, monocytes, basophils, and on a subset of CD8(+) T-cells.
Heterophilic receptor of the signaling lymphocytic activation molecule (SLAM) family; its ligand is CD48. SLAM receptors triggered by homo- or heterotypic cell-cell interactions are modulating the activation and differentiation of a wide variety of immune cells and thus are involved in the regulation and interconnection of both innate and adaptive immune response. Activities are controlled by presence or absence of small cytoplasmic adapter proteins, SH2D1A/SAP and/or SH2D1B/EAT-2. Acts as activating natural killer (NK) cell receptor (PubMed:10359122, PubMed:8376943, PubMed:11714776). Activating function implicates association with SH2D1A and FYN (PubMed:15713798). Downstreaming signaling involves predominantly VAV1, and, to a lesser degree, INPP5D/SHIP1 and CBL. Signal attenuation in the absence of SH2D1A is proposed to be dependent on INPP5D and to a lesser extent PTPN6/SHP-1 and PTPN11/SHP-2 (PubMed:10934222, PubMed:15713798). Stimulates NK cell cytotoxicity, production of IFN-gamma and granule exocytosis (PubMed:8376943, PubMed:11714776). Optimal expansion and activation of NK cells seems to be dependent on the engagement of CD244 with CD48 expressed on neighboring NK cells (By similarity). Acts as costimulator in NK activation by enhancing signals by other NK receptors such as NCR3 and NCR1 (PubMed:10741393). At early stages of NK cell differentiation may function as an inhibitory receptor possibly ensuring the self-tolerance of developing NK cells (PubMed:11917118). Involved in the regulation of CD8(+) T-cell proliferation; expression on activated T-cells and binding to CD48 provides costimulatory-like function for neighboring T-cells (By similarity). Inhibits inflammatory responses in dendritic cells (DCs) (By similarity).
Interacts with CD48 (PubMed:9841922, PubMed:27249817). Interacts (via phosphorylated ITSM 1-4) with SH2D1A (via SH2 domain); SH2D1A probably mediates association with FYN. Interacts (via phosphorylated ITSM 3) with PTPN11/SHP-2, INPP5D/SHIP1, PTPN6/SHP-1 and CSK; binding of SH2D1A/SAP prevents association with PTPN11, PTPN6 and CSK; conflictingly a similar association has been described for phosphorylated ITSM 1 also including GRB2 and PLCG1. Interacts weakly (via phosphorylated ITSM 2) with PTPN11/SHP-2 and CSK (PubMed:10358138, PubMed:10934222, PubMed:12458214, PubMed:24642916, PubMed:26221972, PubMed:15713798). Interacts with SH2D1B (PubMed:12458214, PubMed:24642916). Interacts with PIK3R1; PI3K recruits SH2D1A (PubMed:11815622). Interacts with MHC class I proteins; the interaction is proposed to prevent self-killing of NK cells.
N-linked glycosylation is essential for the binding to its ligand CD48. Also O-glycosylated, in contrast, O-linked sialylation has a negative impact on ligand binding.
Phosphorylated by FYN and CSK on tyrosine residues following activation. Coligation with inhibitory receptors such as KIR2DL1 inhibits phosphorylation upon contact of NK cells with sensitive target cells.
The ITSMs (immunoreceptor tyrosine-based switch motifs) with the consensus sequence T-X-Y-X-X-[VI] present in SLAM family receptors have overlapping specificity for activating and inhibitory SH2 domain-containing binding partners. Especially they mediate the interaction with the SH2 domain of SH2D1A and SH2D1B. A 'three-pronged' mechanism is proposed involving threonine (position -2), phosphorylated tyrosine (position 0) and valine/isoleucine (position +3).
Expressed in liver, heart, brain, kidney and testis.
Interacts with UBE2L3. Interacts with VCP.
May have a ubiquitin-protein ligase activity acting as an E3 ubiquitin-protein ligase or as a ubiquitin-ubiquitin ligase promoting elongation of ubiquitin chains on substrates.
The U-box domain mediates interaction with E2 ubiquitin ligases and is required for the ubiquitin-protein ligase activity.
Activated in response to insulin. Autophosphorylation activates the kinase activity. PTPN1, PTPRE and PTPRF dephosphorylate important tyrosine residues, thereby reducing INSR activity. Inhibited by ENPP1. GRB10 and GRB14 inhibit the catalytic activity of the INSR, they block access of substrates to the activated receptor. SOCS1 and SOCS3 act as negative regulators of INSR activity, they bind to the activated INRS and interfere with the phosphorylation of INSR substrates.
After being transported from the endoplasmic reticulum to the Golgi apparatus, the single glycosylated precursor is further glycosylated and then cleaved, followed by its transport to the plasma membrane.
Autophosphorylated on tyrosine residues in response to insulin. Phosphorylation of Tyr-999 is required for binding to IRS1, SHC1 and STAT5B. Dephosphorylated by PTPRE at Tyr-999, Tyr-1185, Tyr-1189 and Tyr-1190. Dephosphorylated by PTPRF and PTPN1. Dephosphorylated by PTPN2; down-regulates insulin-induced signaling.
Isoform Long and isoform Short are predominantly expressed in tissue targets of insulin metabolic effects: liver, adipose tissue and skeletal muscle but are also expressed in the peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes and skin. Isoform Short is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas.
Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosine residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. In adipocytes, inhibits lipolysis (By similarity).
Tetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains carry the insulin-binding regions, while the beta chains carry the kinase domain. Forms a hybrid receptor with IGF1R, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. Interacts with SORBS1 but dissociates from it following insulin stimulation. Binds SH2B2. Activated form of INSR interacts (via Tyr-999) with the PTB/PID domains of IRS1 and SHC1. The sequences surrounding the phosphorylated NPXY motif contribute differentially to either IRS1 or SHC1 recognition. Interacts (via tyrosines in the C-terminus) with IRS2 (via PTB domain and 591-786 AA); the 591-786 would be the primary anchor of IRS2 to INSR while the PTB domain would have a stabilizing action on the interaction with INSR. Interacts with the SH2 domains of the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro, when autophosphorylated on tyrosine residues. Interacts with SOCS7. Interacts (via the phosphorylated Tyr-999), with SOCS3. Interacts (via the phosphorylated Tyr-1185, Tyr-1189, Tyr-1190) with SOCS1. Interacts with CAV2 (tyrosine-phosphorylated form); the interaction is increased with 'Tyr-27'phosphorylation of CAV2 (By similarity). Interacts with ARRB2 (By similarity). Interacts with GRB10; this interaction blocks the association between IRS1/IRS2 and INSR, significantly reduces insulin-stimulated tyrosine phosphorylation of IRS1 and IRS2 and thus decreases insulin signaling. Interacts with GRB7. Interacts with PDPK1. Interacts (via Tyr-1190) with GRB14 (via BPS domain); this interaction protects the tyrosines in the activation loop from dephosphorylation, but promotes dephosphorylation of Tyr-999, this results in decreased interaction with, and phosphorylation of, IRS1. Interacts (via subunit alpha) with ENPP1 (via 485-599 AA); this interaction blocks autophosphorylation. Interacts with PTPRE; this interaction is dependent of Tyr-1185, Tyr-1189 and Tyr-1190 of the INSR. Interacts with STAT5B (via SH2 domain). Interacts with PTPRF. Interacts with ATIC; ATIC together with PRKAA2/AMPK2 and HACD3/PTPLAD1 is proposed to be part of a signaling netwok regulating INSR autophosphorylation and endocytosis (By similarity). Interacts with the cone snail venom insulin Con-Ins G1 (PubMed:27617429). Interacts with the insulin receptor SORL1; this interaction strongly increases its surface exposure, hence strengthens insulin signal reception (PubMed:27322061). Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via SH2-like region); binding requires autophosphorylation of the INSR C-terminal region (PubMed:25187647). Interacts with GNAI3; the interaction is probably mediated by CCDC88A/GIV (PubMed:25187647). Interacts with LMBRD1 (By similarity).
The tetrameric insulin receptor binds insulin via non-identical regions from two alpha chains, primarily via the C-terminal region of the first INSR alpha chain. Residues from the leucine-rich N-terminus of the other INSR alpha chain also contribute to this insulin binding site. A secondary insulin-binding site is formed by residues at the junction of fibronectin type-III domain 1 and 2.
(Microbial infection) Interacts with herpes simplex virus 1/HHV-1 protein Vhs.
ATP-dependent RNA helicase which is a subunit of the eIF4F complex involved in cap recognition and is required for mRNA binding to ribosome. In the current model of translation initiation, eIF4A unwinds RNA secondary structures in the 5'-UTR of mRNAs which is necessary to allow efficient binding of the small ribosomal subunit, and subsequent scanning for the initiator codon.
Belongs to the DEAD box helicase family. eIF4A subfamily.
eIF4F is a multi-subunit complex, the composition of which varies with external and internal environmental conditions. It is composed of at least EIF4A, EIF4E and EIF4G1/EIFFG3 (By similarity). Interacts with EIF4E. May interact with NOM1.
Belongs to the SLC26A/SulP transporter (TC 2.A.53) family.
Expressed most abundantly in the kidney and liver, with lower levels in the pancreas, testis, brain, small intestine, colon, and lung.
Sodium-independent sulfate anion transporter (PubMed:12713736, PubMed:27125215). Can transport other anions including bicarbonate, thiosulfate and oxalate by mediating sulfate-thiosulfate, sulfate-hydrogencarbonate and sulfate-oxalate anion exchange (PubMed:12713736, PubMed:27125215). Mediates oxalate-hydrogencarbonate anion exchange (By similarity).
Calcium-binding protein (By similarity). Essential for maintaining the structural integrity of the sperm flagella (By similarity).
Identified in a complex with TFAM and SSBP1. Interacts with AGO1 and AGO2. Interacts (via N-terminus) with ZC3HAV1 (via N-terminal domain) in an RNA-independent manner (By similarity). Found in a complex with GRSF1, DDX28, FASTKD2 and FASTKD5 (PubMed:25683715).
RNA-dependent helicase (PubMed:29100085). Plays an important role in the assembly of the mitochondrial large ribosomal subunit (PubMed:25683715, PubMed:29100085). Required for optimal function of the zinc-finger antiviral protein ZC3HAV1 (By similarity). Associates with mitochondrial DNA (PubMed:18063578). Involved in nervous system development and differentiation through its involvement in the up-regulation of a number of genes which are required for neurogenesis, including GSC, NCAM1, neurogenin, and NEUROD (By similarity).
Interacts with DRG1; this interaction prevents DRG1 poly-ubiquitination and degradation by proteasome. DRG1-ZC3H15/DFRP1 complex co-sediments with polysomes. Associates with microtubules.
Protects DRG1 from proteolytic degradation (PubMed:19819225). Stimulates DRG1 GTPase activity likely by increasing the affinity for the potassium ions (PubMed:23711155).
Highest levels in skeletal and cardiac muscles. Detectable in all other tissues tested except brain.
Autoubiquitinated as component of the CTLH E3 ubiquitin-protein ligase complex (in vitro).
Core component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1. MAEA and RMND5A are both required for catalytic activity of the CTLH E3 ubiquitin-protein ligase complex (PubMed:29911972). MAEA is required for normal cell proliferation (PubMed:29911972). The CTLH E3 ubiquitin-protein ligase complex is not required for the degradation of enzymes involved in gluconeogenesis, such as FBP1 (PubMed:29911972). Plays a role in erythroblast enucleation during erythrocyte maturation and in the development of mature macrophages (By similarity). Mediates the attachment of erythroid cell to mature macrophages; this MAEA-mediated contact inhibits erythroid cell apoptosis (PubMed:9763581). Participates in erythroblastic island formation, which is the functional unit of definitive erythropoiesis. Associates with F-actin to regulate actin distribution in erythroblasts and macrophages (By similarity). May contribute to nuclear architecture and cells division events (Probable).
Detected at macrophage membranes (at protein level). Ubiquitous.
Identified in the CTLH complex that contains GID4, RANBP9 and/or RANBP10, MKLN1, MAEA, RMND5A (or alternatively its paralog RMND5B), GID8, ARMC8, WDR26 and YPEL5 (PubMed:17467196, PubMed:29911972). Within this complex, MAEA, RMND5A (or alternatively its paralog RMND5B), GID8, WDR26, and RANBP9 and/or RANBP10 form the catalytic core, while GID4, MKLN1, ARMC8 and YPEL5 have ancillary roles (PubMed:29911972). Interacts with F-actin (PubMed:16510120).
The expected RING-type zinc finger domain is highly divergent and most of the expected Cys residues are not conserved (Probable). Still, the protein is required for CTLH complex E3 ubiquitin-protein transferase activity (PubMed:29911972). In addition, the conserved Cys-314 in this highly divergent region is required for ubiquitination by the yeast GID complex, suggesting a direct role in catalyzing ubiquitination (Probable).
A chromosomal aberration involving PCDH11Y is a cause of multiple congenital abnormalities, including severe bilateral vesicoureteral reflux (VUR) with ureterovesical junction defects. Translocation t(Y;3)(p11;p12) with ROBO2.
Expressed strongly in fetal brain and brain (cortex, amygdala, thalamus, substantia nigra, hippocampus, caudate nucleus and corpus callosum). Expressed at low level in testis. Expressed in apoptosis-resistant cells.
Forms homooligomers and, to a much smaller extent, heterooligomers with DDHD2 (PubMed:22922100).
Highly expressed in testis. Also expressed in brain, spleen and lung. Only expressed in cerebellum in fetal brain.
Phosphatidate (1,2-diacyl-sn-glycero-3-phosphate, PA) can positively regulate phospholipase A1 activity.
Phospholipase A1 (PLA1) that hydrolyzes ester bonds at the sn-1 position of glycerophospholipids producing a free fatty acid and a lysophospholipid (PubMed:20359546, PubMed:22922100) (Probable). Prefers phosphatidate (1,2-diacyl-sn-glycero-3-phosphate, PA) as substrate in vitro, but can efficiently hydrolyze phosphatidylinositol (1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol), PI), as well as a range of other glycerophospholipid substrates such as phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine, PC), phosphatidylethanolamine (1,2-diacyl-sn-glycero-3-phosphoethanolamine, PE), phosphatidylserine (1,2-diacyl-sn-glycero-3-phospho-L-serine, PS) and phosphatidylglycerol (1,2-diacyl-sn-glycero-3-phospho-(1'-sn-glycerol), PG) (PubMed:20359546) (Probable). Involved in the regulation of the endogenous content of polyunsaturated PI and PS lipids in the nervous system. Changes in these lipids extend to downstream metabolic products like PI phosphates PIP and PIP2, which play fundamental roles in cell biology (By similarity). Regulates mitochondrial morphology (PubMed:24599962). These dynamic changes may be due to PA hydrolysis at the mitochondrial surface (PubMed:24599962). May play a regulatory role in spermatogenesis or sperm function (PubMed:24599962).
Transcriptional activator. Isoform 1 may be involved in transcriptional activation of erythroid genes.
A chromosomal aberration involving FEV is found in Ewing tumors. Translocation t(2;21;22)(q23;q22;q12) that forms a EWSR1-FEV fusion protein with a potential oncogenic activity.
Functions as a transcriptional regulator. According to PubMed:12761502, it functions as a transcriptional repressor. Functions in the differentiation and the maintenance of the central serotonergic neurons. May play a role in cell growth.
In brain, exclusively expressed in the major serotonergic neurons of the dorsal and median raphe nuclei located in the midbrain and pons. Also detected in prostate and small intestine.
Belongs to the mitochondrion-specific ribosomal protein mS25 family.
Expressed in brain; detected in frontal and temporal lobes, occipital pole, amygdala and hippocampus (PubMed:11690637, PubMed:29226084). Also expressed in testis (PubMed:11690637, PubMed:29226084) and T cells, B cells, and monocyte (PubMed:29226084). Low expression in many other tissues (PubMed:11690637, PubMed:29226084). Widely expressed in the hippocampus (at protein level).
Forms heterodimer with MTNR1B (PubMed:28827538). Interacts with ARRB1 and ARRB2 in a spontaneous and agonist-independent manner; leading to the internalization of GPR61 in the endosomal compartment (PubMed:28827538).
Orphan G-protein coupled receptor. Constitutively activates the G(s)-alpha/cAMP signaling pathway (PubMed:28827538). Shows a reciprocal regulatory interaction with the melatonin receptor MTNR1B most likely through receptor heteromerization (PubMed:28827538). May be involved in the regulation of food intake and body weight (By similarity).
Detected in normal cervical keratinocytes, and in some cervical carcinoma cell lines.
Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP).
Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Plays an important role in the tumor-like growth properties of embryonic stem cells (By similarity).
Associated with various cancers. DNA copy number loss is found in multiple kinds of malignancies originating from the brain, breast, stomach, kidney, hematopoietic tissue and lung.
E3 ligase activity is robustly activated by 5-hydroxymethylcytosine.
E3 ubiquitin ligase that plays important roles in DNA methylation, histone modifications, cell cycle and DNA repair (PubMed:15178429, PubMed:29506131, PubMed:27743347, PubMed:23404503). Acts as a specific reader for 5-hydroxymethylcytosine (5hmC) and thereby recruits various substrates to these sites to ubiquitinate them (PubMed:27129234, PubMed:24813944). This activity also allows the maintenance of 5mC levels at specific genomic loci and regulates neuron-related gene expression (By similarity). Participates in cell cycle regulation by ubiquitinating cyclins CCND1 and CCNE1 and thereby inducing G1 arrest (PubMed:15178429, PubMed:15361834, PubMed:21952639). Ubiquitinates also PCNP leading to its degradation by the proteasome (PubMed:14741369, PubMed:12176013). Plays an active role in DNA damage repair by ubiquitinating p21/CDKN1A leading to its proteasomal degradation (PubMed:29923055). Promotes also DNA repair by acting as an interstrand cross-links (ICLs) sensor. Mechanistically, cooperates with UHRF1 to ensure recruitment of FANCD2 to ICLs, leading to FANCD2 monoubiquitination and subsequent activation (PubMed:30335751). Contributes to UV-induced DNA damage response by physically interacting with ATR in response to irradiation, thereby promoting ATR activation (PubMed:33848395).
Homodimer; disulfide-linked. Binds methylated CpG containing oligonucleotides. Interacts with H3; the interaction has a preference for the 'Lys-9' trimethylated form of H3 (H3K9me3) (By similarity). Interacts with PCNP (PubMed:12176013, PubMed:14741369). Interacts with HDAC1 (PubMed:15361834). Interacts directly with CCNE1; the interaction ubiquitinates CCNE1 and appears independent of CCNE1 phosphorylation (PubMed:21952639). Interacts with CCND1; the interaction ubiquitinates CCND1 and appears independent of CCND1 phosphorylation (PubMed:21952639). Interacts with p53/TP53 and RB1 (PubMed:21952639). Interacts with UBE2I (PubMed:23404503). Interacts with ZNF618 (PubMed:27129234). Interacts with UHRF1 (PubMed:30335751). Interacts with FANCD2 (PubMed:30335751). Interacts with ATR (PubMed:33848395). Interacts with PCNA (PubMed:28951215).
May be autoubiquitinated; which may lead to proteasomal degradation.
Phosphorylated. Phosphorylation may be mediated by CDK2.
The YDG domain recognizes and binds 5-hydroxymethylcytosine (5hmC).
Up-regulated in proliferating fetal lung fibroblasts and in U-937 myeloid leukemia cells. Down-regulated in these cells by growth arrest and differentiation. In other cell types which cannot leave the cell cycle, such as tumoral HT-1080 and Hep-G2, levels are consistently up-regulated.
Prominent expression is observed in the central and peripheral nervous system in the embryo at Carnagie stage 17 (CS17; gestational day 42); at this stage it is also observed in the mandibular arch, cartilage primordium of the humerus, scapula, and vertebrae; in the limb expression is detected in the perichondrium. Expressed in the cerebral cortex, hippocampus, and faintly in the thalamus in fetal brain at 22 weeks of gestation,.
Recognizes and binds the palindromic sequence 5'-TTGGCNNNNNGCCAA-3' present in viral and cellular promoters and in the origin of replication of adenovirus type 2. These proteins are individually capable of activating transcription and replication.
Defects in CIZ1 may be a cause of adult onset primary cervical dystonia. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. Cervical dystonia or spasmodic torticollis, the most common form of focal dystonia, is characterized by involuntary contractions of the neck muscles, which produce abnormal posturing of the head upon the trunk.
May regulate the subcellular localization of CIP/WAF1.
Detected in kidney (at protein level). Detected in fetal and adult kidney. Detected in epithelial cells of proximal tubules in renal cortex.
Electroneutral antiporter that translocates urate across the apical membrane of proximal tubular cells in exchange for monovalent organic or inorganic anions (PubMed:12024214, PubMed:22194875, PubMed:35144162, PubMed:35462902). Involved in renal reabsorption of urate and helps maintaining blood levels of uric acid (PubMed:12024214, PubMed:22194875). Mediates urate uptake by an exchange with organic anions such as (S)-lactate and nicotinate, and inorganic anion Cl(-) (PubMed:12024214). Other inorganic anions such as Br(-), I(-) and NO3(-) may also act as counteranions that exchange for urate (PubMed:12024214). Also mediates orotate tubular uptake coupled with nicotinate efflux and to a lesser extent with lactate efflux, therefore displaying a potential role in orotate renal reabsorption (PubMed:21350910). Orotate transport is Cl(-)-dependent (PubMed:21350910).
Homodimer (PubMed:15718238, PubMed:16709157). Interacts (via the MENTAL domain) with STARD3NL (PubMed:15718238, PubMed:16709157). Interacts (via phosphorylated FFAT motif) with VAPA (via MSP domain) (PubMed:24105263, PubMed:28377464, PubMed:33124732). Interacts (via phosphorylated FFAT motif) with VAPB (via MSP domain) (PubMed:24105263, PubMed:28377464, PubMed:33124732). Interacts (via phosphorylated FFAT motif) with MOSPD2 (via MSP domain); this interaction allows enrichment of MOSPD2 around endosomes (PubMed:29858488, PubMed:33124732).
Not regulated by increases in total cholesterol content, or by marked alterations in cholesterol flux.
Phosphorylation at Ser-209 is necessary and sufficient for the direct interaction of the phosphorylated FFAT motif with the MSP domain of MOSPD2, VAPA and VAPB and allows the tethering of two membranes that participates in the formation of ER-endosome contacts (PubMed:33124732). Phosphorylation of the FFAT motif leads to conformation changes (PubMed:33124732). Additional phosphorylations around the core FFAT motif (QFYSPPE) are not essential but strengthen the interaction with MOSPD2, VAPA and VAPB (PubMed:33124732). Phosphorylation at Ser-209 of FFAT motif drives membrane tethering between the endoplasmic reticulum and late endosomes via interaction with VAPA and VAPB that in turn allows the efficient transport of sterol mediated by the START domain (PubMed:33124732).
STARD3 was reported to function in cholesterol transport to the mitochondria or to the cell membrane (PubMed:12070139, PubMed:19965586). Other reports however showed that it mediates cholesterol transport from the endoplasmic reticulum to endosomes (PubMed:11053434, PubMed:28377464). Discrepancies may be due to the different cell type used and the cellular physiological state (PubMed:28377464).
Sterol-binding protein that mediates cholesterol transport from the endoplasmic reticulum to endosomes (PubMed:11053434, PubMed:15930133, PubMed:22514632, PubMed:28377464, PubMed:33124732). The sterol transport mechanism is triggered by phosphorylation of FFAT motif that leads to membrane tethering between the endoplasmic reticulum and late endosomes via interaction with VAPA and VAPB (PubMed:24105263, PubMed:28377464, PubMed:33124732). Acts as a lipid transfer protein that redirects sterol to the endosome at the expense of the cell membrane and favors membrane formation inside endosomes (PubMed:28377464). May also mediate cholesterol transport between other membranes, such as mitochondria membrane or cell membrane (PubMed:12070139, PubMed:19965586). However, such results need additional experimental evidences; probably mainly mediates cholesterol transport from the endoplasmic reticulum to endosomes (PubMed:28377464). Does not activate transcriptional cholesterol sensing (PubMed:28377464). Able to bind other lipids, such as lutein, a xanthophyll carotenoids that form the macular pigment of the retina (PubMed:21322544).
The FFAT motif mediates interaction with VAPA, VAPB and MOSPD2.
The MENTAL domain anchors the protein in endosome membranes and exposes the START domain in the cytosol (PubMed:11053434). It binds cholesterol and mediates homotypic as well as heterotypic interactions between STARD3 and STARD3NL (PubMed:15718238, PubMed:16709157).
The START domain mediates lipid-transfer between membranes. It contains a hydrophobic cavity able to accommodate one lipid molecule, thereby serving as a 'hydrophobic bridge' across the aqueous gap between donor and acceptor organelle membranes.
Belongs to the tryptophan 2,3-dioxygenase family.
Heme-dependent dioxygenase that catalyzes the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring and converts L-tryptophan to N-formyl-L-kynurenine. Catalyzes the oxidative cleavage of the indole moiety.
(Microbial infection) Acts as a receptor for Influenzavirus (PubMed:29779930). May play a critical role in allowing virus entry when sialylated and expressed on lung tissues (PubMed:29779930).
(Microbial infection) Interacts with influenzavirus H1 hemagglutinin.
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1C subfamily.
Binding of intracellular calcium through the EF-hand motif inhibits the opening of the channel.
Component of a calcium channel complex consisting of a pore-forming alpha subunit (CACNA1C) and ancillary beta, gamma and delta subunits (PubMed:12181424, PubMed:12176756, PubMed:29742403, PubMed:29078335, PubMed:15141227, PubMed:16299511, PubMed:20953164). The channel complex contains alpha, beta, gamma and delta subunits in a 1:1:1:1 ratio, i.e. it contains only one of each type of subunit (Probable). CACNA1C channel activity is modulated by ancillary subunits, such as CACNB1, CACNB2, CACNB3, CACNA2D1 and CACNA2D4 (PubMed:11741969, PubMed:12181424, PubMed:29742403, PubMed:17224476). Interacts with the gamma subunits CACNG4, CACNG6, CACNG7 and CACNG8 (By similarity). Interacts with CACNB1 (By similarity). Interacts with CACNB2 (PubMed:12176756, PubMed:11741969, PubMed:29742403, PubMed:15141227, PubMed:20953164, PubMed:15863612, PubMed:17224476, PubMed:24728418). Identified in a complex with CACNA2D4 and CACNB3 (PubMed:12181424). Interacts with CACNB3 (PubMed:12181424, PubMed:29742403). Interacts with CACNA2D1 (PubMed:29742403, PubMed:20953164, PubMed:15863612, PubMed:24728418). Interacts with CACNA2D4 (PubMed:12181424). Interacts with CALM1 (PubMed:29742403, PubMed:16299511, PubMed:16338416, PubMed:19279214, PubMed:20953164, PubMed:22518098). Interacts (via the N-terminus and the C-terminal C and IQ motifs) with CABP1; this inhibits Ca(2+)-dependent channel inactivation (PubMed:15140941, PubMed:15980432). The binding via the C motif is calcium independent whereas the binding via IQ requires the presence of calcium and is mutually exclusive with calmodulin binding (PubMed:15140941). The binding to the cytoplasmic N-terminal domain is calcium independent but is essential for the channel modulation. Interacts (via C-terminal CDB motif) with CABP5; in a calcium-dependent manner (By similarity). Interacts with CIB1; the interaction increases upon cardiomyocytes hypertrophy (By similarity). Interacts with STAC2 and STAC3; this inhibits channel inactivation (PubMed:29078335).
Detected throughout the brain, including hippocampus, cerebellum and amygdala, throughout the heart and vascular system, including ductus arteriosus, in urinary bladder, and in retina and sclera in the eye (PubMed:15454078). Expressed in brain, heart, jejunum, ovary, pancreatic beta-cells and vascular smooth muscle. Overall expression is reduced in atherosclerotic vascular smooth muscle.
Inhibited by dihydropyridines (DHP), such as isradipine (PubMed:8392192, PubMed:7737988, PubMed:9607315, PubMed:8099908). Inhibited by nifedipine (By similarity). Channel activity is regulated by Ca(2+) and calmodulin (PubMed:29742403) (Probable). Binding of STAC1, STAC2 or STAC3 to a region that overlaps with the calmodulin binding site inhibits channel inactivation by Ca(2+) and calmodulin (PubMed:29078335). Binding of calmodulin or CABP1 at the same regulatory sites results in opposite effects on the channel function (PubMed:15140941, PubMed:15980432). Shear stress and pressure increases calcium channel activity (PubMed:12176756).
Phosphorylation by PKA at Ser-1981 activates the channel. Elevated levels of blood glucose lead to increased phosphorylation by PKA.
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:8392192, PubMed:7737988, PubMed:9087614, PubMed:9013606, PubMed:9607315, PubMed:12176756, PubMed:17071743, PubMed:11741969, PubMed:8099908, PubMed:12181424, PubMed:29078335, PubMed:29742403, PubMed:16299511, PubMed:20953164, PubMed:15454078, PubMed:15863612, PubMed:17224476, PubMed:24728418, PubMed:26253506, PubMed:27218670, PubMed:23677916, PubMed:30023270, PubMed:30172029, PubMed:34163037). Mediates influx of calcium ions into the cytoplasm, and thereby triggers calcium release from the sarcoplasm (By similarity). Plays an important role in excitation-contraction coupling in the heart. Required for normal heart development and normal regulation of heart rhythm (PubMed:15454078, PubMed:15863612, PubMed:17224476, PubMed:24728418, PubMed:26253506). Required for normal contraction of smooth muscle cells in blood vessels and in the intestine. Essential for normal blood pressure regulation via its role in the contraction of arterial smooth muscle cells (PubMed:28119464). Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group (Probable).
Predominant isoform in atherosclerotic vascular smooth muscle cells.
Expressed in spleen, lymph node, peripheral blood leukocytes, bone marrow, small intestine, stomach, appendix, lung and trachea. Expression was detected in NK cells, activated B-cells, NK-cell line but not in promyelocytic, B-, or T-cell lines. Expressed in monocytes. Isoform 3 is expressed at much lower level than isoform 1.
Isoform 1 binds to SH2D1A when its cytoplasmic tail is phosphorylated in the presence of FYN (in vitro); low affinity binding, the physiological relevance of the interaction is questioned. Interacts with SH2D1B; in NK cells (PubMed:16339536). Interacts (via ITSM phosphorylated on Tyr-302) with SH2D1B, PTPN6/SHP-1, PTPN11/SHP-2, INPP5D/SHIP1, CSK and FYN (By similarity).
Isoform 3 does not mediate any NK cell activation.
Proposed to be involved in systemic lupus erythematosus (SLE) disease process.
Self-ligand receptor of the signaling lymphocytic activation molecule (SLAM) family. SLAM receptors triggered by homo- or heterotypic cell-cell interactions are modulating the activation and differentiation of a wide variety of immune cells and thus are involved in the regulation and interconnection of both innate and adaptive immune response. Activities are controlled by presence or absence of small cytoplasmic adapter proteins, SH2D1A/SAP and/or SH2D1B/EAT-2. Isoform 1 mediates NK cell activation through a SH2D1A-independent extracellular signal-regulated ERK-mediated pathway (PubMed:11698418). Positively regulates NK cell functions by a mechanism dependent on phosphorylated SH2D1B. Downstream signaling implicates PLCG1, PLCG2 and PI3K (PubMed:16339536). In addition to heterotypic NK cells-target cells interactions also homotypic interactions between NK cells may contribute to activation. However, in the absence of SH2D1B, inhibits NK cell function. Acts also inhibitory in T-cells (By similarity). May play a role in lymphocyte adhesion (PubMed:11802771). In LPS-activated monocytes negatively regulates production of pro-inflammatory cytokines (PubMed:23695528).
Heterodimer with TCF3/E12. Interacts with the bHLH domain of TCF3/E12 (By similarity).
Transcription factor that binds to the E-box and functions as inhibitor of transcription. DNA binding requires dimerization with an E protein. Inhibits transcription activation by ASCL1/MASH1 by sequestering E proteins (By similarity).
A chromosomal aberration involving DAB2IP is found in a patient with acute myeloid leukemia (AML). Translocation t(9;11)(q34;q23) with KMT2A/MLL1. May give rise to a KMT2A/MLL1-DAB2IP fusion protein lacking the PH domain (PubMed:14978793).
Down-regulated in prostate cancer and medulloblastoma.
Expressed in endothelial and vascular smooth muscle cells (VSMCs). Expressed in prostate epithelial but poorly in prostate cancer cells. Poorly expressed in medulloblastoma cells compared to cerebellar precursor proliferating progenitor cells (at protein level). Low expression in prostate. Down-regulated in prostate cancer.
Functions as a scaffold protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Involved in several processes such as innate immune response, inflammation and cell growth inhibition, apoptosis, cell survival, angiogenesis, cell migration and maturation. Also plays a role in cell cycle checkpoint control; reduces G1 phase cyclin levels resulting in G0/G1 cell cycle arrest. Mediates signal transduction by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF), interferon (IFN) or lipopolysaccharide (LPS). Modulates the balance between phosphatidylinositol 3-kinase (PI3K)-AKT-mediated cell survival and apoptosis stimulated kinase (MAP3K5)-JNK signaling pathways; sequesters both AKT1 and MAP3K5 and counterbalances the activity of each kinase by modulating their phosphorylation status in response to pro-inflammatory stimuli. Acts as a regulator of the endoplasmic reticulum (ER) unfolded protein response (UPR) pathway; specifically involved in transduction of the ER stress-response to the JNK cascade through ERN1. Mediates TNF-alpha-induced apoptosis activation by facilitating dissociation of inhibitor 14-3-3 from MAP3K5; recruits the PP2A phosphatase complex which dephosphorylates MAP3K5 on 'Ser-966', leading to the dissociation of 13-3-3 proteins and activation of the MAP3K5-JNK signaling pathway in endothelial cells. Mediates also TNF/TRAF2-induced MAP3K5-JNK activation, while it inhibits CHUK-NF-kappa-B signaling. Acts a negative regulator in the IFN-gamma-mediated JAK-STAT signaling cascade by inhibiting smooth muscle cell (VSMCs) proliferation and intimal expansion, and thus, prevents graft arteriosclerosis (GA). Acts as a GTPase-activating protein (GAP) for the ADP ribosylation factor 6 (ARF6) and Ras. Promotes hydrolysis of the ARF6-bound GTP and thus, negatively regulates phosphatidylinositol 4,5-bisphosphate (PIP2)-dependent TLR4-TIRAP-MyD88 and NF-kappa-B signaling pathways in endothelial cells in response to lipopolysaccharides (LPS). Binds specifically to phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 3-phosphate (PtdIns3P). In response to vascular endothelial growth factor (VEGFA), acts as a negative regulator of the VEGFR2-PI3K-mediated angiogenic signaling pathway by inhibiting endothelial cell migration and tube formation. In the developing brain, promotes both the transition from the multipolar to the bipolar stage and the radial migration of cortical neurons from the ventricular zone toward the superficial layer of the neocortex in a glial-dependent locomotion process. Probable downstream effector of the Reelin signaling pathway; promotes Purkinje cell (PC) dendrites development and formation of cerebellar synapses. Functions also as a tumor suppressor protein in prostate cancer progression; prevents cell proliferation and epithelial-to-mesenchymal transition (EMT) through activation of the glycogen synthase kinase-3 beta (GSK3B)-induced beta-catenin and inhibition of PI3K-AKT and Ras-MAPK survival downstream signaling cascades, respectively.
In response to TNF-alpha-induction, phosphorylated at Ser-728; phosphorylation leads to a conformational change, and thus, increases its association with 14-3-3 proteins, MAP3K5, RIPK1 and TRAF2 in endothelial cells; also stimulates regulatory p85 subunit sequestring and PI3K-p85 complex activity inhibition.
On plasma membrane, exists in an inactive form complexed with TNFR1; in response to TNF-alpha, dissociates from TNFR1 complex, translocates to cytoplasm and forms part of an intracellular signaling complex comprising TRADD, RIPK1, TRAF2 and MAP3K5. Interacts with DAB1. Interacts (via NPXY motif) with DAB2 (via PID domain). Interacts (via PH domain) with ERN1 (By similarity). Part of a cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response to TNF-alpha; this complex formation promotes MAP3K5-JNK activation and subsequent apoptosis. Interacts (via N-terminal domain) with JAK2; the interaction occurs in a IFNG/IFN-gamma-dependent manner and inhibits JAK2 autophosphorylation activity. Interacts (via C2 domain) with GSK3B; the interaction stimulates GSK3B kinase activation. Interacts (via C2 domain) with PPP2CA. Interacts (via proline-rich motif) with a regulatory p85 subunit (via SH3 domain) of the PI3K complex; the interaction inhibits the PI3K-AKT complex activity in a TNF-alpha-dependent manner in prostate cancer (PCa) cells. Interacts with AKT1; the interaction is increased in a TNF-alpha-induced manner. Interacts (via C2 domain and active form preferentially) with KDR/VEGFR2 (tyrosine-phosphorylated active form preferentially); the interaction occurs at the late phase of VEGFA response and inhibits KDR/VEGFR2 activity. Interacts (via N-terminus C2 domain) with MAP3K5 ('Ser-966' dephosphorylated form preferentially); the interaction occurs in a TNF-alpha-induced manner. Interacts (via Ras-GAP domain) with the catalytic subunit of protein phosphatase PP2A; the interaction occurs in resting endothelial cells, is further enhanced by TNF-alpha stimulation and is required to bridge PP2A to MAP3K5. Interacts (via C-terminus PER domain) with TRAF2 (via zinc fingers); the interaction occurs in a TNF-alpha-dependent manner. Interacts with 14-3-3 proteins; the interaction occurs in a TNF-alpha-dependent manner. Interacts (via Ras-GAP domain) with RIPK1 (via kinase domain); the interaction occurs in a TNF-alpha-dependent manner.
The C2 and Ras-GAP domains constitutively bind to MAP3K5 and facilitate the release of 14-3-3 proteins from MAP3K5. The PH and Ras-GAP domains, but not the NPXY motif, are crucial for its cell membrane localization and neuronal migration function. The PH domain is necessary but not sufficient to activate the JNK signaling pathway through ERN1 (By similarity). Exists in a closed inactive form by an intramolecular interaction between the N- and the C-terminal domains. The proline-rich motif is critical both for PI3K-AKT activity inhibition and MAP3K5 activation. The PH and C2 domains are necessary for the binding to phosphatidylinositol phosphate. The Ras-GAP domain is necessary for its tumor-suppressive function.
The DAB2IP gene is found epigenetically silenced in numerous aggressive cancers, like prostate cancers and medulloblastoma tumors. Epigenetic suppression of DAB2IP by EZH2 is a major mechanism of DAB2IP inactivation in human prostate cancer and increases metastatic potential (PubMed:20154697, PubMed:22696229).
Belongs to the archaeal Rpo12/eukaryotic RPC10 RNA polymerase subunit family.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and a small RNAs, such as 5S rRNA and tRNAs, respectively.
(Microbial infection) Interacts with HCV non-structural protein 4B/NS4B; this interaction likely initiates the recruitment of replication complexes to lipid droplets.
(Microbial infection) May facilitate human T-lymphotropic virus type 1 (HTLV-1) infection by promoting leukotriene B4 (LTB4) biosynthesis. LTB4 acts as a chemoattractant for HTLV-1-infected CD4-positive T cells and favors cell to cell viral transmission.
(Microbial infection) May play a role in replication and assembly of human hepatitis C virus (HCV) (PubMed:23015700, PubMed:28336330). In response to HCV infection, promotes remodeling of host endoplasmic reticulum membranes to form organelle-like structures called membranous web, where HCV replication occur (PubMed:23015700). Can further mediate translocation of replication complexes to lipid droplets to enable virion assembly (PubMed:23015700, PubMed:28336330).
(Microbial infection) Transcriptionally up-regulated by HTLV-1 Tax.
(Microbial infection) Up-regulated by HCV.
Calcium-independent phospholipase, lysophospholipase and O-acyltransferase involved in phospholipid remodeling with implications in endoplasmic reticulum membrane homeostasis and lipid droplet biogenesis (PubMed:19501189, PubMed:9705332, PubMed:10085124, PubMed:10358058, PubMed:28336330). Preferentially hydrolyzes the ester bond of the fatty acyl group attached at the sn-2 position of phospholipids with choline and ethanolamine head groups, producing lysophospholipids that are used in deacylation-reacylation cycles (PubMed:19501189, PubMed:9705332, PubMed:10085124, PubMed:10358058, PubMed:28336330). Transfers the sn-1 fatty acyl from one lysophospholipid molecule to the sn-2 position of another lysophospholipid to form diacyl, alkylacyl and alkenylacyl glycerophospholipids. Cleaves ester bonds but not alkyl or alkenyl ether bonds at sn-1 position of lysophospholipids (PubMed:19501189, PubMed:15944408). Catalyzes sn-2 fatty acyl transfer from phospholipids to the sn-2 position of 1-O-alkyl or 1-O-alkenyl lysophospholipids with lower efficiency (PubMed:19501189, PubMed:15944408). In response to dietary fatty acids, may play a role in the formation of nascent lipid droplets from the endoplasmic reticulum likely by regulating the phospholipid composition of these organelles (PubMed:28336330).
Not regulated by calcium, coenzyme A or ATP (PubMed:9705332, PubMed:10085124, PubMed:15944408). Lysophospholipase activity is inhibited by palmitoyl-CoA (PubMed:14529291). Lysophospholipase and O-acyltransferase activities are inhibited by methylarachidonoylfluorophosphonate (PubMed:19501189). Lysophospholipase activity is inhibited by phosphatidate or lysophosphatidate (PubMed:19501189). O-acyltransferase activity is up-regulated at low concentration (10-20 uM) of phosphatidate or lysophosphatidate, but inhibited at higher concentrations (PubMed:19501189).
A chromosomal aberration involving MED13L is found in a patient with transposition of the great arteries, dextro-looped and intellectual disability. Translocation t(12;17)(q24.1;q21).
Belongs to the Mediator complex subunit 13 family.
Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. This subunit may specifically regulate transcription of targets of the Wnt signaling pathway and SHH signaling pathway.
Highly expressed in brain (cerebellum), heart (aorta), skeletal muscle, kidney, placenta and peripheral blood leukocytes. Highly expressed in fetal brain.
In contrast to Fong et al. data (PubMed:1310144), isoform 2 is not detected by PCR in any of 24 human tissues examined including the placenta (PubMed:11864635).
This is a receptor for the tachykinin neuropeptide substance P. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: substance P > substance K > neuromedin-K.
Functions as an RNA ligase, in vitro (PubMed:36792600). The ligation reaction entails three nucleotidyl transfer steps (PubMed:36792600). In the first step, the RNA ligase reacts with ATP in the absence of nucleic acid to form a covalent ligase-AMP intermediate and release pyrophosphate (PubMed:36792600). In step 2, the ligase-AMP binds to the nucleic acid and transfers the adenylate to the 5'-PO4 terminus to form an adenylylated intermediate (PubMed:36792600). In step 3, the RNA ligase directs the attack of the 3'-OH on the 5'-phosphoanhydride linkage, resulting in a repaired 3'-5' phosphodiester and release of AMP (PubMed:36792600). Exhibits selectivity for single-stranded RNA substrates and may not have nick-sealing activity on double-stranded DNA-RNA hybrids (PubMed:36792600). May play a role in maintaining RNA integrity under stress conditions, for example in response to reactive oxygen species (ROS) (PubMed:36792600).
Expressed in pancreas, thymus and testis.
Interacts with DLG4. Interacts with neurexin NRXN1; interaction is mediated by heparan sulfate glycan modification on neurexin.
Involved in the development and maintenance of excitatory synapses in the vertebrate nervous system. Regulates surface expression of AMPA receptors and instructs the development of functional glutamate release sites. Acts as a ligand for the presynaptic receptors NRXN1-A and NRXN1-B (By similarity).
Synaptogenic effects are mediated by the extracellular LRR region.
Microtubule-depolymerizing kinesin which plays a role in chromosome congression by reducing the amplitude of preanaphase oscillations and slowing poleward movement during anaphase, thus suppressing chromosome movements. May stabilize the CENPE-BUB1B complex at the kinetochores during early mitosis and maintains CENPE levels at kinetochores during chromosome congression.
Highly expressed in the brain and, more specifically, in oligodendrocytes (at protein level). Expressed in the prostate, and at lower levels in testis, intestine and colon. Overexpressed in most breast cancer cell lines and down-regulated in some colorectal tumors.
Homodimer (PubMed:14567997). Interacts with DYNLL1 and DYNLL2 (By similarity).
Expressed in testis. Expressed in spermatozoa (at protein level). Expressed in olfactory epithelium.
Odorant receptor which may be involved in sperm chemotaxis. Bourgeonal is a strong chemoattractant for sperm in vitro and is shown to be a strong agonist for OR1D2 in vitro. May also function in olfactory reception.
(Microbial infection) Following influenza A virus (IAV) infection, promotes viral mRNA transcription by facilitating the binding of IAV RNA-directed RNA polymerase to capped mRNA.
(Microbial infection) Interacts with influenza A virus nucleoprotein NP and with RNA-directed RNA polymerase subunits PB1 and PB2.
During the cell cycle, expression peaks at the G1/S transition.
Interacts with the transcriptional activator E2F1 (PubMed:20040599). Interacts with serine/threonine-protein phosphatase PP1 subunits PPP1CB and PPP1CC but not with PPP1CA (PubMed:20926688). Interacts with 60S ribosomal proteins RPL5 and RPL27, ribosomal processing protein RRP1/NNP1 and other nucleolar proteins including NOP2/NOL1 and FBL (PubMed:20926688). Also interacts with nucleolar protein NPM1/B23 (PubMed:20926688, PubMed:19710015). Interacts with splicing factor SRSF1 and with LUC7L3/CROP (PubMed:23604122). Interacts with GTPase activator SIPA1 (By similarity). Interacts with CBX5/HP1alpha, H1-10, NCL, PARP1, TRIM28 and YBX3 (PubMed:19710015).
Positively regulates DNA damage-induced apoptosis by acting as a transcriptional coactivator of proapoptotic target genes of the transcriptional activator E2F1 (PubMed:20040599). Likely to play a role in ribosome biogenesis by targeting serine/threonine protein phosphatase PP1 to the nucleolus (PubMed:20926688). Involved in regulation of mRNA splicing (By similarity). Inhibits SIPA1 GTPase activity (By similarity). Involved in regulating expression of extracellular matrix genes (By similarity). Associates with chromatin and may play a role in modulating chromatin structure (PubMed:19710015).
Metabolizes sarcosine and L-pipecolic acid.
Detected in pancreas and epithelium of ovary. Expressed at higher levels in ovarian tumors than in normal tissue.
Localized to zymogen granules, where it functions in trypsinogen activation (By similarity). May indirectly regulate cell motility, cell-cell and cell/extracellular matrix interactions (PubMed:15184879).
Interacts with PFN1. Homodimer and heterodimer with PFN1 (By similarity).
The proline-rich region is required for PFN1 interaction.
Transcriptional repressor; DNA-binding protein that specifically recognizes the core sequence 5'-YAAC[GT]G-3'. Dimerization with PFN1 reduces its DNA-binding capacity (By similarity).
Catalyzes the NADPH-dependent reduction of carbonyl compounds to their corresponding alcohols (PubMed:18493841). Has low NADPH-dependent oxidoreductase activity. Acts on several orthoquinones, acts as well on non-quinone compounds, such as isatin or on the anticancer drug oracin (PubMed:18493841, PubMed:15537833, PubMed:19841672). Best substrates for CBR3 is 1,2- naphthoquinone, hence could play a role in protection against cytotoxicity of exogenous quinones (PubMed:19841672). Exerts activity toward ortho-quinones but not paraquinones. No endogenous substrate for CBR3 except isatin has been identified (PubMed:19841672).
Detected in ovary, pancreas, intestine, colon, kidney, brain, thymus, lung, heart, liver, spleen, leukocyte, prostate and testis.
There are conflicting results on the ability of CBR3 to metabolize menadione. Although menadione was originally reported as a good substrate of CBR3 (PubMed:15537833), results of later studies showed that CBR3 possesses very low or no activity toward menadione (PubMed:19841672, PubMed:18493841).
Disruption of native heterodimer state inhibits primary dihydrolipoamide dehydrogenase activity and induces serine protease activity.
Homodimer (PubMed:15946682). Part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (subunits PDHA (PDHA1 or PDHA2) and PDHB, E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules (by non covalent bonds) (PubMed:14638692, PubMed:20361979). The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2) and DLD (dihydrolipoamide dehydrogenase; E3). It contains multiple copies of the three enzymatic components (E1, E2 and E3). In the nucleus, the 2-oxoglutarate dehydrogenase complex associates with KAT2A (PubMed:29211711). Interacts with PDHX (PubMed:20385101, PubMed:16442803, PubMed:20160912, PubMed:20361979).
Lipoamide dehydrogenase is a component of the glycine cleavage system as well as an E3 component of three alpha-ketoacid dehydrogenase complexes (pyruvate-, alpha-ketoglutarate-, and branched-chain amino acid-dehydrogenase complex) (PubMed:15712224, PubMed:16442803, PubMed:16770810, PubMed:17404228, PubMed:20160912, PubMed:20385101). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion (PubMed:29211711). A fraction of the 2-oxoglutarate dehydrogenase complex also localizes in the nucleus and is required for lysine succinylation of histones: associates with KAT2A on chromatin and provides succinyl-CoA to histone succinyltransferase KAT2A (PubMed:29211711). In monomeric form may have additional moonlighting function as serine protease (PubMed:17404228). Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction (By similarity).
Defects in POGZ may be associated with neuropsychiatric disorders such as autism spectrum disorders (ASD), bipolar affective disorders and early dementia onset. ASD are characterized by impairments in reciprocal social interaction and communication as well as restricted and stereotyped patterns of interest and activities. ASD include forms with moderate to severe cognitive impairment and milder forms with higher cognitive ability (Asperger syndrome).
Interacts with CBX1, CBX3, MAD2L2 and CHAMP1. Interacts with CBX5; POGZ competes with PXVXL motif-containing proteins such as INCENP and TRIM28 for interaction with CBX5. Interacts (via IBM motif) with PSIP1 isoform 1 (via IBD domain); phosphorylation increases its affinity for PSIP1 (PubMed:19244240, PubMed:25082813, PubMed:29997176). Interacts with HDGFL2 (PubMed:26721387).
Plays a role in mitotic cell cycle progression and is involved in kinetochore assembly and mitotic sister chromatid cohesion. Probably through its association with CBX5 plays a role in mitotic chromosome segregation by regulating aurora kinase B/AURKB activation and AURKB and CBX5 dissociation from chromosome arms (PubMed:20562864). Promotes the repair of DNA double-strand breaks through the homologous recombination pathway (PubMed:26721387).
Expression of SRGAP2C in mouse cortical pyramidal neurons leads to the emergence of human-specific traits of synaptic development, characterized by increases in the density of both excitatory and inhibitory synapses received by layer 2/3 pyramidal neurons and neotenic features of excitatory and inhibitory synaptic development (PubMed:22559944, PubMed:27373832, PubMed:34707291). Mice humanized for SRGAP2C expression in all cortical pyramidal neurons show a shift in the fraction of layer 2/3 pyramidal neurons activated by sensory stimulation and an enhanced ability to learn a cortex-dependent sensory-discrimination task (PubMed:34707291).
Homodimer (PubMed:22559944). Interacts (via F-BAR domain) with SRGAP2/SRGAP2A (via F-BAR domain); formation of the heterodimer inhibits SRGAP2/SRGAP2A function (PubMed:22559944, PubMed:28333212, PubMed:34707291).
Human-specific protein that acts as a key modifier of cortical connectivity in the human brain (PubMed:22559944, PubMed:27373832, PubMed:34707291). Acts by inhibiting the functions of ancestral paralog SRGAP2/SRGAP2A, a postsynaptic protein that regulates excitatory and inhibitory synapse maturation and density in cortical pyramidal neurons (PubMed:22559944, PubMed:27373832). SRGAP2C is unstable but is able to heterodimerize with SRGAP2/SRGAP2A, thereby reducing SRGAP2/SRGAP2A levels through proteasome-dependent degradation (PubMed:27373832, PubMed:28333212, PubMed:31822692). Inhibition of SRGAP2/SRGAP2A by SRGAP2C leads to an increase in synaptic density and protracted synaptic maturation of both excitatory and inhibitory synapses (PubMed:27373832, PubMed:34707291). Modifies cortical circuit connectivity by increasing the number of local and long-range cortical inputs received by layer 2/3 pyramidal neurons (PubMed:34707291). Also able to increase the probability of sensory-evoked responses by layer 2/3 pyramidal neurons (PubMed:34707291).
SRGAP2C is truncated at its C-terminus compared to SRGAP2/SRGAP2A (PubMed:28333212). It only contains an extended F-BAR domain that lacks the last C-terminal 49 amino acids of SRGAP2/SRGAP2A, which are replaced with seven unique C-terminal amino acids (PubMed:28333212). In addition, SRGAP2C acquired a series of unique nonsynonymous base pair mutations selectively targeting five arginine residues compared to SRGAP2B (PubMed:28333212). This truncation and these specific arginine mutations reduce solubility of SRGAP2C and increase its ability to heterodimerize with SRGAP2/SRGAP2A to form an insoluble complex (PubMed:28333212).
This is one of the 3 duplications of the ancestral gene SRGAP2/SRGAP2A which has undergone human-specific segmental gene duplications (PubMed:22559944, PubMed:22559943). The appearance of SRGAP2C in the human genome is estimated to 2,4 million years and corresponds to the beginning of neocortex expansion in human evolution (PubMed:22559944, PubMed:22559943, PubMed:34707291). The emergence of SRGAP2C at the birth of the Homo lineage probably contributed to the evolution of specific structural and functional features of cortical circuits in the human cortex (PubMed:34707291).
Ubiquitously expressed with higher expression in cerebellum (PubMed:22559943, PubMed:22559944). Probably expressed in fetal and adult neurons (at protein level) (PubMed:22559943).
Binds with high affinity to the poliovirus receptor (PVR) which causes increased secretion of IL10 and decreased secretion of IL12B and suppresses T-cell activation by promoting the generation of mature immunoregulatory dendritic cells.
Expressed at low levels on peripheral memory and regulatory CD4+ T-cells and NK cells and is up-regulated following activation of these cells (at protein level).
Homodimer in cis; binds with high affinity to PVR, forming a heterotetrameric assembly of two TIGIT and two PVR molecules. Binds with lower affinity to NECTIN2 and NECTIN3.
According to some reports, mediates transmembrane transport of glucose and fructose (PubMed:15033637, PubMed:16186102, PubMed:29548810). However, another group could not confirm transporter activity for glucose or fructose (PubMed:28083649).
Expressed in small intestine and colon (PubMed:15033637). Weakly expressed in testis and prostate (PubMed:15033637).
Expression is increased in presence of fructose.
Glucose and fructose transport are inhibited by the flavonoid apigenin.
Probable sugar transporter (PubMed:28083649). Even if its physiological substrate is subject to discussion, it is able to transport glucose and fructose (PubMed:29548810, PubMed:28083649, PubMed:16186102). Does not transport galactose, 2-deoxy-d-glucose and xylose (PubMed:15033637).
Heterodimerizes with other type I phosphatidylinositol 4-phosphate 5-kinase.
It is unsure if the enzyme has intrinsic kinase activity.
May act as a scaffold to localize and regulate type I PI(4)P 5-kinases to specific compartments within the cell, where they generate PI(4,5)P2 for actin nucleation, signaling and scaffold protein recruitment and conversion to PI(3,4,5)P3.
Homodimer. Interacts (via F-BAR domain) with SNX9 (via SH3 domain). Interacts (via F-BAR domain) with SNX18 and SNX33. Interacts (via SH3 domain 1) with WASL (By similarity). Interacts (via SH3 domain 2) with ITSN1 (PubMed:29887380).
Promotes actin polymerization mediated by SNX9 and WASL.
The F-BAR domain has an atypical, flat shape and binds preferentially to flat membranes (By similarity). Upon heterologous expression, the isolated F-BAR domain is localized at the cell membrane, and causes the formation of cellular protrusions (By similarity).
Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles.
The substance P form is cleaved at Pro-59 by the prolyl endopeptidase FAP (seprase) activity (in vitro) (PubMed:21314817). Substance P is also cleaved and degraded by Angiotensin-converting enzyme (ACE) and neprilysin (MME) (PubMed:6208535).
Homodimer; dityrosine-linked. Homodimerization could be specific of the human protein and enhances the zinc transport efficiency. Interacts with TMEM163 (PubMed:36204728).
Probable proton-coupled zinc ion antiporter mediating zinc import from cytoplasm potentially into the endocytic compartment (PubMed:19521526). Controls zinc deposition in milk (By similarity).
By forskolin and N6,O2'dibutyryl adenosine 3',5'-cyclic monophosphate, but not by 1,9 dideoxyforskolin.
IGF-binding proteins prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cell culture. They alter the interaction of IGFs with their cell surface receptors.
Exerts both phospholipase and triglyceride lipase activities (PubMed:12032167, PubMed:10318835, PubMed:10192396). More active as a phospholipase than a triglyceride lipase (PubMed:12032167). Hydrolyzes triglycerides, both with short-chain fatty acyl groups (tributyrin) and long-chain fatty acyl groups (triolein) with similar levels of activity toward both types of substrates (PubMed:12032167). Hydrolyzes high density lipoproteins (HDL) more efficiently than other lipoproteins (PubMed:12032167, PubMed:10192396).
High level of expression in the liver, placenta, lung, thyroid, kidney, testis and in the corpus luteum of the ovary. Expressed also in coronary artery endothelial cells, umbilical vein endothelial cells and in hepatocytes and osteosarcoma cell lines. Not detected in heart, brain and muscle.
It is termed endothelial lipase due to the fact that it is synthesized in endothelial cells, a characteristic that distinguishes it from other members of the family. However, this protein is also expressed in other cell types.
Endoplasmic reticulum-anchored protein that mediates the formation of contact sites between the endoplasmic (ER) and endosomes, mitochondria or Golgi through interaction with conventionnal- and phosphorylated-FFAT-containing organelle-bound proteins (PubMed:29858488, PubMed:35389430, PubMed:33124732). In addition, forms endoplasmic reticulum (ER)-lipid droplets (LDs) contacts through a direct protein-membrane interaction and participates in LDs homeostasis (PubMed:35389430). The attachment mechanism involves an amphipathic helix that has an affinity for lipid packing defects present at the surface of LDs (PubMed:35389430). Promotes migration of primary monocytes and neutrophils, in response to various chemokines (PubMed:28137892).
Highly expressed in CD14(+) monocytes, and at lower levels in neutrophils. Does not show significant expression in B-cells or T-cells.
Homooligomer (PubMed:33124732). Interacts (via MSP domain) with STARD3NL (via FFAT motif), RMDN3 (via FFAT motif), OSBPL1A (via FFAT motif) and CERT1 (via FFAT motif) (PubMed:29858488, PubMed:33124732). Interacts (via MSP domain) with STARD3 (via phosphorylated FFAT motif); this interaction depends on the critical phosphorylation of STARD3 on 'Ser-209' (PubMed:29858488, PubMed:33124732). Interacts with RB1CC1 (via phosphorylated FFAT motif), MIGA2 (via phosphorylated FFAT motif) and OSBPL1A (via FFAT motif) (PubMed:33124732).
The CRAL-TRIO domain is necessary for the recruitment to lipid droplets (LDs) and mediates the formation of ER-LDs contacts through an amphipathic helix.
The MSP domain is required for binding to the FFAT motif of target proteins.
The transmembrane domain is necessary for binding to LDs.
G-protein coupled opioid receptor that functions as receptor for the endogenous neuropeptide nociceptin. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling via G proteins mediates inhibition of adenylate cyclase activity and calcium channel activity. Arrestins modulate signaling via G proteins and mediate the activation of alternative signaling pathways that lead to the activation of MAP kinases. Plays a role in modulating nociception and the perception of pain. Plays a role in the regulation of locomotor activity by the neuropeptide nociceptin.
Phosphorylation at Ser-363 requires GRK3.
By dihydrotestosterone (DHT) in prostate cancer cells.
Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. Plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway and the steroid hormone signaling pathway. Involved in regulating STAT3 signaling via inhibiting STAT3 DNA-binding and suppressing cell growth. Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation (PubMed:21965678, PubMed:9388184). Sumoylates CCAR2 which promotes its interaction with SIRT1 (PubMed:25406032). Diminishes the sumoylation of ZFHX3 by preventing the colocalization of ZFHX3 with SUMO1 in the nucleus (PubMed:24651376).
Monomer (By similarity). Binds SUMO1 and UBE2I. Interacts with BCL11A, HMGA2, IRF1, MITF and NCOA2. Interacts with STAT5; the interaction occurs on stimulation by PRL. Interacts with GFI1; the interaction relieves the inhibitory effect of PIAS3 on STAT3-mediated transcriptional activity (By similarity). Interacts with AR, PLAG1 and ZFHX3. Interacts with STAT3; the interaction occurs on stimulation by IL6, CNTF or OSM and inhibits the DNA binding activity of STAT3. Interacts with MTA1. Interacts with CCAR2 (via N-terminus). Interacts with TRIM8 (PubMed:20516148). Interacts with PRDM1/Blimp-1 (PubMed:28842558).
The LXXLL motif is a transcriptional coregulator signature.
The PINIT domain of PIAS3 is required for STAT3-PIAS3 interaction and for translocation to the nucleus.
Functions as a transcriptional repressor.
Widely expressed with higher expression in breast, prostate, vulva and pancreas.
Belongs to the poly(ADP-ribose) glycohydrolase family.
Interacts with PCNA (PubMed:21398629). Interacts with NUDT5 (PubMed:27257257).
Poly(ADP-ribose) glycohydrolase that degrades poly(ADP-ribose) by hydrolyzing the ribose-ribose bonds present in poly(ADP-ribose) (PubMed:15450800, PubMed:21892188, PubMed:23102699, PubMed:23474714, PubMed:33186521, PubMed:34321462, PubMed:34019811). PARG acts both as an endo- and exoglycosidase, releasing poly(ADP-ribose) of different length as well as ADP-ribose monomers (PubMed:23102699, PubMed:23481255). It is however unable to cleave the ester bond between the terminal ADP-ribose and ADP-ribosylated residues, leaving proteins that are mono-ADP-ribosylated (PubMed:21892188, PubMed:23474714, PubMed:33186521). Poly(ADP-ribose) is synthesized after DNA damage is only present transiently and is rapidly degraded by PARG (PubMed:23102699, PubMed:34019811). Required to prevent detrimental accumulation of poly(ADP-ribose) upon prolonged replicative stress, while it is not required for recovery from transient replicative stress (PubMed:24906880). Responsible for the prevalence of mono-ADP-ribosylated proteins in cells, thanks to its ability to degrade poly(ADP-ribose) without cleaving the terminal protein-ribose bond (PubMed:33186521). Required for retinoid acid-dependent gene transactivation, probably by removing poly(ADP-ribose) from histone demethylase KDM4D, allowing chromatin derepression at RAR-dependent gene promoters (PubMed:23102699). Involved in the synthesis of ATP in the nucleus, together with PARP1, NMNAT1 and NUDT5 (PubMed:27257257). Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming (PubMed:27257257).
The PIP-box mediates interaction with PCNA and localization to replication foci.
Buffers cytosolic calcium. May stimulate a membrane Ca(2+)-ATPase and a 3',5'-cyclic nucleotide phosphodiesterase.
Ca(2+)-regulated transcription factor that is involved in several processes, including the development and function of the immune, cardiovascular, musculoskeletal, and nervous systems (PubMed:7749981, PubMed:11514544, PubMed:11997522, PubMed:17875713, PubMed:17213202, PubMed:18668201, PubMed:25663301). Involved in T-cell activation, stimulating the transcription of cytokine genes, including that of IL2 and IL4 (PubMed:7749981, PubMed:18668201, PubMed:18347059). Along with NFATC3, involved in embryonic heart development. Involved in mitochondrial energy metabolism required for cardiac morphogenesis and function (By similarity). Transactivates many genes involved in the cardiovascular system, including AGTR2, NPPB/BNP (in synergy with GATA4), NPPA/ANP/ANF and MYH7/beta-MHC (By similarity). Involved in the regulation of adult hippocampal neurogenesis. Involved in BDNF-driven pro-survival signaling in hippocampal adult-born neurons. Involved in the formation of long-term spatial memory and long-term potentiation (By similarity). In cochlear nucleus neurons, may play a role in deafferentation-induced apoptosis during the developmental critical period, when auditory neurons depend on afferent input for survival (By similarity). Binds to and activates the BACE1/Beta-secretase 1 promoter, hence may regulate the proteolytic processing of the amyloid precursor protein (APP) (PubMed:25663301). Plays a role in adipocyte differentiation (PubMed:11997522). May be involved in myoblast differentiation into myotubes (PubMed:17213202). Binds the consensus DNA sequence 5'-GGAAAAT-3' (Probable). In the presence of CREBBP, activates TNF transcription (PubMed:11514544). Binds to PPARG gene promoter and regulates its activity (PubMed:11997522). Binds to PPARG and REG3G gene promoters (By similarity).
Member of the multicomponent NFATC transcription complex that consists of at least two components, a pre-existing cytoplasmic component NFATC2 and an inducible nuclear component NFATC1. Other NFAT proteins, such as NFATC3, or members of the activating protein-1 (AP-1) family and MAF can also bind the complex. NFAT proteins can bind DNA as monomers or dimers (PubMed:7749981). Interacts with CREBBP; this interaction potentiates transcription activation (PubMed:11514544). Interacts with MAPK8/JNK1 and MAPK9/JNK2 (PubMed:17875713). Interacts with GATA4 (via the second Zn finger) (By similarity). Interacts (via N-terminus) with IRAK1 (via C-terminus) (PubMed:18691762). Interacts with RPS6KA3 (PubMed:17213202). Interacts with HOMER1, HOMER2 and HOMER3; this interaction competes with calcineurin/PPP3CA-binding and hence prevents NFATC4 dephosphorylation and activation (PubMed:18218901). Interacts with ESR1 and ESR2; this interaction decreases NFATC4 transcriptional activity (PubMed:18668201). Interacts with MTOR and MAPK7/ERK5 (PubMed:18347059). Interacts with TRIM17; this interaction prevents NFATC3 nuclear localization (By similarity).
Phosphorylated by NFATC-kinases; dephosphorylated by calcineurin/PPP3CA. Phosphorylated on Ser-168 and Ser-170 by MTOR, IRAK1, MAPK7/ERK5 and MAPK14/p38, on Ser-213 and Ser-217 by MAPK8/JNK1 and MAPK9/JNK2, and on Ser-289 and Ser-344 by RPS6KA3 (PubMed:11997522, PubMed:17875713, PubMed:17213202, PubMed:18347059). Phosphorylated by GSK3B (PubMed:18347059). Phosphorylation by GSK3B markedly increases NFATC4 ubiquitination (By similarity). Phosphorylation at Ser-168 and Ser-170 is stimulated by UV irradiation (PubMed:18347059). Phosphorylation determines subcellular location: the hyperphosphorylated protein is cytosolic, while the dephosphorylated form is targeted to the nucleus.
Rel similarity domain (RSD) or Rel homology domain (RHD) allows DNA-binding and cooperative interactions with AP-1 factors.
Transcriptional activity may be repressed by ESR1 and ESR2.
Ubiquitinated, leading to degradation by the proteasome. Ubiquitination may be stimulated by GSK3B-dependent phosphorylation. Polyubiquitin linkage mainly occurs through 'Lys-48'.
Widely expressed, with high levels in placenta, lung, kidney, testis and ovary (PubMed:18675896). Weakly expressed in spleen and thymus (PubMed:18675896). In the hippocampus, expressed in the granular layer of the dentate gyrus, in the pyramidal neurons of CA3 region, and in the hippocampal fissure (PubMed:18675896). Expressed in the heart (at protein level) (PubMed:12370307).
Axonemal dynein assembly factor required for ciliary motility. Involved in neuronal migration during development of the cerebral neocortex. May regulate the stability and proteasomal degradation of the estrogen receptors that play an important role in neuronal differentiation, survival and plasticity.
Disease susceptibility is associated with variants affecting the gene represented in this entry. A chromosomal aberration involving DNAAF4 has been found in a family affected by dyslexia. Translocation t(2;15)(q11;q21).
Expressed in several tissues, including brain, lung, kidney and testis. In brain localizes to a fraction of cortical neurons and white matter glial cells.
Interacts with ZMYND10 (PubMed:29601588). Interacts with ESR1 and ESR2 (PubMed:19423554). Interacts with STUB1 (PubMed:19423554). Interacts with DNAAF2 (PubMed:23872636). Interacts with CCT3, CCT4, CCT5 and CCT8 (By similarity). Interacts with DNAAF6/PIH1D3 (PubMed:28041644).
ATPase activity is enhanced upon binding to G-patch domain-containing proteins (PubMed:32179686). G-patch domain-containing proteins act like a brace that tethers mobile sections of DHX15 together, stabilizing a functional conformation with high RNA affinity, thereby promoting the ATPase activity (PubMed:32179686).
Belongs to the DEAD box helicase family. DEAH subfamily. DDX15/PRP43 sub-subfamily.
Component of the U11/U12 snRNPs that are part of the U12-type spliceosome (PubMed:15146077). Identified in the Intron Large spliceosome complex (IL, also named intron lariat spliceosome), a post-mRNA release spliceosomal complex containing the excised intron, U2, U5 and U6 snRNPs, and splicing factors; the association may be transient (PubMed:19103666, PubMed:30728453). The IL complex exists in two distinct conformations, one with the DHX15 (ILS2) and one without (ILS1) (PubMed:30728453). Interacts with TFIP11 (via G-patch domain); indicative for a recruitment to the IL complex (PubMed:19103666). Interacts with SSB/La (PubMed:12458796). Interacts with GPATCH2 (via G-patch domain); promoting the RNA helicase activity (PubMed:19432882). Interacts with NKRF (via G-patch domain); promoting the RNA helicase activity (PubMed:32179686). Interacts with NLRP6 (PubMed:34161762).
RNA helicase involved in mRNA processing and antiviral innate immunity (PubMed:19432882, PubMed:19103666, PubMed:32179686, PubMed:24990078, PubMed:24782566, PubMed:34161762). Pre-mRNA processing factor involved in disassembly of spliceosomes after the release of mature mRNA (PubMed:19103666). In cooperation with TFIP11 seem to be involved in the transition of the U2, U5 and U6 snRNP-containing IL complex to the snRNP-free IS complex leading to efficient debranching and turnover of excised introns (PubMed:19103666). Plays a key role in antiviral innate immunity by promoting both MAVS-dependent signaling and NLRP6 inflammasome (PubMed:24990078, PubMed:24782566, PubMed:34161762). Acts as an RNA virus sensor: recognizes and binds viral double stranded RNA (dsRNA) and activates the MAVS-dependent signaling to produce interferon-beta and interferon lambda-3 (IFNL3) (PubMed:24990078, PubMed:24782566, PubMed:34161762). Involved in intestinal antiviral innate immunity together with NLRP6: recognizes and binds viral dsRNA and promotes activation of the NLRP6 inflammasome in intestinal epithelial cells to restrict infection by enteric viruses (PubMed:34161762). The NLRP6 inflammasome acts by promoting maturation and secretion of IL18 in the extracellular milieu (PubMed:34161762). Also involved in antibacterial innate immunity by promoting Wnt-induced antimicrobial protein expression in Paneth cells (By similarity).
Acts as an A-kinase anchoring protein by binding to the type II regulatory subunit of protein kinase A and anchoring it to the mitochondrion. Also involved in synchronization of mitochondrial fission (PubMed:12186851). Plays a role in the maturation of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis (PubMed:21255211). Plays an important role in the control of melanin production and melanosome biogenesis (PubMed:23084991). In concert with RAB38, regulates the proper trafficking of melanogenic enzymes TYR, TYRP1 and DCT/TYRP2 to melanosomes in melanocytes (By similarity).
Interacts with ANKRD27 (PubMed:24856514, PubMed:21269460). A decreased interaction with ANKRD27 seen in the presence of SGSM2 (PubMed:21269460).
Regulated by a guanine nucleotide-exchange factor (GEF) and a GTPase-activating protein (GAP) and alternates between an inactive GDP-bound and an active GTP-bound form. The BLOC-3 complex composed of HPS1 and HPS4 acts as its GEF, promotes the exchange of GDP to GTP, converting it from an inactive GDP-bound form into an active GTP-bound form (By similarity). SGSM2 acts as its GAP and inactivates it by stimulating its GTPase activity (PubMed:21269460).
Widely expressed with high levels in heart, liver, kidney, bone marrow, testis, colon and fetal lung.
Interacts (via N-terminus) with NIPBL. Interacts with the multiprotein complex Integrator.
Involved in the regulation of myoblast proliferation during myogenesis.
Isoform 1: Expressed in myoblasts and myotubes. Isoform 2: Expressed in myoblasts and myotubes, with a preference in undifferentiated myoblasts.
Isoform 1: Up-regulated during neuronal differentiation in retinoic acid-treated SH-SY5Y cells (PubMed:25921068). Isoform 2: Down-regulated during myogenesis (PubMed:28344082).
Produced by a back-splicing reaction which joins the 5'-splice site of the first coding exon with the 3'-splice site of the upstream intron resulting in a circular RNA, called circ-ZNF609. The translation starts with the same initiator methionine as that of the linear transcript encoding isoform 1. The stop codon is created upon circularization.
Transcription factor, which activates RAG1, and possibly RAG2, transcription. Through the regulation of RAG1/2 expression, may regulate thymocyte maturation. Along with NIPBL and the multiprotein complex Integrator, promotes cortical neuron migration during brain development by regulating the transcription of crucial genes in this process. Preferentially binds promoters containing paused RNA polymerase II. Up-regulates the expression of SEMA3A, NRP1, PLXND1 and GABBR2 genes, among others.
(Microbial infection) Acts as a receptor for Hantaan virus.
(Microbial infection) In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
(Microbial infection) Integrin ITGA5:ITGB3 acts as a receptor for Human metapneumovirus.
(Microbial infection) Integrin ITGA5:ITGB3 interacts with human metapneumovirus fusion protein.
(Microbial infection) Integrin ITGAV:ITGB3 acts aP05556s a receptor for Human parechovirus 1.
(Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Coxsackievirus A9.
(Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Cytomegalovirus/HHV-5.
(Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Herpes virus 8/HHV-8.
(Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for West nile virus.
(Microbial infection) Integrin ITGAV:ITGB3 interacts with coxsackievirus A9 capsid proteins.
(Microbial infection) Integrin ITGAV:ITGB3 interacts with cytomegalovirus/HHV-5 gH:gL proteins.
(Microbial infection) Integrin ITGAV:ITGB3 interacts with herpes virus 8/HHV-8 glycoprotein B.
(Microbial infection) Integrin ITGAV:ITGB3 interacts with human parechovirus 1 capsid proteins.
(Microbial infection) Integrin ITGAV:ITGB3 interacts with west nile virus envelope protein E.
(Microbial infection) Interacts with HIV-1 Tat (PubMed:10397733). ITGAV:ITGB3 interacts with AGRA2 (PubMed:16982628).
(Microbial infection) Interacts with Hantaan virus glycoprotein G.
Belongs to the integrin beta chain family.
Heterodimer of an alpha and a beta subunit. Beta-3 (ITGB3) associates with either alpha-IIb (ITGA2B) or alpha-V (ITGAV). Isoform Beta-3C interacts with FLNB. Interacts with COMP. Interacts with PDIA6 following platelet stimulation. Interacts with SYK; upon activation by ITGB3 promotes platelet adhesion. Interacts with MYO10. Interacts with DAB2. Interacts with FERMT2. Interacts with EMP2; regulates the levels of the heterodimer ITGA5:ITGB3 integrin expression on the plasma membrane (PubMed:16216233). Integrin ITGAV:ITGB3 interacts with FBLN5 (via N-terminus) (By similarity). ITGAV:ITGB3 interacts with CCN3 (PubMed:12695522). ITGAV:ITGB3 is found in a ternary complex with CX3CR1 and CX3CL1 (PubMed:23125415). ITGAV:ITGB3 is found in a ternary complex with NRG1 and ERBB3 (PubMed:20682778). ITGAV:ITGB3 is found in a ternary complex with FGF1 and FGFR1 (PubMed:18441324). ITGAV:ITGB3 interacts with FGF2; it is likely that FGF2 can simultaneously bind ITGAV:ITGB3 and FGF receptors (PubMed:28302677). ITGAV:ITGB3 binds to IL1B (PubMed:29030430). ITGAV:ITGB3 is found in a ternary complex with IGF1 and IGF1R (PubMed:19578119). ITGAV:ITGB3 interacts with IGF2 (PubMed:28873464). ITGAV:ITGB3 interacts with FBN1 (PubMed:12807887). ITGAV:ITGB3 interacts with CD9, CD81 and CD151 (via second extracellular domain) (PubMed:27993971). Interacts (via the allosteric site (site 2)) with CXCL12 in a CXCR4-independent manner (PubMed:29301984). Interacts with MXRA8/DICAM; the interaction inhibits ITGAV:ITGB3 heterodimer formation (PubMed:22492581). ITGAV:ITGB3 interacts with PTN (PubMed:19141530). Forms a complex with PTPRZ1 and PTN that stimulates endothelial cell migration through ITGB3 Tyr-773 phosphorylation (PubMed:19141530). ITGAV:ITGB3 interacts with SLC6A4. Interacts with SLC6A4 (via C-terminus); this interaction regulates SLC6A4 trafficking (By similarity). ITGA2B:ITGB3 interacts with PPIA/CYPA; the interaction is ROS and PPIase activity-dependent and is increased in the presence of thrombin (By similarity). Interacts with tensin TNS3; TNS3 also interacts with PEAK1, thus acting as an adapter molecule to bridge the association of PEAK1 with ITGB3 (PubMed:35687021).
Integrin alpha-V/beta-3 (ITGAV:ITGB3) is a receptor for cytotactin, fibronectin, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin, vitronectin and von Willebrand factor. Integrin alpha-IIb/beta-3 (ITGA2B:ITGB3) is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. Integrins alpha-IIb/beta-3 and alpha-V/beta-3 recognize the sequence R-G-D in a wide array of ligands. Integrin alpha-IIb/beta-3 recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha-IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial surface. Fibrinogen binding enhances SELP expression in activated platelets (By similarity). ITGAV:ITGB3 binds to fractalkine (CX3CL1) and acts as its coreceptor in CX3CR1-dependent fractalkine signaling (PubMed:23125415, PubMed:24789099). ITGAV:ITGB3 binds to NRG1 (via EGF domain) and this binding is essential for NRG1-ERBB signaling (PubMed:20682778). ITGAV:ITGB3 binds to FGF1 and this binding is essential for FGF1 signaling (PubMed:18441324). ITGAV:ITGB3 binds to FGF2 and this binding is essential for FGF2 signaling (PubMed:28302677). ITGAV:ITGB3 binds to IGF1 and this binding is essential for IGF1 signaling (PubMed:19578119). ITGAV:ITGB3 binds to IGF2 and this binding is essential for IGF2 signaling (PubMed:28873464). ITGAV:ITGB3 binds to IL1B and this binding is essential for IL1B signaling (PubMed:29030430). ITGAV:ITGB3 binds to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1 (PubMed:18635536, PubMed:25398877). ITGAV:ITGB3 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (PubMed:12807887). In brain, plays a role in synaptic transmission and plasticity. Involved in the regulation of the serotonin neurotransmission, is required to localize to specific compartments within the synapse the serotonin receptor SLC6A4 and for an appropriate reuptake of serotonin. Controls excitatory synaptic strength by regulating GRIA2-containing AMPAR endocytosis, which affects AMPAR abundance and composition (By similarity). ITGAV:ITGB3 act as a receptor for CD40LG (PubMed:31331973).
Isoform beta-3A and isoform beta-3C are widely expressed. Isoform beta-3A is specifically expressed in osteoblast cells; isoform beta-3C is specifically expressed in prostate and testis.
Phosphorylated on tyrosine residues in response to thrombin-induced platelet aggregation. Probably involved in outside-in signaling. A peptide (AA 740-762) is capable of binding GRB2 only when both Tyr-773 and Tyr-785 are phosphorylated. Phosphorylation of Thr-779 inhibits SHC binding.
Position 169 is associated with platelet-specific alloantigen HPA-4 (PEN or YUK). HPA-4A/PEN(A)/YUK(A) has Arg-169 and HPA-4B/PEN(B)/YUK(B) has Gln-169. HPA-4B is involved in neonatal alloimmune thrombocytopenia (NAIT or NATP).
Position 433 is associated with platelet-specific alloantigen MO. MO(-) has Pro-433 and MO(+) has Ala-433. MO(+) is involved in NAIT.
Position 515 is associated with platelet-specific alloantigen CA/TU. CA(-)/TU(-) has Arg-515 and CA(+)/TU(+) has Gln-515. CA(+) is involved in NAIT.
Position 59 is associated with platelet-specific alloantigen HPA-1 (ZW or PL(A)). HPA-1A/ZW(A)/PL(A1) has Leu-59 and HPA-1B/ZW(B)/PL(A2) has Pro-59. HPA-1A is involved in fetal-maternal alloimmune thromobocytopenia (FMAIT) as well as in neonatal alloimmune thrombocytopenia (NAIT).
Position 662 is associated with platelet-specific alloantigen SR(A). SR(A)(-) has Arg-662 and SR(A)(+) has Cys-662.
The VWFA domain (or beta I domain) contains three cation-binding sites: the ligand-associated metal ion-binding site (LIMBS or SyMBS), the metal ion-dependent adhesion site (MIDAS), and the adjacent MIDAS site (ADMIDAS). This domain is also part of the ligand-binding site.
Expressed in testis and ovary and in a wide variety of cancers. Detected in uterine myometrium. Expressed from 18 weeks until birth in human fetal testis. In the adult testis, is strongly expressed in spermatogonia and in primary spermatocytes, but not in post-meiotic cells or in testicular somatic cells (at protein level).
Converts gamma-trimethylaminobutyraldehyde into gamma-butyrobetaine with high efficiency (in vitro). Can catalyze the irreversible oxidation of a broad range of aldehydes to the corresponding acids in an NAD-dependent reaction, but with low efficiency.
Detected in brain (at protein level) (PubMed:8645224). High expression in adult liver, skeletal muscle, and kidney. Low levels in heart, pancreas, lung and brain (PubMed:8786138). Expressed in all regions of the brain. Expression levels are variable in the different brain areas, with the highest levels in the spinal cord and the lowest in the occipital pole.
Produced by alternative initiation. Contains a predicted signal peptide at positions 1-24.
Strongly expressed in human embryonic brain (gestational age 12 weeks).
Component of the cytoplasmic core iron-sulfur cluster (ISC) complex composed at least of NFS1, LYRM4, and ISCU; this complex interacts with FXN (PubMed:29309586). Monomer; each monomer binds to the C-terminal regions of NFS1 (cytoplasmic and homodimer form) (PubMed:29097656, PubMed:11060020). Interacts with NFS1 (cytoplasmic and homodimer form); this interaction promotes de novo iron-sulfur cluster formation (PubMed:16527810, PubMed:29309586). Interacts with HSCB (cytoplasmic form); this interaction stabilzes the (Fe-S) clusters on ISCU (PubMed:29309586).
Cysteine persulfide is reduced by thiol-containing molecules such as glutathione and L-cysteine.
Cytoplasmic scaffold protein, of the cytoplasmic core iron-sulfur cluster (ISC) assembly complex that provides the structural architecture on which the Fe-S clusters are assembled and may be involved in the cytoplasmic iron-sulfur protein biogenesis.
Detected in heart, liver, skeletal muscle, brain, pancreas, kidney, lung and placenta.
Homodimer; Tyr-35-mediated dimerization of two iron- and sulfide-containing ISCU subunit bind to the cysteine desulfurase complex (PubMed:31101807, PubMed:34824239). Component of the mitochondrial core iron-sulfur cluster (ISC) complex composed of NFS1, LYRM4, NDUFAB1, ISCU, FXN, and FDX2; this complex is an heterohexamer containing two copies of each monomer (PubMed:21298097, PubMed:31101807) (Probable). Interacts (D-state) with NFS1 (homodimer form); each monomer interacts with the C-terminal regions of each NFS1 monomer (PubMed:23940031, PubMed:11060020). Interacts (monomer form) with FXN (via ferrous form); the interaction is possible when both are bound to the dimeric form of the cysteine desulfurase complex (NFS1:LYRM4) and enhances FXN interaction to the dimeric form of the cysteine desulfurase complex (NFS1:LYRM4) (PubMed:31101807, PubMed:29576242). Interacts with GLRX5 (PubMed:26100117). Interacts (D-state) with HSPA9 (PubMed:23940031, PubMed:26702583). Interacts (S-state) with HSCB; this interaction stimulates the ATPase activity of HSPA9 (PubMed:23940031, PubMed:20668094).
Mitochondrial scaffold protein, of the core iron-sulfur cluster (ISC) assembly complex, that provides the structural architecture on which the [2Fe-2S] clusters are assembled (PubMed:34824239). The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis. This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the scaffold protein ISCU in a FXN-dependent manner. Then this complex is stabilized by FDX2 which provides reducing equivalents to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and GLRX5 (PubMed:30031876, PubMed:34824239, PubMed:24971490, PubMed:29576242) (Probable). Exists as two slow interchanging conformational states, a structured (S) and disordered (D) form (PubMed:23940031). May modulate NFS1 desulfurase activity in a zinc-dependent manner (PubMed:30031876). Modulates the interaction between FXN and the cysteine desulfurase complex (PubMed:29576242).
Mitochondrial scaffold protein, of the core iron-sulfur cluster (ISC) assembly complex, that provides the structural architecture on which the [2Fe-2S] clusters are assembled. The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis. This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the scaffold protein ISCU in a FXN-dependent manner. Then this complex is stabilized by FDX2 which provides reducing equivalents to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and GLRX5. Exists as two slow interchanging conformational states, a structured (S) and disordered (D) form. May modulate NFS1 desulfurase activity in a zinc-dependent manner. Modulates the interaction between FXN and the cysteine desulfurase complex.
Phosphorylation at Ser-14 is required for ISCU protein stabilization in the cytosol, whereas dephosphorylation of Ser-14, due to the inhibition of mTORC1 (mammalian target of rapamycin complex 1) complex, leads to degradation of the precursor form and ultimately to a decrease in the mitochondrial mature form.
Previous publications report that ISCU could provide the architecture on which both [2Fe-2S] and [4Fe-4S] clusters could be assembled (PubMed:23940031, PubMed:16527810, PubMed:16517407). Recent reports confirm that only [2Fe-2S] clusters are formed by the core ISC assembly complex (PubMed:34824239).
Probable E3 ubiquitin-protein ligase which plays an important role in blastocyst development.
Kinesin is a microtubule-associated force-producing protein that may play a role in organelle transport. The light chain may function in coupling of cargo to the heavy chain or in the modulation of its ATPase activity (By similarity).
Binds DNA as a monomer (PubMed:12654265). Interacts with NR0B1; represses ESRRB activity at the GATA6 promoter. Interacts with NANOG; reciprocally modulates their transcriptional activities and activates POU5F1 expression. Interacts with NCOA3; mediates the interaction between ESRRB and RNA polymerase II complexes and allows NCOA3 corecruitment to ESRRB, KLF4, NANOG, and SOX2 enhancer regions to trigger ESRRB-dependent gene activation involved in self-renewal and pluripotency. Interacts with KDM1A; co-occupes the core set of ESRRB targets including ELF5 and EOMES. Interacts with the multiprotein complex Integrator, at least composed of INTS1, INTS2, INTS3, INTS4, INTS5, INTS6, INTS7, INTS8, INTS9/RC74, INTS10, INTS11/CPSF3L and INTS12; ESRRB is probably not a core component of the integrator complex and associates to integrator via its interaction with INTS1 and INTS9; attracts the transcriptional machinery. Interacts with JARID2. Interacts with POU5F1; recruits ESRRB near the POU5F1-SOX2 element in the NANOG proximal promoter leading to activation of NANOG expression; the interaction is DNA independent (By similarity). Interacts with NFE2L2; represses NFE2L2 transcriptional activity (PubMed:17920186). Isoform 1 interacts with ESR1 (PubMed:19755138).
Transcription factor that binds a canonical ESRRB recognition (ERRE) sequence 5'TCAAGGTCA-3' localized on promoter and enhancer of targets genes regulating their expression or their transcription activity (PubMed:17920186, PubMed:19755138). Plays a role, in a LIF-independent manner, in maintainance of self-renewal and pluripotency of embryonic and trophoblast stem cells through different signaling pathways including FGF signaling pathway and Wnt signaling pathways. Upon FGF signaling pathway activation, interacts with KDM1A by directly binding to enhancer site of ELF5 and EOMES and activating their transcription leading to self-renewal of trophoblast stem cells. Also regulates expression of multiple rod-specific genes and is required for survival of this cell type (By similarity). Plays a role as transcription factor activator of GATA6, NR0B1, POU5F1 and PERM1 (PubMed:23836911). Plays a role as transcription factor repressor of NFE2L2 transcriptional activity and ESR1 transcriptional activity (PubMed:17920186, PubMed:19755138). During mitosis remains bound to a subset of interphase target genes, including pluripotency regulators, through the canonical ESRRB recognition (ERRE) sequence, leading to their transcriptional activation in early G1 phase. Can coassemble on structured DNA elements with other transcription factors like SOX2, POU5F1, KDM1A and NCOA3 to trigger ESRRB-dependent gene activation. This mechanism, in the case of SOX2 corecruitment prevents the embryonic stem cells (ESCs) to epiblast stem cells (EpiSC) transition through positive regulation of NR0B1 that inhibits the EpiSC transcriptional program. Also plays a role inner ear development by controlling expression of ion channels and transporters and in early placentation (By similarity).
Transcription factor that binds a canonical ESRRB recognition (ERRE) sequence 5'TCAAGGTCA-3' localized on promoter and enhancer of targets genes regulating their expression or their transcription activity. Positively regulates ESR1 transcriptional activity upon E2 stimulation.
Belongs to the KCNMB (TC 8.A.14.1) family.
Belongs to the KCNMB (TC 8.A.14.1) family. KCNMB2 subfamily.
Expressed in kidney, heart and brain. Highly expressed in ovary. Expressed at low level in other tissues.
Interacts with KCNMA1 tetramer. There are probably 4 molecules of KCMNB per KCNMA1 tetramer.
Interacts with KCNMA1 tetramer. There are probably 4 molecules of KCMNB2 per KCNMA1 tetramer.
Regulatory subunit of the calcium activated potassium KCNMA1 (maxiK) channel. Modulates the calcium sensitivity and gating kinetics of KCNMA1, thereby contributing to KCNMA1 channel diversity.
Regulatory subunit of the calcium activated potassium KCNMA1 (maxiK) channel. Modulates the calcium sensitivity and gating kinetics of KCNMA1, thereby contributing to KCNMA1 channel diversity. Acts as a negative regulator that confers rapid and complete inactivation of KCNMA1 channel complex. May participate in KCNMA1 inactivation in chromaffin cells of the adrenal gland or in hippocampal CA1 neurons.
The ball and chain domain mediates the inactivation of KCNMA1. It occludes the conduction pathway of KCNMA1 channels, and comprises the pore-blocking ball domain (residues 1-17) and the chain domain (residues 20-45) linking it to the transmembrane segment. The ball domain is made up of a flexible N-terminus anchored at a well ordered loop-helix motif. The chain domain consists of a 4-turn helix with an unfolded linker at its C-terminus.
Cys-245 mediates the formation of the interchain disulfide bond for formation of the homodimer. Cys-142, Cys-157 and Cys-169 are involved in intramolecular disulfide bonds formation (By similarity).
Defects in GNPTG have been suggested to play a role in susceptibility to persistent stuttering. Stuttering is a common speech disorder characterized by repetitions, prolongations, and interruptions in the flow of speech.
Homodimer; disulfide-linked. Hexamer of two alpha (GNPTAB), two beta (GNPTAB) and two gamma (GNPTG) subunits; disulfide-linked. The alpha and/or the beta subunits of the enzyme constitute the catalytic subunits.
Non-catalytic subunit of the N-acetylglucosamine-1-phosphotransferase complex, an enzyme that catalyzes the formation of mannose 6-phosphate (M6P) markers on high mannose type oligosaccharides in the Golgi apparatus. Binds and presents the high mannose glycans of the acceptor to the catalytic alpha and beta subunits (GNPTAB). Enhances the rate of N-acetylglucosamine-1-phosphate transfer to the oligosaccharides of acid hydrolase acceptors.
Adaptor protein complex 4 (AP-4) is a heterotetramer composed of two large adaptins (epsilon-type subunit AP4E1 and beta-type subunit AP4B1), a medium adaptin (mu-type subunit AP4M1) and a small adaptin (sigma-type AP4S1) (PubMed:10436028, PubMed:10066790). Interacts with TEPSIN (PubMed:26542808). Interacts with GRIA2; probably indirect it mediates the somatodendritic localization of GRIA2 in neurons (By similarity).
Component of the adaptor protein complex 4 (AP-4). Adaptor protein complexes are vesicle coat components involved both in vesicle formation and cargo selection. They control the vesicular transport of proteins in different trafficking pathways (PubMed:10066790, PubMed:10436028). AP-4 forms a non clathrin-associated coat on vesicles departing the trans-Golgi network (TGN) and may be involved in the targeting of proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal system. It is also involved in protein sorting to the basolateral membrane in epithelial cells and the proper asymmetric localization of somatodendritic proteins in neurons. AP-4 is involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos, but may also recognize other types of sorting signal (Probable).
Interacts (via coiled-coil domain) with AP1G1 (via GAE domain). Interacts with KIF5B. Associates with the Arp2/3 complex.
Necessary for adaptor protein complex 1 (AP-1)-dependent transport between the trans-Golgi network and endosomes. Regulates the membrane association of AP1G1/gamma1-adaptin, one of the subunits of the AP-1 adaptor complex. The direct interaction with AP1G1/gamma1-adaptin attenuates the release of the AP-1 complex from membranes. Regulates endosomal membrane traffic via association with AP-1 and KIF5B thus linking kinesin-based plus-end-directed microtubular transport to AP-1-dependent membrane traffic. May act as effector of AP-1 in calcium-induced endo-lysosome secretion. Inhibits Arp2/3 complex function; negatively regulates cell spreading, size and motility via intracellular sequestration of the Arp2/3 complex.
Chorionic gonadotropin stimulates expression in the ovaries.
Expression in the uterus changes during the menstrual cycle (PubMed:15657371, PubMed:16339169). In endometrium, expression is higher in the menstrual, proliferative, and early secretory phases than in the mid-late secretory phase (PubMed:15657371, PubMed:16339169). In the ovaries, expression is ovulation-dependent, levels are negligible in preovulatory follicles, and increase in postovulatory follicles and in the corpus luteum (PubMed:27169804).
Mediates the transport of prostaglandins (PGs, mainly PGE2, PGE1, PGE3, PGF2alpha, PGD2, PGH2) and thromboxanes (thromboxane B2) across the cell membrane (PubMed:8787677, PubMed:11997326, PubMed:26692285). PGs and thromboxanes play fundamental roles in diverse functions such as intraocular pressure, gastric acid secretion, renal salt and water transport, vascular tone, and fever (PubMed:15044627). Plays a role in the clearance of PGs from the circulation through cellular uptake, which allows cytoplasmic oxidation and PG signal termination (PubMed:8787677). PG uptake is dependent upon membrane potential and involves exchange of a monovalent anionic substrate (PGs exist physiologically as an anionic monovalent form) with a stoichiometry of 1:1 for divalent anions or of 1:2 for monovalent anions (PubMed:29204966). Uses lactate, generated by glycolysis, as a counter-substrate to mediate PGE2 influx and efflux (PubMed:11997326). Under nonglycolytic conditions, metabolites other than lactate might serve as counter-substrates (PubMed:11997326). Although the mechanism is not clear, this transporter can function in bidirectional mode (PubMed:29204966). When apically expressed in epithelial cells, it facilitates transcellular transport (also called vectorial release), extracting PG from the apical medium and facilitating transport across the cell toward the basolateral side, whereupon the PG exits the cell by simple diffusion (By similarity). In the renal collecting duct, regulates renal Na+ balance by removing PGE2 from apical medium (PGE2 EP4 receptor is likely localized to the luminal/apical membrane and stimulates Na+ resorption) and transporting it toward the basolateral membrane (where PGE2 EP1 and EP3 receptors inhibit Na+ resorption) (By similarity). Plays a role in endometrium during decidualization, increasing uptake of PGs by decidual cells (PubMed:16339169). Involved in critical events for ovulation (PubMed:27169804). Regulates extracellular PGE2 concentration for follicular development in the ovaries (By similarity). Expressed intracellularly, may contribute to vesicular uptake of newly synthesized intracellular PGs, thereby facilitating exocytotic secretion of PGs without being metabolized (By similarity). Essential core component of the major type of large-conductance anion channel, Maxi-Cl, which plays essential roles in inorganic anion transport, cell volume regulation and release of ATP and glutamate not only in physiological processes but also in pathological processes (By similarity). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable).
Ubiquitous (PubMed:8787677, PubMed:22331663). Significant expression observed in lung, kidney, spleen, and heart (PubMed:22331663). Expressed in the endometrium (at both mRNA and protein levels) (PubMed:15657371, PubMed:16339169). Expressed in the ovaries (at mRNA and protein levels) (PubMed:27169804). In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed within the tubules (PubMed:35307651).
Expression levels correlate with those of HER-2/neu in breast cancer cells.
Catalyzes the 2-oxoglutarate and iron-dependent C4-lysyl hydroxylation of ETF1 at 'Lys-63' thereby promoting the translational termination efficiency of ETF1.
Interacts with ETF1 (PubMed:24486019). Interacts with the ETF1-GSPT1 complex (PubMed:24486019).
It is uncertain whether Met-1 or Met-47 is the initiator.
Homodimer. Interacts with several proteins involved in the DNA damage response, although not all these interactions may be direct. Interacts with H2AX, which requires phosphorylation of H2AX on 'Ser-139'. Interacts with the MRN complex, composed of MRE11, RAD50, and NBN. Interacts with CHEK2, which requires ATM-mediated phosphorylation of 'Thr-68' within the FHA domain of CHEK2. Interacts constitutively with the BRCA1-BARD1 complex, SMC1A and TP53BP1. Interacts with ATM and FANCD2, and these interactions are reduced upon DNA damage. Also interacts with the PRKDC complex, composed of XRCC6/KU70, XRCC5/KU80 and PRKDC/XRCC7. This interaction may be required for PRKDC autophosphorylation, which is essential for DNA double strand break (DSB) repair. When phosphorylated by ATM, interacts with RNF8 (via FHA domain). Interacts with CEP164. When phosphorylated, interacts with APTX (via FHA-like domain).
Phosphorylated upon exposure to ionizing radiation (IR), ultraviolet radiation (UV), and hydroxyurea (HU). Phosphorylation in response to IR requires ATM, NBN, and possibly CHEK2. Also phosphorylated during the G2/M phase of the cell cycle and during activation of the mitotic spindle checkpoint. Phosphorylation at Thr-4 by ATM stabilizes and enhances homodimerization via the FHA domain.
Required for checkpoint mediated cell cycle arrest in response to DNA damage within both the S phase and G2/M phases of the cell cycle. May serve as a scaffold for the recruitment of DNA repair and signal transduction proteins to discrete foci of DNA damage marked by 'Ser-139' phosphorylation of histone H2AX. Also required for downstream events subsequent to the recruitment of these proteins. These include phosphorylation and activation of the ATM, CHEK1 and CHEK2 kinases, and stabilization of TP53 and apoptosis. ATM and CHEK2 may also be activated independently by a parallel pathway mediated by TP53BP1.
Sumoylation at Lys-1840 by PIAS4 following DNA damage promotes ubiquitin-mediated degradation.
Tandemly repeated BRCT domains are characteristic of proteins involved in DNA damage signaling. In MDC1, these repeats are required for localization to chromatin which flanks sites of DNA damage marked by 'Ser-139' phosphorylation of H2AX.
Ubiquitinated by RNF4, leading to proteasomal degradation; undergoes 'Lys-48'-linked polyubiquitination.
Binds GSK-3 and prevents GSK-3-dependent phosphorylation.
Positively regulates the Wnt signaling pathway by stabilizing beta-catenin through the association with GSK-3.
May have a special functional role during embryogenesis and in adult hematopoietic cells.
Preferentially expressed in adult hematopoietic tissues. High levels in lymphoid and myeloid tissues. Highly expressed in peripheral blood leukocytes, thymus, spleen and lung, followed by placenta, liver and kidney.
Essential for male fertility and sperm mitochondrial sheath formation (By similarity). Required for proper mitochondrial elongation and coiling along the flagellum during the formation of the mitochondrial sheath (By similarity). Facilitates the growth and aggressiveness of neuroblastoma cells (PubMed:30026490). Increases the EZH2 activity and H3K27me3 levels in a RBBP4-dependent manner, and facilitates the enrichment of polycomb repressive complex 2 and H3K27me3 on gene promoters, resulting in transcriptional repression of tumor suppressors affecting the proliferation, invasion, and metastasis of tumor cells (PubMed:30026490).
Interacts with TBC1D15, TBC1D21, GK2 and IMMT (By similarity). Interacts with VDAC2 and VDAC3 in a TBC1D21-dependent manner (By similarity). Interacts (via ARM domains) with RBBP4 (PubMed:30026490).
Testis-specific (PubMed:33536340). Expressed at higher levels in neuroblastoma tissues and cell lines, than those of normal dorsal ganglia (at protein level) (PubMed:30026490). Expressed in breast cancer, colon cancer, hepatocellular carcinoma, lung cancer, pancreas cancer, prostate cancer, renal cancer and gastric cancer, but not in their normal counterparts (PubMed:30026490).
Heterodimer (PubMed:29083303). Interacts with TCF7L2/TCF4, EP300/P300, HDAC1, HDAC5 and HDAC6 (PubMed:17872950, PubMed:16434966). Interacts with TRIB3 which blocks its association with EP300/P300 (PubMed:15775988, PubMed:17872950). Interacts with FOXO3, CEBPB and ATF4 (PubMed:18940792, PubMed:20829347, PubMed:22761832).
Interacts with isoform AltDDIT3 of DDIT3.
Multifunctional transcription factor in ER stress response. Plays an essential role in the response to a wide variety of cell stresses and induces cell cycle arrest and apoptosis in response to ER stress. Plays a dual role both as an inhibitor of CCAAT/enhancer-binding protein (C/EBP) function and as an activator of other genes. Acts as a dominant-negative regulator of C/EBP-induced transcription: dimerizes with members of the C/EBP family, impairs their association with C/EBP binding sites in the promoter regions, and inhibits the expression of C/EBP regulated genes. Positively regulates the transcription of TRIB3, IL6, IL8, IL23, TNFRSF10B/DR5, PPP1R15A/GADD34, BBC3/PUMA, BCL2L11/BIM and ERO1L. Negatively regulates; expression of BCL2 and MYOD1, ATF4-dependent transcriptional activation of asparagine synthetase (ASNS), CEBPA-dependent transcriptional activation of hepcidin (HAMP) and CEBPB-mediated expression of peroxisome proliferator-activated receptor gamma (PPARG). Inhibits the canonical Wnt signaling pathway by binding to TCF7L2/TCF4, impairing its DNA-binding properties and repressing its transcriptional activity. Plays a regulatory role in the inflammatory response through the induction of caspase-11 (CASP4/CASP11) which induces the activation of caspase-1 (CASP1) and both these caspases increase the activation of pro-IL1B to mature IL1B which is involved in the inflammatory response.
Multifunctional transcription factor in endoplasmic reticulum (ER) stress response (PubMed:15322075, PubMed:15775988, PubMed:19672300). Plays an essential role in the response to a wide variety of cell stresses and induces cell cycle arrest and apoptosis in response to ER stress (PubMed:15322075, PubMed:15775988). Plays a dual role both as an inhibitor of CCAAT/enhancer-binding protein (C/EBP) function and as an activator of other genes (By similarity). Acts as a dominant-negative regulator of C/EBP-induced transcription: dimerizes with members of the C/EBP family, impairs their association with C/EBP binding sites in the promoter regions, and inhibits the expression of C/EBP regulated genes (By similarity). Positively regulates the transcription of TRIB3, IL6, IL8, IL23, TNFRSF10B/DR5, PPP1R15A/GADD34, BBC3/PUMA, BCL2L11/BIM and ERO1L (PubMed:15775988, PubMed:17709599, PubMed:22761832, PubMed:20876114). Negatively regulates; expression of BCL2 and MYOD1, ATF4-dependent transcriptional activation of asparagine synthetase (ASNS), CEBPA-dependent transcriptional activation of hepcidin (HAMP) and CEBPB-mediated expression of peroxisome proliferator-activated receptor gamma (PPARG) (PubMed:18940792, PubMed:19672300, PubMed:20829347). Together with ATF4, mediates ER-mediated cell death by promoting expression of genes involved in cellular amino acid metabolic processes, mRNA translation and the unfolded protein response (UPR) in response to ER stress (By similarity). Inhibits the canonical Wnt signaling pathway by binding to TCF7L2/TCF4, impairing its DNA-binding properties and repressing its transcriptional activity (PubMed:16434966). Plays a regulatory role in the inflammatory response through the induction of caspase-11 (CASP4/CASP11) which induces the activation of caspase-1 (CASP1) and both these caspases increase the activation of pro-IL1B to mature IL1B which is involved in the inflammatory response (By similarity). Acts as a major regulator of postnatal neovascularization through regulation of endothelial nitric oxide synthase (NOS3)-related signaling (By similarity).
Phosphorylation at serine residues by MAPK14 enhances its transcriptional activation activity while phosphorylation at serine residues by CK2 inhibits its transcriptional activation activity.
The N-terminal region is necessary for its proteasomal degradation, transcriptional activity and interaction with EP300/P300.
The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving DDIT3 has been found in a patient with malignant myxoid liposarcoma. Translocation t(12;16)(q13;p11) with FUS (PubMed:7503811).
Up-regulated by oxidative stress, amino-acid deprivation, hypoxia and endoplasmic reticulum stress (PubMed:33384352). During ER stress, induced by a EIF2AK3/ATF4 pathway and/or ERN1/ATF6 pathway. Expression is suppressed by TLR-TRIF signaling pathway during prolonged ER stress.
May be a novel gestational hormone required to compensate for absence of other members of the GH/CS cluster during gestation.
Component of the nexin-dynein regulatory complex (N-DRC) a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes (By similarity). Involved in the regulation of flagellar motility (By similarity). Essential for male fertility, sperm head morphogenesis and sperm flagellum formation (By similarity).
Component of the nexin-dynein regulatory complex (N-DRC). Interacts with TCTE1/DRC5 (By similarity). Interacts with DRC3 and GAS8/DRC4 (By similarity).
Monosumoylated at Lys-601 by CBX4 and UHRF2. Sumoylation may potentiate ZNF131 inhibition of estrogen signaling. Sumoylation does not interfere with ubiquitination.
Plays a role during development and organogenesis as well as in the function of the adult central nervous system (By similarity). May be involved in transcriptional regulation as a repressor of ESR1/ER-alpha signaling.
Predominant expression is found in different brain areas such as the occipital and temporal lobe, the nucleus caudatus, hippocampus, and the cerebellum as well as in testis and thymus.
Interacts with POLR1F, EIF3L, TAF1B and TAF1C.
Phosphorylation is required for participation in rDNA transcription (By similarity). Phosphorylated at Thr-200 by MAPK9/JNK2, which abrogates initiation complex formation.
Required for efficient transcription initiation by RNA polymerase I. Required for the formation of the competent preinitiation complex (PIC). Dissociates from pol I as a consequence of transcription. In vitro, cannot activate transcription in a subsequent transcription reaction (By similarity).
Functions in mitochondrial and peroxisomal division (PubMed:9570752, PubMed:9786947, PubMed:11514614, PubMed:12499366, PubMed:17301055, PubMed:17553808, PubMed:17460227, PubMed:18695047, PubMed:18838687, PubMed:19638400, PubMed:19411255, PubMed:19342591, PubMed:23921378, PubMed:23283981, PubMed:23530241, PubMed:29478834, PubMed:32484300, PubMed:27145208, PubMed:26992161, PubMed:27301544, PubMed:27328748). Mediates membrane fission through oligomerization into membrane-associated tubular structures that wrap around the scission site to constrict and sever the mitochondrial membrane through a GTP hydrolysis-dependent mechanism (PubMed:23530241, PubMed:23584531). The specific recruitment at scission sites is mediated by membrane receptors like MFF, MIEF1 and MIEF2 for mitochondrial membranes (PubMed:23921378, PubMed:23283981, PubMed:29899447). While the recruitment by the membrane receptors is GTP-dependent, the following hydrolysis of GTP induces the dissociation from the receptors and allows DNM1L filaments to curl into closed rings that are probably sufficient to sever a double membrane (PubMed:29899447). Acts downstream of PINK1 to promote mitochondrial fission in a PRKN-dependent manner (PubMed:32484300). Plays an important role in mitochondrial fission during mitosis (PubMed:19411255, PubMed:26992161, PubMed:27301544, PubMed:27328748). Through its function in mitochondrial division, ensures the survival of at least some types of postmitotic neurons, including Purkinje cells, by suppressing oxidative damage (By similarity). Required for normal brain development, including that of cerebellum (PubMed:17460227, PubMed:27145208, PubMed:26992161, PubMed:27301544, PubMed:27328748). Facilitates developmentally regulated apoptosis during neural tube formation (By similarity). Required for a normal rate of cytochrome c release and caspase activation during apoptosis; this requirement may depend upon the cell type and the physiological apoptotic cues (By similarity). Required for formation of endocytic vesicles (PubMed:9570752, PubMed:20688057, PubMed:23792689). Proposed to regulate synaptic vesicle membrane dynamics through association with BCL2L1 isoform Bcl-X(L) which stimulates its GTPase activity in synaptic vesicles; the function may require its recruitment by MFF to clathrin-containing vesicles (PubMed:17015472, PubMed:23792689). Required for programmed necrosis execution (PubMed:22265414). Rhythmic control of its activity following phosphorylation at Ser-637 is essential for the circadian control of mitochondrial ATP production (PubMed:29478834).
GTPase activity is increased by binding to phospholipid membranes.
Homotetramer; dimerizes through the N-terminal GTP-middle region of one molecule binding to the GED domain of another DNM1L molecule (PubMed:17553808, PubMed:23530241, PubMed:23584531, PubMed:23977156). Oligomerizes in a GTP-dependent manner to form membrane-associated tubules with a spiral pattern (PubMed:23584531). Interacts with GSK3B and MARCHF5 (PubMed:9731200, PubMed:10749171, PubMed:16874301, PubMed:16936636). Interacts (via the GTPase and B domains) with UBE2I; the interaction promotes sumoylation of DNM1L, mainly in its B domain (PubMed:19638400). Interacts with PPP3CA; the interaction dephosphorylates DNM1L and regulates its transition to mitochondria (PubMed:18838687). Interacts with BCL2L1 isoform BCL-X(L) and CLTA; DNM1L and BCL2L1 isoform BCL-X(L) may form a complex in synaptic vesicles that also contains clathrin and MFF (PubMed:23792689). Interacts with MFF; the interaction is inhibited by C11orf65/MFI (By similarity). Interacts with FIS1; may form part of a larger protein complex at the endoplasmic reticulum-mitochondrial interface during mitochondrial fission (PubMed:18695047, PubMed:24196833). Interacts with CANX (PubMed:24196833). Interacts with BCAP31 (PubMed:24196833). Interacts with MIEF2 and MIEF1; GTP-dependent, regulates GTP hydrolysis and DNM1L oligomerization (PubMed:21508961). Interacts with PGAM5; this interaction leads to dephosphorylation at Ser-656 and activation of GTPase activity and eventually to mitochondria fragmentation (PubMed:22265414). Interacts with RALBP1; during mitosis, recruits DNM1L to the mitochondrion and mediates its activation by the mitotic kinase cyclin B-CDK1 (PubMed:21822277).
Inhibits peroxisomal division when overexpressed.
May be associated with Alzheimer disease through amyloid-beta-induced increased S-nitrosylation of DNM1L, which triggers, directly or indirectly, excessive mitochondrial fission, synaptic loss and neuronal damage.
O-GlcNAcylation augments the level of the GTP-bound active form of DNM1L and induces translocation from the cytoplasm to mitochondria in cardiomyocytes. It also decreases phosphorylation at Ser-637 (By similarity).
Phosphorylation/dephosphorylation events on two sites near the GED domain regulate mitochondrial fission (PubMed:17301055, PubMed:17553808, PubMed:18695047, PubMed:18838687, PubMed:23283981, PubMed:29478834). Phosphorylation on Ser-637 by CAMK1 and PKA inhibits the GTPase activity, leading to a defect in mitochondrial fission promoting mitochondrial elongation (PubMed:17553808, PubMed:18695047, PubMed:23283981, PubMed:29478834). Dephosphorylated on this site by PPP3CA which promotes mitochondrial fission (PubMed:18838687). Phosphorylation on Ser-616 by CDK1 and PINK1 activates the GTPase activity and promotes mitochondrial fission (PubMed:18838687, PubMed:32484300, PubMed:21822277). Phosphorylated in a circadian manner at Ser-637 (PubMed:29478834).
S-nitrosylation increases DNM1L dimerization, mitochondrial fission and causes neuronal damage.
Sumoylated on various lysine residues within the B domain, probably by MUL1. Sumoylation positively regulates mitochondrial fission. Desumoylated by SENP5 during G2/M transition of mitosis. Appears to be linked to its catalytic activity.
The GED domain folds back to interact, in cis, with the GTP-binding domain and middle domain, and interacts, in trans, with the GED domains of other DNM1L molecules, and is thus critical for activating GTPase activity and for DNM1L dimerization.
Ubiquitination by MARCHF5 affects mitochondrial morphology.
Ubiquitously expressed with highest levels found in skeletal muscles, heart, kidney and brain. Isoform 1 is brain-specific. Isoform 2 and isoform 3 are predominantly expressed in testis and skeletal muscles respectively. Isoform 4 is weakly expressed in brain, heart and kidney. Isoform 5 is dominantly expressed in liver, heart and kidney. Isoform 6 is expressed in neurons.
Mono-ADP-ribosyltransferase that mediates mono-ADP-ribosylation of target proteins (PubMed:16061477, PubMed:25043379, PubMed:25635049). Acts as a negative regulator of transcription (PubMed:16061477).
(Microbial infection) Interacts with Epstein-barr virus protein BBLF1.
(Microbial infection) Interacts with HIV-1 Nef.
Associates with AP-1 and AP-3 but not with AP-2 complexes (PubMed:11331585). Interacts with FURIN (By similarity). Forms a ternary complex with FURIN and AP-1 (PubMed:11331585). Interacts with NPHP1; the interaction is dependent of NPHP1 phosphorylation by CK2 (PubMed:16308564). Interacts with PKD2 (via acidic region) (PubMed:15692563). Interacts with SORL1 (PubMed:17855360, PubMed:17646382). Interacts with WDR37 (PubMed:34642815).
Coat protein that is involved in the localization of trans-Golgi network (TGN) membrane proteins that contain acidic cluster sorting motifs. Controls the endosome-to-Golgi trafficking of furin and mannose-6-phosphate receptor by connecting the acidic-cluster-containing cytoplasmic domain of these molecules with the adapter-protein complex-1 (AP-1) of endosomal clathrin-coated membrane pits. Involved in HIV-1 nef-mediated removal of MHC-I from the cell surface to the TGN. Required for normal ER Ca2+ handling in lymphocytes. Together with WDR37, it plays an essential role in lymphocyte development, quiescence and survival. Required for stabilizing peripheral lymphocyte populations (By similarity).
Homooligomer (PubMed:30213940). Heterotrimer with ATP9A and DOP1B; this interaction is retromer-independent (PubMed:30213940). Interacts with SNX3 (PubMed:30213940).
Plays a role in regulating membrane trafficking of cargo proteins. Together with ATP9A and DOP1B, regulates SNX3 retromer-mediated endosomal sorting of WLS away from lysosomal degradation.
The RRM domain mediates integration into cytospeckles.
Binds to the C-terminal coiled coil region of syntaxin family members STX1A, STX3A and STX4A. Forms a heterodimer with ATF4 in osteoblasts.
By bacterial lipopolysaccharides (LPS) in Hep-G2 cells.
Depletion of TXLNG by siRNA decreases the percentage of Hep-G2 cells arrested in G1 phase.
May be involved in intracellular vesicle traffic. Inhibits ATF4-mediated transcription, possibly by dimerizing with ATF4 to form inactive dimers that cannot bind DNA. May be involved in regulating bone mass density through an ATF4-dependent pathway. May be involved in cell cycle progression.
Ubiquitously expressed. Expressed at high level in heart and skeletal muscle. Expressed in brain, placenta, lung, liver, kidney and pancreas.
Belongs to the class I-like SAM-binding methyltransferase superfamily. DOT1 family.
Histone methyltransferase. Methylates 'Lys-79' of histone H3. Nucleosomes are preferred as substrate compared to free histones (PubMed:12123582). Binds to DNA (PubMed:12628190).
In contrast to other lysine histone methyltransferases, it does not contain a SET domain, suggesting the existence of another mechanism for methylation of lysine residues of histones.
Component of numerous DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which consist of a core of DDB1, cullin-4 (CUL4A or CUL4B), DDA1 and RBX1 (PubMed:28437394, PubMed:28302793, PubMed:31693891, PubMed:31686031, PubMed:31819272, PubMed:31693911). Component of the DCX(DCAF15) complex, also named CLR4(DCAF15) complex, composed of DCAF15, DDB1, cullin-4 (CUL4A or CUL4B), DDA1 and RBX1 (PubMed:28437394, PubMed:28302793, PubMed:31693891, PubMed:31686031, PubMed:31819272, PubMed:31693911). Part of the DDD core complex containing DET1, DDA1 and DDB1; the DDD core complex recruits a specific UBE2E enzyme, such as UBE2E1, UBE2E2 UBE2E3, to form specific DDD-E2 complexes (PubMed:17452440).
Functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:17452440, PubMed:28437394, PubMed:28302793, PubMed:31686031, PubMed:31819272). In the DCX complexes, acts as a scaffolding subunit required to stabilize the complex (PubMed:31686031, PubMed:31819272).
(Microbial infection) Interacts (via the substrate recognition component) with HIV-1 Vif.
(Microbial infection) Interacts (via the substrate recognition component) with human adenovirus 5 proteins E1B-55K and E4-orf6.
(Microbial infection) Interacts with herpes virus 8 protein LANA1; this interaction promotes the degradation of NF-kappa-B component RELA.
(Microbial infection) Interacts with molluscum contagiosum virus protein MC132; this interaction promotes the degradation of NF-kappa-B component RELA.
(Microbial infection) Seems to be involved in proteasomal degradation of p53/TP53 stimulated by adenovirus E1B-55 kDa protein.
Component of multiple ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes formed of CUL5, Elongin BC (ELOB and ELOC), RBX2 and a variable SOCS box domain-containing protein as substrate-specific recognition component (PubMed:11384984, PubMed:15601820). Component of the probable ECS(LRRC41) complex with the substrate recognition component LRRC41 (PubMed:11384984). Component of the probable ECS(SOCS1) complex with the substrate recognition component SOCS1 (PubMed:11384984). Component of the probable ECS(WSB1) complex with the substrate recognition subunit WSB1 (PubMed:15601820). Component of the probable ECS(SOCS3) complex with the substrate recognition component SOCS3 (PubMed:15601820). Component of the probable ECS(SPSB1) complex with the substrate recognition component SPSB1 (PubMed:15601820). Component of the probable ECS(SPSB2) complex with the substrate recognition component SPSB2 (PubMed:15601820). Component of the probable ECS(SPSB4) complex with the substrate recognition component SPSB4 (PubMed:15601820). Component of the probable ECS(RAB40C) complex with the substrate recognition subunit RAB40C (PubMed:15601820). Component of the probable ECS(KLHDC1) complex with the substrate recognition component KLHDC1 (PubMed:32200094). May also form complexes containing CUL5, elongin BC complex (ELOB and ELOC), RBX1 and ELOA (PubMed:11384984, PubMed:19920177). May also form complexes containing CUL5, Elongin BC (ELOB and ELOC), RBX1 and VHL (PubMed:10230407, PubMed:18805092). Interacts with RNF7/RBX2, LRRC41, SOCS3, SPSB1, SPSB2, SPSB4 and RAB40C (PubMed:15601820). Interacts with ASB1, ASB2, ASB6, ASB7 and ASB12 (PubMed:16325183, PubMed:21119685). Interacts (when neddylated) with ARIH2; leading to activate the E3 ligase activity of ARIH1 (PubMed:24076655). Interacts with NOS2 in the presence of SPSB1 or SPSB2 or SPSB4 (PubMed:21199876). Interacts with ERCC6; the interaction is induced by DNA damaging agents or inhibitors of RNA polymerase II elongation (PubMed:28292928). Interacts with ELOA (via the BC-box) (PubMed:28292928). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (PubMed:23201271, PubMed:26906416). Component of the probable ECS(PCMTD1) complex with the substrate recognition subunit PCMTD1 (PubMed:35486881).
Core component of multiple SCF-like ECS (Elongin-Cullin 2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:11384984, PubMed:15601820). As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme (PubMed:11384984, PubMed:15601820). The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component (PubMed:11384984, PubMed:15601820). ECS(SOCS1) seems to direct ubiquitination of JAK2 (PubMed:11384984). ECS(KLHDC1) complex is part of the DesCEND (destruction via C-end degrons) pathway and mediates ubiquitination and degradation of truncated SELENOS selenoprotein produced by failed UGA/Sec decoding, which ends with a glycine (PubMed:32200094). As part of a multisubunit complex composed of elongin BC complex (ELOB and ELOC), elongin A/ELOA, RBX1 and CUL5; polyubiquitinates monoubiquitinated POLR2A (PubMed:19920177). May form a cell surface vasopressin receptor (PubMed:9037604).
Neddylated; which enhances the ubiquitination activity of SCF and prevents binding of the inhibitor CAND1. Deneddylated via its interaction with the COP9 signalosome (CSN).
Two inactivating mutations in human TTLL10 (Ser-448 and Lys-467) are proposed to explain the lack of polyglycylation.
Activated at acidic pHs (Probable). Inhibited by amiloride and 5-amino-substituted derivatives (PubMed:17493937). Inhibited by cariporide and eniporide (PubMed:11412833). Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) bind and differentially regulate SLC9A1 activity (PubMed:22020933).
Although PubMed:12809501 report that TESC-binding results in a decrease in activity, studies with rat SLC9A1 show that TESC-binding results in the maturation and accumulation of SLC9A1 at the cell surface.
Electroneutral Na(+) /H(+) antiporter that extrudes Na(+) in exchange for external protons driven by the inward sodium ion chemical gradient, protecting cells from acidification that occurs from metabolism (PubMed:7110335, PubMed:7603840, PubMed:11532004, PubMed:11350981, PubMed:15035633, PubMed:14680478, PubMed:17073455, PubMed:22020933, PubMed:27650500, PubMed:15677483, PubMed:32130622, PubMed:17493937). Exchanges intracellular H(+) ions for extracellular Na(+) in 1:1 stoichiometry (By similarity). Plays a key role in maintening intracellular pH neutral and cell volume, and thus is important for cell growth, proliferation, migration and survival (PubMed:8901634, PubMed:12947095, PubMed:15096511, PubMed:22020933). In addition, can transport lithium Li(+) and functions also as a Na(+)/Li(+) antiporter (PubMed:7603840). SLC9A1 also functions in membrane anchoring and organization of scaffolding complexes that coordinate signaling inputs (PubMed:15096511).
Homodimer; dimerization is crucial for its function (PubMed:34108458, PubMed:15323573, PubMed:17073455). Oligomer (By similarity). Interacts with CALM1 in a calcium-dependent manner (PubMed:12809501, PubMed:30287853, PubMed:18757828). Interacts with TESC (PubMed:11696366, PubMed:30287853, PubMed:12809501). Interacts (via the C-terminal domain) with CHP1; the interaction occurs at the plasma membrane in a calcium-dependent manner and facilitates the maturation, cell surface expression, and function of SLC9A3 (PubMed:8967452, PubMed:8901634, PubMed:11350981, PubMed:15035633, PubMed:17050540, PubMed:34108458). Interacts with CHP2; the interaction occurs in a calcium-dependent manner (PubMed:12226101, PubMed:16710297, PubMed:21392185). Interacts with EZR; regulates the cytoskeletal interactions of SLC9A1 and promotes stress fiber formation (By similarity).
Palmitoylated; may play a major role in SLC9A1 regulation.
Phosphorylation at Thr-779 increases SLC9A1 activity. Specifically dephosphorylated at Thr-779 by PPP3CA that negatively regulates SLC9A1 activity (PubMed:31375679). Phosphorylation at Ser-648 by AKT1 reduces SLC9A1 binding to CALM1 (PubMed:18757828).
Predicted models used for more than 20 years predicted 10-12 transmembrane segments (PubMed:9688597, PubMed:10713111). Recently, the stucture of SLC9A1 has been solved and reveals that SLC9A1 posseses 13 transmembranes (PubMed:34108458).
The C-terminal intracellular domain is subject to extensive post-translational modifications and binding partner interactions which regulate transporter activity, scaffolding functions, downstream events and localization.
The interacting region with TESC is conflicting: Interaction with TESC has been reported via the juxtamembrane region of the cytoplasmic C-terminal domain, including residues 503-545 (PubMed:11696366, PubMed:30287853). In contrast, another publication has reported interaction with TESC via residues 633-815, the region of the cytoplasmic C-terminus more distal to the membrane (PubMed:12809501).
Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is reduced by CHP1.
'Nezha' is a deity in Chinese mythology.
Interacts with PLEKHA7 (PubMed:19041755). Interacts with CAMSAP2 (By similarity). Interacts with KATNA1 and KATNB1; leading to regulate the length of CAMSAP3-decorated microtubule stretches (PubMed:24486153, PubMed:28386021). Interacts with AKAP9; regulating Golgi assembly in epithelial cells (PubMed:28089391). Interacts with MACF1 (PubMed:27693509, PubMed:27802168). Interacts with AKNA (By similarity).
Key microtubule-organizing protein that specifically binds the minus-end of non-centrosomal microtubules and regulates their dynamics and organization (PubMed:19041755, PubMed:23169647). Specifically recognizes growing microtubule minus-ends and autonomously decorates and stabilizes microtubule lattice formed by microtubule minus-end polymerization (PubMed:24486153). Acts on free microtubule minus-ends that are not capped by microtubule-nucleating proteins or other factors and protects microtubule minus-ends from depolymerization (PubMed:24486153). In addition, it also reduces the velocity of microtubule polymerization (PubMed:24486153). Required for the biogenesis and the maintenance of zonula adherens by anchoring the minus-end of microtubules to zonula adherens and by recruiting the kinesin KIFC3 to those junctional sites (PubMed:19041755). Required for orienting the apical-to-basal polarity of microtubules in epithelial cells: acts by tethering non-centrosomal microtubules to the apical cortex, leading to their longitudinal orientation (PubMed:27802168, PubMed:26715742). Plays a key role in early embryos, which lack centrosomes: accumulates at the microtubule bridges that connect pairs of cells and enables the formation of a non-centrosomal microtubule-organizing center that directs intracellular transport in the early embryo (By similarity). Couples non-centrosomal microtubules with actin: interaction with MACF1 at the minus ends of non-centrosomal microtubules, tethers the microtubules to actin filaments, regulating focal adhesion size and cell migration (PubMed:27693509). Plays a key role in the generation of non-centrosomal microtubules by accumulating in the pericentrosomal region and cooperating with KATNA1 to release non-centrosomal microtubules from the centrosome (PubMed:28386021). Through the microtubule cytoskeleton, also regulates the organization of cellular organelles including the Golgi and the early endosomes (PubMed:28089391). Through interaction with AKAP9, involved in translocation of Golgi vesicles in epithelial cells, where microtubules are mainly non-centrosomal (PubMed:28089391). Plays an important role in motile cilia function by facilitatating proper orientation of basal bodies and formation of central microtubule pairs in motile cilia (By similarity).
The CKK domain binds microtubules and specifically recognizes the minus-end of microtubules.
Brain specific mainly in the limbic system and faintly in the spinal cord but not in cerebellum.
It is not sure whether N-glycosylation is on Asn-165 and/or Asn-166.
A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins during embryogenesis (PubMed:9555064, PubMed:11093772, PubMed:14559847, PubMed:12865317, PubMed:17178770). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:9555064, PubMed:11093772, PubMed:14559847, PubMed:12865317, PubMed:17178770). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes 3beta-hydroxyandrost-5-en-17-one (dehydroepiandrosterone, DHEA), a precursor in the biosynthesis of androgen and estrogen steroid hormones (PubMed:9555064, PubMed:17178770). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1), particularly D-ring hydroxylated estrone at the C16-alpha position (PubMed:14559847, PubMed:12865317). Mainly hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in atRA clearance during fetal development (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics including anticonvulsants (PubMed:9555064).
Expressed in fetal liver (at protein level).
Isoform 1 interacts with MARK2; the interaction increases MARK2 microtubule-binding ability (By similarity). Homodimer. Associates (via N- and C-terminus domains) with microtubule filaments. Isoform 2 interacts with MARK2; the interaction is direct.
Microtubule-associated factor involved in the late phase of epithelial polarization and microtubule dynamics regulation. Plays a role in the development and maintenance of non-centrosomal microtubule bundles at the lateral membrane in polarized epithelial cells.
Adapter protein which associates with tyrosine-phosphorylated growth factor receptors, such as KDR and PDGFRB, or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in the DNA damage response, not in the detection of the damage by ATM/ATR, but for efficient activation of downstream effectors, such as that of CHEK2. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling. Modulates the activation of EIF2AK2/PKR by dsRNA. May play a role in cell adhesion and migration through interaction with ephrin receptors.
Interacts (via SH2 domain and SH3 domain 2) with EGFR. Interacts with PAK1 and SOS1. Interacts (via SH3 domains) with PKN2. Associates with BLNK, PLCG1, VAV1 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with SOCS7. This interaction is required for nuclear import. Part of a complex containing PPP1R15B, PP1 and NCK1. Interacts with RALGPS1. Interacts with CAV2 (tyrosine phosphorylated form). Interacts with ADAM15. Interacts with FASLG. Directly interacts with RASA1. Interacts with isoform 4 of MINK1. Interacts with FLT1 (tyrosine phosphorylated). Interacts with KDR (tyrosine phosphorylated). Interacts (via SH2 domain) with EPHB1; activates the JUN cascade to regulate cell adhesion. Interacts with EPHA2. Interacts (via SH2 domain) with PDGFRB (tyrosine phosphorylated). Interacts with the inactive form of EIF2AK2/PKR.
Only the first and third SH3 domains seem to be involved in RASA1-binding; the second SH3 domain and the SH2 domains do not seem to be involved.
Phosphorylated on Ser and Tyr residues. Phosphorylated in response to activation of EGFR and FcERI. Phosphorylated by activated PDGFRB.
A di-leucine motif and a tyrosine-based motif are individually sufficient to induce both endocytosis and delivery to lysosomes.
Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways (PubMed:2470098). In addition to this role of signal transduction in T-cell activation, CD3G plays an essential role in the dynamic regulation of TCR expression at the cell surface (PubMed:8187769). Indeed, constitutive TCR cycling is dependent on the di-leucine-based (diL) receptor-sorting motif present in CD3G.
Phosphorylated on Tyr residues after T-cell receptor triggering by LCK in association with CD4/CD8 (PubMed:2470098). Phosphorylated also by PKC; leading to the TCR complex down-regulation (PubMed:8187769).
Phosphorylated on Tyr residues after T-cell receptor triggering by LCK in association with CD4/CD8.
The TCR-CD3 complex is composed of a CD3D/CD3E and a CD3G/CD3E heterodimers that preferentially associate with TCRalpha and TCRbeta, respectively, to form TCRalpha/CD3E/CD3G and TCRbeta/CD3G/CD3E trimers. In turn, the hexamer interacts with CD3Z homodimer to form the TCR-CD3 complex. Alternatively, TCRalpha and TCRbeta can be replaced by TCRgamma and TCRdelta.
Activity of phosphorylase is controlled both by allosteric means (through the non-covalent binding of metabolites) and by covalent modification. Thus AMP allosterically activates, whereas ATP, ADP, and glucose-6-phosphate allosterically inhibit, phosphorylase B. Activated upon phosphorylation.
Belongs to the glycogen phosphorylase family.
Glycogen phosphorylase that regulates glycogen mobilization (PubMed:27402852). Phosphorylase is an important allosteric enzyme in carbohydrate metabolism (PubMed:3346228). Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates (PubMed:3346228). However, all known phosphorylases share catalytic and structural properties (PubMed:3346228).
Homodimer. Dimers associate into a tetramer to form the enzymatically active phosphorylase A.
Phosphorylated (PubMed:27402852). Phosphorylation of Ser-15 converts phosphorylase B (unphosphorylated) to phosphorylase A (By similarity).
Highest expression in kidney, liver, colon and small intestine. In kidney, expressed apically along brush border of proximal convoluted tubule but not in cortical collecting ducts. Isoform 1 is expressed primarily in adult small intestine and colon. Isoform 2 is highly expressed in fetal liver (PubMed:12167596). Expressed in duodenum with higher expression in enterocytes along the villus axis and lower expression in crypts (at protein level) (PubMed:24725409).
Intermicrovillar adhesion molecule that forms, via its extracellular domain, calcium-dependent heterophilic complexes with CDHR2 on adjacent microvilli. Thereby, controls the packing of microvilli at the apical membrane of epithelial cells. Through its cytoplasmic domain, interacts with microvillus cytoplasmic proteins to form the intermicrovillar adhesion complex/IMAC. This complex plays a central role in microvilli and epithelial brush border differentiation.
Part of the IMAC/intermicrovillar adhesion complex/intermicrovillar tip-link complex composed of ANKS4B, MYO7B, USH1C, CDHR2 and CDHR5 (PubMed:26812018). Interacts (via cytoplasmic domain) with USH1C and MYO7B; required for proper localization of CDHR5 to microvilli tips and its function in brush border differentiation (PubMed:24725409).
Access to the profilin-binding site is masked in the full-length protein.
Expressed mainly in brain, colon, lung and stomach (at protein level). Ubiquitously expressed, with high expression in brain, kidney, lung, and placenta.
Interacts with WASL and WASP, and this interaction results in cytoplasmic relocation of these two proteins along actin filaments. Interacts with NCK2 resulting in the localization to sites of focal adhesions. No interaction was seen with WASF2 and WASF3.
Plays an active role in the formation of cell surface protrusions downstream of activated PDGFB receptors. Plays an important role in actin-microspike formation through cooperation with WASL. May cooperate with WASP and WASL to induce mobilization and reorganization of the actin filament system.
Might be involved in growth regulation, and in myelinization in the peripheral nervous system.
Expression is restricted to functional NK and cytotoxic T lymphocytes. Expressed in viral-specific effector memory and terminally differentiated effector memory CD8+ T cells. Expressed in memory and activated CD4+ T cell subsets (at protein level) (PubMed:9743336, PubMed:18193050, PubMed:11978774, PubMed:25255144). Expressed at high levels in intraepithelial lymphocytes (at protein level) (PubMed:9743336). Expressed in both alpha-beta and gamma-delta CD8+ T cell subsets (at protein level) (PubMed:9743336, PubMed:18193050, PubMed:11978774). Expressed in umbilical vein endothelial cells (at protein level) (PubMed:16809620). Expressed in monocytes and at lower levels in B cells (PubMed:23761635). Isoform 3: Expressed exclusively in activated NK cells (at protein level) (PubMed:19109136).
Homomultimer; disulfide-linked (Probable). Interacts with HLA-G (PubMed:16809620). Interacts with HLA-A2-B2M in complex with an HIV-derived peptide (PubMed:9973372). Interacts with TNFRSF14 (via cysteine-rich domain 1); this interaction is direct (PubMed:18193050). Interacts with LCK and CD247/CD3 zeta chain (PubMed:11978774).
Mutagenesis of Tyr-225 to Phe abolishes intracellular signaling.
Receptor on immune cells capable to deliver stimulatory or inhibitory signals that regulate cell activation and differentiation. Exists as a GPI-anchored and as a transmembrane form, each likely initiating distinct signaling pathways via phosphoinositol 3-kinase in activated NK cells and via LCK and CD247/CD3 zeta chain in activated T cells (PubMed:19109136, PubMed:11978774, PubMed:17307798). Receptor for both classical and non-classical MHC class I molecules (PubMed:9973372, PubMed:12486241). In the context of acute viral infection, recognizes HLA-C and triggers NK cell cytotoxic activity, likely playing a role in anti-viral innate immune response (PubMed:12486241). On CD8+ T cells, binds HLA-A2-B2M in complex with a viral peptide and provides a costimulatory signal to activated/memory T cells (PubMed:9973372). Upon persistent antigen stimulation, such as occurs during chronic viral infection, may progressively inhibit TCR signaling in memory CD8+ T cells, contributing to T cell exhaustion (PubMed:25255144). On endothelial cells, recognizes HLA-G and controls angiogenesis in immune privileged sites (PubMed:16809620). Receptor or ligand for TNF superfamily member TNFRSF14, participating in bidirectional cell-cell contact signaling between antigen presenting cells and lymphocytes. Upon ligation of TNFRSF14, provides stimulatory signal to NK cells enhancing IFNG production and anti-tumor immune response (By similarity). On activated CD4+ T cells, interacts with TNFRSF14 and down-regulates CD28 costimulatory signaling, restricting memory and alloantigen-specific immune response (PubMed:18193050). In the context of bacterial infection, acts as a ligand for TNFRSF14 on epithelial cells, triggering the production of antimicrobial proteins and pro-inflammatory cytokines (By similarity).
The soluble GPI-cleaved form, usually released by activated lymphocytes, might play an immune regulatory role by limiting lymphocyte effector functions.
Up-regulated on CD4+ T cells upon stimulation via T cell receptor plus costimulation via CD28 (PubMed:18193050). Up-regulated by IL15 on immunoregulatory NCAM1/CD56-bright NK cells (PubMed:17237375).
DH domain alone was unable to confer substrate specificity and recognition.
Functions as a RAC1 guanine nucleotide exchange factor (GEF), activating Rac proteins by exchanging bound GDP for free GTP. Its activity is synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and the beta gamma subunits of heterotrimeric G protein. Mediates the activation of RAC1 in a PI3K-dependent manner. May be an important mediator of Rac signaling, acting directly downstream of both G protein-coupled receptors and phosphoinositide 3-kinase.
Isoform 1 is highly expressed in skeletal muscle, heart and placenta, absent from peripheral blood leukocytes. Isoform 2 is expressed in skeletal muscle, kidney, small intestine, and placenta. Isoform 3 is expressed in the heart.
Non-canonical splice intron-exon junction.
PH domain confers substrate specificity and recognition. Able to discriminate between RAC1, RHOA, and CDC42.
Has no 2-lysophosphatidate/LPA phosphatase activity. This is supported by the fact that the phosphatase sequence motifs as well as the His residue acting as a nucleophile in active phosphatases of the PA-phosphatase related phosphoesterase family are not conserved.
May play a role in neurite outgrowth and neurogenesis.
Highly expressed in lymph node. Expressed in thymus, spleen and leukocytes. Weakly expressed in placenta, small intestine, stomach, testis and lung. Overexpressed in B-cell malignancies.
Interacts with ITGB1, ITGB2 and ITGB3 (via cytoplasmic tails).
Isoform 2 may act as a repressor of NF-kappa-B and apoptosis.
Plays a central role in cell adhesion in hematopoietic cells (PubMed:19234463, PubMed:26359933). Acts by activating the integrin beta-1-3 (ITGB1, ITGB2 and ITGB3) (By similarity). Required for integrin-mediated platelet adhesion and leukocyte adhesion to endothelial cells (PubMed:19234460). Required for activation of integrin beta-2 (ITGB2) in polymorphonuclear granulocytes (PMNs) (By similarity).
The FERM domain is not correctly detected by PROSITE or Pfam techniques because it contains the insertion of a PH domain.
Detected in kidney cortex (at protein level) (PubMed:9572993). Expressed in kidney proximal tubule cells, placenta, visceral yolk-sac cells and in absorptive intestinal cells. Expressed in the epithelium of intestine and kidney.
Endocytic receptor which plays a role in lipoprotein, vitamin and iron metabolism by facilitating their uptake (PubMed:9572993, PubMed:10371504, PubMed:11717447, PubMed:11606717, PubMed:14576052). Acts together with LRP2 to mediate endocytosis of high-density lipoproteins, GC, hemoglobin, ALB, TF and SCGB1A1. Acts together with AMN to mediate endocytosis of the CBLIF-cobalamin complex (PubMed:9572993, PubMed:14576052). Binds to ALB, MB, Kappa and lambda-light chains, TF, hemoglobin, GC, SCGB1A1, APOA1, high density lipoprotein, and the CBLIF-cobalamin complex. Ligand binding requires calcium (PubMed:9572993). Serves as important transporter in several absorptive epithelia, including intestine, renal proximal tubules and embryonic yolk sac. May play an important role in the development of the peri-implantation embryo through internalization of APOA1 and cholesterol. Binds to LGALS3 at the maternal-fetal interface.
Interacts with AMN (PubMed:14576052, PubMed:29402915, PubMed:20237569, PubMed:30523278). Component of the cubam complex composed of one CUBN trimer and one AMN chain (PubMed:30523278). The cubam complex can dimerize (By similarity). Interacts with LRP2 in a dual-receptor complex in a calcium-dependent manner. Found in a complex with PID1/PCLI1, LRP1 and CUBNI. Interacts with LRP1 and PID1/PCLI1.
The CUB domains 5 to 8 mediate binding to CBLIF and ALB. CUB domains 1 and 2 mediate interaction with LRP2.
The cubam complex is composed of a 400 Angstrom long stem and a globular crown region. The stem region is probably formed by AMN and the CUBN N-terminal region, including the EGF-like domains. The crown is probably formed by the CUBN CUB domains.
The precursor is cleaved by a trans-Golgi proteinase furin, removing a propeptide.
Adapter protein for SORL1, but not SORT1. Delays SORL1 internalization and affects SORL1 subcellular localization.
Belongs to the heat shock protein 70 family.
Interacts with SORL1 (via cytosolic C-terminus); this interaction affects SORL1 internalization and subcellular localization.
Widely expressed with highest levels in brain, kidney and muscle.
Detected in T-cells and natural killer cells.
Plays a role in T-cell responses in the adaptive immune response. Inhibits the release of IFNG from activated T-cells.
A conserved motif [AVN[ED]CD] within the disintegrin-like domain could be involved in the binding to the integrin receptor.
Expressed predominantly in brain. Slightly detected or not at all in other tissues.
Interacts with LGI1 and LGI4 (By similarity). Interacts with KCNA1/KV1.1, KCNA2/KV1.2, DLG4/PSD-95 and ADAM22 (By similarity).
Probable ligand for integrin in the brain. This is a non catalytic metalloprotease-like protein. Required for localization of the potassium channel subunit proteins KCNA1/KV1.1 and KCNA2/KV1.2 at cerebellar cortex basket cell distal terminals, is thereby involved in ephaptic inhibitory synchronization of Purkinje cell firing and response to stress (By similarity). Plays a role in spatial learning and motor coordination (By similarity). Involved in the nociceptive pain response to chemical-derived stimulation (By similarity).
Belongs to the type I cytokine receptor family. Type 4 subfamily.
Plays an important role in the immune response against parasites by acting as a receptor of IL9.
The gene coding for this protein is located in the pseudoautosomal region 2 (PAR2) of X and Y chromosomes.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Homozygosity for the Leu-55 allele is strongly associated with the development of retinal disease in diabetic patients.
Homodimer. Heterooligomer with phosphate-binding protein (HPBP). Interacts with CLU.
Hydrolyzes the toxic metabolites of a variety of organophosphorus insecticides. Capable of hydrolyzing a broad spectrum of organophosphate substrates and lactones, and a number of aromatic carboxylic acid esters. Mediates an enzymatic protection of low density lipoproteins against oxidative modification and the consequent series of events leading to atheroma formation.
Plasma, associated with HDL (at protein level). Expressed in liver, but not in heart, brain, placenta, lung, skeletal muscle, kidney or pancreas.
Present in two forms, form B contains a disulfide bond, form A does not.
The allelic form of the enzyme with Gln-192 (allozyme A) hydrolyzes paraoxon with a low turnover number and the one with Arg-192 (allozyme B) with a high turnover number.
The preferential association of PON1 with HDL is mediated in part by its signal peptide, by binding phospholipids directly, rather than binding apo AI. The retained signal peptide may allow transfer of the protein between phospholipid surfaces.
During unfolded protein response, a fragment of approximately 60 kDa containing the cytoplasmic transcription factor domain is released by proteolysis. The cleavage is probably performed sequentially by site-1 (MBTPS1, S1P) and site-2 (MBTPS2, S2P) proteases.
Homodimer and heterodimer with ATF6-alpha. The dimer interacts with the nuclear transcription factor Y (NF-Y) trimer through direct binding to NF-Y subunit C (NF-YC).
Precursor of the transcription factor form (Processed cyclic AMP-dependent transcription factor ATF-6 beta), which is embedded in the endoplasmic reticulum membrane (PubMed:11256944). Endoplasmic reticulum stress promotes processing of this form, releasing the transcription factor form that translocates into the nucleus, where it activates transcription of genes involved in the unfolded protein response (UPR) (PubMed:11256944).
The basic domain functions as a nuclear localization signal.
The basic leucine-zipper domain is sufficient for association with the NF-Y trimer and binding to ERSE.
Transcription factor that acts in the unfolded protein response (UPR) pathway by activating UPR target genes induced during ER stress (PubMed:11256944). Binds DNA on the 5'-CCAC[GA]-3' half of the ER stress response element (ERSE) (5'-CCAATN(9)CCAC[GA]-3') when NF-Y is bound to ERSE (PubMed:11256944).
Not induced by bacterial lipopolysaccharideS (LPS) or IL1/interleukin-1 in endothelium, monocytes or neutrophils. Not induced by PHA in lymphocytes.
Widely expressed at low levels with highest levels in small intestine, testis and brain. Very low expression in endothelial cells, monocytes, neutrophils and lymphocytes. Isoform 1 is not expressed in small intestine.
Binds 2 divalent metal cations (Ref.9). Shows activity with Mn(2+), Co(2+) and Mg(2+) but shows no activity with Zn(2+) (By similarity).
Catalyzes the dephosphorylation of the nucleoside 5'-monophosphates deoxyadenosine monophosphate (dAMP), deoxycytidine monophosphate (dCMP), deoxyguanosine monophosphate (dGMP) and deoxythymidine monophosphate (dTMP).
Correction of a non-canonical splice junction.
Expressed in B-cells (PubMed:14506071). Expressed in a subset of endometrial macrophages related to menstruation and in ovarian and peritoneal endometriotic lesions (at protein level)(PubMed:24810263).
Matrix metalloproteinases degrade protein components of the extracellular matrix such as fibronectin, laminin, gelatins and/or collagens.
A chromosomal aberration involving LIFR is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(5;8)(p13;q12) with PLAG1.
Heterodimer composed of LIFR and IL6ST. The heterodimer formed by LIFR and IL6ST interacts with the complex formed by CNTF and CNTFR.
Signal-transducing molecule. May have a common pathway with IL6ST. The soluble form inhibits the biological activity of LIF by blocking its binding to receptors on target cells.
Auxiliary protein of the large-conductance, voltage and calcium-activated potassium channel (BK alpha). Modulates gating properties by producing a marked shift in the BK channel's voltage dependence of activation in the hyperpolarizing direction, and in the absence of calcium. KCNU1 channel auxiliary protein. May modulate KCNU1 gating properties.
Mainly expressed in testis and skeletal muscle.
May interact with KCNU1; this interaction may be required for LRRC52 stability and may change the channel gating properties (By similarity). Interacts with KCNMA1.
Converts testosterone into 5-alpha-dihydrotestosterone and progesterone or corticosterone into their corresponding 5-alpha-3-oxosteroids. It plays a central role in sexual differentiation and androgen physiology.
Its expression is regulated by androgens such as testosterone.
Associates with the mitochondrial ribosome (PubMed:34969438). Interacts with UQCC6 (PubMed:34969438). Interacts with MT-CYB; interacts with newly synthesizes MT-CYB (PubMed:34969438). Forms a complex, named COMB/coordinator of mitochondrial CYTB biogenesis, composed of UQCC1, UQCC2, UQCC4, UQCC5 and UQCC6; regulates MT-CYB synthesis and promotes its membrane insertion (By similarity).
Required for the assembly and stability of the mitochondrial ubiquinol-cytochrome c reductase complex (complex III (CIII) or cytochrome b-c1 complex), a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain (ETC) which drives oxidative phosphorylation (By similarity). Mediates early complex III biogenesis (By similarity). Participates in regulating the levels of electron transport chain proteins, and therefore energy supply, in response to changes in energy demand (By similarity). Also involved in the first steps of cytochrome c oxidase complex (complex IV) assembly (PubMed:34969438).
A chromosomal translocation involving CLPTM1 is found in a family with cleft lip and palate. However, no etiologic link with the disease is characterized. Translocation t(2;19)(q11.2;q13.3).
Involved in GABAergic but not glutamatergic transmission. Binds and traps GABAA receptors in the endoplasmic reticulum (ER). Modulates postsynaptic GABAergic transmission, and therefore inhibitory neurotransmission, by reducing the plasma membrane expression of these receptors. Altered GABAergic signaling is one among many causes of cleft palate (By similarity). Might function as a lipid scramblase, translocating lipids in membranes from one leaflet to the other one (By similarity). Required for efficient glycosylphosphatidylinositol (GPI) inositol deacylation in the ER, which is a crucial step to switch GPI-anchored proteins (GPI-APs) from protein folding to transport states (PubMed:29255114). May play a role in T-cell development (By similarity).
May act as a receptor for annexin II on marrow stromal cells to induce osteoclast formation.
PubMed:16895901 reports that it is a type I membrane protein. However, no clear transmembrane region is detected by prediction methods, suggesting that its localization at the plasma membrane is unsure.
Widely expressed. Highly expressed in lymphocytes. Expressed in both resting CD4(+) and CD8(+) T-cells.
Component of the GINS complex which is a heterotetramer of GINS1, GINS2, GINS3 and GINS4 (PubMed:17545466, PubMed:17557111, PubMed:17652513, PubMed:28414293). Forms a stable subcomplex with GINS4. GINS complex interacts with DNA primase in vitro (PubMed:17545466, PubMed:17557111, PubMed:17652513, PubMed:28414293). Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex (PubMed:34700328, PubMed:34694004, PubMed:32453425).
Component of the GINS complex which is a heterotetramer of GINS1, GINS2, GINS3 and GINS4. Forms a stable subcomplex with GINS4. GINS complex interacts with DNA primase in vitro. Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex.
Required for correct functioning of the GINS complex, a complex that plays an essential role in the initiation of DNA replication, and progression of DNA replication forks. GINS complex is a core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built.
High affinity inhibitor for cathepsin L, cathepsin L2 (cathepsin V), and legumain (PubMed:30425301). Involved in the regulation of epidermal cornification, and hair follicle morphogenesis and maintenance (PubMed:30425301).
Restricted to the stratum granulosum of normal skin, the stratum granulosum/spinosum of psoriatic skin, and the secretory coils of eccrine sweat glands. Low expression levels are found in the nasal cavity.
Substrate for transglutaminases. Acts as an acyl acceptor but not as an acyl donor.
Interacts (unphosphorylated form, via the PXDLS motif) with CTBP1, competitively inhibiting CTBP-ZEB1 interaction (PubMed:25728771). Interacts with CTBP2 (PubMed:25728771). Interacts with MCRIP2 (PubMed:26184334). Interacts with DDX6 (PubMed:26184334).
Phosphorylation by MAPK3/1 (ERK1/2) regulates MCRIP1 binding to CTBP(s) (PubMed:25728771).
The phosphorylation status of MCRIP1 functions as a molecular switch to regulate epithelial-mesenchymal transition. Unphosphorylated MCRIP1 binds to and inhibits the transcriptional corepressor CTBP(s). When phosphorylated by MAPK/ERK, MCRIP1 releases CTBP(s) resulting in transcriptional silencing of the E-cadherin gene and induction of epithelial-mesenchymal transition (PubMed:25728771).
By exposure to bacterial lipopolysaccharides (LPS). Inhibited by dexamethasone.
Found in alveolar macrophages but not in peripheral blood monocytes.
May be involved in tissue injury and remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the P1' site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the P1 site, with small hydrophobic residues (preferably alanine) occupying P3.
Belongs to the adenylate kinase family. AK2 subfamily.
Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism. Adenylate kinase activity is critical for regulation of the phosphate utilization and the AMP de novo biosynthesis pathways. Plays a key role in hematopoiesis.
Consists of three domains, a large central CORE domain and two small peripheral domains, NMPbind and LID, which undergo movements during catalysis. The LID domain closes over the site of phosphoryl transfer upon ATP binding. Assembling and dissambling the active center during each catalytic cycle provides an effective means to prevent ATP hydrolysis.
Present in most tissues. Present at high level in heart, liver and kidney, and at low level in brain, skeletal muscle and skin. Present in thrombocytes but not in erythrocytes, which lack mitochondria. Present in all nucleated cell populations from blood, while AK1 is mostly absent. In spleen and lymph nodes, mononuclear cells lack AK1, whereas AK2 is readily detectable. These results indicate that leukocytes may be susceptible to defects caused by the lack of AK2, as they do not express AK1 in sufficient amounts to compensate for the AK2 functional deficits (at protein level).
Interacts with STAT3. Enhances STAT3 activity by keeping it in the nucleus (By similarity).
Transcription factor that promotes adipocyte differentiation and suppresses osteoblast differentiation in the bone marrow. Enhances the osteoclast-supporting ability of stromal cells. Binds with STAT3 the consensus sequence 5'-CTTCTGGGAAGA-3' of the acute phase response element (APRE). Transactivates several promoters including FOS, OSM and PPARG. Recruits a histone deacetylase complex (By similarity).
Expressed in fetal tissues, including in brain, intestine, lung, kidney and muscle (PubMed:23623388). Isoform 1 is expressed in numerous fetal brain regions. Isoform 3 is highly expressed in numerous fetal brain regions and spinal cord (PubMed:26056227).
Plays a role in interneurons differentiation (PubMed:26056227). Involved in neuronal development and in neuromuscular junction formation.
DNA helicase that modulates androgen receptor (AR)-dependent transactivation in a promoter-dependent manner. Not able to remodel mononucleosomes in vitro (By similarity).
Enzyme activity is enhanced by dsDNA (double-stranded DNA) and ssDNA (single-stranded DNA).
Interacts with AR via its N-terminus. Interacts with DYRK1A. Binds DNA and mononucleosomes, but does not seem to form large multiprotein complexes (By similarity).
Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs are known to be important for the association with nuclear receptors.
Transcriptional repressor. Binds DNA on N-box motifs: 5'-CACNAG-3' (By similarity).
May be involved in the regulation of cell cycle progression (By similarity). Exhibits H3K4me3-binding activity (PubMed:29061846).
Kinesin is a microtubule-associated force-producing protein that may play a role in organelle transport. Plays a role during spermiogenesis in the development of the sperm tail midpiece and in the normal function of spermatozoa (By similarity). May play a role in the formation of the mitochondrial sheath formation in the developing spermatid midpiece (By similarity).
Oligomer composed of two heavy chains and two light chains. Associates with microtubulin in an ATP-dependent manner. Interacts with KIF5C. Interacts with ODF1 (By similarity). Interacts with LRGUK (By similarity). Interacts with VDAC2 (By similarity).
The heptad repeat (HR) motif is sufficient for interaction with kinesin heavy (KHL) chains and ODF1. The TPR region is involved in mitochondrial binding (By similarity).
Activity is increased by binding phosphatidylinositol phosphates, especially phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 4,5-bisphosphate (PubMed:17052953). Inactivated at 37 degrees Celsius by (13S)-hydroperoxy-(9Z,11E)-octadecadienoate (PubMed:8334154).
Detected in monocytes and eosinophils (at protein level). Expressed in airway epithelial cells.
Disease susceptibility may be associated with variants affecting the gene represented in this entry. Met at position 560 may confer interindividual susceptibility to coronary artery disease (CAD) (PubMed:17959182).
Interacts with PEBP1; in response to IL13/interleukin-13, prevents the interaction of PEBP1 with RAF1 to activate the ERK signaling cascade.
Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids generating a spectrum of bioactive lipid mediators (PubMed:1944593, PubMed:8334154, PubMed:17052953, PubMed:24282679, PubMed:25293588, PubMed:32404334). It inserts peroxyl groups at C12 or C15 of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) producing both 12-hydroperoxyeicosatetraenoate/12-HPETE and 15-hydroperoxyeicosatetraenoate/15-HPETE (PubMed:1944593, PubMed:8334154, PubMed:17052953, PubMed:24282679). It may then act on 12-HPETE to produce hepoxilins, which may show pro-inflammatory properties (By similarity). Can also peroxidize linoleate ((9Z,12Z)-octadecadienoate) to 13-hydroperoxyoctadecadienoate/13-HPODE (PubMed:8334154). May participate in the sequential oxidations of DHA ((4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate) to generate specialized pro-resolving mediators (SPMs)like resolvin D5 ((7S,17S)-diHPDHA) and (7S,14S)-diHPDHA, that actively down-regulate the immune response and have anti-aggregation properties with platelets (PubMed:32404334). Can convert epoxy fatty acids to hydroperoxy-epoxides derivatives followed by an intramolecular nucleophilic substitution leading to the formation of monocyclic endoperoxides (PubMed:25293588). Plays an important role during the maintenance of self-tolerance by peroxidizing membrane-bound phosphatidylethanolamine which can then signal the sorting process for clearance of apoptotic cells during inflammation and prevent an autoimmune response. In addition to its role in the immune and inflammatory responses, this enzyme may play a role in epithelial wound healing in the cornea through production of lipoxin A4 (LXA(4)) and docosahexaenoic acid-derived neuroprotectin D1 (NPD1; 10R,17S-HDHA), both lipid autacoids exhibit anti-inflammatory and neuroprotective properties. Furthermore, it may regulate actin polymerization which is crucial for several biological processes such as the phagocytosis of apoptotic cells. It is also implicated in the generation of endogenous ligands for peroxisome proliferator activated receptor (PPAR-gamma), hence modulating macrophage development and function. It may also exert a negative effect on skeletal development by regulating bone mass through this pathway. As well as participates in ER stress and downstream inflammation in adipocytes, pancreatic islets, and liver (By similarity). Finally, it is also involved in the cellular response to IL13/interleukin-13 (PubMed:21831839).
The PLAT domain can bind calcium ions; this promotes association with membranes.
Catalyzes the hydrolysis of triglycerides and phospholipids present in circulating plasma lipoproteins, including chylomicrons, intermediate density lipoproteins (IDL), low density lipoproteins (LDL) of large size and high density lipoproteins (HDL), releasing free fatty acids (FFA) and smaller lipoprotein particles (PubMed:7592706, PubMed:8798474, PubMed:12032167, PubMed:26193433). Also exhibits lysophospholipase activity (By similarity). Can hydrolyze both neutral lipid and phospholipid substrates but shows a greater binding affinity for neutral lipid substrates than phospholipid substrates (By similarity). In native LDL, preferentially hydrolyzes the phosphatidylcholine species containing polyunsaturated fatty acids at sn-2 position (PubMed:26193433).
Genetic variations in LIPC are associated with susceptibility to type 2 diabetes mellitus (T2D) [MIM:125853].
Genetic variations in LIPC define the high density lipoprotein cholesterol level quantitative trait locus 12 (HDLCQ12) [MIM:612797].
Phospholipase A1 and triacylglycerol lipase are inhibited by sphingomyelin.
Protein phosphatase which regulates actin filament dynamics. Dephosphorylates and activates the actin binding/depolymerizing factor cofilin, which subsequently binds to actin filaments and stimulates their disassembly. Inhibitory phosphorylation of cofilin is mediated by LIMK1, which may also be dephosphorylated and inactivated by this protein (PubMed:11832213). Required for spermatogenesis (By similarity). Involved in acrosome biogenesis, probably by regulating cofilin-mediated actin cytoskeleton remodeling during proacrosomal vesicle fusion and/or Golgi to perinuclear vesicle trafficking (By similarity).
Belongs to the sauvagine/corticotropin-releasing factor/urotensin I family.
Hormone regulating the release of corticotropin from pituitary gland (By similarity). Induces NLRP6 in intestinal epithelial cells, hence may influence gut microbiota profile (By similarity).
Interacts (via C-terminus) with CRFR1 (via N-terminal extracellular domain).
Produced by the hypothalamus and placenta.
Belongs to the mitochondrion-specific ribosomal protein mL41 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (PubMed:11551941, PubMed:25278503, PubMed:25838379). Interacts with BCL2 (PubMed:15547950).
Component of the mitochondrial ribosome large subunit (PubMed:28892042, PubMed:25838379, PubMed:25278503). Also involved in apoptosis and cell cycle (PubMed:16024796, PubMed:16256947). Enhances p53/TP53 stability, thereby contributing to p53/TP53-induced apoptosis in response to growth-inhibitory condition. Enhances p53/TP53 translocation to the mitochondria. Has the ability to arrest the cell cycle at the G1 phase, possibly by stabilizing the CDKN1A and CDKN1B (p27Kip1) proteins (PubMed:16024796).
Present in kidney, liver, thymus and testis, and at lower level in brain and spleen (at protein level).
Belongs to the uracil-DNA glycosylase (UDG) superfamily. TDG/mug family.
DNA glycosylase that plays a key role in active DNA demethylation: specifically recognizes and binds 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) in the context of CpG sites and mediates their excision through base-excision repair (BER) to install an unmethylated cytosine. Cannot remove 5-hydroxymethylcytosine (5hmC). According to an alternative model, involved in DNA demethylation by mediating DNA glycolase activity toward 5-hydroxymethyluracil (5hmU) produced by deamination of 5hmC. Also involved in DNA repair by acting as a thymine-DNA glycosylase that mediates correction of G/T mispairs to G/C pairs: in the DNA of higher eukaryotes, hydrolytic deamination of 5-methylcytosine to thymine leads to the formation of G/T mismatches. Its role in the repair of canonical base damage is however minor compared to its role in DNA demethylation. It is capable of hydrolyzing the carbon-nitrogen bond between the sugar-phosphate backbone of the DNA and a mispaired thymine. In addition to the G/T, it can remove thymine also from C/T and T/T mispairs in the order G/T >> C/T > T/T. It has no detectable activity on apyrimidinic sites and does not catalyze the removal of thymine from A/T pairs or from single-stranded DNA. It can also remove uracil and 5-bromouracil from mispairs with guanine.
Homodimer. Interacts with AICDA and GADD45A.
Sumoylation on Lys-330 by either SUMO1 or SUMO2 induces dissociation of the product DNA.
Based on a readthrough transcript which may produce a EPPIN-WFDC6 fusion protein.
In testis, expressed and secreted by Sertoli cells, appearing on the surface of testicular and ejaculate spermatozoa. Expressed in the spermatogonia and the earliest preleptotene spermatocytes. In the epididymis, is expressed and secreted by epithelial cells and covers the surface of epididymal spermatozoa and ciliated epithelial cells (at protein level). Expressed specifically in epididymis and testis. Isoform 2 is expressed only in the epididymis. Weak expression is detected in myoid cells as well as spermatogenic cells.
Might be used as a target for male contraception.
Monomer. Homodimer. Homomultimers. Interacts with SEMG1 (via 164-283 AA). Interacts with LTF. Found in a complex with LTF, CLU, EPPIN and SEMG1.
Serine protease inhibitor that plays an essential role in male reproduction and fertility. Modulates the hydrolysis of SEMG1 by KLK3/PSA (a serine protease), provides antimicrobial protection for spermatozoa in the ejaculate coagulum, and binds SEMG1 thereby inhibiting sperm motility.
The BPTI/Kunitz inhibitor domain is required for elastase inhibitory activity. BPTI/Kunitz inhibitor and WAP domains are involved in the protein antibacterial activity.
Detected in lung vascular smooth muscle (at protein level) (PubMed:27144530). Detected in thyroid and extraocular smooth muscle, but not skeletal muscle (PubMed:2026759). Detected in heart, aorta, skeletal muscle, colon, urinary bladder, uterus, stomach, and small intestine (PubMed:11318603).
Required for proper contractility of visceral smooth muscle cells (PubMed:28292896). Mediates nucleation of actin filaments.
Acts as a proto-oncogene via its ability to monoubiquinate 'Lys-119' of histone H2A (H2AK119Ub): overexpressed in a number of breast cancers and promotes transformation of cells by mediating silencing of tumor suppressor genes (PubMed:25470042).
Associates with the PRC2/EED-EZH2 complex.
E3 ubiquitin-protein ligase required to prevent centriole reduplication (PubMed:15885686, PubMed:23769972). Probably acts by ubiquitinating positive regulators of centriole reduplication (PubMed:23769972). Mediates monoubiquitination of 'Lys-119' of histone H2A (H2AK119Ub), a specific tag for epigenetic transcriptional repression: associates with some Polycomb group (PcG) multiprotein PRC2-like complex and mediates repression of target genes (PubMed:25470042). Also acts as a positive regulator of peroxisome import by mediating monoubiquitination of PEX5 at 'Lys-472': monoubiquitination promotes PEX5 stabilitation by preventing its polyubiquitination and degradation by the proteasome (PubMed:28724525). Has anti-HIV activity (PubMed:24317724).
Overexpressed in a number of breast cancer cell lines.
Ubiquitous (PubMed:10888877). Highly expressed in testis, while it is weakly expressed in other tissues (PubMed:16310976).
Belongs to the squalene monooxygenase family.
Catalyzes the stereospecific oxidation of squalene to (S)-2,3-epoxysqualene, and is considered to be a rate-limiting enzyme in steroid biosynthesis.
Inhibited by NB-598 ((E)N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bi-thiophen-5-yl)methoxy]benzene-methanamine). Contrary to fungal enzymes, the mammalian enzyme is only slightly inhibited by terbinafine (PubMed:30626872). Inhibited by tellurite, tellurium dioxide, selenite, and selenium dioxide (PubMed:10666321).
Interacts (via N-terminal domain) with MARCHF6. Interacts with SMIM22; this interaction modulates lipid droplet formation (PubMed:29765154).
The C-terminal hydrophobic region contains two helices that mediate interaction with membranes. Contrary to predictions, this region does not contain transmembrane helices.
The N-terminal region mediates interaction with MARCHF6, leading to SQLE ubiquitination and proteasomal degradation when cholosterol levels are high (PubMed:24449766, PubMed:26434806, PubMed:28972164). The first part of the N-terminal region contains a hydrophobic region that inserts into the membrane; contrary to predictions, there are no transmembrane helices (PubMed:26434806). The second part contains a region that can form an amphipathic region that associates with membranes. This region is ejected from the membrane by high cholesterol levels and becomes disordered in an aqueous environment. This is critical for cholesterol-dependent proteasomal degradation. Additional parts of the N-terminal region are predicted to be disordered and contribute to flagging the protein for proteasomal degradation already under basal conditions (PubMed:28972164).
Ubiquitinated by MARCHF6 in response to high cholesterol levels in intracellular membranes, leading to proteasomal degradation.
Component of an histone acetyltransferase complex.
Component of an histone acetyltransferase complex. Interacts with H3K4me3 and to a lesser extent with H3K4me2.
Cooperates with p53/TP53 in the negative regulatory pathway of cell growth by modulating p53-dependent transcriptional activation. Implicated as a tumor suppressor gene.
Interacts with H3K4me3 and to a lesser extent with H3K4me2. Interacts with TP53. Isoform 2 interacts with RSL1D1.
Isoform 2 was expressed in all normal tissues and cells examined, as well as in all breast cancer and melanoma cell lines examined. Isoform 3 was expressed in testis, liver, and kidney, weakly expressed in colon and brain and not expressed in breast and cultured melanocytes. Isoform 4 was highly expressed in testis and weakly expressed in brain, but not expressed in breast, colon, kidney, melanocytes, breast cancer or melanoma cell lines.
The polybasic region (PBR) is responsive to the binding to phosphoinositides (PtdInsPs), including phosphatidylinositol 5-phosphate (PtdIns(5)P).
Associates with the cytoplasmic CCR4-NOT deadenylase and RNA exosome complexes to trigger ARE-containing mRNA deadenylation and decay processes (PubMed:15687258, PubMed:18326031, PubMed:25106868). Interacts with CNOT1 (PubMed:25106868). Interacts (via N-terminus) with CNOT6 (PubMed:15687258, PubMed:18326031). Interacts with CNOT7; this interaction is inhibited in response to phorbol 12-myristate 13-acetate (PMA) treatment in a p38 MAPK-dependent manner (PubMed:25106868). Interacts with DCP1A (PubMed:15687258). Interacts (via N-terminus) with DCP2 (PubMed:15687258, PubMed:18326031). Interacts (via N-terminus) with EXOSC2 (PubMed:15687258, PubMed:18326031). Interacts with XRN1 (PubMed:15687258). Interacts (via phosphorylated form) with YWHAB; this interaction occurs in a protein kinase AKT1-dependent manner (PubMed:15538381, PubMed:17030608, PubMed:18326031). Interacts (via phosphorylated form) with YWHAZ; this interaction occurs in a p38 MAPK- and AKT-signaling pathways (By similarity).
Down-regulated under hypoxic conditions in endothelial cells (at protein level) (PubMed:21832157). Up-regulated by growth factor (TGF-beta), cytokines, tumor necrosis factor (TNF-alpha) and epidermal growth factor (EGF) in keratinocytes (PubMed:20166898). Up-regulated also by glucocorticoid dexamethasone in keratinocytes (PubMed:20166898). Up-regulated in keratinocytes in response to wounding in a p38 MAPK-dependent manner (PubMed:20166898, PubMed:27182009). Up-regulated by the parathyroid hormone (PTH) in osteoblast-like cells in a cAMP/PKA-dependent manner (PubMed:15465005, PubMed:19179481). Up-regulated in response to adrenocorticotropic hormone (ACTH) (PubMed:19179481). Up-regulated during monocyte/macrophage differentiation in response to phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) (PubMed:26542173). Down-regulated by butyrate in colorectal cancer cells (PubMed:10367403).
Expressed mainly in the basal epidermal layer, weakly in the suprabasal epidermal layers (PubMed:27182009). Expressed in epidermal keratinocytes (at protein level) (PubMed:27182009). Expressed in osteoblasts (PubMed:15465005).
Phosphorylated (PubMed:19179481). Phosphorylated by RPS6KA1 at Ser-334 upon phorbol 12-myristate 13-acetate (PMA) treatment; this phosphorylation results in dissociation of the CCR4-NOT deadenylase complex and induces p38 MAPK-mediated stabilization of the low-density lipoprotein receptor LDLR mRNA (PubMed:25106868). Phosphorylated by protein kinase AKT1 at Ser-92 and Ser-203 in response to insulin; these phosphorylations stabilize ZFP36L1, increase the association with 14-3-3 proteins and mediate ARE-containing mRNA stabilization (PubMed:15538381, PubMed:17030608). AKT1-mediated phosphorylation at Ser-92 does not impair ARE-containing RNA-binding (PubMed:15538381). Phosphorylated at Ser-54, Ser-92 and Ser-203 by MAPKAPK2; these phosphorylations increase the association with 14-3-3 proteins and mediate ARE-containing mRNA stabilization in a protein kinase AKT1-independent manner (PubMed:18326031). MAPKAPK2-mediated phosphorylations at Ser-54, Ser-92 and Ser-203 do not impair ARE-containing RNA-binding (PubMed:18326031). Phosphorylations increase the association with 14-3-3 proteins and mediate ARE-containing mRNA stabilization during early adipogenesis in a p38 MAPK- and AKT-dependent manner (By similarity).
Ubiquitinated. Ubiquitination leads to proteasomal degradation, a process inhibited by phosphorylations at Ser-90, Ser-92 and Ser-203 (PubMed:17030608).
Zinc-finger RNA-binding protein that destabilizes several cytoplasmic AU-rich element (ARE)-containing mRNA transcripts by promoting their poly(A) tail removal or deadenylation, and hence provide a mechanism for attenuating protein synthesis (PubMed:12198173, PubMed:15538381, PubMed:15467755, PubMed:17030608, PubMed:19179481, PubMed:20702587, PubMed:24700863, PubMed:25106868, PubMed:25014217, PubMed:26542173). Acts as a 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery (PubMed:15687258). Functions by recruiting the CCR4-NOT deadenylase complex and components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs, and hence promotes ARE-mediated mRNA deadenylation and decay processes (PubMed:15687258, PubMed:18326031, PubMed:25106868). Induces also the degradation of ARE-containing mRNAs even in absence of poly(A) tail (By similarity). Binds to 3'-UTR ARE of numerous mRNAs (PubMed:12198173, PubMed:15538381, PubMed:15467755, PubMed:17030608, PubMed:19179481, PubMed:20702587, PubMed:24700863, PubMed:25106868, PubMed:25014217, PubMed:26542173). Positively regulates early adipogenesis by promoting ARE-mediated mRNA decay of immediate early genes (IEGs) (By similarity). Promotes ARE-mediated mRNA decay of mineralocorticoid receptor NR3C2 mRNA in response to hypertonic stress (PubMed:24700863). Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA (PubMed:20702587). Positively regulates monocyte/macrophage cell differentiation by promoting ARE-mediated mRNA decay of the cyclin-dependent kinase CDK6 mRNA (PubMed:26542173). Promotes degradation of ARE-containing pluripotency-associated mRNAs in embryonic stem cells (ESCs), such as NANOG, through a fibroblast growth factor (FGF)-induced MAPK-dependent signaling pathway, and hence attenuates ESC self-renewal and positively regulates mesendoderm differentiation (By similarity). May play a role in mediating pro-apoptotic effects in malignant B-cells by promoting ARE-mediated mRNA decay of BCL2 mRNA (PubMed:25014217). In association with ZFP36L2 maintains quiescence on developing B lymphocytes by promoting ARE-mediated decay of several mRNAs encoding cell cycle regulators that help B cells progress through the cell cycle, and hence ensuring accurate variable-diversity-joining (VDJ) recombination and functional immune cell formation (By similarity). Together with ZFP36L2 is also necessary for thymocyte development and prevention of T-cell acute lymphoblastic leukemia (T-ALL) transformation by promoting ARE-mediated mRNA decay of the oncogenic transcription factor NOTCH1 mRNA (By similarity). Participates in the delivery of target ARE-mRNAs to processing bodies (PBs) (PubMed:17369404). In addition to its cytosolic mRNA-decay function, plays a role in the regulation of nuclear mRNA 3'-end processing; modulates mRNA 3'-end maturation efficiency of the DLL4 mRNA through binding with an ARE embedded in a weak noncanonical polyadenylation (poly(A)) signal in endothelial cells (PubMed:21832157). Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion (PubMed:15967811). Plays a role in vasculogenesis and endocardial development (By similarity). Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis (PubMed:27182009). Plays a role in myoblast cell differentiation (By similarity).
High affinity receptor for urotensin-2 and urotensin-2B. The activity of this receptor is mediated by a G-protein that activate a phosphatidylinositol-calcium second messenger system.
Most abundant expression in the heart and pancreas.
Catalytic subunit of the heterodimeric RalGAP2 complex which acts as a GTPase activator for the Ras-like small GTPases RALA and RALB.
Component of the heterodimeric RalGAP2 complex with RALGAPB. Heterodimerization is required for activity (By similarity).
Electrogenic antiporter that exchanges one cationic monoamine with two intravesicular protons across the membrane of secretory and synaptic vesicles. Uses the electrochemical proton gradient established by the V-type proton-pump ATPase to accumulate high concentrations of monoamines inside the vesicles prior to their release via exocytosis. Transports catecholamines and indolamines with higher affinity for serotonin (PubMed:23337945, PubMed:8643547, PubMed:16326835). Regulates the transvesicular monoaminergic gradient that determines the quantal size. Mediates presynaptic monoaminergic vesicle transport in the amygdala and prefrontal brain regions related with emotion processing in response to environmental stimuli (PubMed:23337945).
Expressed primarily in neuroendocrine tissues. Highly expressed in chromaffin cells of the adrenal medulla (at protein level). Detected in peripheral sympathetic ganglia (at protein level). Found in some paracrine cells in stomach and duodenum (at protein level) (PubMed:8643547). Expressed in substantia nigra (PubMed:23337945).
Strongly inhibited by reserpine. Also inhibited to a lesser extent by ketanserin and fenfluramine. Not significantly inhibited by tetrabenazine.
Catalyzes the NADPH-dependent reduction of 1,5-anhydro-D-fructose (AF) to 1,5-anhydro-D-glucitol (By similarity). Has low NADPH-dependent reductase activity towards 9,10-phenanthrenequinone (in vitro) (PubMed:12604216, PubMed:15118078).
Inhibited by p-chloromercuribenzoic acid and alkyliodines.
Specifically expressed in testis (PubMed:12604216, PubMed:15118078). Expressed in testicular germ cells and testis interstitial cells (PubMed:15118078).
Ligand-gated ion channel with relatively high calcium permeability. Binding to ATP mediates synaptic transmission between neurons and from neurons to smooth muscle. Seems to be linked to apoptosis, by increasing the intracellular concentration of calcium in the presence of ATP, leading to programmed cell death (By similarity).
Core component of box C/D small nucleolar ribonucleoprotein (snoRNP) particles; the core proteins SNU13, NOP56, NOP58 and FBL assemble stepwise onto the snoRNA. Interacts with NOLC1/Nopp140. Interacts with NOPCHAP1, NUFIP1, RUVBL1 and RUVBL2; NOPCHAP1 bridges the association of NOP58 with RUVBL1:RUVBL2 and NUFIP1 (PubMed:33367824). Interacts with PIH1D1 (PubMed:17636026). Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797).
Required for 60S ribosomal subunit biogenesis. Core component of box C/D small nucleolar ribonucleoprotein (snoRNP) particles. Required for the biogenesis of box C/D snoRNAs such as U3, U8 and U14 snoRNAs. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Sumoylation is essential for high-affinity binding to snoRNAs.
Interacts with FTSJ1; the interaction is direct, and required for 2'-O-methylation of position 34 in substrate tRNAs (PubMed:32558197, PubMed:33771871). Interacts with IRS4 (By similarity). Interacts with STK11/LKB1 (PubMed:17216128).
Together with methyltransferase FTSJ1, methylates the 2'-O-ribose of nucleotides at position 34 of the tRNA anticodon loop of substrate tRNAs (PubMed:32558197, PubMed:33771871). Required for the correct positioning of the substrate tRNA for methylation (PubMed:32558197). Required to suppress amino acid starvation-induced autophagy (PubMed:22354037). Enhances the STK11/LKB1-induced cell growth suppression activity (PubMed:17216128).
May participate in the nuclear signaling of EGFR and MAPK1/ERK2. May a have a role in metastasis.
Protein kinase activity is reported (PubMed:24735981). However, no protein kinase domain is detected by any prediction method (PROSITE, Pfam). Its enzyme activity is therefore unsure.
Belongs to the TFIIF alpha subunit family.
Heterodimer of an alpha and a beta subunit. Interacts with GTF2F2, CTDP1, TAF6/TAFII80 and URI1. Interacts with GTF2B (via C-terminus and preferentially via acetylated form); this interaction prevents binding of GTF2B to GTF2F2 (PubMed:8662660, PubMed:12931194).
Phosphorylated on Ser and other residues by TAF1 and casein kinase II-like kinases.
TFIIF is a general transcription initiation factor that binds to RNA polymerase II and helps to recruit it to the initiation complex in collaboration with TFIIB. It promotes transcription elongation.
Was reported to have a protein kinase activity and to autophosphorylates on Ser-385 and Thr-389.
Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.
Neuron-specific, localized primarily within limbic regions of the brain.
Acts either as the functional imidazoline-1 receptor (I1R) candidate or as a membrane-associated mediator of the I1R signaling. Binds numerous imidazoline ligands that induces initiation of cell-signaling cascades triggering to cell survival, growth and migration. Its activation by the agonist rilmenidine induces an increase in phosphorylation of mitogen-activated protein kinases MAPK1 and MAPK3 in rostral ventrolateral medulla (RVLM) neurons that exhibited rilmenidine-evoked hypotension (By similarity). Blocking its activation with efaroxan abolished rilmenidine-induced mitogen-activated protein kinase phosphorylation in RVLM neurons (By similarity). Acts as a modulator of Rac-regulated signal transduction pathways (By similarity). Suppresses Rac1-stimulated cell migration by interacting with PAK1 and inhibiting its kinase activity (By similarity). Also blocks Pak-independent Rac signaling by interacting with RAC1 and inhibiting Rac1-stimulated NF-kB response element and cyclin D1 promoter activation (By similarity). Inhibits also LIMK1 kinase activity by reducing LIMK1 'Tyr-508' phosphorylation (By similarity). Inhibits Rac-induced cell migration and invasion in breast and colon epithelial cells (By similarity). Inhibits lamellipodia formation, when overexpressed (By similarity). Plays a role in protection against apoptosis. Involved in association with IRS4 in the enhancement of insulin activation of MAPK1 and MAPK3. When overexpressed, induces a redistribution of cell surface ITGA5 integrin to intracellular endosomal structures.
Both the presence of the PX domain and the coiled coil region are necessary for its endosomal targeting.
Homooligomer. Interacts with GRB2. Interacts with PIK3R1; probably associates with the PI3-kinase complex. Interacts with IRS4. Found in a complex with ITGA5 and PAK1. Found in a complex with LIMK1 and PAK1. Interacts with ITGA5 (via cytoplasmic domain); this interaction is direct. Interacts with PAK1 (via kinase domain); this interaction is direct and is increased upon activation of PAK1 (By similarity). Interacts with LIMK1 (via PDZ and kinase domain); this interaction is direct (By similarity). Interacts with LIMK2; this interaction depends on LIMK2 activity (By similarity). Interacts with RAC1 (activated state) (By similarity). Interacts with STK11; this interaction may increase STK11 activity.
Isoform 1, isoform 3 and isoform 4 are expressed in brain. Isoform 1 is expressed in endocrine tissues.
Has histone acetyltransferase activity, with a preference for histone H4.
Testis-specific. Detected in spermatids (at protein level).
May play a role in protection against oxidative stress. Overexpression leads to reduced levels of oxidant-induced DNA damage and apoptosis.
Up-regulated in cells which display transient adaptation to mild oxidative stress by treatment with diethylmaleate, a glutathione-depleting agent. Also induced by retinoic acid.
Belongs to the DNA photolyase class-1 family.
Binds 1 5,10-methenyltetrahydrofolate (MTHF) non-covalently per subunit.
Binds 1 FAD per subunit. Only a minority of the protein molecules contain bound FAD. Contrary to the situation in photolyases, the FAD is bound in a shallow, surface-exposed pocket.
Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins (By similarity). Interacts directly with TIMELESS (By similarity). Interacts directly with PER1 and PER3 (By similarity). Interacts directly with PER2; interaction with PER2 inhibits its ubiquitination and vice versa (PubMed:21613214). Interacts with FBXL21 (By similarity). Interacts with FBXL3 (PubMed:17463251). Interacts with PPP5C (via TPR repeats) (PubMed:16790549). Interacts with CLOCK-BMAL1 independently of PER2 and DNA (PubMed:28388406). Interacts with HDAC1, HDAC2 and SIN3B. Interacts with nuclear receptors AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction with at least NR3C1/GR is ligand dependent (PubMed:22170608). Interacts with PRKDC (By similarity). Interacts with the G protein subunit alpha GNAS; the interaction may block GPCR-mediated regulation of cAMP concentrations (PubMed:20852621). Interacts with PRMT5 (PubMed:23133559). Interacts with EZH2 (By similarity). Interacts with MYBBP1A, DOCK7, HNRNPU, RPL7A, RPL8 and RPS3 (By similarity). Interacts with MAP1LC3B (By similarity). Interacts with CLOCK (By similarity). Interacts with BMAL1 (By similarity). Interacts weakly with HDAC3; this interaction is enhanced in the presence of FBXL3 (By similarity). Interacts with TRIM28, KCTD5 and DDB1 (By similarity). Interacts with FOXO1 (By similarity). Interacts with DTL and DDB1-CUL4A complex (PubMed:26431207). Interacts with HNF4A (PubMed:30530698). Interacts with PSMD2 in a KDM8-dependent manner (By similarity). Interacts with KDM8 in a FBXL3-dependent manner (By similarity). Interacts with PPARG in a ligand-dependent manner (By similarity). Interacts with PPARD (via domain NR LBD) and NR1I2 (via domain NR LBD) in a ligand-dependent manner (By similarity). Interacts with PPARA, NR1I3 and VDR (By similarity).
Disease susceptibility is associated with variants affecting the gene represented in this entry. An adenine-to-cytosine transversion within the 5'splice site following exon 11 has been found in multiple members of a DSPD family and segregates with the disorder with autosomal dominant inheritance pattern. This variant is predicted to cause exon 11 skipping and in-frame deletion of 24 residues in the C-terminal region of CRY1. Functional studies show that the mutated protein acts as a more potent transcriptional repressor than wild-type, causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms.
Expression is regulated by light and circadian rhythms and osicllates diurnally. Peak expression in the suprachiasma nucleus (SCN) and eye at the day/night transition (CT12). Levels decrease with BMAL1-CLOCK inhibition as part of the autoregulatory feedback loop.
KL001 (N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-N-(2-furanylmethyl)-methanesulfonamide) binds to CRY1 and stabilizes it by inhibiting FBXL3- and ubiquitin-dependent degradation of CRY1 resulting in lengthening of the circadian periods.
Phosphorylation on Ser-247 by MAPK is important for the inhibition of CLOCK-BMAL1-mediated transcriptional activity. Phosphorylation by CSNK1E requires interaction with PER1 or PER2. Phosphorylation at Ser-71 and Ser-280 by AMPK decreases protein stability. Phosphorylation at Ser-568 exhibits a robust circadian rhythm with a peak at CT8, increases protein stability, prevents SCF(FBXL3)-mediated degradation and is antagonized by interaction with PRKDC.
The LIR motifs (LC3-interacting region) 3 and 5 are required for its interaction with MAP1LC3B and for its autophagy-mediated degradation.
Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. CRY1 and CRY2 have redundant functions but also differential and selective contributions at least in defining the pace of the SCN circadian clock and its circadian transcriptional outputs. More potent transcriptional repressor in cerebellum and liver than CRY2, though more effective in lengthening the period of the SCN oscillator. On its side, CRY2 seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY2, is dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. Interacts with CLOCK-BMAL1 independently of PER proteins and is found at CLOCK-BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK-BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1. Represses the CLOCK-BMAL1 induced transcription of ATF4, MTA1, KLF10 and NAMPT (By similarity). May repress circadian target genes expression in collaboration with HDAC1 and HDAC2 through histone deacetylation. Mediates the clock-control activation of ATR and modulates ATR-mediated DNA damage checkpoint. In liver, mediates circadian regulation of cAMP signaling and gluconeogenesis by binding to membrane-coupled G proteins and blocking glucagon-mediated increases in intracellular cAMP concentrations and CREB1 phosphorylation. Inhibits hepatic gluconeogenesis by decreasing nuclear FOXO1 levels that down-regulates gluconeogenic gene expression (By similarity). Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Plays a key role in glucose and lipid metabolism modulation, in part, through the transcriptional regulation of genes involved in these pathways, such as LEP or ACSL4 (By similarity). Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (By similarity). Plays an essential role in the generation of circadian rhythms in the retina (By similarity). Represses the transcriptional activity of NR1I2 (By similarity).
Ubiquitinated by the SCF(FBXL3) and SCF(FBXL21) complexes, regulating the balance between degradation and stabilization. The SCF(FBXL3) complex is mainly nuclear and mediates ubiquitination and subsequent degradation of CRY1. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY1 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. Ubiquitination at Lys-11 and Lys-107 are specifically ubiquitinated by the SCF(FBXL21) complex but not by the SCF(FBXL3) complex. Ubiquitination may be inhibited by PER2 (PubMed:17463251, PubMed:22798407, PubMed:27565346). Deubiquitinated by USP7 (By similarity).
Undergoes autophagy-mediated degradation in the liver in a time-dependent manner. Autophagic degradation of CRY1 (an inhibitor of gluconeogenesis) occurs during periods of reduced feeding allowing induction of gluconeogenesis and maintenance of blood glucose levels.
Interacts with ITCH and WWP1 (PubMed:19580544). Interacts (via MIT domain) with IST1; leading to the recruitment of SPART to midbodies (PubMed:20719964).
May be implicated in endosomal trafficking, or microtubule dynamics, or both. Participates in cytokinesis (PubMed:20719964).
Ubiquitinated; ubiquitination does not require ITCH and WWP1.
Ubiquitously expressed, with highest levels of expression detected in adipose tissue.
Expressed almost exclusively in embryonic and adult liver, and at lower levels in the kidney (PubMed:11342143, PubMed:11414754). Expressed at lower levels in adult muscle and pancreas (PubMed:11414754). Detected in fetal blood vessels (PubMed:16148032). Expressed in syncytiotrophoblas of placenta during first trimester and at term (PubMed:19015196, PubMed:16148032). Highly expressed in first trimester placenta compared to term placenta (PubMed:19015196).
Symporter that cotransports neutral amino acids and sodium ions from the extraccellular to the intracellular side of the cell membrane (PubMed:11342143, PubMed:19015196, PubMed:33928121). The transport is electrogenic, pH dependent and partially tolerates substitution of Na(+) by Li(+) (PubMed:11414754). Preferentially transports smaller amino acids, such as glycine, L-alanine, L-serine, L-asparagine and L-threonine, followed by L-cysteine, L-histidine, L-proline and L-glutamine and L-methionine (PubMed:11414754, PubMed:33928121).
The disulfide bond plays an important role in substrate transport, but has no effect on trafficking to the cell surface.
There is a disagreement about sodium-independent transport of cationic amino acids, such as L-arginine and L-lysine. While Hatanaka et al (PubMed:11342143) shown that SLC38A4 may mediate sodium-independent transport of cationic amino acids, such as L-arginine and L-lysine (PubMed:11342143). Recent studies by Fairweather et al (PubMed:33928121), using quantitative LC-MS analysis, shown any transport activity of cationic amino acids, such as L-arginine and L-lysine (PubMed:33928121).
As a member of the cohesin complex, involved in sister chromatid cohesion from the time of DNA replication in S phase to their segregation in mitosis, a function that is essential for proper chromosome segregation, post-replicative DNA repair, and the prevention of inappropriate recombination between repetitive regions (PubMed:11509732). The cohesin complex may also play a role in spindle pole assembly during mitosis (PubMed:11590136). In interphase, cohesins may function in the control of gene expression by binding to numerous sites within the genome (By similarity). May control RUNX1 gene expression (Probable). Binds to and represses APOB gene promoter (PubMed:25575569). May play a role in embryonic gut development, possibly through the regulation of enteric neuron development (By similarity).
Cleaved by separase/ESPL1 at the onset of anaphase; this cleavage is required for sister chromatid separation and cytokinesis (PubMed:11509732). Cleaved by caspase-3/CASP3 or caspase-7/CASP7 at the beginning of apoptosis (PubMed:12417729, PubMed:11875078).
Component of the cohesin complex, which consists of an SMC1A/B and SMC3 heterodimer core and 2 non-Smc subunits RAD21 and STAG1/SA1, STAG2/SA2 or STAG3/SA3 (PubMed:10931856, PubMed:11590136, PubMed:22628566, PubMed:25575569, PubMed:32409525). Interacts (via C-terminus) with SMC1A and (via N-terminus) with SMC3; these interactions are direct (PubMed:12198550, PubMed:32409525). The cohesin complex interacts with NUMA1 (PubMed:11590136). The cohesin complex also interacts with CDCA5, PDS5A and PDS5B; this interaction might regulate the ability of the cohesin complex to mediate sister chromatid cohesion (PubMed:15837422). The interaction with PDS5B is direct and is stimulated by STAG1/SA1 (PubMed:19696148). The cohesin complex interacts with the cohesin loading complex subunits NIPBL/Scc2 (via HEAT repeats) and MAU2/Scc4 (PubMed:22628566). NIPBL directly contacts all members of the complex, RAD21, SMC1A/B, SMC3 and STAG1 (PubMed:32409525). The cohesin complex interacts with DDX11/ChIR1 (PubMed:17105772). Directly interacts with WAPL; this interaction is stimulated by STAG1/SA1 (PubMed:19696148). Interacts with the ISWI chromatin remodeling complex component SMARCA5/SNF2h; the interaction is direct (PubMed:12198550). Interacts with the NuRD complex component CHD4; the interaction is direct (PubMed:12198550).
Expressed in the gut (at protein level).
Phosphorylated; becomes hyperphosphorylated in M phase of cell cycle. The large dissociation of cohesin from chromosome arms during prophase may be partly due to its phosphorylation by PLK1.
Regulated in a cell cycle-dependent manner: expression increases in late S phase and reaches maximum in G2 at the nucleotide level (PubMed:8812457). Not regulated during the cell cycle (at protein level) (PubMed:11073952).
The C-terminal part associates with the ATPase head of SMC1A, while the N-terminal part binds to the ATPase head of SMC3.
Highly expressed in skeletal muscle and testis. Expressed to a lesser degree in heart, prostate, and adrenal gland.
Interacts with the nuclear receptors NR3C1 and AR in the presence of ligand. Interacts with DDB1, CUL4A and CUL4B.
Ligand-dependent coactivator of nuclear receptors. Enhance transcriptional activity of the nuclear receptors NR3C1 and AR. May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex.
Binds to the KDR receptor but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth.
By hypoxia. Regulated by growth factors, cytokines, gonadotropins, nitric oxide, hypoglycemia and oncogenic mutations.
Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. Binds to the NRP1/neuropilin-1 receptor. Binding to NRP1 initiates a signaling pathway needed for motor neuron axon guidance and cell body migration, including for the caudal migration of facial motor neurons from rhombomere 4 to rhombomere 6 during embryonic development (By similarity). Also binds the DEAR/FBXW7-AS1 receptor (PubMed:17446437).
Higher expression in pituitary tumors than the pituitary gland.
Homodimer; disulfide-linked (By similarity). Also found as heterodimer with PGF (By similarity). Interacts with NRP1 (PubMed:26503042). Interacts with isoform 2 of BSG (PubMed:25825981).
Participates in the induction of key genes involved in the response to hypoxia and in the induction of angiogenesis such as HIF1A (PubMed:35455969). Involved in protecting cells from hypoxia-mediated cell death (By similarity).
Produced by alternative promoter usage and alternative initiation. Starts at an alternative upstream CUG codon.
Produced by use of an alternative upstream CUG codon and post-translationally processed into the N-terminal N-VEGF form and the C-terminal secreted VEGFA form.
Starts at an alternative upstream CUG codon.
Binding of the ligand triggers homo- and/or heterodimerization of the receptor triggering its autophosphorylation. Heterodimer with ERBB2 (PubMed:10805725). Forms a complex with CCDC88A/GIV (via SH2-like regions) and GNAI3 which leads to enhanced EGFR signaling and triggering of cell migration; binding to CCDC88A requires autophosphorylation of the EGFR C-terminal region, and ligand stimulation is required for recruitment of GNAI3 to the complex (PubMed:20462955, PubMed:25187647). Interacts with ERRFI1; inhibits dimerization of the kinase domain and autophosphorylation (PubMed:18046415). Part of a complex with ERBB2 and either PIK3C2A or PIK3C2B (PubMed:10805725). Interacts with GRB2; an adapter protein coupling the receptor to downstream signaling pathways. Interacts with GAB2; involved in signaling downstream of EGFR. Interacts with STAT3; mediates EGFR downstream signaling in cell proliferation. Interacts with RIPK1; involved in NF-kappa-B activation. Interacts (autophosphorylated) with CBL, CBLB and CBLC; involved in EGFR ubiquitination and regulation; interaction with CBL is reduced in the presence of tensin TNS4 (PubMed:23774213). Interacts with SOCS5; regulates EGFR degradation through ELOC- and ELOB-mediated ubiquitination and proteasomal degradation. Interacts with PRMT5; methylates EGFR and enhances interaction with PTPN6. Interacts (phosphorylated) with PTPN6; inhibits EGFR-dependent activation of MAPK/ERK. Interacts with COPG1; essential for regulation of EGF-dependent nuclear transport of EGFR by retrograde trafficking from the Golgi to the ER. Interacts with TNK2; this interaction is dependent on EGF stimulation and kinase activity of EGFR. Interacts with PCNA; positively regulates PCNA (PubMed:17115032). Interacts with PELP1. Interacts with MUC1. Interacts with AP2M1. Interacts with FER. May interact with EPS8; mediates EPS8 phosphorylation. Interacts (via SH2 domains) with GRB2, NCK1 and NCK2 (PubMed:10026169). Interacts with ATXN2. Interacts with GAREM1. Interacts (ubiquitinated) with ANKRD13A/B/D; the interaction is direct and may regulate EGFR internalization after EGF stimulation. Interacts with GPER1; the interaction occurs in an estrogen-dependent manner. Interacts (via C-terminal cytoplasmic kinase domain) with ZPR1 (via zinc fingers). Interacts with RNF115 and RNF126 (PubMed:23418353). Interacts with GPRC5A (via its transmembrane domain) (PubMed:25311788). Interacts with FAM83B; positively regulates EGFR inducing its autophosphorylation in absence of stimulation by EGF (PubMed:23912460). Interacts with LAPTM4B; positively correlates with EGFR activation (PubMed:28479384). Interacts with STX19 (PubMed:16420529). Interacts with CD44 (PubMed:23589287). Interacts with PGRMC1; the interaction requires PGRMC1 homodimerization (PubMed:26988023). Interacts with PIKFYVE (PubMed:17909029). Interacts with NEU3. Interacts with TRAF4 (PubMed:30352854). Interacts with the ant venom OMEGA-myrmeciitoxin(02)-Mg1a (By similarity).
Endocytosis and inhibition of the activated EGFR by phosphatases like PTPRJ and PTPRK constitute immediate regulatory mechanisms. Upon EGF-binding phosphorylates EPS15 that regulates EGFR endocytosis and activity. Moreover, inducible feedback inhibitors including LRIG1, SOCS4, SOCS5 and ERRFI1 constitute alternative regulatory mechanisms for the EGFR signaling. Up-regulated by NEU3-mediated desialylation of N-linked glycan at Asn-528.
Isoform 2 may act as an antagonist of EGF action.
Methylated. Methylation at Arg-1199 by PRMT5 stimulates phosphorylation at Tyr-1197.
Monoubiquitinated and polyubiquitinated upon EGF stimulation; which does not affect tyrosine kinase activity or signaling capacity but may play a role in lysosomal targeting (PubMed:27153536). Polyubiquitin linkage is mainly through 'Lys-63', but linkage through 'Lys-48', 'Lys-11' and 'Lys-29' also occurs. Deubiquitination by OTUD7B prevents degradation. Ubiquitinated by RNF115 and RNF126 (By similarity). Ubiquitinated by ZNRF1 or CBL at different lysines in response to EGF stimulation; leading to recruitment of the ESCRT machinery and subsequent degradation in the lysosomes (PubMed:33996800). Deubiquitinated by UCHL1 leading to the inhibition of its degradation (By similarity).
Palmitoylated on Cys residues by ZDHHC20. Palmitoylation inhibits internalization after ligand binding, and increases the persistence of tyrosine-phosphorylated EGFR at the cell membrane. Palmitoylation increases the amplitude and duration of EGFR signaling.
Phosphorylated on Tyr residues in response to EGF (PubMed:20462955, PubMed:27153536). Phosphorylation at Ser-695 is partial and occurs only if Thr-693 is phosphorylated. Phosphorylation at Thr-678 and Thr-693 by PRKD1 inhibits EGF-induced MAPK8/JNK1 activation. Dephosphorylation by PTPRJ prevents endocytosis and stabilizes the receptor at the plasma membrane. Autophosphorylation at Tyr-1197 is stimulated by methylation at Arg-1199 and enhances interaction with PTPN6. Autophosphorylation at Tyr-1092 and/or Tyr-1110 recruits STAT3. Dephosphorylated by PTPN1 and PTPN2.
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses (PubMed:2790960, PubMed:10805725, PubMed:27153536). Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF (PubMed:2790960, PubMed:7679104, PubMed:8144591, PubMed:9419975, PubMed:15611079, PubMed:12297049, PubMed:27153536, PubMed:20837704, PubMed:17909029). Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules (PubMed:27153536). May also activate the NF-kappa-B signaling cascade (PubMed:11116146). Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling (PubMed:11602604). Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin (PubMed:11483589). Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration (PubMed:20462955). Plays a role in enhancing learning and memory performance (By similarity). Plays a role in mammalian pain signaling (long-lasting hypersensitivity) (By similarity).
Ubiquitously expressed. Isoform 2 is also expressed in ovarian cancers.
E2-like enzyme involved in autophagy. Acts as an E2-like enzyme that catalyzes the conjugation of ATG12 to ATG5. ATG12 conjugation to ATG5 is required for autophagy. Likely serves as an ATG5-recognition molecule. Not involved in ATG12 conjugation to ATG3 (By similarity). Plays a role in adenovirus-mediated cell lysis.
Interacts with MAP1LC3A. By interacting with MAP1LC3A, it plays a role in the conjugation of ATG12 to ATG5. Also able to directly interact either with ATG5 or ATG7 (By similarity). Interacts with IRGM.
Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion. Functions as a floppase that translocates specifically phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane bilayer into the canaliculi of hepatocytes. Translocation of PC makes the biliary phospholipids available for extraction into the canaliculi lumen by bile salt mixed micelles and therefore protects the biliary tree from the detergent activity of bile salts (PubMed:7957936, PubMed:8898203, PubMed:9366571, PubMed:17523162, PubMed:23468132, PubMed:24806754, PubMed:24723470, PubMed:24594635, PubMed:21820390, PubMed:31873305). Plays a role in the recruitment of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and sphingomyelin (SM) molecules to nonraft membranes and to further enrichment of SM and cholesterol in raft membranes in hepatocytes (PubMed:23468132). Required for proper phospholipid bile formation (By similarity). Indirectly involved in cholesterol efflux activity from hepatocytes into the canalicular lumen in the presence of bile salts in an ATP-dependent manner (PubMed:24045840). Promotes biliary phospholipid secretion as canaliculi-containing vesicles from the canalicular plasma membrane (PubMed:9366571, PubMed:28012258). In cooperation with ATP8B1, functions to protect hepatocytes from the deleterious detergent activity of bile salts (PubMed:21820390). Does not confer multidrug resistance (By similarity).
May interact with RACK1 (PubMed:19674157). Interacts with HAX1 (By similarity).
Phosphorylated (PubMed:24723470). Phosphorylation on Thr-34 is required for PC efflux activity. Phosphorylation occurs on serine and threonine residues in a protein kinase A- or C-dependent manner (PubMed:24723470). May be phosphorylated on Thr-44 and Ser-49 (PubMed:24723470).
Translocation activity is inhibited by the ATPase inhibitor vanadate and the calcium channel blocker verapamil (PubMed:17523162, PubMed:23468132). Translocation activity is enhanced by the addition of the bile salt taurocholate (PubMed:17523162, PubMed:23468132).
Up-regulated by PPARA (PubMed:24122873). Up-regulated by compounds that cause peroxisome proliferation, such as fenofibrate (at protein level). Up-regulated by bezafibrate (PubMed:15258199). Up-regulated by compounds that cause peroxisome proliferation, such as fenofibrate, bezafibrate and gemfibrozil (PubMed:24122873).
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Catalyzes the covalent attachment of ISG15 to other proteins. Mediates the selective degradation of short-lived and abnormal proteins. In vitro also catalyzes 'Lys-48'-linked polyubiquitination.
ISGylation suppresses ubiquitin E2 enzyme activity.
The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:25043029). ANAPC16 associates with the rest of the complex independently of ANAPC2 and ANAPC11.
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1H subfamily.
Channel activity is strongly inhibited by mibefradil (PubMed:9670923, PubMed:9930755). Channel activity is strongly inhibited by Ni(2+) ions (PubMed:9930755).
Expressed in testis, primarily in the germ cells, but not in other portions of the reproductive tract, such as ductus deferens (PubMed:11751928). Expressed in the brain (PubMed:11751928).
Expressed in testis, primarily in the germ cells, but not in other portions of the reproductive tract, such as ductus deferens (PubMed:11751928). Not expressed in the brain (PubMed:11751928).
Expressed in the adrenal glomerulosa (at protein level) (PubMed:25907736, PubMed:27729216). In nonneuronal tissues, the highest expression levels are found in the kidney, liver, and heart. In the brain, most abundant in the amygdala, caudate nucleus, and putamen (PubMed:9670923, PubMed:9930755). In the heart, expressed in blood vessels.
In response to raising of intracellular calcium, the T-type channels are activated by CaM-kinase II.
Interacts (via N-terminal cytoplasmic domain) with STAC.
Voltage-sensitive calcium channel that gives rise to T-type calcium currents. T-type calcium channels belong to the 'low-voltage activated (LVA)' group. A particularity of this type of channel is an opening at quite negative potentials, and a voltage-dependent inactivation (PubMed:9670923, PubMed:9930755, PubMed:27149520). T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle (Probable). They may also be involved in the modulation of firing patterns of neurons (PubMed:15048902). In the adrenal zona glomerulosa, participates in the signaling pathway leading to aldosterone production in response to either AGT/angiotensin II, or hyperkalemia (PubMed:25907736, PubMed:27729216).
Activated by the heterotrimeric G-protein subunits GNA12, GNA13 and GNB1-GNG2. Activated by HRAS, RAP1A, RHOA, RHOB, RHOC, RRAS and RRAS2. Activated by the G(s)-coupled GPCRs ADRB2, PTGER1 and CHRM3 through cyclic-AMP formation and RAP2B activation. Inhibited by G(i)-coupled GPCRs.
Broadly expressed and only absent in peripheral blood leukocytes.
Interacts with RHOA (By similarity). Interacts with GTP-bound HRAS, RAP1A, RAP2A, RAP2B and RRAS (PubMed:11022048, PubMed:12444546, PubMed:16483931, PubMed:16537651). Interacts with AVIL (PubMed:29058690). Interacts with IQGAP1 (PubMed:17086182).
Specifically expressed in placenta, lung and spleen.
The Ras-GEF domain has a GEF activity towards HRAS and RAP1A. Mediates activation of the mitogen-activated protein kinase pathway.
The Ras-associating domain 1 is degenerated and may not bind HRAS. The Ras-associating domain 2 mediates interaction with GTP-bound HRAS, RAP1A, RAP2A and RAP2B and recruitment of HRAS to the cell membrane.
The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. PLCE1 is a bifunctional enzyme which also regulates small GTPases of the Ras superfamily through its Ras guanine-exchange factor (RasGEF) activity. As an effector of heterotrimeric and small G-protein, it may play a role in cell survival, cell growth, actin organization and T-cell activation. In podocytes, is involved in the regulation of lamellipodia formation. Acts downstream of AVIL to allow ARP2/3 complex assembly (PubMed:29058690).
Widely expressed. Expressed in podocytes (PubMed:29058690).
Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex (By similarity). Homodimer. Interacts with CUL3.
Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates the ubiquitination of target proteins, leading most often to their proteasomal degradation.
Antibodies against CILP are detected in patients with early-stage knee osteoarthritis and rheumatoid arthritis.
Cleaved into 2 chains possibly by a furin-like protease upon or preceding secretion.
Probably plays a role in cartilage scaffolding. May act by antagonizing TGF-beta1 (TGFB1) and IGF1 functions. Has the ability to suppress IGF1-induced proliferation and sulfated proteoglycan synthesis, and inhibits ligand-induced IGF1R autophosphorylation. May inhibit TGFB1-mediated induction of cartilage matrix genes via its interaction with TGFB1. Overexpression may lead to impair chondrocyte growth and matrix repair and indirectly promote inorganic pyrophosphate (PPi) supersaturation in aging and osteoarthritis cartilage.
Specifically expressed in cartilage. Localizes in the intermediates layer of articular cartilage but neither in the superficial nor in the deepest regions. Specifically and highly expressed in intervertebral disk tissue. Expression increases with aging in hip articular cartilage. Overexpressed in articular hyaline cartilage from patients with calcium pyrophosphate dihydrate crystal deposition disease (CPPD). Expression in intervertebral disk tissue from individuals with lumbar disk disease increases as disk degeneration progresses.
Was originally thought to constitute the ATP pyrophosphatase enzyme (NTPPH). However, it was later shown (PubMed:12746903, PubMed:15864306) that it is not the case.
Amplified and overexpressed in a number of cancers and is associated with poor prognosis (at protein level).
Belongs to the class I-like SAM-binding methyltransferase superfamily. TrmB family.
Catalytic component of METTL1-WDR4 methyltransferase complex that mediates the formation of N(7)-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs) (PubMed:12403464, PubMed:31031083, PubMed:31031084, PubMed:36599982, PubMed:36599985, PubMed:37379838, PubMed:37369656). Catalyzes the formation of N(7)-methylguanine at position 46 (m7G46) in a large subset of tRNAs that contain the 5'-RAGGU-3' motif within the variable loop (PubMed:12403464, PubMed:34352207, PubMed:34352206, PubMed:36599982, PubMed:36599985, PubMed:37369656). M7G46 interacts with C13-G22 in the D-loop to stabilize tRNA tertiary structure and protect tRNAs from decay (PubMed:36599982, PubMed:36599985). Also acts as a methyltransferase for a subset of internal N(7)-methylguanine in mRNAs (PubMed:31031084, PubMed:37379838). Internal N(7)-methylguanine methylation of mRNAs in response to stress promotes their relocalization to stress granules, thereby suppressing their translation (PubMed:31031084, PubMed:37379838). Also methylates a specific subset of miRNAs, such as let-7 (PubMed:31031083). N(7)-methylguanine methylation of let-7 miRNA promotes let-7 miRNA processing by disrupting an inhibitory secondary structure within the primary miRNA transcript (pri-miRNA) (PubMed:31031083). Acts as a regulator of embryonic stem cell self-renewal and differentiation (By similarity).
Catalytic component of the METTL1-WDR4 complex, composed of METTL1 and WDR4.
In the context of cancer, overexpression of the METTL1-WDR4 methyltransferase complex promotes cancer progression by driving oncogenic transformation (PubMed:34352207, PubMed:34352206, PubMed:34371184). Drives oncogenesis by mediating the formation of N(7)-methylguanine at position 46 (m7G46) in some tRNAs, in particular Arg-TCT-4-1 (TRR-TCT4-1), leading to increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon (PubMed:34352207, PubMed:34352206, PubMed:34371184).
Phosphorylation at Ser-27 by PKB/AKT1 inactivates its methyltransferase activity via a steric interference mechanism in the active site that locally disrupts the catalytic center (PubMed:15861136, PubMed:36599985). Phosphorylation at Ser-27 does not affect the interaction with WDR4 (PubMed:15861136).
Upon tRNA-binding, the alphaC region transforms into a helix, which together with the alpha6 helix secures both ends of the tRNA variable loop (PubMed:36599985). The N-terminal disordered region is part of the catalytic pocket and essential for methyltransferase activity: upon S-adenosyl-L-methionine- and tRNA-binding, the N-terminal disordered region becomes ordered, sandwiched between the bound cofactor and the tRNA, and the WDR4 C-terminus attaches to the METTL1 N-terminus to stabilize the bound tRNA together (PubMed:36599982, PubMed:36599985). Together with WDR4, which also binds tRNAs, tRNAs undergo bending to facilitate G46 flipping into the catalytic pocket to be modified (PubMed:36599982, PubMed:36599985).
Adapter protein that plays a role in T-cell receptor (TCR)-mediated activation of signaling pathways. Required for T-cell activation and integrin-mediated T-cell adhesion in response to TCR stimulation (PubMed:27335501).
Expressed in T-cells (at protein level). Widely expressed.
Interacts with SKAP1, LCK and FYN. The phosphorylated form interacts with LCP2.
Phosphorylation is required for its function in T-cell activation.
Controls the reversible conversion of biologically active glucocorticoids such as cortisone to cortisol, and 11-dehydrocorticosterone to corticosterone in the presence of NADP(H) (PubMed:10497248, PubMed:12460758, PubMed:14973125, PubMed:15152005, PubMed:15280030, PubMed:17593962, PubMed:21453287, PubMed:27927697, PubMed:30902677). Participates in the corticosteroid receptor-mediated anti-inflammatory response, as well as metabolic and homeostatic processes (PubMed:12414862, PubMed:10497248, PubMed:15152005, PubMed:21453287). Plays a role in the secretion of aqueous humor in the eye, maintaining a normotensive, intraocular environment (PubMed:11481269). Bidirectional in vitro, predominantly functions as a reductase in vivo, thereby increasing the concentration of active glucocorticoids (PubMed:12414862, PubMed:10497248, PubMed:11481269, PubMed:12460758). It has broad substrate specificity, besides glucocorticoids, it accepts other steroid and sterol substrates (PubMed:15095019, PubMed:15152005, PubMed:17593962, PubMed:21453287). Interconverts 7-oxo- and 7-hydroxy-neurosteroids such as 7-oxopregnenolone and 7beta-hydroxypregnenolone, 7-oxodehydroepiandrosterone (3beta-hydroxy-5-androstene-7,17-dione) and 7beta-hydroxydehydroepiandrosterone (3beta,7beta-dihydroxyandrost-5-en-17-one), among others (PubMed:17593962). Catalyzes the stereo-specific conversion of the major dietary oxysterol, 7-ketocholesterol (7-oxocholesterol), into the more polar 7-beta-hydroxycholesterol metabolite (PubMed:15095019, PubMed:15152005). 7-oxocholesterol is one of the most important oxysterols, it participates in several events such as induction of apoptosis, accumulation in atherosclerotic lesions, lipid peroxidation, and induction of foam cell formation (PubMed:15095019). Mediates the 7-oxo reduction of 7-oxolithocholate mainly to chenodeoxycholate, and to a lesser extent to ursodeoxycholate, both in its free form and when conjugated to glycine or taurine, providing a link between glucocorticoid activation and bile acid metabolism (PubMed:21453287). Catalyzes the synthesis of 7-beta-25-dihydroxycholesterol from 7-oxo-25-hydroxycholesterol in vitro, which acts as ligand for the G-protein-coupled receptor (GPCR) Epstein-Barr virus-induced gene 2 (EBI2) and may thereby regulate immune cell migration (PubMed:30902677).
Hexose-6-phosphate dehydrogenase (H6PD) provides cosubstrate NADPH, and the glucose-6-phosphate transporter in the ER-membrane supplies the substrate for H6PDH, their activities stimulate the reduction of cortisone and abolish the oxidation of cortisol.
Widely expressed, highest expression in liver, lower in testis, ovary, lung, foreskin fibroblasts, and much lower in kidney (PubMed:1885595). Expressed in liver (at protein level) (PubMed:21453287). Expressed in the basal cells of the corneal epithelium and in the ciliary nonpigmented epithelium (both at mRNA and at protein level) (PubMed:11481269).
EGF stimulates the growth of various epidermal and epithelial tissues in vivo and in vitro and of some fibroblasts in cell culture. Magnesiotropic hormone that stimulates magnesium reabsorption in the renal distal convoluted tubule via engagement of EGFR and activation of the magnesium channel TRPM6. Can induce neurite outgrowth in motoneurons of the pond snail Lymnaea stagnalis in vitro (PubMed:10964941).
Expressed in kidney, salivary gland, cerebrum and prostate.
Interacts with EGFR and promotes EGFR dimerization. Interacts with RHBDF2 (By similarity). Interacts with RHBDF1; may retain EGF in the endoplasmic reticulum and regulates its degradation through the endoplasmic reticulum-associated degradation (ERAD).
O-glycosylated with core 1-like and core 2-like glycans. It is uncertain if Ser-954 or Thr-955 is O-glycosylated. The modification here shows glycan heterogeneity: HexHexNAc (major) and Hex2HexNAc2 (minor).
Doesn't interact with CIITA. Represses MHC class II transcription possibly via dominant-negative association with isoform 1.
Expressed at high levels in heart, kidney, liver and testis, at moderate levels in brain and stomach, and at low levels in lung, muscle, placenta, small intestine and spleen.
Self-associates. Interacts with ZXDA and CIITA.
Sumoylated at Lys-660 with SUMO1, SUMO2 and SUMO3; sumoylation enhances the activity of the transcriptional activation domain.
Acts as a cytotoxic T-lymphocyte tumor antigen, suggesting that it may be used as a target for cancer immunotherapy.
E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination, endocytosis and subsequent degradation of Wnt receptor complex components Frizzled. Acts on both canonical and non-canonical Wnt signaling pathway (PubMed:18313049, PubMed:22575959, PubMed:22895187). Along with RSPO2 and ZNRF3, constitutes a master switch that governs limb specification (By similarity).
Expressed in fetal kidney, fetal lung, in colon cancer tissues, hepatocellular carcinomas and lung adenocarcinomas. Overexpressed in colorectal cancer cell lines.
Interacts with AKAP8L, NONO and SFPQ (PubMed:18313049, PubMed:18655028). Interacts with FZD5 (PubMed:22895187). Identified in a complex composed of RNF43, LGR5 and RSPO1 (PubMed:23756651). Interacts with RSPO2 (PubMed:29769720). Interacts with LMBR1L (By similarity).
Despite its gene name, this protein differs in domain structure from bacterial clpB. Bacterial clpB contains two AAA modules, one in the N-terminal part of the protein and one in the C-terminal part, separated by a coiled coil, while vertebrate CLPB contains a single C-terminal AAA region and an N-terminal ANK repeat region which is absent from bacterial clpB.
Disaggregase activity is inhibited by ADP.
Functions as a regulatory ATPase and participates in secretion/protein trafficking process. Has ATP-dependent protein disaggregase activity and is required to maintain the solubility of key mitochondrial proteins (PubMed:32573439, PubMed:34115842, PubMed:35247700, PubMed:36170828, PubMed:36745679). Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6 (PubMed:31522117). Plays a role in granulocyte differentiation (PubMed:34115842).
Hexamers display robustness and can tolerate some mutant subunits without loss of activity (PubMed:36170828). Subunits containing SCN9-linked variants Lys-496, Gly-561 and Cys-620 inhibit ATPase and disaggregase activities of the hexamer more severely than those containing MGCA7-linked variants Gly-408, Gly-475 and Val-591 (PubMed:36170828).
Homododecamer when substrate-bound; the homododecamer consists of 2 homohexamers stacked head-to-head via ANK repeat-mediated interactions (PubMed:35247700, PubMed:36170828, PubMed:36745679). The active substrate-bound form is likely to exist in a dynamic equilibrium between homohexamers and homododecamers (PubMed:36170828). Homotetradecamer in the unbound state which is remodeled upon substrate binding into the homododecamer (PubMed:36170828, PubMed:36745679). Interacts with PHB and PHB2 (PubMed:31522117). Interacts with MAVS; the interaction is enhanced by Sendai virus infection (PubMed:31522117).
Proteolytically cleaved by protease PARL (PubMed:28288130). ATP-dependent protein disaggregase activity is stimulated by PARL-mediated cleavage of the N-terminal autoinhibitory peptide.
The ankyrin-repeat region is necessary for ATP-dependent protein disaggregase activity (PubMed:32573439, PubMed:36745679). It plays an important role in stabilizing the substrate-bound homododecamer by mediating contacts between the two homohexamers (PubMed:36170828).
Widely expressed (at protein level) (PubMed:25597511). Expressed in fetal, as well as in adult tissues, with highest levels in adult brain, including thalamus, hippocampus, occipital cortex and parietal cortex. Low expression in granulocytes (PubMed:25597510).
Expressed predominantly in liver. Also present in plasma.
Peptides at the N-terminal of HC-II have chemotactic activity for both monocytes and neutrophils.
The N-terminal acidic repeat region mediates, in part, the glycosaminoglycan-accelerated thrombin inhibition.
Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate. In the presence of the latter, HC-II becomes the predominant thrombin inhibitor in place of antithrombin III (AT-III). Also inhibits chymotrypsin, but in a glycosaminoglycan-independent manner.
After cleavage of the signal peptide, the N-terminus is probably further processed by CTSC (PubMed:22474388, PubMed:23904161). Processing by CTSC is probably required for accumulation in cytoplasmic granules; in the absence of CTSC the protein does not accumulate (PubMed:23904161).
Detected in peripheral blood neutrophil granulocytes, but not in other types of leukocytes. Detected in neutrophils and neutrophil precursors in bone marrow (at protein level) (PubMed:22474388, PubMed:23904161). Detected in myeloblasts and promyelocytes in bone marrow (PubMed:23904161).
Inhibited by SERPINA1, SERPINC1 and SERPING1.
Serine protease that cleaves preferentially after Arg residues (PubMed:22474388, PubMed:23904161, PubMed:25156428). Can also cleave after citrulline (deimidated arginine) and methylarginine residues (PubMed:25156428).
Belongs to the inositol 3,4-bisphosphate 4-phosphatase family.
Catalyzes the hydrolysis of the 4-position phosphate of phosphatidylinositol 3,4-bisphosphate, inositol 1,3,4-trisphosphate and inositol 3,4-trisphosphate (PubMed:24070612, PubMed:24591580). Plays a role in the late stages of macropinocytosis by dephosphorylating phosphatidylinositol 3,4-bisphosphate in membrane ruffles (PubMed:24591580). The lipid phosphatase activity is critical for tumor suppressor function. Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival (PubMed:19647222, PubMed:24070612).
Strongly inhibited by inositol hexakisphosphate.
Widely expressed with highest levels occurring in the skeletal muscle and heart.
Expressed in most tissues, but not in skeletal muscle.
Inhibits gastrointestinal motility and gastric acid secretion. Could function as a structural component of gastric mucus, possibly by stabilizing glycoproteins in the mucus gel through interactions with carbohydrate side chains (By similarity).
(Microbial infection) Interacts (SH3 domain) with HCV NS5A.
BIN1 mutations have been found in families segregating autosomal dominant centronuclear myopathy. Patients show adult-onset, mildly progressive muscle weakness affecting selected proximal muscles and all distal muscles of the lower limbs.
Heterodimer with AMPH (By similarity). Binds SH3GLB1 (By similarity). Interacts (via SH3 domain) with DNM1. Interacts with SYNJ1 (By similarity). Interacts (via SH3 domain) with DNM2 (PubMed:17676042). Isoform IIA interacts with CLTC. Isoform IIB does not interact with CLTC. Isoform IIC1 does not interact with CLTC. Isoform IIC2 does not interact with CLTC (PubMed:9603201). Interacts with AP2A2. Interacts with AP2B1 (By similarity). Interacts with MYC (via N-terminal transactivation domain); the interaction requires the integrity of the conserved MYC box regions 1 and 2 (By similarity). Interacts with BIN2 (PubMed:10903846). Interacts with SNX4 (PubMed:12668730). Interacts (via BAR domain) with BACE1 (PubMed:27179792). Binds (via BAR domain) F-actin (PubMed:28893863).
Is a key player in the control of plasma membrane curvature, membrane shaping and membrane remodeling. Required in muscle cells for the formation of T-tubules, tubular invaginations of the plasma membrane that function in depolarization-contraction coupling (PubMed:24755653). Is a negative regulator of endocytosis (By similarity). Is also involved in the regulation of intracellular vesicles sorting, modulation of BACE1 trafficking and the control of amyloid-beta production (PubMed:27179792). In neuronal circuits, endocytosis regulation may influence the internalization of PHF-tau aggregates (By similarity). May be involved in the regulation of MYC activity and the control cell proliferation (PubMed:8782822). Has actin bundling activity and stabilizes actin filaments against depolymerization in vitro (PubMed:28893863).
Ubiquitous. Highest expression in the brain and muscle (PubMed:9182667). Expressed in oligodendrocytes (PubMed:27488240). Isoform IIA is expressed only in the brain, where it is detected in the gray matter, but not in the white matter (PubMed:27488240). Isoform BIN1 is widely expressed with highest expression in skeletal muscle.
(Microbial infection) Host factor required for infection by all flaviviruses tested such as Zika virus and Yellow fever virus (PubMed:33338421). Probably required post-entry of the virus to facilitate the ER membrane remodeling necessary to form replication organelles (PubMed:33338421).
Interacts with BECN1 (By similarity). Interacts with TJP1 (PubMed:17724469). Interacts with TP53INP2 (PubMed:19056683). Interacts with TMEM41B (PubMed:30093494). Interacts with ATP2A2, PLN and SLN; competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2 (PubMed:28890335). Interacts with ATG2A (PubMed:33850023).
Phospholipid scramblase involved in lipid homeostasis and membrane dynamics processes (PubMed:33929485, PubMed:33850023). Has phospholipid scramblase activity toward cholesterol and phosphatidylserine, as well as phosphatidylethanolamine and phosphatidylcholine (PubMed:33929485, PubMed:33850023). Required for autophagosome formation: participates in early stages of autophagosome biogenesis at the endoplasmic reticulum (ER) membrane by reequilibrating the leaflets of the ER as lipids are extracted by ATG2 (ATG2A or ATG2B) to mediate autophagosome assembly (PubMed:28890335, PubMed:30093494, PubMed:30933966, PubMed:33929485, PubMed:33850023). Regulates ATP2A2 activity to control ER-isolation membrane contacts for autophagosome formation (PubMed:28890335). In addition to autophagy, involved in other processes in which phospholipid scramblase activity is required (PubMed:31526472, PubMed:33850023). Modulates ER contacts with lipid droplets, mitochondria and endosomes (PubMed:28890335). Plays an essential role in formation of cell junctions (PubMed:17724469). Upon stress such as bacterial and viral infection, promotes formation of cytoplasmic vacuoles followed by cell death (By similarity). Involved in the cytoplasmic vacuolization of acinar cells during the early stage of acute pancreatitis (By similarity).
Catalyzes the oxidation of medium and long chain aliphatic aldehydes to fatty acids. Active on a variety of saturated and unsaturated aliphatic aldehydes between 6 and 24 carbons in length (PubMed:9133646, PubMed:22633490, PubMed:25047030, PubMed:18035827, PubMed:9662422, PubMed:18182499). Responsible for conversion of the sphingosine 1-phosphate (S1P) degradation product hexadecenal to hexadecenoic acid (PubMed:22633490).
Belongs to the TALE/IRO homeobox family.
Interacts with the vitamin D receptor VDR but doesn't affect its transactivation activity.
Likely to be an important mediator of ventricular differentiation during cardiac development.
Predominantly expressed in cardiac ventricles.
Heterodimer of a catalytic subunit (PIK3CG/p120) and a regulatory (PIK3R5a/p101) subunit. Interacts with beta-gamma G protein dimers.
Regulatory subunit of the PI3K gamma complex. Required for recruitment of the catalytic subunit to the plasma membrane via interaction with beta-gamma G protein dimers. Required for G protein-mediated activation of PIK3CG (By similarity).
The heterodimerization region allows the binding to the catalytic subunit.
Ubiquitously expressed with high expression in fetal brain compared to adult brain. Abundant expression is observed in cerebellum, cerebral cortex, cerebral meninges, and vermis cerebelli.
Probable substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:16325183). Mediates Notch-induced ubiquitination and degradation of TCF3/E2A and JAK2 (PubMed:21119685). May play a role in testis development (By similarity).
Highly expressed in testis and at lower levels in colon, small intestine and thymus.
Histone chaperone that facilitates histone deposition and histone exchange and removal during nucleosome assembly and disassembly (PubMed:11897662, PubMed:14718166, PubMed:15664198, PubMed:16151251, PubMed:21454524, PubMed:26527279). Cooperates with chromatin assembly factor 1 (CAF-1) to promote replication-dependent chromatin assembly (PubMed:11897662, PubMed:14718166, PubMed:15664198, PubMed:16151251). Also involved in the nuclear import of the histone H3-H4 dimer together with importin-4 (IPO4): specifically recognizes and binds newly synthesized histones with the monomethylation of H3 'Lys-9' (H3K9me1) and diacetylation at 'Lys-5' and 'Lys-12' of H4 (H4K5K12ac) marks in the cytosol (PubMed:20953179, PubMed:21454524, PubMed:26527279). Does not participate in replication-independent nucleosome deposition which is mediated by ASF1A and HIRA (PubMed:11897662, PubMed:14718166, PubMed:15664198, PubMed:16151251). Required for gonad development (PubMed:12842904).
Interacts with histone H3 (including both histone H3.1 and H3.3) and histone H4 (PubMed:12842904, PubMed:14718166, PubMed:15664198, PubMed:16537536). Interacts with the CHAF1A, CHAF1B and RBBP4 subunits of the CAF-1 complex (PubMed:11897662, PubMed:14718166, PubMed:16537536, PubMed:16980972). Interacts with HAT1, NASP and TAF1 (PubMed:12842904). Interacts with CDAN1 (PubMed:22407294). Found in a cytosolic complex with IPO4 and histones H3 and H4 (PubMed:20953179, PubMed:21454524, PubMed:22407294). Interacts with CREBBP (PubMed:24616510).
Expressed at high levels in plasmacytoid dendritic cells. High expression in spleen, lymph nodes, peripheral blood leukocytes, and bone marrow, with lower expression in thymus, appendix, and fetal liver.
Acyltransferase activity is inhibited by detergents such as Triton X-100 and 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). Acyltransferase activity is inhibited by the presence of magnesium and calcium.
Belongs to the peptidase S33 family. ABHD4/ABHD5 subfamily.
Coenzyme A-dependent lysophosphatidic acid acyltransferase that catalyzes the transfer of an acyl group on a lysophosphatidic acid (PubMed:18606822). Functions preferentially with 1-oleoyl-lysophosphatidic acid followed by 1-palmitoyl-lysophosphatidic acid, 1-stearoyl-lysophosphatidic acid and 1-arachidonoyl-lysophosphatidic acid as lipid acceptor. Functions preferentially with arachidonoyl-CoA followed by oleoyl-CoA as acyl group donors (By similarity). Functions in phosphatidic acid biosynthesis (PubMed:18606822). May regulate the cellular storage of triacylglycerol through activation of the phospholipase PNPLA2 (PubMed:16679289). Involved in keratinocyte differentiation (PubMed:18832586). Regulates lipid droplet fusion (By similarity).
Detected in fetal epidermis from 49 to 135 days estimated gestational age (at protein level).
Interacts with ADRP, PLIN and PNPLA2. Interacts with PLIN5; promotes interaction with PNPLA2 (By similarity).
Up-regulated upon keratinocyte differentiation (at protein level).
Widely expressed in various tissues, including lymphocytes, liver, skeletal muscle and brain. Expressed by upper epidermal layers and dermal fibroblasts in skin, hepatocytes and neurons (at protein level).
Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins (PubMed:15169837, PubMed:12473658, PubMed:17347651, PubMed:21177865, PubMed:21245471, PubMed:22302004, PubMed:32732290). The protease activity is required for proteolytic activation of ATG8 family proteins: cleaves the C-terminal amino acid of ATG8 proteins to reveal a C-terminal glycine (PubMed:15169837, PubMed:12473658, PubMed:17347651, PubMed:21177865, PubMed:21245471, PubMed:22302004). Exposure of the glycine at the C-terminus is essential for ATG8 proteins conjugation to phosphatidylethanolamine (PE) and insertion to membranes, which is necessary for autophagy (PubMed:15169837, PubMed:12473658, PubMed:17347651, PubMed:21177865, PubMed:21245471, PubMed:22302004). Preferred substrate is GABARAPL2 followed by MAP1LC3A and GABARAP (PubMed:15169837, PubMed:12473658, PubMed:17347651, PubMed:21177865, PubMed:21245471, PubMed:22302004). Protease activity is also required to counteract formation of high-molecular weight conjugates of ATG8 proteins (ATG8ylation): acts as a deubiquitinating-like enzyme that removes ATG8 conjugated to other proteins, such as ATG3 (PubMed:31315929, PubMed:33773106). In addition to the protease activity, also mediates delipidation of ATG8 family proteins (PubMed:29458288, PubMed:33909989). Catalyzes delipidation of PE-conjugated forms of ATG8 proteins during macroautophagy (PubMed:29458288, PubMed:33909989). Compared to ATG4B, the major protein for proteolytic activation of ATG8 proteins, shows weaker ability to cleave the C-terminal amino acid of ATG8 proteins, while it displays stronger delipidation activity (PubMed:29458288). Involved in phagophore growth during mitophagy independently of its protease activity and of ATG8 proteins: acts by regulating ATG9A trafficking to mitochondria and promoting phagophore-endoplasmic reticulum contacts during the lipid transfer phase of mitophagy (PubMed:33773106).
Inhibited by N-ethylmaleimide (PubMed:12473658, PubMed:21177865). Redox-regulated during autophagy since reducing conditions activate ATG4A whereas an oxidizing environment such as the presence of H(2)O(2) inhibits its activity (PubMed:17347651).
Interacts with ATG9A; the interaction is direct.
The LIR motif (LC3-interacting region) is required for the interaction with the ATG8 family proteins (PubMed:28287329). Required for proteolytic activation and delipidation of ATG8 proteins (PubMed:32732290).
Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41 and VPS72/YL1. Component of a NuA4-related complex which contains EP400, TRRAP/PAF400, SRCAP, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, actin, ACTL6A/BAF53A, VPS72 and YEATS4/GAS41. Also part of a multiprotein complex which contains SRCAP and which binds to H2AZ1/H2AZ. Interacts (via N-terminal domain) with heterodimer H2BC11 and H2AZ1 (PubMed:26974126). The interaction with H2AZ1 is enhanced by VPS72 phosphorylation which is promoted by ZNHIT1 (By similarity).
Deposition-and-exchange histone chaperone specific for H2AZ1, specifically chaperones H2AZ1 and deposits it into nucleosomes. As component of the SRCAP complex, mediates the ATP-dependent exchange of histone H2AZ1/H2B dimers for nucleosomal H2A/H2B, leading to transcriptional regulation of selected genes by chromatin remodeling.
Phosphorylation is enhanced by ZNHIT1 and promotes the interaction of VPS72 with histone H2AZ1.
Expressed in sperm (PubMed:20586096). Highly expressed in epidermis of the skin, where it is expressed intracellularily in the deep horny layer (at protein level) (PubMed:21699545). Bone marrow, testis and kidney (PubMed:10493834).
Expression is not significantly up- or down-regulated by ultraviolet irradiation B (UV-B) in epidermis (PubMed:21699545).
Facilitates sperm penetration into the layer of cumulus cells surrounding the egg by digesting hyaluronic acid. Involved in induction of the acrosome reaction in the sperm. Involved in follicular atresia, the breakdown of immature ovarian follicles that are not selected to ovulate. Induces ovarian granulosa cell apoptosis, possibly via apoptotic signaling pathway involving CASP8 and CASP3 activation, and poly(ADP-ribose) polymerase (PARP) cleavage. Has no hyaluronidase activity in embryonic fibroblasts in vitro. Has no hyaluronidase activity in granulosa cells in vitro.
(Microbial infection) In case of viral infections, interactions with SV40 large T antigen, HPV E7 protein or adenovirus E1A protein induce the disassembly of RB1-E2F1 complex thereby disrupting RB1's activity.
(Microbial infection) Interacts with HPV E7 protein.
(Microbial infection) Interacts with SV40 large T antigen.
(Microbial infection) Interacts with adenovirus E1A protein.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 proteins UL82 and UL123.
(Microbial infection) Interacts with molluscum contagiosum virus protein MC007.
Acetylated during keratinocyte differentiation. Acetylation at Lys-873 and Lys-874 regulates subcellular localization. Can be deacetylated by SIRT1.
Expressed in the retina. Expressed in foreskin keratinocytes (at protein level) (PubMed:20940255).
Interacts with ATAD5. Interacts with PRMT2, CDK1 and CDK2 (By similarity). The hypophosphorylated form interacts with and sequesters the E2F1 transcription factor (PubMed:8336704, PubMed:20940255). Interacts with heterodimeric E2F/DP transcription factor complexes containing TFDP1 and either E2F1, E2F3, E2F4 or E2F5, or TFDP2 and E2F4. The unphosphorylated form interacts with EID1, ARID3B, KDM5A, SUV39H1, MJD2A/JHDM3A and THOC1. Interacts with the N-terminal domain of TAF1. Interacts with SNW1, AATF, DNMT1, LIN9, LMNA, KMT5B, KMT5C, PELP1, UHRF2 and TMPO-alpha. May interact with NDC80. Interacts with GRIP1 and UBR4. Interacts with ARID4A and KDM5B. Interacts with E4F1 and LIMD1. Interacts with SMARCA4/BRG1 and HDAC1 (By similarity). Interacts with PSMA3 and USP4. Interacts (when methylated at Lys-860) with L3MBTL1. Interacts with CHEK2; phosphorylates RB1. Interacts with CEBPA (PubMed:15107404). P-TEFB complex interacts with RB1; promotes phosphorylation of RB1 (PubMed:12037672). Interacts with RBBP9; the interaction disrupts RB1 binding to E2F1 (By similarity). Interacts with KAT2B/PCAF and EP300/P300 (By similarity). Interacts with PAX5 (PubMed:10197586).
N-terminus is methylated by METTL11A/NTM1 (By similarity). Monomethylation at Lys-810 by SMYD2 enhances phosphorylation at Ser-807 and Ser-811, and promotes cell cycle progression. Monomethylation at Lys-860 by SMYD2 promotes interaction with L3MBTL1.
Phosphorylated by CDK6 and CDK4, and subsequently by CDK2 at Ser-567 in G1, thereby releasing E2F1 which is then able to activate cell growth. Dephosphorylated at the late M phase. SV40 large T antigen, HPV E7 and adenovirus E1A bind to the underphosphorylated, active form of pRb. Phosphorylation at Thr-821 and Thr-826 promotes interaction between the C-terminal domain C and the Pocket domain, and thereby inhibits interactions with heterodimeric E2F/DP transcription factor complexes. Dephosphorylated at Ser-795 by calcineruin upon calcium stimulation. CDK3/cyclin-C-mediated phosphorylation at Ser-807 and Ser-811 is required for G0-G1 transition. Phosphorylated by CDK1 and CDK2 upon TGFB1-mediated apoptosis.
The Pocket domain binds to the threonine-phosphorylated domain C, thereby preventing interaction with heterodimeric E2F/DP transcription factor complexes.
Tumor suppressor that is a key regulator of the G1/S transition of the cell cycle (PubMed:10499802). The hypophosphorylated form binds transcription regulators of the E2F family, preventing transcription of E2F-responsive genes (PubMed:10499802). Both physically blocks E2Fs transactivating domain and recruits chromatin-modifying enzymes that actively repress transcription (PubMed:10499802). Cyclin and CDK-dependent phosphorylation of RB1 induces its dissociation from E2Fs, thereby activating transcription of E2F responsive genes and triggering entry into S phase (PubMed:10499802). RB1 also promotes the G0-G1 transition upon phosphorylation and activation by CDK3/cyclin-C (PubMed:15084261). Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases SUV39H1, KMT5B and KMT5C, leading to epigenetic transcriptional repression. Controls histone H4 'Lys-20' trimethylation. Inhibits the intrinsic kinase activity of TAF1. Mediates transcriptional repression by SMARCA4/BRG1 by recruiting a histone deacetylase (HDAC) complex to the c-FOS promoter. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC1 repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex (By similarity).
Autophosphorylation on Tyr-264 in the activation loop is required for kinase activity.
Due to an alternative splicing donor site in exon 19. Markedly reduced enzymatic activity.
Possible non-essential role in spermiogenesis.
Cofactor for serine ADP-ribosylation that confers serine specificity on PARP1 and PARP2 and plays a key role in DNA damage response (PubMed:28190768, PubMed:29480802, PubMed:29954836, PubMed:33186521, PubMed:32028527, PubMed:32939087, PubMed:34486521, PubMed:34874266, PubMed:34210965, PubMed:34625544, PubMed:33589610, PubMed:34732825, PubMed:33683197, PubMed:34795260, PubMed:34108479). Initiates the repair of double-strand DNA breaks: recruited to DNA damage sites by PARP1 and PARP2 and switches the amino acid specificity of PARP1 and PARP2 from aspartate or glutamate to serine residues, licensing serine ADP-ribosylation of target proteins (PubMed:28190768, PubMed:29480802, PubMed:29954836, PubMed:32028527, PubMed:32939087, PubMed:34486521, PubMed:34874266, PubMed:34625544, PubMed:33589610, PubMed:34732825, PubMed:33683197, PubMed:34795260). Serine ADP-ribosylation of target proteins, such as histones, promotes decompaction of chromatin and the recruitment of repair factors leading to the reparation of DNA strand breaks (PubMed:27067600, PubMed:28190768, PubMed:32939087, PubMed:33589610). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802). HPF1 acts by completing the active site of PARP1 and PARP2: forms a composite active site composed of residues from HPF1 and PARP1 or PARP2 (PubMed:32028527, PubMed:33589610). While HPF1 promotes the initiation of serine ADP-ribosylation, it restricts the polymerase activity of PARP1 and PARP2 in order to limit the length of poly-ADP-ribose chains (PubMed:34732825, PubMed:33683197, PubMed:34795260). HPF1 also promotes tyrosine ADP-ribosylation, probably by conferring tyrosine specificity on PARP1 (PubMed:29954836, PubMed:30257210).
Interacts with PARP1 (via the PARP catalytic domain) (PubMed:27067600, PubMed:32028527, PubMed:33589610). Interacts with PARP2 (via the PARP catalytic domain) (PubMed:27067600, PubMed:33141820, PubMed:34108479, PubMed:32028527, PubMed:32939087). Interacts with core nucleosomes in a PARP1- and PARP2-dependent manner (PubMed:27067600, PubMed:32939087).
By contact to a reconstituted basement membrane.
Expressed in different endometrial adenocarcinoma cell lines and various other cell lines apart from the prostate cell line LNCaP and the ovarian cancer cell line BG1.
Interacts with VAV1. Interacts with LAT. Interacts constitutively with GRB2, LYN and PLCG2; these interactions increase the activation of PLCG2 and its downstream pathways following B cell receptor stimulation.
May constitute a control point in macrophage inflammatory response, promoting LPS-induced TLR4-mediated TNF production (PubMed:20644716). Determines the threshold for activation of B cells by low-affinity and low-avidity ligands via PLCG2 activation and its downstream pathways (By similarity).
Phosphorylation at Tyr-632 is induced by LPS. Phosphorylated by Src kinases (Lck or Fyn) following BCR engagement.
Component of the transcription complexes of the pulmonary surfactant-associated protein-B (SFTPB) and -C (SFTPC). Enhances homeobox protein Nkx-2.1-activated SFTPB and SFTPC promoter activities.
Ubiquitously expressed. In lung, expression is restricted to the alveolar epithelial cells.
As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning (By similarity). Behaves as a kinesin cargo, providing a functional binding site for kinesin-1 at the nuclear envelope. Hence may contribute to the establishment of secretory epithelial morphology by promoting kinesin-dependent apical migration of the centrosome and Golgi apparatus and basal localization of the nucleus (By similarity).
Core component of LINC complexes which are composed of inner nuclear membrane SUN domain-containing proteins coupled to outer nuclear membrane KASH domain-containing nesprins. SUN and KASH domain-containing proteins seem to bind each other promiscuously; however, differentially expression of LINC complex constituents can give rise to specific assemblies (By similarity). Probably part of a SUN1-containing LINC complex. Interacts with kinesins KIF5B and KLC1 (By similarity).
The KASH domain, which contains a transmembrane domain, mediates the nuclear envelope targeting and is involved in the binding to SUN1 and SUN2 through recognition of their SUN domains.
Highly expressed in the brain and neuro-glial cells.
It is uncertain whether Met-1 or Met-23 is the initiator.
May be involved in cell-cell interaction processes and in cell adhesion.
Kidney-specific, including the thick ascending limb of Henle (TAL).
Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity. Involved in paracellular magnesium reabsorption. Required for a selective paracellular conductance. May form, alone or in partnership with other constituents, an intercellular pore permitting paracellular passage of magnesium and calcium ions down their electrochemical gradients. Alternatively, it could be a sensor of magnesium concentration that could alter paracellular permeability mediated by other factors.
Belongs to the protein-tyrosine phosphatase family. Receptor class 2A subfamily.
Interacts with GRIP1 (By similarity). Interacts with PPFIA1, PPFIA2 and PPFIA3. Interacts with INSR.
Possible cell adhesion receptor. It possesses an intrinsic protein tyrosine phosphatase activity (PTPase) and dephosphorylates EPHA2 regulating its activity.
The first PTPase domain has enzymatic activity, while the second one seems to affect the substrate specificity of the first one.
Belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM2 sub-subfamily.
Highly expressed in brain and peripheral blood cells, such as neutrophils. Also detected in bone marrow, spleen, heart, liver and lung. Isoform 2 is found in neutrophil granulocytes.
Homotetramer (PubMed:30467180). Isoform 1 can interact with isoform 3. This interaction decreases calcium influx through isoform 1 and suppresses susceptibility to oxidative stress-induced cell death.
Inactivated by exposure to extracellular pH between 4.0 and 6.5; irreversibly inactivated when open channels are exposed to extracellular pH between 4.0 and 6.5, while pre-exposure of closed channels to extracellular pH 5.5 gives rise to currents that rapidly inactivate, but protects against irreversible inactivation (PubMed:20660597). Inactivated by intracellular ATP (PubMed:11509734). Activated by arachidonic acid (PubMed:11804595). Inhibited by 2-aminoethyl diphenylborinate (2-APB) (PubMed:28775320).
Lacks cation channel activity and negatively regulates the channel activity of isoform 1. Negatively regulates susceptibility to cell death in reposponse to oxidative stress.
Lacks cation channel activity. Does not mediate cation transport in response to oxidative stress or ADP-ribose.
Nonselective, voltage-independent cation channel that mediates Na(+) and Ca(2+) influx, leading to increased cytoplasmic Ca(2+) levels (PubMed:11960981, PubMed:12594222, PubMed:11385575, PubMed:11509734, PubMed:11804595, PubMed:15561722, PubMed:16601673, PubMed:19171771, PubMed:20660597, PubMed:25620041, PubMed:27383051, PubMed:27068538, PubMed:28775320, PubMed:29745897, PubMed:30467180). Functions as ligand-gated ion channel (PubMed:19171771, PubMed:25620041, PubMed:28775320, PubMed:30467180). Binding of ADP-ribose to the cytoplasmic Nudix domain causes a conformation change; the channel is primed but still requires Ca(2+) binding to trigger channel opening (PubMed:19171771, PubMed:25620041, PubMed:28775320, PubMed:29745897, PubMed:30467180). Extracellular calcium passes through the channel and increases channel activity (PubMed:19171771). Contributes to Ca(2+) release from intracellular stores in response to ADP-ribose (PubMed:19454650). Plays a role in numerous processes that involve signaling via intracellular Ca(2+) levels (Probable). Besides, mediates the release of lysosomal Zn(2+) stores in response to reactive oxygen species, leading to increased cytosolic Zn(2+) levels (PubMed:25562606, PubMed:27068538). Activated by moderate heat (35 to 40 degrees Celsius) (PubMed:16601673). Activated by intracellular ADP-ribose, beta-NAD (NAD(+)) and similar compounds, and by oxidative stress caused by reactive oxygen or nitrogen species (PubMed:11960981, PubMed:11385575, PubMed:11509734, PubMed:11804595, PubMed:15561722, PubMed:16601673, PubMed:19171771, PubMed:25620041, PubMed:27383051, PubMed:27068538, PubMed:30467180). The precise physiological activators are under debate; the true, physiological activators may be ADP-ribose and ADP-ribose-2'-phosphate (PubMed:20650899, PubMed:25918360). Activation by ADP-ribose and beta-NAD is strongly increased by moderate heat (35 to 40 degrees Celsius) (PubMed:16601673). Likewise, reactive oxygen species lower the threshold for activation by moderate heat (37 degrees Celsius) (PubMed:22493272). Plays a role in mediating behavorial and physiological responses to moderate heat and thereby contributes to body temperature homeostasis. Plays a role in insulin secretion, a process that requires increased cytoplasmic Ca(2+) levels (By similarity). Required for normal IFNG and cytokine secretion and normal innate immune immunity in response to bacterial infection. Required for normal phagocytosis and cytokine release by macrophages exposed to zymosan (in vitro). Plays a role in dendritic cell differentiation and maturation, and in dendritic cell chemotaxis via its role in regulating cytoplasmic Ca(2+) levels (By similarity). Plays a role in the regulation of the reorganization of the actin cytoskeleton and filopodia formation in response to reactive oxygen species via its role in increasing cytoplasmic Ca(2+) and Zn(2+) levels (PubMed:27068538). Confers susceptibility to cell death following oxidative stress (PubMed:12594222, PubMed:25562606).
The cytosolic nudix box binds ADP-ribose and is required for channel activation by ADP-ribose (PubMed:15561722, PubMed:16601673, PubMed:30467180).
The isolated nudix hydrolase domain was shown to have low catalytic activity with ADP-ribose upon heterologous expression (PubMed:11385575). However, a more recent publication demonstrates that the nudix hydrolase domain lacks enzyme activity and suggests that spontaneous degradation of the substrate underlies the previously reported low activity (PubMed:27383051).
Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Enhances phosphorylation and proteolytic turnover of the NOTCH intracellular domain in the nucleus through interaction with CDK8. Binds to CREBBP/CBP which promotes nucleosome acetylation at NOTCH enhancers and activates transcription. Induces phosphorylation and localization of CREBBP to nuclear foci. Plays a role in hematopoietic development by regulating NOTCH-mediated lymphoid cell fate decisions.
Interacts (via N-terminus) with NOTCH1, NOTCH2, NOTCH3 and NOTCH4 (via ankyrin repeat region). Interacts (via N-terminus) with p53 (via DNA-binding region). Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1. Also binds CREBBP/CBP and CDK8.Forms a complex with PRAG1, NOTCH1 and MAML1, in a MAML1-dependent manner (By similarity).
The C-terminal region is required for transcriptional activation.
Widely expressed with highest levels in heart, pancreas, peripheral blood leukocytes and spleen.
Component of the EKC/KEOPS complex composed of at least GON7, TP53RK, TPRKB, OSGEP and LAGE3; the whole complex dimerizes. Interacts with PRAME.
Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine. The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37. OSGEP likely plays a direct catalytic role in this reaction, but requires other protein(s) of the complex to fulfill this activity.
Widely expressed at low level. Expressed in heart, placenta, liver, kidney, lung, brain, skeletal muscle and pancreas.
Interacts with RAB5C (By similarity). Interacts with TGFBRAP1 (PubMed:25266290). Component of the putative class C core vacuole/endosome tethering (CORVET) complex; the core of which composed of the class C Vps proteins VPS11, VPS16, VPS18 and VPS33A, is associated with VPS8 and TGFBRAP1 (PubMed:25266290).
Plays a role in vesicle-mediated protein trafficking of the endocytic membrane transport pathway. Believed to act as a component of the putative CORVET endosomal tethering complexes which is proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The CORVET complex is proposed to function as a Rab5 effector to mediate early endosome fusion probably in specific endosome subpopulations (PubMed:25266290). Functions predominantly in APPL1-containing endosomes (PubMed:25266290).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. 5-hydroxytryptamine receptor (TC 1.A.9.2) subfamily. HTR3D sub-subfamily.
Expressed in liver, as well as fetal and adult colon and kidney.
The HA-stretch region of HTR3D seems to confer increased conductance to HTR3A/HTR3D heteropentamers compared to that of HTR3A homopentamers.
Detected in pancreas and pancreatic fluid (at protein level) (PubMed:6698368). Expressed in pancreas and brain (PubMed:8294000). Detected in ileum (PubMed:12021776).
Digestive protease that cleaves proteins preferentially after an Arg residue and has proteolytic activity toward Kunitz-type trypsin inhibitors.
Not inhibited by Kunitz-type trypsin inhibitors.
Belongs to the threonine synthase family.
Acetylated by CREBBP/CBP, preventing methylation of 'Gln-105' of histone H2A (H2AQ104me), without affecting rRNA methylation (PubMed:30540930). Deacetylation by SIRT7 restores methylation of 'Gln-105' of histone H2A (H2AQ104me) (PubMed:30540930).
Belongs to the methyltransferase superfamily. Fibrillarin family.
By homology to other fibrillarins, some or all of the N-terminal domain arginines are modified to asymmetric dimethylarginine (DMA).
Component of box C/D small nucleolar ribonucleoprotein (snoRNP) particles that contain SNU13, FBL, NOP5 and NOP56, plus a guide RNA (PubMed:1714385, PubMed:32017898). It is associated with the U3, U8, U13, X and Y small nuclear RNAs (PubMed:1714385). Component of several ribosomal and nucleolar protein complexes. Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Interacts with PRMT5 and UTP20 (PubMed:14583623, PubMed:17498821). Interacts with DDX5 and C1QBP (PubMed:10837141, PubMed:21536856). Interacts with NOL11 (PubMed:22916032). Interacts with PIH1D1 (PubMed:17636026). Interacts with RRP1B (PubMed:20926688). Interacts with NOLC1 (By similarity). Interacts with SDE2 (PubMed:34365507).
S-adenosyl-L-methionine-dependent methyltransferase that has the ability to methylate both RNAs and proteins (PubMed:24352239, PubMed:30540930, PubMed:32017898). Involved in pre-rRNA processing by catalyzing the site-specific 2'-hydroxyl methylation of ribose moieties in pre-ribosomal RNA (PubMed:30540930). Site specificity is provided by a guide RNA that base pairs with the substrate (By similarity). Methylation occurs at a characteristic distance from the sequence involved in base pairing with the guide RNA (By similarity). Probably catalyzes 2'-O-methylation of U6 snRNAs in box C/D RNP complexes (PubMed:32017898). U6 snRNA 2'-O-methylation is required for mRNA splicing fidelity (PubMed:32017898). Also acts as a protein methyltransferase by mediating methylation of 'Gln-105' of histone H2A (H2AQ104me), a modification that impairs binding of the FACT complex and is specifically present at 35S ribosomal DNA locus (PubMed:24352239, PubMed:30540930). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Ubiquitinated. Ubiquitination leads to proteasomal degradation (PubMed:19208757). Deubiquitinated by USP36 (PubMed:19208757).
Binds to the consensus sequence 5'-AGAGTG-3' and has transcriptional activator activity (By similarity). May play a role in apoptosis.
(Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1; leading to stabilized SUMOylated TOP2A trapped in cleavage complexes, which halts the DNA damage response to TOP2A-induced double-strand DNA breaks.
Belongs to the type II topoisomerase family.
Binds two Mg(2+) per subunit. The magnesium ions form salt bridges with both the protein and the DNA. Can also accept other divalent metal cations, such as Mn(2+) or Ca(2+).
Eukaryotic topoisomerase I and II can relax both negative and positive supercoils, whereas prokaryotic enzymes relax only negative supercoils.
Expressed in the tonsil, spleen, lymph node, thymus, skin, pancreas, testis, colon, kidney, liver, brain and lung (PubMed:9155056). Also found in high-grade lymphomas, squamous cell lung tumors and seminomas (PubMed:9155056).
Homodimer. Interacts with COPS5. Interacts with RECQL5; this stimulates DNA decatenation. Interacts with SETMAR; stimulates the topoisomerase activity (PubMed:18790802, PubMed:20457750). Interacts with DHX9; this interaction occurs in a E2 enzyme UBE2I- and RNA-dependent manner, negatively regulates DHX9-mediated double-stranded DNA and RNA duplex helicase activity and stimulates TOP2A-mediated supercoiled DNA relaxation activity (PubMed:12711669). Interacts with HNRNPU (via C-terminus); this interaction protects the topoisomerase TOP2A from degradation and positively regulates the relaxation of supercoiled DNA in a RNA-dependent manner (By similarity). Interacts with MCM3AP isoform GANP (PubMed:23652018). Interacts with ERCC6 (PubMed:26030138). Interacts with PLSCR1 (PubMed:17567603). Interacts with GCNA; this interaction allows the resolution of topoisomerase II (TOP2A) DNA-protein cross-links (By similarity).
Key decatenating enzyme that alters DNA topology by binding to two double-stranded DNA molecules, generating a double-stranded break in one of the strands, passing the intact strand through the broken strand, and religating the broken strand (PubMed:17567603, PubMed:18790802, PubMed:22013166, PubMed:22323612). May play a role in regulating the period length of BMAL1 transcriptional oscillation (By similarity).
Phosphorylation has no effect on catalytic activity. However, phosphorylation at Ser-1106 by CSNK1D/CK1 promotes DNA cleavable complex formation.
Specifically inhibited by the intercalating agent amsacrine.
The N-terminus has several structural domains; the ATPase domain (about residues 1-265), the transducer domain (about 266-428) and the toprim domain (455-572) (PubMed:25202966). Comparing different structures shows ATP hydrolysis induces domain shifts in the N-terminus that are probably part of the mechanism of DNA cleavage and rejoining (PubMed:25202966).
Catalyzes the phosphorylation of riboflavin (vitamin B2) to form flavin-mononucleotide (FMN), hence rate-limiting enzyme in the synthesis of FAD. Essential for TNF-induced reactive oxygen species (ROS) production. Through its interaction with both TNFRSF1A and CYBA, physically and functionally couples TNFRSF1A to NADPH oxidase. TNF-activation of RFK may enhance the incorporation of FAD in NADPH oxidase, a critical step for the assembly and activation of NADPH oxidase.
Detected in brain, placenta and urinary bladder.
Monomer. Directly interacts with TNFRSF1A death domain. TNFRSF1A-binding may be supported by TRADD. In the absence of TNFRSF1A, interacts with TRADD. Independently of TNFRSF1A, interacts with the NADPH oxidase subunit CYBA.
Belongs to the tRNA-intron endonuclease family.
Constitutes one of the two catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA. It cleaves pre-tRNA at the 5'- and 3'-splice sites to release the intron. The products are an intron and two tRNA half-molecules bearing 2',3'-cyclic phosphate and 5'-OH termini. There are no conserved sequences at the splice sites, but the intron is invariably located at the same site in the gene, placing the splice sites an invariant distance from the constant structural features of the tRNA body.
Constitutes one of the two catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA. It cleaves pre-tRNA at the 5'- and 3'-splice sites to release the intron. The products are an intron and two tRNA half-molecules bearing 2',3'-cyclic phosphate and 5'-OH termini. There are no conserved sequences at the splice sites, but the intron is invariably located at the same site in the gene, placing the splice sites an invariant distance from the constant structural features of the tRNA body. Isoform 1 probably carries the active site for 5'-splice site cleavage. The tRNA splicing endonuclease is also involved in mRNA processing via its association with pre-mRNA 3'-end processing factors, establishing a link between pre-tRNA splicing and pre-mRNA 3'-end formation, suggesting that the endonuclease subunits function in multiple RNA-processing events. Isoform 2 is responsible for processing a yet unknown RNA substrate. The complex containing isoform 2 is not able to cleave pre-tRNAs properly, although it retains endonucleolytic activity.
Isoform 1 and isoform 2 are widely expressed at very low level.
tRNA splicing endonuclease is a heterotetramer composed of isoform 1 of TSEN2, TSEN15, TSEN34/LENG5 and TSEN54. tRNA splicing endonuclease complex also contains proteins of the pre-mRNA 3'-end processing machinery such as CLP1, CPSF1, CPSF4 and CSTF2. Isoform 2 belongs to a different complex that contains TSEN54 but low level of TSEN15 and TSEN34/LENG5.
Component of the CIA complex (PubMed:22678362, PubMed:22678361, PubMed:23585563). In the CIA complex, interacts directly with CIAO2B and CIAO3 (PubMed:23585563). Component of the MMXD complex, composed of CIAO1, ERCC2, CIAO2B, MMS19 and SLC25A5 (PubMed:20797633). Interacts with CIAO2B; the interaction is direct (PubMed:20797633). Interacts with ERCC2/XPD; the interaction is direct (PubMed:11071939, PubMed:23585563). Interacts with ERCC3/XPB and NCOA3/RAC3 (PubMed:11071939, PubMed:11279242). Interacts with RTEL1; the interaction mediates the association of RTEL1 with the CIA complex (PubMed:22678361, PubMed:23585563). Interacts with BRIP1 (PubMed:23585563). Interacts with KIF4A; the interaction facilitates the transfer of Fe-S clusters to KIF4A to ensure proper localization of KIF4A to the mitotic machinery components (PubMed:29848660). Interacts with CCDC117; the interaction is indirect (PubMed:30742009).
Key component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into apoproteins specifically involved in DNA metabolism and genomic integrity (PubMed:29848660). In the CIA complex, MMS19 acts as an adapter between early-acting CIA components and a subset of cellular target iron-sulfur proteins such as ERCC2/XPD, FANCJ and RTEL1, thereby playing a key role in nucleotide excision repair (NER), homologous recombination-mediated double-strand break DNA repair, DNA replication and RNA polymerase II (POL II) transcription (PubMed:22678362, PubMed:22678361, PubMed:29225034, PubMed:23585563). As part of the mitotic spindle-associated MMXD complex, plays a role in chromosome segregation, probably by facilitating iron-sulfur (Fe-S) cluster assembly into ERCC2/XPD (PubMed:20797633). Together with CIAO2, facilitates the transfer of Fe-S clusters to the motor protein KIF4A, which ensures proper localization of KIF4A to mitotic machinery components to promote the progression of mitosis (PubMed:29848660). Indirectly acts as a transcriptional coactivator of estrogen receptor (ER), via its role in iron-sulfur insertion into some component of the TFIIH-machinery (PubMed:11279242).
Ubiquitinated; undergoes 'Lys-48'-linked polyubiquitination by MAGEF1-NSMCE1 ubiquitin ligase complex leading to proteasomal degradation.
Ubiquitously expressed with higher expression in testis.
A chromosomal aberration involving GOLGA5 is found in papillary thyroid carcinomas (PTCs). Translocation t(10;14)(q11;q32) with RET. The translocation generates the RET/GOLGA5 (PTC5) oncogene.
Chimeric cDNA. A chimeric cDNA originating from chromosomes 14 and 10.
Highly phosphorylated during mitosis. Phosphorylation is barely detectable during interphase.
Homodimer. Interacts with RAB1A that has been activated by GTP-binding, and possibly also with OCRL1. Interacts with isoform CASP of CUX1.
Involved in maintaining Golgi structure. Stimulates the formation of Golgi stacks and ribbons. Involved in intra-Golgi retrograde transport.
Ubiquitous. Highly expressed in seminiferous tubules and Leydig cells in testis, and detected at much lower levels in the other tissues tested. Expression is very low or not detectable in spermatozoa.
Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. Isoform Short is inactive.
Isoform Long and isoform Short are expressed in fibroblasts and liver.
Strongly inhibited by MCPA-CoA, a metabolite of hypoglycin which is present in unripened fruit of the ackee tree.
Down-regulated by dexamethasone (in vitro).
Ubiquitous with highest expression in prostate, uterus, fetal brain, mammary gland, adrenal gland, skeletal muscle, small intestine, and kidney, and lower expression in lung, cerebellum, testis, liver, pancreas, bone marrow and ovary.
Homodimer (PubMed:16737969, PubMed:17928286). Forms heterodimers TJP3 (By similarity). Forms a heterodimer (via PDZ2 domain) with TJP2/ZO2 (via PDZ2 domain) (PubMed:17897942, PubMed:9792688). Interacts with OCLN, CALM, claudins, CGN/cingulin, CXADR, GJA12, GJD3 and UBN1 (PubMed:7798316, PubMed:11734628, PubMed:12023291, PubMed:12154091, PubMed:15183511, PubMed:18823282, PubMed:20200156). Interacts (via ZU5 domain) with CDC42BPB and MYZAP (PubMed:20093627, PubMed:21240187). Interacts (via PDZ domain) with GJA1 (PubMed:18636092). Interacts (via PDZ domains) with ANKRD2 (PubMed:22016770). Interacts with BVES (via the C-terminus cytoplasmic tail) (By similarity). Interacts with HSPA4 and KIRREL1 (By similarity). Interacts with DLL1 (By similarity). Interacts with USP53 (via the C-terminal region) (By similarity). Interacts (via ABR region) with F-actin (PubMed:9792688, PubMed:12354695, PubMed:20930113). Interacts with DNMBP (via C-terminal domain); required for the apical cell-cell junction localization of DNMBP (PubMed:17015620). Interacts with SPEF1 (PubMed:31473225). Interacts (via N-terminus) with CTNNA1 (By similarity). Interacts with CLDN18 (By similarity).
Phosphorylated at tyrosine redidues in response to epidermal growth factor (EGF) (PubMed:19332538, PubMed:7542259). This response is dependent on an intact actin microfilament system (PubMed:7542259). Dephosphorylated by PTPRJ (PubMed:19332538).
TJP1, TJP2, and TJP3 are closely related scaffolding proteins that link tight junction (TJ) transmembrane proteins such as claudins, junctional adhesion molecules, and occludin to the actin cytoskeleton (PubMed:7798316, PubMed:9792688). The tight junction acts to limit movement of substances through the paracellular space and as a boundary between the compositionally distinct apical and basolateral plasma membrane domains of epithelial and endothelial cells. Necessary for lumenogenesis, and particularly efficient epithelial polarization and barrier formation (By similarity). Plays a role in the regulation of cell migration by targeting CDC42BPB to the leading edge of migrating cells (PubMed:21240187). Plays an important role in podosome formation and associated function, thus regulating cell adhesion and matrix remodeling (PubMed:20930113). With TJP2 and TJP3, participates in the junctional retention and stability of the transcription factor DBPA, but is not involved in its shuttling to the nucleus (By similarity).
The 244-aa domain between residues 633 and 876 is the primary occludin (OCLN)-binding site and is required for stable association with the tight junction (PubMed:9792688).
The C-terminal region (residues 1151-1372) is an actin-binding region (ABR) that interacts directly with F-actin and plays an important role in the localization of TJP1 at junctions (PubMed:9792688, PubMed:12354695, PubMed:20930113). The ABR is also required for the localization to puncta at the free edge of cells before initiation of cell-cell contact (PubMed:12354695). The ABR is also necessary for TJP1 recruitment to podosomes (PubMed:20930113).
The alpha-containing isoform is found in most epithelial cell junctions. The short isoform is found both in endothelial cells and the highly specialized epithelial junctions of renal glomeruli and Sertoli cells of the seminiferous tubules.
The second PDZ domain (PDZ2) mediates homodimerization and heterodimerization with TJP2 and TJP3 (PubMed:9792688, PubMed:17928286).
Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. Activates JNK1 via CDC42 but not RAC1. Binds to phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 5-monophosphate, phosphatidylinositol 4-monophosphate and phosphatidylinositol 3-monophosphate (By similarity).
The DH domain is necessary for its ability to activate JNK1 via CDC42.
The FYVE-type zinc-finger is necessary for early endosome localization. Recruitment to endosomal membranes via this domain requires the presence of phosphatidylinositol 3-phosphate or other phosphatidylinositides (By similarity).
The PH domain is necessary for localization to the ruffle membrane. Recruitment to ruffle membrane occurs through binding of phosphoinositides by the PH domain. This domain also contributes to the lipid-binding properties of the protein (By similarity).
Heterotetramer of TRAP-alpha, TRAP-beta, TRAP-delta and TRAP-gamma.
TRAP proteins are part of a complex whose function is to bind calcium to the ER membrane and thereby regulate the retention of ER resident proteins.
Interacts with SAE2 and UBE2I. Interacts with ZNF451. Identified in a complex with ZNF451 and UBE2I/UBC9, where one ZNF451 interacts with one UBE2I/UBC9 and two SUMO2 chains, one bound to the UBE2I/UBC9 active site and the other to another region of the same UBE2I/UBC9 molecule. Covalently attached to a number of proteins. Interacts with PELP1. Interacts with USP25; the interaction sumoylates USP25. Interacts with SIMC1, CASP8AP2, RNF111 and SOBP (via SIM domains). Interacts with MTA1 (PubMed:21965678). Interacts with HINT1 (By similarity). Interacts with GCNA (via SIM domains); this interaction allows the GCNA recruitment to DPCs sites (PubMed:30914427).
Monoubiquitinated N-terminally by UBE2W, which primes it for RNF4-dependent polyubiquitination by the UBE2V1-UBE2N heterodimer.
Polymeric chains can be formed through Lys-11 cross-linking. Polymeric SUMO2 chains undergo 'Lys-6'-, 'Lys-11'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination by RNF4.
Ubiquitin-like protein that can be covalently attached to proteins as a monomer or as a lysine-linked polymer. Covalent attachment via an isopeptide bond to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by an E3 ligase such as PIAS1-4, RANBP2, CBX4 or ZNF451 (PubMed:26524494). This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Polymeric SUMO2 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins (PubMed:18408734, PubMed:18538659, PubMed:21965678, PubMed:9556629). Plays a role in the regulation of sumoylation status of SETX (PubMed:24105744).
(Microbial infection) Interacts (via B30.2/SPRY domain) with severe fever with thrombocytopenia syndrome virus (SFTSV) NSs; this interaction activates NFE2L2-mediated transcriptional activation of antioxidant genes.
Autoubiquitinated; does not lead to its proteasomal degradation. Deubiquitinated by USP4; leading to its stabilization.
E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2 (PubMed:26347139, PubMed:16297862, PubMed:16316627, PubMed:16472766, PubMed:16880511, PubMed:18022694, PubMed:18361920, PubMed:18641315, PubMed:18845142, PubMed:19675099). Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination (PubMed:16880511, PubMed:19675099). Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes (PubMed:16880511). A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B ('Thr-187' phosphorylated-form), thereby promoting its degradation by the proteasome (PubMed:16880511). Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling (PubMed:19675099). Negatively regulates IFN-beta production post-pathogen recognition by catalyzing polyubiquitin-mediated degradation of IRF3 (PubMed:18641315). Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway (PubMed:18022694). Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages (By similarity). Plays a role in the regulation of the cell cycle progression (PubMed:16880511). Enhances the decapping activity of DCP2 (PubMed:18361920). Exists as a ribonucleoprotein particle present in all mammalian cells studied and composed of a single polypeptide and one of four small RNA molecules (PubMed:1985094, PubMed:8666824). At least two isoforms are present in nucleated and red blood cells, and tissue specific differences in RO/SSA proteins have been identified (PubMed:8666824). The common feature of these proteins is their ability to bind HY RNAs.2 (PubMed:8666824). Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma (PubMed:26347139). Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1 and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy (PubMed:26347139). Regulates also autophagy through FIP200/RB1CC1 ubiquitination and subsequent decreased protein stability (PubMed:36359729). Represses the innate antiviral response by facilitating the formation of the NMI-IFI35 complex through 'Lys-63'-linked ubiquitination of NMI (PubMed:26342464). During viral infection, promotes cell pyroptosis by mediating 'Lys-6'-linked ubiquitination of ISG12a/IFI27, facilitating its translocation into the mitochondria and subsequent CASP3 activation (PubMed:36426955). When up-regulated through the IFN/JAK/STAT signaling pathway, promotes 'Lys-27'-linked ubiquitination of MAVS, leading to the recruitment of TBK1 and up-regulation of innate immunity (PubMed:29743353). Mediates 'Lys-63'-linked polyubiquitination of G3BP1 in response to heat shock, leading to stress granule disassembly (PubMed:36692217).
Homotrimer (PubMed:17156811) (PubMed:26347139). Interacts (via C-terminus) with IRF8 (via C-terminus) (By similarity). Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Interacts with CALR, CUL1, FBXW11, HSPA5, IKBKB, IRF3, SKP1 and VCP. Interacts with SKP2; the interaction with SKP2 does not depend on an intact F-box domain. Interacts (via N-terminus and C-terminus) with DCP2 (via N-terminus and C-terminus). Interacts with ULK1, BECN1 and with ATG8 family members, including GABARAP, GABARAPL1, GABARAPL2 and MAP1LC3C/LC3C. Interacts with TRIM21 and SQSTM1/sequestosome 1. Interacts with IRF3 (PubMed:26347139, PubMed:12699405, PubMed:16880511, PubMed:17156811, PubMed:18022694, PubMed:18361920, PubMed:18641315, PubMed:19675099, PubMed:8666824) (By similarity). Interacts (via the SPRY domain) with NMI (via coiled-coil domain); the interaction promotes 'Lys-63'-linked ubiquitination of NMI (PubMed:26342464). Interacts with IFI35 and NMI; the interaction facilitates NMI-IFI35 complex formation (PubMed:26342464).
Isoform 1 and isoform 2 are expressed in fetal and adult heart and fetal lung.
The B30.2/SPRY domain is necessary for the cytoplasmic localization, the interaction with IRF3 and for the IRF3-driven interferon beta promoter activity (PubMed:18845142). The B30.2/SPRY domain is necessary for the interaction with NMI (PubMed:26342464).
The RING-type zinc finger is necessary for ubiquitination and for the IRF3-driven interferon beta promoter activity. Interacts with SKP2 and CUL1 in a RING finger-independent manner (PubMed:18845142). The RING-type zinc finger is necessary for ubiquitination of NMI (PubMed:26342464).
The coiled-coil is necessary for the cytoplasmic localization.
Up-regulated by isoform 2 of XBP1. Up-regulated by IFNG/interferon-gamma, with a peak after 2-4 hours of treatment in monocytes/macrophages.
Endocrine hormone of the central and peripheral nervous systems that binds and activates the G protein-coupled receptors GALR1, GALR2, and GALR3. This small neuropeptide may regulate diverse physiologic functions including contraction of smooth muscle of the gastrointestinal and genitourinary tract, growth hormone and insulin release and adrenal secretion.
By a subset of cytokines including those belonging to the interferon, interleukin and colony-stimulating factor families.
Essential negative regulator of type I and type II interferon (IFN) signaling, as well as that of other cytokines, including IL2, IL4, IL6 and leukemia inhibitory factor (LIF) (PubMed:32499645, PubMed:33087723). Downregulates cytokine signaling by inhibiting the JAK/STAT signaling pathway. Acts by binding to JAK proteins and to IFNGR1 and inhibiting their kinase activity. In vitro, suppresses Tec protein-tyrosine activity (PubMed:9341160). Regulates IFN-gamma (IFNG)-mediated sensory neuron survival (By similarity). Probable substrate recognition component of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:11278610, PubMed:11313480).
Expressed in all tissues with high expression in spleen, small intestine and peripheral blood leukocytes.
Interacts with multiple activated signaling proteins of the tyrosine kinase signaling pathway including JAK family kinases, TEC, KIT, GRB2 and VAV. Binding to JAKs is mediated through the KIR and SH2 domains to a phosphorylated tyrosine residue within the JAK JH1 domain. Binds the SH3 domain of GRB2 via diproline determinants in the N-terminus, and the N-terminal regulatory domain of VAV (By similarity). Interacts with the Elongin BC complex (ELOB and ELOC). Component of an ECS CBC(SOCS1) E3 ubiquitin-protein ligase complex which contains Elongin BC, CUL5, RBX1 and SOCS1 (By similarity). Interacts (via SH2 domain and SOCS box) with TRIM8 (By similarity). Interacts with AXL, CUL2 and FGFR3. Interacts with INSR (By similarity). Interacts with TRIM8 (PubMed:12163497). Interacts with DCUN1D1 (PubMed:23401859). Interacts with IFNGR1 (By similarity).
The ESS and SH2 domains are required for JAK phosphotyrosine binding. Further interaction with the KIR domain is necessary for signal and kinase inhibition.
The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes. The Elongin BC complex binding domain is also known as BC-box with the consensus [APST]-L-x(3)-C-x(3)-[AILV] and is part of the SOCS box (By similarity).
Heterodimer of an alpha and a beta subunit. Alpha-X associates with beta-2.
Integrin alpha-X/beta-2 is a receptor for fibrinogen. It recognizes the sequence G-P-R in fibrinogen. It mediates cell-cell interaction during inflammatory responses. It is especially important in monocyte adhesion and chemotaxis.
Predominantly expressed in monocytes and granulocytes.
A possible nuclear localization signal exists in all isoforms where Asp-626--631-Arg are deleted.
ARM repeats 1 to 5 mediate interaction with cadherins.
Belongs to a multiprotein cell-cell adhesion complex that also contains E-cadherin/CDH1, alpha-catenin/CTNNA1, beta-catenin/CTNNB1, and gamma-catenin/JUP (PubMed:20371349, PubMed:15240885). Component of a cadherin:catenin adhesion complex composed of at least of CDH26, beta-catenin/CTNNB1, alpha-catenin/CTNNA1 and p120 catenin/CTNND1 (PubMed:28051089). Binds to the C-terminal fragment of PSEN1 and mutually competes for CDH1. Interacts with ZBTB33 (PubMed:10207085). Interacts with GLIS2 (PubMed:17344476). Interacts with FER (PubMed:7623846). Interacts with NANOS1 (via N-terminal region) (PubMed:17047063). Interacts (via N-terminus) with GNA12; the interaction regulates CDH1-mediated cell-cell adhesion (PubMed:15240885). Interacts with GNA13 (PubMed:15240885). Interacts with CCDC85B (PubMed:25009281). Interacts with PLPP3; negatively regulates the PLPP3-mediated stabilization of CTNNB1 (PubMed:20123964).
Expressed in vascular endothelium. Melanocytes and melanoma cells primarily express the long isoform 1A, whereas keratinocytes express shorter isoforms, especially 3A. The shortest isoform 4A, is detected in normal keratinocytes and melanocytes, and generally lost from cells derived from squamous cell carcinomas or melanomas. The C-terminal alternatively spliced exon B is present in the p120ctn transcripts in the colon, intestine and prostate, but lost in several tumor tissues derived from these organs.
Key regulator of cell-cell adhesion that associates with and regulates the cell adhesion properties of both C-, E- and N-cadherins, being critical for their surface stability (PubMed:14610055, PubMed:20371349). Beside cell-cell adhesion, regulates gene transcription through several transcription factors including ZBTB33/Kaiso2 and GLIS2, and the activity of Rho family GTPases and downstream cytoskeletal dynamics (PubMed:10207085, PubMed:20371349). Implicated both in cell transformation by SRC and in ligand-induced receptor signaling through the EGF, PDGF, CSF-1 and ERBB2 receptors (PubMed:17344476).
Phosphorylated by FER and other protein-tyrosine kinases. Phosphorylated at Ser-288 by PAK5. Dephosphorylated by PTPRJ.
Component of the nuclear body, also known as nuclear domain 10, PML oncogenic domain, and KR body (PubMed:8910577). May be involved in the pathogenesis of acute promyelocytic leukemia and viral infection (PubMed:8910577). May play a role in chromatin-mediated regulation of gene expression although it does not bind to histone H3 tails (PubMed:24267382).
High levels in spleen and peripheral blood leukocytes, much lower levels in tonsils, thymus, prostate, ovary, small intestine, and colon (PubMed:8695863, PubMed:8910577). Very low levels in heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas (PubMed:8910577). Not detected in brain, liver and muscle (PubMed:8695863).
Phosphorylation at Thr-726 promotes binding of PIN1 and subsequent isomerization of Pro-727.
This antigen is recognized by autoantibodies from patients with primary biliary cirrhosis.
Binds zinc and copper in the extracellular domain. Zinc-binding increases heparin binding. No Cu(2+) reducing activity with copper-binding.
Expressed in the cerebral cortex where it is localized to the postsynaptic density (PSD).
May play a role in postsynaptic function. The C-terminal gamma-secretase processed fragment, ALID1, activates transcription activation through APBB1 (Fe65) binding (By similarity). Couples to JIP signal transduction through C-terminal binding. May interact with cellular G-protein signaling pathways. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I.
Monomer and homodimer. Heparin binding promotes homodimerization. Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB and APBA family members, MAPK8IP1 and DAB1 (By similarity). Binding to Dab1 inhibits its serine phosphorylation (By similarity). Interacts with CPEB1. Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Interacts (via NPXY motif) with DAB1 (By similarity).
N- and O-glycosylated. O-glycosylation with core 1 or possibly core 8 glycans. Glycosylation on Ser-227 is the preferred site to Thr-228.
Proteolytically cleaved by caspases during neuronal apoptosis. Cleaved, in vitro, at Asp-620 by caspase-3 (By similarity).
The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The NPXY site is also involved in clathrin-mediated endocytosis.
The gamma-CTF peptide, C30, is a potent enhancer of neuronal apoptosis.
A peptide arising from positions 166 to 174 was originally (PubMed:3087352, PubMed:2437111) termed neurotensin-related peptide (NRP) or kinetensin and was thought to regulate fat digestion, lipid absorption, and blood flow.
A variant structure of albumin could lead to increased binding of zinc resulting in an asymptomatic augmentation of zinc concentration in the blood. The sequence shown is that of variant albumin A.
Acetylated on Lys-223 by acetylsalicylic acid.
Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017).
Interacts with FCGRT; this interaction regulates ALB homeostasis (PubMed:28330995). Interacts with TASOR (By similarity). In plasma, occurs in a covalently-linked complex with chromophore-bound alpha-1-microglobulin with molar ratio 1:2 and 1:1; this interaction does not prevent fatty acid binding to ALB.
Kenitra variant is partially O-glycosylated at Thr-620. It has two new disulfide bonds Cys-600 to Cys-602 and Cys-601 to Cys-606.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Susceptibility to intervertebral disk disease, particularly lumbar disk degeneration, is conferred by a triplet repeat expansion polymorphism. ASPN allele having 14 aspartic acid repeats in the N-terminal region of the protein (D14), is associated with the disorder in some populations (PubMed:18304494).
Disease susceptibility is associated with variants affecting the gene represented in this entry. Susceptibility to osteoarthritis is conferred by a triplet repeat expansion polymorphism. ASPN allele having 14 aspartic acid repeats in the N-terminal region of the protein (D14), is overrepresented relative to the common allele having 13 aspartic acid repeats (D13). The frequency of the D14 allele increases with disease severity. The D14 allele is also overrepresented in individuals with hip osteoarthritis.
Higher levels in osteoarthritic articular cartilage, aorta, uterus. Moderate expression in small intestine, heart, liver, bladder, ovary, stomach, and in the adrenal, thyroid, and mammary glands. Low expression in trachea, bone marrow, and lung. Colocalizes with TGFB1 in chondrocytes within osteoarthritic (OA) lesions of articular cartilage.
Interacts with TGFB1, TGFB2 and TGFB3. DCN, BGN, and FMOD inhibit binding to TGFB1. Interacts with BMP2. Interacts in vitro with type II collagen (By similarity). Interacts with type I collagen. DCN can inhibit collagen binding.
Negatively regulates periodontal ligament (PDL) differentiation and mineralization to ensure that the PDL is not ossified and to maintain homeostasis of the tooth-supporting system. Inhibits BMP2-induced cytodifferentiation of PDL cells by preventing its binding to BMPR1B/BMP type-1B receptor, resulting in inhibition of BMP-dependent activation of SMAD proteins (By similarity). Critical regulator of TGF-beta in articular cartilage and plays an essential role in cartilage homeostasis and osteoarthritis (OA) pathogenesis. Negatively regulates chondrogenesis in the articular cartilage by blocking the TGF-beta/receptor interaction on the cell surface and inhibiting the canonical TGF-beta/Smad signal. Binds calcium and plays a role in osteoblast-driven collagen biomineralization activity.
The LRR 5 repeat can inhibit BMP2-induced cytodifferentiation and may be involved in the interaction with BMP2 (By similarity). The repeats LRR 10, LRR 11 and LRR 12 are involved in binding type I collagen. The poly-Asp region is involved in binding calcium.
The N-linked glycan at Asn-282 is composed of variable structures of GlcNAc, mannose, fucose, HexNAc and hexose.
The poly-Asp region of ASPN is polymorphic and ranges at least from 11 to 17 Asp (PubMed:11152692).
There is no serine/glycine dipeptide sequence expected for the attachment of O-linked glycosaminoglycans and this is probably not a proteoglycan. The O-linked polysaccharide on 54-Ser is probably the mucin type linked to GalNAc.
(Microbial infection) Interacts with influenza A strain H3N2 NS1 protein; the interaction interferes with host cell gene transcription, specifically with that of antiviral genes.
Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Connects PAF1C with the RNF20/40 E3 ubiquitin-protein ligase complex. Involved in polyadenylation of mRNA precursors. Has oncogenic activity in vivo and in vitro.
Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8 (PubMed:19952111, PubMed:20178742). The PAF1 complex interacts with PHF5A (By similarity). Interacts with POLR2A, TCEA1, SKIC3, KMT2A/MLL1, SUPT5H, RNF20 and RNF40 (PubMed:15923622, PubMed:16024656, PubMed:19952111, PubMed:20178742, PubMed:20541477, PubMed:16491129, PubMed:19410543). Interacts with UBE2E1 (PubMed:16307923). Interacts with PINT87aa which is encoded by the circular form of the long non-coding RNA LINC-PINT; the interaction enhances the binding of the PAF1 complex to target gene promoters and may anchor the complex on target gene promoters, sequentially pausing RNA polymerase II-induced mRNA elongation (PubMed:30367041).
Expressed in all tissues tested including blood, brain, heart, kidney, liver, lung, pancreas and skeletal muscle. Expressed in retinal photoreceptors (PubMed:29726989).
Homodimer (By similarity). Heterodimer; efficient DNA binding requires dimerization with another bHLH protein (PubMed:10395741, PubMed:28602820). Interacts with ARNT; the heterodimer ARNT:AHR binds to core DNA sequence 5'-TGCGTG-3' within the dioxin response element (DRE) of target gene promoters and activates their transcription (PubMed:28602820, PubMed:34521881). Binds MYBBP1A (By similarity). Interacts with coactivators including SRC-1, RIP140 and NOCA7, and with the corepressor SMRT (PubMed:10395741). Interacts with NEDD8 and IVNS1ABP (PubMed:12215427, PubMed:16582008). Interacts with BMAL1 (By similarity). Interacts with HSP90AB1 (By similarity). Interacts with TIPARP; leading to mono-ADP-ribosylation of AHR and subsequent inhibition of AHR (PubMed:23275542, PubMed:30373764).
Induced or repressed by TGFB1 and dioxin in a cell-type specific fashion. Repressed by cAMP, retinoic acid, and 12-O-tetradecanoyl phorbol-13 acetate (TPA).
Ligand-activated transcription factor that enables cells to adapt to changing conditions by sensing compounds from the environment, diet, microbiome and cellular metabolism, and which plays important roles in development, immunity and cancer (PubMed:30373764, PubMed:23275542, PubMed:7961644, PubMed:32818467). Upon ligand binding, translocates into the nucleus, where it heterodimerizes with ARNT and induces transcription by binding to xenobiotic response elements (XRE) (PubMed:30373764, PubMed:23275542, PubMed:7961644). Regulates a variety of biological processes, including angiogenesis, hematopoiesis, drug and lipid metabolism, cell motility and immune modulation (PubMed:12213388). Xenobiotics can act as ligands: upon xenobiotic-binding, activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene) (PubMed:7961644). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons (PubMed:7961644, PubMed:34521881). Next to xenobiotics, natural ligands derived from plants, microbiota, and endogenous metabolism are potent AHR agonists (PubMed:18076143). Tryptophan (Trp) derivatives constitute an important class of endogenous AHR ligands (PubMed:32866000, PubMed:32818467). Acts as a negative regulator of anti-tumor immunity: indoles and kynurenic acid generated by Trp catabolism act as ligand and activate AHR, thereby promoting AHR-driven cancer cell motility and suppressing adaptive immunity (PubMed:32818467). Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1 (PubMed:28602820). Inhibits PER1 by repressing the CLOCK-BMAL1 heterodimer mediated transcriptional activation of PER1 (PubMed:28602820). The heterodimer ARNT:AHR binds to core DNA sequence 5'-TGCGTG-3' within the dioxin response element (DRE) of target gene promoters and activates their transcription (PubMed:28602820).
Mono-ADP-ribosylated, leading to inhibit transcription activator activity of AHR.
The PAS 1 domain is essential for dimerization and also required for AHR:ARNT heterodimerization.
Does not differ in the osmotic set point of swelling activation but, activation is more rapid.
Expressed in brain (at protein level) (PubMed:21628467). Highly expressed in heart, brain and kidney. Detected at lower levels in skeletal muscle, placenta, lung and pancreas (PubMed:10600773). Detected in umbilical vein endothelial cells (PubMed:16048901).
Homodimer (PubMed:21628467). Homomultimer and heteromultimer with other K-Cl cotransporters (Probable). Interacts (via C-terminus) with CKB; the interaction may be required for potassium-chloride cotransport activity (PubMed:18566107).
Inhibited following phosphorylation by OXSR1/OSR1 and STK39/SPAK: phosphorylation takes place downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4) in response to hyperosmotic stress and subsequent cell shrinkage (PubMed:19665974, PubMed:21613606). Activated by N-ethylmaleimide (NEM) (PubMed:10600773). Inhibited by DIOA, bumetanide and furosemide (PubMed:10600773).
Mediates electroneutral potassium-chloride cotransport when activated by cell swelling (PubMed:16048901). May contribute to cell volume homeostasis in single cells (Probable).
Mediates electroneutral potassium-chloride cotransport when activated by cell swelling (PubMed:16048901, PubMed:11551954, PubMed:10600773, PubMed:19665974, PubMed:18566107, PubMed:21628467, PubMed:27485015). May contribute to cell volume homeostasis in single cells (PubMed:16048901, PubMed:27485015).
Mediates electroneutral potassium-chloride cotransport when activated by cell swelling (PubMed:16048901, PubMed:34031912, PubMed:33199848). May contribute to cell volume homeostasis in single cells (Probable).
N-terminal loop binds to the intracellular vestibule of the transporter, arresting the transporter in an inhibited state.
Phosphorylated, phosphorylation regulates transporter activity (PubMed:34031912, PubMed:19665974, PubMed:21613606). Phosphorylated at Thr-991 and Thr-1048 by OXSR1/OSR1 and STK39/SPAK downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4), inhibiting the potassium-chloride cotransport activity (PubMed:19665974, PubMed:21613606).
Up-regulated by VEGF. Down-regulated by TNF.
Probable guanine nucleotide exchange factor (GEF).
A chromosomal aberration involving NRG1 produces gamma-heregulin. Translocation t(8;11) with TENM4. The translocation fuses the 5'-end of TENM4 to NRG1 (isoform 8). The product of this translocation was first thought to be an alternatively spliced isoform. Gamma-heregulin is a soluble activating ligand for the ERBB2-ERBB3 receptor complex and acts as an autocrine growth factor in a specific breast cancer cell line (MDA-MB-175). Not detected in breast carcinoma samples, including ductal, lobular, medullary, and mucinous histological types, neither in other breast cancer cell lines.
Detectable at early embryonic ages. Isoform 10 is highly expressed in developing spinal motor neurons and in developing cranial nerve nuclei. Expression is maintained only in both adult motor neurons and dorsal root ganglion neurons. Type IV isoforms are expressed in fetal brain.
Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. The multiple isoforms perform diverse functions such as inducing growth and differentiation of epithelial, glial, neuronal, and skeletal muscle cells; inducing expression of acetylcholine receptor in synaptic vesicles during the formation of the neuromuscular junction; stimulating lobuloalveolar budding and milk production in the mammary gland and inducing differentiation of mammary tumor cells; stimulating Schwann cell proliferation; implication in the development of the myocardium such as trabeculation of the developing heart. Isoform 10 may play a role in motor and sensory neuron development. Binds to ERBB4 (PubMed:10867024, PubMed:7902537). Binds to ERBB3 (PubMed:20682778). Acts as a ligand for integrins and binds (via EGF domain) to integrins ITGAV:ITGB3 or ITGA6:ITGB4. Its binding to integrins and subsequent ternary complex formation with integrins and ERRB3 are essential for NRG1-ERBB signaling. Induces the phosphorylation and activation of MAPK3/ERK1, MAPK1/ERK2 and AKT1 (PubMed:20682778). Ligand-dependent ERBB4 endocytosis is essential for the NRG1-mediated activation of these kinases in neurons (By similarity).
ERBB receptor binding is elicited entirely by the EGF-like domain.
N- and O-glycosylated. Extensive glycosylation precedes the proteolytic cleavage (By similarity).
Potential internal signal sequence at positions 76-100.
Proteolytic cleavage close to the plasma membrane on the external face leads to the release of the soluble growth factor form.
The cytoplasmic domain interacts with the LIM domain region of LIMK1 (By similarity). Forms a ternary complex with ERBB3 and ITGAV:ITGB3 or ITGA6:ITGB4 (PubMed:20682778). Interacts with NRDC and BACE1 (By similarity).
The cytoplasmic domain may be involved in the regulation of trafficking and proteolytic processing. Regulation of the proteolytic processing involves initial intracellular domain dimerization (By similarity).
Type I isoforms are the predominant forms expressed in the endocardium. Isoform alpha is expressed in breast, ovary, testis, prostate, heart, skeletal muscle, lung, placenta liver, kidney, salivary gland, small intestine and brain, but not in uterus, stomach, pancreas, and spleen. Isoform 3 is the predominant form in mesenchymal cells and in non-neuronal organs, whereas isoform 6 is the major neuronal form. Isoform 8 is expressed in spinal cord and brain. Isoform 9 is the major form in skeletal muscle cells; in the nervous system it is expressed in spinal cord and brain. Also detected in adult heart, placenta, lung, liver, kidney, and pancreas. Isoform 10 is expressed in nervous system: spinal cord motor neurons, dorsal root ganglion neurons, and brain. Predominant isoform expressed in sensory and motor neurons. Not detected in adult heart, placenta, lung, liver, skeletal muscle, kidney, and pancreas. Not expressed in fetal lung, liver and kidney. Type IV isoforms are brain-specific.
Acts as an activator of hypoxia-induced mitophagy, an important mechanism for mitochondrial quality control.
Interacts (via YXXL motif) with MAP1 LC3 family proteins MAP1LC3A, MAP1LC3B and GABARAP.
Phosphorylation at Tyr-18 by SRC inhibits activation of mitophagy. Following hypoxia, dephosphorylated at Tyr-18, leading to interaction with MAP1 LC3 family proteins and triggering mitophagy.
The YXXL motif mediates the interaction with MAP1 LC3 family proteins MAP1LC3A, MAP1LC3B and GABARAP.
Expressed by hematopoietic tissues and cells lines.
Mitochondrial amino-acid transporter (By similarity). Transports citrate (By similarity). Does not act as a serine transporter: not able to mediate transport of serine into mitochondria (PubMed:30442778) (By similarity). In brown adipose tissue, plays a role in the regulation of UCP1-dependent thermogenesis probably by supporting mitochondrial glycerol-3-phosphate utilization (By similarity).
Active metalloproteinase with gelatinolytic and collagenolytic activity. Plays a role in the wound healing process. Mediates both heterotypic intraepithelial cell/T-cell interactions and homotypic T-cell aggregation. Inhibits beta-1 integrin-mediated cell adhesion and migration of airway smooth muscle cells. Suppresses cell motility on or towards fibronectin possibly by driving alpha-v/beta-1 integrin (ITAGV-ITGB1) cell surface expression via ERK1/2 inactivation. Cleaves E-cadherin in response to growth factor deprivation. Plays a role in glomerular cell migration. Plays a role in pathological neovascularization. May play a role in cartilage remodeling. May be proteolytically processed, during sperm epididymal maturation and the acrosome reaction. May play a role in sperm-egg binding through its disintegrin domain.
Disintegrin domain binds to integrin alphaV-beta3.
Expressed in colon and small intestine. Expressed in airway smooth muscle and glomerular mesangial cells (at protein level). Ubiquitously expressed. Overexpressed in atherosclerotic lesions. Constitutively expressed in cultured endothelium and smooth muscle. Expressed in chondrocytes. Expressed in airway smooth muscle and glomerular mesangial cells.
Inhibited by hydroxamate-type metalloproteinase inhibitors such as marimastat. Inhibited by metalloproteinase inhibitor 2 (TIMP-2) and TIMP-3 at nanomolar concentrations. Not significantly inhibited by TIMP-1 at concentrations of up to 100 nM. Not activated by PMA or ionomycin.
Interacts with ITAGV-ITGB3 (vitronectin receptor). Interacts with SH3GL2 and SNX9; this interaction occurs preferentially with ADAM15 precursor, rather than the processed form, suggesting it occurs in a secretory pathway compartment prior to the medial Golgi. Interacts with ITAG9-ITGB1 (By similarity). Interacts specifically with Src family protein-tyrosine kinases (PTKs). Interacts with SH3PXD2A. Interacts with ITAGV-ITGB1. Interacts with GRB2, HCK, ITSN1, ITSN2, LYN, MAPK1, MAPK3, NCF1, NCK1, nephrocystin, PTK6, SNX33, LCK and SRC.
Phosphorylation increases association with PTKs.
The cytoplasmic domain is required for SH3GL2- and SNX9-binding.
Forms covalent di- and tetramers. Forms a heteromeric complex with cardiotrophin-like cytokine CLCF1/CLC; the CRLF1-CLCF1 complex is a ligand for the ciliary neurotrophic factor receptor/CNTFR (PubMed:9686600, PubMed:26858303). The CRLF1-CLCF1 heterodimer binds SORL1 (via N-terminal ectodomain); within this complex, the interaction is mediated predominantly by the CRLF1 moiety (PubMed:26858303). The tripartite signaling complex formed by CRLF1, CLCF1 and CNTFR also binds SORL1 (PubMed:26858303).
Highest levels of expression observed in spleen, thymus, lymph node, appendix, bone marrow, stomach, placenta, heart, thyroid and ovary. Strongly expressed also in fetal lung.
In complex with CLCF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development (Probable). May also play a regulatory role in the immune system.
Up-regulated in fibroblast primary cell cultures under stimulation by IFNG/IFN-gamma, TNF and IL6/interleukin-6.
ATP-dependent chromatin remodeler that mediates chromatin-remodeling following DNA damage (PubMed:19661379, PubMed:29220652, PubMed:29220653, PubMed:33357431, PubMed:34486521, PubMed:34874266, PubMed:34210977). Recruited to DNA damage sites through interaction with poly-ADP-ribose: specifically recognizes and binds histones that are poly-ADP-ribosylated on serine residues in response to DNA damage (PubMed:19661379, PubMed:29220652, PubMed:29220653, PubMed:34874266, PubMed:34486521). Poly-ADP-ribose-binding activates the ATP-dependent chromatin remodeler activity, thereby regulating chromatin during DNA repair (PubMed:19661379, PubMed:29220652, PubMed:29220653, PubMed:34874266, PubMed:34486521). Catalyzes nucleosome sliding away from DNA breaks in an ATP-dependent manner (PubMed:19661379, PubMed:29220652, PubMed:29220653). Chromatin remodeling activity promotes PARP2 removal from chromatin (PubMed:33275888).
Adopts an inactive conformation in absence of DNA damage (PubMed:33357431, PubMed:34486521, PubMed:34874266). Binding to poly-ADP-ribosylated histones activates the ATP-dependent chromatin remodeler activity (PubMed:34486521, PubMed:34874266).
Frequently overexpressed in hepatomacellular carcinomas.
Interacts with nucleosomes; interacts with the acidic patch of histones (PubMed:34486521, PubMed:33357431, PubMed:34210977). Interacts (via macro domain) with PARP1; interacts only when PARP1 is poly-ADP-ribosylated (PARylated) (PubMed:19661379, PubMed:29220653). Interacts with CIAO1 (PubMed:23891004).
The macro domain mediates non-covalent poly(ADP-ribose)-binding and recruitment to DNA damage sites (PubMed:19661379, PubMed:29220652, PubMed:29220653). Mediates auto-inhibition of ATPase activity by interacting with the N-terminal ATPase module, encompassing the helicase ATP-binding domain and helicase C-terminal domain (PubMed:29220652, PubMed:29220653). Binding to poly-ADP-ribosylated histones upon DNA damage releases the auto-inhibition by the macro domain and trigger ATPase activity (PubMed:34486521, PubMed:34874266). Does not bind monomeric ADP-ribose and mono-ADP-ribose fails to release the auto-inhibition of the ATPase module by the macro domain (PubMed:29220653).
Based on a readthrough transcript which may produce a ZHX1-C8orf76 fusion protein.
Binds negatively charged membrane lipids, such as phosphatidylserine and phosphoinositides (By similarity). May play a role in cell-cell adhesion processes in the retina, via homomeric interaction between octamers present on the surface of two neighboring cells (PubMed:27114531). Required for normal structure and function of the retina (PubMed:19093009).
Homooctamer of 4 homodimers; disulfide-linked (PubMed:15644328, PubMed:19849666). The homooctamer has a flat, cogwheel structure with a diameter of about 14 nm (PubMed:27798099, PubMed:26812435, PubMed:27114531). Two stacked octamers can assemble to form a hexadecamer (PubMed:27798099, PubMed:26812435, PubMed:27114531).
Restricted to the retina (at protein level) (PubMed:10915776). Detected in the inner segment of the photoreceptors, the inner nuclear layer, the inner plexiform layer and the ganglion cell layer (at protein level). At the macula, expressed in both the outer and inner nuclear layers and in the inner plexiform layer (at protein level) (PubMed:10915776). Detected in retina (PubMed:9326935). Detected only within the photoreceptor cell layer, most prominently within the inner segments of the photoreceptors (PubMed:10915776). Undetectable in the inner plexiform layers and the inner nuclear layer (PubMed:10915776).
Up-regulated during the differentiation of a retinoblastoma cell line.
Appears to play a role in cell sterol metabolism. It may function to protect cells from over-accumulation of cholesterol.
Autoantibodies against TSHR are directly responsible for the pathogenesis and hyperthyroidism of Graves disease. Antibody interaction with TSHR results in an uncontrolled receptor stimulation.
Defects in TSHR are found in patients affected by hyperthyroidism with different etiologies. Somatic, constitutively activating TSHR mutations and/or constitutively activating G(s)alpha mutations have been identified in toxic thyroid nodules (TTNs) that are the predominant cause of hyperthyroidism in iodine deficient areas. These mutations lead to TSH independent activation of the cAMP cascade resulting in thyroid growth and hormone production. TSHR mutations are found in autonomously functioning thyroid nodules (AFTN), toxic multinodular goiter (TMNG) and hyperfunctioning thyroid adenomas (HTA). TMNG encompasses a spectrum of different clinical entities, ranging from a single hyperfunctioning nodule within an enlarged thyroid, to multiple hyperfunctioning areas scattered throughout the gland. HTA are discrete encapsulated neoplasms characterized by TSH-independent autonomous growth, hypersecretion of thyroid hormones, and TSH suppression. Defects in TSHR are also a cause of thyroid neoplasms (papillary and follicular cancers).
Expressed in thyroide cells (at protein level) (PubMed:11847099). Expressed in the thyroid (PubMed:2610690).
Interacts with heterodimer GPHA2:GPHB5; this interaction stimulates cAMP production (PubMed:12045258). Interacts (via the PDZ-binding motif) with SCRIB; regulates TSHR trafficking and function (PubMed:15775968).
Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin (PubMed:11847099, PubMed:12045258). Also acts as a receptor for the heterodimeric glycoprotein hormone (GPHA2:GPHB5) or thyrostimulin (PubMed:12045258). The activity of this receptor is mediated by G proteins which activate adenylate cyclase (PubMed:11847099). Plays a central role in controlling thyroid cell metabolism (By similarity).
Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin. Also acts as a receptor for the heterodimeric glycoprotein hormone (GPHA2:GPHB5) or thyrostimulin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Plays a central role in controlling thyroid cell metabolism.
Sulfated. Sulfation on Tyr-385 plays a role in thyrotropin receptor binding and activation.
The Asp727Glu polymorphism is associated with Graves disease in a Russian population. The Glu727 allele and the heterozygous Asp727Glu genotype are related to higher risk of the disease. The Asp727Glu polymorphism significantly ameliorates G(s)alpha protein activation in the presence of the gain-of-function mutation Ala593Asn although it is functionally inert in the context of the wild-type TSHR.
Acts as a transcriptional activator (PubMed:15649947). In conjunction with NKX2-5, may play a role in both pharyngeal and cardiac embryonic development.
(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) matrix protein; this interaction probably facilitates viral budding.
(Microbial infection) Interacts with rotavirus A NSP4.
Homooligomer (PubMed:25588833). Interacts with GLIPR2 (PubMed:11865038). Interacts with NOSTRIN (PubMed:16807357). Interacts with SNAP25 and STX1A (By similarity). Interacts (via the N-terminus) with DPP4; the interaction is direct (PubMed:17287217). Interacts with CTNNB1, CDH1 and JUP. Interacts with PACSIN2; this interaction induces membrane tubulation (By similarity). Interacts with SLC7A9 (By similarity). Interacts with BMX and BTK (PubMed:11751885). Interacts with TGFBR1 (PubMed:25893292). Interacts with CAVIN3 (via leucine-zipper domain) in a cholesterol-sensitive manner (PubMed:25588833, PubMed:19262564). Interacts with CAVIN1 (PubMed:25588833). Interacts with EHD2 in a cholesterol-dependent manner (PubMed:25588833). Forms a ternary complex with UBXN6 and VCP; mediates CAV1 targeting to lysosomes for degradation (PubMed:21822278, PubMed:23335559). Interacts with ABCG1; this interaction regulates ABCG1-mediated cholesterol efflux (PubMed:24576892). Interacts with NEU3; this interaction enhances NEU3 sialidase activity within caveola. Interacts (via C-terminus) with SPRY1, SPRY2 (via C-terminus), SPRY3, and SPRY4 (By similarity).
May act as a scaffolding protein within caveolar membranes (PubMed:11751885). Forms a stable heterooligomeric complex with CAV2 that targets to lipid rafts and drives caveolae formation. Mediates the recruitment of CAVIN proteins (CAVIN1/2/3/4) to the caveolae (PubMed:19262564). Interacts directly with G-protein alpha subunits and can functionally regulate their activity (By similarity). Involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Its binding to DPP4 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner (PubMed:17287217). Recruits CTNNB1 to caveolar membranes and may regulate CTNNB1-mediated signaling through the Wnt pathway (By similarity). Negatively regulates TGFB1-mediated activation of SMAD2/3 by mediating the internalization of TGFBR1 from membrane rafts leading to its subsequent degradation (PubMed:25893292).
May act as a scaffolding protein within caveolar membranes. Interacts directly with G-protein alpha subunits and can functionally regulate their activity.
Phosphorylated at Tyr-14 by ABL1 in response to oxidative stress.
Skeletal muscle, liver, stomach, lung, kidney and heart (at protein level). Expressed in the brain.
The initiator methionine for isoform 2 is removed during or just after translation. The new N-terminal amino acid is then N-acetylated.
Ubiquitinated. Undergo monoubiquitination and multi- and/or polyubiquitination (PubMed:21822278). Monoubiquitination of N-terminal lysines promotes integration in a ternary complex with UBXN6 and VCP which promotes oligomeric CAV1 targeting to lysosomes for degradation (PubMed:23335559). Ubiquitinated by ZNRF1; leading to degradation and modulation of the TLR4-mediated immune response (PubMed:28593998).
Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development (By similarity).
(Microbial infection) Contributes to arthritogenic alphavirus pathogenesis and acts as a receptor for these viruses.
(Microbial infection) Interacts with chikungunya virus spike glycoprotein E2.
Detected in endothelial cells in mammary tissue, in both large vessels (left internal mammary artery) and small capillaries (vasa vasorum of the adventitia).
Homodimer in cis (By similarity). Does not appear to form trans-homodimers (By similarity). Interacts with ITGB3; the interaction inhibits ITGAV:ITGB3 heterodimer formation (PubMed:22492581).
Transmembrane protein which can modulate activity of various signaling pathways, probably via binding to integrin ITGAV:ITGB3 (PubMed:22492581, PubMed:23386276). Mediates heterophilic cell-cell interactions in vitro (By similarity). Inhibits osteoclastogenesis downstream of TNFSF11/RANKL and CSF1, where it may function by attenuating signaling via integrin ITGB3 and MAP kinase p38 (By similarity). Plays a role in cartilage formation where it promotes proliferation and maturation of growth plate chondrocytes (By similarity). Stimulates formation of primary cilia in chondrocytes (By similarity). Enhances expression of genes involved in the hedgehog signaling pathway in chondrocytes, including the hedgehog signaling molecule IHH; may also promote signaling via the PTHLH/PTHrP pathway (By similarity). Plays a role in angiogenesis where it suppresses migration of endothelial cells and also promotes their apoptosis (PubMed:23386276). Inhibits VEGF-induced activation of AKT and p38 MAP kinase in endothelial cells (PubMed:23386276). Also inhibits VTN (vitronectin)-mediated integrin ITGAV:ITGB3 signaling and activation of PTK2/FAK (PubMed:23386276). May play a role in the maturation and maintenance of the blood-brain barrier (By similarity).
Up-regulated in vein endothelial cells (HUVECs) in response to VEGF signaling.
May be derived from an ancient transposon that has lost its ability to translocate. Exhibits a close evolutionary relationship with ZBED5, but does not contain any zinc finger.
Involved in the biogenesis of the 60S ribosomal subunit in the nucleus.
Forms with the serine/threonine protein phosphatase CTDNEP1 an active complex which dephosphorylates and may activate LPIN1 and LPIN2. LPIN1 and LPIN2 are phosphatidate phosphatases that catalyze the conversion of phosphatidic acid to diacylglycerol and control the metabolism of fatty acids at different levels. May indirectly modulate the lipid composition of nuclear and/or endoplasmic reticulum membranes and be required for proper nuclear membrane morphology and/or dynamics. May also indirectly regulate the production of lipid droplets and triacylglycerol.
Interacts with CTDNEP1; the complex dephosphorylates LPIN1 and LPIN2.
As a component of the mitochondrial large ribosomal subunit, it plays a role in mitochondrial translation (PubMed:23603806). Associates with mitochondrial RNA polymerase to activate transcription.
Belongs to the bacterial ribosomal protein bL12 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:8626705). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (Probable). bL12m interacts with NOA1 (PubMed:19103604).
Forms homodimers and heterodimers with PHETA1. Interacts with OCRL and INPP5B.
Plays a role in endocytic trafficking. Required for receptor recycling from endosomes, both to the trans-Golgi network and the plasma membrane.
The F&H motif, an approximately 12-13 amino-acid sequence centered around Phe and His residues, is essential for binding to OCRL and INPP5B.
Was named after 'sesquipedalian', an unnecessarily long description of a simple thing.
Forms a complex with GRIP1, GRIA2 and STX12 through direct interaction with GRIP1; controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting. Interacts with STX12 (By similarity). Interacts with APP; could regulate APP processing (By similarity). Interacts with FAM171A1 (PubMed:30312582).
Plays a role in the recycling mechanism in neurons of multiple receptors, including AMPAR, APP and L1CAM and acts at the level of early endosomes to promote sorting of receptors toward a recycling pathway. Regulates sorting and recycling of GRIA2 through interaction with GRIP1 and then contributes to the regulation of synaptic transmission and plasticity by affecting the recycling and targeting of AMPA receptors to the synapse (By similarity). Is required for faithful sorting of L1CAM to axons by facilitating trafficking from somatodendritic early endosome or the recycling endosome (By similarity). In an other hand, induces apoptosis via the activation of CASP3 in response to DNA damage (PubMed:20599942, PubMed:20878061).
Up-regulated by TP53 after DNA damage (PubMed:20599942). Up-regulated by genotoxic stress (PubMed:20878061).
Belongs to the Integrator subunit 1 family.
Belongs to the multiprotein complex Integrator, at least composed of INTS1, INTS2, INTS3, INTS4, INTS5, INTS6, INTS7, INTS8, INTS9/RC74, INTS10, INTS11/CPSF3L and INTS12 (PubMed:16239144). Interacts with ESRRB, ESRRB is probably not a core component of the multiprotein complex Integrator and this association is a bridge for the interaction with the multiprotein complex Integrator; attracts the transcriptional machinery (By similarity).
Belongs to the mitochondrion-specific ribosomal protein mS34 family.
Required for mitochondrial translation, plays a role in maintaining the stability of the small ribosomal subunit and the 12S rRNA that are required for mitoribosome formation.
Activated by phosphorylation on Thr-182 (PubMed:14976552). Also activated by phosphorylation on Thr-322 in response to increases in intracellular sodium in parallel with elevations in intracellular calcium through the reversible sodium/calcium exchanger (PubMed:14976552). Inhibited by phosphorylation at Thr-473 and Ser-575, probably by PKA, which triggers interaction with 14-3-3 proteins (PubMed:29211348).
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. AMPK subfamily.
Defects in SIK1 may be associated with some cancers, such as breast cancers. Loss of SIK1 correlates with poor patient outcome in breast cancers (PubMed:19622832).
Interacts with ATP1A1 (By similarity). Interacts (when phosphorylated on Thr-182 and Ser-186) with YWHAZ (PubMed:16306228). Interacts (when phosphorylated at Thr-473 and/or Ser-575) with 14-3-3 proteins; the interaction inhibits kinase activity towards TORCs (PubMed:29211348). There is a cooperative effect of the phosphorylation sites in 14-3-3 binding as the interaction is stronger when both Thr-473 and Ser-575 are modified (PubMed:29211348).
Phosphorylated at Thr-182 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39, leading to its activation. Phosphorylation at Thr-182 promotes autophosphorylation at Ser-186, which is required for sustained activity. Autophosphorylation at Ser-186 is maintained by sequential phosphorylation at Thr-182 by GSK3-beta. GSK3-beta cannot initiate phosphorylation at Thr-182, it can only maintain it. Phosphorylation at Ser-575 in response to cAMP signaling promotes translocation to the cytoplasm (PubMed:29211348). Phosphorylation at Thr-322 by CaMK1 following intracellular sodium concentration leads to activation.
Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression. Phosphorylates HDAC4, HDAC5, PPME1, SREBF1, CRTC1/TORC1. Inhibits CREB activity by phosphorylating and inhibiting activity of TORCs, the CREB-specific coactivators, like CRTC2/TORC2 and CRTC3/TORC3 in response to cAMP signaling (PubMed:29211348). Acts as a tumor suppressor and plays a key role in p53/TP53-dependent anoikis, a type of apoptosis triggered by cell detachment: required for phosphorylation of p53/TP53 in response to loss of adhesion and is able to suppress metastasis. Part of a sodium-sensing signaling network, probably by mediating phosphorylation of PPME1: following increases in intracellular sodium, SIK1 is activated by CaMK1 and phosphorylates PPME1 subunit of protein phosphatase 2A (PP2A), leading to dephosphorylation of sodium/potassium-transporting ATPase ATP1A1 and subsequent increase activity of ATP1A1. Acts as a regulator of muscle cells by phosphorylating and inhibiting class II histone deacetylases HDAC4 and HDAC5, leading to promote expression of MEF2 target genes in myocytes. Also required during cardiomyogenesis by regulating the exit of cardiomyoblasts from the cell cycle via down-regulation of CDKN1C/p57Kip2. Acts as a regulator of hepatic gluconeogenesis by phosphorylating and repressing the CREB-specific coactivators CRTC1/TORC1 and CRTC2/TORC2, leading to inhibit CREB activity. Also regulates hepatic lipogenesis by phosphorylating and inhibiting SREBF1. In concert with CRTC1/TORC1, regulates the light-induced entrainment of the circadian clock by attenuating PER1 induction; represses CREB-mediated transcription of PER1 by phosphorylating and deactivating CRTC1/TORC1 (By similarity).
The RK-rich region determines the subcellular location and is required for cAMP responsiveness.
Catalyzes the hydrolysis of 1-phosphatidylinositol 4,5-bisphosphate into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) and mediates intracellular signaling downstream of G protein-coupled receptors (PubMed:9188725). Regulates the function of the endothelial barrier.
Palmitoylated. Palmitoylation at Cys-17 by ZDHHC21 regulates the signaling activity of PLCB1 and the function of the endothelial barrier. Palmitoylation by ZDHHC21 is stimulated by inflammation.
The receptor-mediated activation of PLC-beta-1 is mediated by two G-protein alpha subunits, alpha-Q and alpha-11.
Component of the U11/U12 snRNPs that are part of the U12-type spliceosome.
Required for sperm flagellum axoneme organization and function (By similarity). Involved in axonemal central pair complex assembly and/or stability (By similarity).
Belongs to the membrane-bound acyltransferase family. Sterol o-acyltransferase subfamily.
Catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates (PubMed:16214399, PubMed:18768481, PubMed:28420705, PubMed:9756920, PubMed:32433611, PubMed:32433610). Highly expressed in epithelial cells of the small intestine and its activity is essential for the absorption of dietary fats (PubMed:18768481). In liver, plays a role in esterifying exogenous fatty acids to glycerol, and is required to synthesize fat for storage (PubMed:16214399). Also present in female mammary glands, where it produces fat in the milk (By similarity). May be involved in VLDL (very low density lipoprotein) assembly (PubMed:18768481). In contrast to DGAT2 it is not essential for survival (By similarity). Functions as the major acyl-CoA retinol acyltransferase (ARAT) in the skin, where it acts to maintain retinoid homeostasis and prevent retinoid toxicity leading to skin and hair disorders (PubMed:16214399). Exhibits additional acyltransferase activities, includin acyl CoA:monoacylglycerol acyltransferase (MGAT), wax monoester and wax diester synthases (By similarity). Also able to use 1-monoalkylglycerol (1-MAkG) as an acyl acceptor for the synthesis of monoalkyl-monoacylglycerol (MAMAG) (PubMed:28420705).
Homodimer or homotetramer; both forms have similar enzymatic activities.
The MBOAT fold forms a reaction chamber in the endoplasmic reticulum membrane that encloses the active sites (PubMed:32433611, PubMed:32433610). The reaction chamber has a tunnel to the cytosolic side and its entrance recognizes the hydrophilic CoA motif of an acyl-CoA molecule (PubMed:32433610). The chamber has separate entrances for each of the two substrates, acyl-CoA and 1,2-diacyl-sn-glycerol (PubMed:32433610).
The disordered N-terminal region is required for the diacylglycerol O-acyltransferase activity and may regulate enzymatic function via its interaction with the MBOAT fold.
3F4, a monoclonal antibody which strongly stains neurofibrillary tangles in Alzheimer disease brains, specifically labels DPYSL2 when phosphorylated on Ser-518, Ser-522 and Thr-509.
Homotetramer, and heterotetramer with CRMP1, DPYSL3, DPYSL4 or DPYSL5. Interacts through its C-terminus with the C-terminus of CYFIP1/SRA1. Interacts with HTR4. Interacts with CLN6. Interacts with MICALL1.
Phosphorylation at Thr-514 by GSK3B abolishes tubulin-binding leading to destabilization of microtubule assembly in axons and neurodegeneration (By similarity). Phosphorylation by DYRK2 at Ser-522 is required for subsequent phosphorylation by GSK3B.
Plays a role in neuronal development and polarity, as well as in axon growth and guidance, neuronal growth cone collapse and cell migration. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. May play a role in endocytosis.
Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney.
Monomer. May also exist as a heterodimer; with ERAP2. Interacts with RBMX.
Catalyzes the transfer of sulfate to position 4 of non-reducing N-acetylgalactosamine (GalNAc) residues in both N-glycans and O-glycans. Participates in biosynthesis of glycoprotein hormones lutropin and thyrotropin, by mediating sulfation of their carbohydrate structures. Has a higher activity toward carbonic anhydrase VI than toward lutropin. Only active against terminal GalNAcbeta1,GalNAcbeta. Isoform 2, but not isoform 1, is active toward chondroitin.
Highly expressed in trachea. Also expressed in fetal lung, adult pancreas, testis and salivary gland. Expressed at low level in pituitary gland, apex of the heart, adult lung, prostate and mammary gland. Weakly or not expressed in heart, liver and spinal cord.
Component of a PRC1-like complex (PubMed:12167701, PubMed:19636380, PubMed:21282530). The composition of the PRC1 complex may differ between the PRC1 complex in pluripotent embryonic stem cells containing RNF2, CBX7 and PCGF2, and the PRC1 complex in differentiating cells containing RNF2, CBX2, CBX4 and BMI1 (By similarity). May interact with H3C15, H3C1 and RNF2 (PubMed:18927235). Interacts (via chromodomain) with histone H3K9Me3 and H3K27me3 (By similarity).
Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development (PubMed:21282530). PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:21282530). Binds to histone H3 trimethylated at 'Lys-9' (H3K9me3) or at 'Lys-27' (H3K27me3) (By similarity). Plays a role in the lineage differentiation of the germ layers in embryonic development (By similarity). Involved in sexual development, acting as activator of NR5A1 expression (PubMed:19361780).
Expressed during interphase and metaphase.
The human orthologuous proteins of Drosophila Polycomb group protein Pc, CBX2, CBX4, CBX6, CBX7 and CBX8, show distinct nuclear localizations, contribute differently to transcriptional repression, and appear to be part of distinct PRC1-like protein complexes. The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different complexes.
Has NAD-dependent 17-beta-hydroxysteroid dehydrogenase activity. Converts oestradiol to oestrone. The physiological substrate is not known. Acts on oestradiol and 5-androstene-3-beta,17-beta-diol (in vitro).
Highly expressed in brain, placenta, liver and kidney.
Activated by cAMP, and at 10-100 times higher concentrations, also by cGMP. cAMP binding promotes tetramerization and formation of an active channel. Compared to other family members, cAMP has less stimulatory effect on HCN1 because part of the molecules already contain bound cAMP and form homotetramers when cAMP levels are low. Inhibited by Cs(1+), zatebradine, capsazepine and ZD7288.
Belongs to the potassium channel HCN family.
Detected in brain, in particular in amygdala and hippocampus, while expression in caudate nucleus, corpus callosum, substantia nigra, subthalamic nucleus and thalamus is very low or not detectable. Detected at very low levels in muscle and pancreas.
Homotetramer (PubMed:28086084). Heterotetramer with HCN2. The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming subunits. Interacts with KCNE2. Interacts with the SH3 domain of CSK (By similarity).
Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions (PubMed:28086084). Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). May mediate responses to sour stimuli.
Isoform 1 is methylated by CARM1 at Arg-655 in immature thymocytes.
Isoform 2 is expressed in brain. Isoform 1 is present in immature thymocytes (at protein level).
Isoform 2 may act as a competitive inhibitor of calmodulin-dependent enzymes such as calcineurin in neurons.
Phosphorylation at Ser-56 favors interaction with CALM1.
ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports a wide variety of conjugated organic anions such as sulfate-, glucuronide- and glutathione (GSH)-conjugates of endo- and xenobiotics substrates (PubMed:10220572, PubMed:10421658, PubMed:11500505, PubMed:16332456). Mediates hepatobiliary excretion of mono- and bis-glucuronidated bilirubin molecules and therefore play an important role in bilirubin detoxification (PubMed:10421658). Mediates also hepatobiliary excretion of others glucuronide conjugates such as 17beta-estradiol 17-glucosiduronic acid and leukotriene C4 (PubMed:11500505). Transports sulfated bile salt such as taurolithocholate sulfate (PubMed:16332456). Transports various anticancer drugs, such as anthracycline, vinca alkaloid and methotrexate and HIV-drugs such as protease inhibitors (PubMed:10220572, PubMed:11500505, PubMed:12441801). Confers resistance to several anti-cancer drugs including cisplatin, doxorubicin, epirubicin, methotrexate, etoposide and vincristine (PubMed:10220572, PubMed:11500505).
Expressed by polarized cells in liver, kidney and intestine. The highest expression is found in liver. Expressed in small intestine (PubMed:28408210).
May bind noncovalently to lysine binding sites present in the kringle structures of plasminogen. This may interfere with the binding of fibrin or alpha-2-antiplasmin to plasminogen and may result in the localization of activity at sites necessary for extracellular matrix destruction.
Can function as a specific repressor of TGF-beta, activin, and BMP signaling through its interaction with the R-SMAD proteins. Antagonizes TGF-beta-induced cell proliferation arrest.
Heart, brain, placenta, lung, liver and skeletal muscle.
Interacts with SMAD1, SMAD2, SMAD3 and SMAD5. Binds to both phosphorylated and unphosphorylated R-SMADS.
Actin-binding protein that promotes actin bundling. May neither bind calcium nor depend on calcium for function.
Expressed predominantly in testis. Weakly expressed in spleen and thymus. Expressed in the ovaries, Fallopian tubes and uterus (PubMed:30388401).
Required for normal meiotic chromosome synapsis. May be involved in the formation of meiotic double-strand breaks (DSBs) in spermatocytes (By similarity).
Susceptibility to azoospermia may be associated with MEI1 variations.
Interacts with PLZ domains of DLG2, DLG3 and DLG4 via its C-terminal TRV domain. Interacts with GRIN2A and GRIN2B via its CUB domains (By similarity).
Involved in the development and/or maintenance of neuronal circuitry. Accessory subunit of the neuronal N-methyl-D-aspartate receptor (NMDAR) critical for maintaining the abundance of GRIN2A-containing NMDARs in the postsynaptic density. Regulates long-term NMDA receptor-dependent synaptic plasticity and cognition, at least in the context of spatial learning and memory (By similarity).
Isoform 1 and isoform 2 are retina-specific. Isoform 3 is found in retina as well as at lower levels in adult and fetal brain.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. GTPBP1 subfamily.
Interacts with EXOSC2/RRP4, EXOSC3/RRP40, EXOSC5/RRP46, HNRNPD, HNRNPR and SYNCRIP. Identified in a complex with AANAT mRNA, but does not bind mRNA by itself (By similarity).
Promotes degradation of target mRNA species. Plays a role in the regulation of circadian mRNA stability. Binds GTP and has GTPase activity (By similarity).
Endothelial cells depleted in EGFL7 by siRNAs display dramatic alterations in adhesion, morphology, and sprouting. The defects are in part due to diminished RhoA expression and impaired focal adhesion localization.
Interacts with ITGAV/ITGB3 in an RGD-dependent manner, increasing endothelial cell's motility.
Regulates vascular tubulogenesis in vivo. Inhibits platelet-derived growth factor (PDGF)-BB-induced smooth muscle cell migration and promotes endothelial cell adhesion to the extracellular matrix and angiogenesis.
Belongs to the glycosyltransferase 18 family.
Glycosyltransferase that acts on alpha-linked mannose of N-glycans and O-mannosyl glycans. Catalyzes the transfer of N-acetylglucosamine (GlcNAc) to the beta 1-6 linkage of the mannose residue of GlcNAc-beta1,2-Man-alpha on both the alpha1,3- and alpha1,6-linked mannose arms in the core structure of N-glycan. Also acts on the GlcNAc-beta1,2-Man-alpha1-Ser/Thr moiety, forming a 2,6-branched structure in brain O-mannosyl glycan. Plays an active role in modulating integrin and laminin-dependent adhesion and migration of neuronal cells via its activity in the O-mannosyl glycan pathway.
Predominantly expressed in brain. Expressed in all areas of the adult and fetal brain. Also expressed at much lower levels in testis, spleen and thymus.
Belongs to the immunoglobulin superfamily. Turtle family.
Expressed in a wide variety of tissues at 8 and 14 weeks of gestation.
Functions in dendrite outgrowth and synapse maturation.
The PDZ-binding motif mediates interactions with MAGI2 and SHANK1.
Isoform 1 is expressed in skeletal muscle, brain, lung, kidney, prostate and testis. Isoform 3 is mainly expressed in skeletal muscle, liver, spleen and thymus. Expressed in many cancer tissues and cell lines.
Endogenous activator of intestinal guanylate cyclase. It stimulates this enzyme through the same receptor binding region as the heat-stable enterotoxins.
Highly expressed in ileum and colon. Found in plasma.
(Microbial infection) Catalyzes ubiquitination of Botulinum neurotoxin A light chain (LC) of C.botulinum neurotoxin type A (BoNT/A).
Belongs to the class I-like SAM-binding methyltransferase superfamily. RMT2 methyltransferase family.
Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor (PubMed:26003046, PubMed:24415674, PubMed:26319512). Important in nervous system development (PubMed:24415674).
Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor.
(Microbial infection) In case of infection by HIV-1, it binds to the loop region of TAR RNA, a region also bound by RNA polymerase II (PubMed:7638159, PubMed:8626763, PubMed:8846792). Binding of TARBP1 and RNA polymerase II to HIV-1 TAR RNA is mutually exclusive, suggesting that TARBP1 may function alone or in conjunction with HIV-1 Tat to disengage RNA polymerase II from HIV-1 TAR RNA (PubMed:7638159, PubMed:8626763, PubMed:8846792).
Probable S-adenosyl-L-methionine-dependent methyltransferase which methylates RNA molecules such as tRNAs.
Heterodimer; heterodimerizes with NOLC1 following monoubiquitination (PubMed:26399832). Part of a large pre-ribosomal ribonucleoprotein (RNP) complex, that consists of at least 62 ribosomal proteins, 45 nonribosomal proteins and both pre-rRNA and mature rRNA species. Within this complex directly interacts with NOP56 in an RNA-independent manner (PubMed:12777385).
Nucleolar protein that acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification (PubMed:12777385, PubMed:26399832). Required for neural crest specification: following monoubiquitination by the BCR(KBTBD8) complex, associates with NOLC1 and acts as a platform to connect RNA polymerase I with enzymes responsible for ribosomal processing and modification, leading to remodel the translational program of differentiating cells in favor of neural crest specification (PubMed:26399832).
Pyrophosphorylated by 5-diphosphoinositol pentakisphosphate (5-IP7). Serine pyrophosphorylation is achieved by Mg(2+)-dependent, but enzyme independent transfer of a beta-phosphate from a inositol pyrophosphate to a pre-phosphorylated serine residue.
Ubiquitinated. Monoubiquitination by the BCR(KBTBD8) complex promotes the formation of a NOLC1-TCOF1 complex that acts as a platform to connect RNA polymerase I with enzymes responsible for ribosomal processing and modification, leading to remodel the translational program of differentiating cells in favor of neural crest specification (PubMed:26399832).
Interacts with SLP-76 to regulate NF-AT activation. Binds to tyrosine-phosphorylated shc.
Interacts with phosphorylated LIME1 upon TCR activation (By similarity). Interacts with phosphorylated LAT and LAX1 upon TCR activation. Interacts with SHB. Interacts with PTPN23.
Acetylated directly and specifically by EP300 (PubMed:20810990). EP300-mediated acetylation of Lys-206, Lys-212 and Lys-335 stabilizes the protein by antagonizing ubiquitin conjugation (By similarity).
Homodimerizes. Interacts with NCL, NEDD4 and YBX1. Interacts with HNRNPU (via RNA-binding RGG-box region); the interaction facilitates the recruitment of long non-coding RNA Blnc1 by ZBTB7B. Interacts with HDAC4 and HDAC5; the interaction allows the recruitment of HDAC4 and HDAC5 on CD8 loci for deacetylation and possible inhibition of CD8 genes expression.
Transcription regulator that acts as a key regulator of lineage commitment of immature T-cell precursors. Exerts distinct biological functions in the mammary epithelial cells and T cells in a tissue-specific manner. Necessary and sufficient for commitment of CD4 lineage, while its absence causes CD8 commitment. Development of immature T-cell precursors (thymocytes) to either the CD4 helper or CD8 killer T-cell lineages correlates precisely with their T-cell receptor specificity for major histocompatibility complex class II or class I molecules, respectively. Cross-antagonism between ZBTB7B and CBF complexes are determinative to CD4 versus CD8 cell fate decision. Suppresses RUNX3 expression and imposes CD4+ lineage fate by inducing the SOCS suppressors of cytokine signaling. induces, as a transcriptional activator, SOCS genes expression which represses RUNX3 expression and promotes the CD4+ lineage fate. During CD4 lineage commitment, associates with multiple sites at the CD8 locus, acting as a negative regulator of the CD8 promoter and enhancers by epigenetic silencing through the recruitment of class II histone deacetylases, such as HDAC4 and HDAC5, to these loci. Regulates the development of IL17-producing CD1d-restricted naural killer (NK) T cells. Also functions as an important metabolic regulator in the lactating mammary glands. Critical feed-forward regulator of insulin signaling in mammary gland lactation, directly regulates expression of insulin receptor substrate-1 (IRS-1) and insulin-induced Akt-mTOR-SREBP signaling (By similarity). Transcriptional repressor of the collagen COL1A1 and COL1A2 genes. May also function as a repressor of fibronectin and possibly other extracellular matrix genes (PubMed:9370309). Potent driver of brown fat development, thermogenesis and cold-induced beige fat formation. Recruits the brown fat lncRNA 1 (Blnc1):HNRNPU ribonucleoprotein complex to activate thermogenic gene expression in brown and beige adipocytes (By similarity).
Ubiquitinated, leading to proteasomal degradation (PubMed:20810990). Competes with acetylation on Lys-206, Lys-212 and Lys-335 (By similarity).
Acts as a RAC1 guanine nucleotide exchange factor (GEF).
Interacts with PAK kinases through the SH3 domain. Interacts with GIT1. Component of cytoplasmic complexes, which also contain PXN, GIT1 and PAK1 (By similarity). Interacts with PARVB. Interacts with BIN2. Identified in a complex with BIN2 and GIT2.
Interacts with SOX15; the interaction recruits FHL3 to FOXK1 promoters where it acts as a transcriptional coactivator of FOXK1.
Recruited by SOX15 to FOXK1 promoters where it acts as a transcriptional coactivator of FOXK1.
By IFN-alpha/beta and IFN-gamma both at the level of CD48 mRNA and cell surface expression.
Glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein that interacts via its N-terminal immunoglobulin domain with cell surface receptors including 2B4/CD244 or CD2 to regulate immune cell function and activation (PubMed:27249817, PubMed:12007789). Participates in T-cell signaling transduction by associating with CD2 and efficiently bringing the Src family protein kinase LCK and LAT to the TCR/CD3 complex (PubMed:19494291). In turn, promotes LCK phosphorylation and subsequent activation (PubMed:12007789). Induces the phosphorylation of the cytoplasmic immunoreceptortyrosine switch motifs (ITSMs) of CD244 initiating a series of signaling events that leads to the generation of the immunological synapse and the directed release of cytolytic granules containing perforin and granzymes by T-lymphocytes and NK-cells (PubMed:9841922, PubMed:27249817).
Interacts with CD2. Interacts with CD244 (PubMed:9841922, PubMed:27249817). Interacts with LCK (PubMed:12007789).
Widely expressed on all hematopoietic cells.
(Microbial infection) Interacts (via LD motif) with rotavirus A NSP3 (via the coiled-coil region).
May be a specific regulator of miRNA biogenesis. Binds to microRNAs MIR7-1, MIR16-2 and MIR29A hairpins recognizing the 'ATA(A/T)' motif in the apical loop.
Antibodies against TRIM68 are found in patients with systemic lupus erythematosus (SLE) and primary Sjoegren syndrome.
Functions as a ubiquitin E3 ligase. Acts as a coactivator of androgen receptor (AR) depending on its ubiquitin ligase activity.
Interacts with AR/androgen receptor (via ligand-binding domain). Interacts with KAT5/TIP60.
The RING domain is essential for ubiquitin E3 ligase activity.
Widely expressed. Expressed at high levels in prostate cancer cell lines. Up-regulation could be restricted to androgen-dependent cells.
A hemichannel or connexon is composed of a hexamer of connexins. A functional gap junction is formed by the apposition of two hemichannels (PubMed:17551008, PubMed:19340074, PubMed:21094651, PubMed:26753910). Interacts with CNST (PubMed:19864490). Forms heteromeric channels with GJB4 (By similarity).
Structural component of gap junctions (PubMed:17551008, PubMed:19340074, PubMed:21094651, PubMed:26753910, PubMed:16849369, PubMed:19384972). Gap junctions are dodecameric channels that connect the cytoplasm of adjoining cells. They are formed by the docking of two hexameric hemichannels, one from each cell membrane (PubMed:17551008, PubMed:19340074, PubMed:21094651, PubMed:26753910). Small molecules and ions diffuse from one cell to a neighboring cell via the central pore (PubMed:21094651, PubMed:16849369, PubMed:19384972).
The role of Thr-34 and Ile-37 variants in deafness was unclear (PubMed:9139825, PubMed:9422505, PubMed:14694360, PubMed:17935238, PubMed:16849369). However, their pathogenicity has been definitely confirmed (PubMed:31160754).
May play a role in neural crest cell migration into the third and fourth pharyngeal pouches.
Widely expressed in fetal and adult tissues. Highest expression in liver, heart and skeletal muscle. Lower levels in pancreas and placenta. Weak expression in brain.
Detected in round and elongating spermatids.
Detected in testis, sperm and a melanoma cell line.
Available under the names Ceredase and Cerenzyme (Genzyme). Used to treat Gaucher disease.
Belongs to the glycosyl hydrolase 30 family.
Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose (PubMed:9201993, PubMed:24211208, PubMed:15916907, PubMed:32144204). Plays a central role in the degradation of complex lipids and the turnover of cellular membranes (PubMed:27378698). Through the production of ceramides, participates in the PKC-activated salvage pathway of ceramide formation (PubMed:19279011). Catalyzes the glucosylation of cholesterol, through a transglucosylation reaction where glucose is transferred from GlcCer to cholesterol (PubMed:24211208, PubMed:26724485, PubMed:32144204). GlcCer containing mono-unsaturated fatty acids (such as beta-D-glucosyl-N-(9Z-octadecenoyl)-sphing-4-enine) are preferred as glucose donors for cholesterol glucosylation when compared with GlcCer containing same chain length of saturated fatty acids (such as beta-D-glucosyl-N-octadecanoyl-sphing-4-enine) (PubMed:24211208). Under specific conditions, may alternatively catalyze the reverse reaction, transferring glucose from cholesteryl 3-beta-D-glucoside to ceramide (PubMed:26724485) (Probable). Can also hydrolyze cholesteryl 3-beta-D-glucoside producing glucose and cholesterol (PubMed:24211208, PubMed:26724485). Catalyzes the hydrolysis of galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine), as well as the transfer of galactose between GalCers and cholesterol in vitro, but with lower activity than with GlcCers (PubMed:32144204). Contrary to GlcCer and GalCer, xylosylceramide/XylCer (such as beta-D-xyosyl-(1<->1')-N-acylsphing-4-enine) is not a good substrate for hydrolysis, however it is a good xylose donor for transxylosylation activity to form cholesteryl 3-beta-D-xyloside (PubMed:33361282).
Interacts with saposin-C (PubMed:10781797). Interacts with SCARB2 (PubMed:18022370). Interacts with TCP1 (PubMed:21098288). May interacts with SNCA; this interaction may inhibit the glucosylceramidase activity (PubMed:23266198). Interacts with GRN; this interaction prevents aggregation of GBA1-SCARB2 complex via interaction with HSPA1A upon stress (PubMed:27789271).
Produced by alternative initiation from a downstream AUG. Two to three times less protein is produced from this downstream AUG.
Synergistically activated by saposin-A and saposin-C, two saposin peptides produced by proteolytic processing of prosaposin/PSAP (PubMed:9201993). Saposin-C activates GBA1 through its recruitment to membranes (PubMed:10781797, PubMed:9201993). The membrane structure and composition in anionic phospholipids are also important for the activation (PubMed:9201993, PubMed:10781797). Activated by PKC in the salvage pathway of ceramide formation (PubMed:19279011). Inhibited by conduritol B epoxide/CBE (PubMed:24211208, PubMed:26724485).
The disease is caused by variants affecting the gene represented in this entry. Perinatal lethal Gaucher disease is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders.
Detected in bone (PubMed:24058703). Detected in osteoblasts and fibroblasts (at protein level) (PubMed:24519609). Detected in bone (PubMed:24058703). Detected in osteoblasts and fibroblasts (PubMed:24519609).
Required for normal bone mineralization.
Interacts with MEI4 (PubMed:31704776). Interacts with IHO1 (PubMed:31704776). Part of the MCD recombinosome complex, at least composed of IHO1, REC114 and MEI4. Interacts with ANKRD31; the interaction is direct.
Required for DNA double-strand breaks (DSBs) formation in unsynapsed regions during meiotic recombination. Probably acts by forming a complex with IHO1 and MEI4, which activates DSBs formation in unsynapsed regions, an essential step to ensure completion of synapsis.
Orphan receptor. Probably involved in the function of nociceptive neurons. May regulate nociceptor function and/or development, including the sensation or modulation of pain. Potently activated by enkephalins (By similarity).
Uniquely localized in a subset of small dorsal root and trigeminal sensory neurons.
Highly expressed in the platelets, lower levels in the brain. Lowest levels in the lung, appendix, pituitary and adrenal gland. Expressed in the spinal cord and in the fetal brain.
Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Required for normal platelet aggregation and blood coagulation.
The transmembrane domain is composed of seven transmembrane helices; most of these are not strictly perpendicular to the plane of the membrane, but are tilted and/or kinked. Agonist binding promotes a conformation change in the extracellular loops that leads to an inward movement of the transmembrane helices. Antagonists such as AZD1283 can bind to an overlapping site, but block the inward movement of the transmembrane helices (PubMed:24670650, PubMed:24784220).
Belongs to the class-II fumarase/aspartase family. Fumarase subfamily.
Catalyzes the dehydration of L-malate to fumarate (By similarity). Fumarate metabolism in the cytosol plays a role during urea cycle and arginine metabolism; fumarate being a by-product of the urea cycle and amino-acid catabolism (By similarity). Also plays a role in DNA repair by promoting non-homologous end-joining (NHEJ) (PubMed:20231875, PubMed:26237645). In response to DNA damage and phosphorylation by PRKDC, translocates to the nucleus and accumulates at DNA double-strand breaks (DSBs): acts by catalyzing formation of fumarate, an inhibitor of KDM2B histone demethylase activity, resulting in enhanced dimethylation of histone H3 'Lys-36' (H3K36me2) (PubMed:26237645).
Catalyzes the hydration of fumarate to L-malate in the tricarboxylic acid (TCA) cycle to facilitate a transition step in the production of energy in the form of NADH.
Catalyzes the reversible stereospecific interconversion of fumarate to L-malate (PubMed:30761759). Experiments in other species have demonstrated that specific isoforms of this protein act in defined pathways and favor one direction over the other (Probable).
Expressed in red blood cells; underexpressed in red blood cells (cytoplasm) of patients with hereditary non-spherocytic hemolytic anemia of unknown etiology.
Homotetramer (PubMed:21445611, PubMed:30761759). Interacts with H2AZ1 (PubMed:26237645).
Phosphorylation at Thr-236 by PRKDC in response to DNA damage promotes translocation to the nucleus and recruitment to DNA double-strand breaks (DSBs).
The disease is caused by variants affecting the gene represented in this entry. Isoform Cytoplasmic: HLRCC is probably caused by an accumulation of fumarate (PubMed:30718813). Accumulation of fumarate coupled with protonation promotes the formation of non-enzymatic post-translational modification cysteine S-succination (S-(2-succinyl)cysteine) on proteins, such as SMARCC1 (PubMed:30718813).
There are 2 substrate-binding sites: the catalytic A site, and the non-catalytic B site that may play a role in the transfer of substrate or product between the active site and the solvent. Alternatively, the B site may bind allosteric effectors.
(Microbial infection) Exploited by retroviruses for inhibiting self-destructing autointegration of retroviral DNA, thereby promoting integration of viral DNA into the host chromosome (PubMed:9465049, PubMed:11005805, PubMed:16680152). EMD and BAF are cooperative cofactors of HIV-1 infection (PubMed:16680152). Association of EMD with the viral DNA requires the presence of BAF and viral integrase (PubMed:16680152). The association of viral DNA with chromatin requires the presence of BAF and EMD (PubMed:16680152).
(Microbial infection) Interacts with HIV-1 pre-integration complex in cytoplasm by binding to viral matrix protein and Gag polyprotein.
(Microbial infection) Phosphorylated at the N-terminus by vaccinia virus (VacV) B1 kinase, leading to BANF1 relocalization to the cytoplasm, loss of dimerization and impaired DNA binding activity (PubMed:24600006, PubMed:16495336). Hyperphosphorylation is linked to the loss of ability to suppress vaccinia virus replication (PubMed:24600006).
(Microbial infection) Phosphorylated by poxvirus B1 kinase (VPK1) on serine and threonine residues, leading to BANF1 relocalization to the cytoplasm, loss of dimerization and impaired DNA binding activity.
Has a helix-hairpin-helix (HhH) structural motif conserved among proteins that bind non-specifically to DNA.
Homodimer (PubMed:16337940, PubMed:22399800, PubMed:28841419). Heterodimerizes with BANF2 (PubMed:16337940). Interacts with ANKLE2/LEM4, leading to decreased phosphorylation by VRK1 and promoting dephosphorylation by protein phosphatase 2A (PP2A) (PubMed:22770216). Binds non-specifically to double-stranded DNA, and is found as a hexamer or dodecamer upon DNA binding. Binds to LEM domain-containing nuclear proteins such as LEMD3/MAN1, TMPO/LAP2 and EMD (emerin) (PubMed:11792822, PubMed:15681850). Interacts with ANKLE1 (via LEM domain); the interaction may favor BANF1 dimerization (PubMed:22399800). Interacts with CRX and LMNA (lamin-A). Binds linker histone H1.1 and core histones H3 (PubMed:16203725). Interacts with LEMD2 (via LEM domain) (PubMed:32494070). Interacts with PARP1; interaction takes place in response to oxidative DNA damage (PubMed:31796734).
LEM domain proteins bind centrally on the BAF dimer.
Non-specific DNA-binding protein that plays key roles in mitotic nuclear reassembly, chromatin organization, DNA damage response, gene expression and intrinsic immunity against foreign DNA (PubMed:10908652, PubMed:11792822, PubMed:12163470, PubMed:18005698, PubMed:25991860, PubMed:28841419, PubMed:31796734, PubMed:32792394). Contains two non-specific double-stranded DNA (dsDNA)-binding sites which promote DNA cross-bridging (PubMed:9465049). Plays a key role in nuclear membrane reformation at the end of mitosis by driving formation of a single nucleus in a spindle-independent manner (PubMed:28841419). Transiently cross-bridges anaphase chromosomes via its ability to bridge distant DNA sites, leading to the formation of a dense chromatin network at the chromosome ensemble surface that limits membranes to the surface (PubMed:28841419). Also acts as a negative regulator of innate immune activation by restricting CGAS activity toward self-DNA upon acute loss of nuclear membrane integrity (PubMed:32792394). Outcompetes CGAS for DNA-binding, thereby preventing CGAS activation and subsequent damaging autoinflammatory responses (PubMed:32792394). Also involved in DNA damage response: interacts with PARP1 in response to oxidative stress, thereby inhibiting the ADP-ribosyltransferase activity of PARP1 (PubMed:31796734). Involved in the recognition of exogenous dsDNA in the cytosol: associates with exogenous dsDNA immediately after its appearance in the cytosol at endosome breakdown and is required to avoid autophagy (PubMed:25991860). In case of poxvirus infection, has an antiviral activity by blocking viral DNA replication (PubMed:18005698).
Ser-4 is the major site of phosphorylation as compared to Thr-2 and Thr-3. Phosphorylation on Thr-2; Thr-3 and Ser-4 disrupts its ability to bind DNA and reduces its ability to bind LEM domain-containing proteins. Non phosphorylated BAF seems to enhance binding between EMD and LMNA. Dephosphorylated by protein phosphatase 2A (PP2A) following interaction with ANKLE2/LEM4 during mitotic exit, leading to mitotic nuclear envelope reassembly.
Widely expressed. Expressed in colon, brain, heart, kidney, liver, lung, ovary, pancreas, placenta, prostate, skeletal muscle, small intestine, spleen and testis. Not detected in thymus and peripheral blood leukocytes.
Binds GDP/GTP and may possess intrinsic GTPase activity.
Might play a role in mitosis. Antigenic molecule. Could be a centromere-associated protein. May induce anti-centromere antibodies.
Interacts with TRPC3 (PubMed:20095964). Interacts with BAG5 and HSPA8; the interaction with HSPA8 is increased in the presence of BAG5 (PubMed:35044787).
Membrane-binding protein that provides a structural bridge between the plasma membrane and the sarcoplasmic reticulum and is required for normal excitation-contraction coupling in cardiomyocytes (PubMed:20095964). Provides a structural foundation for functional cross-talk between the cell surface and intracellular Ca(2+) release channels by maintaining the 12-15 nm gap between the sarcolemma and the sarcoplasmic reticulum membranes in the cardiac dyads (By similarity). Necessary for proper intracellular Ca(2+) signaling in cardiac myocytes via its involvement in ryanodine receptor-mediated calcium ion release (By similarity). Contributes to the construction of skeletal muscle triad junctions (By similarity).
Phosphorylation on Ser-165, probably by PKC, affects RYR1-mediated calcium ion release, interaction with TRPC3, and skeletal muscle myotubule development.
Proteolytically cleaved by calpain in response to cardiac stress. The major cleavage site takes place at the C-terminus and leads to the release of the Junctophilin-2 N-terminal fragment chain (JP2NT).
Specifically expressed in skeletal muscle and heart.
The MORN (membrane occupation and recognition nexus) repeats contribute to the plasma membrane binding, by interacting with phospholipids (PubMed:24001019). Has affinity for phosphatidylserine, and phosphorylated phosphatidylinositols including PtdIns3P, PtdIns4P, PtdIns5P, PtdIns(3,5)P2 and PtdIns(3,4,5)P3 (PubMed:24001019).
The bipartite nuclear localization signal (bNLS) and Ala-rich (alanine-rich; ARR) regions are involved in DNA-binding.
Transcription repressor required to safeguard against the deleterious effects of cardiac stress. Generated following cleavage of the Junctophilin-2 chain by calpain in response to cardiac stress in cardiomyocytes. Following cleavage and release from the membrane, translocates to the nucleus, binds DNA and represses expression of genes implicated in cell growth and differentiation, hypertrophy, inflammation and fibrosis. Modifies the transcription profile and thereby attenuates pathological remodeling in response to cardiac stress. Probably acts by competing with MEF2 transcription factors and TATA-binding proteins.
Calcium channels are probably composed of 3 subunit of PKD2L1 and 1 subunit of PKD1L3.
Component of a calcium channel. May act as a sour taste receptor by forming a calcium channel with PKD1L3 in gustatory cells; however, its contribution to sour taste perception is unclear in vivo and may be indirect.
Highly expressed in placenta, weakly in heart and lung.
PKD1L3 and PKD2L1 have been defined as sour taste receptor in gustatory cells based on a number of indirect evidences in mouse. Some data confirm this hypothesis in human: in 2 patients with sour ageusia that are unresponsive to sour stimuli, but show normal responses to bitter, sweet, and salty stimuli, expression of PKD1L3 and PKD2L1 is absent in the anterior part of the tongue (PubMed:19812697). However, a number of experiments have recently shown that the sour taste receptor activity is probably indirect.
The calcium channel is gated following an off-response property by acid: gated open after the removal of acid stimulus, but not during acid application.
Down-regulated upon retinoic acid addition to F9 stem cells.
Expressed in kidney, epidermal keratinocytes, prostate epithelial cells, bronchial and small airway lung epithelial cells (at protein level). Expressed in malignant kidney and several carcinoma cell lines (at protein level). Expressed in embryonic stem cells, kidney, epidermal keratinocytes, prostate epithelial cells, bronchial and small airway lung epithelial cells. Expressed in embryonal carcinomas, seminomas, malignant kidney and several carcinoma cell lines.
Involved in the reprogramming of X-chromosome inactivation during the acquisition of pluripotency. Required for efficient elongation of TSIX, a non-coding RNA antisense to XIST. Binds DXPas34 enhancer within the TSIX promoter. Involved in ES cell self-renewal (By similarity).
Polyubiquitinated by RNF12, leading to proteasomal degradation.
Activity is increased by oligomerization of the protein into filaments (PubMed:19900410). The oligomerization and the activity of the enzyme are inhibited by phosphorylation at Ser-222 (PubMed:12488245). Inhibited by its product, malonyl-CoA (PubMed:16854592). Activated by citrate (PubMed:16854592). Activation by MID1IP1 is citrate-dependent (PubMed:20457939). Soraphen A, inhibits the enzyme by preventing the formation of active filamentous oligomers (Probable).
Consists of an N-terminal biotin carboxylation/carboxylase (BC) domain that catalyzes the ATP-dependent transient carboxylation of the biotin covalently attached to the central biotinyl-binding/biotin carboxyl carrier (BCC) domain (Probable). The C-terminal carboxyl transferase (CT) domain catalyzes the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA to produce malonyl-CoA (Probable).
Inhibition of ACACB may prevent lipid-induced insulin resistance and type 2 diabetes, making the enzyme a potential pharmaceutical target for treatment of obesity and type 2 diabetes.
Mitochondrial enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA and plays a central role in fatty acid metabolism (PubMed:16854592, PubMed:19236960, PubMed:20457939, PubMed:20952656, PubMed:19900410, PubMed:26976583). Catalyzes a 2 steps reaction starting with the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain followed by the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA (PubMed:19236960, PubMed:20457939, PubMed:20952656, PubMed:26976583). Through the production of malonyl-CoA that allosterically inhibits carnitine palmitoyltransferase 1 at the mitochondria, negatively regulates fatty acid oxidation (By similarity). Together with its cytosolic isozyme ACACA, which is involved in de novo fatty acid biosynthesis, promotes lipid storage (By similarity).
Monomer, homodimer, and homotetramer (PubMed:20952656, PubMed:18772397). Forms filamentous polymers (PubMed:20457939, PubMed:20952656, PubMed:19900410). Interacts with MID1IP1; interaction with MID1IP1 promotes oligomerization and increases its activity in a citrate-dependent manner (PubMed:20952656, PubMed:20457939).
Phosphorylation at Ser-222 by AMPK inactivates the enzyme (PubMed:12488245). Required for the maintenance of skeletal muscle lipid and glucose homeostasis (By similarity).
The biotin cofactor is covalently attached to the central biotinyl-binding domain and is required for the catalytic activity.
Widely expressed with highest levels in heart, skeletal muscle, liver, adipose tissue, mammary gland, adrenal gland and colon (PubMed:9099716). Isoform 3 is expressed in skeletal muscle, adipose tissue and liver (at protein level) (PubMed:19190759). Isoform 3 is detected at high levels in adipose tissue with lower levels in heart, liver, skeletal muscle and testis (PubMed:19190759).
Expressed most strongly in adult and fetal brain.
May play important roles in selective fasciculation and zone-to-zone projection of the primary olfactory axons.
May play a role as a receptor for the recognition of MHC class I HLA-E molecules by NK cells.
According to PubMed:11830526, exclusively expressed in the prostate. Expressed in breast and prostate cancer cell lines. Expressed in prostatic luminal epithelial cells (at protein level). Expression is significantly more abundant in prostate cancer than in benign prostatic tissue (prostatic hyperplasia). According to PubMed:12111373, also expressed in brain, pancreas and skeletal muscle, and at lower levels in small intestine, testis, leukocyte and thymus.
Controlled by regulated intramembrane proteolysis (RIP). Following ER stress a fragment containing the cytoplasmic transcription factor domain is released by proteolysis. The cleavage seems to be performed sequentially by site-1 and site-2 proteases (PS1 and PS2). PS1 cleavage may be suppressed by a determinant in the C-terminal region (By similarity).
N-glycosylated in the C-terminal region.
Transcriptional activator that may play a role in the unfolded protein response. Binds to the UPR element (UPRE) but not to CRE element. Preferentially binds DNA with to the consensus sequence 5'-T[GT]ACGT[GA][GT]-3' and has transcriptional activation activity from UPRE. Binds to NF-kappa-B site and has transcriptional activation activity from NF-kappa-B-containing regulatory elements (By similarity).
Component of several multiprotein Golgi SNARE complexes.
Component of several multiprotein Golgi SNARE complexes. Identified in a SNARE complex with BET1, STX5 and YKT6, in a SNARE complex with BET1L, STX5 and YKT6, in a SNARE complex with STX5, GOSR2, SEC22B and BET1, and in complex with STX5 and COG3. Interacts with GABARAPL2 (By similarity).
Expression induced by hydrogen peroxide in neuronal cells. By monocrotaline in pulmonary epithelial cells (at protein level). Negatively regulated by OSBPL7 via GABARAPL2 leading to degradation on proteasomes (at protein level).
Involved in transport from the ER to the Golgi apparatus as well as in intra-Golgi transport. It belongs to a super-family of proteins called t-SNAREs or soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptor. May play a protective role against hydrogen peroxide induced cytotoxicity under glutathione depleted conditions in neuronal cells by regulating the intracellular ROS levels via inhibition of p38 MAPK (MAPK11, MAPK12, MAPK13 and MAPK14). Participates in docking and fusion stage of ER to cis-Golgi transport. Plays an important physiological role in VLDL-transport vesicle-Golgi fusion and thus in VLDL delivery to the hepatic cis-Golgi.
Cholesterol-binding protein involved in the redistribution of cholesterol from lipid droplets to the endoplasmic reticulum (PubMed:19729679). Required to meet cholesterol demands during erythropoietic differentiation (PubMed:19729679). May play a role in transport processes at the plasma membrane of erythrocytes, including regulating VDAC-mediated ATP export, and import of the heme precursors protoporphyrin IX and 5-aminolevulinic acid (PubMed:27641616, PubMed:30061676, PubMed:31989647).
Expression levels increase during erythrocyte differentiation.
Homotetramer (PubMed:27641616). May also form homodimer (PubMed:27641616).
The C-terminal region mediates cholesterol-binding.
Expressed in the poorly differentiated crypt cells of the small intestine as well as in the mature villous cells. Expressed at very low levels in the colon.
Plays an important role in the final stage of carbohydrate digestion. Isomaltase activity is specific for both alpha-1,4- and alpha-1,6-oligosaccharides.
The precursor is proteolytically cleaved when exposed to pancreatic proteases in the intestinal lumen.
The resulting sucrase and isomaltase subunits stay associated with one another in a complex by non-covalent linkages.
There is a high degree of homology between the isomaltase and sucrase portions (41% of amino acid identity) indicating that this protein is evolved by partial gene duplication.
Is a promoter of calcium phosphate mineralization, playing a critical role in the formation of the compact, mineralized, aprismatic enamel surface layer during the maturation stage of amelogenesis.
Calcium-binding protein that acts as an adapter that bridges unrelated proteins or stabilizes weak protein-protein complexes in response to calcium. Together with PDCD6, acts as calcium-dependent adapter for the BCR(KLHL12) complex, a complex involved in endoplasmic reticulum (ER)-Golgi transport by regulating the size of COPII coats (PubMed:27716508). In response to cytosolic calcium increase, the heterodimer formed with PDCD6 interacts with, and bridges together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export, which is required for neural crest specification (PubMed:27716508). Its role in the heterodimer formed with PDCD6 is however unclear: some evidence shows that PEF1 and PDCD6 work together and promote association between PDCD6 and SEC31 in presence of calcium (PubMed:27716508). Other reports show that PEF1 dissociates from PDCD6 in presence of calcium, and may act as a negative regulator of PDCD6 (PubMed:11278427). Also acts as a negative regulator of ER-Golgi transport; possibly by inhibiting interaction between PDCD6 and SEC31 (By similarity).
Heterodimer; heterodimerizes (via the EF-hand 5) with PDCD6 (PubMed:11278427, PubMed:11883899, PubMed:27716508). Dissociates from PDCD6 in presence of calcium (PubMed:11278427).
Ubiquitinated by the BCR(KLHL12) E3 ubiquitin ligase complex.
Belongs to the small GTPase superfamily. RasD family.
Expressed in a variety of tissues including heart, cardiovascular tissues, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, gastrointestinal and reproductive tissues.
Forms a ternary complex with CAPON and NOS1. Component of a complex, at least composed of APBB1, RASD1/DEXRAS1 and APP. Interacts with APBB1/FE65 (By similarity).
S-nitrosylation stimulates guanine-nucleotide exchange activity.
Small GTPase. Negatively regulates the transcription regulation activity of the APBB1/FE65-APP complex via its interaction with APBB1/FE65 (By similarity).
Belongs to the glycosyltransferase 43 family.
Involved in the biosynthesis of L2/HNK-1 carbohydrate epitope on glycoproteins. Can also play a role in glycosaminoglycan biosynthesis. Substrates include asialo-orosomucoid (ASOR), asialo-fetuin, and asialo-neural cell adhesion molecule. Requires sphingomyelin for activity: stearoyl-sphingomyelin was the most effective, followed by palmitoyl-sphingomyelin and lignoceroyl-sphingomyelin. Activity was demonstrated only for sphingomyelin with a saturated fatty acid and not for that with an unsaturated fatty acid, regardless of the length of the acyl group.
Involved in the recruitment of key centrosomal proteins to the centrosome. Provides centrosomal microtubule-nucleation activity on the gamma-tubulin ring complexes (gamma-TuRCs) and has critical roles in forming a focused bipolar spindle, which is needed for proper tension generation between sister chromatids. Required for localization of KIZ, AKAP9 and gamma-tubulin ring complexes (gamma-TuRCs) (PubMed:19536135). Involved in centriole duplication. Required for CDK5RAP22, CEP152, WDR62 and CEP63 centrosomal localization and promotes the centrosomal localization of CDK2 (PubMed:26297806).
Does not seem to be a disulfide isomerase.
Does not seem to be a disulfide isomerase. Plays an important role in the processing of secretory proteins within the endoplasmic reticulum (ER), possibly by participating in the folding of proteins in the ER.
Homodimer. Part of a large chaperone multiprotein complex comprising CABP1, DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX (PubMed:12475965).
Ubiquitous. Mostly expressed in secretory tissues.
Downstream effector for Rab11 involved in the inhibition of the intracellular ciliogenesis pathway in concert with AKT1 kinase (PubMed:31204173). When the LPAR1 receptor signaling pathway is activated, phosphorylated WDR44 binds to Rab11, thus preventing the formation of the ciliogenic Rab11-Rabin8/RAB3IP-RAB11FIP3 complex (PubMed:31204173). Together with Rab11, also participates in the regulation of vesicle recycling (By similarity).
Interacts with the GTP-bound form of RAB11A and RAB11B (PubMed:31204173). Does not bind to RAB7, RAB10, RAB14, RAB35 and RAB8A (PubMed:31204173).
Phosphorylated by ATK1; the phosphorylation stabilizes its interaction with RAB11A and RAB11B.
Required for the processing of the 27S pre-rRNA.
Specifically interacts with EBV EBNA1. The EBNA1-EBP2 interaction is important for the stable segregation of EBV episomes during cell division (PubMed:10074103). Interacts with WDR46.
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family.
Has a role in pre-mRNA splicing. Phosphorylates SF2/ASF.
Identified in the spliceosome C complex. Interacts with Clk1 C-terminus.
A study showed that INSIG2 is not ubiquitinated by AMFR/gp78 (PubMed:17043353). However, another paper showed that it is ubiquitinated on Cys-215, and that ubiquitination takes place in some tissues only and depends on the differentiation state (PubMed:31953408).
Binds oxysterols in a pocket within their transmembrane domains and interacts with SCAP via transmembrane domains 3 and 4.
Interacts with SCAP; interaction is direct and only takes place in the presence of sterols; it prevents interaction between SCAP and the coat protein complex II (COPII) (PubMed:12242332, PubMed:17428920, PubMed:26160948, PubMed:32322062). Associates with the SCAP-SREBP complex (composed of SCAP and SREBF1/SREBP1 or SREBF2/SREBP2); association is mediated via its interaction with SCAP and only takes place in the presence of sterols (PubMed:12242332, PubMed:32322062). Interacts with RNF139 (PubMed:20068067, PubMed:22143767). Interacts with RNF145 (PubMed:29374057).
Mediates feedback control of cholesterol synthesis.
Oxidized at Cys-215 in differentiated myotubes, preventing ubiquitination at the same site, and resulting in protein stabilization.
Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR (PubMed:12242332, PubMed:16606821, PubMed:32322062). Acts as a negative regulator of cholesterol biosynthesis by mediating the retention of the SCAP-SREBP complex in the endoplasmic reticulum, thereby blocking the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:32322062). Binds oxysterol, including 22-hydroxycholesterol, 24-hydroxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum (PubMed:26160948, PubMed:17428920, PubMed:32322062). In presence of oxysterol, interacts with SCAP, retaining the SCAP-SREBP complex in the endoplasmic reticulum, thereby preventing SCAP from escorting SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi (PubMed:32322062). Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding, disrupting the interaction between INSIG2 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:32322062). Also regulates cholesterol synthesis by regulating degradation of HMGCR: initiates the sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligase RNF139 (PubMed:16606821, PubMed:22143767).
Phosphorylation at Ser-151 by PCK1 reduces binding to oxysterol, disrupting the interaction between INSIG2 and SCAP, thereby promoting nuclear translocation of SREBP proteins (SREBF1/SREBP1 or SREBF2/SREBP2) and subsequent transcription of downstream lipogenesis-related genes.
Polyubiquitinated by AMFR/gp78 at Cys-215 in some tissues such as adipose tissues, undifferentiated myoblasts and liver, leading to its degradation (PubMed:31953408). In differentiated myotubes, Cys-215 oxidation prevents ubiquitination at the same site, resulting in protein stabilization (PubMed:31953408).
The KxHxx motif mediates association with the coatomer complex.
Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini (PubMed:19179534). May have a general role in telomere regulation (PubMed:12676087, PubMed:12699629). Promotes in vitro the ability of TERT to elongate telomeres (PubMed:12676087, PubMed:12699629). Overexpression induces telomere uncapping, chromosomal end-to-end fusions (telomeric DNA persists at the fusion points) and did not perturb TRF2 telomeric localization (PubMed:12676087, PubMed:12699629). Binds to the single-stranded 5'-(GTGTGG)(4)GTGT-3' telomeric DNA, but not to a telomerase RNA template component (TER) (PubMed:12676087, PubMed:12699629).
May form homooligomers (PubMed:20930030). Associated component of the telomerase holoenzyme complex (PubMed:19179534). Interacts with TERT, independently of the telomerase RNA (PubMed:12676087, PubMed:12699629). Interacts with SMG1, SMG5, SMG7, UPF1, UPF2, UPF3B and the PP2A catalytic subunits (PubMed:12554878, PubMed:19060897, PubMed:20930030). Also interacts with the exon junction complex (EJC) composed at least of CASC3, EIF4A3, MAGOH and RBM8A; required for the process of nonsense-mediated mRNA decay (PubMed:20930030). Interacts with DHX34; the interaction is RNA-independent (PubMed:25220460).
Plays a role in nonsense-mediated mRNA decay (PubMed:18974281, PubMed:19060897, PubMed:20930030, PubMed:17053788). Is thought to provide a link to the mRNA degradation machinery as it has endonuclease activity required to initiate NMD, and to serve as an adapter for UPF1 to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation (PubMed:18974281, PubMed:19060897, PubMed:20930030, PubMed:17053788). Degrades single-stranded RNA (ssRNA), but not ssDNA or dsRNA (PubMed:18974281, PubMed:19060897, PubMed:20930030, PubMed:17053788).
The PINc domain confers endonuclease activity and is expected to bind the catalytic metal ion.
Highly expressed in neutrophils, primary monocytes, mast cells, monocytic cell lines and lymphocytes. Also expressed in spleen B and T-cells, and lung. Expressed at low level in non-immune tissue.
May function in immune system as a receptor which activates via the calcineurin/NFAT-signaling pathway the downstream cytokine gene promoters. Activates the transcription of IL-13 and TNF-alpha promoters. May be involved in the regulation of B-cell, but not T-cell, development. Overexpression activates downstream effectors without ligand binding or antibody cross-linking.
No direct interaction with the B-cell antigen receptor (BCR). Interacts with SYK; probably involved in BCR signaling. Interacts with ZAP70 (By similarity).
The ITAM domain displays no close similarity to any existing ITAMs, except for four conserved positions. The phosphorylated ITAM domain binds ZAP70 and SYK.
GSS(-) is a potent inhibitor of TSTD1, since the presence of the sulfur dioxygenase (SDO) strongly increases the TSTD1 catalytic activity (PubMed:24981631).
Highly expressed in kidney, liver and skeletal muscle. Lower levels of expression in heart, colon, thymus, spleen, placenta and lung. Weakly expressed in brain, small intestine and peripheral blood leukocytes. Expressed at high levels in the breast carcinoma cell lines MCF-7 and MDA-MB-468 and at a lower level in the breast carcinoma cell line MDA-MB-231, the colon carcinoma call line LoVo and the lung carcinoma cell line A-549. No expression in the cell lines EFO-27 and HeLa, or the normal breast tissue cell lines MCF-10A and H184A1. Detected in invasive ductal carcinoma, but not in the adjacent tissues.
Thiosulfate:glutathione sulfurtransferase (TST) required to produce S-sulfanylglutathione (GSS(-)), a central intermediate in hydrogen sulfide metabolism (PubMed:24981631). Provides the link between the first step in mammalian H(2)S metabolism performed by the sulfide:quinone oxidoreductase (SQOR) which catalyzes the conversion of H(2)S to thiosulfate, and the sulfur dioxygenase (SDO) which uses GSS(-) as substrate (PubMed:24981631). The thermodynamic coupling of the irreversible SDO and reversible TST reactions provides a model for the physiologically relevant reaction with thiosulfate as the sulfane donor (PubMed:24981631).
Belongs to the Rieske iron-sulfur protein family.
Binds 1 [2Fe-2S] cluster per subunit. Fe-S cluster delivery to the Rieske protein is mediated by components of the iron sulfur (Fe-S) cluster assembly machinery that reside in the mitochondrial matrix (including HSC20 and LYRM7).
Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits. The complex is composed of 3 respiratory subunits cytochrome b, cytochrome c1 and Rieske protein UQCRFS1, 2 core protein subunits UQCRC1/QCR1 and UQCRC2/QCR2, and 6 low-molecular weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, UQCR10/QCR9, UQCR11/QCR10 and subunit 9, the cleavage product of Rieske protein UQCRFS1 (By similarity). The complex exists as an obligatory dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and cytochrome c oxidase (complex IV, CIV), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Incorporation of the Rieske protein UQCRFS1 is the penultimate step in complex III assembly (PubMed:28380382). Interacts with TTC19, which is involved in the clearance of UQCRFS1 fragments (PubMed:28673544).
Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII). Subunit 9 corresponds to the mitochondrial targeting sequence (MTS) of Rieske protein UQCRFS1. It is retained after processing and incorporated inside complex III, where it remains bound to the complex and localizes between the 2 core subunits UQCRC1/QCR1 and UQCRC2/QCR2.
Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII). UQCRFS1 undergoes proteolytic processing once it is incorporated in the complex III dimer. One of the fragments, called subunit 9, corresponds to its mitochondrial targeting sequence (MTS). The proteolytic processing is necessary for the correct insertion of UQCRFS1 in the complex III dimer, but the persistence of UQCRFS1-derived fragments may prevent newly imported UQCRFS1 to be processed and assembled into complex III and is detrimental for the complex III structure and function.
Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation (PubMed:31883641). The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. The cytochrome b-c1 complex catalyzes electron transfer from ubiquinol to cytochrome c, linking this redox reaction to translocation of protons across the mitochondrial inner membrane, with protons being carried across the membrane as hydrogens on the quinol. In the process called Q cycle, 2 protons are consumed from the matrix, 4 protons are released into the intermembrane space and 2 electrons are passed to cytochrome c. The Rieske protein is a catalytic core subunit containing a [2Fe-2S] iron-sulfur cluster. It cycles between 2 conformational states during catalysis to transfer electrons from the quinol bound in the Q(0) site in cytochrome b to cytochrome c1 (By similarity). Incorporation of UQCRFS1 is the penultimate step in complex III assembly (PubMed:28673544).
Proteolytic processing is necessary for the correct insertion of UQCRFS1 in the complex III dimer. Several fragments are generated during UQCRFS1 insertion, most probably due to the endogenous matrix-processing peptidase (MPP) activity of the 2 core protein subunits UQCRC1/QCR1 and UQCRC2/QCR2, which are homologous to the 2 mitochondrial-processing peptidase (MPP) subunits beta-MPP and alpha-MPP respectively. The action of the protease is also necessary for the clearance of the UQCRFS1 fragments.
Several peptides are generated during UQCRFS1 insertion (PubMed:28673544). According to some authors, the identification of the transit peptide as the subunit 9, does not necessary imply that it must be considered as a structural subunit of the complex III dimer as additional fragments from UQCRFS1 are also present (PubMed:28673544).
The Rieske protein is a high potential 2Fe-2S protein.
Binds to the ANK repeat domain of TNKS1 and TNKS2.
Detected in testis, ovary, lung, skeletal muscle, heart, prostate and pancreas, and at very low levels in brain and peripheral blood leukocytes.
Homodimer. May form a heterodimers with other members of the Deltex family. Interacts with NOTCH1.
Regulator of Notch signaling, a signaling pathway involved in cell-cell communications that regulates a broad spectrum of cell-fate determinations. Probably acts both as a positive and negative regulator of Notch, depending on the developmental and cell context (By similarity). Functions as an ubiquitin ligase protein in vitro, suggesting that it may regulate the Notch pathway via some ubiquitin ligase activity.
(Microbial infection) Interacts with EMCV protease 3C; this interaction leads to viral protease ubiquitination.
(Microbial infection) Interacts with HIV-1 Gag polyprotein; this interaction seems to reduce gag production or virus budding.
By interferons alpha and beta (PubMed:25683609). Up-regulated by p53/TP53. Dramatically induced by progesterone in MDA-MB-231-derived ABC28 cells and T47D cells. By interferon gamma (PubMed:35777501). Expression is also modulated in response to several viruses and viral antigens (PubMed:36042495).
Interferon-induced E3 ubiquitin ligase that plays important roles in innate and adaptive immunity (PubMed:25683609, PubMed:35777501). Restricts the replication of many viruses including HIV-1, encephalomyocarditis virus (EMCV), hepatitis B virus (HBV), hepatitis C virus (HCV) or Zika virus (ZIKV) (PubMed:25683609, PubMed:35777501, PubMed:36042495). Mechanistically, negatively regulates HCV replication by promoting ubiquitination and subsequent degradation of viral NS5A (PubMed:25683609). Acts also by promoting the degradation of Zika virus NS1 and NS3 proteins through proteasomal degradation (PubMed:36042495). Acts as a suppressor of basal HIV-1 LTR-driven transcription by preventing Sp1 binding to the HIV-1 promoter (PubMed:26683615). Plays also a role in antiviral immunity by co-regulating together with NT5C2 the RIGI/NF-kappa-B pathway by promoting 'Lys-63'-linked ubiquitination of RIGI, while NT5C2 is responsible for 'Lys-48'-linked ubiquitination of RIGI (PubMed:36159777). Participates in adaptive immunity by suppressing the amount of MHC class II protein in a negative feedback manner in order to limit the extent of MHC class II induction (PubMed:35777501).
Strongly expressed in peripheral blood leukocytes, spleen, thymus, and ovary. Expressed at basal levels in other tissues.
The C-terminal SPRY domain is required for the transcriptional suppressor activity, probably by mediating correct nuclear localization. Residues 491-494 are essential for nuclear localization and nuclear bodies formation.
The RING domain is essential for antiviral activity and for TRIM22 nuclear bodies (NB) formation but is not necessary for nuclear localization.
(Microbial infection) In case of FCV infection, plays a role in the ribosomal termination-reinitiation event leading to the translation of VP2 (PubMed:18056426).
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is composed of 13 subunits: EIF3A, EIF3B, EIF3C, EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L and EIF3M. The eIF-3 complex appears to include 3 stable modules: module A is composed of EIF3A, EIF3B, EIF3G and EIF3I; module B is composed of EIF3F, EIF3H, and EIF3M; and module C is composed of EIF3C, EIF3D, EIF3E, EIF3K and EIF3L. EIF3C of module C binds EIF3B of module A and EIF3H of module B, thereby linking the three modules. EIF3J is a labile subunit that binds to the eIF-3 complex via EIF3B. The eIF-3 complex interacts with RPS6KB1 under conditions of nutrient depletion. Mitogenic stimulation leads to binding and activation of a complex composed of MTOR and RPTOR, leading to phosphorylation and release of RPS6KB1 and binding of EIF4B to eIF-3. Interacts (via C-terminus) with AIFM1 (via N-terminus). Interacts with DHX33; the interaction is independent of RNA (PubMed:26100019).
Phosphorylated. Phosphorylation is enhanced upon serum stimulation.
RNA-binding component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:17581632, PubMed:25849773, PubMed:27462815). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation (PubMed:17581632). The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression (PubMed:25849773). This subunit can bind 18S rRNA.
Interacts with CCDC22, CCDC93, VPS26C and VPS35L, associates with the retriever and CCC complexes.
Catalytic subunit of the SLX1-SLX4 structure-specific endonuclease that resolves DNA secondary structures generated during DNA repair and recombination. Has endonuclease activity towards branched DNA substrates, introducing single-strand cuts in duplex DNA close to junctions with ss-DNA. Has a preference for 5'-flap structures, and promotes symmetrical cleavage of static and migrating Holliday junctions (HJs). Resolves HJs by generating two pairs of ligatable, nicked duplex products.
Found in a segmental duplication on p arm of chromosome 16 giving rise to two identical copies of this gene sharing exons with SULT1A3 and SULT1A4.
By UV irradiation, X-rays, growth arrest and alkylating agents. The induction is mediated by some kinase(s) other than PKC.
In T-cells, functions as a regulator of p38 MAPKs by inhibiting p88 phosphorylation and activity (By similarity). Might affect PCNA interaction with some CDK (cell division protein kinase) complexes; stimulates DNA excision repair in vitro and inhibits entry of cells into S phase.
Interacts with MAPK14 (By similarity). Predominantly monomeric but also forms dimers and other oligomers as concentration increases. Interacts with GADD45GIP1. Interacts weakly with PCNA. Interacts with AURKA, likely to compete with dimerization.
Appears to function in the U7 snRNP complex that is involved in histone 3'-end processing. Increases U7 snRNA levels but not histone 3'-end pre-mRNA processing activity, when overexpressed. Required for cell cycle progression from G1 to S phases. Binds specifically to U7 snRNA. Binds to the downstream cleavage product (DCP) of histone pre-mRNA in a U7 snRNP dependent manner.
Component of the heptameric ring U7 snRNP complex, or U7 Sm protein core complex, at least composed of LSM10, LSM11, SNRPB, SNRPD3, SNRPE, SNRPF, SNRPG and U7 snRNA. Formation of the U7 snRNP is an ATP-dependent process mediated by a specialized SMN complex containing at least the Sm protein core complex and additionally, the U7-specific LSM10 and LSM11 proteins. Interacts with CLNS1A and SMN.
Not methylated. Methylation is not necessary for interaction with SMN.
Activated by Ca(2+)-bound calmodulin following an increase in intracellular Ca(2+). At low Ca(2+) concentrations, the catalytic subunit (also known as calcineurin A) is inactive and is bound to the regulatory subunit (also known as calcineurin B) in which only two high-affinity binding sites are occupied by Ca(2+). In response to elevated calcium levels, the occupancy of the low-affinity sites on calcineurin B by Ca(2+) causes a conformational change of the C-terminal regulatory domain of calcineurin A, resulting in the exposure of the calmodulin-binding domain and in the partial activation of calcineurin A. The subsequent binding of Ca(2+)-bound calmodulin leads to the displacement of the autoinhibitory domain from the active site and possibly of the autoinhibitory segment from the substrate binding site which fully activates calcineurin A.
Belongs to the PPP phosphatase family. PP-2B subfamily.
Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals. Dephosphorylates and activates transcription factor NFATC1. Dephosphorylates and inactivates transcription factor ELK1. Dephosphorylates DARPP32.
Forms a complex composed of a calmodulin-dependent catalytic subunit (also known as calcineurin A) and a regulatory Ca(2+)-binding subunit (also known as calcineurin B) (PubMed:19154138). There are three catalytic subunits, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two regulatory subunits which are also encoded by separate genes (PPP3R1 and PPP3R2). In response to an increase in Ca(2+) intracellular levels, forms a complex composed of PPP3CC/calcineurin A, calcineurin B and calmodulin (By similarity). Interacts (via calmodulin-binding domain) with calmodulin; the interaction depends on calmodulin binding to Ca(2+) (By similarity). Interacts with UNC119 (By similarity). Interacts with SPATA33 (via PQIIIT motif) (PubMed:34446558). Interacts with VDAC2 in a SPATA33-dependent manner (By similarity).
Possible isomerization of Pro-305 within the SAPNY motif triggers a conformation switch which affects the organization and thus accessibility of the active site and the substrate binding region (PxIxIF motif). The trans- to cis-transition may favor calcineurin A activation and substrate binding. The reverse cis- to trans-transition may be enhanced by peptidyl-prolyl isomerases such as PPIA.
The autoinhibitory domain prevents access to the catalytic site.
The autoinhibitory segment prevents access to the substrate binding site.
Monomer (Probable). Interacts with GGA2 and GGA3 (PubMed:14638859). Binds to clathrin and activated ARFs, including ARF1, ARF5 and ARF6 (PubMed:11301005, PubMed:11950392, PubMed:12679809, PubMed:15143060, PubMed:22522702). Interacts with RABEP1 (PubMed:12505986, PubMed:15143060, PubMed:14665628). Interacts with RABGEF1 (PubMed:12505986, PubMed:15143060). Interacts with the type-I membrane proteins LRP3, M6PR/CD-MPR and IGF2R/CI-MPR (PubMed:11390366, PubMed:11387475, PubMed:12060753). Interacts (via N-terminal VHS domain) with SORL1/sorLA and SORT1 (via C-terminal cytosolic domain) (PubMed:11821067, PubMed:17855360, PubMed:20015111). Interacts with EPN4 (PubMed:12538641). Interacts with CCDC91 (PubMed:12808037, PubMed:12858163). Interacts with HEATR5B/p200a (PubMed:12808037, PubMed:15758025). Interacts with SYNRG/gamma-synergin (PubMed:10814529, PubMed:12808037, PubMed:15758025). Interacts (via GAE doamin) with NECAP1 and NECAP2 (PubMed:14665628). Interacts (via GAE domain) with AFTPH/aftiphilin (PubMed:14665628, PubMed:15758025). Interacts with TSG101 and UBC (PubMed:14660606, PubMed:15143060). Interacts with RNF11 (PubMed:20676133). Interacts (via VHS domain) with BACE1 (via DXXLL motif); the interaction highly increases when BACE1 is phosphorylated at 'Ser-498' (PubMed:14567678, PubMed:15886016). Interacts with CNST (By similarity). Interacts with ADRA2B (PubMed:27901063). Interacts with ARL3; the interaction recruits, in collaboration with RABEP1, PKD1:PKD2 complex to trans-Golgi network and is required for ciliary targeting (By similarity).
Phosphorylated by CK2 and dephosphorylated by PP2A. Phosphorylation of GGA1 allows the internal DXXLL motif to bind the VHS domain and to inhibit the recognition of cargo signals.
Plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. Mediates the ARF-dependent recruitment of clathrin to the TGN and binds ubiquitinated proteins and membrane cargo molecules with a cytosolic acidic cluster-dileucine (DXXLL) motif (PubMed:11301005, PubMed:15886016). Mediates export of the GPCR receptor ADRA2B to the cell surface (PubMed:27901063). Required for targeting PKD1:PKD2 complex from the trans-Golgi network to the cilium membrane (By similarity). Regulates retrograde transport of proteins such as phosphorylated form of BACE1 from endosomes to the trans-Golgi network (PubMed:15886016, PubMed:15615712).
Myristoylation regulates subcellular location, and is necessary for activation of JNK.
Ubiquitous. Highest expression seen in heart, placenta, lung, liver, kidney and pancreas.
Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, and enables activation by phosphorylation of Thr-423 (PubMed:10995762, PubMed:11804587, PubMed:15893667, PubMed:9032240). Phosphorylation of Thr-84 by OXSR1 inhibits activation (By similarity).
Autophosphorylated in trans, meaning that in a dimer, one kinase molecule phosphorylates the other one (PubMed:20417602, PubMed:23633677, PubMed:22153498). Activated by autophosphorylation at Thr-423 in response to a conformation change, triggered by interaction with GTP-bound CDC42 or RAC1 (PubMed:10551809). Activated by phosphorylation at Thr-423 by BRSK2 and by PDPK1 (PubMed:10995762, PubMed:22669945). Phosphorylated by JAK2 in response to PRL; this increases PAK1 kinase activity. Phosphorylated at Ser-21 by PKB/AKT; this reduces interaction with NCK1 and association with focal adhesion sites (PubMed:14585966). Upon DNA damage, phosphorylated at Thr-212 and translocates to the nucleoplasm (PubMed:23260667). Phosphorylated at tyrosine residues, which can be enhanced by NTN1 (By similarity).
Homodimer; homodimerization results in autoinhibition (PubMed:30290153). Active as monomer. Interacts with GIT1 (PubMed:27012601). Component of cytoplasmic complexes, which also contains PXN, ARHGEF7 and GIT1. Interacts with NISCH (By similarity). Interacts with DVL1; mediates the formation of a DVL1, MUSK and PAK1 ternary complex involved in AChR clustering (By similarity). Binds to the caspase-cleaved p110 isoform of CDC2L1 and CDC2L2, p110C, but not the full-length proteins (PubMed:12624090). Interacts with ARHGEF7 (PubMed:27012601, PubMed:16101281). Interacts tightly with GTP-bound but not GDP-bound CDC42/P21 and RAC1 (By similarity). Interacts with SCRIB (PubMed:18716323). Interacts with PDPK1 (PubMed:10995762). Interacts (via kinase domain) with RAF1 (PubMed:11733498). Interacts with NCK1 and NCK2 (PubMed:10026169). Interacts with TBCB (PubMed:15831477). Interacts with BRSK2 (By similarity). Interacts with SNAI1 (PubMed:15833848). Interacts with CIB1 isoform 2 (PubMed:23503467). Interacts with CIB1 (via N-terminal region); the interaction is direct, promotes PAK1 activity and occurs in a calcium-dependent manner. Interacts with INPP5K (PubMed:26940976). Interacts with gamma-tubulin (PubMed:27012601).
Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes (PubMed:10551809, PubMed:11896197, PubMed:12876277, PubMed:14585966, PubMed:15611088, PubMed:17726028, PubMed:17989089, PubMed:30290153). Can directly phosphorylate BAD and protects cells against apoptosis (By similarity). Activated by interaction with CDC42 and RAC1 (PubMed:8805275, PubMed:9528787). Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway (PubMed:8805275, PubMed:9528787). Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases (By similarity). Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes (PubMed:9395435, PubMed:9032240). Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton (PubMed:15831477). Plays a role in the regulation of insulin secretion in response to elevated glucose levels (PubMed:22669945). Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ) (By similarity). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2 (PubMed:12624090). Phosphorylates MYL9/MLC2 (By similarity). Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2 (PubMed:11733498). Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus (PubMed:15833848). In podocytes, promotes NR3C2 nuclear localization (By similarity). Required for atypical chemokine receptor ACKR2-induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation (PubMed:23633677). In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation (By similarity). Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion (PubMed:25766321). In response to DNA damage, phosphorylates MORC2 which activates its ATPase activity and facilitates chromatin remodeling (PubMed:23260667). In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in F-actin stabilization (By similarity). In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC) (By similarity). Along with GIT1, positively regulates microtubule nucleation during interphase (PubMed:27012601). Phosphorylates FXR1, promoting its localization to stress granules and activity (PubMed:20417602).
The interaction between DSCAM, PAK1 and RAC1 has beend described. This article has been withdrawn by the authors.
There are data describing interaction and regulation by the product of CRIPAK, a putative single exon gene (PubMed:16278681). However, considering all available data there is no sufficient supporting evidence for the existence of such protein.
Ubiquitous. Highly expressed in heart, liver, skeletal muscle, kidney, spleen, thymus and pancreas. Detected at low levels in lung, placenta and brain.
Expressed primarily in heart, skeletal muscle, kidney, liver and placenta. Relatively high level of expression in spleen, colon and small intestine. Almost no expression in brain, thymus, lung and peripheral blood leukocytes. Expressed in epithelial cells (at protein level) (PubMed:31007603).
May play a role in cell protection during the inflammatory response. In epithelial cells, negatively regulates IL6 production and apoptosis through the regulation of MT2A expression (PubMed:24916366).
Broad expression. In adult eye expressed in sclera, retina, retinal pigment epithelium, and trabecular meshwork but not in choroid and iris.
Contrary to predictions, contains nine transmembrane helices, with an extracellular N-terminus and a cytoplasmic C-terminus (By similarity). Besides, contains one long helix that dips into the membrane and then runs more or less parallel to the membrane surface (By similarity).
Functions as retinol transporter. Accepts all-trans retinol from the extracellular retinol-binding protein RBP4, facilitates retinol transport across the cell membrane, and then transfers retinol to the cytoplasmic retinol-binding protein RBP1 (PubMed:9452451, PubMed:18316031, PubMed:22665496). Retinol uptake is enhanced by LRAT, an enzyme that converts retinol to all-trans retinyl esters, the storage forms of vitamin A (PubMed:18316031, PubMed:22665496). Contributes to the activation of a signaling cascade that depends on retinol transport and LRAT-dependent generation of retinol metabolites that then trigger activation of JAK2 and its target STAT5, and ultimately increase the expression of SOCS3 and inhibit cellular responses to insulin (PubMed:21368206, PubMed:22665496). Important for the homeostasis of vitamin A and its derivatives, such as retinoic acid (PubMed:18316031). STRA6-mediated transport is particularly important in the eye, and under conditions of dietary vitamin A deficiency (Probable). Does not transport retinoic acid (PubMed:18316031).
Homodimer (By similarity). Interacts with JAK2 and STAT5 (PubMed:21368206). Interacts (via extracellular domains) with RBP4 (PubMed:22665496). Interacts (via cytoplasmic domains) with RBP1 (PubMed:22665496).
Mutations in STRA6 may be a cause of isolated colobomatous microphthalmia, a disorder of the eye characterized by an abnormally small ocular globe.
Phosphorylated on tyrosine residues in response to RBP4 binding (PubMed:21368206, PubMed:22665496). Phosphorylation requires the presence of LRAT, suggesting it may be triggered by the uptake of retinol that is then metabolized within the cell to retinoids that function as signaling molecules (PubMed:22665496).
Up-regulated in the colorectal cancer cell line WiDr by the administration of retinoic acid and in tumors with frequent defects in Wnt-1 signaling.
Glycosylation is necessary for secretion and its phospholipid transfer activity.
Mediates the transfer of phospholipids and free cholesterol from triglyceride-rich lipoproteins (low density lipoproteins or LDL and very low density lipoproteins or VLDL) into high-density lipoproteins (HDL) as well as the exchange of phospholipids between triglyceride-rich lipoproteins themselves (PubMed:7654777, PubMed:9132017, PubMed:11013307, PubMed:19321130, PubMed:21515415, PubMed:29883800). Facilitates the transfer of a spectrum of different lipid molecules, including diacylglycerol, phosphatidic acid, sphingomyelin, phosphatidylcholine, phosphatidylinositol, phosphatidylglycerol, cerebroside and phosphatidyl ethanolamine (PubMed:9132017). Plays an important role in HDL remodeling which involves modulating the size and composition of HDL (PubMed:29883800). Also plays a key role in the uptake of cholesterol from peripheral cells and tissues that is subsequently transported to the liver for degradation and excretion (PubMed:21736953). Two distinct forms of PLTP exist in plasma: an active form that can transfer phosphatidylcholine from phospholipid vesicles to HDL, and an inactive form that lacks this capability (PubMed:11013307).
Widely expressed. Highest level of expression in the ovary, thymus and placenta, with moderate levels found in the pancreas, small intestine, testis, lung and prostrate. Low level expression in the kidney, liver and spleen, with very low levels found in the heart, colon, skeletal muscle, leukocytes and brain. Expressed in the cortical neurons.
Heterodimer/heterooligomer; disulfide-linked. The functional high affinity IL12 receptor is composed of I12RB1 and IL12RB2. Il12RB2 binds JAK2 (via its N-terminal) through a membrane-proximal region of the cytoplasmic domain. Interaction, in vitro and in vivo, with SOCS3 (via its SH2 domain) inhibits the STAT4-mediated activation. Binds STAT4 through a membrane-distal C-terminal region.
Heterozygotic variants Gly-313 and Arg-720 are associated with atopy, an immunological condition that can lead to clinical symptoms such as allergic rhinitis, sinusitis, asthma and eczema.
Isoform 2 is expressed at similar levels in both naive and activated T-cells.
Maximum levels in Th1 cells between day 3 and day 8 of activation.
On IL12 binding, phosphorylated on C-terminal tyrosine residues by JAK2. Phosphorylation on Tyr-800 is required for STAT4 binding and activation, and for SOCS3 binding.
Receptor for interleukin-12. This subunit is the signaling component coupling to the JAK2/STAT4 pathway. Promotes the proliferation of T-cells as well as NK cells. Induces the promotion of T-cells towards the Th1 phenotype by strongly enhancing IFN-gamma production.
The beta subunit contains the carboxyl transferase (CT) domain.
The holoenzyme is a dodecamer composed of 6 PCCA/alpha subunits and 6 PCCB/beta subunits.
This is one of the 2 subunits of the biotin-dependent propionyl-CoA carboxylase (PCC), a mitochondrial enzyme involved in the catabolism of odd chain fatty acids, branched-chain amino acids isoleucine, threonine, methionine, and valine and other metabolites (PubMed:6765947, PubMed:15890657). Propionyl-CoA carboxylase catalyzes the carboxylation of propionyl-CoA/propanoyl-CoA to D-methylmalonyl-CoA/(S)-methylmalonyl-CoA (PubMed:6765947, PubMed:15890657). Within the holoenzyme, the alpha subunit catalyzes the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain, while the beta subunit then transfers the carboxyl group from carboxylated biotin to propionyl-CoA (By similarity). Propionyl-CoA carboxylase also significantly acts on butyryl-CoA/butanoyl-CoA, which is converted to ethylmalonyl-CoA/(2S)-ethylmalonyl-CoA at a much lower rate (PubMed:6765947). Other alternative minor substrates include (2E)-butenoyl-CoA/crotonoyl-CoA (By similarity).
Interacts with RSPH6A. Does not appear to be part of the axonemal radial spoke complexes 1 or 2.
May function as part of the axonemal radial spoke complex 3 (RS3). Radial spoke complexes are important for ciliary motility.
Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as SLAMF1, CD244, LY9, CD84, SLAMF6 and SLAMF7. In SLAM signaling seems to cooperate with SH2D1B/EAT-2. Initially it has been proposed that association with SLAMF1 prevents SLAMF1 binding to inhibitory effectors including INPP5D/SHIP1 and PTPN11/SHP-2 (PubMed:11806999). However, by simultaneous interactions, recruits FYN which subsequently phosphorylates and activates SLAMF1 (PubMed:12458214). Positively regulates CD244/2B4- and CD84-mediated natural killer (NK) cell functions. Can also promote CD48-, SLAMF6 -, LY9-, and SLAMF7-mediated NK cell activation. In the context of NK cell-mediated cytotoxicity enhances conjugate formation with target cells (By similarity). May also regulate the activity of the neurotrophin receptors NTRK1, NTRK2 and NTRK3.
Expressed at a high level in thymus and lung, with a lower level of expression in spleen and liver. Expressed in peripheral blood leukocytes, including T-lymphocytes. Tends to be expressed at lower levels in peripheral blood leukocytes in patients with rheumatoid arthritis.
Interacts with NTRK1, NTRK2 and NTRK3 (By similarity). Interacts with CD84, CD244, LY9, SLAMF1 and FYN.
An adapter protein which plays a role in the regulation of immunoreceptor signaling, including PLC-gamma-mediated B-cell antigen receptor (BCR) signaling and FC-epsilon R1-mediated mast cell degranulation (By similarity). Together with FGR, it acts as a negative regulator of natural killer cell-activating receptors and inhibits interferon-gamma production (By similarity). Acts as a positive regulator of both T-cell receptor and natural killer T (NKT) cell receptor signaling in CD4-positive NKT cells (By similarity). Together with MAP4K1, it enhances CD3-triggered activation of T-cells and subsequent IL2 production (By similarity). May be involved in tumor necrosis factor induced cell death by promoting reactive oxidative species generation, and MLKL oligomerization, ultimately leading to necrosis (By similarity). Involved in phosphorylation of LAT (By similarity). May be involved in high affinity immunoglobulin epsilon receptor signaling in mast cells (By similarity).
The N-terminal proline-rich region interacts with the SH3 domain of PLCG1.
The SH2 domain is important for restoration of BCR-induced calcium response and JNK2 activation in BLNK-deficient DT40 cells expressing LAT.
Tyrosine-phosphorylated upon BCR cross-linking. Tyrosine phosphorylation at both Tyr-69 and Tyr-96 are required for BCR-induced calcium response and are essential to restore PLCG2-mediated signaling in BLNK-deficient DT40 cells, but this phosphorylation is dispensable in cells expressing LAT. Interacts with the SH2 domain of PLCG1 via phosphorylated Tyr-96 (By similarity). Tyrosine phosphorylation is increased when complexed with SKAP1 and FYB1 (By similarity).
When phosphorylated, interacts with PLCG1, PLCG2, GRB2, VAV and LAT (By similarity). Interacts with LBR and AGO2 (PubMed:26009488). Interacts with FGR (By similarity). Part of a complex consisting of CLNK, SKAP1 and FYB1 (By similarity). Interacts (via SH2 domain) with FYB1; this interaction allows SKAP1 and FYB1 to promote tyrosine phosphorylation of CLNK by LYN (By similarity). Interacts (via SH2 domain) with MAP4K1 (By similarity).
Highly expressed in skin and detected at lower levels in thymus. In skin, found exclusively in lamellar granules of granular keratinocytes and in the intracellular space of the stratum corneum. Also highly expressed in oral mucosa, tongue, esophagus, and stomach, and at much lower levels in bladder and uterus. Not detected in gastrointestinal mucosa.
May act as a soluble regulator of keratinocyte differentiation. May play an important role in embryonic skin morphogenesis.
Up-regulated in situ in psoriatic skin (at protein level).
Belongs to the natriuretic peptide family.
Hormone which plays a role in endochondral ossification through regulation of cartilaginous growth plate chondrocytes proliferation and differentiation (By similarity). May also be vasoactive and natriuretic (PubMed:1672777). Acts by specifically binding and stimulating NPR2 to produce cGMP (PubMed:1672777, PubMed:21098034). Binds the clearance receptor NPR3 (PubMed:11533490).
In the kidney, predominantly expressed in the distal tubular cells (at protein level).
Interacts with activated forms of GNAI1, GNAO1 and GNAZ.
Palmitoylation on Cys-999 and/or Cys-1000 is required for membrane targeting.
Widely expressed in the central nervous system, with highest levels in spinal cord.
Detected in primary follicles and continued to be expressed in follicles in the antral stage. The highest level of AMH expression is present in granulosa cells of secondary, preantral and small antral follicles <4 mm in diameter, whereas expression is lost from follicles at sizes >8 mm.
In ovaries, AMH is detected in granulosa cells of early growing follicles.
Plasma AMH levels in polycystic ovary syndrome (PCOS) patients are two- to threefold higher than in women with normal ovaries.
Plays an important role in several reproductive functions. Induces Muellerian duct regression during male fetal sexual differentiation (PubMed:3754790, PubMed:34155118, PubMed:8469238). Also plays a role in Leydig cell differentiation and function (By similarity). In female acts as a negative regulator of the primordial to primary follicle transition and decreases FSH sensitivity of growing follicles (PubMed:14742691). AMH signals by binding to a specific type-II receptor, AMHR2, that heterodimerizes with type-I receptors (ACVR1 and BMPR1A), and recruiting SMAD proteins that are translocated to the nucleus to regulate target gene expression (PubMed:20861221, PubMed:34155118).
Preproprotein is proteolytically processed to generate N- and C-terminal cleavage products that homodimerize and associate to form a biologically active non-covalent complex (PubMed:8469238, PubMed:2974034). Binding of the non-covalent complex to AMHR2 induces dissociation of the pro-region from the mature C-terminal dimer (PubMed:20861221). The N-terminal portion of the protein, despite having no intrinsic activity, has the role of amplifying the activity of the C-terminus (PubMed:20861221, PubMed:8469238).
Based on a naturally occurring readthrough transcript which produces a FPGT-TNNI3K fusion protein.
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.
Highly expressed in both adult and fetal heart.
Interacts with TNNI3, ACTC1, ACTA1, MYBPC3, AIP, FABP3 and HADHB.
Detected on plasmacytoid dendritic cells (at protein level). Detected on plasmacytoid dendritic cells, but not on monocytes or B cells.
Functions coreceptor to limit the innate immune responses to viral infections; signaling occurs via FCER1G (PubMed:16735691, PubMed:19564354). Down-regulates the production of IFNA1, IFNA2, IFNA4, IFNB1 and TNF by plasmacytoid dendritic cells that have been exposed to influenza virus or cytidine-phosphate-guanosine (CpG) dinucleotides, indicating it functions as negative regulator of TLR7 and TLR9 signaling cascades (PubMed:16735691, PubMed:19564354, PubMed:24586760). Down-regulates interferon production in response to interaction with BST2 on HIV-1 infected cells (PubMed:26172439). Activates a signaling cascade in complex with FCER1G that results in phosphorylation of Src family and Syk kinases and thereby triggers mobilization of intracellular Ca(2+) (PubMed:16735691, PubMed:19564354). Does not interfere with the differentiation of plasmacytoid dendritic cells into antigen-presenting cells (PubMed:24586760).
Interacts with FCER1G; this stabilizes the expression of both proteins at the cell membrane (PubMed:16735691). Interacts with BST2; leads to activation of LILRA4-mediated signaling and down-regulation of the innate immune response to viral pathogens (PubMed:19564354, PubMed:26172439).
Belongs to the cytochrome c oxidase IV family.
Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits.
Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with AFG1L (PubMed:26759378). Interacts with PHB2; the interaction decreases in absence of SPHK2 (By similarity). Interacts with ABCB7; this interaction allows the regulation of cellular iron homeostasis and cellular reactive oxygen species (ROS) levels in cardiomyocytes (By similarity). Interacts with FLVCR2; this interaction occurs in the absence of heme and is disrupted upon heme binding.
Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
Catalyzes the transfer of phosphatidylinositol and phosphatidylcholine between membranes (in vitro). Binds calcium ions.
Highly expressed in brain, heart, ovary, testis and thymus. Detected in small intestine, prostate, pancreas, skeletal muscle, liver, colon and placenta.
Interacts with PTK2B via its C-terminus (PubMed:10022914). Interacts with CPNE4 (via VWFA domain) (By similarity).
(Microbial infection) Deneddylated by Epstein-Barr virus BPLF1 leading to a S-phase-like environment that is required for efficient replication of the viral genome.
(Microbial infection) Interacts with Epstein-Barr virus BPLF1.
Can self-associate (PubMed:17254749). Component of multiple DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes that seem to consist of DDB1, CUL4A or CUL4B, RBX1 and a variable substrate recognition component which seems to belong to a protein family described as DCAF (Ddb1- and Cul4-associated factor) or CDW (CUL4-DDB1-associated WD40-repeat) proteins (PubMed:14578910, PubMed:12732143, PubMed:15548678, PubMed:14739464, PubMed:29779948, PubMed:30166453). Component of the CSA complex (DCX(ERCC8) complex) containing ERCC8, RBX1, DDB1 and CUL4A; the CSA complex interacts with RNA polymerase II; upon UV irradiation it interacts with the COP9 signalosome and preferentially with the hyperphosphorylated form of RNA polymerase II (PubMed:12732143). Component of the DCX(DET1-COP1) complex with the substrate recognition component DET1 and COP1 (PubMed:14739464). Component of the DCX(DDB2) complex with the substrate recognition component DDB2 (PubMed:15811626, PubMed:16678110). Component of the DCX(DTL) complex with the putative substrate recognition component DTL (PubMed:14578910, PubMed:15448697, PubMed:15548678). Component of DCX complexes part of the DesCEND (destruction via C-end degrons) pathway, which contain either TRPC4AP or DCAF12 as substrate-recognition component (PubMed:29779948). Component of the DCX(AMBRA1) complex with the substrate recognition component AMBRA1 (PubMed:30166453, PubMed:33854232, PubMed:33854239). Interacts with DDB1, RBX1, RNF7, CDT1, TIP120A/CAND1, SKP2, CDKN1B, MDM2, TP53 and HOXA9 (PubMed:16964240, PubMed:16537899, PubMed:22118460, PubMed:16482215, PubMed:12609982, PubMed:10230407, PubMed:14609952, PubMed:16678110). Interacts with DDB2; the interactions with DDB2 and CAND1 are mutually exclusive (PubMed:16678110, PubMed:22118460, PubMed:16482215). Interacts with DCAF1, DTL, DDA1, DCAF6, DCAF4, DCAF16, DCAF17, DET1, WDTC1, DCAF5, DCAF11, WDR24A, COP1, PAFAH1B1, ERCC8, GRWD1, FBXW5, RBBP7, GNB2, WSB1, WSB2, NUP43, PWP1, FBXW8, ATG16L1, KATNB1, RBBP4, RBBP5, LRWD1 and DCAF8 (PubMed:16949367, PubMed:22935713, PubMed:17079684). May interact with WDR26, WDR51B, SNRNP40, WDR61, WDR76, WDR5 (PubMed:17041588). Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1 (PubMed:24076655). The DDB1-CUL4A complex interacts with CRY1 (PubMed:26431207). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (PubMed:23201271, PubMed:26906416).
Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination of target proteins (PubMed:14578910, PubMed:15811626, PubMed:15548678, PubMed:15448697, PubMed:14739464, PubMed:16678110, PubMed:17041588, PubMed:24209620, PubMed:30166453, PubMed:33854232, PubMed:33854239). As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme (PubMed:14578910, PubMed:15811626, PubMed:15548678, PubMed:15448697, PubMed:14739464, PubMed:16678110, PubMed:17041588, PubMed:24209620). The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1 (PubMed:14578910, PubMed:15811626, PubMed:15548678, PubMed:15448697, PubMed:14739464, PubMed:16678110, PubMed:17041588, PubMed:24209620). The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component (PubMed:14578910, PubMed:15811626, PubMed:15548678, PubMed:15448697, PubMed:14739464, PubMed:16678110, PubMed:17041588, PubMed:24209620). DCX(DET1-COP1) directs ubiquitination of JUN (PubMed:14739464). DCX(DDB2) directs ubiquitination of XPC (PubMed:15811626). DCX(DDB2) ubiquitinates histones H3-H4 and is required for efficient histone deposition during replication-coupled (H3.1) and replication-independent (H3.3) nucleosome assembly, probably by facilitating the transfer of H3 from ASF1A/ASF1B to other chaperones involved in histone deposition (PubMed:16678110, PubMed:17041588, PubMed:24209620). DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of p53/TP53 in response to radiation-induced DNA damage and during DNA replication (PubMed:14578910, PubMed:15548678, PubMed:15448697). DCX(DTL) directs autoubiquitination of DTL (PubMed:23478445). In association with DDB1 and SKP2 probably is involved in ubiquitination of CDKN1B/p27kip (PubMed:16537899). Is involved in ubiquitination of HOXA9 (PubMed:14609952). The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1 (PubMed:26431207). A number of DCX complexes (containing either TRPC4AP or DCAF12 as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948). The DCX(AMBRA1) complex is a master regulator of the transition from G1 to S cell phase by mediating ubiquitination of phosphorylated cyclin-D (CCND1, CCND2 and CCND3) (PubMed:33854232, PubMed:33854239). The DCX(AMBRA1) complex also acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes (PubMed:30166453). With CUL4B, contributes to ribosome biogenesis (PubMed:26711351).
Neddylated. Deneddylated via its interaction with the COP9 signalosome (CSN) complex.
Acts as a decoy receptor, counterbalancing TREM1 pro-inflammatory activity through the neutralization of its lignad.
Cell surface receptor that plays important roles in innate and adaptive immunity by amplifying inflammatory responses (PubMed:10799849, PubMed:21393102). Upon activation by various ligands such as PGLYRP1, HMGB1 or HSP70, multimerizes and forms a complex with transmembrane adapter TYROBP/DAP12 (PubMed:25595774, PubMed:17568691, PubMed:29568119). In turn, initiates a SYK-mediated cascade of tyrosine phosphorylation, activating multiple downstream mediators such as BTK, MAPK1, MAPK3 or phospholipase C-gamma (PubMed:21659545, PubMed:14656437). This cascade promotes the neutrophil- and macrophage-mediated release of pro-inflammatory cytokines and/or chemokines, as well as their migration and thereby amplifies inflammatory responses that are triggered by bacterial and fungal infections (PubMed:17568691, PubMed:17098818). By also promoting the amplification of inflammatory signals that are initially triggered by Toll-like receptor (TLR) and NOD-like receptor engagement, plays a major role in the pathophysiology of acute and chronic inflammatory diseases of different etiologies including septic shock and atherosclerosis (PubMed:21393102, PubMed:11323674).
Monomer (PubMed:29568119). Homomultimer; when activated (PubMed:29568119). Interacts with TYROBP/DAP12 (PubMed:10799849, PubMed:15351648). Interacts with TLR4 (PubMed:17098818, PubMed:21393102).
Mostly expressed by immune cells of the myeloid lineage, such as monocytes, macrophages, neutrophils and dendritic cells (PubMed:10799849). Expression is associated with a mature stage of myeloid development (PubMed:11922939). Highly expressed in adult liver, lung and spleen than in corresponding fetal tissue. Also expressed in the lymph node, placenta, spinal cord and heart tissues. Isoform 2 was detected in the lung, liver and mature monocytes.
Up-regulated by bacteria, fungi and bacterial lipopolysaccharides (LPS).
Activated by NEURL1-mediated monoubiquitination, resulting in the growth of new dendritic spines and increased levels of GRIA1 and GRIA2. NEURL1-mediated monoubiquitination facilitates synaptic plasticity and hippocampal-dependent memory storage.
Following neuronal stimulation, cleaved by CAPN2 which abolishes its translational repressor activity, leading to translation of CPEB3 target mRNAs.
Following synaptic activity, forms amyloid-like oligomers (By similarity). Aggregation requires an intact actin cytoskeleton (By similarity). Interacts with STAT5B; this inhibits STAT5B-mediated transcriptional activation (PubMed:20639532). Interacts with E3 ubiquitin-protein ligase NEURL1; this leads to monoubiquitination and activation of CPEB3 (By similarity). Interacts with CAPN2; this leads to cleavage of CPEB3 (By similarity). Interacts (via C-terminal RNA-binding region) with TOB1; TOB1 also binds CNOT7/CAF1 and recruits it to CPEB3 to form a ternary complex (PubMed:21336257). Interacts with SUMO-conjugating enzyme UBC9 (By similarity). Interacts with IPO5; the interaction is enhanced in a RAN-regulated manner following neuronal stimulation and mediates CPEB3 nuclear import (PubMed:22730302). Interacts with exportin XPO1/CRM1 (PubMed:22730302).
Phosphorylation is enhanced by neuronal stimulation.
Sequence-specific RNA-binding protein which acts as a translational repressor in the basal unstimulated state but, following neuronal stimulation, acts as a translational activator (By similarity). In contrast to CPEB1, does not bind to the cytoplasmic polyadenylation element (CPE), a uridine-rich sequence element within the mRNA 3'-UTR, but binds to a U-rich loop within a stem-loop structure (By similarity). Required for the consolidation and maintenance of hippocampal-based long term memory (By similarity). In the basal state, binds to the mRNA 3'-UTR of the glutamate receptors GRIA2/GLUR2 mRNA and negatively regulates their translation (By similarity). Also represses the translation of DLG4, GRIN1, GRIN2A and GRIN2B (By similarity). When activated, acts as a translational activator of GRIA1 and GRIA2 (By similarity). In the basal state, suppresses SUMO2 translation but activates it following neuronal stimulation (By similarity). Binds to the 3'-UTR of TRPV1 mRNA and represses TRPV1 translation which is required to maintain normal thermoception (By similarity). Binds actin mRNA, leading to actin translational repression in the basal state and to translational activation following neuronal stimulation (By similarity). Negatively regulates target mRNA levels by binding to TOB1 which recruits CNOT7/CAF1 to a ternary complex and this leads to target mRNA deadenylation and decay (PubMed:21336257). In addition to its role in translation, binds to and inhibits the transcriptional activation activity of STAT5B without affecting its dimerization or DNA-binding activity. This, in turn, represses transcription of the STAT5B target gene EGFR which has been shown to play a role in enhancing learning and memory performance (PubMed:20639532). In contrast to CPEB1, CPEB2 and CPEB4, not required for cell cycle progression (PubMed:26398195).
The CPEB3 gene contains an intron-encoded self-cleaving ribozyme which is structurally and biochemically related to human hepatitis delta virus ribozymes and which may play a role in the regulation of CPEB3 translation (PubMed:16990549). A polymorphism in the ribozyme sequence which influences cleavage activity of the ribozyme may play a role in episodic memory with carriers of a rare C allele-containing ribozyme showing significantly poorer memory recall performance than T allele carriers (PubMed:19503753).
The N-terminal Gln-rich region is required for the formation of amyloid-like oligomers and for the stability of long-term potentiation and spatial memory.
Under basal unstimulated conditions when CPEB3 is mainly unaggregated, sumoylated and acts as a translational repressor. Following neuronal stimulation, becomes desumoylated and aggregated which is required for the translation of mRNA targets and for dendritic filopodia formation.
Genetic variation in ALDH2 is responsible for individual differences in responses to drinking alcohol [MIM:610251]. Allele ALDH2*2 is associated with a very high incidence of acute alcohol intoxication in Orientals and South American Indians, as compared to Caucasians.
Required for clearance of cellular formaldehyde, a cytotoxic and carcinogenic metabolite that induces DNA damage.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. AMEDS patients carry ADH5 biallelic variants and homozygous or heterozygous ALDH2 variant p.Glu504Lys, affecting protein activity. Cellular and animal studies demonstrate that the simultaneous loss of ALDH2 and ADH5 activities leads to an increase of cellular formaldehyde sensitivity and multisystem abnormalities including hematopoietic failure.
May act as a transcription factor for cell pluripotency and differentiation in the embryo.
Acetylated by CBP/ p300 during cell-growth. Acetylation on Lys-75 is required for stimulation of H4 promoter activity.
Expressed throughout the epithelium of the colon. Also expressed in lamina propria.
Interacts with BRD7, IRF2BP1 and IRF2BP2. Interacts with CREBBP in growing cells; the interaction acetylates IRF2 and regulates IRF2-dependent H4 promoter activity.
Specifically binds to the upstream regulatory region of type I IFN and IFN-inducible MHC class I genes (the interferon consensus sequence (ICS)) and represses those genes. Also acts as an activator for several genes including H4 and IL7. Constitutively binds to the ISRE promoter to activate IL7. Involved in cell cycle regulation through binding the site II (HiNF-M) promoter region of H4 and activating transcription during cell growth. Antagonizes IRF1 transcriptional activation.
The major sites of sumoylation are Lys-137 and Lys-293. Sumoylation with SUMO1 increases its transcriptional repressor activity on IRF1 and diminishes its ability to activate ISRE and H4 promoter.
Unable to bind to IRF2BP1 and IRF2BP2 corepressors and cannot mediate repression.
Component of several N-terminal acetyltransferase complexes (PubMed:20154145, PubMed:29754825, PubMed:32042062). Inhibits the N-terminal acetylation activity of the N-terminal acetyltransferase NAA10-NAA15 complex (also called the NatA complex) (PubMed:29754825, PubMed:32042062). Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells probably while associated with the NatA complex (PubMed:17947297, PubMed:20154145). May play a role in the NatA complex-mediated N-terminal acetylation of PCNP (PubMed:20154145).
Component of the N-terminal acetyltransferase A (NatA)/HYPK complex at least composed of NAA10, NAA15 and HYPK, which has N-terminal acetyltransferase activity (PubMed:20154145, PubMed:29754825, PubMed:32042062). Within the complex interacts with NAA10 (PubMed:29754825, PubMed:32042062). Within the complex interacts with NAA15 (PubMed:20154145, PubMed:29754825, PubMed:32042062). Predominantly interacts with NAA15 in the NAA10-NAA15 complex (also called the NatA complex); the interaction with the NatA complex reduces the acetylation activity of the NatA complex (PubMed:29754825, PubMed:32042062). Interacts with HTT (via N-terminus) (PubMed:17947297). The NatA complex is required for HYPK stability and for reducing polyQ aggregation of HTT (PubMed:20154145, PubMed:29754825, PubMed:32042062). Component of the N-terminal acetyltransferase E (NatE)/HYPK complex at least composed of NAA10, NAA15, NAA50 and HYPK (PubMed:32042062). Within the complex interacts with NAA10 and NAA15 (PubMed:32042062). Does not interact with NAA50 (PubMed:29754825, PubMed:32042062). Interaction with NAA15 reduces the capacity of NAA15 to interact with NAA50 (PubMed:29754825, PubMed:32042062). Its capacity to interact with the NatA complex is reduced by NAA50 (PubMed:32042062). Does not interact with the N-terminal acetyltransferase B (NatB) complex component NAA25 or the N-terminal acetyltransferase C (NatC) complex component NAA35 (PubMed:20154145).
Readthrough transcript SERF2-HYPK/C15orf63.
Component of the gamma-secretase complex.
Non-catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12297508, PubMed:12522139, PubMed:12763021, PubMed:12679784, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Required for normal gamma-secretase assembly (PubMed:12522139, PubMed:12471034, PubMed:12763021, PubMed:19369254). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable).
Potential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors.
The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN/PEN2 (PubMed:12297508, PubMed:12740439, PubMed:19369254, PubMed:25043039, PubMed:26623517, PubMed:26280335, PubMed:30598546, PubMed:30630874).
Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain. Isoform 1 and isoform 2 are nearly expressed at the same level.
Belongs to the aspartyl/asparaginyl beta-hydroxylase family.
Isoform 1 is detected in all tissues tested. Isoform 8 is mainly expressed in pancreas, heart, brain, kidney and liver. Isoform 8 is expressed in kidney (at protein level).
Membrane-bound Ca(2+)-sensing protein, which is a structural component of the ER-plasma membrane junctions. Isoform 8 regulates the activity of Ca(+2) released-activated Ca(+2) (CRAC) channels in T-cells.
Monomer (By similarity). Isoform 8 interacts with ORAI1 and STIM1. Isoform 4 interacts with CASQ2.
Specifically hydroxylates an Asp or Asn residue in certain epidermal growth factor-like (EGF) domains of a number of proteins.
Interacts with PRPF19 (PubMed:19641227).
Interacts with U2AF65 (PubMed:19641227).
RNA-binding protein involved in pre-mRNA splicing (PubMed:19641227). Interacts with the PRP19C/Prp19 complex/NTC/Nineteen complex which is part of the spliceosome (PubMed:19641227). Involved in regulating splice site selection (PubMed:19641227). Binds preferentially RNA with A/C rich sequences and poly-C stretches (PubMed:23144703).
The C-terminal part is necessary for the interaction with the PRP19C/Prp19 complex/NTC/Nineteen complex.
Ubiquitous. Expressed at high level in skeletal muscle, kidney, heart, brain and liver.
Interaction with ATP6AP2 results in a 5-fold increased efficiency in angiotensinogen processing.
Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney.
Expressed in all tissues examined, with high levels in fetal liver, thymus, lymph node, spleen and peripheral blood leukocytes and lower level in bone marrow.
Heterodimer; heterodimerizes with EHMT1/GLP (PubMed:16702210). Interacts with GFI1B and WIZ (PubMed:16688220, PubMed:16702210). Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EHMT1, RING1, RNF2, MBLR, L3MBTL2 and YAF2 (PubMed:12004135). Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (PubMed:21549307). Interacts with UHRF1 (PubMed:19056828). Interacts with CDYL (PubMed:19061646). Interacts with REST only in the presence of CDYL (PubMed:19061646). Part of a complex containing at least CDYL, REST, WIZ, SETB1, EHMT1 and EHMT2 (PubMed:19061646). Interacts with PRDM9 and CDYL; interaction only takes place when PRDM9 is bound to hotspot DNA (By similarity). Interacts with SMYD5 (By similarity). Interacts with MSX1 (via homeobox domain) (By similarity).
Histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also mediates monomethylation of 'Lys-56' of histone H3 (H3K56me1) in G1 phase, leading to promote interaction between histone H3 and PCNA and regulating DNA replication. Also weakly methylates 'Lys-27' of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. May also methylate histone H1. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of 'Lys-373' of p53/TP53. Also methylates CDYL, WIZ, ACIN1, DNMT1, HDAC1, ERCC6, KLF12 and itself. Recruited to the promoters of target genes through interaction with transcriptional repressor MSX1, leading to the inhibition of myoblast differentiation via transcriptional repression of differentiation factors (By similarity).
It is uncertain whether Met-1 or Met-21 is the initiator methionine.
The ANK repeats bind H3K9me1 and H3K9me2.
The SET domain mediates interaction with WIZ.
While NG36 and G9a were originally thought to derive from 2 separate genes, all G9A transcripts also contain the in frame coding sequence of NG36.
Cytokine that functions as an anti-inflammatory and proangiogenic factor (PubMed:34932373). Polarizes adaptive immunity to an anti-inflammatory phenotype through induction of T-helper 2 responses by both down-regulation of IFN-gamma and up-regulation of IL4 and IL13 (PubMed:16365913). Produced by osteocytes, stimulates granulopoiesis and neutrophil formation (By similarity). Exerts its biological effect through a receptor complex consisting of a heterodimer of IL20RA and IL20RB (PubMed:12351624). In turn, activates the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway, and importantly, STAT3 (PubMed:11564763).
by DNA damage through pathways mediated by JUN and cGAS-STING leading to production of the cytokines IL1, IL6, and IL8.
Acyl-CoA synthetases (ACSL) activates long-chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:22633490). Required for the incorporation of fatty acids into phosphatidylcholine, the major phospholipid located on the surface of VLDL (very low density lipoproteins) (PubMed:18003621). Has mainly an anabolic role in energy metabolism. Mediates hepatic lipogenesis. Preferentially uses myristate, laurate, arachidonate and eicosapentaenoate as substrates. Both isoforms exhibit the same level of activity (By similarity).
Actin-binding component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF) (PubMed:9230079). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility (PubMed:9230079). Seems to contact the mother actin filament (PubMed:9230079). In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA (PubMed:29925947). The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs) (PubMed:29925947).
Component of the Arp2/3 complex composed of ACTR2/ARP2, ACTR3/ARP3, ARPC1B/p41-ARC, ARPC2/p34-ARC, ARPC3/p21-ARC, ARPC4/p20-ARC and ARPC5/p16-ARC (PubMed:9230079, PubMed:11741539). Interacts with SHANK3; the interaction probably mediates the association of SHANK3 with the Arp2/3 complex (By similarity). Interacts with DNAI3; this interaction reduces binding of the Arp2/3 complex to the VCA domain of nucleation promoting factors (PubMed:32128961).
Component of the Arp2/3 complex composed of ARP2, ARP3, ARPC1B/p41-ARC, ARPC2/p34-ARC, ARPC3/p21-ARC, ARPC4/p20-ARC and ARPC5/p16-ARC. Interacts with SHANK3; the interaction probably mediates the association of SHANK3 with the Arp2/3 complex.
Functions as actin-binding component of the Arp2/3 complex which is involved in regulation of actin polymerization and together with an activating nucleation-promoting factor (NPF) mediates the formation of branched actin networks.
(Microbial infection) Induced by HIV-1 infection.
(Microbial infection) Positively regulates the degradation of Vesicular stomatitis virus (VSV) G protein via the lysosomal degradation pathway (PubMed:29573664). Represses HIV-1 viral production and may inhibit the translocation of HIV-1 env to the cell surface, resulting in decreased viral cell-cell transmission (PubMed:29573664).
E3 ubiquitin-protein ligase that may mediate ubiquitination of TFRC and CD86, and promote their subsequent endocytosis and sorting to lysosomes via multivesicular bodies. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates (PubMed:14722266, PubMed:16428329). Together with GOPC/CAL mediates the ubiquitination and lysosomal degradation of CFTR (PubMed:23818989). Ubiquitinates and therefore mediates the degradation of DLG1 (PubMed:17980554). Regulates the intracellular trafficking and secretion of alpha1-antitrypsin/SERPINA1 and HP/haptoglobin via ubiquitination and degradation of the cargo receptor ERGIC3 (PubMed:31142615). Negatively regulates the antiviral and antibacterial immune response by repression of the NF-kB and type 1 IFN signaling pathways, via MARCHF2-mediated K48-linked polyubiquitination of IKBKG/NEMO, resulting in its proteasomal degradation (PubMed:32935379). May be involved in endosomal trafficking through interaction with STX6 (PubMed:15689499).
Interacts with STX6; the interaction promotes MARCHF2-mediated ubiquitination and degradation of CFTR (PubMed:23818989). Interacts with MARCHF3 (PubMed:16428329). Interacts with GOPC/CAL; the interaction leads to CFTR ubiquitination and degradation (PubMed:23818989). Interacts with CFTR; the interaction leads to CFTR ubiqtuitination and degradation (PubMed:23818989). Interacts (via PDZ domain) with DLG1 (via PDZ domains); the interaction leads to DLG1 ubiqtuitination and degradation (PubMed:17980554). Interacts with ERGIC3 (PubMed:31142615). Interacts with ADRB2 (PubMed:23166351). Interacts with IKBKG/NEMO; during the late stages of macrophage viral and bacterial infection; the interaction leads to ubiquitination and degradation of IKBKG/NEMO (PubMed:32935379).
Mannosyltransferase involved in the last steps of the synthesis of Man5GlcNAc(2)-PP-dolichol core oligosaccharide on the cytoplasmic face of the endoplasmic reticulum. Catalyzes the addition of the 4th and 5th mannose residues to the dolichol-linked oligosaccharide chain.
GATA4 mutations can predispose to dilated cardiomyopathy (CMD), a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.
Interacts with ZNF260 (By similarity). Interacts with the homeobox domain of NKX2-5 through its C-terminal zinc finger. Also interacts with JARID2 which represses its ability to activate transcription of ANF. Interacts (via the second Zn finger) with NFATC4 (By similarity). Interacts with LMCD1 (By similarity). Forms a complex made of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes. Interacts with NR5A1, ZFPM2 and TBX5. Interacts with TBX18. Interacts with GLYR1; the interaction is required for a synergistic activation of GATA4 target genes transcription (PubMed:35182466).
Methylation at Lys-300 attenuates transcriptional activity.
Transcriptional activator that binds to the consensus sequence 5'-AGATAG-3' and plays a key role in cardiac development and function (PubMed:24000169, PubMed:27984724, PubMed:35182466). In cooperation with TBX5, it binds to cardiac super-enhancers and promotes cardiomyocyte gene expression, while it down-regulates endocardial and endothelial gene expression (PubMed:27984724). Involved in bone morphogenetic protein (BMP)-mediated induction of cardiac-specific gene expression. Binds to BMP response element (BMPRE) DNA sequences within cardiac activating regions (By similarity). Acts as a transcriptional activator of ANF in cooperation with NKX2-5 (By similarity). Promotes cardiac myocyte enlargement (PubMed:20081228). Required during testicular development (PubMed:21220346). May play a role in sphingolipid signaling by regulating the expression of sphingosine-1-phosphate degrading enzyme, sphingosine-1-phosphate lyase (PubMed:15734735).
Interacts with RNF4; regulates TRPS1 repressor activity. Interacts specifically with the activator form of GLI3 (GLI3A) but not with the repressor form (GLI3R).
Sumoylated. Sumoylation in the repressor domain inhibits the transcription repression activity. Sumoylation on Lys-1201 is the major site. Appears to be sumoylated on multiple sites.
Transcriptional repressor. Binds specifically to GATA sequences and represses expression of GATA-regulated genes at selected sites and stages in vertebrate development. Regulates chondrocyte proliferation and differentiation. Executes multiple functions in proliferating chondrocytes, expanding the region of distal chondrocytes, activating proliferation in columnar cells and supporting the differentiation of columnar into hypertrophic chondrocytes.
Ubiquitously expressed in the adult. Found in fetal brain, lung, kidney, liver, spleen and thymus. More highly expressed in androgen-dependent than in androgen-independent prostate cancer cells.
Strongly expressed in lung, breast, immune system and fetal tissues.
Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) to the plasma membrane. Acts as a receptor for adrenomedullin (AM) together with CALCRL.
Detected in endothelial cells in vascular tissue throughout the body. May appear at the surface of neural crest cells during their embryonic migration. Appears to be limited to vascular smooth muscle in normal adult tissues. Associated with tumor progression and the development of metastasis in human malignant melanoma. Expressed most strongly on metastatic lesions and advanced primary tumors and is only rarely detected in benign melanocytic nevi and thin primary melanomas with a low probability of metastasis.
Plays a role in cell adhesion, and in cohesion of the endothelial monolayer at intercellular junctions in vascular tissue. Its expression may allow melanoma cells to interact with cellular elements of the vascular system, thereby enhancing hematogeneous tumor spread. Could be an adhesion molecule active in neural crest cells during embryonic development. Acts as surface receptor that triggers tyrosine phosphorylation of FYN and PTK2/FAK1, and a transient increase in the intracellular calcium concentration.
Intracellular carrier for long-chain fatty acids and related active lipids, such as endocannabinoids, that regulate the metabolism and actions of the ligands they bind. In addition to the cytosolic transport, selectively delivers specific fatty acids from the cytosol to the nucleus, wherein they activate nuclear receptors (PubMed:22170058, PubMed:21395585). Delivers retinoic acid to the nuclear receptor peroxisome proliferator-activated receptor delta; which promotes proliferation and survival. May also serve as a synaptic carrier of endocannabinoid at central synapses and thus controls retrograde endocannabinoid signaling. Modulates inflammation by regulating PTGES induction via NF-kappa-B activation, and prostaglandin E2 (PGE2) biosynthesis during inflammation (By similarity). May be involved in keratinocyte differentiation (PubMed:8092987).
Keratinocytes; highly expressed in psoriatic skin (PubMed:8092987). Expressed in brain gray matter (PubMed:21395585).
While mouse FABP5 is found only in the monomeric form, human FABP5 can exist as a monomer as well as a domain-swapped dimer.
Associates with the nuclear pore complex (NPC).
Testis-specific in adults. In fetal brain expressed only from the paternal allele.
Expressed in testis (at protein level). Strongly expressed in peritubular cells and Leydig cells and weakly expressed in the cytoplasm of spermatocytes.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in flagellum axoneme. May serve to reinforce and thus stabilize the microtubule structure in the sperm flagella.
Belongs to the POU transcription factor family.
ERK1/2-mediated phosphorylation at Ser-111 promotes nuclear exclusion and proteasomal degradation. Phosphorylation at Thr-235 and Ser-236 decrease DNA-binding and alters ability to activate transcription.
Expressed in developing brain. Highest levels found in specific cell layers of the cortex, the olfactory bulb, the hippocampus and the cerebellum. Low levels of expression in adult tissues.
Highly expressed in undifferentiated embryonic stem cells and expression decreases gradually after embryoid body (EB) formation.
Interacts with PKM. Interacts with WWP2. Interacts with UBE2I and ZSCAN10 (By similarity). Interacts with PCGF1 (PubMed:26687479). Interacts with ESRRB; recruits ESRRB near the POU5F1-SOX2 element in the NANOG proximal promoter; the interaction is DNA independent (By similarity). Interacts with ZNF322 (By similarity). Interacts with MAPK8 and MAPK9; the interaction allows MAPK8 and MAPK9 to phosphorylate POU5F1 on Ser-355 (By similarity). Interacts (when phosphorylated on Ser-355) with FBXW8 (By similarity). Interacts with FBXW4 (By similarity). Interacts with SOX2 and SOX15; binds synergistically with either SOX2 or SOX15 to DNA (By similarity). Interacts with DDX56 (By similarity).
Several pseudogenes of POU5F1 have been described on chromosomes 1, 3, 8, 10 and 12. 2 of them, localized in chromosomes 8 and 10, are transcribed in cancer tissues but not in normal ones and may be involved in the regulation of POU5F1 gene activity in carcinogenesis.
Sumoylation enhances the protein stability, DNA binding and transactivation activity. Sumoylation is required for enhanced YES1 expression.
The POU-specific domain mediates interaction with PKM.
Transcription factor that binds to the octamer motif (5'-ATTTGCAT-3'). Forms a trimeric complex with SOX2 or SOX15 on DNA and controls the expression of a number of genes involved in embryonic development such as YES1, FGF4, UTF1 and ZFP206. Critical for early embryogenesis and for embryonic stem cell pluripotency.
Transcriptional activity is positively regulated by PKM.
Ubiquitinated; undergoes 'Lys-63'-linked polyubiquitination by WWP2 leading to proteasomal degradation.
Finds in a complex with ABCB1, TFPI2 and PPP2R3C; leading to the dephosphorylation of ABCB1.
May play a role in the regulation of plasmin-mediated matrix remodeling. Inhibits trypsin, plasmin, factor VIIa/tissue factor and weakly factor Xa. Has no effect on thrombin.
This inhibitor contains three inhibitory domains.
Umbilical vein endothelial cells, liver, placenta, heart, pancreas, and maternal serum at advanced pregnancy.
May be a component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is part of the mitochondrial respiratory chain. This protein may mediate formation of the complex between cytochromes c and c1.
The bc1 complex contains 11 subunits: 3 respiratory subunits (cytochrome b, cytochrome c1 and Rieske/UQCRFS1), 2 core proteins (UQCRC1/QCR1 and UQCRC2/QCR2) and 6 low-molecular weight proteins (UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, UQCR10/QCR9, UQCR11/QCR10 and a cleavage product of Rieske/UQCRFS1).
Promotes caspase-independent apoptosis by regulating the function of two transcriptional regulators, AES and TLE1.
The natural substrate for this enzyme may be peptidyl-tRNAs which drop off the ribosome during protein synthesis.
Cytoplasmic retinol-binding protein (PubMed:22665496, PubMed:26900151, PubMed:28057518). Accepts retinol from the transport protein STRA6, and thereby contributes to retinol uptake, storage and retinoid homeostasis (PubMed:15632377, PubMed:22665496).
Detected in nearly all the tissues with higher expression in adult ovary, pancreas, pituitary gland and adrenal gland, and fetal liver.
Interacts (only as retinol-free apoprotein) with STRA6.
A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:2732228, PubMed:10681376, PubMed:11093772, PubMed:12865317). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:2732228, PubMed:10681376, PubMed:11093772). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228).
By glucocorticoids, such as dexamethesone.
Chimeric transcripts, characterized by CYP3A43 exon 1 joined at canonical splice sites to distinct sets of CYP3A5 exons, have been detected. All are possibly produced by trans-splicing. The chimeric transcripts exist in 2 different combinations: CYP3A43 exon 1 joined in frame to CYP3A5 exon 11-13 and CYP3A43 exon 1 joined in frame to CYP3A5 exon 12-13. All chimeric transcripts are expressed at very low levels in the liver (PubMed:11726664).
Component of intercellular bridges during meiosis. Intercellular bridges are evolutionarily conserved structures that connect differentiating germ cells. Not required for fertility (By similarity).
Homodimer. Interacts with TEX14 (By similarity).
(Microbial infection) Plays a role in human coronavirus SARS-CoV-2 infection, but not in common cold coronaviruses HCoV-229E and HCoV-OC43 infections. Involved in ACE2-independent SARS-CoV-2 cell entry. Required for post-endocytic stage of virus entry, facilitates spike-mediated membrane fusion. Virus attachment and endocytosis can also be mediated by other cell surface receptors.
A TMEM106B truncated C-terminal fragment (residues 120 through 254) was found to aggregate into stable amyloid fibrils in the brain of patients suffering from diverse genetic and sporadic tauopathies, amyloid-beta amyloidoses, synucleinopathies and TDP-43 proteinopathies. It is currently unclear whether TMEM106B fibrils are associated with a pathogenic process or represents a non-specific secondary phenomenon, a general downstream marker of lysosomal stress for instance (PubMed:35247328, PubMed:35344984, PubMed:35344985). TMEM106B amyloid filaments form in an age-dependent manner in human brains, however fibrillization of TMEM106B seems substantially greater in patients with known neurodegeneration compared to age-matched unaffected individuals (PubMed:35344985).
Can form homomers (PubMed:23136129, PubMed:25066864). Interacts (via N-terminus) with MAP6 (via C-terminus) (PubMed:24357581). Interacts (via C-terminus) with the vacuolar-type ATPase subunit ATP6AP1 (PubMed:28728022). Interacts (via N-terminus) with AP2M1 and CLTC (PubMed:25066864). Interacts with TMEM106C (PubMed:25066864).
Expressed in the brain, including in the frontal cortex (at protein level) (PubMed:35247328, PubMed:35344985). Expressed in lung epithelial cells (PubMed:33686287).
In neurons, involved in the transport of late endosomes/lysosomes (PubMed:25066864). May be involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking (PubMed:25066864). May act as a molecular brake for retrograde transport of late endosomes/lysosomes, possibly via its interaction with MAP6 (By similarity). In motoneurons, may mediate the axonal transport of lysosomes and axonal sorting at the initial segment (By similarity). It remains unclear whether TMEM106B affects the transport of moving lysosomes in the anterograde or retrograde direction in neurites and whether it is important in the sorting of lysosomes in axons or in dendrites (By similarity). In neurons, may also play a role in the regulation of lysosomal size and responsiveness to stress (PubMed:25066864). Required for proper lysosomal acidification (By similarity).
The gene represented in this entry acts as a disease modifier.
The gene represented in this entry acts as a disease modifier. Risk alleles confer genetic susceptibility by increasing gene expression (PubMed:20154673, PubMed:21178100). Increased expression may be the result of down-regulation of microRNA miR-132 and miR-212, that repress TMEM106B expression (PubMed:22895706). Thr-185 is a risk allele associated with lower GRN protein levels and early age at onset in GRN UP-FTD mutation carriers: it presents slower protein degradation that leads to higher steady-state TMEM106B levels, leading to alterations in the intracellular versus extracellular partitioning of GRN (PubMed:23742080).
It is unlikely that this protein binds calcium as none of the 2 EF-hand domains seem to contain a canonical calcium-binding site.
Weakly expressed in lung and testis. Weakly or not expressed in other tissues.
(Microbial infection) Interacts with Epstein-Barr virus BNRF1; this interaction targets SMC5-SMC6 complex for proteasomal degradation.
(Microbial infection) SMC5-SMC6 complex interacts with Hepatitis B X protein.
(Microbial infection) SMC5-SMC6 complex is degraded by the activity of Hepatitis B X protein.
Belongs to the SMC family. SMC6 subfamily.
Core component of the SMC5-SMC6 complex, a complex involved in DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). Required for recruitment of telomeres to PML nuclear bodies. SMC5-SMC6 complex may prevent transcription of episomal DNA, such as circular viral DNA genome (PubMed:26983541).
Forms a heterodimer with SMC5 (PubMed:11408570). Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3 (PubMed:18086888). Interacts with NSMCE1 (PubMed:14701739). Interacts with NSMCE2 (PubMed:16055714). Interacts with SLF1 (PubMed:25931565). Interacts with SLF2 (PubMed:25931565). Interacts with RAD18 (PubMed:25931565). Interacts with SIMC1 (PubMed:36373674).
The flexible hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC5, forming a V-shaped heterodimer.
Widely expressed (PubMed:11408570). Strongly expressed in testis (PubMed:11408570).
Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:12124384, PubMed:16428440, PubMed:28977666). Acts as transcriptional repressor and plays a role in gene silencing (PubMed:10947852, PubMed:18644863). Does not bind to methylated DNA by itself (PubMed:12124384, PubMed:16428440). Binds to a lesser degree DNA containing unmethylated CpG dinucleotides (PubMed:24307175). Recruits histone deacetylases and DNA methyltransferases.
Heterodimer (via N-terminus) with MBD2 (PubMed:10947852, PubMed:15701600). Component of the MeCP1 histone deacetylase complex (PubMed:12124384, PubMed:11756549, PubMed:11756549). Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5 (PubMed:33283408, PubMed:12124384, PubMed:15454082, PubMed:28977666, PubMed:16428440, PubMed:16428440, PubMed:27732854). The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes (PubMed:33283408, PubMed:16428440, PubMed:28977666, PubMed:16428440, PubMed:27732854). Interacts with MBD3L2 (via N-terminus); the interaction is direct (PubMed:15701600). Interacts with BCL6 (PubMed:15454082). Interacts with CDK2AP1 (PubMed:20523938). Interacts with HDAC1 (PubMed:12124384). Interacts with MTA2 (PubMed:12124384). Interacts with DNMT1 (PubMed:10947852). Interacts with GATAD2A (PubMed:12183469, PubMed:27732854). Interacts with GATAD2B (PubMed:12183469, PubMed:11756549, PubMed:27732854). Does not interact with PWWP2A (By similarity). Does not interact with PWWP2B (By similarity).
Heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 that can form a complex either with RFC1 or with RAD17. The former interacts with PCNA in the presence of ATP, while the latter has ATPase activity but is not stimulated by PCNA. RFC2 also interacts with PRKAR1A; the complex may be involved in cell survival (PubMed:15655353). Interacts with DDX11 (PubMed:18499658).
RFC2 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region (PubMed:11003705).
The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1. This subunit binds ATP (By similarity).
Endothelins are endothelium-derived vasoconstrictor peptides.
Expressed in lung, but not in placental stem villi vessels or cultured placental villi smooth muscle cells.
PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with N-terminal region of CDC6. Interacts with NOD2 (PubMed:27812135).
Interacts with RIMS1 and RIMS2 (By similarity). Interacts with TSPO.
Predominantly expressed in brain, pituitary gland and thymus in adults. In adult brain, highest expression found in temporal lobe and the putamen, followed by amygdala, caudate nucleus, cerebral cortex, occipital and frontal lobe. A high expression level is also observed in fetal tissues like brain, heart, kidney and thymus.
PubMed:9915832 demonstrated interaction with TSPO but later PubMed:12435798 demonstrated in the rat ortholog that is not associated with TSPO in the brain.
The SH3 and proline-rich domain is required for the interaction with TSPO and the second SH3 domain mediates binding to a proline-rich motif in RIMS1 and RIMS2.
Down-regulated during monocyte to macrophage differentiation.
Exo-alpha-sialidase that catalyzes the hydrolytic cleavage of the terminal sialic acid (N-acetylneuraminic acid, Neu5Ac) of a glycan moiety in the catabolism of glycolipids, glycoproteins and oligosacharides. Efficiently hydrolyzes gangliosides including alpha-(2->3)-sialylated GD1a and GM3 and alpha-(2->8)-sialylated GD3 (PubMed:15847605, PubMed:21521691, PubMed:15213228). Hydrolyzes poly-alpha-(2->8)-sialylated neural cell adhesion molecule NCAM1 likely at growth cones, suppressing neurite outgrowth in hippocampal neurons (By similarity). May desialylate sialyl Lewis A and X antigens at the cell surface, down-regulating these glycan epitopes recognized by SELE/E selectin in the initiation of cell adhesion and extravasation (PubMed:21521691). Has sialidase activity toward mucin, fetuin and sialyllactose (PubMed:15847605).
Highly expressed in brain and at lower levels in kidney and liver.
Predominant form in liver. Also expressed in brain, kidney and colon.
Forms a soluble 1:1 complex with AFM; this prevents oligomerization and is required for prolonged biological activity (PubMed:16227623). The complex with AFM may represent the physiological form in body fluids (PubMed:26902720). Interacts with FZD1 and FZD10. Interacts with FZD4 (in vitro). Interacts with PORCN (By similarity). Interacts with glypican GPC3 (PubMed:16227623). Interacts (via intrinsically disordered linker region) with RECK; interaction with RECK confers ligand selectivity for Wnt7 in brain endothelial cells and allows these cells to selectively respond to Wnt7 (PubMed:30026314).
Ligand for members of the frizzled family of seven transmembrane receptors that functions in the canonical Wnt/beta-catenin signaling pathway (PubMed:30026314). Required for normal fusion of the chorion and the allantois during placenta development (By similarity). Required for central nervous system (CNS) angiogenesis and blood-brain barrier regulation (PubMed:30026314).
Moderately expressed in fetal brain, weakly expressed in fetal lung and kidney, and faintly expressed in adult brain, lung and prostate.
The intrinsically disordered linker region is required for recognition by RECK in brain endothelial cells.
Interacts with KLHL17, CAMK2A and CAMK2B (By similarity). Interacts with MPDZ.
It is uncertain whether Met-1 or Met-16 is the initiator methionine.
Major constituent of the PSD essential for postsynaptic signaling. Inhibitory regulator of the Ras-cAMP pathway. Member of the NMDAR signaling complex in excitatory synapses, it may play a role in NMDAR-dependent control of AMPAR potentiation, AMPAR membrane trafficking and synaptic plasticity. Regulates AMPAR-mediated miniature excitatory postsynaptic currents. Exhibits dual GTPase-activating specificity for Ras and Rap. May be involved in certain forms of brain injury, leading to long-term learning and memory deficits (By similarity).
Phosphorylated by CaM-kinase II. Dephosphorylated upon NMDA receptor activation or SYNGAP1/MPDZ complex disruption. Phosphorylation by PLK2 promotes its activity (By similarity).
The C2 domain is required for RapGAP activity.
Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane (PubMed:35835865). Heterotrimer with RHCE (RHAG)2(RHCE), that transports ammonium and its related derivative methylammonium, in both neutral and ionic forms, across the erythrocyte membrane (PubMed:11861637, PubMed:11062476, PubMed:15856280, PubMed:19273840, PubMed:21849667, PubMed:22012326, PubMed:24077989, PubMed:15572441, PubMed:26354748). The transport of NH4(+) is electrogenic and masks the NH3 transport (PubMed:26354748). Also, may act as a CO2 channel (PubMed:19273840, PubMed:17712059, PubMed:24077989). In vitro, leaks monovalent cations (PubMed:18931342, PubMed:21849667). Moreover in erythrocyte, regulates RHD membrane expression (PubMed:12130520) and is associated with rhesus blood group antigen expression (PubMed:19744193, PubMed:12130520).
Homodimer (PubMed:35835865). Heterotrimer; a RHCE monomer interacts with a RHAG homodimer (PubMed:35835865). Component of the ankyrin-1 complex in the erythrocyte, composed of ANK1, RHCE, RHAG, SLC4A1, EPB42, GYPA, GYPB and AQP1 (PubMed:35835865). Interacts with GYPB (via the N-terminal); this interaction bridges the (RHAG)2(RHCE) heterotrimer with the SLC4A1 Band 3 I dimer complexed with GYPA (PubMed:35835865).
Several mechanisms of transport has been proposed, namely electroneutral NH3 transport (PubMed:15572441, PubMed:19273840) and electroneutral NH4(+)/H(+) exchange (PubMed:11861637, PubMed:19273840, PubMed:15572441). However, Caner T. et al demonstrates that RHAG is unlikely to be NH4(+)/H(+) exchanger, but transports the ionic NH4(+) and the neutral NH3 species and that the transport of NH4(+) is electrogenic (PubMed:26354748).
Monoubiquitinated by RAG1 in lymphoid cells, monoubiquitination is required for V(D)J recombination. Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins.
Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 or isoform M2 of PKM (PKM2) is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin.
The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. During nucleosome assembly the chaperone ASF1A interacts with the histone H3-H4 heterodimer. Interacts with DNAJC9, CHAF1A and CHAF1B (PubMed:33857403).
Associates with microtubules and may play a role in the microtubule-dependent transport of the GABA-B receptor. May play a role in JAK1 signaling and regulate microtubule cytoskeleton rearrangements.
Homodimer. Forms a complex with GABBR1 and KIF5B/kinesin-1. Interacts with JAK1 and TYK2.
Predominantly expressed in neural tissues and lymphoid cells (at protein level). Isoform 2, isoform 3 and isoform 4 are specifically expressed in brain and retina. Isoform 1 and isoform 5 are also detected in liver, lung and skeletal muscle. Also detected in testis and to a lower extent spleen and intestine.
Was originally thought to bind single-stranded RNA molecules and regulate GABA-B receptor expression.
A common polymorphism located in a non-coding region between CELSR2 and PSRC1 alters a CEBP transcription factor binding site and is responsible for changes in hepatic expression of SORT1. Altered SORT1 expression in liver affects low density lipoprotein cholesterol levels in plasma and is associated with susceptibility to myocardial infarction.
Belongs to the VPS10-related sortilin family. SORT1 subfamily.
Expressed in brain and prostate (at protein level). Expressed at high levels in brain, spinal cord, heart, skeletal muscle, thyroid, placenta and testis. Expressed at lower levels in lymphoid organs, kidney, colon and liver.
Functions as a sorting receptor in the Golgi compartment and as a clearance receptor on the cell surface. Required for protein transport from the Golgi apparatus to the lysosomes by a pathway that is independent of the mannose-6-phosphate receptor (M6PR). Lysosomal proteins bind specifically to the receptor in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelysosomal compartment where the low pH mediates the dissociation of the complex (PubMed:16787399). The receptor is then recycled back to the Golgi for another round of trafficking through its binding to the retromer. Also required for protein transport from the Golgi apparatus to the endosomes. Promotes neuronal apoptosis by mediating endocytosis of the proapoptotic precursor forms of BDNF (proBDNF) and NGFB (proNGFB). Also acts as a receptor for neurotensin. May promote mineralization of the extracellular matrix during osteogenic differentiation by scavenging extracellular LPL. Probably required in adipocytes for the formation of specialized storage vesicles containing the glucose transporter SLC2A4/GLUT4 (GLUT4 storage vesicles, or GSVs). These vesicles provide a stable pool of SLC2A4 and confer increased responsiveness to insulin. May also mediate transport from the endoplasmic reticulum to the Golgi.
Genetic variations in SORT1 influence low density lipoprotein cholesterol (LDL-C) variability and contribute to the low density lipoprotein cholesterol level quantitative trait locus 6 (LDLCQ6) [MIM:613589].
Interacts with LPL and SLC2A4 (By similarity). Interacts with the cytosolic adapter proteins GGA1 and GGA2 (PubMed:20015111, PubMed:16787399). Interacts with numerous ligands including the receptor-associated protein LRPAP1/RAP, GM2A and NTS. Forms a complex with NGFR which binds specifically to the precursor forms of NGFB (proNGFB) and BDNF (proBDNF). Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; may regulate their anterograde axonal transport and signaling. Interacts with CLN5 (PubMed:22431521). Interacts with PSAP (PubMed:22431521, PubMed:14657016). Interacts with GRN; this interaction mediates endocytosis and lysosome delivery of progranulin; interaction occurs at the neuronal cell surface in a stressed nervous system (PubMed:21092856). Interacts with the heterotrimeric retromer cargo-selective complex (CSC), also described as vacuolar protein sorting subcomplex (VPS), formed by VPS26 (VPS26A or VPS26B), VPS29 and VPS35; which is involved in retrograde trafficking of the receptor from endosomes to the Golgi apparatus (PubMed:18817523). Interacts with SMPD1; the interaction is required for SMPD1 targeting to lysosomes (PubMed:16787399).
Palmitoylated (PubMed:18817523). Undergoes cysteine S-palmitoylation which promotes the partitioning of the receptor into an endosomal membrane subdomain where it can interact with the retromer cargo-selective complex which mediates its retrograde trafficking to the Golgi apparatus (PubMed:18817523).
Phosphorylation at Ser-825 facilitates the interaction with GGA1.
The N-terminal propeptide is cleaved by furin and possibly other homologous proteases.
The N-terminal propeptide may facilitate precursor transport within the Golgi stack. Intrachain binding of the N-terminal propeptide and the extracellular domain may also inhibit premature ligand binding.
The extracellular domain may be shed following protease cleavage in some cell types.
Probably involved in cell proliferation and cell-cell interactions.
Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3. Interacts with MPDZ (By similarity).
Plays a major role in tight junction-specific obliteration of the intercellular space.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. KIF27 subfamily.
Plays an essential role in motile ciliogenesis.
Testis, pancreatic islet, germ cell tumors and Jurkat T-cells.
First expressed in embryos at 8.5-9 days in facial and branchial arch mesenchyme, otic vesicles and frontonasal ectoderm around olfactory placodes, a day later expression is seen in the developing forebrain in primordia of the ganglionic eminence and ventral diencephalic regions. In day 12.5 embryos, expressed in the brain and bones, and also in all skeletal structures of midgestation embryos after the first cartilage formation. Expression remains unaltered in both brain and skeleton in day 15 embryos and slowly decreases in day 17 embryos.
Phosphorylated. Phosphorylation of Ser-34 and Ser-217 by MAPK14 enhances its transcriptional activity. Phosphorylation by CaMK2 increases its protein stability (By similarity).
Transcriptional factor involved in bone development. Acts as an immediate early BMP-responsive transcriptional activator essential for osteoblast differentiation. Stimulates ALPL promoter activity in a RUNX2-independent manner during osteoblast differentiation. Stimulates SP7 promoter activity during osteoblast differentiation. Promotes cell proliferation by up-regulating MYC promoter activity. Involved as a positive regulator of both chondrogenesis and chondrocyte hypertrophy in the endochondral skeleton. Binds to the homeodomain-response element of the ALPL and SP7 promoter. Binds to the MYC promoter. Requires the 5'-TAATTA-3' consensus sequence for DNA-binding.
Activated by phosphate ions and by potassium ions.
Belongs to the selenophosphate synthase 1 family. Class II subfamily.
Gradually expressed during the cell cycle until G2/M phase and then decreases.
Gradually expressed during the cell cycle until S phase and then decreases.
Homodimer (PubMed:20471958). Heterodimer with isoform 1 (PubMed:20471958).
Homodimer (PubMed:20471958). Heterodimer with isoform 2 (PubMed:20471958).
Homodimer (PubMed:20471958). Heterodimer with isoform 4 (PubMed:20471958).
Homodimer (PubMed:20471958, PubMed:19477186). Heterodimer with isoform 3 (PubMed:20471958).
Synthesizes selenophosphate from selenide and ATP.
The conserved active site Cys (or selenocysteine) residue in position 29 is replaced by a Thr. However, as function in selenoprotein synthesis is proven, it is possible Cys-31 is the active site.
(Microbial infection) Interacts with hepatitis C virus (HCV) protein NS5A.
Member of the repulsive guidance molecule (RGM) family that performs several functions in the developing and adult nervous system. Regulates cephalic neural tube closure, inhibits neurite outgrowth and cortical neuron branching, and the formation of mature synapses. Binding to its receptor NEO1/neogenin induces activation of RHOA-ROCK1/Rho-kinase signaling pathway through UNC5B-ARHGEF12/LARG-PTK2/FAK1 cascade, leading to collapse of the neuronal growth cone and neurite outgrowth inhibition. Furthermore, RGMA binding to NEO1/neogenin leads to HRAS inactivation by influencing HRAS-PTK2/FAK1-AKT1 pathway. It also functions as a bone morphogenetic protein (BMP) coreceptor that may signal through SMAD1, SMAD5, and SMAD8.
Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a heterodimer with MAX. Interacts with SIN3A AND SIN3B. Interacts with RNF17 (By similarity).
Transcriptional repressor. Binds with MAX to form a sequence-specific DNA-binding protein complex which recognizes the core sequence 5'-CAC[GA]TG-3'. Antagonizes MYC transcriptional activity by competing for MAX and suppresses MYC dependent cell transformation (By similarity).
Activity toward QA is slightly repressed by phosphoribosylpyrophosphate (PRPP) in both a competitive and a non-competitive manner (PubMed:17868694). Competitively inhibited by phthalic acid (PHT) (PubMed:24038671).
Involved in the catabolism of quinolinic acid (QA).
Almost exclusively expressed in placenta (PubMed:32329225). Expressed at much lower level in other tissues (PubMed:32329225). Expressed in fetal eye (18 weeks)in the retinal pigment epithelium (RPE), the choroid, Bruch's membrane and in the sclera (PubMed:24899048). Not expressed in the neural retina (PubMed:24899048).
Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles. Fibrillin-2-containing microfibrils regulate the early process of elastic fiber assembly. Regulates osteoblast maturation by controlling TGF-beta bioavailability and calibrating TGF-beta and BMP levels, respectively.
Hormone secreted by trophoblasts that promotes trophoblast invasiveness (PubMed:32329225). Has glucogenic activity: is able to increase plasma glucose levels (By similarity).
Interacts with BMP2, BMP4, BMP7, BMP10 and GDF5 (PubMed:18339631). Interacts with MFAP2 and MFAP5 (PubMed:15131124). Interacts with ADAMTSL5 (PubMed:23010571). Interacts with MFAP4 (PubMed:26601954).
Present at high level in cytotrophoblasts as compared with syncytiotrophoblasts at 8-9 weeks of pregnancy (at protein level) (PubMed:32329225). Levels in the serum increase during pregnancy (at protein level) (PubMed:32329225).
Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity (PubMed:12438418, PubMed:14654001, PubMed:15062103, PubMed:15235793, PubMed:15239953, PubMed:15548592, PubMed:17535814). Required for kinetochore integrity and the organization of stable microtubule binding sites in the outer plate of the kinetochore (PubMed:15548592). The NDC80 complex synergistically enhances the affinity of the SKA1 complex for microtubules and may allow the NDC80 complex to track depolymerizing microtubules (PubMed:23085020).
Can be phosphorylated by AURKA and AURKB.
Component of the NDC80 complex, which consists of NDC80/HEC1, CDCA1, SPBC24 and SPBC25. The NDC80 complex is formed by two subcomplexes composed of NDC80/HEC1-CDCA1 and SPBC24-SPBC25. Each subcomplex is formed by parallel interactions through the coiled-coil domains of individual subunits. Formation of a tetrameric complex is mediated by interactions between the C-terminal regions of both subunits of the NDC80/HEC1-CDCA1 subcomplex and the N-terminal regions of both subunits of the SPBC24-SPBC25 complex. The tetrameric NDC80 complex has an elongated rod-like structure with globular domains at either end. May interact with AURKB/Aurora-B. Directly interacts with CENPE; this interaction determines CENPE kinetochore localization.
Isoform 1 and isoform 2 are highly expressed in placenta, pancreas, and small intestine. Lower expression in colon, ovary, testis, prostate, thymus, spleen, kidney, and liver. No expression detected in heart and brain.
Associates with pre-60S ribosomal particles (PubMed:32669547). Interacts with MINAS-60 (product of an alternative open reading frame of RBM10) (PubMed:35393574).
Belongs to the TRAFAC class OBG-HflX-like GTPase superfamily. OBG GTPase family. NOG subfamily.
Involved in the biogenesis of the 60S ribosomal subunit (PubMed:32669547). Acts as TP53 repressor, preventing TP53 stabilization and cell cycle arrest (PubMed:20308539).
Involved in the biogenesis of the 60S ribosomal subunit.
(Microbial infection) Interacts with hepatitis C virus non-structural protein 5A (NS5A) and less efficiently, with hepatitis C virus non-structural protein 5B (NS5B); a reaction crucial for hepatitis C virus RNA replication.
Calcium-activated substrate recognition component of the SCF (SKP1-cullin-F-box protein) E3 ubiquitin-protein ligase complex, SCF(FBXL2), which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:22020328, PubMed:22323446). Unlike many F-box proteins, FBXL2 does not seem to target phosphodegron within its substrates but rather calmodulin-binding motifs and is thereby antagonized by calmodulin (PubMed:22020328, PubMed:22323446). This is the case for the cyclins CCND2 and CCND3 which polyubiquitination and subsequent degradation are inhibited by calmodulin (PubMed:22020328, PubMed:22323446). Through CCND2 and CCND3 degradation induces cell-cycle arrest in G(0) (PubMed:22020328, PubMed:22323446). SCF(FBXL2) also mediates PIK3R2 ubiquitination and proteasomal degradation thereby regulating phosphatidylinositol 3-kinase signaling and autophagy (PubMed:23604317). PCYT1A monoubiquitination by SCF(FBXL2) and subsequent degradation regulates synthesis of phosphatidylcholine, which is utilized for formation of membranes and of pulmonary surfactant (By similarity). The SCF(FBXL2) complex acts as a regulator of inflammation by mediating ubiquitination and degradation of TRAF proteins (TRAF1, TRAF2, TRAF3, TRAF4, TRAF5 and TRAF6) (By similarity). The SCF(FBXL2) complex acts as a negative regulator of the NLRP3 inflammasome by mediating ubiquitination and degradation of NLRP3 (PubMed:26037928).
Deletion of the F-box domain creates a dominant-negative protein that inhibits replication of hepatitis C virus RNA when overexpressed in a hepatoma cell line; this inhibition could be overcome by NS5A coexpression.
Expressed in brain, heart, kidney, liver, lung, pancreas and placenta.
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL2) composed of CUL1, SKP1, RBX1 and FBXL2 (PubMed:10531037). Interacts with calmodulin; may antagonize substrate ubiquitination by SCF(FBXL2) (PubMed:22020328). May interact with PIK3R1 (PubMed:23604317). Interacts with PTPN13 (PubMed:23604317).
Phosphorylated by GSK-beta (GSK3B), promoting recognition by FBXO3, leading to its ubiquitination by the SCF(FBXO3) complex.
The CAAX motif is a signal for the geranylgeranylation of FBXL2 and is required for its association with cell membranes and the recruitment of substrates to the active SCF(FBXL2) complex.
Ubiquitinated at Lys-201 by the SCF(FBXO3) complex in response to lipopolysaccharide (LPS), leading to its degradation by the proteasome.
Homooligomer; can for homodimers and homotetramers (PubMed:21368133, PubMed:25589040). Interacts with TECTA and TECTB (PubMed:21368133).
Required for proper hearing, plays a role in maintaining the integrity of the tectorial membrane.
Belongs to the NAD(P)-dependent epimerase/dehydratase family. dTDP-glucose dehydratase subfamily.
Detected at low levels in the ductal cells of the salivary gland but not in the acinar cells (at protein level) (PubMed:28153567). Expressed in endometrium (at protein level) (PubMed:24238509). Expressed in epithelial cells within the acinar ducts of the prostate (PubMed:10430935, PubMed:10931945).
Encoded in an alternative reading frame of the T-cell receptor gamma chain gene which is composed of variable (Vgamma), joining (Jgamma), and constant (Cgamma) gene segments. Originates within an intron directly upstream of the Jgamma1.2 gene segment and contains three exons from the Cgamma1 segment.
Expressed in prostate cancer and breast cancer cells with little or no expression detected in normal breast tissue (PubMed:10931945). In prostate cancer cells, increases cell growth rate and changes expression levels of a number of genes including up-regulation of CAV1, CAV2, AREG and CXCL1/GRO1 and down-regulation of IL1B (PubMed:11719440). Localizes to the mitochondrion outer membrane in prostate cancer cells (PubMed:15150260). In acute myeloid leukemia cells, shows perinuclear staining and some localization at the endoplasmic reticulum (PubMed:31371409). Expressed at significantly higher levels in primary salivary adenoid cystic carcinomas (SACC) compared with adjacent non-cancerous tissues and promotes the proliferation, migration and invasion of SACC cells (PubMed:28153567). Expressed at higher levels in endometrial carcinomas than in normal endometrial tissue (PubMed:24238509).
Interacts with DNAJC3 (PubMed:9920933). Interacts with HSF1 (via transactivation domain); this interaction results in the inhibition of heat shock- and HSF1-induced transcriptional activity during the attenuation and recovery phase period of the heat shock response (PubMed:9499401).
Interacts with HSP70 and can stimulate its ATPase activity. Stimulates the association between HSC70 and HIP. Negatively regulates heat shock-induced HSF1 transcriptional activity during the attenuation and recovery phase period of the heat shock response (PubMed:9499401). Stimulates ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B (in vitro) (PubMed:24318877).
Abundantly expressed in kidney and muscle. Expressed in the S1 segment of the proximal tubule close to the glomerulus.
Electrogenic proton/amino acid symporter with a high selectivity for the small side chains amino acids glycine, alanine and proline, where both L- and D-enantiomers are transported. Extension of the backbone length, as in beta-alanine and 4-aminobutanoate or methylation of the amino group, as in sarcosine and N,N-dimethylglycine, are also tolerated but decrease transport efficiency. A free carboxyl group is preferred.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Mutations in SLC36A2 that retain residual transport activity result in the IG phenotype only when combined with haploinsufficiency of the imino acid transporter SLC6A20 or deficiency of the neutral amino acid transporter SLC6A19. Additional polymorphisms and mutations in SLC6A18 can contribute to iminoglycinuria in some families.
Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes (PubMed:32565547). In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals. The BLOC-1 complex, in association with SNARE proteins, is also proposed to be involved in neurite extension. Plays a role in intracellular vesicle trafficking.
Interacts with BLOC1S4, DTNBP1/BLOC1S7 and PI4K2A (By similarity). Component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) composed of BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. Octamer composed of one copy each BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. The BLOC-1 complex associates with the AP-3 protein complex and membrane protein cargos. Interacts with BLOC1S6.
Binds beta-galactoside and lactose. Strong inducer of T-cell apoptosis (PubMed:10527825, PubMed:19497882). Has hemagglutinating activity towards chicken erythrocytes (PubMed:29343868).
Detected in adult and fetal spleen, fetal kidney, adult urinary bladder and placenta. Placental expression originates predominantly from the syncytiotrophoblast.
Belongs to the DDOST 48 kDa subunit family.
Component of the oligosaccharyltransferase (OST) complex (PubMed:31831667). OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits (PubMed:23606741, PubMed:25135935, PubMed:31831667). STT3A complex assembly occurs through the formation of 3 subcomplexes. Subcomplex 1 contains RPN1 and TMEM258, subcomplex 2 contains the STT3A-specific subunits STT3A, DC2/OSTC, and KCP2 as well as the core subunit OST4, and subcomplex 3 contains RPN2, DAD1, and OST48. The STT3A complex can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes (By similarity). Interacts with SMIM22 (PubMed:29765154).
It is uncertain whether Met-1 or Met-18 is the initiator.
Subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation (PubMed:31831667). N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity (By similarity). Required for the assembly of both SST3A- and SS3B-containing OST complexes (PubMed:22467853).
Component of the ESCRT-0 complex composed of STAM or STAM2 and HGS. Part of a complex at least composed of HSG, STAM2 (or probably STAM) and EPS15 (PubMed:12551915). Interacts with STAM (PubMed:9407053). Interacts with STAM2 (By similarity). Interacts with EPS15; the interaction is direct, calcium-dependent and inhibited by SNAP25 (By similarity). Identified in a complex with STAM and LITAF (PubMed:23166352). Found in a complex with STAM and E3 ligase ITCH and DTX3L (PubMed:24790097). Interacts with E3 ligase DTX3L; the interaction brings together STAM and HSG, promotes their recruitment to early endosomes and decreases STAM and HGS ubiquitination by ITCH (PubMed:24790097). Interacts with NF2; the interaction is direct (PubMed:10861283). Interacts with ubiquitin; the interaction is direct (By similarity). Interacts with VPS37C (PubMed:15509564). Interacts with SMAD1, SMAD2 and SMAD3 (By similarity). Interacts with TSG101; the interaction mediates the association with the ESCRT-I complex (PubMed:21070952). Interacts with SNAP25; the interaction is direct and decreases with addition of increasing concentrations of free calcium (By similarity). Interacts with SNX1; the interaction is direct (By similarity). Component of a 550 kDa membrane complex at least composed of HGS and SNX1 but excluding EGFR (By similarity). Interacts with TRAK1 (PubMed:18675823). Interacts with TRAK2 (By similarity). Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3 (PubMed:15772161). Interacts (via UIM domain) with UBQLN1 (via ubiquitin-like domain) (By similarity). Interacts with ARRDC3 (PubMed:23208550). Identified in a complex containing at least ARRDC4, AVPR2 and HGS (PubMed:23236378). Interacts with LAPTM4B; promotes HGS ubiquitination (PubMed:25588945).
Has a double-sided UIM that can bind 2 ubiquitin molecules, one on each side of the helix.
Involved in intracellular signal transduction mediated by cytokines and growth factors. When associated with STAM, it suppresses DNA signaling upon stimulation by IL-2 and GM-CSF. Could be a direct effector of PI3-kinase in vesicular pathway via early endosomes and may regulate trafficking to early and late endosomes by recruiting clathrin. May concentrate ubiquitinated receptors within clathrin-coated regions. Involved in down-regulation of receptor tyrosine kinase via multivesicular body (MVBs) when complexed with STAM (ESCRT-0 complex). The ESCRT-0 complex binds ubiquitin and acts as sorting machinery that recognizes ubiquitinated receptors and transfers them to further sequential lysosomal sorting/trafficking processes. May contribute to the efficient recruitment of SMADs to the activin receptor complex. Involved in receptor recycling via its association with the CART complex, a multiprotein complex required for efficient transferrin receptor recycling but not for EGFR degradation.
Phosphorylated on Tyr-334. A minor site of phosphorylation on Tyr-329 is detected (By similarity). Phosphorylation occurs in response to EGF, IL-2, GM-CSF and HGF.
The FYVE-type zinc finger domain mediates interactions with phosphatidylinositol 3-phosphate in membranes of early endosomes and penetrates bilayers. The FYVE domain insertion into PtdIns(3)P-enriched membranes is substantially increased in acidic conditions.
Ubiquitinated (PubMed:25588945). Ubiquitinated by ITCH (PubMed:14602072, PubMed:24790097).
Ubiquitous expression in adult and fetal tissues with higher expression in testis and peripheral blood leukocytes.
Belongs to the eIF-2B alpha/beta/delta subunits family. MtnA subfamily.
By RhoA activation in cancer cells (at protein level).
Catalyzes the interconversion of methylthioribose-1-phosphate (MTR-1-P) into methylthioribulose-1-phosphate (MTRu-1-P). Independently from catalytic activity, promotes cell invasion in response to constitutive RhoA activation by promoting FAK tyrosine phosphorylation and stress fiber turnover.
A chromosomal aberration involving KCNC2 has been found in a mother and her two children with varying degrees of neurodevelopmental delay and cerebellar ataxia. One child also exhibits episodes of unresponsiveness suggestive of absence seizures and facial dysmorphism. Deletion at 12q21.1 deletes exons 3-5 of KCNC2.
Belongs to the potassium channel family. C (Shaw) (TC 1.A.1.2) subfamily. Kv3.2/KCNC2 sub-subfamily.
Homotetramer and heterotetramer with other channel-forming alpha subunits, such as KCNC1. Interacts with KCNC1. Homotetramer or heterotetramer channel activity is regulated by association with modulating ancillary subunits such as KCNE1, KCNE2 and KCNE3, creating a functionally diverse range of channel complexes. Interacts with KCNE1, KCNE2 and KCNE3.
Inhibited by Stichodactyla helianthus peptide ShK (PubMed:15709110). Inhibited by millimolar levels of tetraethylammonium (TEA). Contrary to other channels, inhibited only by millimolar levels of 4-aminopyridine (4-AP) (By similarity).
Phosphorylated by PKA in cortical synaptosomes. cAMP-dependent phosphorylation inhibits channel activity (By similarity). Histamine H2 receptor- and PKA-induced phosphorylation extends action potential spike duration, reduces action potential spike amplitude, sustains maximum firing frequency in hippocampal interneurons; also reduces the incidence of high-frequency oscillations in hippocampal CA3 pyramidal cell layers.
Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain. Contributes to the regulation of the fast action potential repolarization and in sustained high-frequency firing in neurons of the central nervous system. Homotetramer channels mediate delayed-rectifier voltage-dependent potassium currents that activate rapidly at high-threshold voltages and inactivate slowly. Forms tetrameric channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:15709110). Can form functional homotetrameric and heterotetrameric channels that contain variable proportions of KCNC1, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel. Channel properties may be modulated either by the association with ancillary subunits, such as KCNE1, KCNE2 or KCNE3 or indirectly by nitric oxide (NO) through a cGMP- and PKG-mediated signaling cascade, slowing channel activation and deactivation of delayed rectifier potassium channels (By similarity). Contributes to fire sustained trains of very brief action potentials at high frequency in retinal ganglion cells, thalamocortical and suprachiasmatic nucleus (SCN) neurons and in hippocampal and neocortical interneurons (PubMed:15709110). Sustained maximal action potential firing frequency in inhibitory hippocampal interneurons is negatively modulated by histamine H2 receptor activation in a cAMP- and protein kinase (PKA) phosphorylation-dependent manner. Plays a role in maintaining the fidelity of synaptic transmission in neocortical GABAergic interneurons by generating action potential (AP) repolarization at nerve terminals, thus reducing spike-evoked calcium influx and GABA neurotransmitter release. Required for long-range synchronization of gamma oscillations over distance in the neocortex. Contributes to the modulation of the circadian rhythm of spontaneous action potential firing in suprachiasmatic nucleus (SCN) neurons in a light-dependent manner (By similarity).
Copper ion transmembrane transporter involved in the export of copper out of the cells. It is involved in copper homeostasis in the liver, where it ensures the efflux of copper from hepatocytes into the bile in response to copper overload.
Each HMA domain can bind a copper ion, they are tightly packed and closely interact with each other. Wild-type ATP7B can usually be loaded with an average 5.5 copper atoms per molecule.
Isoform 1 may be proteolytically cleaved at the N-terminus to produce the WND/140 kDa form.
May arise by a -1 programmed ribosomal frameshift at codon 233. A nucleotide 'slippery sequence' followed by an mRNA pseudoknot are found downstream of the frameshift site and direct frameshifting of a gene fragment with about 10% efficiency.
Monomer. Interacts with COMMD1/MURR1 (PubMed:12968035, PubMed:17919502). Interacts with DCTN4, in a copper-dependent manner (PubMed:16554302). Interacts with ATOX1 (PubMed:18558714, PubMed:17919502). Interacts (via C-terminus) with ZBTB16/PLZF (PubMed:16676348).
Most abundant in liver and kidney and also found in brain. Isoform 2 is expressed in brain but not in liver. The cleaved form WND/140 kDa is found in liver cell lines and other tissues.
(Microbial infection) In case of infection, interacts with B.melitensis protein TcpB; TcpB abolishes the TLR4-TIRAP interaction in vitro.
(Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC.
(Microbial infection) Interacts with ebolavirus protein GP; this interaction leads to the production of proinflammatory cytokines and suppressor of cytokine signaling 1/SOCS1.
Allele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS.
Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4 (PubMed:11274165). Binding to bacterial LPS leads to homodimerization. Interacts with LY96 via the extracellular domain (PubMed:17803912, PubMed:19252480). Interacts with MYD88 and TIRAP via their respective TIR domains (By similarity). Interacts with TICAM2 (PubMed:14519765, PubMed:25736436). Interacts with NOX4 (PubMed:15356101). Interacts with CNPY3 (By similarity). Interacts with HSP90B1. The interaction with both CNPY3 and HSP90B1 is required for proper folding in the endoplasmic reticulum. Interacts with MAP3K21; this interaction leads to negative regulation of TLR4 signaling (PubMed:21602844). Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR6 (PubMed:20037584). The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Interacts with TICAM1 in response to LPS in a WDFY1-dependent manner (PubMed:25736436). Interacts with WDFY1 in response to LPS (By similarity). Interacts with SMPDL3B (By similarity). Interacts with CEACAM1; upon lipopolysaccharide stimulation, forms a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome (By similarity). Interacts with RFTN1; the interaction occurs in response to lipopolysaccharide stimulation (PubMed:27022195). Interacts with SCIMP; the interaction occurs in response to lipopolysaccharide stimulation and is enhanced by phosphorylation of SCIMP by LYN (By similarity). This interaction facilitates the phosphorylation of TLR4 by LYN which elicits a selective cytokine response in macrophages (By similarity). Interacts with TRAF3IP3 (PubMed:30573680). Interacts with TREM1; this interaction enhances TLR4-mediated inflammatory response (PubMed:21393102, PubMed:17098818).
Highly expressed in placenta, spleen and peripheral blood leukocytes (PubMed:9435236, PubMed:9237759). Detected in monocytes, macrophages, dendritic cells and several types of T-cells (PubMed:9237759, PubMed:27022195).
His-456 and His-458 are found in TLR4 of human and several other primate species and may be responsible for inflammatory responses triggered by nickel (Ni(2+)). Ni(2+) may cross-link the two receptor monomers through specific histidines, triggering the formation of a dimer that structurally resembles that induced by LPS. This process may be the basis for the development of contact allergy to Ni(2+). A mouse model of contact allergy to Ni(2+) in which TLR4-deficient mice expresses human TLR4 has been proposed.
In some plant proteins and in human SARM1, the TIR domain has NAD(+) hydrolase (NADase) activity (PubMed:28334607). However, despite the presence of the catalytic Asp residue, the isolated TIR domain of human TLR4 lacks NADase activity (PubMed:28334607). Based on this, it is unlikely that Toll-like receptors have NADase activity.
N-glycosylated. Glycosylation of Asn-526 and Asn-575 seems to be necessary for the expression of TLR4 on the cell surface and the LPS-response. Likewise, mutants lacking two or more of the other N-glycosylation sites were deficient in interaction with LPS.
Phosphorylated on tyrosine residues by LYN after binding lipopolysaccharide.
The TIR domain mediates interaction with NOX4.
Transmembrane receptor that functions as a pattern recognition receptor recognizing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) to induce innate immune responses via downstream signaling pathways (PubMed:16622205, PubMed:10835634, PubMed:15809303, PubMed:17478729, PubMed:20037584, PubMed:20711192, PubMed:23880187, PubMed:27022195, PubMed:17292937, PubMed:29038465). At the plasma membrane, cooperates with LY96 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+) (PubMed:20711192). Mechanistically, acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634, PubMed:27022195, PubMed:21393102). Alternatively, CD14-mediated TLR4 internalization via endocytosis is associated with the initiation of a MYD88-independent signaling via the TICAM1-TBK1-IRF3 axis leading to type I interferon production (PubMed:14517278). In addition to the secretion of proinflammatory cytokines, initiates the activation of NLRP3 inflammasome and formation of a positive feedback loop between autophagy and NF-kappa-B signaling cascade (PubMed:32894580). In complex with TLR6, promotes inflammation in monocytes/macrophages by associating with TLR6 and the receptor CD86 (PubMed:23880187). Upon ligand binding, such as oxLDL or amyloid-beta 42, the TLR4:TLR6 complex is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway (PubMed:23880187). In myeloid dendritic cells, vesicular stomatitis virus glycoprotein G but not LPS promotes the activation of IRF7, leading to type I IFN production in a CD14-dependent manner (PubMed:23880187, PubMed:15265881).
Belongs to the myo-inositol oxygenase family.
Expressed in dermal and in synovial fibroblasts. Strongly expressed in gastric cancers compared with the paired normal tissues. Strongly expressed in both ductal carcinoma and invasive breast cancer cells compared with benign epithelial cells (at protein level). Strongly expressed in brain, placenta, prostate, breast, lung and testis. Expressed in fibroblasts, epithelial cells and cancer cells. In ear, it is specifically expressed in inner ear. Expressed in cochlea and vestibule tissues. Strongly expressed in gastric cancers compared with the paired normal tissues. Strongly expressed in colon adenocarcinomas compared with normal colonic mucosas. Strongly expressed in breast cancer as compared to normal breast tissue.
Interacts with EPHA2 and ITPR3. Interacts with HSPA5/BIP; the interaction induces calcium leakage from the endoplasmic reticulum and cell migration. Interacts with clathrin heavy chain/CLTC.
Mediates depolymerization of hyaluronic acid (HA) via the cell membrane-associated clathrin-coated pit endocytic pathway. Binds to hyaluronic acid. Hydrolyzes high molecular weight hyaluronic acid to produce an intermediate-sized product, a process that may occur through rapid vesicle endocytosis and recycling without intracytoplasmic accumulation or digestion in lysosomes. Involved in hyaluronan catabolism in the dermis of the skin and arthritic synovium. Positively regulates epithelial-mesenchymal transition (EMT), and hence tumor cell growth, invasion and cancer dissemination. In collaboration with HSPA5/BIP, promotes cancer cell migration in a calcium and PKC-dependent manner. May be involved in hearing.
N-glycosylated; glycosylation is not necessary for HA-binding.
The signal sequence is essential in mediating its proper translocation, hyaluronic acid (HA) degradation activity and secretion.
Up-regulated by histamine. Up-regulated by the adapter protein complex 1 (AP-1) and NF-kappaB/RELA. Down-regulated by transforming growth factor TGFB1.
(Microbial infection) Interacts with hepatitis E virus/HEV protein ORF3.
Binds heme and transports it to the liver for breakdown and iron recovery, after which the free hemopexin returns to the circulation.
N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. O-glycosylation in the 30-40 region is minor compared to glycosylation at Thr-24 and Thr-29.
The isolated N-terminal domain binds one heme. The full-length protein also binds one heme, but at a different site. The physiological significance of this is not clear (By similarity).
(Microbial infection) Interacts with HIV-1 Nef; this interaction inhibits MAP3K5 signaling.
Abundantly expressed in heart and pancreas.
Activated by various stressors, including oxidative stress, endoplasmic reticulum stress, and calcium overload, as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) and lipopolysaccharide (LPS). Homophilic association of MAP3K5/ASK1 through the C-terminal coiled-coil domains and the heteromeric complex formation of MAP3K5/ASK1 with the reduced form of thioredoxin (TXN), constitutes an inactive form of the kinase (PubMed:17210579, PubMed:9564042). Upon ROS-induced dissociation of TXN from MAP3K5/ASK1, TRAF2 and TRAF6 are reciprocally recruited to MAP3K5/ASK1 and form the active MAP3K5/ASK1 signalosome, in which TRAF2 and TRAF6 appear to facilitate the active configuration of MAP3K5/ASK1 (PubMed:9774977, PubMed:10688666, PubMed:11920685). MAP3K5/ASK1 activity is also regulated through several phosphorylation and dephosphorylation events. Thr-838 is an activating phosphorylation site that is autophosphorylated and phosphorylated by MAP3K6/ASK2 and dephosphorylated by PPP5C (PubMed:11689443). Ser-83 and Ser-1033 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1 (PubMed:11154276, PubMed:15094778). Phosphorylation of Ser-966 induces association of MAP3K5/ASK1 with the 14-3-3 family proteins, which suppresses MAP3K5/ASK1 activity (PubMed:10411906, PubMed:14688258). Calcium/calmodulin-activated protein phosphatase calcineurin (PPP3CA) has been shown to directly dephosphorylate this site (PubMed:14749717). SOCS1 binds to ASK1 by recognizing phosphorylation of Tyr-718 and induces MAP3K5/ASK1 degradation in endothelial cells (PubMed:16407264). Also dephosphorylated and activated by PGAM5. Contains an N-terminal autoinhibitory domain. Once activated targeted for proteasomal degradation by RC3H2-mediated ubiquitination (PubMed:24448648).
Homodimer when inactive. Binds both upstream activators and downstream substrates in multimolecular complexes. Part of a cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response to TNF (PubMed:15310755, PubMed:15701637, PubMed:17210579, PubMed:17389591). This complex formation promotes MAP3K5-JNK activation and subsequent apoptosis. Interacts with SOCS1 which recognizes phosphorylation of Tyr-718 and induces MAP3K5/ASK1 degradation in endothelial cells. Interacts with the 14-3-3 family proteins such as YWHAB, YWHAE, YWHAQ, YWHAH, YWHAZ and SFN (PubMed:10411906, PubMed:15023544, PubMed:15094778). Interacts with ARRB2, BIRC2, DAB2IP, IGF1R, MAP3K6/ASK2, PGAM5, PIM1, PPP5C, SOCS1, STUB1, TRAF2, TRAF6 and TXN (PubMed:9564042, PubMed:9774977, PubMed:10688666, PubMed:11090355, PubMed:11689443, PubMed:12556535, PubMed:12813029, PubMed:15310755, PubMed:16038411, PubMed:16129676, PubMed:16407264, PubMed:17220297, PubMed:17724081, PubMed:18408005, PubMed:19590015, PubMed:19749799). Interacts with ERN1 in a TRAF2-dependent manner (PubMed:14749717). Interacts with calcineurin subunit PPP3R1 (By similarity). Interacts with PPM1L (PubMed:17456047). Interacts (via N-terminus) with RAF1 and this interaction inhibits the proapoptotic function of MAP3K5 (PubMed:11427728). Interacts with DAB2IP (via N-terminus C2 domain); the interaction occurs in a TNF-alpha-dependent manner (PubMed:15310755). Interacts with DUSP13A; may positively regulate apoptosis (PubMed:20358250). Interacts with DAXX (PubMed:9743501). Interacts with RC3H2 (PubMed:24448648). Interacts with PPIA/CYPA (PubMed:26095851). Interacts with PRMT1; the interaction results in MAP3K5 methylation by PRMT1 which inhibits MAP3K5 activation (PubMed:22095282). Interacts with TRAF2; the interaction is inhibited by PRMT1 (PubMed:22095282). Interacts with TRIM48 (PubMed:29186683).
Methylation at Arg-78 and Arg-80 by PRMT1 promotes association of MAP3K5 with thioredoxin and negatively regulates MAP3K5 association with TRAF2, inhibiting MAP3K5 activation (PubMed:22095282). Methylation is blocked by ubiquitination of PRMT1 by TRIM48 (PubMed:29186683).
Phosphorylated at Thr-838 through autophosphorylation and by MAP3K6/ASK2 which leads to activation. Thr-838 is dephosphorylated by PPP5C. Ser-83 and Ser-1033 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1. Phosphorylated at Ser-966 which induces association of MAP3K5/ASK1 with the 14-3-3 family proteins and suppresses MAP3K5/ASK1 activity. Calcineurin (CN) dephosphorylates this site. Also dephosphorylated and activated by PGAM5. Phosphorylation at Ser-966 in response to oxidative stress is negatively regulated by PPIA/CYPA (PubMed:26095851).
Reported to be phosphorylated by AKT2 (PubMed:12697749). However, the publication has been retracted due to image duplication in figures.
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1).
Ubiquitinated (PubMed:16038411, PubMed:17220297, PubMed:29186683). Tumor necrosis factor (TNF) induces TNFR2-dependent ubiquitination, leading to proteasomal degradation (PubMed:17220297). Ubiquitinated by RC3H2 in a TRIM48-dependent manner (PubMed:29186683).
Isoform A is ubiquitous. Isoform B is expressed in brain with high expression in hippocampus and cerebral cortex.
Isoform B is activated by phosphorylation by PKA. Oxidative stress induces phosphorylation. Activated by autophosphorylation at Thr-190 and phosphorylation at this site is essential for its function. Manganese, magnesium and cobalt-dependent autophosphorylation is mainly on threonine residues while zinc-dependent autophosphorylation is on both serine and threonine residues.
Monomer (PubMed:20124694). Interacts with CTTNBP2NL (PubMed:18782753). Interacts with RIPOR1 (via C-terminus); this interaction occurs in a PDCD10-dependent and Rho-independent manner (PubMed:27807006). Interacts with PDCD10; this interaction is required for the association of STK24 with RIPOR1 (PubMed:27807006).
Proteolytically processed by caspases during apoptosis. Proteolytic cleavage results in kinase activation, nuclear translocation of the truncated form (MST3/N) and the induction of apoptosis.
Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation. Mediates oxidative-stress-induced cell death by modulating phosphorylation of JNK1-JNK2 (MAPK8 and MAPK9), p38 (MAPK11, MAPK12, MAPK13 and MAPK14) during oxidative stress. Plays a role in a staurosporine-induced caspase-independent apoptotic pathway by regulating the nuclear translocation of AIFM1 and ENDOG and the DNase activity associated with ENDOG. Phosphorylates STK38L on 'Thr-442' and stimulates its kinase activity. In association with STK26 negatively regulates Golgi reorientation in polarized cell migration upon RHO activation (PubMed:27807006). Regulates also cellular migration with alteration of PTPN12 activity and PXN phosphorylation: phosphorylates PTPN12 and inhibits its activity and may regulate PXN phosphorylation through PTPN12. May act as a key regulator of axon regeneration in the optic nerve and radial nerve.
(Microbial infection) Inhibited by herpes simplex virus US12/ICP47 protein, which blocks the peptide-binding site of TAP1-TAP2.
(Microbial infection) Inhibited by human cytomegalovirus US6 glycoprotein, which binds to the lumenal side of TAP1-TAP2 complex and inhibits peptide translocation by specifically blocking ATP-binding and preventing TAP1-TAP2 conformational rearrangement induced by peptide binding.
(Microbial infection) Interacts with Epstein-Barr virus BLNF2a.
(Microbial infection) Interacts with adenovirus E3-19K glycoprotein, which binds TAP1-TAP2 and acts as a TAPBP inhibitor, preventing TAP1-TAP2 association with MHCI.
(Microbial infection) Interacts with herpes simplex virus US12/ICP47.
4 common alleles are officially recognized: TAP2*01:01 (TAP2A or PSF2A or RING11A), TAP2*01:02 (TAP2E), TAP2*01:03 (TAP2F), and TAP2*02:01 (TAP2B or PSF2B or RING11B). Other relatively common alleles have been identified: TAP2*01D, TAP2*01E, TAP2*01F, TAP2*01G, TAP2*01H, TAP2*02B, TAP2*02C (TAP2*02:02), TAP2*02D, TAP2*02E, TAP2*02F, TAP2*03A and TAP2*04A. The sequence shown is that of TAP2*01:01.
ABC transporter associated with antigen processing. In complex with TAP1 mediates unidirectional translocation of peptide antigens from cytosol to endoplasmic reticulum (ER) for loading onto MHC class I (MHCI) molecules (PubMed:25656091, PubMed:25377891). Uses the chemical energy of ATP to export peptides against the concentration gradient (PubMed:25377891). During the transport cycle alternates between 'inward-facing' state with peptide binding site facing the cytosol to 'outward-facing' state with peptide binding site facing the ER lumen. Peptide antigen binding to ATP-loaded TAP1-TAP2 induces a switch to hydrolysis-competent 'outward-facing' conformation ready for peptide loading onto nascent MHCI molecules. Subsequently ATP hydrolysis resets the transporter to the 'inward facing' state for a new cycle (PubMed:25377891, PubMed:25656091, PubMed:11274390). Typically transports intracellular peptide antigens of 8 to 13 amino acids that arise from cytosolic proteolysis via IFNG-induced immunoproteasome. Binds peptides with free N- and C-termini, the first three and the C-terminal residues being critical. Preferentially selects peptides having a highly hydrophobic residue at position 3 and hydrophobic or charged residues at the C-terminal anchor. Proline at position 2 has the most destabilizing effect (PubMed:7500034, PubMed:9256420, PubMed:11274390). As a component of the peptide loading complex (PLC), acts as a molecular scaffold essential for peptide-MHCI assembly and antigen presentation (PubMed:26611325, PubMed:1538751, PubMed:25377891).
Belongs to the ABC transporter superfamily. ABCB family. MHC peptide exporter (TC 3.A.1.209) subfamily.
Heterodimer of TAP1 and TAP2 (TAP1-TAP2) (PubMed:1538751). A component of the peptide loading complex (PLC), interacts via TAPBP with MHCI heterodimer; this interaction mediates peptide-MHCI assembly (PubMed:26611325). Recruits TAPBP in a 1:1 stoichiometry (PubMed:22638925). Interacts with classical MHCI such as HLA-A*02-B2M; this interaction is obligatory for the loading of peptide epitopes (PubMed:8805302, PubMed:8630735). Interacts with non-classical MHCI molecules including HLA-E-B2M and HLA-F-B2M as well as PLC component CALR before the peptide loading (PubMed:9427624, PubMed:10605026).
Inhibited at high ER lumenal peptide concentrations.
The allele TAP2*Bky2 is commonly found only in the Japanese population. It may be associated with susceptibility to Sjoegren syndrome, an autoimmune disorder characterized by abnormal dryness of the conjunctiva, cornea and mouth due to exocrine glands dysfunction.
The nucleotide-binding domain (NBD) mediates ATP hydrolysis coupled to peptide translocation. Two ATP molecules are accommodated at distinct nucleotide binding sites (NBS) at TAP1-TAP2 dimer interface. Each NBS is formed by Walker A (GxxGxGKST) and Q-loop motifs from NBD of one subunit, while the NBD from the second subunit completes the active site by contributing the C loop motif (LSGGQ). Each ATP molecule is coordinated via the beta- and gamma-phosphates to a Mg2+ ion, which is necessary for ATP hydrolysis.
The peptide-binding site is shared between the cytoplasmic loops of TAP1 and TAP2.
Accessory potassium channel protein which modulates the activity of the pore-forming alpha subunit. Alters the functional properties of Kv1.5.
Alteration of functional properties of alpha subunit is mediated through N-terminal domain of beta subunit.
Brain specific. Most prominent expression in cerebellum. Weaker signals detected in cortex, occipital lobe, frontal lobe and temporal lobe. Not detected in spinal cord, heart, lung, liver, kidney, pancreas, placenta and skeletal muscle.
Forms heteromultimeric complex with alpha subunits.
A soluble form exists; probably released by a metalloprotease. Seems to have the same activity as the membrane-bound form.
Binds activated protein C. Enhances protein C activation by the thrombin-thrombomodulin complex; plays a role in the protein C pathway controlling blood coagulation.
Expressed strongly in the endothelial cells of arteries and veins in heart and lung, less intensely in capillaries in the lung and skin, and not at all in the endothelium of small vessels of the liver and kidney.
Belongs to the proteasome subunit S11 family.
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD13, a base containing 6 ATPases and few additional components.
Transcription repressor involved in the exit of embryonic stem cells (ESCs) from self-renewal. Acts by repressing expression of KLF4.
Part of a SCF (SKP1-cullin-F-box) ubiquitin-protein ligase complex. Interacts with SKP1 and CUL1 (By similarity). Interacts with SNAI1; the interaction requires the phosphorylation of the two serine residues in the substrate destruction motif D-S-G-X(2,3,4)-S.
Substrate-recognition component of some SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin-protein ligase complexes. The SCF(FBXL14) complex acts by mediating ubiquitination and subsequent degradation of SNAI1.
In contrast to other H2B histones, it does not contain the conserved residue in C-terminus that is the target of monoubiquitination.
Interacts with PLCG1, ITK, GRB2, and LAT.
Phosphorylated on Tyr residues quickly after TCR stimulation.
Plays a central role in late thymocyte development by controlling both positive and negative T-cell selection. Required to sustain and/or integrate signals required for proper lineage commitment and maturation of T-cells. Regulates T-cell development through T-cell antigen receptor (TCR) signaling and in particular through the regulation of calcium influx and phosphorylation of Erk.
Highly expressed in heart and liver. Expressed at lower levels in skeletal muscle, spleen, kidney and placenta.
Mitochondrial 3-hydroxyacyl-thioester dehydratase, which may be involved in fatty acid biosynthesis.
This protein is produced by a bicistronic gene which also produces the RPP14 protein from an overlapping reading frame.
Heterodimer of CALCRL and RAMP3 (By similarity). Interacts with GPER1.
Plays a role in cardioprotection by reducing cardiac hypertrophy and perivascular fibrosis in a GPER1-dependent manner. Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) and GPER1 to the plasma membrane. Acts as a receptor for adrenomedullin (AM) together with CALCRL.
Cross-linked envelope protein of keratinocytes.
During squamous differentiation of epidermal keratinocytes.
Binds medium- and long-chain acyl-CoA esters.
Centriolar protein required for centriole subdistal appendage assembly and microtubule anchoring in interphase cells (PubMed:28422092). Together with CCDC120, cooperate with subdistal appendage components ODF2, NIN and CEP170 for hierarchical subdistal appendage assembly (PubMed:28422092).
Expressed in bone marrow, colon, small intestine, spleen, testis, trachea and cutaneous T-cell lymphoma (CTCL).
Interacts with CEP170 (PubMed:28422092).
Essential for male and female fertility, playing a crucial role in regulating germ cell development by ensuring the proper progression of meiosis prophase I (By similarity). Regulates mitotic-to-meiotic transition in spermatogenesis by forming a complex with MEIOC and YTHDC2 which recognizes and down-regulates mitotic transcripts for a successful meiotic entry (By similarity). Required for normal synaptonemal complex formation during meiosis, binding meiotic cohesin subunit mRNAs containing GCCUAU/GUUCGA motifs in their 3'UTRs regions and positively regulating their translation (By similarity). Required for spermatogonial differentiation in both developing and adult testis (By similarity).
Interacts with YTHDC2, MEIOC, MOV10, CNOT6L, DDX4, UPF1 and PABPC1.
May act as Rab effector protein and play a role in vesicle trafficking. Binds phospholipids in the presence of calcium ions (By similarity).
Monomer. Binds NRXN1. Binds RAB27A that has been activated by GTP-binding via its N-terminus (By similarity).
Displays acyl-CoA-dependent lysophospholipid acyltransferase activity with a subset of lysophospholipids as substrates; converts lysophosphatidylethanolamine to phosphatidylethanolamine, lysophosphatidylcholine to phosphatidycholine, 1-alkenyl-lysophatidylethanolamine to 1-alkenyl-phosphatidylethanolamine, lysophosphatidylglycerol and alkyl-lysophosphatidylcholine to phosphatidylglycerol and alkyl-phosphatidylcholine, respectively. In contrast, has no lysophosphatidylinositol, glycerol-3-phosphate, diacylglycerol or lysophosphatidic acid acyltransferase activity. Prefers long chain acyl-CoAs (C16, C18) as acyl donors.
Widely expressed with predominant level in brain.
Expressed in the term myometrium and kidney.
Monomer and homo- or heterodimer. Interacts with MIP (PubMed:16549056). Forms high affinity heterodimers with members of the CNC-bZIP family such as NFE2L1/NRF1 (PubMed:8932385).
Since they lack a putative transactivation domain, the small Mafs behave as transcriptional repressors when they dimerize among themselves (PubMed:8932385). However, they seem to serve as transcriptional activators by dimerizing with other (usually larger) basic-zipper proteins, such as NFE2L1/NRF1, and recruiting them to specific DNA-binding sites. Interacts with the upstream promoter region of the oxytocin receptor gene (PubMed:8932385, PubMed:16549056). May be a transcriptional enhancer in the up-regulation of the oxytocin receptor gene at parturition (PubMed:10527846).
Phosphorylation on Tyr-10 modulates pumping activity. Phosphorylation of Ser-943 by PKA modulates the response of ATP1A1 to PKC. Dephosphorylation by protein phosphatase 2A (PP2A) following increases in intracellular sodium, leading to increase catalytic activity (By similarity).
The sodium/potassium-transporting ATPase is composed of a catalytic alpha subunit, an auxiliary non-catalytic beta subunit and an additional regulatory subunit. Interacts with regulatory subunit FXYD1 (By similarity). Interacts with regulatory subunit FXYD3 (PubMed:21454534). Interacts with SIK1 (By similarity). Binds the HLA class II histocompatibility antigen DR1 (PubMed:1380674). Interacts with SLC35G1 and STIM1 (PubMed:22084111). Interacts with CLN3; this interaction regulates the sodium/potassium-transporting ATPase complex localization at the plasma membrane (Probable).
This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients.
Interacts (via the HTH domain) with VIM/vimentin. Interacts (via C-terminus) with non-muscle myosin MYH10. Interacts (via C-terminus) with DHX9.
Regulates the coordinated translation of type I collagen alpha-1 and alpha-2 mRNAs, CO1A1 and CO1A2. Stabilizes mRNAs through high-affinity binding of a stem-loop structure in their 5' UTR. This regulation requires VIM and MYH10 filaments, and the helicase DHX9.
The RRM domain mediates the association with collagen mRNAs stem-loops.
Expressed in immature and mature dendritic cells (DCs). Not detected in other blood cell types.
Has transcriptional repression activity. Acts as corepressor of ESR1; the function seems to involve CTBP1 and histone deacetylases.
Interacts with ESR1 and NRIP1 (PubMed:17085477). Interacts (via PXDLS motif) with CTBP1 (PubMed:16393996, PubMed:17085477).
Interacts with MTREX; the interaction is direct and stabilizes NRDE2 (PubMed:30842217, PubMed:30538148, PubMed:29902117). Interacts with EXOSC10, EFTUD2 and EIF4A3 (PubMed:30538148).
Protein of the nuclear speckles that regulates RNA degradation and export from the nucleus through its interaction with MTREX an essential factor directing various RNAs to exosomal degradation (PubMed:30842217). Changes the conformation of MTREX, precluding its association with the nuclear exosome and interaction with proteins required for its function in RNA exosomal degradation (PubMed:30842217). Negatively regulates, for instance, the degradation of mRNAs and lncRNAs by inhibiting their MTREX-mediated recruitment to nuclear exosome (PubMed:30842217). By preventing the degradation of RNAs in the nucleus, it promotes their export to the cytoplasm (PubMed:30842217). U5 snRNP-associated RNA splicing factor which is required for efficient splicing of CEP131 pre-mRNA and plays an important role in centrosome maturation, integrity and function during mitosis (PubMed:30538148). Suppresses intron retention in a subset of pre-mRNAs containing short, GC-rich introns with relatively weak 5' and 3' splice sites (PubMed:30538148). Plays a role in DNA damage response (PubMed:29902117).
The MID/MTR4-interacting domain is necessary and sufficient to mediate interaction with MTREX.
Identified in the spliceosome C complex (PubMed:11991638). Interacts with PPIA/CYPA (PubMed:25678563).
Pre-mRNA binding protein in vivo, binds avidly to poly(G) and poly(U) RNA homopolymers in vitro. Involved in splicing. Acts as a receptor for carcinoembryonic antigen in Kupffer cells, may initiate a series of signaling events leading to tyrosine phosphorylation of proteins and induction of IL-1 alpha, IL-6, IL-10 and tumor necrosis factor alpha cytokines.
Activated by phosphorylation by PKN1, followed by autophosphorylation on Thr-161 and Ser-165 (PubMed:12220515, PubMed:12761180, PubMed:15342622, PubMed:26999302). Autophosphorylation in response to ribotoxic stress promotes dissociation from colliding ribosomes and activation (PubMed:32610081, PubMed:32289254).
Activated in response to stress, such as ribosomal stress, osmotic shock and ionizing radiation (PubMed:11042189, PubMed:12761180, PubMed:15342622, PubMed:32289254, PubMed:32610081). Activated by phosphorylation by PKN1, followed by autophosphorylation on Thr-161 and Ser-165 (PubMed:11042189, PubMed:12220515, PubMed:12761180, PubMed:15342622, PubMed:26999302). Inhibited by nilotinib, sorafenib, dabrafenib, rebastinib and vemurafenib (PubMed:26999302). Selectively inhibited by N-(3)-((1H-Pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamide compound 3h (PubMed:28586211). Selectively inhibited by 1,2,3-triazole benzenesulfonamides (PubMed:31244114).
Homodimer (PubMed:10924358, PubMed:26755636). Interacts with ZNF33A (PubMed:12535642). Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, MAP3K20 and MAP2K3 (PubMed:21224381). Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and MAP3K20 (PubMed:21224381). Interacts with EIF2AK4/GCN2; promoting EIF2AK4/GCN2 kinase activity (PubMed:32610081).
Isoform that lacks the C-terminal region that mediates ribosome-binding: does not act as a sensor of ribosome collisions in response to ribotoxic stress (PubMed:32610081, PubMed:32289254, PubMed:35857590). May act as an antagonist of isoform ZAKalpha: interacts with isoform ZAKalpha, leading to decrease the expression of isoform ZAKalpha (PubMed:27859413).
Key component of the stress-activated protein kinase signaling cascade in response to ribotoxic stress or UV-B irradiation (PubMed:32610081, PubMed:32289254, PubMed:35857590). Acts as the proximal sensor of ribosome collisions during the ribotoxic stress response (RSR): directly binds to the ribosome by inserting its flexible C-terminus into the ribosomal intersubunit space, thereby acting as a sentinel for colliding ribosomes (PubMed:32610081, PubMed:32289254). Upon ribosome collisions, activates either the stress-activated protein kinase signal transduction cascade or the integrated stress response (ISR), leading to programmed cell death or cell survival, respectively (PubMed:32610081). Dangerous levels of ribosome collisions trigger the autophosphorylation and activation of MAP3K20, which dissociates from colliding ribosomes and phosphorylates MAP kinase kinases, leading to activation of the JNK and MAP kinase p38 pathways that promote programmed cell death (PubMed:32610081, PubMed:32289254). Less dangerous levels of ribosome collisions trigger the integrated stress response (ISR): MAP3K20 activates EIF2AK4/GCN2 independently of its protein-kinase activity, promoting EIF2AK4/GCN2-mediated phosphorylation of EIF2S1/eIF-2-alpha (PubMed:32610081). Also part of the stress-activated protein kinase signaling cascade triggering the NLRP1 inflammasome in response to UV-B irradiation: ribosome collisions activate MAP3K20, which directly phosphorylates NLRP1, leading to activation of the NLRP1 inflammasome and subsequent pyroptosis (PubMed:35857590). NLRP1 is also phosphorylated by MAP kinase p38 downstream of MAP3K20 (PubMed:35857590). Also acts as a histone kinase by phosphorylating histone H3 at 'Ser-28' (H3S28ph) (PubMed:15684425).
Recognizes stalled ribosomes via two separate and partially redundant sensor domains: the C-terminal domain (CTD) that binds the 18S ribosomal RNA (18S rRNA) and the sensing domain (S).
Stress-activated component of a protein kinase signal transduction cascade that promotes programmed cell death in response to various stress, such as ribosomal stress, osmotic shock and ionizing radiation (PubMed:10924358, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15350844, PubMed:15737997, PubMed:18331592, PubMed:20559024, PubMed:32610081, PubMed:32289254, PubMed:35857590, PubMed:26999302). Acts by catalyzing phosphorylation of MAP kinase kinases, leading to activation of the JNK (MAPK8/JNK1, MAPK9/JNK2 and/or MAPK10/JNK3) and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways (PubMed:11042189, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15172994, PubMed:15737997, PubMed:32610081, PubMed:32289254, PubMed:35857590). Activates JNK through phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7, and MAP kinase p38 gamma (MAPK12) via phosphorylation of MAP2K3/MKK3 and MAP2K6/MKK6 (PubMed:11836244, PubMed:12220515). Involved in stress associated with adrenergic stimulation: contributes to cardiac decompensation during periods of acute cardiac stress (PubMed:15350844, PubMed:21224381, PubMed:27859413). May be involved in regulation of S and G2 cell cycle checkpoint by mediating phosphorylation of CHEK2 (PubMed:15342622).
Ubiquitously expressed. Isoform ZAKbeta is the predominant form in all tissues examined, except for liver, in which isoform ZAKalpha is more highly expressed.
Belongs to the non-repetitive/WGA-negative nucleoporin family.
Disulfide-linked to NUP62. The inner channel of the NPC has a different redox environment from the cytoplasm and allows the formation of interchain disulfide bonds between some nucleoporins, the significant increase of these linkages upon oxidative stress reduces the permeability of the NPC (By similarity).
Essential component of nuclear pore complex. Could be essessential for embryogenesis. Nucleoporins may be involved both in binding and translocating proteins during nucleocytoplasmic transport.
Expressed in all tissues tested, including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Interacts with GLE1. Able to form a heterotrimer with GLE1 and NUP42 in vitro. Forms a complex with NUP35, NUP93, NUP205 and lamin B.
Phosphorylated. Phosphorylation and dephosphorylation may be important for the function of NUP155 and may play a role in the reversible disassembly of the nuclear pore complex during mitosis (By similarity).
Belongs to the thiolase-like superfamily. HMG-CoA synthase family.
Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form HMG-CoA.
Catalyzes the first irreversible step in ketogenesis, condensing acetyl-CoA to acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate.
Expression in liver is 200-fold higher than in any other tissue. Low expression in colon, kidney, testis, and pancreas. Very low expression in heart and skeletal muscle (PubMed:7893153, PubMed:21952825, PubMed:16940161). Not detected in brain (PubMed:21952825).
Highest expression detected in heart and skeletal muscle.
Succinylated. Desuccinylated by SIRT5. Succinylation, at least at Lys-83 and Lys-310, inhibits the enzymatic activity.
Proton-selective channel that specifically transports protons into cells. Proton-selective channel activity is probably required in cell types that use changes in intracellular pH for cell signaling or to regulate biochemical or developmental processes.
Based on its structure and in vitro assays, was initially thought to have guanine nucleotide exchange factor (GEF) activity (PubMed:22977732). However, subsequent studies showed that it does not act as GEF in vivo (PubMed:24095279).
Expressed in fetal lung, kidney, liver, and brain.
Expressed in most tissues tested, including skin, lung, kidney, heart, testis and stomach.
GTPase-activating activity is inhibited in the folliculin complex (LFC), which stabilizes the GDP-bound state of RagA/RRAGA (or RagB/RRAGB), because Arg-164 is located far from the RagC/RRAGC or RagD/RRAGD nucleotide pocket (PubMed:31672913). Disassembly of the LFC complex upon amino acid restimulation liberates the GTPase-activating activity (PubMed:31672913).
Interacts (via C-terminus) with FNIP1 or FNIP2 (via C-terminus) (PubMed:17028174, PubMed:18403135, PubMed:18663353, PubMed:27353360, PubMed:36103527). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913, PubMed:36103527). Interaction with FNIP1 or FNIP2 mediates indirect interaction with the PRKAA1, PRKAB1 and PRKAG1 subunits of 5'-AMP-activated protein kinase (AMPK) (PubMed:17028174). Interacts with HSP90AA1 in the presence of FNIP1 (PubMed:27353360). Interacts with HSP70, STUB1, CDC37, AHSA1, CCT2, STIP1, PTGES3 and PPP5C (PubMed:27353360). Interacts with GABARAP; interaction takes place in the presence of FNIP1 and/or FNIP2 (PubMed:25126726). Interacts with RILP; the interaction is direct and promotes association between RILP and RAB34 (PubMed:27113757). Interacts with KIF3A and KIF3B (PubMed:27072130). Interacts with lactate dehydrogenase LDHA, but not LDHB; the interaction is direct, may preferentially bind LDHA dimers rather than tetramers, and regulates LDHA activity, acting as an uncompetitive inhibitor (PubMed:34381247).
Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, PubMed:31704029, PubMed:31672913, PubMed:34381247, PubMed:32612235, PubMed:36103527, PubMed:37079666). GTPase-activating protein that plays a key role in the cellular response to amino acid availability through regulation of the non-canonical mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, PubMed:24448649, PubMed:31704029, PubMed:31672913, PubMed:32612235, PubMed:36103527, PubMed:37079666). Activates mTORC1 by acting as a GTPase-activating protein: specifically stimulates GTP hydrolysis by RagC/RRAGC or RagD/RRAGD, promoting the conversion to the GDP-bound state of RagC/RRAGC or RagD/RRAGD, and thereby activating the kinase activity of mTORC1 (PubMed:24095279, PubMed:31704029, PubMed:31672913, PubMed:32612235, PubMed:37079666). The GTPase-activating activity is inhibited during starvation and activated in presence of nutrients (PubMed:31672913, PubMed:32612235). Acts as a key component for non-canonical mTORC1-dependent control of the MiT/TFE factors TFEB and TFE3, while it is not involved in mTORC1-dependent phosphorylation of canonical RPS6KB1/S6K1 and EIF4EBP1/4E-BP1 (PubMed:21209915, PubMed:24081491, PubMed:31672913, PubMed:32612235). In low-amino acid conditions, the lysosomal folliculin complex (LFC) is formed on the membrane of lysosomes, which inhibits the GTPase-activating activity of FLCN, inactivates mTORC1 and maximizes nuclear translocation of TFEB and TFE3 (PubMed:31672913). Upon amino acid restimulation, RagA/RRAGA (or RagB/RRAGB) nucleotide exchange promotes disassembly of the LFC complex and liberates the GTPase-activating activity of FLCN, leading to activation of mTORC1 and subsequent cytoplasmic retention of TFEB and TFE3 (PubMed:31672913). Indirectly acts as a positive regulator of Wnt signaling by promoting mTOR-dependent cytoplasmic retention of MiT/TFE factor TFE3 (PubMed:31272105). Required for the exit of hematopoietic stem cell from pluripotency by promoting mTOR-dependent cytoplasmic retention of TFE3, thereby increasing Wnt signaling (PubMed:30733432). Acts as an inhibitor of browning of adipose tissue by regulating mTOR-dependent cytoplasmic retention of TFE3 (By similarity). Involved in the control of embryonic stem cells differentiation; together with LAMTOR1 it is necessary to recruit and activate RagC/RRAGC and RagD/RRAGD at the lysosomes, and to induce exit of embryonic stem cells from pluripotency via non-canonical, mTOR-independent TFE3 inactivation (By similarity). In response to flow stress, regulates STK11/LKB1 accumulation and mTORC1 activation through primary cilia: may act by recruiting STK11/LKB1 to primary cilia for activation of AMPK resided at basal bodies, causing mTORC1 down-regulation (PubMed:27072130). Together with FNIP1 and/or FNIP2, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy (PubMed:25126726). Required for starvation-induced perinuclear clustering of lysosomes by promoting association of RILP with its effector RAB34 (PubMed:27113757). Regulates glycolysis by binding to lactate dehydrogenase LDHA, acting as an uncompetitive inhibitor (PubMed:34381247).
Phosphorylation by ULK1 modulates the interaction with GABARAP and is required to regulate autophagy.
Glycerophosphodiester phosphodiesterase that promotes neurite formation and drives spinal motor neuron differentiation (By similarity). Mediates the cleavage of glycosylphosphatidylinositol (GPI) anchor of target proteins: removes the GPI-anchor of RECK, leading to release RECK from the plasma membrane (By similarity). May contribute to the osmotic regulation of cellular glycerophosphocholine (By similarity).
Interacts with PRDX1; forms a mixed-disulfide with PRDX1, leading to disrupt intramolecular disulfide bond between Cys-25 and Cys-571.
Intramolecular disulfide bond between Cys-25 and Cys-571 is reduced by PRDX1.
Isoform 1 is found in both brain and placenta.
Participates in NRTN-induced 'Ser-727' phosphorylation of STAT3.
Receptor for neurturin. Mediates the NRTN-induced autophosphorylation and activation of the RET receptor. Also able to mediate GDNF signaling through the RET tyrosine kinase receptor.
Expressed mainly in kidney, brain and testis and present in other tissues albeit at lower levels. Also expressed in fetal kidney.
RNA-binding protein implicated in the regulation of pre-mRNA alternative splicing. Mediates exon inclusion and/or exclusion in pre-mRNA that are subject to tissue-specific and developmentally regulated alternative splicing. Specifically activates exon 5 inclusion of TNNT2 in a muscle-specific splicing enhancer (MSE)-dependent manner. Promotes also exon exclusion of INSR pre-mRNA.
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Component of a heterotrimeric complex containing IMP3, IMP4 and MPHOSPH10. Interacts with IMP3 and IMP4 (PubMed:12655004).
Antagonist of isoform 1, shutting down FGF4-induced Erk1/2 phosphorylation.
Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.
Plays an important role in the regulation of embryonic development, cell proliferation, and cell differentiation. Required for normal limb and cardiac valve development during embryogenesis. May play a role in embryonic molar tooth bud development via inducing the expression of MSX1, MSX2 and MSX1-mediated expression of SDC1 in dental mesenchyme cells (By similarity).
Expressed in placenta and adult prostate gland. In placenta, it is present in all cells of the villous cytotrophoblast. The protein is absent in cells from hydatidiform moles. Hydatidiform mole is a gestation characterized by abnormal development of both fetus and trophoblast. The majority of hydatidiform moles are associated with an excess of paternal to maternal genomes and are likely to result from the abnormal expression of imprinted genes (at protein level). Expressed at low levels in adult liver and lung, and fetal liver. Expressed in adult brain and neuroblastoma, medullablastoma and glioblastoma cell lines.
Maternal PHLDA2 allele is activated, while paternal Phlda2 is repressed due to genomic imprinting. Down-regulated by hypoxia. Although highly similar to PHLDA3 protein, it is not regulated by p53/TP53.
Plays a role in regulating placenta growth. May act via its PH domain that competes with other PH domain-containing proteins, thereby preventing their binding to membrane lipids (By similarity).
The PH domain binds phosphoinositides with a broad specificity. It may compete with the PH domain of some other proteins, thereby interfering with their binding to phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) (By similarity).
The PHLDA2 locus is imprinted. Loss of imprinting results in overexpression. Imprinting is dependent on RNAi machinery.
Expressed specifically on red blood cells namely basophil, mast cells and eosinophils.
Putative adhesion molecule that mediates sialic-acid dependent binding to red blood cells (PubMed:10856141, PubMed:10625619). Preferentially binds to alpha-2,3-linked sialic acid. Also binds to alpha-2,6-linked sialic acid. The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface (PubMed:10625619). Recognizes simultaneously epitopes having a terminal N-acetylneuraminic acid (sialic acid) and an underlying 6-O-sulfated galactose. Preferentially binds to Gal-6-sulfated sialyl-Lewis X glycan epitopes (PubMed:27357658).
By homocysteine, 2-mercaptoethanol, tunicamycin in endothelial cells. Induced approximately 20-fold during in vitro differentiation of the colon carcinoma cell lines HT-29-D4 and Caco-2. Induced by oxidative stress in colon cancers. Decreased expression in colon adenomas and adenocarcinomas. Induced by nickel compounds in all tested cell lines. The primary signal for its induction is an elevation of free intracellular calcium ion caused by nickel ion exposure. Okadaic acid, a serine/threonine phosphatase inhibitor, induced its expression more rapidly and more efficiently than nickel.
Interacts with RAB4A (membrane-bound form); the interaction involves NDRG1 in vesicular recycling of CDH1.
Stress-responsive protein involved in hormone responses, cell growth, and differentiation. Acts as a tumor suppressor in many cell types. Necessary but not sufficient for p53/TP53-mediated caspase activation and apoptosis. Has a role in cell trafficking, notably of the Schwann cell, and is necessary for the maintenance and development of the peripheral nerve myelin sheath. Required for vesicular recycling of CDH1 and TF. May also function in lipid trafficking. Protects cells from spindle disruption damage. Functions in p53/TP53-dependent mitotic spindle checkpoint. Regulates microtubule dynamics and maintains euploidy.
Ubiquitous; expressed most prominently in placental membranes and prostate, kidney, small intestine, and ovary tissues. Also expressed in heart, brain, skeletal muscle, lung, liver and pancreas. Low levels in peripheral blood leukocytes and in tissues of the immune system. Expressed mainly in epithelial cells. Also found in Schwann cells of peripheral neurons. Reduced expression in adenocarcinomas compared to normal tissues. In colon, prostate and placental membranes, the cells that border the lumen show the highest expression.
Under stress conditions, phosphorylated in the C-terminal on many serine and threonine residues. Phosphorylated in vitro by PKA. Phosphorylation enhanced by increased intracellular cAMP levels. Homocysteine induces dephosphorylation. Phosphorylation by SGK1 is cell cycle dependent.
Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2 (PubMed:11012666, PubMed:12534281, PubMed:12662155, PubMed:15039077, PubMed:15664838, PubMed:20536396, PubMed:29382749). Acts as a key inhibitor of caspase-1-dependent monocyte and macrophage pyroptosis in resting cells by preventing activation of NLRP1 and CARD8 (PubMed:27820798, PubMed:29967349, PubMed:32796818). Sequesters the cleaved C-terminal part of NLRP1 and CARD8, which respectively constitute the active part of the NLRP1 and CARD8 inflammasomes, in a ternary complex, thereby preventing their oligomerization and activation (PubMed:34019797, PubMed:33731929, PubMed:33731932). The dipeptidyl peptidase activity is required to suppress NLRP1 and CARD8; however, neither NLRP1 nor CARD8 are bona fide substrates of DPP8, suggesting the existence of substrate(s) required for NLRP1 and CARD8 inhibition (By similarity).
Homodimer (PubMed:20536396, PubMed:29382749). Forms a ternary complex with NLRP1, composed of a DPP8 homodimer, one full-length NLRP1 protein, and one cleaved C-terminus of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus) (By similarity). Forms a ternary complex with CARD8, composed of a DPP8 homodimer, one full-length NLRP1 protein, and one cleaved C-terminus of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus) (By similarity). In the ternary complex, only one subunit of the DPP8 homodimer is bound to NLRP1 or CARD8 (By similarity).
Inhibited by zinc. Inhibited by the serine proteinase inhibitor 4-(2-aminoethyl)benzenesulphonyl fluoride (AEBSF), and by di-isopropylfluorophosphate. Specifically inhibited by isoindoline derivatives (PubMed:11012666, PubMed:12662155, PubMed:15664838). Inhibited by Val-boroPro (Talabostat, PT-100), a non-selective inhibitor, which triggers pyroptosis in monocytes and macrophages (PubMed:27820798, PubMed:29967349, PubMed:32796818).
Ubiquitously expressed, with highest levels in testis, placenta, prostate, muscle and brain.
Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation.
Mutations in RET have been detected in patients with renal agenesis suggesting a possible involvement of this gene in disease pathogenesis.
Original thought to be dephosphorylated by PTPRJ on Tyr-905, Tyr-1015 and Tyr-1062. However this paper was retracted due to manipulation of immunoblot data.
Phosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5 (By similarity). The phosphorylated form interacts with PLCG1 and GRB7 (By similarity). Interacts (not phosphorylated) with PTK2/FAK1 (via FERM domain) (PubMed:21454698). Extracellular cell-membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas (PubMed:21357690). Interacts with AIP in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex (PubMed:19366855). Binds to ARTN (By similarity). Interacts (inactive) with CBLC and CD2AP; dissociates upon activation by GDNF which increases CBLC:CD2AP interaction (PubMed:18753381). Interacts (via the extracellular domain) with GFRAL (via the extracellular domain); the interaction mediates cellular signaling upon interaction of GFRAL with its ligand GDF15 (PubMed:28953886, PubMed:28846097, PubMed:28846099). Interaction with GFRAL requires previous GDF15-binding to GFRAL (PubMed:28846097, PubMed:28846099). Interacts with GFRA1; in the presence of SORL1, the GFRA1/RET complex is targeted to endosomes (PubMed:23333276). Interacts with GDNF (PubMed:21994944).
Positively regulated by NKX2-1, PHOX2B, SOX10 and PAX3.
Proteolytically cleaved by caspase-3. The soluble RET kinase fragment is able to induce cell death. The extracellular cell-membrane anchored RET cadherin fragment accelerates cell adhesion in sympathetic neurons.
Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration. Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which induces inhibition of food-intake. Activates MAPK- and AKT-signaling pathways (PubMed:28846097, PubMed:28953886, PubMed:28846099). Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL (PubMed:28846099).
Repressed by 4-(3-hydroxyanilino)-quinolines derivatives, indolin-2-one-derivatives, 2-(alkylsulfanyl)-4-(3-thienyl) nicotinonitrile analogs, 3- and 4-substituted beta-carbolin-1-ones, vandetanib, motesanib, sorafenib (BAY 43-9006), cabozantinib (XL184), sunitinib, and withaferin A (WA). Inactivation by sorafenib both reduces kinase activity and promotes lysosomal degradation.
The Cys-982 polymorphism may be associated with an increased risk for developing Hirschsprung disease.
Treatment with withaferin A (WA) leads tumor regression in medullary thyroid carcinomas (MTC).
Various chromosomal aberrations involving RET are known. Some of them have been found in papillary thyroid carcinomas (PTCs) (PubMed:12787916, PubMed:2406025, PubMed:10980597, PubMed:10439047). Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene (PubMed:2406025). Inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene. Translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene (PubMed:2734021). Translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion (PubMed:10980597). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the Delta RFP/RET oncogene (PubMed:12787916). Translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene (PubMed:10439047). Translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene (PubMed:10439047). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the TRIM27/RET oncogene (PubMed:3037315).
G-protein coupled receptor for glucagon that plays a central role in the regulation of blood glucose levels and glucose homeostasis. Regulates the rate of hepatic glucose production by promoting glycogen hydrolysis and gluconeogenesis. Plays an important role in mediating the responses to fasting. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Promotes activation of adenylate cyclase. Besides, plays a role in signaling via a phosphatidylinositol-calcium second messenger system.
Ligand-binding promotes phosphorylation of serine residues in the C-terminal cytoplasmic domain. Phosphorylation is important for receptor endocytosis after ligand-binding.
Binds DNA with high affinity but does not bind to TATA boxes. Synergises with GMNN and TBP in activation of TATA box-containing promoters and with GMNN and TBPL1 in activation of the NF1 TATA-less promoter. May play a role in cytoplasm movement and removal during spermiogenesis (By similarity).
Homodimer. Interacts with CBX3, CBX5, GMNN, GTF2B, TBPL1 and the polycomb proteins PHCF2, RNF2 and SCMH1 but not with CBX1 or PCGF2 (By similarity).
(Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein Tax; this interaction increases Tax interacting partner CREB1 O-GlcNAcylation.
Belongs to the glycosyl hydrolase 84 family.
Cleaves GlcNAc but not GalNAc from O-glycosylated proteins. Can use p-nitrophenyl-beta-GlcNAc and 4-methylumbelliferone-GlcNAc as substrates but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl-alpha-GlcNAc (in vitro) (PubMed:11148210). Does not bind acetyl-CoA and does not have histone acetyltransferase activity (PubMed:24088714).
Cleaves GlcNAc but not GalNAc from O-glycosylated proteins. Can use p-nitrophenyl-beta-GlcNAc as substrate but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl-alpha-GlcNAc (in vitro), but has about six times lower specific activity than isoform 1.
Inhibited by N-acetylglucosamine and not N-acetylgalactosamine.
Monomer (PubMed:11788610). Interacts with CLOCK (By similarity).
Proteolytically cleaved by caspase-3 during apoptosis. The fragments interact with each other; cleavage does not decrease enzyme activity.
The mouse and rat orthologs were initially identified as bi-functional proteins containing an N-terminal domain with O-GlcNAcase activity and a C-terminal domain with histone acetyltransferase activity. The histone acetyltransferase activity was detected only when the protein was expressed in mammalian cells, but not when expressed in bacterial cells, suggesting that the histone acetyltransferase activity might be due to the presence of a contaminant. Comparison of the human protein with a bacterial putative acetyltransferase (AC Q2CEE2) shows that the residues important for acetyl-CoA binding are not conserved, and that the residues proposed to be important for histone acetyltransferase activity are not in a position where they could participate in catalysis. Characterization of the human protein shows that it does not bind acetyl-CoA and therefore cannot have acetyltransferase activity.
Ubiquitous. Shows highest expression in the brain, placenta and pancreas.
Belongs to the glycosyl hydrolase 39 family.
N-glycosylation at Asn-372 contributes to substrate binding and is required for full enzymatic activity.
Interacts with NPM (via N-terminus) (PubMed:15596447). Forms a pentamer with NPM at a ratio 4:1 (NPM3/NPM). Two pentamers form a decamer (PubMed:22362753).
Plays a role in the regulation of diverse cellular processes such as ribosome biogenesis, chromatin remodeling or protein chaperoning (PubMed:22362753, PubMed:20073534). Modulates the histone chaperone function and the RNA-binding activity of nucleolar phosphoprotein B23/NPM (PubMed:22362753). Efficiently mediates chromatin remodeling when included in a pentamer containing NPM3 and NPM (PubMed:15596447).
Cholesterol efflux transporter in macrophages that is responsible for APOAI/high-density lipoproteins (HDL) formation at the plasma membrane under high cholesterol levels and participates in reverse cholesterol transport (PubMed:25125465). May play a role in the processing of autolysosomes (By similarity).
Expressed in fetal liver, kidney and brain.
Ubiquitously expressed. Highly expressed in testis, skeletal muscle, kidney, liver and placenta. Expressed in both the epithelial and mesenchymal compartments, present within the outer root sheath (ORS) of the hair follicle as well as dermal sheath (PubMed:24831815). Expressed in multiple regions of the brain, including the hippocampus, superior frontal and inferior temporal cortices (PubMed:25125465). Strongly expressed in neurons and moderately in microglia, with only weak expression in astrocytes and oligodendrocytes (PubMed:25125465).
Heterodimer of a catalytic subunit (PIK3CG) and a regulatory (PIK3R6) subunit. The binding of PIK3R6 to PIK3CG may exclude the binding of PIK3R5 to PIK3CG. Interacts with beta-gamma G protein dimers (By similarity). Interacts with PDE3B and RAPGEF3; form a signaling complex that regulates phosphatidylinositol 3-kinase gamma in angiogenesis (PubMed:21393242).
Regulatory subunit of the PI3K gamma complex. Acts as an adapter to drive activation of PIK3CG by beta-gamma G protein dimers. The PIK3CG:PIK3R6 heterodimer is much less sensitive to beta-gamma G protein dimers than PIK3CG:PIK3R5 and its membrane recruitment and beta-gamma G protein dimer-dependent activation requires HRAS bound to PIK3CG. Recruits of the PI3K gamma complex to a PDE3B:RAPGEF3 signaling complex involved in angiogenesis; signaling seems to involve RRAS.
Interacts with VRK3, which seems to activate it's phosphatase activity.
Shows activity both for tyrosine-protein phosphate and serine-protein phosphate, but displays a strong preference toward phosphotyrosines. Specifically dephosphorylates and inactivates ERK1 and ERK2.
A subset of this protein primarily localized at the spindle pole is phosphorylated by NEK6 during mitosis; phosphorylation is required for mitotic function.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. BimC subfamily.
Interacts with the thyroid hormone receptor in the presence of thyroid hormone. Component of a large chromatin remodeling complex, at least composed of MYSM1, PCAF, RBM10 and KIF11/TRIP5. Interacts (via C-terminus) with the kinase NEK6 in both interphase and mitosis. Interacts with RARRES1 and AGBL2 (PubMed:21303978).
Motor protein required for establishing a bipolar spindle during mitosis (PubMed:19001501). Required in non-mitotic cells for transport of secretory proteins from the Golgi complex to the cell surface (PubMed:23857769).
Phosphorylated exclusively on serine during S phase, but on both serine and Thr-926 during mitosis, so controlling the association of KIF11 with the spindle apparatus (probably during early prophase).
Belongs to the metallo-beta-lactamase superfamily. Glyoxalase II family.
Contains four of the five characteristic MBL-fold metal-binding motifs, with two waters completing metal coordination.
Endoribonuclease that catalyzes the hydrolysis of histone-coding pre-mRNA 3'-end. Involved in histone pre-mRNA processing during the S-phase of the cell cycle, which is required for entering/progressing through S-phase (PubMed:30507380). Cleaves histone pre-mRNA at a major and a minor cleavage site after the 5'-ACCCA-3' and the 5'-ACCCACA-3' sequence, respectively, and located downstream of the stem-loop (PubMed:30507380). May require the presence of the HDE element located at the histone pre-RNA 3'-end to avoid non-specific cleavage (PubMed:30507380).
Abundantly expressed in several fetal tissues. In adult tissues, highest expression in lung and placenta. Expressed in resting macrophages.
Phagocytic receptor, strong negative regulator of T-cell proliferation and IL2 production. Potent inhibitor of the alternative complement pathway convertases.
Highly expressed in brain, placenta, liver and kidney. Expressed in retina.
Interacts with DIAPH1 (By similarity). Forms a nuclear ternary complex with MRTFA and SRF.
Tumor suppressor which functions to suppress MRTFA-induced SRF transcriptional activity. May function in the RHOA-DIAPH1 signal transduction pathway and regulate cell migration through transcriptional regulation of ITGB1.
Belongs to the Rab3-GAP regulatory subunit family.
Regulatory subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which has GTPase-activating protein (GAP) activity towards various Rab3 subfamily members (RAB3A, RAB3B, RAB3C and RAB3D), RAB5A and RAB43, and guanine nucleotide exchange factor (GEF) activity towards RAB18 (PubMed:9733780, PubMed:24891604). As part of the Rab3GAP complex, acts as a GAP for Rab3 proteins by converting active RAB3-GTP to the inactive form RAB3-GDP (By similarity). Rab3 proteins are involved in regulated exocytosis of neurotransmitters and hormones (By similarity). The Rab3GAP complex, acts as a GEF for RAB18 by promoting the conversion of inactive RAB18-GDP to the active form RAB18-GTP (PubMed:24891604). Required for recruiting and activating RAB18 at the endoplasmic reticulum (ER) membrane where it maintains proper ER structure (PubMed:24891604). Required for normal eye and brain development (By similarity). May participate in neurodevelopmental processes such as proliferation, migration and differentiation before synapse formation, and non-synaptic vesicular release of neurotransmitters (By similarity).
The Rab3 GTPase-activating complex is a heterodimer composed of RAB3GAP1 and RAB3GAP2 (By similarity). The Rab3 GTPase-activating complex interacts with DMXL2 (By similarity). Interacts with LMAN1 (PubMed:22337587).
Endoplasmic reticulum disulfide reductase involved both in the correct folding of proteins and degradation of misfolded proteins. Required for efficient folding of proteins in the endoplasmic reticulum by catalyzing the removal of non-native disulfide bonds formed during the folding of proteins, such as LDLR. Also involved in endoplasmic reticulum-associated degradation (ERAD) by reducing incorrect disulfide bonds in misfolded glycoproteins recognized by EDEM1. Interaction with HSPA5 is required its activity, not for the disulfide reductase activity, but to facilitate the release of DNAJC10 from its substrate. Promotes apoptotic signaling pathway in response to endoplasmic reticulum stress.
Interacts with EDEM1 (By similarity). Interacts with HSPA5 (via its J domain).
The thioredoxin-like regions Trxb 1 and 2 lack a redox-active CXXC motif.
Thioredoxin domains 3 and 4 are the primary reductase domains.
(Microbial infection) Involved in transcriptional repression of HHV-1 genes TK and gC.
Component of the histone deacetylase complex that includes at least SIN3A, HDAC1 and HDAC2 (By similarity). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (By similarity). Interacts with HDAC1 (PubMed:9651585). Interacts with SIN3A, SIN3B, HDAC2, RBBP4 and NCOR1 (By similarity). Interacts with SAMSN1 (By similarity). Interacts with HCFC1 (PubMed:12670868). Interacts with SAP30BP (PubMed:15496587).
Expressed in all tissues tested with highest levels in pancreas, ovary, PBL, spleen and thymus; lowest levels in brain, placenta, lung and kidney.
Involved in the functional recruitment of the Sin3-histone deacetylase complex (HDAC) to a specific subset of N-CoR corepressor complexes. Capable of transcription repression by N-CoR. Active in deacetylating core histone octamers (when in a complex) but inactive in deacetylating nucleosomal histones.
Belongs to the universal ribosomal protein uL24 family.
Component of the large ribosomal subunit (PubMed:26100019, PubMed:23636399, PubMed:32669547). Interacts with DHX33 (PubMed:26100019).
Component of the large ribosomal subunit (PubMed:26100019, PubMed:23636399, PubMed:32669547). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:26100019, PubMed:23636399, PubMed:32669547).
Ufmylated by UFL1 in response to endoplasmic reticulum stress, promoting reticulophagy of endoplasmic reticulum sheets.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily.
Expressed in peripheral blood leukocytes.
In contrast to other AGC family kinases, the catalytic activity is solely regulated by the binding of substrates and ligands, not by phosphorylation of the kinase domain.
Interacts with the heterodimer formed by GNB1 and GNG2 (By similarity). Interacts with GIT1 (By similarity). Interacts with, and phosphorylates chemokine-stimulated CCR5 (PubMed:10085131). Interacts with ARRB1 (PubMed:9501202). Interacts with LPAR1 and LPAR2 (PubMed:19306925). Interacts with RALA in response to LPAR1 activation (PubMed:19306925). ADRBK1 and RALA mutually inhibit each other's binding to LPAR1 (PubMed:19306925). Interacts with ADRB2 (PubMed:19715378).
Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them (PubMed:19715378). Key regulator of LPAR1 signaling (PubMed:19306925). Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor (PubMed:19306925). Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner (PubMed:19306925). Positively regulates ciliary smoothened (SMO)-dependent Hedgehog (Hh) signaling pathway by facilitating the trafficking of SMO into the cilium and the stimulation of SMO activity (By similarity). Inhibits relaxation of airway smooth muscle in response to blue light (PubMed:30284927).
The PH domain binds anionic phospholipids and helps recruiting ADRBK1 from the cytoplasm to plasma membrane close to activated receptors. It mediates binding to G protein beta and gamma subunits, competing with G-alpha subunits and other G-betagamma effectors.
Each PACE4 isoform exhibits a unique restricted distribution. Isoform PACE4A-I is expressed in heart, brain, placenta, lung, skeletal muscle, kidney, pancreas, but at comparatively higher levels in the liver. Isoform PACE4A-II is at least expressed in placenta. Isoform PACE4B was only found in the embryonic kidney cell line from which it was isolated. Isoform PACE4C and isoform PACE4D are expressed in placenta. Isoform PACE4E-I is expressed in cerebellum, placenta and pituitary. Isoform PACE4E-II is at least present in cerebellum.
Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. Likely functions in the constitutive secretory pathway, with unique restricted distribution in both neuroendocrine and non-neuroendocrine tissues.
The PACE4A-I precursor protein seems to exist in the reticulum endoplasmic as both a monomer and a dimer-sized complex whereas mature PACE4A-I exists only as a monomer, suggesting that propeptide cleavage affects its tertiary or quaternary structure. Interacts (immature form including the propeptide) with RCN3; probably involved in the maturation and the secretion of PCSK6 (PubMed:16433634).
The propeptide domain acts as an intramolecular chaperone assisting the folding of the zymogen within the endoplasmic reticulum. Isoform PACE4D lacks the propeptide domain.
In the N-terminal section; belongs to the HesA/MoeB/ThiF family. UBA4 subfamily.
Plays a central role in 2-thiolation of mcm(5)S(2)U at tRNA wobble positions of cytosolic tRNA(Lys), tRNA(Glu) and tRNA(Gln). Also essential during biosynthesis of the molybdenum cofactor. Acts by mediating the C-terminal thiocarboxylation of sulfur carriers URM1 and MOCS2A. Its N-terminus first activates URM1 and MOCS2A as acyl-adenylates (-COAMP), then the persulfide sulfur on the catalytic cysteine is transferred to URM1 and MOCS2A to form thiocarboxylation (-COSH) of their C-terminus. The reaction probably involves hydrogen sulfide that is generated from the persulfide intermediate and that acts as nucleophile towards URM1 and MOCS2A. Subsequently, a transient disulfide bond is formed. Does not use thiosulfate as sulfur donor; NFS1 acting as a sulfur donor for thiocarboxylation reactions.
DNA-dependent ATPase. May modulate chromosome segregation.
Interacts with UBR1 and UBR2. Interacts with MCM10; this interaction regulates RECQL4 unwinding activity.
Ubiquitously expressed, with highest levels in thymus and testis.
Up-regulated in actively dividing cells.
Component of the IFT complex A (IFT-A) (PubMed:20889716). IFT-A complex is divided into a core subcomplex composed of IFT122:IFT140:WDR19 which is associated with TULP3 and a peripheral subcomplex composed of IFT43:WDR35:TTC21B (PubMed:27932497, PubMed:29220510). Interacts (via C-terminal region) with IFT122 (via C-terminal region) (PubMed:29220510). Interacts with TTC25 (PubMed:25860617). Interacts with TTC21A (PubMed:30929735).
Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs) (PubMed:20889716, PubMed:22503633). Plays a pivotal role in proper development and function of ciliated cells through its role in ciliogenesis and/or cilium maintenance (PubMed:22503633). Required for the development and maintenance of the outer segments of rod and cone photoreceptor cells. Plays a role in maintenance and the delivery of opsin to the outer segment of photoreceptor cells (By similarity).
Contains 3 inactive NDK domains that each lack the active His residue, suggesting that they have no NDP kinase activity.
In the C-terminal section; belongs to the NDK family.
Probably required during the final stages of sperm tail maturation in the testis and/or epididymis, where extensive disulfide bonding of fibrous sheath (FS) proteins occurs. May be involved in the reduction of disulfide bonds within the sperm FS components. In vitro, it has neither NDP kinase nor reducing activity on disulfide bonds.
Restricted to spermiogenesis, starting at the pachytene spermatocyte level and peaking at the round and elongating spermatid stage.
Testis-specific. Expressed only in primary spermatocytes and round spermatids.
May be involved in the biosynthesis of heme A.
Predominantly found in tissues characterized by high rates of oxidative phosphorylation (OxPhos), including muscle, heart, and brain.
Acts as a GTPase-activating protein (GAP) for tubulin in concert with tubulin-specific chaperone C, but does not enhance tubulin heterodimerization.
Acts as a GTPase-activating protein (GAP) involved in trafficking between the Golgi and the ciliary membrane. Involved in localization of proteins, such as NPHP3, to the cilium membrane by inducing hydrolysis of GTP ARL3, leading to the release of UNC119 (or UNC119B). Acts as a GTPase-activating protein (GAP) for tubulin in concert with tubulin-specific chaperone C, but does not enhance tubulin heterodimerization. Acts as guanine nucleotide dissociation inhibitor towards ADP-ribosylation factor-like proteins.
Found in a complex with ARL3, RP2 and UNC119 (or UNC119B); RP2 induces hydrolysis of GTP ARL3 in the complex, leading to the release of UNC119 (or UNC119B). Interacts with ARL3; interaction is direct and stimulated with the activated GTP-bound form of ARL3.
Myristoylated on Gly-2; which may be required for membrane targeting.
Palmitoylated on Cys-3; which may be required for plasma membrane targeting (Probable). Mutation of Cys-3 targets the protein to internal membranes.
Ubiquitous. Expressed in the rod and cone photoreceptors, extending from the tips of the outer segment (OS) through the inner segment (IS) and outer nuclear layer (ONL) and into the synaptic terminals of the outer plexiform layer (ONL). Also detected in the bipolar, horizontal and amacrine cells in the inner nuclear layer (INL), extending to the inner plexiform layer (IPL) and though the ganglion cell layer (GCL) and into the nerve fiber layer (NFL) (at protein level).
Catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Leu-Pro-Ala (PubMed:25609706, PubMed:28476889). Also shows low activity towards peptides with Ala or Ser at the P1 position (PubMed:28476889).
Homodimer (PubMed:28476889). Isoform 1 interacts with TNFRSF1B/TNFR2 (activated) and TRAF2 (PubMed:25609706).
Isoform 1 and isoform 2 are widely expressed, with isoform 1 being more abundant.
Promotes TNFRSF1B-mediated phosphorylation of MAPK8/JNK1 and MAPK9/JNK2, suggesting a function as an adapter protein for TNFRSF1B; the effect is independent of XPNPEP3 peptidase activity. May inhibit apoptotic cell death induced via TNF-TNFRSF1B signaling.
Defects in ATP6AP2 may be involved in a glycosylation disorder with autophagic defects characterized by serum protein hypoglycosylation, immunodeficiency, liver disease, psychomotor impairment, and cutis laxa.
Expressed in brain, heart, placenta, liver, kidney and pancreas. Barely detectable in lung and skeletal muscles. In the kidney cortex it is restricted to the mesangium of glomeruli. In the coronary and kidney artery it is expressed in the subendothelium, associated to smooth muscles where it colocalizes with REN. Expressed in vascular structures and by syncytiotrophoblast cells in the mature fetal placenta.
Interacts with renin (PubMed:12045255). Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase protein pump (PubMed:33065002). Interacts (via N-terminus) with ATP6AP1 (via N-terminus) (PubMed:29127204, PubMed:33065002). Interacts with ATP6V0D1; ATP6V0D1 is a V-ATPase complex subunit and the interaction promotes V-ATPase complex assembly (PubMed:33065002, PubMed:30374053). Interacts with TMEM9; TMEM9 is a V-ATPase assembly regulator and the interaction induces the interaction with ATP6V0D1 (PubMed:30374053). Interacts with VMA21 (via N-terminus); VMA21 is a V-ATPase accessory component (PubMed:29127204).
Multifunctional protein which functions as a renin, prorenin cellular receptor and is involved in the assembly of the lysosomal proton-transporting V-type ATPase (V-ATPase) and the acidification of the endo-lysosomal system (PubMed:12045255, PubMed:29127204, PubMed:30374053, PubMed:32276428). May mediate renin-dependent cellular responses by activating ERK1 and ERK2 (PubMed:12045255). By increasing the catalytic efficiency of renin in AGT/angiotensinogen conversion to angiotensin I, may also play a role in the renin-angiotensin system (RAS) (PubMed:12045255). Through its function in V-type ATPase (v-ATPase) assembly and acidification of the lysosome it regulates protein degradation and may control different signaling pathways important for proper brain development, synapse morphology and synaptic transmission (By similarity).
Proteolytically cleaved by a furin-like convertase in the trans-Golgi network to generate N- and C-terminal fragments.
Expressed in testis and kidney, and at lower level in brain and lung.
The [NKR]KIAxRE motif seems to be a cyclin-binding region.
Acts as a negative mediator of apoptosis and may play a role in tumor progression. Suppresses the TNF-mediated apoptosis by inhibiting caspase-8 activity but not the processing of procaspase-8, subsequently resulting in inhibition of BID cleavage and caspase-3 activation.
By nuclear factor-KB (NF-KB) and TNF. Induction by TNF depends upon activation of NF-KB.
Expressed at high levels in the fetal liver, lung and kidney.
Expressed at high levels in the spleen, lymph node, thymus, thyroid, bone marrow and placenta. Expressed at high levels both in various tumor tissues, unstimulated and cytokine-activated cultured cells. Expressed at low levels in the spinal cord, ovary, lung, adrenal glands, heart, brain, testis and skeletal muscle.
Contains 8 types of repeats which are distributed in 3 regions.
Interacts with SRSF2. Associates with the spliceosome. Interacts with the AML1-MTG8 (AML1-ETO) fusion protein, possibly leading to trigger signals inhibiting leukemogenesis. Interacts with USH1G (PubMed:34023904).
RNA-binding protein that acts as a mRNA splicing cofactor by promoting efficient splicing of transcripts that possess weak splice sites. Specifically promotes splicing of many cell-cycle and DNA-repair transcripts that possess weak splice sites, such as TUBG1, KATNB1, TUBGCP2, AURKB, PCNT, AKT1, RAD23A, and FANCG. Probably acts by facilitating the interaction between Serine/arginine-rich proteins such as SRSF2 and the RNA polymerase II. Also binds to DNA; binds to the consensus DNA sequence: 5'-GA[GT]AN[CG][AG]CC-3'. May indirectly repress hepatitis B virus (HBV) core promoter activity and transcription of HBV genes and production of HBV virions. Essential for correct RNA splicing of multiple genes critical for brain development, neuronal migration and metabolism, including TUBG1, FLNA, PNKP, WDR62, PSMD3, PCK2, PFKL, IDH2, and ACY1 (PubMed:27545680).
Widely expressed, with the higher expression seen in leukocyte and heart.
ATPase required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum. Recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol. This complex then targets to the endoplasmic reticulum by membrane-bound receptors GET1/WRB and CAMLG/GET2, where the tail-anchored protein is released for insertion. This process is regulated by ATP binding and hydrolysis. ATP binding drives the homodimer towards the closed dimer state, facilitating recognition of newly synthesized TA membrane proteins. ATP hydrolysis is required for insertion. Subsequently, the homodimer reverts towards the open dimer state, lowering its affinity for the GET1-CAMLG receptor, and returning it to the cytosol to initiate a new round of targeting. May be involved in insulin signaling.
Expressed in the epithelial cells of the liver, kidney, and stomach wall, in the adrenal medulla, in the islet cells of the pancreas, in the red pulp of the spleen, and in cardiac and skeletal muscle.
Homodimer (By similarity). Component of the Golgi to ER traffic (GET) complex, which is composed of GET1/WRB, CAMLG/GET2 and GET3/TRC40 (PubMed:21444755, PubMed:23041287, PubMed:24392163, PubMed:32910895). Within the complex, CAMLG and GET1 form a heterotetramer which is stabilized by phosphatidylinositol binding and which binds to the GET3 homodimer (PubMed:32910895). Interacts with CAMLG (via N-terminus) (By similarity). GET3 shows a higher affinity for CAMLG than for GET1 (PubMed:24392163). Interacts with SERP1 and SEC61B (PubMed:17382883, PubMed:18477612).
Activated by autophosphorylation on Thr-1400 and Thr-1412 following oligomerization.
Binds both upstream activators and downstream substrates in multimolecular complexes through its N-terminus (PubMed:9808624). Oligomerizes after binding MAP2K4 or TRAF2 (PubMed:9808624). Interacts with AXIN1 (PubMed:12223491, PubMed:15262978). Interacts (via the kinase catalytic domain) with STK38 (PubMed:17906693). Interacts with GRIPAP1 (PubMed:17761173).
Component of a protein kinase signal transduction cascade (PubMed:9808624). Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4 (PubMed:9808624). May phosphorylate the MAPK8/JNK1 kinase (PubMed:17761173). Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway (PubMed:9808624).
Auxiliary subunit of the NALCN sodium channel complex, a voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability (By similarity). Activated by neuropeptides substance P, neurotensin, and extracellular Ca(2+) that regulates neuronal excitability by controlling the sizes of NALCN-dependent sodium-leak current. UNC80 is essential for NALCN sensitivity to extracellular Ca(2+) (By similarity).
Moderately expressed in fetal brain, spinal cord, skeletal muscle, thymus, spleen, fetal liver, small intestine, colon, kidney and uterus. Highly expressed in adrenal gland, prostate and testis, as well as in brain and cerebellum.
NALCN complex consists of NALCN and auxiliary subunits, UNC79, UNC80 and NACL1. These auxiliary subunits are essential for the NALCN complex function (By similarity). Interacts (via N-terminus half) with NALCN; this interaction facilitates NALCN surface localization (By similarity). Interacts with UNC79 (By similarity). UNC80 bridges NALCN to UNC79 (By similarity).
Multifunctional nucleolar protein that terminates ribosomal gene transcription, mediates replication fork arrest and regulates RNA polymerase I transcription on chromatin. Plays a dual role in rDNA regulation, being involved in both activation and silencing of rDNA transcription. Interaction with BAZ2A/TIP5 recovers DNA-binding activity.
Oligomer. The oligomeric structure enables to interact simultaneously with two separate DNA fragments. Interacts with BAZ2A/TIP5. Interacts with CAVIN1. Interacts (via the N-terminal region (NRD) and a C-terminal region) with CDKN2A/ARF; the interaction is direct. Interacts (via C-terminal region) with NPM1/B23.
The N-terminal region (NRD) inhibits DNA-binding via its interaction with the C-terminal region.
(Microbial infection) Up-regulated by live and heat-killed Mycobacterium bovis bacterial cell wall.
Electroneutral divalent metal cation:bicarbonate symporter of the plasma membrane mediating the cellular uptake of zinc and manganese, two divalent metal cations important for development, tissue homeostasis and immunity (PubMed:12504855, PubMed:22898811, PubMed:23403290, PubMed:29337306, PubMed:26637978, PubMed:29453449). Transports an electroneutral complex composed of a divalent metal cation and two bicarbonate anions or alternatively a bicarbonate and a selenite anion (PubMed:27166256, PubMed:31699897). Thereby, it also contributes to the cellular uptake of selenium, an essential trace metal and micronutrient (PubMed:27166256). Also imports cadmium a non-essential metal which is cytotoxic and carcinogenic (PubMed:27466201). May also transport iron and cobalt through membranes (PubMed:22898811). Through zinc import, indirectly regulates the metal-dependent transcription factor MTF1 and the expression of some metalloproteases involved in cartilage catabolism and also probably heart development (PubMed:29337306). Also indirectly regulates the expression of proteins involved in cell morphology and cytoskeleton organization (PubMed:29927450). Indirectly controls innate immune function and inflammatory response by regulating zinc cellular uptake which in turn modulates the expression of genes specific of these processes (PubMed:23403290, PubMed:28056086). Protects, for instance, cells from injury and death at the onset of inflammation (PubMed:18390834). By regulating zinc influx into monocytes also directly modulates their adhesion to endothelial cells and arteries (By similarity). Reclaims manganese from the bile at the apical membrane of hepatocytes, thereby regulating the activity of the manganese-dependent enzymes through the systemic levels of the nutrient (PubMed:28481222). Also participates in manganese reabsorption in the proximal tubule of the kidney (PubMed:26637978). By mediating the extracellular uptake of manganese by cells of the blood-brain barrier, may also play a role in the transport of the micronutrient to the brain (PubMed:26637978, PubMed:31699897). With manganese cellular uptake also participates in mitochondrial proper function (PubMed:29453449). Finally, also probably functions intracellularly, translocating zinc from lysosome to cytosol to indirectly enhance the expression of specific genes during TCR-mediated T cell activation (PubMed:19401385).
N-glycosylated (PubMed:18390834). N-glycosylation is not required for proper iron and zinc transport (By similarity).
Rare variants in SLC39A8 may be a cause of Leigh-like mitochondrial syndrome characterized by profound developmental delay, dystonia, seizures and failure to thrive.
Ubiquitously expressed (PubMed:12504855, PubMed:22898811, PubMed:28056086, PubMed:31699897). Expressed in thymus, placenta, lung, liver, pancreas, salivary gland and, to a lower extent, in spleen, testis, ovary, small intestine, colon, leukocyte, heart. Highest expression is observed in pancreas (PubMed:12504855). Expressed by macrophages (at protein level) (PubMed:28056086). Expressed by microvascular capillary endothelial cells that constitute the blood-brain barrier (at protein level) (PubMed:31699897).
Up-regulated by manganese (PubMed:29453449). Up-regulated by lipopolysaccharides (at protein level) (PubMed:23403290, PubMed:28056086). Up-regulated by inflammatory cytokines like TNF (PubMed:12504855, PubMed:18390834). Down-regulated following phorbol ester treatment (PubMed:12504855). Up-regulated by zinc and T-cell activation (PubMed:19401385).
Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
Proteolytically cleaved and activated by cathepsin CTSG (PubMed:8920993). The activation peptide is cleaved by factor IXa (in the intrinsic pathway), or by factor VIIa (in the extrinsic pathway) (By similarity).
The two chains are formed from a single-chain precursor by the excision of two Arg residues and are held together by 1 or more disulfide bonds. Forms a heterodimer with SERPINA5.
A chromosomal aberration involving RASSF8 is found in a complex type of synpolydactyly referred to as 3/3-prime/4 synpolydactyly associated with metacarpal and metatarsal synostoses. Reciprocal translocation t(12;22)(p11.2;q13.3) with FBLN1.
Widely expressed as a 6.2 kb transcript. A 2.2 kb alternatively spliced transcript is expressed exclusively in testis.
Expressed in multiple organs and tissues, including heart, uterus, ovary, and blood vessel endothelium.
Interacts weakly with EBNA2. Does not interact with any Notch proteins (By similarity).
Putative transcription factor, which cooperates with EBNA2 to activate transcription.
As intracellular fragment AlcICD, suppresses APBB1-dependent transactivation stimulated by APP C-terminal intracellular fragment (AICD), most probably by competing with AICD for APBB1-binding (PubMed:15037614).
Directly interacts with APBA2 (PubMed:12972431). Forms a tripartite complex with APBA2 and APP (By similarity). Interacts with KLC1 (PubMed:17332754, PubMed:21385839).
Expressed in the brain and, a lower level, in the heart, skeletal muscle, kidney and placenta. Accumulates in dystrophic neurites around the amyloid core of Alzheimer disease senile plaques (at protein level).
In complex with APBA2 and C99, a C-terminal APP fragment, abolishes C99 interaction with PSEN1 and thus APP C99 cleavage by gamma-secretase, most probably through stabilization of the direct interaction between APBA2 and APP (PubMed:15037614).
Interacts with APBB1; this interaction stabilizes AlcICD metabolism.
Postsynaptic adhesion molecule that binds to presynaptic neurexins to mediate both excitatory and inhibitory synapse formation (By similarity). Promotes synapse development by acting as a cell adhesion molecule at the postsynaptic membrane, which associates with neurexin-alpha at the presynaptic membrane (By similarity). Also functions as a cargo in axonal anterograde transport by acting as a molecular adapter that promotes KLC1 association with vesicles (PubMed:21385839). Complex formation with APBA2 and APP, stabilizes APP metabolism and enhances APBA2-mediated suppression of beta-APP40 secretion, due to the retardation of intracellular APP maturation (PubMed:12972431).
Proteolytically processed under normal cellular conditions (PubMed:15037614). A primary zeta-cleavage generates a large extracellular (soluble) N-terminal domain (sAlc) and a short C-terminal transmembrane fragment (CTF1) (PubMed:15037614). A secondary cleavage catalyzed by presenilin gamma-secretase within the transmembrane domain releases the beta-Alc-alpha chain in the extracellular milieu and produces an intracellular fragment (AlcICD) (PubMed:15037614). This processing is strongly suppressed in the tripartite complex formed with APBA2 and APP, which seems to prevent the association with PSEN1 (PubMed:15037614).
Expressed only in melanocytes and testis.
Interacts (via C-terminus) with CREBBP. Interacts with EGR2 (By similarity). Homodimer. Binds to RBM14. Interacts (via N-terminus) with HSPA8; the interaction suppresses the association of CITED1 with p300/CBP and SMAD-mediated transcription transactivation. Interacts (via C-terminus) with TOX3 (via HGM box); the interaction increases estrogen-response element (ERE)-dependent transcription and protection against cell death. Interacts with ESR1; the interaction occurs in a estrogen-dependent manner (By similarity). Interacts (unphosphorylated form preferentially and via C-terminus) with EP300.
Phosphorylated. Phosphorylation changes in a cell cycle-dependent manner and reduces its transcriptional coactivator activity.
Transcriptional coactivator of the p300/CBP-mediated transcription complex. Enhances SMAD-mediated transcription by strengthening the functional link between the DNA-binding SMAD transcription factors and the p300/CBP transcription coactivator complex. Stimulates estrogen-dependent transactivation activity mediated by estrogen receptors signaling; stabilizes the interaction of estrogen receptor ESR1 and histone acetyltransferase EP300. Positively regulates TGF-beta signaling through its association with the SMAD/p300/CBP-mediated transcriptional coactivator complex. Induces transcription from estrogen-responsive promoters and protection against cell death. Potentiates EGR2-mediated transcriptional activation activity from the ERBB2 promoter. Acts as an inhibitor of osteoblastic mineralization through a cAMP-dependent parathyroid hormone receptor signaling. May play a role in pigmentation of melanocytes. Associates with chromatin to the estrogen-responsive TGF-alpha promoter region in a estrogen-dependent manner.
Up-regulated by GPR39 in neuronal cells.
Binds to the DNA consensus sequence 5'-GGGGAATCTCC-3'.
Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the N-terminus of INO80. Interacts with UCHL5; NFRKB competes with ADRM1 for interaction with UCHL5.
Expressed in thymus, brain, testes, spleen and liver.
NFRKB seems to be mostly disordered. The wing-helix like domain doesn't bind DNA.
Putative regulatory component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair. Modulates the deubiquitinase activity of UCHL5 in the INO80 complex.
Essential for the degradation of glycogen in lysosomes (PubMed:1856189, PubMed:7717400, PubMed:14695532, PubMed:18429042). Has highest activity on alpha-1,4-linked glycosidic linkages, but can also hydrolyze alpha-1,6-linked glucans (PubMed:29061980).
Phosphorylation of mannose residues ensures efficient transport of the enzyme to the lysosomes via the mannose 6-phosphate receptor.
The different forms of acid glucosidase are obtained by proteolytic processing.
There are three common alleles of GAA: GAA*1, GAA*2 and GAA*4. The sequence shown is that of allele GAA*1, which is the most common. Alleles GAA*2 and GAA*4 are much rarer.
Component of the oligosaccharyltransferase (OST) complex (PubMed:31831667). OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits (PubMed:23606741, PubMed:31831667). STT3A complex assembly occurs through the formation of 3 subcomplexes. Subcomplex 1 contains RPN1 and TMEM258, subcomplex 2 contains the STT3A-specific subunits STT3A, DC2/OSTC, and KCP2 as well as the core subunit OST4, and subcomplex 3 contains RPN2, DAD1, and OST48. The STT3A complex can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes (By similarity).
Subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation (PubMed:31831667). N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity. Specifically involved in maintaining stability of STT3A-containing OST complexes.
Available under the name Thyrogen (Genzyme). Used in combination with other tests to detect recurring or leftover thyroid cancer cells in patients with a history of certain types of thyroid cancer.
Heterodimer of a common alpha chain and a unique beta chain which confers biological specificity to thyrotropin, lutropin, follitropin and gonadotropin.
Indispensable for the control of thyroid structure and metabolism.
Major isoform in peripheral blood leukocytes and thyroid, may form heterodimers with isoform 1.
A chromosomal aberration involving PCM1 is found in a variety of hematological malignancies including atypical chronic myeloid leukemia (atypical CML) and T-cell lymphoma (PubMed:15805263, PubMed:16034466, PubMed:16091753, PubMed:16769584, PubMed:16424865). Translocation t(8;9)(p22;p24) with JAK2 links the protein kinase domain of JAK2 to the major portion of PCM1 (PubMed:15805263, PubMed:16034466, PubMed:16091753, PubMed:16769584, PubMed:16424865).
A chromosomal aberration involving PCM1 is found in papillary thyroid carcinomas (PTCs) (PubMed:10980597). Translocation t(8;10)(p21.3;q11.2) with RET links the protein kinase domain of RET to the major portion of PCM1 (PubMed:10980597).
Expressed in blood, bone marrow, breast, lymph node, ovary and thyroid.
Expression is reduced in breast and ovarian cancer.
Phosphorylated on multiple serine and threonine residues by DYRK3 during the G2-to-M transition, after the nuclear-envelope breakdown (PubMed:29973724). Phosphorylation by DYRK3 promotes disassembly of pericentriolar material (PubMed:29973724). Phosphorylation at Ser-372 mediated by PLK4 is required to maintain the integrity of centriolar satellites (PubMed:30804208).
Required for centrosome assembly and function (PubMed:12403812, PubMed:15659651, PubMed:16943179). Essential for the correct localization of several centrosomal proteins including CEP250, CETN3, PCNT and NEK2 (PubMed:12403812, PubMed:15659651). Required to anchor microtubules to the centrosome (PubMed:12403812, PubMed:15659651). Also involved in cilium biogenesis by recruiting the BBSome, a ciliary protein complex involved in cilium biogenesis, to the centriolar satellites (PubMed:20551181, PubMed:24121310, PubMed:27979967). Recruits the tubulin polyglutamylase complex (TPGC) to centriolar satellites (PubMed:34782749).
Self-associates. Interacts with C2CD3 (By similarity). Interacts with BBS4, BBS8, CETN3, HAP1, NDE1, NDEL1, MAP1LC3B, GABARAPAL2, and GABARAP (PubMed:12403812, PubMed:14520415, PubMed:15107855, PubMed:16291865, PubMed:24089205, PubMed:9361024). Interacts with CEP131; the interaction increases in response to ultraviolet light (UV) radiation (PubMed:24121310). Associates with microtubule; association to microtubule is reduced in response to cellular stress, such as ultraviolet light (UV) radiation or heat shock, in a process that requires p38 MAP kinase signaling (PubMed:24121310). Interacts with CCDC113 (PubMed:25074808). Interacts with SSX2IP (By similarity). Interacts with CCDC13 (PubMed:24816561). Interacts with CEP290 (By similarity). Interacts with PARD6A (PubMed:20719959). Interacts with KIAA0753/OFIP, CEP20/FOR20 and OFD1; the interaction with CEP20/FOR20 and OFD1 may be mediated by KIAA0753/OFIP (PubMed:26643951). Interacts with CCDC66 (PubMed:28235840). Interacts with CCDC61 (PubMed:31789463). Interacts with DZIP1; localizes DZIP1 and the associated BBSome to centriolar satellite (PubMed:27979967). Interacts with CSTPP1, TTLL1, TPGS1 and LRRC49 (PubMed:34782749).
Ubiquitinated. Undergoes monoubiquitination catalyzed by the E3 ubiquitin-protein ligase MIB1 in proliferating cells, preventing cilia formation (PubMed:24121310). Monoubiquitination by MIB1 is inhibited in response to cellular stress, such as ultraviolet light (UV) radiation or heat shock, resulting in cilia formation initiation (PubMed:24121310).
Component of the cap-binding complex (CBC), which binds cotranscriptionally to the 5'-cap of pre-mRNAs and is involved in various processes such as pre-mRNA splicing, translation regulation, nonsense-mediated mRNA decay, RNA-mediated gene silencing (RNAi) by microRNAs (miRNAs) and mRNA export. The CBC complex is involved in mRNA export from the nucleus via its interaction with ALYREF/THOC4/ALY, leading to the recruitment of the mRNA export machinery to the 5'-end of mRNA and to mRNA export in a 5' to 3' direction through the nuclear pore. The CBC complex is also involved in mediating U snRNA and intronless mRNAs export from the nucleus. The CBC complex is essential for a pioneer round of mRNA translation, before steady state translation when the CBC complex is replaced by cytoplasmic cap-binding protein eIF4E. The pioneer round of mRNA translation mediated by the CBC complex plays a central role in nonsense-mediated mRNA decay (NMD), NMD only taking place in mRNAs bound to the CBC complex, but not on eIF4E-bound mRNAs. The CBC complex enhances NMD in mRNAs containing at least one exon-junction complex (EJC) via its interaction with UPF1, promoting the interaction between UPF1 and UPF2. The CBC complex is also involved in 'failsafe' NMD, which is independent of the EJC complex, while it does not participate in Staufen-mediated mRNA decay (SMD). During cell proliferation, the CBC complex is also involved in microRNAs (miRNAs) biogenesis via its interaction with SRRT/ARS2 and is required for miRNA-mediated RNA interference. The CBC complex also acts as a negative regulator of PARN, thereby acting as an inhibitor of mRNA deadenylation. In the CBC complex, NCBP1/CBP80 does not bind directly capped RNAs (m7GpppG-capped RNA) but is required to stabilize the movement of the N-terminal loop of NCBP2/CBP20 and lock the CBC into a high affinity cap-binding state with the cap structure. Associates with NCBP3 to form an alternative cap-binding complex (CBC) which plays a key role in mRNA export and is particularly important in cellular stress situations such as virus infections. The conventional CBC with NCBP2 binds both small nuclear RNA (snRNA) and messenger (mRNA) and is involved in their export from the nucleus whereas the alternative CBC with NCBP3 does not bind snRNA and associates only with mRNA thereby playing a role only in mRNA export. NCBP1/CBP80 is required for cell growth and viability (PubMed:26382858).
Component of the nuclear cap-binding complex (CBC), a heterodimer composed of NCBP1/CBP80 and NCBP2/CBP20 that interacts with m7GpppG-capped RNA. Found in a U snRNA export complex containing PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with PHAX/RNUXA, SRRT/ARS2, EIF4G2, IGF2BP1, HNRNPF, HNRNPH1, KIAA0427/CTIF, PARN, DROSHA, UPF1 and ALYREF/THOC4. May interact with EIF4G1; the interaction is however controversial since it is reported by PubMed:11340157, PubMed:15059963 and PubMed:15361857, but is not observed by PubMed:19648179. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1/CBP80 and POLR2A. Component of an alternative nuclear cap-binding complex (CBC) composed of NCBP1/CBP80 and NCBP3 (PubMed:26382858). Interacts with METTL3 (PubMed:27117702). Interacts with ZFC3H1 in a RNase-insensitive manner (PubMed:27871484). Interacts with MTREX (PubMed:30842217). Interacts with TASOR (By similarity). Interacts with DHX34; the interaction is RNA-dependent (PubMed:25220460). Interacts with KPNA3 (PubMed:34564892).
ATP-dependent microtubule severing protein. Severs microtubules along their length and depolymerizes their ends, primarily the minus-end, that may lead to the suppression of microtubule growth from and attachment to centrosomes. Microtubule severing may promote rapid reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. Microtubule release from the mitotic spindle poles may allow depolymerization of the microtubule end proximal to the spindle pole, leading to poleward microtubule flux and poleward motion of chromosome.
Cleaved into a smaller N-terminal chain and a larger chain that contains the fibrinogen C-terminal domain; both cleaved and uncleaved forms are detected in the extracellular space. The cleaved form is not present within the cell.
Detected in blood plasma (at protein level) (PubMed:29899519). Detected in liver (PubMed:10698685). Detected in white fat tissue and placenta (PubMed:10866690). Expressed at high levels in the placenta, heart, liver, muscle, pancreas and lung but expressed poorly in the brain and kidney.
Forms disulfide-linked dimers and tetramers.
Genetic variations in ANGPTL4 are associated with low plasma triglyceride levels and define the plasma triglyceride level quantitative trait locus (TGQTL) [MIM:615881].
Homooligomer; disulfide-linked via Cys residues in the N-terminal part of the protein (PubMed:19270337). The homooligomer undergoes proteolytic processing to release the ANGPTL4 C-terminal chain, which circulates as a monomer (PubMed:19270337). The homooligomer unprocessed form is able to interact with the extracellular matrix (PubMed:21398697).
Mediates inactivation of the lipoprotein lipase LPL, and thereby plays a role in the regulation of triglyceride clearance from the blood serum and in lipid metabolism (PubMed:19270337, PubMed:21398697, PubMed:27929370, PubMed:29899144). May also play a role in regulating glucose homeostasis and insulin sensitivity (Probable). Inhibits proliferation, migration, and tubule formation of endothelial cells and reduces vascular leakage (PubMed:14583458, PubMed:17068295). Upon heterologous expression, inhibits the adhesion of endothelial cell to the extracellular matrix (ECM), and inhibits the reorganization of the actin cytoskeleton, formation of actin stress fibers and focal adhesions in endothelial cells that have adhered to ANGPTL4-containing ECM (in vitro) (PubMed:17068295). Depending on context, may modulate tumor-related angiogenesis (By similarity).
Mediates inactivation of the lipoprotein lipase LPL, and thereby plays an important role in the regulation of triglyceride clearance from the blood serum and in lipid metabolism (PubMed:19270337, PubMed:21398697, PubMed:27929370, PubMed:29899144). Has higher activity in LPL inactivation than the uncleaved protein (PubMed:19270337, PubMed:21398697).
Up-regulated when cells are exposed to severe hypoxia (in vitro).
Detected in fetal liver, lung and brain. Highly expressed in adult adipose tissue, and at lower levels in adult brain and lung.
Expected to bind 2 Fe(2+) ions per subunit, instead of the Zn(2+) ions seen in the 3D-structure.
Stearoyl-CoA desaturase that utilizes O(2) and electrons from reduced cytochrome b5 to introduce the first double bond into saturated fatty acyl-CoA substrates (PubMed:15907797, PubMed:18765284). Catalyzes the insertion of a cis double bond at the delta-9 position into fatty acyl-CoA substrates including palmitoyl-CoA and stearoyl-CoA (PubMed:15907797, PubMed:18765284). Gives rise to a mixture of 16:1 and 18:1 unsaturated fatty acids (PubMed:15610069). Plays an important role in lipid biosynthesis. Plays an important role in regulating the expression of genes that are involved in lipogenesis and in regulating mitochondrial fatty acid oxidation (By similarity). Plays an important role in body energy homeostasis (By similarity). Contributes to the biosynthesis of membrane phospholipids, cholesterol esters and triglycerides (By similarity).
The histidine box domains are involved in binding the catalytic metal ions.
Activated T-cells. Highly expressed on tonsillar T-cells, which are closely associated with B-cells in the apical light zone of germinal centers, the site of terminal B-cell maturation. Expressed at lower levels in thymus, lung, lymph node and peripheral blood leukocytes. Expressed in the medulla of fetal and newborn thymus.
By phorbol myristate acetate (PMA) and ionomycin. Up-regulated early on T-cells and continues to be expressed into the later phases of T-cell activation.
Enhances all basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines, up-regulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B-cells. Essential both for efficient interaction between T and B-cells and for normal antibody responses to T-cell dependent antigens. Does not up-regulate the production of interleukin-2, but superinduces the synthesis of interleukin-10. Prevents the apoptosis of pre-activated T-cells. Plays a critical role in CD40-mediated class switching of immunoglobin isotypes (By similarity).
Enhances all basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines, up-regulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B-cells. Essential both for efficient interaction between T and B-cells and for normal antibody responses to T-cell dependent antigens. Does not up-regulate the production of interleukin-2, but superinduces the synthesis of interleukin-10. Prevents the apoptosis of pre-activated T-cells. Plays a critical role in CD40-mediated class switching of immunoglobin isotypes.
Essential for the assembly of the distal half of centrioles, required for centriole elongation.
Hyperphosphorylated during recruitment to procentrioles in G2/M phase.
Does not have 2'-5'-OAS activity, but can bind double-stranded RNA. Displays antiviral activity against encephalomyocarditis virus (EMCV) and hepatitis C virus (HCV) via an alternative antiviral pathway independent of RNase L.
Expressed in most tissues, with the highest levels in primary blood Leukocytes and other hematopoietic system tissues, colon, stomach and to some extent in testis.
Has antiviral activity against RNA viruses.
Specifically interacts with the ligand binding domain of the thyroid receptor (TR). TRIP14 does not require the presence of thyroid hormone for its interaction. Binds MBD1.
The ubiquitin-like domains are essential for its antiviral activity.
Highly expressed in cerebellum, cerebrum, heart, skeletal muscle, placenta, pancreatic islet and testis. Detected at lower levels in colon, kidney, small intestine and lung.
Homodimer, or homooligomer. Interacts with TGFA and HBEGF (PubMed:15965977). Interacts with EGF; may retain EGF in the endoplasmic reticulum and regulates its degradation through the endoplasmic reticulum-associated degradation (ERAD) (PubMed:21439629). Interacts (via cytoplasmic N-terminus) with FRMD8/iTAP; this interaction leads to mutual protein stabilization (PubMed:29897333, PubMed:29897336). Interacts with ADAM17/TACE (PubMed:29897333).
Regulates ADAM17 protease, a sheddase of the epidermal growth factor (EGF) receptor ligands and TNF, thereby plays a role in sleep, cell survival, proliferation, migration and inflammation. Does not exhibit any protease activity on its own.
Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development.
The Calx-beta domain binds calcium with high affinity and undergo a major conformational shift upon binding.
Was termed QBRICK because it contains 12 repeats: 'Q' stands for queen and is taken from the queen being the 12th in a suit of playing card, and 'BRICK' stands for the repeating unit.
Pulmonary surfactant associated proteins promote alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces.
Pulmonary surfactant consists of 90% lipid and 10% protein. There are 4 surfactant-associated proteins: 2 collagenous, carbohydrate-binding glycoproteins (SP-A and SP-D) and 2 small hydrophobic proteins (SP-B and SP-C).
May be a substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. May play a role in the initiation of arteriogenesis (By similarity).
Interacts with NCL/nucleolin (PubMed:21474449). Isoform 1 and isoform 2 interact with TERT and isoform 1 exhibits a higher binding affinity for TERT compared to isoform 2 (PubMed:22226966). Isoform 1 interacts with MTREX in an ATP-dependent manner; the interaction is required to associate NVL with nuclear RNA exosome (PubMed:26166824, PubMed:31358741, PubMed:16782053). Isoform 1 interacts with RPL5 in an ATP-dependent manner (PubMed:15469983). Interacts with WDR74 (through WDR repeats); the interaction is independent of RNA or pre-60S ribosome particles (PubMed:28416111).
Participates in the assembly of the telomerase holoenzyme and effecting of telomerase activity via its interaction with TERT (PubMed:22226966). Involved in both early and late stages of the pre-rRNA processing pathways (PubMed:26166824). Spatiotemporally regulates 60S ribosomal subunit biogenesis in the nucleolus (PubMed:15469983, PubMed:16782053, PubMed:29107693, PubMed:26456651). Catalyzes the release of specific assembly factors, such as WDR74, from pre-60S ribosomal particles through the ATPase activity (PubMed:29107693, PubMed:26456651, PubMed:28416111).
Widely expressed. Highest level of expression in heart, placenta, skeletal muscle, pancreas and retina.
EGF2 and EGF3 form a rigid rod via an interdomain calcium ion binding site, while the long linker between EGF1 and EGF2 lends considerable flexibility to EGF1.
Promotes adhesion of endothelial cells through interaction with the alpha-v/beta-3 integrin receptor. Inhibits formation of vascular-like structures. May be involved in regulation of vascular morphogenesis of remodeling in embryonic development.
Autophosphorylates on all three types of residues.
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. Lammer subfamily.
Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Phosphorylates SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.
Lacks the kinase domain. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Leucettine L41 inhibits its kinase activity and affects the regulation of alternative splicing mediated by phosphorylation of SR proteins.
Homodimer (PubMed:17179145). Homooligomer (Probable). Interacts with UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9 and UGT1A10 to form heterodimers (PubMed:17179145). Isoform 1 interacts with isoform 2/i2 suggesting that oligomerization is involved in negative regulation of transferase activity by isoform 2. Isoform 1 also interacts with respective i2 isoforms of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9 and UGT1A10 (PubMed:20610558).
Liver and gastric tissue (PubMed:9271343). Isoform 1 and isoform 2 are expressed in esophagus. Neither isoform is expressed in liver, kidney, colon and small intestine (PubMed:18004212).
There are four common allelic UGT1A7 variants which exhibit significant differences in catalytic activity towards 3-, 7-, and 9-hydroxy-benzo(a)pyrene. UGT1A7*3 exhibits a 5.8-fold lower relative Vmax compared to UGT1A7*1, whereas UGT1A7*2 and UGT1A7*4 have a 2.6- and 2.8-fold lower relative Vmax than UGT1A7*1, respectively, suggesting that these mutations confer slow glucuronidation phenotype.
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15470161, PubMed:18052087, PubMed:18004212, PubMed:18674515, PubMed:18719240, PubMed:20610558, PubMed:23360619). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormone epiestradiol (PubMed:18719240). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558, PubMed:23360619). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161).
UGT1A7 isoform is part of the UGT1A complex locus which displays alternative use of promoters, first exons and terminal exons. The locus is defined by 13 first exons, which are alternatively spliced to 3 other common exons and 2 alternative terminal exons 5. From the 27 possible mRNA isoforms, 9 produce functionally active polypeptides (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9 and 1A10) called isoforms 1 (i1). Use of an alternative exon 5 (5b) as terminal exon is leading to 9 additional alternatively spliced products termed isoforms i2 and which lack transferase activity.
During unfolded protein response, a fragment of approximately 50 kDa containing the cytoplasmic transcription factor domain is released by proteolysis. The cleavage seems to be performed sequentially by site-1 (MBTPS1, S1P) and site-2 (MBTPS2, S2P) proteases.
Homodimer and heterodimer with ATF6-beta. The dimer interacts with the nuclear transcription factor Y (NF-Y) trimer through direct binding to NF-Y subunit C (NF-YC). Interacts also with the transcription factors GTF2I, YY1 and SRF.
Interacts with THBS4 (via EGF-like 3; calcium-binding domain) which facilitates its processing, activation and nuclear translocation (PubMed:22682248). Interacts (via lumenal domain) with THBS1 (By similarity).
Interacts with XBP1 isoform 2; the interaction occurs in a ER stress-dependent manner (PubMed:17765680). Interacts with LACC1 (PubMed:31875558).
N-glycosylated. The glycosylation status may serve as a sensor for ER homeostasis, resulting in ATF6 activation to trigger the unfolded protein response (UPR).
Precursor of the transcription factor form (Processed cyclic AMP-dependent transcription factor ATF-6 alpha), which is embedded in the endoplasmic reticulum membrane (PubMed:10564271, PubMed:11158310, PubMed:11779464). Endoplasmic reticulum stress promotes processing of this form, releasing the transcription factor form that translocates into the nucleus, where it activates transcription of genes involved in the unfolded protein response (UPR) (PubMed:10564271, PubMed:11158310, PubMed:11779464).
Transcription factor that initiates the unfolded protein response (UPR) during endoplasmic reticulum stress by activating transcription of genes involved in the UPR (PubMed:10564271, PubMed:11163209, PubMed:11158310, PubMed:11779464). Binds DNA on the 5'-CCAC[GA]-3'half of the ER stress response element (ERSE) (5'-CCAAT-N(9)-CCAC[GA]-3') and of ERSE II (5'-ATTGG-N-CCACG-3') (PubMed:10564271, PubMed:11158310, PubMed:11779464). Binding to ERSE requires binding of NF-Y to ERSE. Could also be involved in activation of transcription by the serum response factor (PubMed:10564271, PubMed:11158310, PubMed:11779464). May play a role in foveal development and cone function in the retina (PubMed:26029869).
Ubiquitinated by RNF186 at Lys-152, which is required for pattern recognition receptor-induced unfolded protein response-associated outcomes.
Autoinhibited: in the inactive state, the enzymatic TIR domain is held apart by the autoinhibiting ARM repeats (PubMed:27671644, PubMed:31278906, PubMed:32755591, PubMed:33053563). NAD(+)-binding to ARM repeats maintains an inactive state by promoting interaction between ARM repeats and the TIR domain, thereby facilitating inhibition of the enzymatic TIR domain (PubMed:33053563). Following activation, possibly by nicotinamide mononucleotide (NMN), auto-inhibitory interactions are released, allowing self-association of the TIR domains and subsequent activation of the NAD(+) hydrolase (NADase) activity (PubMed:27671644, PubMed:31128467, PubMed:32755591). Self-association of TIR domains is facilitated by the octamer of SAM domains (PubMed:31278906, PubMed:31439792). NAD(+) hydrolase activity is inhibited by nicotinamide (PubMed:28334607). Specifically inhibited by berberine chloride and zinc chloride (PubMed:32828421).
Homooctamer; forms an octameric ring via SAM domains (PubMed:31278906, PubMed:31439792, PubMed:32755591, PubMed:33053563). Interacts with TICAM1/TRIF and thereby interferes with TICAM1/TRIF function (PubMed:16964262). Interacts with MAPK10/JNK3 and SDC2 (via cytoplasmic domain) (By similarity).
NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism (PubMed:25908823, PubMed:27671644, PubMed:28334607). Acts as a negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway by promoting Wallerian degeneration, an injury-induced form of programmed subcellular death which involves degeneration of an axon distal to the injury site (PubMed:15123841, PubMed:16964262, PubMed:20306472, PubMed:25908823). Wallerian degeneration is triggered by NAD(+) depletion: in response to injury, SARM1 is activated and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage promoting cytoskeletal degradation and axon destruction (PubMed:25908823, PubMed:28334607, PubMed:30333228, PubMed:31128467, PubMed:31439793, PubMed:32049506, PubMed:32828421, PubMed:31439792, PubMed:33053563). Also able to hydrolyze NADP(+), but not other NAD(+)-related molecules (PubMed:29395922). Can activate neuronal cell death in response to stress (PubMed:20306472). Regulates dendritic arborization through the MAPK4-JNK pathway (By similarity). Involved in innate immune response: inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38 (PubMed:16964262).
Phosphorylation at Ser-548 by JNK kinases (MAPK8, MAPK9 and /or MAPK10) enhance the NAD(+) hydrolase (NADase) activity (PubMed:30333228). Phosphorylation at Ser-548 and subsequent activation takes place in response to oxidative stress conditions and inhibits mitochondrial respiration (PubMed:30333228).
Predominantly expressed in brain, kidney and liver. Expressed at lower level in placenta.
The ARM repeats inhibit the NAD(+) hydrolase (NADase) activity by binding to NAD(+): NAD(+)-binding to ARM repeats facilitates inhibition of the TIR domain NADase through their domain interface (PubMed:33053563). In contrast to classical ARM repeats, the last helix of ARM 6 does not fold back to interact with the first two helices, but instead turns towards the N-terminus of SARM1 (PubMed:33053563). As a result, the two following motifs ARM 7 and ARM 8 reverse their directions and lie perpendicularly (PubMed:33053563). Moreover, ARM repeats interact with different domains not only within each protomer but also of the adjacent ones (PubMed:33053563).
The TIR domain mediates NAD(+) hydrolase (NADase) activity (PubMed:28334607). Self-association of TIR domains is required for NADase activity (PubMed:27671644, PubMed:31278906).
Up-regulated by lipopolysaccharides (LPS).
Interacts with IL4R; inhibits IL4 signaling (By similarity). Interacts with EGFR. Interacts with ELOB and ELOC; mediates EGFR ubiquitination and degradation.
Phosphorylated. Phosphorylation is induced by EGF.
SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. May be a substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Inhibits for instance EGF signaling by mediating the degradation of the EGF receptor/EGFR. Involved in the regulation of T-helper cell differentiation by inhibiting of the IL4 signaling pathway which promotes differentiation into the Th2 phenotype. Can also partially inhibit IL6 and LIF signaling.
Adapter molecule functioning in neural development. May regulate SIAH1 activity.
Associates with the SH2 domains of SRC, FYN and ABL (By similarity). Interacts (phosphorylated on tyrosine residues) with CRK and CRKL (via respective SH2 domain) (By similarity). Interacts with SIAH1, LRP8 and VLDLR (By similarity). Interacts with LRP1 (PubMed:15272003). Interacts with APLP1 (via NPXY motif) (By similarity). Interacts with DAB2IP (By similarity).
Phosphorylated on Tyr-198 and Tyr-220 upon reelin induction in embryonic neurons. Also phosphorylated on Ser-524 independently of reelin signaling.
The PID domain specifically binds to the Asn-Pro-Xaa-Tyr(P) motif found in many tyrosine-phosphorylated proteins.
Binds to actin and tropomyosin. Interacts with TRIM63. Interacts with STK4/MST1.
Phosphorylated at Ser-42 and Ser-44 by PRKCE; phosphorylation increases myocardium contractile dysfunction (By similarity). Phosphorylated at Ser-23 and Ser-24 by PRKD1; phosphorylation reduces myofilament calcium sensitivity. Phosphorylated preferentially at Thr-31. Phosphorylation by STK4/MST1 alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T).
Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
Interacts with ATG9A (via C-terminus) (PubMed:32610138, PubMed:33106659, PubMed:33850023). Interacts (via WIPI-interacting region) with WDR45B/WIPI3 (PubMed:32483132). Interacts (via WIPI-interacting region) with WDR45/WIPI4 (PubMed:28820312, PubMed:32483132). Interacts with TMEM41B (PubMed:33850023). Interacts with VMP1 (PubMed:33850023).
Lipid transfer protein involved in autophagosome assembly (PubMed:28561066, PubMed:31271352, PubMed:30952800). Tethers the edge of the isolation membrane (IM) to the endoplasmic reticulum (ER) and mediates direct lipid transfer from ER to IM for IM expansion (PubMed:31271352, PubMed:30952800). Binds to the ER exit site (ERES), which is the membrane source for autophagosome formation, and extracts phospholipids from the membrane source and transfers them to ATG9 (ATG9A or ATG9B) to the IM for membrane expansion (PubMed:31271352, PubMed:30952800). Lipid transfer activity is enhanced by WIPI1 and WDR45/WIPI4, which promote ATG2A-association with phosphatidylinositol 3-monophosphate (PI3P)-containing membranes (PubMed:31271352). Also regulates lipid droplets morphology and distribution within the cell (PubMed:22219374, PubMed:28561066).
The chorein N-terminal domain mediates lipid transfer activity.
At Carnegie stage (CS) 14, widely expressed throughout the telencephalon and mesencephalon, with a sharp cutoff at the midbrain-hindbrain boundary. At CS16, found in the lamina terminalis and the floor of the telencephalon. At CS16-CS19, in the developing eye, strongly expressed in the retinal pigment epithelium layer and more weakly in the neural retina, not expressed in the optic nerve itself (at protein level). Retinal expression peaks between CS19 and CS21 and decline in older fetuses. At CS22, detected in the choroid plexus, the dorsal thalamus, and the roof of the mesencephalon. In the developing nasal structures, expressed in the olfactory epithelium of the nasal pits at CS18.
Transcription factor probably involved in the development of the brain and the sense organs. Can bind to the bicoid/BCD target sequence (BTS): 5'-TCTAATCCC-3'.
Interacts with DCC (via cytoplasmic domain) (By similarity). Interacts (tyrosine phosphorylated form) with PTPN11 (By similarity). Interacts (via extracellular domain) with FLRT3 (via extracellular domain) (By similarity). Interacts (via Ig-like C2-type domain) with DSCAM (via extracellular domain) (PubMed:22685302). Interacts (via death domain) with DAPK1 (PubMed:27068745). Interacts (via cytoplasmic domain) with TUBB3; this interaction is decreased by NTN1/Netrin-1 (PubMed:28483977).
Mainly expressed in brain (PubMed:9782087). Expressed in temporal lobe cortical neurons and in neurons of the hippocampal pyramidal layer (PubMed:25419706). Also expressed in kidney (PubMed:9782087). Not expressed in developing or adult lung (PubMed:9782087).
Phosphorylated on different cytoplasmic tyrosine residues. Phosphorylation of Tyr-568 leads to an interaction with PTPN11 phosphatase, suggesting that its activity is regulated by phosphorylation/dephosphorylation. Tyrosine phosphorylation is netrin-dependent.
Receptor for netrin required for axon guidance (By similarity). Mediates axon repulsion of neuronal growth cones in the developing nervous system upon ligand binding (By similarity). NTN1/Netrin-1 binding might cause dissociation of UNC5C from polymerized TUBB3 in microtubules and thereby lead to increased microtubule dynamics and axon repulsion (PubMed:28483977). Axon repulsion in growth cones may also be caused by its association with DCC that may trigger signaling for repulsion (By similarity). Might also collaborate with DSCAM in NTN1-mediated axon repulsion independently of DCC (By similarity). Also involved in corticospinal tract axon guidance independently of DCC (By similarity). Involved in dorsal root ganglion axon projection towards the spinal cord (PubMed:28483977). It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand (By similarity).
A chromosomal aberration involving ROBO2 is a cause of multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. Translocation t(Y;3)(p11;p12) with PCDH11Y. This translocation disrupts ROBO2 and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro.
Belongs to the immunoglobulin superfamily. ROBO family.
Receptor for SLIT2, and probably SLIT1, which are thought to act as molecular guidance cue in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development.
Required for assembly and function of cilia and flagella.
Highly expressed in spleen, testis and lung, followed by kidney, pancreas, heart, placenta and brain. Also expressed in granulocytes and macrophages.
Inhibits NF-kappa-B by complexing with and trapping it in the cytoplasm. Inhibits DNA-binding of NF-kappa-B p50-p65 and p50-c-Rel complexes.
Interacts with RELA, REL, NFKB1 nuclear factor NF-kappa-B p50 subunit and NFKB2 nuclear factor NF-kappa-B p52 subunit.
Serine phosphorylated; followed by proteasome-dependent degradation.
Brain specific. Expressed at higher levels in astrocytomas as compared to the normal brain tissue.
Lacks editing activity. It prevents the binding of other ADAR enzymes to targets in vitro, and decreases the efficiency of these enzymes. Capable of binding to dsRNA but also to ssRNA.
Interacts with the cytoplasmic part of DUOX1 and DUOX2. Interacts with TPO and CYBA.
May act as a redox regulator involved in DUOX proteins folding. The interaction with DUOX1 and DUOX2 suggest that it belongs to a multiprotein complex constituting the thyroid H(2)O(2) generating system. It is however not sufficient to assist DUOX1 and DUOX2 in H(2)O(2) generation.
Widely expressed at low level. Expressed at higher level in thyroid and prostate.
Auto-ubiquitinated, which results in proteasomal degradation.
E3 ubiquitin-protein ligase that promotes 'Lys-48'-linked ubiquitination of target proteins, leading to their proteasomal degradation (PubMed:15673284). Promotes ubiquitination of DIO2, leading to its degradation (PubMed:19651899). Promotes ubiquitination of SQLE, leading to its degradation (PubMed:24449766). E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. May cooperate with UBE2G1 (PubMed:15673284).
Interacts with DIO2 (PubMed:19651899). Interacts with SQLE (PubMed:24449766).
Belongs to the Ca(2+):cation antiporter (CaCA) (TC 2.A.19) family. SLC8 subfamily.
Calcium transport is down-regulated by Na(+) and stimulated by Ca(2+).
Mediates the electrogenic exchange of Ca(2+) against Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes. Contributes to cellular Ca(2+) homeostasis in excitable cells. Contributes to the rapid decrease of cytoplasmic Ca(2+) levels back to baseline after neuronal activation, and thereby contributes to modulate synaptic plasticity, learning and memory. Plays a role in regulating urinary Ca(2+) and Na(+) excretion.
The cytoplasmic Calx-beta domains bind the regulatory Ca(2+). The first Calx-beta domain can bind up to four Ca(2+) ions. The second domain can bind another two Ca(2+) ions that are essential for calcium-regulated ion exchange.
Highly expressed in brain and in Leydig cells in testis (PubMed:12351693, PubMed:35307651). Localized in nests of Leydig cells (at protein level) (PubMed:12351693). Expressed in choroid plexus (at protein level) (PubMed:18687783). Not strongly enriched in cerebral microvessels (PubMed:18687783).
Mediates the Na(+)-independent high affinity transport of organic anions such as the thyroid hormones L-thyroxine (T4), L-thyroxine sulfate (T4S), and 3,3',5'-triiodo-L-thyronine (reverse T3, rT3) at the plasma membrane (PubMed:12351693, PubMed:18566113, PubMed:19129463). Regulates T4 levels in different brain regions by transporting T4, and also by serving as an export pump for T4S, which is a source of T4 after hydrolysis by local sulfatases (PubMed:18566113). Increases the access of these substrates to the intracellular sites where they are metabolized by the deiodinases (PubMed:18566113). Other potential substrates, such as triiodothyronine (T3), 17-beta-glucuronosyl estradiol (17beta-estradiol 17-O-(beta-D-glucuronate)), estrone-3-sulfate (E1S) and sulfobromophthalein (BSP) are transported with much lower efficiency (PubMed:12351693, PubMed:19129463). Transports T4 and E1S in a pH-insensitive manner (PubMed:19129463). Facilitates the transport of thyroid hormones across the blood-brain barrier and into glia and neuronal cells in the brain (PubMed:30296914).
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1G subfamily.
Highly expressed in brain, in particular in the amygdala, subthalamic nuclei, cerebellum and thalamus. Moderate expression in heart; low expression in placenta, kidney and lung. Also expressed in colon and bone marrow and in tumoral cells to a lesser extent. Highly expressed in fetal brain, but also in peripheral fetal tissues as heart, kidney and lung, suggesting a developmentally regulated expression.
Isoform 4, isoform 7, isoform 18, isoform 19, isoform 24, isoform 25 and isoform 31 are adult-specific. Isoform 8, isoform 14, isoform 15, isoform 16, isoform 17, isoform 20, isoform 21, isoform 22, isoform 23, isoform 26, isoform 27, isoform 28, isoform 29 and isoform 30 are fetal-specific. Isoform 1, isoform 2, isoform 6, isoform 9, isoform 11, isoform 12 and isoform 13 are expressed in both fetus and adult.
The linker region between repeat III and IV probably plays a role in the inactivation of the channel. The C-terminal part may be implicated in the anchoring of the protein to the membrane by interfering with or restricting its lateral diffusion.
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the 'low-voltage activated (LVA)' group and are strongly blocked by mibefradil. A particularity of this type of channel is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes.
Component of the cap-binding complex (CBC), which binds co-transcriptionally to the 5' cap of pre-mRNAs and is involved in various processes such as pre-mRNA splicing, translation regulation, nonsense-mediated mRNA decay, RNA-mediated gene silencing (RNAi) by microRNAs (miRNAs) and mRNA export. The CBC complex is involved in mRNA export from the nucleus via its interaction with ALYREF/THOC4/ALY, leading to the recruitment of the mRNA export machinery to the 5' end of mRNA and to mRNA export in a 5' to 3' direction through the nuclear pore. The CBC complex is also involved in mediating U snRNA and intronless mRNAs export from the nucleus. The CBC complex is essential for a pioneer round of mRNA translation, before steady state translation when the CBC complex is replaced by cytoplasmic cap-binding protein eIF4E. The pioneer round of mRNA translation mediated by the CBC complex plays a central role in nonsense-mediated mRNA decay (NMD), NMD only taking place in mRNAs bound to the CBC complex, but not on eIF4E-bound mRNAs. The CBC complex enhances NMD in mRNAs containing at least one exon-junction complex (EJC) via its interaction with UPF1, promoting the interaction between UPF1 and UPF2. The CBC complex is also involved in 'failsafe' NMD, which is independent of the EJC complex, while it does not participate in Staufen-mediated mRNA decay (SMD). During cell proliferation, the CBC complex is also involved in microRNAs (miRNAs) biogenesis via its interaction with SRRT/ARS2, thereby being required for miRNA-mediated RNA interference. The CBC complex also acts as a negative regulator of PARN, thereby acting as an inhibitor of mRNA deadenylation. In the CBC complex, NCBP2/CBP20 recognizes and binds capped RNAs (m7GpppG-capped RNA) but requires NCBP1/CBP80 to stabilize the movement of its N-terminal loop and lock the CBC into a high affinity cap-binding state with the cap structure. The conventional cap-binding complex with NCBP2 binds both small nuclear RNA (snRNA) and messenger (mRNA) and is involved in their export from the nucleus (PubMed:26382858).
Component of the nuclear cap-binding complex (CBC), a heterodimer composed of NCBP1/CBP80 and NCBP2/CBP20 that interacts with m7GpppG-capped RNA (PubMed:26382858). Found in a U snRNA export complex with PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA. Interacts with PHAX/RNUXA, EIF4G1, HNRNPF, HNRNPH1 and ALYREF/THOC4/ALY. Interacts with SRRT/ARS2 and KPNA3 (PubMed:26382858, PubMed:34564892).
Not up-regulated by unfolded protein response (UPR).
Probable disulfide isomerase, which participates in the folding of proteins containing disulfide bonds. May act as a dithiol oxidase.
Widely expressed. Expressed in brain, testis, lung, skin, kidney, uterus, bone, stomach, liver, prostate, placenta, eye and muscle.
Expressed in fetal liver and kidney, but not in any of the adult tissues examined.
Glycosylated. Can be O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS family members. Can be C-glycosylated with one or two mannose molecules on tryptophan residues within the consensus sequence W-X-X-W of the TPRs. Also N-glycosylated. These other glycosylations can also facilitate secretion.
Metalloprotease which has proteolytic activity against the proteoglycan VCAN, cleaving it at the 'Glu-1428-|-1429-Ala' site. Cleaves VCAN in the pericellular matrix surrounding myoblasts, facilitating myoblast contact and fusion which is required for skeletal muscle development and regeneration.
In cancer cells, plays a role in resistance to the chemotherapeutic agent cisplatin.
Widely expressed with highest levels in pancreas, followed by adrenal gland, thyroid, liver, mammary gland, prostate, kidney, and retina; lowest levels in skeletal muscle. Overexpressed in cisplatin-resistant cancer cells (at protein level).
Component of a PRC1-like complex (PubMed:21282530). Distinct PRC1-like core complexes are composed of a RING1 subunit (RING1B or RING1A), one of the six PCGF proteins (PCGF1-6), one PHC protein (PHC1-3) and one of the CBX proteins (CBX2, CBX4, CBX6, CBX7 or CBX8) (PubMed:21282530). Interacts with PCGF1, PCGF2, PCGF3, BMI1, PCGF5, PCGF6, RING1 and RNF2 (PubMed:21282530, PubMed:18927235). May interact with H3C15 and H3C1 (PubMed:18927235). Interacts (via chromodomain) with single-stranded RNA (ssRNA) (By similarity).
Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development (PubMed:21282530). PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Possibly contributes to the target selectivity of the PRC1 complex by binding specific regions of chromatin (PubMed:18927235). Recruitment to chromatin might occur in an H3K27me3-independent fashion (By similarity). May have a PRC1-independent function in embryonic stem cells (By similarity).
The human orthologuous proteins of Drosophila Polycomb group protein Pc, CBX2, CBX4, CBX6, CBX7 and CBX8, show distinct nuclear localizations, contribute differently to transcriptional repression, and appear to be part of distinct PRC1-like protein complexes.
Ubiquitinated. Ubiquitination regulates the function of the Polycomb group (PcG) multiprotein PRC1-like complex. Deubiquitinated by USP26.
Belongs to the adenylate kinase family. UMP-CMP kinase subfamily.
Catalyzes the phosphorylation of pyrimidine nucleoside monophosphates at the expense of ATP. Plays an important role in de novo pyrimidine nucleotide biosynthesis. Has preference for UMP and CMP as phosphate acceptors. Also displays broad nucleoside diphosphate kinase activity.
May be produced from an in-frame upstream initiation codon. However, experimental evidence indicates that use of the downstream initiation codon is more likely (isoform 1 sequence).
Regulates HCFC1 activity by modulating its subcellular localization. Overexpression of HCFC1R1 leads to accumulation of HCFC1 in the cytoplasm. HCFC1R1-mediated export may provide the pool of cytoplasmic HCFC1 required for import of virion-derived VP16 into the nucleus.
Interacts with CACNA1C. Identified in a complex with the L-type calcium channel subunits CACNA1C, CACNA2D1 and either CACNB1 or CACNB2 (PubMed:21127204). Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs) (PubMed:21172611). Interacts with GRIA1 (PubMed:21172611).
Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit (PubMed:21127204). Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs), including GRIA1 and GRIA4. Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization and by mediating their resensitization (PubMed:21172611).
Anti-terminator protein required to prevent early mRNA termination during transcription (PubMed:31104839). Together with SCAF4, acts by suppressing the use of early, alternative poly(A) sites, thereby preventing the accumulation of non-functional truncated proteins (PubMed:31104839). Mechanistically, associates with the phosphorylated C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit (POLR2A), and subsequently binds nascent RNA upstream of early polyadenylation sites to prevent premature mRNA transcript cleavage and polyadenylation (PubMed:31104839). Independently of SCAF4, also acts as a positive regulator of transcript elongation (PubMed:31104839).
Interacts with POLR2A; via C-terminal heptapeptide repeat domain (CTD) phosphorylated at 'Ser-2' and 'Ser-5' (PubMed:18550522, PubMed:9528809, PubMed:31104839). Identified in a complex with CDC5L and other spliceosomal proteins (PubMed:11101529).
Positive regulator of ferroptosis. Selectively mediates ATG5-dependent autophagosome formation during ferroptosis, rather than during starvation, and regulates the degradation of ferritin, GPX4 and lipid droplets to increase iron accumulation and lipid peroxidation, thereby promoting ferroptotic cell death.
Acetylated on Lys-60, Lys-83 and Lys-145 upon aspirin exposure.
Functions as an endogenous inhibitor of enkephalin-degrading enzymes such as DPP3, and as a selective antagonist of the P2RX3 receptor which is involved in pain signaling, these properties implicate it as a regulator of pain and inflammation.
Genetic variations in HBB are involved in resistance to malaria [MIM:611162]. Hemoglobin S (Hb S), which at homozygosity is responsible for sickle cell anemia, is not associated with any clinical abnormality when heterozygous. At heterozygosity, Hb S confers an increase in protection from life-threatening malaria. Additional variants conferring resistance against severe malaria are hemoglobin C (Hb C) and hemoglobin E (Hb E).
Glucose reacts non-enzymatically with the N-terminus of the beta chain to form a stable ketoamine linkage. This takes place slowly and continuously throughout the 120-day life span of the red blood cell. The rate of glycation is increased in patients with diabetes mellitus.
Heterotetramer of two alpha chains and two beta chains in adult hemoglobin A (HbA). Heterotetramer of two zeta chains and two beta chains in hemoglobin Portland-2, detected in fetuses and neonates with homozygous alpha-thalassemia.
It is unclear if hemoglobin Beckman (Hb Beckman) is defined by p.Ala136Glu or p.Ala136Asp. Hb Beckman has been originally identified by reverse phase-HPLC and tandem mass spectrometry, and has been reported as variant p.Ala136Glu (Ref.140). Subsequently, variant p.Ala136Asp has been reported based on HBB gene complete sequencing results (PubMed:19453576). Variant p.Ala136Asp has also been detected by mass spectrometry (PubMed:26209877). Although the name Hb Beckman is currently used for variant p.Ala136Asp, it cannot be ruled out that Hb Beckman is indeed variant p.Ala136Glu (PubMed:19453576).
LVV-hemorphin-7 potentiates the activity of bradykinin, causing a decrease in blood pressure.
One molecule of 2,3-bisphosphoglycerate can bind to two beta chains per hemoglobin tetramer.
S-nitrosylated; a nitric oxide group is first bound to Fe(2+) and then transferred to Cys-94 to allow capture of O(2).
Can form homodimers, however it is likely to function as a monomer (By similarity). Interacts with NFKB1 (PubMed:11468175, PubMed:12393603). Interacts (via N-terminus) with JUN and FOS; these interactions inhibit the binding of active AP1 to its target DNA (By similarity).
Induced in T-lymphocytes by IL2 deprivation.
Inhibits myogenic differentiation and mediates anti-myogenic effects of glucocorticoids by binding and regulating MYOD1 and HDAC1 transcriptional activity resulting in reduced expression of MYOG.
Interacts with MYOD1 (By similarity). Interacts with HDAC1; this interaction affects HDAC1 activity on MYOG promoter and thus inhibits MYOD1 transcriptional activity (By similarity).
Protects T-cells from IL2 deprivation-induced apoptosis through the inhibition of FOXO3A transcriptional activity that leads to the down-regulation of the pro-apoptotic factor BCL2L11 (PubMed:15031210). In macrophages, plays a role in the anti-inflammatory and immunosuppressive effects of glucocorticoids and IL10 (PubMed:12393603). In T-cells, inhibits anti-CD3-induced NFKB1 nuclear translocation and thereby NFKB1 DNA-binding activities (PubMed:11468175). In vitro, suppresses AP-1 transcription factor complex DNA-binding activities (By similarity).
The leucine-zipper is involved in homodimerization.
Ubiquitously expressed, including in the fetal brain and liver (PubMed:26752201). Expressed in brain, lung, spleen and skeletal muscle (PubMed:11313722, PubMed:12393603). Lower levels detected in heart and kidney (PubMed:11313722, PubMed:12393603). Not detected in the pancreas (PubMed:11313722). In non-lymphoid tissues, in the absence of inflammation, the major source of constitutive expression is the macrophage lineage (PubMed:12393603). Also expressed in cells from different hemopoietic cell lineages, including bone marrow cells, CD34+ stem cells, mature B- and T-cells, monocytes and granulocytes (PubMed:11313722). Down-regulated in activated macrophages from inflammatory lesions of delayed-type hypersensitivity (DTH) reactions, such as in tuberculosis and in Crohn disease, whereas in Burkitt lymphoma, persists in macrophages involved in the phagocytosis of apoptotic malignant cells (PubMed:12393603).
METTL27 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of METTL27 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.
(Microbial infection) Probably cleaved by P.falciparum SERA6; the cleavage results in SPTB solubilization causing the disruption of the actin cytoskeleton and the rupture of the erythrocyte cell membrane releasing the merozoites.
Composed of nonhomologous chains, alpha and beta, which aggregate to form dimers, tetramers, and higher polymers.
Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane. It associates with band 4.1 and actin to form the cytoskeletal superstructure of the erythrocyte plasma membrane.
The first phosphorylation event occurs on Ser-2114, followed by Ser-2125, Ser-2123, Ser-2128, Ser-2117, and Thr-2110.
This complex is anchored to the cytoplasmic face of the plasma membrane via another protein, ankyrin, which binds to beta-spectrin and mediates the binding of the whole complex to a transmembrane protein band 3. The interaction of erythrocyte spectrin with other proteins through specific binding domains lead to the formation of an extensive subplasmalemmal meshwork which is thought to be responsible for the maintenance of the biconcave shape of human erythrocytes, for the regulation of plasma membrane components and for the maintenance of the lipid asymmetry of the plasma membrane.
Homodimer (PubMed:33510867). Forms trimers with the co-SMAD SMAD4 (PubMed:9442019). Interacts with PEBP2-alpha subunit and SMURF1. Interacts with SUV39H1 and SUV39H2. Interacts (via MH2 domain) with LEMD3. Interacts with WWP1. Interacts with TMEM119 (By similarity). Interacts with ZNF8 (PubMed:12370310). Interacts with RANBP3L (PubMed:25755279). Interacts with HK1 (PubMed:28675158). Interacts with HGS; this interaction attenuates BMP signaling (PubMed:16516194).
Transcriptional regulator that plays a role in various cellular processes including embryonic development, cell differentiation, angiogenesis and tissue homeostasis (PubMed:16516194, PubMed:12064918). Upon BMP ligand binding to their receptors at the cell surface, is phosphorylated by activated type I BMP receptors (BMPRIs) and associates with SMAD4 to form an heteromeric complex which translocates into the nucleus acting as transcription factor (PubMed:9442019). In turn, the hetero-trimeric complex recognizes cis-regulatory elements containing Smad Binding Elements (SBEs) to modulate the outcome of the signaling network (PubMed:33510867). Non-phosphorylated SMAD5 has a cytoplasmic role in energy metabolism regulation by promoting mitochondrial respiration and glycolysis in response to cytoplasmic pH changes (PubMed:28675158). Mechanistically, interacts with hexokinase 1/HK1 and thereby accelerates glycolysis (PubMed:28675158).
Ubiquitin-mediated proteolysis by SMAD-specific E3 ubiquitin ligase SMURF1.
Forms a soluble 1:1 complex with AFM; this prevents oligomerization and is required for prolonged biological activity (PubMed:26902720). The complex with AFM may represent the physiological form in body fluids (PubMed:26902720). Component of the Wnt-Fzd-LRP5-LRP6 signaling complex that contains a WNT protein, a FZD protein and LRP5 or LRP6. Interacts directly in the complex with LRP6 (PubMed:20093360). Interacts with PKD1 (via extracellular domain) (PubMed:27214281).
Ligand for members of the frizzled family of seven transmembrane receptors (Probable). Functions in the canonical Wnt/beta-catenin signaling pathway. Required for normal embryonic kidney development, and for normal development of the urogenital tract, including uterus and part of the oviduct and the upper vagina in females, and epididymis and vas deferens in males. Activates a signaling cascade in the metanephric mesenchyme that induces tubulogenesis. Acts upstream of WNT4 in the signaling pathways that mediate development of kidney tubules and the Muellerian ducts. Plays a role in cranofacial development and is required for normal fusion of the palate during embryonic development (By similarity).
Moderately expressed in fetal kidney and adult kidney. Also found in brain.
Adopts an atypical protein kinase-like fold: while it adopts a core fold similar to that of well-characterized protein kinase-like domains. The KxGQ motif completely occludes the typical substrate binding pocket. Nucleotide-binding opens the substrate binding pocket and flips the active site from inside the hydrophobic core into a catalytically competent, solvent-exposed posture.
Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration (PubMed:24270420). Its substrate specificity is unclear: does not show any protein kinase activity. Probably acts as a small molecule kinase, possibly a lipid kinase that phosphorylates a prenyl lipid in the ubiquinone biosynthesis pathway. Required for podocyte migration (PubMed:24270420).
Autoinhibited by the N-terminal domain, containing the KxGQ motif, that completely occludes the typical substrate binding pocket. Nucleotide-binding relieves inhibition.
Homodimer; homodimerizes via its transmembrane region (PubMed:25216398). Interacts with COQ6 and COQ7 (PubMed:24270420). Interacts with the multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9 (PubMed:27499296).
Widely expressed, including renal podocytes.
Adopts an immunoglobulin-like beta-sandwich fold forming a hydrophobic cavity that capture N-terminally myristoylated target peptides. Phe residues within the hydrophobic beta sandwich are required for myristate binding (PubMed:22085962).
Found in a complex with ARL3, RP2 and UNC119B; RP2 induces hydrolysis of GTP ARL3 in the complex, leading to the release of UNC119B. Interacts with NPHP3 (when myristoylated). Interacts with CYS1 (when myristoylated). Interacts with MACIR; interaction only takes place when UNC119B is not liganded with myristoylated proteins.
Myristoyl-binding protein that acts as a cargo adapter: specifically binds the myristoyl moiety of a subset of N-terminally myristoylated proteins and is required for their localization. Binds myristoylated NPHP3 and plays a key role in localization of NPHP3 to the primary cilium membrane. Does not bind all myristoylated proteins. Probably plays a role in trafficking proteins in photoreceptor cells.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class 4 subfamily.
Differentially dephosphorylate autophosphorylated tyrosine kinases which are known to be overexpressed in tumor tissues.
Expressed in brain, colon and several tumor-derived cell lines.
Expressed in submandibular and sublingual saliva but not in parotid saliva (at protein level). Expressed in submandibular gland and parotid gland.
Highest levels of expression in the pancreas, thymus, testis, spleen, liver, placenta and leukocytes. Relatively low levels in the lung, kidney, prostate, ovary, small intestine and colon. Hardly detectable, if at all, in the brain, skeletal muscle and heart.
May participate in the regulation of cell proliferation through the E2F/RB pathway. May be involved in molecular regulation of hematopoietic stem cells and progenitor cell lineage commitment and differentiation (By similarity).
CRNN expression is increased in psoriasis patients suggesting a potential role in disease pathogenesis.
Expressed in the basal skin layer (at protein level) (PubMed:30009832). Squamous epithelia cell-specific. Expressed in the esophagus (periphery of the cells of the granular and the upper spinous layers), foreskin (granular and lower cornified cells), scalp skin (granular layer), inner root sheath of the hair follicle and in primary keratinocytes (at protein level). Expressed in the squamous epithelium of the cervix, esophagus, foreskin and larynx. Expressed in the fetal bladder and scalp skin. Expressed at very low levels in the lung, kidney, uterus, skeletal muscle, heart and fetal brain. Undetectable or barely detectable in esophageal and oral squamous cell carcinoma compared with the matched adjacent normal esophageal mucosa. Undetectable or barely detectable in larynx and esophagus from patients with pH-documented laryngopharyngeal reflux (LPR).
Promotes cell proliferation, G1/S cell cycle progression and induces expression of the cell cycle regulator CCND1 (PubMed:30009832). Regulates proliferation induced by pro-inflammatory cytokine response via activation of NFKB1 and PI3K/AKT signaling pathways (PubMed:30009832).
The EF-hand is necessary for the colony survival activity to protect cells from death induced by exposure to DCA.
Up-regulated after heat shock, ponasterone A and deoxycholic acid (PubMed:15896671, PubMed:16640557). Induced in response to pro-inflammatory cytokines (PubMed:30009832).
Citrullination at Arg-55 (H1R54ci) by PADI4 takes place within the DNA-binding site of H1 and results in its displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance.
Belongs to the peptidase C19 family. USP3 subfamily.
Both protease activity and an intact zinc finger are required for H2A monodeubiquitination.
Expressed in all tissues examined, with strongest expression in pancreas.
Hydrolase that deubiquitinates monoubiquitinated target proteins such as histone H2A and H2B. Required for proper progression through S phase and subsequent mitotic entry. May regulate the DNA damage response (DDR) checkpoint through deubiquitination of H2A at DNA damage sites. Associates with the chromatin.
Interacts (via UBP-type domain) with H2A; the interaction is less efficient than with monoubiquitinated H2A.
Made in the liver and heart and secreted into the plasma. It is also found in the kidney.
Might be responsible for some of the extracellular antioxidant defense properties of selenium or might be involved in the transport of selenium. May supply selenium to tissues such as brain and testis.
Phosphorylation sites are present in the extracellular medium.
The C-terminus is not required for endocytic uptake in the proximal tubule epithelium.
By retinoic acid. This induction requires functional NFKB pathway.
Elevated expression during the early S phase of the cell cycle, followed by a gradual decrease during late S phase.
Expressed during myeloid lineage development. Much higher expression in bone marrow neutrophils than in peripheral blood neutrophils (at protein level). Strongly expressed in the prostate, small intestine and colon and moderately expressed in the bone marrow and stomach. Overexpressed in some pancreatic cancer tissues.
Homomultimer; disulfide-linked. Interacts with NDUFA13. Interacts with cell surface lectins (locutions ricinus communis agglutinin I, concanavalin-A and wheat germ agglutinin) and cadherin.
May promote proliferation of pancreatic cancer cells by favoring the transition from the S to G2/M phase. In myeloid leukemic cell lines, inhibits cell growth and induces cell differentiation and apoptosis. May play a role in the inhibition of EIF4EBP1 phosphorylation/deactivation. Facilitates cell adhesion, most probably through interaction with cell surface lectins and cadherin.
The olfactomedin-like domain is involved in the interaction with cadherin.
Catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) to phosphatidylinositol-4-phosphate (PtdIns-4-P) (PubMed:16365287). Does not hydrolyze phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-bisphosphate, inositol 3,5-bisphosphate, inositol 3,4-bisphosphate, phosphatidylinositol 5-monophosphate, phosphatidylinositol 4-monophosphate and phosphatidylinositol 3-monophosphate (PubMed:16365287). Regulates lysosomal positioning by recruiting JIP4 to lysosomal membranes, thus inducing retrograde transport of lysosomes along microtubules (PubMed:29146937). Contributes to assembly of the V-ATPase complex in lipid rafts of the lysosomal membrane and to subsequent amino acid-dependent activation of mTORC1 (PubMed:29644770). May play a role in the regulation of cellular cholesterol metabolism (PubMed:25035345).
Interacts (via transmembrane domain) with ATP6V0D1 (PubMed:29644770). Interacts with LAMTOR1 (PubMed:29644770). Interacts with RRAGA and RRAGC (By similarity).
A chromosomal aberration involving CDH15 and KIRREL3 is found in a patient with severe intellectual disability and dysmorphic facial features. Translocation t(11;16)(q24.2;q24).
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. M-cadherin is part of the myogenic program and may provide a trigger for terminal muscle differentiation.
Binds (via the PDZ domain) to isoform 2A of SYNJ2 (via the unique motif in the C-terminus) (By similarity). Interacts (via C-terminus) with RALBP1. Interacts (via PDZ domain) with ACVR2A (via C-terminus) and ACVR2B (via C-terminus). Forms a ternary complex with ACVR2A and RALBP1 (By similarity). Interacts with MAPK12 (By similarity). Interacts with DLL1; enhances DLL1 protein stability, and promotes notch signaling in endothelial cells (PubMed:24025447).
Regulates endocytosis of activin type 2 receptor kinases through the Ral/RALBP1-dependent pathway and may be involved in suppression of activin-induced signal transduction.
Belongs to the PIEZO (TC 1.A.75) family.
Component of a mechanosensitive channel required for rapidly adapting mechanically activated (MA) currents. Required for Merkel-cell mechanotransduction. Plays a major role in light-touch mechanosensation.
Contaminating sequence at the 3'end. Probable cloning artifact.
Homooligomer, most likely homotetramer. Interacts with STOML3.
Piezo comes from the Greek 'piesi' meaning pressure.
Expressed in skeletal muscle, colon and kidney. Lower levels in the testis, prostate, ovary, and small intestine (PubMed:10444453, PubMed:8843774). In the distal colon, expressed along the cryptal axis (PubMed:8843774).
Plasma membrane Na(+)/H(+) antiporter. Mediates the electroneutral exchange of intracellular H(+) ions for extracellular Na(+) (PubMed:10444453). Major apical Na(+)/H(+) exchanger in the base of the colonic crypt. Controls in the colonic crypt intracellular pH (pHi) to direct colonic epithelial cell differentiation into the absorptive enterocyte lineage at the expense of the secretory lineage (By similarity).
The number, localization and denomination of hydrophobic domains in the Na(+)/H(+) exchangers vary among authors.
Acts as an acyl-protein thioesterase that hydrolyzes fatty acids from acylated residues in proteins (PubMed:31740833). Regulates the mitochondrial S-depalmitoylation of the nucleophilic active site residue of peroxiredoxin-5/PRDX5, a key antioxidant protein, therefore modulating mitochondrial antioxidant ability (PubMed:31740833). Also catalyzes the deglucuronidation of mycophenolic acid acyl-glucuronide, an active metabolite of the immunosuppressant drug mycophenolate (PubMed:22294686).
Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines.
Expressed in adult skeletal muscle and fetal heart.
Interacts with TTN/titin, NEB, NEBL, ACTN2 and CARP.
Carboxypeptidase that catalyzes the release of a C-terminal amino acid, but has little or no action with -Asp, -Glu, -Arg, -Lys or -Pro (PubMed:8806703). Catalyzes the conversion of leukotriene C4 to leukotriene F4 via the hydrolysis of an amide bond (By similarity).
Monomer. May form a complex with proelastase 2.
Cell surface glycoprotein serine protease that participates in extracellular matrix degradation and involved in many cellular processes including tissue remodeling, fibrosis, wound healing, inflammation and tumor growth. Both plasma membrane and soluble forms exhibit post-proline cleaving endopeptidase activity, with a marked preference for Ala/Ser-Gly-Pro-Ser/Asn/Ala consensus sequences, on substrate such as alpha-2-antiplasmin SERPINF2 and SPRY2 (PubMed:14751930, PubMed:16223769, PubMed:16480718, PubMed:16410248, PubMed:17381073, PubMed:18095711, PubMed:21288888, PubMed:24371721). Degrade also gelatin, heat-denatured type I collagen, but not native collagen type I and IV, vitronectin, tenascin, laminin, fibronectin, fibrin or casein (PubMed:9065413, PubMed:2172980, PubMed:7923219, PubMed:10347120, PubMed:10455171, PubMed:12376466, PubMed:16223769, PubMed:16651416, PubMed:18095711). Also has dipeptidyl peptidase activity, exhibiting the ability to hydrolyze the prolyl bond two residues from the N-terminus of synthetic dipeptide substrates provided that the penultimate residue is proline, with a preference for Ala-Pro, Ile-Pro, Gly-Pro, Arg-Pro and Pro-Pro (PubMed:10347120, PubMed:10593948, PubMed:16175601, PubMed:16223769, PubMed:16651416, PubMed:16410248, PubMed:17381073, PubMed:21314817, PubMed:24371721, PubMed:24717288). Natural neuropeptide hormones for dipeptidyl peptidase are the neuropeptide Y (NPY), peptide YY (PYY), substance P (TAC1) and brain natriuretic peptide 32 (NPPB) (PubMed:21314817). The plasma membrane form, in association with either DPP4, PLAUR or integrins, is involved in the pericellular proteolysis of the extracellular matrix (ECM), and hence promotes cell adhesion, migration and invasion through the ECM. Plays a role in tissue remodeling during development and wound healing. Participates in the cell invasiveness towards the ECM in malignant melanoma cancers. Enhances tumor growth progression by increasing angiogenesis, collagen fiber degradation and apoptosis and by reducing antitumor response of the immune system. Promotes glioma cell invasion through the brain parenchyma by degrading the proteoglycan brevican. Acts as a tumor suppressor in melanocytic cells through regulation of cell proliferation and survival in a serine protease activity-independent manner.
Expressed in adipose tissue. Expressed in the dermal fibroblasts in the fetal skin. Expressed in the granulation tissue of healing wounds and on reactive stromal fibroblast in epithelial cancers. Expressed in activated fibroblast-like synoviocytes from inflamed synovial tissues. Expressed in activated hepatic stellate cells (HSC) and myofibroblasts from cirrhotic liver, but not detected in normal liver. Expressed in glioma cells (at protein level). Expressed in glioblastomas and glioma cells. Isoform 1 and isoform 2 are expressed in melanoma, carcinoma and fibroblast cell lines.
Gelatinase activity is inhibited by serine-protease inhibitors, such as phenylmethylsulfonyl fluoride (PMSF), 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride (AEBSF), 4-amidino phenylsulfonyl fluoride (APSF) and diisopropyl fluorophosphate (DFP), N-ethylmaleimide (NEM) and phenylmethylsulfonyl fluoride (PMSF). Dipeptidyl peptidase activity is inhibited by 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid), diisopropylfluorophosphate (DFP). Prolyl endopeptidase activity is inhibited by the boronic acid peptide Ac-Gly-BoroPro, Ac-Gly-Pro-chloromethyl ketone and Thr-Ser-Gly-chloromethyl ketone.
Homodimer; homodimerization is required for activity of both plasma membrane and soluble forms. The monomer is inactive. Heterodimer with DPP4. Interacts with PLAUR; the interaction occurs at the cell surface of invadopodia membranes. Interacts with ITGB1. Interacts with ITGA3. Associates with integrin alpha-3/beta-1; the association occurs in a collagen-dependent manner at the cell surface of invadopodia membranes.
In fibroblasts at times and sites of tissue remodeling during development, tissue repair and carcinogenesis. Up-regulated upon tumor stem cell differentiation. Up-regulated by transforming growth factor-beta, 12-O-tetradecanoyl phorbol-13-acetate and retinoids.
Upstream open reading frames ORF(s)-containing region inhibits the translation of its downstream ORF.
Exhibits low nucleotide-independent RAB35-binding activity. Interacts with clathrin heavy chain/CLTC and with AP2A2, but not with AP2B1.
Guanine nucleotide exchange factor (GEF) which may activate RAB8A, RAB13 and RAB35. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form.
A chromosomal aberration involving RAP1GDS1 has been found in M0 type acute myeloid leukemia. Translocation (t4;11)(q23;p15) with NUP98.
A chromosomal aberration involving RAP1GDS1 has been found in T-cell acute lymphocytic leukemia. Translocation t(4;11)(q23;p15) with NUP98.
Acts as a GEF (guanine nucleotide exchange factor) for prenylated RHOA (PubMed:28630045, PubMed:30190425, PubMed:21242305). Acts as a GEF for RHOC (PubMed:21242305). Chaperones the downstream trafficking and/or processing of small newly prenylated GTPases (PubMed:20709748). Escorts RAC1 to the nucleus (PubMed:12551911).
Acts as a GEF (guanine nucleotide exchange factor) for the Rho family of small GTP-binding proteins (G proteins) that stimulates the dissociation of GDP to enable subsequent binding of GTP (PubMed:28630045, PubMed:30190425, PubMed:1549351, PubMed:11948427, PubMed:20709748). Additionally, appears to chaperone the processing and/or trafficking of small GTPases containing a C-terminal polybasic region independently of GEF activity (PubMed:20709748, PubMed:21242305). Targets include RAP1A/RAP1B, RHOA, RHOB, RHOC, RAC1 and KRAS (PubMed:1549351, PubMed:11948427, PubMed:20709748, PubMed:24415755). Regulates mitochondrial dynamics by controlling RHOT function to promote mitochondrial fission during high calcium conditions (PubMed:27716788). Able to promote the Ca(2+) release from the endoplasmic reticulum via both inositol trisphosphate (Ins3P) and ryanodine sensitive receptors leading to a enhanced mitochondrial Ca(2+) uptake (PubMed:24349085).
Acts as a GEF (guanine nucleotide exchange factor) for unprenylated RHOA (PubMed:30190425, PubMed:28630045, PubMed:24415755). Chaperones the entry and passage of small GTPases through the prenylation pathway (PubMed:20709748). Recognizes the last amino acid in the GTPase C-terminal CAAX motif with a preference for 'Leu' over 'Met', indicating involvement in the geranylgeranylation pathway (PubMed:24415755).
Interacts with RABL3 (PubMed:31406347). Interacts with RHOT1 (PubMed:27716788).
Interacts with prenylated RHOA; the interaction is direct and in a 1:1 stoichiometry (PubMed:28630045, PubMed:30190425, PubMed:20709748, PubMed:12551911). Interacts with RAP1A (PubMed:20709748). Interacts with KRAS (PubMed:20709748, PubMed:24415755). Interacts with RAC1 (PubMed:20709748, PubMed:12551911). Interacts with RAP1B (PubMed:24415755). Preferentially interacts with prenylated GTPases (PubMed:24415755).
Interacts with unprenylated RHOA; the interaction is direct (PubMed:28630045, PubMed:30190425, PubMed:20709748). Interacts with RAP1A (PubMed:20709748). Interacts with KRAS (PubMed:20709748, PubMed:24415755). Interacts with RAC1 (PubMed:20709748). Interacts with RAP1B (PubMed:24415755). Preferentially interacts with unprenylated GTPases that will become geranylgeranylated (PubMed:24415755). May also interact with prenylated GTPases (PubMed:24415755).
Expressed in a variety of fetal and adult organs including brain, lung and kidney. Its expression was greatly reduced in small and non-small cell lung carcinoma. Isoform 1 is predominantly expressed in brain.
In the PI-PLC X-box Asn-458 is present instead of the conserved His which is one of the active site residues. It is therefore expected that this protein lacks catalytic activity.
Interacts with PPP2CA (By similarity). Interacts with Ins(1,4,5)P3, Ins(1,4,5,6)P4, GABARAP, GABA receptor beta subunits, GABA receptor gamma-2 subunits and PPP1C. May form a ternary complex with GABA receptor beta subunit and GABARAP. The formation of a ternary complex with GABA receptor beta subunit and GABARAP could be the key step for facilitating the association of GABARAP with the GABA receptor gamma-2 subunit and to allow it to be transported at the right destination.
Involved in an inositol phospholipid-based intracellular signaling cascade. Shows no PLC activity to phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol. Component in the phospho-dependent endocytosis process of GABA A receptor (By similarity). Regulates the turnover of receptors and thus contributes to the maintenance of GABA-mediated synaptic inhibition. Its aberrant expression could contribute to the genesis and progression of lung carcinoma. Acts as an inhibitor of PPP1C.
Phosphorylated by the catalytic subunit of PKA. Phosphorylation of Thr-93 resulted in dissociation of PPP1C from PRIP1 (By similarity).
Promotes neurite outgrowth and blocks myelin inhibition in neurons (By similarity). Receptor with constitutive G(s) signaling activity that stimulates cyclic AMP production.
Was originally (PubMed:12220620) thought to be a receptor for sphingosine 1-phosphate. It has been demonstrated that it is not the case in human (PubMed:19286662).
Consists of nine domains. Domain 1 contains two EF-hand calcium-binding domains. Domains 2-4, 6, and 8 are almost entirely alpha-helical, configured as a series of peptide repeats of varying regularity, and are thought to form a single-stranded alpha-helical rod stabilized by ionic interactions. Domain 6 is the most regular and may bind KIF directly by ionic interactions. Domains 5 and 7 are less well organized and may induce folds in the molecule. Domain 9 contains the C-terminus, conserved among different species.
Expressed during late differentiation of the epidermis.
Found in the hard keratinizing tissues such as the inner root sheath (IRS) of hair follicles and medulla, and in the filiform papillae of dorsal tongue epithelium.
Intermediate filament-associated protein that associates in regular arrays with keratin intermediate filaments (KIF) of the inner root sheath cells of the hair follicle and the granular layer of the epidermis. It later becomes cross-linked to KIF by isodipeptide bonds. It may serve as scaffold protein, together with involucrin, in the organization of the cell envelope or even anchor the cell envelope to the KIF network. It may be involved in its own calcium-dependent postsynthetic processing during terminal differentiation.
Substrate of transglutaminase. Some 200 arginines are probably converted to citrullines by peptidylarginine deimidase.
Defects in PPP1R15B has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea.
Maintains low levels of EIF2S1 phosphorylation in unstressed cells by promoting its dephosphorylation by PP1.
Part of a complex containing PPP1R15B, PP1 and NCK1/2 (By similarity). Interacts with PP1.
The phosphatase activity of the PPP1R15B-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.
Activator of LATS1/2 in the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. Stimulates the kinase activity of STK38 and STK38L. Acts cooperatively with STK3/MST2 to activate STK38.
Adrenal gland, bone marrow, brain, placenta, prostate, salivary gland, skeletal muscle, testis, thymus, thyroid gland, heart, spinal cord, fetal brain and fetal liver.
Binds STK38 and STK38L. Interacts with LATS1 and LATS2. Forms a tripartite complex with STK38 and STK3/MST2.
Phosphorylated by STK3/MST2 and STK4/MST1 and this phosphorylation enhances its binding to LATS1.
Belongs to the spermidine/spermine synthase family.
Catalyzes the production of spermine from spermidine and decarboxylated S-adenosylmethionine (dcSAM).
Composed of 3 domains: the N-terminal domain has structural similarity to S-adenosylmethionine decarboxylase, the central domain is made up of four beta strands and the C-terminal domain is similar in structure to spermidine synthase. The N- and C-terminal domains are both required for activity.
Homodimer. Dimerization is mediated through the N-terminal domain and seems to be required for activity as deletion of the N-terminal domain causes complete loss of activity.
Belongs to the RNA polymerase beta' chain family.
Component of the RNA polymerase I (Pol I) complex consisting of at least 13 subunits (PubMed:16809778). Interacts with MYO1C (By similarity). Interacts with ERBB2 (PubMed:21555369). Interacts with DDX11 (PubMed:26089203). Interacts with RECQL5 (PubMed:27502483).
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Largest and catalytic core component of RNA polymerase I which synthesizes ribosomal RNA precursors. Forms the polymerase active center together with the second largest subunit. A single stranded DNA template strand of the promoter is positioned within the central active site cleft of Pol I. A bridging helix emanates from RPA1 and crosses the cleft near the catalytic site and is thought to promote translocation of Pol I by acting as a ratchet that moves the RNA-DNA hybrid through the active site by switching from straight to bent conformations at each step of nucleotide addition (By similarity).
Highly expressed in colon, kidney, prostate, intestine and activated lymphocytes. Expressed at much higher levels in the renal cell cancers than in surrounding normal kidney tissue. Moderately expressed in pancreas, ovary and testis. Expressed in sweat glands and bronchiolar epithelium (PubMed:26911677).
Inhibited by coumarins, saccharin, sulfonamide derivatives such as acetazolamide (AZA), benzenesulfonamide and derivatives (4-carboxyethylbenzene-sulfonamide, 4-carboxyethylbenzene-sulfonamide ethyl ester, 4-(acetyl-2-aminoethyl)benzene-sulfonamide, 4-aminoethylbenzene-sulfonamide) and Foscarnet (phosphonoformate trisodium salt).
Enriched in immune tissues, such as lymph nodes, B-lymphocytes, monocytes and spleen.
Mediates the voltage-dependent proton permeability of excitable membranes. Forms a proton-selective channel through which protons may pass in accordance with their electrochemical gradient. Proton efflux, accompanied by membrane depolarization, facilitates acute production of reactive oxygen species in phagocytosis.
Phosphorylation may enhance channel gating.
The C-terminal coiled coil region mediates homodimerization and cooperative channel gating. It is essential for normal subcellular localization.
The dimers display cooperative channel gating (By similarity). The channel activity is inhibited by zinc ions.
The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino acids at every third position. Unlike other voltage-gated ion channels it lacks the pore domain.
(Microbial infection) Stearoylated By S.flexneri N-epsilon-fatty acyltransferase IcsB, thereby disrupting the host actin cytoskeleton.
Forms a SNARE complex composed of VAMP8, SNAP29 and STX17 involved in fusion of autophagosome with lysosome (PubMed:25686604). Found in a number of SNARE complexes with NAPA, SNAP23, SNAP25, STX1A, STX4, STX7, STX8 and VTI1B (PubMed:12130530). Interacts with PICALM (By similarity). SNARE complex formation and binding by PICALM are mutually exclusive processes for VAMP8 (By similarity). Interacts with SBF2/MTMR13 (PubMed:25648148). Interacts with RAB21 (in GTP-bound form) in response to starvation; the interaction probably regulates VAMP8 endolysosomal trafficking (PubMed:25648148). Interacts with STX17; this interaction is increased in the absence of TMEM39A (PubMed:31806350, PubMed:33422265). Interacts with TRIM6 (PubMed:31694946).
SNAREs, soluble N-ethylmaleimide-sensitive factor-attachment protein receptors, are essential proteins for fusion of cellular membranes. SNAREs localized on opposing membranes assemble to form a trans-SNARE complex, an extended, parallel four alpha-helical bundle that drives membrane fusion. VAMP8 is a SNARE involved in autophagy through the direct control of autophagosome membrane fusion with the lysososome membrane via its interaction with the STX17-SNAP29 binary t-SNARE complex (PubMed:23217709, PubMed:25686604). Also required for dense-granule secretion in platelets (PubMed:12130530). Also plays a role in regulated enzyme secretion in pancreatic acinar cells (By similarity). Involved in the abscission of the midbody during cell division, which leads to completely separate daughter cells (By similarity). Involved in the homotypic fusion of early and late endosomes (By similarity). Participates also in the activation of type I interferon antiviral response through a TRIM6-dependent mechanism (PubMed:31694946).
Acts as a mitochondrial iron-sulfur (Fe-S) cluster assembly factor that facilitates (Fe-S) cluster insertion into a subset of mitochondrial proteins (By similarity). Probably acts together with the monothiol glutaredoxin GLRX5 (PubMed:27532772). May protect cells against oxidative stress (PubMed:22746225).
Interacts with GLRX5 (PubMed:22746225, PubMed:27532773, PubMed:27532772).
Was initially reported to be secreted via a non-classical export pathway (PubMed:18548201). It was however later shown that it localizes to mitochondria, in agreement with other members of the family (PubMed:22746225).
A number of inactive tetrameric holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits.
Phosphorylates a large number of substrates in the cytoplasm and the nucleus.
Testis specific. But important tissues such as brain and ovary have not been analyzed for the content of transcript.
(Microbial infection) Interacts (via C-terminus) with Epstein-Barr virus lytic switch protein BZLF1 (via C-terminus); this interaction is involved in the activation of the viral lytic cycle.
A chromosomal aberration involving TP53BP1 is found in a form of myeloproliferative disorder chronic with eosinophilia. Translocation t(5;15)(q33;q22) with PDGFRB creating a TP53BP1-PDGFRB fusion protein.
Asymmetrically dimethylated on Arg residues by PRMT1. Methylation is required for DNA binding.
Double-strand break (DSB) repair protein involved in response to DNA damage, telomere dynamics and class-switch recombination (CSR) during antibody genesis (PubMed:12364621, PubMed:22553214, PubMed:23333306, PubMed:17190600, PubMed:21144835, PubMed:27153538, PubMed:28241136). Plays a key role in the repair of double-strand DNA breaks (DSBs) in response to DNA damage by promoting non-homologous end joining (NHEJ)-mediated repair of DSBs and specifically counteracting the function of the homologous recombination (HR) repair protein BRCA1 (PubMed:22553214, PubMed:23727112, PubMed:23333306, PubMed:27153538). In response to DSBs, phosphorylation by ATM promotes interaction with RIF1 and dissociation from NUDT16L1/TIRR, leading to recruitment to DSBs sites (PubMed:28241136). Recruited to DSBs sites by recognizing and binding histone H2A monoubiquitinated at 'Lys-15' (H2AK15Ub) and histone H4 dimethylated at 'Lys-20' (H4K20me2), two histone marks that are present at DSBs sites (PubMed:23760478, PubMed:27153538, PubMed:28241136, PubMed:17190600). Required for immunoglobulin class-switch recombination (CSR) during antibody genesis, a process that involves the generation of DNA DSBs (PubMed:23345425). Participates in the repair and the orientation of the broken DNA ends during CSR (By similarity). In contrast, it is not required for classic NHEJ and V(D)J recombination (By similarity). Promotes NHEJ of dysfunctional telomeres via interaction with PAXIP1 (PubMed:23727112).
Homoligomer (PubMed:16294047, PubMed:23760478, PubMed:23345425). Interacts with p53/TP53 (via the central domain) (PubMed:12110597, PubMed:11877378). Interacts with DCLRE1C (PubMed:15574327). Interacts with histone H2AX and this requires phosphorylation of H2AX on 'Ser-139' (PubMed:12607005). Interacts with histone H4 that has been dimethylated at 'Lys-20' (H4K20me2) (PubMed:17190600). Has low affinity for histone H4 containing monomethylated 'Lys-20' (H4K20me1) (PubMed:17190600). Does not bind histone H4 containing unmethylated or trimethylated 'Lys-20' (H4K20me3) (PubMed:17190600). Has low affinity for histone H3 that has been dimethylated on 'Lys-79' (PubMed:15525939). Has very low affinity for histone H3 that has been monomethylated on 'Lys-79' (in vitro) (PubMed:15525939). Does not bind unmethylated histone H3 (PubMed:15525939). Interacts with histone H2A monoubiquitinated at 'Lys-15' (H2AK15Ub) (PubMed:23760478). Interacts with PWWP3A/EXPAND1 (PubMed:20347427). Interacts with CHEK2; modulates CHEK2 phosphorylation at 'Thr-68' in response to infrared (PubMed:12364621). Interacts with MSL1; this interaction may be required for MSL1 DNA repair activity, but not for histone acetyltransferase activity (PubMed:19650074). Interacts (when phosphorylated by ATM) with RIF1 (PubMed:23727112, PubMed:23333306, PubMed:28241136). Interacts (via the Tudor-like domain) with NUDT16L1/TIRR; interaction masks the Tudor-like domain and prevents recruitment to chromatin (PubMed:28241136). Interacts with PAXIP1 (PubMed:23727112). Interacts with SHLD2 (PubMed:29789392).
Phosphorylated at basal level in the absence of DNA damage (PubMed:11042216, PubMed:11331310). Phosphorylated by ATM in response to DNA damage: phosphorylation at different sites promotes interaction with different set of proteins: phosphorylation at the N-terminus by ATM (residues from 6-178) promotes interaction with PAXIP1 and non-homologous end joining (NHEJ) of dysfunctional telomeres (PubMed:23727112). Phosphorylation by ATM at residues that are located more C-terminus (residues 300-650) leads to promote interaction with RIF1 (PubMed:23727112, PubMed:23333306, PubMed:28241136). Interaction with RIF1 leads to disrupt interaction with NUDT16L1/TIRR (PubMed:28241136). Phosphorylation at Thr-1609 and Ser-1618 in the UDR motif blocks interaction with H2AK15ub (PubMed:24703952). Dephosphorylated by PPP4C (PubMed:24703952). Hyperphosphorylation during mitosis correlates with its exclusion from chromatin and DNA lesions. Hyperphosphorylated in an ATR-dependent manner in response to DNA damage induced by UV irradiation (PubMed:17553757, PubMed:21144835). Dephosphorylated by PPP5C (PubMed:19176521).
The Tudor-like region mediates binding to histone H4 dimethylated at 'Lys-20' (H4K20me2) (PubMed:17190600). Interaction with NUDT16L1/TIRR masks the Tudor-like domain and prevents recruitment to chromatin (PubMed:28241136).
The UDR (ubiquitin-dependent recruitment) motif specifically recognizes and binds histone H2A monoubiquitinated at 'Lys-15' (H2AK15ub) (PubMed:23760478, PubMed:24703952). Phosphorylation of the UDR blocks interaction with H2AK15ub (PubMed:24703952).
Interacts with PTPN11. Isoform 2 interacts with HIV-1 VPR. Interacts with NOD2 (PubMed:27812135).
May play a role as a scaffolding protein that may be associated with the abnormal phenotype of leukemia cells. Isoform 2 may possess an antiapoptotic effect and protect cells during normal cell survival through its regulation of caspases.
Ubiquitous with high expression in cervix, spleen and brain. Expressed in hematopoietic cells with increased expression in leukemia cells. Isoform 2 is highly expressed in spleen with almost no expression in muscle and brain.
Ablation of expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression.
Belongs to the adenosylhomocysteinase family.
Expression increases markedly during activation of blood and skin DC (Langerhans cells), but is diminished in terminally differentiated tonsil DC.
Forms multimers (PubMed:16793548). Forms heteromultimers with AHCYL2 (via the C-terminal region) (PubMed:19220705). Interacts (when phosphorylated) with ITPR1 (when not phosphorylated); the interaction suppresses inositol 1,4,5-trisphosphate binding to ITPR1 (PubMed:16793548, PubMed:27995898). Interacts with BCL2L10; this strengthens the interaction of AHCYL1 with ITPR1 (PubMed:27995898). Interacts with CFTR and SLC26A6; the interactions take place once AHCYL1 is released from ITPR1 and increase CFTR and SLC26A6 activities (By similarity). Interacts with RRM1; in a phosphorylation- and (dATP)-dependent manner. Interacts (via PEST domain when phosphorylated) with SLC4A4 isoform 1 but not isoform 2; the interaction increases SLC4A4 isoform 1 activity (PubMed:16769890). Interacts (when phosphorylated) with SLC9A3; the interaction is required for SLC9A3 apical location and activity (PubMed:18829453, PubMed:20584908). Interacts (when phosphorylated) with FIP1L1; the interaction is direct and associates AHCYL1 with the CPSF complex and RNA (PubMed:19224921). Interacts with PAPOLA (PubMed:19224921). Interacts with ZCCHC4 (PubMed:31799605). Interacts with AHCY (PubMed:28647132).
In spite of its similarity with AHCY, which catalyzes the reversible hydrolysis of S-adenosyl-L-homocysteine to adenosine and homocysteine, recombinant AHCYL1 expressed in bacteria shows no hydrolase activity, nor does it affect the enzyme activity of AHCY.
Multifaceted cellular regulator which coordinates several essential cellular functions including regulation of epithelial HCO3(-) and fluid secretion, mRNA processing and DNA replication. Regulates ITPR1 sensitivity to inositol 1,4,5-trisphosphate, competing for the common binding site and acting as endogenous 'pseudoligand' whose inhibitory activity can be modulated by its phosphorylation status. Promotes the formation of contact points between the endoplasmic reticulum (ER) and mitochondria, facilitating transfer of Ca(2+) from the ER to mitochondria (PubMed:27995898). Under normal cellular conditions, functions cooperatively with BCL2L10 to limit ITPR1-mediated Ca(2+) release but, under apoptotic stress conditions, dephosphorylated which promotes dissociation of both AHCYL1 and BCL2L10 from mitochondria-associated endoplasmic reticulum membranes, inhibits BCL2L10 interaction with ITPR1 and leads to increased Ca(2+) transfer to mitochondria which promotes apoptosis (PubMed:27995898). In the pancreatic and salivary ducts, at resting state, attenuates inositol 1,4,5-trisphosphate-induced calcium release by interacting with ITPR1 (PubMed:16793548). When extracellular stimuli induce ITPR1 phosphorylation or inositol 1,4,5-trisphosphate production, dissociates from ITPR1 to interact with CFTR and SLC26A6, mediating their synergistic activation by calcium and cAMP that stimulates the epithelial secretion of electrolytes and fluid (By similarity). Also activates basolateral SLC4A4 isoform 1 to coordinate fluid and HCO3(-) secretion (PubMed:16769890). Inhibits the effect of STK39 on SLC4A4 and CFTR by recruiting PP1 phosphatase which activates SLC4A4, SLC26A6 and CFTR through dephosphorylation (By similarity). Mediates the induction of SLC9A3 surface expression produced by Angiotensin-2 (PubMed:20584908). Depending on the cell type, activates SLC9A3 in response to calcium or reverses SLC9A3R2-dependent calcium inhibition (PubMed:18829453). May modulate the polyadenylation state of specific mRNAs, both by controlling the subcellular location of FIP1L1 and by inhibiting PAPOLA activity, in response to a stimulus that alters its phosphorylation state (PubMed:19224921). Acts as a (dATP)-dependent inhibitor of ribonucleotide reductase large subunit RRM1, controlling the endogenous dNTP pool and ensuring normal cell cycle progression (PubMed:25237103). In vitro does not exhibit any S-adenosyl-L-homocysteine hydrolase activity (By similarity).
Phosphorylated at Ser/Thr residues between Ser-68 and Thr-72 in the PEST region: required for interaction with dATP-bound RRM1 and ITPR1. Phosphorylation at Ser-68 by PRKD1 and CAMK4 is required for further phosphorylations by CSNK1A1 (PubMed:16793548). Phosphorylation is induced by oxidative stress (PubMed:19224921). Probably phosphorylated by CAMK2A; phosphorylation at Ser-68 may be required for interaction with SLC9A3 (PubMed:20584908). Dephosphorylated in response to apoptotic stress conditions which causes translocation of both AHCYL1 and BCL2L10 from mitochondria-associated endoplasmic reticulum membranes and promotes apoptosis (PubMed:27995898).
The PEST region is essential for the interaction with ITPR1, and, when phosphorylated, is also the RRM1-binding region. The PDZ-binding region is required for maximal interaction with ITPR1 and is also responsible for the IP3-insensitive interaction with ITPR1 (By similarity).
Pre-mRNA alternative splicing regulator. Regulates alternative splicing of RBFOX2 to enhance the production of mRNA species that are targeted for nonsense-mediated decay (NMD).
Predominantly expressed in brain. Also found in adult and fetal kidney. Very low levels detected in prostate and fetal lung.
(Microbial infection) Interacts with CHKA/Choline Kinase-alpha; CHKA bridges PI4KA and hepatitis C virus (HCV) non-structural protein 5A (NS5A) and potentiates NS5A-stimulated PI4KA activity, which then facilitates the targeting of the ternary complex to the ER for viral replication.
Activated by Triton X-100, insensitive to inhibition by adenosine and inhibited by wortmannin (By similarity). Isoform 2 is activated by detergents such as Triton X-100 and inhibited by adenosine (PubMed:7961848). The PI4K complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (PubMed:23229899, PubMed:26571211). Interaction with TMEM150A regulates PtdIns(4)P synthesis (PubMed:25608530).
Acts on phosphatidylinositol (PtdIns) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate.
Component of a phosphatidylinositol 4-kinase (PI4K) complex, composed of PI4KA, EFR3 (EFR3A or EFR3B), TTC7 (TTC7A or TTC7B) and HYCC (HYCC1 or HYCC2) (PubMed:23229899, PubMed:24417819, PubMed:26571211, PubMed:34415310). Interacts with TMEM150A; regulating recruitment to the plasma membrane (PubMed:25608530). Interacts with TTC7A (PubMed:34415310).
Expressed ubiquitously. Highest levels in placenta and brain. Little or no expression in lung, liver, pancreas, testis or leukocytes.
Antigen 5T4 is overexpressed by a wide spectrum of cancers, including colorectal, ovarian and gastric, but with a limited normal tissue expression. Could be used for tumor immunotherapy.
Expressed by all types of trophoblasts as early as 9 weeks of development. Specific for trophoblastic cells except for amniotic epithelium. In adult tissues, the expression is limited to a few epithelial cell types but is found on a variety of carcinoma.
May function as an inhibitor of Wnt/beta-catenin signaling by indirectly interacting with LRP6 and blocking Wnt3a-dependent LRP6 internalization.
Reduction of TPBG levels by siRNA significantly enhanced the beta-catenin/TCF transcription-based reporter pBAR activation in response to Wnt stimulation.
The C-terminus of LRR N-terminal cap (LRRNT) and LRR 1 are essential for the inhibition of the Wnt signaling pathway.
Component of a complex whose core is composed of ARHGAP17, AMOT, PALS1, PATJ and PARD3/PAR3. Interacts with NHERF1, FNBP1, TRIP10, CAPZA (CAPZA1, CAPZA2 or CAPZA3), CAPZB, CD2AP and SH3KBP1/CIN85.
Rho GTPase-activating protein involved in the maintenance of tight junction by regulating the activity of CDC42, thereby playing a central role in apical polarity of epithelial cells. Specifically acts as a GTPase activator for the CDC42 GTPase by converting it to an inactive GDP-bound state. The complex formed with AMOT acts by regulating the uptake of polarity proteins at tight junctions, possibly by deciding whether tight junction transmembrane proteins are recycled back to the plasma membrane or sent elsewhere. Participates in the Ca(2+)-dependent regulation of exocytosis, possibly by catalyzing GTPase activity of Rho family proteins and by inducing the reorganization of the cortical actin filaments. Acts as a GTPase activator in vitro for RAC1.
The BAR domain mediates the interaction with the coiled coil domain of AMOT, leading to its recruitment to tight junctions.
Ubiquitously expressed. Expressed at higher level in heart and placenta.
Autophosphorylated. Phosphorylated on serine and threonine residues.
Essential for the regulation of ciliary length and required for the long-term survival of photoreceptors (By similarity). Phosphorylates FZR1 in a cell cycle-dependent manner. Plays a role in the transcriptional coactivation of AR. Could play an important function in spermatogenesis. May play a role in chromosomal stability in prostate cancer cells.
Expressed in prostate cancer cell lines at generally higher levels than in normal prostate epithelial cell lines. Isoform 1 is expressed in kidney, testis, lung, trachea, and retina. Isoform 2 is retina-specific where it is expressed in rod and cone photoreceptors.
Interacts with RP1 (By similarity). Interacts with AR and CDK20. Found in a complex containing MAK, AR and NCOA3. Interacts with FZR1 (via WD repeats).
Up-regulated by dihydrotestosterone (DHT) in androgen-sensitive LNCaP prostate cancer cells in a dose-dependent manner. Up-regulation by DHT is transient, reaching maximum levels after 24 hours and decreases slightly after 48 hours.
Expressed in the brain, with expression in the hippocampus, the neuropil in the dentate gyrus, where expression is higher in the outer half of the molecular layer than in the inner half, and in the neuropil of CA4 and CA3 (PubMed:8838578). Expressed in the putamen (at protein level) (PubMed:17296554).
Homohexamer or homotetramer. Interacts with SRCIN1 (PubMed:18662323). Interacts with VAMP2; the interaction is inhibit by interaction of VAPM2 with SEPT8 (By similarity).
Possibly involved in structural functions as organizing other membrane components or in targeting the vesicles to the plasma membrane. Involved in the regulation of short-term and long-term synaptic plasticity (By similarity).
The calcium-binding activity is thought to be localized in the cytoplasmic tail of the protein.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes monoubiquitination and 'Lys-48'-linked polyubiquitination. May be involved in degradation of katenin.
When phosphorylated, interacts with beta-TrCP (BTRC).
Compound heterozygosity for the R402Q polymorphism and a mutant allele of TYR is a common cause of autosomal recessive ocular albinism. The R402Q polymorphism is also found in Waardenburg syndrome type II with ocular albinism in association with a deletion in the MITF gene.
Forms an OPN3-dependent complex with DCT in response to blue light in melanocytes.
Genetic variants in TYR define the skin/hair/eye pigmentation variation locus 3 (SHEP3) [MIM:601800]. Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair.
Increased expression after UVB irradiation.
This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds. Catalyzes the initial and rate limiting step in the cascade of reactions leading to melanin production from tyrosine (By similarity). In addition to hydroxylating tyrosine to DOPA (3,4-dihydroxyphenylalanine), also catalyzes the oxidation of DOPA to DOPA-quinone, and possibly the oxidation of DHI (5,6-dihydroxyindole) to indole-5,6 quinone (PubMed:28661582).
Serine/threonine-protein kinase that acts like an antiapoptotic protein that counters TRAIL/TNFSF10-induced apoptosis by inducing phosphorylation of BIRC5 at 'Thr-34'.
A chromosomal aberration involving LYL1 may be a cause of a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(7;19)(q35;p13) with TCRB.
Interacts with APC2 (By similarity). Interacts with KIF2A (PubMed:18411309). Interacts with ANKRD53; recruits ANKRD53 to the spindle during mitosis (PubMed:26820536).
Required for normal progression through mitosis. Required for normal congress of chromosomes at the metaphase plate, and for normal rate of chromosomal segregation during anaphase. Plays a role in the regulation of mitotic spindle dynamics. Increases the rate of turnover of microtubules on metaphase spindles, and contributes to the generation of normal tension across sister kinetochores. Recruits KIF2A and ANKRD53 to the mitotic spindle and spindle poles. May participate in p53/TP53-regulated growth suppression.
Widely expressed in adult and fetal tissues, with highest expression in the adult brain and fetal thymus. Not detected in adult skeletal muscle.
A chromosomal aberration involving HMGA1 is found in pulmonary chondroid hamartoma. Translocation t(6;14)(p21;q23-24) with RAD51B.
Constitutively phosphorylated on two or three sites. Hyperphosphorylated at early stages of apoptosis, followed by dephosphorylation and methylation, which coincides with chromatin condensation. Isoforms HMG-I and HMG-Y can be phosphorylated by HIPK2. Phosphorylation of HMG-I at Ser-36, Thr-53 and Thr-78 and of HMG-Y at Thr-42 and Thr-67 by HIPK2 modulates DNA-binding affinity.
HMG-I/Y bind preferentially to the minor groove of A+T rich regions in double-stranded DNA. It is suggested that these proteins could function in nucleosome phasing and in the 3'-end processing of mRNA transcripts. They are also involved in the transcription regulation of genes containing, or in close proximity to A+T-rich regions.
Methylation at Arg-58 is mutually exclusive with methylation at Arg-60.
Expressed mainly to the brain, kidney and testis, and to a lesser extent the bone marrow, thymus, prostate, liver and uterus.
Magnesium-independent phospholipid phosphatase (PubMed:17590538). Inhibited by N-ethylmaleimide (PubMed:17590538).
Magnesium-independent phospholipid phosphatase with broad substrate specificity (PubMed:17590538). Preferentially catalyzes the conversion of diacylglycerol pyrophosphate into phosphatidate but can also act on phosphatidate and lysophosphatidate (PubMed:17590538). Phospholipid phosphatases are involved in both the synthesis of lipids and the degradation or generation of lipid-signaling molecules like diacylglycerol (PubMed:28851360).
Disease susceptibility is associated with variants affecting the gene represented in this entry. A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis, suggesting that dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis (PubMed:21506741).
Expressed on surface airway epithelia. Expressed mainly in mucous cells of submucosal glands of airway tissues. Highly expressed in the sublingual gland. Also found in submaxillary glands, endocervix, gall bladder, and pancreas.
Gel-forming mucin that is thought to contribute to the lubricating and viscoelastic properties of whole saliva and cervical mucus.
Highly glycosylated. C-, N- and O-glycosylated. C-mannosylated in the Cys-rich subdomains probably on the first Trp residue of the WXXW motif. Highly O-glycosylated in the Ser/Thr-rich tandem repeat (TR) region. The repeat region is about 59% O-glycosylated with a high abundance of NeuAc(2)Hex(1)HexNac1-ol.
Homomultimer; disulfide-linked (PubMed:31570524). The N- and C-terminus mediate their assembly into higher order structures to form filaments (By similarity). The CTCK domains of two polypeptides associate in the endoplasmic reticulum to generate intermolecularly disulfide-bonded dimers (PubMed:31570524). These dimers progress to the Golgi apparatus, which is a more acidic environment than the endoplasmic reticulum (By similarity). Under acidic conditions, the N-termini form non-covalent intermolecular interactions that juxtapose assemblies from different CTCK-linked dimers to produce long, disulfide-linked polymers that remain highly compact until secretion (By similarity).
Regulated by all-trans-retinoic acid (ATRA) in a cell-type specific manner.
The CTCK domain mediates interchain disulfide bonds with another molecule of MUC5B.
The cysteine residues in the Cys-rich subdomain repeats are not involved in disulfide bonding.
General regulator of phagocytosis. Required to uptake Gram negative bacterium by macrophages.
N-terminal region is required for phagocytosis of Gram negative bacterium.
Forms heterodimers with BAR domain-containing sorting nexins SNX1 and SNX2 (PubMed:23085988). The heterodimers are proposed to self-assemble into helical arrays on the membrane to stabilize and expand local membrane curvature underlying endosomal tubule formation. Thought to be a component of the originally described retromer complex (also called SNX-BAR retromer) which is a pentamer containing the heterotrimeric retromer cargo-selective complex (CSC), also described as vacuolar protein sorting subcomplex (VPS), and a heterodimeric membrane-deforming subcomplex formed between SNX1 or SNX2 and SNX5 or SNX6 (also called SNX-BAR subcomplex); the respective CSC and SNX-BAR subcomplexes associate with low affinity (Probable). Interacts with SNX1, SNX2, VPS26A, VPS29, VPS35, CDKN1B, TGFB receptors, BACE1, BRMS1, PIP5K1C isoform 3. Interacts with DCTN1; the association with DCTN1 is involved in movement of retromer-c ontaining vesicles toward the TGN (PubMed:11279102, PubMed:17148574, PubMed:19935774, PubMed:19619496, PubMed:20354142, PubMed:20830743, PubMed:23085988, PubMed:24610942). Interacts with CDKN1B and GIT1 (By similarity). Interacts with PIM1; translocating SNX6 to the nucleus (PubMed:11591366).
In vitro phosphorylated by PIM1; not affecting PIM1-dependent nuclear translocation (PubMed:11591366).
Involved in several stages of intracellular trafficking.
Involved in several stages of intracellular trafficking. Interacts with membranes phosphatidylinositol 3,4-bisphosphate and/or phosphatidylinositol 4,5-bisphosphate (Probable). Acts in part as component of the retromer membrane-deforming SNX-BAR subcomplex (PubMed:19935774). The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX-BAR subcomplex functions to deform the donor membrane into a tubular profile called endosome-to-TGN transport carrier (ETC) (Probable). Does not have in vitro vesicle-to-membrane remodeling activity (PubMed:23085988). Involved in retrograde endosome-to-TGN transport of lysosomal enzyme receptor IGF2R (PubMed:17148574). May function as link between transport vesicles and dynactin (Probable). Negatively regulates retrograde transport of BACE1 from the cell surface to the trans-Golgi network (PubMed:20354142). Involved in E-cadherin sorting and degradation; inhibits PIP5K1C isoform 3-mediated E-cadherin degradation (PubMed:24610942). In association with GIT1 involved in EGFR degradation. Promotes lysosomal degradation of CDKN1B (By similarity). May contribute to transcription regulation (Probable).
The BAR domain is able to sense membrane curvature upon dimerization. Membrane remodeling seems to implicate insertion of an amphipathic helix (AH) in the membrane (Probable).
The PX domain mediates interaction with membranes enriched in phosphatidylinositol 3,4-bisphosphate and/or phosphatidylinositol 4,5-bisphosphate.
Identified in the spliceosome C complex (PubMed:11991638). Heterodimer with U2AF2 (PubMed:11551507). Interacts (via RS domain) with PHF5A (via N-terminus) (By similarity). Interacts with ZRANB2 (PubMed:11448987). Interacts with SDE2 (PubMed:34365507). Interacts with SF3B1 (PubMed:34365507).
Interacts with U2AF2 and stimulates U2AF splicing activity in vitro. Less efficient than isoform 1.
Plays a critical role in both constitutive and enhancer-dependent splicing by mediating protein-protein interactions and protein-RNA interactions required for accurate 3'-splice site selection. Recruits U2 snRNP to the branch point. Directly mediates interactions between U2AF2 and proteins bound to the enhancers and thus may function as a bridge between U2AF2 and the enhancer complex to recruit it to the adjacent intron.
Produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
The C-terminal SR-rich domain is required for interactions with SR proteins and the splicing regulators TRA and TRA2, and the N-terminal domain is required for formation of the U2AF1/U2AF2 heterodimer.
The gene represented in this entry may be involved in disease pathogenesis. Mutation altering U2AF1 function in the context of specific RNA sequences can lead to aberrant alternative splicing of target genes, some of which may be relevant for MDS pathogenesis.
Beta-1,3-galactosyltransferase that transfers galactose from UDP-galactose to substrates with a terminal beta-linked galactose residue. Has a preference for galactose-beta-1,4-xylose that is found in the linker region of glycosaminoglycans, such as heparan sulfate and chondroitin sulfate. Has no activity towards substrates with terminal glucosamine or galactosamine residues.
PubMed:9892646 describes the wrong protein; the cDNAs used had been switched inadvertently.
Belongs to the SIMIBI class G3E GTPase family. ArgK/MeaB subfamily.
GTPase, binds and hydrolyzes GTP (PubMed:28497574, PubMed:20876572, PubMed:21138732, PubMed:28943303). Involved in intracellular vitamin B12 metabolism, mediates the transport of cobalamin (Cbl) into mitochondria for the final steps of adenosylcobalamin (AdoCbl) synthesis (PubMed:28497574, PubMed:20876572). Functions as a G-protein chaperone that assists AdoCbl cofactor delivery from MMAB to the methylmalonyl-CoA mutase (MMUT) (PubMed:28497574, PubMed:20876572). Plays a dual role as both a protectase and a reactivase for MMUT (PubMed:21138732, PubMed:28943303). Protects MMUT from progressive inactivation by oxidation by decreasing the rate of the formation of the oxidized inactive cofactor hydroxocobalamin (OH2Cbl) (PubMed:21138732, PubMed:28943303). Additionally acts a reactivase by promoting the replacement of OH2Cbl by the active cofactor AdoCbl, restoring the activity of MMUT in the presence and hydrolysis of GTP (PubMed:21138732, PubMed:28943303).
Homodimer (PubMed:20876572). Interacts with MMUT (the apoenzyme form); the interaction is GTP dependent (PubMed:20876572, PubMed:28497574, PubMed:21138732, PubMed:28943303).
Widely expressed. Highest expression is observed in liver and skeletal muscle.
In neuroblastoma cells, may promote autophagy in response to chemotherapy-induced DNA damage and efflux of chemotherapeutics via lysosomal exocytosis, hence protecting cells from cytotoxic agents (PubMed:23801752, PubMed:29968769). Expression levels may correlate with survival in neuroblastoma patients, with low levels in the tumor correlating with long-term patient survival and high expression with poor prognosis (PubMed:23801752). Therefore has been proposed as a biomarker to predict neuroblastoma chemoresistance and treatment outcome (PubMed:23801752).
Interacts with HDAC3 (PubMed:11861901). Interacts with HDAC2 and NCOR2/SMRT (PubMed:11739383). Interacts with HSPA8/HSC70 (PubMed:23801752). Interacts with MSH2 (PubMed:26221039).
Like some other members of the HD type 2 subfamily, such as HDAC4, inhibited by the antitumor drug trichostatin A (TSA).
Polyamine deacetylase (PDAC), which acts preferentially on N(8)-acetylspermidine, and also on acetylcadaverine and acetylputrescine (PubMed:28516954). Exhibits attenuated catalytic activity toward N(1),N(8)-diacetylspermidine and very low activity, if any, toward N(1)-acetylspermidine (PubMed:28516954). Histone deacetylase activity has been observed in vitro (PubMed:11861901, PubMed:11726666, PubMed:11677242, PubMed:11739383). Has also been shown to be involved in MSH2 deacetylation (PubMed:26221039). The physiological relevance of protein/histone deacetylase activity is unclear and could be very weak (PubMed:28516954). May play a role in the promotion of late stages of autophagy, possibly autophagosome-lysosome fusion and/or lysosomal exocytosis in neuroblastoma cells (PubMed:23801752, PubMed:29968769). May play a role in homologous recombination (PubMed:21247901). May promote DNA mismatch repair (PubMed:26221039).
Protein/histone deacetylase activity in vivo is uncertain. The 3D structure analysis of the zebrafish ortholog shows that a glutamate gatekeeper and a sterically constricted active site confer specificity for N(8)-acetylspermidine hydrolysis and disfavour acetyllysine hydrolysis. Supporting this observation, has been shown to exhibit only very low activity, if any, towards acetyl-lysine peptide substrates (PubMed:28516954). However, histone deacetylase activity has been observed in vitro (PubMed:28516954, PubMed:11861901, PubMed:11726666, PubMed:11677242, PubMed:11739383). Has also been shown to be involved in MSH2 deacetylation (PubMed:26221039).
Widely expressed with high levels in liver and kidney.
Odorant receptor (Potential). May be involved in taste perception.
Adapter protein able to interact with different proteins and involved in different biological processes (PubMed:11459825, PubMed:11459826, PubMed:17719540, PubMed:17296730, PubMed:19443654, PubMed:29656893). Mediates the interaction between the error-prone DNA polymerase zeta catalytic subunit REV3L and the inserter polymerase REV1, thereby mediating the second polymerase switching in translesion DNA synthesis (PubMed:20164194). Translesion DNA synthesis releases the replication blockade of replicative polymerases, stalled in presence of DNA lesions (PubMed:20164194). Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs) (PubMed:29656893). During G1 and S phase of the cell cycle, the complex functions downstream of TP53BP1 to promote non-homologous end joining (NHEJ) and suppress DNA end resection (PubMed:29656893). Mediates various NHEJ-dependent processes including immunoglobulin class-switch recombination, and fusion of unprotected telomeres (PubMed:29656893). May also regulate another aspect of cellular response to DNA damage through regulation of the JNK-mediated phosphorylation and activation of the transcriptional activator ELK1 (PubMed:17296730). Inhibits the FZR1- and probably CDC20-mediated activation of the anaphase promoting complex APC thereby regulating progression through the cell cycle (PubMed:11459825, PubMed:17719540). Regulates TCF7L2-mediated gene transcription and may play a role in epithelial-mesenchymal transdifferentiation (PubMed:19443654).
Homooligomer (Probable). Heterodimer with REV3L (PubMed:10660610, PubMed:11485998). This dimer forms the minimal DNA polymerase zeta complex (Pol-zeta2), with REV3L bearing DNA polymerase catalytic activity, although its activity is very low in this context (PubMed:11485998). Component of the tetrameric Pol-zeta complex (Pol-zeta4), which consists of REV3L, MAD2L2, POLD2 and POLD3; Pol-zeta4 is the fully active form of DNA polymerase zeta (PubMed:24449906). Component of the shieldin complex, consisting of SHLD1, SHLD2, SHLD3 and MAD2L2/REV7 (PubMed:29656893, PubMed:29789392). Within the complex, SHLD2 forms a scaffold which interacts with a SHLD3-MAD2L2 subcomplex via its N-terminus, and with SHLD1 via its C-terminus (PubMed:29656893). Interacts with REV1 (PubMed:11485998, PubMed:20164194). Interacts with ADAM9 (PubMed:10527948). Interacts with CHAMP1 (PubMed:21063390). Interacts with FZR1 (in complex with the anaphase promoting complex APC) (PubMed:11459825, PubMed:11459826). Interacts with CDC20; PubMed:11459825 could not detect the interaction (PubMed:11459826). Interacts with RAN (PubMed:19753112). Interacts with ELK1; the interaction is direct and recruits MAD2L2 to ELK1-specific promoters (PubMed:17296730). May interact with the JNK kinases MAPK8 and/or MAPK9 to stimulate ELK1 phosphorylation and transcriptional activity upon DNA damage (PubMed:17296730). Interacts with TCF7L2; prevents its binding to promoters and negatively modulates its transcriptional activity (PubMed:19443654). Interacts with YY1AP1 (PubMed:17541814). Interacts with S.flexneri protein ipaB; prevents the interaction of MAD2L2 with FZR1 and CDC20 resulting in an activation of the anaphase-promoting complex APC and a cell cycle arrest (PubMed:17719540). Interacts with PRCC; the interaction is direct (PubMed:11717438). Interacts with POGZ (PubMed:20850016).
Inhibits estrogen-induced cell proliferation by competing with PLCG for binding to ESR1, blocking the effect of estrogen on PLCG and repressing estrogen-induced proliferation. May play a role in T-cell development and function.
Ubiquitously expressed. Aberrantly expressed in some cancers.
By free ubiquitin: binding of free ubiquitin triggers conformational changes in the OTU domain and formation of a ubiquitin-binding helix in the N-terminus, promoting binding of the conjugated donor ubiquitin in UBE2N/UBC13 to OTUB1.
Hydrolase that can specifically remove 'Lys-48'-linked conjugated ubiquitin from proteins and plays an important regulatory role at the level of protein turnover by preventing degradation (PubMed:12704427, PubMed:14661020, PubMed:12401499, PubMed:23827681). Regulator of T-cell anergy, a phenomenon that occurs when T-cells are rendered unresponsive to antigen rechallenge and no longer respond to their cognate antigen (PubMed:14661020). Acts via its interaction with RNF128/GRAIL, a crucial inductor of CD4 T-cell anergy (PubMed:14661020). Isoform 1 destabilizes RNF128, leading to prevent anergy (PubMed:14661020). In contrast, isoform 2 stabilizes RNF128 and promotes anergy (PubMed:14661020). Surprisingly, it regulates RNF128-mediated ubiquitination, but does not deubiquitinate polyubiquitinated RNF128 (PubMed:14661020). Deubiquitinates estrogen receptor alpha (ESR1) (PubMed:19383985). Mediates deubiquitination of 'Lys-48'-linked polyubiquitin chains, but not 'Lys-63'-linked polyubiquitin chains (PubMed:19211026, PubMed:23827681, PubMed:18954305). Not able to cleave di-ubiquitin (PubMed:23827681, PubMed:18954305). Also capable of removing NEDD8 from NEDD8 conjugates, but with a much lower preference compared to 'Lys-48'-linked ubiquitin (PubMed:23827681, PubMed:18954305).
In addition to ubiquitin-binding at the Cys-91 active site, a proximal ubiquitin-binding site is also present at Cys-23 Occupancy of the active site is needed to enable tight binding to the second site. Distinct binding sites for the ubiquitins may allow to discriminate among different isopeptide linkages (i.e. 'Lys-48'-, 'Lys-63'-linked polyubiquitin) in polyubiquitin substrates and achieve linkage-specific deubiquitination.
In the structure described by PubMed:18954305, the His-265 active site of the catalytic triad is located too far to interact directly with the active site Cys-91 (PubMed:18954305). A possible explanation is that OTUB1 is in inactive conformation in absence of ubiquitin and a conformation change may move His-265 in the proximity of Cys-91 in presence of ubiquitin substrate (PubMed:18954305).
Interacts with FUS and RACK1 (PubMed:18954305). Interacts with UBE2D1/UBCH5A, UBE2W/UBC16 and UBE2N/UBC13 (PubMed:20725033, PubMed:35927303, PubMed:22325355, PubMed:22367539).
Interacts with RNF128 (PubMed:14661020). Does not associate with USP8 (PubMed:14661020).
Interacts with RNF128 (PubMed:14661020). Forms a ternary complex with RNF128 and USP8 (PubMed:14661020). Interacts with the C-terminal UCH catalytic domain of USP8 (PubMed:14661020).
Isoform 1 is ubiquitous. Isoform 2 is expressed only in lymphoid tissues such as tonsils, lymph nodes and spleen, as well as peripheral blood mononuclear cells.
Lacks the catalytic sites for protease activity.
Phosphorylation at Tyr-26 by SRC and SRMS promotes deubiquitination of RPTOR via a non-catalytic process.
Plays a key non-catalytic role in DNA repair regulation by inhibiting activity of RNF168, an E3 ubiquitin-protein ligase that promotes accumulation of 'Lys-63'-linked histone H2A and H2AX at DNA damage sites (PubMed:20725033, PubMed:22325355). Inhibits RNF168 independently of ubiquitin thioesterase activity by binding and inhibiting UBE2N/UBC13, the E2 partner of RNF168, thereby limiting spreading of 'Lys-63'-linked histone H2A and H2AX marks (PubMed:20725033, PubMed:22325355). Inhibition occurs by binding to free ubiquitin: free ubiquitin acts as an allosteric regulator that increases affinity for UBE2N/UBC13 and disrupts interaction with UBE2V1 (PubMed:20725033, PubMed:22325355). The OTUB1-UBE2N/UBC13-free ubiquitin complex adopts a configuration that mimics a cleaved 'Lys48'-linked di-ubiquitin chain (PubMed:20725033, PubMed:22325355). Acts as a regulator of mTORC1 and mTORC2 complexes (PubMed:29382726, PubMed:35927303). When phosphorylated at Tyr-26, acts as an activator of the mTORC1 complex by mediating deubiquitination of RPTOR via a non-catalytic process: acts by binding and inhibiting the activity of the ubiquitin-conjugating enzyme E2 (UBE2D1/UBCH5A, UBE2W/UBC16 and UBE2N/UBC13), thereby preventing ubiquitination of RPTOR (PubMed:35927303). Can also act as an inhibitor of the mTORC1 and mTORC2 complexes in response to amino acids by mediating non-catalytic deubiquitination of DEPTOR (PubMed:29382726).
The P-S-E-R-S-H-H-S repeats give rise to an antiparallel beta-structure.
Hormone involved in different processes, such as regulation of the pH of the duodenal content, food intake and water homeostasis (PubMed:25332973). Exerts its biological effects by binding to secretin receptor (SCTR), a G-protein coupled receptor expressed in the basolateral domain of several cells (PubMed:25332973). Acts as a key gastrointestinal hormone by regulating the pH of the duodenal content (By similarity). Secreted by S cells of the duodenum in the crypts of Lieberkuehn and regulates the pH of the duodenum by (1) inhibiting the secretion of gastric acid from the parietal cells of the stomach and (2) stimulating the production of bicarbonate (NaHCO(3)) from the ductal cells of the pancreas (By similarity). Production of bicarbonate is essential to neutralize the pH and ensure no damage is done to the small intestine by the gastric acid (By similarity). In addition to regulating the pH of the duodenal content, plays a central role in diet induced thermogenesis: acts as a non-sympathetic brown fat (BAT) activator mediating prandial thermogenesis, which consequentially induces satiation (Probable). Mechanistically, secretin released by the gut after a meal binds to secretin receptor (SCTR) in brown adipocytes, activating brown fat thermogenesis by stimulating lipolysis, which is sensed in the brain and promotes satiation (By similarity). Also able to stimulate lipolysis in white adipocytes (By similarity). Also plays an important role in cellular osmoregulation: released into the systemic circulation in response to hyperosmolality and acts at different levels in the hypothalamus, pituitary and kidney to regulate water homeostasis (By similarity). Also plays a role in the central nervous system, possibly by acting as a neuropeptide hormone: required for hippocampal synaptic function and neural progenitor cells maintenance (By similarity).
Serum secretin levels are increased after single-meal ingestion.
(Microbial infection) Integrin ITGAV:ITGB6 acts as a receptor for Coxsackievirus A9 and Coxsackievirus B1.
(Microbial infection) Integrin ITGAV:ITGB6 acts as a receptor for Herpes simplex virus-1/HHV-1 (PubMed:24367260).
(Microbial infection) Integrin ITGAV:ITGB6 interacts with coxsackievirus A9, coxsackievirus B1 capsid proteins (PubMed:9426447, PubMed:15194773).
(Microbial infection) Integrin ITGAV:ITGB6 interacts with herpes simplex virus-1/HHV-1 gH:gL proteins.
Heterodimer of an alpha and a beta subunit (PubMed:11807098, PubMed:17545607, PubMed:17158881). Interacts with FLNB (PubMed:11807098). Interacts with HAX1 (PubMed:17545607). ITGAV:ITGB6 interacts with FBN1 (PubMed:17158881). ITGAV:ITGB6 interacts with TGFB1 (PubMed:22278742, PubMed:28117447).
Integrin alpha-V:beta-6 (ITGAV:ITGB6) is a receptor for fibronectin and cytotactin (PubMed:17545607, PubMed:17158881). It recognizes the sequence R-G-D in its ligands (PubMed:17545607, PubMed:17158881). Internalization of integrin alpha-V/beta-6 via clathrin-mediated endocytosis promotes carcinoma cell invasion (PubMed:17545607, PubMed:17158881). ITGAV:ITGB6 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (PubMed:17158881). Integrin alpha-V:beta-6 (ITGAV:ITGB6) mediates R-G-D-dependent release of transforming growth factor beta-1 (TGF-beta-1) from regulatory Latency-associated peptide (LAP), thereby playing a key role in TGF-beta-1 activation (PubMed:15184403, PubMed:22278742, PubMed:28117447).
Belongs to the DHHC palmitoyltransferase family.
Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates (PubMed:22031296). Palmitoylates sex steroid hormone receptors, including ESR1, PGR and AR, thereby regulating their targeting to the plasma membrane (PubMed:22031296). This affects rapid intracellular signaling by sex hormones via ERK and AKT kinases and the generation of cAMP, but does not affect that mediated by their nuclear receptor (PubMed:22031296). Palmitoylates FYN, regulates its localization in hair follicles and plays a key role in epidermal homeostasis and hair follicle differentiation. Through the palmitoylation of PLCB1 and the regulation of PLCB1 downstream signaling may indirectly regulate the function of the endothelial barrier and the adhesion of leukocytes to the endothelium. Has also a palmitoyltransferase activity toward ADRA1D, positively regulating its activity and expression and may thereby play a role in vascular contraction. May also palmitoylate eNOS and LCK (By similarity).
A regulatory element withinin an intron of the HERC2 gene inhibits OCA2 promoter. There are several single nucleotide polymorphisms within the OCA2 gene and within the HERC2 gene that have a statistical association with human eye color.
E3 ubiquitin-protein ligase that regulates ubiquitin-dependent retention of repair proteins on damaged chromosomes. Recruited to sites of DNA damage in response to ionizing radiation (IR) and facilitates the assembly of UBE2N and RNF8 promoting DNA damage-induced formation of 'Lys-63'-linked ubiquitin chains. Acts as a mediator of binding specificity between UBE2N and RNF8. Involved in the maintenance of RNF168 levels. E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of XPA which influences the circadian oscillation of DNA excision repair activity. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333). Modulates also iron metabolism by regulating the basal turnover of FBXL5 (PubMed:24778179).
Genetic variants in HERC2 define the skin/hair/eye pigmentation variation locus 1 (SHEP1) [MIM:227220]; also known as skin/hair/eye pigmentation type 1, blue/nonblue eyes or skin/hair/eye pigmentation type 1, blue/brown eyes or skin/hair/eye pigmentation type 1, blond/brown hair or eye color, brown/blue or eye color, blue/nonblue or eye color type 3 (EYCL3) or brown eye color type 2 (BEY2) or hair color type 3 (HCL3). Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair.
Interacts (when phosphorylated at Thr-4827 and sumoylated) with RNF8 (via FHA domain); this interaction increases after ionizing radiation (IR) treatment. Interacts with XPA. Interacts with NEURL4. Via its interaction with NEURL4, may indirectly interact with CCP110 and CEP97.
Phosphorylation at Thr-4827 is required for interaction with RNF8.
Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks (DSBs), promoting the interaction with RNF8.
The RCC1 repeats are grouped into three seven-bladed beta-propeller regions.
The ZZ-type zinc finger mediates binding to SUMO1, and at low level SUMO2.
Belongs to the chondroitin N-acetylgalactosaminyltransferase family.
Expressed in brain, spleen, ovary, testis, lung and peripheral mononuclear cells.
Has both beta-1,3-glucuronic acid and beta-1,4-N-acetylgalactosamine transferase activity. Transfers glucuronic acid (GlcUA) from UDP-GlcUA and N-acetylgalactosamine (GalNAc) from UDP-GalNAc to the non-reducing end of the elongating chondroitin polymer. Seems to act as a specific activating factor for CHSY1 in chondroitin polymerization (PubMed:12716890).
Highest activities are measured with Mn(2+). Can also utilize Co(2+).
May facilitate PRKN transport into the mitochondria. In collaboration with PRKN, may enhance cell viability and protect cells from oxidative stress.
Ubiquitous. Highly expressed in pancreas, ovary, brain, heart, skeletal muscle, colon, kidney, liver, stomach, spleen and placenta.
Plays an important role in retinal cone photoreceptor survival (PubMed:25957687). In association with glucose transporter SLC16A1/GLUT1 and BSG, promotes retinal cone survival by enhancing aerobic glycolysis and accelerating the entry of glucose into photoreceptors (PubMed:25957687). May play a role in cone cell viability, slowing down cone degeneration, does not seem to play a role in degenerating rods (By similarity).
Interacts with HTT (via C-terminus) (PubMed:29466333). Interacts with RAB5A (By similarity). Found in a complex with F8A1/F8A2/F8A3, HTT and RAB5A; mediates the recruitment of HTT by RAB5A onto early endosomes (By similarity).
Produced abundantly in a wide variety of cell types.
RAB5A effector molecule that is involved in vesicular trafficking of early endosomes (PubMed:16476778). Mediates the recruitment of HTT by RAB5A onto early endosomes. The HTT-F8A1/F8A2/F8A3-RAB5A complex stimulates early endosomal interaction with actin filaments and inhibits interaction with microtubules, leading to the reduction of endosome motility (PubMed:16476778).
Up-regulated in brain tissue from patients affected by Huntington's disease (at protein level) (PubMed:16476778). In a Huntington's disease mouse model overexpression of F8A1/F8A2/F8A3 impairs proteasome activity leading to the accumulation of mutant HTT and causes defective mitochondrial functions (PubMed:27815841, PubMed:29209146).
Hydrolyzes high molecular weight hyaluronic acid to produce an intermediate-sized product which is further hydrolyzed by sperm hyaluronidase to give small oligosaccharides. Displays very low levels of activity. Associates with and negatively regulates MST1R.
Widely expressed. No expression detected in adult brain.
Directly interacts with BCL2; this interaction prevents the formation of the anti-apoptotic BAX-BCL2 complex.
Induced by TNF through the activation of the NFKB pathway.
Promotes apoptosis by binding to BCL2, hence preventing the formation of protective BCL2-BAX heterodimers.
Widely expressed with highest levels in peripheral blood, skeletal muscle and heart, followed by kidney and liver.
Detected in placenta (at protein level) (PubMed:32337544). Detected in cerebrospinal fluid, fibroblasts and urine (at protein level) (PubMed:25326458, PubMed:36213313). Expressed in the retina (at protein level) (PubMed:29777959). Cerebral white matter and plasma (PubMed:2469524). Isoform V0: Expressed in normal brain, gliomas, medulloblastomas, schwannomas, neurofibromas, and meningiomas (PubMed:8627343). Isoform V1: Expressed in normal brain, gliomas, medulloblastomas, schwannomas, neurofibromas, and meningiomas (PubMed:8627343). Isoform V2: Restricted to normal brain and gliomas (PubMed:8627343). Isoform V3: Found in all these tissues except medulloblastomas (PubMed:8627343).
Expressed in developing photoreceptors and the interphotoreceptor matrix between 12 and 17 weeks post conception (at protein level) (PubMed:29777959). Disappears in aorta after the cartilage development (PubMed:7921538).
May play a role in intercellular signaling and in connecting cells with the extracellular matrix. May take part in the regulation of cell motility, growth and differentiation. Binds hyaluronic acid.
Proteolytically cleaved by ADAMTS5 and ADAMTS15 in the pericellular matrix surrounding myoblasts, facilitating myoblast contact and fusion which is required for skeletal muscle development and regeneration.
The disease is caused by variants affecting the gene represented in this entry. The pathological mechanism involves a quantitative imbalance of the normally occurring splice variants (PubMed:22739342).
(Microbial infection) Directly interacts with HIV-1 protein VPR. Also identified in a complex with NR3C1 and HIV-1 protein VPR.
Expressed at high levels in the CNS, as well as in heart and platelets (at protein level).
Filament-forming cytoskeletal GTPase (By similarity). May play a role in cytokinesis (Potential). May play a role in platelet secretion (By similarity).
In a heterologous system, SEPTIN5 overexpression has been shown to exert dopamine-dependent neurotoxicity. As wild-type PRKN, but not familial-linked PRKN mutants, ubiquitinates mouse SEPTIN5 and promotes its degradation, it has been suggested that a deficiency in SEPTIN5 degradation may contribute to the development of early onset Parkinson disease 2 (PARK2).
Phosphorylated by DYRK1A (By similarity). In platelets, phosphorylated in response to thrombin, phorbol-12-myristate-13-acetate and collagen.
Septins polymerize into heterooligomeric protein complexes that form filaments, and can associate with cellular membranes, actin filaments and microtubules. GTPase activity is required for filament formation (By similarity). Interacts with SEPTIN2 and SEPTIN5. In platelets, associated with a complex containing STX4. Interacts with PRKN; this interaction leads to SEPTIN5 ubiquitination and degradation (By similarity). Interacts with DYRK1A (By similarity). Interacts with STX1A; in the cerebellar cortex (By similarity).
A secreted form is released from the membrane after cleavage by gamma-secretase.
Activity is increased by Mn(2+) and Mg(2+).
Catalyzes the addition of N-acetylglucosamine (GlcNAc) in beta 1-6 linkage to the alpha-linked mannose of biantennary N-linked oligosaccharides (PubMed:10395745, PubMed:30140003). Catalyzes an important step in the biosynthesis of branched, complex-type N-glycans, such as those found on EGFR, TGFR (TGF-beta receptor) and CDH2 (PubMed:10395745, PubMed:22614033, PubMed:30140003). Via its role in the biosynthesis of complex N-glycans, plays an important role in the activation of cellular signaling pathways, reorganization of the actin cytoskeleton, cell-cell adhesion and cell migration. MGAT5-dependent EGFR N-glycosylation enhances the interaction between EGFR and LGALS3 and thereby prevents rapid EGFR endocytosis and prolongs EGFR signaling. Required for efficient interaction between TGFB1 and its receptor. Enhances activation of intracellular signaling pathways by several types of growth factors, including FGF2, PDGF, IGF, TGFB1 and EGF. MGAT5-dependent CDH2 N-glycosylation inhibits CDH2-mediated homotypic cell-cell adhesion and contributes to the regulation of downstream signaling pathways. Promotes cell migration. Contributes to the regulation of the inflammatory response. MGAT5-dependent TCR N-glycosylation enhances the interaction between TCR and LGALS3, limits agonist-induced TCR clustering, and thereby dampens TCR-mediated responses to antigens. Required for normal leukocyte evasation and accumulation at sites of inflammation (By similarity). Inhibits attachment of monocytes to the vascular endothelium and subsequent monocyte diapedesis (PubMed:22614033).
Induced by IFNG treatment in monocytes (in vitro).
Promotes proliferation of umbilical vein endothelial cells and angiogenesis, at least in part by promoting the release of the growth factor FGF2 from the extracellular matrix.
Both the 120 kDa linear IgA disease antigen and the 97 kDa linear IgA disease antigen of COL17A1, represent major antigenic targets of autoantibodies in patients with linear IgA disease (LAD). LAD is a subepidermal blistering disorder characterized by tissue-bound and circulating IgA autoantibodies to the dermal-epidermal junction. These IgA autoantibodies preferentially react with 97 and the 120 kDa forms, but not with the full-length COL17A1, suggesting that the cleavage of the ectodomain generates novel autoantigenic epitopes.
Detected in skin (PubMed:8618013). In the cornea, it is detected in the epithelial basement membrane, the epithelial cells, and at a lower level in stromal cells (at protein level) (PubMed:25676728). Stratified squamous epithelia. Found in hemidesmosomes. Expressed in cornea, oral mucosa, esophagus, intestine, kidney collecting ducts, ureter, bladder, urethra and thymus but is absent in lung, blood vessels, skeletal muscle and nerves.
Homotrimers of alpha 1(XVII)chains. Interacts (via cytoplasmic region) with ITGB4 (via cytoplasmic region). Interacts (via cytoplasmic region) with DST isoform 3 (via N-terminus). Interacts (via N-terminus) with PLEC. Interacts (via cytoplasmic region) with DSP.
May play a role in the integrity of hemidesmosome and the attachment of basal keratinocytes to the underlying basement membrane.
The 120 kDa linear IgA disease antigen is an anchoring filament component involved in dermal-epidermal cohesion. Is the target of linear IgA bullous dermatosis autoantibodies.
The ectodomain is shedded from the surface of keratinocytes resulting in a 120-kDa soluble form, also named as 120 kDa linear IgA disease antigen. The shedding is mediated by membrane-bound metalloproteases. This cleavage is inhibited by phosphorylation at Ser-544.
The intracellular/endo domain is disulfide-linked.
Involved in both glial cell differentiation and axonal network formation during neurogenesis. Promotes astrocyte differentiation and transforms cerebellar astrocytes into radial glia. Also induces axonal extension in small and intermediate neurons of sensory ganglia by activating nearby satellite glia (By similarity).
Interacts with STING1, PIK3C3, and ATG14; the STING1/STEEP1 interaction is increased upon STING1 cGAMP-activation and leads to recruitment of PI3K complex I.
May be duplicated on chromosome 8, within an intron of the ERLIN2 gene.
Stimulates membrane curvature formation and subsequent endoplasmic reticulum exit site (ERES) establishment by recruiting PI3K complex I, leading to COPII vesicle-mediated transport (PubMed:32690950). Promotes endoplasmic reticulum (ER) exit of cGAMP-activated STING1 oligomers (PubMed:32690950).
The N-terminal and the C-terminal half of the protein have a very similar 3D-structure, suggesting they arose from duplication (PubMed:30280012). Requires a bound zinc ion for normal folding and solubility (PubMed:30260988).
Was identified as interaction partner for CCS (PubMed:30260988). Only misfolded mutant protein forms that lack part of the zinc-binding sites interact with CCS. The full-length protein does not interact with CCS. Likewise, mutant protein that lacks all four zinc-binding residues does not interact with CCS (PubMed:30260988).
Transcription factor involved in specification of neuronal cell types and which is required for inner ear and hypothalamus development. Binds to the 5'-CAAGTG-3' core sequence. Controls semicircular canal formation in the inner ear. Also required for hypothalamic/pituitary axis of the CNS (By similarity).
(Microbial infection) During SARS-COV-2 infection, promotes SARS-CoV-2 ORF3A-mediated autophagy but is unlikely to be required for ORF3A-mediated induction of reticulophagy.
(Microbial infection) Interacts with SARS-CoV-2 ORF3A protein; the interaction promotes ORF3A-induced autophagy but is unlikely to be involved in ORF3A-mediated induction of reticulophagy.
Catalyzes the oxidative cleavage of heme at the alpha-methene bridge carbon, released as carbon monoxide (CO), to generate biliverdin IXalpha, while releasing the central heme iron chelate as ferrous iron (PubMed:7703255, PubMed:11121422, PubMed:19556236). Affords protection against programmed cell death and this cytoprotective effect relies on its ability to catabolize free heme and prevent it from sensitizing cells to undergo apoptosis (PubMed:20055707).
Expressed at higher levels in renal cancer tissue than in normal tissue (at protein level).
Heme oxygenase 1 activity is highly inducible by its substrate heme and by various non-heme substances such as heavy metals, bromobenzene, endotoxin, oxidizing agents and UVA.
Homodimer and higher order homooligomer (PubMed:19556236). Oligomerization is crucial for its stability and function in the endoplasmic reticulum (PubMed:19556236). Interacts with FLVCR2; this interaction is potentiated in the presence of heme.
The transmembrane domain is necessary for its oligomerization.
(Microbial infection) Cleaved by foot-and-mouth disease virus leader protease; this cleavage suppresses the formation of cytoplasmic stress granules.
(Microbial infection) Interacts with non-structural protein 3 (via C-terminus) of Sindbis virus and Semliki forest virus; this interaction inhibits the formation of host stress granules on viral mRNAs and the nsp3-G3BP2 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes.
Can mediate both protein-protein and protein-RNA interactions via the NTF2 domain and RNA-binding domain RRM; protein-protein and protein-RNA interactions are essential for undergoing liquid-liquid phase separation (LLPS).
Forms homooligomers (PubMed:23279204). Forms heterodimers with G3BP1 (PubMed:23279204). Interacts with NFKBIA (via N-terminus) (PubMed:10969074). Interacts (via NTF2 domain) with USP10; inhibiting stress granule formation (PubMed:23279204, PubMed:27022092, PubMed:31981475). Interacts (via NTF2 domain) with CAPRIN1; promoting stress granule formation (PubMed:27022092). Associates (via RG-rich region) with 40S ribosome subunits (PubMed:27022092). Interacts with PABPC1 (PubMed:23279204).
Scaffold protein that plays an essential role in cytoplasmic stress granule formation which acts as a platform for antiviral signaling (PubMed:23279204, PubMed:32302570, PubMed:32302571, PubMed:32302572). Plays an essential role in stress granule formation (PubMed:27022092, PubMed:32302570, PubMed:32302571, PubMed:32302572). Stress granules are membraneless compartments that store mRNAs and proteins, such as stalled translation pre-initiation complexes, in response to stress (PubMed:32302570, PubMed:32302571, PubMed:32302572). Promotes formation of stress granules phase-separated membraneless compartment by undergoing liquid-liquid phase separation (LLPS) upon unfolded RNA-binding: functions as a molecular switch that triggers RNA-dependent LLPS in response to a rise in intracellular free RNA concentrations (By similarity).
The NTF2 domain mediates interaction with CAPRIN1 and USP10 regulators, thereby regulating assembly of stress granules.
The acidic disordered region acts as a negative regulator of phase separation.
Under physiological conditions, G3BP2 adopts a compact state that is stabilized by intramolecular interactions between the RG-rich and the acidic regions that inhibit phase separation. Upon stress, polysomes disassemble and mRNAs are released in an unfolded protein-free state. Binding of unfolded mRNA to G3BP2 outcompetes the intramolecular interactions and RNA-bound G3BP2 adopts an expanded conformation in which the RG-rich region becomes exposed to engage in protein-protein and protein-RNA interactions, allowing physical cross-linking of RNA molecules to form protein-RNA condensates, leading to liquid-liquid phase separation (LLPS).
Highly phosphorylated by CDK2; stimulates initiation of DNA replication.
Regulator of DNA replication. Promotes initiation of chromosomal DNA replication by mediating TOPBP1- and CDK2-dependent recruitment of CDC45L onto replication origins (By similarity).
Component of the DBIRD complex. Interacts with CCAR2; the interaction is direct.
Core component of the DBIRD complex, a multiprotein complex that acts at the interface between core mRNP particles and RNA polymerase II (RNAPII) and integrates transcript elongation with the regulation of alternative splicing: the DBIRD complex affects local transcript elongation rates and alternative splicing of a large set of exons embedded in (A + T)-rich DNA regions. May play a role in neuronal differentiation and is able to bind DNA and activate expression in vitro.
(Microbial infection) Able to cleave S.pneumoniae serine-rich repeat protein PsrP.
(Microbial infection) Cleaves and activates HIV-1 virus Envelope glycoprotein gp160.
(Microbial infection) Cleaves and activates anthrax toxin protective antigen (PA).
(Microbial infection) Cleaves and activates diphtheria toxin DT.
(Microbial infection) Facilitates human coronaviruses EMC and SARS-CoV-2 infections by proteolytically cleaving the spike protein at the monobasic S1/S2 cleavage site. This cleavage is essential for spike protein-mediated cell-cell fusion and entry into human lung cells.
(Microbial infection) Facilitates mumps virus infection by proteolytically cleaving the viral fusion protein F.
(Microbial infection) Required for H7N1 and H5N1 influenza virus infection probably by cleaving hemagglutinin.
Contains a cytoplasmic domain responsible for its TGN localization and recycling from the cell surface.
Inhibited by the not secondly cleaved propeptide (PubMed:9130696, PubMed:11799113). Inhibited by m-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)-benzamidine (m-guanidinomethyl-Phac-RVR-Amb) and 4-guanidinomethyl-phenylacetyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148) (PubMed:24666235, PubMed:25974265). Inhibited by Decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decanoyl-RVKR-CMK) (PubMed:32362314). Inhibited by heparin/heparan sulfate-binding (PubMed:2408021).
Interacts with FLNA (By similarity). Binds to PACS1 which mediates TGN localization and connection to clathrin adapters (PubMed:11331585). Interacts with LAMP1, LAMP2 and LAMP3 (PubMed:32295904).
Phosphorylation is required for TGN localization of the endoprotease. In vivo, exists as di-, mono- and non-phosphorylated forms.
The inhibition peptide, which plays the role of an intramolecular chaperone, is autocatalytically removed in the endoplasmic reticulum (ER) and remains non-covalently bound to furin as a potent autoinhibitor. Following transport to the trans Golgi, a second cleavage within the inhibition propeptide results in propeptide dissociation and furin activation.
Ubiquitous endoprotease within constitutive secretory pathways capable of cleavage at the RX(K/R)R consensus motif (PubMed:11799113, PubMed:1629222, PubMed:1713771, PubMed:2251280, PubMed:24666235, PubMed:25974265, PubMed:7592877, PubMed:7690548, PubMed:9130696). Mediates processing of TGFB1, an essential step in TGF-beta-1 activation (PubMed:7737999). Converts through proteolytic cleavage the non-functional Brain natriuretic factor prohormone into its active hormone BNP(1-32) (PubMed:20489134, PubMed:21763278). By mediating processing of accessory subunit ATP6AP1/Ac45 of the V-ATPase, regulates the acidification of dense-core secretory granules in islets of Langerhans cells (By similarity).
Belongs to the PRAME family. LRRC14 subfamily.
Inhibits IGF-mediated growth and developmental rates. IGF-binding proteins prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cell culture. They alter the interaction of IGFs with their cell surface receptors.
The C-terminus is required for IGF-binding and growth inhibition.
Although related to peptidase S1 family vitamin K-dependent clotting factors, it has lost two of the essential catalytic residues and therefore lacks protease activity.
Appears to assist hemostasis by binding thrombin and promoting its association with phospholipid vesicles. Inhibits activity of the coagulation protease factor Xa in the presence of SERPINA10, calcium and phospholipids.
Interacts with PNN. Associates with the 60S ribosomal subunit (By similarity).
Contactins mediate cell surface interactions during nervous system development. Participates in oligodendrocytes generation by acting as a ligand of NOTCH1. Its association with NOTCH1 promotes NOTCH1 activation through the released notch intracellular domain (NICD) and subsequent translocation to the nucleus. Involved in motor coordination (By similarity).
Expressed in nervous system. Highly expressed in cerebellum. Expressed at intermediate level in thalamus, subthalamic nucleus. Weakly expressed in corpus callosum, caudate nucleus and spinal cord.
Acts as a key regulator of dendritic field orientation during development of sensory cortex. Also directs dendrites toward active axon terminals when ectopically expressed (By similarity).
Belongs to the JHDM1 histone demethylase family.
Histone demethylase activity is inhibited by fumarate.
Histone demethylase that demethylates 'Lys-4' and 'Lys-36' of histone H3, thereby playing a central role in histone code (PubMed:16362057, PubMed:17994099, PubMed:26237645). Preferentially demethylates trimethylated H3 'Lys-4' and dimethylated H3 'Lys-36' residue while it has weak or no activity for mono- and tri-methylated H3 'Lys-36' (PubMed:16362057, PubMed:17994099, PubMed:26237645). Preferentially binds the transcribed region of ribosomal RNA and represses the transcription of ribosomal RNA genes which inhibits cell growth and proliferation (PubMed:16362057, PubMed:17994099). May also serve as a substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex (Probable).
Interacts with SKP1, forming heterodimers (PubMed:27568929). The heterodimeric KDM2B-SKP1 complex interacts with the PCGF1-BCORL1 heterodimeric complex to form a homotetrameric polycomb repression complex 1 (PRC1.1) (PubMed:27568929). Directly interacts with CUL1. The SKP1-KDM2B complex interacts with UBB (PubMed:30033217).
The CXXC zinc finger mediates binding to DNA containing unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides.
The F-box domain mediates interaction with UBB.
The JmjC domain mediates demethylation activity (PubMed:17994099). It is also required for repression of ribosomal RNA genes (PubMed:17994099).
The LRR repeats are required for the interaction with the PCGF1-BCORL1 heterodimeric complex.
Activates hepatocyte growth factor (HGF) by converting it from a single chain to a heterodimeric form.
Heterodimer of a short chain and a long chain linked by a disulfide bond.
It is uncertain whether Met-1 is the initiator.
Interacts with the mTORC1 complex; this interaction mediates the recruitment of mTORC1 to the lysosome and its subsequent activation.
Symporter that selectively cotransports sodium ions and amino acids, such as L-glutamine and L-asparagine from the lysosome into the cytoplasm and may participates in mTORC1 activation (PubMed:28416685, PubMed:35561222). The transport activity requires an acidic lysosomal lumen (PubMed:28416685).
Belongs to the class I-like SAM-binding methyltransferase superfamily. TRM61 family.
Catalytic subunit of tRNA (adenine-N(1)-)-methyltransferase, which catalyzes the formation of N(1)-methyladenine at position 58 (m1A58) in initiator methionyl-tRNA (PubMed:16043508). Catalytic subunit of mRNA N(1)-methyltransferase complex, which mediates methylation of adenosine residues at the N(1) position of a small subset of mRNAs: N(1) methylation takes place in tRNA T-loop-like structures of mRNAs and is only present at low stoichiometries (PubMed:29107537, PubMed:29072297).
Heterotetramer; composed of two copies of TRMT6 and two copies of TRMT61A.
Interacts with the cytoplasmic tail of integrins ITGA1, ITGA2, ITGA5, ITGA6, ITGA11 and ITGB1 (By similarity). Interacts with RABGEF1 (via VPS9 domain) (PubMed:17450153). Interacts with ANKRD27 (PubMed:16525121, PubMed:18477474). Interacts with VAMP7 (PubMed:25648148). Interacts (in GTP-bound form) with VAMP8 in response to starvation; the interaction probably regulates VAMP8 endolysosomal trafficking (PubMed:25648148). Interacts (active GTP-bound form) with TMED10; the interaction is indirect and regulates TMED10 abundance and localization at the Golgi (PubMed:31455601).
Small GTPase involved in membrane trafficking control (PubMed:18804435, PubMed:25648148). During the mitosis of adherent cells, controls the endosomal trafficking of integrins which is required for the successful completion of cytokinesis (PubMed:18804435). Regulates integrin internalization and recycling, but does not influence the traffic of endosomally translocated receptors in general (By similarity). As a result, may regulate cell adhesion and migration (By similarity). Involved in neurite growth (By similarity). Following SBF2/MTMT13-mediated activation in response to starvation-induced autophagy, binds to and regulates SNARE protein VAMP8 endolysosomal transport required for SNARE-mediated autophagosome-lysosome fusion (PubMed:25648148). Modulates protein levels of the cargo receptors TMED2 and TMED10, and required for appropriate Golgi localization of TMED10 (PubMed:31455601).
Widely expressed. In jejunal tissue, predominantly expressed in the apical region of the epithelial cell layer of the villi, weak expression, if any, in the crypt epithelium. Capillary endothelium and some cell types in the lamina propria also show expression.
Testis-specific. Isoform 6 is detected in 17 of 18 colon cancer tissues examined.
Homodimer (via SH3-domain) (PubMed:19888460). Interacts with PTPN22 (PubMed:15208781). Interacts with phosphorylated SIT1, PAG1, LIME1 and TGFB1I1; these interactions serve to recruit CSK to the membrane where it can phosphorylate and inhibit Src-family kinases (PubMed:11433379, PubMed:10790433, PubMed:14610046, PubMed:10838081). Interacts with SRCIN1 (PubMed:17525734). Interacts with RHOH (PubMed:20851766). Interacts (via SH2 domain) with SCIMP; this interaction is dependent on phosphorylation of SCIMP 'Tyr-107' (PubMed:21930792). Interacts (via SH2 domain) with PRAG1 (when phosphorylated at 'Tyr-391'); this interaction prevents translocation of CSK from the cytoplasm to the membrane leading to increased activity of CSK (By similarity). Interacts with LRRK1 (PubMed:23526378).
Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN, CSK or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. Suppresses signaling by various surface receptors, including T-cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several positive effectors such as FYN or LCK.
Phosphorylated at Ser-364 by PKA, leading to increased activity. Autophosphorylated.
The architecture of this protein is similar to that of Src-family kinases (SFKs) with one N-terminal SH3 domain, one SH2 domain, and a C-terminal kinase domain.
(Microbial infection) Interacts with Epstein-Barr virus EBNA2.
ATP-dependent 3'-5' DNA helicase, component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. The ATPase activity of XPB/ERCC3, but not its helicase activity, is required for DNA opening. In transcription, TFIIH has an essential role in transcription initiation (PubMed:8157004, PubMed:30894545). When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape (PubMed:8157004). The ATP-dependent helicase activity of XPB/ERCC3 is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription.
Belongs to the helicase family. RAD25/XPB subfamily.
Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription (PubMed:9852112). Interacts with PUF60 (PubMed:10882074, PubMed:11239393). Interacts with ATF7IP (PubMed:19106100). Interacts with KAT2A; leading to KAT2A recruitment to promoters and acetylation of histones (PubMed:30894545).
Belongs to the dynactin 150 kDa subunit family.
Monomer and homodimer (PubMed:23874158). Subunit of dynactin, a multiprotein complex part of a tripartite complex with dynein and a adapter, such as BICDL1, BICD2 or HOOK3. The dynactin complex is built around ACTR1A/ACTB filament and consists of an actin-related filament composed of a shoulder domain, a pointed end and a barbed end. Its length is defined by its flexible shoulder domain. The soulder is composed of 2 DCTN1 subunits, 4 DCTN2 and 2 DCTN3. DCTN1/p150(glued) binds directly to microtubules and to cytoplasmic dynein. The 4 DCNT2 (via N-terminus) bind the ACTR1A filament and act as molecular rulers to determine the length. The pointed end is important for binding dynein-dynactin cargo adapters. Consists of 4 subunits: ACTR10, DCNT4, DCTN5 and DCTN6. The barbed end is composed of a CAPZA1:CAPZB heterodimers, which binds ACTR1A/ACTB filament and dynactin and stabilizes dynactin (By similarity). Interacts with the C-terminus of MAPRE1, MAPRE2 and MAPRE3. Interacts (via C-terminus) with SNX6. Interacts with CLN3, DYNAP, ECPAS and FBXL5. Interacts with MISP; this interaction regulates its distribution at the cell cortex. Interacts with CEP131. Interacts with CEP126 (PubMed:24867236). Interacts with CLIP1 (PubMed:17828275, PubMed:17828277, PubMed:26972003, PubMed:20679239). Interacts with dynein intermediate chain and dynein heavy chain (PubMed:25185702). Interacts with PLK1 (via POLO-box domain) (PubMed:20679239). Interacts with TBCB (PubMed:22777741). Binds preferentially to tyrosinated microtubules than to detyrosinated microtubules (PubMed:26972003, PubMed:26968983). Interacts with PARD6A (PubMed:20719959). Interacts with HPS6 (PubMed:25189619). Interacts with KIF3A. Interacts with BICD2 (By similarity). Interacts with DST (isoform 9) (By similarity). Interacts with DST (isoform 1) (By similarity). Identified in a complex with MREG and RILP (By similarity). Interacts with BCCIP (isoform 2/alpha) (PubMed:28394342). Interacts with DCDC1 (PubMed:22159412). Interacts with AKNA (By similarity). Interacts with DYNC1I2 (By similarity).
Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules (By similarity). Plays a key role in dynein-mediated retrograde transport of vesicles and organelles along microtubules by recruiting and tethering dynein to microtubules. Binds to both dynein and microtubules providing a link between specific cargos, microtubules and dynein. Essential for targeting dynein to microtubule plus ends, recruiting dynein to membranous cargos and enhancing dynein processivity (the ability to move along a microtubule for a long distance without falling off the track). Can also act as a brake to slow the dynein motor during motility along the microtubule (PubMed:25185702). Can regulate microtubule stability by promoting microtubule formation, nucleation and polymerization and by inhibiting microtubule catastrophe in neurons. Inhibits microtubule catastrophe by binding both to microtubules and to tubulin, leading to enhanced microtubule stability along the axon (PubMed:23874158). Plays a role in metaphase spindle orientation (PubMed:22327364). Plays a role in centriole cohesion and subdistal appendage organization and function. Its recruitment to the centriole in a KIF3A-dependent manner is essential for the maintenance of centriole cohesion and the formation of subdistal appendage. Also required for microtubule anchoring at the mother centriole (PubMed:23386061). Plays a role in primary cilia formation (PubMed:25774020).
Phosphorylation by SLK at Thr-145, Thr-146 and Thr-147 targets DCTN1 to the centrosome. It is uncertain if SLK phosphorylates all three threonines or one or two of them. PLK1-mediated phosphorylation at Ser-179 is essential for its localization in the nuclear envelope, promotes its dissociation from microtubules during early mitosis and positively regulates nuclear envelope breakdown during prophase.
The CAP-Gly domain is essential for interactions with microtubules and its binding partners and for its motion along the microtubules. Essential for its preferential binding to tyrosinated microtubules and for promoting the sustained interaction of the dynein motor with microtubules.
Ubiquitinated by a SCF complex containing FBXL5, leading to its degradation by the proteasome.
Atypical histone H2B. Nucleosomes containing it are structurally and dynamically indistinguishable from those containing conventional H2B. However, unlike conventional H2B, does not recruit chromosome condensation factors and does not participate in the assembly of mitotic chromosomes. May be important for telomere function.
Ortholog in primates, but not in rodents.
Testis-specific. Present in sperm cells (at protein level).
There at least 2 alleles for OR4E1. A non-functional allele results from a polymorphism at position 197 (dbSNP rs199890040), which leads to a frameshift, premature truncation of the coding region and hence pseudogenization. The presence of various combinations of functional (olfactory receptors) and non-functional (olfactory receptor segregating pseudogenes) alleles may underlie differences in olfactory sensitivity between individuals (hyperosmia, hyposmia or even anosmia).
Expressed in fetal kidney, cochlea, eye, heart and lung.
Expressed in kidney and lung and to a lower extent in brain, pregnant uterus, placenta, thyroid gland and blood vessels.
Functional ligand of integrin alpha-8/beta-1 in kidney development. Regulates the expression of GDNF with integrin alpha-8/beta-1 which is essential for kidney development. May also play a role in the development and function of various tissues, regulating cell adhesion, spreading and survival through the binding of several integrins (By similarity).
The MAM domain is required for localization at the cell surface.
Antiapoptotic isoform, resistant to caspase-3 cleavage.
Autophosphorylated and/or phosphorylated at Thr-507, within the activation loop; phosphorylation at Thr-507 is not a prerequisite for enzymatic activity (PubMed:19801500). Autophosphorylated at Ser-299, Ser-302 and Ser-304 (PubMed:17603046). Upon TNFSF10/TRAIL treatment, phosphorylated at Tyr-155; phosphorylation is required for its translocation to the endoplasmic reticulum and cleavage by caspase-3 (PubMed:15774464). Phosphorylated at Tyr-313, Tyr-334 and Tyr-567; phosphorylation of Tyr-313 and Tyr-567 following thrombin or zymosan stimulation potentiates its kinase activity (PubMed:17570831). Phosphorylated by protein kinase PDPK1; phosphorylation is inhibited by the apoptotic C-terminal cleavage product of PKN2 (PubMed:11781095). Phosphorylated at Tyr-313 through a SYK and SRC mechanism downstream of C-type lectin receptors activation, promoting its activation (By similarity).
Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine receptor-initiated cell death, is involved in tumor suppression as well as survival of several cancers, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses (PubMed:21810427, PubMed:21406692). Negatively regulates B cell proliferation and also has an important function in self-antigen induced B cell tolerance induction (By similarity). Upon DNA damage, activates the promoter of the death-promoting transcription factor BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and apoptosis (PubMed:21810427, PubMed:21406692). In response to oxidative stress, interact with and activate CHUK/IKKA in the nucleus, causing the phosphorylation of p53/TP53 (PubMed:21810427, PubMed:21406692). In the case of ER stress or DNA damage-induced apoptosis, can form a complex with the tyrosine-protein kinase ABL1 which trigger apoptosis independently of p53/TP53 (PubMed:21810427, PubMed:21406692). In cytosol can trigger apoptosis by activating MAPK11 or MAPK14, inhibiting AKT1 and decreasing the level of X-linked inhibitor of apoptosis protein (XIAP), whereas in nucleus induces apoptosis via the activation of MAPK8 or MAPK9. Upon ionizing radiation treatment, is required for the activation of the apoptosis regulators BAX and BAK, which trigger the mitochondrial cell death pathway. Can phosphorylate MCL1 and target it for degradation which is sufficient to trigger for BAX activation and apoptosis. Is required for the control of cell cycle progression both at G1/S and G2/M phases. Mediates phorbol 12-myristate 13-acetate (PMA)-induced inhibition of cell cycle progression at G1/S phase by up-regulating the CDK inhibitor CDKN1A/p21 and inhibiting the cyclin CCNA2 promoter activity. In response to UV irradiation can phosphorylate CDK1, which is important for the G2/M DNA damage checkpoint activation (By similarity). Can protect glioma cells from the apoptosis induced by TNFSF10/TRAIL, probably by inducing increased phosphorylation and subsequent activation of AKT1 (PubMed:15774464). Is highly expressed in a number of cancer cells and promotes cell survival and resistance against chemotherapeutic drugs by inducing cyclin D1 (CCND1) and hyperphosphorylation of RB1, and via several pro-survival pathways, including NF-kappa-B, AKT1 and MAPK1/3 (ERK1/2). Involved in antifungal immunity by mediating phosphorylation and activation of CARD9 downstream of C-type lectin receptors activation, promoting interaction between CARD9 and BCL10, followed by activation of NF-kappa-B and MAP kinase p38 pathways (By similarity). Can also act as tumor suppressor upon mitogenic stimulation with PMA or TPA. In N-formyl-methionyl-leucyl-phenylalanine (fMLP)-treated cells, is required for NCF1 (p47-phox) phosphorylation and activation of NADPH oxidase activity, and regulates TNF-elicited superoxide anion production in neutrophils, by direct phosphorylation and activation of NCF1 or indirectly through MAPK1/3 (ERK1/2) signaling pathways (PubMed:19801500). May also play a role in the regulation of NADPH oxidase activity in eosinophil after stimulation with IL5, leukotriene B4 or PMA (PubMed:11748588). In collagen-induced platelet aggregation, acts a negative regulator of filopodia formation and actin polymerization by interacting with and negatively regulating VASP phosphorylation (PubMed:16940418). Downstream of PAR1, PAR4 and CD36/GP4 receptors, regulates differentially platelet dense granule secretion; acts as a positive regulator in PAR-mediated granule secretion, whereas it negatively regulates CD36/GP4-mediated granule release (PubMed:19587372). Phosphorylates MUC1 in the C-terminal and regulates the interaction between MUC1 and beta-catenin (PubMed:11877440). The catalytic subunit phosphorylates 14-3-3 proteins (YWHAB, YWHAZ and YWHAH) in a sphingosine-dependent fashion (By similarity). Phosphorylates ELAVL1 in response to angiotensin-2 treatment (PubMed:18285462). Phosphorylates mitochondrial phospholipid scramblase 3 (PLSCR3), resulting in increased cardiolipin expression on the mitochondrial outer membrane which facilitates apoptosis (PubMed:12649167). Phosphorylates SMPD1 which induces SMPD1 secretion (PubMed:17303575).
Interacts with PDPK1 (via N-terminal region) (PubMed:11781095). Interacts with RAD9A (PubMed:12628935). Interacts with CDCP1 (PubMed:15851033). Interacts with MUC1 (PubMed:11877440). Interacts with VASP (PubMed:16940418). Interacts with CAVIN3 (By similarity). Interacts with PRKD2 (via N-terminus and zing-finger domain 1 and 2) in response to oxidative stress; the interaction is independent of PRKD2 tyrosine phosphorylation (PubMed:28428613). Interacts with PLSC3; interaction is enhanced by UV irradiation (PubMed:12649167). Interacts with PRKCH upstream open reading frame 2; the interaction leads to inhibition of kinase activity (PubMed:34593629).
Novel PKCs (PRKCD, PRKCE, PRKCH and PRKCQ) are calcium-insensitive, but activated by diacylglycerol (DAG) and phosphatidylserine. Three specific sites; Thr-507 (activation loop of the kinase domain), Ser-645 (turn motif) and Ser-664 (hydrophobic region), need to be phosphorylated for its full activation. Activated by caspase-3 (CASP3) cleavage during apoptosis. After cleavage, the pseudosubstrate motif in the regulatory subunit is released from the substrate recognition site of the catalytic subunit, which enables PRKCD to become constitutively activated. The catalytic subunit which displays properties of a sphingosine-dependent protein kinase is activated by D-erythro-sphingosine (Sph) or N,N-dimethyl-D-erythrosphingosine (DMS) or N,N,N-trimethyl-D-erythrosphingosine (TMS), but not by ceramide or Sph-1-P and is strongly inhibited by phosphatidylserine (By similarity). Inhibited by PRKCH upstream open reading frame 2 (PubMed:34593629).
Proteolytically cleaved into a catalytic subunit and a regulatory subunit by caspase-3 during apoptosis which results in kinase activation.
The C1 domain, containing the phorbol ester/DAG-type region 1 (C1A) and 2 (C1B), is the diacylglycerol sensor.
The C2 domain is a non-calcium binding domain. It binds proteins containing phosphotyrosine in a sequence-specific manner.
Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB11 is part of the core element with the central large cleft.
Dimer of identical or non-identical chains, which can be either B (brain type) or M (muscle type). With MM being the major form in skeletal muscle and myocardium, MB existing in myocardium, and BB existing in many tissues, especially brain. Interacts with SLC12A6 (via C-terminus); the interaction may be required for SLC12A6 potassium-chloride cotransport activity (PubMed:18566107).
Reversibly catalyzes the transfer of phosphate between ATP and various phosphogens (e.g. creatine phosphate) (PubMed:8186255). Creatine kinase isoenzymes play a central role in energy transduction in tissues with large, fluctuating energy demands, such as skeletal muscle, heart, brain and spermatozoa (Probable). Acts as a key regulator of adaptive thermogenesis as part of the futile creatine cycle: localizes to the mitochondria of thermogenic fat cells and acts by mediating phosphorylation of creatine to initiate a futile cycle of creatine phosphorylation and dephosphorylation (By similarity). During the futile creatine cycle, creatine and N-phosphocreatine are in a futile cycle, which dissipates the high energy charge of N-phosphocreatine as heat without performing any mechanical or chemical work (By similarity).
The internal MTS-like signal (iMTS-L) mediates targeting to mitochondria thermogenic fat cells.
(Microbial infection) Acts as a receptor for Zika virus.
(Microbial infection) Acts as a receptor for rabies virus.
(Microbial infection) Interacts with Zika virus envelope protein E.
(Microbial infection) Interacts with rabies virus glycoprotein.
Interacts with MDK. Found in a complex with SLC39A6, SLC39A10 and with NCAM1; this complex controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-tomesenchymal transition.
This protein is a cell adhesion molecule involved in neuron-neuron adhesion, neurite fasciculation, outgrowth of neurites, etc.
Conserved additional ATG codons are found 5' of the putative initiator codon in transcripts supporting isoform 1. They may initiate the translation of upstream short open reading frames altering the expression of that isoform as described in PubMed:1849734.
Contains a cryptic mitochondrial transit peptide at positions 1-26.
PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules (By similarity). Interacts with TOMM22 (By similarity). Interacts with IER5 (via N- and C-terminal regions) (PubMed:25816751, PubMed:26496226).
The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment. Within the PP2A holoenzyme complex, isoform 2 is required to promote proapoptotic activity (By similarity). Isoform 2 regulates neuronal survival through the mitochondrial fission and fusion balance (By similarity).
The N-terminal 26 residues of isoform 2 constitute a cryptic mitochondrial matrix import signal with critical basic and hydrophobic residues, that is necessary and sufficient for targeting the PP2A holoenzyme to the outer mitochondrial membrane (OMM) and does not affect holoenzyme formation or catalytic activity.
The last WD repeat of isoform 2 constitutes a mitochondrial stop-transfer domain that confers resistance to the unfolding step process required for import and therefore prevents PPP2R2B matrix translocation and signal sequence cleavage.
Component of a PRC1-like complex. Interacts with RING1 RNF2, PCGF1, PCGF2, PCGF3, BMI1, PCGF5 and PCGF6. Interacts with MLLT3 and histone H3. Interacts with PHC2 (By similarity).
Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility.
Expressed in the middle/upper portions of the hair cortex, in the region termed the keratogenous zone.
Cysteine residues in the cytoplasmic tail are probably palmitoylated.
Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocyte.
Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. Likely functions in the constitutive secretory pathway.
DNA deaminase (cytidine deaminase) with restriction activity against viruses, foreign DNA and mobility of retrotransposons. Exhibits antiviral activity against adeno-associated virus (AAV) and human T-cell leukemia virus type 1 (HTLV-1) and may inhibit the mobility of LTR and non-LTR retrotransposons. Selectively targets single-stranded DNA and can deaminate both methylcytosine and cytosine in foreign DNA. Can induce somatic hypermutation in the nuclear and mitochondrial DNA. May also play a role in the epigenetic regulation of gene expression through the process of active DNA demethylation.
Expressed in peripheral leukocytes with higher expression in CD14-positive phagocytic cells. Highly expressed in keratinocytes and in periphery blood monocytes. Also detected in non-lymphoid tissues including lung and adipose tissues. Found at high levels in colorectal adenocarcinoma, Burkitt's lymphoma and chronic myelogenous leukemia.
Interacts with AGO2. Interacts with TRIB3 (via N-terminus).
Up-regulated by interferon and CpG single-stranded DNA (at protein level).
Belongs to the TAF9 family. CENP-S/MHF1 subfamily.
DNA-binding component of the Fanconi anemia (FA) core complex. Required for the normal activation of the FA pathway, leading to monoubiquitination of the FANCI-FANCD2 complex in response to DNA damage, cellular resistance to DNA cross-linking drugs, and prevention of chromosomal breakage (PubMed:20347428, PubMed:20347429). In complex with CENPX (MHF heterodimer), crucial cofactor for FANCM in both binding and ATP-dependent remodeling of DNA. Stabilizes FANCM (PubMed:20347428, PubMed:20347429). In complex with CENPX and FANCM (but not other FANC proteins), rapidly recruited to blocked forks and promotes gene conversion at blocked replication forks (PubMed:20347428). In complex with CENPT, CENPW and CENPX (CENP-T-W-S-X heterotetramer), involved in the formation of a functional kinetochore outer plate, which is essential for kinetochore-microtubule attachment and faithful mitotic progression (PubMed:19620631). As a component of MHF and CENP-T-W-S-X complexes, binds DNA and bends it to form a nucleosome-like structure (PubMed:20347428, PubMed:22304917). DNA-binding function is fulfilled in the presence of CENPX, with the following preference for DNA substates: Holliday junction > double-stranded > splay arm > single-stranded. Does not bind DNA on its own (PubMed:20347428, PubMed:20347429).
Expression varies across the cell cycle, with highest levels in G2 phase (at protein level). No statistically significant changes at the transcript level.
Heterodimer with CENPX, sometimes called MHF; this interaction stabilizes both partners (PubMed:19620631, PubMed:20347428, PubMed:20347429, PubMed:24522885). MHF heterodimers can assemble to form tetrameric structures (PubMed:22304917). MHF also coassemble with CENPT-CENPW heterodimers at centromeres to form the tetrameric CENP-T-W-S-X complex (PubMed:22304917, PubMed:24522885). Forms a discrete complex with FANCM and CENPX, called FANCM-MHF; this interaction, probably mediated by direct binding between CENPS and FANCM, leads to synergistic activation of double-stranded DNA binding and strongly stimulates FANCM-mediated DNA remodeling (PubMed:20347428, PubMed:20347429). Recruited by FANCM to the Fanconi anemia (FA) core complex, which consists of CENPS, CENPX, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM, FAAP24 and FAAP100. The FA core complex associates with Bloom syndrome (BLM) complex, which consists of at least BLM, DNA topoisomerase 3-alpha (TOP3A), RMI1/BLAP75, RPA1/RPA70 and RPA2/RPA32. The super complex between FA and BLM is called BRAFT (PubMed:20347428, PubMed:20347429). Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex is probably recruited on centromeres by the CENPA-NAC complex, composed of at least CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU (PubMed:16622419).
Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, activation of proteolysis of misfolded proteins and the formation and dissociation of protein complexes. Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation. This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. The affinity for polypeptides is regulated by its nucleotide bound state. In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. It goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release (PubMed:26865365). Positive regulator of PRKN translocation to damaged mitochondria (PubMed:24270810).
The N-terminal nucleotide binding domain (NBD) (also known as the ATPase domain) is responsible for binding and hydrolyzing ATP. The C-terminal substrate-binding domain (SBD) (also known as peptide-binding domain) binds to the client/substrate proteins. The two domains are allosterically coupled so that, when ATP is bound to the NBD, the SBD binds relatively weakly to clients. When ADP is bound in the NBD, a conformational change enhances the affinity of the SBD for client proteins.
Guanine nucleotide exchange factor (GEF) with specificity for RAP2A, it doesn't seems to activate other Ras family proteins (in vitro).
Interacts with Ras family proteins (By similarity). Interacts with CCDC124 during cytokinesis.
Up-regulated in macrophages stimulated with IFNG, GPI-mucins or bacterial lipopolysaccharides (LPS).
Acts as a regulator of the antiangiogenic activity on endothelial cells. When overexpressed in endothelial cells, leads to inhibition of cell proliferation and migration and an increase in apoptosis. Inhibits melanoma growth When expressed in tumor-associated vasculature.
Expressed in endothelial cells, colon and colon cancers. In the colon, expressed in the vasculature and muscularis mucosa. In colon cancer, strongly expressed in tumor stroma and the vasculature (at protein level). Expressed in ovarian epithelial cells. Down-regulated in ovarian cancer.
Up-regulated in endothelial cells with the angiogenesis inhibitors endostatin and fumagillin. By endothelial monocyte-activating polypeptide II in endothelial cells.
A proline/serine/threonine rich region at the C-terminus is necessary for transcriptional activation of target genes.
Expressed in gastric cancer tissues (at protein level).
Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters (By similarity). May be involved in the control of cellular proliferation and/or differentiation. In association with ZFHX3, up-regulates CDKN1A promoter activity following TGF-beta stimulation (PubMed:20599712). CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation. CBF complexes binding to the transcriptional silencer is essential for recruitment of nuclear protein complexes that catalyze epigenetic modifications to establish epigenetic ZBTB7B silencing (By similarity).
Heterodimer with CBFB. RUNX3 binds DNA as a monomer and through the Runt domain. DNA-binding is increased by heterodimerization (By similarity). Interacts with TLE1 and SUV39H1 (PubMed:9751710, PubMed:16652147). The tyrosine phosphorylated form (via runt domain) interacts with SRC (via protein kinase domain) (PubMed:20100835). Interacts with FYN and LCK (PubMed:20100835). Interacts with FOXP3 (PubMed:17377532). Interacts with ZFHX3 (PubMed:20599712). Interacts with TBX21 (By similarity).
Phosphorylated on tyrosine residues by SRC. Phosphorylated by LCK and FYN.
Cytochrome b5 is a membrane-bound hemoprotein functioning as an electron carrier for several membrane-bound oxygenases.
(Microbial infection) Able to palmitoylate SARS coronavirus-2/SARS-CoV-2 spike protein following its synthesis in the endoplasmic reticulum (ER). In the infected cell, promotes spike biogenesis by protecting it from premature ER degradation, increases half-life and controls the lipid organization of its immediate membrane environment. Once the virus has formed, spike palmitoylation controls fusion with the target cell.
According to initial studies, defects in ZDHHC8 may contribute to susceptibility to schizophrenia (PubMed:15489219, PubMed:15184899). However, additional studies could not confirm this (PubMed:15992527, PubMed:15631889, PubMed:16150541).
Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates and therefore functions in several unrelated biological processes (Probable). Through the palmitoylation of ABCA1 regulates the localization of the transporter to the plasma membrane and thereby regulates its function in cholesterol and phospholipid efflux (Probable). Could also pamitoylate the D(2) dopamine receptor DRD2 and regulate its stability and localization to the plasma membrane (Probable). Could also play a role in glutamatergic transmission (By similarity).
Displays several functions associated with host defense: it promotes agglutination, bacterial capsular swelling, phagocytosis and complement fixation through its calcium-dependent binding to phosphorylcholine. Can interact with DNA and histones and may scavenge nuclear material released from damaged circulating cells.
Homopentamer. Pentraxin (or pentaxin) have a discoid arrangement of 5 non-covalently bound subunits. Interacts with FCN1; may regulate monocyte activation by FCN1.
The concentration of CRP in plasma increases greatly during acute phase response to tissue injury, infection or other inflammatory stimuli. It is induced by IL1/interleukin-1 and IL6/interleukin-6.
This protein owes its name to its ability precipitate pneumococcal C-polysaccharide in the presence of calcium.
Acts as a positive regulator of ciliary hedgehog signaling (By similarity). Probable regulator of ciliogenesis involved in limb morphogenesis (PubMed:27528616, PubMed:30395363). In cooperation with CBY1 it is involved in the recruitment and fusion of endosomal vesicles at distal appendages during early stages of ciliogenesis (PubMed:27528616, PubMed:30395363). Plays an important role in the mitochondrial function and is essential for maintaining mitochondrial morphology and inner membrane ultrastructure (PubMed:30404948). In vitro, can generate membrane curvature through preferential interaction with negatively charged phospholipids such as phosphatidylinositol 4,5-bisphosphate and cardiolipin and hence orchestrate cristae shape (PubMed:30404948).
Homodimer (via BAR-like domain) (PubMed:27528616, PubMed:30395363). Heterodimer with FAM92B (via BAR-like domains) (PubMed:27528616). Interacts (via BAR-like domain) with CBY1; this interaction is required for targeting FAM92A to centriole and cilium basal body (PubMed:27528616, PubMed:30395363).
Associates with the Ig-mu chain to form a molecular complex that is expressed on the surface of pre-B-cells. This complex presumably regulates Ig gene rearrangements in the early steps of B-cell differentiation.
Interacts with IGLL1 (PubMed:17431183). Interacts with SYNV1/HRD1 (via N-terminus); this interaction leads to increased VPREB1 ubiquitination and degradation in pre-B cells, possibly through a lysosomal, not proteasomal, pathway (By similarity).
Acetylation at Lys-251 impairs antiapoptotic function.
Antiapoptotic factor that may have a role in protein assembly. Negatively regulates ACIN1. By binding to ACIN1, it suppresses ACIN1 cleavage from CASP3 and ACIN1-mediated DNA fragmentation. Also known to efficiently suppress E2F1-induced apoptosis. Its depletion enhances the cytotoxic action of the chemotherapeutic drugs.
Expressed in all tissues tested, including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Highest levels in heart, pancreas and placenta. Highly expressed in several cancers. Preferentially expressed in squamous cell carcinoma versus adenocarcinoma in non-small cell lung cancer.
Two regions, an N-terminal (aa 96-107) and a C-terminal (aa 274-311) are required for binding FGF2.
May play a role in regulated exocytosis. Modulates the localization of synaptophysin/SYP into synaptic-like microvesicles and may therefore play a role in synaptic-like microvesicle formation and/or maturation (By similarity). Involved in the regulation of short-term and long-term synaptic plasticity (By similarity).
Acts in combination with TSN as an endonuclease involved in the activation of the RNA-induced silencing complex (RISC). Possible role in spermatogenesis.
Ring-shaped heterooctamer of six TSN and two TSNAX subunits. Interacts with GOLGA3, TSNAXIP1, SUN1 and AKAP9. Interacts with the homodimeric form of C1D following gamma-radiation. Interacts with TSN and C1D in a mutually exclusive manner.
Component of the KMT2 family MLL2/MLL3 complex (also named ASCOM complex), at least composed of the HMTs KMT2D and/or KMT2C, the common subunits ASH2L, RBBP5, WDR5 and DPY30, and the complex type-specific subunits PAXIP1/PTIP, PAGR1, NCOA6 and KDM6A; PAXIP1 is required for the association with the MLL2/MLL3 complex (PubMed:17500065). Forms a constitutive complex with PAXIP1/PTIP independently of the MLL2/MLL3 complex (By similarity). Interacts with NCOA1, ESR1, NR3C1, AR (PubMed:19039327, PubMed:19124460, PubMed:23161582).
Its association with the histone methyltransferase MLL2/MLL3 complex is suggesting a role in epigenetic transcriptional activation. However, in association with PAXIP1/PTIP is proposed to function at least in part independently of the MLL2/MLL3 complex. Proposed to be recruited by PAXIP1 to sites of DNA damage where the PAGR1:PAXIP1 complex is required for cell survival in response to DNA damage independently of the MLL2/MLL3 complex (PubMed:19124460). However, its function in DNA damage has been questioned (By similarity). During immunoglobulin class switching in activated B-cells is involved in transcription regulation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus independently of the MLL2/MLL3 complex (By similarity). Involved in both estrogen receptor-regulated gene transcription and estrogen-stimulated G1/S cell-cycle transition (PubMed:19039327). Acts as transcriptional cofactor for nuclear hormone receptors. Inhibits the induction properties of several steroid receptors such as NR3C1, AR and PPARG; the mechanism of inhibition appears to be gene-dependent (PubMed:23161582).
The terminology of MLL proteins in mammalia is not consistent also concerning the terminology of MLL protein-containing complexes. The decribed MLL2/MLL3 complex is commonly described as MLL3/MLL4 complex in literature.
Associated component of the WMM complex, a complex that mediates N6-methyladenosine (m6A) methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing (PubMed:29507755). Required for accumulation of METTL3 and METTL14 to nuclear speckle (PubMed:24316715, PubMed:24407421, PubMed:24981863). Acts as a mRNA splicing regulator (PubMed:12444081). Regulates G2/M cell-cycle transition by binding to the 3' UTR of CCNA2, which enhances its stability (PubMed:17088532). Impairs WT1 DNA-binding ability and inhibits expression of WT1 target genes (PubMed:17095724).
Component of the WMM complex, a N6-methyltransferase complex composed of a catalytic subcomplex, named MAC, and of an associated subcomplex, named MACOM (PubMed:24407421, PubMed:24981863, PubMed:24316715, PubMed:29507755, PubMed:29506078, PubMed:29348140). The MAC subcomplex is composed of METTL3 and METTL14 (PubMed:29507755). The MACOM subcomplex is composed of WTAP, ZC3H13, CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B) (PubMed:29507755). Interacts with WT1 (PubMed:11001926, PubMed:17095724). Also a component of a MACOM-like complex, named WTAP complex, composed of WTAP, ZC3H13, CBLL1, VIRMA, RBM15, BCLAF1 and THRAP3 (PubMed:24100041).
In smooth muscle cells, up-regulated after serum withdrawal, when cells become mature and non proliferative.
Belongs to the Mediator complex subunit 16 family.
Belongs to the opioid neuropeptide precursor family.
Increases glutamate release in the striatum and decreases GABA concentration in the striatum.
Increases glutamate release in the striatum.
Met-enkephalin-Arg-Phe neuropeptide acts as a strong ligand of Mu-type opioid receptor OPRM1. Met-enkephalin-Arg-Phe-binding to OPRM1 in the nucleus accumbens of the brain increases activation of OPRM1, leading to long-term synaptic depression of glutamate release.
Neuropeptide that competes with and mimic the effects of opiate drugs. They play a role in a number of physiologic functions, including pain perception and responses to stress.
Processed by ACE to generate Met-enkephalin in the nucleus accumbens of the brain.
Proenkephalin-A is cleaved by CTSL to generate Met-enkephalin.
The N-terminal domain contains 6 conserved cysteines thought to be involved in disulfide bonding and/or processing.
Transfers the sialyl group (N-acetyl-alpha-neuraminyl or NeuAc) from CMP-NeuAc to the non-reducing terminal galactose (Gal) of glycosphingolipids forming gangliosides (important molecules involved in the regulation of multiple cellular processes, including cell proliferation and differentiation, apoptosis, embryogenesis, development, and oncogenesis) (PubMed:9822625, PubMed:16934889). Mainly involved in the biosynthesis of ganglioside GM3 but can also use different glycolipids as substrate acceptors such as D-galactosylceramide (GalCer), asialo-GM2 (GA2) and asialo-GM1 (GA1), although less preferentially than beta-D-Gal-(1->4)-beta-D-Glc-(1<->1)-Cer (LacCer) (PubMed:16934889).
Ubiquitous. High expression in brain, skeletal muscle, placenta, and testis. mRNA widely distributed in human brain, but slightly elevated expression was observed in the cerebral cortex, temporal lobe, and putamen.
Acidification of the cytosol strongly increases channel permeability to glycerol (PubMed:30420639). Initial experiments showed that isoform 2 is permeable to water, but not to glycerol, but these results were obtained without lowering the cytosolic pH (PubMed:11573934).
Detected in epithelial cells on villi in the ileum, and also in stomach, jejunum, colon, rectum, white adipose tissue and placenta (at protein level) (PubMed:15221416, PubMed:23382902). Expressed in duodenum and jejunum. Highest expression in absorptive epithelial cells at the tips of villi in the jejunum (PubMed:11573934, PubMed:12084581). Detected in subcutaneous adipose tissue (PubMed:23382902).
Water channel that mediates water transport across cell membranes irrespective of the cytosolic pH (PubMed:12084581, PubMed:21733844, PubMed:23382902, PubMed:30420639). The channel is permeable to glycerol, especially when the cytosolic pH is acidified (PubMed:21733844, PubMed:30420639). Contributes to adipocyte water and glycerol permeability, and may thereby contribute to the utilization of glycerol derived from phospholipid degradation (PubMed:23382902). May contribute to water transport in the intestine (Probable).
Water channel that mediates water transport across cell membranes, but that is not permeable to glycerol.
Component of the HAUS augmin-like complex. The complex interacts with the gamma-tubulin ring complex and this interaction is required for spindle assembly. Interacts with EML3 (phosphorylated at 'Thr-881') (PubMed:30723163).
Contributes to mitotic spindle assembly, maintenance of centrosome integrity and completion of cytokinesis as part of the HAUS augmin-like complex.
Although assigned as two separate genes (PPP1R12C and LENG3), it is probable that LENG3 does not exist by itself and is a part of the PPP1R12C gene.
PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, and one or several targeting or regulatory subunits. PPP1R12C mediates binding to myosin. Interacts via its N-terminus with PPP1CB. Interacts with IL16. Interacts with the coiled-coil domain of MPRIP. Interacts with NOD2 (PubMed:27812135).
Phosphorylation at Thr-560 is essential for its interaction with PPP1CB.
Ubiquitously expressed. Highly expressed in heart.
Component of the SCF(FBXO11) complex consisting of CUL1, RBX1, SKP1 and FBXO11. Interacts with p53/TP53, BCL6 and DTL (when not phosphorylated). Interacts with PRMD1. Interacts with TRAF3 (PubMed:36897010). Interacts with CIITA (PubMed:37279268). Interacts with BAHD1 (PubMed:33156908).
Defects in FBXO11 may be a cause of diffuse large B-cell lymphoma by allowing the accumulation of BCL6, an oncoprotein that has a critical role in lymphomas.
Has been initially named PRMT9 and reported to act as an arginine methyltransferase that can catalyze the formation of omega-N monomethylarginine (MMA) as well as symmetrical and asymmetrical dimethylarginine (sDMA and aDMA), however no further works support these observations (PubMed:16487488). It should not be confused with official PRMT9 (AC Q6P2P2).
Isoform 5 is expressed in keratinocytes, fibroblasts and melanocytes.
Protein levels increase during G1 and S phases to decline as cells progress through G2 to enter in G1 phase of the next cell cycle.
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as DTL/CDT2, BCL6 and PRDM1/BLIMP1. The SCF(FBXO11) complex mediates ubiquitination and degradation of BCL6, thereby playing a role in the germinal center B-cells terminal differentiation toward memory B-cells and plasma cells. The SCF(FBXO11) complex also mediates ubiquitination and degradation of DTL, an important step for the regulation of TGF-beta signaling, cell migration and the timing of the cell-cycle progression and exit. Binds to and neddylates phosphorylated p53/TP53, inhibiting its transcriptional activity. Plays a role in the regulatiom of erythropoiesis but not myelopoiesis or megakaryopoiesis. Mechanistically, activates erythroid genes by mediating the degradation of BAHD1, a heterochromatin-associated protein that recruits corepressors to H3K27me3 marks (PubMed:33156908). Participates in macrophage cell death and inflammation in response to bacterial toxins by regulating the expression of complement 5a receptor 1/C5AR1 and IL-1beta (PubMed:33156908). Acts as a critical regulator to determine the level of MHC-II by mediating the recognition of degron at the P/S/T domain of CIITA leading to its ubiquitination and subsequent degradation via the proteasome (PubMed:37279268). Participates in the antiviral repsonse by initiating the activation of TBK1-IRF3-IFN-I axis. Mediates the 'Lys-63'-linked ubiquitination of TRAF3 to strengthen the interaction between TRAF3 and TBK1 (PubMed:36897010).
Inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons.
Belongs to the glycosyl hydrolase 99 family.
Highly expressed in the liver and kidney. Expressed at lower levels in muscle, pancreas, heart, placenta, lung and brain.
Undergoes proteolytic cleavage in the C-terminal region.
Catalyzes the ATP-dependent unwinding of U4/U6 RNA duplices, an essential step in the assembly of a catalytically active spliceosome (PubMed:35241646). Plays a role in pre-mRNA splicing as a core component of precatalytic, catalytic and postcatalytic spliceosomal complexes (PubMed:28502770, PubMed:28781166, PubMed:29361316, PubMed:30315277, PubMed:29360106, PubMed:29301961, PubMed:30728453, PubMed:30705154). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). Involved in spliceosome assembly, activation and disassembly. Mediates changes in the dynamic network of RNA-RNA interactions in the spliceosome.
Component of a core complex containing at least PRPF8, SNRNP200, EFTUD2 and SNRNP40. Component of the U5 snRNP and U4/U6-U5 tri-snRNP complexes, building blocks of the spliceosome. Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39 (PubMed:16723661, PubMed:8670905, PubMed:26912367). Component of precatalytic, catalytic and postcatalytic spliceosomal complexes (PubMed:11991638, PubMed:28502770, PubMed:28781166, PubMed:29361316, PubMed:30315277, PubMed:29360106, PubMed:29301961, PubMed:30728453, PubMed:30705154, PubMed:35241646). Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932). Interacts with C9orf78; the interaction is direct and mutually exclusive with its interaction with WBP4 (PubMed:35241646). Interacts with WBP4; the interaction is mutually exclusive with its interaction with C9orf78 (PubMed:35241646). Interacts with PRPF8 (PubMed:35241646). Interacts with TSSC4; the interaction is direct, excludes recruitment of C9ORF78 and WBP4 to SNRNP200 and negatively regulates its RNA helicase activity (PubMed:35188580).
Contains two helicase domains. The N-terminal helicase domain has catalytic activity by itself, contrary to the C-terminal helicase domain that may have a regulatory role and enhance the activity of the first helicase domain.
Degraded by PCSK6 and other endoproteases including FURIN and PCSK5.
Down-regulated by aldosterone (at protein level). No effect at the transcript level.
Interacts with PCSK6 (immature form including the propeptide); probably involved in the maturation and the secretion of PCSK6.
Probable molecular chaperone assisting protein biosynthesis and transport in the endoplasmic reticulum (PubMed:16433634, PubMed:28939891). Required for the proper biosynthesis and transport of pulmonary surfactant-associated protein A/SP-A, pulmonary surfactant-associated protein D/SP-D and the lipid transporter ABCA3 (By similarity). By regulating both the proper expression and the degradation through the endoplasmic reticulum-associated protein degradation pathway of these proteins plays a crucial role in pulmonary surfactant homeostasis (By similarity). Has an anti-fibrotic activity by negatively regulating the secretion of type I and type III collagens (PubMed:28939891). This calcium-binding protein also transiently associates with immature PCSK6 and regulates its secretion (PubMed:16433634).
Belongs to the pyrroline-5-carboxylate reductase family.
Detected in erythrocytes (at protein level) (PubMed:2722838, PubMed:6894153). Expressed in fetal brain (PubMed:25865492).
Homodecamer; composed of 5 homodimers (Probable). Interacts with LTO1 (PubMed:24930674).
Housekeeping enzyme that catalyzes the last step in proline biosynthesis. In some cell types, such as erythrocytes, its primary function may be the generation of NADP(+). Can utilize both NAD and NADP. Has higher affinity for NADP, but higher catalytic efficiency with NADH (PubMed:2722838, PubMed:6894153). Involved in cellular response to oxidative stress (PubMed:25865492).
Subject to competitive inhibition by NADP. Not inhibited by proline.
Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor (PubMed:10464263, PubMed:31932717). May participate in synthesis of oncofetal fibronectin (PubMed:10464263). Has activity toward MUC1A, MUC2, EA2 and fibronectin peptides (PubMed:10464263). Glycosylates FGF23 (PubMed:31932717).
Expressed in placenta and trachea. Weakly expressed in brain and pancreas. Expressed in fibroblast. Weakly or not expressed in lung, liver, muscle, kidney, spleen, thymus, prostate, testis, ovary, intestine, colon, leukocyte, stomach, thyroid, spinal cord, lymph node, trachea, adrenal gland and bone marrow.
A chromosomal aberration involving EVI1 is a cause of chronic myelogenous leukemia (CML). Translocation t(3;21)(q26;q22) with RUNX1/AML1.
A chromosomal aberration involving MDS1 is found in a form of acute myeloid leukemia (AML). Translocation t(3;21) with AML1.
Both zinc finger regions are required for the transcriptional activation of PBX1.
Chimeric cDNA that is the result of a chromosomal aberration involving EVI1 and RUNX1.
Displays histone methyltransferase activity and monomethylates 'Lys-9' of histone H3 (H3K9me1) in vitro. Probably catalyzes the monomethylation of free histone H3 in the cytoplasm which is then transported to the nucleus and incorporated into nucleosomes where SUV39H methyltransferases use it as a substrate to catalyze histone H3 'Lys-9' trimethylation. Likely to be one of the primary histone methyltransferases along with PRDM16 that direct cytoplasmic H3K9me1 methylation.
Functions as a transcriptional regulator binding to DNA sequences in the promoter region of target genes and regulating positively or negatively their expression. Oncogene which plays a role in development, cell proliferation and differentiation. May also play a role in apoptosis through regulation of the JNK and TGF-beta signaling. Involved in hematopoiesis.
Homooligomer. Interacts with SUV39H1 (via SET domain); enhances MECOM transcriptional repression activity (By similarity). Interacts with CTBP1. Interacts with SMAD3 (via MH2 domain); the interaction is direct. Interacts with SMAD4; through interaction with SMAD3. Interacts with CREBBP, KAT2B and histone deacetylases. Interacts with MAPK8 and MAPK9; inhibits JNK signaling (PubMed:10856240, PubMed:11568182, PubMed:15897867, PubMed:9665135).
Produced by alternative promoter usage. Unable to form homooligomers, to interact with CTBP1 and SMAD3 and to repress TGF-beta signaling.
(Microbial infection) Negatively regulates immunodeficiency virus type 1 (HIV-1) replication by preventing the accumulation of viral mRNA transcripts in the cytoplasm.
Arg-739 is dimethylated, probably to asymmetric dimethylarginine (Ref.8). Arg-733 is dimethylated, probably to asymmetric dimethylarginine (By similarity).
Cleaved at Asp-100 by CASP3 during T-cell apoptosis, resulting in a loss of DNA- and chromatin-binding activities (PubMed:9405365, PubMed:10671544).
DNA- and RNA-binding protein involved in several cellular processes such as nuclear chromatin organization, telomere-length regulation, transcription, mRNA alternative splicing and stability, Xist-mediated transcriptional silencing and mitotic cell progression (PubMed:10490622, PubMed:18082603, PubMed:19029303, PubMed:22325991, PubMed:25986610, PubMed:28622508). Plays a role in the regulation of interphase large-scale gene-rich chromatin organization through chromatin-associated RNAs (caRNAs) in a transcription-dependent manner, and thereby maintains genomic stability (PubMed:1324173, PubMed:8174554, PubMed:28622508). Required for the localization of the long non-coding Xist RNA on the inactive chromosome X (Xi) and the subsequent initiation and maintenance of X-linked transcriptional gene silencing during X-inactivation (By similarity). Plays a role as a RNA polymerase II (Pol II) holoenzyme transcription regulator (PubMed:8174554, PubMed:9353307, PubMed:10490622, PubMed:15711563, PubMed:19617346, PubMed:23811339). Promotes transcription initiation by direct association with the core-TFIIH basal transcription factor complex for the assembly of a functional pre-initiation complex with Pol II in a actin-dependent manner (PubMed:10490622, PubMed:15711563). Blocks Pol II transcription elongation activity by inhibiting the C-terminal domain (CTD) phosphorylation of Pol II and dissociates from Pol II pre-initiation complex prior to productive transcription elongation (PubMed:10490622). Positively regulates CBX5-induced transcriptional gene silencing and retention of CBX5 in the nucleus (PubMed:19617346). Negatively regulates glucocorticoid-mediated transcriptional activation (PubMed:9353307). Key regulator of transcription initiation and elongation in embryonic stem cells upon leukemia inhibitory factor (LIF) signaling (By similarity). Involved in the long non-coding RNA H19-mediated Pol II transcriptional repression (PubMed:23811339). Participates in the circadian regulation of the core clock component BMAL1 transcription (By similarity). Plays a role in the regulation of telomere length (PubMed:18082603). Plays a role as a global pre-mRNA alternative splicing modulator by regulating U2 small nuclear ribonucleoprotein (snRNP) biogenesis (PubMed:22325991). Plays a role in mRNA stability (PubMed:17174306, PubMed:17289661, PubMed:19029303). Component of the CRD-mediated complex that promotes MYC mRNA stabilization (PubMed:19029303). Enhances the expression of specific genes, such as tumor necrosis factor TNFA, by regulating mRNA stability, possibly through binding to the 3'-untranslated region (UTR) (PubMed:17174306). Plays a role in mitotic cell cycle regulation (PubMed:21242313, PubMed:25986610). Involved in the formation of stable mitotic spindle microtubules (MTs) attachment to kinetochore, spindle organization and chromosome congression (PubMed:21242313). Phosphorylation at Ser-59 by PLK1 is required for chromosome alignement and segregation and progression through mitosis (PubMed:25986610). Contributes also to the targeting of AURKA to mitotic spindle MTs (PubMed:21242313). Binds to double- and single-stranded DNA and RNA, poly(A), poly(C) and poly(G) oligoribonucleotides (PubMed:1628625, PubMed:8068679, PubMed:8174554, PubMed:9204873, PubMed:9405365). Binds to chromatin-associated RNAs (caRNAs) (PubMed:28622508). Associates with chromatin to scaffold/matrix attachment region (S/MAR) elements in a chromatin-associated RNAs (caRNAs)-dependent manner (PubMed:7509195, PubMed:1324173, PubMed:9204873, PubMed:9405365, PubMed:10671544, PubMed:11003645, PubMed:11909954, PubMed:28622508). Binds to the Xist RNA (PubMed:26244333). Binds the long non-coding H19 RNA (PubMed:23811339). Binds to SMN1/2 pre-mRNAs at G/U-rich regions (PubMed:22325991). Binds to small nuclear RNAs (snRNAs) (PubMed:22325991). Binds to the 3'-UTR of TNFA mRNA (PubMed:17174306). Binds (via RNA-binding RGG-box region) to the long non-coding Xist RNA; this binding is direct and bridges the Xist RNA and the inactive chromosome X (Xi) (By similarity). Also negatively regulates embryonic stem cell differentiation upon LIF signaling (By similarity). Required for embryonic development (By similarity). Binds to brown fat long non-coding RNA 1 (Blnc1); facilitates the recruitment of Blnc1 by ZBTB7B required to drive brown and beige fat development and thermogenesis (By similarity).
Extensively phosphorylated (PubMed:7993898). Phosphorylated on Ser-59 by PLK1 and dephosphorylated by protein phosphatase 2A (PP2A) in mitosis (PubMed:25986610).
Oligomer (via ATPase domain and RNA-binding RGG-box region); oligomerization occurs upon ATP-binding in a chromatin-associated RNAs (caRNAs)- and transcription-dependent manner and is required for chromatin decompaction (PubMed:28622508). ATP hydrolysis is required to cycle from an oligomeric to monomeric state to compact chromatin (PubMed:28622508). Component of the coding region determinant (CRD)-mediated complex, composed of DHX9, HNRNPU, IGF2BP1, SYNCRIP and YBX1 (PubMed:19029303). Identified in the spliceosome C complex (PubMed:11991638). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661, PubMed:19029303). Associates with heterogeneous nuclear ribonucleoprotein (hnRNP) particles (PubMed:8174554, PubMed:9204873, PubMed:9405365, PubMed:11909954). Associates (via middle region) with the C-terminal domain (CTD) RNA polymerase II (Pol II) holoenzyme; this association occurs in a RNA-independent manner (PubMed:10490622). Associates (via middle region) with the core-TFIIH basal transcription factor complex; this association inhibits the CTD phosphorylation of RNA polymerase II holoenzyme by down-regulating TFIIH kinase activity (PubMed:10490622). Associates with the telomerase holoenzyme complex (PubMed:18082603). Associates with spindle microtubules (MTs) in a TPX2-dependent manner (PubMed:21242313). Interacts (via C-terminus) with actin; this interaction is direct and mediates association with the phosphorylated CTD of RNA polymerase II and is disrupted in presence of the long non-coding H19 RNA (PubMed:15711563, PubMed:23811339). Interacts with AURKA (PubMed:21242313, PubMed:25986610). Interacts (via C-terminus) with CBX5; this interaction is, at least in part, RNA-dependent (PubMed:19617346). Interacts with CR2 (PubMed:7753047). Interacts with CRY1 (By similarity). Interacts (via C-terminus) with EP300; this interaction enhances DNA-binding to nuclear scaffold/matrix attachment region (S/MAR) elements (PubMed:11909954). Interacts with ERBB4 (PubMed:20858735). Interacts with GEMIN5 (PubMed:25911097). Interacts with IGF2BP1 (PubMed:17289661, PubMed:23640942). Interacts with IGF2BP2 and IGF2BP3 (PubMed:23640942). Interacts with NCL; this interaction occurs during mitosis (PubMed:21242313). Interacts (via C-terminus) with NR3C1 (via C-terminus) (PubMed:9353307). Interacts with PLK1; this interaction induces phosphorylation of HNRNPU at Ser-59 in mitosis (PubMed:25986610). Interacts with POU3F4 (PubMed:9105675). Interacts with SMARCA4; this interaction occurs in embryonic stem cells and stimulates global Pol II-mediated transcription. Interacts (via C-terminus) with TOP2A; this interaction protects the topoisomerase TOP2A from degradation and positively regulates the relaxation of supercoiled DNA by TOP2A in a RNA-dependent manner (By similarity). Interacts with TPX2; this interaction recruits HNRNPU to spindle microtubules (MTs) (PubMed:21242313, PubMed:25986610). Interacts with UBQLN2 (PubMed:25616961). Interacts (via RNA-binding RGG-box region) with ZBTB7B; the interaction facilitates the recruitment of long non-coding RNA Blnc1 by ZBTB7B (By similarity). Interacts with ERCC6 (PubMed:26030138).
The SAP domain is necessary for specific binding to nuclear scaffold/matrix attachment region (S/MAR) elements in DNA (PubMed:9405365, PubMed:11003645). The RNA-binding RGG-box region is necessary for its association with inactive X chromosome (Xi) regions and to chromatin-associated RNAs (caRNAs) (PubMed:14608463, PubMed:28622508). Both the DNA-binding domain SAP and the RNA-binding RGG-box region are necessary for the localization of Xist RNA on the Xi (By similarity). The ATPase and RNA-binding RGG-box regions are necessary for oligomerization (PubMed:28622508).
Phosphorylated and activated in vitro upon phosphorylation at Ser-74 by CSNK1D/CK1.
Phosphorylates the deoxyribonucleosides deoxycytidine, deoxyguanosine and deoxyadenosine (PubMed:1996353, PubMed:12808445, PubMed:18377927, PubMed:19159229, PubMed:20614893, PubMed:20637175). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents (PubMed:12808445).
Was shown to be phosphorylated and activated by CSNK1D/CK1 in vitro but probably not in vivo.
Regulatory subunit of serine/threonine-protein phosphatase 4. May regulate the activity of PPP4C at centrosomal microtubule organizing centers. The PPP4C-PPP4R2-PPP4R3A PP4 complex specifically dephosphorylates H2AX phosphorylated on 'Ser-140' (gamma-H2AX) generated during DNA replication and required for DNA DSB repair.
Serine/threonine-protein phosphatase 4 (PP4) occurs in different assemblies of the catalytic and one or more regulatory subunits. Component of the PP4 complex PPP4C-PPP4R2-PPP4R3A. Interacts with PPP4C; the interaction requires PPP4R2.
A chromosomal aberration involving CYTSB may be a cause of juvenile myelomonocytic leukemia. Translocation t(5;17)(q33;p11.2) with PDGFRB.
Highly expressed in testis. Barely detectable in other tissues. Also highly expressed in some cancer cell lines.
Expressed in the fetal and adult brain, testis, uterus, spleen and liver.
May have a role in protein folding or as a chaperone.
Not expressed in 8 and 10 weeks old fetuses.
Gene prediction based on EST data and similarity to mouse ortholog.
Cleaves preferentially after uridine bases (PubMed:3467790). Has antimicrobial activity against uropathogenic E.coli (UPEC) (PubMed:33818125). Probably contributes to urinary tract sterility (PubMed:33818125).
Expressed in the cortical and medullary tubules of the kidney, and in the transitional epithelium of the urinary bladder (at protein level).
Belongs to the cyclin-dependent kinase 5 activator family.
Heterodimer of a catalytic subunit and a regulatory subunit.
Myristoylated. The Gly-2-Ala mutant is absent of the cell periphery, suggesting that a proper myristoylation signal is essential for the proper distribution of CDK5R2 (p39).
Abundantly expressed in CNS. Widely expressed at low levels. Detected in dorsal root ganglion (at protein level). Expressed in the keratinocyte layers of the outer root sheath and, to lesser extent, to the matrix of the hair follicles (at protein level).
Belongs to the transient receptor (TC 1.A.4) family. TrpV subfamily. TRPV3 sub-subfamily.
May form a heteromeric channel with TRPV1. Interacts with TRPV1.
Putative receptor-activated non-selective calcium permeant cation channel. It is activated by innocuous (warm) temperatures and shows an increased response at noxious temperatures greater than 39 degrees Celsius. Activation exhibits an outward rectification. May associate with TRPV1 and may modulate its activity. Is a negative regulator of hair growth and cycling: TRPV3-coupled signaling suppresses keratinocyte proliferation in hair follicles and induces apoptosis and premature hair follicle regression (catagen).
Heterodimer with EID2B. Interacts with the C-terminus of EP300. Interacts with HDAC1 and HDAC2. Interacts with SMAD2, SMAD4 and with the MH2 domain of SMAD3.
Interacts with EP300 and acts as a repressor of MYOD-dependent transcription and muscle differentiation. Inhibits EP300 histone acetyltransferase activity. Acts as a repressor of TGFB/SMAD transcriptional responses. May act as a repressor of the TGFB/SMAD3-dependent signaling by selectively blocking formation of TGFB-induced SMAD3-SMAD4 complex.
Most abundantly expressed in placenta. Highly expressed in liver, brain, heart, skeletal muscle, and kidney.
The N-terminal portion of EID2 is required for nuclear localization.
Functions as a component of the PCAF complex. The PCAF complex is capable of efficiently acetylating histones in a nucleosomal context. The PCAF complex could be considered as the human version of the yeast SAGA complex. Also known as a coactivator for p53/TP53-dependent transcriptional activation. Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4.
The PCAF complex is composed of a number of TBP-associated factors (TAFS), such as TAF5, TAF5L, TAF6, TAF6L, TAF9, TAF10 and TAF12, PCAF, and also PCAF-associated factors (PAFs), such as TADA2L/ADA2, TADA3L/ADA3 and SPT3. Interacts directly with TADA2L and PCAF and also with the high-risk HPV oncoprotein E6. Component of the STAGA transcription coactivator-HAT complex, at least composed of SUPT3H, GCN5L2, TAF5L, TAF6L, SUPT7L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9. Component of the TFTC-HAT complex. Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1.
Calcium-dependent lectin that mediates cell adhesion by binding to glycoproteins on neighboring cells (PubMed:12403782, PubMed:28489325, PubMed:28011641). Mediates the adherence of lymphocytes to endothelial cells of high endothelial venules in peripheral lymph nodes. Promotes initial tethering and rolling of leukocytes in endothelia (PubMed:12403782, PubMed:28011641).
Expressed in B-cell lines and T-lymphocytes.
Interaction with SELPLG/PSGL1 and PODXL2 is required for promoting recruitment and rolling of leukocytes. This interaction is dependent on the sialyl Lewis X glycan modification of SELPLG and PODXL2, and tyrosine sulfation modifications of SELPLG. Sulfation on 'Tyr-51' of SELPLG is important for L-selectin binding.
Essential to the formation of horizontal top connectors between outer hair cell stereocilia.
Belongs to the complex I subunit 4 family.
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:8644732, PubMed:8344246, PubMed:15250827). Essential for the catalytic activity and assembly of complex I (PubMed:8644732, PubMed:8344246, PubMed:15250827).
Adapter protein which associates with tyrosine-phosphorylated growth factor receptors or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling.
Interacts with DOCK1, LIMS1 and TGFB1I1. Part of a complex containing PPP1R15B, PP1 and NCK2. Interacts with FASLG (By similarity). Interacts with AXL. Interacts with PAK1, PKN2 and SOS1. Interacts (via SH2 domain) with EGFR. Interacts (via SH2 domain) with DDR1.
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:25849773, PubMed:27462815). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation. The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression (PubMed:25849773).
Specific and highly efficient GDP-D-glucose phosphorylase regulating the levels of GDP-D-glucose in cells.
The orthologs in A.thaliana are GDP-L-galactose phosphorylases catalyzing the first reaction of the Smirnoff-Wheeler pathway, the major route to ascorbate biosynthesis in plants.
Component of a PRC1-like complex (PubMed:12167701, PubMed:15386022, PubMed:19636380, PubMed:21282530). Interacts with CBX4 (PubMed:21282530). Interacts with BMI1, PCGF2, PHC1 and RNF2 (PubMed:9121482, PubMed:9199346, PubMed:12167701). Interacts with CHTOP (By similarity). Interacts with the N-terminal region of the SP1 transcription factor and with MAPKAPK2 (PubMed:10976766, PubMed:15094067).
HD1 motif interacts with SAM domain of PHC1.
Decapping scavenger enzyme that catalyzes the cleavage of a residual cap structure following the degradation of mRNAs by the 3'->5' exosome-mediated mRNA decay pathway.
Decapping scavenger enzyme that catalyzes the cleavage of a residual cap structure following the degradation of mRNAs by the 3'->5' exosome-mediated mRNA decay pathway. Hydrolyzes cap analog structures like 7-methylguanosine nucleoside triphosphate (m7GpppG) with up to 10 nucleotide substrates (small capped oligoribonucleotides) and specifically releases 5'-phosphorylated RNA fragments and 7-methylguanosine monophosphate (m7GMP). Cleaves cap analog structures like tri-methyl guanosine nucleoside triphosphate (m3(2,2,7)GpppG) with very poor efficiency. Does not hydrolyze unmethylated cap analog (GpppG) and shows no decapping activity on intact m7GpppG-capped mRNA molecules longer than 25 nucleotides. Does not hydrolyze 7-methylguanosine diphosphate (m7GDP) to m7GMP (PubMed:22985415). May also play a role in the 5'->3 mRNA decay pathway; m7GDP, the downstream product released by the 5'->3' mRNA mediated decapping activity, may be also converted by DCPS to m7GMP (PubMed:14523240). Binds to m7GpppG and strongly to m7GDP. Plays a role in first intron splicing of pre-mRNAs. Inhibits activation-induced cell death.
Detected in liver, brain, kidney, testis and prostate.
Homodimer. Associates with components of the exosome multienzyme ribonuclease complex, such as EXOSC3 and EXOSC4. Interacts with NDOR1.
The C-terminal histidine triad (HIT) motif and the N-terminal domain are required for the decapping activity. The N-terminus is necessary but not sufficient for binding cap structures.
The hydrolytic product 7-methylguanosine diphosphate (m7GDP) efficiently inhibits the decapping scavenger activity and acts as a competitive inhibitor in vitro. Inhibited by 2,4-diaminoquinazoline.
Up-regulated by menadione. Up-regulated by the transcription factor LTF isoform delta-lactoferrin (at protein level).
Detected only in stomach mucosa and testis, and to a much lesser level in pancreas (at protein level). Detected in gastric cancers (31%), esophageal carcinomas (50%) and ovarian cancers (23%).
Highly N-glycosylated. Appears not to contain significant amounts of O-linked carbohydrates or sialic acid in its sugar moieties.
Belongs to the metallo-beta-lactamase superfamily. RNA-metabolizing metallo-beta-lactamase-like family. CPSF3 subfamily.
Component of the cleavage and polyadenylation specificity factor (CPSF) complex that plays a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. Has endonuclease activity, and functions as mRNA 3'-end-processing endonuclease (PubMed:30507380). Also involved in the histone 3'-end pre-mRNA processing (PubMed:30507380). U7 snRNP-dependent protein that induces both the 3'-endoribonucleolytic cleavage of histone pre-mRNAs and acts as a 5' to 3' exonuclease for degrading the subsequent downstream cleavage product (DCP) of mature histone mRNAs. Cleavage occurs after the 5'-ACCCA-3' sequence in the histone pre-mRNA leaving a 3'hydroxyl group on the upstream fragment containing the stem loop (SL) and 5' phosphate on the downstream cleavage product (DCP) starting with CU nucleotides. The U7-dependent 5' to 3' exonuclease activity is processive and degrades the DCP RNA substrate even after complete removal of the U7-binding site. Binds to the downstream cleavage product (DCP) of histone pre-mRNAs and the cleaved DCP RNA substrate in a U7 snRNP dependent manner. Required for entering/progressing through S-phase of the cell cycle (PubMed:30507380). Required for the selective processing of microRNAs (miRNAs) during embryonic stem cell differentiation via its interaction with ISY1 (By similarity). Required for the biogenesis of all miRNAs from the pri-miR-17-92 primary transcript except miR-92a (By similarity). Only required for the biogenesis of miR-290 and miR-96 from the pri-miR-290-295 and pri-miR-96-183 primary transcripts, respectively (By similarity).
Component of the cleavage and polyadenylation specificity factor (CPSF) complex, composed of CPSF1, CPSF2, CPSF3, CPSF4 and FIP1L1. Interacts with CPSF2, CSTF2 and SYMPK. Interacts with TUT1; the interaction is direct and mediates the recruitment of the CPSF complex on the 3'UTR of pre-mRNAs. Interacts with WDR33. Interacts with ZC3H3 (By similarity).
Sumoylated on Lys-462, Lys-465 and Lys-545, preferentially by SUMO3.
A chromosomal aberration involving TRIP11 may be a cause of acute myelogenous leukemia. Translocation t(5;14)(q33;q32) with PDGFRB. The fusion protein may be involved in clonal evolution of leukemia and eosinophilia.
Highly expressed in pancreas, muscle, heart, testis, peripheral blood leukocytes, and in several leukemia cell lines. Detected at intermediate levels in placenta and kidney, and at low levels in brain and lung. Isoform 1 and isoform 2 are expressed in articular chondrocytes (PubMed:30728324).
Interacts with the active form of RAB2A (PubMed:25473115). Interacts with IFT20 (PubMed:19112494). Binds RB1.
Is a membrane tether required for vesicle tethering to Golgi. Has an essential role in the maintenance of Golgi structure and function (PubMed:25473115, PubMed:30728324). It is required for efficient anterograde and retrograde trafficking in the early secretory pathway, functioning at both the ER-to-Golgi intermediate compartment (ERGIC) and Golgi complex (PubMed:25717001). Binds the ligand binding domain of the thyroid receptor (THRB) in the presence of triiodothyronine and enhances THRB-modulated transcription.
The C-terminus is required for recruitment to the Golgi apparatus and endoplasmic reticulum-Golgi intermediate compartment.
May be involved in several stages of intracellular trafficking. Could play an important role in the regulation of glucose transport by insulin. May act as a downstream effector of RHOQ/TC10 in the regulation of insulin-stimulated glucose transport (By similarity).
Specifically interacts with CDC42 and RHOQ/TC10 through its Rho-GAP domain (By similarity). Interacts with NEK6.
Belongs to the methyltransferase TRM13 family.
tRNA methylase which 2'-O-methylates cytidine(4) in tRNA(Pro) and tRNA(Gly)(GCC), and adenosine(4) in tRNA(His).
Interacts (via N-terminal region) with beta-catenin/CTNNB1 (via the central armadillo domains); interaction is direct and stabilizes CTNNB1 by modulating its phosphorylation by glycogen synthase kinase-3 beta GSK3B.
May be involved in transcriptional regulation. May mediate some of the neuroprotective peptide VIP-associated effects involving normal growth and cancer proliferation. Positively modulates WNT-beta-catenin/CTNN1B signaling, acting by regulating phosphorylation of, and thereby stabilizing, CTNNB1. May be required for neural induction and neuronal differentiation. May be involved in erythroid differentiation (By similarity).
When isolated from the sequence, neuroprotective peptide (NAP) provides neuroprotection against the amyloid-beta peptide.
Widely expressed. Strong expression in heart, skeletal muscle, kidney and placenta. In brain, expression is stronger in the cerebellum and cortex regions. No expression detected in the colon. Strong increase of expression in colon and breast cancer tissues.
Expressed in a tissue-restricted manner compared to HAPSTR1.
Homooligomer (PubMed:36631436). Heterooligomer with HAPSTR1; the interaction is direct and stabilizes HAPSTR1 independently of HUWE1 (PubMed:36631436). Interacts with HUWE1 (PubMed:36631436).
Together with HAPSTR1 plays a central regulatory role in the cellular response to molecular stressors, such as DNA damage, nutrient scarcity, and protein misfolding (PubMed:36631436). Regulates these multiple stress response signaling pathways by stabilizing HAPSTR1, but also independently of HAPSTR1 (PubMed:36631436).
DNA-binding transcriptional factor that plays a role in a broad range of cellular and developmental processes such as eye, bones, cardiovascular, kidney and skin development (PubMed:11782474, PubMed:15299087, PubMed:15684392, PubMed:16492674, PubMed:27907090, PubMed:14506133, PubMed:14578375, PubMed:15277473, PubMed:16449236, PubMed:17210863, PubMed:19793056, PubMed:19279310, PubMed:25786029, PubMed:27804176). Acts either as a transcriptional activator or repressor (PubMed:11782474). Binds to the consensus binding site 5'-[G/C][A/T]AAA[T/C]AA[A/C]-3' in promoter of target genes (PubMed:7957066, PubMed:11782474, PubMed:12533514, PubMed:14506133, PubMed:19793056, PubMed:27804176). Upon DNA-binding, promotes DNA bending (PubMed:7957066, PubMed:14506133). Acts as a transcriptional coactivator (PubMed:26565916). Stimulates Indian hedgehog (Ihh)-induced target gene expression mediated by the transcription factor GLI2, and hence regulates endochondral ossification (By similarity). Acts also as a transcriptional coregulator by increasing DNA-binding capacity of GLI2 in breast cancer cells (PubMed:26565916). Regulates FOXO1 through binding to a conserved element, 5'-GTAAACAAA-3' in its promoter region, implicating FOXC1 as an important regulator of cell viability and resistance to oxidative stress in the eye (PubMed:17993506). Cooperates with transcription factor FOXC2 in regulating expression of genes that maintain podocyte integrity (By similarity). Promotes cell growth inhibition by stopping the cell cycle in the G1 phase through TGFB1-mediated signals (PubMed:12408963). Involved in epithelial-mesenchymal transition (EMT) induction by increasing cell proliferation, migration and invasion (PubMed:20406990, PubMed:22991501). Involved in chemokine CXCL12-induced endothelial cell migration through the control of CXCR4 expression (By similarity). Plays a role in the gene regulatory network essential for epidermal keratinocyte terminal differentiation (PubMed:27907090). Essential developmental transcriptional factor required for mesoderm-derived tissues, such as the somites, skin, bone and cartilage. Positively regulates CXCL12 and stem cell factor expression in bone marrow mesenchymal progenitor cells, and hence plays a role in the development and maintenance of mesenchymal niches for haematopoietic stem and progenitor cells (HSPC). Plays a role in corneal transparency by preventing both blood vessel and lymphatic vessel growth during embryonic development in a VEGF-dependent manner. Involved in chemokine CXCL12-induced endothelial cell migration through the control of CXCR4 expression (By similarity). May function as a tumor suppressor (PubMed:12408963).
Expressed in keratinocytes of epidermis and hair follicle (PubMed:27907090). Expressed strongly in microvascular invasion (MVI) formation, basal-like breast cancer (BLBC) and hepatocellular tumors (PubMed:20406990, PubMed:22991501). Expressed in breast cancers (at protein level) (PubMed:26565916). Expressed in hematopoietic cells (PubMed:8499623).
Monomer. Interacts with C1QBP (PubMed:18676636). Interacts (via N-terminus) with GLI2 (via C-terminal internal region); this interaction is direct and increases GLI2 DNA-binding and transcriptional activity through a smoothened (SMO)-independent Hedgehog (Hh) signaling pathway (PubMed:26565916). Interacts (via C-terminus domain) with PITX2 isoform 3 (via homeobox domain) (PubMed:16449236). Interacts with FLNA and PBX1 (PubMed:15684392).
Phosphorylated (PubMed:11782474, PubMed:19279310, PubMed:25786029). Phosphorylated on Ser-272 in response to epidermal growth factor (EGF) in a ERK1/2 MAPK-dependent signaling pathway; phosphorylation contributes to its protein stability and transcriptional activity (PubMed:16492674).
Sumoylated preferentially with SUMO2 or SUMO3 (PubMed:22493429). Desumoylated by SENP2 (PubMed:22493429).
Ubiquitinated, leading to its proteasomal degradation (PubMed:16492674).
Up-regulated during the progression of epidermal keratinocyte differentiation (at protein level) (PubMed:27907090). Up-regulated upon calcium-mediated keratinocyte differentiation (PubMed:27907090). Up-regulated by transforming growth factor TGFB1 (PubMed:12408963).
(Microbial infection) Probably cleaved by P.falciparum SERA6; the cleavage probably causes the disruption of the actin cytoskeleton and the rupture of the erythrocyte cell membrane releasing the merozoites.
Component of the ankyrin-1 complex in the erythrocyte, composed of ANK1, RHCE, RHAG, SLC4A1, EPB42, GYPA, GYPB and AQP1 (PubMed:35835865). Interacts with a number of integral membrane proteins and cytoskeletal proteins. Interacts (via N-terminus) with SPTB/spectrin (beta chain). Also interacts with TTN/titin. Isoform Mu17 interacts with OBSCN isoform 3/obscurin. Interacts with HIF1AN. Interacts (via ANK 1-5 repeats) with RHCE; this interaction mediates the primary membrane attachment site for ANK1 (PubMed:35835865). Interacts (via ANK 1-2 repeats) with AQP1 (via the N-terminal) (PubMed:35835865). Interacts (via ANK 1-13 repeats) with EPB42 (PubMed:35835865). Interacts directly with SLC4A1 (via the cytoplasmic domain); this interaction is mediated by the SLC4A1 Band 3-II and Band 3-III dimers (PubMed:35835865, PubMed:7665627).
Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane (PubMed:35835865). Attaches integral membrane proteins to cytoskeletal elements; binds to the erythrocyte membrane protein band 4.2, to Na-K ATPase, to the lymphocyte membrane protein GP85, and to the cytoskeletal proteins fodrin, tubulin, vimentin and desmin. Erythrocyte ankyrins also link spectrin (beta chain) to the cytoplasmic domain of the erythrocytes anion exchange protein; they retain most or all of these binding functions.
Hydroxylated by HIF1AN at several asparagine and 1 aspartate residue within ANK repeat region. Hydroxylation seems to increase the conformational stability of this region and may also modulate protein-protein interactions mediated by the ANK repeat region.
Isoform Mu17, isoform Mu18, isoform Mu19 and isoform Mu20 are expressed in skeletal muscle. Isoform Br21 is expressed in brain.
Major erythrocyte-specific isoform. Produced by alternative promoter usage.
Predominant form of minor erythrocyte-specific isoforms. Produced by alternative splicing of isoform Er1.
Produced by alternative splicing of isoform Er1.
Produced by alternative splicing of isoform Mu17.
The 55 kDa regulatory domain is involved in regulating binding of SPTB/spectrin (beta chain) and SLC4A1/erythrocyte membrane protein band 3.
The ANK repeat region forms a spiral around a large central cavity and is involved in binding of ion transporters. Adopts a T-shaped arrangement, in the ankyrin-1 complex, in which ANK 1-5 repeats are orthogonal to ANK 6-24 repeats, with the peptide binding groove of ANK 1-5 repeats oriented toward the membrane (PubMed:35835865). The rearrangement of the ANK 1-5 repeats orients the canonical protein binding groove to directly face the membrane, to interact the membrane-embedded targets RHCE and AQP1 (PubMed:35835865).
The tandem configuration of the two ZU5 and the UPA domains forms a structural supramodule termed ZZU. ZU5-1 mediates interaction with beta-spectrin, and the ZU5-1/UPA interface is required for ankyrin's function other than binding to spectrin (By similarity).
Together with obscurin in skeletal muscle may provide a molecular link between the sarcoplasmic reticulum and myofibrils.
Belongs to the eukaryotic-type primase small subunit family.
Can act both with Mn(2+) and Mg(2+) as cofactor in vitro, but Mn(2+) is the preferred cofactor in vivo (PubMed:25255211, PubMed:25746449, PubMed:27989484, PubMed:30889508, PubMed:30633872). The polymerase activity incorporates correct dNTPs with much higher efficiency with Mn(2+) than with Mg(2+) (PubMed:25255211, PubMed:30889508). The fidelity is slightly more accurate when Mg(2+) is the cofactor compared to Mn(2+) (PubMed:25255211, PubMed:30889508). In the presence of Mn(2+), a conformational transition step from non-productive to productive PRIMPOL:DNA complexes limits the enzymatic turnover, whereas in the presence of Mg(2+), the chemical step becomes rate limiting (PubMed:30633872).
DNA primase and DNA polymerase required to tolerate replication-stalling lesions by bypassing them (PubMed:24126761, PubMed:24207056, PubMed:24240614, PubMed:24267451, PubMed:25255211, PubMed:24682820, PubMed:25262353, PubMed:25746449, PubMed:25550423, PubMed:27989484, PubMed:29608762, PubMed:30889508, PubMed:28534480). Required to facilitate mitochondrial and nuclear replication fork progression by initiating de novo DNA synthesis using dNTPs and acting as an error-prone DNA polymerase able to bypass certain DNA lesions (PubMed:24126761, PubMed:24207056, PubMed:24240614, PubMed:24267451, PubMed:25255211, PubMed:24682820, PubMed:25262353, PubMed:25746449, PubMed:25550423, PubMed:27989484, PubMed:29608762, PubMed:30889508, PubMed:30633872, PubMed:28534480). Shows a high capacity to tolerate DNA damage lesions such as 8oxoG and abasic sites in DNA (PubMed:24126761, PubMed:24207056, PubMed:24240614, PubMed:24267451, PubMed:25746449). Provides different translesion synthesis alternatives when DNA replication is stalled: able to synthesize DNA primers downstream of lesions, such as ultraviolet (UV) lesions, R-loops and G-quadruplexes, to allow DNA replication to continue (PubMed:24240614, PubMed:26626482, PubMed:28534480, PubMed:30478192). Can also realign primers ahead of 'unreadable lesions' such as abasic sites and 6-4 photoproduct (6-4 pyrimidine-pyrimidinone), thereby skipping the lesion (PubMed:25746449). Also able to incorporate nucleotides opposite DNA lesions such as 8oxoG, like a regular translesion synthesis DNA polymerase (PubMed:24207056, PubMed:25255211, PubMed:25746449). Also required for reinitiating stalled forks after UV damage during nuclear DNA replication (PubMed:24240614). Required for mitochondrial DNA (mtDNA) synthesis and replication, by reinitiating synthesis after UV damage or in the presence of chain-terminating nucleotides (PubMed:24207056). Prevents APOBEC family-mediated DNA mutagenesis by repriming downstream of abasic site to prohibit error-prone translesion synthesis (By similarity). Has non-overlapping function with POLH (PubMed:24240614). In addition to its role in DNA damage response, also required to maintain efficient nuclear and mitochondrial DNA replication in unperturbed cells (PubMed:30715459).
Interacts with RPA1; leading to recruitment to chromatin and stimulate DNA primase activity (PubMed:24126761, PubMed:25550423, PubMed:28396594, PubMed:28534480). Interacts with SSBP1 (PubMed:25550423). Interacts with POLDIP2; leading to enhance DNA polymerase activity (PubMed:26984527).
Involved in adaptive response to cisplatin, a chemotherapeutic that causes reversal of replication forks, in cancer cells: reinitiates DNA synthesis past DNA lesions in BRCA1-deficient cancer cells treated with cisplatin via its de novo priming activity (PubMed:31676232). Repriming rescues fork degradation while leading to accumulation of internal ssDNA gaps behind the forks (PubMed:31676232). ATR regulates adaptive response to cisplatin (PubMed:31676232).
The RPA1-binding motifs (RBM) mediate interaction with RPA1 and are essential for recruitment to chromatin (PubMed:28534480). The interaction is primarily mediated by RPA1-binding motif 1, which binds to the basic cleft of RPA1, with motif 2 plays a supporting role in RPA1-binding (PubMed:28534480).
The presence of an Asp-Aaa-Glu (DxE) motif in the metal-binding active site favors the use of Mn(2+) ions to achieve optimal incoming nucleotide stabilization, especially required during primer synthesis (PubMed:30889508). Glu-116 is required to stabilize the incoming nucleotide at the 3'-site (PubMed:30889508).
The zinc knuckle motif binds zinc and is required for the DNA primase activity (PubMed:24682820, PubMed:29608762). It facilitates the binding and selection of the 5'-nucleotide of the newly synthesized primer and the recognition of preferred initiation sites (PubMed:29608762).
(Microbial infection) Interacts with HIV-1 proteins Vif and Gag.
(Microbial infection) Interacts with HIV-2 protein Gag.
(Microbial infection) May act as a chaperone for post-translational events during HIV-1 capsid assembly.
(Microbial infection) Plays a role in the down-regulation of the 2-5A/RNASEL pathway during encephalomyocarditis virus (EMCV) and HIV-1 infections.
Activated by encephalomyocarditis virus (EMCV) and HIV-1.
Belongs to the ABC transporter superfamily. ABCE family.
Interacts with PINK1 (PubMed:29861391). Interacts with CNOT4 (PubMed:29861391). Interacts with PELO (PubMed:29861391). Probably heterodimerizes with RNASEL; this interaction inhibits RNASEL (PubMed:9660177) (Probable).
Nucleoside-triphosphatase (NTPase) involved in ribosome recycling by mediating ribosome disassembly (PubMed:20122402, PubMed:21448132). Able to hydrolyze ATP, GTP, UTP and CTP (PubMed:20122402). Splits ribosomes into free 60S subunits and tRNA- and mRNA-bound 40S subunits (PubMed:20122402, PubMed:21448132). Acts either after canonical termination facilitated by release factors (ETF1/eRF1) or after recognition of stalled and vacant ribosomes by mRNA surveillance factors (PELO/Pelota) (PubMed:20122402, PubMed:21448132). Involved in the No-Go Decay (NGD) pathway: recruited to stalled ribosomes by the Pelota-HBS1L complex, and drives the disassembly of stalled ribosomes, followed by degradation of damaged mRNAs as part of the NGD pathway (PubMed:21448132). Also plays a role in quality control of translation of mitochondrial outer membrane-localized mRNA (PubMed:29861391). As part of the PINK1-regulated signaling, ubiquitinated by CNOT4 upon mitochondria damage; this modification generates polyubiquitin signals that recruit autophagy receptors to the mitochondrial outer membrane and initiate mitophagy (PubMed:29861391). RNASEL-specific protein inhibitor which antagonizes the binding of 2-5A (5'-phosphorylated 2',5'-linked oligoadenylates) to RNASEL (PubMed:9660177). Negative regulator of the anti-viral effect of the interferon-regulated 2-5A/RNASEL pathway (PubMed:9660177, PubMed:9847332, PubMed:11585831).
The ABC transporter domains seem not to be functional.
Ubiquitinated by CNOT4 (PubMed:29861391). Ubiquitination mediates the recruitment of autophagy receptors to the mitochondrial outer membrane and initiates mitophagy (PubMed:29861391).
Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation.
Homodimer (By similarity). Interacts with TLR4.
Homodimerization via the leucine zipper domains is required for autophosphorylation and subsequent activation.
Negative regulator of TLR4 signaling. Does not activate JNK1/MAPK8 pathway, p38/MAPK14, nor ERK2/MAPK1 pathways.
Catalytic activity is higher with Mg(2+).
Catalyzes the biosynthesis of phosphatidylinositol (PtdIns) as well as PtdIns:inositol exchange reaction. May thus act to reduce an excessive cellular PtdIns content. The exchange activity is due to the reverse reaction of PtdIns synthase and is dependent on CMP, which is tightly bound to the enzyme.
Detected in placenta (at protein level). Widely expressed. Higher expression in adult liver and skeletal muscle, slightly lower levels seen in pancreas, kidney, lung, placenta, brain, heart, leukocyte, colon, small intestine, ovary, testis, prostate, thymus and spleen. In fetus, expressed in kidney, liver, lung and brain.
Inhibited by PtdIns (product inhibition), phosphatidylinositol phosphate, and nucleoside di- and tri-phosphates.
Belongs to the bacterial ribosomal protein bL27 family.
Component of a complex at least composed of URM1, CTU2/NCS2 and CTU1/ATPBD3.
Plays a central role in 2-thiolation of mcm(5)S(2)U at tRNA wobble positions of tRNA(Lys), tRNA(Glu) and tRNA(Gln). May act by forming a heterodimer with CTU1/ATPBD3 that ligates sulfur from thiocarboxylated URM1 onto the uridine of tRNAs at wobble position.
The disease may be caused by variants affecting the gene represented in this entry. A homozygous synonymous variant at codon 247 has been identified in 3 consanguineous families. This variant impairs normal splicing, causing a frameshift resulting in a premature termination codon.
During protein synthesis and maturation, CD1 family members bind endogenous lipids that are replaced by lipid or glycolipid antigens when the proteins are internalized and pass through endosomes or lysosomes, before trafficking back to the cell surface.
Heterodimer with B2M (beta-2-microglobulin).
Interacts with ABL1 (By similarity). Interacts with COPS5/JAB1 (PubMed:17123647).
Palmitoyl acyltransferase that mediates palmitoylation of proteins such as PLN and ZDHHC6 (PubMed:28826475). Required during embryonic heart development and cardiac function, possibly by mediating palmitoylation of PLN, thereby affecting PLN phosphorylation and homooligomerization (By similarity). Also required for eye development (By similarity). Palmitoylates ZDHHC6, affecting the quaternary assembly of ZDHHC6, its localization, stability and function (PubMed:28826475). May play a role in DNA damage response (By similarity). May be involved in apoptosis regulation (By similarity). Involved in the proliferation of neural stem cells by regulating the FGF/ERK pathway (By similarity).
Can glycosylate both unmodified peptides and glycopeptides that already contain an O-linked GalNAc sugar. Transfers GalNAc to Thr-/Ser-rich tandem repeats GTTPSPVPTTSTTSAP of MUC5AC, specifically on Thr-3 of non-glycosylated MUC5AC peptide, on Thr-12 and Thr-13 of preglycosylated MUC5AC at Thr-3 (MUC5AC-3), on Thr-3 of preglycosylated MUC5AC at Thr-13 (MUC5AC-13) and on Thr-12 of preglycosylated MUC5AC at Thr-3 and Thr-13 (MUC5AC-3,13).
Can glycosylate both unmodified peptides and glycopeptides that already contain an O-linked GalNAc sugar. Transfers GalNAc to Thr-/Ser-rich tandem repeats GTTPSPVPTTSTTSAP of MUC5AC, specifically on Thr-3 of non-glycosylated MUC5AC peptide, on Thr-12 and Thr-13 of preglycosylated MUC5AC at Thr-3 (MUC5AC-3), on Thr-3 of preglycosylated MUC5AC at Thr-13 (MUC5AC-13) and on Thr-12 of preglycosylated MUC5AC at Thr-3 and Thr-13 (MUC5AC-3,13). Transfers GalNAc to three consecutive serine/threonine residues on SDC3 forming a triplet-Tn epitope expressed in Purkinje cells of the developing brain.
Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine (GalNAc) residue from UDP-GalNAc to a serine or threonine residue on the protein receptor (PubMed:12407114, PubMed:22186971). Generates GalNAc-O-Ser/Thr structure also known as Tn antigen, which itself is immunogenic but also serves as a precursor for the synthesis of different mucin-type O-glycan core structures (PubMed:12407114). Contributes to the synthesis of O-linked glycans on mucins and proteoglycans of the central nervous system. May promote neurogenesis through glycosylation and stabilization of PDPN (PubMed:12407114, PubMed:22186971) (By similarity).
Specifically expressed in neuronal cells. Expressed in fetal brain, whole adult brain, cerebral cortex and cerebellum. Not expressed in other tissues tested.
Binds to type II regulatory subunits (RII).
Binds to type II regulatory subunits of protein kinase A and anchors/targets them.
Present in cilia (at protein level). Expressed in tissues containing axoneme-based organelles (cilia and/or flagella): trachea and testis. Highly expressed in airway cilia.
Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Component of the 5FMC complex, at least composed of PELP1, LAS1L, TEX10, WDR18 and SENP3; the complex interacts with methylated CHTOP and ZNF148. Component of the PELP1 complex, composed of at least PELP1, TEX10 and WDR18. The complex interacts with pre-60S ribosome particles (PubMed:21326211).
Functions as a component of the Five Friends of Methylated CHTOP (5FMC) complex; the 5FMC complex is recruited to ZNF148 by methylated CHTOP, leading to desumoylation of ZNF148 and subsequent transactivation of ZNF148 target genes (PubMed:22872859). Component of the PELP1 complex involved in the nucleolar steps of 28S rRNA maturation and the subsequent nucleoplasmic transit of the pre-60S ribosomal subunit (PubMed:21326211).
Acetylation on lysine residues stabilizes FOXP3 and promotes differentiation of T-cells into induced regulatory T-cells (iTregs) associated with suppressive functions (PubMed:17360565, PubMed:24835996). Acetylation is mediated by a coordinated action of KAT5 and EP300/p300 acetyltransferases: EP300/p300 is required to enhance KAT5 autoacetylation, promoting acetylation of FOXP3 by KAT5 (PubMed:24835996). Deacetylated by SIRT1 (PubMed:22312127).
Down-regulated in regulatory T-cells (Treg) during inflammation (PubMed:23973223). Up-regulated by FOXO3 (PubMed:30513302).
Homodimer (PubMed:21458306, PubMed:25567984). Dimerization is essential for its transcriptional regulator activity (PubMed:21458306). Interacts with IKZF3. Isoform 1 (via LXXLL motif), but not isoform 2, interacts with isoform 4 of RORA (via AF-2 motif). Interacts with STUB1, HSPA8 and HSPA1A/B. Interacts with PPP1CA, PPP1CB and PPP1CG. Interacts with KAT5 and HDAC7. Interacts with HDAC9 in the absence of T-cell stimulation. Interacts with USP7. Interacts with isoform 2 of ZFP90 and can form a complex with TRIM28 in the presence of isoform 2 of ZFP90. Interacts with RUNX1. Interacts with RORC. Interacts with RELA and NFATC2. Interacts with RUNX2, RUNX3 and IKZF4 (By similarity).
Phosphorylation at Ser-418 regulates its transcriptional repressor activity and consequently, regulatory T-cells (Treg) suppressive function. Dephosphorylated at Ser-418 by protein phosphatase 1 (PP1) in Treg cells derived from patients with rheumatoid arthritis. Phosphorylation by CDK2 negatively regulates its transcriptional activity and protein stability (By similarity).
Polyubiquitinated, leading to its proteasomal degradation in regulatory T-cells (Treg) which is mediated by STUB1 in a HSPA1A/B-dependent manner. Deubiquitinated by USP7 and USP44; leading to increase in protein stability.
The fork-head DNA-binding domain is essential for its dimerization and interaction with NFATC2.
Transcriptional regulator which is crucial for the development and inhibitory function of regulatory T-cells (Treg) (PubMed:17377532, PubMed:21458306, PubMed:30513302, PubMed:23947341, PubMed:24354325, PubMed:24722479, PubMed:24835996, PubMed:32644293). Plays an essential role in maintaining homeostasis of the immune system by allowing the acquisition of full suppressive function and stability of the Treg lineage, and by directly modulating the expansion and function of conventional T-cells (PubMed:23169781). Can act either as a transcriptional repressor or a transcriptional activator depending on its interactions with other transcription factors, histone acetylases and deacetylases (PubMed:17377532, PubMed:21458306, PubMed:23947341, PubMed:24354325, PubMed:24722479). The suppressive activity of Treg involves the coordinate activation of many genes, including CTLA4 and TNFRSF18 by FOXP3 along with repression of genes encoding cytokines such as interleukin-2 (IL2) and interferon-gamma (IFNG) (PubMed:17377532, PubMed:21458306, PubMed:23947341, PubMed:24354325, PubMed:24722479). Inhibits cytokine production and T-cell effector function by repressing the activity of two key transcription factors, RELA and NFATC2 (PubMed:15790681). Mediates transcriptional repression of IL2 via its association with histone acetylase KAT5 and histone deacetylase HDAC7 (PubMed:17360565). Can activate the expression of TNFRSF18, IL2RA and CTLA4 and repress the expression of IL2 and IFNG via its association with transcription factor RUNX1 (PubMed:17377532). Inhibits the differentiation of IL17 producing helper T-cells (Th17) by antagonizing RORC function, leading to down-regulation of IL17 expression, favoring Treg development (PubMed:18368049). Inhibits the transcriptional activator activity of RORA (PubMed:18354202). Can repress the expression of IL2 and IFNG via its association with transcription factor IKZF4 (By similarity).
Undergoes proteolytic cleavage in activated regulatory T-cells (Treg), and can be cleaved at either the N- or C-terminal site, or at both sites.
Binds free fatty acids and their coenzyme A derivatives, bilirubin, and some other small molecules in the cytoplasm. May be involved in intracellular lipid transport.
Plays a role in lipoprotein-mediated cholesterol uptake in hepatocytes (PubMed:25732850). Binds cholesterol (PubMed:25732850). Binds free fatty acids and their coenzyme A derivatives, bilirubin, and some other small molecules in the cytoplasm. May be involved in intracellular lipid transport (By similarity).
Can form heteromeric complexes with LRFN1, LRFN2, LRFN3 and LFRN4. Able to form homomeric complexes across cell junctions, between adjacent cells. Does not interact with DLG1, DLG2, DLG3 and DLG4.
Cell adhesion molecule that mediates homophilic cell-cell adhesion in a Ca(2+)-independent manner. Promotes neurite outgrowth in hippocampal neurons.
Lacks a cytoplasmic PDZ-binding motif, which has been implicated in function of related LRFN proteins.
Beta-1,3-N-acetylglucosaminyltransferase that synthesizes the core 3 structure of the O-glycan, an important precursor in the biosynthesis of mucin-type glycoproteins. Plays an important role in the synthesis of mucin-type O-glycans in digestive organs.
Down-regulated in gastric and colorectal carcinomas, suggesting that it may be used as a marker for distinguishing between benign adenomas and premalignant lesions (at protein level).
Injection into nude mice significantly suppress lung metastasis, indicating that the core structures of O-glycans are profoundly involved in the metastatic capacity of cancer cells.
Present in stomach and colon (at protein level). Restricted in the stomach, colon and small intestine, where core 3 structure is present.
Degraded by the proteasome, shielded by interaction with ATF7IP.
Highly up-regulated in Huntington disease patients, suggesting that participates in the altered chromatin modulation and transcription dysfunction observed in Huntington disease. Its down-regulation has salubrious effects on patients, suggesting that it may be a promising treatment in Huntington disease patients.
Histone methyltransferase that specifically trimethylates 'Lys-9' of histone H3. H3 'Lys-9' trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. H3 'Lys-9' trimethylation is coordinated with DNA methylation (PubMed:12869583). Required for HUSH-mediated heterochromatin formation and gene silencing. Forms a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation (PubMed:27732843, PubMed:14536086). Its activity is dependent on MBD1 and is heritably maintained through DNA replication by being recruited by CAF-1 (PubMed:14536086). SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor recruited by KRAB zinc-finger proteins. Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells (PubMed:24623306). Required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs) (PubMed:24623306). In ESCs, in collaboration with TRIM28, is also required for H3K9me3 and silencing of endogenous and introduced retroviruses in a DNA-methylation independent-pathway (By similarity). Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing (PubMed:24623306). The SETDB1-TRIM28-ZNF274 complex may play a role in recruiting ATRX to the 3'-exons of zinc-finger coding genes with atypical chromatin signatures to establish or maintain/protect H3K9me3 at these transcriptionally active regions (PubMed:27029610).
Isoform 2 lacks all domains required for histone methyltransferase activity.
Part of a complex containing at least CDYL, REST, WIZ, SETDB1, EHMT1 and EHMT2 (PubMed:19061646). Forms a complex with ATRX, TRIM28 and ZNF274 (PubMed:27029610). Probably part of a corepressor complex containing ZNF304, TRIM28, SETDB1 and DNMT1 (PubMed:24623306). Interacts with TRIM28/TIF1B (PubMed:11959841). Interacts with ATF7IP and ATF7IP2; the interaction with ATF7IP protects SETDB1 from proteasomal degradation and is required to stimulate histone methyltransferase activity and facilitate the conversion of dimethylated to trimethylated H3 'Lys-9' (PubMed:14536086, PubMed:15691849). Interacts with CBX1 and CBX5 (PubMed:15899859). Interacts with DNMT3A and DNMT3B (PubMed:16682412). Interacts with SUMO2. Interacts with MPHOSPH8 (PubMed:20871592). Interacts with ERG (By similarity). Interacts with HDAC1, HDAC2, SIN3A and SIN3B (By similarity). Interacts with ATRX. Interacts with RESF1 (By similarity). Interacts with ZNF638 (PubMed:30487602). Interacts with TASOR (By similarity). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (PubMed:32051553).
The pre-SET, SET and post-SET domains are all required for methyltransferase activity. The 347-amino-acid insertion in the SET domain has no effect on the catalytic activity.
Was reported to be recruited by MBD1, during DNA replication, to form a S phase-specific complex that would facilitate methylation of H3 'Lys-9' during replication-coupled chromatin assembly and would be at least composed of the CAF-1 subunit CHAF1A, MBD1 and SETDB1 (PubMed:15327775, PubMed:17066076). However, these papers have been retracted because some data, results and conclusions are not reliable (PubMed:30849389, PubMed:31612521).
Was reported to trimethylate H3 'Lys-9', to interact with CHD7, NLK1 and PPARG and to be phosphorylated at Thr-796 (PubMed:17952062). However, this work was later retracted although its role in H3 'Lys-9' trimethylation is supported by other papers (PubMed:25358353).
Widely expressed. High expression in testis.
Probable mitochondrial transporter required for glutathione import into mitochondria (PubMed:34707288). Glutathione, which plays key roles in oxidative metabolism, is produced exclusively in the cytosol and is imported in many organelles (PubMed:34707288). Mitochondrial glutathione is required for the activity and stability of proteins containing iron-sulfur clusters, as well as erythropoiesis (By similarity).
Belongs to the metallo-beta-lactamase superfamily. RNA-metabolizing metallo-beta-lactamase-like family. INTS11 subfamily.
Catalytic component of the Integrator (INT) complex, a complex involved in the small nuclear RNAs (snRNA) U1 and U2 transcription and in their 3'-box-dependent processing. The Integrator complex is associated with the C-terminal domain (CTD) of RNA polymerase II largest subunit (POLR2A) and is recruited to the U1 and U2 snRNAs genes. Mediates the snRNAs 3' cleavage. Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the INT complex (PubMed:23904267).
The HXHXDH motif is essential for the endoribonuclease activity of the CPSF complex.
Involved in the intracellular transport of cholesterol. Binds cholesterol or other sterols.
Belongs to the glycosyl hydrolase 38 family.
Cleaves alpha 1,2-, alpha 1,3-, and alpha 1,6-linked mannose residues on cytoplasmatic free oligosaccharides generated by N-glycoprotein degradation pathways.
Strongly inhibited by swainsonine. Also inhibited to a lesser extent by deoxymannojirimycin (DMM).
Interacts with ADAM10; the interaction promotes ADAM10 maturation and cell surface expression.
Regulates maturation and trafficking of the transmembrane metalloprotease ADAM10 (PubMed:26668317, PubMed:23035126, PubMed:26686862). Negatively regulates ADAM10-mediated cleavage of GP6 (By similarity). Promotes ADAM10-mediated cleavage of CDH5 (By similarity).
Belongs to the WD repeat DDB2/WDR76 family.
Specifically binds 5-hydroxymethylcytosine (5hmC), suggesting that it acts as a specific reader of 5hmC.
Expressed in respiratory cells and sperm (at protein level) (PubMed:33139725, PubMed:36191189). Highly expressed in testis (PubMed:15967112). Up-regulated in hepatocellular carcinoma (HCC) (PubMed:15967112).
Interacts with BRCA2 (PubMed:15967112). Interacts with the CCT chaperonin complex (PubMed:15967112). Interacts with HSP70 (PubMed:15967112). Interacts with AK8 (PubMed:33139725). Interacts with CFAP45 (PubMed:33139725). Interacts with DNAI1 (PubMed:33139725). Interacts with IQDC (By similarity).
May be a good candidate as a diagnostic marker for HCC as well as a potential molecular target for development of novel therapeutic drugs.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme (PubMed:36191189). Important for proper ciliary and flagellar beating. May act in cooperation with CFAP45 and axonemal dynein subunit DNAH11 (PubMed:33139725). May play a role in cell growth and/or survival (PubMed:15967112).
Acts as a cytokine involved in enhancing production of interferon-gamma and interleukin-12 and reducing production of interleukin-10 and is essential in the pathway that leads to type I immunity.
Detected in cerebrospinal fluid and urine (at protein level) (PubMed:25326458, PubMed:36213313). Bone. Found in plasma.
Extensively phosphorylated by FAM20C in the extracellular medium at multiple sites within the S-x-E/pS motif (PubMed:15869464, PubMed:22582013, PubMed:26091039). The phosphorylated form inhibits hydroxyapatite crystallization. Dephosphorylation via a mechanism involving ALPL/TNAP promotes hydroxyapatite crystallization (By similarity).
Forms covalent cross-links mediated by transglutaminase TGM2, between a glutamine and the epsilon-amino group of a lysine residue, forming homopolymers and heteropolymers, increasing its collagen binding properties.
Major non-collagenous bone protein that binds tightly to hydroxyapatite. Appears to form an integral part of the mineralized matrix. Probably important to cell-matrix interaction.
O-glycosylated. Isoform 5 is GalNAc O-glycosylated at Thr-59 or Ser-62.
Essential component of the mitotic checkpoint, which prevents cells from prematurely exiting mitosis. Required for the assembly of the dynein-dynactin and MAD1-MAD2 complexes onto kinetochores (PubMed:11146660, PubMed:11590237, PubMed:15824131). Its function related to the spindle assembly machinery is proposed to depend on its association in the mitotic RZZ complex.
Interacts with ZW10; the interaction is required for stable association with the kinetochore. Component of the RZZ complex composed of KNTC1/ROD, ZW10 and ZWILCH; in the complex interacts directly with ZWILCH.
Associates with PP2A heterodimeric core enzyme PP2A(D), composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A) (PubMed:16916641). Interacts with PPP2CB (By similarity).
PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Acts as a regulatory subunit for serine/threonine-protein phosphatase 2A (PP2A) modulating its activity or substrate specificity, probably by inducing a conformational change in the catalytic subunit, a proposed direct target of the PPIase. Can reactivate inactive phosphatase PP2A-phosphatase methylesterase complexes (PP2A(i)) in presence of ATP and Mg(2+) (By similarity). Reversibly stimulates the variable phosphotyrosyl phosphatase activity of PP2A core heterodimer PP2A(D) in presence of ATP and Mg(2+) (in vitro). The phosphotyrosyl phosphatase activity is dependent of an ATPase activity of the PP2A(D):PPP2R4 complex. Is involved in apoptosis; the function appears to be independent from PP2A.
Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a heterodimer with MAX.
Belongs to the potassium channel family. Calcium-activated (TC 1.A.1.3) subfamily. KCa1.1/KCNMA1 sub-subfamily.
Ethanol and carbon monoxide-bound heme increase channel activation. Heme inhibits channel activation.
Homotetramer; which constitutes the calcium-activated potassium channel. Interacts with RAB11B (By similarity). Interacts with beta subunits KCNMB1, KCNMB2, KCNMB3 and KCNMB4. Interacts with gamma subunits LRRC26, LRRC38, LRRC52 and LRRC55. Beta and gamma subunits are accessory, and modulate its activity.
Palmitoylation by ZDHHC22 and ZDHHC23 within the intracellular linker between the S0 and S1 transmembrane domains regulates localization to the plasma membrane. Depalmitoylated by LYPLA1 and LYPLAL1, leading to retard exit from the trans-Golgi network.
Phosphorylated (Probable). Phosphorylation by kinases such as PKA and/or PKG. In smooth muscles, phosphorylation affects its activity.
Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+) (PubMed:29330545, PubMed:31152168). It is also activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+) concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key role in controlling excitability in a number of systems, such as regulation of the contraction of smooth muscle, the tuning of hair cells in the cochlea, regulation of transmitter release, and innate immunity. In smooth muscles, its activation by high level of Ca(2+), caused by ryanodine receptors in the sarcoplasmic reticulum, regulates the membrane potential. In cochlea cells, its number and kinetic properties partly determine the characteristic frequency of each hair cell and thereby helps to establish a tonotopic map. Kinetics of KCNMA1 channels are determined by alternative splicing, phosphorylation status and its combination with modulating beta subunits. Highly sensitive to both iberiotoxin (IbTx) and charybdotoxin (CTX).
The RCK N-terminal domain mediates the homotetramerization, thereby promoting the assembly of monomers into functional potassium channel. It includes binding sites for Ca(2+) and Mg(2+) (By similarity).
The S0 segment is essential for the modulation by the accessory beta subunits KCNMB1, KCNMB2, KCNMB3 and KCNMB4.
The calcium bowl constitutes one of the Ca(2+) sensors and probably acts as a Ca(2+)-binding site. There are however other Ca(2+) sensors region required for activation of the channel.
The heme-binding motif mediates inhibition of channel activation by heme. Carbon monoxide-bound heme leads to increased channel activation.
The pore-forming domain (also referred as P region) is imbedded into the membrane, and forms the selectivity filter of the pore. It contains the signature sequence of potassium channels that displays selectivity to potassium.
The protein was initially thought to contain two functionally distinct parts: The core channel (from the N-terminus to the S9 segment) that mediates the channel activity, and the cytoplasmic tail (from the S9 segment to the C-terminus) that mediates the calcium sensing. The situation is however more complex, since the core channel also contains binding sites for Ca(2+) and Mg(2+).
Widely expressed. Except in myocytes, it is almost ubiquitously expressed.
Acts as a regulator of store-operated Ca(2+) entry (SOCE) at junctional sites that connect the endoplasmic reticulum (ER) and plasma membrane (PM), called ER-plasma membrane (ER-PM) junction or cortical ER (PubMed:26322679, PubMed:26644574). SOCE is a Ca(2+) influx following depletion of intracellular Ca(2+) stores (PubMed:26322679). Acts by interacting with STIM1, promoting STIM1 conformational switch (PubMed:26322679). Involved in STIM1 relocalization to ER-PM junctions (PubMed:26644574). Contributes to the maintenance and reorganization of store-dependent ER-PM junctions (PubMed:26644574).
Homooligomer (PubMed:26322679). Interacts with STIM1 (PubMed:26322679).
The GXXXG motif may mediate oligomerization (PubMed:26322679). The C-terminus is necessary for its localization at ER-plasma membrane (ER-PM) junctions as well as for the store-dependent rearrangement of ER-PM junctions (PubMed:26644574).
'Lys-48'-linked ubiquitination by DCST1 leads to STAT2 proteasomal degradation.
(Microbial infection) Interacts with Dengue virus NS5; this interaction inhibits the phosphorylation of STAT2, and, when all viral proteins are present (polyprotein), targets STAT2 for degradation.
(Microbial infection) Interacts with Epstein Barr virus (EBV) tegument protein BGLF2; this interaction leads to STAT2 degradation.
(Microbial infection) Interacts with Human cytomegalovirus/HHV-5 protein UL123; this interaction promotes viral growth.
(Microbial infection) Interacts with Rabies virus phosphoprotein.
(Microbial infection) Interacts with Zika virus NS5; this interaction targets STAT2 for degradation.
(Microbial infection) Interacts with heartland virus NSs; this interaction blocks the nuclear translocation and activation of STAT2.
(Microbial infection) Interacts with human cytomegalovirus (HHV-5) immediate early protein IE1; this interaction promotes viral growth and counteracts the antiviral interferon response.
(Microbial infection) Interacts with severe fever with thrombocytopenia syndrome virus (SFTSV) NSs; this interaction leads to STAT2 sequestration into viral inclusion bodies and inhibition of STAT2 phosphorylation thereby suppressing type I IFN-induced nuclear translocation of the transcription factor.
(Microbial infection) Interacts with vaccinia virus protein C6.
Heterodimer with STAT1 upon IFN-alpha/beta induced phosphorylation (By similarity). The heterodimer STAT1:STAT2 forms the interferon-stimulated gene factor 3 complex (ISGF3) with IRF9; interacts with IRF9 in the cytoplasm (By similarity). Interacts with CRSP2 and CRSP6 (PubMed:12509459). Can form a homodimer upon IFN-alpha induced phosphorylation (PubMed:9020188). Interacts with IFNAR1; the interaction requires the phosphorylation of IFNAR1 at 'Tyr-466' (PubMed:9121453). Interacts with IFNAR2; the interaction is direct (PubMed:9121453, PubMed:28165510, PubMed:31836668, PubMed:32092142). Interacts with ARL2BP (By similarity). Interacts with E3 ubiquitin ligase DCST1; the interaction results in STAT2 ubiquitin-mediated proteasomal degradation (PubMed:27782195). Interacts with USP18; the interaction is direct and allows the recruitment of USP18 to IFNAR2.
Signal transducer and activator of transcription that mediates signaling by type I interferons (IFN-alpha and IFN-beta). Following type I IFN binding to cell surface receptors, Jak kinases (TYK2 and JAK1) are activated, leading to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize, associate with IRF9/ISGF3G to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of interferon stimulated genes, which drive the cell in an antiviral state (PubMed:9020188, PubMed:23391734). In addition, has also a negative feedback regulatory role in the type I interferon signaling by recruiting USP18 to the type I IFN receptor subunit IFNAR2 thereby mitigating the response to type I IFNs (PubMed:28165510). Acts as a regulator of mitochondrial fission by modulating the phosphorylation of DNM1L at 'Ser-616' and 'Ser-637' which activate and inactivate the GTPase activity of DNM1L respectively (PubMed:26122121, PubMed:23391734, PubMed:9020188).
Tyrosine phosphorylated in response to IFN-alpha. Phosphorylation at Ser-287 negatively regulates the transcriptional response.
Activity depends on Ca(2+) concentration.
Expressed in all tissues and cell lines tested with the highest level of abundance in testis.
May be a SFC-associated serine kinase (splicing factor compartment-associated serine kinase) with a role in intranuclear SR protein (non-snRNP splicing factors containing a serine/arginine-rich domain) trafficking and pre-mRNA processing.
Myristoylated. Required for membrane association. Prerequisite for palmitoylation to occur.
Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane (PubMed:23229899, PubMed:25608530, PubMed:26571211). The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (Probable). In the complex, EFR3B probably acts as the membrane-anchoring component (PubMed:23229899). Also involved in responsiveness to G-protein-coupled receptors; it is however unclear whether this role is direct or indirect (PubMed:25380825).
Component of a phosphatidylinositol 4-kinase (PI4K) complex, composed of PI4KA, EFR3 (EFR3A or EFR3B), TTC7 (TTC7A or TTC7B) and HYCC (HYCC1 or HYCC2).
Belongs to the NFYC/HAP5 subunit family.
Component of the sequence-specific heterotrimeric transcription factor (NF-Y) which specifically recognizes a 5'-CCAAT-3' box motif found in the promoters of its target genes. NF-Y can function as both an activator and a repressor, depending on its interacting cofactors.
Heterotrimeric transcription factor composed of three components, NF-YA, NF-YB and NF-YC. NF-YB and NF-YC must interact and dimerize for NF-YA association and DNA binding.
(Microbial infection) Acts as coreceptor with CXCR4 for a restricted number of HIV isolates.
Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. Also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines CXCL11 and CXCL12/SDF1 (PubMed:16107333, PubMed:19255243, PubMed:19380869, PubMed:20161793, PubMed:22300987). Chemokine binding does not activate G-protein-mediated signal transduction but instead induces beta-arrestin recruitment, leading to ligand internalization and activation of MAPK signaling pathway (PubMed:16940167, PubMed:18653785, PubMed:20018651). Required for regulation of CXCR4 protein levels in migrating interneurons, thereby adapting their chemokine responsiveness (PubMed:16940167, PubMed:18653785). In glioma cells, transduces signals via MEK/ERK pathway, mediating resistance to apoptosis. Promotes cell growth and survival (PubMed:16940167, PubMed:20388803). Not involved in cell migration, adhesion or proliferation of normal hematopoietic progenitors but activated by CXCL11 in malignant hemapoietic cells, leading to phosphorylation of ERK1/2 (MAPK3/MAPK1) and enhanced cell adhesion and migration (PubMed:17804806, PubMed:18653785, PubMed:19641136, PubMed:20887389). Plays a regulatory role in CXCR4-mediated activation of cell surface integrins by CXCL12 (PubMed:18653785). Required for heart valve development (PubMed:17804806). Regulates axon guidance in the oculomotor system through the regulation of CXCL12 levels (PubMed:31211835).
Expressed in monocytes, basophils, B-cells, umbilical vein endothelial cells (HUVEC) and B-lymphoblastoid cells. Lower expression detected in CD4+ T-lymphocytes and natural killer cells. In the brain, detected in endothelial cells and capillaries, and in mature neurons of the frontal cortex and hippocampus. Expressed in tubular formation in the kidney. Highly expressed in astroglial tumor endothelial, microglial and glioma cells. Expressed at low levels in normal CD34+ progenitor cells, but at very high levels in several myeloid malignant cell lines. Expressed in breast carcinomas but not in normal breast tissue (at protein level).
Homodimer. Can form heterodimers with CXCR4; heterodimerization may regulate CXCR4 signaling activity. Interacts with ARRB1 and ARRB2.
The C-terminal cytoplasmic tail, plays a key role in: correct trafficking to the cell membrane, recruitment of beta-arrestin, ubiquitination, and in chemokine scavenging and signaling functions. The Ser/Thr residues and the Lys residues in the C-terminal cytoplasmic tail are essential for beta-arrestin recruitment and ubiquitination respectively.
The Ser/Thr residues in the C-terminal cytoplasmic tail may be phosphorylated.
Ubiquitinated at the Lys residues in its C-terminal cytoplasmic tail and is essential for correct trafficking from and to the cell membrane. Deubiquitinated by CXCL12-stimulation in a reversible manner.
Up-regulated during cell differentiation in glioma cells.
Was originally thought to be the receptor for VIP.
Binds phospholipid vesicles containing phosphatidylinositol 3-phosphate and participates in early endosomal trafficking.
Broadly expressed, with highest levels in lung, testis, kidney and brain.
Interacts with BMX. May interact with SSB. Interacts with RAB4 and RAB5 that have been activated by GTP-binding.
Phosphorylation on Tyr-389 and/or Tyr-400 is required for interaction with BMX and endosomal targeting.
May be involved in synaptic plasticity regulation through the control of Rac-GTP levels.
Dimeric, linked by one or more disulfide bonds. Inhibin A is a dimer of alpha and beta-A. Inhibin B is a dimer of alpha and beta-B.
Originally found in ovary (granulosa cells) and testis (Sertoli cells), but widely distributed in many tissues including brain and placenta. In adrenal cortex expression is limited to the zona reticularis and the innermost zona fasciculata in the normal gland, extending centripetally into the zona fasciculata in hyperplasia. Also found in adrenocortical tumors. Also expressed in prostate epithelium of benign prostatic hyperplasia, in regions of basal cell hyperplasia and in nonmalignant regions of high grade prostate cancer. Only circulating inhibin B is found in male, whereas circulating inhibins A and B are found in female.
Proteolytic processing yields a number of bioactive forms. The 20/23 kDa forms consist solely of the mature alpha chain, the 26/29 kDa forms consist of the most N-terminal propeptide linked through a disulfide bond to the mature alpha chain, the 50/53 kDa forms encompass the entire proprotein. Each type can be furthermore either mono- or diglycosylated, causing the mass difference.
Expressed in ovary, with isoform 1 being predominant.
Isoform 1, but not isoform 2 or isoform 3, may induce G2 arrest and apoptosis. May also increase cell sensitivity to apoptotic stimuli.
Heterodimer. The active hormones thyrotropin, lutropin and follitropin are heterodimers composed of CGA, a common alpha chain described here and a unique beta chain which confers their biological specificity to the hormones: TSHB for thyrotropin, LHB for lutropin and FSHB for follitropin.
Heterodimer. The active hormones thyrotropin, lutropin, follitropin and choriogonadotropin are heterodimers composed of CGA, a common alpha chain described here and a unique beta chain which confers their biological specificity to the hormones: TSHB for thyrotropin, LHB for lutropin, FSHB for follitropin and choriogonadotropin subunit beta/CGB for choriogonadotropin.
Shared alpha chain of the active heterodimeric glycoprotein hormones thyrotropin/thyroid stimulating hormone/TSH, lutropin/luteinizing hormone/LH, follitropin/follicle stimulating hormone/FSH and choriogonadotropin/CG. These hormones bind specific receptors on target cells that in turn activate downstream signaling pathways.
Based on a readthrough transcript which may produce a ISY1-RAB43 fusion protein.
Component of the spliceosome C complex required for the selective processing of microRNAs during embryonic stem cell differentiation (By similarity). Required for the biogenesis of all miRNAs from the pri-miR-17-92 primary transcript except miR-92a (By similarity). Only required for the biogenesis of miR-290 and miR-96 from the pri-miR-290-295 and pri-miR-96-183 primary transcripts, respectively (By similarity). Required during the transition of embryonic stem cells (ESCs) from the naive to primed state (By similarity). By enhancing miRNA biogenesis, promotes exit of ESCs from the naive state to an intermediate state of poised pluripotency, which precedes transition to the primed state (By similarity). Involved in pre-mRNA splicing as component of the spliceosome.
Identified in the spliceosome C complex (PubMed:11991638, PubMed:29301961). Component of the XAB2 complex, a multimeric protein complex composed of XAB2, PRPF19, AQR, ZNF830, ISY1, and PPIE (PubMed:17981804). Identified in a pentameric intron-binding (IB) complex composed of AQR, XAB2, ISY1, ZNF830 and PPIE that is incorporated into the spliceosome as a preassembled complex (PubMed:25599396). The IB complex does not contain PRPF19 (PubMed:25599396). Interacts with CPSF3; this interaction is in an RNA independent manner (By similarity). Interacts with the microprocessor complex subunits DGCR8 and DROSHA; this interaction is in an RNA dependent manner (By similarity).
Homodimer (via coiled-coil domain) (PubMed:12668758, PubMed:15998640). Heterotetramer consisting of one MTMR2 dimer and one SBF2/MTMR13 dimer (PubMed:15998640). Heterodimer with SBF1/MTMR5 (PubMed:12668758, PubMed:21372139). Heterodimer with MTMR12 (PubMed:12847286).
Interaction with SBF1/MTMR5 increases phosphatase activity.
Phosphatase that acts on lipids with a phosphoinositol headgroup. Has phosphatase activity towards phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate (PubMed:11733541, PubMed:12668758, PubMed:21372139, PubMed:14690594). Binds phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate (By similarity). Stabilizes SBF2/MTMR13 at the membranes (By similarity). Specifically in peripheral nerves, stabilizes SBF2/MTMR13 protein (By similarity).
Phosphorylation at Ser-58 decreases MTMR2 localization to endocytic vesicular structures.
The GRAM domain mediates binding to phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate.
The coiled-coil domain mediates homodimerization (PubMed:12668758, PubMed:15998640). Also mediates interaction with SBF1/MTMR5 (PubMed:12668758). By mediating MTMR2 homodimerization, indirectly involved in SBF2/MTMR13 and MTMR2 heterotetramerization (By similarity).
Acts as GTPase-activating protein for RAB3A, RAB22A, RAB27A, and RAB35. Does not act on RAB2A and RAB6A.
Homotetramer (PubMed:11276087). Interacts with PTEN upstream reading frame protein MP31; the interaction leads to inhibition of mitochondrial lactate dehydrogenase activity, preventing conversion of lactate to pyruvate in mitochondria (PubMed:33406399).
Predominantly expressed in aerobic tissues such as cardiac muscle.
Expressed predominantly in brain, and at lower levels in heart, placenta and skeletal muscle. Down-regulated in brain tumors as compared to control brain tissues.
May inhibit NODAL and BMP signaling during neural patterning (By similarity). May be a tumor suppressor in brain cancers.
Essential ion channel and serine/threonine-protein kinase. Divalent cation channel permeable to calcium and magnesium (PubMed:35561741). Has a central role in magnesium ion homeostasis and in the regulation of anoxic neuronal cell death. Involved in TNF-induced necroptosis downstream of MLKL by mediating calcium influx. The kinase activity is essential for the channel function. May be involved in a fundamental process that adjusts plasma membrane divalent cation fluxes according to the metabolic state of the cell. Phosphorylates annexin A1 (ANXA1).
Homodimer. Interacts with PLCB1 (By similarity). Forms heterodimers with TRPM6.
In the N-terminal section; belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM7 sub-subfamily.
TRPM7 variants have been identified as a potential cause of disease in patients suffering from seizures and muscle cramps due to magnesium deficiency and episodes of hypocalcemia.
Activated by phosphorylation. In primary B lymphocytes, is almost always non-phosphorylated and is thus catalytically inactive. Stimulation of TLR8 and TLR9 causes BTK activation. As a negative feedback mechanism to fine-tune BCR signaling, activated PRKCB down-modulates BTK function via direct phosphorylation of BTK at Ser-180, resulting in translocation of BTK back to the cytoplasmic fraction. PIN1, SH3BP5, and IBTK were also identified as BTK activity inhibitors. Interaction with CAV1 leads to dramatic down-regulation of the kinase activity of BTK. LFM-13A is a specific inhibitor of BTK. Dasatinib, a cancer drug acting as a tyrosine kinase inhibitor, also blocks BTK activity.
Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily.
Following B-cell receptor (BCR) engagement, translocates to the plasma membrane where it gets phosphorylated at Tyr-551 by LYN and SYK. Phosphorylation at Tyr-551 is followed by autophosphorylation of Tyr-223 which may create a docking site for a SH2 containing protein. Phosphorylation at Ser-180 by PRKCB, leads in translocation of BTK back to the cytoplasmic fraction. Phosphorylation at Ser-21 and Ser-115 creates a binding site for PIN1 at these Ser-Pro motifs, and promotes it's recruitment.
Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling (PubMed:19290921). Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation (PubMed:19290921). After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members (PubMed:11606584). PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK (PubMed:11606584). BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways (PubMed:16517732, PubMed:17932028). Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway (PubMed:16517732). The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense (PubMed:16517732). Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells (PubMed:16517732, PubMed:17932028). Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation (PubMed:16415872). BTK also plays a critical role in transcription regulation (PubMed:19290921). Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes (PubMed:19290921). BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B (PubMed:19290921). Acts as an activator of NLRP3 inflammasome assembly by mediating phosphorylation of NLRP3 (PubMed:34554188). Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR (PubMed:9012831). GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression (PubMed:9012831). ARID3A and NFAT are other transcriptional target of BTK (PubMed:16738337). BTK is required for the formation of functional ARID3A DNA-binding complexes (PubMed:16738337). There is however no evidence that BTK itself binds directly to DNA (PubMed:16738337). BTK has a dual role in the regulation of apoptosis (PubMed:9751072).
Part of a complex composed of EEIG1, TNFRSF11A/RANK, PLCG2, GAB2, TEC and BTK; complex formation increases in the presence of TNFSF11/RANKL (By similarity). Binds GTF2I through the PH domain. Interacts with SH3BP5 via the SH3 domain. Interacts with IBTK via its PH domain. Interacts with ARID3A, CAV1, FASLG, PIN1, TLR8 and TLR9.
Predominantly expressed in B-lymphocytes.
Produced by alternative promoter usage. Predominant form in many tumor cells where it may function as an anti-apoptotic cell survival factor.
The PH domain mediates the binding to inositol polyphosphate and phosphoinositides, leading to its targeting to the plasma membrane. It is extended in the BTK kinase family by a region designated the TH (Tec homology) domain, which consists of about 80 residues preceding the SH3 domain.
Expressed in fibroblasts, heart, skeletal muscle, brain and pancreas. Expressed at an intermediate level in lung and kidney, and at a low level in liver and placenta. Expressed at a lower level in fibroblasts from hypertrophic scar lesional skin and in fibroblasts from patients with systemic sclerosis than in normal skin fibroblasts.
Induced by TGFB1, repressed by IL4/interleukin-4.
Seems to mediate adhesion by cell surface integrin binding. May serve as a communication link between the dermal fibroblast cell surface and its extracellular matrix environment. Enhances TGFB1 activity. Inhibits cell proliferation. Accelerates collagen fibril formation, and stabilizes collagen fibrils against low-temperature dissociation (By similarity).
Component of the SET1 complex, at least composed of the catalytic subunit (SETD1A or SETD1B), WDR5, WDR82, RBBP5, ASH2L/ASH2, CXXC1/CFP1 HCFC1 and DPY30. Interacts with SETD1A. Interacts with ZNF335. Interacts with PRDM9; this interaction does not link PRDM9-activated recombination hotspot sites with DSB machinery and is not required for the hotspot recognition pathway. Interacts with histone H3K4me3 (By similarity).
The acidic domain carries the potential to activate transcription.
Transcriptional activator that exhibits a unique DNA binding specificity for CpG unmethylated motifs with a preference for CpGG.
Promotes the exchange of Ras-bound GDP by GTP.
May act as an transcriptional repressor for PCK1 gene expression, in turn may participate in the hepatic gluconeogenesis regulation through the activated AMPK signaling pathway.
Phosphorylation at Ser-470 results in loss of DNA-binding activity.
Ubiquitous (PubMed:17097062). Highly expressed in brain, thymus and spleen (PubMed:17097062).
Homodimer. Component of the multisubunit TRAPP (transport protein particle) complex, which includes at least TRAPPC2, TRAPPC2L, TRAPPC3, TRAPPC3L, TRAPPC4, TRAPPC5, TRAPPC8, TRAPPC9, TRAPPC10, TRAPPC11 and TRAPPC12.
(Microbial infection) Also considered to be a mediator for HTLV-1 Tax oncoprotein activation of NF-kappa-B.
(Microbial infection) Cleaved by hepatitis A virus (HAV) protease 3C allowing the virus to disrupt the host innate immune signaling.
(Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1 on both 'Lys-48' and 'Lys-63'-linked ubiquitin chains; leading to NF-kappa-B signaling inhibition.
(Microbial infection) Interacts with HTLV-1 Tax oncoprotein; the interaction activates IKBKG.
(Microbial infection) Interacts with Molluscum contagiosum virus protein MC005; this interaction inhibits NF-kappa-B activation.
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 virus protein ORF9B (via N-terminus); the interaction inhibits polyubiquitination through 'Lys-63' and NF-kappa-B activation.
(Microbial infection) Interacts with Shigella flexneri ipah9.8; the interaction promotes TNIP1-dependent 'Lys-27'-linked polyubiquitination of IKBKG which perturbs NF-kappa-B activation during bacterial infection.
(Microbial infection) Polyubiquitinated on Lys-309 and Lys-321 via 'Lys-27'-linked ubiquitin by Shigella flexneri E3 ubiquitin-protein ligase ipah9.8, leading to its degradation by the proteasome.
(Microbial infection) Polyubiquitination through 'Lys-63' is interrupted by interaction with SARS coronavirus-2/SARS-CoV-2 virus protein ORF9B which inhibits the NF-kappa-B pathway.
Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Homodimer; disulfide-linked (PubMed:18164680). Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits (PubMed:9751060, PubMed:9891086, PubMed:11080499, PubMed:18462684, PubMed:17977820, PubMed:32935379). The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:9751060, PubMed:9891086, PubMed:11080499). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Interacts with COPS3, CYLD, NALP2, TRPC4AP and PIDD1 (PubMed:15456791, PubMed:16360037, PubMed:12917691, PubMed:11418127). Interacts with ATM; the complex is exported from the nucleus (PubMed:16497931). Interacts with TRAF6 (PubMed:17728323). Interacts with IKBKE (PubMed:23453969). Interacts with TANK; the interaction is enhanced by IKBKE and TBK1 (PubMed:12133833). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833). Interacts with ZFAND5 (PubMed:14754897). Interacts with RIPK2 (PubMed:18079694). Interacts with TNIP1 and TNFAIP3; TNIP1 facilitates the TNFAIP3-mediated de-ubiquitination of IKBKG (PubMed:11389905, PubMed:22099304). Interacts with TNFAIP3; the interaction is induced by TNF stimulation and by polyubiquitin (PubMed:11389905, PubMed:22099304). Binds (via UBAN region) polyubiquitin; binds both 'Lys-63'-linked and linear polyubiquitin, with higher affinity for linear ubiquitin (PubMed:16547522, PubMed:19033441, PubMed:21606507, PubMed:19185524). Interacts with NLRP10 (PubMed:22672233). Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with TRIM29; this interaction induces IKBKG/NEMO ubiquitination and proteolytic degradation (PubMed:27695001). Interacts with TRIM13; this interaction leads to IKBKG/NEMO ubiquitination (PubMed:25152375). Interacts with ARFIP2 (PubMed:26296658). Interacts with RIPK1 (By similarity). Interacts with (ubiquitinated) BCL10; interaction with polyubiquitinated BCL10 via both 'Lys-63'-linked and linear ubiquitin is required for TCR-induced NF-kappa-B activation (PubMed:18287044, PubMed:27777308). Interacts with MARCHF2; during the late stages of macrophage viral and bacterial infection; the interaction leads to ubiquitination and degradation of IKBKG/NEMO (PubMed:32935379).
Neddylated by TRIM40, resulting in stabilization of NFKBIA and down-regulation of NF-kappa-B activity.
Phosphorylation at Ser-68 attenuates aminoterminal homodimerization.
Polyubiquitinated on Lys-285 via 'Lys-63'-linked ubiquitin; the ubiquitination is mediated downstream of NOD2 and RIPK2 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway (PubMed:15620648, PubMed:17562858, PubMed:19136968). Polyubiquitinated on Lys-285 and Lys-399 through 'Lys-63'-linked ubiquitin; the ubiquitination is mediated by BCL10, MALT1 and TRAF6 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway (PubMed:14695475, PubMed:17562858, PubMed:19136968). Monoubiquitinated on Lys-277 and Lys-309; promotes nuclear export (PubMed:14651848). Polyubiquitinated through 'Lys-27' by TRIM23; involved in antiviral innate and inflammatory responses (PubMed:20724660). Linear polyubiquitinated on Lys-111, Lys-143, Lys-226, Lys-246, Lys-264, Lys-277, Lys-285, Lys-292, Lys-302, Lys-309 and Lys-326; the head-to-tail polyubiquitination is mediated by the LUBAC complex and plays a key role in NF-kappa-B activation (PubMed:21455181). Deubiquitinated by USP10 in a TANK-dependent and -independent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage (PubMed:25861989). Ubiquitinated at Lys-326 by MARCHF2 following bacterial and viral infection which leads to its degradation (PubMed:32935379). Polyubiquitinated via 'Lys-29'-linked ubiquitin; leading to lysosomal degradation (PubMed:21518757).
Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor (PubMed:9751060, PubMed:14695475, PubMed:20724660, PubMed:21518757). Its binding to scaffolding polyubiquitin plays a key role in IKK activation by multiple signaling receptor pathways (PubMed:16547522, PubMed:18287044, PubMed:19033441, PubMed:21606507, PubMed:27777308, PubMed:19185524, PubMed:33567255). Can recognize and bind both 'Lys-63'-linked and linear polyubiquitin upon cell stimulation, with a much higher affinity for linear polyubiquitin (PubMed:16547522, PubMed:18287044, PubMed:27777308, PubMed:19033441, PubMed:21606507, PubMed:19185524). Could be implicated in NF-kappa-B-mediated protection from cytokine toxicity. Essential for viral activation of IRF3 (PubMed:19854139). Involved in TLR3- and IFIH1-mediated antiviral innate response; this function requires 'Lys-27'-linked polyubiquitination (PubMed:20724660).
Sumoylated on Lys-277 and Lys-309 with SUMO1; the modification results in phosphorylation of Ser-85 by ATM leading to a replacement of the sumoylation by mono-ubiquitination on these residues.
The leucine-zipper domain and the CCHC NOA-type zinc-fingers constitute the UBAN region and are essential for polyubiquitin binding and for the activation of IRF3.
Down-regulated in some glioma; epigenetic inactivation is a hallmark of glioma patients with long-term survival.
NSUN5 is located in the Williams-Beuren syndrome (WBS) critical region (PubMed:11978965, PubMed:12073013). WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region (PubMed:11978965, PubMed:12073013). Its deletion in WBS results in decreased methylation of the C(5) position of cytosine 3782 (m5C3782) in 28S rRNA (PubMed:31722427).
S-adenosyl-L-methionine-dependent methyltransferase that specifically methylates the C(5) position of cytosine 3782 (m5C3782) in 28S rRNA (PubMed:23913415, PubMed:31428936, PubMed:31722427). m5C3782 promotes protein translation without affecting ribosome biogenesis and fidelity (PubMed:31428936, PubMed:31722427). Required for corpus callosum and cerebral cortex development (By similarity).
Ubiquitous (PubMed:11978965, PubMed:12073013). Detected in placenta, heart and skeletal muscle (PubMed:11978965, PubMed:12073013).
Belongs to the class I-like SAM-binding methyltransferase superfamily. UbiG/COQ3 family.
O-methyltransferase that catalyzes the 2 O-methylation steps in the ubiquinone biosynthetic pathway.
Induces sprouting in endothelial cells through an autocrine and paracrine action.
Widely expressed in heart, small intestine, spleen and stomach. Also found in lower levels in colon, ovary, adrenal gland, skeletal muscle and in prostate.
Belongs to the protein sulfotransferase family.
Catalyzes the O-sulfation of tyrosine residues within acidic motifs of polypeptides, using 3'-phosphoadenylyl sulfate (PAPS) as cosubstrate.
Homodimer (PubMed:23481380). Can also form heterodimers with TPST1 (PubMed:25660941).
Substrate peptides must be flexible in order to adopt an L-shaped conformation in the deep binding cleft.
24 proteolytic products are found in saliva.
Belongs to the histatin/statherin family.
His3-(20-43)-peptide is a homodimer. Histatin-3 and His3-(20-43)-peptide interact with yeast SSA1 and SSA2 proteins.
Histatins are salivary proteins that are considered to be major precursors of the protective proteinaceous structure on tooth surfaces (enamel pellicle). In addition, histatins exhibit antibacterial and antifungal activities. His3-(20-43)-peptide (histatin-5) is especially effective against C.albicans and C.neoformans, and inhibits Lys-gingipain and Arg-gingipain (rgpB) from P.gingivalis. In addition, His3-(20-43)-peptide is a potent inhibitor of metalloproteinases MMP2 and MMP9.
The recommended nomenclature of salivary peptides follows published guidelines (PubMed:20973643). In agreement with the authors, it has been decided to indicate the boundaries of the peptides according to the positions within the precursor, and not in the mature protein, as has formerly been proposed.
There are two alleles of HTN3, HIS2(1) (shown here) and HIS2(2) that codes for the variant histatin-3-2 found primarily and in high frequencies in black populations.
Cellular adhesion molecule that may play an important role in cell-cell interactions at interendothelial junctions (By similarity). Acts as a regulator of cell migration, probably via increasing cell-cell adhesion (PubMed:21402705). Promotes homotypic calcium-dependent aggregation and adhesion and clusters at intercellular junctions (By similarity). Unable to bind to catenins, weakly associates with the cytoskeleton (By similarity).
Cleaved by ADAM10 close to the transmembrane domain to release the Protocadherin-12, secreted form in the serum. Cleavage results in reduced cellular adhesion in a cell migration assay.
Expressed in highly vascularized tissues including the heart and placenta, but most tissues contain a low level of expression (PubMed:11063261). Prominent expression in the spleen (PubMed:11063261). Present in villous and extravillous trophoblast (at protein level) (PubMed:21402705).
Interacts with NINL isoform 2 (PubMed:26485514). Associates with DYNC1H1 and multiple dynein intermediate and light chains as well as actin-binding proteins (PubMed:26485514).
Involved in vesicle transport in photoreceptor cells.
(Microbial infection) Cleavage by Enterovirus 71 protease 3C results in increased translation of apoptosis protease activating factor APAF1, leading to apoptosis.
(Microbial infection) Interacts with HCV NS5B and with the 5'-UTR and 3'-UTR of HCV RNA.
(Microbial infection) May interact with SARS-CoV Nucleoprotein.
(Microbial infection) May play a role in HCV RNA replication.
Arg-194, Arg-206 and Arg-225 are dimethylated, probably to asymmetric dimethylarginine.
Identified in the spliceosome C complex (PubMed:11991638). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Interacts with SEPT6 (PubMed:17229681). Interacts with C9orf72 (PubMed:24549040). Interacts with KHDRBS1 (PubMed:17371836). Interacts with UBQLN2 (PubMed:25616961). Interacts with PPIA/CYPA (PubMed:25678563). Interacts (via the RGG-box) with the HOXB-AS3 peptide; the interaction inhibits binding of HNRNPA1 to the intronic sequences flanking exon 9 of the PKM gene, preventing inclusion of exon 9 and promoting inclusion of exon 10 which suppresses formation of the PKM M2 isoform and promotes production of the M1 isoform (PubMed:28985503).
Involved in the packaging of pre-mRNA into hnRNP particles, transport of poly(A) mRNA from the nucleus to the cytoplasm and modulation of splice site selection (PubMed:17371836). Plays a role in the splicing of pyruvate kinase PKM by binding repressively to sequences flanking PKM exon 9, inhibiting exon 9 inclusion and resulting in exon 10 inclusion and production of the PKM M2 isoform (PubMed:20010808). Binds to the IRES and thereby inhibits the translation of the apoptosis protease activating factor APAF1 (PubMed:31498791). May bind to specific miRNA hairpins (PubMed:28431233).
Is twenty times more abundant than isoform A1-B.
Belongs to the group II decarboxylase family.
Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits. The complex is composed of 3 respiratory subunits cytochrome b, cytochrome c1 and Rieske protein UQCRFS1, 2 core protein subunits UQCRC1/QCR1 and UQCRC2/QCR2, and 6 low-molecular weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, UQCR10/QCR9, UQCR11/QCR10 and subunit 9, the cleavage product of Rieske protein UQCRFS1 (By similarity). The complex exists as an obligatory dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and cytochrome c oxidase (complex IV, CIV), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with STMP1 (By similarity).
(Microbial infection) Glycosylated at Arg-376 by enteropathogenic E.coli protein NleB1 and S.typhimurium protein Ssek3: arginine GlcNAcylation prevents homotypic/heterotypic death domain interactions.
(Microbial infection) Interacts with host TNFRSF1A; this interaction leads to the stimulation of both surface expression and shedding of TNFRSF1A.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL138.
(Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation.
Binding of TNF to the extracellular domain leads to homotrimerization. The aggregated death domains provide a novel molecular interface that interacts specifically with the death domain of TRADD. Various TRADD-interacting proteins such as TRAFS, RIPK1 and possibly FADD, are recruited to the complex by their association with TRADD. This complex activates at least two distinct signaling cascades, apoptosis and NF-kappa-B signaling. Interacts with BAG4, BABAM2, FEM1B, GRB2, SQSTM1 and TRPC4AP (PubMed:10356400, PubMed:10359574, PubMed:10542291, PubMed:15465831, PubMed:8387891, PubMed:9915703). Interacts directly with NOL3 (via CARD domain); inhibits TNF-signaling pathway (By similarity). Interacts with SH3RF2, TRADD and RIPK1. SH3RF2 facilitates the recruitment of RIPK1 and TRADD to TNFRSF1A in a TNF-alpha-dependent process (PubMed:24130170). Interacts with PGLYRP1; this interaction is important for cell death induction (PubMed:26183779). Interacts (via death domain) with MADD (via death domain) (PubMed:9115275).
Both the cytoplasmic membrane-proximal region and the C-terminal region containing the death domain are involved in the interaction with TRPC4AP.
Disease susceptibility is associated with variants affecting the gene represented in this entry. An intronic mutation affecting alternative splicing and skipping of exon 6 directs increased expression of isoform 4 a transcript encoding a C-terminally truncated protein which is secreted and may function as a TNF antagonist.
Disease-associated isoform. Isoform 4 splicing pattern is driven by a variation in the exon 6/intron 6 boundary region that alters exon 6 splicing. Exon 6 skipping introduces a frameshift and the translation of a protein lacking the intracellular, the transmembrane and part of the extracellular domain.
Receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase.
The domain that induces A-SMASE is probably identical to the death domain. The N-SMASE activation domain (NSD) is both necessary and sufficient for activation of N-SMASE.
The soluble form is produced from the membrane form by proteolytic processing.
(Microbial infection) Acts as a receptor for adenovirus subgroup B.
(Microbial infection) Interacts with Orthopoxvirus OPG038/M2 protein, inhibiting the interaction with CTLA4 and CD28.
(Microbial infection) Interacts with adenovirus subgroup b fiber protein.
Expressed by activated B-lymphocytes and monocytes.
Homodimer. Interacts with MARCH8. Interacts (via cytoplasmic domain) with PHB1 and PHB2; the interactions increases after priming with CD40 (By similarity).
Interferes with the formation of CD86 clusters, and thus acts as a negative regulator of T-cell activation.
Polyubiquitinated; which is promoted by MARCH8 and results in endocytosis and lysosomal degradation.
Receptor involved in the costimulatory signal essential for T-lymphocyte proliferation and interleukin-2 production, by binding CD28 or CTLA-4. May play a critical role in the early events of T-cell activation and costimulation of naive T-cells, such as deciding between immunity and anergy that is made by T-cells within 24 hours after activation (PubMed:7527824). Also involved in the regulation of B cells function, plays a role in regulating the level of IgG(1) produced. Upon CD40 engagement, activates NF-kappa-B signaling pathway via phospholipase C and protein kinase C activation (By similarity).
Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase type I family.
Isoprenylation at Cys-409 is required for localization at the membrane.
Phosphatase that specifically hydrolyzes the 5-phosphate of inositol 1,4,5-trisphosphate to inositol 1,4-bisphosphate, and inositol 1,3,4,5-tetrasphosphate to inositol 1,3,4-trisphosphate (PubMed:8013665, PubMed:8769125, PubMed:8626616). Plays a crucial role in the survival of cerebellar Purkinje cells (By similarity).
Predominantly expressed in heart, brain, and skeletal muscle (PubMed:8006039). In brain; high level in Purkinje cells (PubMed:8013665).
Anchoring filament protein which is a component of the basement membrane zone.
Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping. Required for cortical actin clearance prior to oocyte exocytosis (By similarity). Promotes cell motility in conjunction with S100A4 (PubMed:16707441). During cell spreading, plays an important role in cytoskeleton reorganization, focal contact formation (in the margins but not the central part of spreading cells), and lamellipodial retraction; this function is mechanically antagonized by MYH10 (PubMed:20052411).
Genetic variations in MYH9 are associated with non-diabetic end stage renal disease (ESRD).
In the kidney, expressed in the glomeruli. Also expressed in leukocytes.
Myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). Interacts with RASIP1 (By similarity). Interacts with DDR1 (By similarity). Interacts with PDLIM2 (By similarity). Interacts with SVIL (PubMed:12917436, PubMed:17925381). Interacts with HTRA3 (PubMed:22229724). Interacts with Myo7a (By similarity). Interacts with CFAP95 (PubMed:28345668). Interacts with LIMCH1; independently of the integration of MYH9 into the myosin complex (PubMed:28228547). Interacts with RAB3A (PubMed:27325790). Interacts with ZBED4 (PubMed:22693546). Interacts with S100A4; this interaction increases cell motility (PubMed:16707441).
Subjects with mutations in the motor domain of MYH9 present with severe thrombocytopenia and develop nephritis and deafness before the age of 40 years, while those with mutations in the tail domain have a much lower risk of noncongenital complications and significantly higher platelet counts. The clinical course of patients with mutations in the four most frequently affected residues of MYH9 (responsible for 70% of MYH9-related cases) were evaluated. Mutations at residue 1933 do not induce kidney damage or cataracts and cause deafness only in the elderly, those in position 702 result in severe thrombocytopenia and produce nephritis and deafness at a juvenile age, while alterations at residue 1424 or 1841 result in intermediate clinical pictures.
Belongs to the chloride channel (TC 2.A.49) family. ClC-3/CLCN3 subfamily.
Expressed primarily in tissues derived from neuroectoderm. Within the brain, its expression is particularly evident in the hippocampus, olfactory cortex, and olfactory bulb. Highly expressed in aortic and coronary vascular smooth muscle cells, and aortic endothelial cells. Also expressed in tracheal and alveolar epithelial cells, and intima and media of the pulmonary vessels. Expressed in bronchus and colon (at protein level).
Interacts with GOPC, PDZK1 and NHERF1/EBP50.
Isoform 2 contains a C-terminal PDZ-binding motif mediating the interaction with GOPC.
Monomer and homodimer (By similarity). Forms heterodimers with CLCN4 (By similarity).
Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons (By similarity). The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons (PubMed:29845874). The presence of conserved gating glutamate residues is typical for family members that function as antiporters (PubMed:29845874).
Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons.
A IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in HIV-infected men.
Acts as an essential factor in bone homeostasis and on vessels directly or indirectly by induction of VEGF, resulting in increased angiogenesis activity and vascular permeability (PubMed:17075861, PubMed:12794819). Induces, through 'trans-signaling' and synergistically with IL1B and TNF, the production of VEGF (PubMed:12794819). Involved in metabolic controls, is discharged into the bloodstream after muscle contraction increasing lipolysis and improving insulin resistance (PubMed:20823453). 'Trans-signaling' in central nervous system also regulates energy and glucose homeostasis (By similarity). Mediates, through GLP-1, crosstalk between insulin-sensitive tissues, intestinal L cells and pancreatic islets to adapt to changes in insulin demand (By similarity). Also acts as a myokine (Probable). Plays a protective role during liver injury, being required for maintenance of tissue regeneration (By similarity). Also has a pivotal role in iron metabolism by regulating HAMP/hepcidin expression upon inflammation or bacterial infection (PubMed:15124018). Through activation of IL6ST-YAP-NOTCH pathway, induces inflammation-induced epithelial regeneration (By similarity).
Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; first binds to IL6R to associate with the signaling subunit IL6ST (PubMed:12829785). Interacts with IL6R (via the N-terminal ectodomain); this interaction may be affected by IL6R-binding with SORL1, hence decreasing IL6 cis signaling (PubMed:28265003). Interacts with SORL1 (via the N-terminal ectodomain); this interaction leads to IL6 internalization and lysosomal degradation (PubMed:28265003). May form a trimeric complex with the soluble SORL1 ectodomain and soluble IL6R receptor; this interaction might stabilize circulating IL6, hence promoting IL6 trans signaling (PubMed:28265003).
Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism. Binds to IL6R, then the complex associates to the signaling subunit IL6ST/gp130 to trigger the intracellular IL6-signaling pathway (Probable). The interaction with the membrane-bound IL6R and IL6ST stimulates 'classic signaling', whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors on neighboring receiver cells (Probable).
Genetic variations in IL6 may be correlated with bone mineral density (BMD). Low BMD is a risk factor for osteoporotic fracture. Osteoporosis is characterized by reduced bone mineral density, disruption of bone microarchitecture, and the alteration of the amount and variety of non-collagenous proteins in bone. Osteoporotic bones are more at risk of fracture.
IL6 is a potent inducer of the acute phase response. Rapid production of IL6 contributes to host defense during infection and tissue injury, but excessive IL6 synthesis is involved in disease pathology. In the innate immune response, is synthesized by myeloid cells, such as macrophages and dendritic cells, upon recognition of pathogens through toll-like receptors (TLRs) at the site of infection or tissue injury (Probable). In the adaptive immune response, is required for the differentiation of B cells into immunoglobulin-secreting cells. Plays a major role in the differentiation of CD4(+) T cell subsets. Essential factor for the development of T follicular helper (Tfh) cells that are required for the induction of germinal-center formation. Required to drive naive CD4(+) T cells to the Th17 lineage. Also required for proliferation of myeloma cells and the survival of plasmablast cells (By similarity).
Plasma levels are highly increased upon exercise, due to enhanced production by contracting skeletal muscles.
Found in stomach, with highest levels in the upper gastric mucosal cells (at protein level). Detected in goblet cells of the small and large intestine and rectum, small submucosal glands in the esophagus, mucous acini of the sublingual gland, submucosal glands of the trachea, and epithelial cells lining the exocrine pancreatic ducts but not in the remainder of the pancreas (at protein level). Scattered expression is detected in the epithelial cells of the gallbladder and submucosal glands of the vagina, and weak expression is observed in the bronchial goblet cells of the pseudostratified epithelia in the respiratory system (at protein level). Detected in urine (at protein level). Strongly expressed in breast cancer but at low levels in normal mammary tissue. It is regulated by estrogen in MCF-7 cells. Strong expression found in normal gastric mucosa and in the regenerative tissues surrounding ulcerous lesions of gastrointestinal tract, but lower expression found in gastric cancer (at protein level).
Heterodimer with GKN2; disulfide linked.
Stabilizer of the mucous gel overlying the gastrointestinal mucosa that provides a physical barrier against various noxious agents. May inhibit the growth of calcium oxalate crystals in urine.
Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members. Plays a role in synapse function and synaptic signal transmission, and probably mediates its effects by recruiting and clustering other synaptic proteins. May promote the initial formation of synapses, but is not essential for this. In vitro, triggers the de novo formation of presynaptic structures. May be involved in specification of excitatory synapses. Required to maintain wakefulness quality and normal synchrony of cerebral cortex activity during wakefulness and sleep (By similarity). The protein is involved in nervous system development.
Expressed in the blood vessel walls (at protein level). Highly expressed in brain through prenatal stages, and at lower levels in pancreas islet beta cells.
Interacts with neurexins NRXN1, NRXN2 and NRXN3 (By similarity). Interaction with neurexins is mediated by heparan sulfate glycan modification on neurexin (By similarity). Interacts with NLGN3. Interacts with AIP1 and PDZRN3 (By similarity). Interacts (via its C-terminus) with DLG4/PSD-95 (via PDZ domain 3). Interacts with GOPC.
Acts as a molecular chaperone for mitochondrial complex I assembly (PubMed:16200211, PubMed:19384974). Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (PubMed:16200211, PubMed:27626371).
Belongs to the complex I NDUFA12 subunit family.
By MYC. Direct transcriptional target of MYC.
Highly expressed in ESCC cells. Also expressed in heart, skeletal muscle, liver, and in fibroblasts.
(Microbial infection) Interacts with EBV EBNA2; EBNA2 competes with NCOR2 for interaction with SNW1.
(Microbial infection) Interacts with human papillomavirus type-16 (HPV16) E7 protein.
(Microbial infection) Is recruited by HIV-1 Tat to Tat:P-TEFb:TAR RNA complexes and is involved in Tat transcription by recruitment of MYC, MEN1 and TRRAP to the HIV promoter.
(Microbial infection) Proposed to be involved in transcriptional activation by EBV EBNA2 of CBF-1/RBPJ-repressed promoters.
Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:28076346). Associates with U4/U6-U5 tri-small nuclear ribonucleoproteins (U4/U6-U5 tri-snRNPs). Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932). Interacts with SKI, SMAD2,SMAD3, RBPJ, RB1, PABPN1, MAGEA1, SIRT1, FOXN3, U2AF2, DAXX and ATP1B4. Interacts with PPIL1 (PubMed:16595688, PubMed:20007319, PubMed:20368803, PubMed:33220177). Interacts with VDR and RXRA; preferentially associates with VDR:RXRA heterodimers (PubMed:9632709, PubMed:12529369). Interacts with NCOR2 (PubMed:10644367). Interacts with MAML1 (PubMed:21245387). Interacts with NOTCH1 NICD; the interaction involves multimerized NOTCH1 NICD (PubMed:21245387). Forms a complex with NOTCH1 NICD and MAML1; the association is dissociated by RBPJ (PubMed:21245387). Associates with positive transcription elongation factor b (P-TEFb) (PubMed:15905409). Component of the SNARP complex which consists at least of SNIP1, SNW1, THRAP3, BCLAF1 and PNN (PubMed:18794151).
Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28502770, PubMed:28076346). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). Required for the specific splicing of CDKN1A pre-mRNA; the function probably involves the recruitment of U2AF2 to the mRNA. May recruit PPIL1 to the spliceosome. May be involved in cyclin-D1/CCND1 mRNA stability through the SNARP complex which associates with both the 3'end of the CCND1 gene and its mRNA. Involved in transcriptional regulation. Modulates TGF-beta-mediated transcription via association with SMAD proteins, MYOD1-mediated transcription via association with PABPN1, RB1-mediated transcriptional repression, and retinoid-X receptor (RXR)- and vitamin D receptor (VDR)-dependent gene transcription in a cell line-specific manner probably involving coactivators NCOA1 and GRIP1. Is involved in NOTCH1-mediated transcriptional activation. Binds to multimerized forms of Notch intracellular domain (NICD) and is proposed to recruit transcriptional coactivators such as MAML1 to form an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ to form a transcriptional activation complex by releasing SNW1 and redundant NOTCH1 NICD.
Autophosphorylates when part of mTORC1 or mTORC2 (PubMed:9434772, PubMed:15467718). Phosphorylation at Ser-1261, Ser-2159 and Thr-2164 promotes autophosphorylation (PubMed:19487463). Phosphorylation in the kinase domain modulates the interactions of MTOR with RPTOR and AKT1S1/PRAS40 and leads to increased intrinsic mTORC1 kinase activity (PubMed:15905173, PubMed:19145465, PubMed:21576368). Phosphorylation at Ser-2159 by TBK1 in response to growth factors and pathogen recognition receptors promotes mTORC1 activity (PubMed:29150432). Phosphorylation at Thr-2173 in the ATP-binding region by AKT1 strongly reduces kinase activity (PubMed:24247430).
Expressed in numerous tissues, with highest levels in testis.
Part of the mechanistic target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8 and RPTOR (PubMed:12150925, PubMed:12150926, PubMed:12408816, PubMed:12718876, PubMed:18925875, PubMed:24403073, PubMed:20542007, PubMed:23636326, PubMed:27909983, PubMed:26678875, PubMed:29236692, PubMed:31601764, PubMed:34519268, PubMed:36697823, PubMed:34519269). The mTORC1 complex is a 1 Md obligate dimer of two stoichiometric heterotetramers with overall dimensions of 290 A x 210 A x 135 A (PubMed:20542007, PubMed:23636326). It has a rhomboid shape and a central cavity, the dimeric interfaces are formed by interlocking interactions between the two MTOR and the two RPTOR subunits (PubMed:20542007, PubMed:27909983, PubMed:23636326). The MLST8 subunit forms distal foot-like protuberances, and contacts only one MTOR within the complex, while the small AKT1S1/PRAS40 localizes to the midsection of the central core, in close proximity to RPTOR (PubMed:20542007, PubMed:23636326, PubMed:27909983, PubMed:29236692). mTORC1 associates with AKT1S1/PRAS40, which inhibits its activity by blocking MTOR substrate-recruitment site (PubMed:17386266, PubMed:29236692). Part of the mechanistic target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR (PubMed:15268862, PubMed:15467718, PubMed:17599906, PubMed:18925875). Interacts with PLPP7 and PML (By similarity). Interacts with PRR5 and RICTOR; the interaction is direct within the mTORC2 complex and interaction with RICTOR is enhanced by deubiquitination of RICTOR by USP9X (PubMed:17599906, PubMed:33378666, PubMed:34519268). mTORC1 and mTORC2 associate with DEPTOR, which regulates its activity (PubMed:19446321, PubMed:34519268, PubMed:34519269). Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). Interacts with UBQLN1 (PubMed:11853878). Interacts with TTI1 and TELO2 (PubMed:20801936, PubMed:20427287, PubMed:20810650). Interacts with CLIP1; phosphorylates and regulates CLIP1 (PubMed:12231510). Interacts with NBN (PubMed:23762398). Interacts with HTR6 (PubMed:23027611). Interacts with BRAT1 (PubMed:25657994). Interacts with MEAK7 (via C-terminal domain); the interaction increases upon nutrient stimulation (PubMed:29750193). Interacts with TM4SF5; the interaction is positively regulated by arginine and is negatively regulated by leucine (PubMed:30956113). Interacts with GPR137B (PubMed:31036939). Interacts with NCKAP1L (PubMed:32647003). Interacts with TPCN1 and TPCN2; the interaction is required for TPCN1 and TPCN2 sensitivity to ATP (PubMed:23394946). Interacts with ATP6V1A and with CRYAB, forming a ternary complex (By similarity). Interacts with SLC38A7; this interaction mediates the recruitment of mTORC1 to the lysosome and its subsequent activation (PubMed:35561222).
Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084, PubMed:29150432, PubMed:31112131, PubMed:31601708, PubMed:32561715, PubMed:34519269, PubMed:29236692). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins (PubMed:15268862, PubMed:15467718, PubMed:17517883, PubMed:18925875, PubMed:18372248, PubMed:18497260, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704, PubMed:29236692). Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15268862, PubMed:15467718, PubMed:18925875, PubMed:18497260, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704). In response to nutrients, growth factors or amino acids, mTORC1 is recruited to the lysosome membrane and promotes protein, lipid and nucleotide synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084, PubMed:29150432, PubMed:31112131, PubMed:34519269, PubMed:29236692). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (PubMed:24403073, PubMed:29236692). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4 (PubMed:12150925, PubMed:12087098, PubMed:18925875, PubMed:29150432, PubMed:29236692). Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex (PubMed:23429704, PubMed:23429703). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (PubMed:20516213). Activates dormant ribosomes by mediating phosphorylation of SERBP1, leading to SERBP1 inactivation and reactivation of translation (PubMed:36691768). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (By similarity). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). In the same time, mTORC1 inhibits catabolic pathways: negatively regulates autophagy through phosphorylation of ULK1 (PubMed:32561715). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (PubMed:32561715). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (PubMed:20537536). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (PubMed:30704899). Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA (PubMed:23524951, PubMed:25438055). mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor (PubMed:21659604). Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules (PubMed:12231510). The mTORC1 complex is inhibited in response to starvation and amino acid depletion (PubMed:12150925, PubMed:12150926, PubMed:24403073). The non-canonical mTORC1 complex, which acts independently of RHEB, specifically mediates phosphorylation of MiT/TFE factors MITF, TFEB and TFE3 in the presence of nutrients, promoting their cytosolic retention and inactivation (PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:24448649, PubMed:32612235, PubMed:36608670, PubMed:36697823). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:24448649, PubMed:32612235, PubMed:36608670). The mTORC1 complex regulates pyroptosis in macrophages by promoting GSDMD oligomerization (PubMed:34289345). MTOR phosphorylates RPTOR which in turn inhibits mTORC1 (By similarity). As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton (PubMed:15268862, PubMed:15467718). mTORC2 plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1 (PubMed:15718470). mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B (PubMed:15268862). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed:18925875). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (By similarity). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (By similarity). Phosphorylates SQSTM1, promoting interaction between SQSTM1 and KEAP1 and subsequent inactivation of the BCR(KEAP1) complex (By similarity).
The FAT domain forms three discontinuous subdomains of alpha-helical TPR repeats plus a single subdomain of HEAT repeats. The four domains pack sequentially to form a C-shaped a-solenoid that clamps onto the kinase domain (PubMed:23636326).
The kinase domain (PI3K/PI4K) is intrinsically active but has a highly restricted catalytic center.
The mTORC1 complex is activated in response to nutrients, growth factors or amino acids: activation requires relocalization of the mTORC1 complex to lysosomes that is mediated by the Ragulator complex, SLC38A9, and the Rag GTPases RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and RagD/RRAGD (PubMed:18497260, PubMed:20381137, PubMed:25561175, PubMed:25567906). Activation of mTORC1 by growth factors such as insulin involves AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase a potent activator of the protein kinase activity of mTORC1 (PubMed:14651849, PubMed:15545625, PubMed:29236692). Insulin-stimulated and amino acid-dependent phosphorylation at Ser-1261 promotes autophosphorylation and the activation of mTORC1 (PubMed:19487463). On the other hand, low cellular energy levels can inhibit mTORC1 through activation of PRKAA1 while hypoxia inhibits mTORC1 through a REDD1-dependent mechanism which may also require PRKAA1 (PubMed:14651849, PubMed:15545625). The kinase activity of MTOR within the mTORC1 complex is positively regulated by MLST8 (PubMed:12718876). The kinase activity of MTOR is inhibited by DEPTOR and AKT1S1 (PubMed:17386266, PubMed:19446321, PubMed:29236692, PubMed:34519269, PubMed:34519268). The non-canonical mTORC1 complex is independent of the RHEB GTPase and specifically mediates phosphorylation of MiT/TFE factors TFEB and TFE3 but not other mTORC1 substrates: it is activated by FLCN, which activates Rag GTPases RagC/RRAGC and RagD/RRAGD (PubMed:32612235, PubMed:36697823). MTOR is the target of the immunosuppressive and anti-cancer drug rapamycin which acts in complex with FKBP1A/FKBP12, and specifically inhibits its kinase activity (PubMed:10089303, PubMed:8662507). mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive (PubMed:15467718). mTORC2 may also be regulated by RHEB but in an indirect manner through the PI3K signaling pathway (PubMed:15467718).
Catalyzes the omega- and (omega-1)-hydroxylation of various fatty acids such as laurate and palmitate. Shows no activity towards arachidonic acid and prostaglandin A1. Lacks functional activity in the kidney and does not contribute to renal 20-hydroxyeicosatetraenoic acid (20-HETE) biosynthesis.
Interacts with translation initiation factor EIF4E.
Transcription factor, which in cooperation with EMX1, acts to generate the boundary between the roof and archipallium in the developing brain. May function in combination with OTX1/2 to specify cell fates in the developing central nervous system.
Expressed in heart, skeletal muscle, kidney and adult and fetal liver. Primarily expressed in dendrites and monocytes. Weakly expressed in T-cells.
Receptor for thymic stromal lymphopoietin (TSLP). Forms a functional complex with TSLP and IL7R which is capable of stimulating cell proliferation through activation of STAT3 and STAT5. Also activates JAK2 (By similarity). Implicated in the development of the hematopoietic system.
The box 1 motif is important for association with JAKs.
Up-regulated in activated peripheral monocytes and THP-1 cells.
Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
Part of the tectonic-like complex (also named B9 complex). Interacts with TUBG1 (By similarity).
Expressed in heart, liver, skeletal muscle and pancreas.
Belongs to the LanC-like protein family.
Tubulin-binding protein that acts as a negative regulator of Notch signaling pathway. Shuttles between the cytoplasm and the nucleus and mediates the nuclear export of RBPJ/RBPSUH, thereby preventing the interaction between RBPJ/RBPSUH and NICD product of Notch proteins (Notch intracellular domain), leading to down-regulate Notch-mediated transcription. May play a role in neurogenesis.
A chromosomal aberration involving NSD1 is found in an adult form of myelodysplastic syndrome (MDS). Insertion of NUP98 into NSD1 generates a NUP98-NSD1 fusion product.
A chromosomal aberration involving NSD1 is found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NUP98.
Expressed in the fetal/adult brain, kidney, skeletal muscle, spleen, and the thymus, and faintly in the lung.
Histone methyltransferase that dimethylates Lys-36 of histone H3 (H3K36me2). Transcriptional intermediary factor capable of both negatively or positively influencing transcription, depending on the cellular context.
Interacts with the ligand-binding domains of RARA and THRA in the absence of ligand; in the presence of ligand the interaction is severely disrupted but some binding still occurs. Interacts with the ligand-binding domains of RXRA and ESRRA only in the presence of ligand. Interacts with ZNF496 (By similarity). Interacts with AR DNA- and ligand-binding domains.
Acetylated at Lys-162; does not affect methyltransferase activity. Deacetylated at Lys-162 possibly by SIRT2; does not change methyltransferase activity.
Although the SET domain contains the active site of enzymatic activity, both sequences upstream and downstream of the SET domain are required for methyltransferase activity.
Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. PR/SET subfamily.
By HCFC1 C-terminal chain, independently of HCFC1 N-terminal chain. Transiently induced by TGF-beta and during the cell cycle.
Interacts with SIRT2 (phosphorylated form); the interaction is direct, stimulates KMT5A-mediated methyltransferase activity at histone H4 'Lys-20' (H4K20me1) and is increased in a H(2)O(2)-induced oxidative stress-dependent manner.
It is uncertain whether Met-1 or Met-72 is the initiator.
Not detected during G1 phase. First detected during S through G2 phases, and peaks during mitosis (at protein level).
Protein-lysine N-methyltransferase that monomethylates both histones and non-histone proteins (PubMed:12086618, PubMed:12121615, PubMed:15964846, PubMed:17707234, PubMed:27338793). Specifically monomethylates 'Lys-20' of histone H4 (H4K20me1) (PubMed:12086618, PubMed:12121615, PubMed:15964846, PubMed:27338793, PubMed:15200950, PubMed:15933069, PubMed:15933070, PubMed:16517599). H4K20me1 is enriched during mitosis and represents a specific tag for epigenetic transcriptional repression (PubMed:12086618, PubMed:12121615, PubMed:15964846, PubMed:15200950, PubMed:15933069, PubMed:15933070, PubMed:16517599). Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes (PubMed:12086618, PubMed:12121615, PubMed:15964846, PubMed:15200950, PubMed:15933069, PubMed:15933070, PubMed:16517599). Required for cell proliferation, probably by contributing to the maintenance of proper higher-order structure of DNA during mitosis (PubMed:12086618, PubMed:12121615, PubMed:15964846, PubMed:15200950, PubMed:15933069, PubMed:15933070, PubMed:16517599). Involved in chromosome condensation and proper cytokinesis (PubMed:12086618, PubMed:12121615, PubMed:15964846, PubMed:15200950, PubMed:15933069, PubMed:15933070, PubMed:16517599). Nucleosomes are preferred as substrate compared to free histones (PubMed:12086618, PubMed:12121615, PubMed:15964846, PubMed:15200950, PubMed:15933069, PubMed:15933070, PubMed:16517599). Mediates monomethylation of p53/TP53 at 'Lys-382', leading to repress p53/TP53-target genes (PubMed:17707234). Plays a negative role in TGF-beta response regulation and a positive role in cell migration (PubMed:23478445).
Ubiquitinated and degraded by the DCX(DTL) complex.
According to PubMed:9049310, this sequence initiates exclusively at a GTG codon.
Appears to play a role in the switch from cap-dependent to IRES-mediated translation during mitosis, apoptosis and viral infection. Cleaved by some caspases and viral proteases.
Interacts with the serine/threonine protein kinases MKNK1 and MKNK2 (PubMed:9878069). Binds EIF4A and EIF3 (PubMed:9049310, PubMed:9030685). Interacts with MIF4GD (PubMed:18025107). Interacts with DAZAP2 (PubMed:17984221).
Phosphorylation; hyperphosphorylated during mitosis.
This gene has been shown to be extensively edited in the liver of APOBEC1 transgenic animal model. Its aberrant editing could contribute to the potent oncogenesis induced by overexpression of APOBEC1. The aberrant edited sequence, called NAT1, is likely to be a fundamental translational repressor.
Ubiquitously expressed in all adult tissues examined, with high levels in skeletal muscle and heart. Also expressed in fetal brain, lung, liver and kidney.
Unusual initiator. The initiator methionine is coded by a non-canonical GTG valine codon.
Expressed during gastrulation and during a second phase in some adult tissues.
Expressed in fetal tail bud, posterior spinal tissue, intervertebral disk and testis. Also expressed in adult testis, kidney, lung, muscle and thymus.
Forms a dimeric complex with DNA (in vitro).
T-box transcription factor that plays an essential role in the determination of the fate of axial stem cells: neural vs mesodermal. Acts in part by down-regulating, a specific enhancer (N1) of SOX2, to inhibit neural development. Seems to play also an essential role in left/right axis determination and acts through effects on Notch signaling around the node as well as through an effect on the morphology and motility of the nodal cilia (By similarity).
Expressed in brain. Very low expression in lung and liver.
Expressed in kidney and skeletal muscle. Very low expression in brain and heart.
Interacts with RUNX2. Binds consensus element OSE2 (By similarity).
KRAB domain is not required for nuclear targeting or for DNA binding.
May function as a transcription repressor. Binds to 5'-CCACA-3' core sequence. Suppresses osteogenic effects of RUNX2. May be involved in osteoblastic differentiation (By similarity). Plays a role in postnatal myogenesis, may be involved in the regulation of satellite cells self-renewal (By similarity).
Zinc finger region is involved in nuclear targeting and DNA-binding.
Belongs to the Integrator subunit 12 family.
Component of the Integrator complex, a complex involved in the small nuclear RNAs (snRNA) U1 and U2 transcription and in their 3'-box-dependent processing. The Integrator complex is associated with the C-terminal domain (CTD) of RNA polymerase II largest subunit (POLR2A) and is recruited to the U1 and U2 snRNAs genes (PubMed:16239144). Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the INT complex (PubMed:23904267).
Cell adhesion molecule involved in the establishment and/or maintenance of cell integrity. Involved in the formation and regulation of the tight junction (TJ) paracellular permeability barrier in epithelial cells (PubMed:16188940). Plays a role in VAMP3-mediated vesicular transport and recycling of different receptor molecules through its interaction with VAMP3. Plays a role in the regulation of cell shape and movement by modulating the Rho-family GTPase activity through its interaction with ARHGEF25/GEFT. Induces primordial adhesive contact and aggregation of epithelial cells in a Ca(2+)-independent manner. Also involved in striated muscle regeneration and repair and in the regulation of cell spreading (By similarity). Important for the maintenance of cardiac function. Plays a regulatory function in heart rate dynamics mediated, at least in part, through cAMP-binding and, probably, by increasing cell surface expression of the potassium channel KCNK2 and enhancing current density (PubMed:26642364). Is also a caveolae-associated protein important for the preservation of caveolae structural and functional integrity as well as for heart protection against ischemia injury.
Expressed in epithelial cells (at protein level). Expressed in fetal and adult heart and skeletal muscle.
Homodimer. Homodimerization requires the C-terminus cytoplasmic region. Interacts (via the C-terminus cytoplasmic tail) with TJP1. Interacts (via the C-terminus cytoplasmic tail) with ARHGEF25/GEFT (via the DH domain). Interacts (via the C-terminus cytoplasmic tail) with VAMP3 (By similarity). Interacts with KCNK2; the interaction enhances KCNK2 surface expression and is inhibited by cAMP (By similarity) (PubMed:26642364). Interacts with CAV3 (By similarity).
Belongs to the PpiC/parvulin rotamase family. PIN4 subfamily.
Isoform 1 is found in pre-ribosomal ribonucleoprotein (pre-rRNP) complexes.
Isoform 1 is involved as a ribosomal RNA processing factor in ribosome biogenesis. Binds to tightly bent AT-rich stretches of double-stranded DNA.
Isoform 2 is much more stable than isoform 1 (at protein level). Ubiquitous. Isoform 1 and isoform 2 are expressed in kidney, liver, blood vessel, brain, mammary gland, skeletal muscle, small intestine and submandibularis. Isoform 1 transcripts are much more abundant than isoform 2 in each tissue analyzed.
Isoform 2 is sumoylated with SUMO2 and SUMO3.
Phosphorylated. Isoform 1 phosphorylation occurs both in the nucleus and the cytoplasm. Isoform 1 phosphorylation at Ser-19 does not affect its PPIase activity but is required for nuclear localization, and the dephosphorylation is a prerequisite for the binding to DNA. The unphosphorylated isoform 1 associates with the pre-rRNP complexes in the nucleus.
The PPIase domain enhances mitochondrial targeting.
The first 25 amino acids are sufficient for mitochondrial targeting.
Belongs to the WD repeat G protein beta family.
G proteins are composed of 3 units, alpha, beta and gamma (By similarity). The heterodimer formed by GNB1 and GNG2 interacts with ARHGEF5 (PubMed:19713215). The heterodimer formed by GNB1 and GNG2 interacts with GRK2 (By similarity). Forms a complex with GNAO1 and GNG3 (PubMed:34685729). Interacts with ARHGEF18 and RASD2 (PubMed:14512443, PubMed:19255495).
Phosphorylation at His-266 by NDKB contributes to G protein activation by increasing the high energetic phosphate transfer onto GDP.
Microtubule-binding protein required to ensure proper cell division and nuclear envelope reassembly by sequestering the endoplasmic reticulum away from chromosomes during mitosis. Probably acts by clearing the endoplasmic reticulum membrane from metaphase chromosomes.
Cilium- and flagellum-specific protein that plays a role in axonemal structure organization and motility (PubMed:24414207). Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (PubMed:36191189). Involved in the regulation of the size and morphology of cilia (PubMed:24414207). Required for axonemal microtubules polyglutamylation (PubMed:24414207).
Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells. May play an important role in regulating the assembly of the AUM (By similarity).
Putative regulator of protein phosphatase 1 (PP1) activity (PubMed:19389623). May play a role in the endosomal sorting process or in endosome maturation pathway (PubMed:30520571).
Expressed in the lung and lower levels seen in the kidney. Present also in normal and neoplastic prostate tissues, and prostate cancer cell lines.
Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including neurogenesis, vascular development, angiogenesis and osteogenesis (PubMed:31363885). Acts in concert with PTHLH/PTHRP to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction (By similarity). Initiates the canonical BMP signaling cascade by associating with type I receptor BMPR1A and type II receptor BMPR2 (PubMed:25868050, PubMed:8006002). Once all three components are bound together in a complex at the cell surface, BMPR2 phosphorylates and activates BMPR1A. In turn, BMPR1A propagates signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act as activators and repressors of transcription of target genes (PubMed:25868050, PubMed:29212066). Positively regulates the expression of odontogenic development regulator MSX1 via inducing the IPO7-mediated import of SMAD1 to the nucleus (By similarity). Required for MSX1-mediated mesenchymal molar tooth bud development beyond the bud stage, via promoting Wnt signaling (By similarity). Acts as a positive regulator of odontoblast differentiation during mesenchymal tooth germ formation, expression is repressed during the bell stage by MSX1-mediated inhibition of CTNNB1 signaling (By similarity). Able to induce its own expression in dental mesenchymal cells and also in the neighboring dental epithelial cells via an MSX1-mediated pathway (By similarity). Can also signal through non-canonical BMP pathways such as ERK/MAP kinase, PI3K/Akt, or SRC cascades (PubMed:31363885). For example, induces SRC phosphorylation which, in turn, activates VEGFR2, leading to an angiogenic response (PubMed:31363885).
Homodimer; disulfide-linked (By similarity). Interacts with GREM2. Part of a complex consisting of TWSG1 and CHRD. Interacts with the serine proteases, HTRA1 and HTRA3; the interaction with either inhibits BMP4-mediated signaling. The HTRA protease activity is required for this inhibition (By similarity). Interacts with SOSTDC1. Interacts with FBN1 (via N-terminal domain) and FBN2 (PubMed:18339631). Interacts with type I receptor BMPR1A (PubMed:8006002). Interacts with type II receptor BMPR2 (PubMed:29212066). Interacts with FSTL1; this interaction inhibits the activation of the BMP4/Smad1/5/8 signaling pathway (PubMed:29212066). Interacts with SCUBE3 (PubMed:33308444).
Belongs to the GTP cyclohydrolase I family.
GTP shows a positive allosteric effect, and tetrahydrobiopterin inhibits the enzyme activity. Zinc is required for catalytic activity. Inhibited by Mg(2+).
In epidermis, expressed predominantly in basal undifferentiated keratinocytes and in some but not all melanocytes (at protein level).
Phosphorylated by casein kinase II at Ser-81 in HAECs during oscillatory shear stress; phosphorylation at Ser-81 results in increased enzyme activity.
Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown.
Toroid-shaped homodecamer, composed of a dimer of pentamers. The inactive isoforms also form decamers and may possibly be incorporated into GCH1 heterodecamers, decreasing enzyme stability and activity. Interacts with AHSA1 and GCHFR/GFRP.
Up-regulated by IFNG/IFN-gamma, TNF, IL1B/interleukin-1 beta, bacterial lipopolysaccharides (LPS) and phenylalanine, and down-regulated by dibutyryl-cAMP, iloprost and 8-bromo-cGMP in HUVEC cells. Up-regulation of GCH1 expression, in turn, stimulates production of tetrahydrobiopterin, with subsequent elevation of endothelial nitric oxide synthase activity. Cytokine-induced GCH1 up-regulation in HUVECs in response to TNF and IFNG/IFN-gamma involves cooperative activation of both the NF-kappa-B and JAK2/STAT pathways. Also up-regulated by hydrogen peroxide in human aorta endothelial cells (HAECs).
Antiparallel homodimer (PubMed:1469042, PubMed:14522975). Interacts with CENPT (PubMed:19412974). Identified in a centromere complex containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:27499292).
Interacts with centromeric heterochromatin in chromosomes and binds to a specific 17 bp subset of alphoid satellite DNA, called the CENP-B box (PubMed:11726497). May organize arrays of centromere satellite DNA into a higher-order structure which then directs centromere formation and kinetochore assembly in mammalian chromosomes (Probable).
N-terminally methylated by METTL11A/NTM1. Alpha-N-methylation is stimulated in response to extracellular stimuli, including increased cell density and heat shock, and seems to facilitate binding to CENP-B boxes. Chromatin-bound CENP-B is primarily trimethylated.
Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. Known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-13, MMP-14, MMP-15, MMP-16 and MMP-19.
Interacts (via the C-terminal) with MMP2 (via the C-terminal PEX domain); the interaction inhibits the MMP2 activity.
The activity of TIMP2 is dependent on the presence of disulfide bonds.
Belongs to the histidine acid phosphatase family.
Highly expressed in kidney, heart, small intestine, muscle, liver, prostate, testis, ovary and weakly expressed in thymus and colon.
Hydrolyzes lysophosphatidic acid (LPA) containing a medium length fatty acid chain to the corresponding monoacylglycerol. Has highest activity with lysophosphatidic acid containing myristate (C14:0), monounsaturated oleate (C18:1) or palmitate (C16:0), and lower activity with C18:0 and C6:0 lysophosphatidic acid.
Induced with the differentiation from myoblast to myotube.
Was originally reported to be located in the mitochondrion, but the evidence seems to be weak and contradictory with the presence of a cleaved signal sequence.
Although it belongs to the enolase family, Leu-362 is present instead of the conserved Glu which is expected to be an active site residue.
May be required for sperm motility and function.
Synthesized as an approximately 70-kDa precursor, which then undergoes proteolytic cleavage to an approximately 60-kDa enzyme; HOATZ associates directly or indirectly with ENO4 to mediate this process before its transport to mature flagella.
Homooligomer. Interacts with DLG1 and KCNA5; forms a ternary complex. Interacts with TRIM72. Interacts with MUSK; may regulate MUSK signaling. Interacts with DAG1 (via its C-terminal); the interaction prevents binding of DAG1 with DMD (PubMed:10988290). Interacts with DYSF (PubMed:11532985). Interacts with BVES (By similarity). Interacts with CAVIN1 and CAVIN2 (PubMed:24567387). Interacts with CAVIN4 (PubMed:24567387, PubMed:11251997).
May act as a scaffolding protein within caveolar membranes. Interacts directly with G-protein alpha subunits and can functionally regulate their activity. May also regulate voltage-gated potassium channels. Plays a role in the sarcolemma repair mechanism of both skeletal muscle and cardiomyocytes that permits rapid resealing of membranes disrupted by mechanical stress (By similarity). Mediates the recruitment of CAVIN2 and CAVIN3 proteins to the caveolae (PubMed:19262564).
Sumoylation with SUMO3 by PIAS4 may reduce agonist-induced internalization and desensitization of adrenergic receptor ABRD2.
Plays a role in neuronal differentiation as chromatin-associated protein. Acts as inhibitor of HMG20B. Overcomes the repressive effects of the neuronal silencer REST and induces the activation of neuronal-specific genes. Involved in the recruitment of the histone methyltransferase KMT2A/MLL1 and consequent increased methylation of histone H3 lysine 4 (By similarity).
During embryogenesis, detected in liver, lung, skeletal muscle and placenta.
Expressed in heart, placenta, lung, liver, muscle, kidney, tongue, limb, eye and pancreas.
Genetic variations in IGF2 are associated with body mass index (BMI). The BMI is a statistical measurement which compares a person's weight and height.
Interacts with MYORG; this interaction is required for IGF2 secretion (By similarity). Interacts with integrins ITGAV:ITGB3 and ITGA6:ITGB4; integrin-binding is required for IGF2 signaling (PubMed:28873464).
O-glycosylated with core 1 or possibly core 8 glycans. Thr-96 is a minor glycosylation site compared to Thr-99.
Preptin undergoes glucose-mediated co-secretion with insulin, and acts as physiological amplifier of glucose-mediated insulin secretion. Exhibits osteogenic properties by increasing osteoblast mitogenic activity through phosphoactivation of MAPK1 and MAPK3.
Product of 5 different transcripts regulated by 5 different promoters, denominated P0, P1, P2, P3 and P4.
Proteolytically processed by PCSK4, proIGF2 is cleaved at Arg-128 and Arg-92 to generate big-IGF2 and mature IGF2.
The IGF2 locus is imprinted. Paternal inherited gene is expressed, while the maternal inherited gene is imprinted, hence silenced. Transcripts from 5 promoters P0, P1, P2, P3 and P4 code for the same protein but are differentially regulated in a developmental stage and tissue specificity.
The insulin-like growth factors possess growth-promoting activity (By similarity). Major fetal growth hormone in mammals. Plays a key role in regulating fetoplacental development. IGF2 is influenced by placental lactogen. Also involved in tissue differentiation. In adults, involved in glucose metabolism in adipose tissue, skeletal muscle and liver (Probable). Acts as a ligand for integrin which is required for IGF2 signaling (PubMed:28873464). Positively regulates myogenic transcription factor MYOD1 function by facilitating the recruitment of transcriptional coactivators, thereby controlling muscle terminal differentiation (By similarity). Inhibits myoblast differentiation and modulates metabolism via increasing the mitochondrial respiration rate (By similarity).
O-glucosyltransferase that transfers glucose toward fucose with a beta-1,3 linkage. Specifically glucosylates O-linked fucosylglycan on TSP type-1 domains of proteins, thereby contributing to elongation of O-fucosylglycan.
Widely expressed, with highest levels in testis and uterus.
Forms part of the large latent transforming growth factor beta precursor complex; removal is essential for activation of complex (PubMed:9660815). Interacts with LTBP1 and TGFB1 (PubMed:9660815). Interacts with EFEMP2; this interaction promotes fibrillar deposition of EFEMP2 (PubMed:27339457).
Highly expressed in heart, skeletal muscle, pancreas, uterus, and small intestine. Weakly expressed in placenta and lung.
The gene represented in this entry may act as a disease modifier. DMD patients homozygous for the IAAM haplotype consisting of Ile-194, Ala-787, Ala-820 and Met-1141 remain ambulatory significantly longer than those heterozygous or homozygous for the VTTT haplotype consisting of Val-194, Thr-787, Thr-820 and Thr-1141. This may be due to increased binding to TGFB1, resulting in TGFB1 sequestration in the extracellular matrix and reduced TGFB1 signaling which has been linked to improved muscle function and regeneration.
Very low expression in fetal brain, liver, heart, spleen and thymus.
(Microbial infection) Interacts with Epstein-Barr virus protein BPLF1 and TRIM25; leading to inhibition of the type-I IFN response.
Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways (PubMed:14578935, PubMed:15071501, PubMed:15644438, PubMed:16376338, PubMed:16959763, PubMed:31024343, PubMed:9360956). Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif (PubMed:35662396). Binding generally results in the modulation of the activity of the binding partner (PubMed:35662396). Promotes cytosolic retention and inactivation of TFEB transcription factor by binding to phosphorylated TFEB (PubMed:35662396). Induces ARHGEF7 activity on RAC1 as well as lamellipodia and membrane ruffle formation (PubMed:16959763). In neurons, regulates spine maturation through the modulation of ARHGEF7 activity (By similarity).
Interacts with CDK16 and BSPRY (By similarity). Interacts with WEE1 (C-terminal). Interacts with SAMSN1 (By similarity). Interacts with MLF1 (phosphorylated form); the interaction retains it in the cytoplasm (By similarity). Interacts with Thr-phosphorylated ITGB2 (By similarity). Interacts with BCL2L11 (By similarity). Homodimer (PubMed:12865427, PubMed:16376338). Heterodimerizes with YWHAE (PubMed:16376338). Homo- and heterodimerization is inhibited by phosphorylation on Ser-58 (PubMed:16376338). Interacts with FOXO4, NOXA1, SSH1 and ARHGEF2. Interacts with Pseudomonas aeruginosa exoS (unphosphorylated form). Interacts with BAX; the interaction occurs in the cytoplasm. Under stress conditions, MAPK8-mediated phosphorylation releases BAX to mitochondria. Interacts with phosphorylated RAF1; the interaction is inhibited when YWHAZ is phosphorylated on Thr-232 (PubMed:31024343). Interacts with BRAF (PubMed:31024343). Interacts with TP53; the interaction enhances p53 transcriptional activity. The Ser-58 phosphorylated form inhibits this interaction and p53 transcriptional activity. Interacts with ABL1 (phosphorylated form); the interaction retains ABL1 in the cytoplasm. Interacts with PKA-phosphorylated AANAT; the interaction modulates AANAT enzymatic activity by increasing affinity for arylalkylamines and acetyl-CoA and protecting the enzyme from dephosphorylation and proteasomal degradation. It may also prevent thiol-dependent inactivation. Interacts with AKT1; the interaction phosphorylates YWHAZ and modulates dimerization. Interacts with GAB2 and TLK2. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with ZFP36L1 (via phosphorylated form); this interaction occurs in a p38 MAPK- and AKT-signaling pathways (By similarity). Interacts with SLITRK1 (PubMed:19640509). Interacts with AK5, LDB1, MADD, MARK3, PDE1A and SMARCB1 (PubMed:16959763). Interacts with MEFV (PubMed:27030597). Interacts with ADAM22 (via C-terminus) (PubMed:12589811).
The delta, brain-specific form differs from the zeta form in being phosphorylated (Probable). Phosphorylation on Ser-184 by MAPK8; promotes dissociation of BAX and translocation of BAX to mitochondria (PubMed:15071501, PubMed:15696159). Phosphorylation on Thr-232; inhibits binding of RAF1 (PubMed:9360956). Phosphorylated on Ser-58 by PKA and protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion (PubMed:11956222, PubMed:12865427, PubMed:15883165, PubMed:16376338). Phosphorylation on Ser-58 by PKA; disrupts homodimerization and heterodimerization with YHAE and TP53 (PubMed:11956222, PubMed:12865427, PubMed:15883165, PubMed:16376338).
Was originally thought to have phospholipase A2 activity.
Contains a degenerate basic motif not likely to bind DNA.
Efficient DNA binding requires dimerization with another bHLH protein. Interacts with NEUROG3 and NEUROD1. Interacts with ZFPM2; mediates indirect interaction with GATA4. Forms a heterodimer with TCF3; repress transcription of TCF3 and TCF3/NEUROG3 dimer-induced transactivation of E box-dependent promoters.
Expressed in lung, liver, kidney, heart and pancreas. Expressed in endothel of umbilical vessels.
The bHLH domain mediates transcriptional repression by inhibiting TCF3 transcriptional activity through heterodimerization.
Transcription factor that binds a palindromic (canonical) core consensus DNA sequence 5'-CANNTG- 3' known as an E-box element, possibly as a heterodimer with other bHLH proteins (PubMed:24236640). Regulates endothelial cell proliferation, migration and tube-like structures formation (PubMed:24463812). Modulates endothelial cell differentiation through NOS3 (PubMed:24463812). May be implicated in specification and differentiation of neuronal cell lineages in the brain (By similarity). May participate in kidney development and may be involved in podocyte differentiation (By similarity). During early embryonic development is involved in tissue-specific differentiation processes that are dependent on class II bHLH factors and namely modulates the differentiation program initiated by the pro-endocrine factor NEUROG3 (By similarity). During myogenesis, may play a role during the transition of myoblasts from the proliferative phase to the differentiation phase (By similarity). Positively regulates HAMP transcription in two ways, firstly by acting directly on the HAMP promoter via E-boxes binding and indirectly through increased phosphorylation of SMAD protein complex (PubMed:24236640). Repress NEUROG3-dependent gene activation in a gene-specific manner through at least two mechanisms; requires only either the sequestering of a general partner such as TCF3 through heterodimerization, either also requires binding of the bHLH domain to DNA via a basic motif (By similarity).
Associates with microtubules; the association occurs on polyglutamylated tubulin (PubMed:22493317, PubMed:26562023).
Plays a role in microtubule (MT) stabilization and this stabilization involves the maintenance of NUMA1 at the spindle poles. Colocalizes with polyglutamylated MTs to promote MT stabilization and regulate bipolar spindle formation in mitosis. Binding of CCSAP to centrosomes and the spindle around centrosomes during mitosis inhibits MT depolymerization, thereby stabilizing the mitotic spindle (PubMed:26562023). May play a role in embryonic development. May be required for proper cilia beating (By similarity).
A chromosomal aberration involving GMPS is found in acute myeloid leukemias. Translocation t(3,11)(q25,q23) with KMT2A/MLL1.
Catalyzes the conversion of xanthine monophosphate (XMP) to GMP in the presence of glutamine and ATP through an adenyl-XMP intermediate.
Belongs to the VPS10-related sortilin family. SORCS subfamily.
Detected in fetal and infant brain and in fetal retina.
Heterohexamer of two PFD-alpha type and four PFD-beta type subunits (By similarity). Component of the PAQosome complex which is responsible for the biogenesis of several protein complexes and which consists of R2TP complex members RUVBL1, RUVBL2, RPAP3 and PIH1D1, URI complex members PFDN2, PFDN6, PDRG1, UXT and URI1 as well as ASDURF, POLR2E and DNAAF10/WDR92 (PubMed:31738558).
Transcription activator that binds DNA elements with the consensus sequence 5'-CGGTAATTGG-3'. Binds DNA via its homeobox. Required for normal cell death of enteric neurons in the gastrointestinal tract. Required for normal development of the enteric nervous system, and for proper development of normal motility of the gastrointestinal tract (By similarity).
Ubiquitous. Higher expression seen in the liver, testis and ovary.
Belongs to the membrane-bound acyltransferase family.
Highly expressed in liver, pancreas and adipose tissue. Very low expression in skeletal muscle and heart. Detected in neutrophils.
Lysophospholipid O-acyltransferase (LPLAT) that catalyzes the reacylation step of the phospholipid remodeling process also known as the Lands cycle (PubMed:18782225, PubMed:18195019, PubMed:18772128). Catalyzes transfer of the fatty acyl chain from fatty acyl-CoA to 1-acyl lysophospholipid to form various classes of phospholipids. Converts 1-acyl lysophosphatidylcholine (LPC) into phosphatidylcholine (PC) (LPCAT activity), 1-acyl lysophosphatidylserine (LPS) into phosphatidylserine (PS) (LPSAT activity) and 1-acyl lysophosphatidylethanolamine (LPE) into phosphatidylethanolamine (PE) (LPEAT activity) (PubMed:18782225, PubMed:18195019, PubMed:18772128). Favors polyunsaturated fatty acyl-CoAs as acyl donors compared to saturated fatty acyl-CoAs (PubMed:18195019, PubMed:18772128). Has higher activity for LPC acyl acceptors compared to LPEs and LPSs. Can also transfer the fatty acyl chain from fatty acyl-CoA to 1-O-alkyl lysophospholipid or 1-O-alkenyl lysophospholipid with lower efficiency (By similarity). Acts as a major LPC O-acyltransferase in liver and intestine. As a component of the liver X receptor/NR1H3 or NR1H2 signaling pathway, mainly catalyzes the incorporation of arachidonate into PCs of endoplasmic reticulum (ER) membranes, increasing membrane dynamics and enabling triacylglycerols transfer to nascent very low-density lipoprotein (VLDL) particles. Promotes processing of sterol regulatory protein SREBF1 in hepatocytes, likely by facilitating the translocation of SREBF1-SCAP complex from ER to the Golgi apparatus (By similarity). Participates in mechanisms by which the liver X receptor/NR1H3 or NR1H2 signaling pathway counteracts lipid-induced ER stress response and inflammation. Down-regulates hepatic inflammation by limiting arachidonic acid availability for synthesis of inflammatory eicosanoids, such as prostaglandins (By similarity). In enterocytes, acts as a component of a gut-brain feedback loop that coordinates dietary lipid absorption and food intake. Regulates the abundance of PCs containing linoleate and arachidonate in enterocyte membranes, enabling passive diffusion of fatty acids and cholesterol across the membrane for efficient chylomicron assembly (By similarity). In the intestinal crypt, acts as a component of dietary-responsive phospholipid-cholesterol axis, regulating the biosynthesis of cholesterol and its mitogenic effects on intestinal stem cells (By similarity).
The di-lysine motif confers endoplasmic reticulum localization.
Acts as a acyl-protein thioesterase (PubMed:19439193, PubMed:20418879). Hydrolyzes fatty acids from S-acylated cysteine residues in proteins such as trimeric G alpha proteins or HRAS (PubMed:20418879). Has depalmitoylating activity toward KCNMA1 (PubMed:22399288). Could also depalmitoylate ADRB2 (PubMed:27481942). Acts as a lysophospholipase and hydrolyzes lysophosphatidylcholine (lyso-PC) (PubMed:19439193). Also hydrolyzes lysophosphatidylethanolamine (lyso-PE), lysophosphatidylinositol (lyso-PI) and lysophosphatidylserine (lyso-PS) (By similarity). Has much higher thioesterase activity than lysophospholipase activity (PubMed:19439193). Contributes to the production of lysophosphatidic acid (LPA) during blood coagulation by recognizing and cleaving plasma phospholipids to generate lysophospholipids which in turn act as substrates for ENPP2 to produce LPA (PubMed:21393252).
Inhibited by palmostatin-B, leading to impair depalmitoylating of Ras.
Abundantly expressed in tonsil, lymph node, and trachea; strong expression in prostate; lower expression in thyroid, stomach, and colon.
Can bind to the surface of B-lymphoma cells, but not T-lymphoma cells, consistent with a function as a secreted mediator acting upon B-cells.
(Microbial infection) Interacts with Sindbis virus non-structural protein 3 (via C-terminus); this interaction inhibits the formation of host stress granules on viral mRNAs and the nsp3-FXR2 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes.
Disordered region at the C-terminus undergoes liquid-liquid phase separation (LLPS) for the formation of a membraneless compartment that stores mRNAs.
Expressed in all tissues examined including heart, brain, kidney and testis (PubMed:9259278). In brain, present at high level in neurons and especially in the Purkinje cells at the interface between the granular layer and the molecular layer (at protein level) (PubMed:9259278).
Interacts with FMR1 (PubMed:7489725, PubMed:8668200, PubMed:11157796). Interacts with FXR1 (PubMed:7489725). Interacts with TDRD3 (PubMed:18664458). Interacts with HABP4 (PubMed:21771594). Interacts with CYFIP2 but not with CYFIP1 (By similarity).
The tandem Agenet-like domains preferentially recognize trimethylated histone peptides.
mRNA-binding protein that acts as a regulator of mRNAs translation and/or stability, and which is required for adult hippocampal neurogenesis (By similarity). Specifically binds to AU-rich elements (AREs) in the 3'-UTR of target mRNAs (By similarity). Promotes formation of some phase-separated membraneless compartment by undergoing liquid-liquid phase separation upon binding to AREs-containing mRNAs: mRNAs storage into membraneless compartments regulates their translation and/or stability (By similarity). Acts as a regulator of adult hippocampal neurogenesis by regulating translation and/or stability of NOG mRNA, thereby preventing NOG protein expression in the dentate gyrus (By similarity).
Acetylated. Deacetylation at Lys-780 by SIRT6 stimulates its ability to coactivate PPARA.
Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation.
Contains 2 C-terminal transcription activation domains (AD1 and AD2) that can function independently.
Contains four Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. The LXXLL motifs are essential for the association with nuclear receptors and are, at least in part, functionally redundant.
Present in a complex containing NCOA3, IKKA, IKKB, IKBKG and CREBBP (PubMed:11971985, PubMed:9430642). Present in a complex containing CARM1 and EP300/P300. Interacts (via C-terminus) with CREBBP (PubMed:11971985, PubMed:9430642). Interacts (via LXXLL 1, 2 and 3 motifs) with RORA (via AF-2 motif) (PubMed:10478845). Interacts (via LXXLL 1, 2 and 3 motifs) with RORC (via AF-2 motif). Interacts with APEX1 (PubMed:10594042). Interacts with BMAL1 (By similarity). Interacts with CARM1. Interacts with CASP8AP2. Interacts with CLOCK. Interacts with DDX5 (PubMed:11250900). Interacts with ESR1 (PubMed:9430642). Interacts with HIF1A (PubMed:10594042). Interacts with NCOA1 (PubMed:10594042). Interacts with NR4A1/Nur77 (PubMed:18690216). Interacts with NR4A3; potentiates the activity of the NR4A3 (By similarity). Interacts with NR1H3 (PubMed:19481530). Interacts with NR3C1 (PubMed:23508108, PubMed:9590696). Interacts with NR3C2. Interacts with PSMB9 (PubMed:16957778). Interacts with RARA (PubMed:9430642). Interacts with RXRA (PubMed:9430642). Interacts with RWDD3 (PubMed:23508108). Interacts with TTLL5/STAMP (PubMed:17116691).
The LLXXLXXXL motif is involved in transcriptional coactivation and CREBBP/CBP binding.
Transcriptional coactivator for steroid receptors and nuclear receptors (PubMed:8670870, PubMed:23508108, PubMed:9430642). Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1) (PubMed:8670870, PubMed:23508108, PubMed:9430642). Required with NCOA1 to control energy balance between white and brown adipose tissues (PubMed:8670870, PubMed:23508108, PubMed:9430642). Critical regulator of glucose metabolism regulation, acts as RORA coactivator to specifically modulate G6PC1 expression (PubMed:8670870, PubMed:23508108, PubMed:9430642). Involved in the positive regulation of the transcriptional activity of the glucocorticoid receptor NR3C1 by sumoylation enhancer RWDD3 (PubMed:23508108). Positively regulates the circadian clock by acting as a transcriptional coactivator for the CLOCK-BMAL1 heterodimer (By similarity).
Expressed at low level in brain and lung. Isoform 1 is enriched in normal T-cells, isoform 3 is enriched in normal B-cells and chronic lymphocytic leukemia (CLL) B-cells.
Guanine nucleotide-exchange factor (GEF) that activates CDC42 and RAC1 by exchanging bound GDP for free GTP. Essential for dendritic spine morphogenesis in Purkinje cells and in hippocampal neurons, via a CDC42-mediated pathway. Sustains B-cell lymphopoiesis in secondary lymphoid tissues and regulates FCER2/CD23 expression.
Isoforms 1 and 2 are up-regulated in response to IL4 in B-cells but not T-cells.
The DOCKER domain may mediate some GEF activity.
A connexon is composed of a hexamer of connexins. Interacts (via C-terminus) with TJP1 (By similarity). Interacts (via C-terminus) with SRC (via SH3 domain) (By similarity). Interacts (not ubiquitinated) with UBQLN4 (via UBA domain) (By similarity). Interacts with SGSM3 and CNST (By similarity). Interacts with RIC1/CIP150. Interacts with CSNK1D. Interacts with NOV (PubMed:15181016, PubMed:15213231). Interacts with TMEM65 (By similarity).
Acetylated in the developing cortex; leading to delocalization from the cell membrane.
Expressed in the heart and fetal cochlea.
Gap junction protein that acts as a regulator of bladder capacity. A gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. May play a critical role in the physiology of hearing by participating in the recycling of potassium to the cochlear endolymph. Negative regulator of bladder functional capacity: acts by enhancing intercellular electrical and chemical transmission, thus sensitizing bladder muscles to cholinergic neural stimuli and causing them to contract (By similarity). May play a role in cell growth inhibition through the regulation of NOV expression and localization. Plays an essential role in gap junction communication in the ventricles (By similarity).
Phosphorylated at Ser-368 by PRKCG; phosphorylation induces disassembly of gap junction plaques and inhibition of gap junction activity (By similarity). Phosphorylation at Ser-325, Ser-328 and Ser-330 by CK1 modulates gap junction assembly. Phosphorylation at Ser-368 by PRKCD triggers its internalization into small vesicles leading to proteasome-mediated degradation (By similarity).
PubMed:11741837 reported 2 mutations (Phe-11 and Ala-24) linked to non-syndromic autosomal recessive deafness (DFNBG). These mutations have subsequently been shown (PubMed:12457340) to involve the pseudogene of connexin-43 located on chromosome 5.
PubMed:7715640 reported a mutation Pro-364 linked to congenital heart diseases. PubMed:8873667 later shown that it is an artifact.
S-nitrosylation at Cys-271 is enriched at the muscle endothelial gap junction in arteries, it augments channel permeability and may regulate of smooth muscle cell to endothelial cell communication.
Sumoylated with SUMO1, SUMO2 and SUMO3, which may regulate the level of functional Cx43 gap junctions at the plasma membrane. May be desumoylated by SENP1 or SENP2.
Higher expression level in adult testis as compared to 6-week-old fetal testis.
It is uncertain whether Met-1 or Met-50 is the initiator.
Acyltransferase which catalyzes the transfer of an acyl group from an acyl-CoA to a lysophospholipid leading to the production of a phospholipid and participates in the reacylation step of the phospholipid remodeling pathway also known as the Lands cycle (PubMed:18772128). Catalyzes preferentially the acylation of lysophosphatidylethanolamine (1-acyl-sn-glycero-3-phosphoethanolamine or LPE) and lysophosphatidic acid (LPA) and to a lesser extend lysophosphatidylcholine (LPC) and lysophosphatidylserine (LPS) (PubMed:18772128). Prefers oleoyl-CoA as the acyl donor (PubMed:18772128). May be involved in chondrocyte differentiation (By similarity).
Expressed in striated muscles, specifically in type 2a fibers (at protein level).
Heterotetramerization is mediated by the interaction between a coiled-coil of PRKG1 and the leucine/isoleucine zipper of PPP1R12A/MBS, the myosin-binding subunit of the myosin phosphatase.
Induced by 2-fold during pregnancy, including in abdominus rectus muscle.
Key regulator of protein phosphatase 1C (PPP1C). Mediates binding to myosin. As part of the PPP1C complex, involved in dephosphorylation of PLK1. Capable of inhibiting HIF1AN-dependent suppression of HIF1A activity.
PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, and one or several targeting or regulatory subunits. PPP1R12A mediates binding to myosin. Interacts with ARHA and CIT (By similarity). Binds PPP1R12B, ROCK1 and IL16. Interacts directly with PRKG1. Non-covalent dimer of 2 dimers; PRKG1-PRKG1 and PPP1R12A-PPP1R12A. Interacts with SMTNL1 (By similarity). Interacts with PPP1CB; the interaction is direct. Interacts (when phosphorylated at Ser-445, Ser-472 and Ser-910) with 14-3-3. Interacts with ROCK1 and ROCK2. Interacts with isoform 1 and isoform 2 of ZIPK/DAPK3. Interacts with RAF1. Interacts with HIF1AN. Interacts with NCKAP1L (PubMed:16417406).
PP1 comprises a catalytic subunit, and one or several targeting or regulatory subunits.
Phosphorylated by CIT (Rho-associated kinase) (By similarity). Phosphorylated cooperatively by ROCK1 and CDC42BP on Thr-696. Phosphorylated on upon DNA damage, probably by ATM or ATR. In vitro, phosphorylation of Ser-695 by PKA and PKG appears to prevent phosphorylation of the inhibitory site Thr-696, probably mediated by PRKG1. Phosphorylation at Ser-445, Ser-472 and Ser-910 by NUAK1 promotes interaction with 14-3-3, leading to inhibit interaction with myosin light chain MLC2, preventing dephosphorylation of MLC2. May be phosphorylated at Thr-696 by DMPK; may inhibit the myosin phosphatase activity. Phosphorylated at Ser-473 by CDK1 during mitosis, creating docking sites for the POLO box domains of PLK1. Subsequently, PLK1 binds and phosphorylates PPP1R12A.
The KVKF motif mediates interaction with PPP1CB.
Homodimer. Interacts with JAK2 (in vitro) (By similarity). Interacts with CBL (PubMed:15159412). Part of a complex containing CBL and activated EGFR (PubMed:15159412). Interacts with ubiquitin and with mono-ubiquitinated proteins (PubMed:15159412). Interacts with ZAP70 (ubiquitinated form) (PubMed:26903241).
Interferes with CBL-mediated down-regulation and degradation of receptor-type tyrosine kinases. Promotes accumulation of activated target receptors, such as T-cell receptors and EGFR, on the cell surface. Exhibits tyrosine phosphatase activity toward several substrates including EGFR, FAK, SYK, and ZAP70. Down-regulates proteins that are dually modified by both protein tyrosine phosphorylation and ubiquitination.
(Microbial infection) May favor virus entry in case of infection with herpes simplex virus 1 (HSV1) or herpes simplex virus 2 (HSV2).
By glucose deprivation in neuroblastoma cells.
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:17403899, PubMed:25849773, PubMed:27462815). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation (PubMed:17403899). The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression (PubMed:25849773).
Activator of ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases that acts as a as repressor of autophagy (PubMed:31267705, PubMed:17942928, PubMed:20864041). May enhance ubiquitin ligase activity of TRIM28 and stimulate p53/TP53 ubiquitination by TRIM28. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex (PubMed:17942928, PubMed:20864041). May play a role in tumor transformation or aspects of tumor progression (PubMed:17942928, PubMed:20864041). In vitro promotes cell viability in melanoma cell lines (PubMed:17942928).
In vitro experiments measuring cell viability in melanoma cell lines used siRNA specific for MAGEA3 and MAGEA6.
Ubiquitinated by the DCX(DCAF12) complex specifically recognizes the diglutamate (Glu-Glu) at the C-terminus, leading to its degradation.
Component of a nuclear TRAMP-like complex, an ATP-dependent exosome regulatory complex consisting of a helicase (MTREX), an oligadenylate polymerase (TENT4B or TENT4A), and a substrate specific RNA-binding factor (ZCCHC7 or ZCCHC8). Several TRAMP-like complexes exist with specific compositions and are associated with nuclear, or nucleolar RNA exosomes.
Exhibits poor nucleotidyl transferase activity.
Terminal nucleotidyltransferase that catalyzes preferentially the transfer of ATP and GTP on RNA 3' poly(A) tail creating a heterogeneous 3' poly(A) tail leading to mRNAs stabilization by protecting mRNAs from active deadenylation (PubMed:23376078, PubMed:30026317). Also functions as a catalytic subunit of a TRAMP-like complex which has a poly(A) RNA polymerase activity and is involved in a post-transcriptional quality control mechanism. Polyadenylation with short oligo(A) tails is required for the degradative activity of the exosome on several of its nuclear RNA substrates. Has no terminal uridylyltransferase activity, and does not play a role in replication-dependent histone mRNA degradation via uridylation (PubMed:23376078).
Was originally thought to have DNA polymerase activity.
Detected in neutrophils (at protein level) (PubMed:7683678, PubMed:8298140). Expressed in bone marrow and in tissues that are prone to exposure to microorganism (PubMed:9339356). High expression is found in bone marrow as well as in uterus, prostate, salivary gland, stomach, appendix, colon, trachea and lung (PubMed:9339356). Expressed in the medullary tubules of the kidney (PubMed:30418175). Not found in the small intestine or peripheral blood leukocytes (PubMed:9339356).
Expression is activated by the oncoprotein BCR-ABL; BCR-ABL misregulates expression via the JAK/STAT pathway and binding of STAT5A to the promoter (PubMed:19229297). Induced by insulin (PubMed:30418175).
Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development (PubMed:12453413, PubMed:27780864, PubMed:20581821). Binds iron through association with 2,3-dihydroxybenzoic acid (2,3-DHBA), a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell, depending on the context. Iron-bound form (holo-24p3) is internalized following binding to the SLC22A17 (24p3R) receptor, leading to release of iron and subsequent increase of intracellular iron concentration. In contrast, association of the iron-free form (apo-24p3) with the SLC22A17 (24p3R) receptor is followed by association with an intracellular siderophore, iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration. Involved in apoptosis due to interleukin-3 (IL3) deprivation: iron-loaded form increases intracellular iron concentration without promoting apoptosis, while iron-free form decreases intracellular iron levels, inducing expression of the proapoptotic protein BCL2L11/BIM, resulting in apoptosis (By similarity). Involved in innate immunity; limits bacterial proliferation by sequestering iron bound to microbial siderophores, such as enterobactin (PubMed:27780864). Can also bind siderophores from M.tuberculosis (PubMed:15642259, PubMed:21978368).
Monomer (PubMed:7683678, PubMed:1281792). Homodimer; disulfide-linked (PubMed:7683678). Heterodimer; disulfide-linked with MMP9 (PubMed:7683678).
Belongs to the Integrator subunit 4 family.
E1-like activating enzyme involved in the 2 ubiquitin-like systems required for cytoplasm to vacuole transport (Cvt) and autophagy. Activates ATG12 for its conjugation with ATG5 as well as the ATG8 family proteins for their conjugation with phosphatidylethanolamine. Both systems are needed for the ATG8 association to Cvt vesicles and autophagosomes membranes. Required for autophagic death induced by caspase-8 inhibition. Facilitates LC3-I lipidation with phosphatidylethanolamine to form LC3-II which is found on autophagosomal membranes (PubMed:34161705). Required for mitophagy which contributes to regulate mitochondrial quantity and quality by eliminating the mitochondria to a basal level to fulfill cellular energy requirements and preventing excess ROS production. Modulates p53/TP53 activity to regulate cell cycle and survival during metabolic stress. Also plays a key role in the maintenance of axonal homeostasis, the prevention of axonal degeneration, the maintenance of hematopoietic stem cells, the formation of Paneth cell granules, as well as in adipose differentiation. Plays a role in regulating the liver clock and glucose metabolism by mediating the autophagic degradation of CRY1 (clock repressor) in a time-dependent manner (By similarity).
E1-like activating enzyme involved in the 2 ubiquitin-like systems required for cytoplasm to vacuole transport (Cvt) and autophagy. Activates ATG12 for its conjugation with ATG5 as well as the ATG8 family proteins for their conjugation with phosphatidylethanolamine. Both systems are needed for the ATG8 association to Cvt vesicles and autophagosomes membranes. Required for autophagic death induced by caspase-8 inhibition. Required for mitophagy which contributes to regulate mitochondrial quantity and quality by eliminating the mitochondria to a basal level to fulfill cellular energy requirements and preventing excess ROS production. Modulates p53/TP53 activity to regulate cell cycle and survival during metabolic stress.
Expression is up-regulated by the transcription factor HSF1.
Homodimer (PubMed:11096062). Interacts with ATG3 and ATG12 (PubMed:11096062, PubMed:11825910). The complex, composed of ATG3 and ATG7, plays a role in the conjugation of ATG12 to ATG5 (PubMed:11825910). Forms intermediate conjugates with ATG8-like proteins such as GABARAP, GABARAPL1, GABARAPL2 or MAP1LC3A (PubMed:11096062, PubMed:16303767). Interacts with EP300 acetyltransferase (PubMed:19124466). Interacts with FOXO1 (PubMed:20543840).
The C-terminal part of the protein is essential for the dimerization and interaction with ATG3 and ATG12.
The N-terminal FAP motif (residues 15 to 17) is essential for the formation of the ATG89-PE and ATG5-ATG12 conjugates.
Widely expressed, especially in kidney, liver, lymph nodes and bone marrow.
Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. Necessary for the stability of the TFIIH complex and for the presence of normal levels of TFIIH in the cell.
Inhibits NF-kappa-B by complexing with and trapping it in the cytoplasm. However, the unphosphorylated form resynthesized after cell stimulation is able to bind NF-kappa-B allowing its transport to the nucleus and protecting it to further NFKBIA-dependent inactivation. Association with inhibitor kappa B-interacting NKIRAS1 and NKIRAS2 prevent its phosphorylation rendering it more resistant to degradation, explaining its slower degradation.
Interacts with THRB (via ligand-binding domain) (PubMed:7776974). Interacts with RELA and REL (By similarity). Interacts with COMMD1 (PubMed:16573520). Interacts with inhibitor kappa B-interacting Ras-like NKIRAS1 and NKIRAS2 (PubMed:10657303, PubMed:12672800, PubMed:15024091).
Phosphorylated by RPS6KA1; followed by degradation. Interaction with NKIRAS1 and NKIRAS2 probably prevents phosphorylation.
Probably plays a regulatory role in sperm development. May participate in regulation of fibrous sheath (FS) assembly by supporting the formation of disulfide bonds during sperm tail morphogenesis. May also be required to rectify incorrect disulfide pairing and generate suitable pairs between the FS constituents. Can reduce disulfide bonds in vitro in the presence of NADP and thioredoxin reductase.
Testis-specific. Only expressed during spermiogenesis, prominently in round and elongating spermatids.
Expressed in the trachea, retina, spinal cord, hippocampus and other brain regions, and, at lower levels, in testis and ovary.
Involved in the biosynthesis of L2/HNK-1 carbohydrate epitope on both glycolipids and glycoproteins.
Binds to SLC9A3R2 via the PDZ motif at the plasma membrane (By similarity). Binds to YWHAZ in vivo and in vitro through the phosphoserine-binding motif RSHSSP (By similarity). Interacts (via coiled-coil domain) with SMAD2 (via MH1 domain), SMAD3 and SMAD4 (PubMed:18568018). Interacts with MED15 (PubMed:18568018). Interacts with PAX8 and NKX2-1 (PubMed:19010321). Interacts with TEAD1, TEAD2, TEAD3 and TEAD4 (PubMed:19324877). Interacts (via WW domain) with PALS1 (PubMed:21145499). Interacts with LATS1 (By similarity). Interacts with YAP1 (when phosphorylated at 'Ser-127') (By similarity). Interacts (via WW domain) with PRRG4 (via cytoplasmic domain) (PubMed:23873930).
Binds to transcription factors via its WW domain.
Highly expressed in kidney, heart, placenta and lung. Expressed in the thyroid tissue.
Phosphorylated by LATS2 and STK3/MST2. Phosphorylation by LATS2 results in creation of 14-3-3 binding sites, retention in the cytoplasm, and functional inactivation. Phosphorylation results in the inhibition of transcriptional coactivation through YWHAZ-mediated nuclear export.
The PDZ-binding motif is essential for stimulated gene transcription. It localizes the protein into both punctate nuclear foci and plasma membrane-associated complexes (By similarity).
Transcriptional coactivator which acts as a downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:11118213, PubMed:18227151). The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ (PubMed:18227151). WWTR1 enhances PAX8 and NKX2-1/TTF1-dependent gene activation (PubMed:19010321). In conjunction with YAP1, involved in the regulation of TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation (PubMed:18568018). Plays a key role in coupling SMADs to the transcriptional machinery such as the mediator complex (PubMed:18568018). Regulates embryonic stem-cell self-renewal, promotes cell proliferation and epithelial-mesenchymal transition (PubMed:18227151, PubMed:18568018).
Ubiquitinated at Lys-46; leading to proteasomal degradation. Deubiquitinated and stabilized by UCHL1 at Lys-46; leading to osteoclastogenesis inhibition.
60-fold stronger expression found in adult than fetal testis. Detected in spermatocytes and round spermatids of the seminiferous tubule.
Expressed predominantly in testis (at protein level). Expression is lower in patients with obstructive azoospermia than in fertile controls and is not detected in patients with non-obstructive azoospermia.
'Chibby' is Japanese for 'small'; the gene was so named for the RNAi phenotype seen in flies.
Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity (By similarity).
Acetylated. Acetylation promotes interaction with BRD9, and subsequently with RAD54, which is essential for homologous recombination (HR).
Expression increases approximately 3-fold in late G1 phase compared to other phases of the cell cycle.
Homohexamer (By similarity). Interacts (via N-terminus) with RAD51 (PubMed:9321665). Interacts with NAP1L1 (PubMed:24798879). Interacts with BRD9; this interaction orchestrates RAD51-RAD54 complex formation (PubMed:32457312).
Phosphorylated. Phosphorylation at Ser-572 by NEK1 specifically in G2 phase allows efficient removal of RAD51 filaments from DNA.
Plays an essential role in homologous recombination (HR) which is a major pathway for repairing DNA double-strand breaks (DSBs), single-stranded DNA (ssDNA) gaps, and stalled or collapsed replication forks (PubMed:9774452, PubMed:24798879, PubMed:32457312, PubMed:11459989, PubMed:12205100, PubMed:27264870). Acts as a molecular motor during the homology search and guides RAD51 ssDNA along a donor dsDNA thereby changing the homology search from the diffusion-based mechanism to a motor-guided mechanism. Also plays an essential role in RAD51-mediated synaptic complex formation which consists of three strands encased in a protein filament formed once homology is recognized. Once DNA strand exchange occured, dissociates RAD51 from nucleoprotein filaments formed on dsDNA (By similarity).
Component of the mitochondrial core iron-sulfur cluster (ISC) complex composed of NFS1, LYRM4, NDUFAB1, ISCU, FXN, and FDX2; this complex is an heterohexamer containing two copies of each monomer (Probable). Homodimer (PubMed:31101807). Monomer (probable predominant form). Oligomer. Monomers and polymeric aggregates of >1 MDa have been isolated from mitochondria. A small fraction of heterologous overexpressed recombinant frataxin forms high-molecular weight aggregates that incorporate iron (PubMed:11823441, PubMed:12755598, PubMed:15641778, PubMed:15581888). Interacts with LYRM4 (PubMed:17331979). Interacts (via ferrous form) with ISCU; the interaction is possible when both are bound to the dimeric form of the cysteine desulfurase complex (NFS1:LYRM4) and the interaction enhances FXN interaction to the dimeric form of the cysteine desulfurase complex (NFS1:LYRM4)(PubMed:12785837, PubMed:31101807, PubMed:29576242). Interacts with FECH; one iron-bound FXN monomer seems to interact with a FECH homodimer (PubMed:15123683). Interacts with SDHA and SDHB (PubMed:15961414). Interacts with ACO2; the interaction is dependent on citrate (By similarity). Interacts with HSPA9 (PubMed:17331979, PubMed:26702583).
Expressed in the heart, peripheral blood lymphocytes and dermal fibroblasts.
Functions as an activator of persulfide transfer to the scaffoding protein ISCU as component of the core iron-sulfur cluster (ISC) assembly complex and participates to the [2Fe-2S] cluster assembly (PubMed:24971490, PubMed:12785837). Accelerates sulfur transfer from NFS1 persulfide intermediate to ISCU and to small thiols such as L-cysteine and glutathione leading to persulfuration of these thiols and ultimately sulfide release (PubMed:24971490). Binds ferrous ion and is released from FXN upon the addition of both L-cysteine and reduced FDX2 during [2Fe-2S] cluster assembly (PubMed:29576242). The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis. This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the scaffold protein ISCU in a FXN-dependent manner. Then this complex is stabilized by FDX2 which provides reducing equivalents to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and GLRX5 (By similarity). May play a role in the protection against iron-catalyzed oxidative stress through its ability to catalyze the oxidation of Fe(2+) to Fe(3+); the oligomeric form but not the monomeric form has in vitro ferroxidase activity (PubMed:15641778). May be able to store large amounts of iron in the form of a ferrihydrite mineral by oligomerization; however, the physiological relevance is unsure as reports are conflicting and the function has only been shown using heterologous overexpression systems (PubMed:11823441, PubMed:12755598). May function as an iron chaperone protein that protects the aconitase [4Fe-4S]2+ cluster from disassembly and promotes enzyme reactivation (PubMed:15247478). May play a role as a high affinity iron binding partner for FECH that is capable of both delivering iron to ferrochelatase and mediating the terminal step in mitochondrial heme biosynthesis (PubMed:15123683, PubMed:16239244).
Interacts with ACO1 (PubMed:20053667). Interacts with ISCU (cytoplasmic form) (PubMed:16091420).
Modulates the RNA-binding activity of ACO1 (PubMed:20053667). May be involved in the cytoplasmic iron-sulfur protein biogenesis (PubMed:16091420). May contribute to oxidative stress resistance and overall cell survival (PubMed:16608849).
Not highly expressed and may be artifactual.
Processed in two steps by mitochondrial processing peptidase (MPP). MPP first cleaves the precursor to intermediate form and subsequently converts the intermediate to yield frataxin mature form (frataxin(81-210)) which is the predominant form (PubMed:21298097). The additional forms, frataxin(56-210) and frataxin(78-210), seem to be produced when the normal maturation process is impaired; their physiological relevance is unsure.
The unusual migration profile of mature frataxin on SDS-PAGE due to its acidic N-terminus most likely contributed to conflicting reports for the N-terminus of the mature protein. Unlike prokaryotic and yeast frataxin homologs, which self-assemble at high iron concentrations, oligomerization of human frataxin is not induced by iron. The existence of a specialized mitochondrial ferritin in mammalia (FTMT) is suggesting that iron storage would be redundant function, at least in mammalian mitochondria.
Alcohol dehydrogenase (PubMed:1755855). Catalyzes the NAD-dependent oxidation of primary alcohols to the corresponding aldehydes (PubMed:1755855). Oxidizes secondary alcohols to the corresponding ketones (By similarity).
Belongs to the zinc-containing alcohol dehydrogenase family. Class-V subfamily.
Inhibited partially by pyrazole (10 mM) in the reaction mixture containing 100 mM ethanol at pH 10.0.
May play an active role in the motor area of the primate neocortex.
Component of a PRC1-like complex that contains PCGF3, RNF2 and RYBP (PubMed:21282530, PubMed:26151332). Interacts with CBX6, CBX7 and CBX8 (PubMed:21282530). Interacts with BCORL1 (PubMed:27568929).
Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Within the PRC1-like complex, regulates RNF2 ubiquitin ligase activity (PubMed:26151332). Plays a redundant role with PCGF5 as part of a PRC1-like complex that mediates monoubiquitination of histone H2A 'Lys-119' on the X chromosome and is required for normal silencing of one copy of the X chromosome in XX females (By similarity).
Defects in ABI3BP has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea.
Expressed in brain, heart, lung, liver, pancreas kidney and placenta.
Component of the BCR(KLHL42) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL42. Interacts (via the BTB domain) with CUL3. Interacts (via the kelch domains) with KATNA1.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for mitotic progression and cytokinesis. The BCR(KLHL42) E3 ubiquitin ligase complex mediates the ubiquitination and subsequent degradation of KATNA1. Involved in microtubule dynamics throughout mitosis.
Acts as a magnesium-dependent phosphatidate phosphatase enzyme which catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride, phosphatidylcholine and phosphatidylethanolamine biosynthesis in the reticulum endoplasmic membrane. Plays important roles in controlling the metabolism of fatty acids at different levels. Acts also as a nuclear transcriptional coactivator for PPARGC1A to modulate lipid metabolism.
Contains 1 Asp-Xaa-Asp-Xaa-Thr (DXDXT) motif, a catalytic motif known to be essential for phosphatidate phosphatase activity.
Contains one Leu-Xaa-Xaa-Ile-Leu (LXXIL) motif, a motif known to be a transcriptional binding motif.
Expressed in liver, lung, kidney, placenta, spleen, thymus, lymph node, prostate, testes, small intestine, and colon.
Belongs to the HIBADH-related family. 3-hydroxyisobutyrate dehydrogenase subfamily.
Component of the ribosomal small subunit processome for the biogenesis of ribosomes, functions in pre-ribosomal RNA (pre-rRNA) processing (By similarity). Essential for embryonic development in part through the regulation of p53 pathway. Controls the expansion growth of digestive organs and liver (PubMed:25007945, PubMed:27657329, PubMed:23357851). Also involved in the sympathetic neuronal development (By similarity). Mediates, with CAPN3, the proteasome-independent degradation of p53/TP53 (PubMed:23357851, PubMed:27657329).
Interacts with CAPN3; the interaction is required for CAPN3 translocation to the nucleolus.
Phosphorylated. Phosphorylation is required to promote p53/TP53 degradation in the nucleolus which promotes cell cycle progression and liver development.
Acts both as coactivator and as corepressor. May play a role in chromatin remodeling. Activator of the Wnt signaling pathway in a DVL1-dependent manner by negatively regulating the GSK3B phosphotransferase activity. Induces dephosphorylation of GSK3B at 'Tyr-216'. Down-regulates TRIM24-mediated activation of transcriptional activation by AR (By similarity). Transcriptional corepressor that down-regulates the expression of target genes. Binds to target promoters, leading to increased histone H3 acetylation at 'Lys-9' (H3K9ac). Binds to the ESR1 promoter. Recruits BRCA1 and POU2F1 to the ESR1 promoter. Coactivator for TP53-mediated activation of transcription of a set of target genes. Required for TP53-mediated cell-cycle arrest in response to oncogene activation. Promotes acetylation of TP53 at 'Lys-382', and thereby promotes efficient recruitment of TP53 to target promoters. Inhibits cell cycle progression from G1 to S phase.
Interacts with TRIM24, PTPN13 and DVL1. Identified in a complex with SMARCA4/BRG1, SMARCC1/BAF155, SMARCE1/BAF57, DPF2/BAF45D and ARID2, subunits of the SWI/SNF-B (PBAF) chromatin remodeling complex (By similarity). Interacts with IRF2 and HNRPUL1. Interacts (via N-terminus) with TP53. Interacts (via C-terminus) with EP300. Interacts with BRCA1. Interacts (via bromo domain) with histone H3 (via N-terminus) acetylated at 'Lys-14' (H3K14ac). Has low affinity for histone H3 acetylated at 'Lys-9' (H3K9ac). Has the highest affinity for histone H3 that is acetylated both at 'Lys-9' (H3K9ac) and at 'Lys-14' (H3K14ac). Has very low affinity for non-acetylated histone H3. Interacts (via bromo domain) with histone H4 (via N-terminus) acetylated at 'Lys-8' (H3K8ac) (in vitro).
Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD5:PSMC2:PSMC1:PSMD2 module which probably assembles with a PSMD10:PSMC4:PSMC5:PAAF1 module followed by dissociation of PSMD5.
Belongs to the proteasome subunit S5B/HSM3 family.
Interacts with PSMC1, PSMC2, PSMD1 and PSMD6. Part of transient complex containing PSMD5, PSMC2, PSMC1 and PSMD2 formed during the assembly of the 26S proteasome.
Rich in dileucine repeats, which have been implicated in trafficking of a variety of transmembrane proteins.
Expressed in fetal brain, fetal ovary and fetal testis. Expressed in adult brain, ovary, skin, testis, uterus. Highly expressed in skeletal muscle.
Transactivates the HES3 promoter independently of NOTCH proteins. HES3 is a non-canonical NOTCH target gene which lacks binding sites for RBPJ.
Expressed primarily in the cartilaginous cores of the long bone during embryonic and fetal development and in the appendicular skeleton (6-13 weeks). At 13 weeks of gestation, transcripts were present in early chondroblasts of the tarsal bones of the foot, the carpal bones of the hands and the epiphysis of long bones. Highly expressed in placenta and heart, followed by brain, skeletal muscle, kidney and pancreas. Weakly expressed in lung and liver.
Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts. They have a role in regulating cell growth and differentiation in specific cell types. SFRP3/FRZB appears to be involved in limb skeletogenesis. Antagonist of Wnt8 signaling. Regulates chondrocyte maturation and long bone development.
Dioxygenase that acts as on nucleic acids, such as DNA and tRNA (PubMed:18603530, PubMed:27745969, PubMed:27497299). Requires molecular oxygen, alpha-ketoglutarate and iron (PubMed:18603530, PubMed:27497299). A number of activities have been described for this dioxygenase, but recent results suggest that it mainly acts as on tRNAs and mediates their demethylation or oxidation depending on the context and subcellular compartment (PubMed:27745969, PubMed:27497299). Mainly acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs, with a preference for N(1)-methyladenine at position 58 (m1A58) present on a stem loop structure of tRNAs (PubMed:27745969). Acts as a regulator of translation initiation and elongation in response to glucose deprivation: regulates both translation initiation, by mediating demethylation of tRNA(Met), and translation elongation, N(1)-methyladenine-containing tRNAs being preferentially recruited to polysomes to promote translation elongation (PubMed:27745969). In mitochondrion, specifically interacts with mt-tRNA(Met) and mediates oxidation of mt-tRNA(Met) methylated at cytosine(34) to form 5-formylcytosine (f(5)c) at this position (PubMed:27497299). mt-tRNA(Met) containing the f(5)c modification at the wobble position enables recognition of the AUA codon in addition to the AUG codon, expanding codon recognition in mitochondrial translation (PubMed:27497299). Specifically demethylates DNA methylated on the 6th position of adenine (N(6)-methyladenosine) DNA (PubMed:30392959, PubMed:30017583). N(6)-methyladenosine (m6A) DNA is present at some L1 elements in embryonic stem cells and probably promotes their silencing (By similarity). Demethylates mRNAs containing N(3)-methylcytidine modification (PubMed:31188562). Also able to repair alkylated single-stranded DNA by oxidative demethylation, but with low activity (PubMed:18603530). Also has DNA lyase activity and introduces double-stranded breaks at abasic sites: cleaves both single-stranded DNA and double-stranded DNA at abasic sites, with the greatest activity towards double-stranded DNA with two abasic sites (PubMed:19959401). DNA lyase activity does not require alpha-ketboglutarate and iron and leads to the formation of an irreversible covalent protein-DNA adduct with the 5' DNA product (PubMed:19959401, PubMed:23577621). DNA lyase activity is not required during base excision repair and class switch recombination of the immunoglobulin heavy chain during B lymphocyte activation. May play a role in placental trophoblast lineage differentiation (By similarity).
Monomer (PubMed:19959401). Interacts with DNAJB6 (By similarity).
The DNA N6-methyl adenine demethylase activity is subject to discussion. According to a report, biochemical assays do not reveal clear DNA N6-methyl adenine demethylase activity in vivo (PubMed:27745969). According to another study, has clear DNA N6-methyl adenine demethylase activity (PubMed:30017583).
By phorbol ester and inflammatory cytokines, such as TNF or IL1B/interleukin-1 beta, but not by growth factors.
Interacts directly with BAK1, BID, BMF and BBC3 (By similarity). Interacts directly with BCL2L11/BIM. Interacts with BAX isoform Sigma. Interacts directly with PMAIP1. Interacts with RTL10/BOP. Interacts with ING4 (By similarity). Interacts with UBQLN4 (PubMed:34245648).
Retards apoptosis induced by IL-3 deprivation. May function in the response of hemopoietic cells to external signals and in maintaining endothelial survival during infection (By similarity). Can inhibit apoptosis induced by serum starvation in the mammary epithelial cell line HC11 (By similarity).
Seems to be restricted to the hematopoietic compartment. Expressed in peripheral blood, spleen, and bone marrow, at moderate levels in lung, small intestine and testis, at a minimal levels in other tissues. Also found in vascular smooth muscle cells and hematopoietic malignancies.
Trimers composed of three different chains: alpha-1(VI), alpha-2(VI), and alpha-3(VI) or alpha-5(VI) or alpha-6(VI). Interacts with CSPG4.
Expressed in bone, breast, eye, foreskin, heart, parathyroid, small intestine, testis, tonsils, placenta and uterus.
Defects in EMSY may be a cause of sporadic breast cancer and higher-grade ovarian cancers. Overexpressed through amplification almost exclusively in sporadic breast cancer (13%) and higher-grade ovarian cancer (17%). Amplification is associated with worse survival, particularly in node-negative breast cancer, suggesting that it may be of prognostic value.
Homodimer (PubMed:15978617). Interacts with the transactivation domain of BRCA2 (PubMed:14651845). Interacts with CBX1 (via chromoshadow domain) (PubMed:14651845, PubMed:16615912). Interacts with ZMYND11 (PubMed:14651845, PubMed:15947784). Does not interact with CBX3 or CBX5 (PubMed:14651845). Component of a nuclear receptor-mediated transcription complex composed of at least ZNF335, CCAR2 and EMSY; the complex stimulates the transcription of nuclear receptor target genes such as SOX9 and HOXA1 (PubMed:19131338). Within the complex interacts with CCAR2 and ZNF335 (PubMed:19131338). Components of this complex may associate with components of a histone methylation complex to form a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY, MKI67, RBBP5, ASH2L and WDR5 (PubMed:19131338). Within this complex, interacts with ASH2L and RBBP5 (PubMed:19131338).
Regulator which is able to repress transcription, possibly via its interaction with a multiprotein chromatin remodeling complex that modifies the chromatin (PubMed:14651845). Its interaction with BRCA2 suggests that it may play a central role in the DNA repair function of BRCA2 (PubMed:14651845). Mediates ligand-dependent transcriptional activation by nuclear hormone receptors (PubMed:19131338).
Was named EMSY by PubMed:14651845 because the protein sequence contains the word 'SISTER', after the first author's sister, who is a breast cancer nurse.
Probable adapter protein that may provide a link between cell surface epidermal growth factor receptor and the MAPK/ERK signaling pathway.
G proteins are composed of 3 units; alpha, beta and gamma.
Interacts with multiple activated proteins of the tyrosine kinase signaling pathway including IGF1 receptor, insulin receptor and JAK2. Binding to JAK2 is mediated through the KIR and SH2 domains to a phosphorylated tyrosine residue within the JAK2 JH1 domain (PubMed:10421843). Binds specific activated tyrosine residues of the leptin, EPO, IL12, GSCF and gp130 receptors (PubMed:12027890, PubMed:14559241). Interaction with CSNK1E stabilizes SOCS3 protein (PubMed:15070676). Component of the probable ECS(SOCS3) E3 ubiquitin-protein ligase complex which contains CUL5, RNF7/RBX2, Elongin BC complex and SOCS3 (PubMed:15601820). Interacts with CUL5, RNF7, ELOB and ELOC (PubMed:15601820). Interacts with CUL2 (PubMed:15601820). Interacts with FGFR3 (PubMed:16410555). Interacts with INSR (By similarity). Interacts with BCL10; this interaction may interfere with BCL10-binding with PELI2 (By similarity). Interacts with NOD2 (via CARD domain); the interaction promotes NOD2 degradation (PubMed:23019338).
Phosphorylated on tyrosine residues after stimulation by the cytokines, IL-2, EPO or IGF1.
SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. SOCS3 is involved in negative regulation of cytokines that signal through the JAK/STAT pathway. Inhibits cytokine signal transduction by binding to tyrosine kinase receptors including IL6ST/gp130, LIF, erythropoietin, insulin, IL12, GCSF and leptin receptors. Binding to JAK2 inhibits its kinase activity and regulates IL6 signaling. Suppresses fetal liver erythropoiesis. Regulates onset and maintenance of allergic responses mediated by T-helper type 2 cells (By similarity). Probable substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:15601820).
There is some evidence that SOCS3 may be a susceptibility gene for atopic dermatitis linked to 17q25. SOCS3 messenger RNA is significantly more highly expressed in skin from patients with atopic dermatitis than in skin from healthy controls. Furthermore, a genetic association between atopic dermatitis and a haplotype in the SOCS3 gene has been found in two independent groups of patients.
Widely expressed with high expression in heart, placenta, skeletal muscle, peripheral blood leukocytes, fetal and adult lung, and fetal liver and kidney. Lower levels in thymus.
Binds 1 heme c group covalently per subunit.
Electron carrier protein. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transfers this electron to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron-transport chain.
Phosphorylation at Tyr-49 and Tyr-98 both reduce by half the turnover in the reaction with cytochrome c oxidase, down-regulating mitochondrial respiration.
Plays a role in apoptosis. Suppression of the anti-apoptotic members or activation of the pro-apoptotic members of the Bcl-2 family leads to altered mitochondrial membrane permeability resulting in release of cytochrome c into the cytosol. Binding of cytochrome c to Apaf-1 triggers the activation of caspase-9, which then accelerates apoptosis by activating other caspases.
Antibody-mediated surface engagement of the B-cell antigen receptor (BCR) which results in the phosphorylation of BLK on tyrosine residues, stimulates the enzymatic activity.
Expressed in lymphatic organs, pancreatic islets, Leydig cells, striate ducts of salivary glands and hair follicles.
Expression is under the control of NF-kappa-B as well as the B-cell specific transcription factors PAX5 and EBF1.
Interacts with CBL (via SH2 domain). Interacts with CD79A and CD79B (via SH2 domain) (By similarity).
Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling (By similarity). B-cell receptor (BCR) signaling requires a tight regulation of several protein tyrosine kinases and phosphatases, and associated coreceptors (By similarity). Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation (By similarity). Signaling through BLK plays an important role in transmitting signals through surface immunoglobulins and supports the pro-B to pre-B transition, as well as the signaling for growth arrest and apoptosis downstream of B-cell receptor (By similarity). Specifically binds and phosphorylates CD79A at 'Tyr-188'and 'Tyr-199', as well as CD79B at 'Tyr-196' and 'Tyr-207' (By similarity). Phosphorylates also the immunoglobulin G receptors FCGR2A, FCGR2B and FCGR2C (PubMed:8756631). With FYN and LYN, plays an essential role in pre-B-cell receptor (pre-BCR)-mediated NF-kappa-B activation (By similarity). Contributes also to BTK activation by indirectly stimulating BTK intramolecular autophosphorylation (By similarity). In pancreatic islets, acts as a modulator of beta-cells function through the up-regulation of PDX1 and NKX6-1 and consequent stimulation of insulin secretion in response to glucose (PubMed:19667185). Phosphorylates CGAS, promoting retention of CGAS in the cytosol (PubMed:30356214).
Phosphorylated on tyrosine residues after antibody-mediated surface engagement of the B-cell antigen receptor (BCR).
Ubiquitination of activated BLK by the UBE3A ubiquitin protein ligase leads to its degradation by the ubiquitin-proteasome pathway.
(Microbial infection) Forms a complex with Epstein-Barr virus protein EBNA3 which is an active deubiquitinase activity that may select specific substrates to promote B-lymphocyte transformation.
(Microbial infection) Interacts with Epstein-Barr virus protein EBNA3.
Activated by interaction with WDR20 and WDR48 through different allosteric mechanisms.
Deubiquitinating enzyme that plays various roles in the regulation of the immune response and inflammation (PubMed:19075014, PubMed:27373336). In complex with WDR48, acts as a potential tumor suppressor by positively regulating PHLPP1 stability (PubMed:24145035). During TCR engagement and activation, translocates into the cytoplasm and deubiquitinates its substrates LAT and TRAT1 and prevents their lysosome-dependent degradation to stabilize the TCR signaling complex at the plasma membrane (PubMed:26811477). Plays an essential role in the selective LPS-induced macrophage response through the activation of NF-kappa-B pathway (PubMed:28063927). In addition, promotes that antiviral immune response through targeting DNA sensor IFI16 to inhibit its proteasome-dependent degradation (PubMed:37410794). Participates in the interferon signaling pathway and antiviral response independently of its deubiquitinase activity by maintaining nuclear phosphorylated STAT1 levels via inhibition of its CREBBP-mediated acetylation and subsequent dephosphorylation (PubMed:31899788). Plays an intrinsic role in promoting the differentiation, activation and proliferation of CD4(+) T-cell by activating the NF-kappa-B signaling pathway through deubiquitinating and stabilizing B-cell lymphoma/leukemia 10/BCL10 (By similarity). In myeloid-derived suppressor cells promotes the activation of the NF-kappa-B via deubiquitination and stabilization of RELA (By similarity). Regulates the 'Lys-63'-linked polyubiquitin chains of BAX and thereby modulates the mitochondrial apoptotic process (PubMed:36361894).
Interacts with WDR48 (PubMed:19075014, PubMed:27650958, PubMed:27373336). Interacts with WDR20; this interaction promotes translocation of the USP12 complex to the plasma membrane (PubMed:20147737, PubMed:27373336, PubMed:30466959). Component of the USP12/WDR20/WDR48 deubiquitinating complex (PubMed:20147737, PubMed:27373336). Interacts with PHLPP1 (PubMed:24145035). Interacts with RBPJ (PubMed:25855980). Interacts with CBP; this interaction blocks the acetyltransferase activity of CREBBP (PubMed:31899788).
Knockdown of USP12 increases Akt activation.
Interacts with ATG5; the interaction is direct. Interacts with WIPI2. Interacts with the ATG5-ATG12 conjugate, the interaction is however mutually exclusive with ATG16, since it does not interact with ATG12-ATG5-ATG16 complex.
Tethering factor involved in autophagy. Involved in autophagosome maturation by promoting the autophagosome fusion with lysosomes: acts by associating with both the ATG5-ATG12 conjugate and phosphatidylinositol-3-phosphate (PtdIns(3)P) present at the surface of autophagosomes. Also involved in selective autophagy against bacterial pathogens, by being required for phagophore/preautophagosomal structure biogenesis and maturation.
The PH domain mediates the binding to phosphatidylinositol-3-phosphate (PtdIns(3)P). While full-length protein is unable to bind PtdIns(3)P in vitro, it is assumed that the binding to the ATG5-ATG12 conjugate exposes the PH domain, allowing the association with PtdIns(3)P (PubMed:22342342).
Belongs to the FIT family. FIT2 subfamily.
Fatty acyl-coenzyme A (CoA) diphosphatase that hydrolyzes fatty acyl-CoA to yield acyl-4'-phosphopantetheine and adenosine 3',5'-bisphosphate (PubMed:32915949) (By similarity). Preferentially hydrolyzes unsaturated long-chain acyl-CoA substrates such as oleoyl-CoA/(9Z)-octadecenoyl-CoA and arachidonoyl-CoA/(5Z,8Z,11Z,14Z)-eicosatetraenoyl-CoA in the endoplasmic reticulum (ER) lumen (PubMed:32915949) (By similarity). This catalytic activity is required for maintaining ER structure and for lipid droplets (LDs) biogenesis, which are lipid storage organelles involved in maintaining lipid and energy homeostasis (PubMed:18160536, PubMed:32915949) (By similarity). Directly binds to diacylglycerol (DAGs) and triacylglycerol, which is also important for LD biogenesis (By similarity). May support directional budding of nacent LDs from the ER into the cytosol by reducing DAG levels at sites of LD formation (By similarity). Plays a role in the regulation of cell morphology and cytoskeletal organization (PubMed:21834987) (By similarity).
(Microbial infection) Interacts with herpes simplex virus 1 UL46; this interaction activates LCK.
A chromosomal aberration involving LCK is found in leukemias. Translocation t(1;7)(p34;q34) with TCRB.
Autophosphorylated on Tyr-394, increasing enzymatic activity, this site is dephosphorylated by PTN22. Phosphorylated on Tyr-505 by CSK, decreasing activity. Dephosphorylated by PTPRC/CD45. Dephosphorylation at Tyr-394 by PTPN2 negatively regulates T-cell receptor signaling.
Binds to the cytoplasmic domain of cell surface receptors, such as AXL, CD2, CD4, CD5, CD8, CD44, CD45 and CD122. Also binds to effector molecules, such as PI4K, VAV1, RASA1, FYB1 and to other protein kinases including CDK1, RAF1, ZAP70 and SYK. Binds to phosphatidylinositol 3'-kinase (PI3K) from T-lymphocytes through its SH3 domain and to the tyrosine phosphorylated form of KHDRBS1/p70 through its SH2 domain. This interaction inhibits its tyrosine-kinase activity. Interacts with SQSTM1. Interacts with phosphorylated LIME1. Interacts with CBLB and PTPRH. Interacts with RUNX3. Forms a signaling complex with EPHA1, PTK2B and PI3-KINASE; upon activation by EFNA1 which may regulate T-lymphocyte migration. Associates with ZAP70 and RHOH; these interactions allow LCK-mediated RHOH and CD3 subunit phosphorylation in the presence of functional ZAP70. Interacts with UNC119; this interaction plays a crucial role in activation of LCK. Interacts with CEACAM1 (via cytoplasmic domain); mediates CEACAM1 phosphorylation resulting in PTPN6 recruitment that dephosphorylates TCR stimulation-induced CD247 and ZAP70 (PubMed:18424730). Interacts with CD160. Interacts with CD48 (PubMed:12007789).
Expressed specifically in lymphoid cells.
Myristoylation is required prior to palmitoylation.
Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP. Interacts with FYB2 (PubMed:27335501).
Palmitoylation regulates association with the plasma membrane and could be mediated by ZDHHC2.
The SH2 domain mediates interaction with SQSTM1. Interaction is regulated by Ser-59 phosphorylation.
The relative activities of the inhibitory tyrosine-protein kinase CSK and the activating tyrosine-protein phosphatase PTPRC/CD45 determine the level of LCK activity. These interactions allow rapid and efficient activation of LCK in response to TCR stimulation.
GTF2I is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of GTF2I may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.
Homodimer (Potential). Interacts with SRF and PHOX1. Binds a pyrimidine-rich initiator (Inr) and a recognition site (E-box) for upstream stimulatory factor 1 (USF1). Associates with the PH domain of Bruton's tyrosine kinase (BTK). May be a component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST, PHF21A/BHC80, ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I. Interacts with BTK and ARID3A. Interacts with isoform beta of PRKG1.
Interacts with the basal transcription machinery by coordinating the formation of a multiprotein complex at the C-FOS promoter, and linking specific signal responsive activator complexes. Promotes the formation of stable high-order complexes of SRF and PHOX1 and interacts cooperatively with PHOX1 to promote serum-inducible transcription of a reporter gene deriven by the C-FOS serum response element (SRE). Acts as a coregulator for USF1 by binding independently two promoter elements, a pyrimidine-rich initiator (Inr) and an upstream E-box. Required for the formation of functional ARID3A DNA-binding complexes and for activation of immunoglobulin heavy-chain transcription upon B-lymphocyte activation.
Transiently phosphorylated on tyrosine residues by BTK in response to B-cell receptor stimulation. Phosphorylation on Tyr-248 and Tyr-398, and perhaps, on Tyr-503 contributes to BTK-mediated transcriptional activation.
Ubiquitous. Isoform 1 is strongly expressed in fetal brain, weakly in adult brain, muscle, and lymphoblasts and is almost undetectable in other adult tissues, while the other isoforms are equally expressed in all adult tissues.
A NAD(P)H-dependent oxidoreductase that acts as a key inhibitor of ferroptosis (PubMed:31634899, PubMed:31634900, PubMed:35922516). At the plasma membrane, catalyzes reduction of coenzyme Q/ubiquinone-10 to ubiquinol-10, a lipophilic radical-trapping antioxidant that prevents lipid oxidative damage and consequently ferroptosis (PubMed:31634899, PubMed:31634900). Acts in parallel to GPX4 to suppress phospholipid peroxidation and ferroptosis (PubMed:31634899, PubMed:31634900). This anti-ferroptotic function is independent of cellular glutathione levels (PubMed:31634899, PubMed:31634900). Also acts as a potent radical-trapping antioxidant by mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle: catalyzes NAD(P)H-dependent reduction of vitamin K (phylloquinone, menaquinone-4 and menadione) to hydroquinone forms (PubMed:35922516). Hydroquinones act as potent radical-trapping antioxidants inhibitor of phospholipid peroxidation and ferroptosis (PubMed:35922516). May play a role in mitochondrial stress signaling (PubMed:26689472). Upon oxidative stress, associates with the lipid peroxidation end product 4-hydroxy-2-nonenal (HNE) forming a lipid adduct devoid of oxidoreductase activity, which then translocates from mitochondria into the nucleus triggering DNA damage and cell death (PubMed:26689472). Capable of DNA binding in a non-sequence specific way (PubMed:15958387).
Conflicting data exist on the pro-apoptotic function of the protein. It was initially claimed that overexpression of FSP1 induces caspase-independent apoptosis, but new evidence disputes this function.
Detected in most normal tissues as two transcripts of 1.8 and 4.0 kb in length, respectively. Highly expressed in heart, moderately in liver and skeletal muscles, and expressed at low levels in placenta, lung, kidney, and pancreas. Both transcripts expressed following p53/TP53 induction. The shorter 1.8 kb transcript seems to be the major transcript in EB1 colon cancer cells.
Expression detected at 4 hours after induction by p53/TP53. Down-regulated in a wide range of human tumors.
Interacts with importin subunits KPNA2 and IPO5; this interaction likely mediates the translocation into the nucleus upon oxidative stress.
N-myristoylation at Gly-2 mediates the recruitment to lipid droplets and plasma membrane.
The modification by 4-hydroxy-2-nonenal (HNE) adduction in mitochondria results in loss of the oxidoreductase activity and activation of a novel function in mitochondrial oxidative stress signaling.
Dual specificity phosphatase that dephosphorylates MAP kinase MAPK1/ERK2 on both 'Thr-183' and 'Tyr-185', regulating its activity during the meiotic cell cycle.
Expressed at high levels in the lung, liver placenta and pancreas. Moderate levels seen in the heart and skeletal muscle. Lower levels found in the brain and kidney.
Phosphorylation at Ser-359 and Ser-364 by MAPK1/ERK2 and MAPK3/ERK1 reduces its rate of degradation.
Recruited to ligand-activated beta-2 adrenergic receptor/ADRB2, it negatively regulates the adrenergic receptor signaling pathway (PubMed:28388415). May also regulate other G-protein coupled receptors including type-1 angiotensin II receptor/AGTR1 (Probable).
Found to decrease dramatically after birth.
Plays an important role in the organization of the cytoskeleton. Binds to and sequesters actin monomers (G actin) and therefore inhibits actin polymerization (By similarity).
Component of the transcription factor SL1/TIF-IB complex, composed of TBP and at least TAF1A, TAF1B, TAF1C and TAF1D. In the complex interacts directly with TBP, TAF1A and TAF1B. Interaction of the SL1/TIF-IB subunits with TBP excludes interaction of TBP with the transcription factor IID (TFIID) subunits. Interacts with MYC and RRN3. Interacts with p53/TP53; the interaction prevents the association of SL1/TIF-IB with UBTF and represses RNA polymerase I transcription.
Component of the transcription factor SL1/TIF-IB complex, which is involved in the assembly of the PIC (preinitiation complex) during RNA polymerase I-dependent transcription. The rate of PIC formation probably is primarily dependent on the rate of association of SL1/TIF-IB with the rDNA promoter. SL1/TIF-IB is involved in stabilization of nucleolar transcription factor 1/UBTF on rDNA. Formation of SL1/TIF-IB excludes the association of TBP with TFIID subunits. Recruits RNA polymerase I to the rRNA gene promoter via interaction with RRN3.
Binds 1 [4Fe-4S] cluster. The cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.
Probable component of the wybutosine biosynthesis pathway. Wybutosine is a hyper modified guanosine with a tricyclic base found at the 3'-position adjacent to the anticodon of eukaryotic phenylalanine tRNA. Catalyzes the condensation of N-methylguanine with 2 carbon atoms from pyruvate to form the tricyclic 4-demethylwyosine, an intermediate in wybutosine biosynthesis (By similarity).
Inhibits cell growth rate and cell cycle. Induces CDKN1A expression as well as TGF-beta expression. Mediates the inhibitory growth effect of EGR1. Involved in the maturation of snRNAs and snRNA 3'-tail processing (PubMed:28092684).
Interacts with U1, U2, U4, U5 and U6 snRNAs.
Binds dermatan sulfate and chondroitin sulfate.
Promotes matrix assembly and cell adhesiveness. Plays a role in spinal cord formation by regulating the proliferation and differentiation of neural stem cells.
Belongs to the methyltransferase superfamily. RsmH family.
N4-methylcytidine (m4C) methyltransferase responsible for the methylation of position C839 in mitochondrial 12S rRNA (PubMed:31665743, PubMed:32371392). Involved in the stabilization of 12S rRNA folding, therefore facilitating the assembly of the mitochondrial small ribosomal subunits (PubMed:31665743, PubMed:32371392).
Alternatively, could function as a molecular adapter enhancing the formation of the PI3KC3-C1/AIC/autophagy initiation complex to promote autophagy in dopaminergic neurons. Could also regulate the plasma membrane localization of the D(1A) dopamine receptor/DRD1 and dopamine signaling.
Belongs to the TPT transporter family. SLC35D subfamily.
Could interact with ATG14, BECN1 and PIK3C3 that form the PI3KC3-C1/AIC/autophagy initiation complex; enhancing the formation of the AIC and promoting autophagy.
Inhibited by proton uncouplers that directly abolish the proton electrochemical gradient.
Probable UDP-glucose transmembrane transporter involved in UDP-glucose transport from the cytosol to the lumen of synaptic vesicles (PubMed:34269178). It is involved in platelet dense granules maturation (By similarity).
Abundantly expressed in brain. Also found in several tumors such as lung carcinomas, nervous tumors and HL-60 leukemia cells. Isoform 3 is the major form in U-937, GOTO and HL-60 leukemia cells.
Binds actin and PPP1CA; thus inhibiting the protein phosphatase 1 (PP1) activity.
Down-regulated in HL-60 leukemia cells by RA, PMA and dimethyl sulfoxide.
Glycosylation in position Asn-260 is needed for steroid binding.
Major transport protein for glucocorticoids and progestins in the blood of almost all vertebrate species.
N-glycosylated; binds 5 oligosaccharide chains.
Plasma; synthesized in liver. Has also been identified in a number of glycocorticoid responsive cells.
Proteolytic cleavage leads to an important conformation change. This reduces the affinity for steroids.
Has low expression in pericytes and adventitial vascular cells (ASC) derived from adipose tissue. Highly expressed in differentiating mesenchymal stem cells derived from pericytes and ASC.
Plays a role in differentiation and/or proliferation of mesenchymal stem cells. Proposed to be involved in epithelial-to-mesenchymal transition (EMT). However, another study suggests that it is not required for EMT or stem cell self-renewal and acts during later stages of differentiation.
Highest levels in testis, ovary, pancreas, and heart.
Phosphorylated by multiple kinases including MAPK1/ERK2 at THR-526. Phosphorylation regulates the activity of ERF.
Potent transcriptional repressor that binds to the H1 element of the Ets2 promoter. May regulate other genes involved in cellular proliferation. Required for extraembryonic ectoderm differentiation, ectoplacental cone cavity closure, and chorioallantoic attachment (By similarity). May be important for regulating trophoblast stem cell differentiation (By similarity).
The sequence differs from that shown because it seems to be derived from a pre-mRNA.
Expressed at low level in placenta primarily but also detected in heart and brain, cervix, uterus, bladder, esophagus, rib cartilage, chondroblastoma, fibrous tissue and a joint capsule from an arthritic patient.
Metalloproteinase that plays an important role in connective tissue organization, development, inflammation and cell migration. Extracellular matrix (ECM) degrading enzyme that show proteolytic activity toward the hyalectan group of chondroitin sulfate proteoglycans (CSPGs) including ACAN, VCAN, BCAN and NCAN (PubMed:16133547, PubMed:18992360). Cleavage within the hyalectans occurs at Glu-Xaa recognition motifs. Plays a role in embryonic development, including limb and cardiac morphogenesis, and skeletal muscle development through its VCAN remodeling properties. Cleaves VCAN in the pericellular matrix surrounding myoblasts, facilitating myoblast contact and fusion which is required for skeletal muscle development and regeneration (By similarity). Participates in development of brown adipose tissue and browning of white adipose tissue (By similarity). Plays an important role for T-lymphocyte migration from draining lymph nodes following viral infection.
The precursor is cleaved by furin and PCSK7 outside of the cell.
Highly expressed in lung, upper airways and nasopharyngeal regions, including trachea and nasal epithelium (at protein level) (PubMed:11018263, PubMed:11251963, PubMed:12409287, PubMed:11425234, PubMed:26559477). Specifically expressed in the secretory ducts and submucosal glands of tracheobronchial tissues (at protein level) (PubMed:12409287, PubMed:11425234). Also expressed in the eye where it is detected in lacrimal gland, eyelid, conjunctiva and cornea (at protein level) (PubMed:26559477). Specifically localizes to epithelial cell layers in cornea, eyelid (basal epithelium) and conjunctiva (at protein level) (PubMed:26559477). Detected within acinar cells and ducts in the lacrimal and Meibomian glands (at protein level) (PubMed:26559477). In lung, shows highest expression in the trachea and progressive decrease from proximal (bronchial) to distal (bronchiolar) airways (PubMed:12409287). Also expressed in lung cancers and some other types of cancer (PubMed:11251963).
Lipid-binding protein which shows high specificity for the surfactant phospholipid dipalmitoylphosphatidylcholine (DPPC) (PubMed:25223608). Plays a role in the innate immune responses of the upper airways (PubMed:23499554, PubMed:23132494). Reduces the surface tension in secretions from airway epithelia and inhibits the formation of biofilm by pathogenic Gram-negative bacteria, such as P.aeruginosa and K.pneumoniae (PubMed:23499554, PubMed:23132494, PubMed:27145151). Negatively regulates proteolytic cleavage of SCNN1G, an event that is required for activation of the epithelial sodium channel (ENaC), and thereby contributes to airway surface liquid homeostasis and proper clearance of mucus (PubMed:24124190, PubMed:24043776). Plays a role in the airway inflammatory response after exposure to irritants (PubMed:11425234). May attract macrophages and neutrophils (PubMed:23132494).
Monomer. Interacts (via N-terminus) with SCNN1B, a subunit of the heterotrimeric epithelial sodium channel (ENaC); this inhibits proteolytic activation of ENaC.
Reported to bind to bacterial lipopolysaccharide (LPS) in vitro (PubMed:15158712, PubMed:27145151). However, the in vivo significance of this is uncertain since other studies indicate little or no specificity for LPS (PubMed:12920053, PubMed:25223608).
Up-regulated in response to all-trans retinoic acid (ATRA) (PubMed:12409287). Up-regulated in tear fluid of patients suffering from dry eye disease (PubMed:26559477). Up-regulated in response to the pro-inflammatory cytokines IL1B and TNF, and the bacteria E.coli and P.aeruginosa (PubMed:26559477).
Numerous size polymorphism are present in KRTAP4 gene family, which are mainly due to variations in the sequence encoding cysteine-rich repeat segments (PubMed:15955084). Allele shown is KAP4.15 (PubMed:15955084).
Expressed in all tissues except colon and thymus.
Interacts with GOLGA3. Interacts with ZDHHC9.
May be involved in protein transport from Golgi to cell surface. The ZDHHC9-GOLGA7 complex is a palmitoyltransferase specific for HRAS and NRAS.
Palmitoylated on Cys-69 and Cys-72; which is required for Golgi localization and interaction with GOLGA3.
Interacts with LMNA and binds to the farnesylated C-terminal domain.
Ubiquitous. Predominantly expressed in skeletal muscle, heart and brain.
Expressed in the esophagus, particularly in the suprabasilar layers of the epithelium. Expression is largely reduced in esophageal metaplasia, dysplasia, and adenocarcinoma lesions.
Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3). Component of the little elongation complex (LEC), at least composed of ELL (ELL, ELL2 or ELL3), ZC3H8, ICE1 and ICE2. Interacts with AFF4; the interaction is direct and leads to stabilize ELL2 and prevent ELL2 ubiquitination. Interacts with EAF1 and EAF2.
Elongation factor component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. Component of the little elongation complex (LEC), a complex required to regulate small nuclear RNA (snRNA) gene transcription by RNA polymerase II and III (PubMed:22195968). Plays a role in immunoglobulin secretion in plasma cells: directs efficient alternative mRNA processing, influencing both proximal poly(A) site choice and exon skipping, as well as immunoglobulin heavy chain (IgH) alternative processing. Probably acts by regulating histone modifications accompanying transition from membrane-specific to secretory IgH mRNA expression.
Ubiquitinated by SIAH1, leading to its degradation by the proteasome. Interaction with AFF4 stabilizes ELL2 and prevents ELL2 ubiquitination.
Acts as a co-chaperone for HSP90 and is required for proper folding of the myosin motor domain. Plays a role in sarcomere formation during muscle cell development. Is necessary for normal early lens development.
Expressed from 43-day and 54-day embryonic eye development.
Expressed in eye lens tissues. Expressed in muscle (at protein level) (PubMed:33217308).
Interacts with HSP90 in an ATP-independent manner (By similarity). Interacts with UBE4B; the interaction may target UNC45B for proteasomal degradation (PubMed:17369820).
Homodimer in the absence of THRSP. Heterodimer with THRSP. The homodimer interacts with ACACA and ACACB. Promotes polymerization of Acetyl-CoA carboxylase to form complexes that contain MID1IP1 and ACACA and/or ACACB. Interaction with THRSP interferes with ACACA binding (By similarity).
Plays a role in the regulation of lipogenesis in liver. Up-regulates ACACA enzyme activity. Required for efficient lipid biosynthesis, including triacylglycerol, diacylglycerol and phospholipid. Involved in stabilization of microtubules (By similarity).
Component of the RNA exosome complex (PubMed:29906447). Specifically part of the catalytically inactive RNA exosome core (Exo-9) complex which is believed to associate with catalytic subunits EXOSC10, and DIS3 or DIS3L in cytoplasmic- and nuclear-specific RNA exosome complex forms. Exo-9 is formed by a hexameric ring of RNase PH domain-containing subunits specifically containing the heterodimers EXOSC4-EXOSC9, EXOSC5-EXOSC8 and EXOSC6-EXOSC7, and peripheral S1 domain-containing components EXOSC1, EXOSC2 and EXOSC3 located on the top of the ring structure (PubMed:11719186, PubMed:12788944, PubMed:20531389). Interacts (via C-terminus region) with SETX (via N-terminus domain); the interaction enhances SETX sumoylation (PubMed:24105744).
Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC9 binds to ARE-containing RNAs.
Brain-specific, with the highest expression in the cerebellum.
Inhibits DNA binding of TCF3/E47 homodimers and TCF3 (E47)/NEUROD1 heterodimers and acts as a strong repressor of Neurod1 and Myod-responsive genes, probably by heterodimerization with class a basic helix-loop-helix factors. Despite the presence of an intact basic domain, does not bind to DNA (By similarity). In the brain, may function as an area-specific transcription factor that regulates the postmitotic acquisition of area identities and elucidate the genetic hierarchy between progenitors and postmitotic neurons driving neocortical arealization. May be required for the survival of a specific population of inhibitory neurons in the superficial laminae of the spinal cord dorsal horn that may regulate pruritis. Seems to play a crucial role in the retinogenesis, in the specification of amacrine and bipolar subtypes. Forms with PRDM8 a transcriptional repressor complex controlling genes involved in neural development and neuronal differentiation.
Widely expressed at low level. Expressed at higher level in testis, weakly expressed in muscle, colon, lung and spleen. Not detected in 3 non small cell lung carcinoma (NSCLC) cell lines with homozygous deletion of the 9p region, while it is down-regulated in 3 other tumor cell lines.
Cleaved by CASP8 upon death ligand binding such as tumor necrosis factor-alpha. CASP8 cleavage blocks survival-related autophagy and favors apoptosis.
Conjugated to ATG12 at Lys-243. ATG12-conjugation plays a role in regulation of mitochondrial homeostasis and cell death, while it is not involved in PE-conjugation to ATG8-like proteins and autophagy.
E2 conjugating enzyme required for the cytoplasm to vacuole transport (Cvt), autophagy, and mitochondrial homeostasis. Responsible for the E2-like covalent binding of phosphatidylethanolamine to the C-terminal Gly of ATG8-like proteins (GABARAP, GABARAPL1, GABARAPL2 or MAP1LC3A). The ATG12-ATG5 conjugate plays a role of an E3 and promotes the transfer of ATG8-like proteins from ATG3 to phosphatidylethanolamine (PE). This step is required for the membrane association of ATG8-like proteins. The formation of the ATG8-phosphatidylethanolamine conjugates is essential for autophagy and for the cytoplasm to vacuole transport (Cvt). Preferred substrate is MAP1LC3A. Also acts as an autocatalytic E2-like enzyme, catalyzing the conjugation of ATG12 to itself, ATG12 conjugation to ATG3 playing a role in mitochondrial homeostasis but not in autophagy. ATG7 (E1-like enzyme) facilitates this reaction by forming an E1-E2 complex with ATG3. Promotes primary ciliogenesis by removing OFD1 from centriolar satellites via the autophagic pathway.
Interacts with ATG7 and ATG12. The complex, composed of ATG3 and ATG7, plays a role in the conjugation of ATG12 to ATG5. Interacts with FNBP1L.
Widely expressed, with a highest expression in heart, skeletal muscle, kidney, liver and placenta.
As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport. According to PubMed:20613862 it is a putative helicase required for efficient homologous recombination DNA double-strand break repair.
Probably part of the adaptor protein complex 5 (AP-5) a tetramer composed of AP5B1, AP5M1, AP5S1 and AP5Z1. Interacts with ZFYVE26 and SPG11.
Belongs to the even-skipped homeobox family.
Expressed during early embryogenesis and neurogenesis in a biphasic manner.
Carries out a dual function: signal transduction and activation of transcription. Mediates cellular responses to the cytokine KITLG/SCF and other growth factors. Mediates cellular responses to ERBB4. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Binds to the GAS element and activates PRL-induced transcription. Regulates the expression of milk proteins during lactation.
Forms a homodimer or a heterodimer with a related family member. Binds NR3C1 (By similarity). Interacts with NCOA1 and SOCS7 (PubMed:12954634). Interacts with ERBB4 (PubMed:15534001). Interacts with EBF4 (PubMed:35939714).
It was reported that dephosphorylation on tyrosine residues by PTPN2 would negatively regulate prolactin signaling pathway (PubMed:11773439). However, the corresponding article has been retracted (PubMed:24319783).
Tyrosine phosphorylated in response to KITLG/SCF, IL2, IL3, IL7, IL15, CSF2/GMCSF, GH1, PRL, EPO and THPO (By similarity). Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus (PubMed:21135090). Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4 (By similarity). Tyrosine phosphorylation is required for DNA-binding activity and dimerization. Serine phosphorylation is also required for maximal transcriptional activity (By similarity). Tyrosine phosphorylated in response to signaling via activated FLT3; wild-type FLT3 results in much weaker phosphorylation than constitutively activated mutant FLT3 (PubMed:14504097). Alternatively, can be phosphorylated by JAK2 at Tyr-694 (PubMed:12529425).
Guanine nucleotide exchange factor for ARF6 (PubMed:23603394). Induces cytoskeletal remodeling (By similarity).
Interacts with ACTN1. Interacts (ARF6-bound form) with KCNK1; does not interact with KCNK1 in the absence of ARF6 (By similarity).
Expressed in skin, breast, brain and testis. Expressed at the stratum granulosum of palmar skin.
Interacts (via C-terminal 330-amino-acid region) with AKT1; AKT2 and AKT3. Interacts with PPP2CA and PPP1CA.
Plays a major role as an activator of AKT family members by inhibiting PPP2CA-mediated dephosphorylation, thereby keeping AKTs activated. Plays a role in preventing motor neuronal death and accelerating the growth of pancreatic beta cells.
Ubiquitously expressed. Highly expressed in adult brain, testis, aorta and small intestine and weakly expressed in the heart, lung, liver, kidney, pancreas, spleen, thymus, prostate, ovary and colon. Down-regulated in glioma.
Expressed in CD4+ T-cells, but not in CD8+ T-cells. Expressed in the T-cell lines Jurkat, Peer, MOLT-4, HSB, YT and SUP-T1, but not in the T-cell lines HARRIS and HuT 78.
This is a receptor for VIP as well as PACAP-38 and -27, the activity of this receptor is mediated by G proteins which activate adenylyl cyclase. Can be coupled to phospholipase C.
Homo/heterodimer, or complexes of higher-order. The structure of beta-crystallin oligomers seems to be stabilized through interactions between the N-terminal arms (By similarity).
Belongs to the SEC23/SEC24 family. SEC24 subfamily.
COPII is composed of at least five proteins: the Sec23/24 complex, the Sec13/31 complex and Sar1 (PubMed:10214955, PubMed:10075675, PubMed:17499046). Interacts with TMED2 and TMED10 (PubMed:20427317). Interacts with GOSR2 (via IxM motif) and STX5 (via IxM motif); recruits GOSR2 and STX5 into COPII-coated vesicles (PubMed:18843296). Interacts with DDHD1 (PubMed:17428803). Interacts with STING1; promoting STING1 translocation to the COPII vesicles (PubMed:30842662).
Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules for their transport to the Golgi complex (PubMed:10214955, PubMed:17499046, PubMed:18843296, PubMed:20427317). Plays a central role in cargo selection within the COPII complex and together with SEC24D may have a different specificity compared to SEC24A and SEC24B (PubMed:17499046, PubMed:20427317, PubMed:18843296). May more specifically package GPI-anchored proteins through the cargo receptor TMED10 (PubMed:20427317). May also be specific for IxM motif-containing cargos like the SNAREs GOSR2 and STX5 (PubMed:18843296).
Belongs to the WD repeat BOP1/ERB1 family.
Component of the PeBoW complex, composed of BOP1, PES1 and WDR12 (PubMed:16043514, PubMed:16738141, PubMed:17189298, PubMed:17353269). The complex is held together by BOP1, which interacts with PES1 via its N-terminal domain and with WDR12 via a high-affinity interaction between the seven-bladed beta-propeller domains of the 2 proteins. The NOP7 complex associates with the 66S pre-ribosome (By similarity). The PeBoW complex associates with DDX27, BOP1 interacts directly with DDX27 (PubMed:25825154).
Component of the PeBoW complex, which is required for maturation of 28S and 5.8S ribosomal RNAs and formation of the 60S ribosome.
Expression is cell cycle dependent with the highest levels at the end of G1 phase, peaking at the G1-S transition.
Overexpression impairs serum-induced cell cycle progression from the G0/G1 to S phase.
Ubiquitous. High expression in the ventricular zone of the developing central nervous system. High in ovary, testis, prostate, thymus and lung.
Calcium-selective channel required to prevent calcium stores from overfilling, thereby playing a key role in calcium homeostasis (PubMed:27212239). In response to endoplasmic reticulum (ER) overloading, assembles into a homotetramer, forming a functional calcium-selective channel, regulating the calcium content in endoplasmic reticulum store (PubMed:27212239). Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes (PubMed:32820719, PubMed:36261522). The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions (PubMed:36261522). Within the MPT complex, the GEL subcomplex may mediate insertion of transmembrane regions into the membrane (PubMed:36261522).
Calcium-selective channel required to prevent calcium stores from overfilling.
Homodimer and homotetramer (PubMed:27212239). Homodimer under resting conditions; forms homotetramers following and ER calcium overload (PubMed:27212239). Component of the GET- and EMC-like (GEL) complex, composed of RAB5IF/OPTI and TMCO1 (PubMed:36261522). The GEL complex is part of the multi-pass translocon (MPT) complex, composed of three subcomplexes, the GEL complex (composed of RAB5IF/OPTI and TMCO1), the BOS complex (composed of NCLN/Nicalin, NOMO and TMEM147) and the PAT complex (composed of WDR83OS/Asterix and CCDC47) (PubMed:36261522, PubMed:32820719). The MPT complex associates with the SEC61 complex (PubMed:36261522).
Homodimer and homotetramer. Homodimer under resting conditions; forms homotetramers following and ER calcium overload.
Widely expressed in adult and fetal tissues, with higher levels in thymus, prostate, testis and small intestine and lower levels in brain, placenta, lung and kidney (PubMed:10393320, PubMed:20018682). Present in most tissues in the eye, including the trabecular meshwork and retina (at protein level) (PubMed:22714896).
Expressed in skeletal and cardiac muscles, brain, heart and lung. Little or no detectable expression found in pancreas, kidney, liver or placenta.
Transcription factor that binds preferentially to the octamer motif (5'-ATGTTAAT-3'). May exert a regulatory function in meiotic events that are required for terminal differentiation of male germ cell (By similarity).
Interacts with BECN1. Probably associates with the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex (PubMed:24349490). Interacts with UACA (By similarity). Interacts with isoform a of RASSF1 (By similarity). Does not interact with isoform c of RASSF1 (By similarity).
Plays a role in the maturation and acidification of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis. Plays a role in vesicular trafficking. Plays a role in the fusion of phagosomes with lysosomes. Negatively regulates LPS-induced autophagosome formation in macrophages possibly by implicating PI3K (PubMed:24349490). May be involved in multiple neurite formation (By similarity).
Activated by trypsin cleavage in the duodenum. Can also be activated by thrombin or autocatalytically.
Regulated by bile acid salts. Up-regulated by cholate and down-regulated by taurochenodeoxycholate. Cholate-activated rate of hydrolysis is lowered by hypolipidemic drug ezetimibe.
Secretory calcium-dependent phospholipase A2 that primarily targets dietary phospholipids in the intestinal tract (PubMed:1420353, PubMed:10681567, PubMed:17603006). Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) with preference for phosphatidylethanolamines and phosphatidylglycerols over phosphatidylcholines (PubMed:1420353, PubMed:10681567, PubMed:17603006). May play a role in the biosynthesis of N-acyl ethanolamines that regulate energy metabolism and inflammation in the intestinal tract. Hydrolyzes N-acyl phosphatidylethanolamines to N-acyl lysophosphatidylethanolamines, which are further cleaved by a lysophospholipase D to release N-acyl ethanolamines (By similarity). May act in an autocrine and paracrine manner (PubMed:7721806, PubMed:25335547). Upon binding to the PLA2R1 receptor can regulate podocyte survival and glomerular homeostasis (PubMed:25335547). Has anti-helminth activity in a process regulated by gut microbiota. Upon helminth infection of intestinal epithelia, directly affects phosphatidylethanolamine contents in the membrane of helminth larvae, likely controlling an array of phospholipid-mediated cellular processes such as membrane fusion and cell division while providing for better immune recognition, ultimately reducing larvae integrity and infectivity (By similarity).
Selectively expressed in pancreas, lung, liver and kidney. Also detected at lower levels in ovary and testis.
The inactive pro-form is a homotrimer (PubMed:19297324). When anchored into the cell membrane, the inactive homotrimer is likely cleaved either by trypsin or by itself, producing an active trimer. The resulting conformational changes are thought to open up a center hole forming a channel for substrate entry (PubMed:19297324). Interacts with PLA2R1; this interaction mediates intracellular signaling as well as clearance of extracellular PLA2G1B via endocytotic pathway (PubMed:7721806).
Forms homodimers and heterodimers with CASTOR1 (PubMed:26972053). Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is not regulated by arginine (PubMed:26972053).
Functions as a negative regulator of the TORC1 signaling pathway through the GATOR complex. As part of homodimers or heterodimers with CASTOR1, directly binds and inhibits the GATOR subcomplex GATOR2 and thereby mTORC1. Does not directly bind arginine, but binding of arginine to CASTOR1 disrupts the interaction of CASTOR2-containing heterodimers with GATOR2 which can in turn activate mTORC1 and the TORC1 signaling pathway.
Expressed in all immune tissues, spleen, lymph nodes, thymus, tonsils, leukocyte and bone marrow. Expressed also in heart, brain, skeletal muscle, kidney, lung and pancreas. Expressed in primary Schwann cells and very weakly by monocyte-derived macrophages the primary host cells of Mycobacterium leprae, the causative agent of leprosy. Component of Lewy bodies, intraneuronal inclusions found in the brain of Parkinson disease patients.
Forms a large molecular chaperone complex containing heat shock proteins 70 and 90 and chaperonin components. Interacts with STIP1, PRKN, GPR37, HSPA8, TCP1/CCT1, CCT2, CCT3, CCT4, CCT5, CCT6A, CCT7, CCT8. Interacts with MEIG1 (By similarity).
Involved in susceptibility to leprosy (LPRS2) [MIM:607572]. LPRS2 is associated with polymorphisms in the 5'-regulatory region shared by the PRKN gene.
Linked to PRKN in a head-to-head arrangement on opposite DNA strands and share a common 5'-flanking promoter region.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (PubMed:36191189). Suppresses cell death induced by accumulation of unfolded Pael receptor (Pael-R, a substrate of Parkin). Facilitates the formation of inclusions consisting of Pael-R, molecular chaperones, protein degradation molecules and itself when proteasome is inhibited. May play an important role in the formation of Lewy bodies and protection of dopaminergic neurons against Parkinson disease (PubMed:14532270).
Expressed in liver (PubMed:1339448, PubMed:18004212). Expressed in kidney, colon and small intestine (PubMed:18004212). Not expressed in esophagus (PubMed:18004212). Not expressed in skin (PubMed:1339448).
Homodimer (PubMed:17179145). Homooligomer (Probable). Interacts with UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 to form heterodimers (PubMed:17179145). Isoform 1 interacts with isoform 2/i2 suggesting that oligomerization is involved in negative regulation of transferase activity by isoform 2. Isoform 1 also interacts with respective i2 isoforms of UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 (PubMed:20610558).
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:18177842, PubMed:24641623). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:18177842). Involved in the glucuronidation of calcidiol, which is the major circulating form of vitamin D3 essential for the regulation of calcium and phosphate homeostasis (PubMed:24641623). Also glucuronidates the biologically active form of vitamin D3, calcitriol, probably leading to its biliary transport and intestinal reabsorption (PubMed:18177842).
UGT1A4 isoform is part of the UGT1A complex locus which displays alternative use of promoters, first exons and terminal exons. The locus is defined by 13 first exons, which are alternatively spliced to 3 other common exons and 2 alternative terminal exons 5. From the 27 possible mRNA isoforms, 9 produce functionally active polypeptides (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9 and 1A10) called isoforms 1 (i1). Use of an alternative exon 5 (5b) as terminal exon is leading to 9 additional alternatively spliced products termed isoforms i2 and which lack transferase activity.
(Microbial infection) Binds M.bovis cell surface protein Apa via its glycosylated sites; probably also recognizes other bacterial moieties.
(Microbial infection) Binds M.pneumoniae CARDS toxin, serves as one receptor for this pathogen (PubMed:15845487, PubMed:25139904). When SFTPA1 is down-regulated by siRNA, less toxin binds to human cells and less vacuolization (a symptom of M.pneumoniae infection) is seen (PubMed:25139904).
(Microbial infection) Binds to the S.aureus extracellular adherence protein, Eap, thereby enhancing phagocytosis and killing of S.aureus by alveolar macrophages.
(Microbial infection) Interacts with M.pneumoniae CARDS toxin; CARDS probably uses this protein as a receptor.
(Microbial infection) Recognition of M.tuberculosis by dendritic cells may occur partially via this molecule (PubMed:17158455, PubMed:21203928). Can recognize, bind, and opsonize pathogens to enhance their elimination by alveolar macrophages (PubMed:21123169).
At least 5 allelic variants of SFTPA1 are known: 6A, 6A(2), 6A(3), 6A(4) and 6A(5). The sequence shown is that of allele 6A(3).
Disease susceptibility may be associated with variants affecting the gene represented in this entry. The association between SFTPA1 alleles and respiratory distress syndrome in premature infants is dependent on a variation Ile to Thr at position 131 in SFTPB.
In presence of calcium ions, it binds to surfactant phospholipids and contributes to lower the surface tension at the air-liquid interface in the alveoli of the mammalian lung and is essential for normal respiration. Enhances the expression of MYO18A/SP-R210 on alveolar macrophages (By similarity).
Oligomeric complex of 6 set of homotrimers.
Expressed abundantly within the central nervous system in both hypothalamus and hippocampus. In peripheral tissues, the strongest expression was observed in heart, kidney, liver, and small intestine.
Receptor for the hormone galanin and GALP. Receptor for the hormone spexin-1 (PubMed:24517231). The activity of this receptor is mediated by G proteins that activate the phospholipase C/protein kinase C pathway (via G(q)) and that inhibit adenylyl cyclase (via G(i)).
Prediction based on family homologs sequence.
Belongs to the eukaryotic ribosomal protein eL31 family.
Dually lipidated in the C-terminus; prenylation occurs prior to, and is a prerequisite for palmitoylation. It is also required for activity towards long-chain substrates.
Oxidizes medium and long chain saturated and unsaturated aldehydes (PubMed:17382292, PubMed:23721920). Metabolizes also benzaldehyde (PubMed:17382292). Low activity towards acetaldehyde and 3,4-dihydroxyphenylacetaldehyde (PubMed:17382292, PubMed:23721920). May not metabolize short chain aldehydes. Can use both NADP(+) and NAD(+) as electron acceptor (PubMed:17382292). May have a protective role against the cytotoxicity induced by lipid peroxidation (PubMed:17382292).
Interacts with SCYL1 (By similarity). Interacts with RCHY1 and RAB6A/RAB6.
May be involved in ER/Golgi transport and vesicular traffic. Plays a proapoptotic role in cerulenin-induced neuroblastoma apoptosis.
Strong expression in the brain, small intestine, lung, spleen, and pancreas as well as in tumor tissues of the breast, colon, lung and ovary, with a weaker expression in normal tissues of the same patient. High expression in neuroblastic tumors. Strongly expressed in Purkinje cells and more moderately in cells of the molecular and the granular layers in the cerebellum. Detected in neuronal cells, but not in non-neuronal cells in the cerebral cortex, hippocampus, and lateral ventricles.
Both precursor form and mature form have thiol reductase activity.
Chimeric cDNA. N-terminal sequence identical to a region of chromosome 11.
Expressed constitutively in antigen-presenting cells and induced by IFN-gamma in other cell types.
Lysosomal thiol reductase that can reduce protein disulfide bonds. May facilitate the complete unfolding of proteins destined for lysosomal degradation. Plays an important role in antigen processing. Facilitates the generation of MHC class II-restricted epitodes from disulfide bond-containing antigen by the endocytic reduction of disulfide bonds (By similarity). Facilitates also MHC class I-restricted recognition of exogenous antigens containing disulfide bonds by CD8+ T-cells or crosspresentation (By similarity).
N-glycosylated. Sugar chains contain mannose-6-phosphate.
Synthesized as a 35 kDa precursor which is then processed into the mature 30 kDa form via cleavage of N-terminal and C-terminal propeptides. Processing of the precursor is mediated by multiple lysosomal proteases.
Belongs to the thioesterase PaaI family.
Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels (PubMed:16934754, PubMed:19170545). Has acyl-CoA thioesterase activity towards medium (C12) and long-chain (C18) fatty acyl-CoA substrates (By similarity) (PubMed:16934754, PubMed:19170545). Can also hydrolyze 3-hydroxyphenylacetyl-CoA and 3,4-dihydroxyphenylacetyl-CoA (in vitro) (By similarity) (PubMed:16934754, PubMed:19170545). May play a role in controlling adaptive thermogenesis (By similarity).
Homotetramer (PubMed:16934754, PubMed:19170545). Interacts with PCTP (By similarity).
A major expression is found in the colonic epithelium. It is also abundant in the activated macrophages. Expressed in fetal membranes.
Galactose-specific lectin which binds IgE. May mediate with the alpha-3, beta-1 integrin the stimulation by CSPG4 of endothelial cells migration. Together with DMBT1, required for terminal differentiation of columnar epithelial cells during early embryogenesis (By similarity). In the nucleus: acts as a pre-mRNA splicing factor. Involved in acute inflammatory responses including neutrophil activation and adhesion, chemoattraction of monocytes macrophages, opsonization of apoptotic neutrophils, and activation of mast cells. Together with TRIM16, coordinates the recognition of membrane damage with mobilization of the core autophagy regulators ATG16L1 and BECN1 in response to damaged endomembranes.
Probably forms homo- or heterodimers. Interacts with DMBT1 (By similarity). Interacts with CD6 and ALCAM (PubMed:24945728). Forms a complex with the ITGA3, ITGB1 and CSPG4. Interacts with LGALS3BP, LYPD3, ZFTRAF1 and UACA. Interacts with TRIM16; this interaction mediates autophagy of damage endomembranes. Interacts with cargo receptor TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion (PubMed:32272059).
Highest level of expression in skeletal muscle. Also expressed in heart, brain, placenta, liver, kidney and pancreas.
Calcium-dependent N-acyltransferase involved in the biosynthesis of N-acyl ethanolamines (NAEs) in the brain (PubMed:29447909). Transfers the sn-1 fatty acyl chain of phosphatidylcholine (fatty acyl donor) to the amine group of phosphatidylethanolamine (fatty acyl acceptor) to generate N-acyl phosphatidylethanolamine (NAPE). Similarly can use plasmenylethanolamine as a fatty acyl acceptor to form N-acyl plasmenylethanolamine (N-Acyl-PlsEt). Both NAPE and N-Acyl-PlsEt can serve as precursors of bioactive NAEs like N-arachidonoyl phosphatidylethanolamine also called anandamide (PubMed:29447909, PubMed:30517655). Has weak phospholipase A2 and lysophospholipase activities (By similarity). Regulates intracellular membrane trafficking that requires modulation of membrane curvature as it occurs by enrichment in lysophospholipids. Promotes tubule formation involved in clathrin-independent endocytotic trafficking and cargo recycling (By similarity).
Stimulated by cytosolic Ca(2+). Stimulated by anionic phospholipids such as phosphatidylserines, phosphatidates and phosphatidylinositols.
Belongs to the secretoglobin family. UGRP subfamily.
Highly expressed in lung and prostate (PubMed:11481438). Also found in mammary gland, spleen, pancreas, testis and liver (PubMed:11481438). Detected throughout the airway epithelium in lung, with highest expression in large airways (PubMed:12406855). Found in lung submucosal glands where it localizes to acinar and ductile cells (PubMed:12406855). Not detected in respiratory bronchioles, alveolar ducts or alveolar epithelium (PubMed:12406855). In mammary gland, specifically localizes to luminal epithelial cells (PubMed:11481438).
Secreted cytokine-like protein. Inhibits cell growth in vitro.
A chromosomal aberration involving ZBTB16 may be a cause of acute promyelocytic leukemia (APL). Translocation t(11;17)(q32;q21) with RARA.
Acts as a transcriptional repressor (PubMed:10688654, PubMed:24359566). Transcriptional repression may be mediated through recruitment of histone deacetylases to target promoters (PubMed:10688654). May play a role in myeloid maturation and in the development and/or maintenance of other differentiated tissues. Probable substrate-recognition component of an E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:14528312).
Binds EPN1 (PubMed:11161217). Interacts with ZBTB32 and CUL3 (PubMed:10572087, PubMed:14528312). Interacts with ATP7B (PubMed:16676348). Interacts with transcriptional corepressor RUNX1T1 (via its N-terminus); the interaction increases the transcription repression activity of ZBTB16 (PubMed:10688654). Interacts (via C2H2-type zinc finger domains 1 and 2) with RNF112 (PubMed:24359566).
Within the hematopoietic system, PLZF is expressed in bone marrow, early myeloid cell lines and peripheral blood mononuclear cells. Also expressed in the ovary, and at lower levels, in the kidney and lung.
Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. May be involved in metabolic regulation; may be involved in recruitment of the CCR4-NOT complex to deadenylation target mRNAs involved in energy metabolism. Involved in mitotic progression and regulation of the spindle assembly checkpoint by regulating the stability of MAD1L1 mRNA. Can repress transcription and may link the CCR4-NOT complex to transcriptional regulation; the repressive function may involve histone deacetylases. Involved in the maintenance of embryonic stem (ES) cell identity.
Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits. In the complex interacts directly with CNOT2. Interacts with TIP120B and NANOS2. Interacts with EBF1.
Seems to have an artifactual loop-out at the 3'-end deleting 2 full exons and part of 2 others.
Ubiquitous. Highly expressed in brain, heart, thymus, spleen, kidney, liver, small intestine, lung and peripheral blood leukocytes.
(Microbial infection) Interacts with influenza A virus protein PB1-F2.
Homohexamer (PubMed:22386589). Interacts with MAVS (PubMed:18200010). Interacts with TUFM (PubMed:22749352).
Participates in antiviral signaling. Acts as a negative regulator of MAVS-mediated antiviral responses, through the inhibition of the virus-induced RLH (RIG-like helicase)-MAVS interaction (PubMed:18200010). Instead, promotes autophagy by interacting with TUFM and subsequently recruiting the autophagy-related proteins ATG5 and ATG12 (PubMed:22749352). Regulates also MAVS-dependent NLRP3 inflammasome activation to attenuate apoptosis (PubMed:27393910). Has no inhibitory function on NF-kappa-B signaling pathway, but enhances NF-kappa-B and JUN N-terminal kinase dependent signaling through the production of reactive oxygen species (PubMed:18219313). Regulates viral mediated-inflammation and energy metabolism in a sex-dependent manner (By similarity). In females, prevents uncontrolled inflammation and energy metabolism and thus, may contribute to the sex differences observed in infectious and inflammatory diseases (By similarity).
The LRRCT domain mediates homodimerization and LRRNT mediates trimerization of the dimers.
Ubiquitously expressed. Strongest expression in mammary gland, heart and muscle. Detected in HeLa, HEK293T, THP-1, HL-60, Raji and Jurkat cell lines (at protein level).
In germ cells in testis. Lung carcinoma cells.
Role in sperm cell division, maturation, or function. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
Adapter protein required for Golgi and endoplasmic reticulum biogenesis (PubMed:17141156). Involved in Golgi and endoplasmic reticulum maintenance during interphase and in their reassembly at the end of mitosis (PubMed:17141156). The complex formed with VCP has membrane fusion activity; membrane fusion activity requires USO1-GOLGA2 tethering and BET1L (PubMed:17141156). VCPIP1 is also required, but not its deubiquitinating activity (PubMed:17141156). Together with NSFL1C/p47, regulates the centrosomal levels of kinase AURKA/Aurora A during mitotic progression by promoting AURKA removal from centrosomes in prophase (PubMed:23649807). Also, regulates spindle orientation during mitosis (PubMed:23649807).
Interacts with VCP. Does not bind ubiquitin.
Activated by GUCA1A when free calcium ions concentration is low, and inhibited by GUCA1A when free calcium ions concentration is high (By similarity). Negatively regulated by RD3; inhibits the basal and GUCA1A-stimulated guanylate cyclase activity (PubMed:21928830).
Catalyzes the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors. Plays an essential role in phototransduction, by mediating cGMP replenishment (PubMed:21928830, PubMed:30319355, PubMed:26100624, PubMed:9600905, PubMed:15123990). May also participate in the trafficking of membrane-asociated proteins to the photoreceptor outer segment membrane (By similarity).
Homodimer; requires homodimerization for guanylyl cyclase activity (By similarity). Interacts with RD3; promotes the exit of GUCY2D from the endoplasmic reticulum and its trafficking to the photoreceptor outer segments (PubMed:21928830, PubMed:21078983). Interaction with RD3 negatively regulates guanylate cyclase activity (PubMed:21928830).
The gene names for receptor guanylyl cyclases are inconsistent between mouse and human. The ortholog of the mouse Gucy2d gene is a pseudogene in humans.
Antigen in chronic rheumatoid arthritis and in the autoimmune disease Sjoegren syndrome.
Homodimer; disulfide-linked. Interacts with PLK3.
May participate in forming intercisternal cross-bridges of the Golgi complex.
Dephosphorylates a range of proteins, and thereby regulates cellular signaling cascades (PubMed:18559503). Dephosphorylates cellular tyrosine kinases, such as ERBB2 and PTK2B/PYK2, and thereby regulates signaling via ERBB2 and PTK2B/PYK2 (PubMed:17329398, PubMed:27134172). Selectively dephosphorylates ERBB2 phosphorylated at 'Tyr-1112', 'Tyr-1196', and/or 'Tyr-1248' (PubMed:27134172).
Interacts with TGFB1I1 (By similarity). Interacts with PSTPIP1 (PubMed:9857189). Interacts with PTK2B/PYK2 (PubMed:17329398). Interacts with LPXN (By similarity). Interacts with SORBS2; this interaction greatly enhances WASF1 dephosphorylation and might mediate partial translocation to focal adhesion sites (PubMed:18559503).
Phosphorylated by STK24/MST3 and this results in inhibition of its activity.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A6 subfamily.
Expressed abundantly in placenta and skeletal muscle, at intermediate levels in heart, brain, lung, kidney and pancreas and at low levels in liver.
Mediates sodium- and chloride-dependent transport of taurine (PubMed:8382624, PubMed:8010975, PubMed:8654117, PubMed:31345061, PubMed:31903486). Mediates transport of beta-alanine (PubMed:8010975). Can also mediate transport of hypotaurine and gamma-aminobutyric acid (GABA) (By similarity).
Sodium-dependent taurine and beta-alanine transporter. Chloride ions are necessary for optimal uptake.
Taurine transport activity is down-regulated upon Ser-322 phosphorylation.
Taurine transport activity is stimulated by thyrotropin (PubMed:8382624). Taurine transport activity is inhibited by GABA, hypotaurine and beta-alanine (PubMed:8010975, PubMed:8654117).
(Microbial infection) Required for internal initiation of translation of human rhinovirus RNA.
Component of a multi subunit autoregulatory ribonucleoprotein complex (ARC), at least composed of IGF2BP1, PABPC1 and CSDE1 (PubMed:16356927). Interacts with STRAP (PubMed:10049359). Part of a complex associated with the FOS mCRD domain and consisting of PABPC1, PAIP1, HNRPD and SYNCRIP (PubMed:11051545). The interaction with PABPC1 is direct and RNA-independent (PubMed:11051545, PubMed:15314026). Interacts with EIF4ENIF1/4E-T (PubMed:27342281, PubMed:32354837).
RNA-binding protein involved in translationally coupled mRNA turnover (PubMed:11051545, PubMed:15314026). Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain (PubMed:11051545, PubMed:15314026). Required for efficient formation of stress granules (PubMed:29395067).
Isoform 2 length of the poly-Ala region is variable (6 to 27 CTG/CAG triplets) in the normal population and may be expanded (41 to 58 CTG/CAG triplets) in patients suffering from Huntington disease-like type 2.
Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells. Provides a structural foundation for functional cross-talk between the cell surface and intracellular calcium release channels. JPH3 is brain-specific and appears to have an active role in certain neurons involved in motor coordination and memory.
The MORN (membrane occupation and recognition nexus) repeats contribute to the plasma membrane binding, possibly by interacting with phospholipids.
Component of the PEX13-PEX14 docking complex, a translocon channel that specifically mediates the import of peroxisomal cargo proteins bound to PEX5 receptor (PubMed:9653144, PubMed:8858165, PubMed:28765278). The PEX13-PEX14 docking complex forms a large import pore which can be opened to a diameter of about 9 nm (By similarity). Mechanistically, PEX5 receptor along with cargo proteins associates with the PEX14 subunit of the PEX13-PEX14 docking complex in the cytosol, leading to the insertion of the receptor into the organelle membrane with the concomitant translocation of the cargo into the peroxisome matrix (PubMed:9653144, PubMed:8858165, PubMed:28765278). Involved in the import of PTS1- and PTS2-type containing proteins (PubMed:9653144, PubMed:8858165).
Interacts (via SH3 domain) with PEX14 (via SH3-binding motif); forming the PEX13-PEX14 docking complex (PubMed:28765278). Interacts with PEX19 (PubMed:10704444, PubMed:11390669).
It is uncertain whether Met-1 or Met-40 is the initiator.
Guanine nucleotide exchange factor (GEF) that modulates the Rho family of GTPases. Promotes the conversion of some member of the Rho family GTPase from the GDP-bound to the GTP-bound form. Isoform 1 exhibits no activity toward RHOA, RAC1 or CDC42. Isoform 2 exhibits decreased GEF activity toward CDC42. Isoform 3 exhibits a weak but significant activity toward RAC1 and CDC42. Isoform 4 exhibits significant activity toward RHOA and CDC42. The truncated DBL oncogene is active toward RHOA, RAC1 and CDC42.
Interacts with an array of inositol phospholipids such as phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 5-phosphate (PI5P). May interact with CCPG1.
Isoform 1 is expressed only in brain. Isoform 3 is expressed in heart, kidney, spleen, liver and testis. Isoform 4 is expressed in brain, heart, kidney, testis, placenta, stomach and peripheral blood. The protein is detectable in brain, heart, kidney, intestine, muscle, lung and testis.
MCF2 and DBL represent two activated versions of the same proto-oncogene.
Phosphorylation by TNK2 enhances guanine nucleotide exchange factor (GEF) activity toward Rho family proteins.
The CRAL-TRIO domain is involved in interaction with inositol phospholipids.
The DH domain is essential for transforming activity and directly catalyzes GDP-GTP exchange activity. It may interact with CCPG1.
Chromatin-associated, histone tail-binding protein that represses transcription via recruitment of HDAC3 and nuclear hormone receptor corepressors.
Interacts with HDAC3 and nuclear hormone receptor corepressors.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. MCAK/KIF2 subfamily.
HeLa cells lacking KIF2A show asymmetric or monopolar mitotic spindles. Osteosarcoma cells (U2OS) lacking KIF2A or KIF2B show disorganised or monopolar mitotic spindles.
Plus end-directed microtubule-dependent motor required for normal brain development. May regulate microtubule dynamics during axonal growth. Required for normal progression through mitosis. Required for normal congress of chromosomes at the metaphase plate. Required for normal spindle dynamics during mitosis. Promotes spindle turnover. Implicated in formation of bipolar mitotic spindles. Has microtubule depolymerization activity.
Associates (via the heparan sulfate side chains) with fibrillar APP amyloid-beta peptides in primitive and classic amyloid plaques and may be involved in the deposition of these senile plaques in the Alzheimer disease (AD) brain (PubMed:15084524).
Cell surface proteoglycan that bears heparan sulfate. Binds, via the heparan sulfate side chains, alpha-4 (V) collagen and participates in Schwann cell myelination (By similarity). May act as a catalyst in increasing the rate of conversion of prion protein PRPN(C) to PRNP(Sc) via associating (via the heparan sulfate side chains) with both forms of PRPN, targeting them to lipid rafts and facilitating their interaction. Required for proper skeletal muscle differentiation by sequestering FGF2 in lipid rafts preventing its binding to receptors (FGFRs) and inhibiting the FGF-mediated signaling.
Misprocessing of GPC1 is found in fibroblasts of patients with Niemann-Pick Type C1 disease. This is due to the defective deaminative degradation of heparan sulfate chains (PubMed:16645004).
N- and O-glycosylated. N-glycosylation is mainly of the complex type containing sialic acid. O-glycosylated with heparan sulfate. The heparan sulfate chains can be cleaved either by the action of heparanase or, degraded by a deaminative process that uses nitric oxide (NO) released from the S-nitrosylated cysteines. This process is triggered by ascorbate, or by some other reducing agent, in a Cu(2+)- or Zn(2+) dependent manner. Cu(2+) ions are provided by ceruloproteins such as APP, PRNP or CP which associate with GCP1 in intracellular compartments or lipid rafts.
S-nitrosylated in a Cu(2+)-dependent manner. Nitric acid (NO) is released from the nitrosylated cysteines by ascorbate or by some other reducing agent, in a Cu(2+) or Zn(2+) dependent manner. This free nitric oxide is then capable of cleaving the heparan sulfate side chains.
This cell-associated glypican is further processed to give rise to a medium-released species.
Localized in an untranslated region: wrong choice of CDS.
Adhesion molecule that mediates interactions between myelinating cells and neurons by binding to neuronal sialic acid-containing gangliosides and to the glycoproteins RTN4R and RTN4RL2 (By similarity). Not required for initial myelination, but seems to play a role in the maintenance of normal axon myelination. Protects motoneurons against apoptosis, also after injury; protection against apoptosis is probably mediated via interaction with neuronal RTN4R and RTN4RL2. Required to prevent degeneration of myelinated axons in adults; this probably depends on binding to gangliosides on the axon cell membrane (By similarity). Negative regulator of neurite outgrowth; in dorsal root ganglion neurons the inhibition is mediated primarily via binding to neuronal RTN4R or RTN4RL2 and to a lesser degree via binding to neuronal gangliosides. In cerebellar granule cells the inhibition is mediated primarily via binding to neuronal gangliosides. In sensory neurons, inhibition of neurite extension depends only partially on RTN4R, RTN4RL2 and gangliosides. Inhibits axon longitudinal growth (By similarity). Inhibits axon outgrowth by binding to RTN4R (By similarity). Preferentially binds to alpha-2,3-linked sialic acid. Binds ganglioside Gt1b (By similarity).
Both isoform 1 and isoform 2 are detected in myelinated structures in the central and peripheral nervous system, in periaxonal myelin and at Schmidt-Lanterman incisures (PubMed:9495552, PubMed:6200494). Detected in optic nerve, in oligodendroglia and in periaxonal myelin sheaths (PubMed:6200494). Detected in compact myelin (at protein level) (PubMed:6200494). Both isoform 1 and isoform 2 are detected in the central and peripheral nervous system (PubMed:9495552).
Monomer and homodimer (By similarity). Interacts (via the first three N-terminal Ig-like domains) with RTN4R and RTN4RL2 (By similarity). Interacts with RTN4R (PubMed:19052207). Interacts with isoform 2 of BSG (By similarity).
Ubiquitinated, leading to proteasomal degradation.
At the cell surface, may be cleaved by MMP14.
Expressed in spleen. Detected on a number of myeloid cells including CD11b monocytes, CD66b+ neutrophils, at low levels on CD4+ and CD8+ T-cells, and in a subset of NK cells. Not detected on B cells (at protein level). Expressed at high levels in placenta, spleen, plasma blood leukocytes, and lung. Expressed at moderate levels in lymph node, bone marrow, fat, uterus, and trachea. Has low expression levels in other tissues.
Immunoregulatory receptor which inhibits the T-cell response (PubMed:24691993). May promote differentiation of embryonic stem cells, by inhibiting BMP4 signaling (By similarity). May stimulate MMP14-mediated MMP2 activation (PubMed:20666777).
Homodimer (By similarity). Interacts with TTN/titin (By similarity). Interacts with PNKD.
Activated by binding of S100B which releases autoinhibitory N-lobe interactions, enabling ATP to bind and the autophosphorylation of Ser-281. Thr-444 then undergoes calcium-dependent phosphorylation by STK24/MST3. Interactions between phosphorylated Thr-444 and the N-lobe promote additional structural changes that complete the activation of the kinase. Autoinhibition is also released by the binding of MOB1/MOBKL1A and MOB2/HCCA2 to the N-terminal of STK38.
Homodimeric S100B binds two molecules of STK38 (PubMed:14661952). Interacts with MOB1 and MOB2 (PubMed:15067004, PubMed:15197186). Interacts with MAP3K1 and MAP3K2 (via the kinase catalytic domain) (PubMed:17906693). Forms a tripartite complex with MOBKL1B and STK3/MST2 (PubMed:18362890). Interacts with MICAL1; leading to inhibit the protein kinase activity by antagonizing activation by MST1/STK4 (By similarity).
Negative regulator of MAP3K1/2 signaling. Converts MAP3K2 from its phosphorylated form to its non-phosphorylated form and inhibits autophosphorylation of MAP3K2.
Phosphorylated by STK3/MST2 and this is enhanced by MOBKL1B.
Ubiquitously expressed with highest levels observed in peripheral blood leukocytes.
Belongs to the snRNP core protein family.
Core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (PubMed:11991638, PubMed:19325628, PubMed:21516107, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Most spliceosomal snRNPs contain a common set of Sm proteins, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (PubMed:10025403, PubMed:19325628, PubMed:21516107, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Component of the U1 snRNP (PubMed:19325628, PubMed:25555158). The U1 snRNP is composed of the U1 snRNA and the 7 core Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG, and at least three U1 snRNP-specific proteins SNRNP70/U1-70K, SNRPA/U1-A and SNRPC/U1-C (PubMed:19325628, PubMed:25555158). Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39, plus LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 (PubMed:26912367). Component of the minor spliceosome, which splices U12-type introns (PubMed:15146077, PubMed:33509932). Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG; catalyzes core snRNPs assembly (PubMed:16314521). Forms a 6S pICln-Sm complex composed of CLNS1A/pICln, SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG; ring-like structure where CLNS1A/pICln mimics additional Sm proteins and which is unable to assemble into the core snRNP. Interacts with SMN1; the interaction is direct (PubMed:21816274). Interacts with GEMIN2; the interaction is direct (PubMed:21816274, PubMed:31799625). Interacts with SNRPD1; the interaction is direct (PubMed:21816274, PubMed:31799625). Interacts with SNRPF; the interaction is direct (PubMed:21816274, PubMed:31799625).
In the autoimmune disease systemic lupus erythematosus, antinuclear antibodies are developed with Sm specificity.
Plays a role in pre-mRNA splicing as a core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (PubMed:11991638, PubMed:18984161, PubMed:19325628, PubMed:23333303, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Component of both the pre-catalytic spliceosome B complex and activated spliceosome C complexes (PubMed:11991638, PubMed:28502770, PubMed:28781166, PubMed:28076346). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (PubMed:15146077).
Activated by interaction with DLAT. Inhibited by AZD7545, dichloroacetate and radicicol.
Belongs to the PDK/BCKDK protein kinase family.
Expressed in heart, skeletal muscle, spinal cord, as well as fetal and adult brain.
Homodimer. Interacts with the pyruvate dehydrogenase complex subunit DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3).
Inhibits pyruvate dehydrogenase activity by phosphorylation of the E1 subunit PDHA1, and thereby regulates glucose metabolism and aerobic respiration. Can also phosphorylate PDHA2. Decreases glucose utilization and increases fat metabolism in response to prolonged fasting, and as adaptation to a high-fat diet. Plays a role in glucose homeostasis and in maintaining normal blood glucose levels in function of nutrient levels and under starvation. Plays a role in the generation of reactive oxygen species.
Up-regulated in response to hypoxia. Up-regulated in response to fatty acids. Up-regulated by PPARD.
E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins.
Imprinted, expressed from the paternal chromosome only. A deficiency of MKRN3 is not sufficient to cause Prader-Willi syndrome (PWS).
Component of the TRAPP complex, which is involved in endoplasmic reticulum to Golgi apparatus trafficking at a very early stage (PubMed:21525244, PubMed:28777934). Also plays a role in chromosome congression, kinetochore assembly and stability and controls the recruitment of CENPE to the kinetochores (PubMed:25918224).
Component of the multisubunit TRAPP (transport protein particle) complex, which includes at least TRAPPC2, TRAPPC2L, TRAPPC3, TRAPPC3L, TRAPPC4, TRAPPC5, TRAPPC8, TRAPPC9, TRAPPC10, TRAPPC11 and TRAPPC12 (PubMed:21525244). Interacts with CENPE (PubMed:25918224).
Phosphorylated as the cells enter mitosis but is dephosphorylated at or before the onset of anaphase. The phosphorylated form recruits CENPE to kinetochores more efficiently than the non-phosphorylated form.
The disease is caused by variants affecting the gene represented in this entry. Cells display a fragmented Golgi apparatus (PubMed:28777934).
Cleaved to generate C-terminal fragments in hippocampus, neocortex, and spinal cord from individuals affected with ALS and FTLDU.
Consists of an N-terminal domain (NTD) and two tandem RNA recognition motifs, RRM1 and RRM2, followed by a C-terminal glycine-rich region.
Contains a nuclear localization sequence and is mostly nuclear; however, its nuclear export sequence permits it to transport mRNAs to the cytoplasm and even to synapses as part of neuronal granules.
Homodimer (PubMed:20043239, PubMed:24464995). Homooligomer (via its N-terminal domain) (PubMed:28663553, PubMed:29438978). Interacts with BRDT (By similarity). Binds specifically to pyrimidine-rich motifs of TAR DNA and to single stranded TG repeated sequences. Binds to RNA, specifically to UG repeated sequences with a minimum of six contiguous repeats. Interacts with ATXN2; the interaction is RNA-dependent (PubMed:20740007). Interacts with MATR3 (PubMed:24686783). Interacts with UBQLN2 (PubMed:23541532). Interacts with HNRNPA2B1 (PubMed:19429692). Interacts with ZNF106 (By similarity). Interacts with CNOT7/CAF1 (PubMed:30520513). Interacts with CRY2 (PubMed:27123980). Interacts with PPIA/CYPA; the interaction is dependent on RNA-binding activity of TARDBP and PPIase activity of PPIA/CYPA and acetylation of PPIA/CYPA at 'Lys-125' favors the interaction (PubMed:25678563).
Hyperphosphorylated in hippocampus, neocortex, and spinal cord from individuals affected with ALS and FTLDU. Phosphorylated upon cellular stress.
RNA-binding protein that is involved in various steps of RNA biogenesis and processing (PubMed:23519609). Preferentially binds, via its two RNA recognition motifs RRM1 and RRM2, to GU-repeats on RNA molecules predominantly localized within long introns and in the 3'UTR of mRNAs (PubMed:23519609, PubMed:24240615, PubMed:24464995). In turn, regulates the splicing of many non-coding and protein-coding RNAs including proteins involved in neuronal survival, as well as mRNAs that encode proteins relevant for neurodegenerative diseases (PubMed:21358640, PubMed:29438978). Plays a role in maintaining mitochondrial homeostasis by regulating the processing of mitochondrial transcripts (PubMed:28794432). Regulates also mRNA stability by recruiting CNOT7/CAF1 deadenylase on mRNA 3'UTR leading to poly(A) tail deadenylation and thus shortening (PubMed:30520513). In response to oxidative insult, associates with stalled ribosomes localized to stress granules (SGs) and contributes to cell survival (PubMed:23398327, PubMed:19765185). Participates also in the normal skeletal muscle formation and regeneration, forming cytoplasmic myo-granules and binding mRNAs that encode sarcomeric proteins (PubMed:30464263). Plays a role in the maintenance of the circadian clock periodicity via stabilization of the CRY1 and CRY2 proteins in a FBXL3-dependent manner (PubMed:27123980). Negatively regulates the expression of CDK6 (PubMed:19760257). Regulates the expression of HDAC6, ATG7 and VCP in a PPIA/CYPA-dependent manner (PubMed:25678563).
The disease is caused by variants affecting the gene represented in this entry. Neurodegeneration is caused by activation of the cGAS-STING pathway: defects in TARDBP trigger mitochondrial DNA release into the cytosol via the permeability transition pore (PubMed:33031745). Released mitochondrial DNA is then detected by CGAS, leading to activation of the cGAS-STING pathway, triggering type-I interferon production and autoinflammation (PubMed:33031745).
Ubiquitinated in hippocampus, neocortex, and spinal cord from individuals affected with ALS and FTLDU.
Ubiquitously expressed. In particular, expression is high in pancreas, placenta, lung, genital tract and spleen.
Homodimer (PubMed:28369220). Isoform 1 and isoform 2 interact with an oxidized form of GAPDH. GAPDH stimulates the aminoacylation activity of isoform 2 (PubMed:15628863).
Isoform 1, isoform 2 and T1-TrpRS have aminoacylation activity while T2-TrpRS lacks it. Isoform 2, T1-TrpRS and T2-TrpRS possess angiostatic activity whereas isoform 1 lacks it. T2-TrpRS inhibits fluid shear stress-activated responses of endothelial cells. Regulates ERK, Akt, and eNOS activation pathways that are associated with angiogenesis, cytoskeletal reorganization and shear stress-responsive gene expression.
Proteolytic cleavage generates 2 forms; T1-TrpRS and T2-TrpRS.
Deletion or rearrangement of IRF1 are found in preleukemic myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML).
Induced by HPV16 E5 (PubMed:21389130). Induced by HIV (PubMed:19404407). By interferon (IFN) (PubMed:15226432, PubMed:17516545, PubMed:17942705, PubMed:19404407, PubMed:19851330, PubMed:32385160). Induced by N-methyl-N'-nitro-N-nitrosoguanidine (PubMed:22367195).
Monomer (By similarity). Homodimer (By similarity). Interacts with EP300 (PubMed:15509808). Interacts with MYD88 (By similarity). Interacts with PIAS3 (By similarity).
Phosphorylated by CK2 and this positively regulates its activity.
Sumoylation represses the transcriptional activity and displays enhanced resistance to protein degradation (PubMed:17942705). Sumolyated by UBE2I/UBC9 and SUMO1 (By similarity). Inactivates the tumor suppressor activity (PubMed:17942705). Elevated levels in tumor cells (PubMed:17942705). Major site is Lys-275 (PubMed:17942705). Sumoylation is enhanced by PIAS3 (By similarity). Desumoylated by SENP1 in tumor cells and appears to compete with ubiquitination on C-terminal sites (PubMed:17942705).
Transcriptional regulator which displays a remarkable functional diversity in the regulation of cellular responses (PubMed:15226432, PubMed:15509808, PubMed:17516545, PubMed:17942705, PubMed:18497060, PubMed:19404407, PubMed:19851330, PubMed:22367195, PubMed:32385160). Regulates transcription of IFN and IFN-inducible genes, host response to viral and bacterial infections, regulation of many genes expressed during hematopoiesis, inflammation, immune responses and cell proliferation and differentiation, regulation of the cell cycle and induction of growth arrest and programmed cell death following DNA damage (PubMed:15226432, PubMed:15509808, PubMed:17516545, PubMed:17942705, PubMed:18497060, PubMed:19404407, PubMed:19851330, PubMed:22367195). Stimulates both innate and acquired immune responses through the activation of specific target genes and can act as a transcriptional activator and repressor regulating target genes by binding to an interferon-stimulated response element (ISRE) in their promoters (PubMed:15226432, PubMed:15509808, PubMed:17516545, PubMed:17942705, PubMed:18497060, PubMed:19404407, PubMed:19851330, PubMed:21389130, PubMed:22367195). Competes with the transcriptional repressor ZBED2 for binding to a common consensus sequence in gene promoters (PubMed:32385160). Its target genes for transcriptional activation activity include: genes involved in anti-viral response, such as IFN-alpha/beta, RIGI, TNFSF10/TRAIL, ZBP1, OAS1/2, PIAS1/GBP, EIF2AK2/PKR and RSAD2/viperin; antibacterial response, such as GBP2, GBP5 and NOS2/INOS; anti-proliferative response, such as p53/TP53, LOX and CDKN1A; apoptosis, such as BBC3/PUMA, CASP1, CASP7 and CASP8; immune response, such as IL7, IL12A/B and IL15, PTGS2/COX2 and CYBB; DNA damage responses and DNA repair, such as POLQ/POLH; MHC class I expression, such as TAP1, PSMB9/LMP2, PSME1/PA28A, PSME2/PA28B and B2M and MHC class II expression, such as CIITA; metabolic enzymes, such as ACOD1/IRG1 (PubMed:15226432, PubMed:15509808, PubMed:17516545, PubMed:17942705, PubMed:18497060, PubMed:19404407, PubMed:19851330, PubMed:22367195). Represses genes involved in anti-proliferative response, such as BIRC5/survivin, CCNB1, CCNE1, CDK1, CDK2 and CDK4 and in immune response, such as FOXP3, IL4, ANXA2 and TLR4 (PubMed:18641303, PubMed:22200613). Stimulates p53/TP53-dependent transcription through enhanced recruitment of EP300 leading to increased acetylation of p53/TP53 (PubMed:15509808, PubMed:18084608). Plays an important role in immune response directly affecting NK maturation and activity, macrophage production of IL12, Th1 development and maturation of CD8+ T-cells (PubMed:11244049, PubMed:11846971, PubMed:11846974, PubMed:16932750). Also implicated in the differentiation and maturation of dendritic cells and in the suppression of regulatory T (Treg) cells development (PubMed:11244049, PubMed:11846971, PubMed:11846974, PubMed:16932750). Acts as a tumor suppressor and plays a role not only in antagonism of tumor cell growth but also in stimulating an immune response against tumor cells (PubMed:20049431).
Ubiquitinated. Appears to compete with sumoylation on C-terminal sites.
Belongs to the glycine N-acyltransferase family.
Mitochondrial acyltransferase which transfers an acyl group to the N-terminus of glycine and glutamine, although much less efficiently. Can conjugate numerous substrates to form a variety of N-acylglycines, with a preference for benzoyl-CoA over phenylacetyl-CoA as acyl donors. Thereby detoxify xenobiotics, such as benzoic acid or salicylic acid, and endogenous organic acids, such as isovaleric acid.
Predominantly expressed in liver (at protein level) and kidney. Down-regulated in hepatocellular carcinoma and other liver cancers.
Belongs to the tyrosyl-DNA phosphodiesterase family.
DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. Has low 3'exonuclease activity and can remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate.
Phosphorylated on serine and/or threonine residues, but not on tyrosine residues.
Ubiquitously expressed. Similar expression throughout the central nervous system (whole brain, amygdala, caudate nucleus, cerebellum, cerebral cortex, frontal lobe, hippocampus, medulla oblongata, occipital lobe, putamen, substantia nigra, temporal lobe, thalamus, nucleus accumbens and spinal cord) and increased expression in testis and thymus.
Activates transcription presumably by sequestering inhibitory cofactors away from the promoters.
Binds DNA as a homodimer or a heterodimer. Interacts with KAT5; promoting KAT5 autoacetylation and KAT5 deubiquitination by USP7 (PubMed:25865756).
Stress-induced isoform, counteracts the transcriptional repression of isoform 1.
This protein binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Represses transcription from promoters with ATF sites. It may repress transcription by stabilizing the binding of inhibitory cofactors at the promoter.
Belongs to the glycoside-pentoside-hexuronide (GPH) cation symporter transporter (TC 2.A.2) family.
Proton-associated sucrose transporter. May be able to transport also glucose and fructose.
Defects in TMEM65 may cause a mitochondrial disorder characterized by a complex encephalomyopathic phenotype. Clinical features includ microcephaly, dysmorphic features, psychomotor regression, hypotonia, growth retardation, lactic acidosis, intractable seizures, dyskenetics movements, without cardiomyopathy (PubMed:28295037).
May play an important role in cardiac development and function. May regulate cardiac conduction and the function of the gap junction protein GJA1. May contribute to the stability and proper localization of GJA1 to cardiac intercalated disk thereby regulating gap junction communication (By similarity). May also play a role in the regulation of mitochondrial respiration and mitochondrial DNA copy number maintenance (PubMed:28295037).
Monomer (By similarity). Homodimer (PubMed:26403541). Interacts with GJA1 (By similarity). Interacts weakly with DSP (By similarity).
Predominantly expressed the ventricular tissue (at protein level).
(Microbial infection) Interacts with Staphylococcus aureus protein SSL11.
Associates with the Fc epsilon RI gamma 2 receptor inducing tyrosine phosphorylation of gamma 2.
Binds to the Fc region of immunoglobulins alpha. Mediates several functions including cytokine production.
Isoform A.1, isoform A.2 and isoform A.3 are differentially expressed between blood and mucosal myeloid cells. Isoform A.1, isoform A.2 and isoform A.3 are expressed in monocytes. Isoform A.1 and isoform A.2 are expressed in alveolar macrophages; however only one isoform is expressed at alveolar macrophages surfaces.
In normal adults, expressed predominantly in the placenta and peripheral blood leukocytes. High levels were detected in carcinomas of the bladder, lung, kidney and colon.
Ligand of the EGF receptor/EGFR and ERBB4. Stimulates EGFR and ERBB4 tyrosine phosphorylation (PubMed:9419975). Contributes to inflammation, wound healing, tissue repair, and oocyte maturation by regulating angiogenesis and vascular remodeling and by stimulating cell proliferation (PubMed:24631357).
Interacts with the kinesin-binding proteins TRAK1/OIP106 and TRAK2/GRIF1, forming a link between mitochondria and the trafficking apparatus of the microtubules (PubMed:16630562). Interacts with RAP1GDS1 (PubMed:27716788). Interacts with ARMCX1 (By similarity). Found in a complex with KIF5B, OGT, RHOT2 and TRAK1 (PubMed:24995978).
Mitochondrial GTPase involved in mitochondrial trafficking (PubMed:12482879, PubMed:16630562, PubMed:22396657). Probably involved in control of anterograde transport of mitochondria and their subcellular distribution (PubMed:12482879, PubMed:16630562, PubMed:22396657). Promotes mitochondrial fission during high calcium conditions (PubMed:27716788).
Mitochondrial GTPase involved in mitochondrial trafficking.
Ubiquitinated by PRKN during mitophagy, leading to its degradation and enhancement of mitophagy (PubMed:22396657, PubMed:24896179). Deubiquitinated by USP30 (PubMed:24896179).
Ubiquitously expressed. Expressed at high level in heart and skeletal muscle.
Regulates the trafficking to the somatodendritic compartment and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits. Thought to stabilize the calcium channel in an inactivated (closed) state.
The L-type calcium channel is composed of five subunits: alpha-1, alpha-2/delta, beta and gamma. Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CNIH2, CNIH3, CACNG2, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with AP4M1 and GRIA1; associates GRIA1 with the adaptor protein complex 4 (AP-4) to target GRIA1 to the somatodendritic compartment of neurons.
(Microbial infection) Facilitates viral cytoplasmic entry into activated dendritic cells via recognition of sialylated gangliosides pesent on viral membrane.
By interferon-alpha (PubMed:28129379). By viral infection (PubMed:26358190).
Expressed by macrophages in various tissues. High levels are found in spleen, lymph node, perivascular macrophages in brain and lower levels in bone marrow, liver Kupffer cells and lamina propria of colon and lung. Also expressed by inflammatory macrophages in rheumatoid arthritis.
Interacts with TYROBP. Interacts with CLEC10A (By similarity).
Macrophage-restricted adhesion molecule that mediates sialic-acid dependent binding to lymphocytes, including granulocytes, monocytes, natural killer cells, B-cells and CD8 T-cells. Plays a crucial role in limiting bacterial dissemination by engaging sialylated bacteria to promote effective phagocytosis and antigen presentation for the adaptive immune response (PubMed:12940982, PubMed:33489013). Mediates the uptake of various enveloped viruses via sialic acid recognition and subsequently induces the formation of intracellular compartments filled with virions (VCCs)(PubMed:28129379). In turn, enhances macrophage-to-T-cell transmission of several viruses including HIV-1 or SARS-CoV-2 (PubMed:28129379, PubMed:34782760). Acts as an endocytic receptor mediating clathrin dependent endocytosis. Preferentially binds to alpha-2,3-linked sialic acid (PubMed:12940982). Binds to SPN/CD43 on T-cells (By similarity). May play a role in hemopoiesis. Plays a role in the inhibition of antiviral innate immune by promoting TBK1 degradation via TYROBP and TRIM27-mediated ubiquitination (PubMed:26358190).
Belongs to the DNA mismatch repair MutL/HexB family.
Colon, lymphocytes, breast, lung, spleen, testis, prostate, thyroid, gall bladder and heart.
Component of the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1 (PubMed:26300262). Heterodimer of MLH1 and PMS2 (MutL alpha), MLH1 and PMS1 (MutL beta) or MLH1 and MLH3 (MutL gamma). Forms a ternary complex with MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex (PubMed:10783165). This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains (PubMed:10097147). Interacts with MCM9; the interaction recruits MLH1 to chromatin (PubMed:26300262). Interacts with MCM8 (PubMed:26300262). Interacts with PMS2 (PubMed:11427529, PubMed:22753075). Interacts with MBD4 (PubMed:10097147). Interacts with EXO1 (PubMed:11427529, PubMed:11429708, PubMed:12414623, PubMed:14676842, PubMed:22753075). Interacts with MTMR15/FAN1 (PubMed:20603073).
Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast.
Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis.
Some epigenetic changes can be transmitted unchanged through the germline (termed 'epigenetic inheritance'). Evidence that this mechanism occurs in humans is provided by the identification of individuals in whom 1 allele of the MLH1 gene is epigenetically silenced throughout the soma (implying a germline event). These individuals are affected by Lynch syndrome but does not have identifiable mutations in MLH1, even though it is silenced, which demonstrates that an epimutation can phenocopy a genetic disease.
Highly expressed in lung and trachea (PubMed:12406855, PubMed:12175512, PubMed:12847263). Detected throughout the airway epithelium in lung, with slightly higher expression in large airways (PubMed:12406855). Found in lung submucosal gland acinus where it localizes to serous-like cells (PubMed:12406855). Probably expressed in club cells of the bronchioles (PubMed:12847263). Not detected in other tissues tested (PubMed:12847263).
Homodimer; disulfide-linked (PubMed:24213919). Monomer (PubMed:24213919). Interacts with APOA1 (PubMed:12847263).
Secreted cytokine-like protein (PubMed:12847263). Binds to the scavenger receptor MARCO (PubMed:12847263). Can also bind to pathogens including the Gram-positive bacterium L.monocytogenes, the Gram-negative bacterium P.aeruginosa, and yeast (PubMed:12847263). Strongly inhibits phospholipase A2 (PLA2G1B) activity (PubMed:24213919). Seems to have anti-inflammatory effects in respiratory epithelium (By similarity). Also has anti-fibrotic activity in lung (PubMed:24213919). May play a role in fetal lung development and maturation (PubMed:24213919). Promotes branching morphogenesis during early stages of lung development (PubMed:24213919). In the pituitary, may inhibit production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (By similarity).
Microtubule-binding protein that negatively regulates centriole duplication. Binds to and stabilizes microtubules (PubMed:26337392).
Catalyzes the hydrolysis of N-acetylated amino acids to acetate and free amino acids.
Expression is highest in kidney, strong in brain and weaker in placenta and spleen.
Homodimer. Interacts with SPHK1 (By similarity).
Catalyzes the cleavage of glutathione into 5-oxo-L-proline and a Cys-Gly dipeptide. Acts specifically on glutathione, but not on other gamma-glutamyl peptides (PubMed:27913623). Glutathione depletion is an important factor for apoptosis initiation and execution. Acts as a pro-apoptotic component of the unfolded protein response pathway by mediating the pro-apoptotic effects of the ATF4-ATF3-DDIT3/CHOP cascade (PubMed:19109178). Negative regulator of Notch signaling pathway involved in embryonic neurogenesis: acts by inhibiting Notch cleavage by furin, maintaining Notch in an immature inactive form, thereby promoting neurogenesis in embryos (PubMed:22445366).
Induced by chemical activators of the unfolded protein response (UPR) such as tunicamycin, DTT and thapsigargin.
Interacts with NOTCH1 (via extracellular region).
Broad spectrum monooxygenase that catalyzes the oxygenation of a wide variety of nitrogen- and sulfur-containing compounds including xenobiotics (PubMed:32156684). Catalyzes the S-oxygenation of hypotaurine to produce taurine, an organic osmolyte involved in cell volume regulation as well as a variety of cytoprotective and developmental processes (PubMed:32156684). In vitro, catalyzes the N-oxygenation of trimethylamine (TMA) to produce trimethylamine N-oxide (TMAO) and could therefore participate to the detoxification of this compound that is generated by the action of gut microbiota from dietary precursors such as choline, choline containing compounds, betaine or L-carnitine (By similarity).
Expressed mainly in fetal and adult liver.
Its overexpression strongly inhibits HIV-1 release.
Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. Selectively binds to phosphatidylinositol 3,5-bisphosphate PtdIns(3,5)P2 and PtdIns(3,4)P2 in preference to other phosphoinositides tested. Involved in late stages of cytokinesis. Plays a role in endosomal sorting/trafficking of EGF receptor. Isoform 2 prevents stress-mediated cell death and accumulation of reactive oxygen species when expressed in yeast cells.
Probable core component of the endosomal sorting required for transport complex III (ESCRT-III). ESCRT-III components are thought to multimerize to form a flat lattice on the perimeter membrane of the endosome. Several assembly forms of ESCRT-III may exist that interact and act sequentially. Forms a metastable monomer in solution; its core structure (without part of the putative autoinhibitory C-terminal acidic region) oligomerizes into a flat lattice via two different dimerization interfaces. In vitro, heteromerizes with CHMP2A (but not CHMP4) to form helical tubular structures that expose membrane-interacting sites on the outside whereas VPS4B can associate on the inside of the tubule. May interact with IGFBP7; the relevance of such interaction however remains unclear. Interacts with CHMP2A. Interacts with CHMP4A; the interaction requires the release of CHMP4A autoinhibition. Interacts with VPS4A. Interacts with STAMBP; the interaction appears to relieve the autoinhibition of CHMP3. Interacts with VTA1.
The acidic C-terminus and the basic N-termminus are thought to render the protein in a closed, soluble and inactive conformation through an autoinhibitory intramolecular interaction. The open and active conformation, which enables membrane binding and oligomerization, is achieved by interaction with other cellular binding partners, probably including other ESCRT components.
Belongs to the WD repeat striatin family.
Binds calmodulin in a calcium dependent manner. May function as scaffolding or signaling protein.
Interacts with protein phosphatase 2A (PP2A). Interacts with CDC42BPB (PubMed:25743393).
Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.
Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. Dimer formation with HLA-DQB2, but not with HLA-DQB1, is required for efficient exit from the endoplasmic reticulum (ER). In the ER, forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides. Association with HLA-DMA also occurs in skin Langerhans cells, in post-Golgi compartments.
Restricted to skin Langerhans cells, although some expression at low levels may occur at the surface of B lymphoblastoid cells.
Expressed in fetal tissues with higher expression in fetal heart and kidney.
Transporter that may play a role in monocyte differentiation and lipid transport and homeostasis.
Up-regulated during monocyte differentiation into macrophages. Down-regulated by cholesterol loading of macrophages.
Widely expressed with higher expression in heart.
Expressed at high levels in colon, and cervix and at moderate level in tonsil (PubMed:25585381, PubMed:28900043). Highly reduced expression in primary colon cancer tissues compared with that in adjacent tissues (PubMed:25351403). Highest levels of expression detected in stomach and colon; expressed in epithelium of skin and esophagus, and in some tumor and/or tumor adjacent tissues (TAT), including TAT of esophagus cancer, hepatocellular carcinoma (HCC), squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and invasive ductal carcinoma (IDC) tissues (at protein level) (PubMed:25585381). Highly expressed by inflammatory differentiated keratinocytese (PubMed:35704588).
Has antimicrobial activity against Gram-positive bacteria, including Staphylococcus aureus and Actinomyces spec., and Mycoplasma hominis and lentivirus (PubMed:25585381).
Highly cationic protein that has multiple functions. Acts as a chemotactic factor that mediates lymphocytes recruitment to epithelia through binding and activation of the G-protein coupled receptor GPR15 (PubMed:28900043, PubMed:28936214). May be a tumor suppressor; together with SUSD2 has a growth inhibitory effect on colon cancer cells which includes G1 cell cycle arrest (PubMed:25351403). May regulate keratinocyte proliferation (PubMed:29872130). In addition, through activation of Mas-related G protein-coupled receptors (MRGPRs) contributes to pruritogenesis by activating itch-selective sensory neurons and mast cells degranulation (PubMed:35704588).
Interacts with SUSD2; the interaction is direct.
Up-regulated in the skin of psoriasis and atopic dermatitis patients.
Expressed in brain, placenta, kidney, neuron and skeletal muscle. Expressed in the developing eye, pituitary and brain.
Inhibited by a series a OPs such as mipafox (MPX), phenyl saligenin phosphate (PSP), phenyl dipentyl phosphinate (PDPP), diisopropyl fluorophosphate and paraoxon.
Its specific chemical modification by certain organophosphorus (OP) compounds leads to distal axonopathy.
Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho). This deacylation occurs at both sn-2 and sn-1 positions of PtdCho. Catalyzes the hydrolysis of several naturally occurring membrane-associated lipids (PubMed:11927584). Hydrolyzes lysophospholipids and monoacylglycerols, preferring the 1-acyl to the 2-acyl isomer. Does not catalyze hydrolysis of di- or triacylglycerols or fatty acid amides (PubMed:11927584).
May play a role in microtubule-dependent retrograde axonal transport. May function as the motor for the transport of multivesicular body (MVB)-like organelles in dendrites (By similarity).
Cell surface proteoglycan that bears heparan sulfate. May be involved in the development of kidney tubules and of the central nervous system (By similarity).
Acetylated by CREBBP; leading to ubiquitination and subsequent proteasomal degradation.
Directly interacts with SKP1 and CUL1. Interacts with RNF20.
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex that plays a role in different processes including cell migration, cell proliferation or cytoskeletal reorganization (PubMed:24684802, PubMed:29522376). Mediates RHOA ubiquitination and degradation in a ERK2-dependent manner (PubMed:23871831). Induces RAC1 and RAC3 degradation by the proteasome system and thereby regulates TGFB1-induced E-cadherin down-regulation and cell migration (PubMed:24684802, PubMed:23512198). Mediates also ubiquitination and degradation of IL-33-induced receptor IL1RL1 and subsequently blocks IL-33-mediated apoptosis (By similarity). Within the nucleus, binds to DNA containing unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides (PubMed:29276034). Recruits CDK-mediator to chromatin and targets CDK8 to promoters of silent developmental genes leading to induction of these genes during cell differentiation. In addition, plays a critical role in the recruitment of RNF20 to histone H2B leading to H2B mono-ubiquitination (By similarity).
Ubiquitinated; leading to proteasomal degradation.
E3 ubiquitin-protein ligase. Mediates monoubiquitination at multiple sites of TSG101 in the presence of UBE2D1, but not of UBE2G1, nor UBE2H. Plays a role in the regulation of endosome-to-lysosome trafficking. Impairs MC1R- and MC4R-signaling by competing with GNAS-binding to MCRs and inhibiting agonist-induced cAMP production. Does not inhibit ADRB2-signaling. Does not promote MC1R ubiquitination. Acts also as a negative regulator of hedgehog signaling (By similarity).
Interacts with MC1R and MC4R, but not with TBXA2R. Interacts with TSG101. Interacts with mislocalized cytosolically exposed PRNP; this interaction alters MGRN1 subcellular location and causes lysosomal enlargement (By similarity).
The RING finger is required for ubiquitin ligase activity.
Belongs to the snRNP Sm proteins family. SmF/LSm6 subfamily.
Component of the precatalytic spliceosome (spliceosome B complex) (PubMed:28781166). Component of the U4/U6-U5 tri-snRNP complex, a building block of the precatalytic spliceosome (spliceosome B complex) (PubMed:10523320, PubMed:28781166, PubMed:26912367). The U4/U6-U5 tri-snRNP complex is composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39, plus LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 (PubMed:26912367). LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 form a heptameric, ring-shaped subcomplex (the LSM2-8 complex) that is part of the U4/U6-U5 tri-snRNP complex and the precatalytic spliceosome (PubMed:10523320, PubMed:26912367, PubMed:28781166). Component of the heptameric LSM1-LSM7 complex, which consists of LSM1, LSM2, LSM3, LSM4, LSM5, LSM6 and LSM7 (PubMed:12515382).
Plays a role in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex that is involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex) (PubMed:28781166). The heptameric LSM2-8 complex binds specifically to the 3'-terminal U-tract of U6 snRNA (PubMed:10523320). Component of LSm protein complexes, which are involved in RNA processing and may function in a chaperone-like manner, facilitating the efficient association of RNA processing factors with their substrates. Component of the cytoplasmic LSM1-LSM7 complex, which is thought to be involved in mRNA degradation by activating the decapping step in the 5'-to-3' mRNA decay pathway (Probable).
Component of the probable ECS(SPSB4) E3 ubiquitin-protein ligase complex which contains CUL5, RNF7/RBX2, Elongin BC complex and SPSB4 (PubMed:15601820). Interacts with CUL5; RNF7; ELOB and ELOC (PubMed:15601820). Interacts with MET (PubMed:15713673). Interacts (via B30.2/SPRY domain) with PAWR; this interaction occurs in association with the Elongin BC complex (PubMed:20561531). Interacts with NOS2 (PubMed:21199876). Interacts with EPHB2 (PubMed:28931592).
Substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:21199876, PubMed:15601820). Negatively regulates nitric oxide (NO) production and limits cellular toxicity in activated macrophages by mediating the ubiquitination and proteasomal degradation of NOS2 (PubMed:21199876). Acts as a bridge which links NOS2 with the ECS E3 ubiquitin ligase complex components ELOC and CUL5 (PubMed:21199876). Diminishes EphB2-dependent cell repulsive responses by mediating the ubiquitination and degradation of EphB2/CTF2 (PubMed:28931592). Regulates cellular clock function by mediating the ubiquitin/proteasome-dependent degradation of the circadian transcriptional repressor NR1D1 (PubMed:26392558).
The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes (By similarity). Essential for its ability to link NOS2 and the ECS E3 ubiquitin ligase complex components ELOC and CUL5 (PubMed:21199876).
Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, that displays 6-fold radial symmetry. Part of a ternary complex containing STX5A, NSFL1C and VCP. NSFL1C forms a homotrimer that binds to one end of a VCP homohexamer. The complex binds to membranes enriched in phosphatidylethanolamine-containing lipids and promotes Golgi membrane fusion. Binds to a heterodimer of NPLOC4 and UFD1, binding to this heterodimer inhibits Golgi-membrane fusion (PubMed:26471729). Interaction with VCIP135 leads to dissociation of the complex via ATP hydrolysis by VCP. Part of a ternary complex containing NPLOC4, UFD1 and VCP. Interacts with NSFL1C-like protein p37; the complex has membrane fusion activity and is required for Golgi and endoplasmic reticulum biogenesis. Interacts with SELENOS and SYVN1, as well as with DERL1 (via SHP-box motif), DERL2 and DERL3; which probably transfer misfolded proteins from the ER to VCP (PubMed:15215856, PubMed:16289116, PubMed:16186510, PubMed:16186509, PubMed:16449189, PubMed:27714797). Interacts with SVIP. Component of a complex required to couple retrotranslocation, ubiquitination and deglycosylation composed of NGLY1, SAKS1, AMFR, VCP and RAD23B. Directly interacts with UBXN4 and RNF19A. Interacts with CASR. Interacts with UBE4B and YOD1. Interacts with clathrin. Interacts with RNF103. Interacts with TRIM13 and TRIM21. Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of the endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Interacts directly with AMFR/gp78 (via its VIM). Interacts with RHBDD1 (via C-terminal domain). Interacts with SPRTN; leading to recruitment to stalled replication forks (PubMed:23042607, PubMed:23042605). Interacts with WASHC5. Interacts with UBOX5. Interacts (via N-terminus) with UBXN7, UBXN8, and probably several other UBX domain-containing proteins (via UBX domains); the interactions are mutually exclusive with VIM-dependent interactions such as those with AMFR and SELENOS. Forms a complex with UBQLN1 and UBXN4. Interacts (via the PIM motif) with RNF31 (via the PUB domain) (PubMed:24726327). Interacts with RIGI and RNF125; interaction takes place when RIGI is ubiquitinated via 'Lys-63'-linked ubiquitin on its CARD domains, leading to recruit RNF125 and promote ubiquitination and degradation of RIGI (PubMed:26471729). Interacts with BAG6 (PubMed:21636303). Interacts with UBXN10 (PubMed:26389662). Interacts with UBXN6; the interaction with UBXN6 is direct and competitive with UFD1 (PubMed:19174149, PubMed:19275885). Forms a ternary complex with CAV1 and UBXN6 (PubMed:21822278, PubMed:18656546, PubMed:19174149). Interacts with PLAA, UBXN6 and YOD1; may form a complex involved in macroautophagy (PubMed:27753622). Interacts with ANKZF1 (PubMed:28302725). Interacts with ubiquitin-binding protein FAF1 (PubMed:26842564). Interacts with ZFAND2B (via VIM motif); the interaction is direct (PubMed:24160817, PubMed:26337389). Interacts with ZFAND1 (via its ubiquitin-like region); this interaction occurs in an arsenite-dependent manner (PubMed:29804830). Interacts with CCDC47 (By similarity). Interacts with UBAC2 (By similarity). Interacts with LMBR1L (PubMed:31073040). Interacts with ATXN3 (PubMed:30455355). Interacts with TEX264; bridging VCP to covalent DNA-protein cross-links (DPCs) (PubMed:32152270).
It is unclear how it participates in the recruitment of TP53BP1 at DNA damage sites. According to a first report, participates in the recruitment of TP53BP1 by promoting ubiquitination and removal of L3MBTL1 from DNA damage sites (PubMed:22120668). According to a second report, it acts by removing 'Lys-48'-linked ubiquitination from sites of DNA damage (PubMed:22020440).
Methylation at Lys-315 catalyzed by VCPKMT is increased in the presence of ASPSCR1. Lys-315 methylation may decrease ATPase activity.
Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation (PubMed:26565908). Involved in clearance process by mediating G3BP1 extraction from stress granules (PubMed:29804830, PubMed:34739333). Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites (PubMed:22020440, PubMed:22120668). Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage (PubMed:23042607, PubMed:23042605). Together with SPRTN metalloprotease, involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis (PubMed:32152270). Involved in interstrand cross-link repair in response to replication stress by mediating unloading of the ubiquitinated CMG helicase complex (By similarity). Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal (PubMed:35013556). Required for cytoplasmic retrotranslocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation (PubMed:16186510, PubMed:21118995). Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy (PubMed:20104022, PubMed:27753622). Acts as a negative regulator of type I interferon production by interacting with RIGI: interaction takes place when RIGI is ubiquitinated via 'Lys-63'-linked ubiquitin on its CARD domains, leading to recruit RNF125 and promote ubiquitination and degradation of RIGI (PubMed:26471729). May play a role in the ubiquitin-dependent sorting of membrane proteins to lysosomes where they undergo degradation (PubMed:21822278). May more particularly play a role in caveolins sorting in cells (PubMed:21822278, PubMed:23335559). By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333).
Phosphorylated by tyrosine kinases in response to T-cell antigen receptor activation. Phosphorylated in mitotic cells.
The PIM (PUB-interaction motif) motif mediates interaction with the PUB domain of RNF31.
Olfactory receptor that is activated by the binding of organosulfur odorants with thioether groups such as (methylthio)methanetiol (MTMT) (By similarity). Also binds odorants acetophenone and benzaldehyde (By similarity). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase (By similarity). May be involved in the molecular processes underlying fasciculation and targeting of olfactory axons (By similarity).
Belongs to the MORF4 family-associated protein family.
Expressed in the central nervous system and in dorsal root ganglia neurons. Expressed in peripheral tissues (at protein level).
GTPase tethering membranes through formation of trans-homooligomers and mediating homotypic fusion of endoplasmic reticulum membranes. Functions in endoplasmic reticulum tubular network biogenesis (PubMed:18270207, PubMed:19665976, PubMed:27619977).
Interacts with ZFYVE27 (PubMed:23969831). Interacts with REEP5 (PubMed:32075961).
Encoded in an intron of the gene DPH1/OVCA1 (same strand).
Proteolytically degraded in response to RA and 4HPR treatment in a time- and dose-dependent manner in the promyelocytic leukemia cell line HL-60.
Autophosphorylated (PubMed:20351256). Ligand-binding increases phosphorylation on tyrosine residues and promotes its association with the p85 subunit of phosphatidylinositol 3-kinase (PubMed:20682778).
Monomer and homodimer. Heterodimer with each of the other ERBB receptors (Potential). Interacts with CSPG5 (PubMed:15358134). Interacts with GRB7 (PubMed:9516479). Interacts with MUC1 (PubMed:12939402). Interacts with MYOC (By similarity). Interacts with isoform 2 of PA2G4 (PubMed:11325528, PubMed:16832058). Found in a ternary complex with NRG1 and ITGAV:ITGB3 or ITGA6:ITGB4 (PubMed:20682778).
Overexpressed in a subset of human mammary tumors.
The cytoplasmic part of the receptor may interact with the SH2 or SH3 domains of many signal-transducing proteins.
Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins. Binds to neuregulin-1 (NRG1) and is activated by it; ligand-binding increases phosphorylation on tyrosine residues and promotes its association with the p85 subunit of phosphatidylinositol 3-kinase (PubMed:20682778). May also be activated by CSPG5 (PubMed:15358134). Involved in the regulation of myeloid cell differentiation (PubMed:27416908).
Hypophosphorylated EIF4EBP1 competes with EIF4G1/EIF4G3 to interact with EIF4E; insulin stimulated MAP-kinase (MAPK1 and MAPK3) or mTORC1 phosphorylation of EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation (PubMed:12150926, PubMed:16271312, PubMed:17368478, PubMed:17631896, PubMed:22578813, PubMed:7935836, PubMed:8521827, PubMed:25702871). Interacts (via TOS motif) with RPTOR; promoting phosphorylation by mTORC1 (PubMed:12747827, PubMed:24403073, PubMed:29236692).
Phosphorylated on serine and threonine residues in response to insulin, EGF and PDGF (PubMed:12588975, PubMed:12747827, PubMed:22578813, PubMed:7935836, PubMed:9465032, PubMed:24403073, PubMed:29236692). Phosphorylation at Thr-37, Thr-46, Ser-65 and Thr-70, corresponding to the hyperphosphorylated form, is regulated by mTORC1 and abolishes binding to EIF4E (PubMed:12588975, PubMed:12747827, PubMed:22578813, PubMed:7935836, PubMed:9465032, PubMed:24403073, PubMed:29236692).
Repressor of translation initiation that regulates EIF4E activity by preventing its assembly into the eIF4F complex: hypophosphorylated form competes with EIF4G1/EIF4G3 and strongly binds to EIF4E, leading to repress translation. In contrast, hyperphosphorylated form dissociates from EIF4E, allowing interaction between EIF4G1/EIF4G3 and EIF4E, leading to initiation of translation. Mediates the regulation of protein translation by hormones, growth factors and other stimuli that signal through the MAP kinase and mTORC1 pathways.
Ubiquitinated: when eIF4E levels are low, hypophosphorylated form is ubiquitinated by the BCR(KLHL25) complex, leading to its degradation and serving as a homeostatic mechanism to maintain translation and prevent eIF4E inhibition when eIF4E levels are low. Not ubiquitinated when hyperphosphorylated (at Thr-37, Thr-46, Ser-65 and Thr-70) or associated with eIF4E.
3 different light chains, LC1, LC2 and LC3, can associate with MAP1A and MAP1B proteins.
The precursor molecule is cleaved by ATG4 (ATG4A, ATG4B, ATG4C or ATG4D) to expose the glycine at the C-terminus and form the cytosolic form, LC3-I (PubMed:30661429). The processed form is then activated by APG7L/ATG7, transferred to ATG3 and conjugated to phosphatidylethanolamine (PE) phospholipid to form the membrane-bound form, LC3-II (By similarity). During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid (By similarity). ATG4 proteins also mediate the delipidation of PE-conjugated forms (By similarity). In addition, ATG4B and ATG4D mediate delipidation of ATG8 proteins conjugated to PS during non-canonical autophagy (By similarity).
Ubiquitin-like modifier involved in formation of autophagosomal vacuoles (autophagosomes). Plays a role in mitophagy which contributes to regulate mitochondrial quantity and quality by eliminating the mitochondria to a basal level to fulfill cellular energy requirements and preventing excess ROS production. In response to cellular stress and upon mitochondria fission, binds C-18 ceramides and anchors autophagolysosomes to outer mitochondrial membranes to eliminate damaged mitochondria. While LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation.
(Microbial infection) Acts as a receptor for rhinovirus C.
(Microbial infection) Interacts with rhinovirus C capsid proteins.
Asthma susceptibility may be associated with variants affecting the gene represented in this entry in early childhood asthma with severe exacerbations occurring between 2 and 6 years of age.
Expressed in bronchial epithelium from adults and in fetal lung tissue.
Expressed in heart (at protein level) (PubMed:32075961). Expressed in circumvallate papillae and testis (PubMed:16720576).
Monomer (PubMed:32075961). Homodimer; maybe disulfide-linked (PubMed:32075961). Homotrimer (By similarity). Interacts with ATL1 (By similarity). Interacts with ATL2 (PubMed:19665976). Interacts with ATL3 (PubMed:32075961). Interacts with CKAP4 (PubMed:32075961). Interacts with RTN4 (isoforms A and B) (PubMed:32075961). Interacts with ZFYVE27 (PubMed:23969831).
Plays an essential role in heart function and development by regulating the organization and function of the sarcoplasmic reticulum in cardiomyocytes.
The short lumenal loops between transmembrane domains 1 and 2 and between transmembrane domains 3 and 4 may impart a wedge-like configuration, thus deforming membranes.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ11 subfamily.
Defects in KCNJ11 may contribute to non-insulin-dependent diabetes mellitus (NIDDM), also known as diabetes mellitus type 2.
Interacts with ABCC8/SUR. Interacts with ABCC9/SUR2.
Phosphorylation by MAPK1 results in changes in channel gating that destabilize the closed states and reduce the ATP sensitivity.
This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium (By similarity). Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with ABCC9. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation.
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is composed of 13 subunits: EIF3A, EIF3B, EIF3C, EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L and EIF3M. The eIF-3 complex appears to include 3 stable modules: module A is composed of EIF3A, EIF3B, EIF3G and EIF3I; module B is composed of EIF3F, EIF3H, and EIF3M; and module C is composed of EIF3C, EIF3D, EIF3E, EIF3K and EIF3L. EIF3C of module C binds EIF3B of module A and EIF3H of module B, thereby linking the three modules. EIF3J is a labile subunit that binds to the eIF-3 complex via EIF3B. The eIF-3 complex interacts with RPS6KB1 under conditions of nutrient depletion. Mitogenic stimulation leads to binding and activation of a complex composed of MTOR and RPTOR, leading to phosphorylation and release of RPS6KB1 and binding of EIF4B to eIF-3. Identified in a HCV IRES-mediated translation complex, at least composed of EIF3C, IGF2BP1, RPS3 and HCV RNA-replicon. Interacts with ALKBH4, IFIT1 and IFIT2. Interacts with BZW2/5MP1 (PubMed:34260931).
Involved in pre-mRNA alternative splicing.
Strongly expressed in pancreas, spleen and prostate. Weakly expressed in lung, liver and thymus.
Binds to actin filaments and interacts with phosphotyrosine-containing proteins. Interacts with STARD8 (PubMed:17517630). Interacts with protein phosphatase PPP1CA (PubMed:19826001). Interacts (via N-terminus) with Rho GTPase-activating protein DLC1; the interaction is decreased by phosphorylation of TNS1 (PubMed:19826001, PubMed:20798394, PubMed:26427649). Interacts with tyrosine-phosphorylated proteins BCAR1/p130Cas and PTK2/FAK; the interactions are increased by phosphorylation of TNS1 (PubMed:20798394).
By transforming growth factor beta (TGFB) which is dependent on signaling through the transforming growth factor receptor TGFBR1 but is independent of SMAD signaling (PubMed:28005397). ROCK activation, actin polymerization and MRTFA/MLK1 activation are required for TNS1 inducibility by TGFB (PubMed:28005397).
Extensively phosphorylated on serine and threonine residues in a p38 MAPK-dependent manner which reduces interaction with DLC1 and increases interaction with tyrosine-phosphorylated proteins including BCAR1/p130cas and PTK2/FAK. The majority of the phosphorylated Ser/Thr residues are immediately adjacent to a proline residue. Also phosphorylated on tyrosine residues.
In the lung, detected in the alveolar septa (at protein level) (PubMed:28005397). Ubiquitous (PubMed:11023826).
May act as a protein phosphatase and/or a lipid phosphatase (Probable). Involved in fibrillar adhesion formation (PubMed:21768292, PubMed:28005397). Essential for myofibroblast differentiation and myofibroblast-mediated extracellular matrix deposition (PubMed:28005397). Enhances RHOA activation in the presence of DLC1 (PubMed:26427649). Plays a role in cell polarization and migration (PubMed:19826001). May be involved in cartilage development and in linking signal transduction pathways to the cytoskeleton (PubMed:21768292).
Expressed at highest levels in heart. Also detected in kidney, lung, small intestine and colon. Expressed at very low levels, if any, in leukocytes, thymus and skeletal muscle.
Acts as an effector of RAC1 (PubMed:31871319). Associates with CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation (PubMed:29395067). May also play a role in miRNA silencing machinery (PubMed:29395067).
Detected in fetal brain, testis, and skeletal muscle, and at a lower level in adult brain, leukocytes, liver, heart, kidney, spleen, ovary and lung. Isoform 2 is found in all tissues except kidney.
Deubiquitinase that specifically cleaves 'Lys-63'- and linear 'Met-1'-linked polyubiquitin chains and is involved in NF-kappa-B activation and TNF-alpha-induced necroptosis (PubMed:18636086, PubMed:26670046, PubMed:27458237, PubMed:26997266, PubMed:27591049, PubMed:29291351, PubMed:18313383, PubMed:32185393). Negatively regulates NF-kappa-B activation by deubiquitinating upstream signaling factors (PubMed:12917689, PubMed:12917691, PubMed:32185393). Contributes to the regulation of cell survival, proliferation and differentiation via its effects on NF-kappa-B activation (PubMed:12917690). Negative regulator of Wnt signaling (PubMed:20227366). Inhibits HDAC6 and thereby promotes acetylation of alpha-tubulin and stabilization of microtubules (PubMed:19893491). Plays a role in the regulation of microtubule dynamics, and thereby contributes to the regulation of cell proliferation, cell polarization, cell migration, and angiogenesis (PubMed:18222923, PubMed:20194890). Required for normal cell cycle progress and normal cytokinesis (PubMed:17495026, PubMed:19893491). Inhibits nuclear translocation of NF-kappa-B (PubMed:18636086). Plays a role in the regulation of inflammation and the innate immune response, via its effects on NF-kappa-B activation (PubMed:18636086). Dispensable for the maturation of intrathymic natural killer cells, but required for the continued survival of immature natural killer cells (By similarity). Negatively regulates TNFRSF11A signaling and osteoclastogenesis (By similarity). Involved in the regulation of ciliogenesis, allowing ciliary basal bodies to migrate and dock to the plasma membrane; this process does not depend on NF-kappa-B activation (By similarity). Ability to remove linear ('Met-1'-linked) polyubiquitin chains regulates innate immunity and TNF-alpha-induced necroptosis: recruited to the LUBAC complex via interaction with SPATA2 and restricts linear polyubiquitin formation on target proteins (PubMed:26997266, PubMed:26670046, PubMed:27458237, PubMed:27591049). Regulates innate immunity by restricting linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation (PubMed:26997266). Involved in TNF-alpha-induced necroptosis by removing linear ('Met-1'-linked) polyubiquitin chains from RIPK1, thereby regulating the kinase activity of RIPK1 (By similarity). Negatively regulates intestinal inflammation by removing 'Lys-63' linked polyubiquitin chain of NLRP6, thereby reducing the interaction between NLRP6 and PYCARD/ASC and formation of the NLRP6 inflammasome (By similarity). Removes 'Lys-63' linked polyubiquitin chain of MAP3K7, which inhibits phosphorylation and blocks downstream activation of the JNK-p38 kinase cascades (PubMed:29291351). Removes also 'Lys-63'-linked polyubiquitin chains of MAP3K1 and MA3P3K3, which inhibit their interaction with MAP2K1 and MAP2K2 (PubMed:34497368).
Inhibited by phosphorylation at serine residues.
Interacts (via CAP-Gly domain) with IKBKG/NEMO (via proline-rich C-terminal region) (PubMed:12917689, PubMed:12917690, PubMed:12917691, PubMed:15341735). Interacts with TRAF2 and TRIP (PubMed:12917691, PubMed:14676304). Interacts with PLK1, DVL1, DVL3, MAVS, TBK1, IKKE and RIGI (PubMed:17495026, PubMed:18636086, PubMed:20227366, PubMed:32185393). Interacts (via CAP-Gly domain) with microtubules (PubMed:19893491). Interacts with HDAC6 and BCL3 (PubMed:19893491). Interacts with MAP3K7 (By similarity). Identified in a complex with TRAF6 and SQSTM1 (By similarity). Interacts with OPTN and SQSTM1 (PubMed:32185393). Interacts with CEP350 (PubMed:25134987). Interacts with RNF31; the interaction is indirect and is mediated via SPATA2 (PubMed:26997266). Interacts with SPATA2 (via the PUB domain); the interaction is direct and recruits CYLD to the LUBAC complex, thereby regulating TNF-alpha-induced necroptosis (PubMed:27307491, PubMed:27458237, PubMed:27545878, PubMed:27591049).
Phosphorylated on several serine residues by IKKA and/or IKKB in response to immune stimuli. Phosphorylation requires IKBKG. Phosphorylation abolishes TRAF2 deubiquitination, interferes with the activation of Jun kinases, and strongly reduces CD40-dependent gene activation by NF-kappa-B.
Ubiquitinated. Polyubiquitinated in hepatocytes treated with palmitic acid. Ubiquitination is mediated by E3 ligase TRIM47 and leads to proteasomal degradation.
Homodimer. Component of the SIN3 histone deacetylase (HDAC) corepressor complex. Interacts with SIN3A. Interaction with SIN3B enhances the interaction between SIN3B and HDAC1 to form a complex (By similarity). Interacts with HCFC1. Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3/SAP45, ARID4B/SAP180, HDAC1 and HDAC2. Interacts with USP17L2; the interaction is direct. Interacts with FOXK2 (PubMed:25805136).
Polyubiquitinated. 'Lys-63'-polyubiquitinated SUDS3 positively regulates histone deacetylation. Regulated through deubiquitination by USP17L2/USP17 that cleaves 'Lys-63'-linked ubiquitin chains.
Regulatory protein which represses transcription and augments histone deacetylase activity of HDAC1. May have a potential role in tumor suppressor pathways through regulation of apoptosis. May function in the assembly and/or enzymatic activity of the mSin3A corepressor complex or in mediating interactions between the complex and other regulatory complexes.
The C-terminus is involved in transcriptional repression by HDAC-independent mechanisms.
Catalyzes the formation of fatty acid-cholesterol esters, which are less soluble in membranes than cholesterol (PubMed:16154994, PubMed:16647063, PubMed:9020103, PubMed:32433614, PubMed:32433613, PubMed:32944968). Plays a role in lipoprotein assembly and dietary cholesterol absorption (PubMed:16154994, PubMed:9020103). Utilizes oleoyl-CoA ((9Z)-octadecenoyl-CoA) preferentially as susbstrate: shows a higher activity towards an acyl-CoA substrate with a double bond at the delta-9 position (9Z) than towards saturated acyl-CoA or an unsaturated acyl-CoA with a double bond at the delta-7 (7Z) or delta-11 (11Z) positions (PubMed:11294643, PubMed:32433614).
Cholesterol O-acyltransferase activity is inhibited by nevanimibe.
Each protomer consists of 9 transmembrane segments, which enclose a cytosolic tunnel and a transmembrane tunnel that converge at the predicted catalytic site: acyl-CoA enters the active site through the cytosolic tunnel, whereas cholesterol enters from the side through the transmembrane tunnel.
Highly activated by the presence of cholesterol.
Homotetramer; composed of two homodimers (PubMed:32433614, PubMed:32433613). Interacts with UBIAD1 (PubMed:23169578).
Expressed in small intestine, kidney and brain.
Mediates transcriptional and post-transcriptional regulation of SLC5A1. Inhibits a dynamin and PKC-dependent exocytotic pathway of SLC5A1. Also involved in transcriptional regulation of SLC22A2. Exhibits glucose-dependent, short-term inhibition of SLC5A1 and SLC22A2 by inhibiting the release of vesicles from the trans-Golgi network.
The tripeptides QCP and QSP mediate post-transcriptional down-regulation of SLC5A1 at the trans-Golgi network. They inhibit a monosaccharide-dependent exocytotic pathway of SLC5A1.
Component of the BCR(KLHL2) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL2 and RBX1 (PubMed:23838290). Binds actin (PubMed:10397770). Interacts with KLHL12 (PubMed:15383316). Interacts (via N-terminus) with FYN (via SH3 domain) (PubMed:15715669).
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that mediates the ubiquitination of target proteins, such as NPTXR, WNK1, WNK3 and WNK4, leading most often to their proteasomal degradation (PubMed:23838290). The BCR(KLHL2) complex catalyzes ubiquitination and degradation of NPTXR (By similarity). Responsible for degradative ubiquitination of the WNK kinases WNK1, WNK3 and WNK4 (PubMed:23838290). Plays a role in the reorganization of the actin cytoskeleton (PubMed:10397770). Promotes growth of cell projections in oligodendrocyte precursors (PubMed:15715669).
Ubiquitous. Detected throughout the brain.
Belongs to the NUP186/NUP192/NUP205 family.
Part of the nuclear pore complex (NPC) (PubMed:9348540, PubMed:15229283). Forms a complex with NUP35, NUP93, NUP155 and lamin B (PubMed:15703211, PubMed:26878725). Does not interact with TPR (PubMed:12802065).
Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance (PubMed:9348540). May anchor NUP62 and other nucleoporins, but not NUP153 and TPR, to the NPC (PubMed:15229283).
Cytokine that binds to TNFRSF6/FAS, a receptor that transduces the apoptotic signal into cells (PubMed:26334989, PubMed:9228058). Involved in cytotoxic T-cell-mediated apoptosis, natural killer cell-mediated apoptosis and in T-cell development (PubMed:9228058, PubMed:7528780, PubMed:9427603). Initiates fratricidal/suicidal activation-induced cell death (AICD) in antigen-activated T-cells contributing to the termination of immune responses (By similarity). TNFRSF6/FAS-mediated apoptosis has also a role in the induction of peripheral tolerance (By similarity). Binds to TNFRSF6B/DcR3, a decoy receptor that blocks apoptosis (PubMed:27806260).
Cytoplasmic form induces gene transcription inhibition.
Homotrimer (PubMed:27806260). Interacts with ARHGAP9, BAIAP2L1, BTK, CACNB3, CACNB4, CRK, DLG2, DNMBP, DOCK4, EPS8L3, FGR, FYB1, FYN, HCK, ITK, ITSN2, KALRN, LYN, MACC1, MIA, MPP4, MYO15A, NCF1, NCK1, NCK2, NCKIPSD, OSTF1, PIK3R1, PSTPIP1, RIMBP3C, SAMSN1, SH3GL3, SH3PXD2B, SH3PXD2A, SH3RF2, SKAP2, SNX33, SNX9, SORBS3, SPTA1, SRC, SRGAP1, SRGAP2, SRGAP3, TEC, TJP3 and YES1.
Induces FAS-mediated activation of NF-kappa-B, initiating non-apoptotic signaling pathways (By similarity). Can induce apoptosis but does not appear to be essential for this process (PubMed:27806260).
N-glycosylated (PubMed:9228058). Glycosylation enhances apoptotic activity (PubMed:27806260).
Phosphorylated by FGR on tyrosine residues; this is required for ubiquitination and subsequent internalization.
The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form undergoes two successive intramembrane proteolytic cleavages. The first one is processed by ADAM10 producing an N-terminal fragment, which lacks the receptor-binding extracellular domain. This ADAM10-processed FasL (FasL APL) remnant form is still membrane anchored and further processed by SPPL2A that liberates the FasL intracellular domain (FasL ICD). FasL shedding by ADAM10 is a prerequisite for subsequent intramembrane cleavage by SPPL2A in T-cells.
Binds 2 divalent metal cations per subunit. Site 2 has a preference for magnesium and/or manganese ions.
Expressed in brain, heart, lung and skeletal muscle (PubMed:17519386). Expressed in white blood cells (PubMed:8392015).
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes (PubMed:15260978). May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.
Belongs to the pterin-4-alpha-carbinolamine dehydratase family.
Involved in tetrahydrobiopterin biosynthesis. Seems to both prevent the formation of 7-pterins and accelerate the formation of quinonoid-BH2 (By similarity).
Regulates the dimerization of homeodomain protein HNF-1-alpha and enhances its transcriptional activity.
Acts as an acute myeloid leukemia-associated antigen and may be used as a potential immunotherapy target for leukemia (PubMed:17686061, PubMed:19179477).
Belongs to an adhesion system, which plays a role in the organization of homotypic, interneuronal and heterotypic cell-cell adherens junctions (AJs). May connect the nectin-afadin and E-cadherin-catenin system through alpha-actinin and may be involved in organization of the actin cytoskeleton at AJs through afadin and alpha-actinin (By similarity). Involved in cell movement: localizes at the leading edge of moving cells in response to PDGF and is required for the formation of the leading edge and the promotion of cell movement, possibly via activation of Rac signaling (By similarity). Acts as a centrosome maturation factor, probably by maintaining the integrity of the pericentriolar material and proper microtubule nucleation at mitotic spindle poles. The function seems to implicate at least in part WRAP73; the SSX2IP:WRAP73 complex is proposed to act as regulator of spindle anchoring at the mitotic centrosome (PubMed:23816619, PubMed:26545777). Involved in ciliogenesis (PubMed:24356449). It is required for targeted recruitment of the BBSome, CEP290, RAB8, and SSTR3 to the cilia (PubMed:24356449).
Both the N-terminal (up to position 79) and the C-terminal (from position 304) sequences are required for interaction with SSX2.
Expressed in interphase and M phase cells. Down-regulated by the miRNA miR338-3p.
Interacts with afadin and alpha-actinin (By similarity). Interacts with VAV2 (By similarity). Interacts with SSX2 and SSX3. Does not interact with SSX1 and SSX4 (PubMed:12007189). Interacts with PCM1 (By similarity). Interacts with WRAP73 (PubMed:26545777).
Widely expressed, with the highest expression in brain, intermediate expression in kidney, testis, spinal cord, liver, heart, lung, skeletal muscle, ovary, fetal liver and fetal brain, and little to no expression in pancreas and spleen. All specific brain regions showed intermediate to high expression, with highest expression in amygdala. Also expressed in fetal tissues, mainly in liver and brain.
Associated to surface IgM-receptor; may be involved in signal transduction. Involved in regulation of the catalytic activity of the phosphatases PP2A, PP4 and PP6 by protecting their partially folded catalytic subunits from degradative polyubiquitination until they associate with regulatory subunits.
Interacts with partially folded PPP2CA, but not with the fully active protein. Interacts with PPP2CB, and with PP4 and PP6. Interacts with MID1 and MID2. Interacts with ubiquitin.
Monoubiquitination by MID1 triggers calpain-mediated cleavage and switches IGBP1 activity from protective to destructive.
The UIM domain is required for protective effect on PP2A.
Ubiquitously expressed with highest levels in heart, skeletal muscle and pancreas.
Acts as a transcriptional activator by binding to an A/T-rich sequence, the FLAT element, in the insulin gene promoter. Required for development of the roof plate and, in turn, for specification of dorsal cell fates in the CNS and developing vertebrae (By similarity).
Isoform 1 is expressed in many tissues. Not found in heart, liver, spleen and testis. Relatively highly expressed in fetal brain. Isoform LMX1A-4AB is expressed in testis.
Component of the MSL histone acetyltransferase complex at least composed of the KAT8/MOF, MSL1/hampin, MSL2 and MSL3 (PubMed:20018852, PubMed:20657587, PubMed:21217699, PubMed:22547026, PubMed:16543150). Interacts (via the MRG domain) with MSL1 and KAT8/MOF (PubMed:21217699, PubMed:30224647).
Expressed in many tissues including liver, pancreas, heart, lung, kidney, skeletal muscle, brain, and placenta, with highest expression in skeletal muscle and heart.
Has a role in chromatin remodeling and transcriptional regulation (PubMed:20018852, PubMed:20657587, PubMed:20943666, PubMed:21217699, PubMed:30224647). Has a role in X inactivation (PubMed:21217699). Component of the MSL complex which is responsible for the majority of histone H4 acetylation at 'Lys-16' which is implicated in the formation of higher-order chromatin structure (PubMed:16227571, PubMed:20657587, PubMed:16543150, PubMed:30224647). Specifically recognizes histone H4 monomethylated at 'Lys-20' (H4K20Me1) in a DNA-dependent manner and is proposed to be involved in chromosomal targeting of the MSL complex (PubMed:20657587, PubMed:20943666).
By TNF and bacterial lipopolysaccharides (LPS).
By its binding to cytohesin-1 (CYTH1), it modifies activation of ARFs by CYTH1 and its precise function may be to sequester CYTH1 in the cytoplasm.
Expressed in lymph nodes, thymus, spleen, lung, peripheral blood leukocytes and bone marrow.
Interacts with ROPN1 and ROPN1L. Interacts with QRICH2 (PubMed:30683861).
May function as a regulator of both motility- and head-associated functions such as capacitation and the acrosome reaction.
RII-binding site, predicted to form an amphipathic helix, could participate in protein-protein interactions with a complementary surface on the R-subunit dimer.
Testis specific; only expressed in spermatids.
Catalyzes the regio and stereo-specific incorporation of a single molecule of dioxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species (PubMed:9837935, PubMed:9618483, PubMed:21558561). In the skin, acts upstream of ALOXE3 on the lineolate moiety of esterified omega-hydroxyacyl-sphingosine (EOS) ceramides to produce an epoxy-ketone derivative, a crucial step in the conjugation of omega-hydroxyceramide to membrane proteins (PubMed:21558561). Therefore plays a crucial role in the synthesis of corneocytes lipid envelope and the establishment of the skin barrier to water loss (PubMed:21558561). May also play a role in the regulation of the expression of airway mucins (PubMed:22441738).
Expressed in B-cells, hair follicles, foreskin keratinocytes and adult skin. Also expressed in psoriatic tissue.
A chromosomal aberration involving FHIT has been found in a lymphoblastoid cell line established from a family with renal cell carcinoma and thyroid carcinoma. Translocation t(3;8)(p14.2;q24.1) with RNF139. Although the 3p14.2 breakpoint has been shown to interrupt FHIT in its 5-prime non-coding region, it is unlikely that FHIT is causally related to renal or other malignancies.
Associated with digestive tract cancers. Numerous tumor types are found to have aberrant forms of FHIT protein due to deletions in a coding region of chromosome 3p14.2 including the fragile site locus FRA3B.
Homodimer. Interacts with UBE2I. Interacts with MDM2. Interacts with CTNNB1. Identified in a complex with CTNNB1 and LEF1.
Low levels expressed in all tissues tested. Phospho-FHIT observed in liver and kidney, but not in brain and lung. Phospho-FHIT undetected in all tested human tumor cell lines.
Phosphorylation at Tyr-114 by SRC is required for induction of apoptosis.
Possesses dinucleoside triphosphate hydrolase activity (PubMed:12574506, PubMed:15182206, PubMed:8794732, PubMed:9323207, PubMed:9576908, PubMed:9543008). Cleaves P(1)-P(3)-bis(5'-adenosyl) triphosphate (Ap3A) to yield AMP and ADP (PubMed:12574506, PubMed:15182206, PubMed:8794732, PubMed:9323207, PubMed:9576908, PubMed:9543008). Can also hydrolyze P(1)-P(4)-bis(5'-adenosyl) tetraphosphate (Ap4A), but has extremely low activity with ATP (PubMed:8794732). Exhibits adenylylsulfatase activity, hydrolyzing adenosine 5'-phosphosulfate to yield AMP and sulfate (PubMed:18694747). Exhibits adenosine 5'-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5'monophosphoramidate (AMP-NH2) to yield AMP and NH2 (PubMed:18694747). Exhibits adenylylsulfate-ammonia adenylyltransferase, catalyzing the ammonolysis of adenosine 5'-phosphosulfate resulting in the formation of adenosine 5'-phosphoramidate (PubMed:26181368). Also catalyzes the ammonolysis of adenosine 5-phosphorofluoridate and diadenosine triphosphate (PubMed:26181368). Modulates transcriptional activation by CTNNB1 and thereby contributes to regulate the expression of genes essential for cell proliferation and survival, such as CCND1 and BIRC5 (PubMed:18077326). Plays a role in the induction of apoptosis via SRC and AKT1 signaling pathways (PubMed:16407838). Inhibits MDM2-mediated proteasomal degradation of p53/TP53 and thereby plays a role in p53/TP53-mediated apoptosis (PubMed:15313915). Induction of apoptosis depends on the ability of FHIT to bind P(1)-P(3)-bis(5'-adenosyl) triphosphate or related compounds, but does not require its catalytic activity, it may in part come from the mitochondrial form, which sensitizes the low-affinity Ca(2+) transporters, enhancing mitochondrial calcium uptake (PubMed:12574506, PubMed:19622739). Functions as tumor suppressor (By similarity).
Oligomeric complex. Binds to CDC42. Interacts with JAGN1. Interacts with TMED10 (via cytoplasmic domain) (PubMed:11056392).
The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. Coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins.
The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. Coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. In mammals, the coatomer can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins; the complex also influences the Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors (By similarity).
Endoplasmic reticulum (ER)-anchored autophagy regulator which exists in an inactive state under basal conditions but is activated following cellular stress (PubMed:34338405). When activated, induces ER fragmentation and mediates ER delivery into lysosomes through sequestration into autophagosomes via interaction with ATG8 family proteins (PubMed:34338405). Promotes ER membrane curvature and ER tubulation required for subsequent ER fragmentation and engulfment into autophagosomes (PubMed:33826365). Required for collagen quality control in a LIR motif-dependent manner (By similarity). Mediates NRF1-enhanced neurite outgrowth (PubMed:26040720).
Induced by amino acid starvation but not by endoplasmic reticulum stress.
Interacts with ATG8 family modifier proteins MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAP, GABARAPL1 and GABARAPL2 (PubMed:26040720, PubMed:34338405). Interacts with CANX (PubMed:34338405). Interacts with RTN4 isoform B (PubMed:33826365).
The LIR motif interacts with ATG8 family proteins.
Component of the SET1B complex composed of the catalytic subunit SETD1B, WDR5, WDR82, RBBP5, ASH2L/ASH2, CXXC1/CFP1, HCFC1, DPY30 homotrimer and BOD1.
Required for proper chromosome biorientation through the detection or correction of syntelic attachments in mitotic spindles.
Probable component of the exon junction complex (EJC), a multiprotein complex that associates immediately upstream of the exon-exon junction on mRNAs and serves as a positional landmark for the intron exon structure of genes and directs post-transcriptional processes in the cytoplasm such as mRNA export, nonsense-mediated mRNA decay (NMD) or translation.
Probable component of the exon junction complex (EJC); the association is RNA-dependent.
Thought to be involved during neural development in axonal navigation at the ventral midline of the neural tube (By similarity). In spinal cord development plays a role in guiding commissural axons probably by preventing premature sensitivity to Slit proteins thus inhibiting Slit signaling through ROBO1 (By similarity). Required for hindbrain axon midline crossing (PubMed:15105459).
It is uncertain whether Met-1, Met-14 or Met-24 is the initiator.
May play an important role in spermatogenesis and/or testis development.
Was originally thought to be the H-Y antigen.
Belongs to the universal ribosomal protein uS3 family.
Component of the 40S small ribosomal subunit (PubMed:8706699, PubMed:23636399). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Interacts with HNRPD (PubMed:24423872). Interacts with PRMT1; the interaction methylates RPS3 (PubMed:19460357). Interacts with SUMO1; the interaction sumoylates RPS3 (PubMed:21968017). Interacts with UBC9 (PubMed:21968017). Interacts with CDK1; the interaction phosphorylates RPS3 (PubMed:21871177). Interacts with PRKCD; the interaction phosphorylates RPS3 (PubMed:19059439). Interacts with PKB/AKT; the interaction phosphorylates RPS3 (PubMed:20605787). Interacts with E2F1; the interaction occurs in the absence of nerve growth factor and increases transcription of pro-apoptotic proteins BCL2L11/BIM and HRK/Dp5 (PubMed:20605787). Interacts with the base excision repair proteins APEX1 and OGG1; interaction with OGG1 increases OGG1 N-glycosylase activity (PubMed:15518571). Interacts with UNG; the interaction increases the uracil excision activity of UNG1 (PubMed:18973764). Interacts with HSP90; the interaction prevents the ubiquitination and proteasome-dependent degradation of RPS3 and is suppressed by increased ROS levels (PubMed:16314389). Interacts with TOM70; the interaction promotes translocation of RPS3 to the mitochondrion (PubMed:23911537). Interacts (via N-terminus) with RELA (via N-terminus); the interaction enhances the DNA-binding activity of the NF-kappa-B p65-p50 complex (PubMed:18045535). Interacts with NFKBIA; the interaction is direct and may bridge the interaction between RPS3 and RELA (PubMed:24457201). Interacts with IKKB; the interaction phosphorylates RPS3 and enhances its translocation to the nucleus (PubMed:21399639). Interacts (via KH domain) with MDM2 and TP53 (PubMed:19656744). Interacts with TRADD (PubMed:22510408). Interacts (via N-terminus) with E.coli O157:H7 (strain EDL933) nleH1 and nleH2; the interaction with nleH1 inhibits phosphorylation by IKKB, reduces RPS3 nuclear abundance and inhibits transcriptional activation by the NF-kappa-B p65-p50 complex (PubMed:20041225, PubMed:21399639). Interacts with ASCC3 (PubMed:28757607). Identified in a HCV IRES-mediated translation complex, at least composed of EIF3C, IGF2BP1, RPS3 and HCV RNA-replicon (PubMed:19541769). Interacts with CRY1 (By similarity).
Component of the small ribosomal subunit (PubMed:8706699, PubMed:23636399). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:8706699, PubMed:23636399). Has endonuclease activity and plays a role in repair of damaged DNA (PubMed:7775413). Cleaves phosphodiester bonds of DNAs containing altered bases with broad specificity and cleaves supercoiled DNA more efficiently than relaxed DNA (PubMed:15707971). Displays high binding affinity for 7,8-dihydro-8-oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species (ROS) (PubMed:14706345). Has also been shown to bind with similar affinity to intact and damaged DNA (PubMed:18610840). Stimulates the N-glycosylase activity of the base excision protein OGG1 (PubMed:15518571). Enhances the uracil excision activity of UNG1 (PubMed:18973764). Also stimulates the cleavage of the phosphodiester backbone by APEX1 (PubMed:18973764). When located in the mitochondrion, reduces cellular ROS levels and mitochondrial DNA damage (PubMed:23911537). Has also been shown to negatively regulate DNA repair in cells exposed to hydrogen peroxide (PubMed:17049931). Plays a role in regulating transcription as part of the NF-kappa-B p65-p50 complex where it binds to the RELA/p65 subunit, enhances binding of the complex to DNA and promotes transcription of target genes (PubMed:18045535). Represses its own translation by binding to its cognate mRNA (PubMed:20217897). Binds to and protects TP53/p53 from MDM2-mediated ubiquitination (PubMed:19656744). Involved in spindle formation and chromosome movement during mitosis by regulating microtubule polymerization (PubMed:23131551). Involved in induction of apoptosis through its role in activation of CASP8 (PubMed:14988002). Induces neuronal apoptosis by interacting with the E2F1 transcription factor and acting synergistically with it to up-regulate pro-apoptotic proteins BCL2L11/BIM and HRK/Dp5 (PubMed:20605787). Interacts with TRADD following exposure to UV radiation and induces apoptosis by caspase-dependent JNK activation (PubMed:22510408).
Endonuclease activity is inhibited by MgCl2 on apurinic/apyrimidinic DNA but not on UV-irradiated DNA.
Methylation by PRMT1 is required for import into the nucleolus and for ribosome assembly.
Phosphorylation at Thr-221 by CDK1 occurs mainly in G2/M phase (PubMed:21871177). Phosphorylation by PRKCD occurs on a non-ribosomal-associated form which results in translocation of RPS3 to the nucleus and enhances its endonuclease activity (PubMed:19059439). Phosphorylated on Ser-209 by IKKB in response to activation of the NF-kappa-B p65-p50 complex which enhances the association of RPS3 with importin-alpha and mediates the nuclear translocation of RPS3 (PubMed:21399639). Phosphorylation by MAPK is required for translocation to the nucleus following exposure of cells to DNA damaging agents such as hydrogen peroxide (PubMed:17560175). Phosphorylation by PKB/AKT mediates RPS3 nuclear translocation, enhances RPS3 endonuclease activity and suppresses RPS3-induced neuronal apoptosis (PubMed:20605787).
Sumoylation by SUMO1 enhances protein stability through increased resistance to proteolysis. Sumoylation occurs at one or more of the three consensus sites, Lys-18, Lys-214 and Lys-230.
Ubiquitinated; ubiquitination is prevented by interaction with HSP90 which stabilizes the protein (PubMed:16314389). Monoubiquitinated at Lys-214 by RNF10 and ZNF598 when a ribosome has stalled during translation of poly(A) sequences, leading to preclude synthesis of a long poly-lysine tail and initiate the ribosome quality control (RQC) pathway to degrade the potentially detrimental aberrant nascent polypeptide (PubMed:28065601, PubMed:28132843, PubMed:32011234, PubMed:34348161, PubMed:34469731). Deubiquitinated at Lys-214 by USP10, preventing degradation by the proteasome and promoting 40S ribosome subunit recycling following ribosome dissociation (PubMed:31981475, PubMed:34469731).
Component of the ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, a VPS37 protein (VPS37A to -D) and MVB12A or MVB12B in a 1:1:1:1 stoichiometry. Interacts with TSG101, VPS28 and HGS. Component of an ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, VPS37A and UBAP1 in a 1:1:1:1 stoichiometry.
Widely expressed. Examined tissues include heart, brain, placenta, liver, skeletal muscle, kidney and pancreas. More abundant in liver. Strongly decreased or undetected in hepatomas.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A9 subfamily.
Expressed in the brain, kidney, pancreas, lung, placenta and liver.
Interacts with EXOC1; interaction increases the transporter capacity of SLC6A9 probably by promoting its insertion into the cell membrane (By similarity). Interacts with EXOC3 and EXOC4 (By similarity).
Sodium- and chloride-dependent glycine transporter (PubMed:8183239). Essential for regulating glycine concentrations at inhibitory glycinergic synapses.
Sodium- and chloride-dependent glycine transporter.
Highly expressed in fetal oocytes, and in hematopoietic cells of the fetal liver and bone marrow (at protein level).
Highly expressed in germinal center cells of the spleen, tonsil, and reactive lymph nodes, and in the proliferating basal layer of squamous epithelium of tonsil, esophagus, oropharynx, larynx and cervix. Expressed in cytotrophoblastic cells of the placenta and exocrine cells of the pancreas (at protein level). Highly expressed in testis, where expression is restricted to maturing spermatocytes.
Interacts directly with FANCE and FANCI. Interacts with USP1 and MEN1. The ubiquitinated form specifically interacts with BRCA1 and BLM. Both the nonubiquitinated and the monoubiquitinated forms interact with BRCA2; this interaction is mediated by phosphorylated FANCG and the complex also includes XCCR3. The ubiquitinated form specifically interacts with MTMR15/FAN1 (via UBZ-type zinc finger), leading to recruit MTMR15/FAN1 to sites of DNA damage. Interacts with DCLRE1B/Apollo (PubMed:11239454, PubMed:12093742, PubMed:12649160, PubMed:12874027, PubMed:15115758, PubMed:15199141, PubMed:15257300, PubMed:15694335, PubMed:17412408, PubMed:17460694, PubMed:18212739, PubMed:18469862, PubMed:20603015, PubMed:20603016, PubMed:20603073). Interacts with POLN (PubMed:19995904). Interacts with UHRF1 and UHRF2; these interactions promote FANCD2 activation (PubMed:30335751).
Less abundant than isoform 2, may be not functional.
Monoubiquitinated on Lys-561 during S phase and upon genotoxic stress by FANCL in complex with E2 ligases UBE2T or UBE2W (isoform 1 and isoform 2). Deubiquitinated by USP1 as cells enter G2/M, or once DNA repair is completed. Monoubiquitination requires the joint intervention of the FANC core complex, including FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, and FANCM, and proteins involved in cell cycle checkpoints and DNA repair, including RPA1, ATR, CHEK1 and BRCA1, and is mediated by FANCL/PHF9. Ubiquitination is required for binding to chromatin, interaction with BRCA1, BRCA2 and MTMR15/FAN1, DNA repair, and normal cell cycle progression, but not for phosphorylation on Ser-222 or interaction with MEN1.
Phosphorylated in response to various genotoxic stresses by ATM and/or ATR. Upon ionizing radiation, phosphorylated by ATM on Ser-222 and Ser-1404. Phosphorylation on Ser-222 is required for S-phase checkpoint activation, but not for ubiquitination, foci formation, or DNA repair. In contrast, phosphorylation by ATR on other sites may be required for ubiquitination and foci formation.
Required for maintenance of chromosomal stability. Promotes accurate and efficient pairing of homologs during meiosis. Involved in the repair of DNA double-strand breaks, both by homologous recombination and single-strand annealing. May participate in S phase and G2 phase checkpoint activation upon DNA damage. Plays a role in preventing breakage and loss of missegregating chromatin at the end of cell division, particularly after replication stress. Required for the targeting, or stabilization, of BLM to non-centromeric abnormal structures induced by replicative stress. Promotes BRCA2/FANCD1 loading onto damaged chromatin. May also be involved in B-cell immunoglobulin isotype switching.
The C-terminal 24 residues of isoform 2 are required for its function.
Highly expressed in heart, kidney, liver, brain, muscle, and stomach.
Homodimer (PubMed:23530241). Interacts with DNM1L (PubMed:24196833). Interacts with C11orf65/MFI; the interaction inhibits MFF interaction with DNM1L (By similarity).
Plays a role in mitochondrial and peroxisomal fission (PubMed:18353969, PubMed:23530241, PubMed:24196833). Promotes the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface (PubMed:23530241). May be involved in regulation of synaptic vesicle membrane dynamics by recruitment of DNM1L to clathrin-containing vesicles (By similarity).
Plays a role in mitochondrial and peroxisomal fission. Promotes the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface.
Abundantly expressed in kidney. Specifically expressed in podocytes of kidney glomeruli.
Interacts with TJP1/ZO-1 and with NPHS2/podocin (via the C-terminus). Interacts with NPHS1/nephrin (via the Ig-like domains); this interaction is dependent on KIRREL1 glycosylation. Homodimer (via the Ig-like domains). Interacts when tyrosine-phosphorylated with GRB2 (By similarity).
Phosphorylation probably regulates the interaction with NSH2. Phosphorylated at Tyr-605 and Tyr-606 by FYN, leading to GRB2 binding (By similarity).
Required for proper function of the glomerular filtration barrier. It is involved in the maintenance of a stable podocyte architecture with interdigitating foot processes connected by specialized cell-cell junctions, known as the slit diaphragm (PubMed:31472902). It is a signaling protein that needs the presence of TEC kinases to fully trans-activate the transcription factor AP-1 (By similarity).
Cells of the B- and T-lymphocyte lineages.
Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2.
Core component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination. V(D)J recombination assembles a diverse repertoire of immunoglobulin and T-cell receptor genes in developing B and T-lymphocytes through rearrangement of different V (variable), in some cases D (diversity), and J (joining) gene segments. DNA cleavage by the RAG complex occurs in 2 steps: a first nick is introduced in the top strand immediately upstream of the heptamer, generating a 3'-hydroxyl group that can attack the phosphodiester bond on the opposite strand in a direct transesterification reaction, thereby creating 4 DNA ends: 2 hairpin coding ends and 2 blunt, 5'-phosphorylated ends. The chromatin structure plays an essential role in the V(D)J recombination reactions and the presence of histone H3 trimethylated at 'Lys-4' (H3K4me3) stimulates both the nicking and haipinning steps. The RAG complex also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. The introduction of DNA breaks by the RAG complex on one immunoglobulin allele induces ATM-dependent repositioning of the other allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. In the RAG complex, RAG2 is not the catalytic component but is required for all known catalytic activities mediated by RAG1. It probably acts as a sensor of chromatin state that recruits the RAG complex to H3K4me3 (By similarity).
The atypical PHD-type zinc finger recognizes and binds histone H3 trimethylated on 'Lys-4' (H3K4me3). The presence Tyr-445 instead of a carboxylate in classical PHD-type zinc fingers results in an enhanced binding to H3K4me3 in presence of dimethylated on 'Arg-2' (H3R2me2) rather than inhibited. The atypical PHD-type zinc finger also binds various phosphoinositides, such as phosphatidylinositol 3,4-bisphosphate binding (PtdIns(3,4)P2), phosphatidylinositol 3,5-bisphosphate binding (PtdIns(3,5)P2), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate binding (PtdIns(3,4,5)P3) (By similarity).
S-adenosyl-L-methionine-dependent 2'-O-ribose methyltransferase that catalyzes the formation of 2'-O-methylguanosine at position 1145 (Gm1145) in the 16S mitochondrial large subunit ribosomal RNA (mtLSU rRNA), a universally conserved modification in the peptidyl transferase domain of the mtLSU rRNA.
Expressed in lymphoid and pancreatic tissues.
Transcription factor (By similarity). Recognizes and binds to the regulatory elements of target genes, such as visual system homeobox CHX10, negatively modulating transcription (By similarity). Plays a role in establishing motor neuron identity, in concert with LIM domain transcription factor LMO4 (By similarity). Involved in negatively modulating transcription of interneuron genes in motor neurons, acting, at least in part, by blocking regulatory sequence interactions of the ISL1-LHX3 complex (By similarity). Involved in pancreas development and function; may play a role in pancreatic cell fate specification (By similarity).
Expressed in pancreas, skeletal muscle, brain, and heart.
Functions in cell-cell adhesion, cell migration and axon guidance. Mediates cell-cell adhesion via its interactions with ADGRL3 and probably also other latrophilins that are expressed at the surface of adjacent cells. May play a role in the migration of cortical neurons during brain development via its interaction with UNC5D. Mediates axon growth cone collapse and plays a repulsive role in neuron guidance via its interaction with UNC5D, and possibly also other UNC-5 family members. Plays a role in fibroblast growth factor-mediated signaling cascades. Required for normal organization of the cardiac basement membrane during embryogenesis, and for normal embryonic epicardium and heart morphogenesis.
Proteolytic cleavage in the juxtamembrane region gives rise to a soluble ectodomain. Cleavage is probably effected by a metalloprotease.
Self-associates (via leucine-rich repeats), giving rise to homooligomers. Interacts with FGFR1. Interacts with FGFR2. Interacts (via extracellular domain) with ADGRL1/LPHN1. Interacts (via extracellular domain) with ADGRL3 (via olfactomedin-like domain). Interacts (via extracellular domain) with UNC5D (via the first Ig-like domain). Can also interact (via extracellular domain) with UNC5B, but with much lower affinity. Interacts (via extracellular domain) with FN1.
Genetic variations in CALCR may be correlated with bone mineral density (BMD). Low BMD is a risk factor for osteoporotic fracture. Osteoporosis is characterized by reduced bone mineral density, disruption of bone microarchitecture, and the alteration of the amount and variety of non-collagenous proteins in bone. Osteoporotic bones are more at risk of fracture.
Receptor for calcitonin but is unable to couple to G proteins and activate adenylyl cyclase (PubMed:7476993). Does not undergo receptor internalization following ligand binding (PubMed:7476993).
This is a receptor for calcitonin. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. The calcitonin receptor is thought to couple to the heterotrimeric guanosine triphosphate-binding protein that is sensitive to cholera toxin.
(Microbial infection) In case of infection contributes to Salmonella typhimurium pathogenesis by supporting the integrity of the Salmonella-containing vacuole (SCV) probably in concert with the HOPS complex and Rab7.
(Microbial infection) Interacts with Salmonella typhimurium sifA.
Acts as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. Acts as a dual effector of RAB7A and ARL8B that simultaneously binds these GTPases, bringing about clustering and fusion of late endosomes and lysosomes (PubMed:25498145, PubMed:28325809). Required for late stages of endolysosomal maturation, facilitating both endocytosis-mediated degradation of growth factor receptors and autophagosome clearance. Interaction with Arl8b is a crucial factor in the terminal maturation of autophagosomes and to mediate autophagosome-lysosome fusion (PubMed:25498145). Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts (By similarity). May be involved in negative regulation of endocytic transport from early endosome to late endosome/lysosome implicating its association with Rab7 (PubMed:20943950). May have a role in sialyl-lex-mediated transduction of apoptotic signals (PubMed:12820725). Involved in bone resorption (By similarity).
Expressed in placenta, liver, prostate, thymus, spleen, ovary, colon, colon carcinoma and peripheral blood lymphocytes (PBL). Weakly expressed in brain, lung, kidney, and testis. No expression in heart, skeletal muscle, pancreas and small intestine. Predominantly expressed in the breast carcinoma cell line MCF-7.
Interacts (via N- and C-terminus) with RAB7A (GTP-bound form) (PubMed:20943950, PubMed:25500191, PubMed:28325809). Simultaneously interacts with RAB7A and ARL8B; bringing about clustering and fusion of late endosomes and lysosomes (PubMed:28325809). Interacts (via RUN domain) with ARL8B (GTP-bound form); the interaction is required for PLEKHM1 localization to lysosomes and for ARL8B function in delivery and degradation of endocytic and autophagic cargo in lysosomes (PubMed:28325809). PLEKHM1 and PLEKHM2 compete for interaction with ARL8B (PubMed:28325809). Interacts with ARL8A; the interaction is weaker than with ARL8B (PubMed:28325809). Interacts with VPS41, VPS11, VPS18, VPS33A and VPS39; indicative for an association with the HOPS complex; the interactions with, at least, VPS41, VPS11, VPS18 and VPS33A require ARL8B (PubMed:25500191, PubMed:25498145, PubMed:28325809). Interacts with GABARAP, GABARAPL, GABARAPL2, MAP1LC3A, MAP1LC3B and MAP1LC3C (PubMed:25498145). Interacts with PAFAH1B (By similarity). Interacts (via N- and C-terminus) with NDEL1 (By similarity). Interacts (via C-terminus) with MAP3K7 (By similarity). Interacts (via N- and C-terminus) with FAM98A (By similarity). Interacts (via C-terminus) with DEF8; this interaction is weak but increased in a RAB7A-dependent manner (By similarity). In colon carcinoma and breast carcinoma cells, it interacts with sialyl-lex-positive protein (PubMed:12820725).
Sialyl-lex is a carcinoma associated antigen.
The LIR (LC3-interacting region) motif mediates the interaction with ATG8 family proteins GABARAP, GABARAPL, GABARAPL2, and LC3A/B/C.
Found to be expressed in testis and placenta and at lower levels in all the examined tissues with the exception of liver (PubMed:10409426). Isoform 5: Found in leukocytes but not in brain, retina or testis (PubMed:10409426).
Lacks the ATP-binding domain which suggests that it cannot interact with actin.
Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Regulates Rho by stimulating it's GTPase activity in neurons. Required for the regulation of neurite branching and motor neuron axon guidance (By similarity).
Phosphorylated by ALPK1 following monosodium urate monohydrate (MSU)-induced inflammation.
Represents an unconventional myosin. This protein should not be confused with the conventional myosin-9 (MYH9).
Possible involvement in extravasation of leukocytes.
Interacts with PPP1CC isoform gamma-2; the interaction is direct. Interacts with actin, dynein, KIF5B, KIFC1 and tubulin. Associates with microtubules (By similarity).
Regulates phosphatase activity of protein phosphatase 1 (PP1) complexes in the testis.
Plays a role in lysosome motility (By similarity). In neurons, mediates the anterograde axonal long-range transport of presynaptic lysosome-related vesicles required for presynaptic biogenesis and synaptic function (By similarity). May play a role in chromosome segregation (By similarity).
Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily.
Inhibited by triazolodiamine 1 (5-amino-3-([4-(aminosulfonyl)phenyl]amino)-N-(2,6-difluorophenyl)-1H-1,2,4-triazole-1-carbothioamide), (S)-propane-1,2-diol, 2-({6-[(3-chlorophenyl)amino]-9-isopropyl-9H-purin-2-yl}amino)-3-methylbutan-1-ol, N2-[(1R,2S)-2-aminocyclohexyl]-N6-(3-chlorophenyl)-9-ethyl-9H-purine-2,6-diamine and [4-amino-2-(3-chloroanilino)-1,3-thiazol-5-yl](4-fluorophenyl)methanone.
Serine/threonine-protein kinase. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Regulates fast synaptic transmission mediated by glutamate (By similarity).
Interacts (via SH3 domain 3) with PAK2 (PubMed:16374509). Interacts with RAC1 (GTP-bound form) (PubMed:20696164).
The RING finger domain is required for ubiquitin ligase activity and autoubiquitination.
DOCK11 variants have been found in several patients with an early-onset autoimmune disease characterized by cytopenia, systemic lupus erythematosus, inflammatory bowel disease, and immune-related skin manifestations.
Guanine nucleotide-exchange factor (GEF) that activates CDC42 by exchanging bound GDP for free GTP. Required for marginal zone (MZ) B-cell development, is associated with early bone marrow B-cell development, MZ B-cell formation, MZ B-cell number and marginal metallophilic macrophages morphology. Facilitates filopodia formation through the activation of CDC42.
The DOCKER domain is necessary for the GEF activity. The DOCKER domain mediates interaction with activated CDC42 in conjunction with residues 66-126.
May play an important role in neural development; the dorsomedial roof of the third ventricle.
A chromosomal aberration involving NCKIPSD/AF3p21 is found in therapy-related leukemia. Translocation t(3;11)(p21;q23) with KMT2A/MLL1.
Associates with the intermediate filaments, vimentin and desmin. Binds the first and third SH3 domains of NCK. Binds the proline-rich domains of N-WASP through its SH3 domain (By similarity). Similarly, binds diaphanous protein homolog 1 (DRF1). Binds the SH3 domains of GRB2 through its proline-rich domains. Interacts with Helicobacter pylori toxin vacA. Isoform 4 interacts with FHOD1. Interacts with FASLG. Interacts with TMIGD2.
Found in a brain affected by Alzheimer disease. May be due to intron retention.
Has an important role in stress fiber formation induced by active diaphanous protein homolog 1 (DRF1). Induces microspike formation, in vivo (By similarity). In vitro, stimulates N-WASP-induced ARP2/3 complex activation in the absence of CDC42 (By similarity). May play an important role in the maintenance of sarcomeres and/or in the assembly of myofibrils into sarcomeres. Implicated in regulation of actin polymerization and cell adhesion. Plays a role in angiogenesis.
Highest expression in heart, brain, skeletal muscle, kidney and liver. Lower levels in placenta, lung, small intestine and leukocytes. Weak expression in colon, thymus and spleen.
Belongs to the Clp1 family. NOL9/GRC3 subfamily.
Polynucleotide 5'-kinase involved in rRNA processing. The kinase activity is required for the processing of the 32S precursor into 5.8S and 28S rRNAs, more specifically for the generation of the major 5.8S(S) form. In vitro, has both DNA and RNA 5'-kinase activities. Probably binds RNA.
Expressed in placenta, lung, heart, brain, kidney and pancreas.
Homodimer (Probable). Interacts with ARFGEF1/BIG1; both proteins are probably part of the same or very similar macromolecular complexes. Interacts with PRKAR1A, PRKAR2A, PRKAR1B, PRKAR2B, PPP1CC, PDE3A, TNFRSF1A, MYCBP and EXOC7. Interacts with GABRB1, GABRB2 and GABRB3 (By similarity).
In vitro phosphorylated by PKA reducing its GEF activity and dephosphorylated by phosphatase PP1.
Promotes guanine-nucleotide exchange on ARF1 and ARF3 and to a lower extent on ARF5 and ARF6. Promotes the activation of ARF1/ARF5/ARF6 through replacement of GDP with GTP. Involved in the regulation of Golgi vesicular transport. Required for the integrity of the endosomal compartment. Involved in trafficking from the trans-Golgi network (TGN) to endosomes and is required for membrane association of the AP-1 complex and GGA1. Seems to be involved in recycling of the transferrin receptor from recycling endosomes to the plasma membrane. Probably is involved in the exit of GABA(A) receptors from the endoplasmic reticulum. Involved in constitutive release of tumor necrosis factor receptor 1 via exosome-like vesicles; the function seems to involve PKA and specifically PRKAR2B. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways.
Controls the development of red pulp macrophages required for red blood cells recycling and iron homeostasis. Transcription factor that binds to the PU-box, a purine-rich DNA sequence (5'-GAGGA[AT]-3') that can act as a lymphoid-specific enhancer. Regulates VCAM1 gene expression (By similarity).
Preferentially detected in fetal and adult spleen, lymph nodes and at lower levels in bone marrow and fetal liver.
Interacts with histones. Interacts with CASK. Part of a complex containing CASK, TBR1 and TSPYL2 (By similarity).
Part of the CASK/TBR1/TSPYL2 transcriptional complex which modulates gene expression in response to neuronal synaptic activity, probably by facilitating nucleosome assembly. May inhibit cell proliferation by inducing p53-dependent CDKN1A expression.
Phosphorylation at Ser-20 and/or Thr-340 impairs function on cell proliferation.
Synaptic activity down-regulates TSPYL2 protein levels by inducing rapid proteasomal degradation.
Ubiquitously expressed, with highest levels in brain, testis and heart, and lowest levels in liver and pancreas.
Up-regulated in growth-arrested T-cells. Induced by TGFB1 and all-trans retinoic acid (ATRA) in lung cancer cells (at protein level).
Activated upon translocation to the sites of synthesis of PtdIns(3,4,5)P3 in the membrane. Enzymatic activity is enhanced in the presence of phosphatidylserine.
Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family.
Genetic variations in INPPL1 may be a cause of susceptibility to metabolic syndrome. Metabolic syndrome is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia is absent.
Interacts with tyrosine phosphorylated form of SHC1 (PubMed:9660833, PubMed:10194451, PubMed:11349134). Interacts with EGFR (PubMed:11349134). Upon stimulation by the EGF signaling pathway, it forms a complex with SHC1 and EGFR (PubMed:11349134). Interacts with cytoskeletal protein SORBS3/vinexin, promoting its localization to the periphery of cells (PubMed:16302969). Forms a complex with filamin (FLNA or FLNB), actin, GPIb (GP1BA or GP1BB) that regulates cortical and submembraneous actin (PubMed:11739414, PubMed:12676785). Interacts with c-Met/MET, when c-Met/MET is phosphorylated on 'Tyr-1356' (PubMed:15735664). Interacts with p130Cas/BCAR1 (PubMed:11158326). Interacts with CENTD3/ARAP3 via its SAM domain (PubMed:17314030). Interacts with c-Cbl/CBL and CAP/SORBS1 (PubMed:12504111). Interacts with activated EPHA2 receptor (PubMed:17135240). Interacts with receptor FCGR2A (PubMed:12690104). Interacts with receptor FCGR2B (PubMed:11016922). Interacts with tyrosine kinase ABL1 (PubMed:10194451). Interacts with tyrosine kinase TEC (By similarity). Interacts with CSF1R (By similarity). Interacts (via N-terminus) with SH3YL1 (via SH3 domain) (PubMed:21624956). Interacts with FCRL6 (tyrosine phosphorylated form) (PubMed:20933011). Interacts (via SH2 domain) with tyrosine phosphorylated KLRC1 (via ITIM). Interacts with NEDD9/HEF1 (By similarity).
Its ability to confer resistance to dietary obesity suggests that it may serve as a possible therapeutic target in cases of type 2 diabetes and obesity.
Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways (PubMed:16824732). Required for correct mitotic spindle orientation and therefore progression of mitosis (By similarity). Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear (PubMed:9660833). While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking (By similarity). Confers resistance to dietary obesity (By similarity). May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane (By similarity). Part of a signaling pathway that regulates actin cytoskeleton remodeling (PubMed:11739414, PubMed:12676785). Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation (PubMed:15668240). Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thereby regulating membrane ruffling (PubMed:21624956). Regulates cell adhesion and cell spreading (PubMed:12235291). Required for HGF-mediated lamellipodium formation, cell scattering and spreading (PubMed:15735664). Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation (PubMed:17135240). Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5)P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth (By similarity). Acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A) (PubMed:12690104). Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems (PubMed:11016922). Involved in EGF signaling pathway (PubMed:11349134). Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3 (PubMed:11349134). Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity (PubMed:11349134). Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1 (By similarity). In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling (By similarity). Plays a role in the localization of AURKA and NEDD9/HEF1 to the basolateral membrane at interphase in polarized cysts, thereby mediates cell cycle homeostasis, cell polarization and cilia assembly (By similarity). Additionally promotion of cilia growth is also facilitated by hydrolysis of (PtdIns(3,4,5)P3) to PtdIns(3,4)P2 (By similarity). Promotes formation of apical membrane-initiation sites during the initial stages of lumen formation via Rho family-induced actin filament organization and CTNNB1 localization to cell-cell contacts (By similarity). May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6. Involved in endochondral ossification (PubMed:23273569).
The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain.
The SH2 domain interacts with tyrosine phosphorylated forms of proteins such as SHC1 or FCGR2A (PubMed:12690104). It also mediates the interaction with p130Cas/BCAR1 (PubMed:11158326).
Tyrosine phosphorylated by the members of the SRC family after exposure to a diverse array of extracellular stimuli such as insulin, growth factors such as EGF or PDGF, chemokines, integrin ligands and hypertonic and oxidative stress. May be phosphorylated upon IgG receptor FCGR2B-binding. Phosphorylated at Tyr-986 following cell attachment and spreading. Phosphorylated at Tyr-1162 following EGF signaling pathway stimulation. Phosphorylated at Thr-958 in response to PDGF.
Widely expressed, most prominently in skeletal muscle, heart and brain. Present in platelets. Expressed in transformed myeloid cells and in primary macrophages, but not in peripheral blood monocytes.
Cytosolic sensor for calcium, modulates the interaction of STIM1 and ORAI1 upon store depletion and the activation of store-operated Ca(2+) entry (SOCE) and NFAT translocation from cytosol to nucleus (PubMed:30481768). Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (PubMed:36191189).
Interacts with STIM1 and ORAI1; the interactions take place upon Ca(2+)-store depletion and dissociate through a Ca(2+)-dependent mechanism. Interaction with STIM1 inhibits STIM1 interaction with SARAF.
Expressed by glutamatergic neurons (at protein level).
Originally described as a 2-lysophosphatidate/LPA phosphatase (PubMed:12730698). However, following studies suggested it does not have such activity or only a residual one (PubMed:15280885). This is further supported by the fact that the phosphatase sequence motifs as well as the His residue acting as a nucleophile in active phosphatases of the PA-phosphatase related phosphoesterase family are not conserved (PubMed:15280885).
Postsynaptic density membrane protein that indirectly regulates glutamatergic synaptic transmission through lysophosphatidic acid (LPA)-mediated signaling pathways. Binds lysophosphatidic acid (LPA) and mediates its internalization into cells. Could act as receptor or a transporter of this lipid at the post-synaptic membrane (By similarity). Modulates lysophosphatidic acid (LPA) activity in neuron axonal outgrowth during development by attenuating phospholipid-induced axon collapse (By similarity).
Interacts with SPPL2C (via active sites); the interaction stabilizes FREY1 protein and inhibits SPPL2C proteolytic activity. Interacts with IZUMO1; the interaction retains IZUMO1 at the endoplasmic reticulum membrane and coordinates IZUMO1 complex assembly.
Key regulator for male fertility expressed transiently in round spermatids where it recruits IZUMO1 at the endoplasmic reticulum (ER) membrane and coordinates the oolemmal binding multimeric complex (IZUMO1 complex) assembly. Upon complete assembly of the IZUMO1 complex, its ER retention is released, facilitating IZUMO1 complex export to the acrosome. Through the interaction with SPPL2C, inhibits its intramembrane protease activity directly accessing the catalytic center of an I-CLiP.
Down-regulated by muramyl-dipeptide and lipopolysaccharide.
May have an important role in the development and/or progression of some cancers.
Ubiquitously expressed with high levels in brain ant thyroid and low expression in placenta, liver and leukocytes. Expressed as well in six of the seven human breast cancer cell lines examined.
Expression level increases during S phase and drops in G2 phase (at protein level).
Heterodimer of SAE1 and UBA2/SAE2. The heterodimer corresponds to the two domains that are encoded on a single polypeptide chain in ubiquitin-activating enzyme E1. Interacts with UBE2I.
The heterodimer acts as an E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2.
Belongs to the V-ATPase 116 kDa subunit family.
Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (By similarity). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (By similarity). Essential component of the endosomal pH-sensing machinery (PubMed:16415858). May play a role in maintaining the Golgi functions, such as glycosylation maturation, by controlling the Golgi pH (PubMed:18157129). In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation (PubMed:28296633).
The N-terminal peptide may increase IL1B secretion by peripheral blood monocytes; however as this region is probably in the cytosol, the in vivo relevance of this observation needs to be confirmed.
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex (By similarity). The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H (By similarity). The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR (By similarity). Directly interacts with PSCD2 through its N-terminal cytosolic tail in an intra-endosomal acidification-dependent manner (PubMed:16415858). Disruption of this interaction results in the inhibition of endocytosis (PubMed:16415858). Interacts with SPAAR (PubMed:28024296).
Found in a complex with SLC35A2 and SLC35A3.
Mediates the transport of CDP-ribitol (PubMed:34015330). Does not exhibit CMP-sialic acid, UDP-galactose and UDP-N-acetylglucosamine transport activity (PubMed:28167211, PubMed:34015330).
The translation and the expression of this protein may be maintained under stress conditions thanks to the presence of the upstream ORF in transcripts.
One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. Involved in tracer coupling between horizontal cells of the retina. May play a role in the regulation of horizontal cell patterning (By similarity).
Component of the pre-catalytic and catalytic spliceosome complexes (PubMed:9731529, PubMed:11991638, PubMed:28502770, PubMed:28781166, PubMed:28076346, PubMed:30315277, PubMed:29360106, PubMed:29301961). Component of the postcatalytic spliceosome P complex (PubMed:30705154). Part of the U5 snRNP complex. Interacts with PRPF8. Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, WDR57, SNRNP40, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39 (PubMed:16723661). Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932).
Required for pre-mRNA splicing as component of the activated spliceosome (PubMed:11991638, PubMed:28502770, PubMed:28781166, PubMed:28076346, PubMed:30315277, PubMed:29360106, PubMed:29301961, PubMed:30705154). Component of the U5 small nuclear ribonucleoprotein (snRNP) complex and the U4/U6-U5 tri-snRNP complex, building blocks of the spliceosome (PubMed:9774689, PubMed:16723661, PubMed:26912367). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
May play a role in sperm-oocyte fusion during fertilization.
Exhibits adenosine 5'-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5'monophosphoramidate (AMP-NH2) to yield AMP and NH2 (PubMed:17870088). Hydrolyzes lysyl-AMP (AMP-N-epsilon-(N-alpha-acetyl lysine methyl ester)) generated by lysine tRNA ligase (PubMed:17870088). Hydrolyzes 3-indolepropionic acyl-adenylate and fluorogenic purine nucleoside tryptamine phosphoramidates in vitro (PubMed:17870088).
Forms dimers to octamers and even larger oligomer (PubMed:17870088). Interacts with CALM1 (By similarity).
Netrins control guidance of CNS commissural axons and peripheral motor axons.
Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:33283408). Inhibits cell cycle G1/S phase transition by repressing CDK2 expression and activation; represses CDK2 activation by inhibiting its interaction with cyclin E and A (PubMed:23781148). Plays a role in regulating the self-renewal of embryonic stem cells (ESCs) and in maintaining cell survival during terminal differentiation of ESCs (By similarity). Regulates microtubule organization of metaphase II oocytes (By similarity).
Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5 (PubMed:33283408). The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes (PubMed:33283408). Interacts with CDK2AP1 (PubMed:14985111). Interacts with CDK2 (PubMed:23781148). Interacts with MAPK1 (By similarity).
Associated with nucleolar and cytoplasmic pre-60S particles (PubMed:32669547). At the end of biogenesis it dissociates from cytoplasmic pre-60S particles and is likely to be exchanged for its ribosomal homolog, RPL24 (By similarity).
Involved in the biogenesis of the 60S ribosomal subunit. Ensures the docking of GTPBP4/NOG1 to pre-60S particles (By similarity).
Expressed in all tissues; the highest level of expression is detectable in lymph nodes, tonsil, cultured lymphoblasts and ovary.
Seems to be involved in the regulation of chemotactic cell migration and invasion.
Expressed in skeletal muscle, placenta, spinal cord, and various region of brain. Expressed at the base of crypts in colonic and small mucosa stem cells. In premalignant cancer expression is not restricted to the cript base. Overexpressed in cancers of the ovary, colon and liver.
Identified in a complex composed of RNF43, LGR5 and RSPO1 (PubMed:21909076, PubMed:21727895, PubMed:21693646, PubMed:22815884, PubMed:23809763, PubMed:23756651). Also interacts with other R-spondin ligands, including RSPO2, RSPO3 and RSPO4 (PubMed:21909076, PubMed:21727895, PubMed:21693646, PubMed:29769720).
LGR5 is used as a marker of adult tissue stem cells in the intestine, stomach, hair follicle, and mammary epithelium.
Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and acts as a stem cell marker of the intestinal epithelium and the hair follicle. Upon binding to R-spondins (RSPO1, RSPO2, RSPO3 or RSPO4), associates with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. In contrast to classical G-protein coupled receptors, does not activate heterotrimeric G-proteins to transduce the signal. Involved in the development and/or maintenance of the adult intestinal stem cells during postembryonic development.
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. ASIC2 subfamily.
Brain and spinal cord. Isoform 1 is also detected in testis, liver, colon and ovary.
Cation channel with high affinity for sodium, which is gated by extracellular protons and inhibited by the diuretic amiloride. Also permeable for Li(+) and K(+). Generates a biphasic current with a fast inactivating and a slow sustained phase. Heteromeric channel assembly seems to modulate.
Homotrimer or heterotrimer with other ASIC proteins (By similarity). Interacts with STOM; this regulates channel activity (By similarity). Interacts with PRKCABP and ASIC3. Heterotrimer of Asic1a-Asic2a interacts with the snake venom mambalgin-1 (PubMed:23034652). Heterotrimer of Asic1a-Asic2a interacts with the snake venom mambalgin-2 and mambalgin-3 (By similarity). Heterotrimer of Asic1a-Asic2b interacts with the snake venom mambalgin-1 and mambalgin-2 (By similarity).
Inhibited by anti-inflammatory drugs like salicylic acid (By similarity). Regulated by Zn(2+).
Interacts with ER-alpha N-terminal activation domain.
RNA-binding protein that regulates alternative splicing events by binding to 5'-UGCAUGU-3' elements. Prevents binding of U2AF2 to the 3'-splice site. Regulates alternative splicing of tissue-specific exons and of differentially spliced exons during erythropoiesis (By similarity). RNA-binding protein that seems to act as a coregulatory factor of ER-alpha.
Expressed in greatest abundance in peripheral organs, particularly in elements of the gastrointestinal and urogenital systems with highest levels in testes. In central nervous system structures express levels are much lower than those seen in peripheral organs. Within the CNS, has been detected in highest abundance in the cerebellum, dorsal root ganglia, hippocampus, and spinal cord.
Both PH domains are essential for its mitochondrial localization.
Controls the stability of the leptin mRNA harboring an AU-rich element (ARE) in its 3' UTR, in cooperation with the RNA stabilizer ELAVL1 (PubMed:29180010). Decreases the stability of the leptin mRNA by antagonizing the function of ELAVL1 by inducing its atypical recruitment from the nucleus to the cytosol (By similarity). Binds to cardiolipin (CL), phosphatidic acid (PA), phosphatidylinositol 4-phosphate (PtdIns(4)P) and phosphatidylserine (PS) (PubMed:18191643). Promotes apoptosis by enhancing BAX-BAK hetero-oligomerization via interaction with BID in colon cancer cells (PubMed:29531808) (By similarity).
Found in a complex with cytochrome c mRNA and various ribosomal proteins. Interacts with C1QBP (PubMed:18191643). Interacts with ELAVL1 (PubMed:18191643, PubMed:29531808). Interacts with BID (PubMed:29531808).
Phosphorylation is essential for its mitochondrial localization and regulates its interaction with C1QBP.
Ubiquitous (PubMed:18191643). Epressed in several cancer cell lines of differing origin (PubMed:29531808).
Homo/heterodimer, or complexes of higher-order. The structure of beta-crystallin oligomers seems to be stabilized through interactions between the N-terminal arms (By similarity). Interacts with CRYBA1 (PubMed:28083894).
S-methylation and glutathionylation occur in normal young lenses and do not seem to be detrimental.
Specific cleavages in the N-terminal arm occur during lens maturation and give rise to several truncated forms. Cleavages do not seem to have adverse effects on solubility.
Genetic variations in MC4R define the body mass index quantitative trait locus 20 (BMIQ20) [MIM:618406]. MC4R loss-of-function variants are associated with higher body mass index, obesity, type 2 diabetes, and coronary artery disease. Gain-of-function variants have been reported to be associated with lower body mass index and resistance to obesity.
Interacts with ATRNL1 (By similarity). Homodimer; disulfide-linked, also forms higher order oligomers. Interacts with MGRN1, but does not undergo MGRN1-mediated ubiquitination; this interaction competes with GNAS-binding and thus inhibits agonist-induced cAMP production. Interacts with MRAP and MRAP2; these associated factors increase ligand-sensitivity and generation of cAMP.
Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP).
(Microbial infection) Interacts with SFTS phlebovirus protein NSs; may be involved in virus replication.
(Microbial infection) May play a role in the assembly of cytoplasmic inclusion bodies required for SFTS phlebovirus replication.
(Microbial infection) Up-regulated upon SFTS phlebovirus infection (at protein level).
May play a role in regulated exocytosis. In neuronal cells, modulates the localization of synaptophysin/SYP into synaptic-like microvesicles and may therefore play a role in the formation and/or the maturation of this vesicles. May also play a role in GLUT4 storage and transport to the plasma membrane.
Belongs to the G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily.
Belongs to the G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily. CHRM5 sub-subfamily.
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover.
A putative DNA-binding regulatory protein associated with meiosis in spermatogenesis.
Belongs to the JHDM1 histone demethylase family. JHDM1D subfamily.
Histone demethylase required for brain development. Specifically demethylates dimethylated 'Lys-9', 'Lys-27' and 'Lys-36' (H3K9me2, H3K27me2, H3K36me2, respectively) of histone H3 and monomethylated histone H4 'Lys-20' residue (H4K20Me1), thereby playing a central role in histone code (PubMed:20023638, PubMed:20622853). Specifically binds trimethylated 'Lys-4' of histone H3 (H3K4me3), affecting histone demethylase specificity: in presence of H3K4me3, it has no demethylase activity toward H3K9me2, while it has high activity toward H3K27me2. Demethylates H3K9me2 in absence of H3K4me3 (PubMed:20023638). Has activity toward H4K20Me1 only when nucleosome is used as a substrate and when not histone octamer is used as substrate (PubMed:20622853).
The PHD-type zinc finger mediates the binding to H3K4me3. Binding to H3K4me3 prevents its access to H3K9me2.
The linker region is a critical determinant of demethylase specificity. It prevents the active site of JmjC to reach the target H3K9me2 when the PHD-type zinc finger binds to H3K4me3, while it favors selectivity toward H3K27me2.
Component of the XPC complex composed of XPC, RAD23B and CETN2 (PubMed:11279143, PubMed:12509233, PubMed:15964821, PubMed:17897675, PubMed:16627479, PubMed:16533048). Interacts with RAD23A; the interaction is suggesting the existence of a functional equivalent variant XPC complex (PubMed:9372924). Interacts with TDG; the interaction is demonstrated using the XPC:RAD23B dimer (PubMed:12505994, PubMed:20798892). Interacts with SMUG1; the interaction is demonstrated using the XPC:RAD23B dimer (PubMed:20798892). Interacts with DDB2 (PubMed:15882621). Interacts with CCNH, GTF2H1 and ERCC3 (PubMed:10734143, PubMed:12509233). Interacts with E2F1 and KAT2A; leading to KAT2A recruitment to promoters and subsequent acetylation of histones (PubMed:29973595, PubMed:31527837).
In absence of DNA repair, the XPC complex also acts as a transcription coactivator: XPC interacts with the DNA-binding transcription factor E2F1 at a subset of promoters to recruit KAT2A and histone acetyltransferase complexes (HAT) (PubMed:29973595, PubMed:31527837). KAT2A recruitment specifically promotes acetylation of histone variant H2A.Z.1/H2A.Z, but not H2A.Z.2/H2A.V, thereby promoting expression of target genes (PubMed:31527837).
Involved in global genome nucleotide excision repair (GG-NER) by acting as damage sensing and DNA-binding factor component of the XPC complex (PubMed:10734143, PubMed:19609301, PubMed:20649465, PubMed:9734359, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892). Has only a low DNA repair activity by itself which is stimulated by RAD23B and RAD23A. Has a preference to bind DNA containing a short single-stranded segment but not to damaged oligonucleotides (PubMed:10734143, PubMed:19609301, PubMed:20649465). This feature is proposed to be related to a dynamic sensor function: XPC can rapidly screen duplex DNA for non-hydrogen-bonded bases by forming a transient nucleoprotein intermediate complex which matures into a stable recognition complex through an intrinsic single-stranded DNA-binding activity (PubMed:10734143, PubMed:19609301, PubMed:20649465). The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex (PubMed:9734359, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892). The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single-stranded overhangs (PubMed:9734359, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892). The orientation of XPC complex binding appears to be crucial for inducing a productive NER (PubMed:9734359, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892). XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery (PubMed:9734359, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892). Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair (PubMed:9734359, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892). In vitro, the XPC:RAD23B dimer is sufficient to initiate NER; it preferentially binds to cisplatin and UV-damaged double-stranded DNA and also binds to a variety of chemically and structurally diverse DNA adducts (PubMed:20028083). XPC:RAD23B contacts DNA both 5' and 3' of a cisplatin lesion with a preference for the 5' side. XPC:RAD23B induces a bend in DNA upon binding. XPC:RAD23B stimulates the activity of DNA glycosylases TDG and SMUG1 (PubMed:20028083).
Sumoylated; sumoylation promotes ubiquitination by RNF111.
Ubiquitinated upon UV irradiation; the ubiquitination requires the UV-DDB complex, appears to be reversible and does not serve as a signal for degradation (PubMed:15882621, PubMed:23751493). Ubiquitinated by RNF11 via 'Lys-63'-linked ubiquitination (PubMed:23751493). Ubiquitination by RNF111 is polysumoylation-dependent and promotes nucleotide excision repair (PubMed:23751493).
(Microbial infection) Interacts with herpes virus 1/HHV-1 protein US3; this interaction prevents the interaction between LAT and TRAF6.
Engagement of killer inhibitory receptors (KIR) disrupts the interaction of PLCG1 with LAT and blocks target cell-induced activation of PLC, maybe by inducing the dephosphorylation of LAT.
Expressed in thymus, T-cells, NK cells, mast cells and, at lower levels, in spleen. Present in T-cells but not B-cells (at protein level).
Palmitoylation of Cys-26 and Cys-29 is required for raft targeting and efficient phosphorylation.
Phosphorylated on tyrosines by ZAP70 upon TCR activation, or by SYK upon other immunoreceptor activation; which leads to the recruitment of multiple signaling molecules. Is one of the most prominently tyrosine-phosphorylated proteins detected following TCR engagement. May be dephosphorylated by PTPRJ. Phosphorylated by ITK leading to the recruitment of VAV1 to LAT-containing complexes.
Required for TCR (T-cell antigen receptor)- and pre-TCR-mediated signaling, both in mature T-cells and during their development (PubMed:25907557, PubMed:23514740). Involved in FCGR3 (low affinity immunoglobulin gamma Fc region receptor III)-mediated signaling in natural killer cells and FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Couples activation of these receptors and their associated kinases with distal intracellular events such as mobilization of intracellular calcium stores, PKC activation, MAPK activation or cytoskeletal reorganization through the recruitment of PLCG1, GRB2, GRAP2, and other signaling molecules.
When phosphorylated, interacts directly with the PIK3R1 subunit of phosphoinositide 3-kinase and the SH2 domains of GRB2, GRAP, GRAP2, PLCG1 and PLCG2. Interacts indirectly with CBL, SOS, VAV, and LCP2. Interacts with SHB, SKAP2 and CLNK (By similarity). Interacts with FCGR1A. Interacts with GRB2, PLCG1 and THEMIS upon TCR activation in thymocytes (By similarity). Interacts with THEMIS2 (By similarity).
Belongs to the Mediator complex subunit 21 family.
Interacts with PPARG (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with THRA in a ligand-dependent fashion.
Expressed in brain, skeletal muscle and heart.
Glycogen-targeting subunit for protein phosphatase 1 (PP1).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIA2 subfamily.
Homotetramer or heterotetramer of pore-forming glutamate receptor subunits. Tetramers may be formed by the dimerization of dimers. May interact with MPP4. Forms a ternary complex with GRIP1 and CSPG4. Interacts with ATAD1 in an ATP-dependent manner. ATAD1-catalyzed ATP hydrolysis disrupts binding to ATAD1 and to GRIP1 and leads to AMPAR complex disassembly. Interacts with GRIP2. Isoform 1, but not isoform 3, interacts with PICK1/PRKCABP. Interacts with GRIA1 and SYNDIG1. Interacts with LRFN1 (By similarity). Found in a complex with GRIA1, GRIA3, GRIA4, CNIH2, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with CACNG5 (By similarity). Interacts with SNX27 (via PDZ domain); the interaction is required for recycling to the plasma membrane when endocytosed and prevent degradation in lysosomes. Interacts with OLFM2 (By similarity). Interacts with AP4B1, AP4E1 and AP4M1; probably indirect it mediates the somatodendritic localization of GRIA2 in neurons (By similarity). Forms a complex with NSG1, GRIP1 and STX12; controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting (By similarity). Interacts with IQSEC1; the interaction is required for ARF6 activation (By similarity).
Palmitoylated. Depalmitoylated upon glutamate stimulation. Cys-610 palmitoylation leads to Golgi retention and decreased cell surface expression. In contrast, Cys-836 palmitoylation does not affect cell surface expression but regulates stimulation-dependent endocytosis (By similarity).
Partially edited. Fully edited in the brain. The presence of edited GRIA2 subunit in the heteromeric channel reduces the single channel conductance, confers Ca(2+)-impermeability, and results in a linear current-voltage relationship. The unedited (Q) forms are highly permeable to divalent ions.
Phosphorylation at Tyr-876 is required forc interaction with IQSEC1 and ARF6 activation.
Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system (PubMed:31300657). It plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. Through complex formation with NSG1, GRIP1 and STX12 controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting (By similarity).
The M4 transmembrane segment mediates tetramerization and is required for cell surface expression.
The disease is caused by variants affecting the gene represented in this entry. The genetic variation producing the missense variant p.Q607E, associated with NEDLIB, is predicted to deeply affect RNA editing. In a physiological context, the adenosine (A) residue of the original glutamine (Q) codon CAG is post-transcriptionnaly edited to inosine (I) by ADAR2, leading to a codon recognized by the ribosome as arginine (R). The glutamate (E) codon GAG, resulting from the genetic variation, is predicted to be edited 90% less than the normal CAG codon. If edited, the codon GIG would be translated as p.Q607G.
The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds AMPA (quisqualate) > glutamate > kainate.
Ubiquitinated by RNF167, leading to its degradation.
Found in a complex with PUF60 and far upstream element (FUSE) DNA segment. Interacts with PUF60 and JTV1.
Regulates MYC expression by binding to a single-stranded far-upstream element (FUSE) upstream of the MYC promoter. May act both as activator and repressor of transcription.
Ubiquitinated. This targets the protein for proteasome-mediated degradation.
Interacts with MOV10; the interaction is RNA-dependent.
Uridylyltransferase that mediates the terminal uridylation of mRNAs with short (less than 25 nucleotides) poly(A) tails, hence facilitating global mRNA decay (PubMed:19703396, PubMed:25480299). Essential for both oocyte maturation and fertility. Through 3' terminal uridylation of mRNA, sculpts, with TUT7, the maternal transcriptome by eliminating transcripts during oocyte growth (By similarity). Involved in microRNA (miRNA)-induced gene silencing through uridylation of deadenylated miRNA targets (PubMed:25480299). Also functions as an integral regulator of microRNA biogenesiS using 3 different uridylation mechanisms (PubMed:25979828). Acts as a suppressor of miRNA biogenesis by mediating the terminal uridylation of some miRNA precursors, including that of let-7 (pre-let-7). Uridylated pre-let-7 RNA is not processed by Dicer and undergo degradation. Pre-let-7 uridylation is strongly enhanced in the presence of LIN28A (PubMed:22898984). In the absence of LIN28A, TUT7 and TUT4 monouridylate group II pre-miRNAs, which includes most of pre-let7 members, that shapes an optimal 3' end overhang for efficient processing (PubMed:25979828, PubMed:28671666). Add oligo-U tails to truncated pre-miRNAS with a 5' overhang which may promote rapid degradation of non-functional pre-miRNA species (PubMed:25979828). Does not play a role in replication-dependent histone mRNA degradation (PubMed:18172165). Due to functional redundancy between TUT4 and TUT7, the identification of the specific role of each of these proteins is difficult (PubMed:25979828, PubMed:25480299, PubMed:19703396, PubMed:22898984, PubMed:18172165, PubMed:28671666). TUT4 and TUT7 restrict retrotransposition of long interspersed element-1 (LINE-1) in cooperation with MOV10 counteracting the RNA chaperonne activity of L1RE1. TUT7 uridylates LINE-1 mRNAs in the cytoplasm which inhibits initiation of reverse transcription once in the nucleus, whereas uridylation by TUT4 destabilizes mRNAs in cytoplasmic ribonucleoprotein granules (PubMed:30122351).
DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK6 promotes Ret-mediated neurite growth. May have a role in brain development and/or maintenance.
Highly expressed in fetal and adult brain. Highly expressed in the cerebellum. Weak expression in kidney, spinal cord and testis.
Interacts via its PTB domain with phosphorylated RET.
On Ret activation, phosphorylated on one or more C-terminal tyrosine residues by an Src family kinase.
Acts as a cell adhesion ligand for skin epithelial cells and fibroblasts.
Restrictive expression is observed at tissue junctions such as the myotendinous junction in skeletal and heart muscle, the articular cartilage-synovial fluid junction, or the border between the anagen hair follicle and the dermis in the skin. It is deposited in the basement membrane zone of the myotendinous junction and the hair follicle and associated with the extrafibrillar matrix in cartilage.
Directly or indirectly cross-linked to cornifelin (CNFN).
Keratinocytes of epidermis and other stratified squamous epithelia.
Part of the insoluble cornified cell envelope (CE) of stratified squamous epithelia.
Substrate of transglutaminase. Some glutamines and lysines are cross-linked to other involucrin molecules, to other proteins such as keratin, desmoplakin, periplakin and envoplakin, and to lipids like omega-hydroxyceramide.
Component of the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1 (PubMed:26300262). The MutL-beta complex is a heterodimer of PMS1 and MLH1 (PubMed:10748105). Interacts with MCM9 (PubMed:26300262).
Probably involved in the repair of mismatches in DNA.
Glycated. Glycation is found in diabetic subjects, but only at minimal levels in nondiabetic subjects. Glycated CD59 lacks MAC-inhibitory function and confers to vascular complications of diabetes.
Interacts with T-cell surface antigen CD2.
N- and O-glycosylated. The N-glycosylation mainly consists of a family of biantennary complex-type structures with and without lactosamine extensions and outer arm fucose residues. Also significant amounts of triantennary complexes (22%). Variable sialylation also present in the Asn-43 oligosaccharide. The predominant O-glycans are mono-sialylated forms of the disaccharide, Gal-beta-1,3GalNAc, and their sites of attachment are probably on Thr-76 and Thr-77. The GPI-anchor of soluble urinary CD59 has no inositol-associated phospholipid, but is composed of seven different GPI-anchor variants of one or more monosaccharide units. Major variants contain sialic acid, mannose and glucosamine. Sialic acid linked to an N-acetylhexosamine-galactose arm is present in two variants.
Potent inhibitor of the complement membrane attack complex (MAC) action. Acts by binding to the C8 and/or C9 complements of the assembling MAC, thereby preventing incorporation of the multiple copies of C9 required for complete formation of the osmolytic pore. This inhibitor appears to be species-specific. Involved in signal transduction for T-cell activation complexed to a protein tyrosine kinase.
The soluble form from urine retains its specific complement binding activity, but exhibits greatly reduced ability to inhibit MAC assembly on cell membranes.
Interacts (via cytoplasmic domain) with WW domain-containing proteins MAGI1, MAGI3, NEDD4, NEDD4L, WWTR1/TAZ and YAP1.
May control axon guidance across the CNS (PubMed:28859078). Prevents the delivery of ROBO1 at the cell surface and down-regulates its expression (PubMed:28859078).
Widely expressed with highest levels in kidney.
A N-glycosylation site within the signal peptide impedes its proper cleavage and function.
G-protein coupled receptor for CRH (corticotropin-releasing factor), UCN (urocortin), UCN2 and UCN3. Has high affinity for UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors, such as adenylate cyclase. Promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels.
Monomer. Interacts (via N-terminal extracellular domain) with CRF, UCN, UCN2 and UCN3. Has highest affinity for UCN, and considerably lower affinity for CRF, UNC2 and UCN3.
The transmembrane domain is composed of seven transmembrane helices that are arranged in V-shape. Transmembrane helix 7 assumes a sharply kinked structure (By similarity).
The uncleaved pseudo signal peptide prevents receptor's oligomerization and coupling to G(i) subunits. It is also responsible for the rather low receptor localization at the plasma membrane (PubMed:22689579).
Belongs to the diphosphomevalonate decarboxylase family.
Catalyzes the ATP dependent decarboxylation of (R)-5-diphosphomevalonate to form isopentenyl diphosphate (IPP). Functions in the mevalonate (MVA) pathway leading to isopentenyl diphosphate (IPP), a key precursor for the biosynthesis of isoprenoids and sterol synthesis.
Expressed in heart, skeletal muscle, lung, liver, brain, pancreas, kidney and placenta.
Was originally thought to be located in the peroxisome (PubMed:11108725). However, was later shown to be cytosolic (PubMed:14972328).
Activated by ADRM1. Inhibited by interaction with NFRKB.
Component of the 19S (PA700) regulatory complex of the 26S proteasome. Interacts with ADRM1 and NFRKB; in vitro ADRM1 and NFRKB compete for interaction with UCHL5. Component of the INO80 complex; specifically part of a complex module associated with N-terminus of INO80.
Protease that specifically cleaves 'Lys-48'-linked polyubiquitin chains. Deubiquitinating enzyme associated with the 19S regulatory subunit of the 26S proteasome. Putative regulatory component of the INO80 complex; however is inactive in the INO80 complex and is activated by a transient interaction of the INO80 complex with the proteasome via ADRM1.
(Microbial infection) Methylation at Cys-630 by enteropathogenic E.coli protein NleE or S.flexneri protein OspZ: methylation disrupts ability to bind 'Lys-63'-linked ubiquitin.
DNA annealing helicase and endonuclease required to maintain genome stability at stalled or collapsed replication forks by facilitating fork restart and limiting inappropriate recombination that could occur during template switching events (PubMed:21078962, PubMed:22704558, PubMed:22705370, PubMed:22759634, PubMed:26884333). Recruited to the sites of stalled DNA replication by polyubiquitinated PCNA and acts as a structure-specific endonuclease that cleaves the replication fork D-loop intermediate, generating an accessible 3'-OH group in the template of the leading strand, which is amenable to extension by DNA polymerase (PubMed:22759634). In addition to endonuclease activity, also catalyzes the fork regression via annealing helicase activity in order to prevent disintegration of the replication fork and the formation of double-strand breaks (PubMed:22705370, PubMed:22704558).
In contrast to classical helicases that unwing DNA, annealing helicases rewind it.
Interacts (via PIP-box and RanBP2-type zinc finger) with PCNA (when PCNA is polyubiquitinated via 'Lys-63'-linked polyubiquitin).
The PIP-box mediates the interaction with PCNA, while the RanBP2-type zinc finger mediates binding to 'Lys-63'-linked polyubiquitin (PubMed:22704558, PubMed:22705370, PubMed:22759634).
Both wild type and variant Gln-403 are detected in skeletal muscle (at protein level).
Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). Interacts with ECPAS (PubMed:20682791). Interacts (via C-terminus) with LRRC39 (PubMed:20847312).
Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction. Forms regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle.
The rodlike tail sequence is highly repetitive, showing cycles of a 28-residue repeat pattern composed of 4 heptapeptides, characteristic for alpha-helical coiled coils (PubMed:26150528, PubMed:26573747). Four skip residues (Skip1: Thr-1188, Skip2: Glu-1385, Skip3: Glu-1582 and Skip4: Gly-1807) introduce discontinuities in the coiled-coil heptad repeats. The first three skip residues are structurally comparable and induce a unique local relaxation of the coiled-coil superhelical pitch and the fourth skip residue lies within a highly flexible molecular hinge that is necessary for myosin incorporation in the bare zone of sarcomeres (PubMed:26150528).
Contains 2 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. The first one is essential for the association with ESR1 and ESR2.
Highly expressed in adult testis. Expressed in both prostate epithelial and stromal cells, with predominant expression in epithelial cells (at protein level) (PubMed:19126643). Not detected in prostate by RT-PCR (PubMed:19165854). Overexpressed in various cancers.
Interacts with ESR1 and ESR2 in the presence of estradiol/E2. The interaction with ESR2 recruits CCDC62 to ER target genes, including cyclin-D1/CCND1 AP-1 promoter. Interacts with GOPC (By similarity).
Nuclear receptor coactivator that can enhance preferentially estrogen receptors ESR1 and ESR2 transactivation. Modulates also progesterone/PGR, glucocorticoid/NR3C1 and androgen/AR receptors transactivation, although at lower level; little effect on vitamin D receptor/VDR. Required for normal spermiogenesis. It probably plays a role in acrosome formation (By similarity).
Chromatin-binding protein that acts as an adapter between distinct nucleosome components (H3K36me3 or H2A.Z) and chromatin-modifying complexes, contributing to the regulation of the levels of histone acetylation at actively transcribed genes (PubMed:30228260, PubMed:30327463). Competes with CHD4 and MBD3 for interaction with MTA1 to form a NuRD subcomplex, preventing the formation of full NuRD complex (containing CHD4 and MBD3), leading to recruitment of HDACs to gene promoters resulting in turn in the deacetylation of nearby H3K27 and H2A.Z (PubMed:30228260, PubMed:30327463). Plays a role in facilitating transcriptional elongation and repression of spurious transcription initiation through regulation of histone acetylation (By similarity). Essential for proper mitosis progression (PubMed:28645917).
Component of a MTA1-specific subcomplex of the NuRD complex (M1HR), composed of PWWP2A, MTA1/2, HDAC1/2, and RBBP4/7 but does not contain CHD4 and MBD3 (PubMed:30228260, PubMed:30327463). Interacts with MTA1; the interaction mediates the association of PWWP2A with the M1HR complex (PubMed:30228260, PubMed:30327463). Interacts with H2A.Z/H2AZ1 (PubMed:28645917, PubMed:30327463). Interacts (via PWWP domain) with histone H3 trimethylated at 'Lys-36' (H3K36me3) (PubMed:30228260, PubMed:30327463). Does not interact with CHD4 and MBD3 (PubMed:30228260, PubMed:30327463).
Interacts with MTA1 and with HDAC1 in a MTA1-dependent manner (PubMed:30228260). Does not interact with CHD4 and MBD3 (PubMed:30228260).
A chromosomal aberration involving ETV6 and JAK2 is found in an atypical chronic myelogenous leukemia. Translocation t(9;15;12)(p24;q15;p13).
A chromosomal aberration involving ETV6 is found in a form of chronic myelomonocytic leukemia (CMML). Translocation t(5;12)(q33;p13) with PDGFRB. It is characterized by abnormal clonal myeloid proliferation and by progression to acute myelogenous leukemia (AML).
A chromosomal aberration involving ETV6 is found in a form of pre-B acute lymphoid leukemia. Translocation t(9;12)(p24;p13) with JAK2.
A chromosomal aberration involving ETV6 is found in acute eosinophilic leukemia (AEL). Translocation t(5;12)(q31;p13) with ACSL6.
A chromosomal aberration involving ETV6 is found in acute lymphoblastic leukemia. Translocation t(9;12)(p13;p13) with PAX5.
A chromosomal aberration involving ETV6 is found in myelodysplastic syndrome (MDS) with basophilia. Translocation t(5;12)(q31;p13) with ACSL6.
A chromosomal aberration involving ETV6 is found in myelodysplastic syndrome (MDS). Translocation t(1;12)(p36.1;p13) with MDS2.
Can form homodimers or heterodimers with TEL2 or FLI1. Interacts with L3MBTL1 and HDAC9.
Chromosomal aberrations involving ETV6 are found in acute myeloid leukemia (AML). Translocation t(12;22)(p13;q11) with MN1 (PubMed:7731705). Translocation t(4;12)(q12;p13) with CHIC2 (PubMed:10477709).
Chromosomal aberrations involving ETV6 are found in childhood acute lymphoblastic leukemia (ALL). Translocations t(12;21)(p12;q22) and t(12;21)(p13;q22) with RUNX1/AML1.
Phosphorylation of Ser-257 by MAPK14 (p38) inhibits ETV6 transcriptional repression.
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving ETV6 is found in many instances of myeloproliferative disorder chronic with eosinophilia. Translocation t(5;12) with PDGFRB on chromosome 5 creating an ETV6-PDGFRB fusion protein.
Transcriptional repressor; binds to the DNA sequence 5'-CCGGAAGT-3'. Plays a role in hematopoiesis and malignant transformation.
Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments (By similarity). Binds calcium (PubMed:1836432).
Detected in cardiac tissue and platelets, the form found in cardiac tissue is a higher molecular weight than the form found in platelets. Expressed at higher levels in the platelets of hypertensive patients with cardiac hypertrophy than in the platelets of hypertensive patients without cardiac hypertrophy (at protein level).
Homodimer. Heterodimer of an alpha (TPM1, TPM3 or TPM4) and a beta (TPM2) chain.
Putative divalent cation:proton antiporter that exchanges calcium or manganese ions for protons across the Golgi membrane. Mediates the reversible transport of calcium or manganese to the Golgi lumen driven by the proton gradient and possibly the membrane potential generated by V-ATPase. Provides calcium or manganese cofactors to resident Golgi enzymes and contributes to the maintenance of an acidic luminal Golgi pH required for proper functioning of the secretory pathway (PubMed:32047108, PubMed:23569283, PubMed:22683087, PubMed:27008884) (By similarity). Promotes Ca(2+) storage within the Golgi lumen of the mammary epithelial cells to be then secreted into milk (By similarity). The transport mechanism and stoichiometry remains to be elucidated.
Guanine nucleotide exchange factor (GEF) for RHOA and RAC1 GTPases (PubMed:8643598, PubMed:22155786, PubMed:27418539). Involved in coordinating actin remodeling, which is necessary for cell migration and growth (PubMed:10341202, PubMed:22155786). Plays a key role in the regulation of neurite outgrowth and lamellipodia formation (PubMed:32109419). In developing hippocampal neurons, limits dendrite formation, without affecting the establishment of axon polarity. Once dendrites are formed, involved in the control of synaptic function by regulating the endocytosis of AMPA-selective glutamate receptors (AMPARs) at CA1 excitatory synapses (By similarity). May act as a regulator of adipogenesis (By similarity).
Interacts with CARMIL1 (PubMed:19846667). Interacts with PTPRF/LAR (PubMed:8643598). Interacts with ANKRD26 (PubMed:22666460). Interacts with Bassoon/BSN and Piccolo/PCLO (By similarity). Interacts with the cytoplasmic region of the heterodimer formed by NGFR and SORCS2. ProNGF binding mediates dissociation of TRIO from the receptor complex (PubMed:22155786).
The N-terminal DBL/GEF domain specifically catalyzes nucleotide exchange for RAC1, leading to the activation of Jun kinase and the production of membrane ruffles. The second DBL/GEF domain is an exchange factor for rhoa and induces the formation of stress fibers.
Widely expressed, with highest levels in heart, skeletal muscle, and brain.
Assembly factor required for Rieske Fe-S protein UQCRFS1 incorporation into the cytochrome b-c1 (CIII) complex. Functions as a chaperone, binding to this subunit within the mitochondrial matrix and stabilizing it prior to its translocation and insertion into the late CIII dimeric intermediate within the mitochondrial inner membrane.
Associates with the 60S ribosomal subunit. Interacts with NPM1, RPA1 and PRKDC. May interact with NIP7 (PubMed:17643419). Found in a complex consisting of the 60S ribosomal subunit, SBDS and EFL1 (PubMed:26479198). Interacts with EFL1 (PubMed:25991726). Interacts with CLN3 (PubMed:20015955).
Required for the assembly of mature ribosomes and ribosome biogenesis. Together with EFL1, triggers the GTP-dependent release of EIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating EIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export. Required for normal levels of protein synthesis. May play a role in cellular stress resistance. May play a role in cellular response to DNA damage. May play a role in cell proliferation.
Binds lactose. May participate in the apoptosis of adipocytes.
Not widely expressed. Predominantly expressed in adipose tissue.
Interacts with PTPRF. Interacts with DLG4.
N-glycosylated. O-glycosylated; contains sialic acid.
Synaptic adhesion protein. Regulates the formation of excitatory synapses. The trans-synaptic adhesion between LRRC4B and PTPRF regulates the formation of excitatory synapses in a bidirectional manner (By similarity).
The last 4 C-terminal residues bind to the first 2 PDZ domains of DLG4.
Expressed in brain, colon, heart, kidney, liver, lung, megakaryocyte, ovary, pancreas, peripheral blood lymphocytes, placenta, prostate, skeletal muscle, small intestine, spleen, testis, thymus and trachea.
Induced by adriamycin treatment and this effect is counteracted by HGF/SF. Expression is reduced during differentiation.
Interacts specifically with GTP-bound RHOQ. Interacts with DNM2 and PDE6G (By similarity). Homodimerizes, the dimers can polymerize end-to-end to form filamentous structures. Interacts specifically with GTP-bound CDC42. Interacts with AKAP9, ARHGAP17, DAAM1, DIAPH1, DIAPH2, DNM1, FASLG/FASL, GAPVD1, LYN, microtubules, SRC, WAS/WASP and WASL/N-WASP. Interacts with the ligand binding domain of the thyroid receptor (TR) in the presence of thyroid hormone. May interact with CTNNB1 and HD/HTT.
Required for translocation of GLUT4 to the plasma membrane in response to insulin signaling (By similarity). Required to coordinate membrane tubulation with reorganization of the actin cytoskeleton during endocytosis. Binds to lipids such as phosphatidylinositol 4,5-bisphosphate and phosphatidylserine and promotes membrane invagination and the formation of tubules. Also promotes CDC42-induced actin polymerization by recruiting WASL/N-WASP which in turn activates the Arp2/3 complex. Actin polymerization may promote the fission of membrane tubules to form endocytic vesicles. Required for the formation of podosomes, actin-rich adhesion structures specific to monocyte-derived cells. May be required for the lysosomal retention of FASLG/FASL.
The F-BAR domain binds the phospholipid membrane with its concave surface. The end-to-end polymerization of dimers of these domains provides a curved surface that fits best membranes with around 600 A diameter, and may drive tubulation.
Tyrosine phosphorylated. Also phosphorylated by PKA.
Homodimer (By similarity). Interacts with GLMN (PubMed:12604780). Associates with HSP90AA1 and HSP70 in steroid hormone receptor complexes. Also interacts with peroxisomal phytanoyl-CoA alpha-hydroxylase (PHYH). Interacts with NR3C1 and dynein. Interacts with HSF1 in the HSP90 complex. Associates with tubulin. Interacts with MAPT/TAU (By similarity). Interacts (via TPR domain) with S100A1, S100A2 and S100A6; the interaction is Ca(2+) dependent. Interaction with S100A1 and S100A2 (but not with S100A6) leads to inhibition of FKBP4-HSP90 interaction. Interacts with dynein; causes partially NR3C1 transport to the nucleus.
Immunophilin protein with PPIase and co-chaperone activities. Component of steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). May play a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments. The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening. Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria.
Phosphorylation by CK2 results in loss of HSP90 binding activity.
The C-terminal region (AA 375-458) is required to prevent tubulin polymerization.
The PPIase activity is mainly due to the first PPIase FKBP-type domain (1-138 AA).
The TPR repeats mediate mitochondrial localization.
The chaperone activity resides in the C-terminal region, mainly between amino acids 264 and 400.
Belongs to the protein kinase superfamily. RIO-type Ser/Thr kinase family.
Interacts with CASP10 (PubMed:19557502). Interacts with IRF3; RIOK3 probably mediates the interaction of TBK1 with IRF3 (PubMed:24807708). Associated with 40S pre-ribosomal particles.
Involved in regulation of type I interferon (IFN)-dependent immune response which plays a critical role in the innate immune response against DNA and RNA viruses.
Involved in regulation of type I interferon (IFN)-dependent immune response which plays a critical role in the innate immune response against DNA and RNA viruses. May act as an adapter protein essential for the recruitment of TBK1 to IRF3 (PubMed:24807708). Phosphorylates IFIH1 on 'Ser-828' interfering with IFIH1 filament assembly on long dsRNA and resulting in attenuated IFIH1-signaling (PubMed:25865883). Can inhibit CASP10 isoform 7-mediated activation of the NF-kappaB signaling pathway (PubMed:19557502). May play a role in the biogenesis of the 40S ribosomal subunit. Involved in the processing of 21S pre-rRNA to the mature 18S rRNA (PubMed:22418843).
Belongs to the FIT family. FIT1 subfamily.
Plays an important role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis (PubMed:18160536) (By similarity). Directly binds to diacylglycerol (DAGs) and triacylglycerol (By similarity).
Primarily expressed in heart and skeletal muscle.
Acts as a 'third messenger' substrate of protein kinase C-mediated molecular cascades during synaptic development and remodeling. Binds to calmodulin in the absence of calcium (By similarity).
In the cerebral cortex, found in the cell bodies of neurons in layers II-VI, and in apical and basal dendrites of pyramidal neurons. Is not found in the dendrites in patients with Alzheimer disease.
Neurogranin is intrinsically unstructured; however, upon binding with CaM, The IQ domain adopts a helical conformation.
Phosphorylated at Ser-36 by PHK and PKC, phosphorylation prevents interaction with Calmodulin and interrupts several learning- and memory-associated functions.
Homodimer (PubMed:18411262). Interacts with MAG (PubMed:12089450, PubMed:12839991, PubMed:18411262, PubMed:19052207). Interacts with RTN4 (PubMed:12839991, PubMed:19052207). Interacts with NGFR (PubMed:12426574, PubMed:18411262, PubMed:19052207). Interacts with LINGO1 (PubMed:14966521, PubMed:19052207). Interacts with KIAA0319L (PubMed:20697954). Interacts with OLFM1; this inhibits interaction with LINGO1 and NGFR (By similarity). Interacts with OMG (PubMed:12068310, PubMed:12839991, PubMed:19052207).
N-glycosylated. O-glycosylated. Contains terminal sialic acid groups on its glycan chains.
Receptor for RTN4, OMG and MAG (PubMed:12037567, PubMed:12068310, PubMed:12426574, PubMed:12089450, PubMed:16712417, PubMed:18411262, PubMed:12839991, PubMed:19052207). Functions as receptor for the sialylated gangliosides GT1b and GM1 (PubMed:18411262). Besides, functions as receptor for chondroitin sulfate proteoglycans (By similarity). Can also bind heparin (By similarity). Intracellular signaling cascades are triggered via the coreceptor NGFR (PubMed:12426574). Signaling mediates activation of Rho and downstream reorganization of the actin cytoskeleton (PubMed:16712417, PubMed:22325200). Mediates axonal growth inhibition (PubMed:12839991, PubMed:19052207, PubMed:28892071). Plays a role in regulating axon regeneration and neuronal plasticity in the adult central nervous system. Plays a role in postnatal brain development. Required for normal axon migration across the brain midline and normal formation of the corpus callosum. Protects motoneurons against apoptosis; protection against apoptosis is probably mediated via interaction with MAG. Acts in conjunction with RTN4 and LINGO1 in regulating neuronal precursor cell motility during cortical development. Like other family members, plays a role in restricting the number dendritic spines and the number of synapses that are formed during brain development (PubMed:22325200).
Widespread in the brain but highest levels in the gray matter. Low levels in heart and kidney; not expressed in oligodendrocytes (white matter).
Homooligomer and heterooligomer with other family members. Binds LEF1, TCF7, TCF7L1, TCF7L2, UTY, HES1 and HES5.
In all tissues examined, mostly in heart, brain, and muscle.
Transcriptional corepressor that binds to a number of transcription factors. Inhibits the transcriptional activation mediated by CTNNB1 and TCF family members in Wnt signaling. The effects of full-length TLE family members may be modulated by association with dominant-negative AES (By similarity).
WD repeat Groucho/TLE family members are characterized by 5 regions, a glutamine-rich Q domain, a glycine/proline-rich GP domain, a central CcN domain, containing a nuclear localization signal, and a serine/proline-rich SP domain. The most highly conserved are the N-terminal Q domain and the C-terminal WD-repeat domain.
Associates with the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOOL/MIC27, IMMT/MIC60, APOO/MIC23/MIC26 and QIL1/MIC13. This complex was also known under the names MINOS or MitOS complex. The MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1 and MTX2 (together described as components of the mitochondrial outer membrane sorting assembly machinery (SAM) complex) and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9 (PubMed:25997101). The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both mitochondrial membranes termed the mitochondrial intermembrane space bridging (MIB) complex.
Required for mitochondrial inner membrane organization. Seems to function through its association with the MICOS complex and the mitochondrial outer membrane sorting assembly machinery (SAM) complex.
May function as transcriptional repressor. May modulate the expression of genes required for the differentiation and/or maintenance of pancreatic and neuronal cell types. May be important for rod bipolar cell maturation (By similarity).
(Microbial infection) Acts as a receptor for Listeria monocytogenes internalin InlB, mediating entry of the pathogen into cells.
(Microbial infection) Interacts via extracytoplasmic residues 25-656 with L.monocytogenes InlB; MET can bind HGF, its endogenous ligand, and InlB simultaneously (PubMed:11081636, PubMed:17662939). InlB probably dimerizes upon binding to MET, which encourages subsequent dimerization of MET (Probable).
(Microbial infection) Tyrosine phosphorylation is stimulated by L.monocytogenes InlB. Tyrosine phosphorylation is maximal 10-20 minutes after treatment with InlB and disappears by 60 minutes. The phosphorylated residues were not identified.
A common allele in the promoter region of the MET shows genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and altered binding of specific transcription factor complexes.
Activation of MET after rearrangement with the TPR gene produces an oncogenic protein.
Autophosphorylated in response to ligand binding on Tyr-1234 and Tyr-1235 in the kinase domain leading to further phosphorylation of Tyr-1349 and Tyr-1356 in the C-terminal multifunctional docking site. Dephosphorylated by PTPRJ at Tyr-1349 and Tyr-1365. Dephosphorylated by PTPN1 and PTPN2.
Defects in MET may be associated with gastric cancer.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Disease-associated variants identified in 4 families cause the deletion of exon 14. This results in the exclusion of an ubiquitination target site within the cytoplasmic domain, hence in protein stabilization. The persistent presence of MET at the cell surface in conditions of ligand-dependent activation retards osteoblastic differentiation.
Expressed in normal hepatocytes as well as in epithelial cells lining the stomach, the small and the large intestine. Found also in basal keratinocytes of esophagus and skin. High levels are found in liver, gastrointestinal tract, thyroid and kidney. Also present in the brain. Expressed in metaphyseal bone (at protein level) (PubMed:26637977).
Heterodimer made of an alpha chain (50 kDa) and a beta chain (145 kDa) which are disulfide linked. Binds PLXNB1. Interacts when phosphorylated with downstream effectors including STAT3, PIK3R1, SRC, PCLG1, GRB2 and GAB1. Interacts with SPSB1, SPSB2 and SPSB4 (By similarity). Interacts with INPP5D/SHIP1. When phosphorylated at Tyr-1356, interacts with INPPL1/SHIP2. Interacts with RANBP9 and RANBP10, as well as SPSB1, SPSB2, SPSB3 and SPSB4. SPSB1 binding occurs in the presence and in the absence of HGF, however HGF treatment has a positive effect on this interaction. Interacts with MUC20; prevents interaction with GRB2 and suppresses hepatocyte growth factor-induced cell proliferation. Interacts with GRB10. Interacts with PTPN1 and PTPN2. Interacts with LECT2; this interaction may have an antagonistic effect on receptor activation (PubMed:27334921). Interacts with HSP90AA1 and HSP90AB1; the interaction suppresses MET kinase activity (PubMed:26517842). Interacts with tensin TNS3 (PubMed:24814316). Interacts (when phosphorylated) with tensin TNS4 (via SH2 domain); the interaction increases MET protein stability by inhibiting MET endocytosis and subsequent lysosomal degradation (PubMed:24814316).
In its inactive state, the C-terminal tail interacts with the catalytic domain and inhibits the kinase activity. Upon ligand binding, the C-terminal tail is displaced and becomes phosphorylated, thus increasing the kinase activity.
MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies.
O-mannosylation of IPT/TIG domains by TMEM260 is required for protein maturation (PubMed:37186866). O-mannosylated residues are composed of single mannose glycans that are not elongated or modified (PubMed:37186866).
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of neuronal precursors, angiogenesis and kidney formation. During skeletal muscle development, it is crucial for the migration of muscle progenitor cells and for the proliferation of secondary myoblasts (By similarity). In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. May regulate cortical bone osteogenesis (By similarity).
The beta-propeller Sema domain mediates binding to HGF.
The kinase domain is involved in SPSB1 binding.
Ubiquitinated. Ubiquitination by CBL regulates MET endocytosis, resulting in decreasing plasma membrane receptor abundance, and in endosomal degradation and/or recycling of internalized receptors.
May be involved in fusion of retrograde transport vesicles derived from an endocytic compartment with the Golgi complex.
May be a substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
F-actin regulator involved in anterograde Golgi to endosome transport: upon ubiquitination via 'Lys-33'-linked ubiquitin chains by the BCR(KLHL20) E3 ubiquitin ligase complex, interacts with EPS15 and localizes to the trans-Golgi network, where it promotes actin polymerization, thereby facilitating post-Golgi trafficking. May play a role in the maintenance of the Golgi apparatus morphology.
Interacts with clathrin adapter AP1 complex. This interaction takes place at Golgi membranes and not AP1-positive endosomal membranes. Interacts (when ubiquitinated at Lys-472) with EPS15.
Reported to form a E3 ubiquitin-ligase complex and promote degradation of TOB1 (PubMed:21130766). Additional evidence is however required to confirm these data.
The membrane-associated form is phosphorylated on tyrosine residues.
Ubiquitinated via 'Lys-33'-linked ubiquitin chains by the BCR(KLHL20) E3 ubiquitin ligase complex: 'Lys-33'-linked ubiquitination promotes interaction with EPS15 and facilitates actin polymerization at the trans-Golgi network, thereby facilitating post-Golgi trafficking. Deubiquitinated by ZRANB1/TRABID.
Widely expressed. Expressed in the spleen, peripheral leukocytes, testes, brain, thymus and small intestine.
Alpha-galactosidase B was first found to be an isoenzyme of alpha-galactosidases, but apparently it differs from alpha-galactosidase A in substrate specificity and is alpha-N-acetylgalactosaminidase.
Belongs to the glycosyl hydrolase 27 family.
Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides. Required for the breakdown of glycolipids.
ADP-ribosylated by tankyrase TNKS and TNKS2. Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination and subsequent activation of the Wnt signaling pathway.
Inhibitor of the Wnt signaling pathway. Down-regulates beta-catenin. Probably facilitate the phosphorylation of beta-catenin and APC by GSK3B.
Interacts with glycogen synthase kinase-3 beta (GSK3B) and beta-catenin. The interaction between axin and beta-catenin occurs via the armadillo repeats contained in beta-catenin (By similarity). Interacts with SMAD7 and RNF111. Interacts with ANKRD6. Interacts with SIAH1 (PubMed:28546513). Interacts with SIAH2 (PubMed:28546513).
Probably phosphorylated by GSK3B and dephosphorylated by PP2A.
Ubiquitinated by RNF146 when poly-ADP-ribosylated, leading to its degradation and subsequent activation of the Wnt signaling pathway. Deubiquitinated by USP34, deubiquitinated downstream of beta-catenin stabilization step: deubiquitination is important Wnt signaling to positively regulate beta-catenin (CTNBB1)-mediated transcription.
Antibodies against STUB1 are found in patients with chronic lymphocytic leukemia (CLL) and in colorectal cancer patients.
E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation (PubMed:10330192, PubMed:11146632, PubMed:11557750, PubMed:23990462). Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension (PubMed:10330192, PubMed:11146632, PubMed:11557750, PubMed:23990462). Ubiquitinates NOS1 in concert with Hsp70 and Hsp40 (PubMed:15466472). Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90 (PubMed:10330192, PubMed:11146632, PubMed:15466472). Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation (PubMed:11557750, PubMed:23990462). Mediates polyubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB-degradation by the proteasome (PubMed:19713937). Mediates polyubiquitination of CYP3A4 (PubMed:19103148). Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation (PubMed:19567782). Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and promotes ubiquitin-mediated protein degradation (PubMed:27708256). Negatively regulates the suppressive function of regulatory T-cells (Treg) during inflammation by mediating the ubiquitination and degradation of FOXP3 in a HSPA1A/B-dependent manner (PubMed:23973223). Catalyzes monoubiquitination of SIRT6, preventing its degradation by the proteasome (PubMed:24043303). Likely mediates polyubiquitination and down-regulates plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity (PubMed:28813410). Negatively regulates TGF-beta signaling by modulating the basal level of SMAD3 via ubiquitin-mediated degradation (PubMed:24613385). May regulate myosin assembly in striated muscles together with UBE4B and VCP/p97 by targeting myosin chaperone UNC45B for proteasomal degradation (PubMed:17369820). Mediates ubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation (PubMed:29883609).
Expressed in differentiated myotubes (at protein level) (PubMed:17369820). Highly expressed in skeletal muscle, heart, pancreas, brain and placenta (PubMed:10330192, PubMed:11435423). Detected in kidney, liver and lung (PubMed:10330192, PubMed:11435423).
Homodimer (By similarity). Interacts with BAG2 (PubMed:16169850). Interacts with E2 ubiquitin conjugating enzymes UBE2D1, UBE2D2 and UBE2D3 (PubMed:11557750). Detected in a ternary complex containing STUB1, HSPA1A and HSPBP1 (PubMed:15215316). Interacts with MKKS (PubMed:18094050). Interacts with DNAAF4 (PubMed:19423554). Interacts (when monoubiquitinated) with ATXN3. Interacts with UBE2W. Interacts (via the U-box domain) with the UBE2V2-UBE2N heterodimer; the complex has a specific 'Lys-63'-linked polyubiquitination activity (By similarity). Interacts with DNAJB6 (PubMed:22366786). Interacts with FLCN (PubMed:27353360). Interacts with HSP90AA1 (PubMed:27353360, PubMed:24613385). Interacts with HSP90 (PubMed:11146632). Interacts with UBE2N and UBE2V1 (PubMed:16307917). Interacts (via TPR repeats) with the C-terminal domain of HSPA1A (PubMed:10330192). Interacts with the non-acetylated form of HSPA1A and HSPA1B (PubMed:27708256). Interacts (via TPR repeats) with the C-terminal domain of HSPA8 (PubMed:10330192, PubMed:11557750, PubMed:23990462, PubMed:27708256). Interacts with SMAD3 and HSP90AB1 (PubMed:24613385). Interacts with UBE4B (PubMed:17369820). Interacts with PRMT5 (PubMed:33376131).
Monoubiquitinated at Lys-2 following cell stress by UBE2W, promoting the interaction with ATXN3 (By similarity). Auto-ubiquitinated; mediated by UBE2D1 and UBE2D2.
The TPR domain is essential for ubiquitination mediated by UBE2D1.
The U-box domain is required for the ubiquitin protein ligase activity.
Up-regulated by inflammatory signals in regulatory T-cells (Treg).
Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. Plays a role in regulating the actin cytoskeleton and cell shape.
Expressed in fetal heart, brain, lung, kidney and placenta. Less expressed in liver; adult heart, brain, lung, pancreas and skeletal muscle.
Interacts with DBNL/ABP1 and CTTN. May interact with CCPG1 (By similarity). Binds CDC42.
Ancillary protein that assembles as a beta subunit with a voltage-gated potassium channel complex of pore-forming alpha subunits. Modulates the gating kinetics and enhances stability of the channel complex. Assembled with KCNB1 modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1. Associated with KCNH2/HERG is proposed to form the rapidly activating component of the delayed rectifying potassium current in heart (IKr). May associate with KCNQ2 and/or KCNQ3 and modulate the native M-type current. May associate with HCN1 and HCN2 and increase potassium current. Interacts with KCNQ1; forms a heterooligomer complex leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current (PubMed:11101505). KCNQ1-KCNE2 channel associates with Na(+)-coupled myo-inositol symporter in the apical membrane of choroid plexus epithelium and regulates the myo-inositol gradient between blood and cerebrospinal fluid with an impact on neuron excitability.
Highly expressed in brain, heart, skeletal muscle, pancreas, placenta, kidney, colon and thymus. A small but significant expression is found in liver, ovary, testis, prostate, small intestine and leukocytes. Very low expression, nearly undetectable, in lung and spleen.
Interacts with KCNB1 (By similarity). Associates with KCNH2/ERG1 (PubMed:10219239). May associate with KCNQ2 and KCNQ3 (PubMed:11034315). Associates with HCN1 and probably HCN2. Heteromultimer with KCNC2. Interacts with KCNC2 (By similarity). Interacts with KCNQ1; forms a heterooligomer complex that targets to the membrane raft and leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current (PubMed:11101505, PubMed:20533308).
Transcription factor involved in differentiation of certain neurons and mesenchymal cells.
Co-chaperone that binds to numerous proteins and promotes their interaction with Hsp70 and Hsp90.
Expressed in brain, heart, kidney, liver, placenta and skeletal muscle.
Self-associates. Forms complexes with Hsp70 and Hsp90. Interacts with CDC37, FKBP4, PPID and STIP1.
Involved in the development of the olfactory system and in neuronal control of puberty. Induces the collapse and paralysis of neuronal growth cones. Could serve as a ligand that guides specific growth cones by a motility-inhibiting mechanism. Binds to the complex neuropilin-1/plexin-1.
Strong binding to neuropilin is mediated by the carboxy third of the protein.
11-cis retinoids act as allosteric modulators of acyl-CoA retinol O-fatty-acyltransferase (ARAT) activity by suppressing esterification of 9-cis, 13-cis, or all-trans retinols concurrently increasing the enzyme specificity toward 11-cis isomer.
Acyltransferase that catalyzes the formation of ester bonds between fatty alcohols and fatty acyl-CoAs to form wax monoesters (PubMed:15220349, PubMed:15671038, PubMed:16106050, PubMed:28420705). Shows a preference for medium chain acyl-CoAs from C12 to C16 in length and fatty alcohols shorter than C20, as the acyl donors and acceptors, respectively (PubMed:15220349, PubMed:15671038). Also possesses acyl-CoA retinol acyltransferase (ARAT) activity that catalyzes 11-cis-specific retinyl ester synthesis (PubMed:16106050, PubMed:24799687). Shows higher catalytic efficiency toward 11-cis-retinol versus 9-cis-retinol, 13-cis-retinol, and all-trans-retinol substrates (PubMed:24799687).
Belongs to the diacylglycerol acyltransferase family.
Highly expressed in skin, where it is primarily restricted to undifferentiated peripheral sebocytes. Also expressed at lower level in other tissues except pancreas.
(Microbial infection) Involved in Dengue virus pathogenesis via antibody-dependent enhancement (ADE) mechanism. Secondary infection with Dengue virus triggers elevated levels of afucosylated non-neutralizing IgG1s with reactivity to viral envelope/E protein. Viral antigen-IgG1 complexes bind with high affinity to FCGR3A, facilitating virus entry in myeloid cells and subsequent viral replication.
Encoded by one of two nearly identical genes: FCGR3A (shown here) and FCGR3B which are expressed in a tissue-specific manner. The Phe-203 in III-A determines the transmembrane domains whereas the 'Ser-203' in III-B determines the GPI-anchoring.
Expressed in natural killer cells (at protein level) (PubMed:2526846). Expressed in a subset of circulating monocytes (at protein level) (PubMed:27670158).
FCGR3A in mammals is the true ortholog of FCGR4 in rodents. The FCGR2A-HSPA6-FCGR4-FCGR2B module was duplicated in great apes through non-allelic homologous recombination, giving rise to two FCGR4-type genes and to FCGR2C, a hybrid gene combining FCGR2A and FCGR2B. While FCGR3A kept the original FCGR4 functionality, FCGR3B rapidly evolved and acquired specific features coding for a GPI-anchored receptor.
Forms a heterooligomeric complex with ITAM-containing signaling subunits, either a homodimer of CD247, a homodimer of FCER1G or a heterodimer of CD247 and FCER1G (PubMed:2532305, PubMed:1825220, PubMed:28652325). Interacts (via transmembrane domain) with signaling subunits; this interaction is a prerequisite for receptor complex expression on the cell surface and intracellular signal transduction (PubMed:2532305, PubMed:1825220, PubMed:28652325). Binds the Fc region of antigen-complexed IgG with a preference for IgG1 and IgG3 isotypes (PubMed:22023369, PubMed:21768335, PubMed:8609432, PubMed:9242542, PubMed:11711607). Interacts with CD2; this interaction is involved in NK cell activation and cytotoxicity (PubMed:23006327). Interacts with S100A4; this interaction inhibits PKC-dependent phosphorylation of FCGR3A (PubMed:23024279).
Glycosylated. Contains high mannose- and complex-type oligosaccharides. Glycosylation at Asn-180 is mandatory for high affinity binding to the Fc and for discrimination between fucosylated and afucosylated IgG glycoforms.
Phosphorylated at RSSTR motif by PKC. The relevant physiological PKCs might be PRKCI, PRKCG, PRKCE, PRKCH and PRKCQ.
Receptor for the invariable Fc fragment of immunoglobulin gamma (IgG). Optimally activated upon binding of clustered antigen-IgG complexes displayed on cell surfaces, triggers lysis of antibody-coated cells, a process known as antibody-dependent cellular cytotoxicity (ADCC). Does not bind free monomeric IgG, thus avoiding inappropriate effector cell activation in the absence of antigenic trigger (PubMed:24412922, PubMed:25786175, PubMed:21768335, PubMed:22023369, PubMed:8609432, PubMed:9242542, PubMed:25816339, PubMed:11711607, PubMed:28652325). Mediates IgG effector functions on natural killer (NK) cells. Binds antigen-IgG complexes generated upon infection and triggers NK cell-dependent cytokine production and degranulation to limit viral load and propagation. Involved in the generation of memory-like adaptive NK cells capable to produce high amounts of IFNG and to efficiently eliminate virus-infected cells via ADCC (PubMed:25786175, PubMed:24412922). Regulates NK cell survival and proliferation, in particular by preventing NK cell progenitor apoptosis (PubMed:9916693, PubMed:29967280). Fc-binding subunit that associates with CD247 and/or FCER1G adapters to form functional signaling complexes. Following the engagement of antigen-IgG complexes, triggers phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM)-containing adapters with subsequent activation of phosphatidylinositol 3-kinase signaling and sustained elevation of intracellular calcium that ultimately drive NK cell activation. The ITAM-dependent signaling coupled to receptor phosphorylation by PKC mediates robust intracellular calcium flux that leads to production of pro-inflammatory cytokines, whereas in the absence of receptor phosphorylation it mainly activates phosphatidylinositol 3-kinase signaling leading to cell degranulation (PubMed:2532305, PubMed:1825220, PubMed:23024279). Costimulates NK cells and trigger lysis of target cells independently of IgG binding (PubMed:23006327, PubMed:10318937). Mediates the antitumor activities of therapeutic antibodies. Upon ligation on monocytes triggers TNFA-dependent ADCC of IgG-coated tumor cells (PubMed:27670158). Mediates enhanced ADCC in response to afucosylated IgGs (PubMed:34485821).
Undergoes rapid ectodomain shedding upon NK cell stimulation. The soluble form is produced by a proteolytic cleavage mediated by ADAM17. Repeated stimulation causes receptor shedding, a mechanism that allows for increased NK cell motility and detachment from opsonized target cells while avoiding activation-induced NK cell apoptosis.
Up-regulated in a monocyte subset upon exposure to IL10, TGFB and MCSF.
Belongs to the TRAFAC class YlqF/YawG GTPase family.
Possible regulatory or functional link with the histocompatibility cluster.
Contains a large substrate-binding pocket that recognizes alpha-helical transmembranes, which alternately faces the endoplasmic reticulum lumen and cytosol, while remaining accessible to the lipid bilayer through a lateral opening. The translocase alternates between two conformations: inward-open (E1) and outward-open (E2) states. Undergoes a series of conformational changes with ATP-binding, phosphorylation of the Asp active site and subsequent dephosphorylation in a Post-Albers cycle (i.e., E1 -> E1-ATP -> E1P-ADP -> E1P -> E2P -> E2-Pi -> E1). A substrate transmembrane helix with a short, preferentially positively charged lumenal segment binds to the outward-open pocket and the E2P-to-E1 transition flips the transmembrane by a switch from the outward-open to inward-open conformation.
Endoplasmic reticulum translocase required to remove mitochondrial transmembrane proteins mistargeted to the endoplasmic reticulum (PubMed:32973005, PubMed:36264797). Acts as a dislocase that mediates the ATP-dependent extraction of mislocalized mitochondrial transmembrane proteins from the endoplasmic reticulum membrane (PubMed:32973005). Specifically binds mitochondrial tail-anchored transmembrane proteins: has an atypically large substrate-binding pocket that recognizes and binds moderately hydrophobic transmembranes with short hydrophilic lumenal domains (PubMed:32973005).
Was initially thought to mediate manganese transport (PubMed:24392018). However, it was later shown to specifically bind moderately hydrophobic transmembrane with short hydrophilic lumenal domains that misinsert into the endoplasmic reticulum (PubMed:32973005).
A chromosomal aberration involving ZNF81 is found in a severe intellectual disability patient. Translocation t(X;9)(p11.23;q34.3).
Transfers mannosyl residues to the hydroxyl group of serine or threonine residues. The 4 members of the TMTC family are O-mannosyl-transferases dedicated primarily to the cadherin superfamily, each member seems to have a distinct role in decorating the cadherin domains with O-linked mannose glycans at specific regions. Also acts as O-mannosyl-transferase on other proteins such as PDIA3 (PubMed:28973932). Involved in the positive regulation of proteasomal protein degradation in the endoplasmic reticulum (ER), and the control of ER stress response.
Catalyzes the transfer of fucosyl moiety from GDP-beta-L-fucose to the innermost GlcNAc residue in biantennary N-glycan acceptors. Does not fucosylate GlcNAc within type 2 lactosamine unit.
Expressed in fetal tissues including skin, small intestine, liver, kidney, lung, muscle, heart and brain.
Expressed in lung, digestive tract, gall bladder, placenta, kidney, uterus and brain. Not detected in spleen, heart, muscle, liver and pancreas.
Predominantly fucosylates the innermost N-acetyl glucosamine (GlcNAc) residue in biantennary N-glycan acceptors. Postulated to generate core alpha(1->3)-fucose epitope within the chitobiose unit of biantennary N-glycans, providing for a recognition signal to reorient aberrantly folded glycoproteins for degradation (PubMed:19088067). Involved in biosynthesis of Lewis X-carrying biantennary N-glycans that regulate neuron stem cell self-renewal during brain development (By similarity).
TMEM138 and TMEM216 genes are adjacent and are aligned in a head-to-tail configuration. They share some cis regulatory region and display coordinated expression. Genes were joined by chromosomal rearrangement at the amphiboan to reptile evolutionary transition around 340 million years ago (PubMed:22282472).
Expressed in prostate, ovary, testis, placenta and prostate cancer cell lines. Localizes to basal and terminal prostate epithelial cells.
E3 ubiquitin-protein ligase that mediates the ubiquitination and proteasomal degradation of CYLD.
Low expression in most tissues. Higher expression in kidney tubular cells. Overexpressed in astrocytoma tumor cells.
Component of the tRNA-splicing ligase complex.
A chromosomal aberration involving ZC3H12D may be the cause of the transformation of follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL). Translocation t(2;6)(p12;q25) with IGK. Resulting protein may not be expressed.
By prolonged exposure to bacterial lipopolysaccharides (LPS) in acute monocytic leukemia cell line THP-1 cells.
Expressed in normal human lymphocytes but defective in some leukemia/lymphoma cell lines.
Interacts with ZC3H12A (PubMed:26134560).
May regulate cell growth likely by suppressing RB1 phosphorylation (PubMed:19531561). May function as RNase and regulate the levels of target RNA species (Potential). In association with ZC3H12A enhances the degradation of interleukin IL-6 mRNA level in activated macrophages (PubMed:26134560). Serve as a tumor suppressor in certain leukemia cells (PubMed:17210687). Overexpression inhibits the G1 to S phase progression through suppression of RB1 phosphorylation (PubMed:19531561).
Component of multiple ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes formed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and a variable substrate-specific adapter (PubMed:9122164, PubMed:10973499, PubMed:11384984, PubMed:26138980, PubMed:29779948, PubMed:29775578). Component of the ECS(VHL) or CBC(VHL) complex containing VHL (PubMed:9122164, PubMed:10973499, PubMed:11384984). Component of the ECS(MED8) complex with the probable substrate recognition component MED8 (PubMed:12149480). Component of multiple ECS complexes part of the DesCEND (destruction via C-end degrons) pathway, which contain either KLHDC2, KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B or FEM1C as substrate-recognition component (PubMed:23102700, PubMed:26138980, PubMed:29779948, PubMed:29775578). Component of the ECS(LRR1) complex with the probable substrate recognition component LRR1 (PubMed:15601820, PubMed:34700328). Component of a probable ECS E3 ubiquitin-protein ligase complex containing CUL2, RBX1, ELOB, ELOC and FEM1B (PubMed:15601820). Part of an E3 ubiquitin-protein ligase complex including ZYG11B, CUL2 and Elongin BC (PubMed:17304241). Part of an E3 ubiquitin-protein ligase complex including ZER1, CUL2 and Elongin BC (PubMed:17304241). Interacts with RBX1, RNF7, FEM1B and TIP120A/CAND1 (PubMed:10230407, PubMed:12609982). Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2 (PubMed:22286099). Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1 (PubMed:24076655, PubMed:27565346). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (PubMed:23401859, PubMed:23201271, PubMed:24192928, PubMed:26906416). Component of VCB (elongins BC/CUL2/VHL) complex that contains at least DCUN1D1, CUL2 and VHL; this complex triggers CUL2 neddylation and consequently cullin ring ligase (CRL) substrates polyubiquitylation (PubMed:23401859).
Core component of multiple cullin-RING-based ECS (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of target proteins (PubMed:11384984, PubMed:26138980, PubMed:29779948, PubMed:29775578). CUL2 may serve as a rigid scaffold in the complex and may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme (PubMed:9122164, PubMed:10973499, PubMed:11384984, PubMed:12609982, PubMed:24076655). The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1 (PubMed:12609982, PubMed:24076655, PubMed:27565346). The functional specificity of the ECS complex depends on the substrate recognition component (PubMed:9122164, PubMed:10973499, PubMed:26138980, PubMed:29779948, PubMed:29775578). ECS(VHL) mediates the ubiquitination of hypoxia-inducible factor (HIF) (PubMed:9122164, PubMed:10973499). A number of ECS complexes (containing either KLHDC2, KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B or FEM1C as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:26138980, PubMed:29779948, PubMed:29775578). ECS complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). ECS(LRR1) ubiquitinates MCM7 and promotes CMG replisome disassembly by VCP and chromatin extraction during S-phase (By similarity).
Neddylated; which enhances the ubiquitination activity of ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes. CBC(VHL) complex formation seems to promote neddylation. Deneddylated via its interaction with the COP9 signalosome (CSN) complex (By similarity).
Autophosphorylation regulates kinase activity. Phosphorylation on Tyr-518 is required for interaction with SRC and is observed during association with clathrin-coated pits.
Inhibited by AIM-100 (4-amino-5,6-biaryl-furo[2,3-d]pyrimidine), which suppresses activating phosphorylation at Tyr-284. Repressed by dasatinib.
Interacts with NEDD4 (via WW3 domain). NEDD4L and EGF promote association with NEDD4 (By similarity). Homodimer. Interacts with AR, CDC42, WWASL and WWOX. Interacts with CSPG4 (activated). Interacts with MERTK (activated); stimulates autophosphorylation. May interact (phosphorylated) with HSP90AB1; maintains kinase activity. Interacts with NPHP1. Interacts with SNX9 (via SH3 domain). Interacts with SRC (via SH2 and SH3 domain). Interacts with EGFR, and this interaction is dependent on EGF stimulation and kinase activity of EGFR. Interacts (via kinase domain) with AKT1. Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas. Interacts with BCAR1/p130cas via SH3 domains. Forms complexes with GRB2 and numerous receptor tyrosine kinases (RTK) including LTK, AXL or PDGFRL, in which GRB2 promotes RTK recruitment by TNK2.
Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr-287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR. Phosphorylates WASP (PubMed:20110370).
Polyubiquitinated by NEDD4 and NEDD4L. Degradation can be induced by EGF and is lysosome-dependent (By similarity).
The EBD (EGFR-binding domain) domain is necessary for interaction with EGFR.
The SAM-like domain is necessary for NEDD4-mediated ubiquitination. Promotes membrane localization and dimerization to allow for autophosphorylation.
The Tyr-284 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. It also shows a significant increase in expression in prostate cancers during the progressive stages.
The UBA domain binds both poly- and mono-ubiquitin.
A dominant de novo FEM1C variant was identified in a patient with neurodevelopmental disorder with absent speech, pyramidal signs, and limb ataxia.
Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter FEM1C.
Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:29775578, PubMed:33398170, PubMed:33398168). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (PubMed:29779948, PubMed:29775578, PubMed:33398170, PubMed:33398168). The CRL2(FEM1C) complex specifically recognizes proteins with an arginine at the C-terminus: recognizes and binds proteins ending with -Lys/Arg-Xaa-Arg and -Lys/Arg-Xaa-Xaa-Arg C-degrons, such as SIL1 or OR51B2, leading to their ubiquitination and degradation (PubMed:33398170, PubMed:33398168). The CRL2(FEM1C) complex mediates ubiquitination and degradation of truncated MSRB1/SEPX1 selenoproteins produced by failed UGA/Sec decoding (PubMed:26138980). Promotes ubiquitination and degradation of SLBP (PubMed:28118078).
The first seven ANK repeats at the N-terminus (1-242) are essential for recognition of Lys/Arg-Xaa-Arg and -Lys/Arg-Xaa-Xaa-Arg C-degrons.
Was initially thought to be the ortholog of mouse FEM1A.
Widely expressed. Highly expressed in kidney, cardiac tissue, skeletal muscle and testis. Expressed at lower levels in other tissues, including cartilage.
Detected in brain cortex and lung (at protein level).
Has also activity with Mn(2+) (in vitro).
The active enzyme is formed by a heterodimer of an alpha and a beta subunit. Heterodimer with GUCY1B1 (PubMed:9742212, PubMed:23505436, PubMed:24669844).
Expressed in epithelium of small and large intestines (at protein level). Expressed in stomach, duodenum, jejunum, ascending colon, spleen, thymus, lymph node, trachea and leukocytes.
Inhibitory regulator of the Ras-cyclic AMP pathway.
Inhibited by coumarins, sulfonamide derivatives such as acetazolamide (AZA), saccharin and Foscarnet (phosphonoformate trisodium salt).
Strongest expression in heart, pancreas, kidney, placenta, lung, and skeletal muscle. Not expressed in liver.
Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6; in the complex, is required for optimal binding of ELP3 to ELP4.
Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine) (PubMed:29332244). The elongator complex catalyzes formation of carboxymethyluridine in the wobble base at position 34 in tRNAs (PubMed:29332244). Involved in cell migration (By similarity).
Ubiquitously expressed with high levels in heart, brain, liver, skeletal muscle and testis.
Expressed in kidney, brain, pancreas, skeletal muscle, lung, liver, placenta, and heart.
Functions in cell-cell adhesion, cell migration and axon guidance, exerting an attractive or repulsive role depending on its interaction partners. Plays a role in the spatial organization of brain neurons. Plays a role in vascular development in the retina (By similarity). Plays a role in cell-cell adhesion via its interaction with ADGRL3 and probably also other latrophilins that are expressed at the surface of adjacent cells (PubMed:26235030). Interaction with the intracellular domain of ROBO1 mediates axon attraction towards cells expressing NTN1. Mediates axon growth cone collapse and plays a repulsive role in neuron guidance via its interaction with UNC5B, and possibly also other UNC-5 family members (By similarity). Promotes neurite outgrowth (in vitro) (PubMed:14706654). Mediates cell-cell contacts that promote an increase both in neurite number and in neurite length. Plays a role in the regulation of the density of glutamaergic synapses. Plays a role in fibroblast growth factor-mediated signaling cascades. Required for normal morphogenesis during embryonic development, but not for normal embryonic patterning. Required for normal ventral closure, headfold fusion and definitive endoderm migration during embryonic development. Required for the formation of a normal basement membrane and the maintenance of a normal anterior visceral endoderm during embryonic development (By similarity).
Monomer and homodimer. Self-associates (via leucine-rich repeats), giving rise to homooligomers (PubMed:26235030). Interacts with FGFR1. Interacts (via extracellular domain) with ADGRL1/LPHN1 and LPHN2 (via olfactomedin-like domain) (By similarity). Interacts (via extracellular domain) with ADGRL3 (via olfactomedin-like domain); the interaction is direct (PubMed:26235030). Interacts (via extracellular domain) with UNC5B and UNC5D (via extracellular domain); the interaction is direct (PubMed:26235030). Identified in complexes composed of FLRT3, ADGRL3 and UNC5B, respectively FLRT3, ADGRL3 and UNC5D (PubMed:26235030). May also interact (via extracellular domain) with UNC5A and UNC5C. Interacts (via cytoplasmic domain) with ROBO1 (By similarity).
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in FLRT3 also have a mutation in another HH-associated gene including FGFR1, HS6ST1 and FGF17 (PubMed:23643382).
Could be the product of a pseudogene. This gene is longer than the rat and mouse orthologs and also contains a RanBP2-type zinc finger which is not present in those orthologs.
Belongs to the sphingomyelin synthase family.
Brain, heart, kidney, liver, muscle and stomach.
Inhibited by bacterial PC-phospholipase C inhibitor D609.
Major sphingomyelin synthase at the Golgi apparatus (PubMed:17449912, PubMed:14685263). Catalyzes the reversible transfer of phosphocholine moiety in sphingomyelin biosynthesis: in the forward reaction transfers phosphocholine head group of phosphatidylcholine (PC) on to ceramide (CER) to form ceramide phosphocholine (sphingomyelin, SM) and diacylglycerol (DAG) as by-product, and in the reverse reaction transfers phosphocholine from SM to DAG to form PC and CER. The direction of the reaction depends on the levels of CER and DAG in Golgi membranes (PubMed:14685263, PubMed:17449912, PubMed:14976195, PubMed:17982138, PubMed:19454763). Does not use free phosphorylcholine or CDP-choline as donor (PubMed:14976195, PubMed:14685263). Regulates receptor-mediated signal transduction via mitogenic DAG and proapoptotic CER, as well as via SM, a structural component of membrane rafts that serve as platforms for signal transduction and protein sorting (PubMed:14976195, PubMed:17449912, PubMed:17982138). Plays a role in secretory transport via regulation of DAG pool at the Golgi apparatus and its downstream effects on PRKD1 (PubMed:18370930, PubMed:21980337).
Overexpression of the human protein in mouse causes increased non-HDL-sphingomyelin and non-HDL cholesterol levels, decreased HDL-sphingomyelin and HDL-cholesterol levels and increases the atherogenic potential of non-HDL lipoprotein particles.
During centriole duplication, plays a role in the centriole elongation by promoting the recruitment of the microtubule-binding elongation machinery through its interaction with RTTN, leading to the centriole to centrosome conversion (PubMed:30168418, PubMed:30230954). In addition, may play a role in the primary cilia assembly (By similarity).
Interacts with PPP1CA; this interaction mediates the PPP1CA phosphatase activity inhibition (PubMed:19389623, PubMed:30230954). Interacts with RTTN; this interaction allows the mutual recruitment to the centriole (PubMed:30168418).
May play important roles in cardiac development and/or cardiac function.
Part of the core SMN complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP (PubMed:16434402, PubMed:18984161, PubMed:17178713). Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG (PubMed:18984161). Interacts with GEMIN6; the interaction is direct (PubMed:33754639, PubMed:17023415). Interacts with GEMIN7; the interaction is direct (PubMed:33754639, PubMed:17023415, PubMed:17178713). Interacts with SMN1; the interaction is direct (PubMed:17023415, PubMed:33754639, PubMed:17178713). Interacts with GEMIN4; the interaction is direct (PubMed:17178713).
Component of a multiprotein complex with RPA2 and SPATA22. Interacts with the complex BRME1:HSF2BP:BRCA2.
In fetal gonads, specifically expressed in the ovary starting at the 14th weeks post fertilization (PubMed:24068956). In the adult, restricted to testis (PubMed:28206990).
Single-stranded DNA-binding protein required for homologous recombination in meiosis I. Required for double strand breaks (DSBs) repair and crossover formation and promotion of faithful and complete synapsis. Not required for the initial loading of recombinases but required to maintain a proper number of RAD51 and DMC1 foci after the zygotene stage. May act by ensuring the stabilization of recombinases, which is required for successful homology search and meiotic recombination. Displays Single-stranded DNA 3'-5' exonuclease activity in vitro.
Down-regulated in cancer pancreatic cells undergoing differentiation and apoptosis.
May modulate the Rho pathway signaling by providing a scaffold for the Lbc Rho guanine nucleotide exchange factor (ARHGEF1).
Widely expressed. Expressed at lower level in neural tissues and at the highest level in the adrenal gland.
Adapter protein that links activated FGR and NGF receptors to downstream signaling pathways. Plays an important role in the activation of MAP kinases and in the phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, in response to ligand-mediated activation of FGFR1. Modulates signaling via SHC1 by competing for a common binding site on NTRK1.
Highly expressed in heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis.
Part of a complex containing FRS2, GRB2, GAB1, PIK3R1 and SOS1. Part of a complex containing GRB2 and CBL. Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Binds RET (By similarity). Binds ALK, FGFR1, CKS2, MAPK1/ERK2, MAPK3/ERK1 and SRC. The tyrosine-phosphorylated protein binds the SH2 domains of GRB2 and PTPN11. Interacts with NTRK1, NTRK2 and NTRK3 (phosphorylated upon ligand-binding).
Phosphorylated by ULK2 in vitro (By similarity). Phosphorylated on tyrosine residues upon stimulation by NGF or FGF2. Phosphorylated on tyrosine residues by activated ALK and FGFR1. Phosphorylated on tyrosine residues upon activation of FGFR2 and FGFR3. Phosphorylated on threonine residues by MAP kinases; this inhibits tyrosine phosphorylation, and thereby down-regulates FRS2-mediated activation of MAP kinases.
Ubiquitinated when tyrosine phosphorylated and in a complex with GRB2. The unphosphorylated form is not subject to ubiquitination (By similarity).
Expressed in elongating spermatids and spermatozoa (at protein level). Isoform 1 is expressed in testis. Isoform 3 and isoform 5 are also expressed in brain, pancreas and numerous brain tumors.
Interacts with FSCB (By similarity). Isoform 3 self-associates. Isoform 3 and isoform 5 interact with GSK3B. Isoform 1 does not interact with GSK3B.
Isoform 1 is phosphorylated on tyrosine residues during in vitro capacitation. Isoform 3 and isoform 5 are phosphorylated by GSK3B in vitro. Dephosphorylation affects its ability to bind calcium.
May function as a regulator of both motility- and head-associated functions such as capacitation and the acrosome reaction. Isoform 1 binds calcium in vitro. Isoform 2 and isoform 6 probably bind calcium. Isoform 3 and isoform 5 do not bind calcium in vitro. Isoform 4 probably does not bind calcium.
Might play a role in cell proliferation.
Depletion of CEP126 by siRNA results in an increase in cytokinesis aberrant cells.
Expressed in brain, lung, skeletal muscle, kidney, pancreas, testis and ovary.
Participates in cytokinesis (PubMed:19799413). Necessary for microtubules and mitotic spindle organization (PubMed:24867236). Involved in primary cilium formation (PubMed:24867236).
Acetylation at Lys-339 by KAT2A and KAT2B promotes nuclear retention.
DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation (PubMed:25725155, PubMed:25963046, PubMed:29174768, PubMed:26917986, PubMed:27035640, PubMed:8988164). Binds to the core DNA motif of NPPA promoter (PubMed:26926761).
Defects in TBX5 are associated with susceptibility to heart disorders including dilated cardiomyopathy (DCM) and atrial fibrillation (AF). DCM is characterized by ventricular and impaired systolic function, resulting in heart failure and arrhythmia. Patient are at risk of premature death. AF is a common sustained cardiac rhythm disturbance. AF is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure.
Monomer (PubMed:20450920). Homodimer (via the T-box); binds DNA as homodimer (PubMed:26926761). Interacts (via the T-box) with NKX2-5 (via the homeobox); this complex binds DNA (PubMed:26926761). Interacts with GATA4 (PubMed:24000169). Interacts with KAT2A and KAT2B (PubMed:29174768).
The T-Box domain binds to double-stranded DNA (PubMed:26926761).
Association to the cytoskeleton through a N-terminal leucine rich-domain (AA 190-218).
Expressed in early hematopoietic precursors.
Interacts with TEX11 (By similarity). Interacts with ESR1, PBX1, PBX2 and PBX3.
Regulator of pre-B-cell leukemia transcription factors (BPXs) function. Inhibits the binding of PBX1-HOX complex to DNA and blocks the transcriptional activity of E2A-PBX1. Tethers estrogen receptor-alpha (ESR1) to microtubules and allows them to influence estrogen receptors-alpha signaling.
The C-terminal domain (AA 443-731) contains a nuclear export signal.
Heterodimer; heterodimerizes with RFX1 and RFX2, and RFX6.
Transcription factor required for ciliogenesis and islet cell differentiation during endocrine pancreas development. Essential for the differentiation of nodal monocilia and left-right asymmetry specification during embryogenesis. Required for the biogenesis of motile cilia by governing growth and beating efficiency of motile cells. Also required for ciliated ependymal cell differentiation. Regulates the expression of genes involved in ciliary assembly (DYNC2LI1, FOXJ1 and BBS4) and genes involved in ciliary motility (DNAH11, DNAH9 and DNAH5) (By similarity). Together with RFX6, participates in the differentiation of 4 of the 5 islet cell types during endocrine pancreas development, with the exception of pancreatic PP (polypeptide-producing) cells. Regulates transcription by forming a heterodimer with another RFX protein and binding to the X-box in the promoter of target genes (PubMed:20148032). Represses transcription of MAP1A in non-neuronal cells but not in neuronal cells (PubMed:12411430).
Expressed in testis and spermatozoa (at protein level).
Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3. NSMCE1, NSMCE4A or EID3 and NSMCE3 probably form a subcomplex that bridges the head domains of the SMC5:SMC6 heterodimer (PubMed:18086888). Interacts with NSMCE3 (PubMed:27427983).
Component of the SMC5-SMC6 complex, a complex involved in DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). Is involved in positive regulation of response to DNA damage stimulus.
Acetylation at Lys-118 dramatically enhances enzymatic activity and promotes adipogenic differentiation.
Catalyzes the reduction of aromatic alpha-keto acids in the presence of NADH (PubMed:2449162, PubMed:3052244). Plays essential roles in the malate-aspartate shuttle and the tricarboxylic acid cycle, important in mitochondrial NADH supply for oxidative phosphorylation (PubMed:31538237). Catalyzes the reduction of 2-oxoglutarate to 2-hydroxyglutarate, leading to elevated reactive oxygen species (ROS) (PubMed:34012073).
Acts as a substrate for the production of iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3) (PubMed:32025030, PubMed:17532758). The synthesis of T3 and T4 involves iodination of selected tyrosine residues of TG/thyroglobulin followed by their oxidative coupling in the thyroid follicle lumen (PubMed:32025030). Following TG re-internalization and lysosomal-mediated proteolysis, T3 and T4 are released from the polypeptide backbone leading to their secretion into the bloodstream (PubMed:32025030). One dimer produces 7 thyroid hormone molecules (PubMed:32025030).
Iodinated on tyrosine residues by TPO (PubMed:2760035, PubMed:32025030). There are 4 pairs of iodinated tyrosines used for coupling: acceptor Tyr-24 is coupled to donor Tyr-149 or Tyr-234, acceptor Tyr-2573 is coupled to donor Tyr-2540, acceptor Tyr-2766 in monomer 1 is coupled to donor Tyr-2766 in monomer 2 and acceptor Tyr-1310 in monomer 1 is coupled to donor Tyr-108 in monomer 2 (PubMed:32025030).
Monomer (PubMed:32025030). Homodimer (via ChEL region); occurs in the endoplasmic reticulum and is required for export to the Golgi apparatus (PubMed:32025030). Homooligomer; disulfide-linked; stored in this form in the thyroid follicle lumen (PubMed:8626858).
Specifically expressed in the thyroid gland.
Sulfated tyrosines are desulfated during iodination.
The cholinesterase-like (ChEL) region is required for dimerization and export from the endoplasmic reticulum.
The cholinesterase-like (ChEL) region lacks the Ser residue of the catalytic triad suggesting that it has no esterase activity.
Undergoes sequential proteolysis by cathepsins to release thyroxine (T4) and triiodothyronine (T3) hormones. In the thyroid follicle lumen, cross-linked TG (storage form) is solubilized by limited proteolysis mediated by cathepsins CTSB and/or CTSL. Partially cleaved TG is further processed by CTSK/cathepsin K and/or CTSL resulting in the release of T4. Following endocytosis, further processing occurs leading to the release of T3 and more T4 hormones.
Heterodimer with other family members, including GBP1, GBP2 and GBP5 (PubMed:21151871). Dimerization regulates subcellular location.
Interferon (IFN)-inducible GTPase that plays important roles in innate immunity against a diverse range of bacterial, viral and protozoan pathogens (PubMed:22106366). Hydrolyzes GTP very efficiently; GDP rather than GMP is the major reaction product (By similarity). Following infection, recruited to the pathogen-containing vacuoles or vacuole-escaped bacteria and acts as a positive regulator of inflammasome assembly by promoting the release of inflammasome ligands from bacteria (By similarity). Acts by promoting lysis of pathogen-containing vacuoles, releasing pathogens into the cytosol (By similarity). Following pathogen release in the cytosol, promotes recruitment of proteins that mediate bacterial cytolysis: this liberates ligands that are detected by inflammasomes, such as lipopolysaccharide (LPS) that activates the non-canonical CASP4/CASP11 inflammasome or double-stranded DNA (dsDNA) that activates the AIM2 inflammasome (By similarity). Exhibits antiviral activity against influenza virus (PubMed:22106366).
Shows the most prominent antiviral activity in epithelial cells.
Belongs to the peroxiredoxin family. AhpC/Prx1 subfamily.
Homodimer; disulfide-linked, upon oxidation (PubMed:17707404, PubMed:27238969, PubMed:29438714). 6 homodimers assemble to form a ring-like dodecamer (PubMed:17707404, PubMed:27238969, PubMed:29438714). Interacts with NEK6 (PubMed:20873783). Interacts with LRRK2 (PubMed:21850687). Interacts with MAP3K13 (PubMed:12492477). Interacts with RPS6KC1 (via PX domain) (PubMed:15750338).
It is uncertain whether transit peptide cleavage occurs after His-61 or Ala-62. Peptides have been found for both N-termini.
Phosphorylated by LRRK2; phosphorylation reduces perodixase activity.
The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this typical 2-Cys peroxiredoxin, C(R) is provided by the other dimeric subunit to form an intersubunit disulfide. The disulfide is subsequently reduced by thioredoxin.
The enzyme can be inactivated by further oxidation of the cysteine sulfenic acid (C(P)-SOH) to sulphinic acid (C(P)-SO2H) and sulphonic acid (C(P)-SO3H) instead of its condensation to a disulfide bond.
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides (PubMed:7733872, PubMed:17707404, PubMed:29438714, PubMed:33889951). Acts synergistically with MAP3K13 to regulate the activation of NF-kappa-B in the cytosol (PubMed:12492477). Required for the maintenance of physical strength (By similarity).
As a major component of focal adhesion plaques that links integrin to the actin cytoskeleton, may play an important role in cell adhesion. Recruits PIP5K1C to focal adhesion plaques and strongly activates its kinase activity (By similarity).
Expressed in fetal brain, lung and kidney.
Forms homooligomeric complexes which mediate cell homotypic adhesion (Probable). Interacts (via the cytoplasmic juxtamembrane domain) with CTNNB1; may mediate interaction with the cadherin/catenin adhesion complex. Interacts with KIT. May interact with AP3B1.
High levels in brain, pancreas, and skeletal muscle; less in colon, kidney, liver, stomach, and uterus; not expressed in placenta and spleen. Also detected in heart, prostate, lung, thymus, testis and ovary. Ubiquitously expressed in brain. Expressed by hematopoietic stem cells.
Phosphorylated on tyrosine residues upon activation of KIT with stem cell factor (SCF). The 73 kDa proteolytic product is not phosphorylated.
The extracellular domain is proteolytically processed through cleavage within the fibronectin type-III 4 domain (By similarity). In addition to the 190 kDa full-length protein, proteolytic products of 100 kDa, 80 kDa and 73 kDa are observed.
Tyrosine-protein phosphatase which dephosphorylates CTNNB1. Regulates CTNNB1 function both in cell adhesion and signaling. May function in cell proliferation and migration and play a role in the maintenance of epithelial integrity. May play a role in megakaryocytopoiesis.
Up-regulated upon cell contact (at protein level). Down-regulated by phorbol ester (at protein level) and calcium ionophore but up-regulated by phorbol ester in megakaryocytic cells (PubMed:10397721).
Brain specific. Detected in neuronal cells.
Homodimer (By similarity). Heteromultimer with other K-Cl cotransporters (By similarity). Interacts with AP2A1 (By similarity).
Inhibited following phosphorylation by OXSR1/OSR1 and STK39/SPAK: phosphorylation takes place downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4) in response to hyperosmotic stress and subsequent cell shrinkage.
Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis (PubMed:12106695). As major extruder of intracellular chloride, it establishes the low neuronal Cl(-) levels required for chloride influx after binding of GABA-A and glycine to their receptors, with subsequent hyperpolarization and neuronal inhibition (By similarity). Involved in the regulation of dendritic spine formation and maturation (PubMed:24668262).
Phosphorylated at Thr-929 and Thr-1030 by OXSR1/OSR1 and STK39/SPAK downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4), inhibiting the potassium-chloride cotransport activity.
(Microbial infection) ADP-riboxanation by S.flexneri OspC3 blocks CASP4 autoprocessing, preventing CASP4 activation and ability to recognize and cleave GSDMD, thereby thwarting the inflammasome/pyroptosis-mediated defense.
(Microbial infection) In response to the Td92 surface protein of the periodontal pathogen T.denticola, activated by cathepsin CTSG which leads to production and secretion of IL1A and pyroptosis of gingival fibroblasts.
(Microbial infection) Interacts with NleF protein from pathogenic E.coli; this interaction leads to enzyme inhibition.
(Microbial infection) Interacts with cathepsin CTSG; the interaction is promoted by the Td92 surface protein of the periodontal pathogen T.denticola and leads to CASP4 activation.
Activated by homooligomerization induced by direct binding to cytosolic LPS, in a TLR4-independent manner (PubMed:25119034, PubMed:29520027). In addition to LPS, CASP4/CASP11 may also be activated by oxidized phospholipid 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphorylcholine, an oxidized phospholipid (oxPAPC), in dendritic cells, promoting adaptive immunity (By similarity). The role of oxPAPC is however unclear and another report suggests that oxPAPC competes with LPS-binding and inhibits the non-canonical inflammasome in macrophages (PubMed:29520027).
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-4 subunit p20) and a 10 kDa (Caspase-4 subunit p10) subunit (PubMed:32109412). Upon direct LPS-binding, forms large homooligomers, resulting in its activation (By similarity). These oligomers are often referred to as 'non-canonical inflammasomes' (PubMed:25119034). In its precursor form, interacts with TMEM214; this interaction is required for association with the endoplasmic reticulum membrane (PubMed:23661706). Interacts with CASP1 (PubMed:22246630). Interacts with NOD2 (PubMed:18511561). Interacts with SERPINB1; this interaction regulates CASP4 activity (PubMed:30692621).
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-4 subunit p20) and a 10 kDa (Caspase-4 subunit p10) subunit.
In peripheral blood mononuclear cells and purified monocytes, up-regulated by bacterial lipopolysaccharides (LPS) and interferon-beta/IFNB1 at the mRNA level (PubMed:16893518, PubMed:24879791). However, this increase is not observed at the protein level, which remains constant in monocytes and other cell types following LPS treatment (PubMed:25121752) (PubMed:26508369). In monocyte-derived macrophages, some up-regulation at the protein level is observed following treatment with LPS and IFNB1 (PubMed:25964352). In SH-EP1 neuroblastoma cell line, up-regulated by NF-kappa-B RELA/p65 at both mRNA and protein levels.
In response to activation signals, including endoplasmic reticulum stress or treatment with amyloid-beta A4 protein fragments (such as amyloid-beta protein 40), undergoes autoproteolytic cleavage.
Inflammatory caspase that acts as the effector of the non-canonical inflammasome by mediating lipopolysaccharide (LPS)-induced pyroptosis (PubMed:25119034, PubMed:26375003, PubMed:34671164, PubMed:32109412, PubMed:37001519). Also indirectly activates the NLRP3 and NLRP6 inflammasomes (PubMed:7797510, PubMed:23516580, PubMed:26375003, PubMed:32109412). Acts as a thiol protease that cleaves a tetrapeptide after an Asp residue at position P1: catalyzes cleavage of CGAS, GSDMD and IL18 (PubMed:7797510, PubMed:15326478, PubMed:23516580, PubMed:26375003, PubMed:28314590, PubMed:32109412). Effector of the non-canonical inflammasome independently of NLRP3 inflammasome and CASP1: the non-canonical inflammasome promotes pyroptosis through GSDMD cleavage without involving secretion of cytokine IL1B and IL18 (PubMed:25121752, PubMed:25119034, PubMed:26375003, PubMed:31268602, PubMed:32109412). In the non-canonical inflammasome, CASP4 is activated by direct binding to LPS without the need of an upstream sensor (PubMed:25121752, PubMed:25119034, PubMed:29520027). LPS-binding promotes CASP4 activation and CASP4-mediated cleavage of GSDMD, followed by pyroptosis of infected cells and their extrusion into the gut lumen (PubMed:25121752, PubMed:25119034). Also indirectly promotes secretion of mature cytokines (IL1A, IL18 and HMGB1) downstream of GSDMD-mediated pyroptosis via activation of the NLRP3 and NLRP6 inflammasomes (PubMed:26375003, PubMed:32109412). Involved in NLRP3-dependent CASP1 activation and IL1B and IL18 secretion in response to non-canonical activators, such as UVB radiation or cholera enterotoxin (PubMed:22246630, PubMed:23516580, PubMed:24879791, PubMed:25964352, PubMed:26173988, PubMed:26174085, PubMed:26508369). Involved in NLRP6 inflammasome-dependent activation in response to lipoteichoic acid (LTA), a cell-wall component of Gram-positive bacteria, which leads to CASP1 activation and IL1B and IL18 secretion (PubMed:33377178). Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (PubMed:26508369). The non-canonical inflammasome is required for innate immunity to cytosolic, but not vacuolar, bacteria (By similarity). Plays a crucial role in the restriction of S.typhimurium replication in colonic epithelial cells during infection (PubMed:25121752, PubMed:25964352). Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation (PubMed:25121752, PubMed:26375003, PubMed:25964352). May also act as an activator of adaptive immunity in dendritic cells, following activation by oxidized phospholipid 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphorylcholine, an oxidized phospholipid (oxPAPC) (By similarity). Involved in cell death induced by endoplasmic reticulum stress and by treatment with cytotoxic APP peptides found in Alzheimer's patient brains (PubMed:15123740, PubMed:22246630, PubMed:23661706). Cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP4 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32109412). Catalyzes cleavage and maturation of IL18 (PubMed:15326478). In contrast, it does not directly process IL1B (PubMed:7743998, PubMed:7797592, PubMed:7797510). During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590).
May be due to competing acceptor splice site. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
The CARD domain mediates LPS recognition and homooligomerization.
Widely expressed, including in keratinocytes and colonic and small intestinal epithelial cells (at protein level). Not detected in brain.
Chimeric cDNA. A chimeric cDNA originating from chromosomes 1 and 5.
Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs.
Heterodimer with MAGOH. Part of the mRNA splicing-dependent exon junction complex (EJC) complex; the core complex contains CASC3, EIF4A3, MAGOH and RBM8A.
Heterodimer with either MAGOH or MAGOHB (PubMed:10662555, PubMed:12730685, PubMed:23917022, PubMed:12781131). Part of the mRNA splicing-dependent exon junction complex (EJC) complex; the core complex contains CASC3, EIF4A3, MAGOH or MAGOHB, and RBM8A (PubMed:11707413, PubMed:16170325, PubMed:16314458, PubMed:23917022, PubMed:16923391, PubMed:16931718, PubMed:19033377, PubMed:20479275). Interacts with PYM1; the interaction is direct and dissociates the EJC from spliced mRNAs (PubMed:14968132, PubMed:18026120, PubMed:19410547). Part of a complex that contains the EJC core components CASC3, EIF4A3, MAGOH and RBM8A plus proteins involved in nonsense-mediated mRNA decay, such as UPF1, UPF2, UPF3A and UPF3B (PubMed:11546873, PubMed:12718880, PubMed:20479275). Found in a post-splicing complex with NXF1, MAGOH, UPF1, UPF2, UPF3A, UPF3B and RNPS1 (PubMed:11546874). Interacts with DDX39B, MAGOH, DPH1, UPF3B, RNPS1, SRRM1 and ALYREF/THOC4 (PubMed:11013075, PubMed:11118221, PubMed:11707413, PubMed:12944400). Interacts with IPO13; the interaction mediates the nuclear import of the MAGOH-RBM8A heterodimer (PubMed:11447110). Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:29301961). Associates with polysomes (PubMed:12121612).
Required for pre-mRNA splicing as component of the spliceosome (PubMed:28502770, PubMed:29301961). Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). The MAGOH-RBM8A heterodimer inhibits the ATPase activity of EIF4A3, thereby trapping the ATP-bound EJC core onto spliced mRNA in a stable conformation. The MAGOH-RBM8A heterodimer interacts with the EJC key regulator PYM1 leading to EJC disassembly in the cytoplasm and translation enhancement of EJC-bearing spliced mRNAs by recruiting them to the ribosomal 48S preinitiation complex. Its removal from cytoplasmic mRNAs requires translation initiation from EJC-bearing spliced mRNAs. Associates preferentially with mRNAs produced by splicing. Does not interact with pre-mRNAs, introns, or mRNAs produced from intronless cDNAs. Associates with both nuclear mRNAs and newly exported cytoplasmic mRNAs. The MAGOH-RBM8A heterodimer is a component of the nonsense mediated decay (NMD) pathway. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly.
Expressed in placenta, uterus and in fetal perichondrium. Expression levels were increased in both early placentas and molar pregnancies and were reduced in choriocarcinoma cells.
Highly expressed in the early placenta. Expression of epil peptides in the villous cytotrophoblast is different from that displayed by the syncytiotrophoblast. In fetal tissues it was identified in the perichondrium of all four limbs, vertebrae, and ribs. It was abundant in interbone ligaments.
May play an important role in trophoblast development and in the regulation of bone formation.
Interacts with RHOA, GNA12 and GNA13. Homooligomerizes through the coiled coil region. May interact with CCPG1 (By similarity). Interacts with CTNNAL1.
Phosphorylated by PKCA. Angiotensin-2 induced Tyr-738 phosphorylation is mediated by JAK2.
Seems to play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13) subunits (PubMed:9641915, PubMed:9641916). Acts as GTPase-activating protein (GAP) for GNA12 and GNA13, and as guanine nucleotide exchange factor (GEF) for RhoA GTPase (PubMed:9641915, PubMed:9641916, PubMed:8810315, PubMed:30521495). Activated G alpha 13/GNA13 stimulates the RhoGEF activity through interaction with the RGS-like domain (PubMed:9641916). This GEF activity is inhibited by binding to activated GNA12 (PubMed:9641916). Mediates angiotensin-2-induced RhoA activation (PubMed:20098430).
The RGSL domain, also known as rgRGS domain, is necessary but not sufficient for GAP activity.
Plays a role in intracellular vesicle trafficking and exocytosis (PubMed:24843546). May play a role in maintaining insulin-containing dense core vesicles in pancreatic beta-cells and in preventing their degradation. May play a role in insulin secretion (PubMed:24843546). Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) (By similarity).
Expressed in central nervous system, with high level in pituitary, cerebellum and temporal lobe. Expressed in lung, skeletal muscle, peripheral blood leukocyte, stomach, lymph node, trachea and bone marrow. Highly expressed in acute myeloid leukemia.
Interacts with neurotrophin receptor p75NTR/NGFR (By similarity). Interacts with OMP (By similarity).
Phosphorylated. Phosphorylation of Ser-102 protects it from the proteasome.
Signaling adapter molecule involved in p75NTR/NGFR signaling. Plays a role in cell cycle progression and neuronal differentiation. Inhibits neuronal differentiation in response to nerve growth factor (NGF). May act as a link between the cell cycle and neurotrophic factor signaling, possibly by functioning as an upstream modulator of receptor signaling, coordinating biological responses to external signals with internal cellular states (By similarity). In absence of reductive stress, acts as a pseudosubstrate for the CRL2(FEM1B) complex: associates with FEM1B via zinc, thereby preventing association between FEM1B and its substrates (By similarity).
The histidine cluster (His cluster) and Cys-122 mediate zinc-binding.
ADP-ribose glycohydrolase that hydrolyzes ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on glutamate and O-acetyl-ADP-D-ribose (PubMed:23481255, PubMed:23474714, PubMed:21849506). Specifically acts as a glutamate mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to glutamate residues on proteins (PubMed:23481255, PubMed:23474714). Does not act on poly-ADP-ribosylated proteins: the poly-ADP-ribose chain of poly-ADP-ribosylated glutamate residues must by hydrolyzed into mono-ADP-ribosylated glutamate by PARG to become a substrate for OARD1 (PubMed:23481255). Deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins (PubMed:21849506). Catalyzes the deacylation of O-acetyl-ADP-ribose, O-propionyl-ADP-ribose and O-butyryl-ADP-ribose, yielding ADP-ribose plus acetate, propionate and butyrate, respectively (PubMed:21849506).
Defects in OARD1 are found in patients with severe neurodegeneration (PubMed:23481255). Defects were found in an extended consanguineous family with several affected cases in two generations (PubMed:23481255).
Subject to competitive inhibition by the product ADP-ribose.
Expressed in bone, cartilage, joint capsule, ligament, skin, and primary cultured chondrocytes.
Interacts with FAM83D (PubMed:18485706). Interacts with SIAH1 (PubMed:11146551).
Kinesin family member that is involved in spindle formation and the movements of chromosomes during mitosis and meiosis. Binds to microtubules and to DNA (By similarity). Plays a role in congression of laterally attached chromosomes in NDC80-depleted cells (PubMed:25743205).
Ubiquitinated; mediated by SIAH1 and leading to its subsequent proteasomal degradation.
Expressed in nasal epithelial cells. Down-regulated in nasal epithelial cells in patients experiencing an asthma exacerbation as compared to stable asthmatics and healthy controls.
May play a protective role in mucosal tissues by preventing exaggerated allergic responses.
By the synthetic androgen R1881 in prostate carcinoma cells undergoing proliferative arrest. Maximum levels occur 18-20 hours after androgen exposure.
Interacts with the cohesin complex. Interacts with RAD21; the interaction is direct. Interacts with WAPL (via FGF motifs) or CDCA5 (via the FGF motif); the interaction is direct, cohesin-dependent and competitive (Probable).
Regulator of sister chromatid cohesion in mitosis which may stabilize cohesin complex association with chromatin. May couple sister chromatid cohesion during mitosis to DNA replication. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair. Plays a role in androgen-induced proliferative arrest in prostate cells.
Expressed in lymphoid tissues (at protein level). Expressed in brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung, lymphoid tissues and blood leukocytes.
Up-regulated by ionomycin in T-lymphocytes. Down-regulated in acute lymphoblastic leukemia.
Interacts with EME1 and EME2 to form a DNA structure-specific endonuclease with substrate preference for branched DNA structures with a 5'-end at the branch nick. Typical substrates include 3'-flap structures, replication forks and nicked Holliday junctions. Plays an essential role in mitosis for the processing of stalled or collapsed replication forks (PubMed:28575661).
Interacts with EME1 to form a DNA structure-specific endonuclease with substrate preference for branched DNA structures with a 5'-end at the branch nick. Typical substrates include 3'-flap structures, D-loops, replication forks and nicked Holliday junctions. May be required in mitosis for the processing of stalled or collapsed replication fork intermediates. May be required in meiosis for the repair of meiosis-specific double strand breaks subsequent to single-end invasion (SEI).
May self-associate. Interacts with EME1, EME2 and CHEK2. Interacts with BLM, and this interaction may stimulate the endonuclease activity of MUS81. Interacts with SLX4/BTBD12; this interaction is direct and links the MUS81-EME1 complex to SLX4, which may coordinate the action of the structure-specific endonuclease during DNA repair. Interacts with DCLRE1B/Apollo. Interacts with RECQL5; this interaction stimulates mitotic DNA synthesis (PubMed:28575661).
Up-regulated in cells treated with agents that damage DNA or block replication. This up-regulation seems to be independent of transcription.
G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site.
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems.
Specifically expressed in hematopoietic cells. Expressed in epididymis (at protein level).
Involved in mitochondrial RNA maturation and mitochondrial respiratory chain function.
Accessory component of the STT3B-containing form of the oligosaccharyltransferase (OST) complex. OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits. OST can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes. The association of TUSC3 or MAGT1 with the STT3B-containing complex seems to be mutually exclusvice.
Acts as accessory component of the N-oligosaccharyl transferase (OST) complex which catalyzes the transfer of a high mannose oligosaccharide from a lipid-linked oligosaccharide donor to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains. Involved in N-glycosylation of STT3B-dependent substrates. Specifically required for the glycosylation of a subset of acceptor sites that are near cysteine residues; in this function seems to act redundantly with MAGT1. In its oxidized form proposed to form transient mixed disulfides with a glycoprotein substrate to facilitate access of STT3B to the unmodified acceptor site. Has also oxidoreductase-independent functions in the STT3B-containing OST complex possibly involving substrate recognition.
Expressed in most non-lymphoid cells and tissues examined, including prostate, lung, liver, colon, heart, kidney and pancreas.
Acts as an adapter protein that mediates cell signaling pathways involved in cellular functions such as cell adhesion and migration, tissue organization, and the regulation of the immune response (PubMed:12432078, PubMed:20881139). Plays a role in integrin-mediated cell adhesion through BCAR1-CRK-RAPGEF1 signaling and activation of the small GTPase RAP1 (PubMed:12432078). Promotes cell migration and invasion through the extracellular matrix (PubMed:20881139). Required for marginal zone B-cell development and thymus-independent type 2 immune responses (By similarity). Mediates migration and adhesion of B cells in the splenic marginal zone via promoting hyperphosphorylation of NEDD9/CASL (By similarity). Plays a role in CXCL13-induced chemotaxis of B-cells (By similarity). Plays a role in the migration of olfactory sensory neurons (OSNs) into the forebrain and the innervation of the olfactory bulb by the OSN axons during development (By similarity). Required for the efficient tyrosine phosphorylation of BCAR1 in OSN axons (By similarity).
Component of a complex comprised of SH2D3C, BCAR1/CAS, and CRK (PubMed:12432078). Within the complex, interacts with CRK and (via C-terminus) with BCAR1/CAS (via C-terminus) (PubMed:12432078, PubMed:17174122, PubMed:22081014). Interacts with NEDD9/HEF1 (By similarity). Interacts with EPHB2 (By similarity).
Important regulator of chemokine-induced, integrin-mediated T lymphocyte adhesion and migration, acting upstream of RAP1 (By similarity). Required for tissue-specific adhesion of T lymphocytes to peripheral tissues (By similarity). Required for basal and CXCL2 stimulated serine-threonine phosphorylation of NEDD9 (By similarity). May be involved in the regulation of T-cell receptor-mediated IL2 production through the activation of the JNK pathway in T-cells (By similarity).
Interacts (via C-terminus) with BCAR1/CAS (via C-terminus) (By similarity). Interacts with IGF1 (PubMed:20881139).
Interacts with NEDD9/HEF1 (By similarity). Interacts with BCAR1/CAS (By similarity). Interacts with PTK2B (By similarity).
May be involved in the BCAR1/CAS-mediated JNK activation pathway.
Phosphorylated by MAPK/ERK upon T-cell receptor stimulation in T-cells.
The C-terminal Cdc25-homology/Ras-GEF domain adopts a closed conformation rendering it incapable of carrying out canonical exchange factor function, this closed conformation is required for interaction with BCAR1.
Expressed mainly in bladder, lung, head and neck carcinomas. Not expressed in normal tissues except for testis.
Phosphorylated by ULK1 and ULK2; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1, ULK2 and AMPK.
Both the N-terminal core domain and the C-terminal headpiece domain are sufficient for binding to F-actin and necessary for actin bundling activity.
Expressed in platelets (at protein level). Expressed in heart, brain, lung, skeletal muscle, and kidney.
Membrane-cytoskeleton-associated protein with F-actin-binding activity that induces F-actin bundles formation and stabilization. Its F-actin-bundling activity is reversibly regulated upon its phosphorylation by the cAMP-dependent protein kinase A (PKA). Binds to the erythrocyte membrane glucose transporter-1 SLC2A1/GLUT1, and hence stabilizes and attaches the spectrin-actin network to the erythrocytic plasma membrane. Plays a role in maintaining the functional integrity of PKA-activated erythrocyte shape and the membrane mechanical properties. Also plays a role as a modulator of actin dynamics in fibroblasts; acts as a negative regulator of the RhoA activation pathway. In platelets, functions as a regulator of internal calcium mobilization across the dense tubular system that affects platelet granule secretion pathways and aggregation. Also required for the formation of a diverse set of cell protrusions, such as filopodia and lamellipodia, necessary for platelet cell spreading, motility and migration. Acts as a tumor suppressor and inhibits malignant cell transformation.
Monomeric (isoform 2); under reducing conditions. Self-associates. Exists under oxidizing condition as a trimer of two isoforms 2 and isoform 1 linked by disulfide bonds (Probable). Found in a complex with DMTN, F-actin and spectrin. Found in a complex with ADD2, DMTN and SLC2A1. Interacts with F-actin, ITPKB, RASGRF2 and spectrin. Isoform 2 interacts with SLC2A1 (via C-terminus cytoplasmic region). Isoform 1 and isoform 2 interact (phosphorylated form) with plasmodium berghei 14-3-3 protein; the interaction occurs in a PKA-dependent manner.
Phosphorylated. Phosphorylation at Ser-403 by PKA causes the C-terminal headpiece domain to associate with the N-terminal core domain, and leads to the inhibition of its actin bundling activity.
By X-ray irradiation immediately after exposure and is then down-regulated two-fold in an X-ray radiation-resistant cell clone. Responds differently to X-ray radiation in clones of varying radiation responses.
Expressed predominantly in testis followed by prostate and ovary. Low levels found in other tissues including peripheral blood leukocytes, spleen, thymus, small intestine and colon. Also expressed in neuroblastoma, glioma, breast, lung, leukemia, renal, ovarian, prostate and colorectal cancer cell lines.
May be involved in the response of cells to X-ray radiation.
The MBD domain is necessary for chromocentric localization.
Phosphorylated at Ser-210 by AURKB during cytokinesis: together with ZFYVE19/ANCHR, phosphorylated CHMP4C retains abscission-competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis.
Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). Key component of the cytokinesis checkpoint, a process required to delay abscission to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage: upon phosphorylation by AURKB, together with ZFYVE19/ANCHR, retains abscission-competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis. Deactivation of AURKB results in dephosphorylation of CHMP4C followed by its dissociation from ANCHR and VPS4 and subsequent abscission (PubMed:22422861, PubMed:24814515). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. Involved in HIV-1 p6- and p9-dependent virus release. CHMP4A/B/C are required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413).
Probable core component of the endosomal sorting required for transport complex III (ESCRT-III). ESCRT-III components are thought to multimerize to form a flat lattice on the perimeter membrane of the endosome. Several assembly forms of ESCRT-III may exist that interact and act sequentially. Self-associates. Interacts with CHMP2A. Interacts with CHMP4A. Interacts with CHMP4B. Interacts with CHMP6. Interacts with VPS4A. Interacts with PDCD6IP; the interaction is direct.
The acidic C-terminus and the basic N-terminus are thought to render the protein in a closed, soluble and inactive conformation through an autoinhibitory intramolecular interaction. The open and active conformation, which enables membrane binding and oligomerization, is achieved by interaction with other cellular binding partners, probably including other ESCRT components (By similarity).
Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:33065002, PubMed:28296633, PubMed:30374053). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (PubMed:30374053). May play a role in coupling of proton transport and ATP hydrolysis (By similarity). In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation (PubMed:28296633). May play a role in cilium biogenesis through regulation of the transport and the localization of proteins to the cilium (By similarity).
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex (PubMed:33065002). The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H (PubMed:33065002). The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR (PubMed:33065002). Interacts with ATP6AP2; ATP6AP2 is a V-ATPase accessory protein and the interaction promotes v-ATPase complex assembly (PubMed:30374053). Interacts with TMEM9; TMEM9 is a v-ATPase assembly regulator and the interaction induces the interaction with ATP6AP2 (PubMed:30374053). Interacts with PIP4P1 (PubMed:29644770).
Interacts with RBM40. Component of the U11/U12 snRNPs that are part of the U12-type spliceosome.
Gamma-tubulin complex is composed of gamma-tubulin, TUBGCP2, TUBGCP3, TUBGCP4, TUBGCP5 and TUBGCP6. Interacts with ATF5; the ATF5:PCNT:polyglutamylated tubulin (PGT) tripartite unites the mother centriole and the pericentriolar material (PCM) in the centrosome (PubMed:26213385).
Gamma-tubulin complex is necessary for microtubule nucleation at the centrosome.
Gamma-tubulin complex is necessary for microtubule nucleation at the centrosome. Plays a role in neuronal migration.
Expressed in the ovary (at protein level).
Oocyte-specific protein that localizes to centromeres at the dictyate stage and regulates the survival of primordial oocytes.
Activated by GUCA1B when free calcium ions concentration is low, and inhibited by GUCA1B when free calcium ions concentration is high (PubMed:15772651). Inhibited by RD3 (PubMed:29515371).
Homodimer (By similarity). Interacts with RD3; promotes the exit of GUCY2F from the endoplasmic reticulum and its trafficking to the photoreceptor outer segments (By similarity).
Responsible for the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors (PubMed:7777544). Plays an essential role in phototransduction, by mediating cGMP replenishment (By similarity). May also participate in the trafficking of membrane-asociated proteins to the photoreceptor outer segment membrane (By similarity).
Retina. Localized exclusively in the outer nuclear layer and inner segments of the rod and cone photoreceptor cells.
There are 9 conserved cysteine residues in sensory guanylate cyclases, 6 in the extracellular domain, which may be involved in intra- or interchain disulfide bonds.
Forms homodimers or heterodimers with ARFIP2 (PubMed:21239483). Interacts with non-myristoylated GTP-bound ARF3, but not to GDP-bound ARF3 (PubMed:10413101). Interacts with ARF1 (PubMed:10413101, PubMed:22981988). Binds with lower affinity to ARF5 and with very little affinity to ARF6 (PubMed:10413101). Interacts with ARL1 (PubMed:22981988, PubMed:21239483). Interacts with ATG9A (PubMed:30917996).
Phosphorylated by PRKD1; phosphorylation delocalizes ARFIP1 from the Golgi and disrupts its ability to inhibit the activity of ADP-ribosylation factor, an important component of the vesicle scission machinery.
Plays a role in controlling biogenesis of secretory granules at the trans-Golgi network (PubMed:22981988). Mechanistically, binds ARF-GTP at the neck of a growing secretory granule precursor and forms a protective scaffold (PubMed:9038142, PubMed:22981988). Once the granule precursor has been completely loaded, active PRKD1 phosphorylates ARFIP1 and releases it from ARFs (PubMed:22981988). In turn, ARFs induce fission (PubMed:22981988). Through this mechanism, ensures proper secretory granule formation at the Golgi of pancreatic beta cells (PubMed:22981988).
Ubiquitously expressed (PubMed:9038142). Higher levels in liver, pancreas, placenta, skeletal muscle and heart (PubMed:9038142).
Based on x-ray crystallography data, the protein would be constituted of 4 tandem ACT domains instead of the 2 predicted from the sequence.
Forms homodimers and heterodimers with CASTOR2 (PubMed:26972053, PubMed:27487210). Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated by arginine (PubMed:26972053, PubMed:27487210, PubMed:33594058). Interacts with TM4SF5; the interaction is positively regulated by leucine and is negatively regulated by arginine (PubMed:30956113).
Functions as an intracellular arginine sensor within the amino acid-sensing branch of the TORC1 signaling pathway (PubMed:26972053, PubMed:27487210, PubMed:33594058). As a homodimer or a heterodimer with CASTOR2, binds and inhibits the GATOR subcomplex GATOR2 and thereby mTORC1 (PubMed:26972053, PubMed:27487210, PubMed:33594058). Binding of arginine to CASTOR1 allosterically disrupts the interaction of CASTOR1-containing dimers with GATOR2 which can in turn activate mTORC1 and the TORC1 signaling pathway (PubMed:26972053, PubMed:27487210, PubMed:33594058).
Phosphorylation at Ser-14 by AKT1, promoting the interaction between CASTOR1 and RNF167.
Ubiquitinated by RNF167 via 'Lys-29'-polyubiquitination, leading to its degradation, releasing the GATOR2 complex (PubMed:33594058). Ubiquitination by RNF167 is promoted by phosphorylation at Ser-14 by AKT1 (PubMed:33594058).
Calmodulin-binding protein which may function as scaffolding or signaling protein and may play a role in dendritic Ca(2+) signaling.
Interacts with protein phosphatase 2A (PP2A) (Potential). Interacts with CTTNBP2; this interaction may regulate dendritic spine distribution of STRN. Activation of glutamate receptors weakens the interaction with CTTNBP2 (By similarity).
Belongs to the pseudouridine synthase Pus10 family.
Interacts with components of the microprocessor complex DROSHA and DGCR8.
Protein with different functions depending on its subcellular location: involved in miRNA processing in the nucleus and acts as a tRNA pseudouridylate synthase in the cytoplasm (PubMed:31819270, PubMed:33023933). In the cytoplasm, acts as a pseudouridylate synthase by catalyzing synthesis of pseudouridine(54) and pseudouridine(55) from uracil-54 and uracil-55, respectively, in the psi GC loop of a subset of tRNAs (PubMed:30530625, PubMed:31819270, PubMed:33023933). tRNA pseudouridylate synthase activity is enhanced by the presence of 1-methyladenosine at position 53-61 of tRNAs (PubMed:30530625). Does not show tRNA pseudouridylate synthase activity in the nucleus (PubMed:33023933). In the nucleus, promotes primary microRNAs (pri-miRNAs) processing independently of its RNA pseudouridylate synthase activity (PubMed:31819270). Binds pri-miRNAs (PubMed:31819270). Modulator of TRAIL/TNFSF10-induced cell death via activation of procaspase-8 and BID cleavage (PubMed:14527409, PubMed:19712588). Required for the progression of the apoptotic signal through intrinsic mitochondrial cell death (PubMed:19712588).
Proteolytically cleaved during TRAIL-induced cell death (PubMed:19712588). Cleaved, in vitro, either by caspase-3 (CASP3) or caspase-8 (CASP8) (PubMed:19712588).
Contains FG repeats. The FG repeat region is required for acting as a cofactor of HIV-1 Rev.
Interacts with EPS15R and EPS15. Interacts with FCHO1.
Required for vesicle docking or fusion during acrosome biogenesis (By similarity). May play a role in RNA trafficking or localization. In case of infection by HIV-1, acts as a cofactor for viral Rev and promotes movement of Rev-responsive element-containing RNAs from the nuclear periphery to the cytoplasm. This step is essential for HIV-1 replication.
Belongs to the universal ribosomal protein uL1 family.
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:32669547).
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:32669547). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:12962325, PubMed:23636399, PubMed:32669547).
Both EF-hands are required for function.
Mediates cell-cell adhesion in a calcium-dependent manner (By similarity). Able to inhibit growth in several cell lines.
Probably digested extracellularly by an unknown serine protease generating extremely hydrophobic bioactive peptides.
The number of repeats of 17 amino acids in the C-terminal is polymorphic and varies between 3 and 4. The majority of available transcripts lacks one of these repeats. The sequence shown, corresponding to the reference genome (GRCh38/hg38), contains 4 repeats.
Interacts with SIX1, SIX6 and EYA3. Interacts with NCOR1 and HDAC3 through its N-terminus. Interacts with SIN3A through its C-terminus (By similarity). Interacts with SMAD3 and SMAD4.
The DACHbox-N/DD1 domain forms a structure containing a DNA binding motif similar to that of the forkhead/winged helix domain.
Transcription factor that is involved in regulation of organogenesis. Seems to be a regulator of SIX1, SIX6 and probably SIX5. Corepression of precursor cell proliferation in myoblasts by SIX1 is switched to coactivation through recruitment of EYA3 to the SIX1-DACH1 complex. Transcriptional activation seems also to involve association of CREBBP. Seems to act as a corepressor of SIX6 in regulating proliferation by directly repressing cyclin-dependent kinase inhibitors, including the p27Kip1 promoter (By similarity). Inhibits TGF-beta signaling through interaction with SMAD4 and NCOR1. Binds to chromatin DNA via its DACHbox-N domain (By similarity).
Widely expressed. Isoform 2 is found in brain, heart, kidney, liver, leukocytes and spleen. Isoform 3 is found in liver and heart. Isoform 4 is found in spleen.
Chondroitin sulfate-, heparin- and hyaluronan-binding protein (By similarity). May serve to form a basic macromolecular scaffold comprising the insoluble interphotoreceptor matrix (PubMed:9813076).
Expressed in the retina (at protein level) (PubMed:10601738, PubMed:29777959). In the retina, specifically expressed by cone and rod photoreceptor cells (PubMed:9813076). Localizes to cone and rod photoreceptor cells surrounding the interphotoreceptor matrix of the retina (PubMed:9719680).
Expressed in the retina lens at 6 weeks post-conception (WPC) (at protein level) (PubMed:29777959). Expressed in the neural retinal between 6 and 19 WPC (at protein level) (PubMed:29777959). Expressed in developing photoreceptors and emerging interphotoreceptor matrix between 12 and 19 WPC (at protein level) (PubMed:29777959).
Highly glycosylated (N- and O-linked carbohydrates and sialic acid).
Belongs to the complement C6/C7/C8/C9 family.
Monomer, as soluble protein (PubMed:20889983, PubMed:21037563). Homooligomer; homooligomerizes to form a pore-forming ring (PubMed:20889983, PubMed:21037563).
Perforin consists of three domains: (1) the MACPF domain, which includes the central machinery of pore formation, (2) the EGF-like domain, which forms a 'shelf-like' assembly connecting the MACPF and C2 domains, and (3) the C2 domain, which mediates calcium-dependent binding to lipid membranes. The C2 domain is critical for initial calcium-dependent interaction with lipid membranes of the target cell: calcium-binding causes a significant structural rearrangement, leading to oligomerization and deployment of the two transmembrane beta-strands (named CH1/TMH1 and CH2/TMH2) that enter the membrane as amphipathic beta-hairpins. The third calcium-binding site (Ca(2+) 3), which constitutes the weakest affinity site, triggers structural rearrangements in the C2 domain that facilitate its interaction with lipid membranes.
Pore-forming protein that plays a key role in granzyme-mediated programmed cell death, and in defense against virus-infected or neoplastic cells (PubMed:9058810, PubMed:9164947, PubMed:20889983, PubMed:24558045, PubMed:21037563). Plays an important role in killing other cells that are recognized as non-self by the immune system, e.g. in transplant rejection or some forms of autoimmune disease (PubMed:9058810). Can insert into the membrane of target cells in its calcium-bound form, oligomerize and form large pores (PubMed:20889983, PubMed:21037563). Promotes cytolysis and apoptosis of target cells by mediating the passage and uptake of cytotoxic granzymes (PubMed:20038786, PubMed:20225066, PubMed:24558045, PubMed:32299851). Facilitates the delivery of cationic cargo protein, while anionic or neural proteins are not delivered efficiently (PubMed:24558045). Perforin pores allow the release of mature caspase-7 (CASP7) into the extracellular milieu (By similarity).
Both cAMP-dependent kinase (CAPK) and another kinase present in the red-blood cells seem to be able to phosphorylate EPB42.
Component of the ankyrin-1 complex in the erythrocyte, composed of ANK1, RHCE, RHAG, SLC4A1, EPB42, GYPA, GYPB and AQP1 (PubMed:35835865). Interacts with SLC4A1 (via the cytoplasmic domain); this interaction is mediated by the SLC4A1 Band 3-I dimer (PubMed:35835865). Interacts with ANK1 (via ANK 1-13 repeats) (PubMed:35835865). Interacts with AQP1 (via the C-terminal) (PubMed:35835865).
Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane.
The substitution of an Ala for a Cys in the active site may be responsible for the lack of transglutaminase activity of band 4.2.
May form a heteromeric complex composed of ERGIC1, ERGIC2 and ERGIC3 (PubMed:31142615). Interacts with ERGIC3, the interaction is required for the stable expression of both proteins (PubMed:31142615). May interact with EEF1A1 (PubMed:17980171).
Plays a role in transport between endoplasmic reticulum and Golgi.
Negatively regulates N-terminal palmitoylation of SHH by HHAT/SKN.
Interacts with CPNE4 (via VWFA domain) (By similarity). Interacts with SMAD2, SMAD3 and RNF111 (PubMed:17591695). Isoform 1 interacts with WWP1 (PubMed:15221015).
Isoform SNON and isoform SNOA are widely expressed. Highest expression is found in skeletal muscle, followed by placenta and lung. Lowest expression in heart, brain and pancreas. Isoform SNOI expression is restricted to skeletal muscle.
May have regulatory role in cell division or differentiation in response to extracellular signals.
Ubiquitinated by RNF111 and ARK2C, promoting proteasomal degradation, leading to enhance the BMP-Smad signaling.
Binds DNA as a dimer. Can form homodimer or heterodimer with HNF1-alpha. Interacts (via HNF-p1 domain) with PCBD1; the interaction increases its transactivation activity (PubMed:24204001).
Transcription factor that binds to the inverted palindrome 5'-GTTAATNATTAAC-3' (PubMed:7900999, PubMed:17924661). Binds to the FPC element in the cAMP regulatory unit of the PLAU gene (By similarity). Transcriptional activity is increased by coactivator PCBD1 (PubMed:24204001).
Stimulates smooth muscle contraction (By similarity). Induces sighing by acting directly on the pre-Botzinger complex, a cluster of several thousand neurons in the ventrolateral medulla responsible for inspiration during respiratory activity (By similarity). Contributes to the induction of sneezing following exposure to chemical irritants or allergens which causes release of NMB by nasal sensory neurons and activation of NMBR-expressing neurons in the sneeze-evoking region of the brainstem (By similarity). These in turn activate neurons of the caudal ventral respiratory group, giving rise to the sneezing response (By similarity). Contributes to induction of acute itch, possibly through activation of the NMBR receptor on dorsal root ganglion neurons (By similarity). Increases expression of NMBR and steroidogenic mediators STAR, CYP11A1 and HSD3B1 in Leydig cells, induces secretion of testosterone by Leydig cells and also promotes Leydig cell proliferation (By similarity). Plays a role in the innate immune response to influenza A virus infection by enhancing interferon alpha expression and reducing expression of IL6 (PubMed:31601264). Plays a role in CSF1-induced proliferation of osteoclast precursors by contributing to the positive regulation of the expression of the CSF1 receptor CSF1R (By similarity).
May be essential for the survival of the neurosensory epithelium of the inner ear.
Activated by proteolytic cleavage. Proteolytic removal of the N-terminal CUB domain releasing the core domain is necessary for unmasking the receptor-binding epitopes of the core domain. Cleavage after Arg-247 or Arg-249 by urokinase plasminogen activator gives rise to the active form.
Expressed at high levels in the heart, pancreas, adrenal gland and ovary and at low levels in placenta, liver, kidney, prostate, testis, small intestine, spleen and colon. In the kidney, expressed by the visceral epithelial cells of the glomeruli. A widespread expression is also seen in the medial smooth muscle cells of arteries and arterioles, as well as in smooth muscle cells of vasa rectae in the medullary area. Expressed in the adventitial connective tissue surrounding the suprarenal artery. In chronic obstructive nephropathy, a persistent expression is seen in glomerular visceral epithelial cells and vascular smooth muscle cells, as well as de novo expression by periglomerular interstitial cells and by some neointimal cells of atherosclerotic vessels. Expression in normal prostate is seen preferentially in the mesenchyme of the gland while expression is increased and more profuse in prostate carcinoma. Expressed in many ovarian, lung, renal and brain cancer-derived cell lines.
Growth factor that plays an essential role in the regulation of embryonic development, cell proliferation, cell migration, survival and chemotaxis. Potent mitogen for cells of mesenchymal origin. Plays an important role in wound healing. Induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis. Can initiate events that lead to a mesangial proliferative glomerulonephritis, including influx of monocytes and macrophages and production of extracellular matrix (By similarity).
Homodimer; disulfide-linked. Interacts with PDGFRB homodimers, and with heterodimers formed by PDGFRA and PDGFRB.
Not detectable in the earliest stages of glomerulogenesis, and not detected in the metanephric blastema or surrounding cortical interstitial cells. In later stages of glomerulogenesis, localized to epithelial cells transitioning from the early developing nephrons of the comma- and S-shaped stages to the visceral epithelial cells of differentiated glomeruli. In the developing pelvis, expressed at the basement membrane of immature collecting ducts and by presumptive fibroblastic cells in the interstitium.
Methionine-sulfoxide reductase that specifically reduces methionine (R)-sulfoxide back to methionine. While in many cases, methionine oxidation is the result of random oxidation following oxidative stress, methionine oxidation is also a post-translational modification that takes place on specific residue. Upon oxidative stress, may play a role in the preservation of mitochondrial integrity by decreasing the intracellular reactive oxygen species build-up through its scavenging role, hence contributing to cell survival and protein maintenance.
Ubiquitous. Detected in retina, ocular ciliary body, skeletal muscle, heart, colon, bone marrow, cerebellum, small intestine, fetal brain, fetal liver, kidney, spinal cord, lung, placenta and prostate.
Expressed in brain. Expressed at high level in the hypothalamus and at low level in the caudate nucleus.
Interacts with the Trk receptors in a phosphotyrosine-dependent manner and MEGF12. Once activated, binds to GRB2.
Phosphorylated on tyrosines by the Trk receptors.
PubMed:15057824 has shown that SHC2 is poorly phosphorylated by the Trk receptors, in opposite to PubMed:12006576.
Signaling adapter that couples activated growth factor receptors to signaling pathway in neurons. Involved in the signal transduction pathways of neurotrophin-activated Trk receptors in cortical neurons (By similarity).
The PID domain mediates binding to the TrkA receptor.
Highly expressed in muscle. Low-level expression in liver.
Homooligomer and heterooligomer (Probable). Interacts with titin/TTN. Interacts with myosins. Interacts with SQSTM1 and NBR1. Isoform 4 may not able to interact with isoform 1, isoform 2 and isoform 3. Probably interacts with TRIM63 and TRIM54.
May regulate gene expression and protein turnover in muscle cells.
A chromosomal aberration involving ERC1/RAB6IP2 is found in papillary thyroid carcinomas (PTCs). Translocation t(10;12)(q11;p13) involving RET. In vitro, isoform 1, isoform 3 and isoform 5 participating in a ERC1-RET fusion protein activate tyrosine-protein kinase activity.
Part of a complex with CHUK, IKBKB and IKBKG. Interacts with CHUK, IKBKB and IKBKG. The interaction with IKBKG is independent of CHUK and IKBKB. Interacts with NFKBIA. Isoform 4 interacts with PPFIA1, and through its C-terminus with the PDZ domains of RIMS1 and RIMS2. Interacts with ERC2/CAST1. Interacts with the GTB-bound forms of RAB6A isoform 1 and isoform 2 and with RAB6B. The interaction was strongest with RAB6B, followed by RAB6A isoform 2 and weakest with RAB6A isoform 1 (By similarity). Interacts with SDCCAG8.
Regulatory subunit of the IKK complex. Probably recruits IkappaBalpha/NFKBIA to the complex. May be involved in the organization of the cytomatrix at the nerve terminals active zone (CAZ) which regulates neurotransmitter release. May be involved in vesicle trafficking at the CAZ. May be involved in Rab-6 regulated endosomes to Golgi transport.
Widely expressed. Isoform 2 and isoform 4 are abundantly expressed in brain. Isoform 1 and isoform 3 are predominantly expressed in testis and thyroid, and isoform 1 predominates in other tissues tested.
Testis-specific. Present in Sertoli cells and spermatogenic cells (at protein level).
Belongs to the apolipoprotein O/MICOS complex subunit Mic27 family.
Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane. Specifically binds to cardiolipin (in vitro) but not to the precursor lipid phosphatidylglycerol. Plays a crucial role in crista junction formation and mitochondrial function (PubMed:23704930), (PubMed:25764979).
Component of the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOOL/MIC27, IMMT/MIC60, APOO/MIC23/MIC26 and MICOS13/MIC13. This complex was also known under the names MINOS or MitOS complex (PubMed:25764979, PubMed:25781180, PubMed:23704930, PubMed:25764979, PubMed:25781180, PubMed:25997101).The MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1 and MTX2 (together described as components of the mitochondrial outer membrane sorting assembly machinery (SAM) complex) and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9. The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both membranes termed the mitochondrial intermembrane space bridging (MIB) complex. Interacts with MICOS10/MIC10, IMMT/MIC60 and APOO/MIC23/MIC26 (PubMed:25764979, PubMed:25781180, PubMed:23704930, PubMed:25764979, PubMed:25781180, PubMed:25997101).
Binds to EPHB2. Interacts with EPHA8; activates EPHA8 (By similarity). Binds to the receptor tyrosine kinases EPHA2, EPHA3 and EPHB1. Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function.
Cell surface GPI-bound ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Induces compartmentalized signaling within a caveolae-like membrane microdomain when bound to the extracellular domain of its cognate receptor. This signaling event requires the activity of the Fyn tyrosine kinase. Activates the EPHA3 receptor to regulate cell-cell adhesion and cytoskeletal organization. With the receptor EPHA2 may regulate lens fiber cells shape and interactions and be important for lens transparency maintenance. May function actively to stimulate axon fasciculation. The interaction of EFNA5 with EPHA5 also mediates communication between pancreatic islet cells to regulate glucose-stimulated insulin secretion. Cognate/functional ligand for EPHA7, their interaction regulates brain development modulating cell-cell adhesion and repulsion.
Belongs to the ATP-dependent DNA ligase family.
Isoform 3 functions as heterodimer with DNA-repair protein XRCC1 in the nucleus and can correct defective DNA strand-break repair and sister chromatid exchange following treatment with ionizing radiation and alkylating agents. Isoform 1 is targeted to mitochondria, where it functions as DNA ligase in mitochondrial base-excision DNA repair (PubMed:10207110, PubMed:24674627).
Isoform 3 interacts (via BRCT domain) with the nuclear DNA-repair protein XRCC1. Interacts with POLG (PubMed:33855352). Interacts with POLB (PubMed:19336415).
Produced by alternative initiation of isoform 1.
Produced by alternative initiation of isoform 2.
The PARP-type zinc finger is required for DNA ligase activity.
Belongs to the AB hydrolase superfamily. ABHD14 family.
It is uncertain whether Met-1 or Met-30 is the initiator.
Possible role in granule neuron development.
Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. Plays a role in regulating the actin cytoskeleton and cell shape. Activates MAPK8 (By similarity).
Expressed in different tissues, including brain, cerebellum, peripheral nerve, skeletal muscle, heart, uterus, placenta and testis.
The part of the protein spanning the actin filament-binding domain together with the DH domain and the first PH domain is necessary and sufficient for microspike formation. Activation of MAPK8 requires the presence of all domains with the exception of the actin filament-binding domain (By similarity).
Expressed in brain (PubMed:15028294). Expressed in LPS-stimulated monocytes and macrophages, especially in polarized M1 (PubMed:25109685).
Modulates injury-induced and chemical pain hypersensitivity (By similarity). Ligand of FPR1, can chemoattract macrophages, promote phagocytosis and increase ROS release (PubMed:25109685).
Possesses chaperone activity in vitro where it inhibits aggregation of citrate synthase.
Associates with the mitochondrial ribosome.
Mitochondrial ribosome-associated protein involved in the first steps of cytochrome c oxidase complex (complex IV) biogenesis (PubMed:34969438). Stimulates the translation of MT-CO1 mRNA and is a constituent of early MT-CO1 assembly intermediates (PubMed:34969438).
Inhibitor of PPP1CA. Has over 1000-fold higher inhibitory activity when phosphorylated, creating a molecular switch for regulating the phosphorylation status of PPP1CA substrates and smooth muscle contraction.
Isoform 1 is detected in aorta and testis. Isoform 2 is detected in aorta.
Homodimer; disulfide-linked via the cysteine motif. Can also form heterodimers with SYT3, SYT6, SYT7 and SYT10.
May be involved in Ca(2+)-dependent exocytosis of secretory vesicles through Ca(2+) and phospholipid binding to the C2 domain or may serve as Ca(2+) sensors in the process of vesicular trafficking and exocytosis.
Ion transporter that can act both as an ion channel and anion exchanger (PubMed:15800055, PubMed:17673510, PubMed:26801567, PubMed:32818062). Mainly acts as a chloride channel, which mediate uncoupled chloride anion transport in an alternate-access mechanism where a saturable binding site is alternately exposed to either one or the other side of the membrane (PubMed:17673510, PubMed:26801567, PubMed:32818062). Also acts as a DIDS- and thiosulfate- sensitive anion exchanger the exchange of chloride for bicarbonate ions across the cell membrane (PubMed:11834742, PubMed:15800055).
Predominantly expressed in lung at the luminal side of the bronchiolar and alveolar epithelium of lung. To a lower extent, also expressed in pancreas and prostate.
Phosphorylated on Ser and Thr residues at the cytoplasmic C-terminus by G protein-coupled receptor kinases (GRKs).
Receptor for secretin (SCT), which is involved in different processes such as regulation of the pH of the duodenal content, food intake and water homeostasis (PubMed:7612008, PubMed:25332973). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase (By similarity). Upon binding to secretin, regulates the pH of the duodenum by (1) inhibiting the secretion of gastric acid from the parietal cells of the stomach and (2) stimulating the production of bicarbonate (NaHCO(3)) from the ductal cells of the pancreas (By similarity). In addition to regulating the pH of the duodenal content, plays a central role in diet induced thermogenesis: acts as a non-sympathetic brown fat (BAT) activator mediating prandial thermogenesis, which consequentially induces satiation. Mechanistically, secretin released by the gut after a meal binds to secretin receptor (SCTR) in brown adipocytes, activating brown fat thermogenesis by stimulating lipolysis, which is sensed in the brain and promotes satiation. Also able to stimulate lipolysis in white adipocytes. Also plays an important role in cellular osmoregulation by regulating renal water reabsorption. Also plays a role in the central nervous system: required for synaptic plasticity (By similarity).
Belongs to the eukaryotic ribosomal protein eS26 family.
Component of the 40S small ribosomal subunit.
Component of the small ribosomal subunit (PubMed:23636399, PubMed:25901680, PubMed:25957688). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399, PubMed:25901680, PubMed:25957688).
Expressed in circumvallate papillae and testis.
Specifically promotes functional cell surface expression of olfactory receptors, but not of other GPCRs.
Component of the BCR(KLHL12) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL12 and RBX1 (PubMed:22358839). This complex interacts with DVL3 upon activation of the Wnt signaling pathway by WNT3A (PubMed:16547521). Interacts with DRD4, KLHL2 and SEC31A (PubMed:15383316, PubMed:18303015, PubMed:22358839). Interacts with PEF1 and PDCD6/ALG-2; interaction takes place in response to cytosolic calcium increase and leads to bridge together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B) (PubMed:27716508).
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a negative regulator of Wnt signaling pathway and ER-Golgi transport (PubMed:22358839, PubMed:27565346). The BCR(KLHL12) complex is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) acts by mediating monoubiquitination of SEC31 (SEC31A or SEC31B) (PubMed:22358839, PubMed:27565346). The BCR(KLHL12) complex is also involved in neural crest specification: in response to cytosolic calcium increase, interacts with the heterodimer formed with PEF1 and PDCD6/ALG-2, leading to bridge together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export (PubMed:27716508). As part of the BCR(KLHL12) complex, also acts as a negative regulator of the Wnt signaling pathway by mediating ubiquitination and subsequent proteolysis of DVL3 (PubMed:16547521). The BCR(KLHL12) complex also mediates polyubiquitination of DRD4 and PEF1, without leading to degradation of these proteins (PubMed:18303015, PubMed:20100572, PubMed:27716508).
Ubiquitinated by the SCF(FBXL17) complex, leading to its degradation by the proteasome: ubiquitination by the SCF(FBXL17) complex takes place when aberrant BTB domain dimers are formed.
Ubiquitously expressed. Highly expressed in testis and at lower levels in the submandibular salivary gland.
Adiponectin might be used in the treatment of diabetes type 2 and insulin resistance.
Genetic variations in ADIPOQ influence the variance in adiponectin serum levels and define the adiponectin serum levels quantitative trait locus 1 (ADIPQTL1) [MIM:612556].
HMW complexes are more extensively glycosylated than smaller oligomers. Hydroxylation and glycosylation of the lysine residues within the collagen-like domain of adiponectin seem to be critically involved in regulating the formation and/or secretion of HMW complexes and consequently contribute to the insulin-sensitizing activity of adiponectin in hepatocytes.
HMW-complex blood contents are higher in females than in males, are increased in males by castration and decreased again upon subsequent testosterone treatment, which blocks HMW-complex secretion (By similarity). In type 2 diabetic patients, both the ratios of HMW to total adiponectin and the degree of adiponectin glycosylation are significantly decreased as compared with healthy controls.
Homomultimer. Forms trimers, hexamers and 12- to 18-mers. The trimers (low molecular weight complexes / LMW) are assembled via non-covalent interactions of the collagen-like domains in a triple helix and hydrophobic interactions within the globular C1q domain. Several trimers can associate to form disulfide-linked hexamers (middle molecular weight complexes / MMW) and larger complexes (higher molecular weight / HMW). The HMW-complex assembly is also modulated by the degree of lysine hydroxylation and glycosylation. LMW, MMW and HMW complexes bind to HBEGF, MMW and HMW complexes bind to PDGFB, and HMW complex binds to FGF2. Interacts with CTRP9 via the C1q domain (heterotrimeric complex).
Important adipokine involved in the control of fat metabolism and insulin sensitivity, with direct anti-diabetic, anti-atherogenic and anti-inflammatory activities. Stimulates AMPK phosphorylation and activation in the liver and the skeletal muscle, enhancing glucose utilization and fatty-acid combustion. Antagonizes TNF-alpha by negatively regulating its expression in various tissues such as liver and macrophages, and also by counteracting its effects. Inhibits endothelial NF-kappa-B signaling through a cAMP-dependent pathway. May play a role in cell growth, angiogenesis and tissue remodeling by binding and sequestering various growth factors with distinct binding affinities, depending on the type of complex, LMW, MMW or HMW.
O-glycosylated. Not N-glycosylated. O-linked glycans on hydroxylysines consist of Glc-Gal disaccharides bound to the oxygen atom of post-translationally added hydroxyl groups. Sialylated to varying degrees depending on tissue. Thr-22 appears to be the major site of sialylation. Higher sialylation found in SGBS adipocytes than in HEK fibroblasts. Sialylation is not required neither for heterodimerization nor for secretion. Not sialylated on the glycosylated hydroxylysines. Desialylated forms are rapidly cleared from the circulation.
Polymerization and secretion of adiponectin is inhibited by succination of cysteine residues by the Krebs cycle intermediate fumarate, which leads to S-(2-succinyl)cysteine residues.
Succination of Cys-36 by the Krebs cycle intermediate fumarate, which leads to S-(2-succinyl)cysteine residues, inhibits polymerization and secretion of adiponectin. Adiponectin is a major target for succination in both adipocytes and adipose tissue of diabetic mammals. It was proposed that succination of proteins is a biomarker of mitochondrial stress and accumulation of Krebs cycle intermediates in adipose tissue in diabetes and that succination of adiponectin may contribute to the decrease in plasma adiponectin in diabetes.
Synthesized exclusively by adipocytes and secreted into plasma.
The C1q domain is commonly called the globular domain.
The expected hydroxylation of Lys-33 was not identified, probably due to poor representation of the N-terminal peptide in mass fingerprinting.
Variants Arg-84 and Ser-90 show impaired formation of HMW complexes whereas variants Cys-112 and Thr-164 show impaired secretion of adiponectin in any form.
Expressed in embryo as early as the 11th week of gestation.
Significantly enhances POU5F1/OCT4-SOX2-KLF4-MYC (OSKM) mediated reprogramming of mouse embryonic fibroblasts into induced pluripotent stem cells, and can also substitute for SOX2 in this process.
Transcriptional activator (PubMed:15555580). Important for maintenance of pluripotency in embryonic stem cells (By similarity). Binds directly to the POU5F1 distal enhancer and the NANOG proximal promoter, and enhances expression of both genes (By similarity). Can also bind to numerous other gene promoters and regulates expression of many other pluripotency factors, either directly or indirectly (By similarity). Promotes inhibition of MAPK signaling during embryonic stem cell differentiation (By similarity).
Ubiquitous. Highly expressed in heart and skeletal muscle.
Belongs to the phosphohexose mutase family.
Component of adherens-type cell-cell and cell-matrix junctions (PubMed:8175905). Has no phosphoglucomutase activity in vitro (PubMed:8175905).
Detected in smooth and cardiac muscle at high levels and in skeletal muscle at low level. Present in other tissues due to vascular or other smooth muscle component. Low levels are present in liver, kidney, skin and brain (at protein level).
In the developing aorta, expressed at low levels in 10-12 week old fetuses. Levels increase progressively in 24 week fetus, 6 month old child and 1.5 year old child aortic smooth muscle, reaching a maximum at maturity.
Interacts with DMD/dystrophin; the interaction is direct (By similarity). Interacts with UTRN/utrophin (By similarity).
Expressed at high levels in fetal brain and also in the fetal kidney, lung and liver.
Expressed in the heart, kidney, brain, lung, bone marrow, adrenal gland, trachea, spinal cord and thyroid gland.
Homodimer. Binds TLE1, PNRC1 and PNRC2. Binds GRIP1 (By similarity). Interacts with NRIP1, NCOA1 and NCOR2.
No physiological activating ligand is known for this orphan receptor, but 4-hydroxytamoxifen and diethylstilbestrol act as inverse agonists and deactivate ESRRG.
Orphan receptor that acts as transcription activator in the absence of bound ligand. Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements (By similarity). Induces the expression of PERM1 in the skeletal muscle.
Phosphorylation on Ser-45 enhances sumoylation on Lys-40 thus repressing transcriptional activity.
Sumoylation on Lys-40 is enhanced by phosphorylation at Ser-45 and represses transcriptional activity.
By a subset of cytokines, including EPO/erythropoietin and CSF2/GM-CSF.
High expression in heart, placenta, lung, kidney and prostate. Predominantly expressed in pulmonary epithelia cells, specifically type II pneumocytes.
Interacts with IGF1R (PubMed:9727029). Associates with the Elongin BC complex (PubMed:16675548). Interacts with AREL1 (PubMed:31578312). Interacts with PRKCA (By similarity). Interacts with DCUN1D1 (PubMed:23401859).
Phosphorylation at Ser-52 by PKC facilitates its ubiquitination and proteasomal degradation.
SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. SOCS2 appears to be a negative regulator in the growth hormone/IGF1 signaling pathway. Probable substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
Ubiquitinated; mediated by AREL1 and leading to its subsequent proteasomal degradation (PubMed:31578312). Ubiquitination is dependent on its phosphorylation at Ser-52, by PKC (PubMed:31578312). Ubiquitination is stimulated by LPS (By similarity).
Binds 2 manganese ions per subunit. Mn(2+) is inhibitory below pH 8 and activating above pH 8 (PubMed:24892992).
In colorectal cancer tissue, expression is highest in the surface epithelium of normal colonic mucosa adjacent to the cancer tissue but is largely excluded from the crypt bases. Expression is lost or significantly decreased in 80% of tested tumors (at protein level).
Inhibited by AKT1, AKT2 and AKT3. Activated by oleic acid and arachidonic acid (PubMed:24892992).
Interacts with AKT1, AKT3 and PRKCB isoform beta-II (PubMed:17386267, PubMed:18162466, PubMed:19732725). Interacts with STK4, RPS6KB1, RAF1 (PubMed:20513427, PubMed:21986499, PubMed:24530606). Interacts with FKBP5; FKBP5 acts as a scaffold for PHLPP2 and Akt (PubMed:19732725). Interacts with NHERF1; NHERF1 scaffolds a heterotrimeric complex with PTEN (PubMed:21804599).
Protein phosphatase involved in regulation of Akt and PKC signaling. Mediates dephosphorylation in the C-terminal domain hydrophobic motif of members of the AGC Ser/Thr protein kinase family; specifically acts on 'Ser-473' of AKT1, 'Ser-660' of PRKCB isoform beta-II and 'Ser-657' of PRKCA. Akt regulates the balance between cell survival and apoptosis through a cascade that primarily alters the function of transcription factors that regulate pro- and antiapoptotic genes. Dephosphorylation of 'Ser-473' of Akt triggers apoptosis and decreases cell proliferation. Also controls the phosphorylation of AKT3. Dephosphorylates STK4 on 'Thr-387' leading to STK4 activation and apoptosis (PubMed:20513427). Dephosphorylates RPS6KB1 and is involved in regulation of cap-dependent translation (PubMed:21986499). Inhibits cancer cell proliferation and may act as a tumor suppressor. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation. Dephosphorylates RAF1 inhibiting its kinase activity (PubMed:24530606).
Component of the ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, a VPS37 protein (VPS37A to -D) and MVB12A or MVB12B in a 1:1:1:1 stoichiometry. Interacts with TSG101 and MVB12A. Component of the ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, a VPS37 protein (VPS37A to -D) and UBAP1 in a 1:1:1:1 stoichiometry.
VPS37D is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region.
Interacts with STX1A and/or STX1B1, VAMP2 and SNAP25.
May play a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. May be involved in the regulation of synaptic transmission at parallel fiber - Purkinje cell synapses (By similarity).
Interacts with the transcription factors TBP and TFIIB.
Lung and placenta (PubMed:8626802). Predominantly expressed in gastrointestinal tract including stomach (PubMed:29374064).
Probable transcription activator for a number of lung-specific genes (PubMed:8626802). Mediates up-regulation of the E3 ligase IRF2BPL and drives ubiquitination and degradation of CTNNB1 (PubMed:29374064).
Two activation domains, AD1 and AD2, C-terminal of (and distinct from) the forkhead domains are necessary for transcriptional activation.
Promotes cell proliferation (By similarity). Plays a role in tooth germ growth (By similarity). Plays a role in the control of enamel mineralization. Binds the AMBN promoter (PubMed:32167558).
Expressed in adult brain, pancreas, spleen and prostate (PubMed:9676430). Moderate or low expression is seen in most tissues (PubMed:9676430). Not expressed in liver and peripheral blood leukocytes (PubMed:9676430).
Has a threefold preference for the hydrolysis of ATP over ADP.
N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. N-glycan heterogeneity at Asn-66: dHex1Hex5HexNAc4 (major) and dHex1Hex6HexNAc5 (minor).
Negative regulator of hepatic phosphatidylinositol 3-kinase (PI3K) activity.
Highly expressed in the eye lens and in salivary gland. Detected at lower levels in lung, prostate and lymph node. Isoform 2 is lung specific.
Hydrolyzes DNA under acidic conditions. Does not require divalent cations for activity. Participates in the degradation of nuclear DNA during lens cell differentiation.
Belongs to the universal ribosomal protein uS12 family.
Belongs to the mitochondrion-specific ribosomal protein mS23 family.
Component of the putative homotypic fusion and vacuole protein sorting (HOPS) complex; the core of which composed of the class C Vps proteins VPS11, VPS16, VPS18 and VPS33A, is associated with VPS39 and VPS41 (PubMed:23351085, PubMed:25445562, PubMed:25908847, PubMed:33851776). Interacts with RILP, MON1B (PubMed:20434987, PubMed:25445562). Interacts with ARL8B (GTP-bound form); involved in recruitment to lysosomes and probably hierarchial assembly of the HOPS complex at lysosomal membranes (PubMed:25908847). In vitro can self-assemble into a lattice (PubMed:24210660). Associates with adapter protein complex 3 (AP-3) and clathrin:AP-3 complexes (PubMed:21411634). Interacts with STX17; this interaction is increased in the absence of TMEM39A (PubMed:31806350, PubMed:33422265). Interacts with ARL8B and PLEKHM1; the interaction mediates the recruitment of the HOPS complex to lysosomes (PubMed:21802320, PubMed:28325809, PubMed:25908847).
Expressed in cerebral cortex and cerebellum. Highly expressed in Purkinje cells.
Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Believed to act in part as a core component of the putative HOPS endosomal tethering complex is proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The HOPS complex is proposed to be recruited to Rab7 on the late endosomal membrane and to regulate late endocytic, phagocytic and autophagic traffic towards lysosomes (PubMed:23351085, PubMed:33851776). Involved in homotypic vesicle fusions between late endosomes and in heterotypic fusions between late endosomes and lysosomes implicated in degradation of endocytosed cargo (PubMed:9159129, PubMed:23167963, PubMed:25445562, PubMed:25908847). Required for fusion of autophagosomes with lysosomes (PubMed:25783203). Links the HOPS complex to endosomal Rab7 via its association with RILP and to lysosomal membranes via its association with ARL8B, suggesting that these interactions may bring the compartments to close proximity for fusion (PubMed:25445562, PubMed:25908847, PubMed:21802320). Involved in the direct trans-Golgi network to late endosomes transport of lysosomal membrane proteins independently of HOPS (PubMed:23322049). Involved in sorting to the regulated secretory pathway presumably implicating the AP-3 adapter complex (By similarity). May play a role in HOPS-independent function in the regulated secretory pathway (PubMed:24210660).
Protective against both alpha-synuclein and neurotoxic-mediated injury in invertebrate and cellular models of Parkinson's disease (PD); the function requires the AP-3 adapter complex and the HOPS complex.
Glycopeptide transferase involved in O-linked oligosaccharide biosynthesis, which catalyzes the transfer of an N-acetyl-D-galactosamine residue to an already glycosylated peptide. In contrast to other proteins of the family, it does not act as a peptide transferase that transfers GalNAc onto serine or threonine residue on the protein receptor, but instead requires the prior addition of a GalNAc on a peptide before adding additional GalNAc moieties. Some peptide transferase activity is however not excluded, considering that its appropriate peptide substrate may remain unidentified.
Widely expressed. Expressed in uterus, retina, kidney, small intestine, omentum, stomach and CNS.
Belongs to the tubulin polyglutamylase family.
Catalytic subunit of a polyglutamylase complex which modifies tubulin, generating side chains of glutamate on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of tubulin (PubMed:34782749). Probably involved in the side-chain elongation step of the polyglutamylation reaction rather than the initiation step. Modifies both alpha- and beta-tubulins with a preference for the alpha-tail. Unlike most polyglutamylases of the tubulin--tyrosine ligase family, only displays a catalytic activity when in complex with other proteins as it is most likely lacking domains important for autonomous activity. Part of the neuronal tubulin polyglutamylase complex. Mediates cilia and flagella polyglutamylation which is essential for their biogenesis and motility. Involved in respiratory motile cilia function through the regulation of beating asymmetry. Essential for sperm flagella biogenesis, motility and male fertility. Involved in KLF4 glutamylation which impedes its ubiquitination, thereby leading to somatic cell reprogramming, pluripotency maintenance and embryogenesis.
Expressed in a wide range of tissues. Has a stronger expression in heart, brain and testis.
Gln-144 is the main determinant for regioselectivity, which segregates between initiases and elongases in all tubulin--tyrosine ligase family. A glutamine residue at this position is found in elongases TTLL6, TTLL9, TTLL11, TTLL13, TTLL10 and favors glutamate-chain elongation, whereas an arginine residue is found in initiases TTLL2, TTLL4, TTLL5, TTLL3, TTLL8 and favors initiation.
Part of the neuronal tubulin polyglutamylase complex which contains TPGS1, TPGS2, TTLL1, LRRC49 and NICN1. Interacts with PCM1, CSTPP1 and LRRC49 (PubMed:34782749).
Appears to have histone acetyltransferase (HAT) activity, specifically towards histones H2B and H4 in vitro (PubMed:10821277). However, it is not clear if this activity is genuine or caused by contamination with other histone acetyltransferases in the assay.
Binds DNA as a dimer and can form a homodimer in the absence of DNA. Can form a heterodimer with JUN. Heterodimerization is essential for its transcriptional activity. Interacts with SMAD3 and SMAD4. Binds through its N-terminal region to UTF1 which acts as a coactivator of ATF2 transcriptional activity. Interacts with the HK1/VDAC1 complex. Interacts with NBN, MRE11, XPO1, KAT5 and CUL3.
Phosphorylation of Thr-69 by MAPK14 and MAPK11, and at Thr-71 by MAPK1/ERK2, MAPK3/ERK1, MAPK11, MAPK12 and MAPK14 in response to external stimulus like insulin causes increased transcriptional activity (PubMed:9430721, PubMed:12110590). Phosphorylated by PLK3 following hyperosmotic stress (PubMed:21098032). Also phosphorylated and activated by JNK and CaMK4 (PubMed:8855261). ATM-mediated phosphorylation at Ser-490 and Ser-498 stimulates its function in DNA damage response (PubMed:15916964). Phosphorylation at Ser-62, Thr-73 and Ser-121 activates its transcriptional activity (PubMed:15105425). Phosphorylation at Thr-69 or Thr-71 enhances acetylation of histones H2B and H4 (PubMed:10821277).
The nuclear export signal 1 (N-NES) negatively regulates its nuclear localization and transcriptional activity.
Transcriptional activator which regulates the transcription of various genes, including those involved in anti-apoptosis, cell growth, and DNA damage response. Dependent on its binding partner, binds to CRE (cAMP response element) consensus sequences (5'-TGACGTCA-3') or to AP-1 (activator protein 1) consensus sequences (5'-TGACTCA-3'). In the nucleus, contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. In the cytoplasm, interacts with and perturbs HK1- and VDAC1-containing complexes at the mitochondrial outer membrane, thereby impairing mitochondrial membrane potential, inducing mitochondrial leakage and promoting cell death. The phosphorylated form (mediated by ATM) plays a role in the DNA damage response and is involved in the ionizing radiation (IR)-induced S phase checkpoint control and in the recruitment of the MRN complex into the IR-induced foci (IRIF). Exhibits histone acetyltransferase (HAT) activity which specifically acetylates histones H2B and H4 in vitro (PubMed:10821277). In concert with CUL3 and RBX1, promotes the degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. Can elicit oncogenic or tumor suppressor activities depending on the tissue or cell type.
Ubiquitously expressed, with more abundant expression in the brain.
Homodimer (PubMed:25232744). Part of a complex containing CASK, TBR1 and TSPYL2; may modulate gene expression in response to neuronal synaptic activity (By similarity). Interacts with FOXP2 (PubMed:25232744, PubMed:30250039). Interacts with FOXP1 (PubMed:30250039). Interacts with BCL11A (PubMed:30250039).
Transcriptional repressor involved in multiple aspects of cortical development, including neuronal migration, laminar and areal identity, and axonal projection (PubMed:25232744, PubMed:30250039). As transcriptional repressor of FEZF2, it blocks the formation of the corticospinal (CS) tract from layer 6 projection neurons, thereby restricting the origin of CS axons specifically to layer 5 neurons (By similarity).
May play a role in the development of the central system.
Expressed in many tissues, with the exception of uterus.
Could be used as a differentiation marker in the differential diagnosis of tumors.
Found in a heat-sensitive complex at least composed of several cleavage and polyadenylation specific and cleavage stimulation factors (PubMed:16230528). Interacts with CPSF2, CPSF3 and CSTF2 (PubMed:10669729, PubMed:18688255). Interacts (via N-terminus) with HSF1; this interaction is direct and occurs upon heat shock (PubMed:14707147). Interacts with SSU72 (PubMed:20861839, PubMed:23070812).
In testis, expressed in polar epithelia and Sertoli cells but not in vascular endothelia. The protein is detected in stomach, duodenum, pancreas, liver, fetal brain, carcinomas, lens-forming cells, fibroblasts, lymphocytes, lymphoma cells, erythroleukemia cells but not in endothelium of vessels, epidermis, intercalated disks, Purkinje fiber cells of the heart and lymph node.
Scaffold protein that functions as a component of a multimolecular complex involved in histone mRNA 3'-end processing. Specific component of the tight junction (TJ) plaque, but might not be an exclusively junctional component. May have a house-keeping rule. Is involved in pre-mRNA polyadenylation. Enhances SSU72 phosphatase activity.
The HEAT repeats have been determined based on 3D-structure analysis of the D.melanogaster ortholog and are not detected by sequence-based prediction programs.
Found in a critical region of hereditary spastic paraplegia (HSP) SPG14 locus. No causative CCDC50 mutations were found in HSP families.
Isoform 1 and isoform 2 are coexpressed in placenta, liver, lung, kidney and pancreas. Only isoform 1 is detected in skeletal muscle, brain and heart.
Decarboxylates ethylmalonyl-CoA, a potentially toxic metabolite, to form butyryl-CoA, suggesting it might be involved in metabolite proofreading (PubMed:22016388). Acts preferentially on (S)-ethylmalonyl-CoA but has also some activity on the (R)-isomer (By similarity). Also has methylmalonyl-CoA decarboxylase activity at lower level (By similarity).
Activates the U2 small nuclear RNA (snRNA) promoter.
Belongs to the POU transcription factor family. Class-2 subfamily.
Interacts with NR3C1, AR and PGR (PubMed:10480874). Interacts with POU2AF1; the interaction increases POU2F2 transactivation activity (PubMed:7859290).
Isoform 3 is B-cell specific. Isoform 5 is expressed in B-cells and the immunoglobulin-expressing T-cell line MOLT-4, but not in the T-cell line BW5147.
Transactivation activity is enhanced by transcriptional coactivator POU2AF1.
Transcription factor that specifically binds to the octamer motif (5'-ATTTGCAT-3') (PubMed:2904654, PubMed:7859290). Regulates IL6 expression in B cells with POU2AF1 (By similarity). Regulates transcription in a number of tissues in addition to activating immunoglobulin gene expression (PubMed:2901913, PubMed:2904654). Modulates transcription transactivation by NR3C1, AR and PGR (PubMed:10480874).
Regulates chordin (CHRD). May play a role in spatial programing within discrete embryonic fields or lineage compartments during organogenesis. In concert with NKX3-2, plays a role in defining the structural components of the middle ear; required for the development of the entire tympanic ring (By similarity). Probably involved in the regulatory networks that define neural crest cell fate specification and determine mesoderm cell lineages in mammals.
Belongs to the RecA family. DMC1 subfamily.
Double stacked ring-shaped homooctamer (PubMed:15125839). Interacts with BRCA2 (PubMed:20729832). Interacts with the MND1-PSMC3IP heterodimer (By similarity). Interacts with RAD51AP1; the interaction is direct and stimulates DMC1-mediated homologous recombination (PubMed:21307306, PubMed:21903585).
Participates in meiotic recombination, specifically in homologous strand assimilation, which is required for the resolution of meiotic double-strand breaks.
CARD10 and BCL10 bind to each other by CARD-CARD interaction. They both participate in a complex with MALT1, where MALT1 binds to BCL10 (By similarity). Interacts with TMEM43; this interaction is essential for EGFR-mediated NF-kappa-B activation (PubMed:27991920).
Detected in adult heart, kidney and liver; lower levels in intestine, placenta, muscle and lung. Also found in fetal lung, liver and kidney.
Scaffold protein that plays an important role in mediating the activation of NF-kappa-B via BCL10 or EGFR.
Supposed to contain a SH3, a PDZ and a guanylate kinase-like domain. But none of these 3 domains are detected by PROSITE, Pfam or SMART.
Interacts with STOM; may redistribute STOM from the plasma membrane to late endosomes (PubMed:19696025). Interacts with FBXW7 isoform 3 and CDK2 (PubMed:23082202).
May play a role in cholesterol transfer to late endosomes (PubMed:19696025). May play a role in modulating membrane acid-sensing ion channels. Can specifically inhibit proton-gated current of ASIC1 isoform 1. Can increase inactivation speed of ASIC3. May be involved in regulation of proton sensing in dorsal root ganglions (By similarity). May play a role in protecting FBXW7 isoform 3 from degradation (PubMed:23082202).
Ubiquitously expressed at low levels. Expression is highest in brain.
Required for the assembly of axonemal inner and outer dynein arms. Involved in preassembly of dyneins into complexes before their transport into cilia.
Homodimer. May form heterooligomers with other PACSINs. Interacts (via SH3 domain) with DNM1, SYNJ1 and WASL. Interacts with TRPV4 (By similarity).
Phosphorylated by casein kinase 2 (CK2) and protein kinase C (PKC).
Plays a role in endocytosis and regulates internalization of plasma membrane proteins. Overexpression impairs internalization of SLC2A1/GLUT1 and TRPV4 and increases the levels of SLC2A1/GLUT1 and TRPV4 at the cell membrane. Inhibits the TRPV4 calcium channel activity (By similarity).
The F-BAR domain forms a coiled coil and mediates membrane-binding and membrane tubulation.
Widely expressed, with highest levels in heart and skeletal muscle, intermediate levels in placenta, liver and pancreas, and very low levels in brain, lung and kidney.
By DNA damaging agents such as UV, adriamycin, actinomycin-D and cisplatin.
Down-regulated in various cancer tissues.
Part of a multisubunit complex that groups tRNA ligases for Arg (RARS1), Asp (DARS1), Gln (QARS1), Ile (IARS1), Leu (LARS1), Lys (KARS1), Met (MARS1) the bifunctional ligase for Glu and Pro (EPRS1) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18 (PubMed:19131329, PubMed:19289464). Can interact simultaneously with MARS1 and EPRS1 (PubMed:26472928). Forms a linear complex that contains MARS1, EEF1E1, EPRS1 and AIMP2 that is at the core of the multisubunit complex (PubMed:26472928). Interacts with ATM and ATR. The interaction with ATM, which takes place independently of TP53, is induced by DNA damage that may occur during genotoxic stress or cell growth. The interaction with ATR is enhanced by UV irradiation.
Positive modulator of ATM response to DNA damage.
Autophagy factor required for autophagosome formation. Stabilizes ATG13, protecting it from proteasomal degradation.
Interacts with ATG13 (PubMed:19287211, PubMed:19597335, PubMed:26299944). Associates with a complex composed of ATG13, ULK1 and RB1CC1; the association with this complex requires the presence of ATG13 (PubMed:19287211, PubMed:19597335).
Auto-ubiquitinates in an E2-dependent manner leading to its own degradation (PubMed:19229105, PubMed:25474007, PubMed:23770917). Also polyubiquitinated by RNF41 for proteasomal degradation (PubMed:19229105).
Belongs to the RBR family. Parkin subfamily.
Defects in PRKN may be involved in the development and/or progression of ovarian cancer.
Disease susceptibility may be associated with variants affecting the gene represented in this entry. Heterozygous mutations act as susceptibility alleles for late-onset Parkinson disease (PubMed:12730996, PubMed:12629236).
Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6 (PubMed:21532592, PubMed:11078524). Mediates 'Lys-63'-linked polyubiquitination by associating with UBE2V1. Part of a SCF-like complex, consisting of PRKN, CUL1 and FBXW7 (PubMed:12628165). Interacts with SNCAIP (PubMed:11590439, PubMed:15728840). Binds to the C2A and C2B domains of SYT11 (PubMed:12925569). Interacts and regulates the turnover of SEPTIN5 (PubMed:11078524). Part of a complex, including STUB1, HSP70 and GPR37 (PubMed:12150907). The amount of STUB1 in the complex increases during ER stress (PubMed:12150907). STUB1 promotes the dissociation of HSP70 from PRKN and GPR37, thus facilitating PRKN-mediated GPR37 ubiquitination (PubMed:12150907). HSP70 transiently associates with unfolded GPR37 and inhibits the E3 activity of PRKN, whereas, STUB1 enhances the E3 activity of PRKN through promotion of dissociation of HSP70 from PRKN-GPR37 complexes (PubMed:12150907). Interacts with PSMD4 and PACRG (PubMed:12634850, PubMed:14532270). Interacts with LRRK2 (PubMed:16352719). Interacts with RANBP2 (PubMed:16332688). Interacts with SUMO1 but not SUMO2, which promotes nuclear localization and autoubiquitination (PubMed:16955485). Interacts (via first RING-type domain) with AIMP2 (via N-terminus) (PubMed:16135753). Interacts with PSMA7 and RNF41 (PubMed:15987638, PubMed:18541373). Interacts with PINK1 (PubMed:19966284, PubMed:20798600). Forms a complex with PINK1 and PARK7 (PubMed:19229105). Interacts with CHPF, the interaction with isoform 2 may facilitate PRKN transport into the mitochondria (PubMed:22082830). Interacts with MFN2 (phosphorylated), promotes PRKN localization in dysfunctional depolarized mitochondria (PubMed:23620051). Interacts with FBXO7; this promotes translocation to dysfunctional depolarized mitochondria (PubMed:23933751). Interacts with ZNF746 (PubMed:21376232). Interacts with heat shock protein 70 family members, including HSPA1L, HSPA1A and HSPA8; interaction HSPA1L promotes translocation to damaged mitochondria (PubMed:24270810). Interacts with BAG4 and, to a lesser extent, BAG5; interaction with BAG4 inhibits translocation to damaged mitochondria (PubMed:24270810). Forms a complex with PRKN and PARK7 (PubMed:19229105). Interacts with AMBRA1 (By similarity).
Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins (PubMed:10888878, PubMed:10973942, PubMed:11431533, PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, PubMed:21376232, PubMed:21532592, PubMed:23754282, PubMed:23620051, PubMed:24660806, PubMed:24751536, PubMed:32047033, PubMed:29311685, PubMed:22396657). Substrates include SYT11 and VDAC1 (PubMed:32047033, PubMed:29311685). Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and AIMP2 (PubMed:10888878, PubMed:10973942, PubMed:11431533, PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, PubMed:21376232, PubMed:21532592, PubMed:23754282, PubMed:23620051, PubMed:24660806, PubMed:24751536, PubMed:22396657). Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context (PubMed:19229105, PubMed:20889974, PubMed:25621951, PubMed:32047033, PubMed:25474007). Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation (PubMed:17846173, PubMed:19229105). Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation (PubMed:11431533, PubMed:11590439, PubMed:15105460, PubMed:19229105, PubMed:15728840). Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy (PubMed:20889974). Protects against mitochondrial dysfunction during cellular stress, by acting downstream of PINK1 to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components (PubMed:32047033, PubMed:19029340, PubMed:19966284, PubMed:23620051, PubMed:24896179, PubMed:25527291, PubMed:18957282, PubMed:21376232, PubMed:22396657, PubMed:24660806, PubMed:25474007, PubMed:24784582, PubMed:11439185, PubMed:22082830, PubMed:23933751). Depending on the severity of mitochondrial damage and/or dysfunction, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy (PubMed:32047033, PubMed:19029340, PubMed:19801972, PubMed:19966284, PubMed:23620051, PubMed:24896179, PubMed:25527291, PubMed:21376232, PubMed:22396657, PubMed:11439185, PubMed:22082830, PubMed:23933751, PubMed:33499712). Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated phosphorylation of both PRKN and ubiquitin (PubMed:24660806, PubMed:25474007, PubMed:24784582, PubMed:25527291). After mitochondrial damage, functions with PINK1 to mediate the decision between mitophagy or preventing apoptosis by inducing either the poly- or monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 promotes mitophagy, while monoubiquitination of VDAC1 decreases mitochondrial calcium influx which ultimately inhibits apoptosis (PubMed:27534820, PubMed:32047033). When cellular stress results in irreversible mitochondrial damage, promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, MFN1 and USP30 (PubMed:19029340, PubMed:19966284, PubMed:21753002, PubMed:23620051, PubMed:24896179, PubMed:25527291, PubMed:22396657, PubMed:23933751). Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to mitophagy (PubMed:25621951, PubMed:32047033). The PINK1-PRKN pathway also promotes fission of damaged mitochondria by PINK1-mediated phosphorylation which promotes the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2 (PubMed:23620051). This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (PubMed:23620051). Regulates motility of damaged mitochondria via the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma (PubMed:22396657). Involved in mitochondrial biogenesis via the 'Lys-48'-linked polyubiquitination of transcriptional repressor ZNF746/PARIS which leads to its subsequent proteasomal degradation and allows activation of the transcription factor PPARGC1A (PubMed:21376232). Limits the production of reactive oxygen species (ROS) (PubMed:18541373). Regulates cyclin-E during neuronal apoptosis (PubMed:12628165). In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress (PubMed:22082830). Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53 (PubMed:19801972). May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity (PubMed:11439185). May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene (PubMed:12719539).
Highly expressed in the brain including the substantia nigra (PubMed:9560156, PubMed:19501131). Expressed in heart, testis and skeletal muscle (PubMed:9560156). Expression is down-regulated or absent in tumor biopsies, and absent in the brain of PARK2 patients (PubMed:14614460, PubMed:12719539). Overexpression protects dopamine neurons from kainate-mediated apoptosis (PubMed:12628165). Found in serum (at protein level) (PubMed:19501131).
ISGylated. Conjugated to ubiquitin-like protein ISG15 upon IFN-beta stimulation. ISGylation positively regulates its E3 ligase activity.
In the autoinhibited state the side chain of Phe-463 inserts into a hydrophobic groove in RING-0, occluding the ubiquitin acceptor site Cys-431, whereas the REP repressor element binds RING-1 and blocks its E2-binding site (PubMed:23727886, PubMed:23770887). Activation of PRKN requires 2 steps: (1) phosphorylation at Ser-65 by PINK1 and (2) binding to phosphorylated ubiquitin, leading to unlock repression of the catalytic Cys-431 by the RING-0 region via an allosteric mechanism and converting PRKN to its fully-active form (PubMed:24660806, PubMed:25474007, PubMed:24784582, PubMed:25527291). According to another report, phosphorylation at Ser-65 by PINK1 is not essential for activation and only binding to phosphorylated ubiquitin is essential to unlock repression (PubMed:24751536). In addition, ISG15 conjugation positively regulates its ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation (PubMed:27534820).
Members of the RBR family are atypical E3 ligases. They interact with the E2 conjugating enzyme UBE2L3 and function like HECT-type E3 enzymes: they bind E2s via the first RING domain, but require an obligate trans-thiolation step during the ubiquitin transfer, requiring a conserved cysteine residue in the second RING domain.
Phosphorylated (PubMed:23754282, PubMed:24660806, PubMed:24784582, PubMed:18957282, PubMed:25474007). Activation requires phosphorylation at Ser-65 by PINK1 and binding to PINK1 phosphorylated ubiquitin (PubMed:23754282, PubMed:24660806, PubMed:24784582, PubMed:18957282, PubMed:25474007). Phosphorylation at Thr-175 by PINK1 and at Thr-217 is important for mitochondrial localization (PubMed:18957282).
S-nitrosylated. The inhibition of PRKN ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in PD by impairing the ubiquitination of PRKN substrates.
The RING-type 1 zinc finger domain is required to repress p53/TP53 transcription.
The parkin locus (PRKN), adjacent to the 6q telomere is hyper-recombinable and lies within FRA6E, the third most common fragile site in tumor tissue.
The ubiquitin-like domain binds the PSMD4 subunit of 26S proteasomes.
Expressed at high levels in the cerebrum, cerebellum, lung, kidney, and testis. Weakly expressed in the kidney. Isoform 2 is down-regulated during progression of prostate cancer.
Interacts with EPN1; the interaction is direct (PubMed:10393179, PubMed:10557078). Interacts with EPS15; the interaction is direct (PubMed:10393179). Interacts with EPS15L1 (PubMed:10393179). Interacts with RALBP1; can form a ternary complex with activated Ral (RALA or RALB) (PubMed:9422736). Interacts with ASAP1; the interaction is direct and this complex can bind paxillin (PubMed:12149250). Also forms a ternary complex with RALBP1 and ASAP1 (PubMed:12149250). Interacts with GRB2 (PubMed:9422736).
Involved in ligand-dependent receptor mediated endocytosis of the EGF and insulin receptors as part of the Ral signaling pathway (PubMed:9422736, PubMed:12771942, PubMed:10393179). By controlling growth factor receptors endocytosis may regulate cell survival (PubMed:12771942). Through ASAP1 may regulate cell adhesion and migration (PubMed:12149250).
Tyrosine-phosphorylated upon stimulation of cells with EGF. Phosphorylation on Tyr-residues induces its association with the EGF receptor probably indirectly through an adapter like GRB2.
Interacts with FANCD2 (when monoubiquitinated). Interacts with FANCI, MLH1, MLH3 and PMS2.
Nuclease required for the repair of DNA interstrand cross-links (ICL) recruited at sites of DNA damage by monoubiquitinated FANCD2. Specifically involved in repair of ICL-induced DNA breaks by being required for efficient homologous recombination, probably in the resolution of homologous recombination intermediates (PubMed:20603015, PubMed:20603016, PubMed:20603073, PubMed:20671156, PubMed:24981866, PubMed:25430771). Not involved in DNA double-strand breaks resection (PubMed:20603015, PubMed:20603016). Acts as a 5'-3' exonuclease that anchors at a cut end of DNA and cleaves DNA successively at every third nucleotide, allowing to excise an ICL from one strand through flanking incisions. Probably keeps excising with 3'-flap annealing until it reaches and unhooks the ICL (PubMed:25430771). Acts at sites that have a 5'-terminal phosphate anchor at a nick or a 1- or 2-nucleotide flap and is augmented by a 3' flap (PubMed:25430771). Also has endonuclease activity toward 5'-flaps (PubMed:20603015, PubMed:20603016, PubMed:24981866).
Schizophrenia and autism. Schizophrenia is a severe psychiatric disorder characterized by positive, negative, and cognitive symptoms, and it is associated with increased mortality and severely reduced fecundity. Autim is a complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate intellectual disability. Disease susceptibility may be associated with variants affecting the gene represented in this entry.
The KEN box and D-box are required for interaction with FZR1/CDH1 and essential for APC(CDH1)-mediated ubiquitination.
The UBZ4-type zinc finger specifically binds monoubiquitinated FANCD2.
Ubiquitinated and degraded during mitotic exit by the APC/C-Cdh1 complex.
Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors. Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway (PubMed:21909076, PubMed:21727895, PubMed:22615920). During embryonic development, plays a crucial role in limb specification, amplifying the Wnt signaling pathway independently of LGR4-6 receptors, possibly by acting as a direct antagonistic ligand to RNF43 and ZNRF3, hence governing the number of limbs an embryo should form (PubMed:29769720).
Interacts with WNT1 (By similarity). Binds heparin (By similarity). Interacts with LGR4, LGR5 and LGR6 (PubMed:21909076, PubMed:21727895, PubMed:22615920, PubMed:29769720). Interacts with E3 ubiquitin ligases RNF43 and ZNRF3 (PubMed:29769720).
The FU repeat is required for activation and stabilization of beta-catenin.
Associates with ORC complex (PubMed:31160578). Binds to chromatin; association is cell cycle-regulated, absent from mitotic chromosomes, is associated with chromatin from G1 and partially released from chromatin from mid S-phase (PubMed:31160578).
E3 ubiquitin ligase essential for DNA replication origin activation during S phase (PubMed:31160578). Acts as a replication origin selector which selects the origins to be fired and catalyzes the multi-mono-ubiquitination of a subset of chromatin-bound ORC3 and ORC5 during S-phase (PubMed:31160578).
May be involved in epidermal differentiation and inflammation and might therefore be important for the pathogenesis of psoriasis and other diseases.
Belongs to the peptidase M67A family. MYSM1 subfamily.
By DNA from viral infection and intracellular DNA.
Component of a large chromatin remodeling complex, at least composed of MYSM1, PCAF, RBM10 and KIF11/TRIP5. Binds histones (PubMed:17707232). Interacts with NFIL3; this interaction is critical for their correct recruitment to the ID2 locus during natural killer cell maturation (PubMed:24062447).
Contains an N-terminal SANT domain that mediates histone/DNA binding, a central SWIRM domain to mediate interaction with chromatin associated proteins, and a C-terminal MPN domain that contains the metalloprotease activity.
Metalloprotease with deubiquitinase activity that plays important regulator roles in hematopoietic stem cell function, blood cell production and immune response (PubMed:24062447, PubMed:26220525, PubMed:28115216). Participates in the normal programming of B-cell responses to antigen after the maturation process (By similarity). Within the cytoplasm, plays critical roles in the repression of innate immunity and autoimmunity (PubMed:33086059). Removes 'Lys-63'-linked polyubiquitins from TRAF3 and TRAF6 complexes (By similarity). Attenuates NOD2-mediated inflammation and tissue injury by promoting 'Lys-63'-linked deubiquitination of RIPK2 component (By similarity). Suppresses the CGAS-STING1 signaling pathway by cleaving STING1 'Lys-63'-linked ubiquitin chains (PubMed:33086059). In the nucleus, acts as a hematopoietic transcription regulator derepressing a range of genes essential for normal stem cell differentiation including EBF1 and PAX5 in B-cells, ID2 in NK-cell progenitor or FLT3 in dendritic cell precursors (PubMed:24062447). Deubiquitinates monoubiquitinated histone H2A, a specific tag for epigenetic transcriptional repression, leading to dissociation of histone H1 from the nucleosome (PubMed:17707232).
Expressed primarily in trachea and testis, 2 tissues containing axonemal structures. Also expressed in brain but not in adult heart.
Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Involved in sperm motility; implicated in sperm flagellar assembly (PubMed:34237282). Probable inner arm dynein heavy chain.
Component of the gamma-secretase complex (PubMed:10993067, PubMed:30598546, PubMed:30630874). The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN/PEN2 (PubMed:12740439, PubMed:25043039, PubMed:26623517, PubMed:26280335, PubMed:25918421, PubMed:30598546, PubMed:30630874). Binds to proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP) (PubMed:10993067, PubMed:30630874). Interacts with PSEN1 and PSEN2 (PubMed:10993067).
Constitutively expressed in neural cells.
Detected in brain (at protein level) (PubMed:10993067). Widely expressed (PubMed:11396676).
Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:10993067, PubMed:12679784, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels.
Belongs to the phosphoglycerate mutase family.
Expressed in the brain (PubMed:22887998). Expressed in breast tumors (PubMed:21820150). Expressed in glioblastomas (PubMed:22887998).
Fructose-bisphosphatase hydrolyzing fructose-2,6-bisphosphate as well as fructose-1,6-bisphosphate (PubMed:19015259). Acts as a negative regulator of glycolysis by lowering intracellular levels of fructose-2,6-bisphosphate in a p53/TP53-dependent manner, resulting in the pentose phosphate pathway (PPP) activation and NADPH production (PubMed:16839880, PubMed:22887998). Contributes to the generation of reduced glutathione to cause a decrease in intracellular reactive oxygen species (ROS) content, correlating with its ability to protect cells from oxidative or metabolic stress-induced cell death (PubMed:16839880, PubMed:19713938, PubMed:23726973, PubMed:22887998, PubMed:23817040). Plays a role in promoting protection against cell death during hypoxia by decreasing mitochondria ROS levels in a HK2-dependent manner through a mechanism that is independent of its fructose-bisphosphatase activity (PubMed:23185017). In response to cardiac damage stress, mediates p53-induced inhibition of myocyte mitophagy through ROS levels reduction and the subsequent inactivation of BNIP3. Reduced mitophagy results in an enhanced apoptotic myocyte cell death, and exacerbates cardiac damage (By similarity). Plays a role in adult intestinal regeneration; contributes to the growth, proliferation and survival of intestinal crypts following tissue ablation (PubMed:23726973). Plays a neuroprotective role against ischemic brain damage by enhancing PPP flux and preserving mitochondria functions (By similarity). Protects glioma cells from hypoxia- and ROS-induced cell death by inhibiting glycolysis and activating mitochondrial energy metabolism and oxygen consumption in a TKTL1-dependent and p53/TP53-independent manner (PubMed:22887998). Plays a role in cancer cell survival by promoting DNA repair through activating PPP flux in a CDK5-ATM-dependent signaling pathway during hypoxia and/or genome stress-induced DNA damage responses (PubMed:25928429). Involved in intestinal tumor progression (PubMed:23726973).
Interacts with HK2; the interaction increases hexokinase HK2 activity in a hypoxia- and HIF1A-dependent manner, resulting in the regulation of mitochondrial membrane potential, thus increasing NADPH production and decreasing intracellular ROS levels (PubMed:23185017).
Not expected to have any kinase activity.
Up-regulated by p53/TP53 (at protein level) (PubMed:16839880). Rapidly up-regulated by p53/TP53 (PubMed:16140933, PubMed:16839880, PubMed:19713938). Up-regulated in glioma cell line in a p53/TP53-independent manner (PubMed:22887998).
Liver, intestine and at lower level in the kidney.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of estradiol and estrone (PubMed:7779757, PubMed:11884392, PubMed:11006110). Is a key enzyme in estrogen homeostasis, the sulfation of estrogens leads to their inactivation. Also sulfates dehydroepiandrosterone (DHEA), pregnenolone, (24S)-hydroxycholesterol and xenobiotic compounds like ethinylestradiol, equalenin, diethyl stilbesterol and 1-naphthol at significantly lower efficiency (PubMed:11006110, PubMed:19589875). Does not sulfonate cortisol, testosterone and dopamine (PubMed:7779757, PubMed:11006110). May play a role in gut microbiota-host metabolic interaction. O-sulfonates 4-ethylphenol (4-EP), a dietary tyrosine-derived metabolite produced by gut bacteria. The product 4-EPS crosses the blood-brain barrier and may negatively regulate oligodendrocyte maturation and myelination, affecting the functional connectivity of different brain regions associated with the limbic system.
Predominantly expressed in small and large intestines and colon. Weakly expressed in lymphocytes. Not expressed in other tissues. Down-regulated in colonic adenocarcinomas.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues and O-linked sugars of mucin-type acceptors. Acts on the non-reducing terminal GlcNAc of short carbohydrate substrates. However, it does not transfer sulfate to longer carbohydrate substrates that have poly-N-acetyllactosamine structures. Has no activity toward keratan. Not involved in generating HEV-expressed ligands for SELL. Its substrate specificity may be influenced by its subcellular location.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRD sub-subfamily.
A chromosomal aberration involving CREB3L2 is found in low grade fibromyxoid sarcoma (LGFMS). Translocation t(7;16)(q33;p11) with FUS.
Transcription factor involved in unfolded protein response (UPR). In the absence of endoplasmic reticulum (ER) stress, inserted into ER membranes, with N-terminal DNA-binding and transcription activation domains oriented toward the cytosolic face of the membrane. In response to ER stress, transported to the Golgi, where it is cleaved in a site-specific manner by resident proteases S1P/MBTPS1 and S2P/MBTPS2. The released N-terminal cytosolic domain is translocated to the nucleus to effect transcription of specific target genes. Plays a critical role in chondrogenesis by activating the transcription of SEC23A, which promotes the transport and secretion of cartilage matrix proteins, and possibly that of ER biogenesis-related genes (By similarity). In a neuroblastoma cell line, protects cells from ER stress-induced death (PubMed:17178827). In vitro activates transcription of target genes via direct binding to the CRE site (PubMed:17178827).
Ubiquitinated by HRD1/SYVN1; undergoes 'Lys-48'-linked ubiquitination, followed by rapid proteasomal degradation under normal conditions. Upon ER stress, SYVN1 E3 ubiquitin-protein ligase dissociates from its substrate, ubiquitination does not occur and CREB3L2 is stabilized.
Up-regulated by ER stress at the transcript and protein levels, the increase at the protein level is much higher than at the transcript level. This induction is accompanied by increased proteolytic cleavage that releases the N-terminal transcription factor domain.
Upon ER stress, translocated to the Golgi apparatus, where it is processed by regulated intramembrane proteolysis (RIP) to release the cytosol-facing N-terminal transcription factor domain. The cleavage is performed sequentially by site-1 and site-2 proteases (S1P/MBTPS1 and S2P/MBTPS2).
Widely expressed with highest levels in placenta, lung, spleen and intestine, and lowest levels in heart, brain, skeletal muscle, thymus, colon and leukocytes. In fetal tissues, the weakest expression is detected in brain and heart.
Probable microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in flagellum axoneme.
E3 ubiquitin-protein ligase which is a component of the N-end rule pathway (By similarity). Does not bind to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation (By similarity). May play a role in Shh signaling by mediating the ubiquitination of Kif7 (By similarity). May be important for MYH9 function in certain tissues, possibly by regulating the ubiquitination of MYH9 and consequently affecting its interaction with MYO7A (PubMed:27331610).
Catalytic subunit of the KPC complex that acts as E3 ubiquitin-protein ligase (PubMed:15531880, PubMed:16227581, PubMed:25860612). Promotes the ubiquitination and proteasome-mediated degradation of CDKN1B which is the cyclin-dependent kinase inhibitor at the G0-G1 transition of the cell cycle (PubMed:15531880, PubMed:16227581). Also acts as a key regulator of the NF-kappa-B signaling by promoting maturation of the NFKB1 component of NF-kappa-B: acts by catalyzing ubiquitination of the NFKB1 p105 precursor, leading to limited proteasomal degradation of NFKB1 p105 and generation of the active NFKB1 p50 subunit (PubMed:25860612, PubMed:33168738, PubMed:34873064). Functions also as an inhibitor of innate antiviral signaling mediated by RIGI and IFIH1 independently of its E3 ligase activity (PubMed:27312109). Interacts with the N-terminal CARD domains of RIGI and IFIH1 and competes with the downstream adapter MAVS (PubMed:27312109).
Component of the KPC complex composed of RNF123/KPC1 and UBAC1/KPC2 (PubMed:15531880, PubMed:16227581). Interacts with UBAC1 and CDKN1B via its N-terminal domain (PubMed:15531880, PubMed:16227581). Interacts with RIGI (via N-terminus) and IFIH1 (via N-terminus) (PubMed:27312109).
RNF123-mediated maturation of NFKB1 restricts tumor growth by promoting activation of the NF-kappa-B complex, leading to expression of tumor suppressor genes (PubMed:25860612, PubMed:33168738). Activation of NF-kappa-B promotes tumor suppression via CD274/PD-L1 and chemokines-mediated mechanisms (PubMed:33168738).
The WILVRLW sequence, which specifically recognizes and binds NFKB1 could be used to generate a tumor-suppressive PROTA.
Ubiquitinated, leading to its degradation. Deubiquitinated by USP19, thereby stimulating CDKN1B ubiquitin-dependent degradation.
Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Involved in polyadenylation of mRNA precursors. Connects PAF1C to Wnt signaling.
Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8 (PubMed:15632063, PubMed:19952111, PubMed:20178742). The PAF1 complex interacts with PHF5A (By similarity). Interacts with TCEA1, SUPT5H and CTNNB1 (PubMed:16630820, PubMed:19952111, PubMed:20178742). Interacts with SETD5 (By similarity).
Highly expressed in skeletal muscle and heart. Weakly expressed in placenta and liver.
Component of the chaperonin-containing T-complex (TRiC), a heterooligomeric complex of about 850 to 900 kDa that forms two stacked rings, 12 to 16 nm in diameter (PubMed:20080638, PubMed:25467444). Interacts with PACRG (PubMed:14532270). Interacts with DNAAF4 (By similarity). Interacts with DLEC1 (PubMed:33144677).
Sequence-specific DNA-binding transcriptional regulator. Plays a role as a molecular node in a transcriptional network regulating embryonic development and cell fate decision. Stimulates the expression of upstream key transcriptional activators and repressors of the Wnt/beta-catenin and MAPK/ERK pathways, respectively, that are essential for naive pluripotency and self-renewal maintenance of embryonic stem cells (ESCs). Specifically promotes SPRY1 and RSPO1 transcription activation through recognition and direct binding of a specific DNA sequence in their promoter regions. Involved in early embryo development (By similarity). Also plays a role in induced pluripotent stem cells (iPSCs) reprogramming (PubMed:28740264).
Activated by ATP (PubMed:10092647). Inhibited by calcium-activated calmodulin (By similarity). Inhibited by bromoenol lactone (BEL) (By similarity).
Calcium-independent phospholipase involved in phospholipid remodeling with implications in cellular membrane homeostasis, mitochondrial integrity and signal transduction. Hydrolyzes the ester bond of the fatty acyl group attached at sn-1 or sn-2 position of phospholipids (phospholipase A1 and A2 activity respectively), producing lysophospholipids that are used in deacylation-reacylation cycles (PubMed:9417066, PubMed:10092647, PubMed:10336645, PubMed:20886109). Hydrolyzes both saturated and unsaturated long fatty acyl chains in various glycerophospholipid classes such as phosphatidylcholines, phosphatidylethanolamines and phosphatidates, with a preference for hydrolysis at sn-2 position (PubMed:10092647, PubMed:10336645, PubMed:20886109). Can further hydrolyze lysophospholipids carrying saturated fatty acyl chains (lysophospholipase activity) (PubMed:20886109). Upon oxidative stress, contributes to remodeling of mitochondrial phospholipids in pancreatic beta cells, in a repair mechanism to reduce oxidized lipid content (PubMed:23533611). Preferentially hydrolyzes oxidized polyunsaturated fatty acyl chains from cardiolipins, yielding monolysocardiolipins that can be reacylated with unoxidized fatty acyls to regenerate native cardiolipin species (By similarity). Hydrolyzes oxidized glycerophosphoethanolamines present in pancreatic islets, releasing oxidized polyunsaturated fatty acids such as hydroxyeicosatetraenoates (HETEs) (By similarity). Has thioesterase activity toward fatty-acyl CoA releasing CoA-SH known to facilitate fatty acid transport and beta-oxidation in mitochondria particularly in skeletal muscle (PubMed:20886109). Plays a role in regulation of membrane dynamics and homeostasis. Selectively hydrolyzes sn-2 arachidonoyl group in plasmalogen phospholipids, structural components of lipid rafts and myelin (By similarity). Regulates F-actin polymerization at the pseudopods, which is required for both speed and directionality of MCP1/CCL2-induced monocyte chemotaxis (PubMed:18208975). Targets membrane phospholipids to produce potent lipid signaling messengers. Generates lysophosphatidate (LPA, 1-acyl-glycerol-3-phosphate), which acts via G-protein receptors in various cell types (By similarity). Has phospholipase A2 activity toward platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), likely playing a role in inactivation of this potent pro-inflammatory signaling lipid (By similarity). In response to glucose, amplifies calcium influx in pancreatic beta cells to promote INS secretion (By similarity).
Four different transcripts were found to be expressed in a distinct tissue distribution.
Has two putative calmodulin binding domains, the 1-9-14 and IQ motifs. One calmodulin molecule interacts with PLA2G6 dimer, likely through 1-9-14 motif on each monomer (By similarity). Binds calmodulin in a calcium-dependent way (By similarity).
Homodimer formed by catalytic domains tightly interacting through a large hydrophobic interface. The contact area involves 3 alpha helices, several loops and a part of the beta sheet from each monomer. Both active sites of the dimer are in close proximity adopting an open conformation that provide sufficient space for phospholipid access and favoring cooperativity in deacylation-reacylation reactions. Each monomer has 9 ankyrin repeats stacked side-by-side in an elongated structure oriented outwards from the catalytic core.
Lacks the catalytic domain and may act as a negative regulator of the catalytically active isoforms.
Potential target for therapeutic intervention of Barth syndrome.
Arg-345 is dimethylated, probably to asymmetric dimethylarginine.
Binds with high affinity to RNA molecules that contain AU-rich elements (AREs) found within the 3'-UTR of many proto-oncogenes and cytokine mRNAs. Also binds to double- and single-stranded DNA sequences in a specific manner and functions a transcription factor. Each of the RNA-binding domains specifically can bind solely to a single-stranded non-monotonous 5'-UUAG-3' sequence and also weaker to the single-stranded 5'-TTAGGG-3' telomeric DNA repeat. Binds RNA oligonucleotides with 5'-UUAGGG-3' repeats more tightly than the telomeric single-stranded DNA 5'-TTAGGG-3' repeats. Binding of RRM1 to DNA inhibits the formation of DNA quadruplex structure which may play a role in telomere elongation. May be involved in translationally coupled mRNA turnover. Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain. May play a role in the regulation of the rhythmic expression of circadian clock core genes. Directly binds to the 3'UTR of CRY1 mRNA and induces CRY1 rhythmic translation. May also be involved in the regulation of PER2 translation.
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Part of a complex associated with the FOS mCRD domain and consisting of PABPC1, PAIP1, CSDE1/UNR and SYNCRIP. Interacts with IGF2BP2. Interacts with GTPBP1. Interacts with EIF4G1; the interaction requires RNA. Interacts with EIF3B and RPS3.
Methylated by PRMT1, in an insulin-dependent manner. The PRMT1-mediated methylation regulates tyrosine phosphorylation (By similarity).
Was reported to promote CD8+ T cell immunity through effects on mitochondrial respiration (PubMed:25883318). However, the corresponding article has been retracted (PubMed:27980177).
Highly expressed in stomach, colon, prostate, trachea and thyroid glands and weakly in bladder and lung.
Widely expressed in the peripheral system. Expression pattern is high in pancreas, medium in kidney, small intestine, spleen and testis, low in lung, colon, leukocyte, prostate and thymus and not detectable in brain, heart, liver, placenta, skeletal muscle and ovary.
Binds 1 potassium ion per subunit. The potassium ion interacts primarily with the substrate.
Binds 2 magnesium ions per subunit. The magnesium ions interact primarily with the substrate.
Catalyzes the formation of S-adenosylmethionine from methionine and ATP.
Catalyzes the formation of S-adenosylmethionine from methionine and ATP. The reaction comprises two steps that are both catalyzed by the same enzyme: formation of S-adenosylmethionine (AdoMet) and triphosphate, and subsequent hydrolysis of the triphosphate.
Heterotrimer; composed of a catalytic MAT2A homodimer that binds one regulatory MAT2B chain (PubMed:10644686, PubMed:23189196). Heterohexamer; composed of a central, catalytic MAT2A homotetramer flanked on either side by a regulatory MAT2B chain (PubMed:25075345).
Protein expression is regulated by post-transcriptional regulation: in presence of S-adenosyl-L-methionine, METTL16 binds and methylates the first hairpin of the 3'-UTR region of MAT2A mRNA, preventing recognition of their 3'-splice site by U2AF1/U2AF35, thereby inhibiting splicing and protein production of S-adenosylmethionine synthase (PubMed:28525753, PubMed:29262316, PubMed:33930289). In S-adenosyl-L-methionine-limiting conditions, METTL16 binds the 3'-UTR region of MAT2A mRNA without methylating it due to the lack of a methyl donor, preventing N6-methylation and promoting expression of MAT2A (PubMed:28525753).
Calcium-dependent nucleotidase with a preference for UDP. The order of activity with different substrates is UDP > GDP > UTP > GTP. Has very low activity towards ADP and even lower activity towards ATP. Does not hydrolyze AMP and GMP (PubMed:12234496, PubMed:15248776, PubMed:15006348, PubMed:16835225). Involved in proteoglycan synthesis (PubMed:22539336).
Monomer (PubMed:12234496, PubMed:15006348). Homodimer; dimerization is Ca(2+)-dependent (PubMed:16835225). Homodimer; disulfide-linked (membrane form) (PubMed:16835225).
Autophosphorylated (PubMed:20404107, PubMed:22910362, PubMed:18957282). Loss of mitochondrial membrane potential results in the precursor accumulating on the outer mitochondrial membrane (OMM) where it is activated by autophosphorylation (PubMed:20404107, PubMed:22910362, PubMed:18957282). Autophosphorylation at Ser-228 and Ser-402 is sufficient and essential for selective recruitment of PRKN to depolarized mitochondria, via PINK1-dependent phosphorylation of ubiquitin and maybe PRKN (PubMed:22910362, PubMed:18957282).
Highly expressed in heart, skeletal muscle and testis, and at lower levels in brain, placenta, liver, kidney, pancreas, prostate, ovary and small intestine. Present in the embryonic testis from an early stage of development.
Interacts with PRKN (PubMed:20798600, PubMed:19966284). Interacts with FBXO7 (PubMed:23933751). Forms a complex with PRKN and PARK7 (PubMed:19229105). Interacts with NENF (PubMed:31536960).
Proteolytically cleaved (PubMed:19229105, PubMed:22354088, PubMed:30733118). In healthy cells, the precursor is continuously imported into the inner mitochondrial membrane (IMM), where it is proteolytically cleaved by mitochondrial-processing peptidase (MPP) and then undergoes further proteolytic cleavage by PARL or AFG3L2 to give rise to the 52 kDa short form (PubMed:19229105, PubMed:22354088). The 52 kDa short form is then released into the cytosol where it rapidly undergoes proteasome-dependent degradation (PubMed:20404107). In unhealthy cells, when cellular stress conditions lead to the loss of mitochondrial membrane potential, mitochondrial import is impaired leading to the precursor accumulating on the outer mitochondrial membrane (OMM) (PubMed:20404107, PubMed:30733118). If accumulation at the OMM fails and it is imported into the depolarized mitochondria, it undergoes cleavage by the IMM protease OMA1, promoting its subsequent degradation by the proteasome (PubMed:30733118).
Serine/threonine-protein kinase which protects against mitochondrial dysfunction during cellular stress by phosphorylating mitochondrial proteins such as PRKN and DNM1L, to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components (PubMed:14607334, PubMed:18957282, PubMed:18443288, PubMed:15087508, PubMed:19229105, PubMed:19966284, PubMed:20404107, PubMed:22396657, PubMed:20798600, PubMed:23620051, PubMed:23754282, PubMed:23933751, PubMed:24660806, PubMed:24898855, PubMed:24751536, PubMed:24784582, PubMed:24896179, PubMed:25527291, PubMed:32484300, PubMed:20547144). Depending on the severity of mitochondrial damage and/or dysfunction, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy (PubMed:18443288, PubMed:23620051, PubMed:24898855, PubMed:20798600, PubMed:20404107, PubMed:19966284, PubMed:32484300, PubMed:22396657, PubMed:32047033, PubMed:15087508). Mediates the translocation and activation of PRKN at the outer membrane (OMM) of dysfunctional/depolarized mitochondria (PubMed:19966284, PubMed:20404107, PubMed:20798600, PubMed:23754282, PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25474007, PubMed:25527291). At the OMM of damaged mitochondria, phosphorylates pre-existing polyubiquitin chains at 'Ser-65', the PINK1-phosphorylated polyubiquitin then recruits PRKN from the cytosol to the OMM where PRKN is fully activated by phosphorylation at 'Ser-65' by PINK1 (PubMed:19966284, PubMed:20404107, PubMed:20798600, PubMed:23754282, PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25474007, PubMed:25527291). In damaged mitochondria, mediates the decision between mitophagy or preventing apoptosis by promoting PRKN-dependent poly- or monoubiquitination of VDAC1; polyubiquitination of VDAC1 by PRKN promotes mitophagy, while monoubiquitination of VDAC1 by PRKN decreases mitochondrial calcium influx which ultimately inhibits apoptosis (PubMed:32047033). When cellular stress results in irreversible mitochondrial damage, functions with PRKN to promote clearance of damaged mitochondria via selective autophagy (mitophagy) (PubMed:14607334, PubMed:20798600, PubMed:20404107, PubMed:19966284, PubMed:23933751, PubMed:15087508). The PINK1-PRKN pathway also promotes fission of damaged mitochondria by phosphorylating and thus promoting the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2 (PubMed:18443288, PubMed:23620051, PubMed:24898855). This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (PubMed:18443288, PubMed:23620051). Also promotes mitochondrial fission independently of PRKN and ATG7-mediated mitophagy, via the phosphorylation and activation of DNM1L (PubMed:18443288, PubMed:32484300). Regulates motility of damaged mitochondria by promoting the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma (PubMed:22396657). Required for ubiquinone reduction by mitochondrial complex I by mediating phosphorylation of complex I subunit NDUFA10 (By similarity). Phosphorylates LETM1, positively regulating its mitochondrial calcium transport activity (PubMed:29123128).
Heterodimer with RBM8A (PubMed:12730685, PubMed:12781131, PubMed:23917022). Core component of the mRNA splicing-dependent exon junction complex (EJC); the core complex contains CASC3, EIF4A3, MAGOH or MAGOHB, and RBM8A (PubMed:11991638, PubMed:16170325, PubMed:16314458, PubMed:23917022, PubMed:16923391, PubMed:16931718, PubMed:19033377, PubMed:20479275). Interacts with PYM1; the interaction is direct and dissociates the EJC from spliced mRNAs (PubMed:14968132, PubMed:18026120, PubMed:19410547). Identified in a complex composed of the EJC core, UPF3B and UPF2. The EJC core can also interact with UPF3A (in vitro) (PubMed:20479275). Identified in the spliceosome C complex (PubMed:11991638).
Required for pre-mRNA splicing as component of the spliceosome (PubMed:11991638). Plays a redundant role with MAGOHB as core component of the exon junction complex (EJC) and in the nonsense-mediated decay (NMD) pathway (PubMed:23917022). The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). The MAGOH-RBM8A heterodimer inhibits the ATPase activity of EIF4A3, thereby trapping the ATP-bound EJC core onto spliced mRNA in a stable conformation. The MAGOH-RBM8A heterodimer interacts with the EJC key regulator PYM1 leading to EJC disassembly in the cytoplasm and translation enhancement of EJC-bearing spliced mRNAs by recruiting them to the ribosomal 48S preinitiation complex. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly.
Interacts with TRAF1 (PubMed:11313261). Interacts with RELL1, RELL2 and OXSR1 (PubMed:16389068). Interacts with PLSCR1 (PubMed:22052202). Interacts with STK39 (PubMed:16530727).
May play a role in apoptosis (PubMed:28688764, PubMed:19969290). Induces activation of MAPK14/p38 and MAPK8/JNK MAPK cascades, when overexpressed (PubMed:16530727). Involved in dental enamel formation (PubMed:30506946).
Phosphorylated in vitro by OXSR1 (PubMed:16389068). Phosphorylated by STK39 (PubMed:16530727).
Spleen, lymph node, brain, breast and peripheral blood leukocytes (at protein level) (PubMed:28688764). Expressed highly in bone marrow and fetal liver. Very low levels in skeletal muscle, testis and colon. Not detected in kidney and pancreas.
Expressed in embryo Carnegie stage 18 in Rathke's pouch progenitors.
Highly expressed in pancreas, testis and fetal liver. Moderately expressed in heart, prostate and small intestine. Expressed at very low levels in brain, thymus, ovary, colon, fetal lung and fetal kidney. Expressed in muscle. Isoform 3 is expressed in pituitary gland.
Interacts with INHA (By similarity). In PubMed:12385827 does not interact with INHA; standard receptor binding assay. Interacts with ACVR1B; the interaction appears to be ligand-dependent as it is diminished by inhibin B and activin A. Interacts with ACVR2A, ACVR2B, ACVRL1 and BMPR1B. Interacts with HECTD1.
Seems to be a coreceptor in inhibin signaling, but seems not to be a high-affinity inhibin receptor. Antagonizes activin A signaling in the presence or absence of inhibin B (By similarity). Necessary to mediate a specific antagonistic effect of inhibin B on activin-stimulated transcription.
As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates, that form during DNA replication or upon DNA stress. It prevents their reannealing and in parallel, recruits and activates different proteins and complexes involved in DNA metabolism. Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage. In the cellular response to DNA damage, the RPA complex controls DNA repair and DNA damage checkpoint activation. Through recruitment of ATRIP activates the ATR kinase a master regulator of the DNA damage response. It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin in response to DNA damage. Also recruits to sites of DNA damage proteins like XPA and XPG that are involved in nucleotide excision repair and is required for this mechanism of DNA repair. Also plays a role in base excision repair (BER) probably through interaction with UNG. Also recruits SMARCAL1/HARP, which is involved in replication fork restart, to sites of DNA damage. May also play a role in telomere maintenance.
Component of the replication protein A complex (RPA/RP-A), a heterotrimeric complex composed of RPA1, RPA2 and RPA3 (PubMed:2406247, PubMed:19116208, PubMed:10449415). Interacts with PRPF19; the PRP19-CDC5L complex is recruited to the sites of DNA repair where it ubiquitinates the replication protein A complex (RPA) (PubMed:24332808). Interacts with SERTAD3 (PubMed:10982866). Interacts with TIPIN (PubMed:17141802, PubMed:17296725). Interacts with TIMELESS (PubMed:17141802). Interacts with PPP4R2; the interaction is direct, DNA damage-dependent and mediates the recruitment of the PP4 catalytic subunit PPP4C (PubMed:20154705). Interacts (hyperphosphorylated) with RAD51 (PubMed:20154705). Interacts with SMARCAL1; the interaction is direct and mediates the recruitment to the RPA complex of SMARCAL1 (PubMed:19793861, PubMed:19793862, PubMed:19793863). Interacts with RAD52 and XPA; those interactions are direct and associate RAD52 and XPA to the RPA complex (PubMed:7700386, PubMed:8702565, PubMed:17765923, PubMed:11081631). Interacts with FBH1 (PubMed:23319600). Interacts with ETAA1; the interaction is direct and promotes ETAA1 recruitment at stalled replication forks (PubMed:27601467, PubMed:27723720, PubMed:27723717). Interacts with RFWD3 (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575657). Interacts with DDI2 (PubMed:29290612). Interacts (in unphosphorylated form via N-terminus) with EIF4EBP3; the interaction enhances EIF4EBP3-mediated inhibition of EIF4E-mediated mRNA nuclear export (PubMed:22684010).
DNA damage-induced 'Lys-63'-linked polyubiquitination by PRPF19 mediates ATRIP recruitment to the RPA complex at sites of DNA damage and activation of ATR (PubMed:24332808). Ubiquitinated by RFWD3 at stalled replication forks in response to DNA damage: ubiquitination by RFWD3 does not lead to degradation by the proteasome and promotes removal of the RPA complex from stalled replication forks, promoting homologous recombination (PubMed:26474068).
Differentially phosphorylated throughout the cell cycle, becoming phosphorylated at the G1-S transition and dephosphorylated in late mitosis. Mainly phosphorylated at Ser-23 and Ser-29, by cyclin A-CDK2 and cyclin B-CDK1, respectively during DNA replication and mitosis. Dephosphorylation may require the serine/threonine-protein phosphatase 4. Phosphorylation at Ser-23 and Ser-29 is a prerequisite for further phosphorylation. Becomes hyperphosphorylated on additional residues including Ser-4, Ser-8, Thr-21 and Ser-33 in response to DNA damage. Hyperphosphorylation is mediated by ATM, ATR and PRKDC. Primarily recruited to DNA repair nuclear foci as a hypophosphorylated form it undergoes subsequent hyperphosphorylation, catalyzed by ATR. Hyperphosphorylation is required for RAD51 recruitment to chromatin and efficient DNA repair. Phosphorylation at Thr-21 depends upon RFWD3 presence.
Translationally up-regulated in response to DNA damage (at protein level).
Component of the HRD1 complex, which comprises at least SYNV1/HRD1, FAM8A1, HERPUD1/HERP, OS9, SEL1L and UBE2J1. This interaction stabilizes FAM8A1 protein, preventing its proteasomal degradation. FAM8A1 binding to SYNV1 may promote recruitment of HERPUD1 to the HRD1 complex.
Plays a role in the assembly of the HRD1 complex, a complex involved in the ubiquitin-proteasome-dependent process of ER-associated degradation (ERAD).
Ubiquitously expressed, with a higher level of expression in testis.
Interacts with FBN1. May interact with TGFB1.
Promotes FBN1 matrix assembly. Attenuates TGFB signaling, possibly by accelerating the sequestration of large latent complexes of TGFB or active TGFB by FBN1 microfibril assembly, thereby negatively regulating the expression of TGFB regulatory targets, such as POSTN.
Dubious isoform. Alternative initiation from a downstream AUG is supported by ribosome profiling data.
Histone-binding protein (PubMed:23688586). Binds preferentially to unmodified histone H3 but can also bind to a lesser extent to histone H3 trimethylated at 'Lys-9' (H3K9me3) as well as to histone H3 monomethylated at 'Lys-27' (H3K27ac) and trimethylated at 'Lys-27' (H3K27me3) (By similarity). Represses PDGFRA expression, thus playing a role in regulation of mesenchymal cell proliferation (By similarity). Suppresses the expression of CDKN1A/p21 by reducing the level of trimethylation of histone H3 'Lys-4', leading to enhanced proliferation of germinal center B cells (By similarity).
The N-terminal region, including the PHD-type 1 and 2 zinc fingers and the C2HC pre-PHD-type zinc finger, is required for binding to histone H3.
Chromosomal aberrations activating TCL1A are found in chronic T-cell leukemias (T-CLL). Translocation t(14;14)(q11;q32); translocation t(7;14)(q35;q32); inversion inv(14)(q11;q32) that involves the T-cell receptor alpha/delta loci.
Enhances the phosphorylation and activation of AKT1, AKT2 and AKT3. Promotes nuclear translocation of AKT1. Enhances cell proliferation, stabilizes mitochondrial membrane potential and promotes cell survival.
Homodimer. Interacts with AKT1, AKT2 and AKT3 (via PH domain). Interacts with PNPT1; the interaction has no effect on PNPT1 exonuclease activity.
Restricted in the T-cell lineage to immature thymocytes and activated peripheral lymphocytes. Preferentially expressed early in T- and B-lymphocyte differentiation.
Mainly expressed in testis and, at lower level in brain. According to PubMed:12121577, it is widely expressed.
Forms heterodimers with NONO; this involves formation of a coiled coil domain by helices from both proteins. Found in a RNP complex with CAT2 transcribed nuclear RNA (CTN-RNA). Interaction with NONO is required for its targeting to paraspeckles and perinucleolar caps. Interacts with SFPQ (By similarity). Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA.
Regulates, cooperatively with NONO and SFPQ, androgen receptor-mediated gene transcription activity in Sertoli cell line (By similarity). Binds to poly(A), poly(G) and poly(U) RNA homopolymers. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer (By similarity). Together with NONO, required for the formation of nuclear paraspeckles. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway.
Belongs to the eukaryotic ribosomal protein eL38 family.
Forms homohexameric rings (PubMed:33205750). Can form a dodecamer with RUVBL1 made of two stacked hexameric rings; however, even though RUVBL1 and RUVBL2 are present in equimolar ratio, the oligomeric status of each hexamer is not known (PubMed:33205750). Oligomerization may regulate binding to nucleic acids and conversely, binding to nucleic acids may affect the dodecameric assembly. Interaction of the complex with DHX34 results in conformational changes of the N-terminus of the RUVBL2 subunits, resulting in loss of nucleotide binding ability and ATP hydrolysis of the complex (PubMed:33205750). Interacts with the transcriptional activation domain of MYC. Interacts with ATF2. Component of the RNA polymerase II holoenzyme complex. May also act to bridge the LEF1/TCF1-CTNNB1 complex and TBP. Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6. The NuA4 complex interacts with MYC and the adenovirus E1A protein. RUVBL2 interacts with EP400. Component of a NuA4-related complex which contains EP400, TRRAP/PAF400, SRCAP, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, actin, ACTL6A/BAF53A, VPS72 and YEATS4/GAS41. Interacts with NPAT. Component of the chromatin-remodeling INO80 complex; specifically part of a complex module associated with the helicase ATP-binding and the helicase C-terminal domain of INO80. Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Interacts with IGHMBP2. Interacts with TELO2. Interacts with HINT1. Component of a SWR1-like complex. Component of the R2TP complex composed at least of RUVBL1, RUVBL2, RPAP3 and PIHD1 (PubMed:20864032). Component of the PAQosome complex which is responsible for the biogenesis of several protein complexes and which consists of R2TP complex members RUVBL1, RUVBL2, RPAP3 and PIH1D1, URI complex members PFDN2, PFDN6, PDRG1, UXT and URI1 as well as ASDURF, POLR2E and DNAAF10/WDR92 (PubMed:31738558). Interacts with ITFG1 (PubMed:25437307). Interacts with ZMYND10 (PubMed:29601588). Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). Forms a complex with APPL1 and APPL2 (PubMed:19433865). Interacts with ZNHIT2 (via HIT-type zinc finger) in the presence of ATP or ADP; shows a stronger interaction in the presence of ADP (PubMed:28561026). The RUVBL1/RUVBL2 complex interacts with ZNHIT1 (via HIT-type zinc finger), ZNHIT3 (via HIT-type zinc finger), ZNHIT6 (via HIT-type zinc finger) and DDX59/ZNHIT5 (via HIT-type zinc finger) in the presence of ADP (PubMed:28561026). Interacts with NOPCHAP1; the interaction is direct and disrupted upon ATP binding (PubMed:33367824). Interacts with SMG1 (PubMed:33205750).
Possesses single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (5' to 3') activity; hexamerization is thought to be critical for ATP hydrolysis and adjacent subunits in the ring-like structure contribute to the ATPase activity (PubMed:10428817, PubMed:17157868, PubMed:33205750). Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A (PubMed:14966270). This modification may both alter nucleosome -DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription (PubMed:14966270). This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair (PubMed:14966270). The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400 (PubMed:14966270). NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage (PubMed:14966270). Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome (PubMed:24463511). Proposed core component of the chromatin remodeling INO80 complex which exhibits DNA- and nucleosome-activated ATPase activity and catalyzes ATP-dependent nucleosome sliding (PubMed:16230350, PubMed:21303910). Plays an essential role in oncogenic transformation by MYC and also modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex (PubMed:10882073, PubMed:16014379). May also inhibit the transcriptional activity of ATF2 (PubMed:11713276). Involved in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway where it negatively regulates expression of ER stress response genes (PubMed:25652260). May play a role in regulating the composition of the U5 snRNP complex (PubMed:28561026).
The C-terminal domain is required for association with ATF2.
Ubiquitously expressed. Highly expressed in testis and thymus.
Alleviates the exacerbations of multiple sclerosis (MS) (PubMed:8469318, PubMed:8469319). Available under the names Avonex (Biogen), Betaseron (Berlex) and Rebif (Serono) (PubMed:9345408). Betaseron is a slightly modified form of IFNB1 with two residue substitutions (PubMed:9345408).
Type I interferon cytokine that plays a key role in the innate immune response to infection, developing tumors and other inflammatory stimuli (PubMed:6157094, PubMed:6171735, PubMed:8027027, PubMed:7665574, PubMed:8969169, PubMed:10049744, PubMed:10556041). Signals via binding to high-affinity (IFNAR2) and low-affinity (IFNAR1) heterodimeric receptor, activating the canonical Jak-STAT signaling pathway resulting in transcriptional activation or repression of interferon-regulated genes that encode the effectors of the interferon response, such as antiviral proteins, regulators of cell proliferation and differentiation, and immunoregulatory proteins (PubMed:8027027, PubMed:7665574, PubMed:8969169, PubMed:10049744, PubMed:10556041). Signals mostly via binding to a IFNAR1-IFNAR2 heterodimeric receptor, but can also function with IFNAR1 alone and independently of Jak-STAT pathways (By similarity). Elicits a wide variety of responses, including antiviral and antibacterial activities, and can regulate the development of B-cells, myelopoiesis and lipopolysaccharide (LPS)-inducible production of tumor necrosis factor (By similarity). Plays a role in neuronal homeostasis by regulating dopamine turnover and protecting dopaminergic neurons: acts by promoting neuronal autophagy and alpha-synuclein clearance, thereby preventing dopaminergic neuron loss (By similarity). IFNB1 is more potent than interferon-alpha (IFN-alpha) in inducing the apoptotic and antiproliferative pathways required for control of tumor cell growth (By similarity).
Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2. The complex exists in quiescent cells where it represses cell cycle-dependent genes. It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL22. Interacts with CCNF (via the Cyclin N-terminal domain) (PubMed:25557911).
Phosphorylated by cyclin A/CDK2 during S-phase. Phosphorylation at Thr-520 is probably involved in transcriptional activity.
Transcription factor involved in the regulation of cell survival, proliferation, and differentiation. Transactivates the expression of the CLU gene.
In the kidney glomerulus may play a role in linking podocyte foot processes to the glomerular basement membrane. May be involved in stabilization of F-actin by attenuating its depolymerization. Can recruit TGFB1I1 from focal adhesions to podocyte lamellipodia.
Kidney. Reduced expression in patients with focal segmental glomerulosclerosis.
Self-associates. Interacts with TGFB1I1 (By similarity).
A proteolytic cleavage generates a new N-terminus that functions as a tethered ligand.
Highest expression in the megakaryocytes of the bone marrow, lower in mature megakaryocytes, in platelets and in a variety of other tissues such as heart and gut.
Interacts with INSC/inscuteable and probably GPSM2.
Receptor for activated thrombin coupled to G proteins that stimulate phosphoinositide hydrolysis.
Expressed in fetal tissues, including testis, adrenal gland, brain, white blood cells and brain.
G proteins are composed of 3 units, alpha, beta and gamma (By similarity). In this context, interacts with GNB2 (PubMed:28219978). The heterodimer formed by GNB1 and GNG2 interacts with ARHGEF5 (PubMed:19713215). The heterodimer formed by GNB1 and GNG2 interacts with GRK2 (By similarity).
Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity).
(Microbial infection) Interacts with M.tuberculosis PtpA, which blocks the NF-kappa-B signaling pathway.
(Microbial infection) Methylated at Cys-692 by enteropathogenic E.coli protein NleE or S.flexneri protein OspZ: methylation disrupts zinc-binding and ability to bind 'Lys-63'-linked ubiquitin, leading to NF-kappa-B inactivation.
Adapter required to activate the JNK and NF-kappa-B signaling pathways through the specific recognition of 'Lys-63'-linked polyubiquitin chains by its RanBP2-type zinc finger (NZF) (PubMed:14633987, PubMed:14766965, PubMed:15327770, PubMed:22158122). Acts as an adapter linking MAP3K7/TAK1 and TRAF6 to 'Lys-63'-linked polyubiquitin chains (PubMed:14633987, PubMed:14766965, PubMed:15327770, PubMed:22158122, PubMed:36593296). The RanBP2-type zinc finger (NZF) specifically recognizes Lys-63'-linked polyubiquitin chains unanchored or anchored to the substrate proteins such as RIPK1/RIP1 and RIPK2: this acts as a scaffold to organize a large signaling complex to promote autophosphorylation of MAP3K7/TAK1, and subsequent activation of I-kappa-B-kinase (IKK) core complex by MAP3K7/TAK1 (PubMed:15327770, PubMed:18079694, PubMed:22158122).
Degraded in a lysosome-dependent manner following interactiuon with TRIM38.
Interacts with TAB1, TAB2, MAP3K7, TRAF2 and TRAF6 (PubMed:14633987, PubMed:14670075, PubMed:14766965). The minimal TAB3-containing complex (TAB1-MAP3K7-TAB3) appears not to contain TAB2 (PubMed:14670075). However, it seems sensible to consider that TAB2 may also join this complex and may act in a cooperative manner with TAB3 (PubMed:14670075). Interacts with DYNC2I2 (via the WD domains) (PubMed:19521662). Interacts with RBCK1 (PubMed:17449468). Binds 'Lys-63'-linked polyubiquitin chains (PubMed:22158122). Interacts with TRIM5 (PubMed:21512573). Interacts with TRIM38 (via B30.2/SPRY domain), leading to its translocation to lysosomes and degradation (PubMed:24434549).
Phosphorylated at Ser-506 by MAPKAPK2 and MAPKAPK3 following IL1 treatment.
Ubiquitinated; following IL1 stimulation or TRAF6 overexpression (PubMed:14633987). Ubiquitinated by AMFR via 'Lys-27'-linked polyubiquitination; leading to TAK1/MAP3K7 activation (PubMed:36593296).
Widely expressed. Constitutively overexpressed in certain tumor tissues.
Detected in adrenal gland, bone marrow, brain, fetal brain, fetal liver, heart, kidney, lung, liver, peripheral blood leukocytes, placenta, prostate, salivary gland, skeletal muscle, spinal cord, testis, thymus, thyroid, trachea and uterus (PubMed:17897836). Strongly expressed in peripheral blood leukocytes and spleen and, to a lesser extent, in colon (PubMed:9792649). Specifically coexpressed with IL18R1 in T-helper 1 (Th1)cells (PubMed:10925275, PubMed:11046021, PubMed:10653850).
Forms a ternary complex with IL18 and IL18R1 (PubMed:14528293, PubMed:25500532). Within this complex, IL18R1 is involved in ligand-binding and IL18RAP in signaling leading to NF-kappa-B and JNK activation (Probable).
Induced by IFN-alpha and IL12/interleukin-12 in natural killer (NK) cells and T-cells.
Within the IL18 receptor complex, does not mediate IL18-binding, but involved in IL18-dependent signal transduction, leading to NF-kappa-B and JNK activation (PubMed:9792649, PubMed:14528293, PubMed:25500532). May play a role in IL18-mediated IFNG synthesis from T-helper 1 (Th1) cells (Probable).
Functions as guanine nucleotide exchange factor that activates RAC1. May have relatively low activity. Plays a role in the response to class 3 semaphorins and remodeling of the actin cytoskeleton. Plays a role in TNFSF11-mediated osteoclast differentiation, especially in podosome rearrangement and reorganization of the actin cytoskeleton. Regulates the activation of ITGB3, integrin signaling and cell adhesion (By similarity).
Interacts with PLXNA1. Interaction with PLXNA1 or PIP5K1C lowers its guanine nucleotide exchange activity. Dissociates from PLXNA1 when SEMA3A binds to the receptor. Interacts with PIP5K1C via its FERM domain. The interaction with PIP5K1C is enhanced by SEMA3A binding. Interacts with RAC1 (By similarity).
Intramolecular interaction between the DH domain and the PH domains can stabilize the protein in an autoinhibited conformation.
Associates with the BLOC-1 and the AP-3 complexes; the BLOC-1 complex is required for optimal binding of PI4K2A to the AP-3 complex. Interacts with BLOC1S5 and DTNBP1 (PubMed:21998198). Interacts with FOS; this interaction may enhance phosphatidylinositol phosphorylation activity (By similarity). Interacts with ITCH (PubMed:23146885). Interacts with ATG9A (PubMed:30917996).
Membrane-bound phosphatidylinositol-4 kinase (PI4-kinase) that catalyzes the phosphorylation of phosphatidylinositol (PI) to phosphatidylinositol 4-phosphate (PI4P), a lipid that plays important roles in endocytosis, Golgi function, protein sorting and membrane trafficking and is required for prolonged survival of neurons. Besides, phosphorylation of phosphatidylinositol (PI) to phosphatidylinositol 4-phosphate (PI4P) is the first committed step in the generation of phosphatidylinositol 4,5-bisphosphate (PIP2), a precursor of the second messenger inositol 1,4,5-trisphosphate (InsP3).
Palmitoylated by ZDHHC3 and ZDHHC7 in the CCPCC motif. Palmitoylation is cholesterol-dependent, and required for TGN localization.
Ubiquitinated by ITCH; this does not lead to proteasomal degradation.
Widely expressed. Highest expression is observed in kidney, brain, heart, skeletal muscle, and placenta and lowest expression is observed in colon, thymus, and small intestine.
Activated by phosphorylation at Tyr-216. In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1 and RPS6KA3; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by IL22 treatment which also triggers phosphorylation at Ser-9, promoting inactivation (By similarity). Inhibited by lithium.
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. GSK-3 subfamily.
Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1 (PubMed:1846781, PubMed:9072970, PubMed:14690523, PubMed:20937854, PubMed:12554650, PubMed:11430833, PubMed:16484495). Requires primed phosphorylation of the majority of its substrates (PubMed:11430833, PubMed:16484495). In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:8397507). May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:8397507). Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase (PubMed:8397507). In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes (PubMed:12554650). Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA (PubMed:1846781). Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin (PubMed:9072970). Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules (PubMed:14690523). MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease (PubMed:14690523). Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854). Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair (By similarity). Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA) (By similarity). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes (By similarity). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin (PubMed:9819408). Is necessary for the establishment of neuronal polarity and axon outgrowth (PubMed:20067585). Phosphorylates MARK2, leading to inhibition of its activity (By similarity). Phosphorylates SIK1 at 'Thr-182', leading to sustainment of its activity (PubMed:18348280). Phosphorylates ZC3HAV1 which enhances its antiviral activity (PubMed:22514281). Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation (PubMed:15448698, PubMed:15647282). Phosphorylates SFPQ at 'Thr-687' upon T-cell activation (PubMed:20932480). Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including BMAL1, CLOCK and PER2 (PubMed:19946213, PubMed:28903391). Phosphorylates FBXL2 at 'Thr-404' and primes it for ubiquitination by the SCF(FBXO3) complex and proteasomal degradation (By similarity). Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation (PubMed:19946213). Phosphorylates BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation (PubMed:28903391). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed:24391509). Regulates the circadian rhythmicity of hippocampal long-term potentiation and BMAL1 and PER2 expression (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, activating KAT5/TIP60 acetyltransferase activity and promoting acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (PubMed:18846110). Phosphorylates E2F1, promoting the interaction between E2F1 and USP11, stabilizing E2F1 and promoting its activity (PubMed:17050006, PubMed:28992046). Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075). Phosphorylates FXR1, promoting FXR1 ubiquitination by the SCF(FBXO4) complex and FXR1 degradation by the proteasome (By similarity). Phosphorylates interleukin-22 receptor subunit IL22RA1, preventing its proteasomal degradation (By similarity).
Expressed in testis, thymus, prostate and ovary and weakly expressed in lung, brain and kidney. Colocalizes with EIF2AK2/PKR and TAU in the Alzheimer disease (AD) brain.
Higher expression and activity of GSK3B are found in the skeletal muscle (vastus lateralis) of patients with type 2 diabetes (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes (PubMed:19366350).
May play a specific role in axon growth and neurite outgrowth. Reduced binding to AXIN1, reduced ability to phosphorylate MAPT/TAU.
Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity.
Monomer. Interacts with ARRB2, DISC1 and ZBED3 (By similarity). Interacts with CABYR, MMP2, MUC1, NIN and PRUNE1. Interacts with AXIN1; the interaction mediates hyperphosphorylation of CTNNB1 leading to its ubiquitination and destruction. Interacts with and phosphorylates SNAI1. Interacts with DNM1L (via a C-terminal domain). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (By similarity). Interacts with SGK3. Interacts with DAB2IP (via C2 domain); the interaction stimulates GSK3B kinase activation. Interacts (via C2 domain) with PPP2CA. Interacts with the CLOCK-BMAL1 heterodimer (PubMed:19946213). Interacts with the BMAL1 (PubMed:28903391). Interacts with CTNND2 (PubMed:19706605). Interacts with NCYM (PubMed:24391509). The complex composed, at least, of APC, CTNNB1 and GSK3B interacts with JPT1; the interaction requires the inactive form of GSK3B (phosphorylated at 'Ser-9') (PubMed:25169422). Forms a complex composed of PRKAR2A or PRKAR2B, GSK3B and GSKIP through GSKIP interaction; facilitates PKA-induced phosphorylation and regulates GSK3B activity (PubMed:27484798, PubMed:20007971, PubMed:25920809). Interacts with GSKIP (PubMed:16981698). Interacts with GID8 (PubMed:28829046). Interacts with PIWIL2 (By similarity). Interacts with LMBR1L (PubMed:31073040). Interacts with DDX3X (PubMed:18846110). Interacts with BIRC2 (PubMed:18846110). Interacts with TNFRSF10B; TNFRSF10B stimulation inhibits GSK3B kinase activity (PubMed:18846110). Interacts with RICTOR; the interaction results in phosphorylation of RICTOR at 'Thr-1695' by GSK3B which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075). Found in a complex with SLC39A6, SLC39A10 and with GSK3B that controls NCAM1 phosphorylation (By similarity).
Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and deactivates GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216 (PubMed:25169422). Inactivated by phosphorylation at Ser-9 (Probable). Phosphorylated in a circadian manner in the hippocampus (By similarity).
Endoribonuclease that cleaves single-stranded RNAs at 5' of uridylates and releases a product with a 2',3'-cyclic phosphate at the 3'-end. The UU and GU sites are more efficiently cleaved than CU and AU sites.
It has been suggested that the active SMB domain may be permitted considerable disulfide bond heterogeneity or variability, thus two alternate disulfide patterns based on 3D structures are described with 1 disulfide bond conserved in both.
Placental-specific, but also associated with various malignant neoplasms.
Was originally (PubMed:2350438) thought to be a serine protease. However, PubMed:18936097 showed it is not the case.
DNA-binding protein which modulates activity of several transcription factors including RB1 (retinoblastoma-associated protein) and AR (androgen receptor) (By similarity). May function as part of an mSin3A repressor complex (PubMed:14581478). Has no intrinsic transcriptional activity (By similarity). Plays a role in the regulation of epigenetic modifications at the PWS/AS imprinting center near the SNRPN promoter, where it might function as part of a complex with RB1 and ARID4B (By similarity). Involved in spermatogenesis, together with ARID4B, where it acts as a transcriptional coactivator for AR and enhances expression of genes required for sperm maturation. Regulates expression of the tight junction protein CLDN3 in the testis, which is important for integrity of the blood-testis barrier (By similarity). Plays a role in myeloid homeostasis where it regulates the histone methylation state of bone marrow cells and expression of various genes involved in hematopoiesis. May function as a leukemia suppressor (By similarity).
Identified in mSin3A corepressor complexes together with SIN3A, SIN3B, RBBP4, RBBP7, SAP30, BRMS1, HDAC1 and HDAC2 (PubMed:14581478). Interacts with BRMS1 (PubMed:14581478). Interacts with RB1 (PubMed:8414517, PubMed:8455946). Interacts with ARID4B (PubMed:17043311). Interacts with AR (PubMed:23487765).
The function of the Tudor-knot domain, also named chromodomain-like, is uncertain (PubMed:22247551, PubMed:29408527). One study suggests that it mediates binding to lysine-methylated histone tails, with strongest affinity for H4K20me3 and H3K36me3 (PubMed:22247551). However, another study failed to find any interaction between this domain and histone H4K20me3 peptide (PubMed:29408527).
Degraded by the APC/C complex during G1 phase and reaccumulates at the G1/S phase transition.
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXW5) composed of CUL1, SKP1, RBX1 and FBXW5. Component of the DCX(FBXW5) E3 ubiquitin ligase complex, at least composed of (CUL4A or CUL4B), DDB1, FBXW5 and RBX1. Interacts with CDC20, EPS8, TSC1, TSC2 and SASS6. Interacts with TNFAIP8L1; TNFAIP8L1 competes with TSC2 to bind FBXW5 increasing TSC2 stability by preventing its ubiquitination.
Phosphorylated at Ser-151 by PLK4 during the G1/S transition, leading to inhibit its ability to ubiquitinate SASS6.
Substrate recognition component of both SCF (SKP1-CUL1-F-box protein) and DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes. Substrate recognition component of the SCF(FBXW5) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of SASS6 during S phase, leading to prevent centriole reduplication. The SCF(FBXW5) complex also mediates ubiquitination and degradation of actin-regulator EPS8 during G2 phase, leading to the transient degradation of EPS8 and subsequent cell shape changes required to allow mitotic progression. Substrate-specific adapter of the DCX(FBXW5) E3 ubiquitin-protein ligase complex which mediates the polyubiquitination and subsequent degradation of TSC2. May also act as a negative regulator of MAP3K7/TAK1 signaling in the interleukin-1B (IL1B) signaling pathway.
The D-box (destruction box) mediate the interaction with APC proteins, and acts as a recognition signal for degradation via the ubiquitin-proteasome pathway.
The F-box domain mediates interaction with components of SCF (SKP1-CUL1-F-box protein) complexes, while WD repeats mediate interaction with components of DCX (DDB1-CUL4-X-box) complexes.
Ubiquitinated and degraded by the APC/C complex during mitosis and G1 phase.
Binds to the N-terminus of isoforms 2/3 of TPM3 and to actin.
Blocks the elongation and depolymerization of the actin filaments at the pointed end. The Tmod/TM complex contributes to the formation of the short actin protofilament, which in turn defines the geometry of the membrane skeleton. May play an important role in regulating the organization of actin filaments by preferentially binding to a specific tropomyosin isoform at its N-terminus.
Highly expressed in the erythrocyte, heart and skeletal muscle.
Component or associated component of some histone methyltransferase complexes may regulate transcription through recruitment of those complexes on gene promoters (PubMed:19131338, PubMed:23178126). Enhances ligand-dependent transcriptional activation by nuclear hormone receptors (PubMed:12215545, PubMed:18180299, PubMed:19131338). Plays an important role in neural progenitor cell proliferation and self-renewal through the regulation of specific genes involved brain development, including REST (PubMed:23178126). Also controls the expression of genes involved in somatic development and regulates, for instance, lymphoblast proliferation (PubMed:23178126).
Interacts with NCOA6; may enhance ligand-dependent transcriptional activation by nuclear hormone receptors (PubMed:12215545). Interacts with CNOT6 (PubMed:18180299). Interacts with CNOT9; the interaction is direct (PubMed:18180299). Component of a nuclear receptor-mediated transcription complex composed of at least ZNF335, CCAR2 and EMSY; the complex stimulates the transcription of nuclear receptor target genes such as SOX9 and HOXA1 (PubMed:19131338). Within the complex interacts with EMSY and interacts (via C-terminus) with CCAR2 (PubMed:19131338). Interacts with members of histone H3'Lys4'(H3K4) methyltransferase complexes ASH2L, CXXC1, KMT2A/MLL1, RBBP5, SETD1A and WDR5 (PubMed:23178126). Component of a histone methylation complex composed of at least ZNF335, RBBP5, ASH2L and WDR5; the complex may have histone H3-specific methyltransferase activity, however does not have specificity for 'Lys-4' of histone H3 (PubMed:19131338). Interacts with RBBP5 and WDR5 (PubMed:19131338). Interacts with ASHL2 (PubMed:19131338). Components of this complex may associate with components of the ZNF335-CCAR2-EMSY nuclear receptor-mediated transcription complex to form a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY, MKI67, RBBP5, ASH2L and WDR5 (PubMed:19131338). Within this complex also interacts with HCFC1 and MKI67 (PubMed:19131338).
Widely expressed in fetal tissues including fetal brain.
Belongs to the FMN-dependent alpha-hydroxy acid dehydrogenase family.
Broad substrate specificity (S)-2-hydroxy-acid oxidase that preferentially oxidizes glycolate (PubMed:10777549, PubMed:17669354, PubMed:18215067, PubMed:10978532). The glyoxylate produced by the oxidation of glycolate can then be utilized by alanine-glyoxylate aminotransferase for the peroxisomal synthesis of glycine; this pathway appears to be an important step for the detoxification of glyoxylate which, if allowed to accumulate, may be metabolized to oxalate with formation of kidney stones (PubMed:10978532, PubMed:17669354). Can also catalyze the oxidation of glyoxylate, and long chain hydroxyacids such as 2-hydroxyhexadecanoate and 2-hydroxyoctanoate, albeit with much lower catalytic efficiency (PubMed:10777549, PubMed:17669354, PubMed:18215067). Active in vitro with the artificial electron acceptor 2,6-dichlorophenolindophenol (DCIP), but O2 is believed to be the physiological electron acceptor, leading to the production of H2O2 (PubMed:10777549, PubMed:17669354, PubMed:18215067, PubMed:10978532). Is not active on L-lactate and 2-hydroxybutanoate (PubMed:10777549).
Inhibited by its product oxalate (PubMed:17669354). Inhibited by high concentrations of dichlorophenolindophenol (DCIP) in vitro (PubMed:17669354).
Expressed in metastatic melanoma, liver, skin, kidney, heart, lung, lymph node, skeletal muscle and brain, and also in A2058 melanoma cells and activated T-cells (at protein level). Expressed in blood vessels. Strongly expressed in endothelial cells, cytotrophoblasts, and poorly differentiated. colon adenocarcinoma cells found in lymphatics.
Plays a role in angiogenesis and cell migration. In smooth muscle cell migration, may act through the RhoA pathway.
Found in spleen, testis, prostate and fetal liver. Expression limited to vascular muscle of testis, smooth muscle of prostate stroma, heart muscle, skeletal muscle, crypts of small intestine, and red pulp of spleen. B lymphocytes express isoform 2 only; peripheral blood T lymphocytes express isoform 3 only; granulocytes and monocytes express neither isoform 2 nor isoform 3. During development of T lymphocytes, bone marrow progenitor cells express isoform 2 only; thymocytes at different stages of maturation express predominantly isoform 2 and weakly isoform 3, and mature thymocytes express only isoform 2.
May play a role in the development of the nervous system such as in neurite outgrowth and elongation. May be involved in motor axon growth and guidance.
Produced by alternative splicing of isoform 2.
(Microbial infection) Ubiquitinated via human cytomegalovirus/HCMV protein IE1 that assembles a HES1 ubiquitination complex; leading to HES1 proteasomal degradation.
The bHLH, as well as cooperation between the central Orange domain and the C-terminal WRPW motif, is required for transcriptional repressor activity.
Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family. Interacts (via WPRW motif) with TLE1, and more weakly with TLE2. Interacts with HES6 (By similarity). Interacts with SIRT1. Interacts with an FA complex, composed of FANCA, FANCF, FANCG and FANCL, but not of FANCC, nor FANCE.
Transcriptional repressor of genes that require a bHLH protein for their transcription. May act as a negative regulator of myogenesis by inhibiting the functions of MYOD1 and ASH1. Binds DNA on N-box motifs: 5'-CACNAG-3' with high affinity and on E-box motifs: 5'-CANNTG-3' with low affinity (By similarity). May play a role in a functional FA core complex response to DNA cross-link damage, being required for the stability and nuclear localization of FA core complex proteins, as well as for FANCD2 monoubiquitination in response to DNA damage.
Belongs to the Mediator complex subunit 11 family.
Plays a role in the regulation of the epidermis formation during early development. Required both as an inhibitor of basal cell proliferation and a promoter of differentiation of basal progenitor cell progeny (By similarity).
(Microbial infection) Essential for the initiation of translation on type-1 viral ribosomal entry sites (IRESs), like for HCV, PV, EV71 or BEV translation (PubMed:23766293, PubMed:24357634).
Interacts with EIF4G1 (By similarity). Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is composed of 13 subunits: EIF3A, EIF3B, EIF3C, EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L and EIF3M. The eIF-3 complex appears to include 3 stable modules: module A is composed of EIF3A, EIF3B, EIF3G and EIF3I; module B is composed of EIF3F, EIF3H, and EIF3M; and module C is composed of EIF3C, EIF3D, EIF3E, EIF3L and EIF3K. EIF3C of module C binds EIF3B of module A and EIF3H of module B, thereby linking the three modules. EIF3J is a labile subunit that binds to the eIF-3 complex via EIF3B. The eIF-3 complex interacts with RPS6KB1 under conditions of nutrient depletion. Mitogenic stimulation leads to binding and activation of a complex composed of MTOR and RPTOR, leading to phosphorylation and release of RPS6KB1 and binding of EIF4B to eIF-3. Also interacts with KRT7 and PIWIL2.
RNA-binding component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:17581632, PubMed:25849773). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation (PubMed:17581632, PubMed:11169732). The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression (PubMed:25849773, PubMed:27462815).
Expressed in the brain, specifically in microglia and in the fusiform gyrus (at protein level) (PubMed:28802038, PubMed:28855300, PubMed:27477018, PubMed:29752066). Expressed on macrophages and dendritic cells but not on granulocytes or monocytes (PubMed:10799849, PubMed:28855301). In the CNS strongest expression seen in the basal ganglia, corpus callosum, medulla oblongata and spinal cord (PubMed:12080485).
Forms a receptor signaling complex with TYROBP which mediates signaling and cell activation following ligand binding (PubMed:10799849). Acts as a receptor for amyloid-beta protein 42, a cleavage product of the amyloid-beta precursor protein APP, and mediates its uptake and degradation by microglia (PubMed:27477018, PubMed:29518356). Binding to amyloid-beta 42 mediates microglial activation, proliferation, migration, apoptosis and expression of pro-inflammatory cytokines, such as IL6R and CCL3, and the anti-inflammatory cytokine ARG1 (By similarity). Acts as a receptor for lipoprotein particles such as LDL, VLDL, and HDL and for apolipoproteins such as APOA1, APOA2, APOB, APOE, APOE2, APOE3, APOE4, and CLU and enhances their uptake in microglia (PubMed:27477018). Binds phospholipids (preferably anionic lipids) such as phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and sphingomyelin (PubMed:29794134). Regulates microglial proliferation by acting as an upstream regulator of the Wnt/beta-catenin signaling cascade (By similarity). Required for microglial phagocytosis of apoptotic neurons (PubMed:24990881). Also required for microglial activation and phagocytosis of myelin debris after neuronal injury and of neuronal synapses during synapse elimination in the developing brain (By similarity). Regulates microglial chemotaxis and process outgrowth, and also the microglial response to oxidative stress and lipopolysaccharide (By similarity). It suppresses PI3K and NF-kappa-B signaling in response to lipopolysaccharide; thus promoting phagocytosis, suppressing pro-inflammatory cytokine and nitric oxide production, inhibiting apoptosis and increasing expression of IL10 and TGFB (By similarity). During oxidative stress, it promotes anti-apoptotic NF-kappa-B signaling and ERK signaling (By similarity). Plays a role in microglial MTOR activation and metabolism (By similarity). Regulates age-related changes in microglial numbers (PubMed:29752066). Triggers activation of the immune responses in macrophages and dendritic cells (PubMed:10799849). Mediates cytokine-induced formation of multinucleated giant cells which are formed by the fusion of macrophages (By similarity). In dendritic cells, it mediates up-regulation of chemokine receptor CCR7 and dendritic cell maturation and survival (PubMed:11602640). Involved in the positive regulation of osteoclast differentiation (PubMed:12925681).
Monomer (PubMed:27995897). After ectodomain shedding, the extracellular domain oligomerizes, which is enhanced and stabilized by binding of phosphatidylserine (PubMed:29794134). Interacts with TYROBP/DAP12 (PubMed:11602640, PubMed:25957402). Interaction with TYROBP is required for stabilization of the TREM2 C-terminal fragment (TREM2-CTF) which is produced by proteolytic processing (PubMed:25957402).
Undergoes ectodomain shedding through proteolytic cleavage by ADAM10 and ADAM17 to produce a transmembrane segment, the TREM2 C-terminal fragment (TREM2-CTF), which is subsequently cleaved by gamma-secretase.
Strongly expressed in the adult male and female urogenital tracts.
Cholesterylation is required for N-product targeting to lipid rafts and multimerization.
Expressed in embryonic lung, and in adult kidney and liver.
Interacts with BOC and CDON (PubMed:20519495). Interacts with PTCH1 (PubMed:21537345). Interacts with glypican GPC3 (By similarity).
N-palmitoylation by HHAT of N-product is required for indian hedgehog protein N-product multimerization and full activity.
The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity (By similarity). Both activities result in the cleavage of the full-length protein and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product (By similarity). The N-product is the active species in both local and long-range signaling, whereas the C-product is degraded in the reticulum endoplasmic (By similarity).
The C-terminal part of the indian hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity (By similarity). Both activities result in the cleavage of the full-length protein into two parts followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product (By similarity). Both activities occur in the reticulum endoplasmic (By similarity). Plays a role in hedgehog paracrine signaling (PubMed:24342078). Associated with the very-low-density lipoprotein (VLDL) particles to function as a circulating morphogen for endothelial cell integrity maintenance (PubMed:20839884).
The dually lipidated indian hedgehog protein N-product is a morphogen which is essential for a variety of patterning events during development. Binds to the patched (PTCH1) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes (By similarity). Plays a role in morphogenesis of the skeleton by coordinating growth and differentiation of the endochondral skeleton (By similarity). Positively regulates PTHLH expression during endochondral bone formation preventing chondrocyte hypertrophy. In contrast, participates in normal chondrocyte proliferation in a PTHLH-independent pathway (By similarity).
Down-regulated in primary multiple tumors derived from ovary, vulva, uterus, cervix, breast, testis, kidney bladder and liver. The reduced expression is owing to DNA methylation and could be reversed by pharmacologic demethylation (PubMed:19364627).
Microtubule-associated protein that exhibits cell cycle-dependent localization and can inhibit cell proliferation and migration.
Widely expressed in normal tissues. Down-regulated in multiple primary tumors.
(Microbial infection) Acts as a co-receptor for hepatitis C virus (HCV) in hepatocytes (PubMed:17325668, PubMed:20375010, PubMed:24038151). Associates with CD81 and the CLDN1-CD81 receptor complex is essential for HCV entry into host cell (PubMed:20375010). Acts as a receptor for dengue virus (PubMed:24074594).
(Microbial infection) Interacts with dengue virus small envelope protein M.
(Microbial infection) Interacts with hepatitis c virus heterodimer E1/E2.
Claudins function as major constituents of the tight junction complexes that regulate the permeability of epithelia. While some claudin family members play essential roles in the formation of impermeable barriers, others mediate the permeability to ions and small molecules. Often, several claudin family members are coexpressed and interact with each other, and this determines the overall permeability. CLDN1 is required to prevent the paracellular diffusion of small molecules through tight junctions in the epidermis and is required for the normal barrier function of the skin. Required for normal water homeostasis and to prevent excessive water loss through the skin, probably via an indirect effect on the expression levels of other proteins, since CLDN1 itself seems to be dispensable for water barrier formation in keratinocyte tight junctions (PubMed:23407391).
Homopolymers interact with CLDN3, but not CLDN2, homopolymers. Can form homo- and heteropolymers with other claudin family members (PubMed:23704991). Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3. Interacts with MPDZ and PATJ (By similarity). Interacts with OCLN, CLDN4, CLDN6 and CLDN9 (PubMed:20375010). Interacts with CD81 (PubMed:20375010, PubMed:21516087).
Strongly expressed in liver and kidney. Expressed in heart, brain, spleen, lung and testis.
Belongs to the peroxiredoxin-like PRXL2 family. Prostamide/prostaglandin F synthase subfamily.
Catalyzes the reduction of prostaglandin-ethanolamide H(2) (prostamide H(2)) to prostamide F(2alpha) with NADPH as proton donor. Also able to reduce prostaglandin H(2) to prostaglandin F(2alpha) (By similarity).
Expressed in a variety of lymphoid and solid tumor lines cultured in vitro.
Transcription factor that specifically recognizes the sequence 5'-YAAC[GT]G-3' (PubMed:8058310, PubMed:7987850). Acts as a master regulator of male meiosis by promoting expression of piRNAs: activates expression of both piRNA precursor RNAs and expression of protein-coding genes involved in piRNA metabolism (By similarity). The piRNA metabolic process mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons, which is essential for the germline integrity (By similarity). Transcriptional activator of SOX30 (By similarity).
Equally expressed in various parts of the brain.
Highly expressed in heart, skeletal muscle and placenta.
Ig-like V-type domain mediates binding to lymphocyte.
O-glycosylated with sialylated oligosaccharides.
Receptor which may mediate L-selectin-dependent lymphocyte rollings. Binds SELL in a calcium dependent manner. Binds lymphocyte (By similarity).
A stop codon at position Arg-192 in the gene coding for this protein is responsible for functional diversity thus producing a pseudogene. The stop codon is more frequent in non-Africans than in African-Americans.
Homohexamer; disulfide-linked homotrimers. The trimers associate via N-terminal cysteine residues to form disulfide-linked hexamers (PubMed:27418511). May form oligomers with CBLN2, CBLN3 AND CBLN4 prior to secretion. Once secreted, does not interact with other CBLN family members. Interacts with GRID1 (By similarity). Interacts with NRXN1 and NRXN2 long (alpha) and short (beta) isoforms produced by alternative promoter usage. Competes with NLGN1 for NRXN1-binding. Weakly interacts with NRXN3 short isoform and not at all with NRXN3 long isoform (PubMed:27418511). Interacts (via C1q domain) with GRID2; GRID2-binding is calcium-independent; CBLN1 hexamers anchor GRID2 N-terminal domain dimers to monomeric NRXN1 isoform beta; promotes synaptogenesis and mediates the D-Serine-dependent long term depression signals and AMPA receptor endocytosis (PubMed:27418511). Interacts with OTOL1 (By similarity).
In the Purkinje cells postsynaptic structures. In the cerebellum, cerebellin is much less abundant than [des-Ser1]-cerebellin.
Low at birth, the cerebellin concentration increases between day 5 and 15, and reaches peak values between day 21 and 56.
Required for synapse integrity and synaptic plasticity. During cerebellar synapse formation, essential for the matching and maintenance of pre- and post-synaptic elements at parallel fiber-Purkinje cell synapses, the establishment of the proper pattern of climbing fiber-Purkinje cell innervation, and induction of long-term depression at parallel fiber-Purkinje cell synapses. Plays a role as a synaptic organizer that acts bidirectionally on both pre- and post-synaptic components. On the one hand induces accumulation of synaptic vesicles in the pre-synaptic part by binding with NRXN1 and in other hand induces clustering of GRID2 and its associated proteins at the post-synaptic site through association of GRID2. NRXN1-CBLN1-GRID2 complex directly induces parallel fiber protrusions that encapsulate spines of Purkinje cells leading to accumulation of GRID2 and synaptic vesicles. Required for CBLN3 export from the endoplasmic reticulum and secretion (By similarity). NRXN1-CBLN1-GRID2 complex mediates the D-Serine-dependent long term depression signals and AMPA receptor endocytosis (PubMed:27418511). Essential for long-term maintenance but not establishment of excitatory synapses (By similarity). Inhibits the formation and function of inhibitory GABAergic synapses in cerebellar Purkinje cells (By similarity).
The cerebellin peptide exerts neuromodulatory functions. Directly stimulates norepinephrine release via the adenylate cyclase/PKA-dependent signaling pathway; and indirectly enhances adrenocortical secretion in vivo, through a paracrine mechanism involving medullary catecholamine release (By similarity).
The proteolytic processing to yield cerebellin seems to occur either prior to the secretion by presynaptic neurons and subsequent oligomerization or in some other location after release of the mature protein.
Expressed in skin. Also found in heart, placenta, liver, skeletal muscle and pancreas.
Hydroxylation by PHD1/EGLN2 at Pro-2313 promotes ubiquitination.
Interacts with SHBG (PubMed:15862967). Interacts with PLK4; this interaction mediates the formation of a ternary complex composed by PLK4, TENT5C and CEP192 (PubMed:32433990).
Required for mitotic centrosome maturation and bipolar spindle assembly (PubMed:25042804, PubMed:17980596, PubMed:18207742). Appears to be a major regulator of pericentriolar material (PCM) recruitment, centrosome maturation, and centriole duplication (PubMed:25042804, PubMed:17980596, PubMed:18207742). Centrosome-specific activating scaffold for AURKA and PLK1 (PubMed:25042804).
Ubiquitinated by a SCF(SKP2) complex following proline hydroxylation.
Ubiquitinated in a FBXL13-dependent manner, leading to proteasomal degradation.
Interacts with ACTB (PubMed:21969592, PubMed:28604741). Interacts with COMMD1; this interaction stabilizes COMMD1 in the nucleus (PubMed:28604741). Interacts with MAP1A (PubMed:20543869). Interacts with PRDX1 (PubMed:21969592). Interacts with F-actin (By similarity).
Stress-inducible actin-binding protein that plays a role in synaptic and cognitive functions by modulating actin filamentous (F-actin) dynamics. Mediates polymerization of globular actin to F-actin. Also binds to, stabilizes and bundles F-actin. Involved in synaptic function by regulating neurite outgrowth in an actin-dependent manner and for the acquisition of hippocampus-dependent cognitive function, such as learning and long-term memory (By similarity). Plays a role in the actin and microtubule cytoskeleton organization; negatively regulates focal adhesion (FA) assembly promoting malignant glial cell migration in an actin-, microtubule- and MAP1A-dependent manner (PubMed:20543869). Also involved in neuroblastoma G1/S phase cell cycle progression and cell proliferation inhibition by stimulating ubiquitination of NF-kappa-B subunit RELA and NF-kappa-B degradation in a COMMD1- and actin-dependent manner (PubMed:10564580, PubMed:28604741). May play a role in tumor development (PubMed:10564580).
Widely expressed (PubMed:10564580). Expressed in neurons (PubMed:20543869). Expressed in malignant glial tumors (PubMed:20543869). Expression is reduced or absent in a number of cancer cell lines (PubMed:10564580).
Glycosylated; contains mannose 6-phosphate sugars.
The p76 protein is synthesized as a 80 kDa precursor which is then processed into a N-terminal 32 kDa form and a C-terminal 45 kDa form.
Ubiquitously expressed, with highest levels in heart, brain and liver.
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. ASIC5 subfamily.
Cation channel that gives rise to very low constitutive currents in the absence of activation. The activated channel exhibits selectivity for sodium, and is inhibited by amiloride.
Detected in small intestine, duodenum and jejunum. Detected at very low levels in testis and rectum.
Acts as a negative regulator of the Toll-like and IL-1R receptor signaling pathways. Attenuates the recruitment of receptor-proximal signaling components to the TLR4 receptor, probably through an TIR-TIR domain interaction with TLR4. Through its extracellular domain interferes with the heterodimerization of Il1R1 and IL1RAP.
Down-regulated during inflammation by inhibition of an SP1-mediated pathway.
Interacts with IL1R1, IRAK1, TLR4, TLR5, TLR9 and TRAF6. Upon IL-1 stimulation found in a complex at least composed of IL1R1, SIGIRR, MYD88, IRAK1 and TRAF6. Upon stimulation with LPC found in a complex at least composed of TLR4, SIG1IR, MYD88, IRAK1 and TRAF6. Interacts with PALM3.
Mainly expressed in epithelial tissues such as kidney, lung and gut.
Endoplasmic reticulum-Golgi intermediate compartment lumen
Interacts with the LRP1/alpha-2-macroglobulin receptor heavy and light chains; the interaction is transient and coincides with a reduction of ligand binding by the receptor (PubMed:1712782, PubMed:1400426, PubMed:7774585, PubMed:16938309, PubMed:16678114, PubMed:32296178). Interacts with LRP2/glycoprotein 330 (PubMed:1400426). Interacts with LRP1B; binding is followed by internalization and degradation (PubMed:11384978). Interacts with LDLR (PubMed:16630895). Interacts with SORL1 (PubMed:8940146, PubMed:11294867, PubMed:12530537, PubMed:15053742, PubMed:15364913, PubMed:26858303). Interacts with LRP1; this interaction is followed by rapid internalization (PubMed:15053742).
Molecular chaperone for LDL receptor-related proteins that may regulate their ligand binding activity along the secretory pathway.
Belongs to the tRNA pseudouridine synthase TruA family.
Monomer (PubMed:23707380, PubMed:24722331). Forms a complex with RARG and the SRA1 RNA in the nucleus (By similarity).
Pseudouridylate synthase that catalyzes pseudouridylation of tRNAs and mRNAs (PubMed:15772074, PubMed:24722331). Acts on positions 27/28 in the anticodon stem and also positions 34 and 36 in the anticodon of an intron containing tRNA (PubMed:24722331). Also catalyzes pseudouridylation of mRNAs: mediates pseudouridylation of mRNAs with the consensus sequence 5'-UGUAG-3' (PubMed:31477916, PubMed:35051350). Acts as a regulator of pre-mRNA splicing by mediating pseudouridylation of pre-mRNAs at locations associated with alternatively spliced regions (PubMed:35051350). Pseudouridylation of pre-mRNAs near splice sites directly regulates mRNA splicing and mRNA 3'-end processing (PubMed:35051350). Involved in regulation of nuclear receptor activity through pseudouridylation of SRA1 mRNA (PubMed:24722331).
Widely expressed (PubMed:15108122). High levels of expression found in brain and skeletal muscle (PubMed:15108122).
Activated in cells undergoing apoptosis.
Expression in fetal tissues is significantly lower than in adult tissues.
May function in the process of apoptosis.
Widely expressed. Highest levels in heart, testis, kidney, pituitary gland, adrenal gland and placenta.
Belongs to the Clp1 family. Clp1 subfamily.
Component of the tRNA splicing endonuclease complex, composed of CLP1, TSEN2, TSEN15, TSEN34 and TSEN54 (PubMed:24766809). Component of pre-mRNA cleavage complex II (CF-II). Also associates with numerous components of the pre-mRNA cleavage complex I (CF-I/CFIm), including NUDT21, CPSF2, CPSF3, CPSF6 and CPSF7. Interacts with CSTF2 and SYMPK.
Polynucleotide kinase that can phosphorylate the 5'-hydroxyl groups of double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), double-stranded DNA (dsDNA) and double-stranded DNA:RNA hybrids. dsRNA is phosphorylated more efficiently than dsDNA, and the RNA component of a DNA:RNA hybrid is phosphorylated more efficiently than the DNA component. Plays a key role in both tRNA splicing and mRNA 3'-end formation. Component of the tRNA splicing endonuclease complex: phosphorylates the 5'-terminus of the tRNA 3'-exon during tRNA splicing; this phosphorylation event is a prerequisite for the subsequent ligation of the two exon halves and the production of a mature tRNA (PubMed:24766809, PubMed:24766810). Its role in tRNA splicing and maturation is required for cerebellar development (PubMed:24766809, PubMed:24766810). Component of the pre-mRNA cleavage complex II (CF-II), which seems to be required for mRNA 3'-end formation. Also phosphorylates the 5'-terminus of exogenously introduced short interfering RNAs (siRNAs), which is a necessary prerequisite for their incorporation into the RNA-induced silencing complex (RISC). However, endogenous siRNAs and microRNAs (miRNAs) that are produced by the cleavage of dsRNA precursors by DICER1 already contain a 5'-phosphate group, so this protein may be dispensible for normal RNA-mediated gene silencing.
The disease is caused by variants affecting the gene represented in this entry. Neurodegeneration is due to defects in tRNA splicing (PubMed:24766809, PubMed:24766810).
Both SDE2-UBL and the mature SDE2 are polyubiquitinated.
Inhibits translesion DNA synthesis by preventing monoubiquitination of PCNA, this is necessary to counteract damage due to ultraviolet light-induced replication stress (PubMed:27906959). SDE2 is cleaved following PCNA binding, and its complete degradation is necessary to allow S-phase progression following DNA damage (PubMed:27906959).
Interacts (via PIP-box) with PCNA; the interaction is direct and prevents ultraviolet light induced monoubiquitination of PCNA (PubMed:27906959). Interacts with FBL/fibrillarin (PubMed:34365507). Interacts with CACTIN (PubMed:34365507). Interacts with SF3B1 (PubMed:34365507). Interacts with U2AF1 (PubMed:34365507).
Plays a role in pre-mRNA splicing by facilitating excision of relatively short introns featuring weak 3'-splice sites (ss) and high GC content (PubMed:34365507). May recruit CACTIN to the spliceosome (By similarity).
Plays a role in ribosome biogenesis by enabling SNORD3- and SNORD118-dependent cleavage of the 47S rRNA precursor (PubMed:34365507). Binds ncRNA (non-coding RNA) including the snoRNAs SNORD3 and SNORD118 (PubMed:34365507).
The PIP-box (PCNA interacting peptide) motif mediates both the interaction with PCNA and cleavage of the SDE2 precursor by a deubiquitinating enzyme.
The SAP domain is necessary for specific binding to DNA.
The propeptide displays a ubiquitin-like fold.
Ubiquitously expressed; enriched in brain, lung and liver.
Upon binding to PCNA, the N-terminal UBL (ubiquitin-like) propeptide is cleaved at Gly-77 by an unidentified deubiquitinating enzyme; the resulting mature SDE2 is degraded by the DCX(DTL) complex in a cell cycle- and DNA damage dependent manner.
In the process of mRNA degradation, seems to play a role in mRNA decapping. Component of a complex containing DCP2 and DCP1A which functions in decapping of ARE-containing mRNAs. Promotes complex formation between DCP1A and DCP2. Enhances the catalytic activity of DCP2 (in vitro).
Part of a decapping complex consisting of DCP1A, DCP2, EDC3, EDC4 and probably DDX6. Part of a complex consisting of DCP1A, EDC3, EDC4 and DDX6. Part of a complex consisting of DCP1B, EDC3, EDC4 and DDX6. Interacts with DCP2 (PubMed:16364915). Interacts with RC3H1 (By similarity). Interacts with NBDY (PubMed:27918561). Interacts with TEX19 (By similarity). Interacts with LSM14A (PubMed:29510985). Interacts with DDX6 (PubMed:31422817).
Abundantly expressed in peripheral blood Leukocytes and is specifically expressed in monocytes and macrophages. Also found in the spleen, lymph node, bone marrow, T-cells and dendritic cells. A lower expression seen in placenta, heart, lung, fetal liver, thymus, and pancreas. Isoform 2 is expressed in many myeloid cell lines.
Acts as a transcription factor for its own parent gene, in association with NF-kappa-B p50 subunit, at least in autoimmune and proliferative B-cell diseases. The presence of Delta4BAFF is essential for soluble BAFF release by IFNG/IFN-gamma-stimulated monocytes and for B-cell survival. It can directly or indirectly regulate the differential expression of a large number of genes involved in the innate immune response and the regulation of apoptosis.
Cytokine that binds to TNFRSF13B/TACI and TNFRSF17/BCMA. TNFSF13/APRIL binds to the same 2 receptors. Together, they form a 2 ligands -2 receptors pathway involved in the stimulation of B- and T-cell function and the regulation of humoral immunity. A third B-cell specific BAFF-receptor (BAFFR/BR3) promotes the survival of mature B-cells and the B-cell response.
Homotrimer. Isoform 2 heteromultimerizes with isoform 1, probably limiting the amount of functional isoform 1 on the cell surface. Isoform 3 is unlikely form trimers or bind to BAFF receptors.
Isoform 2 is not efficiently shed from the membrane unlike isoform 1.
Isoform 2 seems to inhibit isoform 1 secretion and bioactivity.
Up-regulated by exposure to IFNG/IFN-gamma. Down-regulated by phorbol myristate acetate/ionomycin treatment.
Interacts with EGLN3/PHD3. Interacts with ERK signaling proteins MAP2K1/MEK1, MAP2K2/MEK2, LAMTOR3, ARAF/Raf-1, MAPK1/ERK2 and MAPK3/ERK1 (By similarity). Identified in the spliceosome C complex.
Molecular scaffold protein for various multimeric protein complexes. Acts as a module in the assembly of a multicomponent scaffold for the ERK pathway, linking ERK responses to specific agonists. At low concentrations it enhances ERK activation, whereas high concentrations lead to the inhibition of ERK activation. Also involved in response to hypoxia by acting as a negative regulator of HIF1A/HIF-1-alpha via its interaction with EGLN3/PHD3. May promote degradation of HIF1A. May act by recruiting signaling complexes to a specific upstream activator (By similarity). May also be involved in pre-mRNA splicing.
Binds to DNA as a homomultimer. Dimerization is induced by binding to calcium (PubMed:17962406). Interacts with the C-terminus of PSEN1 and PSEN2 and with PSEN2 CTF subunit. Associates with KCN1. Component of heteromultimeric potassium channels. Identified in potassium channel complexes containing KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (By similarity). Interacts with KCND2 and KCND3.
Calcium-dependent transcriptional repressor that binds to the DRE element of genes including PDYN and FOS. Affinity for DNA is reduced upon binding to calcium and enhanced by binding to magnesium. Seems to be involved in nociception (By similarity).
Highly expressed in brain. Widely expressed at lower levels. Expression levels are elevated in brain cortex regions affected by Alzheimer disease.
May play a role in the regulation of PSEN2 proteolytic processing and apoptosis. Together with PSEN2 involved in modulation of amyloid-beta formation.
Palmitoylated. Palmitoylation enhances association with the plasma membrane (By similarity).
Phosphorylation at Ser-63 inhibits cleavage by CASP3.
Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels, such as KCND2/Kv4.2 and KCND3/Kv4.3. Modulates channel expression at the cell membrane, gating characteristics, inactivation kinetics and rate of recovery from inactivation in a calcium-dependent and isoform-specific manner.
It is uncertain whether Met-1 or Met-57 is the initiator.
Mainly expressed in breast and testis. A very faint signal is detected in placenta. Also expressed in many breast cancer cells.
Highly expressed in testis. Expressed at a low level in wide range of tissues including bone marrow, brain, heart, kidney, colon, liver, placenta, spleen, skeletal muscle, salivary gland, thyroid gland, thymus, trachea and uterus. Expressed at a slightly higher level in adrenal gland, cerebellum, small intestine, lung, prostate and trachea. Expression is cell cycle-dependent, being restricted to cells in G1/S phase.
Interacts with CDK1 (By similarity). Interacts with CDK2 (PubMed:11980914, PubMed:12839962, PubMed:12972555, PubMed:28666995). May interact with CDKN1B/KIP1 (PubMed:12972555). Identified in a complex with CDK2 and CDKN1B/KIP1, where it interacts primarily with CDK2 (PubMed:12972555, PubMed:28666995).
Regulates the G1/S phase transition of the cell cycle by binding and activating CDK1 and CDK2 (PubMed:12972555). Contributes to CDK2 activation without promoting CDK2 phosphorylation, by inducing a conformation change of the CDK2 T-loop that obstructs the substrate-binding cleft prior to kinase activation (PubMed:28666995). Mediates cell survival during the DNA damage process through activation of CDK2 (PubMed:12839962).
The C-terminus is required for CDK2-activation, but not CDK2-binding.
Exhibits arylsulfatase activity and highly specific endoglucosamine-6-sulfatase activity (PubMed:12368295, PubMed:12686563). It can remove sulfate from the C-6 position of glucosamine within specific subregions of intact heparin (PubMed:12368295, PubMed:12686563). Diminishes HSPG (heparan sulfate proteoglycans) sulfation, inhibits signaling by heparin-dependent growth factors, diminishes proliferation, and facilitates apoptosis in response to exogenous stimulation (PubMed:12686563).
Expressed at highest levels in testis, stomach, skeletal muscle, lung, kidney, pancreas, small intestine and colon. It is also detected in normal ovarian surface epithelial cells. Down-regulation seen in ovarian carcinoma cell lines, ovarian cancers, breast, pancreatic, renal and hepatocellular carcinoma cell lines.
Processing by furin produces a secreted form.
Isoform A binds to IL-18 and inhibits its activity. Functions as an inhibitor of the early TH1 cytokine response.
N- and O-glycosylated. O-glycosylated with core 1-like and core 2-like glycans. O-glycan heterogeneity at Ser-53: HexHexNAc (major) and Hex2HexNAc2 (minor). N-glycan heterogeneity at Asn-103: Hex5HexNAc4 (minor), dHex1Hex5HexNAc4 (major) and Hex6HexNAc5 (minor); N-glycan at Asn-147: dHex1Hex5HexNAc4.
Strongly expressed in heart, lung, placenta and spleen.
High expression in placenta, skeletal muscle, kidney and pancreas tissues. Absent or very faint expression in heart, brain, lung and liver. Expressed during adipogenic differentiation of mesenchymal stem cells (at protein level).
Was reported to be transcribed but not translated (PubMed:11890990). However, it was later shown that it is expressed at protein level (PubMed:19531736).
Down-regulated by DNA damage in a p53-dependent manner.
Interacts with CEP290/NPHP6; IQCB1/NPHP5 and CEP290 are proposed to form a functional NPHP5-6 module/NPHP6; localized to the centrosome. Interacts with calmodulin, ATXN10 (PubMed:16322217, PubMed:15723066, PubMed:18723859, PubMed:21565611, PubMed:23446637, PubMed:25552655). Interacts with NPHP1, INVS, NPHP4 and RPGRIP1L; these interactions likely require additional interactors (By similarity). Associates with the BBSome complex; interacts with BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 and BBS9 (PubMed:25552655).
Involved in ciliogenesis. The function in an early step in cilia formation depends on its association with CEP290/NPHP6 (PubMed:21565611, PubMed:23446637). Involved in regulation of the BBSome complex integrity, specifically for presence of BBS2 and BBS5 in the complex, and in ciliary targeting of selected BBSome cargos. May play a role in controlling entry of the BBSome complex to cilia possibly implicating CEP290/NPHP6 (PubMed:25552655).
The IQ domains mediate the interaction with calmodulin.
Ubiquitously expressed in fetal and adult tissues. Localized to the outer segments and connecting cilia of photoreceptor cells. Up-regulated in a number of primary colorectal and gastric tumors.
(Microbial infection) Antiviral activity is neutralized by the HIV-1 virion infectivity factor (Vif), that prevents its incorporation into progeny HIV-1 virions by both inhibiting its translation and/or by inducing its ubiquitination and subsequent degradation by the 26S proteasome.
(Microbial infection) Interacts with human foamy virus protein Bet; this interaction does not induce APOBEC3C degradation but prevents its dimerization and incorporation into the virion by binding of Bet close to or within the APOBEC3C dimerization site.
DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA. The resultant detrimental levels of mutations in the proviral genome, along with a deamination-independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells. Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single- or double-stranded RNA. Exhibits antiviral activity against simian immunodeficiency virus (SIV), hepatitis B virus (HBV), herpes simplex virus 1 (HHV-1) and Epstein-Barr virus (EBV) and may inhibit the mobility of LTR and non-LTR retrotransposons. May also play a role in the epigenetic regulation of gene expression through the process of active DNA demethylation.
Expressed in spleen, testes, peripherical blood lymphocytes, heart, thymus, prostate and ovary.
Homodimer (PubMed:22977230, PubMed:23001005). Interacts with TRIB3 (PubMed:22977230). Interacts with AGO2 (PubMed:22915799).
Hydrolase highly specific for thiamine triphosphate (ThTP).
Expressed in liver, colon and small intestine. Not expressed in kidney, esophagus and skin.
Expressed in liver, colon, small intestine and kidney. Not expressed in esophagus and skin.
Genetic variation in UGT1A1 defines the bilirubin serum levels quantitative trait locus 1 (BILIQTL1) [MIM:601816]. Variation in serum bilirubin is associated with altered cardiovascular disease risk and drug metabolism.
Homodimer (PubMed:17179145). Homooligomer (Probable). Interacts with UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 to form heterodimers (PubMed:17179145). Isoform 1 interacts with isoform 2/i2 suggesting that oligomerization is involved in negative regulation of transferase activity by isoform 2 (PubMed:17187418, PubMed:20610558). Isoform 1 also interacts with respective i2 isoforms of UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 (PubMed:20610558).
The disease may be caused by variants affecting the gene represented in this entry. The defect has been ascribed to various breast milk substances, but the component or combination of components that is responsible remains unclear. Defects of UGT1A1 are an underlying cause of the prolonged unconjugated hyperbilirubinemia associated with breast milk. One or more components in the milk may trigger the jaundice in infants who have such mutations. Mutations are identical to those detected in patients with Gilbert syndrome, a risk factor of neonatal non-physiologic hyperbilirubinemia and a genetic factor in fasting hyperbilirubinemia.
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004206, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:15472229, PubMed:18719240, PubMed:23288867). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (PubMed:17187418, PubMed:18004206, PubMed:19830808). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558).
UGT1A1 isoform is part of the UGT1A complex locus which displays alternative use of promoters, first exons and terminal exons. The locus is defined by 13 first exons, which are alternatively spliced to 3 other common exons and 2 alternative terminal exons 5. From the 27 possible mRNA isoforms, 9 produce functionally active polypeptides (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9 and 1A10) called isoforms 1 (i1). Use of an alternative exon 5 (5b) as terminal exon is leading to 9 additional alternatively spliced products termed isoforms i2 and which lack transferase activity.
Belongs to the Mediator complex subunit 19 family.
Required for the assembly of dynein arms.
Belongs to the G-protein coupled receptor 1 family. Endothelin receptor subfamily. EDNRB sub-subfamily.
Expressed in placental stem villi vessels, but not in cultured placental villi smooth muscle cells.
Heterozygous mutations in EDNRB may be responsible for Waardenburg syndrome 2, an autosomal dominant disorder characterized by sensorineural deafness and pigmentary disturbances.
Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
Palmitoylation of Cys-402 was confirmed by the palmitoylation of Cys-402 in a deletion mutant lacking both Cys-403 and Cys-405.
It is unsure whether Met-1 or Met-5 is the initiator.
Monomer. Interacts with YWHAZ (PubMed:16959763).
Nucleoside monophosphate (NMP) kinase that catalyzes the reversible transfer of the terminal phosphate group between nucleoside triphosphates and monophosphates. Active on AMP and dAMP with ATP as a donor. When GTP is used as phosphate donor, the enzyme phosphorylates AMP, CMP, and to a small extent dCMP. Also displays broad nucleoside diphosphate kinase activity.
Belongs to the class I-like SAM-binding methyltransferase superfamily. HNMT family.
Inactivates histamine by N-methylation. Plays an important role in degrading histamine and in regulating the airway response to histamine.
Variant Ile-105 has a reduced activity and seems to be linked with a predisposition to asthma.
(Microbial infection) May recognize HLA-E in complex with HIV-1 gag/Capsid protein p24-derived peptide (AISPRTLNA) on infected cells and may inhibit NK cell cytotoxicity, a mechanism that allows HIV-1 to escape immune recognition.
(Microbial infection) Upon SARS-CoV-2 infection, may contribute to functional exhaustion of cytotoxic NK cells and CD8-positive T cells (PubMed:32203188, PubMed:32859121). On NK cells, may recognize HLA-E in complex with SARS-CoV-2 S/Spike protein S1-derived peptide (LQPRTFLL) expressed on the surface of lung epithelial cells, inducing NK cell exhaustion and dampening antiviral immune surveillance (PubMed:32859121).
(Microbial infection) Viruses like human cytomegalovirus have evolved an escape mechanism whereby virus-induced down-regulation of host MHC class I molecules is coupled to the binding of viral peptides to HLA-E, restoring HLA-E expression and inducing HLA-E-dependent NK cell immune tolerance to infected cells. Recognizes HLA-E in complex with human cytomegalovirus UL40-derived peptide (VMAPRTLIL) and inhibits NK cell cytotoxicity.
Heterodimer with KLRD1; disulfide-linked (PubMed:18083576, PubMed:18332182, PubMed:18448674). KLRD1-KLRC1 heterodimer interacts with peptide-bound HLA-E-B2M heterotrimeric complex (PubMed:18083576). Competes with KLRC2 for its interaction with HLA-E (PubMed:18083576). Interacts (via ITIM) with INPP5D/SHIP-1 and INPPL1/SHIP-2 (via SH2 domain).
Immune inhibitory receptor involved in self-nonself discrimination. In complex with KLRD1 on cytotoxic and regulatory lymphocyte subsets, recognizes non-classical major histocompatibility (MHC) class Ib molecule HLA-E loaded with self-peptides derived from the signal sequence of classical MHC class Ia molecules. Enables cytotoxic cells to monitor the expression of MHC class I molecules in healthy cells and to tolerate self (PubMed:9486650, PubMed:18083576, PubMed:9430220, PubMed:37264229). Upon HLA-E-peptide binding, transmits intracellular signals through two immunoreceptor tyrosine-based inhibition motifs (ITIMs) by recruiting INPP5D/SHP-1 and INPPL1/SHP-2 tyrosine phosphatases to ITIMs, and ultimately opposing signals transmitted by activating receptors through dephosphorylation of proximal signaling molecules (PubMed:9485206, PubMed:12165520). Key inhibitory receptor on natural killer (NK) cells that regulates their activation and effector functions (PubMed:9486650, PubMed:9430220, PubMed:9485206, PubMed:30860984). Dominantly counteracts T cell receptor signaling on a subset of memory/effector CD8-positive T cells as part of an antigen-driven response to avoid autoimmunity (PubMed:12387742). On intraepithelial CD8-positive gamma-delta regulatory T cells triggers TGFB1 secretion, which in turn limits the cytotoxic programming of intraepithelial CD8-positive alpha-beta T cells, distinguishing harmless from pathogenic antigens (PubMed:18064301). In HLA-E-rich tumor microenvironment, acts as an immune inhibitory checkpoint and may contribute to progressive loss of effector functions of NK cells and tumor-specific T cells, a state known as cell exhaustion (PubMed:30503213, PubMed:30860984).
Predominantly expressed in NK cells (at protein level) (PubMed:9430220, PubMed:9485206, PubMed:20952657). Expressed in intraepithelial CD8-positive T cell subsets with higher frequency in gamma-delta T cells than alpha-beta T cells (at protein level) (PubMed:18064301). Expressed in memory gamma-delta T cells (at protein level) (PubMed:20952657). Restricted to a subset of memory/effector CD8-positive alpha-beta T cells (at protein level) (PubMed:12387742). Expressed in intratumoral NK and CD8-positive T cells (PubMed:30503213). Expressed in melanoma-specific cytotoxic T cell clones (at protein level) (PubMed:9485206). KLRD1-KLRC1 and KLRD1-KLRC2 are differentially expressed in NK and T cell populations, with only minor subsets expressing both receptor complexes (at protein level) (PubMed:20952657).
The cytosolic N-terminus contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which are essential for the association with INPP5D/SHIP-1 and INPPL1/SHIP-2 phosphatases and functional inhibition.
Up-regulated in memory CD8-positive alpha-beta T cell clones upon antigen-specific stimulation.
Contains at least one active inhibitory domain for trypsin (domain 6).
Highly expressed in the thymus and stratum corneum. Also found in the oral mucosa, parathyroid gland, Bartholin's glands, tonsils, and vaginal epithelium. Very low levels are detected in lung, kidney, and prostate.
Proteolytically processed by furin in individual domains (D1, D5, D6, D8 through D11, and D9 through D15) exhibiting various inhibitory potentials for multiple proteases.
Serine protease inhibitor, probably important for the anti-inflammatory and/or antimicrobial protection of mucous epithelia. Contribute to the integrity and protective barrier function of the skin by regulating the activity of defense-activating and desquamation-involved proteases. Inhibits KLK5, it's major target, in a pH-dependent manner. Inhibits KLK7, KLK14 CASP14, and trypsin.
Interacts with AGTR1. Interacts with FLNA (via filamin repeat 21); increases PKA-mediated phosphorylation of FLNA (PubMed:26460884).
Receptor for angiotensin 1-7 (By similarity). Acts specifically as a functional antagonist of AGTR1 (angiotensin-2 type 1 receptor), although it up-regulates AGTR1 receptor levels. Positive regulation of AGTR1 levels occurs through activation of the G-proteins GNA11 and GNAQ, and stimulation of the protein kinase C signaling cascade. The antagonist effect on AGTR1 function is probably due to AGTR1 being physically altered by MAS1.
The MAS oncogene has a weak focus-inducing activity in transfected NIH 3T3 cells.
Was originally thought to be a receptor for angiotensin II.
Expressed in testis and fetal heart, as well as in non small cell lung carcinoma and neuroblastoma cell line.
Found in all tissues examined with highest expression in liver, heart and skeletal muscle. Lower levels in pancreas and placenta. Weak expression in brain.
Increased levels in several tumor cell lines, including lung and colon adenocarcinomas and mammary carcinomas. Strongly induced in Burkitt's lymphoma and lymphocytes transformed by EBV.
Brain. Down-regulated in primary glioma tissues compared to the normal tissues. The soluble monomeric form is expressed in the glioblastoma multiforme (GBM) and breast cancer cells (at protein level).
Cell surface GPI-bound ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. Plays an important role in angiogenesis and tumor neovascularization. The recruitment of VAV2, VAV3 and PI3-kinase p85 subunit by phosphorylated EPHA2 is critical for EFNA1-induced RAC1 GTPase activation and vascular endothelial cell migration and assembly. Exerts anti-oncogenic effects in tumor cells through activation and down-regulation of EPHA2. Activates EPHA2 by inducing tyrosine phosphorylation which leads to its internalization and degradation. Acts as a negative regulator in the tumorigenesis of gliomas by down-regulating EPHA2 and FAK. Can evoke collapse of embryonic neuronal growth cone and regulates dendritic spine morphogenesis.
Monomer. Homodimer. Forms heterodimers with EPHA2. Binds to the receptor tyrosine kinases EPHA2, EPHA3, EPHA4, EPHA5, EPHA6 and EPHA7. Also binds with low affinity to EPHA1.
N-Glycosylation is required for binding to EPHA2 receptor and inducing its internalization.
Undergoes proteolysis by a metalloprotease to give rise to a soluble monomeric form.
Preferentially and highly expressed in colon.
Probably functions as a 3'-phosphoadenylyl sulfate:adenosine 3',5'-bisphosphate antiporter at the Golgi membranes. Mediates the transport from the cytosol into the lumen of the Golgi of 3'-phosphoadenylyl sulfate/adenosine 3'-phospho 5'-phosphosulfate (PAPS), a universal sulfuryl donor for sulfation events that take place in that compartment.
Adapter protein that binds F-actin and DNM1, and thereby plays a role in receptor-mediated endocytosis. Plays a role in the reorganization of the actin cytoskeleton, formation of cell projections, such as neurites, in neuron morphogenesis and synapse formation via its interaction with WASL and COBL. Does not bind G-actin and promote actin polymerization by itself. Required for the formation of organized podosome rosettes (By similarity). May act as a common effector of antigen receptor-signaling pathways in leukocytes. Acts as a key component of the immunological synapse that regulates T-cell activation by bridging TCRs and the actin cytoskeleton to gene activation and endocytic processes.
Interacts with SHANK2, SHANK3 and SYN1. Interacts with FGD1 and DNM1. Interacts with ANKRD54. Interacts with COBL. Interacts with WASL and WIPF1 (By similarity). Interacts with MAP4K1 and PRAM1.
The SH3 domain mediates interaction with SHANK2, SHANK3 and PRAM1.
Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward palmitoyl-CoA (hexadecanoyl-CoA; C16:0-CoA) (PubMed:17977534, PubMed:17609214, PubMed:23530041, PubMed:26887952, PubMed:31916624). Can use other acyl donors, but with less efficiency (By similarity). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively (PubMed:17977534, PubMed:23530041, PubMed:26887952, PubMed:31916624). Ceramides generated by CERS6 play a role in inflammatory response (By similarity). Acts as a regulator of metabolism and hepatic lipid accumulation (By similarity). Under high fat diet, palmitoyl- (C16:0-) ceramides generated by CERS6 specifically bind the mitochondrial fission factor MFF, thereby promoting mitochondrial fragmentation and contributing to the development of obesity (By similarity).
Phosphorylated at the C-terminus by CK2.
Some prediction bioinformatics tools predict the presence of a homeobox domain (By similarity). However, the domain is degenerate and residues that are important for DNA-binding are absent (By similarity). Moreover, the protein localizes in the endoplasmic reticulum and not in the nucleus, strongly suggesting that it does not constitute a canonical homeobox domain (By similarity).
Up-regulated in adipose tissues in obese patients.
Detected at low levels in brain, and at very low levels in heart, adrenal gland, testis, liver and kidney.
Forms non-fusogenic complexes with SNAP25 and STX1A and may thereby modulate the formation of functional SNARE complexes and exocytosis.
Part of a ternary complex containing SNAP25 and STX1A that can be dissociated by NAPA and NSF. Interacts with STX4A.
Cytosolic tripeptidyl-peptidase that releases N-terminal tripeptides from polypeptides and is a component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway (PubMed:25525876, PubMed:30533531). It plays an important role in intracellular amino acid homeostasis (PubMed:25525876). Stimulates adipogenesis (By similarity).
The limitation of proteolytic products to tripeptides is achieved by tailoring the size of the substrate-binding cleft: the two negatively charged residues Glu-305 and Glu-331 that are blocking position P4 limit the number of residues that can be accommodated in the binding cleft and thus create a molecular ruler. At the same time, they orient substrates so that the tripeptides are removed exclusively from the N-terminus (By similarity).
Highly N-glycosylated and O-glycosylated.
May regulate TLP1 expression and telomerase activity, thus enabling certain prostatic cells to resist apoptosis.
Widely expressed with highest levels in heart, kidney and placenta.
Found in spleen, thymus, peripheral blood leukocytes, pancreas, lung, and colon (PubMed:9188469). Expressed in neuronal fibers in dorsal root ganglia and in peripheral tissues including stomach, white adipose tissue and prostate (at protein level) (PubMed:21266581).
Interacts with PLA2R1; this interaction mediates PLA2G10 clearance and inactivation.
Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids (PubMed:9188469, PubMed:12021277). Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids with preference for phosphatidylcholines and phosphatidylglycerols over phosphatidylethanolamines. Preferentially releases sn-2 omega-6 and omega-3 polyunsaturated fatty acyl (PUFA) chains over saturated fatty acyls (PubMed:12359733, PubMed:12021277). Contributes to phospholipid remodeling of very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles (PubMed:12021277). Hydrolyzes LDL phospholipids releasing unsaturated fatty acids that regulate macrophage differentiation toward foam cells (PubMed:12021277). Efficiently hydrolyzes and inactivates platelet activating factor (PAF), a potent lipid mediator present in oxidized LDL (PubMed:16962371). May act in an autocrine and paracrine manner. Secreted by lung epithelium, targets membrane phospholipids of infiltrating eosinophils, releasing arachidonate and boosting eicosanoid and cysteinyl leukotriene synthesis involved in airway inflammatory response (By similarity). Secreted by gut epithelium, hydrolyzes dietary and biliary phosphatidylcholines in the gastrointestinal lumen (By similarity). Plays a stem cell regulator role in colon epithelium. Within intracellular compartment, mediates Paneth-like cell differentiation and its stem cell supporting functions by inhibiting the Wnt signaling pathway in intestinal stem cell (ISC). Secreted in the intestinal lumen upon inflammation, acts in an autocrine way and promotes prostaglandin E2 synthesis that stimulates Wnt signaling pathway in ISCs and tissue regeneration (By similarity). May participate in hair follicle morphogenesis by regulating phosphatidylethanolamines metabolism at the outermost epithelial layer and facilitating melanin synthesis (By similarity). By releasing lysophosphatidylcholines (LPCs) at sperm acrosome, controls sperm cell capacitation, acrosome reaction and overall fertility (By similarity). May promote neurite outgrowth in neuron fibers involved in nociception (By similarity). Contributes to lipid remodeling of cellular membranes and generation of lipid mediators involved in pathogen clearance. Cleaves sn-2 fatty acyl chains of phosphatidylglycerols and phosphatidylethanolamines, which are major components of membrane phospholipids in bacteria (PubMed:12359733). Displays bactericidal activity against Gram-positive bacteria by directly hydrolyzing phospholipids of the bacterial membrane (PubMed:11694541). In pulmonary epithelium, may contribute to host defense response against adenoviral infection. Prevents adenovirus entry into host cells by hydrolyzing host cell plasma membrane, releasing C16:0 LPCs that inhibit virus-mediated membrane fusion and viral infection. Likely prevents adenoviral entry into the endosomes of host cells (PubMed:16146426). May play a role in maturation and activation of innate immune cells including macrophages, group 2 innate lymphoid cells and mast cells (By similarity).
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. ASIC1 subfamily.
Channel opening involves a conformation change that affects primarily the extracellular domain and the second transmembrane helix and its orientation in the membrane. In the open state, the second transmembrane helix is nearly perpendicular to the plane of the membrane; in the desensitized state it is strongly tilted. Besides, the second transmembrane domain is discontinuously helical in the open state. The GAS motif of the selectivity filter is in an extended conformation, giving rise to a distinct kink in the polypeptide chain. A domain swap between subunits gives rise to a full-length transmembrane helix (By similarity).
Homotrimer or heterotrimer with other ASIC proteins (By similarity). Interacts with STOM and ASIC2 (By similarity). Interacts with PRKCABP. Homotrimer of Asic1a (ASIC1 isoform 2) interacts with spider venom psalmotoxin-1 (PubMed:19654327, PubMed:22760635). Homotrimer of Asic1a (ASIC1 isoform 2) and Asic1b (ASIC1 isoform 3) interacts with the spider venom pi-theraphotoxin-Hm3a (PubMed:28327374). Homotrimer of Asic1a (ASIC1 isoform 2) interacts with the snake venom mambalgin-1 (PubMed:23034652). Heterotrimer of Asic1a-Asic2a (ASIC1 isoform 2-ASIC2 isoform 1) interacts with the snake venom mambalgin-1 (PubMed:23034652).
Inhibited by the diuretic amiloride. Inhibited by Cs(1+) ions. Inhibited by spider venom psalmotoxin-1; this locks the channel into its desensitized conformation.
Isoform 1 does not display proton-gated cation channel activity.
Isoform 2 and isoform 3 function as proton-gated sodium channels; they are activated by a drop of the extracellular pH and then become rapidly desensitized. The channel generates a biphasic current with a fast inactivating and a slow sustained phase. Has high selectivity for sodium ions and can also transport lithium ions with high efficiency. Isoform 2 can also transport potassium, but with lower efficiency. It is nearly impermeable to the larger rubidium and cesium ions. Isoform 3 can also transport calcium ions. Mediates glutamate-independent Ca(2+) entry into neurons upon acidosis. This Ca(2+) overloading is toxic for cortical neurons and may be in part responsible for ischemic brain injury. Heteromeric channel assembly seems to modulate channel properties. Functions as a postsynaptic proton receptor that influences intracellular Ca(2+) concentration and calmodulin-dependent protein kinase II phosphorylation and thereby the density of dendritic spines. Modulates activity in the circuits underlying innate fear.
Phosphorylation by PKA regulates interaction with PRKCABP and subcellular location. Phosphorylation by PKC may regulate the channel.
Potentiated by Ca(2+), Mg(2+), Ba(2+) and multivalent cations. Inhibited by anti-inflammatory drugs like salicylic acid (By similarity). Potentiated by FMRFamide-related neuropeptides. PH dependence may be regulated by serine proteases.
Osteosarcoma, and at lower levels in liver, kidney and brain.
Chaperone protein which promotes assembly of the 20S proteasome. May cooperate with PSMG1-PSMG2 heterodimers to orchestrate the correct assembly of proteasomes.
Homodimer. Interacts with PSMG4. Interacts directly with alpha and beta subunits of the 20S proteasome but dissociates before the formation of half-proteasomes, probably upon recruitment of POMP.
Expressed in the occipital lobe of the cerebral cortex of the brain. Expressed at higher levels in some astrocytic brain tumors such as astrocytomas, oligodendrogliomas, glioblastomas, gangliogliomas and primitive neuroectodermal tumors.
Abundant expression in kidney, also detected in liver, placenta and small intestine. In the kidney, expression is restricted to the distal tubules and collecting ducts (PubMed:9812978). Not expressed in proximal tubules or glomeruli (PubMed:9812978).
Inhibited by quinine, quinidine and external acidification.
pH-dependent, outwardly rectifying potassium channel (PubMed:9812978). Outward rectification is lost at high external K(+) concentrations (PubMed:9812978).
Probably catalyzes the deacetylation of acetylated carbohydrates an important step in the degradation of oligosaccharides.
Belongs to the CND2 H2 (condensin-2 subunit 2) family.
Component of the condensin-2 complex, which contains the SMC2 and SMC4 heterodimer, and three non SMC subunits, NCAPG2, NCAPH2 and NCAPD3 that probably regulate the complex.
Regulatory subunit of the condensin-2 complex, a complex that seems to provide chromosomes with an additional level of organization and rigidity and in establishing mitotic chromosome architecture (PubMed:14532007). May promote the resolution of double-strand DNA catenanes (intertwines) between sister chromatids. Condensin-mediated compaction likely increases tension in catenated sister chromatids, providing directionality for type II topoisomerase-mediated strand exchanges toward chromatid decatenation. Required for decatenation of chromatin bridges at anaphase. Early in neurogenesis, may play an essential role to ensure accurate mitotic chromosome condensation in neuron stem cells, ultimately affecting neuron pool and cortex size (By similarity). Seems to have lineage-specific role in T-cell development (PubMed:14532007).
Isoform 1, isoform 2, isoform 3, and isoform 4 are expressed in testis. Isoform 4 is expressed in myometrium.
Specifically phosphorylates the activated forms of G protein-coupled receptors. GRK4-alpha can phosphorylate rhodopsin and its activity is inhibited by calmodulin; the other three isoforms do not phosphorylate rhodopsin and do not interact with calmodulin. GRK4-alpha and GRK4-gamma phosphorylate DRD3. Phosphorylates ADRB2.
Expressed in K-562 and HeLa cell lines and in brain.
May act as a transcription factor that regulates the expression of coproporphyrinogen oxidase by binding to a promoter regulatory element.
Antimicrobial host-defense peptide. Has an antiplasmodial activity.
Expressed on differentiated macrophage phagocytizing plasmodium falciparum-parasitized erythrocytes.
Homodimer; homodimerization takes place upon caspase cleavage (PubMed:33725486). Interacts with the processed C-terminus of XRCC4 (protein XRCC4, C-terminus); interaction promotes the phospholipid scramblase activity (PubMed:33725486).
Homodimerizes upon caspase cleavage (By similarity). Phospholipid scramblase activity is activated following interaction with the processed C-terminus of XRCC4 (protein XRCC4, C-terminus) (PubMed:33725486).
Phospholipid scramblase activity is activated upon caspase cleavage to generate the XK-related protein 4, processed form (By similarity). Does not act prior the onset of apoptosis (By similarity).
Phospholipid scramblase that promotes phosphatidylserine exposure on apoptotic cell surface (PubMed:25231987, PubMed:33725486). Phosphatidylserine is a specific marker only present at the surface of apoptotic cells and acts as a specific signal for engulfment (PubMed:25231987, PubMed:33725486).
Undergoes proteolytic processing by caspase-3 (CASP3), caspase-6 (CASP6) and caspase-7 (CASP7) to generate the XK-related protein 4, processed form, leading to its activation.
Amino acid transport activity is increased by sodium and is most active at acidic pH (PubMed:25561175, PubMed:31295473). Transport of L-glutamine, leucine and tyrosine is increased by arginine binding (PubMed:29053970, PubMed:31295473).
Associated component of the Ragulator complex (composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5) (PubMed:25561175, PubMed:32868926, PubMed:28336668, PubMed:25567906, PubMed:29053970). Associated component of the Rag GTPases heterodimers (composed of RRAGA, RRAGB, RRAGC and RRAGD); this interaction is independent of the Ragulator complex but depends on the nucleotide loading state of the Rag GTPase heterodimer (PubMed:25561175, PubMed:32868926, PubMed:28336668, PubMed:30181260, PubMed:25567906, PubMed:29053970). Interacts with TM4SF5 (PubMed:30956113). Interacts with NPC1; this interaction inhibits cholesterol-mediated mTORC1 activation via its sterol transport activity (PubMed:28336668).
Belongs to the amino acid/polyamine transporter 2 family. SLC38A9 subfamily.
Lysosomal amino acid transporter involved in the activation of mTORC1 in response to amino acid levels (PubMed:25567906, PubMed:25561175, PubMed:29053970). Probably acts as an amino acid sensor of the Rag GTPases and Ragulator complexes, 2 complexes involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids (PubMed:25567906, PubMed:29053970). Following activation by amino acids, the Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated (PubMed:25567906, PubMed:25561175). SLC38A9 mediates transport of amino acids with low capacity and specificity with a slight preference for polar amino acids (PubMed:25561175, PubMed:25567906). Acts as an arginine sensor (PubMed:25567906, PubMed:29053970, PubMed:31295473). Following activation by arginine binding, mediates transport of L-glutamine, leucine and tyrosine with high efficiency, and is required for the efficient utilization of these amino acids after lysosomal protein degradation (PubMed:29053970, PubMed:31295473). However, the transport mechanism is not well defined and the role of sodium is not clear (PubMed:25561175, PubMed:31295473). Can disassemble the lysosomal folliculin complex (LFC), and thereby triggers GAP activity of FLCN:FNIP2 toward RRAGC (PubMed:32868926). Acts as an cholesterol sensor that conveys increases in lysosomal cholesterol, leading to lysosomal recruitment and activation of mTORC1 via the Rag GTPases (PubMed:28336668). Guanine exchange factor (GEF) that, upon arginine binding, stimulates GDP release from RRAGA and therefore activates the Rag GTPase heterodimer and the mTORC1 pathway in response to nutrient sufficiency (PubMed:30181260).
The cytosolic N-terminus part of the protein mediates interaction with the Ragulator complex (PubMed:25561175, PubMed:25567906). The cytosolic N-terminus part of the protein destabilizes the LFC and thereby triggers GAP activity of FLCN:FNIP2 toward RRAGC (PubMed:32868926). The cytosolic N-terminus part of the protein mediates interaction with the Rag GTPase heterodimer in a RRAGA GDP-loaded state dependent and upon arginine binding, leading to the GDP release and SLC38A9 dissociation from the activated Rag GTPase heterodimer (PubMed:30181260, PubMed:25561175, PubMed:25567906). The cytosolic N-terminus part of the protein exists at least in two distinct conformations; The first is when the N-terminus is bound snugly in the arginine binding site (in the absence of arginine, low luminal arginine state) and the second is where the N-terminus is released and the substrate-binding site is occupied by arginine (in the presence of arginine, high luminal arginine state) (By similarity).
the CARC and CRAC motifs mediate binding to cholesterol.
Bridging factor that mediates the recruitment of CYLD to the LUBAC complex, thereby regulating TNF-alpha-induced necroptosis (PubMed:27307491, PubMed:27458237, PubMed:27545878, PubMed:27591049). Acts as a direct binding intermediate that bridges RNF31/HOIP, the catalytic subunit of the LUBAC complex, and the deubiquitinase (CYLD), thereby recruiting CYLD to the TNF-R1 signaling complex (TNF-RSC) (PubMed:27458237, PubMed:27545878, PubMed:27591049). Required to activate the 'Met-1'- (linear) and 'Lys-63'-linked deubiquitinase activities of CYLD (PubMed:27458237, PubMed:27591049). Controls the kinase activity of RIPK1 and TNF-alpha-induced necroptosis by promoting 'Met-1'-linked deubiquitination of RIPK1 by CYLD (By similarity).
Interacts (via the PIM motif) with RNF31/HOIP (via the PUB domain); the interaction is direct (PubMed:27458237, PubMed:27545878, PubMed:28189684, PubMed:27591049). Interacts (via the PUB domain) with CYLD; the interaction is direct (PubMed:27307491, PubMed:27458237, PubMed:27545878, PubMed:27591049).
Present at high level in Sertoli cells, but not detected in spermatogenic cells (at protein level) (PubMed:10222154, PubMed:11079456). Low expression in spleen, thymus and prostate (PubMed:10222154).
By INS or IGF1 through the PI-3 kinase/mTOR pathway.
Expressed in the central nervous system. Also expressed in testis and skeletal muscle. Weakly expressed in heart, liver, kidney, prostate, colon and peripheral blood leukocytes.
Inhibited by pyridoxal 5'-phosphate, 4,7-diphenyl-1,10-phenanthroline, tannic acid, and mercurials (mercury dichloride, mersalyl acid, p-hydroxymercuribenzoate).
Mitochondrial transporter that imports/exports pyrimidine nucleotides into and from mitochondria. Selectively transports uridine, thymidine, guanosine, cytosine and inosine (deoxy)nucleoside di- and triphosphates by an antiport mechanism (PubMed:25320081). May import (deoxy)nucleoside triphosphates in exchange for intramitochondrial (deoxy)nucleoside diphosphates, thus providing precursors necessary for de novo synthesis of mitochondrial DNA and RNA while exporting products of their catabolism (PubMed:25320081). Participates in mitochondrial genome maintenance, regulation of mitochondrial membrane potential and mitochondrial respiration (PubMed:20453889). Upon INS or IGF1 stimulation regulates cell growth and proliferation by controlling mitochondrial DNA replication and transcription, the ratio of mitochondria-to nuclear-encoded components of the electron transport chain resulting in control of mitochondrial ROS production (PubMed:20453889, PubMed:17596519). Participates in dendritic cell endocytosis and may associate with mitochondrial oxidative phosphorylation (PubMed:14715278).
Required for the function of coenzyme Q in the respiratory chain. May serve as a chaperone or may be involved in the transport of Q6 from its site of synthesis to the catalytic sites of the respiratory complexes (By similarity).
Required for the function of coenzyme Q in the respiratory chain. May serve as a chaperone or may be involved in the transport of Q6 from its site of synthesis to the catalytic sites of the respiratory complexes.
Downstream regulator in the Wnt/Frizzled-signaling pathway. Associated with cell survival. Attenuates p53-mediated apoptosis in response to DNA damage through activation of AKT kinase. Up-regulates the anti-apoptotic Bcl-X(L) protein. Adheres to skin and melanoma fibroblasts. In vitro binding to skin fibroblasts occurs through the proteoglycans, decorin and biglycan.
Expressed in heart, kidney, lung, pancreas, placenta, ovary, small intestine and spleen. Isoform 2 is expressed predominantly in scirrhous gastric carcinoma and, weakly in placenta. Overexpression is associated with several cancers including breast cancer and colon tumors. Isoform 2 is overexpressed in scirrhous gastric carcinoma.
Highly expressed in placenta, heart, kidney and small intestine. Detected at lower levels in neuronal cells in the brain, in skeletal muscle, spleen, liver, testes and colon.
Release of an N-terminal amino acid, cleaves before cysteine, leucine as well as other amino acids. Degrades peptide hormones such as oxytocin, vasopressin and angiotensin III, and plays a role in maintaining homeostasis during pregnancy. May be involved in the inactivation of neuronal peptides in the brain. Cleaves Met-enkephalin and dynorphin. Binds angiotensin IV and may be the angiotensin IV receptor in the brain.
The pregnancy serum form is derived from the membrane-bound form by proteolytic processing.
Central and peripheral nervous systems, synthesized exclusively in neuronal and neuroendocrine cells.
Has bactericidal activity against M. luteus, and antifungal activity against P. Pastoris.
Interacts with HSPA8 on cell membrane (PubMed:28934328). Interacts with C3AR1 (By similarity). Interacts with C1QBP (By similarity).
Multiple peptides are derived from VGF, with activities in synaptic plasticity, antidepression, penile erection, autonomic activation, and increases in energy expenditure.
Plays a role in the control of body fluid homeostasis by regulating vasopressin release. Activates GABAergic interneurons which are inhibitory neurons of the nervous system and thereby suppresses presynaptic glutamatergic neurons (By similarity). Stimulates also feeding behavior in an orexin-dependent manner in the hypothalamus (By similarity). Functions as a positive regulator for the activation of orexin neurons resulting in elevated gastric acid secretion and gastric emptying (By similarity).
Plays a role in the control of body fluid homeostasis by regulating vasopressin release. Suppresses presynaptic glutamatergic neurons connected to vasopressin neurons.
Plays a role in the regulation of memory formation and depression-related behaviors potentially by influencing synaptic plasticity and neurogenesis. Induces acute and transient activation of the NTRK2/TRKB receptor and subsequent CREB phosphorylation (By similarity). Induces also insulin secretion in insulinoma cells by increasing intracellular calcium mobilization (By similarity).
Secreted multifunctional neuropeptide that binds to different cell receptors and thereby plays multiple physiological roles including modulation of energy expenditure, pain, response to stress, gastric regulation, glucose homeostasis as well as lipolysis (By similarity). Activates the G-protein-coupled receptor C3AR1 via a folding-upon-binding mechanism leading to enhanced lipolysis in adipocytes (By similarity). Interacts with C1QBP receptor in macrophages and microglia causing increased levels of intracellular calcium and hypersensitivity (By similarity).
Secreted polyprotein that is packaged and proteolytically processed by prohormone convertases PCSK1 and PCSK2 in a cell-type-specific manner (By similarity). VGF and peptides derived from its processing play many roles in neurogenesis and neuroplasticity associated with learning, memory, depression and chronic pain (By similarity).
Belongs to the mitochondrion-specific ribosomal protein mL42 family.
Has also been found in a preparation of mitochondrial small ribosomal subunits. Was erroneously (PubMed:11279123, PubMed:11551941) assigned to be MRP-S32.
Belongs to the RBR family. RNF19 subfamily.
E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes UBE2L3 and UBE2L6 in the form of a thioester and then directly transfers the ubiquitin to targeted substrates, such as SNCAIP or CASR. Specifically ubiquitinates pathogenic SOD1 variants, which leads to their proteasomal degradation and to neuronal protection.
Interacts with UBE2L3 and UBE2L6. Interacts with transcription factor Sp1. Interacts with VCP, CASR, SNCAIP and with some SOD1 variants which cause amyotrophic lateral sclerosis, but not with wild-type SOD1.
Widely expressed, with highest levels in heart. Ubiquitously expressed in the central nervous system.
Early endosomal protein that functions to recruit SMAD2/SMAD3 to intracellular membranes and to the TGF-beta receptor. Plays a significant role in TGF-mediated signaling by regulating the subcellular location of SMAD2 and SMAD3 and modulating the transcriptional activity of the SMAD3/SMAD4 complex. Possibly associated with TGF-beta receptor internalization.
Interacts (via the SBD region) with SMAD2; the interaction recruits SMAD2 to the TGF-beta receptor and is disrupted by phosphorylation of SMAD2 upon TGF-beta receptor activation. Interacts with SMAD3. Interacts with TGFBR1 and TGFBR2; the interaction recruits SMAD2 to the TGF-beta receptor. Interacts with PML.
The FYVE-type zinc finger is necessary and sufficient for its localization into early endosomes and mediates the association with PI3P.
The SMAD binding domain (SBD) interacts with the MH2 domains of SMAD2 or SMAD3.
Ubiquitous. In the brain found primarily in the cerebrovascular smooth muscle cells and reactive astrocytes.
Expressed in colonic crypts (at protein level) (PubMed:30389919). Ubiquitous, except peripheral blood leukocytes (PubMed:8654366).
Monomer, and homodimer. Part of a complex composed of SEPTIN4 isoform ARTS, XIAP and BCL2, within the complex interacts with SEPTIN4 isoform ARTS and BCL2, SEPTIN4 isoform ARTS acts as a scaffold protein and stabilizes the complex (PubMed:29020630). Interacts (via BIR3 domain) with DIABLO/SMAC; the interaction inhibits apoptotic suppressor activity (PubMed:21695558, PubMed:11140637, PubMed:11257230). Interacts with HTRA2/PRSS25; the interaction inhibits apoptotic suppressor activity (PubMed:11604410). Interacts with TAB1/MAP3K7IP1 and AIFM1. Interaction with DIABLO/SMAC hinders binding of TAB1/MAP3K7IP1 and AIFM1. Interacts with TCF25 and COMMD1. Interacts (via BIR3 domain) with SEPTIN4 isoform ARTS (PubMed:21695558, PubMed:15029247). Interacts (via BIR3 domain) with SEPTIN4 (By similarity). Interacts with RIP1, RIP2, RIP3, RIP4, CCS and USP19. Interacts (via BIR 2 domain and BIR 3 domain) with HAX1 (via C-terminus) and this interaction blocks ubiquitination of XIAP/BIRC4. Interacts with the monomeric form of BIRC5/survivin. Interacts with TLE3 and TCF7L2/TCF4. Interacts (via BIR 3 and RING domains) with PDCL3 (PubMed:19012568).
Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis (PubMed:11447297, PubMed:12121969, PubMed:9230442, PubMed:11257230, PubMed:11257231, PubMed:12620238, PubMed:17967870, PubMed:19473982, PubMed:20154138, PubMed:22103349, PubMed:17560374). Acts as a direct caspase inhibitor (PubMed:11257230, PubMed:11257231, PubMed:12620238). Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry (PubMed:11257230, PubMed:11257231, PubMed:16352606, PubMed:16916640). Inactivates CASP9 by keeping it in a monomeric, inactive state (PubMed:12620238). Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, RIPK2, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS, PTEN and BIRC5/survivin (PubMed:17967870, PubMed:19473982, PubMed:20154138, PubMed:22103349, PubMed:22607974, PubMed:30026309, PubMed:29452636, PubMed:17560374). Acts as an important regulator of innate immunity by mediating 'Lys-63'-linked polyubiquitination of RIPK2 downstream of NOD1 and NOD2, thereby transforming RIPK2 into a scaffolding protein for downstream effectors, ultimately leading to activation of the NF-kappa-B and MAP kinases signaling (PubMed:19667203, PubMed:22607974, PubMed:30026309, PubMed:29452636). 'Lys-63'-linked polyubiquitination of RIPK2 also promotes recruitment of the LUBAC complex to RIPK2 (PubMed:22607974, PubMed:29452636). Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation (PubMed:17560374). Ubiquitination of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation (PubMed:20154138). Ubiquitination of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation (PubMed:17967870, PubMed:22103349). Plays a role in copper homeostasis by ubiquitinating COMMD1 and promoting its proteasomal degradation (PubMed:14685266). Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation (PubMed:21145488). Ubiquitinates and therefore mediates the proteasomal degradation of BCL2 in response to apoptosis (PubMed:29020630). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner (PubMed:22095281). Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8 (PubMed:22095281). Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES (PubMed:22304967). Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program (PubMed:22304967).
S-Nitrosylation down-regulates its E3 ubiquitin-protein ligase activity.
The first BIR domain is involved in interaction with TAB1/MAP3K7IP1 and is important for dimerization (PubMed:17560374). The second BIR domain is sufficient to inhibit CASP3 and CASP7, while the third BIR is involved in CASP9 inhibition (PubMed:11257231, PubMed:12620238). The interactions with DIABLO/SMAC and HTRA2/PRSS25 are mediated by the second and third BIR domains.
Was originally shown to be phosphorylated at Ser-87 by PKB, protecting the protein from ubiquitination and proteasomal degradation (PubMed:14645242). However, this work was later retracted (PubMed:27825084).
Protease that acts as a positive regulator of the cGAS-STING pathway by catalyzing desumoylation of CGAS. Desumoylation of CGAS promotes DNA-binding activity of CGAS, subsequent oligomerization and activation (By similarity). Deconjugates SUMO2 and SUMO3 from targeted proteins, but not SUMO1 (PubMed:18799455). Catalyzes the deconjugation of poly-SUMO2 and poly-SUMO3 chains (PubMed:18799455). Has very low efficiency in processing full-length SUMO proteins to their mature forms (PubMed:18799455).
Expressed in fetal kidney, fetal lung, fetal liver and at low levels in fetal brain.
Highly expressed in tissues which produce large amounts of secreted proteins such as kidney, liver and placenta. Also expressed in colon, heart, lung, ovary, pancreas, peripheral leukocyte, prostate, spleen and thymus. Expressed at low levels throughout the brain.
Required for protein translocation and folding in the endoplasmic reticulum (ER). Functions as a nucleotide exchange factor for the ER lumenal chaperone HSPA5.
Ubiquitinated by the CRL2(FEM1A) and CRL2(FEM1C) complexes, which recognize the -Lys-Xaa-Xaa-Arg C-degron at the C-terminus, leading to its degradation.
Phosphorylation at Ser-33 inhibits the kinase and activates the bisphosphatase.
Belongs to the membrane magnesium transporter (TC 1.A.67) family.
Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins (PubMed:30415835, PubMed:29809151, PubMed:29242231, PubMed:32459176, PubMed:32439656). Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues (PubMed:30415835, PubMed:29809151, PubMed:29242231). Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices (PubMed:30415835, PubMed:29809151). It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes (PubMed:29809151, PubMed:29242231). By mediating the proper cotranslational insertion of N-terminal transmembrane domains in an N-exo topology, with translocated N-terminus in the lumen of the ER, controls the topology of multi-pass membrane proteins like the G protein-coupled receptors (PubMed:30415835). By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes (By similarity). May be involved in Mg(2+) transport (By similarity).
Involved in mitochondrial metabolism by regulating the balance between mitochondrial fusion and fission. May act as a regulator of mitochondrial fission that promotes DNM1L-dependent fission through activation of DNM1L. May be involved in peroxisome organization.
Up-regulated in bone marrow-derived mesenchymal stem cells during differentiation into adipocytes compared to osteoblasts.
A chromosomal aberration involving PDGFRB is found in a form of chronic myelomonocytic leukemia (CMML). Translocation t(5;12)(q33;p13) with EVT6/TEL. It is characterized by abnormal clonal myeloid proliferation and by progression to acute myelogenous leukemia (AML).
Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation at Tyr-579, and to a lesser degree, at Tyr-581, is important for interaction with SRC family kinases. Phosphorylation at Tyr-740 and Tyr-751 is important for interaction with PIK3R1. Phosphorylation at Tyr-751 is important for interaction with NCK1. Phosphorylation at Tyr-771 and Tyr-857 is important for interaction with RASA1/GAP. Phosphorylation at Tyr-857 is important for efficient phosphorylation of PLCG1 and PTPN11, resulting in increased phosphorylation of AKT1, MAPK1/ERK2 and/or MAPK3/ERK1, PDCD6IP/ALIX and STAM, and in increased cell proliferation. Phosphorylation at Tyr-1009 is important for interaction with PTPN11. Phosphorylation at Tyr-1009 and Tyr-1021 is important for interaction with PLCG1. Phosphorylation at Tyr-1021 is important for interaction with CBL; PLCG1 and CBL compete for the same binding site. Dephosphorylated by PTPRJ at Tyr-751, Tyr-857, Tyr-1009 and Tyr-1021. Dephosphorylated by PTPN2 at Tyr-579 and Tyr-1021.
Interacts with homodimeric PDGFB and PDGFD, and with heterodimers formed by PDGFA and PDGFB. May also interact with homodimeric PDGFC. Monomer in the absence of bound ligand. Interaction with homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD, leads to receptor dimerization, where both PDGFRA homodimers and heterodimers with PDGFRB are observed. Interacts with SH2B2/APS. Interacts directly (tyrosine phosphorylated) with SHB. Interacts (tyrosine phosphorylated) with PIK3R1 and RASA1. Interacts (tyrosine phosphorylated) with CBL. Interacts (tyrosine phosphorylated) with SRC and SRC family kinases. Interacts (tyrosine phosphorylated) with PIK3C2B, maybe indirectly. Interacts (tyrosine phosphorylated) with SHC1, GRB7, GRB10 and NCK1. Interaction with GRB2 is mediated by SHC1. Interacts (via C-terminus) with NHERF1.
Present in an inactive conformation in the absence of bound ligand. Binding of PDGFB and/or PDGFD leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by imatinib.
The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving PDGFRB has been found in a patient with AML. Translocation t(5;14)(q33;q32) with TRIP11 (PubMed:9373237).
The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving PDGFRB has been found in a patient with JMML. Translocation t(5;17)(q33;p11.2) with SPECC1 (PubMed:15087372).
The gene represented in this entry may be involved in disease pathogenesis. Chromosomal aberrations involving PDGFRB have been found in many instances of chronic myeloproliferative disorder with eosinophilia. Translocation t(5;12) with ETV6 on chromosome 12 creating an PDGFRB-ETV6 fusion protein (PubMed:12181402). Translocation t(5;15)(q33;q22) with TP53BP1 creating a PDGFRB-TP53BP1 fusion protein (PubMed:15492236). Translocation t(1;5)(q23;q33) that forms a PDE4DIP-PDGFRB fusion protein (PubMed:12907457). Translocation t(5;6)(q33-34;q23) with CEP85L that fuses the 5'-end of CEP85L (isoform 4) to the 3'-end of PDGFRB (PubMed:21938754).
Tyrosine-protein kinase that acts as cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Plays a role in the migration of vascular smooth muscle cells and the formation of neointima at vascular injury sites. Required for normal development of the cardiovascular system. Required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. Promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. Binding of its cognate ligands - homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or of the C-terminus of PTPN11, creates a binding site for GRB2, resulting in the activation of HRAS, RAF1 and down-stream MAP kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and STAM. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor.
Ubiquitinated. After autophosphorylation, the receptor is polyubiquitinated, leading to its degradation.
Widely expressed. Expressed at high levels in lung, thymus, skeletal muscle, colon and ovary.
(Microbial infection) Interacts with vaccinia virus protein C6 (PubMed:21931555).
Adapter protein which constitutively binds TBK1 and IKBKE playing a role in antiviral innate immunity.
Detected in leukocytes, lung, placenta, small intestine, liver, kidney, spleen, muscle, heart, brain and at low levels in thymus.
Homodimer. May form a heterodimer with NAP1. Interacts with TKB1 and IKBKE. Weakly interacts with DDX3X (PubMed:27980081).
Isoform PKP3a is found in desmosomes of most simple and stratified epithelia. Not found in foreskin fibroblasts and various sarcoma-derived cell lines. Beside dendritic reticular cells of lymphatic follicles not found in non-epithelial desmosome-bearing tissues. Isoform PKP3b is abundant in the desmosomes of stratified epithelial cell but absent in simple epithelial cells, it is also expressed in the colon and its tumors.
Expressed in all tissues, except liver, with high expression in placenta, lung, spleen and veins.
Homodimer (PubMed:17640864). Interacts with ARFGEF2/BIG2; both proteins are probably part of the same or very similar macromolecular complexes (PubMed:10716990). Interacts with FKBP2 (PubMed:12606707). Interacts with MYO9B (PubMed:15644318). Interacts with PRKAR1A and PRKAR2A (PubMed:12571360). Interacts with PPP1CC (PubMed:17360629). Interacts with NCL, FBL, NUP62 and U3 small nucleolar RNA (PubMed:14973189, PubMed:18292223). Interacts with DPY30 (PubMed:19651892). Interacts with PDE3A (PubMed:19332778). Interacts with KANK1 (PubMed:22084092). Interacts with TBC1D22A and TBC1D22B (PubMed:23572552). Interacts (via N-terminus) with ARL1 (PubMed:27373159, PubMed:27436755).
Phosphorylated. In vitro phosphorylated by PKA reducing its GEF activity and dephosphorylated by phosphatase PP1.
Promotes guanine-nucleotide exchange on ARF1 and ARF3. Promotes the activation of ARF1/ARF3 through replacement of GDP with GTP. Involved in vesicular trafficking. Required for the maintenance of Golgi structure; the function may be independent of its GEF activity. Required for the maturaion of integrin beta-1 in the Golgi. Involved in the establishment and persistence of cell polarity during directed cell movement in wound healing. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways. Inhibits GAP activity of MYO9B probably through competitive RhoA binding. The function in the nucleus remains to be determined.
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 ORF3A protein; the interaction is direct and sequestrates VPS39, thereby preventing HOPS complex from interacting with the autophagosomal SNARE protein STX17 (PubMed:33422265). ORF3A enhances the interaction of VPS39 with VPS11 and VPS18, while its interaction with the VPS16:VPS33A module is attenuated (PubMed:23167963).
Homooligomer (PubMed:11448994). Interacts with TGFBR2 and, less efficiently, with TGFBR1; interaction with TGFBR2 is independent of the receptor kinase activity and of the presence of TGF-beta. Also interacts with ACVR2B, but not with BMPR2. Interacts with SMAD4, preferentially following TGF-beta treatment. Does not interact with SAMD2 or SMAD3 (PubMed:12941698). Component of the putative homotypic fusion and vacuole protein sorting (HOPS) complex; the core of which composed of the class C Vps proteins VPS11, VPS16, VPS18 and VPS33A, is associated with VPS39 and VPS41 (PubMed:23351085, PubMed:23901104, PubMed:25908847, PubMed:33422265). Interacts with PLEKHM2; involved in VPS39 recruitment to ARL8B-containing lysosomes (PubMed:25908847). Associates with adaptor protein complex 3 (AP-3) and clathrin:AP-3 complexes (By similarity). Interacts with STX17; this interaction is increased in the absence of TMEM39A (PubMed:31806350).
Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Acts as a component of the putative HOPS endosomal tethering complex which is proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The HOPS complex is proposed to be recruited to Rab7 on the late endosomal membrane and to regulate late endocytic, phagocytic and autophagic traffic towards lysosomes (PubMed:23351085). Involved in homotypic vesicle fusions between late endosomes and in heterotypic fusions between late endosomes and lysosomes (PubMed:11448994, PubMed:23351085, PubMed:23167963). Required for fusion of endosomes and autophagosomes with lysosomes (PubMed:25783203).
Regulator of TGF-beta/activin signaling, inhibiting SMAD3- and activating SMAD2-dependent transcription. Acts by interfering with SMAD3/SMAD4 complex formation, this would lead to inhibition of SMAD3-dependent transcription and relieve SMAD3 inhibition of SMAD2-dependent promoters, thus increasing SMAD2-dependent transcription. Does not affect TGF-beta-induced SMAD2 or SMAD3 phosphorylation, nor SMAD2/SMAD4 complex formation.
Widely expressed, with highest levels in heart, skeletal muscle, kidney, pancreas, brain, placenta and spleen.
ATP-binding component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF) (PubMed:9000076). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility (PubMed:9000076). Seems to contact the pointed end of the daughter actin filament (PubMed:9000076). In podocytes, required for the formation of lamellipodia downstream of AVIL and PLCE1 regulation (PubMed:29058690). In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA (PubMed:17220302, PubMed:29925947). The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs) (PubMed:29925947).
Belongs to the actin family. ARP2 subfamily.
Component of the Arp2/3 complex composed of ACTR2/ARP2, ACTR3/ARP3, ARPC1B/p41-ARC, ARPC2/p34-ARC, ARPC3/p21-ARC, ARPC4/p20-ARC and ARPC5/p16-ARC. Interacts with AVIL (PubMed:29058690).
Contaminating sequence and several conflicts. Sequence of unknown origin in the N-terminal part of the CDS.
Interacts with dynein intermediate chain, tubulin, RAB8A, RAB3IP, NUDC, PAFAH1B1 and DCTN1 (PubMed:22159412).
Microtubule-binding protein which plays an important role in mediating dynein-dependent transport of RAB8A-positive vesicles to the midbody during cytokinesis (PubMed:22159412).
Strongly expressed in hepatocellular carcinoma (HCC) compared with their non-cancerous counterparts.
Almost ubiquitous (PubMed:10544037). Largely expressed in adult heart, skeletal muscle, ovary, and fetal kidney (PubMed:10544037). Moderate amounts in adult liver, kidney, pancreas, spleen, and fetal lung, and small amounts in placenta, adult lung, prostate, testis, colon, fetal brain and liver (PubMed:10544037).
Interacts with MAGI3 and NDP (By similarity). Component of a complex, at least composed of TSPAN12, FZD4 and norrin (NDP) (By similarity). Interacts (via FZ domain) with TSKU; TSKU competes with WNT2B for binding to FZD4, inhibiting Wnt signaling and repressing peripheral eye development (By similarity). Interacts with glypican GPC3 (PubMed:24496449).
Receptor for Wnt proteins (PubMed:30135577). Most frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes (PubMed:30135577). Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP) (By similarity). In retina, it can be activated by Wnt protein-binding and also by Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs (By similarity). A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues.
(Microbial infection) Interacts with Hepatitis B virus (HBV) protein X; leading to prevent ubiquitination of TRPC4AP by SKP2.
Component of the DCX(TRPC4AP) E3 ubiquitin ligase complex, at least composed of CUL4A, DDB1, TRPC4AP/TRUSS and RBX1 (PubMed:20551172, PubMed:19966799). Interacts with MYC (PubMed:20551172). Constitutively associated with TNFRSF1A (By similarity). Directly interacts with TRADD, TRAF2, CHUK, IKBKB and IKBKG (By similarity). Interacts with TRPC1, TRPC4 and TRPC5 (By similarity).
Phosphorylated by GSK3B; phosphorylation is required for ubiquitination.
Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control (PubMed:20551172, PubMed:29779948). The DCX(TRPC4AP) complex specifically mediates the polyubiquitination and subsequent degradation of MYC as part of the DesCEND (destruction via C-end degrons) pathway (PubMed:20551172, PubMed:29779948). The DesCEND (destruction via C-end degrons) pathway recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948). The DCX(TRPC4AP) complex specifically recognizes proteins with an arginine at the minus 3 position (R-3 motif) at the C-terminus, such as MYC, leading to their ubiquitination and degradation (PubMed:29779948). Also participates in the activation of NFKB1 in response to ligation of TNFRSF1A, possibly by linking TNFRSF1A to the IKK signalosome (By similarity). Involved in JNK activation via its interaction with TRAF2 (By similarity). Also involved in elevation of endoplasmic reticulum Ca(2+) storage reduction in response to CHRM1 (By similarity).
Ubiquitinated by a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase containing SKP2, leading to its degradation (PubMed:26038816). Phosphorylation by GSK3B is required for ubiquitination (PubMed:26038816).
Downstream effector molecule for Rab11 GTPase which acts as a regulator of endocytic trafficking and intracellular ciliogenesis by participating in membrane delivery (PubMed:16148947, PubMed:15601896, PubMed:17628206, PubMed:17394487, PubMed:18511905, PubMed:19327867, PubMed:20026645, PubMed:25673879, PubMed:26258637, PubMed:31204173). Recruited by Rab11 to endosomes where it links Rab11 to dynein motor complex (PubMed:20026645). The functional Rab11-RAB11FIP3-dynein complex then regulates the movement of peripheral sorting endosomes (SE) along microtubule tracks toward the microtubule organizing center/centrosome, generating the endocytic recycling compartment (ERC) during interphase of cell cycle (PubMed:17394487, PubMed:20026645). Facilitates the interaction between dynein and dynactin and activates dynein processivity (PubMed:25035494). Binding with ASAP1 is also needed to regulates the pericentrosomal localization of recycling endosomes (By similarity). The Rab11-RAB11FIP3 complex is also implicated in the transport and fusion of vesicles derived from recycling endosomes to the cleavage furrow during late cytokinesis and abscission (PubMed:16148947, PubMed:15601896). Also regulates cleavage furrow ingression and abscission together with RACGAP1 (PubMed:18511905). Required for ARF6 recruitment to the cleavage furrow during cytokinesis (PubMed:17628206). Involved in the Rab11-Rabin8-Rab8 ciliogenesis cascade by facilitating the orderly assembly of a ciliary targeting complex containing Rab11, ASAP1, Rabin8/RAB3IP, RAB11FIP3 and ARF4, which direct preciliary vesicle trafficking to mother centriole and ciliogenesis initiation (PubMed:26258637, PubMed:31204173). Also promotes the activity of Rab11 and ASAP1 in the ARF4-dependent Golgi-to-cilia transport of the sensory receptor rhodopsin (PubMed:25673879). Competes with WDR44 for binding to Rab11, which controls intracellular ciliogenesis pathway (PubMed:31204173). May play a role in breast cancer cell motility by regulating actin cytoskeleton (PubMed:19327867).
Homodimer (PubMed:17007872, PubMed:17030804). Interacts with RAB11A; the interaction is direct and is required for the recruitment to endosomes (PubMed:11495908, PubMed:15601896, PubMed:17229837, PubMed:31204173, PubMed:17030804). Interacts with RAB11B (PubMed:11495908). Forms a ternary complex with RAB11A and dynein intermediate chain DYNC1LI1; RAB11FIP3 links RAB11A to dynein and the interaction regulates endocytic trafficking (PubMed:20026645). Interacts with dynein intermediate chain and dynactin (DCTN1); the interaction activates dynein processivity (PubMed:25035494). Forms a complex with Rab11 (RAB11A or RAB11B) and ARF6 (PubMed:16148947, PubMed:17628206, PubMed:17030804). Interacts with RACGAP1/MgcRacGAP; interaction takes place during late stage of cytokinesis and is required for recruitment to the midbody (PubMed:18511905). Forms a complex with RAB11A and Rabin8/RAB3IP, probably a heterohexamer with two of each protein subunit, where RAB3IP and RAB11FIP3 simultaneously bind to RAB11A; the complex promotes preciliary trafficking (PubMed:26258637, PubMed:31204173). Forms a complex containing RAB11A, ASAP1, RAB3IP, RAP11FIP3 and ARF4; the complex promotes preciliary trafficking; the complex binds to RHO in photoreceptor cells and promotes RHO ciliary transport (PubMed:25673879, PubMed:26258637). Interacts with EXOC7 (PubMed:16148947). Interacts with RAB11FIP4 (PubMed:12470645). Interacts with RAB25 (PubMed:11495908).
Phosphorylated at Ser-102 by CDK1 during metaphase, and dephosphorylated as cells enter telophase.
Was initially shown not to interact with ARF5 (PubMed:16148947). Another study later demonstrated the interaction (PubMed:17030804).
Catalyzes the phosphorylation of hexose, such as D-glucose and D-fructose, to hexose 6-phosphate (D-glucose 6-phosphate and D-fructose 6-phosphate, respectively) (PubMed:8717435). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (PubMed:8717435).
Hexokinase is an allosteric enzyme inhibited by its product D-glucose 6-phosphate.
The N- and C-terminal halves of this hexokinase contain a hexokinase domain. The catalytic activity is associated with the C-terminus while regulatory function is associated with the N-terminus.
May control cell-cell adhesion, cell migration and proliferation, cell morphology, and protects renal epithelial cells from oxidative cell injury to promote cell survival.
Belongs to the universal ribosomal protein uS14 family.
Component of the mitochondrial small ribosomal subunit (mt-SSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (PubMed:25838379). Interacts with LIAT1 (By similarity).
Expressed in all tissues examined, with highest expression in heart, skeletal muscle and pancreas.
May act as a repressor of NR2C2-mediated transactivation by suppressing the binding between NR2C2/TR4 and the TR4-response element in target genes.
Interacts with HSP90B1; this interaction is disrupted in the presence of ATP. Interacts with TLR1, TLR2, TLR4 and TLR9 (By similarity). Strongest interaction with TLR4 (By similarity).
Toll-like receptor (TLR)-specific co-chaperone for HSP90B1. Required for proper TLR folding, except that of TLR3, and hence controls TLR exit from the endoplasmic reticulum. Consequently, required for both innate and adaptive immune responses (By similarity).
E3 ubiquitin-protein and E3 SUMO-protein ligase that acts as a regulator of innate immunity (PubMed:23056470). Acts as a negative regulator of type I interferon IFN-beta production by catalyzing 'Lys-48'-linked polyubiquitination of AZI2/NAP1, leading to its degradation (By similarity). Mediates 'Lys-48'-linked polyubiquitination and proteasomal degradation of the critical TLR adapter TICAM1, inhibiting TLR3-mediated type I interferon signaling (PubMed:23056470). Acts as positive regulator of the cGAS-STING pathway by acting as a E3 SUMO-protein ligase: mediates sumoylation of CGAS and STING, preventing their degradation and thereby activating the innate immune response to DNA virus (By similarity). Also acts as a negative regulator of NF-kappa-B signaling independently of its E3 protein ligase activity by promoting lysosome-dependent degradation of TAB2 and TAB3 adapters (PubMed:24434549).
Interacts (via B30.2/SPRY domain) with TAB2 and TAB3.
Catalyzes the first committed step in the biosynthesis of complex N-glycans. It controls conversion of high mannose to complex N-glycans; the final hydrolytic step in the N-glycan maturation pathway.
Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers. Required for cytokinesis, stress fiber formation and transcriptional activation of the serum response factor. Binds to GTP-bound form of Rho and to profilin: acts in a Rho-dependent manner to recruit profilin to the membrane, where it promotes actin polymerization. DFR proteins couple Rho and Src tyrosine kinase during signaling and the regulation of actin dynamics. Also acts as an actin nucleation and elongation factor in the nucleus by promoting nuclear actin polymerization inside the nucleus to drive serum-dependent SRF-MRTFA activity.
Increased expression in S phase and mitotic cells; levels decrease as cells enter in G0/G1 phase due to proteasomal degradation (at protein level).
The DAD domain regulates activation via by an autoinhibitory interaction with the GBD/FH3 domain. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments.
The disease is caused by variants affecting the gene represented in this entry. A disease-causing mutation in the conserved 5'-UTR leads to increased protein expression.
Inhibited by pembrolizumab (also named MK-3475 or lambrolizumab), a monoclonal antibody that prevents the interaction with CD274/PDCD1L1 (PubMed:27734966, PubMed:27325296). Inhibited by nivolumab (also named ONO-4538, BMS-936558 or Opdivo), a monoclonal antibody that prevents the interaction with CD274/PDCD1L1 (PubMed:28165004). The interaction with nivolumab is not dependent on glycosylation and depends on a loop at the N-terminus (N-terminal loop, corresponding to residues 25-34) (PubMed:28165004). Targeting the interaction between PDCD1 and CD274/PDCD1L1 with pembrolizumab and nivolumab antibodies has demonstrated great promise as a strategy for controlling and eradicating cancer (PubMed:22658127, PubMed:25034862, PubMed:25399552). Pembrolizumab and nivolumab are used for treatment of patients with advanced melanoma (PubMed:25034862, PubMed:25399552). These antibodies are also effective against other cancers, such as non-small cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin's lymphoma (PubMed:25034862).
Inhibitory receptor on antigen activated T-cells that plays a critical role in induction and maintenance of immune tolerance to self (PubMed:21276005). Delivers inhibitory signals upon binding to ligands CD274/PDCD1L1 and CD273/PDCD1LG2 (PubMed:21276005). Following T-cell receptor (TCR) engagement, PDCD1 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation (By similarity). Suppresses T-cell activation through the recruitment of PTPN11/SHP-2: following ligand-binding, PDCD1 is phosphorylated within the ITSM motif, leading to the recruitment of the protein tyrosine phosphatase PTPN11/SHP-2 that mediates dephosphorylation of key TCR proximal signaling molecules, such as ZAP70, PRKCQ/PKCtheta and CD247/CD3zeta (By similarity).
Monomer (PubMed:26602187). Interacts with CD274/PDCD1L1 (PubMed:26602187). Interacts with CD273/PDCD1LG2 (By similarity). Interacts with FBXO38; leading to ubiquitination and degradation of PDCD1 by the proteasome (PubMed:30487606).
N-glycosylation at Asn-58 contains at least two N-acetylglucosamine units and one fucose (PubMed:28165004). N-glycosylation does not affect binding to nivolumab drug (PubMed:28165004).
The PDCD1-mediated inhibitory pathway is exploited by tumors to attenuate anti-tumor immunity and escape destruction by the immune system, thereby facilitating tumor survival (PubMed:28951311). The interaction with CD274/PDCD1L1 inhibits cytotoxic T lymphocytes (CTLs) effector function (PubMed:28951311). The blockage of the PDCD1-mediated pathway results in the reversal of the exhausted T-cell phenotype and the normalization of the anti-tumor response, providing a rationale for cancer immunotherapy (PubMed:22658127, PubMed:25034862, PubMed:25399552).
Tyrosine phosphorylated at Tyr-223 (within ITIM motif) and Tyr-248 (ITSM motif) upon ligand binding. Phosphorylation at Tyr-248 promotes the recruitment of the protein tyrosine phosphatase PTPN11/SHP-2 that mediates dephosphorylation of key TCR proximal signaling molecules, such as ZAP70, PRKCQ/PKCtheta and CD247/CD3zeta.
Ubiquitinated at Lys-233 by the SCF(FBXO38) complex, leading to its proteasomal degradation (PubMed:30487606). Ubiquitinated via 'Lys-48'-linked polyubiquitin chains (PubMed:30487606).
Homodimer (PubMed:29097656, PubMed:31101807). Component of the mitochondrial core iron-sulfur cluster (ISC) complex composed of NFS1, LYRM4, NDUFAB1, ISCU, FXN, and FDX2; this complex is an heterohexamer containing two copies of each monomer (Probable). Component of the cyteine desulfurase complex composed of NFS1, LYRM4 and NDUFAB1; this complex contributes to the stability and cysteine desulfurase activity of NFS1 (PubMed:34824239, PubMed:31664822). Interacts with FXN; this interaction is nickel-dependent (PubMed:17331979). Forms a complex with the cytoplasmic form of NFS1; this complex increases the stability and cysteine desulfurase activity of NFS1 (PubMed:18650437, PubMed:19454487). Interacts with NFS1 (PubMed:29097656). Component of a complex composed of FXN, NFS1, LYRM4 and ISCU (By similarity).
Reduced mRNA levels in Friedreich ataxia patients.
Stabilizing factor, of the core iron-sulfur cluster (ISC) assembly complex, that regulates, in association with NDUFAB1, the stability and the cysteine desulfurase activity of NFS1 and participates in the [2Fe-2S] clusters assembly on the scaffolding protein ISCU (PubMed:31664822, PubMed:17331979). The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis. This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the scaffold protein ISCU in a FXN-dependent manner. Then this complex is stabilized by FDX2 which provides reducing equivalents to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and GLRX5 (By similarity). May also participates in the iron-sulfur protein biogenesis in the cytoplasm through its interaction with the cytoplasmic form of NFS1 (PubMed:19454487).
Belongs to the peptidase C69 family. Secernin subfamily.
Acetylated in erythroid cells by CREB-binding protein (CBP). Acetylation augments the DNA-binding activity of NFE2, but has no effect on binding NFE2.
Highly expressed in skeletal muscle. Also expressed in heart and brain.
Homodimer or heterodimer. Homodimerization leads to transcriptional repression. Forms high affinity heterodimers with members of the CNC-bZIP family such as NFE2, NFE2L1/NRF1, NFE2L2/NRF2 and NFE2L3/NRF3 (PubMed:8932385, PubMed:9421508, PubMed:11154691). Interacts with CREBBP; the interaction leads to acetylation of the basic region of MAFG and stimulation of NFE2 transcriptional activity through increased DNA binding.
Since they lack a putative transactivation domain, the small Mafs behave as transcriptional repressors when they dimerize among themselves (PubMed:11154691). However, they seem to serve as transcriptional activators by dimerizing with other (usually larger) basic-zipper proteins, such as NFE2, NFE2L1 and NFE2L2, and recruiting them to specific DNA-binding sites (PubMed:8932385, PubMed:9421508, PubMed:11154691). Small Maf proteins heterodimerize with Fos and may act as competitive repressors of the NFE2L2 transcription factor (PubMed:11154691). Transcription factor, component of erythroid-specific transcription factor NFE2L2 (PubMed:11154691). Activates globin gene expression when associated with NFE2L2 (PubMed:11154691). May be involved in signal transduction of extracellular H(+) (By similarity).
Sumoylation at Lys-14 is required for active transcriptional repression.
Essential for embryonic kidney development. Plays an important role in the compact adhesion between mesenchymal cells adjacent to the ureteric buds, possibly by interacting with MYH10. This could lead to the establishment of the basolateral integrity of the mesenchyme and the polarized expression of ITGA8, which maintains the GDNF expression required for further ureteric bud attraction. Although it seems to lack ATPase activity it is constitutively associated with microtubules (By similarity).
Phosphorylation at Thr-1855 and Ser-1958 by CDKs, mainly CDK2 and CDK5, enhances the interaction with NEDD4, polyubiquitination, and subsequent proteasomal degradation. Phosphorylation occurs upon loss of interaction with microtubules (By similarity).
Polyubiquitinated by NEDD4, resulting in proteasomal degradation.
Plays a role in primary ciliogenesis by modulating actin polymerization.
Strongly expressed in round and elongating spermatids, weakly in pachytene spermatocytes. Expressed in Leydig cells (at protein level). Expressed in testis, placenta, prostate and lung, and moderately in ovary and brain.
Expressed in lung and pancreas (at protein level).
Expressed in lung, pancreas and spleen (at protein level).
Expressed in spleen, pancreas and placenta (at protein level).
Forms heterodimers either with the pro-apoptotic protein BAX or the anti-apoptotic protein BCL2 (By similarity). Interacts with PLEKHN1 (PubMed:29531808).
Forms heterodimers either with the pro-apoptotic protein BAX or the anti-apoptotic protein BCL2.
Induces ICE-like proteases and apoptosis.
Induces caspase activation and apoptosis (PubMed:15661737, PubMed:32029622). Allows the release of cytochrome c (PubMed:32029622).
Induces caspases and apoptosis (PubMed:14583606). Counters the protective effect of BCL2 (By similarity).
Induces caspases and apoptosis. Counters the protective effect of BCL2.
Interacts with ITCH (PubMed:20392206). Interacts with humanin; the interaction prevents BID-induced apoptosis (PubMed:15661737). Interacts with MTCH2 (By similarity).
Interacts with humanin; forms fibers with humanin which results in BID conformational changes and sequestering of BID into the fibers, preventing BID activation.
TNF-alpha induces caspase-mediated cleavage into a major p15 and minor p13 and p11 products (By similarity). Cleaved by CASP6 into a major p15 and minor p13 products, leading to release of cytochrome c and subsequent nonalcoholic steatohepatitis (PubMed:32029622).
Ubiquitinated by ITCH; ubiquitination results in proteasome-dependent degradation.
Catalyzes the second step in the biosynthesis of coenzyme A from vitamin B5, where cysteine is conjugated to 4'-phosphopantothenate to form 4-phosphopantothenoylcysteine (PubMed:11923312, PubMed:12906824, PubMed:29754768). Has a preference for ATP over CTP as a cosubstrate (PubMed:11923312).
(Microbial infection) Interacts with HIV-1 Nef protein.
(Microbial infection) Interacts with M.tuberculosis PtpA, which blocks V-ATPase trafficking and phagosome acidification.
Belongs to the V-ATPase H subunit family.
Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:33065002). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (By similarity). Subunit H is essential for V-ATPase activity, but not for the assembly of the complex (By similarity). Involved in the endocytosis mediated by clathrin-coated pits, required for the formation of endosomes (PubMed:12032142).
Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments.
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex (PubMed:33065002). The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H (PubMed:33065002). The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR (PubMed:33065002). Interacts with AP2M1 (PubMed:12032142). Interacts with TM9SF4 in colon cancer cells (PubMed:25659576).
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex.
(Microbial infection) Interacts (via TPR repeat 2) with E1 proteins of HPV types 11, 18 and 3; this interaction blocks E1 helicase activity and viral replication.
By type I interferons, dsRNAs and viruses.
Component of an interferon-dependent multiprotein complex, at least composed of IFIT1, IFIT2 and IFIT3. Interacts (via TPR repeats 4-7) with EEF1A1 (By similarity). Interacts with EIF3C (By similarity). Interacts with IFIT2 and IFIT3. Interacts (via TPR repeats 1-4) with RPL15. Interacts with STING1/MITA and disrupts its interaction with MAVS or TBK1. Interacts with EIF3E.
Interferon-induced antiviral RNA-binding protein that specifically binds single-stranded RNA bearing a 5'-triphosphate group (PPP-RNA), thereby acting as a sensor of viral single-stranded RNAs and inhibiting expression of viral messenger RNAs. Single-stranded PPP-RNAs, which lack 2'-O-methylation of the 5' cap and bear a 5'-triphosphate group instead, are specific from viruses, providing a molecular signature to distinguish between self and non-self mRNAs by the host during viral infection. Directly binds PPP-RNA in a non-sequence-specific manner. Viruses evolved several ways to evade this restriction system such as encoding their own 2'-O-methylase for their mRNAs or by stealing host cap containing the 2'-O-methylation (cap snatching mechanism). Exhibits antiviral activity against several viruses including human papilloma and hepatitis C viruses.
RNA recognition is mediated by a convoluted intramolecular fold of the TPR repeats (TPR eddy), which scaffolds unique additional helices that form an RNA binding cleft.
Component of the lateral elements of synaptonemal complexes (By similarity). Homotetramer; the tetrameric helix bundles assemble end to end into long homopolimeric fibers that exhibit a transversal striation with a periodicity of about 20 nm (in vitro) (PubMed:24950965). Interacts with SYCP2 (By similarity). Forms a complex with EWSR1, PRDM9, REC8 and SYCP1; complex formation is dependent of phosphorylated form of REC8 and requires PRDM9 bound to hotspot DNA; EWSR1 joins PRDM9 with the chromosomal axis through REC8 (By similarity).
Component of the synaptonemal complexes (SCS), formed between homologous chromosomes during meiotic prophase. Required for centromere pairing during meiosis in male germ cells (By similarity). Required for normal meiosis during spermatogenesis and male fertility (PubMed:14643120). Plays a lesser role in female fertility. Required for efficient phosphorylation of HORMAD1 and HORMAD2 (By similarity).
Composed of a long central coiled coil domain. The N-terminal and C-terminal regions interact with DNA.
B-lymphocyte-specific membrane protein that plays a role in the regulation of cellular calcium influx necessary for the development, differentiation, and activation of B-lymphocytes (PubMed:3925015, PubMed:7684739, PubMed:12920111). Functions as a store-operated calcium (SOC) channel component promoting calcium influx after activation by the B-cell receptor/BCR (PubMed:7684739, PubMed:12920111, PubMed:18474602).
Epitope 1, mapped in PubMed:16785532, is predicted to be buried in the membrane. Its accessibility to the extracellular space, and thus to antibody recognition, is not explained.
Forms homotetramers (PubMed:7684739, PubMed:18474602). Interacts with the heavy and light chains of cell surface IgM, the antigen-binding components of the BCR (PubMed:18474602).
Monoclonal antibodies (mAb) against CD20 are used to treat B-cell non-Hodgkin lymphoma (NHL). These antibodies include Rituximab (Mabthera), Britumomab (Zevalin) and Tositumomab (Bexxar). CD20 engaged by mAb can generate transmembrane signals capable of directly controlling cell growth and triggering cell death in certain tumors. Alternatively, mAb can mediate complement-dependent cytotoxicity.
Phosphorylated on serines and threonines in resting B-cells. Protein kinase C/PKC can use CD20 as substrate.
May play a role in the molecular organization of synapses and neuronal cell signaling. Could be an adapter protein linking ion channel to the subsynaptic cytoskeleton. May induce enrichment of PSD-95/SAP90 at the plasma membrane.
Microtubule-associated force-producing protein involved in producing microtubule bundles and able to bind and hydrolyze GTP. Most probably involved in vesicular trafficking processes, in particular endocytosis (By similarity).
Can bind directly to TATA-box binding protein (TBP). Interacts (via bromo domains) with acetylated lysine residues on the N-terminus of histone H1.4, H2A, H2B, H3 and H4 (in vitro).
May act as a functional substitute for TAF1/TAFII250 during male meiosis, when sex chromosomes are transcriptionally silenced.
Testis specific, expressed apparently in germ cells.
Expressed predominantly in the striatum.
Probable G-protein coupled receptor implicated in a large repertoire of behavioral responses that engage motor activities, spatial learning, and emotional processing. May play a role in the regulation of cognitive and motor function.
Interacts with CTNND1 (PubMed:22846708). Interacts with ITGB5 (via cytoplasmic domain) and ROCK1 (PubMed:25448675).
May be involved in regulation of cell migration (PubMed:22846708, PubMed:25448675). May regulate cell-matrix interactions via its interaction with ITGB5 and modifying ITGB5 cytoplasmic tail interactions such as with FERMT2 and TLN1. May regulate ROCK1 kinase activity possibly involved in regulation of actin stress fiber formation (PubMed:25448675).
Atypical tyrosine-protein kinase that plays a central role in chromatin remodeling and acts as a transcription regulator (PubMed:19092802). Involved in DNA damage response by phosphorylating 'Tyr-142' of histone H2AX (H2AXY142ph) (PubMed:19092802, PubMed:19234442). H2AXY142ph plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress (PubMed:19092802, PubMed:19234442). Regulatory subunit of the ATP-dependent WICH-1 and WICH-5 ISWI chromatin remodeling complexes, which form ordered nucleosome arrays on chromatin and facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair (PubMed:11980720, PubMed:28801535). Both complexes regulate the spacing of nucleosomes along the chromatin and have the ability to slide mononucleosomes to the center of a DNA template (PubMed:28801535). The WICH-1 ISWI chromatin remodeling complex has a lower ATP hydrolysis rate than the WICH-5 ISWI chromatin remodeling complex (PubMed:28801535). The WICH-5 ISWI chromatin-remodeling complex regulates the transcription of various genes, has a role in RNA polymerase I transcription (By similarity). Within the B-WICH complex has a role in RNA polymerase III transcription (PubMed:16603771). Mediates the recruitment of the WICH-5 ISWI chromatin remodeling complex to replication foci during DNA replication (PubMed:15543136).
BAZ1B is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of BAZ1B may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.
Belongs to the WAL family. BAZ1B subfamily.
Component of the WICH-1 ISWI chromatin remodeling complex, at least composed of SMARCA1 and BAZ1B/WSTF, which regulates the spacing of histone octamers on the DNA template to facilitate access to DNA (PubMed:28801535). Within the WICH-1 ISWI chromatin remodeling complex interacts with SMARCA1; the interaction is direct (PubMed:28801535). Component of the WICH-5 ISWI chromatin remodeling complex (also called the WICH complex), at least composed of SMARCA5/SNF2H and BAZ1B/WSTF, which regulates the spacing of histone octamers on the DNA template to facilitate access to DNA (PubMed:11980720, PubMed:28801535). Within the WICH-5 ISWI chromatin remodeling complex interacts with SMARCA5/SNF2H; the interaction is direct (PubMed:11980720, PubMed:15543136, PubMed:28801535). Component of the B-WICH chromatin remodeling complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21 (PubMed:16603771). Within the B-WICH chromatin remodeling complex, interacts with SMARCA5/SNF2H, DDX21, DEK, MYBBP1A, SF3B1, ERCC6 and MYO1C (PubMed:16603771). Interacts with PCNA; the interaction is direct and is required for BAZ1B/WSTF binding to replication foci during S phase (PubMed:15543136). Interacts with CDT1 (PubMed:18162579).
Expressed at equal levels in 19-23 weeks old fetal tissues.
Ubiquitously expressed with high levels of expression in heart, brain, placenta, skeletal muscle and ovary.
Was shown to interact with VDR and with acetylated histones via its Bromo domain, but this work has later been retracted.
Candidate gene for the Cat Eye Syndrome (CES), a developmental disorder associated with the duplication of a 2 Mb region of 22q11.2. Duplication usually takes in the form of a surpernumerary bisatellited isodicentric chromosome, resulting in four copies of the region (represents an inv dup(22)(q11)). CES is characterized clinically by the combination of coloboma of the iris and anal atresia with fistula, downslanting palpebral fissures, preauricular tags and/or pits, frequent occurrence of heart and renal malformations, and normal or near-normal mental development.
Belongs to the grh/CP2 family. CP2 subfamily.
Binds a variety of cellular and viral promoters including fibrinogen, alpha-globin, SV40 and HIV-1 promoters. Activation of the alpha-globin promoter in erythroid cells is via synergistic interaction with UBP1 (By similarity). Functions as part of the SSP (stage selector protein) complex. Facilitates the interaction of the gamma-globin genes with enhancer elements contained in the locus control region in fetal erythroid cells. Interacts by binding to the stage selector element (SSE) in the proximal gamma-globin promoter.
Binds to DNA as a dimer, isoform 3 does not bind to DNA or affect the binding of isoform 1 to DNA. Interacts with UBP1 and PIAS1, and is probably part of a complex containing TFCP2, UBP1 and PIAS1 (By similarity). Component of the SSP (stage selector protein) complex, which appears to be a heteromer of TFCP2 and 2 copies of NFE4.
In PubMed:8114710 authors noted that a 10-fold molar excess of isoform 3 over isoform 1 inhibited DNA-binding.
Ubiquitous. Expressed in brain, ovary, kidney, thymus, spleen, liver, adrenal, heart and lung (at protein level).
A chromosomal aberration involving PICALM is found in diffuse histiocytic lymphomas. Translocation t(10;11)(p13;q14) with MLLT10.
Binds to clathrin; involves primarily the C-terminal sequences, but the full-length protein is required for full binding capacity. Binds phosphatidylinositol 4,5- bisphosphate. Interacts with PIMREG; this interaction may change the subcellular location into the nucleus (PubMed:16491119). Interacts with AP2A1 (via its alpha-appendage domain) (PubMed:16262731). Interacts (via N-terminus) with VAMP2; VAMP3; VAMP7 and VAMP8 (Via N-terminus) (PubMed:22118466, PubMed:21808019, PubMed:23741335). Interacts with LC3/MAP1LC3A (PubMed:24067654).
Cytoplasmic adapter protein that plays a critical role in clathrin-mediated endocytosis which is important in processes such as internalization of cell receptors, synaptic transmission or removal of apoptotic cells. Recruits AP-2 and attaches clathrin triskelions to the cytoplasmic side of plasma membrane leading to clathrin-coated vesicles (CCVs) assembly (PubMed:10436022, PubMed:16262731, PubMed:27574975). Furthermore, regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature (PubMed:25898166). In addition to binding to clathrin, mediates the endocytosis of small R-SNARES (Soluble NSF Attachment Protein REceptors) between plasma membranes and endosomes including VAMP2, VAMP3, VAMP4, VAMP7 or VAMP8 (PubMed:22118466, PubMed:21808019, PubMed:23741335). In turn, PICALM-dependent SNARE endocytosis is required for the formation and maturation of autophagic precursors (PubMed:25241929). Modulates thereby autophagy and the turnover of autophagy substrates such as MAPT/TAU or amyloid precursor protein cleaved C-terminal fragment (APP-CTF) (PubMed:25241929, PubMed:24067654).
Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Functions in FASLG, ITM2B and TNF processing (PubMed:16829952, PubMed:16829951, PubMed:17557115, PubMed:17965014). Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF-alpha (TNF), which promotes the release of the intracellular domain (ICD) for signaling to the nucleus (PubMed:16829952). Also responsible for the intramembrane cleavage of Fas antigen ligand FASLG, which promotes the release of the intracellular FasL domain (FasL ICD) (PubMed:17557115). Essential for degradation of the invariant chain CD74 that plays a central role in the function of antigen-presenting cells in the immune system (By similarity). Plays a role in the regulation of innate and adaptive immunity (PubMed:16829952). Catalyzes the intramembrane cleavage of the simian foamy virus envelope glycoprotein gp130 independently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis (PubMed:23132852).
The PAL motif is required for normal active site conformation. The catalytic domains embedded in the membrane are in the opposite orientation to that of the presenilin protein family; therefore, it is predicted to cleave type II-oriented substrate peptides like the prototypic protease SPP. The C-terminal tail is necessary for lysosomal transport.
Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD. Interacts with PPP2CB (By similarity). Part of a supercomplex made of cofactors A to E. Cofactors A and D function by capturing and stabilizing tubulin in a quasi-native conformation. Cofactor E binds to the cofactor D-tubulin complex; interaction with cofactor C then causes the release of tubulin polypeptides that are committed to the native state (PubMed:10831612). Interacts with ARL2; interaction is enhanced with the GDP-bound form of ARL2 (PubMed:10831612, PubMed:27666374). Does not interact with ARL3, ARL4A and ARL4D (PubMed:10831612). Interacts with beta tubulin (PubMed:10831612, PubMed:27666370, PubMed:27666374). Interacts with TBCE (PubMed:27666374).
Tubulin-folding protein implicated in the first step of the tubulin folding pathway and required for tubulin complex assembly. Involved in the regulation of microtubule polymerization or depolymerization, it modulates microtubule dynamics by capturing GTP-bound beta-tubulin (TUBB). Its ability to interact with beta tubulin is regulated via its interaction with ARL2. Acts as a GTPase-activating protein (GAP) for ARL2. Induces microtubule disruption in absence of ARL2. Increases degradation of beta tubulin, when overexpressed in polarized cells. Promotes epithelial cell detachment, a process antagonized by ARL2. Induces tight adherens and tight junctions disassembly at the lateral cell membrane (PubMed:10722852, PubMed:10831612, PubMed:11847227, PubMed:20740604, PubMed:27666370, PubMed:28158450). Required for correct assembly and maintenance of the mitotic spindle, and proper progression of mitosis (PubMed:27666370). Involved in neuron morphogenesis (PubMed:27666374).
A cytochrome P450 monooxygenase with a key role in vitamin D catabolism and calcium homeostasis. Via C24- and C23-oxidation pathways, catalyzes the inactivation of both the vitamin D precursor calcidiol (25-hydroxyvitamin D(3)) and the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:24893882, PubMed:15574355, PubMed:8679605, PubMed:11012668, PubMed:16617161, PubMed:29461981). With initial hydroxylation at C-24 (via C24-oxidation pathway), performs a sequential 6-step oxidation of calcitriol leading to the formation of the biliary metabolite calcitroic acid (PubMed:24893882, PubMed:15574355). With initial hydroxylation at C-23 (via C23-oxidation pathway), catalyzes sequential oxidation of calcidiol leading to the formation of 25(OH)D3-26,23-lactone as end product (PubMed:11012668, PubMed:8679605). Preferentially hydroxylates at C-25 other vitamin D active metabolites, such as CYP11A1-derived secosteroids 20S-hydroxycholecalciferol and 20S,23-dihydroxycholecalciferol (PubMed:25727742). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via FDXR/adrenodoxin reductase and FDX1/adrenodoxin (PubMed:8679605).
Specifically expressed in macrophages. Lacks the transit peptide. May be a dominant negative-acting isoform possibly by sequestering vitamin D metabolites.
By TNF and IL1B/interleukin-1 beta in adipose tissue. Up-regulated by androgens, including testosterone and dihydrotestosterone (DHT).
Can also utilize FMN (PubMed:30337524). Can also utilize riboflavin.
Homotrimer (PubMed:30337524). Interacts with PTK2/FAK1; the interaction may regulate PTK2 phosphorylation.
Integral membrane protein that functions as NADPH-dependent ferric-chelate reductase, using NADPH from one side of the membrane to reduce a Fe(3+) chelate that is bound on the other side of the membrane. Mediates sequential transmembrane electron transfer from NADPH to FAD and onto heme, and finally to the Fe(3+) chelate (PubMed:30337524). Can also reduce Cu(2+) to Cu(1+) (By similarity). Plays a role in systemic metabolic homeostasis, integrating inflammatory and metabolic responses (By similarity). Associated with obesity and insulin-resistance (PubMed:18430367, PubMed:18381574). Involved in inflammatory arthritis, through the regulation of inflammatory cytokines (PubMed:19660107). Inhibits anchorage-independent cell proliferation (PubMed:19787193).
Ubiquitous. Highly expressed in adipose tissue. Expressed in placenta, lung, heart and prostate. Detected at lower levels in liver, skeletal muscle, pancreas, testis and small intestine. Highly expressed in joints of patients with rheumatoid arthritis and localized with CD68 cells, a marker for macrophages.
Belongs to the purine nucleoside phosphorylase YfiH/LACC1 family.
Interacts with FASN (PubMed:27478939). Interacts with SDHA (PubMed:28593945). Interacts with ATF6, EIF2AK3 and ERN1 (PubMed:31875558).
Purine nucleoside enzyme that catalyzes the phosphorolysis of adenosine, guanosine and inosine nucleosides, yielding D-ribose 1-phosphate and the respective free bases, adenine, guanine and hypoxanthine (PubMed:31978345). Also catalyzes the phosphorolysis of S-methyl-5'-thioadenosine into adenine and S-methyl-5-thio-alpha-D-ribose 1-phosphate (PubMed:31978345). Also has adenosine deaminase activity (PubMed:31978345). Acts as a regulator of innate immunity in macrophages by modulating the purine nucleotide metabolism, thereby regulating the metabolic function and bioenergetic state of macrophages (PubMed:31978345). Enables a purine nucleotide cycle between adenosine and inosine monophosphate and adenylosuccinate that prevents cytoplasmic acidification and balances the cytoplasmic-mitochondrial redox interface (PubMed:31978345). The purine nucleotide cycle consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity (PubMed:31978345). Participates in pattern recognition receptor (PRR)-induced cytokines in macrophages: associates with the NOD2-signaling complex and promotes optimal NOD2-induced signaling, cytokine secretion and bacterial clearance (PubMed:28593945, PubMed:31875558). Localizes to the endoplasmic reticulum upon PRR stimulation of macrophages and associates with endoplasmic reticulum-stress sensors, promoting the endoplasmic reticulum unfolded protein response (UPR) (PubMed:31875558). Does not show laccase activity (PubMed:27959965, PubMed:31978345).
Ubiquitously expressed, with higher expression levels in immune-related tissues such as lymph nodes and spleen (PubMed:27959965). Expressed in both intestinal and peripheral myeloid-derived cells (PubMed:28593945).
Up-regulated by phorbol 12-myristate 13-acetate (PMA) (PubMed:27959965). Down-regulated by PPAR ligands (PubMed:27959965). Up-regulated upon pattern recognition receptor (PRR) stimulation (PubMed:28593945).
Heterodimer (By similarity). Interacts with the BAF multiprotein chromatin-remodeling complex subunits SMARCB1 and SMARCD1 (By similarity). Interacts with ARID1A and JUN (By similarity).
Expressed at high levels in normal urothelial and breast epithelial cells. Also expressed in the smooth muscle and endothelial cells. Reduced expression seen in advanced bladder and breast carcinomas (at protein level). Ubiquitous. Expressed at highest levels in the heart, skeletal muscle, kidney, liver and testis.
Interacts specifically with keratin proteins including, KRT5, KRT6A, KRT8, KRT14, KRT16 and KRT18 (PubMed:15731013). Interacts with KCTD17 (PubMed:25270598).
Tumor suppressor which has the ability to inhibit cell growth and be pro-apoptotic during cell stress. Inhibits cell growth in bladder and prostate cancer cells by a down-regulation of HSPB1 by inhibiting its phosphorylation. May act as a 'capping' or 'branching' protein for keratin filaments in the cell periphery. May regulate K8/K18 filament and desmosome organization mainly at the apical or peripheral regions of simple epithelial cells (PubMed:15731013, PubMed:18931701). Is a negative regulator of ciliogenesis (PubMed:25270598).
Ubiquitinated. Ubiquitination by the BCR(KCTD17) E3 ubiquitin ligase complex results in proteasomal degradation, and induces ciliogenesis.
Down-regulated by bacterial lipopolysaccharide (LPS) in monocytes and dendritic cells.
Expressed in monocytes and dendritic cells.
Interacts with components of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), such as UQCRC1/QCR1, UQCRC2/QCR2 and UQCR10/QCR9 (By similarity). Interacts with components of the cytochrome c oxidase (mitochondrial respiratory chain complex IV) complex, such as MT-CO2 (PubMed:35450818).
Microprotein involved in mitochondrial respiratory chain complex III (ubiquinol-cytochrome c oxidoreductase) and complex IV (mitochondrial cytochrome c oxidase complex) assembly (PubMed:35450818). Required for the formation of mitochondrial supercomplexes (SCs) (PubMed:35450818). Also required for the activation of the NLRP3 inflammasome (By similarity).
Selectively catalyzes the oxidative deamination of D-aspartate and its N-methylated derivative, N-methyl D-aspartate.
Component of a receptor complex composed of IL6ST/GP130, IL27RA/WSX1 and CNTFR which interacts with the neuroprotective peptide humanin.
Highly expressed in lymphoid tissues such as spleen, lymph nodes and peripheral blood leukocytes. Weakly expressed in other tissues examined including heart, brain, fetal and adult lung, liver, skeletal muscle, kidney, pancreas, prostate, testis, ovary, small intestine, kidney and colon. In the lymphoid system, higher level expression in CD4+ T-cell subsets than in CD8+ T-cell subsets. Also weaker expression in CD19+ B-cells and monocytes.
Receptor for IL27. Requires IL6ST/GP130 to mediate signal transduction in response to IL27. This signaling system acts through STAT3 and STAT1. Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL6ST/GP130 and CNTFR (PubMed:19386761). Involved in the regulation of Th1-type immune responses. Also appears to be involved in innate defense mechanisms.
Component of an interferon-dependent multiprotein complex, at least composed of IFIT1, IFIT2 and IFIT3 (PubMed:21642987). Interacts with IFIT1 and IFIT2 (PubMed:21190939, PubMed:21642987). Interacts (via N-terminus) with MAVS, TBK1, TRAF6 and RIGI (PubMed:21813773). Interacts with COPS5 (PubMed:17050680).
Expression significantly higher in peripheral blood mononuclear cells (PBMCs) and monocytes from systemic lupus erythematosus (SLE) patients than in those from healthy individuals (at protein level). Spleen, lung, leukocytes, lymph nodes, placenta, bone marrow and fetal liver.
IFN-induced antiviral protein which acts as an inhibitor of cellular as well as viral processes, cell migration, proliferation, signaling, and viral replication. Enhances MAVS-mediated host antiviral responses by serving as an adapter bridging TBK1 to MAVS which leads to the activation of TBK1 and phosphorylation of IRF3 and phosphorylated IRF3 translocates into nucleus to promote antiviral gene transcription. Exhibits an antiproliferative activity via the up-regulation of cell cycle negative regulators CDKN1A/p21 and CDKN1B/p27. Normally, CDKN1B/p27 turnover is regulated by COPS5, which binds CDKN1B/p27 in the nucleus and exports it to the cytoplasm for ubiquitin-dependent degradation. IFIT3 sequesters COPS5 in the cytoplasm, thereby increasing nuclear CDKN1B/p27 protein levels. Up-regulates CDKN1A/p21 by down-regulating MYC, a repressor of CDKN1A/p21. Can negatively regulate the apoptotic effects of IFIT2.
Common junctional plaque protein. The membrane-associated plaques are architectural elements in an important strategic position to influence the arrangement and function of both the cytoskeleton and the cells within the tissue. The presence of plakoglobin in both the desmosomes and in the intermediate junctions suggests that it plays a central role in the structure and function of submembranous plaques. Acts as a substrate for VE-PTP and is required by it to stimulate VE-cadherin function in endothelial cells. Can replace beta-catenin in E-cadherin/catenin adhesion complexes which are proposed to couple cadherins to the actin cytoskeleton (By similarity).
Expressed in the heart (at protein level).
Homodimer. Component of an E-cadherin/catenin adhesion complex composed of at least E-cadherin/CDH1 and gamma-catenin/JUP, and possibly alpha-catenin/CTNNA1; the complex is located to adherens junctions. The stable association of CTNNA1 is controversial as CTNNA1 was shown not to bind to F-actin when assembled in the complex. Interacts with MUC1. Interacts with CAV1 (By similarity). Interacts with PTPRJ. Interacts with DSG1. Interacts with DSC1 and DSC2. Interacts with PKP2 (PubMed:11790773, PubMed:22781308).
The entire ARM repeats region mediates binding to CDH1/E-cadherin. The N-terminus and first three ARM repeats are sufficient for binding to DSG1. The N-terminus and first ARM repeat are sufficient for association with CTNNA1. DSC1 association requires both ends of the ARM repeat region.
Expressed predominantly in testis, and weakly in other tissues. Overexpressed in several tumors.
Responsible for the post-transcriptional adenylation of the 3'-terminal of mRNA precursors and several small RNAs including signal recognition particle (SRP) RNA, nuclear 7SK RNA, U2 small nuclear RNA, and ribosomal 5S RNA.
Highly expressed in placenta, with lower levels in prostate and colon and some expression in kidney (PubMed:9348093). Detected in plasma (at protein level) (PubMed:28572090, PubMed:29046435).
Homodimer; disulfide-linked (PubMed:29046435). Interacts with GFRAL; ligand of GFRAL which mediates GDF15 internalization and cellular signaling through interaction with RET (PubMed:28953886, PubMed:28846097, PubMed:28846098, PubMed:28846099).
Plasma levels are increased in children with concomitant heart disease and failure to thrive but not in children with heart disease and normal body weight.
Regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses (PubMed:28953886, PubMed:28846097, PubMed:28846098, PubMed:28846099, PubMed:23468844, PubMed:29046435). Binds to its receptor, GFRAL, and activates GFRAL-expressing neurons localized in the area postrema and nucleus tractus solitarius of the brainstem (PubMed:28953886, PubMed:28846097, PubMed:28846098, PubMed:28846099). It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitutes part of the 'emergency circuit' that shapes feeding responses to stressful conditions (PubMed:28953886). On hepatocytes, inhibits growth hormone signaling (By similarity).
Has a role as neurotrophic factor involved in neuronal survival and neurobiological functions.
Transcriptional activator that binds the sequence 5'-ATCAATCAA-3'.
(Microbial infection) Contributes to the overall stabilization and trans-activation capability of the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 during HSV-1 infection.
(Microbial infection) Interacts with Epstein-Barr virus EBNA1; the interaction is independent and simultaneous to EBNA1 interaction with USP7 as well as necessary for PML nuclear bodies disruption by EBNA1 (PubMed:14506283, PubMed:24216761). EBNA1, USP7 and CSNK2B form a ternary complex. EBNA1 shows a 10-fold higher affinity than p53/TP53 and can compete with it for USP7 binding (PubMed:14506283).
(Microbial infection) Interacts with herpes virus 8/HHV-8 protein vIRF-2; this interaction modulates antiviral signaling via disruption of USP7 interactions with innate immune signaling proteins TRAF3 and TRAF6 thus affecting their ubiquitination.
(Microbial infection) Interacts with herpes virus 8/HHV-8 proteins vIRF-1 and vIRF-3; these interactions may disrupt TP53 signaling pathway during viral infection by decreasing the availability of USP7 for deubiquitinating and stabilizing TP53.
(Microbial infection) Interacts with human cytomegalovirus proteins UL35 and UL35A; these interactions inhibit the ability of USP7 to form nuclear bodies.
(Microbial infection) Isoform 1 and isoform 2 interact with herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 (PubMed:9034339, PubMed:14506283, PubMed:16160161, PubMed:18590780). Binding to ICP0/VMW110 may modulate the substrate specificity or activity of USP7 to stabilize viral proteins.
(Microbial infection) Upon infection with Epstein-Barr virus, the interaction with viral EBNA1 increases the association of USP7 with PML proteins, which is required for the polyubiquitylation and degradation of PML.
Expressed in neural progenitor cells (at protein level) (PubMed:21258371). Widely expressed. Overexpressed in prostate cancer.
Hydrolase that deubiquitinates target proteins such as FOXO4, DEPTOR, KAT5, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX (PubMed:11923872, PubMed:15053880, PubMed:16964248, PubMed:18716620, PubMed:25283148, PubMed:25865756, PubMed:26678539, PubMed:28655758, PubMed:35216969). Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation (PubMed:15053880, PubMed:16845383, PubMed:18566590, PubMed:20153724). Deubiquitinates p53/TP53, preventing degradation of p53/TP53, and enhances p53/TP53-dependent transcription regulation, cell growth repression and apoptosis (PubMed:25283148). Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis (PubMed:11923872, PubMed:26786098). Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity (PubMed:16964248). In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML (PubMed:18716620). Deubiquitinates KMT2E/MLL5 preventing KMT2E/MLL5 proteasomal-mediated degradation (PubMed:26678539). Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6 (PubMed:22466611, PubMed:22466612). Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1 (PubMed:21745816, PubMed:22411829). Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex (PubMed:20601937). Able to mediate deubiquitination of histone H2B; it is however unsure whether this activity takes place in vivo (PubMed:20601937). Exhibits a preference towards 'Lys-48'-linked ubiquitin chains (PubMed:22689415). Increases regulatory T-cells (Treg) suppressive capacity by deubiquitinating and stabilizing the transcription factor FOXP3 which is crucial for Treg cell function (PubMed:23973222). Plays a role in the maintenance of the circadian clock periodicity via deubiquitination and stabilization of the CRY1 and CRY2 proteins (PubMed:27123980). Deubiquitinates REST, thereby stabilizing REST and promoting the maintenance of neural progenitor cells (PubMed:21258371). Deubiquitinates SIRT7, inhibiting SIRT7 histone deacetylase activity and regulating gluconeogenesis (PubMed:28655758). Involved in the regulation of WASH-dependent actin polymerization at the surface of endosomes and the regulation of endosomal protein recycling (PubMed:26365382). It maintains optimal WASH complex activity and precise F-actin levels via deubiquitination of TRIM27 and WASHC1 (PubMed:26365382). Mediates the deubiquitination of phosphorylated DEPTOR, promoting its stability and leading to decreased mTORC1 signaling (PubMed:35216969).
Inhibited by N-ethyl-maleimide (NEM) and divalent cations. Tolerates high concentrations of NaCl but is inhibited at concentrations of 195 mM and higher.
Isoform 1 and isoform 2: Not sumoylated.
Isoform 1 and isoform 2: Polyubiquitinated by herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110; leading to its subsequent proteasomal degradation. Isoform 1: Ubiquitinated at Lys-869.
Isoform 1: Phosphorylated. Isoform 1 is phosphorylated at positions Ser-18 and Ser-963. Isoform 2: Not phosphorylated.
Isoform 1: Polyneddylated. Isoform 2: Not Polyneddylated.
Monomer. Homodimer. Part of a complex with DAXX, MDM2, RASSF1 and USP7 (PubMed:18566590). Part of a complex with DAXX, MDM2 and USP7 (PubMed:16845383). Interacts with MDM2; the interaction is independent of p53/TP53. Interacts with DAXX; the interaction is direct and independent of MDM2 and p53/TP53 (PubMed:16845383). Component of a complex composed of KMT2E/MLL5 (isoform 3), OGT (isoform 1) and USP7; the complex stabilizes KMT2E/MLL5, preventing KMT2E/MLL5 ubiquitination and proteasomal-mediated degradation (PubMed:26678539). Interacts (via MATH domain) with KMT2E/MLL5 isoform 3 (PubMed:26678539). Interacts with OGT isoform 1 (PubMed:26678539). Interacts with FOXO4; the interaction is enhanced in presence of hydrogen peroxide and occurs independently of p53/TP53 (PubMed:16964248). Interacts with p53/TP53; the interaction is enhanced in response to DNA damage (PubMed:25283148). Interacts with TSPYL5; this impairs interaction with p53/TP53 (PubMed:21170034). Interacts with PTEN; the interaction is direct (PubMed:18716620). Interacts with ATXN1 and the strength of interaction is influenced by the length of the poly-Gln region in ATXN1 (PubMed:12093161). A weaker interaction seen with mutants having longer poly-Gln regions (PubMed:12093161). Interacts with KIAA1530/UVSSA (PubMed:22466611, PubMed:22466612). Interacts with ABRAXAS2; the interaction is direct (PubMed:25283148). Identified in a complex with TP53/p53 and ABRAXAS2 (PubMed:25283148). Interacts with MEX3C and antagonizes its ability to degrade mRNA (PubMed:22863774). Interacts with DNMT1 and UHRF1 (PubMed:21745816, PubMed:22411829). Interacts with FOXP3 (PubMed:23973222). Interacts (via MATH domain) with RNF220. Associated component of the Polycomb group (PcG) multiprotein PRC1-like complex (PubMed:20601937). Interacts with EPOP (By similarity). Interacts with OTUD4 and USP9X; the interaction is direct (PubMed:25944111). Interacts with CRY2 (PubMed:27123980). Interacts with REST (PubMed:21258371). Interacts with ERCC6 (PubMed:26030138). Part of a complex consisting of USP7, MAGEL2 and TRIM27; directly interacts with MAGEL2; directly interacts with TRIM27 (PubMed:26365382).
The C-terminus plays a role in its oligomerization.
Up-regulated in regulatory T-cells (Treg). Down-regulated during neural progenitor cell differentiation (PubMed:21258371).
Was reported to interact with UBXN6 but the corresponding article has been retracted (PubMed:18768758).
Heterohexamer; composed of 3 copies of TIMM9 and 3 copies of TIMM10/TIM10A, named soluble 70 kDa complex. The complex forms a 6-bladed alpha-propeller structure and associates with the TIMM22 component of the TIM22 complex. Interacts with multi-pass transmembrane proteins in transit. Also forms a complex composed of TIMM9, TIMM10/TIM10A and FXC1/TIM10B.
Mitochondrial intermembrane chaperone that participates in the import and insertion of multi-pass transmembrane proteins into the mitochondrial inner membrane. May also be required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. Acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space.
The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space. However, during the transit of TIMM10 from cytoplasm into mitochondrion, the Cys residues probably coordinate zinc, thereby preventing folding and allowing its transfer across mitochondrial outer membrane (Probable).
May play a role in spermatid differentiation. Modulates thymic stromal cell proliferation and thymus function.
Abundantly expressed in the skin and is expressed by keratinocytes in the epidermis. Also expressed in the brain, mammary gland, cerebellum, spinal cord and kidney. Lower levels in salivary glands, uterus, thymus, thyroid, placenta, trachea and testis. Up-regulated in ovarian carcinoma, especially late-stage serous carcinoma, compared with normal ovaries and benign adenomas (at protein level).
By estrogens and glucocorticoids in a breast carcinoma cell line.
Inhibited by Zn2+ and Cu2+ at low micromolar concentrations. Inhibited by SERPINA12.
May catalyze the degradation of intercellular cohesive structures in the cornified layer of the skin in the continuous shedding of cells from the skin surface. Specific for amino acid residues with aromatic side chains in the P1 position. Cleaves insulin A chain at '14-Tyr-|-Gln-15' and insulin B chain at '6-Leu-|-Cys-7', '16-Tyr-|-Leu-17', '25-Phe-|-Tyr-26' and '26-Tyr-|-Thr-27'. Could play a role in the activation of precursors to inflammatory cytokines.
(Microbial infection) Glucosylated at Thr-35 by P.sordellii toxin TcsL.
Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).
Fatty-acylated at Lys-169 and/or Lys-170.
Interacts (active GTP-bound form preferentially) with RGS14 (By similarity). Interacts (active GTP-bound form) with RASSF7 (PubMed:21278800).
Mutations which change AA 12, 13 or 61 activate the potential of Ras to transform cultured cells and are implicated in a variety of human tumors.
Palmitoylated by the ZDHHC9-GOLGA7 complex (PubMed:16000296). Depalmitoylated by ABHD17A, ABHD17B and ABHD17C (PubMed:26701913). A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi (PubMed:16000296, PubMed:15705808, PubMed:2661017, PubMed:26701913).
Phosphorylation at Ser-89 by STK19 enhances NRAS-association with its downstream effectors.
Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.
Expressed in lung cancers, including adenocarcinoma, squamous cell carcinoma and small-cell carcinoma (at protein level) (PubMed:25893292). Widely expressed. Expressed in fetal kidney, liver, lung and brain. In adult highest expression in heart and placenta.
Monomer and homodimer (By similarity). Interacts with SDC1, SDC2, SDC3, SDC4, NRXN2, EPHA7, EPHB1, NF2 isoform 1, TGFA and IL5RA. Interacts with NFASC and PTPRJ (By similarity). Interacts with SDCBP2 (PubMed:11152476). Interacts with PDCD6IP (PubMed:22660413). Forms a complex with PDCD6IP and SDC2 (PubMed:22660413). Interacts (via C-terminus) with TGFBR1 (PubMed:25893292). Binds to FZD7; this interaction is increased by inositol trisphosphate (IP3) (PubMed:27386966). Interacts with SMO (By similarity).
Multifunctional adapter protein involved in diverse array of functions including trafficking of transmembrane proteins, neuro and immunomodulation, exosome biogenesis, and tumorigenesis (PubMed:26291527). Positively regulates TGFB1-mediated SMAD2/3 activation and TGFB1-induced epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types. May increase TGFB1 signaling by enhancing cell-surface expression of TGFR1 by preventing the interaction between TGFR1 and CAV1 and subsequent CAV1-dependent internalization and degradation of TGFR1 (PubMed:25893292). In concert with SDC1/4 and PDCD6IP, regulates exosome biogenesis (PubMed:22660413). Regulates migration, growth, proliferation, and cell cycle progression in a variety of cancer types (PubMed:26539120). In adherens junctions may function to couple syndecans to cytoskeletal proteins or signaling components. Seems to couple transcription factor SOX4 to the IL-5 receptor (IL5RA) (PubMed:11498591). May also play a role in vesicular trafficking (PubMed:11179419). Seems to be required for the targeting of TGFA to the cell surface in the early secretory pathway (PubMed:10230395).
Forms homodimers and possibly oligomers (By similarity). May forms heterooligomers with GIT2 (By similarity). Interacts with G protein-coupled receptor kinases, including GRK2, GRK3, GRK5 and GRK6 (By similarity). Interacts with PPFIA1, PPFIA2 and PPFIA4 (By similarity). Interacts with GRIP1 and forms a ternary complex with PPFIA1 and GRIP1 (By similarity). Directly interacts with ARHGEF7/beta-PIX, forming in vitro a heptameric complex made of a GIT1 dimer and an ARHGEF7 trimer (PubMed:10896954, PubMed:27012601). Directly interacts with PXN/paxillin; this interaction is enhanced in the presence of ARHGEF7 (PubMed:10896954, PubMed:10938112, PubMed:27012601). Directly interacts (via C-terminus) with TGFB1I1/Hic-5 (via LD motif 3) (PubMed:12153727). Directly interacts with PTK2/FAK1 (By similarity). May interact with PTK2B/PYK2; this interaction may be indirect (By similarity). Interacts with AMPA receptors GRIA2/3 (By similarity). Directly interacts with protein Piccolo/PCLO (By similarity). Forms a complex with Ephrin-B1/EFNB1 and NCK2/GRB4 (via SH2); this interaction is important for spine morphogenesis and synapse formation. Interaction with NCK2 is transient and depends upon GIT1 phosphorylation at Tyr-383 (By similarity). Interacts with GRIN3A/GluN3A (via C-terminus); this interaction competes with GIT1 interaction with ARHGEF7 and limits synaptic localization of GIT1 (By similarity). Interacts with IKBKG/NEMO in resting bone mesenchymal stem cells, as well as in TNF-stimulated cells; this interaction may increase IKBKG affinity for 'Lys-63'-linked polyubiquitin chains (PubMed:31502302). Interacts with GABA(A) receptors, including GABRB3 and GABRG2 (By similarity). Interacts with SCRIB (PubMed:15182672, PubMed:19041750). Interacts (via N- and C-terminus) with ENTR1/SDCCAG3 (via N-terminus); this interaction is direct (PubMed:23108400). May form a tripartite complex with ENTR1 and PTPN13 (PubMed:23108400). Interacts with YWHAZ (By similarity). Interacts with PAK1 (PubMed:27012601). Interacts with PAK3 (PubMed:10896954). Directly interacts (via N-terminus) with gamma-tubulin (PubMed:27012601). Interacts with MAPK1 and MAPK3; this interaction is required for MAPK1/3 recruitment to focal adhesions (By similarity).
GTPase-activating protein for ADP ribosylation factor family members, including ARF1. Multidomain scaffold protein that interacts with numerous proteins and therefore participates in many cellular functions, including receptor internalization, focal adhesion remodeling, and signaling by both G protein-coupled receptors and tyrosine kinase receptors (By similarity). Through PAK1 activation, positively regulates microtubule nucleation during interphase (PubMed:27012601). Plays a role in the regulation of cytokinesis; for this function, may act in a pathway also involving ENTR1 and PTPN13 (PubMed:23108400). May promote cell motility both by regulating focal complex dynamics and by local activation of RAC1 (PubMed:10938112, PubMed:11896197). May act as scaffold for MAPK1/3 signal transduction in focal adhesions. Recruits MAPK1/3/ERK1/2 to focal adhesions after EGF stimulation via a Src-dependent pathway, hence stimulating cell migration (PubMed:15923189). Plays a role in brain development and function. Involved in the regulation of spine density and synaptic plasticity that is required for processes involved in learning (By similarity). Plays an important role in dendritic spine morphogenesis and synapse formation (PubMed:12695502, PubMed:15800193). In hippocampal neurons, recruits guanine nucleotide exchange factors (GEFs), such as ARHGEF7/beta-PIX, to the synaptic membrane. These in turn locally activate RAC1, which is an essential step for spine morphogenesis and synapse formation (PubMed:12695502). May contribute to the organization of presynaptic active zones through oligomerization and formation of a Piccolo/PCLO-based protein network, which includes ARHGEF7/beta-PIX and FAK1 (By similarity). In neurons, through its interaction with liprin-alpha family members, may be required for AMPA receptor (GRIA2/3) proper targeting to the cell membrane (By similarity). In complex with GABA(A) receptors and ARHGEF7, plays a crucial role in regulating GABA(A) receptor synaptic stability, maintaining GPHN/gephyrin scaffolds and hence GABAergic inhibitory synaptic transmission, by locally coordinating RAC1 and PAK1 downstream effector activity, leading to F-actin stabilization (PubMed:25284783). May also be important for RAC1 downstream signaling pathway through PAK3 and regulation of neuronal inhibitory transmission at presynaptic input (By similarity). Required for successful bone regeneration during fracture healing (By similarity). The function in intramembranous ossification may, at least partly, exerted by macrophages in which GIT1 is a key negative regulator of redox homeostasis, IL1B production, and glycolysis, acting through the ERK1/2/NRF2/NFE2L2 axis (By similarity). May play a role in angiogenesis during fracture healing (By similarity). In this process, may regulate activation of the canonical NF-kappa-B signal in bone mesenchymal stem cells by enhancing the interaction between NEMO and 'Lys-63'-ubiquitinated RIPK1/RIP1, eventually leading to enhanced production of VEGFA and others angiogenic factors (PubMed:31502302). Essential for VEGF signaling through the activation of phospholipase C-gamma and ERK1/2, hence may control endothelial cell proliferation and angiogenesis (PubMed:19273721).
Phosphorylated by PAK1 (PubMed:27012601). Phosphorylation on tyrosine residues may be catalyzed by PTK2/FAK1 and SRC in growing fibroblasts. Phosphorylation at Tyr-383 is induced by activation of Ephrin-B1/EFNB1 and catalyzed by SRC family kinases. It is required for the interaction with NCK2 and for GIT1 recruitment to synapses in hippocampal neurons (By similarity).
The coiled coil region mediates dimerization.
Up-regulated at the transcriptional level by MYC.
Isoform 2 expression is limited to several subcortical nuclei of the basal gangli and the spinal cord. Isoform 1 is widely expressed.
May play a role in signal transduction cascades in terminally differentiated cells.
Anchored to cell periphery via its N-terminal PDZ domain.
Binds via its LIM zinc-binding 3 domain (LIM 3) to endocytic codes of INSR, but not with those of IGF1R, LDLR, TFRC, or EGFR. Interacts with various PKC isoforms through the LIM zinc-binding domains. Binds to RET in a phosphorylation-independent manner via its LIM zinc-binding domain 2 (LIM 2). Probably part of a complex with SHC and the RET dimer. Interacts with TPM2. Interacts with TBX4 and TBX5 (By similarity).
Isoform 1 and isoform 2 are expressed ubiquitously, however, isoform 2 predominates in skeletal muscle, isoform 1 is more abundant in lung, spleen, leukocytes and fetal liver.
May function as a scaffold on which the coordinated assembly of proteins can occur. May play a role as an adapter that, via its PDZ domain, localizes LIM-binding proteins to actin filaments of both skeletal muscle and nonmuscle tissues. Involved in both of the two fundamental mechanisms of bone formation, direct bone formation (e.g. embryonic flat bones mandible and cranium), and endochondral bone formation (e.g. embryonic long bone development). Plays a role during fracture repair. Involved in BMP6 signaling pathway (By similarity).
Same activity as isoform 1 in bone nodule induction.
The LIM zinc-binding 2 (LIM 2) domain interacts with TBX4.
The LIM zinc-binding 3 (LIM 3) domain provides the structural basis for recognition of tyrosine-containing tight turn structures. This domain is necessary and sufficient for interaction with TBX5 (By similarity).
Interacts (via its PDZ domain) with GLS2. Interacts (via its PDZ domain) with RTKN (via the C-terminal region); this interaction facilitates Rho-mediated activation of the FOS serum response element (SRE). Interacts (via its PDZ domain) with CTNNB1; this interaction inhibits the transcriptional activity of CTNNB1. Interacts with HTLV-1 TAX protein. Interacts (via PDZ domain) with ARHGEF16. Interacts (via PDZ domain) with KCNJ4 (via C-terminus). Competes with LIN7A for KCNJ4 binding. Interacts with ADGRB2 (PubMed:21787750).
May regulate a number of protein-protein interactions by competing for PDZ domain binding sites. Binds CTNNB1 and may thereby act as an inhibitor of the Wnt signaling pathway. Competes with LIN7A for KCNJ4 binding, and thereby promotes KCNJ4 internalization. May play a role in the Rho signaling pathway. May play a role in activation of CDC42 by the viral protein HPV16 E6.
Ubiquitous. Detected in brain, heart, kidney, lung, small intestine and skeletal muscle. Detected in various cell lines including HeLa. Weakly expressed in peripheral blood leukocytes.
(Microbial infection) Acts as an attachment receptor for Ebolavirus.
(Microbial infection) Acts as an attachment receptor for HIV-1.
(Microbial infection) Acts as an attachment receptor for Hepatitis C virus.
(Microbial infection) Acts as an attachment receptor for Human coronavirus 229E.
(Microbial infection) Acts as an attachment receptor for Human cytomegalovirus/HHV-5.
(Microbial infection) Acts as an attachment receptor for Influenzavirus.
(Microbial infection) Acts as an attachment receptor for Japanese encephalitis virus.
(Microbial infection) Acts as an attachment receptor for Marburg virus glycoprotein.
(Microbial infection) Acts as an attachment receptor for SARS-CoV.
(Microbial infection) Acts as an attachment receptor for West-nile virus.
(Microbial infection) Interacts with HIV-1 gp120 (PubMed:21277928, PubMed:12502850).
(Microbial infection) Interacts with Japanese encephalitis virus E protein.
(Microbial infection) Interacts with M.bovis LprG.
(Microbial infection) Interacts with Marburg virus glycoprotein.
(Microbial infection) Interacts with SARS-CoV spike glycoprotein.
(Microbial infection) Interacts with ebola virus glycoprotein (PubMed:12050398, PubMed:12502850).
(Microbial infection) Interacts with hepatitis C virus E1 and E2 protein (PubMed:15371595, PubMed:16816373).
(Microbial infection) Interacts with human coronavirus 229E spike glycoprotein.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 gB protein.
(Microbial infection) Interacts with influenzavirus hemagglutinin.
(Microbial infection) Interacts with west-nile virus envelope protein E.
(Microbial infection) Recognition of M.bovis by dendritic cells may occur partially via this molecule.
In vitro, is a receptor for HIV-1 and transmits HIV-1 to permissive T-cells.
Non-canonical intron-exon splice junction.
Predominantly highly expressed in liver sinusoidal endothelial cells and in lymph node. Found in placental endothelium but not in macrophages. Expressed in type II alveolar cells and lung endothelial cells.
Probable pathogen-recognition receptor involved in peripheral immune surveillance in liver. May mediate the endocytosis of pathogens which are subsequently degraded in lysosomal compartments. Is a receptor for ICAM3, probably by binding to mannose-like carbohydrates.
The number of repeats in the tandem repeat domain is shown to vary between 3 and 9 per allele thus contributing to a further variability in addition to alternative splicing. The shown 7 repeat-containing form has been shown to be the most frequent one (53.9%) in a study with 350 Caucasian individuals.
The tandem repeat domain, also called neck domain, mediates oligomerization.
ATP-gated nonselective transmembrane cation channel permeable to potassium, sodium and calcium (PubMed:9016352). Activated by extracellularly released ATP, it plays multiple role in immunity and central nervous system physiology (PubMed:35165166). Plays a key role in initial steps of T-cell activation and Ca(2+) microdomain formation (By similarity). Participates also in basal T-cell activity without TCR/CD3 stimulation (By similarity). Promotes the differentiation and activation of Th17 cells via expression of retinoic acid-related orphan receptor C/RORC (PubMed:35165166). Upon activation, drives microglia motility via the PI3K/Akt pathway (By similarity). Could also function as an ATP-gated cation channel of lysosomal membranes (By similarity).
Activated by ATP (PubMed:9016352). pH-dependent and inhibited by acidic pH (By similarity).
Functional P2XRs are organized as homomeric and heteromeric trimers. Interacts with P2X7 (via C-terminus); this interaction is functional only in the presence of ATP (PubMed:26456657). Interacts with AP1M2 (By similarity).
Component of the 3M complex, composed of core components CUL7, CCDC8 and OBSL1 (PubMed:21737058, PubMed:24793695). Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats); may link the 3M complex to histone deacetylases including HDAC4 and HDAC5 (PubMed:25752541).
Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity. It is unclear how the 3M complex regulates microtubules, it could act by controlling the level of a microtubule stabilizer (PubMed:24793695, PubMed:24793696). Required for localization of CUL7 to the centrosome (PubMed:24793695).
The PxLPxI/L motif mediates interaction with ankyrin repeats of ANKRA2.
Widely expressed with low levels in spleen, skeletal muscle, small intestine, kidney and liver.
Component of the post-replicative DNA mismatch repair system (MMR) (PubMed:30653781, PubMed:35189042). Heterodimerizes with MLH1 to form MutL alpha. DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Possesses an ATPase activity, but in the absence of gross structural changes, ATP hydrolysis may not be necessary for proficient mismatch repair (PubMed:35189042).
Heterodimer of PMS2 and MLH1 (MutL alpha); this interaction is required for the stability of both partners (PubMed:35189042). Forms a ternary complex with MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with MTMR15/FAN1.
Interacts with MYO10 (By similarity). Interacts with RGMA and RGMB. Interacts with BMP2, BMP4, BMP6, and BMP7.
Knockdown of NEO1 in C2C12 cells results in the enhancement of the BMP-2-induced processes of osteoblastic differentiation and phosphorylation of Smad1, Smad5, and Smad8. Conversely, overexpression suppresses these processes.
Multi-functional cell surface receptor regulating cell adhesion in many diverse developmental processes, including neural tube and mammary gland formation, myogenesis and angiogenesis. Receptor for members of the BMP, netrin, and repulsive guidance molecule (RGM) families. Netrin-Neogenin interactions result in a chemoattractive axon guidance response and cell-cell adhesion, the interaction between NEO1/Neogenin and RGMa and RGMb induces a chemorepulsive response.
The Fibronectin repeats 5 and 6 mediate interaction with RGM family molecules.
Widely expressed and also in cancer cell lines.
Brain, placenta, skeletal muscle, kidney, pancreas, heart, ovary, testis, colon, small intestine, prostate and pancreas. No expression in adult thymus, spleen, lung, liver and peripheral blood leukocytes.
In the nervous system, could hydrolyze ATP and other nucleotides to regulate purinergic neurotransmission. Hydrolyzes ADP only to a marginal extent. The order of activity with different substrates is ATP > GTP > CTP = ITP > UTP >> ADP = UDP.
Transcriptional regulator which regulates the development, differentiation, and function of thymic epithelial cells (TECs) both in the prenatal and postnatal thymus. Acts as a master regulator of the TECs lineage development and is required from the onset of differentiation in progenitor TECs in the developing fetus to the final differentiation steps through which TECs mature to acquire their full functionality. Regulates, either directly or indirectly the expression of a variety of genes that mediate diverse aspects of thymus development and function, including MHC Class II, DLL4, CCL25, CTSL, CD40 and PAX1. Regulates the differentiation of the immature TECs into functional cortical TECs (cTECs) and medullary TECs (mTECs). Essential for maintenance of mTECs population in the postnatal thymus. Involved in the morphogenesis and maintenance of the three-dimensional thymic microstructure which is necessary for a fully functional thymus. Plays an important role in the maintenance of hematopoiesis and particularly T lineage progenitors within the bone marrow niche with age. Essential for the vascularization of the thymus anlage. Promotes the terminal differentiation of epithelial cells in the epidermis and hair follicles, partly by negatively regulating the activity of protein kinase C (By similarity). Plays a crucial role in the early prenatal stages of T-cell ontogeny (PubMed:21507891).
Belongs to the complex I NDUFA1 subunit family.
May mediate extracellular or intracellular signaling of cortical neurons during forebrain development.
2-oxoglutarate(2OG)-dependent dioxygenase that catalyzes the conversion of 2-oxoglutarate to succinate and CO(2) in an iron-dependent manner (PubMed:21530488). However, does not couple 2OG turnover to the hydroxylation of acyl-coenzyme A derivatives, implying that it is not directly involved in phytanoyl coenzyme-A metabolism (PubMed:21530488). Does not show detectable activity towards fatty acid CoA thioesters (PubMed:21530488).
Activity is increased by ascorbate. Inhibited by myristoyl-CoA.
Belongs to the PhyH family. PHYHD1 subfamily.
Isoform 2 probably lacks enzyme activity.
Isoform 3 probably lacks enzyme activity.
(Microbial infection) Catalyzes the high-risk human papilloma virus E6-mediated ubiquitination of p53/TP53, contributing to the neoplastic progression of cells infected by these viruses.
(Microbial infection) Interacts with HCV core protein and targets it to degradation.
(Microbial infection) Interacts with the E6 protein of the cancer-associated human papillomavirus types 16 and 18. The E6/E6-AP complex binds to and targets the p53/TP53 tumor-suppressor protein for ubiquitin-mediated proteolysis.
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates (PubMed:10373495, PubMed:16772533, PubMed:19204938, PubMed:19233847, PubMed:19325566, PubMed:19591933, PubMed:22645313, PubMed:24273172, PubMed:24728990, PubMed:30020076). Several substrates have been identified including the BMAL1, ARC, LAMTOR1, RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B (PubMed:10373495, PubMed:19204938, PubMed:19325566, PubMed:19591933, PubMed:22645313, PubMed:24728990, PubMed:30020076). Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins (PubMed:19233847). Finally, UBE3A also promotes its own degradation in vivo. Plays an important role in the regulation of the circadian clock: involved in the ubiquitination of the core clock component BMAL1, leading to its proteasomal degradation (PubMed:24728990). Acts as transcriptional coactivator of progesterone receptor PGR upon progesterone hormone activation (PubMed:16772533). Acts as a regulator of synaptic development by mediating ubiquitination and degradation of ARC (By similarity). Required for synaptic remodeling in neurons by mediating ubiquitination and degradation of LAMTOR1, thereby limiting mTORC1 signaling and activity-dependent synaptic remodeling (By similarity). Synergizes with WBP2 in enhancing PGR activity (PubMed:16772533).
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates.
Phosphorylation at Tyr-659 by ABL1 impairs E3 ligase activity and protects p53/TP53 from degradation in (HPV)-infected cells.
The active form is probably a homotrimer. Binds UBQLN1 and UBQLN2. Interacts with the 26S proteasome. Interacts with BPY2. Interacts with HIF1AN, MAPK6 and NEURL4; interaction with MAPK6 may be mediated by NEURL4. Interacts with the proteasomal subunit PSMD4. Interacts with ESR1 and WBP2 (PubMed:16772533, PubMed:21642474). Interacts with BMAL1 (PubMed:24728990). Interacts with ARC (By similarity).
Binds directly to large unilamellar vesicles (LUVs) containing phosphatidylinositol 4,5-bisphosphate (PIP2) or inositol 1,4,5-trisphosphate (InsP3). The PIP2-binding site corresponds to the myosin tail domain (PH-like) present in its tail domain (By similarity).
Interacts (via its IQ motifs) with CABP1 and CIB1; the interaction with CABP1 and CIB1 is calcium-dependent (By similarity). Interacts (via tail domain) with PLEKHB1 (via PH domain); the interaction is not affected by the presence or absence of calcium and CALM (By similarity). Interacts with POLR1A (By similarity). Interacts with POLR2A (By similarity). Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21 (PubMed:16603771). Interacts (via its IQ motifs) with CALM; this precludes interaction with YWHAB (PubMed:24636949). Interacts with YWHAB; this precludes interaction with CALM (PubMed:24636949). Interacts with RPS6 (PubMed:16877530). Interacts with actin (PubMed:16877530). Interacts with LLPH (By similarity). Interacts with GLUT4 (By similarity). Interacts (via its IQ motifs) with SH3BGRL3; the interaction is dependent on calcium and takes place at membrane ruffles (PubMed:34380438).
Involved in regulation of transcription. Associated with transcriptional active ribosomal genes. Appears to cooperate with the WICH chromatin-remodeling complex to facilitate transcription. Necessary for the formation of the first phosphodiester bond during transcription initiation.
Isoform 2 contains a N-acetylmethionine at position 1.
Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Their highly divergent tails are presumed to bind to membranous compartments, which would be moved relative to actin filaments. Involved in glucose transporter recycling in response to insulin by regulating movement of intracellular GLUT4-containing vesicles to the plasma membrane. Component of the hair cell's (the sensory cells of the inner ear) adaptation-motor complex. Acts as a mediator of adaptation of mechanoelectrical transduction in stereocilia of vestibular hair cells. Binds phosphoinositides and links the actin cytoskeleton to cellular membranes.
Fetal ovary and fetal testis (at protein level).
Interacts with PUM2, SNAPIN and CTNNB1. Interacts (via N-terminal region) with CTNND1. Interacts with DDX20 (via N-terminal region).
May act as a translational repressor which regulates translation of specific mRNAs by forming a complex with PUM2 that associates with the 3'-UTR of mRNA targets. Capable of interfering with the proadhesive and anti-invasive functions of E-cadherin. Up-regulates the production of MMP14 to promote tumor cell invasion.
Testis and ovary (at protein level). Predominantly expressed in testis. Specifically expressed during germline development. In adult tissues, it is mainly expressed in spermatogonia, the stem cells of the germline. Also expressed during meiosis in spermatocytes. Not present in late, post-meiotic stage germ cells. Expressed in fetal ovaries, while it is weakly or not expressed in mature postmeiotic oocytes, suggesting that it may be expressed in premeiotic female germ cells. Expressed at high levels only in the E-cadherin deficient cell lines. Highly expressed in lung carcinomas and mostly detected in invasive tumor cells and its expression correlates with tumor aggressiveness.
The N-terminal region and C-terminal zinc-finger RNA-binding domain are both necessary for interaction with SNAPIN.
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). Interacts with ALKBH4 (PubMed:23145062).
Expressed at high levels in pre B-cells, mature B-cells and pre T-cells. Expressed at low levels in mature T-cells and plasma B-cells. Expressed in germinal center B-cells, splenic marginal zone cells and B-cell lymphomas. Expressed in neuronal cells in the cerebral cortex, epithelial cells in tonsil, adrenal glands, zymogen-producing cells in the stomach and epithelial cells in seminal vesicles.
Interacts (via coiled-coil domain) with ITPR3. Interacts with SUN1 and SUN2. Interacts with microtubules.
It is uncertain whether Met-1 or Met-57 is the initiator methionine. However, according to PubMed:8021504, the initiator methionine is coded by a non-canonical CTG leucine codon; This leucine codon is in an excellent Kozak consensus located 39 bp upstream of the corresponding first mouse ATG.
Plays a role in the delivery of peptides to major histocompatibility complex (MHC) class I molecules; this occurs in a transporter associated with antigen processing (TAP)-independent manner. May play a role in taste signal transduction via ITPR3. May play a role during fertilization in pronucleus congression and fusion. Plays a role in maintaining nuclear shape, maybe as a component of the LINC complex and through interaction with microtubules.
The removal of the C-terminal lumenal domain occurs by proteolytic processing.
G protein-coupled receptor for follitropin, the follicle-stimulating hormone (PubMed:11847099, PubMed:24058690, PubMed:24692546). Through cAMP production activates the downstream PI3K-AKT and ERK1/ERK2 signaling pathways (PubMed:24058690).
G protein-coupled receptor for follitropin, the follicle-stimulating hormone. Through cAMP production activates the downstream PI3K-AKT and ERK1/ERK2 signaling pathways.
Homotrimer. Functions as a homotrimer binding the FSH hormone heterodimer composed of CGA and FSHB (PubMed:24692546). Interacts with ARRB2 (By similarity). Interacts with APPL2; interaction is independent of follicle stimulating hormone stimulation (PubMed:17030088).
N-glycosylated; indirectly required for FSH-binding, possibly via a conformational change that allows high affinity binding of hormone.
Sertoli cells and ovarian granulosa cells.
Interacts with AMPAR subunits GRIA1 and GRIA2.
May regulate trafficking and current kinetics of AMPA-type glutamate receptor (AMPAR) at synapses.
Receptor for bile acid. Bile acid-binding induces its internalization, activation of extracellular signal-regulated kinase and intracellular cAMP production. May be involved in the suppression of macrophage functions by bile acids.
Ubiquitously expressed. Expressed at higher level in spleen and placenta. Expressed at lower level in other tissues. In digestive tissues, it is expressed in stomach, duodenum, ileocecum, ileum, jejunum, ascending colon, transverse colon, descending colon, cecum and liver, but not in esophagus and rectum.
Belongs to the complex I NDUFB2 subunit family.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). CF(0) has three main subunits: a, b and c. Component of an ATP synthase complex composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5PD, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and ATP5MJ (By similarity). Interacts with DNAJC30; interaction is direct (PubMed:30318146).
Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Key component of the proton channel; it may play a direct role in the translocation of protons across the membrane.
Expressed in fetal heart, heart, skeletal muscle, pancreas and placenta.
Expressed in heart as early as the 24th week of gestation.
Involved in transcriptional regulation as an activator.
It is uncertain whether Met-1 or Met-20 is the initiator. A 'GT' insertion (rs59214675) allows to extend the sequence in the N-terminus. The majority of mRNAs do not have this insertion and the corresponding protein sequences start at Met-20.
(Microbial infection) Cleaved and inactivated by hepatitis C virus NS3/NS4A.
E2-dependent E3 ubiquitin-protein ligase that functions as a RIGI coreceptor in the sensing of viral RNAs in cell cytoplasm and the activation of the antiviral innate immune response (PubMed:19017631, PubMed:19484123, PubMed:21147464, PubMed:23950712, PubMed:28469175, PubMed:31006531). Together with the UBE2D3, UBE2N and UB2V1 E2 ligases, catalyzes the 'Lys-63'-linked polyubiquitination of RIGI oligomerized on viral RNAs, an essential step in the activation of the RIG-I signaling pathway (PubMed:19017631, PubMed:21147464, PubMed:28469175, PubMed:31006531). Through a ubiquitin-independent parallel mechanism, which consists in bridging RIGI filaments forming on longer viral RNAs, further activates the RIG-I signaling pathway (PubMed:31006531). This second mechanism that synergizes with the ubiquitin-dependent one would thereby allow an RNA length-dependent regulation of the RIG-I signaling pathway (Probable). Associated with the E2 ligase UBE2N, also constitutively synthesizes unanchored 'Lys-63'-linked polyubiquitin chains that may also activate the RIG-I signaling pathway (PubMed:28469175, PubMed:31006531).
Expressed in skeletal muscle, spleen, kidney, placenta, prostate, stomach, thyroid and tongue. Also weakly expressed in heart, thymus, liver and lung.
Homodimer (PubMed:31006531). Interacts (homodimer) with RIGI (double-stranded RNA-bound oligomeric form); involved in both RIGI ubiquitination, oligomerization into filaments associated with viral RNAs and the bridging of these filaments (PubMed:19017631, PubMed:19484123, PubMed:23950712, PubMed:28469175, PubMed:31006531). Interacts with UBE2D3 and UBE2N; E2 ubiquitin ligases involved in RNF135-mediated ubiquitination of RIGI and activation of the RIG-I signaling pathway (PubMed:28469175). Interacts with PCBP2 (PubMed:19881509).
The B30.2/SPRY domain mediates the interaction with the substrate RIGI.
The coiled-coil domains mediate homodimerization and the bridging of viral RNA-associated RIGI filaments.
Dimer or oligomer; disulfide-linked. Interacts with IL12RB2 to form the high affinity IL12 receptor. Heterodimer with IL23R; in presence of IL23. The heterodimer forms the IL23 receptor.
Functions as an interleukin receptor which binds interleukin-12 with low affinity and is involved in IL12 transduction. Associated with IL12RB2 it forms a functional, high affinity receptor for IL12. Associates also with IL23R to form the interleukin-23 receptor which functions in IL23 signal transduction probably through activation of the Jak-Stat signaling cascade.
Homodimer, and heterodimer of GMEB1 and GMEB2. GMEB1 and GMEB2 form the parvovirus initiator complex (PIF). Interacts with the glucocorticoid receptor (NR3C1) and NCOA2/TIF2 (By similarity). May interact with HSP27 and CREB-binding protein (CBP).
Trans-acting factor that binds to glucocorticoid modulatory elements (GME) present in the TAT (tyrosine aminotransferase) promoter and increases sensitivity to low concentrations of glucocorticoids. Binds also to the transferrin receptor promoter. Essential auxiliary factor for the replication of parvoviruses.
Belongs to the GTP-binding elongation factor family. EF-G/EF-2 subfamily.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EF-G/EF-2 subfamily.
Mitochondrial GTPase that catalyzes the GTP-dependent ribosomal translocation step during translation elongation. During this step, the ribosome changes from the pre-translocational (PRE) to the post-translocational (POST) state as the newly formed A-site-bound peptidyl-tRNA and P-site-bound deacylated tRNA move to the P and E sites, respectively. Catalyzes the coordinated movement of the two tRNA molecules, the mRNA and conformational changes in the ribosome. Does not mediate the disassembly of ribosomes from messenger RNA at the termination of mitochondrial protein biosynthesis.
By concanavalin-A in peripheral blood leukocytes.
Highly expressed in proliferative tissues such as adult thymus and testis, and expressed at lower levels in uterus, small intestine, colon, and peripheral blood mononuclear cells. Also expressed in neoplastic cell lines including those derived from myeloid and lymphoid leukemias.
Plays an essential role in normal development and survival. Involved in regulation of the expansion or survival of lymphoid cells. Required for de novo or maintenance DNA methylation. May control silencing of the imprinted CDKN1C gene through DNA methylation. May play a role in formation and organization of heterochromatin, implying a functional role in the regulation of transcription and mitosis (By similarity).
A cytochrome P450 monooxygenase involved in the metabolism of retinoates (RAs), the active metabolites of vitamin A, and critical signaling molecules in animals (PubMed:10823918, PubMed:22020119). RAs exist as at least four different isomers: all-trans-RA (atRA), 9-cis-RA, 13-cis-RA, and 9,13-dicis-RA, where atRA is considered to be the biologically active isomer, although 9-cis-RA and 13-cis-RA also have activity (Probable). Catalyzes the hydroxylation of atRA primarily at C-4 and C-18, thereby contributing to the regulation of atRA homeostasis and signaling (PubMed:10823918). Hydroxylation of atRA limits its biological activity and initiates a degradative process leading to its eventual elimination (PubMed:10823918, PubMed:22020119). Involved in the convertion of atRA to all-trans-4-oxo-RA. Can oxidize all-trans-13,14-dihydroretinoate (DRA) to metabolites which could include all-trans-4-oxo-DRA, all-trans-4-hydroxy-DRA, all-trans-5,8-epoxy-DRA, and all-trans-18-hydroxy-DRA (By similarity). Shows preference for the following substrates: atRA > 9-cis-RA > 13-cis-RA (PubMed:10823918, PubMed:22020119). Plays a central role in germ cell development: acts by degrading RAs in the developing testis, preventing STRA8 expression, thereby leading to delay of meiosis. Required for the maintenance of the undifferentiated state of male germ cells during embryonic development in Sertoli cells, inducing arrest in G0 phase of the cell cycle and preventing meiotic entry. Plays a role in skeletal development, both at the level of patterning and in the ossification of bone and the establishment of some synovial joints (PubMed:22019272). Essential for postnatal survival (By similarity).
Has also a significant activity in oxidation of tazarotenic acid and may therefore metabolize that xenobiotic in vivo.
Highly expressed in brain, particularly in the cerebellum and pons.
Interacts directly with activated KRAS in a GTP-dependent manner.
Potential tumor suppressor. May act as a KRAS effector protein. May promote apoptosis and cell cycle arrest.
Widely expressed. Frequently down-regulated in tumor cell lines.
As a component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is required in ciliogenesis and ciliary protein trafficking (PubMed:27932497, PubMed:29220510). Involved in cilia formation during neuronal patterning. Acts as a negative regulator of Shh signaling. Required to recruit TULP3 to primary cilia (By similarity).
Component of the IFT complex A (IFT-A) complex (PubMed:20889716, PubMed:27932497). IFT-A complex is divided into a core subcomplex composed of IFT122:IFT140:WDR19 which is associated with TULP3 and a peripheral subcomplex composed of IFT43:WDR35:TTC21B (PubMed:27932497, PubMed:29220510). Interacts with IFT43:WDR35; the interaction connects the 2 IFT-A subcomplexes (PubMed:29220510). Interacts with IFTAP; the interaction associates IFTAP with IFT-A complex (PubMed:30476139).
Expressed in many tissues. Predominant expression in testis and pituitary.
Forms the trimeric core subcomplex IFT122:IFT140:WDR19 via the C-terminal region, whereas it interacts with IFT43:WDR35 via the N-terminal region containing the WD repeats.
Monomer (PubMed:8294464). Heterotrimer composed of RABGGTA, RABGGTB and CHML; within this trimer, RABGGTA and RABGGTB form the catalytic component B, while CHML (component A) mediates Rab protein binding (PubMed:12356470). Interacts with RAB1A, RAB7A and RAB27A, but has much lower affinity for RAB1A, RAB7A and RAB27A than CHM (PubMed:15186776). Interacts with the non-phosphorylated forms of RAB3A, RAB3B, RAB3C, RAB3D, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB35, and RAB43 (PubMed:26824392, PubMed:29125462).
Substitutes for REP-1 thereby preventing widespread tissue abnormalities in patients with choroideremia who lack REP-1.
Substrate-binding subunit (component A) of the Rab geranylgeranyltransferase (GGTase) complex. Binds unprenylated Rab proteins and presents the substrate peptide to the catalytic component B. The component A is thought to be regenerated by transferring its prenylated Rab back to the donor membrane. Less effective than CHM in supporting prenylation of Rab3 family.
Expressed in preleptotene spermatocytes, pachytene spermatocytes, round spermatids and elongated spermatids (at protein level).
Interacts with IFT20 (PubMed:30929735). Interacts with IFT52 (PubMed:30929735). Interacts with IFT140 (PubMed:30929735).
Intraflagellar transport (IFT)-associated protein required for spermatogenesis (PubMed:30929735). Required for sperm flagellar formation and intraflagellar transport (PubMed:30929735).
Expressed in lymphocytes, CD4 positive T-cells and bone marrow-derived cells. Also expressed in lung, colon, thymus and brain.
May play an important role in lymphopoiesis.
Up-regulated in cells resistant to 25-hydroxy cholesterol (25-OHC). Down-regulated in lymphocytes activated by treatment with phytohemagglutinin (PHA).
Required for vesicular transport from the ER to the Golgi complex. Functions as a SNARE involved in the docking process of ER-derived vesicles with the cis-Golgi membrane (By similarity).
Expressed in several tissues, including brain, pituitary, testis and trachea, with highest levels in testis.
Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP (By similarity).
The dynein complex consists of at least two heavy chains and a number of intermediate and light chains.
Cross-link to form 2 major subcomplexes: one consisting of SGCB, SGCD and SGCG and the other consisting of SGCB and SGCD. The association between SGCB and SGCG is particularly strong while SGCA is loosely associated with the other sarcoglycans (By similarity).
Cross-link to form 2 major subcomplexes: one consisting of SGCB, SGCD and SGCG and the other consisting of SGCB and SGCD. The association between SGCB and SGCG is particularly strong while SGCA is loosely associated with the other sarcoglycans.
Highest expression in heart and skeletal muscle. Low expression in brain, kidney, placenta, pancreas and lung. High expression in fetal brain. Also found in fetal lung, kidney and liver.
Heterodimer with GPN3 (PubMed:21768307). Binds to RNA polymerase II (RNAPII) (PubMed:17643375, PubMed:20864038, PubMed:21844196). Interacts directly with RNAPII subunits RPB4 and RPB7 and the CTD of RPB1 (PubMed:21768307). Interacts with XPA (PubMed:11058119).
Small GTPase required for proper nuclear import of RNA polymerase II (RNAPII) (PubMed:20855544, PubMed:21768307). May act at an RNAP assembly step prior to nuclear import (PubMed:21768307). Forms an interface between the RNA polymerase II enzyme and chaperone/scaffolding proteins, suggesting that it is required to connect RNA polymerase II to regulators of protein complex formation (PubMed:17643375). May be involved in nuclear localization of XPA (PubMed:11058119).
Small GTPase required for proper nuclear import of RNA polymerase II (RNAPII). May act at an RNAP assembly step prior to nuclear import.
Choline/H+ antiporter, mainly in mitochodria (PubMed:10677542, PubMed:20665236, PubMed:33789160, PubMed:23651124). Also acts as a low-affinity ethanolamine/H+ antiporter, regulating the supply of extracellular ethanolamine (Etn) for the CDP-Etn pathway, redistribute intracellular Etn and balance the CDP-Cho and CDP-Etn arms of the Kennedy pathway (PubMed:33789160).
Does not exhibit choline transporter activity.
Expressed in inner ear vestibular tissue.
Present in supporting cells of the inner ear (at protein level).
Expressed in adult heart, brain, placenta, lung and kidney, but not in adult liver and skeletal muscle. In 17-day old embryo, detected in liver, skeletal muscle, brain, heart and small intestine.
May be involved in the transcriptional activation of MDM2 and EP300 genes.
Expressed in most tissues including pancreas, thymus and testis.
Isoform 4 is specifically expressed in liver. Ubiquitously expressed with higher expression in kidney, liver and placenta.
Non-canonical splice sites for exon 9 and exon 10.
Interacts with SIRT2; the interaction is direct.
Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. Binds to the DNA sequence 5'-AA[AT]TTTTATTAC-3'.
Component of the BCR(KLHL9-KLHL13) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL9, KLHL13 and RBX1. Interacts with AURKB.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for mitotic progression and cytokinesis. The BCR(KLHL9-KLHL13) E3 ubiquitin ligase complex mediates the ubiquitination of AURKB and controls the dynamic behavior of AURKB on mitotic chromosomes and thereby coordinates faithful mitotic progression and completion of cytokinesis.
Bifunctional glycosyltransferase with both alpha-1,3-xylosyltransferase and beta-1,3-glucuronyltransferase activities involved in the maturation of alpha-dystroglycan (DAG1) by glycosylation leading to DAG1 binding to laminin G-like domain-containing extracellular proteins with high affinity (PubMed:22223806, PubMed:15752776, PubMed:15661757, PubMed:25279699, PubMed:25279697, PubMed:23125099, PubMed:21987822). Elongates the glucuronyl-beta-1,4-xylose-beta disaccharide primer structure initiated by B4GAT1 by adding repeating units [-3-Xylose-alpha-1,3-GlcA-beta-1-] to produce a heteropolysaccharide (PubMed:22223806, PubMed:25279699, PubMed:25279697, PubMed:25138275, PubMed:32975514, PubMed:23125099). Requires the phosphorylation of core M3 (O-mannosyl trisaccharide) by POMK to elongate the glucuronyl-beta-1,4-xylose-beta disaccharide primer (PubMed:21987822). Plays a key role in skeletal muscle function and regeneration (By similarity).
Binds 2 Mn(2+) ions per subunit. The xylosyltransferase part binds one Mn(2+) and the beta-1,3-glucuronyltransferase part binds one Mn(2+).
In the C-terminal section; belongs to the glycosyltransferase 49 family.
In the N-terminal section; belongs to the glycosyltransferase 8 family.
Interacts with DAG1 (via the N-terminal domain of alpha-DAG1); the interaction increases binding of DAG1 to laminin (By similarity). Interacts with B4GAT1 (PubMed:19587235).
Ubiquitous. Highest expression in heart, brain and skeletal muscle.
Expressed in various tissues, including heart, skeletal muscle, placenta, liver, lung, kidney and pancreas.
Lipid phosphatase which efficiently dephosphorylates phosphatidylinositol 3-phosphate (PtdIns3P) and PtdIns(3,5)P2; inactive toward PtdIns4P, PtdIns(3,4)P2, PtdIns(4,5)P2 and PtdIns(3,4,5)P3.
The gene represented in this entry may act as a disease modifier. MTMR14 mutations affecting enzymatic function have been found in sporadic cases of centronuclear myopathy, one of them carrying a disease-associated mutation in DNM2 (PubMed:17008356). This raises the possibility of MTMR14 being a modifier of the phenotype in some cases of centronuclear myopathy (PubMed:17008356).
May have histone acetyltransferase activity.
(Microbial infection) Immediate early protein IE1 of human cytomegalovirus (HHV-5) interferes with the sumoylation of SP100.
(Microbial infection) Interacts with Epstein-Barr virus EBNA-LP; this interaction is important for EBNA-LP coactivator activity.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123; may play a role in infection by the virus.
Contains one Pro-Xaa-Val-Xaa-Leu (PxVxL) motif, which is required for interaction with chromoshadow domains. This motif requires additional residues -7, -6, +4 and +5 of the central Val which contact the chromoshadow domain.
Homodimer; isoforms are able to heterodimerize. Interacts with members of the HP1 family of nonhistone chromosomal protein, such as CBX5 and CBX3 via the PxVxL motif. Interacts with ETS1; the interaction is direct and modulates ETS1 transcriptional activity. Interacts with the MRN complex which is composed of two heterodimers RAD50/MRE11 associated with a single NBN; recruits the complex to PML-related bodies. Interacts with HIPK2; positively regulates TP53-dependent transcription. Interacts with CASP8AP2; may negatively regulate CASP8AP2 export from the nucleus to the cytoplasm. Interacts with SUMO1P1/SUMO5 (PubMed:27211601).
Sumoylated. Sumoylated with SUMO1. Sumoylation depends on a functional nuclear localization signal but is not necessary for nuclear import or nuclear body targeting. Sumoylation may stabilize the interaction with CBX5.
Sumoylated. Sumoylation depends on a functional nuclear localization signal but is not necessary for nuclear import or nuclear body targeting.
The HSR domain is important for the nuclear body targeting as well as for the dimerization.
The major isoform Sp100-A, has a calculated molecular weight of 54 kDa, but exhibits aberrant electrophoretic mobilities, with an apparent molecular weight of 100 kDa.
Together with PML, this tumor suppressor is a major constituent of the PML bodies, a subnuclear organelle involved in a large number of physiological processes including cell growth, differentiation and apoptosis. Functions as a transcriptional coactivator of ETS1 and ETS2 according to PubMed:11909962. Under certain conditions, it may also act as a corepressor of ETS1 preventing its binding to DNA according to PubMed:15247905. Through the regulation of ETS1 it may play a role in angiogenesis, controlling endothelial cell motility and invasion. Through interaction with the MRN complex it may be involved in the regulation of telomeres lengthening. May also regulate TP53-mediated transcription and through CASP8AP2, regulate FAS-mediated apoptosis. Also plays a role in infection by viruses, including human cytomegalovirus and Epstein-Barr virus, through mechanisms that may involve chromatin and/or transcriptional regulation.
Up-regulated by interferon, retinoic acid, TNF-alpha/TNFA and lipopolysaccharide (at protein level). Up-regulated following heat-shock.
Widely expressed. Sp100-B is expressed only in spleen, tonsil, thymus, mature B-cell line and some T-cell line, but not in brain, liver, muscle or non-lymphoid cell lines.
Expressed in adrenal cortex, testis, breast, thyroid, lymph node, ovary and fat. Expressed in adipose tissues.
Homodimer and heterodimer. Forms antiparallel homodimers and heterodimers with MRAP2. Interacts with MC1R, MC2R, MC3R, MC4R and MC5R.
Modulator of melanocortin receptors (MC1R, MC2R, MC3R, MC4R and MC5R). Acts by increasing ligand-sensitivity of melanocortin receptors and enhancing generation of cAMP by the receptors. Required both for MC2R trafficking to the cell surface of adrenal cells and for signaling in response to corticotropin (ACTH). May be involved in the intracellular trafficking pathways in adipocyte cells.
Highly expressed in hypovascular connective tissues such as tendons. Has also strong expression in adipose tissue.
Acts as a repressor of nuclear receptor-dependent transcription possibly by interfering with CREBBP-dependent coactivation. May function as a coinhibitor of other CREBBP/EP300-dependent transcription factors.
Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3; EID3 seems to be a testis-specific subunit. NSMCE1, NSMCE4A or EID3 and NSMCE3 probably form a subcomplex that bridges the head domains of the SMC5:SMC6 heterodimer. Homodimer, and heterodimer with EID2 (By similarity). Interacts with the C-terminal region of CREBBP.
Component of the SMC5-SMC6 complex, that promotes sister chromatid alignment after DNA damage and facilitates double-stranded DNA breaks (DSBs) repair via homologous recombination between sister chromatids.
Tissue-specific component of the SMC5-SMC6 complex, a complex involved in repair of DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination and mediates sumoylation of shelterin complex (telosome) components.
Catalyzes the cleavage of serine to glycine accompanied with the production of 5,10-methylenetetrahydrofolate, an essential intermediate for purine biosynthesis (PubMed:24075985, PubMed:29364879, PubMed:33015733, PubMed:25619277, PubMed:33015733). Serine provides the major source of folate one-carbon in cells by catalyzing the transfer of one carbon from serine to tetrahydrofolate (PubMed:25619277). Contributes to the de novo mitochondrial thymidylate biosynthesis pathway via its role in glycine and tetrahydrofolate metabolism: thymidylate biosynthesis is required to prevent uracil accumulation in mtDNA (PubMed:21876188). Also required for mitochondrial translation by producing 5,10-methylenetetrahydrofolate; 5,10-methylenetetrahydrofolate providing methyl donors to produce the taurinomethyluridine base at the wobble position of some mitochondrial tRNAs (PubMed:29452640, PubMed:29364879). Associates with mitochondrial DNA (PubMed:18063578). In addition to its role in mitochondria, also plays a role in the deubiquitination of target proteins as component of the BRISC complex: required for IFNAR1 deubiquitination by the BRISC complex (PubMed:24075985).
Homotetramer; in the presence of bound pyridoxal 5'-phosphate (PubMed:29180469, PubMed:25619277). Homodimer; in the absence of bound pyridoxal 5'-phosphate (PubMed:29180469, PubMed:25619277). Pyridoxal 5'-phosphate binding mediates an important conformation change that is required for tetramerization (PubMed:25619277). Interacts with ABRAXAS2; the interaction is direct. Identified in a complex with ABRAXAS2 and the other subunits of the BRISC complex, at least composed of the ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Identified in a complex with ABRAXAS2 and IFNAR1 (PubMed:24075985). Interacts with KIRREL3 (PubMed:25902260).
Hydroxymethyltransferase is inhibited by succinylation at Lys-280.
In eukaryotes there are two forms of the enzymes: a cytosolic one and a mitochondrial one.
Succinylation at Lys-280 inhibits the hydroxymethyltransferase activity. Desuccinylation by SIRT5 restores the activity, leading to promote cell proliferation.
Expressed in the olfactory mucosa, very low expression in brain, lung and kidney.
The chimpanzee and orangutan orthologous proteins do not exist, their genes are pseudogenes.
Auto-ubiquitinated in presence of NDFIP1 (PubMed:23087404). Ubiquitinated by the SCF(FBXL15) complex at Lys-381 and Lys-383, leading to its degradation by the proteasome. Lys-383 is the primary ubiquitination site.
E3 ubiquitin-protein ligase that acts as a negative regulator of BMP signaling pathway. Mediates ubiquitination and degradation of SMAD1 and SMAD5, 2 receptor-regulated SMADs specific for the BMP pathway. Promotes ubiquitination and subsequent proteasomal degradation of TRAF family members and RHOA. Promotes ubiquitination and subsequent proteasomal degradation of MAVS (PubMed:23087404). Acts as an antagonist of TGF-beta signaling by ubiquitinating TGFBR1 and targeting it for degradation (PubMed:21791611). Plays a role in dendrite formation by melanocytes (PubMed:23999003).
Interacts with TRAF4. Interacts (via HECT domain) with FBXL15 (via LRR repeats). Interacts with SMAD7 and TGFBR1; SMAD7 recruits SMURF1 to TGFBR1 and regulates TGF-beta receptor degradation. Interacts with MAVS; the interaction is mediated by NDFIP1 (PubMed:23087404).
The C2 domain mediates membrane localization and substrate selection.
(Microbial infection) In case of infection, may act as a fusion receptor for cytomegalovirus (HCMV) strain AD169.
Plays a role in primary cilia formation (PubMed:26365339). May act as a downstream effector of HOXC8 possibly by transducing or transmitting extracellular information required for axial skeletal patterning during development (By similarity). May be involved in cartilage and bone development (By similarity). May play a role in the differentiation of cranial neural crest cells (By similarity).
Found in fetal small intestine and thymus.
Highly expressed in omental adipose tissue where it is found in stromal vascular cells but not in fat cells but is barely detectable in subcutaneous adipose tissue (at protein level) (PubMed:16531507). Highly expressed in the small intestine. Also found in the heart, testis, colon, salivary gland, skeletal muscle, pancreas and thyroid and, to a lesser degree, in the uterus, spleen, prostate, lymph node and thymus.
Homotrimer; disulfide-linked (PubMed:11313366, PubMed:17621593, PubMed:26148048). May interact with LTF (PubMed:11747454, PubMed:23921499).
Lectin that specifically recognizes microbial carbohydrate chains in a calcium-dependent manner (PubMed:11313366, PubMed:26148048). Binds to microbial glycans that contain a terminal acyclic 1,2-diol moiety, including beta-linked D-galactofuranose (beta-Galf), D-phosphoglycerol-modified glycans, D-glycero-D-talo-oct-2-ulosonic acid (KO) and 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) (PubMed:26148048). Binds to glycans from Gram-positive and Gram-negative bacteria, including K.pneumoniae, S.pneumoniae, Y.pestis, P.mirabilis and P.vulgaris (PubMed:26148048). Does not bind human glycans (PubMed:26148048). Probably plays a role in the defense system against microorganisms (Probable). May function as adipokine that has no effect on basal glucose uptake but enhances insulin-stimulated glucose uptake in adipocytes (PubMed:16531507). Increases AKT phosphorylation in the absence and presence of insulin (PubMed:16531507). May interact with lactoferrin/LTF and increase its uptake, and may thereby play a role in iron absorption (PubMed:11747454, PubMed:23921499).
Homotetramer and heterooligomer with other family members. Binds LEF1, TCF7 and TCF7L1 (By similarity). Binds FOXA2. Interacts with XIAP/BIRC4 and TCF7L2/TCF4. Interacts with TBX18 (via engrailed homology 1 repressor motif), leading to decreased of TBX18 transcriptional activity.
Ubiquitinated by XIAP/BIRC4. This ubiquitination does not affect its stability, nuclear localization, or capacity to tetramerize but inhibits its interaction with TCF7L2/TCF4.
Belongs to the sulfotransferase 1 family. NDST subfamily.
Essential bifunctional enzyme that catalyzes both the N-deacetylation and the N-sulfation of glucosamine (GlcNAc) of the glycosaminoglycan in heparan sulfate. Modifies the GlcNAc-GlcA disaccharide repeating sugar backbone to make N-sulfated heparosan, a prerequisite substrate for later modifications in heparin biosynthesis. Plays a role in determining the extent and pattern of sulfation of heparan sulfate. Required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413).
The presence of 4 different heparan sulfate N-deacetylase/N-sulfotransferase enzymes in mammals, as well as differences in their enzyme activity suggest that some initiate heparan sulfate modification/sulfation reactions, whereas other later on fill in or extend already modified heparan sulfate sequences.
Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase. Interacts with CDC6 and KAT7/HBO1. Interacts with LRWD1 predominantly during the G1 phase and with less affinity during mitosis, when phosphorylated.
Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent, however specific DNA sequences that define origins of replication have not been identified so far. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication.
Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication.
Expression is cell-cycle regulated, it starts to accumulate in mid-G1 phase, reaches a peak at the G1/S boundary, and decreases to a basal level in S phase (at protein level).
The BAH domain mediates binding to dimethylated histone H4 'Lys-20' (H4K20me2), which is enriched at replication origins.
Dubious isoform due to intron retention.
Expressed strongly in colorectal cancer tissues compared to wild-type colon samples (at protein level) (PubMed:28040436). Expressed strongly in colorectal cancer tissues compared to wild-type colon samples (PubMed:28040436).
Homodimer (PubMed:28040436). Component of the tRNA-splicing ligase complex (PubMed:21311021, PubMed:24870230). Interacts with FAM98A (PubMed:28040436).
Positively stimulates PRMT1-induced protein arginine dimethylated arginine methylation (PubMed:28040436).
Actin maturation protease that specifically mediates the cleavage of immature acetylated N-terminal actin, thereby contributing to actin maturation (PubMed:36173861). Cleaves N-terminal acetylated methionine of immature cytoplasmic beta- and gamma-actins ACTB and ACTG1 after translation (PubMed:36173861). Cleaves N-terminal acetylated cysteine of muscle alpha-actins ACTA1, ACTC1 and ACTA2 after canonical removal of N-terminal methionine (By similarity).
Interacts (via N-terminus) with PFN2 isoforms IIa and IIb; the interactions may facilitate efficient cleavage of the acetylated N-terminus of immature actin (PubMed:36173861). Interacts with PFN1 (PubMed:36173861).
The N-terminal proline-rich disordered region contributes to the interaction with PFN2.
Identified in the spliceosome C complex (PubMed:28502770, PubMed:29301961). Component of the mRNA splicing-dependent exon junction complex (EJC), which contains at least CASC3, EIF4A3, MAGOH, NXF1 and RBM8A/Y14 (PubMed:15166247, PubMed:16170325, PubMed:16314458, PubMed:16923391, PubMed:16931718, PubMed:19033377, PubMed:20479275). Identified in a complex composed of the EJC core, UPF3B and UPF2. The EJC core can also interact with UPF3A (in vitro) (PubMed:20479275). Forms homooligomers (By similarity). Interacts with STAU in an RNA-dependent manner (By similarity). Interacts with DHX34; the interaction is RNA-independent (PubMed:25220460).
Required for pre-mRNA splicing as component of the spliceosome (PubMed:28502770, PubMed:29301961). Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). Stimulates the ATPase and RNA-helicase activities of EIF4A3. Plays a role in the stress response by participating in cytoplasmic stress granules assembly and by favoring cell recovery following stress. Component of the dendritic ribonucleoprotein particles (RNPs) in hippocampal neurons. May play a role in mRNA transport. Binds spliced mRNA in sequence-independent manner, 20-24 nucleotides upstream of mRNA exon-exon junctions. Binds poly(G) and poly(U) RNA homomer.
The coiled coil domain may be involved in oligomerization.
Widely expressed. Overexpressed in breast cancers and metastasis, as well as in gastric cancers.
Cytokine that plays a critical role in modulating tissue responses during inflammation (PubMed:17204547). Plays an essential role in the regeneration of epithelial cells to maintain barrier function after injury and for the prevention of further tissue damage (PubMed:17204547). Unlike most of the cytokines, has no effect on immune cells. Signals through a heterodimeric receptor composed of two subunits, the specific receptor IL22RA1 which is present on non-immune cells in many organs and the shared subunit IL10RB (PubMed:10875937, PubMed:18599299). Ligation of IL22RA1 with IL22 induces activation of the tyrosine kinases JAK1 and TYK2, which in turn activates STAT3. In turn, promotes cell survival and proliferation through STAT3, ERK1/2 and PI3K/AKT pathways (PubMed:25793261, PubMed:31311100). Promotes phosphorylation of GSK3B at 'Ser-9' and CTTN (By similarity). Promotes epithelial cell spreading (By similarity).
Co-chaperone of Hsc70. Stimulates ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B (in vitro) (PubMed:24318877).
Consists of three domains, a large central CORE domain and two small peripheral domains, NMPbind and LID, which undergo movements during catalysis. The LID domain closes over the site of phosphoryl transfer upon GTP binding. Assembling and dissambling the active center during each catalytic cycle provides an effective means to prevent GTP hydrolysis.
Highly expressed in heart, skeletal muscle and liver, moderately expressed in pancreas and kidney, and weakly expressed in placenta, brain and lung.
Involved in maintaining the homeostasis of cellular nucleotides by catalyzing the interconversion of nucleoside phosphates. Has GTP:AMP phosphotransferase and ITP:AMP phosphotransferase activities.
Interacts with CPLANE1. Interacts with INTU and FUZ; FUZ, INTU and WDPCP probably form the core CPLANE (ciliogenesis and planar polarity effectors) complex.
It is uncertain whether Met-1 or Met-34 is the initiator.
Mutations in WDPCP may act as modifiers of the phenotypic expression of Bardet-Biedl syndrome and Meckel syndrome by interacting in trans with primary BBS and MKS loci.
Probable effector of the planar cell polarity signaling pathway which regulates the septin cytoskeleton in both ciliogenesis and collective cell movements. Together with FUZ and WDPCP proposed to function as core component of the CPLANE (ciliogenesis and planar polarity effectors) complex involved in the recruitment of peripheral IFT-A proteins to basal bodies (By similarity).
Identified in the spliceosome C complex (PubMed:11991638). Component of the U11/U12 snRNPs that are part of the U12-type spliceosome (PubMed:15146077). Component of splicing factor SF3B which is composed of at least eight subunits; SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6, PHF5A and DDX42 (PubMed:12234937, PubMed:12738865, PubMed:27720643, PubMed:28541300). SF3B associates with the splicing factor SF3A and a 12S RNA unit to form the U2 small nuclear ribonucleoproteins complex (U2 snRNP) (PubMed:12234937). Interacts directly with SF3B4 (PubMed:25737013). The SF3B complex composed of SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6 and PHF5A interacts with U2AF2 (PubMed:27720643). Found in a complex with PRMT9, SF3B2 and SF3B4 (PubMed:25737013). Interacts (Arg-508-methylated form) with SMN1 (via Tudor domain) (PubMed:25737013). Interacts with RBM7 (PubMed:27905398). Interacts with ERCC6 (PubMed:26030138). Component of the minor spliceosome (PubMed:15146077, PubMed:33509932). Within this complex, interacts with SCNM1 and CRIPT (PubMed:33509932).
Involved in pre-mRNA splicing as a component of the splicing factor SF3B complex (PubMed:27720643). SF3B complex is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA (PubMed:12234937). May also be involved in the assembly of the 'E' complex (PubMed:10882114). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (PubMed:15146077) (Probable).
Methylation at Arg-508 by PRMT9 is required for the interaction with SMN1.
Polymerase that creates the 3'-poly(A) tail of mRNA's.
Monomer in endoplasmic reticulum, endoplasmic reticulum-Golgi intermediate compartment and cis-Golgi network. Interacts (via C-terminus) with COPG1; the interaction involves dimeric TMED3; however, there are conflicting reports on the interaction. Interacts with GORASP1 and GORASP2 (By similarity).
Potential role in vesicular protein trafficking, mainly in the early secretory pathway. Contributes to the coupled localization of TMED2 and TMED10 in the cis-Golgi network.
Expressed at high levels in brain, liver, and pancreas.
Mitochondrial glutamate/H(+) symporter. Responsible for the transport of glutamate from the cytosol into the mitochondrial matrix with the concomitant import of a proton (PubMed:11897791). Plays a role in the control of glucose-stimulated insulin secretion (By similarity).
Catalytically inactive since it lacks the active site but may have an alternative function.
Catalyzes the third of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of two carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme catalyzes the dehydration of the 3-hydroxyacyl-CoA intermediate into trans-2,3-enoyl-CoA, within each cycle of fatty acid elongation. Thereby, it participates in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.
In tooth development, may play a role in the recruitment and the differentiation of cells that contribute to cementum formation. May also bind hydroxyapatite and regulate its crystal nucleation to form cementum.
Isoform 1 is highly expressed in the myocardium, and to a lesser extent in skeletal and smooth muscular tissues including those from stomach, jejunum, and bladder. Also detected in gingival fibroblasts, periodontal ligament cells, osteoblasts and cementoblasts (PubMed:11054553, PubMed:22067203). Isoform 2 is specifically expressed by cementoblasts but also detected in periodontal ligament cells, heart, liver and kidney (at protein level) (PubMed:22067203).
Isoform 1 shares some similarity with tyrosine phosphatase proteins but it has probably no phosphatase activity.
Isoform 1: May interact with enzymes of the ELO family (including ELOVL1); with those enzymes that mediate condensation, the first of the four steps of the reaction cycle responsible for fatty acids elongation, may be part of a larger fatty acids elongase complex (PubMed:18554506). Isoform 2: Homooligomer. Self-assembles into spheres which then aggregates to form strings and a meshwork that may support hydroxyapatite crystal nucleation (PubMed:25263524).
Belongs to the cyclophilin-type PPIase family. PPIase A subfamily.
It is one of six related genes or pseudogenes found in a cluster, thought to result from gene duplication, on chromosome 1.
Expressed in the colon. Expression is significantly decreased in adenomas (polyps) and adenocarcinomas of the colon.
Interacts with CFTR, SLC26A6 and NHERF1 (By similarity). Interacts with PDZK1 (PubMed:15766278). Interacts (via PDZ-binding motif) with NHERF4 (via the third PDZ domain); interaction leads to decreased expression of SLC26A3 on the cell membrane resulting in its reduced exchanger activity (PubMed:22627094).
Mediates chloride-bicarbonate exchange with a chloride bicarbonate stoichiometry of 2:1 in the intestinal epithelia (PubMed:16606687, PubMed:19321737, PubMed:22159084, PubMed:22627094). Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation (By similarity).
N-glycosylation is required for efficient cell surface expression, and protection from proteolytic degradation.
Component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum (PubMed:34388369). Enhances the enzymatic activity of SPC and facilitates the interactions between different components of the translocation site (By similarity).
Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3 (PubMed:34388369). Component of the signal peptidase complex paralog C (SPC-C) composed of a catalytic subunit SEC11C and three accessory subunits SPCS1, SPCS2 and SPCS3 (PubMed:34388369). Within the complex, interacts with SEC11A or SEC11C and SPCS1 (PubMed:34388369). The complex induces a local thinning of the ER membrane which is used to measure the length of the signal peptide (SP) h-region of protein substrates (PubMed:34388369). This ensures the selectivity of the complex towards h-regions shorter than 18-20 amino acids (PubMed:34388369).
Can form homodimers (via C-terminus) (PubMed:23341463). Interacts (via C-terminus) with MAPKBP1 (via C-terminus) (PubMed:23341463, PubMed:28089251). Interacts with CDK5RAP2, CEP152, CEP63 and KIAA0753 (PubMed:26297806). CEP63, CDK5RAP2, CEP152, WDR62 are proposed to form a stepwise assembled complex at the centrosome forming a ring near parental centrioles (PubMed:26297806).
Present in fetal brain, enriched within the ventricular and subventricular zone (at protein level). In the embryonic brain it is expressed in mitotic neural precursor cells.
Required for cerebral cortical development. Plays a role in neuronal proliferation and migration (PubMed:20890278, PubMed:20729831). Plays a role in mother-centriole-dependent centriole duplication; the function seems also to involve CEP152, CDK5RAP2 and CEP63 through a stepwise assembled complex at the centrosome that recruits CDK2 required for centriole duplication (PubMed:26297806).
Activated by diarachidonoyl phosphatidic acid (DAPA), when 1,2-dipalmitoyl-PI4P is used as a substrate.
Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2/PIP2), a lipid second messenger that regulates several cellular processes such as signal transduction, vesicle trafficking, actin cytoskeleton dynamics, cell adhesion, and cell motility (PubMed:8955136, PubMed:21477596, PubMed:22942276). PtdIns(4,5)P2 can directly act as a second messenger or can be utilized as a precursor to generate other second messengers: inositol 1,4,5-trisphosphate (IP3), diacylglycerol (DAG) or phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3/PIP3) (PubMed:19158393, PubMed:20660631). PIP5K1A-mediated phosphorylation of PtdIns(4)P is the predominant pathway for PtdIns(4,5)P2 synthesis (By similarity). Can also use phosphatidylinositol (PtdIns) as substrate in vitro (PubMed:22942276). Together with PIP5K1C, is required for phagocytosis, both enzymes regulating different types of actin remodeling at sequential steps (By similarity). Promotes particle ingestion by activating the WAS GTPase-binding protein that induces Arp2/3 dependent actin polymerization at the nascent phagocytic cup (By similarity). Together with PIP5K1B, is required, after stimulation by G-protein coupled receptors, for the synthesis of IP3 that will induce stable platelet adhesion (By similarity). Recruited to the plasma membrane by the E-cadherin/beta-catenin complex where it provides the substrate PtdIns(4,5)P2 for the production of PtdIns(3,4,5)P3, IP3 and DAG, that will mobilize internal calcium and drive keratinocyte differentiation (PubMed:19158393). Positively regulates insulin-induced translocation of SLC2A4 to the cell membrane in adipocytes (By similarity). Together with PIP5K1C has a role during embryogenesis (By similarity). Independently of its catalytic activity, is required for membrane ruffling formation, actin organization and focal adhesion formation during directional cell migration by controlling integrin-induced translocation of the small GTPase RAC1 to the plasma membrane (PubMed:20660631). Also functions in the nucleus where it acts as an activator of TUT1 adenylyltransferase activity in nuclear speckles, thereby regulating mRNA polyadenylation of a select set of mRNAs (PubMed:18288197).
Highly expressed in heart, placenta, skeletal muscle, kidney and pancreas. Detected at lower levels in brain, lung and liver.
Interacts with RAC1 (By similarity). Interacts with TUT1 (PubMed:18288197). Forms a complex with CDH1/E-cadherin, CTNNB1/beta-catenin and CTNND1 at the plasma membrane upon calcium stimulation (PubMed:18288197). Found in a ternary complex with IRS1 and DGKZ in the absence of insulin stimulation (By similarity). Interacts with DGKZ (PubMed:15157668). Interacts with PIP4K2C; the interaction inhibits PIP5K1A kinase activity (PubMed:31091439).
Belongs to the bacterial ribosomal protein bL32 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:25278503, PubMed:25838379, PubMed:28892042). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. bL32m has a zinc binding site.
Binds to and represses JUN and MYB via the leucine zipper regions present in these proteins. Also binds to and represses PPARGC1A: this interaction is abrogated when PPARGC1A is phosphorylated by MAPK1/ERK. Binds to and stimulates transcription by AHR. Binds to KPNA2. Interacts with CLOCK and CRY1 (By similarity). Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21.
May activate or repress transcription via interactions with sequence specific DNA-binding proteins (By similarity). Repression may be mediated at least in part by histone deacetylase activity (HDAC activity) (By similarity). Acts as a corepressor and in concert with CRY1, represses the transcription of the core circadian clock component PER2 (By similarity). Preferentially binds to dimethylated histone H3 'Lys-9' (H3K9me2) on the PER2 promoter (By similarity). Has a role in rRNA biogenesis together with PWP1 (PubMed:29065309).
May be due to competing donor and acceptor splice sites.
Belongs to the JARID1 histone demethylase family.
Expression is highly down-regulated in metastatic prostate tumors.
Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. May play a role in spermatogenesis. Involved in transcriptional repression of diverse metastasis-associated genes; in this function seems to cooperate with ZMYND8. Suppresses prostate cancer cell invasion. Regulates androgen receptor (AR) transcriptional activity by demethylating H3K4me3 active transcription marks.
The JmjC domain is required for enzymatic activity.
Adapter protein that plays a role in regulating cell-surface expression of adrenergic receptors and probably also other G protein-coupled receptors (PubMed:20559325, PubMed:21982743, PubMed:23208550). Plays a role in NEDD4-mediated ubiquitination and endocytosis af activated ADRB2 and subsequent ADRB2 degradation (PubMed:20559325, PubMed:23208550). May recruit NEDD4 to ADRB2 (PubMed:20559325). Alternatively, may function as adapter protein that does not play a major role in recruiting NEDD4 to ADRB2, but rather plays a role in a targeting ADRB2 to endosomes (PubMed:23208550).
By troglitazone and pioglitazone (selective PPARG agonists), by prostaglandin J2 (PGJ2) and by L165,041 (a PPARD ligand), by vitamin D3 and, to a lesser extent, by phorbol myristate acetate (PMA) in the promyelocytic leukemia HL-60 cells. No induction by retinoic acid, nor by clofibrate (a specific PPARA agonist) (PubMed:16269462). Up-regulated by fasting (PubMed:21982743).
Highly expressed in skeletal muscle, placenta, kidney, lung, liver, blood, adrenal gland, lymph node, mammary gland, thyroid, and trachea (PubMed:16269462, PubMed:21982743). Very low levels in colon, thymus, spleen, small intestine, bladder and bone marrow (PubMed:16269462). Strong expression in differentiated adipocytes compared to preadipocytes (PubMed:16269462). Detected in omental fat and subcutaneous fat tissue (PubMed:21982743).
Interacts (via PPxY motifs) with NEDD4 (via WW domains) (PubMed:20559325, PubMed:23208550, PubMed:24379409). Interacts with ADRB2 (PubMed:20559325, PubMed:21982743, PubMed:25220262). Interacts with ADRB3 (PubMed:21982743). Interacts with HGS (via PPxY motifs) (PubMed:23208550). Does not bind TXN (thioredoxin) (PubMed:16269462). Interacts with ITCH (PubMed:23886940). Interacts with WWP1 (via WW domains) (PubMed:21191027).
Isoform TGN46 is widely expressed. Isoform TGN51 is more abundant in fetal lung and kidney. Isoform TGN48 is barely expressed in embryonic kidney and promyelocytic cells.
May be involved in regulating membrane traffic to and from trans-Golgi network.
Casoxin D acts as opioid antagonist and has vasorelaxing activity mediated by bradykinin B1 receptors.
Heteromultimers of alpha-s1 casein and kappa-casein; disulfide-linked.
Important role in the capacity of milk to transport calcium phosphate.
In milk, the alpha s1- and beta-caseins precipitate in presence of calcium (so-called calcium-sensitive caseins). Kappa-casein prevents the precipitation of the other caseins by calcium through the formation of large stable colloidal particles termed micelles.
Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment.
Functions as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway through the GATOR complex. In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents TORC1 signaling. Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:25263562, PubMed:26449471). This stress-inducible metabolic regulator may also play a role in protection against oxidative and genotoxic stresses (By similarity). May positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1 (PubMed:23274085). Moreover, may prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein (By similarity). Was originally reported to contribute to oxidative stress resistance by reducing PRDX1 (PubMed:15105503). However, this could not be confirmed (By similarity).
Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated by leucine (PubMed:25263562, PubMed:26449471). Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them (PubMed:25259925). Interacts with KEAP1, RBX1 and SQSTM1; in the SQSTM1-dependent autophagic degradation of KEAP1 (PubMed:23274085). May interact with PRDX1 (PubMed:15105503).
Isoform T2 and isoform T3 are induced by genotoxic stress (UV, gamma-irradiation and cytotoxic drugs) in a p53/TP53-dependent manner. Isoform T1 is not induced by p53/TP53.
The N-terminal domain may have an alkylhydroperoxide reductase activity.
Available under the names Kogenate (Bayer) and Recombinate (Baxter and American Home Products). Used to treat hemophilia A.
Domain F5/8 type C 2 is responsible for phospholipid-binding and essential for factor VIII activity.
Factor VIII, along with calcium and phospholipid, acts as a cofactor for F9/factor IXa when it converts F10/factor X to the activated form, factor Xa.
Interacts with VWF/vWF. vWF binding is essential for the stabilization of F8 in circulation.
Proteolytically cleaved by cathepsin CTSG to produce a partially activated form.
Sulfation on Tyr-1699 is essential for binding vWF.
The disease is caused by variants affecting the gene represented in this entry. Of particular interest for the understanding of the function of F8 is the category of CRM (cross-reacting material) positive patients (approximately 5%) that have considerable amount of F8 in their plasma (at least 30% of normal), but the protein is non-functional; i.e. the F8 activity is much less than the plasma protein level. CRM-reduced is another category of patients in which the F8C antigen and activity are reduced to approximately the same level. Most mutations are CRM negative, and probably affect the folding and stability of the protein.
Retinol dehydrogenase with a clear preference for NADP. Oxidizes all-trans-retinol, but seems to reduce all-trans-retinal with much higher efficiency (PubMed:18039331). Has no activity toward steroids (PubMed:18039331).
Was originally thought to lack retinol dehydrogenase (RDH) activity. However, a more recent publication demonstrates a retinol dehydrogenase activity for RDH13.
Widely expressed (PubMed:18039331). In the retina, detected in the inner segment of the photoreceptor cells. Weak signals are observed in a small population of inner nuclear neurons and the inner plexiform layer (PubMed:12226107).
Expressed in brain; detected in the frontal cortex, with lower levels in the thalamus, caudate, hypothalamus and midbrain.
Orphan receptor. May play a role in brain function.
Belongs to the saccharopine dehydrogenase family.
Binds mRNA from germ cells. Interacts with PUM2 (By similarity).
Ovary, testis and brain (at protein level). In the ovaries, expressed during multiple stages of oogenesis, including primordial, primary, secondary and antral follicles with the highest expression in the oocytes. In the testis, expressed in germ cells, type A spermatogonia (SA), primary spermatocytes (S1), round spermatids (S3) and elongated spermatids.
Plays a role in the maintenance of the undifferentiated state of germ cells regulating the spermatogonia cell cycle and inducing a prolonged transit in G1 phase. Affects cell proliferation probably by repressing translation of specific mRNAs. Maintains the germ cell lineage by suppressing both Bax-dependent and -independent apoptotic pathways. Essential in the early stage embryo to protect the migrating primordial germ cells (PGCs) from apoptosis.
Belongs to the potassium channel family. S (TC 1.A.1.2) subfamily. Kv9.1/KCNS1 sub-subfamily.
Detected in all tissues tested with the exception of skeletal muscle. Highly expressed in adult and fetal brain, fetal kidney and lung, and adult prostate and testis (PubMed:10484328).
Heterotetramer with KCNB1 (PubMed:10484328). Heterotetramer with KCNB2 (By similarity). Does not form homomultimers (PubMed:10484328).
Potassium channel subunit that does not form functional channels by itself. Can form functional heterotetrameric channels with KCNB1 and KCNB2; modulates the delayed rectifier voltage-gated potassium channel activation and deactivation rates of KCNB1 and KCNB2 (PubMed:10484328).
Interacts with an array of inositol phospholipids such as phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 5-phosphate (PI5P). PIP-binding enhances membrane association.
Its exogenous expression in a sarcoma cell line decreases the expression of ABCB1 (P-glycoprotein 1) and increases cellular sensitivity to an anticancer drug (adriamycin).
Myristoylated. Essential for membrane association.
Necessary for abscisic acid (ABA) binding on the cell membrane and activation of the ABA signaling pathway in granulocytes.
Highly expressed in adrenal gland, placenta, thyroid gland, heart, skeletal muscle and small intestine. Weakly expressed in testis, ovary, colon, pancreas, kidney and stomach.
Interacts with PPP1CA, PPP1CB and PPP1CC/PPP1G isoform 1.
Regulatory subunit of protein phosphatase 1.
Belongs to the mandelate racemase/muconate lactonizing enzyme family. ENOSF1 subfamily.
Plays a role in the catabolism of L-fucose, a sugar that is part of the carbohydrates that are attached to cellular glycoproteins. Catalyzes the dehydration of L-fuconate to 2-keto-3-deoxy-L-fuconate by the abstraction of the 2-proton to generate an enediolate intermediate that is stabilized by the magnesium ion (PubMed:24697329).
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. A common ENOSF1 haplotype (defined by rs699517, rs2790 and rs1512643) in the presence of TYMS germline variants result in severe thymidylate synthase deficiency and disease. The pathogenic mechanism involves increased expression of ENOSF1 relative to TYMS, and post-transcriptional inhibition of TYMS translation through ENOSF1-TYMS RNA-RNA interactions.
Was originally (PubMed:8493092) identified as a gene coding for an antisense RNA to thymidylate synthase, and was proposed to down-regulate TYMS activity (PubMed:8869746), possibly by promoting the degradation of TYMS mRNA via an antisense RNA-based mechanism (PubMed:12084460).
Highly expressed in brain. Also expressed at lower level in developing lung, cartilage, kidney and hematopoietic and immune tissues.
Interacts with the cytoplasmic part of DCC (By similarity). Interacts with GNAI2 via its cytoplasmic part (PubMed:12359238). Interacts (via death domain) with DAPK1 (via death domain) (PubMed:15729359, PubMed:18582460). Interacts (via extracellular domain) with FLRT3 (via extracellular domain); the interaction is direct (PubMed:26235030). Interacts (via extracellular domain) with FLRT2 and FLRT3 (via extracellular domain), but has higher affinity for FLRT3 (PubMed:25374360). Identified in a complex with FLRT3 and ADGRL3; does not interact with ADGRL3 by itself (PubMed:26235030).
Palmitoylation is required for pro-apoptotic activity, but not for location at lipid rafts.
Phosphorylated on cytoplasmic tyrosine residues.
Receptor for netrin required for axon guidance. Mediates axon repulsion of neuronal growth cones in the developing nervous system upon ligand binding. Axon repulsion in growth cones may be caused by its association with DCC that may trigger signaling for repulsion (By similarity). Functions as netrin receptor that negatively regulates vascular branching during angiogenesis. Mediates retraction of tip cell filopodia on endothelial growth cones in response to netrin (By similarity). It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand (PubMed:12598906). Mediates apoptosis by activating DAPK1. In the absence of NTN1, activates DAPK1 by reducing its autoinhibitory phosphorylation at Ser-308 thereby increasing its catalytic activity (By similarity).
Although initially thought (PubMed:17846994) to be a zinc-finger protein, it was later shown (PubMed:17376863) that it binds 1 2Fe-2S cluster instead.
Belongs to the CISD protein family. CISD2 subfamily.
Homodimer. Interacts with BCL2; the interaction is direct and disrupted by BIK interaction with BCL2. Interacts with BCL2L1. Interacts with ITPR1.
Regulator of autophagy that contributes to antagonize BECN1-mediated cellular autophagy at the endoplasmic reticulum. Participates in the interaction of BCL2 with BECN1 and is required for BCL2-mediated depression of endoplasmic reticulum Ca(2+) stores during autophagy. Contributes to BIK-initiated autophagy, while it is not involved in BIK-dependent activation of caspases. Involved in life span control, probably via its function as regulator of autophagy.
Testis, small intestine, kidney, lung, brain, heart, pancreas and platelets.
Adaptor protein complex 1 (AP-1) is a heterotetramer composed of two large adaptins (gamma-type subunit AP1G1 and beta-type subunit AP1B1), a medium adaptin (mu-type subunit AP1M1 or AP1M2) and a small adaptin (sigma-type subunit AP1S1 or AP1S2 or AP1S3). Binds to MUC1.
Highly expressed in stem cells where it may be involved in regulation of pluripotency. In embryonic stem cells (ESCs), important for normal expression of the pluripotency regulators POU5F1/OCT4 and KLF4. Also important for expression of the ectodermal marker gene NES and the endodermal marker gene GATA4. Promotes stem cell proliferation in vitro.
Associated with late 40S pre-ribosomal particles (PubMed:16037817, PubMed:21081503). Interacts with PLK1 (via its N-terminus) (PubMed:21880710).
Autophosphorylated (in vitro) (PubMed:19564402, PubMed:21880710). Phosphorylation at Ser-335, Ser-380, Ser-548 by PLK1 affects the timing of the metaphase-anaphase transition (PubMed:21880710).
Serine/threonine-protein kinase involved in the final steps of cytoplasmic maturation of the 40S ribosomal subunit. Involved in export of the 40S pre-ribosome particles (pre-40S) from the nucleus to the cytoplasm. Its kinase activity is required for the release of NOB1, PNO1 and LTV1 from the late pre-40S and the processing of 18S-E pre-rRNA to the mature 18S rRNA (PubMed:19564402). Regulates the timing of the metaphase-anaphase transition during mitotic progression, and its phosphorylation, most likely by PLK1, regulates this function (PubMed:21880710).
Detected in heart, brain, lung, spleen and placenta.
Monomer. Homodimer. Interacts with SEMA7A.
Receptor for SEMA7A, for smallpox semaphorin A39R, vaccinia virus semaphorin A39R and for herpesvirus Sema protein. Binding of semaphorins triggers cellular responses leading to the rearrangement of the cytoskeleton and to secretion of IL6 and IL8 (By similarity).
Highly expressed in all hematopoietic tissues, including spleen, lymph node, peripheral blood, bone marrow, thymus, and fetal liver, with highest expression in thymus and fetal liver. Expression is also high in heart, brain, kidney, and skeletal muscle.
May be involved in transcription regulation of the alpha 2(I) collagen gene where it binds to the single-stranded polypyrimidine sequences in the promoter region.
Expressed in skin, pancreas and keratinocytes.
Highly expressed in testis. Very low expression in thymus. No expression in other tissues tested. Expressed in a differentiation stage-specific manner in mesenchymal chondrogenic progenitor cells.
(Microbial infection) The Legionella effector RavZ is a deconjugating enzyme that hydrolyzes the amide bond between the C-terminal glycine residue and an adjacent aromatic residue in ATG8 proteins conjugated to phosphatidylethanolamine (PE), producing an ATG8 protein that is resistant to reconjugation by the host machinery due to the cleavage of the reactive C-terminal glycine (PubMed:23112293, PubMed:31722778). RavZ is also able to mediate delipidation of ATG8 proteins conjugated to phosphatidylserine (PS) (PubMed:33909989).
Interacts with ATG13, OPRK1, RB1CC1 and ULK1 (PubMed:16431922, PubMed:23043107). Interacts with TP53INP1 and TP53INP2 (PubMed:22470510). Directly interacts with SQSTM1 (PubMed:17580304). Interacts with ATG3, ATG7 and MAP15. Interacts with TECPR2 (PubMed:20562859). Interacts with TBC1D5 (PubMed:22354992). Interacts with MAPK15 (PubMed:22948227). Interacts with TRIM5 (PubMed:25127057). Interacts with MEFV and TRIM21 (PubMed:26347139). Interacts with WDFY3 (PubMed:24668264). Interacts with the reticulophagy receptor TEX264 (PubMed:31006538, PubMed:31006537). Interacts with UBA5 (PubMed:26929408). Interacts with KBTBD6 and KBTBD7; the interaction is direct (PubMed:25684205). Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3 (PubMed:34338405). Interacts with IRGM (PubMed:29420192).
The precursor molecule is cleaved by ATG4 (ATG4A, ATG4B, ATG4C or ATG4D) to expose the glycine at the C-terminus and form the cytosolic form, GABARAPL1-I (PubMed:20404487, PubMed:29458288, PubMed:30661429, PubMed:28287329). The processed form is then activated by APG7L/ATG7, transferred to ATG3 and conjugated to phosphatidylethanolamine (PE) phospholipid to form the membrane-bound form, GABARAPL1-II (PubMed:20404487, PubMed:29458288). During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid (PubMed:33909989). ATG4 proteins also mediate the delipidation of PE-conjugated forms required for GABARAPL1 recycling when autophagosomes fuse with lysosomes (PubMed:20404487, PubMed:29458288, PubMed:33909989). In addition, ATG4B and ATG4D mediate delipidation of ATG8 proteins conjugated to PS during non-canonical autophagy (PubMed:33909989). ATG4B constitutes the major protein for proteolytic activation (PubMed:30661429). ATG4D is the main enzyme for delipidation activity (By similarity).
Ubiquitin-like modifier that increases cell-surface expression of kappa-type opioid receptor through facilitating anterograde intracellular trafficking of the receptor (PubMed:16431922). Involved in formation of autophagosomal vacuoles (PubMed:20404487). While LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation (PubMed:20404487). Through its interaction with the reticulophagy receptor TEX264, participates in the remodeling of subdomains of the endoplasmic reticulum into autophagosomes upon nutrient stress, which then fuse with lysosomes for endoplasmic reticulum turnover (PubMed:31006538, PubMed:31006537).
Ubiquitous. Expressed at very high levels in the brain, heart, peripheral blood leukocytes, liver, kidney, placenta and skeletal muscle. Expressed at very low levels in thymus and small intestine. In the brain, expression is particularly intense in motoneurons in the embryo and in neurons involved in somatomotor and neuroendocrine functions in the adult, particularly in the substantia nigra pars compacta.
Phosphorylated. Phosphorylation on Ser-560 occurs specifically during mitosis.
TPR repeats 1-7 mediate homodimerization, while the C-terminal TPR repeats bind to CDC26, burying its hydrophobic N-terminus.
V-shaped homodimer. The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:25043029). Interacts with PPP5C and CDC20 (PubMed:9628895, PubMed:9405394). Interacts with CDC26 (PubMed:19668213). Interacts with FBXO43.
Homodimer or oligomer (By similarity). Interacts with CD2AP and SH3BP1; probably part of a complex at cell junctions (PubMed:22891260).
May be involved in anchoring the apical junctional complex, especially tight junctions, to actin-based cytoskeletons.
Smooth muscle, spleen, testis, fetal brain, amygdala, corpus callosum, cerebellum, thalamus and subthalamic nucleus of adult brain.
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration inv(15)(q21.2;q21.3) has been found in patients with aromatase excess syndrome. The inversion moves the promoter of the CGNL1 gene into a 5-prime position in relation to the aromatase coding region.
The head region is responsible for both junction and actin filament-based distribution.
Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Required for the CCR4-NOT complex structural integrity. Can repress transcription and may link the CCR4-NOT complex to transcriptional regulation; the repressive function may specifically involve the N-Cor repressor complex containing HDAC3, NCOR1 and NCOR2. Involved in the maintenance of embryonic stem (ES) cell identity.
Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits. In the complex interacts directly with CNOT3. Interacts with NCOR1, NCOR2. HDAC3 and GPS2.
Ubiquitous. Highly expressed in brain, heart, thymus, spleen, kidney, liver, small intestine, placenta, lung and peripheral blood leukocytes.
Asn-157 is present instead of the conserved Asp which is expected to be an active site residue.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. STKL subfamily.
Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Is not required for association of CNOT7 to the CCR4-NOT complex.
Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits. CNOT10 and CNOT11 form a subcomplex docked to the CNOT1 scaffold.
Heterotrimer with MON2 and DOP1B; this complex regulates SNX3-retromer mediated endosomal sorting of WLS (PubMed:30213940). Interacts with RAB5A and RAB11A (PubMed:36604604).
Plays a role in regulating membrane trafficking of cargo proteins, namely endosome to plasma membrane recycling, probably acting through RAB5 and RAB11 activation (PubMed:27733620, PubMed:30213940, PubMed:36604604). Also involved in endosome to trans-Golgi network retrograde transport (PubMed:27733620, PubMed:30213940). In complex with MON2 and DOP1B, regulates SNX3 retromer-mediated endosomal sorting of WLS, a transporter of Wnt morphogens in developing tissues. Participates in the formation of endosomal carriers that direct WLS trafficking back to Golgi, away from lysosomal degradation (PubMed:30213940). Appears to be implicated in intercellular communication by negatively regulating the release of exosomes (PubMed:30947313). The flippase activity towards membrane lipids and its role in membrane asymmetry remains to be proved (PubMed:30947313). Required for the maintenance of neurite morphology and synaptic transmission (By similarity).
According to PubMed:10602361, expressed only in testis. According to PubMed:10756092, expressed also in brain and kidney. Isoform 2 is found only in transformed lymphoblasts. Isoform 3 is found in all tissues tested.
May function as a subunit of a cation channel and play a role in fertilization.
Belongs to the bacterial ribosomal protein bL9 family.
As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids (PubMed:20381137, PubMed:29123114, PubMed:29158492, PubMed:29107538, PubMed:28935770). Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator plays a dual role for the small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD): it (1) acts as a guanine nucleotide exchange factor (GEF), activating the small GTPases Rag and (2) mediates recruitment of Rag GTPases to the lysosome membrane (PubMed:22980980, PubMed:30181260, PubMed:29123114, PubMed:29158492, PubMed:29107538, PubMed:28935770). Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated (PubMed:22980980, PubMed:29123114, PubMed:29158492, PubMed:29107538). Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2 (By similarity).
Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980, PubMed:29285400, PubMed:29123114, PubMed:29158492, PubMed:29107538, PubMed:28935770, PubMed:31601708, PubMed:32868926, PubMed:35338845, PubMed:36103527, PubMed:36697823). LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:20381137, PubMed:22980980). Interacts with LAMTOR1 and LAMTOR3; the interaction is direct (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and RagD/RRAGD; regulated by amino acid availability (PubMed:20381137, PubMed:22980980, PubMed:32868926). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Interacts with MAPK1 and MAP2K1 (By similarity). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913, PubMed:32868926).
Homodimer (By similarity). Interacts with PTCD1.
Widely expressed. Highly expressed in heart, placenta, liver, skeletal muscle, kidney, pancreas, testis and ovary. Weakly expressed in brain, lung, spleen, thymus, prostate, small intestine, colon and leukocytes.
Zinc phosphodiesterase, which displays mitochondrial tRNA 3'-processing endonuclease activity. Involved in tRNA maturation, by removing a 3'-trailer from precursor tRNA (PubMed:21593607). Associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly (PubMed:24703694).
Essential bifunctional enzyme that catalyzes both the N-deacetylation and the N-sulfation of glucosamine (GlcNAc) of the glycosaminoglycan in heparan sulfate. Modifies the GlcNAc-GlcA disaccharide repeating sugar backbone to make N-sulfated heparosan, a prerequisite substrate for later modifications in heparin biosynthesis. Has high deacetylase activity but low sulfotransferase activity.
Expressed in brain, kidney, liver, fetal and adult lung, adult pancreas, placenta, fetal spleen and fetal thymus. Not detected in adult/ fetal heart and skeletal muscle.
Expressed in brain, heart, skeletal muscle, testes, prostate.
In disagreement with experimental results in mouse, PubMed:22961547 reports lack of histone methyltransferase activity on core histones generally, and on histone H3 specifically.
Interacts with EPM2A and NHLRC1. This interaction sequesters EPM2A and NHLRC1 to the nucleus (PubMed:22961547). Interacts with BHLHE22 (By similarity).
Probable histone methyltransferase, preferentially acting on 'Lys-9' of histone H3 (By similarity). Involved in the control of steroidogenesis through transcriptional repression of steroidogenesis marker genes such as CYP17A1 and LHCGR (By similarity). Forms with BHLHE22 a transcriptional repressor complex controlling genes involved in neural development and neuronal differentiation (By similarity). In the retina, it is required for rod bipolar and type 2 OFF-cone bipolar cell survival (By similarity).
Component of the dolichol-phosphate mannose (DPM) synthase complex composed of DPM1, DPM2 and DPM3; within the complex, directly interacts with DPM3 (PubMed:10835346, PubMed:16280320). This interaction stabilizes DPM1 (PubMed:10835346, PubMed:19576565).
Transfers mannose from GDP-mannose to dolichol monophosphate to form dolichol phosphate mannose (Dol-P-Man) which is the mannosyl donor in pathways leading to N-glycosylation, glycosyl phosphatidylinositol membrane anchoring, and O-mannosylation of proteins; catalytic subunit of the dolichol-phosphate mannose (DPM) synthase complex.
Acts as a transcriptional repressor (PubMed:14550261, PubMed:19409814, PubMed:31587868). Plays a role as a transcriptional corepressor of the Notch-mediated signaling required for T-cell development (PubMed:19409814). Also involved in the TNF and IL-1 induced NF-kappa-B activation. Associates with chromatin at the Notch-regulated SKP2 promoter.
Component of the Notch corepressor complex. Interacts with CIR1 and HDAC3.
Ferric-chelate reductases reduce Fe(3+) to Fe(2+) before its transport from the endosome to the cytoplasm.
Homodimer, and heterodimer with MTNR1A and MTNR1B.
Abnormally high expression of soluble isoforms (isoform 2, isoform 3 or isoform 4) may be a cause of preeclampsia.
Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation at Tyr-1169 is important for interaction with PLCG. Phosphorylation at Tyr-1213 is important for interaction with PIK3R1, PTPN11, GRB2, and PLCG. Phosphorylation at Tyr-1333 is important for endocytosis and for interaction with CBL, NCK1 and CRK. Is probably dephosphorylated by PTPRB.
Can contribute to cancer cell survival, proliferation, migration, and invasion, and tumor angiogenesis and metastasis. May contribute to cancer pathogenesis by promoting inflammatory responses and recruitment of tumor-infiltrating macrophages.
Detected in normal lung, but also in placenta, liver, kidney, heart and brain tissues. Specifically expressed in most of the vascular endothelial cells, and also expressed in peripheral blood monocytes. Isoform 2 is strongly expressed in placenta. Isoform 3 is expressed in corneal epithelial cells (at protein level). Isoform 3 is expressed in vascular smooth muscle cells (VSMC).
Has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion.
Interacts with VEGFA, VEGFB and PGF. Monomer in the absence of bound VEGFA, VEGFB or PGF. Homodimer in the presence of bound VEGFA, VEGFB and PGF. Can also form a heterodimer with KDR. Interacts (when tyrosine phosphorylated) with CBL, CRK, GRB2, NCK1, PIK3R1, PLCG, PSEN1 and PTPN11. Probably interacts also with PTPRB. Interacts with RACK1. Identified in a complex with CBL and CD2AP.
May function as decoy receptor for VEGFA.
Present in an inactive conformation in the absence of bound ligand. Binding of VEGFA, VEGFB or PGF leads to dimerization and activation by autophosphorylation on tyrosine residues.
The second and third Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFA binding.
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. Acts as a positive regulator of postnatal retinal hyaloid vessel regression (By similarity). May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1 (PubMed:16685275).
Ubiquitinated after VEGFA-mediated autophosphorylation, leading to proteolytic degradation.
Up-regulated in coculture of VSMC/endothelial cell (EC) or by direct exposure to VEGF of VSMC monoculture. Up-regulated from the second trimester of pregnancy to the term and in the placenta of women with preeclampsia (PE). Up-regulated in monocytes exposed to bacterial lipopolysaccharide (LPS).
Highly and selectively expressed in smooth muscle cells.
May influence blood pressure by functioning as a GTPase-activating protein for RHOA in vascular smooth muscle.
DNA ligase that seals nicks in double-stranded during DNA repair (PubMed:30395541). Also involved in DNA replication and DNA recombination.
Interacts with PCNA (PubMed:24911150). Interacts with POLB (PubMed:19336415).
Belongs to the eukaryotic ribosomal protein eL37 family.
Found predominantly in human melanomas and in certain fetal tissues; also found in liver, epithelium, umbilical chord, placenta and sweat gland ducts.
Involved in iron cellular uptake. Seems to be internalized and then recycled back to the cell membrane. Binds a single atom of iron per subunit. Could also bind zinc.
Belongs to the complex I NDUFC1 subunit family.
As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs.
Component of the minor spliceosome. Within this complex, interacts with ARMC7 and PRPF8/PRP8.
Detected in blood serum (at protein level).
Plays a role in the innate immune response. Binds to the lipid A moiety of bacterial lipopolysaccharides (LPS), a glycolipid present in the outer membrane of all Gram-negative bacteria (PubMed:7517398, PubMed:24120359). Acts as an affinity enhancer for CD14, facilitating its association with LPS. Promotes the release of cytokines in response to bacterial lipopolysaccharide (PubMed:7517398, PubMed:24120359).
Plays a role in the innate immune response. Binds to the lipid A moiety of bacterial lipopolysaccharides (LPS), a glycolipid present in the outer membrane of all Gram-negative bacteria. Acts as an affinity enhancer for CD14, facilitating its association with LPS. Promotes the release of cytokines in response to bacterial lipopolysaccharide.
When bound to LPS, interacts (via C-terminus) with soluble and membrane-bound CD14.
Acetylation prevents ubiquitination and degradation mediated by SMURF1.
Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access (PubMed:21791611). Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.
Interacts with WWP1 (By similarity). Interacts with COPS5. Interacts with NEDD4L. Interacts with STAMBP. Interacts with RNF111, AXIN1 and AXIN2. Interacts with PPP1R15A. Interacts (via MH2 domain) with EP300. Interacts with ACVR1B, SMURF1, SMURF2 and TGFBR1; SMAD7 recruits SMURF1 and SMURF2 to the TGF-beta receptor and regulates its degradation (PubMed:9892009, PubMed:11163210, PubMed:11278251, PubMed:12023024, PubMed:21791611). Interacts with PDPK1 (via PH domain). Interacts with TSC22D1/TSC-22; the interaction requires TGF-beta and the interaction is inhibited by TGFBR1 (PubMed:21791611).
Phosphorylation on Ser-249 does not affect its stability, nuclear localization or inhibitory function in TGFB signaling; however it affects its ability to regulate transcription (By similarity). Phosphorylated by PDPK1.
Ubiquitinated by WWP1 (By similarity). Polyubiquitinated by RNF111, which is enhanced by AXIN1 and promotes proteasomal degradation (PubMed:14657019, PubMed:16601693). In response to TGF-beta, ubiquitinated by SMURF1; which promotes its degradation (PubMed:11278251).
Ubiquitous with higher expression in the lung and vascular endothelium.
Catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins to generate free fatty acids and cholesterol.
Glycosylation is not essential for catalytic activity.
Most abundantly expressed in brain, lung, kidney and mammary gland, a moderate expression seen in placenta and expressed at low levels in the liver and heart.
Expressed in G2/M phase. Not detected in quiescent cells.
May be involved in p53-induced cell cycle arrest in G2/M phase by interfering with microtubule rearrangements that are required to enter mitosis. Overexpression delays G2/M phase progression.
Interacts with TBP and JUN (By similarity). Part of the nascent polypeptide-associated complex (NAC), which is a heterodimer of NACA and BTF3 (via NAC-A/B domains). NAC associates with ribosomes through the BTF3/NACB subunit and contacts the ribosomal protein L23, which is positioned near the exiting site. Both subunits can contact nascent polypeptide chains. NACA may also form homodimers, and only this form binds DNA.
Phosphorylation of Thr-159 by GSK3B may promote proteasome mediated degradation (By similarity). Phosphorylation of Ser-43 by ILK during cell adhesion may promote nuclear localization.
Prevents inappropriate targeting of non-secretory polypeptides to the endoplasmic reticulum (ER). Binds to nascent polypeptide chains as they emerge from the ribosome and blocks their interaction with the signal recognition particle (SRP), which normally targets nascent secretory peptides to the ER. Also reduces the inherent affinity of ribosomes for protein translocation sites in the ER membrane (M sites). May act as a specific coactivator for JUN, binding to DNA and stabilizing the interaction of JUN homodimers with target gene promoters.
The positively charged inner surface of the NAC-A/B domain is crucial for NACA localization in the nucleus and DNA-binding. This region is blocked from binding nucleic acids in the heterodimeric complex by a helix region in the beta-subunit, it also displays much higher affinity for RNA than DNA.
Belongs to the GcvT family. CAF17 subfamily.
Expressed in skin fibroblasts and skeletal muscle (at protein level).
Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway.
Acetylation at Lys-680 by KAT8/MOF promotes its dissociation from pRNA, affecting heterochromatin formation, nucleosome positioning and rDNA silencing. Deacetylation by SIRT1 in late S phase enhances pRNA-binding, allowing de novo DNA methylation and heterochromatin formation. Acetylation is high during S phase and declines to background levels in late S phase when the silent copies of rRNA genes are replicated (By similarity).
Component of the NoRC-1 ISWI chromatin remodeling complex at least composed of SMARCA1 and BAZ2A/TIP5, which regulates the spacing of histone octamers on the DNA template to facilitate access to DNA (PubMed:28801535). Within the NoRC-1 ISWI chromatin remodeling complex interacts with SMARCA1; the interaction is direct (PubMed:28801535). Component of the NoRC-5 ISWI chromatin remodeling complex (also called the NoRC nucleolar-remodeling complex), at least composed of SMARCA5/SNF2H and BAZ2A/TIP5, which regulates the spacing of histone octamers on the DNA template to facilitate access to DNA (PubMed:28801535). Within the NoRC-5 ISWI chromatin remodeling complexes interacts with SMARCA5/SNF2H; the interaction is direct (PubMed:28801535). Interacts with TTF1; the interaction is required for recruitment of the NoRC-5 ISWI chromatin remodeling complex to rDNA (By similarity). Interacts with HDAC1 (By similarity). Interacts with SIN3A (By similarity). Interacts with DNMT1 and DNM3B (By similarity). Interacts with BEND3 and USP21 (PubMed:26100909).
Expressed at moderate levels in most tissues analyzed, including heart, brain, placenta, lung, skeletal muscle, kidney and pancreas.
Regulatory subunit of the ATP-dependent NoRC-1 and NoRC-5 ISWI chromatin remodeling complexes, which form ordered nucleosome arrays on chromatin and facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair (PubMed:28801535). Both complexes regulate the spacing of nucleosomes along the chromatin and have the ability to slide mononucleosomes to the center of a DNA template (PubMed:28801535). Directly stimulates the ATPase activity of SMARCA5 in the NoRC-5 ISWI chromatin remodeling complex (PubMed:28801535). The NoRC-1 ISWI chromatin remodeling complex has a lower ATP hydrolysis rate than the NoRC-5 ISWI chromatin remodeling complex (PubMed:28801535). Within the NoRC-5 ISWI chromatin remodeling complex, mediates silencing of a fraction of rDNA by recruiting histone-modifying enzymes and DNA methyltransferases, leading to heterochromatin formation and transcriptional silencing (By similarity). In the complex, it plays a central role by being recruited to rDNA and by targeting chromatin modifying enzymes such as HDAC1, leading to repress RNA polymerase I transcription (By similarity). Recruited to rDNA via its interaction with TTF1 and its ability to recognize and bind histone H4 acetylated on 'Lys-16' (H4K16ac), leading to deacetylation of H4K5ac, H4K8ac, H4K12ac but not H4K16ac (By similarity). Specifically binds pRNAs, 150-250 nucleotide RNAs that are complementary in sequence to the rDNA promoter; pRNA-binding is required for heterochromatin formation and rDNA silencing (By similarity).
The MBD (methyl-CpG-binding) domain, also named TAM domain, specifically recognizes and binds a conserved stem-loop structure the association within pRNA. Binding to pRNA induces a conformational change of BAZ2A/TIP5 and is essential for targeting the NoRC complex to the nucleolus.
The bromo domain and the PHD-type zinc finger recognize and bind histone H4 acetylated on 'Lys-16' (H4K16ac). These 2 domains play a central role in the recruitment of chromatin silencing proteins such as DNMT1, DNMT3B and HDAC1.
Ubiquitinated. Deubiquitinated by USP21 leading to its stabilization.
Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B), and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific (PubMed:8895581). Component of the BAF complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C (PubMed:18765789). In muscle cells, the BAF complex also contains DPF3. Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin (By similarity). Component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin (ACTB) (PubMed:22952240, PubMed:26601204). Component of SWI/SNF (GBAF) subcomplex, which includes at least BICRA or BICRAL (mutually exclusive), BRD9, SS18, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, SMARCC1/BAF155, and SMARCD1/BAF60A (PubMed:29374058). Specifically interacts with the VDR heterodimer complex (PubMed:14698202). Interacts with ESR1, NR3C1, NR1H4, PGR, SMARCA4, SMARCC1 and SMARCC2 (PubMed:12917342, PubMed:30879640). Interacts with DPF2 (PubMed:20460684). Interacts with DPF3a (isoform 2 of DPF3/BAF45C) and with HDGFL2 in a DPF3a-dependent manner (PubMed:32459350). Interacts with FOS, FOSB isoform 1 and 2, FOSL1 and FOSL2 (By similarity).
Expressed in all tissues tested, including brain, heart, kidney, liver, lung, muscle, pancreas and placenta.
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner (PubMed:8804307, PubMed:29374058). Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Has a strong influence on vitamin D-mediated transcriptional activity from an enhancer vitamin D receptor element (VDRE). May be a link between mammalian SWI-SNF-like chromatin remodeling complexes and the vitamin D receptor (VDR) heterodimer (PubMed:14698202). Mediates critical interactions between nuclear receptors and the BRG1/SMARCA4 chromatin-remodeling complex for transactivation (PubMed:12917342). Interacts with AKIRIN2 (By similarity).
Based on a readthrough transcript which may produce a TWE-PRIL (TNFSF12-TNFSF13) fusion protein. Expressed at protein level in primary T-lymphocytes and monocytic cell lines.
Binds to FN14 and possibly also to TNRFSF12/APO3. Weak inducer of apoptosis in some cell types. Mediates NF-kappa-B activation. Promotes angiogenesis and the proliferation of endothelial cells. Also involved in induction of inflammatory cytokines. Promotes IL8 secretion.
Highly expressed in adult heart, pancreas, skeletal muscle, brain, colon, small intestine, lung, ovary, prostate, spleen, lymph node, appendix and peripheral blood lymphocytes. Low expression in kidney, testis, liver, placenta, thymus and bone marrow. Also detected in fetal kidney, liver, lung and brain.
Homotrimer (Probable). Interacts with the angiogenic factor AGGF1/VG5Q.
(Microbial infection) In case of herpes simplex virus 1/HHV-1 infection, forms hetero-amyloid structures with HHV-1 protein RIR1/ICP6 which may inhibit ZBP1-mediated necroptosis, thereby preventing host cell death pathway and allowing viral evasion.
(Microbial infection) Interacts (via RIP homotypic interaction motif/RHIM) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RHIM); this interaction may induce heteromeric amyloid assemblies and prevent necroptosis activation (PubMed:33348174). Interacts with human herpes simplex virus 1/HHV-1 protein ICP0 (Probable).
(Microbial infection) The RIP homotypic interaction motif (RHIM) mediates interaction with the RHIM motif of the herpes simplex virus 1/HHV-1 protein RIR1/ICP6 to form hetero-amyloid structures.
Highly expressed in lymphatic tissues including lymph node, leukocytes, tonsil, bone marrow and spleen (PubMed:11842111). Expressed to a lesser extent in thymus, lung and liver (PubMed:11842111).
Homodimer (By similarity). Interacts (via RIP homotypic interaction motif) with RIPK3; leading to RIPK3 activation and necroptosis; interaction is enhanced by CASP6 (By similarity). Interacts (via RIP homotypic interaction motif) with RIPK1 (By similarity). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity).
Key innate sensor that recognizes and binds Z-RNA structures, which are produced by a number of viruses, such as herpesvirus, orthomyxovirus or flavivirus, and triggers different forms of cell death (PubMed:32200799). ZBP1 acts as an essential mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an integral part of host defense against pathogens, by activating RIPK3, caspase-8 (CASP8), and the NLRP3 inflammasome (By similarity). Key activator of necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members, via its ability to bind Z-RNA: once activated upon Z-RNA-binding, ZBP1 interacts and stimulates RIPK3 kinase, which phosphorylates and activates MLKL, triggering execution of programmed necrosis (By similarity). In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: ZBP1 recognizes and binds Z-RNA structures that are produced in infected nuclei by orthomyxoviruses, such as the influenza A virus (IAV), leading to ZBP1 activation, RIPK3 stimulation and subsequent MLKL phosphorylation, triggering disruption of the nuclear envelope and leakage of cellular DNA into the cytosol (PubMed:32200799). ZBP1-dependent cell death in response to IAV infection promotes interleukin-1 alpha (IL1A) induction in an NLRP3-inflammasome-independent manner: IL1A expression is required for the optimal interleukin-1 beta (IL1B) production, and together, these cytokines promote infiltration of inflammatory neutrophils to the lung, leading to the formation of neutrophil extracellular traps (By similarity). In addition to its direct role in driving necroptosis via its ability to sense Z-RNAs, also involved in PANoptosis triggered in response to bacterial infection: component of the AIM2 PANoptosome complex, a multiprotein complex that triggers PANoptosis (By similarity). Also acts as the apical sensor of fungal infection responsible for activating PANoptosis (By similarity). Involved in CASP8-mediated cell death via its interaction with RIPK1 but independently of its ability to sense Z-RNAs (By similarity). In some cell types, also able to restrict viral replication by promoting cell death-independent responses (By similarity). In response to Zika virus infection in neurons, promotes a cell death-independent pathway that restricts viral replication: together with RIPK3, promotes a death-independent transcriptional program that modifies the cellular metabolism via up-regulation expression of the enzyme ACOD1/IRG1 and production of the metabolite itaconate (By similarity). Itaconate inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (By similarity).
The Z-binding domains recognize and bind left-handed double-stranded Z-RNA structures, but not A-RNA, the right-handed double-stranded RNAs that are structurally very different from Z-RNAs. The second Z-binding domain (also named Zalpha2) acts as a molecular switch regulating pyroptosis, necroptosis and apoptosis (PANoptosis). The second Z-binding domain is essential for sensing influenza A virus (IAV) Z-RNAs.
ZBP1-dependent necroptosis is normally inhibited by RIPK1: RIPK1 inhibits the ZBP1-induced activation of RIPK3 via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis.
Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA. Specifically mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles. Specifically mediates the symmetric dimethylation of histone H4 'Arg-3' to form H4R3me2s. Plays a role in gene imprinting by being recruited by CTCFL at the H19 imprinted control region (ICR) and methylating histone H4 to form H4R3me2s, possibly leading to recruit DNA methyltransferases at these sites. May also play a role in embryonic stem cell (ESC) pluripotency. Also able to mediate the arginine methylation of histone H2A and myelin basic protein (MBP) in vitro; the relevance of such results is however unclear in vivo.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Protein arginine N-methyltransferase family. PRMT7 subfamily.
Homodimer and heterodimer (By similarity). Interacts with CTCFL (By similarity). Interacts with PRMT5 and SNRPD3.
May be involved in etoposide-induced cytotoxicity, a chemotherapeutic agent frequently used for testicular cancer and small-cell lung cancer that can cause cytotoxicity in the treatment of other cancers. Down-regulation confers increased sensitivity to the Top1 inhibitor camptothecin (CPT).
Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Involved in centrosome migration to the apical cell surface during early ciliogenesis. Required for ciliary structure and function, including a role in regulating length and appropriate number through modulating centrosome duplication. Required for cell branching morphology.
Part of the tectonic-like complex (also named B9 complex) (PubMed:26595381). Interacts with TMEM107 (PubMed:26595381). Interacts with TCTN3, AHI1, TCTN1, TCTN2, CC2D2A (By similarity). Interacts with FLNA (PubMed:22121117). Interacts with TMEM67 (PubMed:17185389). Interacts with B9D1 and B9D2 (By similarity).
Binds to mRNA in a sequence-independent manner. May play a role in regulation of pre-mRNA splicing or in the assembly of rRNA into ribosomal subunits. May be involved in mRNA transport. May be involved in epigenetic regulation of muscle differentiation through regulation of activity of the histone-lysine N-methyltransferase KMT5B.
Expressed in adult muscle, lymphocytes, fetal brain, muscle, and placenta. Also expressed in the smooth muscle of arteries and veins, the sweat glands and the epidermis.
Homodimer and homotetramer in solution. Identified in the spliceosome C complex. Interacts with KMT5B (via C-terminus). Interacts (via N-terminus) with KPNA2 and NXF1/TAP. Interacts with F-actin with a stoichiometry of 2:1. Interacts with GARIN3, SMN1 and PABPN1 (PubMed:17103222).
The gene represented in this entry may be involved in disease pathogenesis. Overexpression of human FRG1 in mice leads to development of facioscapulohumeral muscular dystrophy (FSHD1)-like symptoms such as kyphosis, progressive muscle dystrophy and skeletal muscle atrophy (PubMed:16341202). It also causes aberrant pre-mRNA splicing of TNNT3 and MTMR1, affects the localization and activity of KMT5B, and leads to increased levels of EID3, resulting in inhibited muscle differentiation (PubMed:23720823). These results suggest that FSHD1 results from inappropriate overexpression of FRG1 which leads to abnormal alternative splicing of specific pre-mRNAs.
Was originally thought to be located in nuclear speckles based on overexpression of the protein (PubMed:15060122). However, the endogenous protein was later shown not be expressed in nuclear speckles (PubMed:21699900).
Component of the core-TFIIH basal transcription factor involved in nucleotide excision repair (NER) of DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II.
May be involved in several stages of intracellular trafficking.
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is composed of 13 subunits: EIF3A, EIF3B, EIF3C, EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L and EIF3M. The eIF-3 complex appears to include 3 stable modules: module A is composed of EIF3A, EIF3B, EIF3G and EIF3I; module B is composed of EIF3F, EIF3H, and EIF3M; and module C is composed of EIF3C, EIF3D, EIF3E, EIF3K and EIF3L. EIF3C of module C binds EIF3B of module A and EIF3H of module B, thereby linking the three modules. EIF3J is a labile subunit that binds to the eIF-3 complex via EIF3B. The eIF-3 complex interacts with RPS6KB1 under conditions of nutrient depletion. Mitogenic stimulation leads to binding and activation of a complex composed of MTOR and RPTOR, leading to phosphorylation and release of RPS6KB1 and binding of EIF4B to eIF-3. Interacts with COPS3, COPS6, COPS7 (COPS7A or COPS7B), EIF4G1, EPAS1, MCM7, NCBP1, PSMC6, TRIM27 and UPF2. Interacts with the HTLV-1 protein Tax-1. Interacts with IFIT1 and IFIT2 (PubMed:16023166, PubMed:16973618). Interacts with BZW2/5MP1 (PubMed:21745818).
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:17581632, PubMed:25849773, PubMed:27462815). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation (PubMed:17581632). The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression (PubMed:25849773). Required for nonsense-mediated mRNA decay (NMD); may act in conjunction with UPF2 to divert mRNAs from translation to the NMD pathway (PubMed:17468741). May interact with MCM7 and EPAS1 and regulate the proteasome-mediated degradation of these proteins (PubMed:17310990, PubMed:17324924).
Ubiquitously expressed. Expressed at highest levels in appendix, lymph, pancreas, skeletal muscle, spleen and thymus.
Interacts with the SH3-domain of DOCK1 via its SH3-binding site. Probably part of a complex with DOCK1 and RAC1. Probably part of a complex with DOCK1 and CRK isoform CRK-II. Interacts with ARHGEF16, DOCK4 and EPHA2; mediates activation of RAC1 by EPHA2 (PubMed:20679435). Interacts with ADGRB3 (PubMed:24567399). Interacts with AUTS2; the interaction is direct (By similarity).
Involved in cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility. Acts in association with DOCK1 and CRK. Was initially proposed to be required in complex with DOCK1 to activate Rac Rho small GTPases. May enhance the guanine nucleotide exchange factor (GEF) activity of DOCK1.
Widely expressed, with a higher expression in skeletal muscle, kidney and placenta.
A chromosomal aberration involving KIRREL3 and CDH15 is found in a patient with severe intellectual disability and dysmorphic facial features. Translocation t(11;16)(q24.2;q24).
Expressed in fetal and adult brain (PubMed:19012874). Also expressed in kidney, specifically in podocytes of kidney glomeruli (PubMed:12424224). Also expressed in skeletal muscle (PubMed:25488023).
Homodimer; mediates homophilic interactions to promote cell adhesion. Interacts with NPHS1; forms heterodimers with NPHS1 (By similarity). Interacts with NPHS2/podocin (via the C-terminus) (PubMed:12424224). Interacts with CASK (PubMed:19012874). Interacts (via extracellular region) with MAP1B (PubMed:25902260). Interacts (via extracellular region) with MYO16 (PubMed:25902260). Interacts (via intracellular region) with ATP1B1 (PubMed:25902260). Interacts (via intracellular region) with SHMT2 (PubMed:25902260). Interacts (via intracellular region) with UFC1 (PubMed:25902260).
Synaptic adhesion molecule required for the formation of target-specific synapses. Required for formation of target-specific synapses at hippocampal mossy fiber synapses. Required for formation of mossy fiber filopodia, the synaptic structures connecting dentate granule and GABA neurons. Probably acts as a homophilic adhesion molecule that promotes trans-cellular interactions and stabilize mossy fiber filipodia contact and subsequent synapse formation. Required for the coalescence of vomeronasal sensory neuron axons. May be involved in the hematopoietic supportive capacity of stroma cells; the secreted extracellular domain is directly responsible for supporting hematopoietic stem cells.
Undergoes proteolysis by a metalloprotease and gives rise to a soluble form.
Expressed in a variety of organs, but most strongly in adult testis and ovary followed by small intestine, colon, prostate, thymus, spleen, pancreas, skeletal muscle, heart, brain and kidney. Also expressed in umbilical vein endothelial cells, foreskin fibroblast and Hep-G2 cells.
(Microbial infection) Upon dengue virus infection.
E3 ubiquitin ligase that plays an important role in antiviral immunity by restricting different viral infections including dengue virus or vesicular stomatitis indiana virus (PubMed:23131556, PubMed:30142214, PubMed:31375575, PubMed:31578292). Ubiquitinates viral proteins such as dengue virus NS3 thereby limiting infection (PubMed:30844644). In addition, acts as a key mediator of type I interferon induced microtubule stabilization by directly associating to microtubules independently of its E3 ligase activity (PubMed:36251989). Plays also a role in cataract formation together with TP53 (PubMed:30844644). Mechanistically, inhibits UVB-induced cell apoptosis and reactive oxygen species (ROS) production by inducing TP53 ubiquitination (PubMed:30844644).
Homo-multimer; required for antiviral activity (PubMed:31578292, PubMed:33021497). Interacts with PML (By similarity).
Phosphorylated. Phosphorylation is necessary for nuclear localization.
The RING-type zinc finger domain is responsible for E3 ubiquitin ligase activity and for nuclear localization and aggregation.
Component of the chromosomal passenger complex (CPC) composed of at least BIRC5/survivin, CDCA8/borealin, INCENP, AURKB or AURKC; in the complex binds directly to AURKB or AURKC via the IN box, and forms a triple-helix bundle-based subcomplex with BIRC5 and CDCA8 via its N-terminus (PubMed:17956729, PubMed:27332895). The reported homodimerization is questioned as the SAH domain is shown to be monomeric (By similarity). Interacts with H2AZ1 (By similarity). Interacts with CBX1 and CBX3. Interacts with tubulin beta chain. Interacts with EVI5. Interacts with CBX5; POGZ and INCENP compete for interaction with CBX5; regulates INCENP (and probably CPC) localization to centromeres in interphase and not required for proper mitotic progression or sister chromatid cohesion. Interacts with POGZ. Interacts with JTB.
Component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Acts as a scaffold regulating CPC localization and activity. The C-terminus associates with AURKB or AURKC, the N-terminus associated with BIRC5/survivin and CDCA8/borealin tethers the CPC to the inner centromere, and the microtubule binding activity within the central SAH domain directs AURKB/C toward substrates near microtubules (PubMed:15316025, PubMed:12925766, PubMed:27332895). The flexibility of the SAH domain is proposed to allow AURKB/C to follow substrates on dynamic microtubules while ensuring CPC docking to static chromatin (By similarity). Activates AURKB and AURKC (PubMed:27332895). Required for localization of CBX5 to mitotic centromeres (PubMed:21346195). Controls the kinetochore localization of BUB1 (PubMed:16760428).
Originally predicted to contain a coiled coil domain but shown to contain a stable SAH domain instead.
Phosphorylation by AURKB or AURKC at its C-terminal part is important for AURKB or AURKC activation by INCENP.
PubMed:11139336 experiments have been carried out partly in chicken and partly in human.
The IN box mediates interaction with AURKB and AURKC.
The SAH (single alpha-helix) region is characterized by a high content of charged residues which are predicted to stabilize the alpha-helical structure by ionic bonds. It can refold after extension suggesting an in vivo force-dependent function. The isolated SAH domain is monomeric.
Interacts with GTP-bound ARF1 (PubMed:15107860, PubMed:21454700). Interacts with SACM1L and VAPA and/or VAPB to form a ternary complex (PubMed:30659099).
Plays a role in regulation of vesicular cargo transport from the trans-Golgi network (TGN) to the plasma membrane (PubMed:15107860). Regulates Golgi phosphatidylinositol 4-phosphate (PtdIns(4)P) levels and activates the PtdIns(4)P phosphatase activity of SACM1L when it binds PtdIns(4)P in 'trans' configuration (PubMed:30659099). Binds preferentially to PtdIns(4)P (PubMed:11001876, PubMed:15107860). Negatively regulates APOB secretion from hepatocytes (PubMed:30659099).
The PH domain binds the small GTPase ARF1 and phosphatidylinositol-4-phosphate (PtdIns4P) with high selectivity, and is required for its recruitment to the trans-Golgi network (TGN).
Essential for neural crest development, converting cells from an epidermal fate to a neural crest cell fate. Binds to DNA (By similarity).
Galactose (Gal) transferase involved in the synthesis of terminal N-acetyllactosamine (LacNac) unit present on glycan chains of glycoproteins and glycosphingolipids (PubMed:9792633, PubMed:17690104, PubMed:12511560, PubMed:32827291). Catalyzes the transfer of Gal residue via a beta1->4 linkage from UDP-Gal to the non-reducing terminal N-acetyl glucosamine 6-O-sulfate (6-O-sulfoGlcNAc) in the linearly growing chain of both N- and O-linked keratan sulfate proteoglycans. Cooperates with B3GNT7 N-acetyl glucosamine transferase and CHST6 and CHST1 sulfotransferases to construct and elongate mono-and disulfated disaccharide units [->3Galbeta1->4(6-sulfoGlcNAcbeta)1->] and [->3(6-sulfoGalbeta)1->4(6-sulfoGlcNAcbeta)1->] within keratan sulfate polymer (PubMed:17690104). Transfers Gal residue via a beta1->4 linkage to terminal 6-O-sulfoGlcNAc within the LacNac unit of core 2 O-glycans forming 6-sulfo-sialyl-Lewis X (sLex). May contribute to the generation of sLex epitope on mucin-type glycoproteins that serve as ligands for SELL/L-selectin, a major regulator of leukocyte migration (PubMed:12511560). In the biosynthesis pathway of neolacto-series glycosphingolipids, transfers Gal residue via a beta1->4 linkage to terminal GlcNAc of a lactotriaosylceramide (Lc3Cer) acceptor to form a neolactotetraosylceramide (PubMed:9792633).
Highest expression is observed in placenta, pancreas, kidney and heart (PubMed:9792633). Expressed in corneal epithelial cells (PubMed:17690104).
Interacts with SLC35A2 (isoform 2; UGT1).
According to a report, it is incorporated into stress granules upon arsenite-induced stress and associates with heme-regulated kinase and eIF-2-alpha (EIF2S1) in regulating eIF-2-alpha phosphorylation (PubMed:20154146). However, no effect in eIF-2-alpha phosphorylation have been observed by another study (PubMed:24550447).
Prolyl 3-hydroxylase that catalyzes 3-hydroxylation of 'Pro-62' of small ribosomal subunit uS12 (RPS23), thereby regulating protein translation termination efficiency. Involved in stress granule formation.
Highly expressed in placenta followed by spleen, thymus, prostate, testis, small intestine and colon. Weakly expressed in pancreas, lung, liver, heart and skeletal muscle. Also expressed in fetal brain, spleen and thymus.
The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. In KLF6, the motif is inactive.
Transcriptional activator (By similarity). Binds a GC box motif. Could play a role in B-cell growth and development.
Allosterically activated by magnesium, and possibly also other divalent metal cations. Allosterically activated by ATP, ADP or GTP. Competitively inhibited by malonate.
Belongs to the serine/threonine dehydratase family.
Brain: expressed at high levels in hippocampus and corpus callosum, intermediate levels in substantia nigra and caudate, and low levels in amygdala, thalamus, and subthalamic nuclei. Expressed in heart, skeletal muscle, kidney and liver.
Catalyzes the synthesis of D-serine from L-serine. D-serine is a key coagonist with glutamate at NMDA receptors. Has dehydratase activity towards both L-serine and D-serine.
S-nitrosylated, leading to decrease the enzyme activity.
Detected in spleen and thyroid, and at lower levels in kidney, brain, lung and pancreas.
Interacts with SRC. Interacts with LCK when tyrosine phosphorylated.
May play a role in a signaling cascade by enhancing the kinase activity of SRC. Contributes to SRC-regulated transcription activation.
ATP-dependent RNA helicase required during spermatogenesis to repress transposable elements and prevent their mobilization, which is essential for germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. Involved in the primary piRNA metabolic process. Specifically binds to piRNA precursors and promotes the generation of intermediate piRNA processing fragments that are subsequently loaded to Piwi proteins. Acts via its ATP-dependent RNA helicase activity: displays 5'-3' RNA unwinding activity and probably mediates unwinding and funneling of single-stranded piRNA precursor transcripts to the endonuclease that catalyzes the first cleavage step of piRNA processing to generate piRNA intermediate fragments that are subsequently loaded to Piwi proteins.
Belongs to the DNA2/NAM7 helicase family. SDE3 subfamily.
Interacts with PIWIL1. Interacts with PIWIL2. Interacts with PIWIL4. Interacts with HSPA2. Interacts with PLD6.
(Microbial infection) Acts as a receptor for hepatitis C virus (HCV) entry into hepatic cells.
Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3 (By similarity). Interacts with CLDN1, CD81 and OCLN (PubMed:20375010).
Expressed in the liver, in peripheral blood mononuclear cells and hepatocarcinoma cell lines.
As a component of the tetrameric DNA polymerase delta complex (Pol-delta4), plays a role in high fidelity genome replication and repair. Within this complex, increases the rate of DNA synthesis and decreases fidelity by regulating POLD1 polymerase and proofreading 3' to 5' exonuclease activity (PubMed:16510448, PubMed:19074196, PubMed:20334433). Pol-delta4 participates in Okazaki fragment processing, through both the short flap pathway, as well as a nick translation system (PubMed:24035200). Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR), a mechanism that may induce segmental genomic duplications of up to 200 kb (PubMed:24310611). Involved in Pol-delta4 translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites (PubMed:19074196). Its degradation in response to DNA damage is required for the inhibition of fork progression and cell survival (PubMed:24022480).
Belongs to the DNA polymerase delta subunit 4 family.
Component of the tetrameric DNA polymerase delta complex (Pol-delta4), which consists of POLD1/p125, POLD2/p50, POLD3/p66/p68 and POLD4/p12, with POLD1 bearing DNA polymerase and 3' to 5' proofreading exonuclease activities (PubMed:16510448, PubMed:17317665, PubMed:22801543). Within this complex, directly interacts with POLD1 and POLD2 (PubMed:12403614, PubMed:16510448). Directly interacts with PCNA, as do POLD1 and POLD3; this interaction stimulates Pol-delta4 polymerase activity (PubMed:24022480). As POLD1 and POLD2, directly interacts with WRNIP1; this interaction stimulates DNA polymerase delta-mediated DNA synthesis, independently of the presence of PCNA. This stimulation may be due predominantly to an increase of initiation frequency and also to increased processivity (PubMed:15670210). Upon genotoxic stress induced by DNA damaging agents or by replication stress, POLD4 is proteolytically degraded and Pol-delta4 is converted into a trimeric form of the complex (Pol-delta3) which has an increased proofreading activity (PubMed:22801543, PubMed:17317665). The DNA polymerase delta complex interacts with POLDIP2; this interaction is probably mediated through direct binding to POLD2 (PubMed:12522211).
Expression is cell cycle-dependent, with highest levels in G2/M phase and a drastic drop in S phase (PubMed:22801543, PubMed:23913683). This trough may be mediated by DCX(DTL) E3 ubiquitin ligase complex (also called CRL4(CDT2))-mediated proteasomal degradation (PubMed:23913683).
In response to DNA damage, genotoxic stress and replication stress, following UV irradiation, ionizing radiation, treatment with methyl methanesulfonate, hydroxyurea, or with aphidicolin, protein expression drops to undetectable levels, due to proteasomal degradation (PubMed:17317665, PubMed:22801543, PubMed:23233665, PubMed:23913683, PubMed:24300032). This down-regulation is ATR-dependent (PubMed:17317665).
Ubiquitinated; undergoes 'Lys-48'-linked ubiquitination in response to UV irradiation, leading to proteasomal degradation (PubMed:17317665, PubMed:16934752, PubMed:23233665, PubMed:23913683). This modification is partly mediated by RNF8 and by the DCX(DTL) E3 ubiquitin ligase complex (also called CRL4(CDT2)) (PubMed:23233665, PubMed:24022480). Efficient degradation requires the presence of PCNA and is required for the inhibition of fork progression after DNA damage (PubMed:24022480).
Expressed in the terminally differentiated epidermis of palms and soles.
Induced by intrinsic regulatory mechanisms and by extrinsic signals from a subset of dermal palmoplantar fibroblasts.
May serve an important special function either in the mature palmar and plantar skin tissue or in the morphogenetic program of the formation of these tissues. Plays a role in keratin filament assembly.
Was originally thought to be a 60 kDa chain of placental scatter protein.
Component of the 3M complex, composed of core components CUL7, CCDC8 and OBSL1. Interacts with CCDC8. Interacts with CUL7; the interaction is direct. Interacts with FBXW8. Interacts (via N-terminal Ig-like domain) with TTN/titin (via C-terminal Ig-like domain); the interaction is direct.
Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity. It is unclear how the 3M complex regulates microtubules, it could act by controlling the level of a microtubule stabilizer (PubMed:24793695, PubMed:24793696). Acts as a regulator of the Cul7-RING(FBXW8) ubiquitin-protein ligase, playing a critical role in the ubiquitin ligase pathway that regulates Golgi morphogenesis and dendrite patterning in brain. Required to localize CUL7 to the Golgi apparatus in neurons.
Widely expressed, with predominant levels found in the heart.
Highly expressed in heart, kidney, small intestine, placenta, lung and peripheral blood leukocyte. Weakly expressed in skeletal muscle and spleen. Not expressed in brain, colon and thymus.
Nucleotide sugar antiporter transporting UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-glucose (UDP-Glc) from the cytosol into the lumen of the Golgi in exchange of UMP. By supplying UDP-N-acetylglucosamine, a donor substrate to heparan sulfate synthases, probably takes part in the synthesis of these glycoconjugates.
ATP-dependent RNA helicase required during spermatogenesis (PubMed:10920202, PubMed:21034600). Required to repress transposable elements and preventing their mobilization, which is essential for the germline integrity (By similarity). Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons (By similarity). Involved in the secondary piRNAs metabolic process, the production of piRNAs in fetal male germ cells through a ping-pong amplification cycle (By similarity). Required for PIWIL2 slicing-triggered piRNA biogenesis: helicase activity enables utilization of one of the slice cleavage fragments generated by PIWIL2 and processing these pre-piRNAs into piRNAs (By similarity).
Belongs to the DEAD box helicase family. DDX4/VASA subfamily.
Expressed only in ovary and testis. Expressed in migratory primordial germ cells in the region of the gonadal ridge in both sexes.
Found in a mRNP complex, at least composed of TDRD1, TDRD6, TDRD7 and DDX4 (By similarity). Interacts with RANBP9 (PubMed:27622290). Interacts with RANBP10. Interacts with PIWIL2 and MAEL. Interacts with BMAL1 and CLOCK. Interacts with Tex19.1 and, probably, Tex19.2 (By similarity). Interacts with RBM46 (By similarity).
(Microbial infection) Plays an essential role in the targeting of HIV-1 Gag to the plasma membrane, this function is dependent on it's RING domain, and hence it's E3 ligase activity.
Autoubiquitinated (PubMed:20696164). Ubiquitinated by SH3RF2, leading to proteasome-mediated degradation (By similarity).
Contaminating sequence. Sequence of unknown origin in the middle of the protein.
Has E3 ubiquitin-protein ligase activity. In the absence of an external substrate, it can catalyze self-ubiquitination (PubMed:15659549, PubMed:20696164). Stimulates ubiquitination of potassium channel KCNJ1, enhancing it's dynamin-dependent and clathrin-independent endocytosis (PubMed:19710010). Acts as a scaffold protein that coordinates with MAPK8IP1/JIP1 in organizing different components of the JNK pathway, including RAC1 or RAC2, MAP3K11/MLK3 or MAP3K7/TAK1, MAP2K7/MKK7, MAPK8/JNK1 and/or MAPK9/JNK2 into a functional multiprotein complex to ensure the effective activation of the JNK signaling pathway. Regulates the differentiation of CD4(+) and CD8(+) T-cells and promotes T-helper 1 (Th1) cell differentiation. Regulates the activation of MAPK8/JNK1 and MAPK9/JNK2 in CD4(+) T-cells and the activation of MAPK8/JNK1 in CD8(+) T-cells. Plays a crucial role in the migration of neocortical neurons in the developing brain. Controls proper cortical neuronal migration and the formation of proximal cytoplasmic dilation in the leading process (PCDLP) in migratory neocortical neurons by regulating the proper localization of activated RAC1 and F-actin assembly (By similarity).
Interacts with RAC1; in a GTP-dependent manner (PubMed:20696164). Interacts with MAP3K10/MLK2 and MAP3K11/MLK3. Interacts with MAPK8IP; this interaction leads to the PJAC complex (POSH-JIP or SH3RF1/MAPK8IP apoptotic complex) with a 1:1 ratio. Interacts with SIAH1. Interacts with HERP1. Probably part of a signaling complex that may contain SH3RF1, MAPK8IP, DLK1, MAP2K4/MKK4, MAP2K7/MKK7, MAPK8/JNK1, MAPK9/JNK2, AKT1 and AKT2 (PubMed:12514131, PubMed:14504284, PubMed:16230351, PubMed:16571722, PubMed:17420289, PubMed:17535800). Found in a complex with RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2. Found in a complex with RAC1, MAP3K11/MLK3, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK8/JNK1. Interacts with SH3RF2 (By similarity).
Phosphorylated at Ser-304 by AKT1 and AKT2. When phosphorylated, it has reduced ability to bind Rac.
Cytokine that binds to TNFRSF13B/TACI and to TNFRSF17/BCMA. Plays a role in the regulation of tumor cell growth. May be involved in monocyte/macrophage-mediated immunological processes.
Down-regulated by phorbol myristate acetate/ionomycin treatment.
Expressed at high levels in transformed cell lines, cancers of colon, thyroid, lymphoid tissues and specifically expressed in monocytes and macrophages.
Does not exhibit calcium-activated chloride channel (CaCC) activity. Can inhibit the activity of ANO1.
Highly expressed in the brain. Intermediate levels in the retina and heart and low levels in the placenta, liver, lung, duodenum, kidney, testis and spleen. In brain areas, highest expression in the frontal and occipital cortices and in the cerebellum. Lower expression in the fetal brain than in the adult brain.
Interacts with CAMSAP3 and CTNND1 (PubMed:19041755). Interacts (via WW domains) with TSPAN33 (via cytoplasmic domain) and with PDZD11; the interaction with TSPAN33 is dependent on PDZD11 being bound to PLEKHA7 and facilitates the docking of ADAM10 to zonula adherens through interaction of TSPAN33 with ADAM10 (PubMed:30463011).
Required for zonula adherens biogenesis and maintenance (PubMed:19041755). Acts via its interaction with CAMSAP3, which anchors microtubules at their minus-ends to zonula adherens, leading to the recruitment of KIFC3 kinesin to the junctional site (PubMed:19041755). Mediates docking of ADAM10 to zonula adherens through a PDZD11-dependent interaction with the ADAM10-binding protein TSPAN33 (PubMed:30463011).
Mitochondrial transporter of arginine, lysine, homoarginine, methylarginine and, to a much lesser extent, ornithine and histidine (PubMed:19287344, PubMed:24652292). Does not transport carnitine nor acylcarnitines (PubMed:24652292). Functions by both counter-exchange and uniport mechanisms (PubMed:24652292). Plays a physiolocical role in the import of basic amino acids into mitochondria for mitochondrial protein synthesis and amino acid degradation (PubMed:19287344, PubMed:24652292).
Was initially proposed to transport palmitoylcarnitine, based on complementation experiments in yeast mutants lacking CRC1 and CIT2 and release of radiolabeled carnitine from mitochondria incubated with radiolabeled palmitoylcarnithine (By similarity). Later experiments done primarily with human indicate the protein functions instead as transporter of basic amino acids (PubMed:24652292).
Homomultimer. Forms trimers, hexamers and high molecular weight oligomers (By similarity).
Involvement in food intake and energy was only observed when the protein was externally administered in the brain, but not when this protein was overexpressed in vivo.
May be involved in the regulation of the inflammatory network. Its role as pro- or anti-inflammatory seems to be context dependent (PubMed:21658842, PubMed:27086950). Seems to have some role in regulating food intake and energy balance when administered in the brain. This effect is sustained over a two-day period, and it is accompanied by decreased expression of orexigenic neuropeptides in the hypothalamus 3 hours post-injection (By similarity).
There are conflicting results in its involvement in the inflammatory network. It was first described to be a pro-inflammatory cytokine by inducing the activation of NF-kappa-B signaling pathway and up-regulates IL6 production in liver carcinoma cells (PubMed:21658842). While it seems to have the opposite effect in macrophages (PubMed:27086950).
Widely expressed at low levels (PubMed:21658842). Highest levels in adipocyte tissue and brain (PubMed:24366864).
Brain specific. Present in all brain sections tested, highest levels in the caudate nucleus and hippocampus, weakest levels in the thalamus.
Monomer. Interacts with ATN1; the interaction represses the transcription.
Orphan receptor that binds DNA as a monomer to hormone response elements (HRE) containing an extended core motif half-site sequence 5'-AAGGTCA-3' in which the 5' flanking nucleotides participate in determining receptor specificity (By similarity). May be required to pattern anterior brain differentiation. Involved in the regulation of retinal development and essential for vision. During retinogenesis, regulates PTEN-Cyclin D expression via binding to the promoter region of PTEN and suppressing its activity (By similarity). May be involved in retinoic acid receptor (RAR) regulation in retinal cells.
Component of the U7 snRNP complex that is involved in the histone 3'-end pre-mRNA processing (PubMed:11574479, PubMed:16914750, PubMed:33230297). Increases U7 snRNA levels but not histone 3'-end pre-mRNA processing activity, when overexpressed (PubMed:11574479, PubMed:16914750). Required for cell cycle progression from G1 to S phases (By similarity). Binds specifically to the Sm-binding site of U7 snRNA (PubMed:11574479, PubMed:16914750).
Component of the heptameric ring U7 snRNP complex, or U7 Sm protein core complex, at least composed of LSM10, LSM11, SNRPB, SNRPD3, SNRPE, SNRPF, SNRPG and U7 snRNA (PubMed:12975319, PubMed:11574479). Formation of the U7 snRNP is an ATP-dependent process mediated by a specialized SMN complex containing at least the Sm protein core complex and additionally, the U7-specific LSM10 and LSM11 proteins (PubMed:11574479). Identified in a histone pre-mRNA complex, at least composed of ERI1, LSM11, SLBP, SNRPB, SYNCRIP and YBX1 (By similarity). Interacts (via the Sm domains) with CLNS1A (By similarity). Interacts with SMN and ZNF473 (PubMed:12975319, PubMed:16714279). Interacts with PRMT5 and WDR77 (By similarity).
The C-terminal SM 1 domain is both necessary for the binding to the Sm-binding site of U7 snRNA and U7 snRNP assembly (By similarity). The N-terminal domain is essential for histone pre-mRNA cleavage (By similarity). Amino acids 63-82 are sufficient to interact with ZNF473 (By similarity).
The disease is caused by variants affecting the gene represented in this entry. Impaired histone 3'-end pre-mRNA processing caused by disease variants affects chromatin structure, relieving CGAS inhibition by nucleosomes (PubMed:33230297). This activates the cGAS-STING pathway, triggering type-I interferon production and autoinflammation (PubMed:33230297).
Heterodimer with NXF1 (PubMed:11583626). Forms a complex with RANGAP1, RANBP2/NUP358 and NXF1 (PubMed:14729961). Interacts (via NTF2 domain) with NXF1 (PubMed:11583626). Stabilizes the NTF2 domain of NXF1 by heterodimerization (PubMed:11583626). The formation of NXF1-NXT1 heterodimers is required for the NXF1-mediated nuclear mRNA export (PubMed:11583626). Preferentially binds Ran-GTP (PubMed:10567585). Associates with NXF2, NXF3 and NXF5. Does not bind nucleoporins (NPC) directly, its association to NPC is mediated by NXF1 (PubMed:11583626).
Stimulator of protein export for NES-containing proteins (PubMed:10567585). Also plays a role in the nuclear export of U1 snRNA, tRNA, and mRNA (PubMed:10848583). The NXF1-NXT1 heterodimer is involved in the export of HSP70 mRNA in conjunction with ALYREF/THOC4 and THOC5 (PubMed:19165146, PubMed:11259602).
(Microbial infection) In case of infection, interacts with B.melitensis protein TcpB.
(Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC; suppressing Toll-like receptor (TLR)-mediated cytokine production.
(Microbial infection) In case of infection, interacts with uropathogenic E.faecalis protein TcpF; suppressing Toll-like receptor (TLR)-mediated cytokine production.
(Microbial infection) Interacts with human metapneumovirus protein M2-2; this interaction prevents MYD88-mediated cytokine secretion.
Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response (PubMed:15361868, PubMed:18292575, PubMed:33718825). Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:15361868, PubMed:24316379, PubMed:19506249). Increases IL-8 transcription (PubMed:9013863). Involved in IL-18-mediated signaling pathway. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. Upon TLR8 activation by GU-rich single-stranded RNA (GU-rich RNA) derived from viruses such as SARS-CoV-2, SARS-CoV and HIV-1, induces IL1B release through NLRP3 inflammasome activation (PubMed:33718825). MyD88-mediated signaling in intestinal epithelial cells is crucial for maintenance of gut homeostasis and controls the expression of the antimicrobial lectin REG3G in the small intestine (By similarity).
Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response.
Defects in MYD88 are frequently found in many hematological malignancies, such as activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL), cutaneous diffuse large B cell lymphoma (CBCL) and primary central nervous system lymphoma (PCNSL).
Homodimer. Also forms heterodimers with TIRAP (PubMed:17322885, PubMed:19948740, PubMed:19506249). Binds to TLR2, TLR4, TLR5, IRAK1, IRAK2 and IRAK4 via their respective TIR domains. Interacts with IL18R1. Interacts with BMX, IL1RL1, IKBKE and IRF7. Interacts with LRRFIP1 and LRRFIP2; this interaction positively regulates Toll-like receptor (TLR) signaling in response to agonist. Interacts with FLII. LRRFIP1 and LRRFIP2 compete with FLII for MYD88-binding. Interacts with IRF1. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and TRAF6; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. May interact with PIK3AP1. Interacts (via TIR domain) with DHX9 (via H2A and OB-fold regions); this interaction is direct (PubMed:20696886). Interacts with OTUD4 deubiquitinase; the interaction is direct (PubMed:29395066).
Homodimer. Also forms heterodimers with TIRAP. Binds to TLR2, TLR4, IRAK1, IRAK2 and IRAK4 via their respective TIR domains.
The intermediate domain (ID) is required for the phosphorylation and activation of IRAK.
Ubiquitinated; undergoes 'Lys-63'-linked polyubiquitination. OTUD4 specifically hydrolyzes 'Lys-63'-linked polyubiquitinated MYD88.
A genome-wide association analysis shows PRDM11 association with forced vital capacity (FVC), a spirometric measure of pulmonary function, that reflects lung volume and is used to diagnose and monitor lung diseases.
Differential expressed during pseudoglandular and canalicular stages of lung development.
Highly expressed in lung, including bronchial epithelial cells and airway smooth muscle cells, as well as in peripheral blood mononuclear cells. In tonsils, expressed in B-cell types, including naive B-cells, centroblasts, centrocytes and memory B-cells (at protein level). In benign hyperplastic lymph nodes, expressed in germinal center cells in both the dark and light zones, as well as in scattered cells in the mantle zone and the interfollicular area (at protein level).
May be involved in transcription regulation.
Belongs to the activator 1 large subunit family.
Heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 that can form a complex either with RFC1 or with RAD17. The former interacts with PCNA in the presence of ATP, while the latter has ATPase activity but is not stimulated by PCNA.
Interacts with C-terminus of PCNA. 5' phosphate residue is required for binding of the N-terminal DNA-binding domain to duplex DNA, suggesting a role in recognition of non-primer template DNA structures during replication and/or repair.
The disease is caused by variants affecting the gene represented in this entry. The disease is caused by intronic AAGGG repeat expansions in intron 2.
The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins PCNA and activator 1. This subunit binds to the primer-template junction. Binds the PO-B transcription element as well as other GA rich DNA sequences. Could play a role in DNA transcription regulation as well as DNA replication and/or repair. Can bind single- or double-stranded DNA.
Wide tissue distribution. Undetectable in placental tissue.
(Microbial infection) Alternative coreceptor with CD4 for HIV-1 infection.
(Microbial infection) Interacts with HIV-1 protein Tat.
In eosinophils as well as trace amounts in neutrophils and monocytes.
Overexpression of CCR3 together with its ligands appears to be a characteristic of ulcerative colitis (UC). The production of CCR3 ligands by human colonic epithelial cells suggests further that the epithelium can play a role in modulating pathological T-cell-mediated mucosal inflammation (PubMed:21077277).
Receptor for C-C type chemokine. Binds and responds to a variety of chemokines, including CCL11, CCL26, CCL7, CCL13, RANTES(CCL5) and CCL15 (PubMed:7622448, PubMed:8642344, PubMed:8676064). Subsequently transduces a signal by increasing the intracellular calcium ions level (PubMed:8676064). In addition acts as a possible functional receptor for NARS1 (PubMed:30171954).
Up-regulated during osteoclastogenesis induced by treatment of peripheral blood mononuclear cells with CSF1 and TNFSF11, as well as during osteoblastogenesis.
Widely expressed with highest levels in obvary, muscle, blood and lung.
Interacts with AARS; the interaction is direct.
Required to prevent the misactivation of serine (Ser) with tRNA(Ala) by promoting the hydrolysis of Ser-mischarged tRNA(Ala), thereby playing a role in translational fidelity. Binds directly to the catalytic domain of AARS/AlaRS and captures Ser that is misactivated by AARS/AlaRS, preventing the charging of Ser adenylates to tRNA(Ala) and precluding Ser misincorporation in nascent peptides.
Side chains of Lys-102, Lys-135 and Lys-165 capture Ser that is misactivated by AARS/AlaRS.
Plays a role in the regulation of heme biosynthesis and in the regulation of the expression of core clock genes.
Up-regulated by hemin and 5-aminolevulinic acid.
Interacts with COA1 (PubMed:22356826). Found in a complex with TMEM177, COX20, MT-CO2/COX2, COX18, SCO1 and SCO2 (PubMed:29154948). Interacts with MT-CO2/COX2 and SCO2 (PubMed:25959673). Interacts with SCO1 (PubMed:26160915). Interacts with COX20 in a MT-CO2/COX2- and COX18-dependent manner (PubMed:29154948, PubMed:28330871). Interacts with COX16 (PubMed:29381136).
Involved in the maturation of the mitochondrial respiratory chain complex IV subunit MT-CO2/COX2. Thereby, may regulate early steps of complex IV assembly. Mitochondrial respiratory chain complex IV or cytochrome c oxidase is the component of the respiratory chain that catalyzes the transfer of electrons from intermembrane space cytochrome c to molecular oxygen in the matrix and as a consequence contributes to the proton gradient involved in mitochondrial ATP synthesis. May also be required for efficient formation of respiratory supercomplexes comprised of complexes III and IV.
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is composed of 13 subunits: EIF3A, EIF3B, EIF3C, EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L and EIF3M. The eIF-3 complex appears to include 3 stable modules: module A is composed of EIF3A, EIF3B, EIF3G and EIF3I; module B is composed of EIF3F, EIF3H, and EIF3M; and module C is composed of EIF3C, EIF3D, EIF3E, EIF3K and EIF3L. EIF3C of module C binds EIF3B of module A and EIF3H of module B, thereby linking the three modules. EIF3J is a labile subunit that binds to the eIF-3 complex via EIF3B. The eIF-3 complex interacts with RPS6KB1 under conditions of nutrient depletion. Mitogenic stimulation leads to binding and activation of a complex composed of MTOR and RPTOR, leading to phosphorylation and release of RPS6KB1 and binding of EIF4B to eIF-3. Interacts with RNF139; the interaction leads to protein translation inhibitions in a ubiquitination-dependent manner. Interacts with DTX1, the interaction is required for deubiquitinating activity towards NOTCH1.
Deubiquitinates activated NOTCH1, promoting its nuclear import, thereby acting as a positive regulator of Notch signaling.
Phosphorylation is enhanced upon serum stimulation. Phosphorylated during apoptosis by caspase-processed CDK11.
The MPN domain mediates deubiquitinating activity.
Plays an important role in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking. May catalyze the remodeling of phosphatidylglycerol and be involved in the transacylation-acylation reaction to produce phosphatidylglycerol-36:1. May be involved in bis(monoacylglycerol)phosphate biosynthetic pathway.
Widely expressed, with predominant expression in fetal skeletal muscle and adult brain. In the brain, highest levels are found in the frontal and occipital cortices, cerebellum and hippocampus.
Detected in germinal center of lymph node (at protein level). Expressed in spleen, lymph node and tonsil.
Interacts with p53/TP53; the interaction is direct.
May play a role in p53/TP53-mediated apoptosis.
A chromosomal aberration involving BRCC3 is a cause of pro-lymphocytic T-cell leukemia (T-PLL). Translocation t(X;14)(q28;q11) with TCRA.
Belongs to the peptidase M67A family. BRCC36 subfamily.
Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:20656690, PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, babam2 and BABAM1/NBA1. In the BRCA1-A complex, interacts directly with ABRAXAS1 and babam2 (PubMed:18077395, PubMed:19261748). Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985, PubMed:25283148, PubMed:26344097). Identified in a complex with SHMT2 and the other subunits of the BRISC complex (PubMed:24075985). In the BRISC complex, interacts directly with ABRAXAS2 (PubMed:20656690, PubMed:26344097). Identified in a complex with ABRAXAS2 and NUMA1 (PubMed:26195665). The BRISC complex interacts with the CSN complex. Component of the BRCA1/BRCA2 containing complex (BRCC), which also contains BRCA1, BRCA2, BARD1, BABAM2 and RAD51. BRCC is a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage. Interacts with BRCA1. Binds polyubiquitin. Interacts with PWWP2B (By similarity). Interacts with HDAC1; this interaction is enhanced in the presence of PWWP2B (By similarity).
Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Aberrantly expressed in the vast majority of breast tumors.
Metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains (PubMed:19214193, PubMed:20656690, PubMed:24075985, PubMed:26344097). Does not have activity toward 'Lys-48'-linked polyubiquitin chains (PubMed:19214193, PubMed:20656690, PubMed:24075985, PubMed:26344097). Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs) (PubMed:14636569, PubMed:19202061, PubMed:16707425, PubMed:17525341, PubMed:19261748, PubMed:19261749, PubMed:19261746). In the BRCA1-A complex, it specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX, antagonizing the RNF8-dependent ubiquitination at double-strand breaks (DSBs) (PubMed:20656690). Catalytic subunit of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:20656690, PubMed:24075985, PubMed:26195665, PubMed:26344097). Mediates the specific 'Lys-63'-specific deubiquitination associated with the COP9 signalosome complex (CSN), via the interaction of the BRISC complex with the CSN complex (PubMed:19214193). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985, PubMed:26344097). Acts as a regulator of the NLRP3 inflammasome by mediating deubiquitination of NLRP3, leading to NLRP3 inflammasome assembly (By similarity). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985). Deubiquitinates HDAC1 and PWWP2B leading to their stabilization (By similarity).
Histone methyltransferase that sequentially mono-, di-, and tri-methylates both 'Lys-4' (H3K4) and 'Lys-36' (H3K36) of histone H3 to produce respectively trimethylated 'Lys-4' (H3K4me3) and trimethylated 'Lys-36' (H3K36me3) histone H3 and plays a key role in meiotic prophase by determining hotspot localization thereby promoting meiotic recombination (PubMed:24634223, PubMed:24095733, PubMed:26833727, PubMed:27129774). Can also methylate all four core histones with H3 being the best substrate and the most highly modified (PubMed:24095733, PubMed:24634223, PubMed:26833727). Is also able, on one hand, to mono and di-methylate H4K20 and on other hand to trimethylate H3K9 with the di-methylated H3K9 as the best substrate (By similarity). During meiotic prophase, binds specific DNA sequences through its zinc finger domains thereby determining hotspot localization where it promotes local H3K4me3 and H3K36me3 enrichment on the same nucleosomes through its histone methyltransferase activity (PubMed:26833727). Thereby promotes double-stranded breaks (DSB) formation, at this subset of PRDM9-binding sites, that initiates meiotic recombination for the proper meiotic progression (By similarity). During meiotic progression hotspot-bound PRDM9 interacts with several complexes; in early leptonema binds CDYL and EHMT2 followed by EWSR1 and CXXC1 by the end of leptonema. EWSR1 joins PRDM9 with the chromosomal axis through REC8 (By similarity). In this way, controls the DSB repair pathway, pairing of homologous chromosomes and sex body formation (By similarity). Moreover plays a central role in the transcriptional activation of genes during early meiotic prophase thanks to H3K4me3 and H3K36me3 enrichment that represents a specific tag for epigenetic transcriptional activation (By similarity). In addition performs automethylation (By similarity). Acetylation and phosphorylation of histone H3 attenuate or prevent histone H3 methylation (By similarity).
Homodimer (PubMed:26833727, PubMed:24095733, Ref.10). Interacts with EHMT2 and CDYL; interaction only takes place when PRDM9 is bound to hotspot DNA. Interacts with CXXC1; this interaction does not link PRDM9-activated recombination hotspot sites with DSB machinery and is not required for the hotspot recognition pathway. Forms a complex with EWSR1, REC8, SYCP3 and SYCP1; complex formation is dependent of phosphorylated form of REC8 and requires PRDM9 bound to hotspot DNA; EWSR1 joins PRDM9 with the chromosomal axis through REC8 (By similarity).
Inhibited by suramin with an IC(50) of 4.1 uM.
Mono-methylated; automethylated. Tri-methylated; automethylated. Mono-methylation is predominant; automethylation is lower and slower than H3 peptide methylation and is in a highest S-adenosyl-L-methionine concentration-dependent. There are two major sites for automethylation at Lys-368 and Lys-374. Lysines can be simultaneously methylated, such as Lys-368(me3)/Lys-372(me1), Lys-368(me1)/Lys-374(me1) and Lys-368(me1)/Lys-372(me1)/Lys-374(me1). Automethylation is an intramolecular (cis) process.
Several alleles exist depending on both the number of zinc finger C2H2 type domains and their identity (PubMed:26833727). Each allele binds to a specific hotspot set (PubMed:26833727). Variations in the zinc finger C2H2 type domains are associated with significant differences in affinity towards DNA-binding motif (PubMed:26833727). The sequence shown is that of allele B.
The C2H2-type zinc fingers determine the hotspot localization through its binding to specific DNA sequences. Variations in their sequence affect affinity towards DNA-binding motif.
Acts as a transcriptional repressor (PubMed:20797634). Represses cAMP-responsive element (CRE)-mediated transcriptional activation (PubMed:21706167). In addition, has a role in translesion DNA synthesis. Requires for UV-inducible RAD18 loading, PCNA monoubiquitination, POLH recruitment to replication factories and efficient translesion DNA synthesis (PubMed:24657165). Plays a key role in the transcriptional regulation of T lymphocyte development (By similarity).
Both the BTB domain and C2H2-type motifs are necessary for transcriptional repression activity. The BTB domain is also necessary for oligomerization and efficient sumoylation. The hydrophobic cluster preceding Lys-328 enhanced sumoylation efficiency (PubMed:20797634).
Homodimer. Homooligomer. Isoform 1 and isoform 2 can homodimerize. Heterodimer of isoform 1 and isoform 2. Interacts (via BTB domain) with TRIM28 (unphosphorylated or phosphorylated form) (PubMed:24657165).
Sumoylated with SUMO2 at Lys-328 and to a lesser extent at Lys-265. Sumoylation inhibits its transcriptional repression activity and regulates its subcellular localization.
The UBZ-type zinc finger domain is required for targeting ZBTB1 to UV damage sites and for PCNA monoubiquitination. UBZ-type zinc finger domain mediates binding to 'Lys-63'-linked polyubiquitin chains (in vitro).
Catalyzes the deimination of arginine residues of proteins (By similarity). In oocytes, is released during cortical reaction and plays a role in preimplantation cleavage and early embryonic development (By similarity). May be involved in cytoskeletal reorganization in the egg and early embryo (PubMed:27545678).
Catalyzes the deimination of arginine residues of proteins (By similarity). May be involved in cytoskeletal reorganization in the egg and early embryo (PubMed:27545678).
Highly expressed in oocytes and weakly expressed in other somatic tissues.
Phosphorylation at Ser-10, possibly by RSK-type kinases, and Ser-446 creates binding sites for 14-3-3 proteins.
Abundantly expressed in heart, pancreas, prostate and ovary. Moderately expressed in lung, liver, kidney, spleen, thymus, colon and peripheral lymphocytes. Abundantly expressed in both the epidermal and dermal compartments of the hair follicle. Present in scalp skin Highly expressed in the hair follicle dermal papilla, the matrix, and the hair shaft (at protein level).
Homodimer. Interacts with LRP5 and WNT3A.
Negative regulator of the Wnt signaling pathway. Inhibits Wnt signaling in a cell-autonomous manner and functions upstream of beta-catenin. May act via its interaction with Wnt and LRP proteins. May play a role in colorectal tumorigenesis.
Target gene of the Wnt/Beta-catenin pathway, transcriptionally regulated by the CTNNB1/TF7L2 complex.
Component of the BCR(KLHL8) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL8 and RBX1. Interacts with RAPSN.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex required for The BCR(KLHL8) ubiquitin ligase complex mediates ubiquitination and degradation of RAPSN.
Expressed in motor neurons in the spinal cord and cortical neurons in the frontal lobe (at protein level). Highly expressed in brain, testis and adipose tissue.
Interacts with LDAF1 to form an oligomeric complex.
Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis (PubMed:19278620, PubMed:21533227, PubMed:31708432, PubMed:30293840). In association with LDAF1, defines the sites of LD formation in the ER (PubMed:31708432). Also required for growth and maturation of small nascent LDs into larger mature LDs (PubMed:27564575). Mediates the formation and/or stabilization of endoplasmic reticulum-lipid droplets (ER-LD) contacts, facilitating protein and lipid delivery from the ER into growing LDs (PubMed:31178403, PubMed:27879284). Regulates the maturation of ZFYVE1-positive nascent LDs and the function of the RAB18-ZFYVE1 complex in mediating the formation of ER-LD contacts (PubMed:30970241). Binds anionic phospholipids including phosphatidic acid (PubMed:30293840). Plays an important role in the differentiation and development of adipocytes (By similarity).
Undecamer (an oligomer having eleven subunits) (PubMed:30293840). Oligomerization is important for its function in lipid droplet formation (PubMed:30293840). Interacts with LDAF1 to form an oligomeric complex (PubMed:31708432, PubMed:30901948). Interacts with RAB18 (PubMed:30970241). Interacts with ZFYVE1 in a RAB18-dependent manner (PubMed:30970241).
Expressed in spleen, thymus, pancreas, testis, ovary, small intestine, colon and lymphocytes.
The POM-ZP3 transcript appears to have arisen from a partial duplication and fusion of a 5' portion of a POM121 homolog and exons 5-8 of ZP3.
Ferritin receptor that mediates non-transferrin-dependent delivery of iron. Mediates cellular uptake of ferritin-bound iron by stimulating ferritin endocytosis from the cell surface with consequent iron delivery within the cell. Delivery of iron to cells by ferritin is required for the development of specific cell types, suggesting the existence of cell type-specific mechanisms of iron traffic in organogenesis, which alternatively utilize transferrin or non-transferrin iron delivery pathways. Ferritin mediates iron uptake in capsule cells of the developing kidney. Preferentially binds ferritin light chain (FTL) compared to heavy chain (FTH1).
Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, the core components of this complex being COA3/MITRAC12 and COX14.
Involved in the biosynthetic pathway of cholesterol.
Activated by MAP kinase (Erk1/2) phosphorylation just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. Phosphorylation at Ser-1859 by RPS6KB1 downstream of MTOR promotes oligomerization and stimulates dihydroorotase activity. Phosphorylation at Ser-1406 reduces sensitivity to feedback inhibition by UTP.
Allosterically regulated and controlled by phosphorylation. 5-phosphoribose 1-diphosphate (PRPP) is an activator while UMP and UTP are inhibitors of the CPSase reaction.
Binds 3 Zn(2+) ions per subunit (for dihydroorotase activity).
Binds 4 magnesium or manganese ions per subunit.
GATase (glutamine amidotransferase) and CPSase (carbamoyl phosphate synthase) form together the glutamine-dependent CPSase (GD-CPSase) (EC 6.3.5.5).
Homohexamer (PubMed:24332717). Interacts with CIPC (PubMed:26657846).
In the central section; belongs to the metallo-dependent hydrolases superfamily. DHOase family. CAD subfamily.
This protein is a 'fusion' protein encoding four enzymatic activities of the pyrimidine pathway (GATase, CPSase, ATCase and DHOase).
Transcriptionally repressed following hypoxia by HIF1A.
Has E3 ubiquitin-protein ligase activity (PubMed:24130170). Acts as an anti-apoptotic regulator of the JNK pathway by ubiquitinating and promoting the degradation of SH3RF1, a scaffold protein that is required for pro-apoptotic JNK activation (PubMed:22128169). Facilitates TNF-alpha-mediated recruitment of adapter proteins TRADD and RIPK1 to TNFRSF1A and regulates PAK4 protein stability via inhibition of its ubiquitin-mediated proteasomal degradation (PubMed:24130170). Inhibits PPP1CA phosphatase activity (PubMed:19945436, PubMed:19389623).
Heart (at protein level). Up-regulated in colon cancer tissues as compared to normal colon tissues (at protein level). Testis. In the heart, present in the apex, left atrium, right atrium, left ventricle and right ventricle, but not in the aorta.
Interacts with FASLG and PPP1CA (PubMed:19389623, PubMed:19807924, PubMed:19945436). Interacts with PAK4 and TNFRSF1A (PubMed:24130170). Interacts with DLK1, MAP3K10/MLK2, MAPK8IP1/JIP1, MAPK8IP2/JIP2 and MAPK8IP3/JIP3. Interacts with RAC1 (both active GTP- or inactive GDP-bound forms) (By similarity).
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:19858781, PubMed:18719240, PubMed:23756265, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:19858781, PubMed:23756265). Catalyzes the glucuronidation of endogenous estrogen hormone estradiol (PubMed:18719240, PubMed:23288867). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Shows a potential role in detoxification of toxic waste compounds in the amniotic fluid before birth, and air-born chemical after birth (PubMed:19858781).
UGT2A2 isoform is part of the UGT2A complex locus which displays alternative use of promoters and exons. The locus is defined by 2 alternative promoters resulting in 2 fonctionally active polypeptides UGT2A1 and UGT2A2. Alternative splicing of exons results in additional isoforms for each protein class.
Expressed in liver, skin, small intestine, salivary gland and prostate.
Homodimer and heterodimer (PubMed:15683364). Able to interact with SPRED1 to form heterodimers (PubMed:15683364). Interacts with RAS (By similarity). May interact with ZDHHC13 (via ANK repeats) and ZDHHC17 (via ANK repeats) (By similarity). Interacts with TESK1 (By similarity). Interacts with NF1 (PubMed:34626534).
Negatively regulates Ras signaling pathways and downstream activation of MAP kinases (PubMed:15683364, PubMed:34626534). Recruits and translocates NF1 to the cell membrane, thereby enabling NF1-dependent hydrolysis of active GTP-bound Ras to inactive GDP-bound Ras (PubMed:34626534). Inhibits fibroblast growth factor (FGF)-induced retinal lens fiber differentiation, probably by inhibiting FGF-mediated phosphorylation of ERK1/2 (By similarity). Inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells (By similarity).
Phosphorylated on serine and threonine residues (PubMed:15683364). Phosphorylated on tyrosine. Phosphorylation of Tyr-228 and Tyr-231 are required for ubiquitination (PubMed:17094949).
Ubiquitinated; leading to degradation by the proteasome.
Belongs to the WD repeat NOL10/ENP2 family.
Heterodimer of a catalytic (PDP1) and a regulatory (PDPR) subunit.
Antibodies against TINAG are found in sera of patients with tubulointerstitial nephritis, a rare autoimmune disorder that causes acute and chronic renal injury.
Expressed in the kidney cortex, small intestine and cornea.
Initially observed in the Bowman capsule during early glomerular capillary loop formation in the kidney. In more developmentally mature glomeruli, following transition from early to mid-capillary loop stage, expression is higher in the proximal tubular basement membrane than in the distal basement membrane and Bowman capsule.
It has been suggested that the active SMB domain may be permitted considerable disulfide bond heterogeneity or variability, thus 2 alternate disulfide patterns based on 3D structures are described with 1 disulfide bond conserved in both.
Mediates adhesion of proximal tubule epithelial cells via integrins alpha3-beta1 and alphaV-beta3. This is a non catalytic peptidase C1 family protein.
Acyl-CoA thioesterases are a group of enzymes that catalyze the hydrolysis of acyl-CoAs to the free fatty acid and coenzyme A (CoASH), providing the potential to regulate intracellular levels of acyl-CoAs, free fatty acids and CoASH (PubMed:33219126). Has an acyl-CoA thioesterase activity towards the long chain fatty acyl-CoA thioester palmitoyl-CoA (hexadecanoyl-CoA; C16:0-CoA) (PubMed:33219126). Displays a substrate preference for fatty acyl-CoAs with chain-lengths C12-C18 (PubMed:33219126). Possesses beta-lactamase activity, catalyzing the hydrolysis of penicillin G and nitrocefin (PubMed:31434986). Exhibits no activity towards other beta-lactam antibiotic classes including cephalosporins (cefotaxime) and carbapenems (imipenem) (PubMed:31434986).
Beta-lactamase activity is inhibited by sulbactam.
Catalyzes the irreversible transamination of the L-tryptophan metabolite L-kynurenine to form kynurenic acid (KA), an intermediate in the tryptophan catabolic pathway which is also a broad spectrum antagonist of the three ionotropic excitatory amino acid receptors among others. May catalyze the beta-elimination of S-conjugates and Se-conjugates of L-(seleno)cysteine, resulting in the cleavage of the C-S or C-Se bond. Has transaminase activity towards L-kynurenine, tryptophan, phenylalanine, serine, cysteine, methionine, histidine, glutamine and asparagine with glyoxylate as an amino group acceptor (in vitro). Has lower activity with 2-oxoglutarate as amino group acceptor (in vitro).
The first non-coding exon of CCBL2 is in common with that of RBMXL1.
Forms homodimers (via head domain) (PubMed:32375023). Interacts with CEP170 (PubMed:30354798, PubMed:31789463). Interacts with PCM1 and CEP131 (PubMed:31789463). Binds tubulin (PubMed:31789463).
Microtubule-binding centrosomal protein required for centriole cohesion, independently of the centrosome-associated protein/CEP250 and rootletin/CROCC linker (PubMed:31789463). In interphase, required for anchoring microtubule at the mother centriole subdistal appendages and for centrosome positioning (PubMed:31789463). During mitosis, may be involved in spindle assembly and chromatin alignment by regulating the organization of spindle microtubules into a symmetrical structure (PubMed:30354798). Has been proposed to play a role in CEP170 recruitment to centrosomes (PubMed:30354798). However, this function could not be confirmed (PubMed:31789463). Plays a non-essential role in ciliogenesis (PubMed:31789463, PubMed:32375023).
The N-terminal 3D structure (head domain) resembles that of NHEJ1/XLF, PAXX, SASS6 and XRCC4.
The coiled-coil domains are involved in microtubule-binding.
Acts as component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. Core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built (PubMed:32453425, PubMed:34694004, PubMed:34700328, PubMed:35585232, PubMed:16899510). The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity (PubMed:32453425).
Component of the MCM2-7 complex (PubMed:17296731, PubMed:16899510). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (PubMed:17296731, PubMed:16899510, PubMed:32453425). Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex (PubMed:34700328, PubMed:34694004, PubMed:32453425). Interacts with ANKRD17 (PubMed:23711367). Interacts with MCMBP (PubMed:17296731). Interacts with TONSL; the interaction is direct (PubMed:26527279).
(Microbial infection) Interacts with SARS-COV-2 protein ORF10.
(Microbial infection) Ubiquitinated; leading to proteasomal degradation in the presence of herpes simplex virus 1/HHV-1.
Interacts with ELOC/Elongin C. Part of an E3 ubiquitin ligase complex including ZYG11B, CUL2 and Elongin BC.
Serves as substrate adapter subunit in the E3 ubiquitin ligase complex ZYG11B-CUL2-Elongin BC. Acts to target substrates bearing N-terminal degrons for proteasomal degradation with the first four residues of substrates being the key recognition elements (PubMed:33093214, PubMed:34214466, PubMed:35636250). Prefers Nt-Gly but also has the capacity to recognize Nt-Ser, -Ala and -Cys (PubMed:36496439). Involved in the clearance of proteolytic fragments generated by caspase cleavage during apoptosis since N-terminal glycine degrons are strongly enriched at caspase cleavage sites. Also important in the quality control of protein N-myristoylation in which N-terminal glycine degrons are conditionally exposed after a failure of N-myristoylation (PubMed:31273098). In addition, plays a role in the amplification of cGAS to enhance innate immune response. Mechanistically, strengthens the processes of cGAS binding with dsDNA and assembling oligomers and also accelerates and stabilizes cGAS-DNA condensation, thereby enhancing production of antiviral IFNs and inflammatory cytokines (PubMed:36933219).
An out-of-frame translation product, PYST2SB, has been experimentally demonstrated to be formed from the alternative promoter. The expression of the in-frame product has not yet been shown.
Dual specificity protein phosphatase (PubMed:9788880). Shows high activity towards MAPK1/ERK2 (PubMed:9788880). Also has lower activity towards MAPK14 and MAPK8 (PubMed:9788880). In arrested oocytes, plays a role in meiotic resumption (By similarity). Promotes nuclear envelope breakdown and activation of the CDK1/Cyclin-B complex in oocytes, probably by dephosphorylating and inactivating the conventional protein kinase C (cPKC) isozyme PRKCB (By similarity). May also inactivate PRKCA and/or PRKCG (By similarity). Also important in oocytes for normal chromosome alignment on the metaphase plate and progression to anaphase, where it might regulate activity of the spindle-assembly checkpoint (SAC) complex (By similarity).
Interacts with MAPK1/ERK2; the interaction enhances DUSP7 phosphatase activity.
Strongly expressed in liver (PubMed:8670865). Expressed at significantly higher levels in malignant hematopoietic cells than in corresponding non-malignant cells (PubMed:14576828).
Strongly inhibited by sodium orthovanadate.
Contributes to the regulation of the Wnt signaling pathway. Down-regulates CTNNB1-mediated transcriptional activation of target genes, such as CCND1, and may thereby act as tumor suppressor. May be involved in dendritic cell and neuron differentiation.
Has some similarity to hydrolases, but lacks the conserved Ser-His-Asp catalytic triad. Has no hydrolase activity towards p-nitrophenylbutyrate (in vitro).
Highly expressed in brain, heart, skeletal muscle and salivary gland, and moderately in kidney and liver. Expressed in dendritic cells, but not in other blood cells. Expression levels are low in pancreatic and liver cancer tissues; absent in meningioma. Expressed in low-grade gliomas but present at low levels in glioblastoma. Isoform 1 and isoform 2 are present in brain neurons and up-regulated in Alzheimer disease (at protein level).
Specifically expressed during dendritic cell differentiation (in vitro). Expression is low in fetal brain and increases during brain postnatal development.
Detected in liver, heart, skeletal muscle, brain and retina, where it is concentrated in the inner segment and in the outer plexiform layers.
May act as scaffold protein (By similarity). May play a role in the development of the retina. Has been suggested to play a role in axon guidance.
Disulfide bond formation at Cys-242 occurs in case of membrane damage that cause the entry of the oxidized milieu of the extracellular space, resulting in homooligomerization.
Homooligomer; disulfide-linked. Interacts with DYSF and CAV3 (By similarity).
Muscle-specific protein that plays a central role in cell membrane repair by nucleating the assembly of the repair machinery at injury sites. Specifically binds phosphatidylserine. Acts as a sensor of oxidation: upon membrane damage, entry of extracellular oxidative environment results in disulfide bond formation and homooligomerization at the injury site. This oligomerization acts as a nucleation site for recruitment of TRIM72-containing vesicles to the injury site, leading to membrane patch formation. Probably acts upstream of the Ca(2+)-dependent membrane resealing process. Required for transport of DYSF to sites of cell injury during repair patch formation. Regulates membrane budding and exocytosis. May be involved in the regulation of the mobility of KCNB1-containing endocytic vesicles (By similarity).
S-nitrosylation at Cys-144 stabilizes TRIM72 and protects against oxidation-induced protein degradation and cell death.
Monomer. Part of a ternary complex containing KHSRP, PTBP1, PTBP2 and HNRPH1. Interacts with RAVER1 and SFPQ.
Plays a role in pre-mRNA splicing and in the regulation of alternative splicing events. Activates exon skipping of its own pre-mRNA during muscle cell differentiation. Binds to the polypyrimidine tract of introns. May promote RNA looping when bound to two separate polypyrimidine tracts in the same pre-mRNA. May promote the binding of U2 snRNP to pre-mRNA. Cooperates with RAVER1 to modulate switching between mutually exclusive exons during maturation of the TPM1 pre-mRNA. Represses the splicing of MAPT/Tau exon 10 (PubMed:15009664). Binds to polypyrimidine-rich controlling element (PCE) of CFTR and promotes exon skipping of CFTR exon 9, thereby antagonizing TIA1 and its role in exon inclusion of CFTR exon 9 (PubMed:14966131). Plays a role in the splicing of pyruvate kinase PKM by binding repressively to a polypyrimidine tract flanking PKM exon 9, inhibiting exon 9 inclusion and resulting in exon 10 inclusion and production of the PKM M2 isoform (PubMed:20010808). In case of infection by picornaviruses, binds to the viral internal ribosome entry site (IRES) and stimulates the IRES-mediated translation (PubMed:21518806).
Interacts with RAC1 (GTP-bound form preferentially).
Negatively regulates RAC1 signaling and RAC1-driven cytoskeletal remodeling (PubMed:31285585, PubMed:30250061). Regulates chemotaxis, cell migration and epithelial polarization by controlling the polarity, plasticity, duration and extent of protrusions. Limits Rac1 mediated activation of the Scar/WAVE complex, focuses protrusion signals and regulates pseudopod complexity by inhibiting Scar/WAVE-induced actin polymerization (PubMed:30250061). Protects against Salmonella bacterial infection. Attenuates processes such as macropinocytosis, phagocytosis and cell migration and restrict sopE-mediated bacterial entry (PubMed:31285585). Restricts also infection mediated by Mycobacterium tuberculosis and Listeria monocytogenes (By similarity). Involved in the regulation of mitochondrial dynamics and oxidative stress (PubMed:29059164).
Protein levels are negatively regulated by Salmonella.
Ubiquitinated at Lys-74 upon Salmonella bacterial infection.
Acts directly on vascular smooth muscle as a potent vasoconstrictor, affects cardiac contractility and heart rate through its action on the sympathetic nervous system, and alters renal sodium and water absorption through its ability to stimulate the zona glomerulosa cells of the adrenal cortex to synthesize and secrete aldosterone (PubMed:10619573, PubMed:17138938). Acts by binding to angiotensin receptors AGTR1 and AGTR2 (PubMed:1567413). Also binds the DEAR/FBXW7-AS1 receptor (By similarity).
Beta-decarboxylation of Asp-34 in angiotensin-2, by mononuclear leukocytes produces alanine (PubMed:17138938). The resulting peptide form, angiotensin-A, has the same affinity for the AT1 receptor as angiotensin-2, but a higher affinity for the AT2 receptor (PubMed:17138938).
During pregnancy, exists as a disulfide-linked 2:2 heterotetramer with the proform of PRG2 and as a complex (probably a 2:2:2 heterohexamer) with pro-PRG2 and C3dg.
Essential component of the renin-angiotensin system (RAS), a potent regulator of blood pressure, body fluid and electrolyte homeostasis.
In response to low blood pressure, the enzyme renin/REN cleaves angiotensinogen to produce angiotensin-1 (PubMed:12045255). Angiotensin-1 is a substrate of ACE (angiotensin converting enzyme) that removes a dipeptide to yield the physiologically active peptide angiotensin-2 (PubMed:4322742, PubMed:10969042). Angiotensin-1 and angiotensin-2 can be further processed to generate angiotensin-3, angiotensin-4 (PubMed:10969042, PubMed:11815627). Angiotensin 1-9 is cleaved from angiotensin-1 by ACE2 and can be further processed by ACE to produce angiotensin 1-7, angiotensin 1-5 and angiotensin 1-4 (PubMed:10969042, PubMed:11815627). Angiotensin 1-7 has also been proposed to be cleaved from angiotensin-2 by ACE2 or from angiotensin-1 by MME (neprilysin) (PubMed:15283675).
Is a ligand for the G-protein coupled receptor MAS1 (By similarity). Has vasodilator and antidiuretic effects. Has an antithrombotic effect that involves MAS1-mediated release of nitric oxide from platelets (By similarity).
The disulfide bond is labile. Angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized disulfide-bonded form, which preferentially interacts with receptor-bound renin.
Interacts with histone H3. Interacts with histone H4.
Maternal factor that plays a role in epigenetic chromatin reprogramming during early development of the zygote. Involved in the regulation of gametic DNA demethylation by inducing the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC).
B-type lamins undergo a series of modifications, such as farnesylation and phosphorylation. Increased phosphorylation of the lamins occurs before envelope disintegration and probably plays a role in regulating lamin associations.
Lamins are components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane, which is thought to provide a framework for the nuclear envelope and may also interact with chromatin.
The structural integrity of the lamina is strictly controlled by the cell cycle, as seen by the disintegration and formation of the nuclear envelope in prophase and telophase, respectively.
DNAJC27/RBJ knockdown in several colorectal cancer cell lines is correlated to inhibition of MEK/ERK activation, cell proliferation, colony formation and in vivo tumor growth.
GTPase which can activate the MEK/ERK pathway and induce cell transformation when overexpressed. May act as a nuclear scaffold for MAPK1, probably by association with MAPK1 nuclear export signal leading to enhanced ERK1/ERK2 signaling.
Interacts directly with MAPK1 (wild-type and kinase-deficient forms). Interacts directly (in GTP-bound form) with MAP2K1 (wild-type and kinase-deficient forms).
Overexpressed in gastrointestinal cancers; expression correlates with later tumor-node-metastasis stages of colorectal cancers.
Expressed by peripheral blood T-lymphocytes.
Interacts with PVR and NECTIN2. Competes with PVRIG for NECTIN2-binding.
Involved in intercellular adhesion, lymphocyte signaling, cytotoxicity and lymphokine secretion mediated by cytotoxic T-lymphocyte (CTL) and NK cell (PubMed:8673704). Cell surface receptor for NECTIN2. Upon ligand binding, stimulates T-cell proliferation and cytokine production, including that of IL2, IL5, IL10, IL13, and IFNG. Competes with PVRIG for NECTIN2-binding (PubMed:26755705).
ADP-ribosylated by PARP1 or PARP2 on Ser-7 (H2BS6ADPr) in response to DNA damage (PubMed:34874266). H2BS6ADPr promotes recruitment of CHD1L (PubMed:34874266). Mono-ADP-ribosylated on Glu-3 (H2BE2ADPr) by PARP3 in response to single-strand breaks (PubMed:27530147). Poly ADP-ribosylation on Glu-36 (H2BE35ADPr) by PARP1 regulates adipogenesis: it inhibits phosphorylation at Ser-37 (H2BS36ph), thereby blocking expression of pro-adipogenetic genes (By similarity).
GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes.
Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.
Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.
Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation (PubMed:12757711). Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.
Belongs to the leukocyte receptor complex/polymeric immunoglobulin receptor (PIR/LRC) family.
Regulator of osteoclastogenesis which plays an important bone-specific function in osteoclast differentiation.
3'-> 5'-exoribonuclease involved in ribosome biogenesis in the processing of the 12S pre-rRNA. Displays a strong specificity for a 3'-end containing a free hydroxyl group.
Expressed in all tissues tested, including spleen, lymph node, thymus, tonsil, peripheral blood leukocyte, bone marrow, liver, heart, brain, placenta, lung, skeletal muscle, kidney and pancreas.
Likely derived from retrogene insertion of an NLRP2/NLRP7-like gene, it was originally considered a pseudogene. However, it turns out to be functional and under purifying selection.
May function as a negative regulator of NF-kappa-B by preventing RELA/p65 phosphorylation at 'Ser-536', thereby inhibiting its transcriptional activity. Through NF-kappa-B regulation may control cytokine release upon Toll-like receptors activation and therefore play a role in modulation of innate immunity. May also play a role in cell cycle progression and apoptotic process.
Up-regulated by inflammatory stimulus (LPS).
A chromosomal aberration involving NR4A3 is a cause of a form of extraskeletal myxoid chondrosarcomas (EMC). Translocation t(9;17)(q22;q11) with TAF2N.
Induced by inflammatory stimuli in endothelial cells through an NF-kappa-B-dependent transactivation of the NR4A3 Promoter.
Interacts with SIX3 (via homeobox); differentially regulates the transcriptional activities of NR4A3 (PubMed:12543801). Interacts with the constituents of DNA-PK heterotrimer PRKDC, XRCC6 and XRCC5; phosphorylates and prevents NR4A3 ubiquitinylation and degradation (PubMed:25852083). Interacts with NCOA2; potentiates the activity of the NR4A3. Interacts with NCOA1, NCOA3, MED1 and KAT2B. Interacts with EP300 and NCOA2; mediates the recruitment of MED1 in the coactivator complex (By similarity). Interacts with NR3C1 (via nuclear receptor DNA-binding domain); the interactions represses transcription activity of NR4A3 on the POMC promoter Nur response element (NurRE). Interacts with TRIM28; the interactions potentiates NR4A3 activity on NurRE promoter. Binds DNA as a monomer and homodimer. Interacts with PARP1; activates PARP1 by improving acetylation of PARP1 and suppressing the interaction between PARP1 and SIRT1 (By similarity).
Isoform alpha is highly expressed in skeletal muscle. Isoform beta is highly expressed in skeletal muscle and low expressed in fetal brain and placenta.
The AF-1 domain mediates transcription activation. The N-terminal region (1-292) directly interacts with the C-terminal LBD (380-627): the interaction is potentiated by AF-1-mediated recruitment of NCOA2.
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving NR4A3 is found in patients with Erwing sarcoma. Translocation t(9;22)(q22-31;q11-12) with EWSR1.
Transcriptional activator that binds to regulatory elements in promoter regions in a cell- and response element (target)-specific manner. Induces gene expression by binding as monomers to the NR4A1 response element (NBRE) 5'-AAAAGGTCA-3' site and as homodimers to the Nur response element (NurRE) site in the promoter of their regulated target genes (By similarity). Plays a role in the regulation of proliferation, survival and differentiation of many different cell types and also in metabolism and inflammation. Mediates proliferation of vascular smooth muscle, myeloid progenitor cell and type B pancreatic cells; promotes mitogen-induced vascular smooth muscle cell proliferation through transactivation of SKP2 promoter by binding a NBRE site (By similarity). Upon PDGF stimulation, stimulates vascular smooth muscle cell proliferation by regulating CCND1 and CCND2 expression. In islets, induces type B pancreatic cell proliferation through up-regulation of genes that activate cell cycle, as well as genes that cause degradation of the CDKN1A (By similarity). Negatively regulates myeloid progenitor cell proliferation by repressing RUNX1 in a NBRE site-independent manner. During inner ear, plays a role as a key mediator of the proliferative growth phase of semicircular canal development (By similarity). Mediates also survival of neuron and smooth muscle cells; mediates CREB-induced neuronal survival, and during hippocampus development, plays a critical role in pyramidal cell survival and axonal guidance. Is required for S phase entry of the cell cycle and survival of smooth muscle cells by inducing CCND1, resulting in RB1 phosphorylation. Binds to NBRE motif in CCND1 promoter, resulting in the activation of the promoter and CCND1 transcription (By similarity). Also plays a role in inflammation; upon TNF stimulation, mediates monocyte adhesion by inducing the expression of VCAM1 and ICAM1 by binding to the NBRE consensus site (By similarity) (PubMed:20558821). In mast cells activated by Fc-epsilon receptor cross-linking, promotes the synthesis and release of cytokines but impairs events leading to degranulation (By similarity). Also plays a role in metabolism; by modulating feeding behavior; and by playing a role in energy balance by inhibiting the glucocorticoid-induced orexigenic neuropeptides AGRP expression, at least in part by forming a complex with activated NR3C1 on the AGRP- glucocorticoid response element (GRE), and thus weakening the DNA binding activity of NR3C1. Upon catecholamines stimulation, regulates gene expression that controls oxidative metabolism in skeletal muscle (By similarity). Plays a role in glucose transport by regulating translocation of the SLC2A4 glucose transporter to the cell surface (PubMed:24022864). Finally, during gastrulation plays a crucial role in the formation of anterior mesoderm by controlling cell migration. Inhibits adipogenesis (By similarity). Also participates in cardiac hypertrophy by activating PARP1 (By similarity).
Forms a distorted beta-barrel structure, with two helices that are packed against the outer surface of the barrel. Porphyrins are expected to bind to a hydrophobic patch on the outer surface of the beta-barrel structure (By similarity).
May bind free porphyrinogens that may be present in the cell and thus facilitate removal of these potentially toxic compound. Binds with a high affinity to one molecule of heme or porphyrins. It binds metalloporphyrins, free porphyrins and N-methylprotoporphyrin with similar affinities.
Defects in KCTD7 are a cause of opsoclonus-myoclonus ataxia-like syndrome. Opsoclonus myoclonus ataxia syndrome (OMS) is a rare pervasive and frequently permanent disorder that usually develops in previously healthy children with normal premorbid psychomotor development and characterized by association of abnormal eye movements (opsoclonus), severe dyskinesia (myoclonus), cerebellar ataxia, functional regression, and behavioral problems. The syndrome is considered to be an immune-mediated disorder and may be tumor-associated or idiopathic. OMS is one of a few steroid responsive disorders of childhood. KCTD7 mutations have been found in a patient with an atypical clinical presentation characterized by non-epileptic myoclonus and ataxia commencing in early infancy, abnormal opsoclonus-like eye movements, improvement of clinical symptoms under steroid treatment, and subsequent development of generalized epilepsy (PubMed:22638565).
May be involved in the control of excitability of cortical neurons.
Expressed at high levels in the skeletal muscle, placenta and ovary. Expressed at intermediate levels in the liver and pancreas and at low levels in the kidney and heart.
Functions as low-affinity, high capacity permease involved in the transport of the cationic amino acids (L-arginine, L-lysine, L-ornithine and L-homoarginine).
Functions as permease involved in the transport of the cationic amino acids (L-arginine, L-lysine, L-ornithine and L-homoarginine); the affinity for its substrates differs between isoforms created by alternative splicing (PubMed:9174363, PubMed:28684763). May play a role in classical or alternative activation of macrophages via its role in arginine transport (By similarity).
Functions as permease that mediates the transport of the cationic amino acids (L-arginine, L-lysine, L-ornithine and L-homoarginine). Shows a much higher affinity for L-arginine and L-homoarginine than isoform 2.
Homodimer (via PDZ domain) (PubMed:24675079). Interacts with DYSF; the interaction is direct and Ca(2+)-independent (PubMed:17185750).
Channel-forming protein essential for import of protein precursors into mitochondria (PubMed:15644312, PubMed:31206022). Plays a role in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) by forming a complex with BCAP31 and mediating the translocation of Complex I components from the cytosol to the mitochondria (PubMed:31206022).
Forms part of the preprotein translocase complex of the outer mitochondrial membrane (TOM complex) which consists of at least 7 different proteins (TOMM5, TOMM6, TOMM7, TOMM20, TOMM22, TOMM40 and TOMM70). Interacts with mitochondrial targeting sequences (PubMed:12198123, PubMed:15644312, PubMed:18331822). Interacts with TIMM29; linking the TIM22 complex to the TOM complex (PubMed:27554484). Forms a complex with BCAP31 (via C-terminus) which mediates the translocation of components of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) from the cytosol to the mitochondria (PubMed:31206022). Interacts (via N-terminus) with CYP1A1 (via mitochondrial targeting signal); this interaction is required for CYP1A1 translocation across the mitochondrial outer membrane (By similarity).
Arg-456-His, Arg-611-His and Ile-720-Val polymorphisms are in tight linkage disequilibrium with one another and associated with type 1 diabetes in Japanese.
Highly expressed in heart followed by brain, placenta, lung and pancreas. Weakly expressed in liver, kidney and skeletal muscle. Also expressed in islet and beta-cell insulinoma cell line.
Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store (PubMed:16989814). Negatively regulates the ER stress response and positively regulates the stability of V-ATPase subunits ATP6V1A and ATP1B1 by preventing their degradation through an unknown proteasome-independent mechanism (PubMed:23035048).
Expressed in airway epithelium and submucosal gland (at protein level). Colocalizes with bikunin at the ciliary border. Present in bronchoalveolar lavage fluid (at protein level) (PubMed:16873769). Expressed in mesenchymal stem cells (PubMed:16771708). Found in the synovial fluid of patients with rheumatoid arthritis.
Interacts (via Link domain) with inter-alpha-inhibitor (I-alpha-I) component bikunin (PubMed:15917224). Interacts with ITIH2/HC2; this interaction is required for transesterification of the HC to hyaluronan (PubMed:20463016). Interacts (via Link and CUB domains) with ITIH1 (PubMed:26468290). Chondroitin sulfate may be required for the stability of the complex (PubMed:7516184). Interacts (via Link domain) with various C-X-C and C-C chemokines including PF4, CXCL8, CXCL11, CXCL12, CCL2, CCL7, CCL19, CCL21, and CCL27; this interaction interferes with chemokine binding to glycosaminoglycans (PubMed:24501198, PubMed:27044744). Interacts (primarily via Link domain) with BMP2; this interaction is inhibited by hyaluronan (PubMed:16771708). Interacts (via both Link and CUB domains) with TNFSF11 (PubMed:18586671). Interacts (via CUB domain) with FN1 (via type III repeats 9-14); this interaction enhances fibronectin fibril assembly. TNFAIP6 may act as a bridging molecule between FN1 and THBS1 (PubMed:18042364).
Major regulator of extracellular matrix organization during tissue remodeling (PubMed:18042364, PubMed:26823460, PubMed:15917224). Catalyzes the transfer of a heavy chain (HC) from inter-alpha-inhibitor (I-alpha-I) complex to hyaluronan. Cleaves the ester bond between the C-terminus of the HC and GalNAc residue of the chondroitin sulfate chain in I-alpha-I complex followed by transesterification of the HC to hyaluronan. In the process, potentiates the antiprotease function of I-alpha-I complex through release of free bikunin (PubMed:20463016, PubMed:15917224, PubMed:16873769). Acts as a catalyst in the formation of hyaluronan-HC oligomers and hyaluronan-rich matrix surrounding the cumulus cell-oocyte complex, a necessary step for oocyte fertilization (PubMed:26468290). Assembles hyaluronan in pericellular matrices that serve as platforms for receptor clustering and signaling. Enables binding of hyaluronan deposited on the surface of macrophages to LYVE1 on lymphatic endothelium and facilitates macrophage extravasation. Alters hyaluronan binding to functionally latent CD44 on vascular endothelium, switching CD44 into an active state that supports leukocyte rolling (PubMed:26823460, PubMed:15060082). Modulates the interaction of chemokines with extracellular matrix components and proteoglycans on endothelial cell surface, likely preventing chemokine gradient formation (PubMed:27044744). In a negative feedback mechanism, may limit excessive neutrophil recruitment at inflammatory sites by antagonizing the association of CXCL8 with glycosaminoglycans on vascular endothelium (PubMed:24501198). Has a role in osteogenesis and bone remodeling. Inhibits BMP2-dependent differentiation of mesenchymal stem cell to osteoblasts (PubMed:18586671, PubMed:16771708). Protects against bone erosion during inflammation by inhibiting TNFSF11/RANKL-dependent osteoclast activation (PubMed:18586671).
The CUB domain is necessary for calcium ion binding and transesterification reaction (PubMed:26468290). It is required for binding to FN1 (PubMed:18042364).
The Link domain interacts with various extracellular matrix components, including heparin, heparan sulfates, hyaluronan and I-alpha-I complex (PubMed:15917224, PubMed:15060082). It is required for binding to various chemokines (PubMed:27044744).
Up-regulated in peripheral blood mononuclear cells, high endothelial venules, airway epithelium and submucosal gland in response to inflammatory cytokine TNF (PubMed:1730767, PubMed:16873769). Down-regulated upon differentiation of mesenchymal stem cells to osteoblasts (PubMed:16771708).
Component of the tRNA(Sec) complex composed at least of EEFSEC, SECISBP2, SEPHS1, SEPSECS, TRNAU1AP and tRNA(Sec). Found in a complex with tRNA(Sec). Interacts with SEPSECS. Associates with mRNP and/or polysomes (By similarity). Found in a complex with EEFSEC, SECISBP2, TRNAU1AP and tRNA(Sec).
Involved in the early steps of selenocysteine biosynthesis and tRNA(Sec) charging to the later steps resulting in the cotranslational incorporation of selenocysteine into selenoproteins. Stabilizes the SECISBP2, EEFSEC and tRNA(Sec) complex. May be involved in the methylation of tRNA(Sec). Enhances efficiency of selenoproteins synthesis (By similarity).
Contains chondroitin sulfate and heparan sulfate O-linked oligosaccharides.
Highly expressed in brain. Also found in lung and testis.
May participate in diverse steps of neurogenesis. Binds calcium.
Belongs to the mitochondrion-specific ribosomal protein mL46 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379, PubMed:25278503). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. mL46 is located at the central protuberance.
Minus-end microtubule-dependent motor protein. Involved in apically targeted transport (By similarity). Required for zonula adherens maintenance.
Highly expressed in the prostate, ovary, liver, testis, uterus, colon and small intestine. Intermediate levels in brain, skeletal muscle, heart and spleen. Low levels in placenta, pancreas, thymus and peripheral blood leukocytes. According to PubMed:10608886, high levels in kidney, whereas according to PubMed:9923614, levels are low. High expression is observed in the adrenal cortex (PubMed:24601690).
Involved in the control of reactive oxygen species levels and the regulation of mitochondrial redox homeostasis (PubMed:24601690). Maintains thioredoxin in a reduced state. May play a role in redox-regulated cell signaling.
The active site is a redox-active disulfide bond. The selenocysteine residue is essential for enzymatic activity (By similarity).
Endogenous ligand for the apelin receptor (APLNR) (PubMed:25639753, PubMed:28137936). Hormone required for mesendodermal differentiation, blood vessels formation and heart morphogenesis during early development and for adult cardiovascular homeostasis (PubMed:25639753, PubMed:28137936). Drives internalization of APLNR. Acts as a motogen by promoting mesendodermal cell migration during gastrulation by binding and activating APLNR. Acts as an early embryonic regulator of cellular movement with a role in migration and development of cardiac progenitor cells. May act as a chemoattractant for the activation of angioblast migration toward the embryonic midline, i.e. the position of the future vessel formation, during vasculogenesis. Positively regulates sinus venosus (SV)-derived endothelial cells migration into the developing heart to promote coronary blood vessel sprouting. Plays a role in placental vascular development; promotes placental trophoblast invasion and spiral artery remodeling in the uterus. Involved in the regulation of maternal cardiovascular homeostasis to prevent gestational hypertension and for potent cardioprotective functions during heart failure. Mediates myocardial contractility in an ERK1/2-dependent manner (By similarity).
Expressed in the intima of blood vessels (PubMed:28137936). Expressed in endothelial cells in blood vessels in the heart and lung (PubMed:28137936). Expressed in cytotrophoblasts and syncytiotrophoblasts of first-trimester placental tissue and term placentas (at protein level) (PubMed:28663440). Not detected in smooth muscle cells or cardiomyocytes (at protein level) (PubMed:28137936). Expressed in kidney (PubMed:25639753). Expressed in blood vessels (PubMed:28137936). Expressed in embryonic (ESCs) and induced (iPSCs) pluripotent stem cells (PubMed:25639753). Most highly expressed in undifferentiated embryonic stem cell and is rapidly down-regulated during differentiation (PubMed:24316148).
A long coiled coil structure formed by 3 polypeptide chains connects the central nodule to the C-terminal domains (distal nodules). The long C-terminal ends of the alpha chains fold back, contributing a fourth strand to the coiled coil structure.
Cleaved by the protease thrombin to yield monomers which, together with fibrinogen alpha (FGA) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix. Fibrin has a major function in hemostasis as one of the primary components of blood clots. In addition, functions during the early stages of wound repair to stabilize the lesion and guide cell migration during re-epithelialization. Was originally thought to be essential for platelet aggregation, based on in vitro studies using anticoagulated blood. However subsequent studies have shown that it is not absolutely required for thrombus formation in vivo. Enhances expression of SELP in activated platelets. Maternal fibrinogen is essential for successful pregnancy. Fibrin deposition is also associated with infection, where it protects against IFNG-mediated hemorrhage. May also facilitate the antibacterial immune response via both innate and T-cell mediated pathways.
Conversion of fibrinogen to fibrin is triggered by thrombin, which cleaves fibrinopeptides A and B from alpha and beta chains, and thus exposes the N-terminal polymerization sites responsible for the formation of the soft clot. The soft clot is converted into the hard clot by factor XIIIA which catalyzes the epsilon-(gamma-glutamyl)lysine cross-linking between gamma chains (stronger) and between alpha chains (weaker) of different monomers.
Detected in blood plasma (at protein level).
Heterohexamer; disulfide linked. Contains 2 sets of 3 non-identical chains (alpha, beta and gamma). The 2 heterotrimers are in head to head conformation with the N-termini in a small central domain.
The disease is caused by variants affecting the gene represented in this entry. Patients with congenital fibrinogen abnormalities can manifest different clinical pictures. Some cases are clinically silent, some show a tendency toward bleeding and some show a predisposition for thrombosis with or without bleeding.
Component of a ribonucleoprotein complex containing mRNAs and RNA-binding proteins including DDX5, HNRNPH2 and SRSF1 as well as splicing regulator ARVCF (PubMed:24644279). Interacts with TXNL4/DIM1 (PubMed:11054566).
This protein is a component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes which provide the substrate for the processing events that pre-mRNAs undergo before becoming functional, translatable mRNAs in the cytoplasm. Binds poly(RG).
Activated by phosphorylation at Ser-360, Thr-581 and Thr-700 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha, and by further autophosphorylation of Ser-212, Ser-376 and Ser-381 by the activated C-terminal kinase domain. The active N-terminal kinase domain finally phosphorylates downstream substrates, as well as Ser-750, Ser-752 and Ser-758 in its own C-terminal region.
Enzyme activity requires the presence of both kinase domains.
Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells which transiently dissociates following mitogenic stimulation. Also associates with MAPK14/p38-alpha. Activated RPS6KA5 associates with and phosphorylates the NF-kappa-B p65 subunit RELA. Interacts with CREBBP and EP300.
Ser-376 and Thr-581 phosphorylation is required for kinase activity. Ser-376 and Ser-212 are autophosphorylated by the C-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain. Phosphorylated at Ser-360, Thr-581 and Thr-700 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha. Autophosphorylated at Ser-750, Ser-752 and Ser-758 by the N-terminal kinase domain.
Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factors RELA, STAT3 and ETV1/ER81, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes (PubMed:11909979, PubMed:12569367, PubMed:12763138, PubMed:9687510, PubMed:18511904, PubMed:9873047). Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin (PubMed:11909979, PubMed:9873047). Plays an essential role in the control of RELA transcriptional activity in response to TNF and upon glucocorticoid, associates in the cytoplasm with the glucocorticoid receptor NR3C1 and contributes to RELA inhibition and repression of inflammatory gene expression (PubMed:12628924, PubMed:18511904). In skeletal myoblasts is required for phosphorylation of RELA at 'Ser-276' during oxidative stress (PubMed:12628924). In erythropoietin-stimulated cells, is necessary for the 'Ser-727' phosphorylation of STAT3 and regulation of its transcriptional potential (PubMed:12763138). Phosphorylates ETV1/ER81 at 'Ser-191' and 'Ser-216', and thereby regulates its ability to stimulate transcription, which may be important during development and breast tumor formation (PubMed:12569367). Directly represses transcription via phosphorylation of 'Ser-1' of histone H2A (PubMed:15010469). Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN (PubMed:12773393). May also phosphorylate 'Ser-28' of histone H3 (PubMed:12773393). Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14) (PubMed:12773393). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro-inflammatory cytokines (By similarity). Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors (By similarity). Plays a role in neuronal cell death by mediating the downstream effects of excitotoxic injury (By similarity). Phosphorylates TRIM7 at 'Ser-107' in response to growth factor signaling via the MEK/ERK pathway, thereby stimulating its ubiquitin ligase activity (PubMed:25851810).
Widely expressed with high levels in heart, brain and placenta. Less abundant in lung, kidney and liver.
Depletion of MIF4GD results in cell death and reduced histone mRNA translation.
Functions in replication-dependent translation of histone mRNAs which differ from other eukaryotic mRNAs in that they do not end with a poly-A tail but a stem-loop. May participate in circularizing those mRNAs specifically enhancing their translation.
Interacts with EIF4G1, EIF4G2 and SLBP; probably tethered by SLBP to the 3'-end of mRNAs ending with the histone stem-loop, it also interacts with EIF4G1 which is bound to their 5'-end.
Expressed in most tissues with the exception of lung, muscle and pancreas. Highly expressed in placenta.
Inhibited by both 1-deoxymannojirimycin and kifunensine.
Involved in the maturation of Asn-linked oligosaccharides. Trim alpha-1,2-linked mannose residues from Man(9)GlcNAc(2) to produce first Man(8)GlcNAc(2) then Man(6)GlcNAc and a small amount of Man(5)GlcNAc.
Shows growth cone collapsing activity on dorsal root ganglion (DRG) neurons in vitro. May be a stop signal for the DRG neurons in their target areas, and possibly also for other neurons. May also be involved in the maintenance and remodeling of neuronal connections.
Palmitoyltransferase that could catalyze the addition of palmitate onto protein substrates including the D(2) dopamine receptor DRD2.
The C-terminal di-lysine motif confers endoplasmic reticulum localization.
Enhances production of pro-inflammatory cytokines induced by TNF, IL1B, and TLR ligands. Has a role in TNF activation of both the NF-kappaB and MAPK pathways.
CD200 and CD200R1 interact via their respective N-terminal Ig-like domains.
Costimulates T-cell proliferation. May regulate myeloid cell activity in a variety of tissues.
Interacts with SLC35A2; the interaction is reduced in the presence of SLC35A4 (PubMed:23089177, PubMed:28167211). Found in a complex with SLC35A2 and SLC35A4 (PubMed:28167211). Interacts with MGAT4B (PubMed:34981577).
O-Glcnacylation regulates the stability of SLC35A3 and the specific complex formation with MGAT4B.
The disease is caused by variants affecting the gene represented in this entry. In Golgi vesicles isolated from patient fibroblasts the transport of the respective nucleotide sugar is significantly reduced causing a massive decrease in the content of cell surface expressed highly branched N-glycans and a concomitant sharp increase of lower branched glycoforms.
Transports diphosphate-N-acetylglucosamine (UDP-GlcNAc) from the cytosol into the lumen of the Golgi apparatus, functioning as an antiporter that exchanges UDP-N-acetyl-alpha-D-glucosamine for UMP (PubMed:10393322). May supply UDP-GlcNAc as substrate for Golgi-resident glycosyltransferases that generate highly branched, multiantennary complex N-glycans and keratan sulfate (PubMed:23766508, PubMed:34981577). However, the exact role of SLC35A3 still needs to be elucidated, it could be a member of a catalytically more efficient multiprotein complex rather than function independently as a single transporter (PubMed:32938718).
Has been the subject of controversy surrounding its catalytic capabilities. Early characterization of PEAK1 gave a weak in vitro tyrosine kinase activity (PubMed:20534451). The crystal structure indicates that the kinase-domain contains a closed nucleotide-binding cleft that in this conformation may deleteriously affect nucleotide binding (PubMed:29212708). Furthermore PEAK1 is devoid of nucleotide binding activity, as detected by a thermal-shift assay (PubMed:24107129). So it seems probable that PEAK1 is an inactive kinase.
Homodimer (PubMed:29212708). Interacts with BCAR1 and CRK (PubMed:20534451). Interacts with PRAG1 (PubMed:29079850). Interacts (when phosphorylated at Tyr-1188) with SHC1 (via PID domain) (PubMed:23846654, PubMed:35687021). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1. Interacts (when phosphorylated at Tyr-635) with tensin TNS3 (when phosphorylated on the SH2 domain); TNS3 also interacts with integrins ITGB1, ITGB3 and ITGB5 and mediates their association with PEAK1 (PubMed:35687021). Interacts with RASAL2 and GRB2 (PubMed:35687021).
Phosphorylated on tyrosine in a CSK-dependent manner in response to adhesion to fibronectin and to EGF stimulation (PubMed:20534451). Phosphorylation at Tyr-665 by a Src family kinase controls subcellular localization to focal adhesion and focal adhesion dynamics (PubMed:20534451). Phosphorylation at Tyr-1188 is essential for binding to SHC1 (PubMed:23846654). Phosphorylation at Tyr-635 promotes interaction with tensin TNS3 (PubMed:35687021).
Probable catalytically inactive kinase. Scaffolding protein that regulates the cytoskeleton to control cell spreading and migration by modulating focal adhesion dynamics (PubMed:23105102, PubMed:20534451, PubMed:35687021). Acts as a scaffold for mediating EGFR signaling (PubMed:23846654).
Arg-185 is dimethylated, probably to asymmetric dimethylarginine.
Cleavage of initiator Met is partial. If Met-1 is not removed, it is acetylated. If it is removed, Val-2 is acetylated.
Expressed strongly in oral keratinocytes, but only weakly detected in oral squamous cell carcinomas (at protein level).
Homomultimer. Interacts with SAFB/SAFB1 (By similarity). Found in the supraspliceosome complex. Identified in the spliceosome C complex. Interacts with KHDRBS3. Forms a complex with ILF2, ILF3, YLPM1, KHDRBS1, NCOA5 and PPP1CA. Interacts with CLK2, KHDRBS2, SAFB, TRA2B and YTHDC1. Interacts with ERAP1; the interaction is RNA-independent (PubMed:18445477). Interacts with PPIA/CYPA (PubMed:25678563).
RNA-binding protein that plays several role in the regulation of pre- and post-transcriptional processes. Implicated in tissue-specific regulation of gene transcription and alternative splicing of several pre-mRNAs. Binds to and stimulates transcription from the tumor suppressor TXNIP gene promoter; may thus be involved in tumor suppression. When associated with SAFB, binds to and stimulates transcription from the SREBF1 promoter. Associates with nascent mRNAs transcribed by RNA polymerase II. Component of the supraspliceosome complex that regulates pre-mRNA alternative splice site selection. Can either activate or suppress exon inclusion; acts additively with TRA2B to promote exon 7 inclusion of the survival motor neuron SMN2. Represses the splicing of MAPT/Tau exon 10. Binds preferentially to single-stranded 5'-CC[A/C]-rich RNA sequence motifs localized in a single-stranded conformation; probably binds RNA as a homodimer. Binds non-specifically to pre-mRNAs. Also plays a role in the cytoplasmic TNFR1 trafficking pathways; promotes both the IL-1-beta-mediated inducible proteolytic cleavage of TNFR1 ectodomains and the release of TNFR1 exosome-like vesicles to the extracellular compartment.
The RRM domain is necessary for RNA-binding, but not for splice site selection, indicating that its splicing activity does not require direct binding to RNA.
Intramolecular proteolysis generates 2 subunits, alpha and beta, which reassemble through a non-covalent association to form the fully active enzyme.
Protease responsible for KMT2A/MLL1 processing and activation (PubMed:14636557). It also activates KMT2D/MLL2 (By similarity). Through substrate activation, it controls the expression of HOXA genes, and the expression of key cell cycle regulators including CCNA1, CCNB1, CCNE1 and CDKN2A (By similarity) (PubMed:14636557).
Acts as a lysosomal membrane arginine sensor (PubMed:30956113). Forms a complex with MTOR and SLC38A9 on lysosomal membranes in an arginine-regulated manner, leading to arginine efflux which enables the activation of mTORC1 which subsequently leads to RPS6KB1 and EIF4EBP1 phosphorylations (PubMed:30956113). Facilitates cell cycle G1/S phase progression and the translocation of the CDK4-CCND1 complex into the nucleus (PubMed:20399237). CDKN1B and RHOA/ROCK signaling activity are involved in TM4SF5-mediated acceleration of G1/S phase progression (PubMed:20399237).
Interacts with MTOR; the interaction is positively regulated by arginine and is negatively regulated by leucine (PubMed:30956113). Interacts with SLC38A9 (PubMed:30956113). Interacts with SLC7A1; the interaction is negatively regulated by arginine (PubMed:30956113). Interacts with CASTOR1; the interaction is positively regulated by leucine and is negatively regulated by arginine (PubMed:30956113).
Intestine. Overexpressed in pancreatic cancers.
Anorexigenic peptide, seems to play an important role in hypothalamic pathways regulating food intake and energy homeostasis, acting in a leptin-independent manner. May also exert hypertensive roles and modulate blood pressure through directly acting on peripheral arterial resistance.
Calcium-binding protein which may have a role in calcium homeostasis (By similarity). Acts as a non-receptor guanine nucleotide exchange factor which binds to and activates guanine nucleotide-binding protein (G-protein) alpha subunit GNAI3 (By similarity).
Interacts (via GBA motif) with guanine nucleotide-binding protein G(i) alpha subunit GNAI3 (By similarity). Preferentially interacts with inactive rather than active GNAI3 (By similarity). Interaction with GNAI3 is inhibited when NUCB2 binds calcium, probably due to a conformational change which renders the GBA motif inaccessible (By similarity). Binds to the postmitotic growth suppressor NDN; coexpression abolishes NUCB2 secretion (By similarity).
NEFA stands for N=DNA-binding; EF=EF-hand; A=Acidic region.
Predominantly expressed in spleen, testis and normal stomach.
The GBA (G-alpha binding and activating) motif mediates binding to the alpha subunits of guanine nucleotide-binding proteins (G proteins).
Heterodimer of PSME1 and PSME2, which forms a hexameric ring. PSME1 can form homoheptamers.
Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.
The transactivation domains TAM and TAC (for transactivation domain in the middle and at the C-terminus, respectively) are required to contact transcriptional coactivators and basal transcriptional machinery components and thereby induce gene transactivation.
Transcription factor that may play a role in central nervous system, limb and facial development. May be involved in male sex determination. Binds the consensus motif 5'-[AT][AT]CAA[AT]G-3' (By similarity).
(Microbial infection) Interacts with Epstein-Barr virus protein BNRF1.
(Microbial infection) Interacts with Puumala hantavirus nucleoprotein.
(Microbial infection) Interacts with human adenovirus 5 E1B-55K protein; this interaction might alterate the normal interactions of DAXX, PML, and TP53, which may contribute to cell transformation.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 tegument phosphoprotein pp71 and protein UL123.
Homomultimer. Interacts (via C-terminus) with TNFRSF6 (via death domain). Interacts with PAX5, SLC2A4/GLUT4, MAP3K5, TGFBR2, phosphorylated dimeric HSPB1/HSP27, CENPC, ETS1, sumoylated PML, UBE2I, MCRS1 and TP53. Interacts (via N-terminus) with HIPK2 and HIPK3. Interacts with HIPK1, which induces translocation from PML/POD/ND10 nuclear bodies to chromatin and enhances association with HDAC1. Interacts (non-phosphorylated) with PAX3, PAX7, DEK, HDAC1, HDAC2, HDAC3, acetylated histone H4 and histones H2A, H2B, H3, H3.3 and H4. Interacts with SPOP; mediating CUL3-dependent proteasomal degradation. Interacts with CBP; the interaction is dependent the sumoylation of CBP and suppresses CBP transcriptional activity via recruitment of HDAC2 directly in the complex with TP53 and HIPK2. Interacts with AXIN1; the interaction stimulates the interaction of DAXX with TP53, stimulates 'Ser-46' phosphorylation of TP53 on and induces cell death on UV irradiation. Interacts with MDM2; the interaction is direct. Interacts with USP7; the interaction is direct and independent of MDM2 and TP53. Part of a complex with DAXX, MDM2 and USP7 under non-stress conditions. Interacts (via N-terminus) with RASSF1 (via C-terminus); the interaction is independent of MDM2 and TP53; RASSF1 isoform A disrupts interactions among MDM2, DAXX and USP7, thus contributing to the efficient activation of TP53 by promoting MDM2 self-ubiquitination in cell-cycle checkpoint control in response to DNA damage. Interacts with ATRX to form the chromatin remodeling complex ATRX:DAXX. Interacts with HSF1 (via homotrimeric form preferentially); this interaction relieves homotrimeric HSF1 from repression of its transcriptional activity by HSP90-dependent multichaperone complex upon heat shock (PubMed:15016915). Interacts with SUMO1P1/SUMO5 (PubMed:27211601).
Markedly decreased affinity for PML and TP53/p53, unable to repress p53-mediated transcription.
Phosphorylated by HIPK1 upon glucose deprivation.
Polyubiquitinated; which is promoted by CUL3 and SPOP and results in proteasomal degradation. Ubiquitinated by MDM2; inducing its degradation. Deubiquitinated by USP7; leading to stabilize it.
Sumoylated with SUMO1 on multiple lysine residues.
The Sumo interaction motif mediates Sumo binding, and is required both for sumoylation and binding to sumoylated targets.
Transcription corepressor known to repress transcriptional potential of several sumoylated transcription factors. Down-regulates basal and activated transcription. Its transcription repressor activity is modulated by recruiting it to subnuclear compartments like the nucleolus or PML/POD/ND10 nuclear bodies through interactions with MCSR1 and PML, respectively. Seems to regulate transcription in PML/POD/ND10 nuclear bodies together with PML and may influence TNFRSF6-dependent apoptosis thereby. Inhibits transcriptional activation of PAX3 and ETS1 through direct protein-protein interactions. Modulates PAX5 activity; the function seems to involve CREBBP. Acts as an adapter protein in a MDM2-DAXX-USP7 complex by regulating the RING-finger E3 ligase MDM2 ubiquitination activity. Under non-stress condition, in association with the deubiquitinating USP7, prevents MDM2 self-ubiquitination and enhances the intrinsic E3 ligase activity of MDM2 towards TP53, thereby promoting TP53 ubiquitination and subsequent proteasomal degradation. Upon DNA damage, its association with MDM2 and USP7 is disrupted, resulting in increased MDM2 autoubiquitination and consequently, MDM2 degradation, which leads to TP53 stabilization. Acts as histone chaperone that facilitates deposition of histone H3.3. Acts as targeting component of the chromatin remodeling complex ATRX:DAXX which has ATP-dependent DNA translocase activity and catalyzes the replication-independent deposition of histone H3.3 in pericentric DNA repeats outside S-phase and telomeres, and the in vitro remodeling of H3.3-containing nucleosomes. Does not affect the ATPase activity of ATRX but alleviates its transcription repression activity. Upon neuronal activation associates with regulatory elements of selected immediate early genes where it promotes deposition of histone H3.3 which may be linked to transcriptional induction of these genes. Required for the recruitment of histone H3.3:H4 dimers to PML-nuclear bodies (PML-NBs); the process is independent of ATRX and facilitated by ASF1A; PML-NBs are suggested to function as regulatory sites for the incorporation of newly synthesized histone H3.3 into chromatin. In case of overexpression of centromeric histone variant CENPA (as found in various tumors) is involved in its mislocalization to chromosomes; the ectopic localization involves a heterotypic tetramer containing CENPA, and histones H3.3 and H4 and decreases binding of CTCF to chromatin. Proposed to mediate activation of the JNK pathway and apoptosis via MAP3K5 in response to signaling from TNFRSF6 and TGFBR2. Interaction with HSPB1/HSP27 may prevent interaction with TNFRSF6 and MAP3K5 and block DAXX-mediated apoptosis. In contrast, in lymphoid cells JNC activation and TNFRSF6-mediated apoptosis may not involve DAXX. Shows restriction activity towards human cytomegalovirus (HCMV). Plays a role as a positive regulator of the heat shock transcription factor HSF1 activity during the stress protein response (PubMed:15016915).
Upon mitogenic stimulation by concanavalin-A.
Catalyzes the post-translational formation of 4-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins.
Expressed in the heart, liver, skeletal muscle, kidney, placenta, lung and pancreas.
Heterotetramer of two alpha-1 chains and two beta chains (P4HB)(the beta chain is the multi-functional PDI), where P4HB plays the role of a structural subunit; this tetramer catalyzes the formation of 4-hydroxyproline in collagen.
Expressed in blood leukocyte, lung, placenta, small intestine, liver, kidney, spleen, thymus, colon, skeletal muscle and heart.
Probable receptor, which is involved in the internalization of lipophilic molecules and/or signal transduction. May be involved in the uptake of lipoprotein APOE in liver (By similarity).
Belongs to the potassium channel family. Calcium-activated (TC 1.A.1.3) subfamily. KCa4.1/KCNT1 sub-subfamily.
Highest expression in liver, brain and spinal cord. Lowest expression in skeletal muscle.
Interacts (via C-terminus) with FMR1; this interaction alters gating properties of KCNT1 (PubMed:20512134). Interacts with CRBN via its cytoplasmic C-terminus (By similarity).
Outwardly rectifying potassium channel subunit that may coassemble with other Slo-type channel subunits. Activated by high intracellular sodium or chloride levels. Activated upon stimulation of G-protein coupled receptors, such as CHRM1 and GRIA1. May be regulated by calcium in the absence of sodium ions (in vitro) (By similarity).
Phosphorylated by protein kinase C. Phosphorylation of the C-terminal domain increases channel activity (By similarity).
Highest levels in prostate, lower levels in thymus, placenta, and skeletal muscle. Expressed in embryonic and adult tissues.
Target-derived survival factor for peripheral sensory sympathetic neurons.
Binds ssDNA (PubMed:29290614). Interacts (via N-terminal region) with BLM; the interaction is direct. Directly interacts with RMI1. Component of the RMI complex, containing at least TOP3A, RMI1 and RMI2. The RMI complex interacts with BLM.
High expression is found in testis, heart, skeletal muscle and pancreas.
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(5'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 3'-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 3'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone. As an essential component of the RMI complex it is involved in chromosome separation and the processing of homologous recombination intermediates to limit DNA crossover formation in cells. Has DNA decatenation activity (PubMed:30057030). It is required for mtDNA decatenation and segregation after completion of replication, in a process that does not require BLM, RMI1 and RMI2 (PubMed:29290614).
Probably functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus (By similarity).
Belongs to the universal ribosomal protein uL10 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379, PubMed:25278503). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. uL10m contributes a single cysteine residue to a zinc-binding site with mL66.
Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane. Together with RAB11A, RAB3IP, RAB8A, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis (By similarity).
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts with CNTRL. Interacts with RAB11A in a GTP-dependent manner (By similarity).
Expressed in subcutaneous fat, heart, skeletal muscle, brain, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung and peripheral blood leukocyte.
Found in a complex with PID1/PCLI1, LRP1 and CUBNI. Interacts with LRP1 and CUBN.
Increases proliferation of preadipocytes without affecting adipocytic differentiation.
Some sequences seem to have a duplication of exon 2.
Enzyme that catalyzes the last step in proline biosynthesis. Proline is synthesized from either glutamate or ornithine; both are converted to pyrroline-5-carboxylate (P5C), and then to proline via pyrroline-5-carboxylate reductases (PYCRs). PYCRL is exclusively linked to the conversion of ornithine to proline.
Defects in DIDO1 may be a cause of myeloid neoplasms.
Displaces isoform 4 at the onset of differentiation, required for repression of stemness genes.
Interacts specifically (via PHD-type zinc finger) with histone H3 that is trimethylated at 'Lys-4' (H3K4me3), histone phosphorylation at 'Thr-3' or 'Thr-6' disrupts this binding and promotes translocation of DIDO1 from chromatin to the mitotic spindle during mitosis.
Putative transcription factor, weakly pro-apoptotic when overexpressed (By similarity). Tumor suppressor. Required for early embryonic stem cell development.
The PHD-type zinc finger forms an aromatic cage around H3K4me3.
Belongs to the type 2 lipid phosphate phosphatase family.
Expressed strongly in kidney and heart, followed by brain, colon, small intestine and lung. Not detected in skeletal muscle, thymus, spleen, liver, placenta, and peripheral blood leukocytes.
Has specific phosphohydrolase activity towards sphingoid base 1-phosphates. Has high phosphohydrolase activity against dihydrosphingosine-1-phosphate and sphingosine-1-phosphate (S1P) in vitro (PubMed:12411432). Sphingosine-1-phosphate phosphatase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway (By similarity). May play a role in attenuating intracellular sphingosine 1-phosphate (S1P) signaling. May play a role in pro-inflammatory signaling (PubMed:17113265). Plays a role in the regulation of pancreatic islet beta-cell endoplasmic reticulum stress and proliferation (By similarity).
Strongly induced by TNF, also induced by bacterial lipopolycaccharides (LPS) in neutrophils, endothelial cells, and other cell types. Not induced by growth-related factors.
Auto-ubiquitinated. Controls the development of T-cell clonal anergy by ubiquitination.
Binding to E2 ubiquitin-conjugating enzyme requires an intact RING finger domain.
E3 ubiquitin-protein ligase that catalyzes 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains formation. Functions as an inhibitor of cytokine gene transcription. Inhibits IL2 and IL4 transcription, thereby playing an important role in the induction of the anergic phenotype, a long-term stable state of T-lymphocyte unresponsiveness to antigenic stimulation associated with the blockade of interleukin production. Ubiquitinates ARPC5 with 'Lys-48' linkages and COR1A with 'Lys-63' linkages leading to their degradation, down-regulation of these cytosleletal components results in impaired lamellipodium formation and reduced accumulation of F-actin at the immunological synapse. Functions in the patterning of the dorsal ectoderm; sensitizes ectoderm to respond to neural-inducing signals.
Induced under anergic conditions. Up-regulated during T-cell anergy induction following signaling through the T-cell antigen receptor.
Interacts with BSG; interaction mediates SLC16A3 targeting to the plasma membrane.
Proton-dependent transporter of monocarboxylates such as L-lactate and pyruvate (PubMed:11101640, PubMed:23935841, PubMed:31719150). Plays a predominant role in L-lactate efflux from highly glycolytic cells (By similarity).
Two basolateral sorting signals (BSS) in its C-terminal cytoplasmic tail are required to direct SLC16A3 to the basolateral membrane.
Up-regulated by hypoxia through a HIF1A-mediated mechanism.
Was initially assigned as monocarboxylate transporter 3 (MCT3) (PubMed:9425115). However, it was later shown that it corresponds to monocarboxylate transporter 4 (MCT4).
Was initially thought to be considered to be a low affinity lactate transporter with negligible affinity for pyruvate (PubMed:11101640). However, it was later shown that SLC16A3 is a high affinity lactate transporter with physiologically relevant affinity for pyruvate (PubMed:31719150).
Each quasi-RRM repeat bound poly(RG), while only the N-terminal QRRM bound poly(RC) and poly(RU). None of the repeats bound detectable amounts of poly(RA).
Part of a ternary complex containing FUBP2, PTBP1, PTBP2 and HNRNPH1. Identified in the spliceosome C complex. Interacts with IGF2BP1. Interacts with CUGBP1; the interaction is RNA-dependent. Interacts with MBNL1; the interaction in RNA-independent.
This protein is a component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes which provide the substrate for the processing events that pre-mRNAs undergo before becoming functional, translatable mRNAs in the cytoplasm. Mediates pre-mRNA alternative splicing regulation. Inhibits, together with CUGBP1, insulin receptor (IR) pre-mRNA exon 11 inclusion in myoblast. Binds to the IR RNA. Binds poly(RG).
Functions as a positive regulator of TNF-induced NF-kappa-B signaling (PubMed:27671354). Regulates angiogenesis and cellular metabolism through interaction with PKM (PubMed:27199445).
Oligomer (PubMed:29133832). Dimer (PubMed:29133832). Interacts with PKM; regulates angiogenesis and metabolism (PubMed:27199445).
Acts as a transcription activator for MET and as a key regulator of HGF-MET signaling. Promotes cell motility, proliferation and hepatocyte growth factor (HGF)-dependent scattering in vitro and tumor growth and metastasis in vivo.
Preferentially expressed in metastasizing tumors.
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. SCNN1G subfamily.
ENaC cleavage by furin, and subsequently by prostasin (PRSS8), leads to a stepwise increase in the open probability of the channel as a result of release of the alpha and gamma subunit inhibitory tracts, respectively. Interaction of ENaC subunit SCNN1B with BPIFA1 protects ENaC against proteolytic activation.
Heterotrimer containing an alpha/SCNN1A, a beta/SCNN1B and a gamma/SCNN1G subunit. An additional delta/SCNN1D subunit exists only in some organisms and can replace the alpha/SCNN1A subunit to form an alternative channel with specific properties (PubMed:7762608). Interacts with NEDD4; via the WW domains (PubMed:11244092, PubMed:12167593). Interacts with NEDD4L; via the WW domains (PubMed:11244092). Interacts with WWP1; via the WW domains (PubMed:9169421). Interacts with WWP2; via the WW domains (PubMed:9169421, PubMed:12167593). Interacts with the full-length immature form of PCSK9 (pro-PCSK9) (PubMed:22493497).
Ubiquitinated; this targets individual subunits for endocytosis and proteasome-mediated degradation.
Component of the nuclear pore complex that has a direct role in nuclear protein import (PubMed:20016008). Actively displaces NLSs from importin-alpha, and facilitates disassembly of the importin-alpha:beta-cargo complex and importin recycling (PubMed:20016008). Interacts with regulatory proteins of cell cycle progression including CDKN1B (By similarity). This interaction is required for correct intracellular transport and degradation of CDKN1B (By similarity).
Contrarily to Npap60L, Npap60S does not displaces NLSs, but stabilizes their binding to importin-alpha.
Interacts with Importin alpha-2, Importin beta, Importin beta-2, NUP153, Ran binding protein 7, CDKN1B and itself (By similarity). Does not interact with TPR.
Ubiquitous. Highest levels in testis, peripheral blood leukocytes and fetal liver.
Highly expressed in duodenum, esophagus, pancreas, prostate, salivary gland, thymus and urinary bladder.
May act as a scaffold to regulate the recruitment and assembly of spindle midzone components. Required for the localization of AURKB and PLK1 to the spindle midzone.
Involved in cytokinesis and spindle organization. May play a role in actin cytoskeleton organization and microtubule stabilization and hence required for proper cell adhesion and migration.
May interact with both microtubules and actin cytoskeleton.
Detected in adult lung. Detected at low levels in adult brain, heart, testis, placenta, cervix, pancreas, uterus, stomach, rectum, small intestine, colon, esophagus, thymus, skin, and skin keratinocyte. Expression is higher in psoriasis lesions relative to unaffected skin from psoriasis patients. Detected in fetal kidney, skin and lung.
Oxidoreductase with strong preference for NAD (PubMed:18926804). Active in both the oxidative and reductive directions (PubMed:18926804). Oxidizes all-trans-retinol in all-trans-retinaldehyde (PubMed:18926804). No activity was detected with 11-cis-retinol or 11-cis-retinaldehyde as substrates with either NAD(+)/NADH or NADP(+)/NADPH (PubMed:18926804).
Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Preferentially hydrolyzes the basic residues Arg and Lys.
Defects in the expression of this gene may cause improper antigen processing, possibly leading to favor tumor escape from the immune surveillance.
Ubiquitously expressed. Highly expressed in spleen and leukocytes.
May play a role in male fertility. May act as a retinoid carrier protein within the epididymis.
Interacts with LUC7L3 and SRRM1. Specifically associates with functional splicing complexes, including Sm proteins and U1, U2, U4, U5 and U6 snRNAs. Associates with exon junction complex (EJC) proteins, including APEX1, DDX39B, NCBP1, RBM8A and RNPS1. Interaction with NCBP1 is RNA-dependent.
RNA-binding protein that acts as a regulator of alternative pre-mRNA splicing. Involved in apoptotic cell death through the regulation of the apoptotic factor BCL2L1 isoform expression. Modulates the ratio of proapoptotic BCL2L1 isoform S to antiapoptotic BCL2L1 isoform L mRNA expression. When overexpressed, stimulates proapoptotic BCL2L1 isoform S 5'-splice site (5'-ss) selection, whereas its depletion caused the accumulation of antiapoptotic BCL2L1 isoform L. Promotes BCL2L1 isoform S 5'-ss usage through the 5'-CGGGCA-3' RNA sequence. Its association with LUC7L3 promotes U1 snRNP binding to a weak 5' ss in a 5'-CGGGCA-3'-dependent manner. Binds to the exonic splicing enhancer 5'-CGGGCA-3' RNA sequence located within exon 2 of the BCL2L1 pre-mRNA. Also involved in the generation of an abnormal and truncated splice form of SCN5A in heart failure.
The PWI domain binds nucleic acids with significant help from its N-terminal flanking basic region. It has an equal preference for binding to single- or double-stranded species, and it contributes to RBM25 role in modulation of alternative splicing, maybe by mediating RNA-dependent association with LUC7L3.
Found in collagen I-containing tissues: both isoform 1 and isoform 2 appear in amnion, chorion, skeletal muscle, small intestine, and in cell culture of dermal fibroblasts, keratinocytes and endothelial cells. Only isoform 2 is found in lung, placenta, kidney and a squamous cell carcinoma cell line. Isoform 1 is also present in the corneal epithelial Bowman's membrane (BM) and the interfibrillar matrix of the corneal stroma, but it is not detected in the limbal BM.
Hydroxylation on proline residues within the sequence motif, GXPG, is most likely to be 4-hydroxy as this fits the requirement for 4-hydroxylation in vertebrates.
Isoform 1 O-glycosylation; glycosaminoglycan of chondroitin-sulfate type.
The triple-helical tail is stabilized by disulfide bonds at each end.
Trimer of identical chains each containing 190 kDa of non-triple-helical sequences.
Type XII collagen interacts with type I collagen-containing fibrils, the COL1 domain could be associated with the surface of the fibrils, and the COL2 and NC3 domains may be localized in the perifibrillar matrix.
Involved in an early step of the mitochondrial complex IV assembly process.
Isoform 1 is expressed in brain, pancreas, stomach, the colon cancer cell line LoVo and the T-lymphoblastoma Jurkat, but not in heart, placenta, liver, lung, skeletal muscle, kidney or the stomach cancer cell line AGS. Expressed at high levels in the small cell lung cancer cell line NCI-H510, at lower levels in NCI-H345, NCI-H69 and GLC-28 cell lines, not expressed in GLC-19 cell line. Within the stomach, expressed at high levels in the mucosa of the gastric fundus and at low levels in the antrum and duodenum. Isoform 2 is present in pancreatic cancer cells and colorectal cancer cells, but not in normal pancreas or colonic mucosa. Isoform 3 is expressed in brain, pancreas, stomach, the stomach cancer cell line AGS and the colon cancer cell line LoVo.
Isoform 2 is constitutively activated and may regulate cancer cell proliferation via a gastrin-independent mechanism.
Receptor for gastrin and cholecystokinin. The CCK-B receptors occur throughout the central nervous system where they modulate anxiety, analgesia, arousal, and neuroleptic activity. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
(Microbial infection) Cleaved by enterovirus D68 protease 2A; leading to inhibition of NF-kappa-B or IFN-beta triggered by TRAF3.
(Microbial infection) Interacts (via N-terminus) with New York hantavirus glycoprotein N (via C-terminus); this interaction inhibits the formation of TRAF3-TBK1 complexes.
(Microbial infection) Interacts with Andes hantavirus glycoprotein N (via C-terminus); this interaction inhibits the formation of TRAF3-TBK1 complexes.
(Microbial infection) Interacts with Epstein-Barr virus protein LMP1.
(Microbial infection) Interacts with Tula hantavirus glycoprotein N (via C-terminus); this interaction inhibits the formation of TRAF3-TBK1 complexes.
Belongs to the TNF receptor-associated factor family.
Cytoplasmic E3 ubiquitin ligase that regulates various signaling pathways, such as the NF-kappa-B, mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF) pathways, and thus controls a lot of biological processes in both immune and non-immune cell types (PubMed:33148796, PubMed:33608556). In TLR and RLR signaling pathways, acts as an E3 ubiquitin ligase promoting the synthesis of 'Lys-63'-linked polyubiquitin chains on several substrates such as ASC that lead to the activation of the type I interferon response or the inflammasome (PubMed:25847972, PubMed:27980081). Following the activation of certain TLRs such as TLR4, acts as a negative NF-kappa-B regulator, possibly to avoid unregulated inflammatory response, and its degradation via 'Lys-48'-linked polyubiquitination is required for MAPK activation and production of inflammatory cytokines. Alternatively, when TLR4 orchestrates bacterial expulsion, TRAF3 undergoes 'Lys-33'-linked polyubiquitination and subsequently binds to RALGDS, mobilizing the exocyst complex to rapidly expel intracellular bacteria back for clearance (PubMed:27438768). Acts also as a constitutive negative regulator of the alternative NF-kappa-B pathway, which controls B-cell survival and lymphoid organ development. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. Down-regulates proteolytic processing of NFKB2, and thereby inhibits non-canonical activation of NF-kappa-B. Promotes ubiquitination and proteasomal degradation of MAP3K14.
Homotrimer. Heterotrimer with TRAF2 and TRAF5. Interacts with LTBR/TNFRSF3, TNFRSF4, TNFRSF5/CD40, TNFRSF8/CD30, TNFRSF13C TNFRSF17/BCMA, TLR4 and EDAR. Interacts with MAP3K5, MAP3K14, TRAIP/TRIP, TDP2/TTRAP, TANK/ITRAF and TRAF3IP1. Interaction with TNFRSF5/CD40 is modulated by TANK/ITRAF, which competes for the same binding site. Interacts with TICAM1. Interacts with TRAFD1. Interacts with OTUB1, OTUB2 and OTUD5. Interacts with RNF216, OPTN and TBK1. Identified in a complex with TRAF2, MAP3K14 and BIRC3. Interacts with BIRC2 and BIRC3. Upon exposure to bacterial lipopolysaccharide (LPS), recruited to a transient complex containing TLR4, TRAF3, TRAF6, IKBKG, MAP3K7, MYD88, TICAM1, BIRC2, BIRC3 and UBE2N (By similarity). Interacts (via RING-type zinc finger domain) with SRC. Interacts with CARD14. Interacts (via MATH domain) with PTPN22; the interaction promotes TRAF3 polyubiquitination (PubMed:23871208). Interacts with MAVS (PubMed:19893624, PubMed:27980081). Directly interacts with DDX3X; this interaction stimulates TRAF3 'Lys-63' ubiquitination (PubMed:27980081). Interacts with IRF3 (PubMed:27980081). Interacts with IKBKE in the course of Sendai virus infection (PubMed:27980081). Interacts with TRIM35 (PubMed:32562145). Interacts with GAPDH; promoting TRAF3 ubiquitination (PubMed:27387501). Interacts with PPP3CA and PPP3CB (By similarity). Interacts with ATP1B1; promoting TRAF3 ubiquitination (PubMed:27387501). Interacts with RALGDS (PubMed:27438768). Interacts with FBXO11 (PubMed:36897010).
The Ring-type zinc finger domain is required for its function in down-regulation of NFKB2 proteolytic processing.
Undergoes 'Lys-48'-linked polyubiquitination, leading to its proteasomal degradation in response to signaling by TNFSF13B, TLR4 or through CD40. 'Lys-48'-linked polyubiquitinated form is deubiquitinated by OTUD7B, preventing TRAF3 proteolysis and over-activation of non-canonical NF-kappa-B. Undergoes 'Lys-63'-linked ubiquitination during early stages of virus infection, and 'Lys-48'-linked ubiquitination during later stages. Undergoes both 'Lys-48'-linked and 'Lys-63'-linked ubiquitination in response to TLR3 and TLR4 signaling. 'Lys-63'-linked ubiquitination can be mediated by TRIM35. Deubiquitinated by OTUB1, OTUB2 and OTUD5. Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to terminate the pattern-recognition receptors/PRRs pathways (By similarity). Undergoes also 'Lys-29'-linked ubiquitination on Cys-56 and Cys-124 by NEDD4L; leading to increased 'Lys-48'- and 'Lys-63'-linked ubiquitination as well as increased binding to TBK1 (PubMed:33608556). TLR4 signals emanating from bacteria containing vesicles trigger 'Lys-33'-linked polyubiquitination that promotes the assembly of the exocyst complex thereby connecting innate immune signaling to the cellular trafficking apparatus (PubMed:27438768). Deubiquitinated by USP25 during viral infection, leading to TRAF3 stabilization and type I interferon production (By similarity). Ubiquitinated at Lys-329 by the SCF(FBXL2) complex, leading to its degradation by the proteasome (By similarity). 'Lys-63'-linked ubiquitination by FBXO11 in a NEDD8-dependent manner promotes the amplification of IFN-I signaling (PubMed:36897010).
Abundantly expressed in adult and fetal thymus, peripheral blood leukocytes, bone marrow and several regions of the adult brain.
Adapter protein that regulates and/or fission of intracellular vesicles such as lysosomes (PubMed:11984006, PubMed:25216107). Might regulate trafficking of effectors involved in exocytosis (PubMed:25425525). In cytotoxic T-cells and natural killer (NK) cells, has role in the regulation of size, number and exocytosis of lytic granules (PubMed:26478006). In macrophages and dendritic cells, regulates phagosome maturation by controlling the conversion of early phagosomal compartments into late phagosomes (By similarity). In macrophages and dendritic cells, specifically involved in TLR3- and TLR4-induced production of pro-inflammatory cytokines by regulating the endosomal TLR3- TICAM1/TRIF and TLR4- TICAM1/TRIF signaling pathways (PubMed:27881733).
May form homodimers and heterodimers with TMCC2 or TMCC3 via the coiled-coil domains (PubMed:24454821). Interacts with ribosomal proteins RPL4 and RPS6 (PubMed:24454821).
Widely expressed, with highest levels in brain, spinal cord and testis.
Was named RRNAD1 by HGNC because a ribosomal RNA adenine dimethylase signature is detected by PROSITE. However, it probably constitutes a false positive and the ribosomal RNA adenine dimethylase signature is not conserved in orthologs.
Expressed in epididymis, predominantly in the caput (at protein level).
Has a salt-sensitive antimicrobial activity against Gram-negative bacteria, including E.coli, Gram-positive, including S.aureus, and fungi, including C.albicans. Binds to and neutralizes bacterial lipopolysaccharides (LPS), abolishing TNF production by macrophages challenged with LPS. Rescues the LPS-induced reduction of sperm motility in vitro and may protect from LPS-induced lethality.
Belongs to the uracil-DNA glycosylase (UDG) superfamily. UNG family.
Excises uracil residues from the DNA which can arise as a result of misincorporation of dUMP residues by DNA polymerase or due to deamination of cytosine.
Isoform 1 is processed by cleavage of a transit peptide.
Isoform 1 is widely expressed with the highest expression in skeletal muscle, heart and testicles. Isoform 2 has the highest expression levels in tissues containing proliferating cells.
Implicated in oncotic cell death, characterized by cell swelling, organelle swelling, vacuolization and increased membrane permeability.
Ubiquitous. Not expressed in ovary. Expressed in keratinocytes.
According to Rosetta Stone theory, the existence of a fusion protein in one genome predicts that the separate polypeptides expressed in other organisms function in the same cellular or biochemical pathway. In Drosophila melanogaster and Caenorhabditis elegans, NitFhit is a fusion protein composed of a C-terminal Fhit domain and a domain related to plant and bacterial nitrilase.
Based on a naturally occurring readthrough transcript which produces a NIT1-DEDD fusion protein. The last 4 amino acids of this isoform (PVSS) are encoded by the last DEDD exon.
Belongs to the carbon-nitrogen hydrolase superfamily. NIT1/NIT2 family.
Catalyzes the hydrolysis of the amide bond in N-(4-oxoglutarate)-L-cysteinylglycine (deaminated glutathione), a metabolite repair reaction to dispose of the harmful deaminated glutathione. Plays a role in cell growth and apoptosis: loss of expression promotes cell growth, resistance to DNA damage stress and increased incidence to NMBA-induced tumors. Has tumor suppressor properties that enhances the apoptotic responsiveness in cancer cells; this effect is additive to the tumor suppressor activity of FHIT. It is also a negative regulator of primary T-cells.
Detected in heart, brain, placenta, liver, skeletal muscle, kidney and pancreas.
Forms functional homodimers and homooligomers that are not required for substrate recognition and catalytic activity (By similarity). Can also form heterooligomers with PLPP2 and PLPP3 (By similarity).
Magnesium-independent phospholipid phosphatase (PubMed:9305923). Insensitive to N-ethylmaleimide (PubMed:9305923). Inhibited by sphingosine, zinc ions and modestly by propanolol (PubMed:9305923, PubMed:9705349). Inhibited by vanadate (PubMed:10962286).
Magnesium-independent phospholipid phosphatase of the plasma membrane that catalyzes the dephosphorylation of a variety of glycerolipid and sphingolipid phosphate esters including phosphatidate/PA, lysophosphatidate/LPA, diacylglycerol pyrophosphate/DGPP, sphingosine 1-phosphate/S1P and ceramide 1-phosphate/C1P (PubMed:9305923, PubMed:9705349, PubMed:9607309, PubMed:10962286, PubMed:17379599). Also acts on N-oleoyl ethanolamine phosphate/N-(9Z-octadecenoyl)-ethanolamine phosphate, a potential physiological compound (PubMed:9607309). Through its extracellular phosphatase activity allows both the hydrolysis and the cellular uptake of these bioactive lipid mediators from the milieu, regulating signal transduction in different cellular processes (PubMed:10962286, PubMed:12909631, PubMed:15461590, PubMed:17379599). It is for instance essential for the extracellular hydrolysis of S1P and subsequent conversion into intracellular S1P (PubMed:17379599). Involved in the regulation of inflammation, platelets activation, cell proliferation and migration among other processes (PubMed:12909631, PubMed:15461590). May also have an intracellular activity to regulate phospholipid-mediated signaling pathways (By similarity).
N-glycosylated (PubMed:9305923, PubMed:10962286). N-linked sugars are of the complex type. N-glycosylation is not required for the phosphatase activity (By similarity).
Predominant in kidney, lung, placenta and liver.
Some reports could not detect a significant activity with sphingosine 1-phosphate as substrate.
Widely expressed with highest expression found in prostate (PubMed:9305923). Found to be down-regulated in colon adenocarcinomas (PubMed:9570154).
C2 is a major histocompatibility complex class-III protein.
C2a interacts with Schistosoma haematobium TOR (via N-terminal extracellular domain). This results in inhibition of the classical and lectin pathway of complement activation, probably due to interference with binding of C2a to C4b such that C3 convertase cannot be formed. This infers resistance to complement-mediated cell lysis, allowing parasite survival and infection.
Component C2 which is part of the classical pathway of the complement system is cleaved by activated factor C1 into two fragments: C2b and C2a. C2a, a serine protease, then combines with complement factor C4b to generate the C3 or C5 convertase.
Disease susceptibility may be associated with variants affecting the gene represented in this entry. Haplotype analyses have identified a statistically significant common risk haplotype and two protective haplotypes. CFB variant His-9 and C2 variant Asp-318, as well as CFB variant Gln-32 and a variant in intron 10 of C2, confer a significantly reduced risk of AMD.
The MIDAS-like motif in the VWFA domain binds divalent metal cations.
Contaminating sequence. Sequence of unknown origin in the N-terminal part (676-679).
Dubious isoform. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Highly expressed in estrogen receptor positive breast tumors and in osteosarcoma tumors.
Interacts with ESR1 and NCOA3 and these interactions are enhanced by estradiol. Interacts with acetylated lysine residues on histone H1.4, H2A, H2B and H3 (in vitro).
May be a transcriptional coactivator of the nuclear receptor ESR1 required to induce the expression of a subset of estradiol target genes, such as CCND1, MYC and E2F1. May play a role in the recruitment or occupancy of CREBBP at some ESR1 target gene promoters. May be required for histone hyperacetylation. Involved in the estrogen-induced cell proliferation and cell cycle progression of breast cancer cells.
Up-regulated in breast, uterus, colon, ovary, and stomach tumors. Induced in breast cancer cells overexpressing NCOA3 or treated with estrogen. Down-regulated in 5-fluorouracil-resistant derivatives of the colon cancer cell line HCT 116.
Homodimer. Heterodimer with ARID3B. Interacts with E2F1. Interacts with GTF2I and BTK.
Transcription factor which may be involved in the control of cell cycle progression by the RB1/E2F1 pathway and in B-cell differentiation.
Widely expressed, with highest expression in skeletal muscle, thalamus, and colon.
Associates with the MRE11-RAD50-NBN (MRN) damage-sensing complex; this association is constitutive (PubMed:27568553). Interacts with MRE11 (PubMed:27568553). Interacts with NBN (PubMed:27568553). Interacts with RAD50 (PubMed:27568553).
Phosphorylated; phosphorylation is constitutive and occurs in the absence of any DNA-damaging stimulus. Phosphorylation on Ser-115 is necessary for its nuclear retention.
Plays a role in the cellular response to DNA damage and the maintenance of genome stability through its association with the MRN damage-sensing complex (PubMed:27568553). Promotes chromatin loading and activity of the MRN complex to facilitate subsequent ATM-mediated DNA damage response signaling and DNA repair (PubMed:27568553).
Belongs to the glycosyltransferase 8 family.
Glycosyltransferase which elongates the O-linked glucose attached to EGF-like repeats in the extracellular domain of Notch proteins by catalyzing the addition of xylose.
Acts as a suppressor of the SAPK signaling pathways by associating with and dephosphorylating MAP3K7/TAK1 and MAP3K5, and by attenuating the association between MAP3K7/TAK1 and MAP2K4 or MAP2K6.
Interacts with MAP3K7/TAK1 (By similarity). Interacts with MAP3K5.
Ubiquitous. Highly expressed in heart, placenta, lung, liver, kidney and pancreas.
Exclusively expressed in the central nervous system, most abundantly in the ventrolateral region of caudate putamen, the habenular nucleus, the zona incerta, and the medial mammillary nucleus.
May play a significant role in p53/TP53-mediating signaling pathway.
Strongly expressed in testis. Weakly expressed in heart, placenta and skeletal muscle.
Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER) (PubMed:34020957). The SRP complex interacts with the signal sequence in nascent secretory and membrane proteins and directs them to the membrane of the ER (PubMed:34020957). The SRP complex targets the ribosome-nascent chain complex to the SRP receptor (SR), which is anchored in the ER, where SR compaction and GTPase rearrangement drive cotranslational protein translocation into the ER (PubMed:34020957). Binds the signal recognition particle RNA (7SL RNA) in presence of SRP68 (PubMed:27899666, PubMed:21073748). Can bind 7SL RNA with low affinity (PubMed:27899666, PubMed:21073748). The SRP complex possibly participates in the elongation arrest function (By similarity).
Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER).
Heterodimer with SRP68 (PubMed:16672232, PubMed:28369529, PubMed:27899666). SRP68-SRP72 heterodimer formation is stabilized by the presence of 7SL RNA (By similarity). Component of a signal recognition particle (SRP) complex that consists of a 7SL RNA molecule of 300 nucleotides and six protein subunits: SRP72, SRP68, SRP54, SRP19, SRP14 and SRP9 (By similarity). Within the SRP complex, interacts (via N-terminus) with SRP68 (via C-terminus) (PubMed:16672232, PubMed:28369529, PubMed:27899666).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRA3 sub-subfamily.
Generally pentameric. There are five types of GABA(A) receptor chains: alpha, beta, gamma, delta, and rho. Binds UBQLN1 (By similarity). Interacts with GPHN (PubMed:26613940).
Expressed by most tissues. Present in plasma.
IGF-binding proteins prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cell culture. They alter the interaction of IGFs with their cell surface receptors. Also exhibits IGF-independent antiproliferative and apoptotic effects mediated by its receptor TMEM219/IGFBP-3R. Inhibits the positive effect of humanin on insulin sensitivity (PubMed:19623253). Promotes testicular germ cell apoptosis (PubMed:19952275).
IGFBP3 levels are higher during extrauterine life and peak during puberty.
Interacts with XLKD1 (By similarity). Binds IGF2 more than IGF1. Forms a ternary complex of about 140 to 150 kDa with IGF1 or IGF2 and a 85 kDa glycoprotein (ALS). Interacts with humanin; humanin competes with importin KPNB1 for binding to IGFBP3, blocking IGFBP3 nuclear import and IGFBP3-mediated apoptosis (PubMed:14561895, PubMed:19623253, PubMed:26216267). Interacts with TMEM219.
The thyroglobulin type-1 domain mediates interaction with HN.
Up-regulated in the presence of IGF1, insulin and other growth-stimulating factors such as growth hormone, EGF and phorbol esters.
Acts as a signaling molecule that communicates proliferative growth signals from the cytoplasm to the nucleus. It is involved in the positive regulation of cell cycle progression (PubMed:29851065). Plays a role for the localization and accumulation of the survival motor neuron protein SMN1 in sub-nuclear bodies, including gems and Cajal bodies. Induces neuron differentiation and stimulates axonal growth and formation of growth cone in spinal cord motor neurons. Plays a role in the splicing of cellular pre-mRNAs. May be involved in H(2)O(2)-induced neuronal cell death.
Component of an import snRNP complex composed of KPNB1, SNUPN, SMN1 and ZNF259. Interacts (via C-terminal region) with SMN1 (via C-terminal region); the interaction occurs after treatment with serum. Interacts with elongation factor 1-alpha EEF1A1; the interaction occurs in a epidermal growth factor (EGF)-dependent manner. Interacts (via zinc fingers) with EGFR (via C-terminal cytoplasmic kinase domain); the interaction is negatively regulated in response to epidermal growth factor (EGF) stimulation and the EGFR kinase activity. May also bind to the PDGFR receptor.
Expressed in fibroblast; weakly expressed in fibroblast of spinal muscular atrophy (SMA) patients.
A paper describing the function, enzyme activity and expression patterns of this protein has been retracted due to concerns of image manipulation.
Aminopeptidase which catalyzes the hydrolysis of amino acid residues from the N-terminus of peptide or protein substrates.
Belongs to the sterol desaturase family.
Catalyzes a dehydrogenation to introduce C5-6 double bond into lathosterol in cholesterol biosynthesis.
The histidine box domains may contain the active site and/or be involved in metal ion binding.
Efficient DNA binding requires dimerization with another bHLH protein. Forms homodimers and heterodimers with TCF3 gene products E12 and E47, HAND1 and HEY1, HEY2 and HEYL (hairy-related transcription factors) (By similarity).
Essential for cardiac morphogenesis, particularly for the formation of the right ventricle and of the aortic arch arteries. Required for vascular development and regulation of angiogenesis, possibly through a VEGF signaling pathway. Also plays an important role in limb development, particularly in the establishment of anterior-posterior polarization, acting as an upstream regulator of sonic hedgehog (SHH) induction in the limb bud. Is involved in the development of branchial arches, which give rise to unique structures in the head and neck. Binds DNA on E-box consensus sequence 5'-CANNTG-3' (By similarity).
Component of striatin-interacting phosphatase and kinase (STRIPAK) complex (By similarity). Interacts with CDC42BPB (PubMed:25743393). Interacts with CTTNBP2NL (PubMed:18782753).
Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the cortical actin filament dynamics and cell shape.
In the embryo, expressed in melanoblasts. In the fetus, expressed in melanocytes. Not detected in retinal pigment epithelial cells.
Required for melanocyte differentiation.
Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling (PubMed:16314507, PubMed:16854980, PubMed:21362118, PubMed:29884772). Specifically recognizes PEX5 monoubiquitinated at 'Cys-11', and pulls it out of the peroxisome lumen through the PEX2-PEX10-PEX12 retrotranslocation channel (PubMed:29884772). Extraction by the PEX1-PEX6 AAA ATPase complex is accompanied by unfolding of the TPR repeats and release of bound cargo from PEX5 (PubMed:29884772).
Expressed in the retina, at higher levels in the photoreceptor layer at the joint between the outer and inner segments.
Interacts with PEX1; forming the PEX1-PEX6 AAA ATPase complex, which is composed of a heterohexamer formed by a trimer of PEX1-PEX6 dimers (PubMed:12717447, PubMed:16854980, PubMed:21362118). Interacts with PEX26; interaction is direct and promotes recruitment to peroxisomal membranes (PubMed:12717447, PubMed:16854980). Interacts with ZFAND6 (PubMed:21980954).
Interacts with LETMD1 (PubMed:17943721). Interacts with BRI3 (isoforms 1 and 2); the interaction with isoform 2 is weaker than with isoform 1 (PubMed:11860200, PubMed:30983867). Interacts with BRI3; the interaction is weak (PubMed:30983867). Interacts with TMEM238L (PubMed:33112233).
Involved in tumorigenesis and may function by stabilizing p53/TP53.
Most abundantly expressed in brain, liver and kidney (PubMed:11860200). Overexpressed in leukemia and lymphoma cell lines, as well as in various carcinomas (PubMed:17943721).
First processed into 3 peptides of 70 kDa, 42 kDa (D) and 13/15 kDa (E). The 70 kDa peptide is further processed into three peptides (A, B and C). The A, B and C peptides are disulfide-linked.
Necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover. Cleaves all known types of alpha-mannosidic linkages.
DNA-binding transcription regulator that regulates endothelial cell proliferation and G1/S cell-cycle progression. Specifically binds the 5'-[AT]NTNN[GT]GGCA[AGT]-3' core DNA sequence and acts by modulating expression of pRB-E2F cell-cycle target genes, including RRM1. Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1. May also have pro-apoptotic activity by potentiating both serum-withdrawal and TNF-induced apoptosis.
Highly expressed in heart, skeletal muscle, kidney and liver. Weaker expression in brain and placenta.
Homodimer (PubMed:28299530). Interacts with PAWR. Component of a THAP1/THAP3-HCFC1-OGT complex that contains, either THAP1 or THAP3, HCFC1 and OGT. Interacts with OGT. Interacts (via the HBM) with HCFC1 (via the Kelch-repeat domain); the interaction recruits HCFC1 to the RRM1 promoter (PubMed:12717420, PubMed:20144952, PubMed:20200153).
(Microbial infection) Functions as a transcriptional coactivator for the Epstein-Barr virus nuclear antigen 2 (EBNA2).
(Microbial infection) Interacts with EAV NSP1 (PubMed:12917451). Binds to acidic transactivation domain of EBNA2 (PubMed:7651391).
Endonuclease that mediates miRNA decay of both protein-free and AGO2-loaded miRNAs (PubMed:28546213, PubMed:18453631). As part of its function in miRNA decay, regulates mRNAs involved in G1-to-S phase transition (PubMed:28546213). Functions as a bridging factor between STAT6 and the basal transcription factor (PubMed:12234934). Plays a role in PIM1 regulation of MYB activity (PubMed:9809063). Functions as a transcriptional coactivator for STAT5 (By similarity).
Endonuclease that mediates miRNA decay of both protein-free and AGO2-loaded miRNAs.
Forms a ternary complex with STAT6 and POLR2A (PubMed:12234934). Associates with the RNA-induced silencing complex (RISC) (PubMed:14508492, PubMed:28546213). Interacts with the RISC components AGO2, FMR1 and TNRC6A (PubMed:14508492, PubMed:28546213). Interacts with GTF2E1 and GTF2E2 (PubMed:7651391). Interacts with PIM1 (PubMed:9809063). Interacts with STAT5 (By similarity). Interacts with SYT11 (via C2 2 domain); the interaction with SYT11 is direct (By similarity).
Component of the chaperonin-containing T-complex (TRiC), a heterooligomeric complex of about 850 to 900 kDa that forms two stacked rings, 12 to 16 nm in diameter (PubMed:1630492, PubMed:20080638, PubMed:25467444). Interacts with PACRG (PubMed:14532270). Interacts with GBA1 (PubMed:21098288). Interacts with DLEC1 (PubMed:33144677).
G protein-coupled receptor for PPY/pancreatic polypeptide/PP, NPY/neuropeptide Y and PYY/peptide YY that is negatively coupled to cAMP (PubMed:7592911, PubMed:7493937). The rank order of affinity for these polypeptides and their derivatives is PP, PP (2-36) and [Ile-31, Gln-34] PP > [Pro-34] PYY > PYY and [Leu-31, Pro-34] NPY > NPY > PYY (3-36) and NPY (2-36) > PP (13-36) > PP (31-36) > NPY free acid.
Highest levels found in brain, coronary artery and ileum. Low levels in pancreas and kidney. Detected in colon and small intestine.
Binds PPFIA3 (By similarity). Does not bind RAB3.
Expressed in a variety of fetal tissues.
Homodimer; binds DNA as a dimer. Forms a complex with CDKN2A and TP53. Interactions with TP53, RB1, ANP32A, BMI1 and FHL2 regulate E4F1 activity. Interacts with HDAC1, HMGA2 and RASSF1.
Identified as a cellular target of the adenoviral oncoprotein E1A, it is required for both transcriptional activation and repression of viral genes.
May be sumoylated by UBE2I upon interaction with CDKN2A.
May function as a transcriptional repressor. May also function as a ubiquitin ligase mediating ubiquitination of chromatin-associated TP53. Functions in cell survival and proliferation through control of the cell cycle. Functions in the p53 and pRB tumor suppressor pathways and regulates the cyclin CCNA2 transcription.
Phosphorylated; p120E4F and p50E4F are both phosphorylated. Phosphorylation is cell cycle-dependent and differentially regulates DNA-binding activity and function of both forms.
Proteolytic cleavage produces a 50 kDa N-terminal peptide (p50E4F) which has a DNA-binding activity and activates transcription in presence of the adenoviral E1A protein. The major full-length protein (p120E4F) functions as a repressor of transcription.
A chromosomal aberration involving APPL2/DIP13B is found in patients with chromosome 22q13.3 deletion syndrome. Translocation t(12;22)(q24.1;q13.3) with SHANK3/PSAP2.
High levels in brain, heart, kidney and skeletal muscle.
Homodimer (PubMed:18034774, PubMed:23055524). Homotetramer (PubMed:23055524). Binds RAB5A/Rab5 through an N-terminal domain. This interaction is essential for its recruitment to endosomal membranes as well as its role in cell proliferation (PubMed:15016378). Binds subunits of the NuRD/MeCP1 complex (PubMed:15016378). Interacts with FSHR; interaction is independent of follicle stimulating hormone stimulation (PubMed:17030088). Interacts with APPL1; the interaction is decreased by adiponectin in a time-dependent manner (PubMed:17030088, PubMed:18034774). Forms a complex comprising APPL1, RUVBL2, CTNNB1, HDAC1 and HDAC2; interaction reduces interaction between CTNNB1, HDAC1, HDAC2 and RUVBL2 leading to the decrease of deacetylase activity of this complex; affects the recruitment of repressive complexes to the Wnt target genes (PubMed:19433865). Interacts (via BAR domain) with TBC1D1; interaction is dependent of TBC1D1 phosphorylation at 'Ser-235'; interaction diminishes the phosphorylation of TBC1D1 at 'Thr-596', resulting in inhibition of SLC2A4 translocation and glucose uptake (PubMed:24879834). Interacts with ANXA2; targets APPL2 to endosomes and acting in parallel to RAB5A (PubMed:21645192). Interacts with RAB31 (in GTP-bound form); interaction contributes to or enhances recruitment of APPL2 to the phagosomes; interaction enhances Fc-gamma receptor-mediated phagocytosis through PI3K/Akt signaling in macrophages (PubMed:23055524). Interacts with PIK3R1; forms a complex with PIK3R1 and APPL1 (By similarity). Interacts (via BAR domain) with ADIPOR1; hinders the accessibility of APPL1 to ADIPOR1; negatively regulates adiponectin signaling; ADIPOQ dissociates this interaction and facilitates the recruitment of APPL1 to ADIPOR1 (By similarity). Interacts (via BAR domain) with ADIPOR2; ADIPOQ dissociates this interaction (By similarity).
Multifunctional adapter protein that binds to various membrane receptors, nuclear factors and signaling proteins to regulate many processes, such as cell proliferation, immune response, endosomal trafficking and cell metabolism (PubMed:26583432, PubMed:15016378, PubMed:24879834). Regulates signaling pathway leading to cell proliferation through interaction with RAB5A and subunits of the NuRD/MeCP1 complex (PubMed:15016378). Plays a role in immune response by modulating phagocytosis, inflammatory and innate immune responses. In macrophages, enhances Fc-gamma receptor-mediated phagocytosis through interaction with RAB31 leading to activation of PI3K/Akt signaling. In response to LPS, modulates inflammatory responses by playing a key role on the regulation of TLR4 signaling and in the nuclear translocation of RELA/NF-kappa-B p65 and the secretion of pro- and anti-inflammatory cytokines. Also functions as a negative regulator of innate immune response via inhibition of AKT1 signaling pathway by forming a complex with APPL1 and PIK3R1 (By similarity). Plays a role in endosomal trafficking of TGFBR1 from the endosomes to the nucleus (PubMed:26583432). Plays a role in cell metabolism by regulating adiponecting ans insulin signaling pathways and adaptative thermogenesis (PubMed:24879834) (By similarity). In muscle, negatively regulates adiponectin-simulated glucose uptake and fatty acid oxidation by inhibiting adiponectin signaling pathway through APPL1 sequestration thereby antagonizing APPL1 action (By similarity). In muscles, negativeliy regulates insulin-induced plasma membrane recruitment of GLUT4 and glucose uptake through interaction with TBC1D1 (PubMed:24879834). Plays a role in cold and diet-induced adaptive thermogenesis by activating ventromedial hypothalamus (VMH) neurons throught AMPK inhibition which enhances sympathetic outflow to subcutaneous white adipose tissue (sWAT), sWAT beiging and cold tolerance (By similarity). Also plays a role in other signaling pathways namely Wnt/beta-catenin, HGF and glucocorticoid receptor signaling (PubMed:19433865) (By similarity). Positive regulator of beta-catenin/TCF-dependent transcription through direct interaction with RUVBL2/reptin resulting in the relief of RUVBL2-mediated repression of beta-catenin/TCF target genes by modulating the interactions within the beta-catenin-reptin-HDAC complex (PubMed:19433865). May affect adult neurogenesis in hippocampus and olfactory system via regulating the sensitivity of glucocorticoid receptor. Required for fibroblast migration through HGF cell signaling (By similarity).
The BAR domain is necessary and sufficient for mediating homotypic and heterotypic interactions; associates with cytoplasmic membrane structures; mediates interaction with TBC1D1 and ADIPOR1 (PubMed:18034774) (By similarity). The PH and PID domains mediate phosphoinositide binding (PubMed:18034774). The PID domain mediates phosphatidylserine binding and allows localization to cytosolic membrane structures and nucleus (PubMed:18034774). The PH domain allows localization to the plasma membrane, cytosolic vesicles and distinct nuclear and perinuclear structures and is sufficient for RUVBL2 interaction (PubMed:18034774, PubMed:19433865).
(Microbial infection) Interacts (via its SH3 domain) with hepatitis E virus/HEV protein ORF3.
Autophosphorylated at Tyr-420 (By similarity). Phosphorylation on the C-terminal tail at Tyr-531 by CSK maintains the enzyme in an inactive state (PubMed:1699196). PTPRC/CD45 dephosphorylates Tyr-531 leading to activation (PubMed:1533589). Ultraviolet B (UVB) strongly increase phosphorylation at Thr-12 and kinase activity, and promotes translocation from the cytoplasm to the nucleus (PubMed:15537652). Dephosphorylation at Tyr-420 by PTPN2 negatively regulates T-cell receptor signaling (PubMed:22080863). Phosphorylated at tyrosine residues, which can be enhanced by NTN1 (By similarity).
Inhibited by phosphorylation of Tyr-531 by leukocyte common antigen and activated by dephosphorylation of this site.
Interacts (via its SH3 domain) with PIK3R1 and PRMT8. Interacts with FYB1, PAG1, and SH2D1A. Interacts with CD79A (tyrosine-phosphorylated form); the interaction increases FYN activity. Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (By similarity). Interacts with TOM1L1 (phosphorylated form). Interacts with KDR (tyrosine phosphorylated). Interacts (via SH3 domain) with KLHL2 (via N-terminus) (By similarity). Interacts with SH2D1A and SLAMF1. Interacts with ITCH; the interaction phosphorylates ITCH and negatively regulates its activity. Interacts with FASLG. Interacts with RUNX3. Interacts with KIT. Interacts with EPHA8; possible downstream effector of EPHA8 in regulation of cell adhesion. Interacts with PTK2/FAK1; this interaction leads to PTK2/FAK1 phosphorylation and activation. Interacts with CAV1; this interaction couples integrins to the Ras-ERK pathway. Interacts with UNC119. Interacts (via SH2 domain) with PTPRH (phosphorylated form) (By similarity). Interacts with PTPRO (phosphorylated form) (By similarity). Interacts with PTPRB (phosphorylated form) (By similarity). Interacts with FYB2 (PubMed:27335501). Interacts with DSCAM (By similarity). Interacts with SKAP1 and FYB1; this interaction promotes the phosphorylation of CLNK (By similarity). Interacts with NEDD9; in the presence of PTK2 (PubMed:9360983).
Isoform 1 is highly expressed in the brain. Isoform 2 is expressed in cells of hemopoietic lineages, especially T-lymphocytes.
Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance. Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta-catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL1 and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Phosphorylates PTK2B/PYK2 in response to T-cell receptor activation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1. In mast cells, phosphorylates CLNK after activation of immunoglobulin epsilon receptor signaling (By similarity).
Palmitoylated. Palmitoylation at Cys-3 and Cys-6, probably by ZDHHC21, regulates subcellular location.
Acetylation at Lys-413 dramatically reduces catalytic activity. Deacetylated by SIRT3.
Belongs to the isocitrate and isopropylmalate dehydrogenases family.
Binds 1 Mg(2+) or Mn(2+) ion per subunit.
Plays a role in intermediary metabolism and energy production (PubMed:22416140, PubMed:19228619). It may tightly associate or interact with the pyruvate dehydrogenase complex (PubMed:22416140, PubMed:19228619).
enetic variations are associated with cartilaginous tumors such as enchondroma or chondrosarcoma.
Photoreceptor that binds cis-retinaldehydes (PubMed:15674244). Contributes to pupillar reflex, photoentrainment and other non-image forming responses to light (By similarity). May be involved in the optokinetic visual tracking response (By similarity). May be involved in the regulation of retinal hyaloid vessel growth and regression (By similarity).
Belongs to the protein N5-glutamine methyltransferase family.
N5-glutamine methyltransferase responsible for the methylation of the glutamine residue in the universally conserved GGQ motif of the mitochondrial translation release factors MTRF1, MTRF1L, MRPL58/ICT1 and MTRFR.
High levels in adult lung, liver, skeletal muscle and pancreas. Moderate levels in fetal liver, adult bone marrow and placenta. The short form is the major species and the longer form was detected only in very low abundance. CCL23(19-99), CCL23(22-99), CCL23(27-99), CCL23(30-99) are found in high levels in synovial fluids from rheumatoid patients.
Shows chemotactic activity for monocytes, resting T-lymphocytes, and neutrophils, but not for activated lymphocytes. Inhibits proliferation of myeloid progenitor cells in colony formation assays. This protein can bind heparin. Binds CCR1. CCL23(19-99), CCL23(22-99), CCL23(27-99), CCL23(30-99) are more potent chemoattractants than CCL23.
The N-terminal is proteolytically cleaved by proteases associated with inflammatory responses. The processed forms, CCL23(19-99), CCL23(22-99), CCL23(27-99) and CCL23(30-99) exhibit increase in CCR1-mediated signaling and chemotaxis assays in vitro.
Interacts with GABA(A)R (GABA type A receptor) subunits GABRA1, GABRA2 and GABRG2; the interaction is direct. Does not interact with GABRB2 and GABRB3 subunits. May interact with AMPAR subunits GRIA1, GRIA2 and GRIA3 and AMPAR auxiliary proteins SHISA6 and SHISA7. May interact (via PDZ-binding motif) with DLG4/PSD-95 (via PDZ domain); the interaction is direct.
SHISA7 has been reported to interact with AMPAR subunit GRIA1 in heterologous conditions and in the brain (By similarity). However, it was later demonstrated that SHISA7 does not colocalize neither interact with AMPAR, but with GABA(A)R (By similarity). Therefore additional experiments are needed to understand the discrepancy for SHISA7 function.
The GRID (GABA(A)R-interacting domain) is critical for its subcellular localization and interaction with GABA(A)R.
The PDZ-binding motif interacts with PDZ-domain of scaffolding protein DLG4.
Transmembrane protein that regulates gamma-aminobutyric acid type A receptor (GABA(A)R) trafficking, channel deactivation kinetics and pharmacology, necessary for fast inhibitory transmission in the brain. Enhances the action of benzodiazepine, a primary GABA(A)Rs target drug, in the brain. May affect channel kinetics of AMPA-type glutamate receptors (AMPAR), the brain's main excitatory neurotransmitter, necessary for synaptic hippocampal plasticity, and memory recall. May regulate the induction and maintenance of long-term potentiation at Schaffer collaterals/CA3-CA1 excitatory synapses.
Belongs to the bacterial ribosomal protein bS18 family. Mitochondrion-specific ribosomal protein mS40 subfamily.
Component of the mitochondrial small ribosomal subunit (mt-SSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. mS40 has a zinc binding site.
There are 3 mitochondrial isoforms of bS18 in mammalia, localizing to 3 distinct sites in the mitoribosome. bS18m (bs18c) binds to the same site as bacterial bS18, mS40 (bS18b, this protein) binds to a novel location of the 28S small subunit, and mL66 (bS18a) binds to the 39S large subunit.
ATPase involved both in DNA repair and rescue of stalled ribosomes (PubMed:22055184, PubMed:28757607, PubMed:32099016, PubMed:32579943, PubMed:36302773). 3'-5' DNA helicase involved in repair of alkylated DNA: promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3, enabling ALKBH3 to process alkylated N3-methylcytosine (3mC) within double-stranded regions (PubMed:22055184). Also involved in activation of the ribosome quality control (RQC) pathway, a pathway that degrades nascent peptide chains during problematic translation (PubMed:28757607, PubMed:32099016, PubMed:32579943, PubMed:36302773). Drives the splitting of stalled ribosomes that are ubiquitinated in a ZNF598-dependent manner, as part of the ribosome quality control trigger (RQT) complex (PubMed:28757607, PubMed:32099016, PubMed:32579943, PubMed:36302773). Part of the ASC-1 complex that enhances NF-kappa-B, SRF and AP1 transactivation (PubMed:12077347).
Identified in the ASCC complex that contains ASCC1, ASCC2 and ASCC3 (PubMed:12077347, PubMed:29144457, PubMed:29997253). Functions as scaffolding subunit that interacts directly with both ASCC1 and ASCC2 (PubMed:29144457, PubMed:29997253). Interacts directly with ALKBH3, and thereby recruits ALKBH3 to the ASCC complex (PubMed:22055184, PubMed:29144457). Part of the ASC-1/TRIP4 complex, that contains TRIP4, ASCC1, ASCC2 and ASCC3 (PubMed:12077347). Part of the RQT (ribosome quality control trigger) complex, that contains ASCC2, ASCC3 and TRIP4 (PubMed:32099016, PubMed:32579943, PubMed:36302773). Associates with ribosomes; recruited to collided ribosomes (PubMed:32099016, PubMed:32579943, PubMed:36302773). Interacts with ZCCHC4 (PubMed:31799605). Interacts with ZNF598 (PubMed:28757607). Interacts with RPS3 (PubMed:28757607).
Phosphorylation by CDK10 at Ser-220 and Ser-225 creates a phosphodegron that targets ETS2 for proteasomal degradation.
Transcription factor activating transcription. Binds specifically the DNA GGAA/T core motif (Ets-binding site or EBS) in gene promoters and stimulates transcription.
An alanine stretch that varies from 12 to 19 residues is present. This polymorphisms can be used as a marker to study the role of FOXE1 in other cases of thyroid dysgenesis, especially in familial cases.
Detected in adult brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, heart, colon, small intestine testis and thymus. Expression was strongest in heart and pancreas.
Transcription factor that binds consensus sites on a variety of gene promoters and activate their transcription. Involved in proper palate formation, most probably through the expression of MSX1 and TGFB3 genes which are direct targets of this transcription factor. Also implicated in thyroid gland morphogenesis. May indirectly play a role in cell growth and migration through the regulation of WNT5A expression.
Component of the nexin-dynein regulatory complex (N-DRC) a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes (By similarity). Plays a critical role in the assembly of N-DRC and also stabilizes the assembly of multiple inner dynein arms and radial spokes (PubMed:23354437, PubMed:34169321). Coassembles with CCDC65/DRC2 to form a central scaffold needed for assembly of the N-DRC and its attachment to the outer doublet microtubules (PubMed:23354437).
Component of the nexin-dynein regulatory complex (N-DRC). Interacts with CCDC65/DRC2, DRC3, GAS8/DRC4 and TCTE1/DRC5 (PubMed:34169321).
Component of a complex whose core is composed of ARHGAP17, AMOT, PALS1, PATJ and PARD3/PAR3. Interacts with MAGI1. Isoform 1 interacts with angiostatin.
Expressed in placenta and skeletal muscle. Found in the endothelial cells of capillaries as well as larger vessels of the placenta.
Plays a central role in tight junction maintenance via the complex formed with ARHGAP17, which acts by regulating the uptake of polarity proteins at tight junctions. Appears to regulate endothelial cell migration and tube formation. May also play a role in the assembly of endothelial cell-cell junctions.
Polyubiquitinated by NEDD4, NEDD4L and ITCH, leading to proteasomal degradation.
The angiostatin binding domain (871-1005) allows the binding to angiostatin.
The coiled coil domain interacts directly with the BAR domain of ARHGAP17.
Activated by phosphorylation on Thr-174, potentially by autophosphorylation.
Interacts with TSSK1B. Interacts with HSP90; this interaction stabilizes TSSK2 (By similarity).
Testis-specific serine/threonine-protein kinase required during spermatid development. Phosphorylates TSKS at 'Ser-288' and SPAG16. Involved in the late stages of spermatogenesis, during the reconstruction of the cytoplasm. During spermatogenesis, required for the transformation of a ring-shaped structure around the base of the flagellum originating from the chromatoid body.
Testis-specific. Present in mature spermatozoa (at protein level).
Microtubule-binding protein which might play a role in microtubule bundling.
A chromosomal aberration involving ZFYVE19 is associated with acute myeloblastic leukemia (AML). Translocation t(11;15)(q23;q14) with KMT2A/MLL1 (PubMed:12618766).
Detected in brain, heart, skeletal muscle and kidney (PubMed:12618766). Expressed in the liver (at protein level) (PubMed:12618766, PubMed:32737136).
Interacts (via MIM1-B) with VPS4A; interaction takes place at the midbody ring following cytokinesis checkpoint activation.
It is uncertain whether Met-1 or Met-76 is the initiator. In the liver, the main translation initiation site may be Met-76.
Key regulator of abscission step in cytokinesis: part of the cytokinesis checkpoint, a process required to delay abscission to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage. Together with CHMP4C, required to retain abscission-competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis. Deactivation of AURKB results in dephosphorylation of CHMP4C followed by its dissociation from ZFYVE19/ANCHR and VPS4 and subsequent abscission.
Phosphorylated in vitro at Ser-22 by AURKB; however, phosphorylation at this site could not be confirmed in vivo.
The FYVE-type zinc finger mediates binding to phosphatidylinositol-3-phosphate (PtdIns(3)P).
The MIM1-B motif mediates interaction with VPS4A.
The disease is caused by variants affecting the gene represented in this entry. Some evidences point to Met-76 as the main translation initiation site. In this context, PFIC9-associated variant p.M76V can disrupt translation initiation.
Detected in cerebellum, kidney and heart.
Interacts with CRY2, but not with CRY1 (in vitro).
Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway. Probably involved in the binding of an intermediate of Fe/S cluster assembly.
A soluble form (tumor necrosis factor binding protein 2) is produced from the membrane form by proteolytic processing.
Available under the name Enbrel (Immunex and Wyeth-Ayerst). Used to treat moderate to severe rheumatoid arthritis (RA). Enbrel consist of the extracellular ligand-binding portion of TNFRSF1B linked to an immunoglobulin Fc chain. It binds to TNF-alpha and blocks its interactions with receptors.
Binds to TRAF2 (PubMed:8069916, PubMed:10206649). Interacts with BMX (PubMed:12370298). Interacts (activated form) with XPNPEP3 (PubMed:25609706).
Phosphorylated; mainly on serine residues and with a very low level on threonine residues.
Receptor with high affinity for TNFSF2/TNF-alpha and approximately 5-fold lower affinity for homotrimeric TNFSF1/lymphotoxin-alpha. The TRAF1/TRAF2 complex recruits the apoptotic suppressors BIRC2 and BIRC3 to TNFRSF1B/TNFR2. This receptor mediates most of the metabolic effects of TNF-alpha. Isoform 2 blocks TNF-alpha-induced apoptosis, which suggests that it regulates TNF-alpha function by antagonizing its biological activity.
Appears to be membrane-associated, despite the absence of the seven-transmembrane domain.
Detected in brain cortex, thalamus, subthalamic nucleus, substantia nigra, hypothalamus, hippocampus, corpus callosum, caudate nucleus and amygdala.
Highest levels observed in human skeletal muscle (e.g. gastrocnemious muscle), differentiated cultures of primary human muscle cells and rhabdomyosarcoma cells cultured in low serum medium. Expressed in C2 muscle cell myoblasts and myotubes.
(Microbial infection) Interacts with Rift valley fever virus glycoprotein N; this interaction is important for viral RNA production.
(Microbial infection) Interacts with protein E7 from papilloma virus HPV-16, HPV-6B and HPV-11.
E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. Together with clathrin, forms meshwork structures involved in membrane morphogenesis and cytoskeletal organization. Regulates integrin-mediated signaling. May play a role in activation of FAK in response to cell-matrix interactions. Mediates ubiquitination of ACLY, leading to its subsequent degradation.
(Microbial infection) The Legionella effector RavZ is a deconjugating enzyme that hydrolyzes the amide bond between the C-terminal glycine residue and an adjacent aromatic residue in ATG8 proteins conjugated to phosphatidylethanolamine (PE), producing an ATG8 protein that is resistant to reconjugation by the host machinery due to the cleavage of the reactive C-terminal glycine (PubMed:23112293, PubMed:32686895, PubMed:31722778). RavZ is also able to mediate delipidation of ATG8 proteins conjugated to phosphatidylserine (PS) (PubMed:33909989).
3 different light chains, LC1, LC2 and LC3, can associate with MAP1A and MAP1B proteins (By similarity). Interacts with TP53INP1 and TP53INP2 (PubMed:19056683, PubMed:22470510). Directly interacts with SQSTM1; this interaction leads to MAP1LC3A recruitment to inclusion bodies containing polyubiquitinated protein aggregates and to inclusion body degradation by autophagy (PubMed:17580304). Interacts with ATG13 (PubMed:24290141, PubMed:23043107). Interacts with ULK1 (PubMed:23043107). Interacts with TBC1D5 (PubMed:22354992). Found in a complex with UBQLN1 and UBQLN2 (PubMed:20529957). Interacts with UBQLN4 (via STI1 1 and 2 domains). Interacts with UBQLN1 in the presence of UBQLN4 (PubMed:23459205). Interacts with TRIM5 (PubMed:25127057). Interacts with MEFV (PubMed:26347139). Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3 (PubMed:26040720, PubMed:34338405). Interacts with PICALM. Interacts with the reticulophagy receptor TEX264 (PubMed:31006538, PubMed:31006537). Interacts with MOAP1 (via LIR motif) (PubMed:33783314). Interacts with IRGM (PubMed:29420192).
Most abundant in heart, brain, liver, skeletal muscle and testis but absent in thymus and peripheral blood leukocytes.
Phosphorylation at Ser-12 by PKA inhibits conjugation to phosphatidylethanolamine (PE).
The precursor molecule is cleaved by ATG4 (ATG4A, ATG4B, ATG4C or ATG4D) to expose the glycine at the C-terminus and form the cytosolic form, LC3-I (PubMed:15187094, PubMed:30661429). The processed form is then activated by APG7L/ATG7, transferred to ATG3 and conjugated to phosphatidylethanolamine (PE) phospholipid to form the membrane-bound form, LC3-II (PubMed:15187094). During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid (PubMed:33909989). ATG4 proteins also mediate the delipidation of PE-conjugated forms (PubMed:32686895, PubMed:33909989). In addition, ATG4B and ATG4D mediate delipidation of ATG8 proteins conjugated to PS during non-canonical autophagy (PubMed:33909989). ATG4B constitutes the major protein for proteolytic activation (PubMed:30661429, PubMed:33909989). ATG4D is the main enzyme for delipidation activity (By similarity).
Ubiquitin-like modifier involved in formation of autophagosomal vacuoles (autophagosomes) (PubMed:20713600, PubMed:24290141). While LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation (PubMed:20713600). Through its interaction with the reticulophagy receptor TEX264, participates in the remodeling of subdomains of the endoplasmic reticulum into autophagosomes upon nutrient stress, which then fuse with lysosomes for endoplasmic reticulum turnover (PubMed:31006538, PubMed:31006537).
Plays an important role in the regulation of interdigestive gastrointestinal motility and indirectly causes rhythmic contraction of duodenal and colonic smooth muscle.
As part of the MCIA complex, involved in the assembly of the mitochondrial complex I (PubMed:32320651, PubMed:27374773, PubMed:27374774). Participates in constructing the membrane arm of complex I (PubMed:24191001).
Part of the mitochondrial complex I assembly/MCIA complex that comprises at least the core subunits TMEM126B, NDUFAF1, ECSIT and ACAD9 and complement subunits such as COA1 and TMEM186 (PubMed:32320651). Associates with the intermediate 370 kDa subcomplex of incompletely assembled complex I (PubMed:24191001). Interacts with TMEM70 (PubMed:33753518).
Homo- and heterotetramers (By similarity). Phosphofructokinase (PFK) enzyme functions as a tetramer composed of different combinations of 3 types of subunits, called PFKM (where M stands for Muscle), PFKL (Liver) and PFKP (Platelet). The composition of the PFK tetramer differs according to the tissue type it is present in. In muscles, it is composed of 4 PFKM subunits (also called M4). In the liver, the predominant form is a tetramer of PFKL subunits (L4). In erythrocytes, both PFKM and PFKL subunits randomly tetramerize to form M4, L4 and other combinations (ML3, M2L2, M3L). The kinetic and regulatory properties of the tetrameric enzyme are dependent on the subunit composition, hence can vary across tissues (Probable). Interacts (via C-terminus) with HK1 (via N-terminal spermatogenic cell-specific region) (By similarity).
(Microbial infection) Acts as a chromatin anchor for Epstein-Barr virus EBNA2 to mediate the assembly of EBNA2 chromatin complexes in B-cells (PubMed:28968461). In addition, binds to the viral LMP1 proximal promoter and promotes its expression during latency (PubMed:26819314).
(Microbial infection) Interacts with Epstein-barr virus protein EBNA2.
Homodimer (PubMed:20592035). Interacts with ZNF423 and ZNF521, leading to prevent EBF1 to bind DNA and activate target genes (PubMed:14630787). Interacts with CCR4-NOT component CNOT3 (PubMed:14630787).
Key pioneer transcription factor of B-cell specification and commitment (PubMed:27807034). Recognizes variations of the palindromic sequence 5'-ATTCCCNNGGGAATT-3'. Operates in a transcription factor network to activate B-cell-specific genes and repress genes associated with alternative cell fates. For instance, positively regulates many B-cell specific genes including BCR or CD40 while repressing genes that direct cells into alternative lineages, including GATA3 and TCF7 for the T-cell lineage. In addition to its role during lymphopoiesis, controls the thermogenic gene program in adipocytes during development and in response to environmental cold (By similarity).
Core component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1. MAEA and RMND5A are both required for catalytic activity of the CTLH E3 ubiquitin-protein ligase complex (PubMed:29911972). Catalytic activity of the complex is required for normal cell proliferation (PubMed:29911972). The CTLH E3 ubiquitin-protein ligase complex is not required for the degradation of enzymes involved in gluconeogenesis, such as FBP1 (PubMed:29911972).
Identified in the CTLH complex that contains GID4, RANBP9 and/or RANBP10, MKLN1, MAEA, RMND5A (or alternatively its paralog RMND5B), GID8, ARMC8, WDR26 and YPEL5 (PubMed:29911972). Within this complex, MAEA, RMND5A (or alternatively its paralog RMND5B), GID8, WDR26, and RANBP9 and/or RANBP10 form the catalytic core, while GID4, MKLN1, ARMC8 and YPEL5 have ancillary roles (PubMed:29911972).
C-terminus cleavage is induced by interaction with CTNND1 and enhanced by Src tyrosine kinase.
Can act either as a transcriptional repressor or as a transcriptional activator, depending on the cell context. Acts as a repressor of the Hedgehog signaling pathway (By similarity). Represses the Hedgehog-dependent expression of Wnt4 (By similarity). Necessary to maintain the differentiated epithelial phenotype in renal cells through the inhibition of SNAI1, which itself induces the epithelial-to-mesenchymal transition (By similarity). Represses transcriptional activation mediated by CTNNB1 in the Wnt signaling pathway. May act by recruiting the corepressors CTBP1 and HDAC3. May be involved in neuron differentiation (By similarity).
Expressed at high levels in kidney and at low levels in heart, lung and placenta. Expressed in colon.
Interacts with CTBP1 and HDAC3 (By similarity). Interacts with CTNNB1 (By similarity). Interacts with SUFU (By similarity). Interacts with CTNND1.
The C2H2-type zinc finger 1 has a major repressor function and is required for CTNNB1 binding.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in flagellum axoneme, which is required for flagellum beating. May serve to reinforce and thus stabilize the microtubule structure in the sperm flagella (By similarity). Involved in the regulation of sperm motility (By similarity).
Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate (PubMed:10049595, PubMed:20133940, PubMed:29162720). Forms a heterotetrameric complex with the closed conformation form of MAD2L1 (C-MAD2) at unattached kinetochores during prometaphase, recruits an open conformation of MAD2L1 (O-MAD2) and promotes the conversion of O-MAD2 to C-MAD2, which ensures mitotic checkpoint signaling (PubMed:29162720).
Defects in MAD1L1 are involved in the development and/or progression of various types of cancer.
Expressed in hepatocellular carcinomas and hepatoma cell lines (at protein level).
Homodimer (PubMed:9546394, PubMed:29162720). Dimerizes via its N- and C- terminal regions (PubMed:29162720). Heterodimerizes with MAD2L1 in order to form a tetrameric MAD1L1-MAD2L1 core complex (PubMed:22351768, PubMed:9546394, PubMed:18981471, PubMed:12006501). Interacts with the closed conformation form of MAD2L1 (C-MAD2) and open conformation form of MAD2L1 (O-MAD2) (PubMed:29162720). It is unclear whether MAD1L1 dimerization promotes the conversion of closed to open conformation of MAD2L1 (PubMed:29162720). Formation of a heterotetrameric core complex containing two molecules each of MAD1L1 and of MAD2L1 promotes binding of another molecule of MAD2L1 to each MAD2L1, resulting in a heterohexamer (PubMed:12006501). Perturbation of the original MAD1L1-MAD2L1 structure by the spindle checkpoint may decrease MAD2L1 affinity for MAD1L1 (PubMed:12006501). CDC20 can compete with MAD1L1 for MAD2L1 binding, until the attachment and/or tension dampen the checkpoint signal, preventing further release of MAD2L1 on to CDC20 (PubMed:12006501). Also able to interact with the BUB1/BUB3 complex (PubMed:10198256). Interacts with NEK2 (PubMed:14978040). Interacts with TTK (PubMed:29162720). Interacts with TPR; the interactions occurs in a microtubule-independent manner (PubMed:18981471, PubMed:19273613, PubMed:20133940). Interacts with IK (PubMed:22351768). Interacts with the viral Tax protein (PubMed:9546394). Interacts with PRAP1 (PubMed:24374861).
Interacts with MAD2L1; this interaction leads to the cytoplasmic sequestration of MAD2L1 (PubMed:19010891). Interacts with PRAP1 (PubMed:24374861).
Phosphorylated; by BUB1 (PubMed:10198256). Become hyperphosphorylated in late S through M phases or after mitotic spindle damage (PubMed:9546394). Phosphorylated; by TTK (PubMed:29162720).
Sequesters MAD2L1 in the cytoplasm preventing its function as an activator of the mitotic spindle assembly checkpoint (SAC) resulting in SAC impairment and chromosomal instability in hepatocellular carcinomas.
According to a first report, interacts with ALK leading to stimulation of ALK tyrosine phosphorylation (PubMed:11278720). According to a second report, ALK is phosphorylated independently of a direct interaction with PTN but through PTPRZ1 which is inactivated in PTN-stimulated cells; the sites that are autophosphorylated in ALK no longer can be dephosphorylated by PTPRZ1; thus, autoactivation and tyrosine phosphorylation of ALK rapidly increase (PubMed:17681947).
Interacts with ALK and NEK6 (PubMed:11278720, PubMed:20873783). Interacts with PTPRZ1 (via chondroitin sulfate groups); promotes formation of homooligomers; oligomerization impairs tyrosine phosphatase activity (PubMed:16814777) (Probable). Forms a complex with PTPRZ1 and CTNNB1; this complex inactivates PTPRZ1 protein tyrosine phosphatase activity through PTN interaction and stimulates tyrosine phosphorylation of CTNNB1 (PubMed:10706604). Interacts with ITGB3 and ITGA5 (PubMed:19141530). Forms a complex with PTPRZ1 and integrin alpha-V/beta-3 (ITGAV:ITGB3) that stimulates endothelial cell migration through ITGB3 'Tyr-773' phosphorylation (PubMed:19141530). Interacts with SDC3 (via heparan sulfate chains); this interaction mediates the neurite outgrowth-promoting signal from PTN to the cytoskeleton of growing neurites; this interaction mediates osteoblast recruitment. Interacts with GPC2 (via heparan sulfate); this interaction promotes neurite outgrowth through binding of PTN with chondroitin sulfate of proteoglycans, thereby releasing PTPRS of chondroitin sulfate proteoglycans (CSPGs) and leading to binding with heparan sulfate of GPC2 (By similarity).
Secreted growth factor that mediates its signal through cell-surface proteoglycan and non-proteoglycan receptors (PubMed:16814777, PubMed:11278720, PubMed:19141530). Binds cell-surface proteoglycan receptor via their chondroitin sulfate (CS) groups (PubMed:26896299, PubMed:27445335). Thereby regulates many processes like cell proliferation, cell survival, cell growth, cell differentiation and cell migration in several tissues namely neuron and bone (PubMed:1733956, PubMed:1768439, PubMed:11278720, PubMed:19141530, PubMed:27445335, PubMed:30667096, PubMed:19442624). Also plays a role in synaptic plasticity and learning-related behavior by inhibiting long-term synaptic potentiation (By similarity). Binds PTPRZ1, leading to neutralization of the negative charges of the CS chains of PTPRZ1, inducing PTPRZ1 clustering, thereby causing the dimerization and inactivation of its phosphatase activity leading to increased tyrosine phosphorylation of each of the PTPRZ1 substrates like ALK, CTNNB1 or AFAP1L2 in order to activate the PI3K-AKT pathway (PubMed:17681947, PubMed:27445335, PubMed:30667096, PubMed:16814777, PubMed:10706604). Through PTPRZ1 binding controls oligodendrocyte precursor cell differentiation by enhancing the phosphorylation of AFAP1L2 in order to activate the PI3K-AKT pathway (PubMed:27445335, PubMed:30667096). Forms a complex with PTPRZ1 and integrin alpha-V/beta-3 (ITGAV:ITGB3) that stimulates endothelial cell migration through SRC dephosphorylation and activation that consequently leads to ITGB3 'Tyr-773' phosphorylation (PubMed:19141530). In adult hippocampus promotes dendritic arborization, spine development, and functional integration and connectivity of newborn granule neurons through ALK by activating AKT signaling pathway (By similarity). Binds GPC2 and chondroitin sulfate proteoglycans (CSPGs) at the neuron surface, leading to abrogation of binding between PTPRS and CSPGs and neurite outgrowth promotion (By similarity). Binds SDC3 and mediates bone formation by recruiting and attaching osteoblasts/osteoblast precursors to the sites for new bone deposition (By similarity). Binds ALK and promotes cell survival and cell proliferation through MAPK pathway activation (PubMed:11278720). Inhibits proliferation and enhances differentiation of neural stem cells by inhibiting FGF2-induced fibroblast growth factor receptor signaling pathway (By similarity). Mediates regulatory mechanisms in normal hemostasis and in hematopoietic regeneration and in maintaining the balance of myeloid and lymphoid regeneration (By similarity). In addition may play a role in the female reproductive system, auditory response and the progesterone-induced decidualization pathway (By similarity).
By type I interferon, predominantly IFN-beta.
Has enzymatic activity similar to isoform 1 and interferes with type I interferon signaling. Major deISGylation enzyme for nuclear proteins (PubMed:22170061).
Interacts with STAT2; the interaction is direct (PubMed:28165510, PubMed:31836668, PubMed:32092142). Interacts with IFNAR2; indirectly via STAT2, it negatively regulates the assembly of the ternary interferon-IFNAR1-IFNAR2 complex and inhibits type I interferon signaling (PubMed:28165510). Interacts with STING1. Interacts with USP20.
Interferon-induced ISG15-specific protease that plays a crucial role for maintaining a proper balance of ISG15-conjugated proteins in cells (PubMed:11788588). Regulates protein ISGylation by efficiently cleaving ISG15 conjugates linked via isopeptide bonds. Regulates T-cell activation and T-helper 17 (Th17) cell differentiation by deubiquitinating TAK1, likely to keep TAK1-TAB complexes in steady conditions (PubMed:23825189). In turn, restricts activation of NF-kappa-B, NFAT, and JNK as well as expression of IL2 in T-cells after TCR activation (PubMed:23825189). Acts as a molecular adapter with USP20 to promote innate antiviral response through deubiquitinating STING1 (PubMed:27801882). Involved also in the negative regulation of the inflammatory response triggered by type I interferon (PubMed:28165510, PubMed:27325888). Upon recruitment by STAT2 to the type I interferon receptor subunit IFNAR2 interferes with the assembly of the ternary interferon-IFNAR1-IFNAR2 complex and acts as a negative regulator of the type I interferon signaling pathway (PubMed:28165510).
Produced by alternative initiation at a CTG start codon. An IRES Element in the 5' region contributes to expression.
Mediates the second step in the final reaction sequence of coenzyme Q (CoQ) biosynthesis (PubMed:15153069, PubMed:17374725, PubMed:16400613, PubMed:20526342). Catalyzes the prenylation of para-hydroxybenzoate (PHB) with an all-trans polyprenyl donor (such as all-trans-decaprenyl diphosphate) (PubMed:15153069, PubMed:17374725, PubMed:16400613, PubMed:20526342). The length of the polyprenyl side chain varies depending on the species, in humans, the side chain is comprised of 10 isoprenyls (decaprenyl) producing CoQ10 (also known as ubiquinone), whereas rodents predominantly generate CoQ9 (PubMed:15153069, PubMed:16400613). However, this specificity is not complete, human tissues have low amounts of CoQ9 and rodent organs contain some CoQ10 (PubMed:15153069). Plays a central role in the biosynthesis of CoQ10 (PubMed:15153069, PubMed:17374725, PubMed:16400613). CoQ10 is a vital molecule that transports electrons from mitochondrial respiratory chain complexes (PubMed:17374725, PubMed:27493029, PubMed:16400613). CoQs also function as cofactors for uncoupling protein and play a role as regulators of the extracellularly-induced ceramide-dependent apoptotic pathway (PubMed:17374725, PubMed:16400613). Regulates mitochondrial permeability transition pore (mPTP) opening and ROS production (pivotal events in cell death) in a tissue specific manner (By similarity).
Potential minor and functional isoform produced by alternative initiation.
Widely expressed. Present in all of the tissues tested. Expressed at higher level in skeletal muscle, adrenal glands and the heart.
Highly expressed in liver, kidney and colon. Moderately expressed in small intestine. Down-regulated in a number of liver and colon cancers (PubMed:12117771, PubMed:15534908). Expressed in duodenum with higher expression in enterocytes along the villus axis and lower expression in crypts (at protein level) (PubMed:24725409).
Intermicrovillar adhesion molecule that forms, via its extracellular domain, calcium-dependent heterophilic complexes with CDHR5 on adjacent microvilli. Thereby, controls the packing of microvilli at the apical membrane of epithelial cells. Through its cytoplasmic domain, interacts with microvillus cytoplasmic proteins to form the intermicrovillar adhesion complex/IMAC. This complex plays a central role in microvilli and epithelial brush border differentiation (PubMed:24725409). May also play a role in cell-cell adhesion and contact inhibition in epithelial cells (PubMed:12117771).
Part of the IMAC/intermicrovillar adhesion complex/intermicrovillar tip-link complex composed of ANKS4B, MYO7B, USH1C, CDHR2 and CDHR5 (PubMed:26812018). Interacts with MAST2 (PubMed:12117771). Interacts (via cytoplasmic domain) with USH1C and MYO7B; required for proper localization of CDHR2 to microvilli tips and its function in brush border differentiation (PubMed:24725409, PubMed:26812017).
The cadherin 1 domain is required for binding to CDHR5.
Functions as a RAC guanine nucleotide exchange factor (GEF), which activates the Rac proteins by exchanging bound GDP for free GTP. Its activity is synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and the beta gamma subunits of heterotrimeric G protein. May function downstream of heterotrimeric G proteins in neutrophils.
Interacts preferentially with RAC2. Interacts with RAC1. Interacts with AUTS2.
Mainly expressed in peripheral blood leukocytes and brain. Expressed at intermediate level in spleen and lymph nodes, and weakly expressed in other tissues.
Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Interacts with ACTL6A/BAF53A, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A and PBRM1/BAF180 (By similarity).
Involved in transcription activity regulation by chromatin remodeling. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and is required for the proliferation of neural progenitors. During neural development a switch from a stem/progenitor to a post-mitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to post-mitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity).
It is uncertain whether Met-1 or Met-89 is the initiator.
Forms dimers and possibly higher-order oligomers.
Knockdown of NUP210 causes nuclear membranes to accumulate aberrant structures termed twinned and fusion-arrested membranes and nuclear pore complex to cluster. Induces cell death and chromatin disruptions.
N-glycosylated, but not all potential glycosylation sites may be used. Contains high-mannose type oligosaccharides (By similarity).
Nucleoporin essential for nuclear pore assembly and fusion, nuclear pore spacing, as well as structural integrity.
Phosphorylated at Ser-1881 in mitosis specifically; not phosphorylated in interphase.
Recognized by antinuclear autoantibodies in primary biliary cirrhosis.
Ubiquitous expression, with highest levels in lung, liver, pancreas, testis, and ovary, intermediate levels in brain, kidney, and spleen, and lowest levels in heart and skeletal muscle.
Probable receptor, which may be involved in the internalization of lipophilic molecules and/or signal transduction. Its precise role is however unclear, since it does not bind to very low density lipoprotein (VLDL) or to LRPAP1 in vitro.
Widely expressed. Highly expressed in skeletal muscle and ovary. Expressed at intermediate level in heart, brain, liver, pancreas, prostate and small intestine. Weakly expressed in testis, colon and leukocyte.
An additional N-terminally truncated cytoplasmic isoform was previously reported to exist. However, the paper was subsequently retracted due to concerns regarding duplication of panels in some figures.
Autophosphorylated. Binding of FGF family members together with heparan sulfate proteoglycan or heparin promotes receptor dimerization and autophosphorylation on tyrosine residues. Autophosphorylation occurs in trans between the two FGFR molecules present in the dimer.
Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines.
FGFR4 variants may be involved in the pathogenesis of various cancers. Variant Arg-388 predisposes cancer patients to accelerated disease progression and may be associated with poor prognosis. It has been found in prostate cancer as well as cancers of the breast, colon, head and neck, larynx, lung, skin.
Monomer. Homodimer after ligand binding. Interacts with FGF1, FGF2, FGF4, FGF6, FGF8, FGF9, FGF16, FGF17, FGF18, FGF19, FGF21 and FGF23 (in vitro). Binding affinity for FGF family members is enhanced by interactions between FGFs and heparan sulfate proteoglycans. Interacts with KLB; this strongly increases the affinity for FGF19 and FGF23. Affinity for FGF19 is strongly increased by KLB and sulfated glycosaminoglycans. KLB and KL both interact with the core-glycosylated FGFR4 in the endoplasmic reticulum and promote its degradation, so that only FGFR4 with fully mature N-glycans is expressed at the cell surface. Identified in a complex with NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Interacts with MMP14 and HIP1 (PubMed:11433297, PubMed:16597617, PubMed:17623664, PubMed:18670643, PubMed:20683963, PubMed:20798051, PubMed:21653700, PubMed:7518429, PubMed:8663044). Interacts with STAT3 (PubMed:26675719).
N-glycosylated. Full maturation of the glycan chains in the Golgi is essential for high affinity interaction with FGF19.
Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by autophosphorylation on tyrosine residues.
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling.
Ubiquitinated. Subject to proteasomal degradation when not fully glycosylated.
(Microbial infection) Interacts (via WD repeats) with SV40 large T antigen (via CPD region).
Homodimer; homodimerization plays a role in substrate binding and/or ubiquitination and degradation (PubMed:22608923, PubMed:17434132, PubMed:28007894). Component of the SCF(FBXW7) complex consisting of CUL1, RBX1, SKP1 and FBXW7 (PubMed:11565034, PubMed:15103331, PubMed:22748924, PubMed:34741373, PubMed:26774286, PubMed:28007894, PubMed:26976582, PubMed:28727686). Interacts (via F-box domain) with SKP1 (PubMed:11585921, PubMed:17434132, PubMed:28007894, PubMed:26976582, PubMed:28727686). Interacts (via F-box domain) with pseudophosphatase STYX; the interaction is direct and prevents FBXW7 interaction with SKP1 (PubMed:28007894). Interacts with cyclin-E (CCNE1 or CCNE2) (PubMed:11565034, PubMed:17434132). Interacts with PSEN1 (PubMed:12354302). Forms a trimeric complex with NOTCH1 and SGK1 (PubMed:21147854). Interacts with NOTCH1 intracellular domain/NICD and NOTCH4 intracellular domain/NICD (PubMed:11585921). Interacts with NOTCH2 intracellular domain (N2ICD) (PubMed:29149593). Interacts with MYC (when phosphorylated) (PubMed:17873522, PubMed:25775507, PubMed:28007894). Interacts with USP28, counteracting ubiquitination of MYC (PubMed:17873522). Interacts with JUN (PubMed:14739463, PubMed:22608923). Found in a complex with JUN and PRR7 (PubMed:27458189). Interacts with JUN and PRR7; the interaction inhibits ubiquitination-mediated JUN degradation, promoting its phosphorylation and transcriptional activity (PubMed:27458189). Interacts (when phosphorylated at Thr-205) with PIN1, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Interacts with UBE2QL1 (PubMed:24000165). Interacts with FAM83D; promotes FBXW7 degradation (PubMed:24344117). Interacts with MYCN; FBXW7 competes with AURKA for binding to unphosphorylated MYCN but not for binding to phosphorylated MYCN (PubMed:27837025). Interacts with STOML1 (PubMed:23082202). Interacts with NFE2L1 (By similarity). Interacts with USP36, counteracting ubiquitination of MYC (PubMed:25775507). Interacts with NR1D1 (PubMed:27238018). Interacts with RICTOR; mediates RICTOR ubiquitination and degradation (PubMed:25897075). Interacts with USP38, counteracting ubiquitination of MYC (PubMed:34102342).
Phosphorylation at Thr-205 promotes interaction with PIN1, leading to disrupt FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Phosphorylated by ATM at Ser-26 in response to DNA damage, promoting recruitment to DNA damage sites and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4 (PubMed:26774286).
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:22748924, PubMed:34741373, PubMed:17434132, PubMed:26976582, PubMed:28727686, PubMed:35395208). Recognizes and binds phosphorylated sites/phosphodegrons within target proteins and thereafter brings them to the SCF complex for ubiquitination (PubMed:22748924, PubMed:34741373, PubMed:26774286, PubMed:17434132, PubMed:26976582, PubMed:28727686). Identified substrates include cyclin-E (CCNE1 or CCNE2), DISC1, JUN, MYC, NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2, MCL1, MLST8, RICTOR, and probably PSEN1 (PubMed:11565034, PubMed:12354302, PubMed:11585921, PubMed:15103331, PubMed:14739463, PubMed:17558397, PubMed:17873522, PubMed:22608923, PubMed:22748924, PubMed:29149593, PubMed:25775507, PubMed:28007894, PubMed:26976582, PubMed:28727686, PubMed:25897075, PubMed:34102342). Acts as a negative regulator of JNK signaling by binding to phosphorylated JUN and promoting its ubiquitination and subsequent degradation (PubMed:14739463). Involved in bone homeostasis and negative regulation of osteoclast differentiation (PubMed:29149593). Regulates the amplitude of the cyclic expression of hepatic core clock genes and genes involved in lipid and glucose metabolism via ubiquitination and proteasomal degradation of their transcriptional repressor NR1D1; CDK1-dependent phosphorylation of NR1D1 is necessary for SCF(FBXW7)-mediated ubiquitination (PubMed:27238018). Also able to promote 'Lys-63'-linked ubiquitination in response to DNA damage (PubMed:26774286). The SCF(FBXW7) complex facilitates double-strand break repair following phosphorylation by ATM: phosphorylation promotes localization to sites of double-strand breaks and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4, enhancing DNA non-homologous end joining (PubMed:26774286).
The F-box domain mediates interaction with SKP1.
The WD repeats mediate interaction with substrates of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex.
Ubiquitinated: autoubiquitinates following phosphorylation at Thr-205 and subsequent interaction with PIN1. Ubiquitination leads to its proteasomal degradation (PubMed:22608923).
Expressed in most tissues, except in ovary and prostate. Isoform 1 is exclusively expressed in brain, heart and testis, and this form predominates in liver and kidney. Isoform 2 predominates in lung.
Homodimer (Probable). Interacts with RNF4 and JUN (By similarity).
The atypical PHD domain functions as a negative modulator of cofactor binding.
Transcriptional activator that binds to the regulatory region of MMP3 and thereby controls stromelysin expression. It stimulates the activity of various transcriptional activators such as JUN, SP1, PAX6 and ETS1, suggesting a function as a coactivator.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of internal galactose (Gal) residues of keratan. Cooperates with B4GALT4 and B3GNT7 glycosyltransferases and CHST6 sulfotransferase to construct and elongate disulfated disaccharide unit [->3(6-sulfoGalbeta)1->4(6-sulfoGlcNAcbeta)1->] within keratan sulfate polymer (PubMed:17690104, PubMed:9405439, PubMed:10642612). Has a preference for sulfating keratan sulfate, but it also transfers sulfate to the unsulfated polymer (PubMed:9405439). Involved in biosynthesis of phosphacan, a major keratan sulfate proteoglycan in the developing brain (By similarity). Involved in biosynthesis of 6-sulfoGalbeta-containing O-linked glycans in high endothelial venules of lymph nodes. May act in a synergistic manner with CHST4 to generate sialyl 6',6-disulfo Lewis X motif, a recognition determinant for immune cell receptors implicated in leukocyte trafficking (PubMed:10330415). Catalyzes sulfation of N-acetyllactosamine (LacNAc) oligosaccharides with highest efficiency for sialylated LacNAc structures (PubMed:10642612).
Was originally (PubMed:9639683) thought to be the ortholog of chicken CHST3 and therefore named C6ST. However, it has no strong chondroitin 6-sulfotransferase activity.
Widely expressed at low level. Expressed in brain and skeletal muscle. Expressed by high endothelial cells (HEVs) and leukocytes.
Expressed in skeletal muscle, brain, placenta and spleen.
Transcriptional coactivator. Stimulates the transcriptional activity of MEF2C. Stimulates MYOD1 activity in part via MEF2, resulting in an enhancement of skeletal muscle differentiation (By similarity).
Homooligomer; in contrast to TRMT61A, does not form a heterotetramer.
Methyltransferase that catalyzes the formation of N(1)-methyladenine at position 58 (m1A58) in various tRNAs in mitochondrion, including tRNA(Leu) (deciphering codons UUA or UUG), tRNA(Lys) and tRNA(Ser) (deciphering codons UCA, UCU, UCG or UCC) (PubMed:23097428). Catalyzes the formation of 1-methyladenosine at position 947 of mitochondrial 16S ribosomal RNA and this modification is most likely important for mitoribosomal structure and function (PubMed:27631568). In addition to tRNA N(1)-methyltransferase activity, also acts as a mRNA N(1)-methyltransferase by mediating methylation of adenosine residues at the N(1) position of MT-ND5 mRNA, leading to interfere with mitochondrial translation (PubMed:29107537).
The identity of the enzyme catalyzing mitochondrial mRNA N(1)-methyltransferase is unclear. According to a report, mitochondrial mRNA N(1)-methyltransferase activity is catalyzed by TRMT61B (PubMed:29107537). According to a second report, it is mediated by TRMT10C (AC Q7L0Y3) (PubMed:29072297). As both reports only tested one protein (either TRMT61B or TRMT10C), it is possible that both proteins have this activity.
Expressed at high levels in the placenta and at moderate levels in the pancreas, kidney, heart, liver, lung, brain and skeletal muscle.
Binds to membranes enriched in phosphatidylinositol 3-phosphate (PtdIns(P3)) and phosphatidylinositol 4,5-bisphosphate. May be involved in several stages of intracellular trafficking.
Highly expressed in fetus liver, but only weakly expressed in brain, skeleton muscle, smooth muscle, and cardiac muscle, kidney, and adrenal gland.
Strongly expressed in colon, liver, lung, skeletal muscle and kidney.
Expressed in adult brain, fetal brain, cerebellum, heart, lung, prostate and thyroid.
Interacts with CTNNB1, CTNNA1, PRKCI, PARD6B, FYB1.
Regulates cell junction organization in epithelial cells. May play a role in the transition from adherens junction to tight junction assembly. May regulate F-actin polymerization required for tight junctional localization dynamics and affect the junctional localization of PARD6B. During podocyte differentiation may negatively regulate activity of FYN and subsequently the abundance of nephrin (By similarity).
Interacts with SRSF1 (By similarity). Interacts with SRSF2 (By similarity). Interacts with SRSF3 (PubMed:26876937, PubMed:28984244). Interacts with SRSF7 (By similarity). Interacts with SRSF10 (PubMed:26876937). Interacts with CPSF6 (By similarity). Interacts with KHDRBS1/SAM68 (By similarity). Interacts with TRA2B (By similarity). Interacts with KHDRBS3 (By similarity). Interacts with EMD (PubMed:12755701). Interacts with RBMX (PubMed:19282290). Interacts with ZCCHC8 (PubMed:28984244).
Regulator of alternative splicing that specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs (PubMed:25242552, PubMed:26318451, PubMed:26876937, PubMed:28984244). M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in the efficiency of mRNA splicing, processing and stability (PubMed:25242552, PubMed:26318451). Acts as a key regulator of exon-inclusion or exon-skipping during alternative splicing via interaction with mRNA splicing factors SRSF3 and SRSF10 (PubMed:26876937). Specifically binds m6A-containing mRNAs and promotes recruitment of SRSF3 to its mRNA-binding elements adjacent to m6A sites, leading to exon-inclusion during alternative splicing (PubMed:26876937). In contrast, interaction with SRSF3 prevents interaction with SRSF10, a splicing factor that promotes exon skipping: this prevents SRSF10 from binding to its mRNA-binding sites close to m6A-containing regions, leading to inhibit exon skipping during alternative splicing (PubMed:26876937). May also regulate alternative splice site selection (PubMed:20167602). Also involved in nuclear export of m6A-containing mRNAs via interaction with SRSF3: interaction with SRSF3 facilitates m6A-containing mRNA-binding to both SRSF3 and NXF1, promoting mRNA nuclear export (PubMed:28984244). Involved in S-adenosyl-L-methionine homeostasis by regulating expression of MAT2A transcripts, probably by binding m6A-containing MAT2A mRNAs (By similarity). Also recognizes and binds m6A on other RNA molecules (PubMed:27602518). Involved in random X inactivation mediated by Xist RNA: recognizes and binds m6A-containing Xist and promotes transcription repression activity of Xist (PubMed:27602518). Also recognizes and binds m6A-containing single-stranded DNA (PubMed:32663306). Involved in germline development: required for spermatogonial development in males and oocyte growth and maturation in females, probably via its role in alternative splicing (By similarity).
Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, and regulates mRNA stability. M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in mRNA stability and processing.
Belongs to the activator 1 small subunits family. CTF18 subfamily.
Chromosome cohesion factor involved in sister chromatid cohesion and fidelity of chromosome transmission. Component of one of the cell nuclear antigen loader complexes, CTF18-replication factor C (CTF18-RFC), which consists of CTF18, CTF8, DCC1, RFC2, RFC3, RFC4 and RFC5. The CTF18-RFC complex binds to single-stranded and primed DNAs and has weak ATPase activity that is stimulated by the presence of primed DNA, replication protein A (RPA) and by proliferating cell nuclear antigen (PCNA). The CTF18-RFC complex catalyzes the ATP-dependent loading of PCNA onto primed and gapped DNA. Interacts with and stimulates DNA polymerase POLH. During DNA repair synthesis, involved in loading DNA polymerase POLE at the sites of local damage (PubMed:20227374).
Component of the CTF18-RFC complex, which consists of CTF18, CTF8, DCC1, RFC2, RFC3, RFC4 and RFC5 (PubMed:12766176, PubMed:12930902). During assembly of the CTF18-RFC complex, CTF18 may first assemble into a subcomplex with RFC2, RFC3, RFC4 and RFC5. CTF18 then interacts directly with CTF8, which in turn interacts with DCC1 (PubMed:12766176, PubMed:12930902). The CTF18-RFC complex associates with PCNA and with DNA polymerase POLH (PubMed:12766176, PubMed:17545166). The CTF18-RFC complex does not interact with the Rad9/Rad1/Hus1 complex (PubMed:12766176). CTF18 interacts with SMC1A and RAD21 (PubMed:12930902). Interacts with DDX11 (PubMed:18499658).
Hydroxylation at Asn-246 by HIF1AN may provide an oxygen-dependent regulation mechanism for the function of ASB4 in promoting vascular differentiation.
Interacts with HIF1AN. Component of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex formed of CUL2 or CUL5, Elongin BC (ELOB and ELOC), RBX1 and ASB4.
Probable substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Promotes differentiation and maturation of the vascular lineage by an oxygen-dependent mechanism (By similarity).
Behaves as a cell cycle-dependent transcriptional repressor, promoting inhibition of S-phase DNA synthesis.
Interacts with GNAI1 (PubMed:18434541). Interacts with GNAI2 and GNAI3; the interactions are GDP-dependent (By similarity).
Regulates G protein-coupled receptor signaling cascades. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form.
The GoLoco domain is necessary for interaction with GNAI1, GNAI2 and GNAI3.
May activate the NF-kappa-B signaling pathway.
Undergoes ER-associated degradation (ERAD).
A chromosomal aberration involving FUS is a cause of acute myeloid leukemia (AML). Translocation t(16;21)(p11;q22) with ERG.
A chromosomal aberration involving FUS is found in a patient with malignant myxoid liposarcoma. Translocation t(12;16)(q13;p11) with DDIT3.
Arg-216 and Arg-218 are dimethylated, probably to asymmetric dimethylarginine.
DNA/RNA-binding protein that plays a role in various cellular processes such as transcription regulation, RNA splicing, RNA transport, DNA repair and damage response (PubMed:27731383). Binds to nascent pre-mRNAs and acts as a molecular mediator between RNA polymerase II and U1 small nuclear ribonucleoprotein thereby coupling transcription and splicing (PubMed:26124092). Binds also its own pre-mRNA and autoregulates its expression; this autoregulation mechanism is mediated by non-sense-mediated decay (PubMed:24204307). Plays a role in DNA repair mechanisms by promoting D-loop formation and homologous recombination during DNA double-strand break repair (PubMed:10567410). In neuronal cells, plays crucial roles in dendritic spine formation and stability, RNA transport, mRNA stability and synaptic homeostasis (By similarity).
Phosphorylated in its N-terminal serine residues upon induced DNA damage. ATM and DNA-PK are able to phosphorylate FUS N-terminal region.
Self-oligomerizes (via N-terminal region) (PubMed:25453086). Oligomerization is essential for chromatin binding (PubMed:25453086). Component of nuclear riboprotein complexes. Interacts with ILF3, TDRD3 and SF1 (PubMed:9660765). Interacts through its C-terminus with SFRS13A (PubMed:9774382). Interacts with OTUB1 and SARNP. Interacts with LRSAM1 (PubMed:27615052). Interacts with SAFB1 in a DNA-dependent manner; this interaction tethers FUS to chromatin (PubMed:27731383). Interacts with MATR3 (PubMed:27731383). Interacts with SNRNP70 and POLR2A; these interactions couple RNA transcription and splicing (PubMed:26124092). Interacts (through its RNA-binding domain) with RALY (through its RNA-binding domain); both are components of the same RNPs (PubMed:30354839).
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving FUS is found in a patient with angiomatoid fibrous histiocytoma. Translocation t(12;16)(q13;p11.2) with ATF1 generates a chimeric FUS/ATF1 protein.
Catalytic component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum (PubMed:34388369). Specifically cleaves N-terminal signal peptides that contain a hydrophobic alpha-helix (h-region) shorter than 18-20 amino acids (PubMed:34388369).
Component of the signal peptidase complex paralog C (SPC-C) composed of a catalytic subunit SEC11C and three accessory subunits SPCS1, SPCS2 and SPCS3 (PubMed:34388369). Within the complex, interacts with SPCS2 and SPCS3 (PubMed:34388369). The complex induces a local thinning of the ER membrane which is used to measure the length of the signal peptide (SP) h-region of protein substrates (PubMed:34388369). This ensures the selectivity of the complex towards h-regions shorter than 18-20 amino acids (PubMed:34388369).
Component of the signal peptidase complex.
May undergo processing at the N-terminus.
The C-terminal short (CTS) helix is essential for catalytic activity (PubMed:34388369). It may be accommodated as a transmembrane helix in the thinned membrane environment of the complex, similarly to the signal peptide in the complex substrates (Probable).
Interacts with OGT (via TPR repeats domain); the interaction takes place mainly in the nucleus (By similarity). Forms a DNA-binding heterodimer with transcription factor PBX1 (PubMed:9191052).
Sequence-specific transcription factor (By similarity). Regulates multiple developmental processes including brainstem, inner and outer ear, abducens nerve and cardiovascular development and morphogenesis as well as cognition and behavior (PubMed:16155570). Also part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. Acts on the anterior body structures. Seems to act in the maintenance and/or generation of hindbrain segments (By similarity). Activates transcription in the presence of PBX1A and PKNOX1 (By similarity).
Brain and retina. Neuron-specific in the central and peripheral nervous system. Increased in the cerebrospinal fluid of Alzheimer disease patients (at protein level).
Regulates (in vitro) the inhibition of rhodopsin phosphorylation in a calcium-dependent manner.
A chromosomal aberration involving SLC34A2 is found in a glioblastoma multiforme cell line U-118MG. Results in the formation of a SLC34A2-ROS1 chimeric protein that retains a constitutive kinase activity.
Highly expressed in lung. Also detected in pancreas, kidney, small intestine, ovary, testis, prostate and mammary gland. In lung, it is found in alveolar type II cells but not in bronchiolar epithelium.
Involved in actively transporting phosphate into cells via Na(+) cotransport.
Factor XIII is activated by thrombin and calcium ion to a transglutaminase that catalyzes the formation of gamma-glutamyl-epsilon-lysine cross-links between fibrin chains, thus stabilizing the fibrin clot. Also cross-link alpha-2-plasmin inhibitor, or fibronectin, to the alpha chains of fibrin.
Tetramer of two A chains (F13A1) and two B (F13B) chains.
The activation peptide is released by thrombin.
There are four main allelic forms of this protein; F13A*1A, F13A*1B, F13A*2A and F13A*2B. In addition two other intermediate forms (F13A*(2)A and F13A*(2)B) seem to exist. The sequence shown is that of F13A*1B.
Belongs to the metallo-beta-lactamase superfamily. RNA-metabolizing metallo-beta-lactamase-like family. CPSF2/YSH1 subfamily.
Component of the cleavage and polyadenylation specificity factor (CPSF) complex that play a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. Involved in the histone 3' end pre-mRNA processing.
Component of the cleavage and polyadenylation specificity factor (CPSF) complex, composed of CPSF1, CPSF2, CPSF3, CPSF4 and FIP1L1. Interacts with CPSF3, CSTF2 and SYMPK. Interacts with ZC3H3 (By similarity).
2-oxoglutarate dehydrogenase (E1o) component of the 2-oxoglutarate dehydrogenase complex (OGDHC) (PubMed:24495017, PubMed:25210035, PubMed:28435050). Participates in the first step, rate limiting for the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2) catalyzed by the whole OGDHC (PubMed:24495017, PubMed:25210035, PubMed:28435050). Catalyzes the irreversible decarboxylation of 2-oxoglutarate (alpha-ketoglutarate) via the thiamine diphosphate (ThDP) cofactor and subsequent transfer of the decarboxylated acyl intermediate on an oxidized dihydrolipoyl group that is covalently amidated to the E2 enzyme (dihydrolipoyllysine-residue succinyltransferase or DLST) (PubMed:24495017, PubMed:25210035, PubMed:28435050). Plays a key role in the Krebs (citric acid) cycle, which is a common pathway for oxidation of fuel molecules, including carbohydrates, fatty acids, and amino acids (PubMed:25210035). Can catalyze the decarboxylation of 2-oxoadipate in vitro, but at a much lower rate than 2-oxoglutarate (PubMed:28435050). Mainly active in the mitochondrion (PubMed:29211711). A fraction of the 2-oxoglutarate dehydrogenase complex also localizes in the nucleus and is required for lysine succinylation of histones: associates with KAT2A on chromatin and provides succinyl-CoA to histone succinyltransferase KAT2A (PubMed:29211711).
Calcium ions and ADP stimulate, whereas ATP and NADH reduce catalytic activity.
The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2) and DLD (dihydrolipoamide dehydrogenase; E3). It contains multiple copies of the three enzymatic components (E1, E2 and E3). In the nucleus, the 2-oxoglutarate dehydrogenase complex associates with KAT2A (PubMed:29211711).
The mitochondrial 2-oxoglutarate and 2-oxoadipate dehydrogenase complexes (OGDHC and OADHC, respectively) share their E2 (DLST) and E3 (dihydrolipoyl dehydrogenase or DLD) components, but the E1 component is specific to each complex (E1o and E1a (DHTK1), respectively).
Component of a cell-surface receptor complex that mediates cell-cell interactions between muscle precursor cells. Promotes differentiation of myogenic cells.
Detected in skeletal muscle, heart, thymus, kidney and small intestine. Detected at lower levels in brain, placenta, lung and colon mucosa.
Part of a complex that contains BOC, CDON, NEO1, cadherins and CTNNB1. Interacts with NTN3 (By similarity). Interacts with SHH, DHH and IHH. Interacts with CDH2 and CTNNB1. Interacts with CDH15 only during the early stages of myoblast differentiation.
The C-terminal cytoplasmic domain is not required for the stimulation of myogenesis.
Abundant in the brain and CNS, where it is expressed in tissues of the blood-brain barrier and secreted into the cerebro-spinal fluid. Abundantly expressed in the heart. In the male reproductive system, it is expressed in the testis, epididymis and prostate, and is secreted into the seminal fluid. Expressed in the eye and secreted into the aqueous humor. Lower levels detected in various tissue fluids such as serum, normal urine, ascitic fluid and tear fluid. Also found in a number of other organs including ovary, fimbriae of the fallopian tubes, kidney, leukocytes.
By IL1B/interleukin-1 beta and thyroid hormone. Probably induced by dexamethasone, dihydrotestosterone (DHT), progesterone, retinoic acid and retinal. Repressed by the Notch-Hes signaling pathway.
Catalyzes the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation (PubMed:20667974). Involved in a variety of CNS functions, such as sedation, NREM sleep and PGE2-induced allodynia, and may have an anti-apoptotic role in oligodendrocytes. Binds small non-substrate lipophilic molecules, including biliverdin, bilirubin, retinal, retinoic acid and thyroid hormone, and may act as a scavenger for harmful hydrophobic molecules and as a secretory retinoid and thyroid hormone transporter. Possibly involved in development and maintenance of the blood-brain, blood-retina, blood-aqueous humor and blood-testis barrier. It is likely to play important roles in both maturation and maintenance of the central nervous system and male reproductive system (PubMed:20667974, PubMed:9475419). Involved in PLA2G3-dependent maturation of mast cells. PLA2G3 is secreted by immature mast cells and acts on nearby fibroblasts upstream to PTDGS to synthesize PGD2, which in turn promotes mast cell maturation and degranulation via PTGDR (By similarity).
Expression in the amniotic fluid increases dramatically during weeks 12 to 25 of pregnancy. Levels decrease slowly after 25 weeks.
It has been proposed that the urinary and serum levels may provide a sensitive indicator of renal damage in diabetes mellitus and hypertension. Elevated levels in the coronary circulation may also be associated with angina. Changes in charge and molecular weight microheterogeneity, due to modification of the N-linked oligosaccharides, may be associated with neurodegenerative disease and multiple sclerosis. Detected in meningioma but not in other brain tumors and may be considered a specific cell marker for meningioma. Expression levels in amniotic fluid are altered in abnormal pregnancies. Levels are lower in pregnancies with trisomic fetuses and fetuses with renal abnormalities.
N- and O-glycosylated. Both N-glycosylation recognition sites are almost quantitatively occupied by N-glycans of the biantennary complex type, with a considerable proportion of structures bearing a bisecting GlcNAc. N-glycan at Asn-78: dHex1Hex5HexNAc4. Agalacto structure as well as sialylated and nonsialylated oligosaccharides bearing alpha2-3- and/or alpha2-6-linked NeuNAc are present.
B7-H3 locus underwent genomic duplication leading to tandemly repeated immunoglobulin-like V and C domains (VC domains). The dominantly expressed human B7-H3 isoform contains tandemly duplicated VC domains. In contrast, mouse B7-H3 transcript contains only one single VC domain form due to an exon structure corresponding to V domain-(pseudoexon C)-(pseudoexon V)-C domain. This duplication appearing in primates is suggested to be very recent supporting a model of multiple independent emergence of tandem VC repeats within human and monkey species.
By bacterial lipopolysaccharides (LPS) in monocytes and by ionomycin in T and B-lymphocytes. Up-regulated in cells mediating rejection of human transplants.
Contains tandemly repeated immunoglobulin-like V and C domains.
Interacts with TREML2 and this interaction enhances T-cell activation.
May participate in the regulation of T-cell-mediated immune response. May play a protective role in tumor cells by inhibiting natural-killer mediated cell lysis as well as a role of marker for detection of neuroblastoma cells. May be involved in the development of acute and chronic transplant rejection and in the regulation of lymphocytic activity at mucosal surfaces. Could also play a key role in providing the placenta and fetus with a suitable immunological environment throughout pregnancy. Both isoform 1 and isoform 2 appear to be redundant in their ability to modulate CD4 T-cell responses. Isoform 2 is shown to enhance the induction of cytotoxic T-cells and selectively stimulates interferon gamma production in the presence of T-cell receptor signaling.
Minor transcript. Contains one single set of immunoglobulin-like V and C domains.
Ubiquitous but not detectable in peripheral blood lymphocytes or granulocytes. Weakly expressed in resting monocytes. Expressed in dendritic cells derived from monocytes. Expressed in epithelial cells of sinonasal tissue. Expressed in extravillous trophoblast cells and Hofbauer cells of the first trimester placenta and term placenta.
Glycosyltransferase that catalyzes the transfer of an N-acetylglucosamine (GlcNAc) moiety in beta1-6 linkage from UDP-GlcNAc onto mucin-type core 1 O-glycan to form the branched mucin-type core 2 O-glycan (PubMed:1329093, PubMed:23027862). The catalysis is metal ion-independent and occurs with inversion of the anomeric configuration of sugar donor (By similarity). Selectively involved in synthesis of mucin-type core 2 O-glycans that serve as scaffolds for the display of selectin ligand sialyl Lewis X epitope by myeloid cells, with an impact on homeostasis and recruitment to inflammatory sites (By similarity). Can also act on glycolipid substrates. Transfers GlcNAc moiety to GalGb4Cer globosides in a reaction step to the synthesis of stage-specific embryonic antigen 1 (SSEA-1) determinant (By similarity). Can use Galbeta1-3GalNAcalpha1- and Galbeta1-3GalNAcbeta1- oligosaccharide derivatives as acceptor substrates (By similarity).
Highly expressed in activated T-lymphocytes and myeloid cells.
Interacts with GOLPH3; may control GCNT1 retention in the Golgi.
Enhanced expression in spleen, testis and peripheral blood leukocytes.
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Role in neural transmission (By similarity).
Component of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes. Plays an important role in the assembly of the N-DRC linker (By similarity). Plays dual roles at both the primary (or non-motile) cilia to regulate hedgehog signaling and in motile cilia to coordinate cilia movement. Required for proper motile cilia functioning (PubMed:26387594, PubMed:27120127, PubMed:27472056). Positively regulates ciliary smoothened (SMO)-dependent Hedgehog (Hh) signaling pathway by facilitating the trafficking of SMO into the cilium and the stimulation of SMO activity in a GRK2-dependent manner (By similarity).
Component of the nexin-dynein regulatory complex (N-DRC). Interacts with microtubules (By similarity). Interacts with SMO (PubMed:21659505). Interacts (via coiled-coil domains) with RAB3B (in GTP-bound form) (By similarity). Interacts with DRC1 (PubMed:34169321). Interacts with DRC7 (By similarity).
Expressed in respiratory epithelial cells (at protein level) (PubMed:26387594). Expressed in the heart, skeletal muscle, pancreas, liver, brain, trachea and lung. Weakly or not expressed in placenta and kidney (PubMed:9790751).
(Microbial infection) The homodimer binds two molecules of herpes virus 8/HHV-8 protein vIL-6.
Binds to the soluble IL6:sIL6R complex (hyper-IL6), thereby blocking IL6 trans-signaling. Inhibits sIL6R-dependent acute phase response (PubMed:11121117, PubMed:21990364, PubMed:30279168). Also blocks IL11 cluster signaling through IL11R (PubMed:30279168).
Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; associates with the complex IL6:IL6R but does not interact with IL6 (PubMed:12829785, PubMed:2261637). Forms heterodimers composed of LIFR and IL6ST (type I OSM receptor) which are activated by LIF and OSM (PubMed:8999038). Also forms heterodimers composed of OSMR and IL6ST (type II receptor) which are activated by OSM but not by LIF (PubMed:8999038). Component of a receptor complex composed of IL6ST/GP130, IL27RA/WSX1 and CNTFR which interacts with the neuroprotective peptide humanin (PubMed:19386761). Interacts with HCK (PubMed:9406996). Interacts with INPP5D/SHIP1 (By similarity). Interacts with SRC and YES (PubMed:25731159). Interacts with ARMH4; this interaction prevents IL6ST protein homodimerization and bridges ARMH4 with IL6R and STAT3 and therefore inhibits phosphorylation of STAT3 at 'Tyr-705' (PubMed:26927669).
Expressed in blood serum (at protein level) (PubMed:24629561).
Found in all the tissues and cell lines examined (PubMed:2261637). Expression not restricted to IL6 responsive cells (PubMed:2261637).
Heavily N-glycosylated (PubMed:11098061, PubMed:16335952, PubMed:19159218, PubMed:19139490, PubMed:11251120). Glycosylation is required for protein stability and localization in plasma membrane but not for ligand binding (PubMed:19915009).
LIF and OSM activate the type I OSM receptor while only OSM can activate the type II OSM receptor.
Phosphorylation of Ser-782 down-regulates cell surface expression.
Signal-transducing molecule (PubMed:2261637). The receptor systems for IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize IL6ST for initiating signal transmission. Binding of IL6 to IL6R induces IL6ST homodimerization and formation of a high-affinity receptor complex, which activates the intracellular JAK-MAPK and JAK-STAT3 signaling pathways (PubMed:2261637, PubMed:19915009, PubMed:23294003). That causes phosphorylation of IL6ST tyrosine residues which in turn activates STAT3 (PubMed:19915009, PubMed:23294003, PubMed:25731159). In parallel, the IL6 signaling pathway induces the expression of two cytokine receptor signaling inhibitors, SOCS1 and SOCS3, which inhibit JAK and terminate the activity of the IL6 signaling pathway as a negative feedback loop (By similarity). Also activates the yes-associated protein 1 (YAP) and NOTCH pathways to control inflammation-induced epithelial regeneration, independently of STAT3 (By similarity). Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL27RA/WSX1 and CNTFR (PubMed:19386761). Mediates signals which regulate immune response, hematopoiesis, pain control and bone metabolism (By similarity). Has a role in embryonic development (By similarity). Essential for survival of motor and sensory neurons and for differentiation of astrocytes (By similarity). Required for expression of TRPA1 in nociceptive neurons (By similarity). Required for the maintenance of PTH1R expression in the osteoblast lineage and for the stimulation of PTH-induced osteoblast differentiation (By similarity). Required for normal trabecular bone mass and cortical bone composition (By similarity).
Two extracellular parts of IL6ST/gp130 linked to the Fc-portions of a human IgG1 antibody (sgp130Fc) inhibit IL6 trans-signaling by the IL6:IL6R complex and has no affinity of IL6 or IL6R alone (PubMed:11121117, PubMed:21990364, PubMed:30279168). Also blocks IL11 cluster signaling through IL11R (PubMed:30279168, PubMed:26876177).
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. May play an important role in retinal development.
Expressed mainly in brain but also found in other tissues.
Catalyzes the hydroxylation of 2-polyprenyl-3-methyl-6-methoxy-1,4-benzoquinol (DMQH2) during ubiquinone biosynthesis (By similarity). Has also a structural role in the COQ enzyme complex, stabilizing other COQ polypeptides (By similarity). Involved in lifespan determination in a ubiquinone-independent manner (By similarity). Plays a role in modulating mitochondrial stress responses, acting in the nucleus, perhaps via regulating gene expression, independent of its characterized mitochondrial function in ubiquinone biosynthesis (PubMed:25961505).
Component of a multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9 (By similarity). Interacts with COQ8B and COQ6 (PubMed:24270420). Interacts with COQ9 (PubMed:25339443).
Expressed dominantly in heart and skeletal muscle.
Expressed in various tissues, highest expression in brain.
Increased expression upon apoptotic stimuli.
Interacts with APP (via intracellular domain) (PubMed:10081969). Interacts with APLP1 and APLP2 (via intracellular domain) (PubMed:10081969).
May modulate the internalization of amyloid-beta precursor protein.
Acts as a sensor component of the NLRC4 inflammasome that specifically recognizes and binds needle protein CprI from pathogenic bacteria C.violaceum. Association of pathogenic bacteria proteins drives in turn drive assembly and activation of the NLRC4 inflammasome, promoting caspase-1 activation, cytokine production and macrophage pyroptosis. The NLRC4 inflammasome is activated as part of the innate immune response to a range of intracellular bacteria such as C.violaceum and L.pneumophila.
Anti-apoptotic protein which acts by inhibiting the activities of CASP3, CASP7 and CASP9. Can inhibit the autocleavage of pro-CASP9 and cleavage of pro-CASP3 by CASP9. Capable of inhibiting CASP9 autoproteolysis at 'Asp-315' and decreasing the rate of auto proteolysis at 'Asp-330'. Acts as a mediator of neuronal survival in pathological conditions. Prevents motor-neuron apoptosis induced by a variety of signals. Possible role in the prevention of spinal muscular atrophy that seems to be caused by inappropriate persistence of motor-neuron apoptosis: mutated or deleted forms of NAIP have been found in individuals with severe spinal muscular atrophy.
Both the BIR and NACHT domains are essential for effective inhibition of pro-CASP9 cleavage. BIR3 domain binds to procaspase-9 and the NACHT domain interacts with the NACHT domain of APAF1 forming a bridge between pro-CASP9 and APAF1.
Expressed in motor neurons, but not in sensory neurons. Found in liver and placenta, and to a lesser extent in spinal cord.
Interacts (via NACHT domain) with APAF1 (via CARD and NACHT domains). Interacts with C.violaceum needle protein CprI.
Negative regulator of HIF1A transactivation.
Activity is controlled by protein kinases that target the regulatory region. Phosphorylation inactivates both ds DNA-binding and cofactor function, but does not affect binding to ssDNA. Seems to be phosphorylated in vivo by CK2 in at least 7 sites in the N-terminal Ser-rich region.
Belongs to the transcriptional coactivator PC4 family.
General coactivator that functions cooperatively with TAFs and mediates functional interactions between upstream activators and the general transcriptional machinery. May be involved in stabilizing the multiprotein transcription complex. Binds single-stranded DNA. Also binds, in vitro, non-specifically to double-stranded DNA (ds DNA).
Belongs to the RBR family. RNF144 subfamily.
E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes UBE2L3 and UBE2L6 in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates the ubiquitination and degradation of the DNA damage kinase PRKDC.
Lacks the His residue in the RING-type domain 2 that is one of the conserved features of the family.
Homooligomer (PubMed:31653868). Interacts (via C-terminus) with endoplasmic reticulum (ER) protein CLCC1; the interaction occurs at the mitochondria-associated ER membrane, a zone of contact between the ER and mitochondrial membranes, but does not appear to play a role in ER-mitochondria tethering and is not affected by ER stress (PubMed:31653868).
Plays a role in regulation of the unfolded protein response triggered by endoplasmic reticulum (ER) stress resulting from the presence of unfolded proteins in the ER lumen.
(Microbial infection) Interacts with HIV-1 Tat (via activation domain).
Monomer. Binds nuclear transport receptors XPO4, IPO5/RANBP5, IPO7, IPO9 and KPNB1 as well as GCN1L1/GCN1 and LRPPRC probably through their HEAT repeats. Binds NCOA5/CIA. Isoform 2 binds the proteasome subunit PSMD4/s5a through its N-terminus.
Mutagenesis of Leu-154 and Leu-157 or Cys-158, Cys-160 and Cys-161 abolishes antiapoptotic effect.
Oxidoreductase required for tumor suppression. NADPH-bound form inhibits nuclear import by competing with nuclear import substrates for binding to a subset of nuclear transport receptors. May act as a redox sensor linked to transcription through regulation of nuclear import. Isoform 1 is a metastasis suppressor with proapoptotic as well as antiangiogenic properties. Isoform 2 has an antiapoptotic effect.
Ubiquitous. Highest level in liver. High levels in lung, skeletal muscle, pancreas and placenta. Moderate levels in heart and kidney. Low levels in brain. Not expressed or low levels in variant small cell lung carcinomas, 33% of hepatocellular carcinomas and neuroblastomas.
Unique C-terminus confers high proteasome-dependent instability to isoform 2.
Was originally (PubMed:9482853, PubMed:10698937) thought to be a transcriptional coregulator with protein kinase activity. However, crystal structure reveals a short chain dehydrogenase/reductase fold binding NADPH rather than ATP.
Heterodimer with IFNAR2; forming the receptor for type I interferon (PubMed:7665574, PubMed:10049744, PubMed:21854986). Interacts with TYK2 (PubMed:7526154, PubMed:15337770, PubMed:24704786). Interacts with STAT1 and STAT2; the interaction requires its phosphorylation at Tyr-466 (PubMed:9121453). Interacts (serine-phosphorylated form) with FBXW11, the substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex (PubMed:14532120, PubMed:15337770, PubMed:18056411). Interacts with SHMT2; this promotes interaction with ABRAXAS2 and the BRISC complex (PubMed:24075985). Interacts with TRIM10; this interaction prevents association between IFNAR1 and TYK2 (PubMed:33811647).
IFN receptors are present in all tissues and even on the surface of most IFN-resistant cells. Isoform 1, isoform 2 and isoform 3 are expressed in the IFN-alpha sensitive myeloma cell line U266B1. Isoform 2 and isoform 3 are expressed in the IFN-alpha resistant myeloma cell line U266R. Isoform 1 is not expressed in IFN-alpha resistant myeloma cell line U266R.
Palmitoylation at Cys-463 is required for the activation of STAT1 and STAT2.
Phosphorylated on tyrosine residues in response to interferon-binding: phosphorylation by TYK2 tyrosine kinase creates docking sites for STAT proteins (PubMed:7526154, PubMed:10049744). Phosphorylated on serine residues in response to interferon binding; this promotes interaction with FBXW11 and ubiquitination (PubMed:14532120, PubMed:15337770, PubMed:24075985).
Together with IFNAR2, forms the heterodimeric receptor for type I interferons (including interferons alpha, beta, epsilon, omega and kappa) (PubMed:2153461, PubMed:7813427, PubMed:10049744, PubMed:14532120, PubMed:15337770, PubMed:24075985, PubMed:21854986, PubMed:31270247, PubMed:33252644, PubMed:35442418). Type I interferon binding activates the JAK-STAT signaling cascade, resulting in transcriptional activation or repression of interferon-regulated genes that encode the effectors of the interferon response (PubMed:7665574, PubMed:10049744, PubMed:21854986). Mechanistically, type I interferon-binding brings the IFNAR1 and IFNAR2 subunits into close proximity with one another, driving their associated Janus kinases (JAKs) (TYK2 bound to IFNAR1 and JAK1 bound to IFNAR2) to cross-phosphorylate one another (PubMed:7813427, PubMed:7665574, PubMed:21854986, PubMed:32972995). The activated kinases phosphorylate specific tyrosine residues on the intracellular domains of IFNAR1 and IFNAR2, forming docking sites for the STAT transcription factors (PubMed:7813427, PubMed:7526154, PubMed:7665574, PubMed:21854986, PubMed:32972995). STAT proteins are then phosphorylated by the JAKs, promoting their translocation into the nucleus to regulate expression of interferon-regulated genes (PubMed:7813427, PubMed:7665574, PubMed:9121453, PubMed:19561067, PubMed:21854986, PubMed:32972995). Can also act independently of IFNAR2: form an active IFNB1 receptor by itself and activate a signaling cascade that does not involve activation of the JAK-STAT pathway (By similarity).
Ubiquitinated, leading to its internalization and degradation (PubMed:14532120, PubMed:15337770). Polyubiquitinated via 'Lys-48'-linked and 'Lys-63'-linked ubiquitin chains, leading to receptor internalization and lysosomal degradation (PubMed:18056411). The 'Lys-63'-linked ubiquitin chains are cleaved off by the BRISC complex (PubMed:24075985).
(Microbial infection) Alternative coreceptor with CD4 for HIV-1 infection; may be involved in the development of AIDS dementia (PubMed:11090199).
Expressed in heart, brain, kidney, stomach, spleen, thymus, lung, ovary, small intestine and colon, adipose tissues and pancreas (PubMed:8294032, PubMed:25639753). Expressed in glial cells, astrocytes and neuronal subpopulations (PubMed:8294032). Expressed in embryonic (ESCs) and induced (iPSCs) pluripotent stem cells (PubMed:25639753).
Receptor for apelin receptor early endogenous ligand (APELA) and apelin (APLN) hormones coupled to G proteins that inhibit adenylate cyclase activity (PubMed:11090199, PubMed:25639753, PubMed:28137936). Plays a key role in early development such as gastrulation, blood vessels formation and heart morphogenesis by acting as a receptor for APELA hormone (By similarity). May promote angioblast migration toward the embryonic midline, i.e. the position of the future vessel formation, during vasculogenesis (By similarity). Promotes sinus venosus (SV)-derived endothelial cells migration into the developing heart to promote coronary blood vessel development (By similarity). Also plays a role in various processes in adults such as regulation of blood vessel formation, blood pressure, heart contractility and heart failure (PubMed:25639753, PubMed:28137936).
(Microbial infection) Interacts (via C-terminus) with HIV-1 Nef; the interaction is direct.
Brefeldin A induces dissociation from the Golgi of the beta-COP and presumably the other coatomer subunits.
Oligomeric complex that consists of at least the alpha, beta, beta', gamma, delta, epsilon and zeta subunits. Interacts with SCYL1. Interacts with COPG1. Interacts (via trunk domain) with ARF1 (via switch I region); the interaction is direct. Interacts with KCNK2/TREK (via N-terminus); this interaction increases the channel-mediated whole cell currents and promotes plasma membrane expression of KCNK2/TREK. Interacts with anthrax lethal factor (LF); this interaction may facilitate endosomal vesicle membrane translocation of LF and its release from the lumen of endosomal vesicles to external milieu. Interacts with CAPN8 and PRKCE (By similarity). Interacts with ARF1 (myristoylated); this interaction is required for binding of COPB1 to Golgi membranes (By similarity). Interacts with STX17 (By similarity). Interacts with TMEM115. Interacts with HLA-G-B2M complex; this interaction mediates the endoplasmic reticulum (ER) retrieval of HLA-E-B2M complexes that bind low affinity peptides. Interacts with TMEM41B (PubMed:30352685).
Proteolytically cleaved between Ser-528 and Ser-529 by CAPN8.
The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. Coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. In mammals, the coatomer can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins; the complex also influences the Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors. Plays a functional role in facilitating the transport of kappa-type opioid receptor mRNAs into axons and enhances translation of these proteins. Required for limiting lipid storage in lipid droplets. Involved in lipid homeostasis by regulating the presence of perilipin family members PLIN2 and PLIN3 at the lipid droplet surface and promoting the association of adipocyte surface triglyceride lipase (PNPLA2) with the lipid droplet to mediate lipolysis (By similarity). Involved in the Golgi disassembly and reassembly processes during cell cycle. Involved in autophagy by playing a role in early endosome function. Plays a role in organellar compartmentalization of secretory compartments including endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC), Golgi, trans-Golgi network (TGN) and recycling endosomes, and in biosynthetic transport of CAV1. Promotes degradation of Nef cellular targets CD4 and MHC class I antigens by facilitating their trafficking to degradative compartments.
May be a receptor for the CD200/OX2 cell surface glycoprotein.
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family. NifS/IscS subfamily.
Cysteine desulfurase, of the core iron-sulfur cluster (ISC) assembly complex, that catalyzes the desulfuration of L-cysteine to L-alanine, as component of the cysteine desulfurase complex, leading to the formation of a cysteine persulfide intermediate at the active site cysteine residue and participates in the [2Fe-2S] clusters assembly on the scaffolding protein ISCU (PubMed:29097656, PubMed:31101807, PubMed:18650437). The persulfide is then transferred on the flexible Cys loop from the catalytic site of NFS1 to the surface of NFS1 (PubMed:29097656). After the NFS1-linked persulfide sulfur is transferred to one of the conserved Cys residues of the scaffold, a reaction assisted by FXN (By similarity). The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis. This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the scaffold protein ISCU in a FXN-dependent manner. Then this complex is stabilized by FDX2 which provides reducing equivalents to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and GLRX5 (By similarity).
Cysteine persulfide intermediate is reduced by thiol-containing molecules like glutathione and L-cysteine. Persulfide reduction is a rate-limiting step of cysteine desulfurase catalytic cycle.
Homodimer (PubMed:29097656, PubMed:31101807). Component of the mitochondrial core iron-sulfur cluster (ISC) complex composed of NFS1, LYRM4, NDUFAB1, ISCU, FXN, and FDX2; this complex is an heterohexamer containing two copies of each monomer (Probable). Component of cyteine desulfurase complex composed of NFS1, LYRM4 and NDUFAB1; this complex contributes to the activation of cysteine desulfurase activity and NFS1 stabilization (PubMed:34824239, PubMed:31664822). Interacts (homodimer form) with ISCU (D-state); each monomer interacts with the C-terminal regions of each NFS1 monomer (PubMed:29097656, PubMed:11060020, PubMed:23940031). Interacts with HSPA9 (PubMed:26702583). Interacts (via homodimer form) with FDX2 (PubMed:29097656). Interacts (via homodimer form) with FXN (PubMed:31101807). Interacts with LYRM4 (PubMed:29097656, PubMed:19454487). Component of a complex composed of FXN, NFS1, LYRM4 and ISCU (By similarity).
May catalyze the desulfuration of L-cysteine to L-alanine as component of the cysteine desulfurase complex (NFS1:LYRM4), leading to the formation of a cysteine persulfide intermediate (PubMed:18650437, PubMed:16527810). Acts as a sulfur donor for MOCS3 by transferring the sulfur of the cysteine persulfide intermediate on MOCS3 (PubMed:18650437, PubMed:23593335).
Monomer (PubMed:16527810). Homodimer (PubMed:16527810, PubMed:18650437, PubMed:23593335). Oligomer (PubMed:18650437). Interacts with ISCU (PubMed:16527810). Component of the cysteine desulfurase complex composed of NFS1 and LYRM4; this complex contributes to the activation of cysteine desulfurase activity (PubMed:18650437). Interacts with MOCS3 (PubMed:18650437, PubMed:23593335).
Predominantly expressed in heart and skeletal muscle. Also found in brain, liver and pancreas.
Acetylation, on DNA damage, is required for activation of the kinase activity, dimer-monomer transition, and subsequent autophosphorylation on Ser-1981 (PubMed:12556884, PubMed:16141325, PubMed:16858402, PubMed:17923702, PubMed:21144835). Acetylated in vitro by KAT5/TIP60 (PubMed:16141325). Deacetylated by SIRT7 during the late stages of DNA damage response, promoting ATM dephosphorylation and subsequent deactivation (PubMed:30944854).
Belongs to the PI3/PI4-kinase family. ATM subfamily.
Defects in ATM may contribute to B-cell chronic lymphocytic leukemia (BCLL). BCLL is the commonest form of leukemia in the elderly. It is characterized by the accumulation of mature CD5+ B-lymphocytes, lymphadenopathy, immunodeficiency and bone marrow failure.
Defects in ATM may contribute to B-cell non-Hodgkin lymphomas (BNHL), including mantle cell lymphoma (MCL).
Defects in ATM may contribute to T-cell acute lymphoblastic leukemia (TALL) and T-prolymphocytic leukemia (TPLL). TPLL is characterized by a high white blood cell count, with a predominance of prolymphocytes, marked splenomegaly, lymphadenopathy, skin lesions and serous effusion. The clinical course is highly aggressive, with poor response to chemotherapy and short survival time. TPLL occurs both in adults as a sporadic disease and in younger AT patients.
Found in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, spleen, thymus, testis, ovary, small intestine, colon and leukocytes.
Homodimer (PubMed:28508083). Dimers or tetramers in inactive state. On DNA damage, autophosphorylation dissociates ATM into monomers rendering them catalytically active. Binds p53/TP53, ABL1, BRCA1, NBN/nibrin and TERF1. Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBN protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with RAD17; DNA damage promotes the association. Interacts with EEF1E1; the interaction, induced on DNA damage, up-regulates TP53. Interacts with DCLRE1C, KAT8, KAT5, NABP2, ATMIN and CEP164. Interacts with AP2B1 and AP3B2; the interaction occurs in cytoplasmic vesicles (By similarity). Interacts with TELO2 and TTI1. Interacts with DDX1. Interacts with BRAT1. Interacts with CYREN (via XLF motif) (By similarity). Interacts (via microbody targeting signal) with PEX5; promoting translocation to peroxisomes in response to reactive oxygen species (ROS) (PubMed:26344566).
Phosphorylated by NUAK1/ARK5 (PubMed:12409306). Autophosphorylation on Ser-367, Ser-1893, Ser-1981 correlates with DNA damage-mediated activation of the kinase (PubMed:12556884, PubMed:16141325, PubMed:16858402, PubMed:21144835, PubMed:27664052). During the late stages of DNA damage response, dephosphorylated following deacetylation by SIRT7, leading to ATM deactivation (PubMed:30944854).
Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor (PubMed:9733514, PubMed:10550055, PubMed:10839545, PubMed:10910365, PubMed:12556884, PubMed:14871926, PubMed:15456891, PubMed:15448695, PubMed:15916964, PubMed:17923702). Recognizes the substrate consensus sequence [ST]-Q (PubMed:9733514, PubMed:10550055, PubMed:10839545, PubMed:10910365, PubMed:12556884, PubMed:14871926, PubMed:15456891, PubMed:15448695, PubMed:15916964, PubMed:17923702). Phosphorylates 'Ser-139' of histone variant H2AX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism (By similarity). Also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. After the introduction of DNA breaks by the RAG complex on one immunoglobulin allele, acts by mediating a repositioning of the second allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates DYRK2, CHEK2, p53/TP53, FBXW7, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, UFL1, RAD9, UBQLN4 and DCLRE1C (PubMed:9843217, PubMed:9733515, PubMed:10550055, PubMed:10766245, PubMed:10839545, PubMed:10910365, PubMed:10802669, PubMed:10973490, PubMed:11375976, PubMed:12086603, PubMed:15456891, PubMed:19965871, PubMed:30612738, PubMed:30886146, PubMed:26774286). May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. Plays a role in replication-dependent histone mRNA degradation. Binds DNA ends. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation (PubMed:19965871). Phosphorylates ATF2 which stimulates its function in DNA damage response (PubMed:15916964). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878). Phosphorylates TTC5/STRAP at 'Ser-203' in the cytoplasm in response to DNA damage, which promotes TTC5/STRAP nuclear localization (PubMed:15448695). Also involved in pexophagy by mediating phosphorylation of PEX5: translocated to peroxisomes in response to reactive oxygen species (ROS), and catalyzes phosphorylation of PEX5, promoting PEX5 ubiquitination and induction of pexophagy (PubMed:26344566).
The FATC domain is required for interaction with KAT5.
Activated by potassium ions, but not sodium ions.
Succinylation at Lys-268, adjacent to a coenzyme A binding site. Desuccinylated by SIRT5 (By similarity).
This is one of the enzymes that catalyzes the last step of the mitochondrial beta-oxidation pathway, an aerobic process breaking down fatty acids into acetyl-CoA (PubMed:1715688, PubMed:7728148, PubMed:9744475). Using free coenzyme A/CoA, catalyzes the thiolytic cleavage of medium- to long-chain 3-oxoacyl-CoAs into acetyl-CoA and a fatty acyl-CoA shortened by two carbon atoms (PubMed:1715688, PubMed:7728148, PubMed:9744475). The activity of the enzyme is reversible and it can also catalyze the condensation of two acetyl-CoA molecules into acetoacetyl-CoA (PubMed:17371050). Thereby, it plays a major role in ketone body metabolism (PubMed:17371050, PubMed:1715688, PubMed:7728148, PubMed:9744475).
Interacts (via N-terminus) with PLK4; the interaction is mutally exclusive with a PLK4:CEP192 interaction (PubMed:21059844, PubMed:20852615, PubMed:24997597). Interacts (via C-terminus) with CENPJ (via-N-terminus) (PubMed:20852615). Interacts with CINP (PubMed:21131973). Interacts with CDK5RAP2, WDR62, CEP63 and CEP131 (PubMed:21983783, PubMed:24613305, PubMed:26297806). CEP63, CDK5RAP2, CEP152, WDR62 are proposed to form a stepwise assembled complex at the centrosome forming a ring near parental centrioles (PubMed:26297806). Interacts with DEUP1; this interaction recruits CEP152 to the deuterosome. The interactions with CEP63 and DEUP1 are mutually exclusive (By similarity).
Necessary for centrosome duplication; the function seems also to involve CEP63, CDK5RAP2 and WDR62 through a stepwise assembled complex at the centrosome that recruits CDK2 required for centriole duplication (PubMed:26297806). Acts as a molecular scaffold facilitating the interaction of PLK4 and CENPJ, 2 molecules involved in centriole formation (PubMed:21059844, PubMed:20852615). Proposed to snatch PLK4 away from PLK4:CEP92 complexes in early G1 daughter centriole and to reposition PLK4 at the outer boundary of a newly forming CEP152 ring structure (PubMed:24997597). Also plays a key role in deuterosome-mediated centriole amplification in multiciliated that can generate more than 100 centrioles (By similarity). Overexpression of CEP152 can drive amplification of centrioles (PubMed:20852615).
(Microbial infection) The ESCRT machinery functions in topologically equivalent membrane fission events, such as the budding of enveloped viruses (HIV-1 and other lentiviruses). Involved in HIV-1 p6- and p9-dependent virus release.
ISGylated in a CHMP5-dependent manner. Isgylation weakens and inhibits its interactions with VPS4A and VTA1 respectively.
Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis (PubMed:21310966). Together with SPAST, the ESCRT-III complex promotes nuclear envelope sealing and mitotic spindle disassembly during late anaphase (PubMed:26040712). Recruited to the reforming nuclear envelope (NE) during anaphase by LEMD2 (PubMed:28242692). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4.
Probable core component of the endosomal sorting required for transport complex III (ESCRT-III). ESCRT-III components are thought to multimerize to form a flat lattice on the perimeter membrane of the endosome. Several assembly forms of ESCRT-III may exist that interact and act sequentially. In vitro, heteromerizes with CHMP3 (but not CHMP4) to form helical tubular structures that expose membrane-interacting sites on the outside whereas VPS4B can associate on the inside of the tubule. Interacts with CHMP1B, CHMP2B, CHMP3, CHMP4A, CHMP4B, CHMP4C and CHMP5. Interacts with VPS4A; the interaction is direct. Interacts with VPS4B; the interaction is direct. Interacts with MITD1. Interacts with VTA1; the interaction probably involves the open conformation of CHMP2A.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. Aurora subfamily.
Component of the chromosomal passenger complex (CPC) composed of at least BIRC5/survivin, CDCA8/borealin, INCENP, AURKB or AURKC; predominantly independent AURKB- and AURKC-containing complexes exist; in the complex interacts directly with BIRC5/survivin and INCENP. Interacts with TACC1.
Expression is cell cycle-regulated, with an increase during G2 and M phases.
Isoform 1 and isoform 2 are expressed in testis. Elevated expression levels were seen only in a subset of cancer cell lines such as Hep-G2, Huh-7 and HeLa. Expression is maximum at M phase.
Okadaic acid, an inhibitor of protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A) and protein phosphatase 5 (PP5), increases AURKC activity. AURKC is also stabilized through its interaction with INCENP, which acts also as an activator.
Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Also plays a role in meiosis and more particularly in spermatogenesis. Has redundant cellular functions with AURKB and can rescue an AURKB knockdown. Like AURKB, AURKC phosphorylates histone H3 at 'Ser-10' and 'Ser-28'. AURKC phosphorylates the CPC complex subunits BIRC5/survivin and INCENP leading to increased AURKC activity. Phosphorylates TACC1, another protein involved in cell division, at 'Ser-228'.
Transcription factor involved in the control of neuronal proliferation and differentiation in the brain. Regulates dendrite development and branching, dendritic spine formation, and synaptogenesis in cortical layers II-III. Binds to DNA in a sequence-specific manner.
Belongs to the N-CoR nuclear receptor corepressors family.
Contains only the C-terminal receptor-interacting domain and acts as an antirepressor.
Forms a large corepressor complex that contains SIN3A/B and histone deacetylases HDAC1 and HDAC2. This complex associates with the thyroid (TR) and the retinoid acid receptors (RAR) in the absence of ligand, and may stabilize their interaction with TFIIB. Interacts directly with RARA in the absence of ligand; the interaction represses RARA activity. Interacts (isoform SMRT) with HDAC10. Interacts with MINT. Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:10809664, PubMed:10944117, PubMed:11931768, PubMed:19858209, PubMed:21240272). Interacts with CBFA2T3 and ATXN1L. Interacts with RARB; the interaction is weak and does not repress RARB transactivational activity. Interacts with HDAC7 and C1D. Interacts with NR4A2; this interaction increases in the absence of PITX3. Interacts with BCL6 (via the BTB domain), required for BCL6 transcriptional repressor activity on a subset of target genes. Forms ternary complexes with BCOR and BCL6 on target gene promoters but, on enhancer elements, interacts with BCL6 and HDAC3 to repress proximal gene expression. May interact with DEAF1. Interacts with RXRA. Interacts with MECP2 (By similarity). Interacts with ZBTB7A (PubMed:20812024). Interacts with AR (PubMed:20812024). Interacts with TBL1Y (PubMed:30341416). Interacts with SANBR (via the BTB domain) (By similarity).
Regulated during cell cycle progression.
The N-terminal region contains repression functions that are divided into three independent repression domains (RD1, RD2 and RD3). The C-terminal region contains the nuclear receptor-interacting domains that are divided in two separate interaction domains (ID1 and ID2).
The two interaction domains (ID) contain a conserved sequence referred to as the CORNR box. This motif is required and sufficient to permit binding to unligated TR and RARS. Sequences flanking the CORNR box determine nuclear hormone receptor specificity.
Transcriptional corepressor (PubMed:20812024). Mediates the transcriptional repression activity of some nuclear receptors by promoting chromatin condensation, thus preventing access of the basal transcription. Isoform 1 and isoform 4 have different affinities for different nuclear receptors. Involved in the regulation BCL6-dependent of the germinal center (GC) reactions, mainly through the control of the GC B-cells proliferation and survival. Recruited by ZBTB7A to the androgen response elements/ARE on target genes, negatively regulates androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024).
Ubiquitous. High levels of expression are detected in lung, spleen and brain.
Associates with KCNQ2 or KCNQ5 to form a potassium channel with essentially identical properties to the channel underlying the native M-current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons as well as the responsiveness to synaptic inputs. Therefore, it is important in the regulation of neuronal excitability. KCNQ2-KCNQ3 channel is selectively permeable to other cations besides potassium, in decreasing order of affinity K(+) > Rb(+) > Cs(+) > Na(+). Associates with Na(+)-coupled myo-inositol symporter SLC5A3 forming a coregulatory complex that alters ion selectivity, increasing Na(+) and Cs(+) permeation relative to K(+) permeation (PubMed:28793216).
Belongs to the potassium channel family. KQT (TC 1.A.1.15) subfamily. Kv7.3/KCNQ3 sub-subfamily.
Defects in KCNQ3 may be involved in epileptic disorders. These are characterized by paroxysmal transient disturbances of the electrical activity of the brain that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system.
Heterotetramer with KCNQ2; form the heterotetrameric M potassium channel (PubMed:27564677). Interacts with calmodulin; the interaction is calcium-independent, constitutive and participates in the proper assembly of a functional heterotetrameric M channel (PubMed:27564677). Heteromultimer with KCNQ5 (PubMed:11159685). May associate with KCNE2 (PubMed:11034315). Interacts with IQCJ-SCHIP1 (By similarity). Interacts (via the pore module) with SLC5A3; forms a coregulatory complex that alters ion selectivity, voltage dependence and gating kinetics of the channel.
KCNQ2/KCNQ3 are ubiquitinated by NEDD4L. Ubiquitination leads to protein degradation (Probable). Degradation induced by NEDD4L is inhibited by USP36 (PubMed:27445338).
Mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the first alpha-1,4-mannose to GlcN-acyl-PI during GPI precursor assembly.
A chromosomal aberration involving AFDN is associated with acute leukemias. Translocation t(6;11)(q27;q23) with KMT2A/MLL1. The result is a rogue activator protein.
Belongs to an adhesion system, probably together with the E-cadherin-catenin system, which plays a role in the organization of homotypic, interneuronal and heterotypic cell-cell adherens junctions (AJs) (By similarity). Nectin- and actin-filament-binding protein that connects nectin to the actin cytoskeleton (PubMed:11024295). May play a key role in the organization of epithelial structures of the embryonic ectoderm (By similarity). Essential for the organization of adherens junctions (PubMed:30463011).
Homodimer. Interacts with F-actin, nectin and NECTIN3. Essential for the association of nectin and E-cadherin. Isoform 1/s-afadin does not interact with F-actin. Interacts with ZO-1 and occludin, but probably in an indirect manner. Interacts with RIT1 and RIT2 (By similarity). Interacts with NRXN1 and BCR. Interacts with ADAM10; the interaction locks ADAM10 at adherens junctions following ADAM10 recruitment to adherens junctions by TSPAN33 (PubMed:30463011).
The PDZ/DHR domain interacts with the C-terminus of nectin and the Pro-rich C-terminal domain interacts with F-actin.
Acts as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDK1 before the onset of mitosis by mediating phosphorylation of CDK1 on 'Tyr-15'. Specifically phosphorylates and inactivates cyclin B1-complexed CDK1 reaching a maximum during G2 phase and a minimum as cells enter M phase. Phosphorylation of cyclin B1-CDK1 occurs exclusively on 'Tyr-15' and phosphorylation of monomeric CDK1 does not occur. Its activity increases during S and G2 phases and decreases at M phase when it is hyperphosphorylated. A correlated decrease in protein level occurs at M/G1 phase, probably due to its degradation.
Dephosphorylated at Thr-239 by CTDP1 (PubMed:22692537). Dephosphorylated at Ser-53 and Ser-123 by the serine/threonine-protein phosphatase 2A preventing its ubiquitin-mediated degradation (PubMed:33108758).
Phosphorylated during M and G1 phases. Also autophosphorylated. Phosphorylation at Ser-642 by BRSK1 and BRSK2 in post-mitotic neurons, leads to down-regulate WEE1 activity in polarized neurons. Phosphorylated at Ser-53 and Ser-123 by PLK1 and CDK1, respectively, generating an signal for degradation that can be recognized by the SCF(BTRC) complex, leading to its ubiquitination and degradation at the onset of G2/M phase.
Synthesis is increased during S and G2 phases, presumably by an increase in transcription; activity is decreased by phosphorylation during m phase. Protein levels fall in M phase as a result of decreased synthesis combined with degradation. Activity seems to be negatively regulated by phosphorylation upon entry into mitosis, although N-terminal phosphorylation might also regulate the protein stability via protection from proteolysis or might regulate the subcellular location.
Ubiquitinated and degraded at the onset of G2/M phase.
ADP-ribosylated by PARP1 or PARP2 on Ser-7 (H2BS6ADPr) in response to DNA damage (PubMed:27723750, PubMed:34874266). H2BS6ADPr promotes recruitment of CHD1L (PubMed:34874266). Mono-ADP-ribosylated on Glu-3 (H2BE2ADPr) by PARP3 in response to single-strand breaks (PubMed:27530147). Poly ADP-ribosylation on Glu-36 (H2BE35ADPr) by PARP1 regulates adipogenesis: it inhibits phosphorylation at Ser-37 (H2BS36ph), thereby blocking expression of pro-adipogenetic genes (By similarity).
GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).
In phase II clinical trial. The drug is being developed by Amrad to assist embryo implantation in women who have failed to become pregnant despite assisted reproductive technologies (ART).
LIF has the capacity to induce terminal differentiation in leukemic cells. Its activities include the induction of hematopoietic differentiation in normal and myeloid leukemia cells, the induction of neuronal cell differentiation, and the stimulation of acute-phase protein synthesis in hepatocytes.
E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. May be involved in pancreatic homeostasis. Binds leucine and is a negative regulator of the leucine-mTOR signaling pathway, thereby controlling cell growth.
Expressed in pancreas and adipose tissues.
(Microbial infection) Binding to N.meningitidis NadA stimulates monocytes (PubMed:21949862). Seems to interfere with N.meningitidis NadA-mediated invasion of human cells (Probable).
(Microbial infection) Protein on the cell surface interacts with N.meningitidis serogroup B adhesin A (nadA).
Cleaved following oxidative stress resulting in HSP90AB1 protein radicals formation; disrupts the chaperoning function and the degradation of its client proteins.
In the resting state, through the dimerization of its C-terminal domain, HSP90 forms a homodimer which is defined as the open conformation. Upon ATP-binding, the N-terminal domain undergoes significant conformational changes and comes in contact to form an active closed conformation. After HSP90 finishes its chaperoning tasks of assisting the proper folding, stabilization and activation of client proteins under the active state, ATP molecule is hydrolyzed to ADP which then dissociates from HSP90 and directs the protein back to the resting state.
Methylated by SMYD2; facilitates dimerization and chaperone complex formation; promotes cancer cell proliferation.
Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function (PubMed:16478993, PubMed:19696785). Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself. Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone. After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle (PubMed:27295069, PubMed:26991466). Apart from its chaperone activity, it also plays a role in the regulation of the transcription machinery. HSP90 and its co-chaperones modulate transcription at least at three different levels. They first alter the steady-state levels of certain transcription factors in response to various physiological cues. Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment. Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression (PubMed:25973397). Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation (PubMed:24613385). Promotes cell differentiation by chaperoning BIRC2 and thereby protecting from auto-ubiquitination and degradation by the proteasomal machinery (PubMed:18239673). Main chaperone involved in the phosphorylation/activation of the STAT1 by chaperoning both JAK2 and PRKCE under heat shock and in turn, activates its own transcription (PubMed:20353823). Involved in the translocation into ERGIC (endoplasmic reticulum-Golgi intermediate compartment) of leaderless cargos (lacking the secretion signal sequence) such as the interleukin 1/IL-1; the translocation process is mediated by the cargo receptor TMED10 (PubMed:32272059).
Monomer (PubMed:24880080). Homodimer (PubMed:7588731, PubMed:18400751). Forms a complex with CDK6 and CDC37 (PubMed:9482106, PubMed:25486457). Interacts with UNC45A; binding to UNC45A involves 2 UNC45A monomers per HSP90AB1 dimer (PubMed:16478993). Interacts with CHORDC1 (By similarity). Interacts with DNAJC7 (PubMed:18620420). Interacts with FKBP4 (PubMed:15159550). May interact with NWD1 (PubMed:24681825). Interacts with SGTA (PubMed:16580629). Interacts with HSF1 in an ATP-dependent manner. Interacts with MET; the interaction suppresses MET kinase activity. Interacts with ERBB2 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity. Interacts with HIF1A, KEAP1 and RHOBTB2 (PubMed:26517842). Interacts with STUB1 and SMAD3 (PubMed:24613385). Interacts with XPO1 and AHSA1 (PubMed:22022502, PubMed:25486457). Interacts with BIRC2 (PubMed:25486457). Interacts with KCNQ4; promotes cell surface expression of KCNQ4 (PubMed:23431407). Interacts with BIRC2; prevents auto-ubiquitination and degradation of its client protein BIRC2 (PubMed:18239673). Interacts with NOS3 (PubMed:23585225). Interacts with AHR; interaction is inhibited by HSP90AB1 phosphorylation on Ser-226 and Ser-255 (PubMed:15581363). Interacts with STIP1 and CDC37; upon SMYD2-dependent methylation (PubMed:24880080). Interacts with JAK2 and PRKCE; promotes functional activation in a heat shock-dependent manner (PubMed:20353823). Interacts with HSP90AA1; interaction is constitutive (PubMed:20353823). HSP90AB1-CDC37 chaperone complex interacts with inactive MAPK7 (via N-terminal half) in resting cells; the interaction is MAP2K5-independent and prevents from ubiquitination and proteasomal degradation (PubMed:23428871). Interacts with CDC25A; prevents heat shock-mediated CDC25A degradation and contributes to cell cycle progression (PubMed:22843495). Interacts with TP53 (via DNA binding domain); suppresses TP53 aggregation and prevents from irreversible thermal inactivation (PubMed:15358771). Interacts with TGFB1 processed form (LAP); inhibits latent TGFB1 activation (PubMed:20599762). Interacts with TRIM8; prevents nucleus translocation of phosphorylated STAT3 and HSP90AB1 (By similarity). Interacts with NR3C1 (via domain NR LBD) and NR1D1 (via domain NR LBD) (By similarity). Interacts with PDCL3 (By similarity). Interacts with TTC4 (via TPR repeats) (PubMed:18320024). Interacts with IL1B; the interaction facilitates cargo translocation into the ERGIC (PubMed:32272059).
Phosphorylation at Tyr-301 by SRC is induced by lipopolysaccharide (PubMed:23585225). Phosphorylation at Ser-226 and Ser-255 inhibits AHR interaction (PubMed:15581363).
S-nitrosylated; negatively regulates the ATPase activity.
The TPR repeat-binding motif mediates interaction with TPR repeat-containing proteins.
Ubiquitinated in the presence of STUB1-UBE2D1 complex (in vitro).
Glutathione may be required to regulate its activity in the endoplasmic reticulum.
Highly expressed in the digestive tract, including the duodenum and lower digestive tract. In the stomach, highly expressed in enzyme-producing chief cells (at protein level). In the pancreas, expressed in islets of Langerhans and, at lower levels, in enzyme-secreting cells (at protein level). Detected at low level in many other tissues.
Homodimer; disulfide-linked. Heterodimer with ERO1A; disulfide-linked. Also detected as monomer. Homodimers may be somewhat less active than monomers. Interacts with P4HB. Interacts with ERP44.
Oxidoreductase involved in disulfide bond formation in the endoplasmic reticulum. Efficiently reoxidizes P4HB/PDI, the enzyme catalyzing protein disulfide formation, in order to allow P4HB to sustain additional rounds of disulfide formation. Other protein disulfide isomerase family members can also be reoxidized, but at lower rates compared to P4HB, including PDIA2 (50% of P4HB reoxidation rate), as well as PDIA3, PDIA4, PDIA6 and NXNDC12 (<10%). Following P4HB reoxidation, passes its electrons to molecular oxygen via FAD, leading to the production of reactive oxygen species (ROS) in the cell. May be involved in oxidative proinsulin folding in pancreatic cells, hence may play a role in glucose homeostasis.
The Cys-90/Cys-95 and Cys-393/Cys-396 disulfide bonds constitute the redox-active center. The Cys-90/Cys-95 disulfide bond accepts electron from P4HB and funnel them to the active site disulfide Cys-393/Cys-396. The Cys-81/Cys-390 disulfide bond may be critical for structural stability. Two long-range disulfide bonds participate in loose feedback regulation. The Cys-90/Cys-130 disulfide bond may be the predominant regulatory switch to modulate the catalytic activity, while the Cys-100/Cys-262 disulfide bond may play an auxiliary regulatory role.
Up-regulated by inducers of the unfolded protein response (UPR).
Expressed in several hematopoietic cell lines examined.
Interacts with THBS4 (via the acidic amphipathic C-terminus).
RNA-binding protein that mediates pre-mRNA alternative splicing regulation. Plays a role in the regulation of cell proliferation, differentiation and migration. Positive regulator of EPO-dependent erythropoiesis. Participates in cell differentiation regulation by repressing tissue-specific exons. Promotes FAS exon 6 skipping. Binds RNA, preferentially to both poly(G) and poly(U).
Expressed in adrenal gland, ovary and thyroid gland and less abundantly in lymph node, prostate, spinal chord, testis and trachea.
Ubiquitous expression, differentially expressed in kidney and pancreas relatively to isoform 1.
Detected in embryos at 14.5 dpc, but not at 10.5 dpc and 19.5 dpc. Preferentially expressed in the neuroepithelia of the isthmus and septum of the embryonic brain at 14.5 dpc.
Plays an important role in the regulation of embryonic development and as signaling molecule in the induction and patterning of the embryonic brain. Required for normal brain development.
Preferentially expressed in the embryonic brain.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in FGF17 also have a mutation in another HH-associated gene including FGFR1, HS6ST1 and FLRT3 (PubMed:23643382).
Heterodimer with DRAP1. DR1 exists in solution as a homotetramer that dissociates during interaction with TBP and then, after complexing with TBP, reassociates at a slow rate, to reconstitute the tetramer. Interacts with NFIL3. Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1.
Phosphorylation regulates its interaction with TBP. Not phosphorylated when bound to DRAP1.
The association of the DR1/DRAP1 heterodimer with TBP results in a functional repression of both activated and basal transcription of class II genes. This interaction precludes the formation of a transcription-competent complex by inhibiting the association of TFIIA and/or TFIIB with TBP. Can bind to DNA on its own. Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4.
During endoplasmic reticulum (ER) stress or when cellular ceramide levels increase, may induce contacts between the ER and medial-Golgi complex to facilitate non-vesicular transport of ceramides from the ER to the Golgi complex where they are converted to complex sphingolipids, preventing toxic ceramide accumulation.
The SMP-LTD domain is a barrel-like domain that can bind various types of glycerophospholipids in its interior and mediate their transfer between two adjacent bilayers.
May be a negative regulator of NF-kappa-B and p53-mediated gene transcription.
Strongly expressed in heart, brain, placenta, lung, skeletal muscle, kidney, spleen, thymus, prostate, liver, pancreas, testis, ovary, small intestine, colon and peripheral blood leukocytes.
Detected at very low levels in testis, lung and brain.
May be a regulator of microtubule physiology.
Acts as a transcriptional repressor (PubMed:17974029). Has mitogenic activity for fibroblasts (PubMed:11751870, PubMed:26845719). Heparin-binding protein (PubMed:15491618).
Does not have mitogenic activity for fibroblasts (PubMed:26845719). Does not bind heparin (PubMed:26845719).
Has mitogenic activity for fibroblasts (PubMed:26845719). Heparin-binding protein (PubMed:26845719).
Interacts with cytoskeletal proteins such as actin, dynein, tubulin and vimentin (PubMed:26845719).
Interacts with cytoskeletal proteins such as dynein and tubulin but does not interact with actin or vimentin (PubMed:26845719).
Interacts with nuclear proteins NCL and YBX1/YB1 (PubMed:26845719).
Monomer, and domain-swapped homodimer (PubMed:17270212).
Phosphorylation at Ser-165 is likely to be required for secretion.
Sumoylated with SUMO1. Sumoylation prevents binding to chromatin.
The N-terminal region does not contain a typical signal sequence but is required for secretion (By similarity). It also determines exosomal location (PubMed:26845719).
The PWWP domain harbors the heparin-binding sites and is responsible for DNA-binding, while the C-terminal region is essentially unstructured.
A chromosomal aberration involving NCOA4 is found in papillary thyroid carcinomas (PTCs). Inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene.
Enhances the androgen receptor transcriptional activity in prostate cancer cells. Ligand-independent coactivator of the peroxisome proliferator-activated receptor (PPAR) gamma.
Interacts with the androgen receptor and the retinoid X receptor (RXR) in a ligand-dependent manner.
Widely expressed. Also detected in adipose tissues and in different cell lines. Isoform Beta is only expressed in testis.
Antiporter that mediates the transport of conjugated steroids and other specific organic anions at the basal membrane of syncytiotrophoblast and at the apical membrane of proximal tubule epithelial cells, in exchange for anionic compounds (PubMed:10660625, PubMed:11907186, PubMed:15291761, PubMed:15037815, PubMed:15102942, PubMed:15576633, PubMed:17229912, PubMed:18501590, PubMed:26277985, PubMed:28027879). May be responsible for placental absorption of fetal-derived steroid sulfates such as estrone sulfate (E1S) and the steroid hormone precursor dehydroepiandrosterone sulfate (DHEA-S), as well as clearing waste products and xenobiotics from the fetus (PubMed:12409283). Maybe also be involved in placental urate homeostasis (PubMed:17229912). Facilitates the renal reabsorption of organic anions such as urate and derived steroid sulfates (PubMed:15037815, PubMed:17229912). Organic anion glutarate acts as conteranion for E1S renal uptake (PubMed:15037815, PubMed:17229912). Possible transport mode may also include DHEA-S/E1S exchange (PubMed:28027879). Also interacts with inorganic anions such as chloride and hydroxyl ions, therefore possible transport modes may include E1S/Cl(-), E1S/OH(-), urate/Cl(-) and urate/OH(-) (PubMed:17229912). Also mediates the transport of prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may be involved in their renal excretion (PubMed:11907186). Also able to uptake anionic drugs, diuretics, bile salts and ochratoxin A (PubMed:10660625, PubMed:26277985). Mediates the unidirectional efflux of glutamate and aspartate (PubMed:28027879). Glutamate efflux down its transmembrane gradient may drive SLC22A11/OAT4-mediated placental uptake of E1S (PubMed:26277985).
Expressed in placental trophoblasts, syncytiotrophoblast and cytotrophoblast (PubMed:10660625, PubMed:12409283, PubMed:26277985). Also located in the proximal tubules in kidneys (PubMed:10660625, PubMed:15037815, PubMed:26277985).
N-glycosylated. Contains several complex-type N-glycans.
Was originally thought to be involved in both the uptake and efflux of glutarate, thereby acting as a bidirectional organic anion:dicarboxylate exchanger (PubMed:15037815). However, another study did not show any significant uptake of glutarate by SLC22A11/OAT4 (PubMed:17229912). Although initial results showed that SLC22A11/OAT4 drove DHEA-S and E1S uptake in a Na(+)-independent manner (PubMed:10660625), further studies demonstrated that both the uptake of DHEA-S and E1S by SLC22A11/OAT4 was partly Na(+)-dependent (about 50%) (PubMed:18501590, PubMed:10660625). The mechanism of SLC22A11/OAT4-mediated transport of E1S is unclear. Most studies have demonstrated a translocation of E1S through the plasma membrane into the cytosol, which would highlight a role of SLC22A11/OAT4 in placental and renal absorption (PubMed:10660625, PubMed:15037815, PubMed:17229912, PubMed:18501590, PubMed:26277985). Instead, SLC22A11/OAT4 was later proposed to mediate both the insertion into and the extraction from the plasma membrane of E1S without being translocated into the cytosol (PubMed:28027879).
Binds phospholipids via its C-terminal CRAL-TRIO domain. Binds primarily glycerophospholipids with monounsaturated C18:1 and/or C16:1 fatty acid moieties and a phosphatidylethanolamine or phosphatidylcholine headgroup. Has lesser affinity for lipids containing phosphatidylserine and phosphatidylinositol.
Detected in brain, peripheral nerve, lung, colon and muscle.
Interacts with HTR6 (PubMed:23027611). Interacts with SPRED2 (PubMed:34626534).
Stimulates the GTPase activity of Ras. NF1 shows greater affinity for Ras GAP, but lower specific activity. May be a regulator of Ras activity.
The stop codon (UGA) at position 1306 is created by RNA editing. Various levels of RNA editing occurs in peripheral nerve-sheath tumor samples (PNSTs) from patients with NF1. Preferentially observed in transcripts containing exon 23A.
Was originally thought to be associated with LEOPARD (LS), an autosomal dominant syndrome.
May be involved in the maintenance of mitochondrial organization and mitochondrial cristae structure.
The disease is caused by variants affecting the gene represented in this entry. The pathological events leading to disease involve fragmentation of the mitochondrial network, mitochondrial ultrastructural abnormalities including loss, disorganization and dilatation of cristae, and mitochondrial dysfunction associated with respiratory chain deficiency (PubMed:24934289).
Ubiquitously expressed. Higher expression is observed in heart and liver.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Catalyzes isomerization reactions that contribute to the biosynthesis of steroid hormones. Efficiently catalyze obligatory double-bond isomerizations of delta(5)-androstene-3,17-dione and delta(5)-pregnene-3,20-dione, precursors to testosterone and progesterone, respectively. Has substantial activity toward aflatoxin B1-8,9-epoxide (By similarity).
Sphingomyelin synthases synthesize sphingolipids through transfer of a phosphatidyl head group on to the primary hydroxyl of ceramide. SAMD8 is an endoplasmic reticulum (ER) transferase that has no sphingomyelin synthase activity but can convert phosphatidylethanolamine (PE) and ceramide to ceramide phosphoethanolamine (CPE) albeit with low product yield. Appears to operate as a ceramide sensor to control ceramide homeostasis in the endoplasmic reticulum rather than a converter of ceramides. Seems to be critical for the integrity of the early secretory pathway.
The SAM domain is required to retain SMAD8 in the endoplasmic reticulum.
Expressed at high levels in liver and kidney and lower levels in heart, intestine and skeletal muscle.
Serine hydrolase that catalyzes the hydrolytic activation of amino acid ester prodrugs of nucleoside analogs such as valacyclovir and valganciclovir. Activates valacyclovir to acyclovir. May play a role in detoxification processes. It is a specific alpha-amino acid ester hydrolase that prefers small, hydrophobic, and aromatic side chains and does not have a stringent requirement for the leaving group other than preferring a primary alcohol.
Highest levels found in skeletal muscle. Also found in pancreas and heart.
Interacts strongly with CDK6, weakly with CDK4. Inhibits cell growth and proliferation with a correlated dependence on endogenous retinoblastoma protein RB.
Can form homo- and heteropolymers with other CLDN.
Broadly expressed, with highest levels in heart and skeletal muscle, and lowest levels in liver, small intestine and thymus. Well expressed in retinal ganglion cells, epidermal skin cells, and leukocytes. Up-regulated together with N-myc in some neuroblastoma cell lines.
Component of the NRZ complex composed of NBAS, ZW10 and RINT1/TIP20L; NRZ associates with SNAREs STX18, USE1, BNIP1/SEC20L and SEC22B (the assembly has been described as syntaxin 18 complex); links NRZ to SNARE USE1 (PubMed:19369418).
Involved in Golgi-to-endoplasmic reticulum (ER) retrograde transport; the function is proposed to depend on its association in the NRZ complex which is believed to play a role in SNARE assembly at the ER (PubMed:19369418). Required for normal embryonic development (By similarity). May play a role in the nonsense-mediated decay pathway of mRNAs containing premature stop codons (By similarity).
NBAS mutations have been found in a multisystem disease affecting the liver, eye, immune system, connective tissue, and bone. Clinical manifestations include a progeroid appearance, short stature, slender bones, epiphyseal dysplasia with multiple phalangeal pseudo-epiphyses, cervical instability, myelopathy, elevated transaminases, hypogammaglobulinemia, reduced natural killer cells, Pelger-Huet anomaly of granulocytes, and in some cases retinal dystrophy and optic atrophy.
Amidase that may catalyze the last step of diphthamide biosynthesis using ammonium and ATP (PubMed:23169644). Diphthamide biosynthesis consists in the conversion of an L-histidine residue in the translation elongation factor (EEF2) to diphthamide (By similarity).
Belongs to the Diphthine--ammonia ligase family.
When transfected in S.cerevisiae, able to restore diphthamide biosynthesis in a strain lacking DPH6.
Genetic variations in PCSK1 define the body mass index quantitative trait locus 12 (BMIQ12) [MIM:612362]. Variance in body mass index is a susceptibility factor for obesity.
Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. Substrates include POMC, renin, enkephalin, dynorphin, somatostatin, insulin and AGRP.
Belongs to the purine/pyrimidine phosphoribosyltransferase family.
Binds 2 magnesium ions per subunit. The magnesium ions are essentially bound to the substrate and have few direct interactions with the protein.
Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway.
Adaptor protein complex 4 (AP-4) is a heterotetramer composed of two large adaptins (epsilon-type subunit AP4E1 and beta-type subunit AP4B1), a medium adaptin (mu-type subunit AP4M1) and a small adaptin (sigma-type AP4S1) (PubMed:10066790, PubMed:10436028). Interacts with TEPSIN; this interaction requires the presence of a functional AP-4 complex (PubMed:22472443, PubMed:26542808, PubMed:26756312). Interacts with GRIA2; probably indirect it mediates the somatodendritic localization of GRIA2 in neurons (By similarity).
Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling (By similarity).
At least 6 alleles of SFTPA2 are known: 1A, 1A(0), 1A(1), 1A(2), 1A(3) and 1A(4). The sequence shown is that of allele 1A(2).
In presence of calcium ions, it binds to surfactant phospholipids and contributes to lower the surface tension at the air-liquid interface in the alveoli of the mammalian lung and is essential for normal respiration.
Inhibited by aprotinin, leupeptin, benzamidine, SERPINA1, SPINT1 and SPINT2.
Interacts with LDB1 (via the LIM zinc-binding domains).
Probable transcription factor required for the expression of a subset of genes involved in interneurons migration and development. Functions in the specification of cortical interneuron subtypes and in the migration of GABAergic interneuron precursors from the subpallium to the cerebral cortex (By similarity).
A chromosomal aberration involving TRIM33 is found in papillary thyroid carcinomas (PTCs). Translocation t(1;10)(p13;q11) with RET. The translocation generates the TRIM33/RET (PTC7) oncogene.
Acts as an E3 ubiquitin-protein ligase. Promotes SMAD4 ubiquitination, nuclear exclusion and degradation via the ubiquitin proteasome pathway. According to PubMed:16751102, does not promote a decrease in the level of endogenous SMAD4. May act as a transcriptional repressor. Inhibits the transcriptional response to TGF-beta/BMP signaling cascade. Plays a role in the control of cell proliferation. Its association with SMAD2 and SMAD3 stimulates erythroid differentiation of hematopoietic stem/progenitor (By similarity). Monoubiquitinates SMAD4 and acts as an inhibitor of SMAD4-dependent TGF-beta/BMP signaling cascade (Monoubiquitination of SMAD4 hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade).
Expressed in stem cells at the bottom of the crypts of the colon (at protein level). Expressed in colon adenomas and adenocarcinomas (at protein level). Expressed in brain, lung, liver, spleen, thymus, prostate, kidney, testis, heart, placenta, pancreas, small intestine, ovary, colon, skeletal muscle and hematopoietic progenitors.
Homooligomer and heterooligomer with TRIM24 and TRIM28 family members. Interacts with SMAD4 in unstimulated cells. Found in a complex with SMAD2 and SMAD3 upon addition of TGF-beta. Interacts with SMAD2 and SMAD3. Interacts with SMAD4 under basal and induced conditions and, upon TGF-beta signaling, with activated SMAD2. Forms a ternary complex with SMAD4 and SMAD2 upon TGF-beta signaling.
Contaminating sequence. Cloning artifact and potential poly-A sequence.
Ribosome profiling data indicate that translation initiates from the non-AUG (CUG) codon used here.
CGRP induces vasodilation. It dilates a variety of vessels including the coronary, cerebral and systemic vasculature. Its abundance in the CNS also points toward a neurotransmitter or neuromodulator role. It also elevates platelet cAMP.
Calcitonin causes a rapid but short-lived drop in the level of calcium and phosphate in blood by promoting the incorporation of those ions in the bones.
Katacalcin is a potent plasma calcium-lowering peptide.
Interacts with BCL9 via The PHD-type zinc finger motiv, and thereby becomes part of the nuclear beta-catenin/TCF complex. Identified in a complex with BCL9L, CDC73, CTNNB1 and PYGO1. Interacts with histone H3 mono-, di- or tri-methylated at 'Lys4' (H3K4me1, H3K4me2, H3K4me3); the interaction is enhanced by the interaction with BCL9.
Represents an unconventional myosin. This protein should not be confused with the conventional myosin-15 (MYH15).
Unknown, due to the absence of a functional motor domain.
Was thought be the product of a pseudogene due to the substitution or deletion of many conserved amino acids in the motor domain. However it has been observed with several high-quality proteotypic peptides in several independent proteomic studies.
Homodimer; probably only forms homodimers in testis (By similarity). Heterodimer; heterodimerizes with RFX1 and RFX3 (PubMed:10330134).
Transcription factor that acts as a key regulator of spermatogenesis. Acts by regulating expression of genes required for the haploid phase during spermiogenesis, such as genes required for cilium assembly and function (By similarity). Recognizes and binds the X-box, a regulatory motif with DNA sequence 5'-GTNRCC(0-3N)RGYAAC-3' present on promoters (PubMed:10330134). Probably activates transcription of the testis-specific histone gene H1-6 (By similarity).
Catalyzes specifically the phosphorylation of ceramide to form ceramide 1-phosphate (PubMed:11956206, PubMed:16269826, PubMed:19168031). Acts efficiently on natural and analog ceramides (C6, C8, C16 ceramides, and C8-dihydroceramide), to a lesser extent on C2-ceramide and C6-dihydroceramide, but not on other lipids, such as various sphingosines (PubMed:11956206, PubMed:16269826, PubMed:19168031). Shows a greater preference for D-erythro isomer of ceramides (PubMed:16269826). Binds phosphoinositides (PubMed:19168031).
High level expression in heart, brain, skeletal muscle, kidney and liver; moderate in peripheral blood leukocytes and thymus; very low in spleen, small intestine, placenta and lung.
Inhibited by sulfatide (PubMed:19168031). Inhibited by sphinganine, sphingenine, and N,N-Dimethylsphingosine (DMS) (PubMed:16269826). Cardiolipin at 0.1 uM significantly increases activity, whereas at concentrations >1 uM has an inhibitory effect (PubMed:27725450).
(Microbial infection) Interacts with Epstein-Barr virus EBNA3 proteins.
(Microbial infection) Interacts with hepatitis C virus (HCV) F protein.
Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2.
Down-regulated by antioxidants BO-653 and probucol. Up-regulated by bacterial lipopolysaccharides (LPS) and TNF.
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:26657688, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:26657688, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:26657688, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:26657688, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). Interacts with AURKB (PubMed:14674694). Interacts with CDKN1A (PubMed:11350925). Interacts with MDM2 and RB1 (PubMed:16337594). Interacts with the C-terminus of TBXA2R isoform 2 (PubMed:17499743). Interacts with DNAJB2 (PubMed:15936278).
Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR2 subfamily.
Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2808 and Ser-2814 increases the open probability of the calcium channel. Phosphorylation is increased in failing heart, leading to calcium leaks and increased cytoplasmic Ca(2+) levels.
Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering cardiac muscle contraction. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) cytosolic levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development.
Detected in heart muscle (at protein level). Heart muscle, brain (cerebellum and hippocampus) and placenta.
Expressed in myometrium during pregnancy.
Homotetramer. Can also form heterotetramers with RYR1 and RYR3 (By similarity). Interacts with FKBP1A and FKBP1B; these interactions may stabilize the channel in its closed state and prevent Ca(2+) leaks. Interacts with CALM and S100A1; these interactions regulate channel activity. Identified in a complex composed of RYR2, FKBP1B, PKA catalytic subunit, PRKAR2A, AKAP6, and the protein phosphatases PP2A and PP1. Interacts directly with FKBP1B, PKA, PP1 and PP2A. Interacts with SELENON (By similarity). In cardiac muscles, identified in a complex, composed of FSD2, CMYA5 and RYR2 (By similarity).
Phosphorylation at Ser-2031 by PKA enhances the response to lumenal calcium.
The calcium release channel activity resides in the C-terminal region while the remaining part of the protein resides in the cytoplasm.
The calcium release is activated by increased cytosolic calcium levels, by nitric oxyde (NO), caffeine and ATP. Channel activity is modulated by the alkaloid ryanodine that binds to the open Ca-release channel with high affinity. At low concentrations, ryanodine maintains the channel in an open conformation. High ryanodine concentrations inhibit channel activity. Channel activity is regulated by calmodulin (CALM). Channel activity is inhibited by magnesium ions, possibly by competition for calcium binding sites.
Cytokine that induces the release of T-cell-attracting chemokines from monocytes and, in particular, enhances the maturation of CD11c(+) dendritic cells. Can induce allergic inflammation by directly activating mast cells.
Interacts with a receptor composed of CRLF2 and IL7R. Binding of TSLP to CRLF2/TSLPR is a mechanistic prerequisite for recruitment of IL7R to the high-affinity ternary complex.
Isoform 1 is expressed in a number of tissues including heart, liver and prostate. Isoform 2 is the predominant form in keratinocytes of oral mucosa, skin and in salivary glands. It is secreted into saliva.
May act as an antimicrobial peptide in the oral cavity and on the skin.
Released by primary epithelial cells in response to certain microbial products, physical injury, or inflammatory cytokines.
Homodimers and homomultimers. Found in a complex with RIP60 and RIP100.
Sequence-specific double-stranded DNA-binding protein required for initiation of chromosomal DNA replication. Binds on 5'-ATT-3' reiterated sequences downstream of the origin of bidirectional replication (OBR) and a second, homologous ATT sequence of opposite orientation situated within the OBR zone. Facilitates DNA bending.
As a component of the GATOR2 complex, functions as an activator of the amino acid-sensing branch of the mTORC1 signaling pathway (PubMed:25457612, PubMed:23723238, PubMed:27487210, PubMed:36528027, PubMed:36577058, PubMed:35831510). The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex (PubMed:23723238, PubMed:27487210, PubMed:36528027, PubMed:35831510). GATOR2 probably acts as a E3 ubiquitin-protein ligase toward GATOR1 (PubMed:36528027). In the presence of abundant amino acids, the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027). In the absence of amino acids, GATOR2 is inhibited, activating the GATOR1 complex (PubMed:25457612, PubMed:27487210).
Component of the GATOR2 subcomplex, composed of MIOS, SEC13, SEH1L, WDR24 and WDR59 (PubMed:23723238, PubMed:36528027, PubMed:35831510). The GATOR2 complex interacts with CASTOR1 and CASTOR2; the interaction is negatively regulated by arginine (PubMed:26972053). The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612). Interacts with DDB1-CUL4A/B E3 ligase complexes (By similarity).
The E3 ubiquitin-protein ligase activity of the GATOR2 complex is subject to discussion (PubMed:35831510, PubMed:36528027). According to a report, the GATOR2 complex does not catalyze ubiquitination of the GATOR1 complex (PubMed:35831510). In contrast, another publication showed that the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027).
The GATOR2 complex is negatively regulated by the upstream amino acid sensors CASTOR1 and SESN2, which sequester the GATOR2 complex in absence of amino acids (PubMed:26972053, PubMed:25457612, PubMed:27487210). In the presence of abundant amino acids, GATOR2 is released from CASTOR1 and SESN2 and activated (PubMed:26972053, PubMed:25457612, PubMed:27487210).
(Microbial infection) In case of infection by polyomavirus, involved in the virus endoplasmic reticulum membrane penetration and infection via interaction with DNAJB12, DNAJB14 and HSPA8/Hsc70 (PubMed:24675744).
(Microbial infection) Interacts with SARS-CoV accessory protein 7a.
(Microbial infection) Interacts with Vpu and Gag from HIV-1.
Co-chaperone that binds misfolded and hydrophobic patches-containing client proteins in the cytosol. Mediates their targeting to the endoplasmic reticulum but also regulates their sorting to the proteasome when targeting fails (PubMed:28104892). Functions in tail-anchored/type II transmembrane proteins membrane insertion constituting with ASNA1 and the BAG6 complex a targeting module (PubMed:28104892). Functions upstream of the BAG6 complex and ASNA1, binding more rapidly the transmembrane domain of newly synthesized proteins (PubMed:28104892, PubMed:25535373). It is also involved in the regulation of the endoplasmic reticulum-associated misfolded protein catabolic process via its interaction with BAG6: collaborates with the BAG6 complex to maintain hydrophobic substrates in non-ubiquitinated states (PubMed:23129660, PubMed:25179605). Competes with RNF126 for interaction with BAG6, preventing the ubiquitination of client proteins associated with the BAG6 complex (PubMed:27193484). Binds directly to HSC70 and HSP70 and regulates their ATPase activity (PubMed:18759457).
Homodimer (PubMed:15708368). Homooligomer (By similarity). Interacts with DNAJC5 and DNAJC5B. Interacts (via TPR repeats) with HSP90AA1 (PubMed:15708368). Interacts (via Gln-rich region) with SLC2A1 (PubMed:15708368). Interacts with HSP90AB1 (PubMed:16580629). Interacts (via TPR repeats) with HSPA8/Hsc70; the interaction is direct (PubMed:24675744). Interacts with BAG6 (via ubiquitin-like domain); interaction prevents interaction between BAG6 and RNF126 (PubMed:23129660, PubMed:25179605, PubMed:27193484). Forms a multiprotein complex, at least composed of DNAJB12, DNAJB14, HSPA8/Hsc70 and SGTA; interaction with DNAJB14 and HSPA8/Hsc70 is direct (PubMed:24675744).
The second tetratricopeptide repeat (TPR 2) mediates the interaction with SARS-CoV accessory protein 7a.
Essential component of the ubiquitin-dependent proteolytic pathway which degrades ubiquitin fusion proteins. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. It may be involved in the development of some ectoderm-derived structures (By similarity). Acts as a negative regulator of type I interferon production via the complex formed with VCP and NPLOC4, which binds to RIGI and recruits RNF125 to promote ubiquitination and degradation of RIGI (PubMed:26471729).
Found in adult heart, skeletal muscle and pancreas, and in fetal liver and kidney.
Heterodimer with NPLOC4, this heterodimer binds VCP and inhibits Golgi membrane fusion (PubMed:11574150, PubMed:26471729). Interacts with USP13 (PubMed:21571647). Interacts with ZFAND2B; probably through VCP (PubMed:24160817).
A chromosomal aberration involving CNTNAP2 is found in a patient with autism spectrum disorder. Paracentric inversion 46,XY,inv(7)(q11.22;q35). The inversion breakpoints disrupt the genes AUTS2 and CNTNAP2.
Predominantly expressed in nervous system.
Required for gap junction formation (Probable). Required, with CNTNAP1, for radial and longitudinal organization of myelinated axons. Plays a role in the formation of functional distinct domains critical for saltatory conduction of nerve impulses in myelinated nerve fibers. Demarcates the juxtaparanodal region of the axo-glial junction.
ATR-dependent phosphorylation of XPA at Ser-196 is important for cell survival in response to UV damage.
Expressed in various cell lines and in skin fibroblasts.
Interacts with GPN1. Interacts with RPA1 and RPA2; the interaction is direct and associates XPA with the RPA complex. Interacts (via N-terminus) with CEP164 upon UV irradiation. Interacts with HERC2.
Involved in DNA excision repair. Initiates repair by binding to damaged sites with various affinities, depending on the photoproduct and the transcriptional state of the region. Required for UV-induced CHEK1 phosphorylation and the recruitment of CEP164 to cyclobutane pyrimidine dimmers (CPD), sites of DNA damage after UV irradiation.
Ubiquitinated by HERC2 leading to degradation by the proteasome.
A chromosomal aberration involving MACROD1 is found in acute leukemia. Translocation t(11;21)(q13;q22) that forms a RUNX1-MACROD1 fusion protein.
Interacts with ESR1; Interacts in a manner that is estrogen independent but is enhanced by estrogen. Interacts (via macro domain) with AR.
Overexpressed by estrogens in breast cancer MCF-7 cells, probably via an activation of nuclear receptors for steroids (ESR1 but not ESR2). Significantly increased by estrogens in ESR1-positive Ishikawa endometrial cancer cells. Up-regulated in 17-beta-estradiol-responsive BG-1 ovarian cancer cells but down-regulated in estrogen-resistant SKOV3 ovarian cancer cells. Induced by androgen.
Overexpression may promote MCF-7 cells proliferation. There is an approximate one-third increase of the invasive capacity of MACROD1-overexpressing cells. The expression of CDH1 is repressed by MACROD1. Further analysis demonstrates that MACROD1 inhibits CDH1 transactivation in a dose-dependent manner. Inhibition is abolished by estrogen deprivation, indicating that the down-regulation of CDH1 transcription by MACROD1 requires ESR1 mediation. Binding of ESR1 to the CDH1 promoter is antagonized by MACROD1, suggesting that MACROD1 could interfere with ESR1-mediated transcription. Knockdown of MACROD1 leads to impaired AR function and greatly attenuates the coactivation of AR by other AR coactivators such as UXT and NCOA1. This interference also markedly inhibits the androgen-stimulated proliferation of androgen-sensitive LNCaP prostate cancer cells. MACROD1 knockdown does not significantly affect the growth rate of AR-negative PC-3 prostate cancer cells.
Removes ADP-ribose from aspartate and glutamate residues in proteins bearing a single ADP-ribose moiety (PubMed:23474714, PubMed:23474712). Inactive towards proteins bearing poly-ADP-ribose (PubMed:23474714, PubMed:23474712). Deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins (PubMed:21257746). Plays a role in estrogen signaling (PubMed:17893710, PubMed:17914104, PubMed:19403568). Binds to androgen receptor (AR) and amplifies the transactivation function of AR in response to androgen (PubMed:19022849). May play an important role in carcinogenesis and/or progression of hormone-dependent cancers by feed-forward mechanism that activates ESR1 transactivation (PubMed:17893710, PubMed:17914104). Could be an ESR1 coactivator, providing a positive feedback regulatory loop for ESR1 signal transduction (PubMed:17914104). Could be involved in invasive growth by down-regulating CDH1 in endometrial cancer cells (PubMed:17893710). Enhances ESR1-mediated transcription activity (PubMed:17914104).
Belongs to the cyclin family. Cyclin J subfamily.
Belongs to the cyclic nucleotide phosphodiesterase family. PDE2 subfamily.
Contains a transit peptide at positions 1-17.
Regulates mitochondrial cAMP levels and respiration (By similarity). Involved in the regulation of mitochondria morphology/dynamics and apoptotic cell death via local modulation of cAMP/PKA signaling in the mitochondrion, including the monitoring of local cAMP levels at the outer mitochondrial membrane and of PKA-dependent phosphorylation of DNM1L (PubMed:28463107).
The 3',5'-cyclic-AMP phosphodiesterase activity is stimulated by 3',5'-cyclic GMP.
The GAF 1 domain functions as a dimerization domain.
The GAF 2 domains binds cGMP, which acts as an allosteric activator.
Widely expressed (PubMed:9210593, PubMed:29392776). Expressed in brain, with high expression observed in the corpus striatum (PubMed:29392776). Also expressed in heart, placenta, lung, skeletal muscle, kidney and pancreas (PubMed:9210593, PubMed:29392776).
cGMP-activated cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes (PubMed:9210593, PubMed:29392776, PubMed:15938621). Has a higher efficiency with cGMP compared to cAMP (PubMed:15938621). Plays a role in cell growth and migration (PubMed:24705027).
Broadly expressed in: skin, heart, lung, and the reproductive tracts.
Laminin is a complex glycoprotein, consisting of three different polypeptide chains (alpha, beta, gamma), which are bound to each other by disulfide bonds into a cross-shaped molecule comprising one long and three short arms with globules at each end. Gamma-3 is a subunit of laminin-12 (laminin-213), laminin-14 (laminin-423) and laminin-15 (laminin-523).
Deubiquitinating enzyme (DUB) that controls levels of cellular ubiquitin through processing of ubiquitin precursors and ubiquitinated proteins. Thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of either ubiquitin or NEDD8. Has a 10-fold preference for Arg and Lys at position P3'', and exhibits a preference towards 'Lys-48'-linked ubiquitin chains. Deubiquitinates ENAC in apical compartments, thereby regulating apical membrane recycling. Indirectly increases the phosphorylation of IGFIR, AKT and FOXO1 and promotes insulin-signaling and insulin-induced adipogenesis. Required for stress-response retinal, skeletal muscle and germ cell maintenance. May be involved in working memory. Can hydrolyze UBB(+1), a mutated form of ubiquitin which is not effectively degraded by the proteasome and is associated with neurogenerative disorders.
Highly expressed in heart, skeletal muscle, and testis.
Identified as a tumor-specific antigen in colon cancer.
Inhibited by monoubiquitin and diubiquitin.
Preferentially binds diubiquitin; the interaction does not hydrolyze diubiquitin but, in vitro, inhibits the hydrolyzing activity on other substrates.
Highly expressed in spleen (at protein level) (PubMed:8836175, PubMed:25075772). Has little or no expression in healthy kidneys (at protein level) (PubMed:25075772). Detected in interstitial leukocytes in infected kidneys (at protein level) (PubMed:25075772). Expressed in ureter where it localizes to urothelial and submucosal leukocytes (at protein level) (PubMed:25075772). Strong expression in lung and thymus, and lower expression in heart, placenta, pancreas, liver, brain and skeletal muscle (PubMed:8836175, PubMed:25075772). Also expressed in monocytes and neutrophils (PubMed:8836175).
Interacts (via N-terminus) with bacterial lipopolysaccharide (LPS).
Ribonuclease which shows a preference for the pyrimidines uridine and cytosine (PubMed:8836175, PubMed:27013146). Has potent antibacterial activity against a range of Gram-positive and Gram-negative bacteria, including P.aeruginosa, A.baumanii, M.luteus, S.aureus, E.faecalis, E.faecium, S.saprophyticus and E.coli (PubMed:25075772, PubMed:27089320). Causes loss of bacterial membrane integrity, and also promotes agglutination of Gram-negative bacteria (PubMed:27089320). Probably contributes to urinary tract sterility (PubMed:25075772). Bactericidal activity is independent of RNase activity (PubMed:27089320).
Up-regulated in CD14+ monocytes in response to the uropathogenic E.coli strain CFT073.
Can also utilize other divalent cations, such as Mn(2+) and Co(2+) (in vitro).
Interacts with PRP19 and DNTTIP1. Forms a ternary complex with DNTTIP2 and core histone. Released from this complex by PCNA. Interacts with TRERF1 (PubMed:16371131).
Template-independent DNA polymerase which catalyzes the random addition of deoxynucleoside 5'-triphosphate to the 3'-end of a DNA initiator. One of the in vivo functions of this enzyme is the addition of nucleotides at the junction (N region) of rearranged Ig heavy chain and T-cell receptor gene segments during the maturation of B- and T-cells.
Component of the elastin-associated microfibrils.
Heterohexamer; possibly composed of 3 copies of TIMM8B and 3 copies of TIMM13, named soluble 70 kDa complex. Associates with the TIM22 complex, whose core is composed of TIMM22 (By similarity).
Probable mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane. Also required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. Acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space (By similarity).
The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space. However, during the transit of TIMM8B from cytoplasm into mitochondrion, the Cys residues probably coordinate zinc, thereby preventing folding and allowing its transfer across mitochondrial outer membrane (By similarity).
Cytokine that promotes the proliferation, survival and differentiation of monocytes and macrophages. Promotes the release of pro-inflammatory chemokines, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, and in the regulation of bone resorption. Signaling via CSF1R and its downstream effectors stimulates phosphorylation of MAPK1/ERK2 AND MAPK3/ERK1.
Detected in the sinusoidal epithelium in the red pulp of spleen (at protein level). Predominantly expressed in spleen. Also detected in a range of other tissues including heart, brain, lung, liver, kidney, thymus, testis, ovary, small intestine, prostate and colon.
Probable palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates.
Belongs to the cytochrome c oxidase subunit 6A family.
Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (By similarity). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (By similarity).
Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules unsing 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix. Plays a role in the assembly and stabilization of complex IV (PubMed:31155743).
Expressed specifically in heart and muscle (PubMed:31155743). Not detected in brain, colon, spleen, kidney, liver, lung and pancreas (PubMed:31155743).
Belongs to the Mediator complex subunit 14 family.
Interacts with GATA1 (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with AR, ESR1, SREBF1 and STAT2.
A chromosomal aberration disrupting SRGAP2 has been found in a patient with early infantile epileptic encephalopathy. Balanced translocation t(1;9)(q32;q13) (PubMed:22106086).
Activity is strongly inhibited by SRGAP2C, which heterodimerize with SRGAP2/SRGAP2A, thereby reducing SRGAP2/SRGAP2A levels through proteasome-dependent degradation.
Homodimer (PubMed:20810653, PubMed:26365803, PubMed:28333212). Heterodimer; forms a heterodimer with SRGAP2C, altering SRGAP2 function (PubMed:22559944, PubMed:27373832, PubMed:28333212). Forms a heterooligomer with SRGAP1 and SRGAP3 through its F-BAR domain (PubMed:22467852). Interacts (via SH3 domain) with GPHN (By similarity). Interacts (via SH3 domain) with FMNL1 (activated by RAC1); regulates the actin filament severing activity of FMNL1 and actin dynamics (PubMed:21148482). Interacts (via SH3 domain) with FMNL3 (PubMed:21148482). Interacts with RAC1; specifically stimulates RAC1 GTPase activity (PubMed:21148482). Interacts (via F-BAR domain) with HOMER1 (By similarity). Interacts with ROBO1 and ROBO2 (PubMed:11672528, PubMed:21148482, PubMed:26365803). Interacts with FASLG (PubMed:19807924). Interacts with PRMT5 (PubMed:20810653).
Methylation at Arg-927 is required for the stimulation of cell migration, dimerization and localization at the plasma membrane protrusions.
Postsynaptic RAC1 GTPase activating protein (GAP) that plays a key role in neuronal morphogenesis and migration mainly during development of the cerebral cortex (PubMed:20810653, PubMed:27373832, PubMed:28333212). Regulates excitatory and inhibitory synapse maturation and density in cortical pyramidal neurons (PubMed:22559944, PubMed:27373832). SRGAP2/SRGAP2A limits excitatory and inhibitory synapse density through its RAC1-specific GTPase activating activity, while it promotes maturation of both excitatory and inhibitory synapses through its ability to bind to the postsynaptic scaffolding protein HOMER1 at excitatory synapses, and the postsynaptic protein GPHN at inhibitory synapses (By similarity). Mechanistically, acts by binding and deforming membranes, thereby regulating actin dynamics to regulate cell migration and differentiation (PubMed:27373832). Promotes cell repulsion and contact inhibition of locomotion: localizes to protrusions with curved edges and controls the duration of RAC1 activity in contact protrusions (By similarity). In non-neuronal cells, may also play a role in cell migration by regulating the formation of lamellipodia and filopodia (PubMed:20810653, PubMed:21148482).
There are 3 duplications of SRGAP2 in the human genome as a result of segmental gene duplications. SRGAP2C is the only one to be fixed at a diploid state in the human genome. Moreover, SRGAP2C is functional, interacts with and inhibits SRGAP2 and is human-specific. The appearance of SRGAP2C in the human genome is estimated to 2,4 million years ago, which corresponds to the beginning of neocortex expansion in human evolution and it may have played an important role in this process through its interaction with SRGAP2 function.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. SelB subfamily.
Translation factor necessary for the incorporation of selenocysteine into proteins. It probably replaces EF-Tu for the insertion of selenocysteine directed by the UGA codon. SelB binds GTP and GDP.
Serine protease inhibitor selective for kallikreins. Efficiently inhibits KLK4, KLK5, KLK6, KLK7, KLK12, KLK13 and KLK14. Doesn't inhibit KLK8.
Belongs to the transaldolase family. Type 1 subfamily.
Catalyzes the rate-limiting step of the non-oxidative phase in the pentose phosphate pathway. Catalyzes the reversible conversion of sedheptulose-7-phosphate and D-glyceraldehyde 3-phosphate into erythrose-4-phosphate and beta-D-fructose 6-phosphate (PubMed:8955144, PubMed:18687684). Not only acts as a pentose phosphate pathway enzyme, but also affects other metabolite pathways by altering its subcellular localization between the nucleus and the cytoplasm (By similarity).
Catalyzes the rate-limiting step of the non-oxidative phase in the pentose phosphate pathway. Catalyzes the reversible conversion of sedheptulose-7-phosphate and D-glyceraldehyde 3-phosphate into erythrose-4-phosphate and beta-D-fructose 6-phosphate.
Homodimer (PubMed:10869557). Heterodimer with isoform 2 (By similarity). Interacts with KPNA1 and KPNA4 (By similarity).
The first 10 amino acids are essential for nuclear localization.
(Microbial infection) Interacts with herpes simplex virus 1/HHV-1 protein ICP0; this interaction mediates MORC3 degradation, which leads to de-repression of a MORC3-regulated DNA element (MRE) adjacent to the IFNB1 locus.
(Microbial infection) Interacts with influenza A virus PA and PB1 polymerase subunits during infection (PubMed:26202233). Interacts (via CW domain) with influenza A protein NS1 (PubMed:31006586).
(Microbial infection) May be required for influenza A transcription during viral infection (PubMed:26202233).
Dimerization of the ATPase domain is strictly required for the catalytic activity and binding to double-stranded DNA. Disrupting the interface between ATPase and the CW domains releases autoinhibition since the CW domain sterically impedes binding of the ATPase domain to DNA.
Expressed in heart, placenta, skeletal muscle, brain, pancreas, lung, liver, but not kidney.
Homodimer (PubMed:17332504, PubMed:30850548). The sumoylated form interacts with PML (via SUMO-interacting motif) (PubMed:20501696, PubMed:17332504). Interacts with TP53 (PubMed:17332504).
Nuclear matrix protein which forms MORC3-NBs (nuclear bodies) via an ATP-dependent mechanism and plays a role in innate immunity by restricting different viruses through modulation of the IFN response (PubMed:27440897, PubMed:34759314). Mechanistically, possesses a primary antiviral function through a MORC3-regulated element that activates IFNB1, and this function is guarded by a secondary IFN-repressing function (PubMed:34759314). Sumoylated MORC3-NBs associates with PML-NBs and recruits TP53 and SP100, thus regulating TP53 activity (PubMed:17332504, PubMed:20501696). Binds RNA in vitro (PubMed:11927593). Histone methylation reader which binds to non-methylated (H3K4me0), monomethylated (H3K4me1), dimethylated (H3K4me2) and trimethylated (H3K4me3) 'Lys-4' on histone H3 (PubMed:26933034). The order of binding preference is H3K4me3 > H3K4me2 > H3K4me1 > H3K4me0 (PubMed:26933034).
Sumoylation is involved in interaction with PML and localization to PML nuclear bodies.
Belongs to the bacterial ribosomal protein bS6 family.
Component of nuclear RNase P and RNase MRP ribonucleoproteins (PubMed:12003489, PubMed:15096576, PubMed:16723659, PubMed:20215441, PubMed:28115465, PubMed:30454648). RNase P consists of a catalytic RNA moiety and 10 different protein chains; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40 (PubMed:12003489, PubMed:16723659, PubMed:20215441, PubMed:30454648). Within the RNase P complex, POP1, POP7 and RPP25 form the 'finger' subcomplex, POP5, RPP14, RPP40 and homodimeric RPP30 form the 'palm' subcomplex, and RPP21, POP4 and RPP38 form the 'wrist' subcomplex. All subunits of the RNase P complex interact with the catalytic RNA (PubMed:30454648). Several subunits of RNase P are also part of the RNase MRP complex. RNase MRP consists of a catalytic RNA moiety and about 8 protein subunits; POP1, POP7, RPP25, RPP30, RPP38, RPP40 and possibly also POP4 and POP5 (PubMed:15096576, PubMed:16723659, PubMed:28115465). POP7 forms a heterodimer with RPP25 that binds to the P3 stem loop of the catalytic RNA (PubMed:20215441, PubMed:29625199).
Component of ribonuclease P, a ribonucleoprotein complex that generates mature tRNA molecules by cleaving their 5'-ends (PubMed:12003489, PubMed:16723659, PubMed:30454648). Also a component of the MRP ribonuclease complex, which cleaves pre-rRNA sequences (PubMed:28115465).
According to PubMed:11956595, ubiquitously expressed. According to PubMed:12011995, expressed specifically in testis and ovary.
Heterodimer with VANGL2. Interacts through its C-terminal region with the N-terminal half of DVL1, DVL2 and DVL3. The PDZ domain of DVL1, DVL2 and DVL3 is required for the interaction (By similarity).
Expressed in breast cancer tissues. Little or no expression observed in normal breast tissues. Expressed in skin; wide expression is observed throughout the dermis with minimal expression in the epidermis.
Interacts (via C-terminus) with HSPG2 (via C-terminus). Interacts with EFEMP1/FBLN3 and LAMB3. Interacts with MMP9.
Involved in endochondral bone formation as negative regulator of bone mineralization. Stimulates the proliferation of endothelial cells and promotes angiogenesis. Inhibits MMP9 proteolytic activity.
(Microbial infection) Interacts (via SH2 domain) with HCV non-structural protein 5A (via N-terminus).
(Microbial infection) Interacts with HEV ORF3 protein; via the SH3 domain.
Dephosphorylated at Tyr-530 by PTPRJ (By similarity). Phosphorylated on Tyr-530 by c-Src kinase (CSK). The phosphorylated form is termed pp60c-src. Dephosphorylated by PTPRJ at Tyr-419. Normally maintained in an inactive conformation with the SH2 domain engaged with Tyr-530, the SH3 domain engaged with the SH2-kinase linker, and Tyr-419 dephosphorylated. Dephosphorylation of Tyr-530 as a result of protein tyrosine phosphatase (PTP) action disrupts the intramolecular interaction between the SH2 domain and Tyr-530, Tyr-419 can then become autophosphorylated, resulting in SRC activation. Phosphorylation of Tyr-530 by CSK allows this interaction to reform, resulting in SRC inactivation. CDK5-mediated phosphorylation at Ser-75 targets SRC to ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. Phosphorylated by PTK2/FAK1; this enhances kinase activity. Phosphorylated by PTK2B/PYK2; this enhances kinase activity. Upon activation of IL6ST by IL6, Tyr-419 is phosphorylated and Tyr-530 dephosphorylated (PubMed:25731159).
Displays enhanced levels of autophosphorylation at Tyr-419 compared to isoform 1 (By similarity). Shows reduced phosphorylation at Tyr-527 compared to isoforms 1 and 2 (By similarity).
Displays enhanced levels of autophosphorylation at Tyr-419 compared to isoform 1.
Displays reduced levels of autophosphorylation at Tyr-419 compared to isoforms 2 and 3.
Expressed at higher levels in fetal brain than in adult brain.
Expressed at higher levels in fetal liver than in adult liver.
Expressed at similar levels in adult and fetal brain.
Expressed ubiquitously. Platelets, neurons and osteoclasts express 5-fold to 200-fold higher levels than most other tissues.
Myristoylated at Gly-2, and this is essential for targeting to membranes.
Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN) (Probable). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN) (PubMed:21411625). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin-43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1 (Probable). Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors (By similarity). Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1 (PubMed:11389730). Plays a role in EGF-mediated calcium-activated chloride channel activation (PubMed:18586953). Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr-1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of GRK2, leading to beta-arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor (Probable). Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus (PubMed:7853507). Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function (PubMed:8755529, PubMed:14585963). Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (PubMed:12615910). Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation (PubMed:16186108). Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731' (PubMed:20100835, PubMed:21309750). Enhances RIGI-elicited antiviral signaling (PubMed:19419966). Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376' (PubMed:14585963). Phosphorylates BCAR1 at 'Tyr-128' (PubMed:22710723). Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity (PubMed:20525694). Phosphorylates synaptic vesicle protein synaptophysin (SYP) (By similarity). Involved in anchorage-independent cell growth (PubMed:19307596). Required for podosome formation (By similarity). Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration (PubMed:25731159). Phosphorylates OTUB1, promoting deubiquitination of RPTOR (PubMed:35927303).
Non-receptor protein tyrosine kinase which phosphorylates synaptophysin with high affinity.
Non-receptor protein tyrosine kinase which shows higher basal kinase activity than isoform 1, possibly due to weakened intramolecular interactions which enhance autophosphorylation of Tyr-419 and subsequent activation (By similarity). The SH3 domain shows reduced affinity with the linker sequence between the SH2 and kinase domains which may account for the increased basal activity (By similarity). Displays altered substrate specificity compared to isoform 1, showing weak affinity for synaptophysin and for peptide substrates containing class I or class II SH3 domain-binding motifs (By similarity). Plays a role in L1CAM-mediated neurite elongation, possibly by acting downstream of L1CAM to drive cytoskeletal rearrangements involved in neurite outgrowth (By similarity).
Non-receptor protein tyrosine kinase which shows higher basal kinase activity than isoform 1, possibly due to weakened intramolecular interactions which enhance autophosphorylation of Tyr-419 and subsequent activation (By similarity). The SH3 domain shows reduced affinity with the linker sequence between the SH2 and kinase domains which may account for the increased basal activity (By similarity). Displays altered substrate specificity compared to isoform 1, showing weak affinity for synaptophysin and for peptide substrates containing class I or class II SH3 domain-binding motifs (By similarity). Plays a role in neurite elongation (By similarity).
Part of a complex comprised of PTPRA, BCAR1, BCAR3 (via SH2 domain) and SRC; the formation of the complex is dependent on integrin mediated-tyrosine phosphorylation of PTPRA (PubMed:22801373). Interacts with DDEF1/ASAP1; via the SH3 domain (By similarity). Interacts with CCPG1 (By similarity). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN (By similarity). Interacts with ERBB2, STAT1 and PNN (By similarity). Interacts with DDR1, DDR2 and DAB2 (By similarity). Interacts with CDCP1, TGFB1I1 and TOM1L2 (PubMed:15851033, PubMed:16479011, PubMed:17202804). Interacts with the cytoplasmic domain of MUC1, phosphorylates it and increases binding of MUC1 with beta-catenin (PubMed:11152665). Interacts with RALGPS1; via the SH3 domain (PubMed:10747847). Interacts with CAV2 (tyrosine phosphorylated form) (PubMed:12091389, PubMed:15504032). Interacts (via the SH3 domain and the protein kinase domain) with ARRB1; the interaction is independent of the phosphorylation state of SRC C-terminus (By similarity). Interacts with ARRB1 and ARRB2 (PubMed:10753943, PubMed:9924018). Interacts with SRCIN1 (PubMed:17525734). Interacts with NDFIP2 and more weakly with NDFIP1 (PubMed:20534535). Interacts with PIK3CA and/or PIK3C2B, PTK2/FAK1 and ESR1 (dimethylated on arginine) (PubMed:18657504, PubMed:21411625). Interacts with FASLG (PubMed:19807924). Interacts (via SH2 domain) with the 'Tyr-402' phosphorylated form of PTK2B/PYK2 (PubMed:14585963). Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated) (By similarity). Interacts with PDGFRA (tyrosine phosphorylated) (By similarity). Interacts with CSF1R (By similarity). Interacts (via SH2 and SH3 domain) with TNK2 (PubMed:21309750). Interacts (via protein kinase domain) with the tyrosine phosphorylated form of RUNX3 (via runt domain) (PubMed:20100835). Interacts with TRAF3 (via RING-type zinc finger domain) (PubMed:19419966). Interacts with RIGI, MAVS and TBK1 (PubMed:19419966). Interacts (via SH2 domain) with RACK1; the interaction is enhanced by tyrosine phosphorylation of RACK1 and inhibits SRC activity (PubMed:9584165, PubMed:11279199). Interacts with EPHB1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:12925710). Interacts with FCAMR (PubMed:8759729). Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1 (PubMed:18024423). Interacts with AMOTL2; this interaction regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites (PubMed:17293535). Interacts with TRAP1 (PubMed:23564345). Interacts with CBLC; the interaction is enhanced when SRC is phosphorylated at Tyr-419 (PubMed:14661060, PubMed:22888118). Interacts with ARHGEF5 (By similarity). Interacts (via cytoplasmic domain) with CEACAM1 (via SH2 domain); this interaction is regulated by trans-homophilic cell adhesion (PubMed:7478590). Interacts with MPP2 (PubMed:19665017). Interacts with PRR7 (PubMed:21460222). Interacts (via kinase domain and to a lesser extent the SH2 domain) directly with PDLIM4; this interaction results in PTPN13-mediated dephosphorylation of this protein leading to its inactivation (PubMed:19307596). Interacts with P85 (PIK3R1 or PIK3R2) (PubMed:28903391). Interacts with HNRNPA2B1 (PubMed:31320558). Interacts with IL6ST/gp130 (PubMed:25731159). Interacts (via SH3 domain) with PELP1 in the presence of 17-beta-estradiol. Interacts with AMBRA1 (By similarity).
Phosphorylation by CSK at Tyr-530 inhibits kinase activity. Inhibitory phosphorylation at Tyr-530 is enhanced by heme. Further phosphorylation by CDK1 partially reactivates CSK-inactivated SRC and facilitates complete reactivation by protein tyrosine phosphatase PTPRC. Integrin engagement stimulates kinase activity. Phosphorylation by PTK2/FAK1 enhances kinase activity. Butein and pseudosubstrate-based peptide inhibitors like CIYKYYF act as inhibitors. Phosphorylation at Tyr-419 increases kinase activity.
S-nitrosylation is important for activation of its kinase activity.
SRC kinase activity has been shown to be increased in several tumor tissues and tumor cell lines such as colon carcinoma cells.
The SH2 and SH3 domains are important for the intramolecular and intermolecular interactions that regulate catalytic activity, localization, and substrate recruitment.
Ubiquitinated in response to CDK5-mediated phosphorylation. Ubiquitination mediated by CBLC requires SRC autophosphorylation at Tyr-419 and may lead to lysosomal degradation.
Ubiquitous. Expression levels are highest in skeletal muscle and brain, intermediate in heart, pancreas, and placenta, and lowest in kidney, liver, and lung.
Expressed in various tumor cell lines. In insulinoma tissue predominantly expressed in precancerous lesions.
Found in cancer tissues with expression in the tumor bodies and surrounding normal cells.
Homodimer. Interacts with ALK (PubMed:12122009). Interacts with LRP1; promotes neuronal survival (PubMed:10772929). Interacts with LRP2 (PubMed:10772929). Interacts with NCAM1 (PubMed:10772929). Interacts (via C-terminal) with PTPRZ1 (via chondroitin sulfate chains); this interaction is inhibited by PTN; this interaction promotes neuronal migration (PubMed:10212223). Interacts with NCL; this interaction promotes NCL clustering and lateral movements of this complex into lipid rafts leading to MDK internalization (PubMed:12147681). Interacts with LRP6 and LRP8: this interaction is calcium dependent (PubMed:12573468). Interacts with ITGA4 (PubMed:15466886). Interacts with ITGA6 (PubMed:15466886). Interacts with ITGB1 (PubMed:15466886). Interacts with ITGA4:ITGB1 complex; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation (PubMed:15466886). Interacts with ITGA6:ITGB1 complex; this interaction mediates MDK-induced neurite outgrowth (PubMed:15466886). Interacts with NOTCH2; this interaction mediates a nuclear accumulation of NOTCH2 and therefore activation of NOTCH2 signaling leading to interaction between HES1 and STAT3 (PubMed:18469519). Interacts with GPC2 (via heparan sulfate chain); this interaction is inhibited by heparin followed by chondroitin sulfate E; this interaction induces GPC2 clustering through heparan sulfate chain; this interaction induces neuronal cell adhesion and neurite outgrowth (PubMed:12084985). Interacts with SDC3; this interaction induces SDC3 clustering; this interaction induces neuronal cell adhesion and neurite outgrowth (PubMed:12084985). Interacts with SDC1 (By similarity). Interacts with CSPG5; this interaction promotes elongation of oligodendroglial precursor-like cells (By similarity).
Secreted protein that functions as cytokine and growth factor and mediates its signal through cell-surface proteoglycan and non-proteoglycan receptors (PubMed:18469519, PubMed:12573468, PubMed:12122009, PubMed:10212223, PubMed:24458438, PubMed:15466886, PubMed:12084985, PubMed:10772929). Binds cell-surface proteoglycan receptors via their chondroitin sulfate (CS) groups (PubMed:12084985, PubMed:10212223). Thereby regulates many processes like inflammatory response, cell proliferation, cell adhesion, cell growth, cell survival, tissue regeneration, cell differentiation and cell migration (PubMed:12573468, PubMed:12122009, PubMed:10212223, PubMed:10683378, PubMed:24458438, PubMed:22323540, PubMed:12084985, PubMed:15466886, PubMed:10772929). Participates in inflammatory processes by exerting two different activities. Firstly, mediates neutrophils and macrophages recruitment to the sites of inflammation both by direct action by cooperating namely with ITGB2 via LRP1 and by inducing chemokine expression (PubMed:10683378, PubMed:24458438). This inflammation can be accompanied by epithelial cell survival and smooth muscle cell migration after renal and vessel damage, respectively (PubMed:10683378). Secondly, suppresses the development of tolerogenic dendric cells thereby inhibiting the differentiation of regulatory T cells and also promote T cell expansion through NFAT signaling and Th1 cell differentiation (PubMed:22323540). Promotes tissue regeneration after injury or trauma. After heart damage negatively regulates the recruitment of inflammatory cells and mediates cell survival through activation of anti-apoptotic signaling pathways via MAPKs and AKT pathways through the activation of angiogenesis (By similarity). Also facilitates liver regeneration as well as bone repair by recruiting macrophage at trauma site and by promoting cartilage development by facilitating chondrocyte differentiation (By similarity). Plays a role in brain by promoting neural precursor cells survival and growth through interaction with heparan sulfate proteoglycans (By similarity). Binds PTPRZ1 and promotes neuronal migration and embryonic neurons survival (PubMed:10212223). Binds SDC3 or GPC2 and mediates neurite outgrowth and cell adhesion (PubMed:12084985, PubMed:1768439). Binds chondroitin sulfate E and heparin leading to inhibition of neuronal cell adhesion induced by binding with GPC2 (PubMed:12084985). Binds CSPG5 and promotes elongation of oligodendroglial precursor-like cells (By similarity). Also binds ITGA6:ITGB1 complex; this interaction mediates MDK-induced neurite outgrowth (PubMed:15466886, PubMed:1768439). Binds LRP1; promotes neuronal survival (PubMed:10772929). Binds ITGA4:ITGB1 complex; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation (PubMed:15466886). Binds anaplastic lymphoma kinase (ALK) which induces ALK activation and subsequent phosphorylation of the insulin receptor substrate (IRS1), followed by the activation of mitogen-activated protein kinase (MAPK) and PI3-kinase, and the induction of cell proliferation (PubMed:12122009). Promotes epithelial to mesenchymal transition through interaction with NOTCH2 (PubMed:18469519). During arteriogenesis, plays a role in vascular endothelial cell proliferation by inducing VEGFA expression and release which in turn induces nitric oxide synthase expression. Moreover activates vasodilation through nitric oxide synthase activation (By similarity). Negatively regulates bone formation in response to mechanical load by inhibiting Wnt/beta-catenin signaling in osteoblasts (By similarity). In addition plays a role in hippocampal development, working memory, auditory response, early fetal adrenal gland development and the female reproductive system (By similarity).
Forms hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens. These hydroxylysines serve as sites of attachment for carbohydrate units and are essential for the stability of the intermolecular collagen cross-links.
Highly expressed in pancreas and muscle. Isoform 1 and isoform 2 are expressed in the majority of the examined cell types. Isoform 2 is specifically expressed in skin, lung, dura and aorta.
The disease is caused by variants affecting the gene represented in this entry. The molecular defect leading to Bruck syndrome is an aberrant cross-linking of bone collagen, due to underhydroxylation of lysine residues within the telopeptides of type I collagen, whereas the lysine residues in the triple helix are normal.
Belongs to the potassium channel family. C (Shaw) (TC 1.A.1.2) subfamily. Kv3.1/KCNC1 sub-subfamily.
Heteromultimer with KCNG3, KCNG4 and KCNV2 (By similarity). Heteromultimer with KCNC2 (By similarity). Heterotetramer with KCNC3 (PubMed:23734863). Interacts with the ancillary subunits KCNE1 and KCNE2; the interaction modulates channel activity (By similarity).
N-glycosylated; contains sialylated glycans.
The tail may be important in modulation of channel activity and/or targeting of the channel to specific subcellular compartments.
Voltage-gated potassium channel that plays an important role in the rapid repolarization of fast-firing brain neurons. The channel opens in response to the voltage difference across the membrane, forming a potassium-selective channel through which potassium ions pass in accordance with their electrochemical gradient (PubMed:25401298). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNC2, and possibly other family members as well. Contributes to fire sustained trains of very brief action potentials at high frequency in pallidal neurons.
GTPase-activating protein (GAP) that stimulates the GTPase activity of Rho-type GTPases. Thereby, controls Rho-type GTPases cycling between their active GTP-bound and inactive GDP-bound states. Acts as a GAP at least for CDC42 and RAC1 (PubMed:11431473). In neurons, is involved in dendritic spine formation and synaptic plasticity in a specific RAC1-GAP activity (By similarity). Limits the initiation of exploratory dendritic filopodia. Recruited to actin-patches that seed filopodia, binds specifically to plasma membrane sections that are deformed inward by acto-myosin mediated contractile forces. Acts through GAP activity on RAC1 to reduce actin polymerization necessary for filopodia formation (By similarity). In association with SHANK3, promotes GRIA1 exocytosis from recycling endosomes and spine morphological changes associated to long-term potentiation (By similarity).
Highly expressed in brain. Expressed at weak level in other tissues.
Interacts with BST2 (via cytoplasmic domain). Interacts (probably via PDZ-binding motif) with SHANK3 (via PDZ domain); the interaction takes place in dendritic spines and promotes GRIA1 exocytosis.
Rho-GAP domain is required to promote GRIA1 exocytosis from recycling endosomes. Rho-GAP and BAR domains are necessary for the control of long-term potentiation in hippocampal neurons (By similarity). In dendrites, BAR domain mediates the recruitment to patches where plasma membrane is deformed by acto-myosin mediated contractile forces (By similarity).
Isoform 1 is expressed in calcified atherosclerotic plaque and chondrocyte-like cells.
May act as a negative regulator of collagen matrix deposition.
E3 ubiquitin-protein ligase (Probable). E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates.
Found in a complex with XPO7, EIF4A1, ARHGAP1, VPS26A, VPS29, VPS35 and SFN. Interacts with BNIPL.
GTPase activator for the Rho, Rac and Cdc42 proteins, converting them to the putatively inactive GDP-bound state. Cdc42 seems to be the preferred substrate.
Expressed in brain, testis, kidney, placenta and liver.
Forms a complex with CASK and CASKIN1 (By similarity). Component of the brain-specific heterotrimeric complex (LIN-10-LIN-2-LIN-7 complex) composed of at least APBA1, CASK, and LIN7, which associates with the motor protein KIF17 to transport vesicles along microtubules (By similarity). Can also interact with other modular proteins containing protein-protein interaction domains like PALS1, PALS2, MPP7, DLG1, DLG2 and DLG3 through its L27 domain. Interacts with DLG4, GRIN2B and MARCHF11 as well as CDH1 and CTNNB1, the channels KCNJ12/Kir2.2, KCNJ4/Kir2.3 and probably KCNJ2/Kir2.1 and SLC6A12/BGT-1 via its PDZ domain. The association of LIN7A with cadherin and beta-catenin is calcium-dependent, occurs at synaptic junctions and requires the actin cytoskeleton. Interacts with EGFR, ERBB2, ERBB3 and ERBB4 with both PDZ and KID domains. Associates with KIF17 via APBA1. Interacts with HTR4 (By similarity). Forms a tripartite complex composed of DLG1, MPP7 and LIN7 (LIN7A or LIN7C).
Plays a role in establishing and maintaining the asymmetric distribution of channels and receptors at the plasma membrane of polarized cells. Forms membrane-associated multiprotein complexes that may regulate delivery and recycling of proteins to the correct membrane domains. The tripartite complex composed of LIN7 (LIN7A, LIN7B or LIN7C), CASK and APBA1 associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules (By similarity). This complex may have the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Ensures the proper localization of GRIN2B (subunit 2B of the NMDA receptor) to neuronal postsynaptic density and may function in localizing synaptic vesicles at synapses where it is recruited by beta-catenin and cadherin. Required to localize Kir2 channels, GABA transporter (SLC6A12) and EGFR/ERBB1, ERBB2, ERBB3 and ERBB4 to the basolateral membrane of epithelial cells.
The L27 domain mediates interaction with CASK and is involved in the formation of multimeric complexes and the association of LIN7 to membranes.
The PDZ domain regulates endocytosis and recycling of the receptor at the membrane.
The kinase interacting site is required for proper delivery of ERBB2 to the basolateral membrane.
Divided into three regions: a N-terminal motor (head) domain, followed by a neck domain consisting of a calmodulin-binding linker domain and a single IQ motif, and a C-terminal tail region with a three-helix bundle region, a SAH domain and a unique globular domain required for interaction with other proteins such as cargo-binding.
Expressed in most tissues examined including heart, brain, placenta, pancreas, spleen, thymus, prostate, testis, ovary, small intestine and colon. Highest levels in brain, pancreas, testis and small intestine. Also expressed in fetal brain and cochlea. Isoform 1 and isoform 2, containing the small insert, and isoform 4, containing neither insert, are expressed in unpolarized epithelial cells.
Homodimer; dimerization seems to implicate the unfolding of the three-helix bundle region creating an additional calmodulin binding site, and cargo binding (By similarity). Able to function as a monomer under specific conditions in vitro (PubMed:15044955). Forms a complex with CFTR and DAB2 in the apical membrane of epithelial cells (PubMed:15247260). Component of the DISP/DOCK7-induced septin displacement complex, at least composed of DOCK7, LRCH3 and MYO6 (PubMed:29467281). Binding to calmodulin through a unique insert, not found in other myosins, located in the neck region between the motor domain and the IQ domain appears to contribute to the directionality reversal (By similarity). This interaction occurs only if the C-terminal lobe of calmodulin is occupied by calcium (By similarity). Interaction with F-actin/ACTN1 occurs only at the apical brush border domain of the proximal tubule cells (By similarity). Interacts with DAB2 (PubMed:11967127). In vitro, the C-terminal globular tail binds a C-terminal region of DAB2 (By similarity). Interacts with CFTR (PubMed:15247260). Interacts with CABP5 (By similarity). Interacts with TOM1 (PubMed:23023224, PubMed:31371777). Interacts with OPTN (PubMed:31371777). Interacts with TAX1BP1 and CALCOCO2/NDP52 (PubMed:31371777). Interacts with TOM1L2 (PubMed:23023224).
Myosins are actin-based motor molecules with ATPase activity (By similarity). Unconventional myosins serve in intracellular movements (By similarity). Myosin 6 is a reverse-direction motor protein that moves towards the minus-end of actin filaments (PubMed:10519557). Has slow rate of actin-activated ADP release due to weak ATP binding (By similarity). Functions in a variety of intracellular processes such as vesicular membrane trafficking and cell migration (By similarity). Required for the structural integrity of the Golgi apparatus via the p53-dependent pro-survival pathway (PubMed:16507995). Appears to be involved in a very early step of clathrin-mediated endocytosis in polarized epithelial cells (PubMed:11447109). Together with TOM1, mediates delivery of endocytic cargo to autophagosomes thereby promoting autophagosome maturation and driving fusion with lysosomes (PubMed:23023224). Links TOM1 with autophagy receptors, such as TAX1BP1; CALCOCO2/NDP52 and OPTN (PubMed:31371777). May act as a regulator of F-actin dynamics (By similarity). As part of the DISP complex, may regulate the association of septins with actin and thereby regulate the actin cytoskeleton (PubMed:29467281). May play a role in transporting DAB2 from the plasma membrane to specific cellular targets (By similarity). May play a role in the extension and network organization of neurites (By similarity). Required for structural integrity of inner ear hair cells (By similarity). Modulates RNA polymerase II-dependent transcription (PubMed:16949370).
Originally predicted to contain a coiled coil domain but generally accepted to contain a stable SAH domain instead.
Phosphorylation in the motor domain, induced by EGF, results in translocation of MYO6 from the cell surface to membrane ruffles and affects F-actin dynamics. Phosphorylated in vitro by p21-activated kinase (PAK).
Represents an unconventional myosin. This protein should not be confused with the conventional myosin-6 (MYH6).
The SAH (single alpha-helix) region is characterized by a high content of charged residues which are predicted to stabilize the alpha-helical structure by ionic bonds (PubMed:18511944). Its contribution to the mechanism confering the myosin movement on actin filaments is debated (PubMed:18511944).
Belongs to the cytochrome c oxidase subunit 5A family.
Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with AFG1L (PubMed:26759378). Interacts with RAB5IF (PubMed:31536960).
Expression detected in Purkinje and granular cells in cerebellum, and in brain neocortex but not in corpus callosum. Expressed in glioma cells and embryonic kidney cells (at protein level). Expressed in brain, liver, pancreas and placenta, with weak expression detected also in lung and kidney. Expressed in several glioma cell lines.
Interacts (via cytoplasmic domain) with RAC1 and ARHGDIA (By similarity). Binds MET and MST1R. Interacts (via cytoplasmic domain) with FSCN1. Interacts with RIT2/RIN. May form homodimers (via Sema domain).
Receptor for SEMA5A that plays a role in axon guidance, invasive growth and cell migration. Stimulates neurite outgrowth and mediates Ca(2+)/Mg(2+)-dependent cell aggregation. In glioma cells, SEMA5A stimulation of PLXNB3 results in the disassembly of F-actin stress fibers, disruption of focal adhesions and cellular collapse as well as inhibition of cell migration and invasion through ARHGDIA-mediated inactivation of RAC1.
It is uncertain whether Met-1, Met-5 or Met-17 is the initiator.
May be involved in vesicle transport between the ER and the Golgi complex.
Arginine methyltransferase involved in the assembly or stability of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I) (PubMed:20406883, PubMed:24089531, PubMed:24838397). Acts by mediating symmetric dimethylation of 'Arg-118' of NDUFS2 after it assembles into the complex I, stabilizing the early intermediate complex (PubMed:24089531).
Defects in NDUFAF7 may be a cause of susceptibility to pathologic myopia, a genetically heterogeneous disorder characterized by extreme, familial, early-onset vision loss and described as myopia accompanied by severe deformation of the eye besides excessive elongation of the eye.
Interacts with NDUFS2 (PubMed:20406883, PubMed:24089531).
Stoichiometry of the protein is unclear. According to a report, it forms a homodimer (PubMed:20406883). According to another publication, it is mainly monomeric (PubMed:24838397).
Part of the SNAPc complex composed of 5 subunits: SNAPC1, SNAPC2, SNAPC3, SNAPC4 and SNAPC5. SNAPC3 interacts with SNAPC1.
Interacts with ZFC3H1 in a RNase-insensitive manner.
Belongs to the actin family. ARP3 subfamily.
Detected in fetal brain. Detected throughout the adult brain, in neurons from gray matter, but not in white matter. Detected in liver, skeletal muscle and pancreas. Detected in lung adenocarcinoma cells with low metastatic potential, but not in lung adenocarcinoma cells with high metastatic potential.
Interacts with the Arp2/3 complex composed of ARP2, ARP3, ARPC1B, ARPC1B/p41-ARC, ARPC2/p34-ARC, ARPC3/p21-ARC, ARPC4/p20-ARC and ARPC5/p16-ARC.
Plays a role in the organization of the actin cytoskeleton. May function as ATP-binding component of the Arp2/3 complex which is involved in regulation of actin polymerization and together with an activating nucleation-promoting factor (NPF) mediates the formation of branched actin networks. May decrease the metastatic potential of tumors.
Functions in an early step of clathrin-mediated endocytosis (PubMed:30822429). Has both a membrane binding/bending activity and the ability to recruit proteins essential to the formation of functional clathrin-coated pits. May regulate Bmp signaling by regulating clathrin-mediated endocytosis of Bmp receptors. Involved in the regulation of T-cell poliferation and activation (PubMed:30822429, PubMed:32098969). Affects TCR clustering upon receptor triggering and modulates its internalisation, playing a role in TCR-dependent T-cell activation (PubMed:32098969).
May oligomerize and form homotetramer (By similarity). Interacts with AP2A2 and AP2B1; 2 subunits of the adaptor protein complex AP-2 (By similarity). Interacts with DAB2. Interacts with clathrin (CLTC or CLTCL1). Interacts with EPS15, EPS15R and ITSN1. Interacts with AGFG1 and CALM. May interact with ACVR1; linking this receptor to clathrin-mediated endocytosis (PubMed:22484487).
Predominantly expressed in lymphoid cells.
Ubiquitously expressed in 16 tissues examined.
Contains 2 copies of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases.
Glycosylated. Glycosylation at Asn-100 is critical for regulating ligand recognition.
Homodimer; disulfide-linked (PubMed:10887109). Interacts with PTPN6/SHP-1 and PTPN11/SHP-2 upon phosphorylation (PubMed:10556798, PubMed:10206955). Interacts with C1QA (via C-terminus); this interaction activates CD33 inhibitory motifs (PubMed:28325905).
Monocytic/myeloid lineage cells. In the brain, CD33 is mainly expressed on microglial cells.
Mostly detected on NKL and myeloid cell lines but poorly expressed on B-cell lines and T-lymphocytes.
Phosphorylation of Tyr-340 is involved in binding to PTPN6 and PTPN11. Phosphorylation of Tyr-358 is involved in binding to PTPN6. LCK phosphorylates Tyr-340 efficiently and Tyr-358 to a lesser extent.
Sialic-acid-binding immunoglobulin-like lectin (Siglec) that plays a role in mediating cell-cell interactions and in maintaining immune cells in a resting state (PubMed:10611343, PubMed:15597323, PubMed:11320212). Preferentially recognizes and binds alpha-2,3- and more avidly alpha-2,6-linked sialic acid-bearing glycans (PubMed:7718872). Upon engagement of ligands such as C1q or syalylated glycoproteins, two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) located in CD33 cytoplasmic tail are phosphorylated by Src-like kinases such as LCK (PubMed:28325905, PubMed:10887109). These phosphorylations provide docking sites for the recruitment and activation of protein-tyrosine phosphatases PTPN6/SHP-1 and PTPN11/SHP-2 (PubMed:10556798, PubMed:10206955, PubMed:10887109). In turn, these phosphatases regulate downstream pathways through dephosphorylation of signaling molecules (PubMed:10206955, PubMed:10887109). One of the repressive effect of CD33 on monocyte activation requires phosphoinositide 3-kinase/PI3K (PubMed:15597323).
Relatively highly expressed in kidney, thymus, testis, ovary, brain, lung, placenta, and prostate, and relatively low expression in heart, liver, skeletal muscle, pancreas, spleen, and small intestine.
Component of the CSN complex, composed of COPS1/GPS1, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7 (COPS7A or COPS7B), COPS8 and COPS9 isoform 1 (PubMed:11337588, PubMed:18850735, PubMed:26456823). In the complex, it probably interacts directly with COPS1, COPS4, COPS5, COPS6 and COPS7 (COPS7A or COPS7B) (PubMed:11337588, PubMed:18850735). Specifically interacts with the ligand binding domain of the thyroid receptor (TR). Does not require the presence of thyroid hormone for its interaction (By similarity). Interacts with CUL1 and CUL2 (PubMed:11337588). Interacts with IRF8/ICSBP1 and with nuclear receptors NR2F1 and NR0B1 (PubMed:10207062, PubMed:10713076, PubMed:10991940). Interacts with NIF3L1 (By similarity).
Essential component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8/ICSBP, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. Involved in early stage of neuronal differentiation via its interaction with NIF3L1.
Expressed in the skin throughout the epidermis.
This is an intracellular thiol proteinase inhibitor. Has an important role in desmosome-mediated cell-cell adhesion in the lower levels of the epidermis.
Lysines at the third position of the tripeptide repeating unit (G-X-Y) are hydroxylated in all cases and bind carbohydrates.
May contain numerous cysteine residues involved in inter- and intramolecular disulfide bonding.
Plays an adhesive role by integrating collagen bundles. It is probably associated with the surface of interstitial collagen fibrils via COL1. The COL2 domain may then serve as a rigid arm which sticks out from the fibril and protrudes the large N-terminal globular domain into the extracellular space, where it might interact with other matrix molecules or cell surface receptors (By similarity).
Isoform 2 interacts with TRPM8 (via N-terminus and C-terminus domains); the interaction inhibits TRPM8 channel activity. Interacts with TRPV6.
Isoform 2 is expressed in the prostate and in cancerous prostate samples.
Negatively regulates the plasma membrane cation channel TRPM8 activity. Involved in the recruitment of TRPM8 to the cell surface. Promotes prostate cancer cell migration stimulation in a TRPM8-dependent manner.
Belongs to the potassium channel family. C (Shaw) (TC 1.A.1.2) subfamily. Kv3.4/KCNC4 sub-subfamily.
Homotetramer (Probable). Heterotetramer of potassium channel proteins (By similarity).
Phosphorylation of serine residues in the inactivation gate inhibits rapid channel closure.
This protein mediates the voltage-dependent potassium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a potassium-selective channel through which potassium ions may pass in accordance with their electrochemical gradient.
Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPases.
Expressed in whole blood, testis and spleen. Also expressed in the brain.
Forms a complex with RUVBL1 and RUVBL2 (PubMed:33205750). Part of a complex composed of SMG1, DHX34 and UPF1; within the complex DHX34 acts as a scaffolding protein to facilitate SMG1 phosphorylation of UPF1 (PubMed:26841701). Interacts with UPF1, MOV10, EIF4A3, XRN2, SMG6, SMG7, SMG9, UPF3A, UPF3B, CASC3/MLN51, XRN1, DIS3 and DCP1A; the interactions are RNA-independent (PubMed:25220460). Interacts with NCBP1/CPB80; the interaction is RNA-dependent (PubMed:25220460). Interacts (via C-terminus) with SMG1; the interaction is RNA-independent (PubMed:25220460, PubMed:26841701).
Probable ATP-binding RNA helicase required for nonsense-mediated decay (NMD) degradation of mRNA transcripts containing premature stop codons (PubMed:25220460, PubMed:33205750). Promotes the phosphorylation of UPF1 along with its interaction with key NMD pathway proteins UPF2 and EIF4A3 (PubMed:25220460). Interaction with the RUVBL1-RUVBL2 complex results in loss of nucleotide binding ability and ATP hydrolysis of the complex (PubMed:33205750). Negatively regulates the nucleotide binding ability and ATP hydrolysis of the RUVBL1-RUVBL2 complex via induction of N-terminus conformation changes of the RUVBL2 subunits (PubMed:33205750).
Does not transport any of the organic anions transported by the other multidrug resistance-associated proteins (MRPs) in vesicular transport assays, nor does it confer resistance to cytotoxic agents in intact cell assays.
Expressed in testis (at protein level). Widely expressed at low level (PubMed:11483364, PubMed:11688999, PubMed:12011458, PubMed:17472575). Isoform 5 is specifically expressed in brain, testis and breast cancer cells (PubMed:11483364, PubMed:11688999, PubMed:12011458).
Probable transporter, its substrate specificity is unknown.
Probable role in regulating adaptive and innate immune responses. Binds in a calcium-dependent manner to terminal galactose and N-acetylgalactosamine units, linked to serine or threonine. These sugar moieties are known as Tn-Ag and are expressed in a variety of carcinoma cells.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB9 is part of the upper jaw surrounding the central large cleft and thought to grab the incoming DNA template (By similarity).
Cytoskeletal protein that may act as an adapter that brings other proteins (like kinases) to the cytoskeleton (PubMed:10861853). Involved in assembly, disassembly and directioning of stress fibers in fibroblasts. Required for the localization of ACTN1 and PALLD to stress fibers. Required for cell migration and in maintaining cell polarity of fibroblasts (By similarity).
Interacts with ACTN1, ACTN2 and ACTN4 (PubMed:10861853, PubMed:10753915, PubMed:11110697). Interacts with PDLIM4 (By similarity).
Strongly expressed in the heart and skeletal muscle, moderately expressed in the spleen, small intestine, colon, placenta, and lung. A lower level expression is seen in liver, thymus, kidney, prostate and pancreas and is not found in the brain, testis, ovary, and peripheral blood leukocytes.
ATP hydrolysis is inhibited by Mg(2+), already at a concentration of 0.4 mM.
Detected in optic cup in 5.5 weeks-old embryos. Expressed in retinal pigment epithelium, cochlear and vestibular neuroepithelia, and olfactory epithelium at 8 weeks. At 19 weeks, present in both pigment epithelium and photoreceptor cells. At 24-28 weeks, expression in pigment epithelium and photoreceptor cells increases. Present in pigment epithelium and photoreceptor cells in adult.
Expressed in the pigment epithelium and the photoreceptor cells of the retina. Also found in kidney, liver, testis, cochlea, lymphocytes. Not expressed in brain.
Might homodimerize in a two headed molecule through the formation of a coiled-coil rod (By similarity). Identified in a complex with USH1C and USH1G (PubMed:21709241). Interacts with MYRIP (PubMed:11964381). Interacts with RPE65 (PubMed:21493626). Interacts with CIB2 (PubMed:23023331). May interact with CALM (PubMed:15300860). Interacts with WHRN (By similarity). Interacts with PLEKHB1 (via PH domain) (By similarity). Interacts with PCDH15 (By similarity). Interacts with TWF2 (By similarity). Interacts with USH1G (By similarity). Interacts with MYH9 (By similarity). Interacts (via MyTH4-FERM domains) with cytoplasmic regions of ADGRV1 and USH2A. Interacts with PDZD7 (via MyTH4-FERM domains) (By similarity).
Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Their highly divergent tails bind to membranous compartments, which are then moved relative to actin filaments. In the retina, plays an important role in the renewal of the outer photoreceptor disks. Plays an important role in the distribution and migration of retinal pigment epithelial (RPE) melanosomes and phagosomes, and in the regulation of opsin transport in retinal photoreceptors. In the inner ear, plays an important role in differentiation, morphogenesis and organization of cochlear hair cell bundles. Involved in hair-cell vesicle trafficking of aminoglycosides, which are known to induce ototoxicity (By similarity). Motor protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal hearing.
Originally predicted to contain a coiled coil domain but proposed to contain a stable SAH domain instead.
Represents an unconventional myosin. This protein should not be confused with the conventional myosin-7 (MYH7).
The SAH (single alpha-helix) region is characterized by a high content of charged residues which are predicted to stabilize the alpha-helical structure by ionic bonds.
Skeletal muscle troponin C binds four calcium ions.
Epididymis-specific expression (at protein level). Both subunits are associated with apical membranes of efferent ductule and proximal epididymal duct epithelia. Mainly expressed in the nonciliated principal cells of the proximal excurrent ducts. Specifically over-expressed in Ewing sarcomas but also up-regulated in a number of carcinomas derived from prostate, kidney or lung.
Heterodimer of 2 chains generated by proteolytic processing; the large extracellular N-terminal fragment and the membrane-bound C-terminal fragment predominantly remain associated and non-covalently linked.
Orphan receptor. Could be involved in a signal transduction pathway controlling epididymal function and male fertility. May regulate fluid exchange within epididymis.
Component of the outer dense fibers (ODF) of spermatozoa which could be involved in sperm tail structure, sperm movement and general organization of cellular cytoskeleton.
Expressed in testis and sperm; especially localized to sperm tail (at protein level).
Belongs to the proteasome subunit S10 family.
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD6, a base containing 6 ATPases and few additional components.
Expressed in all tissues, with highest expression in lung and ovary.
(Microbial infection) Interacts with C.jejuni invasion antigen D (CiaD).
(Microbial infection) Interacts with ebolavirus vp40.
(Microbial infection) Interacts with human cytomegalovirus protein UL5.
Expressed in the placenta, lung, and kidney. A lower level expression is seen in the heart, liver, skeletal muscle and pancreas.
Interacts with CDC42; the interaction is demonstrated with IQGAP1 in GTP-bound and in nucleotide-free state (PubMed:15355962). Interacts with RAC1 (PubMed:15355962). Does not interact with RHOA. Interacts with TSG101 (PubMed:17853893). Interacts with PAK6 (PubMed:18642328). Interacts with TMEM14B; this interaction increases IQGAP1 phosphorylation and induces its nuclear translocation (PubMed:29033352). Interacts with SASH1 (PubMed:23333244). Interacts with PJVK (By similarity). Interacts with SLC26A4; this interaction enhances the chloride-bicarbonate exchange activity of SLC26A4 (PubMed:35601831).
Phosphorylation of Ser-1443 by PKC/PRKCE prevents interaction between C1 and C2, allowing binding of nucleotide-free CDC42. Ser-1443 phosphorylation enhances the ability to promote neurite outgrowth.
Plays a crucial role in regulating the dynamics and assembly of the actin cytoskeleton. Binds to activated CDC42 but does not stimulate its GTPase activity. It associates with calmodulin. Could serve as an assembly scaffold for the organization of a multimolecular complex that would interface incoming signals to the reorganization of the actin cytoskeleton at the plasma membrane. May promote neurite outgrowth (PubMed:15695813). May play a possible role in cell cycle regulation by contributing to cell cycle progression after DNA replication arrest (PubMed:20883816).
Regions C1 and C2 can either interact with nucleotide-free CDC42, or interact together, depending on the phosphorylation state of Ser-1443. When Ser-1443 is not phosphorylated, C1 and C2 interact, which prevents binding of nucleotide-free CDC42 and promotes binding of GTP-bound CDC42. Phosphorylation of Ser-1443 prevents interaction between C1 and C2, which opens the structure of the C-terminus and allows binding and sequestration of nucleotide-free CDC42 on both C1 and C2.
A polymorphism in PDGFRL has been reported to be associated with susceptibility to Behcet disease (PubMed:22926996). Behcet disease is a complex multiple-system disorder characterized by recurrent oral ulcerations, recurrent genital ulcerations, typical skin lesions, and uveitis. Behcet disease also involves joints, blood vessels, musculoskeletal, neurological systems, and the gastrointestinal tract.
Forms a complex composed of PDGFRL, TNK2 and GRB2.
G protein-coupled receptor that is activated by short chain fatty acids (SCFAs), such as propionate. Hence may play a role in the regulation of whole-body energy homeostasis and/or in intestinal immunity.
The sequence shown in this entry differs from the translation of the reference genome assembly (GRCh38/hg38) due to a missense variant at position 174 in the reference genome, that results in the loss of response to short chain fatty acids, including propionate.
The sequence shown in this entry differs from the translation of the reference genome assembly (GRCh38/hg38) due to a missense variant at position 174, p.Arg174Trp, in the reference genome, that results in the loss of response to short chain fatty acids, including propionate. The sequence shown in this entry is that of variant p.Trp174Arg. This variant is activated by propionate and has a frequency of about 15% in the human population according to the Genome Aggregation Database (gnomAD v2.1.1).
Detected in brain where it is concentrated in cerebellar Purkinje cells (at protein level).
Enhances Ca(2+)-mediated inhibition of inositol 1,4,5-triphosphate receptor (ITPR) Ca(2+) release.
Belongs to the FOG (Friend of GATA) family.
Interacts with corepressor CTBP2; this interaction is however not essential for corepressor activity (By similarity). Interacts with the N-terminal zinc-finger of GATA1, GATA2 and probably GATA3.
Mainly expressed in hematopoietic tissues. Also expressed in adult cerebellum, stomach, lymph node, liver and pancreas. Expressed in fetal heart, liver and spleen.
The CCHC FOG-type zinc fingers 1, 2, 3 and 5 directly bind to GATA-type zinc fingers. The Tyr residue adjacent to the last Cys of the CCHC FOG-type zinc finger is essential for the interaction with GATA-type zinc fingers (By similarity).
Transcription regulator that plays an essential role in erythroid and megakaryocytic cell differentiation. Essential cofactor that acts via the formation of a heterodimer with transcription factors of the GATA family GATA1, GATA2 and GATA3. Such heterodimer can both activate or repress transcriptional activity, depending on the cell and promoter context. The heterodimer formed with GATA proteins is essential to activate expression of genes such as NFE2, ITGA2B, alpha- and beta-globin, while it represses expression of KLF1. May be involved in regulation of some genes in gonads. May also be involved in cardiac development, in a non-redundant way with ZFPM2/FOG2 (By similarity).
Binds with high affinity to CRF receptors 2-alpha and 2-beta.
Suppresses food intake, delays gastric emptying and decreases heat-induced edema. Might represent an endogenous ligand for maintaining homeostasis after stress.
Interacts (via SAM domain) with EPHA2 (via SAM domain) (PubMed:22332920). Interacts with EPHA8; EPHA8 kinase activity-independent but stimulated by EPHA8 ubiquitination. Interacts (via SAM domain) with EPHA6 (via SAM domain) (By similarity).
Phosphorylated on tyrosine residues in response to EGF and PDGF.
Regulator of different signaling pathways. Regulates EPHA8 receptor tyrosine kinase signaling to control cell migration and neurite retraction (By similarity).
Binds to DLG1 and DLG4. Interacts (when phosphorylated at Ser-1381 and Ser-1410) with 14-3-3.
Involved in reorganization of the cortical cytoskeleton. Regulates axon formation by promoting the formation of extra axons. May be functionally important for the intracellular trafficking of MAGUKs and associated protein complexes.
Phosphorylated at Ser-1381 and Ser-1410 by MARK2, promoting interaction with 14-3-3 and inhibiting microtubule-dependent accumulation and formation of axons.
By phorbol myristate acetate (PMA) or VEGF in endothelial cell culture.
Endothelial cell-specific membrane protein involved in the formation of the diaphragms that bridge endothelial fenestrae. It is also required for the formation of stomata of caveolae and transendothelial channels. Functions in microvascular permeability, endothelial fenestrae contributing to the passage of water and solutes and regulating transcellular versus paracellular flow in different organs. Plays a specific role in embryonic development.
Expressed in lung, kidney, heart, aorta, placenta, muscle, pituitary gland, adrenals, mammary gland, bladder, lymph node, bone marrow, trachea, digestive tract, liver and tumor-associated endothelium.
A chromosomal aberration involving CEP85L is found in a patient with T-lymphoblastic lymphoma (T-ALL) and an associated myeloproliferative neoplasm (MPN) with eosinophilia. Translocation t(5;6)(q33-34;q23) with PDGFRB. The translocation fuses the 5'-end of CEP85L (isoform 4) to the 3'-end of PDGFRB.
Isoform 1 and isoform 4 are expressed in spleen, lymph, thymus, tonsil and peripheral blood leukocytes, with isoform 1 expressed at higher levels. Isoform 4 is detected in K-562 leukemia cells and in the blood of precursor T lymphoblastic lymphoma (T-ALL) patients.
Plays an essential role in neuronal cell migration.
Can form homooligomers (monomers, dimers, trimers and tetramers) and heterooligomers with matrilin-1 (By similarity). Interacts with COMP. Component of a complex containing at least CRELD2, MANF, MATN3 and PDIA4 (By similarity).
Expressed only in cartilaginous tissues, such as vertebrae, ribs and shoulders.
Major component of the extracellular matrix of cartilage and may play a role in the formation of extracellular filamentous networks.
In testis, detected in male germ cells inside the seminiferous tubules, especially in spermatogonia and round spermatids (at protein level) (PubMed:31451685). In the ovary, expressed in primordial follicles and oocytes but not the external follicle cells (at protein level) (PubMed:31451685).
Inhibits PRC2/EED-EZH1 and PRC2/EED-EZH2 complex function by inhibiting EZH1/EZH2 methyltransferase activity, thereby causing down-regulation of histone H3 trimethylation on 'Lys-27' (H3K27me3) (PubMed:29909548, PubMed:31086175, PubMed:31451685, PubMed:30923826). Probably inhibits methyltransferase activity by limiting the stimulatory effect of cofactors such as AEBP2 and JARID2 (PubMed:30923826). Inhibits H3K27me3 deposition during spermatogenesis and oogenesis (By similarity).
Interacts with PRC2/EED-EZH1 complex member EZH1 and with PRC2/EED-EZH2 complex member EZH2; the interaction blocks EZH1/EZH2 methyltransferase activity (PubMed:29909548, PubMed:31086175, PubMed:31451685, PubMed:30923826). Interacts (via C-terminus) with SUZ12 which is a member of the PRC2/EED-EZH1 and PRC2/EED-EZH2 complexes (PubMed:29909548, PubMed:30923826).
Acts as an inhibitor of histone acetyltransferase activity; prevents acetylation of all core histones by the EP300/p300 histone acetyltransferase at p53/TP53-regulated target promoters in a histone deacetylases (HDAC)-independent manner. Acts as a transcription corepressor of p53/TP53- and TP63-mediated transactivation of the p21/CDKN1A promoter. Involved in the regulation of p53/TP53-dependent apoptosis. Associates together with TP63 isoform TA*-gamma to the p21/CDKN1A promoter.
Interacts with p53/TP53. Interacts (via the N- and C-terminus domains) with AURKB (via the middle kinase domain). Interacts with TP63 isoform TA*-gamma (via activation domain). Interacts with histone H3 (via N-terminus and non-acetylated form preferentially). Associates with core histones and nucleosomes.
Up-regulated by IL4 and CD40L in B-cells.
Interacts with the MH2 domains of SMAD2 and SMAD3.
The FM region is required for binding SMAD2/SMAD4 complexes. FM2 is more effective than FM1 and only interacts with phosphorylated SMAD2 that is in an activated SMAD complex (By similarity).
Transcriptional activator. Recognizes and binds to the DNA sequence 5'-TGT[GT][GT]ATT-3'. Required for induction of the goosecoid (GSC) promoter by TGF-beta or activin signaling. Forms a transcriptionally active complex containing FOXH1/SMAD2/SMAD4 on a site on the GSC promoter called TARE (TGF-beta/activin response element).
Association analysis reveals significant frequency of a synonymous (Ser-225) sequence polymorphism among clinical groups with different sperm traits: the donor group, which has the highest sperm count and motility level, has a significant higher polymorphism frequency compared to normal and asthenozoopermia groups.
Essential for spermiogenesis and male fertility (By similarity). Involved in the formation of sperm acrosome during spermatogenesis.
The disease is caused by variants affecting the gene represented in this entry. An autosomal recessive variation of SPATA16 has been shown to be responsible for the disease in a consanguineous family with members homozygous for the variation.
Acts as a chaperone that facilitates biogenesis and trafficking of functional transporter heteromers to the plasma membrane (PubMed:16825196, PubMed:10588648, PubMed:32817565, PubMed:32494597, PubMed:11318953, PubMed:16609684, PubMed:8486766, PubMed:7686906, PubMed:8663184, PubMed:8663357) (By similarity). Associates with SLC7A9 to form a functional transporter complex that mediates the electrogenic exchange between cationic amino acids and neutral amino acids, with a stoichiometry of 1:1. SLC7A9-SLC3A1 transporter has system b(0,+)-like activity with high affinity for extracellular cationic amino acids and L-cystine and lower affinity for intracellular neutral amino acids. Substrate exchange is driven by high concentration of intracellular neutral amino acids and the intracellular reduction of L-cystine to L-cysteine. SLC7A9-SLC3A1 acts as a major transporter for reabsorption of L-cystine and dibasic amino acids across the brush border membrane in early proximal tubules (PubMed:10588648, PubMed:11318953, PubMed:16609684, PubMed:16825196, PubMed:32494597, PubMed:32817565, PubMed:7686906, PubMed:8486766, PubMed:8663184, PubMed:8663357). Associates with SLC7A13 to form a functional complex that transports anionic and neutral amino acids via exchange or facilitated diffusion. SLC7A13-SLC3A1 may act as a major transporter for L-cystine in late proximal tubules, ensuring its reabsorption from the luminal fluid in exchange for cytosolic L-glutamate or L-aspartate (By similarity).
Disulfide-linked heterodimer composed of the catalytic light subunit SLC7A9 and the heavy subunit SLC3A1. The heterodimer is the minimal functional unit. Assembles in non-covalently linked heterotetramers (dimers of heterodimers) and higher order oligomers; the oligomerization is mediated by SLC3A1 likely to prevent degradation in the endoplasmic reticulum and facilitate heteromer trafficking to the plasma membrane (PubMed:10588648, PubMed:12167606, PubMed:16825196, PubMed:32494597, PubMed:32817565). Disulfide-linked heterodimer composed of the catalytic light subunit SLC7A13 and the heavy subunit SLC3A1 (By similarity).
Expressed in the brush border membrane in the kidney (at protein level). Predominantly expressed in the kidney, small intestine and pancreas. Weakly expressed in liver.
The disease is caused by variants affecting the gene represented in this entry. Hypotonia-cystinuria syndrome is a contiguous gene syndrome caused by a homozygous deletion on chromosome 2p21 that disrupts the gene represented in this entry and PREPL (PubMed:16385448, PubMed:21686663). A homozygous 77.4-kb deletion that disrupts the gene represented in this entry, PREPL, and CAMKMT, causes atypical hypotonia-cystinuria syndrome, characterized by mild to moderate intellectual disability and respiratory chain complex IV deficiency (PubMed:21686663).
Expressed in keratinocytes (at protein level). Highest levels in skeletal muscle. Also found in placenta, cardiac muscle, lung, liver, kidney and pancreas. Expressed in the inner ear hair cells. Expressed abundantly by normal mast cells in different tissues and by mast cells in mastocytoma lesions.
Forms a complex with the monomeric form of beta-tryptase.
May be involved in the regulation of serine proteinases present in the brain or extravasated from the blood (By similarity). Inhibitor of cathepsin G, kallikrein-8 and thrombin. May play an important role in the inner ear in the protection against leakage of lysosomal content during stress and loss of this protection results in cell death and sensorineural hearing loss.
Forms coiled-coil structures that mediate homo- and heteromultimerization. Interacts with NFATC2; interaction is reduced by AKT activation (PubMed:18218901). Interacts with NFATC1 and NFATC4 (PubMed:18218901). Interacts with DAGLA (via PPXXF motif); this interaction is required for the cell membrane localization of DAGLA (By similarity).
Postsynaptic density scaffolding protein. Binds and cross-links cytoplasmic regions of GRM1, GRM5, ITPR1, DNM3, RYR1, RYR2, SHANK1 and SHANK3. By physically linking GRM1 and GRM5 with ER-associated ITPR1 receptors, it aids the coupling of surface receptors to intracellular calcium release. May also couple GRM1 to PI3 kinase through its interaction with AGAP2. Isoforms can be differently regulated and may play an important role in maintaining the plasticity at glutamatergic synapses (PubMed:9808459). Required for normal hearing (PubMed:25816005). Negatively regulates T cell activation by inhibiting the calcineurin-NFAT pathway. Acts by competing with calcineurin/PPP3CA for NFAT protein binding, hence preventing NFAT activation by PPP3CA (PubMed:18218901).
Acts as component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NFX1 pathway. The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production. THOC5 in conjunction with ALYREF/THOC4 functions in NXF1-NXT1 mediated nuclear export of HSP70 mRNA; both proteins enhance the RNA binding activity of NXF1 and are required for NXF1 localization to the nuclear rim. Involved in transcription elongation and genome stability. Involved in alternative polyadenylation site choice by recruiting CPSF6 to 5' region of target genes; probably mediates association of the TREX and CFIm complexes.
Interacts with phosphorylated CSF1R (By similarity). Component of the THO complex, which is composed of THOC1, THOC2, THOC3, THOC5, THOC6 and THOC7; together with at least ALYREF/THOC4, DDX39B, SARNP/CIP29 and CHTOP, THO forms the transcription/export (TREX) complex which seems to have a dynamic structure involving ATP-dependent remodeling. Interacts with ALYREF/THOC4, and THOC7. Interacts (via N-terminus) with the NTF2 domain of NXF1. Forms a complex with CEBPB. Interacts with CPSF6; indicative for an association with the cleavage factor Im (CFIm) complex. Interacts with THOC1 (By similarity). Interacts with LUZP4. Interacts with NCBP3 (PubMed:26382858).
Phosphorylated on tyrosine upon binding to activated CSF1R; which causes a dissociation of the two proteins. Phosphorylation on Ser-5 and/or Ser-6 is required for nuclear export. Phosphorylated on Thr-328 in insulin-stimulated adipocytes (By similarity). Phosphorylation at Tyr-225 modulates mRNA binding.
Regulates the expression of myeloid transcription factors CEBPA, CEBPB and GAB2 by enhancing the levels of phosphatidylinositol 3,4,5-trisphosphate. May be involved in the differentiation of granulocytes and adipocytes. Essential for hematopoietic primitive cell survival and plays an integral role in monocytic development.
An article reported the identification and characterization of this protein as zinc metalloprotease in different tissues; however, this paper was later retracted.
Binds 2 Zn(2+) ions per subunit. One is catalytic, whereas the other seems to have a structural role.
Component of splicing factor SF3A which is composed of three subunits; SF3A3/SAP61, SF3A2/SAP62 and SF3A1/SAP114 (PubMed:10882114, PubMed:11533230, PubMed:21349847). SF3A1 functions as scaffold that interacts directly with both SF3A2 and SF3A3 (PubMed:11533230, PubMed:21349847). SF3A associates with the splicing factor SF3B and a 12S RNA unit to form the mature 17S U2 small nuclear ribonucleoprotein complex (17S U2 snRNP) (PubMed:10882114, PubMed:11533230). Identified in the spliceosome 'E' complex, a precursor of the spliceosome 'A' complex (PubMed:10882114). Identified in the spliceosome 'A' and 'B' complexes (PubMed:10882114, PubMed:29361316, PubMed:29360106, PubMed:30315277). Identified in the spliceosome 'C' complex (PubMed:11991638). Interacts with HTATSF1 (PubMed:9710584).
Involved in pre-mRNA splicing as a component of the splicing factor SF3A complex that contributes to the assembly of the 17S U2 snRNP, and the subsequent assembly of the pre-spliceosome 'E' complex and the pre-catalytic spliceosome 'A' complex (PubMed:10882114, PubMed:11533230). Involved in pre-mRNA splicing as a component of pre-catalytic spliceosome 'B' complexes, including the Bact complex (PubMed:29361316, PubMed:29360106, PubMed:30315277). Interacts directly with the duplex formed by U2 snRNA and the intron (PubMed:29360106).
Essential for elastic fiber formation, is involved in the assembly of continuous elastin (ELN) polymer and promotes the interaction of microfibrils and ELN (PubMed:18185537). Stabilizes and organizes elastic fibers in the skin, lung and vasculature (By similarity). Promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. Vascular ligand for integrin receptors which may play a role in vascular development and remodeling (PubMed:10428823). May act as an adapter that mediates the interaction between FBN1 and ELN (PubMed:17255108).
Expressed in skin fibroblasts (at protein level)(PubMed:17035250). Expressed predominantly in heart, ovary, and colon but also in kidney, pancreas, testis, lung and placenta. Not detectable in brain, liver, thymus, prostate, or peripheral blood leukocytes (PubMed:10428823).
Homodimer (PubMed:20007835). Monomer (PubMed:15790312, PubMed:19617354), homodimerizes in presence of Ca(2+) (PubMed:19617354). Interacts with ELN (PubMed:17035250, PubMed:15790312). Interacts (via N-terminus) with the integrins ITGAV/ITGB3, ITGAV/ITGB5 and ITGA9/ITGB1 (By similarity). Interacts with FBN1 (via N-terminal domain). Forms a ternary complex with ELN and FBN1 (PubMed:17255108). Interacts with EFEMP2 with moderate affinity (PubMed:19570982).
The disease is caused by variants affecting the gene represented in this entry. Mutations affecting this gene can modify the phenotype of diseases caused by ELN mutations.
(Microbial infection) Interacts with herpes simplex virus 1 ICP4.
Autophosphorylates on Ser residues (PubMed:8625415). Inhibited by retinoblastoma tumor suppressor protein, RB1 (PubMed:9858607). Binding to TAF7 or CIITA inhibits the histone acetyltransferase activity (PubMed:11592977, PubMed:22711989).
Component of the TFIID basal transcription factor complex, composed of TATA-box-binding protein TBP, and a number of TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:7680771, PubMed:33795473). Interacts with TAF7; the interaction is direct (PubMed:25412659, PubMed:11592977). TAF1, when part of the TFIID complex, interacts with C-terminus of TP53 (PubMed:15053879). Part of a TFIID-containing RNA polymerase II pre-initiation complex that is composed of TBP and at least GTF2A1, GTF2A2, GTF2E1, GTF2E2, GTF2F1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2B, TCEA1, ERCC2, ERCC3, TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:27007846). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975). RB1 interacts with the N-terminal domain of TAF1 (PubMed:9858607). Interacts with ASF1A and ASF1B (PubMed:10759893, PubMed:12093919, PubMed:12842904). Interacts (via bromo domains) with acetylated lysine residues on the N-terminus of histone H1.4, H2A, H2B, H3 and H4 (in vitro) (PubMed:22464331).
Contaminating sequence. Sequence of unknown origin in the N-terminal and C-terminal part.
Includes a downstream (d) exon and is preferentially expressed in brain (Probable). May play a role in the regulation of genes involved in dopamine processing and transport (Probable).
May be produced at very low levels due to a premature stop CC codon in the mRNA, leading to nonsense-mediated mRNA decay (Probable). Includes a downstream (d) exon and is preferentially expressed in brain (Probable). May play a role in the regulation of genes involved in dopamine processing and transport (Probable).
May be produced at very low levels due to a premature stop CC codon in the mRNA, leading to nonsense-mediated mRNA decay.
Only detected in brain, highest expression in the caudate nucleus.
Phosphorylated by casein kinase II in vitro.
The Bromo domain mediates interaction with histones that have acetylated lysine residues at specific positions (PubMed:22464331). The second domain also recognizes and binds histones that are butyrylated and crotonylated (PubMed:26365797).
The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription (PubMed:33795473). TFIID recognizes and binds promoters with or without a TATA box via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC) (PubMed:33795473). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473). TAF1 is the largest component and core scaffold of the TFIID complex, involved in nucleating complex assembly (PubMed:25412659, PubMed:27007846, PubMed:33795473). TAF1 forms a promoter DNA binding subcomplex of TFIID, together with TAF7 and TAF2 (PubMed:33795473). Contains novel N- and C-terminal Ser/Thr kinase domains which can autophosphorylate or transphosphorylate other transcription factors (PubMed:25412659, PubMed:8625415). Phosphorylates TP53 on 'Thr-55' which leads to MDM2-mediated degradation of TP53 (PubMed:25412659). Phosphorylates GTF2A1 and GTF2F1 on Ser residues (PubMed:25412659). Possesses DNA-binding activity (PubMed:25412659). Essential for progression of the G1 phase of the cell cycle (PubMed:11278496, PubMed:15053879, PubMed:2038334, PubMed:8450888, PubMed:8625415, PubMed:9660973, PubMed:9858607). Exhibits histone acetyltransferase activity towards histones H3 and H4 (PubMed:15870300).
In placenta, associated with trophoblast cells.
Sodium-dependent lysophosphatidylcholine (LPC) symporter, which plays an essential role for blood-brain barrier formation and function (PubMed:24828040, PubMed:34135507, PubMed:32572202). Specifically expressed in endothelium of the blood-brain barrier of micro-vessels and transports LPC into the brain (By similarity). Transport of LPC is essential because it constitutes the major mechanism by which docosahexaenoic acid (DHA), an omega-3 fatty acid that is essential for normal brain growth and cognitive function, enters the brain (PubMed:34135507, PubMed:26005868). Transports LPC carrying long-chain fatty acids such LPC oleate and LPC palmitate with a minimum acyl chain length of 14 carbons (By similarity). Does not transport docosahexaenoic acid in unesterified fatty acid (By similarity). Specifically required for blood-brain barrier formation and function, probably by mediating lipid transport (By similarity). Not required for central nervous system vascular morphogenesis (By similarity). Acts as a transporter for tunicamycin, an inhibitor of asparagine-linked glycosylation (PubMed:21677192). In placenta, acts as a receptor for ERVFRD-1/syncytin-2 and is required for trophoblast fusion (PubMed:18988732, PubMed:23177091).
Interacts with CEP250 and CEP68. Interacts with NEK2; the interaction leads to phosphorylation of CNTLN.
Phosphorylated directly or indirectly by NEK2.
Required for centrosome cohesion and recruitment of CEP68 to centrosomes.
Detected in thymus, uterus and esophagus.
Up-regulated in differentiating keratinocytes.
Auxillary component of the N-terminal acetyltransferase C (NatC) complex which catalyzes acetylation of N-terminal methionine residues. Involved in regulation of apoptosis and proliferation of smooth muscle cells.
ATP-dependent protease which is essential for axonal and neuron development. In neurons, mediates degradation of SMDT1/EMRE before its assembly with the uniporter complex, limiting the availability of SMDT1/EMRE for MCU assembly and promoting efficient assembly of gatekeeper subunits with MCU (PubMed:27642048). Required for paraplegin (SPG7) maturation (PubMed:30252181). After its cleavage by mitochondrial-processing peptidase (MPP), it converts paraplegin into a proteolytically active mature form (By similarity). Required for the maturation of PINK1 into its 52kDa mature form after its cleavage by mitochondrial-processing peptidase (MPP) (PubMed:22354088, PubMed:30252181). Involved in the regulation of OMA1-dependent processing of OPA1 (PubMed:32600459, PubMed:30252181). Contributes to the proteolytic degradation of GHITM upon hyperpolarization of mitochondria (PubMed:35912435). Progressive GHITM degradation upon persistent hyperpolarization leads to respiratory complex I degradation and broad reshaping of the mitochondrial proteome by AFG3L2 (PubMed:35912435).
Homooligomer. Forms heterooligomers with SPG7 and AFG3L1 (PubMed:17101804). Interacts with SPG7; the interaction is required for the efficient assembly of mitochondrial complex I (PubMed:14623864, PubMed:26387735, PubMed:30252181). Interacts with AFG3L1 (By similarity). Interacts with MAIP1 (PubMed:27499296, PubMed:27642048). Interacts with DNAJC19 and PHB2 (By similarity). Interacts with GHITM (PubMed:35912435).
Ubiquitous. Highly expressed in the cerebellar Purkinje cells.
Upon import into the mitochondrion, the N-terminal transit peptide is cleaved to generate an intermediate form which undergoes autocatalytic proteolytic processing to generate the proteolytically active mature form.
Interacts with TBC1D32; may play a role in cilium assembly.
Involved in the localization of proteins to the cilium and cilium assembly. Indirectly regulates the signaling functions of the cilium, being required for normal SHH/smoothened signaling and proper development.
Phosphorylated on tyrosines; probably via autophosphorylation.
Secreted tyrosine-protein kinase that mediates phosphorylation of extracellular proteins and endogenous proteins in the secretory pathway, which is essential for patterning at organogenesis stages. Mediates phosphorylation of MMP1, MMP13, MMP14, MMP19 and ERP29 (PubMed:25171405). Probably plays a role in platelets: rapidly and quantitatively secreted from platelets in response to stimulation of platelet degranulation (PubMed:25171405). May also have serine/threonine protein kinase activity. Required for longitudinal bone growth through regulation of chondrocyte differentiation. May be indirectly involved in protein transport from the Golgi apparatus to the plasma membrane (By similarity).
ATP dependent phosphorylation of adenosine and other related nucleoside analogs to monophosphate derivatives.
Activity is inhibited by 5-iodotubercidin and 5'-amino-5'-deoxyadenosine.
Belongs to the carbohydrate kinase PfkB family.
Catalyzes the phosphorylation of the purine nucleoside adenosine at the 5' position in an ATP-dependent manner. Serves as a potential regulator of concentrations of extracellular adenosine and intracellular adenine nucleotides.
Widely expressed. Highest level in placenta, liver, muscle and kidney.
Catalyzes the transfer of galactose to ceramide, a key enzymatic step in the biosynthesis of galactocerebrosides, which are abundant sphingolipids of the myelin membrane of the central nervous system and peripheral nervous system (PubMed:9125199). Galactosylates both hydroxy- and non-hydroxy fatty acid-containing ceramides and diglycerides (By similarity).
Poly-ADP-ribosylated (PARsylated) by tankyrase TNKS during late G2 and prophase, leading to translocation to mitotic centrosomes.
Required during prometaphase for centrosome maturation. Following poly-ADP-ribosylation (PARsylation) by TNKS, translocates from the Golgi apparatus to mitotic centrosomes and plays a key role in the formation of robust microtubules for prompt movement of chromosomes: anchors AKAP9/CG-NAP, a scaffold protein of the gamma-tubulin ring complex and promotes centrosome maturation.
Adapter protein, which negatively regulates T-cell receptor (TCR) signaling. Inhibits T-cell antigen-receptor induced activation of nuclear factor of activated T-cells. Involved in the negative regulation of positive selection and mitosis of T-cells. May act by linking signaling proteins such as ZAP70 with CBL, leading to a CBL dependent degradation of signaling proteins.
By all-trans retinoic acid (ATRA). Induction is indirect and is mediated through other proteins.
Expressed in lung and fetal brain. Weakly expressed in heart, adult brain, placenta, liver, skeletal muscle, kidney and pancreas.
Interacts with EPHA2, VAV1, LCP2 and PDGFRB (By similarity). Homodimer. Homodimerization and interaction with phosphorylated CBL occurs via its C-terminal domain. Interacts with phosphorylated proteins ZAP70, CD3Z, SYK and LAT via its SH2 domain.
The C-terminal domain is essential for the homodimerization and the interaction with CBL. While the interaction with CBL is apparently mediated via the hydrophobic region of this domain, the highly charged region is apparently required for the homodimerization.
Detected in the germinal center (GC) of lymphoid follicles (at protein level) (PubMed:11418631). Expressed abundantly on follicular dendritic cells (FDCs) (PubMed:10727470).
Interacts (via LDL-receptor class A domains) with TCN2 (PubMed:27411955).
Receptor for transcobalamin saturated with cobalamin (TCbl) (PubMed:18779389). Plays an important role in cobalamin uptake (PubMed:18779389, PubMed:20524213). Plasma membrane protein that is expressed on follicular dendritic cells (FDC) and mediates interaction with germinal center B cells (PubMed:10727470). Functions as costimulator to promote B cell responses to antigenic stimuli; promotes B cell differentiation and proliferation (PubMed:10727470, PubMed:11418631). Germinal center-B (GC-B) cells differentiate into memory B-cells and plasma cells (PC) through interaction with T-cells and follicular dendritic cells (FDC) (PubMed:11418631). CD320 augments the proliferation of PC precursors generated by IL-10 (PubMed:11418631).
Autoubiquitinated in a RING finger- and UBE2D2-dependent manner. Monoubiquitinated by TRIM21. Deubiquitinated by Yersinia YopJ. Ubiquitination may not lead to proteasomal degradation.
Can form homodimers and homotrimers. In addition to lower-order dimerization, also exhibits a higher-order multimerization and both low- and high-order multimerizations are essential for its restriction activity. Isoform Delta interacts with BTBD1 and BTBD2. Interacts with PSMC4, PSMC5, PSMD7 and HSPA8/HSC70 (By similarity). Interacts (via B30.2/SPRY domain) with HSPA1A/B. Interacts with PSMC2, MAP3K7/TAK1, TAB2 and TAB3 (PubMed:21512573, PubMed:22078707). Interacts with SQSTM1 (PubMed:20357094, PubMed:25127057). Interacts with TRIM6 and TRIM34 (PubMed:21680743, PubMed:17156811). Interacts with ULK1 (phosphorylated form), GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3C and BECN1 (PubMed:25127057).
Capsid-specific restriction factor that prevents infection from non-host-adapted retroviruses. Blocks viral replication early in the life cycle, after viral entry but before reverse transcription. In addition to acting as a capsid-specific restriction factor, also acts as a pattern recognition receptor that activates innate immune signaling in response to the retroviral capsid lattice. Binding to the viral capsid triggers its E3 ubiquitin ligase activity, and in concert with the heterodimeric ubiquitin conjugating enzyme complex UBE2V1-UBE2N (also known as UBC13-UEV1A complex) generates 'Lys-63'-linked polyubiquitin chains, which in turn are catalysts in the autophosphorylation of the MAP3K7/TAK1 complex (includes TAK1, TAB2, and TAB3). Activation of the MAP3K7/TAK1 complex by autophosphorylation results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes, thereby leading to an innate immune response in the infected cell. Restricts infection by N-tropic murine leukemia virus (N-MLV), equine infectious anemia virus (EIAV), simian immunodeficiency virus of macaques (SIVmac), feline immunodeficiency virus (FIV), and bovine immunodeficiency virus (BIV) (PubMed:17156811). Plays a role in regulating autophagy through activation of autophagy regulator BECN1 by causing its dissociation from its inhibitors BCL2 and TAB2 (PubMed:25127057). Also plays a role in autophagy by acting as a selective autophagy receptor which recognizes and targets HIV-1 capsid protein p24 for autophagic destruction (PubMed:25127057).
Degraded in a proteasome-independent fashion in the absence of viral infection but in a proteasome-dependent fashion following exposure to restriction sensitive virus.
Has dominant-negative activity against TRIM5alpha. Does not inhibit HIV-1 replication.
The B box-type zinc finger domain and the coiled-coil domain contribute to the higher and low order multimerization respectively which is essential for restriction activity (PubMed:22482711). The coiled coil domain is important for higher order multimerization by promoting the initial dimerization (By similarity).
The B30.2/SPRY domain acts as a capsid recognition domain. Polymorphisms in this domain explain the observed species-specific differences among orthologs (PubMed:22482711).
The RING-type zinc finger domain confers E3 ubiquitin ligase activity and is essential for retrovirus restriction activity, autoubiquitination and higher-order multimerization.
Binds SYTL1, SLAC2B, MYRIP, SYTL3, SYTL4 and SYTL5. Interacts with RPH3A and RPH3A (By similarity). Binds MLPH and SYTL2. Interacts with UNC13D. Does not interact with the BLOC-3 complex (heterodimer of HPS1 and HPS4) (PubMed:20048159). Interacts (GDP-bound form preferentially) with DENND10 (PubMed:30771381).
Found in all the examined tissues except in brain. Low expression was found in thymus, kidney, muscle and placenta. Detected in melanocytes, and in most tumor cell lines examined. Expressed in cytotoxic T-lymphocytes (CTL) and mast cells.
Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. Activated by GEFs such as DENND10.
Small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate homeostasis of late endocytic pathway, including endosomal positioning, maturation and secretion (PubMed:30771381). Plays a role in cytotoxic granule exocytosis in lymphocytes. Required for both granule maturation and granule docking and priming at the immunologic synapse.
A proline/serine/threonine rich region at the C-terminus is necessary for transcriptional activation of target genes and contains the phosphorylation sites.
Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX.
Heterodimer of an alpha and a beta subunit. The alpha subunit binds DNA as a monomer and through the Runt domain. DNA-binding is increased by heterodimerization. Interacts with XRCC6 (Ku70) and XRCC5 (Ku80). Interacts with HIVEP3. Interacts with IFI204. Interaction with SATB2; the interaction results in enhanced DNA binding and transactivation by these transcription factors. Binds to HIPK3. Interacts with FOXO1 (via a C-terminal region); the interaction inhibits RUNX2 transcriptional activity towards BGLAP. This interaction is prevented on insulin or IGF1 stimulation as FOXO1 is exported from the nucleus (By similarity). Interacts with CCNB1, KAT6A and KAT6B. Interacts with FOXP3. Interacts with TMEM119 (By similarity). Interacts with OLFM2 (By similarity). Interacts with IPO7; the interaction inhibits RUNX2 nuclear translocation in osteoblasts (By similarity).
Phosphorylated; probably by MAP kinases (MAPK). Phosphorylation by HIPK3 is required for the SPEN/MINT and FGF2 transactivation during osteoblastic differentiation (By similarity). Phosphorylation at Ser-451 by CDK1 promotes endothelial cell proliferation required for tumor angiogenesis probably by facilitating cell cycle progression. Isoform 3 is phosphorylated on Ser-340.
The disease is caused by variants affecting the gene represented in this entry. Analysis for copy-number variations revealed that a 105 kb duplication within RUNX2 segregated with the MDMHB phenotype in a region with maximum linkage. Real-time PCR for copy-number variation in genomic DNA in eight samples, as well as sequence analysis of fibroblast cDNA from one subject with MDMHB confirmed that affected family members were heterozygous for the presence of an intragenic duplication encompassing exons 3 to 5 of RUNX2. These three exons code for the Q/A domain and the functionally essential DNA-binding Runt domain of RUNX2. The RUNX2 duplication found in individuals with MDMHB leads to a gain of function (PubMed:23290074).
Transcription factor involved in osteoblastic differentiation and skeletal morphogenesis (PubMed:28505335, PubMed:28738062, PubMed:28703881). Essential for the maturation of osteoblasts and both intramembranous and endochondral ossification. CBF binds to the core site, 5'-PYGPYGGT-3', of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, osteocalcin, osteopontin, bone sialoprotein, alpha 1(I) collagen, LCK, IL-3 and GM-CSF promoters. In osteoblasts, supports transcription activation: synergizes with SPEN/MINT to enhance FGFR2-mediated activation of the osteocalcin FGF-responsive element (OCFRE) (By similarity). Inhibits KAT6B-dependent transcriptional activation.
Filament disassembly during mitosis is promoted by phosphorylation at Ser-55 as well as by nestin (By similarity). One of the most prominent phosphoproteins in various cells of mesenchymal origin. Phosphorylation is enhanced during cell division, at which time vimentin filaments are significantly reorganized. Phosphorylation by PKN1 inhibits the formation of filaments. Phosphorylated at Ser-56 by CDK5 during neutrophil secretion in the cytoplasm (PubMed:21465480). Phosphorylated by STK33 (PubMed:18811945). Phosphorylated on tyrosine residues by SRMS (PubMed:29496907).
Highly expressed in fibroblasts, some expression in T- and B-lymphocytes, and little or no expression in Burkitt's lymphoma cell lines. Expressed in many hormone-independent mammary carcinoma cell lines.
Homomer assembled from elementary dimers (PubMed:20176112). Identified in complexes that contain VIM, EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, PRX and spectrin (By similarity). Interacts with BCAS3 (PubMed:17505058). Interacts with LGSN (By similarity). Interacts with SYNM (By similarity). Interacts (via rod region) with PLEC (via CH 1 domain) (By similarity). Interacts with PLEC isoform 1C (PubMed:24940650). Interacts with STK33 (PubMed:18811945). Interacts with LARP6 (PubMed:21746880). Interacts with RAB8B (By similarity). Interacts with TOR1A; the interaction associates TOR1A with the cytoskeleton (PubMed:16361107, PubMed:18827015). Interacts with TOR1AIP1 (PubMed:16361107). Interacts with DIAPH1 (PubMed:23325789). Interacts with EPPK1; interaction is dependent of higher-order structure of intermediate filament (PubMed:16923132). Interacts with the non-receptor tyrosine kinase SRMS; the interaction leads to phosphorylation of VIM (PubMed:29496907). Interacts with NOD2 (PubMed:27812135). Interacts (via head region) with CORO1C (By similarity). Interacts with HDGF (isoform 2) (PubMed:26845719). Interacts with PRKCE (via phorbol-ester/DAG-type 2 domain) (PubMed:18408015). Interacts with BFSP2 (By similarity). Interacts with PPL (By similarity). Interacts (via rod domain) with PKP1 (PubMed:10852826). Interacts with PKP2 (PubMed:10852826).
Involved with LARP6 in the stabilization of type I collagen mRNAs for CO1A1 and CO1A2.
The central alpha-helical coiled-coil IF rod domain mediates elementary homodimerization.
Up-regulated by muramyl-dipeptide and lipopolysaccharide.
Vimentins are class-III intermediate filaments found in various non-epithelial cells, especially mesenchymal cells. Vimentin is attached to the nucleus, endoplasmic reticulum, and mitochondria, either laterally or terminally.
Was reported to interact with SLC6A4, however the paper was retracted as some results and conclusions are not reliable.
Interacts with PSEN1 and PSEN2. Binds OPA1.
P-beta is proteolytically processed (beta-cleavage) in a PARL-dependent manner. The cleavage is inhibited when residues Ser-65, Thr-69 and Ser-70 are all phosphorylated.
Required for the control of apoptosis during postnatal growth. Essential for proteolytic processing of an antiapoptotic form of OPA1 which prevents the release of mitochondrial cytochrome c in response to intrinsic apoptotic signals (By similarity). Required for the maturation of PINK1 into its 52kDa mature form after its cleavage by mitochondrial-processing peptidase (MPP) (PubMed:22354088). Promotes cleavage of serine/threonine-protein phosphatase PGAM5 in damaged mitochondria in response to loss of mitochondrial membrane potential (PubMed:22915595). Mediates differential cleavage of PINK1 and PGAM5 depending on the health status of mitochondria, disassociating from PINK1 and associating with PGAM5 in response to mitochondrial membrane potential loss (PubMed:22915595). Required for processing of CLPB into a form with higher protein disaggregase activity by removing an autoinhibitory N-terminal peptide (PubMed:28288130, PubMed:32573439). Promotes processing of DIABLO/SMAC in the mitochondrion which is required for DIABLO apoptotic activity (PubMed:28288130). Also required for cleavage of STARD7 and TTC19 (PubMed:28288130). Promotes changes in mitochondria morphology regulated by phosphorylation of P-beta domain (PubMed:14732705, PubMed:17116872).
Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1 (PubMed:19103755). Interacts via (ZZ-type zinc finger) with histone H3 in a methylation-independent manner and acetylation on 'Lys-4' (H3K4ac) moderately enhances the interaction (PubMed:30217978).
Histone H3 reader that is required for the ATAC complex-mediated maintenance of histone acetylation and gene activation (PubMed:30217978). Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4 (PubMed:19103755).
Belongs to the complex I NDUFA2 subunit family.
May be involved in the intracellular transport of sterols or other lipids. May bind cholesterol or other sterols (By similarity).
Belongs to the G-protein coupled receptor 2 family. LN-TM7 subfamily.
Receptor that may have an important role in cell/cell signaling during nervous system formation.
Expressed in brain. Not detectable in other tissues tested.
May play an important role in neural organelle transport, and in transduction of nerve signals or in nerve growth. May play a role in neurite extension. May play a role in memory consolidation (By similarity).
Highly expressed in the bone marrow and expressed at lower levels in non-hematopoietic tissues. Highly expressed in erythroleukemia cell lines. Up-regulated in CD34+ hematopoietic progenitors cultured toward red blood cells.
SMIM1 is responsible for the Vel blood group system (VEL) [MIM:615264]. The Vel antigen is present on red blood cells from all people except rare Vel-negative individuals who can form antibodies to Vel in response to transfusion or pregnancy. These antibodies may cause severe hemolytic reactions in blood recipients. In most cases, Vel-negative individuals are homozygous for a 17-nucleotide frameshift deletion in exon 3. In some cases, Vel-negative are heterozygous for the 17-nucleotide frameshift deletion and a missense variant at position 51.
The extracellular domain carries the Vel antigen.
Detected at low levels in brain, cerebral cortex, uterus and small intestine.
Divalent metal cations. Highest activities are measured with Co(2+), Mn(2+) and Cd(2+).
Has both beta-1,3-glucuronic acid and beta-1,4-N-acetylgalactosamine transferase activity. Transfers glucuronic acid (GlcUA) from UDP-GlcUA and N-acetylgalactosamine (GalNAc) from UDP-GalNAc to the non-reducing end of the elongating chondroitin polymer. Specific activity is much reduced compared to CHSY1.
Component of the IFT complex B, at least composed of IFT20, IFT22, IFT25, IFT27, IFT46, IFT52, TRAF3IP1/IFT54, IFT57, IFT74, IFT80, IFT81, and IFT88 (By similarity). Interacts with IFT88 (By similarity). Interacts with TTC25 (PubMed:25860617). Interacts with TTC21A (PubMed:30929735). Interacts with IFT70A1, IFT70A2, IFT70B and KIF17 (By similarity). Interacts with USH1G (PubMed:31637240).
Involved in ciliogenesis as part of a complex involved in intraflagellar transport (IFT), the bi-directional movement of particles required for the assembly, maintenance and functioning of primary cilia (PubMed:27466190). Required for the anterograde transport of IFT88 (PubMed:27466190).
Component of the DCX DET1-COP1 ubiquitin ligase complex at least composed of RBX1, DET1, DDB1, CUL4A and COP1.
Component of the E3 ubiquitin ligase DCX DET1-COP1 complex, which is required for ubiquitination and subsequent degradation of target proteins. The complex is involved in JUN ubiquitination and degradation.
Highly expressed in the ovary, some lymphoid organs and resting leukocytes.
Belongs to the UPL family. TOM1/PTR1 subfamily.
Chimeric cDNA, contains the C-terminal part of ATP5ME.
E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:15989957, PubMed:19713937, PubMed:15567145, PubMed:15767685, PubMed:18488021, PubMed:17567951, PubMed:19037095, PubMed:20534529, PubMed:30217973). Regulates apoptosis by catalyzing the polyubiquitination and degradation of MCL1 (PubMed:15989957). Mediates monoubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair (PubMed:19713937). Also ubiquitinates the p53/TP53 tumor suppressor and core histones including H1, H2A, H2B, H3 and H4 (PubMed:15567145, PubMed:15767685, PubMed:15989956). Ubiquitinates MFN2 to negatively regulate mitochondrial fusion in response to decreased stearoylation of TFRC (PubMed:26214738). Ubiquitination of MFN2 also takes place following induction of mitophagy; AMBRA1 acts as a cofactor for HUWE1-mediated ubiquitination (PubMed:30217973). Regulates neural differentiation and proliferation by catalyzing the polyubiquitination and degradation of MYCN (PubMed:18488021). May regulate abundance of CDC6 after DNA damage by polyubiquitinating and targeting CDC6 to degradation (PubMed:17567951). Mediates polyubiquitination of isoform 2 of PA2G4 (PubMed:19037095). Acts in concert with MYCBP2 to regulate the circadian clock gene expression by promoting the lithium-induced ubiquination and degradation of NR1D1 (PubMed:20534529). Binds to an upstream initiator-like sequence in the preprodynorphin gene (By similarity). Mediates HAPSTR1 degradation, but is also a required cofactor in the pathway by which HAPSTR1 governs stress signaling (PubMed:35776542).
Interacts with isoform p14ARF of CDKN2A which strongly inhibits HUWE1 ubiquitin ligase activity. Interacts with MYCN, POLB and CDC6. Interacts with isoform 2 of PA2G4. Interacts with NR1D1 (PubMed:20534529). Interacts with AMBRA1 (PubMed:30217973). Interacts with HAPSTR1 (PubMed:35776542). Interacts with HAPSTR2 (PubMed:36631436).
Phosphorylated on tyrosine; phosphorylation is probably required for its ability to inhibit TP53 transactivation.
The HECT domain mediates inhibition of the transcriptional activity of p53.
Weakly expressed in heart, brain and placenta but not in other tissues. Expressed in a number of cell lines, predominantly in those from colorectal carcinomas.
Heterohexamer of two PFD-alpha type and four PFD-beta type subunits. Interacts with URI1; the interaction is phosphorylation-dependent and occurs in a growth-dependent manner.
Component of a complex at least composed of ELL, SNF8/EAP30, VPS25/EAP20 and VPS36/EAP45 (By similarity). Component of the endosomal sorting complex required for transport II (ESCRT-II), composed of SNF8, VPS36 and 2 copies of VPS25. Interacts with CFTR; the interaction requires misfolded CFTR. Interacts (via C-terminal half) with the ESCRT-III subunit CHMP6 (via N-terminal half).
Component of the ESCRT-II complex (endosomal sorting complex required for transport II), which is required for multivesicular body (MVB) formation and sorting of endosomal cargo proteins into MVBs. The MVB pathway mediates delivery of transmembrane proteins into the lumen of the lysosome for degradation. The ESCRT-II complex is probably involved in the recruitment of the ESCRT-III complex. The ESCRT-II complex may also play a role in transcription regulation, possibly via its interaction with ELL. The ESCRT-II complex may be involved in facilitating the budding of certain RNA viruses.
Expressed at the mRNA level in kidney, liver, pancreas, and placenta. Lower levels of expression are found in heart, skeletal muscle, brain and lung.
Belongs to the fatty acyl-CoA reductase family.
Catalyzes the reduction of saturated and unsaturated C16 or C18 fatty acyl-CoA to fatty alcohols (PubMed:15220348, PubMed:24108123). It plays an essential role in the production of ether lipids/plasmalogens which synthesis requires fatty alcohols (PubMed:20071337, PubMed:24108123, PubMed:33239752). In parallel, it is also required for wax monoesters production since fatty alcohols also constitute a substrate for their synthesis (By similarity).
Down-regulated by ether lipids/plasmalogen that induce its degradation (at protein level).
Interacts with PEX19; PEX19 mediates the targeting of FAR1 to peroxisomes.
Activated by phosphorylation at Ser-343, Thr-568 and Thr-687 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha, and by further autophosphorylation of Ser-196, Ser-360 and Ser-365 by the activated C-terminal kinase domain.
Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells which transiently dissociates following mitogenic stimulation. Also associates with MAPK14/p38-alpha. Activated RPS6KA4 associates with and phosphorylates the NF-kappa-B p65 subunit RELA.
Ser-343 and Thr-568 phosphorylation is required for kinase activity. Ser-343 and Ser-196 are autophosphorylated by the C-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain. Phosphorylated at Ser-343, Thr-568 and Thr-687 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha. Autophosphorylated at Ser-737 and Ser-745 by the N-terminal kinase domain (By similarity).
Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factor RELA, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes. Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin. Plays an essential role in the control of RELA transcriptional activity in response to TNF. Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate 'Ser-28' of histone H3. Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro-inflammatory cytokines. Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors.
Adapter protein for the cul3 E3 ubiquitin-protein ligase complex (By similarity). Involved in late neuronal development and muscle formation (By similarity).
Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II. The NELF complex, which acts via an association with the DSIF complex and causes transcriptional pausing, is counteracted by the P-TEFb kinase complex.
PubMed:12612062 has shown that it is not involved in Wolf-Hirschhorn syndrome.
The HDAg-like domain is essential for transcriptional repression, and mediates the interaction with the RNA polymerase II complex.
The NELF complex is composed of NELFA, NELFB, NELFCD (isoform NELF-C or isoform NELF-D) and NELFE; NELFA and NELFCD form a stable subcomplex that binds to the N-terminus of NELFB (PubMed:11387440). In vitro, the NELFA:NELFCD subcomplex binds to ssDNA and ssRNA in a sequence- and structure-dependent manner (PubMed:27282391). Interacts with the RNA polymerase II complex when it is not phosphorylated by P-TEFb (PubMed:10199401).
Ubiquitous. Expressed in heart, brain, placenta, liver, skeletal muscle, kidney and pancreas. Expressed at lower level in adult lung. Expressed in fetal brain, lung, liver and kidney.
Chemokine that acts as chemoattractant for monocytes, macrophages and dendritic cells (PubMed:16455961, PubMed:23115081). Plays a role in angiogenesis and possibly in the development of tumors (PubMed:16989774, PubMed:23115081). Acts as an anti-inflammatory in the stomach (PubMed:23115081). May play a role in the innate defense against infections (PubMed:17307946). Activates the C-X-C chemokine receptor GPR35 to induce a rapid and transient rise in the level of intracellular calcium ions (PubMed:25411203).
Detected in trachea, stomach, lung and skeletal muscle. Detected in intestine and in normal and asthmatic lung (at protein level). Breast tumors showed 3- to 24-fold up-regulation.
Found to be up-regulated in duodenal mucosa during acute cholera.
Likely to undergo an endoproteolytic process to form a four-cysteine-containing mature peptide with a canonical CXC chemokine scaffold after secretion.
Seems to exhibit much higher chemoattractant potency on monocytes and macrophages than 6-Cys CXCL17.
Phosphorylated at Ser-191 and Ser-216 by RPS6KA1 and RPS6KA5; phosphorylation activates transcriptional activity.
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving ETV1 is found in patients with Ewing sarcoma. Translocation t(7;22)(p22;q12) with EWSR1.
Transcriptional activator that binds to DNA sequences containing the consensus pentanucleotide 5'-CGGA[AT]-3' (PubMed:7651741). Required for olfactory dopaminergic neuron differentiation; may directly activate expression of tyrosine hydroxylase (TH) (By similarity).
Very highly expressed in brain, highly expressed in testis, lung and heart, moderately in spleen, small intestine, pancreas and colon, weakly in liver, prostate and thymus, very weakly in skeletal muscle, kidney and ovary and not in placenta and peripheral blood leukocytes.
Detected in monocytes and dendritic cells.
Homodimer; disulfide-linked. Interacts with TYROBP. This interaction results in the recruitment of SYK.
Immunoglobulin-like cell surface receptor involved in the negative regulation of receptor tyrosine kinase-coupled signaling processes.
Immunoglobulin-like cell surface receptor involved in the negative regulation of receptor tyrosine kinase-coupled signaling processes. Participates also in the recruitment of tyrosine kinase SYK. Triggers activation of myeloid cells when associated with TYROBP (PubMed:10604985).
Conflicting results have been published concerning SLC22A7/OAT2 isoform 1 function (PubMed:15901346). Was initially demonstrated to function as an organic anion (OA)/dicarboxylate antiporter where dicarboxylates such as fumarate or succinate act as counteranion in exchange for E1S uptake (PubMed:15901346). The same authors also showed that E1S, dehydroepiandrosterone sulfate (DHEA-S), L-ascorbate and glutarate were transported by isoform 1 (PubMed:15901346). However, other authors demonstrated a complete loss of transport activity as a result of a lack of plasma membrane localization and inability to transport cGMP, E1S or DHEA-S (PubMed:18216183, PubMed:26500550).
Functions as a Na(+)-independent bidirectional multispecific transporter (PubMed:11327718, PubMed:18216183, PubMed:21446918, PubMed:28945155). Contributes to the renal and hepatic elimination of endogenous organic compounds from the systemic circulation into the urine and bile, respectively (PubMed:11327718, PubMed:25904762). Capable of transporting a wide range of purine and pyrimidine nucleobases, nucleosides and nucleotides, with cGMP, 2'deoxyguanosine and GMP being the preferred substrates (PubMed:11327718, PubMed:18216183, PubMed:26377792, PubMed:28945155). Functions as a pH- and chloride-independent cGMP bidirectional facilitative transporter that can regulate both intracellular and extracellular levels of cGMP and may be involved in cGMP signaling pathways (PubMed:18216183, PubMed:26377792). Mediates orotate/glutamate bidirectional exchange and most likely display a physiological role in hepatic release of glutamate into the blood (PubMed:21446918). Involved in renal secretion and possible reabsorption of creatinine (PubMed:25904762, PubMed:28945155). Able to uptake prostaglandin E2 (PGE2) and may contribute to PGE2 renal excretion (Probable). Also transports alpha-ketoglutarate and urate (PubMed:11327718, PubMed:26377792). Apart from the orotate/glutamate exchange, the counterions for the uptake of other SLC22A7/OAT2 substrates remain to be identified (PubMed:26377792).
Involved in the uptake of clinically used drugs such as penciclovir and anciclovir, and contributes to renal and hepatic drug elimination.
Involved in the uptake of prostaglandin F2-alpha (PGF2-alpha).
Mainly expressed in liver and kidney (PubMed:11327718, PubMed:18216183, PubMed:21446918, PubMed:25904762). In kidney, expressed in proximal tubular cells (PubMed:25904762). Also expressed in pancreas, small intestine, spinal cord, lung, brain and heart (PubMed:18216183). Expressed in fetal liver (PubMed:21446918).
Was shown to transport estrone-3-sulfate (E1S) (PubMed:28945155). However, E1S transport wasn't observed by other authors (PubMed:26500550). Although shown to transport alpha-ketoglutarate, it is unlikely that it is used as counteranion in exchange for isoform 2-mediated substrate uptake (PubMed:11327718, PubMed:26377792).
Belongs to the FKBP-type PPIase family. FKBP1 subfamily.
Interacts with TGFBR1; prevents TGFBR1 phosphorylation by TGFBR2 and stabilizes it in the inactive conformation (PubMed:9233797). Interacts with ACVR1B and SMAD7 (PubMed:16720724). Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1) (By similarity). Interacts directly with RYR2 and RYR3 (PubMed:10358090, PubMed:22100703). Interacts with GLMN; rapamycin and FK506 abolish the interaction with GLMN in a dose dependent manner (PubMed:8955134). Interacts directly with RYR1 (By similarity).
Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruits SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
Detected in rheumatoid synovial fluid (at protein level).
Interacts with MMP1, MMP3, MMP10 and MMP13, but has only very low affinity for MMP14. Interacts with CD63; identified in a complex with CD63 and ITGB1.
Metalloproteinase inhibitor that functions by forming one to one complexes with target metalloproteinases, such as collagenases, and irreversibly inactivates them by binding to their catalytic zinc cofactor. Acts on MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13 and MMP16. Does not act on MMP14. Also functions as a growth factor that regulates cell differentiation, migration and cell death and activates cellular signaling cascades via CD63 and ITGB1. Plays a role in integrin signaling. Mediates erythropoiesis in vitro; but, unlike IL3, it is species-specific, stimulating the growth and differentiation of only human and murine erythroid progenitors.
The activity of TIMP1 is dependent on the presence of disulfide bonds.
Interacts with DTNA (By similarity). Interacts with TRIM28.
Could act as a repressor of canonical hedgehog signaling by antagonizing the effects of SMO, as suggested by down-regulation of hedgehog target genes, including GLI1, PTCH1, and PTCH2 in PTCHD4-expressing cells.
Copper metallochaperone essential for the synthesis and maturation of cytochrome c oxidase subunit II (MT-CO2/COX2). Involved in transporting copper to the Cu(A) site on MT-CO2/COX2 (PubMed:15229189, PubMed:17189203). Also acts as a thiol-disulfide oxidoreductase to regulate the redox state of the cysteines in SCO1 during maturation of MT-CO2/COX2 (PubMed:19336478).
Homodimer (PubMed:15229189). Interacts with COA6 (PubMed:25959673). Found in a complex with TMEM177, COX20, COA6, MT-CO2/COX2, COX18 and SCO1 (PubMed:29154948). Interacts with TMEM177 in a COX20-dependent manner (PubMed:29154948). Interacts with COX20 in a MT-CO2/COX2- and COX18-dependent manner (PubMed:29154948, PubMed:24403053, PubMed:28330871). Interacts with COX16 (PubMed:29381136).
Highly expressed in pancreas. Not detectable in the other tissues tested.
Inhibited by Ba(2+), quinine, quinidine, chloroform and halothane. Activated at alkaline pH.
Outward rectifying potassium channel. Produces rapidly activating and non-inactivating outward rectifier K(+) currents.
Forms homodimers in trans (molecules expressed by two different cells). Forms promiscuous heterodimers in cis (at the plasma membrane of the same cell) with other protocadherins.
Homodimer. Interacts and may form heterodimers with STAT3.
Transcription factor which binds the E box motif 5'-CA[TC][AG]TG-3'. Involved in regulating energy expenditure, body mass, voluntary physical activity, mating behavior and reproductive longevity, acting through the hypothalamic-pituitary-gonadal axis. Acts as a transcriptional activator of target genes, including NDN, PCSK1, MC4R (By similarity). Is also a transcriptional activator of KISS1 (PubMed:35066646). May act centrally to regulate function of both white and brown adipose tissue. Together with NHLH1, required to maintain migration and survival of cells in the anterior extramural migration stream (aes), which forms the precerebellar nuclei. Also, in concert with NHLH1, may determine fate of gonadotropin releasing hormone-1 (GnRH-1) neurons.
Lacks the conserved active site residues. Probably catalytically inactive.
Required for sperm flagellum formation and maturation of elongating spermatids, thus playing an essential role in male fertility. Contributes to in vitro proteolytic cleavage of SEPT10 in a calmodulin-dependent manner.
Disulfide reductase. May participate in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyze dithiol-disulfide exchange reactions. Modulates TNF-alpha signaling and NF-kappa-B activation. Has peroxidase activity and may contribute to the elimination of cellular hydrogen peroxide.
The oxidized protein is reduced by TRXR1.
Binds the armadillo repeat of CTNNB1 and forms a stable complex (PubMed:9488439, PubMed:9783587). Interacts with TLE5, TLE1, TLE2, TLE3 and TLE4 (PubMed:9783587, PubMed:11266540). Interacts with MLLT11 (PubMed:26079538). Long isoform interacts (via N-terminus) with SOX13; inhibits WNT-mediated transcriptional activity (PubMed:17218525, PubMed:20028982). Interacts with DAZAP2 (PubMed:19304756).
Predominantly expressed in T-cells. Also detected in proliferating intestinal epithelial cells and in the basal epithelial cells of mammary gland epithelium.
Produced by alternative splicing of isoform 4L.
Produced by alternative splicing of isoform 4S.
Transcriptional activator involved in T-cell lymphocyte differentiation. Necessary for the survival of CD4(+) CD8(+) immature thymocytes. Isoforms lacking the N-terminal CTNNB1 binding domain cannot fulfill this role. Binds to the T-lymphocyte-specific enhancer element (5'-WWCAAAG-3') found in the promoter of the CD3E gene. Represses expression of the T-cell receptor gamma gene in alpha-beta T-cell lineages (By similarity). Required for the development of natural killer receptor-positive lymphoid tissue inducer T-cells (By similarity). TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by TCF7 and CTNNB1.May also act as feedback transcriptional repressor of CTNNB1 and TCF7L2 target genes.
Strongly expressed in lung and placenta, whereas it is weakly expressed in brain and heart. Abundantly expressed in the axons and Schwann cells of peripheral nerves.
Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases, including the receptors of insulin (INS), insulin-like growth factor I (IGF1), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), platelet-derived growth factor (PDGF) and fibroblast growth factors (FGFs). In growth hormone (GH) signaling, autophosphorylated ('Tyr-813') JAK2 recruits SH2B1, which in turn is phosphorylated by JAK2 on tyrosine residues. These phosphotyrosines form potential binding sites for other signaling proteins. GH also promotes serine/threonine phosphorylation of SH2B1 and these phosphorylated residues may serve to recruit other proteins to the GHR-JAK2-SH2B1 complexes, such as RAC1. In leptin (LEP) signaling, binds to and potentiates the activation of JAK2 by globally enhancing downstream pathways. In response to leptin, binds simultaneously to both, JAK2 and IRS1 or IRS2, thus mediating formation of a complex of JAK2, SH2B1 and IRS1 or IRS2. Mediates tyrosine phosphorylation of IRS1 and IRS2, resulting in activation of the PI 3-kinase pathway. Acts as positive regulator of NGF-mediated activation of the Akt/Forkhead pathway; prolongs NGF-induced phosphorylation of AKT1 on 'Ser-473' and AKT1 enzymatic activity. Enhances the kinase activity of the cytokine receptor-associated tyrosine kinase JAK2 and of other receptor tyrosine kinases, such as FGFR3 and NTRK1. For JAK2, the mechanism seems to involve dimerization of both, SH2B1 and JAK2. Enhances RET phosphorylation and kinase activity. Isoforms seem to be differentially involved in IGF-I and PDGF-induced mitogenesis (By similarity).
Phosphorylated on tyrosine residues in response to receptor kinase stimulation. Phosphorylated by RET.
Self-associates. Homopentamer (By similarity). Forms a heteromultimeric complex with SH2B2 (By similarity). Interacts with SH2B2. Isoform 1 interacts via its SH2 domain with JAK2. Isoform 2 interacts via its SH2 domain and its N-terminus with JAK2; the SH2 domain is required for the major interaction with JAK2 phosphorylated on tyrosine residues; the N-terminus provides a low-affinity binding to JAK2 independent of JAK2 phosphorylation. Isoform 3 interacts via its SH2 domain with JAK2. Isoform 1 interacts via its SH2 domain with INSR; the interaction requires receptor activation. Isoform 3 interacts via its SH2 domain with INSR; the interaction requires receptor activation and requires INSR phosphorylation at 'Tyr-1185'. Isoform 1 interacts with IGF1R; the interaction requires receptor activation. Isoform 2 interacts with PRKAR1A/RET (PTC2) fusion protein; the interaction requires RET 'Tyr-905' and Tyr-981'. Isoform 2 interacts via its SH2 domain with FGFR3; the interaction requires FGFR3 'Tyr-724' and 'Tyr-760'. Isoform 2 interacts with RET; the interaction requires RET kinase activity and RET 'Tyr-981'. Isoform 2 interacts with RAC1. Isoform 2 interacts with PDGFRA and/or PDGFRB; the interaction requires receptor activation. Interacts with ISR1 and ISR2. Isoform 3 is probably part of a complex consisting of INSR, ISR1 and SH2B1. Probably part of a ternary complex consisting of SH2B1, JAK2 and ISR1 or ISR2. May interact with FCER1G (By similarity). Interacts (via SH2 domain) with NTRK1 (phosphorylated) (By similarity).
Widely expressed with highest levels in skeletal muscle and ovary.
Could have a role in patterning the central nervous system during embryogenesis. Has a key role in regulating the distinct phenotypic features that distinguish two major classes of ventral interneurons, V0 and V1 neurons. Regulates the transcription factor profile, neurotransmitter phenotype, intraspinal migratory path and axonal trajectory of V0 neurons, features that differentiate them from an adjacent set of V1 neurons (By similarity).
Belongs to the major facilitator superfamily. MFSD6 family.
Widely expressed. Expression levels in peripheral blood mononuclear cells are highly variable between individuals, including no expression at all.
Anti-proliferative protein; the function is mediated by association with deadenylase subunits of the CCR4-NOT complex (PubMed:8632892, PubMed:23236473). Mediates CPEB3-accelerated mRNA deadenylation by binding to CPEB3 and recruiting CNOT7 which leads to target mRNA deadenylation and decay (PubMed:21336257).
Interacts with ERBB2 (PubMed:8632892). Interacts with CNOT7 (PubMed:19276069, PubMed:21336257, PubMed:23236473). Interacts with CPEB3 (via C-terminal RNA-binding region); recruits CNOT7 to CPEB3 to form a ternary complex required for mRNA deadenylation and decay (PubMed:21336257). Interacts with CNOT8 (PubMed:23236473). Interacts with CPEB4 (PubMed:21336257).
Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria, a process driven by mitochondrial motive force with an overall impact on glycolysis, glutaminolysis and glutathione-dependent redox balance. Continuous export of oxaloacetate and related four-carbon dicarboxylates from mitochondrial matrix into the cytosol negatively regulates the oxidation of acetyl-CoA substrates via the Krebs cycle, lowering the ATP/ADP ratio and reactive oxygen species (ROS) production (PubMed:24395786). Proton transporter activity is debated, but if it occurs it may mediate inducible proton re-entry into the mitochondrial matrix affecting ATP turnover as a protection mechanism against oxidative stress. Proton re-entry may be coupled to metabolite transport to allow for proton flux switching and optimal ATP turnover (PubMed:11171965, PubMed:33373220, PubMed:11278935, PubMed:22524567, PubMed:26182433) (By similarity). Regulates the use of glucose as a source of energy. Required for glucose-induced DRP1-dependent mitochondrial fission and neuron activation in the ventromedial nucleus of the hypothalamus (VMH). This mitochondrial adaptation mechanism modulates the VMH pool of glucose-excited neurons with an impact on systemic glucose homeostasis (By similarity). Regulates ROS levels and metabolic reprogramming of macrophages during the resolution phase of inflammation. Attenuates ROS production in response to IL33 to preserve the integrity of the Krebs cycle required for persistent production of itaconate and subsequent GATA3-dependent differentiation of inflammation-resolving alternatively activated macrophages (By similarity). Can unidirectionally transport anions including L-malate, L-aspartate, phosphate and chloride ions (PubMed:24395786, PubMed:22524567, PubMed:26182433). Does not mediate adaptive thermogenesis (By similarity).
Genetic variations in UCP2 define the body mass index quantitative trait locus 4 (BMIQ4) [MIM:607447]. A common polymorphism in the promoter of UCP2 has been shown to be associated with a decreased risk of obesity in middle-aged individuals.
Homotetramer. Adopts an asymmetrical dimer of dimers functional form.
Inhibited by pyridoxal- 5'-phosphate, bathophenanthroline, tannic acid, bromocresol purple, butylmalonate and phenylsuccinate (PubMed:24395786). Proton conductance is activated by cardiolipin and long-chain free fatty acids and inhibited by purine nucleotides ATP and ADP. Chloride ion transporter activity is inhibited by long-chain free fatty acids (PubMed:22524567, PubMed:26182433).
The role of UCP2/SLC25A8 in mitochondrial proton transport is a matter of debate. It was initially suggested that it mediates proton leak that increases net proton conductance in response to ROS such as reactive alkenals generated during fatty acid oxidation in mitochondria. By lowering the proton motive force, it would provide for feedback control of mitochondrial ROS metabolism limiting extensive ROS production and protecting cells against oxidative stress. This activity and its potential regulation by ubiquinones and nucleotides was disputed by later studies, which failed to reproduce the effect on proton conductance under physiological conditions. Rather than 'uncoupling' the link between electron transfer and ATP synthesis, it may couple metabolite transport to proton re-entry to allow for proton flux switching and optimal ATP turnover.
Widely expressed in adult human tissues, including tissues rich in macrophages. Most expressed in white adipose tissue and skeletal muscle.
Interacts with RGS14; the interaction is GTP-dependent (By similarity). Heterodimer with RABEP1. The heterodimer binds RAB4A and RAB5A that have been activated by GTP-binding. Interacts with RAB21, and with 100-fold lower affinity also with RAB22. Binds TSC2, GGA1, GGA2, GGA3, AP1G1 and AP1G2. Interacts with ubiquitinated EGFR.
Rab effector protein acting as linker between gamma-adaptin, RAB4A or RAB5A. Involved in endocytic membrane fusion and membrane trafficking of recycling endosomes. Stimulates nucleotide exchange on RAB5A. Can act as a ubiquitin ligase (By similarity).
Specifically expressed in B-lymphocytes.
Belongs to the nuclear hormone receptor family. NR0 subfamily.
Homodimer. Interacts with NR5A1, NR5A2, NR0B2 and with COPS2. Interacts with ESRRB; represses ESRRB activity at the GATA6 promoter (By similarity).
Homodimerization involved an interaction between amino and carboxy termini involving LXXLL motifs and steroid binding domain (AF-2 motif). Heterodimerizes with NR5A1 and NROB2 through its N-terminal LXXLL motifs.
More abundant than isoform 1 in all tissues tested except testis where they are nearly equal.
Orphan nuclear receptor. Component of a cascade required for the development of the hypothalamic-pituitary-adrenal-gonadal axis. Acts as a coregulatory protein that inhibits the transcriptional activity of other nuclear receptors through heterodimeric interactions. May also have a role in the development of the embryo and in the maintenance of embryonic stem cell pluripotency (By similarity).
Orphan nuclear receptor. Component of a cascade required for the development of the hypothalamic-pituitary-adrenal-gonadal axis. Acts as a coregulatory protein that inhibits the transcriptional activity of other nuclear receptors through heterodimeric interactions. May also have a role in the development of the embryo and in the maintenance of embryonic stem cell pluripotency.
The disease is caused by variants affecting the gene represented in this entry. XY individuals with a duplication of part of the short arm of the X chromosome and an intact SRY gene develop as females. The single X chromosome in these individuals does not undergo X-chromosome inactivation; therefore, these individuals presumably carry 2 active copies of genes, including the NR0B1 gene, in the duplicated region. Individuals with deletion of this region develop as males. Genes within the dosage-sensitive sex reversal region are, therefore, not essential for testis development, but, when present in a double dose, interfere with testis formation.
Ceramide synthase activity is inhibited by sphingosine-1-phosphate.
Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward very-long-chain fatty acyl-CoA (chain length C22-C27) (PubMed:17977534, PubMed:18165233, PubMed:18541923, PubMed:19728861, PubMed:20937905, PubMed:22144673, PubMed:22661289, PubMed:26887952, PubMed:29632068). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively (By similarity) (PubMed:17977534, PubMed:18165233, PubMed:18541923, PubMed:19728861, PubMed:20937905, PubMed:22144673, PubMed:22661289, PubMed:26887952, PubMed:29632068). Plays a non-redundant role in the synthesis of ceramides with very-long-chain fatty acids in kidney, liver and brain. Regulates the abundance of myelin-specific sphingolipids galactosylceramide and sulfatide that affects myelin sheath architecture and motor neuron functions (By similarity).
Contains a predicted homeobox domain which is degenerated and lacks residues that are important for DNA-binding. The protein localizes in the endoplasmic reticulum and not in the nucleus, which also argues against homeobox function (PubMed:18165233).
Expressed in kidney, liver, brain, heart, placenta and lung.
Interacts with ATP6V0C, ASGR1, ASGR2 and SLC22A1/OCT1 (PubMed:11543633). Interacts with ELOV1, HSD17B12 and TECR (PubMed:20937905). Interacts with NDUFS2 (By similarity).
Phosphorylated at the C-terminus by CK2, leading to increase the ceramide synthase activity.
Some prediction bioinformatics tools predict the presence of a homeobox domain (By similarity). However, the domain is degenerate and residues that are important for DNA-binding are absent (By similarity). Moreover, the protein localizes in the endoplasmic reticulum and not in the nucleus, strongly suggesting that it does not constitute a canonical homeobox domain (PubMed:18165233).
The last loop motif confers selectivity toward behenoyl-CoA (docosanoyl-CoA; C22:0-CoA) and lignoceroyl-CoA (tetracosanoyl-CoA; C24:0-CoA) as acyl donors.
Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:28076346). Present in a spliceosome complex assembled in vitro containing CRNKL1, HPRP8BP and SNRPB2 (PubMed:12084575). Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932). Isoform 2 seems to be predominant in the spliceosome complex (PubMed:12084575). Interacts with PPIL2 (via the PPIase cyclophilin-type domain); they may form a trimeric complex with HSP90 (PubMed:15189447).
Involved in pre-mRNA splicing process (PubMed:11991638, PubMed:12084575, PubMed:28076346, PubMed:28502770). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
Widely expressed (PubMed:11342225). Highly expressed in testis (PubMed:12084575). Not detected in brain and lung (PubMed:12084575).
Belongs to the exonuclease superfamily. TREX family.
Binds 2 Mg(2+) per subunit. The second magnesium ion interacts with only one residue. Substitution with Mn(2+) results in partial activity.
Detected in thymus, spleen, liver, brain, heart, small intestine and colon.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Enhanced immune sensing of oxidized DNA may be involved in the phototoxicity experienced by SLE patients. Exposure to UV-light produces DNA oxidative damage. Oxidized DNA being a poor TREX1 substrate, it accumulates in skin, leading to enhanced auto-immune reactivity and eventually skin lesions (PubMed:23993650).
Homodimer (By similarity). Interacts (via proline-rich region) with TCERG1/CA150 (via the second WW domain) (By similarity). Component of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and TREX1 (PubMed:16818237). Within this complex, directly interacts with SET; this interaction does not result in TREX1 inhibition (PubMed:16818237). Also interacts with NME1, but only following translocation to the nucleus (PubMed:16818237). Directly interacts with UBQLN1 (via ubiquitin-like domain); the interaction may control TREX1 subcellular location (PubMed:23979357).
Major cellular 3'-to-5' DNA exonuclease which digests single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3' termini (PubMed:10391904, PubMed:10393201, PubMed:17293595). Prevents cell-intrinsic initiation of autoimmunity (PubMed:10391904, PubMed:10393201, PubMed:17293595). Acts by metabolizing DNA fragments from endogenous retroelements, including L1, LTR and SINE elements (PubMed:10391904, PubMed:10393201, PubMed:17293595). Plays a key role in degradation of DNA fragments at cytosolic micronuclei arising from genome instability: its association with the endoplasmic reticulum membrane directs TREX1 to ruptured micronuclei, leading to micronuclear DNA degradation (PubMed:33476576). Micronuclear DNA degradation is required to limit CGAS activation and subsequent inflammation (PubMed:33476576). Unless degraded, these DNA fragments accumulate in the cytosol and activate the cGAS-STING innate immune signaling, leading to the production of type I interferon (PubMed:33476576). Prevents chronic ATM-dependent checkpoint activation, by processing ssDNA polynucleotide species arising from the processing of aberrant DNA replication intermediates (PubMed:18045533). Inefficiently degrades oxidized DNA, such as that generated upon antimicrobial reactive oxygen production or upon absorption of UV light (PubMed:23993650). During GZMA-mediated cell death, contributes to DNA damage in concert with NME1 (PubMed:16818237). NME1 nicks one strand of DNA and TREX1 removes bases from the free 3' end to enhance DNA damage and prevent DNA end reannealing and rapid repair (PubMed:16818237).
The gene for this protein is either identical to or adjacent to that of ATRIP. Some of the mRNAs that encode ATRIP also encode TREX1 in another reading frame.
Ubiquitinated, but not targeted to proteasomal degradation. Ubiquitination may be important for interaction with UBQLN1.
Anchors the catalytic subunits of asymmetric AChE to the synaptic basal lamina.
Found at the end plate of skeletal muscle.
Homotrimer. Component of the asymmetric form of AChE, a disulfide-bonded oligomer composed of the collagenic subunits (Q) and a variable number of asymmetric catalytic subunits (T). The N-terminal of a collagenic subunit (Q) associates with the C-terminal of a catalytic subunit (T).
The proline-rich attachment domain (PRAD) binds the AChE catalytic subunits.
Expressed during in vitro differentiation of bronchial epithelial cells. In fetal lung, expression is barely detectable at 10 weeks post-conception but is strong in airway epithelium at 12.3 weeks post-conception (PubMed:15242845, PubMed:19213785). Expressed in late pachytene spermatocytes (PubMed:28601408). Expressed within the flagellum of elongating spermatids from stage V up to the spermiation in stage II (PubMed:28601408).
Expressed in testis (PubMed:28601408). Strongly expressed in ciliated epithelial cells with lower levels in goblet cells (at protein level) (PubMed:15242845).
May participate in intramanchette transport and midpiece formation of the sperm tail. May play a potential role in somatic cell proliferation.
Cartilage, placenta and some tumor or virally transformed cell lines. Isoforms using exon IIA or IIB are found in the cartilage while isoforms using only exon IIB are found in the tendon.
Acts as a potent immunoadjuvant, capable to interact with antigen-presenting cells and generating efficient CD8(+) T-cell responses. May be used as adjuvant to enhance effect of vaccine G1F/M2, a candidate vaccine against respiratory syncytial virus (RSV), a major respiratory pathogen in newborns (PubMed:18851947). May also be used as adjuvant to prepare antigenic fusion protein for the therapeutics of cancers (PubMed:15930317).
Component of ribosome-associated complex (RAC), a heterodimer composed of Hsp70/DnaK-type chaperone HSPA14 and Hsp40/DnaJ-type chaperone DNAJC2.
Component of the ribosome-associated complex (RAC), a complex involved in folding or maintaining nascent polypeptides in a folding-competent state. In the RAC complex, binds to the nascent polypeptide chain, while DNAJC2 stimulates its ATPase activity.
Isoform 2 is expressed at high levels in brain, thymus, ovary, testis, leukocyte, liver, small intestine and prostate. Isoform 1 is expressed in the brain, testis and adrenal gland. It is activated in tumorigenic breast cancer cell lines and in the primary tumor of breast cancer patients. Activation also correlates with metastatic lymph node invasion and can be detected in metastatic epithelial cells from the lymph nodes and in the bone marrow of patients.
Belongs to the eukaryotic ribosomal protein eL13 family.
Component of the 60S large ribosomal subunit (LSU).
Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:31630789, PubMed:23636399, PubMed:32669547). The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules (Probable). The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain (Probable). The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel (Probable). As part of the LSU, it is probably required for its formation and the maturation of rRNAs (PubMed:31630789). Plays a role in bone development (PubMed:31630789).
Higher levels of expression in benign breast lesions than in carcinomas.
Co-chaperone for HSP70 and HSC70 chaperone proteins. Acts as a nucleotide-exchange factor (NEF) promoting the release of ADP from the HSP70 and HSC70 proteins thereby triggering client/substrate protein release. Nucleotide release is mediated via its binding to the nucleotide-binding domain (NBD) of HSPA8/HSC70 where as the substrate release is mediated via its binding to the substrate-binding domain (SBD) of HSPA8/HSC70 (PubMed:27474739, PubMed:9873016, PubMed:24318877). Inhibits the pro-apoptotic function of PPP1R15A, and has anti-apoptotic activity (PubMed:12724406). Markedly increases the anti-cell death function of BCL2 induced by various stimuli (PubMed:9305631).
Homodimer. Forms a heteromeric complex with HSP70/HSC70 (PubMed:9305631). Binds to the ATPase domain of HSP/HSC70 chaperones. Isoform 1, isoform 3 and isoform 4 but not isoform 2 interact with HSPA8/HSC70 (PubMed:27474739, PubMed:24318877, PubMed:9305631, PubMed:9679980). Interacts with NR3C1 (PubMed:10477749). Interacts with the N-terminal region of MAPRE2 (PubMed:15986447). Interacts with PPP1R15A (PubMed:12724406). Interacts with BCL2 in an ATP-dependent manner. Isoform 2 does not interact with BCL2 (PubMed:9305631). Interacts with SIAH1 (PubMed:9582267). Interacts with HSPA8 (via NBD) (PubMed:27474739, PubMed:24318877). Interacts with HSPA1A (via NBD) and HSPA1B (via NBD) (PubMed:24318877). Interacts with SIAH2 (By similarity).
Isoform 4 is the most abundantly expressed isoform. It is ubiquitously expressed throughout most tissues, except the liver, colon, breast and uterine myometrium. Isoform 1 is expressed in the ovary and testis. Isoform 4 is expressed in several types of tumor cell lines, and at consistently high levels in leukemia and lymphoma cell lines. Isoform 1 is expressed in the prostate, breast and leukemia cell lines. Isoform 3 is the least abundant isoform in tumor cell lines (at protein level).
Produced by alternative initiation at Met-116 of isoform 1.
Produced by alternative initiation at Met-72 of isoform 1.
Up-regulated during differentiation of bladder epithelial cells and down-regulated during differentiation of prostate epithelium.
May be involved in the regulation of cell migration.
Belongs to the complex IV NDUFA4 subunit family.
Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:22902835, PubMed:23746447, PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (Probable). Interacts with RAB5IF (PubMed:31536960). Interacts with FLVCR2; this interaction occurs in the absence of heme and is disrupted upon heme binding.
Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules unsing 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix (PubMed:22902835). NDUFA4 is required for complex IV maintenance (PubMed:22902835).
During complex IV purifications dissociates from complex IV upon treatment with standard detergent DDM (decyl beta-D-maltoside) in high concentrations (PubMed:22902835, PubMed:23746447).
Was initially believed to be a subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I).
Transcription repressor that binds to the promoter of target genes and prevents their expression. Acts as a negative regulator of epithelial-mesenchymal transition and metastasis in breast cancer. Specifically binds the 5'-CACCC-3' sequence in the promoter of ID1, a key metastasis regulator in breast cancer, and repress its expression. May be a germ cell-specific transcription factor that plays important roles in spermatid differentiation and oocyte development (By similarity).
Associates with alpha-, beta- and delta-catenins.
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. Cadherin-24 mediate strong cell-cell adhesion.
Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope (Probable). Required for proper protein transport into the nucleus (PubMed:32275884).
Copy number variations of NUP188 gene may be a cause of heterotaxy, a congenital heart disease resulting from abnormalities in left-right (LR) body patterning.
Thiol S-methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-l-methionine to hydrogen sulfide and other thiol compounds including dithiothreitol, 7alpha-thiospironolactone, L-penicillamine, and captopril.
Acts as a membrane potential-dependent organic anion transporter, the transport requires a low concentration of chloride ions (By similarity). Mediates chloride-dependent transport of urate (By similarity). Can actively transport inorganic phosphate into cells via Na(+) cotransport (By similarity).
Expressed in the small intestine, kidney, spleen and testis. Not detected in fetal brain, bone marrow, and mammary gland.
Heart, placenta, liver, skeletal muscle, and pancreas and, with weaker intensity, in several other tissues.
Interacts (in GTP-bound form) with DIAPH2 isoform 3, DAPK3, FILIP1 and WHAMM. Interacts with PAK5. Interacts (independent of GTP-loaded status) with ANKFY1.
Involved in endosome dynamics. May coordinate membrane transport with the function of the cytoskeleton. Involved in the internalization and trafficking of activated tyrosine kinase receptors such as PDGFRB. Participates in the reorganization of actin cytoskeleton; the function seems to involve WHAMM and includes regulation of filopodia formation and actin filament bundling. Can modulate the effect of DAPK3 in reorganization of actin cytoskeleton and focal adhesion dissolution.
Belongs to the Mediator complex subunit 29 family.
Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Associates with the MED18/MED20 heteromer.
Functions as an endocytic receptor on a small subset of myeloid cells specialized for the uptake and processing of material from dead cells. Recognizes filamentous form of actin in association with particular actin-binding domains of cytoskeletal proteins, including spectrin, exposed when cell membranes are damaged, and mediate the cross-presentation of dead-cell associated antigens in a Syk-dependent manner.
In peripheral blood highly restricted on the surface of BDCA31(+) dendritic cells and on a small subset of CD14(+) and CD16(-) monocytes.
Belongs to the protein phosphatase inhibitor 1 family.
Inhibitor of protein-phosphatase 1. This protein may be important in hormonal control of glycogen metabolism. Hormones that elevate intracellular cAMP increase I-1 activity in many tissues. I-1 activation may impose cAMP control over proteins that are not directly phosphorylated by PKA. Following a rise in intracellular calcium, I-1 is inactivated by calcineurin (or PP2B). Does not inhibit type-2 phosphatases.
Phosphorylation of Thr-35 is required for activity.
Available under the names Activase (Genentech) and Retavase (Centocor and Roche) [Retavase is a fragment of TPA that contains kringle 2 and the protease domain; it was also known as BM 06.022]. Used in Acute Myocardial Infarction (AMI), in Acute Ischemic Stroke (AIS) and Pulmonary Embolism (PE) to initiate fibrinolysis.
Both FN1 and EGF-like domains are important for binding to LRP1.
Both FN1 and one of the kringle domains are required for binding to fibrin.
Characterization of O-linked glycan was studied in Bowes melanoma cell line.
Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By controlling plasmin-mediated proteolysis, it plays an important role in tissue remodeling and degradation, in cell migration and many other physiopathological events. During oocyte activation, plays a role in cortical granule reaction in the zona reaction, which contributes to the block to polyspermy (By similarity).
Differential cell-specific N-linked glycosylation gives rise to two glycoforms, type I (glycosylated at Asn-219) and type II (not glycosylated at Asn-219). The single chain type I glycoform is less readily converted into the two-chain form by plasmin, and the two-chain type I glycoform has a lower activity than the two-chain type II glycoform in the presence of fibrin.
Heterodimer of chain A and chain B held by a disulfide bond. Forms a heterodimer with SERPINA5. Binds to fibrin with high affinity. This interaction leads to an increase in the catalytic efficiency of the enzyme between 100-fold and 1000-fold, due to an increase in affinity for plasminogen. Similarly, binding to heparin increases the activation of plasminogen. Binds to annexin A2, cytokeratin-8, fibronectin and laminin. Binds to mannose receptor and the low-density lipoprotein receptor-related protein (LRP1); these proteins are involved in TPA clearance. Yet unidentified interactions on endothelial cells and vascular smooth muscle cells (VSMC) lead to a 100-fold stimulation of plasminogen activation. In addition, binding to VSMC reduces TPA inhibition by PAI-1 by 30-fold. Binds LRP1B; binding is followed by internalization and degradation. In complex with SERPINE1, interacts with SORL1 (PubMed:15053742).
Increased activity of TPA results in increased fibrinolysis of fibrin blood clots that is associated with excessive bleeding. Defective release of TPA results in hypofibrinolysis that can lead to thrombosis or embolism.
N-glycosylation of Asn-152; the bound oligomannosidic glycan is involved in the interaction with the mannose receptor.
Synthesized in numerous tissues (including tumors) and secreted into most extracellular body fluids, such as plasma, uterine fluid, saliva, gingival crevicular fluid, tears, seminal fluid, and milk.
The FN1 domain mediates binding to annexin A2.
The second kringle domain is implicated in binding to cytokeratin-8 and to the endothelial cell surface binding site.
The single chain, almost fully active enzyme, can be further processed into a two-chain fully active form by a cleavage after Arg-310 catalyzed by plasmin, tissue kallikrein or factor Xa.
(Microbial infection) Glucosylated at Thr-46 by P.sordellii toxin TcsL from strain 6018 (PubMed:8858106). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form (PubMed:8858106). Not glucosylated by TcsL from strain VPI 9048 (PubMed:8858106).
Activated in an LPA-dependent manner by LPAR1 and in an LPA-independent manner by LPAR2.
Interacts (via effector domain) with RALBP1; during mitosis, recruits RALBP1 to the mitochondrion where it promotes DNM1L phosphorylation and mitochondrial fission (PubMed:7673236, PubMed:21822277). Interacts with EXOC2/Sec5 and EXOC8/Exo84; binding to EXOC2 and EXOC8 is mutually exclusive (PubMed:14525976, PubMed:18756269, PubMed:15920473). Interacts with Clostridium exoenzyme C3 (PubMed:16177825, PubMed:15809419). Interacts with RALGPS1 (PubMed:10747847). Interacts with LPAR1 and LPAR2. Interacts with GRK2 in response to LPAR1 activation. RALA and GRK2 binding to LPAR1 is mutually exclusive (PubMed:19306925). Interacts with CDC42 (By similarity).
Multifunctional GTPase involved in a variety of cellular processes including gene expression, cell migration, cell proliferation, oncogenic transformation and membrane trafficking. Accomplishes its multiple functions by interacting with distinct downstream effectors (PubMed:18756269, PubMed:19306925, PubMed:20005108, PubMed:21822277, PubMed:30500825). Acts as a GTP sensor for GTP-dependent exocytosis of dense core vesicles. The RALA-exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling (PubMed:20005108). Key regulator of LPAR1 signaling and competes with GRK2 for binding to LPAR1 thus affecting the signaling properties of the receptor. Required for anchorage-independent proliferation of transformed cells (PubMed:19306925). During mitosis, supports the stabilization and elongation of the intracellular bridge between dividing cells. Cooperates with EXOC2 to recruit other components of the exocyst to the early midbody (PubMed:18756269). During mitosis, also controls mitochondrial fission by recruiting to the mitochondrion RALBP1, which mediates the phosphorylation and activation of DNM1L by the mitotic kinase cyclin B-CDK1 (PubMed:21822277).
Phosphorylated. Phosphorylation at Ser-194 by AURKA/Aurora kinase A, during mitosis, induces RALA localization to the mitochondrion where it regulates mitochondrial fission.
Prenylation is essential for membrane localization. The geranylgeranylated form and the farnesylated mutant do not undergo alternative prenylation in response to geranylgeranyltransferase I inhibitors (GGTIs) and farnesyltransferase I inhibitors (FTIs).
First expressed in embryos at 8.5-9 days in facial and branchial arch mesenchyme, otic vesicles and frontonasal ectoderm around olfactory placodes, a day later expression is seen in the developing forebrain in primordia of the ganglionic eminence and ventral diencephalic regions. In day 12.5 embryos, expressed in the brain and bones, and also in all skeletal structures of midgestation embryos after the first cartilage formation, and expression progressively declines in both brain and skeleton in day 15 embryos.
Belongs to the HAD-like hydrolase superfamily. MasA/MtnC family.
Bifunctional enzyme that catalyzes the enolization of 2,3-diketo-5-methylthiopentyl-1-phosphate (DK-MTP-1-P) into the intermediate 2-hydroxy-3-keto-5-methylthiopentenyl-1-phosphate (HK-MTPenyl-1-P), which is then dephosphorylated to form the acireductone 1,2-dihydroxy-3-keto-5-methylthiopentene (DHK-MTPene).
C-terminal Ser or Thr residues may be phosphorylated.
Does not bind to CRF with high affinity.
G-protein coupled receptor for CRH (corticotropin-releasing factor) and UCN (urocortin). Has high affinity for CRH and UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors, such as adenylate cyclase. Promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels. Inhibits the activity of the calcium channel CACNA1H. Required for normal embryonic development of the adrenal gland and for normal hormonal responses to stress. Plays a role in the response to anxiogenic stimuli.
Heterodimer; heterodimerizes with GPER1 (By similarity). Interacts (via N-terminal extracellular domain) with CRH and UCN. Interacts with DLG1; this inhibits endocytosis of CRHR1 after agonist binding.
Phosphorylation at Ser-330 by PKA prevents maximal coupling to Gq-protein, and thereby negatively regulates downstream signaling.
Predominantly expressed in the cerebellum, pituitary, cerebral cortex and olfactory lobe.
The transmembrane domain is composed of seven transmembrane helices that are arranged in V-shape. Transmembrane helix 7 assumes a sharply kinked structure. The antagonist CP-376395 binds at an allosteric site, far from the presumed binding site for the physiological peptide ligand.
A conditional disulfide bridge can form within the protein that dislocates a critical phosphate-coordinating arginine Arg-100 away from the active site, disabling the enzyme.
Catalyzes the reversible phosphorylytic cleavage of uridine and deoxyuridine to uracil and ribose- or deoxyribose-1-phosphate (PubMed:12849978, PubMed:21855639). The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis (Probable). Shows broad substrate specificity and accepts uridine, deoxyuridine, and thymidine as well as the two pyrimidine nucleoside analogs 5-fluorouridine and 5-fluoro-2(')-deoxyuridine as substrates (PubMed:12849978).
Catalyzes the reversible phosphorylytic cleavage of uridine and deoxyuridine to uracil and ribose- or deoxyribose-1-phosphate. The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis.
Belongs to the GPI inositol-deacylase family.
Involved in inositol deacylation of GPI-anchored proteins. GPI inositol deacylation may important for efficient transport of GPI-anchored proteins from the endoplasmic reticulum to the Golgi (By similarity).
Specifically expressed in testis. Low expression is detected also in liver.
Expression detected in spleen, thymus, testis, ovary, colon, heart, smooth muscle, kidney, brain, lung, liver and white adipose tissue with highest expression in heart, smooth muscle, liver and thyroid.
Found in a complex with GRSF1, DDX28, DHX30 and FASTKD2. Associates with the 12S mitochondrial rRNA (12S mt-rRNA).
Plays an important role in the processing of non-canonical mitochondrial mRNA precursors (PubMed:25683715).
Its expression is closely related to cellular differentiation in both normal and malignant squamous cells.
May act as a papain-like cysteine protease inhibitor to modulate the host immune response against tumor cells. Also functions as an inhibitor of UV-induced apoptosis via suppression of the activity of c-Jun NH(2)-terminal kinase (JNK1).
Squamous cells. Expressed in some hepatocellular carcinoma (at protein level).
Strongly up-regulated in the upper epidermis of sun-exposed skin.
AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3) (PubMed:21543851). Interacts with FNIP1 and FNIP2. Associates with internalized insulin receptor/INSR complexes on Golgi/endosomal membranes; PRKAA2/AMPK2 together with ATIC and HACD3/PTPLAD1 is proposed to be part of a signaling network regulating INSR autophosphorylation and endocytosis (PubMed:25687571).
Activated by phosphorylation on Thr-172 (PubMed:15980064). Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-172 (PubMed:15980064). AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-172 (PubMed:15980064). ADP also stimulates Thr-172 phosphorylation, without stimulating already phosphorylated AMPK (PubMed:15980064). ATP promotes dephosphorylation of Thr-172, rendering the enzyme inactive (PubMed:15980064). Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP. AMPK is activated by antihyperglycemic drug metformin, a drug prescribed to patients with type 2 diabetes: in vivo, metformin seems to mainly inhibit liver gluconeogenesis. However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo (PubMed:11602624). Selectively inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol. Salicylate/aspirin directly activates kinase activity, primarily by inhibiting Thr-172 dephosphorylation.
Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism (PubMed:17307971, PubMed:17712357). In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation (PubMed:17307971, PubMed:17712357). AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators (PubMed:17307971, PubMed:17712357). Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively (PubMed:7959015). Promotes lipolysis of lipid droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2) (PubMed:34077757). Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3 (By similarity). Involved in insulin receptor/INSR internalization (PubMed:25687571). AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160 (By similarity). Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A (PubMed:11554766, PubMed:11518699, PubMed:15866171, PubMed:17711846, PubMed:18184930). Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm (By similarity). In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription (By similarity). Acts as a key regulator of cell growth and proliferation by phosphorylating FNIP1, TSC2, RPTOR, WDR24 and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2 (PubMed:14651849, PubMed:20160076, PubMed:21205641). Also phosphorylates and inhibits GATOR2 subunit WDR24 in response to nutrient limitation, leading to suppress glucose-mediated mTORC1 activation (PubMed:36732624). In response to energetic stress, phosphorylates FNIP1, inactivating the non-canonical mTORC1 signaling, thereby promoting nuclear translocation of TFEB and TFE3, and inducing transcription of lysosomal or autophagy genes (PubMed:37079666). In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1 (PubMed:21205641). In that process also activates WDR45/WIPI4 (PubMed:28561066). Phosphorylates CASP6, thereby preventing its autoprocessing and subsequent activation (PubMed:32029622). AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it (By similarity). May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it (By similarity). Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin (PubMed:17486097). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (PubMed:12519745, PubMed:20074060). Plays an important role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes, in response to glucose starvation (By similarity). Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1 (By similarity).
Phosphorylated at Thr-172 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-172 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-172, but at much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK. Dephosphorylated by PPM1A and PPM1B at Thr-172 (mediated by STK11/LKB1).
The AIS (autoinhibitory sequence) region shows some sequence similarity with the ubiquitin-associated domains and represses kinase activity.
Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity (PubMed:14738735). Required for kinetochore integrity and the organization of stable microtubule binding sites in the outer plate of the kinetochore (PubMed:14738735). The NDC80 complex synergistically enhances the affinity of the SKA1 complex for microtubules and may allow the NDC80 complex to track depolymerizing microtubules (PubMed:23085020).
(Microbial infection) Kinase activity is required for SARS coronavirus-2/SARS-CoV-2 replication.
Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis (PubMed:14617358, PubMed:7628435, PubMed:33637724). As part of PI3KC3-C1, promotes endoplasmic reticulum membrane curvature formation prior to vesicle budding (PubMed:32690950). Involved in regulation of degradative endocytic trafficking and required for the abcission step in cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20208530, PubMed:20643123). Involved in the transport of lysosomal enzyme precursors to lysosomes (By similarity). Required for transport from early to late endosomes (By similarity).
Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex the core of which is composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 associating with additional regulatory/auxilliary subunits to form alternative complex forms. Alternative complex forms containing a forth regulatory subunit in a mutually exclusive manner are: the PI3K complex I (PI3KC3-C1) containing ATG14, and the PI3K complex II (PI3KC3-C2) containing UVRAG. PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex. Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits such as RUBCN, SH3GLB1/Bif-1 and AMBRA1 (PubMed:7628435, PubMed:19050071, PubMed:20643123, PubMed:19270696, PubMed:23878393, PubMed:25490155). PI3KC3-C1 probably associates with PIK3CB (By similarity). Interacts with RAB7A in the presence of PIK3R4 (PubMed:14617358). Interacts with AMBRA1 (By similarity). Interacts with BECN1P1/BECN2 (PubMed:23954414). Interacts with SLAMF1(PubMed:22493499). May be a component of a complex composed of RAB5A (in GDP-bound form), DYN2 and PIK3C3 (By similarity). Interacts with NCKAP1L (PubMed:16417406). Interacts with ATG14; this interaction is increased in the absence of TMEM39A (PubMed:31806350). Interacts with STEEP1; the interaction is STING1-dependent and required for trafficking of STING1 from the endoplasmic reticulum (PubMed:32690950). Interacts with YWHAG (PubMed:33473107).
Ubiquitinated via 'Lys-29'- and 'Lys-48'-linked ubiquitination by UBE3C, promoting its degradation (PubMed:33637724). Deubiquitination by ZRANB1/TRABID promotes its stabilization, leading to autophagosome maturation (PubMed:33637724).
Ubiquitously expressed, with a highest expression in skeletal muscle.
Expressed in B-cell-enriched tissues but not in fetal or adult thymus. Expressed in fetal and adult spleen, lymph node, tonsil, bone marrow and peripheral leukocytes. Not expressed in T-cells. In pro-B, pre-B, and mature B-cell lines, it colocalizes with RAG1.
Homodimer; disulfide-linked (Potential). The relevance of homodimerization is however unsure. May interact with phosphorylated proteins in resting B-cells, including HCK.
Inhibited by phenyl beta-GalNAc(4,6-SO(4)).
Sulfotransferase that transfers sulfate from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the C-6 hydroxyl group of the GalNAc 4-sulfate residue of chondroitin sulfate A and forms chondroitin sulfate E containing GlcA-GalNAc(4,6-SO(4)) repeating units. It also transfers sulfate to a unique non-reducing terminal sequence, GalNAc(4SO4)-GlcA(2SO4)-GalNAc(6SO4), to yield a highly sulfated structure similar to the structure found in thrombomodulin chondroitin sulfate. May also act as a B-cell receptor involved in BCR ligation-mediated early activation that mediate regulatory signals key to B-cell development and/or regulation of B-cell-specific RAG expression; however such results are unclear in vivo.
Binds 8 zinc ions per octamer. Requires four zinc ions per octamer for full catalytic activity. Can bind up to 2 zinc ions per subunit.
Can alternate between a fully active homooctamer and a low-activity homohexamer. A bound magnesium ion may promote the assembly of the fully active homooctamer. The magnesium-binding site is absent in the low-activity homohexamer. Inhibited by compounds that favor the hexameric state. Inhibited by divalent lead ions. The lead ions partially displace the zinc cofactor.
Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen.
Genetic variation in ALAD influences susceptibility to lead poisoning in individuals exposed to high amount of environmental lead. There are two common alleles: allele ALAD*1 and allele ALAD*2 resulting in 3 isozymes: ALAD 1-1, ALAD 1-2, and ALAD 2-2. Individuals with ALAD 1-2 or ALAD 2-2 isozymes have levels of blood lead higher than those in individuals with ALAD 1-1 isozyme. The sequence shown corresponds to allele ALAD*1.
Homooctamer; active form. Homohexamer; low activity form.
Functions as component of the Arp2/3 complex which is involved in regulation of actin polymerization and together with an activating nucleation-promoting factor (NPF) mediates the formation of branched actin networks. Arp2/3 complex plays a critical role in the control of cell morphogenesis via the modulation of cell polarity development.
May be a component of the Arp2/3 complex in which it may replace ARPC5.
May function as component of the Arp2/3 complex which is involved in regulation of actin polymerization and together with an activating nucleation-promoting factor (NPF) mediates the formation of branched actin networks.
Confers resistance to ET-743 (trabectedin, Yondelis) and PM00104 (Zalypsis), 2 marine derived compounds with antitumor activity in cancer cell lines.
Expressed early during embryonic development.
Transcription factor specifically required to repress long interspersed nuclear element 1 (L1) retrotransposons: recognizes and binds L1 sequences and repress their expression by recruiting a repressive complex containing TRIM28/KAP1 (PubMed:25274305). Not able to repress expression of all subtypes of L1 elements. Binds to the 5' end of L1PA4, L1PA5 and L1PA6 subtypes, and some L1PA3 subtypes. Does not bind to L1PA7 or older subtypes nor at the most recently evolved L1PA2 and L1Hs. 50% of L1PA3 elements have lost the ZNF93-binding site, explaining why ZNF93 is not able to repress their expression (PubMed:25274305).
ZNF93 is only present in primates and evolved to repress the primate L1 lineage until 12.5 million years. Evolution stopped when the L1PA3-subfamily of retrotransposons, that escape repression by ZNF93 through the removal of the ZNF93-binding site, appeared (PubMed:25274305).
(Microbial infection) Interacts with P.falciparum SBP1.
Detected in erythrocytes, brain, kidney, testis, ovary, heart, lung, placenta and spleen (at protein level). Ubiquitous. Strongly expressed in brain, spinal cord, pituitary gland, kidney, heart, skeletal muscle, pancreas, ovary and testis.
Functions as glutathione transferase. Catalyzes conjugation of the glutathione (GSH) to artificial substrates 1-chloro-2,4-dinitrobenzene (CDNB) and p-nitrophenyl acetate. Mitigates neuronal oxidative stress during normal postnatal development and in response to oxidative stresses probably through GSH antioxidant defense mechanism (By similarity). May play a role in EPS8 signaling. Binds glutathione (PubMed:19528316).
Interacts with the C-terminal of STOM (PubMed:9512664). Interacts with the EPS8 SH3 domain. Interaction with EPS8 is inhibited by glutathione binding (PubMed:19528316).
Was originally thought to be a G-protein coupled receptor.
Transcription factor required for normal development of thymus, parathyroid glands, ultimobranchial bodies, teeth, skeletal elements of skull and larynx as well as distal limbs.
Belongs to the fructosamine kinase family.
Ketosamine-3-kinase involved in protein deglycation by mediating phosphorylation of ribuloselysine and psicoselysine on glycated proteins, to generate ribuloselysine-3 phosphate and psicoselysine-3 phosphate, respectively (PubMed:14633848, PubMed:15137908). Ribuloselysine-3 phosphate and psicoselysine-3 phosphate adducts are unstable and decompose under physiological conditions (PubMed:14633848, PubMed:15137908). Not able to phosphorylate fructoselysine (PubMed:14633848).
The ATP-binding domain is structurally related to aminoglycoside phosphotransferase family.
Widely expressed; except in skeletal muscle where it is expressed at very low level (PubMed:15331600). Expressed in erythrocytes (PubMed:15137908).
Abundantly expressed in testis and spleen. Relatively low levels observed in thymus, prostate, ovary and colon.
Interacts with RAD51 through the NH2-terminal domain. Immunoprecipitation experiments show that the interaction is constitutive and not induced by ionizing radiation. The interaction may be indirect.
Involved in DNA repair and mitotic recombination. May play an active role in recombination processes in concert with other members of the RAD52 epistasis group.
Component of the little elongation complex (LEC), a complex required to regulate small nuclear RNA (snRNA) gene transcription by RNA polymerase II and III (PubMed:22195968, PubMed:23932780). Specifically acts as a scaffold protein that promotes the LEC complex formation and recruitment and RNA polymerase II occupancy at snRNA genes in subnuclear bodies (PubMed:23932780).
Component of the little elongation complex (LEC), at least composed of ELL (ELL, ELL2 or ELL3), ZC3H8, ICE1 and ICE2. Interacts (via N-terminus domain) with ELL. Interacts (via C-terminus domain) with ICE2 and ZC3H8.
The N-termimus domain is necessary and sufficient for its targeting to subnuclear cajal and histone locus bodies.
Found in all tissues tested, abundantly expressed in heart, liver, skeletal muscle, kidney and pancreas, and to a lesser extent in lung and placenta. Overexpressed in keratinocytes of psoriatic lesions.
HCR*WWCC is associated with susceptibility to psoriasis. Psoriasis is a chronic inflammatory dermatosis that affects approximately 2% of the population. It is a multifactorial disease characterized by red, scaly skin lesions that are usually found on the scalp, elbows, and knees, and may be associated with severe arthritis. The lesions are caused by hyperproliferative keratinocytes and infiltration of inflammatory cells into the dermis and epidermis. The usual age of onset of psoriasis is between 15 and 30 years, although it can present at any age. Association of HCR with psoriasis seem to be due to linkage disequilibrium with Cw*06:02 (PubMed:11348465). HCR is unlikely to be directly involved in psoriasis development.
May be a regulator of keratinocyte proliferation or differentiation.
Expressed in spleen, lymph node, thymus, peripheral blood leukocytes, and fetal liver.
May be a transcription factor that may be involved in hematopoiesis, oncogenesis, and immune responses (PubMed:11352661). Plays a role in postnatal myogenesis, may be involved in the regulation of satellite cells self-renewal (By similarity).
(Microbial infection) Dominant palmitoyltransferase responsible for lipidation of SARS coronavirus-2/SARS-CoV-2 spike protein. Through a sequential action with ZDHHC9, rapidly and efficiently palmitoylates spike protein following its synthesis in the endoplasmic reticulum (ER). In the infected cell, promotes spike biogenesis by protecting it from premature ER degradation, increases half-life and controls the lipid organization of its immediate membrane environment. Once the virus has formed, spike palmitoylation controls fusion with the target cell.
Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates (PubMed:27153536, PubMed:29326245, PubMed:33219126). Catalyzes palmitoylation of Cys residues in the cytoplasmic C-terminus of EGFR, and modulates the duration of EGFR signaling by modulating palmitoylation-dependent EGFR internalization and degradation (PubMed:27153536). Has a preference for acyl-CoA with C16 fatty acid chains (PubMed:29326245). Can also utilize acyl-CoA with C14 and C18 fatty acid chains (PubMed:29326245).
Activity is enhanced by binding to the pyruvate dehydrogenase subunit DLAT. Inhibited by ADP and pyruvate; these compounds interfere with DLAT binding and thereby inhibit kinase activity. Inhibited by dichloroacetate. Inhibited by AZD7545; this compound interferes with DLAT binding and thereby inhibits kinase activity.
Down-regulated by insulin. Up-regulated by reactive oxygen species and cigarette smoke extract. Up-regulated by PPARD.
Expressed in many tissues, with the highest level in heart and skeletal muscle, intermediate levels in brain, kidney, pancreas and liver, and low levels in placenta and lung.
Homodimer, and heterodimer with PDK1. Interacts with the pyruvate dehydrogenase complex subunit DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3).
Kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.
(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) matrix protein; this interaction probably facilitates viral replication.
Belongs to the actin-binding proteins ADF family.
Binds to F-actin and exhibits pH-sensitive F-actin depolymerizing activity (PubMed:11812157). In conjunction with the subcortical maternal complex (SCMC), plays an essential role for zygotes to progress beyond the first embryonic cell divisions via regulation of actin dynamics (PubMed:15580268). Required for the centralization of the mitotic spindle and symmetric division of zygotes (By similarity). Plays a role in the regulation of cell morphology and cytoskeletal organization in epithelial cells (PubMed:21834987). Required for the up-regulation of atypical chemokine receptor ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation (PubMed:23633677). Required for neural tube morphogenesis and neural crest cell migration (By similarity).
Can bind G- and F-actin in a 1:1 ratio of cofilin to actin (PubMed:11812157). It is a major component of intranuclear and cytoplasmic actin rods (By similarity). Interacts with the subcortical maternal complex (SCMC) via interaction with TLE6 isoform 1 and NLRP5 (By similarity). Interacts with C9orf72 (By similarity).
Inactivated by phosphorylation on Ser-3. Phosphorylated on Ser-3 in resting cells (By similarity). Dephosphorylated by PDXP/chronophin; this restores its activity in promoting actin filament depolymerization. The phosphorylation of Ser-24 may prevent recognition of the nuclear localization signal (By similarity). Phosphorylated via a ARRB1-RAC1-LIMK1-PAK1 cascade upon active ligand stimulation of atypical chemokine receptor ACKR2.
Up-regulated in response to enterovirus 71 (EV71) infection (at protein level).
Component of the TSC-TBC complex (also named Rhebulator complex), composed of 2 molecules of TSC1, 2 molecules of TSC2 and 1 molecule of TBC1D7 (PubMed:17658474, PubMed:22795129, PubMed:24529379, PubMed:33436626). Interacts with TSC1 (via C-terminal half of the coiled-coil domain) (PubMed:17658474, PubMed:26893383).
Highly expressed in heart, and slightly in kidney, liver and placenta.
Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth (PubMed:22795129, PubMed:24529379). The TSC-TBC complex acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 (PubMed:22795129, PubMed:24529379). In absence of nutrients, the TSC-TBC complex inhibits mTORC1, thereby preventing phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) by the mTORC1 signaling (PubMed:22795129). The TSC-TBC complex is inactivated in response to nutrients, relieving inhibition of mTORC1 (PubMed:24529379).
Was initially identified as a negative regulator of the TSC-TBC complex (PubMed:17658474). However, it was later shown that TBC1D7 is part of the TSC-TBC complex and participates in GTPase-activating protein activity, leading to inhibition of the TOR signaling cascade (PubMed:22795129). The differences between 2 reports might be explained by experimental conditions in the initial report, in which they overexpressed the TBC1D7 subunit, possibly leading to disrupt the stoichiometric complex and its downstream functions.
(Microbial infection) Secretion is activated by bacteria such as P. aeruginos, N. gonorrhoeae and others, this activation results in the release of ceramide in the outer leaflet of the plasma membrane which facilitates the infection.
(Microbial infection) Secretion is activated by human coronaviruses SARS-CoV and SARS-CoV-2 as well as Zaire ebolavirus, this activation results in the release of ceramide in the outer leaflet of the plasma membrane which facilitates the infection.
(Microbial infection) The secretory form is activated by P. aeruginosa, this activation results in the release of ceramide in the outer leaflet of the plasma membrane.
(Microbial infection) The secretory form is activated by human coronavirus SARS-CoV-2, this activation results in the release of ceramide in the outer leaflet of the plasma membrane.
A common polymorphism arises from a variable number of hexanucleotide repeat sequence within the signal peptide region.
Binds 2 Zn(2+) ions per subunit (PubMed:27349982, PubMed:27725636).
Both lysosomal and secreted forms are glycosylated but they show a differential pattern of glycosylation.
Converts sphingomyelin to ceramide (PubMed:1840600, PubMed:18815062, PubMed:27659707, PubMed:25920558, PubMed:25339683, PubMed:33163980, PubMed:12563314). Exists as two enzymatic forms that arise from alternative trafficking of a single protein precursor, one that is targeted to the endolysosomal compartment, whereas the other is released extracellularly (PubMed:21098024, PubMed:9660788, PubMed:20807762). However, in response to various forms of stress, lysosomal exocytosis may represent a major source of the secretory form (PubMed:20530211, PubMed:12563314, PubMed:20807762, PubMed:9393854, PubMed:22573858).
Hydrolysis of liposomal sphingomyelin is stimulated by incorporation of diacylglycerol (DAG), ceramide and free fatty acids into the liposomal membranes (PubMed:25339683). Phosphatidylcholine hydrolysis is inhibited by incorporation of cholesterol, ceramide, DAG, monoacylglycerol and fatty acids (PubMed:25339683). Antidepressants, namely amitriptyline, imipramine, desipramine, fluoxetine, sertraline, escitalopram, and maprotiline inhibit sphingomyelin phosphodiesterase activity (PubMed:33163980, PubMed:22573858).
In the lysosomes, converts sphingomyelin to ceramide (PubMed:20807762, PubMed:21098024). Plays an important role in the export of cholesterol from the intraendolysosomal membranes (PubMed:25339683). Also has phospholipase C activities toward 1,2-diacylglycerolphosphocholine and 1,2-diacylglycerolphosphoglycerol (PubMed:25339683). Modulates stress-induced apoptosis through the production of ceramide (PubMed:8706124).
Lacks residues that bind the cofactor Zn(2+) and has no enzyme activity.
Monomer. Interacts with SORT1; the interaction is required for SMPD1 targeting to lysosomes (PubMed:16787399).
Phosphorylated at Ser-510 by PRKCD upon stress stimuli. Phosphorylation is required for secretion.
Proteolytically processed (PubMed:21098024, PubMed:9030779). Mature lysosomal form arises from C-terminal proteolytic processing of pro-sphingomyelin phosphodiesterase (PubMed:21098024).
There are two types of sphingomyelinases: ASM (acid), and NSM (neutral).
This form is generated following cleavage by CASP7 in the extracellular milieu (PubMed:21157428). It shows increased activity (By similarity).
This form is generated following cleavage by CASP7 in the extracellular milieu in response to bacterial infection (PubMed:21157428). It shows increased ability to convert sphingomyelin to ceramide and promotes plasma membrane repair (By similarity). Plasma membrane repair by ceramide counteracts the action of gasdermin-D (GSDMD) perforin (PRF1) pores that are formed in response to bacterial infection (By similarity).
Variants Gln-294 and Val-485 have been originally reported as disease-causing mutations in NPDA and NPDB (PubMed:12369017, PubMed:15221801). These variants have been reclassified as benign polymorphisms (PubMed:23430512).
When secreted, modulates cell signaling with its ability to reorganize the plasma membrane by converting sphingomyelin to ceramide (PubMed:12563314, PubMed:20807762, PubMed:17303575). Secreted form is increased in response to stress and inflammatory mediators such as IL1B, IFNG or TNF as well as upon infection with bacteria and viruses (PubMed:12563314, PubMed:20807762, PubMed:9393854). Produces the release of ceramide in the outer leaflet of the plasma membrane playing a central role in host defense (PubMed:12563314, PubMed:20807762, PubMed:9393854). Ceramide reorganizes these rafts into larger signaling platforms that are required to internalize P. aeruginosa, induce apoptosis and regulate the cytokine response in infected cells (PubMed:12563314). In wounded cells, the lysosomal form is released extracellularly in the presence of Ca(2+) and promotes endocytosis and plasma membrane repair (PubMed:20530211).
A report observed N-glycosylation at Asn-89 (PubMed:19139490). However, as the protein is not predicted to localize in an extracellular compartment of the cell, additional evidence is required to confirm this result.
May increase cell susceptibility to TNF-induced apoptosis.
Was shown to be an inhibitor of protein-phosphatase 1, to promote cell growth and cell cycle progress at the G1/S transition and to interact with PPP1CB (PubMed:18310074). The article has later been withdrawn by the authors.
C2 domain 1 is involved in binding calcium and phospholipids. Calcium binds with low affinity but with high specificity and induces a large conformational change.
Interacts with BSN, ERC2/CAST1, RIMS1 and UNC13A (By similarity). Interacts (via C-terminus) with TRIO (via N-terminus) (By similarity). Interacts with CTBP1 (By similarity). Interacts with SIAH1; this interaction negatively regulates SIAH1 E3 ligase activity (By similarity). Directly interacts with GIT1 and GIT2 (By similarity).
Moderately expressed in the developing cerebral cortex.
Scaffold protein of the presynaptic cytomatrix at the active zone (CAZ) which is the place in the synapse where neurotransmitter is released (By similarity). After synthesis, participates in the formation of Golgi-derived membranous organelles termed Piccolo-Bassoon transport vesicles (PTVs) that are transported along axons to sites of nascent synaptic contacts (By similarity). At the presynaptic active zone, regulates the spatial organization of synaptic vesicle cluster, the protein complexes that execute membrane fusion and compensatory endocytosis (By similarity). Organizes as well the readily releasable pool of synaptic vesicles and safeguards a fraction of them to be not immediately available for action potential-induced release (By similarity). Functions also in processes other than assembly such as the regulation of specific presynaptic protein ubiquitination by interacting with SIAH1 or the regulation of presynaptic autophagy (By similarity). Mediates also synapse to nucleus communication leading to reconfiguration of gene expression by associating with the transcriptional corepressor CTBP1 and by subsequently reducing the size of its pool available for nuclear import (By similarity).
Belongs to the JHDM2 histone demethylase family.
Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Preferentially demethylates mono- and dimethylated H3 'Lys-9' residue, with a preference for dimethylated residue, while it has weak or no activity on trimethylated H3 'Lys-9'. Demethylation of Lys residue generates formaldehyde and succinate. Involved in hormone-dependent transcriptional activation, by participating in recruitment to androgen-receptor target genes, resulting in H3 'Lys-9' demethylation and transcriptional activation. Involved in spermatogenesis by regulating expression of target genes such as PRM1 and TNP1 which are required for packaging and condensation of sperm chromatin. Involved in obesity resistance through regulation of metabolic genes such as PPARA and UCP1.
Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs are known to mediate the association with nuclear receptors.
The JmjC domain and the C6-type zinc-finger are required for the demethylation activity.
Associates with F-actin. Interacts with DCTN1; this interaction regulates DCTN1 distribution at the cell cortex. Interacts with PTK2/FAK and MAPRE1.
Phosphorylated by CDK1 and PLK1. CDK1 is the priming kinase for PLK1 phosphorylation. Phosphorylation by PLK1 is required for proper spindle orientation at metaphase.
Plays a role in mitotic spindle orientation and mitotic progression. Regulates the distribution of dynactin at the cell cortex in a PLK1-dependent manner, thus stabilizing cortical and astral microtubule attachments required for proper mitotic spindle positioning. May link microtubules to the actin cytospkeleton and focal adhesions. May be required for directed cell migration and centrosome orientation. May also be necessary for proper stacking of the Golgi apparatus.
Regulated in a cell-cycle dependent manner. Weakly expressed in G1 and S phases. Expression increases in G2/M phases and persisting until the end of mitosis (at protein level).
Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity. May act through the stabilization of endothelial cell junctions (By similarity). May function as a scaffold protein for MAP2K3-MAP3K3 signaling. Seems to play a major role in the modulation of MAP3K3-dependent p38 activation induced by hyperosmotic shock (By similarity).
Part of a complex with MAP2K3, MAP3K3 and RAC1. Binds RAC1 directly and independently of its nucleotide-bound state (By similarity). Interacts with HEG1 and KRIT1; KRIT1 greatly facilitates the interaction with HEG1 (By similarity). Interacts with PDCD10.
The C-terminal region constitutes an independently folded domain that has structural similarity with the USH1C (harmonin) N-terminus, despite very low sequence similarity.
Expressed in retinal choroid, ciliary epithelium, longitudinal and circular ciliary muscles, iris, small intestine and platelet membranes.
Receptor for prostaglandin D2 (PGD2). The activity of this receptor is mainly mediated by G(s) proteins that stimulate adenylate cyclase, resulting in an elevation of intracellular cAMP. A mobilization of calcium is also observed, but without formation of inositol 1,4,5-trisphosphate (By similarity). Involved in PLA2G3-dependent maturation of mast cells. PLA2G3 is secreted by immature mast cells and acts on nearby fibroblasts upstream to PTDGS to synthesize PGD2, which in turn promotes mast cell maturation and degranulation via PTGDR (By similarity).
Highly expressed in adrenal gland, thyroid gland, testis, ovary and prostate (PubMed:12359240). Moderate expression in trachea, spinal cord, stomach, colon, small intestine and spleen (PubMed:12359240, PubMed:30374053). Low expression in bone marrow, lymph node, thymus and peripheral blood lymphocytes (PubMed:12359240). Expression is detected in hematopoietic cell lines including those of myeloid, erythroid, B- and T-cell origin (PubMed:12359240).
Interacts with the v-ATPase accessory protein ATP6AP2 and with the v-ATPase complex subunit ATP6V0D1; these interactions lead to the assembly of the v-ATPase complex.
The transmembrane domain (TMD) is essential for the interaction with ATP6AP2.
Transmembrane protein that binds to and facilitates the assembly of lysosomal proton-transporting V-type ATPase (v-ATPase), resulting in enhanced lysosomal acidification and trafficking (PubMed:30374053). By bringing the v-ATPase accessory protein ATP6AP2 and the v-ATPase subunit ATP6V0D1 together, allows v-ATPase complex formation and activation (PubMed:30374053). TMEM9-controlled vesicular acidification induces hyperactivation of Wnt/beta-catenin signaling, involved in development, tissue homeostasis and tissue regeneration, through lysosomal degradation of adenomatous polyposis coli/APC (PubMed:30374053, PubMed:32380568). In the liver, involved in hepatic regeneration (PubMed:32380568).
Interacts with CEP290 (PubMed:23644468). Interacts with CPNE4 (By similarity). Interacts with alpha-tubulin (By similarity).
Promotes ectopic assembly of transition zone components at cilia tips when targeted outside distal ends of centrioles, generating extra-long cilia with strikingly swollen tips.
Required to promote assembly of the transition zone in primary cilia. Acts by specifically recognizing and binding the axonemal microtubule. Localizes to the distal ends of centrioles before ciliogenesis and directly binds to axonemal microtubule, thereby promoting and restricting transition zone formation specifically at the cilia base. Required to mediate CEP290 association with microtubules.
Was initially thought to regulate chromosome segregation and mitotic spindle assembly (PubMed:16302001). However, it was later shown that its absence neither affect mitosis nor centriole duplication (PubMed:23644468).
Ciliary dysfunction leads to a broad spectrum of disorders, collectively termed ciliopathies. Overlapping clinical features include retinal degeneration, renal cystic disease, skeletal abnormalities, fibrosis of various organ, and a complex range of anatomical and functional defects of the central and peripheral nervous system. The ciliopathy range of diseases includes Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, nephronophtisis, Senior-Loken syndrome, and Jeune asphyxiating thoracic dystrophy among others. Single-locus allelism is insufficient to explain the variable penetrance and expressivity of such disorders, leading to the suggestion that variations across multiple sites of the ciliary proteome, including RPGRIP1L, influence the clinical outcome.
Interacts with NPHP4 and NPHP1; NPHP1, NPHP4 and RPGRIP1L are proposed to form a functional NPHP1-4-8 module localized to cell-cell contacts and the ciliary transition zone; NPHP4 mediates the interaction between NPHP1 and RPGRIP1L. Interacts with IQCB1; the interaction likely requires additional interactors (By similarity). Interacts with TBXA2R (via C-terminus). Interacts with RPGR. Interacts with NEK4. Interacts with NPHP4, INVS and DVL2; the complex is proposed to be involved in DVL2 stabilization.
Negatively regulates signaling through the G-protein coupled thromboxane A2 receptor (TBXA2R) (PubMed:19464661). May be involved in mechanisms like programmed cell death, craniofacial development, patterning of the limbs, and formation of the left-right axis (By similarity). Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module. Does not seem to be strictly required for ciliogenesis (PubMed:19464661). Involved in establishment of planar cell polarity such as in cochlear sensory epithelium and is proposed to implicate stabilization of disheveled proteins (By similarity). Involved in regulation of proteasomal activity at the primary cilium probably implicating association with PSDM2 (By similarity).
Ubiquitously expressed with relatively high level of expression in hypothalamus and islet. During early development, expressed in multiple organs including brain, eye, forelimb and kidney.
A 70 kDa form is created by proteolytic cleavage. Cleavage is elevated during myogenic differentiation and the cleaved form enhances cell adhesion and spreading on laminin.
ADP-ribosylated on at least two sites of the extracellular domain in skeletal myotubes.
Heterodimer of an alpha and a beta subunit. The alpha subunit is composed of a heavy and a light chain linked by a disulfide bond. Alpha-7 associates with beta-1. Interacts with COMP (By similarity). Interacts (via C-terminus intracellular tail region) with CIB1; the interaction is stabilized/increased in a calcium- and magnesium-dependent manner.
In renewing intestinal epithelium, expression of isoforms containing segment B correlates with the onset of enterocytic differentiation.
Integrin alpha-7/beta-1 is the primary laminin receptor on skeletal myoblasts and adult myofibers. During myogenic differentiation, it may induce changes in the shape and mobility of myoblasts, and facilitate their localization at laminin-rich sites of secondary fiber formation. It is involved in the maintenance of the myofibers cytoarchitecture as well as for their anchorage, viability and functional integrity. Isoform Alpha-7X2B and isoform Alpha-7X1B promote myoblast migration on laminin 1 and laminin 2/4, but isoform Alpha-7X1B is less active on laminin 1 (In vitro). Acts as Schwann cell receptor for laminin-2. Acts as a receptor of COMP and mediates its effect on vascular smooth muscle cells (VSMCs) maturation (By similarity). Required to promote contractile phenotype acquisition in differentiated airway smooth muscle (ASM) cells.
Isoforms containing segment A are predominantly expressed in skeletal muscle. Isoforms containing segment B are abundantly expressed in skeletal muscle, moderately in cardiac muscle, small intestine, colon, ovary and prostate and weakly in lung and testes. Isoforms containing segment X2D are expressed at low levels in fetal and adult skeletal muscle and in cardiac muscle, but are not detected in myoblasts and myotubes. In muscle fibers isoforms containing segment A and B are expressed at myotendinous and neuromuscular junctions; isoforms containing segment C are expressed at neuromuscular junctions and at extrasynaptic sites. Isoforms containing segments X1 or X2 or, at low levels, X1X2 are expressed in fetal and adult skeletal muscle (myoblasts and myotubes) and cardiac muscle.
Exists as an octamer composed of four MTCK homodimers.
Mitochondrial creatine kinase binds cardiolipin.
(Microbial infection) In the mosquito midgut, binds to the surface of parasite P.falciparum gametocytes and protects the parasite from alternative complement pathway-mediated elimination.
(Microbial infection) Interacts (via sushi 4-6 domains) with P.falciparum surface protein PF92; the interaction recruits CFH onto the merozoite surface preventing complement-mediated cell lysis (PubMed:26700768). The interaction does not affect CFH activity (PubMed:26700768). Interacts (via sushi 6-7 domains) with P.falciparum (strain NF54) GAP50; the interaction occurs in the vector mosquito midgut at the surface of the activated parasite gametocytes; the interaction protects the parasite from alternative complement pathway-mediated elimination (PubMed:23332154).
(Microbial infection) Interacts (via sushi 4-6 domains) with P.falciparum surface protein PF92; the interaction recruits FHL-1 isoform onto the merozoite surface preventing complement-mediated cell lysis (PubMed:26700768). The interaction does not affect FHL-1 isoform activity (PubMed:26700768). Interacts (via sushi 6-7 domains) with P.falciparum (strain NF54) GAP50; the interaction occurs in the vector mosquito midgut at the surface of the activated parasite gametocytes; the interaction protects the parasite from alternative complement pathway-mediated elimination (PubMed:23332154).
(Microbial infection) Interacts with Borrelia burgdorferi outer surface protein E/OspE; this interaction recruits complement regulator factor H onto the bacterial surface to evade complement-mediated cell lysis.
(Microbial infection) Interacts with C.albicans GPD2; the interaction is direct and leads to the degradation of C3 which enables the pathogen to evade the host innate immune system.
(Microbial infection) Interacts with Neisseria meningitidis protein fHbp.
(Microbial infection) Interacts with Staphylococcus aureus protein Sbi; this interaction inhibits the complement activation of the alternative pathway.
(Microbial infection) Interacts with Staphylococcus aureus surface protein serine-aspartate repeat protein E/SdrE; this interaction sequesters CFH on the surface of S.aureus for complement evasion.
(Microbial infection) Interacts with Streptococcus pneumoniae protein virulence factor choline-binding protein A/CbpAN; this interaction enables Streptococcus pneumoniae to evade surveillance by human complement system.
(Microbial infection) Interacts with West nile virus non-structural protein 1 (NS1); this interaction leads to the degradation of C3.
According to a report, Asn-217 is not glycosylated (PubMed:17591618). Another study observed glycosylation at this position (PubMed:19139490).
Disease susceptibility is associated with variants affecting the gene represented in this entry. Other genes may play a role in modifying the phenotype.
Expressed in the retinal pigment epithelium (at protein level) (PubMed:25136834). CFH is one of the most abundant complement components in blood where the liver is the major source of CFH protein in vivo. in addition, CFH is secreted by additional cell types including monocytes, fibroblasts, or endothelial cells (PubMed:6444659, PubMed:2968404, PubMed:2139673, PubMed:25136834).
Glycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation. Acts as a soluble inhibitor of complement, where its binding to self markers such as glycan structures prevents complement activation and amplification on cell surfaces (PubMed:21285368, PubMed:25402769). Accelerates the decay of the complement alternative pathway (AP) C3 convertase C3bBb, thus preventing local formation of more C3b, the central player of the complement amplification loop (PubMed:19503104, PubMed:26700768). As a cofactor of the serine protease factor I, CFH also regulates proteolytic degradation of already-deposited C3b (PubMed:23332154, PubMed:18252712, PubMed:28671664). In addition, mediates several cellular responses through interaction with specific receptors. For example, interacts with CR3/ITGAM receptor and thereby mediates the adhesion of human neutrophils to different pathogens. In turn, these pathogens are phagocytosed and destroyed (PubMed:9558116, PubMed:20008295).
Homodimer (PubMed:18005991, PubMed:19505476). Forms also homooligomers (PubMed:19505476). Interacts with complement protein C3b; this interaction inhibits complement activation (PubMed:16601698, PubMed:19503104, PubMed:20378178, PubMed:21285368, PubMed:28671664). Interacts with complement protein C3d (PubMed:20378178, PubMed:21285368, PubMed:29190743). Interacts with CR3/ITGAM; this interaction mediates adhesion of neutrophils to pathogens leading to pathogen clearance (PubMed:9558116, PubMed:20008295). Interacts with complement factor I (PubMed:28671664).
Sushi 1-3 domain represents the minimal unit capable of cofactor activity (PubMed:18252712). The property to discriminate self surfaces from non-self surfaces depends on the C-terminal region made of Sushis 19-20 (PubMed:21285368).
(Microbial infection) Binds tightly to the human immunodeficiency virus-type 1 (HIV-1) integrase in vitro and stimulates its DNA-joining activity. Interacts with human papillomavirus 18 E1 protein to stimulate its viral replication (PubMed:10365963). Interacts with Epstein-Barr virus protein EBNA-2 (PubMed:8709224).
Component of the multiprotein chromatin-remodeling complexes SWI/SNF.
Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B) and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific (Probable). Component of the BAF complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57 SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C. In muscle cells, the BAF complex also contains DPF3 (PubMed:8895581, PubMed:18765789). Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin (By similarity). Component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin (PubMed:26601204). Binds to double-stranded DNA. Interacts with CEBPB (when not methylated) (PubMed:20111005). Interacts with PIH1D1 (PubMed:22368283). Interacts with MYK and MAEL (PubMed:10319872). Interacts with PPP1R15A (PubMed:10490642, PubMed:12016208). Interacts with DPF2 (PubMed:20460684). Interacts with YWHAZ (PubMed:16959763). Interacts with ERCC6 (PubMed:24874740). Interacts with FOS, FOSB isoform 1 and 2, FOSL1 and FOSL2 (By similarity).
Core component of the BAF (hSWI/SNF) complex. This ATP-dependent chromatin-remodeling complex plays important roles in cell proliferation and differentiation, in cellular antiviral activities and inhibition of tumor formation. The BAF complex is able to create a stable, altered form of chromatin that constrains fewer negative supercoils than normal. This change in supercoiling would be due to the conversion of up to one-half of the nucleosomes on polynucleosomal arrays into asymmetric structures, termed altosomes, each composed of 2 histones octamers. Stimulates in vitro the remodeling activity of SMARCA4/BRG1/BAF190A. Involved in activation of CSF1 promoter. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Plays a key role in cell-cycle control and causes cell cycle arrest in G0/G1.
The N-terminal DNA-binding region is structurally similar to winged helix domains.
Acts as a transcriptional repressor. Corepressor for REST. Interacts with MXI1 to repress MYC responsive genes and antagonize MYC oncogenic activities. Also interacts with MXD1-MAX heterodimers to repress transcription by tethering SIN3A to DNA. Acts cooperatively with OGT to repress transcription in parallel with histone deacetylation. Involved in the control of the circadian rhythms. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex through histone deacetylation. Cooperates with FOXK1 to regulate cell cycle progression probably by repressing cell cycle inhibitor genes expression (By similarity). Required for cortical neuron differentiation and callosal axon elongation (By similarity).
Expressed in the developing brain, with highest levels of expression detected in the ventricular zone of various cortical regions.
Interacts with ARID4B, BRMS1L, HCFC1, HDAC1, HDAC2, MXI1, SAP30L, SAP130, SFPQ and TOPORS (PubMed:11259580, PubMed:11897684, PubMed:12670868, PubMed:12724404, PubMed:15451426, PubMed:16820529, PubMed:17803295). Interacts with OGT (via TPRs 1-6); the interaction mediates transcriptional repression in parallel with histone deacetylase (PubMed:12150998). Interacts with BAZ2A, MXD1, MXD3, MXD4, MBD2, DACH1, NCOR1, NR4A2, REST, RLIM, SAP30, SETDB1, SMYD2, and SUDS3 (PubMed:14525983). Interacts with PHF12 in a complex composed of HDAC1, PHF12 and SAP30 (By similarity). Interacts with TET1; the interaction recruits SIN3A to gene promoters (PubMed:21490601). The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A (By similarity). Interacts with KLF11 (By similarity). Interacts with PPHLN1 (PubMed:17963697). Found in a complex with YY1, GON4L and HDAC1 (By similarity). Interacts (via PAH2) with FOXK1 (By similarity). Interacts with FOXK2 (By similarity). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1. Interacts with SINHCAF (By similarity). Interacts with SPHK2 (PubMed:19729656).
SUMO1 sumoylated by TOPORS. Probably desumoylated by SENP2.
Although highly similar to the deubiquitinase OTULIN, lacks the conserved active site Cys at position 139 which is replaced by an Asp residue, and does not show deubiquitinase activity.
Belongs to the peptidase C65 family. Otulin subfamily.
Does not bind ubiquitin or ubiquitin-like proteins.
The N-terminal region that precedes the OTU domain mediates interaction with cellular membranes.
While belonging to the class-I pyridoxal-phosphate-dependent aminotransferase family, it lacks a number of residues which are necessary for activity thus suggesting that it lacks enzymatic activity.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv10.2/KCNH5 sub-subfamily.
Detected in brain, skeletal muscle, heart, placenta, lung and liver, and at low levels in kidney.
Pore-forming (alpha) subunit of voltage-gated potassium channel. Elicits a non-inactivating outward rectifying current. Channel properties may be modulated by cAMP and subunit assembly.
The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming alpha subunits that can associate with modulating beta subunits. Heteromultimer with KCNH1/EAG (Probable).
Isoform 1 interacts with PPP2CA. Isoform 2 does not interact with PPP2CA. Interacts with PPP2CB, PPP4C and PPP6C. Interacts with IGBP1; the interaction is dependent on PPP2CA. Associates with a protein phosphatase 2A PP2A(C):IGBP1 complex. Interacts with PPP4C and PPP4R2.
May be a allosteric regulator of serine/threonine-protein phosphatase 2A (PP2A). Isoform 1 inhibits catalytic activity of the PP2A(D) core complex in vitro. The PP2A(C):TIPRL complex does not show phosphatase activity. Acts as negative regulator of serine/threonine-protein phosphatase 4 probably by inhibiting the formation of the active PPP4C:PPP4R2 complex; the function is proposed to implicate it in DNA damage response by promoting H2AX phosphorylated on Ser-140 (gamma-H2AX). May play a role in the regulation of ATM/ATR signaling pathway controlling DNA replication and repair.
Highly expressed in testis, placenta and pancreas. Moderately expressed in heart, lung and mammary gland. Weakly expressed in brain, colon, kidney, liver, ovary, prostate, small intestine, spleen and thymus.
In humans, 3-beta-sulfooxy-androst-5-en-17-one (DHEAS) is the most abundant circulating steroid sulfate in the human body, it is mainly synthesized from adrenal glands and gonads, whereas rats and mice have low circulating concentrations of DHEAS in the periphery as they can only produce DHEAS in their gonads.
Transports sulfoconjugated steroid hormones from the extracellular compartment into the cytosol in a sodium-dependent manner without hydrolysis (PubMed:17491011, PubMed:23667501, PubMed:24717977, PubMed:28951227). Steroid sulfate hormones are commonly considered to be biologically inactive metabolites, that may be activated by steroid sulfatases into free steroids (PubMed:23667501, PubMed:24717977). May play an important role by delivering sulfoconjugated steroids to specific target cells in reproductive organs (By similarity). May play a role transporting the estriol precursor 16alpha-hydroxydehydroepiandrosterone 3-sulfate (16a-OH-DHEAS) at the fetal blood vessel endothelium (PubMed:24717977). Can also transport other sulfoconjugated molecules such as taurolithocholic acid-3-sulfate and sulfoconjugated pyrenes (PubMed:17491011).
2 alleles have been identified: UGT2B7*1 (His-268) and UGT2B7*2 (Tyr-268). The sequence shown is that of allele UGT2B7*2.
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:10702251, PubMed:15472229, PubMed:15470161, PubMed:18674515, PubMed:18719240, PubMed:19022937, PubMed:23288867, PubMed:23756265, PubMed:26220143, PubMed:17442341). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:15470161, PubMed:18674515, PubMed:23756265). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (epitestosterone, androsterone) and estrogens (estradiol, epiestradiol, estriol, catechol estrogens) (PubMed:2159463, PubMed:15472229, PubMed:18719240, PubMed:19022937, PubMed:23288867, PubMed:26220143, PubMed:17442341). Also regulates the levels of retinoic acid, a major metabolite of vitamin A involved in apoptosis, cellular growth and differentiation, and embryonic development (PubMed:10702251). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, caderastan and zolarsatan, drugs which can inhibit the effect of angiotensin II (PubMed:18674515). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161).
Expressed at low level in testis and undifferentiated embryonic stem cells.
Transcription factor that acts as activator.
(Microbial infection) Interacts with SV40 Large T antigen; this interaction allows viral DNA replication.
(Microbial infection) Interacts with herpes simplex virus 1/HHV-1 replication origin-binding protein UL9.
A 165 kDa form is probably produced by proteolytic cleavage at Lys-124.
Autoinhibited in apo-primosome, where the zinc motif of POLA1 and oligonucleotide/olicosaccharide-binding domain of POLA2 are placed into the active site blocking RNA:DNA duplex entry.
Catalytic subunit of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which plays an essential role in the initiation of DNA synthesis. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, a regulatory subunit POLA2 and two primase subunits PRIM1 and PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes. In the cytosol, responsible for a substantial proportion of the physiological concentration of cytosolic RNA:DNA hybrids, which are necessary to prevent spontaneous activation of type I interferon responses (PubMed:27019227).
Component of the alpha DNA polymerase complex (also known as the alpha DNA polymerase-primase complex) consisting of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and the primase complex subunits PRIM1 and PRIM2 respectively (PubMed:9705292, PubMed:26975377). Interacts with PARP1; this interaction functions as part of the control of replication fork progression (PubMed:9518481). Interacts with MCM10 and WDHD1; these interactions recruit the polymerase alpha complex to the pre-replicative complex bound to DNA (PubMed:19608746). Interacts with RPA1; this interaction stabilizes the replicative complex and reduces the misincorporation rate of DNA polymerase alpha by acting as a fidelity clamp (PubMed:9214288).
In eukaryotes there are five DNA polymerases: alpha, beta, gamma, delta, and epsilon which are responsible for different reactions of DNA synthesis.
The CysA-type zinc finger is required for PCNA-binding.
The disease is caused by variants affecting the gene represented in this entry. XLPDR is caused by a recurrent intronic mutation that results in missplicing and reduced POLA1 expression. This leads to a decrease in cytosolic RNA:DNA hybrids and constitutive activation of type I interferon responses, but has no effect on cell replication.
As component of the WDR11 complex acts together with TBC1D23 to facilitate the golgin-mediated capture of vesicles generated using AP-1 (PubMed:29426865). May have a role in spermatogenesis.
Component of the complex WDR11 composed of C17orf75, FAM91A1 and WDR11; FAM91A1 and WDR11 are required for proper location of the complex (PubMed:29426865). Interacts with TBC1D23; this interaction may be indirect and recruits TBC1D23 to AP-1-derived vesicles (PubMed:29084197, PubMed:29426865).
Highly expressed in testis and also expressed in fetal testis.
E3 ubiquitin-protein ligase mediating 'Lys-48'-linked polyubiquitination of LIMK1 and its subsequent targeting to the proteasome for degradation (By similarity). Negatively regulates axonal outgrowth through regulation of the LIMK1 turnover (By similarity). Mediates 'Lys-6' and 'Lys-27'-linked polyubiquitination of AR/androgen receptor thereby modulating its transcriptional activity (PubMed:19345326). May also bind DNA and function as a transcriptional regulator (By similarity). Mediates polyubiquitination of QKI in macrophages, leading to its degradation (By similarity).
Weakly expressed in peripheral blood, spleen, prostate, testis and ovary (PubMed:19345326). According to a report, it is preferentially expressed in testis and ovary and hardly detected in other tissues (PubMed:18368307).
May be a substrate-specific adapter of a CUL3-based E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins during spermatogenesis.
Self-associates (Probable). Interacts with CUL3; indicative for the participation in an E3 ubiquitin ligase complex (By similarity).
Interacts with KATNA1 and KATNB1; katanin complex formation KATNA1:KATNB1 is required for the association.
Involved in mitotic spindle regulation and coordination of mitotic processes. The function in regulating microtubule dynamics at spindle poles including spindle orientation, astral microtubule density and poleward microtubule flux seems to depend on the association with the katanin complex formed by KATNA1 and KATNB1. Enhances the microtubule lattice severing activity of KATNA1 by recruiting the katanin complex to microtubules. Can block microtubule minus-end growth and reversely this function can be enhanced by the katanin complex (PubMed:28436967). May have a preferential role in regulating neurogenesis.
F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units (PubMed:14980219). Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of corepressor complexes that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of transcription repressor complexes, thereby allowing cofactor exchange (PubMed:21240272).
Homotetramer; dimer of dimers (PubMed:21240272). Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:10809664, PubMed:21240272). Interacts with GPS2 (when sumoylated); leading to protect GPS2 against degradation by the proteasome (PubMed:24943844). Component of a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X (PubMed:11389839). Probably part of other corepressor complexes, that do not contain NCOR1 and NCOR2. Interacts with histones H2B, H3a and H4. Interacts with MECP2; recruits TBL1X to the heterochromatin foci (By similarity). Interacts with USP44 (PubMed:27880911).
Autophosphorylated. Phosphorylated and activated by JNK1.
Interacts with Nkx1-2, Nkx2-5, MYB, PARK7, DAXX and p53/TP53. Part of a cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response to TNF. This complex formation promotes MAP3K5-JNK activation and subsequent apoptosis.
Serine/threonine-protein kinase involved in transcription regulation and TNF-mediated cellular apoptosis. Plays a role as a corepressor for homeodomain transcription factors. Phosphorylates DAXX and MYB. Phosphorylates DAXX in response to stress, and mediates its translocation from the nucleus to the cytoplasm. Inactivates MYB transcription factor activity by phosphorylation. Prevents MAP3K5-JNK activation in the absence of TNF. TNF triggers its translocation to the cytoplasm in response to stress stimuli, thus activating nuclear MAP3K5-JNK by derepression and promoting apoptosis. May be involved in anti-oxidative stress responses. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis. Promotes angiogenesis and to be involved in erythroid differentiation. May be involved in malignant squamous cell tumor formation. Phosphorylates PAGE4 at 'Thr-51' which is critical for the ability of PAGE4 to potentiate the transcriptional activator activity of JUN (PubMed:24559171).
Sumoylated. When conjugated it is directed to nuclear speckles. SENP1-mediated desumoylation is mediated by TNF in response to stress stimuli, triggering transient translocation from nucleus to cytoplasm.
Ubiquitously expressed with highest levels in skeletal muscle and heart. Overexpressed in breast cancer cell lines. Isoform 2 is highly expressed in testis. Expressed in both androgen-dependent and androgen-independent prostate cancer cells (PubMed:28289210).
Homotetramer (PubMed:25478839). Interacts with BNIP3.
In the production of energy from fats, this is one of the enzymes that catalyzes the last step of the mitochondrial beta-oxidation pathway, an aerobic process breaking down fatty acids into acetyl-CoA (Probable). Using free coenzyme A/CoA, catalyzes the thiolytic cleavage of medium- to long-chain unbranched 3-oxoacyl-CoAs into acetyl-CoA and a fatty acyl-CoA shortened by two carbon atoms (Probable). Also catalyzes the condensation of two acetyl-CoA molecules into acetoacetyl-CoA and could be involved in the production of ketone bodies (Probable). Also displays hydrolase activity on various fatty acyl-CoAs (PubMed:25478839). Thereby, could be responsible for the production of acetate in a side reaction to beta-oxidation (Probable). Abolishes BNIP3-mediated apoptosis and mitochondrial damage (PubMed:18371312).
Binds two calcium ions per molecule with an affinity similar to that of the S-100 proteins.
Facilitates the differentiation and the cornification of keratinocytes.
Phosphorylation at Thr-10 by PRKCA significantly suppresses homodimerization and promotes association with NCL/nucleolin which induces nuclear translocation.
Component of the RZZ complex composed of KNTC1/ROD, ZW10 and ZWILCH; in the complex interacts directly with KNTC1/ROD.
Essential component of the mitotic checkpoint, which prevents cells from prematurely exiting mitosis. Required for the assembly of the dynein-dynactin and MAD1-MAD2 complexes onto kinetochores. Its function related to the spindle assembly machinery is proposed to depend on its association in the mitotic RZZ complex (PubMed:15824131).
Essential component of the mitotic checkpoint, which prevents cells from prematurely exiting mitosis. Required for the assembly of the dynein-dynactin and MAD1-MAD2 complexes onto kinetochores. Its function related to the spindle assembly machinery is proposed to depend on its association in the mitotic RZZ complex.
ZWILCH gene is deleted in a patient suffering from colorectal cancer with chromosomal instability.
Abundant in skeletal muscle and also detectable in brain and heart.
Belongs to the chloride channel (TC 2.A.49) family. ClC-4/CLCN4 subfamily.
Monomer (PubMed:28972156). Forms heterodimers with CLCN3 (PubMed:28972156).
Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons (PubMed:18063579, PubMed:28972156, PubMed:23647072, PubMed:27550844, PubMed:25644381). The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons (PubMed:29845874). The presence of conserved gating glutamate residues is typical for family members that function as antiporters (PubMed:29845874).
Detected in taste bud cells in fungiform papillae (at protein level) (PubMed:19812697). Ubiquitous (PubMed:9748274). Expressed in adult heart, skeletal muscle, brain, spleen, testis, retina and liver (PubMed:9748274, PubMed:9878261). Isoform 4 appears to be expressed only in transformed lymphoblasts.
Homotetramer (PubMed:25820328, PubMed:30004384). Heterotetramer with either PKD1L1, PKD1L3 or PKD1; the heterotetrameric complex probably contains three PKD1L2 chains plus one chain from another family member (PubMed:25820328, PubMed:23212381). Interacts with PKD1L1, forming a ciliary calcium channel (PubMed:24336289). Interacts with PKD1L3, forming a cation channel that is activated by low extracellular pH (PubMed:25820328, PubMed:23212381). Interacts with PKD1 (By similarity). Interacts with RACK1; inhibits the channel activity possibly by impairing localization to the cell membrane (PubMed:22174419).
Interaction of the cytoplasmic N- and C-terminal domains is important for channel activity.
Palmitoylation is important for expression at the cell membrane and for channel activity.
Pore-forming subunit of a heterotetrameric, non-selective cation channel that is permeable to Ca(2+) (PubMed:10517637, PubMed:11959145, PubMed:25820328, PubMed:27754867, PubMed:29425510, PubMed:23212381, PubMed:30004384). Pore-forming subunit of a calcium-permeant ion channel formed by PKD1L2 and PKD1L1 in primary cilia, where it controls cilium calcium concentration, but does not affect cytoplasmic calcium concentration (PubMed:24336289). The channel formed by PKD1L2 and PKD1L1 in primary cilia regulates sonic hedgehog/SHH signaling and GLI2 transcription (PubMed:24336289). Pore-forming subunit of a channel formed by PKD1L2 and PKD1L3 that contributes to sour taste perception in gustatory cells (PubMed:19812697). The heteromeric channel formed by PKD1L2 and PKD1L3 is activated by low pH, but opens only when the extracellular pH rises again (PubMed:23212381). May play a role in the perception of carbonation taste (By similarity). May play a role in the sensory perception of water, via a mechanism that activates the channel in response to dilution of salivary bicarbonate and changes in salivary pH (By similarity).
The EF-hand domain probably mediates calcium-binding. It is not required for channel activation (PubMed:11959145).
The active channel complex is an obligate tetramer (PubMed:25820328, PubMed:30004384). In contrast, the isolated cytoplasmic C-terminal domain forms homotrimers in vitro (PubMed:20408813, PubMed:25820328, PubMed:23212381). Likewise, photobleaching experiments suggest formation of homotrimers in the membrane (PubMed:23212381).
The cation channel is gated following an off-response property by acid: gated open after the removal of acid stimulus, but not during acid application (PubMed:23212381). Channel activity is inhibited by phosphatidylinositol-4,5-bisphosphate (PIP2) (PubMed:29425510).
Catalyzes the irreversible transamination of the L-tryptophan metabolite L-kynurenine to form kynurenic acid (KA), an intermediate in the tryptophan catabolic pathway which is also a broad spectrum antagonist of the three ionotropic excitatory amino acid receptors among others (PubMed:19338303, PubMed:28097769). Also metabolizes the cysteine conjugates of certain halogenated alkenes and alkanes to form reactive metabolites (PubMed:7883047). Catalyzes the beta-elimination of S-conjugates and Se-conjugates of L-(seleno)cysteine, resulting in the cleavage of the C-S or C-Se bond (PubMed:7883047).
Inhibited by tryptophan, indole-3-pyruvic acid, 3-indolepropionic acid, DL-indole-3-lactic acid, indole-3-acetic acid (IAC), amino-oxyacetate (AOAA), aminooxy-phenylpropionic acid (AOPP) and Tris.
Interacts with GNA12 and GNA13 through the RGS domain. Interacts with RHOA, PLXNB1 and PLXNB2. Interacts with SLC1A6 (By similarity). Interacts (via DH domain) with GCSAM (via C-terminus).
May play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase and may act as GTPase-activating protein (GAP) for GNA12 and GNA13. Involved in neurotrophin-induced neurite outgrowth.
Phosphorylated by MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14).
The poly-Pro region is essential for plasma membrane localization upon stimulation.
Ubiquitinated by the BCR(KLHL20) E3 ubiquitin ligase complex when previously phosphorylated by MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14), leading to its degradation, thereby restricting RhoA activity and facilitating growth cone spreading and neurite outgrowth.
May complex with itself or/and other proteins within the membrane, to function as part of a cell-surface receptor.
Activated by autocatalytic processing at pH 4.
Has a strict specificity for hydrolysis of asparaginyl bonds (PubMed:23776206). Can also cleave aspartyl bonds slowly, especially under acidic conditions (PubMed:23776206). Involved in the processing of proteins for MHC class II antigen presentation in the lysosomal/endosomal system (PubMed:9872320). Also involved in MHC class I antigen presentation in cross-presenting dendritic cells by mediating cleavage and maturation of Perforin-2 (MPEG1), thereby promoting antigen translocation in the cytosol (By similarity). Required for normal lysosomal protein degradation in renal proximal tubules (By similarity). Required for normal degradation of internalized EGFR (By similarity). Plays a role in the regulation of cell proliferation via its role in EGFR degradation (By similarity).
Homodimer before autocatalytic removal of the propeptide (PubMed:23776206). Monomer after autocatalytic processing (PubMed:23776206). May interact with integrins (PubMed:23776206).
In the zymogen form, the uncleaved propeptide blocks access to the active site.
Ubiquitous. Particularly abundant in kidney, heart and placenta.
A chromosomal aberration involving ZFHX4 is found in one patient with ptosis. Translocation t(1;8)(p34.3;q21.12).
Expressed in brain, skeletal muscle and liver. Very low expression in stomach.
May play a role in neural and muscle differentiation (By similarity). May be involved in transcriptional regulation.
Belongs to the myelin P0 protein family.
Widely expressed. In fetal tissues, highest expression in the inner ear. In adult tissues, highest levels in thymus and lung.
Could be involved in calcium-dependent cell adhesion or intercellular interactions. May contribute to the elastic fiber assembly and/or maintenance (PubMed:26601954).
Homodimer. Can also form higher oligomers. Interacts with FBN1, FBN2 and LOX. Interacts with COL1A1 in a Ca (2+)-dependent manner. Interacts with ELN in a Ca (2+)-dependent manner; this interaction promotes ELN self-assembly (PubMed:26601954).
Acts as a translational activator of mitochondrially-encoded cytochrome c oxidase 1.
Homooligomer and heterooligomer with other family members. Binds RUNX1, RUNX3, FOXA2, KDM6A, UTY, histone H3, HESX1, ESRRG and the NF-kappa-B subunit RELA. Interacts with HES1 (via WRPW motif). Binds TCF7, LEF1, TCF7L1 and TCF7L2 (By similarity). Interacts with SIX3. Interacts with EFNB1. Interacts with TLE4 (By similarity). Interacts with FOXG1/BF-1; the interaction is inhibited by TLE6/GRG6 (By similarity).
In all tissues examined, mostly in brain, liver and muscle.
Phosphorylated, probably by CDK1. The degree of phosphorylation varies throughout the cell cycle, and is highest at the G2/M transition. Becomes hyperphosphorylated in response to cell differentiation and interaction with HES1 or RUNX1.
Transcriptional corepressor that binds to a number of transcription factors. Inhibits NF-kappa-B-regulated gene expression. Inhibits the transcriptional activation mediated by FOXA2, and by CTNNB1 and TCF family members in Wnt signaling. Enhances FOXG1/BF-1- and HES1-mediated transcriptional repression (By similarity). The effects of full-length TLE family members may be modulated by association with dominant-negative AES. Unusual function as coactivator for ESRRG.
Forms heterodimers with the anti-apoptotic proteins, Bcl-X(L), Bcl-2 and Bcl-W. Also binds protein S100A10 (By similarity). The Ser-75/Ser-99 phosphorylated form binds 14-3-3 proteins (By similarity). Interacts with AKT1 and PIM3. Interacts (via BH3 domain) with NOL3 (via CARD domain); preventing the association of BAD with BCL2 (By similarity). Interacts with HIF3A (via C-terminus domain); the interaction reduces the binding between BAD and BAX (By similarity). Interacts with GIMAP3/IAN4 and GIMAP5/IAN5 (PubMed:16509771).
Methylation at Arg-94 and Arg-96 by PRMT1 inhibits Akt-mediated phosphorylation at Ser-99.
Phosphorylated on one or more of Ser-75, Ser-99, Ser-118 and Ser-134 in response to survival stimuli, which blocks its pro-apoptotic activity. Phosphorylation on Ser-99 or Ser-75 promotes heterodimerization with 14-3-3 proteins. This interaction then facilitates the phosphorylation at Ser-118, a site within the BH3 motif, leading to the release of Bcl-X(L) and the promotion of cell survival. Ser-99 is the major site of AKT/PKB phosphorylation, Ser-118 the major site of protein kinase A (CAPK) phosphorylation. Phosphorylation at Ser-99 by PKB/AKT1 is almost completely blocked by the apoptotic C-terminus cleavage product of PKN2 generated by caspases-3 activity during apoptosis.
Promotes cell death. Successfully competes for the binding to Bcl-X(L), Bcl-2 and Bcl-W, thereby affecting the level of heterodimerization of these proteins with BAX. Can reverse the death repressor activity of Bcl-X(L), but not that of Bcl-2 (By similarity). Appears to act as a link between growth factor receptor signaling and the apoptotic pathways.
The protein name 'Bcl2 antagonist of cell death' may be misleading. The protein antagonises Bcl2-mediated repression of cell death, hence it promotes apoptosis.
Interacts with voltage-dependent calcium channels CACNB1, CACNB2, CACNB3 and CACNB4 beta subunits; prevents their interaction with the CACNA1C alpha subunit thereby negatively regulating the activity of the corresponding calcium channels.
Negatively regulates voltage-gated calcium channels by preventing the interaction between their alpha and beta subunits. Thereby, negatively regulates calcium channels activity at the plasma membrane and indirectly inhibits calcium-regulated exocytosis.
(Microbial infection) Interacts (via IBD domain) with human HIV-1 integrase protein (HIV-1 IN), determining its nuclear localization, its tight association with chromatin and its protection from the proteasome.
(Microbial infection) Interacts with HIV-2 IN.
A chromosomal aberration involving PSIP1 is associated with pediatric acute myeloid leukemia (AML) with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes. Translocation t(9;11)(p22;p15) with NUP98. The chimeric transcript is an in-frame fusion of NUP98 exon 8 to PSIP1 exon 4.
Less active than isoform 2 as transcriptional coactivator, but more abundant in cells.
Monomer (PubMed:15895093). Interacts with IFRD1/PC4 (PubMed:9822615). Isoform 2 interacts with SFRS1 (PubMed:9885563). Isoform 1 interacts (via IBD domain) with POGZ (via IBM motif) and CDCA7L (via IBM motifs) (PubMed:19244240, PubMed:25082813, PubMed:29997176). Interacts (via IBD domain) with KMT2A (via IBM motifs) with a moderate affinity whereas interacts with the KMT2A-MEN1 complex with a greater affinity; MEN1 enhances interaction of KMT2A with PSIP1 (PubMed:22327296, PubMed:25305204, PubMed:25082813, PubMed:29997176). Interacts with fusion protein KMT2A-MLLT3 (PubMed:25305204). Interacts (via IBD domain) with IWS1 (via IBM motif), MED1 (via IBM motif) and DBF4 (via IBM motifs) (PubMed:29997176).
Transcriptional coactivator involved in neuroepithelial stem cell differentiation and neurogenesis. Involved in particular in lens epithelial cell gene regulation and stress responses. May play an important role in lens epithelial to fiber cell terminal differentiation. May play a protective role during stress-induced apoptosis. Isoform 2 is a more general and stronger transcriptional coactivator. Isoform 2 may also act as an adapter to coordinate pre-mRNA splicing. Cellular cofactor for lentiviral integration.
Widely expressed. Expressed at high level in the thymus. Expressed in fetal and adult brain. Expressed in neurons, but not astrocytes. Markedly elevated in fetal as compared to adult brain. In the adult brain, expressed in the subventricular zone (SVZ), in hippocampus, and undetectable elsewhere. In the fetal brain, expressed in the germinal neuroepithelium and cortical plate regions.
Acts as guanine nucleotide exchange factor (GEF) for CDC42. Promotes formation of GPHN clusters (By similarity).
Acts as guanine nucleotide exchange factor (GEF) for CDC42. Promotes formation of GPHN clusters.
Detected in brain. Detected at low levels in heart.
Exhibits a shorter half-life than isoform 1, degraded via a proteasome-dependent pathway.
Expressed in pancreas, bone marrow, trachea, mammary gland, liver, prostate, and regions of intestine, brain, lung, placenta, testis, kidney, and heart.
Sodium-dependent, pyrimidine- and purine-selective (PubMed:11032837, PubMed:15861042, PubMed:16446384, PubMed:17140564, PubMed:21998139). Involved in the homeostasis of endogenous nucleosides (PubMed:11032837, PubMed:15861042). Exhibits the transport characteristics of the nucleoside transport system cib or N3 subtype (N3/cib) (with marked transport of both thymidine and inosine) (PubMed:11032837). Employs a 2:1 sodium/nucleoside ratio (PubMed:11032837). Transports uridine (PubMed:21795683). Also able to transport gemcitabine, 3'-azido-3'-deoxythymidine (AZT), ribavirin and 3-deazauridine (PubMed:11032837, PubMed:17140564).
Up-regulated by phorbol myristate acetate (PMA) in HL-60 cells.
Probable cell membrane receptor for the IGF-like family proteins. Binds IGFL1 and IGFL3 with a higher affinity. May also bind IGFL2.
Up-regulated by the pro-inflammatory cytokine TNFA and in skin upon tissue inflammation.
The ubiquitous expression and the conservation of the sequence in distant animal species suggest that the gene codes for a protein with housekeeping functions.
A non-coding SNP (dbSNP:rs12821256) has been shown to be associated with classic blond hair color in Europeans. This SNP is located 350 kb upstream from KITLG, in an enhancer specifically active in the hair follicle environment. It alters a LEF1 binding site, reducing LEF1 responsiveness in cultured keratinocytes. This SNP is not associated with eye pigmentation. It is most prevalent in Northern Europe (PubMed:24880339).
A soluble form (sKITLG) is produced by proteolytic processing of isoform 1 in the extracellular domain.
A soluble form exists as a cleavage product of the extracellular domain.
Acts in the early stages of hematopoiesis.
Found in two differentially glycosylated forms, LMW-SCF and HMW-SCF. LMW-SCF is fully N-glycosylated at Asn-145, partially N-glycosylated at Asn-90, O-glycosylated at Ser-167, Thr-168 and Thr-180, and not glycosylated at Asn-97 or Asn-118. HMW-SCF is N-glycosylated at Asn-118, Asn-90 and Asn-145, O-glycosylated at Ser-167, Thr-168 and Thr-180, and not glycosylated at Asn-97.
Genetic variants in KITLG define the skin/hair/eye pigmentation variation locus 7 (SHEP7) [MIM:611664]. Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair.
Homodimer, non-covalently linked (Probable). Heterotetramer with KIT, binding two KIT molecules; thereby mediates KIT dimerization and subsequent activation by autophosphorylation.
Ligand for the receptor-type protein-tyrosine kinase KIT. Plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. KITLG/SCF binding can activate several signaling pathways. Promotes phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and subsequent activation of the kinase AKT1. KITLG/SCF and KIT also transmit signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. KITLG/SCF and KIT promote activation of STAT family members STAT1, STAT3 and STAT5. KITLG/SCF and KIT promote activation of PLCG1, leading to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KITLG/SCF acts synergistically with other cytokines, probably interleukins.
Transcription regulator acting downstream of both FOXA2 and Brachyury (T) during notochord development. Required for node morphogenesis. Is essential for cilia formation in the posterior notochord (PNC) and for left-right patterning; acts upstream of FOXJ1 and RFX3 in this process and is required for the expression of various components important for axonemal assembly and function. Plays a role in regulating axial versus paraxial cell fate. Activates the transcription of ciliary proteins C11orf97 homolog, FAM183B and SPACA9 in the embryonic ventral node (By similarity).
Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Responsible for cross-linking epidermal proteins during formation of the stratum corneum. Involved in cell proliferation (PubMed:26220141).
The membrane anchorage region possesses a cluster of five cysteines within which fatty acid(s) may become thioester-linked. It is subject to phorbol ester-stimulated phosphorylation and is hypersensitive to proteolysis, which releases the enzyme in a soluble form.
Binds cAMP-dependent protein kinase (PKA). Interacts with PRKCA; only the cytoplasmic form is capable of interacting with PRKCA.
Expressed in brain, heart, lung, pancreas and placenta.
Expressed in brain, heart, lung, pancreas and skeletal muscle.
Probably targets cAMP-dependent protein kinase (PKA) to the cellular membrane or cytoskeletal structures. The membrane-associated form reduces epithelial sodium channel (ENaC) activity, whereas the free cytoplasmic form may negatively regulate ENaC channel feedback inhibition by intracellular sodium.
Targets the cAMP-dependent protein kinase (PKA) to the plasma membrane, and permits functional coupling to the L-type calcium channel. The membrane-associated form reduces epithelial sodium channel (ENaC) activity, whereas the free cytoplasmic form may negatively regulate ENaC channel feedback inhibition by intracellular sodium.
Acts as a RAC1 guanine nucleotide exchange factor (GEF) and can induce membrane ruffling. Functions in cell migration, attachment and cell spreading. Promotes targeting of RAC1 to focal adhesions (By similarity). May function as a positive regulator of apoptosis. Downstream of NMDA receptors and CaMKK-CaMK1 signaling cascade, promotes the formation of spines and synapses in hippocampal neurons.
Interacts with PAK kinases through the SH3 domain. Interacts with GIT1 and TGFB1I1. Interacts with PTK2/FAK1 and RAC1. Interacts with ITCH and PARVB (By similarity). Interacts with unphosphorylated PAK1. Interacts with SCRIB; interaction is direct and may play a role in regulation of apoptosis. Interacts with FRMPD4 (via N-terminus). Interacts with CaMK1. Interacts with BIN2. Isoform 1 and isoform 5 interact with SNX27. Interacts with YWHAZ (By similarity).
Phosphorylated by PTK2/FAK1; this promotes interaction with RAC1 (By similarity). Phosphorylated on Ser-694 by CaMK1; enhancement of GEF activity and downstream activation of RAC1.
A chromosomal aberration involving WDR11 is found in a form of Kallmann syndrome. Translocation 46,XY,t(10;12)(q26.12;q13.11).
A chromosomal aberration involving WDR11 is found in a form of glioblastoma. Translocation t(10;19)(q26;q13.3) with ZNF320.
Component of the complex WDR11 composed of C17orf75, FAM91A1 and WDR11; FAM91A1 and WDR11 are required for proper location of the complex (PubMed:29426865). Interacts (via the N-terminal and the central portion of the protein) with EMX1 (PubMed:20887964). Interacts with GLI3; the interaction associateS EMX1 with GLI3 (PubMed:29263200). Interacts with TBC1D23; this interaction may be indirect and recruits TBC1D23 to AP-1-derived vesicles (PubMed:29084197, PubMed:29426865).
Involved in the Hedgehog (Hh) signaling pathway, is essential for normal ciliogenesis (PubMed:29263200). Regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotropin-releasing hormone production (PubMed:29263200). WDR11 complex facilitates the tethering of Adaptor protein-1 complex (AP-1)-derived vesicles. WDR11 complex acts together with TBC1D23 to facilitate the golgin-mediated capture of vesicles generated using AP-1 (PubMed:29426865).
Adhesion molecule that promotes lamina-specific synaptic connections in the retina and is specifically required for the formation of neuronal circuits that detect motion. Acts by promoting formation of synapses between two specific retinal cell types: the retinal ganglion cells W3B-RGCs and the excitatory amacrine cells VG3-ACs. Formation of synapses between these two cells plays a key role in detection of motion. Promotes synaptic connectivity via homophilic interactions.
Homodimer; mediates homophilic interactions to promote cell adhesion. Interacts (via PDZ-binding motif) with MAGI1, MAGI2, DLG2, DLG3 and DLG4.
the PDZ-binding motif mediates interaction with PDZ domain-containing proteins MAGI1, MAGI2, DLG2, DLG3 and DLG4 and is required for is required for synaptic localization in photoreceptors.
Unlike its mouse ortholog has no catalytic hyaluronic acid-degrading activity, but acts as a regulator of hyaluronan (HA) metabolism through regulation of expression of CEMIP and HAS2, two enzymes involved in HA depolymerization and HA synthesis, respectively.
Up-regulated in by proinflammatory cytokines in normal human dermal fibroblasts (NHDF).
Transcription factor which plays a role in hair follicle differentiation. Regulates FOXQ1 expression and that of other hair-specific genes (By similarity).
Catalyzes the biosynthesis of histamine from histidine.
Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is not regulated by leucine (PubMed:25263562, PubMed:26449471). Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them (PubMed:25259925). Interacts with the TORC2 complex; through RICTOR (By similarity).
May function as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway (PubMed:25263562). May also regulate the insulin-receptor signaling pathway through activation of TORC2 (By similarity). This metabolic regulator may also play a role in protection against oxidative and genotoxic stresses (By similarity). May prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein (By similarity).
Acts as a transcriptional regulator in adaptive response to low oxygen tension. Acts as a regulator of hypoxia-inducible gene expression (PubMed:11573933, PubMed:16126907, PubMed:19694616, PubMed:20416395, PubMed:21069422). Functions as an inhibitor of angiogenesis in hypoxic cells of the cornea. Plays a role in the development of the cardiorespiratory system. May also be involved in apoptosis (By similarity).
Attenuates the ability of transcription factor HIF1A and EPAS1/HIF2A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation (PubMed:16126907, PubMed:17998805, PubMed:19694616, PubMed:20416395). May act as a tumor suppressor and inhibits malignant cell transformation (PubMed:17998805).
Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation.
Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Also inhibits hypoxia-inducible ARNT-mediated gene expression.
Expressed in vascular cells (at protein level) (PubMed:21069422). Expressed in kidney (PubMed:11573933, PubMed:19694616). Expressed in lung epithelial cells (PubMed:16775626). Expressed in endothelial cells (venous and arterial cells from umbilical cord and aortic endothelial cells) and in vascular smooth muscle cells (aorta) (PubMed:21069422). Strongly expressed in the heart, placenta, and skeletal muscle, whereas a weak expression profile was found in the lung, liver, and kidney (PubMed:12538644). Expressed weakly in cell renal cell carcinoma (CC-RCC) compared to normal renal cells (PubMed:16126907). Expression is down-regulated in numerous kidney tumor cells compared to non tumor kidney tissues (PubMed:16126907). Isoform 2 is expressed in heart, placenta, lung, liver, skeletal muscle and pancreas and in numerous cancer cell lines (PubMed:20416395). Isoform 3 and isoform 4 are weakly expressed in heart, placenta, lung, liver, skeletal muscle and pancreas (PubMed:20416395). Isoform 4 is expressed in fetal tissues, such as heart, brain, thymus, lung, liver, skeletal kidney and spleen (PubMed:20416395). Isoform 3 is weakly expressed in fetal tissues, such as liver and kidney (PubMed:20416395).
In normoxia, hydroxylated on Pro-492 in the oxygen-dependent degradation domain (ODD) by prolyl hydroxylase(s) (PHD). The hydroxylated proline promotes interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation.
Isoform 2 interacts (via ODD domain) with VHL (via beta domain) (PubMed:12538644). Isoform 4 interacts with HIF1A; the interaction inhibits the binding of HIF1A to hypoxia-responsive element (HRE) and HIF1A/ARNT-dependent transcriptional activation (PubMed:16126907). Isoform 4 interacts with ARNT; the interaction occurs in a HIF1A- and DNA-binding-independent manner and does not induce HIF1A/ARNT-dependent transcriptional activation (PubMed:16126907). Isoform 4 interacts with EPAS1 (PubMed:17998805). Interacts with BAD, BCL2L2 and MCL1 (By similarity).
Ubiquitinated; ubiquitination occurs in a VHL- and oxygen-dependent pathway and subsequently targeted for proteasomal degradation.
Up-regulated by hypoxia (at protein level) (PubMed:16775626). Induced by hypoxia (PubMed:16775626). Isoform 2, isoform 3, isoform 4 and isoform 5 are up-regulated by hypoxia in a HIF1A- and EPAS1/HIF2A-dependent manner (PubMed:19694616, PubMed:20416395, PubMed:21069422). Isoform 4 is down-regulated by hypoxia and up-regulated upon restoring normoxia in embryonic kidney cells (PubMed:16126907).
Expressed at highest levels in kidney and brain. Expressed at high levels in skeletal muscle, heart, liver, placenta and white blood cells. Expressed at moderate levels in lung and spleen. Expressed at low levels in thymus, small intestine and colon. Expressed in several intestinal tumor cell lines.
Expressed at low levels at 20-25 weeks of gestation in fetal brain, lung, liver and kidney.
Inhibited by gamma-aminobutyric acid and drugs including quinidine and levofloxacin.
Organic zwitterion/cation transporter with apparent specificity for amino acids and their derivatives. Has low affinity for its substrates and may regulate their flux across the plasma membrane at high substrate concentrations (PubMed:33124720). Bidirectionally transports carnitine and acetylcarnitine, possibly regulating their cytosolic abundance and further fatty acid catabolism via beta oxidation (PubMed:33124720). Displays high transport activity toward zwitterionic substrates such as glycine betaine and diet-derived ergothioneine and carnosine. Can transport cations having an indole skeleton such as thiamine with lower efficiency. Does not transports agmatine (PubMed:33124720, PubMed:15028572). The transport mechanism, symport with sodium or facilitated diffusion allosterically regulated by sodium, remains to be elucidated (Probable).
(Microbial infection) Acts as an RNA-dependent RNA polymerase when associated with small delta antigen of Hepatitis delta virus, acting both as a replicate and transcriptase for the viral RNA circular genome.
(Microbial infection) Interacts with herpes simplex virus 1 protein ICP22; this interaction causes loss of CTD 'Ser-2' phosphorylation from pol II engaged in transcription (PubMed:23029222).
Among tandem heptapeptide repeats of the C-terminal domain (CTD) some do not match the Y-S-P-T-S-P-S consensus, the seventh serine residue 'Ser-7' being replaced by a lysine. 'Lys-7' in these non-consensus heptapeptide repeats can be alternatively acetylated, methylated and dimethylated. EP300 is one of the enzyme able to acetylate 'Lys-7'. Acetylation at 'Lys-7' of non-consensus heptapeptide repeats is associated with 'Ser-2' phosphorylation and active transcription. Regulates initiation or early elongation steps of transcription specially for inducible genes.
Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits (PubMed:9852112). Component of a complex which is at least composed of HTATSF1/Tat-SF1, the P-TEFb complex components CDK9 and CCNT1, RNA polymerase II, SUPT5H, and NCL/nucleolin (PubMed:10454543, PubMed:10393184, PubMed:17234882). The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (active) (PubMed:28076779). Interacts (via the C-terminal domain (CTD)) with U2AF2; recruits PRPF19 and the Prp19 complex to the pre-mRNA and may couple transcription to pre-mRNA splicing (PubMed:21536736). Interacts (via the C-terminal domain (CTD)) with SMN1/SMN2; recruits SMN1/SMN2 to RNA Pol II elongation complexes (PubMed:26700805). Interacts via the phosphorylated C-terminal domain with WDR82 and with SETD1A and SETD1B only in the presence of WDR82 (PubMed:17998332). When phosphorylated at 'Ser-5', interacts with MEN1; the unphosphorylated form, or phosphorylated at 'Ser-2' does not interact (PubMed:14992727). When phosphorylated at 'Ser-5', interacts with ZMYND8; the form phosphorylated at 'Ser-2' does not interact (PubMed:26700805). When phosphorylated at 'Ser-2', interacts with SUPT6H (via SH2 domain) (PubMed:17234882). Interacts with RECQL5 and TCEA1; binding of RECQL5 prevents TCEA1 binding (PubMed:20231364, PubMed:23748380). The phosphorylated C-terminal domain interacts with FNBP3 (PubMed:12381297). The phosphorylated C-terminal domain interacts with SYNCRIP (PubMed:12376575). Interacts with ATF7IP (PubMed:19106100). Interacts with DDX5 (PubMed:12527917). Interacts with WWP2 (By similarity). Interacts with SETX (PubMed:23149945, PubMed:26700805). Interacts (phosphorylated) with PIH1D1 (PubMed:24656813). Interacts (via the C-terminal domain (CTD)) with TDRD3 (PubMed:26700805). Interacts with PRMT5 (PubMed:26700805). Interacts with XRN2 (PubMed:26700805). Interacts with SAFB/SAFB1 (PubMed:9671816). Interacts with CCNL1 (Probable). Interacts with CCNL2 (PubMed:14684736). Interacts with MYO1C (By similarity). Interacts with PAF1 (PubMed:16491129). Interacts with SFRS19 (PubMed:15992770). Interacts (via C-terminus) with CMTR1 (PubMed:18533109). Interacts (via C-terminus) with CTDSP1 (PubMed:17157258). Interacts (via C-terminus) with SCAF8 (PubMed:18550522). Interacts (via the C-terminal domain (CTD)) with CCNT2 (PubMed:15563843). Interacts with FUS (PubMed:26124092). Interacts with MCM3AP isoform GANP (PubMed:23652018). Interacts with kinase SRPK2; the interaction occurs during the co-transcriptional formation of inappropriate R-loops (PubMed:28076779). Interacts with SETD2 (PubMed:16118227, PubMed:16314571). Interacts with UVSSA (PubMed:32142649). Interacts with ERCC6 (PubMed:32142649). Interacts with the TFIIH complex (PubMed:32142649).
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Largest and catalytic component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Forms the polymerase active center together with the second largest subunit. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB1 is part of the core element with the central large cleft, the clamp element that moves to open and close the cleft and the jaws that are thought to grab the incoming DNA template. At the start of transcription, a single-stranded DNA template strand of the promoter is positioned within the central active site cleft of Pol II. A bridging helix emanates from RPB1 and crosses the cleft near the catalytic site and is thought to promote translocation of Pol II by acting as a ratchet that moves the RNA-DNA hybrid through the active site by switching from straight to bent conformations at each step of nucleotide addition. During transcription elongation, Pol II moves on the template as the transcript elongates. Elongation is influenced by the phosphorylation status of the C-terminal domain (CTD) of Pol II largest subunit (RPB1), which serves as a platform for assembly of factors that regulate transcription initiation, elongation, termination and mRNA processing. Regulation of gene expression levels depends on the balance between methylation and acetylation levels of tha CTD-lysines (By similarity). Initiation or early elongation steps of transcription of growth-factors-induced immediate early genes are regulated by the acetylation status of the CTD (PubMed:24207025). Methylation and dimethylation have a repressive effect on target genes expression (By similarity).
Methylated at Arg-1810 prior to transcription initiation when the CTD is hypophosphorylated, phosphorylation at Ser-1805 and Ser-1808 preventing this methylation. Symmetrically or asymmetrically dimethylated at Arg-1810 by PRMT5 and CARM1 respectively. Symmetric or asymmetric dimethylation modulates interactions with CTD-binding proteins like SMN1/SMN2 and TDRD3. SMN1/SMN2 interacts preferentially with the symmetrically dimethylated form while TDRD3 interacts with the asymmetric form. Through the recruitment of SMN1/SMN2, symmetric dimethylation is required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination. CTD dimethylation may also facilitate the expression of select RNAs. Among tandem heptapeptide repeats of the C-terminal domain (CTD) some do not match the Y-S-P-T-S-P-S consensus, the seventh serine residue 'Ser-7' being replaced by a lysine. 'Lys-7' in these non-consensus heptapeptide repeats can be alternatively acetylated, methylated, dimethylated and trimethylated. Methylation occurs in the earliest transcription stages and precedes or is concomitant to 'Ser-5' and 'Ser-7' phosphorylation. Dimethylation and trimehtylation at 'Lys-7' of non-consensus heptapeptide repeats are exclusively associated with phosphorylated CTD.
The C-terminal domain (CTD) serves as a platform for assembly of factors that regulate transcription initiation, elongation, termination and mRNA processing.
The binding of ribonucleoside triphosphate to the RNA polymerase II transcribing complex probably involves a two-step mechanism. The initial binding seems to occur at the entry (E) site and involves a magnesium ion temporarily coordinated by three conserved aspartate residues of the two largest RNA Pol II subunits. The ribonucleoside triphosphate is transferred by a rotation to the nucleotide addition (A) site for pairing with the template DNA. The catalytic A site involves three conserved aspartate residues of the RNA Pol II largest subunit which permanently coordinate a second magnesium ion.
The tandem heptapeptide repeats in the C-terminal domain (CTD) can be highly phosphorylated (PubMed:28076779). The phosphorylation activates Pol II. Phosphorylation occurs mainly at residues 'Ser-2' and 'Ser-5' of the heptapeptide repeat and is mediated, at least, by CDK7 and CDK9. CDK7 phosphorylation of POLR2A associated with DNA promotes transcription initiation by triggering dissociation from DNA. Phosphorylation also takes place at 'Ser-7' of the heptapeptide repeat, which is required for efficient transcription of snRNA genes and processing of the transcripts. The phosphorylation state is believed to result from the balanced action of site-specific CTD kinases and phosphatases, and a 'CTD code' that specifies the position of Pol II within the transcription cycle has been proposed. Dephosphorylated by the protein phosphatase CTDSP1. Dephosphorylated at 'Ser-2' following UV irradiation.
Ubiquitinated by WWP2 leading to proteasomal degradation (By similarity). Following transcription stress, the elongating form of RNA polymerase II (RNA pol IIo) is ubiquitinated by NEDD4 on Lys-1268 at DNA damage sites without leading to degradation: ubiquitination promotes RNA pol IIo backtracking to allow access by the transcription-coupled nucleotide excision repair (TC-NER) machinery (PubMed:32142649, PubMed:32142654, PubMed:22466610, PubMed:35633597). At stalled RNA pol II where TC-NER has failed, RBX1-mediated polybiquitination at Lys-1268 may lead to proteasome-mediated degradation in a UBAP2- and UBAP2L-dependent manner; presumably to halt global transcription and enable 'last resort' DNA repair pathways (PubMed:35633597).
(Microbial infection) Interacts with HIV-1 capsid complexes.
(Microbial infection) Interacts with matrix protein of Nipah virus; this interaction inhibits the IKBKE-dependent activation of the type I interferon signaling pathway.
(Microbial infection) Ubiquitinates ebolavirus protein VP35 leading to enhanced viral transcriptase activity.
Chimeric cDNA. The in vivo relevance of this transcript of the TRIM34 (AC Q9BYJ4) and TRIM6 genes that codes for a chimeric protein of 842 residues is uncertain.
E3 ubiquitin ligase that plays a crucial role in the activation of the IKBKE-dependent branch of the type I interferon signaling pathway (PubMed:24882218, PubMed:31694946). In concert with the ubiquitin-conjugating E2 enzyme UBE2K, synthesizes unanchored 'Lys-48'-linked polyubiquitin chains that promote the oligomerization and autophosphorylation of IKBKE leading to stimulation of an antiviral response (PubMed:24882218). Ubiquitinates also MYC and inhibits its transcription activation activity, maintaining the pluripotency of embryonic stem cells (By similarity). Promotes the association of unanchored 'Lys-48'-polyubiquitin chains with DHX16 leading to enhanced RIGI-mediated innate antiviral immune response (PubMed:35263596).
Homotrimer (PubMed:17156811). Forms heteromultimers (via B30.2/SPRY domain) with TRIM5 (PubMed:21680743). Interacts with MYC (By similarity). Interacts (via SPRY domain) with IKBKE (PubMed:24882218). Interacts with VAMP8; this interaction contributes to the activation of the type I interferon antiviral response (PubMed:31694946). Interacts with DHX16 (PubMed:35263596).
The B-box zinc finger and the linker region between the coiled coil and B30.2/SPRY domains contribute to higher order self-association.
E3 ubiquitin-protein ligase required for the repair of DNA interstrand cross-links (ICL) in response to DNA damage (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575657, PubMed:28575658). Plays a key role in RPA-mediated DNA damage signaling and repair (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575657, PubMed:28575658, PubMed:28691929). Acts by mediating ubiquitination of the RPA complex (RPA1, RPA2 and RPA3 subunits) and RAD51 at stalled replication forks, leading to remove them from DNA damage sites and promote homologous recombination (PubMed:26474068, PubMed:28575657, PubMed:28575658). Also mediates the ubiquitination of p53/TP53 in the late response to DNA damage, and acts as a positive regulator of p53/TP53 stability, thereby regulating the G1/S DNA damage checkpoint (PubMed:20173098). May act by catalyzing the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome (PubMed:20173098). In response to ionizing radiation, interacts with MDM2 and enhances p53/TP53 ubiquitination, possibly by restricting MDM2 from extending polyubiquitin chains on ubiquitinated p53/TP53 (PubMed:20173098).
Interacts with MDM2 and p53/TP53 (PubMed:20173098). Binds to the RPA complex via direct interaction with RPA2 (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575658). Interacts with RAD51 (PubMed:28575658).
Phosphorylated at Ser-46 and Ser-63 upon DNA damage by ATM or ATR. ATM phosphorylation occurs at early times upon DNA damage, while ATR is the major kinase at later times. Phosphorylation by ATM and ATR is required to stabilize p53/TP53. Part of the phosphorylation depends upon RPA2 presence.
The coiled coil domain may be involved in RPA2-binding.
Interacts with DOC2B; the interaction is direct, occurs at the cell membrane, excludes interaction with STX4 and regulates glucose-stimulated insulin secretion (By similarity). Interacts with STX4.
Phosphorylated by PKC in platelets in response to thrombin stimulation; phosphorylation inhibits binding to STX4.
Together with STX4 and VAMP2, may play a role in insulin-dependent movement of GLUT4 and in docking/fusion of intracellular GLUT4-containing vesicles with the cell surface in adipocytes.
BRDT is a promising target for male contraception. Inhibition by thienodiazepine inhibitor (+)-JQ1 that binds Asn-109, prevents recognition of acetylated histone H4, causing a complete and reversible contraceptive effect in male mice (PubMed:22901802).
Bromo domains mediate interaction with histones that have acetylated lysine residues at specific positions (PubMed:22464331). Bromo domain 1 mediates binding with histone H4 acetylated at 'Lys-5' and 'Lys-8' (H4K5ac and H4K8ac, respectively) (PubMed:22901802). The bromo domains also recognize and bind a subset of butyrylated histones: able to bind histone H4 butyrylated at 'Lys-8' (H4K8ac), while it is not able to bind H4 butyrylated at 'Lys-5' (H4K5ac) (By similarity).
Interacts with mRNA splicing machinery proteins SRSF2, DDX5, HNRNPK and TARDBP. Interacts with the acetylated N-terminus of histone H1, H2, H3 and H4. Interacts with P-TEFb components CDK9 and CCNT1/cyclin-T1. Interacts with SMARCE1 (By similarity). Interacts with the acetylated N-terminus of histone H1.4, H2A, H2B, H3 and H4.
Testis-specific chromatin protein that specifically binds histone H4 acetylated at 'Lys-5' and 'Lys-8' (H4K5ac and H4K8ac, respectively) and plays a key role in spermatogenesis (PubMed:22464331, PubMed:22901802). Required in late pachytene spermatocytes: plays a role in meiotic and post-meiotic cells by binding to acetylated histones at the promoter of specific meiotic and post-meiotic genes, facilitating their activation at the appropriate time (PubMed:22901802). In the post-meiotic phase of spermatogenesis, binds to hyperacetylated histones and participates in their general removal from DNA (PubMed:22901802). Also recognizes and binds a subset of butyrylated histones: able to bind histone H4 butyrylated at 'Lys-8' (H4K8ac), while it is not able to bind H4 butyrylated at 'Lys-5' (H4K5ac) (By similarity). Also acts as a component of the splicing machinery in pachytene spermatocytes and round spermatids and participates in 3'-UTR truncation of specific mRNAs in post-meiotic spermatids (By similarity). Required for chromocenter organization, a structure comprised of peri-centromeric heterochromatin.
Testis-specific. A 3-fold higher expression is seen in adult testis than in embryo testis. Expression seems to be correlated with histone H4 hyperacetylation during the haploid phase of spermatogenesis (spermiogenesis). No expression, or very low expression is seen in patients' testes with abnormal spermatogenesis. Expressed in cancers such as non-small cell lung cancer and squamous cell carcinomas of the head and neck as well as of esophagus, but not in melanoma or in cancers of the colon, breast, kidney and bladder.
Mitochondrial tRNA methyltransferase that mediates methylation of cytosine to 5-methylcytosine (m5C) at position 34 of mt-tRNA(Met) (PubMed:27497299, PubMed:27214402, PubMed:27356879). mt-tRNA(Met) methylation at cytosine(34) takes place at the wobble position of the anticodon and initiates the formation of 5-formylcytosine (f(5)c) at this position (PubMed:27497299, PubMed:27214402, PubMed:27356879). mt-tRNA(Met) containing the f(5)c modification at the wobble position enables recognition of the AUA codon in addition to the AUG codon, expanding codon recognition in mitochondrial translation (PubMed:27497299, PubMed:27356879).
Expressed specifically in heart and skeletal muscle.
Interacts via its C-terminus with spectrin repeats 3 and 4 of ACTN2. Interacts with ACTN1, LDB3, MYOT and PPP3CA.
Belongs to the ubiquitin-activating E1 family. ULA1 subfamily.
Binding of TP53BP2 to the regulatory subunit NAE1 decreases neddylation activity.
Heterodimer of UBA3 and NAE1. The complex binds NEDD8 and UBE2M. Binds APP and TP53BP2.
NAE1 and UBA3 correspond to the N-terminal and the C-terminal part of yeast UBA3. In yeast the two subunits form a single polypeptide chain.
Regulatory subunit of the dimeric UBA3-NAE1 E1 enzyme. E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Necessary for cell cycle progression through the S-M checkpoint. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation. The covalent attachment of NEDD8 to target proteins is known as 'neddylation' and the process is involved in the regulation of cell growth, viability and development.
Ubiquitinated by TRIP12, leading to its degradation by the proteasome.
Ubiquitous in fetal tissues. Expressed throughout the adult brain.
A cytochrome P450 monooxygenase involved in vitamin D metabolism and in calcium and phosphorus homeostasis. Catalyzes the rate-limiting step in the activation of vitamin D in the kidney, namely the hydroxylation of 25-hydroxyvitamin D3/calcidiol at the C1alpha-position to form the hormonally active form of vitamin D3, 1alpha,25-dihydroxyvitamin D3/calcitriol that acts via the vitamin D receptor (VDR) (PubMed:10518789, PubMed:9486994, PubMed:22862690, PubMed:10566658, PubMed:12050193). Has 1alpha-hydroxylase activity on vitamin D intermediates of the CYP24A1-mediated inactivation pathway (PubMed:10518789, PubMed:22862690). Converts 24R,25-dihydroxyvitamin D3/secalciferol to 1-alpha,24,25-trihydroxyvitamin D3, an active ligand of VDR. Also active on 25-hydroxyvitamin D2 (PubMed:10518789). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via FDXR/adrenodoxin reductase and FDX1/adrenodoxin (PubMed:22862690).
Activated by cardiolipin and dioleoyl phosphatidylethanolamine (DOPE), phospholipids found in the inner mitochondrial membrane. Inhibited by high substrate concentration.
Expressed in the upper matrix and in the entire hair cortex.
Both phosphorylation at Thr-172 and binding of a D-type cyclin are necessary for enzymatic activity. Full activation of the cyclin-D-CDK4 complex appears to require other factors such as recruitment of the substrate via a substrate recruitment motif, and/or formation of the CDKN1B ternary complex. Inhibited by INK4 family members. In resting cells, the non-tyrosine-phosphorylated form of CDKN1B prevents phosphorylation at Thr-172 and inactivation, while, in proliferating cells, tyrosine phosphorylation of CDKN1B allows phosphorylation of Thr-172 of CDK4 and subsequent activation.
Component of the D-CDK4 complex, composed of CDK4 and some D-type G1 cyclin (CCND1, CCND2 or CCND3). Interacts directly in the complex with CCND1, CCND2 or CCND3. Interacts with SEI1 and ZNF655. Forms a ternary complex, cyclin D-CDK4-CDKN1B, involved in modulating CDK4 enzymatic activity. Interacts directly with CDKN1B (phosphorylated on 'Tyr-88' and 'Tyr-89'); the interaction allows assembly of the cyclin D-CDK4 complex, Thr-172 phosphorylation, nuclear translocation and enhances the cyclin D-CDK4 complex activity. CDK4 activity is either inhibited or enhanced depending on stoichiometry of complex. The non-tyrosine-phosphorylated form of CDKN1B prevents T-loop phosphorylation of CDK4 producing inactive CDK4. Interacts (unphosphorylated form) with CDK2. Also forms ternary complexes with CDKN1A or CDKN2A. Interacts directly with CDKN1A (via its N-terminal); the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4. Interacts with CCND1; the interaction is prevented with the binding of CCND1 to INSM1 during cell cycle progression. Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Interacts with FNIP1 and FNIP2 (PubMed:27353360).
Phosphorylation at Thr-172 is required for enzymatic activity. Phosphorylated, in vitro, at this site by CCNH-CDK7, but, in vivo, appears to be phosphorylated by a proline-directed kinase. In the cyclin D-CDK4-CDKN1B complex, this phosphorylation and consequent CDK4 enzyme activity, is dependent on the tyrosine phosphorylation state of CDKN1B. Thus, in proliferating cells, CDK4 within the complex is phosphorylated on Thr-172 in the T-loop. In resting cells, phosphorylation on Thr-172 is prevented by the non-tyrosine-phosphorylated form of CDKN1B.
Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.
Expressed in liver, kidney, intestine and pancreas.
Interacts with ATRAID; the interaction is direct and both proteins are mutually dependent for their stability.
Unlike the other SLC37 members, lacks glucose-6-phosphate antiporter activity (PubMed:21949678). In osteoclasts, forms a transporter complex with ATRAID for nitrogen-containing-bisphophonates (N-BPs) required for releasing N-BP molecules that have trafficked to lysosomes through fluid-phase endocytosis into the cytosol (PubMed:29745899).
Interacts with CYTH3 (By similarity). Interacts with PARD3 (By similarity). Interacts with CYTH1 (By similarity).
Member of GRP1 signaling complexes that are acutely recruited to plasma membrane ruffles in response to insulin receptor signaling. May function as a scaffolding protein that regulates epithelial cell polarity by connecting ARF6 activation with the PAR3 complex. Plays a redundant role with FRMD4A in epithelial polarization.
(Microbial infection) Interacts with human immunodeficiency virus (HIV-1) Nef (via middle region); this interaction enhances ACOT8 Acyl-CoA thioesterase activity and occurs in a Nef myristoylation-independent manner (PubMed:9299485). According to a second report, the interaction with HIV-1 Nef occurs in a Nef myristoylation-independent manner but does not enhance ACOT8 Acyl-CoA thioesterase activity (PubMed:9153233).
(Microbial infection) May mediate Nef-induced down-regulation of CD4 cell-surface expression (PubMed:9153233).
Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels (PubMed:9299485, PubMed:9153233, PubMed:15194431). Displays no strong substrate specificity with respect to the carboxylic acid moiety of Acyl-CoAs (By similarity). Hydrolyzes medium length (C2 to C20) straight-chain, saturated and unsaturated acyl-CoAS but is inactive towards substrates with longer aliphatic chains (PubMed:9299485, PubMed:9153233). Moreover, it catalyzes the hydrolysis of CoA esters of bile acids, such as choloyl-CoA and chenodeoxycholoyl-CoA and competes with bile acid CoA:amino acid N-acyltransferase (BAAT) (By similarity). Is also able to hydrolyze CoA esters of dicarboxylic acids (By similarity). It is involved in the metabolic regulation of peroxisome proliferation (PubMed:15194431).
Detected in a T-cell line (at protein level). Ubiquitous (PubMed:9153233, PubMed:9299485).
Inhibited by CoASH (IC(50)=10-15 uM). Also inhibited by cysteine-reactive agents.
Regulated by peroxisome proliferator (such as Clofibrate), via the peroxisome proliferator-activated receptors (PPARs).
Autoubiquitinated upon DNA stimulation; autoubiquitination at Lys-458 promotes interaction with SQSTM1/p62 and recruitment of AIM2 to autophagosomes.
Binds cytoplasmic tail of integrin alpha-1 (PubMed:11331580). Interacts with the HN peptide (By similarity). Interacts with PHOX2B (By similarity). Interacts (when autoubiquitinated) with SQSTM1/p62; promoting AIM2 recruitment to autophagosomes (PubMed:27498865). Interacts with AIM2; promoting its autophagy-dependent degradation (PubMed:27498865).
E3 ubiquitin-protein ligase that promotes the degradation of insoluble ubiquitinated proteins, including insoluble PAX6, poly-Gln repeat expanded HTT and poly-Ala repeat expanded ARX (By similarity). Mediates PAX6 ubiquitination leading to proteasomal degradation, thereby modulating cortical neurogenesis (By similarity). May also inhibit PAX6 transcriptional activity, possibly in part by preventing the binding of PAX6 to its consensus sequences (By similarity). May contribute to the regulation of the intracellular level of HN (humanin) or HN-containing proteins through the proteasomal degradation pathway (By similarity). Mediates MED15 ubiquitination leading to proteasomal degradation (PubMed:16904669). May contribute to the innate restriction of retroviruses (PubMed:18248090). Upon overexpression, reduces HIV-1 and murine leukemia virus infectivity, by suppressing viral gene expression (PubMed:18248090). Antiviral activity depends on a functional E3 ubiquitin-protein ligase domain (PubMed:18248090). May regulate TRIM5 turnover via the proteasome pathway, thus counteracting the TRIM5-mediated cross-species restriction of retroviral infection at early stages of the retroviral life cycle (PubMed:18248090). Acts as an inhibitor of the AIM2 inflammasome by promoting autophagy-dependent degradation of AIM2 (PubMed:27498865). Mechanistically, undergoes autoubiquitination upon DNA stimulation, promoting interaction with AIM2 and SQSTM1/p62, leading to AIM2 recruitment to autophagosomes (PubMed:27498865).
The B30.2 domain may be involved cellular protein quality control by promoting the degradation of insoluble ubiquitinated proteins.
The coiled-coil domain and the B30.2 domain are both necessary for interaction with HN and PAX6 (By similarity). They are also involved in MED15-binding (PubMed:16904669).
Belongs to the aconitase/IPM isomerase family.
Binds 1 [4Fe-4S] cluster per subunit. [4Fe-4S]-binding affects RNA-binding activity, thereby inhibiting activity of the protein.
Interacts with RBCK1 isoform 1 and isoform 2 only in iron-rich conditions (PubMed:12629548). Interacts (when associated with the 4Fe-4S) with FBXL5 (PubMed:19762596, PubMed:19762597). Interacts with CIAO1 and CIAO2A (PubMed:23891004).
RNA-binding protein that binds to iron-responsive elements (IRES), which are stem-loop structures found in the 5'-UTR of ferritin, and delta aminolevulinic acid synthase mRNAs, and in the 3'-UTR of transferrin receptor mRNA. Binding to the IRE element in ferritin results in the repression of its mRNA translation. Binding of the protein to the transferrin receptor mRNA inhibits the degradation of this otherwise rapidly degraded mRNA.
Ubiquitinated and degraded by the proteasome in presence of high level of iron and oxygen. Ubiquitinated by a SCF complex containing FBXL5. Upon iron and oxygen depletion FBXL5 is degraded, preventing ubiquitination and allowing its RNA-binding activity.
CAMK2 is composed of 4 different chains: alpha (CAMK2A), beta (CAMK2B), gamma (CAMK2G), and delta (CAMK2D). The different isoforms assemble into homo- or heteromultimeric holoenzymes composed of 12 subunits with two hexameric rings stacked one on top of the other (PubMed:14722083, Ref.20). Interacts with SYNGAP1 and CAMK2N2 (By similarity). Interacts with MPDZ (PubMed:15312654). Interacts with FOXO3 (By similarity). Interacts (when in a kinase inactive state not associated with calmodulin) with ARC; leading to target ARC to inactive synapses (By similarity). Interacts with CAMK2N1; this interaction requires CAMK2B activation by Ca(2+) (By similarity).
Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in dendritic spine and synapse formation, neuronal plasticity and regulation of sarcoplasmic reticulum Ca(2+) transport in skeletal muscle (PubMed:16690701). In neurons, plays an essential structural role in the reorganization of the actin cytoskeleton during plasticity by binding and bundling actin filaments in a kinase-independent manner. This structural function is required for correct targeting of CaMK2A, which acts downstream of NMDAR to promote dendritic spine and synapse formation and maintain synaptic plasticity which enables long-term potentiation (LTP) and hippocampus-dependent learning. In developing hippocampal neurons, promotes arborization of the dendritic tree and in mature neurons, promotes dendritic remodeling. Also regulates the migration of developing neurons (PubMed:29100089). Participates in the modulation of skeletal muscle function in response to exercise (PubMed:16690701). In slow-twitch muscles, is involved in regulation of sarcoplasmic reticulum (SR) Ca(2+) transport and in fast-twitch muscle participates in the control of Ca(2+) release from the SR through phosphorylation of triadin, a ryanodine receptor-coupling factor, and phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2. In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of STAT1, stimulating the JAK-STAT signaling pathway (By similarity). Phosphorylates reticulophagy regulator RETREG1 at 'Ser-151' under endoplasmic reticulum stress conditions which enhances RETREG1 oligomerization and its membrane scission and reticulophagy activity (PubMed:31930741).
Widely expressed. Expressed in adult and fetal brain. Expression is slightly lower in fetal brain. Expressed in skeletal muscle.
May play a role in the respiratory chain.
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits. As part of the RNA polymerase III (Pol III) complex, interacts with PKP2 (PubMed:11416169).
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Largest and catalytic core component of RNA polymerase III which synthesizes small RNAs, such as 5S rRNA and tRNAs. Forms the polymerase active center together with the second largest subunit. A single-stranded DNA template strand of the promoter is positioned within the central active site cleft of Pol III. A bridging helix emanates from RPC1 and crosses the cleft near the catalytic site and is thought to promote translocation of Pol III by acting as a ratchet that moves the RNA-DNA hybrid through the active site by switching from straight to bent conformations at each step of nucleotide addition (By similarity). Plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF- Kappa-B through the RIG-I pathway.
Expressed in the brain, in the cortex and the white matter (at protein level).
Interacts with STIM1; the interaction is inhibit by th interaction of STIM1 with EFHB.
Negative regulator of store-operated Ca(2+) entry (SOCE) involved in protecting cells from Ca(2+) overfilling. In response to cytosolic Ca(2+) elevation after endoplasmic reticulum Ca(2+) refilling, promotes a slow inactivation of STIM (STIM1 or STIM2)-dependent SOCE activity: possibly act by facilitating the deoligomerization of STIM to efficiently turn off ORAI when the endoplasmic reticulum lumen is filled with the appropriate Ca(2+) levels, and thus preventing the overload of the cell with excessive Ca(2+) ions.
The cytoplasmic C-terminal region mediates interaction with STIM1, while the N-terminal lumenal region mediates regulation of SOCE activity.
Autoubiquitinated; MIOS is required to prevent autoubiquitination.
Catalytic component of the GATOR2 complex, a multiprotein complex that acts as an activator of the amino acid-sensing branch of the mTORC1 signaling pathway (PubMed:23723238, PubMed:26449471, PubMed:26586190, PubMed:27487210, PubMed:36528027, PubMed:35831510, PubMed:36732624). The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex (PubMed:23723238, PubMed:26449471, PubMed:26586190, PubMed:27487210, PubMed:36528027, PubMed:35831510, PubMed:36732624). GATOR2 probably acts as a E3 ubiquitin-protein ligase toward GATOR1 (PubMed:36528027, PubMed:36732624). In the presence of abundant amino acids, the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027, PubMed:36732624). In the absence of amino acids, GATOR2 is inhibited, activating the GATOR1 complex (PubMed:26449471, PubMed:26586190, PubMed:27487210). In addition to its role in regulation of the mTORC1 complex, promotes the acidification of lysosomes and facilitates autophagic flux (PubMed:27166823). Within the GATOR2 complex, WDR24 constitutes the catalytic subunit that mediates 'Lys-6'-linked ubiquitination of NPRL2 (PubMed:36528027, PubMed:36732624).
Component of the GATOR2 subcomplex, composed of MIOS, SEC13, SEH1L, WDR24 and WDR59 (PubMed:23723238, PubMed:36528027, PubMed:35831510). The GATOR2 complex interacts with CASTOR1 and CASTOR2; the interaction is negatively regulated by arginine (PubMed:26972053). The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:26586190). SESN1, SESN2 and SESN3 convey leucine availability via direct interaction with SEH1L and WDR24 (PubMed:35831510).
Phosphorylation at Ser-155 by AMPK in response to glucose deprivation inactivates WDR24 by promoting interaction with 14-3-3 proteins, such as YWHAG, preventing assembly of the GATOR2 complex.
The E3 ubiquitin-protein ligase activity of the GATOR2 complex is subject to discussion (PubMed:35831510, PubMed:36528027). According to a report, the GATOR2 complex does not catalyze ubiquitination of the GATOR1 complex (PubMed:35831510). In contrast, two studies from a same group show that the WDR24 component of the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027, PubMed:36732624).
The GATOR2 complex is negatively regulated by the upstream amino acid sensors CASTOR1 and SESN2, which sequester the GATOR2 complex in absence of amino acids (PubMed:26972053, PubMed:26449471, PubMed:26586190, PubMed:27487210, PubMed:36528027, PubMed:35831510). In the presence of abundant amino acids, GATOR2 is released from CASTOR1 and SESN2 and activated (PubMed:26972053, PubMed:26449471, PubMed:26586190, PubMed:27487210, PubMed:36528027, PubMed:35831510).
Imprinted. Promoter methylation of the maternal allele may restrict expression to the paternal allele in placenta.
Widely expressed. Mostly abundant in testis and adult and fetal brain.
Expressed in keratinocytes (at protein level). Highly expressed in placenta, prostate, brain and kidney. Lower-level expression in a variety of epithelial tissues such as thymus, lung, salivary gland, mammary gland and digestive tract. Expressed in the cochlear. Expressed in corneal epithelial cells, but not in the endothelium or stroma (PubMed:29499165).
Expressed in proliferating cells, the expression decreases during senescence. In keratinocytes, expression levels decrease upon calcium exposure.
GRHL genes (GRHL1, GRHL2 and GRHL3) show a paradoxal lack of redundancy despite their extensive sequence identity in the DNA-binding and protein dimerization domains and the fact that the core consensus DNA binding sites are identical. They have related but remarkably different functions during embryogenesis because of their differential spatiotemporal expression patterns during development.
Homodimer, also forms heterodimers with GRHL1 or GRHL3.
Transcription factor playing an important role in primary neurulation and in epithelial development (PubMed:29309642, PubMed:25152456). Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' acting as an activator and repressor on distinct target genes (By similarity). During embryogenesis, plays unique and cooperative roles with GRHL3 in establishing distinct zones of primary neurulation. Essential for closure 3 (rostral end of the forebrain), functions cooperatively with GRHL3 in closure 2 (forebrain/midbrain boundary) and posterior neuropore closure (By similarity). Regulates epithelial morphogenesis acting as a target gene-associated transcriptional activator of apical junctional complex components. Up-regulates of CLDN3 and CLDN4, as well as of RAB25, which increases the CLDN4 protein and its localization at tight junctions (By similarity). Comprises an essential component of the transcriptional machinery that establishes appropriate expression levels of CLDN4 and CDH1 in different types of epithelia. Exhibits functional redundancy with GRHL3 in epidermal morphogenetic events and epidermal wound repair (By similarity). In lung, forms a regulatory loop with NKX2-1 that coordinates lung epithelial cell morphogenesis and differentiation (By similarity). In keratinocytes, plays a role in telomerase activation during cellular proliferation, regulates TERT expression by binding to TERT promoter region and inhibiting DNA methylation at the 5'-CpG island, possibly by interfering with DNMT1 enzyme activity (PubMed:19015635, PubMed:20938050). In addition, impairs keratinocyte differentiation and epidermal function by inhibiting the expression of genes clustered at the epidermal differentiation complex (EDC) as well as GRHL1 and GRHL3 through epigenetic mechanisms (PubMed:23254293).
Expressed in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas (PubMed:23300339).
Interacts (via phosphorylated form and BSD domain) with AKT1; this interaction is enhanced in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation and activates AKT1 (PubMed:23300339).
Phosphorylated. Phosphorylation increases in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation.
Plays a role in adipocyte differentiation by promoting mTORC2-mediated phosphorylation of AKT1 at 'Ser-473' after growth factor stimulation (PubMed:23300339).
Binds to scaffold/matrix attachment region (S/MAR) DNA. Can function as an estrogen receptor corepressor and can also inhibit cell proliferation.
Expressed at high levels in the CNS and at low levels in the liver. Expressed in a wide number of breast cancer cell lines.
Interacts with SAFB/SAFB1 and SCAM1. Interacts with isoform 2 SRPK1 and inhibits its activity.
Detected in biliary epithelial cells on bile ducts at the hepatic hilum (at protein level).
Interacts promiscuously (via SAM domain) with EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3 and EPHB4 (via SAM domain) (in vitro).
Component of the condensin-2 complex, which contains the SMC2 and SMC4 heterodimer, and 3 non SMC subunits that probably regulate the complex: NCAPH2, NCAPD3 and NCAPG2. Interacts with BRD4 (isoform B), leading to insulate chromatin from DNA damage response pathway.
Regulatory subunit of the condensin-2 complex, a complex which establishes mitotic chromosome architecture and is involved in physical rigidity of the chromatid axis (PubMed:14532007). May promote the resolution of double-strand DNA catenanes (intertwines) between sister chromatids. Condensin-mediated compaction likely increases tension in catenated sister chromatids, providing directionality for type II topoisomerase-mediated strand exchanges toward chromatid decatenation. Specifically required for decatenation of centromeric ultrafine DNA bridges during anaphase. Early in neurogenesis, may play an essential role to ensure accurate mitotic chromosome condensation in neuron stem cells, ultimately affecting neuron pool and cortex size (PubMed:27737959).
Adenosine deaminase that may contribute to the degradation of extracellular adenosine, a signaling molecule that controls a variety of cellular responses. Requires elevated adenosine levels for optimal enzyme activity. Binds to cell surfaces via proteoglycans and may play a role in the regulation of cell proliferation and differentiation, independently of its enzyme activity.
Belongs to the metallo-dependent hydrolases superfamily. Adenosine and AMP deaminases family. ADGF subfamily.
Detected in blood plasma (at protein level). Widely expressed, with most abundant expression in human adult heart, lung, lymphoblasts, and placenta as well as fetal lung, liver, and kidney. In embryo, expressed in the outflow tract and atrium of the developing heart, the VII/VIII cranial nerve ganglion, and the notochord.
High-affinity binding to heparin/glycosaminoclycan (GAG) is mediated by a large, highly positively charged surface at the interface of dimer's subunits involving approximately residues 30-45, 389-396, and 422-428.
Homodimer. Interacts with adenosine receptors. Binds heparin.
The PRB domain is involved in receptor binding, and may be responsible for the cytokine-like growth factor activity due to it's sharing of several structural properties with chemokines.
Weakly expressed. Expressed at intermediate level in testis and ovary.
Required during spermiogenesis to participate in the repression transposable elements and prevent their mobilization, which is essential for the germline integrity. Probably acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons. Required for chromatoid body (CB) assembly (By similarity).
Required during spermiogenesis to participate in the repression transposable elements and prevent their mobilization, which is essential for the germline integrity. Probably acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons. Required for chromatoid body (CB) assembly.
I-alpha-I plasma protease inhibitors are assembled from one or two heavy chains (HC) and one light chain, bikunin. Pre-alpha-inhibitor (P-alpha-I) is composed of ITIH3/HC3 and bikunin.
Belongs to the small GTPase superfamily. Rheb family.
Binds GTP and exhibits intrinsic GTPase activity. May activate NF-kappa-B-mediated gene transcription. Promotes signal transduction through MTOR, activates RPS6KB1, and is a downstream target of the small GTPase-activating proteins TSC1 and TSC2.
Ubiquitously expressed. Expression increased at least 2-fold in several tumor cell lines.
Interacts with ACB10; this interaction stabilizes SLC25A37 and enhances the function of SLC25A37 to import mitochondrial iron during erythroid differentiation.
Mitochondrial iron transporter that specifically mediates iron uptake in developing erythroid cells, thereby playing an essential role in heme biosynthesis.
Belongs to the endoribonuclease YbeY family.
Single strand-specific metallo-endoribonuclease involved in rRNA maturation.
Transcription repressor. Required for the specification of corticospinal motor neurons and other subcerebral projection neurons. May play a role in layer and neuronal subtype-specific patterning of subcortical projections and axonal fasciculation. Controls the development of dendritic arborization and spines of large layer V pyramidal neurons. May be involved in innate immunity (By similarity).
Strong expression in brain and central nervous system.
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts (via PH domain) with GTP-bound RALA and RALB (PubMed:14525976, PubMed:18756269). Interacts with SH3BP1; required for the localization of both SH3BP1 and the exocyst to the leading edge of migrating cells (PubMed:21658605).
Interacts with tetraspanin-3/TSPAN3 (By similarity). Interacts with OCLN (PubMed:20375010).
Belongs to the complex I subunit 5 family.
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:15250827). Essential for the catalytic activity and assembly of complex I (PubMed:15250827).
According to experiments made in rat, this enzyme is unable to transfer GalNAc onto serine or threonine residue on the protein receptor, but instead requires the prior addition of a GalNAc on a peptide before adding additional GalNAc moieties, thereby acting as a glycopeptide transferase.
Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Has activity toward Muc5Ac and EA2 peptide substrates.
Widely expressed. Expressed at high level in small intestine, and at intermediate levels in stomach, pancreas, ovary, thyroid gland and spleen. Weakly expressed in other tissues.
May be required for the maturation and the transport from the endoplasmic reticulum to the plasma membrane of functional DUOX1.
Specifically expressed in thyroid gland. Also detected in esophagus.
Protease that catalyzes two essential functions in the SUMO pathway: processing of full-length SUMO3 to its mature form and deconjugation of SUMO2 and SUMO3 from targeted proteins. Has weak proteolytic activity against full-length SUMO1 or SUMO1 conjugates. Required for cell division.
Phosphorylation on Ser-208 by CDK1 promotes spindle pole localization and association with SCC1/RAD21.
The C2 domain is required for the repression.
Transcription factor that binds specifically to the DRE (dual repressor element) and represses HTR1A gene transcription in neuronal cells. The combination of calcium and ATP specifically inactivates the binding with FRE. May play a role in the altered regulation of HTR1A associated with anxiety and major depression. Mediates HDAC-independent repression of HTR1A promoter in neuronal cell. Performs essential function in controlling functional maturation of synapses (By similarity). Plays distinct roles depending on its localization. When cytoplasmic, acts as a scaffold protein in the PI3K/PDK1/AKT pathway. Repressor of HTR1A when nuclear. In the centrosome, regulates spindle pole localization of the cohesin subunit SCC1/RAD21, thereby mediating centriole cohesion during mitosis.
Belongs to the eukaryotic ribosomal protein eL33 family.
Component of the large ribosomal subunit (PubMed:23636399, PubMed:32669547). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399, PubMed:32669547). Required for the proliferation and viability of hematopoietic cells (PubMed:18535205).
Knockdown of RPL35A in hematopoietic cell lines results in decreased cell proliferation, increased apoptosis, decreased biogenesis of mature 60S ribosomal subunit, and abnormal processing of large ribosomal subunit rRNA.
Component of a PRC1-like complex (PubMed:19636380, PubMed:26151332). Interacts with BMI1/PCGF4, RING1 and RNF2 (PubMed:12167161). Interacts with KDM5D (PubMed:17320162). Interacts with CBX4, CBX6, CBX7 and CBX8 (PubMed:21282530).
Phosphorylated during mitosis. Phosphorylated on Ser-30 by CDK7 in vitro.
Transcriptional repressor (PubMed:12167161). May modulate the levels of histone H3K4Me3 by activating KDM5D histone demethylase (PubMed:17320162). Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:12167161). Within the PRC1-like complex, regulates RNF2 ubiquitin ligase activity (PubMed:26151332).
Catalyzes the hydrolysis of the free cytosolic methylated adenosine nucleotide N(6)-methyl-AMP (N6-mAMP) to produce inositol monophosphate (IMP) and methylamine (PubMed:21755941, PubMed:29884623). Is required for the catabolism of cytosolic N6-mAMP, which is derived from the degradation of mRNA containing N6-methylated adenine (m6A) (PubMed:21755941, PubMed:29884623). Catalyzes the removal of different alkyl groups not only from N6-substituted purine or 2-aminopurine nucleoside monophosphates but also from O6-substituted compounds in vitro (PubMed:21755941).
Associates with the PRC2 complex, which consists of the core components EED, EZH1 or EZH2, SUZ12, and RBBP4, and various combinations of accessory subunits including AEBP2, JARID2, PHF19, MTF2 and EPOP (PubMed:31959557). Forms a dimeric PRC2.1 (class 1, PRC-PCL) complex consisting of at least SUZ12, RBBP4, and PHF19 or MTF2; PHF19 and MTF2 stabilize the dimeric structure which enhances PRC2 interaction with chromatin (PubMed:31959557).
Polycomb group (PcG) protein that specifically binds histone H3 trimethylated at 'Lys-36' (H3K36me3) and recruits the PRC2 complex, thus enhancing PRC2 H3K27me3 methylation activity (PubMed:23142980, PubMed:23228662, PubMed:31959557). Regulates the transcriptional networks during embryonic stem cell self-renewal and differentiation (By similarity). Promotes recruitment of the PRC2 complex to the inactive X chromosome in differentiating XX ES cells and PRC2 recruitment to target genes in undifferentiated ES cells (By similarity). Required to repress Hox genes by enhancing H3K27me3 methylation of the PRC2 complex (By similarity). In some conditions may act as an inhibitor of PRC2 activity: able to activate the CDKN2A gene and promote cellular senescence by suppressing the catalytic activity of the PRC2 complex locally (By similarity). Binds to the metal-regulating-element (MRE) of MT1A gene promoter (By similarity).
The Tudor domain recognizes and binds H3K36me3 (PubMed:23142980, PubMed:23228662).
Laminin is a complex glycoprotein, consisting of three different polypeptide chains (alpha, beta, gamma), which are bound to each other by disulfide bonds into a cross-shaped molecule comprising one long and three short arms with globules at each end. Gamma-1 is a subunit of laminin-1 (laminin-111 or EHS laminin), laminin-2 (laminin-211 or merosin), laminin-3 (laminin-121 or S-laminin), laminin-4 (laminin-221 or S-merosin), laminin-6 (laminin-311 or K-laminin), laminin-7 (laminin-321 or KS-laminin), laminin-8 (laminin-411), laminin-9 (laminin-421), laminin-10 (laminin-511) and laminin-11 (laminin-521).
Expressed in brain, colon, heart, kidney, liver, lung, muscle, peripheral blood leukocytes, placenta, small intestine, spleen and thymus.
Negatively regulates the PAK1 kinase. PAK1 is a member of the PAK kinase family, which has been shown to play a positive role in the regulation of signaling pathways involving MAPK8 and RELA. PAK1 exists as an inactive homodimer, which is activated by binding of small GTPases such as CDC42 to an N-terminal regulatory domain. PAK1IP1 also binds to the N-terminus of PAK1, and inhibits the specific activation of PAK1 by CDC42. May be involved in ribosomal large subunit assembly (PubMed:24120868).
Core component of at least two putative endosomal tethering complexes, the homotypic fusion and vacuole protein sorting (HOPS) complex and the class C core vacuole/endosome tethering (CORVET) complex. Their common core is composed of the class C Vps proteins VPS11, VPS16, VPS18 and VPS33A, which in HOPS further associates with VPS39 and VPS41 and in CORVET with VPS8 and TGFBRAP1 (PubMed:11382755, PubMed:25783203, PubMed:23901104, PubMed:25266290). Interacts with RAB5C (By similarity). Interacts with STX17, MON1B (PubMed:20434987, PubMed:24554770). Associates with adapter protein complex 3 (AP-3) and clathrin:AP-3 complexes (By similarity).
Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Believed to act as a core component of the putative HOPS and CORVET endosomal tethering complexes which are proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The HOPS complex is proposed to be recruited to Rab7 on the late endosomal membrane and to regulate late endocytic, phagocytic and autophagic traffic towards lysosomes. The CORVET complex is proposed to function as a Rab5 effector to mediate early endosome fusion probably in specific endosome subpopulations (PubMed:11382755, PubMed:23351085, PubMed:24554770, PubMed:25266290, PubMed:25783203). Required for recruitment of VPS33A to the HOPS complex (PubMed:23901104). Required for fusion of endosomes and autophagosomes with lysosomes; the function is dependent on its association with VPS33A but not VPS33B (PubMed:25783203). The function in autophagosome-lysosome fusion implicates STX17 but not UVRAG (PubMed:24554770).
The disease is caused by variants affecting the gene represented in this entry. The transmission pattern of DYT30 in most families is consistent with autosomal dominant inheritance. However, a homozygous VPS16 variant has been found in a multigenerational consanguineous family with autosomal recessive inheritance of DYT30.
Accessory component of the STT3B-containing form of the N-oligosaccharyl transferase (OST) complex which catalyzes the transfer of a high mannose oligosaccharide from a lipid-linked oligosaccharide donor to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains (PubMed:31831667). Involved in N-glycosylation of STT3B-dependent substrates (PubMed:31831667). Specifically required for the glycosylation of a subset of acceptor sites that are near cysteine residues; in this function seems to act redundantly with TUSC3. In its oxidized form proposed to form transient mixed disulfides with a glycoprotein substrate to facilitate access of STT3B to the unmodified acceptor site. Has also oxidoreductase-independent functions in the STT3B-containing OST complex possibly involving substrate recognition.
Accessory component of the STT3B-containing form of the oligosaccharyltransferase (OST) complex (PubMed:31831667). OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits (PubMed:31831667). OST can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes. The association of TUSC3 or MAGT1 with the STT3B-containing complex seems to be mutually exclusvice.
Although MAGT1 has been reported to be involved in intellectual disability (PubMed:18455129), its pathological role is questionable (PubMed:23871722).
May be involved in Mg(2+) transport in epithelial cells.
Ubiquitous. Expressed at very low levels in brain, lung and kidney.
Up-regulated by low extracellular Mg(2+).
(Microbial infection) Acts as a receptor for measles virus.
(Microbial infection) Can facilitate HIV-1 infection via its interaction with virus-associated PPIA/CYPA.
(Microbial infection) Can facilitate human SARS coronavirus (SARS-CoV-1) infection via its interaction with virus-associated PPIA/CYPA.
(Microbial infection) Does not interact with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein, even if previous works were based on a putative interaction.
(Microbial infection) Erythrocyte receptor for P.falciparum RH5 which is essential for erythrocyte invasion by the merozoite stage of P.falciparum isolates 3D7 and Dd2.
(Microbial infection) Erythrocyte receptor for P.falciparum RH5 which is essential for erythrocyte invasion by the merozoite stage of P.falciparum isolates 3D7, Dd2, 7G8 and HB3 (PubMed:22080952, PubMed:26195724). Binding of P.falciparum RH5 results in BSG dimerization which triggers an increase in intracellular Ca(2+) in the erythrocyte (PubMed:28409866). This essential step leads to a rearrangement of the erythrocyte cytoskeleton required for the merozoite invasion (PubMed:28409866).
(Microbial infection) First described as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is not required for SARS-CoV-2 infection.
(Microbial infection) Interacts with P.falciparum (isolate 3D7) RH5/PfRH5; the interaction is required for the invasion of the host erythrocytes by the parasite at the merozoite stage.
(Microbial infection) Interacts with P.falciparum (isolates 3D7 or 7G8) RH5/PfRH5; the interaction is required for the invasion of the host erythrocytes by the parasite at the merozoite stage.
(Microbial infection) Promotes entry of pentamer-expressing human cytomegalovirus (HCMV) into epithelial and endothelial cells.
Essential for normal retinal maturation and development (By similarity). Acts as a retinal cell surface receptor for NXNL1 and plays an important role in NXNL1-mediated survival of retinal cone photoreceptors (PubMed:25957687). In association with glucose transporter SLC16A1/GLUT1 and NXNL1, promotes retinal cone survival by enhancing aerobic glycolysis and accelerating the entry of glucose into photoreceptors (PubMed:25957687). May act as a potent stimulator of IL6 secretion in multiple cell lines that include monocytes (PubMed:21620857).
Expressed in erythrocytes (at protein level) (PubMed:26195724, PubMed:28409866). Highly expressed in melanoma cell lines (at protein level) (PubMed:11992541). Highly expressed in the heart, kidney, skeletal muscle and testis (PubMed:21536654).
Highly expressed in the bone marrow, fetal liver, lung, testis and thymus.
Homooligomer (PubMed:18430721). Forms heterooligomers with isoform 3 (PubMed:21536654). Interacts with VEGFA and KDR/VEGFR2 (PubMed:25825981). Interacts with PPIA/CYPA (PubMed:11353871, PubMed:11943775, PubMed:15688292, PubMed:21245143). Interacts with PPIL2; regulates BSG transport to the cell membrane (PubMed:15946952). Interacts with SLC16A1; interaction mediates SLC16A3 targeting to the plasma membrane (PubMed:17127621). Interacts with SLC16A12 (PubMed:21778275). Interacts with SLC16A11 (PubMed:28666119). Interacts with AJAP1 (PubMed:17267690). Interacts with SLC1A3, ATP1B2, MAG and L1CAM (By similarity). Interacts with SLC16A3; interaction mediates SLC16A3 targeting to the plasma membrane.
Homooligomer (PubMed:19768682). Interacts with NXNL1 (PubMed:25957687). Interacts with SLC2A1 and SLC16A1/GLUT1 (By similarity). Interacts with XKR8; promoting its localization at the cell membrane (PubMed:27503893).
Interacts with SLC16A6; this interaction mediates targeting to the plasma membrane.
Potential candidate for the development of parasite blood stage vaccines. In vitro and in vivo, neutralizing antibodies are capable of inhibiting merozoite invasion of host erythrocytes.
Retina-specific (PubMed:25957687). Expressed in retinal cone photoreceptors (at protein level) (PubMed:25957687).
Signaling receptor for cyclophilins, essential for PPIA/CYPA and PPIB/CYPB-dependent signaling related to chemotaxis and adhesion of immune cells (PubMed:11943775, PubMed:11688976). Plays an important role in targeting monocarboxylate transporters SLC16A1/GLUT1, SLC16A11 and SLC16A12 to the plasma membrane (PubMed:17127621, PubMed:21778275, PubMed:28666119). Acts as a coreceptor for vascular endothelial growth factor receptor 2 (KDR/VEGFR2) in endothelial cells enhancing its VEGFA-mediated activation and downstream signaling (PubMed:25825981). Promotes angiogenesis through EPAS1/HIF2A-mediated up-regulation of VEGFA (isoform VEGF-165 and VEGF-121) and KDR/VEGFR2 in endothelial cells (PubMed:19837976). Plays a key role in regulating tumor growth, invasion, metastasis and neoangiogenesis by stimulating the production and release of extracellular matrix metalloproteinases and KDR/VEGFR2 by both tumor cells and stromal cells (fibroblasts and endothelial cells) (PubMed:12553375, PubMed:11992541, PubMed:15833850).
Highly expressed in brain, lung, kidney and small intestine. Weakly expressed in placenta, liver, spleen, thymus, ovary and colon.
RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion. Binds both poly(A) and poly(U) homopolymers. Phosphorylation by PTK6 inhibits its RNA-binding ability (By similarity). Induces an increased concentration-dependent incorporation of exon in CD44 pre-mRNA by direct binding to purine-rich exonic enhancer. Can regulate alternative splicing of NRXN1 in the laminin G-like domain 6 containing the evolutionary conserved neurexin alternative spliced segment 4 (AS4) involved in neurexin selective targeting to postsynaptic partners. Regulates cell-type specific alternative splicing of NRXN1 at AS4 and acts synergystically with SAM68 in exon skipping. In contrast acts antagonistically with SAM68 in NRXN3 exon skipping at AS4. Its phosphorylation by FYN inhibits its ability to regulate splice site selection. May function as an adapter protein for Src kinases during mitosis.
Self-associates to form homooligomers (By similarity). Interacts with KHDRBS1/SAM68; heterooligomer formation of KHDRBS family proteins may modulate RNA substrate specificity (By similarity). Interacts with RBMX (PubMed:19282290). Interacts with SAFB, SFRS9 and YTHDC1. Interacts with FYN and PLCG1 (via SH3 domain). Interacts (phosphorylated) with FYN, GRB2, PLCG1 and RASA1 (via SH2 domain) (By similarity).
Tyrosine phosphorylated by FYN, PTK6 and SRC. Tyrosine phosphorylated by SRC during mitosis (By similarity).
During in vitro ciliogenesis translocalizes from the cytoplasm to the ciliary transition zone during epithelial cell polarization.
Interacts with BCAR1, PTK2B/PYK2 and tensin. Interacts with INVS and NPHP3. Interacts with PACS1; the interaction is dependent on NPHP1 phosphorylation by CK2. Interacts with KIF7. Interacts with AHI1 and TNK2. Interacts with NPHP4 in a complex containing NPHP1, NPHP4 and RPGRIP1L. Interacts with IQCB1; the interaction likely requires additional interactors. Interacts with ANKS3 (By similarity).Interacts with SPATA7 (By similarity). Interacts with FLNA (By similarity).
Nephronophthisis type 1 patients deficient for NPHP1 show normal overall integrity of respiratory cilia.
Phosphorylation by CK2 is required for the interaction with PACS1 and the targeting to the base region of cilia.
The SH3 domain mediates the stable interaction with Cas.
Together with BCAR1 it may play a role in the control of epithelial cell polarity (By similarity). Involved in the organization of apical junctions in kidney cells together with NPHP4 and RPGRIP1L/NPHP8 (By similarity). Does not seem to be strictly required for ciliogenesis (By similarity). Seems to help to recruit PTK2B/PYK2 to cell matrix adhesions, thereby initiating phosphorylation of PTK2B/PYK2 and PTK2B/PYK2-dependent signaling (By similarity). May play a role in the regulation of intraflagellar transport (IFT) during cilia assembly. Required for normal retina development (By similarity). In connecting photoreceptor cilia influences the movement of some IFT proteins such as IFT88 and WDR19. Involved in spermatogenesis (By similarity).
Widespread expression, with highest levels in pituitary gland, spinal cord, thyroid gland, testis, skeletal muscle, lymph node and trachea. Weakly expressed in heart, kidney and pancreas. Expressed in nasal epithelial cells (at protein level) (PubMed:16308564). Expressed in the renal collecting duct (at protein level) (PubMed:18477472).
Expressed in ovaries, testes and pancreas. Expressed within all stages of the adult female germline, from primordial follicles through to MII oocytes.
Transcription factor which may play a role in oogenesis. Binds preferentially to the DNA sequences 5'-TAATTG-3', 5'-TAGTTG-3' and 5'-TAATTA-3'.
Negatively regulates myogenesis and skeletal muscle regeneration via its association with ITGB1 (By similarity). Modulates ITGB1 activation by decreasing ITGB1-LAMB1 interaction and inhibiting ITGB1-mediated intracellular signaling during myogenesis (By similarity).
A helix bundle is formed by helices from the N-terminal and the C-terminal part of the protein. The GTPase domain cannot be expressed by itself, without the helix bundle. Rearrangement of the helix bundle and/or of the coiled coil domains may bring membranes from adjacent mitochondria into close contact, and thereby play a role in mitochondrial fusion.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. Dynamin/Fzo/YdjA family. Mitofusin subfamily.
Forms homomultimers and heteromultimers with MFN1 (PubMed:26085578). Oligomerization is essential for mitochondrion fusion (Probable). Interacts with VAT1 (By similarity). Interacts with STOML2; may form heterooligomers (PubMed:17121834). Interacts (phosphorylated) with PRKN (PubMed:23620051). Interacts with EIF2AK3 (By similarity). Interacts with THG1L; THG1L probably functions as a guanyl-nucleotide exchange factor/GEF, activating MFN2.
Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion (PubMed:11181170, PubMed:11950885, PubMed:26214738, PubMed:28114303). Mitochondria are highly dynamic organelles, and their morphology is determined by the equilibrium between mitochondrial fusion and fission events (PubMed:28114303). Overexpression induces the formation of mitochondrial networks (PubMed:28114303). Membrane clustering requires GTPase activity and may involve a major rearrangement of the coiled coil domains (Probable). Plays a central role in mitochondrial metabolism and may be associated with obesity and/or apoptosis processes (By similarity). Plays an important role in the regulation of vascular smooth muscle cell proliferation (By similarity). Involved in the clearance of damaged mitochondria via selective autophagy (mitophagy) (PubMed:23620051). Is required for PRKN recruitment to dysfunctional mitochondria (PubMed:23620051). Involved in the control of unfolded protein response (UPR) upon ER stress including activation of apoptosis and autophagy during ER stress (By similarity). Acts as an upstream regulator of EIF2AK3 and suppresses EIF2AK3 activation under basal conditions (By similarity).
Ubiquitinated by non-degradative ubiquitin by PRKN, promoting mitochondrial fusion; deubiquitination by USP30 inhibits mitochondrial fusion (PubMed:23620051). Ubiquitinated by HUWE1 when dietary stearate (C18:0) levels are low; ubiquitination inhibits mitochondrial fusion (PubMed:26214738, PubMed:30217973).
Ubiquitous; expressed at low level. Highly expressed in heart and kidney.
ADP-ribosyltransferase activity is regulated via an allosteric activation mechanism (PubMed:22582261, PubMed:26626479, PubMed:32358582, PubMed:26626480, PubMed:32241924). In absence of activation signal, PARP1 is autoinhibited by the PARP alpha-helical domain (also named HD region), which prevents effective NAD(+)-binding (PubMed:26626479, PubMed:26626480, PubMed:32241924). Activity is highly stimulated by signals, such as DNA strand breaks (PubMed:20388712, PubMed:32358582, PubMed:32241924). Binding to damaged DNA unfolds the PARP alpha-helical domain, relieving autoinhibition (PubMed:22582261, PubMed:26626479, PubMed:26626480, PubMed:32241924). Poly-ADP-ribosyltransferase activity is tightly regulated and PARP1 is removed from damaged chromatin following initial poly-ADP-ribosylation of chromatin to avoid prolonged residence (trapping) that has cytotoxic consequences (PubMed:34210965, PubMed:34625544, PubMed:35013556). A number of factors (VCP/p97) or post-translational modifications (auto-poly-ADP-ribosylation or ubiquitination) promote PARP1 removal from chromatin (PubMed:34210965, PubMed:34625544, PubMed:35013556). ADP-ribosyltransferase activity is inhibited by a number of PARP inhibitors (PARPi) compounds, that are used the treatment of breast or ovarian cancers that have defects in DNA repair by homologous recombination (PubMed:32358582, PubMed:29487285, PubMed:32241924). PARPi molecules can be classified in three categories: type I compounds (EB-47, UKTT15 and BAD) that promote allosteric retention of PARP1 on DNA, type II inhibitors (talazoparib and olaparib) that mediate a non-allosteric inhibition, and type III inhibitors (rucaparib, niraparib, and veliparib) that promote allosteric release from DNA (PubMed:29487285, PubMed:32241924, PubMed:33361107). Trapping to chromatin by PARPi molecules triggers activation of the cGAS-STING pathway (PubMed:32844745).
Homodimer; PARP-type zinc-fingers from separate PARP1 molecules form a dimer module that specifically recognizes DNA strand breaks (PubMed:22683995). Heterodimer; heterodimerizes with PARP2 (By similarity). Interacts (via the PARP catalytic domain) with HPF1 (PubMed:27067600, PubMed:28190768, PubMed:29954836, PubMed:32028527, PubMed:33589610). Interacts with NMNAT1 (By similarity). Interacts with nucleosomes; with a preference for nucleosomes containing H2A.X (PubMed:15607977, PubMed:31848352). Interacts with APTX (PubMed:15044383). Component of a base excision repair (BER) complex, containing at least XRCC1, PARP1, PARP2, POLB and LRIG3 (By similarity). Interacts with SRY (PubMed:16904257). The SWAP complex consists of NPM1, NCL, PARP1 and SWAP70 (By similarity). Interacts with TIAM2 (By similarity). Interacts with PARP3; leading to activate PARP1 in absence of DNA (PubMed:20064938). Interacts (when poly-ADP-ribosylated) with CHD1L (via macro domain) (PubMed:19661379, PubMed:29220653). Interacts with the DNA polymerase alpha catalytic subunit POLA1; this interaction functions as part of the control of replication fork progression (PubMed:9518481). Interacts with EEF1A1 and TXK (PubMed:17177976). Interacts with RNF4 (PubMed:19779455). Interacts with RNF146 (PubMed:21799911). Interacts with ZNF423 (PubMed:22863007). Interacts with APLF (PubMed:17396150). Interacts with SNAI1 (via zinc fingers); the interaction requires SNAI1 to be poly-ADP-ribosylated and non-phosphorylated (active) by GSK3B (PubMed:21577210). Interacts (when poly-ADP-ribosylated) with PARP9 (PubMed:23230272). Interacts with NR4A3; activates PARP1 by improving acetylation of PARP1 and suppressing the interaction between PARP1 and SIRT1 (By similarity). Interacts (via catalytic domain) with PUM3; the interaction inhibits the poly-ADP-ribosylation activity of PARP1 and the degradation of PARP1 by CASP3 following genotoxic stress (PubMed:21266351). Interacts with ZNF365 (PubMed:23966166). Interacts with RRP1B (PubMed:19710015). Interacts with TIMELESS; the interaction is direct (PubMed:26344098). Interacts with CGAS; leading to impede the formation of the PARP1-TIMELESS complex (PubMed:30356214). Interacts with KHDC3L, the interaction is increased following the formation of DNA double-strand breaks (PubMed:31609975). Interacts (when auto-poly-ADP-ribosylated) with XRCC1; leading to inhibit PARP1 ADP-ribosyltransferase activity (PubMed:34102106, PubMed:34811483). Interacts with SPINDOC; promoting PARP1 ADP-ribosyltransferase activity (PubMed:34737271). Interacts with BANF1; leading to inhibit PARP1 ADP-ribosyltransferase activity in response to oxidative DNA damage (PubMed:31796734). Interacts (when sumoylated and ubiquitinated) with VCP/p97; leading to its extraction from chromatin (PubMed:35013556). Interacts with YARS1; Interacts with PACMP micropeptide; interaction (PubMed:25533949). Interacts with PACMP micropeptide; Interacts with PACMP micropeptide; interaction (PubMed:35219381). Interacts (when poly-ADP-ribosylated) with isoform 1 of MACROH2A1; MACROH2A1 specifically binds to poly-ADP-ribose chains and inhibits PARP1 activity, limiting the consumption of nuclear NAD(+) (By similarity). Interacts with CARM1; promoting recruitment to replication forks (PubMed:33412112).
Interacts (when auto-poly-ADP-ribosylated) with AIFM1.
Phosphorylated at Thr-594 by PRKDC in response to DNA damage following virus infection, promoting its translocation to the cytosol (PubMed:10467406, PubMed:35460603). Phosphorylated by TXK (PubMed:17177976).
Poly-ADP-ribosylated on serine, glutamate and aspartate residues by autocatalysis (PubMed:19764761, PubMed:20388712, PubMed:22582261). Auto-ADP-ribosylation on serine takes place following interaction with HPF1 (PubMed:28190768, PubMed:34625544). Auto poly-ADP-ribosylation on serine residues promotes its dissociation from chromatin (PubMed:15607977, PubMed:30675909, PubMed:32358582, PubMed:34210965, PubMed:34625544). Poly-ADP-ribosylated by PARP2; poly-ADP-ribosylation mediates the recruitment of CHD1L to DNA damage sites (PubMed:19661379). Mono-ADP-ribosylated at Lys-521 by SIRT6 in response to oxidative stress, promoting recruitment to double-strand breaks (DSBs) sites (PubMed:21680843, PubMed:22753495, PubMed:27568560).
Poly-ADP-ribosyltransferase that mediates poly-ADP-ribosylation of proteins and plays a key role in DNA repair (PubMed:17177976, PubMed:18172500, PubMed:20388712, PubMed:19344625, PubMed:19661379, PubMed:21680843, PubMed:23230272, PubMed:25043379, PubMed:26344098, PubMed:32028527, PubMed:30104678, PubMed:33186521, PubMed:31796734, PubMed:32358582, PubMed:34737271, PubMed:34465625, PubMed:18055453, PubMed:22582261, PubMed:26626479, PubMed:26626480, PubMed:32241924). Mediates glutamate, aspartate, serine, histidine or tyrosine ADP-ribosylation of proteins: the ADP-D-ribosyl group of NAD(+) is transferred to the acceptor carboxyl group of target residues and further ADP-ribosyl groups are transferred to the 2'-position of the terminal adenosine moiety, building up a polymer with an average chain length of 20-30 units (PubMed:7852410, PubMed:9315851, PubMed:19764761, PubMed:25043379, PubMed:28190768, PubMed:29954836, PubMed:35393539). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:33186521, PubMed:34874266). Specificity for the different amino acids is conferred by interacting factors, such as HPF1 and NMNAT1 (PubMed:28190768, PubMed:29954836, PubMed:32028527, PubMed:33186521, PubMed:34874266, PubMed:34625544, PubMed:33589610). Following interaction with HPF1, catalyzes serine ADP-ribosylation of target proteins; HPF1 confers serine specificity by completing the PARP1 active site (PubMed:28190768, PubMed:29954836, PubMed:32028527, PubMed:33186521, PubMed:34874266, PubMed:34625544, PubMed:33589610). Also catalyzes tyrosine ADP-ribosylation of target proteins following interaction with HPF1 (PubMed:30257210, PubMed:29954836). Following interaction with NMNAT1, catalyzes glutamate and aspartate ADP-ribosylation of target proteins; NMNAT1 confers glutamate and aspartate specificity (By similarity). PARP1 initiates the repair of DNA breaks: recognizes and binds DNA breaks within chromatin and recruits HPF1, licensing serine ADP-ribosylation of target proteins, such as histones (H2BS6ADPr and H3S10ADPr), thereby promoting decompaction of chromatin and the recruitment of repair factors leading to the reparation of DNA strand breaks (PubMed:17177976, PubMed:18172500, PubMed:19344625, PubMed:19661379, PubMed:23230272, PubMed:27067600, PubMed:34874266, PubMed:34465625). HPF1 initiates serine ADP-ribosylation but restricts the polymerase activity of PARP1 in order to limit the length of poly-ADP-ribose chains (PubMed:34732825, PubMed:33683197, PubMed:34795260). In addition to base excision repair (BER) pathway, also involved in double-strand breaks (DSBs) repair: together with TIMELESS, accumulates at DNA damage sites and promotes homologous recombination repair by mediating poly-ADP-ribosylation (PubMed:26344098, PubMed:30356214). Mediates the poly-ADP-ribosylation of a number of proteins, including itself, APLF, CHFR and NFAT5 (PubMed:17396150, PubMed:19764761, PubMed:34049076). In addition to proteins, also able to ADP-ribosylate DNA: catalyzes ADP-ribosylation of DNA strand break termini containing terminal phosphates and a 2'-OH group in single- and double-stranded DNA, respectively (PubMed:27471034). Required for PARP9 and DTX3L recruitment to DNA damage sites (PubMed:23230272). PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites (PubMed:23230272). PARP1-mediated DNA repair in neurons plays a role in sleep: senses DNA damage in neurons and promotes sleep, facilitating efficient DNA repair (By similarity). In addition to DNA repair, also involved in other processes, such as transcription regulation, programmed cell death, membrane repair, adipogenesis and innate immunity (PubMed:17177976, PubMed:19344625, PubMed:15607977, PubMed:27256882, PubMed:32844745, PubMed:32315358, PubMed:35124853, PubMed:35460603, PubMed:35393539). Acts as a repressor of transcription: binds to nucleosomes and modulates chromatin structure in a manner similar to histone H1, thereby altering RNA polymerase II (PubMed:15607977, PubMed:22464733). Acts both as a positive and negative regulator of transcription elongation, depending on the context (PubMed:27256882, PubMed:35393539). Acts as a positive regulator of transcription elongation by mediating poly-ADP-ribosylation of NELFE, preventing RNA-binding activity of NELFE and relieving transcription pausing (PubMed:27256882). Acts as a negative regulator of transcription elongation in response to DNA damage by catalyzing poly-ADP-ribosylation of CCNT1, disrupting the phase separation activity of CCNT1 and subsequent activation of CDK9 (PubMed:35393539). Involved in replication fork progression following interaction with CARM1: mediates poly-ADP-ribosylation at replication forks, slowing fork progression (PubMed:33412112). Poly-ADP-ribose chains generated by PARP1 also play a role in poly-ADP-ribose-dependent cell death, a process named parthanatos (By similarity). Also acts as a negative regulator of the cGAS-STING pathway (PubMed:32844745, PubMed:32315358, PubMed:35460603). Acts by mediating poly-ADP-ribosylation of CGAS: PARP1 translocates into the cytosol following phosphorylation by PRKDC and catalyzes poly-ADP-ribosylation and inactivation of CGAS (PubMed:35460603). Acts as a negative regulator of adipogenesis: catalyzes poly-ADP-ribosylation of histone H2B on 'Glu-35' (H2BE35ADPr) following interaction with NMNAT1, inhibiting phosphorylation of H2B at 'Ser-36' (H2BS36ph), thereby blocking expression of pro-adipogenetic genes (By similarity). Involved in the synthesis of ATP in the nucleus, together with NMNAT1, PARG and NUDT5 (PubMed:27257257). Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming (PubMed:27257257).
Promotes AIFM1-mediated apoptosis (PubMed:33168626). This form, which translocates into the cytoplasm following cleavage by caspase-3 (CASP3) and caspase-7 (CASP7) in response to apoptosis, is auto-poly-ADP-ribosylated and serves as a poly-ADP-ribose carrier to induce AIFM1-mediated apoptosis (PubMed:33168626).
Proteolytically cleaved by caspase-3 (CASP3) and caspase-7 (CASP7) in response to apoptosis to generate the Poly [ADP-ribose] polymerase 1, processed N-terminus and Poly [ADP-ribose] polymerase 1, processed C-terminus forms (PubMed:7596430, PubMed:10497198, PubMed:16374543, PubMed:22464733, PubMed:22451931, PubMed:33168626, PubMed:35104452). CASP3-mediated cleavage is promoted by the TP53/p53-induced long non-coding RNA SPARCLE, which binds PARP1 in response to genotoxic stress (PubMed:35104452).
S-nitrosylated, leading to inhibit transcription regulation activity.
Sumoylated with SUMO1 or SUMO2 by PIAS4 following prolonged residence (trapping) to chromatin (PubMed:35013556). Sumoylation promotes ubiquitination by RNF4 and removal from chromatin by VCP/p97 (PubMed:35013556).
The BRCT domain is able to bind intact DNA without activating the poly-ADP-ribosyltransferase activity (PubMed:34919819). The BRCT domain mediates DNA intrastrand transfer (named 'monkey-bar mechanism') that allows rapid movements of PARP1 through the nucleus (PubMed:34919819).
The PADR1-type (also named Zn3) zinc-finger mediates an interdomain contact and is required for the ability of PARP1 to regulate chromatin structure.
The PARP alpha-helical domain (also named HD region) prevents effective NAD(+)-binding in absence of activation signal (PubMed:26626479, PubMed:26626480). Binding to damaged DNA unfolds the PARP alpha-helical domain, relieving autoinhibition (PubMed:26626479, PubMed:26626480).
The WGR domain bridges two nucleosomes, with the broken DNA aligned in a position suitable for ligation. The bridging induces structural changes in PARP1 that signal the recognition of a DNA break to the catalytic domain of PARP1, promoting HPF1 recruitment and subsequent activation of PARP1, licensing serine ADP-ribosylation of target proteins.
The two PARP-type zinc-fingers (also named Zn1 and Zn2) specifically recognize DNA strand breaks: PARP-type zinc-finger 1 binds PARP-type zinc-finger 2 from a separate PARP1 molecule to form a dimeric module that specifically recognizes DNA strand breaks.
This cleavage form irreversibly binds to DNA breaks and interferes with DNA repair, promoting DNA damage-induced apoptosis.
Ubiquitinated by RNF4 following sumoylation by PIAS4 in response to prolonged residence (trapping) to chromatin (PubMed:35013556). Ubiquitination promotes removal from chromatin by VCP/p97 (PubMed:35013556).
Eight alleles have been characterized (APOA-IV*0 to APOA-IV*7). APOA-IV*1 is the major allele (90%), APOA-IV*2 is also common (8%), the others are rare alleles.
May have a role in chylomicrons and VLDL secretion and catabolism. Required for efficient activation of lipoprotein lipase by ApoC-II; potent activator of LCAT. Apoa-IV is a major component of HDL and chylomicrons.
Nine of the thirteen 22-amino acid tandem repeats (each 22-mer is actually a tandem array of two, A and B, related 11-mers) occurring in this sequence are predicted to be highly alpha-helical, and many of these helices are amphipathic. They may therefore serve as lipid-binding domains with lecithin:cholesterol acyltransferase (LCAT) activating abilities.
Synthesized primarily in the intestine and secreted in plasma.
Activated by phosphorylation at Thr-229, probably by autophosphorylation.
Expressed at high levels in adult and fetal kidney and liver, and adult colon. Expressed in fetal renal proximal tubules (at protein level). Expressed at lower levels in heart, brain and lung.
May act as a transporter of organic cations based on a proton efflux antiport mechanism. May play a role in the transport of chloroquine and quinidine-related compounds in kidney.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ15 subfamily.
Aquaporins facilitate the transport of water and small neutral solutes across cell membranes.
Expressed at low levels in many tissues, including smooth muscle, brain, uterus, pancreas, cartilage, adipose, spleen and testis.
Renders cells highly sensitive to the activation by cytokines and lipopolysaccharide (LPS).
Mediates pre-mRNA alternative splicing regulation. Acts either as activator or repressor of splicing on specific pre-mRNA targets. Inhibits cardiac troponin-T (TNNT2) pre-mRNA exon inclusion but induces insulin receptor (IR) pre-mRNA exon inclusion in muscle. Antagonizes the alternative splicing activity pattern of CELF proteins. May play a role in myotonic dystrophy pathophysiology (DM). Could inhibit terminal muscle differentiation, acting at approximately the time of myogenin induction.
Belongs to the eukaryotic ribosomal protein eS6 family.
Component of the 40S small ribosomal subunit (PubMed:8706699, PubMed:23636399). Plays an important role in controlling cell growth and proliferation through the selective translation of particular classes of mRNA (PubMed:17220279). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Mono-ADP-ribosylation at Glu-35 by PARP16 inhibits polysome assembly and mRNA loading, thereby inhibiting protein translation.
Ribosomal protein S6 is the major substrate of protein kinases in eukaryote ribosomes. The phosphorylation is stimulated by growth factors, tumor promoting agents, and mitogens. It is dephosphorylated at growth arrest. Phosphorylated at Ser-235 and Ser-236 by RPS6KA1 and RPS6KA3; phosphorylation at these sites facilitates the assembly of the pre-initiation complex.
Specifically hydroxylated (with R stereochemistry) at C-3 of Arg-137 by KDM8.
Growth factor involved in bone and cartilage formation. During cartilage development regulates differentiation of chondrogenic tissue through two pathways. Firstly, positively regulates differentiation of chondrogenic tissue through its binding of high affinity with BMPR1B and of less affinity with BMPR1A, leading to induction of SMAD1-SMAD5-SMAD8 complex phosphorylation and then SMAD protein signaling transduction (PubMed:24098149, PubMed:21976273, PubMed:15530414, PubMed:25092592). Secondly, negatively regulates chondrogenic differentiation through its interaction with NOG (PubMed:21976273). Required to prevent excessive muscle loss upon denervation. This function requires SMAD4 and is mediated by phosphorylated SMAD1/5/8 (By similarity). Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205).
Homodimer; disulfide-linked (By similarity). Interacts with serine proteases, HTRA1 and HTRA3 (By similarity). Following LPS binding, may form a complex with CXCR4, HSP90AA1 and HSPA8. Interacts with high affinity with NOG; inhibits chondrogenesis. Interacts with high affinity with BMPR1B and lower affinity with BMPR1A; positively regulates chondrocyte differentiation and induces SMAD dependent signaling. Interacts with FBN1 (via N-terminal domain) and FBN2 (PubMed:18339631).
Predominantly expressed in long bones during embryonic development. Expressed in monocytes (at protein level).
The disease is caused by variants affecting the gene represented in this entry. Some BDC patients with GDF5 mutations also manifest clinical features of ASPED angel-shaped phalango-epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. This suggests that BDC and ASPED are part of the same clinical spectrum (PubMed:22828468).
Belongs to the krueppel C2H2-type zinc-finger protein family. Hic subfamily.
Binds actin and the Arp2/3 complex. Interacts with BAIAP2. Component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1/NAP1 (NCKAP1l/HEM1 in hematopoietic cells) and WASF2/WAVE2 (PubMed:16417406). Directly interacts with BRK1. Interacts with FNBP1L (via the SH3 domain) (PubMed:19798448).
Binds and activates the Arp2/3 complex via the C-terminal domain. Interacts with actin via the WH2 domain.
Downstream effector molecule involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. Promotes formation of actin filaments. Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex.
Expressed in all tissues with strongest expression in placenta, lung, and peripheral blood leukocytes, but not in skeletal muscle.
Preferentially expressed in the placenta.
Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds to multiple functional elements of the human chorionic somatomammotropin-B gene enhancer.
Microtubule-dependent motor required for normal distribution of mitochondria and lysosomes. Can induce formation of neurite-like membrane protrusions in non-neuronal cells in a ZFYVE27-dependent manner (By similarity). Regulates centrosome and nuclear positioning during mitotic entry. During the G2 phase of the cell cycle in a BICD2-dependent manner, antagonizes dynein function and drives the separation of nuclei and centrosomes (PubMed:20386726). Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation (By similarity). Through binding with PLEKHM2 and ARL8B, directs lysosome movement toward microtubule plus ends (Probable). Involved in NK cell-mediated cytotoxicity. Drives the polarization of cytolytic granules and microtubule-organizing centers (MTOCs) toward the immune synapse between effector NK lymphocytes and target cells (PubMed:24088571).
Oligomer composed of two heavy chains and two light chains. Interacts with GRIP1 and PPP1R42 (By similarity). Interacts with SYBU (PubMed:15459722). Interacts with JAKMIP1 (PubMed:17532644). Interacts with PLEKHM2 (PubMed:15905402). Interacts with ECPAS (PubMed:20682791). Interacts with ZFYVE27 (By similarity). Found in a complex with OGT, RHOT1, RHOT2 and TRAK1 (PubMed:24995978). Interacts with APP (via cytoplasmic domain) (PubMed:23011729).
Highly expressed in liver, pancreas, testis, lung and small intestine. Lower levels are detected in spleen, kidney, brain and heart.
Inhibited by pyridoxal 5'-phosphate as well as by mercurials (mersalyl, p-chloromercuribenzene sulfonate, and mercuric chloride), N-ethylmaleimide and spermine.
Mitochondrial ornithine-citrulline antiporter (PubMed:12807890, PubMed:22262851) (Probable). Catalyzes the exchange between cytosolic ornithine and mitochondrial citrulline plus an H(+), the proton compensates the positive charge of ornithine thus leading to an electroneutral transport. Plays a crucial role in the urea cycle, by connecting the cytosolic and the intramitochondrial reactions of the urea cycle (PubMed:12807890, PubMed:22262851) (Probable). Lysine and arginine are also transported by the antiport mechanism (PubMed:12807890) (Probable). In addition, catalyzes an electroneutral exchange of ornithine or lysine for H(+), a reaction driven by the pH gradient across the inner membrane (By similarity).
May function as protein hydroxylase; can catalyze auto-hydroxylation at Leu-110 (in vitro), but this activity may be due to the absence of the true substrate (PubMed:25122757). Required to induce programmed necrosis in response to DNA damage caused by cytotoxic alkylating agents. Acts by triggering the collapse of mitochondrial membrane potential and loss of mitochondrial function that leads to energy depletion and cell death (PubMed:23666923). ALKBH7-mediated necrosis is probably required to prevent the accumulation of cells with DNA damage (PubMed:23666923). Does not display DNA demethylase activity (PubMed:23666923). Involved in fatty acid metabolism (By similarity).
Was initially reported to localize both in cytoplasm and nucleus (PubMed:17979886). However, it was later shown it localizes in mitochondrion (PubMed:23666923). The discrepancy is probably due to the use of a fusion protein with an N-terminal tag in the initial report (PubMed:17979886).
Widely expressed, with highest expression in pancreas, followed by spleen, prostate, ovary and placenta.
Highly expressed in testis. Expressed at low levels in prostate, female breast, placenta, ovary and thymus.
May play a role in testicular physiology, most probably in the process of spermatogenesis or spermatid development.
Phosphorylated on serine residue(s) by STK22A/TSSK1 and STK22B/TSSK2.
Defects in TOP2B may be involved in global developmental delay with autism spectrum disorder (ASD).
Expressed in the tonsil, spleen, lymph node, thymus, skin, pancreas, testis, colon, kidney, liver, brain and lung (PubMed:9155056). Also found in breast, colon and lung carcinomas, Hodgkin's disease, large-cell non-Hodgkin's lymphoma, lymphocytic lymphomas and seminomas (PubMed:9155056).
Homodimer (PubMed:21778401). Interacts with KIAA1210 (By similarity). Interacts with PLSCR1 (PubMed:19690332).
Key decatenating enzyme that alters DNA topology by binding to two double-stranded DNA molecules, generating a double-stranded break in one of the strands, passing the intact strand through the broken strand, and religating the broken strand. Plays a role in B-cell differentiation.
Interacts with POLD2. Interacts with NCBP1 and EIF4A3. Associates with the multiprotein exon junction complex (EJC). Interacts with RPS6KB1 (activated). Interacts with ERH. Interacts with THOC2, DDX39B and ZC3H11A; the interactions are ATP-dependent and indicative for an association with the TREX complex.
Is involved in regulation of translation. Is preferentially associated with CBC-bound spliced mRNA-protein complexes during the pioneer round of mRNA translation. Contributes to enhanced translational efficiency of spliced over nonspliced mRNAs. Recruits activated ribosomal protein S6 kinase beta-1 I/RPS6KB1 to newly synthesized mRNA. Involved in nuclear mRNA export; probably mediated by association with the TREX complex.
Phosphorylated at Ser-383 and Ser-385 by RPS6KB1.
Binds ROCK1 and MARF1 (Ref.9, PubMed:11018042, PubMed:10436159). Interacts with NISCH (By similarity).
Phosphorylated on serine and/or threonine residues by ROCK1.
Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics (PubMed:10436159, PubMed:11018042). Acts downstream of several Rho family GTPase signal transduction pathways (PubMed:10436159, PubMed:11018042). Involved in astral microtubule organization and mitotic spindle orientation during early stages of mitosis by mediating phosphorylation of TPPP (PubMed:22328514). Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro (PubMed:8537403). Suppresses ciliogenesis via multiple pathways; phosphorylation of CFL1, suppression of directional trafficking of ciliary vesicles to the ciliary base, and by facilitating YAP1 nuclear localization where it acts as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1 (PubMed:25849865).
Expressed almost exclusively in skeletal muscle and selected areas of the brain, such amygdala, hippocampus, caudate nucleus, thalamus and hypothalamus. Weak expression is also find in substantia nigra.
Olfactory receptor specific for trimethylamine, a trace amine. Also activated at lower level by dimethylethylamine. Trimethylamine is a bacterial metabolite found in some animal odors, and to humans it is a repulsive odor associated with bad breath and spoiled food. This receptor is probably mediated by the G(s)-class of G-proteins which activate adenylate cyclase.
Polymorphic variants of this gene are not associated with specific anosmia for trimethylamine.
Component of the PHF2-ARID5B complex, at least composed of PHF2 and ARID5B (PubMed:21532585). Interacts with HNF4A and NR1H4 (PubMed:21532585). Interacts with RELA (By similarity).
Enzymatically inactive by itself, and become active following phosphorylation by PKA.
In contrast to the related histone demethylases JHDM1D and PHF8, the conserved active His in position 321 is replaced by a Tyr. However, the presence of a Tyr residue neither affects binding to the catalytic iron nor abolishes demethylase activity (PubMed:21167174).
Lysine demethylase that demethylates both histones and non-histone proteins (PubMed:20129925, PubMed:21167174, PubMed:21532585). Enzymatically inactive by itself, and becomes active following phosphorylation by PKA: forms a complex with ARID5B and mediates demethylation of methylated ARID5B (PubMed:21532585). Demethylation of ARID5B leads to target the PHF2-ARID5B complex to target promoters, where PHF2 mediates demethylation of dimethylated 'Lys-9' of histone H3 (H3K9me2), followed by transcription activation of target genes (PubMed:21532585). The PHF2-ARID5B complex acts as a coactivator of HNF4A in liver. PHF2 is recruited to trimethylated 'Lys-4' of histone H3 (H3K4me3) at rDNA promoters and promotes expression of rDNA (PubMed:21532585). Involved in the activation of toll-like receptor 4 (TLR4)-target inflammatory genes in macrophages by catalyzing the demethylation of trimethylated histone H4 lysine 20 (H4K20me3) at the gene promoters (By similarity).
Phosphorylated by PKA on specific serine residues, leading to the formation of an active lysine demethylase complex.
The PHD-type zinc finger mediates the binding to H3K4me2 and H3K4me3.
Widely expressed, including in liver (at protein level).
Identified in a complex containing STX6, STX12, VAMP4 and VTI1A (By similarity). Interacts with BAIAP3; this interaction is increased in the presence of calcium (PubMed:28626000).
Involved in the pathway that functions to remove an inhibitor (probably synaptotagmin-4) of calcium-triggered exocytosis during the maturation of secretory granules. May be a marker for this sorting pathway that is critical for remodeling the secretory response of granule.
(Microbial infection) Acts as a receptor for hepatitis B virus.
(Microbial infection) Interacts with hepatitis B virus large envelope protein.
As a major transporter of conjugated bile salts from plasma into the hepatocyte, it plays a key role in the enterohepatic circulation of bile salts necessary for the solubilization and absorption of dietary fat and fat-soluble vitamins (PubMed:8132774, PubMed:14660639, PubMed:24867799, PubMed:34060352). It is strictly dependent on the extracellular presence of sodium (PubMed:8132774, PubMed:14660639, PubMed:24867799, PubMed:34060352). It exhibits broad substrate specificity and transports various bile acids, such as taurocholate, cholate, as well as non-bile acid organic compounds, such as estrone sulfate (PubMed:14660639, PubMed:34060352). Works collaboratively with the ileal transporter (NTCP2), the organic solute transporter (OST), and the bile salt export pump (BSEP), to ensure efficacious biological recycling of bile acids during enterohepatic circulation (PubMed:33222321).
Expressed in liver (PubMed:11031103, PubMed:12409283). Expressed in placental trophoblasts (PubMed:12409283).
Belongs to the NAD(P)-dependent epimerase/dehydratase family.
Catalyzes two distinct but analogous reactions: the reversible epimerization of UDP-glucose to UDP-galactose and the reversible epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. The reaction with UDP-Gal plays a critical role in the Leloir pathway of galactose catabolism in which galactose is converted to the glycolytic intermediate glucose 6-phosphate. It contributes to the catabolism of dietary galactose and enables the endogenous biosynthesis of both UDP-Gal and UDP-GalNAc when exogenous sources are limited. Both UDP-sugar interconversions are important in the synthesis of glycoproteins and glycolipids.
Contrary to the human enzyme, the E.coli ortholog (AC P09147) does not catalyze the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. Compared to the E.coli enzyme, the sugar-binding pocket of the active site is 15% larger for the human enzyme, making it possible to accommodate the acetyl group.
Heparin-binding protein which binds to FGF2, prevents binding of FGF2 to heparin and probably inhibits immobilization of FGF2 on extracellular matrix glycosaminoglycans, allowing its release and subsequent activation of FGFR signaling which leads to increased vascular permeability.
Based on a naturally occurring readthrough transcript which produces an IQCJ-SCHIP1 fusion protein.
Highly expressed in brain and to a lower extent in heart and kidney.
Homooligomer (via coiled coil domain). Interacts (via IQ domain) with calmodulin; the interaction is direct and lost in presence of calcium (By similarity). Interacts with ANK3 (via ANK repeats); required for localization at axon initial segments (AIS) and nodes of Ranvier (PubMed:25950943). Interacts with SPTBN4. Interacts with KCNQ2 and KCNQ3 (By similarity).
Isoform IQCJ-SCHIP1-1 and isoform IQCJ-SCHIP1-2 are expressed in fetal brain, kidney, spleen and skeletal muscle. Isoform IQCJ-SCHIP1-2 is also detected in fetal heart and lung.
May play a role in action potential conduction in myelinated cells through the organization of molecular complexes at nodes of Ranvier and axon initial segments (PubMed:25950943). May also play a role in axon outgrowth and guidance (By similarity).
Detected predominantly in the skin, with strongest expression in the inner root sheath of the hair follicle.
Has a role in LIPH-mediated synthesis of 2-acyl lysophosphatidic acid (LPA). LPA is a bioactive lipid mediator involved in different biological processes, and necessary to promote hair formation and growth.
Up-regulated following treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) in the pancreatic cancer cell line HPAF-II. The up-regulation by TPA is triggered at the promoter level.
Belongs to the uroporphyrinogen decarboxylase family.
Catalyzes the sequential decarboxylation of the four acetate side chains of uroporphyrinogen to form coproporphyrinogen and participates in the fifth step in the heme biosynthetic pathway (PubMed:14633982, PubMed:11069625, PubMed:21668429, PubMed:11719352, PubMed:18004775). Isomer I or isomer III of uroporphyrinogen may serve as substrate, but only coproporphyrinogen III can ultimately be converted to heme (PubMed:14633982, PubMed:11069625, PubMed:21668429, PubMed:11719352). In vitro also decarboxylates pentacarboxylate porphyrinogen I (PubMed:12071824).
Expressed predominantly in adipose tissue.
Multimers (predominantly trimers). Interacts with ADIPOQ via the C1q domain to form a heterotrimeric complex (By similarity). Interacts with CTRP9B. Forms heterotrimers and heterooligomeric complexes with CTRP9B.
Probable adipokine. Activates AMPK, AKT, and p44/42 MAPK signaling pathways.
Defects in SIX1 could be a cause of branchiootorenal syndrome (BOR). BOR is an autosomal dominant disorder manifested by various combinations of preauricular pits, branchial fistulae or cysts, lacrimal duct stenosis, hearing loss, structural defects of the outer, middle, or inner ear, and renal dysplasia. Associated defects include asthenic habitus, long narrow facies, constricted palate, deep overbite, and myopia. Hearing loss may be due to mondini type cochlear defect and stapes fixation. Penetrance of BOR syndrome is high, although expressivity can be extremely variable.
Interacts with DACH1 (By similarity). Interacts with EYA1 (By similarity). Interacts with EYA2 (PubMed:23435380, PubMed:19497856). Interacts with CDH1 (PubMed:17130831). Interacts with TBX18 (PubMed:26235987). Interacts with CEBPA (PubMed:27923061). Interacts with CEBPB (PubMed:27923061). Interacts with EBF2 (PubMed:27923061).
Phosphorylated during interphase; becomes hyperphosphorylated during mitosis. Hyperphosphorylation impairs binding to promoter elements.
Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development (By similarity). Plays an important role in the development of several organs, including kidney, muscle and inner ear (By similarity). Depending on context, functions as transcriptional repressor or activator (By similarity). Lacks an activation domain, and requires interaction with EYA family members for transcription activation (PubMed:15141091). Mediates nuclear translocation of EYA1 and EYA2 (PubMed:19497856). Binds the 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the MYOG promoter and CIDEA enhancer (PubMed:27923061, PubMed:23435380, PubMed:15141091, PubMed:19497856). Regulates the expression of numerous genes, including MYC, CCND1 and EZR (By similarity). Acts as activator of the IGFBP5 promoter, probably coactivated by EYA2 (By similarity). Repression of precursor cell proliferation in myoblasts is switched to activation through recruitment of EYA3 to the SIX1-DACH1 complex (By similarity). During myogenesis, seems to act together with EYA2 and DACH2 (By similarity). Regulates the expression of CCNA1 (PubMed:15123840). Promotes brown adipocyte differentiation (By similarity).
Ubiquitinated by the anaphase promoting complex (APC), leading to its proteasomal degradation.
Ubiquitously expressed, but the highest levels are found in epididymis, testis and trachea.
(Microbial infection) Binds to the enhancer of the adenovirus E1A gene and acts as a transcriptional activator; the core-binding sequence is 5'-[AC]GGA[AT]GT-3'.
Sumoylated; enhanced upon ERK/MAP kinase pathway activation, it positively regulates the transcriptional activator capacity. Sumoylation at Lys-96 probably requires phosphorylation at Ser-101. Transiently polysumoylated and desumoylated by SENP1. Sumoylation is a prerequisite to polyubiquitination which in turn increases proteasomal-mediated degradation. Probably polyubiquitinated by RNF4 and deubiquitinated by USP2.
Transcriptional activator (PubMed:19307308, PubMed:31552090). May play a role in keratinocyte differentiation (PubMed:31552090).
Expressed strongly in testis, less in spleen, thymus, prostate, colon and leukocytes.
(Microbial infection) Interacts with parasite T.gondii RH strain MAF1b1; the interaction is probably indirect and results in the disruption of the MIB complex and the formation of SPOTs (structures positive for outer mitochondrial membrane (OMM)), a cellular response to OMM stress, which leads to the constitutive shedding of OMM vesicles.
Associates with the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOOL/MIC27, IMMT/MIC60, APOO/MIC23/MIC26 and QIL1/MIC13 (PubMed:25781180, PubMed:25997101). This complex was also known under the names MINOS or MitOS complex. The MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1 and MTX2 (together described as components of the mitochondrial outer membrane sorting assembly machinery (SAM) complex) and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9 (PubMed:25781180, PubMed:25997101). The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both membranes termed the mitochondrial intermembrane space bridging (MIB) complex (PubMed:25997101). Interacts with CHCHD3/MIC19 (PubMed:21081504). Interacts with ARMC1 (PubMed:31644573).
Its C-terminal part seems to contain many membrane-spanning sided beta-sheets, that have the potential to adopt a transmembrane beta-barrel type structure.
Plays a crucial role in the maintenance of the structure of mitochondrial cristae and the proper assembly of the mitochondrial respiratory chain complexes (PubMed:22252321, PubMed:25781180). Required for the assembly of TOMM40 into the TOM complex (PubMed:15644312).
A PTB-like motif (DNXYH sequence) is required for the targeting to the leading edge. This motif represents a minimal protein-protein interaction core motif that is not regulated by tyrosine phosphorylation (By similarity).
Expressed in many epithelial and some endothelial and smooth muscle cells.
Interacts (via the C-terminus 4300-4400 AA) with ATN1 (PubMed:19131340). Interacts with RERE (PubMed:19131340).
Plays an essential role for cellular polarization, directed cell migration and modulating cell-cell contact.
Undergoes proteolytic cleavage. The extracellular domain is cleaved off and the cytoplasmic domain (about 400 AA) shuttles to the nucleus.
Belongs to the sal C2H2-type zinc-finger protein family.
Expressed in testis. Constitutively expressed in acute myeloid leukemia (AML).
Interacts with POU5F1/OCT4 (PubMed:23012367). Interacts with NANOG (By similarity). Interacts with BEND3 (PubMed:21914818). Interacts with NSD2 (via PHD-type zinc fingers 1, 2 and 3) (By similarity). Interacts with NRBP1 (PubMed:22510880).
Isoform SALL4B exists primarily as a ubiquitinated form.
Sumoylation with both SUMO1 and SUMO2 regulates the stability, subcellular localization, transcriptional activity, and may reduce interaction with POU5F1/OCT4.
Transcription factor with a key role in the maintenance and self-renewal of embryonic and hematopoietic stem cells.
Homodimer. Forms a heterodimer with the C-terminal cleavage product (45 kDa form). Forms a heterodimer with the N-terminal cleavage product (15 kDa form). Interacts with PEX5. Interacts with LONP2.
Peroxisomal protease that mediates both the removal of the leader peptide from proteins containing a PTS2 target sequence and processes several PTS1-containing proteins. Catalyzes the processing of PTS1-proteins involved in the peroxisomal beta-oxidation of fatty acids.
Self-cleavage gives rise to an N-terminal 15-kDa fragment and C-terminal 45-kDa fragment upon import into the peroxisomes. The full-lengh TYSND1 is the active the proteolytic processing of PTS1- and PTS2-proteins and in self-cleavage, and intermolecular self-cleavage of TYSND1 down-regulates its protease activity.
Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. Interacts with beta-1 and beta-2, but not with beta-3.
Component of the SET1 complex, at least composed of the catalytic subunit (SETD1A or SETD1B), WDR5, WDR82, RBBP5, ASH2L/ASH2, CXXC1/CFP1, HCFC1 and DPY30 (PubMed:16253997, PubMed:17355966, PubMed:17998332, PubMed:18838538). Core component of several methyltransferase-containing complexes including MLL1/MLL, MLL2/3 (also named ASCOM complex) and MLL4/WBP7 (PubMed:15199122, PubMed:15960975, PubMed:17500065). Each complex is at least composed of ASH2L, RBBP5, WDR5, DPY30, one or more specific histone methyltransferases (KMT2A/MLL1, KMT2D/MLL2, KMT2C/MLL3 and KMT2B/MLL4), and the facultative components PAGR1, BAP18, CHD8, E2F6, HCFC1, HCFC2, HSP70, INO80C, KDM6A, KANSL1, LAS1L, MAX, MCRS1, MEN1, MGA, MYST1/MOF, NCOA6, PAXIP1/PTIP, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9, TEX10 and alpha- and beta-tubulin (PubMed:14992727, PubMed:15199122, PubMed:15960975, PubMed:17500065). Component of a histone methylation complex composed of at least ZNF335, RBBP5, ASH2L and WDR5; the complex may have histone H3-specific methyltransferase activity, however does not have specificity for 'Lys-4' of histone H3 (PubMed:19131338). Interacts with ZNF335 (PubMed:19131338, PubMed:23178126). Interacts with ASH2L; the interaction is direct (PubMed:19131338, PubMed:19556245, PubMed:21220120). Interacts with WDR5; the interaction is direct (PubMed:19556245, PubMed:21220120). Components of the ZNF335-RBBP5-ASH2L-WDR5 histone methylation complex may associate with components of a nuclear receptor-mediated transcription complex to form a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY, MKI67, RBBP5, ASH2L and WDR5 (PubMed:19131338). Within this complex interacts with EMSY (PubMed:19131338). Found in a complex with RBBP5, ASH2L, DPY30, KMT2A, KMT2D and WDR5 (By similarity). Interacts with SETD1A (PubMed:17998332). Interacts with WDR82 (PubMed:18838538).
In embryonic stem (ES) cells, plays a crucial role in the differentiation potential, particularly along the neural lineage, regulating gene induction and H3 'Lys-4' methylation at key developmental loci, including that mediated by retinoic acid (By similarity). Does not affect ES cell self-renewal (By similarity). Component or associated component of some histone methyltransferase complexes which regulates transcription through recruitment of those complexes to gene promoters (PubMed:19131338). As part of the MLL1/MLL complex, involved in mono-, di- and trimethylation at 'Lys-4' of histone H3 (PubMed:19556245). Histone H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation (PubMed:19556245). In association with ASH2L and WDR5, stimulates the histone methyltransferase activities of KMT2A, KMT2B, KMT2C, KMT2D, SETD1A and SETD1B (PubMed:22266653, PubMed:21220120).
E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins (PubMed:12874243, PubMed:17675297). Involved in the TLR and IL-1 signaling pathways via interaction with the complex containing IRAK kinases and TRAF6 (PubMed:12874243). Mediates 'Lys-63'-linked polyubiquitination of IRAK1 (PubMed:12874243). Can activate AP1/JUN and ELK1 (PubMed:12874243). Acts as a regulator of innate immunity by mediating 'Lys-63'-linked polyubiquitination of RIPK2 downstream of NOD1 and NOD2, thereby transforming RIPK2 into a scaffolding protein for downstream effectors, ultimately leading to activation of the NF-kappa-B and MAP kinases signaling (By similarity). Catalyzes 'Lys-63'-linked polyubiquitination of RIPK2 in parallel of XIAP (By similarity).
Highly expressed in brain, heart and testis, and at lower level in kidney, liver, lung, placenta, small intestine, spleen and stomach. Isoform 1 is not expressed in lung.
Interacts with TRAF6, MAP3K14 and MAP3K7.
Phosphorylated by IRAK1 enhancing its E3 ligase activity.
Interacts with CLUAP1; the interaction is direct and mediates interaction with the intraflagellar transport complex B (IFT-B) (PubMed:26389662). Interacts with VCP; the interaction is direct (PubMed:26389662).
VCP/p97-binding protein required for ciliogenesis (PubMed:26389662). Acts as a tethering factor that facilitates recruitment of VCP/p97 to the intraflagellar transport complex B (IFT-B) in cilia (PubMed:26389662). UBX domain-containing proteins act as tethering factors for VCP/p97 and may specify substrate specificity of VCP/p97 (PubMed:26389662).
One of the multiple factors required for polyadenylation and 3'-end cleavage of mammalian pre-mRNAs. This subunit is directly involved in the binding to pre-mRNAs (By similarity).
The CSTF complex is composed of CSTF1 (50 kDa subunit), CSTF2 (64 kDa subunit) and CSTF3 (77 kDa subunit). CSTF2 directly interacts with CSTF3, SYMPK and RPO2TC1. Interacts with HSF1 in heat-stressed cells. Interacts with CPSF2, CPSF3 and FIP1L1. Interacts with DDX1.
Up-regulated during the G0 to S phase transition.
Expressed in normal mammary epithelial cells. Expression is reduced or absent in breast carcinomas.
Phosphorylated. Phosphorylation status depends on the cell cycle and is a signal for ubiquitination and proteasome-mediated degradation.
Probable DNA-binding transcriptional activator. Key determinant of the keratinocyte proliferation-differentiation switch involved in appropriate epidermal development (By similarity). Plays a role in regulating mammary epithelial cell proliferation (By similarity). May regulate WDR65 transcription (By similarity).
Binds DNA as a heterodimer with MAX and represses transcription. Binds to the canonical E box sequence 5'-CACGTG-3' and, with higher affinity, to 5'-CACGCG-3'.
Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a homodimer or a heterodimer with MAX.
Unknown. Cellular response protein to viral infection.
Up-regulated in response to viral infection. Induced by the E1A adenoviral protein.
Widely expressed. Highly expressed in colon, prostate, trachea and stomach. Expressed at lower level in testis, muscle, lymphoid tissues, white blood cells and spleen. Predominantly expressed by cells of the epithelial lineage. Expressed at low level in normal liver. Expression significantly increases in virus (HBV, HCV) infected liver. Expression does not increase in liver disease due to non-viral causes (alcohol-induced liver disease, autoimmune hepatitis). Increased expression in hepatocytes appears to be a general feature of advanced liver disease. In liver tissue from patients with adult giant-cell hepatitis (GCH), it is strongly expressed in hepatocytes-derived syncytial giant cells. Constitutively expressed by biliary epithelial cells but not by hepatocytes.
'Lys-48'-linked polyubiquitinated; leading to proteasomal degradation (PubMed:35675826). Deubiquitinated and stabilized by OTUD3 (PubMed:35675826).
Heterodimer with the retinoid X receptor. Interacts (via domain NR LBD) with CRY1 and CRY2 in a ligand-dependent manner (By similarity).
Ligand-activated transcription factor key mediator of energy metabolism in adipose tissues (PubMed:35675826). Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand.
Ubiquitous with maximal levels in placenta and skeletal muscle.
Although related to the Ser/Thr protein kinase family, has no protein kinase activity and acts as a mannose kinase instead.
Highest expression is observed in brain, skeletal muscle, kidney and heart in fetal and adult tissues.
Protein O-mannose kinase that specifically mediates phosphorylation at the 6-position of an O-mannose of the trisaccharide (N-acetylgalactosamine (GalNAc)-beta-1,3-N-acetylglucosamine (GlcNAc)-beta-1,4-mannose) to generate phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-1,3-N-acetylglucosamine-beta-1,4-(phosphate-6-)mannose). Phosphorylated O-mannosyl trisaccharide is a carbohydrate structure present in alpha-dystroglycan (DAG1), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity. Only shows kinase activity when the GalNAc-beta-3-GlcNAc-beta-terminus is linked to the 4-position of O-mannose, suggesting that this disaccharide serves as the substrate recognition motif.
Activated by the AGRIN-induced phosphorylation which is mediated by MUSK.
Belongs to the protein prenyltransferase subunit alpha family.
Essential subunit of both the farnesyltransferase and the geranylgeranyltransferase complex. Contributes to the transfer of a farnesyl or geranylgeranyl moiety from farnesyl or geranylgeranyl diphosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. May positively regulate neuromuscular junction development downstream of MUSK via its function in RAC1 prenylation and activation.
Heterodimer of FNTA and FNTB (farnesyltransferase) (PubMed:8419339, PubMed:11687658, PubMed:12036349, PubMed:12825937, PubMed:15170324, PubMed:15451670, PubMed:16893176, PubMed:19246009). Heterodimer of FNTA and PGGT1B (geranylgeranyltransferase) (By similarity).
Phosphorylated. Phosphorylation is mediated by MUSK upon AGRIN stimulation and results in the activation of FNTA (By similarity).
Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:12705869, PubMed:28977666). Plays a role in maintenance of the normal epithelial architecture through the repression of SNAI1 transcription in a histone deacetylase-dependent manner, and thus the regulation of E-cadherin levels (PubMed:12705869). Contributes to transcriptional repression by BCL6 (PubMed:15454082).
Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5 (PubMed:33283408, PubMed:12705869, PubMed:15454082, PubMed:28977666, PubMed:16428440). The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes (PubMed:28977666, PubMed:16428440). Interacts with BCL6 (PubMed:15454082). Interacts with NACC2 (PubMed:22926524). Interacts with PWWP2B (By similarity).
Expressed in germinal centers of lymphoid tissues. No expression in nonepithelial cells.
(Microbial infection) Interacts with vaccinia protein B12; this interaction inhibits the repressive activity of the vaccinia virus B12 pseudokinase on viral replication factory formation.
Active in presence of Mn(2+), Mg(2+) and Zn(2+), but is not functional with Ca(2+) or Cu(2+) (PubMed:11883897). Has a higher affinity for Mn(2+) than for Mg(2+) (PubMed:11883897). RAN inhibits its autophosphorylation and its ability to phosphorylate histone H3 (PubMed:18617507).
Autophosphorylated at various serine and threonine residues (PubMed:11883897, PubMed:14645249, PubMed:19103756, PubMed:21543316). Autophosphorylation does not impair its ability to phosphorylate p53/TP53 (PubMed:11883897). Phosphorylation by PLK3 leads to induction of Golgi fragmentation during mitosis (PubMed:19103756).
Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. VRK subfamily.
Serine/threonine kinase involved in cell cycle, nuclear condensation and transcription regulation (PubMed:14645249, PubMed:18617507, PubMed:19103756). Involved in Golgi disassembly during the cell cycle: following phosphorylation by PLK3 during mitosis, required to induce Golgi fragmentation (PubMed:19103756). Phosphorylates 'Thr-18' of p53/TP53 and may thereby prevent the interaction between p53/TP53 and MDM2 (PubMed:10951572). Phosphorylates KAT5 in response to DNA damage, promoting KAT5 association with chromatin and histone acetyltransferase activity (PubMed:33076429). Phosphorylates BANF1: disrupts its ability to bind DNA, reduces its binding to LEM domain-containing proteins and causes its relocalization from the nucleus to the cytoplasm (PubMed:16495336). Phosphorylates ATF2 which activates its transcriptional activity (PubMed:15105425).
Widely expressed. Highly expressed in fetal liver, testis and thymus.
Forms part of the preprotein translocase complex of the outer mitochondrial membrane (TOM complex) which consists of at least 7 different proteins (TOMM5, TOMM6, TOMM7, TOMM20, TOMM22, TOMM40 and TOMM70).
Required for assembly and stability of the TOM complex. Positive regulator of PRKN translocation to damaged mitochondria. Acts probably by stabilizing PINK1 on the outer membrane of depolarized mitochondria.
Probably involved in nervous system development and function.
The disease is caused by variants affecting the gene represented in this entry. SCA27B is caused by GAA(n) trinucleotide repeat expansions with a size above 250 repeats in FGF14 intron 1. Expansions ranging from 250 to 300 repeats are pathogenic albeit with reduced penetrance, whereas those above 300 are fully penetrant.
Expressed predominantly in testis, also found in placenta and to a lesser extent in thymus and small intestine; abundantly expressed in tumor-derived cell lines (PubMed:16006562). Ubiquitously expressed (PubMed:12819961).
May be involved in drug clearance in the placenta.
May be involved in the development and/or progression of nosopharyngeal carcinoma.
The polymorphism 'Glu58Gly' (described in PubMed:12819961) is in fact an error, the G to A change described representing a synonymous mutation that does not induce any amino acid change in Gly-32.
Anti-proliferative protein; the function is mediated by association with deadenylase subunits of the CCR4-NOT complex. Activates mRNA deadenylation in a CNOT6 and CNOT7-dependent manner. In vitro can inhibit deadenylase activity of CNOT7 and CNOT8. Involved in cell cycle regulation. Could be involved in the growth arrest and differentiation of the neuronal precursors (By similarity). Modulates transcription regulation mediated by ESR1. Involved in mitochondrial depolarization and neurite outgrowth.
Interacts with PRKCABP (By similarity). Interacts with CNOT7 and CNOT8; indicative for an association with the CCR4-NOT complex. Interacts with PIN1, inducing mitochondrial depolarization.
Phosphorylated at Ser-147 by MAPK1/ERK2 and MAPK3/ERK1, and at Ser-149 by MAPK14, leading to PIN1-binding and mitochondrial depolarization.
Interacts with EIF4B, IMP8, PRMT5 and TNRC6B. Interacts with APOBEC3F, APOBEC3G and APOBEC3H. Interacts with EDC4.
Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) and represses the translation of mRNAs which are complementary to them. Proposed to be involved in stabilization of small RNA derivates (siRNA) derived from processed RNA polymerase III-transcribed Alu repeats containing a DR2 retinoic acid response element (RARE) in stem cells and in the subsequent siRNA-dependent degradation of a subset of RNA polymerase II-transcribed coding mRNAs by recruiting a mRNA decapping complex involving EDC4. Possesses RNA slicer activity but only on select RNAs bearing 5'- and 3'-flanking sequences to the region of guide-target complementarity (PubMed:29040713).
Ubiquitinated on surface-exposed lysines by a SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 during target-directed microRNA degradation (TDMD), a process that mediates degradation of microRNAs (miRNAs). Ubiquitination by the SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 leads to its subsequent degradation, thereby exposing miRNAs for degradation. ZSWIM8 recognizes and binds AGO3 when it is engaged with a TDMD target.
Binds to mammalian-wide interspersed repeat (MIRs) sequences in euchromatin and promoter regions of genes at the consensus sequence 5'-GCTGTGTG-[N20]-CCTCTCTG-3', consisting of two anchor regions connected by a linker region; the linker region probably does not contribute to the binding specificity (PubMed:30476274). Required for cell homeostasis (PubMed:34404770). May be involved in transcriptional regulation (Probable).
Interacts (via zinc-finger domains) with TP53 (via N-terminus); interaction might be facilitated by TP53 oligomerization state (PubMed:34404770). Interacts with ELP3 (PubMed:30476274).
May be phosphorylated at residue 'Ser-5' of the tandem heptapeptide repeats in the N-terminus (PubMed:30476274). Phosphorylation might be increased upon RAS pathway activation and negatively regulate protein stability (PubMed:34404770).
Homooligomer (PubMed:23022098, PubMed:25604853).
Required for mitochondrial translation, possibly by coordinating the assembly or maintenance of the mitochondrial ribosome (PubMed:23022098, PubMed:25604853).
Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. TrmE GTPase family.
GTPase involved in the 5-carboxymethylaminomethyl modification (mnm(5)s(2)U34) of the wobble uridine base in mitochondrial tRNAs.
Val-250 variation may influence aminoglycoside-induced deafness (AID) [MIM:580000]. AID is characterized by deafness, varying from profond congenital hearing loss to normal hearing, and is caused by homoplasmic A1555G mutation in the mitochondrial 12S rRNA. Val-250 may affect the accuracy of codon-anticodon interaction, leading to modulate the translational efficiency and thereby affecting the severity of deafness in patients homozygous for 12S rRNA A1555G mutation.
Inhibits phosphatase activities of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) complexes.
Substrate for cGMP-dependent protein kinase.
Substrate for cGMP-dependent protein kinase. Phosphorylated by PRKG1 isoform alpha. Phosphorylation of Thr-68 and Thr-119 is required for its phosphatase activity (By similarity).
Transcriptional repressor of Notch-mediated signaling. Required for spermatogenesis.
A 4-nucleotides insertion of unknown origin disrupts the reading frame.
GAP activity stimulated by phosphatidylinositol 3,4,5-trisphosphate (PIP3) and, to a lesser extent, by phosphatidylinositol 4,5-bisphosphate (PIP2). Phosphatidic acid potentiates PIP2 stimulation.
GTPase-activating protein for ARF1 and, to a lesser extent, ARF5. Directly and specifically regulates the adapter protein 3 (AP-3)-dependent trafficking of proteins in the endosomal-lysosomal system.
Homodimer. Interacts with several subunits of the AP-3 protein complex: AP3M1, AP3S1 and AP3S2. Interacts with GUCY1A3 and GUCY1B3.
A chromosomal aberration involving SUZ12 may be a cause of endometrial stromal tumors. Translocation t(7;17)(p15;q21) with JAZF1. The translocation generates the JAZF1-SUZ12 oncogene consisting of the N-terminus part of JAZF1 and the C-terminus part of SUZ12. It is frequently found in all cases of endometrial stromal tumors, except in endometrial stromal sarcomas, where it is rarer.
Belongs to the VEFS (VRN2-EMF2-FIS2-SU(Z)12) family.
Component of the PRC2 complex, which consists of the core subunits EED, EZH1 or EZH2, SUZ12, and RBBP4, and various combinations of accessory subunits including AEBP2, JARID2, PHF19, MTF2 and EPOP (PubMed:12435631, PubMed:12351676, PubMed:15385962, PubMed:15099518, PubMed:15225548, PubMed:15684044, PubMed:16224021, PubMed:19026781, PubMed:18285464, PubMed:29499137, PubMed:31959557). Within the complex, interacts (via C2H2 zinc finger domain) with JARID2 and EPOP; JARID2 and EPOP compete for SUZ12 binding (PubMed:29499137). Also interacts with AEBP2 and PHF19 (PubMed:29499137). Forms a monomeric PRC2.2 (class 2) complex consisting of at least SUZ12, RBBP4, AEBP2 and JARID2 (PubMed:29499137). Forms a dimeric PRC2.1 (class 1, PRC-PCL) complex consisting of at least SUZ12, RBBP4, and PHF19 or MTF2; PHF19 and MTF2 stabilize the dimeric structure which enhances PRC2 interaction with chromatin (PubMed:31959557). The minimum components required for methyltransferase activity of the PRC2/EZH2 complex are EED, EZH2 and SUZ12 (PubMed:12435631, PubMed:12351676, PubMed:15385962, PubMed:15099518, PubMed:15225548, PubMed:15684044, PubMed:16431907, PubMed:18086877, PubMed:18285464). The PRC2 complex may also interact with DNMT1, DNMT3A, DNMT3B and PHF1 via the EZH2 subunit and with SIRT1 via the SUZ12 subunit (PubMed:15684044, PubMed:18285464). Interacts with WDR77 (PubMed:16712789). Interacts with histone H1 (PubMed:16431907). Interacts with CDYL (PubMed:22009739). Interacts with BMAL1 (By similarity). Interacts with EZHIP (via C-terminal region) (PubMed:30923826). Interacts with ARMC12 (PubMed:30026490).
Expressed at low levels in quiescent cells. Expression rises at the G1/S phase transition.
Overexpressed in breast and colon cancer.
Polycomb group (PcG) protein. Component of the PRC2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene (PubMed:15225548, PubMed:15231737, PubMed:15385962, PubMed:16618801, PubMed:17344414, PubMed:18285464, PubMed:28229514, PubMed:29499137, PubMed:31959557). The PRC2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems (PubMed:12435631, PubMed:12351676, PubMed:15385962, PubMed:15099518, PubMed:15225548, PubMed:15684044, PubMed:16431907, PubMed:18086877, PubMed:18285464). Genes repressed by the PRC2 complex include HOXC8, HOXA9, MYT1 and CDKN2A (PubMed:15231737, PubMed:16618801, PubMed:17200670, PubMed:31959557).
Active as an ATPase due to the absence of exon 13.
Belongs to the SNF2/RAD54 helicase family. ISWI subfamily.
Catalytically inactive when either DNA or nucleosomes are the substrate and does not possess chromatin-remodeling activity (PubMed:15310751, PubMed:28801535). Acts as a negative regulator of chromatin remodelers by generating inactive complexes (PubMed:15310751).
Expressed in lung, breast, kidney, ovary, skeletal muscle and brain.
Helicase that possesses intrinsic ATP-dependent chromatin-remodeling activity (PubMed:15310751, PubMed:14609955, PubMed:15640247, PubMed:28801535). ATPase activity is substrate-dependent, and is increased when nucleosomes are the substrate, but is also catalytically active when DNA alone is the substrate (PubMed:15310751, PubMed:14609955, PubMed:15640247). Catalytic subunit of ISWI chromatin-remodeling complexes, which form ordered nucleosome arrays on chromatin and facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair (PubMed:15310751, PubMed:14609955, PubMed:15640247, PubMed:28801535). Within the ISWI chromatin-remodeling complexes, slides edge- and center-positioned histone octamers away from their original location on the DNA template (PubMed:28801535). Catalytic activity and histone octamer sliding propensity is regulated and determined by components of the ISWI chromatin-remodeling complexes (PubMed:28801535). The BAZ1A-, BAZ1B-, BAZ2A- and BAZ2B-containing ISWI chromatin-remodeling complexes regulate the spacing of nucleosomes along the chromatin and have the ability to slide mononucleosomes to the center of a DNA template (PubMed:28801535). The CECR2- and RSF1-containing ISWI chromatin-remodeling complexes do not have the ability to slide mononucleosomes to the center of a DNA template (PubMed:28801535). Within the NURF-1 and CERF-1 ISWI chromatin remodeling complexes, nucleosomes are the preferred substrate for its ATPase activity (PubMed:14609955, PubMed:15640247). Within the NURF-1 ISWI chromatin-remodeling complex, binds to the promoters of En1 and En2 to positively regulate their expression and promote brain development (PubMed:14609955). May promote neurite outgrowth (PubMed:14609955). May be involved in the development of luteal cells (PubMed:16740656).
Inactive as an ATPase due to the presence of exon 13, but retains its ability to correctly fold and incorporate into complexes.
Mainly expressed in non-neuronal tissues such as lung, breast, kidney, and ovary.
May form homodimers (PubMed:15310751). Component of the ACF-1 ISWI chromatin remodeling complex at least composed of SMARCA1 and BAZ1A, which regulates the spacing of histone octamers on the DNA template to facilitate access to DNA (PubMed:28801535). Within the complex interacts with BAZ1A; the interaction is direct (PubMed:28801535). Component of the WICH-1 ISWI chromatin remodeling complex at least composed of SMARCA1 and BAZ1B/WSTF (PubMed:28801535). Within the complex interacts with BAZ1B/WSTF (PubMed:28801535). Component of the NoRC-1 ISWI chromatin remodeling complex at least composed of SMARCA1 and BAZ2A/TIP5 (PubMed:28801535). Within the complex interacts with BAZ2A/TIP5 (PubMed:28801535). Component of the BRF-1 ISWI chromatin remodeling complex at least composed of SMARCA1 and BAZ2B (PubMed:28801535). Within the complex interacts with BAZ2B (PubMed:28801535). Component of the NURF-1 ISWI chromatin remodeling complex (also called the nucleosome-remodeling factor (NURF) complex) at least composed of SMARCA1, BPTF, RBBP4 and RBBP7 (PubMed:14609955, PubMed:15640247, PubMed:28801535). Within the complex interacts with BPTF (PubMed:15310751, PubMed:14609955, PubMed:28801535). Within the complex interacts with RBBP4 and RBBP7 (PubMed:15310751, PubMed:14609955). Component of the CERF-1 ISWI chromatin remodeling complex (also called the CECR2-containing-remodeling factor (CERF) complex) at least composed of CECR2 and SMARCA1 (PubMed:15640247, PubMed:28801535). Within the complex interacts with CECR2 (PubMed:28801535). Component of the RSF-1 ISWI chromatin remodeling complex at least composed of SMARCA1 and RSF1 (PubMed:15640247, PubMed:28801535). Within the complex interacts with RSF1 (PubMed:28801535). Interacts with PRLR (PubMed:16740656). Interacts with ERCC6 (PubMed:26030138).
May form homodimers (PubMed:15310751). Component of the BPFT-SMARCA1 complex at least composed of SMARCA1, BPFT, RBBP4 and RBBP7; the complex is catalytically inactive and does not remodel chromatin (PubMed:15310751). Within the complex interacts with BPTF, RBBP4 and RBBP7 (PubMed:15310751). Component of the BAZ1A-1-SMARCA1 complex at least composed of SMARCA1 and BAZ1A; the complex is catalytically inactive and does not remodel chromatin (PubMed:28801535). Component of the BAZ1B-1-SMARCA1 complex at least composed of SMARCA1 and BAZ1B; the complex is catalytically inactive and does not remodel chromatin (PubMed:28801535).
Belongs to the clathrin heavy chain family.
Clathrin is the major protein of the polyhedral coat of coated pits and vesicles. Two different adapter protein complexes link the clathrin lattice either to the plasma membrane or to the trans-Golgi network (By similarity).
Clathrin triskelions, composed of 3 heavy chains and 3 light chains, are the basic subunits of the clathrin coat (By similarity). In the presence of light chains, hub assembly is influenced by both the pH and the concentration of calcium (Probable). May interact with OCRL (By similarity). Interacts with AFTPH/aftiphilin (PubMed:15758025).
Maximal levels in skeletal muscle. High levels in heart and testis. Low expression detected in all other tissues.
The C-terminal third of the heavy chains forms the hub of the triskelion. This region contains the trimerization domain and the light-chain binding domain involved in the assembly of the clathrin lattice.
The N-terminal seven-bladed beta-propeller is formed by WD40-like repeats, and projects inward from the polyhedral outer clathrin coat. It constitutes a major protein-protein interaction node (By similarity).
Broadly expressed, with lowest levels in brain and thymus, and highest levels detectable in heart, ovary and testis.
E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes UBE2L3 and UBE2L6 in the form of a thioester and then directly transfers the ubiquitin to targeted substrates such as LCMT2, thereby promoting their degradation. Induces apoptosis via a p53/TP53-dependent but caspase-independent mechanism. However, its overexpression also produces a decrease of the ubiquitin-dependent stability of BAX, a pro-apoptotic protein, ultimately leading to protection of cell death; But, it is not an anti-apoptotic protein per se.
Interacts with UBE2L3, UBE2L6 and LCMT2, as well as with BAX.
The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme (By similarity). The transmembrane domain is essential for translocation to the mitochondria upon induction of apoptosis.
At the mRNA level, widely expressed (PubMed:18992174). At protein level, restricted to epididymis (PubMed:19137000). Expressed in spermatozoa (sperm head and neck), with higher levels on ejaculated and epididymal sperm than on testicular sperm (at protein level). Expressed in the epithelial cells of the epididymal tubule (at protein level). Not detected in muscle.
Detected in bone marrow, adrenal gland, trachea, lymph node, spinal cord, peripheral blood leukocytes, thyroid and stomach.
GTPase activating protein that acts on ARF6. Plays a role in clathrin-dependent endocytosis. May play a role in erythropoiesis (By similarity).
Interacts with ARF6. Interacts with clathrin heavy chains via the clathrin box-like motif (By similarity).
Homodimerizes, the dimers can polymerize end-to-end to form filamentous structures (By similarity). Interacts with GTP-bound CDC42 (PubMed:15260990). Interacts with DAAM1, DIAPH1, DIAPH2, DNM1, DNM2 and WASL/N-WASP (PubMed:16326391, PubMed:16630611, PubMed:16418535). Interacts with ATG3 (PubMed:19342671). Interacts (via SH3 domain) with ABI1, WASF2, CDC42 and WIPF1 (PubMed:19798448).
Required to coordinate membrane tubulation with reorganization of the actin cytoskeleton during endocytosis. May bind to lipids such as phosphatidylinositol 4,5-bisphosphate and phosphatidylserine and promote membrane invagination and the formation of tubules. Also promotes CDC42-induced actin polymerization by activating the WASL/N-WASP-WASPIP/WIP complex, the predominant form of WASL/N-WASP in cells. Actin polymerization may promote the fission of membrane tubules to form endocytic vesicles. Essential for autophagy of intracellular bacterial pathogens.
The F-BAR domain binds the phospholipid membrane with its concave surface. The end-to-end polymerization of dimers of these domains provides a curved surface that fits best membranes with around 600 A diameter, and may drive tubulation (By similarity).
Adapter protein involved in asymmetrical cell division and cell polarization processes. Probably involved in formation of epithelial tight junctions. Association with PARD3 may prevent the interaction of PARD3 with F11R/JAM1, thereby preventing tight junction assembly. The PARD6-PARD3 complex links GTP-bound Rho small GTPases to atypical protein kinase C proteins.
Expressed in pancreas and in both adult and fetal kidney. Weakly expressed in placenta and lung. Not expressed in other tissues.
Interacts with PARD3. Interacts with GTP-bound forms of CDC42 and RAC1. Interacts with GTP-bound RHOQ/TC10. Interacts with PALS1 (By similarity). Interacts with the N-terminal part of PRKCI and PRKCZ. Part of a complex with PARD3, CDC42 or RAC1 and PRKCI or PRKCZ. Part of a complex with LLGL1 and PRKCI. Interacts with PARD3B. Interacts with ECT2.
The PDZ domain mediates interaction with PALS1.
Forms a ternary complex with BGN and ELN. Interacts with FBN1 (via N-terminal domain) and FBN2.
Forms intermolecular disulfide bonds either with other MAGP-1 molecules or with other components of the microfibrils. May form transglutaminase cross-links.
Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. SET7 subfamily.
Histone methyltransferase that specifically monomethylates 'Lys-4' of histone H3 (PubMed:11779497, PubMed:11850410, PubMed:12588998, PubMed:12540855, PubMed:16141209). H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation (PubMed:12588998, PubMed:12540855, PubMed:16141209). Plays a central role in the transcriptional activation of genes such as collagenase or insulin (PubMed:16141209, PubMed:12588998). Recruited by IPF1/PDX-1 to the insulin promoter, leading to activate transcription (PubMed:16141209). Has also methyltransferase activity toward non-histone proteins such as CGAS, p53/TP53, TAF10, and possibly TAF7 by recognizing and binding the [KR]-[STA]-K in substrate proteins (PubMed:15099517, PubMed:35210392, PubMed:15525938, PubMed:16415881). Monomethylates 'Lys-189' of TAF10, leading to increase the affinity of TAF10 for RNA polymerase II (PubMed:15099517, PubMed:16415881). Monomethylates 'Lys-372' of p53/TP53, stabilizing p53/TP53 and increasing p53/TP53-mediated transcriptional activation (PubMed:17108971, PubMed:15525938, PubMed:16415881). Monomethylates 'Lys-491' of CGAS, promoting interaction between SGF29 and CGAS (By similarity).
The SET domain is necessary but not sufficient for histone methyltransferase activity.
Widely expressed. Expressed in pancreatic islets.
Catalyzes the transfer of endogenously produced octanoic acid from octanoyl-acyl-carrier-protein onto the lipoyl domains of lipoate-dependent enzymes, which catalyze essential redox reactions (PubMed:28757203). Lipoyl-ACP can also act as a substrate although octanoyl-ACP is likely to be the physiological substrate (By similarity).
In the reaction, the free carboxyl group of octanoic acid is attached via an amide linkage to the epsilon-amino group of a specific lysine residue of lipoyl domains of lipoate-dependent enzymes.
Parathymosin may mediate immune function by blocking the effect of prothymosin alpha which confers resistance to certain opportunistic infections.
Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane protein substrates in or close to their luminal transmembrane domain boundaries (PubMed:16873890, PubMed:25354954, PubMed:25827571). Acts like a sheddase by mediating the proteolytic release and secretion of active site-containing ectodomains of glycan-modifiying glycosidase and glycosyltransferase enzymes such as MGAT5, B4GAT1 and B4GALT1 (PubMed:25354954, PubMed:25827571). Catalyzes the intramembrane cleavage of the envelope glycoprotein gp130 and/or the leader peptide gp18LP of the simian foamy virus independent of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis (PubMed:23132852). May also have the ability to serve as a shedding protease for subsequent intramembrane proteolysis by SPPL2A and SPPL2B of the envelope glycoprotein gp130 (PubMed:23132852). Plays a role in the regulation of cellular glycosylation processes (PubMed:25354954). Required to link T-cell antigen receptor (TCR) and calcineurin-NFAT signaling cascades in lymphocytes by promoting the association of STIM1 and ORAI1 during store-operated calcium entry (SOCE) in a protease-independent manner (PubMed:25384971).
Its proteolytic activity is blocked by a signal peptide peptidase (SPP) inhibitor, (ZLL)2-ketone (ZLL) or a gamma-secretase inhibitor, LY411,575 (PubMed:16873890). However, is not inhibited by ZLL and LY411,575 for activity on simian foamy virus envelope glycoprotein gp130 (PubMed:23132852).
Monomer (PubMed:15385547, PubMed:15998642, PubMed:16873890). Homodimer (PubMed:15385547, PubMed:15998642, PubMed:16873890). Interacts with STIM1 (via the transmembrane region and the SOAR/CAD domain); the interaction promotes the binding of STIM1 to ORAI1 (PubMed:25384971). Interacts with the simian foamy virus envelope glycoprotein gp130 and its processed leader peptide gp18LP; preferentially interacts with the envelope glycoprotein gp130 (PubMed:23132852).
Not glycosylated (PubMed:15385547, PubMed:15998642).
The first transmembrane domain may act as a type I signal anchor (PubMed:15385547). The catalytic loops is exposed toward the lumen (PubMed:15385547). The PAL motif is required for normal active site conformation. The catalytic domains embedded in the membrane are in the opposite orientation to that of the presenilin protein family (By similarity).
Widely expressed (PubMed:15385547). Expressed in the brain (PubMed:11978763).
Comprised of a NH2-terminal actin-binding domain, 24 immunoglobulin-like internally homologous repeats and two hinge regions. Repeat 24 and the second hinge domain are important for dimer formation. Filamin repeat 20 interacts with filamin repeat 21 masking the ligand binding site on filamin repeat 21, resulting in an autoinhibited conformation (PubMed:17690686). The autoinhibition can be relieved by ligands like ITGB7 or FBLIM1 (PubMed:21524097). Filamin repeats 19 and 21 can simultaneously engage ligands (PubMed:21524097).
Defects in FLNA may be a cause of macrothrombocytopenia, a disorder characterized by subnormal levels of blood platelets. Blood platelets are abnormally enlarged (PubMed:21960593).
Homodimer. Interacts with PDLIM2 (By similarity). Interacts with RFLNA and RFLNB (By similarity). Interacts with FCGR1A, FLNB, FURIN, HSPB7, INPPL1, KCND2, MYOT, MYOZ1, ARHGAP24, PSEN1, PSEN2 and ECSCR. Interacts also with various other binding partners in addition to filamentous actin. Interacts (via N-terminus) with MIS18BP1 (via N-terminus). Interacts (via N-terminus) with TAF1B. Interacts with TMEM67 (via C-terminus) and MKS1. Interacts (via actin-binding domain) with MICALL2 (via CH domain). Interacts (via filamin repeat 5) with SYK; docks SYK to the plasma membrane (PubMed:20713593). Interacts (via filamin repeats 19 and 21) with DRD3; increased PKA-mediated phosphorylation at Ser-2152. Interacts (via filamin repeat 21) with MAS1, AGTR1 and ADRA1D; increases PKA-mediated phosphorylation of FLNA at Ser-2152 (PubMed:26460884). Interacts (via filamin repeats 4, 9, 12, 17, 19, 21, and 23) with GP1BA (high affinity), ITGB7, ITGB2 and FBLIM1 (PubMed:19828450, PubMed:21524097, PubMed:25666618). Interacts with CEACAM1 (via cytoplasmic domain); inhibits cell migration and cell scattering by interfering with the interaction between FLNA and RALA (PubMed:16291724). Interacts with FOXC1 (PubMed:15684392). Interacts (via calponin-homology (CH) domain 1 and filamin repeat 24) with CRMP1; the interaction alters FLNA ternary structure and thus promotes FLNA dissociation from F-actin (PubMed:25358863). Interacts with DPYSL3/CRMP3 and DPYSL4/CRMP4 (PubMed:25358863).
Phosphorylation at Ser-2152 is negatively regulated by the autoinhibited conformation of filamin repeats 19-21. Ligand binding induces a conformational switch triggering phosphorylation at Ser-2152 by PKA.
Phosphorylation extent changes in response to cell activation.
Polyubiquitination in the CH1 domain by a SCF-like complex containing ASB2 leads to proteasomal degradation. Prior dissociation from actin may be required to expose the target lysines (PubMed:24052262). Ubiquitinated in endothelial cells by RNF213 downstream of the non-canonical Wnt signaling pathway, leading to its degradation by the proteasome (PubMed:26766444).
Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton and serves as a scaffold for a wide range of cytoplasmic signaling proteins. Interaction with FLNB may allow neuroblast migration from the ventricular zone into the cortical plate. Tethers cell surface-localized furin, modulates its rate of internalization and directs its intracellular trafficking (By similarity). Involved in ciliogenesis. Plays a role in cell-cell contacts and adherens junctions during the development of blood vessels, heart and brain organs. Plays a role in platelets morphology through interaction with SYK that regulates ITAM- and ITAM-like-containing receptor signaling, resulting in by platelet cytoskeleton organization maintenance (By similarity). During the axon guidance process, required for growth cone collapse induced by SEMA3A-mediated stimulation of neurons (PubMed:25358863).
Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negatively regulates the kinase activity of PDPK1.
Expressed mainly in the brain and present in other tissues albeit at lower levels.
Homodimer (By similarity). Interacts with many nuclear hormone receptors and cofactors including AR, ESR1, ESR2, MC2R, NR3C1, NRIP1, PPARBP and THRA. Interacts with ABL1 (phosphorylated form); the interaction retains it in the cytoplasm. Interacts with ARHGEF28 and CDK16 (By similarity). Weakly interacts with CDKN1B. Interacts with GAB2. Interacts with KCNK18 in a phosphorylation-dependent manner. Interacts with SAMSN1 (By similarity). Interacts with the 'Ser-241' phosphorylated form of PDPK1. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with SLITRK1 (PubMed:19640509). Interacts with MEFV (PubMed:27030597).
Phosphorylated on Ser-59 by protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion.
Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.
High levels of expression are found in brain (highest in corpus callosum), heart, kidney, liver, lung, small intestine, colon and skeletal muscle. Expression is low in organs composed mainly of smooth muscle, such as aorta, uterus and urinary bladder. No detectable expression is found in thymus, spleen, placenta and lymphocytes.
Myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2).
Component of the SKA1 complex, a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation (PubMed:17093495, PubMed:19289083, PubMed:23085020). Required for timely anaphase onset during mitosis, when chromosomes undergo bipolar attachment on spindle microtubules leading to silencing of the spindle checkpoint (PubMed:17093495). The SKA1 complex is a direct component of the kinetochore-microtubule interface and directly associates with microtubules as oligomeric assemblies (PubMed:19289083). The complex facilitates the processive movement of microspheres along a microtubule in a depolymerization-coupled manner (PubMed:17093495, PubMed:19289083). In the complex, it is required for SKA1 localization (PubMed:19289083). Affinity for microtubules is synergistically enhanced in the presence of the ndc-80 complex and may allow the ndc-80 complex to track depolymerizing microtubules (PubMed:23085020).
Component of the SKA1 complex, composed of SKA1, SKA2 and SKA3. Forms a heterodimer with SKA1; the heterodimer interacting with SKA3. The core SKA1 complex is composed of 2 SKA1-SKA2 heterodimers, each heterodimer interacting with a molecule of the SKA3 homodimer. The core SKA1 complex associates with microtubules and forms oligomeric assemblies. Interacts directly with SKA1. Binds directly to microtubules; but with a much lower affinity than SKA1. May interact with NR3C1; the relevance of such interaction remains unclear in vivo.
Not induced by endoplasmic reticulum stress.
Trophic factor for dopamine neurons. Prevents the 6-hydroxydopamine (6-OHDA)-induced degeneration of dopaminergic neurons. When administered after 6-OHDA-lesioning, restores the dopaminergic function and prevents the degeneration of dopaminergic neurons in substantia nigra (By similarity).
Widely expressed in neuronal and non-neuronal tissues. In the brain, highest levels in the optic nerve and corpus callosum.
Detected in aqueous humor (PubMed:12697062). Detected in the eye (at protein level) (PubMed:11431441). Widely expressed. Highly expressed in various types of muscle, ciliary body, papillary sphincter, skeletal muscle, heart, and bone marrow-derived mesenchymal stem cells. Expressed predominantly in the retina. In normal eyes, found in the inner uveal meshwork region and the anterior portion of the meshwork. In contrast, in many glaucomatous eyes, it is found in more regions of the meshwork and seems to be expressed at higher levels than in normal eyes, regardless of the type or clinical severity of glaucoma. The myocilin 35 kDa fragment is detected in aqueous humor and to a lesser extent in iris and ciliary body.
Different isoforms may arise by post-translational modifications.
Homodimer (via N-terminus). Can also form higher oligomers (PubMed:9497363). Interacts with OLFM3, FN1, NRCAM, GLDN and NFASC (PubMed:12019210, PubMed:11773026, PubMed:23897819). Interacts (via N-terminus) with MYL2 (PubMed:11773029). Interacts with SFRP1, FRZB, FZD7, FZD10, FZD1 and WIF1; regulates Wnt signaling (PubMed:19188438). Interacts with SNTA1; regulates muscle hypertrophy. Interacts with ERBB2 and ERBB3; activates ERBB2-ERBB3 signaling pathway. Interacts with SNCG; affects its secretion and its aggregation (By similarity).
Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration. Promotes substrate adhesion, spreading and formation of focal contacts. Negatively regulates cell-matrix adhesion and stress fiber assembly through Rho protein signal transduction. Modulates the organization of actin cytoskeleton by stimulating the formation of stress fibers through interactions with components of Wnt signaling pathways. Promotes cell migration through activation of PTK2 and the downstream phosphatidylinositol 3-kinase signaling. Plays a role in bone formation and promotes osteoblast differentiation in a dose-dependent manner through mitogen-activated protein kinase signaling. Mediates myelination in the peripheral nervous system through ERBB2/ERBB3 signaling. Plays a role as a regulator of muscle hypertrophy through the components of dystrophin-associated protein complex. Involved in positive regulation of mitochondrial depolarization. Plays a role in neurite outgrowth. May participate in the obstruction of fluid outflow in the trabecular meshwork.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. MYOC mutations may contribute to GLC3A via digenic inheritance with CYP1B1 and/or another locus associated with the disease (PubMed:15733270).
Undergoes a calcium-dependent proteolytic cleavage at Arg-226 by CAPN2 in the endoplasmic reticulum. The result is the production of two fragments, one of 35 kDa containing the C-terminal olfactomedin-like domain, and another of 20 kDa containing the N-terminal leucine zipper-like domain.
Up-regulated by dexamethasone, a glucocorticoid.
Detected in liver (at protein level). Predominantly expressed in skeletal muscle. Intermediate levels in heart, liver and pancreas. Low in brain, placenta, lung and kidney.
Fourteen CLPP subunits assemble into 2 heptameric rings which stack back to back to give a disk-like structure with a central cavity. Component of the Clp complex formed by the assembly of two CLPP heptameric rings with two CLPX hexameric rings, giving rise to a symmetrical structure with two central CLPP rings flanked by a CLPX ring at either end of the complex.
Protease component of the Clp complex that cleaves peptides and various proteins in an ATP-dependent process. Has low peptidase activity in the absence of CLPX. The Clp complex can degrade CSN1S1, CSN2 and CSN3, as well as synthetic peptides (in vitro) and may be responsible for a fairly general and central housekeeping function rather than for the degradation of specific substrates (PubMed:11923310, PubMed:15522782). Cleaves PINK1 in the mitochondrion (PubMed:22354088).
Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits. The complex is composed of 3 respiratory subunits cytochrome b, cytochrome c1 and Rieske protein UQCRFS1, 2 core protein subunits UQCRC1/QCR1 and UQCRC2/QCR2, and 6 low-molecular weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, UQCR10/QCR9, UQCR11/QCR10 and subunit 9, the cleavage product of Rieske protein UQCRFS1 (By similarity). The complex exists as an obligatory dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and cytochrome c oxidase (complex IV, CIV), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with UQCC6 (By similarity).
Acetylated. Deacetylation at Lys-48 enhances cytoplasmic localization and kinase activity in vitro.
Activated by forming a complex with STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta): STRADA (or STRADB)-binding promotes a conformational change of STK11/LKB1 in an active conformation, which is stabilized by CAB39/MO25alpha (or CAB39L/MO25beta) interacting with the STK11/LKB1 activation loop. Sequestration in the nucleus by NR4A1 prevents it from phosphorylating and activating cytoplasmic AMPK.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. LKB1 subfamily.
Catalytic component of a trimeric complex composed of STK11/LKB1, STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta): the complex tethers STK11/LKB1 in the cytoplasm and stimulates its catalytic activity. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with p53/TP53, SMAD4, STK11IP and WDR6. Interacts with NR4A1. Interacts with NISCH; this interaction may increase STK11 activity. Interacts with PTEN; leading to PTEN phosphorylation. Interacts with SIRT1; the interaction deacetylates STK11. Interacts with CDKN1A.
Defects in STK11 are associated with some sporadic cancers, especially lung cancers. Frequently mutated and inactivated in non-small cell lung cancer (NSCLC). Defects promote lung cancerigenesis process, especially lung cancer progression and metastasis. Confers lung adenocarcinoma the ability to trans-differentiate into squamous cell carcinoma. Also able to promote lung cancer metastasis, via both cancer-cell autonomous and non-cancer-cell autonomous mechanisms.
Its phosphorylation by PKC/PRKCZ at Ser-428 is reported to promote peroxynitrite-induced nuclear export of STK11, leading to PTEN activation and subsequent inhibition of PI3K/AKT signaling and induction of apoptosis in vein endothelial cells (PubMed:18321849). However this paper was withdrawn by the authors due to concerns of image duplication in the figures. Its phosphorylation by PKC/PRKCZ has been confirmed in other studies (PubMed:18854309, PubMed:23612973).
Phosphorylated by ATM at Thr-363 following ionizing radiation (IR). Phosphorylation at Ser-428 by RPS6KA1 and/or some PKA is required to inhibit cell growth. Phosphorylation at Ser-428 is also required during neuronal polarization to mediate phosphorylation of BRSK1 and BRSK2 (By similarity). Phosphorylation by PKC/PRKCZ at Ser-399 in isoform 2 promotes metformin (or peroxynitrite)-induced nuclear export of STK11 and activation of AMPK. UV radiation-induced phosphorylation at Thr-363 mediates CDKN1A degradation (By similarity).
Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. Acts by phosphorylating the T-loop of AMPK family proteins, thus promoting their activity: phosphorylates PRKAA1, PRKAA2, BRSK1, BRSK2, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, SIK1, SIK2, SIK3 and SNRK but not MELK. Also phosphorylates non-AMPK family proteins such as STRADA, PTEN and possibly p53/TP53. Acts as a key upstream regulator of AMPK by mediating phosphorylation and activation of AMPK catalytic subunits PRKAA1 and PRKAA2 and thereby regulates processes including: inhibition of signaling pathways that promote cell growth and proliferation when energy levels are low, glucose homeostasis in liver, activation of autophagy when cells undergo nutrient deprivation, and B-cell differentiation in the germinal center in response to DNA damage. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton. Required for cortical neuron polarization by mediating phosphorylation and activation of BRSK1 and BRSK2, leading to axon initiation and specification. Involved in DNA damage response: interacts with p53/TP53 and recruited to the CDKN1A/WAF1 promoter to participate in transcription activation. Able to phosphorylate p53/TP53; the relevance of such result in vivo is however unclear and phosphorylation may be indirect and mediated by downstream STK11/LKB1 kinase NUAK1. Also acts as a mediator of p53/TP53-dependent apoptosis via interaction with p53/TP53: translocates to the mitochondrion during apoptosis and regulates p53/TP53-dependent apoptosis pathways. Regulates UV radiation-induced DNA damage response mediated by CDKN1A. In association with NUAK1, phosphorylates CDKN1A in response to UV radiation and contributes to its degradation which is necessary for optimal DNA repair (PubMed:25329316).
Ubiquitously expressed. Strongest expression in testis and fetal liver.
Catalyzes the addition of sialic acid in alpha 2,8-linkage to the sialic acid moiety of the ganglioside GM3 to form ganglioside GD3; gangliosides are a subfamily of complex glycosphinglolipds that contain one or more residues of sialic acid (PubMed:7937974, PubMed:8058740, PubMed:8195250, PubMed:8631981, PubMed:8706663, PubMed:18348864, PubMed:22885356). Can catalyze the addition of a second alpha-2,8-sialic acid to GD3 to form GT3 (PubMed:8631981). Can use GM1b, GD1a and GT1b as acceptor substrates to synthesize GD1c, GT1a and GQ1b respectively (PubMed:8706663). Can synthesize unusual tetra- and pentasialylated lactosylceramide derivatives identified as GQ3 (II3Neu5Ac4-Gg2Cer) and GP3 (II3Neu5Ac5-Gg2Cer) in breast cancer cells (PubMed:22885356).
Strongly expressed in melanoma cell lines, adult and fetal brain and to a lesser extent in adult and fetal lung.
A study described a function as serine protease towards extracellular matrix proteins in the liver; however, this article was later retracted.
Cytoplasmic domain mediates HAMP suppression via proximal promoter element(s).
Membrane-bound serine protease (PubMed:18976966, PubMed:20518742, PubMed:25156943, PubMed:25588876). Through the cleavage of cell surface HJV, a regulator of the expression of the iron absorption-regulating hormone hepicidin/HAMP, plays a role in iron homeostasis (PubMed:25156943, PubMed:18408718, PubMed:18976966).
The disease is caused by variants affecting the gene represented in this entry. Mutations leading to abrogation of TMPRSS6 activity are associated with IRIDA due to elevated levels of hepcidin, a negative regulator of plasma iron pool (PubMed:20232450).
The single-chain zymogen undergoes autoproteolytic processing (PubMed:20518742, PubMed:25156943, PubMed:18976966). This results in TMPRSS6 shedding from the cell surface and conversion into an activated two-chains form which is released extracellularly (PubMed:20518742, PubMed:25156943, PubMed:18976966). The process involves a trans-activation mechanism that requires TMPRSS6 oligomerization (PubMed:20518742, PubMed:25156943).
Highest expression is found in liver followed by skeletal muscle, kidney, heart, brain, placenta, lung and pancreas.
Irreversible conversion of delta-1-pyrroline-5-carboxylate (P5C), derived either from proline or ornithine, to glutamate. This is a necessary step in the pathway interconnecting the urea and tricarboxylic acid cycles. The preferred substrate is glutamic gamma-semialdehyde, other substrates include succinic, glutaric and adipic semialdehydes.
Catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses.
Interacts with UQCC2 (PubMed:24385928). Interacts with UQCC3. Forms a complex, named COMB/coordinator of mitochondrial CYTB biogenesis, composed of UQCC1, UQCC2, UQCC4, UQCC5 and UQCC6; stabilizes nascent cytochrome b/MT-CYB and promotes its membrane insertion. Forms a complex, named COMB/coordinator of mitochondrial CYTB biogenesis, composed of UQCC1, UQCC2, UQCC4, UQCC5 and UQCC6; stabilizes nascent cytochrome b/MT-CYB and promotes its membrane insertion. Forms a complex, named COMA, composed of UQCC1, UQCC2 and UQCC4; activates MT-CYB translation. Forms a complex, named COMC, composed of UQCC1, UQCC2; UQCC3 and UQCC4; mediates MT-CYB hemylation and association with the first nuclear-encoded CIII subunit UQCRQ (By similarity).
Required for the assembly of the ubiquinol-cytochrome c reductase complex (mitochondrial respiratory chain complex III or cytochrome b-c1 complex). Involved in cytochrome b translation and/or stability.
Essential component of the PAM complex, a complex required for the translocation of transit peptide-containing proteins from the inner membrane into the mitochondrial matrix in an ATP-dependent manner (By similarity). Seems to control the nucleotide-dependent binding of mitochondrial HSP70 to substrate proteins (PubMed:11311562).
Probable component of the PAM complex at least composed of a mitochondrial HSP70 protein, GRPEL1 or GRPEL2, TIMM44, TIMM16/PAM16 and TIMM14/DNAJC19 (By similarity). Binds to HSP70, HSC70 and HSJ1B (PubMed:11311562).
Binds and exchanges GTP and GDP. Binds and modulates the activation of POU4F1 as gene expression regulator.
Interacts with AFDN, the C-terminal domain of RALGDS and RLF, but not with RIN1 and PIK3CA. RLF binds exclusively to the active GTP-bound form (By similarity). Binds calmodulin. Interacts with PLXNB3. Interacts with POU4F1 (via N-terminus); the interaction controls POU4F1 transactivation activity on some neuronal target genes (By similarity).
Homodimer. May form a heterodimer with other members of the Deltex family. Interacts with NOTCH1.
Regulator of Notch signaling, a signaling pathway involved in cell-cell communications that regulates a broad spectrum of cell-fate determinations. Probably acts both as a positive and negative regulator of Notch, depending on the developmental and cell context. Mediates the antineural activity of Notch, possibly by inhibiting the transcriptional activation mediated by MATCH1. Functions as a ubiquitin ligase protein in vitro, suggesting that it may regulate the Notch pathway via some ubiquitin ligase activity.
The WWE domains are thought to mediate some protein-protein interaction, and are frequently found in ubiquitin ligases.
CGM1a, the predominant CGM1 transcript, is granulocyte-specific. Not detected out of the granulocytic lineage, such as monocytes, lymphocytes, spleen, testis, colon, brain, liver, pancreas, thymus, ovary, placenta, skeletal muscle, prostate, small intestine, heart, lung and kidney.
Interacts with S100A9/calprotectin. This interaction is calcium-dependent, but independent of CEACAM3 phosphorylation.
Major granulocyte receptor mediating recognition and efficient opsonin-independent phagocytosis of CEACAM-binding microorganisms, including Neissiria, Moxarella and Haemophilus species, thus playing an important role in the clearance of pathogens by the innate immune system. Responsible for RAC1 stimulation in the course of pathogen phagocytosis.
The cytosolic domain is involved in S100A9 interaction.
This is not the ortholog of rat CEACAM3.
Tyrosine-phosphorylated in response to microbial binding. Tyr-230 and Tyr-241 are both required for phosphorylation to be detected.
Component of the large ribosomal subunit (PubMed:26290468). Plays a role in the formation of actively translating ribosomes (PubMed:26290468). May play a role in the embryonic brain development (PubMed:25316788).
Component of the large ribosomal subunit. Mature ribosomes consist of a small (40S) and a large (60S) subunit. The 40S subunit contains about 33 different proteins and 1 molecule of RNA (18S). The 60S subunit contains about 49 different proteins and 3 molecules of RNA (28S, 5.8S and 5S).
Disease susceptibility is associated with variants affecting the gene represented in this entry. RPL10 is involved in autism only in rare cases. Two hypomorphic variants affecting the translation process have been found in families with autism spectrum disorders, suggesting that aberrant translation may play a role in disease mechanisms.
Down-regulated during adipocyte, kidney, and heart differentiation.
Mitochondrial GTPase that mediates the disassembly of ribosomes from messenger RNA at the termination of mitochondrial protein biosynthesis (PubMed:19716793, PubMed:33878294). Acts in collaboration with MRRF (PubMed:19716793, PubMed:33878294). Promotes mitochondrial ribosome recycling by dissolution of intersubunit contacts (PubMed:33878294). GTP hydrolysis follows the ribosome disassembly and probably occurs on the ribosome large subunit (PubMed:19716793). Not involved in the GTP-dependent ribosomal translocation step during translation elongation (PubMed:19716793).
This protein may be expected to contain an N-terminal transit peptide but none has been predicted.
Component of the TIM23 complex at least composed of TIMM23, TIMM17 (TIMM17A or TIMM17B) and TIMM50; within this complex, directly interacts with TIMM50. The complex interacts with the TIMM44 component of the PAM complex and with DNAJC15.
(Microbial infection) Acts as an uncoating receptor for a panel of echoviruses including Echovirus 5, 6, 7, 9, 11, 13, 25 and 29.
(Microbial infection) Interacts with Echovirus 6, Echovirus 11 and Echovirus 30 capsid protein VP1.
Cell surface receptor that transfers passive humoral immunity from the mother to the newborn. Binds to the Fc region of monomeric immunoglobulin gamma and mediates its selective uptake from milk (PubMed:7964511, PubMed:10933786). IgG in the milk is bound at the apical surface of the intestinal epithelium. The resultant FcRn-IgG complexes are transcytosed across the intestinal epithelium and IgG is released from FcRn into blood or tissue fluids. Throughout life, contributes to effective humoral immunity by recycling IgG and extending its half-life in the circulation. Mechanistically, monomeric IgG binding to FcRn in acidic endosomes of endothelial and hematopoietic cells recycles IgG to the cell surface where it is released into the circulation (PubMed:10998088). In addition of IgG, regulates homeostasis of the other most abundant circulating protein albumin/ALB (PubMed:24469444, PubMed:28330995).
Expressed in full-term placenta, heart, lung, liver, muscle, kidney, pancreas, and both fetal and adult small intestine.
FcRn complex consists of two subunits: p51, and p14 which is equivalent to beta-2-microglobulin. It forms an MHC class I-like heterodimer (By similarity). Interacts with albumin/ALB; this interaction regulates ALB homeostasis (PubMed:24469444, PubMed:28330995).
Covalently linked to the telopeptides of type II collagen by lysine-derived cross-links.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Susceptibility to intervertebral disk disease is conferred by variant p.Arg103Trp (PubMed:11308397).
Heterotrimer of an alpha 1(IX), an alpha 2(IX) and an alpha 3(IX) chain.
Structural component of hyaline cartilage and vitreous of the eye.
Component of the nuclear exosome targeting (NEXT) complex composed of MTREX, ZCCHC8, and RBM7 that directs a subset of non-coding short-lived RNAs for exosomal degradation (PubMed:27905398, PubMed:27871484, PubMed:25189701). Interacts with ZCCHC8 and SF3B2/SAP145 (PubMed:27905398, PubMed:27871484, PubMed:16263084). Binds to MTREX through ZCCHC8 (PubMed:27871484). Interacts with YWHAE and YWHAZ; these interactions are stress-dependent and RBM7 phosphorylation dependent; release RNA from the NEXT complex and may affect RNA targeting to the nuclear RNA exosomome for degradation (PubMed:25189701). Interacts with MEPCE and LARP7, the core subunits of 7SK snRNP; upon genotoxic stress this interaction is enhanced, triggering the release of inactive P-TEFb complex from the core and P-TEFb complex activation (PubMed:30824372).
Phosphorylated at Ser-136 by MAPK14/p38-alpha-activated MAPKAPK2/MK2; this phosphorylation is stress-dependent; this phosphorylation decreases its RNA-binding capacity therefore affecting RNA nuclear exosome-mediated degradation (PubMed:25525152, PubMed:25189701). This phosphorylation mediates YWHAE and YWHAZ interactions (PubMed:25189701).
RNA-binding subunit of the trimeric nuclear exosome targeting (NEXT) complex, a complex that functions as an RNA exosome cofactor that directs a subset of non-coding short-lived RNAs for exosomal degradation (PubMed:25189701, PubMed:25578728, PubMed:25525152, PubMed:25852104, PubMed:27871484). NEXT is involved in surveillance and turnover of aberrant transcripts and non-coding RNAs (PubMed:25189701, PubMed:27871484, PubMed:25852104). Binds preferentially polyuridine sequences and associates with newly synthesized RNAs, including pre-mRNAs and short-lived exosome substrates such as promoter upstream transcripts (PROMPTs), enhancer RNAs (eRNAs), and 3'-extended products from small nuclear RNAs (snRNAs) (PubMed:25189701, PubMed:25578728, PubMed:25525152, PubMed:25852104). Participates in several biological processes including DNA damage response (DDR) and stress response (PubMed:25525152, PubMed:30824372). During stress response, activation of the p38MAPK-MK2 pathway decreases RBM7-RNA-binding and subsequently the RNA exosome degradation activities, thereby modulating the turnover of non-coding transcriptome (PubMed:25525152). Participates in DNA damage response (DDR), through its interaction with MEPCE and LARP7, the core subunits of 7SK snRNP complex, that release the positive transcription elongation factor b (P-TEFb) complex from the 7SK snRNP. In turn, activation of P-TEFb complex induces the transcription of P-TEFb-dependent DDR genes to promote cell viability (PubMed:30824372).
The RRM domain mediates RNA binding; the RNA must have four nucleotides for efficient binding (PubMed:25852104). Mediates the interaction of NEXT complex with promoter upstream transcripts (PROMPTs) and potentially aberrant forms of other non coding RNAs, such as snRNAs (PubMed:25852104). The RRM domain exhibits specificity for polyuridine sequences (PubMed:25852104).
Acetylated; acetylation is increased upon pulsatile shear stress and decreased upon oscillatory shear stress.
Chromosomal aberrations involving RARA are commonly found in acute promyelocytic leukemia. Translocation t(11;17)(q32;q21) with ZBTB16/PLZF; translocation t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with NPM. The PML-RARA oncoprotein requires both the PML ring structure and coiled-coil domain for both interaction with UBE2I, nuclear microspeckle location and sumoylation. In addition, the coiled-coil domain functions in blocking RA-mediated transactivation and cell differentiation.
Does not bind nor transactivate RARE on its own but may do so as a heterodimer with Alpha-1.
Expression is induced ba retinoic acid (PubMed:19398580). Down-regulated by aging (PubMed:26463675). Induced by pulsatile shear stress (PubMed:28167758).
Heterodimer; with RXRA (via C-terminus); association with RXRA is enhanced by pulsatile shear stress (PubMed:28167758, PubMed:10698945, PubMed:10882070, PubMed:20215566, PubMed:15509776). Binds DNA preferentially as a heterodimer (PubMed:10698945, PubMed:28167758). RXRA serves as enhancer to induce RARA binding to RARE (PubMed:30468856). Interacts with RXRG (PubMed:28167758). Interacts with coactivators NCOA3 and NCOA6 (PubMed:9267036, PubMed:10567404). Interacts with NCOA7; the interaction requires ligand-binding (PubMed:11971969). Interacts (via the ligand-binding domain) with PRAME; the interaction is ligand (retinoic acid)-dependent (PubMed:16179254). Interacts with AKT1; the interaction phosphorylates RARA and represses transactivation (PubMed:16417524). Interacts with PRKAR1A; the interaction negatively regulates RARA transcriptional activity (PubMed:20215566). Interacts with NCOR1 and NCOR2 (PubMed:20543827). Interacts with PRMT2 (PubMed:12039952). Interacts with LRIF1 (PubMed:17455211). Interacts with ASXL1 and NCOA1 (PubMed:16606617). Interacts with ACTN4 (PubMed:22351778). In a complex with HDAC3, HDAC5 and HDAC7; the HDACs serve as corepressors of RARA, causing its deacetylation and inhibition of RARE DNA element binding; association with HDAC3, HDAC5 and HDAC7 is increased upon oscillatory shear stress (PubMed:28167758). Interacts with CDK7 (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863).
Phosphorylated on serine and threonine residues. Phosphorylation does not change during cell cycle. Phosphorylation on Ser-77 is crucial for transcriptional activity (By similarity). Phosphorylation by AKT1 is required for the repressor activity but has no effect on DNA binding, protein stability nor subcellular localization. Phosphorylated by PKA in vitro. This phosphorylation on Ser-219 and Ser-369 is critical for ligand binding, nuclear localization and transcriptional activity in response to FSH signaling.
Receptor for retinoic acid (PubMed:19850744, PubMed:16417524, PubMed:20215566). Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes (PubMed:28167758). The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 (PubMed:28167758, PubMed:19398580). In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone deacetylation, chromatin condensation and transcriptional suppression (PubMed:16417524). On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation (PubMed:9267036, PubMed:19850744, PubMed:20215566). Formation of a complex with histone deacetylases might lead to inhibition of RARE DNA element binding and to transcriptional repression (PubMed:28167758). Transcriptional activation and RARE DNA element binding might be supported by the transcription factor KLF2 (PubMed:28167758). RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis (By similarity). Has a role in the survival of early spermatocytes at the beginning prophase of meiosis (By similarity). In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes (By similarity). In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Together with RXRA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells (PubMed:28167758). In association with HDAC3, HDAC5 and HDAC7 corepressors, plays a role in the repression of microRNA-10a and thereby promotes the inflammatory response (PubMed:28167758).
Sumoylated with SUMO2, mainly on Lys-399 which is also required for SENP6 binding. On all-trans retinoic acid (ATRA) binding, a confromational change may occur that allows sumoylation on two additional site, Lys-166 and Lys-171. Probably desumoylated by SENP6. Sumoylation levels determine nuclear localization and regulate ATRA-mediated transcriptional activity.
Trimethylation enhances heterodimerization with RXRA and positively modulates the transcriptional activation.
Exo-alpha-sialidase that catalyzes the hydrolytic cleavage of the terminal sialic acid (N-acetylneuraminic acid, Neu5Ac) of a glycan moiety in the catabolism of glycolipids, glycoproteins and oligosacharides. Displays high catalytic efficiency for gangliosides including alpha-(2->3)-sialylated GD1a and GM3 and alpha-(2->8)-sialylated GD3 (PubMed:11298736, PubMed:15847605, PubMed:10861246, PubMed:20511247, PubMed:28646141, PubMed:10405317, PubMed:12011038). Plays a role in the regulation of transmembrane signaling through the modulation of ganglioside content of the lipid bilayer and by direct interaction with signaling receptors, such as EGFR (PubMed:17334392, PubMed:25922362). Desialylates EGFR and activates downstream signaling in proliferating cells (PubMed:25922362). Contributes to clathrin-mediated endocytosis by regulating sorting of endocytosed receptors to early and recycling endosomes (PubMed:26251452).
Highly expressed in skeletal muscle, testis, adrenal gland and thymus, followed by pancreas, liver, heart and thymus. Weakly expressed in kidney, placenta, brain and lung.
Interacts with CAV1; this interaction enhances NEU3 sialidase activity within caveola (PubMed:12011038). Interacts with EGFR; this interaction mediates desialylation of EGFR and enhances downstream signaling (PubMed:17334392).
Palmitoylated; may regulate intracellular trafficking and anchorage to plasma membrane and endomembranes.
Interacts with AXN1, AXN2 and CSNK1E/CKI-epsilon.
Recruits CKI-epsilon to the beta-catenin degradation complex that consists of AXN1 or AXN2 and GSK3-beta and allows efficient phosphorylation of beta-catenin, thereby inhibiting beta-catenin/Tcf signals.
Expressed in fetal kidney, lung and liver.
Probable transporter which may play a role in macrophage lipid transport and homeostasis.
Up-regulated during monocyte differentiation into macrophages (PubMed:10639163). Down-regulated by cholesterol loading of macrophages (PubMed:10639163, PubMed:24028821).
Widely expressed with higher expression in liver.
Electroneutral sodium- and bicarbonate-dependent cotransporter with a Na(+):HCO3(-) 1:1 stoichiometry (PubMed:10347222, PubMed:12403779, PubMed:14736710, PubMed:14578046). Mediates the sodium-dependent bicarbonate transport important for pH recovery after acid load as well as for regulation of steady-state pH in the duodenum and vascular smooth muscle cells (By similarity). Plays a key role in macrophage acidification, mediating bicarbonate import into the cytoplasm which is crucial for net acid extrusion and maintenance of cytoplasmic pH during phagocytosis (PubMed:29779931). Provides cellular bicarbonate for de novo purine and pyrimidine synthesis and is a key mediator of de novo nucleotide synthesis downstream of mTORC1 signaling in proliferating cells (PubMed:35772404).
Expressed in skeletal muscle and heart muscle.
Highly expressed in testis and spleen. Also expressed in retina, colon, small intestine, ovary, thymus, prostate, muscle, heart and kidney.
In response to growth factor stimuli, mTORC1 activation, through the RPS6KA1-dependent EIF4B phosphorylation, stimulates SLC4A7 mRNA translation (at protein level) (PubMed:35772404). Strongly induced upon macrophage differentiation (PubMed:29779931).
Interacts with CFTR through NHERF1/EBP50. Interacts with USH1C. Forms a complex with ATP6V1B1 and NHERF1/EBP50. Interacts in a pH dependent-manner with CA2/carbonic anhydrase 2.
Plays a key role in macrophage acidification, mediating bicarbonate import into the cytoplasm which is crucial for net acid extrusion and maintenance of cytoplasmic pH during phagocytosis.
The PDZ-binding motif mediates interaction with the CFTR, NHERF1/EBP50 complex and probably with USH1C.
Transporter activity is regulated by CA2/carbonic anhydrase 2, cAMP and PKA. Insensitive to stilbene derivatives. Inhibited by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA).
Associates with the 60S ribosomal subunit (PubMed:21536732). Found in a complex consisting of the 60S ribosomal subunit, SBDS and EFL1 (PubMed:22814378). Interacts with SBDS and binds to GTP and GDP; the interaction with SBDS decreases EFL1 affinity for GDP and facilitates GDP release (PubMed:25991726).
Expressed at low levels in brain. Expression is highly increased in glioma tissues.
Involved in the biogenesis of the 60S ribosomal subunit and translational activation of ribosomes. Together with SBDS, triggers the GTP-dependent release of EIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating EIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export. Has low intrinsic GTPase activity. GTPase activity is increased by contact with 60S ribosome subunits.
'Asrij' stands for 'blood' in Sanskrit as this protein is strongly expressed in blood vessels.
Isoform 1 is highly expressed in many tissues, including testis, brain, placenta, ovary, prostate and mammary gland. Isoform 2 expression is restricted to the central nervous system including brain, cerebellum and spinal cord.
Maintains stem cell potency (By similarity). Increases STAT3 phosphorylation and controls ERK phosphorylation (By similarity). May act as a scaffold, increasing STAT3 recruitment onto endosomes (By similarity). Involved in integrin-mediated cancer cell adhesion and colony formation in ovarian cancer (PubMed:20515946).
The OCIA domain is necessary and sufficient for endosomal localization.
Expressed in subsets of taste receptor cells of the tongue and exclusively in gustducin-positive cells. Expressed in airway epithelia.
Gustducin-coupled receptor immplicated in the perception of bitter compounds in the oral cavity and the gastrointestinal tract. Signals through PLCB2 and the calcium-regulated cation channel TRPM5. Activated by the sulfonyl amide sweeteners saccharin and acesulfame K. In airway epithelial cells, binding of bitter compounds increases the intracellular calcium ion concentration and stimulates ciliary beat frequency. May act as chemosensory receptors in airway epithelial cells to detect and eliminate potential noxious agents from the airways (By similarity).
Acetylation at Lys-95 by KAT5 promotes the transcription activator activity and is required during myoblast differentiation (PubMed:26291311). Acetylation by KAT5 abolishes the interaction between SOX4 and HDAC1 and switches SOX4 into a transcriptional activator (PubMed:26291311).
Interacts with UBE2I (PubMed:16631117). Interacts with HDAC1; interaction inhibits the transcriptional activator activity (PubMed:16631117).
Transcriptional activator that binds with high affinity to the T-cell enhancer motif 5'-AACAAAG-3' motif (PubMed:30661772). Required for IL17A-producing Vgamma2-positive gamma-delta T-cell maturation and development, via binding to regulator loci of RORC to modulate expression (By similarity). Involved in skeletal myoblast differentiation by promoting gene expression of CALD1 (PubMed:26291311).
G-protein coupled receptor for PEN, a neuropeptide produced from the precursor protein, proSAAS (encoded by PCSK1N). Acts through a G(i)- and G(q)-alpha-alpha-mediated pathway in response to PEN (PubMed:27117253). Plays a role in food intake and body weight regulation. May contribute to the regulation of anxiety-related behaviors (By similarity).
Highly expressed in the brain and spinal cord, and found in lower concentrations in the thymus and other tissues.
NPY has been reported to be a ligand for GPR83 (in vitro) (By similarity). However, a more recent study found that radiolabeled PEN binding to GPR83 is not affected by NPY concentrations below 1 mM, only very high, non-physiological concentrations causes a partial, displacement of PEN binding (By similarity).
Belongs to the YTHDF family. YTHDF1 subfamily.
Interacts with CNOT1; promoting recruitment of the CCR4-NOT complex (PubMed:32492408). Interacts with ribosomes (PubMed:26046440). Interacts with eIF3 (EIF3A or EIF3B) (PubMed:26046440). Interacts with YTHDF3 (PubMed:28106072).
Specifically recognizes and binds N6-methyladenosine (m6A)-containing mRNAs, and regulates their stability (PubMed:24284625, PubMed:32492408, PubMed:26318451). M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in mRNA stability and processing (PubMed:24284625, PubMed:32492408). Acts as a regulator of mRNA stability by promoting degradation of m6A-containing mRNAs via interaction with the CCR4-NOT complex (PubMed:32492408). The YTHDF paralogs (YTHDF1, YTHDF2 and YTHDF3) shares m6A-containing mRNAs targets and act redundantly to mediate mRNA degradation and cellular differentiation (PubMed:28106072, PubMed:32492408). Required to facilitate learning and memory formation in the hippocampus by binding to m6A-containing neuronal mRNAs (By similarity). Acts as a regulator of axon guidance by binding to m6A-containing ROBO3 transcripts (By similarity). Acts as a negative regulator of antigen cross-presentation in myeloid dendritic cells (By similarity). In the context of tumorigenesis, negative regulation of antigen cross-presentation limits the anti-tumor response by reducing efficiency of tumor-antigen cross-presentation (By similarity). Promotes formation of phase-separated membraneless compartments, such as P-bodies or stress granules, by undergoing liquid-liquid phase separation upon binding to mRNAs containing multiple m6A-modified residues: polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their disordered regions and thereby leading to phase separation (PubMed:31388144, PubMed:31292544, PubMed:32451507). The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated membraneless compartments, such as P-bodies, stress granules or neuronal RNA granules (PubMed:31292544).
Was initially reported to act as a regulator of mRNA translation efficiency by promoting ribosome loading to m6A-containing mRNAs and by interacting with translation initiation factors eIF3 (EIF3A or EIF3B), thereby facilitating translation initiation (PubMed:26046440, PubMed:26593424). These studies suggested that the 3 different paralogs (YTHDF1, YTHDF2 and YTHDF3) have unique functions with limited redundancy (PubMed:26046440, PubMed:26593424). However, later studies showed that YTHDF1, YTHDF2 and YTHDF3 paralogs have redundant functions to a profound extent and directly promote degradation of m6A-containing mRNAs (PubMed:32492408). The effect on translation efficiency observed earlier is probably indirect (PubMed:32492408).
Expressed in brain, eye, ovary and testis, and at lower levels in muscle, placenta, liver and lung.
Isoform 3 may be a Ca(2+)-independent and swelling-activated chloride channel, possibly involved in regulation of cell volume.
Probable chloride channel. May be involved in cell adhesion (By similarity).
Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance and lamellipodial and filopodial dynamics in migrating cells. EVL enhances actin nucleation and polymerization.
Homotetramer (By similarity). Binds to the SH3 domains of ABL1, LYN and SRC. Also binds to profilin, with preference for isoform IIa of PFN2, and the WW domain of APBB1/FE65. Binds to SEMA6A. Interacts, via the Pro-rich region, with the C-terminal SH3 domain of DNMBP. Interacts with RAPH1. Binds, via the EVH1 domain, the Pro-rich domain of Listeria monocytogenes actA (By similarity). Binds, via the EVH1 domain, the Pro-rich domain of ZYX. Interacts with FYB1 (PubMed:10747096). Interacts with ZDHHC17 (PubMed:28882895).
Phosphorylated by PKA; phosphorylation abolishes binding to SH3 domains of ABL and SRC.
Required to transform actin polymerization into active movement for the propulsive force of Listeria monocytogenes.
Inhibitor of HGFAC (PubMed:9045658). Inhibits serine protease activity of ST14/matriptase in vitro (PubMed:28710277). Inhibits serine protease activity of TMPRSS13, via the BPTI/Kunitz inhibitor 1 domain (PubMed:20977675).
Interacts with HGFAC (PubMed:15713485). Interacts with TMPRSS13; the interaction promotes the phosphorylation and cell membrane localization of TMPRSS13 (PubMed:28710277).
Expressed in heart of 25 and 17 weeks embryos.
Highly expressed in heart, and expressed at low levels in placenta, lung, skeletal muscle, kidney and liver.
Transcriptional activator which may act in mitogen-activated protein kinase signaling pathway.
Belongs to the NAD(P)-dependent epimerase/dehydratase family. Fucose synthase subfamily.
Catalyzes the two-step NADP-dependent conversion of GDP-4-dehydro-6-deoxy-D-mannose to GDP-fucose, involving an epimerase and a reductase reaction.
Abundant protease in the cytosolic granules of cytotoxic T-cells and NK-cells which activates caspase-independent pyroptosis when delivered into the target cell through the immunological synapse (PubMed:3262682, PubMed:3263427, PubMed:1985927). It cleaves after Asp (PubMed:8258716, PubMed:1985927). Once delivered into the target cell, acts by catalyzing cleavage of gasdermin-E (GSDME), releasing the pore-forming moiety of GSDME, thereby triggering pyroptosis and target cell death (PubMed:32188940, PubMed:31953257). Seems to be linked to an activation cascade of caspases (aspartate-specific cysteine proteases) responsible for apoptosis execution. Cleaves caspase-3, -9 and -10 (CASP3, CASP9 and CASP10, respectively) to give rise to active enzymes mediating apoptosis (PubMed:9852092). Cleaves and activates CASP7 in response to bacterial infection, promoting plasma membrane repair (By similarity).
Belongs to the peptidase S1 family. Granzyme subfamily.
By staphylococcal enterotoxin A (SEA) in peripheral blood leukocytes.
Inactivated by the serine protease inhibitor diisopropylfluorophosphate.
Three homologous proteins DHRS4, DHRS4L1, and DHRS4L2 are derived from gene duplication of DHRS4, and the gene cluster is arranged in tandem in chromosome 14.
Can stimulate E2F-dependent transcription. Binds DNA cooperatively with E2F family members through the E2 recognition site, 5'-TTTC[CG]CGC-3', found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication (PubMed:8405995, PubMed:7739537). The E2F1:DP complex appears to mediate both cell proliferation and apoptosis. Blocks adipocyte differentiation by repressing CEBPA binding to its target gene promoters (PubMed:20176812).
Component of the E2F:DP transcription factor complex. Forms heterodimers with E2F family members. The complex can interact with hypophosphorylated retinoblastoma protein RB1 and related proteins (RBL1 and RBL2) that inhibit the E2F transactivation domain. This repression involves recruitment of histone deacetylase (HDAC). During the cell cycle, from mid-to-late G1 phase, RB family members become phosphorylated, detach from the DRTF1/E2F complex to render E2F transcriptionally active. Viral oncoproteins, notably E1A, T-antigen and HPV E7, are capable of sequestering RB protein, thus releasing the active complex. Part of the E2F6.com-1 complex in G0 phase is composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EUHMTASE1, RING1, RNF2, MBLR, L3MBTL2 YAF2. Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2. The complex exists in quiescent cells where it represses cell cycle-dependent genes. It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2. The complex TFDP1:E2F1 interacts with CEBPA; the interaction prevents CEBPA binding to target gene promoters and represses its transcriptional activity (PubMed:20176812).
E2F/DP transactivation can be mediated by several cofactors including TBP, TFIIH, MDM2 and CBP.
Highest levels in muscle. Also expressed in brain, placenta, liver and kidney. Lower levels in lung and pancreas. Not detected in heart.
Phosphorylation by E2F1-bound cyclin A-CDK2, in the S phase, inhibits E2F-mediated DNA binding and transactivation.
Ubiquitinated by the BCR(KBTBD5) complex, leading to its subsequent degradation.
Supercomplex made of cofactors A to E. Cofactors A and D function by capturing and stabilizing tubulin in a quasi-native conformation. Cofactor E binds to the cofactor D-tubulin complex; interaction with cofactor C then causes the release of tubulin polypeptides that are committed to the native state.
Tubulin-folding protein; involved in the early step of the tubulin folding pathway.
Component of the 9-1-1 cell-cycle checkpoint response complex that plays a major role in DNA repair. The 9-1-1 complex is recruited to DNA lesion upon damage by the RAD17-replication factor C (RFC) clamp loader complex. Acts then as a sliding clamp platform on DNA for several proteins involved in long-patch base excision repair (LP-BER). The 9-1-1 complex stimulates DNA polymerase beta (POLB) activity by increasing its affinity for the 3'-OH end of the primer-template and stabilizes POLB to those sites where LP-BER proceeds; endonuclease FEN1 cleavage activity on substrates with double, nick, or gap flaps of distinct sequences and lengths; and DNA ligase I (LIG1) on long-patch base excision repair substrates. The 9-1-1 complex is necessary for the recruitment of RHNO1 to sites of double-stranded breaks (DSB) occurring during the S phase. RAD9A possesses 3'->5' double stranded DNA exonuclease activity. Its phosphorylation by PRKCD may be required for the formation of the 9-1-1 complex.
Component of the toroidal 9-1-1 (RAD9-RAD1-HUS1) complex, composed of RAD9A, RAD1 and HUS1. The 9-1-1 complex associates with LIG1, POLB, FEN1, RAD17, HDAC1, RPA1 and RPA2. The 9-1-1 complex associates with the RAD17-RFC complex. RAD9A interacts with BCL2L1, FEN1, PRKCD, RAD9B, HUS1, RAD1, ABL1, RPA1, ATAD5 and RPA2. Interacts with DNAJC7 and RHNO1.
Constitutively phosphorylated on serine and threonine amino acids in absence of DNA damage. Hyperphosphorylated by PRKCD and ABL1 upon DNA damage. Its phosphorylation by PRKCD may be required for the formation of the 9-1-1 complex.
Expressed in kidney cortical epithelial cells and brain.
Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. Is involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-depending refilling of readily releasable vesicle pool (RRP) (By similarity). Essential for synaptic vesicle maturation in a subset of excitatory/glutamatergic but not inhibitory/GABA-mediated synapses (By similarity). In collaboration with UNC13A, facilitates neuronal dense core vesicles fusion as well as controls the location and efficiency of their synaptic release (By similarity).
Essential for survival of retinal photoreceetors.
Expressed in small intestine, kidney, pancreas, placenta as well as in retina. Weaker expression in lung, liver and heart. Not expressed in brain and skeletal muscle.
Functions as a regulator of gene expression.
Interacts with REEP6 (By similarity). Interacts with PRPH2 in rod and cone photoreceptors (By similarity). Interacts with ROM1 (By similarity). Interacts with SNAP25 (By similarity). Interacts with VAMP2 (By similarity).
Potentially involved in docking of synaptic vesicles at presynaptic active zones. Apical receptor involved in membrane fusion of apical vesicles.
(Microbial infection) Abundantly expressed in tracheal epithelial cells following influenza A virus infection (at protein level).
(Microbial infection) Interacts (via N-terminus) with influenza A virus RNA polymerase subunit PB1 (via C-terminus); the interaction competitively inhibits the interaction between the subunits PB1 and PB2.
(Microbial infection) mRNA levels increase in response to P.gingivalis challenge while protein expression decreases, suggesting proteasomal degradation in response to P.gingivalis infection of gingival epithelial cells.
Detected in heart right ventricle (at protein level). Expressed in gingival epithelial, endothelial and fibroblast cells (at protein level) (PubMed:34368962). Faintly expressed in tracheal epithelial cells (at protein level) (PubMed:28169297). Widely expressed. Found at desmosomal plaques in simple and stratified epithelia and in non-epithelial tissues such as myocardium and lymph node follicles. In most stratified epithelia found in the desmosomes of the basal cell layer and seems to be absent from suprabasal strata.
Interacts with DSC2 (PubMed:21062920). Interacts with JUP (PubMed:22781308, PubMed:11790773). Interacts with KRT5/CK5, KRT8/CK8, KRT14/CK14, KRT18/CK18 and VIM (PubMed:10852826). Interacts (via N-terminus) with MARK3/C-TAK1 (PubMed:12941695). Interacts with DSP (PubMed:11790773, PubMed:22781308). Interacts with DSG1, DSG2 and DSG3 (PubMed:11790773). Interacts (via N-terminus) with CTNNB1 (PubMed:11790773). Interacts with CDH1 (PubMed:11790773). Interacts with the RNA polymerase III (Pol III) complex proteins POLR3A/RPC155, POLR3F/RPC39 and POLR3C/RPC82 (PubMed:11416169). Interacts with CTNNA3 (PubMed:17535849). Interacts (via N-terminus) with SCN5A/Nav1.5 (By similarity).
Regulates focal adhesion turnover resulting in changes in focal adhesion size, cell adhesion and cell spreading, potentially via transcriptional modulation of beta-integrins (PubMed:23884246). Required to maintain gingival epithelial barrier function (PubMed:34368962). Required for cardiac sodium current propagation and electrical synchrony in cardiac myocytes (By similarity). Required for the formation of desmosome cell junctions in cardiomyocytes, thereby required for the correct formation of the heart, specifically trabeculation and formation of the atria walls (By similarity). Loss of desmosome cell junctions leads to mis-localization of DSP and DSG2 resulting in disruption of cell-cell adhesion and disordered intermediate filaments (By similarity). Modulates profibrotic gene expression in cardiomyocytes via regulation of DSP expression and subsequent activation of downstream TGFB1 and MAPK14/p38 MAPK signaling (By similarity). May play a role in junctional plaques (PubMed:22781308). Involved in the inhibition of viral infection by influenza A viruses (IAV) (PubMed:28169297). Acts as a host restriction factor for IAV viral propagation, potentially via disrupting the interaction of IAV polymerase complex proteins (PubMed:28169297).
Activated by oncostatin-M (PubMed:8999038). Up-regulated by IFNG/IFN-gamma (PubMed:15184896, PubMed:21261663). Up-regulated by bacterial lipopolysaccharides (LPS) (PubMed:15184896). Up-regulated by triacylated lipoprotein (Pam3Cys) (PubMed:21261663).
Associates with IL31RA to form the IL31 receptor. Binds IL31 to activate STAT3 and possibly STAT1 and STAT5. Capable of transducing OSM-specific signaling events.
Expressed in keratinocytes (at protein level) (PubMed:21261663). Expressed at relatively high levels in all neural cells as well as fibroblast and epithelial cells (PubMed:8999038).
Heterodimer composed of OSMR and IL6ST (type II OSM receptor). Heterodimer with IL31RA to form the IL31 receptor.
May be derived from an ancient transposon that has lost its ability to translocate.
Acts as an important p53/TP53-apoptotic effector. Regulates TNF-alpha-mediated apoptosis in a p53/TP53-dependent manner.
Highly expressed in brain. Expressed at lower level in heart, skeletal muscle, kidney, pancreas and liver. Weakly or not expressed in placenta and lung.
The LITAF domain is stabilized by a bound zinc ion. The LITAF domain contains an amphipathic helix that mediates interaction with lipid membranes.
Does not homooligomerize (PubMed:10500148). Does not interact with SNRPB (PubMed:10500148).
Expressed in a wide variety of tissues. Expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. Also seen at high levels in spinal cord. Present in osteoclasts and mononuclear cells (at protein level).
Homooligomer; may form higher order homooligomers in the dimer to octamer range (PubMed:26092730, PubMed:10500148, PubMed:14715275, PubMed:21816274, PubMed:17178713, PubMed:23022347). Part of the core SMN complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP (PubMed:9323129, PubMed:17178713). Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG (PubMed:12065586, PubMed:18984161). Component of an import snRNP complex composed of KPNB1, RNUT1, SMN1 and ZNF259 (PubMed:12095920). Interacts with DDX20, FBL, NOLA1, RNUT1, SYNCRIP and with several spliceosomal snRNP core Sm proteins, including SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE and ILF3 (PubMed:11574476, PubMed:12095920, PubMed:10500148). Interacts with GEMIN2; the interaction is direct (PubMed:26092730, PubMed:10500148, PubMed:21816274, PubMed:31799625, PubMed:17178713, PubMed:22607171, PubMed:23022347). Interacts with GEMIN3; the interaction is direct (PubMed:17178713). Interacts with GEMIN8; the interaction is direct (PubMed:33754639, PubMed:17178713). Interacts with SNRPB; the interaction is direct (PubMed:10500148). Interacts (via Tudor domain) with SNRPD1 (via C-terminus); the interaction is direct (PubMed:10500148, PubMed:11135666). Interacts with SNRPD2; the interaction is direct (PubMed:10500148). Interacts (via Tudor domain) with SNRPD3 (via C-terminus); the interaction is direct (PubMed:10500148, PubMed:11135666, PubMed:22101937, PubMed:12628254). Interacts with SNRPE; the interaction is direct (PubMed:10500148). Interacts with OSTF1, LSM10, LSM11 and RPP20/POP7 (PubMed:11551898, PubMed:12975319, PubMed:16087681, PubMed:14715275). Interacts (via C-terminal region) with ZPR1 (via C-terminal region) (PubMed:11283611). Interacts (via Tudor domain) with COIL (PubMed:11641277). Interacts with SETX; recruits SETX to POLR2A (PubMed:21700224, PubMed:26700805). Interacts with POLR2A (via the C-terminal domain (CTD)) (PubMed:26700805). Interacts with PRMT5 (PubMed:26700805). Interacts with XRN2 (PubMed:26700805). Interacts (via C-terminus) with FMR1 (via C-terminus); the interaction is direct and occurs in a RNA-independent manner (PubMed:18093976). Interacts (via Tudor domain) with SF3B2 ('Arg-508'-methylated form) (PubMed:25737013). Interacts with WRAP53/TCAB1 (PubMed:21072240). Interacts (via Tudor domain) with ELAVL4 in an RNA-independent manner; the interaction is required for localization of ELAVL4 to RNA granules (PubMed:21088113, PubMed:21389246, PubMed:29061699). Interacts with FRG1 (PubMed:17103222).
The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs (PubMed:9845364, PubMed:18984161). Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (Sm core) (PubMed:18984161). In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP (PubMed:18984161). To assemble core snRNPs, the SMN complex accepts the trapped 5Sm proteins from CLNS1A forming an intermediate (PubMed:18984161). Within the SMN complex, SMN1 acts as a structural backbone and together with GEMIN2 it gathers the Sm complex subunits (PubMed:21816274, PubMed:22101937, PubMed:17178713). Binding of snRNA inside 5Sm ultimately triggers eviction of the SMN complex, thereby allowing binding of SNRPD3 and SNRPB to complete assembly of the core snRNP (PubMed:31799625). Ensures the correct splicing of U12 intron-containing genes that may be important for normal motor and proprioceptive neurons development (PubMed:23063131). Also required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination (PubMed:26700805). May also play a role in the metabolism of small nucleolar ribonucleoprotein (snoRNPs).
The SMN gene is present in two highly homologous and functional copies (TelSMN/SMN1 and CenSMN/SMN2). The telomeric copy of SMN gene (TelSMN/SMN1) seems to be the SMA-determining gene while the centromeric copy seems unaffected.
The Tudor domain mediates association with dimethylarginines, which are common in snRNP proteins.
Thought to be a non-functional protein that lacks the capacity to oligomerize and thus cannot interact with Sm proteins. Primarily derived from SMN2 gene.
Catalytic subunit of protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of a wide variety of enzymes, signal transduction pathways, and cellular events (Probable). PP2A can modulate the activity of phosphorylase B kinase, casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase.
Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD. Interacts with TBCD (By similarity). PP2A consists of a common heterodimeric core enzyme (composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65) (subunit A)) that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Binds PPME1. May indirectly interact with SGO1, most probably through regulatory B56 subunits. Interacts with CTTNBP2NL. Interacts with PTPA (PubMed:12952889).
Expression is up-regulated by androgen, but not by glucocorticoids.
Expressed in various types of thyroid tumor such as papillary thyroid carcinomas and oxyphilic thyroid tumors but not in normal thyroid tissue (at protein level). Strongly expressed in heart, skeletal muscle, pancreas, white blood cells and prostate with moderate expression in colon and spleen. Expressed in renal carcinoma cells but not in normal kidney.
Regulates phosphorylation of a number of proteins involved in translation regulation including EIF2A, EIF4EBP1 and RPS6KB1. May be involved in the endoplasmic reticulum stress response (By similarity).
Dioxygenase that can both act as a arginine demethylase and a lysyl-hydroxylase (PubMed:24498420, PubMed:17947579, PubMed:20684070, PubMed:21060799, PubMed:22189873). Acts as a lysyl-hydroxylase that catalyzes 5-hydroxylation on specific lysine residues of target proteins such as U2AF2/U2AF65 and LUC7L2. Regulates RNA splicing by mediating 5-hydroxylation of U2AF2/U2AF65, affecting the pre-mRNA splicing activity of U2AF2/U2AF65 (PubMed:19574390). Hydroxylates its own N-terminus, which is required for homooligomerization (PubMed:22189873). Plays a role in the regulation of nucleolar liquid-liquid phase separation (LLPS) by post-translationally modifying LIAT1 at its lysine-rich domain which inhibits LIAT1 nucleolar targeting (By similarity). In addition to peptidyl-lysine 5-dioxygenase activity, may act as an RNA hydroxylase, as suggested by its ability to bind single strand RNA (PubMed:20679243, PubMed:29176719). Also acts as an arginine demethylase which preferentially demethylates asymmetric dimethylation (PubMed:17947579, PubMed:24498420, PubMed:24360279). Demethylates histone H3 at 'Arg-2' (H3R2me) and histone H4 at 'Arg-3' (H4R3me), including mono-, symmetric di- and asymmetric dimethylated forms, thereby playing a role in histone code (PubMed:17947579, PubMed:24360279). However, histone arginine demethylation may not constitute the primary activity in vivo (PubMed:17947579, PubMed:21060799, PubMed:22189873). In collaboration with BRD4, interacts with the positive transcription elongation factor b (P-TEFb) complex in its active form to regulate polymerase II promoter-proximal pause release for transcriptional activation of a large cohort of genes. On distal enhancers, so called anti-pause enhancers, demethylates both histone H4R3me2 and the methyl cap of 7SKsnRNA leading to the dismissal of the 7SKsnRNA:HEXIM1 inhibitor complex. After removal of repressive marks, the complex BRD4:JMJD6 attract and retain the P-TEFb complex on chromatin, leading to its activation, promoter-proximal polymerase II pause release, and transcriptional activation (PubMed:24360279). Demethylates other arginine methylated-proteins such as ESR1 (PubMed:24498420). Has no histone lysine demethylase activity (PubMed:21060799). Required for differentiation of multiple organs during embryogenesis. Acts as a key regulator of hematopoietic differentiation: required for angiogenic sprouting by regulating the pre-mRNA splicing activity of U2AF2/U2AF65 (By similarity). Seems to be necessary for the regulation of macrophage cytokine responses (PubMed:15622002).
Highly expressed in the heart, skeletal muscle and kidney. Expressed at moderate or low level in brain, placenta, lung, liver, pancreas, spleen, thymus, prostate, testis and ovary. Up-regulated in many patients with chronic pancreatitis. Expressed in nursing thymic epithelial cells.
Homooligomerizes; requires lysyl-hydroxylase activity (PubMed:22189873, PubMed:24360279). Interacts with LUC7L2, LUC7L3 and U2AF2/U2AF65 (PubMed:19574390). Interacts with CDK9 and CCNT1; the interaction is direct with CDK9 and associates the P-TEFb complex when active (PubMed:24360279). Interacts (via JmjC and N-terminal domains) with BRD4 (via NET domain); the interaction is stronger in presence of ssRNA and recruits JMJD6 on distal enhancers (PubMed:21555454, PubMed:24360279, PubMed:29176719).
Hydroxylates its own N-terminus; hydroxylation is required for homooligomerization.
The nuclear localization signal motifs are necessary and sufficient to target it into the nucleus.
Up-regulated upon cytokine treatment, but not upon TNF treatment.
Was initially thought to constitute the phosphatidylserine receptor, a receptor that mediates recognition of phosphatidylserine, a specific marker only present at the surface of apoptotic cells. Phosphatidylserine receptor probably participates in apoptotic cell phagocytosis. This protein was identified using phage display expressing mAb 217, an antibody that specifically recognizes phosphatidylserine receptor. However, its nuclear localization and the fact that mAb 217 antibody still recognizes the phosphatidylserine receptor in mice lacking JMJD6, strongly suggest that it does not constitute the receptor for phosphatidylserine and is not involved in apoptotic cell removal.
Belongs to the class-II aminoacyl-tRNA synthetase family. Type 1 subfamily.
Belongs to the eukaryotic AdoMetDC family.
Binds 1 pyruvoyl group covalently per subunit.
Both proenzyme processing and catalytic activity are stimulated by putrescine. Catalytic activity is inhibited by iodoacetic acid.
Essential for biosynthesis of the polyamines spermidine and spermine. Promotes maintenance and self-renewal of embryonic stem cells, by maintaining spermine levels.
Heterotetramer of two alpha and two beta chains.
Is synthesized initially as an inactive proenzyme. Formation of the active enzyme involves a self-maturation process in which the active site pyruvoyl group is generated from an internal serine residue via an autocatalytic post-translational modification. Two non-identical subunits are generated from the proenzyme in this reaction, and the pyruvate is formed at the N-terminus of the alpha chain, which is derived from the carboxyl end of the proenzyme. The post-translation cleavage follows an unusual pathway, termed non-hydrolytic serinolysis, in which the side chain hydroxyl group of the serine supplies its oxygen atom to form the C-terminus of the beta chain, while the remainder of the serine residue undergoes an oxidative deamination to produce ammonia and the pyruvoyl group blocking the N-terminus of the alpha chain.
A chromosomal aberration involving FCRL4 is found in multiple myeloma (MM). Translocation t(1;14)(q21;q32) that forms a FCRL4-IGHA1 fusion protein.
A chromosomal aberration involving FCRL4 is found in non-Hodgkin lymphoma (NHG). Translocation t(1;1)(p36.3; q21.1-2).
May function as an inhibitor of the B-cell receptor signaling. May function in the B-cell-mediated immune response.
Phosphorylated on cytoplasmic tyrosines upon activation.
Specifically expressed by memory and monocytoid B-cells which populate spleen and lymph nodes. Preferentially expressed in memory B-cells associated with mucosal tissue (at protein level).
Promotes the degradation of p53/TP53 protein and inhibits its transactivity.
By radiation, 12-O-tetradecanoyl phorbol-13 acetate (TPA), okadaic acid, TNF and NUPR1.
Interacts with the PPP2R5C-PP2A holoenzyme and ERK kinases; regulates ERK dephosphorylation.
May play a role in the ERK signaling pathway by inhibiting the dephosphorylation of ERK by phosphatase PP2A-PPP2R5C holoenzyme. Acts also as an ERK downstream effector mediating survival. As a member of the NUPR1/RELB/IER3 survival pathway, may provide pancreatic ductal adenocarcinoma with remarkable resistance to cell stress, such as starvation or gemcitabine treatment.
Phosphorylated at Thr-18, Thr-123 and Ser-126 by MAPK1/ERK2 and probably MAPK3/ERK1. Upon phosphorylation by MAPK1/ERK2 and MAPK3/ERK1, acquires the ability to inhibit cell death induced by various stimuli.
'Quiescin Q6' means that it was the sixth clone to be found at a higher level of expression in quiescent fibroblasts.
Belongs to the quiescin-sulfhydryl oxidase (QSOX) family.
Catalyzes the oxidation of sulfhydryl groups in peptide and protein thiols to disulfides with the reduction of oxygen to hydrogen peroxide (PubMed:17331072, PubMed:18393449, PubMed:23704371, PubMed:30367560, PubMed:23867277). Plays a role in disulfide bond formation in a variety of extracellular proteins (PubMed:17331072, PubMed:30367560, PubMed:22801504, PubMed:23867277). In fibroblasts, required for normal incorporation of laminin into the extracellular matrix, and thereby for normal cell-cell adhesion and cell migration (PubMed:23704371, PubMed:30367560, PubMed:23867277).
Catalyzes the oxidation of sulfhydryl groups in peptide and protein thiols to disulfides with the reduction of oxygen to hydrogen peroxide.
Expressed in heart, placenta, lung, liver, skeletal muscle, pancreas and very weakly in brain and kidney.
Induced in quiescent cells just as fibroblasts begin to leave the proliferative cycle and enter quiescence.
N-glycosylated (PubMed:17331072, PubMed:29757379). O-glycosylated on Thr and Ser residues (PubMed:29757379).
Binds to actin filaments (F-actin) and shows cross-linking activity. Binds along the sides of the F-actin. May be involved in neurite formation. Inhibits protein phosphatase 1-alpha activity (By similarity).
Interacts with p70-S6K via its PDZ domain.
Possibly exists as a homodimer, homotrimer or a homotetramer. Interacts with F-actin, protein phosphatase 1 (PP1), neurabin-2 and p70-S6K (By similarity).
The PP1 binding region is natively unstructured, upon PP1 binding, it acquires structure, blocks a substrate-binding site, and restricts PP1 phosphatase specificity to a subset of substrates.
Hypothalamus. Found in neurons of the ventrolateral part of the arcuate nucleus, in the external zone of the median eminence, and also found in terminals in the periventricular part of the paraventricular nucleus.
Satiety factor closely associated with the actions of leptin and neuropeptide Y; this anorectic peptide inhibits both normal and starvation-induced feeding and completely blocks the feeding response induced by neuropeptide Y and regulated by leptin in the hypothalamus. It promotes neuronal development and survival in vitro.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to heparan sulfate. The substrate-specific O-sulfation generates an enzyme-modified heparan sulfate which acts as a binding receptor to Herpes Simplex Virus-1 (HSV-1) and permits its entry. Unlike 3-OST-1, does not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate.
IRBP shuttles 11-cis and all trans retinoids between the retinol isomerase in the pigment epithelium and the visual pigments in the photoreceptor cells of the retina.
Detected in cardiac progenitor cells with expression levels increasing as progenitor cells differentiate into cardiomyocytes.
Expressed in developing cardiac tissue and cardiomyocytes (at protein level).
Protein kinase that recognizes phosphorylation sites in which the surrounding peptides have an alpha-helical conformation (PubMed:10021370). Regulates cardiac development and cardiomyocyte differentiation by negatively regulating Wnt/beta-catenin signaling (PubMed:29888752).
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(0) seems to have nine subunits: a, b, c, d, e, f, g, F6 and 8 (or A6L). Component of an ATP synthase complex composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5PD, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and ATP5MJ (By similarity). Interacts with FLVCR2; this interaction occurs in the absence of heme and is disrupted upon heme binding (By similarity).
Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(0) domain and the peripheric stalk, which acts as a stator to hold the catalytic alpha(3)beta(3) subcomplex and subunit a/ATP6 static relative to the rotary elements.
Cytosolic isoform that specifically recognizes and binds mRNA transcripts modified by internal N(7)-methylguanine (m7G) (PubMed:37379838). Interaction with G3BP1 promotes localization of m7G-containing mRNAs into stress granules in response to stress, thereby suppressing their translation (PubMed:37379838). Acts as a negative regulator of angiogenesis by binding to mRNAs encoding CDH5, NLGN1 and TNFAIP6, promoting their degradation (PubMed:32732889). Can also induce apoptosis in the cytoplasm (By similarity). Heterodimerization with other isoforms results in nuclear translocation of isoform QKI7 and suppression of apoptosis (By similarity). Also binds some microRNAs: promotes stabilitation of miR-122 by mediating recruitment of poly(A) RNA polymerase TENT2, leading to 3' adenylation and stabilization of miR-122 (PubMed:31792053).
Cytosolic isoform that specifically recognizes and binds mRNA transcripts modified by internal N(7)-methylguanine (m7G) (PubMed:37379838). Interaction with G3BP1 promotes localization of m7G-containing mRNAs into stress granules in response to stress, thereby suppressing their translation (PubMed:37379838). Acts as a translational repressor for HNRNPA1 and GLI1 (By similarity). Translation inhibition of HNRNPA1 during oligodendrocyte differentiation prevents inclusion of exon 12 in MAG pre-mRNA splicing (By similarity). Involved in astrocyte differentiation by regulating translation of target mRNAs (By similarity).
Expressed in the frontal cortex of brain. Down-regulated in the brain of schizophrenic patients.
Expression is activated by CEBPA furing macrophage differentiation.
Homodimer; does not require RNA to homodimerize (PubMed:23630077). Able to heterodimerize with BICC1 (By similarity).
Interacts with G3BP1; directing N(7)-methylguanine (m7G)-containing mRNAs to stress granules to suppress mRNA translation (PubMed:37379838). Interacts with TENT2; promoting stabilization of miR-122 (PubMed:31792053).
Interacts with G3BP1; directing N(7)-methylguanine (m7G)-containing mRNAs to stress granules to suppress mRNA translation.
Nuclear isoform that acts as an indirect regulator of mRNA splicing (By similarity). Regulates mRNA splicing of MAG pre-mRNA by inhibiting translation of HNRNPA1 mRNA, thereby preventing MAG exon 12 alternative splicing (By similarity). Involved in oligodendrocyte differentiation by promoting stabilization of SIRT2 mRNA (By similarity). Acts as a negative regulator of the interferon response by binding to MAVS mRNA, downregulating its expression (PubMed:31829086). Also inhibits the interferon response by binding to fibrinectin FN1 pre-mRNA, repressing EDA exon inclusion in FN1 (PubMed:34428287). Delays macrophage differentiation by binding to CSF1R mRNA, promoting its degradation (PubMed:22398723). In addition to its RNA-binding activity, also acts as a nuclear transcription coactivator for SREBF2/SREBP2, promoting SREBF2/SREBP2-dependent cholesterol biosynthesis (By similarity). SREBF2/SREBP2-dependent cholesterol biosynthesis participates to myelinization and is required for eye lens transparency (By similarity).
RNA reader protein, which recognizes and binds specific RNAs, thereby regulating RNA metabolic processes, such as pre-mRNA splicing, circular RNA (circRNA) formation, mRNA export, mRNA stability and/or translation (PubMed:22398723, PubMed:25768908, PubMed:27029405, PubMed:31331967, PubMed:23630077, PubMed:37379838). Involved in various cellular processes, such as mRNA storage into stress granules, apoptosis, lipid deposition, interferon response, glial cell fate and development (PubMed:25768908, PubMed:31829086, PubMed:34428287, PubMed:37379838). Binds to the 5'-NACUAAY-N(1,20)-UAAY-3' RNA core sequence (PubMed:23630077). Acts as a mRNA modification reader that specifically recognizes and binds mRNA transcripts modified by internal N(7)-methylguanine (m7G) (PubMed:37379838). Promotes the formation of circular RNAs (circRNAs) during the epithelial to mesenchymal transition and in cardiomyocytes: acts by binding to sites flanking circRNA-forming exons (PubMed:25768908). CircRNAs are produced by back-splicing circularization of pre-mRNAs (PubMed:25768908). Plays a central role in myelinization via 3 distinct mechanisms (PubMed:16641098). First, acts by protecting and promoting stability of target mRNAs such as MBP, SIRT2 and CDKN1B, which promotes oligodendrocyte differentiation (By similarity). Second, participates in mRNA transport by regulating the nuclear export of MBP mRNA (By similarity). Finally, indirectly regulates mRNA splicing of MAG pre-mRNA during oligodendrocyte differentiation by acting as a negative regulator of MAG exon 12 alternative splicing: acts by binding to HNRNPA1 mRNA splicing factor, preventing its translation (By similarity). Involved in microglia differentiation and remyelination by regulating microexon alternative splicing of the Rho GTPase pathway (By similarity). Involved in macrophage differentiation: promotes monocyte differentiation by regulating pre-mRNA splicing in naive peripheral blood monocytes (PubMed:27029405). Acts as an important regulator of muscle development: required for the contractile function of cardiomyocytes by regulating alternative splicing of cardiomyocyte transcripts (By similarity). Acts as a negative regulator of thermogenesis by decreasing stability, nuclear export and translation of mRNAs encoding PPARGC1A and UCP1 (By similarity). Also required for visceral endoderm function and blood vessel development (By similarity). May also play a role in smooth muscle development (PubMed:31331967). In addition to its RNA-binding activity, also acts as a nuclear transcription coactivator for SREBF2/SREBP2 (By similarity).
The KH domain and the Qua2 region are involved in RNA binding.
Tyrosine phosphorylated at its C-terminus, probably by FYN. Phosphorylation leads to decreased mRNA-binding affinity, affecting transport and/or stabilization of MBP mRNA (By similarity).
Ubiquitinated by RNF6 in macrophages, leading to its degradation.
Male-specific histone demethylase that catalyzes trimethylated 'Lys-27' (H3K27me3) demethylation in histone H3. Has relatively low lysine demethylase activity.
Acts as the sensor component of the NLRP6 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to maturation and secretion of IL1B and IL18 (PubMed:30392956, PubMed:34678144). Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (PubMed:30674671). Acts as a recognition receptor (PRR): recognizes and binds specific pathogens and other damage-associated signals, such as lipoteichoic acid (LTA), a cell-wall component of Gram-positive bacteria, or double stranded RNA (dsRNA) (PubMed:30392956, PubMed:34678144, PubMed:33377178). May also recognize and bind lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria; however, LPS is probably not a major activator of the NLRP6 inflammasome (PubMed:31932628, PubMed:34678144). Following LTA- or dsRNA-binding, NLRP6 undergoes liquid-liquid phase separation (LLPS), enhancing multivalent interactions, an essential step for the formation of the NLRP6 inflammasome polymeric complex (PubMed:34678144). The NLRP6 inflammasome acts by promoting recruitment of effector pro-inflammatory caspases (CASP1 and/or CASP4) that catalyze maturation and secretion of IL1B and IL18 in the extracellular milieu (PubMed:30674671, PubMed:12387869, PubMed:30392956, PubMed:34678144). The NLRP6 inflammasome plays a central role in the maintenance of epithelial integrity and host defense against microbial infections in the intestine (PubMed:30392956). Required to restrict infection against Gram-positive bacteria by recognizing lipoteichoic acid (LTA), leading to recruitment of CASP4 and CASP1, and subsequent maturation and secretion of IL1B and IL18 (PubMed:30392956, PubMed:33377178). Involved in intestinal antiviral innate immunity together with DHX15: recognizes and binds viral dsRNA to restrict infection by enteric viruses through the interferon pathway and GSDMD-dependent release of IL18 (PubMed:34678144, PubMed:34161762). Required to prevent infection by the apicomplexan parasite Cryptosporidium in enterocytes by promoting GSDMD-dependent release of IL18 (By similarity). The NLRP6 inflammasome may also regulate the gut microbiota composition by acting as a sensor of microbiota-associated metabolites to form a PYCARD/ASC-dependent inflammasome for downstream IL18 release and secretion of antimicrobial peptides (By similarity). Essential for gut mucosal self-renewal and proliferation (By similarity). Regulate mucus secretion in an inflammasome- and autophagy-dependent manner to prevent invasion by enteric bacteria, (By similarity). During systemic bacterial infections, the NLRP6 inflammasome negatively regulates neutrophil recruitment and neutrophil extracellular traps (NETs) formation (By similarity). May promote peripheral nerve recovery following injury via an inflammasome-independent mechanism (By similarity).
Expressed in peripheral blood leukocytes, predominantly in granulocytes and, at lower levels, in CD4(+) and CD8(+) T-cells (PubMed:12387869). Expressed in colonic myofibroblasts (at protein level) (PubMed:21593405).
Homomultimer; forms the NLRP6 inflammasome polymeric complex, a filament composed of homopolymers in response to pathogens and other damage-associated signals (PubMed:31932628, PubMed:34678144, PubMed:30674671). The core of NLRP6 inflammasomes consists of a signal sensor component (NLRP6), an adapter (PYCARD/ASC), which recruits effector pro-inflammatory caspases (CASP1 and CASP4) (PubMed:34678144, PubMed:30674671). Interacts (via pyrin domain) with PYCARD/ASC (via pyrin domain); interaction takes place following NLRP6 activation and formation of liquid-liquid phase separation (LLPS), initiating nucleation which greatly enhances further addition of soluble PYCARD/ASC molecules to the speck in a prion-like polymerization process (PubMed:34678144, PubMed:30674671). Clustered PYCARD/ASC nucleates the formation of CASP1 (or possibly CASP4) filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization (PubMed:34678144). CASP1 filament formation increases local enzyme concentration, resulting in trans-autocleavage and activation (PubMed:34678144). Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response (PubMed:34678144). Interacts with DHX15 (PubMed:34161762).
Polyubiquitinated with 'Lys-63'-linked chains, promoting the interaction with PYCARD/ASC and formation of the NLRP6 inflammasome. Deubiquitination by CYLD decreases the interaction with PYCARD/ASC.
The poly-Lys disordered region (352-356) mediates the formation of liquid-liquid phase separation (LLPS), an essential step for nucleation and formation of the NLRP6 inflammasome complex.
Up-regulated by rosiglitazone, a PPARG agonist, in Caco2 and HCT116 colorectal carcinoma cells (PubMed:21088234, PubMed:23470617). Down-regulated by CRH (at protein level) (PubMed:23470617).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Glycine receptor (TC 1.A.9.3) subfamily. GLRA1 sub-subfamily.
Channel activity is potentiated by nanomolar concentrations of Zn(2+); half-maximal activation is observed with 37 nM Zn(2+) (PubMed:16144831). Inhibited by higher Zn(2+) levels; haf-maximal inhibition occurs at 20 uM Zn(2+) (PubMed:16144831). Inhibited by strychnine (PubMed:2155780, PubMed:16144831, PubMed:25445488). Inhibited by lindane (PubMed:25445488). Inhibited by picrotoxin (PubMed:22715885, PubMed:23994010, PubMed:25730860). Strychnine binding locks the channel in a closed conformation and prevents channel opening in response to extracellular glycine (By similarity).
Glycine receptors are ligand-gated chloride channels (PubMed:23994010, PubMed:25730860). Channel opening is triggered by extracellular glycine (PubMed:2155780, PubMed:7920629, PubMed:14551753, PubMed:16144831, PubMed:22715885, PubMed:22973015, PubMed:25973519, PubMed:9009272). Channel opening is also triggered by taurine and beta-alanine (PubMed:16144831, PubMed:9009272). Channel characteristics depend on the subunit composition; heteropentameric channels are activated by lower glycine levels and display faster desensitization (PubMed:14551753). Plays an important role in the down-regulation of neuronal excitability (PubMed:8298642, PubMed:9009272). Contributes to the generation of inhibitory postsynaptic currents (PubMed:25445488). Channel activity is potentiated by ethanol (PubMed:25973519). Potentiation of channel activity by intoxicating levels of ethanol contribute to the sedative effects of ethanol (By similarity).
Homopentamer (in vitro) (PubMed:22715885, PubMed:22973015, PubMed:23994010, PubMed:25730860). Interacts with GLRB to form heteropentameric channels; this is probably the predominant form in vivo (PubMed:22715885, PubMed:22973015, PubMed:25445488). Heteropentamer composed of two GLRA1 and three GLRB (PubMed:22715885). Heteropentamer composed of three GLRA1 and two GLRB (PubMed:22973015). Both homopentamers and heteropentamers form functional ion channels, but their characteristics are subtly different (PubMed:14551753, PubMed:22715885, PubMed:22973015, PubMed:25445488, PubMed:23994010, PubMed:25730860). Interacts with GLRB (PubMed:35526563).
The channel pore is formed by pentameric assembly of the second transmembrane domain from all five subunits. In the absence of the extracellular domain, the channel is in a constitutively open conformation (PubMed:23994010). Channel opening is effected by an outward rotation of the transmembrane domains that increases the diameter of the pore (By similarity).
Monomer. Component of the conserved oligomeric Golgi (COG) complex which is composed of eight different subunits and is required for normal Golgi morphology and localization (PubMed:19651599). Mediates interaction of SCFD1 with the COG complex (PubMed:19536132). Interacts with STX5 (PubMed:19536132).
Required for normal Golgi function (PubMed:19536132, PubMed:30290151). Plays a role in SNARE-pin assembly and Golgi-to-ER retrograde transport via its interaction with SCFD1 (PubMed:19536132).
As a component of the outer core of AMPAR complex, may be involved in synaptic transmission in the central nervous system. In hippocampal neurons, in presynaptic terminals, plays an important role in the final steps of neurotransmitter release, possibly by regulating Ca(2+)-sensing. In the cerebellum, may inhibit SNARE complex formation and down-regulate short-term facilitation.
Component of the outer core of AMPAR complex (PubMed:25915028). AMPAR complex consists of an inner core made of 4 pore-forming GluA/GRIA proteins (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged in a twofold symmetry. One of the two pairs of distinct binding sites is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR complex is complemented by outer core constituents binding directly to the GluA/GRIA proteins at sites distinct from the interaction sites of the inner core constituents. Outer core constituents include at least PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the inner and outer core serve as a platform for other, more peripherally associated AMPAR constituents. Alone or in combination, these auxiliary subunits control the gating and pharmacology of the AMPAR complex and profoundly impact their biogenesis and protein processing (By similarity). Interacts with intersectin 1/ITSN1 (By similarity). Interacts with SNARE complex components, including SNAP25, STX1A, SYT1 and SYT2; this interaction may inhibit SNARE complex formation (PubMed:25915028, PubMed:22832103).
The disease is caused by variants affecting the gene represented in this entry. Disease-causing mutations that produce truncation of the C-terminus of the protein alter subcellular location, from plasma membrane to cytoplasm (PubMed:22101681).
May be a regulatory element in the beta-catenin signaling pathway and a target for chemoprevention of hapatocellular carcinoma.
(Microbial infection) Endogenous ligand for the apelin receptor (APLNR), an alternative coreceptor with CD4 for HIV-1 infection (PubMed:11090199). Inhibits HIV-1 entry in cells coexpressing CD4 and APLNR (PubMed:11090199). Apelin-36 has a greater inhibitory activity on HIV infection than other synthetic apelin derivatives (PubMed:11090199).
Endogenous ligand for the apelin receptor (APLNR) (PubMed:10525157). Drives internalization of the apelin receptor (By similarity). Apelin-36 dissociates more hardly than (pyroglu)apelin-13 from APLNR (By similarity). Hormone involved in the regulation of cardiac precursor cell movements during gastrulation and heart morphogenesis (By similarity). Has an inhibitory effect on cytokine production in response to T-cell receptor/CD3 cross-linking; the oral intake of apelin in the colostrum and the milk might therefore modulate immune responses in neonates (By similarity). Plays a role in early coronary blood vessels formation (By similarity). Mediates myocardial contractility in an ERK1/2-dependent manner (By similarity). May also have a role in the central control of body fluid homeostasis by influencing vasopressin release and drinking behavior (By similarity).
Expressed in the brain with highest levels in the frontal cortex, thalamus, hypothalamus and midbrain (PubMed:10617103). Secreted by the mammary gland into the colostrum and the milk.
Several active peptides may be produced by proteolytic processing of the peptide precursor.
Accelerates the intermembrane transfer of various glycolipids. Catalyzes the transfer of various glycosphingolipids between membranes but does not catalyze the transfer of phospholipids. May be involved in the intracellular translocation of glucosylceramides.
Detected in fibroblasts (at protein level). Detected in fibroblasts and in various cancer cell lines.
Interacts with Sec23/24 complex components SEC24B and SEC24D (PubMed:24405750). Interacts with CCR5 (PubMed:24405750). Interacts with ADRB2 in the early secretory pathway (PubMed:24405750).
Involved in G protein-coupled receptors (GPCRs) trafficking from the endoplasmic reticulum to the cell surface; it promotes the exit of GPCRs from the early secretory pathway, likely through interaction with the COPII machinery (PubMed:24405750).
Homodimer (PubMed:15949439). Under normal circumstances, held in an inactive conformation by an intramolecular interaction (PubMed:15949439). Interacts with BAX (PubMed:11060313, PubMed:16199525). Binding to RASSF1 isoform A (RASSF1A) relieves this inhibitory interaction and allows further binding to BAX (PubMed:15949439). Binds also to BCL2 and BCLX (PubMed:11060313). Recruited to the TNFRSF1A and TNFRSF10A complexes in response to their respective cognate ligand, after internalization (PubMed:15949439). Interacts with TRIM39 (PubMed:19100260). Interacts with RASSF6 (By similarity). Interacts with ATG8 proteins MAP1LC3A, MAP1LC3B and MAP1LC3C (PubMed:33783314). Does not interact with ATG8 proteins GABARAPL1, GABARAPL2 and GABARAP (PubMed:33783314). Interacts with SQSTM1; promoting dissociation of SQSTM1 inclusion bodies that sequester KEAP1 (PubMed:33393215).
Retrotransposon-derived protein that forms virion-like capsids (By similarity). Acts as an effector of BAX during apoptosis: enriched at outer mitochondria membrane and associates with BAX upon induction of apoptosis, facilitating BAX-dependent mitochondrial outer membrane permeabilization and apoptosis (PubMed:11060313, PubMed:16199525). Required for death receptor-dependent apoptosis (PubMed:11060313). When associated with RASSF1, promotes BAX conformational change and translocation to mitochondrial membranes in response to TNF and TNFSF10 stimulation (PubMed:15949439). Also promotes autophagy: promotes phagophore closure via association with ATG8 proteins (PubMed:33783314). Acts as an inhibitor of the NFE2L2/NRF2 pathway via interaction with SQSTM1: interaction promotes dissociation of SQSTM1 inclusion bodies that sequester KEAP1, relieving inactivation of the BCR(KEAP1) complex (PubMed:33393215).
The BH3-like domain is required for association with BAX and for mediating apoptosis (PubMed:11060313). The three BH domains (BH1, BH2, and BH3) of BAX are all required for mediating protein-protein interaction (PubMed:11060313).
The LIR motif (LC3-interacting region) is required for the interaction with the ATG8 family proteins MAP1LC3A, MAP1LC3B and MAP1LC3C.
The protein is evolutionarily related to retrotransposon Gag proteins: it contains the capsid (CA)subdomain of gag.
Ubiquitinated and degraded during mitotic exit by APC/C-Cdh1, this modification is inhibited by TRIM39.
Widely expressed, with high levels in heart and brain.
Homodimer or heterodimer (PubMed:27456980, PubMed:33845046). Interacts with LMBRD1; this interaction induces the translocation of ABCD4 from the ER to the lysosome membrane (PubMed:27456980, PubMed:28572511). Interacts with LMBRD1 and MMACHC; this interaction ensures the transport of cobalamin from the lysosome to the cytosol (PubMed:25535791).
Lysosomal membrane protein that transports cobalamin (Vitamin B12) from the lysosomal lumen to the cytosol in an ATP-dependent manner (PubMed:22922874, PubMed:33845046, PubMed:28572511, PubMed:31467407). Targeted by LMBRD1 lysosomal chaperone from the endoplasmic reticulum to the lysosomal membrane (PubMed:27456980). Then forms a complex with lysosomal chaperone LMBRD1 and cytosolic MMACHC to transport cobalamin across the lysosomal membrane (PubMed:25535791).
Originally proposed to be a peroxisomal protein (PubMed:9266848). Recent studies have suggested its localization to the endoplasmic reticulum and within the lysosome (PubMed:27456980).
Binds to the ATPase domain of HSP/HSC70 chaperones (PubMed:9873016). May interact with NWD1 (PubMed:24681825). Interacts with HSPA1A (via NBD), HSPA1B (via NBD) and HSPA8 (PubMed:24318877). May interact with DNJC9; the interaction seems to be histone-dependent (PubMed:33857403).
Co-chaperone for HSP70 and HSC70 chaperone proteins. Acts as a nucleotide-exchange factor (NEF) promoting the release of ADP from the HSP70 and HSC70 proteins thereby triggering client/substrate protein release (PubMed:24318877, PubMed:9873016).
Binds to the C-terminal propeptide of type I procollagen and enhances procollagen C-proteinase activity.
C-terminal processed part of PCPE (CT-PCPE) may have an metalloproteinase inhibitory activity.
C-terminally processed at multiple positions.
Adapter protein involved in endocytic machinery. Involved in the synaptic vesicle recycling. May facilitate clathrin-coated vesicle uncoating.
Interacts with the second C2 domain of synaptotagmins SYT1 and SYT2. Interacts with EPS15, EPS15R and ITSN1. Interacts indirectly with the AP-2 adapter complex. Interacts with TOR1A and COPS4; the interaction controls STON2 protein stability.
Neddylated; deneddylated via its interaction with the COP9 signalosome (CSN) complex through TOR1A and COPS4.
The Asn-Pro-Phe (NPF) motifs, which are found in proteins involved in the endocytic pathway, mediate the interaction with the EH domain of SYT1, SYT2, EPS15, EPS15R and ITSN1.
A highly mobile activation loop at the dimer-dimer interface is important for enzyme activity.
Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate, the main excitatory neurotransmitter in the brain (PubMed:30575854, PubMed:30239721, PubMed:30970188).
Homotetramer, dimer of dimers (PubMed:22538822, PubMed:26988803, PubMed:28526749, PubMed:29317493). The tetramers can assemble into rod-like oligomers (in vitro), but the physiological significance of this is not clear (By similarity). Interacts with RAF1 and MAP2K2 (PubMed:22538822). Interacts with ATCAY; the interaction is direct and may control GLS localization, negatively regulating its activity.
Isoform 1 and isoform 3 are activated by phosphate. Inhibited by BPTES. BPTES binds between subunits and favors dissociation of the tetramer into dimers (PubMed:22049910). Inhibited by 6-diazo-5-oxo-L-norleucine (DON) (PubMed:24451979). Enzyme activity is stimulated by phosphorylation (PubMed:22538822).
Isoform 1 and isoform 3 are detected in brain cortex. Isoform 3 is highly expressed in astrocytoma, ganglioglioma and ependymoma. Isoform 1 is highly expressed in brain and kidney, but not detected in liver. Isoform 3 is highly expressed in heart and pancreas, detected at lower levels in placenta, lung, pancreas and kidney, but is not detected in liver. Isoform 2 is expressed in cardiac and skeletal muscle.
Isoform 3 is predicted to be expressed at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Contrary to expectations, it has been shown to be well expressed, and the encoded protein is detected in mitochondria (PubMed:11015561, PubMed:17940881, PubMed:22228304).
Synthesized as a 74-kDa cytosolic precursor which is proteolytically processed by the mitochondrial-processing peptidase (MPP) via a 72-kDa intermediate to yield the mature mitochondrial 68- and 65-kDa subunits.
The C-terminal ANK repeats prevent the assembly of the supra-tetrameric filaments.
(Microbial infection) Acts as an endosomal entry receptor for ebolavirus.
(Microbial infection) Interacts with ebolavirus glycoprotein.
A cysteine-rich N-terminal domain and a C-terminal domain containing a di-leucine motif necessary for lysosomal targeting are critical for mobilization of cholesterol from lysosomes.
Interacts (via the second lumenal domain) with NPC2 (PubMed:18772377, PubMed:27238017, PubMed:27551080). Interacts with TMEM97 (PubMed:19583955). Interacts with TIM1 (PubMed:25855742). Interacts with SLC38A9; this interaction inhibits cholesterol-mediated mTORC1 activation via its sterol transport activity (PubMed:28336668).
Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment (PubMed:9211849, PubMed:9927649, PubMed:10821832, PubMed:18772377, PubMed:27238017, PubMed:12554680). Unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes is transferred by NPC2 to the cholesterol-binding pocket in the N-terminal domain of NPC1 (PubMed:9211849, PubMed:9927649, PubMed:18772377, PubMed:19563754, PubMed:27238017, PubMed:28784760). Cholesterol binds to NPC1 with the hydroxyl group buried in the binding pocket (PubMed:19563754). Binds oxysterol with higher affinity than cholesterol. May play a role in vesicular trafficking in glia, a process that may be crucial for maintaining the structural and functional integrity of nerve terminals (Probable). Inhibits cholesterol-mediated mTORC1 activation throught its interaction with SLC38A9 (PubMed:28336668).
Has over 600-fold higher inhibitory activity when phosphorylated, creating a molecular switch for regulating the phosphorylation status of PPP1CA substrates and smooth muscle contraction (By similarity). The main inhibitory site appears to be Thr-73.
Inhibitor of the PP1 regulatory subunit PPP1CA.
(Microbial infection) Acts as a receptor for Cytomegalovirus/HHV-5.
(Microbial infection) Acts as a receptor for Epstein-Barr virus/HHV-4.
(Microbial infection) Acts as a receptor for Mammalian reovirus.
(Microbial infection) ITGA5:ITGB1 interacts with SARS coronavirus-2/SARS-CoV-2 spike protein.
(Microbial infection) In case of HIV-1 infection, integrin ITGA5:ITGB1 binding to extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
(Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human echoviruses 1 and 8.
(Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human rotavirus.
(Microbial infection) Integrin ITGA2:ITGB1 interacts with human echoviruses 1 and 8 capsid proteins.
(Microbial infection) Integrin ITGA2:ITGB1 interacts with human rotavirus VP4 protein.
(Microbial infection) Integrin ITGA5:ITGB1 acts as a receptor for Human parvovirus B19.
(Microbial infection) Integrin ITGA5:ITGB1 interacts with HIV-1 Tat.
(Microbial infection) Integrin ITGA5:ITGB1 interacts with human parvovirus B19 capsid protein.
(Microbial infection) Interacts with CotH proteins expressed by fungi of the order mucorales, the causative agent of mucormycosis, which plays an important role in epithelial cell invasion by the fungi (PubMed:32487760). Integrin ITGA3:ITGB1 may act as a receptor for R.delemar CotH7 in alveolar epithelial cells, which may be an early step in pulmonary mucormycosis disease progression (PubMed:32487760).
(Microbial infection) Interacts with Epstein-Barr virus/HHV-4 gB protein.
(Microbial infection) Interacts with N.meningitidis serogroup B adhesin A (nadA).
(Microbial infection) Interacts with R.delemar CotH7 on the surface of alveolar epithelial cells.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 envelope glycoprotein B/gB.
(Microbial infection) Interacts with mammalian reovirus capsid proteins.
(Microbial infection) May serve as a receptor for adhesin A (nadA) of N.meningitidis.
Antibodies against integrin beta-1 ITGB1 protects epithelial cells from invasion by the fungus R.delemar, a causative agent of mucormycosis, and could thus potentially be used to treat mucormycosis disease (PubMed:32487760). Antibodies against the protein also protect a neutropenic mouse model against mucormycosis (PubMed:32487760).
Expressed in placenta (at protein level) (PubMed:33962943). Widely expressed, other isoforms are generally coexpressed with a more restricted distribution (PubMed:1551917, PubMed:7545396, PubMed:7681433).
Expressed in skin, liver, skeletal muscle, cardiac muscle, placenta, umbilical vein endothelial cells, neuroblastoma cells, lymphoma cells, hepatoma cells and astrocytoma cells.
Expressed specifically in striated muscle (skeletal and cardiac muscle).
Heterodimer of an alpha and a beta subunit (PubMed:33962943). Beta-1 associates with either alpha-1, alpha-2, alpha-3, alpha-4, alpha-5, alpha-6, alpha-7, alpha-8, alpha-9, alpha-10, alpha-11 or alpha-V. ITGA6:ITGB1 is found in a complex with CD9; interaction takes place in oocytes and is involved in sperm-egg fusion (By similarity). Interacts with seprase FAP (seprase); the interaction occurs at the cell surface of invadopodia membrane in a collagen-dependent manner. Binds LGALS3BP and NMRK2, when associated with alpha-7, but not with alpha-5. Interacts with FGR and HCK. Interacts (via the cytoplasmic region) with RAB25 (via the hypervariable C-terminal region). Interacts with RAB21. Interacts with KRT1 in the presence of RACK1 and SRC. Interacts with JAML; integrin alpha-4/beta-1 may regulate leukocyte to endothelial cells adhesion by controlling JAML homodimerization. Interacts with FLNA, FLNB and RANBP9. Interacts with MYO10. Interacts with DAB2. Interacts with FERMT2; the interaction is inhibited in presence of ITGB1BP1. Interacts with ITGB1BP1 (via C-terminal region); the interaction is a prerequisite for focal adhesion disassembly. Interacts with TLN1; the interaction is prevented by competitive binding of ITGB1BP1. Interacts with ACAP1; required for ITGB1 recycling. Interacts with ASAP3. Interacts with EMP2; the interaction may be direct or indirect and ITGB1 has a heterodimer form (By similarity). ITGA5:ITGB1 interacts with CCN3. ITGA4:ITGB1 is found in a ternary complex with CX3CR1 and CX3CL1 (PubMed:23125415). ITGA5:ITGB1 interacts with FBN1 (PubMed:12807887, PubMed:17158881). ITGA5:ITGB1 interacts with IL1B (PubMed:29030430). ITGA4:ITGB1 interacts with MDK; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation (PubMed:15466886). ITGA6:ITGB1 interacts with MDK; this interaction mediates MDK-induced neurite-outgrowth (PubMed:15466886). ITGA5:ITGB1 interacts with ACE2 (PubMed:33102950). Interacts with TMEM182 and LAMB1 (By similarity). Interacts with tensin TNS3; TNS3 also interacts with PEAK1, thus acting as an adapter molecule to bridge the association of PEAK1 with ITGB1 (PubMed:35687021). Interacts with tensin TNS4; the interaction displaces tensin TNS3 from the ITGB1 cytoplasmic tail and promotes ITGB1 stability (PubMed:17643115, PubMed:24814316).
Induced in alveolar epithelial cells during exposure to the fungus R.delemar, a causative agent of mucormycosis.
Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen. Integrins alpha-1/beta-1 and alpha-2/beta-2 recognize the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Integrins alpha-2/beta-1, alpha-3/beta-1, alpha-4/beta-1, alpha-5/beta-1, alpha-8/beta-1, alpha-10/beta-1, alpha-11/beta-1 and alpha-V/beta-1 are receptors for fibronectin. Alpha-4/beta-1 recognizes one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. Integrin alpha-5/beta-1 is a receptor for fibrinogen. Integrin alpha-1/beta-1, alpha-2/beta-1, alpha-6/beta-1 and alpha-7/beta-1 are receptors for lamimin. Integrin alpha-6/beta-1 (ITGA6:ITGB1) is present in oocytes and is involved in sperm-egg fusion (By similarity). Integrin alpha-4/beta-1 is a receptor for VCAM1. It recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-9/beta-1 is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. Integrin alpha-3/beta-1 is a receptor for epiligrin, thrombospondin and CSPG4. Alpha-3/beta-1 may mediate with LGALS3 the stimulation by CSPG4 of endothelial cells migration. Integrin alpha-V/beta-1 is a receptor for vitronectin. Beta-1 integrins recognize the sequence R-G-D in a wide array of ligands. When associated with alpha-7 integrin, regulates cell adhesion and laminin matrix deposition. Involved in promoting endothelial cell motility and angiogenesis. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process and the formation of mineralized bone nodules. May be involved in up-regulation of the activity of kinases such as PKC via binding to KRT1. Together with KRT1 and RACK1, serves as a platform for SRC activation or inactivation. Plays a mechanistic adhesive role during telophase, required for the successful completion of cytokinesis. Integrin alpha-3/beta-1 provides a docking site for FAP (seprase) at invadopodia plasma membranes in a collagen-dependent manner and hence may participate in the adhesion, formation of invadopodia and matrix degradation processes, promoting cell invasion. ITGA4:ITGB1 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling (PubMed:23125415, PubMed:24789099). ITGA4:ITGB1 and ITGA5:ITGB1 bind to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1 (PubMed:18635536, PubMed:25398877). ITGA5:ITGB1 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (PubMed:12807887, PubMed:17158881). ITGA5:ITGB1 acts as a receptor for fibronectin FN1 and mediates R-G-D-dependent cell adhesion to FN1 (PubMed:33962943). ITGA5:ITGB1 is a receptor for IL1B and binding is essential for IL1B signaling (PubMed:29030430). ITGA5:ITGB3 is a receptor for soluble CD40LG and is required for CD40/CD40LG signaling (PubMed:31331973). Plays an important role in myoblast differentiation and fusion during skeletal myogenesis (By similarity).
Interacts with ACE2 (PubMed:15276642). Interacts with alpha-7B in cardiomyocytes of adult heart and alpha-7A and alpha-7B in adult skeletal muscle (By similarity).
Interacts with the C-terminal region of FLNC.
Interferes with isoform 1 resulting in a dominant negative effect on cell adhesion and migration (in vitro).
Isoform 5 displaces isoform 1 in striated muscles.
Together with isoform 3, is expressed in muscle, kidney, liver, placenta, cervical epithelium, umbilical vein endothelial cells, fibroblast cells, embryonal kidney cells, platelets and several blood cell lines. Rather than isoform 3, is selectively expressed in peripheral T-cells.
Together with isoform 4, is expressed in muscle, kidney, liver, placenta, cervical epithelium, umbilical vein endothelial cells, fibroblast cells, embryonal kidney cells, platelets and several blood cell lines. Expressed in non-proliferating and differentiated prostate gland epithelial cells and in platelets, on the surface of erythroleukemia cells and in various hematopoietic cell lines.
ACVRIB is abundantly expressed in systemic sclerosis patient fibroblasts and production of collagen is also induced by activin-A/INHBA. This suggests that the activin/ACRV1B signaling mechanism is involved in systemic sclerosis.
Activin receptor type-2 (ACVR2A or ACVR2B) activates the type-1 receptor through phosphorylation of its regulatory GS domain.
Autophosphorylated. Phosphorylated by activin receptor type-2 (ACVR2A or ACVR2B) in response to activin-binding at serine and threonine residues in the GS domain. Phosphorylation of ACVR1B by activin receptor type-2 regulates association with SMAD7.
Expressed in many tissues, most strongly in kidney, pancreas, brain, lung, and liver.
Forms an activin receptor complex with activin receptor type-2 (ACVR2A or ACVR2B) (PubMed:8196624, PubMed:8622651, PubMed:9032295). Part of a complex consisting of MAGI2/ARIP1, ACVR2A, ACVR1B and SMAD3 (By similarity). Interacts with SMAD2 and SMAD3 (PubMed:9892009). Interacts with SMAD7 (PubMed:9892009, PubMed:12023024, PubMed:16720724). Interacts with FKBP1A (PubMed:16720724). Interacts with IGSF1 (PubMed:11266516). Interacts with CRIPTO (PubMed:11909953). Interacts with TDP2 (By similarity). Interacts with TSC22D1/TSC-22 (PubMed:21791611).
The GS domain is a 30-amino-acid sequence adjacent to the N-terminal boundary of the kinase domain and highly conserved in all other known type-1 receptors but not in type-2 receptors. The GS domain is the site of activation through phosphorylation by the II receptors.
Transmembrane serine/threonine kinase activin type-1 receptor forming an activin receptor complex with activin receptor type-2 (ACVR2A or ACVR2B). Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating a many physiological and pathological processes including neuronal differentiation and neuronal survival, hair follicle development and cycling, FSH production by the pituitary gland, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. Activin is also thought to have a paracrine or autocrine role in follicular development in the ovary. Within the receptor complex, type-2 receptors (ACVR2A and/or ACVR2B) act as a primary activin receptors whereas the type-1 receptors like ACVR1B act as downstream transducers of activin signals. Activin binds to type-2 receptor at the plasma membrane and activates its serine-threonine kinase. The activated receptor type-2 then phosphorylates and activates the type-1 receptor such as ACVR1B. Once activated, the type-1 receptor binds and phosphorylates the SMAD proteins SMAD2 and SMAD3, on serine residues of the C-terminal tail. Soon after their association with the activin receptor and subsequent phosphorylation, SMAD2 and SMAD3 are released into the cytoplasm where they interact with the common partner SMAD4. This SMAD complex translocates into the nucleus where it mediates activin-induced transcription. Inhibitory SMAD7, which is recruited to ACVR1B through FKBP1A, can prevent the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. Activin signal transduction is also antagonized by the binding to the receptor of inhibin-B via the IGSF1 inhibin coreceptor. ACVR1B also phosphorylates TDP2.
Ubiquitinated. Level of ubiquitination is regulated by the SMAD7-SMURF1 complex.
E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins (PubMed:20657603). May operate on tyrosine-phosphorylated SRC substrates (PubMed:22252131).
Exclusively expressed in testis and sperm, including spermatocytes, round and elongated spermatids, and Leydig cells.
The HYB domain forms a phosphotyrosine-binding pocket upon dimerization, and mediates as well the recognition of its flanking acidic amino acids.
Catalyzes intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein, resulting in the release of the fragment from the ER membrane into the cytoplasm. Required to generate lymphocyte cell surface (HLA-E) epitopes derived from MHC class I signal peptides (PubMed:11714810). May be necessary for the removal of the signal peptide that remains attached to the hepatitis C virus core protein after the initial proteolytic processing of the polyprotein (PubMed:12145199). Involved in the intramembrane cleavage of the integral membrane protein PSEN1 (PubMed:12077416, PubMed:11714810, PubMed:14741365). Cleaves the integral membrane protein XBP1 isoform 1 in a DERL1/RNF139-dependent manner (PubMed:25239945). May play a role in graft rejection (By similarity).
Monomer (PubMed:15385547, PubMed:15998642). Homodimer (PubMed:15385547, PubMed:15998642). Interacts with RNF139 (PubMed:19720873, PubMed:25239945). Interacts with DERL1 and XBP1 isoform 1 (PubMed:25239945).
The first transmembrane domain may act as a type I signal anchor (PubMed:12077416, PubMed:15385547). The PAL motif is required for normal active site conformation (By similarity).
Widely expressed with highest levels in kidney, liver, placenta, lung, leukocytes and small intestine and reduced expression in heart and skeletal muscle. Expressed abundantly in the CNS with highest levels in thalamus and medulla.
Adapter protein involved in neuronal nitric-oxide (NO) synthesis regulation via its association with nNOS/NOS1. The complex formed with NOS1 and synapsins is necessary for specific NO and synapsin functions at a presynaptic level. Mediates an indirect interaction between NOS1 and RASD1 leading to enhance the ability of NOS1 to activate RASD1. Competes with DLG4 for interaction with NOS1, possibly affecting NOS1 activity by regulating the interaction between NOS1 and DLG4 (By similarity). In kidney podocytes, plays a role in podosomes and filopodia formation through CDC42 activation (PubMed:33523862).
Expressed in kidney glomeruli podocytes.
Genetic variation in NOS1AP influences the electrocardiographic QT interval [MIM:610141]. The QT interval is defined as the time from the beginning of the Q wave to the end of the T wave, representing the duration of ventricular electrical activity. The QT interval, a measure of cardiac repolarization, is a genetically influenced quantitative trait with considerable medical relevance: both high and low values are associated with increased risk of cardiovascular morbidity and mortality.
Interacts with the PDZ domain of NOS1 or the second PDZ domain of DLG4 through its C-terminus. Interacts with RASD1 and SYN1, SYN2 and SYN3 via its PID domain. Forms a ternary complex with NOS1 and RASD1. Forms a ternary complex with NOS1 and SYN1.
Expressed in peripheral blood mononuclear cells (at protein level).
Induces disassembly of actin filaments in conjunction with ADF/cofilin family proteins (PubMed:15629458, PubMed:27557945, PubMed:29751004). Enhances cofilin-mediated actin severing (By similarity). Involved in cytokinesis. Involved in chemotactic cell migration by restricting lamellipodial membrane protrusions (PubMed:18494608). Involved in myocardium sarcomere organization. Required for cardiomyocyte growth and maintenance (By similarity). Involved in megakaryocyte maturation and platelet shedding. Required for the establishment of planar cell polarity (PCP) during follicular epithelium development and for cell shape changes during PCP; the function seems to implicate cooperation with CFL1 and/or DSTN/ADF. Involved in the generation/maintenance of cortical tension (By similarity). Involved in assembly and maintenance of epithelial apical cell junctions and plays a role in the organization of the perijunctional actomyosin belt (PubMed:25792565).
Forms homooligomers. Interacts with MFN2; may form heterooligomers. Interacts with CACNA2D2 (By similarity). Interacts with PHB1 and PHB2; recruits them to cardiolipin-enriched mitochondrial membranes and stabilizes them.
Hyperphosphorylated at Ser-17 in some patients with monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and Waldenstrom macroglobulinemia due to impaired dephosphorylation by PP2A.
Mitochondrial protein that probably regulates the biogenesis and the activity of mitochondria. Stimulates cardiolipin biosynthesis, binds cardiolipin-enriched membranes where it recruits and stabilizes some proteins including prohibitin and may therefore act in the organization of functional microdomains in mitochondrial membranes. Through regulation of the mitochondrial function may play a role into several biological processes including cell migration, cell proliferation, T-cell activation, calcium homeostasis and cellular response to stress. May play a role in calcium homeostasis through negative regulation of calcium efflux from mitochondria. Required for mitochondrial hyperfusion a pro-survival cellular response to stress which results in increased ATP production by mitochondria. May also regulate the organization of functional domains at the plasma membrane and play a role in T-cell activation through association with the T-cell receptor signaling complex and its regulation.
Paratarg-7/STOML2 is a frequent autoantigenic target in monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and Waldenstrom macroglobulinemia, 3 B-cell neoplasms associated with excessive secretion of a single monoclonal gammaglobulin (also named paraprotein) in the blood.
Ubiquitously expressed at low levels. Expressed in lymphoid tissues (at protein level).
Up-regulated in activated B- and T-cells and upon mitochondrial stress by chloramphenicol.
Adapter protein that binds to and probably organizes the subcellular localization of a variety of proteins. May link various receptors to the actin cytoskeleton and the dystrophin glycoprotein complex (By similarity). May participate in regulating the subcellular location of diacylglycerol kinase-zeta to ensure that diacylglycerol is rapidly inactivated following receptor activation.
Brain specific. In CNS, it is expressed in the perikaryon and proximal portion of the neuronal processes. Strong expression in the hippocampus, neuron-rich dendate granule cells, and pyramidal cell layers. Highly expressed in neurons of the cerebral cortex. Also expressed in the cerebellar cortex, deep cerebellar nuclei, thalamus, and basal ganglia. No expression in muscle cells.
Isoform 1, but not isoform 2, interacts with the dystrophin protein DMD and related proteins DTNA and DTNB. Interacts with DGKZ.
The PDZ domain binds to the last three or four amino acids of DGKZ. The association with dystrophin or related proteins probably leaves the PDZ domain available to recruit proteins to the membrane.
Heterodimer of a catalytic subunit PIK3CA and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3) (PubMed:26593112). Interacts with IRS1 in nuclear extracts (By similarity). Interacts with RUFY3 (By similarity). Interacts with RASD2 (By similarity). Interacts with APPL1. Interacts with HRAS and KRAS (By similarity). Interaction with HRAS/KRAS is required for PI3K pathway signaling and cell proliferation stimulated by EGF and FGF2 (By similarity). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467).
PIK3CA mutations are involved in various type of cancer. Most of the cancer-associated mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS/KRAS. Interaction with HRAS/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis.
Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396, PubMed:23936502, PubMed:28676499). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396, PubMed:28676499). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. In addition to its lipid kinase activity, it displays a serine-protein kinase activity that results in the autophosphorylation of the p85alpha regulatory subunit as well as phosphorylation of other proteins such as 4EBP1, H-Ras, the IL-3 beta c receptor and possibly others (PubMed:23936502, PubMed:28676499). Plays a role in the positive regulation of phagocytosis and pinocytosis (By similarity).
The PI3K-ABD domain and the PI3K-RBD domain interact with the PI3K/PI4K kinase domain. The C2 PI3K-type domain may facilitate the recruitment to the plasma membrane. The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1, and the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1.
The avian sarcoma virus 16 genome encodes an oncogene derived from PIK3CA.
The disease may be caused by variants affecting the gene represented in this entry. The tissue distribution of the clinical manifestations in CLAPO seems to follow a pattern of somatic mosaicism.
The disease may be caused by variants affecting the gene represented in this entry. The tissue distribution of the clinical manifestations in MADAC seems to follow a pattern of somatic mosaicism.
(Microbial infection) Binds B.burgdorferi OspC, the interaction is inhibited by complement factor C2 (PubMed:28873507). This binding may inhibit the complement cascade and allow the bacteria to survive in the host bloodstream (Probable).
Circulates in blood as a disulfide-linked trimer of alpha, beta and gamma chains. C4b interacts with CR1 (via Sushi 1 and Sushi 2 domains).
Circulates in blood as a disulfide-linked trimer of an alpha, beta and gamma chain.
Complement component C4 is expressed at highest levels in the liver, at moderate levels in the adrenal cortex, adrenal medulla, thyroid gland, and the kidney, and at lowest levels in the heart, ovary, small intestine, thymus, pancreas and spleen. The extra-hepatic sites of expression may be important for the local protection and inflammatory response.
Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Interindividual copy-number variation (CNV) of complement component C4 and associated polymorphisms result in different susceptibilities to SLE. The risk of SLE susceptibility has been shown to be significantly increased among subjects with only two copies of total C4. A high copy number is a protective factor against SLE.
During cDNA synthesis, the 5' end has been inverted (PubMed:3838531).
N- and O-glycosylated. O-glycosylated with a core 1 or possibly core 8 glycan.
Non-enzymatic component of C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.
Non-enzymatic component of the C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.
Prior to secretion, the single-chain precursor is enzymatically cleaved to yield non-identical chains alpha, beta and gamma. During activation, the alpha chain is cleaved by C1 into C4a and C4b, and C4b stays linked to the beta and gamma chains. Further degradation of C4b by C1 into the inactive fragments C4c and C4d blocks the generation of C3 convertase. The proteolytic cleavages often are incomplete so that many structural forms can be found in plasma.
The complement component C4 is the most polymorphic protein of the complement system. It is the product of 2 closely linked and highly homologous genes, C4A and C4B. Once polymorphic variation is discounted, the 2 isotypes differ by only 4 amino acids at positions 1120-1125: PCPVLD for C4A and LSPVIH for C4B. The 2 isotypes bear several antigenic determinants defining Chido/Rodgers blood group system [MIM:614374]. Rodgers determinants are generally associated with C4A allotypes, and Chido with C4B. Variations at these loci involve not only nucleotide polymorphisms, but also gene number and gene size. Some individuals may lack either C4A, or C4B gene. Partial deficiency of C4A or C4B is the most commonly inherited immune deficiency known in humans with a combined frequency over 31% in the normal Caucasian population (PubMed:11367523). C4A6 allotype is deficient in hemolytic activity. Allotype C4A13 is infrequent. Common copy-number variants of C4A and C4B affecting expression of complement component C4 in the brain have been associated with schizophrenia risk (PubMed:26814963).
The complement component C4 is the most polymorphic protein of the complement system. It is the product of 2 closely linked and highly homologous genes, C4A and C4B. Once polymorphic variation is discounted, the 2 isotypes differ by only 4 amino acids at positions 1120-1125: PCPVLD for C4A and LSPVIH for C4B. The 2 isotypes bear several antigenic determinants defining Chido/Rodgers blood group system [MIM:614374]. Rodgers determinants are generally associated with C4A allotypes, and Chido with C4B. Variations at these loci involve not only nucleotide polymorphisms, but also gene number and gene size. The second copy of C4B gene present in some individuals has been called C4B_2 by the HUGO Gene Nomenclature Committee (HGNC). Some individuals may lack either C4A, or C4B gene. Partial deficiency of C4A or C4B is the most commonly inherited immune deficiency known in humans with a combined frequency over 31% in the normal Caucasian population (PubMed:11367523). Common copy-number variants of C4A and C4B affecting expression of complement component C4 in the brain have been associated with schizophrenia risk (PubMed:26814963).
Phosphorylated on a cytoplasmic Ser residue.
Expressed in placenta, prostate, hippocampus and brain medulla. Also expressed in brain tumor, salivary gland tumor, head and neck tumor.
Acyl-CoA binding protein which acts as the peroxisome receptor for pexophagy but is dispensable for aggrephagy and nonselective autophagy. Binds medium- and long-chain acyl-CoA esters.
Belongs to the 6-phosphogluconate dehydrogenase family.
Catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate and CO(2), with concomitant reduction of NADP to NADPH.
According to PubMed:10464311, highest levels of expression in uterus and heart, intermediate levels in skeletal muscle and intermediate to low levels in pancreas, kidney and placenta. According to PubMed:10486209, also found in brain, colon, lung, small intestine, stomach, testis, salivary glands, thyroid glands and prostate. Very low levels in peripheral blood lymphocytes, fetal brain and fetal liver.
Heterodimer of an alpha and a beta subunit. Alpha-11 associates with beta-1. Interacts with RAB21.
Integrin alpha-11/beta-1 is a receptor for collagen.
Strongly up-regulated in differentiating fetal muscle cells (in vitro).
Expressed in fetal and adult testis, in germ cells but not somatic cells.
May play a regulatory role in spermatogenesis.
Expressed in myocardium (at protein level).
Has calcium-dependent phospholipase and lysophospholipase activities with a potential role in membrane lipid remodeling and biosynthesis of lipid mediators (PubMed:29158256). Preferentially hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) (PubMed:29158256). Selectively hydrolyzes sn-2 arachidonoyl group from membrane phospholipids, providing the precursor for eicosanoid biosynthesis (PubMed:29158256). In myocardial mitochondria, plays a major role in arachidonate release that is metabolically channeled to the formation of cardioprotective eicosanoids, epoxyeicosatrienoates (EETs) (PubMed:29158256).
(Microbial infection) Isoform 2 interacts with HHV-1 ICP27 protein.
Activated by phosphorylation on Ser-51 and Ser-555.
Isoform 2 is predominantly expressed in the testis but is also present at lower levels in heart, ovary, small intestine, liver, kidney, pancreas and skeletal muscle. Isoform 1 is only seen in the testis, at lower levels than isoform 2. Highly expressed in different erythroid and lymphoid cell lines, with isoform 2 being far more abundant than isoform 1.
Monomer. Isoform 2 is found in a multisubunit complex containing seven proteins, named toposome, which separates entangled circular chromatin DNA during chromosome segregation. Isoform 2 interacts with DNAJC8 and AHSA1/AHA1 and this mediates formation of a complex with the Hsp70 /Hsp90 machinery. Isoform 1 is found in a complex with: DHX9, MOV10, MATR3, HNRNPU, NCL, DDX21, HSD17B4, PABPC1, HNRNPM, IGF2BP1, SYNCRIP, RPL3, VIM, YBX1, NPM1, HNRNPA2B1, HNRNPC, RPLP0, RPL7A and RALY. Isoform 2 binds to IGF2BP1, SYNCRIP, HNRNPA2B1 and HNRNPC. Isoform 1 and isoform 2 interact with SAFB which inhibits its activity. Isoform 2 interacts with SAFB2 which inhibits its activity.
Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing. Plays a central role in the regulatory network for splicing, controlling the intranuclear distribution of splicing factors in interphase cells and the reorganization of nuclear speckles during mitosis. Can influence additional steps of mRNA maturation, as well as other cellular activities, such as chromatin reorganization in somatic and sperm cells and cell cycle progression. Isoform 2 phosphorylates SFRS2, ZRSR2, LBR and PRM1. Isoform 2 phosphorylates SRSF1 using a directional (C-terminal to N-terminal) and a dual-track mechanism incorporating both processive phosphorylation (in which the kinase stays attached to the substrate after each round of phosphorylation) and distributive phosphorylation steps (in which the kinase and substrate dissociate after each phosphorylation event). The RS domain of SRSF1 binds first to a docking groove in the large lobe of the kinase domain of SRPK1. This induces certain structural changes in SRPK1 and/or RRM2 domain of SRSF1, allowing RRM2 to bind the kinase and initiate phosphorylation. The cycles continue for several phosphorylation steps in a processive manner (steps 1-8) until the last few phosphorylation steps (approximately steps 9-12). During that time, a mechanical stress induces the unfolding of the beta-4 motif in RRM2, which then docks at the docking groove of SRPK1. This also signals RRM2 to begin to dissociate, which facilitates SRSF1 dissociation after phosphorylation is completed. Isoform 2 can mediate hepatitis B virus (HBV) core protein phosphorylation. It plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles. Isoform 1 and isoform 2 can induce splicing of exon 10 in MAPT/TAU. The ratio of isoform 1/isoform 2 plays a decisive role in determining cell fate in K-562 leukaemic cell line: isoform 2 favors proliferation where as isoform 1 favors differentiation.
Activated by phosphorylation on Thr-806. Catalytically active only when complexed with MAP3K5, with MAP3K5 supporting the stability and the active configuration of MAP3K6 and MAP3K6 activating MAP3K5 by direct phosphorylation.
Binds both upstream activators and downstream substrates in multimolecular complexes.
Component of a protein kinase signal transduction cascade. Activates the JNK, but not ERK or p38 kinase pathways.
Exhibits acyl-CoA:lysocardiolipin acyltransferase (ALCAT) activity; catalyzes the reacylation of lyso-cardiolipin to cardiolipin (CL), a key step in CL remodeling (By similarity). Recognizes both monolysocardiolipin and dilysocardiolipin as substrates with a preference for linoleoyl-CoA and oleoyl-CoA as acyl donors (By similarity). Also exhibits 1-acyl-sn-glycerol-3-phosphate acyltransferase activity (AGPAT) activity; converts 1-acyl-sn-glycerol-3- phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3- phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone (PubMed:16620771). Possesses both lysophosphatidylinositol acyltransferase (LPIAT) and lysophosphatidylglycerol acyltransferase (LPGAT) activities (PubMed:19075029). Required for establishment of the hematopoietic and endothelial lineages (By similarity).
Expressed at higher level in heart, kidney and pancreas than in brain, spleen, liver, lung, small intestine and placenta.
PubMed:16620771 does not detect acyl-CoA:lysocardiolipin acyltransferase activity.
Plays an important role in centriole assembly and/or stability and ciliogenesis. Involved in early steps of centriole duplication, as well as in the later steps of centriole length control. Acts in concert with POC1B to ensure centriole integrity and proper mitotic spindle formation.
The disease is caused by variants affecting the gene represented in this entry. Cells derived from affected individuals have abnormal mitotic mechanics with multipolar spindles, in addition to clearly impaired ciliogenesis.
(Microbial infection) Interacts (via C-terminus) with HRSV membrane protein SH; this interaction is direct.
BCAP31 is deleted in the chromosome Xq28 deletion syndrome which involves BCAP31 and the and the promoter region of ABCD1.
Functions as a chaperone protein (PubMed:9396746, PubMed:18287538). Is one of the most abundant endoplasmic reticulum (ER) proteins (PubMed:9396746, PubMed:18287538). Plays a role in the export of secreted proteins in the ER, the recognition of abnormally folded protein and their targeting to the ER associated-degradation (ERAD) (PubMed:9396746, PubMed:18287538). Also serves as a cargo receptor for the export of transmembrane proteins (By similarity). Plays a role in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) by stimulating the translocation of NDUFS4 and NDUFB11 from the cytosol to the mitochondria via interaction with TOMM40 (PubMed:31206022). In response to ER stress, delocalizes from the ER-mitochondria contact sites and binds BCL2 (PubMed:31206022). May be involved in CASP8-mediated apoptosis (PubMed:10958671).
Homodimer and heterodimer with BCAP29 (PubMed:9334338, PubMed:23967155). Binds CASP8 (isoform 9) as a complex containing BCAP31, BCAP29, BCL2 and/or BCL2L1 (PubMed:9334338, PubMed:11917123, PubMed:31206022). Forms a complex (via C-terminus) with TOMM40 which mediates the translocation of components of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) from the cytosol to the mitochondria; within the complex BCAP31 interacts directly with unprocessed and processed NDUFS4 and NDUFB11 (PubMed:31206022). Interacts with VDAC1 (PubMed:31206022). Interacts with VAMP3, VAMP1 and membrane IgD immunoglobulins (By similarity). Interacts with HACD2 (PubMed:15024066). Interacts with DNM1L; may form part of a larger protein complex at the endoplasmic reticulum-mitochondrial interface during mitochondrial fission (PubMed:24196833).
Ubiquitous. Highly expressed in neurons and discrete endocrine cells.
Interacts with TBCB. Interacts with CUL3. Part of a complex that contains CUL3, RBX1 and GAN. Interacts (via BTB domain) with UBA1. Interacts (via Kelch domains) with MAP1B (via C-terminus) and MAP1S (via C-terminus).
Probable cytoskeletal component that directly or indirectly plays an important role in neurofilament architecture. May act as a substrate-specific adapter of an E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Controls degradation of TBCB. Controls degradation of MAP1B and MAP1S, and is critical for neuronal maintenance and survival.
Ubiquitinated by E3 ubiquitin ligase complex formed by CUL3 and RBX1 and probably targeted for proteasome-independent degradation.
Catalyzes the oxidative decarboxylation of (S)-malate in the presence of NADP(+) and divalent metal ions, and decarboxylation of oxaloacetate.
Divalent metal cations. Prefers magnesium or manganese.
Expressed in all tissues tested including liver, placenta and white adipose tissue.
DMRT3 is a marker for a subset of spinal cord neurons (dI6).
Probable transcription factor that plays a role in configuring the spinal circuits controlling stride in vertebrates. Involved in neuronal specification within specific subdivision of spinal cord neurons and in the development of a coordinated locomotor network controlling limb movements. May regulate transcription during sexual development (By similarity).
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins.
Belongs to the G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRA2C sub-subfamily.
The Del322-325 variant has a significant loss of function. It is approximately 10 times more frequent in African-Americans compared with Caucasians (allele frequencies 0.381 versus 0.040).
A soluble form (sIL1R2) can also be produced by proteolytic cleavage at the cell surface (shedding) involving a metalloproteinase; hovever, several sIL1R2 forms ranging from 45 and 60 kDa are reported.
Associates with IL1RAP to form a non-signaling interleukin-1 receptor complex.
Non-signaling receptor for IL1A, IL1B and IL1RN. Reduces IL1B activities. Serves as a decoy receptor by competitive binding to IL1B and preventing its binding to IL1R1. Also modulates cellular response through non-signaling association with IL1RAP after binding to IL1B. IL1R2 (membrane and secreted forms) preferentially binds IL1B and poorly IL1A and IL1RN. The secreted IL1R2 recruits secreted IL1RAP with high affinity; this complex formation may be the dominant mechanism for neutralization of IL1B by secreted/soluble receptors.
(Microbial infection) Seems to enhance replication of some viruses, including yellow fever virus, in response to type I interferon.
Catalyzes the transfer of one adenosine molecule from an ATP to an mRNA poly(A) tail bearing a 3'-OH terminal group and enhances mRNA stability and gene expression (PubMed:32009146, PubMed:28931820, PubMed:34048638). Can also elongate RNA oligos ending with uridine molecule, provided that the sequence is adenosine-rich (PubMed:34048638). Mainly targets mRNAs encoding endoplasmic reticulum-targeted protein (PubMed:28931820).
Interacts with BCCIP and PABPC1; the interaction has no effect on TENT5C poly(A) polymerase function (PubMed:28931820). Interacts with PLK4; this interaction leads to the TENT5C recruitment into the centrosome (PubMed:32433990).
Protein kinase that phosphorylates human TP53 at Ser-9, and thus induces TP53 repression of BIRC5 promoter (By similarity). May act as a corepressor of transcription factors (Potential).
DNA-binding factor that regulates the expression of a subset of genes and plays a key role in tangential, radial, and lateral expansion of the brain neocortex. Regulates neural stem cells proliferation and the production of intermediate neural progenitors and basal radial glial cells affecting the process of cerebral cortex gyrification. May control the proliferation rate of cells by regulating their progression through key cell-cycle transition points (By similarity).
Expression is detected in the ventricular zone and neuronal layers of the developing cerebral cortex at 12, 18 and 21 gestation weeks. Differences in regional expression seem to correlate with the process of gyrification of the cortex. Highly expressed in germinal layers of the precentral and parahippocampal gyri, that exhibit little radial expansion and folding, and weakly expressed in germinal layers of the occipital and temporal lobes, that undergo greater expansion and folding.
Interacts with TMF1; may regulate TRNP1 proteasomal degradation.
Expressed in the brain, in oligodendrocytes. Strongly expressed in oligodendrogliomas, while expression is weak to moderate in astrocytomas. Expression in glioblastomas is highly variable.
Promotes formation and maturation of oligodendrocytes, especially within the brain. Cooperates with OLIG2 to establish the pMN domain of the embryonic neural tube (By similarity).
Found in adult stomach, kidney and thyroid gland, and in fetal kidney and liver.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation. Sulfonates p-nitrophenol, a small phenolic compond. Does not sulfonate steroids, dopamine, acetaminophen, or alpha-naphthol (PubMed:9852044, PubMed:10783263, PubMed:10481272). Catalyzes the sulfonation of the carcinogenic N-Hydroxy-2-acetylaminofluorene leading to highly reactive intermediates capable of forming DNA adducts, potentially resulting in mutagenesis (PubMed:9852044).
E3 ubiquitin-protein ligase which promotes polyubiquitination and degradation by the proteasome pathway of ZIC2.
The RING-type zinc finger domain mediates polyubiquitination of the interacting protein.
Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide (By similarity). Does not exhibit calcium-activated chloride channel (CaCC) activity (PubMed:22178883). Can inhibit the activity of ANO1 (PubMed:20056604, PubMed:22946059).
Meiosis-specific telomere-associated protein involved in meiotic telomere attachment to the nucleus inner membrane, a crucial step for homologous pairing and synapsis. Component of the MAJIN-TERB1-TERB2 complex, which promotes telomere cap exchange by mediating attachment of telomeric DNA to the inner nuclear membrane and replacement of the protective cap of telomeric chromosomes: in early meiosis, the MAJIN-TERB1-TERB2 complex associates with telomeric DNA and the shelterin/telosome complex. During prophase, the complex matures and promotes release of the shelterin/telosome complex from telomeric DNA. In the complex, MAJIN acts as the anchoring subunit to the nucleus inner membrane. MAJIN shows DNA-binding activity, possibly for the stabilization of telomere attachment on the nucleus inner membrane.
Adapter protein containing an immunoreceptor tyrosine-based activation motif (ITAM) that transduces activation signals from various immunoreceptors. As a component of the high-affinity immunoglobulin E (IgE) receptor, mediates allergic inflammatory signaling in mast cells. As a constitutive component of interleukin-3 receptor complex, selectively mediates interleukin 4/IL4 production by basophils, priming T-cells toward effector T-helper 2 subset. Associates with pattern recognition receptors CLEC4D and CLEC4E to form a functional signaling complex in myeloid cells. Binding of mycobacterial trehalose 6,6'-dimycolate (TDM) to this receptor complex leads to phosphorylation of ITAM, triggering activation of SYK, CARD9 and NF-kappa-B, consequently driving maturation of antigen-presenting cells and shaping antigen-specific priming of T-cells toward effector T-helper 1 and T-helper 17 cell subtypes. May function cooperatively with other activating receptors. Functionally linked to integrin beta-2/ITGB2-mediated neutrophil activation. Also involved in integrin alpha-2/ITGA2-mediated platelet activation.
IgE Fc receptor is a tetramer of an alpha chain, a beta chain, and two disulfide-linked gamma chains. Associates with FCGR1A; forms a functional signaling complex (PubMed:8611682). The signaling subunit of immunoglobulin gamma (IgG) Fc receptor complex. As a homodimer or a heterodimer of CD247 and FCER1G, associates with the ligand binding subunit FCGR3A to form a functional receptor complex (PubMed:28652325) (By similarity). Associated with CLEC6A (By similarity). Interacts with CLEC4E (PubMed:18776906). Interacts (via ITAM domain) with SYK (via SH2 domains); activates SYK, enabling integrin-mediated activation of neutrophils and macrophages (By similarity). Interacts with CSF2RB and recruits SYK in response to IL3 stimulation; this interaction is direct (By similarity). Interacts with CD300LH; the interaction may be indirect (By similarity). Interacts with CD300LD (By similarity). Interacts with TARM1 (PubMed:26311901).
Forms a heterodimer with RRAGA, in a sequence-independent manner, and RRAGB (PubMed:11073942, PubMed:14660641, PubMed:32868926). Heterodimerization stabilizes proteins of the heterodimer (PubMed:11073942). The GDP-bound form of RRAGC (in complex with the GTP-bound form of RRAGA or RRAGB), interacts with RPTOR, thereby promoting recruitment of mTORC1 to the lysosomes (PubMed:18497260, PubMed:31601764, PubMed:31601708). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913, PubMed:32868926). Interacts with NOL8 (PubMed:14660641). Interacts with SH3BP4; the interaction with this negative regulator is most probably direct, preferentially occurs with the inactive GDP-bound form of RRAGB, is negatively regulated by amino acids and prevents interaction with RPTOR (PubMed:22575674). The Rag heterodimer interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906, PubMed:32868926). Interacts with SESN1, SESN2 and SESN3 (PubMed:25259925). Interacts with PIP4P1 (By similarity). The Rag heterodimer interacts with the Ragulator complex (PubMed:32868926). The GDP-bound form interacts with TFEB (PubMed:32612235, PubMed:36697823). The GDP-bound form interacts with TFE3 (By similarity). The Rag heterodimer interacts with the Ragulator complex (PubMed:32868926).
Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade (PubMed:20381137, PubMed:24095279, PubMed:27234373, PubMed:31601764, PubMed:31601708, PubMed:32612235, PubMed:36697823). Forms heterodimeric Rag complexes with RagA/RRAGA or RagB/RRAGB and cycles between an inactive GTP-bound and an active GDP-bound form: RagC/RRAGC is in its active form when GDP-bound RagC/RRAGC forms a complex with GTP-bound RagA/RRAGA (or RagB/RRAGB) and in an inactive form when GTP-bound RagC/RRAGC heterodimerizes with GDP-bound RagA/RRAGA (or RagB/RRAGB) (PubMed:24095279, PubMed:32868926, PubMed:31601764, PubMed:31601708). In its GDP-bound active form, promotes the recruitment of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB (PubMed:20381137, PubMed:24095279, PubMed:27234373, PubMed:32612235, PubMed:32612235, PubMed:36697823). This is a crucial step in the activation of the MTOR signaling cascade by amino acids (PubMed:20381137, PubMed:24095279, PubMed:27234373). Also plays a central role in the non-canonical mTORC1 complex, which acts independently of RHEB and specifically mediates phosphorylation of MiT/TFE factors TFEB and TFE3: GDP-bound RagC/RRAGC mediates recruitment of MiT/TFE factors TFEB and TFE3 (PubMed:32612235, PubMed:36697823).
Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade.
RRAGC mutations have been found in a patient with idiopathic dilated cardiomyopathy with ventricular dilation and systolic dysfunction, bilateral cataracts, and mild facial dysmorphisms.
The activation of RagC/RRAGC is mediated by a GTPase activating protein (GAP) (PubMed:24095279). In high-amino acid conditions, activated by GTPase activating protein FLCN that stimulates RRAGC GTPase activity to turn it into its active GDP-bound form (PubMed:24095279). In response to amino acid depletion, the GATOR1 complex inactivates RagC/RRAGC by securing the GTP-bound inactive form (PubMed:35338845).
Interacts with the microtubules. Part of a low affinity complex that associates with, but is distinct from, the postsynaptic density. Interacts with SNTB2.
Microtubule-associated protein essential for correct brain development (PubMed:30449657). Appears to link the dystrophin/utrophin network with microtubule filaments via the syntrophins. Phosphorylation of DMD or UTRN may modulate their affinities for associated proteins (By similarity).
Accumulates in a hypoacetylated/phosphorylated form in response to cisplatin treatment.
Acetylation on Lys-52 by KAT5/TIP60 promotes its proteasomal degradation. This effect is counterbalanced by HDAC6, which positively controls SRSF2 protein level by deacetylating it and preventing its proteasomal degradation.
Extensively phosphorylated on serine residues in the RS domain. Phosphorylated by SRPK2 and this causes its redistribution from the nuclear speckle to nucleoplasm and controls cell fate decision in response to cisplatin treatment. KAT5/TIP60 inhibits its phosphorylation by preventing SRPK2 nuclear translocation.
Interacts with BRDT (By similarity). In vitro, self-associates and binds SRSF1/SFRS1 (ASF/SF2), SNRNP70 and U2AF1 but not U2AF2. Binds SREK1/SFRS12. Interacts with CCNL1 and CCNL2. Interacts with SCAF11. Interacts with ZRSR2/U2AF1-RS2. Interacts with CCDC55 (via C-terminus).
Necessary for the splicing of pre-mRNA. It is required for formation of the earliest ATP-dependent splicing complex and interacts with spliceosomal components bound to both the 5'- and 3'-splice sites during spliceosome assembly. It also is required for ATP-dependent interactions of both U1 and U2 snRNPs with pre-mRNA. Interacts with other spliceosomal components, via the RS domains, to form a bridge between the 5'- and 3'-splice site binding components, U1 snRNP and U2AF. Binds to purine-rich RNA sequences, either 5'-AGSAGAGTA-3' (S=C or G) or 5'-GTTCGAGTA-3'. Can bind to beta-globin mRNA and commit it to the splicing pathway. The phosphorylated form (by SRPK2) is required for cellular apoptosis in response to cisplatin treatment.
By UV irradiation. By ATF3 in response to UV-stress.
Expressed predominantly in liver, pancreas and placenta. Not detected in heart or brain. Highly expressed in a number of tumors, especially esophageal tumors, in anaplastic thyroid carcinomas, adrenocortical carcinomas, and in non-small-cell lung cancer lines.
Interacts (when monoubiquitinated at Lys-15 and Lys-24) with PCNA. Interacts with isoform 2/p33ING1b of ING1. Interacts with BRCA1.
Monoubiquitinated at Lys-15 and Lys-24 during normal S phase, promoting its association with PCNA. Also diubiquitinated at these 2 sites. Following DNA damage, monoubiquitin chains at Lys-15 and Lys-24 are probably extended, leading to disrupt the interaction with PCNA. Polyubiquitinated by the APC/C complex at the mitotic exit, leading to its degradation by the proteasome.
Overexpression in adrenocortical neoplasms (ACC), may promote growth and invasion in adrenal cancer.
PCNA-binding protein that acts as a regulator of DNA repair during DNA replication. Following DNA damage, the interaction with PCNA is disrupted, facilitating the interaction between monoubiquitinated PCNA and the translesion DNA synthesis DNA polymerase eta (POLH) at stalled replisomes, facilitating the bypass of replication-fork-blocking lesions. Also acts as a regulator of centrosome number.
Present only during S and G2 phases of the cell cycle. Peaks at the G2/M phase of the cell cycle and drops rapidly at mitotic exit in an APC/C-dependent manner (at protein level).
The D-box (destruction box) mediates the interaction with APC/C proteins, and acts as a recognition signal for degradation via the ubiquitin-proteasome pathway.
The PIP-box mediates the interaction with PCNA (PubMed:21628590, PubMed:23000965).
The initiation motif is required for efficient chain initiation by the APC/C complex E2 ligase UBE2C. It determines the rate of substrate's degradation without affecting its affinity for the APC/C, a mechanism used by the APC/C to control the timing of substrate proteolysis during the cell cycle (PubMed:21700221).
Belongs to the type IB topoisomerase family.
Divalent metal ions (calcium or magnesium).
Releases the supercoiling and torsional tension of DNA introduced during duplication of mitochondrial DNA by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then rotates around the intact phosphodiester bond on the opposing strand, thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity).
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at the specific target site 5'-[CT]CCTTp site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone.
Ubiquitous; highest in skeletal muscle, heart, brain and fetal liver.
A serine-rich region promotes activation of the serum response element (SRE).
Contains a central domain (substrate domain) containing multiple potential SH2-binding sites and a C-terminal domain containing a divergent helix-loop-helix (HLH) motif. The SH2-binding sites putatively bind CRK, NCK and ABL1 SH2 domains. The HLH motif is absolutely required for the induction of pseudohyphal growth in yeast and mediates heterodimerization with NEDD9 (By similarity).
Docking protein which plays a central coordinating role for tyrosine kinase-based signaling related to cell adhesion (PubMed:12832404, PubMed:12432078). Implicated in induction of cell migration and cell branching (PubMed:12432078, PubMed:12832404, PubMed:17038317). Involved in the BCAR3-mediated inhibition of TGFB signaling (By similarity).
Expressed in B-cells (at protein level) (PubMed:9020138). Widely expressed with an abundant expression in the testis (PubMed:10639512). Low level of expression seen in the liver, thymus, and peripheral blood leukocytes (PubMed:10639512).
Forms complexes in vivo with PTK2/FAK1, adapter protein CRKL and LYN kinase (PubMed:9020138). Heterodimerizes with NEDD9 (PubMed:10502414). Component of a complex comprised of SH2D3C, BCAR1/CAS, and CRK (PubMed:12432078). Within the complex, interacts with SH2D3C (via C-terminus), and CRK (PubMed:12432078, PubMed:17174122). Part of a complex comprised of PTPRA, BCAR1, BCAR3 (via SH2 domain) and SRC; the formation of the complex is dependent on intergrin mediated-tyrosine phosphorylation of PTPRA (PubMed:22801373). Interacts with BCAR3 (via Ras-GEF domain); the interaction regulates adhesion-dependent serine phosphorylation (PubMed:22081014). Interacts with SMAD2 and SMAD3 (By similarity). Interacts with NPHP1 (By similarity). Interacts with PTK2B/PYK2 (PubMed:9020138, PubMed:19086031). Interacts (via C-terminus) with SH2D3C/CHAT isoform 2 (via C-terminus) (PubMed:17174122, PubMed:22081014). Interacts with activated CSPG4. Interacts with BMX, INPPL1/SHIP2 and PEAK1. Part of a collagen-stimulated complex involved in cell migration made of CDC42, CRK, TNK2 and BCAR1/p130cas. Interacts with TNK2 via SH3 domains. Interacts (when tyrosine-phosphorylated) with tensin TNS1; the interaction is increased by phosphorylation of TNS1 (PubMed:20798394).
PTK2/FAK1 activation mediates phosphorylation at the YDYVHL motif; phosphorylation is most likely catalyzed by SRC family members. SRC-family kinases are recruited to the phosphorylated sites and can phosphorylate other tyrosine residues. Tyrosine phosphorylation is triggered by integrin-mediated adhesion of cells to the extracellular matrix.
Phosphorylated by SRC kinase in a EDN1- and PTK2B-mediated manner; phosphorylation strengthens its interaction with BCAR3 as part of the PTK2B/BCAR1/BCAR3/RAP1 signaling pathway.
The SH3 domain is necessary for the localization of the protein to focal adhesions and interacts with one proline-rich region of PTK2/FAK11.
Belongs to the ALG10 glucosyltransferase family.
Highly expressed in heart, placenta, liver, kidney and pancreas. Weakly expressed in lung, skeletal muscle and brain.
Putative alpha-1,2-glucosyltransferase, which adds the third glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation. Transfers glucose from dolichyl phosphate glucose (Dol-P-Glc) onto the lipid-linked oligosaccharide Glc(2)Man(9)GlcNAc(2)-PP-Dol (By similarity). When coupled to KCNH2 may reduce KCNH2 sensitivity to classic proarrhythmic drug blockade, possibly by mediating glycosylation of KCNH2 (PubMed:14525949). Has a role in maintenance of cochlear outer hair cell function (By similarity).
GTPase-activating protein for p21-rac. Insufficient expression of beta-2 chimaerin is expected to lead to higher Rac activity and could therefore play a role in the progression from low-grade to high-grade tumors.
Highest levels in the brain and pancreas. Also expressed in the heart, placenta, and weakly in the kidney and liver. Expression is much reduced in the malignant gliomas, compared to normal brain or low-grade astrocytomas.
In the inactive state, the N terminus protrudes into the active site of the Rho-GAP domain, sterically blocking Rac binding. Phospholipid binding to the Phorbol-ester/DAG-type zinc-finger/C1 domain triggers the cooperative dissociation of these interactions, allowing the N-terminus to move out of the active site and thereby activating the enzyme.
Associates with IL23A to form the IL-23 interleukin, a heterodimeric cytokine which functions in innate and adaptive immunity. IL-23 may constitute with IL-17 an acute response to infection in peripheral tissues. IL-23 binds to a heterodimeric receptor complex composed of IL12RB1 and IL23R, activates the Jak-Stat signaling cascade, stimulates memory rather than naive T-cells and promotes production of pro-inflammatory cytokines. IL-23 induces autoimmune inflammation and thus may be responsible for autoimmune inflammatory diseases and may be important for tumorigenesis.
Cytokine that can act as a growth factor for activated T and NK cells, enhance the lytic activity of NK/lymphokine-activated killer cells, and stimulate the production of IFN-gamma by resting PBMC.
Heterodimer with IL12A; disulfide-linked. The heterodimer is known as interleukin IL-12. Heterodimer with IL23A; disulfide-linked. The heterodimer is known as interleukin IL-23. Also secreted as a monomer. Interacts with NBR1; this interaction promotes IL-12 secretion (By similarity).
Known to be C-mannosylated in the recombinant protein; it is not yet known for sure if the wild-type protein is also modified.
Highly expressed in the brain and weakly expressed in the heart, placenta, lung and skeletal muscle.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to an N-unsubstituted glucosamine linked to a 2-O-sulfo iduronic acid unit on heparan sulfate (PubMed:9988768). Catalyzes the O-sulfation of glucosamine in GlcA2S-GlcNS (PubMed:9988768). Unlike HS3ST1/3-OST-1, does not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate (PubMed:9988768).
Highly expressed in brain, ovary and mammary gland. Moderately expressed in lung, salivary gland, kidney, skin, adipose tissue, intestine and spleen. Weakly expressed in skeletal muscle, liver and stomach. Expressed in pleiomorphic and undifferentiated liposarcomas, osteosarcomas and breast carcinomas.
Expressed at highest levels in liver and kidney; intermediate expression in skeletal muscle, pancreas, heart and placenta; low expression in brain and lung. Expressed in epidermis and hair follicles.
Interacts with PLK1; phosphorylation-dependent.
May play a role in maintenance of cell cycle integrity by regulating mitosis or cytokinesis.
Phosphorylated during mitosis in the cell cycle probably by CDK1.
Catalytically inactive phosphatase (PubMed:23847209). Acts as a nuclear anchor for MAPK1/MAPK3 (ERK1/ERK2) (PubMed:23847209). Modulates cell-fate decisions and cell migration by spatiotemporal regulation of MAPK1/MAPK3 (ERK1/ERK2) (PubMed:23847209). By binding to the F-box of FBXW7, prevents the assembly of FBXW7 into the SCF E3 ubiquitin-protein ligase complex, and thereby inhibits degradation of its substrates (PubMed:28007894). Plays a role in spermatogenesis (By similarity).
Contains a Gly residue instead of a conserved Cys residue at position 120 in the dsPTPase catalytic loop which renders it catalytically inactive as a phosphatase. The binding pocket is however sufficiently preserved to bind phosphorylated substrates, and may protect them from phosphatases.
Interacts with MAPK1; independently of MAPK1 phosphorylation status (PubMed:23847209). Interacts with CARHSP1/Crhsp-24 (By similarity). Interacts (via FQQ motif) with FBXW7 isoforms 1 (via F-box domain) and 3 (via F-box domain); the interaction is direct and prevents FBXW7 interaction with SKP1, a component of the SCF(FBXW7) complex (PubMed:28007894). Does not interact with FBXW7 isoform 2 (PubMed:28007894).
Gene prediction based on EST data and similarity to mouse and macaca fascicularis orthologs.
Contaminating sequence. Potential poly-A sequence starting in position 553.
Contaminating sequence. Potential poly-A sequence starting in position 627.
Full activation of the protein kinase domain requires both phosphorylation of Tyr-32341, preventing it from blocking the catalytic aspartate residue, and binding of Ca/CALM to the C-terminal regulatory tail of the molecule which results in ATP binding to the kinase.
In some isoforms, after the PEVK repeat region there is a long PEVK duplicated region. On account of this region, it has been very difficult to sequence the whole protein. The length of this region (ranging from 183 to 2174 residues), may be a key elastic element of titin.
Interacts with MYOM1, MYOM2, tropomyosin and myosin. Interacts with actin, primarily via the PEVK domains and with MYPN (By similarity). Interacts with FHL2, NEB, CRYAB, LMNA/lamin-A and LMNB/lamin-B. Interacts with TCAP/telethonin and/or ANK1 isoform Mu17/ank1.5, via the first two N-terminal immunoglobulin domains. Interacts with TRIM63 and TRIM55, through several domains including immunoglobulin domains 141 and 142. Interacts with ANKRD1, ANKRD2 and ANKRD23, via the region between immunoglobulin domains 77 and 78 and interacts with CAPN3, via immunoglobulin domain 79. Interacts with NBR1 through the protein kinase domain. Interacts with CALM/calmodulin. Isoform 6 interacts with OBSCN isoform 3. Interacts with CMYA5.
Isoforms 3, 7 and 8 are expressed in cardiac muscle. Isoform 4 is expressed in vertebrate skeletal muscle. Isoform 6 is expressed in skeletal muscle (at protein level).
Key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The size and extensibility of the cross-links are the main determinants of sarcomere extensibility properties of muscle. In non-muscle cells, seems to play a role in chromosome condensation and chromosome segregation during mitosis. Might link the lamina network to chromatin or nuclear actin, or both during interphase.
The PEVK region may serve as an entropic spring of a chain of structural folds and may also be an interaction site to other myofilament proteins to form interfilament connectivity in the sarcomere.
ZIS1 and ZIS5 regions contain multiple SPXR consensus sites for ERK- and CDK-like protein kinases as well as multiple SP motifs. ZIS1 could adopt a closed conformation which would block the TCAP-binding site.
Abundant in the brain and lower levels in other tissues.
Monomer and homodimer. Interacts (via N-terminus) with extracellular ligands TULP1 and GAS6 (By similarity). Interacts with PIK3R1; this interaction increases PI3-kinase activity (By similarity).
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including TULP1 or GAS6. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of TYRO3 on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with PIK3R1 and thereby enhances PI3-kinase activity. Activates the AKT survival pathway, including nuclear translocation of NF-kappa-B and up-regulation of transcription of NF-kappa-B-regulated genes. TYRO3 signaling plays a role in various processes such as neuron protection from excitotoxic injury, platelet aggregation and cytoskeleton reorganization. Also plays an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3.
Transcriptional activator of STAT3 involved in the regulation of immune homeostasis. Also able to activate STAT1 transcription.
Belongs to the pICln (TC 1.A.47) family.
Component of the methylosome, a 20S complex containing at least PRMT5/SKB1, WDR77/MEP50 and CLNS1A/pICln (PubMed:21081503, PubMed:11747828, PubMed:18984161). May mediate SNRPD1 and SNRPD3 methylation. Forms a 6S pICln-Sm complex composed of CLNS1A/pICln, SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG; ring-like structure where CLNS1A/pICln mimics additional Sm proteins and which is unable to assemble into the core snRNP (PubMed:18984161). Interacts with LSM10 and LSM11 (PubMed:16087681).
Involved in both the assembly of spliceosomal snRNPs and the methylation of Sm proteins (PubMed:21081503, PubMed:18984161, PubMed:10330151, PubMed:11713266). Chaperone that regulates the assembly of spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs (PubMed:18984161, PubMed:10330151). Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (Sm core) (PubMed:10330151). In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP (PubMed:10330151, PubMed:18984161). Dissociation by the SMN complex of CLNS1A from the trapped Sm proteins and their transfer to an SMN-Sm complex triggers the assembly of core snRNPs and their transport to the nucleus (PubMed:10330151, PubMed:18984161).
By TNF and by IFNG/IFN-gamma in keratinocytes. By Aspergillus fumigatus conidia in peripheral blood mnonocytes; involves CLEC7A and SYK.
Cytokine that binds to and signals through the IL1RL2/IL-36R receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells. Part of the IL-36 signaling system that is thought to be present in epithelial barriers and to take part in local inflammatory response; similar to the IL-1 system with which it shares the coreceptor IL1RAP. Seems to be involved in skin inflammatory response by acting on keratinocytes, dendritic cells and indirectly on T-cells to drive tissue infiltration, cell maturation and cell proliferation. In cultured keratinocytes induces the expression of macrophage, T-cell, and neutrophil chemokines, such as CCL3, CCL4, CCL5, CCL2, CCL17, CCL22, CL20, CCL5, CCL2, CCL17, CCL22, CXCL8, CCL20 and CXCL1; also stimulates its own expression and that of the prototypic cutaneous pro-inflammatory parameters TNF-alpha, S100A7/psoriasin and inducible NOS. May play a role in pro-inflammatory responses during particular neutrophilic airway inflammation: activates mitogen-activated protein kinases and NF-kappa B in primary lung fibroblasts, and stimulates the expression of IL-8 and CXCL3 and Th17 chemokine CCL20 in lung fibroblasts. May be involved in the innate immune response to fungal pathogens, such as Aspergillus fumigatus.
Highly expressed in tissues containing epithelial cells: skin, lung, stomach and esophagus. Expressed in bronchial epithelial. In skin is expressed only in keratinocytes but not in fibroblasts, endothelial cells or melanocytes. Up-regulated in lesional psoriasis skin. Expressed in monocyte-derived dendritic cells and M1 macrophages.
N-terminal truncation leads to a dramatic enhancement of its activity (>1000-fold) (PubMed:21965679). Proteolytically cleaved by cathepsin CTSG (PubMed:30804664).
Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum. Forms with the glucose-6-phosphate transporter (SLC37A4/G6PT) the complex responsible for glucose production in the terminal step of glycogenolysis and gluconeogenesis. Hence, it is the key enzyme in homeostatic regulation of blood glucose levels.
May act as a GTPase-activating protein of RAB6A. May play a role in microtubule nucleation by centrosome. May participate in a RAB6A-mediated pathway involved in the metaphase-anaphase transition.
Activated by cleavage after Arg-444. The uncleaved zymogen is inactive towards synthetic substrates, but has sufficient activity to effect autocatalytic cleavage.
Homodimer; disulfide-linked. Binds MBL2. Isoform 2 binds to MASP1. Binds SERPING1. Dimerization and MBL2 binding requires calcium ions.
Serum protease that plays an important role in the activation of the complement system via mannose-binding lectin. After activation by auto-catalytic cleavage it cleaves C2 and C4, leading to their activation and to the formation of C3 convertase.
Part of the ACTR1A/ACTB filament around which the dynactin complex is built. The dynactin multiprotein complex activates the molecular motor dynein for ultra-processive transport along microtubules.
Part of the ACTR1A/ACTB filament around which the dynactin complex is built. The filament contains 8 copies of ACTR1A and 1 ACTB. Interacts with dynein and adapters such as BICD2 (By similarity). Interacts with BCCIP (isoform 2/alpha) (PubMed:28394342).
Essential for male fertility. Plays an important role in spermatogenesis and regulates sperm motility by controlling the development of the flagellar bending of sperm.
Heterodimer of NR1H3 and RXR (retinoic acid receptor). Interacts with CCAR2 (via N-terminus) in a ligand-independent manner. Interacts with SIRT1 and this interaction is inhibited by CCAR2 (PubMed:25661920). Interacts with GPS2 (PubMed:19481530).
Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity (PubMed:19481530, PubMed:25661920). Interaction with retinoic acid receptor (RXR) shifts RXR from its role as a silent DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXRES (By similarity). LXRES are DR4-type response elements characterized by direct repeats of two similar hexanuclotide half-sites spaced by four nucleotides (By similarity). Plays an important role in the regulation of cholesterol homeostasis, regulating cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8 (PubMed:19481530). Interplays functionally with RORA for the regulation of genes involved in liver metabolism (By similarity). Induces LPCAT3-dependent phospholipid remodeling in endoplasmic reticulum (ER) membranes of hepatocytes, driving SREBF1 processing and lipogenesis (By similarity). Via LPCAT3, triggers the incorporation of arachidonate into phosphatidylcholines of ER membranes, increasing membrane dynamics and enabling triacylglycerols transfer to nascent very low-density lipoprotein (VLDL) particles. Via LPCAT3 also counteracts lipid-induced ER stress response and inflammation, likely by modulating SRC kinase membrane compartmentalization and limiting the synthesis of lipid inflammatory mediators (By similarity).
Visceral organs specific expression. Strong expression was found in liver, kidney and intestine followed by spleen and to a lesser extent the adrenals.
Expressed in endothelial cell (EC) and protein-induced pluripotent stem (PiPS) endothelial cell (EC) (at protein level).
It is uncertain whether Met-1 or Met-11 is the initiator.
Plays a role as a transcriptional activator involved in the early stage of somatic cell reprogramming. Promotes the differentiation of protein-induced pluripotent stem (PiPS) cells into endothelial cells and the formation of vascular-like tubes (in vitro). Involved in the transcription induction of vascular endothelial-cadherin (VE-cadherin) expression. Associates to the VE-cadherin gene promoter.
Probable retrogene derived from SET transcript.
Up-regulated during protein-induced pluripotent stem (PiPS) endothelial cell differention. Up-regulated by VEGFA and POU2F1 (at protein level).
Expressed in placenta, pancreas and kidney. Also expressed in prostate, testis, ovary and blood.
May be involved in the regulation of cellular proliferation and/or differentiation.
Component of the RNA polymerase I (Pol I) and RNA polymerase III (Pol III) complexes consisting of at least 13 and 17 subunits, respectively.
Contrary to isoform 2, isoform 1 contains an RNA polymerase domain and has DNA-dependent RNA polymerase function. Synteny studies in vertebrates suggest that this isoform has been created by a mammalian-specific retrotransposition event of an ancestral gene which has been lost later on in this lineage.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common core component of RNA polymerases I and III which synthesize ribosomal RNA precursors and small RNAs, such as 5S rRNA and tRNAs, respectively.
POLR1D isoform 2 lacks an RNA polymerase domain and therefore cannot have DNA-dependent RNA polymerase function.
Acts as an adapter protein of the FYN and LCP2 signaling cascades in T-cells (By similarity). May play a role in linking T-cell signaling to remodeling of the actin cytoskeleton (PubMed:10747096, PubMed:16980616). Modulates the expression of IL2 (By similarity). Involved in platelet activation (By similarity). Prevents the degradation of SKAP1 and SKAP2 (PubMed:15849195). May be involved in high affinity immunoglobulin epsilon receptor signaling in mast cells (By similarity).
Expressed in hematopoietic tissues such as myeloid and T-cells, spleen and thymus. Not expressed in B-cells, nor in non-lymphoid tissues.
Part of a complex consisting of SKAP2, FYB1 and PTPNS1 (By similarity). Part of a complex consisting of SKAP2, FYB1 and LILRB3 (By similarity). Part of a complex consisting of SKAP1, FYB1 and CLNK (By similarity). Interacts with CLNK (via its SH2 domain); this interaction allows SKAP1 and FYB1 to recruit FYN to the complex, thus promoting the phosphorylation of CLNK by FYN (By similarity). Interacts with FYN (PubMed:9207119, PubMed:15849195, PubMed:27335501). Interacts with LCP2 (PubMed:9207119, PubMed:27335501). Interacts with SKAP1 (PubMed:9755858, PubMed:9748251, PubMed:9671755, PubMed:10856234, PubMed:15849195, PubMed:16461356, PubMed:27335501). Interacts with SKAP2 (PubMed:9755858, PubMed:9671755, PubMed:10942756). Interacts with FASLG (PubMed:19807924). Interacts with EVL (PubMed:10747096). Interacts with TMEM47 (By similarity). Interacts with LCK (PubMed:27335501).
T-cell receptor ligation leads to increased tyrosine phosphorylation.
Belongs to the mitochondrion-specific ribosomal protein mL48 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379, PubMed:25278503). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. mL48 is located at the central protuberance (PubMed:25278503, PubMed:25838379). Interacts with OXA1L (By similarity).
Chloride channel activity is allosterically activated by lumenal H(+) and Cl(-) leading to synaptic vesicles acidification. The L-glutamate transport activity is allosterically activated by lumenal H(+) and Cl(-). The allosteric requirement for H(+) efficiently prevents non-vesicular efflux across the plasma membrane. The L-glutamate uniporter activity exhibits a biphasic dependence on chloride concentration.
Multifunctional transporter that transports L-glutamate as well as multiple ions such as chloride, proton, potassium, sodium and phosphate (PubMed:33440152, PubMed:11698620). At the synaptic vesicle membrane, mainly functions as a uniporter which transports preferentially L-glutamate but also, phosphate from the cytoplasm into synaptic vesicles at presynaptic nerve terminals of excitatory neural cells (PubMed:11698620). The L-glutamate or phosphate uniporter activity is electrogenic and is driven by the proton electrochemical gradient, mainly by the electrical gradient established by the vacuolar H(+)-ATPase across the synaptic vesicle membrane (PubMed:11698620). In addition, functions as a chloride channel that allows the chloride permeation through the synaptic vesicle membrane therefore affects the proton electrochemical gradient and promotes synaptic vesicles acidification (By similarity). Moreover, functions as a vesicular K(+)/H(+) antiport allowing to maintain the electrical gradient and to decrease chemical gradient and therefore sustain vesicular glutamate uptake (By similarity). The vesicular H(+)/H(+) antiport activity is electroneutral (By similarity). At the plasma membrane, following exocytosis, functions as a symporter of Na(+) and phosphate from the extracellular space to the cytoplasm allowing synaptic phosphate homeostasis regulation (Probable) (PubMed:10820226). The symporter activity is driven by an inside negative membrane potential and is electrogenic (Probable). Also involved in the regulation of retinal hyaloid vessel regression during postnatal development (By similarity). May also play a role in the endocrine glutamatergic system of other tissues such as pineal gland and pancreas (By similarity).
Predominantly expressed in adult brain (PubMed:10820226). Expressed in amygdala, caudate nucleus, cerebral cortex, frontal lobe, hippocampus, medulla, occipital lobe, putamen, spinal cord, substantia nigra, subthalamic nucleus, temporal lobe and thalamus (PubMed:10820226).
Highly expressed in the brain,peripheral blood leukocytes and ovary, whereas lower levels of expression is observed in kidney and liver.
Increased under sterol-deprived conditions and decreased by the addition of exogenous sterols.
Probable lipid transporter that modulates cholesterol sequestration in the late endosome/lysosome by regulating the intracellular sphingolipid metabolism, in turn participates in cholesterol homeostasis (PubMed:15238223, PubMed:21810484, PubMed:24201375) (Probable). May alter the transbilayer distribution of ceramide in the intraluminal membrane lipid bilayer, favoring its retention in the outer leaflet that results in increased acid ceramidase activity in the late endosome/lysosome, facilitating ceramide deacylation to sphingosine leading to the sequestration of free cholesterol in lysosomes (PubMed:24201375). In addition regulates amyloid-beta production either by activating a signaling pathway that regulates amyloid precursor protein transcription through the modulation of sphingolipid metabolism or through its role in gamma-secretase processing of APP (PubMed:22086926, PubMed:26510981). May play a role in myelin formation (By similarity).
Weakly expressed in brain and highly in peripheral blood leukocytes.
Expressed in a broader range of tissues including brain, kidney, testis, thymus, placenta, prostate, salivary gland, thyroid and colon.
High affinity receptor for INSL5. Also acts as receptor for RLN3/relaxin-3, as well as bradykinin and kallidin. Binding of the ligand inhibit cAMP accumulation.
Expressed in uterus and pancreas (at protein level).
Forms a complex with CDH1 and CTNNB1; interacts directly with CTNNB1. Interacts with AP1M2. Interacts with isoform 2 of BSG/CD147.
Plays a role in cell adhesion and cell migration.
Thr-237 and Ser-239 may be phosphorylated; however as this position is probably extracellular, the in vivo relevance is not proven.
A chromosomal aberration involving DIRC2 has been found in a family with renal carcinoma. Translocation t(2;3)(q35;q21) (PubMed:11912179).
Cleaved in lysosomes by cathepsin L between Leu-214 and Ala-261, generating a N-glycosylated N-terminal and a non-glycosylated C-terminal fragment.
Mediates H(+)-dependent pyridoxine transport.
Ubiquitous. Expressed in proximal tubular cells of the kidney. Highly expressed in the placenta, brain and heart.
Belongs to the DEAD box helicase family. DEAH subfamily. DDX8/PRP22 sub-subfamily.
Expressed in skin, cervix and nerve. Also expressed in the brain.
Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:28076346). Interacts with ARRB2; the interaction is detected in the nucleus upon OR1D2 stimulation (PubMed:16820410). Interacts with SRRM2 (PubMed:28062851). Interacts with CACTIN (PubMed:28062851).
Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28502770, PubMed:28076346). Facilitates nuclear export of spliced mRNA by releasing the RNA from the spliceosome (PubMed:8608946).
The RS domain confers a nuclear localization signal, and appears to facilitate the interaction with the spliceosome.
APE1 displaces NTHL1 from the N-glycosylase-generated AP site in DNA, thereby increasing the turnover of the DNA N-glycosylase activity (PubMed:11287425, PubMed:12519758). AP lyase activity is stimulated by YBX1 (PubMed:11287425). ERCC5/XPG stimulates NTHL1 activity and NTHL1 binding to its DNA substrate (PubMed:9927729).
Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage (PubMed:9927729, PubMed:29610152). The DNA N-glycosylase activity releases the damaged DNA base from DNA by cleaving the N-glycosidic bond, leaving an AP site. The AP-lyase activity cleaves the phosphodiester bond 3' to the AP site by a beta-elimination. Primarily recognizes and repairs oxidative base damage of pyrimidines. Has also 8-oxo-7,8-dihydroguanine (8-oxoG) DNA glycosylase activity. Acts preferentially on DNA damage opposite guanine residues in DNA. Is able to process lesions in nucleosomes without requiring or inducing nucleosome disruption.
Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage. The DNA N-glycosylase activity releases the damaged DNA base from DNA by cleaving the N-glycosidic bond, leaving an AP site. The AP lyase activity cleaves the phosphodiester bond 3' to the AP site by a beta-elimination. Primarily recognizes and repairs oxidative base damage of pyrimidines.
Expression levels are regulated during the cell cycle with increased levels during early and mid S-phase.
Interacts with YBX1 (By similarity) (PubMed:11287425). Interacts with ERCC5/XPG; the interaction stimulates NTHL1 activity and NTHL1 binding to its DNA substrate (PubMed:9927729).
Widely expressed with highest levels in heart and lowest levels in lung and liver.
Autophosphorylated. In response to nutrient limitation, probably phosphorylated and activated by AMPK, leading to activate autophagy.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. APG1/unc-51/ULK1 subfamily.
Interacts with SYNGAP1 (By similarity). Component of a complex consisting of ATG13/KIAA0652, ULK1 and RB1CC1/FIP200. Interacts (via C-terminus) with ATG13/KIAA0652. Associates with the mammalian target of rapamycin complex 1 (mTORC1) through an interaction with RPTOR.
Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK, also acts as a negative regulator of AMPK through phosphorylation of the AMPK subunits PRKAA1, PRKAB2 and PRKAG1. May phosphorylate ATG13/KIAA0652, FRS2, FRS3 and RPTOR; however such data need additional evidences. Not involved in ammonia-induced autophagy or in autophagic response of cerebellar granule neurons (CGN) to low potassium concentration. Plays a role early in neuronal differentiation and is required for granule cell axon formation: may govern axon formation via Ras-like GTPase signaling and through regulation of the Rab5-mediated endocytic pathways within developing axons.
The CTD-like region mediates membrane-binding and incorporation into large protein complexes.
Binding to anionic phospholipids, predominantly to cardiolipin inhibits its phosphotransfer activity.
Homohexamer (PubMed:10799505). Interacts with OPA1 (PubMed:23150663). Interacts with CAPN8 (By similarity).
Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate. Through the catalyzed exchange of gamma-phosphate between di- and triphosphonucleosides participates in regulation of intracellular nucleotide homeostasis (PubMed:10799505). Binds to anionic phospholipids, predominantly to cardiolipin; the binding inhibits its phosphotransfer activity (PubMed:18635542, PubMed:23150663). Acts as mitochondria-specific NDK; its association with cardiolipin-containing mitochondrial inner membrane is coupled to respiration suggesting that ADP locally regenerated in the mitochondrion innermembrane space by its activity is directly taken up via ANT ADP/ATP translocase into the matrix space to stimulate respiratory ATP regeneration (PubMed:18635542). Proposed to increase GTP-loading on dynamin-related GTPase OPA1 in mitochondria (PubMed:24970086). In vitro can induce liposome cross-linking suggesting that it can cross-link inner and outer membranes to form contact sites, and promotes intermembrane migration of anionic phosphoplipids. Promotes the redistribution of cardiolipin between the mitochondrial inner membrane and outer membrane which is implicated in pro-apoptotic signaling (PubMed:18635542, PubMed:17028143, PubMed:23150663).
Widely distributed. Found at very high levels in prostate, heart, liver, small intestine, and skeletal muscle tissues, and in low amounts in the brain and in blood leukocytes.
An homozygous partial MICU1 deletion is responsible for a disorder manifesting in childhood with fatigue, lethargy and muscle weakness. The disease is caused by variants affecting the gene represented in this entry.
Belongs to the MICU1 family. MICU1 subfamily.
Expressed in epithelial cell lines. Strongly expressed in epidermal keratinocytes and dermal endothelial cells.
Homohexamer; in absence of calcium (PubMed:24514027). Forms a homohexamer in absence of calcium and rearranges into a heterodimer in presence of calcium (PubMed:26489515, PubMed:24514027). Heterodimer; disulfide-linked; heterodimerizes with MICU2 (PubMed:24560927). The heterodimer formed with MICU2 associates with MCU at low calcium concentration and dissociates from MCU at high calcium level (PubMed:26387864). Component of the uniplex complex, composed of MCU, MCUB, MICU1, MICU2 and EMRE/SMDT1 (PubMed:24231807). Interacts (via polybasic region) with EMRE/SMDT1; the interaction is direct (PubMed:27099988). Interacts (via polybasic region) with MCU (via coiled coil domains); the interaction is direct and precedes formation of the heterodimer with MICU2 (PubMed:21685886, PubMed:23101630, PubMed:23178883, PubMed:24332854, PubMed:26387864). Interacts with SLC25A23 (PubMed:24430870). Interacts with CHCHD4/MIA40; which introduces the interchain disulfide bond with MICU2 (PubMed:26387864).
Key regulator of mitochondrial calcium uniporter (MCU) that senses calcium level via its EF-hand domains (PubMed:20693986, PubMed:23101630, PubMed:23747253, PubMed:24313810, PubMed:24332854, PubMed:24503055, PubMed:24560927, PubMed:26341627, PubMed:26903221, PubMed:27099988). MICU1 and MICU2 form a disulfide-linked heterodimer that stimulates and inhibits MCU activity, depending on the concentration of calcium. MICU1 acts both as an activator or inhibitor of mitochondrial calcium uptake (PubMed:26903221). Acts as a gatekeeper of MCU at low concentration of calcium, preventing channel opening (PubMed:26903221). Enhances MCU opening at high calcium concentration, allowing a rapid response of mitochondria to calcium signals generated in the cytoplasm (PubMed:24560927, PubMed:26903221). Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake (PubMed:22904319). Induces T-helper 1-mediated autoreactivity, which is accompanied by the release of IFNG (PubMed:16002733).
The C-helix is required for assembling the Ca(2+)-free homohexamer (PubMed:24514027). It also plays a key role in mitochondrial calcium uptake, probably by mediating interaction with MICU2 (PubMed:24503055, PubMed:24514027).
The EF-hand domains have high affinity for calcium and act as sensors of calcium levels (PubMed:23101630, PubMed:24560927).
The disease is caused by variants affecting the gene represented in this entry. The complex phenotype is due to alterations in mitochondrial calcium signaling characterized by increased mitochondrial Ca(2+) load (PubMed:24336167).
The topology is subject to discussion. According to some reports, localizes at the outer surface of the mitochondrion inner membrane (PubMed:20693986, PubMed:24332854). According to another publication, forms an intramembrane hairpin loop without crossing the membrane (PubMed:23747253). Recent studies rather suggest that it contains a transmembrane region that crosses the mitochondrial inner membrane, with the main part of the protein localized in the mitochondrial intermembrane space (PubMed:26387864, PubMed:26489515).
Was initially thought to act as an inhibitor of MCU based on effects following MICU1 depletion (PubMed:20693986, PubMed:23101630). However, depletion of MICU1 also eliminates MICU2, explaining the initial conclusion. It was later shown to act as a stimulator of MCU activity instead (PubMed:24560927).
E3 ligase that plays essential roles in innate antiviral response (PubMed:28169297, PubMed:29760876, PubMed:29899090, PubMed:31979016). Directly binds to influenza A virus or vesicular stomatitis virus nucleoproteins and targets them for ubiquitination and proteasomal degradation, thereby limiting viral infections (PubMed:29899090, PubMed:31979016, PubMed:28169297). Activates the innate antiviral response by catalyzing monoubiquitination of CGAS, thereby activating CGAS (PubMed:29760876). Also involved in innate antiviral response by mediating 'Lys-63'-linked polyubiquitylation of BCL10 which in turn hubs NEMO for activation of NF-kappa-B and IRF3 pathways (By similarity). Catalyzes the ubiquitin-mediated degradation of other substrates including protein kinase C, ZSCAN21 or TOP3B suggesting additional roles besides its function in immune response (PubMed:17893151, PubMed:33378676).
Expressed in multiple tissues with the highest levels in heart and skeletal muscle.
Interacts with PRKCA (PubMed:17893151). Interacts with NOD2 (PubMed:27812135). Interacts with TRIM17; this interaction prevents TRIM41 activity on ZSCAN2 (By similarity).
Homotrimer (PubMed:27626375). Functional P2XRs are organized as homomeric and heteromeric trimers (By similarity).
Receptor for ATP that acts as a ligand-gated cation channel (PubMed:27626375). Plays a role in sensory perception. Required for normal perception of pain. Required for normal taste perception (By similarity).
Belongs to the TTC30/dfy-1/fleer family.
Interacts with the IFT B complex components IFT27, IFT46, IFT74, IFT52, IFT57, IFT80, IFT81 and IFT88 (By similarity). Interacts with KIF17 (By similarity).
Required for polyglutamylation of axonemal tubulin. Plays a role in anterograde intraflagellar transport (IFT), the process by which cilia precursors are transported from the base of the cilium to the site of their incorporation at the tip.
Component of the SNARE complex composed of STX4, SNAP23 and VAMP7 that binds SYT7 during lysosomal exocytosis. Component of the SNARE complex composed of STX7, STX8, VAMP7 and VTI1B that is required for heterotypic fusion of late endosomes with lysosomes. May interact with STX17 (By similarity). Interacts with PICALM (PubMed:23741335). Interacts with RAB21 (PubMed:25648148).
Involved in the targeting and/or fusion of transport vesicles to their target membrane during transport of proteins from the early endosome to the lysosome. Required for heterotypic fusion of late endosomes with lysosomes and homotypic lysosomal fusion. Required for calcium regulated lysosomal exocytosis. Involved in the export of chylomicrons from the endoplasmic reticulum to the cis Golgi. Required for exocytosis of mediators during eosinophil and neutrophil degranulation, and target cell killing by natural killer cells. Required for focal exocytosis of late endocytic vesicles during phagosome formation.
Loss-of-function mutant (antisense inhibition) displays impaired granzyme B release and target cell killing by natural killer cells.
Sequence of unknown origin in the C-terminal part.
Beta-galactosyltransferase that transfers beta-galactose to hydroxylysine residues of collagen.
Fetal expression in the adrenal gland, brain, heart, intestine, kidney, liver and lung. Except for fetal brain that shows no imprinting, expression was found preferentially from the maternal allele.
Inhibited by interaction with the metallocarboxypeptidase inhibitor (MCPI) from N.versicolor that binds to the catalytic zinc ion.
Metalloprotease that could be involved in the histone hyperacetylation pathway (PubMed:10383164). Releases a C-terminal amino acid, with preference for -Phe, -Leu, -Ile, -Met, -Tyr and -Val (PubMed:20385563).
Up-regulated by inhibitors of histone dacetylation.
Hair follicles, and epidermis at very low levels.
Based on sequence similarity, it has been suggested that C15orf41 might encode a divalent metal-ion dependent restriction endonuclease, although nuclease activity could not be experimentally proven.
Plays a role in erythroid cell differentiation.
Functions as a negative regulator of the PI3 kinase/PI3K activity associated with endosomal membranes via BECN1, a core subunit of the PI3K complex. By modifying the phosphatidylinositol 3-phosphate/PtdInsP3 content of endosomal membranes may regulate endosome fusion, recycling, sorting and early to late endosome transport (PubMed:26783301). It is for instance, required for the delivery of cargos like BST2/tetherin from early to late endosome and thereby participates indirectly to their degradation by the lysosome (PubMed:27126989). May play a role in meiosis (By similarity).
Interacts with WDR81; involved in early to late endosome cargo transport (PubMed:26783301, PubMed:27126989). Interacts with BECN1; negatively regulates the PI3 kinase/PI3K activity associated with endosomal membranes (PubMed:26783301).
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro, in the presence or in the absence of BRCA1-BARD1 E3 ubiquitin-protein ligase complex, catalyzes the synthesis of 'Lys-48'-linked polyubiquitin chains. Does not transfer ubiquitin directly to but elongates monoubiquitinated substrate protein. Mediates the selective degradation of short-lived and abnormal proteins, such as the endoplasmic reticulum-associated degradation (ERAD) of misfolded lumenal proteins. Ubiquitinates huntingtin. May mediate foam cell formation by the suppression of apoptosis of lipid-bearing macrophages through ubiquitination and subsequence degradation of p53/TP53. Proposed to be involved in ubiquitination and proteolytic processing of NF-kappa-B; in vitro supports ubiquitination of NFKB1. In case of infection by cytomegaloviruses may be involved in the US11-dependent degradation of MHC class I heavy chains following their export from the ER to the cytosol. In case of viral infections may be involved in the HPV E7 protein-dependent degradation of RB1.
Expressed in all tissues tested, including spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocytes, T-lymphocytes, monocytes, granulocytes and bone marrow mononuclear cells. Highly expressed in brain, with highest levels found in cortex and striatum and at lower levels in cerebellum and brainstem.
Interacts with RNF138/NARF. Interacts with BRCA1.
Sumoylation at Lys-14 impairs catalytic activity.
Contains an active site 4-methylidene-imidazol-5-one (MIO), which is formed autocatalytically by cyclization and dehydration of residues Ala-Ser-Gly.
Muscle contraction. Required for cytoskeleton organization (By similarity).
Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). Interacts with GCSAM.
Represents a conventional myosin. This protein should not be confused with the unconventional myosin-2 (MYO2).
Binds beta-galactoside and lactose. Strong inducer of T-cell apoptosis.
Homooligomer; homooligomerizes into virion-like capsids (PubMed:25748042). Interacts with SH3GL1/endophilin-2, SH3GL3/endophilin-3 and DNM2/DYN2 (By similarity). Interacts with CAMK2B (in the kinase inactive state); leading to target ARC to inactive synapses (By similarity). Interacts with PSEN1 (By similarity).
Master regulator of synaptic plasticity that self-assembles into virion-like capsids that encapsulate RNAs and mediate intercellular RNA transfer in the nervous system. ARC protein is released from neurons in extracellular vesicles that mediate the transfer of ARC mRNA into new target cells, where ARC mRNA can undergo activity-dependent translation. ARC capsids are endocytosed and are able to transfer ARC mRNA into the cytoplasm of neurons. Acts as a key regulator of synaptic plasticity: required for protein synthesis-dependent forms of long-term potentiation (LTP) and depression (LTD) and for the formation of long-term memory. Regulates synaptic plasticity by promoting endocytosis of AMPA receptors (AMPARs) in response to synaptic activity: this endocytic pathway maintains levels of surface AMPARs in response to chronic changes in neuronal activity through synaptic scaling, thereby contributing to neuronal homeostasis. Acts as a postsynaptic mediator of activity-dependent synapse elimination in the developing cerebellum by mediating elimination of surplus climbing fiber synapses. Accumulates at weaker synapses, probably to prevent their undesired enhancement. This suggests that ARC-containing virion-like capsids may be required to eliminate synaptic material. Required to transduce experience into long-lasting changes in visual cortex plasticity and for long-term memory (By similarity). Involved in postsynaptic trafficking and processing of amyloid-beta A4 (APP) via interaction with PSEN1 (By similarity). In addition to its role in synapses, also involved in the regulation of the immune system: specifically expressed in skin-migratory dendritic cells and regulates fast dendritic cell migration, thereby regulating T-cell activation (By similarity).
Palmitoylation anchors the protein into the membrane by allowing direct insertion into the hydrophobic core of the lipid bilayer.
Phosphorylation at Ser-260 by CaMK2 prevents homooligomerization into virion-like capsids by disrupting an interaction surface essential for high-order oligomerization. Phosphorylation by CaMK2 inhibits synaptic activity.
The protein is evolutionarily related to retrotransposon Gag proteins: it contains large N- and C-terminal domains that form a bi-lobar architecture similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. It contains structural elements found within viral Gag polyproteins originated from the Ty3/gypsy retrotransposon family and retains the ability to form virion-like capsid structures that can mediate mRNA transfer between cells. Tetrapod and fly Arc protein-coding genes originated independently from distinct lineages of Ty3/gypsy retrotransposons.
Ubiquitinated by UBE3A, leading to its degradation by the proteasome, thereby promoting AMPA receptors (AMPARs) expression at synapses (By similarity). Ubiquitinated by RNF216 at Lys-268 and Lys-269 limiting ARC protein levels induced by synaptic activity and thus regulating ARC-dependent forms of synaptic plasticity (PubMed:24945773).
Expressed at highest levels in placenta and at lower levels in lung, liver, kidney and pancreas. Expressed in thalamus, hippocampus, cerebral cortex, and cerebellum (in neurons rather than glia).
Involved in the planar cell polarity pathway that controls convergent extension during gastrulation and neural tube closure. Convergent extension is a complex morphogenetic process during which cells elongate, move mediolaterally, and intercalate between neighboring cells, leading to convergence toward the mediolateral axis and extension along the anteroposterior axis. Necessary for nuclear localization of REST. May serve as nuclear receptor.
Binds to F-actin. May be involved in regulation of the actin cytoskeleton (By similarity).
Present in skeletal muscle and weakly in brain, spinal cord, bone marrow and retina.
Interacts (in GTP-bound form) with PICK1 (via PDZ domain); a PICK1 homodimer may allow simultaneous association of RAB39B and GRIA2 to PICK1 which is involved in GRIA2 trafficking. Interacts with isoform c of RASSF1; the interaction is strong (By similarity). Interacts with isoform a of RASSF1; the interaction is weak (By similarity). Interacts with the DLG4/PSD-95 (By similarity).
Small GTPases Rab involved in autophagy (PubMed:27103069). The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (PubMed:27103069). May regulate the homeostasis of SNCA/alpha-synuclein. Together with PICK1 proposed to ensure selectively GRIA2 exit from the endoplasmic reticulum to the Golgi and to regulate AMPAR compostion at the post-synapses and thus synaptic transmission (By similarity).
The disease is caused by variants affecting the gene represented in this entry. Its association with Parkinson disease is however unclear (PubMed:26739247, PubMed:27459931). According to a number of studies, variations affecting this gene are not a frequent cause of Parkinson disease, suggesting that RAB39B does not play a major role in Parkinson disease etiology (PubMed:26739247, PubMed:27459931).
3'-5' RNA exonuclease which cleaves in situ on specific transcripts in both nucleus and mitochondrion. Involved in regulating spatially segregated organellar RNA processing, acts as a coordinator of nucleo-mitochondrial crosstalk (PubMed:31081026). In nucleolus, processes pre-ribosomal RNA involved in ribosome assembly and alters cytoplasmic translation. In mitochondrial matrix, processes 3'-termini of the mito-ribosomal and messenger RNAs and controls translation of mitochondrial proteins (Probable).
Several works have found that mRNA expression is elevated in the skin of vitiligo patients.
Belongs to the zinc-containing alcohol dehydrogenase family. Class-IV subfamily.
Catalyzes the NAD-dependent oxidation of all-trans-retinol, alcohol, and omega-hydroxy fatty acids and their derivatives (PubMed:15369820, PubMed:16787387, PubMed:9600267). Oxidizes preferentially all trans-retinol, all-trans-4-hydroxyretinol, 9-cis-retinol, 2-hexenol, and long chain omega-hydroxy fatty acids such as juniperic acid (PubMed:15369820, PubMed:16787387, PubMed:9600267). In vitro can also catalyzes the NADH-dependent reduction of all-trans-retinal and aldehydes and their derivatives (PubMed:15369820, PubMed:16787387, PubMed:9600267). Reduces preferentially all trans-retinal, all-trans-4-oxoretinal and hexanal (PubMed:15369820, PubMed:16787387). Catalyzes in the oxidative direction with higher efficiency (PubMed:16787387, PubMed:15369820). Therefore may participate in retinoid metabolism, fatty acid omega-oxidation, and elimination of cytotoxic aldehydes produced by lipid peroxidation (PubMed:9600267, PubMed:15369820, PubMed:16787387).
Retinol oxidation is inhibited by the detergent Tween 80 (PubMed:15369820). Ethanol inhibits both all-trans-retinol and 9-cis-retinol oxidation (PubMed:9600267). 13-cis-retinol is an effective competitive inhibitor of the 9-cis-retinol oxidation (PubMed:9600267). All-trans-retinoic acid is a powerful inhibitor of all-trans-retinol oxidation (PubMed:9600267). 13-cis-retinoic acid is a powerful inhibitor of all-trans-retinol oxidation (PubMed:9600267). Cimetidine competitively inhibited ethanol oxidation (PubMed:9600267).
Zinc chaperone that directly transfers zinc cofactor to target metalloproteins, thereby activating them (By similarity). Catalyzes zinc insertion into the active site of methionine aminopeptidase METAP1, which function to cleave the initiator methionine from polypeptides during or after protein translation (PubMed:35584702). Mechanistically, the N-terminal psi-PxLVp motif binds to the C6H2-type zinc finger of inactive form of METAP1 (By similarity). After formation of the docked complex, zinc is transferred from the CXCC motif in the GTPase domain of ZNG1F to the zinc binding site in the peptidase domain of METAP1 in a process requiring GTP hydrolysis (By similarity). GTP/GDP exchange is required for release of active METAP1 (By similarity).
Expressed in brain microglia (at protein level). Elevated expression levels seen in the brain of patients with Alzheimer disease. Expressed by osteoblast-like cells in bone tissues and follicular dendritic cells in lymphoid tissues.
Plays an important role in bone formation and normal bone mineralization. Promotes the differentiation of myoblasts into osteoblasts (PubMed:20025746). May induce the commitment and differentiation of myoblasts into osteoblasts through an enhancement of BMP2 production and interaction with the BMP-RUNX2 pathway. Up-regulates the expression of ATF4, a transcription factor which plays a central role in osteoblast differentiation. Essential for normal spermatogenesis and late testicular differentiation (By similarity).
Belongs to the beta-defensin family. LAP/TAP subfamily.
Exhibits antimicrobial activity against Gram-negative bacteria and Gram-positive bacteria, with highest activity against Gram-negative bacteria (PubMed:9202117, PubMed:10837369). Antimicrobial activity against P.aruginosa seems to be salt-sensitive and is reduced with high salt concentrations greater than 25 mM (PubMed:10837369). Also exhibits antimicrobial activity against the yeast C.albicans (PubMed:9202117, PubMed:10837369, PubMed:30050988). Permeabilizes C.albicans cell membranes via targeting plasma membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2), thereby leading to cell fragmentation and cell death (PubMed:30050988). Acts as a ligand for C-C chemokine receptor CCR6 (PubMed:10521347, PubMed:20068036). Binds to CCR6 and induces chemotactic activity of CCR6-expressing cells, such as immature dendritic cells and memory T cells (PubMed:10521347, PubMed:20068036).
Expressed in lung epithelial cells (at protein level) (PubMed:10837369). Expressed in foreskin, lung and trachea (PubMed:9202117). Lower expression in kidney, uterus and salivary gland tissue (PubMed:9202117). Expressed in epithelial cells of the respiratory tract, with higher expression in distal parenchyma of the lung, trachea, and tonsils, and lower expression in pharynx and adenoid, and low expression in tongue and larynx (PubMed:9831658, PubMed:10837369).
Monomer (PubMed:11300761). Homodimer (PubMed:10906336).
Up-regulated by TNF, IL1B, Gram-negative and Gram-positive bacteria, C.albicans and bacterial lipopolysaccharides (LPS) (PubMed:9202117, PubMed:10837369). Up-regulated by inflammation in skin keratinocytes in epidermal tissue (PubMed:9831658).
(Microbial infection) Interaction with human immunodeficiency virus type 1/HIV-1 envelope glycoprotein GP160.
(Microbial infection) Interacts with SARS coronavirus/SARS-CoV nsp2 protein.
(Microbial infection) Interacts with human enterovirus 71/EV-71 capsid protein VP0, protein 3CD and protease 3C.
Expression increases approximately 3-fold upon entry into G1 phase compared with other phases of the cell cycle. Also induced following inhibition of mitochondrial protein synthesis by thiamphenicol.
In the mitochondria, together with PHB2, forms large ring complexes (prohibitin complexes) in the inner mitochondrial membrane (IMM) and functions as chaperone protein that stabilizes mitochondrial respiratory enzymes and maintains mitochondrial integrity in the IMM, which is required for mitochondrial morphogenesis, neuronal survival, and normal lifespan (Probable). The prohibitin complex, with DNAJC19, regulates cardiolipin remodeling and the protein turnover of OMA1 in a cardiolipin-binding manner (By similarity). Regulates mitochondrial respiration activity playing a role in cellular aging (PubMed:11302691). The prohibitin complex plays a role of mitophagy receptor involved in targeting mitochondria for autophagic degradation (PubMed:28017329). Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6 (PubMed:31522117).
In the nucleus, acts as a transcription coregulator, enhances promoter binding by TP53, a transcription factor it activates, but reduces the promoter binding by E2F1, a transcription factor it represses (PubMed:14500729). Interacts with STAT3 to affect IL17 secretion in T-helper Th17 cells (PubMed:31899195).
In the plasma membrane, cooperates with CD86 to mediate CD86-signaling in B lymphocytes that regulates the level of IgG1 produced through the activation of distal signaling intermediates (By similarity). Upon CD40 engagement, required to activate NF-kappa-B signaling pathway via phospholipase C and protein kinase C activation (By similarity).
Levels of expression in fibroblasts decrease heterogeneously during cellular aging (PubMed:11302691). In CD4(+) T cells, expression increases during polarization towards T-helper Th17, Th1 and Th2 (PubMed:31899195).
Protein with pleiotropic attributes mediated in a cell-compartment- and tissue-specific manner, which include the plasma membrane-associated cell signaling functions, mitochondrial chaperone, and transcriptional co-regulator of transcription factors in the nucleus (PubMed:11302691, PubMed:20959514, PubMed:28017329, PubMed:31522117). Plays a role in adipose tissue and glucose homeostasis in a sex-specific manner (By similarity). Contributes to pulmonary vascular remodeling by accelerating proliferation of pulmonary arterial smooth muscle cells (By similarity).
The mitochondrial prohibitin complex consists of two subunits (PHB1 and PHB2), assembled into a membrane-associated ring-shaped supercomplex of approximately 1 mDa (PubMed:11302691, PubMed:20959514, PubMed:28017329, PubMed:31522117). Interacts with STOML2 (PubMed:21746876). Interacts with MAP1LC3B (membrane-bound form LC3-II); the interaction requires PHB2 and takes place upon Parkin-mediated mitochondrial damage (PubMed:28017329). Interacts with STAT3 (unphosphorylated or phosphorylated at 'Ser-727') (PubMed:31899195). Interacts with CLPB (PubMed:31522117). Interacts with CD86 (via cytoplasmic domain); the interactions increases after priming with CD40 (By similarity).
Abundantly expressed in the fetal brain. Present throughout the gray and white matter of the developing spinal cord at 18-22 gestational weeks. Expressed at low levels in adult brain and spinal cord and reexpressed in neurodegenerative diseases (at protein level).
Interacts with MAZ (PubMed:10727212). Interacts with KEAP1 (PubMed:15379550). Component of the NURF-1 ISWI chromatin remodeling complex (also called the nucleosome-remodeling factor (NURF) complex) at least composed of SMARCA1 (isoform 2), BPTF, RBBP4 and RBBP7 (PubMed:14609955, PubMed:28801535). Within the complex interacts with isoform 2 of SMARCA1 (PubMed:14609955, PubMed:15310751, PubMed:28801535). Component of the BPFT-SMARCA1 complex at least composed of SMARCA1 (isoform 1), BPFT, RBBP4 and RBBP7; the complex is catalytically inactive and does not remodel chromatin (PubMed:15310751). Within the complex interacts with isoform 1 of SMARCA1 (PubMed:15310751). Component of the NURF-5 ISWI chromatin remodeling complex at least composed of SMARCA5/SNF2H and BPTF (PubMed:28801535). Within NURF-5 ISWI chromatin remodeling complex interacts with SMARCA5/SNF2H (PubMed:28801535).
Regulatory subunit of the ATP-dependent NURF-1 and NURF-5 ISWI chromatin remodeling complexes, which form ordered nucleosome arrays on chromatin and facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair (PubMed:14609955, PubMed:28801535). The NURF-1 ISWI chromatin remodeling complex has a lower ATP hydrolysis rate than the NURF-5 ISWI chromatin remodeling complex (PubMed:28801535). Within the NURF-1 ISWI chromatin-remodeling complex, binds to the promoters of En1 and En2 to positively regulate their expression and promote brain development (PubMed:14609955). Histone-binding protein which binds to H3 tails trimethylated on 'Lys-4' (H3K4me3), which mark transcription start sites of active genes (PubMed:16728976, PubMed:16728978). Binds to histone H3 tails dimethylated on 'Lys-4' (H3K4Me2) to a lesser extent (PubMed:16728976, PubMed:16728978, PubMed:18042461). May also regulate transcription through direct binding to DNA or transcription factors (PubMed:10575013).
Several sequencing errors in the N-terminal part.
The second PHD-type zinc finger mediates binding to histone H3K4Me3. Has specificity for trimethyllysine; introducing a mutation in the Tyr-2876 residue can induce binding to dimethyllysine.
Ubiquitously expressed, with highest levels in testis. Present in kidney, liver and brain. In the brain, highest levels are found in motor cortex (at protein level).
May form homodimers and heterodimers with GLP1R.
N-glycosylation is required for cell surface expression and lengthens receptor half-life by preventing degradation in the ER.
This is a receptor for GIP. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Belongs to the dihydroxyacetone kinase (DAK) family.
Catalyzes both the phosphorylation of dihydroxyacetone and of glyceraldehyde, and the splitting of ribonucleoside diphosphate-X compounds among which FAD is the best substrate. Represses IFIH1-mediated cellular antiviral response (PubMed:17600090).
Detected in erythrocytes (at protein level).
DhaK and DhaL domains have differential roles, individually DhaK is inactive and DhaL displays cyclase but not kinase activity.
Each activity is inhibited by the substrate(s) of the other.
Homodimer (By similarity). Interacts with IFIH1 (via the CARD domains), the interaction is inhibited by viral infection (PubMed:17600090).
Manganese or cobalt are requested for FAD-AMP lyase activity.
Antiporter that transports nucleotide sugars across the endoplasmic reticulum (ER) membrane in exchange for another nucleotide sugar. May couple UDP-alpha-D-glucuronate (UDP-GlcA) or UDP-alpha-D-xylose (UDP-Xyl) efflux to UDP-alpha-D-glucuronate (UDP-GlcA) influx into the ER lumen, which in turn stimulates glucuronidation and excretion of endobiotics and xenobiotics.
Has UDP-GlcA:UDP-GlcNAc antiporter activity.
It was initially reported to localize to the Golgi apparatus, but this was later found to be artifactual mislocalization due to C-terminal tagging interfering with the ER retention signal.
Belongs to the methylmalonyl-CoA epimerase family.
Methylmalonyl-CoA epimerase involved in propionyl-CoA metabolism.
Acetylated on lysine residues. BLOC1S1 is required for acetylation.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). CF(0) has three main subunits: a, b and c (By similarity). Interacts with ATPAF2 (PubMed:11410595). Interacts with HRG; the interaction occurs on the surface of T-cells and alters the cell morphology when associated with concanavalin (in vitro) (PubMed:19285951). Interacts with PLG (angiostatin peptide); the interaction inhibits most of the angiogenic properties of angiostatin (PubMed:10077593). Component of an ATP synthase complex composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5PD, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and ATP5MJ (By similarity). Interacts with BLOC1S1 (PubMed:22309213). Interacts with BCL2L1 isoform BCL-X(L); the interaction mediates the association of BCL2L1 isoform BCL-X(L) with the mitochondrial membrane F(1)F(0) ATP synthase and enhances neurons metabolic efficiency (By similarity). Interacts with CLN5 and PPT1 (By similarity). Interacts with S100A1; this interaction increases F1-ATPase activity (By similarity). Interacts with ABCB7; this interaction allows the regulation of cellular iron homeostasis and cellular reactive oxygen species (ROS) levels in cardiomyocytes (By similarity).
Fetal lung, heart, liver, gut and kidney. Expressed at higher levels in the fetal brain, retina and spinal cord.
Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Subunits alpha and beta form the catalytic core in F(1). Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits. Subunit alpha does not bear the catalytic high-affinity ATP-binding sites (By similarity). Binds the bacterial siderophore enterobactin and can promote mitochondrial accumulation of enterobactin-derived iron ions (PubMed:30146159).
Produces ATP from ADP in the presence of a proton gradient across the membrane.
The siderophore enterobactin (Ent) produced by enteric bacteria binds Fe(3+) and helps bacteria scavenge iron ions from the environment (PubMed:30146159). As a consequence, the mammalian siderocalin LCN2 plays an important role in defense against bacterial infections by sequestering iron bound to microbial siderophores. LCN2 can also bind iron bound to endogenous or nutrient-derived iron chelators and plays an important role in cellular iron homeostasis. Enterobactin produced by non-pathogenic E.coli strains can facilitate mitochondrial iron assimilation, suggesting that iron bound to siderophores from non-pathogenic bacteria may contribute to iron absorption by the host (PubMed:30146159).
Catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a cellular oxygen sensor and, under normoxic conditions, may target HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
Widely expressed with highest levels in adult pancreas, heart, skeletal muscle, brain, placenta, kidney and adrenal gland. Expressed at lower levels in epiphyseal cartilage and in fibroblasts.
A disulfide bond between Cys-338 and Cys-388 is observed in a structure (PubMed:27627798). Its existence is however unsure in vivo.
Heterodimer; heterodimerizes with METTL3 to form an antiparallel heterodimer that constitutes an active methyltransferase (PubMed:27627798, PubMed:27373337, PubMed:27281194). Component of the WMM complex, a N6-methyltransferase complex composed of a catalytic subcomplex, named MAC, and of an associated subcomplex, named MACOM (PubMed:24407421, PubMed:24981863, PubMed:24316715, PubMed:29507755, PubMed:29348140). The MAC subcomplex is composed of METTL3 and METTL14 (PubMed:24407421, PubMed:24981863, PubMed:24316715, PubMed:29507755). The MACOM subcomplex is composed of WTAP, ZC3H13, CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B) (PubMed:29507755).
The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N(6) position of some mRNAs and regulates the circadian clock, differentiation of embryonic stem cells and cortical neurogenesis (PubMed:24316715, PubMed:24407421, PubMed:25719671, PubMed:29348140, PubMed:27373337, PubMed:27281194). In the heterodimer formed with METTL3, METTL14 constitutes the RNA-binding scaffold that recognizes the substrate rather than the catalytic core (PubMed:27627798, PubMed:27373337, PubMed:27281194, PubMed:29348140). N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in mRNA stability and processing (PubMed:24316715, PubMed:24407421, PubMed:25719671). M6A acts as a key regulator of mRNA stability by promoting mRNA destabilization and degradation (By similarity). In embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization (By similarity). M6A regulates spermatogonial differentiation and meiosis and is essential for male fertility and spermatogenesis (By similarity). M6A also regulates cortical neurogenesis: m6A methylation of transcripts related to transcription factors, neural stem cells, the cell cycle and neuronal differentiation during brain development promotes their destabilization and decay, promoting differentiation of radial glial cells (By similarity).
The ability of METTL14 to have catalytic activity is unclear and a number of experimental evidence suggests that it has no methyltransferase activity by itself (PubMed:27627798, PubMed:27281194, PubMed:27373337). According to some reports, has some methyltransferase activity in vitro (PubMed:24316715). However, other studies showed that METTL14 constitutes the RNA-binding scaffold that recognizes the substrate rather than the catalytic core (PubMed:27627798, PubMed:27281194, PubMed:27373337). 3D-structure studies showed that METTL14 contains a degenerate active site that is unable to accommodate donor and acceptor substrates (PubMed:27627798).
The effect of phosphorylation at Ser-399 is unclear. According to a report, phosphorylation at Ser-399 is important for interaction with METTL3: phosphorylated Ser-399 forms a salt bridge with 'Arg-471' of METTL3 (PubMed:27281194). According to another report, phosphorylation at Ser-399 does not affect interaction with METTL3 (PubMed:29348140).
Detected in blood serum. Detected in macrophages (at protein level).
Has in vitro nucleotide phosphodiesterase activity with nucleoside triphosphates, such as ATP (PubMed:25288789, PubMed:26783088). Has in vitro activity with p-nitrophenyl-TMP (PubMed:25288789). Has lower activity with nucleoside diphosphates, and no activity with nucleoside monophosphates (PubMed:25288789, PubMed:26783088). Has in vitro activity with CDP-choline, giving rise to CMP and phosphocholine. Has in vitro activity with CDP-ethanolamine (PubMed:26783088). Does not have sphingomyelin phosphodiesterase activity (PubMed:25288789, PubMed:26783088).
Requires micromolar levels of Zn(2+) for activity (PubMed:26783088). Inhibited by millimolar levels of Zn(2+) (PubMed:25288789, PubMed:26783088).
Up-regulated in macrophages in response to cholesterol accumulation. Up-regulated by cAMP.
Removes sulfate groups from chondroitin-4-sulfate (C4S) and regulates its degradation (PubMed:19306108). Involved in the regulation of cell adhesion, cell migration and invasion in colonic epithelium (PubMed:19306108). In the central nervous system, is a regulator of neurite outgrowth and neuronal plasticity, acting through the control of sulfate glycosaminoglycans and neurocan levels (By similarity).
The protein represented in this entry is involved in disease pathogenesis. Arylsulfatase B activity is impaired in multiple sulfatase deficiency due to mutations in SUMF1. SUMF1 mutations result in defective post-translational modification of ARSB at residue Cys-91 that is not converted to 3-oxoalanine.
Belongs to the proton-activated chloride channel family.
Proton-activated chloride channel that mediates import of chloride ion in response to extracellular acidic pH (PubMed:31023925, PubMed:31318332). Involved in acidosis-induced cell death by mediating chloride influx and subsequent cell swelling (PubMed:31023925, PubMed:31318332).
Expressed in many tissues, the highest levels among the tissues studied being in the skeletal muscle, testis and pancreas. Expressed in cartilage.
May modulate the formation of a collagenous extracellular matrix.
G-proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. Interacts with ADGRB2 (PubMed:28891236).
Highly expressed in heart. Detected at lower levels in placenta and pancreas.
Interacts with Ras family members that have been activated by GTP binding. Interacts with HRAS, RAP1A, RAP2, RRAS, RAF1 and RRAS2. Interacts with MYH9 and ARHGAP29 (By similarity).
Required for the proper formation of vascular structures that develop via both vasculogenesis and angiogenesis. Acts as a critical and vascular-specific regulator of GTPase signaling, cell architecture, and adhesion, which is essential for endothelial cell morphogenesis and blood vessel tubulogenesis. Regulates the activity of Rho GTPases in part by recruiting ARHGAP29 and suppressing RhoA signaling and dampening ROCK and MYH9 activities in endothelial cells (By similarity). May act as effector for Golgi-bound HRAS and other Ras-like proteins. May promote HRAS-mediated transformation. Negative regulator of amino acid starvation-induced autophagy.
Essential for sperm motility and male fertility (PubMed:26677959). Not required for the completion of spermatogenesis (By similarity).
Mainly found in round spermatids. Localized on the principle piece in the sperm (at protein level). Testis-specific. Expression significantly decreased in the testis of elderly men.
'Vav' stands for the sixth letter of the Hebrew alphabet.
Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation.
Interacts with SHB (PubMed:12084069). Interacts with SH2B2, GRB2, GRB3, DOCK2, SLA, TEC and ZNF655/VIK (PubMed:12393632, PubMed:12400014, PubMed:15558030). Interacts with SIAH2; without leading to its degradation (PubMed:10207103). Associates with BLNK, PLCG1, GRB2 and NCK1 in a B-cell antigen receptor-dependent fashion (PubMed:9697839). Interacts with CBLB; which inhibits tyrosine phosphorylation and down-regulates activity (PubMed:9399639). May interact with CCPG1. Interacts with CLNK. Interacts with THEMIS2 (By similarity). Interacts with NEK3 and this interaction is prolactin-dependent (PubMed:15618286). Interacts with ITK (PubMed:15661896). Interacts with PTK2B/PYK2 (By similarity). Interacts with HCK. Interacts with PTK2B/PYK2 (PubMed:19207108). Interacts (via SH2 domain) with SYK (PubMed:8986718). Interacts with ANKRD54. Interacts with CD6 (By similarity). Interacts with isoform 2 of CRACR2A (PubMed:27016526).
Phosphorylated on tyrosine residues by HCK in response to IFNG and bacterial lipopolysaccharide (LPS) (By similarity). Phosphorylated by FYN.
Widely expressed in hematopoietic cells but not in other cell types.
Catalyzes the oxidation of sulfhydryl groups in peptide and protein thiols to disulfides with the reduction of oxygen to hydrogen peroxide. May contribute to disulfide bond formation in a variety of secreted proteins. Also seems to play a role in regulating the sensitization of neuroblastoma cells for interferon-gamma-induced apoptosis.
Expressed in pancreas, brain, placenta, kidney, heart and fetal tissues. Weakly expressed in lung, liver and skeletal muscles.
The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. In SP9, the motif is inactive.
Transcription factor which plays a key role in limb development. Positively regulates FGF8 expression in the apical ectodermal ridge (AER) and contributes to limb outgrowth in embryos (By similarity).
N-glycosylation is necessary for assembly and functional expression of the pump at the plasma membrane.
The ATPase pump is composed of two subunits: alpha (catalytic) and beta (regulatory). Interacts with alpha subunit ATP12A; this interaction is required for the formation of a functionally active pump and targeting at the plasma membrane (By similarity). Interacts (via N-terminus) with alpha subunit ATP4A (via the P-domain) (By similarity).
The beta subunit of the gastric H(+)/K(+) ATPase pump which transports H(+) ions in exchange for K(+) ions across the apical membrane of parietal cells. Plays a structural and regulatory role in the assembly and membrane targeting of a functionally active pump (By similarity). Within a transport cycle, the transfer of a H(+) ion across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation of the alpha subunit that shifts the pump conformation from inward-facing (E1) to outward-facing state (E2). Interacts with the phosphorylation domain of the alpha subunit and functions as a ratchet, stabilizing the lumenal-open E2 conformation and preventing the reverse reaction of the transport cycle (By similarity).
Smooth muscle; contractile or vascular (for the long form).
Interacts with PTPN6/SHP-1 upon phosphorylation.
Predominantly expressed by resting and activated natural killer cells and at lower levels by granulocytes and monocytes. High expression found in placenta, liver, lung, spleen, and peripheral blood leukocytes.
Putative adhesion molecule that mediates sialic-acid dependent binding to cells. Preferentially binds to alpha-2,3- and alpha-2,6-linked sialic acid. Also binds disialogangliosides (disialogalactosyl globoside, disialyl lactotetraosylceramide and disialyl GalNAc lactotetraoslylceramide). The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface. In the immune response, may act as an inhibitory receptor upon ligand induced tyrosine phosphorylation by recruiting cytoplasmic phosphatase(s) via their SH2 domain(s) that block signal transduction through dephosphorylation of signaling molecules. Mediates inhibition of natural killer cells cytotoxicity. May play a role in hemopoiesis. Inhibits differentiation of CD34+ cell precursors towards myelomonocytic cell lineage and proliferation of leukemic myeloid cells (in vitro).
Cooperates with ASF1A to promote replication-independent chromatin assembly. Required for the periodic repression of histone gene transcription during the cell cycle. Required for the formation of senescence-associated heterochromatin foci (SAHF) and efficient senescence-associated cell cycle exit.
Expressed at high levels in kidney, pancreas and skeletal muscle and at lower levels in brain, heart, liver, lung, and placenta.
Interacts with histone H3-3B, PAX3 and PAX7 (By similarity). Interacts with histone H3.Y (PubMed:28334823). Interacts with CCNA1, HIRIP3, NFU1/HIRIP5 and histone H2B. Part of a complex which includes ASF1A, CABIN1, histone H3.3, histone H4 and UBN1 (PubMed:11238922, PubMed:14680630, PubMed:14718166, PubMed:15621527, PubMed:16980972, PubMed:19029251, PubMed:9710638).
Phosphorylated by CDK2/CCNA1 and CDK2/CCNE1 on Thr-555 in vitro. Also phosphorylated on Thr-555 and Ser-687 in vivo.
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO33) formed of CUL1, SKP1, RBX1 and FBXO33. Interacts via its N-terminus with YBX1 CSD domain. Directly interacts with SKP1 and CUL1 (By similarity).
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Probably recognizes and binds to phosphorylated target proteins. Recognizes YBX1 (By similarity).
Acts as a positive regulator of ciliary hedgehog signaling. Required for centriole stability.
Interacts with TEDC1. Found in a complex with TEDC1, TEDC2, TUBE1 and TUBD1.
Involved in mitochondrial ribosome assembly. 5-methylcytosine rRNA methyltransferase that probably is involved in mitochondrial ribosome small subunit (SSU) maturation by methylation of mitochondrial 12S rRNA; the function is independent of MTERFD2/MTERF4 and assembled mitochondrial ribosome large subunit (LSU). Targeted to LSU by MTERFD2/MTERF4 and probably is involved in a final step in ribosome biogenesis to ensure that SSU and LSU are assembled. In vitro can methylate 16S rRNA of the LSU; the methylation is enhanced by MTERFD/MTERF4.
Activates angiogenesis and cell migration (PubMed:28052032). Downregulates the expression of the endothelial adhesion molecules ICAM1 and VCAM1 (PubMed:28052032).
Expressed in several normal and cancer cell lines, including A549, HUVEC, MCF7, HeLa, A172 and ADF cells (at protein level) (PubMed:28052032). Up-regulated in high-grade glioma samples (PubMed:28052032).
Expressed in the promyelocytic cell line HL-60, the granulocyte-macrophage colony-stimulating factor-dependent leukemic cell line F-36P, and the IL3 and erythropoietin-dependent leukemic cell line F-36E. Expressed predominantly in epithelial cells and lymphocytes. Enhanced expression at high cell density.
Monomer. Interacts with CTNNB1 (phosphorylated) and JUP (phosphorylated). Interacts with FLT3 (phosphorylated). Interacts with GAB1 and GRB2.
Originally thought to dephosphorylate RET. However this paper was retracted due to manipulation of immunoblot data.
Tyrosine phosphatase which dephosphorylates or contributes to the dephosphorylation of CTNND1, FLT3, PDGFRB, MET, KDR, LYN, SRC, MAPK1, MAPK3, EGFR, TJP1, OCLN, PIK3R1 and PIK3R2 (PubMed:10821867, PubMed:12062403, PubMed:12370829, PubMed:12475979, PubMed:18348712, PubMed:19494114, PubMed:19922411, PubMed:21262971). Plays a role in cell adhesion, migration, proliferation and differentiation (PubMed:12370829, PubMed:14709717, PubMed:16682945, PubMed:19836242). Involved in vascular development (By similarity). Regulator of macrophage adhesion and spreading (By similarity). Positively affects cell-matrix adhesion (By similarity). Positive regulator of platelet activation and thrombosis. Negative regulator of cell proliferation (PubMed:16682945). Negative regulator of PDGF-stimulated cell migration; through dephosphorylation of PDGFR (PubMed:21091576). Positive regulator of endothelial cell survival, as well as of VEGF-induced SRC and AKT activation; through KDR dephosphorylation (PubMed:18936167). Negative regulator of EGFR signaling pathway; through EGFR dephosphorylation (PubMed:19836242). Enhances the barrier function of epithelial junctions during reassembly (PubMed:19332538). Negatively regulates T-cell receptor (TCR) signaling (PubMed:9531590, PubMed:9780142, PubMed:11259588). Upon T-cell TCR activation, it is up-regulated and excluded from the immunological synapses, while upon T-cell-antigen presenting cells (APC) disengagement, it is no longer excluded and can dephosphorylate PLCG1 and LAT to down-regulate prolongation of signaling (PubMed:11259588, PubMed:12913111).
Binds U2AF2. Interacts with U1 snRNA. Binds EWSR1, FUS and TAF15. Interacts with RBM17.
Detected in lung, ovary, adrenal gland, colon, kidney, muscle, pancreas, thyroid, placenta, brain, liver and heart.
Necessary for the ATP-dependent first step of spliceosome assembly. Binds to the intron branch point sequence (BPS) 5'-UACUAAC-3' of the pre-mRNA. May act as transcription repressor.
Necessary for the splicing of pre-mRNA. Has a role in the recognition of the branch site (5'-UACUAAC-3'), the pyrimidine tract and the 3'-splice site at the 3'-end of introns.
Phosphorylation on Ser-20 interferes with U2AF2 binding and spliceosome assembly. Isoform 6 is phosphorylated on Ser-463.
Efficient DNA binding requires dimerization with another bHLH protein. Homodimer.
Transcription factor that activates both viral and cellular genes by binding to the symmetrical DNA sequence 5'-CAGCTG-3'.
In adult brain, highly expressed in putamen with no expression in cerebral cortex. Expressed in adult and fetal lung and fetal liver. Also expressed at high levels in some brain tumors including medulloblastomas and primitive neuroectodermal tumors.
Regulator of neurite outgrowth required for normal hearing and vision.
Belongs to the glycosyltransferase 65 family.
Catalyzes the reaction that attaches fucose through an O-glycosidic linkage to a conserved serine or threonine residue found in the consensus sequence C2-X(4,5)-[S/T]-C3 of EGF domains, where C2 and C3 are the second and third conserved cysteines. Specifically uses GDP-fucose as donor substrate and proper disulfide pairing of the substrate EGF domains is required for fucose transfer. Plays a crucial role in NOTCH signaling. Initial fucosylation of NOTCH by POFUT1 generates a substrate for FRINGE/RFNG, an acetylglucosaminyltransferase that can then extend the fucosylation on the NOTCH EGF repeats. This extended fucosylation is required for optimal ligand binding and canonical NOTCH signaling induced by DLL1 or JAGGED1. Fucosylates AGRN and determines its ability to cluster acetylcholine receptors (AChRs).
Highly expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Homooligomer and heterooligomer with other family members. Interacts with PAX5 (By similarity). Interacts with LEF1, TCF7, TCF7L1 and TCF7L2 (By similarity). Interacts with ZNF703; TLE4 may mediate ZNF703 transcriptional repression (By similarity). Interacts with SIX3 and SIX6 (By similarity). Interacts with PAX2 (PubMed:24676634). Interacts with TLE1 (By similarity).
In all tissues examined, mostly in brain, and muscle.
Phosphorylated. PAX5 binding increases phosphorylation.
Transcriptional corepressor that binds to a number of transcription factors. Inhibits the transcriptional activation mediated by PAX5, and by CTNNB1 and TCF family members in Wnt signaling. The effects of full-length TLE family members may be modulated by association with dominant-negative AES. Essential for the transcriptional repressor activity of SIX3 during retina and lens development and for SIX3 transcriptional auto-repression (By similarity). Involved in transcriptional repression of GNRHR and enhances MSX1-mediated transcriptional repression of CGA/alpha-GSU (By similarity).
Interacts with GCC2 (PubMed:18195106). Interacts with BAIAP3; this interaction is increased in the presence of calcium (PubMed:28626000).
SNARE involved in vesicular transport from the late endosomes to the trans-Golgi network.
The gene represented in this entry is involved in disease pathogenesis. Microdeletions involving STX16 can cause loss of methylation at exon A/B of GNAS, resulting in PHP1B.
GRAM domain is required for specific location to endoplasmic reticulum-plasma membrane contact sites (EPCS). Mediates interaction to phosphatidylinositol lipids and binding to plasma membrane.
Participates in the organization of endoplasmic reticulum-plasma membrane contact sites (EPCS) with pleiotropic functions including STIM1 recruitment and calcium homeostasis. Constitutive tether that co-localize with ESYT2/3 tethers at endoplasmic reticulum-plasma membrane contact sites in a phosphatidylinositol lipid-dependent manner. Pre-marks the subset of phosphtidylinositol 4,5-biphosphate (PI(4,5)P2)-enriched EPCS destined for the store operated calcium entry pathway (SOCE).
Can form homodimers and heterodimers. Interacts with CBX5, CBX1 and CBX3 via PxVxL motif (By similarity).
May function as transcription repressor; The repressive effects are mediated, at least in part, by recruitment of deacetylase activity. May play a role as negative regulator of postmeiotic genes acting through CBX3 complex formation and centromere association (By similarity).
By the tumor promoter phorbol 12-myristate 13-acetate (PMA) in the presence of cycloheximide.
Endothelial cells, and to a lesser extent, in vascular smooth muscle cells, fibroblasts, melanocytes, and cells of epithelioid origin.
G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activation of RAC1, SRC, PTK2/FAK1 and MAP kinases. Plays an important role in cell migration, probably via its role in the reorganization of the actin cytoskeleton and the formation of lamellipodia in response to stimuli that increase the activity of the sphingosine kinase SPHK1. Required for normal chemotaxis toward sphingosine 1-phosphate. Required for normal embryonic heart development and normal cardiac morphogenesis. Plays an important role in the regulation of sprouting angiogenesis and vascular maturation. Inhibits sprouting angiogenesis to prevent excessive sprouting during blood vessel development. Required for normal egress of mature T-cells from the thymus into the blood stream and into peripheral lymphoid organs. Plays a role in the migration of osteoclast precursor cells, the regulation of bone mineralization and bone homeostasis (By similarity). Plays a role in responses to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine by pulmonary endothelial cells and in the protection against ventilator-induced lung injury.
Palmitoylated by ZDHHC5. Palmitoylation is required for targeting to plasma membrane, enabling G(i) coupling.
S1P-induced endothelial cell migration requires the PKB/AKT1-mediated phosphorylation of the third intracellular loop at the Thr-236 residue.
Catalyzes the transfer of one adenosine molecule from an ATP to an mRNA poly(A) tail bearing a 3'-OH terminal group.
Chromatin reader component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4 (PubMed:18838386, PubMed:19103755, PubMed:27103431). YEATS2 specifically recognizes and binds histone H3 crotonylated at 'Lys-27' (H3K27cr) (PubMed:27103431). Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:27103431).
Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, SGF29 and DR1.
The YEATS domain specifically recognizes and binds crotonylated histones.
Binds 3 calcium via EF-hand domains. The cryptic EF-hand 1 does not bind calcium.
Calcium-binding protein that may play a role in the regulation of voltage-dependent calcium channels (PubMed:28398555). May also play a role in cyclic-nucleotide-mediated signaling through the regulation of adenylate and guanylate cyclases (By similarity).
Myristoylation facilitates association with membranes.
Oligomer; oligomerization is calcium-dependent (PubMed:28398555). May interact with the voltage-dependent P/Q- and N-type calcium channels CACNA1A and CACNA1B (PubMed:28398555).
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to an N-unsubstituted glucosamine linked to a 2-O-sulfo iduronic acid unit on heparan sulfate (PubMed:10520990, PubMed:9988768, PubMed:10608887, PubMed:15304505). Catalyzes the O-sulfation of glucosamine in IdoUA2S-GlcNS and also in IdoUA2S-GlcNH2 (PubMed:10520990, PubMed:9988768, PubMed:15304505). The substrate-specific O-sulfation generates an enzyme-modified heparan sulfate which acts as a binding receptor to Herpes simplex virus-1 (HSV-1) and permits its entry (PubMed:10520990). Unlike HS3ST1/3-OST-1, does not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate (PubMed:10520990).
Ubiquitous. Most abundant in heart and placenta, followed by liver and kidney.
Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:21282113, PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. In the BRCA1-A complex, interacts directly with ABRAXAS1, BRCC3/BRCC36 and BABAM1/NBA1. Binds polyubiquitin. Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19214193, PubMed:21282113, PubMed:24075985, PubMed:25283148). Identified in a complex with SHMT2 and the other subunits of the BRISC complex (PubMed:24075985). Component of the BRCA1/BRCA2 containing complex (BRCC), which also contains BRCA1, BRCA2, BARD1, BRCC3/BRCC36 and RAD51. BRCC is a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage. May interact with FAS and TNFRSF1A (PubMed:15465831).
Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX (PubMed:17525341, PubMed:19261746, PubMed:19261749, PubMed:19261748). In the BRCA1-A complex, it acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity and modulating the E3 ubiquitin ligase activity of the BRCA1-BARD1 heterodimer (PubMed:21282113, PubMed:19261748). Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:19214193, PubMed:24075985, PubMed:25283148, PubMed:26195665). Within the BRISC complex, acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity (PubMed:21282113). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). The BRISC complex plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985). May play a role in homeostasis or cellular differentiation in cells of neural, epithelial and germline origins. May also act as a death receptor-associated anti-apoptotic protein, which inhibits the mitochondrial apoptotic pathway. May regulate TNF-alpha signaling through its interactions with TNFRSF1A; however these effects may be indirect (PubMed:15465831).
Contains 2 ubiquitin-conjugating enzyme family-like (UEV-like) regions. These regions lack the critical Cys residues required for ubiquitination but retain the ability to bind ubiquitin.
Down-regulated by DNA-damaging agents in fibroblasts, by retinoic acid in brain glioma U-251MG and promyelocytic HL-60 cell lines, and by bacterial lipopolysaccharides (LPS) in peripheral blood mononuclear cells (PBMC).
Expressed in all cell lines examined. Highly expressed in placenta.
Interacts with PHB2; the interaction associates DNAJC19 with the prohibitin complex. Interacts with TIMM16/PAM16 (By similarity). May be a component of the PAM complex at least composed of a mitochondrial HSP70 protein, GRPEL1 or GRPEL2, TIMM44, TIMM16/PAM16 and TIMM14/DNAJC19 (By similarity).
Mitochondrial co-chaperone which forms a complex with prohibitins to regulate cardiolipin remodeling (By similarity). May be a component of the PAM complex, a complex required for the translocation of transit peptide-containing proteins from the inner membrane into the mitochondrial matrix in an ATP-dependent manner. May act as a co-chaperone that stimulate the ATP-dependent activity (By similarity).
Homodimer (Probable). Heterodimer with KCNK1.
Inhibited by external acidification. Activated by halothane and isoflurane.
Widespread expression in adult. Strongest expression in pancreas and placenta. Lower expression in brain, lung, prostate, heart, kidney, uterus, small intestine and colon.
pH-dependent, voltage-insensitive, background potassium channel protein. Rectification direction results from potassium ion concentration on either side of the membrane. Acts as an outward rectifier when external potassium concentration is low. When external potassium concentration is high, current is inward.
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. LI-cadherin may have a role in the morphological organization of liver and intestine. Involved in intestinal peptide transport.
Expressed in the gastrointestinal tract and pancreatic duct. Not detected in kidney, lung, liver, brain, adrenal gland and skin.
(Microbial infection) Interacts with zika virus serine protease NS3; this interaction disorganizes the centrosome.
CEP63 and DEUP1 paralogs are both involved in centriole amplification: while CEP63 mediates mother-centriole-dependent centriole duplication, DEUP1 mediates de novo centriole amplification in multiciliated cells.
Interacts with CEP152 and CDK1; these interactions recruit both ligands to centrosomes (PubMed:21406398). Interacts with CDK2, CDK5RAP2, WDR62, CEP90, KIAA0753/moonraker and CCDC14 (PubMed:21406398, PubMed:26297806). CEP63, CDK5RAP2, CEP152, WDR62 are proposed to form a stepwise assembled complex at the centrosome forming a ring near parental centrioles (PubMed:21406398, PubMed:21983783, PubMed:26297806). Interacts with CCDC57; the interaction is required for their location to proximal end of centrioles (PubMed:32402286). Interacts with FXR1; promoting its stabilization (PubMed:35989368).
Polyubiquitinated via 'Lys-48'-linked ubiquitin, leading to its degradation (PubMed:35989368). Deubiquitinated by USP36, promoting its stabilization (PubMed:35989368).
Required for normal spindle assembly (PubMed:21406398, PubMed:21983783, PubMed:26297806, PubMed:35793002). Plays a key role in mother-centriole-dependent centriole duplication; the function seems also to involve CEP152, CDK5RAP2 and WDR62 through a stepwise assembled complex at the centrosome that recruits CDK2 required for centriole duplication (PubMed:21983783, PubMed:26297806). Reported to be required for centrosomal recruitment of CEP152; however, this function has been questioned (PubMed:21983783, PubMed:26297806). Also recruits CDK1 to centrosomes (PubMed:21406398). Plays a role in DNA damage response (PubMed:21406398). Following DNA damage, such as double-strand breaks (DSBs), is removed from centrosomes; this leads to the inactivation of spindle assembly and delay in mitotic progression (PubMed:21406398). Promotes stabilization of FXR1 protein by inhibiting FXR1 ubiquitination (PubMed:35989368).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. NR3A/GRIN3A subfamily.
Forms heteromeric channel of a zeta subunit (GRIN1), a epsilon subunit (GRIN2A, GRIN2B, GRIN2C or GRIN2D) and a third subunit (GRIN3A or GRIN3B). Does not form functional homomeric channels. Found in a complex with GRIN1, GRIN2A or GRIN2B and PPP2CB (By similarity). Probably interacts with PPP2CB. No complex with PPP2CB is detected when NMDARs are stimulated by NMDA (PubMed:11588171). Interacts (via C-terminus) with GIT1, but not with GRIA1/GluA1, nor with synaptophysin/SYP; this interaction competes with GIT1 interaction with ARHGEF7/beta-PIX (By similarity).
NMDA receptor subtype of glutamate-gated ion channels with reduced single-channel conductance, low calcium permeability and low voltage-dependent sensitivity to magnesium. Mediated by glycine. During the development of neural circuits, plays a role in the synaptic refinement period, restricting spine maturation and growth. By competing with GIT1 interaction with ARHGEF7/beta-PIX, may reduce GIT1/ARHGEF7-regulated local activation of RAC1, hence affecting signaling and limiting the maturation and growth of inactive synapses. May also play a role in PPP2CB-NMDAR mediated signaling mechanism.
A homozygous deletion of RMI2 has been found in a family with a Bloom-like syndrome and is probable responsible for the phenotype. Patients manifest depigmented skin lesions, multiple cafe-au-lait macules, and growth deficiency. Cells from affected individuals show a high rate of sister chromatid exchange and increased chromosomal breaks.
Component of the RMI complex, containing at least TOP3A, RMI1 and RMI2. The RMI complex interacts with BLM.
Essential component of the RMI complex, a complex that plays an important role in the processing of homologous recombination intermediates. It is required to regulate sister chromatid segregation and to limit DNA crossover. Essential for the stability, localization, and function of BLM, TOP3A, and complexes containing BLM. In the RMI complex, it is required to target BLM to chromatin and stress-induced nuclear foci and mitotic phosphorylation of BLM.
May play a role in the correct development and proper functioning of the peripheral and central nervous system and be involved in cell adhesion and intercellular communication.
As a component of the inner core of AMPAR complex, modifies AMPA receptor (AMPAR) gating.
Component of the inner core of AMPAR complex. AMPAR complex consists of an inner core made of 4 pore-forming GluA/GRIA proteins (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged in a twofold symmetry. One of the two pairs of distinct binding sites is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR complex is complemented by outer core constituents binding directly to the GluA/GRIA proteins at sites distinct from the interaction sites of the inner core constituents. Outer core constituents include at least PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the inner and outer core serve as a platform for other, more peripherally associated AMPAR constituents. Alone or in combination, these auxiliary subunits control the gating and pharmacology of the AMPAR complex and profoundly impact their biogenesis and protein processing (By similarity).
Transcriptional repressor that suppresses transcription from the FASLG, FOXO3 and FOXO4 promoters. May have a role in the organization of the testicular vasculature (By similarity).
Forms a complex with CASK and CASKIN1 (By similarity). Component of the brain-specific heterotrimeric complex (LIN-10-LIN-2-LIN-7 complex) composed of at least APBA1, CASK, and LIN7, which associates with the motor protein KIF17 to transport vesicles along microtubules (By similarity). Forms a heterotrimeric complex composed of MMP5, LIN7B and PATJ; the N-terminal L27 domain of PALS1 interacts with the L27 domain of PATJ and the C-terminal L27 domain of PALS1 interacts with the L27 domain of LIN7B (By similarity). Forms a heterotrimeric complex with DLG1 and CASK via their L27 domains (PubMed:11742811, PubMed:17237226). Interacts with DLG4 and GRIN2B as well as CDH1 and CTNNB1, the channels KCNJ12/Kir2.2, KCNJ4/Kir2.3 and probably KCNJ2/Kir2.1 and SLC6A12/BGT-1 via its PDZ domain (PubMed:11742811). The association of LIN7A with cadherin and beta-catenin is calcium-dependent, occurs at synaptic junctions and requires the actin cytoskeleton. Interacts with EGFR, ERBB2, ERBB3 and ERBB4 with both PDZ and KID domains (PubMed:12967566). Associates with KIF17 via APBA1 (By similarity). Interacts with ASIC3 (PubMed:15317815). Interacts with TOPK. Interacts with RTKN (PubMed:16979770). Interacts with APBA1 (By similarity). Interacts with MPP7 (PubMed:17237226). Interacts with DLG2 (By similarity). Interacts with DLG3 (By similarity).
Plays a role in establishing and maintaining the asymmetric distribution of channels and receptors at the plasma membrane of polarized cells. Forms membrane-associated multiprotein complexes that may regulate delivery and recycling of proteins to the correct membrane domains. The tripartite complex composed of LIN7 (LIN7A, LIN7B or LIN7C), CASK and APBA1 associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules (By similarity). This complex may have the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Ensures the proper localization of GRIN2B (subunit 2B of the NMDA receptor) to neuronal postsynaptic density and may function in localizing synaptic vesicles at synapses where it is recruited by beta-catenin and cadherin. Required to localize Kir2 channels, GABA transporter (SLC6A12) and EGFR/ERBB1, ERBB2, ERBB3 and ERBB4 to the basolateral membrane of epithelial cells. May increase the amplitude of ASIC3 acid-evoked currents by stabilizing the channel at the cell surface (By similarity).
Critical regulator of endosomal recycling of numerous surface proteins, including integrins, signaling receptor and channels (PubMed:15121882, PubMed:15769472). Binds to NPxY sequences in the cytoplasmic tails of target cargos (PubMed:21512128). Associates with retriever and CCC complexes to prevent lysosomal degradation and promote cell surface recycling of numerous cargos such as integrins ITGB1, ITGB5 and their associated alpha subunits (PubMed:28892079, PubMed:22492727). Also required for maintenance of normal cell surface levels of APP and LRP1 (PubMed:16712798, PubMed:19005208). Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) (PubMed:16712798).
Monomer (PubMed:21512128). Interacts with APP (via cytoplasmic YXNPXY motif) (By similarity). Interacts with KIF1B (By similarity). Interacts with the C-termini of P-selectin, PTC, LDLR, VLDLR, LRP1 and LRP8 (PubMed:11237770, PubMed:14739284, PubMed:15769472, PubMed:19005208). Interacts with KRIT1 (via N-terminus) (PubMed:16712798). Interacts with HRAS (PubMed:21512128). Interacts with ITGB1 and ITGB5 (via NPxY motif) (PubMed:22492727). Interacts with CCDC22, CCDC93, VPS26C and VPS35L; the interaction with VPS26C is direct and associates SNX17 with the retriever and CCC complexes (PubMed:28892079).
The PTB-like F3 module within the FERM-like domain mediates cargo recognition via their NPxY sequences, while the F1 module (Ras-associating) is responsible for interaction with membrane-bound HRAS.
The PX domain mediates specific binding to phosphatidylinositol 3-phosphate (PtdIns(P3)). Required for association with endosomes.
Within the ovary, required for the organization of somatic cells and oocytes into discrete follicular structures.
Binds to filamentous actin (F-actin), but not to monomeric G-actin, independently of its phosphorylation status.
Controls cell movement by regulating actin cytoskeleton homeostasis and filopodium and lamellipodium formation (PubMed:22751924). When unphosphorylated, induces cell migration (By similarity). When phosphorylated by MAPK8, induces actin bundles formation and stabilization, thereby reducing actin plasticity, hence restricting cell movement, including neuronal migration (By similarity). May be involved in coupling the protein kinase C and calmodulin signal transduction systems (By similarity).
Phosphorylated. Phosphorylation at Ser-120 and Thr-178 is non-redundantly catalyzed by MAPK8 in vivo. Phosphorylation at Thr-148 is preferentially catalyzed by MAPK8 in vivo, but this modification can also be catalyzed by other kinases in the absence of MAPK8. May be phosphorylated by protein kinase C, which disrupts the interaction with calmodulin.
Detected in placenta (at protein level).
Placental ALP is highly polymorphic, there are at least three common alleles.
Belongs to the ERCC1/RAD10/SWI10 family.
Heterodimer composed of ERCC1 isoform 1 and ERCC4/XPF (PubMed:16076955, PubMed:16338413, PubMed:24036546, PubMed:25538220, PubMed:32034146). Interacts with USP45 (PubMed:25538220).
Non-catalytic component of a structure-specific DNA repair endonuclease responsible for the 5'-incision during DNA repair. Responsible, in conjunction with SLX4, for the first step in the repair of interstrand cross-links (ICL). Participates in the processing of anaphase bridge-generating DNA structures, which consist in incompletely processed DNA lesions arising during S or G2 phase, and can result in cytokinesis failure. Also required for homology-directed repair (HDR) of DNA double-strand breaks, in conjunction with SLX4.
Not functional in the nucleotide excision repair pathway.
Ubiquitinated with both 'Lys-48' and 'Lys-63' linkages (PubMed:25538220). Deubiquitinated by USP45 (PubMed:25538220).
'Pegasus' was the winged horse in Greek mythology.
C-terminal zinc fingers mediate homodimerization.
Expressed in brain, heart, skeletal muscle, kidney, and liver. Expressed in the hematopoietic cell lines MOLT-4, NALM-6 and K-562. Highly expressed in THP-1 and M-07e cell lines, which have characteristics of myeloid and early megakaryocytic cells respectively.
Self-associates. Interacts with other family members; IKZF1, IKZF2, IKZF3 and IKZF4.
The N-terminal zinc fingers are involved in sequence-specific DNA binding and heterotypic associations with other family members.
Transcriptional repressor that binds the core 5'GNNTGTNG-3' DNA consensus sequence (PubMed:10978333, PubMed:31217188). Involved in megakaryocyte differentiation.
ADP-ribosylated by SIRT4, leading to inactivate glutamate dehydrogenase activity (PubMed:16959573). Stoichiometry shows that ADP-ribosylation occurs in one subunit per catalytically active homohexamer (PubMed:16023112).
Belongs to the Glu/Leu/Phe/Val dehydrogenases family.
Homohexamer (By similarity). Interacts with HADH; this interaction inhibits the activation of GLUD1 (By similarity).
Mitochondrial glutamate dehydrogenase that catalyzes the conversion of L-glutamate into alpha-ketoglutarate. Plays a key role in glutamine anaplerosis by producing alpha-ketoglutarate, an important intermediate in the tricarboxylic acid cycle (PubMed:11032875, PubMed:16959573, PubMed:11254391, PubMed:16023112). Plays a role in insulin homeostasis (PubMed:9571255, PubMed:11297618). May be involved in learning and memory reactions by increasing the turnover of the excitatory neurotransmitter glutamate (By similarity).
Subject to allosteric regulation. Activated by ADP (PubMed:11903050). Inhibited by GTP and ATP (PubMed:11254391, PubMed:11032875, PubMed:9571255, PubMed:11903050, PubMed:11297618). ADP can occupy the NADH binding site and activate the enzyme (PubMed:16023112). Inhibited by SIRT4 (PubMed:16959573). Inhibited by HADH (By similarity).
Interacts with SPAST and ATL1; it preferentially interacts with SPAST isoform 1 (PubMed:20200447). Interacts (via C-terminus) with microtubules (PubMed:20200447). Interacts with odorant receptor proteins (By similarity). Interacts with ZFYVE27 (PubMed:23969831).
Required for endoplasmic reticulum (ER) network formation, shaping and remodeling; it links ER tubules to the cytoskeleton. May also enhance the cell surface expression of odorant receptors (PubMed:20200447). May play a role in long-term axonal maintenance (PubMed:24478229).
Chromosomal aberrations involving TCF3 are cause of forms of pre-B-cell acute lymphoblastic leukemia (B-ALL). Translocation t(1;19)(q23;p13.3) with PBX1. TCF3-PBX1 transforms cells by constitutively activating transcription of genes regulated by PBX1 or by other members of the PBX protein family (PubMed:1967983, PubMed:1671560). Translocation t(17;19)(q22;p13.3) with HLF (PubMed:1386162). Inversion inv(19)(p13;q13) with TFPT (PubMed:10086727).
Facilitates ATOH7 binding to DNA at the consensus sequence 5'-CAGGTG-3', and positively regulates transcriptional activity.
Forms a heterodimer with ATOH7; required for ATOH7 DNA-binding.
Homodimer (PubMed:2112746, PubMed:14752053). Heterodimer; efficient DNA binding requires dimerization with another bHLH protein (By similarity). Forms a heterodimer with ASH1, TWIST1 and TWIST2 (By similarity). Forms a heterodimer with MYOG; heterodimerization enhances MYOG DNA-binding and transcriptional activities (By similarity). Forms a heterodimer with NEUROD1; the heterodimer is inhibited in presence of ID2, but not NR0B2, to E-box element (PubMed:14752053). Forms a heterodimer with TCF15; the heterodimer binds E-box element (By similarity). Forms a heterodimer with ATOH8; repress transcription of TCF3 and TCF3/NEUROG3 dimer-induced transactivation of E box-dependent promoters (By similarity). Component of a nuclear TAL-1 complex composed at least of CBFA2T3, LDB1, TAL1 and TCF3 (By similarity). Interacts with NEUROD2, PTF1A and TGFB1I1 (By similarity). Interacts with EP300 and UBE2I (PubMed:9409784, PubMed:14752053). Interacts with BHLHA9 (PubMed:25466284). Interacts with ASB2; the interaction is mediated by SKP2 and targets TCF3 for Notch-induced proteasomal degradation (PubMed:21119685).
Phosphorylated following NGF stimulation.
The bHLH domain encompassing amino acids 546 to 599 is sufficient to mediate DNA-binding and homodimerization. Combined mutagenesis of Phe-566 and Leu-569 to Asp-566 and Glu-569, mutagenesis of Lys-585 to Ala-585 or combined mutagenesis of Ile-588 and Leu-589 to Asp-588 and Glu-589 prevents DNA-binding and homodimerization. Mutagenesis of Arg-548 to Lys-548, combined mutagenesis of Arg-547 and Arg-548 to Gly-547 and Gly-548, mutagenesis of Arg-556 to Lys-556, mutagenesis of Arg-558 to Lys-558, or combined mutagenesis of Arg-556 and Arg-558 to Gly-556 and Gly-558, alter DNA-binding but not dimerization.
Transcriptional regulator involved in the initiation of neuronal differentiation and mesenchymal to epithelial transition (By similarity). Heterodimers between TCF3 and tissue-specific basic helix-loop-helix (bHLH) proteins play major roles in determining tissue-specific cell fate during embryogenesis, like muscle or early B-cell differentiation (By similarity). Together with TCF15, required for the mesenchymal to epithelial transition (By similarity). Dimers bind DNA on E-box motifs: 5'-CANNTG-3' (By similarity). Binds to the kappa-E2 site in the kappa immunoglobulin gene enhancer (PubMed:2493990). Binds to IEB1 and IEB2, which are short DNA sequences in the insulin gene transcription control region (By similarity).
Undergoes Notch-induced ubiquitination and subsequent proteasomal degradation which is mediated by ASB1 or ASB2, the substrate-recognition components of probable ECS E3 ubiquitin-protein ligase complexes.
Epididymis, with predominant expression in the corpus region. Moderately expressed in the vas deferens; only low levels are detectable in the caput and cauda regions.
Identified in the spliceosome C complex. Found in the Intron Large (IL) complex, a post-mRNA release spliceosomal complex containing the excised intron, U2, U5 and U6 snRNPs, and splicing factors. Interacts with TUFT1. Interacts with DHX15; indicative for a recruitment of DHX15 to the IL complex. Interacts with GCFC2.
Involved in pre-mRNA splicing, specifically in spliceosome disassembly during late-stage splicing events. Intron turnover seems to proceed through reactions in two lariat-intron associated complexes termed Intron Large (IL) and Intron Small (IS). In cooperation with DHX15 seems to mediate the transition of the U2, U5 and U6 snRNP-containing IL complex to the snRNP-free IS complex leading to efficient debranching and turnover of excised introns. May play a role in the differentiation of ameloblasts and odontoblasts or in the forming of the enamel extracellular matrix.
May be a component of ribonuclease P or MRP.
Magnesium-dependent phosphatidate phosphatase enzyme which catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride, phosphatidylcholine and phosphatidylethanolamine biosynthesis therefore regulates fatty acid metabolism.
Significant expression in intestine and other regions of the gastrointestinal tract.
A chromosomal aberration involving ELF4 has been found in a case of acute myeloid leukemia (AML). Translocation t(X;21)(q25-26;q22) with ERG.
Abundantly expressed in the placenta and in a variety of myeloid leukemia cell lines. Moderate levels of expression in heart, lung, spleen, thymus, peripheral blood lymphocytes, ovary and colon. Lower levels of expression in Jurkat T-cells and other T-cell lines and no expression in brain.
By ponisterone A in erythroleukemia cells.
Interacts with RUNX1 (via the Runt domain); the interaction transactivates the IL3 promoter. Interacts (via its C-terminus) with PML; the interaction translocates ELF4 to PML nuclear bodies and enhances transactivation of LYZ.
Transcriptional activator that binds to DNA sequences containing the consensus 5'-WGGA-3'. Transactivates promoters of the hematopoietic growth factor genes CSF2, IL3, IL8, and of the bovine lysozyme gene. Acts synergistically with RUNX1 to transactivate the IL3 promoter (By similarity). Transactivates the PRF1 promoter in natural killer (NK) cells and CD8+ T cells (PubMed:34326534). Plays a role in the development and function of NK and NK T-cells and in innate immunity. Controls the proliferation and homing of CD8+ T-cells via the Kruppel-like factors KLF4 and KLF2 (By similarity). Controls cell senescence in a p53-dependent manner. Can also promote cellular transformation through inhibition of the p16 pathway. Is a transcriptional regulator of inflammation, controlling T-helper 17 (Th17) cells and macrophage inflammatory responses. Required for sustained transcription of anti-inflammatory genes, including IL1RN (PubMed:34326534, PubMed:35266071). Is a negative regulator of pro-inflammatory cytokines expression including IL17A, IL1B, IL6, TNFA and CXCL1 (PubMed:34326534, PubMed:35266071). Down-regulates expression of TREM1, a cell surface receptor involved in the amplification of inflammatory responses (By similarity) (PubMed:34326534, PubMed:35266071).
Cell surface GPI-bound ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. May play a role in the interaction between activated B-lymphocytes and dendritic cells in tonsils.
Expressed in the adult spleen, lymph node, prostate, ovary, small intestine, and colon, and in fetal heart, lung, liver and kidney. Also detected in hematopoietic cell lines.
Detected in oocytes (at protein level). Detected in brain cortex, hypothalamus, hippocampus and olfactory bulb. Detected in oocytes.
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain and in opiate-mediated analgesia. Plays a role in developing analgesic tolerance to morphine.
May form homooligomers. Forms a heterodimer with OPRM1 (By similarity). Interacts with GPRASP1 (PubMed:12142540, PubMed:15086532). Interacts with RTP4; the interaction promotes cell surface localization of the OPRD1-OPRM1 heterodimer (By similarity).
Ubiquitinated. A basal ubiquitination seems not to be related to degradation. Ubiquitination is increased upon formation of OPRM1:OPRD1 oligomers leading to proteasomal degradation; the ubiquitination is diminished by RTP4.
Could coordinate an aspect of bone turnover.
Belongs to the sterol desaturase family. SCS7 subfamily.
Binds 2 Zn(2+) ions per subunit that likely form a catalytic dimetal center.
Catalyzes the hydroxylation of free fatty acids at the C-2 position to produce 2-hydroxy fatty acids, which are building blocks of sphingolipids and glycosphingolipids common in neural tissue and epidermis (PubMed:15337768, PubMed:15863841, PubMed:17355976, PubMed:22517924). FA2H is stereospecific for the production of (R)-2-hydroxy fatty acids (PubMed:22517924). Plays an essential role in the synthesis of galactosphingolipids of the myelin sheath (By similarity). Responsible for the synthesis of sphingolipids and glycosphingolipids involved in the formation of epidermal lamellar bodies critical for skin permeability barrier (PubMed:17355976). Participates in the synthesis of glycosphingolipids and a fraction of type II wax diesters in sebaceous gland, specifically regulating hair follicle homeostasis (By similarity). Involved in the synthesis of sphingolipids of plasma membrane rafts, controlling lipid raft mobility and trafficking of raft-associated proteins (By similarity).
Detected in differentiating cultured keratinocytes (at protein level). Detected in epidermis and cultured keratinocytes (PubMed:17355976). Highly expressed in brain and colon. Detected at lower levels in testis, prostate, pancreas and kidney (PubMed:15337768).
The N-terminal cytochrome b5 heme-binding domain is essential for catalytic activity.
Up-regulated during keratinocyte differentiation.
Belongs to the small GTPase superfamily. Di-Ras family.
Displays low GTPase activity and exists predominantly in the GTP-bound form.
Acetylated by EP300; acetylation leads both to the decreased of SIRT2-mediated alpha-tubulin deacetylase activity and SIRT2-mediated down-regulation of TP53 transcriptional activity.
Belongs to the sirtuin family. Class I subfamily.
Deacetylates EP300, alpha-tubulin and histone H3 and H4.
Inhibited by Sirtinol, A3 and M15 small molecules (PubMed:11483616). Inhibited by nicotinamide. Inhibited by a macrocyclic peptide inhibitor S2iL5 (PubMed:24389023). Inhibited by EP300-induced acetylation (PubMed:18722353).
Interacts with CDC20, FOXO3 and FZR1. Associates with microtubules in primary cortical mature neurons (By similarity). Homotrimer. Isoform 1 and isoform 2 interact (via both phosphorylated, unphosphorylated, active or inactive forms) with HDAC6; the interaction is necessary for the complex to interact with alpha-tubulin, suggesting that these proteins belong to a large complex that deacetylates the cytoskeleton. Interacts with FOXO1; the interaction is disrupted upon serum-starvation or oxidative stress, leading to increased level of acetylated FOXO1 and induction of autophagy. Interacts with RELA; the interaction occurs in the cytoplasm and is increased in a TNF-alpha-dependent manner. Interacts with HOXA10; the interaction is direct. Interacts with YWHAB and YWHAG; the interactions occur in a AKT-dependent manner and increase SIRT2-dependent TP53 deacetylation. Interacts with MAPK1/ERK2 and MAPK3/ERK1; the interactions increase SIRT2 stability and deacetylation activity. Interacts (phosphorylated form) with KMT5A isoform 2; the interaction is direct, stimulates KMT5A-mediated methyltransferase activity on histone at 'Lys-20' (H4K20me1) and is increased in a H(2)O(2)-induced oxidative stress-dependent manner. Interacts with G6PD; the interaction is enhanced by H(2)O(2) treatment. Interacts with a G1/S-specific cyclin E-CDK2 complex. Interacts with AURKA, CDK5R1 (p35 form) and CDK5 and HIF1A. Isoform 1, isoform 2 and isoform 5 interact (via C-terminus region) with EP300 (PubMed:24177535). Interacts with the tRNA ligase SARS1; recruited to the VEGFA promoter via interaction with SARS1 (PubMed:24940000). Interacts with BEX4; negatively regulates alpha-tubulin deacetylation by SIRT2 (PubMed:27512957).
Isoform 1 is expressed in heart, liver and skeletal muscle, weakly expressed in the cortex. Isoform 2 is strongly expressed in the cortex, weakly expressed in heart and liver. Weakly expressed in several malignancies including breast, liver, brain, kidney and prostate cancers compared to normal tissues. Weakly expressed in glioma cell lines compared to normal brain tissues (at protein level). Widely expressed. Highly expressed in heart, brain and skeletal muscle, while it is weakly expressed in placenta and lung. Down-regulated in many gliomas suggesting that it may act as a tumor suppressor gene in human gliomas possibly through the regulation of microtubule network.
Lacks deacetylation activity, at least toward known SIRT2 targets.
NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and alpha-tubulin as well as many other proteins such as key transcription factors (PubMed:24177535, PubMed:12620231, PubMed:16648462, PubMed:18249187, PubMed:18332217, PubMed:18995842, PubMed:20587414, PubMed:21081649, PubMed:20543840, PubMed:22014574, PubMed:21726808, PubMed:21949390, PubMed:22771473, PubMed:23468428, PubMed:23908241, PubMed:24940000, PubMed:24769394, PubMed:24681946). Participates in the modulation of multiple and diverse biological processes such as cell cycle control, genomic integrity, microtubule dynamics, cell differentiation, metabolic networks, and autophagy (PubMed:24177535, PubMed:12620231, PubMed:16648462, PubMed:18249187, PubMed:18332217, PubMed:18995842, PubMed:20587414, PubMed:21081649, PubMed:20543840, PubMed:22014574, PubMed:21726808, PubMed:21949390, PubMed:22771473, PubMed:23468428, PubMed:23908241, PubMed:24940000, PubMed:24769394, PubMed:24681946). Plays a major role in the control of cell cycle progression and genomic stability (PubMed:12697818, PubMed:17488717, PubMed:16909107, PubMed:17726514, PubMed:19282667, PubMed:23468428). Functions in the antephase checkpoint preventing precocious mitotic entry in response to microtubule stress agents, and hence allowing proper inheritance of chromosomes (PubMed:12697818, PubMed:17488717, PubMed:16909107, PubMed:17726514, PubMed:19282667, PubMed:23468428). Positively regulates the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex activity by deacetylating CDC20 and FZR1, then allowing progression through mitosis (PubMed:22014574). Associates both with chromatin at transcriptional start sites (TSSs) and enhancers of active genes (PubMed:23468428). Plays a role in cell cycle and chromatin compaction through epigenetic modulation of the regulation of histone H4 'Lys-20' methylation (H4K20me1) during early mitosis (PubMed:23468428). Specifically deacetylates histone H4 at 'Lys-16' (H4K16ac) between the G2/M transition and metaphase enabling H4K20me1 deposition by KMT5A leading to ulterior levels of H4K20me2 and H4K20me3 deposition throughout cell cycle, and mitotic S-phase progression (PubMed:23468428). Deacetylates KMT5A modulating KMT5A chromatin localization during the mitotic stress response (PubMed:23468428). Deacetylates also histone H3 at 'Lys-57' (H3K56ac) during the mitotic G2/M transition (PubMed:20587414). Upon bacterium Listeria monocytogenes infection, deacetylates 'Lys-18' of histone H3 in a receptor tyrosine kinase MET- and PI3K/Akt-dependent manner, thereby inhibiting transcriptional activity and promoting late stages of listeria infection (PubMed:23908241). During oocyte meiosis progression, may deacetylate histone H4 at 'Lys-16' (H4K16ac) and alpha-tubulin, regulating spindle assembly and chromosome alignment by influencing microtubule dynamics and kinetochore function (PubMed:24940000). Deacetylates histone H4 at 'Lys-16' (H4K16ac) at the VEGFA promoter and thereby contributes to regulate expression of VEGFA, a key regulator of angiogenesis (PubMed:24940000). Deacetylates alpha-tubulin at 'Lys-40' and hence controls neuronal motility, oligodendroglial cell arbor projection processes and proliferation of non-neuronal cells (PubMed:18332217, PubMed:18995842). Phosphorylation at Ser-368 by a G1/S-specific cyclin E-CDK2 complex inactivates SIRT2-mediated alpha-tubulin deacetylation, negatively regulating cell adhesion, cell migration and neurite outgrowth during neuronal differentiation (PubMed:17488717). Deacetylates PARD3 and participates in the regulation of Schwann cell peripheral myelination formation during early postnatal development and during postinjury remyelination (PubMed:21949390). Involved in several cellular metabolic pathways (PubMed:20543840, PubMed:21726808, PubMed:24769394). Plays a role in the regulation of blood glucose homeostasis by deacetylating and stabilizing phosphoenolpyruvate carboxykinase PCK1 activity in response to low nutrient availability (PubMed:21726808). Acts as a key regulator in the pentose phosphate pathway (PPP) by deacetylating and activating the glucose-6-phosphate G6PD enzyme, and therefore, stimulates the production of cytosolic NADPH to counteract oxidative damage (PubMed:24769394). Maintains energy homeostasis in response to nutrient deprivation as well as energy expenditure by inhibiting adipogenesis and promoting lipolysis (PubMed:20543840). Attenuates adipocyte differentiation by deacetylating and promoting FOXO1 interaction to PPARG and subsequent repression of PPARG-dependent transcriptional activity (PubMed:20543840). Plays a role in the regulation of lysosome-mediated degradation of protein aggregates by autophagy in neuronal cells (PubMed:20543840). Deacetylates FOXO1 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagy (PubMed:20543840). Deacetylates a broad range of transcription factors and co-regulators regulating target gene expression. Deacetylates transcriptional factor FOXO3 stimulating the ubiquitin ligase SCF(SKP2)-mediated FOXO3 ubiquitination and degradation (By similarity). Deacetylates HIF1A and therefore promotes HIF1A degradation and inhibition of HIF1A transcriptional activity in tumor cells in response to hypoxia (PubMed:24681946). Deacetylates RELA in the cytoplasm inhibiting NF-kappaB-dependent transcription activation upon TNF-alpha stimulation (PubMed:21081649). Inhibits transcriptional activation by deacetylating p53/TP53 and EP300 (PubMed:18249187, PubMed:18995842). Deacetylates also EIF5A (PubMed:22771473). Functions as a negative regulator on oxidative stress-tolerance in response to anoxia-reoxygenation conditions (PubMed:24769394). Plays a role as tumor suppressor (PubMed:22014574). In addition to protein deacetylase activity, also has activity toward long-chain fatty acyl groups and mediates protein-lysine demyristoylation and depalmitoylation of target proteins, such as ARF6 and KRAS, thereby regulating their association with membranes (PubMed:25704306, PubMed:29239724, PubMed:32103017).
Peaks during mitosis. After mitosis, it is probably degraded by the 26S proteasome.
Phosphorylated at phosphoserine and phosphothreonine. Phosphorylated at Ser-368 by a mitotic kinase CDK1/cyclin B at the G2/M transition; phosphorylation regulates the delay in cell-cycle progression. Phosphorylated at Ser-368 by a mitotic kinase G1/S-specific cyclin E/Cdk2 complex; phosphorylation inactivates SIRT2-mediated alpha-tubulin deacetylation and thereby negatively regulates cell adhesion, cell migration and neurite outgrowth during neuronal differentiation. Phosphorylated by cyclin A/Cdk2 and p35-Cdk5 complexes and to a lesser extent by the cyclin D3/Cdk4 and cyclin B/Cdk1, in vitro. Dephosphorylated at Ser-368 by CDC14A and CDC14B around early anaphase.
Up-regulated in response to low levels of glucose and anoxia-reoxygenation stress. Up-regulated by trichostatin A. Down-regulated in response to high levels of glucose. Down-regulated by histone deacetylation in several tumors.
Activated by L- and D-histidine (PubMed:16807956). Activated by L- and D-phenylalanine (PubMed:16686544). Activated by L-adrenaline (PubMed:17127057). Inhibited by coumarins, sulfonamide derivatives such as acetazolamide and Foscarnet (phosphonoformate trisodium salt) (PubMed:17314045, PubMed:19186056, PubMed:19206230, PubMed:18618712). Activated by histamine (PubMed:17127057).
Mitochondrial carbonic anhydrase that catalyzes the reversible conversion of carbon dioxide to bicarbonate/HCO3 (PubMed:8356065, PubMed:24530203). Mitochondria are impermeable to HCO3, and thus this intramitochondrial carbonic anhydrase is pivotal in providing HCO3 for multiple mitochondrial enzymes that catalyze the formation of essential metabolites of intermediary metabolism in the urea and Krebs cycles (PubMed:24530203).
Abundantly expressed in heart, skeletal muscle, kidney, liver and pancreas.
PA2 catalyzes the calcium-dependent hydrolysis of the 2-acyl groups in 3-sn-phosphoglycerides. Does not exhibit detectable activity toward sn-2-arachidonoyl- or linoleoyl-phosphatidylcholine or -phosphatidylethanolamine.
Absent during G1 phase, accumulates during S, G2, and M phases, and disappears at the time of the metaphase-anaphase transition.
Homotetramer (PubMed:15313623, PubMed:15260975, PubMed:15378034, PubMed:19906994). Interacts with CDT1; this inhibits binding of the MCM complex to origins of replication (PubMed:14993212, PubMed:21543332, PubMed:15260975, PubMed:19906994). The complex with CDT1 exists in two forms, a 'permissive' heterotrimer and an 'inhibitory' heterohexamer (PubMed:14993212, PubMed:15260975, PubMed:19906994). Interacts (via coiled-coil domain) with IDAS (via coiled-coil domain); this targets GMNN to the nucleus (PubMed:21543332). The heterodimer formed by GMNN and MCIDAS has much lower affinity for CDT1 than the GMNN homodimer (PubMed:24064211). Interacts with a subset of Hox proteins, affinity increasing from anterior to posterior types, the strongest interaction being with HOXB1, HOXC9 and HOXD10 (PubMed:22615398). Interacts with LRWD1 from G1/S to mitosis (PubMed:22645314).
Inhibits DNA replication by preventing the incorporation of MCM complex into pre-replication complex (pre-RC) (PubMed:9635433, PubMed:14993212, PubMed:20129055, PubMed:24064211). It is degraded during the mitotic phase of the cell cycle (PubMed:9635433, PubMed:14993212, PubMed:24064211). Its destruction at the metaphase-anaphase transition permits replication in the succeeding cell cycle (PubMed:9635433, PubMed:14993212, PubMed:24064211). Inhibits histone acetyltransferase activity of KAT7/HBO1 in a CDT1-dependent manner, inhibiting histone H4 acetylation and DNA replication licensing (PubMed:20129055). Inhibits the transcriptional activity of a subset of Hox proteins, enrolling them in cell proliferative control (PubMed:22615398).
Phosphorylated during mitosis. Phosphorylation at Ser-184 by CK2 results in enhanced binding to Hox proteins and more potent inhibitory effect on Hox transcriptional activity.
Based on a readthrough transcript which may produce a BCL2L2-PABPN1 fusion protein.
Expressed (at protein level) in a wide range of tissues with highest levels in brain, spinal cord, testis, pancreas, heart, spleen and mammary glands. Moderate levels found in thymus, ovary and small intestine. Not detected in salivary gland, muscle or liver. Also expressed in cell lines of myeloid, fibroblast and epithelial origin. Not detected in most lymphoid cell lines.
Interacts with HIF3A (via C-terminus domain). Interacts with BOP.
Promotes cell survival. Blocks dexamethasone-induced apoptosis. Mediates survival of postmitotic Sertoli cells by suppressing death-promoting activity of BAX.
The BH1 and BH2 motifs form a hydrophobic groove which acts as a docking site for the BH3 domain of some pro-apoptotic proteins. The C-terminal residues of BCL2L2 fold into the BH3-binding cleft and modulate pro-survival activity by regulating ligand access. When BH3 domain-containing proteins bind, they displace the C-terminus, allowing its insertion into the membrane and neutralizing the pro-survival activity of BCL2L2.
The BH4 motif seems to be involved in the anti-apoptotic function.
A chromosomal aberration involving CEP43 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(6;8)(q27;p11) with FGFR1. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins CEP43-FGFR1 or FGFR1-CEP43 may exhibit constitutive kinase activity and be responsible for the transforming activity (PubMed:9949182).
Homodimer (PubMed:16690081). Part of a ternary complex that contains CEP350, CEP43 and MAPRE1. Interacts directly with CEP350 and MAPRE1 (PubMed:16314388). Interacts with CEP19 (PubMed:28625565, PubMed:28428259, PubMed:28659385). Interacts (via N-terminus) with CEP350 (via C-terminus) (PubMed:28625565, PubMed:28428259).
Interacting region of CEP19 is conflicting: According to a report, interacts via N-terminus (PubMed:28428259). According to another report, interacts via C-terminus (PubMed:28659385).
Required for anchoring microtubules to the centrosomes (PubMed:16314388, PubMed:28659385). Required for ciliation (PubMed:28625565, PubMed:28659385).
Ubiquitous. Highly expressed in heart, liver, muscle, kidney, intestine, colon, adrenal gland, prostate, testis, and pancreas.
Ceramide synthase that catalyzes formation of ceramide from sphinganine and acyl-CoA substrates, with high selectivity toward long and very-long chains (C18:0-C22:0) as acyl donor.
Some prediction bioinformatics tools predict the presence of a homeobox domain (By similarity). However, the domain is degenerate and residues that are important for DNA-binding are absent (By similarity).
The last loop motif confers selectivity toward stearoyl-CoA (octadecanoyl-CoA; C18:0-CoA) to behenoyl-CoA (docosanoyl-CoA; C22:0-CoA) as acyl donors.
On early hematopoietic progenitor cells.
Phosphorylated on serine residues by PKC.
Possible adhesion molecule with a role in early hematopoiesis by mediating the attachment of stem cells to the bone marrow extracellular matrix or directly to stromal cells. Could act as a scaffold for the attachment of lineage specific glycans, allowing stem cells to bind to lectins expressed by stromal cells or other marrow components. Presents carbohydrate ligands to selectins.
Selectively expressed on hematopoietic progenitor cells and the small vessel endothelium of a variety of tissues.
Component of the cornified envelope of keratinocytes. May link the cornified envelope to desmosomes and intermediate filaments.
Exclusively expressed in stratified squamous epithelia.
May form a homodimer or a heterodimer with PPL.
Mitochondrial transporter that imports/exports pyrimidine nucleotides into and from mitochondria. Selectively transports cytosine, guanosine, inosine and uridine (deoxy)nucleoside mono-, di-, and triphosphates by antiport mechanism. Catalyzes uniport at much lower rate (PubMed:25320081). May import (deoxy)nucleoside triphosphates in exchange for intramitochondrial (deoxy)nucleoside mono- and diphosphates, thus providing precursors necessary for de novo synthesis of mitochondrial DNA and RNA while exporting products of their catabolism (PubMed:25320081). Participates in mitochondrial genome maintenance, regulation of mitochondrial membrane potential and mitochondrial respiration.
Widely expressed at moderate level. Expressed most strongly in pancreas (PubMed:34971397).
(Microbial infection) Receptor for E.coli Dr adhesins. Binding of E.coli Dr adhesins leads to dissociation of the homodimer.
Cell surface glycoprotein that plays a role in cell adhesion, intracellular signaling and tumor progression (PubMed:2803308, PubMed:10910050, PubMed:10864933). Mediates homophilic and heterophilic cell adhesion with other carcinoembryonic antigen-related cell adhesion molecules, such as CEACAM6 (PubMed:2803308). Plays a role as an oncogene by promoting tumor progression; induces resistance to anoikis of colorectal carcinoma cells (PubMed:10910050).
Complex immunoreactive glycoprotein with a MW of 180 kDa comprising 60% carbohydrate.
Expressed in columnar epithelial and goblet cells of the colon (at protein level) (PubMed:10436421). Found in adenocarcinomas of endodermally derived digestive system epithelium and fetal colon.
Can form homodimers both in trans (interaction between CLDN10 molecules in opposing membranes) and in cis (interaction between CLDN10 molecules within one membrane).
Expressed in the kidney, eccrine sweat glands and in all layers of the epidermis. In the kidney, it is detected in the thick ascending limb of Henle's loop (TAL) (PubMed:28771254, PubMed:28686597). In the sweat glands, it is expressed in cells from secretory portions, corresponding to the clear cells (PubMed:28686597).
Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity. Involved in the regulation of paracellular epithelia permeability to ions in multiple organs. It acts as a paracellular ion channel probably forming permselective pores; isoform 1 appears to create pores preferentially permeable to cations and isoform 2 for anions. In sweat glands and in the thick ascending limb (TAL) of Henle's loop in kidney, it controls paracellular sodium permeability which is essential for proper sweat production and renal function (PubMed:19383724, PubMed:28771254, PubMed:28686597).
The fourth transmembrane region (161-181) is necessary for integration into tight junctions.
Acts as a positive regulator of ERK phosphorylation downstream of fibroblast growth factor-receptor activation (PubMed:23862974, PubMed:28157540). Involved in the regulation of both caspase-dependent apoptosis and caspase-independent cell death (PubMed:15178406). In the skin, it plays a predominant role in suppressing caspase-dependent apoptosis in response to UV stress in a range of dermal cell types (PubMed:28157540).
Predominantly expressed in skeletal muscle and testis. Expressed in basolateral and apical membranes of all tubular epithelia. Expressed in thin ascending limb of the loop of Henle and the distal convoluted tubule. Expressed in all layers of transitional ureteric epithelium and in the ureteric smooth-muscle cells. Weakly expressed in heart, brain, placenta, kidney, pancreas, spleen, thymus, prostate, uterus, small intestine, white blood cells, stomach, spinal cord and adrenal gland. Is widely distributed in the CNS. Also detected in several tumor cell lines. Expressed in the skin (PubMed:28157540).
Plays a role in store-operated Ca(2+) entry (SOCE).
Belongs to the protein kinase superfamily. BUD32 family.
Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine (PubMed:22912744, PubMed:27903914). The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37 (PubMed:22912744, PubMed:27903914). TP53RK has ATPase activity in the context of the EKC/KEOPS complex and likely plays a supporting role to the catalytic subunit OSGEP (By similarity). Atypical protein kinase that phosphorylates 'Ser-15' of p53/TP53 protein and may therefore participate in its activation (PubMed:11546806).
Highly expressed in testis. Weakly expressed in heart kidney and spleen.
This protein is considered an atypical serine/threonine kinase, because it lacks the conventional structural elements necessary for the substrate recognition as well as a lysine residue that in all other serine/threonine kinases participates in the catalytic event. TP53RK has protein kinase activity in vitro, but in the context of the EKC/KEOPS complex, the catalytic subunit OSGEP switches the activity of TP53RK from kinase into ATPase (By similarity).
By Epstein-Barr virus (EBV). Up-regulated in aorta endothelial cells in response to complement activation.
Detected in brain, heart and liver (at protein level). Highly expressed in liver, skeletal muscle, kidney and pancreas. Detected at lower levels in heart, brain and placenta. Detected in aorta endothelial cells. Overexpressed in colon, breast, prostate, bladder, lung, and ovarian cancer tissues.
Interacts with SMAD3 (By similarity). Interacts with CDK1 and PLK1.
Modulates the activity of cell cycle-specific kinases. Enhances CDK1 activity. May contribute to the regulation of the cell cycle. May inhibit growth of glioma cells by promoting arrest of mitotic progression at the G2/M transition. Fibrogenic factor contributing to the pathogenesis of renal fibrosis through fibroblast activation.
Expressed in polymorphonuclear leukocytes (at protein level) (PubMed:2033050, PubMed:7897245, PubMed:3198760). Expressed in neutrophils (at protein level) (PubMed:28240246, PubMed:18462208, PubMed:21193407, PubMed:22266279, PubMed:17244676). Expressed in differentiating neutrophils (PubMed:18462208).
Induced during CSF3/G-CSF-mediated neutrophil differentiation.
Inhibited by phenylmethanesulfonyl fluoride (PMSF) and diisopropyl fluorophosphate (DFP).
Is the major autoantigen in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (Wegener's granulomatosis) (PubMed:2377228, PubMed:2679910). This complex, systemic disease is characterized by granulomatous inflammation with necrotizing lesions in the respiratory tract, glomerulonephritis, vasculitis, and anti-neutrophil cytoplasmatic autoantibodies detected in patient sera (PubMed:2377228, PubMed:2679910). PRTN3 causes emphysema when administered by tracheal insufflation to hamsters (PubMed:3198760).
May form dimers (PubMed:28240246). Interacts with CD177; the interaction tethers PRTN3 to the cell surface; the interaction is direct (PubMed:17244676, PubMed:28240246). Interacts with SERPINB1 (PubMed:30692621).
Serine protease that degrades elastin, fibronectin, laminin, vitronectin, and collagen types I, III, and IV (in vitro) (PubMed:3198760, PubMed:2033050, PubMed:28240246). By cleaving and activating receptor F2RL1/PAR-2, enhances endothelial cell barrier function and thus vascular integrity during neutrophil transendothelial migration (PubMed:23202369). May play a role in neutrophil transendothelial migration, probably when associated with CD177 (PubMed:22266279).
Has chemotactic response in monocytes, neutrophils and lymphocytes (PubMed:11415443). Binds CCR4 (PubMed:16137713).
Isoform 1, isoform 2, isoform 3 and isoform 4 have highest expression levels in adult spleen, lung, testis, ovary, peripheral blood leukocyte, placenta, pancreas, and in fetal brain, skeletal muscle, thymus and heart. Lower expression levels in adult skeletal muscle, liver, thymus colon, prostate and fetal spleen and liver.
May play an important role in inflammation and regeneration of skeletal muscle (PubMed:11415443). Essential for embryonic development (By similarity).
Belongs to the eukaryotic ribosomal protein eS8 family. Ribosome biogenesis protein NSA2 subfamily.
Component of the pre-66S ribosomal particle.
Involved in the biogenesis of the 60S ribosomal subunit. May play a part in the quality control of pre-60S particles (By similarity).
Involved in the biogenesis of the 60S ribosomal subunit. May play a part in the quality control of pre-60S particles.
Expressed primarily on activated lymphoid cells. Also expressed in endothelial tissues. Isoform 1 and isoform 3 are present in both placenta and umbilical vein, whereas isoform 2 is present in placenta only.
In the nervous system, could hydrolyze ATP and other nucleotides to regulate purinergic neurotransmission. Could also be implicated in the prevention of platelet aggregation by hydrolyzing platelet-activating ADP to AMP. Hydrolyzes ATP and ADP equally well.
Expressed in primary cortical astrocytes (at protein level) (PubMed:23690594). Expressed in the central nervous system (PubMed:9539149).
G-protein coupled receptor (PubMed:27072655). Has been shown to bind the neuroprotective and glioprotective factor prosaposin (PSAP), leading to endocytosis followed by an ERK phosphorylation cascade (PubMed:23690594). However, other studies have shown that prosaposin does not increase activity (PubMed:27072655, PubMed:28688853). It has been suggested that GPR37L1 is a constitutively active receptor which signals through the guanine nucleotide-binding protein G(s) subunit alpha (PubMed:27072655). Participates in the regulation of postnatal cerebellar development by modulating the Shh pathway (By similarity). Regulates baseline blood pressure in females and protects against cardiovascular stress in males (By similarity). Mediates inhibition of astrocyte glutamate transporters and reduction in neuronal N-methyl-D-aspartate receptor activity (By similarity).
Has been reported to act as a receptor for prosaposin (PSAP) (PubMed:23690594). However, it has also been shown that prosaposin does not increase activity (PubMed:27072655, PubMed:28688853). It has been suggested that GPR37L1 is a constitutively active receptor (PubMed:27072655).
The N-terminal region is required for constitutive signal transduction.
Undergoes metalloprotease-mediated cleavage which reduces its constitutive activity.
Expressed in pancreas, placenta, spleen, liver, kidney, bone marrow, peripheral blood leukocytes and tonsil.
Involved in the lipid remodeling steps of GPI-anchor maturation. Lipid remodeling steps consist in the generation of 2 saturated fatty chains at the sn-2 position of GPI-anchor proteins (GPI-AP). Has phospholipase A2 activity that removes an acyl-chain at the sn-2 position of GPI-anchors during the remodeling of GPI. Required for the shedding of the GPI-AP CRIPTO, but not CFC1, at the cell surface. Shedding of CRIPTO modulates Nodal signaling by allowing soluble CRIPTO to act as a Nodal coreceptor on other cells (PubMed:27881714). Also indirectly involved in the translocation of RAC1 from the cytosol to the plasma membrane by maintaining the steady state amount of CAV1-enriched plasma membrane subdomains, stabilizing RAC1 at the plasma membrane (PubMed:27835684). In contrast to myomaker (TMEM8C), has no fusogenic activity (PubMed:26858401).
Repressed during activation of CD4+ and CD8+ T-lymphocytes.
Essential bifunctional enzyme that catalyzes both the N-deacetylation and the N-sulfation of glucosamine (GlcNAc) of the glycosaminoglycan in heparan sulfate. Modifies the GlcNAc-GlcA disaccharide repeating sugar backbone to make N-sulfated heparosan, a prerequisite substrate for later modifications in heparin biosynthesis. Has low deacetylase activity but high sulfotransferase activity (By similarity).
Alcohol dehydrogenase (PubMed:2738060). Oxidizes primary as well as secondary alcohols. Ethanol is a very poor substrate (PubMed:2738060).
Dimer of identical or heterodimer of closely related subunits alpha, beta, or gamma that are encoded by genes ADH1A, ADH1B, and ADH1C, respectively.
There are 7 different ADH's isozymes in human: three belongs to class-I: ADH1A, ADH1B, and ADH1C, one to class-II: ADH4, one to class-III: ADH5, one to class-IV: ADH7 and one to class-V: ADH6.
Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3 (By similarity). The phosphorylated form interacts with EPCAM (PubMed:16054130). Does not interact with CD81 (PubMed:20375010).
Expressed in kidney, lung and prostate. Isoform 1 seems to be predominant, except in some normal prostate samples, where isoform 2 is the major form. Down-regulated in breast cancers, including ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS) and invasive ductal carcinoma (IDC) (at protein level), as well as in several cancer cell lines. Loss of expression correlates with histological grade, occurring predominantly in high-grade lesions.
Expressed at high levels in fetal lung, kidney and heart.
Has also a palmitoyltransferase activity-independent function in DNA virus-triggered and CGAS-mediated innate immune response (PubMed:25299331). Functions as an activator of STING1 by promoting its cGAMP-induced oligomerization and the recruitment of downstream signaling components (PubMed:25299331).
Interacts with STING1; ZDHHC1 constitutively interacts with STING1 and in presence of DNA viruses activates it by promoting its cGAMP-induced oligomerization and the recruitment of downstream signaling components.
Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates (By similarity). Has a palmitoyltransferase activity toward NCDN and regulates NCDN association with endosome membranes through this palmitoylation.
Widely expressed with significant expression in heart, brain, placenta, lung, liver, kidney, testis, thymus and small intestine (PubMed:16647879). Expressed at lower levels in adult pancreas and lung (PubMed:10395086).
Expressed in 30 days old embryos. Almost undetectable in 60 days old embryos and in adults.
The C2H2 domain is necessary for the transcriptional repression.
Interacts with MDM2; this interaction, which occurs in the nucleoplasm, stabilizes MDM2. Indirectly interacts with TP53, via MDM2-binding. Interacts with TERF1; this interaction probably occurs in the nucleoplasm and is increased during mitosis, when the nucleolus is disassembled. This binding may promote TERF1 homodimerization. Interacts with TERT.
Stabilizes TERF1 telomeric association by preventing TERF1 recruitment by PML. Stabilizes TERF1 protein by preventing its ubiquitination and hence proteasomal degradation. Does so by interfering with TERF1-binding to FBXO4 E3 ubiquitin-protein ligase. Required for cell proliferation. By stabilizing TRF1 protein during mitosis, promotes metaphase-to-anaphase transition. Stabilizes MDM2 protein by preventing its ubiquitination, and hence proteasomal degradation. By acting on MDM2, may affect TP53 activity. Required for normal processing of ribosomal pre-rRNA. Binds GTP.
Up-regulated during mitosis and down-regulated in the G1 phase.
Endosomal Na(+), K(+)/H(+) antiporter (PubMed:15522866, PubMed:31676550, PubMed:32277048, PubMed:28635961). Mediates the electroneutral exchange of endosomal luminal H(+) for a cytosolic Na(+) or K(+). By facilitating proton efflux, SLC9A6 counteracts the acidity generated by vacuolar (V)-ATPase, thereby limiting luminal acidification. Responsible for alkalizing and maintaining the endosomal pH, and consequently in, e.g., endosome maturation and trafficking of recycling endosomal cargo (PubMed:15522866, PubMed:31676550, PubMed:32277048, PubMed:28635961). Plays a critical role during neurodevelopment by regulating synaptic development and plasticity (By similarity). Implicated in the maintenance of cell polarity in a manner that is dependent on its ability to modulate intravesicular pH (PubMed:20130086). Regulates intracelular pH in some specialized cells, osteoclasts and stereocilia where this transporter localizes to the plasma membrane (By similarity).
Homodimer (PubMed:30296617, PubMed:32277048). Interacts with RACK1; regulates the distribution of SLC9A6 between endosomes and the plasma membrane (PubMed:18057008, PubMed:28635961).
Ubiquitous. High expression in brain, skeletal muscle, and heart, but is also detected at lower levels in most other tissues.
Was originally (PubMed:9507001) identified as a mitochondrial inner membrane protein, but was later shown to be localized in early and recycling endosomes and not mitochondria (PubMed:11940519, PubMed:11641397).
Autoubiquitinated. Polyubiquitinated in the presence of E2 enzymes UBE2D1, UBE2D2 and UBE2D3, but only monoubiquitinated in the presence of UBE2E1.
E3 ubiquitin-protein ligase that promotes the ubiquitination of various substrates (PubMed:23645206, PubMed:25165885). In turn, participates in the regulation of many biological processes including cell cycle, apoptosis, osteoclastogenesis as well as innate or adaptive immunity (PubMed:25165885, PubMed:28708287). Acts as negative regulator of NF-kappa-B-dependent transcription by promoting the ubiquitination and stabilization of the NF-kappa-B inhibitor TNFAIP3 (PubMed:25165885). May promote the ubiquitination of TRAF6 as well (PubMed:28708287). Acts also as a negative regulator of T-cell activation (PubMed:25165885). Inhibits cellular dsRNA responses and interferon production by targeting MAVS component for proteasomal degradation (PubMed:25165885). Ubiquitinates the CDK inhibitor CDKN1A leading to its degradationand probably also CDKN1B and CDKN1C (PubMed:23645206). This activity stimulates cell cycle G1-to-S phase transition and suppresses cellular senescence. May play a role in spermatogenesis.
Expressed in numerous tissues, including skin, CD4 lymphocytes and dendritic cells. Highest levels in testis.
Interacts with XAF1, the interaction increases XAF1 stability and proapoptotic effects, and may regulate IFN signaling.
May interact with EIF4A1, EIF4A2 and EIF4A3. Interacts with PPP1CA and PPP1CC.
Plays a role in targeting PPP1CA to the nucleolus.
Acts as a hormone-regulated adipokine/pro-inflammatory cytokine that is implicated in causing chronic inflammation, affecting cellular expansion and blunting insulin response in adipocytes. May have a role in the onset of insulin resistance.
Associates with immunoglobulin M (IgM) heavy and light chains and promotes IgM assembly and secretion. May exert its effect by acting as a molecular chaperone or as an oxidoreductase as it displays a low level of oxidoreductase activity (By similarity). Isoform 2 may be involved in regulation of apoptosis. Helps to diversify peripheral B-cell functions by regulating Ca(2+) stores, antibody secretion and integrin activation.
Down-regulated in primary B-cells early after ligand-stimulated activation. Up-regulated in bacterial lipopolysaccharides (LPS)-stimulated peritoneal macrophages.
Forms an interchain disulfide bond with IgM monomers.
Part of the ER chaperone complex, a multi-protein complex in the endoplasmic reticulum containing a large number of molecular chaperones which associates with unassembled incompletely folded immunoglobulin heavy chains (By similarity). Isoform 2 interacts with CASP2 and CASP9. Interacts with HSP90B1 and PDIA3 in a calcium-dependent manner (By similarity).
Widely expressed with highest levels in adult brain, small intestine and lymphoid tissues such as thymus and spleen. Expression is frequently lower in intestinal-type gastric cancer. In obese patients, more abundant in omental than in subcutaneous fat.
Expressed in subsets of taste receptor cells of the tongue and exclusively in gustducin-positive cells. Expressed in testis (PubMed:16720576).
Variations in TAS2R38 are associated with the ability to taste phenylthiocarbamide (PTC tasting) [MIM:171200]; also called thiourea tasting. The ability to taste the substance PTC and a number of related substances is genetically controlled. Genetic studies have demonstrated complex inheritance for this trait. For some people (and some chimpanzees also), the chemical PTC tastes very bitter. For others, it is tasteless. Actually, substantial variation in taste sensitivity exists in human. Five haplotypes arising from three coding SNPs in the TAS2R38 gene are associated with distinct phenotypes of PTC taste sensitivity.
Binds NHERF1 (PubMed:9430655). Interacts with NHERF1, NHERF2, LAYN, MME/NEP and ICAM2. Interacts with CPNE1 (via VWFA domain) and CPNE4 (via VWFA domain). Interacts (via FERM domain) with SPN/CD43 cytoplasmic tail (By similarity). Interacts with CD44 (By similarity).
Probably plays a crucial role in the binding of the barbed end of actin filaments to the plasma membrane.
The N-terminal domain interacts with the C-terminal domain of LAYN. An interdomain interaction between its N-terminal and C-terminal domains inhibits its ability to bind LAYN. In the presence of acidic phospholipids, the interdomain interaction is inhibited and this enhances binding to LAYN (By similarity).
Hydrolyzes semenogelin-1 thus leading to the liquefaction of the seminal coagulum.
Inhibited by SERPINA5. Activity is strongly inhibited by Zn2+, 100 times more abundant in semen than in serum. This inhibition is relieved by exposure to semenogelins, which are avid zinc binders.
Component of some HBO1 complex composed of KAT7/HBO1, MEAF6, ING5, and BRPF1 (PubMed:24065767). Component of the MOZ/MORF complex composed at least of ING5, KAT6A, KAT6B, MEAF6 and one of BRPF1, BRD1/BRPF2 and BRPF3 (PubMed:16387653, PubMed:18794358, PubMed:27939640). Interacts (via PHD-type zinc finger domains) with unmethylated histone H3 at 'Lys-4' (H3K4me0) (PubMed:24065767). Interacts with trimethylated 'Lys-36' of histone H3 (H3K36me3) (PubMed:20400950, PubMed:21720545). Interacts with ING5; interaction directs BRPF1 to H4K4me3-enriched chromatin at the 5' of active genes (PubMed:24065767). Interacts with KAT7 (PubMed:27939640).
Scaffold subunit of various histone acetyltransferase (HAT) complexes, such as the MOZ/MORF and HBO1 complexes, which have a histone H3 acetyltransferase activity (PubMed:16387653, PubMed:24065767, PubMed:27939640). Plays a key role in HBO1 complex by directing KAT7/HBO1 specificity towards histone H3 'Lys-14' acetylation (H3K14ac) (PubMed:24065767). Some HAT complexes preferentially mediate histone H3 'Lys-23' (H3K23ac) acetylation (PubMed:27939640). Positively regulates the transcription of RUNX1 and RUNX2 (PubMed:18794358).
Probable transcription factor that binds to the DNA sequence 5'-GC[TA][AC]ATTA[GA]-3'. Activates the transcription of the GHRH gene. Plays an important role in pituitary development.
Potential effector of the planar cell polarity signaling pathway. Plays a role in targeted membrane trafficking most probably at the level of vesicle fusion with membranes. Involved in cilium biogenesis by regulating the transport of cargo proteins to the basal body and to the apical tips of cilia. More generally involved in exocytosis in secretory cells (By similarity).
Detected in physiological fluids including amniotic fluid and serum.
Expressed at the morula stage (at protein level) (PubMed:29262349). Expressed in extravillous trophoblast and cytotrophoblast (PubMed:26460007, PubMed:16210391, PubMed:7589701). Expressed in fetal eye and thymus (PubMed:2336406).
Expressed in adult eye (PubMed:1570318). Expressed in immune cell subsets including monocytes, myeloid and plasmacytoid dendritic cells and regulatory T cells (Tr1)(at protein level) (PubMed:20448110). Secreted by follicular dendritic cell and follicular helper T cells (PubMed:24453251).
Expressed in placenta, amniotic membrane, skin, cord blood and peripheral blood mononuclear cells.
Forms a heterotrimer with B2M and a self-peptide (peptide-bound HLA-G-B2M) (PubMed:7584149, PubMed:8805247). HLA-G-B2M complex interacts with components of the antigen processing machinery TAPBP and TAP1-TAP2 complex; this interaction is required for loading of high affinity peptides and heterotrimer translocation to the cell surface (PubMed:7584149). Interacts with CALCR; this interaction is required for appropriate folding (PubMed:9640257). Interacts with COPB1; this interaction mediates the endoplasmic reticulum (ER) retrieval of HLA-G-B2M complexes that bind low affinity peptides (PubMed:11520457, PubMed:12582157). On the cell surface, peptide-bound HLA-G-B2M molecules (referred to as monomers) can form disulfide-linked homomultimers, homodimers and homotrimers (PubMed:12454284, PubMed:12874224, PubMed:16455647). Interacts with KIR2DL4; this interaction is direct (PubMed:10190900, PubMed:16366734). Interacts with LILRB1 and LILRB2 receptors; this interaction is direct (PubMed:16455647, PubMed:16366734, PubMed:17056715, PubMed:12853576). Interacts with CD160; this interactions is direct (PubMed:16809620). Interacts with CD8A homodimer; this interaction is direct and might down-regulate T cell receptor signaling (PubMed:12853576). Isoform 2: Forms a non-disulfide-linked homodimer and interacts with LILRB2 (PubMed:28348268).
Likely does not bind B2M and presents peptides.
Likely does not bind B2M and presents peptides. Negatively regulates NK cell- and CD8+ T cell-mediated cytotoxicity (PubMed:11290782).
Non-classical major histocompatibility class Ib molecule involved in immune regulatory processes at the maternal-fetal interface (PubMed:23184984, PubMed:29262349, PubMed:19304799). In complex with B2M/beta-2 microglobulin binds a limited repertoire of nonamer self-peptides derived from intracellular proteins including histones and ribosomal proteins (PubMed:7584149, PubMed:8805247). Peptide-bound HLA-G-B2M complex acts as a ligand for inhibitory/activating KIR2DL4, LILRB1 and LILRB2 receptors on uterine immune cells to promote fetal development while maintaining maternal-fetal tolerance (PubMed:23184984, PubMed:29262349, PubMed:16366734, PubMed:19304799, PubMed:20448110). Upon interaction with KIR2DL4 and LILRB1 receptors on decidual NK cells, it triggers NK cell senescence-associated secretory phenotype as a molecular switch to promote vascular remodeling and fetal growth in early pregnancy (PubMed:23184984, PubMed:29262349, PubMed:16366734, PubMed:19304799). Through interaction with KIR2DL4 receptor on decidual macrophages induces pro-inflammatory cytokine production mainly associated with tissue remodeling (PubMed:19304799). Through interaction with LILRB2 receptor triggers differentiation of type 1 regulatory T cells and myeloid-derived suppressor cells, both of which actively maintain maternal-fetal tolerance (PubMed:20448110). Reprograms B cells toward an immune suppressive phenotype via LILRB1 (PubMed:24453251).
Non-classical major histocompatibility class Ib molecule involved in immune regulatory processes at the maternal-fetal interface (PubMed:23184984, PubMed:29262349, PubMed:19304799). In complex with B2M/beta-2 microglobulin binds a limited repertoire of nonamer self-peptides derived from intracellular proteins including histones and ribosomal proteins (PubMed:7584149, PubMed:8805247). Peptide-bound HLA-G-B2M complex acts as a ligand for inhibitory/activating KIR2DL4, LILRB1 and LILRB2 receptors on uterine immune cells to promote fetal development while maintaining maternal-fetal tolerance (PubMed:23184984, PubMed:29262349, PubMed:16366734, PubMed:19304799, PubMed:20448110, PubMed:27859042). Upon interaction with KIR2DL4 and LILRB1 receptors on decidual NK cells, it triggers NK cell senescence-associated secretory phenotype as a molecular switch to promote vascular remodeling and fetal growth in early pregnancy (PubMed:23184984, PubMed:29262349, PubMed:16366734, PubMed:19304799). Through interaction with KIR2DL4 receptor on decidual macrophages induces pro-inflammatory cytokine production mainly associated with tissue remodeling (PubMed:19304799). Through interaction with LILRB2 receptor triggers differentiation of type 1 regulatory T cells and myeloid-derived suppressor cells, both of which actively maintain maternal-fetal tolerance (PubMed:20448110, PubMed:27859042). May play a role in balancing tolerance and antiviral-immunity at maternal-fetal interface by keeping in check the effector functions of NK, CD8+ T cells and B cells (PubMed:10190900, PubMed:11290782, PubMed:24453251). Reprograms B cells toward an immune suppressive phenotype via LILRB1 (PubMed:24453251). May induce immune activation/suppression via intercellular membrane transfer (trogocytosis), likely enabling interaction with KIR2DL4, which resides mostly in endosomes (PubMed:20179272, PubMed:26460007). Through interaction with the inhibitory receptor CD160 on endothelial cells may control angiogenesis in immune privileged sites (PubMed:16809620).
Produced by proteolytic cleavage at the cell surface (shedding) by matrix metalloproteinase MMP2.
The VL9 peptide/epitope (VMAPRTLFL) derived from the signal sequence is loaded onto HLA-E and enables HLA-E expression at the plasma membrane. Confers strong recognition by KLRD1-KLRC1 or KLRD1-KLRC2 receptors on NK cells.
Up-regulated by immunosuppressive cytokine IL10 on dendritic cells and CD4+ T cells (PubMed:20448110). Up-regulated by progesterone in cytotrophoblasts (PubMed:16210391).
Detected in skin keratinocytes and on endothelial cells from skin blood vessels (at protein level). Expressed in fibroblasts, keratinocytes, melanocytes, placenta, testis, ovary, spleen, brain, spinal chord, lung, heart, adrenal gland, lymph nodes, thymus, intestine and kidney.
Genetic variations in SEMA7A define the John Milton Hagen blood group system (JMH) [MIM:614745]. Three different JMH phenotypes have been identified based on the presence or absence of the high-frequency JMH antigen: JMH-weak, JMH-negative, and JMH-variant. The JMH-weak and -negative phenotypes can be either acquired or inherited and are characterized by a reduction or complete loss of JMH expression on red blood cells. Individuals with the JMH-variant phenotype are usually JMH-positive and have alloantibodies compatible with JMH-negative red blood cells. The JMH-variant phenotype results from rare SEMA7A missense variants.
Interacts with ITGA1 and ITGB1 (Probable). Interacts with PLXNC1.
Plays an important role in integrin-mediated signaling and functions both in regulating cell migration and immune responses. Promotes formation of focal adhesion complexes, activation of the protein kinase PTK2/FAK1 and subsequent phosphorylation of MAPK1 and MAPK3. Promotes production of pro-inflammatory cytokines by monocytes and macrophages. Plays an important role in modulating inflammation and T-cell-mediated immune responses. Promotes axon growth in the embryonic olfactory bulb. Promotes attachment, spreading and dendrite outgrowth in melanocytes.
Up-regulated in UV-irradiated fibroblasts, but not in UV-irradiated keratinocytes.
Binds synaptic Ca(2+) with its cytoplasmic domain.
Postsynaptic adhesion molecule that binds to presynaptic neurexins to mediate synapse formation, and which is involved in learning and memory (By similarity). Promotes synapse development by acting as a cell adhesion molecule at the postsynaptic membrane, which associates with neurexin-alpha at the presynaptic membrane (By similarity).
Proteolytically processed under normal cellular conditions (PubMed:15037614). A primary zeta-cleavage generates a large extracellular (soluble) N-terminal domain (sAlc) and a short C-terminal transmembrane fragment (CTF1) (PubMed:15037614). A secondary cleavage catalyzed by gamma-secretase within the transmembrane domain releases the beta-Alc-gamma chain in the extracellular milieu and produces an intracellular fragment (AlcICD) (PubMed:15037614). This processing is strongly suppressed in the tripartite complex formed with APBA2 and APP, which seems to prevent the association with PSEN1 (PubMed:15037614).
A chromosomal aberration involving RUNX1T1 is frequently found in acute myeloid leukemia with maturation (AML-M2). Translocation t(8;21)(q22;q22) with RUNX1/AML1 that results in the production of AML1-MTG8/ETO fusion protein.
Homooligomer. Homotetramerization is mediated by nervy homology region 2 (NRH2). Can interact with CBFA2T2 and CBFA2T3; heterotetramerization between members of the CBFA2T family is proposed. Interacts with TCF12, SIN3A, HDAC1, HDAC2, HDAC3, NCOR1, NCOR2. Interacts with ATN1 (via its N-terminus); the interaction enhances the transcriptional repression. Interacts (via its N-terminus) with ZBTB16; the interaction increases the transcription repression activity of ZBTB16 (PubMed:10688654). AML1-MTG8/ETO fusion protein interacts with CBFB. AML1-MTG8/ETO is part of a stable transcription factor complex AETFC in leukemic cells; AETFC formation seems to be involved in recruitment of EP300. AML1-MTG8/ETO nervy homology region 2-mediated oligomerization is proposed to be homotypic, required for AML1-MTG8/ETO-mediated transformation of primary hematopoietic cells and is required for AML1-MTG8/ETO interaction with TCF12.
Most abundantly expressed in brain. Lower levels in lung, heart, testis and ovary.
The TAFH domain mediates interaction with transcription regulators.
Transcriptional corepressor which facilitates transcriptional repression via its association with DNA-binding transcription factors and recruitment of other corepressors and histone-modifying enzymes (PubMed:12559562, PubMed:15203199, PubMed:10688654). Can repress the expression of MMP7 in a ZBTB33-dependent manner (PubMed:23251453). Can repress transactivation mediated by TCF12 (PubMed:16803958). Acts as a negative regulator of adipogenesis (By similarity). The AML1-MTG8/ETO fusion protein frequently found in leukemic cells is involved in leukemogenesis and contributes to hematopoietic stem/progenitor cell self-renewal (PubMed:23812588).
Belongs to the eukaryotic ribosomal protein eL21 family.
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25957688, PubMed:25901680).
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25957688, PubMed:25901680). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:12962325, PubMed:23636399, PubMed:25957688, PubMed:25901680).
Asn-183 is present instead of the conserved Asp which is expected to be an active site residue.
Abundant in brain, heart and skeletal muscle.
Has phosphatase activity with synthetic phosphatase substrates and negatively regulates mitogen-activated protein kinase activity, presumably by catalysing their dephosphorylation. Expected to display protein phosphatase activity toward phosphotyrosine, phosphoserine and phosphothreonine residues.
Interacts (via the POU domain) with POU2AF1 and POU2AF2 in a DNA-dependent manner; this interaction recruits POU2AF2 to chromatin and increases POU2F3 transactivation activity.
Specifically expressed in epidermis and cultured keratinocytes.
Transcription factor that binds to the octamer motif (5'-ATTTGCAT-3') and regulates cell type-specific differentiation pathways. Involved in the regulation of keratinocytes differentiation (PubMed:11329378). The POU2F3-POU2AF2/POU2AF3 complex drives the expression of tuft-cell-specific genes, a rare chemosensory cells that coordinate immune and neural functions within mucosal epithelial tissues (PubMed:35576971).
ALDHs play a major role in the detoxification of alcohol-derived acetaldehyde (Probable). They are involved in the metabolism of corticosteroids, biogenic amines, neurotransmitters, and lipid peroxidation (Probable). Oxidizes medium and long chain aldehydes into non-toxic fatty acids (PubMed:1737758). Preferentially oxidizes aromatic aldehyde substrates (PubMed:1737758). Comprises about 50 percent of corneal epithelial soluble proteins (By similarity). May play a role in preventing corneal damage caused by ultraviolet light (By similarity).
High levels in stomach, esophagus and lung; low level in the liver and kidney.
Component of intercellular desmosome junctions. Plays a role in stratified epithelial integrity and cell-cell adhesion by promoting desmosome assembly.
Expressed in skin, heart, placental, liver, pancreas, keratinocytes and dermal fibroblasts.
Plays a role as an effector in the TP53-dependent apoptotic pathway.
Heterodimer of an alpha and a beta subunit. The beta subunit is common to the IL3, IL5 and GM-CSF receptors. The signaling GM-CSF receptor complex is a dodecamer of two head-to-head hexamers of two alpha, two beta, and two ligand subunits.
Low affinity receptor for granulocyte-macrophage colony-stimulating factor. Transduces a signal that results in the proliferation, differentiation, and functional activation of hematopoietic cells.
Autophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity.
Highest levels in heart, placenta, lung > skeletal muscle > brain, liver, pancreas > kidney.
Inhibited by calmodulin with an IC(50) of 50 nM. Calmodulin inhibits GRK5 association with receptor and phospholipid.
Interacts with ST13 (via the C-terminus 303-319 AA) (PubMed:21728385). Interacts with TP53/p53 (PubMed:20124405). Interacts with HTR4 (via C-terminus 330-346 AA); this interaction is promoted by 5-HT (serotonin) (PubMed:19661922). Interacts with HDAC5 (By similarity). Interacts with GIT1 (By similarity).
Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro).
Variant Leu-41 variant is rare in European-Americans individuals but common in African-Americans individuals (40% of the African-American individuals studied carry at least one allele). Variant leu-41 is associated with decreased mortality in African-Americans with heart failure or cardiac ischemia.
Dimer formed of alpha-2-2 and delta-2 chains; disulfide-linked. Voltage-dependent calcium channels are multisubunit complexes, consisting of alpha-1 (CACNA1), alpha-2 (CACNA2D), beta (CACNB) and delta (CACNA2D) subunits in a 1:1:1:1 ratio (Probable). Interacts with CACNA1C and CACNB3.
In contrast to CACNA2D1 and CACNA2D2, it does not bind gabapentin, an antiepileptic drug.
May be proteolytically processed into subunits alpha-2-4 and delta-4 that are disulfide-linked. It is however unclear whether such cleavage really takes place in vivo and has a functional role (By similarity).
Predominantly expressed in certain types of endocrine cells. Present in the Paneth cells of the small intestine. Also present in the erythroblasts in the fetal liver, in the cells of the zona reticularis of the adrenal gland and in the basophils of the pituitary. Present at low level in some brain regions such as the cerebellum (at protein level).
The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.
By oxygen in a concentration-dependent manner (PubMed:11213471). Up-regulated by S-nitroso-N-acetyl-D-penicillamine (PubMed:11133847).
Disulfide-linked heterodimer with the amino acid transport protein SLC3A2/4F2hc; this interaction mediates cell membrane localization.
Expressed in term placenta and primary term cytotrophoblast (PubMed:34120018). Expressed mainly in the brain, but also in pancreas (PubMed:11417227).
Heterodimer with SLC3A2, that functions as an antiporter by mediating the exchange of extracellular anionic L-cystine and intracellular L-glutamate across the cellular plasma membrane (PubMed:15151999, PubMed:34880232, PubMed:35352032, PubMed:35245456, PubMed:11417227, PubMed:14722095, PubMed:11133847). Provides L-cystine for the maintenance of the redox balance between extracellular L-cystine and L-cysteine and for the maintenance of the intracellular levels of glutathione that is essential for cells protection from oxidative stress (By similarity). The transport is sodium-independent, electroneutral with a stoichiometry of 1:1, and is drove by the high intracellular concentration of L-glutamate and the intracellular reduction of L-cystine (PubMed:11417227, PubMed:11133847). In addition, mediates the import of L-kynurenine leading to anti-ferroptotic signaling propagation required to maintain L-cystine and glutathione homeostasis (PubMed:35245456). Moreover, mediates N-acetyl-L-cysteine uptake into the placenta leading to subsequently down-regulation of pathways associated with oxidative stress, inflammation and apoptosis (PubMed:34120018). In vitro can also transport L-aspartate (PubMed:11417227). May participate in astrocyte and meningeal cell proliferation during development and can provide neuroprotection by promoting glutathione synthesis and delivery from non-neuronal cells such as astrocytes and meningeal cells to immature neurons (By similarity). Controls the production of pheomelanin pigment directly (By similarity).
In the PMID:15151999, a typographical error has been introduced leading to L-cysteine spelling instead of L-cystine.
Inhibited by erastin and sulfasalazine (PubMed:35352032). Inhibited by (S)-lactate (PubMed:11417227). Inactivated by p-chloromercuribenzoic acid and p-chloromercuribenzenesulfonic acid (PubMed:14722095).
Interacts with calmodulin preferentially in the inactive, GDP-bound form (PubMed:9115241, PubMed:18056528). Binds CAMKII which is capable of phosphorylating RAD in vitro (PubMed:9115241). Interacts with CAMK2D (PubMed:18056528). Interacts with CACNB2; interaction may be involved in beta-adrenergic regulation of heart rate and contractile force (By similarity). Interaction with CACNB2 regulates the trafficking of CACNA1C to the cell membrane (By similarity).
May regulate basal voltage-dependent L-type Ca(2+) currents and be required for beta-adrenergic augmentation of Ca(2+) influx in cardiomyocytes, thereby regulating increases in heart rate and contractile force (By similarity). May play an important role in cardiac antiarrhythmia via the strong suppression of voltage-gated L-type Ca(2+) currents (By similarity). Regulates voltage-dependent L-type calcium channel subunit alpha-1C trafficking to the cell membrane (By similarity). Inhibits cardiac hypertrophy through the calmodulin-dependent kinase II (CaMKII) pathway (PubMed:18056528). Inhibits phosphorylation and activation of CAMK2D (PubMed:18056528).
Most abundantly expressed in the heart. Also found in the skeletal muscle and lung. Lesser amounts in placenta and kidney. Also detected in adipose tissue. Overexpressed in muscle of type II diabetic humans.
Belongs to the P-Pant transferase superfamily. AcpS family.
Catalyzes the post-translational modification of target proteins by phosphopantetheine. Can transfer the 4'-phosphopantetheine moiety from coenzyme A, regardless of whether the CoA is presented in the free thiol form or as an acetyl thioester, to a serine residue of a broad range of acceptors including the acyl carrier domain of FASN.
Detected in heart, skeletal muscle, placenta, testis, brain, pancreas, liver and kidney.
Component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF) (PubMed:9230079). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility (PubMed:9230079). In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA (PubMed:29925947). The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs) (PubMed:29925947).
Alternative splicing in the MOCS1A-MOCS1B joining region.
Binds 2 [4Fe-4S] clusters. Binds 1 [4Fe-4S] cluster coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine and 1 [4Fe-4S] cluster coordinated with 3 cysteines and the GTP-derived substrate.
In the C-terminal section; belongs to the MoaC family.
In the N-terminal section; belongs to the radical SAM superfamily. MoaA family.
Isoform MOCS1A and isoform 2 are widely expressed.
Isoform MOCS1A and isoform MOCS1B probably form a complex that catalyzes the conversion of 5'-GTP to cyclic pyranopterin monophosphate (cPMP). MOCS1A catalyzes the cyclization of GTP to (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate and MOCS1B catalyzes the subsequent conversion of (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate to cPMP.
Isoform MOCS1A and isoform MOCS1B probably form a heterooligomer.
Multidomain protein with inactive MOCS1A and active MOCS1B.
The C-terminus of MOCS1A was previously believed to be thiocarboxylated, but it is now known not to be the case.
The MOCS1 locus has initially been reported to produce MOCS1A and MOCS1B from non-overlapping reading frames within a bicistronic transcript. However, only isoform MOCS1A seems to be translated from the bicistronic transcript. Isoform MOCS1B seems to be translated from a monocistronic mRNA that is derived by alternative splicing.
Interacts with ubiquitin (PubMed:19423704). Interacts with UBXN6, VCP and YOD1; may form a complex involved in macroautophagy (PubMed:27753622, PubMed:19887378).
Plays a role in protein ubiquitination, sorting and degradation through its association with VCP (PubMed:27753622). Involved in ubiquitin-mediated membrane proteins trafficking to late endosomes in an ESCRT-dependent manner, and hence plays a role in synaptic vesicle recycling (By similarity). May play a role in macroautophagy, regulating for instance the clearance of damaged lysosomes (PubMed:27753622). Plays a role in cerebellar Purkinje cell development (By similarity). Positively regulates cytosolic and calcium-independent phospholipase A2 activities in a tumor necrosis factor alpha (TNF-alpha)- or lipopolysaccharide (LPS)-dependent manner, and hence prostaglandin E2 biosynthesis (PubMed:18291623, PubMed:28007986).
The PFU domain mediates interaction with ubiquitin.
The PUL domain is composed of 6 armadillo-like repeats and mediates the interaction with VCP C-terminus.
Up-regulated by tumor necrosis factor alpha (TNF-alpha) (at protein level) (PubMed:18291623).
A very small segment of 1p36 located within CAMTA1 is deleted in all oligodendroglial tumors with 1p LOH. This minimal deleted region (MDR) also overlaps the neuroblastoma 1p36 MDR. CAMTA1 shows no evidence of inactivation by somatic mutations.
Detected at low levels at interphase and in resting cells. Up-regulated during S phase and mitosis. Levels decrease at the end of mitosis.
Normally expressed in non-neoplastic adult central nervous system tissues: detected in whole brain, cerebellum, brain cortex, occipital lobe, frontal lobe, temporal lobe, putamen. Expression levels are low in oligodendroglial tumors, and are reduced by half in oligodendroglioma and astrocytoma cases with 1p loss of heterozygosity. Detected in neuroblastic-type cultured neuroblastoma cells. Expressed in heart and kidney.
Essential for hematopietic stem cell development through the regulation of p53/TP53 pathway.
Acetylated by EP300. Lys-227 as is the major acetylation site for EP300; the dynamicly regulated acetylation inhibits heterodimerization with RXRA and transactivation activity. Deacetylated by SIRT1.
Heterodimer (via C-terminus) with RXRA (via DBD); the heterodimerization enhances the binding affinity for LXXLL motifs from coactivators (PubMed:23462506, PubMed:30275017). Binds DNA predominantly as a heterodimer with RXRA. After activation by agonist binding interacts with coactivators. Interacts with NCOA1, NCOA2, PPARGC1A, CARM1, SETD7, PRMT1, GPS2, SMARCA4 and MED1 (PubMed:15202934, PubMed:14684751, PubMed:15187081, PubMed:15471871, PubMed:15911693, PubMed:17895379, PubMed:18755856, PubMed:19805516, PubMed:23462506, PubMed:12718892, PubMed:12718893, PubMed:18621523, PubMed:18391212, PubMed:19410460, PubMed:19586769). Interacts with EP300 and SMARCD1 (By similarity). Interacts with XRCC5 and XRCC6; decreasing NR1H4/FXR transactivation activity towards ABCB11/BSEP (PubMed:19833092). Interacts with PAGR1 and NCOA6; indicative for an association with an MLL2/MLL3 complex (ASCOM) (PubMed:19556342).
Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415). The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'-AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity (By similarity). In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis) (By similarity). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:12754200, PubMed:15471871, PubMed:17895379). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:10514450, PubMed:15239098, PubMed:16269519). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression (PubMed:12815072, PubMed:19085950). The function also involves the coordinated induction of hepatic KLB/beta-klotho expression (By similarity). Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA (PubMed:12806625, PubMed:16946559). Modulates lipid homeostasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly (PubMed:12660231, PubMed:12554753, PubMed:15337761). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance) (PubMed:11579204). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element (PubMed:11927623, PubMed:21804189). Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase) (PubMed:12891557). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3) (By similarity). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance (PubMed:20447400). Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier (By similarity). Down-regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells (PubMed:21242261). Mediates trans-repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2 (PubMed:19864602). Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays an anti-inflammatory role in liver inflammation; proposed to inhibit pro-inflammatory (but not antiapoptotic) NF-kappa-B signaling) (By similarity).
Liver and hepatocyte-related cells express mainly FXRalpha1-type isoforms with isoform 3 and isoform 4 in approximately equal proportions. In intestine and kidney mainly FXRalpha2-type isoforms are expressed with isoform 1 and isoform 2 in approximately equal proportions. Expressed in pancreatic beta cells and macrophages.
May be involved in cholesterol cholelithiasis.
May be involved in intrahepatic cholestasis of pregnancy.
Methylation may increase transactivation of target genes.
Phosphorylation by PKC/PRKCA increases transactivation activity by promoting association with PPARGC1A.
Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, ACA and DCA), NR0B2/SHP (inducible by unconjugated CDCA, ACA and DCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; most efficient isoform compared to isoforms 1 to 3; not inducible by taurine- and glycine-amidated CDCA.
Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA), NR0B2/SHP (inducible by unconjugated CDCA DCA and ACA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; not inducible by taurine- and glycine-amidated CDCA.
Promotes transcriptional activation of target genes NR0B2/SHP (inducible by unconjugated CDCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; low activity for ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA); not inducible by taurine- and glycine-amidated CDCA.
Promotes transcriptional activation of target genes NR0B2/SHP (inducible by unconjugated CDCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and IBAP; low activity for ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA); not inducible by taurine- and glycine-amidated CDCA.
Ursodeoxycholic acid (UDCA), a natural agonist of FXR, is approved to treat primary biliary cirrhosis. However, effects are discussed controversial. UDCA is also used to dissolve (cholesterol) gallstones as alternative to surgery.
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.4/SCN4A subfamily.
Channel activity is regulated by the ancillary beta subunit SCN1B (PubMed:29992740). SCN1B strongly enhances the presence of the pore-forming alpha subunit at the cell surface (PubMed:29992740, PubMed:30190309). Interaction with SCN1B is required for rapid channel inactivation and rapid recovery after inactivation, and prevents decrease of channel activity in response to repetitive, high-frequency depolarizations (By similarity). The channel is inhibited by tetrodotoxin and saxitoxin (PubMed:30190309).
Component of a voltage-sensitive sodium channel complex that consists of an ion-conducting pore-forming alpha subunit and one or more regulatory beta subunits (PubMed:29992740, PubMed:30190309). Interacts with SCN1B (PubMed:29992740, PubMed:30190309). Heterooligomer with SCN2B or SCN4B; disulfide-linked (By similarity). Interacts with the PDZ domain of the syntrophins SNTA1, SNTB1 and SNTB2 (By similarity). Interacts with the conotoxin GVIIJ (PubMed:24497506).
Phosphorylation at Ser-1328 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents.
Pore-forming subunit of a voltage-gated sodium channel complex through which Na(+) ions pass in accordance with their electrochemical gradient. Alternates between resting, activated and inactivated states (PubMed:12766226, PubMed:29992740, PubMed:30190309, PubMed:15318338, PubMed:16890191, PubMed:18690054, PubMed:17898326, PubMed:19347921, PubMed:25707578, PubMed:26700687). Required for normal muscle fiber excitability, normal muscle contraction and relaxation cycles, and constant muscle strength in the presence of fluctuating K(+) levels (PubMed:12766226, PubMed:15318338, PubMed:16890191, PubMed:19347921, PubMed:25707578, PubMed:26700687, PubMed:26659129).
SCN4A mutations are the cause of an autosomal recessive neuromuscular disorder characterized by severe fetal hypokinesia, neonatal hypotonia and congenital myopathy of variable severity. The most severe clinical features include reduced or absent fetal movements, in-utero upper and lower limb contractures, talipes and hydrops, and intrauterine or early postnatal death. Mildly affected patients present with generalized hypotonia and weakness at birth or within the first few days of life, mild-to-moderate facial muscle weakness without ptosis, significant early respiratory and feeding difficulties, and skeletal abnormalities of the spine and palate. Symptoms improve over time in patients who survive infancy, resulting in gain of muscle strength and motor skills and concomitant resolution of early respiratory and feeding difficulties. In contrast to other SCN4A-related channelopathies, affected individuals manifest in-utero or neonatal onset of permanent muscle weakness, rather than later-onset episodic muscle weakness.
Isomerization of 3-trans,5-cis-dienoyl-CoA to 2-trans,4-trans-dienoyl-CoA.
Mainly expressed in the neuromuscular system. Located in and around synaptic myonuclei in adult muscle. Expression is dysregulated after nerve injury. Also found in the testis, ovary and placenta.
Associates with the pre-60S ribosomal particles.
Trans-acting factor in ribosome biogenesis required for efficient 40S and 60S subunit production.
(Microbial infection) Associates with the VP16-induced complex; binding to HCFC1 activates the viral transcriptional activator VP16 for association with POU2F1, to form a multiprotein-DNA complex responsible for activating transcription of the viral immediate early genes (PubMed:10629049). Interacts with the viral transactivator protein VP16 (PubMed:9271389, PubMed:9389645, PubMed:10629049).
(Microbial infection) In case of human herpes simplex virus (HSV) infection, HCFC1 forms a multiprotein-DNA complex with the viral transactivator protein VP16 and POU2F1 thereby enabling the transcription of the viral immediate early genes.
Composed predominantly of six polypeptides ranging from 110 to 150 kDa and a minor 300 kDa polypeptide (PubMed:10920196). The majority of N- and C-terminal cleavage products remain tightly, albeit non-covalently, associated (PubMed:10920196). Interacts with POU2F1, CREB3, ZBTB17, EGR2, E2F4, CREBZF, SP1, GABP2, Sin3 HDAC complex (SIN3A, HDAC1, HDAC2, SUDS3), SAP30, SIN3B and FHL2 (PubMed:9271389, PubMed:9389645, PubMed:10675337, PubMed:10976766, PubMed:10629049, PubMed:10871379, PubMed:10984507, PubMed:12244100, PubMed:14532282, PubMed:12670868, PubMed:15705566, PubMed:16624878). Component of a MLL1 complex, composed of at least the core components KMT2A/MLL1, ASH2L, HCFC1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, DPY30, E2F6, HCFC2, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MEN1, MGA, KAT8, PELP1, PHF20, PRP31, RING2, RUVBL1, RUVBL2, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15199122, PubMed:15960975). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1 (PubMed:20200153). Interacts directly with THAP3 (via its HBM) (PubMed:20200153). Interacts (via the Kelch-repeat domain) with THAP1 (via the HBM); the interaction recruits HCHC1 to the RRM1 (PubMed:20200153). Interacts directly with OGT; the interaction, which requires the HCFC1 cleavage site domain, glycosylates and promotes the proteolytic processing of HCFC1, retains OGT in the nucleus and impacts the expression of herpes simplex virus immediate early viral genes (PubMed:12670868, PubMed:21285374, PubMed:23353889). Component of the SET1 complex, at least composed of the catalytic subunit (SETD1A or SETD1B), WDR5, WDR82, RBBP5, ASH2L, CXXC1, HCFC1 and DPY30 (PubMed:17998332, PubMed:18838538). Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1 (PubMed:20018852). Component of a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY, MKI67, RBBP5, ASH2L and WDR5; the complex is formed as a result of interactions between components of a nuclear receptor-mediated transcription complex and a histone methylation complex (PubMed:19131338). Within the complex interacts with ZNF335 (PubMed:19131338). Interacts with TET2 and TET3 (PubMed:23353889). Interacts with HCFC1R1 (PubMed:12235138). Interacts with THAP11 (By similarity). Interacts (via Kelch domain) with KMT2E/MLL5 isoform 3 (via HBM motif) (PubMed:23629655). Interacts with E2F1 (PubMed:23629655).
Highly expressed in fetal tissues and the adult kidney. Present in all tissues tested.
O-glycosylated. GlcNAcylation by OGT promotes proteolytic processing.
Proteolytically cleaved at one or several PPCE--THET sites within the HCF repeats (PubMed:7590226, PubMed:10920196, PubMed:21285374). Further cleavage of the primary N- and C-terminal chains results in a 'trimming' and accumulation of the smaller chains. Cleavage is promoted by O-glycosylation (PubMed:21285374, PubMed:28302723, PubMed:28584052).
The HCF repeat is a highly specific proteolytic cleavage signal.
The N- and the C-terminal fragments fail to associate.
The kelch repeats fold into a 6-bladed kelch beta-propeller called the beta-propeller domain which mediates interaction with HCFC1R1.
Transcriptional coregulator (By similarity). Involved in control of the cell cycle (PubMed:10629049, PubMed:10779346, PubMed:15190068, PubMed:16624878, PubMed:23629655). Also antagonizes transactivation by ZBTB17 and GABP2; represses ZBTB17 activation of the p15(INK4b) promoter and inhibits its ability to recruit p300 (PubMed:10675337, PubMed:12244100). Coactivator for EGR2 and GABP2 (PubMed:12244100, PubMed:14532282). Tethers the chromatin modifying Set1/Ash2 histone H3 'Lys-4' methyltransferase (H3K4me) and Sin3 histone deacetylase (HDAC) complexes (involved in the activation and repression of transcription, respectively) together (PubMed:12670868). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1 (PubMed:20200153). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852). Recruits KMT2E/MLL5 to E2F1 responsive promoters promoting transcriptional activation and thereby facilitates G1 to S phase transition (PubMed:23629655). Modulates expression of homeobox protein PDX1, perhaps acting in concert with transcription factor E2F1, thereby regulating pancreatic beta-cell growth and glucose-stimulated insulin secretion (By similarity). May negatively modulate transcriptional activity of FOXO3 (By similarity).
Ubiquitinated. Lys-1807 and Lys-1808 are ubiquitinated both via 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. BAP1 mediated deubiquitination of 'Lys-48'-linked polyubiquitin chains; deubiquitination by BAP1 does not seem to stabilize the protein.
(Microbial infection) Helicase activity is important for packaging viral RNA into virions during West Nile virus infection.
(Microbial infection) Interacts with EMCV protein 3C; this interaction leads to inhibition of type I interferon production.
(Microbial infection) Interacts with West Nile virus capsid protein C.
(Microbial infection) Interacts with foot-and-mouth disease virus protein 3A; this interaction leads to inhibition of type I interferon production.
(Microbial infection) Plays a positive role in EMCV replication by interrupting IRF3 phosphorylation and its nucleus translocation.
(Microbial infection) Plays a positive role in foot-and-mouth disease virus replication by inhibiting the phosphorylation of IRF3 leading to inhibition of type I interferon.
Belongs to the DEAD box helicase family. DDX56/DBP9 subfamily.
Detected in heart, brain, liver, pancreas, placenta and lung.
May form homooligomeric complexes. Interacts with IRF3 (PubMed:31340999). Interacts with OCT4 and POU5F1 (By similarity).
Nucleolar RNA helicase that plays a role in various biological processes including innate immunity, ribosome biogenesis or nucleolus organization (PubMed:31340999, PubMed:33789112). Plays an essential role in maintaining nucleolar integrity in planarian stem cells (PubMed:33789112). Maintains embryonic stem cells proliferation by conventional regulation of ribosome assembly and interaction with OCT4 and POU5F1 complex (By similarity). Regulates antiviral innate immunity by inhibiting the virus-triggered signaling nuclear translocation of IRF3 (PubMed:31340999). Mechanistically, acts by disrupting the interaction between IRF3 and importin IPO5 (PubMed:31340999). May play a role in later stages of the processing of the pre-ribosomal particles leading to mature 60S ribosomal subunits. Has intrinsic ATPase activity.
Guanine nucleotide exchange factor (GEF) which may activate RAB10. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form.
Acts as a co-chaperone for HSP90AA1 (PubMed:27353360). Mediates the association of the molecular chaperones HSPA8/HSC70 and HSP90 (By similarity).
Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Forms a complex with HSPA8/HSC70, HSPCA/HSP-86 and HSPCB/HSP-84 (By similarity). Interacts with PACRG (PubMed:14532270). Interacts with EEF1AKMT3 (PubMed:23349634). Interacts with HSP90/HSP90AA1; the interaction dissociates the PPP5C:HSP90AA1 interaction (PubMed:9195923, PubMed:27353360). Interacts with FLCN, FNIP1 and FNIP2 (PubMed:27353360). Interacts with HSPA8/HSC70 (By similarity). Interacts with HSP90AB1; upon SMYD2-dependent HSP90AB1 methylation (PubMed:24880080).
The TPR 1 repeat interacts with the C-terminal of HSC70. The TPR 4, 5 and 6 repeats (also called TPR2A domain) and TPR 7, 8 and 9 repeats (also called TPR2B domain) interact with HSP90.
Embryonic stem (ES) cell-specific transcription factor required to maintain ES cell pluripotency. Can both activate and /or repress expression of target genes, depending on the context. Specifically binds the 5'-[GA]CGCNNGCG[CT]-3' DNA consensus sequence. Regulates expression of POU5F1/OCT4, ZSCAN4 and ALYREF/THOC4.
Belongs to the universal ribosomal protein uL11 family.
Ubiquitinated at Lys-48 and Lys-83 by RNF14 and RNF25 in response to ribosome collisions (ribosome stalling).
Involved in skeletal muscle differentiation. May act as a scaffold protein for AKT1 during muscle differentiation.
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. Ligand for integrins alpha-E/beta-7, ITGAE:ITGAB7, alpha-4/beta-7, ITGA4:ITGAB7 and alpha-4/beta-1, ITGA4:ITGAB1 through which modulates CD4(+) T cells activation (PubMed:28051089).
Expressed by epithelial cells of gastrointestinal tissue.
Homodimer (PubMed:28051089). Component of a cadherin:catenin adhesion complex composed of at least of CDH26, beta-catenin/CTNNB1, alpha-catenin/CTNNA1 and p120 catenin/CTNND1 (PubMed:28051089).
Both isoforms are expressed in different tissues like heart, placenta, brain, skeletal muscle and pancreas. Isoform beta is especially found in liver.
Interacts with DLG5 through its third SH3 domain (By similarity). Interacts with vinculin by the first two SH3 domains and the proline rich region of vinculin. Binds to SOS (guanine nucleotide exchange factor of RAS and RAC), through its third SH3 domain. The formation of this complex is down-regulated by phosphorylation of SOS. Interacts with INPPL1/SHIP2, SAFB2, SOCS7 and SRCIN1. Interacts with FASLG. Interacts with MAPK1/ERK2 (By similarity).
Phosphorylated at Ser-530 by MAPK1/ERK2 during cell spreading.
Vinexin alpha isoform promotes up-regulation of actin stress fiber formation. Vinexin beta isoform plays a role in cell spreading and enhances the activation of JNK/SAPK in response to EGF stimulation by using its third SH3 domain.
Belongs to the Schlafen family. Subgroup I subfamily.
Interacts (via C-terminus) with DNAAF11 (via CS domain); this interaction stabilizes DNAAF11 at the protein level (PubMed:23891469, PubMed:23891471, PubMed:29601588). Interacts (via C-terminus) with DNAL1; this interaction stabilizes DNAL1 at the protein level (PubMed:29601588). Interacts with DNAAF4, HSPA8, IQUB, RUVBL2 and DYNTL5 (PubMed:29601588).
Plays a role in axonemal structure organization and motility (PubMed:23891469, PubMed:23891471). Involved in axonemal pre-assembly of inner and outer dynein arms (IDA and ODA, respectively) for proper axoneme building for cilia motility (By similarity). May act by indirectly regulating transcription of dynein proteins (By similarity).
Flagellar protein involved in sperm flagellum axoneme organization and function (By similarity). Involved in the regulation of the beating frequency of motile cilia on the epithelial cells of the respiratory tract (By similarity).
Bcl-X(S) is expressed at high levels in cells that undergo a high rate of turnover, such as developing lymphocytes. In contrast, Bcl-X(L) is found in tissues containing long-lived postmitotic cells, such as adult brain.
Forms heterodimers with BAX, BAK or BCL2; heterodimerization with BAX does not seem to be required for anti-apoptotic activity (PubMed:7644501). Interacts with isoform 1 of SIVA1; the interaction inhibits the anti-apoptotic activity (PubMed:12011449). Interacts with IKZF3 (PubMed:11714801). Interacts with RTL10/BOP (PubMed:23055042). Interacts with DNM1L and CLTA; DNM1L and BCL2L1 isoform BCL-X(L) may form a complex in synaptic vesicles that also contains clathrin and MFF (PubMed:23792689). Interacts (via the loop between motifs BH4 and BH3) with NLRP1 (via LRR repeats), but not with NLRP2, NLRP3, NLRP4, PYCARD, nor MEFV (PubMed:17418785). Interacts with BECN1 (PubMed:22498477, PubMed:17337444).
Homodimer. Interacts with BCL2L11 (By similarity). Interacts with BAD. Interacts with PGAM5. Interacts with HEBP2. Interacts with p53/TP53 and BBC3; interaction with BBC3 disrupts the interaction with p53/TP53. Interacts with ATP5F1A and ATP5F1B; the interactions mediate the association of isoform Bcl-X(L) with the mitochondrial membrane ATP synthase F(1)F(0) ATP synthase. Interacts with VDAC1 (PubMed:25296756). Interacts with BCL2L11 (via BH3) (PubMed:27013495). Interacts with RNF183 (PubMed:29507230). Interacts with GIMAP3/IAN4 and GIMAP5/IAN5 (PubMed:16509771). Interacts with GIMAP5 and HSPA8/HSC70; the interaction between HSPA8 and BCL2L1 is impaired in the absence of GIMAP5 (By similarity). Interacts with isoform 4 of CLU; this interaction releases and activates BAX and promotes cell death (PubMed:21567405).
Isoform Bcl-X(L) also regulates presynaptic plasticity, including neurotransmitter release and recovery, number of axonal mitochondria as well as size and number of synaptic vesicle clusters. During synaptic stimulation, increases ATP availability from mitochondria through regulation of mitochondrial membrane ATP synthase F(1)F(0) activity and regulates endocytic vesicle retrieval in hippocampal neurons through association with DMN1L and stimulation of its GTPase activity in synaptic vesicles. May attenuate inflammation impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785).
Phosphorylated on Ser-62 by CDK1. This phosphorylation is partial in normal mitotic cells, but complete in G2-arrested cells upon DNA-damage, thus promoting subsequent apoptosis probably by triggering caspases-mediated proteolysis. Phosphorylated by PLK3, leading to regulate the G2 checkpoint and progression to cytokinesis during mitosis. Phosphorylation at Ser-49 appears during the S phase and G2, disappears rapidly in early mitosis during prometaphase, metaphase and early anaphase, and re-appears during telophase and cytokinesis.
Potent inhibitor of cell death. Inhibits activation of caspases. Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.
Proteolytically cleaved by caspases during apoptosis. The cleaved protein, lacking the BH4 motif, has pro-apoptotic activity.
The BH4 motif is required for anti-apoptotic activity. The BH1 and BH2 motifs are required for both heterodimerization with other Bcl-2 family members and for repression of cell death.
The loop between motifs BH4 and BH3 is required for the interaction with NLRP1.
Ubiquitinated by RNF183 during prolonged ER stress, leading to degradation by the proteosome.
Belongs to the V-ATPase E subunit family.
Component of SWI/SNF chromatin remodeling subcomplex GBAF that carries out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner (PubMed:29374058). May play a role in BRD4-mediated gene transcription (PubMed:21555454).
Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B) and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific. Component of the SWI/SNF (GBAF) subcomplex, which includes at least BICRA or BICRAL (mutually exclusive), BRD9, SS18, the core BAF subunits, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, SMARCC1/BAF155, and SMARCD1/BAF60A (PubMed:29374058). Interacts with BRD4; the interaction bridges BRD4 to the GBAF complex (PubMed:29374058, PubMed:21555454).
Expressed at moderate levels in heart, brain, placenta, skeletal muscle, and pancreas, and at lower levels in lung, liver and kidney.
Component of the SMG1C complex composed of SMG1, SMG8 and SMG9; the recruitment of SMG8 to SMG1 N-terminus induces a large conformational change in the SMG1 C-terminal head domain containing the catalytic domain (PubMed:33205750). Component of the transient SURF (SMG1-UPF1-eRF1-eRF3) complex. Part of a complex composed of SMG1, DHX34 and UPF1; within the complex DHX34 acts as a scaffolding protein to facilitate SMG1 phosphorylation of UPF1 (PubMed:26841701). Interacts with PRKCI. Interacts with TELO2 and TTI1. Interacts with RUVBL1 and RUVBL2 (PubMed:33205750). Interacts with UPF2. Interacts with DHX34 (via C-terminus); the interaction is RNA-independent (PubMed:25220460, PubMed:33205750).
Inhibited by caffeine, LY294002 and wortmannin.
Serine/threonine protein kinase involved in both mRNA surveillance and genotoxic stress response pathways. Recognizes the substrate consensus sequence [ST]-Q. Plays a central role in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by phosphorylating UPF1/RENT1. Recruited by release factors to stalled ribosomes together with SMG8 and SMG9 (forming the SMG1C protein kinase complex), and UPF1 to form the transient SURF (SMG1-UPF1-eRF1-eRF3) complex. In EJC-dependent NMD, the SURF complex associates with the exon junction complex (EJC) through UPF2 and allows the formation of an UPF1-UPF2-UPF3 surveillance complex which is believed to activate NMD. Also acts as a genotoxic stress-activated protein kinase that displays some functional overlap with ATM. Can phosphorylate p53/TP53 and is required for optimal p53/TP53 activation after cellular exposure to genotoxic stress. Its depletion leads to spontaneous DNA damage and increased sensitivity to ionizing radiation (IR). May activate PRKCI but not PRKCZ.
This gene is located in a region of chromosome 16 that contains 2 segmental duplications. Other genes that are highly related to this exist, but they probably represent pseudogenes.
Widely expressed, with highest level in heart and skeletal muscle. Expressed in placenta, brain, lung and spleen, but not in liver.
May be required for stable YIPF1 and YIPF2 protein expression.
Predominantly interacts with YIPF1 or YIPF2, but may also form a ternary complex with YIPF1 and YIPF2. This interaction may stabilize YIPF1 and YIPF2.
May act as a component of a corepressor complex that represses transcription.
Transcription factor, which represses ZNF609 transcription.
Mediates the side-chain deamidation of N-terminal glutamine residues to glutamate, an important step in N-end rule pathway of protein degradation. Conversion of the resulting N-terminal glutamine to glutamate renders the protein susceptible to arginylation, polyubiquitination and degradation as specified by the N-end rule. Does not act on substrates with internal or C-terminal glutamine and does not act on non-glutamine residues in any position. Does not deaminate acetylated N-terminal glutamine. With the exception of proline, all tested second-position residues on substrate peptides do not greatly influence the activity. In contrast, a proline at position 2, virtually abolishes deamidation of N-terminal glutamine.
Gustducin-coupled receptor implicated in the perception of bitter compounds in the oral cavity and the gastrointestinal tract. Signals through PLCB2 and the calcium-regulated cation channel TRPM5 (By similarity).
Essentially unstructured in the absence of calcium ions. Requires calcium ions for folding.
Interacts in a calcium-dependent manner with LMAN1.
The MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins. Plays a role in the secretion of coagulation factors.
Expressed in a subset of small lymphocytes (at protein level). Expressed at high concentration in kidney, lymph node and thymus. Expressed at moderate concentration in stomach, jejunum, ileum, appendix, spleen, leukocytes, trachea, lung and thyroid gland. Expressed at low concentration in whole brain, esophagus, duodenum, ileocecum, colon, skeletal muscle, bone marrow, placenta and mammary gland (PubMed:14593528). Isoform 1a, isoform 1b, isoform 1c and isoform 1d are highly expressed in brain, bone marrow, colon, kidney, lung, skeletal muscle, spleen, thymus and thyroid. Not expressed in heart and liver. Isoform 2a, isoform 2b, isoform 2c and isoform 2d are expressed in brain, bone marrow, kidney, skeletal muscle, spleen, thymus and thyroid. Not expressed in heart, liver and lung (PubMed:12590732).
Expressed in several fetal tissues including kidney, thymus, spleen and lung.
Homodimer (PubMed:16143324). Interacts with RRAS (PubMed:18270267). Interacts (phosphorylated form) with VAPA (PubMed:16143324, PubMed:25447204). Interacts with OSBPL6 (By similarity).
Phosphoinositide-binding protein which associates with both cell and endoplasmic reticulum (ER) membranes (PubMed:16143324). Can bind to the ER membrane protein VAPA and recruit VAPA to plasma membrane sites, thus linking these intracellular compartments (PubMed:25447204). The ORP3-VAPA complex stimulates RRAS signaling which in turn attenuates integrin beta-1 (ITGB1) activation at the cell surface (PubMed:18270267, PubMed:25447204). With VAPA, may regulate ER morphology (PubMed:16143324). Has a role in regulation of the actin cytoskeleton, cell polarity and cell adhesion (PubMed:18270267). Binds to phosphoinositides with preference for PI(3,4)P2 and PI(3,4,5)P3 (PubMed:16143324). Also binds 25-hydroxycholesterol and cholesterol (PubMed:17428193).
Phosphorylation is enhanced in vitro by phorbol-12-myristate-13-acetate (PMA), forskolin and calcium ionophore A23187 (PubMed:25447204). Phosphorylation seems to be stimulated in conditions of low cell-cell (or cell-matrix) adhesion (PubMed:18270267).
The FFAT 2 motif is required for interaction with VAPA and regulation of the endoplasmic reticulum targeting of ORP3. The FFAT 1 motif may contribute to VAPA binding.
The PH domain binds phosphoinositides, with a preference for PI(3,4)P2 and PI(3,4,5)P3. The PH domain mediates targeting to the plasma membrane (PubMed:18270267).
Antiporter that transports nucleotide sugars across the endoplasmic reticulum (ER) membrane in exchange for either their cognate nucleoside monophosphate or another nucleotide sugar (PubMed:16965264, PubMed:17599910, PubMed:31423530). Transports various UDP-sugars including UDP-N-acetyl-alpha-D-glucosamine (UDP-GlcNAc), UDP-N-acetyl-alpha-D-galactosamine (UDP-GalNAc) and UDP-alpha-D-glucuronate (UDP-GlcA), which are used by ER glucosyltransferases as sugar donors for the synthesis of sugar chains of glycoproteins, glycolipids and oligosaccharides (PubMed:11322953, PubMed:16965264, PubMed:17599910, PubMed:31423530, PubMed:17952091). May couple UDP-GlcNAc or UDP-GalNAc efflux to UDP-GlcA influx into the ER lumen that in turn stimulates glucuronidation and subsequent excretion of endobiotics and xenobiotics (PubMed:16965264, PubMed:17599910). Plays a role in chondroitin sulfate biosynthesis, which is important for formation of cartilage extracellular matrix and normal skeletal development (By similarity).
The use of uridine 5'-monophosphate (UMP) as a counter-anion is disputed and needs further investigation.
Highly expressed in the visceral fat depot.
Involved in processes that promote adipocyte differentiation, lipid accumulation, and glucose uptake in mature adipocytes.
In plasma, interacts with APOA1 and mainly associated with large high density lipoprotein particles.
May play a role in lipid exchange and transport throughout the body. May participate in reverse cholesterol transport from peripheral cells to the liver.
Plasma. Found on APOA-I-containing high density lipoprotein (HDL3). Expressed in pancreas, lung, prostate, liver, placenta and spleen.
Activated by threonine and tyrosine phosphorylation by either of two dual specificity kinases, MAP2K4 and MAP2K7. MAP2K4 shows a strong preference for Tyr-185 while MAP2K7 phosphorylates Tyr-183 preferentially. Inhibited by dual specificity phosphatases, such as DUSP1.
Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4, which activates the enzyme. Autophosphorylated in vitro.
Interacts with MECOM (By similarity). Interacts with DCLK2 (By similarity). Binds to at least four scaffolding proteins, MAPK8IP1/JIP-1, MAPK8IP2/JIP-2, MAPK8IP3/JIP-3/JSAP1 and SPAG9/MAPK8IP4/JIP-4. These proteins also bind other components of the JNK signaling pathway (By similarity). Interacts with NFATC4 (PubMed:17875713). Interacts with ATF7; the interaction does not phosphorylate ATF7 but acts as a docking site for ATF7-associated partners such as JUN (PubMed:10376527). Interacts with BCL10 (PubMed:17189706). Interacts with CTNNB1 and GSK3B (PubMed:19675674). Interacts with MAPKBP1 (PubMed:28089251). Interacts with POU5F1; phosphorylates POU5F1 at 'Ser-355'. Found in a complex with SH3RF1, RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK8/JNK1 (By similarity).
MAPK9 isoforms display different binding patterns: alpha-1 and alpha-2 preferentially bind to JUN, whereas beta-1 and beta-2 bind to ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. JUNB is not a substrate for JNK2 alpha-2, and JUND binds only weakly to it.
Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as pro-inflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK9/JNK2. In turn, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase 1-specific transcription initiation factor RRN3. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including TP53 and YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Upon T-cell receptor (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in the osmotic stress-induced epithelial tight-junctions disruption. When activated, promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692). Phosphorylates POU5F1, which results in the inhibition of POU5F1's transcriptional activity and enhances its proteasomal degradation (By similarity).
AGTR2 has been reported to be involved in X-linked intellectual disability (PubMed:12089445). Its pathological role is however questionable (PubMed:23871722).
Helix VIII may act as a gatekeeper for either suppression or activation of the receptor, depending on post-translational modifications and interactions with various receptor partners (PubMed:28379944). Helix VIII is found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G-proteins or beta-arrestins (PubMed:28379944). Upon switching to a membrane-bound conformation, helix VIII can support the recruitment of G proteins and beta-arrestins (PubMed:28379944).
In adult, highly expressed in myometrium with lower levels in adrenal gland and fallopian tube. Expressed in the cerebellum. Very highly expressed in fetal kidney and intestine.
Receptor for angiotensin II, a vasoconstricting peptide (PubMed:8185599, PubMed:28379944, PubMed:29967536, PubMed:31899086). Signals primarily via a non-canonical G-protein- and beta-arrestin independent pathways (PubMed:28379944). Cooperates with MTUS1 to inhibit ERK2 activation and cell proliferation (PubMed:15123706).
Highly expressed in various brain regions. Expressed in amygdala, anterior cingulate cortex, caudate, cerebellar hemisphere, cerebellum, cortex, frontal cortex, hippocampus, hypothalamus, nucleus accumbens, putamen, spinal cord and substantia nigra (PubMed:31820119). Also widely expressed among other tissues, including liver, heart, placenta, lung, kidney, pancreas and skeletal muscle (PubMed:8354390, PubMed:8631325).
Predominantly expressed in developing brain (PubMed:31820119). Preferentially expressed in the developing cortex and cerebellum from gestational weeks 14, 20 and 28 and in the frontal cortex of brains from weeks 21 and 23 (at protein level) (PubMed:31820119).
The disease is caused by variants affecting the gene represented in this entry. A recurrent, pathogenic variant affecting the translation initiation codon of isoform 2 has been found in multiple DEE83 families. The variant results in the absence of isoform 2 and leads to reduced levels of functional UGP2 enzyme in neural stem cells. The absence of isoform 2 is compensated by an increased abundance of a functional isoform 1, carrying variant p.Met12Val, which may explain the survival of the patients. A complete absence of functional UGP2 in all cells would be embryonic lethal.
The human genome was initially thought to contain 2 genes for UTP--glucose-1-phosphate uridylyltransferase: UGP1 and UGP2 (PubMed:8354390, PubMed:8631325). However, the sequence defined as UGP1 (PubMed:8354390) probably does not exist and corresponds to UGP2.
UTP--glucose-1-phosphate uridylyltransferase catalyzing the conversion of glucose-1-phosphate into UDP-glucose, a crucial precursor for the production of glycogen.
Antiapoptotic protein which protects cells uniquely from Fas-induced apoptosis. Regulates Fas-mediated apoptosis in neurons by interfering with caspase-8 activation. May play a role in cerebellar development by affecting cerebellar size, internal granular layer (IGL) thickness, and Purkinje cell (PC) development.
Highly expressed in breast carcinoma tissues. Enhanced expression correlates with the grade of the tumor (grade II/grade III) in primary breast tumors (at protein level). Widely expressed. Expressed at high levels in the brain especially in the hippocampus.
Regulated by the AKT1/LEF1 pathway in breast cancer cell lines.
Essential acyltransferase that catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. Required for synthesis and storage of intracellular triglycerides (PubMed:27184406). Probably plays a central role in cytosolic lipid accumulation. In liver, is primarily responsible for incorporating endogenously synthesized fatty acids into triglycerides (By similarity). Functions also as an acyl-CoA retinol acyltransferase (ARAT) (By similarity). Also able to use 1-monoalkylglycerol (1-MAkG) as an acyl acceptor for the synthesis of monoalkyl-monoacylglycerol (MAMAG) (PubMed:28420705).
Forms multimeric complexes consisting of several DGAT2 subunits (By similarity). Interacts with SLC27A1 and this interaction is enhanced in the presence of ZFYVE1 (PubMed:30970241).
Predominantly expressed in liver and white adipose tissue. Expressed at lower level in mammary gland, testis and peripheral blood leukocytes. Expressed in sebaceous glands of normal skin but decreased psoriatic skin.
Co-chaperonin implicated in mitochondrial protein import and macromolecular assembly. Together with Hsp60, facilitates the correct folding of imported proteins. May also prevent misfolding and promote the refolding and proper assembly of unfolded polypeptides generated under stress conditions in the mitochondrial matrix (PubMed:7912672, PubMed:1346131, PubMed:11422376). The functional units of these chaperonins consist of heptameric rings of the large subunit Hsp60, which function as a back-to-back double ring. In a cyclic reaction, Hsp60 ring complexes bind one unfolded substrate protein per ring, followed by the binding of ATP and association with 2 heptameric rings of the co-chaperonin Hsp10. This leads to sequestration of the substrate protein in the inner cavity of Hsp60 where, for a certain period of time, it can fold undisturbed by other cell components. Synchronous hydrolysis of ATP in all Hsp60 subunits results in the dissociation of the chaperonin rings and the release of ADP and the folded substrate protein (Probable).
Homoheptamer arranged in a ring structure (PubMed:25918392). 2 heptameric Hsp10 rings interact with a Hsp60 tetradecamer in the structure of a back-to-back double heptameric ring to form the symmetrical football complex (PubMed:25918392).
Belongs to the cyclin family. Cyclin C subfamily.
Regulatory subunit of cyclin-dependent kinases that mediates activation of target kinases. Plays a role in transcriptional regulation via its role in regulating the phosphorylation of the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A).
Regulatory subunit of cyclin-dependent kinases. Identified in a complex with a kinase and the RNA polymerase II holoenzyme. Interacts with POLR2A. Interacts with CDK12 and CDK13. Interacts with CDK9 according to PubMed:10574912; does not interact with CDK9 according to PubMed:22012619.
Widely expressed. Highest levels in testis.
Interacts with calcium ATPase ATP2A1/SERCA1. Interact with ATP2A2; the inhibition decreases ATP2A1 Ca(2+) affinity (PubMed:28890335). Interacts with VMP1; VMP1 competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2 (PubMed:28890335).
Reversibly inhibits the activity of ATP2A1 and ATP2A2 in sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+). Modulates calcium re-uptake during muscle relaxation and plays an important role in calcium homeostasis in muscle. Required for muscle-based, non-shivering thermogenesis (By similarity).
Expressed preferentially in adipose, skeletal muscle and CNS.
IL17D nucleotide sequence has been submitted under the name IL27 in INSDC AY078238 (Ref.2). However, the protein shown in this entry should not be confused with the actual IL27 protein, which forms a heterodimeric cytokine by interaction with EBI3. In order to avoid any ambiguity, we strongly recommend using the official HGNC nomenclature.
Induces expression of IL6, CXCL8/IL8, and CSF2/GM-CSF from endothelial cells.
Interacts (secreted) with SLC1A5; mainly at cell surface.
May play a role in trophoblasts syncytialization, the spontaneous fusion of their plasma membranes, an essential process in placental development. May negatively regulate cell-cell fusion by interacting with SLC1A5, the probable receptor on the cell surface of the fusogenic syncytin-1/ERVW-1.
Specifically expressed in placenta by extravillous trophoblasts and syncytiotrophoblasts (at protein level).
Acts as an antigenic peptide recognized by cytolytic T-lymphocytes in a melanoma.
Interacts with TP53BP1 (via BRCT domain); the interaction is not dependent on its phosphorylation status. Binds nucleosomes. Interacts with trimethylated 'Lys-36' of histone H3 (H3K36me3) (in vitro).
Involved in the DNA damage response pathway by contributing to the maintenance of chromatin architecture. Recruited to the vicinity of DNA breaks by TP53BP1 and plays an accessory role to facilitate damage-induced chromatin changes and promoting chromatin relaxation. Required for efficient DNA repair and cell survival following DNA damage.
The PWWP domain mediates the interaction with nucleosomes.
Homodimer; disulfide-linked (PubMed:26919518, PubMed:31215115). Interacts directly with ACVR2B (By similarity). Interacts directly with ACVR2A (By similarity). Interacts with ACVR1B, TGFBR1 and ACVR1C in an ACVR2B-dependent manner (By similarity). Interacts with FST isoform 2/FS-288 (PubMed:28257634).
In the embryo, strong expression is seen in the palatal epithelia, including the medial edge epithelial and midline epithelial seam of the palatal shelves. Less pronounced expression is also seen throughout the palatal shelf and tongue mesenchyme.
Secreted signal that acts globally to regulate anterior/posterior axial patterning during development. May play critical roles in patterning both mesodermal and neural tissues (By similarity). It is required for proper vertebral patterning and orofacial development (PubMed:31215115). Signals through activin receptors type-2, ACVR2A and ACVR2B, and activin receptors type-1, ACVR1B, ACVR1C and TGFBR1 leading to the phosphorylation of SMAD2 and SMAD3 (PubMed:28257634).
Synthesized as large precursor molecule that undergoes proteolytic cleavage by furin-like proteases (PubMed:31215115). This produces an inactive form consisting of the mature C-terminal portion non-covalently bound to its cleaved N-terminal propeptide. Activation of the mature form requires additional cleavage of the propeptide by a tolloid-like metalloproteinase.
A peptide sequence containing only AA 28-79 retains substantial Kip1 cyclin A/CDK2 inhibitory activity.
Decreased levels of p27Kip1, mainly due to proteasomal degradation, are found in various epithelial tumors originating from lung, breast, colon, ovary, esophagus, thyroid and prostate.
Expressed in kidney (at protein level) (PubMed:15509543). Expressed in all tissues tested (PubMed:8033212). Highest levels in skeletal muscle, lowest in liver and kidney (PubMed:8033212).
Forms a ternary complex composed of CCNE1, CDK2 and CDKN1B. Interacts directly with CCNE1; the interaction is inhibited by CDK2-dependent phosphorylation on Thr-187. Interacts with COPS5, subunit of the COP9 signalosome complex; the interaction leads to CDKN1B degradation. Interacts with NUP50; the interaction leads to nuclear import and degradation of phosphorylated CDKN1B. Interacts with CCND1 and SNX6 (By similarity). Interacts (Thr-198-phosphorylated form) with 14-3-3 proteins, binds strongly YWHAQ, weakly YWHAE and YWHAH, but not YWHAB nor YWHAZ; the interaction with YWHAQ results in translocation to the cytoplasm (PubMed:14504289). Interacts with AKT1 and LYN; the interactions lead to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest (PubMed:12042314, PubMed:12244301, PubMed:17254966). Forms a ternary complex with CCNA2 and CDK2; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements. Interacts (unphosphorylated form) with CDK2. Forms a complex with CDK2 and SPDYA, but does not directly interact with SPDYA (PubMed:12972555, PubMed:28666995). Forms a ternary complex composed of cyclin D, CDK4 and CDKN1B. Interacts (phosphorylated on Tyr-88 and Tyr-89) with CDK4; the interaction is required for cyclin D and CDK4 complex assembly, induces nuclear translocation and activates the CDK4 kinase activity. Interacts with GRB2 (PubMed:16195327). Interacts with PIM1 (PubMed:18593906). Identified in a complex with SKP1, SKP2 and CKS1B (PubMed:16209941). Interacts with UHMK1; the interaction leads to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest (PubMed:12093740). Interacts also with CDK1 (PubMed:16007079). Dephosphorylated on Thr-187 by PPM1H, leading to CDKN1B stability (PubMed:22586611).
Important regulator of cell cycle progression. Inhibits the kinase activity of CDK2 bound to cyclin A, but has little inhibitory activity on CDK2 bound to SPDYA (PubMed:28666995). Involved in G1 arrest. Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. Forms a complex with cyclin type D-CDK4 complexes and is involved in the assembly, stability, and modulation of CCND1-CDK4 complex activation. Acts either as an inhibitor or an activator of cyclin type D-CDK4 complexes depending on its phosphorylation state and/or stoichometry.
Maximal levels in quiescence cells and early G(1). Levels decrease after mitogen stimulation as cells progress toward S-phase.
Phosphorylated; phosphorylation occurs on serine, threonine and tyrosine residues. Phosphorylation on Ser-10 is the major site of phosphorylation in resting cells, takes place at the G(0)-G(1) phase and leads to protein stability. Phosphorylation on other sites is greatly enhanced by mitogens, growth factors, cMYC and in certain cancer cell lines. The phosphorylated form found in the cytoplasm is inactivate. Phosphorylation on Thr-198 is required for interaction with 14-3-3 proteins. Phosphorylation on Thr-187, by CDK1 and CDK2 leads to protein ubiquitination and proteasomal degradation. Tyrosine phosphorylation promotes this process. Phosphorylation by PKB/AKT1 can be suppressed by LY294002, an inhibitor of the catalytic subunit of PI3K. Phosphorylation on Tyr-88 and Tyr-89 has no effect on binding CDK2, but is required for binding CDK4. Dephosphorylated on tyrosine residues by G-CSF.
Subject to degradation in the lysosome. Interaction with SNX6 promotes lysosomal degradation (By similarity).
Ubiquitinated; in the cytoplasm by the KPC complex (composed of RNF123/KPC1 and UBAC1/KPC2) and, in the nucleus, by SCF(SKP2). The latter requires prior phosphorylation on Thr-187. Ubiquitinated; by a TRIM21-containing SCF(SKP2)-like complex; leads to its degradation.
Belongs to the carotenoid/retinoid oxidoreductase family.
Interacts with COX5B; this interaction may contribute to localize PYROXD2 to the inner face of the inner mitochondrial membrane.
Probable oxidoreductase that may play a role as regulator of mitochondrial function.
Protein phosphatase 6 (PP6) holoenzyme is proposed to be a heterotrimeric complex formed of the catalytic subunit, a SAPS domain-containing subunit (PP6R) and an ankyrin repeat-domain containing regulatory subunit (ARS). Interacts with PPP6C and NFKBIE. Interacts with ANKRD28, ANKRD44 and ANKRD52.
Ubiquitous with higher expression in testis.
CNS specific. Expression is restricted to brain, spinal cord, and sciatic nerve. According to PubMed:12881038, expression is abundant in skeletal muscle, liver, and heart, and to a minor degree in pancreas and kidney.
Belongs to the ribonucleoside diphosphate reductase small chain family.
Heterodimer of a large and a small subunit. Interacts (via Cy motif and when phosphorylated at Thr-33) with CCNF; the interaction occurs exclusively in G2 and early M (PubMed:22632967).
Phosphorylation on Ser-20 relieves the inhibitory effect on Wnt signaling. Phosphorylated on Thr-33 by CDK1 and CDK2; predominantly in G2 and M phase (PubMed:22632967).
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. Inhibits Wnt signaling.
Ubiquitinated by the SCF(CCNF) E3 ubiquitin-protein ligase complex; leading to its degradation by the proteasome.
Up-regulated in response to DNA damage induced by doxorubicin, camptothecin, UV-C, methyl methanesulfonate, nocodazole, or gamma-irradiation.
Highly expressed in brain, particularly in the substantia nigra. Also expressed in the corpus callosum, heart, skeletal muscle, ovary, testis, colon and spleen. Weak expression in pancreas, kidney and lung.
May be a centrosome-associated protein. Interacts with MYOC; affects its secretion and its aggregation (By similarity).
May be a centrosome-associated protein. Interacts with MYOC; affects its secretion and its aggregation.
Phosphorylated. Phosphorylation by GRK5 appears to occur on residues distinct from the residue phosphorylated by other kinases.
Plays a role in neurofilament network integrity. May be involved in modulating axonal architecture during development and in the adult. In vitro, increases the susceptibility of neurofilament-H to calcium-dependent proteases (By similarity). May also function in modulating the keratin network in skin. Activates the MAPK and Elk-1 signal transduction pathway (By similarity).
Detected at 67 dpc in the primary ossification center and is tightly restricted to the pericellular region of the hypertrophic chondrocytes and lacunae at the very center of the future diaphysis. At fetal 20-week highly abundant in the hypertrophic zone at the chondroosseous junction. Weakly detected around cells in the resting and proliferative zone of the cartilaginous plate, but the intense detection occurred deep in the hypertrophic zone near the newly formed bone. Detected throughout the extracellular matrix (ECM) in this zone it is also closely situated around hypertrophic chondrocytes.
Plays a role during the calcification of cartilage and the transition of cartilage to bone.
(Microbial infection) Interacts with SARS-CoV Orf7a protein.
Heterodimer of an alpha and a beta subunit (PubMed:12526797). The ITGAL alpha subunit associates with the ITGB2 beta subunit (PubMed:12526797). Interacts with THBD (PubMed:27055590).
In resting T-cells, up to 40% of surface ITGAL is constitutively phosphorylated. Phosphorylation causes conformational changes needed for ligand binding and is necessary for activation by some physiological agents.
Integrin ITGAL/ITGB2 is a receptor for ICAM1, ICAM2, ICAM3 and ICAM4. Integrin ITGAL/ITGB2 is a receptor for F11R (PubMed:11812992, PubMed:15528364). Integrin ITGAL/ITGB2 is a receptor for the secreted form of ubiquitin-like protein ISG15; the interaction is mediated by ITGAL (PubMed:29100055). Involved in a variety of immune phenomena including leukocyte-endothelial cell interaction, cytotoxic T-cell mediated killing, and antibody dependent killing by granulocytes and monocytes. Contributes to natural killer cell cytotoxicity (PubMed:15356110). Involved in leukocyte adhesion and transmigration of leukocytes including T-cells and neutrophils (PubMed:11812992). Required for generation of common lymphoid progenitor cells in bone marrow, indicating a role in lymphopoiesis (By similarity). Integrin ITGAL/ITGB2 in association with ICAM3, contributes to apoptotic neutrophil phagocytosis by macrophages (PubMed:23775590).
The integrin I-domain (insert) is a VWFA domain (PubMed:2537322). Integrins with I-domains do not undergo protease cleavage. The I-domain is necessary and sufficient for interaction with ICAM1 and F11R (PubMed:15528364).
Belongs to the polyribonucleotide nucleotidyltransferase family.
Homotrimer; in free form (PubMed:19509288). Homooligomer (PubMed:19509288). Component of the mitochondrial degradosome (mtEXO) complex which is a heteropentamer containing 2 copies of SUPV3L1 and 3 copies of PNPT1 (PubMed:19509288, PubMed:29967381). As part of the mitochondrial degradosome complex, interacts with GRSF1 in an RNA-dependent manner; the interaction enhances the activity of the complex (PubMed:29967381). Interacts with TCL1A; the interaction has no effect on PNPT1 exonuclease activity (PubMed:16934922).
RNA-binding protein implicated in numerous RNA metabolic processes. Catalyzes the phosphorolysis of single-stranded polyribonucleotides processively in the 3'-to-5' direction. Mitochondrial intermembrane factor with RNA-processing exoribonulease activity. Component of the mitochondrial degradosome (mtEXO) complex, that degrades 3' overhang double-stranded RNA with a 3'-to-5' directionality in an ATP-dependent manner. Involved in the degradation of non-coding mitochondrial transcripts (MT-ncRNA) and tRNA-like molecules (PubMed:29967381). Required for correct processing and polyadenylation of mitochondrial mRNAs. Plays a role as a cytoplasmic RNA import factor that mediates the translocation of small RNA components, like the 5S RNA, the RNA subunit of ribonuclease P and the mitochondrial RNA-processing (MRP) RNA, into the mitochondrial matrix. Plays a role in mitochondrial morphogenesis and respiration; regulates the expression of the electron transport chain (ETC) components at the mRNA and protein levels. In the cytoplasm, shows a 3'-to-5' exoribonuclease mediating mRNA degradation activity; degrades c-myc mRNA upon treatment with IFNB1/IFN-beta, resulting in a growth arrest in melanoma cells. Regulates the stability of specific mature miRNAs in melanoma cells; specifically and selectively degrades miR-221, preferentially. Also plays a role in RNA cell surveillance by cleaning up oxidized RNAs. Binds to the RNA subunit of ribonuclease P, MRP RNA and miR-221 microRNA.
The disease is caused by variants affecting the gene represented in this entry. Both genetic variants associated so far with this disease are affecting splicing.
Up-regulated in cells upon senescence and terminal differentiation. Up-regulated after treatment with IFNB1/IFN-beta.
Activator of LATS1/2 in the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. Stimulates the kinase activity of STK38L.
Adrenal gland, bone marrow, brain, lung, placenta, prostate, salivary gland, skeletal muscle, testis, thymus, thyroid gland, uterus, colon with mucosa, fetal brain and fetal liver.
Binds STK38L. Interacts with LATS1 and LATS2.
Expressed specifically in the middle/uper portions of the hair cortex. Not detected in the hair matrix or cuticle.
Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward very- and ultra-long-chain fatty acyl-CoA (chain length greater than C22) (PubMed:17977534, PubMed:22038835, PubMed:26887952). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively (PubMed:17977534, PubMed:22038835, PubMed:26887952). It is crucial for the synthesis of ultra-long-chain ceramides in the epidermis, to maintain epidermal lipid homeostasis and terminal differentiation (PubMed:23754960).
Contains a predicted homeobox domain which is degenerated, lacking residues important for DNA-binding. Moreover, the protein localizes in the endoplasmic reticulum and not in the nucleus, which also argues against homeobox function (By similarity).
Expressed in the epidermis, where it localizes at the interface between the stratum granulosum and the stratum corneum (at protein level).
Interacts (via the LIR motif) with ATG8 family proteins MAP1LC3A, MAP1LC3B, GABARAP and GABARAPL1 (PubMed:31006537, PubMed:31006538). Interacts with VCP/p97; bridging VCP/p97 to covalent DNA-protein cross-links (DPCs) (PubMed:32152270). Interacts with TOP1 (when sumoylated) (PubMed:32152270).
Major reticulophagy (also called ER-phagy) receptor that acts independently of other candidate reticulophagy receptors to remodel subdomains of the endoplasmic reticulum into autophagosomes upon nutrient stress, which then fuse with lysosomes for endoplasmic reticulum turnover (PubMed:31006538, PubMed:31006537). The ATG8-containing isolation membrane (IM) cradles a tubular segment of TEX264-positive ER near a three-way junction, allowing the formation of a synapse of 2 juxtaposed membranes with trans interaction between the TEX264 and ATG8 proteins (PubMed:31006537). Expansion of the IM would extend the capture of ER, possibly through a 'zipper-like' process involving continued trans TEX264-ATG8 interactions, until poorly understood mechanisms lead to the fission of relevant membranes and, ultimately, autophagosomal membrane closure (PubMed:31006537). Also involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis: acts by bridging VCP/p97 to covalent DNA-protein cross-links (DPCs) and initiating resolution of DPCs by SPRTN (PubMed:32152270).
The LIR motif in the cytosol-facing C-terminal region is involved in the interaction with ATG8 proteins.
The disordered region is required for autophagosome binding and reticulophagy, probably via bridging the long distance between endoplasmic reticulum and autophagosome membranes, because ribosomes exist on endoplasmic reticulum membranes that attach to autophagic membranes.
Expressed by peripheral blood leukocytes (neutrophils and monocytes but not eosinophils). Found in liver, fetal liver, bone marrow, placenta, spleen and in lower levels in skeletal muscle, fetal brain, stomach, lung, thymus, prostate, brain, mammary, adrenal gland, colon, trachea, cerebellum, testis, small intestine and spinal cordon.
Putative adhesion molecule that mediates sialic-acid dependent binding to cells. Preferentially binds to alpha-2,3- or alpha-2,6-linked sialic acid. The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface.
Belongs to the metallophosphoesterase superfamily. MPPE1 family.
Interacts with GPI-anchor proteins. Interacts with TMED10.
Metallophosphoesterase required for transport of GPI-anchor proteins from the endoplasmic reticulum to the Golgi. Acts in lipid remodeling steps of GPI-anchor maturation by mediating the removal of a side-chain ethanolamine-phosphate (EtNP) from the second Man (Man2) of the GPI intermediate, an essential step for efficient transport of GPI-anchor proteins.
The di-lysine motif (KxKxx) acts as an endoplasmic reticulum retrieval signal.
Glutathione S-transferase that catalyzes the nucleophilic attack of the sulfur atom of glutathione on the electrophilic groups of a wide range of exogenous and endogenous compounds (Probable). Involved in the formation of glutathione conjugates of both prostaglandin A2 (PGA2) and prostaglandin J2 (PGJ2) (PubMed:9084911). It also catalyzes the isomerization of D5-androstene-3,17-dione (AD) into D4-androstene-3,17-dione and may therefore play an important role in hormone biosynthesis (PubMed:11152686). Through its glutathione-dependent peroxidase activity toward the fatty acid hydroperoxide (13S)-hydroperoxy-(9Z,11E)-octadecadienoate/13-HPODE it is also involved in the metabolism of oxidized linoleic acid (PubMed:16624487).
The C-terminal domain may form a component of the hydrophobic substrate-binding site, but in contrast appears not to be directly involved in GSH binding and is not absolutely essential for catalytic activity.
The isomerase activity is inhibited by S-methylglutathione (GSMe).
(Microbial infection) By Dengue virus infection (at protein level).
(Microbial infection) Following Dengue virus infection, required for induction of lipophagy which facilitates production of virus progeny particles.
(Microbial infection) Interacts with Dengue virus NS4A; the interaction occurs in the presence of Dengue virus NS4B and induces lipophagy which facilitates production of virus progeny.
(Microbial infection) Not ubiquitinated following Dengue virus infection.
Detected in blood platelets and leukocytes (at protein level). Ubiquitous. Highly expressed in placenta, liver, kidney, skeletal muscle, heart and brain.
Identified in a complex that contains SEL1L, OS9, FAF2/UBXD8, UBE2J1/UBC6E and AUP1 (PubMed:18711132). Interacts with the cytoplasmic tail of ITGA2B, ITGA1, ITGA2, ITGA5, ITGAV and ITGAM (PubMed:12042322). Interacts (via C-terminus) with ubiquitin-conjugating enzyme UBE2G2; the interaction recruits UBE2G2 to lipid droplets (PubMed:21127063, PubMed:23223569). Interacts with ubiquitin ligases AMFR/gp78 and RNF139/TRC8; this promotes interaction of UBE2G2 with AMFR and RNF139 (PubMed:23223569). Interacts with apolipoprotein APOB (PubMed:28183703).
Plays a role in the translocation of terminally misfolded proteins from the endoplasmic reticulum lumen to the cytoplasm and their degradation by the proteasome (PubMed:18711132, PubMed:21857022). Plays a role in lipid droplet formation (PubMed:21857022). Induces lipid droplet clustering (PubMed:24039768). Recruits ubiquitin-conjugating enzyme UBE2G2 to lipid droplets which facilitates its interaction with ubiquitin ligases AMFR/gp78 and RNF139/TRC8, leading to sterol-induced ubiquitination of HMGCR and its subsequent proteasomal degradation (PubMed:23223569, PubMed:21127063). Also required for the degradation of INSIG1, SREBF1 and SREBF2 (PubMed:23223569). Plays a role in regulating assembly and secretion of very low density lipoprotein particles and stability of apolipoprotein APOB (PubMed:28183703).
The CUE domain is required for interaction with the ER quality control machinery and misfolded substrates, ubiquitination, lipid clustering and interaction with AMFR but is not required for localization to lipid droplets.
(Microbial infection) Glycosylated on Arg residue by S.typhimurium protein Ssek3.
Monomer (PubMed:10549288). Can interact with TRADD and RIPK1. Interacts with HCMV protein UL141; this interaction prevents TNFRSF10B cell surface expression. Two TNFRSF10B monomers interact with a UL141 homodimer. Three TNFRSF10B molecules interact with TNFSF10 homotrimer (PubMed:10549288). In the absence of stimulation, interacts with BIRC2, DDX3X and GSK3B. The interaction with BIRC2 and DDX3X is further enhanced upon receptor stimulation and accompanied by DDX3X and BIRC2 cleavage (PubMed:18846110).
Receptor for the cytotoxic ligand TNFSF10/TRAIL (PubMed:10549288). The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Promotes the activation of NF-kappa-B. Essential for ER stress-induced apoptosis.
Widely expressed in adult and fetal tissues; very highly expressed in tumor cell lines such as HeLaS3, K-562, HL-60, SW480, A-549 and G-361; highly expressed in heart, peripheral blood lymphocytes, liver, pancreas, spleen, thymus, prostate, ovary, uterus, placenta, testis, esophagus, stomach and throughout the intestinal tract; not detectable in brain.
Expressed in the odontoblast and nerves in the dental pulp. Also expressed in trachea and to a lesser extent in the brain, liver, lung and kidney.
Mediates spermatid-Sertoli adhesion during spermatogenesis.
Expressed in neuroblastoma, brain and adrenal gland.
Involved in the development of several major noradrenergic neuron populations, including the locus coeruleus. Transcription factor which could determine a neurotransmitter phenotype in vertebrates. Enhances second-messenger-mediated activation of the dopamine beta-hydrolase and c-fos promoters, and of several enhancers including cAMP-response element and serum-response element.
Expressed in placenta, spleen, breast, skin and lung. Also detected in intestinal tract, testis, brain, heart and thymus. No expression found in prostate, bladder, kidney, ovary, muscle, bone marrow, liver and uterus. Isoform 1 is expressed only in placenta. Isoform 2 is expressed in placenta and breast and at lower level in spleen, skin, thymus and stomach.
Isoform 1 may play a role in establishing and maintaining successful pregnancy.
Isoform 2 is a receptor for IL22. Binds to IL22, prevents interaction with the functional IL-22R complex and blocks the activity of IL22 (in vitro). May play an important role as an IL22 antagonist in the regulation of inflammatory responses.
Orphan receptor. Could be a receptor for trace amines. Trace amines are biogenic amines present in very low levels in mammalian tissues. Although some trace amines have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative. Trace amines are likely to be involved in a variety of physiological functions that have yet to be fully understood.
Part of a Cul7-RING ubiquitin-protein ligase complex, consisting of CUL7, RBX1, SKP1 and FBXW8. Interacts with GLMN isoform 1. Interacts with CUL7. Interacts with OBSL1, CUL1, CUL2, SKP1, CCT6B, PFDN5, CCT2, CCT3, CCT6A, CCT7, VBP1, CCDC8, ARF1, TRIP13, PDCD5 and GORASP1. Interacts with IRS1 (when phosphorylated). Interacts with MAP4K1/HPK1 (when autophosphorylated). Associated component of the 3M complex. Interacts with POUF51 (when phosphorylated on 'Ser-355') (By similarity).
Substrate-recognition component of a Cul7-RING ubiquitin-protein ligase complex, which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. The Cul7-RING(FBXW8) complex mediates ubiquitination and consequent degradation of GORASP1, acting as a component of the ubiquitin ligase pathway that regulates Golgi morphogenesis and dendrite patterning in brain (PubMed:21572988). Mediates ubiquitination and degradation of IRS1 in a mTOR-dependent manner: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2) (PubMed:18498745). The Cul7-RING(FBXW8) complex also mediates ubiquitination of MAP4K1/HPK1: recognizes and binds autophosphorylated MAP4K1/HPK1, leading to its degradation, thereby affecting cell proliferation and differentiation (PubMed:24362026). Associated component of the 3M complex, suggesting that it mediates some of 3M complex functions (PubMed:24793695).
Beta-oxidation of fatty acids. The highest activity concerns the C6 to C10 chain length substrate. Converts the end product of pristanic acid beta oxidation, 4,8-dimethylnonanoyl-CoA, to its corresponding carnitine ester.
Activation domains C-terminal of (and distinct from) the forkhead domains are necessary for transcriptional activation.
Probable transcription activator for a number of lung-specific genes.
Abundantly expressed in pancreas, liver, colon and small intestine, less in kidney. Not detected in the adrenal glands, brain, placenta, heart, testis, skeletal muscle, and lungs.
Acts as a membrane potential-dependent organic anion transporter, the transport requires a low concentration of chloride ions (PubMed:22460716). Mediates chloride-dependent transport of urate (PubMed:22460716). Mediates sodium-independent high affinity transport of thyroid hormones including L-thyroxine (T4) and 3,3',5-triiodo-L-thyronine (T3) (PubMed:30367059, PubMed:34937426). Can actively transport inorganic phosphate into cells via Na(+) cotransport (PubMed:22460716).
As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids (PubMed:20381137, PubMed:22980980, PubMed:30181260, PubMed:29107538, PubMed:29123114, PubMed:29158492, PubMed:28935770). Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator plays a dual role for the small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD): it (1) acts as a guanine nucleotide exchange factor (GEF), activating the small GTPases Rag and (2) mediates recruitment of Rag GTPases to the lysosome membrane (PubMed:22980980, PubMed:30181260, PubMed:29107538, PubMed:29123114, PubMed:29158492, PubMed:28935770). Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated (PubMed:22980980, PubMed:30181260, PubMed:29107538, PubMed:29123114, PubMed:29158492, PubMed:28935770). Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2 (By similarity).
Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980, PubMed:29285400, PubMed:29107538, PubMed:29123114, PubMed:29158492, PubMed:28935770, PubMed:31601708, PubMed:32868926, PubMed:35338845, PubMed:36103527, PubMed:36697823). LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:20381137, PubMed:22980980). Interacts with LAMTOR1 and LAMTOR2; the interaction is direct (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and RagD/RRAGD; regulated by amino acid availability (PubMed:20381137, PubMed:32868926). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906, PubMed:32868926). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913, PubMed:32868926). Interacts with MAP2K1/MEK1 and MAPK2 (By similarity). Interacts with MORG1 (By similarity).
Binds ATP, opioids and phosphatidylethanolamine. Has lower affinity for phosphatidylinositol and phosphatidylcholine. Serine protease inhibitor which inhibits thrombin, neuropsin and chymotrypsin but not trypsin, tissue type plasminogen activator and elastase (By similarity). Inhibits the kinase activity of RAF1 by inhibiting its activation and by dissociating the RAF1/MEK complex and acting as a competitive inhibitor of MEK phosphorylation.
HCNP may be involved in the function of the presynaptic cholinergic neurons of the central nervous system. HCNP increases the production of choline acetyltransferase but not acetylcholinesterase. Seems to be mediated by a specific receptor (By similarity).
Has a tendency to form dimers by disulfide cross-linking (By similarity). Interacts with RAF1 and this interaction is enhanced if RAF1 is phosphorylated on residues 'Ser-338', 'Ser-339', 'Tyr-340' and 'Tyr-341'. Interacts with ALOX15; in response to IL13/interleukin-13, prevents the interaction of PEBP1 with RAF1 to activate the ERK signaling cascade.
Involved in the modulation of mTOR signaling and expression of mTOR complex components (PubMed:27040691, PubMed:23977024). Involved in the regulation of cell proliferation and growth (PubMed:23977024, PubMed:24576458). Involved in the control of actin-cytoskeleton organization (PubMed:23977024).
A chromosomal aberration involving PHF23 is found in a patient with acute myeloid leukemia (AML). Translocation t(11;17)(p15;p13) with NUP98.
Acts as a negative regulator of autophagy, through promoting ubiquitination and degradation of LRSAM1, an E3 ubiquitin ligase that promotes autophagy in response to starvation or infecting bacteria.
The PHD-type zinc-finger domain is required for interaction with LRSAM1 and negative regulation of autophagy.
Widely expressed in human tissues and various cell lines.
An intact death domain is needed for apoptosis.
Component of the THO complex, which is composed of THOC1, THOC2, THOC3, THOC5, THOC6 and THOC7; together with at least ALYREF/THOC4, DDX39B, SARNP/CIP29 and CHTOP, THO forms the transcription/export (TREX) complex which seems to have a dynamic structure involving ATP-dependent remodeling. Binds to the hypophosphorylated form of RB1. Interacts with THOC2, DDX39B and RNA polymerase II. Interacts with THOC5 (By similarity). Interacts with LUZP4.
Expression is altered specifically during apoptosis and is accompanied by the appearance of novel forms with smaller apparent molecular mass.
Participates in an apoptotic pathway which is characterized by activation of caspase-6, increases in the expression of BAK1 and BCL2L1 and activation of NF-kappa-B. This pathway does not require p53/TP53, nor does the presence of p53/TP53 affect the efficiency of cell killing. Activates a G2/M cell cycle checkpoint prior to the onset of apoptosis. Apoptosis is inhibited by association with RB1.
Polyubiquitinated, leading to proteasomal degradation; probably involves NEDD4.
Required for efficient export of polyadenylated RNA. Acts as component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NFX1 pathway. The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production. Regulates transcriptional elongation of a subset of genes. Involved in genome stability by preventing co-transcriptional R-loop formation. May play a role in hair cell formation, hence may be involved in hearing (By similarity).
Ubiquitous. Expressed in various cancer cell lines. Expressed at very low levels in normal breast epithelial cells and highly expressed in breast tumors. Expression is strongly associated with an aggressive phenotype of breast tumors and expression correlates with tumor size and the metastatic state of the tumor progression.
Abundantly expressed in brain, heart and pancreas, and at lower levels in kidney and placenta. Up-regulated in the lumbar spinal cord from patients with sporadic amyotrophic lateral sclerosis (ALS) compared with controls, with highest levels of expression in individuals with predominant lower motor neuron involvement.
Homodimer. Interacts with CDK16 (By similarity). Interacts with RGS7 (phosphorylated form) (PubMed:10862767). Interacts with SSH1. Interacts with CDKN1B ('Thr-198' phosphorylated form); the interaction translocates CDKN1B to the cytoplasm. Interacts with GAB2. Interacts with the 'Ser-241' phosphorylated form of PDPK1. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with SLITRK1 (PubMed:19640509). Interacts with RIPOR2 isoform 2 (PubMed:25588844). Interacts with INAVA; the interaction increases upon PRR (pattern recognition receptor) stimulation and is required for cellular signaling pathway activation and cytokine secretion (PubMed:28436939). Interacts with MARK2, MARK3 and MARK4 (PubMed:16959763). Interacts with MEFV (PubMed:27030597).
Ser-232 is probably phosphorylated by CK1.
Can form homodimers. Interacts with TFAP2A, TFAP2B and TFAP2C via the BTB domain.
Expressed in mammary gland, kidney, brain and ovary.
May repress the transcriptional activity of AP-2 family members, including TFAP2A, TFAP2B and TFAP2C to various extent.
Expressed in breast cancer cell lines. Not expressed in normal tissues such as duct, mammary gland, lung, heart, liver, kidnay, bone marrow.
Participates in the regulation of systemic glucose homeostasis, where it negatively regulates insulin granule biogenesis in pancreatic islet beta cells (By similarity). Also regulates glucagon granule production in pancreatic alpha cells (By similarity). Inhibits nuclear translocation of the transcriptional coregulator PHB2 and may enhance estrogen receptor alpha (ESR1) transcriptional activity in breast cancer cells (PubMed:19496786).
Binds to the retinoblastoma protein (RB). Interacts with GATA3.
Highly expressed in retinoblastoma cell lines and in brain tumors. Also expressed in a number of other cell lines and in brain, heart, skeletal muscle, liver and spleen. Isoform 1 is expressed in testis at much higher level than isoform 3.
Produced by alternative initiation at Met-202 of isoform 1.
S-adenosyl-L-methionine-dependent histone methyltransferase that specifically methylates 'Lys-9' of histone H3. May function as a DNA-binding transcription factor. Binds to the macrophage-specific TPA-responsive element (MTE) of the HMOX1 (heme oxygenase 1) gene and may act as a transcriptional activator of this gene.
Component of nuclear RNase P and RNase MRP ribonucleoproteins (PubMed:9630247, PubMed:16723659, PubMed:28115465, PubMed:30454648). RNase P consists of a catalytic RNA moiety and about 10 protein subunits; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40 (PubMed:9630247, PubMed:16723659, PubMed:30454648). Within the RNase P complex, POP1, POP7 and RPP25 form the 'finger' subcomplex, POP5, RPP14, RPP40 and homodimeric RPP30 form the 'palm' subcomplex, and RPP21, POP4 and RPP38 form the 'wrist' subcomplex. All subunits of the RNase P complex interact with the catalytic RNA (PubMed:30454648). Several subunits of RNase P are also part of the RNase MRP complex. RNase MRP consists of a catalytic RNA moiety and about 8 protein subunits; POP1, POP7, RPP25, RPP30, RPP38, RPP40 and possibly also POP4 and POP5 (PubMed:16723659, PubMed:28115465).
Expressed in cultured primary dermal lymphatic endothelial cells.
Orphan receptor that regulates migration of lymphatic endothelial cells in vitro via the small GTPases RhoA and CDC42 (PubMed:24178298). Regulates B-cell development (By similarity). Seems to signal through G-alpha(q)-proteins (PubMed:22575658).
=Produced by alternative splicing of isoform 1.
Can induce long, well-organized actin bundles frequently orientated in parallel along the long axis of the cell showing characteristics of contractile ventral stress fibers.
Detected in myoblasts within 24 hours after induction of myogenic differentiation preceeding the expression of sarcomeric alpha-actinin. Specifically at early stages colocalizes with ZYX at focal adhesions.
Expressed in heart muscle. Isoform 5 is specifically expressed in skeletal muscle.
Has an actin-binding and actin-bundling activity. Can induce the formation of F-actin networks in an isoform-specific manner (PubMed:24005909, PubMed:23225103). At the sarcomeric Z lines is proposed to act as adapter protein that links nascent myofibers to the sarcolemma via ZYX and may play a role in early assembly and stabilization of the Z lines. Involved in autophagosome formation. May play a role in chaperone-assisted selective autophagy (CASA) involved in Z lines maintenance in striated muscle under mechanical tension; may link the client-processing CASA chaperone machinery to a membrane-tethering and fusion complex providing autophagosome membranes (By similarity). Involved in regulation of cell migration (PubMed:22915763, PubMed:25883213). May be a tumor suppressor (PubMed:16885336).
Involved in regulation of cell migration in part dependent on the Rho-ROCK cascade; can promote formation of nascent focal adhesions, actin bundles at the leading cell edge and lamellipodia (PubMed:22915763, PubMed:25883213). Can induce formation of thick, irregular actin bundles in the cell body; the induced actin network is associated with enhanced cell migration in vitro.
Involved in regulation of cell migration. Can induce an amorphous actin meshwork throughout the cell body containing a mixture of long and short, randomly organized thick and thin actin bundles.
Involved in regulation of cell migration. Can induce formation of thick, irregular actin bundles in the cell body.
Involved in regulation of cell migration. Can induce long, well-organized actin bundles frequently orientated in parallel along the long axis of the cell showing characteristics of contractile ventral stress fibers.
May self-associate in muscle cells under oxidative stress. Binds F-actin (PubMed:23225103). Interacts with ACTN2; ACTN2 is proposed to anchor SYOP2 at Z lines in mature myocytes (PubMed:20554076). Interacts with AKAP6, PPP3CA and CAMK2A. Interacts (phosphorylated form) with YWHAB; YWHAB competes with ACTN2 for interaction with SYNPO2. Interacts with KPNA2; mediating nuclear import of SYNOP2; dependent on interaction with YWHAB (By similarity). Interacts with IPO13; may be implicated in SYNOP2 nuclear import (PubMed:17828378). Interacts with ZYX, FLNC, ILK (PubMed:16885336, PubMed:20554076, PubMed:21643011). Interacts with BAG3 (via WW 1 domain). May associate with the CASA complex consisting of HSPA8, HSPB8 and BAG3. Interacts with VPS18 (PubMed:23434281).
Phosphorylated by PKA, and by CaMK2 at multiple sites. Dephosphorylated by calcineurin; abrogating interaction with YWHAB and impairing nuclear import (By similarity). Phosphorylated by ILK.
The PPPY motif interacts with the WW domain 1 of BAG3.
Can form heteromeric complexes with LRFN1, LRFN2, LRFN3 and LRFN5. Unable to form homophilic interactions across cell junctions (By similarity). Interacts with DLG1, DLG2, DLG3 and DLG4.
Promotes neurite outgrowth in hippocampal neurons. May play a role in redistributing DLG4 to the cell periphery (By similarity).
The PDZ-binding motif is required for neurite outgrowth promotion (By similarity). This motif is also involved in DLG1-, DLG3- and DLG4-binding.
Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. Mediates VEGF-induced CDC42 activation. May regulate proangiogenic action of VEGF in vascular endothelial cells, including network formation, directional movement and proliferation. May play a role in regulating the actin cytoskeleton and cell shape.
Expressed in endothelial cells (at protein level).
A chromosomal aberration involving MFHAS1 may be a cause of B-cell lymphoma. Translocation t(8;14)(p23.1;q21) with a cryptic exon named '14q21 element'. The resulting fusion protein named 'chimeric MASL1' is tumorigenic in nude mice.
Interacts with RAF1 (PubMed:23327923). Interacts with HSPD1 (PubMed:24286120). Interacts with PPP2CA; retains PPP2CA into the cytoplasm and excludes it from the nucleus (PubMed:28609714). Interacts with PPP2R2A; the interaction is direct (PubMed:28609714). Interacts with PJA2 (PubMed:28471450).
Probable GTP-binding protein (PubMed:24286120). Functions in innate immunity and more specifically the inflammatory response as a regulator of the Toll-like receptor TLR2 and TLR4 signaling pathways (PubMed:26599367, PubMed:28471450, PubMed:28609714). Negatively regulates the part of the TLR4 signaling pathway that leads to the activation of the transcription factor AP-1. By retaining the phosphatase complex PP2A into the cytoplasm, prevents the dephosphorylation of the AP-1 subunit JUN which is required for proper activation of the transcription factor (PubMed:28609714). Both inhibits and activates the TLR2-dependent signaling pathway (PubMed:26599367). Positively regulates the TLR2 signaling pathway to activate specifically the downstream p38 and JNK MAP kinases and promote the polarization of macrophages toward the pro-inflammatory M1 phenotype (PubMed:28471450). It may also play a role in the regulation of inflammation induced by high glucose through the PKB/AKT signaling pathway (PubMed:29168081). Also involved in erythrocyte differentiation through activation of the ERK1/ERK2 signaling pathway (PubMed:23327923).
Ubiquitinated. Ubiquitination by PJA2 does not lead MFHAS1 to proteasomal degradation but positively regulates its function in polarization of macrophages.
Ubiquitously expressed. Overexpressed in malignant fibrous histiocytomas (PubMed:9973190). Expressed in red blood cells (at protein level) (PubMed:23327923).
Up-regulated during erythroid cells differentiation (at protein level) (PubMed:23327923). Up-regulated upon Toll-like receptor TLR2 stimulation (PubMed:26599367). Up-regulated in macrophages upon M. tuberculosis infection (PubMed:20616063). Up-regulated upon sepsis (PubMed:26599367). Up-regulated by glucose (PubMed:29168081).
Transcription factor involved in SHH-dependent neural patterning. Together with NKX2-2 and NKX6-1 acts to restrict the generation of motor neurons to the appropriate region of the neural tube. Belongs to the class I proteins of neuronal progenitor factors, which are repressed by SHH signals. Involved in the transcriptional repression of MNX1 in non-motor neuron cells. Acts as a regulator of energy metabolism.
Belongs to the nuclear hormone receptor family. NR6 subfamily.
Homodimer. Interacts with UIMC1 (By similarity).
Orphan nuclear receptor. Binds to a response element containing the sequence 5'-TCAAGGTCA-3'. May be involved in the regulation of gene expression in germ cell development during gametogenesis (By similarity).
Shows highest expression in the germ cells of the adult testis.
Expressed in several fetal tissues, including gut, heart, brain, muscle, lung, testis and liver.
Found in fetal lung and small intestine, and at lower level in fetal skin and muscle.
In the adult, detected in placenta, kidney and pancreas. Abundant in the endothelial cells of tumors from ovary, colon, breast and lung, but is not detected in endothelial cells from the corresponding normal tissues (PubMed:10581036, PubMed:11751519). Highly expressed in salivary glands and liver, with lower levels of expression in brain, spleen kidney, muscle and pancreas. Expressed in acinar cells of salivary glands (at protein level) (PubMed:22778404).
Multifunctional anion transporter that operates via two distinct transport mechanisms, namely proton-coupled anion cotransport and membrane potential-dependent anion transport (PubMed:15510212, PubMed:21781115, PubMed:22778404, PubMed:23889254). Electroneutral proton-coupled acidic monosaccharide symporter, with a sugar to proton stoichiometry of 1:1. Exports glucuronic acid and free sialic acid derived from sialoglycoconjugate degradation out of lysosomes, driven by outwardly directed lysosomal pH gradient. May regulate lysosome function and metabolism of sialylated conjugates that impact oligodendrocyte lineage differentiation and myelinogenesis in the central nervous system (PubMed:15510212, PubMed:21781115, PubMed:22778404, PubMed:23889254) (By similarity). Electrogenic proton-coupled nitrate symporter that transports nitrate ions across the basolateral membrane of salivary gland acinar cells, with nitrate to proton stoichiometry of 2:1. May contribute to nitrate clearance from serum by salivary glands, where it is further concentrated and secreted in the saliva (PubMed:22778404). Uses membrane potential to drive the uptake of acidic amino acids and peptides into synaptic vesicles. Responsible for synaptic vesicular storage of L-aspartate and L-glutamate in pinealocytes as well as vesicular uptake of N-acetyl-L-aspartyl-L-glutamate neuropeptide, relevant to aspartegic-associated glutamatergic neurotransmission and activation of metabotropic receptors that inhibit subsequent transmitter release (PubMed:21781115, PubMed:22778404, PubMed:23889254) (By similarity).
Receptor for CM101, a polysaccharide produced by group B Streptococcus with antipathoangiogenic properties.
Belongs to the mitochondrion-specific ribosomal protein mL55 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins.
C-terminal half (amino acids 134-284) contains cytoplasmic retention domains as well as determinants involved in its stress-induced nucleolar accumulation.
Heat-shock stress up-regulated mRNA expression of isoform 10 and isoform 11. Heat-shock stress down-regulated short N-terminal mRNA expression of isoform 2, isoform 4, isoform 6 and isoform 9.
May confer resistance to the antitumor agent cisplatin. Binds to DNA and RNA.
Produced by alternative splicing of isoform 1. In cells exposed to a mild heat schock.
Produced by alternative splicing of isoform 2. In cells exposed to a mild heat schock.
A catalytically active cytoplasmic form (p65) is produced by proteolytic cleavage of either isoform 1, isoform 2 or isoform 3.
Expressed in giant cell tumor (osteoclastoma rich in multinucleated osteoclastic cells).
Isoform 1 and isoform 2 act as a negative regulator of FceRI-mediated signal transduction leading to cytokine production and degranulation, most likely by acting at the level of SYK to affect downstream events such as phosphorylation of SLP76 and LAT and mobilization of Ca(2+).
Isoform 1 and isoform 2 are phosphorylated on tyrosine residues by tyrosine kinase Neu.
Isoform 1 plays a critical role in signaling transduction pathways and phosphoprotein network topology in red blood cells. May play a role in osteoclast formation and function (By similarity).
Isoform 2 acts as a negative regulator of insulin receptor (IR) signaling in skeletal muscle. Regulates insulin-induced tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate 1 (IRS-1), phosphorylation of protein kinase B and glycogen synthase kinase-3 and insulin induced stimulation of glucose uptake (By similarity).
Monomer. Isoform 2: Homodimer. Can form oligomers. Dimerization is increased by oxidative stress and decreased by EGFR. Isoform 2 interacts with GRB2 (By similarity).
Produced by alternative initiation at Met-86 of isoform 1.
The tyrosine-protein phosphatase 2 domain (D2) mediates dimerization. The extreme N- and C- termini of the D2 domain act to inhibit dimerization and removal of these sequences increases dimerization and inhibits enzyme activity (By similarity).
Up-regulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) in HL-60 cells.
By T-cell receptor stimulation in a process that requires p38 MAP kinase and ERK signaling.
Complete loss of expression when naive B-cells proliferates and differentiates into Ig-producing plasma cells under in vitro stimulation.
Expressed on the majority of peripheral mononuclear cells, including natural killer (NK) cells, T-cells, B-cells, monocytes, and dendritic cells. Highly expressed in naive T-cells and B-cells but no expression on germinal center B-cells. Abnormally low expression in naive B-cells from HIV-1 infected patients. Very low expression in NK cells from a patient with chronic active Epstein-Barr virus infection.
Functions as an inhibitory receptor in NK cells and T-cells.
Functions as an inhibitory receptor that plays a constitutive negative regulatory role on cytolytic function of natural killer (NK) cells, B-cells and T-cells. Activation by Tyr phosphorylation results in recruitment and activation of the phosphatases PTPN6 and PTPN11. It also reduces the increase of intracellular calcium evoked by B-cell receptor ligation. May also play its inhibitory role independently of SH2-containing phosphatases. Modulates cytokine production in CD4+ T-cells, down-regulating IL2 and IFNG production while inducing secretion of transforming growth factor beta. Down-regulates also IgG and IgE production in B-cells as well as IL8, IL10 and TNF secretion. Inhibits proliferation and induces apoptosis in myeloid leukemia cell lines as well as prevents nuclear translocation of NF-kappa-B p65 subunit/RELA and phosphorylation of I-kappa-B alpha/CHUK in these cells. Inhibits the differentiation of peripheral blood precursors towards dendritic cells.
ITIM (immunoreceptor tyrosine-based inhibitor motif) motif is a cytoplasmic motif present in 2 copies in the intracellular part of LAIR1. When phosphorylated, ITIM motif can bind the SH2 domain of several SH2-containing phosphatases, leading to down-regulation of cell activation.
Interacts with SH2 domains of tyrosine-protein phosphatases PTPN6 and PTPN11. The interaction with PTPN6 is constitutive. Interacts with the SH2 domain of CSK. Binds with high affinity to extracellular matrix collagens, the interaction is functionally important.
Phosphorylation at Tyr-251 and Tyr-281 activates it. May be phosphorylated by LCK.
Expressed in dendritic cells, T-cells, B-cells and natural killer cells. Expressed in secondary lymphoid organs such as spleen and mesenteric, axillary and brachial lymph nodes.
Interacts (via C-terminus) with SRSF1. Interacts (via C-terminus) with SRSF2.
RNA-binding protein that mediates pre-mRNA alternative splicing regulation.
Stimulates prolactin (PRL) release and regulates the expression of prolactin through its receptor GPR10. May stimulate lactotrophs directly to secrete PRL.
Involved in pre-mRNA splicing as component of the spliceosome.
Belongs to the OHCU decarboxylase family.
Catalyzes the stereoselective decarboxylation of 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) to (S)-allantoin.
Could be the product of a pseudogene. In primates the genes coding for the enzymes for the degradation of uric acid were inactivated and converted to pseudogenes (PubMed:16462750).
Activated by extracellular calcium and inhibited by extracellular protons.
Belongs to the chloride channel (TC 2.A.49) family. CLCNKA subfamily.
Expressed predominantly in the kidney. All nephron segments expressing BSND also express CLCNK proteins.
Homodimer (PubMed:17562318). Interacts with BSND. Forms heteromers with BSND in the thin ascending limb of Henle (By similarity).
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Loss-of-function of both CLCNKA and CLCNKB results in the disease phenotype (PubMed:18310267).
Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport. May be important in urinary concentrating mechanisms.
Expressed strongly in liver, moderately in skeletal muscle and weakly in kidney, pancreas, spleen and prostate.
Isoform 1 and isoform 2 act as DNA-dependent transcriptional repressors.
Isoforms 1 and 2 can both homo- and hetero-associate.
Binds mitochondrial DNA and plays a role in the regulation of transcription of mitochondrial mRNA and rRNA species.
Expressed in skeletal muscle, heart, liver and pancreas.
Electrogenic Na(+)-coupled sugar simporter that actively transports D-glucose at the plasma membrane, with a Na(+) to sugar coupling ratio of 1:1. Transporter activity is driven by a transmembrane Na(+) electrochemical gradient set by the Na(+)/K(+) pump (PubMed:20980548, PubMed:28592437, PubMed:34880493). Has a primary role in D-glucose reabsorption from glomerular filtrate across the brush border of the early proximal tubules of the kidney (By similarity).
Forms a heterodimer with PDZK1IP1; this interaction enhances the transporter activity over a hundred-fold.
Inhibited by phlorizin. Inhibited by diabetic drugs that lower blood sugar levels, including empagliflozin and dapagliflozin.
Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism in response to prolonged fasting and starvation. Plays an important role in maintaining normal blood glucose levels under starvation, and is involved in the insulin signaling cascade. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. In the fed state, mediates cellular responses to glucose levels and to a high-fat diet. Regulates both fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role in the generation of reactive oxygen species. Protects detached epithelial cells against anoikis. Plays a role in cell proliferation via its role in regulating carbohydrate and fatty acid metabolism.
Ubiquitous; highest levels of expression in heart and skeletal muscle.
Up-regulated by prolonged fasting, in glucose-deprived cells and in response to a high-fat diet. Down-regulated by insulin. Up-regulated by PPARD.
Acetylated; acetylation impairs nuclear localization and ability to transactivate expression of target genes. Deacetylated by SIRT1.
Homodimer; homodimerization is required for activity (By similarity). Interacts (via C-terminus) with ZNF219; forming a complex that binds to the COL2A1 promoter and activates COL2A1 expression (By similarity). Interacts with DDRGK1 (PubMed:28263186). Interacts with EP300/p300 (PubMed:12732631). Interacts with beta-catenin (CTNNB1); inhibiting CTNNB1 activity by competing with the binding sites of TCF/LEF within CTNNB1 (By similarity).
Phosphorylation at Ser-64 and Ser-211 by PKA increases transcriptional activity and may help delay chondrocyte maturation downstream of PTHLH/PTHrP signaling. Phosphorylation at either Ser-64 or Ser-211 is required for sumoylation, but phosphorylation is not dependent on sumoylation. Phosphorylated on tyrosine residues; tyrosine dephosphorylation by PTPN11/SHP2 blocks SOX9 phosphorylation by PKA and subsequent SUMOylation.
Sumoylated; phosphorylation at either Ser-64 or Ser-211 is required for sumoylation. Sumoylation is induced by BMP signaling pathway.
The PQA region (for proline, glutamine and alanine-rich) helps stabilize SOX9 and facilitates transactivation (PubMed:31194875). It lacks intrinsic transactivation capability (PubMed:31194875).
Transcription factor that plays a key role in chondrocytes differentiation and skeletal development (PubMed:24038782). Specifically binds the 5'-ACAAAG-3' DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis, including cartilage matrix protein-coding genes COL2A1, COL4A2, COL9A1, COL11A2 and ACAN, SOX5 and SOX6 (PubMed:8640233). Also binds to some promoter regions (By similarity). Plays a central role in successive steps of chondrocyte differentiation (By similarity). Absolutely required for precartilaginous condensation, the first step in chondrogenesis during which skeletal progenitors differentiate into prechondrocytes (By similarity). Together with SOX5 and SOX6, required for overt chondrogenesis when condensed prechondrocytes differentiate into early stage chondrocytes, the second step in chondrogenesis (By similarity). Later, required to direct hypertrophic maturation and block osteoblast differentiation of growth plate chondrocytes: maintains chondrocyte columnar proliferation, delays prehypertrophy and then prevents osteoblastic differentiation of chondrocytes by lowering beta-catenin (CTNNB1) signaling and RUNX2 expression (By similarity). Also required for chondrocyte hypertrophy, both indirectly, by keeping the lineage fate of chondrocytes, and directly, by remaining present in upper hypertrophic cells and transactivating COL10A1 along with MEF2C (By similarity). Low lipid levels are the main nutritional determinant for chondrogenic commitment of skeletal progenitor cells: when lipids levels are low, FOXO (FOXO1 and FOXO3) transcription factors promote expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (By similarity). Mechanistically, helps, but is not required, to remove epigenetic signatures of transcriptional repression and deposit active promoter and enhancer marks at chondrocyte-specific genes (By similarity). Acts in cooperation with the Hedgehog pathway-dependent GLI (GLI1 and GLI3) transcription factors (By similarity). In addition to cartilage development, also acts as a regulator of proliferation and differentiation in epithelial stem/progenitor cells: involved in the lung epithelium during branching morphogenesis, by balancing proliferation and differentiation and regulating the extracellular matrix (By similarity). Controls epithelial branching during kidney development (By similarity).
Ubiquitinated; ubiquitination leads to proteasomal degradation and is negatively regulated by DDRGK1.
Binds to oleoyl-L-alpha-lysophosphatidic acid (LPA). Intracellular cAMP is involved in the receptor activation. Important for the maintenance of hair growth and texture.
Expressed ubiquitously, including in skin and hair follicle cells. Detected in both Henle's and Huxley's layers of the inner root sheath of the hair follicle and in suprabasal layers of the epidermis (at protein level). Expressed at low levels in peripheral blood leukocytes.
Markedly up-regulated in promyelocytic HL60 cells induced to differentiate along the monocyte/macrophage pathway. Not detectable in undifferentiated HL60 cells and only low levels after the induction of differentiation along the granulocytic pathway.
This is a nested gene within intron 17 of the retinoblastoma gene.
Forms a soluble 1:1 complex with AFM; this prevents oligomerization and is required for prolonged biological activity (PubMed:26902720). The complex with AFM may represent the physiological form in body fluids (PubMed:26902720).Interacts with PORCN. Interacts with WLS (By similarity).
Ligand for members of the frizzled family of seven transmembrane receptors (Probable). Functions in the canonical Wnt signaling pathway that results in activation of transcription factors of the TCF/LEF family (PubMed:26902720). Required for normal gastrulation, formation of the primitive streak, and for the formation of the mesoderm during early embryogenesis. Required for normal formation of the apical ectodermal ridge (By similarity). Required for normal embryonic development, and especially for limb development (PubMed:14872406).
A high level of expression seen in the nervous system (brain, cerebellum and spinal cord) as well as adrenal gland. Expressed at high levels in noneuroblastoma, rhabdomyosarcoma, melanoma and some osteosarcoma cell lines, whereas at only low levels in cancer cell lines of liver, breast, thyroid and colon. Expression is significantly higher in favorable tumors than aggressive ones.
Belongs to the PPase class C family. Prune subfamily.
Down-regulated after NGF-induced differentiation, and up-regulated during the NGF-depletion-induced apoptosis.
Induced during the G1 phase of the cell cycle.
May play an important role in regulating differentiation, survival and aggressiveness of the tumor cells.
PRUNE2/BMCC1 and PCA3, one of the most prostate cancer specific markers are overlapping genes in reverse orientation. However, they do not appear to be coregulated.
Detected in Leydig cells, syncytiotrophoblast, duodenal villi epithelial cells and neutrophils from kidney and cutaneous squamous cell carcinoma (at protein level).
Interacts (through the Ig-like domains) with NLGN2.
May be involved in cell-cell interactions.
A chromosomal aberration involving DOCK3 has been found in a family with early-onset behavioral/developmental disorder with features of attention deficit-hyperactivity disorder and intellectual disability. Inversion inv(3)(p14:q21). The inversion disrupts DOCK3 and SLC9A9.
In normal brains, it is localized in the neuropil, and occasionally in the pyramidal cells, while in Alzheimer disease brains, it is associated with neurofibrillary tangles.
Interacts with presenilin proteins PSEN1 and PSEN2. Interacts with CRK (By similarity).
Potential guanine nucleotide exchange factor (GEF). GEF proteins activate some small GTPases by exchanging bound GDP for free GTP. Its interaction with presenilin proteins as well as its ability to stimulate Tau/MAPT phosphorylation suggest that it may be involved in Alzheimer disease. Ectopic expression in nerve cells decreases the secretion of amyloid-beta APBA1 protein and lowers the rate of cell-substratum adhesion, suggesting that it may affect the function of some small GTPase involved in the regulation of actin cytoskeleton or cell adhesion receptors (By similarity).
Interacts (via C-terminal domain) with VCP. Interacts with ubiquitin and ubiquitinated proteins (By similarity). Interacts with BIK and STEAP3.
Intramembrane-cleaving serine protease that cleaves single transmembrane or multi-pass membrane proteins in the hydrophobic plane of the membrane, luminal loops and juxtamembrane regions. Involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors. Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded membrane proteins. Required for the degradation process of some specific misfolded endoplasmic reticulum (ER) luminal proteins. Participates in the transfer of misfolded proteins from the ER to the cytosol, where they are destroyed by the proteasome in a ubiquitin-dependent manner. Functions in BIK, MPZ, PKD1, PTCRA, RHO, STEAP3 and TRAC processing. Involved in the regulation of exosomal secretion; inhibits the TSAP6-mediated secretion pathway. Involved in the regulation of apoptosis; modulates BIK-mediated apoptotic activity. Also plays a role in the regulation of spermatogenesis; inhibits apoptotic activity in spermatogonia.
One study reported that the protein is not localized in the mitochondrion.
Up-regulated by endoplasmic reticulum stress agents that induce the unfolded protein response (UPR).
Expressed in most tissues, with the highest levels in ovary, prostate, heart, kidney and thyroid. In the kidney, expression is confined to the nephron, specifically in the distal convoluted tubule and in the collecting tubule. Not detected in the brain, liver, spleen, peripheral blood leukocytes and adrenal medulla.
Stimulates renal phosphate reabsorption, and could therefore prevent hypercalcemia.
Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocyte, bone marrow, lymph node and lung.
Highly glycosylated (N- and O-linked carbohydrates).
May play a role in the cell adhesion to the extracellular matrix.
Acetylated at Lys-167; deacetylated at Lys-167 by SIRT3.
Associates with the mitochondrial membrane ATP synthase F(1)F(0) ATP synthase; the association is increased by inorganic phosphate (Pi) and decreased by cyclosporin A (CsA) (By similarity). Interacts with ATP5F1B; ATP5PD and ATP5PO (By similarity). Interacts with SLC25A3; the interaction is impaired by CsA (By similarity). Interacts with BCL2; the interaction is impaired by CsA (PubMed:19228691). Interacts with TP53; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by CsA (PubMed:22726440). Interacts with C1QBP (PubMed:20950273). Interacts with MCUR1 (PubMed:26976564). Component of the mitochondrial permeability transition pore complex (mPTPC), at least composed of SPG7, VDAC1 and PPIF (PubMed:26387735). Interacts with SPG7 (PubMed:26387735).
Inhibited by cyclosporin A (CsA) (PubMed:20676357). Is displaced by CsA from the mPTP leading to a lower open probability of the mPTP.
PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding (PubMed:20676357). Involved in regulation of the mitochondrial permeability transition pore (mPTP) (PubMed:26387735). It is proposed that its association with the mPTP is masking a binding site for inhibiting inorganic phosphate (Pi) and promotes the open probability of the mPTP leading to apoptosis or necrosis; the requirement of the PPIase activity for this function is debated (PubMed:26387735). In cooperation with mitochondrial p53/TP53 is involved in activating oxidative stress-induced necrosis (PubMed:22726440). Involved in modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels (By similarity). Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis (PubMed:19228691).
Component of the centrioles controlling mother and daughter centrioles length. Recruits to the centriole IFT88 and centriole distal appendage-specific proteins including CEP164 (By similarity). Involved in the biogenesis of the cilium, a centriole-associated function. The cilium is a cell surface projection found in many vertebrate cells required to transduce signals important for development and tissue homeostasis (PubMed:33934390). Plays an important role in development by regulating Wnt signaling and the specification of the left-right axis. Only OFD1 localized at the centriolar satellites is removed by autophagy, which is an important step in the ciliogenesis regulation (By similarity).
Homooligomer. Interacts with LCA5. Interacts with RUVBL1; the interaction is direct and may mediate interaction with the NuA4 histone acetyltransferase complex. Interacts with SDCCAG8; the interaction is direct. Interacts with MAP1LC3B. Interacts with C2CD3; OFD1 may act as a negative regulator of C2CD3. Forms a complex with KIAA0753/OFIP and CEP20/FOR20; the interaction with CEP20 is detected only in the presence of KIAA0753. Interacts with PCM1; this interaction may be mediated by KIAA0753/OFIP (PubMed:26643951). Interacts with TBC1D31; regulates OFD1 activity in cilium assembly (PubMed:33934390).
Phosphorylated. Phosphorylation at Ser-735, by the cAMP-dependent protein kinase PKA, triggers ubiquitination and proteasomal degradation of OFD1. Also increases its interaction with TBC1D31 and regulates its function in ciliogenesis.
Ubiquitinated by PJA2, upon phosphorylation at Ser-735 by PKA, leads to the proteasomal degradation of OFD1.
Widely expressed. Expressed in 9 and 14 weeks old embryos in metanephric mesenchyme, oral mucosa, lung, heart, nasal and cranial cartilage, and brain. Expressed in metanephros, brain, tongue, and limb.
Expressed mostly in heart, skeletal muscle and brain. Isoform 1 and isoform 2 are highly expressed in testis.
Has a transcriptional repressor activity.
Interacts (via the KRAB domain) with TRIM28 (via the RBCC domain).
Highly expressed in bone marrow. Weak expression found in kidney, liver, small intestine, spleen, thymus, peripheral leukocyte, lung, fetal spleen and neutrophils.
Homodimer; disulfide-linked (PubMed:16354652, PubMed:15769462). Interacts with HSPA1A; this interaction forms a cytotoxic complex that is released by lymphokine-activated killer cells (By similarity). Interacts with HSPBP1; this interaction blocks the cytotoxic activity of the PGLYRP1-HSPA1A complex (PubMed:21247889). Interacts with TNFRSF1A; this interaction is important for cell death induction (PubMed:26183779). Interacts with S100A4; this complex acts as a chemoattractant that promotes lymphocyte movement (PubMed:26654597, PubMed:30713770). Interacts with TREM1 (PubMed:25595774).
Innate immunity protein that plays several important functions in antimicrobial and antitumor defense systems. Acts as a pattern receptor that binds to murein peptidoglycans (PGN) of Gram-positive bacteria and thus provides bactericidal activity (PubMed:9707603). Forms an equimolar complex with heat shock protein HSPA1A and induces programmed cell death through apoptosis and necroptosis in tumor cell lines by activating the TNFR1 receptor on the target cell membrane (PubMed:21247889, PubMed:26183779). In addition, acts in complex with the Ca(2+)-binding protein S100A4 as a chemoattractant able to induce lymphocyte movement (PubMed:26654597). Mechanistically, this complex acts as a ligand of the chemotactic receptors CCR5 and CXCR3 which are present on the cells of the immune system (PubMed:30713770). Promotes also the activation of lymphocytes that become able to kill virus-infected cells as well as tumor cells by modulating the spectrum of their target-cell specificity (PubMed:29083508, PubMed:28977785). Induction of cytotoxicity on monocyte surface requires interaction with TREM1 receptor (PubMed:28977785, PubMed:25595774).
N-glycosylated. N-glycosylation is required for bactericidal activity.
CSMD1 may be a candidate for oral and oropharyngeal squamous cell carcinomas (OSCCs). PubMed:12696061 and PubMed:14506705 are however in disagreement: while PubMed:14506705 considers CSMD1 as a strong candidate for OSCCs, PubMed:12696061 thinks it is not.
Potential suppressor of squamous cell carcinomas.
Weakly expressed in most tissues, except in brain. Expressed at intermediate level in brain, including cerebellum, substantia nigra, hippocampus and fetal brain.
Component of the heterotetramer complex KAR (3-ketoacyl-[acyl carrier protein] reductase or 3-ketoacyl-[ACP] reductase) that forms part of the mitochondrial fatty acid synthase (mtFAS). Beta-subunit of the KAR heterotetramer complex, responsible for the 3-ketoacyl-ACP reductase activity of the mtFAS, reduces 3-oxoacyl-[ACP] to (3R)-hydroxyacyl-[ACP] in a NADPH-dependent manner with no chain length preference, thereby participating in mitochondrial fatty acid biosynthesis (PubMed:25203508). The homotetramer has NADPH-dependent quinone reductase activity (in vitro), hence could play a role in protection against cytotoxicity of exogenous quinones (PubMed:19000905). As a heterotetramer, it can also reduce 9,10-phenanthrenequinone, 1,4-benzoquinone and various other o-quinones and p-quinones (in vitro) (PubMed:19000905, PubMed:19571038, PubMed:25203508).
Detected in liver and kidney (at protein level) (PubMed:19000905). Displays the highest expression in neuronal and muscle tissues (PubMed:25203508).
Homotetramer (in vitro) (PubMed:19000905). Heterotetramer with HSD17B8; contains two molecules each of HSD17B8 and CBR4 (PubMed:19571038, PubMed:25203508). Does not form homotetramers when HSD17B8 is coexpressed, only heterotetramers (in vitro) (PubMed:25203508).
Expressed in most tissues. Highest levels in testis, thyroid, duodenum, skeletal muscle, and pancreatic islets.
Transcription factor involved in the regulation of podocyte-expressed genes (PubMed:24042019, PubMed:28059119). Essential for the specification of dorsal limb fate at both the zeugopodal and autopodal levels.
Forms a SNARE complex with STX7, STX8 and VAMP8 which functions in the homotypic fusion of late endosomes. Component of the SNARE complex composed of STX7, STX8, VAMP7 and VIT1B that is required for heterotypic fusion of late endosomes with lysosomes (By similarity). May interact with STX17 (PubMed:23217709). Interacts with CLINT1 (PubMed:18033301).
V-SNARE that mediates vesicle transport pathways through interactions with t-SNAREs on the target membrane. These interactions are proposed to mediate aspects of the specificity of vesicle trafficking and to promote fusion of the lipid bilayers. May be concerned with increased secretion of cytokines associated with cellular senescence.
Farnesylation is required for nuclear envelope localization.
Monomer (PubMed:22162750). Interacts with CHMP4B (PubMed:18190528, PubMed:22162750, PubMed:22484091, PubMed:34818527). Interacts with CHMP5: this interaction allows the recruitment of BROX to cellular membranes (PubMed:22484091). Interacts with SYN2; this interaction promotes SYN2 ubiquitination and facilitates the relaxation of mechanical stress imposed by compressive actin fibers at the rupture site (PubMed:34818527).
Nuclear envelope-associated factor that is involved in the nuclear envelope ruptures during interphase (NERDI) repair, where it is locally recruited by CHMP5 and reduces cytoskeletal stress through its action on SYN2 to help reseal the ruptured membrane.
(Microbial infection) Plays an important role in virion production of flaviviruses such as West Nile virus, Japanese enchephalitis virus, Dengue virus type 2 and Yellow Fever virus.
Essential component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum (PubMed:27499293, PubMed:34388369). Essential for the SPC catalytic activity, possibly by stabilizing and positioning the active center of the complex close to the lumenal surface (By similarity).
Component of the cleavage and polyadenylation specificity factor (CPSF) module of the pre-mRNA 3'-end processing complex. Interacts with CPSF3/CPSF73.
Essential for both cleavage and polyadenylation of pre-mRNA 3' ends.
Belongs to the eukaryotic ribosomal protein eL18 family.
Acts as Baeyer-Villiger monooxygenase on a broad range of substrates. Catalyzes the insertion of an oxygen atom into a carbon-carbon bond adjacent to a carbonyl, which converts ketones to esters (PubMed:28783300, PubMed:26771671, PubMed:20947616). Active on diverse carbonyl compounds, whereas soft nucleophiles are mostly non- or poorly reactive (PubMed:26771671, PubMed:7872795). In contrast with other forms of FMO it is non- or poorly active on 'classical' substrates such as drugs, pesticides, and dietary components containing soft nucleophilic heteroatoms (Probable) (PubMed:7872795). Able to oxidize drug molecules bearing a carbonyl group on an aliphatic chain, such as nabumetone and pentoxifylline (PubMed:28783300). Also, in the absence of substrates, shows slow but yet significant NADPH oxidase activity (PubMed:26771671). Acts as a positive modulator of cholesterol biosynthesis as well as glucose homeostasis, promoting metabolic aging via pleiotropic effects (By similarity).
Belongs to the myelin proteolipid protein family.
The submitted sequence only contains the last exon but the authors annotated a CDS including all exons of that gene.
This is the major myelin protein from the central nervous system. It plays an important role in the formation or maintenance of the multilamellar structure of myelin.
Catalyzes the reduction of N-oxygenated molecules, acting as a counterpart of cytochrome P450 and flavin-containing monooxygenases in metabolic cycles (PubMed:21029045, PubMed:24423752). As a component of prodrug-converting system, reduces a multitude of N-hydroxylated prodrugs particularly amidoximes, leading to increased drug bioavailability (PubMed:21029045, PubMed:24423752). May be involved in mitochondrial N(omega)-hydroxy-L-arginine (NOHA) reduction, regulating endogenous nitric oxide levels and biosynthesis (PubMed:21029045). Postulated to cleave the N-OH bond of N-hydroxylated substrates in concert with electron transfer from NADH to cytochrome b5 reductase then to cytochrome b5, the ultimate electron donor that primes the active site for substrate reduction (PubMed:21029045).
Component of a complex composed of cytochrome b5, NADH-cytochrome b5 reductase (CYB5R3) and MTARC2.
Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis. May act as an inhibitor of EIF4E1 activity (By similarity).
eIF4F is a multi-subunit complex, the composition of which varies with external and internal environmental conditions. It is composed of at least eIF4A, eIF4E and eIF4G (By similarity). EIF4E3 interacts with EIF4G1, but not with EIF4EBP1, EIF4EBP2 and EIF4EBP3 (By similarity).
Amidation of salusin-alpha(29-Gly) by peptidylglycine alpha-amidating monooxygenase, PAM, converts Lys-241-Gly-242 to Lys-241-NH2 and gives raise to salusin-alpha.
Homohexamer. Interacts with TOR1AIP1 (By similarity).
Isoform 1 is expressed ubiquitously, except in cardiac and endothelial tissues.
Isoform 4 is ubiquitously expressed, with high level in vascular endothelial cells and vascular smooth muscle cells.
Salusins -alpha and -beta may be endocrine and/or paracrine factors able to increase intracellular calcium concentrations and induce cell mitogenesis. Salusins may also be potent hypotensive peptides.
Salusins -alpha and -beta peptides are derived from isoform 4.
Transcriptional activator of GFAP, essential for proper brain development (PubMed:30388402). Recognizes and binds the palindromic sequence 5'-TTGGCNNNNNGCCAA-3' present in viral and cellular promoters and in the origin of replication of adenovirus type 2. These proteins are individually capable of activating transcription and replication.
Endoplasmic reticulum-localized palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates and be involved in a variety of cellular processes (By similarity). Has a palmitoyltransferase activity toward NCDN and regulates NCDN association with endosome membranes through this palmitoylation (By similarity). May play a role in cell proliferation (PubMed:28331227).
Has also a palmitoyltransferase activity-independent function in DNA virus-triggered and CGAS-mediated innate immune response (PubMed:28331227). Functions as an adapter that recruits IRF3 to STING1 to promote the activation of that key transcriptional regulator of type I interferon (IFN)-dependent immune response (PubMed:28331227).
Interacts with IRF3 and STING1; in presence of DNA viruses recruits IRF3 to STING1 promoting IRF3 phosphorylation and activation.
Predominantly expressed in adult forebrain. Expressed in fetal brain, lung and kidney.
Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors. During neural development involved in axonal navigation at the ventral midline of the neural tube and projection of axons to different regions (By similarity). SLIT1 and SLIT2 together seem to be essential for midline guidance in the forebrain by acting as repulsive signal preventing inappropriate midline crossing by axons projecting from the olfactory bulb.
Expressed at highest levels in aorta, at intermediate levels in kidney and placenta and at lowest levels in brain, heart, liver, lung and skeletal muscle. Within the aorta, the strongest expression is found in the tunica media of the proximal ascending aorta, the descending thoracic aorta, the abdominal aorta and the coronary arteries. Within the kidney, expression is found in the interstitial cells.
May act as an inhibitor of TGF-beta signaling.
N-glycosylated. N-glycan heterogeneity at Asn-117: Hex5HexNAc4 (minor), dHex1Hex5HexNAc4 (major), Hex6HexNAc5 (minor) and dHex1Hex6HexNAc5 (minor).
Acts as an actin nucleation factor, remains associated with the slow-growing pointed end of the new filament (PubMed:21620703). Involved in intracellular vesicle transport along actin fibers, providing a novel link between actin cytoskeleton dynamics and intracellular transport (By similarity). Required for asymmetric spindle positioning and asymmetric cell division during meiosis (PubMed:21620703). Required for normal formation of the cleavage furrow and for polar body extrusion during female germ cell meiosis (PubMed:21620703). Also acts in the nucleus: together with SPIRE1 and SPIRE2, promotes assembly of nuclear actin filaments in response to DNA damage in order to facilitate movement of chromatin and repair factors after DNA damage (PubMed:26287480).
Binds to actin monomers via the WH2 domain.
The Spir-box targets binding to intracellular membrane structures.
Expressed in testis (PubMed:33077892). Expressed in the retina with higher expression levels in the macular than in the peripheral region (PubMed:33077892).
Granulocyte orphan receptor that acts as an trigger efficient phagocytosis of attached particles.
Interacts through its phosphorylated ITAM domain with the SH2 domain-containing cytoplasmic proteins involved in signaling processes during phagocytosis.
The cytoplasmic ITAM-like sequence becomes tyrosine phosphorylated by SRC family PTKs upon ligand-mediated receptor clustering and allows to initiate phagocytosis of bound ligand.
To study the function of the orphan receptor CEACAM4 chimeric proteins containing the extracellular bacteria-binding domain of CEACAM3 and the transmembrane and cytoplasmic part of CEACAM4 has been used.
(Microbial infection) In case of infection, interacts with H.pylori CagA, leading to inhibit kinase activity and junctional and polarity defects.
Autophosphorylated. Phosphorylated at Thr-208 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Phosphorylation at Thr-208 by TAOK1 activates the kinase activity, leading to phosphorylation and detachment of MAPT/TAU from microtubules. Phosphorylation at Ser-212 by GSK3-beta (GSK3B) inhibits the kinase activity. Phosphorylation by CaMK1 promotes activity and is required to promote neurite outgrowth. Phosphorylation at Thr-596 by PRKCZ/aPKC in polarized epithelial cells inhibits the kinase activity and promotes binding to 14-3-3 protein YWHAZ, leading to relocation from cell membrane to cytoplasm.
High levels of expression in heart, brain, skeletal muscle and pancreas, lower levels observed in lung, liver and kidney.
Homodimer. Interacts with PAK5; leading to inhibit the protein kinase activity (By similarity). Interacts with MAPT/TAU (PubMed:23666762). Interacts with MTCL1 isoform 1; the interaction is direct and increases MARK2 microtubule-binding ability (PubMed:23902687). Interacts (when phosphorylated at Thr-596) with YWHAZ (PubMed:15324659). Interacts with YWHAB, YWHAG and YWHAQ (PubMed:16959763).
Inhibited by PAK5; inhibition is independent of the kinase activity of PAK5 (By similarity). Activated by phosphorylation on Thr-208. Inhibited by phosphorylation at Ser-212 and Thr-596. Inhibited by hymenialdisine. Specifically inhibited by the H.pylori CagA peptide FPLKRHDKVDDLSK that mimics host substrates and binds to the kinase substrate-binding site.
Produced by alternative splicing of isoform 6.
Serine/threonine-protein kinase (PubMed:23666762). Involved in cell polarity and microtubule dynamics regulation. Phosphorylates CRTC2/TORC2, DCX, HDAC7, KIF13B, MAP2, MAP4 and RAB11FIP2. Phosphorylates the microtubule-associated protein MAPT/TAU (PubMed:23666762). Plays a key role in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Regulates epithelial cell polarity by phosphorylating RAB11FIP2. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Regulates axogenesis by phosphorylating KIF13B, promoting interaction between KIF13B and 14-3-3 and inhibiting microtubule-dependent accumulation of KIF13B. Also required for neurite outgrowth and establishment of neuronal polarity. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3). Modulates the developmental decision to build a columnar versus a hepatic epithelial cell apparently by promoting a switch from a direct to a transcytotic mode of apical protein delivery. Essential for the asymmetric development of membrane domains of polarized epithelial cells.
The KA1 domain mediates binding to phospholipids and targeting to membranes.
The UBA domain does not seem to bind ubiquitin and ubiquitin-like and might play a role in regulating the enzyme conformation and localization. Activation of the kinase activity following phosphorylation at Thr-208 is accompanied by a conformational change that alters the orientation of the UBA domain with respect to the catalytic domain.
Unknown. The protein may play some role in a cellular membrane location. May reside within an internal membrane compartment and function in pathways such as those involved in protein and/or vesicle trafficking. Alternatively, the mature protein may be localized in the plasma membrane and serve as a site of interaction for other molecules through its highly charged C-terminal domain.
Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex the core of which is composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 associating with additional regulatory/auxilliary subunits to form alternative complex forms. Alternative complex forms containing a forth regulatory subunit in a mutually exclusive manner are PI3K complex I (PI3KC3-C1) containing ATG14, and PI3K complex II (PI3KC3-C2) containing UVRAG (PubMed:8999962, PubMed:19270696, PubMed:23878393, PubMed:25490155). PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex (PubMed:25490155). Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits, such as RUBCN, SH3GLB1/Bif-1, AMBRA1 and NRBF2 (PubMed:19270696, PubMed:20643123, PubMed:24785657). PI3KC3-C1 probably associates with PIK3CB (By similarity). Interacts with RAB7A in the presence of PIK3C3/VPS34 (PubMed:14617358). Interacts with NRBF2 (PubMed:24785657).
Regulatory subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20643123).
Component of multiple DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes that seem to be formed of DDB1, CUL4A or CUL4B, RBX1 and a variable substrate recognition component which seems to belong to a protein family described as DCAF (Ddb1- and Cul4-associated factor) or CDW (CUL4-DDB1-associated WD40-repeat) proteins (PubMed:18593899, PubMed:10230407, PubMed:16678110, PubMed:17041588). Component of the DCX(DTL) complex with the putative substrate recognition component DTL (PubMed:17041588). Component of the DCX(DDB2) complex with the putative substrate recognition component DDB2 (PubMed:16678110). Component of DCX complexes part of the DesCEND (destruction via C-end degrons) pathway, which contain either TRPC4AP or DCAF12 as substrate-recognition component (PubMed:29779948). Component of the DCX(AMBRA1) complex with the substrate recognition component AMBRA1 (PubMed:30166453, PubMed:33854232, PubMed:33854239). Part of a complex with RBX1 and TIP120A/CAND1 (PubMed:12609982, PubMed:22118460). Interacts with RBX1, GRWD1, MLST8, SMU1, TLE2, TLE3, DCAF1, DDA1, DCAF6, DCAF17, DDB2, DCAF8, TIP120A/CAND1 and TMEM113 (PubMed:17041588, PubMed:16949367, PubMed:18235224). Interacts with cyclin E (CCNE1 or CCNE2) and with importins alpha-1 (KPNA2), alpha-3 (KPNA4), alpha-5 (KPNA1) and beta-1 (KPNB1) (PubMed:16322693, PubMed:19801544). May interact with WDR26, WDR51B, SNRNP40, WDR61, WDR76 and WDR5 (PubMed:17041588). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (PubMed:23201271, PubMed:26906416).
Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:14578910, PubMed:16322693, PubMed:16678110, PubMed:18593899, PubMed:29779948, PubMed:30166453, PubMed:33854232, PubMed:33854239, PubMed:22118460). The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition subunit (PubMed:14578910, PubMed:16678110, PubMed:18593899, PubMed:29779948, PubMed:22118460). CUL4B may act within the complex as a scaffold protein, contributing to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme (PubMed:14578910, PubMed:16678110, PubMed:18593899, PubMed:22118460). Plays a role as part of the E3 ubiquitin-protein ligase complex in polyubiquitination of CDT1, histone H2A, histone H3 and histone H4 in response to radiation-induced DNA damage (PubMed:14578910, PubMed:16678110, PubMed:18593899). Targeted to UV damaged chromatin by DDB2 and may be important for DNA repair and DNA replication (PubMed:16678110). A number of DCX complexes (containing either TRPC4AP or DCAF12 as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948). The DCX(AMBRA1) complex is a master regulator of the transition from G1 to S cell phase by mediating ubiquitination of phosphorylated cyclin-D (CCND1, CCND2 and CCND3) (PubMed:33854232, PubMed:33854239). The DCX(AMBRA1) complex also acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes (PubMed:30166453). Required for ubiquitination of cyclin E (CCNE1 or CCNE2), and consequently, normal G1 cell cycle progression (PubMed:16322693, PubMed:19801544). Regulates the mammalian target-of-rapamycin (mTOR) pathway involved in control of cell growth, size and metabolism (PubMed:18235224). Specific CUL4B regulation of the mTORC1-mediated pathway is dependent upon 26S proteasome function and requires interaction between CUL4B and MLST8 (PubMed:18235224). With CUL4A, contributes to ribosome biogenesis (PubMed:26711351).
Probable dioxygenase that requires molecular oxygen, alpha-ketoglutarate and iron.
Widely expressed, with highest expression in testis and pancreas.
It is uncertain whether Met-1 or Met-100 is the initiator.
Mitochondrial aminoacyl-tRNA synthetase that activate and transfer the amino acids to their corresponding tRNAs during the translation of mitochondrial genes and protein synthesis.
Binds phospholipids; exhibits strong binding to phosphatidic acid and weak binding to phosphatidylinositol 3-phosphate (By similarity). Stabilizes GTP-bound RAB7A on late endosomes/lysosomes and alters functional properties of late endocytic compartments via its interaction with RAB7A (PubMed:16176980). Binds 25-hydroxycholesterol and cholesterol (PubMed:17428193).
Interacts (via FFAT motif) with VAPA and VAPB (PubMed:33124732). Interacts with the GTP-bound form of RAB7A (PubMed:17081983). Interacts with OAS1B (By similarity). Interacts (via FFAT motif) with MOSPD2 (via MSP domain) (PubMed:29858488, PubMed:33124732).
The FFAT motif is required for interaction with MOSPD2, VAPA and VAPB.
In vitro, the TRIAP1:PRELID3A complex mediates the transfer of phosphatidic acid (PA) between liposomes and probably functions as a PA transporter across the mitochondrion intermembrane space. Phosphatidic acid import is required for cardiolipin (CL) synthesis in the mitochondrial inner membrane.
Acts as a transcriptional activator (PubMed:9722527). Involved in the transcriptional regulation of type 1 receptor for pituitary adenylate cyclase-activating polypeptide.
The gene represented in this entry is involved in disease pathogenesis. Imprinted expression of PLAGL1 is relaxed in patients with transient neonatal diabetes (TND) (PubMed:11935319). Aberrant hypomethylation of the TND differentially methylated region within the PLAGL1 promoter as well as other imprinted loci at chromosome 6q24 is caused by ZFP57 mutations (PubMed:18622393).
Adapter protein that binds to and probably organizes the subcellular localization of a variety of membrane proteins. May link various receptors to the actin cytoskeleton and the dystrophin glycoprotein complex. May play a role in the regulation of secretory granules via its interaction with PTPRN.
Lacks domains required for interaction with dystrophin related proteins. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Monomer and homodimer (Probable). Interacts with the other members of the syntrophin family: SNTA1 and SNTB1; and with the sodium channel proteins SCN4A and SCN5A. Interacts with SAST, MAST205, microtubules and microtubule-associated proteins (By similarity). Interacts with the dystrophin protein DMD and related proteins DTNA and UTRN, and with the neuroregulin receptor ERBB4. Interacts with PTPRN when phosphorylated, protecting PTPRN from protein cleavage by CAPN1. Dephosphorylation upon insulin stimulation disrupts the interaction with PTPRN and results in the cleavage of PTPRN. Interacts with DTNB (By similarity).
Phosphorylated. Partially dephosphorylated upon insulin stimulation.
Ubiquitous. Isoform 1 is the predominant isoform. Weak level of isoform 2 is present in all tested tissues, except in liver and heart where it is highly expressed.
Receptor protein-tyrosine phosphatase that mediates homotypic cell-cell interactions and plays a role in adipogenic differentiation via modulation of p120 catenin/CTNND1 phosphorylation (PubMed:17761881, PubMed:10753936). Promotes CTNND1 dephosphorylation and prevents its cytoplasmic localization where it inhibits SLC2A4 membrane trafficking. In turn, SLC2A4 is directed to the plasma membrane and performs its glucose transporter function (PubMed:21998202).
Component of a complex that binds and activates STK11/LKB1. In the complex, required to stabilize the interaction between CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta) and STK11/LKB1.
Component of a trimeric complex composed of STK11/LKB1, STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta): the complex tethers STK11/LKB1 in the cytoplasm and stimulates its catalytic activity.
A chromosomal aberration involving TAL1 may be a cause of some T-cell acute lymphoblastic leukemias (T-ALL). Translocation t(1;14)(p32;q11) with T-cell receptor alpha chain (TCRA) genes.
Efficient DNA binding requires dimerization with another bHLH protein. Forms heterodimers with TCF3. Binds to the LIM domain containing protein LMO2 and to DRG1. Can assemble in a complex with LDB1 and LMO2. Component of a TAL-1 complex composed at least of CBFA2T3, LDB1, TAL1 and TCF3. Interacts with SBNO2; this interaction inhibits TAL1 occupancy of the DCSTAMP promoter, leading to the activation of the DCSTAMP promoter by the transcription factor MITF.
Implicated in the genesis of hemopoietic malignancies. It may play an important role in hemopoietic differentiation. Serves as a positive regulator of erythroid differentiation (By similarity).
Phosphorylated on serine residues. Phosphorylation of Ser-122 is strongly stimulated by hypoxia (By similarity).
The helix-loop-helix domain is necessary and sufficient for the interaction with DRG1.
Ubiquitinated; subsequent to hypoxia-dependent phosphorylation of Ser-122, ubiquitination targets the protein for rapid degradation via the ubiquitin system. This process may be characteristic for microvascular endothelial cells, since it could not be observed in large vessel endothelial cells (By similarity).
Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle. Calcium ions are bound by clusters of acidic residues at the protein surface, especially at the interface between subunits. Can bind around 60 Ca(2+) ions. Regulates the release of lumenal Ca(2+) via the calcium release channel RYR2; this plays an important role in triggering muscle contraction. Plays a role in excitation-contraction coupling in the heart and in regulating the rate of heart beats.
Monomer, homodimer and homooligomer. Mostly monomeric in the absence of calcium. Forms higher oligomers in a calcium-dependent manner. Dimers associate to form tetramers, that then form linear homomer chains. Interacts with ASPH and TRDN.
Phosphorylation in the C-terminus, probably by CK2, moderately increases calcium buffering capacity.
Binds tightly to hydroxyapatite. Appears to form an integral part of the mineralized matrix. Probably important to cell-matrix interaction. Promotes Arg-Gly-Asp-dependent cell attachment.
It is possible that the segments of clustered carboxyl groups mediate the strong binding to hydroxyapatite.
N-glycosylated; glycans consist of sialylated and core-fucosylated bi-, tri- and tetraantennary chains.
O-glycosylated at eight sites; mucin-type glycans contain Gal, GlcNAc, GalNAc and terminal NeuAc.
Expressed in choriocarcinoma cancer cell lines (at protein level) (PubMed:10692253). Expressed by epithelial cells of the proximal tubule cells and the glomerulus of the nephron. Also found in a variety of other tissues.
Regulates central hypertension through its calcium-modulated preference to cleave N-terminal acidic residues from peptides such as angiotensin II.
Substrate specificity is modulated by calcium which enhances the enzymatic activity for cleavage of acidic residues while reducing its activity with basic residues. Inhibited by aminopeptidase inhibitors amastatin and bestatin.
Apical membrane anion-exchanger with wide epithelial distribution that plays a role as a component of the pH buffering system for maintaining acid-base homeostasis. Acts as a versatile DIDS-sensitive inorganic and organic anion transporter that mediates the uptake of monovalent anions like chloride, bicarbonate, formate and hydroxyl ion and divalent anions like sulfate and oxalate. Functions in multiple exchange modes involving pairs of these anions, which include chloride-bicarbonate, chloride-oxalate, oxalate-formate, oxalate-sulfate and chloride-formate exchange. Apical membrane chloride-bicarbonate exchanger that mediates luminal chloride absorption and bicarbonate secretion by the small intestinal brush border membrane and contributes to intracellular pH regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption, possibly by providing a bicarbonate import pathway. Mediates also intestinal chloride absorption and oxalate secretion, thereby preventing hyperoxaluria and calcium oxalate urolithiasis. Transepithelial oxalate secretion, chloride-formate, chloride-oxalate and chloride-bicarbonate transport activities in the duodenum are inhibited by PKC activation in a calcium-independent manner. The apical membrane chloride-bicarbonate exchanger provides also a major route for fluid and bicarbonate secretion into the proximal tubules of the kidney as well as into the proximal part of the interlobular pancreatic ductal tree, where it mediates electrogenic chloride-bicarbonate exchange with a chloride-bicarbonate stoichiometry of 1:2, and hence will dilute and alkalinize protein-rich acinar secretion. Mediates also the transcellular sulfate absorption and oxalate secretion across the apical membrane in the duodenum and the formate ion efflux at the apical brush border of cells in the proximal tubules of kidney. Plays a role in sperm capacitation by increasing intracellular pH.
Apical membrane chloride-bicarbonate exchanger. Its association with carbonic anhydrase CA2 forms a bicarbonate transport metabolon; hence maximizes the local concentration of bicarbonate at the transporter site.
Chloride, bicarbonate and sulfate transport activities are inhibited by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS).
Down-regulated by pro-inflammatory cytokine IFN gamma.
Expressed in heart, brain, placenta, lung, liver, kidney, pancreas, spleen, thymus, prostate, testis and ovary.
Expressed weakly in placenta, lung, liver and pancreas.
Glycosylation at Asn-167 and Asn-172 positively regulates its chloride oxalate exchanger activity.
Interacts (via C-terminal domain) with PDZK1 (via C-terminal PDZ domain); the interaction induces chloride and oxalate exchange transport. Interacts with CFTR and SLC26A3 (By similarity). Interacts with AHCYL1; the interaction increases SLC26A6 activity (By similarity).
Interacts with NHERF1 (via the PDZ domains) and NHERF2 (via the PDZ domains) (PubMed:12444019). Interacts (via C-terminal cytoplasmic domain) with CA2; the interaction stimulates chloride-bicarbonate exchange activity (PubMed:15990874).
Interacts with NHERF1 (via the PDZ domains) and NHERF2 (via the PDZ domains).
Oxalate transport activity is inhibited by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS).
Phosphorylated on serine residues by PKC; the phosphorylation disrupts interaction with carbonic anhydrase CA2 and reduces bicarbonate transport activity in a phorbol myristate acetate (PMA)-induced manner.
Ubiquitous. Highest levels in kidney and pancreas. Lower expression in heart, skeletal muscle, liver and placenta. Also found in lung and brain.
Ubiquitously expressed. Highest levels expressed in the kidney and pancreas.
Essential excecutor of PIWIL4-piRNA pathway directed transposon DNA methylation and silencing in the male embryonic germ cells (By similarity). Associates with the de novo DNA methylation machinery and repressive chromatin remodeling complexes (By similarity). Tethering of PIWIL4 to a nascent transposable element transcript recruits repressive chromatin remodeling activities and the de novo methylation apparatus through SPOCD1 (By similarity). Not required for piRNA biosynthesis (By similarity).
Interacts with DNMT3A, DNMT3C and DNMT3L.
Specifically expressed during early development: expression starts to increase at the 4-cell (4C) stage and culminates at the 8-cell (8C) stage.
Transcription factor expressed after fertilization required for zygotic genome activation (ZGA), a critical event in early embryonic development during which the developmental control passes from maternally provided mRNAs to the expression of the zygotic genome after fertilization (PubMed:35314832, PubMed:36074823). Binds and activates expression of key ZGA marker genes, such as NANOGNB, ZSCAN4, DUXB, KLF5 and DPPA3 (PubMed:36074823). Binds to regulatory DNA sequences containing a 5'-TAATCC-3' sequence motif (PubMed:36074823).
Belongs to the CoA-transferase III family.
Catalyzes the succinyl-CoA-dependent conversion of glutarate to glutaryl-CoA. Can use different dicarboxylic acids as CoA acceptors, the preferred ones are glutarate, succinate, adipate, and 3-hydroxymethylglutarate.
Highly expressed in kidney. Intermediate expression in liver, skeletal muscle and pancreas. Little to no expression detected in other tissues examined.
Interacts with microtubules (PubMed:11290329, PubMed:15631994, PubMed:15955847, PubMed:26003921). Interacts with MAPRE1; probably required for targeting to the growing microtubule plus ends (PubMed:15631994, PubMed:19632184, PubMed:26003921). Interacts with CLIP2, ERC1, MAPRE3, PHLDB2 and RSN (PubMed:11290329, PubMed:15631994). The interaction with ERC1 may be mediated by PHLDB2 (PubMed:16824950). Interacts with GCC2; recruits CLASP2 to Golgi membranes (PubMed:17543864). Interacts with MACF1 (By similarity).
Microtubule plus-end tracking protein that promotes the stabilization of dynamic microtubules (PubMed:26003921). Involved in the nucleation of noncentrosomal microtubules originating from the trans-Golgi network (TGN). Required for the polarization of the cytoplasmic microtubule arrays in migrating cells towards the leading edge of the cell. May act at the cell cortex to enhance the frequency of rescue of depolymerizing microtubules by attaching their plus-ends to cortical platforms composed of ERC1 and PHLDB2 (PubMed:16824950). This cortical microtubule stabilizing activity is regulated at least in part by phosphatidylinositol 3-kinase signaling. Also performs a similar stabilizing function at the kinetochore which is essential for the bipolar alignment of chromosomes on the mitotic spindle (PubMed:16866869, PubMed:16914514). Acts as a mediator of ERBB2-dependent stabilization of microtubules at the cell cortex.
Phosphorylated by GSK3B. Phosphorylation reduces MAPRE1 binding (PubMed:26003921). Phosphorylation by GSK3B may negatively regulate binding to microtubule lattices in lamella.
The two SXIP sequence motifs mediate interaction with MAPRE1; this is necessary for targeting to growing microtubule plus ends.
Two TOG regions display structural characteristics similar to HEAT repeat domains and mediate interaction with microtubules.
Promotes cell adhesion to laminin-332 and fibronectin.
Restricted to cartilage and breast. Also expressed in breast cancers.
Calcium-dependent phospholipid-binding protein that plays a role in calcium-mediated intracellular processes. Binds phospholipid membranes in a calcium-dependent manner (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003).
Interacts (via second C2 domain) with OS9 (via C-terminus); this interaction occurs in a calcium-dependent manner in vitro (By similarity). May interact with NECAB1 (PubMed:12044471).
The C2 domain 1 binds phospholipids in a calcium-independent manner and is not necessary for calcium-mediated translocation and association to the plasma membrane. The C2 domain 2 binds phospholipids in a calcium-dependent manner and is necessary for calcium-mediated translocation and association to the plasma membrane. The linker region contributes to the calcium-dependent translocation and association to the plasma membrane. The VWFA domain is necessary for association with intracellular clathrin-coated vesicles in a calcium-dependent manner.
Widely expressed in the brain (PubMed:9645480, PubMed:10403379, PubMed:12949241). Expressed weakly in the kidney, liver and fetal heart (PubMed:12949241). Expressed in melanocytes (PubMed:23999003).
According to a well-established model, RNF168 cannot initiate H2A 'Lys-63'-linked ubiquitination and is recruited following RNF8-dependent histone ubiquitination to amplify H2A 'Lys-63'-linked ubiquitination (PubMed:19500350, PubMed:19203578, PubMed:19203579). However, other data suggest that RNF168 is the priming ubiquitin ligase by mediating monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub respectively) (PubMed:22980979). These data suggest that RNF168 might be recruited to DSBs sites in a RNF8-dependent manner by binding to non-histone proteins ubiquitinated via 'Lys-63'-linked and initiates monoubiquitination of H2A, which is then amplified by RNF8 (PubMed:22980979). Additional evidence is however required to confirm these data.
E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the RNF8-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).
Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks (DSBs).
The MIU motif (motif interacting with ubiquitin) mediates the interaction with both 'Lys-48'- and 'Lys-63'-linked ubiquitin chains (PubMed:19500350). The UMI motif mediates interaction with ubiquitin with a preference for 'Lys-63'-linked ubiquitin (PubMed:21041483). The specificity for different types of ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU and UMI motifs) with LR motifs (LRMs) (PubMed:22742833).
All cysteine residues are involved in intrachain or interchain disulfide bonds.
Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V. Also acts as a chaperone for coagulation factor VIII, delivering it to the site of injury, stabilizing its heterodimeric structure and protecting it from premature clearance from plasma.
The von Willebrand antigen 2 is required for multimerization of vWF and for its targeting to storage granules.
Belongs to the transient receptor (TC 1.A.4) family. Polycystin subfamily. MCOLN3 sub-subfamily.
Homotetramer (PubMed:29106414). Can heterooligomerize with MCOLN1; heteromeric assemblies have different channel properties as compared to the respective homooligomers and may be tissue-specific (PubMed:19885840). May heterooligomerize with TRPV5 to form a functional distinct ion channel (PubMed:23469151). Interacts with GABARAPL2 (By similarity).
Inhibited by lumenal H(+) and Na(+) (PubMed:18369318, PubMed:29106414). The channel pore shows dynamic behavior and undergoes spontaneous, Ca(2+)-dependent modulation when conducting Ca(2+) (PubMed:20378547).
Nonselective ligand-gated cation channel probably playing a role in the regulation of membrane trafficking events. Acts as Ca(2+)-permeable cation channel with inwardly rectifying activity (PubMed:18369318, PubMed:19497048, PubMed:19522758, PubMed:19885840, PubMed:29106414). Mediates release of Ca(2+) from endosomes to the cytoplasm, contributes to endosomal acidification and is involved in the regulation of membrane trafficking and fusion in the endosomal pathway (PubMed:21245134). Does not seem to act as mechanosensory transduction channel in inner ear sensory hair cells. Proposed to play a critical role at the cochlear stereocilia ankle-link region during hair-bundle growth (By similarity). Involved in the regulation of autophagy (PubMed:19522758). Through association with GABARAPL2 may be involved in autophagosome formation possibly providing Ca(2+) for the fusion process (By similarity). Through a possible and probably tissue-specific heteromerization with MCOLN1 may be at least in part involved in many lysosome-dependent cellular events (PubMed:19885840). Possible heteromeric ion channel assemblies with TRPV5 show pharmacological similarity with TRPML3 (PubMed:23469151).
Interacts with BAX (PubMed:11278245, PubMed:23235460). Interacts with BCL2 and BCL2L1/BCLX (PubMed:11278245, PubMed:11593390). Interacts with APAF1 (By similarity). Interacts with ITPR1, ITPR2 and ITPR3; the interaction with ITPR1 is increased in the presence of AHCLY1 (PubMed:27995898). Interacts with AHCYL1 (PubMed:27995898). Interacts with HIP1R (via ENTH and I/LWEQ domains) (PubMed:19255499). Interacts with CASP9 (PubMed:19255499). Interacts with BCL2L11/BIM (PubMed:22498477, PubMed:23563182, PubMed:23235460). Interacts with BIK (PubMed:23563182, PubMed:23235460). Interacts with UBQLN4 (PubMed:34245648). Interacts with NME2/NM23-H2 (PubMed:17532299). Interacts with PMAIP1/NOXA (PubMed:23563182). Interacts with TPX2 (By similarity). Interacts with UBQLN1; in the cytoplasm (PubMed:22233804). Interacts (via BH1 domain) with BECN1 (PubMed:22498477).
Monoubiquitinated by UBQLN1; results in stabilization of BCL2L10 protein abundance and in relocalization from mitochondria to cytoplasm.
Promotes cell survival by suppressing apoptosis induced by BAX but not BAK (PubMed:11689480, PubMed:11278245). Increases binding of AHCYL1/IRBIT to ITPR1 (PubMed:27995898). Reduces ITPR1-mediated calcium release from the endoplasmic reticulum cooperatively with AHCYL1/IRBIT under normal cellular conditions (PubMed:27995898). Under apoptotic stress conditions, dissociates from ITPR1 and is displaced from mitochondria-associated endoplasmic reticulum membranes, leading to increased Ca(2+) transfer to mitochondria which promotes apoptosis (PubMed:27995898). Required for the correct formation of the microtubule organizing center during oocyte cell division, potentially via regulation of protein abundance and localization of other microtubule organizing center components such as AURKA and TPX2 (By similarity).
Widely expressed in adult tissues. Preferentially expressed in lung, liver and kidney.
Autorepressed by intramolecular binding of the C-terminus which dissociates following phosphorylation by NEK2 isoform 1 in G1/S-arrested cells. NEK2 isoform 2 is largely not present in the nucleolus, and does not appear to phosphorylate NEK11. Activated in response to DNA damage. Inhibited by zinc.
Phosphorylated by NEK2. Phosphorylation at Ser-273 is important for its activation.
Poorly expressed in cerebellum, trachea, lung, appendix, and uterus.
Predominantly expressed at S/G2/M phase.
Protein kinase which plays an important role in the G2/M checkpoint response to DNA damage. Controls degradation of CDC25A by directly phosphorylating it on residues whose phosphorylation is required for BTRC-mediated polyubiquitination and degradation.
Part of a SCF (SKP1-cullin-F-box) protein ligase complex. Interacts with SKP1 and CUL1.
Predominantly expressed in brain, heart and kidney. Expressed at lower levels in liver and lung.
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides.
Filament-forming cytoskeletal GTPase (By similarity). May play a role in cytokinesis (Potential).
Phosphorylated by PKG on serine residues. Phosphorylated by PKG on Ser-91 (By similarity).
Septins polymerize into heterooligomeric protein complexes that form filaments, and can associate with cellular membranes, actin filaments and microtubules. GTPase activity is required for filament formation (By similarity).
Up-regulated during neuronal differentiation.
Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4. May function as a scaffold for the ATAC complex to promote ATAC complex stability. Has also weak histone acetyltransferase activity toward histone H4. Required for the normal progression through G1 and G2/M phases of the cell cycle.
Expressed in skeletal muscle, heart, lung, placenta, brain, liver, pancreas and kidney. High expression in skeletal muscle and heart. Lower expression in lung.
Interacts with the LIM 1 domain of CSRP2. Component of the ADA2A-containing complex (ATAC), composed of CSRP2BP, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1. In the complex, it probably interacts directly with KAT2A, MBIP and WDR5.
Heterotetramer of two type I and two type II keratins (PubMed:16000376). Forms a heterodimer with KRT18 (PubMed:10852826, PubMed:24940650). Associates with KRT20 (PubMed:10973561, PubMed:16608857). Interacts with PLEC isoform 1C, when in a heterodimer with KRT18 (PubMed:24940650). Interacts with PNN (PubMed:10809736). When associated with KRT19, interacts with DMD. Interacts with TCHP (PubMed:15731013). Interacts with APEX1 (PubMed:19188445). Interacts with GPER1 (PubMed:21149639). Interacts with EPPK1 (By similarity). Interacts with PKP1 and PKP2 (PubMed:10852826).
O-glycosylated. O-GlcNAcylation at multiple sites increases solubility, and decreases stability by inducing proteasomal degradation.
Observed in muscle fibers accumulating in the costameres of myoplasm at the sarcolemma membrane in structures that contain dystrophin and spectrin. Expressed in gingival mucosa and hard palate of the oral cavity.
Phosphorylation on serine residues is enhanced during EGF stimulation and mitosis. Ser-74 phosphorylation plays an important role in keratin filament reorganization.
Together with KRT19, helps to link the contractile apparatus to dystrophin at the costameres of striated muscle.
Homodimer. Dimerization may be necessary for its function in neuronal dendritic development. Interacts (via C-terminus) with CREBBP (via N-terminus), EP300 and SMARCA4/BRG1. Interacts with the nBAF complex. Association with CREBBP facilitates transcription while the association with SMARCA4/BRG1 suppresses CREST-mediated transcription in resting neurons (By similarity).
The MFD (multi-functional domain) domain is involved in transcription transactivation, nuclear body targeting and dimerization.
Transcriptional activator which is required for calcium-dependent dendritic growth and branching in cortical neurons. Recruits CREB-binding protein (CREBBP) to nuclear bodies. Component of the CREST-BRG1 complex, a multiprotein complex that regulates promoter activation by orchestrating a calcium-dependent release of a repressor complex and a recruitment of an activator complex. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC1 repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex. At the same time, there is increased recruitment of CREBBP to the promoter by a CREST-dependent mechanism, which leads to transcriptional activation. The CREST-BRG1 complex also binds to the NR2B promoter, and activity-dependent induction of NR2B expression involves a release of HDAC1 and recruitment of CREBBP (By similarity).
Ubiquitous; with lowest levels in spleen.
Acetylation at Lys-12 and Lys-25 by KAT2B/PCAF under stress impairs pre-rRNA processing (PubMed:26867678). Deacetylation by SIRT7 enhances RRP9-binding to U3 snoRNA, which is a prerequisite for pre-rRNA processing (PubMed:26867678).
Component of a nucleolar small nuclear ribonucleoprotein particle (snoRNP) thought to participate in the processing and modification of pre-ribosomal RNA (pre-rRNA) (PubMed:26867678). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Interacts specifically with the U3 small nucleolar RNA (U3 snoRNA) (PubMed:10982864, PubMed:12381732). Binds a sub-fragment of the U3 snoRNA surrounding the B/C motif (3UBC) (PubMed:10982864, PubMed:12381732). This association with the U3BC RNA is dependent on the binding of a protein called 15.5K to the box B/C motif (PubMed:10982864, PubMed:12381732). The association of the protein with the U3BC RNA was found to be also dependent on a conserved RNA structure that flanks the box B/C motif (PubMed:10982864, PubMed:12381732). Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797).
The WD domains are required for nucleolar localization and U3 small nucleolar RNAs binding.
Expressed in microvessels of the brain (at protein level) (PubMed:25809983). Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas (PubMed:10329687).
Sodium-dependent multivitamin transporter that mediates the electrogenic transport of pantothenate, biotin, lipoate and iodide (PubMed:10329687, PubMed:15561972, PubMed:19211916, PubMed:21570947, PubMed:20980265, PubMed:22015582, PubMed:25971966, PubMed:25809983, PubMed:28052864, PubMed:27904971, PubMed:31754459). Functions as a Na(+)-coupled substrate symporter where the stoichiometry of Na(+):substrate is 2:1, creating an electrochemical Na(+) gradient used as driving force for substrate uptake (PubMed:10329687, PubMed:20980265). Required for biotin and pantothenate uptake in the intestine across the brush border membrane (PubMed:19211916). Plays a role in the maintenance of intestinal mucosa integrity, by providing the gut mucosa with biotin (By similarity). Contributes to the luminal uptake of biotin and pantothenate into the brain across the blood-brain barrier (PubMed:25809983).
The C-terminal tail is important for biotin uptake as well as apical localization in polarized cells.
May act as a positive regulator of L-type calcium channels.
Widely expressed. Most abundant in heart and skeletal muscle.
Prolines at the third position of the tripeptide repeating unit (G-X-P) are hydroxylated in some or all of the chains. Probably 3-hydroxylated on Pro-919 and Pro-1156 by LEPREL1.
Trimers of two alpha 1(V) and one alpha 2(V) chains in most tissues and trimers of one alpha 1(V), one alpha 2(V), and one alpha 3(V) chains in placenta.
Type V collagen is a member of group I collagen (fibrillar forming collagen). It is a minor connective tissue component of nearly ubiquitous distribution. Type V collagen binds to DNA, heparan sulfate, thrombospondin, heparin, and insulin. Type V collagen is a key determinant in the assembly of tissue-specific matrices (By similarity).
Accumulates to a maximum during the G2 and M phases, declines to a nearly undetectable level following mitosis and throughout G1 phase, and then begins to accumulate again during S phase.
Activated by phosphorylation of Thr-210 by AURKA; phosphorylation by AURKA is enhanced by BORA. Once activated, activity is stimulated by binding target proteins. Binding of target proteins has no effect on the non-activated kinase. Several inhibitors targeting PLKs are currently in development and are under investigation in a growing number of clinical trials, such as BI 2536, an ATP-competitive PLK1 inhibitor or BI 6727, a dihydropteridinone that specifically inhibits the catalytic activity of PLK1.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CDC5/Polo subfamily.
Catalytic activity is enhanced by phosphorylation of Thr-210. Phosphorylation at Thr-210 is first detected on centrosomes in the G2 phase of the cell cycle, peaks in prometaphase and gradually disappears from centrosomes during anaphase. Dephosphorylation at Thr-210 at centrosomes is probably mediated by protein phosphatase 1C (PP1C), via interaction with PPP1R12A/MYPT1. Autophosphorylation and phosphorylation of Ser-137 may not be significant for the activation of PLK1 during mitosis, but may enhance catalytic activity during recovery after DNA damage checkpoint. Phosphorylated in vitro by STK10.
Defects in PLK1 are associated with some cancers, such as gastric, thyroid or B-cell lymphomas. Expression is cancer increased in tumor tissues with a poor prognosis, suggesting a role in malignant transformations and carcinogenesis.
Interacts with CEP170 and EVI5. Interacts and phosphorylates ERCC6L. Interacts with FAM29A. Interacts with SLX4/BTBD12 and TTDN1. Interacts with BUB1B. Interacts (via POLO-box domain) with the phosphorylated form of BUB1, CENPU and CDC25C. Interacts with isoform 3 of SGO1. Interacts with BORA, KIF2A and AURKA. Interacts with TOPORS and CYLD. Interacts with ECT2; the interaction is stimulated upon phosphorylation of ECT2 on 'Thr-444'. Interacts with PRC1. Interacts with KIF20A/MKLP2 (when phosphorylated), leading to the recruitment at the central spindle. Interacts (via POLO box domains) with PPP1R12A/MYPT1 (when previously phosphorylated by CDK1). Part of an astrin (SPAG5)-kinastrin (SKAP) complex containing KNSTRN, SPAG5, PLK1, DYNLL1 and SGO2. Interacts with BIRC6/bruce. Interacts with CDK1-phosphorylated FRY; this interaction occurs in mitotic cells, but not in interphase cells. FRY interaction facilitates AURKA-mediated PLK1 phosphorylation. Interacts with CDK1-phosphorylated DCTN6 during mitotic prometaphase; the interaction facilitates recruitment to kinetochores. Interacts with CEP68; the interaction phosphorylates CEP68 (PubMed:25503564). Interacts (via POLO-box domain) with DCTN1 (PubMed:20679239). Interacts with CEP20 in later G1, S, G2 and M phases of the cell cycle; this interaction recruits PLK1 to centrosomes, a step required for S phase progression (PubMed:24018379). Interacts with HSF1; this interaction increases upon heat shock but does not modulate neither HSF1 homotrimerization nor DNA-binding activities (PubMed:15661742, PubMed:18794143). Interacts with HNRNPU; this interaction induces phosphorylation of HNRNPU in mitosis (PubMed:25986610). Interacts (via its N-terminus) to RIOK2 (PubMed:21880710). Interacts with KLHL22 (PubMed:24067371, PubMed:23455478). Interacts (via POLO box domains) with NEDD9/HEF1 (via C-terminus) (PubMed:29191835). Interacts with FIRRM (via N-terminus region); required for maintaining, but not activating, PLK1 kinase activity (PubMed:34260926).
Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. Polo-like kinase proteins acts by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates BORA, BUB1B/BUBR1, CCNB1, CDC25C, CEP55, ECT2, ERCC6L, FBXO5/EMI1, FOXM1, KIF20A/MKLP2, CENPU, NEDD1, NINL, NPM1, NUDC, PKMYT1/MYT1, KIZ, PPP1R12A/MYPT1, PRC1, RACGAP1/CYK4, SGO1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1, WEE1 and HNRNPU. Plays a key role in centrosome functions and the assembly of bipolar spindles by phosphorylating KIZ, NEDD1 and NINL. NEDD1 phosphorylation promotes subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. Phosphorylation of NINL component of the centrosome leads to NINL dissociation from other centrosomal proteins. Involved in mitosis exit and cytokinesis by phosphorylating CEP55, ECT2, KIF20A/MKLP2, CENPU, PRC1 and RACGAP1. Recruited at the central spindle by phosphorylating and docking PRC1 and KIF20A/MKLP2; creates its own docking sites on PRC1 and KIF20A/MKLP2 by mediating phosphorylation of sites subsequently recognized by the POLO box domains. Phosphorylates RACGAP1, thereby creating a docking site for the Rho GTP exchange factor ECT2 that is essential for the cleavage furrow formation. Promotes the central spindle recruitment of ECT2. Plays a central role in G2/M transition of mitotic cell cycle by phosphorylating CCNB1, CDC25C, FOXM1, CENPU, PKMYT1/MYT1, PPP1R12A/MYPT1 and WEE1. Part of a regulatory circuit that promotes the activation of CDK1 by phosphorylating the positive regulator CDC25C and inhibiting the negative regulators WEE1 and PKMYT1/MYT1. Also acts by mediating phosphorylation of cyclin-B1 (CCNB1) on centrosomes in prophase. Phosphorylates FOXM1, a key mitotic transcription regulator, leading to enhance FOXM1 transcriptional activity. Involved in kinetochore functions and sister chromatid cohesion by phosphorylating BUB1B/BUBR1, FBXO5/EMI1 and STAG2/SA2. PLK1 is high on non-attached kinetochores suggesting a role of PLK1 in kinetochore attachment or in spindle assembly checkpoint (SAC) regulation. Required for kinetochore localization of BUB1B. Regulates the dissociation of cohesin from chromosomes by phosphorylating cohesin subunits such as STAG2/SA2. Phosphorylates SGO1: required for spindle pole localization of isoform 3 of SGO1 and plays a role in regulating its centriole cohesion function. Mediates phosphorylation of FBXO5/EMI1, a negative regulator of the APC/C complex during prophase, leading to FBXO5/EMI1 ubiquitination and degradation by the proteasome. Acts as a negative regulator of p53 family members: phosphorylates TOPORS, leading to inhibit the sumoylation of p53/TP53 and simultaneously enhance the ubiquitination and subsequent degradation of p53/TP53. Phosphorylates the transactivation domain of the transcription factor p73/TP73, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates BORA, and thereby promotes the degradation of BORA. Contributes to the regulation of AURKA function. Also required for recovery after DNA damage checkpoint and entry into mitosis. Phosphorylates MISP, leading to stabilization of cortical and astral microtubule attachments required for proper spindle positioning (PubMed:8991084, PubMed:11202906, PubMed:12207013, PubMed:12447691, PubMed:12524548, PubMed:12738781, PubMed:12852856, PubMed:12939256, PubMed:14532005, PubMed:14734534, PubMed:15070733, PubMed:15148369, PubMed:15469984, PubMed:16198290, PubMed:16247472, PubMed:16980960, PubMed:17081991, PubMed:17351640, PubMed:17376779, PubMed:17617734, PubMed:18174154, PubMed:18331714, PubMed:18418051, PubMed:18477460, PubMed:18521620, PubMed:18615013, PubMed:19160488, PubMed:19351716, PubMed:19468300, PubMed:19468302, PubMed:19473992, PubMed:19509060, PubMed:19597481, PubMed:23455478, PubMed:23509069). Together with MEIKIN, acts as a regulator of kinetochore function during meiosis I: required both for mono-orientation of kinetochores on sister chromosomes and protection of centromeric cohesin from separase-mediated cleavage (By similarity). Phosphorylates CEP68 and is required for its degradation (PubMed:25503564). Regulates nuclear envelope breakdown during prophase by phosphorylating DCTN1 resulting in its localization in the nuclear envelope (PubMed:20679239). Phosphorylates the heat shock transcription factor HSF1, promoting HSF1 nuclear translocation upon heat shock (PubMed:15661742). Phosphorylates HSF1 also in the early mitotic period; this phosphorylation regulates HSF1 localization to the spindle pole, the recruitment of the SCF(BTRC) ubiquitin ligase complex induicing HSF1 degradation, and hence mitotic progression (PubMed:18794143). Regulates mitotic progression by phosphorylating RIOK2 (PubMed:21880710). Through the phosphorylation of DZIP1 regulates the localization during mitosis of the BBSome, a ciliary protein complex involved in cilium biogenesis (PubMed:27979967).
The POLO box domains act as phosphopeptide-binding module that recognize and bind serine-[phosphothreonine/phosphoserine]-(proline/X) motifs. PLK1 recognizes and binds docking proteins that are already phosphorylated on these motifs, and then phosphorylates them. PLK1 can also create its own docking sites by mediating phosphorylation of serine-[phosphothreonine/phosphoserine]-(proline/X) motifs subsequently recognized by the POLO box domains.
Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) in anaphase and following DNA damage, leading to its degradation by the proteasome. Ubiquitination is mediated via its interaction with FZR1/CDH1. Ubiquitination and subsequent degradation prevents entry into mitosis and is essential to maintain an efficient G2 DNA damage checkpoint. Monoubiquitination at Lys-492 by the BCR(KLHL22) ubiquitin ligase complex does not lead to degradation: it promotes PLK1 dissociation from phosphoreceptor proteins and subsequent removal from kinetochores, allowing silencing of the spindle assembly checkpoint (SAC) and chromosome segregation.
Associates with KCNQ3 to form a potassium channel with essentially identical properties to the channel underlying the native M-current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons as well as the responsiveness to synaptic inputs. Therefore, it is important in the regulation of neuronal excitability. KCNQ2/KCNQ3 current is blocked by linopirdine and XE991, and activated by the anticonvulsant retigabine (PubMed:9836639, PubMed:11572947, PubMed:14534157, PubMed:12742592, PubMed:17872363). As the native M-channel, the potassium channel composed of KCNQ2 and KCNQ3 is also suppressed by activation of the muscarinic acetylcholine receptor CHRM1 (PubMed:10684873). KCNQ2-KCNQ3 channel is selectively permeable to other cations besides potassium, in decreasing order of affinity K(+) > Rb(+) > Cs(+) > Na(+). Associates with Na(+)-coupled myo-inositol symporter SLC5A3 forming a coregulatory complex that alters ion selectivity, increasing Na(+) and Cs(+) permeation relative to K(+) permeation.
Belongs to the potassium channel family. KQT (TC 1.A.1.15) subfamily. Kv7.2/KCNQ2 sub-subfamily.
Heterotetramer with KCNQ3; form the heterotetrameric M potassium channel (PubMed:9836639, PubMed:27564677). Interacts with calmodulin; the interaction is calcium-independent, constitutive and participates in the proper assembly of a functional heterotetrameric M channel (PubMed:27564677). May associate with KCNE2 (PubMed:11034315). Interacts with IQCJ-SCHIP1 (By similarity). Interacts (via the pore module) with SLC5A3; forms a coregulatory complex that alters ion selectivity, voltage dependence and gating kinetics of the channel.
In adult and fetal brain. Highly expressed in areas containing neuronal cell bodies, low in spinal cord and corpus callosum. Isoform 2 is preferentially expressed in differentiated neurons. Isoform 6 is prominent in fetal brain, undifferentiated neuroblastoma cells and brain tumors.
Inclusion of isoform 6 in heteromultimers results in attenuation of potassium current. Prominent expression of isoform 6 in the developing brain may alter firing repertoires of immature neurons excitability to provide cues for proliferation rather than differentiation.
KCNQ2/KCNQ3 heteromeric current can be increased by intracellular cyclic AMP, an effect that depends on phosphorylation of Ser-52 in the N-terminal region.
Component of the signal recognition particle (SRP) complex receptor (SR) (PubMed:16439358). Ensures, in conjunction with the SRP complex, the correct targeting of the nascent secretory proteins to the endoplasmic reticulum membrane system (PubMed:16675701, PubMed:34020957). Forms a guanosine 5'-triphosphate (GTP)-dependent complex with the SRP subunit SRP54 (PubMed:34020957). SRP receptor compaction and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER (PubMed:34020957).
Heterodimer with SRPRB (PubMed:16439358). Interacts with the signal recognition particle (SRP) complex subunit SRP54 (PubMed:34020957).
The NG domain region, also named G domain, is a special guanosine triphosphatase (GTPase) domain, which forms a guanosine 5'-triphosphate (GTP)-dependent complex with a homologous NG domain in the signal recognition particle (SRP) complex subunit SRP54 (PubMed:34020957). The two NG domains undergo cooperative rearrangements upon their assembly, which culminate in the reciprocal activation of the GTPase activity of one another (PubMed:34020957). GTPase induced rearrangement of SR drives SRP-mediated cotranslational protein translocation into the ER (PubMed:34020957).
Inhibits the Wnt/beta-catenin signaling pathway. Crucial for heart development and acts downstream of GATA factors in the pre-cardiac mesoderm to specify lineage commitment of cardiomyocyte development.
Present in the thicker 16-17 nm junctions of mammalian lens fiber cells, where it may contribute to cell junctional organization. Acts as a receptor for calmodulin. May play an important role in both lens development and cataractogenesis.
Seems to be associated with itself or another lens membrane component via disulfide bonds.
Binds as a monomer with high affinity to interleukin-13 (IL13), but not to interleukin-4 (IL4).
Belongs to the complex I NDUFB6 subunit family.
Found in mRNA splicing-dependent exon junction complexes (EJC). Found in a post-splicing complex with NXF1, RBM8A, UPF1, UPF2, UPF3A, UPF3B and RNPS1. Component of the heterotrimeric ASAP (apoptosis- and splicing-associated protein) and PSAP complexes consisting of RNPS1, SAP18 and either ACIN1 or PNN, respectively; the ASAP and PSAP complexes probably are formed mutually exclusive. Component of the active spliceosome. Associates with polysomes. Interacts with the cleaved p110 isoform of CDC2L1, CSNK2A1, PNN, SART3, SRP54, SRRM1 and TRA2B/SFRS10.
Part of pre- and post-splicing multiprotein mRNP complexes. Auxiliary component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. Component of the ASAP and PSAP complexes which bind RNA in a sequence-independent manner and are proposed to be recruited to the EJC prior to or during the splicing process and to regulate specific excision of introns in specific transcription subsets. The ASAP complex can inhibit RNA processing during in vitro splicing reactions. The ASAP complex promotes apoptosis and is disassembled after induction of apoptosis. Enhances the formation of the ATP-dependent A complex of the spliceosome. Involved in both constitutive splicing and, in association with SRP54 and TRA2B/SFRS10, in distinctive modulation of alternative splicing in a substrate-dependent manner. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the activity is different from the established EJC assembly and function. Participates in mRNA 3'-end cleavage. Involved in UPF2-dependent nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Also mediates increase of mRNA abundance and translational efficiency. Binds spliced mRNA 20-25 nt upstream of exon-exon junctions.
Phosphorylated on one or more of the four Ser/Thr residues (Ser-43, Thr-49, Ser-52 or Ser-53). Ser-53 phosphorylation site is important for splicing and translation stimulation activity in vitro.
The RRM domain is required for the formation of the ASAP complex.
Abundantly expressed in pancreas, less in liver, very low levels in heart and lung. Expressed in the Hep-G2 cell line. Isoform 1 and isoform 2 seem to be present in fetal and adult liver and Hep-G2 cells.
Binds DNA as a monomer (By similarity). Interacts with GRIP1, NCOA2 and NR0B2 (PubMed:15707893, PubMed:15723037, PubMed:15897460, PubMed:16289203). Interacts (when sumoylated) with GPS2; interaction with GPS2 onto hepatic acute phase protein promoters prevents N-Cor corepressor complex dissociation (PubMed:20159957).
Does not induce CYP7A promoter activity.
Nuclear receptor that acts as a key metabolic sensor by regulating the expression of genes involved in bile acid synthesis, cholesterol homeostasis and triglyceride synthesis. Together with the oxysterol receptors NR1H3/LXR-alpha and NR1H2/LXR-beta, acts as an essential transcriptional regulator of lipid metabolism. Plays an anti-inflammatory role during the hepatic acute phase response by acting as a corepressor: inhibits the hepatic acute phase response by preventing dissociation of the N-Cor corepressor complex (PubMed:20159957). Binds to the sequence element 5'-AACGACCGACCTTGAG-3' of the enhancer II of hepatitis B virus genes, a critical cis-element of their expression and regulation. May be responsible for the liver-specific activity of enhancer II, probably in combination with other hepatocyte transcription factors. Key regulator of cholesterol 7-alpha-hydroxylase gene (CYP7A) expression in liver. May also contribute to the regulation of pancreas-specific genes and play important roles in embryonic development. Activates the transcription of CYP2C38 (By similarity).
Sumoylated by SUMO1 at Lys-270 during the hepatic acute phase response, leading to promote interaction with GPS2 and prevent N-Cor corepressor complex dissociation.
Contributes to the release of free fatty acids from fatty acid synthase (FASN). Has broad substrate specificity, giving rise to a range of free fatty acids with chain lengths between 10 and 16 carbon atoms (C10 - C16).
Detected both in lactating and non-lactating breast epithelium (at protein level) (PubMed:6589427). Isoform 2 is up-regulated in bone marrow-derived mononuclear cells of rheumatoid arthritis patients (PubMed:17082220).
Binds sperm in vitro and promotes sperm capacitation. Specifically promotes capacitation induced by high density lipoproteins (HDLs). Also binds heparin, phospholipid liposomes, and weakly to gelatin. Does not bind chondroitin sulfate B.
Interacts with B3GAT3; the interaction increases the 2-phosphoxylose phosphatase activity of PXYLP1 during completion of linkage region formation in a B3GAT3-mediated manner.
Responsible for the 2-O-dephosphorylation of xylose in the glycosaminoglycan-protein linkage region of proteoglycans thereby regulating the amount of mature glycosaminoglycan (GAG) chains. Sulfated glycosaminoglycans (GAGs), including heparan sulfate and chondroitin sulfate, are synthesized on the so-called common GAG-protein linkage region (GlcUAbeta1-3Galbeta1-3Galbeta1-4Xylbeta1-O-Ser) of core proteins, which is formed by the stepwise addition of monosaccharide residues by the respective specific glycosyltransferases. Xylose 2-O-dephosphorylation during completion of linkage region formation is a prerequisite for the initiation and efficient elongation of the repeating disaccharide region of GAG chains.
Widely expressed. Strongly expressed in spleen, fetal liver, moderately in placenta, pancreas, kidney, thymus and colon.
Candidate for the putative colorectal tumor suppressor gene located at 5q21. Suppresses cell proliferation and the Wnt/b-catenin pathway in colorectal cancer cells. Inhibits DNA binding of b-catenin/TCF/LEF transcription factors. Involved in cell migration independently of RAC1, CDC42 and p21-activated kinase (PAK) activation (PubMed:18591935, PubMed:19555689, PubMed:22480440). Represses the beta-catenin pathway (canonical Wnt signaling pathway) in a CCAR2-dependent manner by sequestering CCAR2 to the cytoplasm, thereby impairing its ability to inhibit SIRT1 which is involved in the deacetylation and negative regulation of beta-catenin (CTNB1) transcriptional activity (PubMed:24824780).
Interacts with SCRIB (via phosphorylated PDZ-binding motif), EZR, SNX27, NHERF1 and NHERF2. Interacts with CTNNB1; the interaction is enhanced upon Wnt stimulation. Interacts with MYH10. Interacts with CCAR2.
Predominantly expressed in brain, heart, lung and fetal kidney. Low levels in liver and adult kidney.
Putative adhesion receptor, that could be involved in cell-cell or cell-matrix interactions required for normal cell differentiation and migration.
Belongs to the serine-aspartate repeat-containing protein (SDr) family.
Expressed in germ cells of the testis (at protein level) (PubMed:27718356). Detected in skeletal muscle, liver, kidney, pancreas, heart, lung and brain (PubMed:11714101). Expressed throughout spermatogenesis, from spermatogonia to elongated spermatids, in normal adult testis (at protein level) (PubMed:33963445).
Interacts (via SIM domains) with SUMO2; this interaction allows the GCNA recruitment to DPCs sites (PubMed:30914427). Interacts with TOP2A; this interaction allows the resolution of topoisomerase II (TOP2A) DNA-protein cross-links (By similarity).
May play a role in DNA-protein cross-links (DPCs) clearance through a SUMO-dependent recruitment to sites of DPCs, ensuring the genomic stability by protecting germ cells and early embryos from various sources of damage (PubMed:30914427). Can resolve the topoisomerase II (TOP2A) DPCs (By similarity).
SUMO interaction motif 1 (SIM) mediates the binding to polysumoylated substrates.
Homooligomer, heterooligomer with ZNF746 (PubMed:31856708). Interacts (via C2H2-type zinc fingers) with PRKN (By similarity).
May act as a downstream effector of PRKN and contribute to neurodegeneration in Parkinson disease cases caused by defects in PRKN: its accumulation due to the absence of PRKN, followed by up-regulation of PPARGC1A, could lead to the selective loss of dopamine neurons in the substantia nigra.
Transcription repressor that specifically binds to the 5'-TATTTT[T/G]-3' consensus sequence on promoters and repress transcription of PGC-1-alpha (PPARGC1A), thereby playing a role in regulation of neuron death.
Ubiquitinated by PRKN. 'Lys-48'-linked polyubiquitination by PRKN leads to degradation by the proteasome and may play a key role in regulation of neuron death.
Binds to the inner side of the nucleosomal DNA thus altering the interaction between the DNA and the histone octamer. May be involved in the process which maintains transcribable genes in a unique chromatin conformation. Inhibits the phosphorylation of nucleosomal histones H3 and H2A by RPS6KA5/MSK1 and RPS6KA3/RSK2 (By similarity).
Interacts with transcriptional regulator SEHBP.
Partially edited. A new initiator methionine may be created by a single uridine insertion in the 5'-UTR, causing an N-terminal extension of 45 amino acids. The existence of the RNA edited version is supported by direct protein sequencing by MS/MS of the following peptides specific to that version: 23-31 and 40-48. The RNA edited version is called ET-HMGN1.
Phosphorylation on Ser-21 and Ser-25 weakens binding to nucleosomes and increases the rate of H3 phosphorylation (By similarity). Phosphorylation favors cytoplasmic localization.
ESCRT-III-like protein involved in cytokinesis, nuclear envelope reassembly and endosomal tubulation (PubMed:19129479, PubMed:26040712, PubMed:28242692). Is required for efficient abscission during cytokinesis (PubMed:19129479). Involved in recruiting VPS4A and/or VPS4B to the midbody of dividing cells (PubMed:19129480, PubMed:19129479). During late anaphase, involved in nuclear envelope reassembly and mitotic spindle disassembly together with the ESCRT-III complex: IST1 acts by mediating the recruitment of SPAST to the nuclear membrane, leading to microtubule severing (PubMed:26040712). Recruited to the reforming nuclear envelope (NE) during anaphase by LEMD2 (PubMed:28242692). Regulates early endosomal tubulation together with the ESCRT-III complex by mediating the recruitment of SPAST (PubMed:23897888).
Interacts with CHMP1A, CHMP1B, VPS4A and VTA1. Interacts with SPAST, STAMBP, and USP8. May interact with VPS37B. May associate with the ESCRT-I complex. Interacts with MITD1, in competition with VSP4 (PubMed:23015756). Interacts with SPART (via MIT domain); leading to the recruitment of SPART to midbodies (PubMed:20719964). Interacts with SPAST (PubMed:23897888, PubMed:26040712).
Belongs to the peptidase C19 family. USP21 subfamily.
Deubiquitinates histone H2A, a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator (By similarity). Deubiquitination of histone H2A releaves the repression of di- and trimethylation of histone H3 at 'Lys-4', resulting in regulation of transcriptional initiation (By similarity). Regulates gene expression via histone H2A deubiquitination (By similarity). Deubiquitinates BAZ2A/TIP5 leading to its stabilization (PubMed:26100909). Also capable of removing NEDD8 from NEDD8 conjugates but has no effect on Sentrin-1 conjugates (PubMed:10799498). Also acts as a negative regulator of the ribosome quality control (RQC) by mediating deubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS20/uS10, thereby antagonizing ZNF598-mediated 40S ubiquitination (PubMed:32011234).
Highly expressed in heart, pancreas and skeletal muscle. Also expressed in brain, placenta, liver and kidney, and at very low level in lung.
Associates with the pre-60S ribosomal particle. Interacts (via WD repeats) with uL18 (By similarity). Interacts (via UBL domain) with MDN1 (via VWFA/MIDAS domain) (PubMed:26601951).
Plays a role in regulating Notch activity. Plays a role in regulating the expression of CDKN1A and several members of the Wnt pathway, probably via its effects on Notch activity. Required during embryogenesis for inner mass cell survival (By similarity).
Transfers 1,4-N-acetylgalactosamine (GalNAc) from UDP-GalNAc to the non-reducing end of glucuronic acid (GlcUA). Required for addition of the first GalNAc to the core tetrasaccharide linker and for elongation of chondroitin chains.
Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates: SRSF1, SRSF3 and PTPN1 (PubMed:10480872, PubMed:19168442). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells (PubMed:19168442).
Regulates splicing of its own pre-mRNA according to its kinase activity; increased expression of the catalytically active form influences splicing to generate the catalytically inactive splicing variant lacking the kinase domain. Leucettine L41 inhibits its kinase activity and affects the regulation of alternative splicing mediated by phosphorylation of SR proteins.
Belongs to the eukaryotic RPC7 RNA polymerase subunit family.
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits (By similarity). Found a trimeric complex with POLR3C and POLR3G (PubMed:24107381). Directly interacts with POLR3C (PubMed:21358628, PubMed:24107381, PubMed:26394183).
Component of the RNA polymerase III (Pol III) complex.
Up-regulated in embryonic stem cells upon retinoic acid-induced differentiation into embroid bodies (at protein level) (PubMed:28494942). No significant changes in mRNA levels between dividing and non-dividing cells, although levels tends to be slightly higher in non-dividing cells (PubMed:20154270, PubMed:24107381).
Contains mostly chondroitin sulfate, but also keratan sulfate chains, N-linked and O-linked oligosaccharides. The release of aggrecan fragments from articular cartilage into the synovial fluid at all stages of human osteoarthritis is the result of cleavage by aggrecanase.
Detected in fibroblasts (at protein level) (PubMed:36213313). Restricted to cartilage (PubMed:7524681).
Expression was detected in chondrocytes throughout the developing skeleton.
Interacts with FBLN1 (By similarity). Interacts with COMP.
This proteoglycan is a major component of extracellular matrix of cartilagenous tissues. A major function of this protein is to resist compression in cartilage. It binds avidly to hyaluronic acid via an N-terminal globular region.
Two globular domains, G1 and G2, comprise the N-terminus of the proteoglycan, while another globular region, G3, makes up the C-terminus. G1 contains Link domains and thus consists of three disulfide-bonded loop structures designated as the A, B, B' motifs. G2 is similar to G1. The keratan sulfate (KS) and the chondroitin sulfate (CS) attachment domains lie between G2 and G3.
Appears to be the first example of a new class of functional RNAs also able to encode a protein.
Functional RNA which acts as a transcriptional coactivator that selectively enhances steroid receptor-mediated transactivation ligand-independently through a mechanism involving the modulating N-terminal domain (AF-1) of steroid receptors. Also mediates transcriptional coactivation of steroid receptors ligand-dependently through the steroid-binding domain (AF-2). Enhances cellular proliferation and differentiation and promotes apoptosis in vivo. May play a role in tumorigenesis.
Highly expressed in liver and skeletal muscle and to a lesser extent in brain. Also expressed in both normal and tumorigenic breast epithelial cell lines. Significantly up-regulated in human tumors of the breast, ovary, and uterus.
SRA1 RNA exists in a ribonucleoprotein complex containing NCOA1. The RNA also forms a complex with PUS1 and RARG in the nucleus. Interacts with AR.
Heterohexamer (Probable). Oligomerizes with other LRRC8 proteins (LRRC8A, LRRC8C, LRRC8D and/or LRRC8E) to form a heterohexamer (PubMed:24790029, PubMed:26824658, PubMed:28193731). In vivo, the subunit composition may depend primarily on expression levels, and heterooligomeric channels containing various proportions of the different LRRC8 proteins may coexist (Probable).
Non-essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes (PubMed:24790029, PubMed:26824658, PubMed:28193731). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine. Channel activity requires LRRC8A plus at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (PubMed:24790029, PubMed:26824658, PubMed:28193731).
The volume-regulated anion channel (VRAC) channel forms a trimer of dimers, with symmetry mismatch between the pore-forming domain and the cytosolic LRR repeats, a topology similar to gap junction proteins.
Homooligomer; upon reaching the lysosomes (PubMed:21224396). Interacts with MCOLN1 (PubMed:21224396). Interacts with NEDD4; may play a role in the lysosomal sorting of LAPTM4B; enhances HGS association with NEDD4; mediates inhibition of EGFR degradation (PubMed:22096579, PubMed:25588945). Interacts with PIP5K1C; promotes SNX5 association with LAPTM4B; kinase activity of PIP5K1C is required; interaction is regulated by phosphatidylinositol 4,5-bisphosphate generated by PIP5K1C (PubMed:25588945). Interacts with HGS; promotes HGS ubiquitination (PubMed:25588945). Interacts with SNX5 (PubMed:25588945). Interacts with SLC3A2 and SLC7A5; recruits SLC3A2 and SLC7A5 to lysosomes to promote leucine uptake into these organelles and is required for mTORC1 activation (PubMed:25998567). Interacts with LRRC32; decreases TGFB1 production in regulatory T cells (PubMed:26126825). Interacts with BECN1; competes with EGFR for LAPTM4B binding; regulates EGFR activity (PubMed:28479384). Interacts with EGFR; positively correlates with EGFR activation (PubMed:28479384).
Required for optimal lysosomal function (PubMed:21224396). Blocks EGF-stimulated EGFR intraluminal sorting and degradation. Conversely by binding with the phosphatidylinositol 4,5-bisphosphate, regulates its PIP5K1C interaction, inhibits HGS ubiquitination and relieves LAPTM4B inhibition of EGFR degradation (PubMed:25588945). Recruits SLC3A2 and SLC7A5 (the Leu transporter) to the lysosome, promoting entry of leucine and other essential amino acid (EAA) into the lysosome, stimulating activation of proton-transporting vacuolar (V)-ATPase protein pump (V-ATPase) and hence mTORC1 activation (PubMed:25998567). Plays a role as negative regulator of TGFB1 production in regulatory T cells (PubMed:26126825). Binds ceramide and facilitates its exit from late endosome in order to control cell death pathways (PubMed:26280656).
Undergoes proteolytic cleavage following delivery to the lysosomes.
Belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM8 sub-subfamily.
Expressed in prostate. Also expressed in prostate tumors and in non-prostatic primary tumors such as colon, lung, breast and skin tumors.
Homotetramer (By similarity). Isoform 2 and isoform 3 interact with the C-terminus of isoform 1 in a thermosensitive manner with decreased interaction at 21 degrees Celsius compared to 37 degrees Celsius. Interacts (via N-terminus and C-terminus domains) with TCAF1; the interaction stimulates TRPM8 channel activity (PubMed:25559186). Interacts (via N-terminus and C-terminus domains) with TCAF2 isoform 2; the interaction inhibits TRPM8 channel activity (PubMed:25559186).
Its expression in most prostate tumors as well as the presence of an immunogenic epitope suggest that it may be suitable for the design of peptide vaccination strategies for prostate cancers.
Receptor-activated non-selective cation channel involved in detection of sensations such as coolness, by being activated by cold temperature below 25 degrees Celsius. Activated by icilin, eucalyptol, menthol, cold and modulation of intracellular pH. Involved in menthol sensation. Permeable for monovalent cations sodium, potassium, and cesium and divalent cation calcium. Temperature sensing is tightly linked to voltage-dependent gating. Activated upon depolarization, changes in temperature resulting in graded shifts of its voltage-dependent activation curves. The chemical agonist menthol functions as a gating modifier, shifting activation curves towards physiological membrane potentials. Temperature sensitivity arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing. In prostate cancer cells, shows strong inward rectification and high calcium selectivity in contrast to its behavior in normal cells which is characterized by outward rectification and poor cationic selectivity. Plays a role in prostate cancer cell migration (PubMed:25559186). Isoform 2 and isoform 3 negatively regulate menthol- and cold-induced channel activity by stabilizing the closed state of the channel.
The 192-residue sequence submitted as AAS45276 has been confirmed by the authors of PubMed:22128173 to be incorrect as translation starts from a downstream methionine.
The coiled coil region is required for multimerization.
The sensation of coolness triggered by eucalyptol or menthol may be explained by the fact that menthol and cool temperatures sensations are detected by this protein.
Expression is very low or not detectable.
Catalyzes the methylation of 5-carboxymethyl uridine to 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in tRNA via its methyltransferase domain (PubMed:20123966, PubMed:20308323, PubMed:31079898). Catalyzes the last step in the formation of 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in target tRNA (PubMed:20123966, PubMed:20308323). Has a preference for tRNA(Arg) and tRNA(Glu), and does not bind tRNA(Lys)(PubMed:20308323). Binds tRNA and catalyzes the iron and alpha-ketoglutarate dependent hydroxylation of 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in tRNA via its dioxygenase domain, giving rise to 5-(S)-methoxycarbonylhydroxymethyluridine; has a preference for tRNA(Gly) (PubMed:21285950). Required for normal survival after DNA damage (PubMed:20308323). May inhibit apoptosis and promote cell survival and angiogenesis (PubMed:19293182).
May be due to competing donor splice site.
Up-regulated after DNA damage. Induction is mediated via ATM.
Widely expressed, with highest expression in spleen, followed by pancreas and lung.
Has a neutrophil chemotactic activity. Also a positive regulator of chondrocyte proliferation (PubMed:9524238). Does not show metalloendopeptidase activity (PubMed:27334921).
Highly expressed in adult and fetal liver and weakly in testis. Not expressed in bone marrow.
Belongs to the MsrA Met sulfoxide reductase family.
Cytoplasmic and nuclear. Produced by alternative promoter usage.
Cytoplasmic. Produced by alternative initiation.
Cytoplasmic. Produced by alternative promoter usage.
Has an important function as a repair enzyme for proteins that have been inactivated by oxidation. Catalyzes the reversible oxidation-reduction of methionine sulfoxide in proteins to methionine.
Mitochondrial. Produced by alternative splicing.
Ubiquitous. Highest expression in adult kidney and cerebellum, followed by liver, heart ventricles, bone marrow and hippocampus.
Expression seems restricted to cells of myeloid lineage.
Forms complexes with the CD300 family members with exception of CD300c.
Acyltransferase which transfers an acyl group to the N-terminus of glutamine. Can use phenylacetyl-CoA as an acyl donor.
Expressed in liver and kidney and, at lower levels, in pancreas, testis, ovary and stomach.
Belongs to the protease inhibitor I39 (alpha-2-macroglobulin) family.
Belongs to the calcium channel beta subunit family.
Detected in heart ventricle (at protein level) (PubMed:15615847). Isoform 1 and isoform 3 are expressed in brain, heart, spleen, central nervous system and neuroblastoma cells. Isoform 2 is expressed in skeletal muscle.
Regulatory subunit of L-type calcium channels (PubMed:1309651, PubMed:8107964, PubMed:15615847). Regulates the activity of L-type calcium channels that contain CACNA1A as pore-forming subunit (By similarity). Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit and increases the presence of the channel complex at the cell membrane (PubMed:15615847). Required for functional expression L-type calcium channels that contain CACNA1D as pore-forming subunit (PubMed:1309651). Regulates the activity of L-type calcium channels that contain CACNA1B as pore-forming subunit (PubMed:8107964).
Regulatory subunit of L-type calcium channels that consist of a pore-forming alpha subunit and auxiliary beta, gamma and delta subunits (By similarity). Interacts with CACNA1A, CACNA1B, CACNA1C and CACNA1S (By similarity). Component of a calcium channel complex consisting of a pore-forming alpha subunit (CACNA1S) and the ancillary subunits CACNB1 or CACNB2, CACNG1 and CACNA2D1. Identified in a complex with CACNA1C (PubMed:15615847). Identified in a complex with the L-type calcium channel subunits CACNA1C, CACNA2D1, CACNB1 and one of the gamma subunits (CACNG4, CACNG6, CACNG7, or CACNG8) (By similarity). Part of a L-type calcium channel complex that contains CACNA1D, CACNA2D1 and CACNB1 (PubMed:1309651). Part of a L-type calcium channel complex that contains CACNA1B, CACNA2D1 and CACNB1 (PubMed:8107964). Interacts with JSRP1. Interacts with RYR1 (By similarity). Interacts with CBARP (By similarity).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIK4 subfamily.
Forms a heteromeric channel with GRIK1 or GRIK3.
DNA-binding component of the Fanconi anemia (FA) core complex. Required for the normal activation of the FA pathway, leading to monoubiquitination of the FANCI-FANCD2 complex in response to DNA damage, cellular resistance to DNA cross-linking drugs, and prevention of chromosomal breakage (PubMed:20347428, PubMed:20347429). In complex with CENPS (MHF heterodimer), crucial cofactor for FANCM in both binding and ATP-dependent remodeling of DNA. Stabilizes FANCM. In complex with CENPS and FANCM (but not other FANC proteins), rapidly recruited to blocked forks and promotes gene conversion at blocked replication forks (PubMed:20347428, PubMed:20347429). In complex with CENPS, CENPT and CENPW (CENP-T-W-S-X heterotetramer), involved in the formation of a functional kinetochore outer plate, which is essential for kinetochore-microtubule attachment and faithful mitotic progression (PubMed:19620631). As a component of MHF and CENP-T-W-S-X complexes, binds DNA and bends it to form a nucleosome-like structure (PubMed:20347428, PubMed:20347429). DNA-binding function is fulfilled in the presence of CENPS, with the following preference for DNA substates: Holliday junction > double-stranded > splay arm > single-stranded. Does not bind DNA on its own (PubMed:20347429).
Expression varies across the cell cycle, with highest levels in S phase (at protein level). No statistically significant changes at the transcript level.
Heterodimer with CENPX, sometimes called MHF; this interaction stabilizes both partners (PubMed:19620631, PubMed:20347428, PubMed:20347429, PubMed:24522885). MHF heterodimers can assemble to form tetrameric structures (PubMed:22304917). MHF also coassemble with CENPT-CENPW heterodimers at centromeres to form the tetrameric CENP-T-W-S-X complex (PubMed:22304917, PubMed:24522885). Forms a discrete complex with FANCM and CENPX, called FANCM-MHF; this interaction, probably mediated by direct binding between CENPS and FANCM, leads to synergistic activation of double-stranded DNA binding and strongly stimulates FANCM-mediated DNA remodeling (PubMed:20347428, PubMed:20347429). Recruited by FANCM to the Fanconi anemia (FA) core complex, which consists of CENPS, CENPX, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM, FAAP24 and FAAP100. The FA core complex associates with Bloom syndrome (BLM) complex, which consists of at least BLM, DNA topoisomerase 3-alpha (TOP3A), RMI1/BLAP75, RPA1/RPA70 and RPA2/RPA32. The super complex between FA and BLM is called BRAFT (PubMed:20347428, PubMed:20347429).
Strongly expressed in testis and pancreas. Weak expression in placenta.
Associates with D-amino acid oxidase (DAAO).
Expressed in amygdala, caudate nucleus, spinal cord and testis.
By genotoxic agents such as cisplatin and camptothecin.
Expressed at highest levels in testis and at lower levels in adrenal gland, bone marrow, brain, colon, heart, kidney, liver, muscle, ovary, pancreas, placenta, prostate, skeletal muscle, skin, small intestine, spleen, stomach, testis, thymus, thyroid and uterus. Expressed in the alveolar epithelium of the lung. Expression is commonly decreased in colon adenocarcinomas and lung cancers.
Functions as an E3 ubiquitin-protein ligase and as an E3 SUMO1-protein ligase. Probable tumor suppressor involved in cell growth, cell proliferation and apoptosis that regulates p53/TP53 stability through ubiquitin-dependent degradation. May regulate chromatin modification through sumoylation of several chromatin modification-associated proteins. May be involved in DNA damage-induced cell death through IKBKE sumoylation.
Interacts with PARK7/DJ-1 (By similarity). Interacts with TOP1. Interacts with p53/TP53; can both ubiquitinate and sumoylate p53/TP53. Interacts with the SUMO1 conjugating enzyme UBE2I. Interacts with SUMO1. Interacts with NKX3-1; polyubiquitinates NKX3-1 and induces its proteasomal degradation. Interacts with SIN3A; sumoylates SIN3A. Interacts with IKBKE; induced by DNA damage.
Phosphorylation at Ser-98 regulates the E3 ubiquitin-protein ligase activity but not the SUMO1-protein ligase activity. Phosphorylation at Ser-718 increases the E3 ubiquitin-protein ligase activity versus the SUMO1-protein ligase activity resulting in increased p53/TP53 ubiquitination and degradation.
Was originally thought to bind to the palindromic consensus sequence 5'-TCCCAGCACTTTGGGA-3' and to regulate the transcription of numerous genes in the lung.
HLA-DRB3, HLA-DRB4 and HLA-DRB5 may represent a unique gene.
Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.
Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to down-regulation of MHC class II.
Interacts with SP1 (PubMed:10976766). Interacts with MIS18A. Identified in a complex containing MIS18A, OIP5/MIS18B, MIS18BP1, RBBP7 and RBBP4 (PubMed:17199038). Interacts with KAT7/HBO1 (PubMed:27270040). Interacts (via N-terminus) with FLNA (via N-terminus) (By similarity).
Interacts with BBS1, BBS2, BBS4, BBS5, BBS6, BBS7 and TTC8/BBS8. Interacts with MAPKAP1/SIN1 isoform 1 and RICTOR.
Involved in ciliogenesis. Regulates cilia length through its interaction with MAPKAP1/SIN1 but independently of mTORC2 complex. Modulates mTORC2 complex assembly and function, possibly enhances AKT1 phosphorylation. Does not seem to modulate assembly and function of mTORC1 complex.
Contributes to the maintenance of intracerebral BDNF levels within the normal range, which is necessary for the preservation of spatial learning and the resistance to neuronal cell death caused by ischemic stress (By similarity). May enhance growth factor-induced ERK1 and ERK2 phosphorylation, including that induced by PDGF and FGF. May attenuate NGF-promoted ELK1 phosphorylation in a microtubule-dependent manner.
Expressed in a cell cycle-specific manner in glioblastoma multiple cells. Low levels in G2/M cells increase with progression through G1 phase and entry and progression through S phase.
Expressed predominantly in brain and heart (at protein level). In the brain, detected in astrocytes. Isoform 1 and isoform 2 are only expressed in brain. Isoform 3 is expressed in both heart and brain. Up-regulated in glioblastoma multiforme cells.
Phosphorylated in an aortic smooth muscle cell line, following PDGF treatment.
A Rab11 effector protein involved in the endosomal recycling process. Also involved in controlling membrane trafficking along the phagocytic pathway and in phagocytosis.
Homooligomer (isoform 2). Isoform 2 interacts with RAB4A, RAB11A, RAB11B and RAB25. According to PubMed:15280022, RAB4A binding to RAB11FIP1 is of very low affinity in vitro and in vivo.
Isoform 2 is expressed in brain, heart, testis, lung, spleen, ovary and small intestine.
Antibodies against GRIPAP1 have been found in sera of a patient who developed Raynaud's syndrome and telangiectasias.
Functions as a scaffold protein to facilitate MAP3K1/MEKK1-mediated activation of the JNK1 kinase by phosphorylation, possibly by bringing MAP3K1/MEKK1 and JNK1 in close proximity.
Interacts with GRIP1, GRIP2 and AMPA receptors (By similarity). Interacts (via C-terminus) with MAPK8/JNK1 and MAP3K1/MEKK1; the interaction promotes MAP3K1-mediated phosphorylation of MAPK8 (PubMed:17761173). Interacts (via N-terminus) with RAB4A (in GTP-bound form) (PubMed:20098723). Interacts (via C-terminus) with STX12 (By similarity).
Proteolytically cleaved by caspase-3. A minor C-terminal proteolytic fragment of 30 kDa is produced. Proteolytic cleavage is required for JNK signaling activation.
Regulates the endosomal recycling back to the neuronal plasma membrane, possibly by connecting early and late recycling endosomal domains and promoting segregation of recycling endosomes from early endosomal membranes. Involved in the localization of recycling endosomes to dendritic spines, thereby playing a role in the maintenance of dendritic spine morphology. Required for the activity-induced AMPA receptor recycling to dendrite membranes and for long-term potentiation and synaptic plasticity (By similarity).
May be involved in modulating the expression of photoreceptor specific genes. Binds to the Ret-1 and Bat-1 element within the rhodopsin promoter.
The Homeobox transactivates the Ret-1 element in the presence of CRX and NRL.
Expressed in fetal testis and ovary. In the developing ovary, detected at least from Carnegie stages (CS) 22/23. Expression seems to peak at 15/16 weeks post conception (wpc) (PubMed:34402903). In the developing testis, expressed at CS22/23 and until at least 19/20 wpc (PubMed:34402903).
Interacts with RAD51D and XRCC3; involved in homologous recombination repair. Interacts with SWSAP1; they form a functional complex involved in homologous recombination repair and stabilize each other.
Involved in early stages of the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. Required for meiotic progression, hence for fertility (PubMed:32719396, PubMed:33713115, PubMed:34402903).
Widely distributed in the adult CNS with highest expression in the corpus callosum, caudate nucleus, cerebral cortex, medulla, putamen, spinal cord, substantia nigra and subthalamic nucleus. Weak expression was detected in the adult heart.
Autophosphorylated. Autophosphorylation is blocked by interaction with SUFU.
Interacts (via protein kinase domain) with SUFU.
Serine/threonine protein kinase that acts as a regulator of Sonic hedgehog (SHH) signaling and autophagy. Acts as a negative regulator of SHH signaling in the absence of SHH ligand: interacts with SUFU, thereby inactivating the protein kinase activity and preventing phosphorylation of GLI proteins (GLI1, GLI2 and/or GLI3). Positively regulates SHH signaling in the presence of SHH: dissociates from SUFU, autophosphorylates and mediates phosphorylation of GLI2, activating it and promoting its nuclear translocation. Phosphorylates in vitro GLI2, as well as GLI1 and GLI3, although less efficiently. Also acts as a regulator of autophagy: following cellular senescence, able to induce autophagy.
Widely expressed. Highest levels observed in fetal brain. In adult tissues, high levels in brain, liver and kidney, moderate levels in testis and adrenal gland and low levels in heart, lung, stomach, thymus, prostate and placenta. In the brain, highest expression in the hippocampus, high levels also detected in the cerebellum, olfactory bulb and optic nerve. In the central nervous system, lowest levels in the spinal cord.
Binds with a high affinity to glycophorin and with lower affinity to band III protein. Associates with the nuclear mitotic apparatus. Interacts with calmodulin (PubMed:10692436). Interacts with CENPJ (PubMed:11003675). Interacts with DLG1 (PubMed:7937897). Also found to associate with contractile apparatus and tight junctions. Interacts with NUMA1; this interaction is negatively regulated by CDK1 during metaphase and promotes anaphase-specific localization of NUMA1 in symmetrically dividing cells (PubMed:23870127). Interacts with ATP2B1; regulates small intestinal calcium absorption through regulation of membrane expression of ATP2B1 (By similarity).
O-glycosylated; contains N-acetylglucosamine side chains in the C-terminal domain.
Phosphorylated at multiple sites by different protein kinases and each phosphorylation event selectively modulates the protein's functions.
Phosphorylation on Tyr-660 reduces the ability of 4.1 to promote the assembly of the spectrin/actin/4.1 ternary complex.
Protein 4.1 is a major structural element of the erythrocyte membrane skeleton. It plays a key role in regulating membrane physical properties of mechanical stability and deformability by stabilizing spectrin-actin interaction. Recruits DLG1 to membranes. Required for dynein-dynactin complex and NUMA1 recruitment at the mitotic cell cortex during anaphase (PubMed:23870127).
Catalyzes the covalent attachment of ubiquitin to other proteins (By similarity). Specific substrate for UBA6, not charged with ubiquitin by UBE1. May be involved in apoptosis regulation.
Widely expressed. Highly in placenta, pancreas, spleen and testis.
Interacts with the DEPDC5 subunit of the GATOR1 complex; interaction is disrupted when BMT2/SAMTOR binds S-adenosyl-L-methionine (PubMed:29123071, PubMed:29590090, PubMed:35776786). Interacts with the KICSTOR complex; interaction is disrupted when BMT2/SAMTOR binds S-adenosyl-L-methionine (PubMed:29123071, PubMed:35776786).
S-adenosyl-L-methionine-binding protein that acts as an inhibitor of mTORC1 signaling via interaction with the GATOR1 and KICSTOR complexes (PubMed:29123071, PubMed:35776786). Acts as a sensor of S-adenosyl-L-methionine to signal methionine sufficiency to mTORC1: in presence of methionine, binds S-adenosyl-L-methionine, leading to disrupt interaction with the GATOR1 and KICSTOR complexes and promote mTORC1 signaling (PubMed:29123071, PubMed:35776786). Upon methionine starvation, S-adenosyl-L-methionine levels are reduced, thereby promoting the association with GATOR1 and KICSTOR, leading to inhibit mTORC1 signaling (PubMed:29123071, PubMed:35776786). Probably also acts as a S-adenosyl-L-methionine-dependent methyltransferase (Potential).
Displays thioredoxin reductase, glutaredoxin and glutathione reductase activities. Catalyzes disulfide bond isomerization. Promotes disulfide bond formation between GPX4 and various sperm proteins and may play a role in sperm maturation by promoting formation of sperm structural components (By similarity).
The N-terminal glutaredoxin domain does not contain the C-X-X-C redox-active motif normally found in glutaredoxins but activity may be mediated through a single cysteine. The C-terminal Cys-Sec motif of one subunit of the homodimer may transfer electrons from the thiol-disulfide center to the glutaredoxin domain of the other subunit (By similarity).
The thioredoxin reductase active site is a redox-active disulfide bond. The selenocysteine residue is also essential for catalytic activity (By similarity).
(Microbial infection) May bind HIV-1 gag/Capsid protein p24-derived peptide (AISPRTLNA) on infected cells and may inhibit NK cell cytotoxicity, a mechanism that allows HIV-1 to escape immune recognition.
(Microbial infection) Upon SARS-CoV-2 infection, may contribute to functional exhaustion of cytotoxic NK cells and CD8-positive T cells (PubMed:32859121). Binds SARS-CoV-2 S/Spike protein S1-derived peptide (LQPRTFLL) expressed on the surface of lung epithelial cells, inducing NK cell exhaustion and dampening of antiviral immune surveillance (PubMed:32859121).
(Microbial infection) Viruses like human cytomegalovirus have evolved an escape mechanism whereby virus-induced down-regulation of host MHC class I molecules is coupled to the binding of viral peptides to HLA-E, restoring HLA-E expression and inducing HLA-E-dependent NK cell immune tolerance to infected cells.
Expressed in extravillous trophoblast (at protein level).
Expressed in secretory endometrial cells during pregnancy (at protein level). The expression in nonlymphoid tissues is restricted to endothelial cells from all types of vessels, including arteries, veins, capillaries, and lymphatics (at protein level). In lymphoid organs, it is mainly expressed in endothelial venules, B and T cells, monocytes, macrophages, NK cells and megakaryocytes (at protein level).
Forms a heterotrimer with B2M and a self- or a pathogen-derived peptide (peptide-bound HLA-E-B2M) (PubMed:18339401, PubMed:30087334, PubMed:35705051). Similarly to MHC class Ia assembly, HLA-E-B2M heterodimer interacts with components of the antigen processing machinery TAPBP and TAP1-TAP2 complex; this interaction is required for peptide loading and translocation to the cell surface (PubMed:9427624). Interacts with CALCR; this interaction is required for appropriate folding (PubMed:9427624). The optimum binding peptide is a nonamer (VL9) that is primarily derived from amino-acid residues 3-11 of the signal sequences of most HLA-A, -B, -C and -G molecules (PubMed:9754572, PubMed:18083576, PubMed:9660937, PubMed:18339401). The VL9 peptide anchors to five main sites in the peptide-binding groove of HLA-E (PubMed:18339401). Peptide-bound HLA-E-B2M complex interacts with KLRD1-KLRC1 receptor on NK cells (PubMed:9486650, PubMed:18083576). Binds with lower affinity to activating KLRD1-KLRC2 (PubMed:18083576, PubMed:23335510). The common subunit KLRC1 plays a prominent role in directly interacting with HLA-E (PubMed:18083576). Peptide-bound HLA-E-B2M interacts with the alpha-beta TCR on unconventional CD8+ T cells (PubMed:16474394). Peptide-free HLA-E interacts with HLA-F-B2M complex; this interaction may regulate the intracellular trafficking and the stability of peptide-free MHC class I open conformers (OCs).
Non-classical major histocompatibility class Ib molecule involved in immune self-nonself discrimination. In complex with B2M/beta-2-microglobulin binds nonamer self-peptides derived from the signal sequence of classical MHC class Ia molecules (VL9 peptides - VMAPRT[V/L][L/V/I/F]L) (PubMed:9754572, PubMed:18083576, PubMed:37264229, PubMed:18339401, PubMed:35705051). Peptide-bound HLA-E-B2M heterotrimeric complex primarily functions as a ligand for natural killer (NK) cell inhibitory receptor KLRD1-KLRC1, enabling NK cells to monitor the expression of other MHC class I molecules in healthy cells and to tolerate self (PubMed:9754572, PubMed:9486650, PubMed:17179229, PubMed:18083576, PubMed:37264229). Upon cellular stress, preferentially binds signal sequence-derived peptides from stress-induced chaperones and is no longer recognized by NK cell inhibitory receptor KLRD1-KLRC1, resulting in impaired protection from NK cells (PubMed:12461076). Binds signal sequence-derived peptides from non-classical MHC class Ib HLA-G molecules and acts as a ligand for NK cell activating receptor KLRD1-KLRC2, likely playing a role in the generation and effector functions of adaptive NK cells and in maternal-fetal tolerance during pregnancy (PubMed:9754572, PubMed:30134159, PubMed:37264229). Besides self-peptides, can also bind and present pathogen-derived peptides conformationally similar to VL9 peptides to alpha-beta T cell receptor (TCR) on unconventional CD8-positive cytotoxic T cells, ultimately triggering antimicrobial immune response (PubMed:16474394, PubMed:30087334, PubMed:20195504, PubMed:34228645). Presents HIV gag peptides (immunodominant KAFSPEVIPMF and subdominant KALGPAATL epitopes) predominantly to CD8-positive T cell clones expressing a TRAV17-containing TCR, triggering HLA-E-restricted T cell responses (PubMed:34228645). Presents mycobacterial peptides to HLA-E-restricted CD8-positive T cells eliciting both cytotoxic and immunoregulatory functions (PubMed:20195504, PubMed:35705051).
Pro-inflammatory cytokines including TNF, IL1B and IFNG up-regulate membrane bound HLA-E expression on endothelial and NK cells and induce the release of soluble HLA-E (sHLA-E) in the extracellular compartment.
The following alleles are known: E*01:01 and E*01:03 (PubMed:3131426, PubMed:10064069, PubMed:16702430, PubMed:16570139, PubMed:28127896). The frequency of E*01:01 and E*01:03 alleles in the population is about equal suggesting balanced selection in diverse populations. Evolutionary studies suggest that E*01:03 is the original allele (PubMed:12445303). Two other alleles has been described E*01:02 and E*01:04 (PubMed:3260916, PubMed:1977695). Allele E*01:02 was found to be identical to HLA E*01:01 (PubMed:3260916, PubMed:22665232). The existence of allele E*01:04 is uncertain as it could not be confirmed in further studies (PubMed:1977695, PubMed:12445303). The sequence shown is that of E*01:03 (PubMed:10064069, PubMed:16702430, PubMed:16570139, PubMed:28127896).
The soluble form (sHLA-E) can be partly produced by proteolytic cleavage at the cell surface (shedding) by a matrix metalloproteinase. Alternative splicing is also suggested as a mechanism for generation of sHLA-E, although it remains to be proved.
Highly expressed in most breast cancers (at protein level).
Interacts (via the SH2 and SH3 domains) with DOK1 (PubMed:23822091). Interacts with KHDRBS1/SAM68 and VIM (PubMed:29496907).
Non-receptor tyrosine-protein kinase which phosphorylates DOK1 on tyrosine residues (PubMed:23822091). Also phosphorylates KHDRBS1/SAM68 and VIM on tyrosine residues (PubMed:29496907). Phosphorylation of KHDRBS1 is EGF-dependent (PubMed:29496907). Phosphorylates OTUB1, promoting deubiquitination of RPTOR (PubMed:35927303).
The N-terminal region regulates its kinase activity.
Although it belongs to the non-receptor class myotubularin subfamily, lacks the conserved active site cysteine residue at position 375 in the dsPTPase catalytic loop, suggesting that it has no phosphatase activity.
Expressed in bone marrow, spleen and thymus.
Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling (By similarity).
The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA (By similarity).
Belongs to the transient receptor (TC 1.A.4) family. TrpV subfamily. TRPV1 sub-subfamily.
Channel activity is activated via the interaction with PIRT and phosphatidylinositol 4,5-bisphosphate (PIP2). Both PIRT and PIP2 are required to activate channel activity (By similarity). The channel is sensitized by ATP binding. Repeated stimulation with capsaicin gives rise to progressively smaller responses, due to desensitization. This desensitization is triggered by the influx of calcium ions and is inhibited by elevated ATP levels. Ca(2+) and CALM displace ATP from its binding site and trigger a conformation change that leads to a closed, desensitized channel. Intracellular PIP2 inhibits desensitization. The double-knot toxin (DkTx) from the Chinese earth tiger tarantula activates the channel and traps it in an open conformation (By similarity). The Scolopendra mutilans RhTx toxin potentiates the heat activation pathway mediated by this channel by binding to the charge-rich outer pore region (in an activated state) (By similarity).
Interacts with PIRT (By similarity). Homotetramer (By similarity). Interacts with TRPV3 and may also form a heteromeric channel with TRPV3 (PubMed:12077606). Interacts with CALM, PRKCM and CSK. Interacts with PRKCG and NTRK1, probably by forming a trimeric complex (By similarity). Interacts with the Scolopendra mutilans RhTx toxin (By similarity). Interacts with TMEM100 (By similarity). Interacts with PACS2 (PubMed:29656858).
Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular acidosis in nociceptive neurons. Involved in mediation of inflammatory pain and hyperalgesia. Sensitized by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases, which involves PKC isozymes and PCL. Activation by vanilloids, like capsaicin, and temperatures higher than 42 degrees Celsius, exhibits a time- and Ca(2+)-dependent outward rectification, followed by a long-lasting refractory state. Mild extracellular acidic pH (6.5) potentiates channel activation by noxious heat and vanilloids, whereas acidic conditions (pH <6) directly activate the channel. Can be activated by endogenous compounds, including 12-hydroperoxytetraenoic acid and bradykinin. Acts as ionotropic endocannabinoid receptor with central neuromodulatory effects. Triggers a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamine in the hippocampus and nucleus accumbens by affecting AMPA receptors endocytosis.
Phosphorylation by PKA reverses capsaicin-induced dephosphorylation at multiple sites, probably including Ser-117 as a major phosphorylation site. Phosphorylation by CAMKII seems to regulate binding to vanilloids. Phosphorylated and modulated by PRKCE, PRKCM and probably PRKCZ. Dephosphorylation by calcineurin seems to lead to receptor desensitization and phosphorylation by CAMKII recovers activity.
Responses evoked by low pH and heat, and capsaicin can be antagonized by capsazepine.
The association domain (AD) is necessary for self-association.
Widely expressed at low levels. Expression is elevated in dorsal root ganglia. In skin, expressed in cutaneous sensory nerve fibers, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands (at protein level).
Belongs to the GST superfamily. Sigma family.
Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide.
Expressed in a number of megakaryocytic cell lines but not in platelets. Highly expressed in adipose tissue, macrophages and placenta. Also expressed at lower levels in lung, heart, lymph nodes, appendix, bone marrow and fetal liver.
Glutathione is required for the prostaglandin D synthase activity.
Highest levels in immature megakaryocytic cells. Disappears after final differentiation to platelets.
Prostaglandin PGD2 synthesis is stimulated by calcium and magnesium ions. One calcium or magnesium ion is bound between the subunits of the homodimer. The interactions with the protein are for the most part mediated via water molecules. Magnesium increases the affinity for glutathione, while calcium has no effect on the affinity for glutathione.
Highly expressed in placenta, muscle, kidney and testis. Moderately expressed in heart, brain, lung, liver and intestine. Isoform 2 is widely expressed and expressed in fetal and adult testes, and spermatozoa.
Interacts with PALLD. Associates with actin. However, does not bind F-actin directly.
Plays a role in actin regulation at the ectoplasmic specialization, a type of cell junction specific to testis. Important for establishment of sperm polarity and normal spermatid adhesion. May also promote integrity of Sertoli cell tight junctions at the blood-testis barrier.
Up-regulated by all-trans-retinoic acid (ATRA) in retinal pigment epithelial cells (ARPE-19).
Belongs to the phosphatidylethanolamine-binding protein family. Mitochondrion-specific ribosomal protein mL38 subfamily.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379, PubMed:25278503). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. mL38 is located at the central protuberance.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A19 subfamily.
Interacts in a tissue-specific manner with ACE2 in small intestine and with CLTRN in the kidney (By similarity). Interacts with CLTRN; this interaction is required for trafficking of SLC6A19 to the plasma membrane and for its catalytic activation in kidneys (By similarity). Interacts with ACE2; this interaction is required for trafficking of SLC6A19 to the plasma membrane and for its catalytic activation in intestine (PubMed:32132184). Interacts with ANPEP; the interaction positively regulates its amino acid transporter activity (By similarity).
Robust expression in kidney and small intestine, with minimal expression in pancreas (PubMed:18424768, PubMed:15286787). Also expressed in stomach, liver, duodenum, ileocecum, colon and prostate. Not detected in testis, whole brain, cerebellum, fetal liver, spleen, skeletal muscle, uterus, heart or lung.
The disease may be caused by variants affecting the gene represented in this entry. SLC6A19 deficiency combined with haploinsufficiency of SLC6A20 or partially inactivating mutations in SLC36A2, can be responsible for hyperglycinuria.
The disease may be caused by variants affecting the gene represented in this entry. SLC6A19 deficiency combined with haploinsufficiency of SLC6A20 or partially inactivating mutations in SLC36A2, can be responsible for iminoglycinuria. Additional polymorphisms and mutations in SLC6A18 can contribute to the IG phenotype in some families.
Transporter that mediates resorption of neutral amino acids across the apical membrane of renal and intestinal epithelial cells (PubMed:15286787, PubMed:15286788, PubMed:18424768, PubMed:18484095, PubMed:19185582, PubMed:26240152). This uptake is sodium-dependent and chloride-independent (PubMed:15286787, PubMed:19185582, PubMed:15286788). Requires CLTRN in kidney or ACE2 in intestine for cell surface expression and amino acid transporter activity (PubMed:19185582, PubMed:18424768).
Acts as histone chaperone in nucleosome assembly.
Interacts with core (H2A, CD2APH2B, H3, H4) and linker (H1) histones.
Phosphorylated at the G0/G1 boundary but it is not phosphorylated in S-phase. Phosphorylated protein remains in the cytoplasm in a complex with histones during the G0/G1 transition, whereas dephosphorylation triggers its transport into the nucleus at the G1/S-boundary.
Polyglutamylated by TTLL4, a modification that occurs exclusively on glutamate residues and results in polyglutamate chains on the gamma-carboxyl group. Some residues may also be monoglycylated but not polyglycylated due to the absence of functional TTLL10 in human (By similarity).
Ubiquitous. Biallelically expressed in fetal and adult tissues. Highest levels in testis.
Increased surface expression on T-cells of systemic lupus erythematosus (SLE) patients.
Interacts with SH2D1A, SH2D1B and INPP5D. Interacts (via phosphorylated cytoplasmic domain) with PTPN11; the interaction is blocked by SH2D1A.
Self-ligand receptor of the signaling lymphocytic activation molecule (SLAM) family. SLAM receptors triggered by homo- or heterotypic cell-cell interactions are modulating the activation and differentiation of a wide variety of immune cells and thus are involved in the regulation and interconnection of both innate and adaptive immune response. Activities are controlled by presence or absence of small cytoplasmic adapter proteins, SH2D1A/SAP and/or SH2D1B/EAT-2. May participate in adhesion reactions between T lymphocytes and accessory cells by homophilic interaction. Promotes T-cell differentiation into a helper T-cell Th17 phenotype leading to increased IL-17 secretion; the costimulatory activity requires SH2D1A (PubMed:22184727). Promotes recruitment of RORC to the IL-17 promoter (PubMed:22989874). May be involved in the maintenance of peripheral cell tolerance by serving as a negative regulator of the immune response. May disable autoantibody responses and inhibit IFN-gamma secretion by CD4(+) T-cells. May negatively regulate the size of thymic innate CD8(+) T-cells and the development of invariant natural killer T (iNKT) cells (By similarity).
Belongs to the SelWTH family. Selenoprotein T subfamily.
Induced by Parkinson disease-inducing neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
May contain a selenide-sulfide bond between Cys-46 and Sec-49. This bond is speculated to serve as redox-active pair (By similarity).
Selenoprotein with thioredoxin reductase-like oxidoreductase activity (By similarity). Protects dopaminergic neurons against oxidative stress and cell death (PubMed:26866473). Involved in ADCYAP1/PACAP-induced calcium mobilization and neuroendocrine secretion (By similarity). Plays a role in fibroblast anchorage and redox regulation (By similarity). In gastric smooth muscle, modulates the contraction processes through the regulation of calcium release and MYLK activation (By similarity). In pancreatic islets, involved in the control of glucose homeostasis, contributes to prolonged ADCYAP1/PACAP-induced insulin secretion (By similarity).
Ubiquitous. Highly expressed in the endocrine pancreas.
mRNA levels are increased more than 200-folds in the caudate putamen from Parkinson disease (PD) patients compared to control subjects. In conditional brain knockout mice, treatment with PD-inducing neurotoxins provoke rapid and severe parkinsonian-like motor defects.
Anchoring protein that binds preferentially to the type I regulatory subunit of c-AMP-dependent protein kinase (PKA type I) and targets it to distinct subcellular compartments. May act as a converging factor linking cAMP and sphingosine signaling pathways. Plays a regulatory role in the modulation of SPHK1.
Highly expressed in heart. Both isoforms abundantly expressed in ventricle. Also expressed in spleen, ovary and brain.
Interacts (via the PKA-RII subunit binding domain) with the RI subunit of PKA. Interacts with SPHK1; the interaction greatly reduces SPHK1 activity.
A chromosomal aberration involving PRKX is a cause of sex reversal disorder. Translocation t(X;Y)(p22;p11) with PRKY. Chromosomal translocations proximal to PRKY account for about 30% of the cases of sex reversal disorder in XX males and XY females.
Binding of cAMP to the PRKAR1A or PRKAR1B regulatory subunits induces dissociation of the holoenzyme heterotetramer. The released monomeric PRKX is then active and able to phosphorylate its substrates.
Expression is developmentally regulated being high and specific in a wide range of developing tissues including liver, kidney, brain and pancreas (at protein level).
Like other cAMP-dependent protein kinases, the inactive holoenzyme is probably composed of 2 PRKX catalytic subunits and a dimer of regulatory subunits. Interacts (cAMP-dependent) specifically with the regulatory subunits PRKAR1A and PRKAR1B. Compared to other cAMP-dependent serine/threonine protein kinases, does not interact with the 2 other PKA regulatory subunits PRKAR2A and PRKAR2B. Interacts with cAMP-dependent protein kinase inhibitor/PKI proteins; inhibits PRKX. Interacts with GPKOW. Interacts with SMAD6. Interacts with PKD1; involved in differentiation and controlled morphogenesis of the kidney. Interacts with PIN1 (via WW domain).
Phosphorylated; autophosphorylates in vitro.
Serine/threonine protein kinase regulated by and mediating cAMP signaling in cells. Acts through phosphorylation of downstream targets that may include CREB, SMAD6 and PKD1 and has multiple functions in cellular differentiation and epithelial morphogenesis. Regulates myeloid cell differentiation through SMAD6 phosphorylation. Involved in nephrogenesis by stimulating renal epithelial cell migration and tubulogenesis. Also involved in angiogenesis through stimulation of endothelial cell proliferation, migration and vascular-like structure formation.
Up-regulated by phorbol 12-myristate 13-acetate (PMA).
Widely expressed (at protein level). Specifically expressed in blood by macrophages and granulocytes according to PubMed:9860982.
Gatekeeper of meiotic initiation in both male and female germ cells. In complex with STRA8, directly activates the transcription of a subset of critical meiotic genes playing a central role in cell-cycle switching from mitosis to meiosis. Temporal expression of MEIOSIN is required for meiotic entry decision.
Inhibited by O-phenanthroline and MGTA and activated by cobalt.
Specifically removes C-terminal basic residues (Arg or Lys) from peptides and proteins. It is believed to play important roles in the control of peptide hormone and growth factor activity at the cell surface, and in the membrane-localized degradation of extracellular proteins.
May play a role in apoptosis. May act as a tumor suppressor.
Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM. The complex is not found in FA patients. In complex with FANCF, FANCG and FANCL, but not with FANCC, nor FANCE, interacts with HES1; this interaction may be essential for the stability and nuclear localization of FA core complex proteins. The complex with FANCC and FANCG may also include EIF2AK2 and HSP70. Interacts with FAAP20/C1orf86; interaction is direct.
DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function. May be involved in interstrand DNA cross-link repair and in the maintenance of normal chromosome stability.
Phosphorylation is required for the formation of the nuclear complex. Not phosphorylated in cells derived from groups A, B, C, E, F, G, and H.
Deubiquitinating enzyme that hydrolyzes 'Lys-6'- and 'Lys-11'-linked polyubiquitin. Also hydrolyzes heterotypic (mixed and branched) and homotypic chains (PubMed:23827681, PubMed:32011234, PubMed:35675826). Important regulator of energy metabolism (PubMed:35675826). Glucose and fatty acids trigger its nuclear translocation by CBP-dependent acetylation (PubMed:35675826). In the nucleus, deubiquitinates and stabilizes the nuclear receptor PPARD regulating the expression of various genes involved in glucose and lipid metabolism and oxidative phosphorylation (PubMed:35675826). Also acts as a negative regulator of the ribosome quality control (RQC) by mediating deubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS20/uS10, thereby antagonizing ZNF598-mediated 40S ubiquitination (PubMed:32011234).
Glucose and fatty acids stimulate CREBBP-dependent acetylation, promoting its nuclear translocation.
Specificity is given by the S1' ubiquitin-binding site within the OTU domain composed of the Cys-, His- and Variable-loops.
The UBA-like domain has no influence on ubiquitin hydrolysis.
Belongs to the twisted gastrulation protein family.
Expressed in brain throughout development.
Interacts with CHRD and BMP4. This interaction enhances CHRD/BMP4 complex formation. Interacts with BMP7 (By similarity).
May be involved in dorsoventral axis formation. Seems to antagonize BMP signaling by forming ternary complexes with CHRD and BMPs, thereby preventing BMPs from binding to their receptors. In addition to the anti-BMP function, also has pro-BMP activity, partly mediated by cleavage and degradation of CHRD, which releases BMPs from ternary complexes. May be an important modulator of BMP-regulated cartilage development and chondrocyte differentiation. May play a role in thymocyte development (By similarity).
The N-terminal domain is sufficient to interact with BMP4.
Acts as transcriptional repressor involved in developmental processes of a variety of tissues and organs, including the heart and coronary vessels, the ureter and the vertebral column. Required for embryonic development of the sino atrial node (SAN) head area.
Homodimer. Can form a heterodimer with TBX15. Interacts with GATA4 and NKX2-5. Interacts with PAX3 (By similarity). Interacts (via engrailed homology 1 repressor motif) with TLE3; this interaction represses TBX18 transcriptional activity (By similarity) (PubMed:26235987). Interacts with SIX1 (PubMed:26235987).
In adults, expressed most abundantly in heart, liver and skeletal muscle, moderately abundant in kidney and pancreas, and barely detectable in lung. In fetal tissues, expressed most abundantly in kidney and very low amounts in heart, lung and liver.
Interacts with HCFC1; the interaction inhibits CREB3 transcriptional activity (PubMed:10871379, PubMed:15705566). Interacts with CREB3; the interaction occurs only in combination with HCFC1 (PubMed:15705566).
Named 'Zhangfei' after a legendary Chinese warrior who was contemporary with Luman in around 220 AD.
Strongly activates transcription when bound to HCFC1. Suppresses the expression of HSV proteins in cells infected with the virus in a HCFC1-dependent manner. Also suppresses the HCFC1-dependent transcriptional activation by CREB3 and reduces the amount of CREB3 in the cell. Able to down-regulate expression of some cellular genes in CREBZF-expressing cells.
Interacts with PLCE1 (PubMed:16537651). Interacts (active GTP-bound form preferentially) with RGS14 (By similarity). Interacts with OSBPL3 (PubMed:18270267, PubMed:16537651, PubMed:20074548) (By similarity). Interacts with ZDHHC19 (PubMed:20074548).
Regulates the organization of the actin cytoskeleton (PubMed:16537651, PubMed:18270267). With OSPBL3, modulates integrin beta-1 (ITGB1) activity (PubMed:18270267).
S-palmitoylated by ZDHHC19, leading to increased association with membranes and with rafts/caveolae as well as enhanced cell viability.
Activated by actinomycin-D induced DNA damage.
Belongs to the cyclin family. Cyclin G subfamily.
Expression levels increase through the cell cycle to peak in the mid/late-S phase and decrease during G2/M phase.
High levels in cerebellum, thymus, spleen and prostate. Low levels in skeletal muscle.
May play a role in growth regulation and in negative regulation of cell cycle progression.
Auto-ubiquitinated; leads to proteasomal degradation.
E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of SIN3B (By similarity). Independently of its E3 ligase activity, acts as a CTNNB1 stabilizer through USP7-mediated deubiquitination of CTNNB1 promoting Wnt signaling (PubMed:25266658, PubMed:33964137). Plays a critical role in the regulation of nuclear lamina (PubMed:33964137).
Interacts with SIN3B (By similarity). Interacts with CTNNB1 (via Armadillo repeats 2-8) (PubMed:25266658, PubMed:33964137). Interacts with USP7 (via MATH domain) (PubMed:25266658).
Ubiquitously expressed. Abundant in brain and spinal cord, particularly in the cerebellum and cerebral cortex. In fetal tissues expressed in the cerebellum, spinal cord and cortex.
(Microbial infection) Interacts with Hendra virus protein M; this interaction promotes nuclear localization of M.
(Microbial infection) Interacts with Measles virus protein M.
(Microbial infection) Interacts with Sendai virus protein M.
(Microbial infection) Interacts with influenza virus B protein PB2; this interaction strongly supports influenza B virus replication.
(Microbial infection) Plays an essential role in influenza A and B viral genome replication (PubMed:33045004, PubMed:31217244). Also plays a role in foamy virus mRNA export from the nucleus to the cytoplasm (PubMed:21159877).
Expressed in heart, lung, pancreas, prostate and in spleen, thymus and placenta.
Histone binding is mediated by the concave surface of the LRR region.
Interacts with histones H3 and H4 (PubMed:20538007). Interacts with KLF5; this interaction induces promoter region-specific histone incorporation and inhibition of histone acetylation by ANP32B (PubMed:18039846).
Multifunctional protein that is involved in the regulation of many processes including cell proliferation, apoptosis, cell cycle progression or transcription (PubMed:20015864, PubMed:18039846). Regulates the proliferation of neuronal stem cells, differentiation of leukemic cells and progression from G1 to S phase of the cell cycle. As negative regulator of caspase-3-dependent apoptosis, may act as an antagonist of ANP32A in regulating tissue homeostasis (PubMed:20015864). Exhibits histone chaperone properties, able to recruit histones to certain promoters, thus regulating the transcription of specific genes (PubMed:20538007, PubMed:18039846). Also plays an essential role in the nucleocytoplasmic transport of specific mRNAs via the uncommon nuclear mRNA export receptor XPO1/CRM1 (PubMed:17178712). Participates in the regulation of adequate adaptive immune responses by acting on mRNA expression and cell proliferation (By similarity).
Belongs to the glycosyl hydrolase 35 family.
Cleaves beta-linked terminal galactosyl residues from gangliosides, glycoproteins, and glycosaminoglycans.
Detected in placenta (at protein level) (PubMed:8383699). Detected in fibroblasts and testis (PubMed:2511208).
Has no beta-galactosidase catalytic activity, but plays functional roles in the formation of extracellular elastic fibers (elastogenesis) and in the development of connective tissue. Seems to be identical to the elastin-binding protein (EBP), a major component of the non-integrin cell surface receptor expressed on fibroblasts, smooth muscle cells, chondroblasts, leukocytes, and certain cancer cell types. In elastin producing cells, associates with tropoelastin intracellularly and functions as a recycling molecular chaperone which facilitates the secretions of tropoelastin and its assembly into elastic fibers.
Homodimer (PubMed:22128166). May form higher multimers (Probable).
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv10.1/KCNH1 sub-subfamily.
Channel activity is inhibited by interaction with Ca(2+)-bound calmodulin (PubMed:10880439, PubMed:27325704, PubMed:27005320, PubMed:27618660). Interaction of a single pore-forming alpha subunit with a calmodulin chain is sufficient to promote channel closure (PubMed:10880439). Channel activity is not regulated by cyclic nucleotides (By similarity). Channel activity is inhibited by binding intracellular phosphatidylinositol-3,5-bisphosphate and phosphatidylinositol-4,5-bisphosphate (PIP2), but is not inhibited by phosphatidylinositol 4-phosphate (PubMed:27005320). Inhibited by the spider kappa-theraphotoxin-Aa1a and mu/kappa-theraphotoxin-Ap1a (PubMed:30149017).
Channel activity is regulated via tyrosine phosphorylation/dephosphorylation by SRC and PTPN6 (PubMed:24587194).
Highly expressed in brain and in myoblasts at the onset of fusion, but not in other tissues. Detected in HeLa (cervical carcinoma), SH-SY5Y (neuroblastoma) and MCF-7 (epithelial tumor) cells, but not in normal epithelial cells.
Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel (PubMed:9738473, PubMed:11943152, PubMed:10880439, PubMed:22732247, PubMed:25556795, PubMed:27325704, PubMed:27005320, PubMed:27618660). Channel properties are modulated by subunit assembly (PubMed:11943152). Mediates IK(NI) current in myoblasts (PubMed:9738473). Involved in the regulation of cell proliferation and differentiation, in particular adipogenic and osteogenic differentiation in bone marrow-derived mesenchymal stem cells (MSCs) (PubMed:23881642).
The C-terminal region interacts with the cyclic nucleotide-binding domain and contributes to regulate channel gating.
The PAS and PAC domain interact with the cyclic nucleotide-binding domain and contribute to the regulation of channel gating (PubMed:27325704). Calmodulin binding clamps together the PAS and PAC domain with the cyclic nucleotide-binding domain from a neighboring subunit and causes a conformation change that leads to channel closure.
The cyclic nucleotide-binding domain lacks residues that are essential for nucleotide-binding and cannot bind cyclic nucleotides. Instead, residues from the C-terminal domain (the so-called intrinsic ligand) bind in the cavity that would be expected to bind cyclic nucleotides. Interaction with the C-terminal region hinders interaction with CALM and reduces the affinity for CALM.
The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming alpha subunits that can associate with modulating beta subunits. Heteromultimer with KCNH5/EAG2 (PubMed:11943152). Interacts with ALG10B (By similarity). Interacts with RABEP1 (By similarity). Interacts (via C-terminus) with CTTN (PubMed:23144454). Interacts (via C-terminal cytoplasmic region) with Ca(2+)-bound calmodulin (PubMed:10880439, PubMed:27325704, PubMed:27618660). Interacts with the spider kappa-theraphotoxin-Aa1a and mu/kappa-theraphotoxin-Ap1a (PubMed:30149017).
Component of the large ribosomal subunit (LSU). Part of a LSU subcomplex, the 5S RNP which is composed of the 5S RNA, RPL5 and RPL11 (PubMed:24120868). Interacts with isoform 1 of NVL in an ATP-dependent manner (PubMed:15469983). Interacts with RRP1B (PubMed:20926688). Interacts with IPO5, IPO7 and KPNB1; these interactions may be involved in RPL5 nuclear import for the assembly of ribosomal subunits (PubMed:9687515).
Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules. The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain. The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel. As part of the 5S RNP/5S ribonucleoprotein particle it is an essential component of the LSU, required for its formation and the maturation of rRNAs (PubMed:12962325, PubMed:19061985, PubMed:24120868, PubMed:23636399). It also couples ribosome biogenesis to p53/TP53 activation. As part of the 5S RNP it accumulates in the nucleoplasm and inhibits MDM2, when ribosome biogenesis is perturbed, mediating the stabilization and the activation of TP53 (PubMed:24120868).
Associates with the RNA exosome complex, probably mediated by EXOSC10 (PubMed:29906447). Interacts with ARHGAP18, EXOSC10 and MTREX.
RNA-binding protein that associates with the RNA exosome complex. Involved in the 3'-processing of the 7S pre-RNA to the mature 5.8S rRNA and play a role in recruiting the RNA exosome complex to pre-rRNA; this function may include C1D.
Expressed in testis and thymus. Expressed in the B-cell lines WI-L2-NS and Namalwa (at protein level).
Interacts (phosphorylated and unphosphorylated form) with SMC3. Interacts with SYCP3. Interacts (phosphorylated and unphosphorylated form) with SMC1B. Does not interact with SMC1A. Interacts with RAD51 (By similarity). Forms a complex with EWSR1, PRDM9, SYCP3 and SYCP1; complex formation is dependent of phosphorylated form of REC8 and requires PRDM9 bound to hotspot DNA; EWSR1 joins PRDM9 with the chromosomal axis through REC8 (By similarity).
Required during meiosis for separation of sister chromatids and homologous chromosomes. Proteolytic cleavage of REC8 on chromosome arms by separin during anaphase I allows for homologous chromosome separation in meiosis I and cleavage of REC8 on centromeres during anaphase II allows for sister chromatid separation in meiosis II (By similarity).
May play a role in proper chromosome biorientation through the detection or correction of syntelic attachments in mitotic spindles.
Activated by binding to the GTPase-activating protein RAP1GAP. Activated by guanine nucleotide-exchange factor (GEF) EPAC2 in a cAMP-dependent manner.
GTP-binding protein that possesses intrinsic GTPase activity. Contributes to the polarizing activity of KRIT1 and CDH5 in the establishment and maintenance of correct endothelial cell polarity and vascular lumen. Required for the localization of phosphorylated PRKCZ, PARD3 and TIAM1 to the cell junction. Plays a role in the establishment of basal endothelial barrier function.
Heterodimer with RAP1GAP (PubMed:18309292). Interacts with EPAC2 (PubMed:18660803). Interacts with SGSM1 (PubMed:17509819). Interacts with SGSM2 (PubMed:17509819). Interacts with SGSM3 (PubMed:17509819). Interacts with KRIT1 (PubMed:22577140). Interacts with RAP1GDS1 (PubMed:24415755).
Found in cerebellum and frontal cortex. Detected at high levels in hippocampus, amygdala and trachea; at moderate levels in fetal brain, pituitary gland and prostate. Not in caudate, accumbens, kidney or liver. Also detected at high levels in lung carcinoma.
Interacts specifically with a number of opioid ligands. Receptor for neuropeptides B and W, which may be involved in neuroendocrine system regulation, food intake and the organization of other signals. Has a higher affinity for neuropeptide B.
Interacts with GNB5 (PubMed:12761221, PubMed:10339615, PubMed:10521509). Interacts with RGS7BP, leading to regulate the subcellular location of the heterodimer formed with GNB5 (By similarity). Interacts with GNAI1 (PubMed:18434541).
Regulates G protein-coupled receptor signaling cascades. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form. The RGS6/GNB5 dimer enhances GNAO1 GTPase activity (PubMed:10521509).
The RGS domain interacts avidly with Galpha and mediates the acceleration of Galpha-mediated GTP hydrolysis.
(Microbial infection) In conjunction with the ESCRT machinery also appears to function in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and enveloped virus budding (HIV-1 and other lentiviruses).
Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly, possibly in combination with membrane fission. Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. It is required for proper accomplishment of various processes including the regulation of endosome size, primary cilium organization, mitotic spindle organization, chromosome segregation, and nuclear envelope sealing and spindle disassembly during anaphase (PubMed:33186545). Involved in cytokinesis: retained at the midbody by ZFYVE19/ANCHR and CHMP4C until abscission checkpoint signaling is terminated at late cytokinesis. It is then released following dephosphorylation of CHMP4C, leading to abscission (PubMed:24814515). VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413). Critical for normal erythroblast cytokinesis and correct erythropoiesis (PubMed:33186543).
Proposed to be monomeric or homodimeric in nucleotide-free form and to oligomerize upon binding to ATP to form two stacked hexameric or heptameric rings with a central pore through which ESCRT-III substrates are translocated in an ATP-dependent manner (By similarity). Interacts with CHMP1A, CHMP1B, CHMP2A, CHMP2B, CHMP3, CHMP4A, CHMP4B, CHMP4C and CHMP6. Interacts with VPS4B; the interaction suggests a heteromeric assembly with VPS4B. Interacts with SPAST. Interacts with IST1. Interacts with ZFYVE19/ANCHR; leading to retain it at midbody.
The MIT domain serves as an adapter for ESCRT-III proteins. It forms an asymmetric three-helix bundle that binds amphipathic MIM (MIT interacting motif) helices along the groove between MIT helices 2 and 3 present in a subset of ESCRT-III proteins thus establishing the canonical MIM-MIT interaction. In an extended conformation along the groove between helices 1 and 3, also binds to a type-2 MIT interacting motif (MIM2).
Catalyzes the covalent attachment of ubiquitin or ISG15 to other proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Promotes ubiquitination and subsequent proteasomal degradation of FLT3.
Interacts with RNF19A, RNF19B and RNF144B. Interacts with FLT3 (tyrosine phosphorylated).
Present in natural killer cells (at protein level).
ATP-dependent low-affinity peptide transporter which translocates a broad spectrum of peptides from the cytosol to the lysosomal lumen for degradation (PubMed:15863492, PubMed:17977821, PubMed:18434309, PubMed:22641697, PubMed:25646430, PubMed:30877195, PubMed:31417173, PubMed:30353140). Displays a broad peptide length specificity from 6-mer up to at least 59-mer peptides with an optimum of 23-mers (PubMed:15863492, PubMed:25646430). Binds and transports smaller and larger peptides with the same affinity (PubMed:31417173). Favors positively charged, aromatic or hydrophobic residues in the N- and C-terminal positions whereas negatively charged residues as well as asparagine and methionine are not favored (PubMed:15863492, PubMed:17977821, PubMed:18434309).
Divided into an N-terminal domain (TMD0) comprising four transmembrane helices and the following core domain (coreABCB9) (PubMed:18952056). TMD0 is required for lysosomal localization and LAMP1, LAMP2 and YIF1B interaction (PubMed:15577206, PubMed:18175933, PubMed:20377823, PubMed:22641697, PubMed:30877195). The core domain is required for homodimerization and peptide transport activity (PubMed:18952056, PubMed:20377823).
Has also been detected in the endoplasmic reticulum but appears to be a lysosomal protein in vivo.
Highly expressed in testis, and at moderate levels in brain, spinal cord, and thyroid. Not expressed in monocytes but strongly expressed during differentiation of monocytes to dendritic cells and macrophages.
Homodimer (PubMed:15863492, PubMed:30353140). Interacts (via TMD0 region) with LAMP1; this interaction strongly stabilizes ABCB9 and protects ABCB9 against lysosomal degradation (PubMed:22641697). Interacts (via TMD0 region) with LAMP2 (isoform LAMP-2B) (PubMed:22641697). Interacts (via TMD0) with YIF1B; this interaction allows (but is not essential) the ER-to-Golgi trafficking and strongly depends on a salt bridge within TMD0 (PubMed:30877195).
Transport activity is limited by threshold levels of luminal peptide (PubMed:25646430). ATP hydrolysis is reduced in the presence of the spatial challenging 18-mer peptide by 50% and the branched 16-mer peptide by 75% (PubMed:31417173). Transport rate of the longer peptides is strongly reduced (PubMed:31417173).
Lysozyme C is capable of both hydrolysis and transglycosylation; it shows also a slight esterase activity. It acts rapidly on both peptide-substituted and unsubstituted peptidoglycan, and slowly on chitin oligosaccharides.
Lysozymes have primarily a bacteriolytic function; those in tissues and body fluids are associated with the monocyte-macrophage system and enhance the activity of immunoagents.
Possible architectural role during spermatogenesis. May be involved in spermatid differentiation.
Homodimer (By similarity). Component of the PET complex, at least composed of EXD1, PIWIL2, TDRD12 and piRNAs (By similarity).
RNA-binding component of the PET complex, a multiprotein complex required for the processing of piRNAs during spermatogenesis. The piRNA metabolic process mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposable elements, preventing their mobilization, which is essential for the germline integrity (By similarity). The PET complex is required during the secondary piRNAs metabolic process for the PIWIL2 slicing-triggered loading of PIWIL4 piRNAs. In the PET complex, EXD1 probably acts as an RNA adapter. EXD1 is an inactive exonuclease (By similarity).
The 3'-5' exonuclease domain lacks the conserved Asp-Glu-Asp-Asp (DEDD) residues that coordinates divalent ions essential for exonuclease activity.
Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8/ICSBP, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively.
Component of the CSN complex, composed of COPS1/GPS1, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7 (COPS7A or COPS7B), COPS8 and COPS9 isoform 1 (PubMed:11337588, PubMed:18850735, PubMed:26456823). In the complex, it probably interacts directly with COPS3, COPS4 and COPS7 (COPS7A or COPS7B) (PubMed:18850735).
Interacts (via ankyrin repeat region) with LYN (via SH3-domain) in an activation-independent status of LYN. Forms a multiprotein complex with LYN and HCLS1. Interacts with TSN2, VAV1, DBNL and LASP1.
Plays an important role in regulating intracellular signaling events associated with erythroid terminal differentiation.
Binds TGFB1, TGFB2 and TGFB3 in the picomolar affinity range without the participation of additional receptors. Blocks activation of SMAD2 and SMAD3 by TGFB1.
Has transforming growth factor beta-activated receptor activity.
Homodimer. Heterohexamer; TGFB1, TGFB2 and TGFB3 homodimeric ligands assemble a functional receptor composed of two TGFBR1 and TGFBR2 heterodimers to form a ligand-receptor heterohexamer. The respective affinity of TGFRB1 and TGFRB2 for the ligands may modulate the kinetics of assembly of the receptor and may explain the different biological activities of TGFB1, TGFB2 and TGFB3. Component of a complex composed of TSC22D1 (via N-terminus), TGFBR1 and TGFBR2; the interaction between TSC22D1 and TGFBR1 is inhibited by SMAD7 and promoted by TGFB1 (PubMed:21791611). Interacts with DAXX. Interacts with DYNLT4. Interacts with ZFYVE9; ZFYVE9 recruits SMAD2 and SMAD3 to the TGF-beta receptor. Interacts with and is activated by SCUBE3; this interaction does not affect TGFB1-binding to TGFBR2. Interacts with VPS39; this interaction is independent of the receptor kinase activity and of the presence of TGF-beta. Interacts with CLU (PubMed:8555189).
Phosphorylated on a Ser/Thr residue in the cytoplasmic domain.
The disease is caused by variants affecting the gene represented in this entry. TGFBR2 mutations Cys-460 and His-460 have been reported to be associated with thoracic aortic aneurysms and dissection (TAAD). This phenotype, also known as thoracic aortic aneurysms type 3 (AAT3), is distinguised from LDS2 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit descending aortic disease and aneurysms of other arteries (PubMed:16027248), they have been considered as LDS2 by the OMIM resource.
Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFRB1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways.
Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and thus regulates a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways.
Mitochondrial S-adenosyl-L-methionine/S-adenosyl-L-homocysteine antiporter. Mediates the exchange of cytosolic S-adenosyl-L-methionine, the predominant methyl-group donor for macromolecule methylation processes, for mitochondrial S-adenosylhomocysteine(SAH), a by-product of methylation reactions.
Strongly inhibited by tannic acid and Bromocresol Purple.
Widely expressed. Highly expressed in testis, with moderate expression in brain, heart, kidney, lung, skeletal muscle, pancreas, small intestine and liver, and low expression in spleen.
Component of the Golgi to ER traffic (GET) complex, which is composed of GET1/WRB, CAMLG/GET2 and GET3/TRC40 (PubMed:21444755, PubMed:23041287, PubMed:24392163, PubMed:32910895). Within the complex, GET1 and CAMLG form a heterotetramer which is stabilized by phosphatidylinositol binding and which binds to the GET3 homodimer (PubMed:32910895). Interacts with CAMLG (via C-terminus) (PubMed:23041287, PubMed:31417168, PubMed:32187542). GET3 shows a higher affinity for CAMLG than for GET1 (PubMed:24392163).
Required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (ER) (PubMed:21444755, PubMed:23041287, PubMed:24392163, PubMed:27226539). Together with CAMLG/GET2, acts as a membrane receptor for soluble GET3/TRC40, which recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol (PubMed:21444755, PubMed:23041287, PubMed:24392163, PubMed:27226539). Required to ensure correct topology and ER insertion of CAMLG (PubMed:31417168, PubMed:32187542).
May play a role in neuropeptide signaling processes. Ligand for LGR7, RXFP3 and RXFP4.
(Microbial infection) Required for intoxication by Pseudomonas aeruginosa exotoxin A and Campylobacter jejuni CDT. May contribute to the retrograde transport of bacterial toxins, including cholera toxin, from the trans-Golgi network to the endoplasmic reticulum.
Cleaved by FURIN to yield two fragments of 17 and 35 kDa that remain associated via a disulfide bond.
Has been proposed to act as a receptor for neuronostatin, a peptide derived from the somatostatin/SST precursor (PubMed:22933024). Involved in blood sugar regulation through the induction of glucagon in response to low glucose (By similarity).
Allele B*07:02: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and mainly a Leu anchor residue at the C-terminus (PubMed:7743181). Presents a long peptide (APRGPHGGAASGL) derived from the cancer-testis antigen CTAG1A/NY-ESO-1, eliciting a polyclonal CD8-positive T cell response against tumor cells (PubMed:29531227). Presents viral epitopes derived from HIV-1 gag-pol (TPQDLNTML) and Nef (RPQVPLRPM) (PubMed:25808313). Presents an immunodominant epitope derived from SARS-CoV-2 N/nucleoprotein (SPRWYFYYL) (PubMed:32887977). Displays self-peptides including a peptide derived from the signal sequence of HLA-DPB1 (APRTVALTA) (PubMed:7743181).
Allele B*08:01: Presents to CD8-positive T cells viral epitopes derived from EBV/HHV-4 EBNA3 (QAKWRLQTL), eliciting cytotoxic T cell response.
Allele B*13:02: Presents multiple HIV-1 epitopes derived from gag (RQANFLGKI, GQMREPRGSDI), nef (RQDILDLWI), gag-pol (RQYDQILIE, GQGQWTYQI) and rev (LQLPPLERL), all having in common a Gln residue at position 2 and mainly hydrophobic amino acids Leu, Ile or Val at the C-terminus. Associated with succesful control of HIV-1 infection.
Allele B*18:01: Preferentially presents octomeric and nonameric peptides sharing a common motif, namely a Glu at position 2 and Phe or Tyr anchor residues at the C-terminus (PubMed:14978097, PubMed:23749632, PubMed:18991276). Presents an EBV/HHV-4 epitope derived from BZLF1 (SELEIKRY) (PubMed:23749632). May present to CD8-positive T cells an antigenic peptide derived from MAGEA3 (MEVDPIGHLY), triggering an anti-tumor immune response (PubMed:12366779). May display a broad repertoire of self-peptides with a preference for peptides derived from RNA-binding proteins (PubMed:14978097).
Allele B*27:05: Presents to CD8-positive T cells immunodominant viral epitopes derived from HCV POLG (ARMILMTHF), HIV-1 gag (KRWIILGLNK), IAV NP (SRYWAIRTR), SARS-CoV-2 N/nucleoprotein (QRNAPRITF), EBV/HHV-4 EBNA4 (HRCQAIRKK) and EBV/HHV-4 EBNA6 (RRIYDLIEL), confering longterm protection against viral infection (PubMed:19139562, PubMed:18385228, PubMed:15113903, PubMed:9620674, PubMed:32887977). Can present self-peptides derived from cytosolic and nuclear proteins. All peptides carry an Arg at position 2 (PubMed:1922338). The peptide-bound form interacts with NK cell inhibitory receptor KIR3DL1 and inhibits NK cell activation in a peptide-specific way, being particularly sensitive to the nature of the amino acid side chain at position 8 of the antigenic peptide (PubMed:8879234, PubMed:15657948). KIR3DL1 fails to recognize HLA-B*27:05 in complex with B2M and EBV/HHV-4 EBNA6 (RRIYDLIEL) peptide, which can lead to increased activation of NK cells during infection (PubMed:15657948). May present an altered repertoire of peptides in the absence of TAP1-TAP2 and TAPBPL (PubMed:9620674).
Allele B*40:01: Presents immunodominant viral epitopes derived from EBV/HHV-4 LMP2 (IEDPPFNSL) and SARS-CoV-2 N/nucleoprotein (MEVTPSGTWL), triggering memory CD8-positive T cell response (PubMed:18991276, PubMed:32887977). Displays self-peptides sharing a signature motif, namely a Glu at position 2 and a Leu anchor residue at the C-terminus (PubMed:18991276).
Allele B*41:01: Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Ala or Pro anchor residues at the C-terminus.
Allele B*44:02: Presents immunodominant viral epitopes derived from EBV/HHV-4 EBNA4 (VEITPYKPTW) and EBNA6 (AEGGVGWRHW, EENLLDFVRF), triggering memory CD8-positive T cell response (PubMed:9620674, PubMed:18991276). Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Phe, Tyr or Trp anchor residues at the C-terminus (PubMed:18991276).
Allele B*45:01: Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Ala or Pro anchor residues at the C-terminus.
Allele B*46:01: Preferentially presents nonameric peptides sharing a signature motif, namely Ala and Leu at position 2 and Tyr, Phe, Leu, or Met anchor residues at the C-terminus. The peptide-bound form interacts with KIR2DL3 and inhibits NK cell cytotoxic response in a peptide-specific way.
Allele B*47:01: Displays self-peptides sharing a signature motif, namely an Asp at position 2 and Leu or Met anchor residues at the C-terminus.
Allele B*49:01: Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Ile or Val anchor residues at the C-terminus.
Allele B*50:01: Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Ala or Pro anchor residues at the C-terminus.
Allele B*51:01: Presents an octomeric HIV-1 epitope derived from gag-pol (TAFTIPSI) to the public TRAV17/TRBV7-3 TCR clonotype, strongly suppressing HIV-1 replication.
Allele B*54:01: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and Ala anchor residue at the C-terminus.
Allele B*55:01: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and Ala anchor residue at the C-terminus.
Allele B*56:01: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and Ala anchor residue at the C-terminus.
Allele B*57:01: The peptide-bound form recognizes KIR3DL1 and inhibits NK cell cytotoxic response. Presents HIV gag peptides (immunodominant KAFSPEVIPMF and subdominant KALGPAATL epitopes) predominantly to CD8-positive T cell clones expressing a TRAV41-containing TCR, triggering HLA-B-restricted T cell responses.
Allele B*67:01: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and Leu anchor residue at the C-terminus.
Allele group B*08 is associated with increased susceptibility to rheumatoid arthritis, where affected individuals have antibodies to cyclic citrullinated peptide (anti-CCP-positive rheumatoid arthritis).
Antigen-presenting major histocompatibility complex class I (MHCI) molecule. In complex with B2M/beta 2 microglobulin displays primarily viral and tumor-derived peptides on antigen-presenting cells for recognition by alpha-beta T cell receptor (TCR) on HLA-B-restricted CD8-positive T cells, guiding antigen-specific T cell immune response to eliminate infected or transformed cells (PubMed:25808313, PubMed:29531227, PubMed:9620674, PubMed:23209413). May also present self-peptides derived from the signal sequence of secreted or membrane proteins, although T cells specific for these peptides are usually inactivated to prevent autoreactivity (PubMed:7743181, PubMed:18991276). Both the peptide and the MHC molecule are recognized by TCR, the peptide is responsible for the fine specificity of antigen recognition and MHC residues account for the MHC restriction of T cells (PubMed:29531227, PubMed:9620674, PubMed:24600035). Typically presents intracellular peptide antigens of 8 to 13 amino acids that arise from cytosolic proteolysis via constitutive proteasome and IFNG-induced immunoproteasome (PubMed:23209413). Can bind different peptides containing allele-specific binding motifs, which are mainly defined by anchor residues at position 2 and 9 (PubMed:25808313, PubMed:29531227).
Disease susceptibility is associated with variants affecting the gene represented in this entry. A restricted number of HLA-B*27 subtypes can be associated with ankylosing spondylitis and other B*27-related diseases, and an elevated frequency of the B*27:02 allele in ankylosing spondylitis patients is identified. The allele B*27:07 seems to have a protective role in some populations because it was found only in the healthy controls.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Increased susceptibility to Stevens-Johnson syndrome is conferred by allele B*15:02.
Heterotrimer that consists of an alpha chain HLA-B, a beta chain B2M and a peptide (peptide-HLA-B-B2M) (PubMed:25808313, PubMed:29531227, PubMed:15657948, PubMed:17057332, PubMed:22020283, PubMed:24600035). Early in biogenesis, HLA-B-B2M dimer interacts with the components of the peptide-loading complex composed of TAPBP, TAP1-TAP2, TAPBPL, PDIA3/ERP57 and CALR (PubMed:9036970, PubMed:9620674, PubMed:26439010, PubMed:26416272). Interacts with TAP1-TAP2 transporter via TAPBP; this interaction is obligatory for the loading of peptide epitopes delivered to the ER by TAP1-TAP2 transporter (PubMed:9036970, PubMed:9620674). Interacts with TAPBPL; TAPBPL binds peptide-free HLA-B-B2M complexes or those loaded with low affinity peptides, likely facilitating peptide exchange for higher affinity peptides (PubMed:26439010). Only optimally assembled peptide-HLA-B-B2M trimer translocates to the surface of antigen-presenting cells, where it interacts with TCR and CD8 coreceptor on the surface of T cells. HLA-B (via polymorphic alpha-1 and alpha-2 domains) interacts with antigen-specific TCR (via CDR1, CDR2 and CDR3 domains) (PubMed:29531227, PubMed:24600035). One HLA-B molecule (mainly via nonpolymorphic alpha-3 domain) interacts with one CD8A homodimer (via CDR-like loop); this interaction ensures peptide-HLA-B-B2M recognition by CD8-positive T cells only (PubMed:29531227). Allele B*57:01 interacts (via Bw4 motif) with KIR3DL1 (via Ig-like C2-type domain); this interaction may interfere with peptide binding (PubMed:22020283, PubMed:25480565). Allele B*46:01 interacts with KIR2DL3 (PubMed:28514659).
The VL9 peptide/epitope (VMAPRT[V/L][L/V/I/F]L) derived from the signal sequence is loaded onto HLA-E and enables HLA-E expression at the plasma membrane. Distinct VL9 peptides presented by HLA-E variably affect its recognition by KLRD1-KLRC1 or KLRD1-KLRC2 receptors on NK cells. Most HLA-B allotypes contain VL9 peptides with low affinity for HLA-E. The VL9 peptide derived from HLA-B*07, B*08, B*14, B*38, B*39, B*42 and B*48 allotypes, displays high affinity for HLA-E yet fails to drive NK cell activation. It outcompetes other VL9 peptides derived from HLA-A and HLA-C for binding to HLA-E, lowering the threshold of NK cell activation.
The alpha-1 domain is a structural part of the peptide-binding cleft (PubMed:25808313). Residues 101-107 determine Bw4/Bw6 motifs, which serologically distinguish HLA-B alleles. Each HLA-B allele posseses either the Bw4 or Bw6 motif. Only HLA-B alleles bearing the Bw4 epitope are recognized by NK cell inhibitory receptor KIR3DL1 (PubMed:25480565, PubMed:22020283).
The alpha-2 domain is a structural part of the peptide-binding cleft (PubMed:25808313). Mediates the interaction with TAP1-TAP2 complex (By similarity).
The alpha-3 Ig-like domain mediates the interaction with CD8 coreceptor.
The most polymorphic of the mammalian genome. Polymorphic residues encode for alpha-1 and alpha-2 domains of the peptide-binding cleft, where they contribute to variations in peptide binding and TCR recognition among different alleles. The human population is estimated to have millions of HLA-B alleles. But only 17 common HLA-A alleles are considered core alleles, representing all functionally significant variation (polymorphism) in alpha-1 and alpha-2 domains. These are: B*07:02; B*08:01; B*13:02; B*15:01; B*18:01; B*27:05; B*35:01; B*37:01; B*38:01; B*40:01; B*44:02; B*45:01; B*51:01; B*54:01; B*57:01 and B*73:01. Among these, B*07:02; B*15:01; B*18:01; B*37:01; B*51:01; B*54:01; B*57:01 and B*73:01, were likely passed by introgression from archaic to modern humans. Functional alleles of more recent origin (non-core) were derived by recombination (PubMed:28650991). The sequence shown is that of B*07:02. The sequences of core alleles and common representative alleles of serologically distinct allele groups are described as variants of B*07:02. Allelic variations of HLA-B signal peptide regulate HLA-E recognition by KLRD1-KLRC1 and KLRD1-KLRC2 receptors in viral infection and tumorigenesis by affecting its processing and by changing the affinity of HLA-E-VL9 complex for KLRD1-KLRC1 and KLRD1-KLRC2 receptors.
The presence of allele B*57:01 is associated with increased susceptibility to abacavir hypersensitivity [MIM:142830] in HIV-1 patients.
There is evidence that HLA-B*51 is associated with susceptibility to Behcet disease (BD). However, it is not certain whether HLA-B*51 itself or a closely linked gene is responsible for susceptibility. The world distribution of HLA-B*51 in healthy people corresponds to the global distribution of BD; in Southern hemisphere countries (Africa, South Pacific, etc.) and in some parts of Europe, the prevalence of HLA-B*51 in healthy people is low or null, corresponding to a low prevalence of BD. The wide variation that exists in the relative risk of HLA-B*51 would support other nongenetic risk factors.
Belongs to the glycosyl hydrolase 23 family.
A chromosomal aberration involving RABGAP1L has been found in bone marrow cells from a child with leukemia, acute myelogenous. Translocation der(Y)t(Y;1)(q12;q25). The breakpoint at 1q25 disrupts RABGAP1L.
GTP-hydrolysis activating protein (GAP) for small GTPase RAB22A, converting active RAB22A-GTP to the inactive form RAB22A-GDP (PubMed:16923123). Plays a role in endocytosis and intracellular protein transport. Recruited by ANK2 to phosphatidylinositol 3-phosphate (PI3P)-positive early endosomes, where it inactivates RAB22A, and promotes polarized trafficking to the leading edge of the migrating cells. Part of the ANK2/RABGAP1L complex which is required for the polarized recycling of fibronectin receptor ITGA5 ITGB1 to the plasma membrane that enables continuous directional cell migration (By similarity).
Interacts (via Rab-GAP TBC domain) with ANK2 (via death domain).
Up-regulated in esophageal squamous cell carcinomas. Expression is strongly inhibited in the medial septum and hippocampus brain regions of some Alzheimer disease patients.
AP-3 associates with the BLOC-1 complex (By similarity). Adaptor protein complex 3 (AP-3) is a heterotetramer composed of two large adaptins (delta-type subunit AP3D1 and beta-type subunit AP3B1 or AP3B2), a medium adaptin (mu-type subunit AP3M1 or AP3M2) and a small adaptin (sigma-type subunit APS1 or AP3S2).
May be involved in the calcium-dependent regulation of rhodopsin phosphorylation. Binds three calcium ions.
Retina, cerebrum, cerebellum, brain stem, spinal cord, testis, ovary and small intestine.
Expressed predominantly in brain and heart and at lower levels in various other tissues.
Binds bacterial lipopolysaccharide (LPS) (PubMed:17803912, PubMed:17569869). Cooperates with TLR4 in the innate immune response to bacterial lipopolysaccharide (LPS), and with TLR2 in the response to cell wall components from Gram-positive and Gram-negative bacteria (PubMed:11160242, PubMed:11593030). Enhances TLR4-dependent activation of NF-kappa-B (PubMed:10359581). Cells expressing both LY96 and TLR4, but not TLR4 alone, respond to LPS (PubMed:10359581).
Heterogeneous homomer formed from homodimers; disulfide-linked (PubMed:11593030, PubMed:12642668). Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4 (PubMed:11274165). Binds to the extracellular domains of TLR2 and TLR4 (PubMed:10359581, PubMed:11593030, PubMed:17803912). Ligand binding induces interaction with TLR4 and oligomerization of the complex.
Binds three calcium ions (via EF-hand 2, 3 and 4).
Stimulates guanylyl cyclase 1 (GC1) and GC2 when free calcium ions concentration is low and inhibits guanylyl cyclases when free calcium ions concentration is elevated. This Ca(2+)-sensitive regulation of guanylyl cyclase (GC) is a key event in recovery of the dark state of rod photoreceptors following light exposure.
(Microbial infection) Acts as a receptor for Dengue virus envelope protein E.
(Microbial infection) Acts as phagocytic receptor for bacteria, fungi and other pathogens.
(Microbial infection) Interacts with Dengue virus.
(Microbial infection) Interacts with Hepatitis B virus envelope protein.
(Microbial infection) May act as a receptor for hepatitis B virus, enabling uptake of the virus in hepatic dendritic cells.
Genetic variations in MRC1 may influence susceptibility or resistance to leprosy in some populations. Particularly, Gly-396 seems to be a risk factor for leprosy when associated with Ala-399 and Phe-407.
Mediates the endocytosis of glycoproteins by macrophages. Binds both sulfated and non-sulfated polysaccharide chains.
The C-type lectin domains, also called carbohydrate-recognition domains or CRDs, 1-3 have at most very weak affinity for carbohydrates. C-type lectin domain 4 shows the highest affinity binding and has multispecificity for a variety of monosaccharides. At least 3 C-type lectin domains (4, 5, and 7) are required for high affinity binding and endocytosis of multivalent glycoconjugates.
Belongs to the ABC transporter superfamily.
May mediate the cholesterol and gangliosides transport from the plasma membrane to intracellular vesicles in an ATP hydrolysis dependent manner, thus playing a role in their internalization by endocytic retrograde transport and may also participate in the endocytosis of synaptic vesicle in cortical neurons.
Significantly expressed in the bone marrow, trachea, testis, thyroid and lung as well as in skin fibroblasts.
Probably functions as a guanine nucleotide exchange factor.
Significantly expressed in brain and modestly in pancreas, brain and testis.
A chromosomal aberration involving MALT1 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(11;18)(q21;q21) with BIRC2. This translocation is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphoma.
Highly expressed in peripheral blood mononuclear cells. Detected at lower levels in bone marrow, thymus and lymph node, and at very low levels in colon and lung.
Homooligomer; forms oligomers which bind to TRAF6 (PubMed:15125833). Forms a complex with CARD14 and MALT1; resulting in the formation of a CBM (CARD14-BCL10-MALT1) complex (PubMed:27113748). Forms a complex with CARD11 and MALT1; resulting in the formation of a CBM (CARD11-BCL10-MALT1) complex (PubMed:28628108, PubMed:24074955). Forms a complex with CARD9 and MALT1; resulting in the formation of a CBM (CARD9-BCL10-MALT1) complex (By similarity).
Protease that enhances BCL10-induced activation: acts via formation of CBM complexes that channel adaptive and innate immune signaling downstream of CARD domain-containing proteins (CARD9, CARD11 and CARD14) to activate NF-kappa-B and MAP kinase p38 pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:11262391, PubMed:18264101, PubMed:24074955). Mediates BCL10 cleavage: MALT1-dependent BCL10 cleavage plays an important role in T-cell antigen receptor-induced integrin adhesion (PubMed:11262391, PubMed:18264101). Involved in the induction of T helper 17 cells (Th17) differentiation (PubMed:11262391, PubMed:18264101). Cleaves RC3H1 and ZC3H12A in response to T-cell receptor (TCR) stimulation which releases their cooperatively repressed targets to promote Th17 cell differentiation (By similarity). Also mediates cleavage of N4BP1 in T-cells following TCR-mediated activation, leading to N4BP1 inactivation (PubMed:31133753). May also have ubiquitin ligase activity: binds to TRAF6, inducing TRAF6 oligomerization and activation of its ligase activity (PubMed:14695475).
Interacts with NDC1, the interaction is required for nuclear pore localization (PubMed:19782045). Interacts with the inactive form aurora kinase AURKA (PubMed:26246606). Interacts with PGRMC2 (PubMed:27754849).
Plays a role in the normal development of the peripheral and central nervous system (PubMed:11062474, PubMed:11159947, PubMed:16022285). Required for the correct localization of aurora kinase AURKA and the microtubule minus end-binding protein NUMA1 as well as a subset of AURKA targets which ensures proper spindle formation and timely chromosome alignment (PubMed:26246606).
Widely expressed (PubMed:11159947, PubMed:16022285). Particularly abundant in cerebellum, corpus callosum, adrenal gland, pituitary gland, gastrointestinal structures and fetal lung (PubMed:11159947).
Expressed in liver, kidney, pancreas, heart and skeletal muscle.
Homodimer (PubMed:10231530, PubMed:10840044, PubMed:16725361). Interacts with GLUD1; this interaction inhibits the activation of glutamate dehydrogenase 1 (GLUD1) (By similarity).
Mitochondrial fatty acid beta-oxidation enzyme that catalyzes the third step of the beta-oxidation cycle for medium and short-chain 3-hydroxy fatty acyl-CoAs (C4 to C10) (PubMed:10231530, PubMed:11489939, PubMed:16725361). Plays a role in the control of insulin secretion by inhibiting the activation of glutamate dehydrogenase 1 (GLUD1), an enzyme that has an important role in regulating amino acid-induced insulin secretion (By similarity).
Succinylation at Lys-81, adjacent to a coenzyme A binding site. Desuccinylated by SIRT5.
Ancillary protein that assembles as a beta subunit with a voltage-gated potassium channel complex of pore-forming alpha subunits. Modulates the gating kinetics and enhances stability of the channel complex. May associate with KCNQ1/KVLTQ1 and inhibit potassium current.
Interacts with KCNQ1; impairs KCNQ1 localization in lipid rafts and inhibits voltage-gated potassium channel activity.
Predominantly expressed in embryo and adult uterus. Low expression found in kidney, small intestine, lung and heart.
An alternative product iASPP(RAI) has been described (PubMed:15489900, PubMed:10336463). However, it is not detected in vivo and is most probably a cloning artifact (PubMed:15489900).
Highly expressed in heart, placenta and prostate. Weakly expressed in brain, liver, skeletal muscle, testis and peripheral blood leukocyte.
Interacts with RELA NF-kappa-B subunit and with SP1 via its C-terminus part. Interacts (via SH3 domain and ANK repeats) with p53/TP53; the interaction inhibits pro-apoptotic activity of p53/TP53 (PubMed:12524540). Interacts with TP63 and TP73.
Regulator that plays a central role in regulation of apoptosis and transcription via its interaction with NF-kappa-B and p53/TP53 proteins. Blocks transcription of HIV-1 virus by inhibiting the action of both NF-kappa-B and SP1. Also inhibits p53/TP53 function, possibly by preventing the association between p53/TP53 and ASPP1 or ASPP2, and therefore suppressing the subsequent activation of apoptosis (PubMed:12524540).
The ANK repeats and the SH3 domain are required for specific interactions with p53/TP53.
The N-terminal region is required for cytoplasmic localization.
Expressed in airway epithelial cells (at protein level) (PubMed:29391451). Found in skin and kidney. Detected in prostate basal cells (at protein level). Expression is increased in benign prostate hyperplasia and tumor tissues (at protein level).
The ATPase activity is regulated by monovalent cations and pH. Up-regulated by K(+) ions in a dose-dependent way. Down-regulated by Na(+) ions (PubMed:11341842). Inhibited by Na(+)/K(+)-ATPase inhibitor ouabain and H(+)/K(+)-ATPase inhibitor SCH-28080 with an intermediate sensitivity to completely resistant Na(+)/K(+)-ATPases and highly sensitive H(+)/K(+)-ATPases (PubMed:7485470, PubMed:8853415, PubMed:11341842).
The ATPase pump is composed of a catalytic alpha subunit and an auxiliary non-catalytic beta subunit. The alpha subunit pairs with the beta subunit of gastric H(+)/K(+) ATPase ATP4B or the beta subunit of Na(+)/K(+) ATPases ATP1B1 and ATP1B3; this interaction is required for the formation of a functionally active pump and its targeting at the plasma membrane.
The catalytic subunit of a H(+)/K(+) ATPase and/or Na(+)/K(+) ATPase pump which transports K(+) ions in exchange for Na(+) and/or H(+) ions across the apical membrane of epithelial cells. Uses ATP as an energy source to pump K(+) ions into the cell while transporting Na(+) and/or H(+) ions to the extracellular compartment (PubMed:9774385, PubMed:7485470, PubMed:8853415, PubMed:11341842). Involved in the maintenance of electrolyte homeostasis through K(+) ion absorption in kidney and colon (By similarity). In the airway epithelium, may play a primary role in mucus acidification regulating its viscosity and clearance (PubMed:29391451).
Up-regulated by inflammatory cytokine IL13.
Belongs to the iron-containing alcohol dehydrogenase family. Hydroxyacid-oxoacid transhydrogenase subfamily.
Catalyzes the cofactor-independent reversible oxidation of gamma-hydroxybutyrate (GHB) to succinic semialdehyde (SSA) coupled to reduction of 2-ketoglutarate (2-KG) to D-2-hydroxyglutarate (D-2-HG). D,L-3-hydroxyisobutyrate and L-3-hydroxybutyrate (L-3-OHB) are also substrates for HOT with 10-fold lower activities.
Belongs to the phosphoglycerate mutase family. BPG-dependent PGAM subfamily.
Both isoform 1 and isoform 2 are phosphorylated by the RIPK1/RIPK3 complex under necrotic conditions. This phosphorylation increases PGAM5 phosphatase activity.
Dimer. Forms a ternary complex with NFE2L2 and KEAP1. Interacts with BCL2L1 and MAP3K5. Upon TNF-induced necrosis, forms in complex with RIPK1, RIPK3 and MLKL; the formation of this complex leads to PGAM5 phosphorylation. Isoform 2, but not isoform 1, interacts with DNM1L; this interaction leads to DNM1L dephosphorylation and activation and eventually to mitochondria fragmentation.
Displays phosphatase activity for serine/threonine residues, and, dephosphorylates and activates MAP3K5 kinase. Has apparently no phosphoglycerate mutase activity. May be regulator of mitochondrial dynamics. Substrate for a KEAP1-dependent ubiquitin ligase complex. Contributes to the repression of NFE2L2-dependent gene expression. Acts as a central mediator for programmed necrosis induced by TNF, by reactive oxygen species and by calcium ionophore.
Proteolytically cleaved by PARL in response to loss of mitochondrial membrane potential.
The N-terminal 35 amino acids, including the potential transmembrane alpha-helix, function as a non-cleaved mitochondrial targeting sequence that targets the protein to the cytosolic side of the outer mitochondrial membrane.
Variable expression in multiple hemopoietic cell lines.
(Microbial infection) In case of HIV-1 infection, interacts with and deacetylates the viral Tat protein. The viral Tat protein inhibits SIRT1 deacetylation activity toward RELA/NF-kappa-B p65, thereby potentiates its transcriptional activity and SIRT1 is proposed to contribute to T-cell hyperactivation during infection.
Acetylated at various Lys residues. Deacetylated via an autocatalytic mechanism. Autodeacetylation at Lys-238 promotes its protein deacetylase activity.
Calf histone H1 is used as substrate in the in vitro deacetylation assay (PubMed:15469825). As, in vivo, interaction occurs between SIRT1 with H1-4, deacetylation has been validated only for H1-4.
Catalytically inactive 75SirT1 may be involved in regulation of apoptosis. May be involved in protecting chondrocytes from apoptotic death by associating with cytochrome C and interfering with apoptosome assembly.
Deacetylates 'Lys-382' of p53/TP53, however with lower activity than isoform 1. In combination, the two isoforms exert an additive effect. Isoform 2 regulates p53/TP53 expression and cellular stress response and is in turn repressed by p53/TP53 presenting a SIRT1 isoform-dependent auto-regulatory loop.
Inhibited by nicotinamide. Activated by resveratrol (3,5,4'-trihydroxy-trans-stilbene), butein (3,4,2',4'-tetrahydroxychalcone), piceatannol (3,5,3',4'-tetrahydroxy-trans-stilbene), Isoliquiritigenin (4,2',4'-trihydroxychalcone), fisetin (3,7,3',4'-tetrahydroxyflavone) and quercetin (3,5,7,3',4'-pentahydroxyflavone). MAPK8/JNK1 and RPS19BP1/AROS act as positive regulators of deacetylation activity. Negatively regulated by CCAR2.
Interacts with XBP1 isoform 2 (PubMed:20955178). Found in a complex with PCAF and MYOD1. Interacts with FOXO1; the interaction deacetylates FOXO1, resulting in its nuclear retention and promotion of its transcriptional activity Component of the eNoSC complex, composed of SIRT1, SUV39H1 and RRP8. Interacts with HES1, HEY2 and PML. Interacts with RPS19BP1/AROS. Interacts with CCAR2 (via N-terminus); the interaction disrupts the interaction between SIRT1 and p53/TP53. Interacts with SETD7; the interaction induces the dissociation of SIRT1 from p53/TP53 and increases p53/TP53 activity. Interacts with MYCN, NR1I2, CREBZF, TSC2, TLE1, FOS, JUN, NR0B2, PPARG, NCOR, IRS1, IRS2 and NMNAT1. Interacts with HNF1A; the interaction occurs under nutrient restriction. Interacts with SUZ12; the interaction mediates the association with the PRC4 histone methylation complex which is specific as an association with PCR2 and PCR3 complex variants is not found. Interacts with BCL6; leads to a epigenetic repression of specific target genes. Interacts with CLOCK, BMAL1 and PER2 (By similarity). Interacts with PPARA; the interaction seems to be modulated by NAD(+) levels (PubMed:24043310). Interacts with NR1H3 and this interaction is inhibited in the presence of CCAR2. Interacts with CHEK2. Interacts with p53/TP53. Exhibits a preferential interaction with sumoylated CCAR2 over its unmodified form. Interacts with PACS2 (PubMed:29656858). Interacts with SIRT7 (By similarity). Interacts with PUS7 (PubMed:31451225). Interacts with TULP3 (PubMed:35397207). Interacts with MORN3; the interaction enhances the ubiquitination of p53/TP53 (PubMed:29681526).
Methylated on multiple lysine residues; methylation is enhanced after DNA damage and is dispensable for deacetylase activity toward p53/TP53.
NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metabolism, apoptosis and autophagy (PubMed:11672523, PubMed:12006491, PubMed:14976264, PubMed:14980222, PubMed:15126506, PubMed:15152190, PubMed:15205477, PubMed:15469825, PubMed:15692560, PubMed:16079181, PubMed:16166628, PubMed:16892051, PubMed:16998810, PubMed:17283066, PubMed:17290224, PubMed:17334224, PubMed:17505061, PubMed:17612497, PubMed:17620057, PubMed:17936707, PubMed:18203716, PubMed:18296641, PubMed:18662546, PubMed:18687677, PubMed:19188449, PubMed:19220062, PubMed:19364925, PubMed:19690166, PubMed:19934257, PubMed:20097625, PubMed:20100829, PubMed:20203304, PubMed:20375098, PubMed:20620956, PubMed:20670893, PubMed:20817729, PubMed:20955178, PubMed:21149730, PubMed:21245319, PubMed:21471201, PubMed:21504832, PubMed:21555002, PubMed:21698133, PubMed:21701047, PubMed:21775285, PubMed:21807113, PubMed:21841822, PubMed:21890893, PubMed:21947282, PubMed:22274616, PubMed:24415752, PubMed:24824780, PubMed:29765047, PubMed:30409912, PubMed:29681526). Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression (PubMed:15469825). Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively (PubMed:15152190, PubMed:14980222, PubMed:14976264). Serves as a sensor of the cytosolic ratio of NAD(+)/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction (PubMed:15205477). Is essential in skeletal muscle cell differentiation and in response to low nutrients mediates the inhibitory effect on skeletal myoblast differentiation which also involves 5'-AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT) (By similarity). Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes (PubMed:18485871). The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus (PubMed:18485871, PubMed:21504832). Deacetylates 'Lys-266' of SUV39H1, leading to its activation (PubMed:21504832). Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1 (PubMed:19188449). Deacetylates H2A and 'Lys-26' of H1-4 (PubMed:15469825). Deacetylates 'Lys-16' of histone H4 (in vitro). Involved in NR0B2/SHP corepression function through chromatin remodeling: Recruited to LRH1 target gene promoters by NR0B2/SHP thereby stimulating histone H3 and H4 deacetylation leading to transcriptional repression (PubMed:20375098). Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting (By similarity). Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1 (PubMed:15469825, PubMed:18004385). Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2 (PubMed:18004385, PubMed:21504832). This increase in SUV39H1 levels enhances SUV39H1 turnover in CH, which in turn seems to accelerate renewal of the heterochromatin which correlates with greater genomic integrity during stress response (PubMed:18004385, PubMed:21504832). Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence (PubMed:11672523, PubMed:12006491). Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I (By similarity). Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability (PubMed:19364925, PubMed:21807113). Deacetylates FOXO3 in response to oxidative stress thereby increasing its ability to induce cell cycle arrest and resistance to oxidative stress but inhibiting FOXO3-mediated induction of apoptosis transcriptional activity; also leading to FOXO3 ubiquitination and protesomal degradation (PubMed:14980222, PubMed:14976264, PubMed:21841822). Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis (PubMed:15126506). Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor activity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing (PubMed:21947282). Deacetylates RELA/NF-kappa-B p65 thereby inhibiting its transactivating potential and augments apoptosis in response to TNF-alpha (PubMed:15152190). Deacetylates HIF1A, KAT5/TIP60, RB1 and HIC1 (PubMed:17620057, PubMed:17283066, PubMed:20100829, PubMed:20620956). Deacetylates FOXO1 resulting in its nuclear retention and enhancement of its transcriptional activity leading to increased gluconeogenesis in liver (PubMed:15692560). Inhibits E2F1 transcriptional activity and apoptotic function, possibly by deacetylation (PubMed:16892051). Involved in HES1- and HEY2-mediated transcriptional repression (PubMed:12535671). In cooperation with MYCN seems to be involved in transcriptional repression of DUSP6/MAPK3 leading to MYCN stabilization by phosphorylation at 'Ser-62' (PubMed:21698133). Deacetylates MEF2D (PubMed:16166628). Required for antagonist-mediated transcription suppression of AR-dependent genes which may be linked to local deacetylation of histone H3 (PubMed:17505061). Represses HNF1A-mediated transcription (By similarity). Required for the repression of ESRRG by CREBZF (PubMed:19690166). Deacetylates NR1H3 and NR1H2 and deacetylation of NR1H3 at 'Lys-434' positively regulates transcription of NR1H3:RXR target genes, promotes NR1H3 proteasomal degradation and results in cholesterol efflux; a promoter clearing mechanism after reach round of transcription is proposed (PubMed:17936707). Involved in lipid metabolism: deacetylates LPIN1, thereby inhibiting diacylglycerol synthesis (PubMed:20817729, PubMed:29765047). Implicated in regulation of adipogenesis and fat mobilization in white adipocytes by repression of PPARG which probably involves association with NCOR1 and SMRT/NCOR2 (By similarity). Deacetylates p300/EP300 and PRMT1 (By similarity). Deacetylates ACSS2 leading to its activation, and HMGCS1 deacetylation (PubMed:21701047). Involved in liver and muscle metabolism. Through deacetylation and activation of PPARGC1A is required to activate fatty acid oxidation in skeletal muscle under low-glucose conditions and is involved in glucose homeostasis (PubMed:23142079). Involved in regulation of PPARA and fatty acid beta-oxidation in liver. Involved in positive regulation of insulin secretion in pancreatic beta cells in response to glucose; the function seems to imply transcriptional repression of UCP2. Proposed to deacetylate IRS2 thereby facilitating its insulin-induced tyrosine phosphorylation. Deacetylates SREBF1 isoform SREBP-1C thereby decreasing its stability and transactivation in lipogenic gene expression (PubMed:17290224, PubMed:20817729). Involved in DNA damage response by repressing genes which are involved in DNA repair, such as XPC and TP73, deacetylating XRCC6/Ku70, and facilitating recruitment of additional factors to sites of damaged DNA, such as SIRT1-deacetylated NBN can recruit ATM to initiate DNA repair and SIRT1-deacetylated XPA interacts with RPA2 (PubMed:15205477, PubMed:17334224, PubMed:16998810, PubMed:17612497, PubMed:20670893, PubMed:21149730). Also involved in DNA repair of DNA double-strand breaks by homologous recombination and specifically single-strand annealing independently of XRCC6/Ku70 and NBN (PubMed:15205477, PubMed:17334224, PubMed:20097625). Promotes DNA double-strand breaks by mediating deacetylation of SIRT6 (PubMed:32538779). Transcriptional suppression of XPC probably involves an E2F4:RBL2 suppressor complex and protein kinase B (AKT) signaling. Transcriptional suppression of TP73 probably involves E2F4 and PCAF. Deacetylates WRN thereby regulating its helicase and exonuclease activities and regulates WRN nuclear translocation in response to DNA damage (PubMed:18203716). Deacetylates APEX1 at 'Lys-6' and 'Lys-7' and stimulates cellular AP endonuclease activity by promoting the association of APEX1 to XRCC1 (PubMed:19934257). Catalyzes deacetylation of ERCC4/XPF, thereby impairing interaction with ERCC1 and nucleotide excision repair (NER) (PubMed:32034146). Increases p53/TP53-mediated transcription-independent apoptosis by blocking nuclear translocation of cytoplasmic p53/TP53 and probably redirecting it to mitochondria. Deacetylates XRCC6/Ku70 at 'Lys-539' and 'Lys-542' causing it to sequester BAX away from mitochondria thereby inhibiting stress-induced apoptosis. Is involved in autophagy, presumably by deacetylating ATG5, ATG7 and MAP1LC3B/ATG8 (PubMed:18296641). Deacetylates AKT1 which leads to enhanced binding of AKT1 and PDK1 to PIP3 and promotes their activation (PubMed:21775285). Proposed to play role in regulation of STK11/LBK1-dependent AMPK signaling pathways implicated in cellular senescence which seems to involve the regulation of the acetylation status of STK11/LBK1. Can deacetylate STK11/LBK1 and thereby increase its activity, cytoplasmic localization and association with STRAD; however, the relevance of such activity in normal cells is unclear (PubMed:18687677, PubMed:20203304). In endothelial cells is shown to inhibit STK11/LBK1 activity and to promote its degradation. Deacetylates SMAD7 at 'Lys-64' and 'Lys-70' thereby promoting its degradation. Deacetylates CIITA and augments its MHC class II transactivation and contributes to its stability (PubMed:21890893). Deacetylates MECOM/EVI1 (PubMed:21555002). Deacetylates PML at 'Lys-487' and this deacetylation promotes PML control of PER2 nuclear localization (PubMed:22274616). During the neurogenic transition, represses selective NOTCH1-target genes through histone deacetylation in a BCL6-dependent manner and leading to neuronal differentiation. Regulates the circadian expression of several core clock genes, including BMAL1, RORC, PER2 and CRY1 and plays a critical role in maintaining a controlled rhythmicity in histone acetylation, thereby contributing to circadian chromatin remodeling (PubMed:18662546). Deacetylates BMAL1 and histones at the circadian gene promoters in order to facilitate repression by inhibitory components of the circadian oscillator (By similarity). Deacetylates PER2, facilitating its ubiquitination and degradation by the proteasome (By similarity). Protects cardiomyocytes against palmitate-induced apoptosis (By similarity). Deacetylates XBP1 isoform 2; deacetylation decreases protein stability of XBP1 isoform 2 and inhibits its transcriptional activity (PubMed:20955178). Deacetylates PCK1 and directs its activity toward phosphoenolpyruvate production promoting gluconeogenesis (PubMed:30193097). Involved in the CCAR2-mediated regulation of PCK1 and NR1D1 (PubMed:24415752). Deacetylates CTNB1 at 'Lys-49' (PubMed:24824780). In POMC (pro-opiomelanocortin) neurons, required for leptin-induced activation of PI3K signaling (By similarity). In addition to protein deacetylase activity, also acts as protein-lysine deacylase by mediating protein depropionylation and decrotonylation (PubMed:28497810). Mediates depropionylation of Osterix (SP7) (By similarity). Catalyzes decrotonylation of histones; it however does not represent a major histone decrotonylase (PubMed:28497810). Deacetylates SOX9; promoting SOX9 nuclear localization and transactivation activity (By similarity). Involved in the regulation of centrosome duplication. Deacetylates CENATAC in G1 phase, allowing for SASS6 accumulation on the centrosome and subsequent procentriole assembly (PubMed:31722219). Deacetylates NDC80/HEC1 (PubMed:30409912).
Phosphorylated. Phosphorylated by STK4/MST1, resulting in inhibition of SIRT1-mediated p53/TP53 deacetylation. Phosphorylation by MAPK8/JNK1 at Ser-27, Ser-47, and Thr-530 leads to increased nuclear localization and enzymatic activity. Phosphorylation at Thr-530 by DYRK1A and DYRK3 activates deacetylase activity and promotes cell survival. Phosphorylation by mammalian target of rapamycin complex 1 (mTORC1) at Ser-47 inhibits deacetylation activity. Phosphorylated by CaMK2, leading to increased p53/TP53 and NF-kappa-B p65/RELA deacetylation activity (By similarity). Phosphorylation at Ser-27 implicating MAPK9 is linked to protein stability. There is some ambiguity for some phosphosites: Ser-159/Ser-162 and Thr-544/Ser-545.
Proteolytically cleaved by cathepsin B upon TNF-alpha treatment to yield catalytic inactive but stable SirtT1 75 kDa fragment (75SirT1).
Red wine, which contains resveratrol, may participate in activation of sirtuin proteins, and may therefore participate in an extended lifespan as it has been observed in yeast.
S-nitrosylated by GAPDH, leading to inhibit the NAD-dependent protein deacetylase activity.
The reported ADP-ribosyltransferase activity of sirtuins is likely some inefficient side reaction of the deacetylase activity and may not be physiologically relevant.
Up-regulated by methyl methanesulfonate (MMS). In H293T cells by presence of rat calorie restriction (CR) serum.
Interacts with SELPLG (PubMed:18196517). Interaction with SELPLG is controversial.
May play a role in cellular vesicle trafficking. Has been proposed to function as a sorting protein that targets SELPLG into endosomes, but has no effect on SELPLG internalization from the cell surface, or on SELPLG-mediated cell-cell adhesion.
The PX domain binds phosphatidylinositol 3-phosphate which is necessary for localization to the endosomes.
May be involved in retinal laminar formation. Promotes epithelial to mesenchymal transition.
Present in most secretory epithelia (at protein level).
Up-regulation and/or mislocalization in breast cancer and liver carcinoma cells is strongly correlated with metastasis formation and survival.
(Microbial infection) Cleaved by Seneca Valley virus protease 3C allowing the virus to suppress interferon type-I through both RIG-I and Toll-like receptor-dependent pathways.
(Microbial infection) Cleaved by encephalomyocarditis virus (EMCV) protease 3C (PubMed:26363073). This cleavage allows the virus to disrupt the TANK-TBK1-IKKepsilon-IRF3 complex, thereby inhibiting the induction of the IFN-beta signal pathway (PubMed:28487378).
(Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction allows the cleavage of TANK and subsequent suppression of host innate immunity.
Adapter protein involved in I-kappa-B-kinase (IKK) regulation which constitutively binds TBK1 and IKBKE playing a role in antiviral innate immunity. Acts as a regulator of TRAF function by maintaining them in a latent state. Blocks TRAF2 binding to LMP1 and inhibits LMP1-mediated NF-kappa-B activation. Negatively regulates NF-kappaB signaling and cell survival upon DNA damage (PubMed:25861989). Plays a role as an adapter to assemble ZC3H12A, USP10 in a deubiquitination complex which plays a negative feedback response to attenuate NF-kappaB activation through the deubiquitination of IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage (PubMed:25861989). Promotes UBP10-induced deubiquitination of TRAF6 in response to DNA damage (PubMed:25861989). May control negatively TRAF2-mediated NF-kappa-B activation signaled by CD40, TNFR1 and TNFR2.
Homodimer. Found in a deubiquitination complex with TANK, USP10 and ZC3H12A; this complex inhibits genotoxic stress- or interleukin-1-beta-mediated NF-kappaB activation by promoting IKBKG or TRAF6 deubiquitination (PubMed:25861989). Interacts with IKBKG; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with TRAF6; this interaction increases in response to DNA damage and recruits USP10 to the ubiquitinated TRAF6 (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with TBK1 (PubMed:10581243, PubMed:21931631, PubMed:29251827). Interacts with IKBKE (PubMed:17568778). Interacts also with TRAF1, TRAF2, and TRAF3 by binding to their TRAF-C domains; the interaction with TRAF2 is disrupted by the phosphorylation of TANK by IKBKE (PubMed:10759890, PubMed:12005438). Interacts more strongly with TRAF1 and TRAF2 than TRAF3 (PubMed:10759890, PubMed:12005438). Interacts with IKBKG; the interaction is enhanced by IKBKE and TBK1 (PubMed:12133833). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833).
It is uncertain whether Met-1 or Met-87 is the initiator methionine.
Detected in skin epidermis, eccrine sweat glands and ducts, mucous cells in the submandibular salivary gland, mucous cells in the throat, ciliary body epithelial cells of the eye, small intestine, colon, stomach and in mature epithelial cells of the tongue (at protein level). High expression in skin and esophagus. Expressed also to a much lesser extent in the tonsils and thymus.
Homodimer; disulfide-linked. Heterodimer with PGLYRP3; disulfide-linked.
Highly expressed in thymocytes and peripheral blood lymphocytes. Also expressed in spleen cells and testis. Present in T-cells (at protein level).
Homodimer (PubMed:9195899). Interacts with FYN (PubMed:9195899). Interacts with PTPRC (PubMed:11909961). Interacts with GRB2 when phosphorylated on Tyr-271 (PubMed:12171928). Interacts with FYB1, which is required for SKAP2 protein stability (PubMed:9748251, PubMed:9671755, PubMed:10856234, PubMed:15849195, PubMed:16461356, PubMed:27335501). Part of a complex consisting of SKAP1, FYB1 and CLNK (By similarity). Interacts with RASGRP1 (PubMed:17658605). Interacts with FYB2 (PubMed:27335501).
Phosphorylated on tyrosines. Phosphorylation by FYN on Tyr-271 is required for GRB2 interaction. Phosphorylation by FYN on Tyr-295 abolishes interaction with FYB1. Tyr-232 is dephosphorylated by PTPRC (Probable).
Positively regulates T-cell receptor signaling by enhancing the MAP kinase pathway. Required for optimal conjugation between T-cells and antigen-presenting cells by promoting the clustering of integrin ITGAL on the surface of T-cells. May be involved in high affinity immunoglobulin epsilon receptor signaling in mast cells.
Antibodies against PNMA1 are present in sera from patients suffering of paraneoplastic neurological disorders.
Testis- and brain-specific. In some cancer patients, specifically expressed by paraneoplastic tumor cells.
Component of the HAUS augmin-like complex. The complex interacts with the gamma-tubulin ring complex and this interaction is required for spindle assembly. Associates with microtubules. The interaction with microtubules is strong during mitosis, while it is weak or absent during interphase. It is unclear whether this interaction is direct or indirect. Interacts with EML3 (phosphorylated at 'Thr-881') (PubMed:30723163).
HAUS1-depleted cells retain functional cell cycle checkpoints, but the depletion decreases the G2/M cell cycle compartment and induces apoptosis. The protein level remains constant through the cell cycle.
Widely expressed. Expressed in pancreas, kidney, skeletal muscle, liver and heart. Weakly expressed in lung, brain and placenta.
Binds to actin and affects the structure of the cytoskeleton. At high concentrations, profilin prevents the polymerization of actin, whereas it enhances it at low concentrations. By binding to PIP2, it inhibits the formation of IP3 and DG.
Highly expressed in brain, skeletal muscle and kidney and less strongly in heart, placenta, lung and liver.
Interacts with ACTMAP (via N-terminus); the interaction may facilitate efficient cleavage of the acetylated N-terminus of immature actin by ACTMAP.
Occurs in many kinds of cells as a complex with monomeric actin in a 1:1 ratio (PubMed:7758455). Interacts with PFN2 (By similarity).
Actin-binding protein involved in actin cytoskeleton regulation and dynamics. Increases the number and size of actin stress fibers and inhibits membrane ruffling. Inhibits actin filament depolymerization. Bundles actin filaments, delays filament nucleation and reduces formation of branched filaments (PubMed:12566430). Plays a role in cholesterol homeostasis. Influences plasma cholesterol levels through regulation of intestinal cholesterol absorption. May act as a scaffold protein by regulating NPC1L1 transportation, an essential protein for cholesterol absorption, to the plasma membrane by recruiting MYO5B to NPC1L1, and thus facilitates cholesterol uptake (By similarity).
Contains at least 2 actin-binding domains, one on each side of the LIM domain. Both domains bind actin monomers and filaments. The C-terminal domain binds filaments more efficiently than the N-terminus.
Down-regulated in some cancer cell lines. Isoform Alpha is induced by serum. Isoform Beta is constitutively expressed.
Genetic variations in LIMA1 influence low density lipoprotein cholesterol (LDL-C) variability and contribute to the low density lipoprotein cholesterol level quantitative trait locus 8 (LDLCQ8) [MIM:618079].
Highly expressed in placenta, kidney, pancreas, prostate, ovary, spleen and heart. Also detected in lung, liver, brain, skeletal muscle, thymus, testis and intestine. Not detected in leukocytes. Isoform Beta expressed generally at very low levels. Isoform Alpha abundant in epithelial cells from mammary gland, prostate and in normal oral keratinocytes. Low levels in aortic endothelial cells and dermal fibroblasts. Not detectable in myocardium.
Interacts with NPCL1; bridges NPC1L1 with MYO5B (PubMed:29880681). Interacts with MYO5B; bridges NPC1L1 with MYO5B (PubMed:29880681). Interacts with PXN; this complex stabilizes actin dynamics (PubMed:24694988). Interacts with F-actin and G-actin (PubMed:12566430).
Phosphorylation of the C-terminal region by MAPK1/MAPK3 reduces its association with F-actin and contributes to actin filament reorganization and enhances cell motility.
Produced by alternative splicing of isoform Beta.
Regulates drug efflux through modulation of ABCB1 localization and activity.
Interacts with PCM1 (PubMed:34782749). Interacts with TTLL1, TPGS1, TPGS2 and LRRC49; the interactions link CSTPP1 to the complex TPGC (PubMed:34782749). Binds to alpha-tubulin (PubMed:34782749).
Regulator of the tubulin polyglutamylase complex (TPGC) that controls cytoskeletal organization, nuclear shape, and cilium disassembly by balancing microtubule and actin assembly (PubMed:34782749). Regulates the assembly and stability of the TPGC and thereby modulates polyglutamylation of the microtubule, which antagonizes MAP4 binding (PubMed:34782749).
Interacts with TRIP4; the interaction with TRIP4 is direct (PubMed:25219498). Interacts (via PCI domain) with UFL1 (PubMed:25219498, PubMed:32160526). Interacts with (unphosphorylated) ERN1/IRE1-alpha; interaction is dependent on UFM1 and takes place in response to endoplasmic reticulum stress, regulating ERN1/IRE1-alpha stability (PubMed:28128204). Interacts with NFKBIA (PubMed:23675531). Interacts with CDK5RAP3 (PubMed:20228063). Interacts with SOX9 (PubMed:28263186).
Substrate adapter for ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to substrate proteins, which plays a key role in reticulophagy (also called ER-phagy) (PubMed:32160526). In response to endoplasmic reticulum stress, promotes recruitment of the E3 UFM1-protein ligase UFL1 to the endoplasmic reticulum membrane: in turn, UFL1 mediates ufmylation of proteins such as RPN1 and RPL26/uL24, promoting reticulophagy of endoplasmic reticulum sheets (PubMed:32160526). Ufmylation-dependent reticulophagy inhibits the unfolded protein response (UPR) by regulating ERN1/IRE1-alpha stability (PubMed:28128204, PubMed:32160526). Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis or inflammatory response (By similarity). Required for TRIP4 ufmylation, thereby regulating nuclear receptors-mediated. transcription (PubMed:25219498). May play a role in NF-kappa-B-mediated transcription through regulation of the phosphorylation and the degradation of NFKBIA, the inhibitor of NF-kappa-B (PubMed:23675531). Plays a role in cartilage development through SOX9, inhibiting the ubiquitin-mediated proteasomal degradation of this transcriptional regulator (PubMed:28263186).
Ubiquitinated. Ubiquitination probably triggers proteasomal degradation and is negatively regulated by UFL1, the enzyme involved in the ufmylation of DDRGK1.
Ufmylated; conjugated to ubiquitin-like protein UFM1, probably at Lys-267 by UFL1 (PubMed:20018847, PubMed:28128204). The relevance of ufmylation is however unclear: as DDRGK1 acts as substrate adapters for ufmylation, it is uncertain whether ufmylation is a collatoral effect of ufmylation process or is required to regulate its activity (PubMed:32160526).
Widely expressed (at protein level). In the brain, highest levels in medulla oblongata, followed by cerebral cortex, cerebellum and frontal lobe.
Binds DNA as a heterodimer with TCFL4/MLX.
Expressed in liver, heart, kidney, cerebellum and intestinal tissues.
Phosphorylation at Ser-556 by AMPK inactivates the DNA-binding activity.
Transcriptional repressor. Binds to the canonical and non-canonical E box sequences 5'-CACGTG-3' (By similarity).
WBSCR14 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of WBSCR14 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.
Activated by 200-1000 micromolar concentrations of calcium and inhibited by calpastatin.
Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Proteolytically cleaves MYOC at 'Arg-226' (PubMed:17650508). Proteolytically cleaves CPEB3 following neuronal stimulation which abolishes CPEB3 translational repressor activity, leading to translation of CPEB3 target mRNAs (By similarity).
Forms a heterodimer with a small (regulatory) subunit (CAPNS1). Interacts with CPEB3; this leads to cleavage of CPEB3.
Expressed very weakly in neurons and not detected in astrocytes, brain or liver.
May catalyze the decarboxylation of L-aspartate, 3-sulfino-L-alanine (cysteine sulfinic acid), and L-cysteate to beta-alanine, hypotaurine and taurine, respectively. Does not exhibit any decarboxylation activity toward glutamate.
Guanine nucleotide exchange factor for ARF6 and ARL14/ARF7. Through ARL14 activation, controls the movement of MHC class II-containing vesicles along the actin cytoskeleton in dendritic cells. Involved in membrane recycling. Interacts with several phosphatidylinositol phosphate species, including phosphatidylinositol 3,4-bisphosphate, phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 4,5-bisphosphate.
Widely expressed. Highest levels of expression are found in placenta, pancreas, spleen, thymus and peripheral blood.
Associates with mature 80S ribosomes (PubMed:23636399, PubMed:36691768, PubMed:32687489). Interacts with EEF2/eEF2; interaction sequesters EEF2/eEF2 at the A-site of the ribosome, thereby blocking the interaction sites of the mRNA-tRNA complex, promoting ribosome stabilization and hibernation (By similarity). Interacts with SPIN1 (By similarity). Interacts with CHD3 and TDRD3 (PubMed:12505151, PubMed:18632687). Interacts with ZDHHC17 (via ANK repeats) (PubMed:28882895).
Expressed at high level in the heart, skeletal muscle and kidney, and at low levels in placenta, liver and brain.
Phosphorylation by MTOR inhibits SERBP1 and relieves ribosome hibernation.
Ribosome-binding protein that promotes ribosome hibernation, a process during which ribosomes are stabilized in an inactive state and preserved from proteasomal degradation (PubMed:36691768). Acts via its association with EEF2/eEF2 factor, sequestering EEF2/eEF2 at the A-site of the ribosome and promoting ribosome stabilization and storage in an inactive state (By similarity). May also play a role in the regulation of mRNA stability: binds to the 3'-most 134 nt of the SERPINE1/PAI1 mRNA, a region which confers cyclic nucleotide regulation of message decay (PubMed:11001948). Seems to play a role in PML-nuclear bodies formation (PubMed:28695742).
Controversial data exist concerning the topology of PRSS55. One study in mouse shows that PRS55 is a GPI-anchored protein (By similarity). An other study does not confirm the GPI-anchor status of PRSS55 (PubMed:18844450). However as a GPI-anchor motif is detected, the possibility of a GPI-anchor instead of a single-pass type I membrane protein is probable.
Only detected in testis. Expressed in spermatogonia, spermatocytes, spermatids, Leydig and Sertoli cells. Expressed in prostate cancer and ovarian cancer (at protein level).
Probable serine protease, which plays a crucial role in the fertility of male mice including sperm migration and sperm-egg interaction.
Binds to TRAF1, TRAF2, and TRAF3, but not TRAF5 and TRAF6. Binds through its C-terminus to SIVA1/SIVA.
Expressed in lymph node, peripheral blood leukocytes and weakly in spleen.
Receptor for TNFSF18. Seems to be involved in interactions between activated T-lymphocytes and endothelial cells and in the regulation of T-cell receptor-mediated cell death. Mediated NF-kappa-B activation via the TRAF2/NIK pathway.
Up-regulated in peripherical mononuclear cells after antigen stimulation/lymphocyte activation.
At synaptic junctions, cleaved at two conserved sites, alpha and beta, by neurotrypsin. Cleavage at the alpha-site produces the agrin N-terminal 110-kDa subunit and the agrin C-terminal 110-kDa subunit. Further cleavage of agrin C-terminal 110-kDa subunit at the beta site produces the C-terminal fragments, agrin C-terminal 90 kDa fragment and agrin C-terminal 22 kDa fragment. Excessive cleavage at the beta-site releases large amounts of the agrin C-terminal 22 kDa fragment leading to destabilization at the neuromuscular junction (NMJ).
Both laminin G-like 2 (G2) and laminin G-like 3 (G3) domains are required for alpha-dystroglycan/DAG1 binding. G3 domain is required for C-terminal heparin, heparan sulfate and sialic acid binding (By similarity).
Cleaved C-terminal fragments may be used as a biomarker for sarcopenia, age-related progressive loss of skeletal muscle.
Contains heparan and chondroitin sulfate chains and alpha-dystroglycan as well as N-linked and O-linked oligosaccharides. Glycosaminoglycans (GAGs), present in the N-terminal 110 kDa fragment, are required for induction of filopodia in hippocampal neurons. The first cluster (Gly/Ser-rich) for GAG attachment contains heparan sulfate (HS) chains and the second cluster (Ser/Thr-rich), contains chondroitin sulfate (CS) chains. Heparin and heparin sulfate binding in the G3 domain is independent of calcium ions. Binds heparin with a stoichiometry of 2:1. Binds sialic acid with a stoichiometry of 1:1 and binding requires calcium ions (By similarity).
Expressed in basement membranes of lung and kidney. Muscle- and neuron-specific isoforms are found. Isoforms (y+) with the 4 AA insert and (z+8) isoforms with the 8 AA insert are all neuron-specific. Isoforms (z+11) are found in both neuronal and non-neuronal tissues.
Heparan sulfate basal lamina glycoprotein that plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ) and directs key events in postsynaptic differentiation. Component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Calcium ions are required for maximal AChR clustering. AGRN function in neurons is highly regulated by alternative splicing, glycan binding and proteolytic processing. Modulates calcium ion homeostasis in neurons, specifically by inducing an increase in cytoplasmic calcium ions. Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain.
Is involved in regulation of neurite outgrowth probably due to the presence of the glycosaminoglcan (GAG) side chains of heparan and chondroitin sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also involved in modulation of growth factor signaling (By similarity).
Isoform 1, isoform 4 and isoform 5: neuron-specific (z+) isoforms that contain C-terminal insertions of 8-19 AA are potent activators of AChR clustering. Isoform 5, agrin (z+8), containing the 8-AA insert, forms a receptor complex in myotubules containing the neuronal AGRN, the muscle-specific kinase MUSK and LRP4, a member of the LDL receptor family. The splicing factors, NOVA1 and NOVA2, regulate AGRN splicing and production of the 'z' isoforms.
Isoform 3 and isoform 6: lack any 'z' insert, are muscle-specific and may be involved in endothelial cell differentiation.
Monomer (By similarity). Interacts (N-terminal subunit) with TGF-beta family members, BMP2 and BMP4; the interactions inhibit the activity of these growth factors. Interacts with TGFB1; the interaction enhances the activity of TGFB1 (By similarity). Component of the AGRN-LRP4 complex that consists of a tetramer of two AGRN-LRP4 heterodimers. Interacts (via the laminin G-like 3 domain) directly with LRP4; the interaction is required for activation of MUSK and clustering of AChR and requires the 'z8' insert present in the z(+8) isoforms. Interacts with DAG1; the interaction is influenced by cell surface glycosaminoglycans and by alternative splicing of AGRN.
Produced by usage of an alternative first exon.
The NtA domain, absent in TM-agrin, is required for binding laminin and connecting to basal lamina.
The unknown residue 'x' in the transmembrane isoform is probably a proline residue by similarity to mouse and rat sequences.
This released fragment is important for agrin signaling and to exert a maximal dendritic filopodia-inducing effect. All 'z' splice variants (z+) of this fragment also show an increase in the number of filopodia.
Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases.
Found in the sera of cancer patients with a wide variety of cancers including breast, prostate, lung and ovarian cancers, leukemias, and lymphomas. Not found in the serum of healthy volunteers or patients with disorders other than cancer. Probably shed into serum by cancer cells. Found on the cell borders of renal, kidney and ovarian carcinomas but not on the borders of surrounding non-cancerous stromal cells.
Has several properties associated with prions including resistance to proteases, resistance to cyanogen bromide digestion, and the ability to form amyloid filaments resembling those of spongiform encephalopathies.
Inhibited by the antitumor sulfonylurea LY181984, the vabilloid capsaicin, and retinoids.
May be involved in cell growth. Probably acts as a terminal oxidase of plasma electron transport from cytosolic NAD(P)H via hydroquinones to acceptors at the cell surface. Hydroquinone oxidase activity alternates with a protein disulfide-thiol interchange/oxidoreductase activity which may control physical membrane displacements associated with vesicle budding or cell enlargement. The activities oscillate with a period length of 22 minutes and play a role in control of the ultradian cellular biological clock.
Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.
Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. The cylin/CDK pair formed by CCNC/CDK8 also associates with the large subunit of RNA polymerase II. Interacts with CTNNB1, GLI3 and MAML1.
Belongs to the strictosidine synthase family.
Exhibits strong arylesterase activity with beta-naphthyl acetate and phenyl acetate. May play a role in adipocyte differentiation.
Liver, glomerular and tubular structures of the kidney, endothelial cells, arterial wall and pancreatic islets of Langerhans (at protein level). Found ubiquitously in adult as well as in embryonic tissues. In adult tissue, the highest expression is found in the liver, placenta and heart. Found on the cell surface of monocytes. In embryonic tissue, the highest expression levels is found in the liver and the kidney.
Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer.
Activated in response to stimuli that lead to increased intracellular Ca(2+) levels; this activation is indirect and may be mediated by calcium-mediated production of reactive oxygen species (ROS). Activated by autophosphorylation at Tyr-402; this creates a binding site for SRC family kinases and leads to phosphorylation at additional tyrosine residues. Phosphorylation at Tyr-402, Tyr-579 and Tyr-580 is required for optimal kinase activity. Inhibited by PF-562,271, BIRB796, PF-4618433 and by PF-431396, PF-2318841 and their derivatives. Inhibited by sulfoximine-substituted trifluoromethylpyrimidines. Inhibited by 4-amino and 5-aryl substituted pyridinone compounds.
Homodimer, or homooligomer. Interacts with SIRPA and SH2D3C. Interacts with ARHGAP10. Interacts with DLG4 (By similarity). Interacts with KCNA2 (By similarity). Interacts with NPHP1, ASAP1, ASAP2, ARHGAP26, SKAP2 and TGFB1I1. The Tyr-402 phosphorylated form interacts with SRC (via SH2 domain) and SRC family members. Forms a signaling complex with EPHA1, LCK and phosphatidylinositol 3-kinase; upon activation by EFNA1. Interacts with GRB2 (via SH2 domain). Interacts with P53/TP53 and MDM2. Interacts with MYLK. Interacts with BCAR1. Interacts with PDPK1. Interacts (hypophosphorylated) with PXN. Interacts with RB1CC1. Interacts with RHOU. Interacts with VAV1. Interacts with LPXN and PTPN12.
Most abundant in the brain, with highest levels in amygdala and hippocampus. Low levels in kidney (at protein level). Also expressed in spleen and lymphocytes.
Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T-cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at 'Tyr-9, 'Tyr-373', and 'Tyr-376'. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca(2+) levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2.
Phosphorylated on tyrosine residues in response to various stimuli that elevate the intracellular calcium concentration; this activation is indirect and may be mediated by production of reactive oxygen species (ROS). Tyr-402 is the major autophosphorylation site, but other kinases can also phosphorylate Tyr-402. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation at Tyr-402 promotes interaction with SRC and SRC family members, leading to phosphorylation at Tyr-579; Tyr-580 and Tyr-881. Phosphorylation at Tyr-881 is important for interaction with GRB2. Phosphorylated on tyrosine residues upon activation of FGR and PKC. Recruitment by NPHP1 to cell matrix adhesions initiates Tyr-402 phosphorylation. In monocytes, adherence to substrata is required for tyrosine phosphorylation and kinase activation. Angiotensin II, thapsigargin and L-alpha-lysophosphatidic acid (LPA) also induce autophosphorylation and increase kinase activity. Phosphorylation by MYLK promotes ITGB2 activation and is thus essential to trigger neutrophil transmigration during lung injury. Dephosphorylated by PTPN12.
Promotes bone resorption, and thus PTK2B/PYK2 inhibitors might be used to treat osteoporosis.
Component of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex composed at least by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2 (PubMed:16162815). Interacts directly with PIGA; this interaction regulates glycosylphosphatidylinositol-N-acetylglucosaminyltransferase activity (PubMed:16162815). Does not interact with Ras proteins (PubMed:16162815).
PREY and PIGY, 2 apparently unrelated proteins, are respectively the product of an upstream and a downstream ORF contained in a single bicistronic transcript.
Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis (PubMed:16162815). May act by regulating the catalytic subunit PIGA (PubMed:16162815).
Found in a complex composed of MORF4L1, MRFAP1 and RB1. Interacts via its N-terminus with MORF4L1. Interacts with CSTB and MORF4L2.
Catalyzes the hydrolysis of pseudosubstrates such as p-nitrocatechol sulfate and p-nitrophenyl sulfate (PubMed:23986440). Catalyzes the hydrolysis of the 2-sulfate groups of the 2-O-sulfo-D-glucuronate residues of chondroitin sulfate, heparin and heparitin sulfate (PubMed:28055182, PubMed:34916232). Acts selectively on 2-sulfoglucuronate and lacks activity against 2-sulfoiduronate (PubMed:28055182).
Expressed at high levels in the placenta and pancreas (PubMed:23986440). Expressed at intermediate levels in the lung, brain, heart, liver and kidney and at low levels in the muscle (PubMed:23986440).
N-glycosylated with both high mannose and complex type sugars.
The 75-kDa precursor undergoes proteolytic processing to yield a 23 kDa form.
Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932). Interacts with PRKX (PubMed:16491121). Interacts with DHX16 (PubMed:25296192). Interacts with PRKACB (PubMed:21880142).
Phosphorylation regulates its ability to bind RNA.
RNA-binding protein involved in pre-mRNA splicing. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
Detected at low levels in several somatic tissues (PubMed:12504854, PubMed:15701600). Highly expressed in the ovarian teratocarcinoma cell line PA-1 (PubMed:12504854).
Interacts (via N-terminus) with MBD3; the interaction is direct (PubMed:15701600). Interacts with MTA1 (PubMed:15701600). Interacts with HDAC1 (PubMed:15701600). Interacts with HDAC2 (PubMed:15701600). Interacts with RBBP4 (PubMed:15701600). Interacts with RBBP7 (PubMed:15701600).
May displace the NuRD complex from chromatin.
Detected in fetal cartilage (at protein level) (PubMed:28115524). Weak expression in heart, lung, ovary and skeletal muscle (PubMed:8723724).
Identified in a complex with PLOD1 and P3H4.
Part of a complex composed of PLOD1, P3H3 and P3H4 that catalyzes hydroxylation of lysine residues in collagen alpha chains and is required for normal assembly and cross-linkling of collagen fibrils. Required for normal hydroxylation of lysine residues in type I collagen chains in skin, bone, tendon, aorta and cornea. Required for normal skin stability via its role in hydroxylation of lysine residues in collagen alpha chains and in collagen fibril assembly. Apparently not required for normal prolyl 3-hydroxylation on collagen chains, possibly because it functions redundantly with other prolyl 3-hydroxylases.
Although assigned as two separate genes (c20orf57 and DUSP15), it is probable that C20orf57 does not exist by itself and is a part of the DUSP15 gene.
Highly expressed in testis (PubMed:15138252). Expressed in brain; up-regulated in patients with multiple sclerosis gray matter lesions (PubMed:22792334).
May dephosphorylate MAPK13, ATF2, ERBB3, PDGFRB and SNX6 (PubMed:22792334).
May play a role in the regulation of oligodendrocyte differentiation. May play a role in the regulation of myelin formation (By similarity). Involved in the regulation of Erk1/2 phosphorylation in Schwann cells; the signaling may be linked to the regulation of myelination (By similarity).
Phosphorylated by DYRK1A; phosphorylation increases RNF169 ability to block accumulation of TP53BP1 at the DSB sites.
Probable E3 ubiquitin-protein ligase that acts as a regulator of double-strand breaks (DSBs) repair following DNA damage. Functions in a non-canonical fashion to harness RNF168-mediated protein recruitment to DSB-containing chromatin, thereby contributing to regulation of DSB repair pathway utilization (PubMed:22492721, PubMed:30773093). Once recruited to DSB repair sites by recognizing and binding ubiquitin catalyzed by RNF168, competes with TP53BP1 and BRCA1 for association with RNF168-modified chromatin, thereby favouring homologous recombination repair (HRR) and single-strand annealing (SSA) instead of non-homologous end joining (NHEJ) mediated by TP53BP1 (PubMed:30104380, PubMed:30773093). E3 ubiquitin-protein ligase activity is not required for regulation of DSBs repair.
The MIU motif (motif interacting with ubiquitin) mediates the interaction with both 'Lys-48'- and 'Lys-63'-linked ubiquitin chains (PubMed:22733822, PubMed:22492721). The UMI motif also mediates interaction with ubiquitin. The specificity for different types of ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU and UMI motifs) with LR motifs (LRMs) (PubMed:22742833).
A cytochrome P450 monooxygenase involved in corticoid and androgen biosynthesis (PubMed:9452426, PubMed:27339894, PubMed:22266943, PubMed:25301938). Catalyzes 17-alpha hydroxylation of C21 steroids, which is common for both pathways. A second oxidative step, required only for androgen synthesis, involves an acyl-carbon cleavage. The 17-alpha hydroxy intermediates, as part of adrenal glucocorticoids biosynthesis pathway, are precursors of cortisol (PubMed:9452426, PubMed:25301938) (Probable). Hydroxylates steroid hormones, pregnenolone and progesterone to form 17-alpha hydroxy metabolites, followed by the cleavage of the C17-C20 bond to form C19 steroids, dehydroepiandrosterone (DHEA) and androstenedione (PubMed:9452426, PubMed:27339894, PubMed:22266943, PubMed:25301938, PubMed:36640554). Has 16-alpha hydroxylase activity. Catalyzes 16-alpha hydroxylation of 17-alpha hydroxy pregnenolone, followed by the cleavage of the C17-C20 bond to form 16-alpha-hydroxy DHEA (PubMed:36640554). Also 16-alpha hydroxylates androgens, relevant for estriol synthesis (PubMed:27339894, PubMed:25301938). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:9452426, PubMed:27339894, PubMed:22266943, PubMed:25301938).
Phosphorylation is necessary for 17,20-lyase, but not for 17-alpha-hydroxylase activity.
Regulated predominantly by intracellular cAMP levels (PubMed:10720067). The 17,20-lyase activity is stimulated by cytochrome b5, which acts as an allosteric effector increasing the Vmax of the lyase activity (PubMed:9452426, PubMed:27339894).
Belongs to the class I-like SAM-binding methyltransferase superfamily. TRM5/TYW2 family.
Contaminating sequence. Potential poly-A sequence starting in position 371.
S-adenosyl-L-methionine-dependent transferase that acts as a component of the wybutosine biosynthesis pathway. Wybutosine is a hyper modified guanosine with a tricyclic base found at the 3'-position adjacent to the anticodon of eukaryotic phenylalanine tRNA. Catalyzes the transfer of the alpha-amino-alpha-carboxypropyl (acp) group from S-adenosyl-L-methionine to the C-7 position of 4-demethylwyosine (imG-14) to produce wybutosine-86.
Essential for normal spermatogenesis and male fertility (PubMed:16533358). Required for proper cell restructuring and DNA condensation during the elongation phase of spermiogenesis. Involved in the histone-protamine transition of sperm chromatin and the subsequent production of functional sperm. Binds both double-stranded and single-stranded DNA, ATP and protamine-1.
It is uncertain whether Met-1 or Met-22 is the initiator.
Non-mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase that catalyzes a cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in ketogenesis, the products of which support energy production in nonhepatic animal tissues.
Expressed at a low level in a large number of cells of hematopoietic origin. Isoform 1 and isoform 2 are always found to be coexpressed.
Homodimer (PubMed:25538044). Interacts with ATXN2L.
Receptor for thrombopoietin that acts as a primary regulator of megakaryopoiesis and platelet production. May represent a regulatory molecule specific for TPO-R-dependent immune responses.
Ubiquitination at Lys-553 and Lys-573 targets MPL for degradation by both the lysosomal and proteasomal pathways. The E3 ubiquitin-protein ligase CBL significantly contributes to this ubiquitination.
Acetylated at Ser-565 by SPHK1. During neuroinflammation, acetylation by SPHK1 promotes neuronal secretion of specialized preresolving mediators (SPMs), especially 15-R-lipoxin A4, which results in an increase of phagocytic microglia.
Belongs to the prostaglandin G/H synthase family.
Binds 1 heme b (iron(II)-protoporphyrin IX) group per subunit.
By cytokines and mitogens. Up-regulated by IL1B (PubMed:26282205, PubMed:9545330). Up-regulated by lipopolysaccharide (LPS) (PubMed:9545330).
Conversion of arachidonate to prostaglandin H2 is mediated by 2 different isozymes: the constitutive PTGS1 and the inducible PTGS2. PTGS1 is expressed constitutively and generally produces prostanoids acutely in response to hormonal stimuli to fine-tune physiological processes requiring instantaneous, continuous regulation (e.g. hemostasis). PTGS2 is inducible and typically produces prostanoids that mediate responses to physiological stresses such as infection and inflammation.
Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate, AA, C20:4(n-6)), with a particular role in the inflammatory response (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593, PubMed:11939906, PubMed:19540099). The cyclooxygenase activity oxygenates AA to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide prostaglandin H2 (PGH2), the precursor of all 2-series prostaglandins and thromboxanes (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593). This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593). Similarly catalyzes successive cyclooxygenation and peroxidation of dihomo-gamma-linoleate (DGLA, C20:3(n-6)) and eicosapentaenoate (EPA, C20:5(n-3)) to corresponding PGH1 and PGH3, the precursors of 1- and 3-series prostaglandins (PubMed:11939906, PubMed:19540099). In an alternative pathway of prostanoid biosynthesis, converts 2-arachidonoyl lysophopholipids to prostanoid lysophopholipids, which are then hydrolyzed by intracellular phospholipases to release free prostanoids (PubMed:27642067). Metabolizes 2-arachidonoyl glycerol yielding the glyceryl ester of PGH2, a process that can contribute to pain response (PubMed:22942274). Generates lipid mediators from n-3 and n-6 polyunsaturated fatty acids (PUFAs) via a lipoxygenase-type mechanism. Oxygenates PUFAs to hydroperoxy compounds and then reduces them to corresponding alcohols (PubMed:11034610, PubMed:11192938, PubMed:9048568, PubMed:9261177). Plays a role in the generation of resolution phase interaction products (resolvins) during both sterile and infectious inflammation (PubMed:12391014). Metabolizes docosahexaenoate (DHA, C22:6(n-3)) to 17R-HDHA, a precursor of the D-series resolvins (RvDs) (PubMed:12391014). As a component of the biosynthetic pathway of E-series resolvins (RvEs), converts eicosapentaenoate (EPA, C20:5(n-3)) primarily to 18S-HEPE that is further metabolized by ALOX5 and LTA4H to generate 18S-RvE1 and 18S-RvE2 (PubMed:21206090). In vascular endothelial cells, converts docosapentaenoate (DPA, C22:5(n-3)) to 13R-HDPA, a precursor for 13-series resolvins (RvTs) shown to activate macrophage phagocytosis during bacterial infection (PubMed:26236990). In activated leukocytes, contributes to oxygenation of hydroxyeicosatetraenoates (HETE) to diHETES (5,15-diHETE and 5,11-diHETE) (PubMed:22068350, PubMed:26282205). Can also use linoleate (LA, (9Z,12Z)-octadecadienoate, C18:2(n-6)) as substrate and produce hydroxyoctadecadienoates (HODEs) in a regio- and stereospecific manner, being (9R)-HODE ((9R)-hydroxy-(10E,12Z)-octadecadienoate) and (13S)-HODE ((13S)-hydroxy-(9Z,11E)-octadecadienoate) its major products (By similarity). During neuroinflammation, plays a role in neuronal secretion of specialized preresolving mediators (SPMs) 15R-lipoxin A4 that regulates phagocytic microglia (By similarity).
PTGS1 and PTGS2 are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin and ibuprofen (PubMed:27710942, PubMed:26859324, PubMed:27226593). Aspirin is able to produce an irreversible inactivation of the enzyme through a serine acetylation (PubMed:26859324). Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. PTGS2 is the principal isozyme responsible for production of inflammatory prostaglandins. New generation PTGSs inhibitors strive to be selective for PTGS2, to avoid side effects such as gastrointestinal complications and ulceration.
S-nitrosylation by NOS2 (iNOS) activates enzyme activity. S-nitrosylation may take place on different Cys residues in addition to Cys-526.
The conversion of arachidonate to prostaglandin H2 is a 2 step reaction: a cyclooxygenase (COX) reaction which converts arachidonate to prostaglandin G2 (PGG2) and a peroxidase reaction in which PGG2 is reduced to prostaglandin H2 (PGH2). The cyclooxygenase reaction occurs in a hydrophobic channel in the core of the enzyme. The peroxidase reaction occurs at a heme-containing active site located near the protein surface. The nonsteroidal anti-inflammatory drugs (NSAIDs) binding site corresponds to the cyclooxygenase active site.
The cyclooxygenase activity is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, flurbiprofen, celecoxib, flufenamic, mefenamic and tolfenamic acids as well as by hydroperoxide scavenger erythrocyte glutathione peroxidase GPX1 (PubMed:26859324, PubMed:27226593, PubMed:7592599, PubMed:9048568). Aspirin triggers enzyme acetylation turning off its ability to generate pro-inflammatory prostaglandins, but switches on its capacity to produce anti-inflammatory lipid mediators involved in inflammation resolution (PubMed:11034610, PubMed:12391014). Aspirin enhances lipoxygenase-type activity toward production of epimers with R stereochemistry such as 15R-HETE, 18R-HEPE, 15R-HEPE and 17R-HDHA (PubMed:11034610, PubMed:11192938, PubMed:22068350, PubMed:12391014, PubMed:9048568, PubMed:21206090). Atorvastatin, a cholesterol-lowering drug, triggers enzyme S-nitrosylation increasing production of 13-series resolvins (RvTs) (PubMed:26236990).
Interacts through its C-terminal region with the PDZ domain-containing proteins GRIP1, GRIP2 and PICK1. Interacts with PDZ domains 4 and 5 of GRIP1 and with the PDZ domain of PICK1.
Only detected in the pituitary gland and in all cell types of pituitary adenomas.
Receptor for prolactin-releasing peptide (PrRP). Implicated in lactation, regulation of food intake and pain-signal processing.
Repressed by bromocriptine, a dopamine agonist.
Associates with ribosomes; promoting ribosome inactivation.
Expressed in many tissues including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Ribosome-binding protein that acts as an inhibitor of mRNA translation by promoting ribosome inactivation (PubMed:30355441). Associates with the P- and E-sites of the ribosome and inserts a C-terminal helix into the mRNA exit channel to preclude translation (By similarity).
Contains two Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. The LXXLL motifs are essential for the association with nuclear receptors (By similarity).
Histone demethylase that specifically demethylates both mono- and dimethylated 'Lys-9' of histone H3. May act as a transcription regulator controlling hair biology (via targeting of collagens), neural activity, and cell cycle.
Strongest expression of isoforms 1 and 2 is seen in the small intestine, weaker expression in brain and colon, and trace expression is found in liver, pancreas, spleen, thymus, stomach, salivary gland, appendix and trachea. Isoform 1 is always the most abundant. Isoform 1 is exclusively expressed at low levels in kidney and testis. Isoform 2 is exclusively expressed at high levels in the skin.
Although it belongs to the non-receptor class myotubularin subfamily, lacks the conserved active site cysteine residue at position 403 in the dsPTPase catalytic loop, suggesting that it has no phosphatase activity.
High expression in heart, pancreas and liver, medium in placenta and kidney, low in brain, skeletal muscle and lung.
Required for the biosynthesis of the tetrasaccharide linkage region of proteoglycans, especially for small proteoglycans in skin fibroblasts.
Abundant in testes, skeletal muscle and heart tissue.
Belongs to the mitochondrion-specific ribosomal protein mS39 family.
Component of the mitochondrial small ribosomal subunit (mt-SSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. Associated with the 12S mitochondrial rRNA (12S mt-rRNA).
Mitochondrial RNA-binding protein that has a role in mitochondrial translation.
Type X collagen is a product of hypertrophic chondrocytes and has been localized to presumptive mineralization zones of hyaline cartilage.
Highly expressed in the kidney (at protein level) (PubMed:11274445). High expression in adult thyroid, lower expression in adult and fetal kidney and fetal brain. Not expressed in other tissues (PubMed:9398842).
Interacts with IQGAP1; this interaction enhances the chloride-bicarbonate exchange activity of SLC26A4.
Sodium-independent transporter of chloride and iodide (PubMed:10192399, PubMed:12107249, PubMed:11932316, PubMed:16684826, PubMed:24051746). Mediates electroneutral chloride-bicarbonate, chloride-iodide and chloride-formate exchange with 1:1 stoichiometry (PubMed:10644529, PubMed:15155570, PubMed:35601831, PubMed:24051746). Mediates electroneutral iodide-bicarbonate exchange (By similarity).
Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase.
Interacts (via C-terminus) with TOP1 (PubMed:11818025). Interacts with TRIM5 isoform Delta (PubMed:12878161). Interacts with CUL3 (PubMed:14528312).
Probable substrate-specific adapter of an E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:14528312). Seems to regulate expression levels and/or subnuclear distribution of TOP1, via an unknown mechanism (By similarity). May play a role in mesenchymal differentiation where it promotes myogenic differentiation and suppresses adipogenesis (By similarity).
Ubiquitous; highest levels in testes, heart and skeletal muscle.
Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone, and 17-beta-estradiol. Regulates the plasma metabolic clearance rate of steroid hormones by controlling their plasma concentration.
Isoform 1 and isoform 2 are present in liver and testis.
Variant Asn-356 contains one N-linked (GlcNAc...) at position 356.
Interacts with HSP90AA1, ROCK1 and ROCK2. Interacts with HSP90AB1 and PPP5C (By similarity).
Regulates centrosome duplication, probably by inhibiting the kinase activity of ROCK2 (PubMed:20230755). Proposed to act as co-chaperone for HSP90 (PubMed:20230755). May play a role in the regulation of NOD1 via a HSP90 chaperone complex (PubMed:20230755). In vitro, has intrinsic chaperone activity (PubMed:20230755). This function may be achieved by inhibiting association of ROCK2 with NPM1 (PubMed:20230755). Plays a role in ensuring the localization of the tyrosine kinase receptor EGFR to the plasma membrane, and thus ensures the subsequent regulation of EGFR activity and EGF-induced actin cytoskeleton remodeling (PubMed:32053105). Involved in stress response (PubMed:20230755). Prevents tumorigenesis (PubMed:20230755).
Underexpressed in many breast and lung cancers.
Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols (PubMed:9565553, PubMed:18087047, PubMed:12732097, PubMed:19013440, PubMed:19563777). Displays strong enzymatic activity toward all-trans-retinal, 9-cis-retinal, and 13-cis-retinal (PubMed:12732097, PubMed:18087047). Plays a critical role in detoxifying dietary and lipid-derived unsaturated carbonyls, such as crotonaldehyde, 4-hydroxynonenal, trans-2-hexenal, trans-2,4-hexadienal and their glutathione-conjugates carbonyls (GS-carbonyls) (PubMed:19013440, PubMed:19563777). Displays no reductase activity towards glucose (PubMed:12732097).
Found in many tissues. Highly expressed in small intestine, colon and adrenal gland.
Has no counterpart in murine and rat species.
Overexpressed in certain types of cancers, including hepatocellular carcinoma and lung cancer associated with tobacco smoking.
Retinaldehyde reductase activity is inhibited by tolrestat.
Interacts (GTP-bound) with DYNLRB1; the interaction is direct (PubMed:18044744). Interacts with BICD1 (PubMed:12447383). Interacts with BICD2; the interaction is direct (PubMed:12447383, PubMed:25962623, PubMed:20386726, PubMed:23664119). Interacts (GTP-bound) with VPS13B (PubMed:25492866).
Interacts with BICD1 (PubMed:12447383). Interacts (GDP-bound) with DYNLRB1; the interaction is direct (PubMed:18044744). Interacts (GTP-bound) with VPS13B (PubMed:25492866).
Interacts with BICDL1; leads to its accumulation in the pericentrosomal region (By similarity). Interacts with SCYL1BP1 (PubMed:18997784). Interacts with VSP52 (PubMed:15878329). Interacts with RABGAP1 (PubMed:10202141). Interacts with GCC2 (via its GRIP domain) (PubMed:18243103). Interacts with RAB6IP1 (via its RUN 1 domain) (PubMed:19141279). Interacts with TMF1 (PubMed:17698061). Interacts with CIMAP3 (PubMed:20643351). Interacts (GTP-bound) with APBA1/MINT1 isoform 2, also called Mint1_826, but not with isoform 1 (PubMed:23737971). Interacts with RIC1; the interaction is direct with a preference for RAB6A-GDP (PubMed:23091056). Interacts with RGP1; the interaction is direct with a preference for RAB6A-GDP (PubMed:23091056).
Regulator of COPI-independent retrograde transport from the Golgi apparatus towards the endoplasmic reticulum (ER) (PubMed:25962623). Has a low GTPase activity (PubMed:25962623). Recruits VPS13B to the Golgi membrane (PubMed:25492866). Plays a role in neuron projection development (Probable).
(Microbial infection) Expressed in cytomegalovirus (CMV)-infected effector CD8(+) T-cells (at protein level) (PubMed:20921622).
(Microbial infection) Up-regulated by cytomegalovirus (CMV) infection in long-lived effector CD8(+) T-cells (PubMed:20921622).
Expressed in terminally differentiated effector CD8(+) T-cells, but not in naive and central memory cells (PubMed:26179882). Expressed in terminally differentiated natural killer (NK) cells and natural killer (NKT) T-cells (at protein level) (PubMed:26179882). Expressed strongly in effector-type CD8(+) T-cells and weakly in naive and memory CD8(+) T-cells (PubMed:26179882). Expressed in terminally differentiated natural killer (NK) cells (PubMed:26179882). Isoform 2 is strongly expressed in effector CD8(+) T and natural killer (NK) cells (PubMed:26179882). Isoform 1 is expressed in effector CD8(+) T and natural killer (NK) cells (PubMed:26179882).
Lacks transcriptional repressor activity. Binds to DNA within promoter regions of the transcriptional repressor PRDM1/BLIMP1 target sites. Unable to regulate interferon-gamma (IFN-gamma) production in cytomegalovirus (CMV)-infected effector CD8(+) T-cells.
The C2H2-type zinc finger are necessary for DNA-binding (PubMed:26179882).
Transcription factor that mediates a transcriptional program in various innate and adaptive immune tissue-resident lymphocyte T-cell types such as tissue-resident memory T (Trm), natural killer (trNK) and natural killer T (NKT) cells and negatively regulates gene expression of proteins that promote the egress of tissue-resident T-cell populations from non-lymphoid organs. Plays a role in the development, retention and long-term establishment of adaptive and innate tissue-resident lymphocyte T cell types in non-lymphoid organs, such as the skin and gut, but also in other nonbarrier tissues like liver and kidney, and therefore may provide immediate immunological protection against reactivating infections or viral reinfection. Also plays a role in the differentiation of both thymic and peripheral NKT cells. Negatively regulates the accumulation of interferon-gamma (IFN-gamma) in NKT cells at steady state or after antigenic stimulation. Positively regulates granzyme B production in NKT cells after innate stimulation. Associates with the transcriptional repressor PRDM1/BLIMP1 to chromatin at gene promoter regions.
Transcriptional repressor that binds to DNA within promoter regions of the transcriptional repressor PRDM1/BLIMP1 target sites. Regulates interferon-gamma (IFN-gamma) production in cytomegalovirus (CMV)-infected effector CD8(+) T cells.
Expressed in fetal brain, lung, liver and kidney. Widely expressed in adult tissues.
Interacts in a RNA-independent manner with distinct U5 snRNP-containing complexes, the mono-U5 snRNP and the post-splicing U5 snRNP-PRPF19 complex (PubMed:34131137). Interacts with SNRNP200; the interaction is direct, excludes recruitment of C9ORF78 and WBP4 to SNRNP200 and negatively regulates its RNA helicase activity (PubMed:35188580). Interacts with PRPF8; the interaction is direct (PubMed:35188580).
Protein associated with the U5 snRNP, during its maturation and its post-splicing recycling and which is required for spliceosomal tri-snRNP complex assembly in the nucleus (PubMed:34131137, PubMed:35188580). Has a molecular sequestering activity and transiently hinders SNRNP200 binding sites for constitutive splicing factors that intervene later during the assembly of the spliceosome and splicing (PubMed:35188580). Together with its molecular sequestering activity, may also function as a molecular adapter and placeholder, coordinating the assembly of the U5 snRNP and its association with the U4/U6 di-snRNP (PubMed:34131137).
Interacts with HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, NCOR1, NCOR2, SIN3A, SIN3B, RBBP4, RBBP7, MTA1L1, SAP30 and MBD3. Interacts with the 14-3-3 protein YWHAE, MEF2A, MEF2B and MEF2C (By similarity). Interacts with KAT5 and EDNRA. Interacts with KDM5B. Interacts with ZMYND15 (By similarity). Interacts with PML (isoform PML-4). Interacts with FOXP3. Interacts with RARA (PubMed:28167758).
Its activity is inhibited by Trichostatin A (TSA), a known histone deacetylase inhibitor.
May be phosphorylated by CaMK1. Phosphorylated by the PKC kinases PKN1 and PKN2, impairing nuclear import. Phosphorylation at Ser-155 by MARK2, MARK3 and PRKD1 promotes interaction with 14-3-3 proteins and export from the nucleus. Phosphorylation at Ser-155 is a prerequisite for phosphorylation at Ser-181.
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer factors such as MEF2A, MEF2B and MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors (By similarity). May be involved in Epstein-Barr virus (EBV) latency, possibly by repressing the viral BZLF1 gene. Positively regulates the transcriptional repressor activity of FOXP3 (PubMed:17360565). Serves as a corepressor of RARA, causing its deacetylation and inhibition of RARE DNA element binding (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758).
May play a role in embryonic and postnatal development of the brain. Increased resistance to cell death induced by serum starvation in cultured cells. Regulates cAMP-induced GFAP gene expression via STAT3 phosphorylation (By similarity).
Interacts with SIX1 and DACH1, and probably SIX2, SIX4, SIX5.
Ser-266 phosphorylation is required for localization at sites of DNA damage and directing interaction with H2AX.
Tyrosine phosphatase that specifically dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph). 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress. Promotes efficient DNA repair by dephosphorylating H2AX, promoting the recruitment of DNA repair complexes containing MDC1 (PubMed:19234442, PubMed:19351884). Its function as histone phosphatase probably explains its role in transcription regulation during organogenesis. Coactivates SIX1, and seems to coactivate SIX2, SIX4 and SIX5. The repression of precursor cell proliferation in myoblasts by SIX1 is switched to activation through recruitment of EYA3 to the SIX1-DACH1 complex and seems to be dependent on EYA3 phosphatase activity (By similarity). May be involved in development of the eye.
In approximately 50% of the complexes the exclusion domain is cleaved at position 58 or 61. The two parts of the exclusion domain are held together by a disulfide bond.
N-glycosylated. While glycosylation at Asn-53, Asn-119 and Asn-276 is mediated by STT3A-containing complexes, glycosylation at Asn-29 is mediated STT3B-containing complexes.
Strongly inhibited by the cysteine peptidase inhibitors mersalyl acid, iodoacetic acid and cystatin. Inhibited by N-ethylmaleimide, Gly-Phe-diazomethane, TLCK, TPCK and, at low pH, by dithiodipyridine. Not inhibited by the serine peptidase inhibitor PMSF, the aminopeptidase inhibitor bestatin, or metal ion chelators.
Tetramer of heterotrimers consisting of exclusion domain, heavy- and light chains.
Thiol protease (PubMed:1586157). Has dipeptidylpeptidase activity (PubMed:1586157). Active against a broad range of dipeptide substrates composed of both polar and hydrophobic amino acids (PubMed:1586157). Proline cannot occupy the P1 position and arginine cannot occupy the P2 position of the substrate (PubMed:1586157). Can act as both an exopeptidase and endopeptidase (PubMed:1586157). Activates serine proteases such as elastase, cathepsin G and granzymes A and B (PubMed:8428921).
Ubiquitous. Highly expressed in lung, kidney and placenta. Detected at intermediate levels in colon, small intestine, spleen and pancreas.
Up-regulated in lymphocytes by IL2/interleukin-2.
Binds to the CACCC box of erythroid cell-expressed genes. May play a role in hematopoiesis (By similarity).
Sumoylated with SUMO1. Sumoylation is enhanced by PIAS1, PIAS2alpha and PIAS2beta, and PIAS4, but not by Pc2. Enhances transcriptional repression, but has no effect on DNA binding. Sumoylation on Lys-198 is the major site (By similarity).
The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. In KLF3, the motif is inactive.
In p53/TP53-dependent manner in response to low levels of DNA damage. Not induced when DNA damage is severe.
Involved in the modulation of the mitochondrial apoptotic pathway by ensuring the accumulation of cardiolipin (CL) in mitochondrial membranes. In vitro, the TRIAP1:PRELID1 complex mediates the transfer of phosphatidic acid (PA) between liposomes and probably functions as a PA transporter across the mitochondrion intermembrane space to provide PA for CL synthesis in the inner membrane (PubMed:23931759). Likewise, the TRIAP1:PRELID3A complex mediates the transfer of phosphatidic acid (PA) between liposomes (in vitro) and probably functions as a PA transporter across the mitochondrion intermembrane space (in vivo) (PubMed:26071602). Mediates cell survival by inhibiting activation of caspase-9 which prevents induction of apoptosis (PubMed:15735003).
Monomer (PubMed:26071602). Interacts with APAF1 and HSP70 (PubMed:15735003). Forms a complex with PRELID1 in the mitochondrion intermembrane space (PubMed:23931759). Interacts with PRELID3A (PubMed:26071602).
A chromosomal aberration involving SSX2 may be a cause of synovial sarcoma. Translocation t(X;18)(p11.2;q11.2). The translocation is specifically found in more than 80% of synovial sarcoma. The fusion products SSXT-SSX1 or SSXT-SSX2 are probably responsible for transforming activity. Heterogeneity in the position of the breakpoint can occur (low frequency).
Expressed at high level in the testis. Expressed at low level in thyroid. Not detected in tonsil, colon, lung, spleen, prostate, kidney, striated and smooth muscles. Detected in rhabdomyosarcoma and fibrosarcoma cell lines. Not detected in mesenchymal and epithelial cell lines.
Interacts via its N-terminal region with RAB3IP and SSX2IP.
Belongs to the metallophosphoesterase superfamily. CPPED1 family.
Expressed in subcutaneous adipose tissue.
Expression levels are slightly decreased in subcutaneous adipose tissue following weight loss. Expression levels may be not affected by preadipocyte differentiation.
Protein phosphatase that dephosphorylates AKT family kinase specifically at 'Ser-473', blocking cell cycle progression and promoting cell apoptosis. May play an inhibitory role in glucose uptake by adipocytes.
Transactivated by the large envelope protein of the hepatitis B virus (HBV).
Interacts (via the PDZ 2 domain) with CTNND2 (via the extreme C-terminus). Interacts (via the PDZ 2 domain) with PKP4 (via the extreme C-terminus); this interaction directed FRMPD2 to the basolateral membranes. Interacts (via the PDZ 2 domain) with ARVCF (via the extreme C-terminus).
May play a role in the regulation of tight junction formation. Binds phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2).
The FERM and PDZ 2 domains are necessary for localization to the basolateral cell membrane. The FERM domain binds to phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) and is sufficient for membrane localization.
Interacts (via N-terminal domain) with SPACA3; the interaction occurs during fertilization.
Oocyte-specific oolemmal receptor involved in sperm and egg adhesion and fertilization. Plays a role in the polyspermy inhibition. Probably acts as a protease for the post-fertilization cleavage of ZP2. Cleaves the sperm-binding ZP2 at the surface of the zona pellucida after fertilization and cortical granule exocytosis, rendering the zona pellucida unable to support further sperm binding.
Alpha-2,8-sialyltransferase that prefers O-glycans to N-glycans or glycolipids as acceptor substrates. The minimal acceptor substrate is the NeuAc-alpha-2,3(6)-Gal sequence at the non-reducing end of their carbohydrate groups.
May be signaling molecules that resemble neuropeptides and that act by binding to alpha-neurexins and possibly other receptors.
May be signaling molecules that resemble neuropeptides.
Interacts with AURKA, AURKB, BIRC5 and INCENP. May be a component of the CPC at least composed of BIRC5/survivin, CDCA8/borealin, INCENP and AURKB/Aurora-B.
Protein levels increase during the S phase of the cell cycle, are highest during G2 and mitosis, and decrease to low levels at G1. Levels are lowest at the transition from G1 to S phase.
Required for normal cytokinesis during mitosis. Plays a role in the regulation of cell proliferation. May be a component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Increases AURKB activity. Inhibits apoptosis induced by TGFB1 (By similarity). Overexpression induces swelling of mitochondria and reduces mitochondrial membrane potential (By similarity).
Ubiquitous. Expressed in all normal human tissues studied but overexpressed or underexpressed in many of their malignant counterparts.
Interacts with MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAP, GABARAPL1, GABARAPL2. Interacts with VPS29 and VPS35; indicative for an association with retromer CSC subcomplex. MAP1LC3A and VPS29 compete for binding to TBC1D5 (PubMed:20923837, PubMed:22354992). Interacts with AP2M1; indicative for an association with the AP2 complex. Interacts with ULK1 and ATG13 (phosphorylated); indicative for an association with the activated ULK1-ATG13-FIP200 complex. Interacts with ATG9A; the interactions seems to be restricted to the AP2-clathrin-associated fraction of ATG9A (PubMed:24603492).
May act as a GTPase-activating protein (GAP) for Rab family protein(s). May act as a GAP for RAB7A. Can displace RAB7A and retromer CSC subcomplex from the endosomal membrane to the cytosol; at least retromer displacement seems to require its catalytic activity (PubMed:19531583, PubMed:20923837). Required for retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN); the function seems to require its catalytic activity. Involved in regulation of autophagy (PubMed:22354992). May act as a molecular switch between endosomal and autophagosomal transport and is involved in reprogramming vesicle trafficking upon autophagy induction. Involved in the trafficking of ATG9A upon activation of autophagy. May regulate the recruitment of ATG9A-AP2-containing vesicles to autophagic membranes (PubMed:24603492).
The LIR (LC3-interacting region) motif mediates the interaction with ATG8 family proteins. LIR 1 is also implicated in interaction with retromer; LIR 2 is only implicated in interaction with ATG8 family proteins.
Interacts with the N-terminal zinc-finger of GATA4, GATA5 and probably GATA6. Interacts with retinoid nuclear receptor RXRA when ligand bound (By similarity). Interacts with corepressor CTBP2; this interaction is however not essential for corepressor activity. Able to bind GATA1 in vitro. Interacts with NR2F2 and NR2F6 (By similarity). Interacts with ATOH8; mediates indirect interaction with GATA4 (By similarity).
Sumoylation reduces transcriptional repression activity.
Transcription regulator that plays a central role in heart morphogenesis and development of coronary vessels from epicardium, by regulating genes that are essential during cardiogenesis. Essential cofactor that acts via the formation of a heterodimer with transcription factors of the GATA family GATA4, GATA5 and GATA6. Such heterodimer can both activate or repress transcriptional activity, depending on the cell and promoter context. Also required in gonadal differentiation, possibly be regulating expression of SRY. Probably acts a corepressor of NR2F2 (By similarity).
Expressed on CD16+ monocytes and myeloid dendritic cells (at protein level). By contrast, not detected in lymphocytes nor granulocytes (at protein level).
May play an important role in innate immunity by mediating a signal for the production of a neutrophil chemoattractant.
The sequence shown in this entry differs from the translation of the reference genome assembly (GRCh38/hg38) due to a variant (called allele 'A') in the reference genome which abolishes the intron 1 donor splice site, leading to the loss of CD300H transcripts and consequently loss of protein. The variant shown in this entry (NM_001324073.1:c.61+1A>G, rs905709) restores the splicing of intron 1 and protein expression (PubMed:26221034). This variant is common in the human population with a frequency of about 62% according to the Genome Aggregation Database (gnomAD v3.1.2).
The sequence shown in this entry differs from the translation of the reference genome assembly (GRCh38/hg38) due to a variant (dbSNP:rs905709) in the reference genome which abolishes the intron 1 donor splice site leading to loss of CD300H transcripts.
Required for the development and function of the thalamic reticular nucleus (TRN), a part of the thalamus that is critical for thalamocortical transmission, generation of sleep rhythms, sensorimotor processing and attention.
Widely expressed, including in various regions of the brain with highest expression in the gray and white cerebellum, followed by the cerebellar vermis and the pituitary gland.
Detected in testis and spermatogonia. Not detected in spermatocytes. Detected in blood leukocytes.
Interacts with VAMP3. Interacts with LY6K. Interacts with DPEP3; co-localized on the cell surface of spermatocytes, spermatids, and testicular spermatozoa, co-localized only in cytoplasmic droplets of caput and corpus epididymal sperm. Interacts with ADAM5.
N-glycosylated; by high mannose and/or biantennary complex and/or certain types of hybrid oligosaccharides; possesses different oligosaccharides chains according to its subcellular localization in the testis.
Plays a role in fertilization by controlling binding of sperm to zona pellucida and migration of spermatozoa into the oviduct (By similarity). May play a role in signal transduction and promote protein tyrosine phosphorylation (By similarity).
Sheds from membrane raft by ACE and released from the cell surface of epididymal sperm while it passes through the caput epididymis leading to disappearance of TEX101 on spermatozoa; is essential to produce fertile spermatozoa.
Expression is predominantly restricted in hematopoietic tissues. Expressed in heart, spleen, liver, intestine, muscle and testis. Expressed in immune cells, including monocytes, dendritic, B- and T-cells. No expression was seen in peripheral blood leukocytes. Expressed in the leukocyte cell line THP-1.
Expressed in brain (at protein level) (PubMed:12074842, PubMed:12507886). Expressed on mononuclear phagocytes and monocyte-derived macrophages in the gastric mucosa (at protein level) (PubMed:24509909). Expressed in normal pancreatic tissue but not in pancreatic tumor tissue (PubMed:11875720). Reduced or no expression is observed in some glioblastomas (PubMed:12507886).
Inhibits angiogenesis in a CD36-dependent manner.
Interacts with ELMO1 and DOCK (By similarity). When bound to ELMO1 and DOCK1, acts as a module to promote apoptotic cell engulfment (By similarity). Interacts with MDM2; the interaction results in inhibition of MDM2-mediated ubiquitination and degradation of DLG4/PSD95 (By similarity). Interacts with PARD3 and TIAM1; the interaction is required for correct dendritic. localization of PARD3 and TIAM1 and for dendritic spine formation (PubMed:23595754). Interacts with MAGI1 (PubMed:9647739). Interacts with MAGI3 (PubMed:10748157). Interacts with BAIAP2 (PubMed:10343108). Interacts with PHYHIP (By similarity). Interacts with DLG4 (via PDZ domain) (PubMed:23782696). Vasculostatin-120: Interacts with CD36 (PubMed:19176395). Vasculostatin-120: Interacts with ARRB2 (PubMed:23782696). Interacts with BAIAP3; this interaction is direct (PubMed:9790924).
Phosphatidylserine receptor which enhances the engulfment of apoptotic cells (PubMed:24509909). Also mediates the binding and engulfment of Gram-negative bacteria (PubMed:26838550). Stimulates production of reactive oxygen species by macrophages in response to Gram-negative bacteria, resulting in enhanced microbicidal macrophage activity (PubMed:26838550). In the gastric mucosa, required for recognition and engulfment of apoptotic gastric epithelial cells (PubMed:24509909). Promotes myoblast fusion (By similarity). Activates the Rho pathway in a G-protein-dependent manner (PubMed:23782696). Inhibits MDM2-mediated ubiquitination and degradation of DLG4/PSD95, promoting DLG4 stability and regulating synaptic plasticity (By similarity). Required for the formation of dendritic spines by ensuring the correct localization of PARD3 and TIAM1 (By similarity). Potent inhibitor of angiogenesis in brain and may play a significant role as a mediator of the p53/TP53 signal in suppression of glioblastoma (PubMed:11875720).
Proteolytically cleaved to produce vasculostatin-40 and vasculostatin-120 (PubMed:15782143, PubMed:22333914, PubMed:22330140). Vasculostatin-40 is the major form and is produced through proteolytic cleavage by MMP14 between residues 321 and 329 with cleavage likely to be between Ser-326 and Leu-327 (PubMed:22330140).
The TSP type-1 repeats in the extracellular domain mediate binding to phosphatidylserine. They are also required for bacterial recognition and binding to bacterial outer membrane lipopolysaccharide.
(Microbial infection) Binds to Japanese encephalitis virus (JEV) and Dengue virus (DEN) RNAs.
(Microbial infection) Exhibits antiviral activity against HIV-1 in lymphocytes by decreasing the abundance of HIV-1 viral RNA species.
(Microbial infection) Oligomerization is necessary for antiviral activity (PubMed:23355615).
(Microbial infection) Rapidly degraded in activated T-cells in response to phorbol 13-acetate 12-myristate (PMA) during HIV-1 viral infection (PubMed:24191027).
(Microbial infection) The C3H1-type zinc finger domain is necessary for JEV and DEN viral RNA-binding and antiviral activity (PubMed:23355615).
(Microbial infection) Up-regulated in response to Japanese encephalitis virus (JEV) and dengue virus (DEN) infections (PubMed:23355615).
Endoribonuclease involved in various biological functions such as cellular inflammatory response and immune homeostasis, glial differentiation of neuroprogenitor cells, cell death of cardiomyocytes, adipogenesis and angiogenesis. Functions as an endoribonuclease involved in mRNA decay (PubMed:19909337). Modulates the inflammatory response by promoting the degradation of a set of translationally active cytokine-induced inflammation-related mRNAs, such as IL6 and IL12B, during the early phase of inflammation (PubMed:26320658). Prevents aberrant T-cell-mediated immune reaction by degradation of multiple mRNAs controlling T-cell activation, such as those encoding cytokines (IL6 and IL2), cell surface receptors (ICOS, TNFRSF4 and TNFR2) and transcription factor (REL) (By similarity). Inhibits cooperatively with ZC3H12A the differentiation of helper T cells Th17 in lungs. They repress target mRNA encoding the Th17 cell-promoting factors IL6, ICOS, REL, IRF4, NFKBID and NFKBIZ. The cooperation requires RNA-binding by RC3H1 and the nuclease activity of ZC3H12A (By similarity). Together with RC3H1, destabilizes TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in its 3'UTR (By similarity). Self regulates by destabilizing its own mRNA (By similarity). Cleaves mRNA harboring a stem-loop (SL), often located in their 3'-UTRs, during the early phase of inflammation in a helicase UPF1-dependent manner (PubMed:19909337, PubMed:26320658, PubMed:26134560, PubMed:22561375). Plays a role in the inhibition of microRNAs (miRNAs) biogenesis (PubMed:22055188). Cleaves the terminal loop of a set of precursor miRNAs (pre-miRNAs) important for the regulation of the inflammatory response leading to their degradation, and thus preventing the biosynthesis of mature miRNAs (PubMed:22055188). Also plays a role in promoting angiogenesis in response to inflammatory cytokines by inhibiting the production of antiangiogenic microRNAs via its anti-dicer RNase activity (PubMed:24048733). Affects the overall ubiquitination of cellular proteins (By similarity). Positively regulates deubiquitinase activity promoting the cleavage at 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains on TNF receptor-associated factors (TRAFs), preventing JNK and NF-kappa-B signaling pathway activation, and hence negatively regulating macrophage-mediated inflammatory response and immune homeostasis (By similarity). Induces also deubiquitination of the transcription factor HIF1A, probably leading to its stabilization and nuclear import, thereby positively regulating the expression of proangiogenic HIF1A-targeted genes (PubMed:24048733). Involved in a TANK-dependent negative feedback response to attenuate NF-kappaB activation through the deubiquitination of IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage (PubMed:25861989). Prevents stress granule (SGs) formation and promotes macrophage apoptosis under stress conditions, including arsenite-induced oxidative stress, heat shock and energy deprivation (By similarity). Plays a role in the regulation of macrophage polarization; promotes IL4-induced polarization of macrophages M1 into anti-inflammatory M2 state (By similarity). May also act as a transcription factor that regulates the expression of multiple genes involved in inflammatory response, angiogenesis, adipogenesis and apoptosis (PubMed:16574901, PubMed:18364357). Functions as a positive regulator of glial differentiation of neuroprogenitor cells through an amyloid precursor protein (APP)-dependent signaling pathway (PubMed:19185603). Attenuates septic myocardial contractile dysfunction in response to lipopolysaccharide (LPS) by reducing I-kappa-B-kinase (IKK)-mediated NF-kappa-B activation, and hence myocardial pro-inflammatory cytokine production (By similarity).
Expressed in heart, placenta, spleen, kidney, liver and lung (PubMed:19909337). Expressed in leukocytes (PubMed:19909337). Expressed in monocyte (PubMed:16574901).
Increased expression of ZC3H12A is associated with ischemic heart disease (PubMed:16574901).
Mg(2+) is required for RNase activity (PubMed:22561375).
Oligomer (PubMed:22055188, PubMed:23355615). Found in a deubiquitination complex with TANK, USP10 and ZC3H12A; this complex inhibits genotoxic stress- or interleukin-1-beta-mediated NF-kappaB activation by promoting IKBKG or TRAF6 deubiquitination (PubMed:25861989). Interacts with IKBKG; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with TANK; this interaction increases in response to DNA damage and serves as a bridge to anchor both TANK and USP10 into a deubiquitinating complex (PubMed:25861989). Interacts with TRAF6; this interaction increases in response to DNA damage and is stimulated by TANK (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage and serves as a bridge to anchor both TANK and USP10 into a deubiquitinating complex (PubMed:25861989). Interacts with ZC3H12D (PubMed:26134560). Interacts with TNRC6A (PubMed:26134560). Interacts with IKBKB/IKKB (PubMed:22037600). Interacts with IKBKB/IKKB. Interacts with BTRC; the interaction occurs when ZC3H12A is phosphorylated in a IKBKB/IKKB-dependent manner (By similarity). Interacts with IRAK1; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB (By similarity). Interacts with UPF1; this interaction occurs in a mRNA translationally active- and termination-dependent manner and is essential for ZC3H12A-mediated degradation of target mRNAs (By similarity). Associates with ribosomes (By similarity). Interacts with ubiquitin (By similarity).
Phosphorylated by IRAK1; phosphorylation is necessary for subsequent phosphorylation by the I-kappa-B-kinase (IKK) complex. Phosphorylated by I-kappa-B-kinase (IKK) subunits IKBKB/IKKB and CHUK/IKKA at Ser-438 and Ser-442; these phosphorylations promote ubiquitin proteasome-mediated degradation of ZC3H12A and hence facilitates rapid and robust production of IL-6 mRNA in response to toll-like receptor (TLR) or IL-1 receptor stimuli (By similarity).
Proteolytically cleaved between Arg-111 and Arg-214 by MALT1 in activated T-cells; cleavage at Arg-111 is critical for promoting ZC3H12A degradation in response to T-cell receptor (TCR) stimulation, and hence is necessary for prolonging the stability of a set of mRNAs controlling T-cell activation and Th17 cell differentiation.
The C3H1-type zinc finger domain and C-terminal region are necessary for pre-miRNA binding (PubMed:22055188). The C-terminal region and proline-rich domain are necessary for oligomerization (PubMed:22055188).
Ubiquitinated; ubiquitination is induced in response to interleukin IL1 receptor stimuli in a IKBKB/IKKB and IRAK1-dependent manner, leading to proteasome-mediated degradation (By similarity).
Up-regulated by the transcription factor ELK1 in a interleukin IL1B-dependent manner through activation of the NF-kappa-B and ERK signaling pathways (PubMed:19747262, PubMed:20137095, PubMed:22037600). Up-regulated by chemokine CCL2 in endothelial cells and in peripheral blood monocytes (PubMed:16574901, PubMed:18364357). Up-regulated in activated T lymphocytes (PubMed:23185455). Up-regulated by phorbol 12-myristate 13-acetate (PMA) in primary T lymphocytes (PubMed:19909337, PubMed:23185455). Up-regulated by interleukin IL17 in keratinocytes (PubMed:26320658). Up-regulated by lipopolysaccharide (LPS) (PubMed:19909337). Up-regulated by tumor necrosis factor TNF-alpha and interleukin IL1 in acute monocytic leukemia cell line THP-1 cells (PubMed:18178554, PubMed:19909337). Up-regulated by amyloid precursor protein (APP) (PubMed:19185603).
Was originally proposed to bind to DNA and act as transcription factor.
Expressed strongly in fetal brain and brain (cortex, amygdala, thalamus, substantia nigra, hippocampus, caudate nucleus and corpus callosum). Expressed at low level in testis.
Chimeric cDNA. The in vivo relevance of this transcript of the STON1 (AC Q9Y6Q2) and GTF2A1L genes creating a chimeric protein of 1182 residues is uncertain.
Down-regulated in Sertoli cell-only syndrome (SCOS) patients.
May function as a testis specific transcription factor. Binds DNA in conjunction with GTF2A2 and TBP (the TATA-binding protein) and together with GTF2A2, allows mRNA transcription.
Testis specific. Detected in adult testis mostly in round and elongating spermatids (at protein level). Detected in testis.
Activated by Ca(2+)/calmodulin. Binding of calmodulin may relieve intrasteric autoinhibition. Partially inhibited upon phosphorylation by PRCAKA/PKA (By similarity). May be regulated through phosphorylation by CAMK1 and CAMK4.
Appears to be autophosphorylated in a Ca(2+)/calmodulin-dependent manner. Phosphorylated at multiple sites by PRCAKA/PKA. Phosphorylation of Ser-458 is blocked upon binding to Ca(2+)/calmodulin. In vitro, phosphorylated by CAMK1 and CAMK4 (By similarity).
Calcium/calmodulin-dependent protein kinase that belongs to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Phosphorylates CAMK1, CAMK1D, CAMK1G and CAMK4. Involved in regulating cell apoptosis. Promotes cell survival by phosphorylating AKT1/PKB that inhibits pro-apoptotic BAD/Bcl2-antagonist of cell death.
The RP domain (arginine/proline-rich) is involved in the recognition of CAMKI and CAMK4 as substrates.
The autoinhibitory domain overlaps with the calmodulin binding region and may be involved in intrasteric autoinhibition.
Lacks transmembrane domains and is probably not involved in transport.
Belongs to the copper type II ascorbate-dependent monooxygenase family.
Expressed in fetal liver and fetal brain.
Highly expressed in lung, kidney, brain and spinal cord.
Core component of at least two putative endosomal tethering complexes, the homotypic fusion and vacuole protein sorting (HOPS) complex and the class C core vacuole/endosome tethering (CORVET) complex. Their common core is composed of the class C Vps proteins VPS11, VPS16, VPS18 and VPS33A, which in HOPS further associates with VPS39 and VPS41 and in CORVET with VPS8 and TGFBRAP1 (PubMed:23351085, PubMed:25783203, PubMed:23901104). Interacts with RAB5C (By similarity). Interacts with HOOK1 (By similarity). Interacts with STX7, MON1B (PubMed:20434987, PubMed:24554770). Associates with adaptor protein complex 3 (AP-3) and clathrin:AP-3 complexes (By similarity). Interacts with SYNPO2 (PubMed:23434281). Interacts with PLEKHM1 (PubMed:28325809).
Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Believed to act as a core component of the putative HOPS and CORVET endosomal tethering complexes which are proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The HOPS complex is proposed to be recruited to Rab7 on the late endosomal membrane and to regulate late endocytic, phagocytic and autophagic traffic towards lysosomes. The CORVET complex is proposed to function as a Rab5 effector to mediate early endosome fusion probably in specific endosome subpopulations (PubMed:11382755, PubMed:23351085, PubMed:24554770, PubMed:25783203). Required for fusion of endosomes and autophagosomes with lysosomes (PubMed:25783203). Involved in dendrite development of Pukinje cells (By similarity).
Ubiquitous. Expression was highest in heart and low in lung.
Although it shares weak sequence similarity with GTF2B/TFIIB, displays a similar subdomain organization as GTF2B/TFIIB, with a N-terminal zinc finger, a connecting region (composed of B-reader and B-linker regions), followed by 2 cyclin folds. The RRN7-type zinc finger plays an essential postrecruitment role in Pol I transcription at a step preceding synthesis of the first 40 nucleotides (PubMed:21921198, PubMed:21921199).
Component of RNA polymerase I core factor complex that acts as a GTF2B/TFIIB-like factor and plays a key role in multiple steps during transcription initiation such as pre-initiation complex (PIC) assembly and postpolymerase recruitment events in polymerase I (Pol I) transcription. Binds rDNA promoters and plays a role in Pol I recruitment as a component of the SL1/TIF-IB complex and, possibly, directly through its interaction with RRN3.
Interacts with FLNA (via N-terminus) (By similarity). Component of the transcription factor SL1/TIF-IB complex, composed of TBP and at least TAF1A, TAF1B, TAF1C and TAF1D. In the complex interacts directly with TBP, TAF1A and TAF1C. Interaction of the SL1/TIF-IB subunits with TBP excludes interaction of TBP with the transcription factor IID (TFIID) subunits. Interacts with TBP and RRN3.
By expression of p53/TP53 and by DNA damage in a TP53-dependent manner.
Expressed in placenta and prostate. Weaker expression in thymus. Not expressed in thalamus, hippocampus, pons or cerebellum. Overexpressed in squamous cell carcinoma of the lung.
Receptor for lysophosphatidic acid (LPA). Necessary for p53/TP53-dependent survival in response to DNA damage.
Component of the LUBAC complex which conjugates linear polyubiquitin chains in a head-to-tail manner to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation (PubMed:21455173, PubMed:21455180, PubMed:21455181). LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways (PubMed:21455173, PubMed:21455180, PubMed:21455181). Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation (PubMed:21455173, PubMed:21455180, PubMed:21455181). LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex (PubMed:21455173, PubMed:21455180, PubMed:21455181). The LUBAC complex is also involved in innate immunity by conjugating linear polyubiquitin chains at the surface of bacteria invading the cytosol to form the ubiquitin coat surrounding bacteria (PubMed:28481331). LUBAC is not able to initiate formation of the bacterial ubiquitin coat, and can only promote formation of linear polyubiquitins on pre-existing ubiquitin (PubMed:28481331). The bacterial ubiquitin coat acts as an 'eat-me' signal for xenophagy and promotes NF-kappa-B activation (PubMed:28481331). Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis (PubMed:23708998).
Highly expressed in skeletal muscle and placenta and at lower levels in brain, heart, colon without mucosa, thymus, spleen, kidney, liver, small intestine, lung and peripheral blood leukocytes. Up-regulated in various tumor tissues such as kidney, liver, ovary and pancreas tumors.
Monomer and homodimer (By similarity). Component of the LUBAC complex (linear ubiquitin chain assembly complex) which consists of SHARPIN, RBCK1 and RNF31 (PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:22549881, PubMed:28481331). LUBAC has a MW of approximately 600 kDa suggesting a heteromultimeric assembly of its subunits (PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:22549881). Associates with the TNF-R1 signaling complex (TNF-RSC) in a stimulation-dependent manner (PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:22549881). Interacts with EYA1, EYA2, SHANK1 and SHANK3 (via ANK repeats) (By similarity).
The RanBP2-type zinc fingers mediate the specific interaction with ubiquitin. Binds preferentially linear polyubiquitin chains and 'Lys-63'-linked polyubiquitin chains over 'Lys-48'-linked polyubiquitin chains. Also binds monoubiquitin.
The Ubiquitin-like domain is required for the interaction with RNF31.
(Microbial infection) Interacts with Epstein-Barr virus BSFL2/BMLF1.
A chromosomal aberration involving RBM15 may be a cause of acute megakaryoblastic leukemia. Translocation t(1;22)(p13;q13) with MKL1. Although both reciprocal fusion transcripts are detected in acute megakaryoblastic leukemia (AMKL, FAB-M7), the RBM15-MKL1 chimeric protein has all the putative functional domains encoded by each gene and is the candidate oncogene.
Component of the WMM complex, a N6-methyltransferase complex composed of a catalytic subcomplex, named MAC, and of an associated subcomplex, named MACOM (PubMed:27602518). The MAC subcomplex is composed of METTL3 and METTL14 (PubMed:27602518). The MACOM subcomplex is composed of WTAP, ZC3H13, CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B) (PubMed:27602518). Also a component of a MACOM-like complex, named WTAP complex, composed of WTAP, ZC3H13, CBLL1, VIRMA, RBM15, BCLAF1 and THRAP3 (PubMed:24100041). Interacts with RBPJ (By similarity). Interacts (via SPOC domain) with SETD1B (PubMed:22927943). Interacts with NXF1, the interaction is required to promote mRNA export (PubMed:17001072). Interacts with SF3B1 (PubMed:26575292).
Methylated at Arg-578 by PRMT1, leading to promote ubiquitination by CNOT4 and subsequent degradation by the proteasome.
RNA-binding protein that acts as a key regulator of N6-methyladenosine (m6A) methylation of RNAs, thereby regulating different processes, such as hematopoietic cell homeostasis, alternative splicing of mRNAs and X chromosome inactivation mediated by Xist RNA (PubMed:27602518). Associated component of the WMM complex, a complex that mediates N6-methyladenosine (m6A) methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing (By similarity). Plays a key role in m6A methylation, possibly by binding target RNAs and recruiting the WMM complex (PubMed:27602518). Involved in random X inactivation mediated by Xist RNA: acts by binding Xist RNA and recruiting the WMM complex, which mediates m6A methylation, leading to target YTHDC1 reader on Xist RNA and promoting transcription repression activity of Xist (PubMed:27602518). Required for the development of multiple tissues, such as the maintenance of the homeostasis of long-term hematopoietic stem cells and for megakaryocyte (MK) and B-cell differentiation (By similarity). Regulates megakaryocyte differentiation by regulating alternative splicing of genes important for megakaryocyte differentiation; probably regulates alternative splicing via m6A regulation (PubMed:26575292). Required for placental vascular branching morphogenesis and embryonic development of the heart and spleen (By similarity). Acts as a regulator of thrombopoietin response in hematopoietic stem cells by regulating alternative splicing of MPL (By similarity). May also function as an mRNA export factor, stimulating export and expression of RTE-containing mRNAs which are present in many retrotransposons that require to be exported prior to splicing (PubMed:17001072, PubMed:19786495). High affinity binding of pre-mRNA to RBM15 may allow targeting of the mRNP to the export helicase DBP5 in a manner that is independent of splicing-mediated NXF1 deposition, resulting in export prior to splicing (PubMed:17001072, PubMed:19786495). May be implicated in HOX gene regulation (PubMed:11344311).
Ubiquitinated by CNOT4 following methylation at Arg-578 by PRMT1.
Highly expressed in placenta, skeletal muscle, liver, brain, kidney, heart, thymus, spinal cord, lung, peripheral blood leukocytes, pancreas, lymph nodes, spleen, prostate, testis, ovary, small intestine, colon, mammary gland, breast and breast carcinoma, and in common-type meningioma. Highly expressed in fetal liver, heart and brain.
Oligomerizes and associates with TNKS. Interacts with the cytoplasmic domain of LNPEP/Otase in SLC2A4/GLUT4-vesicles (PubMed:11802774). Binds to the N-terminus of Grb14 and TRF1 with its ankyrin repeat region (PubMed:11802774). Interacts with HIF1AN (PubMed:18936059, PubMed:21251231). Interacts with RNF146; this interaction leads to ubiquitination and proteasomal degradation (PubMed:21799911). Interacts with NUMA1 (PubMed:12080061).
Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking (PubMed:11739745, PubMed:11802774, PubMed:19759537, PubMed:21478859, PubMed:23622245, PubMed:25043379). Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation (PubMed:19759537, PubMed:21478859). Also mediates poly-ADP-ribosylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination (PubMed:21478859). Mediates poly-ADP-ribosylation of TERF1, thereby contributing to the regulation of telomere length (PubMed:11739745). Stimulates 26S proteasome activity (PubMed:23622245).
Specifically inhibited by XAV939, a small molecule, leading to inhibit the Wnt signaling pathway by stabilizing AXIN1 and AXIN2 (PubMed:19759537). Inhibited by talazoparib (PubMed:33361107).
The crystallographic evidence suggests that the 3-hydroxyhistidine may be the (3S) stereoisomer.
Ubiquitinated at 'Lys-48' and 'Lys-63' by RNF146 when auto-poly-ADP-ribosylated; this leads to degradation.
Forms a heterodimer with SIMC1 (PubMed:36373674). Interacts with SLF1 (via N-terminus); this interaction links RAD18 to the SMC5-SMC6 complex (PubMed:25931565, PubMed:36333305, PubMed:36373674). Interacts with RAD18; this interaction is increased in a SLF1-dependent manner (PubMed:25931565, PubMed:36333305). Interacts with SMC5 and SMC6 (PubMed:25931565).
Localized in the locus associated with inherited infantile onset spinocerebellar ataxia (IOSCA). No mutation were found associated with IOSCA compared to control subjects. The expression level in the brain was not different between the 2 populations.
Plays a role in the DNA damage response (DDR) pathway by regulating postreplication repair of UV-damaged DNA and genomic stability maintenance (PubMed:25931565). The SLF1-SLF2 complex acts to link RAD18 with the SMC5-SMC6 complex at replication-coupled interstrand cross-links (ICL) and DNA double-strand breaks (DSBs) sites on chromatin during DNA repair in response to stalled replication forks (PubMed:25931565). Promotes the recruitment of the SMC5-SMC6 complex to DNA lesions (PubMed:25931565). Plays a role in SMC5-SMC6 complex recruitment for viral restriction. Forms a complex with SIMC1 and this complex is required to recruit SMC5-SMC6 complex to PML nuclear bodies and sites of viral replication (PubMed:36373674).
Widely expressed (PubMed:12459258, PubMed:36333305). Expressed at higher level in skeletal muscle and at slightly lower level in brain, liver and heart, than in lung, kidney, spleen and thymus (PubMed:12459258).
Forms homodimers and heterodimers with FOXP1 and FOXP2. Dimerization is required for DNA-binding (By similarity).
The leucine-zipper is required for dimerization and transcriptional repression.
Transcriptional repressor that represses lung-specific expression.
Homodimer (By similarity). Interacts with TBP (PubMed:7982918). Interacts with TAF1A (PubMed:7491500). Interacts with RASL11A (By similarity). Binds to IRS1 and PIK3CA (By similarity). Interacts with DHX33 (PubMed:21930779). Interacts with PHF6 (PubMed:23229552). Interacts with CEBPA (isoform 1 and isoform 4) (PubMed:20075868). Interacts with DDX11 (PubMed:26089203). Interacts with NOP53 (PubMed:27729611). Interacts with ALKBH2.
Recognizes the ribosomal RNA gene promoter and activates transcription mediated by RNA polymerase I through cooperative interactions with the transcription factor SL1/TIF-IB complex. It binds specifically to the upstream control element.
Detected in keratinocytes, liver and placenta (PubMed:15610520). Expressed in a subset of cells in pediatric medulloblastoma (PubMed:18619852).
Interacts with PPARA, PPARD and PPARG. Interacts with RARA, RARG and RXRA in the presence of bound ligand (PubMed:15610520). Interacts with SCOC (PubMed:22354037). Associates with the PI3K complex I (PI3KC3-C1); the direct binding partner in the complex is reported variably as PIK3R4 or ATG14 (PubMed:24785657).
Involved in starvation-induced autophagy probably by its association with PI3K complex I (PI3KC3-C1). However, effects has been described variably. Involved in the induction of starvation-induced autophagy (PubMed:24785657). Stabilzes PI3KC3-C1 assembly and enhances ATG14-linked lipid kinase activity of PIK3C3 (By similarity). Proposed to negatively regulate basal and starvation-induced autophagy and to inhibit PIK3C3 activity by modulating interactions in PI3KC3-C1 (PubMed:25086043). May be involved in autophagosome biogenesis (PubMed:25086043). May play a role in neural progenitor cell survival during differentiation (By similarity).
May modulate transcriptional activation by target nuclear receptors. Can act as transcriptional activator (in vitro).
Catalyzes the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to the N-acetyl glucosamine (GlcNAc) of a distal alpha2,3 sialylated lactosamine unit of a glycoprotein- or a glycolipid-linked sialopolylactosamines chain or of a distal or internal lactosamine unit of a neutral glycoprotein- or a glycolipid-linked polylactosamines chain through an alpha-1,3 glycosidic linkage and participates in surface expression of the sialyl Lewis X (sLe(x)), Lewis X (Le(x)) and non sialylated VIM2 determinants (PubMed:9451035, PubMed:1520296, PubMed:1339443, PubMed:7650030, PubMed:17604274, PubMed:9363434, PubMed:10728707, PubMed:29593094). Moreover transfers fucose to H-type 2 (Fucalpha1-2Galbeta1-4GlcNAc) chain acceptor substrates and participates in difucosylated sialyl Lewis x determinants (PubMed:17604274, PubMed:1339443). Also fucosylates a polylactosamine substrate having a 6 sulfate modification at the GlcNAc moiety and gives rise to sialyl and non-sialyl 6-sulfo lewis X (PubMed:10728707). Does not have activity towards type 1 ((Galbeta1-3GlcNAc)) and H-type 1 chain (Fucalpha1-2Galbeta1-3GlcNAc) acceptors substrates (PubMed:1339443, PubMed:17604274, PubMed:9363434).
Does not have alpha(1,3)-fucosyltransferase activity.
Expression of alpha(1,3)-fucosyltransferase in plasma can vary among different populations. 9% of individuals on the isle of Java (Indonesia) do not express this enzyme. Ninety-five percent of plasma alpha(1,3)-fucosyltransferase-deficient individuals have Lewis negative phenotype on red cells, suggesting strong linkage disequilibrium between these two traits. Variations in FUT6 are responsible for plasma alpha(1,3)-fucosyltransferase deficiency [MIM:613852].
Homodimer and monomer (PubMed:9451035). Monomer (secreted form) (PubMed:9451035).
Kidney, liver, colon, small intestine, bladder, uterus and salivary gland.
Proteolytic cleavage releases a secreted glycoform of 43 kDa.
Allosterically activated by phosphatidylinositol 5-phosphate (PI5P).
Heterodimer with MTMR12 (PubMed:12847286, PubMed:23818870). Interacts with KMT2A/MLL1 (via SET domain) (PubMed:9537414). Interacts with DES in skeletal muscle but not in cardiac muscle (PubMed:21135508). Interacts with SPEG (PubMed:25087613).
Lipid phosphatase which dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) (PubMed:11001925, PubMed:10900271, PubMed:12646134, PubMed:14722070). Has also been shown to dephosphorylate phosphotyrosine- and phosphoserine-containing peptides (PubMed:9537414). Negatively regulates EGFR degradation through regulation of EGFR trafficking from the late endosome to the lysosome (PubMed:14722070). Plays a role in vacuolar formation and morphology. Regulates desmin intermediate filament assembly and architecture (PubMed:21135508). Plays a role in mitochondrial morphology and positioning (PubMed:21135508). Required for skeletal muscle maintenance but not for myogenesis (PubMed:21135508). In skeletal muscles, stabilizes MTMR12 protein levels (PubMed:23818870).
The GRAM domain mediates binding to PI(3,5)P2 and, with lower affinity, to other phosphoinositides.
Homodimer (PubMed:35613257). Found in the forms of complex and dynamic macromolecular complexes (By similarity). Binds NHERF1 and NHERF2 (By similarity). Interacts with CHP1; increases SLC9A3 trafficking and activity at the plasma membrane (PubMed:35613257). Interacts with CHP2 and SHANK2. Interacts with PDZK1 (via C-terminal PDZ domain) (By similarity). Interacts with NHERF4 and interaction decrease in response to elevated calcium ion levels. Interacts with AHCYL1; the interaction is required for SLC9A3 activity (PubMed:18829453, PubMed:20584908). Interacts with SNX27 (via PDZ domains); directs SLC9A3 membrane insertion from early endosomes to the plasma membrane (PubMed:25851603). Interacts with EZR; interaction targets SLC9A3 to the apical membrane (By similarity).
Phosphorylated by PKA, which inhibits activity. Phosphorylation at Ser-663 by SGK1 is associated with increased abundance at the cell membrane. Phosphorylation at Ser-718 by CSNK2A1 regulates SLC9A3 activity through the formation of multiple signaling complexes (By similarity).
Plasma membrane Na(+)/H(+) antiporter (PubMed:26358773, PubMed:35613257, PubMed:18829453). Exchanges intracellular H(+) ions for extracellular Na(+) in 1:1 stoichiometry, playing a key role in salt and fluid absorption and pH homeostasis (By similarity). Major apical Na(+)/H(+) exchanger in kidney and intestine playing an important role in renal and intestine Na(+) absorption and blood pressure regulation (PubMed:26358773, PubMed:24622516).
Seems to switch between active and inactive modes in response to various stimuli (PubMed:35613257). Activated directly or indirectly by membrane phosphatidylinositol (PIs) (PubMed:35613257). Regulated by a variety of auxiliary proteins, which facilitate the maturation, cell surface expression and function of the transporter (PubMed:35613257, PubMed:25851603, PubMed:18829453). Inhibited specifically by the drug tenapanor (PubMed:24622516).
Expression at transcriptional level is activated by the expression of the neighboring long non-coding RNA (lncRNA) EMICERI.
Modulates LATS1 expression in the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis.
Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses (By similarity). Interacts (via SAM domain) with ANKS1A (via SAM domain) (By similarity).
Receptor tyrosine kinase which binds promiscuously GPI-anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling (By similarity).
Belongs to the copper transporter (Ctr) (TC 1.A.56) family. SLC31A subfamily.
Copper(1+) transport is stimulated by extracellular acidic pH and high potassium ions concentrations (PubMed:11734551). Copper(1+) import is regulated by a copper(1+)-dependent recycling of SLC31A1 (PubMed:19740744).
Homotrimer (PubMed:11734551, PubMed:15326162, PubMed:16501047); is stabilized by cisplatin (PubMed:15326162) via interactions between cisplatin and the methionine-rich clusters(PubMed:15326162), and could be crucial for the copper(2+) reduction process and copper(1+) stabilization (PubMed:32914794, PubMed:11734551, PubMed:16501047, PubMed:15326162). Heterotrimer between SLC31A1, CCS and SOD1; this heterotrimer is copper(1+)-mediated and its maintenance is regulated through SOD1 activation (PubMed:31292775). Interacts with KDR; this interaction is induced upon VEGFA stimulation leading to SLC31A1 and KDR subsequent co-internalization to early endosomes, thereby activating KDR downstream signaling in endothelial cells (PubMed:35027734). Interacts (via C-terminal domain) with ATOX1 (via dimer form); this interaction improves ATOX1 stability and controls intracellular copper(1+) levels (PubMed:24837030, PubMed:26745413). Interacts with SLC31A2; this interaction stabilizes SLC31A2 and protects its from ubiquitination and degradation (PubMed:26205368). Interacts (via C-terminal domain) with CCS; this interaction is copper(1+)-mediated (PubMed:31292775).
Mobilizes copper(1+) out of the endosomal compartment, making copper(1+) available for export out of the cells.
O-Glycosylation at Thr-27 protects from proteolytic cleavage in the N-terminal extracellular domain.
Proteolytic cleavage, leading to a truncated form, is facilitated by SLC31A2 (PubMed:24167251) and initiated preferentially by CTSL and to a minor extend by CTSB in endolysosomal compartments (PubMed:27143361, PubMed:24167251). In vitro, is cleaved by CTSL/cathepsin L between residues 8 and 9 from the amino terminus (PubMed:27143361). A post-CTSL/cathepsin L processing occurs to yield to the fully truncated form (PubMed:27143361).
Sulfenylated at Cys-189 after stimulation with VEGFA, which induces SLC31A1-KDR disulfide bond formation and their co-internalization to early endosomes, driving to a sustained VEGFR2 signaling.
The C-terminal domain mediates copper(1+) binding (PubMed:26745413) and is involved in the copper(1+)-dependent-ATOX1 interaction (PubMed:26745413, PubMed:24837030). The C-terminal domain appears to act to limit transport through the pore by regulating the rate of exit of copper ions at the intracellular side (PubMed:23658018). The N-terminal domain can collect copper(2+) from copper(2+) carriers in blood (PubMed:30489586). The N-terminal domain, in the trimeric arrangement, tunes its reactivity with copper, promoting copper(2+) reduction and copper(1+) stabilization thanks to the presence of histidine (His) and methionine (Met) motifs (PubMed:32914794, Ref.24). The bis-His motif directly coordinate to copper(2+), whereas the Mets motif is involved in copper(1+) binding (Ref.24). The ligand switching between the bis-His motif and the Mets motif is regulated by pH (PubMed:35601835).
Uniporter that mediates the transport of copper(1+) from the extracellular space to the cytoplasm, across the plasma membrane (PubMed:11734551, PubMed:16135512, PubMed:17525160, PubMed:19740744, PubMed:20451502, PubMed:20569931, PubMed:23658018) and delivers directly copper(1+) to specific chaperone such as ATOX1, via a copper(1+)- mediated transient interaction between the C-terminal domain and a copper(1+) chaperone, thus controlling intracellular copper(1+) levels (PubMed:26745413, PubMed:11734551, PubMed:17525160, PubMed:20451502, PubMed:19740744, PubMed:16135512, PubMed:23658018, PubMed:20569931). May function in copper(1+) import from the apical membrane thus may drive intestinal copper absorption (By similarity). The copper(1+) transport mechanism is sodium-independent, saturable and of high-affinity (PubMed:11734551). Also mediates the uptake of silver(1+) (PubMed:20569931). May function in the influx of the platinum-containing chemotherapeutic agents (PubMed:20451502, PubMed:20569931). The platinum-containing chemotherapeutic agents uptake is saturable (By similarity). In vitro, mediates the transport of cadmium(2+) into cells (PubMed:33294387). Also participates in the first step of copper(2+) acquisition by cells through a direct transfer of copper(2+) from copper(2+) carriers in blood, such as ALB to the N-terminal domain of SLC31A1, leading to copper(2+) reduction and probably followed by copper(1+) stabilization (PubMed:30489586). In addition, functions as a redox sensor to promote angiogenesis in endothelial cells, in a copper(1+) transport independent manner, by transmitting the VEGF-induced ROS signal through a sulfenylation at Cys-189 leadin g to a subsequent disulfide bond formation between SLC31A1 and KDR (PubMed:35027734). The SLC31A1-KDR complex is then co-internalized to early endosomes, driving a sustained VEGFR2 signaling (PubMed:35027734).
Does not bind to glycogen (PubMed:18617530). Lacks phosphatase activity and might function as a dominant-negative regulator for the phosphatase activity of isoform 1 and isoform 7 (PubMed:18617530, PubMed:22036712).
Expressed in heart, skeletal muscle, kidney, pancreas and brain. Isoform 4 is also expressed in the placenta.
Homodimer (PubMed:16971387, PubMed:18617530, PubMed:23922729, PubMed:25538239, PubMed:25544560). Interacts with itself (PubMed:14532330). Interacts with PPP1R3B, PPP1R3C, PPP1R3D, HIRIP5, and EPM2AIP1 (PubMed:12782127, PubMed:12915448, PubMed:14532330, PubMed:16901901, PubMed:18070875). Binds glycogen and Lafora bodies (PubMed:11739371, PubMed:14532330, PubMed:14706656, PubMed:15102711, PubMed:18617530, PubMed:22036712). Interacts with NHLRC1/malin (via the NHL repeats) (PubMed:15930137, PubMed:22036712, PubMed:23922729). Forms a complex with NHLRC1/malin and HSP70 (PubMed:19036738). Interacts with PPP1R3D; in the presence of NHLC1/malin the interaction leads to ubiquitination and autophagic degradation of PPP1R3D. Interacts (via the phosphatase domain) with MAPT/Tau; the interaction dephosphorylates MAPT (PubMed:19542233). Isoform 1 and isoform 2 interact to form a heterodimeric complex that lacks phosphatase activity (in vitro) (PubMed:18617530). Active phosphatase isoform 7 and isoform 1 interact with each other, but give rise to lower phosphatase activity than isoform 1 or isoform 7 by themselves (in vitro) (PubMed:22036712). Active phosphatase isoform 7 and inactive isoform 2 interact with each other, but give rise to lower phosphatase activity than isoform 7 by itself (in vitro) (PubMed:22036712). Interacts with PRDM8 (PubMed:22961547).
Phosphorylation on Ser-25 by AMPK affects the phosphatase activity of the enzyme and its ability to homodimerize and interact with NHLRC1, PPP1R3C or PRKAA2.
Plays an important role in preventing glycogen hyperphosphorylation and the formation of insoluble aggregates, via its activity as glycogen phosphatase, and by promoting the ubiquitination of proteins involved in glycogen metabolism via its interaction with the E3 ubiquitin ligase NHLRC1/malin. Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates (PubMed:16901901, PubMed:23922729, PubMed:26231210, PubMed:25538239, PubMed:25544560). Dephosphorylates phosphotyrosine and synthetic substrates, such as para-nitrophenylphosphate (pNPP), and has low activity with phosphoserine and phosphothreonine substrates (in vitro) (PubMed:11001928, PubMed:11220751, PubMed:11739371, PubMed:14532330, PubMed:16971387, PubMed:18617530, PubMed:22036712, PubMed:23922729, PubMed:14722920). Has been shown to dephosphorylate MAPT (By similarity). Forms a complex with NHLRC1/malin and HSP70, which suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Acts as a scaffold protein to facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin (PubMed:23922729). Also promotes proteasome-independent protein degradation through the macroautophagy pathway (PubMed:20453062).
Produced by alternative initiation at Met-244 of isoform 1. Transcript amplified but protein not detected.
Produced by alternative splicing. Active phosphatase.
Produced by alternative splicing. May be due to an intron retention.
The CBM20 domain mediates binding to cytoplasmic glycogen and to Lafora polyglucosan bodies.
Catalyzes the oxidation of the less abundant 1,2-dihydro-beta-NAD(P) and 1,6-dihydro-beta-NAD(P) to form beta-NAD(P)(+). The enzyme hormone is secreted by the kidney, and circulates in blood and modulates cardiac function and systemic blood pressure. Lowers blood pressure in vivo by decreasing cardiac contractility and heart rate and preventing a compensatory increase in peripheral vascular tone, suggesting a causal link to the increased plasma catecholamine and heightened cardiovascular risk. High concentrations of catecholamines activate plasma renalase and promotes its secretion and synthesis.
Secreted into the blood by the kidney. Highly expressed in the kidney, expressed at lower level in heart, skeletal muscle and small intestine. Its plasma concentration is markedly reduced in patients with end-stage renal disease, as compared with healthy subjects.
Component of the nexin-dynein regulatory complex (N-DRC). Interacts with CFAP52 (By similarity).
A stop codon in the gene coding for this protein at position Gln-194 is responsible for functional diversity thus producing a pseudogene. The stop codon is more frequent in non-Africans than in African-Americans.
Belongs to the SPEC3 family. Stum subfamily.
As part of the BORC complex may play a role in lysosomes movement and localization at the cell periphery. Associated with the cytosolic face of lysosomes, the BORC complex may recruit ARL8B and couple lysosomes to microtubule plus-end-directed kinesin motor.
Component of the BLOC-one-related complex (BORC) which is composed of BLOC1S1, BLOC1S2, BORCS5, BORCS6, BORCS7, BORCS8, KXD1 and SNAPIN.
Expressed in acute myelogenous leukemia (AML) and in acute lymphoblastic leukemia (ALL).
Interacts with GNAQ (PubMed:18434541, PubMed:19478087, PubMed:28784619). Does not interact with GNAI1 and GNAI3 (PubMed:18434541, PubMed:19478087). Interacts with EIF2B5 (PubMed:19736320). Interacts with PRKG1 (isoform alpha) (PubMed:14608379).
Lacks type V adenylyl cyclase (AC) inhibitory function.
Phosphorylated by protein kinase C. Phosphorylation by PRKG1 leads to activation of RGS2 activity.
Regulates G protein-coupled receptor signaling cascades. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form (PubMed:11063746, PubMed:19478087). It is involved in the negative regulation of the angiotensin-activated signaling pathway (PubMed:28784619). Plays a role in the regulation of blood pressure in response to signaling via G protein-coupled receptors and GNAQ. Plays a role in regulating the constriction and relaxation of vascular smooth muscle (By similarity). Binds EIF2B5 and blocks its activity, thereby inhibiting the translation of mRNA into protein (PubMed:19736320).
Acts as co-chaperone regulating the molecular chaperones HSP70 and HSP90 in folding of steroid receptors, such as the glucocorticoid receptor and the progesterone receptor. Proposed to act as a recycling chaperone by facilitating the return of chaperone substrates to early stages of chaperoning if further folding is required. In vitro, induces ATP-independent dissociation of HSP90 but not of HSP70 from the chaperone-substrate complexes. Recruits NR1I3 to the cytoplasm (By similarity).
Associates with complexes containing chaperones HSP70 and HSP90. Interacts with the GAP domain of NF1. Interacts with HSP90AA1. Interacts with HSPA1A/B; the interaction is enhanced by ATP. Interacts with HSP90AB1. Interacts with PGR. Interacts with RAD9A; the interaction is interrupted by UV and heat shock treatments. Interacts with HUS1 and RAD1. Interacts with NR1I3. The DNAJC7-NR1I3 complex may also include HSP90 (By similarity). Interacts with HSPA8.
RNA-binding factor which binds specifically to the very 3'-UTR ends of both histone H1 and H3.3 mRNAs, encompassing the polyadenylation signal. Might play a central role in the negative regulation of histone variant synthesis in the developing brain (By similarity).
As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway (PubMed:23723238, PubMed:25457612, PubMed:29769719, PubMed:31548394, PubMed:29590090, PubMed:35338845). In response to amino acid depletion, the GATOR1 complex has GTPase activating protein (GAP) activity and strongly increases GTP hydrolysis by RagA/RRAGA (or RagB/RRAGB) within heterodimeric Rag complexes, thereby turning them into their inactive GDP-bound form, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling (PubMed:23723238, PubMed:25457612, PubMed:29769719, PubMed:29590090, PubMed:35338845). In the presence of abundant amino acids, the GATOR1 complex is negatively regulated by GATOR2, the other GATOR subcomplex, in this amino acid-sensing branch of the TORC1 pathway (PubMed:23723238, PubMed:25457612, PubMed:29769719). Within the GATOR1 complex, DEPDC5 mediates direct interaction with the nucleotide-binding pocket of small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD) and coordinates their nucleotide loading states by promoting RagA/RRAGA or RagB/RRAGB into their GDP-binding state and RagC/RRAGC or RagD/RRAGD into their GTP-binding state (PubMed:29590090, PubMed:35338845). However, it does not execute the GAP activity, which is mediated by NPRL2 (PubMed:29590090).
Expressed in developing and adult brain.
Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins, including DEPDC5, are detected in glioblastoma and ovarian tumors and are associated with loss of heterozygosity events. Inactivation of GATOR1 proteins promotes constitutive localization of mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation following amino acid withdrawal (PubMed:23723238).
Phosphorylation at Ser-1002 and Ser-1530 by AKT1 and PIM1 inhibit the activity of DEPDC5, releasing inhibition of the mTORC1 pathway.
The DEP domain mediates the interaction with KLHL22.
Ubiquitinated (PubMed:29769719). Amino acid-induced 'Lys-48'-linked polyubiquitination of DEPDC5 by the BCR(KLHL22) ubiquitin ligase complex leads to DEPDC5 proteasomal degradation and inhibition of the GATOR1 complex (PubMed:29769719). Ubiquitination may occur at multiple lysines (PubMed:29769719).
Within the GATOR complex, component of the GATOR1 subcomplex, made of DEPDC5, NPRL2 and NPRL3 (PubMed:23723238, PubMed:25366275, PubMed:29590090, PubMed:35338845). GATOR1 mediates the strong interaction of the GATOR complex with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD) heterodimers (PubMed:23723238, PubMed:29590090). Interacts with BMT2/SAMTOR; interaction is direct and takes place in presence of methionine, leading to inhibit the activity of the GATOR1 complex (PubMed:29590090).
Broad specificity mitochondrial dioxygenase that mediates the asymmetric oxidative cleavage of carotenoids. Cleaves carotenes (pure hydrocarbon carotenoids) such as all-trans-beta-carotene and lycopene as well as xanthophylls (oxygenated carotenoids) such as zeaxanthin, lutein and beta-cryptoxanthin at both the 9,10 and the 9',10' carbon-carbon double bond. Through its function in carotenoids metabolism regulates oxidative stress and the production of important signaling molecules.
Highly expressed in retinal pigment epithelium. Also expressed in stomach, small intestine, liver, testis, kidney, adrenal gland, pancreas, heart, skeletal muscle and prostate (at protein level).
Belongs to the ELO family. ELOVL6 subfamily.
Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme that elongates fatty acids with 12, 14 and 16 carbons with higher activity toward C16:0 acyl-CoAs. Catalyzes the synthesis of unsaturated C16 long chain fatty acids and, to a lesser extent, C18:0 and those with low desaturation degree. May participate in the production of saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.
The reaction is stimulated by the presence of HSD17B12, the enzyme catalyzing the second step of the elongation cycle.
Mainly expressed in the kidney. Up-regulated in lung adenocarcinomas and prostate cancers.
Belongs to the clathrin light chain family.
Clathrin coats are formed from molecules containing 3 heavy chains and 3 light chains. Interacts (via N-terminus) with HIP1. Interacts with HIP1R.
Clathrin is the major protein of the polyhedral coat of coated pits and vesicles.
Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structure.
eIF4F is a multi-subunit complex, the composition of which varies with external and internal environmental conditions. It is composed of at least EIF4A, EIF4E and EIF4G (By similarity).
Belongs to the D-glutamate cyclase family.
D-glutamate cyclase that converts D-glutamate to 5-oxo-D-proline.
Belongs to the phospholipase D family. MitoPLD/Zucchini subfamily.
Evidence for subcellular location in the Golgi was determined in pachytene spermatocytes and spermatids in mouse testes. They observe that the ectopically expressed PLD6 protein was localized to the mitochondria in PLD6-transfected cells. Authors claim a possible explanation for the contradictory results is that previous studies have reported the localization of exogenous PLD6, but not endogenous PLD6, in cultured cells. The reason for differences observed in subcellular localization of exogenous and endogenous PLD6 is not clear but one attributable reason may be that different types of anti-PLD6 antibodies have been used in previous studies.
Homodimer (PubMed:17028579). Interacts with MOV10L1 (By similarity). Interacts with MIGA1 and MIGA2; possibly facilitating homodimer formation (PubMed:26711011). Interacts with GK2 (PubMed:28852571).
In contrast to other members of the phospholipase D family, contains only one PLD phosphodiesterase domain, suggesting that it has a single half-catalytic and requires homodimerization to form a complete active site.
MYC stimulates its phospholipase activity (PubMed:26678338). MIGA1 and MIGA2 increase PLD6 self-association affinity and affects the homodimer conformation facilitating its phospholipase activity over the nuclease activity (PubMed:26711011). Single stranded DNA (ssDNA) hydrolase activity does not depend upon, but is stimulated by the presence of Ca(2+) and Mn(2+) (By similarity).
Predominantly expressed in testis and ovary, but not limited to gonads (at protein level) (PubMed:17028579, PubMed:21397847). It is also found in brain, heart, pituitary gland, prostate, pancreas, thyroid, bone marrow, lung and muscle (PubMed:21397847).
Presents phospholipase and nuclease activities, depending on the different physiological conditions (PubMed:17028579, PubMed:21397847, PubMed:28063496). Interaction with Mitoguardin (MIGA1 or MIGA2) affects the dimer conformation, facilitating the lipase activity over the nuclease activity (PubMed:26711011). Plays a key role in mitochondrial fusion and fission via its phospholipase activity (PubMed:17028579, PubMed:24599962, PubMed:26678338). In its phospholipase role, it uses the mitochondrial lipid cardiolipin as substrate to generate phosphatidate (PA or 1,2-diacyl-sn-glycero-3-phosphate), a second messenger signaling lipid (PubMed:17028579, PubMed:26711011). Production of PA facilitates Mitofusin-mediated fusion, whereas the cleavage of PA by the Lipin family of phosphatases produces diacylgycerol (DAG) which promotes mitochondrial fission (PubMed:24599962). Both Lipin and DAG regulate mitochondrial dynamics and membrane fusion/fission, important processes for adapting mitochondrial metabolism to changes in cell physiology. Mitochondrial fusion enables cells to cope with the increased nucleotide demand during DNA synthesis (PubMed:26678338). Mitochondrial function and dynamics are closely associated with biological processes such as cell growth, proliferation, and differentiation (PubMed:21397848). Mediator of MYC activity, promotes mitochondrial fusion and activates AMPK which in turn inhibits YAP/TAZ, thereby inducing cell growth and proliferation (PubMed:26678338). The endonuclease activity plays a critical role in PIWI-interacting RNA (piRNA) biogenesis during spermatogenesis (PubMed:21397847, PubMed:21397848). Implicated in spermatogenesis and sperm fertility in testicular germ cells, its single strand-specific nuclease activity is critical for the biogenesis/maturation of PIWI-interacting RNA (piRNA). MOV10L1 selectively binds to piRNA precursors and funnels them to the endonuclease that catalyzes the first cleavage step of piRNA processing to generate piRNA intermediate fragments that are subsequently loaded to Piwi proteins. Cleaves either DNA or RNA substrates with similar affinity, producing a 5' phosphate end, in this way it participates in the processing of primary piRNA transcripts. piRNAs provide essential protection against the activity of mobile genetic elements. piRNA-mediated transposon silencing is thus critical for maintaining genome stability, in particular in germline cells when transposons are mobilized as a consequence of wide-spread genomic demethylation (By similarity). PA may act as signaling molecule in the recognition/transport of the precursor RNAs of primary piRNAs (PubMed:21397847). Interacts with tesmin in testes, suggesting a role in spermatogenesis via association with its interacting partner (By similarity).
Detected at high levels in caudate nucleus, hippocampus and amygdala; at moderate levels in the adult brain, thalamus, parietal cortex, pituitary gland, adrenal gland and lymph nodes.
Interacts specifically with a number of opioid ligands. Receptor for neuropeptides B and W, which may be involved in neuroendocrine system regulation, food intake and the organization of other signals.
Expressed predominantly in the cerebellum and kidney.
The L-type calcium channel is composed of four subunits: alpha-1, alpha-2, beta and gamma (PubMed:11880487). Interacts with FASLG (PubMed:19807924). Interacts with CBARP (By similarity).
The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting.
Unable to interact with the alpha-1 subunit.
Expressed in lymph node, spleen, thymus and bone marrow.
May play a role in B-lineage commitment and/or modulation of signaling through the B-cell receptor.
Inhibits the interaction of APBA2 with amyloid-beta precursor protein (APP), and hence allows formation of amyloid-beta. May enhance the activity of HIF1A and thus promote glycolysis under normoxic conditions; the function requires its ABM domain and may implicate the stabilization of the interaction between HIF1AN and APBA3.
Interacts with the N-terminal domain of APBA2. Interacts with NEK2. Interacts with APBA3; APBA3 seems to mediate the interaction between NECAB3 and HIF1AN.
May result from the retention of an intron in the cDNA.
Strongly expressed in heart and skeletal muscle, moderately in brain and pancreas.
Higher expression in lung, colon, mammary gland, cervix, stomach and small intestine.
Over-expression suppresses AP1, CREB, NFAT, and NF-kB transcriptional activation, and delays cell cycle progression at S phase.
Transcription regulator required for brain development (PubMed:20346720). Probably acts as a transcription factor that binds to the promoter of target genes and recruits PHF8 histone demethylase, leading to activated expression of genes involved in neuron development, such as KDM5C (PubMed:20346720, PubMed:31691806). May compete with transcription factor ARX for activation of expression of KDM5C (PubMed:31691806).
Antiparallel homodimer; disulfide-linked (PubMed:7664082). Interaction with LMBR1L has been observed in PubMed:16423471, but not in PubMed:23964685 (PubMed:16423471, PubMed:23964685).
Binds phosphatidylcholine, phosphatidylinositol, polychlorinated biphenyls (PCB) and weakly progesterone, potent inhibitor of phospholipase A2.
Club cells (nonciliated cells of the surface epithelium of the pulmonary airways).
Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II (PubMed:12612062). The NELF complex, which acts via an association with the DSIF complex and causes transcriptional pausing, is counteracted by the P-TEFb kinase complex (PubMed:10199401).
Produced by alternative initiation at Met-10 of isoform NELF-C.
The NELF complex is composed of NELFA, NELFB, NELFCD (isoform NELF-C or isoform NELF-D) and NELFE; NELFA and NELFCD form a stable subcomplex that binds primarily through NELFCD to the N-terminus of NELFB (PubMed:27282391, PubMed:12612062). Binds RNA which may help to stabilize the NELF complex on nucleic acid (PubMed:27282391). In vitro, the NELFA:NELFCD subcomplex binds to ssDNA and ssRNA in a sequence- and structure-dependent manner (PubMed:27282391). Interacts with ARAF (PubMed:11952167). Interacts with PCF11 (PubMed:23884411). Interacts with KAT8 (By similarity).
Widely expressed. Expressed in heart, brain, lung, placenta, liver, skeletal and cardiac muscle, adrenal, thyroid, kidney and pancreas.
Activated by autophosphorylation. Protein phosphatase 1 represses autophosphorylation and activation of isoform 1 by dephosphorylation. Phosphorylation by STK3/MST2 is necessary for its localization to the centrosome.
Expression and activity peak in the G2 phase of the mitotic cycle and decrease once the cells have entered mitosis due to degradation by the anaphase promoting complex APC/C-CDC20. In G1 phase, both isoform 1 and isoform 2 are almost undetectable. However, at the G1/S transition, there is an increase in expression of both isoforms which then remain at this increased level throughout S and G2. At the onset of mitosis, isoform 1 undergoes a rapid disappearance whereas isoform 2 continues to be present at about the same level as in G2. During the rest of mitosis, isoform 1 remains absent, while isoform 2 only begins to decline upon re-entry into the next G1 phase.
Isoform 1 and isoform 2 are expressed in peripheral blood T-cells and a wide variety of transformed cell types. Isoform 1 and isoform 4 are expressed in the testis. Up-regulated in various cancer cell lines, as well as primary breast tumors.
Isoform 1 is inhibited by ionizing radiation in the presence of PPP1CA. Its catalytic activity is inhibited by the inhibitor CCT241950. In the presence of this inhibitor, displays an autoinhibited conformation: Tyr-70 side chain points into the active site, interacts with the activation loop, and blocks the alphaC helix.
Isoform 1, isoform 2 and isoform 4 form homo- and heterodimers. Interacts with NECAB3 and HMGA2 (By similarity). Isoform 1 interacts with CDC20, CTNB1, MAD1L1, MAPK, NEK11, NPM1, NDC80, PCNT and SGO1 (PubMed:14978040, PubMed:15358203, PubMed:15388344, PubMed:15161910, PubMed:17621308, PubMed:18086858, PubMed:18297113, PubMed:20599736, PubMed:20034488). Isoform 1 interacts with STK3/MST2 (via SARAH domain) and SAV1 (via SARAH domain) (PubMed:21076410). Isoform 1 and isoform 2 interact with MAD2L1 (PubMed:20034488). Isoform 1 and isoform 4 interact with PPP1CA and PPP1CC (PubMed:15659832, PubMed:17283141). Interacts with CEP68; the interaction leads to phosphorylation of CEP68. Interacts with CNTLN; the interaction leads to phosphorylation of CNTLN (PubMed:24554434). Isoform 1 interacts with CEP85 (PubMed:26220856). Interacts with CCDC102B; the interaction leads to phosphorylation of CCDC102B (PubMed:30404835).
Not present in the nucleolus and, in contrast to isoform 1, does not phosphorylate and activate NEK11 in G1/S-arrested cells.
Phosphorylates and activates NEK11 in G1/S-arrested cells.
Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and NINL, resulting in their displacement from the centrosomes. Regulates kinetochore microtubule attachment stability in mitosis via phosphorylation of NDC80. Involved in regulation of mitotic checkpoint protein complex via phosphorylation of CDC20 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGO1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Phosphorylates CEP68 and CNTLN directly or indirectly (PubMed:24554434). NEK2-mediated phosphorylation of CEP68 promotes CEP68 dissociation from the centrosome and its degradation at the onset of mitosis (PubMed:25704143). Involved in the regulation of centrosome disjunction (PubMed:26220856). Phosphorylates CCDC102B either directly or indirectly which causes CCDC102B to dissociate from the centrosome and allows for centrosome separation (PubMed:30404835).
The leucine-zipper domain is required for its dimerization and activation.
Asn-335 is present instead of the conserved Asp which is expected to be an active site residue. This enzyme has been shown to be catalytically inactive.
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.
Binds to the IL-1 type I receptor following IL-1 engagement, triggering intracellular signaling cascades leading to transcriptional up-regulation and mRNA stabilization.
Expressed in spleen, thymus, prostate, lung, liver, skeletal muscle, kidney, pancreas and peripheral blood leukocytes.
Interacts with MYD88. IL-1 stimulation leads to the formation of a signaling complex which dissociates from the IL-1 receptor following the binding of PELI1.
Expressed predominantly in brain and testis. Expressed in motor neurons.
May play a role in lipid metabolic process.
Peripherally associated with AMPAR complex. AMPAR complex consists of an inner core made of 4 pore-forming GluA/GRIA proteins (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged in a twofold symmetry. One of the two pairs of distinct binding sites is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR complex is complemented by outer core constituents binding directly to the GluA/GRIA proteins at sites distinct from the interaction sites of the inner core constituents. Outer core constituents include at least PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the inner and outer core serve as a platform for other, more peripherally associated AMPAR constituents, including CPT1C. Alone or in combination, these auxiliary subunits control the gating and pharmacology of the AMPAR complex and profoundly impact their biogenesis and protein processing (By similarity). Interacts with ATL1 (PubMed:25751282).
Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. Probably binds BUB3 as part of transport cargo. Required for the efficient progression through mitosis (By similarity).
Homodimer. The cytoplasmic dynein 1 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs); the composition seems to vary in respect to the IC, LIC and LC composition. The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits. The ICs and LICs bind directly to the HC dimer and the LCs assemble on the IC dimer. DYNLT1 and DYNLT3 compete for association with dynein IC (DYNC1I1 or DYNC1I2). Self-associates. Interacts with DYNC1I1 and DYNC1I2 (By similarity). Interacts with BUB3. Interacts with SATB1 in nucleus to form complex with matrix attachment regions (MARs) of DNA.
Was originally thought to be a candidate for RP3.
Cadherin repeats 1 and 2 mediate calcium-dependent heterophilic interaction with PCDH15.
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells. CDH23 is required for establishing and/or maintaining the proper organization of the stereocilia bundle of hair cells in the cochlea and the vestibule during late embryonic/early postnatal development. It is part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal hearing.
Particularly strong expression in the retina (PubMed:11138009). Found also in the cochlea.
antiparallel heterodimer with PCDH15 (By similarity). Interacts with USH1C and USH1G (PubMed:19297620, PubMed:21436032).
Essential component of the PAM complex, a complex required for the translocation of transit peptide-containing proteins from the inner membrane into the mitochondrial matrix in an ATP-dependent manner (By similarity). Recruits mitochondrial HSP70 to drive protein translocation into the matrix using ATP as an energy source (By similarity).
Probable component of the PAM complex at least composed of a mitochondrial HSP70 protein, GRPEL1 or GRPEL2, TIMM44, TIMM16/PAM16 and TIMM14/DNAJC19 (By similarity). The complex interacts with the TIMM23 component of the TIM23 complex. Interacts with SLC25A4/ANT1 and SLC25A5/ANT2; leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (By similarity).
Homomer (Probable). Interacts with GULP1 and ABCA1. Interacts with AP2M1 (PubMed:17643423). Does not interact with MEGF11 (PubMed:17498693). Binds with high affinity to complement C1q (PubMed:27170117). Interacts (via the cytoplasmic domain) with NOTCH1 (via NICD domain) (PubMed:28498977).
Membrane receptor involved in phagocytosis by macrophages and astrocytes of apoptotic cells. Receptor for C1q, an eat-me signal, that binds phosphatidylserine expressed on the surface of apoptotic cells (PubMed:27170117). Cooperates with ABCA1 within the process of engulfment. Promotes the formation of large intracellular vacuoles and may be responsible for the uptake of amyloid-beta peptides (PubMed:20828568, PubMed:17643423). Necessary for astrocyte-dependent apoptotic neuron clearance in the developing cerebellum (PubMed:27170117). Plays role in muscle cell proliferation, adhesion and motility. Is also an essential factor in the regulation of myogenesis. Controls the balance between skeletal muscle satellite cells proliferation and differentiation through regulation of the notch signaling pathway (PubMed:28498977, Ref.16). May also function in the mosaic spacing of specific neuron subtypes in the retina through homotypic retinal neuron repulsion. Mosaics provide a mechanism to distribute each cell type evenly across the retina, ensuring that all parts of the visual field have access to a full set of processing elements (PubMed:17498693, PubMed:17643423, PubMed:20828568, PubMed:22101682, PubMed:27170117, PubMed:28498977).
Phosphorylated on tyrosine residues. Phosphorylation at Tyr-1030 may be important for muscle cell proliferation.
The EMI and EGF-like domains work in concert to promote self-assembly.
Ubiquitinated; mono- and polyubiquitinated forms are detected.
Belongs to the WD repeat gemin-5 family.
Part of the core SMN complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP (PubMed:20513430, PubMed:27507887, PubMed:16314521, PubMed:19377484, PubMed:17178713). Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG (PubMed:11714716, PubMed:20513430, PubMed:16314521). Interacts with GEMIN2; the interaction is direct (PubMed:17178713). Interacts with SMN1, SNRPB, SNRPD1, SNRPD2, SNRPD3 and SNRPE; the interaction is direct (PubMed:11714716). Interacts with cytosolic DDX20/GEMIN3 and GEMIN4 (PubMed:19750007, PubMed:27507887, PubMed:33963192). Interacts with SNRNP70 and HNRNPU (PubMed:27507887). Identified in a complex with 80S ribosomes; binds to the 60S large ribosomal subunit (PubMed:27507887). Interacts with the ribosomal subunits RPL3 and RPL4 (PubMed:27507887).
The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs (PubMed:16857593, PubMed:18984161, PubMed:20513430, PubMed:33963192). Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (Sm core). In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP (PubMed:18984161). To assemble core snRNPs, the SMN complex accepts the trapped 5Sm proteins from CLNS1A forming an intermediate (PubMed:18984161). Binding of snRNA inside 5Sm ultimately triggers eviction of the SMN complex, thereby allowing binding of SNRPD3 and SNRPB to complete assembly of the core snRNP. Within the SMN complex, GEMIN5 recognizes and delivers the small nuclear RNAs (snRNAs) to the SMN complex (PubMed:11714716, PubMed:16857593, PubMed:19377484, PubMed:19750007, PubMed:20513430, PubMed:27834343, PubMed:27881600, PubMed:27881601, PubMed:16314521). Binds to the 7-methylguanosine cap of RNA molecules (PubMed:19750007, PubMed:27834343, PubMed:27881600, PubMed:27881601, Ref.27). Binds to the 3'-UTR of SMN1 mRNA and regulates its translation; does not affect mRNA stability (PubMed:25911097). May play a role in the regulation of protein synthesis via its interaction with ribosomes (PubMed:27507887).
The WD repeat domain mediates binding to U1 snRNA and to U4 snRNA (PubMed:19377484, PubMed:19750007, PubMed:27834343, PubMed:27881600, PubMed:27881601). The WD repeat domain also mediates binding to the 7-methylguanosine cap that is found both on mRNA and snRNA molecules (PubMed:19750007, PubMed:27834343, PubMed:27881600, PubMed:27881601, Ref.27). The regions that bind snRNA molecules and the isolated 7-methylguanosine cap overlap at least partially (PubMed:27834343, PubMed:27881600, PubMed:27881601). Besides, the WD repeat domain mediates interaction with the 60S large ribosomal subunit (PubMed:27507887).
Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code.
Deubiquitinase that can remove conjugated ubiquitin from target proteins, such as RAB7A and LAMTOR1 (PubMed:36476874). Acts as a positive regulator of the mTORC1 signaling by mediating deubiquitination of LAMTOR1, thereby promoting the association between LAMTOR1 and the lysosomal V-ATPase complex and subsequent activation of the mTORC1 complex (PubMed:36476874).
Interacts with BOC and CDON (PubMed:20519495). Interacts with HHIP (PubMed:19561611).
N-palmitoylation by HHAT of DhhN is required for desert hedgehog protein N-product multimerization and full activity (By similarity).
Partially autoproteolyzed (PubMed:30298535, PubMed:24342078). The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity (By similarity). Both activities result in the cleavage of the full-length protein and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-terminal fragment (DhhN) (By similarity).
The C-terminal domain regulates the auto-processing and controls the juxtacrine signaling.
The C-terminal part of the desert hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity (By similarity). Both activities result in the cleavage of the full-length protein into two parts (N-product and C-product) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product (By similarity). Both activities occur in the reticulum endoplasmic (By similarity). Functions in cell-cell mediated juxtacrine signaling (PubMed:24342078). Promotes endothelium integrity (PubMed:33063110). Binds to PTCH1 receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes in endothelial cells (PubMed:33063110). In Schwann cells, controls the development of the peripheral nerve sheath and the transition of mesenchymal cells to form the epithelium-like structure of the perineurial tube (By similarity).
The dually lipidated desert hedgehog protein N-product is essential for a variety of patterning events during development (By similarity). Binds to the patched (PTCH1) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes (PubMed:11472839, PubMed:33063110). Required for normal testis development and spermatogenesis, namely for the formation of adult-type Leydig cells and normal development of peritubular cells and seminiferous tubules (By similarity). Activates primary cilia signaling on neighboring valve interstitial cells through a paracrine mechanism (By similarity). May induce motor neurons in lateral neural tube and may have a polarizing activity (PubMed:11472839). Prevents the desert hedgehog protein precursor binding to PTCH1 (PubMed:33063110).
Blood plasma. Sperm. Highly expressed in the lower head and midpiece of sperm. Significantly reduced levels found in the sperms of asthenozoospermia and leukocytospermia patients (at protein level).
Has bactericidal activity. May act as a ligand for C-C chemokine receptor CCR6. Positively regulates the sperm motility and bactericidal activity in a CCR6-dependent manner. Binds to CCR6 and triggers Ca2+ mobilization in the sperm which is important for its motility (PubMed:25122636).
Monomer (PubMed:23938203). Homodimer (PubMed:23938203).
Belongs to the MICU1 family. MICU2 subfamily.
Heterodimer; disulfide-linked; heterodimerizes with MICU1 (PubMed:24560927). Interacts with MCU (PubMed:26341627). The heterodimer formed with MICU1 associates with MCU at low calcium concentration and dissociates from MCU at high calcium level (PubMed:26387864). Component of the uniplex complex, composed of MCU, MCUB, MICU1, MICU2 and EMRE/SMDT1 (PubMed:24231807).
Key regulator of mitochondrial calcium uniporter (MCU) required to limit calcium uptake by MCU when cytoplasmic calcium is low (PubMed:24503055, PubMed:24560927, PubMed:26903221). MICU1 and MICU2 form a disulfide-linked heterodimer that stimulate and inhibit MCU activity, depending on the concentration of calcium (PubMed:24560927). MICU2 acts as a gatekeeper of MCU that senses calcium level via its EF-hand domains: prevents channel opening at resting calcium, avoiding energy dissipation and cell-death triggering (PubMed:24560927).
The EF-hand domains have high affinity for calcium and act as sensors of mitochondrial matrix calcium levels (PubMed:24503055). It is unclear which EF-hand binds calcium as none of the 4 EF-hand domains seem to contain a canonical calcium-binding site.
Anion antiporter that mediates the transport of urate, orotate and nicotinate in exchange for organic or inorganic anions (PubMed:18411268, PubMed:35144162, PubMed:31780526, PubMed:35462902). Translocates urate and orotate across the apical membrane of proximal tubule epithelial cells and involved in urate renal reabsorption (PubMed:18411268, PubMed:35144162, PubMed:31780526). Possibly involved in orotate renal reabsorption and nicotinate intestinal reabsorption (PubMed:18411268, PubMed:35144162). Mediates urate uptake by an exchange with organic anions such as (S)-lactate, succinate, glutathione and nicotinate (PubMed:18411268). Urate and orotate transports are Cl(-)-dependent (PubMed:35144162, PubMed:35462902). Shows similar transport characteristics as the urate/orotate renal antiporter SLC22A12/URAT1 and may act as a compensator of SLC22A12/URAT1 in certain conditions (Probable).
Ubiquitous (PubMed:10072596). Highly expressed in kidneys and to a weaker extent in brain, heart, and intestine (PubMed:18411268). In kidneys, expressed in proximal convoluted tubule (PubMed:18411268, PubMed:31780526, PubMed:35462902). In kidneys, also expressed in cortical collecting duct, whereas glomerulus and thick ascending limb exhibit no expression (PubMed:18411268).
Expressed in fetal lung, liver, and kidney and in adult brain, prostate, submaxillary gland, and endothelium.
A chromosomal aberration involving USP6 is a common genetic feature of aneurysmal bone cyst, a benign osseous neoplasm. Translocation t(16;17)(q22;p13) with CDH11. The translocation generates a fusion gene in which the strong CDH11 promoter is fused to the entire USP6 coding sequence, resulting in USP6 transcriptional up-regulation (PubMed:15026324).
Deubiquitinase with an ATP-independent isopeptidase activity, cleaving at the C-terminus of the ubiquitin moiety. Catalyzes its own deubiquitination. In vitro, isoform 2, but not isoform 3, shows deubiquitinating activity. Promotes plasma membrane localization of ARF6 and selectively regulates ARF6-dependent endocytic protein trafficking. Is able to initiate tumorigenesis by inducing the production of matrix metalloproteinases following NF-kappa-B activation.
Interacts with RAC1 and CDC42. Interacts (via Rab-GAP TBC domain) with ARF6. Interacts with calmodulin (CALM1, CALM2 and/or CALM3); the interaction is calcium-dependent.
Monubiquitinated; ubiquitination is calmodulin and calcium dependent.
Testis specific. Expressed in various cancer cell lines.
The Rab-GAP TBC domain lacks GTPase activator activity but is necessary for interaction with ARF6.
The USP6 gene only exists in the primate lineage.
Was shown to be tumorigenic in transfected mice and seems not to act as GTPase activating protein.
Autoproteolytically cleaved into 2 subunits, an extracellular alpha subunit and a seven-transmembrane subunit.
By far is the largest known cell surface protein.
Cleaved ADGRV1 beta-subunit couples with G-alpha(i)-proteins, GNAI1/2/3, and constitutively inhibits adenylate cyclase (AC) activity with a stronger effect than full ADGRV1.
Expressed at low levels in adult tissues.
Forms a heterodimer, consisting of a large extracellular region (alpha subunit) non-covalently linked to a seven-transmembrane moiety (beta subunit) (By similarity). Component of USH2 complex, composed of ADGRV1, PDZD7, USH2A and WHRN. Interacts with USH2A and WHRN (PubMed:16434480). Interacts (via the cytoplasmic region) with PDZD7 (PubMed:20440071). Interacts (via the cytoplasmic region) with MYO7A (via MyTH4-FERM domains) (By similarity).
G-protein coupled receptor which has an essential role in the development of hearing and vision. Couples to G-alpha(i)-proteins, GNAI1/2/3, G-alpha(q)-proteins, GNAQ, as well as G-alpha(s)-proteins, GNAS, inhibiting adenylate cyclase (AC) activity and cAMP production. Required for the hair bundle ankle formation, which connects growing stereocilia in developing cochlear hair cells of the inner ear. In response to extracellular calcium, activates kinases PKA and PKC to regulate myelination by inhibiting the ubiquitination of MAG, thus enhancing the stability of this protein in myelin-forming cells of the auditory pathway. In retina photoreceptors, the USH2 complex is required for the maintenance of periciliary membrane complex that seems to play a role in regulating intracellular protein transport. Involved in the regulation of bone metabolism.
Isoform 1 is 4 times more abundant than isoform 2 in most tissues tested, despite wide variations in absolute levels of expression. Isoform 3 is expressed at about 1.5 times isoform 1 levels in most tissues examined. In fetal testis, isoform 3 is expressed almost exclusively.
The 7 transmembrane domain is required in hair cells for the hair bundle ankle formation.
Component of the FTS/Hook/FHIP complex (FHF complex). The FHF complex may function to promote vesicle trafficking and/or fusion via the homotypic vesicular protein sorting complex (the HOPS complex). Contributes to the establishment and maintenance of centrosome function. May function in the positioning or formation of aggresomes, which are pericentriolar accumulations of misfolded proteins, proteasomes and chaperones. FHF complex promotes the distribution of AP-4 complex to the perinuclear area of the cell (PubMed:32073997).
Self-associates (PubMed:18799622). Component of the FTS/Hook/FHIP complex (FHF complex), composed of AKTIP/FTS, FHIP1B, and one or more members of the Hook family of proteins HOOK1, HOOK2, and HOOK3 (PubMed:18799622). May interact directly with AKTIP/FTS, HOOK1 and HOOK3 (PubMed:18799622, PubMed:32073997). Associates with several subunits of the homotypic vesicular sorting complex (the HOPS complex) including VPS16 and VPS41; these interactions may be indirect (PubMed:18799622). Interacts with CNTRL (PubMed:17140400). Interacts with microtubules (PubMed:11238449). Interacts with ZC3H14 (PubMed:19273536). Interacts with LRGUK (via guanylate kinase-like domain) (By similarity). Interacts with CCDC181 (By similarity). Interacts with AP4M1; the interaction is direct, mediates the interaction between FTS-Hook-FHIP (FHF) complex and AP-4 and the perinuclear distribution of AP-4 (PubMed:32073997).
Expressed in a variety of tissues including bone marrow, kidney, small intestine, liver, placenta and testis.
Interacts with CDK1 and CDK2. Interacts with AURKB.
Promotes progression through the cell cycle via binding and activation of CDK1 and CDK2. Involved in the spindle-assembly checkpoint. Required for recruitment of MAD2L1, BUBR1 and BUB1 to kinetochores. Required for the correct localization of the active form of Aurora B in prometaphase.
Increased levels in lung tissue in cancer patients.
Interacts with MDM2; this interaction stabilizes MDM2 (By similarity). Interaction with MDM2 occurs in the nucleoplasm and is triggered by a nucleolar release mechanism, such as mitosis-induced nucleolar disassembly (By similarity). Indirectly interacts with TP53, via MDM2-binding (PubMed:12464630). Interacts with TSC22D1 isoform 2 (PubMed:34681573).
May be required to maintain the proliferative capacity of stem cells. Stabilizes MDM2 by preventing its ubiquitination, and hence proteasomal degradation (By similarity).
The basic domain (B) allows nucleolar localization in the absence of GTP. The intermediate domain (I) inhibits nucleolar localization by the B domain and is required for exit from the nucleolus. Exit from the nucleolus to the nucleoplasm requires both the I and the acidic (A) domains, and may be triggered by GTP hydrolysis (By similarity).
Functions as a guanine nucleotide exchange factor (GEF) that promotes the exchange of GDP to GTP, converting inactive GDP-bound small GTPases into their active GTP-bound form (PubMed:12628187, PubMed:16464467). Involved in regulation of adherens junction between cells (PubMed:12628187). Plays a role in cell migration (PubMed:20679435).
Has a higher guanine nucleotide exchange factor activity compared to other isoforms.
Interacts with nucleotide-free Rap1; functions as a guanine nucleotide exchange factor (GEF) for Rap1 (PubMed:12628187). Interacts (via DOCKER domain) with RAC1; functions as a guanine nucleotide exchange factor (GEF) for RAC1 (PubMed:16464467). Interacts with the SH3 domain of CRK (PubMed:12628187). Interacts with FASLG (PubMed:19807924). Interacts with ELMO2 and EPHA2; mediates activation of RAC1 by EPHA2 (PubMed:20679435). Interacts with USH1C (via PDZ 1 domain) (PubMed:16464467).
May be specifically expressed in the brain and eye.
The DOCKER domain mediates interaction with small GTPases like RAC1 and is required for their activation.
Widely expressed at low level. Highly expressed in skeletal muscle, prostate and ovary.
Homodimer (PubMed:25862789). Interacts with FANCD2; the interaction is direct. Interacts with FANCL. Interacts with MTMR15/FAN1 (PubMed:17412408, PubMed:17460694, PubMed:20603015, PubMed:21775430). Interacts with POLN (PubMed:19995904). Interacts with UBL5; the interaction promotes FANCI homodimerization (PubMed:25862789).
Monoubiquitinated by FANCL on Lys-523 during S phase and upon genotoxic stress. Deubiquitinated by USP1 as cells enter G2/M, or once DNA repair is completed. Monoubiquitination requires the FANCA-FANCB-FANCC-FANCE-FANCF-FANCG-FANCM complex. Ubiquitination is required for binding to chromatin, DNA repair, and normal cell cycle progression. Monoubiquitination is stimulated by DNA-binding.
Phosphorylated in response to DNA damage by ATM and/or ATR.
Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA repair sites. Required for maintenance of chromosomal stability. Specifically binds branched DNA: binds both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). Participates in S phase and G2 phase checkpoint activation upon DNA damage.
The C-terminal 30 residues are probably required for function in DNA repair.
The region from 1 to 163 was deduced from the genomic sequence and ESTs by similarity to the mouse sequence.
Interacts with the regulatory subunit p85 of PI3-kinase; increased by EGFR activation (PubMed:22886303). Interacts with RAF1; increased by EGFR activation it activates RAF1 (PubMed:22886303, PubMed:24736947).
Probable proto-oncogene that functions in the epidermal growth factor receptor/EGFR signaling pathway. Activates both RAS/MAPK and PI3K/AKT/TOR signaling cascades downstream of EGFR. Required for the RAS/MAPK signaling cascade activation upon EGFR stimulation, it also activates both signaling cascades independently of EGFR activation.
Brain white matter, skeletal muscle, kidney, adrenal glands, lung and liver.
Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate. NAA occurs in high concentration in brain and its hydrolysis NAA plays a significant part in the maintenance of intact white matter. In other tissues it acts as a scavenger of NAA from body fluids.
(Microbial infection) Proteolytically cleaved by HIV-1 protease when incorporated into HIV-1 particles in a nucleocapsid-dependent-manner. Cleavage by HIV-1 protease probably ensures optimal infectivity of the mature virion.
Belongs to the YTHDF family. YTHDF3 subfamily.
Has some antiviral activity against HIV-1 virus: incorporated into HIV-1 particles in a nucleocapsid-dependent manner and reduces viral infectivity in the next cycle of infection (PubMed:32053707). May interfere with this early step of the viral life cycle by binding to N6-methyladenosine (m6A) modified sites on the HIV-1 RNA genome (PubMed:32053707).
Interacts with CNOT1; promoting recruitment of the CCR4-NOT complex (PubMed:32492408). Interacts with YTHDF1 (PubMed:28106072). Interacts with YTHDF2 (PubMed:28106072). Interacts with PAN3 (By similarity).
Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, and regulates their stability (PubMed:28106072, PubMed:28106076, PubMed:28281539, PubMed:32492408). M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in mRNA stability and processing (PubMed:22575960, PubMed:24284625, PubMed:28106072, PubMed:28281539, PubMed:32492408). Acts as a regulator of mRNA stability by promoting degradation of m6A-containing mRNAs via interaction with the CCR4-NOT complex or PAN3 (PubMed:32492408). The YTHDF paralogs (YTHDF1, YTHDF2 and YTHDF3) share m6A-containing mRNAs targets and act redundantly to mediate mRNA degradation and cellular differentiation (PubMed:28106072, PubMed:28106076, PubMed:32492408). Acts as a negative regulator of type I interferon response by down-regulating interferon-stimulated genes (ISGs) expression: acts by binding to FOXO3 mRNAs (By similarity). Binds to FOXO3 mRNAs independently of METTL3-mediated m6A modification (By similarity). Can also act as a regulator of mRNA stability in cooperation with YTHDF2 by binding to m6A-containing mRNA and promoting their degradation (PubMed:28106072). Recognizes and binds m6A-containing circular RNAs (circRNAs); circRNAs are generated through back-splicing of pre-mRNAs, a non-canonical splicing process promoted by dsRNA structures across circularizing exons (PubMed:28281539). Promotes formation of phase-separated membraneless compartments, such as P-bodies or stress granules, by undergoing liquid-liquid phase separation upon binding to mRNAs containing multiple m6A-modified residues: polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their disordered regions and thereby leading to phase separation (PubMed:31388144, PubMed:31292544, PubMed:32451507). The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated membraneless compartments, such as P-bodies, stress granules or neuronal RNA granules (PubMed:31292544). May also recognize and bind N1-methyladenosine (m1A)-containing mRNAs: inhibits trophoblast invasion by binding to m1A-methylated transcripts of IGF1R, promoting their degradation (PubMed:32194978).
Was initially reported to act as a regulator of mRNA translation efficiency in cooperation with YTHDF1 by binding to m6A-containing mRNAs and interacting with 40S and 60S ribosome subunits (PubMed:28106072, PubMed:28106076, PubMed:28281539). These studies suggested that the 3 different paralogs (YTHDF1, YTHDF2 and YTHDF3) have unique functions with limited redundancy (PubMed:28106072, PubMed:28106076, PubMed:28281539). However, later studies showed that YTHDF1, YTHDF2 and YTHDF3 paralogs have redundant functions to a profound extent and directly promote degradation of m6A-containing mRNAs (PubMed:32492408). The effect on translation efficiency observed earlier is probably indirect (PubMed:32492408).
Controls V(D)J recombination during T-cell development by repressing T-cell receptor (TCR) beta enhancer function. Binds to scaffold/matrix attachment region beta (S/MARbeta), an ATC-rich DNA sequence located upstream of the TCR beta enhancer. Represses cyclin D1 transcription by recruiting HDAC1 to its promoter, thereby diminishing H3K9ac, H3S10ph and H4K8ac levels. Promotes TP53 activation, which causes cell cycle arrest (By similarity).
Down-regulated in breast cancer cell lines.
Interacts with TP53 (By similarity). Interacts with CUX1/CDP (By similarity). Interacts with HDAC1 (PubMed:16166625). Part of a corepressor complex containing BANP, HDAC1, SIN3A, SIN3B, RBL1 and RBL2 (PubMed:16166625).
Expressed strongly in trachea, lung, stomach, colon, prostate and small intestine. Expressed weakly in pituitary gland, salivary gland, mammary gland, bladder, appendix, ovary, fetal lung, uterus, pancreas, kidney, fetal kidney, testis, placenta, thyroid gland and in estrogen receptor (ER)-positive breast cancer cell lines.
Monomer and homodimer (PubMed:23274113). Interacts with LYPD3 and DAG1 (alphaDAG1) (PubMed:12592373). Interacts with MUC2; disulfide-linked (PubMed:19359471, PubMed:34237462).
Required for MUC2 post-transcriptional synthesis and secretion. May play a role in the production of mucus by intestinal cells (By similarity). Proto-oncogene that may play a role in cell migration, cell differentiation and cell growth. Promotes cell adhesion (PubMed:23274113).
Ca(2+)-dependent Ras GTPase-activating protein, that switches off the Ras-MAPK pathway following a stimulus that elevates intracellular calcium. Functions as an adaptor for Cdc42 and Rac1 during FcR-mediated phagocytosis.
The PH domain does not bind phosphatidylinositol 4,5-bisphosphate or phosphatidylinositol 3,4,5-trisphosphate. This lack of binding activity is due to Leu-592, compared to Arg found in other family members.
A disulfide bond links the activated corin protease fragment and the N-terminal propeptide. The disulfide bond also links the activated corin protease fragment with soluble fragments (100 kDa, 160 kDa and 180 kDa fragments).
Activated through proteolytic processing by a trypsin-like protease; cleaved into a N-terminal propeptide and an activated corin protease fragment. Different soluble forms are produced by cleavage and autocatalytic cleavage: Atrial natriuretic peptide-converting enzyme, 180 kDa soluble fragment is produced by cleavage by ADAM10, while 160 kDa and 100 kDa soluble fragments are produced by autocatalytic cleavage. Cleavage by ADAM10 to produce soluble 180 kDa soluble fragment takes place after the transmembrane region and before FZ 1.
Has weaker endopeptidase activity compared to isoform 1.
Highly expressed in heart. Expressed in heart myocytes. Also expressed in pregnant uterus. Detected in blood, in plasma as well as in serum (at protein level).
Inhibited in a dose-dependent manner by non-specific trypsin-like serine protease inhibitors including benzamidine.
Initially named CORIN due to its abundant expression in the heart.
N-glycosylated; required for processing and activation.
Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing (PubMed:10880574, PubMed:21288900, PubMed:20489134, PubMed:21763278). Converts through proteolytic cleavage the non-functional propeptides NPPA and NPPB into their active hormones, ANP and BNP(1-32) respectively, thereby regulating blood pressure in the heart and promoting natriuresis, diuresis and vasodilation (PubMed:10880574, PubMed:21288900, PubMed:20489134, PubMed:21763278). Proteolytic cleavage of pro-NPPA also plays a role in female pregnancy by promoting trophoblast invasion and spiral artery remodeling in uterus (PubMed:22437503). Also acts as a regulator of sodium reabsorption in kidney (By similarity).
The DDNN motif is required for targeting to the cell membrane and enzyme activation.
Belongs to the HAD-like hydrolase superfamily. SerB family.
Catalyzes the last irreversible step in the biosynthesis of L-serine from carbohydrates, the dephosphorylation of O-phospho-L-serine to L-serine (PubMed:12213811, PubMed:15291819, PubMed:9222972, PubMed:14673469, PubMed:25080166). L-serine can then be used in protein synthesis, to produce other amino acids, in nucleotide metabolism or in glutathione synthesis, or can be racemized to D-serine, a neuromodulator (PubMed:14673469). May also act on O-phospho-D-serine (Probable).
Essential for muscle regeneration and satellite cell maintenance in skeletal muscle (PubMed:21131290).
Interacts with RYR1, RYR2 and RYR3 (PubMed:18713863).
Isoform 1 and isoform 2 are expressed in skeletal muscle, brain, lung and placenta. Isoform 2 is also expressed in heart, diaphragm and stomach.
Plays an important role in cell protection against oxidative stress and in the regulation of redox-related calcium homeostasis. Regulates the calcium level of the ER by protecting the calcium pump ATP2A2 against the oxidoreductase ERO1A-mediated oxidative damage. Within the ER, ERO1A activity increases the concentration of H(2)O(2), which attacks the luminal thiols in ATP2A2 and thus leads to cysteinyl sulfenic acid formation (-SOH) and SEPN1 reduces the SOH back to free thiol (-SH), thus restoring ATP2A2 activity (PubMed:25452428). Acts as a modulator of ryanodine receptor (RyR) activity: protects RyR from oxidation due to increased oxidative stress, or directly controls the RyR redox state, regulating the RyR-mediated calcium mobilization required for normal muscle development and differentiation (PubMed:19557870, PubMed:18713863).
The N-terminus (first 61 amino acids) contains an endoplasmic reticulum addressing and retention targeting signal.
The UGA codon present in position 428 is either a selenocysteine or a real stop codon.
The UGA codons present in position 127 and 462 are either a selenocysteine or a real stop codon.
(Microbial infection) Acts as a receptor for P.falciparum (isolate 3D7) MSP9 and thus, facilitates merozoite invasion of erythrocytes.
(Microbial infection) Interacts (via N-terminus) with P.falciparum (isolate K1) aldolase FBPA; the interaction inhibits FBPA catalytic activity.
(Microbial infection) Interacts (via the 5ABC region) with P.falciparum (isolate 3D7) MSP9/ABRA (via N-terminus).
A dimer in solution, but in its membrane environment, it exists primarily as a mixture of dimers and tetramers and spans the membrane asymmetrically (PubMed:35835865). Component of the ankyrin-1 complex in the erythrocyte, composed of ANK1, RHCE, RHAG, SLC4A1, EPB42, GYPA, GYPB and AQP1 (PubMed:35835865). Interacts with STOM; this interaction positively regulates SLC4A1 activity (PubMed:23219802, PubMed:28387307). Interacts with GYPA; a GYPA monomer is bound at each end of the SLC4A1 dimer forming an heterotetramer (PubMed:35835865). Three SLC4A1 dimers (Band 3-I, Band 3-II and Band 3-III) participates in the ankyrin-1 complex (PubMed:35835865). Interacts (via the cytoplasmic domain) with EPB42; this interaction is mediated by the SLC4A1 Band 3-I dimer (PubMed:35835865). Interacts (via the cytoplasmic domain) directly with ANK1; this interaction is mediated by the SLC4A1 Band 3-II and Band 3-III dimers (PubMed:35835865, PubMed:7665627).
Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein (PubMed:35835865, PubMed:10926824, PubMed:14734552, PubMed:16227998, PubMed:24121512, PubMed:28387307, PubMed:1538405, PubMed:20151848). Component of the ankyrin-1 complex of the erythrocyte membrane; required for normal flexibility and stability of the erythrocyte membrane and for normal erythrocyte shape via the interactions of its cytoplasmic domain with cytoskeletal proteins, glycolytic enzymes, and hemoglobin (PubMed:35835865, PubMed:1538405, PubMed:20151848). Functions as a transporter that mediates the 1:1 exchange of inorganic anions across the erythrocyte membrane. Mediates chloride-bicarbonate exchange in the kidney, and is required for normal acidification of the urine (PubMed:10926824, PubMed:14734552, PubMed:16227998, PubMed:24121512, PubMed:28387307).
Genetic variations in SLC4A1 are involved in resistance to malaria [MIM:611162].
Interacts with TMEM139 (PubMed:26049106).
Phenyl isothiocyanate inhibits anion transport in vitro.
Phosphorylated on Tyr-359 and Tyr-904 most likely by LYN. PP1-inhibited phosphorylation that follows Tyr-8 and Tyr-21 phosphorylation.
Phosphorylated on Tyr-8 and Tyr-21 most likely by SYK. PP1-resistant phosphorylation that precedes Tyr-359 and Tyr-904 phosphorylation.
SLC4A1 is responsible for the Diego blood group system [MIM:110500]. The molecular basis of the Di(a)=Di1/Di(b)/Di2 blood group antigens is a single variation in position 854; Leu-854 corresponds to Di(a) and Pro-854 to Di(b). The molecular basis of the Wr(a)=Di3/Wr(b)/Di4 blood group antigens is a single variation in position 658; Lys-658 corresponds to Wr(a) and Glu-658 to Wr(b). The blood group antigens Wd(a)=Di5 (Waldner-type) has Met-557; Rb(a)=Di6 has Leu-548 and WARR=Di7 has Ile-552.
SLC4A1 is responsible for the Froese blood group system (FR) [MIM:601551]. FR(a+) has a Lys at position 480 and FR(a-) has a Glu.
SLC4A1 is responsible for the Swann blood group system (SW) [MIM:601550]. Sw(a+) has a Gln or a Trp at position 646 and Sw(a-) has an Arg.
Interacts (via olfactomedin-like domain) with FLRT3 (via extracellular domain); the interaction is direct (PubMed:26235030). Identified in a complex with FLRT3 and UNC5B; does not interact with UNC5B by itself (PubMed:26235030). Identified in a complex with FLRT3 and UNC5D; does not interact with UNC5D by itself (PubMed:26235030). Interacts (via olfactomedin-like domain) with FLRT1 (via extracellular domain). Interacts (via olfactomedin-like domain) with FLRT2 (via extracellular domain). Interacts (via extracellular domain) with TENM1. Interacts (via extracellular domain) with TENM3 (By similarity).
O-glycosylated (major) and N-glycosylated.
Plays a role in cell-cell adhesion and neuron guidance via its interactions with FLRT2 and FLRT3 that are expressed at the surface of adjacent cells (PubMed:26235030). Plays a role in the development of glutamatergic synapses in the cortex. Important in determining the connectivity rates between the principal neurons in the cortex.
The Olfactomedin-like domain is required for the synapse-promoting function and the interaction with FLRT3. The Olfactomedin-like and the SUEL-type lectin domains are required for the interaction with TENM1 (By similarity).
Expressed at highest levels in prostate, followed by testis, retina, trachea and optic nerve. Also detected in brain, epididymis, lung, vagina and pituitary. In the prostate, tends to be up-regulated during malignant progression compared to normal epithelium (at protein level).
May interact with HSP90AA1, HSP90AB1 and BAG2.
May play a role in the control of androgen receptor (AR) protein steady-state levels.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIK1 subfamily.
Homotetramer or heterotetramer of pore-forming glutamate receptor subunits. Tetramers may be formed by the dimerization of dimers (Probable). The unedited version (Q) assembles into a functional kainate-gated homomeric channel, whereas the edited version (R) is unable to produce channel activity when expressed alone. Both edited and unedited versions can form functional channels with GRIK4 and GRIK5. Interacts with KLHL17 (By similarity).
Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus.
Most abundant in the cerebellum and the suprachiasmatic nuclei (SCN) of the hypothalamus.
The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds domoate > kainate > L-glutamate = quisqualate > CNQX = DNQX > AMPA > dihydrokainate > NMDA.
Carriers of the polymorphic Gln-399 allele may be at greater risk for tobacco- and age-related DNA damage.
Expressed in fibroblasts, retinal pigmented epithelial cells and lymphoblastoid cells (at protein level).
Homodimer (PubMed:16397295). Interacts with polynucleotide kinase (PNK), DNA polymerase-beta (POLB) and DNA ligase III (LIG3) (PubMed:19336415, PubMed:19155274). Interacts with APTX and APLF (PubMed:14755728, PubMed:15044383, PubMed:15380105, PubMed:17507382, PubMed:17353262). Interacts with APEX1; the interaction is induced by SIRT1 and increases with the acetylated form of APEX1 (PubMed:19934257). Interacts with (poly-ADP-ribosylated) PARP1 (PubMed:34811483).
Phosphorylation of Ser-371 causes dimer dissociation. Phosphorylation by CK2 promotes interaction with APTX and APLF.
Scaffold protein involved in DNA single-strand break repair by mediating the assembly of DNA break repair protein complexes (PubMed:11163244, PubMed:28002403). Negatively regulates ADP-ribosyltransferase activity of PARP1 during base-excision repair in order to prevent excessive PARP1 activity (PubMed:34102106, PubMed:34811483, PubMed:28002403). Recognizes and binds poly-ADP-ribose chains: specifically binds auto-poly-ADP-ribosylated PARP1, limiting its activity (PubMed:14500814, PubMed:34102106, PubMed:34811483).
Interacts with CDK5R1 (p35 form) (By similarity). CDK5RAP1, CDK5RAP2 and CDK5RAP3 show competitive binding to CDK5R1. May form a complex with CDK5R1 and CDK5 (By similarity). Interacts with pericentrin/PCNT; the interaction is leading to centrosomal and Golgi localization of CDK5RAP2 and PCNT (PubMed:20466722). Interacts with AKAP9; the interaction targets CDK5RAP2 and AKAP9 to Golgi apparatus (PubMed:20466722). Interacts with MAPRE1; the interaction is direct and targets CDK5RAP2 and EB1/MAPRE1 to microtubule plus ends (PubMed:19553473). Interacts with TUBG1; the interaction is leading to the centrosomal localization of CDK5RAP2 and TUBG1 (PubMed:17959831). Interacts with TUBGCP3 (PubMed:17959831). Interacts with CALM1 (PubMed:20466722). Interacts with CDC20 (PubMed:19282672). Interacts with CEP68; degradation of CEP68 in early mitosis leads to removal of CDK5RAP2 from the centrosome which promotes centriole disengagement and subsequent centriole separation (PubMed:25503564). Interacts with NCKAP5L (PubMed:26485573). Forms a pericentrosomal complex with AKAP9, MAPRE1 and PDE4DIP isoform 13/MMG8/SMYLE; within this complex, MAPRE1 binding to CDK5RAP2 may be mediated by PDE4DIP (PubMed:29162697). Interacts with LGALS3BP; this interaction may connect the pericentrosomal complex to the gamma-tubulin ring complex (gamma-TuRC) to promote microtubule assembly and acetylation (PubMed:29162697).
Potential regulator of CDK5 activity via its interaction with CDK5R1. Negative regulator of centriole disengagement (licensing) which maintains centriole engagement and cohesion. Involved in regulation of mitotic spindle orientation (By similarity). Plays a role in the spindle checkpoint activation by acting as a transcriptional regulator of both BUBR1 and MAD2 promoter. Together with EB1/MAPRE1, may promote microtubule polymerization, bundle formation, growth and dynamics at the plus ends. Regulates centrosomal maturation by recruitment of the gamma-tubulin ring complex (gamma-TuRC) onto centrosomes (PubMed:26485573). In complex with PDE4DIP isoform 13/MMG8/SMYLE, MAPRE1 and AKAP9, contributes to microtubules nucleation and extension from the centrosome to the cell periphery (PubMed:29162697). Required for the recruitment of AKAP9 to centrosomes (PubMed:29162697). Plays a role in neurogenesis (By similarity).
Present in saliva within small membrane particles (at protein level). Expressed in kidney, prostate, trachea, esophagus, salivary gland, thyroid gland, mammary gland adrenal gland, placenta, stomach, spinal cord and liver. In submucosal tumor, expressed in spindle-shaped or stellate stromal cells. Expressed in prostate cancer cell lines.
Actin-binding protein that regulates actin polymerization, filopodia dynamics and increases the branching of proximal dendrites of developing neurons.
Depletion of ABITRAM by siRNA or neutralizing antibodies results in cell death within a few hours.
Interacts with F-actin (By similarity). Interacts with G-actin (By similarity).
Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.
Expressed at highest levels in heart. Expressed at lower levels in liver, skeletal muscle and pancreas and at very low levels in brain.
Homodimer (PubMed:18093521). Interacts with NRXN1 in a calcium-dependent manner (PubMed:18093521). Interaction with neurexins is mediated by heparan sulfate glycan modification on neurexin (By similarity). Interacts through its C-terminus with DLG4/PSD-95 third PDZ domain (PubMed:9278515, PubMed:11368788).
Expressed in fetal liver and bone marrow (PubMed:28978694). Expressed in peripheral blood lymphocyte B cells (PubMed:28978694).
Probable B cell-associated cytokine that plays a role in the regulation of humoral immune responses. Involved in lymphocyte B cell development and immunoglobulin/IgA production.
A cytochrome P450 monooxygenase that catalyzes the in-chain oxidation of fatty acids (PubMed:19090726, PubMed:29018033). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates lauric and myristic acids predominantly at the omega-4 and omega-2 positions, respectively (PubMed:19090726, PubMed:29018033). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA). Displays an absolute stereoselectivity in the epoxidation of arachidonic acid producing the 14(S),15(R)-epoxyeicosatrienoic acid (EET) enantiomer (PubMed:29018033). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:19090726, PubMed:29018033).
Preferentially detected in breast carcinoma tissue and mammary gland, whereas only marginal expression is found in all other tested tissues.
Can form heteromeric complexes with LRFN2, LRFN3, LRFN4 and LRFN5 (By similarity). Forms homomeric complexes, but not across cell junctions (By similarity). Interacts with DLG1, DLG2, DLG3 and DLG4. Interacts with 2 AMPA receptor subunits GRIA1 and GRIA2 and NMDA receptor subunit GRIN1 (By similarity).
Promotes neurite outgrowth in hippocampal neurons. Involved in the regulation and maintenance of excitatory synapses. Induces the clustering of excitatory postsynaptic proteins, including DLG4, DLGAP1, GRIA1 and GRIN1 (By similarity).
The PDZ-binding motif is required for neurite outgrowth promotion and for DLG1-, DLG3- and DLG4-binding.
Abundantly expressed in testis, skeletal muscle, brain, and heart.
Exhibits both phospholipase A1/2 and acyltransferase activities (PubMed:21880860, PubMed:26503625). Shows phospholipase A1 (PLA1) and A2 (PLA2) activity, catalyzing the calcium-independent release of fatty acids from the sn-1 or sn-2 position of glycerophospholipids (PubMed:21880860, PubMed:22825852, PubMed:27623847). Shows O-acyltransferase activity, catalyzing the transfer of a fatty acyl group from glycerophospholipid to the hydroxyl group of lysophospholipid (PubMed:21880860). Shows N-acyltransferase activity, catalyzing the calcium-independent transfer of a fatty acyl group at the sn-1 position of phosphatidylcholine (PC) and other glycerophospholipids to the primary amine of phosphatidylethanolamine (PE), forming N-acylphosphatidylethanolamine (NAPE) which serves as precursor for N-acylethanolamines (NAEs) (PubMed:21880860, PubMed:22825852, PubMed:27623847).
Highly expressed in the testis, skeletal muscle, brain, heart, and thyroid.
Expressed mainly in hematopoietic cells and testis.
In T-cells, expressed 20 minutes following activation.
Probable transcription factor involved in muscle spindle development.
Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds to the SPH and GT-IIC 'enhansons' (5'-GTGGAATGT-3'). May be involved in the gene regulation of neural development. Binds to the M-CAT motif.
Although strongly related to the ABRAXAS1 protein, lacks the C-terminal pSXXF that constitutes a specific recognition motif for the BRCT domain of BRCA1.
Belongs to the FAM175 family. Abro1 subfamily.
Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked polyubiquitin, leaving the last ubiquitin chain attached to its substrates (PubMed:19214193, PubMed:20032457, PubMed:20656690, PubMed:24075985). May act as a central scaffold protein that assembles the various components of the BRISC complex and retains them in the cytoplasm (PubMed:20656690). Plays a role in regulating the onset of apoptosis via its role in modulating 'Lys-63'-linked ubiquitination of target proteins (By similarity). Required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activities by enhancing its stability and cell surface expression (PubMed:24075985, PubMed:26344097). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985). Required for normal induction of p53/TP53 in response to DNA damage (PubMed:25283148). Independent of the BRISC complex, promotes interaction between USP7 and p53/TP53, and thereby promotes deubiquitination of p53/TP53, preventing its degradation and resulting in increased p53/TP53-mediated transcription regulation and p53/TP53-dependent apoptosis in response to DNA damage (PubMed:25283148).
Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19214193, PubMed:20032457, PubMed:21282113, PubMed:24075985, PubMed:25283148, PubMed:26344097, PubMed:26195665). Interacts with BRCC3/BRCC36; the interaction is direct (PubMed:20032457, PubMed:20656690, PubMed:26344097). Interacts with BABAM1 (PubMed:21282113). Does not interact with BRCA1 (PubMed:17525340, PubMed:21282113). Interacts with SHMT1 and SHMT2; the interaction is direct. Identified in a complex with SHMT2 and the other subunits of the BRISC complex (PubMed:24075985). The BRISC complex binds monoubiquitin and both 'Lys-48'- and 'Lys-63'-linked polyubiquitin (PubMed:20032457). Identified in complexes with IFNAR1, IFNAR2 and SHMT2 (PubMed:24075985). Interacts with THAP5 (PubMed:21195082). Interacts with ATF4 (PubMed:22974638). Identified in a complex with p53/TP53 and USP7; interacts directly with both proteins (PubMed:25283148). Interacts with NUMA1 (PubMed:26195665). Interacts with microtubule minus ends (PubMed:26195665). Binds polyubiquitin (PubMed:19261749).
Detected in heart muscle (at protein level). Detected in heart and muscle, and at much lower levels in brain (PubMed:21195082).
Up-regulated in response to DNA damage (PubMed:25283148). Up-regulated in myocardial infarction area (at protein level) (PubMed:21195082).
Expressed in normal mammary, prostate, cervical, and epidermal tissues. It is greatly reduced or undetectable in transformed cells.
Interacts with MYO10, the interaction is calcium-dependent and essential for MYO10 function in filopodial extension.
May function as a specific light chain of unconventional myosin-10 (MYO10), also enhances MYO10 translation, possibly by acting as a chaperone for the emerging MYO10 heavy chain protein. May compete with calmodulin by binding, with different affinities, to cellular substrates.
Belongs to the DEAD box helicase family. DDX21/DDX50 subfamily.
Belongs to the chromogranin/secretogranin protein family.
Detected in cerebrospinal fluid and urine (at protein level) (PubMed:25326458). Expressed in the adrenal medulla, and in pheochromocytoma. Not expressed in liver.
Extensively processed by limited proteolysis at conserved basic residues. Alternative processing are seen in different tissues (By similarity).
Secretogranin-1 is a neuroendocrine secretory granule protein, which may be the precursor for other biologically active peptides.
Belongs to the IPP isomerase type 1 family.
Catalyzes the 1,3-allylic rearrangement of the homoallylic substrate isopentenyl (IPP) to its highly electrophilic allylic isomer, dimethylallyl diphosphate (DMAPP).
Down-regulated during myeloid differentiation.
Expressed in all hematopoietic cell lineages, but the highest level of expression is found in early myeloid progenitor cells. Expressed in brain, bone marrow, thymus and lung. Expressed at low level in liver, kidney and spleen. Not detected in heart.
Homooligomer (PubMed:24262037). Heterodimer with ARL6IP5. Interacts with ARL6 (By similarity). Interacts with TMEM33 (PubMed:25612671). Interacts with ATL1 (PubMed:24262037).
Positively regulates SLC1A1/EAAC1-mediated glutamate transport by increasing its affinity for glutamate in a PKC activity-dependent manner. Promotes the catalytic efficiency of SLC1A1/EAAC1 probably by reducing its interaction with ARL6IP5, a negative regulator of SLC1A1/EAAC1-mediated glutamate transport (By similarity). Plays a role in the formation and stabilization of endoplasmic reticulum tubules (PubMed:24262037). Negatively regulates apoptosis, possibly by modulating the activity of caspase-9 (CASP9). Inhibits cleavage of CASP9-dependent substrates and downstream markers of apoptosis but not CASP9 itself (PubMed:12754298). May be involved in protein transport, membrane trafficking, or cell signaling during hematopoietic maturation (PubMed:10995579).
The transmembrane domains are required for its ability to shape the endoplasmic reticulum membrane into tubules.
Splicing factor that seems to antagonize SR proteins in pre-mRNA splicing regulation.
Binds to the consensus sequence 5'-A[AT]T[AG]TTTGTTT-3' and acts as a transcriptional repressor (PubMed:11891324). Also acts as a transcriptional activator (PubMed:11891324). Negatively regulates transcription of transcriptional repressor RHIT/ZNF205 (PubMed:22306510). Promotes development of neural crest cells from neural tube progenitors (PubMed:11891324). Restricts neural progenitor cells to the neural crest lineage while suppressing interneuron differentiation (PubMed:11891324). Required for maintenance of pluripotent cells in the pre-implantation and peri-implantation stages of embryogenesis (PubMed:11891324).
Expressed in chronic myeloid leukemia, Jurkat T-cell leukemia and teratocarcinoma cell lines, but not in any other cell lines or normal tissues examined.
In spleen levels are higher in adult than in fetal tissue.
Anti-oncogene that plays a role in cell cycle regulation; decreases cell doubling time and anchorage-dependent growth; shortens the duration of G1 transit time and G1/S transition. When constitutively expressed, increases CDK4 and CDK6 kinases activity and CCND1/cyclin D1 protein level, as well as G1 cyclin/CDK complex formation. Involved in translation initiation; promotes recruitment of aminoacetyled initiator tRNA to P site of 40S ribosomes. Can promote release of deacylated tRNA and mRNA from recycled 40S subunits following ABCE1-mediated dissociation of post-termination ribosomal complexes into subunits. Plays a role as translation enhancer; recruits the density-regulated protein/DENR and binds to the cap complex of the 5'-terminus of mRNAs, subsequently altering the mRNA translation profile; up-regulates protein levels of BCL2L2, TFDP1, MRE11, CCND1 and E2F1, while mRNA levels remains constant. Hyperactivates DNA damage signaling pathway; increased gamma-irradiation-induced phosphorylation of histone H2AX, and induces damage foci formation. Increases the overall number of chromosomal abnormalities such as larger chromosomes formation and multiple chromosomal fusions when overexpressed in gamma-irradiated cells. May play a role in promoting lymphoid tumor development: lymphoid cell lines overexpressing MCTS1 exhibit increased growth rates and display increased protection against apoptosis. May contribute to the pathogenesis and progression of breast cancer via promotion of angiogenesis through the decline of inhibitory THBS1/thrombospondin-1, and inhibition of apoptosis. Involved in the process of proteasome degradation to down-regulate Tumor suppressor p53/TP53 in breast cancer cell; Positively regulates phosphorylation of MAPK1 and MAPK3. Involved in translation initiation; promotes aminoacetyled initiator tRNA to P site of 40S ribosomes. Can promote release of deacylated tRNA and mRNA from recycled 40S subunits following ABCE1-mediated dissociation of post-termination ribosomal complexes into subunits.
By DNA damaging agents such as gamma irradiation, adriamycin or taxol in lymphoid cells, but not by stress stimuli such as heat shock. This induction of protein expression does not occur at the RNA level, and does not require new protein synthesis.
Phosphorylation is critical for stabilization and promotion of cell proliferation.
The PUA RNA-binding domain is critical for cap binding, but not sufficient for translation enhancer function. MCT1 N-terminal region is required to enhance translation possibly through interaction with other proteins.
Ubiquitous. Over-expressed in T-cell lymphoid cell lines and in non-Hodgkin lymphoma cell lines as well as in a subset of primary large B-cell lymphomas.
According to PubMed:18021396, it binds DNA and acts as a transcription factor. However, the localization in lysosomes which was confirmed by different groups and the presence of transmembrane region strongly suggests that it does not have coactivator activity.
Highly N-glycosylated. N-glycosylation is essential for GLMP stability and for MFSD1 lysosomal localization.
Interacts (via lumenal domain) with lysosomal protein MFSD1; the interaction starts while both proteins are still in the endoplasmic reticulum and is required for stability and lysosomal localization of MFSD1.
Required to protect lysosomal transporter MFSD1 from lysosomal proteolysis and for MFSD1 lysosomal localization.
Expression restricted to nervous system and testis. Is also detected in several tumors types, most notably prostate cancer.
Abundantly expressed in placenta. Less abundant expression in mammary gland and ovary. Expression is barely detectable levels in all other tissues tested.
Conflict in position 933 in the human genome assembly due to a frameshift.
May be involved in transcriptional regulation during the post-meiotic stages of spermatogenesis.
Belongs to the krueppel C2H2-type zinc-finger protein family. ZFP57 subfamily.
In contrast to mice, transcripts are undetectable in the oocyte and during the earliest stages of embryonic development, increasing only after zygotic genome activation.
The KRAB domain is required for function as transcriptional repressor.
Transcription regulator required to maintain maternal and paternal gene imprinting, a process by which gene expression is restricted in a parent of origin-specific manner by epigenetic modification of genomic DNA and chromatin, including DNA methylation. Acts by controlling DNA methylation during the earliest multicellular stages of development at multiple imprinting control regions (ICRs) (PubMed:18622393, PubMed:30602440). Acts together with ZNF445, but ZNF445 seems to be the major factor in human early embryonic imprinting maintenance. In contrast, in mice, ZFP57 plays the predominant role in imprinting maintenance (PubMed:30602440). Required for the establishment of maternal methylation imprints at SNRPN locus. Acts as a transcriptional repressor in Schwann cells. Binds to a 5'-TGCCGC-3' consensus sequence and recognizes the methylated CpG within this element (By similarity).
Zinc fingers 3 and 4 mediate recognition of the target element, ZF3 interacting with the 5' half (TGC) and ZF4 interacting with the 3' half (CGC).
Prenylcysteine oxidase that cleaves the thioether bond of prenyl-L-cysteines, such as farnesylcysteine and geranylgeranylcysteine (PubMed:10585463, PubMed:11078725, PubMed:12186880). Only active against free prenylcysteines and not prenylcysteine residues within prenylated proteins or peptides (By similarity). Involved in the final step in the degradation of prenylated proteins, by degrading prenylcysteines after the protein has been degraded (PubMed:10585463).
Was originally thought to be a lyase and was therefore termed prenylcysteine lyase.
Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long.
Expressed in brain. Little or no expression in other tissues. Overexpressed specifically in gastric cancers. A 2- to 20-fold increase is found in over 50% of gastric cancer tissues.
Transcription repressor. Involved in the axonal projection and proper termination of olfactory sensory neurons (OSN). Plays a role in rostro-caudal patterning of the diencephalon and in prethalamic formation. Expression is required in OSN to cell-autonomously regulate OSN axon projections. Regulates non-cell-autonomously the layer formation of the olfactory bulb development and the interneurons. May be required for correct rostral migration of the interneuron progenitors (By similarity).
Triggers oncogenic activity specifically in gastric tumors through activation of KRAS in the ERK signaling pathway.
Minor apolipoprotein that associates with LDL. Inhibits cholesteryl ester transfer protein (CETP) activity and appears to be an important regulator of cholesterol transport. Also associates to a lesser degree with VLDL, Apo-AI and Apo-AII.
Catalyzes the reversible oxidation of 3-phospho-D-glycerate to 3-phosphonooxypyruvate, the first step of the phosphorylated L-serine biosynthesis pathway. Also catalyzes the reversible oxidation of 2-hydroxyglutarate to 2-oxoglutarate and the reversible oxidation of (S)-malate to oxaloacetate.
Induced by 17-beta-estradiol (estrogenic ligand) and 4-hydroxytamoxifen (agonist/antagonist ligand). Positively regulated by the transcription factors SP1 and NF-Y.
Expressed at the highest level in both brain and testis, with lower levels in the prostate, bladder and lung.
IGF-binding proteins prolong the half-life of IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs in cell culture. They alter the interaction of IGFs with their cell surface receptors (By similarity). May be a putative tumor suppressor protein.
Interacts with the large mitochondrial ribosomal subunit.
Required for the assembly and stability of the mitochondrial ribosome (PubMed:24948607). Is a positive regulator of mitochondrial protein synthesis (PubMed:24948607).
May act in concert with RAB3A in regulating aspects of synaptic vesicle membrane flow within the nerve terminal.
The GTP bound form of RAB15 interacts with REP15. Interacts (GTP-bound form) with MICAL1, MICAL3, MICALCL, EHBP1 and EHBP1L1.
Cleaves the alpha-chain at multiple sites and the beta-chain between 'Lys-53' and 'Lys-54' but not the gamma-chain of fibrinogen and therefore does not initiate the formation of the fibrin clot and does not cause the fibrinolysis directly. It does not cleave (activate) prothrombin and plasminogen but converts the inactive single chain urinary plasminogen activator (pro-urokinase) to the active two chain form. Activates coagulation factor VII (PubMed:8827452, PubMed:10754382, PubMed:11217080). May function as a tumor suppressor negatively regulating cell proliferation and cell migration (PubMed:26222560).
Heterodimer; disulfide-linked. Heterodimer of a 50 kDa heavy and a 27 kDa light chain linked by a disulfide bond (By similarity).
Proteolytic cleavage at Gly-23 or Met-27 can give rise to the 50 kDa heavy chain and cleavage at Arg-313 or Lys-319 can give rise to the 27 kDa light chain. The heavy chain can undergo further proteolytic cleavage at Lys-169 or Arg-170 to give rise to 2 inactive 26 kDa fragments and the light chain can undergo further proteolytic cleavage at Arg-480 to give rise to inactive 17 kDa and 8 kDa fragments (By similarity).
Efficient DNA binding requires dimerization with another bHLH protein (PubMed:14701734, PubMed:24465693). Heterodimer; forms a heterodimer with ARNT, ARNT2 or BMAL1 (PubMed:14701734, PubMed:24465693).
Transcription factor expressed in neurons of the brain that regulates the excitatory-inhibitory balance within neural circuits and is required for contextual memory in the hippocampus (By similarity). Plays a key role in the structural and functional plasticity of neurons (By similarity). Acts as an early-response transcription factor in both excitatory and inhibitory neurons, where it induces distinct but overlapping sets of late-response genes in these two types of neurons, allowing the synapses that form on inhibitory and excitatory neurons to be modified by neuronal activity in a manner specific to their function within a circuit, thereby facilitating appropriate circuit responses to sensory experience (By similarity). In excitatory neurons, activates transcription of BDNF, which in turn controls the number of GABA-releasing synapses that form on excitatory neurons, thereby promoting an increased number of inhibitory synapses on excitatory neurons (By similarity). In inhibitory neurons, regulates a distinct set of target genes that serve to increase excitatory input onto somatostatin neurons, probably resulting in enhanced feedback inhibition within cortical circuits (By similarity). The excitatory and inhibitory balance in neurons affects a number of processes, such as short-term and long-term memory, acquisition of experience, fear memory, response to stress and social behavior (By similarity). Acts as a regulator of dendritic spine development in olfactory bulb granule cells in a sensory-experience-dependent manner by regulating expression of MDM2 (By similarity). Efficient DNA binding requires dimerization with another bHLH protein, such as ARNT, ARNT2 or BMAL1 (PubMed:14701734). Can activate the CME (CNS midline enhancer) element (PubMed:14701734).
Ubiquitinated, leading to degradation by the proteosome.
Belongs to the dystrophin family. Dystrobrevin subfamily.
Highly expressed in brain, skeletal and cardiac muscles, and expressed at lower levels in lung, liver and pancreas. Isoform 2 is not expressed in cardiac muscle. Isoform 7 and isoform 8 are only expressed in muscle.
Interacts with dystrophin, utrophin and the syntrophins SNTA1, SNTB1, SNTB2, SNTG1 and SNTG2. Isoform 7 and isoform 8 do not interact with dystrophin. Binds dystrobrevin binding protein 1. Interacts with MAGEE1 (By similarity).
May be involved in the formation and stability of synapses as well as being involved in the clustering of nicotinic acetylcholine receptors.
Phosphorylation of DTN-1 on tyrosine kinase substrate domain present in the C-terminus.
The coiled coil domain mediates the interaction with dystrophin and utrophin.
Interacts with BRI3BP (PubMed:11860200, PubMed:30983867). Interacts with MGAT1 and IFITM3 (PubMed:30983867).
Interacts with BRI3BP, MGAT1 and IFITM3; the interactions are weaker than with isoform 1.
Participates in tumor necrosis factor-alpha (TNF)-induced cell death (PubMed:14592447). May be a target of Wnt/beta-catenin signaling in the liver (PubMed:20538055).
Up-regulated during TNF-mediated inflammation and immunity (By similarity). Up-regulated by beta-catenin and TCF4 (PubMed:20538055).
Binds calcium. May be involved in terminal differentiation of keratinocytes.
Particularly abundant in the epidermis where its expression is directly related to keratinocyte differentiation. Very low expression in lung.
Citrullination at Arg-57 (H1R54ci) by PADI4 takes place within the DNA-binding site of H1 and results in its displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance.
In the embryo, expressed in neural stem cells of the hindbrain.
May be involved in transcriptional regulation. Is required for the differentiation of KISS1-expressing neurons in the arcuate (Arc) nucleus of the hypothalamus. Is a critical regulator of GABAergic cell fate in the cerebellum, required for normal postnatal cerebellar development (By similarity).
Prominent expression detected in the developing hypothalamus and cerebellar primordium at Carnegie stage 23.
(Microbial infection) In case of infection by poliovirus, binds to the viral internal ribosome entry site (IRES) and stimulates the IRES-mediated translation (PubMed:12414943, PubMed:24371074). Also plays a role in initiation of viral RNA replication in concert with the viral protein 3CD (PubMed:12414943).
(Microbial infection) Proteolytically cleaved by picornavirus proteinase 3CD.
Identified in a mRNP complex, at least composed of DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1 (PubMed:19029303). Interacts with IFIH1 and RNF135 (PubMed:19881509). Interacts with MAVS (via C-terminus) and ITCH (via WW domains) (PubMed:19881509). Interacts with CGAS; preventing the formation of liquid-like droplets in which CGAS is activated (PubMed:35322803).
Phosphorylated. The non-phosphorylated form(s) exhibited the strongest poly(rC)-binding activity.
Single-stranded nucleic acid binding protein that binds preferentially to oligo dC (PubMed:7607214, PubMed:12414943). Major cellular poly(rC)-binding protein (PubMed:12414943). Binds also poly(rU) (PubMed:12414943). Acts as a negative regulator of antiviral signaling (PubMed:19881509, PubMed:35322803). Negatively regulates cellular antiviral responses mediated by MAVS signaling (PubMed:19881509). It acts as an adapter between MAVS and the E3 ubiquitin ligase ITCH, therefore triggering MAVS ubiquitination and degradation (PubMed:19881509). Negativeley regulates the cGAS-STING pathway via interaction with CGAS, preventing the formation of liquid-like droplets in which CGAS is activated (PubMed:35322803). Together with PCBP1, required for erythropoiesis, possibly by regulating mRNA splicing (By similarity).
The KH domains mediates poly(C) binding.
Belongs to the WD repeat WDR90/POC16 family.
Required for efficient primary cilium formation.
Acts as a receptor for urokinase plasminogen activator. Plays a role in localizing and promoting plasmin formation. Mediates the proteolysis-independent signal transduction activation effects of U-PA. It is subject to negative-feedback regulation by U-PA which cleaves it into an inactive form.
Expressed in neurons of the rolandic area of the brain (at protein level). Expressed in the brain.
Monomer (Probable). Interacts with MRC2. Interacts (via the UPAR/Ly6 domains) with SRPX2. Interacts with FAP (seprase); the interaction occurs at the cell surface of invadopodia membrane. Interacts with SORL1 (via N-terminal ectodomain); this interaction decreases PLAUR internalization (PubMed:14764453, PubMed:23486467). The ternary complex composed of PLAUR-PLAU-SERPINE1 also interacts with SORL1 (PubMed:15053742).
Broadly expressed, with highest levels in kidney and pancreas.
Protease that catalyzes two essential functions in the NEDD8 pathway: processing of full-length NEDD8 to its mature form and deconjugation of NEDD8 from targeted proteins such as cullins or p53.
Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. Prevents helicase DHX37 to be recruited before post-A1 state.
Acts as an intracellular estrogen-binding protein. May be involved in modulating cellular levels and biological functions of estrogens in the pancreas. May act as a chaperone that inhibits aggregation of misfolded proteins.
Highly expressed in pancreas (at protein level).
Monomer; predominantly as monomer under reducing conditions. Homodimer; disulfide-linked. Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX.
The disulfide-linked homodimer exhibits an enhanced chaperone activity.
DHRS7 was originally reported to be anchored in the endoplasmic reticulum membrane and facing the lumen (PubMed:24246760). However, the catalytic moiety was later shown to be facing the cytosol (PubMed:28457967).
Found predominantly in the adrenal glands, liver, thyroid, prostate, small intestine, colon, stomach, kidney and brain (PubMed:26466768). Lower levels observed in skeletal muscle, the lung and the spleen (PubMed:26466768).
NADPH-dependent oxidoreductase which catalyzes the reduction of a variety of compounds bearing carbonyl groups including steroids, retinoids and xenobiotics (PubMed:24246760, PubMed:26466768, PubMed:28687384, PubMed:28457967). Catalyzes the reduction/inactivation of 5alpha-dihydrotestosterone to 3alpha-androstanediol, with a possible role in the modulation of androgen receptor function (PubMed:28687384, PubMed:28457967). Involved in the reduction of all-trans-retinal to all-trans-retinol (PubMed:26466768). Converts cortisone to 20beta-dihydrocortisone in vitro, although the physiological relevance of this activity is questionable (PubMed:28457967). Reduces exogenous compounds such as quinones (1,2-naphtoquinone, 9,10-phenantrenequinone and benzoquinone) and other xenobiotics (alpha-diketones) in vitro, suggesting a role in the biotransformation of xenobiotics with carbonyl group (PubMed:24246760, PubMed:26466768). A dehydrogenase activity has not been detected so far (PubMed:24246760). May play a role as tumor suppressor (PubMed:26311046).
Belongs to the complex I 23 kDa subunit family.
Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits (PubMed:12611891). This is a component of the iron-sulfur (IP) fragment of the enzyme (By similarity). Interacts with RAB5IF (PubMed:31536960).
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:22499348). Essential for the catalytic activity and assembly of complex I (PubMed:22499348).
Expressed in all tissues with the highest level in heart and skeletal muscle and the lowest level in lung.
Acetylated; can be acetylated on both Lys-274 and Lys-288. Acetylation on Lys-274 (by CBP) appears to be the major site affecting EKLF transactivation activity (By similarity).
Expression restricted to adult bone marrow and fetal liver. Not expressed in myeloid nor lymphoid cell lines.
Genetic variations in KLF1 underlie the blood group-Lutheran inhibitor (In(Lu)) phenotype [MIM:111150]; also known as dominant Lu (a-b-) phenotype. In(Lu) is characterized phenotypically by the apparent absence of the Lu antigen (BCAM) on red blood cells during serologic tests: Lu(a-b-).
Genetic variations in KLF1 underlie the fetal hemoglobin quantitative trait locus 6 (HBFQTL6) [MIM:613566]. Classic hereditary persistence of fetal hemoglobin (HPFH) is characterized by a substantial elevation of fetal hemoglobin (HbF) in adult red blood cells. There are no other phenotypic or hematologic manifestations. In healthy adults, fetal hemoglobin (HbF) is present at residual levels (less than 0.06% of total hemoglobin) with over 20-fold variation. Ten to fifteen percent of adults fall within the upper tail of the distribution.
Interacts with PCAF; the interaction does not acetylate EKLF and inhibits its transactivation activity (By similarity). Interacts with CREBBP/CBP and EP300; the interactions enhance the transactivation activity. Interacts with TFB1.
Phosphorylated primarily on serine residues in the transactivation domain. Phosphorylation on Thr-23 is critical for the transactivation activity (By similarity).
Sumoylated; sumoylation, promoted by PIAS1, leads to repression of megakaryocyte differentiation. Also promotes the interaction with the CDH4 subunit of the NuRD repression complex (By similarity).
Transcription regulator of erythrocyte development that probably serves as a general switch factor during erythropoiesis. Is a dual regulator of fetal-to-adult globin switching. Binds to the CACCC box in the beta-globin gene promoter and acts as a preferential activator of this gene. Furthermore, it binds to the BCL11A promoter and activates expression of BCL11A, which in turn represses the HBG1 and HBG2 genes. This dual activity ensures that, in most adults, fetal hemoglobin levels are low. Able to activate CD44 and AQP1 promoters. When sumoylated, acts as a transcriptional repressor by promoting interaction with CDH2/MI2beta and also represses megakaryocytic differentiation.
Catalytic subunit of the phosphorylase b kinase (PHK), which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase. May regulate glycogeneolysis in the testis. In vitro, phosphorylates PYGM (By similarity).
Hexadecamer of 4 heterotetramers, each composed of alpha, beta, gamma, and delta subunits. Alpha (PHKA1 or PHKA2) and beta (PHKB) are regulatory subunits, gamma (PHKG1 or PHKG2) is the catalytic subunit, and delta is calmodulin.
ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both essential cofactors for processing and trafficking of newly synthesized proteins in the secretory pathway (PubMed:16192278, PubMed:30923126, PubMed:21187401, PubMed:12707275, PubMed:20439740). Within a catalytic cycle, acquires Ca(2+) or Mn(2+) ions on the cytoplasmic side of the membrane and delivers them to the lumenal side. The transfer of ions across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing to outward-facing state (PubMed:16192278, PubMed:16332677, PubMed:30923126). Plays a primary role in the maintenance of Ca(2+) homeostasis in the trans-Golgi compartment with a functional impact on Golgi and post-Golgi protein sorting as well as a structural impact on cisternae morphology (PubMed:20439740, PubMed:14632183). Responsible for loading the Golgi stores with Ca(2+) ions in keratinocytes, contributing to keratinocyte differentiation and epidermis integrity (PubMed:14632183, PubMed:10615129, PubMed:20439740). Participates in Ca(2+) and Mn(2+) ions uptake into the Golgi store of hippocampal neurons and regulates protein trafficking required for neural polarity (By similarity). May also play a role in the maintenance of Ca(2+) and Mn(2+) homeostasis and signaling in the cytosol while preventing cytotoxicity (PubMed:21187401).
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIA subfamily.
Catalyzes the hydrolysis of ATP coupled with the transport of calcium.
Found in most tissues except colon, thymus, spleen and leukocytes (PubMed:15831496). Expressed in keratinocytes (at protein level) (PubMed:15831496, PubMed:14632183).
A chromosomal aberration involving PRDM16 is found in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Reciprocal translocation t(1;3)(p36;q21). Isoform 4 is specifically expressed in adult T-cell leukemia.
Binds DNA and functions as a transcriptional regulator (PubMed:12816872). Displays histone methyltransferase activity and monomethylates 'Lys-9' of histone H3 (H3K9me1) in vitro (By similarity). Probably catalyzes the monomethylation of free histone H3 in the cytoplasm which is then transported to the nucleus and incorporated into nucleosomes where SUV39H methyltransferases use it as a substrate to catalyze histone H3 'Lys-9' trimethylation (By similarity). Likely to be one of the primary histone methyltransferases along with MECOM/PRDM3 that direct cytoplasmic H3K9me1 methylation (By similarity). Functions in the differentiation of brown adipose tissue (BAT) which is specialized in dissipating chemical energy in the form of heat in response to cold or excess feeding while white adipose tissue (WAT) is specialized in the storage of excess energy and the control of systemic metabolism (By similarity). Together with CEBPB, regulates the differentiation of myoblastic precursors into brown adipose cells (By similarity). Functions as a repressor of TGF-beta signaling (PubMed:19049980).
Binds DNA and functions as a transcriptional regulator (PubMed:12816872). Functions as a repressor of TGF-beta signaling (PubMed:14656887). May regulate granulocyte differentiation (PubMed:12816872).
Expressed in uterus and kidney. Expressed in both cardiomyocytes and interstitial cells.
Interacts with CEBPA, CEBPB and CEBPD; the interaction is direct. Interacts with PPARG and PPARA; controls brown adipocytes differentiation. Interacts with CTBP1 and CTBP2; represses the expression of WAT-specific genes. Interacts with PPARGC1A and PPARGC1B; interaction with PPARGC1A or PPARGC1B activates the transcription of BAT-specific gene (By similarity). Interacts with HDAC1, SKI, SMAD2 and SMAD3; the interaction with SKI promotes the recruitment of SMAD3-HDAC1 complex on the promoter of TGF-beta target genes (PubMed:19049980). Interacts with ZNF516; the interaction is direct and may play a role in the transcription of brown adipose tissue-specific gene (PubMed:25578880).
Interacts with the syntrophin SNTA1. Cross-link to form 2 major subcomplexes: one consisting of SGCB, SGCD and SGCG and the other consisting of SGCB and SGCD. The association between SGCB and SGCG is particularly strong while SGCA is loosely associated with the other sarcoglycans (By similarity). Interacts with FLNC.
Component of the EvC complex composed of EFCAB7, IQCE, EVC2 and EVC; built from two subcomplexes, EVC2:EVC and EFCAB7:IQCE. Interacts with EVC. Interacts (via N-terminal end) with EFCAB7. Interacts (via N-terminal end) with IQCE.
Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling. Plays a critical role in bone formation and skeletal development. May be involved in early embryonic morphogenesis.
Found in the heart, placenta, lung, liver, skeletal muscle, kidney and pancreas.
A hemichannel or connexon is composed of a hexamer of connexins. A functional gap junction is formed by the apposition of two hemichannels. Forms heteromeric channels with GJA8.
Structural component of lens fiber gap junctions (PubMed:30044662). Gap junctions are dodecameric channels that connect the cytoplasm of adjoining cells (By similarity). They are formed by the docking of two hexameric hemichannels, one from each cell membrane. Small molecules and ions diffuse from one cell to a neighboring cell via the central pore (PubMed:30044662).
Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during the synthesis of uridine diphosphate/UDP-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways including protein N- and O-glycosylation.
Found in many tissues except lung. Relatively high expression in pancreas, heart, liver, and placenta, and relatively low expression in brain, skeletal muscle and kidney.
Component of the MLL3 complex (also named ASCOM complex), at least composed of catalytic subunit KMT2C/MLL3, ASH2L, RBBP5, WDR5, NCOA6, DPY30, KDM6A, PAXIP1/PTIP, PAGR1 and alpha- and beta-tubulin (PubMed:17021013, PubMed:17500065, PubMed:23508102). Forms a core complex with the evolutionary conserved subcomplex WRAD composed of WDR5, RBBP5, ASH2L/ASH2 and DPY30 subunits; WRAD differentially stimulates the methyltransferase activity (PubMed:25561738). Interacts (via WIN motif) with WDR5 (PubMed:22665483, PubMed:22266653).
Found in a critical region of chromosome 7, which is commonly deleted in malignant myeloid disorders. Partial duplication of the KMT2C gene are found in the juxtacentromeric region of chromosomes 1, 2, 13 and 21. Juxtacentromeric reshuffling of the KMT2C gene has generated the BAGE genes.
Highly expressed in testis and ovary, followed by brain and liver. Also expressed in placenta, peripherical blood, fetal thymus, heart, lung and kidney. Within brain, expression was highest in hippocampus, caudate nucleus, and substantia nigra. Not detected in skeletal muscle and fetal liver.
Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4) (PubMed:25561738). Part of chromatin remodeling machinery predominantly forms H3K4me1 methylation marks at active chromatin sites where transcription and DNA repair take place (PubMed:25561738, PubMed:24081332, PubMed:22266653). Likely plays a redundant role with KMT2D in enriching H3K4me1 mark on primed and active enhancer elements (PubMed:24081332).
The SET domain interacts with histone H3 but not H2A, H2B and H4, and may have a H3 lysine specific methylation activity.
Contributes to the neddylation of all cullins by transferring NEDD8 from N-terminally acetylated NEDD8-conjugating E2s enzyme to different cullin C-terminal domain-RBX complexes and may play a role in the cell cycle progression by regulating the SCF ubiquitin E3 ligase complex, after UV damage (PubMed:23201271, PubMed:19617556, PubMed:27542266, PubMed:18823379). At the cell membrane, can promote and as well inhibit cullins neddylation (PubMed:19617556, PubMed:26906416, PubMed:25349211).
Part of a complex containing DCUN1D3, CUL3 and RBX1 (PubMed:19617556). Interacts (via the DCUN1 domain) with the unneddylated cullins: interacts with CUL1, CUL2, CUL3, CUL4A, CUL4B and CUL5; these interactions promote the cullin neddylation and the identity of the cullin dictates the affinity of the interaction (PubMed:26906416, PubMed:23201271, PubMed:27542266). Interacts preferentially with CUL3; this interaction triggers the relocalization of CUL3 to the cell membrane where CUL3 is neddylated (PubMed:19617556). Interacts (via DCUN1 domain) with RBX1 (PubMed:26906416, PubMed:25349211). May also interact with regulators or subunits of cullin-RING ligases such as RNF7, ELOB and DDB1; these interactions are bridged by cullins (PubMed:26906416). Interacts (via DCUN1 domain) with CAND1; this interaction is bridged by cullins and strongly inhibits cullin neddylation (PubMed:26906416, PubMed:27542266). These CAND-cullin-DCNL complexes can only be neddylated in the presence of a substrate adapter (PubMed:26906416). Interacts (via DCUN1 domain) with the N-terminally acetylated form of UBE2M and UBE2F (PubMed:23201271, PubMed:25349211, PubMed:19617556).
Tends to be down-regulated in different type of cancers, including lung neuroendocrine carcinoma, thyroid Huerthle cell carcinoma and lung squamous cell carcinoma (PubMed:25349211). Mostly expressed in testis and brain (PubMed:26906416). Highly expressed in liver, bladder and renal normal tissue than their tumor tissue counterparts (PubMed:18823379). Palmitoylation stabilizes DCUN1D3 at the cell membrane (PubMed:19617556).
The DCUN1 domain, also known as PONY domain, mediates the interaction with different cullins (PubMed:23201271, PubMed:19617556). The DCUN1 domain mediates the interaction with the N-terminally acetylated NEDD8-conjugating E2s enzyme leading to the NEDD8 transfer from N-terminally acetylated NEDD8-conjugating E2s enzyme to different cullin C-terminal domain-RBX complexes; the neddylation efficiency correlates with the DCUN1D5-cullin and DCUN1D5-E2 interaction affinities (PubMed:23201271). This domain is also involved in CAND1-, cullins- and RBX1-binding (PubMed:25349211, PubMed:26906416).
ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated (PubMed:11809724, PubMed:15716377, PubMed:16219033, PubMed:17389232, PubMed:20530212, PubMed:22637577, PubMed:26875866). Preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold (PubMed:26875866). Severing activity is not dependent on tubulin acetylation or detyrosination (PubMed:26875866). Microtubule severing promotes reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. It is critical for the biogenesis and maintenance of complex microtubule arrays in axons, spindles and cilia. SPAST is involved in abscission step of cytokinesis and nuclear envelope reassembly during anaphase in cooperation with the ESCRT-III complex (PubMed:19000169, PubMed:21310966, PubMed:26040712). Recruited at the midbody, probably by IST1, and participates in membrane fission during abscission together with the ESCRT-III complex (PubMed:21310966). Recruited to the nuclear membrane by IST1 and mediates microtubule severing, promoting nuclear envelope sealing and mitotic spindle disassembly during late anaphase (PubMed:26040712). Required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and endosome recycling (PubMed:23897888). Recruited by IST1 to endosomes and regulates early endosomal tubulation and recycling by mediating microtubule severing (PubMed:23897888). Probably plays a role in axon growth and the formation of axonal branches (PubMed:15716377).
ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated. Preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold. Severing activity is not dependent on tubulin acetylation or detyrosination. Microtubule severing promotes reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. It is critical for the biogenesis and maintenance of complex microtubule arrays in axons, spindles and cilia. SPAST is involved in abscission step of cytokinesis and nuclear envelope reassembly during anaphase in cooperation with the ESCRT-III complex. Recruited at the midbody, probably by IST1, and participates in membrane fission during abscission together with the ESCRT-III complex. Recruited to the nuclear membrane by IST1 and mediates microtubule severing, promoting nuclear envelope sealing and mitotic spindle disassembly during late anaphase. Required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and endosome recycling. Recruited by IST1 to endosomes and regulates early endosomal tubulation and recycling by mediating microtubule severing. Probably plays a role in axon growth and the formation of axonal branches.
Allosteric enzyme with a cooperative mechanism; at least two neighbor subunits influence each other strongly in spastin hexamers (PubMed:22637577). Microtubule binding promotes cooperative interactions among spastin subunits (PubMed:22637577). ATP-bound enzyme interacts strongly and cooperatively with microtubules; this interaction stimulates ATP hydrolysis (PubMed:23745751).
Allosteric enzyme with a cooperative mechanism; at least two neighbor subunits influence each other strongly in spastin hexamers. Microtubule binding promotes cooperative interactions among spastin subunits.
Belongs to the AAA ATPase family. Spastin subfamily.
Expressed in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle. The short isoforms may predominate in brain and spinal cord.
Expressed in fetal brain, heart, kidney, liver, lung, skeletal muscle, spleen and thymus.
Homohexamer (PubMed:17389232, PubMed:22637577). Mostly monomeric, but assembles into hexameric structure for short periods of time. Oligomerization seems to be a prerequisite for catalytic activity (PubMed:17389232, PubMed:22637577). Binding to ATP in a cleft between two adjacent subunits stabilizes the homohexameric form (PubMed:17389232, PubMed:22637577). Binds to microtubules at least in part via the alpha-tubulin and beta-tubulin tails (PubMed:15269182, PubMed:15716377, PubMed:23272056). The hexamer adopts a ring conformation through which microtubules pass prior to being severed (PubMed:17389232, PubMed:22637577). Does not interact strongly with tubulin heterodimers (PubMed:15269182, PubMed:15716377, PubMed:23272056). Interacts (via MIT domain) with CHMP1B; the interaction is direct (PubMed:15537668, PubMed:18997780). Interacts with SSNA1 (PubMed:15269182, PubMed:25390646). Interacts with ATL1 (PubMed:16339213, PubMed:16815977). Interacts with RTN1 (PubMed:16602018). Interacts with ZFYVE27 (PubMed:16826525, PubMed:23969831). Isoform 1 but not isoform 3 interacts with RTN2 (PubMed:22232211). Interacts with REEP1 (PubMed:20200447). Interacts (via MIT domain) with IST1 (PubMed:23897888, PubMed:26040712).
Homohexamer. Mostly monomeric, but assembles into hexameric structure for short periods of time. Oligomerization seems to be a prerequisite for catalytic activity. Binding to ATP in a cleft between two adjacent subunits stabilizes the homohexameric form. Binds to microtubules at least in part via the alpha-tubulin and beta-tubulin tails. The hexamer adopts a ring conformation through which microtubules pass prior to being severed. Does not interact strongly with tubulin heterodimers. Interacts (via MIT domain) with CHMP1B; the interaction is direct. Interacts with SSNA1. Interacts with ATL1. Interacts with RTN1. Interacts with ZFYVE27. Interacts with REEP1. Interacts (via MIT domain) with IST1.
Involved in lipid metabolism by regulating the size and distribution of lipid droplets.
Produced by alternative promoter usage and alternative splicing. May also be produced by alternative initiation at Met-87 of isoform 2.
Produced by alternative promoter usage. May also be produced by alternative initiation at Met-87 of isoform 1. Major isoform.
Expressed in all structures of brain, with a high expression in cerebellum. Expressed in cortical projection neurons.
Interacts with AP5Z1, AP5B1, AP5S1 and ZFYVE26.
May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport.
Activating cyclin for the cyclin-associated kinase CDK10.
Associates with CDK10 to promote its kinase activity. Interacts with SALL1.
Belongs to the cyclin family. Cyclin-like FAM58 subfamily.
Silencing with siRNAs phenocopies CDK10 silencing in increasing c-Raf and in conferring tamoxifen resistance to breast cancer cells.
May play a role in the development and maintenance of the vertebrate nervous system. Exhibits strong synaptogenic activity, restricted to excitatory presynaptic differentiation (By similarity).
Peripherally associated with AMPAR complex. AMPAR complex consists of an inner core made of 4 pore-forming GluA/GRIA proteins (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged in a twofold symmetry. One of the two pairs of distinct binding sites is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR complex is complemented by outer core constituents binding directly to the GluA/GRIA proteins at sites distinct from the interaction sites of the inner core constituents. Outer core constituents include at least PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the inner and outer core serve as a platform for other, more peripherally associated AMPAR constituents, including LRRTM4. Alone or in combination, these auxiliary subunits control the gating and pharmacology of the AMPAR complex and profoundly impact their biogenesis and protein processing (By similarity).
Expressed in fetal brain and in adult brain, heart, small intestine and colon.
Monomer. Interacts with ARMCX3 at the mitochondrial outer membrane surface. Interacts with PAX3 (PubMed:21965087).
Transcription factor that plays a central role in developing and mature glia (By similarity). Specifically activates expression of myelin genes, during oligodendrocyte (OL) maturation, such as DUSP15 and MYRF, thereby playing a central role in oligodendrocyte maturation and CNS myelination (By similarity). Once induced, MYRF cooperates with SOX10 to implement the myelination program (By similarity). Transcriptional activator of MITF, acting synergistically with PAX3 (PubMed:21965087). Transcriptional activator of MBP, via binding to the gene promoter (By similarity).
Required for S phase entry of the cell cycle.
Widely expressed. Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocytes with the highest expression in testis.
Interacts with OPRM1 (By similarity). Interacts with palmitoyltransferase ZDHHC17/HIP14; the interaction leads to palmitoylation of GPM6A (PubMed:24705354).
Involved in neuronal differentiation, including differentiation and migration of neuronal stem cells. Plays a role in neuronal plasticity and is involved in neurite and filopodia outgrowth, filopodia motility and probably synapse formation. GPM6A-induced filopodia formation involves mitogen-activated protein kinase (MAPK) and Src signaling pathways. May be involved in neuronal NGF-dependent Ca(2+) influx. May be involved in regulation of endocytosis and intracellular trafficking of G-protein-coupled receptors (GPCRs); enhances internalization and recycling of mu-type opioid receptor.
Expressed primarily in skeletal muscle and to a lesser extent in heart. Also detected in brain and placenta.
Interacts via its LIM domains with various PKC isoforms (By similarity). Interacts via its PDZ domain with the ACTN2 C-terminal region. Interacts with MYOZ1, MYOZ2 and MYOZ3.
May function as an adapter in striated muscle to couple protein kinase C-mediated signaling via its LIM domains to the cytoskeleton.
Restricted to hair root, not detected in any other tissues. Expressed in cuticle layers of differentiating hair follicles.
Antibodies against NIN are present in sera from patients with autoimmune diseases that developed autoantibodies against centrosomal proteins.
Centrosomal protein required in the positioning and anchorage of the microtubule minus-end in epithelial cells (PubMed:15190203, PubMed:23386061). May also act as a centrosome maturation factor (PubMed:11956314). May play a role in microtubule nucleation, by recruiting the gamma-tubulin ring complex to the centrosome (PubMed:15190203). Overexpression does not perturb nucleation or elongation of microtubules but suppresses release of microtubules (PubMed:15190203). Required for centriole organization and microtubule anchoring at the mother centriole (PubMed:23386061).
Homooligomer. Interacts with GSK3B/GSK3-beta via its C-terminal domain (PubMed:11004522). Interacts with C14ORF166, such interaction may prevent its phosphorylation by GSK3B (PubMed:15147888). Interacts with AUNIP (via N-terminus) (PubMed:20596670). Identified in a complex with AUNIP and AURKA (PubMed:20596670). Interacts with CCDC120 (PubMed:28422092). Interacts (via C-terminus) with CEP250 (By similarity). Interacts with CEP170 (By similarity). Interacts with the gamma-tubulin ring complex component TUBGCP3 (By similarity). Interacts with gamma-tubulin (By similarity). Isoform 6 does not interact with CEP170 or CEP250 (By similarity).
In interphase cells, it is localized in the centrosome. Decreases in metaphase and anaphase and reappears in telophase.
Phosphorylated by AURKA/Aurora kinase A and PKA kinases but not CK2 or AURKB/ Aurora kinase B.
Several sequencing errors and frameshifts.
The N-terminal domain is important for targeting to the mother centriole, although it is not sufficient by itself for centrosomal localization.
There is conflicting information regarding the regions required for centrosomal localization. One study shows that the region 1601-1682 is necessary and sufficient for targeting to the centrosome (PubMed:12927815). Another study shows that a separate region, 1291-1575, is important for centrosomal localization (PubMed:15190203). However, a third study shows that the coiled-coil region (373-1885) is not sufficient for centrosomal localization and instead localizes to cytoplasmic speckles (By similarity). The observed differences might be due to oligomerization of the longer coiled-coil domain-containing sequence, which would mask the shorter centrosomal targeting sequences (By similarity).
Ubiquitous. Highly expressed in heart and skeletal muscle. Isoform 1 is more expressed than isoform 5.
A chromosomal aberration involving BCL3 may be a cause of B-cell chronic lymphocytic leukemia (B-CLL). Translocation t(14;19)(q32;q13.1) with immunoglobulin gene regions.
Component of a complex consisting of the NF-kappa-B p52-p52 homodimer and BCL3. Component of a complex consisting of the NF-kappa-B p50-p50 homodimer and BCL3. Interacts with N4BP2, COPS5 and PIR. Interacts with CYLD (By similarity).
Contributes to the regulation of transcriptional activation of NF-kappa-B target genes. In the cytoplasm, inhibits the nuclear translocation of the NF-kappa-B p50 subunit. In the nucleus, acts as transcriptional activator that promotes transcription of NF-kappa-B target genes. Contributes to the regulation of cell proliferation (By similarity).
Polyubiquitinated. Ubiquitination via 'Lys-63'-linked ubiquitin chains is required for nuclear accumulation. Deubiquitinated by CYLD, which acts on 'Lys-63'-linked ubiquitin chains. Deubiquitination by CYLD prevents nuclear accumulation (By similarity).
In (PubMed:9545258) and in (PubMed:10051563) experimental information is given for a truncated version of TGFBRAP1 (sequence of 474-860), which was later shown to act as a dominant negative.
Interacts with TGFBR2 and ACVR2B; in the absence of ligand stimulation. Interacts with TGFBR1, ACVRL1, BMPR1A and ACVR1B; in the absence of ligand stimulation and to a less extent. Interacts with SMAD4; the interaction seems to be mutually exclusive with the interaction of SMAD4 and phosphorylated SMAD2 (PubMed:9545258, PubMed:11278302). May interact with ALOX5 (PubMed:10051563). Interacts with RAB5C (By similarity). Interacts with VPS8, VPS11 and VPS16. Component of the putative class C core vacuole/endosome tethering (CORVET) complex; the core of which composed of the class C Vps proteins VPS11, VPS16, VPS18 and VPS33A, is associated with VPS8 and TGFBRAP1 (PubMed:25266290).
Plays a role in the TGF-beta/activin signaling pathway. It associates with inactive heteromeric TGF-beta and activin receptor complexes, mainly through the type II receptor, and is released upon activation of signaling. May recruit SMAD4 to the vicinity of the receptor complex and facilitate its interaction with receptor-regulated Smads, such as SMAD2.
Plays a role in vesicle-mediated protein trafficking of the endocytic membrane transport pathway. Believed to act as a component of the putative CORVET endosomal tethering complexes which is proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The CORVET complex is proposed to function as a Rab5 effector to mediate early endosome fusion probably in specific endosome subpopulations (PubMed:25266290). Functions predominantly in APPL1-containing endosomes and in degradative but not recycling trafficking of endocytosed cargo (PubMed:25266290).
Has sometimes been referred to as ADAM-12.
Interacts with SH3GL2 and SNX9 through its cytoplasmic tail (PubMed:10531379). Interacts with ITGA6.
May act as alpha-secretase for amyloid precursor protein (APP).
Metalloprotease that cleaves and releases a number of molecules with important roles in tumorigenesis and angiogenesis, such as TEK, KDR, EPHB4, CD40, VCAM1 and CDH5. May mediate cell-cell, cell-matrix interactions and regulate the motility of cells via interactions with integrins.
Phosphorylation is induced in vitro by phorbol-12-myristate-13-acetate (PMA).
Proteolytically cleaved in the trans-Golgi network before it reaches the plasma membrane to generate a mature protein. The removal of the pro-domain occurs via cleavage at two different sites. Processed most likely by a pro-protein convertase such as furin, at the boundary between the pro-domain and the catalytic domain. An additional upstream cleavage pro-protein convertase site (Arg-56/Glu-57) has an important role in the activation of ADAM9.
Synthesized as an inactive form which is proteolytically cleaved to generate an active enzyme. Processing at the upstream site is particularly important for activation of the proenzyme, whereas processing at the boundary between the pro-domain and the catalytic domain does not appear to be essential. Inhibited by hydroxamic acid-based inhibitors.
Widely expressed. Expressed in chondrocytes. Isoform 2 is highly expressed in liver and heart.
Activated by calcium/calmodulin (PubMed:12747803). Inhibited by high concentrations of the substrate Ins(1,2,4)P3, and allosterically activated by the product Ins(1,3,4,5)P4.
Catalyzes the phosphorylation of 1D-myo-inositol 1,4,5-trisphosphate (InsP3) into 1D-myo-inositol 1,3,4,5-tetrakisphosphate and participates to the regulation of calcium homeostasis (PubMed:11085927, PubMed:12747803). Can phosphorylate inositol 2,4,5-triphosphate to inositol 2,4,5,6-tetraphosphate (By similarity).
Highly expressed in pancreas, skeletal muscle, liver, placenta and weakly in kidney and brain.
Expression is restricted to non-neuronal tissues. Highest expression in pancreas and lowest in liver.
Monomer (By similarity). Interacts with REST.
Preferentially catalyzes the dephosphorylation of 'Ser-5' within the tandem 7 residue repeats in the C-terminal domain (CTD) of the largest RNA polymerase II subunit POLR2A. Negatively regulates RNA polymerase II transcription, possibly by controlling the transition from initiation/capping to processive transcript elongation. Recruited by REST to neuronal genes that contain RE-1 elements, leading to neuronal gene silencing in non-neuronal cells. May contribute to the development of sarcomas.
Bone marrow, peripheral blood mononuclear cells, fibroblasts and Epstein-Barr virus-transformed lymphoblastoid cell lines. Strongly expressed in granulocytic cells, and weakly on lymphocytes cells.
Required for granulocyte differentiation and functionality of hematopoietic progenitor cells through the control of cell cycle progression and survival of hematopoietic progenitor cells.
Some glutamate residues at the C-terminus are polyglutamylated, resulting in polyglutamate chains on the gamma-carboxyl group. Polyglutamylation plays a key role in microtubule severing by spastin (SPAST). SPAST preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity by SPAST increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold. Glutamylation is also involved in cilia motility (By similarity).
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-iodophenyl-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca(2+) ions from intracellular stores. Regulates neuronal activity via the activation of short transient receptor potential calcium channels in the brain, and thereby modulates the activation of pro-opiomelacortin neurons and the release of CRH that then regulates the release of corticosterone. Plays a role in the regulation of appetite and eating behavior, responses to anxiogenic stimuli and stress. Plays a role in insulin sensitivity and glucose homeostasis.
Interacts with MPDZ (PubMed:11150294). Interacts with ARRB2 (PubMed:16319069). Interacts with MPP3; this interaction stabilizes the receptor at the plasma membrane and prevents the desensitization of the HTR2C receptor-mediated calcium response (PubMed:14988405, PubMed:16914526).
Partially edited. RNA editing generates receptor isoforms that differ in their ability to interact with the phospholipase C signaling cascade in a transfected cell line, suggesting that this RNA processing event may contribute to the modulation of serotonergic neurotransmission in the central nervous system.
The PDZ domain-binding motif is involved in the interaction with MPDZ.
In contrast to the orthologous protein found in other species, the C-terminal part differs and lacks the fourth beta/gamma crystallin 'Greek key' domain. Moreover, its non-specific tissue specificity suggests that it may have lost its function (PubMed:15853812).
Heterodimer with ALG13 isoform 2 to form a functional enzyme.
Involved in protein N-glycosylation. May play a role in the second step of the dolichol-linked oligosaccharide pathway. May anchor the catalytic subunit ALG13 to the ER.
Exerts an anti-apoptotic effect in the immune system and is involved in responses to infections.
Expressed in the spleen, intestine, liver, and colon, as well as in lung, placenta, kidney, muscle, and heart. Extremely low expression, if any, in brain, in thymus, bone marrow, and blood leukocytes (PubMed:15474311). Detected in T-cells (PubMed:23454188).
(Microbial infection) Interacts with EIAV p9.
(Microbial infection) Interacts with HIV-1 p6 (PubMed:14505569, PubMed:17350572, PubMed:17277784, PubMed:18066081). Interacts with HIV-1 p9 (PubMed:18066081).
(Microbial infection) Interacts with Murine leukemia virus Gag polyprotein (via LYPX(n)L motif).
(Microbial infection) Interacts with ebola virus protein VP40 (via YPx(n)L/I motif).
(Microbial infection) Involved in HIV-1 virus budding. Can replace TSG101 it its role of supporting HIV-1 release; this function requires the interaction with CHMP4B. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as enveloped virus budding (HIV-1 and other lentiviruses).
May be phosphorylated on tyrosine residues by activated PDGFRB.
Multifunctional protein involved in endocytosis, multivesicular body biogenesis, membrane repair, cytokinesis, apoptosis and maintenance of tight junction integrity. Class E VPS protein involved in concentration and sorting of cargo proteins of the multivesicular body (MVB) for incorporation into intralumenal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome. Binds to the phospholipid lysobisphosphatidic acid (LBPA) which is abundant in MVBs internal membranes. The MVB pathway requires the sequential function of ESCRT-O, -I,-II and -III complexes (PubMed:14739459). The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis (PubMed:17853893, PubMed:17556548). Adapter for a subset of ESCRT-III proteins, such as CHMP4, to function at distinct membranes. Required for completion of cytokinesis (PubMed:17853893, PubMed:17556548, PubMed:18641129). May play a role in the regulation of both apoptosis and cell proliferation. Regulates exosome biogenesis in concert with SDC1/4 and SDCBP (PubMed:22660413). By interacting with F-actin, PARD3 and TJP1 secures the proper assembly and positioning of actomyosin-tight junction complex at the apical sides of adjacent epithelial cells that defines a spatial membrane domain essential for the maintenance of epithelial cell polarity and barrier (By similarity).
Self-associates (PubMed:14505570, PubMed:14519844). Interacts with SH3KBP1/CIN85 (By similarity). Interacts with PDCD6 in a calcium -dependent manner (PubMed:16957052, PubMed:18256029, PubMed:18940611). Interacts with TSG101 in a calcium-dependent manner; PDCD6IP homooligomerization may be required for TSG101-binding (PubMed:14505570, PubMed:14519844, PubMed:18641129, PubMed:19520058, PubMed:17350572). Interacts with SGSM3 (PubMed:15849434). Directly interacts with CHMP4A, CHMP4B and CHMP4C (PubMed:12860994, PubMed:14505569, PubMed:14505570, PubMed:14519844, PubMed:14678797, PubMed:14583093, PubMed:17428861, PubMed:17350572, PubMed:18511562). Directly interacts with CEP55 in a 1:2 stoechiometry (PubMed:17853893, PubMed:17556548, PubMed:18641129, PubMed:18948538). The interaction with CEP55 is required for PDCD6IP targeting to the midbody (PubMed:18641129). May interact with PDGFRB (PubMed:20494825). Interacts with SH3GL1 and SH3GL2/endophilin-1 (PubMed:17350572). Forms a complex with SDCBP and SDC2 (PubMed:22660413). Found in a complex with F-actin, TJP1/ZO-1 and PARD3 (By similarity). Interacts with CD2AP (PubMed:17853893). Interacts with ARRDC1 (PubMed:21191027).
(Microbial infection) Plays a role in human papillomavirus 16/HPV-16 endocytosis upon binding to cell surface receptor.
CD151 defines the MER2=RAPH1 antigen of the RAPH blood group system. 92% of Caucasians are MER2-positive and 8% are apparently MER2-negative.
Essential for the proper assembly of the glomerular and tubular basement membranes in kidney.
Expressed in a variety of tissues including vascular endothelium and epidermis. Expressed on erythroid cells, with a higher level of expression in erythroid precursors than on mature erythrocytes.
Interacts with integrins ITGA3:ITGB1, ITGA5:ITGB1, ITGA3:ITGB1 and ITGA6:ITGB4 and with CD9 and CD181 (PubMed:11907260). Interacts (via the second extracellular domain) with integrin ITGAV:ITGB3 (PubMed:27993971).
Palmitoylated. Palmitoylation by ZDHHC2 regulates CD151 expression, association with other tetraspanin family proteins and function in cell adhesion.
Interacts with ADAM12. Isoform 4 and isoform 5 (but not isoform 1 and isoform 2) interact with ADAM9, ADAM10, ADAM15 and ADAM17. Interacts with SH3GL1 SH3 domain. Interacts via SH3 3 and SH3 4 or SH3 4 and SH3 5 domains with SOS2. Probably forms a trimeric complex with SH3GL1 and SOS2. Interacts with SH3YL1 (By similarity).
May play a role in regulating A disintegrin and metalloproteases (ADAMs) in the signaling of EGFR-ligand shedding. May be involved in suppression of Ras-induced cellular transformation and Ras-mediated activation of ELK1. Plays a role in the regulation of cell morphology and cytoskeletal organization.
Widely expressed with highest levels in heart, skeletal muscle, kidney, liver, placenta, small intestine and lung. Expressed at low levels in colon, thymus, spleen and leukocytes.
Cleaves 'Lys-63'-linked poly-ubiquitin chains, and with lesser efficiency 'Lys-48'-linked poly-ubiquitin chains (in vitro). May act as a deubiquitinating enzyme.
Enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities. Reduces hydroxypyruvate to D-glycerate, glyoxylate to glycolate, oxidizes D-glycerate to hydroxypyruvate.
Ubiquitous. Most abundantly expressed in the liver.
Expressed in endiothelial cells (at protein level) (PubMed:21063504). Expressed in bone marrow, thymic cells and nephroblastoma. Increased expression in Wilms tumor of the stromal type.
Expressed in primitive compartments of umbilical vein cord.
Expression is down-regulated by WT1. Expression is down-regulated by pro-inflammatory stimuli such as TNF or IL1B (PubMed:24722330, PubMed:21063504). Expression is induced by laminar shear stress and statins (PubMed:21063504).
Immediate-early protein playing a role in various cellular processes including proliferation, adhesion, migration, differentiation and survival (PubMed:15181016, PubMed:15611078, PubMed:12695522, PubMed:21344378, PubMed:12050162). Acts by binding to integrins or membrane receptors such as NOTCH1 (PubMed:12695522, PubMed:21344378, PubMed:15611078). Essential regulator of hematopoietic stem and progenitor cell function (PubMed:17463287). Inhibits myogenic differentiation through the activation of Notch-signaling pathway (PubMed:12050162). Inhibits vascular smooth muscle cells proliferation by increasing expression of cell-cycle regulators such as CDKN2B or CDKN1A independently of TGFB1 signaling (PubMed:20139355). Ligand of integrins ITGAV:ITGB3 and ITGA5:ITGB1, acts directly upon endothelial cells to stimulate pro-angiogenic activities and induces angiogenesis. In endothelial cells, supports cell adhesion, induces directed cell migration (chemotaxis) and promotes cell survival (PubMed:12695522). Also plays a role in cutaneous wound healing acting as integrin receptor ligand. Supports skin fibroblast adhesion through ITGA5:ITGB1 and ITGA6:ITGB1 and induces fibroblast chemotaxis through ITGAV:ITGB5. Seems to enhance bFGF-induced DNA synthesis in fibroblasts (PubMed:15611078). Involved in bone regeneration as a negative regulator (By similarity). Enhances the articular chondrocytic phenotype, whereas it repressed the one representing endochondral ossification (PubMed:21871891). Impairs pancreatic beta-cell function, inhibits beta-cell proliferation and insulin secretion (By similarity). Plays a role as negative regulator of endothelial pro-inflammatory activation reducing monocyte adhesion, its anti-inflammatory effects occur secondary to the inhibition of NF-kappaB signaling pathway (PubMed:21063504). Contributes to the control and coordination of inflammatory processes in atherosclerosis (By similarity). Attenuates inflammatory pain through regulation of IL1B- and TNF-induced MMP9, MMP2 and CCL2 expression. Inhibits MMP9 expression through ITGB1 engagement (PubMed:21871891).
Interacts with FBLN1. Interacts (via CTCK domain) with NOTCH1 (via the EGF-like repeat region) (PubMed:12050162). Interacts with GJA1/CX43 (PubMed:15181016, PubMed:15213231). Interacts with ITGA5:ITGB1, ITGAV:ITGB3 and ITGAV:ITGB5 (PubMed:12695522, PubMed:15611078). Interacts with ZDHHC22; the interaction may lead to CCN3 palmitoylation (By similarity).
May be palmitoylated on Cys-244, which is important for extracellular secretion.
E3 ubiquitin ligase that plays a role in antifungal immunity by mediating 'Lys-27'-linked ubiquitination of CARD9 downstream of C-type lectin receptors; leading to CARD9 activation, followed by activation of NF-kappa-B and MAP kinase p38 pathways (PubMed:26488816). E3 ubiquitin ligase activity is dependent on E2 ubiquitin-conjugating enzyme UBE2D2 (PubMed:23402750).
Interacts with the ubiquitin-conjugating enzyme, UBE2D2.
Polyubiquitinated, autoubiquitinated in the presence of UBE2D2.
Belongs to the ferroportin (FP) (TC 2.A.100) family. SLC40A subfamily.
Detected in erythrocytes (at protein level) (PubMed:23219802). Expressed in placenta, intestine, muscle and spleen (PubMed:10747949). Highly expressed in mature red blood (PubMed:29599243).
During elevated serum iron levels, liver-derived hepcidin/HAMP negatively regulates cell surface ferroportin/SLC40A1 by inducing its ubiquitination, internalization, and degradation. Indeed, hepcidin/HAMP affinity towards ferroportin/SLC40A1 increases by 80-fold in the presence of iron.
Identified in a complex with STOM (PubMed:23219802). Interacts with HAMP; this interaction promotes SLC40A1 rapid ubiquitination (PubMed:22682227, PubMed:29237594).
Manganese Mn(2+) transport by SLC40A1 remains controversial. Some in vitro studies have suggested that SLC40A1 transports minimal amounts of Mn(2+) (PubMed:22178646, PubMed:30247984). Other groups have suggested that it does not (PubMed:24304836, PubMed:29792530). The affinity of SLC40A1 for Mn(2+) is extremely low compared with iron, implying that any SLC40A1-mediated Mn(2+) transport in vivo would likely be trivial (PubMed:24304836). A recent study examined the role of SLC40A1 in Mn(2+) homeostasis by using Tmprss6-O mice, which express high levels of hepcidin/HAMP and therefore have very low SLC40A1 levels in their tissues. These mice show frank iron deficiency and reduced iron levels in most tissues, but manganese levels are largely unaffected (By similarity). These studies suggest that manganese is propably not the physiological substrate of SLC40A1.
Polyubiquitinated by RNF217; leading to proteasomal degradation. Ubiquitination is necessary for its internalization by hepcidin/HAMP (PubMed:22682227).
Transports Fe(2+) from the inside of a cell to the outside of the cell, playing a key role for maintaining systemic iron homeostasis (PubMed:15692071, PubMed:24304836, PubMed:22178646, PubMed:29599243, PubMed:30247984, PubMed:22682227, PubMed:29237594). Transports iron from intestinal, splenic, hepatic cells, macrophages and erythrocytes into the blood to provide iron to other tissues (By similarity). Controls therefore dietary iron uptake, iron recycling by macrophages and erythrocytes, and release of iron stores in hepatocytes (By similarity). When iron is in excess in serum, circulating HAMP/hepcidin levels increase resulting in a degradation of SLC40A1, thus limiting the iron efflux to plasma (PubMed:22682227, PubMed:29237594, PubMed:32814342).
Expressed in pancreas in islets and ductal cells (at protein level) (PubMed:22138752). Expressed in melanocytes (PubMed:27857118).
Sequence-specific RNA-binding protein that binds to the cytoplasmic polyadenylation element (CPE), an uridine-rich sequence element (consensus sequence 5'-UUUUUAU-3') within the mRNA 3'-UTR (PubMed:24990967). RNA binding results in a clear conformational change analogous to the Venus fly trap mechanism (PubMed:24990967). Regulates activation of unfolded protein response (UPR) in the process of adaptation to ER stress in liver, by maintaining translation of CPE-regulated mRNAs in conditions in which global protein synthesis is inhibited (By similarity). Required for cell cycle progression, specifically for cytokinesis and chromosomal segregation (PubMed:26398195). Plays a role as an oncogene promoting tumor growth and progression by positively regulating translation of t-plasminogen activator/PLAT (PubMed:22138752). Stimulates proliferation of melanocytes (PubMed:27857118). In contrast to CPEB1 and CPEB3, does not play role in synaptic plasticity, learning and memory (By similarity).
The 2 RRM domains and the C-terminal region mediate interaction with CPE-containing RNA (PubMed:24990967). The interdomain linker (564-579) acts as a hinge to fix the relative orientation of the 2 RRMs (PubMed:24990967). The ZZ domain (509-566) coordinates 2 Zn ions and is probably implicated in mediating interactions with other proteins in addition to increasing the affinity of the RRMs for the CPEs (By similarity). Unlike in CPEB1, a continuous polar interface is formed between the 2 RRMs (PubMed:24990967).
(Microbial infection) Interacts with Ebola virus NP, VP30 and VP35.
(Microbial infection) Interacts with HERV-K rec and gag proteins.
(Microbial infection) Interacts with HIV-1 GAG polyprotein.
(Microbial infection) Interacts with influenza virus NS1 protein.
(Microbial infection) Plays a role in virus particles production of many viruses including of HIV-1, HERV-K, ebola virus and influenza virus. Acts by interacting with various viral proteins involved in particle budding process.
Binds double-stranded RNA (regardless of the sequence) and tubulin. May play a role in specific positioning of mRNAs at given sites in the cell by cross-linking cytoskeletal and RNA components, and in stimulating their translation at the site.
Binds tubulin. Binds with low affinity single-stranded RNA or DNA homopolymers. Interacts with CASC3 in an RNA-dependent manner (By similarity). Identified in a mRNP complex, at least composed of DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1.
One of the DRDB could be involved in RER binding.
The C-terminal contains the tubulin binding domain (TBD).
Widely expressed. Expressed in brain, pancreas, heart, skeletal muscles, liver, lung, kidney and placenta.
Binds to CBY2 (By similarity). Found in a complex with CFAP410, NEK1 and SPATA7 (PubMed:26167768). Interacts with CFAP410 (PubMed:26167768). Interacts (via Ser-1052 phosphorylated form) with 14-3-3 proteins (By similarity).
High fetal expression in the brain and kidney.
Phosphorylates serines and threonines, but also appears to possess tyrosine kinase activity (PubMed:20230784). Involved in DNA damage checkpoint control and for proper DNA damage repair (PubMed:20230784). In response to injury that includes DNA damage, NEK1 phosphorylates VDAC1 to limit mitochondrial cell death (PubMed:20230784). May be implicated in the control of meiosis (By similarity). Involved in cilium assembly (PubMed:21211617).
The disease is caused by variants affecting the gene represented in this entry. In some cases NEK1 mutations result in disease phenotype in the presence of mutations in DYNC2H1 indicating digenic inheritance (digenic short rib-polydactyly syndrome 3/6 with polydactyly) (PubMed:21211617).
Inhibits protein phosphatase 1 activity toward phosphorylase, myosin light chain and myosin substrates.
Ubiquitously present in many human cell lines of different embryological derivation.
Inactive as a kinase due to its inability to bind ATP.
Inactive kinase that suppresses ERK activity by promoting phosphatase activity of DUSP3 which specifically dephosphorylates and inactivates ERK in the nucleus.
Interacts with DUSP3 (By similarity). Interacts with RAN.
Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B) and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific (Probable). Component of the BAF complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM, SMARCA4/BRG1, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C. In muscle cells, the BAF complex also contains DPF3 (PubMed:18765789). Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin. Component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin (PubMed:22952240, PubMed:26601204). May also interact with the SIN3A histone deacetylase transcription repressor complex in conjunction with SMARCA2 and SMARCA4 (PubMed:11238380). Interacts with SMARD1 (PubMed:12917342). Interacts with KDM6B (By similarity). Interaction with RCOR1 (PubMed:12192000). Interacts with DPF2 (PubMed:28533407). Interacts with ERCC6 (PubMed:24874740). Interacts with FOS (By similarity).
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner (PubMed:11018012). Can stimulate the ATPase activity of the catalytic subunit of these complexes (PubMed:10078207). May be required for CoREST dependent repression of neuronal specific gene promoters in non-neuronal cells (PubMed:12192000). Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Critical regulator of myeloid differentiation, controlling granulocytopoiesis and the expression of genes involved in neutrophil granule formation (By similarity).
Mono-ADP-ribosylation at Lys-312 by SIRT6 promotes recruitment to the enhancer region of the Heme oxygenase-1 (HO-1) locus, leading to transcription activation of the locus.
A report observed N-glycosylation at Asn-815 (PubMed:19139490). However, as the protein is not predicted to localize in an extracellular compartment of the cell, additional evidence is required to confirm this result.
Component of the 43S pre-initiation complex (43S PIC), which binds to the mRNA cap-proximal region, scans mRNA 5'-untranslated region, and locates the initiation codon. This protein enhances formation of the cap-proximal complex. Together with EIF1, facilitates scanning, start codon recognition, promotion of the assembly of 48S complex at the initiation codon (43S PIC becomes 48S PIC after the start codon is reached), and dissociation of aberrant complexes. After start codon location, together with EIF5B orients the initiator methionine-tRNA in a conformation that allows 60S ribosomal subunit joining to form the 80S initiation complex. Is released after 80S initiation complex formation, just after GTP hydrolysis by EIF5B, and before release of EIF5B. Its globular part is located in the A site of the 40S ribosomal subunit. Its interaction with EIF5 during scanning contribute to the maintenance of EIF1 within the open 43S PIC. In contrast to yeast orthologs, does not bind EIF1.
Component of the 43S pre-initiation complex (43S PIC), which is composed of the 40S ribosomal subunit, EIF1, eIF1A (EIF1AX), eIF3 complex, EIF5 and eIF2-GTP-initiator tRNA complex (eIF2 ternary complex). Interacts with EIF5; this interaction contributes to the maintenance of EIF1 within the open 43S PIC. Interacts through its C-terminal domain (CTD) with the CTD of EIF5B; from the location of the start codon by the 43S complex until the formation of the 80S complex.
Allosteric enzyme whose activity is greatly influenced by the end products of its metabolic pathway, dCTP and dTTP.
Supplies the nucleotide substrate for thymidylate synthetase.
Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Has a highest activity toward Muc7, EA2 and Muc2, with a lowest activity than GALNT2. Glycosylates 'Thr-57' of SELPLG.
The ricin B-type lectin domain directs the glycopeptide specificity. It is required in the glycopeptide specificity of enzyme activity but not for activity with naked peptide substrates, suggesting that it triggers the catalytic domain to act on GalNAc-glycopeptide substrates.
Ubiquitous. Highly expressed in mucous cells.
Plays a role in endocytosis and/or membrane trafficking at the trans-Golgi network (TGN) (PubMed:15758025). May act by linking the adapter protein complex AP-1 to other proteins (Probable). Component of clathrin-coated vesicles (PubMed:15758025). Component of the aftiphilin/p200/gamma-synergin complex, which plays roles in AP1G1/AP-1-mediated protein trafficking including the trafficking of transferrin from early to recycling endosomes, and the membrane trafficking of furin and the lysosomal enzyme cathepsin D between the trans-Golgi network (TGN) and endosomes (PubMed:15758025).
Self-associates (PubMed:15758025). Interacts with GGA1 (via GAE domain) (PubMed:10814529, PubMed:14665628, PubMed:15758025). Interacts with GGA2 and GGA3 (PubMed:10814529). Interacts with AP1G1 (via GAE domain), a subunit of adapter protein complex AP-1 (PubMed:10477754, PubMed:10814529, PubMed:12538641, PubMed:14665628). Interacts with AP1G2 (via GAE domain) a subunit of adapter protein complex AP-1 (PubMed:10814529, PubMed:14665628). Component of the aftiphilin/p200/gamma-synergin complex, at least composed of AFTPH/aftiphilin, HEATR5B/p200a and SYNRG/gamma-synergin, which plays a role in the AP1G1/AP-1-mediated trafficking of transferrin from early to recycling endosomes (PubMed:15758025). Within the complex interacts with AFTPH/aftiphilin and HEATR5B/p200a; the interactions are direct (PubMed:15758025). Interacts (via EH domain) with SCAMP1 (By similarity).
The DFXDF motifs mediate the interaction with gamma-appendage subunits AP1G1 and AP1G2.
Acetylated by p300 on several sites in diffentiating myocytes. Acetylation on Lys-4 increases DNA binding and transactivation (By similarity).
Expression is highest during the early stages of postnatal development, at later stages levels greatly decrease.
Forms a complex with class II HDACs in undifferentiating cells. On myogenic differentiation, HDACs are released into the cytoplasm allowing MEF2s to interact with other proteins for activation. Interacts with EP300 in differentiating cells; the interaction acetylates MEF2C leading to increased DNA binding and activation (By similarity). Interacts with HDAC7 and CARM1 (By similarity). Interacts with HDAC4 and HDAC9; the interaction with HDACs represses transcriptional activity (PubMed:10523670, PubMed:11535832). Interacts with LPIN1. Interacts with MYOCD. Interacts with AKAP13 (By similarity). Interacts with FOXK1; the interaction inhibits MEF2C transactivation activity (By similarity). Interacts (via N-terminus) with HABP4; this interaction decreases DNA-binding activity of MEF2C in myocardial cells in response to mechanical stress (PubMed:15862299). Interacts with JPH2; interaction specifically takes place with the Junctophilin-2 N-terminal fragment cleavage product of JPH2 (By similarity). Interacts (via MADS box) with SOX18 (By similarity).
Phosphorylation on Ser-59 enhances DNA binding activity (By similarity). Phosphorylation on Ser-396 is required for Lys-391 sumoylation and inhibits transcriptional activity.
Proteolytically cleaved in cerebellar granule neurons, probably by caspase 7, following neurotoxicity. Preferentially cleaves the CDK5-mediated hyperphosphorylated form which leads to neuron apoptosis and transcriptional inactivation.
Sumoylated on Lys-391 with SUMO2 but not by SUMO1 represses transcriptional activity.
The beta domain, missing in a number of isoforms, is required for enhancement of transcriptional activity.
Transcription activator which binds specifically to the MEF2 element present in the regulatory regions of many muscle-specific genes. Controls cardiac morphogenesis and myogenesis, and is also involved in vascular development. Enhances transcriptional activation mediated by SOX18. Plays an essential role in hippocampal-dependent learning and memory by suppressing the number of excitatory synapses and thus regulating basal and evoked synaptic transmission. Crucial for normal neuronal development, distribution, and electrical activity in the neocortex. Necessary for proper development of megakaryocytes and platelets and for bone marrow B-lymphopoiesis. Required for B-cell survival and proliferation in response to BCR stimulation, efficient IgG1 antibody responses to T-cell-dependent antigens and for normal induction of germinal center B-cells. May also be involved in neurogenesis and in the development of cortical architecture (By similarity). Isoforms that lack the repressor domain are more active than isoform 1.
Belongs to the proteasome subunit S1 family.
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD1 (PubMed:27428775, PubMed:27342858). Interacts with ADRM1 (PubMed:16990800, PubMed:16906146). Interacts with ZFAND1 (PubMed:29804830).
A CAG trinucleotide repeat occurs in the 5'-UTR of this gene. This repeat has been found to be highly polymorphic, although expanded alleles have not yet been definitely linked with any phenotypic abnormality.
Expressed in brain, cerebellum and skeletal muscle.
Monomer (PubMed:27271801). Homodecamer; composed of 2 back to back homopentamers (PubMed:27271801). The protein may exist as monomer in solution and oiligomerizes upon ligand binding (PubMed:27271801).
Putative nucleotidyltransferase required for several aspects of embryonic development including normal development of the eye (PubMed:27103078, PubMed:30487245). It is unclear whether it displays nucleotidyltransferase activity in vivo (PubMed:27271801). Binds single-stranded RNA (ssRNA) (PubMed:27271801).
While it shares structure similarities with CGAS, it also features a number of differences. The crystal structure is in inactive conformation and the enzyme would require a conformational change to be active. The nucleotidyltransferase activity is therefore unclear.
3-alpha-hydroxysteroid dehydrogenase that converts 3-alpha-tetrahydroprogesterone (allopregnanolone) to dihydroxyprogesterone and 3-alpha-androstanediol to dihydroxyprogesterone (PubMed:11294878, PubMed:29541409). Also plays a role in the biosynthesis of retinoic acid from retinaldehyde (PubMed:11304534, PubMed:12618084). Can utilize both NADH and NADPH.
Highly expressed in trachea and epidermis. Detected at lower levels in spinal cord, bone marrow, brain, tongue, esophagus, heart, colon, testis, placenta, lung, skeletal muscle and lymph node.
Guanine nucleotide exchange factor (GEF) for RAP1A and RAP2A small GTPases that is activated by binding cAMP. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which it activates the PI3K gamma complex and which is involved in angiogenesis. Plays a role in the modulation of the cAMP-induced dynamic control of endothelial barrier function through a pathway that is independent on Rho-mediated signaling. Required for the actin rearrangement at cell-cell junctions, such as stress fibers and junctional actin.
Interacts with PDE3B and PIK3R6; form a signaling complex that regulates phosphatidylinositol 3-kinase gamma in angiogenesis.
It is uncertain whether Met-1 or Met-43 is the initiator.
The DEP domain is involved in membrane localization independent from regulation by cAMP.
Widely expressed with highest levels in adult kidney, heart, thyroid and brain, and fetal kidney.
A conserved motif AVN[ED]CD within the disintegrin-like domain could be involved in the binding to the integrin receptor.
Can bind to LGI1 and LGI4 (By similarity). Ligand for integrin alpha-V/beta-3.
Highly expressed in the brain and weakly expressed in the heart. In the brain, expressed prominently in the amygdala, caudate nucleus, hypothalamus, thalamus, cerebral cortex and occipital pole.
May play a role in cell-cell and cell-matrix interactions. This is a non-catalytic metalloprotease-like protein.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. 5-hydroxytryptamine receptor (TC 1.A.9.2) subfamily. HTR3A sub-subfamily.
Expressed in cerebral cortex, amygdala, hippocampus, and testis. Detected in monocytes of the spleen and tonsil, in small and large intestine, uterus, prostate, ovary and placenta.
Forms homopentameric as well as heteropentameric serotonin-activated cation-selective channel complexes with HTR3B or HTR3C or HTR3D or HTR3E. The homomeric complex is functional but exhibits low conductance with modified voltage dependence, and decreased agonist and antagonist affinity. Heteropentameric complexes display properties which resemble that of neuronal serotonin-activated channels in vivo (PubMed:15809299, PubMed:10521471, PubMed:17392525, PubMed:9950429). Interacts with RIC3 (PubMed:15809299).
The HA-stretch region of HTR3A seems to be responsible for the low conductance of HTR3A homomers compared to that of HTR3A/HTR3B heteromers.
Autocleaves. This function, which is not essential for its protease activity, is unknown.
Caspase-like protease, which plays a central role in the chromosome segregation by cleaving the SCC1/RAD21 subunit of the cohesin complex at the onset of anaphase. During most of the cell cycle, it is inactivated by different mechanisms.
Interacts with PTTG1. Interacts with RAD21.
Phosphorylated by CDK1. There are 8 Ser/Thr phosphorylation sites. Among them, Ser-1126 phosphorylation is the major site, which conducts to the enzyme inactivation.
Regulated by at least two independent mechanisms. First, it is inactivated via its interaction with securin/PTTG1, which probably covers its active site. The association with PTTG1 is not only inhibitory, since PTTG1 is also required for activating it, the enzyme being inactive in cells in which PTTG1 is absent. PTTG1 degradation at anaphase, liberates it and triggers RAD21 cleavage. Second, phosphorylation at Ser-1126 inactivates it. The complete phosphorylation during mitosis, is removed when cells undergo anaphase. Activation of the enzyme at the metaphase-anaphase transition probably requires the removal of both securin and inhibitory phosphate.
Essential for survival of retinal photoreceptor cells.
Belongs to the eukaryotic ribosomal protein eL27 family.
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25957688, PubMed:25901680, PubMed:32669547). Interacts with RRP1B (PubMed:20926688). Interacts with DHX33 (PubMed:26100019).
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25957688, PubMed:25901680, PubMed:32669547). Required for proper rRNA processing and maturation of 28S and 5.8S rRNAs (PubMed:25424902).
(Microbial infection) Interacts with HTLV-1 protein Gag.
(Microbial infection) Interacts with ebola virus protein VP40.
Auto-ubiquitinated and ubiquitinated by RNF11.
Binds KLF2 and HIVEP3 (By similarity). Binds SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2, DRPLA and adenovirus type 2 PIII. Interacts with RNF11 (By similarity). Interacts with SPART. Interacts with ERBB4 isoforms JM-B CYT-1 and JM-A CYT-1. Interacts with SMAD1, SMAD2, SMAD3, SMAD5, SMAD6, SMAD7, TGFBR1 and TGFBR2. Associates with the TGFBR1:TGFBR2 receptor complex in presence of SMAD7. Interacts with SKIL isoform 1. Interacts with TP63 isoform 1 and isoform 2. Interacts with STAMBP and RNF11. Interacts with NDFIP1 and NDFIP2 (Probable); this interaction activates the E3 ubiquitin-protein ligase. Interacts with TGIF. Interacts (via WW domains) with ARRDC1, ARRDC2 and ARRDC3 (PubMed:21191027).
Detected in heart, placenta, pancreas, kidney, liver, skeletal muscle, bone marrow, fetal brain, and at much lower levels in adult brain and lung. Isoform 1 and isoform 5 predominate in all tissues tested, except in testis and bone marrow, where isoform 5 is expressed at much higher levels than isoform 1.
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Ubiquitinates ERBB4 isoforms JM-A CYT-1 and JM-B CYT-1, KLF2, KLF5 and TP63 and promotes their proteasomal degradation. Ubiquitinates RNF11 without targeting it for degradation. Ubiquitinates and promotes degradation of TGFBR1; the ubiquitination is enhanced by SMAD7. Ubiquitinates SMAD6 and SMAD7. Ubiquitinates and promotes degradation of SMAD2 in response to TGF-beta signaling, which requires interaction with TGIF.
Adopts an atypical protein kinase-like fold: while it adopts a core fold similar to that of well-characterized protein kinase-like domains, a number of features are positioned to inhibit the kinase activity: (1) an atypical AAAS motif in an alanine-rich (A-rich) loop that replaces the canonical glycine-rich (G-rich) nucleotide-binding loop and limits ATP binding by establishing an unusual selectivity for ADP and (2) an N-terminal domain, containing the KxGQ motif, that completely occludes the typical substrate binding pocket (PubMed:25498144). Nucleotide-binding opens the substrate binding pocket and flips the active site from inside the hydrophobic core into a catalytically competent, solvent-exposed posture (PubMed:27499294).
Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration (PubMed:25498144, PubMed:21296186, PubMed:25540914, PubMed:27499294). Its substrate specificity is unclear: does not show any protein kinase activity (PubMed:25498144, PubMed:27499294). Probably acts as a small molecule kinase, possibly a lipid kinase that phosphorylates a prenyl lipid in the ubiquinone biosynthesis pathway, as suggested by its ability to bind coenzyme Q lipid intermediates (PubMed:25498144, PubMed:27499294). Shows an unusual selectivity for binding ADP over ATP (PubMed:25498144).
Autoinhibited by the N-terminal domain, containing the KxGQ motif, that completely occludes the typical substrate binding pocket. Nucleotide-binding relieves inhibition (PubMed:27499294).
Homodimer; homodimerizes via its transmembrane region (PubMed:25216398). Interacts with the multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9 (PubMed:27499294, PubMed:27499296).
Widely expressed, with highest levels in adrenal gland, heart, pancreas, nasal mucosa, stomach, uterus and skeletal muscle.
Component of the CatSper complex or CatSpermasome composed of the core pore-forming members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 as well as auxiliary members CATSPERB, CATSPERG, CATSPERD, CATSPERE, CATSPERZ, C2CD6/CATSPERT, TMEM249, TMEM262 and EFCAB9 (By similarity). HSPA1 may be an additional auxiliary complex member (By similarity). The core complex members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 form a heterotetrameric channel (By similarity). The auxiliary CATSPERB, CATSPERG, CATSPERD and CATSPERE subunits form a pavilion-like structure over the pore which stabilizes the complex through interactions with CATSPER4, CATSPER3, CATSPER1 and CATSPER2 respectively (By similarity). TMEM262/CATSPERH interacts with CATSPERB, further stabilizing the complex. C2CD6/CATSPERT interacts at least with CATSPERD and is required for targeting the CatSper complex in the flagellar membrane (By similarity). Interacts with Ca(v)3.3/CACNA1I, leading to suppression of T-type calcium channel activity (PubMed:16740636).
Down-regulated in patients lacking sperm motility.
Expressed meiotically and post-meiotically.
Detected in testis, and on the acrosomal cap of spermatids.
Consists of an N-terminal biotin carboxylation/carboxylase (BC) domain that catalyzes the transient carboxylation of the biotin covalently attached to the C-terminal biotinyl-binding/biotin carboxyl carrier (BCC) domain.
The biotin cofactor is covalently attached to the C-terminal biotinyl-binding domain and is required for the catalytic activity (PubMed:10329019). Biotinylation is catalyzed by HLCS (PubMed:7753853, PubMed:20443544).
The holoenzyme is a dodecamer composed of 6 PCCA/alpha subunits and 6 PCCB/beta subunits (PubMed:6765947, PubMed:20725044). Interacts (via the biotin carboxylation domain) with SIRT4 (PubMed:23438705). Interacts with SIRT3 and SIRT5 (PubMed:23438705).
This is one of the 2 subunits of the biotin-dependent propionyl-CoA carboxylase (PCC), a mitochondrial enzyme involved in the catabolism of odd chain fatty acids, branched-chain amino acids isoleucine, threonine, methionine, and valine and other metabolites (PubMed:8434582, PubMed:6765947). Propionyl-CoA carboxylase catalyzes the carboxylation of propionyl-CoA/propanoyl-CoA to D-methylmalonyl-CoA/(S)-methylmalonyl-CoA (PubMed:8434582, PubMed:6765947, PubMed:10101253). Within the holoenzyme, the alpha subunit catalyzes the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain, while the beta subunit then transfers the carboxyl group from carboxylated biotin to propionyl-CoA (By similarity). Propionyl-CoA carboxylase also significantly acts on butyryl-CoA/butanoyl-CoA, which is converted to ethylmalonyl-CoA/(2S)-ethylmalonyl-CoA at a much lower rate (PubMed:6765947). Other alternative minor substrates include (2E)-butenoyl-CoA/crotonoyl-CoA (By similarity).
(Microbial infection) Plays a positive role in exosome-mediated trafficking of HIV-1 virus and its entry into immune cells.
Belongs to the immunoglobulin superfamily. TIM family.
Interacts with MERTK; this interaction enhances TIMD4-mediated efferocytosis (PubMed:32640697). Interacts with EPHA2 (PubMed:34067457).
Phosphatidylserine receptor that plays different role in immune response including phagocytosis of apoptotic cells and T-cell regulation. Controls T-cell activation in a bimodal fashion, decreasing the activation of naive T-cells by inducing cell cycle arrest, while increasing proliferation of activated T-cells by activating AKT1 and ERK1/2 phosphorylations and subsequent signaling pathways (By similarity). Also plays a role in efferocytosis which is the process by which apoptotic cells are removed by phagocytic cells (PubMed:32703939, PubMed:34067457). Mechanistically, promotes the engulfment of apoptotic cells or exogenous particles by securing them to phagocytes through direct binding to phosphatidylserine present on apoptotic cells, while other engulfment receptors such as MERTK efficiently recognize apoptotic cells and mediate their ingestion (PubMed:32640697). Additionally, promotes autophagy process by suppressing NLRP3 inflammasome activity via activation of LKB1/PRKAA1 pathway in a phosphatidylserine-dependent mechanism (By similarity).
Recognizes phosphatidyl serine via its immunoglobulin domain.
The residues that bind the substrate in other aspartate aminotransferases are not conserved.
Interacts with JAK2, HSPA9B and IFN-gammaR2 chain. Interacts with Ras GTPase-activating protein 1 (RASA1). Isoform 2 interacts with MUSK (via the cytoplasmic domain) (By similarity).
Modulates apoptotic signal transduction or effector structures within the mitochondrial matrix. Affect cytochrome C release from the mitochondria and caspase 3 activation, but not caspase 8 activation. Isoform 1 increases apoptosis triggered by both TNF and the DNA-damaging agent mytomycin C; in sharp contrast, isoform 2 suppresses apoptosis. Can modulate IFN-gamma-mediated transcriptional activity. Isoform 2 may play a role in neuromuscular junction development as an effector of the MUSK signaling pathway.
Modulation of apoptosis, i.e. proapoptotic activity of isoform 1 and antiapoptotic activity of isoform 2, is J domain-dependent.
Widely expressed with highest levels in heart, liver, lung and skeletal muscles. Also expressed in keratinocytes.
Deubiquitinating enzyme that plays a role in many cellular processes including cellular antiviral response, epithelial morphogenesis, DNA repair or B-cell development (PubMed:33127822, PubMed:34614178). Plays a role in pre-mRNA splicing as a component of the U4/U6-U5 tri-snRNP, one of the building blocks of the precatalytic spliceosome (PubMed:11350945, PubMed:26912367). Specifically regulates immunoglobulin gene rearrangement in a spliceosome-dependent manner, which involves modulating chromatin interactions at the Igh locus and therefore plays an essential role in B-cell development (By similarity). Regulates AURKB mRNA levels, and thereby plays a role in cytokinesis and in the spindle checkpoint (PubMed:18728397). Regulates apoptosis and G2/M cell cycle checkpoint in response to DNA damage by deubiquitinating and stabilizing CHK2 (PubMed:30771428). Plays also an important role in DNA repair by controlling the recruitment of XRCC4/LIG4 to DNA double-strand breaks for non-homologous end-joining repair (PubMed:34614178). Participates in antiviral activity by affecting the type I IFN signaling by stabilizing STAT1 and decreasing its 'Lys-6'-linked ubiquitination (PubMed:33127822). Contributes to non-canonical Wnt signaling during epidermal differentiation (By similarity). Acts as a negative regulator NF-kappa-B activation through deubiquitination of 'Lys-48'-linked ubiquitination of NFKBIA (PubMed:36651806).
Lacks the conserved His and Cys residues that are essential for the activity of de-ubiquitinating enzymes. Lacks ubiquitin C-terminal hydrolase activity (PubMed:18728397).
The U4/U6-U5 tri-snRNP complex is a building block of the precatalytic spliceosome (spliceosome B complex) (PubMed:11350945, PubMed:26912367). Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39, plus LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 (PubMed:16723661, PubMed:26912367).
(Microbial infection) Interacts (via N-terminus) with human adenovirus 5 E1B-55K protein; this interaction leads to the inhibition of TP53 function and/or its degradation.
(Microbial infection) Interacts with Kaposi's sarcoma-associated herpesvirus/HHV-8 protein ORF45; this interaction results in the cytoplasmic localization of TP53 thereby decreasing its transcriptional activity.
(Microbial infection) Interacts with cancer-associated/HPV E6 viral proteins leading to ubiquitination and degradation of TP53 giving a possible model for cell growth regulation. This complex formation requires an additional factor, E6-AP, which stably associates with TP53 in the presence of E6.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123.
Acetylation of Lys-382 by CREBBP enhances transcriptional activity (PubMed:10656795, PubMed:15448695, PubMed:20228809, PubMed:23431171). Acetylation of Lys-382 by EP300 (PubMed:10656795, PubMed:15448695, PubMed:20228809, PubMed:23431171). Deacetylation of Lys-382 by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence (PubMed:10656795, PubMed:15448695, PubMed:20228809, PubMed:23431171). Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner (PubMed:10656795, PubMed:15448695, PubMed:20228809, PubMed:23431171, PubMed:29681526). Acetylation at Lys-381 increases stability (PubMed:29474172). Deacetylation at Lys-381 by SIRT6 decreases its stability, thereby regulating cell senescence (PubMed:29474172).
Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type (PubMed:11025664, PubMed:12524540, PubMed:12810724, PubMed:15186775, PubMed:15340061, PubMed:17317671, PubMed:17349958, PubMed:19556538, PubMed:20673990, PubMed:20959462, PubMed:22726440, PubMed:24051492, PubMed:9840937, PubMed:24652652). Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process (PubMed:11025664, PubMed:12524540, PubMed:12810724, PubMed:15186775, PubMed:15340061, PubMed:17317671, PubMed:17349958, PubMed:19556538, PubMed:20673990, PubMed:20959462, PubMed:22726440, PubMed:24051492, PubMed:9840937, PubMed:24652652). One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (PubMed:12524540). However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (PubMed:12524540). In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-BMAL1-mediated transcriptional activation of PER2 (PubMed:24051492).
Dephosphorylated by PP2A-PPP2R5C holoenzyme at Thr-55. SV40 small T antigen inhibits the dephosphorylation by the AC form of PP2A.
Expressed in quiescent lymphocytes. Seems to be non-functional. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Forms homodimers and homotetramers (PubMed:19011621). Binds DNA as a homotetramer. Interacts with AXIN1. Probably part of a complex consisting of TP53, HIPK2 and AXIN1 (By similarity). Interacts with histone acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and recruits them to promoters. Interacts (via C-terminus) with TAF1; when TAF1 is part of the TFIID complex. Interacts with ING4; this interaction may be indirect. Found in a complex with CABLES1 and TP73. Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX. May interact with HCV core protein. Interacts with USP7 and SYVN1. Interacts with HSP90AB1. Interacts with CHD8; leading to recruit histone H1 and prevent transactivation activity (By similarity). Interacts with ARMC10, CDKN2AIP, NUAK1, STK11/LKB1, UHRF2 and E4F1. Interacts with YWHAZ; the interaction enhances TP53 transcriptional activity. Phosphorylation of YWHAZ on 'Ser-58' inhibits this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-terminus). Interacts with MKRN1. Interacts with PML (via C-terminus). Interacts with MDM2; leading to ubiquitination and proteasomal degradation of TP53. Directly interacts with FBXO42; leading to ubiquitination and degradation of TP53. Interacts (phosphorylated at Ser-15 by ATM) with the phosphatase PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent inhibition of cell proliferation. Interacts with PPP2R2A. Interacts with AURKA, DAXX, BRD7 and TRIM24. Interacts (when monomethylated at Lys-382) with L3MBTL1. Isoform 1 interacts with isoform 2 and with isoform 4. Interacts with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in response to DNA damage. Interacts with CDK5 in neurons. Interacts with AURKB, SETD2, UHRF2 and NOC2L. Interacts (via N-terminus) with PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG. Interacts with PPIF; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by cyclosporin A (CsA). Interacts with SNAI1; the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts with KAT6A. Interacts with UBC9. Interacts with ZNF385B; the interaction is direct. Interacts (via DNA-binding domain) with ZNF385A; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest. Interacts with ANKRD2. Interacts with RFFL and RNF34; involved in p53/TP53 ubiquitination. Interacts with MTA1 and COP1. Interacts with CCAR2 (via N-terminus). Interacts with MORC3 (PubMed:17332504). Interacts (via C-terminus) with POU4F2 isoform 1 (via C-terminus) (PubMed:17145718). Interacts (via oligomerization region) with NOP53; the interaction is direct and may prevent the MDM2-mediated proteasomal degradation of TP53 (PubMed:22522597). Interacts with AFG1L; mediates mitochondrial translocation of TP53 (PubMed:27323408). Interacts with UBD (PubMed:25422469). Interacts with TAF6 isoform 1 and isoform 4 (PubMed:20096117). Interacts with C10orf90/FATS; the interaction inhibits binding of TP53 and MDM2 (By similarity). Interacts with NUPR1; interaction is stress-dependent (PubMed:18690848). Forms a complex with EP300 and NUPR1; this complex binds CDKN1A promoter leading to transcriptional induction of CDKN1A (PubMed:18690848). Interacts with PRMT5 in response to DNA damage; the interaction is TTC5/STRAP dependent (PubMed:19011621). Interacts with PPP1R13L (via SH3 domain and ANK repeats); the interaction inhibits pro-apoptotic activity of p53/TP53 (PubMed:12524540). Interacts with PPP1R13B/ASPP1 and TP53BP2/ASPP2; the interactions promotes pro-apoptotic activity (PubMed:12524540). When phosphorylated at Ser-15, interacts with DDX3X and gamma-tubulin (PubMed:28842590). Interacts with KAT7/HBO1; leading to inhibit histone acetyltransferase activity of KAT7/HBO1 (PubMed:17954561). Interacts (via N-terminus) with E3 ubiquitin-protein ligase MUL1; the interaction results in ubiquitination of cytoplasmic TP53 at Lys-24 and subsequent proteasomal degradation (PubMed:21597459). Interacts with S100A4; this interaction promotes TP53 degradation (PubMed:23752197, PubMed:32442400). Interacts with BANP (By similarity). Interacts with TTC5/STRAP; the interaction may result in increased mitochondrial-dependent apoptosis (PubMed:25168243). Interacts with NQO1; this interaction is NADH-dependent, stabilizes TP53 in response to oxidative stress and protects it from ubiquitin-independent degradation by the 20S proteasome (PubMed:15687255). Interacts with DAZAP2 at TP53 target gene promoters; the interaction is triggered by DNA damage and leads to modulation of the expression of a subset of TP53 target genes, reducing DNA damage-induced cell death by limiting the expression of cell death-mediating TP53 target genes (PubMed:33591310). Interacts (via N-terminus) with ZNF768 (via zinc-finger domains); interaction might be facilitated by TP53 oligomerization state (PubMed:34404770). Forms a ternary complex with ALDOB and G6PD; this interaction is direct. ALDOB stabilizes the complex inhibiting G6PD activity and keeping oxidative pentose phosphate metabolism in check. Interacts with MORN3; the interactions mediate post-transcriptional modifications of TP53 by MDM2 and SIRT1 (PubMed:29681526).
Interaction with BANP was reported to enhance phosphorylation on Ser-15 upon ultraviolet irradiation (PubMed:15701641). However, the publication has been retracted due to image duplication and manipulation. Interaction with BANP has been confirmed in mouse studies (By similarity). Phosphorylation at Ser-15 has been confirmed by other studies (PubMed:10570149, PubMed:11554766, PubMed:16219768, PubMed:15866171, PubMed:17317671, PubMed:17954561, PubMed:20959462, PubMed:25772236). Its nuclear and cytoplasmic localization has been confirmed by other studies (PubMed:15340061, PubMed:17170702, PubMed:19011621, PubMed:21597459, PubMed:22726440, PubMed:17591690, PubMed:18206965).
May be O-glycosylated in the C-terminal basic region. Studied in EB-1 cell line.
Monomethylated at Lys-372 by SETD7, leading to stabilization and increased transcriptional activation (PubMed:15525938, PubMed:16415881). Monomethylated at Lys-370 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity (PubMed:17108971). Lys-372 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-370 (PubMed:17108971). Dimethylated at Lys-373 by EHMT1 and EHMT2 (PubMed:20118233). Monomethylated at Lys-382 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity (PubMed:17707234). Dimethylation at Lys-370 and Lys-382 diminishes p53 ubiquitination, through stabilizing association with the methyl reader PHF20 (PubMed:22864287). Demethylation of dimethylated Lys-370 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation (PubMed:17805299). Monomethylated at Arg-333 and dimethylated at Arg-335 and Arg-337 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity (PubMed:19011621).
Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylated by HIPK1 (By similarity). Phosphorylation at Ser-9 by HIPK4 increases repression activity on BIRC5 promoter. Phosphorylated on Thr-18 by VRK1. Phosphorylated on Ser-20 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-20 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Phosphorylated on Thr-55 by TAF1, which promotes MDM2-mediated degradation. Phosphorylated on Ser-33 by CDK7 in a CAK complex in response to DNA damage. Phosphorylated on Ser-46 by HIPK2 upon UV irradiation. Phosphorylation on Ser-46 is required for acetylation by CREBBP. Phosphorylated on Ser-392 following UV but not gamma irradiation. Phosphorylated by NUAK1 at Ser-15 and Ser-392; was initially thought to be mediated by STK11/LKB1 but it was later shown that it is indirect and that STK11/LKB1-dependent phosphorylation is probably mediated by downstream NUAK1 (PubMed:21317932). It is unclear whether AMP directly mediates phosphorylation at Ser-15. Phosphorylated on Thr-18 by isoform 1 and isoform 2 of VRK2. Phosphorylation on Thr-18 by isoform 2 of VRK2 results in a reduction in ubiquitination by MDM2 and an increase in acetylation by EP300. Stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-15, Ser-33 and Ser-46, leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes. Phosphorylated by DYRK2 at Ser-46 in response to genotoxic stress. Phosphorylated at Ser-315 and Ser-392 by CDK2 in response to DNA-damage. Phosphorylation at Ser-15 is required for interaction with DDX3X and gamma-tubulin (PubMed:28842590).
Produced by alternative promoter usage and alternative splicing.
Sumoylated with SUMO1. Sumoylated at Lys-386 by UBC9.
TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma.
The nuclear export signal acts as a transcriptional repression domain. The TADI and TADII motifs (residues 17 to 25 and 48 to 56) correspond both to 9aaTAD motifs which are transactivation domains present in a large number of yeast and animal transcription factors.
Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal degradation (PubMed:10722742, PubMed:12810724, PubMed:15340061, PubMed:17170702, PubMed:19880522, PubMed:29681526). Ubiquitinated by RFWD3, which works in cooperation with MDM2 and may catalyze the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome (PubMed:10722742, PubMed:12810724, PubMed:20173098). Ubiquitinated by MKRN1 at Lys-291 and Lys-292, which leads to proteasomal degradation (PubMed:19536131). Deubiquitinated by USP10, leading to its stabilization (PubMed:20096447). Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation (PubMed:19556538). Ubiquitination by TOPORS induces degradation (PubMed:19473992). Deubiquitination by USP7, leading to stabilization (PubMed:15053880). Isoform 4 is monoubiquitinated in an MDM2-independent manner (PubMed:15340061). Ubiquitinated by COP1, which leads to proteasomal degradation (PubMed:19837670). Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2 (PubMed:25732823). Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-linkage independent and non-proteolytic, leading to TP53 stabilization (By similarity). Polyubiquitinated by MUL1 at Lys-24 which leads to proteasomal degradation (PubMed:21597459).
Ubiquitous. Isoforms are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine.
Up-regulated in response to DNA damage. Isoform 2 is not induced in tumor cells in response to stress.
Associates with collagen and binds to collagen fibrils.
Potential negative modulator of chondrocyte differentiation. Inhibits collagen fibrillogenesis in vitro. May influence chondrocyte's differentiation by acting on its cellular collagenous microenvironment.
(Microbial infection) Interacts (via hemopexin repeat 2) with P.falciparum (isolate CDC / Honduras) SERA5 P47 (via C-terminus); may form heterotetramers of two VTN and SERA5 P47 heterodimers; the interaction may protect merozoites from phagocytosis by host monocytes; VTN glycosylation appears to be dispensable for the interaction.
Exists in two forms: a single chain 75 kDa form (V75) and a clipped form composed of two chains (65 kDa and 10 kDa) (V65+V10) which are held together by a disulfide bond. Interacts with SERPINE1/PAI1, insulin and C1QBP.
Expressed in the retina pigment epithelium (at protein level) (PubMed:25136834). Expressed in plasma (at protein level) (PubMed:2448300). Expressed in serum (at protein level) (PubMed:29567995).
Phosphorylation on Thr-69 and Thr-76 favors cell adhesion and spreading.
Somatomedin-B is a growth hormone-dependent serum factor with protease-inhibiting activity.
The SMB domain mediates interaction with SERPINE1/PAI1. The heparin-binding domain mediates interaction with insulin.
Vitronectin is a cell adhesion and spreading factor found in serum and tissues. Vitronectin interact with glycosaminoglycans and proteoglycans. Is recognized by certain members of the integrin family and serves as a cell-to-substrate adhesion molecule. Inhibitor of the membrane-damaging effect of the terminal cytolytic complement pathway.
Highly expressed in aorta, heart, placenta, kidney and a colorectal adenocarcinoma cell line. Moderately expressed in skeletal muscle, pancreas, lung, lymph nodes, adrenal gland, bone marrow and thyroid. Weakly expressed in colon, small intestine, ovary, spleen, testis and prostate. Predominantly found in vascular smooth muscle cells, but also in cardiac and skeletal muscle cells as well as kidney.
May be implicated in the adrenocortical zonation and in mechanisms for repressing the CYP11B1 gene expression in adrenocortical cells. This is a non catalytic peptidase C1 family protein (By similarity).
Expressed in a number of normal tissues, including male reproductive system, regions of the respiratory tract and nasopharynx. Highly expressed in a number of tumors cells lines, such ovarian, colon, breast, lung and renal cells lines. Initially described as being exclusively transcribed in the epididymis.
Expressed mainly in the brain, kidney, muscle, testis, thyroid, uterus, peripheral blood cells and bone marrow.
Receptor for relaxin. The activity of this receptor is mediated by G proteins leading to stimulation of adenylate cyclase and an increase of cAMP. May also be a receptor for Leydig insulin-like peptide (INSL3).
Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex (PubMed:22801543, PubMed:17317665, PubMed:24449906). As a component of the trimeric and tetrameric DNA polymerase delta complexes (Pol-delta3 and Pol-delta4, respectively), plays a role in high fidelity genome replication, including in lagging strand synthesis, and repair (PubMed:12403614, PubMed:16510448, PubMed:19074196, PubMed:20334433, PubMed:24035200). Pol-delta3 and Pol-delta4 are characterized by the absence or the presence of POLD4. They exhibit differences in catalytic activity. Most notably, Pol-delta3 shows higher proofreading activity than Pol-delta4 (PubMed:19074196, PubMed:20334433). Although both Pol-delta3 and Pol-delta4 process Okazaki fragments in vitro, Pol-delta3 may also be better suited to fulfill this task, exhibiting near-absence of strand displacement activity compared to Pol-delta4 and stalling on encounter with the 5'-blocking oligonucleotides. Pol-delta3 idling process may avoid the formation of a gap, while maintaining a nick that can be readily ligated (PubMed:24035200). Along with DNA polymerase kappa, DNA polymerase delta carries out approximately half of nucleotide excision repair (NER) synthesis following UV irradiation (PubMed:20227374). Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR) (PubMed:24310611). Involved in the translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites performed by Pol-delta4, independently of DNA polymerase zeta (REV3L) or eta (POLH). Facilitates abasic site bypass by DNA polymerase delta by promoting extension from the nucleotide inserted opposite the lesion. Also involved in TLS as a component of the DNA polymerase zeta complex (PubMed:24449906). Along with POLD3, dramatically increases the efficiency and processivity of DNA synthesis of the DNA polymerase zeta complex compared to the minimal zeta complex, consisting of only REV3L and REV7 (PubMed:24449906).
Belongs to the DNA polymerase delta/II small subunit family.
Component of both the DNA polymerase delta and DNA polymerase zeta complexes (PubMed:22801543, PubMed:17317665, PubMed:24449906). Component of the tetrameric DNA polymerase delta complex (Pol-delta4), which consists of POLD1/p125, POLD2/p50, POLD3/p66/p68 and POLD4/p12, with POLD1 bearing DNA polymerase and 3' to 5' proofreading exonuclease activities (PubMed:22801543, PubMed:17317665). Within Pol-delta4, directly interacts with POLD1, POLD3 and POLD4 (PubMed:11328591, PubMed:16510448). Following stress caused by DNA damaging agents or by replication stress, POLD4 is degraded and Pol-delta4 is converted into a trimeric form of the complex (Pol-delta3), which consists of POLD1, POLD2 and POLD3. Pol-delta3 is the major form occurring at S phase replication sites, as well as DNA damage sites (PubMed:22801543, PubMed:17317665). Also observed as a dimeric complex with POLD2 (Pol-delta2 complex). Pol-delta2 is relatively insensitive to the PCNA stimulation (2-5-fold) compared to Pol-delta4 that is stimulated by over 50-fold (PubMed:12403614). Contrary to the other components of Pol-delta4, does not directly interact with PCNA (PubMed:12403614, PubMed:16510448). As POLD1 and POLD4, directly interacts with WRNIP1; this interaction stimulates DNA polymerase delta-mediated DNA synthesis, independently of the presence of PCNA. This stimulation may be due predominantly to an increase of initiation frequency and also to increased processivity (PubMed:15670210). Directly interacts with POLDIP2 and POLDIP3 (PubMed:12522211). Directly interacts with KCTD13/PDIP1; in the presence of PCNA, this interaction may stimulate DNA polymerase activity (PubMed:11593007). Component of the tetrameric Pol-zeta complex (Pol-zeta4), which consists of REV3L, MAD2L2, POLD2 and POLD3, with REV3L bearing DNA polymerase catalytic activity (PubMed:24449906). Interacts with KCTD10 (By similarity).
Expression is cell cycle-dependent, with highest levels in G2/M phase and lowest in S.
Detected in most adult tissues. Highest levels were found in heart and skeletal muscle. Low levels are found in brain.
Infant brain has higher levels of WNT10B than adult brain.
Member of the Wnt ligand gene family that encodes for secreted proteins, which activate the Wnt signaling cascade. Specifically activates canonical Wnt/beta-catenin signaling and thus triggers beta-catenin/LEF/TCF-mediated transcriptional programs. Involved in signaling networks controlling stemness, pluripotency and cell fate decisions. Acts in the immune system, mammary gland, adipose tissue, bone and skin.
The disease is caused by variants affecting the gene represented in this entry. Potential genotype-phenotype correlation between variants and the positions of missing teeth.
Adds the first Dol-P-Man derived mannose in an alpha-1,3 linkage to Man5GlcNAc2-PP-Dol.
Belongs to the glycosyltransferase 58 family.
(Microbial infection) Required for the translation of viral proteins and viral replication during human coronavirus SARS-CoV-2 infection.
By homocysteine (HC), may mediate accelerated synthesis of free thiol-containing proteins in response to HC-induced oxidative stress.
Found in a nuclear export complex with XPO5, EEF1A1, Ran and aminoacylated tRNA (PubMed:12426392, PubMed:12426393). Interacts with PARP1 (PubMed:17177976). Interacts with KARS1 (PubMed:18029264). May interact with ERGIC2 (PubMed:17980171). Interacts with IFIT1 (via TPR repeats 4-7) (By similarity). Interacts with DLC1, facilitating distribution to the membrane periphery and ruffles upon growth factor stimulation (PubMed:19158340). Interacts with ZPR1; the interaction occurs in a epidermal growth factor (EGF)-dependent manner (PubMed:8650580). Interacts with PPP1R16B (PubMed:26497934). Interacts with SPHK1 and SPHK2; both interactions increase SPHK1 and SPHK2 kinase activity (PubMed:18263879).
Inhibited by plitidepsin, a chemical compound extracted from the ascidian Aplidium albicans (PubMed:33495306). Specifically inhibited by didemnin B, a natural product that triggers ribosome stalling by preventing aminoacyl-tRNA (aa-tRNA) release from EEF1A1 on the ribosome (PubMed:26651998, PubMed:36264623). Specifically inhibited by ternatin-4, a small-molecule inhibitor that triggers ribosome stalling by traping EEF1A1 on the ribosome and preventing aminoacyl-tRNA (aa-tRNA) accommodation (PubMed:26651998, PubMed:36264623, PubMed:36123449, PubMed:36638793). Ribosome stalling by ternatin-4 causes ubiquitination and degradation of EEF1A1 (PubMed:36638793). Specifically inhibited by ternatin SR-A3, which differs from ternatin-4 by the addition of a single oxygen atom into the side chain of N-Me-Leu (PubMed:36123449). Inhibition by ternatin-4 can be reversed, while it is not the case for didemnin B (PubMed:36264623).
Phosphorylated by TXK (PubMed:17177976). Phosphorylation by PASK increases translation efficiency (PubMed:17595531). Phosphorylated by ROCK2 (PubMed:26497934). Phosphorylation by TGFBR1 inhibits translation elongation (PubMed:20832312).
Translation elongation factor that catalyzes the GTP-dependent binding of aminoacyl-tRNA (aa-tRNA) to the A-site of ribosomes during the elongation phase of protein synthesis (PubMed:26651998, PubMed:26593721, PubMed:36264623, PubMed:36123449, PubMed:36638793). Base pairing between the mRNA codon and the aa-tRNA anticodon promotes GTP hydrolysis, releasing the aa-tRNA from EEF1A1 and allowing its accommodation into the ribosome (PubMed:26651998, PubMed:26593721, PubMed:36264623, PubMed:36123449, PubMed:36638793). The growing protein chain is subsequently transferred from the P-site peptidyl tRNA to the A-site aa-tRNA, extending it by one amino acid through ribosome-catalyzed peptide bond formation (PubMed:26651998, PubMed:26593721, PubMed:36264623, PubMed:36123449). Also plays a role in the positive regulation of IFNG transcription in T-helper 1 cells as part of an IFNG promoter-binding complex with TXK and PARP1 (PubMed:17177976).
Trimethylated at Lys-79 by EEF1AKMT1 (PubMed:26545399). Methylated at Lys-165 by EEF1AKMT3, methylation by EEF1AKMT3 is dynamic as well as inducible by stress conditions, such as ER-stress, and plays a regulatory role on mRNA translation (PubMed:28108655). Trimethylated at Lys-318 by EEF1AKMT2 (PubMed:25144183). Mono-, di-, and trimethylated at Lys-36 by EEF1AKMT4; trimethylated form is predominant. Methylation by EEF1AKMT4 contributes to the fine-tuning of translation rates for a subset of tRNAs (PubMed:28520920). Trimethylated at Gly-2 by METTL13 (PubMed:30143613). Mono- and dimethylated at Lys-55 by METTL13; dimethylated form is predominant (PubMed:30143613, PubMed:30612740).
Ubiquitinated at Lys-385 by RNF14 in response to ribosome collisions (ribosome stalling), leading to its degradation by the proteasome and rescue of stalled ribosomes.
Interacts with Geminin/GMNN, which inhibits transcriptional activity.
Increased activity at pH lower than 8.0 (PubMed:31356773). sulfate/sulfate exchange activity is inhibited strongly by pyridoxal 5'-phosphate, bathophenanthroline and the organic mercurials mersalyl, p-chloromercuribenzoate and HgCl2 (PubMed:31356773). Proton conductance is activated by cardiolipin and long-chain free fatty acids and inhibited by purine nucleotides ATP and ADP. Chloride ion transporter activity is inhibited by long-chain free fatty acids.
Mainly expressed in brain (PubMed:10928996). Some expression in testis and pituitary (PubMed:10928996).
Transports inorganic anions (sulfate, sulfite, thiosulfate and phosphate) and, to a lesser extent, a variety of dicarboxylates (e.g. malonate, malate and citramalate) and, even more so, aspartate and glutamate and tricarboxylates (PubMed:31356773). May catalyze the export of sulfite and thiosulfate (the hydrogen sulfide degradation products) from the mitochondria, thereby modulating the level of the hydrogen sulfide (Probable). Also can mediate a very low unidirectional transport of anions including sulfate, phosphate, (S)-malate, citrate, L-aspartate and L-glutamate (PubMed:31356773). Maintains oxidative balance (through uncoupling activities) and ATP production (by modifying mitochondrial membrane potential) (PubMed:20600837). Is able to transport protons across lipid membranes (PubMed:22524567, PubMed:26182433). Also exhibits transmembrane chloride transport activity to a lesser extent(PubMed:22524567, PubMed:26182433). May modify mitochondrial respiratory efficiency and mitochondrial oxidant production (By similarity).
Highly expressed in the colon and lung with comparatively high levels also detectable in the lymph nodes, placenta, duodenum, peripheral blood mononuclear cells and spleen (PubMed:25929859).
Is not markedly up- or down-regulated by DNA damage, nutrient deprivation or by exposure to TNF-alpha and IFN-gamma (PubMed:25929859).
Modulator of macroautophagy that causes accumulation of autophagosomes under basal conditions and enhances autophagic flux (PubMed:25929859). Represses cell death and promotes long-term clonogenic survival of cells grown in the absence of glucose in a macroautophagy-independent manner (PubMed:25929859). May have some role in extracellular matrix engulfment or growth factor receptor recycling, both of which can modulate cell survival (PubMed:25929859).
Component of the GINS complex which is a heterotetramer of GINS1, GINS2, GINS3 and GINS4 (PubMed:17170760, PubMed:17417653, PubMed:17545466, PubMed:17557111, PubMed:17652513, PubMed:28414293, PubMed:32453425). Forms a stable subcomplex with GINS2 (PubMed:17170760, PubMed:17417653, PubMed:17545466, PubMed:17557111, PubMed:17652513, PubMed:28414293). GINS complex interacts with DNA primase in vitro (PubMed:17170760, PubMed:17417653, PubMed:17545466, PubMed:17557111, PubMed:17652513, PubMed:28414293). Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex (PubMed:34700328, PubMed:34694004, PubMed:32453425).
The GINS complex plays an essential role in the initiation of DNA replication.
Chromosomal aberrations involving SLX4IP are found in acute lymphoblastic leukemia. A site-specific deletion within the 5' region of SLX4IP is found in 30% of childhood acute lymphoblastic leukemia in general and more than 60% of ETV6/RUNX1-rearranged acute lymphoblastic leukemia. Breakpoints within SLX4IP reveal junctions with typical characteristics of illegitimate V(D)J mediated recombination. SLX4IP deletions are significantly associated with male gender and ETV6/RUNX1-rearranged acute lymphoblastic leukemia.
Interacts with SLX4/BTBD12; subunit of different structure-specific endonucleases.
Cell adhesion protein that participates in lymphocyte extravasation and recirculation by mediating the binding of lymphocytes to peripheral lymph node vascular endothelial cells in an L-selectin-independent fashion. Has semicarbazide-sensitive (SSAO) monoamine oxidase activity. May play a role in adipogenesis.
Devoid of the semicarbazide-sensitive amine oxidase (SSAO) activity.
Homodimer; disulfide-linked. Can heterodimerize with isoform 2 leading to reduced surface expression. Forms a heterodimer with AOC2.
Strongly expressed on the high endothelial venules of peripheral lymph nodes and on hepatic endothelia. Also highly expressed in appendix, lung and small intestine. Expressed also in adipose tissue, in bone marrow, colon, heart, kidney, ovary, pancreas, placenta, prostate, skeletal muscle, spleen and testis. Isoform 2 seems to be the predominant transcript in fetal kidneys, fetal cartilage and fetal tonsils. The highest relative expression of isoform 2 occurs in skeletal muscle, heart, pancreas, kidney, and lung.
Confers strong transcriptional repression to the AP-2-alpha gene. Binds to a regulatory element (A32) in the AP-2-alpha gene promoter.
The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. In KLF12, the motif is inactive.
RTL8B is one of at least 11 genes called Mar or Mart related to long terminal repeat retrotransposons. They do not correspond to functional retrotransposons, but rather to neofunctionalized retrotransposons genes.
Highly expressed in heart and skeletal muscle. Weakly expressed in brain, thymus, spleen, kidney, liver, small intestine, placenta and lung.
May induce apoptosis through the lysosomal-mitochondrial pathway. Translocates to the lysosome initiating the permeabilization of lysosomal membrane (LMP) and resulting in the release of CTSD and CTSL to the cytoplasm. Triggers the caspase-independent apoptosis by altering mitochondrial membrane permeabilization (MMP) resulting in the release of PDCD8.
PH and FYVE-type zinc finger domains are required for lysosomal location.
Activated after Ras induction via a mechanism involving reactive oxygen species.
Expressed in the brain, isoform 2 is more abundant than isoform 1. Isoform 3 is ubiquitously expressed. Isoform 1 is most abundant in the skeletal muscle. Isoform 4 is ubiquitously expressed with relative high levels in brain, skeletal muscle, pancreas and testis.
Interacts with TANC1 (By similarity). Interacts with RAP2A. Isoform 4 interacts with NCK1.
Isoform 4 can activate the JNK pathway. Involved in the regulation of actin cytoskeleton reorganization, cell-matrix adhesion, cell-cell adhesion and cell migration.
Serine/threonine kinase which acts as a negative regulator of Ras-related Rap2-mediated signal transduction to control neuronal structure and AMPA receptor trafficking. Required for normal synaptic density, dendrite complexity, as well as surface AMPA receptor expression in hippocampal neurons. Can activate the JNK and MAPK14/p38 pathways and mediates stimulation of the stress-activated protein kinase MAPK14/p38 MAPK downstream of the Raf/ERK pathway. Phosphorylates: TANC1 upon stimulation by RAP2A, MBP and SMAD1. Has an essential function in negative selection of thymocytes, perhaps by coupling NCK1 to activation of JNK1.
May be a component of the linker structure that bridges the ciliary membrane and peripheral singlet microtubules.
Interacts with the secreted angiogenic factor TNFSF12.
Promotes angiogenesis and the proliferation of endothelial cells. Able to bind to endothelial cells and promote cell proliferation, suggesting that it may act in an autocrine fashion.
Widely expressed. Expressed in endothelial cells, vascular smooth muscle cells and osteoblasts. Expressed in umbilical vein endothelial cells and microvascular endothelial cells.
Involved in the degradation of asparagine-linked glycoproteins. Hydrolyze of N-acetyl-beta-D-glucosamine (1-4)N-acetylglucosamine chitobiose core from the reducing end of the bond, it requires prior cleavage by glycosylasparaginase.
Generates phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as second messengers (By similarity). May play a role in SDF1A-stimulated chemotaxis (By similarity).
Highly expressed in liver, prostate and testis. Lower levels in small intestine, kidney and pancreas.
By UV irradiation and repressed by p53/TP53.
Component of the PAQosome complex which is responsible for the biogenesis of several protein complexes and which consists of R2TP complex members RUVBL1, RUVBL2, RPAP3 and PIH1D1, URI complex members PFDN2, PFDN6, PDRG1, UXT and URI1 as well as ASDURF, POLR2E and DNAAF10/WDR92.
May play a role in chaperone-mediated protein folding.
Predominantly expressed in normal testis and exhibits reduced but detectable expression in other organs.
Forms protease inhibiting heterodimers in extracellular body fluids with serine proteases such as activated protein C/coagulation factor V/F5, acrosin/ACR, chymotrypsinogen B/CTRB1, prothrombin/F2, factor Xa/F10, factor XI/F11, kallikrein/KLKB1, tissue kallikrein, trypsin/PRSS1, prostate specific antigen/KLK3, tissue plasminogen activator/PLAT and urinary plasminogen activator/PLAU. Forms membrane-anchored serine proteases inhibiting heterodimers with TMPRSS7 and TMPRSS11E. Interacts with SEMG2.
Heparin-dependent serine protease inhibitor acting in body fluids and secretions. Inactivates serine proteases by binding irreversibly to their serine activation site. Involved in the regulation of intravascular and extravascular proteolytic activities. Plays hemostatic roles in the blood plasma. Acts as a procoagulant and pro-inflammatory factor by inhibiting the anticoagulant activated protein C factor as well as the generation of activated protein C factor by the thrombin/thrombomodulin complex. Acts as an anticoagulant factor by inhibiting blood coagulation factors like prothrombin, factor XI, factor Xa, plasma kallikrein and fibrinolytic enzymes such as tissue- and urinary-type plasminogen activators. In seminal plasma, inactivates several serine proteases implicated in the reproductive system. Inhibits the serpin acrosin; indirectly protects component of the male genital tract from being degraded by excessive released acrosin. Inhibits tissue- and urinary-type plasminogen activator, prostate-specific antigen and kallikrein activities; has a control on the sperm motility and fertilization. Inhibits the activated protein C-catalyzed degradation of SEMG1 and SEMG2; regulates the degradation of semenogelin during the process of transfer of spermatozoa from the male reproductive tract into the female tract. In urine, inhibits urinary-type plasminogen activator and kallikrein activities. Inactivates membrane-anchored serine proteases activities such as MPRSS7 and TMPRSS11E. Inhibits urinary-type plasminogen activator-dependent tumor cell invasion and metastasis. May also play a non-inhibitory role in seminal plasma and urine as a hydrophobic hormone carrier by its binding to retinoic acid.
Its inhibitory activity is greatly enhanced in the presence of glycosaminoglycans, heparin, thrombomodulin and phospholipids vesicles.
N- and O-glycosylated. N-glycosylation consists of a mixture of sialylated bi- (including sialyl-Lewis X epitopes), tri- and tetra-antennary complex-type chains; affects the maximal heparin- and thrombomodulin-enhanced rates of thrombin inhibition. O-glycosylated with core 1 or possibly core 8 glycans. Further modified with 2 sialic acid residues.
Predominantly expressed in the epithelium of seminal vesicles. Expressed in the proximal tubular epithelium of the kidney. Expressed in the superficial and more differentiated epidermal keratinocytes of the skin. Expressed in megakaryocytes and platelets. Expressed poorly in kidney tumor cells compared to non tumor kidney tissues. Expressed in spermatozoa. Present in very high concentration in seminal plasma. Present in high concentration in plasma, synovial and Graaf follicle fluids. Present in low concentration in breast milk and in amniotic fluids. Present in very low concentration in urine, cerebrospinal fluids, saliva and tears (at protein level). Strongly expressed in liver. Expressed in kidney, spleen, pancreas, skeletal muscle, heart, testes, ovary, interstitial Leydig cells, epididymal glands, seminal vesicles and prostate.
Proteolytically cleaved. Inhibition of proteases is accompanied by formation of a stable enzyme-inhibitor complex and by degradation of the serpin to lower molecular weight derivatives. Proteolytically cleaved at the N-terminus; inhibits slightly the heparin- and thrombomodulin-enhanced rates of thrombin inhibition.
Radial spoke stalk protein that binds heme under oxidizing conditions. Required for the coordinated beating of multiple cilia maybe by functioning in a redox signaling pathway.
Component of activated spliceosome complexes (PubMed:29360106). Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932). Binds SMAD4 and CREBBP/EP300. Binds the SMAD1/OAZ1/PSMB4 complex. Interacts with DROSHA and SMARCA4. Component of the SNARP complex which consists at least of SNIP1, SNW1, THRAP3, BCLAF1 and PNN.
Degraded by the proteasome upon binding to the SMAD1/OAZ1/PSMB4 complex.
Required for pre-mRNA splicing as component of the spliceosome (PubMed:29360106). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). Down-regulates NF-kappa-B signaling by competing with RELA for CREBBP/EP300 binding. Involved in the microRNA (miRNA) biogenesis. May be involved in cyclin-D1/CCND1 mRNA stability through the SNARP complex which associates with both the 3'end of the CCND1 gene and its mRNA.
Ubiquitous, with highest expression in heart and skeletal muscle.
Core component of the 7SK RNP complex, at least composed of 7SK RNA, LARP7, MEPCE, HEXIM1 (or HEXIM2) and P-TEFb (composed of CDK9 and CCNT1/cyclin-T1) (PubMed:18483487, PubMed:18281698, PubMed:19906723). Interacts with METTL16 (PubMed:29051200). Interacts with RBM7; upon genotoxic stress this interaction is enhanced, triggering the release of inactive P-TEFb complex from the core, yielding to P-TEFb complex activation (PubMed:30824372). Associates with box C/D small nucleolar ribonucleoprotein (snoRNP) complexes (PubMed:32017898).
RNA-binding protein that specifically binds distinct small nuclear RNA (snRNAs) and regulates their processing and function (PubMed:18249148, PubMed:32017898). Specifically binds the 7SK snRNA (7SK RNA) and acts as a core component of the 7SK ribonucleoprotein (RNP) complex, thereby acting as a negative regulator of transcription elongation by RNA polymerase II (PubMed:18249148, PubMed:18483487). The 7SK RNP complex sequesters the positive transcription elongation factor b (P-TEFb) in a large inactive 7SK RNP complex preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation (PubMed:18249148, PubMed:18483487). The 7SK RNP complex also promotes snRNA gene transcription by RNA polymerase II via interaction with the little elongation complex (LEC) (PubMed:28254838). LARP7 specifically binds to the highly conserved 3'-terminal U-rich stretch of 7SK RNA; on stimulation, remains associated with 7SK RNA, whereas P-TEFb is released from the complex (PubMed:18483487, PubMed:18281698). LARP7 also acts as a regulator of mRNA splicing fidelity by promoting U6 snRNA processing (PubMed:32017898). Specifically binds U6 snRNAs and associates with a subset of box C/D RNP complexes: promotes U6 snRNA 2'-O-methylation by facilitating U6 snRNA loading into box C/D RNP complexes (PubMed:32017898). U6 snRNA 2'-O-methylation is required for mRNA splicing fidelity (PubMed:32017898). Binds U6 snRNAs with a 5'-CAGGG-3' sequence motif (PubMed:32017898). U6 snRNA processing is required for spermatogenesis (By similarity).
The xRRM domain binds the 3' end of 7SK snRNA (7SK RNA) at the top of stem-loop 4.
Does not interact with the Elongin BC complex, likely to be a negative regulator of isoform 1.
Predominantly expressed in testis, kidney, and liver.
Substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes at least two forms of creatine kinase, CKB and CKMT1A.
Available under the names Humulin or Humalog (Eli Lilly) and Novolin (Novo Nordisk). Used in the treatment of diabetes. Humalog is an insulin analog with 52-Lys-Pro-53 instead of 52-Pro-Lys-53.
Heterodimer of a B chain and an A chain linked by two disulfide bonds (PubMed:25423173).
Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
Available under the names Replagal (from Shire) and Fabrazyme (from Genzyme). Used as a long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease. The differences between Replagal (also known as agalsidase alpha) and Fabrazyme (also known as agalsidase beta) lies in the glycosylation patterns. Agalsidase beta is produced in the hamster CHO cell line while agalsidase alpha is produced in human cell lines.
Catalyzes the hydrolysis of glycosphingolipids and participates in their degradation in the lysosome.
Galactosylgalactosylglucosylceramidase activity is stimulated by saposin B and ammonium chloride.
Component of the MIS12 complex composed of MIS12, DSN1, NSL1/DC8 and PMF1. Interacts with KNL1.
Part of the MIS12 complex which is required for normal chromosome alignment and segregation and kinetochore formation during mitosis.
Activated by histamine, L-adrenaline, D-phenylalanine, L- and D-histidine. Inhibited by coumarins, saccharin, sulfonamide derivatives such as acetazolamide and Foscarnet (phosphonoformate trisodium salt).
Catalyzes the reversible hydration of carbon dioxide into bicarbonate and protons and thus is essential to maintaining intracellular and extracellular pH (PubMed:15563508, PubMed:17652713, PubMed:7625839, PubMed:16807956, PubMed:16686544, PubMed:17705204, PubMed:17127057, PubMed:17314045, PubMed:19186056, PubMed:19206230, PubMed:18618712). May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis (PubMed:15563508). It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid (PubMed:15563508).
Expressed in the endothelium of the choriocapillaris in eyes (at protein level). Not expressed in the retinal epithelium at detectable levels.
The disease is caused by variants affecting the gene represented in this entry. Defective acid overload removal from retina and retinal epithelium, due to mutant CA4, is responsible for photoreceptor degeneration, indicating that impaired pH homeostasis is the most likely cause underlying the RP17 phenotype.
Cytotoxic chymotrypsin-like serine protease with preference for bulky and aromatic residues at the P1 position and acidic residues at the P3' and P4' sites. Probably necessary for target cell lysis in cell-mediated immune responses. Participates in the antiviral response via direct cleavage of several proteins essential for viral replication.
Belongs to the complex I NDUFA5 subunit family.
Expressed in all tissues examined with highest levels in heart, skeletal muscle and brain.
Interacts with L1CAM; this interaction occurs in axonal growth cones. Interacts with actin filament retrograde flow; this interaction is enhanced in a netrin-1- and PAK1-dependent manner and promotes F-actin-substrate coupling and concomitant formation of traction forces at axonal growth cones. Interacts with RUFY3. Interacts with PFN2. Interacts (via N-terminus) with KIF20B; this interaction is direct and promotes the association of SHTN1 to microtubules in primary neurons. Associates with microtubule.
Involved in the generation of internal asymmetric signals required for neuronal polarization and neurite outgrowth. Mediates netrin-1-induced F-actin-substrate coupling or 'clutch engagement' within the axon growth cone through activation of CDC42, RAC1 and PAK1-dependent signaling pathway, thereby converting the F-actin retrograde flow into traction forces, concomitantly with filopodium extension and axon outgrowth. Plays a role in cytoskeletal organization by regulating the subcellular localization of phosphoinositide 3-kinase (PI3K) activity at the axonal growth cone. Also plays a role in regenerative neurite outgrowth. In the developing cortex, cooperates with KIF20B to promote both the transition from the multipolar to the bipolar stage and the radial migration of cortical neurons from the ventricular zone toward the superficial layer of the neocortex. Involved in the accumulation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the growth cone of primary hippocampal neurons.
Phosphorylated on Ser-101 and Ser-249 by PAK1 through a CDC42- and RAC1-dependent signaling pathway, which enhances its association with F-actin retrograde flow in filopodia and lamellipodia of axonal growth cones. Phosphorylation on Ser-101 and Ser-249 is increased by netrin-1.
The N-terminus region is necessary for interaction with actin retrograde filament flow and accumulation in neuronal growth cones.
Essential for RNA polymerase III to make a number of small nuclear and cytoplasmic RNAs, including 5S RNA, tRNA, and adenovirus-associated (VA) RNA of both cellular and viral origin. Has histone acetyltransferase activity (HAT) with unique specificity for free and nucleosomal H3. May cooperate with GTF3C5 in facilitating the recruitment of TFIIIB and RNA polymerase through direct interactions with BRF1, POLR3C and POLR3F. May be localized close to the A box.
Part of the TFIIIC subcomplex TFIIIC2, consisting of six subunits, GTF3C1, GTF3C2, GTF3C3, GTF3C4, GTF3C5 and GTF3C6. Interacts with BRF1, GTF3C1, GTF3C2, GTF3C5, GTF3C6, POLR3C and POLR3F.
Expressed in 5-month-old fetal tissues, including stomach, intestine, colon, liver, brain, lung, heart, spleen and kidney (PubMed:17525738). Undetectable in non-cancerous adult tissues (PubMed:17525738). Expressed in many primary gastric carcinoma, but almost not in adjacent normal mucosa (PubMed:17525738). Expressed preferentially in M and G1 phases, compared to S and G2 phases (PubMed:17525738). Expression is up-regulated in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) tissues (at protein level) (PubMed:23704824).
Interacts with a spindle orientation complex at least composed of GNAI1, GPSM2 and NUMA1 (PubMed:26766442). Interacts with GPSM2 (via TPR motifs); this interaction is required to prevent GPSM2 anchoring at the mitotic apical cortex and is inhibited in presence of NUMA1 in a dose dependent manner (PubMed:26766442). Interacts with PARD3 (PubMed:26766442).
Plays a role in planar mitotic spindle orientation in retinal progenitor cells (RPCs) and promotes the production of symmetric terminal divisions (By similarity). Negatively regulates the mitotic apical cortex localization of GPSM2 (PubMed:26766442). Involved also in positive regulation of cell proliferation and tumor cell growth (PubMed:23576022, PubMed:23704824).
(Microbial infection) Interacts with M.tuberculosis protein Rv3654c, which probably leads to the cleavage of PSF, diminishes the level of caspase-8 in macrophages and suppresses macrophage apoptosis by blocking the extrinsic pathway. Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA.
A chromosomal aberration involving SFPQ may be a cause of papillary renal cell carcinoma (PRCC). Translocation t(X;1)(p11.2;p34) with TFE3.
DNA- and RNA binding protein, involved in several nuclear processes. Essential pre-mRNA splicing factor required early in spliceosome formation and for splicing catalytic step II, probably as a heteromer with NONO. Binds to pre-mRNA in spliceosome C complex, and specifically binds to intronic polypyrimidine tracts. Involved in regulation of signal-induced alternative splicing. During splicing of PTPRC/CD45, a phosphorylated form is sequestered by THRAP3 from the pre-mRNA in resting T-cells; T-cell activation and subsequent reduced phosphorylation is proposed to lead to release from THRAP3 allowing binding to pre-mRNA splicing regulatotry elements which represses exon inclusion. Interacts with U5 snRNA, probably by binding to a purine-rich sequence located on the 3' side of U5 snRNA stem 1b. May be involved in a pre-mRNA coupled splicing and polyadenylation process as component of a snRNP-free complex with SNRPA/U1A. The SFPQ-NONO heteromer associated with MATR3 may play a role in nuclear retention of defective RNAs. SFPQ may be involved in homologous DNA pairing; in vitro, promotes the invasion of ssDNA between a duplex DNA and produces a D-loop formation. The SFPQ-NONO heteromer may be involved in DNA unwinding by modulating the function of topoisomerase I/TOP1; in vitro, stimulates dissociation of TOP1 from DNA after cleavage and enhances its jumping between separate DNA helices. The SFPQ-NONO heteromer binds DNA (PubMed:25765647). The SFPQ-NONO heteromer may be involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination and may stabilize paired DNA ends; in vitro, the complex strongly stimulates DNA end joining, binds directly to the DNA substrates and cooperates with the Ku70/G22P1-Ku80/XRCC5 (Ku) dimer to establish a functional preligation complex. SFPQ is involved in transcriptional regulation. Functions as transcriptional activator (PubMed:25765647). Transcriptional repression is mediated by an interaction of SFPQ with SIN3A and subsequent recruitment of histone deacetylases (HDACs). The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional activity. SFPQ isoform Long binds to the DNA binding domains (DBD) of nuclear hormone receptors, like RXRA and probably THRA, and acts as transcriptional corepressor in absence of hormone ligands. Binds the DNA sequence 5'-CTGAGTC-3' in the insulin-like growth factor response element (IGFRE) and inhibits IGF-I-stimulated transcriptional activity. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex through histone deacetylation (By similarity). Required for the assembly of nuclear speckles (PubMed:25765647). Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728).
Heterodimer with NONO (PubMed:25765647). Monomer and component of the SFPQ-NONO complex, which is probably a heterotetramer of two 52 kDa (NONO) and two 100 kDa (SFPQ) subunits (PubMed:8439294, PubMed:25765647). The coiled coil domain mediates interaction with NONO, and can also mediate formation of long, linear homooligomers (in vitro) (PubMed:25765647). SFPQ is a component of spliceosome and U5.4/6 snRNP complexes (PubMed:9409622, PubMed:8045264, PubMed:12403470). Interacts with SNRPA/U1A (PubMed:9848648). Component of a snRNP-free complex with SNRPA/U1A (PubMed:9848648). Part of complex consisting of SFPQ, NONO and MATR3 (PubMed:11525732). Interacts with polypyrimidine tract-binding protein 1/PTB (PubMed:10653975). Part of a complex consisting of SFPQ, NONO and NR5A1 (PubMed:11897684). Interacts with RXRA, probably THRA, and SIN3A (PubMed:11259580). Interacts with TOP1 (PubMed:9756848). Part of a complex consisting of SFPQ, NONO and TOP1 (PubMed:9756848). Interacts with SNRNP70 in apoptotic cells (PubMed:11514619). Interacts with PSPC1. Interacts with RNF43 (PubMed:18655028). Interacts with PITX3 and NR4A2/NURR1 (By similarity). Interacts with PTK6 (PubMed:19439179). Interacts with THRAP3; the interaction is dependent on SFPQ phosphorylation at 'Thr-687' and inhibits binding of SFPQ to a ESS1 exonic splicing silencer element-containing RNA (PubMed:20932480). The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A. Interacts with PER1 and PER2 (By similarity). Interacts with PQBP1 (PubMed:21933836). Component of a multiprotein complex with NONO and WASL (PubMed:16767080). Interacts with ERCC6 (PubMed:26030138).
Phosphorylated on multiple serine and threonine residues during apoptosis. In vitro phosphorylated by PKC. Phosphorylation stimulates binding to DNA and D-loop formation, but inhibits binding to RNA. Phosphorylation of C-terminal tyrosines promotes its cytoplasmic localization, impaired its binding to polypyrimidine RNA and led to cell cycle arrest. In resting T-cells is phosphorylated at Thr-687 by GSK3B which is proposed to promote association with THRAP and to prevent binding to PTPRC/CD45 pre-mRNA; T-cell activation leads to reduced phosphorylation at Thr-687.
The coiled coil domain mediates interaction with NONO, and can also mediate formation of long, linear homooligomers (in vitro). The coiled coil domain is required for optimal DNA binding, and optimal transcription activation.
Was originally thought to be myoblast cell surface antigen 24.1D5 and a possible membrane-bound protein ectokinase.
In vivo measurements suggest this protein is glycosylated (PubMed:19159218). In contrast, in vitro experiments failed to detect glycosylation (PubMed:16549277).
May have a role during the programmed cell death of hematopoietic cells (By similarity). Acts as an E3 ubiquitin-protein ligase.
Ubiquitously expressed. Highly expressed in leukocytes. Not expressed in erythroblasts.
Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A4 subfamily.
Expressed mostly in brain, muscle, and pancreas but detected in all tissues examined.
Sodium-dependent neutral amino-acid transporter that mediates transport of alanine, serine, cysteine, proline, hydroxyproline and threonine.
Detected in most tissues, highest expression found in placenta, thymus and brain. Low expression is found in liver and skeletal muscle. Up-regulated in colon adenocarcinoma.
In the C-terminal section; belongs to the formate--tetrahydrofolate ligase family.
In the N-terminal section; belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.
May participate in the progression of colorectal cancer by conferring growth advantage. Could be a new molecular target for cancer therapy.
May provide the missing metabolic reaction required to link the mitochondria and the cytoplasm in the mammalian model of one-carbon folate metabolism complementing thus the enzymatic activities of MTHFD2.
This monofunctional enzyme consists of two major domains: an N-terminal inactive methylene-THF dehydrogenase and cyclohydrolase domain and an active larger formyl-THF synthetase C-terminal domain.
Was originally thought to be a trifunctional enzyme but only a formyltetrahydrofolate synthetase activity was detected and not a dehydrogenase/cyclohydrogenase activity.
Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6 (PubMed:11714725, PubMed:22854966).
Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine) (PubMed:29332244). The elongator complex catalyzes the formation of carboxymethyluridine in the wobble base at position 34 in tRNAs (PubMed:29332244).
The disease is caused by variants affecting the gene represented in this entry. A disease-causing mutation is located in intron 9 of ELP4. The mutation does not alter normal ELP4 expression and function, but disrupts a long-range cis-regulatory element of PAX6 expression, known as SIMO. SIMO is contained within ELP4 intron 9 and located 150 kb downstream of PAX6.
Actin is a highly conserved protein that polymerizes to produce filaments that form cross-linked networks in the cytoplasm of cells (PubMed:29581253). Actin exists in both monomeric (G-actin) and polymeric (F-actin) forms, both forms playing key functions, such as cell motility and contraction (PubMed:29581253). In addition to their role in the cytoplasmic cytoskeleton, G- and F-actin also localize in the nucleus, and regulate gene transcription and motility and repair of damaged DNA (PubMed:29925947). Part of the ACTR1A/ACTB filament around which the dynactin complex is built. The dynactin multiprotein complex activates the molecular motor dynein for ultra-processive transport along microtubules (By similarity).
Methylated at His-73 by SETD3 (PubMed:30526847, PubMed:30626964, PubMed:30785395, PubMed:31388018). Methylation at His-73 is required for smooth muscle contraction of the laboring uterus during delivery (By similarity).
Monomethylation at Lys-84 (K84me1) regulates actin-myosin interaction and actomyosin-dependent processes (PubMed:23673617). Demethylation by ALKBH4 is required for maintaining actomyosin dynamics supporting normal cleavage furrow ingression during cytokinesis and cell migration (PubMed:23673617).
Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix (PubMed:28604741, PubMed:16685646). Each actin can bind to 4 others (PubMed:28604741, PubMed:16685646). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Component of the BAF complex, which includes at least actin (ACTB), ARID1A, ARID1B/BAF250, SMARCA2, SMARCA4/BRG1, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57 SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more of SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C (PubMed:18765789). In muscle cells, the BAF complex also contains DPF3 (PubMed:18765789). Found in a complex with XPO6, Ran, ACTB and PFN1 (PubMed:14592989). Interacts with XPO6 and EMD (PubMed:15328537). Interacts with ERBB2 (PubMed:21555369). Interacts with GCSAM (PubMed:17823310). Interacts with TBC1D21 (By similarity). Interacts with CPNE1 (via VWFA domain) and CPNE4 (via VWFA domain) (By similarity). Interacts with DHX9 (via C-terminus); this interaction is direct and mediates the attachment to nuclear ribonucleoprotein complexes (PubMed:11687588). Interacts with FAM107A (PubMed:21969592, PubMed:28604741). Part of the ACTR1A/ACTB filament around which the dynactin complex is built. The filament contains 8 copies of ACTR1A and 1 ACTB (By similarity).
Catalyzes the 2-thiolation of uridine at the wobble position (U34) of mitochondrial tRNA(Lys), tRNA(Glu) and tRNA(Gln). Required for the formation of 5-taurinomethyl-2-thiouridine (tm5s2U) of mitochondrial tRNA(Lys), tRNA(Glu), and tRNA(Gln) at the wobble position. ATP is required to activate the C2 atom of the wobble base.
During the reaction, ATP is used to activate the C2 atom of U34 by adenylation. After this, the persulfide sulfur on the catalytic cysteine is transferred to the C2 atom of the wobble base (U34) of mitochondrial tRNA(Lys), tRNA(Glu) and tRNA(Gln). The reaction probably involves hydrogen sulfide that is generated from the persulfide intermediate and that acts as nucleophile towards the activated C2 atom on U34. Subsequently, a transient disulfide bond is formed between the two active site cysteine residues (By similarity).
The gene represented in this entry acts as a disease modifier. DFNI is caused by mutations in mitochondrial rRNA genes, including homoplasmic A1555G and C1494T mutations in the highly conserved decoding site of the mitochondrial 12S rRNA. Mutated TRMU modulates the phenotypic manifestation of these mutations.
Ubiquitous. Abundantly expressed in tissues with high metabolic rates including heart, liver, kidney, and brain.
Was originally thought to be a 5-methylaminomethyl-2-methyltransferase involved in tRNA modification.
ADP-ribosylated at Tyr-155 by PARP1 in presence of HPF1.
Belongs to the eukaryotic ribosomal protein eS1 family.
Component of the small ribosomal subunit (PubMed:23636399). Mature ribosomes consist of a small (40S) and a large (60S) subunit (PubMed:23636399). The 40S subunit contains about 33 different proteins and 1 molecule of RNA (18S). The 60S subunit contains about 49 different proteins and 3 molecules of RNA (28S, 5.8S and 5S) (PubMed:23636399). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Binds with high affinity to IPO4 (PubMed:11823430). Interacts with DDIT3. Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797).
Component of the small ribosomal subunit. Mature ribosomes consist of a small (40S) and a large (60S) subunit. The 40S subunit contains about 33 different proteins and 1 molecule of RNA (18S). The 60S subunit contains about 49 different proteins and 3 molecules of RNA (28S, 5.8S and 5S). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Binds with high affinity to IPO4. Interacts with DDIT3.
Component of the small ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797). May play a role during erythropoiesis through regulation of transcription factor DDIT3 (By similarity).
May play a role during erythropoiesis through regulation of transcription factor DDIT3.
Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC.
Genetic variation in FOLH1 may be associated with low folate levels and consequent hyperhomocysteinemia. This condition can result in increased risk of cardiovascular disease, neural tube defects, and cognitive deficits.
Has both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. Has a preference for tri-alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N-aceylaspartylglutamate (NAAG), thereby releasing glutamate. Involved in prostate tumor progression.
Highly expressed in prostate epithelium. Detected in urinary bladder, kidney, testis, ovary, fallopian tube, breast, adrenal gland, liver, esophagus, stomach, small intestine, colon and brain (at protein level). Detected in the small intestine, brain, kidney, liver, spleen, colon, trachea, spinal cord and the capillary endothelium of a variety of tumors. Expressed specifically in jejunum brush border membranes. In the brain, highly expressed in the ventral striatum and brain stem. Also expressed in fetal liver and kidney. Isoform PSMA' is the most abundant form in normal prostate. Isoform PSMA-1 is the most abundant form in primary prostate tumors. Isoform PSMA-9 is specifically expressed in prostate cancer.
In the prostate, up-regulated in response to androgen deprivation.
PSMA is used as a diagnostic and prognostic indicator of prostate cancer, and as a possible marker for various neurological disorders such as schizophrenia, Alzheimer disease and Huntington disease.
The NAALADase activity is inhibited by beta-NAAG, quisqualic acid, 2-(phosphonomethyl) pentanedioic acid (PMPA) and EDTA. Activated by cobalt.
The first two amino acids at the N-terminus of isoform PSMA' appear to be cleaved by limited proteolysis.
Belongs to the G-protein coupled receptor 1 family. 5-hydroxytryptamine receptor subfamily. HTR1A sub-subfamily.
Detected in lymph nodes, thymus and spleen. Detected in activated T-cells, but not in resting T-cells.
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores. Plays a role in the regulation of 5-hydroxytryptamine release and in the regulation of dopamine and 5-hydroxytryptamine metabolism. Plays a role in the regulation of dopamine and 5-hydroxytryptamine levels in the brain, and thereby affects neural activity, mood and behavior. Plays a role in the response to anxiogenic stimuli.
Heterodimer; heterodimerizes with GPER1. Interacts with YIF1B (By similarity).
A soluble form may also be produced by proteolytic cleavage at the cell surface (shedding).
Associated with CD177-negative phenotype.
By CSF3/G-CSF in resting granulocytes (PubMed:10753836). Induced during CSF3/G-CSF-mediated neutrophil differentiation (PubMed:17244676, PubMed:18462208). Induced during pregnancy (PubMed:12675722). Induced in patients with polycythemia vera (PV) and with essential thrombocythemia (ET) (PubMed:10753836, PubMed:12377969).
Expressed in neonatal and adult neutrophils.
Found in a complex with integrin ITGAM/CD11b and ITGB2/CD18 (PubMed:28807980, PubMed:21193407). Interacts with PECAM1 (via Ig-like C2-type domain 6); the interaction is Ca(2+)-dependent; the interaction is direct (PubMed:17580308). Interacts with serine protease PRTN3/myeloblastin; the interaction tethers PRTN3 to the cell surface; the interaction is direct (PubMed:17244676, PubMed:28240246).
Highly expressed in normal bone marrow and weakly expressed in fetal liver (PubMed:10753836). During neutrophil differentiation, expression begins at the metamyelocyte stage and continues throughout the subsequent stages (at protein level) (PubMed:17244676, PubMed:18462208, PubMed:24926686). Expressed by a subset of mature neutrophils (at protein level) (PubMed:10753836, PubMed:28240246, PubMed:12377969, PubMed:18462208, PubMed:12675722, PubMed:17244676, PubMed:17580308, PubMed:21193407, PubMed:24926686, PubMed:28807980, PubMed:27227454). The percentage of neutrophils expressing CD177 varies across the population (PubMed:17244676, PubMed:27227454). Expressed in granulocytes of patients with polycythemia vera (PV) and with essential thrombocythemia (ET) (PubMed:10753836, PubMed:12377969).
In association with beta-2 integrin heterodimer ITGAM/CD11b and ITGB2/CD18, mediates activation of TNF-alpha primed neutrophils including degranulation and superoxide production (PubMed:21193407). In addition, by preventing beta-2 integrin internalization and attenuating chemokine signaling favors adhesion over migration (PubMed:28807980). Heterophilic interaction with PECAM1 on endothelial cells plays a role in neutrophil transendothelial migration in vitro (PubMed:17580308). However, appears to be dispensable for neutrophil recruitment caused by bacterial infection in vivo (PubMed:23461681). Acts as a receptor for the mature form of protease PRTN3 allowing its display at the cell surface of neutrophils (PubMed:17244676, PubMed:18462208). By displaying PRTN3 at the neutrophil cell surface, may play a role in enhancing endothelial cell junctional integrity and thus vascular integrity during neutrophil diapedesis (PubMed:23202369).
There is a significant association between the variants Ala-3, Leu-251 and Thr-348 and a low expression of CD177 on neutrophils (PubMed:12623849, PubMed:14692971). Expression of CD177 on neutrophils is a trait determined by ratio of CD177/CD177P1 alleles (PubMed:27227454). The phenotype of CD177 null neutrophils is due to recombination between exon 7 of CD177 and the pseudogene CD177P1 through gene conversion, changing Lys-263 codon into stop codon (PubMed:27227454). The lack of CD177 expression affects 1-10 percent of the population placing them at risk for formation of anti-neutrophil antibodies that can cause transfusion-related acute lung injury and neonatal alloimmune neutropenia.
Specifically expressed in testis. Expressed by cancer cell lines.
Belongs to the eukaryotic RPA43 RNA polymerase subunit family.
Component of the RNA polymerase I (Pol I) complex consisting of at least 13 subunits (By similarity). Interacts with RRN3/TIF-IA.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase I which synthesizes ribosomal RNA precursors. Through its association with RRN3/TIF-IA may be involved in recruitment of Pol I to rDNA promoters.
Widely expressed. Expressed in all fetal and adult tissues tested, with highest expression in fetal lung, liver, and kidney, and low expression in all adult tissues.
Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity (By similarity). Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits ERK1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establish and maintain correct endothelial cell polarity and vascular lumen and these effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction, and cell junction stabilization. Plays a role in integrin signaling via its interaction with ITGB1BP1; this prevents the interaction between ITGB1 and ITGB1BP1. Microtubule-associated protein that binds to phosphatidylinositol 4,5-bisphosphate (PIP2)-containing membranes in a GTP-bound RAP1-dependent manner. Plays an important role in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage. Regulates the homeostasis of intracellular ROS through an antioxidant pathway involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1 (CCND1) levels required for cell transition from proliferative growth to quiescence by preventing the accumulation of intracellular ROS through the modulation of FOXO1 and SOD2 levels. May play a role in the regulation of macroautophagy through the down-regulation of the mTOR pathway (PubMed:26417067).
Contains 4 ANK repeats that precede the FERM domain.
Interacts with CDH5 (PubMed:20332120). Found in a complex, at least composed of ITGB1BP1, KRIT1 and RAP1A. Interacts (via C-terminus FERM domain) with RAP1A (active GTP-bound form preferentially); the interaction does not induce the opening conformation of KRIT1. Interacts (via FERM domain) with RAP1B. Interacts (via N-terminus NPXY motif) with ITGB1BP1; the interaction induces the opening conformation of KRIT1 and competes with ITGB1 for ITGB1BP1 interaction. Interacts with HEG1 and CCM2; greatly facilitates CCM2-binding to HEG1. Associates (via N-terminus and C-terminus regions) with microtubules; the interaction is inhibited in presence of ITGB1BP1 and active GTP-bound RAP1A.
Low levels in brain. Very weak expression found in heart and muscle.
The FERM domain mediates binding to RAP1A and RAP1B and is necessary for binding to phosphatidylinositol 4,5-bisphosphate (PIP2).
The N-terminal domain has structural similarity to the nudix hydrolase domain, despite the absence of a nudix box and low sequence similarity with nudix hydrolase domains. The N-terminus and the C-terminus part associate together via the NPAY binding motif and adopt a lose conformation that is disrupted by ITGB1BP1, but not by RAP1A.
Binds directly and specifically 1,2-Diacyl-sn-glycero-3-phospho-(1'-myo-inositol-3',4',5'-bisphosphate) (PIP3) leading to the recruitment of PIP3 to mitochondria and may play a role in the regulation of the platelet activation via AKT/GSK3B/cGMP signaling pathways (PubMed:29786068). May act as transcription factor that regulates SREBP1 (isoform SREBP-1C) expression in order to modulate triglyceride (TG) homeostasis in hepatocytes (PubMed:29187281, PubMed:25855506).
Highly expressed in platelets (at protein level).
Transcription elongation factor which increases mitochondrial RNA polymerase processivity. Regulates transcription of the mitochondrial genome, including genes important for the oxidative phosphorylation machinery.
E3 ubiquitin-protein ligase that plays a key role in endosome organization by retaining vesicles in the perinuclear cloud (PubMed:27368102). Acts as a platform for perinuclear positioning of the endosomal system by mediating ubiquitination of SQSTM1 through interaction with the ubiquitin conjugating enzyme UBE2J1 (PubMed:27368102, PubMed:33472082). Ubiquitinated SQSTM1 attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102, PubMed:33472082). Also acts as a regulator of type I interferon production in response to viral infection by mediating the formation of 'Lys-11'-linked polyubiquitin chains on TMEM173/STING, leading to stabilize TMEM173/STING (PubMed:25254379, PubMed:32614325). Also required to limit type I interferon response by promoting autophagic degradation of IRF3 (PubMed:25254379).
Interacts with INCA1 (PubMed:21750715). Interacts with TMEM43, ENDOD1, TMEM33 and TMED1 to form a complex capable of modulating innate immune signaling through the cGAS-STING pathway (PubMed:32614325). Interacts with UBE2J1; this interaction is important for SQSTM1 ubiquitination (PubMed:33472082).
Ubiquitous. Up-regulated in several cancer cell lines.
Catalyzes the transfer of a geranylgeranyl moiety from geranylgeranyl diphosphate to both cysteines of Rab proteins with the C-terminal sequence -XXCC, -XCXC and -CCXX, such as RAB1A, RAB3A, RAB5A and RAB7A.
Heterotrimer composed of RABGGTA, RABGGTB and CHM; within this trimer, RABGGTA and RABGGTB form the catalytic component B, while CHM (component A) mediates peptide substrate binding (PubMed:7991565). The Rab GGTase dimer (RGGT) interacts with CHM (component A) prior to Rab protein binding; the association is stabilized by geranylgeranyl pyrophosphate (GGpp). The CHM:RGGT:Rab complex is destabilized by GGpp (PubMed:18532927). Interacts with non-phosphorylated form of RAB8A; phosphorylation of RAB8A at 'Thr-72' disrupts this interaction (PubMed:26824392).
The enzymatic reaction requires the aid of a Rab escort protein (also called component A), such as CHM.
Modulates exocytosis of dense-core granules and secretion of hormones in the pancreas and the pituitary. Interacts with vesicles containing negatively charged phospholipids in a Ca(2+)-independent manner (By similarity).
Part of a ternary complex containing STX1A and RAB27A. Can bind both dominant negative and dominant active mutants of RAB27A. Binds STXBP1, RAB3A, RAB8A and RAB27B. Interacts with MYO5A (By similarity).
Belongs to the complex I 24 kDa subunit family.
Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. This is a component of the flavoprotein-sulfur (FP) fragment of the enzyme.
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
Belongs to the sulfatase-modifying factor family.
Monomer, homodimer and heterodimer with SUMF2.
N-glycosylated. Contains high-mannose-type oligosaccharides.
Oxidase that catalyzes the conversion of cysteine to 3-oxoalanine on target proteins, using molecular oxygen and an unidentified reducing agent (PubMed:12757706, PubMed:15657036, PubMed:15907468, PubMed:25931126, PubMed:16368756, PubMed:21224894). 3-oxoalanine modification, which is also named formylglycine (fGly), occurs in the maturation of arylsulfatases and some alkaline phosphatases that use the hydrated form of 3-oxoalanine as a catalytic nucleophile (PubMed:12757706, PubMed:15657036, PubMed:15907468, PubMed:25931126, PubMed:16368756). Known substrates include GALNS, ARSA, STS and ARSE (PubMed:12757706, PubMed:15907468, PubMed:15657036).
The catalytic copper is required to activate oxygen and catalyze oxidative C-H activation.
The disease is caused by variants affecting the gene represented in this entry. SUMF1 mutations result in defective post-translational modification of sulfatases.
The disulfide bond observed in the structure does not exist in vivo (PubMed:15907468). The enzyme reaction was initially thought to act via a redox-active disulfide bond mechanism; however the disulfide bond only takes place with inactive enzyme that lacks the copper cofactor (PubMed:25931126). The catalytic copper is required to activate oxygen and catalyze oxidative C-H activation (PubMed:25931126).
The resulting 3-oxoalanine in the substrate protein is called C(alpha)-formylglycine by many authors. It should not be confused with N-formylglycine.
Ubiquitous. Highly expressed in kidney, pancreas and liver. Detected at lower levels in leukocytes, lung, placenta, small intestine, skeletal muscle and heart.
Associates with the SH2 and SH3 domains of LCK. Binding to he LCK SH3 domain occurs constitutively, while binding to the LCK SH2 domain occurs only upon TCR stimulation. A similar binding pattern was observed with LYN, but not with FYN in which the FYN SH2 region associates upon TCR stimulation but the FYN SH3 region does not associate regardless of TCR stimulation. Directly associates with HAX1, through binding to its C-terminal region. Interacts with HS1BP3. Interacts with FES/FPS (By similarity). Interacts (via SH2 domain) with FGR. Forms a multiprotein complex with LYN and ANKRD54 (By similarity).
Expressed in early stage of myeloid and erythroid differentiation.
Expressed only in tissues and cells of hematopoietic origin.
Phosphorylated by FES (By similarity). Phosphorylated by LYN, FYN and FGR after cross-linking of surface IgM on B-cells. Phosphorylation by LYN, FYN and FGR requires prior phosphorylation by SYK or FES.
Substrate of the antigen receptor-coupled tyrosine kinase. Plays a role in antigen receptor signaling for both clonal expansion and deletion in lymphoid cells. May also be involved in the regulation of gene expression.
Expressed in erythroid tissues, including thymus, bone marrow and fetal liver, and in several nonerythroid tissues, such as heart, placenta, skeletal muscle, thyroid and trachea, as well as in skin fibroblasts. Expression is low or undetectable in other tissues.
XG is responsible for the Xg blood group system.
Expressed in a wide range of tissues with High expression in Placenta, kidney and lung.
Likely interchromosomal Alu-mediated fusion between IGSF3 on 1p13.1 and GGT on 22q11.2. Breakpoints occurred inside Alu elements as well as in the 5' or 3' ends of them.
Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins (PubMed:19135894, PubMed:25944111, PubMed:18254724, PubMed:22371489, PubMed:29626158). May therefore play an important regulatory role at the level of protein turnover by preventing degradation of proteins through the removal of conjugated ubiquitin (PubMed:19135894, PubMed:25944111, PubMed:22371489, PubMed:18254724, PubMed:29626158). Specifically hydrolyzes 'Lys-63'-, 'Lys-48'-, 'Lys-29'- and 'Lys-33'-linked polyubiquitins chains (PubMed:25944111, PubMed:18254724, PubMed:33378666). Essential component of TGF-beta/BMP signaling cascade (PubMed:19135894). Specifically deubiquitinates monoubiquitinated SMAD4, opposing the activity of E3 ubiquitin-protein ligase TRIM33 (PubMed:19135894). Deubiquitinates alkylation repair enzyme ALKBH3 (PubMed:25944111). OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Deubiquitinates mTORC2 complex component RICTOR at 'Lys-294' by removing 'Lys-63'-linked polyubiquitin chains, stabilizing RICTOR and enhancing its binding to MTOR, thus promoting mTORC2 complex assembly (PubMed:33378666). Regulates chromosome alignment and segregation in mitosis by regulating the localization of BIRC5/survivin to mitotic centromeres (PubMed:16322459). Involved in axonal growth and neuronal cell migration (PubMed:24607389). Regulates cellular clock function by enhancing the protein stability and transcriptional activity of the core circadian protein BMAL1 via its deubiquitinating activity (PubMed:29626158). Acts as a regulator of peroxisome import by mediating deubiquitination of PEX5: specifically deubiquitinates PEX5 monoubiquitinated at 'Cys-11' following its retrotranslocation into the cytosol, resetting PEX5 for a subsequent import cycle (PubMed:22371489). Deubiquitinates PEG10 (By similarity).
Interacts with SMAD4, MARK4, NUAK1 and BIRC5/survivin. Interacts with DCX. Interacts with OTUD4 and USP7; the interaction is direct (PubMed:25944111).
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'- and 'Lys-48'-, as well as 'Lys-63'-linked polyubiquitination. Catalyzes the ISGylation of influenza A virus NS1 protein.
Homodimerizes (PubMed:31311869). Interacts with CRK isoform CRK-II; the interaction requires PEAK3 homodimerization (PubMed:31311869).
Probable catalytically inactive kinase (Probable). Interacts with CRK-II and antagonizes CRK-II-signaling. Prevents the formation of CRK-II-dependent membrane ruffling and lamellipodia-like extensions (PubMed:31311869).
Expressed at high levels ovary, heart, testis, prostate, brain, spleen and colon. Expressed at very low levels in liver and thymus. Not expressed in peripheral blood leukocytes. Not or reduced expressed in lung, prostate, colon, pancreas and ovarian carcinomas.
Regulates mitochondrial transport during axon regeneration. Increases the proportion of motile mitochondria by recruiting stationary mitochondria into the motile pool. Enhances mitochondria movement and neurite growth in both adult axons and embryonic neurons. Promotes neuronal survival and axon regeneration after nerve injury. May link mitochondria to the Trak1-kinesin motor complex via its interaction with MIRO1.
Phosphorylates deoxyguanosine and deoxyadenosine in the mitochondrial matrix, with the highest efficiency for deoxyguanosine (PubMed:8692979, PubMed:8706825, PubMed:11687801, PubMed:17073823, PubMed:23043144). In non-replicating cells, where cytosolic dNTP synthesis is down-regulated, mtDNA synthesis depends solely on DGUOK and TK2. Phosphorylates certain nucleoside analogs (By similarity). Widely used as target of antiviral and chemotherapeutic agents.
Ubiquitous. Highest expression in muscle, brain, liver and lymphoid tissues.
DNA-binding homotrimer in stressed or heat shocked cells, otherwise found as a homodimer.
DNA-binding protein that specifically binds heat shock promoter elements (HSE) and activates transcription. In higher eukaryotes, HSF is unable to bind to the HSE unless the cells are heat shocked.
According to some authors, RBMXL1 is a RBMX retrogene on chromosome X which is likely to be functional.
RNA-binding protein which may be involved in pre-mRNA splicing.
The first non-coding exon of RBMXL1 is in common with that of CCBL2.
Transcription factor that plays a key role in neuronal differentiation by specifically repressing expression of non-neuronal genes during neuron differentiation. In contrast to other transcription repressors that inhibit specific lineages, mediates repression of multiple differentiation programs. Also represses expression of negative regulators of neurogenesis, such as members of the Notch signaling pathway, including HES1. The combination of three transcription factors, ASCL1, POU3F2/BRN2 and MYT1L, is sufficient to reprogram fibroblasts and other somatic cells into induced neuronal (iN) cells in vitro. Directly binds the 5'-AAGTT-3' core motif present on the promoter of target genes and represses transcription by recruiting a multiprotein complex containing SIN3B. The 5'-AAGTT-3' core motif is absent from the promoter of neural genes.
Detected in heart left ventricle (PubMed:21127204). Widely expressed.
Interacts with CACNA1C. Identified in a complex with the L-type calcium channel subunits CACNA1C, CACNA2D1 and either CACNB1 or CACNB2 (PubMed:21127204). Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs), such as GRIA1 and GRIA2 (PubMed:21172611).
Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit (PubMed:21127204). Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization and by mediating their resensitization. Displays subunit-specific AMPA receptor regulation. Shows specificity only for GRIA1 and GRIA2 (PubMed:21172611).
(Microbial infection) Interacts with alphaviruses SINV, CHIKV, RRV, VEEV and EEEV capsid proteins; the interactions lead to inhibition of IRAK1-dependent signaling.
Following recruitment on the activated receptor complex, phosphorylated on Thr-209, probably by IRAK4, resulting in a conformational change of the kinase domain, allowing further phosphorylations to take place. Thr-387 phosphorylation in the activation loop is required to achieve full enzymatic activity.
Homodimer (By similarity). Forms a complex with TRAF6, PELI1, IRAK4 and MYD88 (PubMed:16951688). Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression (PubMed:16951688). The TRAF6-PELI1-IRAK4-MYD88 complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation (PubMed:16951688). Interaction with MYD88 recruits IRAK1 to the stimulated receptor complex (PubMed:9430229). Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation (PubMed:10854325). Interacts with IL1RL1 (PubMed:16286016). Interacts with PELI1 and TRAF6 (PubMed:12496252). Interacts (when polyubiquitinated) with IKBKG/NEMO (PubMed:18347055). Interacts with RSAD2/viperin (By similarity). Interacts with IRAK1BP1 (By similarity). Interacts with PELI2 (By similarity). Interacts with ZC3H12A; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB (By similarity). Interacts with IRAK4 (PubMed:11960013). Interacts with PELI3 (PubMed:12874243). Interacts with INAVA; the interaction takes place upon PRR stimulation (PubMed:28436939). Interacts (via C-terminus) with NFATC4 (via N-terminus) (PubMed:18691762).
Isoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2.
Polyubiquitinated by TRAF6 after cell stimulation with IL-1-beta by PELI1, PELI2 and PELI3. Polyubiquitination occurs with polyubiquitin chains linked through 'Lys-63'. Ubiquitination promotes interaction with NEMO/IKBKG. Also sumoylated; leading to nuclear translocation.
Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.
The ProST region is composed of many proline and serine residues (more than 20 of each) and some threonines. This region is the site of IRAK-1 hyperphosphorylation.
Does not have alcohol dehydrogenase activity. Binds NADP and acts through a one-electron transfer process. Orthoquinones, such as 1,2-naphthoquinone or 9,10-phenanthrenequinone, are the best substrates (in vitro). May act in the detoxification of xenobiotics. Interacts with (AU)-rich elements (ARE) in the 3'-UTR of target mRNA species. Enhances the stability of mRNA coding for BCL2. NADPH binding interferes with mRNA binding.
A paper showing involvement in Hermansky-Pudlak syndrome 9 was retracted due to image duplication.
Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals. The BLOC-1 complex, in association with SNARE proteins, is also proposed to be involved in neurite extension. May play a role in intracellular vesicle trafficking, particularly in the vesicle-docking and fusion process.
Interacts with BLOC1S4 and DTNBP1/BLOC1S7 (By similarity). Homodimer. Component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) composed of BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. Octamer composed of one copy each BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. The BLOC-1 complex associates with the AP-3 protein complex and membrane protein cargos. Interacts with BLOC1S5, F-actin, SNAP25 isoform 1 and isoform 2, SNAP47 and STX12.
Autocatalytic cleavage of USP1 following UV irradiation inactivates it, leading to an increase in ubiquitinated PCNA, recruitment of POLH and translesion synthesis.
Cell cycle-regulated. Highest level during S phase.
HEK293T cells expressing reduced levels of USP1 show a higher level of ubiquitinated PCNA and an increase in point mutations upon UV irradiation.
Interacts with FANCD2 and PCNA (PubMed:15694335, PubMed:16531995). Interacts with WDR48 (PubMed:18082604, PubMed:26388029). Interacts with ATAD5; the interaction regulates USP1-mediated PCNA deubiquitination (PubMed:20147293).
Negative regulator of DNA damage repair which specifically deubiquitinates monoubiquitinated FANCD2 (PubMed:15694335). Also involved in PCNA-mediated translesion synthesis (TLS) by deubiquitinating monoubiquitinated PCNA (PubMed:16531995, PubMed:20147293). Has almost no deubiquitinating activity by itself and requires the interaction with WDR48 to have a high activity (PubMed:18082604, PubMed:26388029).
Ubiquitinated by the CRL2(KLHDC2) complex following autocatalytic cleavage, leading to its degradation: the CRL2(KLHDC2) complex recognizes the diglycine (Gly-Gly) at the C-terminus.
Salivary gland, pancreas and prostate > epididymis, ovary, thymus and colon.
Interacts with AFG3L2 (PubMed:27499296, PubMed:27642048). Interacts with SPG7 (PubMed:27499296). Interacts with SMDT1/EMRE (via the N-terminal transit peptide); interaction is direct and takes place before maturation of SMDT1/EMRE (PubMed:27642048).
Promotes sorting of SMDT1/EMRE in mitochondria by ensuring its maturation (PubMed:27642048). Interacts with the transit peptide region of SMDT1/EMRE precursor protein in the mitochondrial matrix, leading to protect it against protein degradation by YME1L1, thereby ensuring SMDT1/EMRE maturation by the mitochondrial processing peptidase (PMPCA and PMPCB) (PubMed:27642048).
Acts as a transcriptional regulator. Together with NKX2-2, initiates transcriptional activation of NEUROD1. Involved in neurogenesis. Also required for the specification of a common precursor of the 4 pancreatic endocrine cell types (By similarity).
Efficient DNA binding requires dimerization with another bHLH protein. Interacts with ATOH8.
Heteropentamer with NPTX1 and/or NPTX2. Also binds taipoxin-associated calcium-binding protein 49 (TCBP49/RCN2). Interacts with KLHL2 (By similarity).
May be involved in mediating uptake of synaptic material during synapse remodeling or in mediating the synaptic clustering of AMPA glutamate receptors at a subset of excitatory synapses.
Ubiquitinated by a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing KLHL2.
Belongs to the phytoene/squalene synthase family.
Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP) moieties to form squalene.
Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP) moieties to form squalene. Proceeds in two distinct steps. In the first half-reaction, two molecules of FPP react to form the stable presqualene diphosphate intermediate (PSQPP), with concomitant release of a proton and a molecule of inorganic diphosphate. In the second half-reaction, PSQPP undergoes heterolysis, isomerization, and reduction with NADPH or NADH to form squalene. It is the first committed enzyme of the sterol biosynthesis pathway.
Plays essential roles in both eye and limb development. Probable regulator of osteoblast differentiation.
Widely expressed in many tissues with a strongest signal in ovary. No expression in spleen.
Expression is independent of the cell cycle in lung fibroblasts.
Highest levels in adult heart, brain and skeletal muscle. Lower levels in adult placenta, lung, kidney and pancreas. Also high levels in fetal brain and lower levels in fetal lung, liver and kidney. Also abundant in testis and thyroid.
Belongs to the protease inhibitor I27 (calpastatin) family.
Each of the four flexible inhibitory domains can inhibit one calcium-bound calpain molecule by occupying both sides of the active site.
Specific inhibition of calpain (calcium-dependent cysteine protease). Plays a key role in postmortem tenderization of meat and have been proposed to be involved in muscle protein degradation in living tissue.
(Microbial infection) In case of infection, polyubiquitinated by the bacterial E3 ubiquitin-protein ligase SspH1, leading to its proteasomal degradation.
(Microbial infection) Interacts (via the second REM repeat) with S.typhimurium E3 ubiquitin-protein ligase SspH1 (via the leucine-rich repeat region) (PubMed:16611232, PubMed:24248594).
Activated by limited proteolysis with trypsin.
Autophosphorylated; preferably on serine. Phosphorylated during mitosis.
Found ubiquitously. Expressed in heart, brain, placenta, lung, skeletal muscle, kidney and pancreas. Expressed in numerous tumor cell lines, especially in breast tumor cells.
Interacts with ZFAND6 (By similarity). Interacts with AR (PubMed:12514133). Interacts with PRKCB (PubMed:20228790). Interacts (via REM 1 and REM 2 repeats) with RAC1 (PubMed:14514689, PubMed:18006505). Interacts (via REM 1 repeat) with RHOA (PubMed:10619026, PubMed:8571126). Interacts with RHOB (PubMed:9478917). Interacts (via C-terminus) with PDPK1 (PubMed:10792047). Interacts with CCNT2; enhances MYOD1-dependent transcription (PubMed:16331689). Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK (PubMed:21224381).
Kinase activity is activated upon binding to Rho proteins (RHOA, RHOB and RAC1). Activated by lipids, particularly cardiolipin and to a lesser extent by other acidic phospholipids. Activated by caspase-3 (CASP3) cleavage during apoptosis. Two specific sites, Thr-774 (activation loop of the kinase domain) and Ser-916 (turn motif), need to be phosphorylated for its full activation.
PKC-related serine/threonine-protein kinase involved in various processes such as regulation of the intermediate filaments of the actin cytoskeleton, cell migration, tumor cell invasion and transcription regulation. Part of a signaling cascade that begins with the activation of the adrenergic receptor ADRA1B and leads to the activation of MAPK14. Regulates the cytoskeletal network by phosphorylating proteins such as VIM and neurofilament proteins NEFH, NEFL and NEFM, leading to inhibit their polymerization. Phosphorylates 'Ser-575', 'Ser-637' and 'Ser-669' of MAPT/Tau, lowering its ability to bind to microtubules, resulting in disruption of tubulin assembly. Acts as a key coactivator of androgen receptor (AR)-dependent transcription, by being recruited to AR target genes and specifically mediating phosphorylation of 'Thr-11' of histone H3 (H3T11ph), a specific tag for epigenetic transcriptional activation that promotes demethylation of histone H3 'Lys-9' (H3K9me) by KDM4C/JMJD2C. Phosphorylates HDAC5, HDAC7 and HDAC9, leading to impair their import in the nucleus. Phosphorylates 'Thr-38' of PPP1R14A, 'Ser-159', 'Ser-163' and 'Ser-170' of MARCKS, and GFAP. Able to phosphorylate RPS6 in vitro.
The C1 domain does not bind the diacylglycerol (DAG).
Monomer. Interacts specifically with NCR3, but not with other natural killer cell-activating receptors, including NCR1, NCR2 and KLRK1.
Not detected in any normal tissue tested. Expressed at the surface of several tumor cell lines including T and B-lymphomas, myeloid leukemias, melanomas, carcinomas and large T SV40 antigen-transformed cells (at protein level).
The C-terminal part is similar to retroviral Gag protein. This putative protein seems to be the result of a fusion between an Ig-like domain-containing protein and a ERV.
Triggers NCR3-dependent natural killer cell activation.
(Microbial infection) Interacts with C.difficile toxin TcdB, suggesting that it may contribute to TcdB toxin entry into cells (PubMed:26038560). It was however shown that NECTIN3/PVRL3 does not act as a major receptor for TcdB (PubMed:27680706).
Cis- and trans-homodimer. Can form trans-heterodimers with NECTIN1, NECTIN2, PVR, IGSF4B/Necl-1 and with IGSF4. Interaction between NECTIN1 and NECTIN3 on the pre- and postsynaptic sites, respectively, initiates the formation of puncta adherentia junctions between axons and dendrites. Interacts (via Cytoplasmic domain) with AFDN, providing a connection with the actin cytoskeleton. Binds with low affinity to TIGIT.
Plays a role in cell-cell adhesion through heterophilic trans-interactions with nectin-like proteins or nectins, such as trans-interaction with NECTIN2 at Sertoli-spermatid junctions. Trans-interaction with PVR induces activation of CDC42 and RAC small G proteins through common signaling molecules such as SRC and RAP1. Also involved in the formation of cell-cell junctions, including adherens junctions and synapses. Induces endocytosis-mediated down-regulation of PVR from the cell surface, resulting in reduction of cell movement and proliferation. Plays a role in the morphology of the ciliary body.
Predominantly expressed in testis and placenta as well as in many cell lines, including epithelial cell lines.
Belongs to the ubiquitin conjugation factor E4 family.
Ubiquitin-protein ligase that probably functions as an E3 ligase in conjunction with specific E1 and E2 ligases. May also function as an E4 ligase mediating the assembly of polyubiquitin chains on substrates ubiquitinated by another E3 ubiquitin ligase. Mediates 'Lys-48'-linked polyubiquitination of substrates.
Acetylation impairs ability to promote interaction between Akt/AKT1 and PHLPP1 (PubMed:28147277). Deacetylation by SIRT7 promotes interaction between Akt/AKT1 and PHLPP1, leading to suppress Akt/AKT1 activation (PubMed:28147277).
Immunophilin protein with PPIase and co-chaperone activities (PubMed:11350175). Component of unligated steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). Plays a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors maintaining the complex into the cytoplasm when unliganded (PubMed:12538866). Acts as a regulator of Akt/AKT1 activity by promoting the interaction between Akt/AKT1 and PHLPP1, thereby enhancing dephosphorylation and subsequent activation of Akt/AKT1 (PubMed:28147277). Interacts with IKBKE and IKBKB which facilitates IKK complex assembly leading to increased IKBKE and IKBKB kinase activity, NF-kappaB activation, and IFN production (PubMed:26101251, PubMed:31434731).
Part of a heteromultimeric cytoplasmic complex with HSP90AA1, HSPA1A/HSPA1B and steroid receptors. Upon ligand binding dissociates from the complex and FKBP4 takes its place (By similarity). Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP (PubMed:7693698). Interacts with NR3C1 (By similarity). Interacts with Akt/AKT1 and PHLPP1; enhancing dephosphorylation and subsequent activation of Akt/AKT1 (PubMed:28147277). Interacts with IFI44L; this interaction modulates the kinase activity of IKBKB and IKBKE (PubMed:31434731). Interacts with IKBKB and IKBKE (PubMed:26101251, PubMed:31434731).
Widely expressed, enriched in testis compared to other tissues.
Expressed in the fetal brain, liver and kidney.
A chromosomal aberration involving PDE4DIP may be the cause of a myeloproliferative disorder (MBD) associated with eosinophilia. Translocation t(1;5)(q23;q33) that forms a PDE4DIP-PDGFRB fusion protein.
Functions as an anchor sequestering components of the cAMP-dependent pathway to Golgi and/or centrosomes (By similarity).
Highly expressed in adult and fetal heart, in skeletal muscle and, to a lower extent, in brain and placenta.
Interacts with PDE4D (By similarity). Isoform 13 interacts with MAPRE1 and MAPRE3 (PubMed:25217626, PubMed:28814570, PubMed:29162697). Isoform 13 forms a pericentrosomal complex with AKAP9, CDK5RAP2 and EB1/MAPRE1; within this complex, may mediate MAPRE1-binding to CDK5RAP2 (PubMed:29162697). Interaction of isoform 13 with AKAP9 stabilizes both proteins (PubMed:25217626, PubMed:27666745). Isoform 13 interacts (via N-terminus) with CAMSAP2; this interaction is much stronger in the presence of AKAP9 (PubMed:27666745). In complex with AKAP9, Isoform 13 recruits CAMSAP2 to the Golgi apparatus (PubMed:27666745, PubMed:28814570). Isoform 13 interacts with unglycosylated LGALS3BP; this interaction may connect the pericentrosomal complex to the gamma-tubulin ring complex (gamma-TuRC) to promote microtubule assembly and acetylation (PubMed:25217626, PubMed:29162697).
Mutagenesis at position 311-312:LP->AA (loss of MAPRE1- and MAPRE3-binding and loss of association with microtubule ends, no effect on AKAP9- and CDK5RAP2-binding, relocalizes from EB1/MAPRE1 microtubule ends to centrosomal area).
Participates in microtubule dynamics, promoting microtubule assembly. Depending upon the cell context, may act at the level of the Golgi apparatus or that of the centrosome (PubMed:25217626, PubMed:27666745, PubMed:28814570, PubMed:29162697). In complex with AKAP9, recruits CAMSAP2 to the Golgi apparatus and tethers non-centrosomal minus-end microtubules to the Golgi, an important step for polarized cell movement (PubMed:27666745, PubMed:28814570). In complex with AKAP9, EB1/MAPRE1 and CDK5RAP2, contributes to microtubules nucleation and extension from the centrosome to the cell periphery, a crucial process for directed cell migration, mitotic spindle orientation and cell-cycle progression (PubMed:29162697).
Residues 1-150 are involved in AKAP9-binding.
Was initially reported to localize in the cytoplasm and nucleus (PubMed:11374908). However, many reports in different species have shown that it is associated with the Golgi apparatus and the centrosome.
Interferon-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response. In addition, it may also play a role in other cellular processes such as apoptosis, cell growth, differentiation and gene regulation. Synthesizes preferentially dimers of 2'-5'-oligoadenylates (2-5A) from ATP which then bind to the inactive monomeric form of ribonuclease L (RNase L) leading to its dimerization and subsequent activation. Activation of RNase L leads to degradation of cellular as well as viral RNA, resulting in the inhibition of protein synthesis, thus terminating viral replication. Can mediate the antiviral effect via the classical RNase L-dependent pathway or an alternative antiviral pathway independent of RNase L. Displays antiviral activity against Chikungunya virus (CHIKV), Dengue virus, Sindbis virus (SINV) and Semliki forest virus (SFV).
OAS domain 3 is catalytically active. OAS domain 1 has no catalytic activity but is essential for recognition of long dsRNAs.
Present at high level in placenta trophoblast.
Produced as a latent enzyme which is activated by dsRNA generated during the course of viral infection (Probable). Strongly activated by long dsRNAs at least 50 nucleotides in length (PubMed:25775560). ssRNA does not activate the enzyme (PubMed:25775560).
(Microbial infection) Interacts with encephalomyocarditis virus (EMCV) major capsid proteins VP1 and VP2.
(Microbial infection) Positively regulates the replication of encephalomyocarditis virus (EMCV) via autophagy-dependent pathway.
Interacts with SACM1L, SEC23A and SEC24A.
Regulates autophagy by controlling the spatial distribution and levels of the intracellular phosphatidylinositol 4-phosphate (PtdIns(4)P) pools (PubMed:31806350). Modulates (PtdIns(4)P) levels by regulating the ER-to-Golgi trafficking of the phosphatidylinositide phosphatase SACM1L (PubMed:31806350).
Up-regulated in brain tumor glioblastoma multiforme cells (at protein level).
Belongs to the nucleoporin Nup84/Nup107 family.
Part of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:12802065, PubMed:15229283, PubMed:26411495). Forms part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and Nup96; this complex plays a role in RNA export and in tethering Nup98 and NUP153 to the nucleus (PubMed:11564755, PubMed:11684705, PubMed:26411495, PubMed:30179222). Does not interact with TPR (PubMed:12802065). Interacts with ZNF106 (By similarity).
Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance (PubMed:12552102, PubMed:15229283, PubMed:30179222). Required for the assembly of peripheral proteins into the NPC (PubMed:15229283, PubMed:12552102). May anchor NUP62 to the NPC (PubMed:15229283). Involved in nephrogenesis (PubMed:30179222).
A cytochrome P450 monooxygenase involved in activation of vitamin D precursors. Catalyzes hydroxylation at C-25 of both forms of vitamin D, vitamin D(2) and D(3) (calciol) (PubMed:12867411, PubMed:15465040, PubMed:18511070). Can metabolize vitamin D analogs/prodrugs 1alpha-hydroxyvitamin D(2) (doxercalciferol) and 1alpha-hydroxyvitamin D(3) (alfacalcidol) forming 25-hydroxy derivatives (PubMed:15465040, PubMed:18511070). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:12867411, PubMed:15465040, PubMed:18511070).
May mediate the control of various cellular processes by insulin.
A mutation in PYROXD1 is the cause of autosomal recessive limb-girdle muscular dystrophy. The affected individual with a homozygous recessive PYROXD1 mutation showed progressive muscle weakness with an onset at the age of 9 years. Initial symptoms included excessive falling while running, with slowly progressive weakness. Difficulty navigating stairs by the age if 18, and loss of ambulation at the age of 37 years. Neurological examination showed proximal symmetrical muscle weakness and wasting, along with calf muscle pseudohypertrophy.
Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family. PYROXD1 subfamily.
Probable FAD-dependent oxidoreductase; involved in the cellular oxidative stress response (PubMed:27745833). Required for normal sarcomere structure and muscle fiber integrity (By similarity).
Belongs to the mitochondrion-specific ribosomal protein mS31 family.
Expressed in all cardiac subcompartments and in the brain, with highest levels in the atrioventricular node and brain.
G proteins are composed of 3 units, alpha, beta and gamma. In this context, interacts with GNAI2 and GNG2 (PubMed:28219978). Interacts with ARHGEF18 and RASD2. Interacts with ATXN10. Interacts with SCN8A (PubMed:26900580).
Expressed in bone marrow and thymic cells. Also expressed one of two Wilms tumors tested.
Major connective tissue mitoattractant secreted by vascular endothelial cells. Promotes proliferation and differentiation of chondrocytes. Mediates heparin- and divalent cation-dependent cell adhesion in many cell types including fibroblasts, myofibroblasts, endothelial and epithelial cells. Enhances fibroblast growth factor-induced DNA synthesis.
Monomer (PubMed:1654338). Interacts with TSKU (PubMed:30232710).
Has low, barely detectable phosphoribosyltransferase activity (in vitro). Binds GMP, IMP and alpha-D-5-phosphoribosyl 1-pyrophosphate (PRPP). Is not expected to contribute to purine metabolism or GMP salvage.
Lacks the conserved active site Asp and has no significant phosphoribosyltransferase activity.
ABHD11 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region.
Essential for spermiogenesis and fertilization (PubMed:36321563). May be required for manchette assembly in elongating spermatids (By similarity).
May play a role in maintenance and/or transport of vesicles.
Required for normal spermatogenesis (PubMed:1770140, PubMed:30032984, PubMed:30298696). It functions as a scaffold protein that attaches the sperm head-tail connecting piece to the nuclear envelope, thus maintaining sperm head and tail integrity (PubMed:30032984). May also be involved in the general organization of cellular cytoskeleton (By similarity).
Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. May enhance HIF1A function by sequestering HIF1AN away from HIF1A. Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury. Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO).
Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with DNER, DTX1, DTX2 and RBPJ/RBPSUH. Also interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH1 (PubMed:11101851, PubMed:12370315). The NOTCH1 intracellular domain interacts with SNW1; the interaction involves multimerized NOTCH1 NICD and is implicated in a formation of an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ (PubMed:10713164). The activated membrane-bound form interacts with AAK1 which promotes NOTCH1 stabilization. Forms a trimeric complex with FBXW7 and SGK1. Interacts with HIF1AN. HIF1AN negatively regulates the function of notch intracellular domain (NICD), accelerating myogenic differentiation (PubMed:17573339). Interacts (via NICD) with SNAI1 (via zinc fingers); the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts (via NICD) with MDM2A. Interacts (via NICD) with BCL6; the interaction decreases MAML1 recruitment by NOTCH1 NICD on target genes DNA and inhibits NOTCH1 transcractivation activity. Interacts with THBS4 (By similarity). Interacts (via the EGF-like repeat region) with CCN3 (via CTCK domain) (PubMed:12050162). Interacts (via EGF-like domains) with DLL4 (via N-terminal DSL and MNNL domains) (By similarity). Interacts with ZMIZ1. Interacts (via NICD domain) with MEGF10 (via the cytoplasmic domain). Interacts with DLL1 and JAG1 (By similarity). Interacts (via NICD domain) with PRAG1 (By similarity). Forms a complex with PRAG1, N1ICD and MAML1, in a MAML1-dependent manner (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (PubMed:30598546). Interacts with ZFP64 (By similarity).
Hydroxylated at Asn-1955 by HIF1AN. Hydroxylated at Asn-2022 by HIF1AN (By similarity). Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD (By similarity).
In fetal tissues most abundant in spleen, brain stem and lung. Also present in most adult tissues where it is found mainly in lymphoid tissues.
Interaction with PSEN1 causes partial unwinding of the transmembrane helix, facilitating access to the scissile peptide bond.
O-glycosylated on the EGF-like domains (PubMed:24226769). O-glucosylated at Ser-435 by KDELC1 and KDELC2 (PubMed:30127001). Contains both O-linked fucose and O-linked glucose in the EGF-like domains 11, 12 and 13, which are interacting with the residues on DLL4 (By similarity). O-linked glycosylation by GALNT11 is involved in determination of left/right symmetry: glycosylation promotes activation of NOTCH1, possibly by promoting cleavage by ADAM17, modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO) (PubMed:24226769). MFNG-, RFNG- and LFNG-mediated modification of O-fucose residues at specific EGF-like domains results in inhibition of its activation by JAG1 and enhancement of its activation by DLL1 via an increased binding to DLL1 (By similarity).
Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form (By similarity). Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by ADAM17 to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (PubMed:24226769). Following endocytosis, this fragment is then cleaved by one of the catalytic subunits of gamma-secretase (PSEN1 or PSEN2), to release a Notch-derived peptide containing the intracellular domain (NICD) from the membrane (PubMed:30598546).
Ubiquitinated. Undergoes 'Lys-29'-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1 (PubMed:18628966, PubMed:23886940). Monoubiquitination at Lys-1759 is required for activation by gamma-secretase cleavage, it promotes interaction with AAK1, which stabilizes it. Deubiquitination by EIF3F is necessary for nuclear import of activated Notch (PubMed:24226769).
Interacts with PLCG1 and GRB2; the association is increased with prolonged stimulation of the TCR and may facilitate the assembly of the LAT signalosome. Interacts with ITPR1. Also interacts with ITPR3 (By similarity). Interacts with HSPA9.
May be phosphorylated in response to store-operated Ca(+2) entry.
Required for the development and maturation of T-cells, its function being essential for the late stages of thymocyte development (By similarity). Plays a role in T-cell antigen receptor (TCR)-mediated activation of the ERK and NFAT signaling pathways, possibly by serving as a scaffolding protein that promotes the assembly of the LAT signalosome in thymocytes. May play a role in the regulation of inositol 1,4,5-trisphosphate receptor-mediated Ca(2+) release and mitochondrial Ca(2+) uptake via the mitochondria-associated endoplasmic reticulum membrane (MAM) compartment.
Broadly expressed, with highest levels in placenta, lung, testis and ovary. Up-regulated in tumor tissues.
Dephosphorylates 26S nuclear proteasomes, thereby decreasing their proteolytic activity (PubMed:21949367, PubMed:28539385). Recruited to the 19S regulatory particle of the 26S proteasome through its interaction with 19S component PSMD2/RPN1 (PubMed:28539385). Once recruited, dephosphorylates 19S component PSMC2/RPT1 which impairs PSMC2 ATPase activity and disrupts 26S proteasome assembly (PubMed:28539385). Has also been reported to stimulate the proteolytic activity of the 26S proteasome (PubMed:32071216).
Interacts (via ubiquitin-like domain) with PSMD2/RPN1 (via C-terminus) which is a 19S regulatory particle subunit of the 26S proteasome.
The Ubiquitin-like domain mediates interaction with proteasomes.
Isoform 2 (via its cytoplasmic part) interacts with EZR.
Isoform 2 is down-regulated in nasopharyngeal carcinoma cells.
May function as a regulator of the EGFR pathway. Probable tumor suppressor which may function in cell growth, proliferation and adhesion.
Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation.
Testis specific. Also expressed in several cancers.
A soluble form (sIL1R1) is probably produced by proteolytic cleavage at the cell surface (shedding).
Expressed in T-helper cell subsets. Preferentially expressed in T-helper 1 (Th1) cells.
Rapidly phosphorylated on Tyr-496 in response to IL-1, which creates a SH2 binding site for the PI 3-kinase regulatory subunit PIK3R1.
Receptor for IL1A, IL1B and IL1RN (PubMed:2950091). After binding to interleukin-1 associates with the coreceptor IL1RAP to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B, MAPK and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. Binds ligands with comparable affinity and binding of antagonist IL1RN prevents association with IL1RAP to form a signaling complex. Involved in IL1B-mediated costimulation of IFNG production from T-helper 1 (Th1) cells (PubMed:10653850).
The interleukin-1 receptor complex is a heterodimer of IL1R1 and IL1RAP. Interacts with PIK3R1. Interacts with IL1A (PubMed:2950091).
Component of the DRTF1/E2F transcription factor complex. Binds cooperatively with TFDP1/Dp-1 to E2F sites. The E2F4/TFDP1 dimer interacts preferentially with pocket protein RBL1, which inhibits the E2F transactivation domain. Lower affinity interaction has been found with retinoblastoma protein RB1. Interacts with TRRAP, which probably mediates its interaction with histone acetyltransferase complexes, leading to transcription activation. Interacts with HCFC1. Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2. The complex exists in quiescent cells where it represses cell cycle-dependent genes. It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2. Interacts with PML (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5). Interacts with CEBPA (when phosphorylated) (PubMed:15107404).
Found in all tissue examined including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Present in the growth-arrested state, its abundance does not change significantly as cells move into and through the cell cycle.
The poly-Ser region of E2F4 is polymorphic and the number of Ser varies in the population (from 8 to 17). The variation might be associated with tumorigenesis.
Transcription activator that binds DNA cooperatively with DP proteins through the E2 recognition site, 5'-TTTC[CG]CGC-3' found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication. The DRTF1/E2F complex functions in the control of cell-cycle progression from G1 to S phase. E2F4 binds with high affinity to RBL1 and RBL2. In some instances can also bind RB1. Specifically required for multiciliate cell differentiation: together with MCIDAS and E2F5, binds and activate genes required for centriole biogenesis.
ADP-ribosylated by PARP1 or PARP2 on Ser-7 (H2BS6ADPr) in response to DNA damage (PubMed:34874266). H2BS6ADPr promotes recruitment of CHD1L (PubMed:34874266). Poly ADP-ribosylation on Glu-36 (H2BE35ADPr) by PARP1 regulates adipogenesis: it inhibits phosphorylation at Ser-37 (H2BS36ph), thereby blocking expression of pro-adipogenetic genes (By similarity).
The mouse orthologous protein seems not to exist.
Metal-dependent single-stranded DNA (ssDNA) exonuclease involved in mitochondrial genome maintenance. Has preference for 5'-3' exonuclease activity but is also capable of endoduclease activity on linear substrates. Necessary for maintenance of proper 7S DNA levels. Probably involved in mitochondrial DNA (mtDNA) repair, possibly via the processing of displaced DNA containing Okazaki fragments during RNA-primed DNA synthesis on the lagging strand or via processing of DNA flaps during long-patch base excision repair. Specifically binds 5-hydroxymethylcytosine (5hmC)-containing DNA in stem cells.
3 different light chains, LC1, LC2 and LC3, can associate with MAP1A and MAP1B proteins (By similarity). Interacts with TP53INP1 and TP53INP2 (PubMed:22470510). Interacts with CALCOCO2 (PubMed:23022382). Interacts with TECPR2 (PubMed:20562859). Interacts with TBC1D5 (PubMed:22354992). Found in a complex with UBQLN1 and UBQLN2 (PubMed:20529957). Interacts with UBQLN4 (via STI1 1 and 2 domains) (PubMed:23459205). Interacts with UBQLN1 in the presence of UBQLN4 (PubMed:23459205). Interacts with TRIM5 (PubMed:25127057). Interacts with ATG13 (PubMed:24290141). Interacts with MEFV and TRIM21 (PubMed:26347139). Interacts with WDR81; recruits MAP1LC3C to ubiquitinated protein aggregates in the aggrephagy process (PubMed:28404643). Interacts with MOAP1 (via LIR motif) (PubMed:33783314). Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3 (PubMed:34338405). Interacts with TAX1BP1 (PubMed:26451915). Interacts with IRGM (PubMed:29420192).
Most abundant in placenta, lung and ovary.
Phosphorylation at Ser-96 and Ser-98 by TBK1 prevents interaction with ATG4 (ATG4A, ATG4B, ATG4C or ATG4D) (PubMed:31709703). Phosphorylation by TBK1 on autophagosomes prevents their delipidation by ATG4 and premature removal from nascent autophagosomes (PubMed:31709703).
The precursor molecule is cleaved by ATG4 (ATG4A, ATG4B, ATG4C or ATG4D) to expose the glycine at the C-terminus and form the cytosolic form, LC3-I (PubMed:15187094, PubMed:20818167, PubMed:30661429, PubMed:31709703). The processed form is then activated by APG7L/ATG7, transferred to ATG3 and conjugated to phosphatidylethanolamine (PE) phospholipid to form the membrane-bound form, LC3-II (PubMed:15187094). During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid (PubMed:33909989). ATG4 proteins also mediate the delipidation of PE-conjugated forms (PubMed:33909989, PubMed:31709703). In addition, ATG4B and ATG4D mediate delipidation of ATG8 proteins conjugated to PS during non-canonical autophagy (PubMed:33909989).
Ubiquitin-like modifier that plays a crucial role in antibacterial autophagy (xenophagy) through the selective binding of CALCOCO2 (PubMed:23022382). Recruits all ATG8 family members to infecting bacteria such as S.typhimurium (PubMed:23022382). May also play a role in aggrephagy, the macroautophagic degradation of ubiquitinated and aggregated proteins (PubMed:28404643).
Functions as a GTPase-activating protein for the small GTPases RHOA, RHOB, RHOC and CDC42, terminating their downstream signaling. This induces morphological changes and detachment through cytoskeletal reorganization, playing a critical role in biological processes such as cell migration and proliferation. Also functions in vivo as an activator of the phospholipase PLCD1. Active DLC1 increases cell migration velocity but reduces directionality. Required for growth factor-induced epithelial cell migration; in resting cells, interacts with TNS3 while PTEN interacts with the p85 regulatory subunit of the PI3K kinase complex but growth factor stimulation induces phosphorylation of TNS3 and PTEN, causing them to change their binding preference so that PTEN interacts with DLC1 and TNS3 interacts with p85 (PubMed:26166433). The PTEN-DLC1 complex translocates to the posterior of migrating cells to activate RHOA while the TNS3-p85 complex translocates to the leading edge of migrating cells to promote RAC1 activation (PubMed:26166433).
Highest level of expression in the spleen, with rather lower levels in prostate, testis, ovary, small intestine and colon, but none in the thymus.
Interacts with EF1A1, facilitates EF1A1 distribution to the membrane periphery and ruffles upon growth factor stimulation and suppresses cell migration (PubMed:19158340). Interacts with tensin TNS1 (via N-terminus); the interaction is decreased by phosphorylation of TNS1 (PubMed:19826001, PubMed:20798394, PubMed:26427649). Interacts with TNS3 and PTEN; in resting cells, interacts with TNS3 (via C2 tensin-type domain) but, following growth factor stimulation, TNS3 and PTEN are phosphorylated which leads to weakened interaction with TNS3 and enhanced interaction with PTEN (PubMed:26166433). Interacts (via C-terminus) with tensin TNS4 (via SH2 domain); the interaction is independent of tyrosine phosphorylation of DLC1 (PubMed:17190795).
Produced by alternative promoter usage. ubiquitously expressed, significantly down-regulated in multiple carcinoma cell lines.
The SAM domain mediates interaction with EF1A1, and functions as an autoinhibitory regulator of RhoGAP Activity.
The polybasic cluster is required for activation and mediates binding to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P(2)) containing membranes.
Ubiquitous. Highly expressed in fetal brain and liver, poorly expressed in salivary gland, heart, skin and ovary. Expressed in colorectal carcinomas and ovarian cancers. Overexpressed in colorectal carcinomas as compared to normal colonic mucosa.
Up-regulated by estrogens, androgens and glucocorticoids.
Expressed specifically in kidney (PubMed:11273702). Highly expressed in immature dendritic cells, expression rapidly downregulates after maturation. Also expressed in macrophages (PubMed:18820681).
G protein-coupled receptor for succinate able to mediate signaling through Gq/GNAQ or Gi/GNAI second messengers depending on the cell type and the processes regulated (By similarity) (PubMed:15141213, PubMed:34133934, PubMed:23770096). Succinate-SUCNR1 signaling serves as a link between metabolic stress, inflammation and energy homeostasis (PubMed:18820681, PubMed:34133934). In macrophages, plays a range of immune-regulatory roles. During inflammation, succinate-SUCNR1 signaling may act as an anti-inflammatory mediator or boost inflammation depending on the inflammatory status of cells (By similarity). Hyperpolarizes M2 macrophages versus M1 phenotype through Gq signaling by regulating the transcription of genes involoved in immune function (PubMed:34133934). In activated M1 macrophages, plays a pro-inflammatory role in response to LPS (By similarity). Expressed in dendritic cells, where it is involved in the sensing of immunological danger and enhances immunity. Mediates succinate triggered intracelleular calcium mobilization, induces migratory responses and acts in synergy with Toll-like receptor ligands for the production of proinflammatory cytokines as well as an enhancement of antigen-specific activation of helper T cells (PubMed:18820681). In the small intestine, mediates the activation of tuft cells by dietary succinate and triggers type 2 immunity (By similarity). In adipocytes, plays an important role in the control of energy metabolism. In response to succinate, controls leptin expression in an AMPK-JNK-CEBPA-dependent as well as circadian clock-regulated manner (By similarity). In muscle tissue, is expressed in non-muscle cells and coordinates muscle remodeling in response to the succinate produced during exercise training in a paracrine manner (By similarity). In retina, acts as a mediator of vessel growth during retinal development. In response to succinate, regulates the production of angiogenic factors, including VEGF, by retinal ganglion neurons (By similarity).
Expressed in the tubular cells of the kidney. Most abundant protein in normal urine (at protein level). Synthesized exclusively in the kidney. Expressed exclusively by epithelial cells of the thick ascending limb of Henle's loop (TALH) and of distal convoluted tubule lumen.
Functions in biogenesis and organization of the apical membrane of epithelial cells of the thick ascending limb of Henle's loop (TALH), where it promotes formation of complex filamentous gel-like structure that may play a role in the water barrier permeability (Probable). May serve as a receptor for binding and endocytosis of cytokines (IL-1, IL-2) and TNF (PubMed:3498215). Facilitates neutrophil migration across renal epithelia (PubMed:20798515).
Homodimer that then polymerizes into long filaments (PubMed:19005207, PubMed:26673890, PubMed:26811476, PubMed:32815518, PubMed:33196145). The filaments can additionally assemble laterally to form a sheet (PubMed:33196145). The filaments consist of a zigzag-shaped backbone with laterally protruding arms which interact with bacterial adhesin fimH (PubMed:32616672, PubMed:33196145). Two fimH molecules can bind to a single UMOD monomer (PubMed:32616672).
In the urine, may contribute to colloid osmotic pressure, retards passage of positively charged electrolytes, and inhibits formation of liquid containing supersaturated salts and subsequent formation of salt crystals (By similarity). Protects against urinary tract infections by binding to type 1 fimbriated E.coli (PubMed:11134021, PubMed:32616672). Binds to bacterial adhesin fimH which mediates the stable formation of bacterial aggregates, prevents the binding of E.coli to uroplakins UPK1A and UPK1B which act as urothelial receptors for type I fimbriae, and allows for pathogen clearance through micturation (PubMed:11134021, PubMed:32616672). Also promotes aggregation of other bacteria including K.pneumoniae, P.aeruginosa and S.mitis and so may also protect against other uropathogens (PubMed:32616672).
N-glycosylated (PubMed:19005207, PubMed:26673890, PubMed:26811476, PubMed:32815518, PubMed:33196145). N-glycan heterogeneity at Asn-232: Hex7HexNAc6 (major) and dHex1Hex7HexNAc6 (minor); at Asn-322: dHex1Hex6HexNAc5 (minor), dHex1Hex7HexNAc6 (major) and dHex1Hex8HexNAc7 (minor); at Asn-396: Hex6HexNAc5 (major), dHex1Hex6HexNAc5 (minor) and Hex7HexNAc6 (minor) (PubMed:22171320). Glycosylated Asn-232 interacts with E.coli adhesin fimH (PubMed:32616672). Other complex glycosylation sites may serve as binding sites for proteins from other bacteria inclduding K.pneumoniae, P.aeruginosa and S.mitis (PubMed:32616672).
Proteolytically cleaved at a conserved C-terminal proteolytic cleavage site to generate the secreted form found in urine (PubMed:18375198, PubMed:19005207). This cleavage is catalyzed by HPN (PubMed:26673890).
The ZP domain mediates polymerization, leading to the formation of long filaments. The core of the filament consists of interlocked ZP domains which assemble into a helical structure. Each ZP domain consists of an N-terminal (ZP-N) and C-terminal (ZP-C) region connected by a flexible linker; the linker allows the ZP domain to wrap around the ZP-C subdomain of the preceding subunit. The heavily glycosylated N-terminal part of the protein (containing several EGF-like domains) forms branches which protrude from the core and are involved in pathogen capture.
A chromosomal aberrations involving GRIN2B has been found in patients with intellectual disability. Translocations t(9;12)(p23;p13.1) and t(10;12)(q21.1;p13.1) with a common breakpoint in 12p13.1.
A hydrophobic region that gives rise to the prediction of a transmembrane span does not cross the membrane, but is part of a discontinuously helical region that dips into the membrane and is probably part of the pore and of the selectivity filter.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. NR2B/GRIN2B subfamily.
Component of NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:8768735, PubMed:26919761, PubMed:26875626, PubMed:28126851). Sensitivity to glutamate and channel kinetics depend on the subunit composition (PubMed:8768735, PubMed:26875626). In concert with DAPK1 at extrasynaptic sites, acts as a central mediator for stroke damage. Its phosphorylation at Ser-1303 by DAPK1 enhances synaptic NMDA receptor channel activity inducing injurious Ca2+ influx through them, resulting in an irreversible neuronal death. Contributes to neural pattern formation in the developing brain. Plays a role in long-term depression (LTD) of hippocampus membrane currents and in synaptic plasticity (By similarity).
Heterotetramer. Forms heterotetrameric channels composed of two zeta subunits (GRIN1), and two epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) (in vitro) (PubMed:8768735, PubMed:26919761, PubMed:26875626, PubMed:28126851, PubMed:26912815). Can also form heterotetrameric channels that contain at least one zeta subunit (GRIN1), at least one epsilon subunit, plus GRIN3A or GRIN3B (By similarity). In vivo, the subunit composition may depend on the expression levels of the different subunits (Probable). Found in a complex with GRIN1 and GRIN3B. Found in a complex with GRIN1, GRIN3A and PPP2CB. Interacts with PDZ domains of PATJ, DLG3 and DLG4. Interacts with HIP1 and NETO1 (By similarity). Interacts with MAGI3 (PubMed:10748157). Interacts with DAPK1 (By similarity). Found in a complex with GRIN1 and PRR7 (PubMed:27458189). Interacts with PRR7 (PubMed:27458189). Interacts with CAMK2A (PubMed:28130356). Interacts with ARC; preventing ARC oligomerization (By similarity). Interacts with TMEM25 (By similarity).
Phosphorylated on tyrosine residues (By similarity). Phosphorylation at Ser-1303 by DAPK1 enhances synaptic NMDA receptor channel activity (By similarity).
Primarily found in the fronto-parieto-temporal cortex and hippocampus pyramidal cells, lower expression in the basal ganglia.
Catalyzes the conversion of isovaleryl-CoA/3-methylbutanoyl-CoA to 3-methylbut-2-enoyl-CoA as an intermediate step in the leucine (Leu) catabolic pathway (PubMed:7640268). To a lesser extent, is also able to catalyze the oxidation of other saturated short-chain acyl-CoA thioesters as pentanoyl-CoA, hexenoyl-CoA and butenoyl-CoA (PubMed:7640268).
Expressed in adult pancreas, small intestine, stomach, spinal cord and testis. Less pronounced expression in prostate, colon mucosal lining, and ovary.
Stimulates the release of tumor necrosis factor alpha and IL-1-beta from the monocytic cell line THP-1.
Component of a SNARE complex consisting of STX5, YKT6, GOSR2 and BET1L.
Vesicle SNARE required for targeting and fusion of retrograde transport vesicles with the Golgi complex. Required for the integrity of the Golgi complex (By similarity).
The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space. However, during the transit of TIMM9 from cytoplasm into mitochondrion, the Cys residues probably coordinate zinc, thereby preventing folding and allowing its transfer across mitochondrial outer membrane (Probable).
Low level of expression; detected in uterus, testis, skeletal muscle and stomach.
May affect the movement of lipids in the cytoplasm or allow the binding of lipids to organelles.
(Microbial infection) Activated by phosphorylation by M.tuberculosis EsxA in T-cells leading to inhibition of IFN-gamma production; phosphorylation is apparent within 15 minutes and is inhibited by kinase-specific inhibitors SB203580 and siRNA (PubMed:21586573).
Acetylated at Lys-53 and Lys-152 by KAT2B and EP300. Acetylation at Lys-53 increases the affinity for ATP and enhances kinase activity. Lys-53 and Lys-152 are deacetylated by HDAC3.
Activated by cell stresses such as DNA damage, heat shock, osmotic shock, anisomycin and sodium arsenite, as well as pro-inflammatory stimuli such as bacterial lipopolysaccharide (LPS) and interleukin-1. Activation occurs through dual phosphorylation of Thr-180 and Tyr-182 by either of two dual specificity kinases, MAP2K3/MKK3 or MAP2K6/MKK6, and potentially also MAP2K4/MKK4, as well as by TAB1-mediated autophosphorylation. MAPK14 phosphorylated on both Thr-180 and Tyr-182 is 10-20-fold more active than MAPK14 phosphorylated only on Thr-180, whereas MAPK14 phosphorylated on Tyr-182 alone is inactive. whereas Thr-180 is necessary for catalysis, Tyr-182 may be required for auto-activation and substrate recognition. Phosphorylated at Tyr-323 by ZAP70 in an alternative activation pathway in response to TCR signaling in T-cells. This alternative pathway is inhibited by GADD45A. Inhibited by dual specificity phosphatases, such as DUSP1, DUSP10, and DUSP16. Specifically inhibited by the binding of pyridinyl-imidazole compounds, which are cytokine-suppressive anti-inflammatory drugs (CSAID). Isoform Mxi2 is 100-fold less sensitive to these agents than the other isoforms and is not inhibited by DUSP1. Isoform Exip is not activated by MAP2K6. SB203580 is an inhibitor of MAPK14.
Brain, heart, placenta, pancreas and skeletal muscle. Expressed to a lesser extent in lung, liver and kidney.
Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK (PubMed:21224381). Binds to a kinase interaction motif within the protein tyrosine phosphatase, PTPRR (By similarity). This interaction retains MAPK14 in the cytoplasm and prevents nuclear accumulation (By similarity). Interacts with SPAG9 and GADD45A (By similarity). Interacts with CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H and TAB1. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B. Interacts with PPM1D. Interacts with CDK5RAP3; recruits PPM1D to MAPK14 and may regulate its dephosphorylation (PubMed:21283629). Interacts with DUSP2; this interaction does not lead to catalytic activation of DUSP2 and dephosphrylation of MAPK14 (By similarity).
Dually phosphorylated on Thr-180 and Tyr-182 by the MAP2Ks MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. Dual phosphorylation can also be mediated by TAB1-mediated autophosphorylation. TCR engagement in T-cells also leads to Tyr-323 phosphorylation by ZAP70. Dephosphorylated and inactivated by DUPS1, DUSP10 and DUSP16. PPM1D also mediates dephosphorylation and inactivation of MAPK14 (PubMed:21283629).
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as pro-inflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1 (PubMed:9687510, PubMed:9792677). RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery (PubMed:9687510, PubMed:9792677). On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2 (PubMed:11154262). MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53 (PubMed:10747897). In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3 (PubMed:17003045). MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9 (PubMed:19893488). Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors (PubMed:16932740). Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17 (PubMed:20188673). Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A (PubMed:9430721, PubMed:9858528, PubMed:10330143). The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation (PubMed:11333986). Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation (PubMed:20932473). The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression (PubMed:10943842). Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113' (PubMed:15905572). Phosphorylates NLRP1 downstream of MAP3K20/ZAK in response to UV-B irradiation and ribosome collisions, promoting activation of the NLRP1 inflammasome and pyroptosis (PubMed:35857590).
Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway.
In contrast to its official gene name, it is not a regulatory subunit of protein phosphatase 1. This name was given due to its similarity with a protein that binds to protein phosphatase 1.
Interacts with P53/TP53; the interaction promotes pro-apoptotic activity.
Reduced expression in breast carcinomas expressing a wild-type TP53 protein.
Regulator that plays a central role in regulation of apoptosis via its interaction with p53/TP53 (PubMed:11684014, PubMed:12524540). Regulates TP53 by enhancing the DNA binding and transactivation function of TP53 on the promoters of proapoptotic genes in vivo.
The ankyrin repeats and the SH3 domain are required for specific interactions with TP53.
Component of the SKI complex which consists of SKIC2, SKIC3 and SKIC8 (PubMed:16024656, PubMed:32006463, PubMed:35120588). Interacts with HBS1L isoform 2 (PubMed:28204585).
Helicase component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways (PubMed:16024656, PubMed:32006463, PubMed:35120588). The SKI complex catalyzes mRNA extraction from 80S ribosomal complexes in the 3'-5' direction and channels mRNA to the cytosolic exosome for degradation (PubMed:32006463, PubMed:35120588). SKI-mediated extraction of mRNA from stalled ribosomes allow binding of the Pelota-HBS1L complex and subsequent ribosome disassembly by ABCE1 for ribosome recycling (PubMed:32006463). In the nucleus, the SKI complex associates with transcriptionally active genes in a manner dependent on PAF1 complex (PAF1C) (PubMed:16024656).
Involved in neutrophil activation. In vitro, ENA-78(8-78) and ENA-78(9-78) show a threefold higher chemotactic activity for neutrophil granulocytes.
Monomer (PubMed:24695525). Homodimer (PubMed:24695525).
N-terminal processed forms ENA-78(8-78) and ENA-78(9-78) are produced by proteolytic cleavage after secretion from peripheral blood monocytes.
Interacts (GTP-bound) with BICD1 (via C-terminus); the interaction is direct (PubMed:17707369). Interacts (GDP-bound) with DYNLRB1 (PubMed:18044744). Interacts (GTP-bound) with APBA1/MINT1 isoform 2, also called Mint1_826, but not with isoform 1 (PubMed:23737971). Interacts (GTP-bound) with VPS13B isoform 2 (PubMed:25492866).
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between active GTP-bound and inactive GDP-bound states. In their active state, drive transport of vesicular carriers from donor organelles to acceptor organelles to regulate the membrane traffic that maintains organelle identity and morphology (Probable). Recruits VPS13B to the Golgi membrane (PubMed:25492866). Regulates the compacted morphology of the Golgi (PubMed:26209634). Seems to have a role in retrograde membrane traffic at the level of the Golgi complex. May function in retrograde transport in neuronal cells (PubMed:17707369). Plays a role in neuron projection development (PubMed:25492866).
Catalyzes the transfer of phosphatidylinositol and phosphatidylcholine between membranes (in vitro) (By similarity). Binds calcium ions.
Detected in brain and spleen, and at low levels in ovary.
Interacts with PTK2B via its C-terminus.
Broad specificity aminopeptidase which preferentially hydrolyzes an N-terminal methionine, citrulline or glutamine.
Inhibited by calcium but not affected by chloride ions. Inhibited by amastatin and to a lower extent by bestatin. Weakly inhibited by puromycin.
Ubiquitously expressed. Expressed at relatively higher levels in heart and skeletal muscle.
Binds DNA. Can associate with the proximal promoter regions of PAX6 and SP4, and their known targets including ARR3, RHO, OPN1MW2 and OPN1SW.
In the retina, expressed in the outer and inner nuclear layers, and the ganglion cell layer.
Transcriptional regulator that plays a role in retinal development and maintenance.
Belongs to the DEAD box helicase family. DDX49/DBP8 subfamily.
Functions as a substrate recognition component for CUL4-DDB1 E3 ubiquitin-protein ligase complex, which mediates ubiquitination and proteasome-dependent degradation of nuclear proteins.
Interacts with WIP and actin (PubMed:19121306). Interacts with TBC1D23 (PubMed:29084197).
May be involved in the cytoskeletal organization of neuronal growth cones. Seems to be inactive as a PPIase (By similarity). Involved in the transport of early endosomes at the level of transition between microfilament-based and microtubule-based movement.
The PPIase FKBP-type domain seems to be inactive both for FK506-binding and enzymatic activity.
The central coiled-coil region is responsible for association with early endosomes.
Interacts with PRMT5; the interaction is direct (PubMed:33376131). Interacts with WDR77 (PubMed:33376131).
Promotes histone methylation by localizing the arginine methyltransferase PRMT5 to chromatin.
(Microbial infection) In case of HIV-1 infection, interaction with the viral Tat protein leads to KAT5 polyubiquitination and targets it to degradation.
Acyltransferase and acetyltransferase activities are activated by phosphorylation and autoacetylation (PubMed:20100829, PubMed:30704899). Autoacetylation activates the histone acetyltransferase activity (PubMed:20100829, PubMed:25865756, PubMed:30704899).
Autoacetylated (PubMed:20100829, PubMed:24835996, PubMed:25301942, PubMed:26291311, PubMed:33938178). Autoacetylation is required for histone acetyltransferase activity (PubMed:20100829, PubMed:25865756). Autoacetylation at Lys-327 is facilitated by interaction with EP300/p300: it prevents ubiquitination and subsequent degradation by the proteasome and promotes acetylation of target proteins (PubMed:24835996). Deacetylated by HDAC3 and SIRT1 (PubMed:20100829, PubMed:25301942). Deacetylation by HDAC3 promotes its ubiquitination and cytoplasmic localization (PubMed:25301942).
Catalytic subunit of the NuA4 histone acetyltransferase complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H2A and H4 (PubMed:12776177, PubMed:15042092, PubMed:15121871, PubMed:15310756, PubMed:14966270, PubMed:16387653, PubMed:19909775, PubMed:25865756, PubMed:27153538, PubMed:29335245, PubMed:29174981, PubMed:33076429, PubMed:32822602). Histone acetylation alters nucleosome-DNA interactions and promotes interaction of the modified histones with other proteins which positively regulate transcription (PubMed:12776177, PubMed:15042092, PubMed:15121871, PubMed:15310756, PubMed:14966270). The NuA4 histone acetyltransferase complex is required for the activation of transcriptional programs associated with proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair (PubMed:17709392, PubMed:19783983, PubMed:32832608). The NuA4 complex plays a direct role in repair of DNA double-strand breaks (DSBs) by promoting homologous recombination (HR): the complex inhibits TP53BP1 binding to chromatin via MBTD1, which recognizes and binds histone H4 trimethylated at 'Lys-20' (H4K20me), and KAT5 that catalyzes acetylation of 'Lys-15' of histone H2A (H2AK15ac), thereby blocking the ubiquitination mark required for TP53BP1 localization at DNA breaks (PubMed:27153538, PubMed:32832608). Also involved in DSB repair by mediating acetylation of 'Lys-5' of histone H2AX (H2AXK5ac), promoting NBN/NBS1 assembly at the sites of DNA damage (PubMed:17709392, PubMed:26438602). The NuA4 complex plays a key role in hematopoietic stem cell maintenance and is required to maintain acetylated H2A.Z/H2AZ1 at MYC target genes (By similarity). The NuA4 complex is also required for spermatid development by promoting acetylation of histones: histone hyperacetylation is required for histone replacement during the transition from round to elongating spermatids (By similarity). Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome (PubMed:24463511). Also acetylates non-histone proteins, such as BMAL1, ATM, AURKB, CHKA, CGAS, ERCC4/XPF, LPIN1, NDC80/HEC1, NR1D2, RAN, SOX4, FOXP3, ULK1 and RUBCNL/Pacer (PubMed:16141325, PubMed:17360565, PubMed:17996965, PubMed:24835996, PubMed:26829474, PubMed:29040603, PubMed:30409912, PubMed:30704899, PubMed:32034146, PubMed:32817552, PubMed:34077757). Directly acetylates and activates ATM (PubMed:16141325). Promotes nucleotide excision repair (NER) by mediating acetylation of ERCC4/XPF, thereby promoting formation of the ERCC4-ERCC1 complex (PubMed:32034146). Relieves NR1D2-mediated inhibition of APOC3 expression by acetylating NR1D2 (PubMed:17996965). Acts as a regulator of regulatory T-cells (Treg) by catalyzing FOXP3 acetylation, thereby promoting FOXP3 transcriptional repressor activity (PubMed:17360565, PubMed:24835996). Involved in skeletal myoblast differentiation by mediating acetylation of SOX4 (PubMed:26291311). Catalyzes acetylation of APBB1/FE65, increasing its transcription activator activity (PubMed:33938178). Promotes transcription elongation during the activation phase of the circadian cycle by catalyzing acetylation of BMAL1, promoting elongation of circadian transcripts (By similarity). Together with GSK3 (GSK3A or GSK3B), acts as a regulator of autophagy: phosphorylated at Ser-86 by GSK3 under starvation conditions, leading to activate acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Acts as a regulator of the cGAS-STING innate antiviral response by catalyzing acetylation the N-terminus of CGAS, thereby promoting CGAS DNA-binding and activation (PubMed:32817552). Also regulates lipid metabolism by mediating acetylation of CHKA or LPIN1 (PubMed:34077757). Promotes lipolysis of lipid droplets following glucose deprivation by mediating acetylation of isoform 1 of CHKA, thereby promoting monomerization of CHKA and its conversion into a tyrosine-protein kinase (PubMed:34077757). Acts as a regulator of fatty-acid-induced triacylglycerol synthesis by catalyzing acetylation of LPIN1, thereby promoting the synthesis of diacylglycerol (PubMed:29765047). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA) and 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), and is able to mediate protein crotonylation and 2-hydroxyisobutyrylation, respectively (PubMed:29192674, PubMed:34608293). Acts as a key regulator of chromosome segregation and kinetochore-microtubule attachment during mitosis by mediating acetylation or crotonylation of target proteins (PubMed:26829474, PubMed:29040603, PubMed:30409912, PubMed:34608293). Catalyzes acetylation of AURKB at kinetochores, increasing AURKB activity and promoting accurate chromosome segregation in mitosis (PubMed:26829474). Acetylates RAN during mitosis, promoting microtubule assembly at mitotic chromosomes (PubMed:29040603). Acetylates NDC80/HEC1 during mitosis, promoting robust kinetochore-microtubule attachment (PubMed:30409912). Catalyzes crotonylation of MAPRE1/EB1, thereby ensuring accurate spindle positioning in mitosis (PubMed:34608293).
Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 (PubMed:12963728, PubMed:10966108, PubMed:15196461, PubMed:14966270, PubMed:29174981). KAT5/TIP60, EPC1, and ING3 together constitute a minimal HAT complex termed Piccolo NuA4. The NuA4 complex interacts with MYC (PubMed:12776177). Interacts with ATM (PubMed:16141325). Interacts with JADE1 (PubMed:15502158). Interacts with PLA2G4A/CPLA2, EDNRA and HDAC7 (PubMed:11416127, PubMed:11262386, PubMed:12551922). Interacts with the cytoplasmic tail of APP and APBB1/FE65 (PubMed:33938178). Interacts with TRIM24 and TRIM68 (PubMed:18451177, PubMed:19909775). Forms a complex with SENP6 and UBE2I in response to UV irradiation. Identified in a complex with HINT1 (PubMed:16835243). Interacts with ATF2 and CUL3 (PubMed:18397884). Interacts with NR1D2 (via N-terminus) (PubMed:17996965). Component of a SWR1-like complex (PubMed:24463511). Interacts with FOXP3 (PubMed:17360565, PubMed:24835996). Interacts with ZBTB49 (PubMed:25245946). Interacts with SRF (By similarity). Interacts with ATF3; promoting autoacetylation and deubiquitination by USP7 (PubMed:25865756). Interacts with EP300/p300; interaction promotes KAT5 autoacetylation (PubMed:24835996). Interacts with PRKDC; interaction is impaired following KAT5 sumoylation (PubMed:32832608).
Phosphorylated on Ser-86 and Ser-90; enhanced during G2/M phase (PubMed:12468530, PubMed:26829474, PubMed:29335245). The phosphorylated form has a higher activity (PubMed:12468530, PubMed:29335245). Phosphorylation at Ser-90 by CDK1 or CDK9 is a prerequisite for phosphorylation at Ser-86 by GSK3 (PubMed:26829474, PubMed:30704899). Phosphorylation at Ser-86 by GSK3 (GSK3A or GSK3B) activates acetyltransferase and acyltransferase activities (PubMed:30704899). Phosphorylation at Ser-90 by CDK9 promotes KAT5 recruitment to chromatin (PubMed:29335245). Phosphorylation by VRK1 following DNA damage promotes KAT5 association with chromatin and histone acetyltransferase activity (PubMed:33076429).
Sumoylated by UBE2I at Lys-430 and Lys-451, leading to increase of its histone acetyltransferase activity in UV-induced DNA damage response, as well as its translocation to nuclear bodies (PubMed:17704809). Sumoylation with SUMO2 by PIAS4 at Lys-430 promotes repair of DNA double-strand breaks (DSBs) via homologous recombination (HR) (PubMed:32832608). Sumoylation by PIAS4 impairs interaction with PRKDC, inhibiting non-homologous end joining (NHEJ)-mediated repair of DSBs, thereby facilitating HR (PubMed:32832608). Desumoylated by SENP3 (PubMed:32832608).
The role of the Tudor-knot domain, also named chromo barrel or chromodomain, is unclear. Based on its similarity with some chromo domains, it was first reported to bind histone H3 trimethylated on 'Lys-4' and/or 'Lys-9' (H3K4me3 and/or H3K9me3, respectively) (PubMed:19783983, PubMed:25560918). However, another group was not able to see any binding to methylated histones (PubMed:29494751). The 3D structure of the domain suggests that the inability to bind histones is caused by occlusion of the putative peptide-binding site by a basic amino acid side chain within a unique beta hairpin (PubMed:29494751).
Ubiquitinated by MDM2, leading to its proteasome-dependent degradation (PubMed:11927554, PubMed:24835996). Ubiquitination is prevented by autoacetylation at Lys-327 (PubMed:24835996). Ubiquitinated following deacetylation by HDAC3, leading to cytoplasmic localization (PubMed:25301942). Deubiquitinated by USP7 following interaction with ATF3, promoting its stabilization (PubMed:25865756).
May be involved in meiosis or the maturation of germ cells.
Ubiquitous. Expressed at higher levels in testis and ovary.
(Microbial infection) Interacts with adenovirus E1B 19K protein; this interaction blocks BAX oligomerization (PubMed:11462023).
(Microbial infection) Interacts with enterovirus protein 2B; this interaction activates BAX-induced apoptosis.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein vMIA/UL37.
Expressed in a wide variety of tissues. Isoform Psi is found in glial tumors. Isoform Alpha is expressed in spleen, breast, ovary, testis, colon and brain, and at low levels in skin and lung. Isoform Sigma is expressed in spleen, breast, ovary, testis, lung, colon, brain and at low levels in skin. Isoform Alpha and isoform Sigma are expressed in pro-myelocytic leukemia, histiocytic lymphoma, Burkitt's lymphoma, T-cell lymphoma, lymphoblastic leukemia, breast adenocarcinoma, ovary adenocarcinoma, prostate carcinoma, prostate adenocarcinoma, lung carcinoma, epidermoid carcinoma, small cell lung carcinoma and colon adenocarcinoma cell lines.
Homodimer. Forms higher oligomers under stress conditions. Forms heterooligomers with BAK (PubMed:29531808). Interacts with BCL2L11. Interaction with BCL2L11 promotes BAX oligomerization and association with mitochondrial membranes, with subsequent release of cytochrome c. Forms heterodimers with BCL2, BCL2L1 isoform Bcl-X(L), BCL2L2, MCL1 and A1 (PubMed:25609812). Interacts with SH3GLB1. Interacts with humanin; forms fibers with humanin which results in BAX conformational changes and sequestering of BAX into the fibers, preventing BAX activation (PubMed:12732850, PubMed:31690630). Interacts with SFN and YWHAZ; the interaction occurs in the cytoplasm. Under stress conditions, JNK-mediated phosphorylation of SFN and YWHAZ, releases BAX to mitochondria. Interacts with RNF144B, which regulates the ubiquitin-dependent stability of BAX. Interacts with CLU under stress conditions that cause a conformation change leading to BAX oligomerization and association with mitochondria. Does not interact with CLU in unstressed cells. Interacts with FAIM2/LFG2. Interacts with RTL10/BOP. Interacts (via a C-terminal 33 residues) with NOL3 (via CARD domain); inhibits BAX activation and translocation and consequently cytochrome c release from mitochondria. Interacts with GIMAP3/IAN4 and GIMAP5/IAN5; this interaction is increased, when cells initiate apoptosis upon IL2 withdrawal (PubMed:16509771). Interacts with IRF3; the interaction is direct, increases upon Sendai virus infection and mediates the formation of the apoptosis complex TOMM70:HSP90AA1:IRF3:BAX (PubMed:25609812). Interacts with MOAP1, facilitating BAX-dependent mitochondrial outer membrane permeabilization and apoptosis (PubMed:11060313, PubMed:16199525). Interacts with BCL2L10/BCL-B (PubMed:23235460).
Interacts with BCL2A1 and BCL2L1 isoform Bcl-X(L).
Plays a role in the mitochondrial apoptotic process (PubMed:10772918, PubMed:16113678, PubMed:18948948, PubMed:21199865, PubMed:21458670, PubMed:25609812, PubMed:8358790, PubMed:8521816, PubMed:11060313, PubMed:16199525, PubMed:36361894). Under normal conditions, BAX is largely cytosolic via constant retrotranslocation from mitochondria to the cytosol mediated by BCL2L1/Bcl-xL, which avoids accumulation of toxic BAX levels at the mitochondrial outer membrane (MOM) (PubMed:21458670). Under stress conditions, undergoes a conformation change that causes translocation to the mitochondrion membrane, leading to the release of cytochrome c that then triggers apoptosis (PubMed:11060313, PubMed:16199525, PubMed:10772918, PubMed:16113678, PubMed:18948948, PubMed:21199865, PubMed:21458670, PubMed:25609812, PubMed:8358790, PubMed:8521816). Promotes activation of CASP3, and thereby apoptosis (PubMed:11060313, PubMed:16199525, PubMed:10772918, PubMed:16113678, PubMed:18948948, PubMed:21199865, PubMed:21458670, PubMed:25609812, PubMed:8358790, PubMed:8521816).
Ubiquitinated on Lys-128 and Lys-190. 'Lys-63'-linked polyubiquitin chains on Lys-128 are removed by USP12.
Hydrolyzes a wide range of dipeptides including the conversion of leukotriene D4 to leukotriene E4 (PubMed:2303490, PubMed:6334084, PubMed:31442408, PubMed:32325220). Hydrolyzes cystinyl-bis-glycine (cys-bis-gly) formed during glutathione degradation (PubMed:32325220). Possesses also beta lactamase activity and can hydrolyze the beta-lactam antibiotic imipenem (PubMed:6334084, PubMed:32325220).
Independently of its dipeptidase activity, acts as an adhesion receptor for neutrophil recruitment from bloodstream into inflamed lungs and liver.
Inhibited by L-penicillamine (PubMed:31442408). Beta-lactamase activity is inhibited by cilastatin (PubMed:6334084, PubMed:31442408).
It is uncertain whether Met-1 or Met-38 is the initiator. Orthologous sequences cannot be extended.
Activated by micromolar levels of Ca(2+).
Detected primarily in heart and at lower levels in brain (PubMed:1374913). Expressed in cardiac sarcolemma, brain, kidney, liver, pancreas, skeletal muscle, placenta and lung (PubMed:1476165).
Mediates the exchange of one Ca(2+) ion against three to four Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes (PubMed:1374913, PubMed:11241183, PubMed:1476165). Contributes to Ca(2+) transport during excitation-contraction coupling in muscle (PubMed:1374913, PubMed:11241183, PubMed:1476165). In a first phase, voltage-gated channels mediate the rapid increase of cytoplasmic Ca(2+) levels due to release of Ca(2+) stores from the endoplasmic reticulum (PubMed:1374913, PubMed:11241183, PubMed:1476165). SLC8A1 mediates the export of Ca(2+) from the cell during the next phase, so that cytoplasmic Ca(2+) levels rapidly return to baseline (PubMed:1374913, PubMed:11241183, PubMed:1476165). Required for normal embryonic heart development and the onset of heart contractions (By similarity).
Binds to the consensus sequence 5'-AGAGTG-3' and has transcriptional activator activity. Plays a role in apoptosis (By similarity).
Cholesterol-binding protein that acts as a regulator of mTORC1 signaling pathway (PubMed:36007018). Acts as a sensor of cholesterol to signal cholesterol sufficiency to mTORC1: in presence of cholesterol, binds cholesterol, leading to disrupt interaction between the GATOR1 and KICSTOR complexes and promote mTORC1 signaling (PubMed:36007018). Upon cholesterol starvation, GPR155/LYCHOS is unable to perturb the association between GATOR1 and KICSTOR, leading to mTORC1 signaling inhibition (PubMed:36007018).
Interacts with the GATOR1 complex; preventing interaction between GATOR1 and KICSTOR; interaction is disrupted upon cholesterol starvation.
May be a component of the FTS/Hook/FHIP complex (FHF complex), composed of AKTIP/FTS, FHIP1B, and one or more members of the Hook family of proteins HOOK1, HOOK2, and HOOK3. May interact directly with AKTIP/FTS.
Probable component of the FTS/Hook/FHIP complex (FHF complex) (PubMed:32073997). FHF complex promotes the distribution of AP-4 complex to the perinuclear area of the cell (PubMed:32073997).
A chromosomal aberration involving CCDC28A has been identified in acute leukemias. Translocation t(6;11)(q24.1;p15.5) with NUP98. The chimeric transcript is an in-frame fusion of NUP98 exon 13 to CCDC28A exon 2. Ectopic expression of NUP98-CCDC28A in mouse promotes the proliferative capacity and self-renewal potential of hematopoietic progenitors and rapidly induced fatal myeloproliferative neoplasms and defects in the differentiation of the erythro-megakaryocytic lineage.
It is uncertain whether Met-1 or Met-91 is the initiator. The first 90 residues are not conserved and orthologous sequences, including rat and mouse ones, contain a stop codon upstream of the conserved methionine.
Belongs to the pyridoxine kinase family.
Catalytic activity is inhibited competitively by 4-deoxypyridoxine, and is also inhibited by the benzodiazepine receptor ligands 1012S and ethyl-beta-carboline-3-carboxylate (PubMed:9099727). Inhibited by ginkgotoxin, theophylline, lamotrigine, enprofylline, theobromine, and caffeine (PubMed:22879864). Activity is increased in the presence of K(+)or Na(+) (PubMed:17766369).
Catalyzes the phosphorylation of the dietary vitamin B6 vitamers pyridoxal (PL), pyridoxine (PN) and pyridoxamine (PM) to form pyridoxal 5'-phosphate (PLP), pyridoxine 5'-phosphate (PNP) and pyridoxamine 5'-phosphate (PMP), respectively (PubMed:9099727, PubMed:10987144, PubMed:17766369, PubMed:19351586, PubMed:31187503) (Probable). PLP is the active form of vitamin B6, and acts as a cofactor for over 140 different enzymatic reactions.
Transcriptionally regulated by Sp1 transcription factor.
Ubiquitous (PubMed:9099727, PubMed:31187503). Highly expressed in testis (PubMed:9099727).
Zn(2+) is the most effective divalent metal cation in vitro, followed by Co(2+), Mn(2+) and Mg(2+).
(Microbial infection) Interacts with bovine papillomavirus type 1 regulatory protein E2; this interaction stimulates the recruitment of E2 onto mitotic chromosomes.
(Microbial infection) Required for bovine papillomavirus type 1 regulatory protein E2 loading onto mitotic chromosomes during DNA replication for the viral genome to be maintained and segregated.
ATPase activity is stimulated by high magnesium salt levels (up to a 0.1 M), and potassium salts (glutamate, chloride or acetate) are more effective than the corresponding sodium salts (PubMed:10648783, PubMed:18499658). ATPase activity is enhanced by the long non-coding RNA (lncRNA) cohesion regulator noncoding RNA (CONCR) (PubMed:27477908). Double-stranded DNA helicase activity is maximal with magnesium ions at low concentrations (0.5-1 mM) whereas is markedly inhibited at higher levels (5 mM and above) (PubMed:10648783, PubMed:18499658). Double-stranded DNA helicase activity is stimulated by 25-50 mM potassium acetate, stimulated to a lesser extent by 25 mM of ammonium acetate, and markedly inhibited by sodium acetate (PubMed:18499658).
Associates with the CTF18-RFC complex (PubMed:18499658). Associates with a cohesin complex composed of RAD21, SMC1 proteins and SMC3 (PubMed:17105772). Interacts with CHTF18 (PubMed:18499658). Interacts with DSCC1 (PubMed:18499658). Interacts with FEN1; this interaction is direct and increases flap endonuclease activity of FEN1 (PubMed:18499658). Interacts with PCNA (PubMed:18499658). Interacts with POLR1A and UBTF (PubMed:26089203). Interacts with RAD21, SMC1 proteins and SMC3 (PubMed:17105772). Interacts with RFC2 (PubMed:18499658). Interacts with TIMELESS; this interaction increases recruitment of both proteins onto chromatin in response to replication stress induction by hydroxyurea (PubMed:20124417, PubMed:26503245).
Belongs to the DEAD box helicase family. DEAH subfamily. DDX11/CHL1 sub-subfamily.
DNA-dependent ATPase and ATP-dependent DNA helicase that participates in various functions in genomic stability, including DNA replication, DNA repair and heterochromatin organization as well as in ribosomal RNA synthesis (PubMed:10648783, PubMed:21854770, PubMed:23797032, PubMed:26089203, PubMed:26503245). Its double-stranded DNA helicase activity requires either a minimal 5'-single-stranded tail length of approximately 15 nt (flap substrates) or 10 nt length single-stranded gapped DNA substrates of a partial duplex DNA structure for helicase loading and translocation along DNA in a 5' to 3' direction (PubMed:18499658, PubMed:22102414). The helicase activity is capable of displacing duplex regions up to 100 bp, which can be extended up to 500 bp by the replication protein A (RPA) or the cohesion CTF18-replication factor C (Ctf18-RFC) complex activities (PubMed:18499658). Shows also ATPase- and helicase activities on substrates that mimic key DNA intermediates of replication, repair and homologous recombination reactions, including forked duplex, anti-parallel G-quadruplex and three-stranded D-loop DNA molecules (PubMed:22102414, PubMed:26503245). Plays a role in DNA double-strand break (DSB) repair at the DNA replication fork during DNA replication recovery from DNA damage (PubMed:23797032). Recruited with TIMELESS factor upon DNA-replication stress response at DNA replication fork to preserve replication fork progression, and hence ensure DNA replication fidelity (PubMed:26503245). Cooperates also with TIMELESS factor during DNA replication to regulate proper sister chromatid cohesion and mitotic chromosome segregation (PubMed:17105772, PubMed:18499658, PubMed:20124417, PubMed:23116066, PubMed:23797032). Stimulates 5'-single-stranded DNA flap endonuclease activity of FEN1 in an ATP- and helicase-independent manner; and hence it may contribute in Okazaki fragment processing at DNA replication fork during lagging strand DNA synthesis (PubMed:18499658). Its ability to function at DNA replication fork is modulated by its binding to long non-coding RNA (lncRNA) cohesion regulator non-coding RNA DDX11-AS1/CONCR, which is able to increase both DDX11 ATPase activity and binding to DNA replicating regions (PubMed:27477908). Also plays a role in heterochromatin organization (PubMed:21854770). Involved in rRNA transcription activation through binding to active hypomethylated rDNA gene loci by recruiting UBTF and the RNA polymerase Pol I transcriptional machinery (PubMed:26089203). Plays a role in embryonic development and prevention of aneuploidy (By similarity). Involved in melanoma cell proliferation and survival (PubMed:23116066). Associates with chromatin at DNA replication fork regions (PubMed:27477908). Binds to single- and double-stranded DNAs (PubMed:9013641, PubMed:18499658, PubMed:22102414).
Expressed in melanoma cells. Not detected in epidermal melanocytes of normal skin (at protein level) (PubMed:23116066). Highly expressed in spleen, B-cells, thymus, testis, ovary, small intestine and pancreas (PubMed:9013641). Very low expression seen in brain (PubMed:9013641). Expressed in dividing cells and/or cells undergoing high levels of recombination (PubMed:9013641). No expression detected in cells signaled to terminally differentiate (PubMed:9013641). Expressed weakly in keratinocytes (PubMed:8798685).
Up-regulated by serum (at protein level) (PubMed:26089203). Up-regulated by fibroblast growth factor FGF7 (PubMed:8798685). Expressed in keratinocyte growth factor-stimulated cells but not in EGF and IL1-beta-treated keratinocytes (PubMed:8798685). Up-regulated with progression from noninvasive to invasive melanoma (PubMed:23116066).
Belongs to the succinate/malate CoA ligase beta subunit family. GTP-specific subunit beta subfamily.
GTP-specific succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of GTP and thus represents the only step of substrate-level phosphorylation in the TCA. The beta subunit provides nucleotide specificity of the enzyme and binds the substrate succinate, while the binding sites for coenzyme A and phosphate are found in the alpha subunit.
Heterodimer of an alpha and a beta subunit. The beta subunit determines specificity for GTP.
Mainly expressed in liver, kidney, heart, spleen and skeletal muscle. Also found in intestine and colon, and in low amounts in lung, brain, prostate, testis and ovary.
Acts as a transcriptional regulator of PAX6. Acts as a transcriptional activator of PF4 in complex with PBX1 or PBX2. Required for hematopoiesis, megakaryocyte lineage development and vascular patterning. May function as a cofactor for HOXA7 and HOXA9 in the induction of myeloid leukemias.
Expressed at low level in normal immunohepatopoietic tissues, including the fetal liver. Expressed in a subset of myeloid leukemia cell lines, with the highest expression seen in those with a megakaryocytic-erythroid phenotype. Also expressed at high levels in the cerebellum.
Interacts with the N-terminal region of PBX1 to form a heterodimer which binds DNA including a cAMP-responsive sequence in CYP17. Also forms heterodimers with PBX2. Forms heterotrimers with PBX1 or PBX2 and a number of HOX proteins including HOXA9, HOXD4 and HOXD9 where it acts as a non-DNA-binding partner. Also forms heterotrimers with PBX1 and HOX proteins including HOXD9 and HOXD10 where PBX1 is the non-DNA-binding partner. Heterodimer with DLX3 (PubMed:26550823). Heterodimer with HOXB13 (PubMed:28473536).
Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex. Modulates the kinetochore-bound levels of NDC80 complex.
Brain (most abundant in hippocampus and amygdala), placenta and lung.
RNA-binding protein. Might be involved in alternative splicing regulation through an interaction with G-quartet RNA structure.
The disease is caused by variants affecting the gene represented in this entry. It is caused either by silencing of the AFF2 gene as a consequence of a CCG expansion located upstream of this gene or by deletion within the gene. Loss of AFF2 expression is correlated with FRAXE CCG(N) expansion. Normal individuals have 6-35 copies of the repeat, whereas cytogenetically positive, developmentally delayed males have more than 200 copies and show methylation of the associated CPG island.
(Microbial infection) Interacts with C.botulinum neurotoxin type A2 (BoNT/A, botA) (PubMed:29649119). Interaction is improved by glycosylation of SV2 (PubMed:29649119).
(Microbial infection) Receptor for the C.botulinum neurotoxin type A2 (BoNT/A, botA); glycosylation is not essential but enhances the interaction (PubMed:29649119). Probably also serves as a receptor for the closely related C.botulinum neurotoxin type A1.
Interacts with SYT1 in a calcium-independent manner. Forms a complex with SYT1, syntaxin-1 and SNAP25 (By similarity).
Probably plays a role in the control of regulated secretion in neural and endocrine cells.
The N-terminal cytoplasmic domain is phosphorylated by CK1.
Found in a complex with SMAD4 and YY1. Interacts with HGS, NANOG and ZCCHC12 (By similarity). Upon C-terminus phosphorylation: forms trimers with another SMAD1 and the co-SMAD SMAD4 (PubMed:21454478, PubMed:33667543). Interacts with PEBP2-alpha subunit, CREB-binding protein (CBP), p300, SMURF1, SMURF2, USP15 and HOXC8. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with SKOR1. Interacts (via MH2 domain) with LEMD3. Binding to LEMD3 results in at least a partial reduction of receptor-mediated phosphorylation. Forms a ternary complex with PSMB4 and OAZ1 before PSMB4 is incorporated into the 20S proteasome. Found in a macromolecular complex with FAM83G. Interacts (via MH2 domain) with FAM83G (via MH2 domain); in a SMAD4-independent manner. Interacts with ZC3H3 (By similarity). Interacts with TMEM119 (By similarity). Interacts (via MH1 and MH2 domains) with ZNF8 (By similarity). Interacts with RANBP3L; the interaction increases when SMAD1 is not phosphorylated and mediates SMAD1 nuclear export (PubMed:25755279). Interacts with EGR1; this interaction inhibits SMAD1 dephosphorylation (By similarity). Interacts with SMAD6 (PubMed:33667543). Interacts with YAP1 (PubMed:21685363).
Phosphorylation of the C-terminal SVS motif by BMP type 1 receptor kinase activates SMAD1 by promoting dissociation from the receptor and trimerization with SMAD4. Phosphorylation by ERK2 MAP kinase in response to EGF or HGF prevents SMAD1 nuclear accumulation and transcriptional activity in response to BMP (PubMed:9335504). Dephosphorylation, probably by PPM1A, induces its export from the nucleus to the cytoplasm (By similarity). Dephosphorylation is inhibited by association with EGR1 (By similarity). Phosphorylation by CDK8/9 creates binding sites for YAP1, and subsequent phosphorylation by GSK3 switches off YAP1 binding and adds binding sites for SMURF1 (PubMed:21685363).
SMAD1 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.
The MH2 domain mediates phosphorylation-dependent trimerization through L3 loop binding of phosphoserines in the adjacent subunit.
Transcriptional modulator that plays a role in various cellular processes, including embryonic development, cell differentiation, and tissue homeostasis (PubMed:9335504). Upon BMP ligand binding to their receptors at the cell surface, is phosphorylated by activated type I BMP receptors (BMPRIs) and associates with SMAD4 to form an heteromeric complex which translocates into the nucleus acting as transcription factor (PubMed:33667543). In turn, the hetero-trimeric complex recognizes cis-regulatory elements containing Smad Binding Elements (SBEs) to modulate the outcome of the signaling network (PubMed:33667543). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1. Positively regulates BMP4-induced expression of odontogenic development regulator MSX1 following IPO7-mediated nuclear import (By similarity).
Ubiquitinated by SMAD-specific E3 ubiquitin ligase SMURF1, leading to its degradation. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes. Dephosphorylation, probably by PPM1A, induces its export from the nucleus to the cytoplasm (By similarity). Phospho-SMAD1 is ubiquitinated by CHIP leading to disruption of the SMAD1-SMAD4 complex (PubMed:21454478).
Ubiquitous. Highest expression seen in the heart and skeletal muscle.
Belongs to the phosphatidyl serine synthase family.
Catalyzes a base-exchange reaction in which the polar head group of phosphatidylethanolamine (PE) or phosphatidylcholine (PC) is replaced by L-serine (PubMed:19014349, PubMed:24241535). Catalyzes mainly the conversion of phosphatidylcholine (PubMed:19014349, PubMed:24241535). Also converts, in vitro and to a lesser extent, phosphatidylethanolamine (PubMed:19014349, PubMed:24241535).
Requires calcium ions (PubMed:19014349). Inhibited by exogenous phosphatidylserine (PubMed:24241535).
Genetic variations in IL10RB influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424].
Shared cell surface receptor required for the activation of five class 2 cytokines: IL10, IL22, IL26, IL28, and IFNL1. The IFNLR1/IL10RB dimer is a receptor for the cytokine ligands IFNL2 and IFNL3 and mediates their antiviral activity. The ligand/receptor complex stimulate the activation of the JAK/STAT signaling pathway leading to the expression of IFN-stimulated genes (ISG), which contribute to the antiviral state.
Expressed in normal breast tissues. Down-regulated in breast cancer cells (at protein level) (PubMed:29367600).
Negatively regulates the canonical Wnt signaling in breast cancer cells. Exerts an inhibitory effect on breast cancer growth by inhibiting CTNNB1 stabilization and nucleus translocation, which reduces the activity of Wnt targets (PubMed:29367600).
Belongs to the peptidase S26 family. IMP2 subfamily.
Catalyzes the removal of transit peptides required for the targeting of proteins from the mitochondrial matrix, across the inner membrane, into the inter-membrane space. Known to process the nuclear encoded protein DIABLO.
Expressed in all tissues tested except adult liver and lung.
Heterodimer of 2 subunits, IMMPL1 and IMMPL2.
Expressed preferentially in skeletal muscle and heart but not in the lens.
Interacts with DMPK; may enhance its kinase activity.
Catalyzes the conversion of GTP to GDP through hydrolysis of the gamma-phosphate bond in GTP (PubMed:29915238, PubMed:23711155). Appears to have an intrinsic GTPase activity that is stimulated by ZC3H15/DFRP1 binding likely by increasing the affinity for the potassium ions (PubMed:23711155). When hydroxylated at C-3 of 'Lys-22' by JMJD7, may bind to RNA and play a role in translation (PubMed:19819225, PubMed:29915238). Binds to microtubules and promotes microtubule polymerization and stability that are required for mitotic spindle assembly during prophase to anaphase transition. GTPase activity is not necessary for these microtubule-related functions (PubMed:28855639).
High levels in skeletal muscle, heart, and kidney. Intermediate levels in liver, placenta and brain. Low levels in colon, thymus, spleen, small intestine, lung and leukocytes.
Hydroxylated (with S stereochemistry) at C-3 of Lys-22 by JMJD7; this modification hinders trypsin-catalyzed proteolysis in vitro.
Interacts (via its C-terminal) with TAL1. Interacts with DFRP1/ZC3H15; this interaction prevents DRG1 poly-ubiquitination and degradation by the proteasome. DRG1-ZC3H15/DFRP1 complex co-sediments with polysomes (PubMed:19819225). Interacts with STK16 (PubMed:18184589). Interacts with JMJD7 (PubMed:29915238). Associates with microtubules either in an immobile or diffusive manner; in vitro binds to tubulin lacking the negatively charged C-terminal domain (PubMed:28855639).
Polyubiquitinated; this modification induces proteolytic degradation and is impaired by interaction with ZC3H15.
Sumoylated by UBE2I in response to MEKK1-mediated stimuli.
The GTPase activity is enhanced by potassium ions as well as by DFRP1 binding.
The ThrRS, GTPase, SpoT (TGS) domain is not necessary for GTP binding nor for the GTPase activity. It appears to play a regulatory role favoring GTP hydrolysis mediated by DFRP1/ZC3H15.
Interacts with NELL1; the interaction promotes osteoblastic differentiation and mineralization. Interacts with SLC37A3; the interaction is direct and both proteins are mutually dependent for their stability (PubMed:29745899).
Promotes osteoblast cell differentiation and terminal mineralization. Plays a role in inducing the cell cycle arrest via inhibiting CCND1 expression in all-trans-retinoic acid (ATRA) signal pathway. In osteoclasts, forms a transporter complex with ATRAID for nitrogen-containing-bisphophonates (N-BPs) required for releasing N-BP molecules that have trafficked to lysosomes through fluid-phase endocytosis into the cytosol (PubMed:29745899).
Up-regulated by all-trans-retinoic acid (ATRA) in several tumor cell lines.
Weakly expressed in hematopoietic cell lines.
Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.
N-terminal region of PAH is thought to contain allosteric binding sites for phenylalanine and to constitute an 'inhibitory' domain that regulates the activity of a catalytic domain in the C-terminal portion of the molecule.
Phosphorylation at Ser-16 increases basal activity and facilitates activation by the substrate phenylalanine.
The Glu-274 variant occurs on approximately 4% of African-American PAH alleles. The enzyme activity of the variant protein is indistinguishable from that of the wild-type form.
Absent from the genome of domestic mammals and New World monkeys it is found in the genome of hominids and Old World monkeys. Likely derived from retrogene insertion of an NLRP2/NLRP7-like gene, it has probably arisen recently in the mammalian genomes where it is under purifying selection.
Interacts with PYCARD/ASC (via pyrin domain) (PubMed:17339483, PubMed:17178784). Interacts with NLRP2 (via pyrin domain) (PubMed:17178784).
May play a role in innate immunity by disrupting the interaction between PYCARD and NLRP3, thereby regulating the NLRP3 inflammasome (PubMed:17339483, PubMed:17178784). May also inhibit NF-kappa-B signaling distally by affecting the nuclear accumulation of RELA (PubMed:17339483, PubMed:24871464).
Predominantly expressed in peripheral blood. Weakly expressed in testis.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. 5-hydroxytryptamine receptor (TC 1.A.9.2) subfamily. HTR3E sub-subfamily.
The HA-stretch region of HTR3E seems to confer increased conductance to HTR3A/HTR3E heteropentamers compared to that of HTR3A homopentamers.
Down-regulated in differentiated embryonic stem (ESC) cells, compared with strong expression in undifferentiated ESC cells.
Expressed in primordial germ (PGC), embryonic germ (EGC) and embryonic stem (ESC) cells. Not detected in embryonic carcinoma (ECC) cells.
Involved in the maintenance of embryonic stem (ES) cell pluripotency. Dispensable for self-renewal of pluripotent ES cells and establishment of germ cells. Associates with specific target mRNAs (By similarity).
Lacks ADP-ribosylation enhancing activity.
Interacts with TGF-beta receptor type-1 (TGFBR1) and inhibits dissociation of activated SMAD2 from TGFBR1, impeding its nuclear accumulation and resulting in impaired TGF-beta signaling. May also affect FOXO, Hippo and Wnt signaling.
The PH domain is required for membrane targeting.
Disease susceptibility may be associated with variants affecting the gene represented in this entry. A variation Ile to Thr at position 131 influences the association between specific alleles of SFTPA1 and respiratory distress syndrome in premature infants.
Pulmonary surfactant-associated proteins promote alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces. SP-B increases the collapse pressure of palmitic acid to nearly 70 millinewtons per meter.
Autophosphorylated. Phosphorylation at Thr-559 is required to activates its kinase activity and 'Lys-63'-linked polyubiquitination. Phosphorylated by CHUK/IKKA leading to MAP3K14 destabilization.
Interacts with TRAF2, TRAF5, TRAF6, IKKA and NFKB2/P100 (By similarity). Interacts with TRAF3 and PELI3. Interacts with NIBP; the interaction is direct. Interacts with ARRB1 and ARRB2. Interacts with GRB10. Interacts with ZFP91. Interacts with NLRP12; this interaction promotes proteasomal degradation of MAP3K14. Directly interacts with DDX3X (PubMed:30341167). Interacts (via C-terminus and kinase domain) with PPPC3A (via N-terminus) and PPP3CB (By similarity).
Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity. Promotes proteolytic processing of NFKB2/P100, which leads to activation of NF-kappa-B via the non-canonical pathway. Could act in a receptor-selective manner.
Ubiquitinated. Undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. 'Lys-48'-linked polyubiquitination leads to its degradation by the proteasome, while 'Lys-63'-linked polyubiquitination stabilizes and activates it.
Weakly expressed in testis, small intestine, spleen, thymus, peripheral blood leukocytes, prostate, ovary and colon.
Interacts with CREB1; regulates CREB1 phosphorylation, stability and transcriptional activity.
Probable regulator of CREB1 transcriptional activity which is involved in adipose cells differentiation. May also play a regulatory role in the cell cycle. Identification in a chromosomal region frequently deleted in various cancers suggests that it might act as a tumor suppressor.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Beta-1/CHRNB1 sub-subfamily.
(Microbial infection) Interacts with HCV NS5B.
Coordinated expression with SEPTIN2 and SEPTIN7.
Filament-forming cytoskeletal GTPase. Required for normal organization of the actin cytoskeleton. Involved in cytokinesis. May play a role in HCV RNA replication. Forms a filamentous structure with SEPTIN12, SEPTIN6, SEPTIN2 and probably SEPTIN4 at the sperm annulus which is required for the structural integrity and motility of the sperm tail during postmeiotic differentiation (PubMed:25588830).
Septins polymerize into heterooligomeric protein complexes that form filaments, and associate with cellular membranes, actin filaments and microtubules. GTPase activity is required for filament formation. Filaments are assembled from asymmetrical heterotrimers, composed of SEPTIN2, SEPTIN6 and SEPTIN7 that associate head-to-head to form a hexameric unit. Within the trimer, directly interacts with SEPTIN2 and SEPTIN7. Also interacts with SEPTIN9 and SEPTIN12. Interaction with SEPTIN12 alters filament structure. Component of a septin core octameric complex consisting of SEPTIN12, SEPTIN7, SEPTIN6 and SEPTIN2 or SEPTIN4 in the order 12-7-6-2-2-6-7-12 or 12-7-6-4-4-6-7-12 and located in the sperm annulus. Interacts with SOCS7. Interacts with HNRNPA1.
Belongs to the cAMP-dependent kinase regulatory chain family.
Expressed at high levels in the pituitary, diencephalon, mesencephalon, and hypothalamus in embryos at Carnegie stage 22.
Four types of regulatory chains are found: I-alpha, I-beta, II-alpha, and II-beta. Their expression varies among tissues and is in some cases constitutive and in others inducible.
Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells.
The inactive holoenzyme is composed of two regulatory chains and two catalytic chains. Activation by cAMP releases the two active catalytic monomers and the regulatory dimer. Interacts with PRKX; regulates this cAMP-dependent protein kinase. Interacts with C2orf88/smAKAP; this interaction may target PRKAR1B to the plasma membrane.
The pseudophosphorylation site binds to the substrate-binding region of the catalytic chain, resulting in the inhibition of its activity.
Homotrimer; self-association is mediated by the N-terminal coiled coil (By similarity). Interacts with EML2 but not with EML1 (PubMed:25740311). Interacts (phosphorylated at Thr-881) with TUBG1, HAUS1, HAUS2, HAUS3, HAUS4, HAUS5, HAUS6, HAUS7 and HAUS8.
Phosphorylation at Thr-881 during mitosis is required for interaction with TUBG1, HAUS1, HAUS2, HAUS3, HAUS4, HAUS5, HAUS6, HAUS7 and HAUS8 and their recruitment to spindle microtubules.
Regulates mitotic spindle assembly, microtubule (MT)-kinetochore attachment and chromosome separation via recruitment of HAUS augmin-like complex and TUBG1 to the existing MTs and promoting MT-based MT nucleation (PubMed:30723163). Required for proper alignnment of chromosomes during metaphase (PubMed:18445686).
Belongs to the ribonuclease III family. Mitochondrion-specific ribosomal protein mL44 subfamily.
Component of the 39S subunit of mitochondrial ribosome. May have a function in the assembly/stability of nascent mitochondrial polypeptides exiting the ribosome.
Homodimer. Forms a tripartite complex with CDC42BPA/CDC42BPB and LURAP1 with the latter acting as an adapter connecting CDC42BPA/CDC42BPB and MYO18A. Binds F-actin; regulated by ADP and GOLPH3. Interacts with GOLPH3; the interaction is direct and may link Golgi membranes to the actin cytoskeleton. Interacts with JAK3. Interacts with MSR1 and CD14 (PubMed:25965346). Isoform 5 interacts with CD11B (PubMed:25965346).
May link Golgi membranes to the cytoskeleton and participate in the tensile force required for vesicle budding from the Golgi. Thereby, may play a role in Golgi membrane trafficking and could indirectly give its flattened shape to the Golgi apparatus (PubMed:19837035, PubMed:23345592). Alternatively, in concert with LURAP1 and CDC42BPA/CDC42BPB, has been involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration (PubMed:18854160). May be involved in the maintenance of the stromal cell architectures required for cell to cell contact (By similarity). Regulates trafficking, expression, and activation of innate immune receptors on macrophages. Plays a role to suppress inflammatory responsiveness of macrophages via a mechanism that modulates CD14 trafficking (PubMed:25965346). Acts as a receptor of surfactant-associated protein A (SFTPA1/SP-A) and plays an important role in internalization and clearance of SFTPA1-opsonized S.aureus by alveolar macrophages (PubMed:16087679, PubMed:21123169). Strongly enhances natural killer cell cytotoxicity (PubMed:27467939).
The TIAF1 protein is coded in the 3'-UTR region of MYO18A.
The myosin motor domain binds ADP and ATP but has no intrinsic ATPase activity. Mediates ADP-dependent binding to actin (PubMed:23990465).
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs (PubMed:9169443). Shows high catalytic efficiency for hydrolysis of cocaine, 4-methylumbelliferyl acetate, heroin and 6-monoacetylmorphine (PubMed:9169443). Hydrolyzes aspirin, substrates with large alcohol group and small acyl group and endogenous lipids such as triacylglycerol (PubMed:28677105). Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes of 2-arachidonoylglycerol and prostaglandins (PubMed:21049984).
Preferentially expressed in intestine with moderate expression in liver. Within the intestine, highest expression is found in small intestine with lower expression in colon and rectum.
Probably produced by alternative initiation of isoform 1. Does not contain a signal peptide. The biological function of the extra amino acids in the N-terminus remains to be determined.
Probably produced by alternative initiation of isoform 2. Does not contain a signal peptide. The biological function of the extra amino acids in the N-terminus remains to be determined.
Acts as a transcriptional repressor by inhibiting gene expression at the NUPR1 promoter in a p53/TP53-dependent manner in cancer cells (PubMed:25899918). Involved in the G1 cell cycle arrest, and in a decrease in cell viability and cell proliferation (PubMed:25899918). Plays a role as a negative regulator of the protumoral factor NUPR1 (PubMed:25899918).
Up-regulated by p53/TP53 in cancer cells (PubMed:25899918). Up-regulated by DNA damage stimulus or starvation (PubMed:25899918).
Expressed in gonadotrope cells, acts as an inhibin B coreceptor and regulates follicle-stimulating hormone (FSH) levels and female fertility.
Expressed in pituitary gland gonadotrope cells.
Expressed in many tumors of several types, such as melanoma, head and neck squamous cell carcinoma, lung carcinoma and breast carcinoma, but not in normal tissues except for testes and placenta.
Antizyme inhibitor (AZI) protein that positively regulates ornithine decarboxylase (ODC) activity and polyamine uptake. AZI is an enzymatically inactive ODC homolog that counteracts the negative effect of ODC antizymes (AZs) OAZ1, OAZ2 and OAZ3 on ODC activity by competing with ODC for antizyme-binding (PubMed:17900240). Inhibits antizyme-dependent ODC degradation and releases ODC monomers from their inactive complex with antizymes, leading to formation of the catalytically active ODC homodimer and restoring polyamine production (PubMed:17900240). Participates in the morphological integrity of the trans-Golgi network (TGN) and functions as a regulator of intracellular secretory vesicle trafficking (PubMed:20188728).
Belongs to the Orn/Lys/Arg decarboxylase class-II family. ODC antizyme inhibitor subfamily.
Expressed in the neocortex, thalamus, hippocampus, cerebellum, medulla oblongata, gray and white matter. Expressed in neurons, oligodendrocytes, basket, Purkinje and pyramidal cells. Expressed in spermatocytes and Leydig cells of the testis. Expressed in luteal theca cells lining corpus luteum cysts and in hilus cells of the ovary. Expressed in primary and neoplastic mast cells (MC) (at protein level). Highly expressed in brain. Also expressed in testis.
Monomer. Interacts with OAZ1, OAZ2 and OAZ3; this interaction disrupts the interaction between the antizyme and ODC1. Does not form a heterodimer with ODC1.
The N-terminus domain is necessary for its localization to the ER-Golgi intermediate compartment (ERGIC).
Ubiquitinated, leading to its proteasomal degradation; a process that is reduced in presence of antizymes. May also be degraded through the lysosomal degradative pathway in a proteasomal-independent manner.
Was initially reported to have ornithine decarboxylase (PubMed:11587527) or arginine decarboxylase (PubMed:14738999) activities, but it was later found that the mouse ortholog does not possess either of them.
General Rab protein regulator required for vesicle formation from the Golgi complex. May control vesicle docking and fusion by mediating the action of Rab GTPases to the SNARE complexes. In addition it inhibits the removal of Rab GTPases from the membrane by GDI.
Homodimer. Interacts with VAMP2 (synaptobrevin-2), GDI1, and PCLO (By similarity). Interacts specifically with prenylated Rab proteins; strongly with RAB4B, RAB5A and RAB5C, and weakly with RAB4A, RAB6, RAB7A, RAB17 and RAB22. Interacts with NDRG1.
In contrast to the mouse ortholog, it does not interact with Ras.
In fetal tissues, it is more abundant in kidney and lung.
Ubiquitous. Strongest expression found in placenta, pituitary gland, kidney, lung and stomach.
A chromosomal aberration involving MLLT11 is found in acute leukemias. Translocation t(1;11)(q21;q23) with KMT2A/MLL1.
Cofactor for the transcription factor TCF7 (PubMed:26079538). Involved in regulation of lymphoid development by driving multipotent hematopoietic progenitor cells towards a T cell fate (PubMed:21715312).
Expressed in myoepithelial cells of normal breast tissue (at protein level) (PubMed:26079538). Highly expressed in thymus (PubMed:7833468). Expressed in colon, small intestine, prostate and ovary. Not detected in peripheral blood lymphocytes and spleen (PubMed:7833468).
Interacts with HSPA8 and LAMP2 isoform A; the interaction may target MLLT11 for degradation via chaperone-mediated autophagy (PubMed:24880125). Interacts with TCF7 (PubMed:26079538).
Belongs to the uroporphyrinogen-III synthase family.
Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins (PubMed:11689424, PubMed:18004775). Porphyrins act as cofactors for a multitude of enzymes that perform a variety of processes within the cell such as methionine synthesis (vitamin B12) or oxygen transport (heme).
The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes (PubMed:18361507). This phospholipase activity is very sensitive to calcium. May be important for formation and maintenance of the neuronal network in the postnatal brain (By similarity).
Forms homohexamers via its SAM-like domain (PubMed:26906118). Interacts with MTA1; which is indispensable for TFCP2l1-mediated self-renewal-promoting effect and endoderm-inhibiting action (By similarity).
Highly expressed in placental JEG-3 cells and very low levels of expression in non-steroidogenic cells. No expression was seen in adrenal NCI-H295A cells or in adrenal tissue.
The Grh/CP2 DB domain is required for direct DNA-binding (PubMed:26906118). The Grh/CP2 DB domain is essential to maintain the undifferentiated state of embryonic stem cells (By similarity).
The SAM-like domain is required for homohexamerization (PubMed:26906118).
Transcription factor that facilitates establishment and maintenance of pluripotency in embryonic stem cells (ESCs) (PubMed:25215486, PubMed:26906118). With KLF2, acts as the major effector of self-renewal that mediates induction of pluripotency downstream of LIF/STAT3 and Wnt/beta-catenin signaling (By similarity). Required for normal duct development in the salivary gland and kidney (By similarity). Coordinates the development of the kidney collecting ducts intercalated (IC) and principal (PC) cells, which regulate acid-base and salt-water homeostasis, respectively (By similarity). Regulates the expression of IC genes including subunits B1 and D2 of the V-ATPase complex, OXGR1, CA12, SLC4A1, AQP6 and IC-specific transcription factor FOXI1 (By similarity). Regulates also the expression of JAG1 and subsequent notch signaling in the collecting duct (By similarity). JAG1 initiates notch signaling in PCs but inhibits notch signaling in ICs (By similarity). Acts as a transcriptional suppressor that may suppress UBP1-mediated transcriptional activation (By similarity). Modulates the placental expression of CYP11A1 (PubMed:10644752).
Component of an NADPH oxidase complex composed of a heterodimer formed by the membrane proteins CYBA and CYBB and the cytosolic subunits NCF1, NCF2 and NCF4. Interacts (via C-terminus) with NCF2 (via the C-terminal SH3 domain). Interacts with NCF4. Interacts with CYBB. Interacts (via the second SH3 domain) with CYBA. Interacts with NOXA1. Interacts with ADAM15. Interacts with TRAF4. Interacts with FASLG. Interacts with PARK7 (via C-terminus); the interaction is enhanced by LPS and modulates NCF1 phosphorylation and membrane translocation (By similarity).
Detected in peripheral blood monocytes and neutrophils (at protein level).
NCF2, NCF1, and a membrane bound cytochrome b558 are required for activation of the latent NADPH oxidase (necessary for superoxide production).
Phosphorylated by PRKCD; phosphorylation induces activation of NCF1 and NADPH oxidase activity.
The PX domain mediates interaction with phosphatidylinositol 3,4-bisphosphate and other anionic phospholipids. In the autoinhibited, unphosphorylated state an intramolecular interaction with the C-terminal SH3 domain precludes phospholipid binding and interaction with CYBA. Phosphorylation disrupts the autoinhibited state.
Belongs to the ANT/ATPSC lysine N-methyltransferase family.
Contains an atypical, non-cleavable mitochondrial targeting sequence responsible for its localization to mitochondria.
Mitochondrial protein-lysine N-methyltransferase that trimethylates ATP synthase subunit C, ATP5MC1 and ATP5MC2. Trimethylation is required for proper incorporation of the C subunit into the ATP synthase complex and mitochondrial respiration (PubMed:29444090, PubMed:30530489). Promotes chronic pain (PubMed:29444090). Involved in persistent inflammatory and neuropathic pain: methyltransferase activity in the mitochondria of sensory neurons promotes chronic pain via a pathway that depends on the production of reactive oxygen species (ROS) and on the engagement of spinal cord microglia (PubMed:29444090).
Expressed only in a subset of type 2 skeletal muscle fibers.
F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein.
Homodimer; antiparallel. Also forms heterodimers with ACTN2. Interacts with MYOZ1.
The sequence shown in this entry differs from the translation of the reference genome assembly (GRCh38/hg38) due to a nonsense variant creating stop codon at position 577 in the reference genome, leading to ACTN3 deficiency. However, the presence of this variant is not associated with any disease phenotype [MIM:617749]. The sequence shown in this entry is that of variant p.Ter577Arg, which has a frequency of about 62% in the human population according to the Genome Aggregation Database (gnomAD v3.1.2).
The sequence shown in this entry differs from the translation of the reference genome assembly (GRCh38/hg38) due to a nonsense variant creating stop codon at position 577 in the reference genome.
Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and acts as a marker of multipotent stem cells in the epidermis. Upon binding to R-spondins (RSPO1, RSPO2, RSPO3 or RSPO4), associates with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. In contrast to classical G-protein coupled receptors, does not activate heterotrimeric G-proteins to transduce the signal. May act as a tumor suppressor.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. Very large inducible GTPase (VLIG) family.
By HBxAg. Up-regulated in gastric cancer tissues and also in gastric cancer cell lines (at protein level).
May be involved in cell cycle progression through the regulation of cyclin D1 expression. May participate in the development of hepatocellular carcinoma (HCC) by promoting hepatocellular growth and survival. May play an important role in development of gastric cancer.
Strongly expressed in hepatitis B virus-infected liver and in HCC cells. Also highly expressed in well-differentiated gastric cancer tissues and various gastric cancer cell lines.
Interacts with EZR/VIL2 C-terminal domain.
May be myristoylated; myristoylation may target it to Golgi compartment.
May play a role in regulating cell adhesion/migration complexes in migrating cells.
Binds and transactivates the retinoic acid response elements that control expression of the retinoic acid receptor beta 2 and alcohol dehydrogenase 3 genes. Transactivates both the phenobarbital responsive element module of the human CYP2B6 gene and the CYP3A4 xenobiotic response element.
Composed by a short N-terminal domain followed by the DNA binding, hinge, and ligand binding/dimerization domains.
Interacts with ECT2 (By similarity). Heterodimer of NR1I3 and RXR. Interacts with PSMC4. Directly interacts with DNAJC7. The DNAJC7-NR1I3 complex may also include HSP90 (By similarity). Interacts with CRY1 (By similarity). Interacts with CRY2 in a ligand-dependent manner (By similarity).
Phosphorylated at Thr-38 by PKC, dephosphorylation of Thr-38 is required for nuclear translocation and activation.
Component of the XPC complex composed of XPC, RAD23B and CETN2. Interacts with NGLY1 and PSMC1. Interacts with ATXN3 (PubMed:30455355). Interacts with PSMD4 and PSMC5. Interacts with AMFR. Interacts with VCP; the interaction is indirect and mediated by NGLY1 (By similarity).
Highly expressed in the testis and in ejaculated spermatozoa.
Involved in global genome nucleotide excision repair (GG-NER) by acting as component of the XPC complex. Cooperatively with CETN2 appears to stabilize XPC. May protect XPC from proteasomal degradation.
Multiubiquitin chain receptor involved in modulation of proteasomal degradation. Binds to polyubiquitin chains. Proposed to be capable to bind simultaneously to the 26S proteasome and to polyubiquitinated substrates and to deliver ubiquitinated proteins to the proteasome. May play a role in endoplasmic reticulum-associated degradation (ERAD) of misfolded glycoproteins by association with PNGase and delivering deglycosylated proteins to the proteasome.
The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex. The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single-stranded overhangs. The orientation of XPC complex binding appears to be crucial for inducing a productive NER. XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery. Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair. In vitro, the XPC:RAD23B dimer is sufficient to initiate NER; it preferentially binds to cisplatin and UV-damaged double-stranded DNA and also binds to a variety of chemically and structurally diverse DNA adducts. XPC:RAD23B contacts DNA both 5' and 3' of a cisplatin lesion with a preference for the 5' side. XPC:RAD23B induces a bend in DNA upon binding. XPC:RAD23B stimulates the activity of DNA glycosylases TDG and SMUG1.
Catalyzes the synthesis of acetyl-CoA from short-chain fatty acids (PubMed:10843999, PubMed:28003429). Acetate is the preferred substrate (PubMed:10843999, PubMed:28003429). Can also utilize propionate with a much lower affinity (By similarity).
Inhibited by acetylation at Lys-661 and activated by deacetylation mediated by the deacetylases SIRT1 and SIRT3.
Reversibly acetylated at Lys-661 (By similarity). The acetyl-CoA synthase activity is inhibited by acetylation and activated by deacetylation mediated by the deacetylases SIRT1 and SIRT3 (By similarity).
Can form homodimers and heterodimers with DACT1 or DACT3. Interacts with CSNK1D, PKA catalytic subunit, PKC-type kinase, CSNK2B, DVL1, DVL2, DVL3, VANGL1, VANGL2, TGFBR1, CTNNB1, CTNND2, CTNND1, LEF1, TCF7, TCF7L1 and HDAC1 (By similarity).
Involved in regulation of intracellular signaling pathways during development. Negatively regulates the Nodal signaling pathway, possibly by promoting the lysosomal degradation of Nodal receptors, such as TGFBR1. May be involved in control of the morphogenetic behavior of kidney ureteric bud cells by keeping cells epithelial and restraining their mesenchymal character. May play an inhibitory role in the re-epithelialization of skin wounds by attenuating TGF-beta signaling (By similarity).
The C-terminal PDZ-binding motif may mediate interaction with the PDZ domains of DSH (Dishevelled) family proteins.
Cytotoxicity-activating receptor that may contribute to the increased efficiency of activated natural killer (NK) cells to mediate tumor cell lysis.
Interacts with TYROBP/DAP12. Interacts with KMT2E isoform NKp44L.
Selectively expressed by activated NK cells and by in vitro cultured (i.e. activated) TCRg/d lymphoid cells.
Alanine--glyoxylate aminotransferase activity is inhibited by 1 mM (aminooxy)acetic acid by 97.5%.
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family.
Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification (PubMed:10960483, PubMed:12777626, PubMed:24055001, PubMed:23229545, PubMed:26149463). Also catalyzes the transamination between L-serine and pyruvate and contributes to gluconeogenesis from the L-serine metabolism (PubMed:10347152).
Polymorphism at position 11 acts synergistically with different mutations in AGXT producing specific enzymatic phenotypes in HP1 patients. The combined presence of Leu-11 and Met-340 polymorphisms defines the minor AGXT allele, whereas their absence defines the major allele. The minor allele has frequencies of 20% in normal European and North American populations, and 50% in HP1 patients.
The intracellular compartmentalization of AGTX in mammalian hepatocytes is species dependent. In human and rabbit, AGTX is peroxisomal. In new world monkeys (marmoset) and rodents (rat and mouse), it is distributed approximately evenly between peroxisomes and mitochondria. In carnivores, like cat, the great majority of the enzyme is mitochondrial with only a small proportion being peroxisomal.
Along with MDM2, contributes to TP53 regulation (PubMed:32300648). Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.
Cancer-specific isoform, may counteract MDM2/MDM4-mediated p53 degradation.
Down-regulated by cisplatin (at protein level).
Expressed in all tissues tested with high levels in thymus.
Interacts with MDM2 (PubMed:16163388, PubMed:19838211, PubMed:32300648). Interacts with TP53, TP73 and USP2. Found in a trimeric complex with USP2, MDM2 and MDM4. Interacts (phosphorylated) with YWHAG; negatively regulates MDM4 activity toward TP53.
Phosphorylated. Phosphorylation at Ser-367 promotes interaction with YWHAG and subsequent ubiquitination and degradation. Phosphorylation at Ser-342 also induces ubiquitination and degradation but to a lower extent.
Region I is sufficient for binding TP53 and inhibiting its G1 arrest and apoptosis functions. It also binds TP73. Region II contains most of a central acidic region and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc mediates the heterooligomerization with MDM2.
Ubiquitinated and degraded by MDM2. Deubiquitination by USP2 on the other hand stabilizes the MDM4 protein.
Belongs to the eukaryotic/archaeal PrmC-related family.
Heterodimer; heterodimerization with TRMT112 is required for S-adenosyl-L-methionine-binding.
Methyltransferase that can methylate proteins and, to a lower extent, arsenic (PubMed:18539146, PubMed:21193388, PubMed:30017583, PubMed:31636962, PubMed:31061526). Catalytic subunit of a heterodimer with TRMT112, which monomethylates 'Lys-12' of histone H4 (H4K12me1), a modification present at the promoters of numerous genes encoding cell cycle regulators (PubMed:31061526). Catalytic subunit of a heterodimer with TRMT112, which catalyzes N5-methylation of Glu residue of proteins with a Gly-Gln-Xaa-Xaa-Xaa-Arg motif (PubMed:18539146, PubMed:31632689, PubMed:31636962). Methylates ETF1 on 'Gln-185'; ETF1 needs to be complexed to ERF3 in its GTP-bound form to be efficiently methylated (PubMed:18539146, PubMed:20606008, PubMed:31636962, PubMed:31061526). May also play a role in the modulation of arsenic-induced toxicity by mediating the conversion of monomethylarsonous acid (3+) into the less toxic dimethylarsonic acid (PubMed:21193388, PubMed:25997655). It however only plays a limited role in arsenic metabolism compared with AS3MT (PubMed:25997655).
Was reported to have N(6)-adenine-specific DNA methyltransferase by mediating methylation of DNA on the 6th position of adenine (N(6)-methyladenosine) (PubMed:30017583). The existence of N(6)-methyladenosine on DNA is unclear in mammals (PubMed:32203414). According to a report, the majority of N(6)-methyladenosine in DNA originates from RNA catabolism via a nucleotide salvage pathway and is misincorporated by DNA polymerases, arguing against a role as epigenetic DNA mark in mammalian cells (PubMed:32203414). Moreover, subsequent studies could not confirm the role of N6AMT1 as a N(6)-adenine-specific DNA methyltransferase (PubMed:30392959, PubMed:31632689, PubMed:31636962).
Widely expressed, with highest expression in parathyroid and pituitary glands, followed by adrenal gland and kidney, and lowest expression in leukocytes and mammary gland.
Belongs to the cytochrome c oxidase VIIc family.
Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with RAB5IF (PubMed:31536960).
Expressed in bladder cancer tissues (at protein level).
ATP-binding subunit of the mitochondrial potassium channel located in the mitochondrial inner membrane (PubMed:31435016). Together with CCDC51/MITOK, forms a protein complex localized in the mitochondria that mediates ATP-dependent potassium currents across the inner membrane (that is, mitoK(ATP) channel) (PubMed:31435016). Plays a role in mitochondrial iron transport (PubMed:30623799). Required for maintenance of normal cardiac function, possibly by influencing mitochondrial iron export and regulating the maturation of cytosolic iron sulfur cluster-containing enzymes (By similarity).
SP1 transcription factor binds to the ABCB8 core promoter region, possibly regulating its transcription.
The mitochondrial potassium channel (mitoK(ATP)) is composed of 4 subunits of CCDC51/MITOK and 4 subunits of ABCB8/MITOSUR (Probable). Interacts with C10orf88/PAAT (PubMed:25063848). Interacts with NRP1; NRP1 regulates ABCB8/MITOSUR protein levels in mitochondria (PubMed:30623799).
Autophosphorylated. Autophosphorylation is activated by RAP2A and induces association to the cytoskeletal fraction.
Expressed ubiquitously. Highest levels observed in heart, brain and skeletal muscle. Expressed in normal colonic epithelia and colorectal cancer tissues.
Interacts (via the CNH domain) with RAP2A (GTP-bound form preferentially); the interaction is direct and required for the activation of TNIK by RAP2A. Interacts with NEDD4; recruits RAP2A to NEDD4. Interacts with TRAF2 and NCK. Interacts with TCF7L2/TCF4 and CTNNB1; the interaction is direct. Interacts with TANC1.
Serine/threonine kinase that acts as an essential activator of the Wnt signaling pathway. Recruited to promoters of Wnt target genes and required to activate their expression. May act by phosphorylating TCF4/TCF7L2. Appears to act upstream of the JUN N-terminal pathway. May play a role in the response to environmental stress. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. More generally, it may play a role in cytoskeletal rearrangements and regulate cell spreading. Phosphorylates SMAD1 on Thr-322.
Inhibited by micromolar concentrations of copper and zinc ions.
N-terminal asparagine deamidase that mediates deamidation of N-terminal asparagine residues to aspartate. Required for the ubiquitin-dependent turnover of intracellular proteins that initiate with Met-Asn. These proteins are acetylated on the retained initiator methionine and can subsequently be modified by the removal of N-acetyl methionine by acylaminoacid hydrolase (AAH). Conversion of the resulting N-terminal asparagine to aspartate by NTAN1/PNAD renders the protein susceptible to arginylation, polyubiquitination and degradation as specified by the N-end rule. This enzyme does not act on substrates with internal or C-terminal asparagines and does not act on glutamine residues in any position, nor on acetylated N-terminal peptidyl Asn.
Component of the NF-kappa-B p65-p50 complex (PubMed:1740106, PubMed:7830764). Homodimer; component of the NF-kappa-B p50-p50 complex. Component of the NF-kappa-B p105-p50 complex (PubMed:1423592). Component of the NF-kappa-B p50-c-Rel complex (PubMed:15102766, PubMed:8152812). Component of a complex consisting of the NF-kappa-B p50-p50 homodimer and BCL3 (PubMed:10469655). Also interacts with MAP3K8 (PubMed:9950430, PubMed:15485931). NF-kappa-B p50 subunit interacts with NCOA3 coactivator, which may coactivate NF-kappa-B dependent expression via its histone acetyltransferase activity (PubMed:11094166). Interacts with TSC22D3; this interaction prevents nuclear translocation and DNA-binding (PubMed:11468175, PubMed:12393603). Interacts with SPAG9 and UNC5CL (PubMed:14769797, PubMed:14743216). NFKB1/p105 interacts with CFLAR; the interaction inhibits p105 processing into p50 (PubMed:13679070). NFKB1/p105 forms a ternary complex with MAP3K8 and TNIP2 (PubMed:15169888). Interacts with GSK3B; the interaction prevents processing of p105 to p50 (PubMed:12871932). NFKB1/p50 interacts with NFKBIE (PubMed:9315679). NFKB1/p50 interacts with NFKBIZ (By similarity). Nuclear factor NF-kappa-B p50 subunit interacts with NFKBID (By similarity). Directly interacts with MEN1 (PubMed:11526476). Interacts with HIF1AN (PubMed:17003112). Interacts with FEM1A; interaction is direct (By similarity).
Constitutes the active form, which associates with RELA/p65 to form the NF-kappa-B p65-p50 complex to form a transcription factor (PubMed:1740106, PubMed:7830764). Together with RELA/p65, binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions (PubMed:1740106, PubMed:7830764).
Generation of the NF-kappa-B p50 (Nuclear factor NF-kappa-B p50 subunit) transcription factor takes place both cotranslationally and post-translationally via non-mutually exclusive mechanisms (PubMed:8628291, PubMed:9529257, PubMed:10970863, PubMed:25860612). A cotranslational processing allows the production of both p50 and p105 (Nuclear factor NF-kappa-B p105 subunit) from a single NFKB1 mRNA (PubMed:8628291, PubMed:9529257, PubMed:10970863). While translation occurs, the particular unfolded structure after the GRR repeat region acts as a substrate for the proteasome, promoting degradation of the C-terminus (PubMed:9529257, PubMed:10970863). The GRR acts as a proteasomal 'stop signal', protecting the region upstream of the GRR from degradation and promoting generation of p50 (PubMed:9529257, PubMed:10970863). It is unclear if limited proteasome degradation during cotranslational processing depends on ubiquitination (PubMed:9529257, PubMed:10970863). NF-kappa-B p50 is also generated post-translationally following ubiquitination by the KPC complex, leading to limited processing by the proteasome downstream of the GRR region, thereby generating p50 (PubMed:25860612).
Glycine-rich region (GRR) is a critical element in the generation of p50 (Nuclear factor NF-kappa-B p50 subunit) by acting as a proteasomal 'stop signal', which leads to limited proteasomal degradation of the C-terminus, while generating p50.
NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105.
P105 is the precursor of the active p50 subunit (Nuclear factor NF-kappa-B p50 subunit) of the nuclear factor NF-kappa-B (PubMed:1423592). Acts as a cytoplasmic retention of attached NF-kappa-B proteins by p105 (PubMed:1423592).
Phosphorylation at the C-terminus by IKBKB/IKKB acts as a signal for ubiquitination and promotes either complete degradation or processing to generate the NF-kappa-B p50 (Nuclear factor NF-kappa-B p50 subunit) (PubMed:8626394, PubMed:10835356, PubMed:11297557, PubMed:11158290, PubMed:12482991, PubMed:14673179, PubMed:25860612). Phosphorylation at Ser-903 and Ser-907 primes p105 for proteolytic processing in response to TNF-alpha stimulation (PubMed:12871932). Phosphorylation at Ser-923, Ser-927 and Ser-932 are required for BTRC/BTRCP-mediated ubiquitination and proteolysis (PubMed:10835356, PubMed:11297557, PubMed:11158290, PubMed:12482991, PubMed:14673179). Phosphorylation at Ser-927 is also required for ubiquitination by the KPC complex and limited processing to generate NF-kappa-B p50 (Nuclear factor NF-kappa-B p50 subunit) (PubMed:25860612).
Polyubiquitinated at multiple Lys residues in the C-terminus (PubMed:11158290, PubMed:14673179, PubMed:25860612). Polyubiquitinated by the SCF(FBXW11) and SCF(BTRC) complexes following phosphorylation at Ser-923, Ser-927 and Ser-932, leading to its complete degradation (PubMed:11158290). In contrast, polyubiquitination by the KPC complex following phosphorylation at Ser-927 leads to limited proteosomal processing and generation of the active NF-kappa-B p50 (Nuclear factor NF-kappa-B p50 subunit) (PubMed:25860612).
S-nitrosylation of Cys-61 affects DNA binding.
The C-terminus of p105 might be involved in cytoplasmic retention, inhibition of DNA-binding, and transcription activation.
The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation.
Associates with translationally inactive ribosomes in the nonrotated state (PubMed:32687489). Interacts with RASGEF1B (PubMed:23894443).
Ribosome-binding protein involved in ribosome hibernation: associates with translationally inactive ribosomes and stabilizes the nonrotated conformation of the 80S ribosome, thereby promoting ribosome preservation and storage (PubMed:32687489). Also required for proper progression of late cytokinetic stages (PubMed:23894443).
Interacts (via N-terminus) with DVL3. Interacts with FLII. Weakly interacts with MYD88 in resting cells. Following LPS-stimulation, the interaction with MYD88 is rapidly enhanced; the complex gradually dissociates to basal levels after 6 hours of stimulation. Interaction with MYD88 is regulated by LPS-induced phosphorylation at Ser-202. In the presence of LPS, competes with FLII for MYD88-binding.
May function as activator of the canonical Wnt signaling pathway, in association with DVL3, upstream of CTNNB1/beta-catenin. Positively regulates Toll-like receptor (TLR) signaling in response to agonist probably by competing with the negative FLII regulator for MYD88-binding.
Ser-190 and Ser-202 are phosphorylated in response to LPS stimulation. Ser-202 phosphorylation regulates the LPS-induced interaction with MYD88.
Widely expressed, with highest levels in heart and skeletal muscle.
Can degrade fibronectin, gelatins of type I, III, IV, and V; weakly collagens III, IV, and V. Activates procollagenase.
Binds to the inner side of the nucleosomal DNA thus altering the interaction between the DNA and the histone octamer. May be involved in the process which maintains transcribable genes in a unique chromatin conformation (By similarity).
Phosphorylation favors cytoplasmic localization.
Component of a complex at least composed of ELL, SNF8/EAP30, VPS25/EAP20 and VPS36/EAP45 (By similarity). Component of the endosomal sorting complex required for transport II (ESCRT-II), composed of SNF8, VPS36 and two copies of VPS25 (PubMed:14519844). Interacts with VPS25, SNF8, TSG101 and CHMP6 (PubMed:14505570, PubMed:14519844, PubMed:16973552, PubMed:18539118). Interacts (via GLUE domain) with ubiquitin (PubMed:17057716). Interacts with RILPL1 (via the C-terminal domain); which recruits ESCRT-II to the endosome membranes (PubMed:17010938). Interacts with ECPAS (PubMed:20682791).
Component of the ESCRT-II complex (endosomal sorting complex required for transport II), which is required for multivesicular body (MVB) formation and sorting of endosomal cargo proteins into MVBs. The MVB pathway mediates delivery of transmembrane proteins into the lumen of the lysosome for degradation. The ESCRT-II complex is probably involved in the recruitment of the ESCRT-III complex. Its ability to bind ubiquitin probably plays a role in endosomal sorting of ubiquitinated cargo proteins by ESCRT complexes. The ESCRT-II complex may also play a role in transcription regulation, possibly via its interaction with ELL. Binds phosphoinosides such as PtdIns(3,4,5)P3.
The GLUE domain (GRAM-like ubiquitin-binding in EAP45) mediates binding to ubiquitin and phosphoinosides.
Antibodies against RBM39 are present in sera from a patient with hepatocellular carcinoma who developed several autoantibodies.
Aryl sulfonamide anticancer drugs, such as indisulam (E7070) or E7820, promote ubiquitination and subsequent degradation by the DCX(DCAF15) complex (PubMed:31693891, PubMed:28437394, PubMed:28302793). RBM39 degradation results in splicing defects and death in cancer cell lines (PubMed:31693891, PubMed:28437394, PubMed:28302793). Aryl sulfonamide anticancer drugs change the substrate specificity of DCAF15 by acting as a molecular glue that promotes binding between DCAF15 and weak affinity interactor RBM39 (PubMed:31686031, PubMed:31819272).
Interacts with NCOA6 and JUN. Interacts with ESR1 and ESR2, in the presence of estradiol (E2) (By similarity). Interacts with RSRC1 (via Arg/Ser-rich domain) (PubMed:15798186). Interacts with SF3B1 (PubMed:24795046). Interacts with ZNF106 (via N-terminus) (By similarity).
RNA-binding protein that acts as a pre-mRNA splicing factor (PubMed:15694343, PubMed:31271494, PubMed:28437394, PubMed:28302793, PubMed:24795046). Acts by promoting exon inclusion via regulation of exon cassette splicing (PubMed:31271494). Also acts as a transcriptional coactivator for steroid nuclear receptors ESR1/ER-alpha and ESR2/ER-beta, and JUN/AP-1, independently of the pre-mRNA splicing factor activity (By similarity).
Widely expressed. Highly expressed in pancreas, skeletal muscle, lung and brain (PubMed:8227358). Expressed at intermediate level in kidney, liver and heart (PubMed:8227358).
Expressed in heart, skeletal muscle, colon, spleen, kidney, liver, small intestine and lung. Highest expression is seen in brain and placenta. Loss of expression is seen in some breast, cervical, hepatocellular, lung, thyroid, gastric and renal cell-cancer lines. Highly expressed in secretory cell lines. Expressed in almost all regions of the brain, in cerebellum, anterior frontal cortex, and striatum.
May play an important role in the development of cancers in a broad range of tissues.
Detected in brain, heart and skeletal muscle, and at low levels in placenta, kidney and pancreas (PubMed:11161817). Expressed in circumvallate papillae (PubMed:16720576).
Interacts with odorant receptor proteins.
Required for endoplasmic reticulum (ER) network formation, shaping and remodeling. May enhance the cell surface expression of odorant receptors (By similarity).
Aminopeptidase with broad substrate specificity for several peptides. Involved in proteolytic events essential for cell growth and viability. May act as regulator of neuropeptide activity. Plays a role in the antigen-processing pathway for MHC class I molecules. Involved in the N-terminal trimming of cytotoxic T-cell epitope precursors. Digests the poly-Q peptides found in many cellular proteins. Digests tau from normal brain more efficiently than tau from Alzheimer disease brain.
Detected in liver, epithelium of renal tubules, epithelium of small and large intestine, gastric epithelial cells, and alveoli of the lung (at protein level).
It is uncertain whether Met-1 or Met-45 is the initiator. N-terminal sequencing in PubMed:10978616 suggests that Met-45 is used, followed by methionine initiator removal.
Strongly inhibited by bestatin, leuhistin, actinonin, amastatin, 1,10-phenanthroline, DFP, PCMBS, Zn(2+), Cd(2+), Co(2+), Cu(2+), Hg(2+), EDTA and puromycin. Not inhibited by PMSF, and only slightly inhibited by leupeptin and aprotinin. Activity is increased by Mg(2+) and Ca(2+).
Interacts with EHD1, RAB4A, RAB5A, RAB14, RAB22A, RAB24 and VPS45 (PubMed:11062261, PubMed:15020713, PubMed:16034420). Binds simultaneously to RAB4A and RAB5A in vitro (PubMed:16034420). Interacts with RAB4A and RAB5A that has been activated by GTP binding (PubMed:11062261, PubMed:16034420, PubMed:20098723, PubMed:11788822).
Rab4/Rab5 effector protein acting in early endocytic membrane fusion and membrane trafficking of recycling endosomes. Required for endosome fusion either homotypically or with clathrin coated vesicles. Plays a role in the lysosomal trafficking of CTSD/cathepsin D from the Golgi to lysosomes. Also promotes the recycling of transferrin directly from early endosomes to the plasma membrane. Binds phospholipid vesicles containing phosphatidylinositol 3-phosphate (PtdInsP3) (PubMed:11062261, PubMed:11788822, PubMed:15020713). Plays a role in the recycling of transferrin receptor to the plasma membrane (PubMed:22308388).
Binds to two alpha/beta-tubulin heterodimers. Interacts with KIST.
Down-regulated in response to enterovirus 71 (EV71) infection (at protein level).
Involved in the regulation of the microtubule (MT) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Phosphorylation at Ser-16 may be required for axon formation during neurogenesis. Involved in the control of the learned and innate fear (By similarity).
Many different phosphorylated forms are observed depending on specific combinations among the sites which can be phosphorylated. MAPK is responsible for the phosphorylation of stathmin in response to NGF. Phosphorylation at Ser-16 seems to be required for neuron polarization (By similarity). Phosphorylation at Ser-63 reduces tubulin binding 10-fold and suppresses the MT polymerization inhibition activity.
Ubiquitous. Expression is strongest in fetal and adult brain, spinal cord, and cerebellum, followed by thymus, bone marrow, testis, and fetal liver. Expression is intermediate in colon, ovary, placenta, uterus, and trachea, and is readily detected at substantially lower levels in all other tissues examined. Lowest expression is found in adult liver. Present in much greater abundance in cells from patients with acute leukemia of different subtypes than in normal peripheral blood lymphocytes, non-leukemic proliferating lymphoid cells, bone marrow cells, or cells from patients with chronic lymphoid or myeloid leukemia.
Component of the IRAK1-dependent TNFRSF1A signaling pathway that leads to NF-kappa-B activation and is required for cell survival. Acts by enhancing RELA transcriptional activity (By similarity).
Interacts with IRAK1 and RELA. Interacts with HSPA8 and HSPA1 (By similarity).
Phosphorylation at Ser-56 and/or Ser-62 is required for full activity. Phosphorylated on at least one of Ser-235, Thr-237, Ser-242 and Thr-247 upon TNF-alpha activation, which favors nuclear translocation (By similarity).
The disordered region interacts with HSPA1 and HSPA8.
Highest levels of expression in adult testis; modest levels in fetal kidney and brain.
Belongs to the WD repeat PAAF1/RPN14 family.
Inhibits proteasome 26S assembly and proteolytic activity by impairing the association of the 19S regulatory complex with the 20S core. In case of HIV-1 infection, recruited by viral Tat to the HIV-1 promoter, where it promotes the recruitment of 19S regulatory complex through dissociation of the proteasome 26S. This presumably promotes provirus transcription efficiency. Protects SUPT6H from proteasomal degradation.
Interacts with PSMC1, PSMC2, PSMC3, PSMC4, PSMC5 and PSMC6. Interacts with SUPT6H.
Ubiquitously expressed, with highest levels in kidney, brain and testis.
(Microbial infection) Interacts (via N-terminus) with human cytomegalovirus (HHV-5) US28.
(Microbial infection) Interacts with P.falciparum (strain 3D7) CBP1 and CBP2 (via their extracellular domains); the interaction mediates the adhesion of infected erythrocytes with endothelial cells.
(Microbial infection) Interacts with pox virus crmD; this inhibits cell migration mediated by CX3CL1.
(Microbial infection) Mediates the cytoadherence of erythrocytes infected with parasite P.falciparum (strain 3D7) with endothelial cells by interacting with P.falciparum CBP1 and CBP2 expressed at the surface of erythrocytes (PubMed:27653778). The adhesion prevents the elimination of infected erythrocytes by the spleen (Probable).
A soluble short 95 kDa form may be released by proteolytic cleavage from the long membrane-anchored form.
By TNF and IL1/interleukin-1 in pulmonary endothelial cells and umbilical vein endothelial cells.
Chemokine that acts as a ligand for both CX3CR1 and integrins ITGAV:ITGB3 and ITGA4:ITGB1 (PubMed:9782118, PubMed:12055230, PubMed:23125415, PubMed:9931005, PubMed:21829356). The CX3CR1-CX3CL1 signaling exerts distinct functions in different tissue compartments, such as immune response, inflammation, cell adhesion and chemotaxis (PubMed:9024663, PubMed:9177350, PubMed:9782118, PubMed:12055230). Regulates leukocyte adhesion and migration processes at the endothelium (PubMed:9024663, PubMed:9177350). Can activate integrins in both a CX3CR1-dependent and CX3CR1-independent manner (PubMed:23125415, PubMed:24789099). In the presence of CX3CR1, activates integrins by binding to the classical ligand-binding site (site 1) in integrins (PubMed:23125415, PubMed:24789099). In the absence of CX3CR1, binds to a second site (site 2) in integrins which is distinct from site 1 and enhances the binding of other integrin ligands to site 1 (PubMed:23125415, PubMed:24789099).
Expressed in the seminal plasma, endometrial fluid and follicular fluid (at protein level). Small intestine, colon, testis, prostate, heart, brain, lung, skeletal muscle, kidney and pancreas. Most abundant in the brain and heart.
Monomer (PubMed:9931005). Forms a ternary complex with CX3CR1 and ITGAV:ITGB3 or ITGA4:ITGB1 (PubMed:23125415).
The membrane-bound form promotes adhesion of those leukocytes to endothelial cells.
The soluble form is chemotactic for T-cells and monocytes, but not for neutrophils.
Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors (PubMed:29769720). Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway (PubMed:21727895, PubMed:21909076).
Binds heparin (By similarity). Interacts with LGR4, LGR5 and LGR6.
Tyr-112 may be phosphorylated; however as this position is probably extracellular, the vivo relevance is not proven.
Binds free ubiquitin non-covalently via its RING-type zinc finger. Ubiquitin-binding leads to enhance the E3 ubiquitin-protein ligase activity by stabilizing the ubiquitin-conjugating enzyme E2 (donor ubiquitin) in the 'closed' conformation and activating ubiquitin transfer.
E3 ubiquitin-protein ligase (PubMed:26656854). Required for mesoderm patterning during embryonic development (By similarity). Acts as an enhancer of the transcriptional responses of the SMAD2/SMAD3 effectors, which are activated downstream of BMP (PubMed:14657019, PubMed:16601693). Acts by mediating ubiquitination and degradation of SMAD inhibitors such as SMAD7, inducing their proteasomal degradation and thereby enhancing the transcriptional activity of TGF-beta and BMP (PubMed:14657019, PubMed:16601693). In addition to enhance transcription of SMAD2/SMAD3 effectors, also regulates their turnover by mediating their ubiquitination and subsequent degradation, coupling their activation with degradation, thereby ensuring that only effectors 'in use' are degraded (By similarity). Activates SMAD3/SMAD4-dependent transcription by triggering signal-induced degradation of SNON isoform of SKIL (PubMed:17591695). Associates with UBE2D2 as an E2 enzyme (PubMed:22411132). Specifically binds polysumoylated chains via SUMO interaction motifs (SIMs) and mediates ubiquitination of sumoylated substrates (PubMed:23751493). Catalyzes 'Lys-63'-linked ubiquitination of sumoylated XPC in response to UV irradiation, promoting nucleotide excision repair (PubMed:23751493). Mediates ubiquitination and degradation of sumoylated PML (By similarity). The regulation of the BMP-SMAD signaling is however independent of sumoylation and is not dependent of SUMO interaction motifs (SIMs) (By similarity).
Monomer (PubMed:26656854). Interacts with SMAD6, SMAD7, AXIN1, AXIN2 and SKIL isoform SNON (PubMed:16601693, PubMed:17591695). Interacts with (phosphorylated) SMAD2 and SMAD3 (By similarity). Part of a complex containing RNF111, AXIN1 and SMAD7 (PubMed:16601693). Interacts (via SIM domains) with SUMO1 and SUMO2 (PubMed:23086935).
The RING-type zinc finger mediates the E3 ubiquitin-protein ligase activity and binds directly to free ubiquitin (PubMed:26656854). Non-covalent ubiquitin-binding stabilizes the ubiquitin-conjugating enzyme E2 (donor ubiquitin) in the 'closed' conformation and stimulates ubiquitin transfer (By similarity).
The SUMO interaction motifs (SIMs) mediates the binding to polysumoylated substrate.
By high glucose through TGFB1-mediated pathways in mesangial cell. Down-regulated in tumor cell lines.
Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop. Down-regulates the BMP4 signaling in a dose-dependent manner (By similarity). Antagonist of BMP2; inhibits BMP2-mediated differentiation of osteoblasts (in vitro) (PubMed:27036124). Acts as inhibitor of monocyte chemotaxis. Can inhibit the growth or viability of normal cells but not transformed cells when is overexpressed (By similarity).
Highly expressed in small intestine, fetal brain and colon. Expression is restricted to intestinal subepithelial myofibroblasts (ISEMFs) at the crypt base. In subjects with HMPS1, by contrast, GREM1 is expressed, not only in basal ISEMFs, but also at very high levels in epithelial cells (predominantly colonocytes), with expression extending most of the way up the sides of the crypt. Weakly expressed in brain, ovary, prostate, pancreas and skeletal muscle. In brain found in the region localized around the internal capsule in the large subcortical nuclei, including caudate, putamen, substantia nigra, thalamus and subthalamus. Predominantly expressed in normal cells including neurons, astrocytes and fibroblasts.
Homodimer; can also form homooligomers (PubMed:27036124). Interacts with BMP2; can form higher oligomers with BMP2 (PubMed:27036124). Interacts with SLIT1 and SLIT2 in a glycosylation-dependent manner (By similarity).
The disease is caused by variants affecting the gene represented in this entry. HMPS1 is caused by a duplication spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. This duplication is associated with increased allele-specific GREM1 expression that may cause reduced bone morphogenetic protein (BMP) pathway activity. This mechanism also underlies tumorigenesis in juvenile polyposis of the large bowel (PubMed:22561515).
Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons (PubMed:19417104). Is recruited by release factors to stalled ribosomes together with SMG1 and SMG8 (forming the SMG1C protein kinase complex) and, in the SMG1C complex, is required for the efficient association between SMG1 and SMG8 (PubMed:19417104). Plays a role in brain, heart, and eye development (By similarity).
Self-associates to form homodimers and forms heterodimers with SMG8; these assembly forms may represent SMG1C intermediate forms (PubMed:20817927). Component of the SMG1C complex composed of SMG1, SMG8 and SMG9 (PubMed:33205750). Interacts with DHX34; the interaction is RNA-independent (PubMed:25220460).
Aquaporins contain two tandem repeats each containing three membrane-spanning domains and a pore-forming loop with the signature motif Asn-Pro/Ala-Ala/Ser (NPA).
Detected in the sperm head (at protein level) (PubMed:28042826). Detected in white adipose tissue (PubMed:9405233).
Forms a channel that mediates water and glycerol transport across cell membranes at neutral pH (PubMed:9405233, PubMed:11952783, PubMed:30423801, PubMed:30420639). The channel is also permeable to urea (PubMed:9405233). Plays an important role in body energy homeostasis under conditions that promote lipid catabolism, giving rise to glycerol and free fatty acids. Mediates glycerol export from adipocytes. After release into the blood stream, glycerol is used for gluconeogenesis in the liver to maintain normal blood glucose levels and prevent fasting hypoglycemia. Required for normal glycerol reabsorption in the kidney (By similarity).
Genetic variations in AQP7 are responsible for changes in glycerol release during exercise and define the glycerol quantitative trait locus (GLYCQTL) [MIM:614411].
Homotetramer (Probable). Interacts (via N-terminus) with PLIN1 (PubMed:27832861).
Inhibited by mercury ions (PubMed:9405233). Fully active at pH 6.5 to 7.5. Activity decreases with decreasing pH. Inactive at pH 5.5 (PubMed:30423801, PubMed:30420639).
Highly expressed in heart, skeletal muscle, prostate and ovary. Lower levels in lung, kidney, pancreas, thymus, testis and small intestine. Little or no expression in brain, placenta, liver, spleen, colon or peripheral blood leukocytes.
Induces cardiac myocyte hypertrophy in vitro. Binds to and activates the ILST/gp130 receptor.
A chromosomal aberration involving ASXL2 is a cause of therapy-related myelodysplastic syndrome. Translocation t(2;8)(p23;p11.2) with KAT6A generates a KAT6A-ASXL2 fusion protein.
Contains two Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs, which may be required for an association with nuclear receptors.
Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. PcG proteins are not required to initiate repression, but to maintain it during later stages of development. They probably act via methylation of histones, rendering chromatin heritably changed in its expressibility (By similarity). Involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as peroxisome proliferator-activated receptor gamma (PPARG). Acts as coactivator for PPARG and enhances its adipocyte differentiation-inducing activity; the function seems to involve differential recruitment of acetylated and methylated histone H3.
May have a regulatory bifunctional role.
Histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code (PubMed:17851529, PubMed:17713478, PubMed:17761849). Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-27' (PubMed:17851529, PubMed:17713478, PubMed:17761849). Plays a central role in regulation of posterior development, by regulating HOX gene expression (PubMed:17851529). Demethylation of 'Lys-27' of histone H3 is concomitant with methylation of 'Lys-4' of histone H3, and regulates the recruitment of the PRC1 complex and monoubiquitination of histone H2A (PubMed:17761849). Plays a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression (By similarity).
Interacts with TLE1 (By similarity). Component of the MLL2/3 complex (also named ASCOM complex), at least composed of KMT2D/MLL2 or KMT2C/MLL3, ASH2L, RBBP5, WDR5, NCOA6, DPY30, KDM6A (or KDM6B), PAXIP1/PTIP, PAGR1 and alpha- and beta-tubulin (PubMed:17500065, PubMed:17713478). Interacts with SUPT6H. Interacts with SMARCA4 (By similarity). Interacts with PROSER1 (PubMed:34667079).
Belongs to the dynactin subunit 2 family.
Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules. In the dynactin soulder domain, binds the ACTR1A filament and acts as a molecular ruler to determine the length (By similarity). Modulates cytoplasmic dynein binding to an organelle, and plays a role in prometaphase chromosome alignment and spindle organization during mitosis. Involved in anchoring microtubules to centrosomes. May play a role in synapse formation during brain development (By similarity).
Subunit of dynactin, a multiprotein complex part of a tripartite complex with dynein and a adapter, such as BICDL1, BICD2 or HOOK3. The dynactin complex is built around ACTR1A/ACTB filament and consists of an actin-related filament composed of a shoulder domain, a pointed end and a barbed end. Its length is defined by its flexible shoulder domain. The soulder is composed of 2 DCTN1 subunits, 4 DCTN2 and 2 DCTN3. The 4 DCNT2 (via N-terminus) bind the ACTR1A filament and act as molecular rulers to determine the length. The pointed end is important for binding dynein-dynactin cargo adapters and consists of 4 subunits: ACTR10, DCNT4, DCTN5 and DCTN6. The barbed end is composed of a CAPZA1:CAPZB heterodimers, which binds ACTR1A/ACTB filament and dynactin and stabilizes dynactin (By similarity). Interacts with BICD2 and CEP135 (By similarity). Interacts with DYNAP (PubMed:20978158). Interacts with ECPAS (PubMed:20682791). Interacts with MAPRE1 (PubMed:10226031).
Expressed at relatively low levels in colonic mucosa, ovary, peripheral leukocytes, prostate and small intestine, and at higher levels in spleen, testis and thymus. Expressed in multiple regions of the brain and CNS including amygdala, caudate, corpus callosum, hippocampus, substantia nigra and subthalamic nucleus. Isoform 1 is the predominant isoform in monocytes, macrophages and neutrophils, isoform 2 is most strongly expressed in peripheral blood leukocytes and quiescent CD34 positive cells, and isoform 3 is expressed at low levels in all hematopoietic cell types. Expression is frequently reduced in non-small-cell lung carcinomas (NSCLC) due to hemizygous gene deletion, strongly suggesting that this locus is haploinsufficient for tumor suppression. Loss of this locus frequently occurs in tumors which retain wild-type CDKN2A/ARF and p53/TP53 loci. Hemizygous gene deletion has also been observed in leukemic blasts from patients with abnormalities of the long arm of chromosome 7.
Interacts with the D-type cyclins CCND1, CCND2 and CCND3. Interaction with D-type cyclins may modulate transcriptional activation by this protein.
Isoform 2 expression is down-regulated during myeloid differentiation, while the expression of isoform 1 and isoform 3 remain constant.
Phosphorylated by the cyclin-D2/CDK4, cyclin-D3/CDK4 and cyclin-D2/CDK6 complexes and to a lesser extent by the cyclin-D1/CDK4 complex.
Transcriptional activator which activates the CDKN2A/ARF locus in response to Ras-Raf signaling, thereby promoting p53/TP53-dependent growth arrest (By similarity). Binds to the consensus sequence 5'-CCCG[GT]ATGT-3' (By similarity). Isoform 1 may cooperate with MYB to activate transcription of the ANPEP gene. Isoform 2 may antagonize transcriptional activation by isoform 1.
(Microbial infection) Has an antiviral effect against flaviviruses by affecting viral RNA transcription and translation through the sequestration of elongation factor 1-alpha (EEF1A1). This results in decreased viral RNA synthesis and decreased viral protein translation.
(Microbial infection) Interacts with West Nile virus and Dengue virus capsid protein C; this interaction results in EXOC1 degradation through the proteasome degradation pathway.
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8. Interacts with EEF1A1 (PubMed:19889084). Interacts with SLC6A9; interaction increases the transporter capacity of SLC6A9 probably by promoting its insertion into the cell membrane (PubMed:16181645).
Binds TNR and probably TNC (By similarity). Interacts with ERBB3 and GOPC. Interacts with MDK; this interaction is independent of the presence of chondroitin sulfate chains and promotes elongation of oligodendroglial precursor-like cells (By similarity).
Detected in cerebrospinal fluid (at protein level) (PubMed:25326458). Expressed in brain (at protein level) (PubMed:9950058).
Different forms of various molecular weight have been observed. Such forms are possibly due to different levels of glycosylation, phosphorylation and/or protein cleavage (By similarity).
Expressed in brain of 3 months, 5 and 10-year-old individuals.
May function as a growth and differentiation factor involved in neuritogenesis. May induce ERBB3 activation.
O-glycosylated; contains chondroitin sulfate glycans (PubMed:25326458). Part-time proteoglycan, expressed in part as a proteoglycan exhibiting chondroitin sulfate glycans and in part as a non-proteoglycan form (By similarity). The relative amount of both forms depends on tissues and tissue maturation (By similarity).
Phosphorylated; in intracellular and extracellular parts.
Expressed in heart, brain, skeletal muscle and lung.
May be proteolytically processed by a furin-like protease.
Interacts with VPS4B. Interacts with CHMP1B. Interacts with CHMP2A; the interaction probably involves the open conformation of (polymerized) CHMP2A. Interacts with CHMP3. Interacts with CHMP5; the interaction involves soluble CHMP5. Interacts with IST1.
Involved in the endosomal multivesicular bodies (MVB) pathway. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. Thought to be a cofactor of VPS4A/B, which catalyzes disassembles membrane-associated ESCRT-III assemblies. Involved in the sorting and down-regulation of EGFR (By similarity). Involved in HIV-1 budding.
Expressed in dermal papilla cells with aggregative behavior.
A chromosomal aberration involving AFF4 is found in acute lymphoblastic leukemia (ALL). Insertion ins(5;11)(q31;q13q23) that forms a KMT2A/MLL1-AFF4 fusion protein.
Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3) (PubMed:12065898, PubMed:20471948, PubMed:20159561, PubMed:22195968, PubMed:22483617, PubMed:30134174). Interacts with ELL3; the interaction is direct (By similarity). Interacts with ELL2; the interaction is direct and leads to stabilize ELL2 and prevent ELL2 ubiquitination and degradation (PubMed:22483617).
Expressed in fetal heart, lung, brain and to a lower extent liver.
Key component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. In the SEC complex, AFF4 acts as a central scaffold that recruits other factors through direct interactions with ELL proteins (ELL, ELL2 or ELL3) and the P-TEFb complex. In case of infection by HIV-1 virus, the SEC complex is recruited by the viral Tat protein to stimulate viral gene expression.
Ubiquitously expressed. Strongly expressed in heart, placenta, skeletal muscle, pancreas and to a lower extent in brain.
Binds SXL. Associates with the spliceosome. Interacts with SF3B1, SF1 and U2AF2.
Splice factor that binds to the single-stranded 3'AG at the exon/intron border and promotes its utilization in the second catalytic step. Involved in the regulation of alternative splicing and the utilization of cryptic splice sites.
Splice factor that binds to the single-stranded 3'AG at the exon/intron border and promotes its utilization in the second catalytic step. Involved in the regulation of alternative splicing and the utilization of cryptic splice sites. Promotes the utilization of a cryptic splice site created by the beta-110 mutation in the HBB gene. The resulting frameshift leads to sickle cell anemia.
In lens, first detected at 16 weeks when expression is weakly and uniformly distributed. Subsequently, expression becomes much stronger in the epithelium of the anterior part at 25 weeks and later. In retina, weakly expressed at 15 weeks in the nerve fiber and ganglion cell layers (NFL and GCL). From 25 weeks onwards, much stronger expression is observed in the endfeet of Mueller cells, the NFL, and GCL, and much lower expression is observed in a minor subpopulation of cells in the inner cell layer (INL). At 30 and 36 weeks, expression remains in the neural retina, and subsequently becomes stronger in the NFL, GCL, and INL and is decreased in Mueller cells. At 36 weeks, also expressed at the external border of the outer nuclear layer (ONL) (at protein level).
Interacts with GFAP and VIM (By similarity). Isoform 1 interacts with TLN1 and VCL. Isoform 2 interacts with DES and DTNA. Isoform 1 and isoform 2 interact with DMD and UTRN.
Isoform 2 is strongly detected in adult heart, fetal skeletal muscles and fetal heart. Isoform 1 is weakly detected in fetal heart and also in fetal skeletal muscle. Isoform 1 and isoform 2 are detected in adult bladder (at protein level). The mRNA is predominantly expressed in heart and muscle with some expression in brain which may be due to tissue-specific isoforms.
Type-VI intermediate filament (IF) which plays an important cytoskeletal role within the muscle cell cytoskeleton. It forms heteromeric IFs with desmin and/or vimentin, and via its interaction with cytoskeletal proteins alpha-dystrobrevin, dystrophin, talin-1, utrophin and vinculin, is able to link these heteromeric IFs to adherens-type junctions, such as to the costameres, neuromuscular junctions, and myotendinous junctions within striated muscle cells.
Belongs to the aromatic-ring hydroxylase family. KMO subfamily.
Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn) (PubMed:29429898, PubMed:23575632, PubMed:26752518, PubMed:28604669, PubMed:29208702). Required for synthesis of quinolinic acid, a neurotoxic NMDA receptor antagonist and potential endogenous inhibitor of NMDA receptor signaling in axonal targeting, synaptogenesis and apoptosis during brain development. Quinolinic acid may also affect NMDA receptor signaling in pancreatic beta cells, osteoblasts, myocardial cells, and the gastrointestinal tract (Probable).
Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn). Required for synthesis of quinolinic acid, a neurotoxic NMDA receptor antagonist and potential endogenous inhibitor of NMDA receptor signaling in axonal targeting, synaptogenesis and apoptosis during brain development. Quinolinic acid may also affect NMDA receptor signaling in pancreatic beta cells, osteoblasts, myocardial cells, and the gastrointestinal tract.
Highest levels in placenta and liver. Detectable in kidney.
Increased in neuroinflammatory conditions. Inhibitors are investigated as potential neuroprotective drugs since they lead to an increased level of kynurenic acid, a neuroprotective NMDA receptor agonist.
Transmembrane domains are required for enzymatic activity.
Detected in pancreas islets (at protein level). Detected in brain and pancreas.
Found in a complex containing CABLES1, CDK17 and TDRD7. Interacts with YWHAH, YWHAQ and YWHAZ. Interacts with NSF. Identified in a complex with NSF, syntaxin-1, synaptotagmin, SYN1, SYP and CDK5R1 (By similarity). Interacts with BRSK2. Interacts with CCNY; this increases the CDK16 kinase activity.
Phosphorylation at Ser-153 inhibits kinase activity.
Protein kinase that plays a role in vesicle-mediated transport processes and exocytosis. Regulates GH1 release by brain neurons. Phosphorylates NSF, and thereby regulates NSF oligomerization. Required for normal spermatogenesis. Regulates neuron differentiation and dendrite development (By similarity). Plays a role in the regulation of insulin secretion in response to changes in blood glucose levels. Can phosphorylate CCNY at 'Ser-336' (in vitro).
Expressed predominantly in skeletal muscle.
Unlike most P2XRs, P2RX6 does not seem to form homotrimers or heterotrimers.
Interacts with MCL1, BCL2, BCL2L1/BCL-Xl, BCL2A1 and BCL2L2/BCL-w. Interacts with the myosin V actin motor complex through its binding to DLC2 (By similarity).
Isoform 1 is mainly expressed in B-lymphoid cells. Isoform 2 and isoform 3 are mainly expressed in B-CLL and normal B-cells.
May play a role in apoptosis. Isoform 1 seems to be the main initiator.
Component of the HBO1 complex composed of KAT7/HBO1, MEAF6, ING5, and one scaffold subunit: complexes containing BRPF scaffold (BRPF1, BRD1/BRPF2 or BRPF3) direct KAT7/HBO1 specificity towards H3K14ac, while complexes containing JADE scaffold (JADE1, JADE2 and JADE3) mediate acetylation of histone H4 (PubMed:16387653, PubMed:24065767). Component of the MOZ/MORF complex composed at least of ING5, KAT6A, KAT6B, MEAF6 and one of BRPF1, BRD1/BRPF2 and BRPF3 (PubMed:16387653, PubMed:18794358). Interacts with H3K4me3 and to a lesser extent with H3K4me2 (PubMed:16728974, PubMed:18623064). Interacts with EP300 and p53/TP53 (PubMed:12750254). Interacts with INCA1 (PubMed:21750715).
Component of the HBO1 complex, which specifically mediates acetylation of histone H3 at 'Lys-14' (H3K14ac) and, to a lower extent, acetylation of histone H4 (PubMed:24065767). Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity (PubMed:16387653). Through chromatin acetylation it may regulate DNA replication and may function as a transcriptional coactivator (PubMed:12750254, PubMed:16387653). Inhibits cell growth, induces a delay in S-phase progression and enhances Fas-induced apoptosis in an INCA1-dependent manner (PubMed:21750715).
Down-regulated in bone marrow cells in acute myeloid leukemia patients as compared with normal bone marrow cells.
DLEC1 silencing due to promoter methylation and aberrant transcription are implicated in the development of different cancers, including esophageal (ESCR), renal and lung cancers (LNCR).
Essential for spermatogenesis and male fertility (By similarity). May play an important role in sperm head and tail formation (By similarity). May act as a tumor suppressor by inhibiting cell proliferation.
Expressed in all tissues examined. Expression is highest in prostate and testis.
Interacts with alpha- and beta-tubulin (PubMed:33144677). Interacts with BBS2, BBS4, BBS5, MKKS, TCP1, CCT2, CCT3, CCT4, CCT5 and CCT7 (PubMed:33144677).
Levels of this splice isoform are increased in cancer cell lines and primary cancers.
Levels of this splice isoform may be increased in cancer cell lines and primary cancers.
The gene represented in this entry may be involved in disease pathogenesis. DLEC1 silencing due to promoter methylation and aberrant transcription are implicated in the development of lung cancer.
The gene represented in this entry may be involved in disease pathogenesis. DLEC1 silencing due to promoter methylation and aberrant transcription may be implicated in the development of esophageal cancer.
(Microbial infection) Interacts with herpes virus 8 protein vPK; this interaction inhibits the Wnt signaling pathway.
A chromosomal aberration involving CTNNB1 is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with PLAG1.
A paper showing an interaction with TBP and phosphorylation at Tyr-86 and Tyr-654 has been retracted due to panel duplication in several figures.
Activating mutations in CTNNB1 have oncogenic activity resulting in tumor development. Somatic mutations are found in various tumor types, including colon cancers, ovarian and prostate carcinomas, hepatoblastoma (HB), hepatocellular carcinoma (HCC). HBs are malignant embryonal tumors mainly affecting young children in the first three years of life.
Expressed in several hair follicle cell types: basal and peripheral matrix cells, and cells of the outer and inner root sheaths. Expressed in colon. Present in cortical neurons (at protein level). Expressed in breast cancer tissues (at protein level) (PubMed:29367600).
Key downstream component of the canonical Wnt signaling pathway (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). Involved in the regulation of cell adhesion, as component of an E-cadherin:catenin adhesion complex (By similarity). Acts as a negative regulator of centrosome cohesion (PubMed:18086858). Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization (PubMed:21262353). Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2 (PubMed:18957423). Disrupts PML function and PML-NB formation by inhibiting RANBP2-mediated sumoylation of PML (PubMed:22155184). Promotes neurogenesis by maintaining sympathetic neuroblasts within the cell cycle (By similarity). Involved in chondrocyte differentiation via interaction with SOX9: SOX9-binding competes with the binding sites of TCF/LEF within CTNNB1, thereby inhibiting the Wnt signaling (By similarity). Acts as a positive regulator of odontoblast differentiation during mesenchymal tooth germ formation, via promoting the transcription of differentiation factors such as LEF1, BMP2 and BMP4 (By similarity). Activity is repressed in a MSX1-mediated manner at the bell stage of mesenchymal tooth germ formation which prevents premature differentiation of odontoblasts (By similarity).
O-glycosylation at Ser-23 decreases nuclear localization and transcriptional activity, and increases localization to the plasma membrane and interaction with E-cadherin CDH1.
Phosphorylated at Thr-556 by herpes virus 1/HHV-1 leading to CTNNB1 inhibition.
Phosphorylation at Ser-552 by AMPK promotes stabilization of the protein, enhancing TCF/LEF-mediated transcription (By similarity). Phosphorylation by GSK3B requires prior phosphorylation of Ser-45 by another kinase (PubMed:10966653, PubMed:12051714, PubMed:12027456). Phosphorylation proceeds then from Thr-41 to Ser-37 and Ser-33 (PubMed:12077367, PubMed:25169422). Phosphorylated by NEK2 (PubMed:18086858). EGF stimulates tyrosine phosphorylation (PubMed:10187801). Phosphorylated on Ser-33 and Ser-37 by HIPK2 and GSK3B, this phosphorylation triggers proteasomal degradation (PubMed:20307497). Phosphorylation on Ser-191 and Ser-246 by CDK5 (PubMed:17009320). Phosphorylation by CDK2 regulates insulin internalization (PubMed:21262353). Phosphorylation by PTK6 at Tyr-64, Tyr-142, Tyr-331 and/or Tyr-333 with the predominant site at Tyr-64 is not essential for inhibition of transcriptional activity (PubMed:20026641). Phosphorylation by SRC at Tyr-333 promotes interaction with isoform M2 of PKM (PKM2); promoting transcription activation (PubMed:22056988).
S-nitrosylation at Cys-619 within adherens junctions promotes VEGF-induced, NO-dependent endothelial cell permeability by disrupting interaction with E-cadherin, thus mediating disassembly adherens junctions.
Two separate complex-associated pools are found in the cytoplasm. The majority is present as component of an E-cadherin:catenin adhesion complex composed of at least E-cadherin/CDH1 and beta-catenin/CTNNB1, and possibly alpha-catenin/CTNNA1; the complex is located to adherens junctions. The stable association of CTNNA1 is controversial as CTNNA1 was shown not to bind to F-actin when assembled in the complex. Alternatively, the CTNNA1-containing complex may be linked to F-actin by other proteins such as LIMA1. Another cytoplasmic pool is part of a large complex containing AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. Wnt-dependent activation of DVL antagonizes the action of GSK3B. When GSK3B activity is inhibited the complex dissociates, CTNNB1 is dephosphorylated and is no longer targeted for destruction. The stabilized protein translocates to the nucleus, where it binds TCF/LEF-1 family members, BCL9, BCL9L and possibly also RUVBL1 and CHD8. Binds CTNNBIP and EP300. CTNNB1 forms a ternary complex with LEF1 and EP300 that is disrupted by CTNNBIP1 binding. Interacts with TAX1BP3 (via the PDZ domain); this interaction inhibits the transcriptional activity of CTNNB1. Interacts with AJAP1, BAIAP1, CARM1, CTNNA3, CXADR and PCDH11Y. Binds NHERF1. Interacts with GLIS2 and MUC1. Interacts with SLC30A9. Interacts with XIRP1. Interacts directly with AXIN1; the interaction is regulated by CDK2 phosphorylation of AXIN1. Interacts with SCRIB. Interacts with RAPGEF2. Interacts with PTPRU (via the cytoplasmic juxtamembrane domain). Interacts with EMD. Interacts with TNIK and TCF7L2. Interacts with SESTD1 and TRPC4. Interacts with CAV1. Interacts with TRPV4. The TRPV4 and CTNNB1 complex can interact with CDH1. Interacts with VCL. Interacts with PTPRJ. Interacts with PKT7 and CDK2. Interacts with FAT1 (via the cytoplasmic domain). Interacts with NANOS1 and NDRG2. Interacts with isoform 1 of NEK2. Interacts with both isoform 1 and isoform 2 of CDK5. Interacts with PTK6. Interacts with SOX7; this interaction may lead to proteasomal degradation of active CTNNB1 and thus inhibition of Wnt/beta-catenin-stimulated transcription. Identified in a complex with HINT1 and MITF. Interacts with FHIT. The CTNNB1 and TCF7L2/TCF4 complex interacts with PML (isoform PML-4). Interacts with FERMT2. Identified in a complex with TCF7L2/TCF4 and FERMT2 (PubMed:29739711, PubMed:22699938). Interacts with RORA. May interact with P-cadherin/CDH3. Interacts with RNF220 (PubMed:25266658). Interacts with CTNND2 (PubMed:25807484). Interacts (via the C-terminal region) with CBY1 (PubMed:12712206, PubMed:16424001). The complex composed, at least, of APC, CTNNB1 and GSK3B interacts with JPT1; the interaction requires the inactive form of GSK3B (phosphorylated at 'Ser-9') (PubMed:25169422). Interacts with DLG5 (By similarity). Interacts with FAM53B; promoting translocation to the nucleus (PubMed:25183871). Interacts with TMEM170B (PubMed:29367600). Interacts with AHI1 (PubMed:21623382). Interacts with GID8 (PubMed:28829046). Component of an cadherin:catenin adhesion complex composed of at least of CDH26, beta-catenin/CTNNB1, alpha-catenin/CTNNA1 and p120 catenin/CTNND1 (PubMed:28051089). Forms a complex comprising APPL1, RUVBL2, APPL2, HDAC1 and HDAC2 (PubMed:19433865). Interacts with IRF2BPL; mediates the ubiquitination and degradation of CTNNB1 (PubMed:29374064). Interacts with AMFR (By similarity). Interacts with LMBR1L (PubMed:31073040). Interacts with SOX30; prevents interaction of CTNNB1 with TCF7L2/TCF4 and leads to inhibition of Wnt signaling (PubMed:29739711). Interacts with SOX9; inhibiting CTNNB1 activity by competing with the binding sites of TCF/LEF within CTNNB1, thereby inhibiting the Wnt signaling (By similarity). Interacts with SPN/CD43 cytoplasmic tail (PubMed:15003504). Interacts (when phosphorylated at Tyr-333) with isoform M2 of PKM (PKM2); promoting transcription activation (PubMed:22056988). Interacts with PKP2 (via HEAD domain) (PubMed:11790773). Interacts with CDH1 (PubMed:11790773). Interacts (when unphosphorylated) with FLYWCH1, perhaps preventing interaction of CTNNB1 with TCF4, and thereby regulating transcription activation; phosphorylation of CTNNB1 may inhibit the interaction (PubMed:30097457). Interacts (via the central armadillo domains) with probable transcriptional regulator ADNP (via N-terminal region); interaction is direct and stabilizes CTNNB1 by modulating its phosphorylation by glycogen synthase kinase-3 beta GSK3B (By similarity).
Ubiquitinated by the SCF(BTRC) E3 ligase complex when phosphorylated by GSK3B, leading to its degradation (PubMed:12077367). Ubiquitinated by a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X, leading to its subsequent proteasomal degradation (PubMed:11389839, PubMed:11389840, PubMed:20307497). Ubiquitinated and degraded following interaction with SOX9 (By similarity).
Composed of an N- and a C-terminal domain. The N-terminal domain carries the tetrahydrofolate (THF)-binding site and the C-terminal domain is presumably involved in positioning the Met-tRNA substrate for the formylation reaction.
Methionyl-tRNA formyltransferase that formylates methionyl-tRNA in mitochondria and is crucial for translation initiation.
Component of the nexin-dynein regulatory complex (N-DRC). Directly interacts with SKP1 and CUL1. Interacts with TCTE1/DRC5.
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Component of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes. Specifically targets CEP192 isoform 3 for ubiquitin-mediated proteolysis and thereby acts as a regulator of microtubule nucleation activity (PubMed:29348145).
Cleaved by ELANE; proteolysis is blocked by SLPI and is concentration- and time-dependent and induces CXCL8/IL-8 production; granulin-3 and granulin-4 are resistant to ELANE (PubMed:12526812, PubMed:28743268). Cleaved by CTSL in lysosome thus regulating the maturation and turnover of progranulin within the lysosome (PubMed:28743268).
In myelogenous leukemic cell lines of promonocytic, promyelocytic, and proerythroid lineage, in fibroblasts, and very strongly in epithelial cell lines. Present in inflammatory cells and bone marrow. Highest levels in kidney.
Increased in response to lysosome alkalization.
Inhibits epithelial cell proliferation and induces epithelial cells to secrete IL-8.
Progranulin is secreted as a homodimer (PubMed:23364791). Interacts with SLPI; interaction protects progranulin from proteolysis (PubMed:12526812). Interacts (via region corresponding to granulin-7 peptide) with CTSD; stabilizes CTSD and increases its proteolytic activity (PubMed:28453791). Interacts (via region corresponding to granulin-7 peptide) with SORT1; this interaction mediates endocytosis and lysosome delivery of progranulin; interaction occurs at the neuronal cell surface in a stressed nervous system (PubMed:21092856). Interacts with PSAP; facilitates lysosomal delivery of progranulin from the extracellular space and the biosynthetic pathway (PubMed:26370502). Forms a complex with PSAP and M6PR; PSAP bridges the binding between progranulin and M6PR (PubMed:26370502). Forms a complex with PSAP and SORT1; progranulin bridges the interaction between PSAP and SORT1; facilitates lysosomal targeting of PSAP via SORT1; interaction enhances PSAP uptake in primary cortical neurons (PubMed:28541286). Interacts (via regions corresponding to granulin-2 and granulin-7 peptides) with GBA1; this interaction prevents aggregation of GBA1-SCARB2 complex via interaction with HSPA1A upon stress (PubMed:27789271). Interacts (via region corresponding to granulin-7 peptide) with HSPA1A; mediates recruitment of HSPA1A to GBA1 and prevents GBA1 aggregation in response to stress (PubMed:27789271).
Promotes proliferation of the epithelial cell line A431 in culture.
Secreted protein that acts as a key regulator of lysosomal function and as a growth factor involved in inflammation, wound healing and cell proliferation (PubMed:28541286, PubMed:28073925, PubMed:18378771, PubMed:28453791, PubMed:12526812). Regulates protein trafficking to lysosomes and, also the activity of lysosomal enzymes (PubMed:28453791, PubMed:28541286). Facilitates also the acidification of lysosomes, causing degradation of mature CTSD by CTSB (PubMed:28073925). In addition, functions as wound-related growth factor that acts directly on dermal fibroblasts and endothelial cells to promote division, migration and the formation of capillary-like tubule structures (By similarity). Also promotes epithelial cell proliferation by blocking TNF-mediated neutrophil activation preventing release of oxidants and proteases (PubMed:12526812). Moreover, modulates inflammation in neurons by preserving neurons survival, axonal outgrowth and neuronal integrity (PubMed:18378771).
Stabilizes CTSD through interaction with CTSD leading to maintain its aspartic-type peptidase activity.
Histone H3 reader which may act as a transcriptional coactivator for KLF6 and KLF9 transcription factors.
Interacts with KLF6 and KLF9 (PubMed:33227311). Interacts via (ZZ-type 2 zinc finger) with histone H3 trimethylated at 'Lys-4' (H3K4me3) and histone H3 acetylated at 'Lys-4' (H3K4ac) (PubMed:33227311).
Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family.
Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A3 subfamily.
Contains eight transmembrane regions plus two helical hairpins that dip into the membrane. These helical hairpin structures play an important role in the transport process. The first enters the membrane from the cytoplasmic side, the second one from the extracellular side. During the transport cycle, the regions involved in amino acid transport, and especially the helical hairpins, move vertically by about 15-18 Angstroms, alternating between exposure to the aqueous phase and reinsertion in the lipid bilayer. In contrast, the regions involved in trimerization do not move.
Detected in brain (PubMed:8218410, PubMed:7521911, PubMed:8123008). Detected at very much lower levels in heart, lung, placenta and skeletal muscle (PubMed:7521911, PubMed:8123008). Highly expressed in cerebellum, but also found in frontal cortex, hippocampus and basal ganglia (PubMed:7521911).
Expressed throughout the CNS, both in gray matter and axonal tracts, at levels ranging between 10% and 20% of isoform 1. Localizes to ER, has no functional glutamate uptake activity, and exerts a dominant negative effect isoform 1.
Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:7521911, PubMed:8123008, PubMed:20477940, PubMed:26690923, PubMed:28032905, PubMed:28424515). Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion (PubMed:20477940). Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport (PubMed:20477940). Plays a redundant role in the rapid removal of released glutamate from the synaptic cleft, which is essential for terminating the postsynaptic action of glutamate (By similarity).
A 9 kDa form is produced by proteolytic processing of a 15 kDa protein.
Antimicrobial protein that kills intracellular pathogens. Active against a broad range of microbes, including Gram-positive and Gram-negative bacteria, fungi, and parasites. Kills Mycobacterium tuberculosis.
By T-cell growth factor and IL2/interleukin-2.
Expressed in natural killer and T-cells.
Interacts with CSNK1A1; recruits CSNK1A1 to keratin filaments. Interacts with KRT18 and probably other keratins.
May play a major role in the structural organization and calcification of developing enamel (PubMed:18252228). May play a role in keratin cytoskeleton disassembly by recruiting CSNK1A1 to keratin filaments. Thereby, it may regulate epithelial cell migration (PubMed:23902688).
Down-regulated by 1,25-dihydroxyvitamin D3 in prostate cancer samples from patients assigned to receive weekly high-dose 1,25-dihydroxyvitamin D3 before radical prostatectomy. Also down-regulated by 1,25-dihydroxyvitamin D3 in the human androgen-sensitive prostate cancer cell line LNCaP and in the estrogen-sensitive breast cancer cell line MCF-7.
Establishes the cardiac repolarization gradient by its repressive actions on the KCND2 potassium-channel gene. Required for retinal cone bipolar cell differentiation. May regulate contrast adaptation in the retina and control specific aspects of visual function in circuits of the mammalian retina (By similarity). Could be involved in the regulation of both the cell cycle and apoptosis in prostate cancer cells. Involved in craniofacial and gonadal development. Modulates the migration of progenitor cell populations in branchial arches and gonads by repressing CXCL12.
ACTL6A mutations have been found in patients with intellectual disability of variable severity, developmental delay, dysmorphic features and digit abnormalities. Additional features may include genitourinary and cardiac defects. The disease phenotype resembles Coffin-Siris syndrome and brachymorphism-onychodysplasia-dysphalangism syndrome.
Component of numerous complexes with chromatin remodeling and histone acetyltransferase activity. Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 (PubMed:12963728, PubMed:10966108, PubMed:15196461, PubMed:14966270). The NuA4 complex interacts with MYC and the adenovirus E1A protein (PubMed:11509179). Component of a NuA4-related complex which contains EP400, TRRAP/PAF400, SRCAP, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, actin, ACTL6A/BAF53A, VPS72 and YEATS4/GAS41 (PubMed:11509179, PubMed:14966270). Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B) and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific (Probable). Component of the BAF complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C (PubMed:9845365, PubMed:18765789). In muscle cells, the BAF complex also contains DPF3. Component of the BAF53 complex, at least composed of ACTL6A/BAF53A, RUVBL1/TIP49, SMARCA2/BRM/BAF190B and TRRAP/PAF400, and which may also include a HAT activity related to, but distinct from, that of KAT5 (PubMed:11839798). Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Component of SWI/SNF (GBAF) subcomplex, which includes at least BICRA or BICRAL (mutually exclusive), BRD9, SS18, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, SMARCC1/BAF155, and SMARCD1/BAF60A (PubMed:29374058). May be a component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin (PubMed:26601204). Interacts with SMARCA4/BRG1/BAF190A (PubMed:28649782). Interacts with PHF10/BAF45A (By similarity). Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the DBINO domain of INO80 (PubMed:16230350, PubMed:18026119, PubMed:18922472, PubMed:21303910). Interacts with DPF2 (PubMed:28533407).
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Required for maximal ATPase activity of SMARCA4/BRG1/BAF190A and for association of the SMARCA4/BRG1/BAF190A containing remodeling complex BAF with chromatin/nuclear matrix. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and is required for the proliferation of neural progenitors. During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage. Putative core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.
Cytokine that is chemotactic for monocytes but not for neutrophils. Binds to CCR8.
Weakly expressed in tongue, but not skin or in any other tissues or organs examined.
Belongs to the polyadenylate-binding protein type-1 family.
Binds the poly(A) tail of mRNA. May be involved in cytoplasmic regulatory processes of mRNA metabolism. Binds poly(A) with a slightly lower affinity as compared to PABPC1.
Ubiquitous, with higher levels in heart, placenta and kidney.
A cytochrome P450 monooxygenase involved in neural cholesterol clearance through bile acid synthesis (PubMed:25201972, PubMed:10748047). Catalyzes 7-alpha hydroxylation of (24S)-hydroxycholesterol, a neural oxysterol that is metabolized to bile acids in the liver (PubMed:25201972, PubMed:10748047). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:25201972, PubMed:10748047).
Variations in CYP39A1 are associated with elevated serum (24S)-hydroxycholesterol levels among a cohort of American residents.
Monomer (By similarity). Homodimer (Probable). Interacts with LRP4; the heterodimer forms an AGRIN receptor complex that binds AGRIN resulting in activation of MUSK (By similarity). Forms a heterotetramer composed of 2 DOK7 and 2 MUSK molecules which facilitates MUSK trans-autophosphorylation on tyrosine residue and activation. Interacts (via cytoplasmic part) with DOK7 (via IRS-type PTB domain); requires MUSK phosphorylation. Interacts with DVL1 (via DEP domain); the interaction is direct and mediates the formation of a DVL1, MUSK and PAK1 ternary complex involved in AChR clustering (By similarity). Interacts with PDZRN3; this interaction is enhanced by agrin (By similarity). Interacts with FNTA; the interaction is direct and mediates AGRIN-induced phosphorylation and activation of FNTA (By similarity). Interacts with CSNK2B; mediates regulation by CK2 (By similarity). Interacts (via the cytoplasmic domain) with DNAJA3 (By similarity). Interacts with NSF; may regulate MUSK endocytosis and activity (By similarity). Interacts with CAV3; may regulate MUSK signaling (By similarity). Interacts with RNF31 (By similarity).
Phosphorylated (By similarity). Phosphorylation is induced by AGRIN in a LRP4-dependent manner (By similarity). Autophosphorylated (PubMed:25029443). Autophosphorylation at Tyr-554 is required for interaction with DOK7 which in turn stimulates the phosphorylation and the activation of MUSK (By similarity).
Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle (PubMed:25537362). Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. May regulate AChR phosphorylation and clustering through activation of ABL1 and Src family kinases which in turn regulate MUSK. DVL1 and PAK1 that form a ternary complex with MUSK are also important for MUSK-dependent regulation of AChR clustering. May positively regulate Rho family GTPases through FNTA. Mediates the phosphorylation of FNTA which promotes prenylation, recruitment to membranes and activation of RAC1 a regulator of the actin cytoskeleton and of gene expression. Other effectors of the MUSK signaling include DNAJA3 which functions downstream of MUSK. May also play a role within the central nervous system by mediating cholinergic responses, synaptic plasticity and memory formation (By similarity).
The disease is caused by variants affecting the gene represented in this entry. MUSK mutations lead to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction.
Ubiquitinated by PDZRN3. Ubiquitination promotes endocytosis and lysosomal degradation (By similarity).
Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter APPBP2 (PubMed:29779948, PubMed:29775578). Interacts with APP; APP interaction inhibits the E3 ubiquitin-protein ligase activity of the CRL2(APPBP2) complex (PubMed:9843960, PubMed:29775578).
E3 ubiquitin-protein ligase activity of the CRL2(APPBP2) complex is inhibited by APP.
Rapidly degraded by the proteasome upon overexpression of a C-terminal fragment of APP.
Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:29775578). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (PubMed:29779948, PubMed:29775578). The CRL2(APPBP2) complex specifically recognizes proteins with a -Arg-Xaa-Xaa-Gly degron at the C-terminus, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:29775578). The CRL2(APPBP2) complex mediates ubiquitination and degradation of truncated SELENOV selenoproteins produced by failed UGA/Sec decoding, which end with a -Arg-Xaa-Xaa-Gly degron (PubMed:26138980). May play a role in intracellular protein transport: may be involved in the translocation of APP along microtubules toward the cell surface (PubMed:9843960).
Mutarotase that catalyzes the interconversion of beta-D-galactose and alpha-D-galactose during galactose metabolism (PubMed:12753898). Beta-D-galactose is metabolized in the liver into glucose 1-phosphate, the primary metabolic fuel, by the action of four enzymes that constitute the Leloir pathway: GALM, GALK1 (galactokinase), GALT (galactose-1-phosphate uridylyltransferase) and GALE (UDP-galactose-4'-epimerase) (PubMed:30451973). Involved in the maintenance of the equilibrium between the beta- and alpha-anomers of galactose, therefore ensuring a sufficient supply of the alpha-anomer for GALK1 (PubMed:12753898). Also active on D-glucose although shows a preference for galactose over glucose (PubMed:12753898).
Mutarotase that catalyzes the interconversion of beta-D-galactose and alpha-D-galactose during galactose metabolism.
Mediates the electroneutral exchange of acylcarnitines (O-acyl-(R)-carnitine or L-acylcarnitine) of different acyl chain lengths (ranging from O-acetyl-(R)-carnitine to long-chain O-acyl-(R)-carnitines) with free carnitine ((R)-carnitine or L-carnitine) across the mitochondrial inner membrane, via a ping-pong mechanism (PubMed:12892634, PubMed:18307102) (Probable). Key player in the mitochondrial oxidation pathway, it translocates the fatty acids in the form of acylcarnitines into the mitochondrial matrix, where the carnitine palmitoyltransferase 2 (CPT-2) activates them to undergo fatty acid beta-oxidation (Probable). Catalyzes the unidirectional transport (uniport) of carnitine at lower rates than the antiport (exchange) (PubMed:18307102).
Belongs to the chloride channel (TC 2.A.49) family. ClC-6/CLCN6 subfamily.
N-glycosylated on several asparagine residues.
Testis, ovary, small intestine, brain and skeletal muscle. Low level expression in aortic and coronary vascular smooth muscle cells, and aortic endothelial cells. Isoform 3 is only detected in kidney.
Voltage-gated channel mediating the exchange of chloride ions against protons. Functions as antiporter and contributes to the acidification of the late endosome lumen. The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The presence of conserved gating glutamate residues is typical for family members that function as antiporters.
Abundantly expressed in skeletal muscle and heart, moderately in kidney, liver, brain and placenta and sparingly in the pancreas and lung. Easily detectable in cell lines such as MOLT-4, HEK293 and Jurkat.
C-terminal fragments could be released during apoptosis via caspase-3-dependent cleavage.
Heterodimer or homodimer. Interacts with CK2 and actin capping subunits (capping protein CP-alpha and CP-beta). CKIP1 and CK2 together inhibit the activity of actin capping protein at the barbed ends of actin filaments. Interacts with ATM, IFP35, JUN, JUND, NMI and PI3K. Interacts with AKT1, AKT2 and AKT3 (each isozyme of PKB), PtdIns(3,5)P2, PtdIns(4,5)P2 and PtdIns(3,4,5)P2.
Plays a role in the regulation of the actin cytoskeleton through its interactions with actin capping protein (CP). May function to target CK2 to the plasma membrane thereby serving as an adapter to facilitate the phosphorylation of CP by protein kinase 2 (CK2). Appears to target ATM to the plasma membrane. Appears to also inhibit tumor cell growth by inhibiting AKT-mediated cell-survival. Also implicated in PI3K-regulated muscle differentiation, the regulation of AP-1 activity (plasma membrane bound AP-1 regulator that translocates to the nucleus) and the promotion of apoptosis induced by tumor necrosis factor TNF. When bound to PKB, it inhibits it probably by decreasing PKB level of phosphorylation.
Up-regulated by IFNG/IFN-gamma and IL2/interleukin-2 or in C2C12 cells.
ADP-ribosylated by tankyrase TNKS and TNKS2. Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination at 'Lys-48' and subsequent activation of the Wnt signaling pathway.
Component of the beta-catenin destruction complex required for regulating CTNNB1 levels through phosphorylation and ubiquitination, and modulating Wnt-signaling (PubMed:12192039, PubMed:27098453, PubMed:28829046). Controls dorsoventral patterning via two opposing effects; down-regulates CTNNB1 to inhibit the Wnt signaling pathway and ventralize embryos, but also dorsalizes embryos by activating a Wnt-independent JNK signaling pathway (PubMed:12192039). In Wnt signaling, probably facilitates the phosphorylation of CTNNB1 and APC by GSK3B (PubMed:12192039). Likely to function as a tumor suppressor. Enhances TGF-beta signaling by recruiting the RNF111 E3 ubiquitin ligase and promoting the degradation of inhibitory SMAD7 (PubMed:16601693). Also a component of the AXIN1-HIPK2-TP53 complex which controls cell growth, apoptosis and development (PubMed:17210684). Facilitates the phosphorylation of TP53 by HIPK2 upon ultraviolet irradiation (PubMed:17210684).
Homodimer (By similarity). Interacts with ZBED3; the interaction is direct, enhanced by protein kinase GSK3B and casein kinase CSNK1E activities and decreases GSK3B-induced beta-catenin serine and threonine phosphorylations (By similarity). Component of the beta-catenin destruction complex, containing at least, CTNNB1, an axin and GSK3B, that regulates CTNNB1 protein levels through phosphorylation and ubiquitination. Interacts with CTNNB1 (via the armadillo repeats 2-7). Interacts with GSK3B; the interaction hyperphosphorylates CTNNB1 leading to its ubiquitination and destruction (PubMed:17318175, PubMed:12554650, PubMed:28546513). Component of the AXIN1-HIPK2-TP53 complex (PubMed:17210684). Interacts directly in the complex with TP53 and HIPK2 (PubMed:17210684). Interacts with DAXX; the interaction stimulates the interaction of DAXX with TP53, stimulates 'Ser-46' phosphorylation of TP53 and induces cell death on UV irradiation (PubMed:17210684). Also binds APC, SMAD6, SMAD7 and RNF111 (PubMed:16601693, PubMed:10811618). Interacts with DIXDC1; prevents interaction with MAP3K1 (PubMed:15262978). Interacts with MAP3K4 (PubMed:15262978). Interacts with ANKRD6 and AIDA (By similarity). Interacts with MDFI; the interaction decreases AXIN1-mediated JUN N-terminal kinase (JNK) activation (PubMed:12192039). Interacts with MDFIC; the interaction inhibits beta-cateninin-mediated signaling and AXIN1-mediated JUN N-terminal kinase (JNK) activation (PubMed:12192039). Interacts with LRP5 (via its phosphorylated PPPSP motifs); the interaction is stimulated by WNT1 and GSK3B and activates beta-catenin signaling (PubMed:11336703). Interacts (via the C-terminal) with PPP1CA; the interaction dephosphorylates AXIN1 and regulates interaction with GSK3B (PubMed:9920888). Interacts with PPP2CA; the interaction dephosphorylates AXIN1 (PubMed:9920888). Interacts with MACF1 (By similarity). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (By similarity). Interacts with TNKS (PubMed:19759537, PubMed:21478859, PubMed:21799911). Interacts with DAB2; the interaction is mutually exclusive with the AXIN1:PPP1CA interaction (PubMed:12805222). Interacts with WDR26 (PubMed:27098453). Interacts with GID8 (PubMed:28829046). Interacts with SIAH1 and SIAH2; both probably catalyze AXIN1 ubiquitination and subsequent proteasome-mediated ubiquitin-dependent degradation (PubMed:28546513). Interaction with GSK3B and AXIN1 is competitive (PubMed:28546513).
Phosphorylation and dephosphorylation of AXIN1 regulates assembly and function of the beta-catenin complex. Phosphorylated by CK1 and GSK3B. Dephosphorylated by PPP1CA and PPP2CA. Phosphorylation by CK1 enhances binding of GSK3B to AXIN1.
The disease is caused by variants affecting the gene represented in this entry. Caudal duplication anomaly is associated with hypermethylation of the AXIN1 promoter.
Ubiquitinated by RNF146 when poly-ADP-ribosylated, leading to its degradation and subsequent activation of the Wnt signaling pathway. Sumoylation at Lys-857 and Lys-860 prevents ubiquitination and degradation. Sumoylation is required for AXIN1-mediated JNK activation. Deubiquitinated by USP34, deubiquitinated downstream of beta-catenin stabilization step: deubiquitination is important for nuclear accumulation during Wnt signaling to positively regulate beta-catenin (CTNBB1)-mediated transcription. Ubiquitination by SIAH1 and SIAH2 induces its proteasomal degradation as part of the activation of the Wnt signaling pathway (PubMed:28546513).
Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways (PubMed:2470098). In addition of this role of signal transduction in T-cell activation, CD3E plays an essential role in correct T-cell development. Initiates the TCR-CD3 complex assembly by forming the two heterodimers CD3D/CD3E and CD3G/CD3E. Participates also in internalization and cell surface down-regulation of TCR-CD3 complexes via endocytosis sequences present in CD3E cytosolic region (PubMed:10384095, PubMed:26507128).
The TCR-CD3 complex is composed of a CD3D/CD3E and a CD3G/CD3E heterodimers that preferentially associate with TCRalpha and TCRbeta, respectively, to form TCRalpha/CD3E/CD3G and TCRbeta/CD3G/CD3E trimers. In turn, the hexamer interacts with CD3Z homodimer to form the TCR-CD3 complex. Alternatively, TCRalpha and TCRbeta can be replaced by TCRgamma and TCRdelta. Interacts with CD6 (PubMed:15294938). Interacts with NCK1 (PubMed:15972658). Interacts with NUMB; this interaction is important for TCR-CD3 internalization and subsequent degradation (PubMed:26507128).
Acts as a ligand for vascular selectins. Mediates rapid rolling of leukocytes over vascular surfaces through high affinity divalent cation-dependent interactions with E-, P- and L-selectins.
Expressed in T-cells, B-cells and monocytes. Expression is higher on memory and germinal center cells than on naive B-cells (at protein level). Highly expressed in brain. Moderately expressed in pancreas, kidney and lymphoid node. Weakly expressed in liver. Detected in both endothelial cells and CD34+ bone marrow cells.
Homodimer; disulfide-linked. Interacts with SELL, SELE and SELP.
O-glycosylated; contains chondroitin sulfate. Displays sialylated O-linked oligosaccharides.
Sulfation is necessary for interaction with SELL. Sialylated O-linked oligosaccharides are necessary for interaction with SELL, SELE and SELP.
In the male reproductive tract, binds to sperm heads where it modulates sperm capacitance by inhibiting calcium uptake and nitrogen oxide (NO) production.
Serine protease inhibitor which exhibits anti-trypsin activity (PubMed:7142173). In the pancreas, protects against trypsin-catalyzed premature activation of zymogens (By similarity).
Belongs to the G-protein coupled receptor 1 family. Bradykinin receptor subfamily. BDKRB2 sub-subfamily.
Forms a complex with PECAM1 and GNAQ. Interacts with PECAM1.
Receptor for bradykinin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system.
Ubiquitous. Widespread in normal smooth muscle tissue and neurons.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIK3 subfamily.
Homotetramer, and heterotetramer with either GRIK4 or GRIK5. Interacts with PRKCABP (By similarity). Interacts with NETO2 (By similarity).
Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds domoate > kainate >> L-glutamate = quisqualate >> AMPA = NMDA.
Belongs to the Antp homeobox family. Proboscipedia subfamily.
Associates non-covalently with VPREB1 (PubMed:17431183). Interacts with SYNV1/HRD1 (via N-terminus); this interaction leads to increased IGLL1 ubiquitination and degradation in pre-B cells, possibly through a lysosomal, not proteasomal, pathway (By similarity).
Expressed only in pre-B-cells and a special B-cell line (which is surface Ig negative).
May act as a protein that binds a hydrophobic ligand.
Homodimer; disulfide-linked (Probable). May also form heterodimer with either TENM1 or TENM2 or TENM3 (By similarity).
Involved in neural development, regulating the establishment of proper connectivity within the nervous system. Plays a role in the establishment of the anterior-posterior axis during gastrulation. Regulates the differentiation and cellular process formation of oligodendrocytes and myelination of small-diameter axons in the central nervous system (CNS) (PubMed:26188006). Promotes activation of focal adhesion kinase. May function as a cellular signal transducer (By similarity).
Broadly expressed during the 11th week of gestation, with highest levels in the central nervous system, spinal ganglia, osteoblasts and osteocytes (at protein level).
Limited to cell-lines of leukemic origin.
May play a role in the regulation of pre-mRNA splicing.
Belongs to the actin-binding proteins ADF family. Coactosin subfamily.
Binds to F-actin in a calcium-independent manner. Has no direct effect on actin depolymerization. Acts as a chaperone for ALOX5 (5LO), influencing both its stability and activity in leukotrienes synthesis.
Interacts with 5-lipoxygenase (ALOX5/5LO) in a calcium-independent manner. Binds to F-actin with a stoichiometry of 1:2.
Widely expressed with highest levels in placenta, lung, kidney and peripheral blood leukocytes and lower levels in brain, liver and pancreas.
Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a homodimer or a heterodimer. Forms a heterodimer with TCF3.
Expressed in lymphoid tissues, B-cell lines and activated B-cells.
Transcription repressor capable of inhibiting the transactivation capability of TCF3/E47. May play a role in regulating antigen-dependent B-cell differentiation.
Component of a SNARE complex consisting of STX18, USE1L, BNIP1/SEC20L and SEC22B. Interacts directly with STX18.
SNARE that may be involved in targeting and fusion of Golgi-derived retrograde transport vesicles with the ER.
Interacts with RNF2 (By similarity). Interacts (via SAM domain) with SAMD1 (via SAM domain); the interaction mediates L3MBTL3 binding to chromatin (PubMed:33980486). Interacts with RBPJ; the interaction is required for L3MBTL3 localization to chromatin and is impaired by Notch-derived peptides containing the intracellular domain (NICD) (PubMed:29030483). Interacts (via SAM domain) with KDM1A (PubMed:29030483). Interacts with DCAF5 (PubMed:29691401). Interacts with DNMT1 (PubMed:29691401). Interacts with E2F1 (PubMed:29691401). Interacts with SOX2 (PubMed:30442713). Interacts with SFMBT1 (By similarity).
Is a negative regulator of Notch target genes expression, required for RBPJ-mediated transcriptional repression (PubMed:29030483). It recruits KDM1A to Notch-responsive elements and promotes KDM1A-mediated H3K4me demethylation (PubMed:29030483). Involved in the regulation of ubiquitin-dependent degradation of a set of methylated non-histone proteins, including SOX2, DNMT1 and E2F1. It acts as an adapter recruiting the CRL4-DCAF5 E3 ubiquitin ligase complex to methylated target proteins (PubMed:30442713, PubMed:29691401). Required for normal maturation of myeloid progenitor cells (By similarity).
Has E3 ubiquitin ligase activity, promoting ubiquitination and degradation of target proteins (PubMed:11823428, PubMed:22159038, PubMed:26575292). Involved in activation of the JAK/STAT pathway (PubMed:11823428, PubMed:22159038). Catalyzes ubiquitination of methylated RBM15 (PubMed:26575292). Plays a role in quality control of translation of mitochondrial outer membrane-localized mRNA (PubMed:29861391). As part of the PINK1-regulated signaling, upon mitochondria damage, ubiquitinates ABCE1 and thereby recruits autophagy receptors to the mitochondrial outer membrane to initiate mitophagy (PubMed:29861391).
Interacts with CNOT1 via its C-terminus but does not stably associate with the CCR4-NOT complex (PubMed:11823428). Interacts (via RING domain) with UBE2D2 (PubMed:15001359). Interacts with ABCE1, PINK1 and PELO (PubMed:29861391).
Essential for synapsis surveillance during meiotic prophase via the recruitment of ATR activity. Plays a key role in the male mid-pachytene checkpoint and the female meiotic prophase checkpoint: required for efficient build-up of ATR activity on unsynapsed chromosome regions, a process believed to form the basis of meiotic silencing of unsynapsed chromatin (MSUC) and meiotic prophase quality control in both sexes. Required for the DNA double-strand break-independent, BRCA1-dependent activation of ATR on the sex chromosomes that is essential for normal sex body formation (By similarity).
Highly expressed in testis (at protein level). Expressed in lung adenocarcinoma and squamous cell carcinoma (at protein level). Expressed at lower levels in the liver, brain and kidney.
Phosphorylated in a SPO11-dependent manner.
Binds to target promoter DNA and functions as transcription regulator. Regulates transcription from the PADI1 and CDH2 promoter. May be one regulator of transcriptional events during hemopoietic development.
Preferentially expressed in differentiating myeloid cells. Detected in osteoblasts.
Interacts with mRNA decapping proteins DCP1A, DCP2 and EDC4.
Promotes dispersal of P-body components and is likely to play a role in the mRNA decapping process.
Was previously thought to be non-coding but has been shown to be translated and functional.
Glycosaminoglycans biosynthesis (PubMed:25893793). Involved in forming the linkage tetrasaccharide present in heparan sulfate and chondroitin sulfate. Transfers a glucuronic acid moiety from the uridine diphosphate-glucuronic acid (UDP-GlcUA) to the common linkage region trisaccharide Gal-beta-1,3-Gal-beta-1,4-Xyl covalently bound to a Ser residue at the glycosaminylglycan attachment site of proteoglycans. Can also play a role in the biosynthesis of l2/HNK-1 carbohydrate epitope on glycoproteins. Shows strict specificity for Gal-beta-1,3-Gal-beta-1,4-Xyl, exhibiting negligible incorporation into other galactoside substrates including Galbeta1-3Gal beta1-O-benzyl, Galbeta1-4GlcNAc and Galbeta1-4Glc. Stimulates 2-phosphoxylose phosphatase activity of PXYLP1 in presence of uridine diphosphate-glucuronic acid (UDP-GlcUA) during completion of linkage region formation (PubMed:24425863).
Homodimer; disulfide-linked. Interacts with PXYLP1; the interaction increases the 2-phosphoxylose phosphatase activity of PXYLP1 during completion of linkage region formation in a B3GAT3-mediated manner.
Ubiquitous (but weakly expressed in all tissues examined).
Contains a region with structural similarity to RNase H, but lacks RNase H activity.
Contains a region with structural similarity to reverse transcripase, presenting the classical thumb, fingers and palm architecture, but lacks enzyme activity, since the essential metal-binding residues are not conserved.
Contains a region with structural similarity to type-2 restriction endonucleases, but the residues that would bind catalytic metal ions in endonucleases are instead involved in hydrogen bonds that stabilize the protein structure.
Part of the U5 snRNP complex (PubMed:2532307, PubMed:2527369). Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39 (PubMed:2479028, PubMed:16723661, PubMed:26912367). Component of the U5.U4atac/U6atac snRNP complexes in U12-dependent spliceosomes (PubMed:11971955). Within the minor spliceosome, which acts on U12-type introns, interacts with PPIL2 and RBM48 (PubMed:33509932). Core component of U2-type precatalytic, catalytic and postcatalytic spliceosomal complexes (PubMed:10411133, PubMed:28502770, PubMed:28781166, PubMed:28076346, PubMed:29361316, PubMed:30315277, PubMed:29360106, PubMed:29301961, PubMed:30728453, PubMed:30705154). Found in a mRNA splicing-dependent exon junction complex (EJC) with SRRM1. Interacts with U5 snRNP proteins SNRP116 and SNRNP40. Interacts with EFTUD2. Interacts (via the MPN (JAB/Mov34) domain) with PRPF3 ('Lys-63'-linked polyubiquitinated); may stabilize the U4/U6-U5 tri-snRNP complex. Interacts (via RNase H homology domain) with AAR2 (PubMed:26527271). Interacts with RPAP3 and URI1 in a ZNHIT2-dependent manner (PubMed:28561026). Interacts with C9orf78 (PubMed:35167828, PubMed:35241646). Interacts with SNRNP200; the interaction is direct (PubMed:35241646, PubMed:35188580). Interacts with TSSC4; the interaction is direct (PubMed:35188580).
Plays a role in pre-mRNA splicing as core component of precatalytic, catalytic and postcatalytic spliceosomal complexes, both of the predominant U2-type spliceosome and the minor U12-type spliceosome (PubMed:10411133, PubMed:11971955, PubMed:28502770, PubMed:28781166, PubMed:28076346, PubMed:29361316, PubMed:30315277, PubMed:29360106, PubMed:29301961, PubMed:30728453, PubMed:30705154). Functions as a scaffold that mediates the ordered assembly of spliceosomal proteins and snRNAs. Required for the assembly of the U4/U6-U5 tri-snRNP complex, a building block of the spliceosome. Functions as scaffold that positions spliceosomal U2, U5 and U6 snRNAs at splice sites on pre-mRNA substrates, so that splicing can occur. Interacts with both the 5' and the 3' splice site.
The MPN (JAB/Mov34) domain mediates interaction with TSSC4 and SNRNP200 (PubMed:35188580). Has structural similarity with deubiquitinating enzymes, but lacks the residues that would bind the catalytic metal ion.
Heterodimer of an alpha and a beta subunit. ITGAM associates with ITGB2. Found in a complex with CD177 and ITGB2/CD18 (PubMed:21193407). Interacts with JAM3 (PubMed:15194813, PubMed:12208882). Interacts with THBD (PubMed:27055590). Interacts with complement factor H/CFH; this interaction mediates adhesion of neutrophils to pathogens leading to pathogen clearance.
Integrin ITGAM/ITGB2 is implicated in various adhesive interactions of monocytes, macrophages and granulocytes as well as in mediating the uptake of complement-coated particles and pathogens (PubMed:9558116, PubMed:20008295). It is identical with CR-3, the receptor for the iC3b fragment of the third complement component. It probably recognizes the R-G-D peptide in C3b. Integrin ITGAM/ITGB2 is also a receptor for fibrinogen, factor X and ICAM1. It recognizes P1 and P2 peptides of fibrinogen gamma chain. Regulates neutrophil migration (PubMed:28807980). In association with beta subunit ITGB2/CD18, required for CD177-PRTN3-mediated activation of TNF primed neutrophils (PubMed:21193407). May regulate phagocytosis-induced apoptosis in extravasated neutrophils (By similarity). May play a role in mast cell development (By similarity). Required with TYROBP/DAP12 in microglia to control production of microglial superoxide ions which promote the neuronal apoptosis that occurs during brain development (By similarity).
Predominantly expressed in monocytes and granulocytes (PubMed:1346576). Expressed in neutrophils (at protein level) (PubMed:21193407).
In the nucleus, phosphorylated by PKC/PRKCD.
Monomer. Homodimer. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Found in a complex with FGFBP1, FGF1 and FGF2. Interacts with FGFBP1. Part of a Cu(2+)-dependent multiprotein aggregate containing FGF1, S100A13 and SYT1. Interacts with SYT1. Interacts with S100A13. Interacts with LRRC59. Interacts with CSNKA, CSNKB and FIBP. While binding with LRRC59, CSNKA and FIBP seem mutually exclusive, CSNKB and FIBP may cooperatively interact with FGF1. Forms a ternary complex with FGFR1 and ITGAV:ITGB3 and induces the recruitment of PTPN11 to the complex (PubMed:20422052).
Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro. Acts as a ligand for FGFR1 and integrins. Binds to FGFR1 in the presence of heparin leading to FGFR1 dimerization and activation via sequential autophosphorylation on tyrosine residues which act as docking sites for interacting proteins, leading to the activation of several signaling cascades. Binds to integrin ITGAV:ITGB3. Its binding to integrin, subsequent ternary complex formation with integrin and FGFR1, and the recruitment of PTPN11 to the complex are essential for FGF1 signaling. Induces the phosphorylation and activation of FGFR1, FRS2, MAPK3/ERK1, MAPK1/ERK2 and AKT1 (PubMed:18441324, PubMed:20422052). Can induce angiogenesis (PubMed:23469107).
Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro. Acts as a ligand for FGFR1 and integrins. Binds to FGFR1 in the presence of heparin leading to FGFR1 dimerization and activation via sequential autophosphorylation on tyrosine residues which act as docking sites for interacting proteins, leading to the activation of several signaling cascades. Binds to integrins. Its binding to integrins and subsequent ternary complex formation with integrins and FGFR1 are essential for FGF1 signaling.
Predominantly expressed in kidney and brain. Detected at much lower levels in heart and skeletal muscle.
It is uncertain whether Met-1 or Met-51 is the initiator.
Belongs to the potassium channel KCNN family. KCa3.1/KCNN4 subfamily.
Forms a voltage-independent potassium channel that is activated by intracellular calcium (PubMed:26148990). Activation is followed by membrane hyperpolarization which promotes calcium influx. Required for maximal calcium influx and proliferation during the reactivation of naive T-cells (PubMed:17157250, PubMed:18796614). Plays a role in the late stages of EGF-induced macropinocytosis (PubMed:24591580).
Heterotetramer of potassium channel proteins (Probable). Interacts with MTMR6.
Phosphorylation at His-358 by NDKB activates the channel, and conversely it's dephosphorylation by PHPT1 inhibits the channel.
The channel is inhibited by clotrimazole and charybdotoxin but is insensitive to apamin.
Up-regulated by phorbol myristate acetate (PMA) and phytohemagglutinin (PHA) in T-cells.
Widely expressed in non-excitable tissues.
Plays a vital role in regulating thiol metabolism and preserving oxygen homeostasis by oxidizing the sulfur of cysteamine and N-terminal cysteine-containing proteins to their corresponding sulfinic acids using O2 as a cosubstrate (PubMed:17581819, PubMed:29752763, PubMed:31273118, PubMed:32601061). Catalyzes the oxidation of cysteamine (2-aminoethanethiol) to hypotaurine (PubMed:17581819, PubMed:29752763, PubMed:32601061). Catalyzes the oxidation of regulators of G-protein signaling 4 (RGS4) and 5 (RGS5) and interleukin-32 (IL32) (PubMed:31273118, PubMed:32601061).
A MPS3B mutation at position 100 was erroneously reported (PubMed:9950362) as an amino acid change from Arg to His. The right amino acid change is from His to Arg.
Belongs to the glycosyl hydrolase 89 family.
Involved in the degradation of heparan sulfate.
Liver, ovary, peripheral blood leukocytes, testis, prostate, spleen, colon, lung, placenta and kidney.
Dual specificity phosphatase that dephosphorylates MAPK8/JNK and MAPK14/p38, but not MAPK1/ERK2, in vitro (PubMed:21360282). Exhibits intrinsic phosphatase activity towards both phospho-seryl/threonyl and -tyrosyl residues, with similar specific activities in vitro (PubMed:10585869).
Highly expressed in the testis (at protein level) (PubMed:10585869, PubMed:15252030). Also found in the skeletal muscle (PubMed:15252030).
Interacts with PPP1R35; this interaction allows the mutual recruitment to the centriole.
Involved in the genetic cascade that governs left-right specification. Plays a role in the maintenance of a normal ciliary structure. Required for correct asymmetric expression of NODAL, LEFTY and PITX2.
Intron retention. This sequence is incomplete at the 5'- and 3'-ends and extensively differs from that shown due to multiple introns.
Interacts with IGF2BP1 (PubMed:17289661). Interacts with MAP1B light chain LC1 (By similarity).
RNA-binding protein that binds to the 3' untranslated region (3'UTR) of target mRNAs (By similarity). Seems to recognize a GAAA motif (By similarity). Can bind to its own 3'UTR, the FOS 3'UTR and the ID 3'UTR (By similarity).
(Microbial infection) Interacts (via F-BAR domain) with Rous sarcoma virus p2B; this interaction allows PACSIN2 recruitment to viral assembly sites.
(Microbial infection) Interacts (via N-terminus) with Hepatatis C virus (HCV) non-structural protein 5A (via N-terminus); this interaction attenuates protein kinase C alpha (PRKCA)-mediated phosphorylation of PACSIN2 at Ser-313 by disrupting the interaction between PACSIN2 and PRKCA.
(Microbial infection) Interacts with ubiquitinated HIV-1 gag (via p6-gag domain); this interaction allows PACSIN2 recruitment to viral assembly sites and its subsequent incorporation into virions.
(Microbial infection) Specifically enhances the efficiency of HIV-1 virion spread by cell-to-cell transfer (PubMed:29891700). Also promotes the protrusion engulfment during cell-to-cell spread of bacterial pathogens like Listeria monocytogenes (PubMed:31242077). Involved in lipid droplet formation, which is important for HCV virion assembly (PubMed:31801866).
(Microbial infection) The SH3 domain is required for the cell-to-cell spreading of HIV-1 virions.
Homodimer (By similarity). May form heterooligomers with other PACSINs (By similarity). Interacts (via NPF motifs) with EHD1 (via EH domain) (PubMed:23596323). Interacts (via NPF motifs) with EHD2 (via EH domain); this interaction probably stabilizes the caveolae (PubMed:22323287). Interacts with EHD3 (PubMed:23596323). Interacts (via the SH3 domain) with MICALL1 (PubMed:23596323). Interacts with RAC1 (PubMed:21693584). Interacts (via SH3 domain) with DNM1, SYN1, SYNJ1 and WASL (By similarity). Interacts (via F-BAR domain) with CAV1 (By similarity). Interacts with TRPV4 (By similarity).
Phosphorylated by casein kinase 2 (CK2). Phosphorylation by PKC probably decreases the membrane binding and tubulation capacities of PACSIN2, thereby modulating the lifetime of caveolae (By similarity).
Regulates the morphogenesis and endocytosis of caveolae (By similarity). Lipid-binding protein that is able to promote the tubulation of the phosphatidic acid-containing membranes it preferentially binds. Plays a role in intracellular vesicle-mediated transport. Involved in the endocytosis of cell-surface receptors like the EGF receptor, contributing to its internalization in the absence of EGF stimulus.
The F-BAR domain forms a coiled coil and mediates membrane-binding and membrane tubulation (PubMed:19549836). Autoinhibition of these functions is mediated by an interaction between the SH3 and F-BAR domains (PubMed:20188097, PubMed:23236520). The F-Bar domain also mediates the binding to the cell actin cytoskeleton through the interaction with CAV-1 (By similarity).
May be required for ribosome biogenesis.
Belongs to the pyridoxal phosphate-binding protein YggS/PROSC family.
Pyridoxal 5'-phosphate (PLP)-binding protein, which may be involved in intracellular homeostatic regulation of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6.
Binds copper, nickel, and fatty acids as well as, and bilirubin less well than, serum albumin. Only a small percentage (less than 2%) of the human AFP shows estrogen-binding properties.
Dimeric and trimeric forms have been found in addition to the monomeric form.
Independent studies suggest heterogeneity of the N-terminal sequence of the mature protein and of the cleavage site of the signal sequence.
Occurs in the plasma of fetuses more than 4 weeks old, reaches the highest levels during the 12th-16th week of gestation, and drops to trace amounts after birth. The serum level in adults is usually less than 40 ng/ml. AFP occurs also at high levels in the plasma and ascitic fluid of adults with hepatoma.
Plasma. Synthesized by the fetal liver and yolk sac.
Interacts with SIRT2 (via both phosphorylated, unphosphorylated, active or inactive forms); the interaction is necessary for the complex to interact with alpha-tubulin (PubMed:12620231, PubMed:17516032). Under proteasome impairment conditions, interacts with UBD via its histone deacetylase 1 and UBP-type zinc-finger regions (PubMed:19033385, PubMed:25422469). Interacts with BBIP1, CBFA2T3, CYLD, DDIT3/CHOP, ZMYND15, F-actin and HDAC11 (PubMed:19893491, PubMed:11533236, PubMed:11948178, PubMed:19081074, PubMed:17872950). Interacts with RIPOR2; this interaction occurs during early myogenic differentiation and prevents HDAC6 to deacetylate tubulin (PubMed:24687993). Interacts with AURKA; AURKA-mediated phosphorylation of HDAC6 promotes deacetylation of alpha-tubulin (PubMed:17604723). Interacts with DYSF; this interaction occurs during early myogenic differentiation (PubMed:24687993). Interacts with TPPP; inhibiting the tubulin deacetylase activity of HDAC6 (PubMed:20308065, PubMed:23093407). Interacts with DYNLL1 (PubMed:31505170). Interacts with ATP13A2; the interaction results in recruitment of HDAC6 to lysosomes to promote CTTN deacetylation (PubMed:30538141). Interacts with CCDC141 (via the N-terminal region); inhibiting the deacetylase activity of HDAC6 (By similarity). Interacts with IPO7; the interaction facilitates HDAC6 nuclear translocation in dental papilla cells (By similarity).
Phosphorylated by AURKA; phosphorylation increases HDAC6-mediated deacetylation of alpha-tubulin and subsequent disassembly of cilia.
Required for TGF-beta1-activated gene expression associated with epithelial-mesenchymal transition (EMT) in A549 cells.
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:10220385). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:10220385). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:10220385). In addition to histones, deacetylates other proteins: plays a central role in microtubule-dependent cell motility by mediating deacetylation of tubulin (PubMed:12024216, PubMed:20308065, PubMed:26246421). Required for cilia disassembly; via deacetylation of alpha-tubulin (PubMed:17604723, PubMed:26246421). Promotes deacetylation of CTTN, leading to actin polymerization, promotion of autophagosome-lysosome fusion and completion of autophagy (PubMed:30538141). Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer (PubMed:24413532). Promotes odontoblast differentiation following IPO7-mediated nuclear import and subsequent repression of RUNX2 expression (By similarity). In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome (PubMed:17846173). Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy (PubMed:17846173).
Ubiquitinated. Its polyubiquitination however does not lead to its degradation.
Functions as a regulator of the BMP signaling pathway and may be involved in epidermal differentiation.
Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate. Probably has a role in normal hematopoiesis by inhibition of granulocyte differentiation and induction of apoptosis.
Preferentially expressed at early stages of myeloid differentiation of highly purified CD34+ cells.
Homooligomerizes (via the BTB/POZ domain), multimerization is required for DNA binding. Interacts (via the C-terminal zinc fingers) with GIF1; the interaction results in the recruitment of MYB to the CDKN1A/p21 and CDKN1B promoters and repression of transcription. Interacts with TRAF2, interfering with the binding of UBC13 to TRAF2, and inhibiting TRAF2 E3 ligase activity. Interacts with MYC (via the C-terminal helix-loop-helix motif); the interaction inhibits ZBTB17 transactivation and growth arrest activities and renders it insoluble in the nucleus. Also interacts with HCFC1, MAGEA4 and TMPRSS11A. Interacts with BCL6; the interaction inhibits ZBTB17 transactivation activity on target genes involved in cell cycle arrest. Interacts with ZBTB49 isoform 3/ZNF509S1; this interaction blocks ZBTB17-mediated repression of RB1 (PubMed:25245946).
Transcription factor that can function as an activator or repressor depending on its binding partners, and by targeting negative regulators of cell cycle progression. Plays a critical role in early lymphocyte development, where it is essential to prevent apoptosis in lymphoid precursors, allowing them to survive in response to IL7 and undergo proper lineage commitment. Has been shown to bind to the promoters of adenovirus major late protein and cyclin D1 and activate transcription. Required for early embryonic development during gastrulation. Represses RB1 transcription; this repression can be blocked by interaction with ZBTB49 isoform 3/ZNF509S1 (PubMed:25245946).
Undergoes 'Lys-48'-linked polyubiquitination at Lys-397 and Lys-481 and subsequent proteasomal degradation in a TRAF2-dependent manner.
Interacts with EHMT1, EHMT2, CTBP1 and CTBP2 (By similarity). Part of a complex containing at least CDYL, REST, WIZ, SETB1, EHMT1 and EHMT2.
May link EHMT1 and EHMT2 histone methyltransferases to the CTBP corepressor machinery. May be involved in EHMT1-EHMT2 heterodimer formation and stabilization (By similarity).
The C2H2-type zinc finger 11 mediates interaction with EHMT1 and EHMT2.
A reversible disulfide bond can be formed between the two subunits in the homodimer; this has no effect on GDF2 activity.
Can promote osteogenic differentiation in vitro (PubMed:25237187, PubMed:25751889). This is probably not physiologically relevant.
Homodimer; disulfide-linked (PubMed:25237187, PubMed:28564608). Detected in extracellular fluid as mature homodimer, and in complex with its propeptide (PubMed:21710321, PubMed:25237187). Interacts with ACVRL1, BMPR2 and ACVR2B with high affinity (in vitro) (PubMed:22799562, PubMed:22347366, PubMed:25237187, PubMed:25751889). Identified in a complex with ACVRL1 and ACVR2B (PubMed:22718755). Has ten times lower affinity for ACVR2A (in vitro) (PubMed:25751889). Interacts with ENG, forming a heterotetramer with a 2:2 stoichiometry (PubMed:21737454, PubMed:28564608). Can form a heteromeric complex with ENG and ACVRL1 (PubMed:28564608). Interacts with type I receptor ACVR1 (PubMed:20628059).
Potent circulating inhibitor of angiogenesis. Signals through the type I activin receptor ACVRL1 but not other Alks. Signaling through SMAD1 in endothelial cells requires TGF-beta coreceptor endoglin/ENG.
Both isoforms are widely expressed, including kidney, lung, liver, heart, testis and several brain regions, such as cerebellum. Also expressed in the frontal cortex and in lymphoblasts (at protein level).
Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:27193190, PubMed:27103069, PubMed:27617292, PubMed:28195531, PubMed:32303654). In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PubMed:27103069). The C9orf72-SMCR8 complex also acts as a regulator of autophagy initiation by interacting with the ULK1/ATG1 kinase complex and modulating its protein kinase activity (PubMed:27617292). As part of the C9orf72-SMCR8 complex, stimulates RAB8A and RAB11A GTPase activity in vitro (PubMed:32303654). Positively regulates initiation of autophagy by regulating the RAB1A-dependent trafficking of the ULK1/ATG1 kinase complex to the phagophore which leads to autophagosome formation (PubMed:27334615). Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates (PubMed:27559131). Plays a role in endosomal trafficking (PubMed:24549040). May be involved in regulating the maturation of phagosomes to lysosomes (By similarity). Promotes the lysosomal localization and lysosome-mediated degradation of CARM1 which leads to inhibition of starvation-induced lipid metabolism (By similarity). Regulates actin dynamics in motor neurons by inhibiting the GTP-binding activity of ARF6, leading to ARF6 inactivation (PubMed:27723745). This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of cofilin, leading to CFL1/cofilin activation (PubMed:27723745). Positively regulates axon extension and axon growth cone size in spinal motor neurons (PubMed:27723745). Required for SMCR8 protein expression and localization at pre- and post-synaptic compartments in the forebrain, also regulates protein abundance of RAB3A and GRIA1/GLUR1 in post-synaptic compartments in the forebrain and hippocampus (By similarity). Plays a role within the hematopoietic system in restricting inflammation and the development of autoimmunity (By similarity).
Component of the C9orf72-SMCR8 complex, at least composed of C9orf72, SMCR8 and WDR41 (PubMed:27193190, PubMed:27103069, PubMed:27559131, PubMed:27617292, PubMed:28195531, PubMed:32303654). The complex is formed of two protomers, each individually consisting of one molecule each of C9orf72, SMCR8 and WDR41 (PubMed:32303654). The protomers homodimerize via an interaction between C9orf72 (via C-terminus) and SMCR8 (via N-terminus) (PubMed:32303654). Within each protomer SMCR8 (via DENN domain) acts as a bridging protein between WDR41 (via C-terminus and N-terminus) and C9orf72 (via C-terminus) (PubMed:32303654). The C9orf72-SMCR8 complex associates with the ULK1/ATG1 kinase complex (PubMed:27617292, PubMed:28195531). Interacts with ULK1/ATG1 kinase complex members ULK1, ATG13 and RB1CC1 (PubMed:27334615). Interacts with SMCR8; the interaction is direct (PubMed:27559131, PubMed:27617292, PubMed:32303654). Interacts with HNRNPA1, HNRNPA2B1 and UBQLN2 (PubMed:24549040). Interacts with small Rab GTPase RAB1A; the interaction mediates recruitment of RAB1A to the ULK1/ATG1 kinase complex (PubMed:27334615). Also interacts with small Rab GTPase RAB7A (By similarity). Interacts with cofilin (PubMed:27723745). Interacts with GTP-binding proteins ARF1 and ARF6 (By similarity). Interacts with the DLG4/PSD-95 (By similarity). Interacts with CARM1 (via PH domain-like fold) (By similarity).
Does not play a role in regulation of stress granule assembly in response to cellular stress.
Encoded by 2 transcripts differing in the 5' non-coding region.
Regulates stress granule assembly in response to cellular stress.
The disease is caused by variants affecting the gene represented in this entry. In the first intron of the gene, the expansion of a GGGGCC hexanucleotide that can vary from 10 to thousands of repeats, represents the most common genetic cause of both familial and sporadic FTDALS. The hexanucleotide repeat expansion (HRE) is structurally polymorphic and during transcription, is responsible for the formation of RNA and DNA G-quadruplexes resulting in the production of aborted transcripts at the expense of functional transcripts. The accumulation of those aborted transcripts may cause nucleolar stress and indirectly cell death (PubMed:24598541). The expanded GGGGCC repeats are bidirectionally transcribed into repetitive RNA, which forms sense and antisense RNA foci. Remarkably, despite being within a non-coding region, these repetitive RNAs can be translated in every reading frame to form five different dipeptide repeat proteins (DPRs) -- poly-GA, poly-GP, poly-GR, poly-PA and poly-PR -- via a non-canonical mechanism known as repeat-associated non-ATG (RAN) translation. These dipeptide repeat proteins (DPRs) co-aggregate in the characteristic SQSTM1-positive TARDBP negative inclusions found in FTLD/ALS patients with C9orf72 repeat expansion (PubMed:24132570).
Lipid transfer protein required for both autophagosome formation and regulation of lipid droplet morphology and dispersion (PubMed:22219374, PubMed:31721365). Tethers the edge of the isolation membrane (IM) to the endoplasmic reticulum (ER) and mediates direct lipid transfer from ER to IM for IM expansion (PubMed:22219374, PubMed:31721365). Binds to the ER exit site (ERES), which is the membrane source for autophagosome formation, and extracts phospholipids from the membrane source and transfers them to ATG9 (ATG9A or ATG9B) to the IM for membrane expansion (By similarity). Lipid transfer activity is enhanced by WDR45/WIPI4, which promotes ATG2B-association with phosphatidylinositol 3-monophosphate (PI3P)-containing membranes (PubMed:31721365).
Expression localized to the epithelia of bile ducts and to the sacroplasm of heart muscle and skeletal muscle. In the pancreas, localized to a subpopulation of Langerhans islet cells and in the salivary gland, expressed in acinar cells (at protein level) (PubMed:15063763). Expressed in adult heart, placenta, lung, liver, skeletal muscle and kidney (PubMed:15063763, PubMed:18487197). Detected in fetal heart, spleen, lung, liver skeletal muscle and kidney (PubMed:18487197).
Inhibited by pyridine 2,4-dicarboxylate, an analog of 2-oxoglutarate.
Prolyl 3-hydroxylase that catalyzes the post-translational formation of 3-hydroxyproline on collagens (PubMed:18487197). Contributes to proline 3-hydroxylation of collagen COL4A1 and COL1A1 in tendons, the eye sclera and in the eye lens capsule (By similarity). Has high activity with the type IV collagen COL4A1, and lower activity with COL1A1 (PubMed:18487197). Catalyzes hydroxylation of the first Pro in Gly-Pro-Hyp sequences where Hyp is 4-hydroxyproline (PubMed:18487197). Has no activity on substrates that lack 4-hydroxyproline in the third position (PubMed:18487197).
'Lys-63'-linked polyubiquitination by MIB1 after RNA virus infection, or by NRDP1 after LPS stimulation at Lys-30 and Lys-401, participates in kinase activation. 'Lys-48'-linked polyubiquitination at Lys-670 by DTX4 leads to proteasomal degradation. 'Lys-48'-linked polyubiquitination by TRAIP also leads to proteasomal degradation. 'Lys-48'-linked polyubiquitination by TRAF7; leading to proteasomal degradation (PubMed:37086853). 'Lys-63'-linked polyubiquitination by RNF128 at Lys-30 and Lys-401 leads to the activation of antiviral responses. 'Lys-48'-linked polyubiquitination after 'lys-33'-linked deubiquitination by USP38 promotes TBK1 degradation (PubMed:27692986).
(Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1 on both 'Lys-48' and 'Lys-63'-linked ubiquitin chains; leading to inhibition of type I interfewron production.
(Microbial infection) Interaction with SARS-CoV-2 M protein induces 'Lys-48'-linked ubiquitination which leads to proteasomal degradation.
(Microbial infection) Interacts (via N-terminus) with Severe fever with thrombocytopenia virus (SFTSV) NSs; this interaction antagonizes TBK1 phosphorylation and sequesters TBK1 in NSs-induced cytoplasmic inclusion bodies thereby inhibiting the IFN responses.
(Microbial infection) Interacts with Borna disease virus (BDV) P protein leading to its phosphorylation.
(Microbial infection) Interacts with Ebola virus protein VP35.
(Microbial infection) Interacts with HCV NS3; this interaction leads to inhibition of cellular antiviral response by blocking necessary interactions between the TBK1 and its substrates IRF3 and IRF7.
(Microbial infection) Interacts with SARS-CoV-2 non-structural protein 6; this interaction decreases IRF3 phosphorylation by 57%, which leads to reduced IFN-beta (IFNB) production (PubMed:32979938). Interacts with SARS-CoV-2 helicase; this interaction inhibits TBK1 phosphorylation and decreases IRF3 phosphorylation by 75%, which leads to reduced IFN-beta production (PubMed:32979938). Interacts with SARS-CoV-2 M protein; the interaction promotes TBK1 degradation via 'Lys-48'-linked ubiquitination (PubMed:34084167).
(Microbial infection) Interacts with Zika virus non-structural protein 1/NS1 and non-structural protein 4B/NS4B.
(Microbial infection) Interacts with heartland virus NSs; this interaction antagonizes TBK1 phosphorylation and inhibits TBK1-IRF3 interaction and thus the establishment of an antiviral state.
(Microbial infection) Interacts with human cytomegalovirus protein UL35; this interaction inhibits type I interferon production.
(Microbial infection) Interacts with human herpesvirus 1 protein ICP34.5.
Autophosphorylation at Ser-172 activates the kinase, and is an essential step for virus-triggered signaling. Phosphorylated by IKBKB/IKKB at Ser-172. Phosphorylation requires homodimerization and ubiquitination at Lys-30 and Lys-401. Dephosphorylated at Ser-172 by PPM1B and this negatively regulates its role in mediating antiviral response.
Comprises A N-terminal kinase domain, a ubiquitin-like domain and a C-terminal coiled-coil region mediating homodimerization.
Homodimer (PubMed:21145761). Interacts with DDX3X, TIRAP and TRAF2 (PubMed:10581243, PubMed:14530355). Part of a ternary complex consisting of TANK, TRAF2 and TBK1 (PubMed:10581243). Interacts with AZI2, TANK and TBKBP1; these interactions are mutually exclusive and mediate TBK1 activation (PubMed:14560022, PubMed:21931631, PubMed:23453972, PubMed:10581243, PubMed:29251827). Interacts with GSK3B; this interaction promotes TBK1 self-association and autophosphorylation (PubMed:21145761). Interacts with SIKE1; SIKE1 is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection or TLR3 stimulation (PubMed:16281057). Interacts with IRF3, leading to IRF3 phosphorylation (PubMed:14703513, PubMed:25636800). Interacts with RIGI (PubMed:16281057). Interacts with CYLD (PubMed:18636086, PubMed:32185393). Interacts with OPTN and TRAF3 (PubMed:20174559). Interacts with SRC (PubMed:19419966). Interacts with the exocyst complex subunit SEC5/EXOC2; this interaction is sufficient to trigger TBK1 activity (PubMed:17018283). Interacts with STING1, leading to STING1 phosphorylation (PubMed:19416887, PubMed:25636800, PubMed:30842653). Interacts with IFIT3 (via N-terminus) (PubMed:21813773). Interacts with MAVS; interaction only takes place in the presence of IFIT3 and leads to MAVS phosphorylation (PubMed:21813773, PubMed:25636800, PubMed:28011935). Interacts (via protein kinase domain) with TTLL12 (via TTL domain); the interaction prevents MAVS binding to TBK1 (PubMed:28011935). Interacts with TICAM1; this interaction is enhanced in the presence of WDFY1 and leads to TICAM1 phosphorylation (PubMed:14530355, PubMed:14739303, PubMed:25736436, PubMed:25636800). Interacts with TRIM26 (PubMed:26611359). Interacts with TRIM23 (PubMed:28871090). Interacts with TTC4 and IKBKE (PubMed:29251827). Interacts with HNRNPA2B1 (PubMed:31320558). Interacts with DDX3X (PubMed:20375222). Interacts with TRIM14 (PubMed:32404352). Interacts with CEP170; efficient complex formation may be dependent on the presence of CCDC61 (PubMed:30354798). Interacts with TRAF3IP3 (PubMed:32366851). Interacts with HSP90AA1; the interaction mediates TBK1 association with TOMM70 (PubMed:20628368). Interacts with TAX1BP1 (PubMed:33226137).
In cancer cells, pathological TBK1 activation promotes oncogenic transformation by suppressing programmed cell death. Mechanistically, the RALB-SEC5/EXOC2-TBK1 signaling cascade seems to participate in both innate immune signaling and cell transformation. Additionally, TBK1 supports oncogenesis by directly phosphorylating and activating AKT1 at the exocyst (PubMed:21042276).
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents (PubMed:12692549, PubMed:14703513, PubMed:18583960, PubMed:12702806, PubMed:15367631, PubMed:10581243, PubMed:11839743, PubMed:15485837, PubMed:21138416, PubMed:25636800, PubMed:23453971, PubMed:23453972, PubMed:23746807, PubMed:26611359, PubMed:32404352). Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X (PubMed:12692549, PubMed:14703513, PubMed:18583960, PubMed:12702806, PubMed:15367631, PubMed:25636800). This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB (PubMed:12702806, PubMed:15367631, PubMed:25636800, PubMed:32972995). In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli (PubMed:23453971, PubMed:23453972, PubMed:23746807). Plays a key role in IRF3 activation: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 (PubMed:25636800, PubMed:30842653). Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce expression of interferons (PubMed:25636800). Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes (PubMed:21931631). Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus (PubMed:10783893, PubMed:15489227). Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy (PubMed:21617041). Phosphorylates SMCR8 component of the C9orf72-SMCR8 complex, promoting autophagosome maturation (PubMed:27103069). Phosphorylates ATG8 proteins MAP1LC3C and GABARAPL2, thereby preventing their delipidation and premature removal from nascent autophagosomes (PubMed:31709703). Phosphorylates and activates AKT1 (PubMed:21464307). Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity (By similarity). Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C (PubMed:21270402). Phosphorylates Borna disease virus (BDV) P protein (PubMed:16155125). Plays an essential role in the TLR3- and IFN-dependent control of herpes virus HSV-1 and HSV-2 infections in the central nervous system (PubMed:22851595). Acts both as a positive and negative regulator of the mTORC1 complex, depending on the context: activates mTORC1 in response to growth factors by catalyzing phosphorylation of MTOR, while it limits the mTORC1 complex by promoting phosphorylation of RPTOR (PubMed:29150432, PubMed:31530866).
The disease may be caused by variants affecting the gene represented in this entry. A copy number variation on chromosome 12q14 consisting of a 300 kb duplication that includes TBK1, XPOT, RASSF3 and GNS has been found in individuals affected by glaucoma. TBK1 is the most likely candidate for the disorder (PubMed:21447600).
Ubiquitous with higher expression in testis. Expressed in the ganglion cells, nerve fiber layer and microvasculature of the retina.
Involved in several stages of intracellular trafficking. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) or phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) (PubMed:16179610). Acts in part as component of the retromer membrane-deforming SNX-BAR subcomplex (PubMed:17101778). The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX-BAR subcomplex functions to deform the donor membrane into a tubular profile called endosome-to-TGN transport carrier (ETC) (Probable). Can sense membrane curvature and has in vitro vesicle-to-membrane remodeling activity (PubMed:23085988). Required for retrograde endosome-to-TGN transport of TGN38 (PubMed:20138391). Promotes KALRN- and RHOG-dependent but retromer-independent membrane remodeling such as lamellipodium formation; the function is dependent on GEF activity of KALRN (PubMed:20604901).
Predominantly forms heterodimers with BAR domain-containing sorting nexins SNX5, SNX6 and SNX32; can self-associate to form homodimers (PubMed:23085988). The heterodimers are proposed to self-assemble into helical arrays on the membrane to stabilize and expand local membrane curvature underlying endosomal tubule formation. Thought to be a component of the originally described retromer complex (also called SNX-BAR retromer) which is a pentamer containing the heterotrimeric retromer cargo-selective complex (CSC), also described as vacuolar protein sorting subcomplex (VPS), and a heterodimeric membrane-deforming subcomplex formed between SNX1 or SNX2 and SNX5 or SNX6 (also called SNX-BAR subcomplex); the respective CSC and SNX-BAR subcomplexes associate with low affinity (Probable). Interacts with SNX5, SNX6, SNX32, VPS26A, VPS29, VPS35, FNBP1, KALRN, RHOG (GDP-bound form) (PubMed:11438682, PubMed:14596906, PubMed:17101778, PubMed:19935774, PubMed:19619496, PubMed:20604901, PubMed:23085988).
The BAR domain is able to sense membrane curvature upon dimerization. Membrane remodeling seems to implicate insertion of a N-terminal amphipathic helix (AH) in the membrane (Probable).
Homodimer. Stabilized through interaction with STK3/MST2 or STK4/MST1. Interacts (via SARAH domain) with isoform 1 of NEK2. Interacts with ESR1 only in the presence of STK3/MST2. Interacts with WTIP and AJUBA.
Phosphorylated by STK3/MST2 and STK4/MST1. Phosphorylation is not required for SAV1 stability and may increase the number of protein binding sites on the scaffold molecule.
Regulator of STK3/MST2 and STK4/MST1 in the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. SAV1 is required for STK3/MST2 and STK4/MST1 activation and promotes cell-cycle exit and terminal differentiation in developing epithelial tissues. Plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosomes, and its ability to phosphorylate CROCC and CEP250. In conjunction with STK3/MST2, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation.
Ubiquitously expressed in adult tissues with highest expression in the pancreas, aorta and interventricular septum and lowest expression in skeletal muscle. Expression was higher in fetal than in the adult heart. Expressed in various cell lines.
Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate to the interior of cells. Isoform Short does not bind folate.
May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Variant in position: 150:MSAHPTWGPGSGRSTRAGAKSAF->ECSPNLGPWIRQVNQSWRKERILNVPLCKEDCERW WEDCRTSYTCKSNWHKGWNWTSGINECPAGALCSTFESYFPTPAALCEGLWSHSFKVSNYSRG.
Spleen, thymus, bone marrow, ovarian carcinoma, and uterine carcinoma.
By IFN-alphas and IFNG/IFN-gamma in hematopoietic cancer cells.
Expressed in spleen, lymph node and peripheral blood leukocytes, and at lower levels in thymus, bone marrow and fetal liver. Down-regulated in breast tumors.
Major mediator of the tumor suppressor activity of IFN in breast cancer cells. Promotes ubiquitination and subsequent degradation of MDM2, which leads to p53/TP53 stabilization. Promotes ubiquitination and subsequent degradation of HDAC1, which in turn enhances maspin expression, and impairs invasive activity of cancer cells.
The HIN-200 domain mediates interaction with MDM2.
Interacts with incompletely assembled mitochondrial NADH:ubiquinone oxidoreductase complex (complex I).
Required for the assembly of the mitochondrial NADH:ubiquinone oxidoreductase complex (complex I). Involved in the assembly of the distal region of complex I.
Plays a role in mitochondrial aerobic respiration. Regulates mitochondrial organization and fission.
Component of the spliceosome B complex (PubMed:28781166). Interacts with PRPF38A (via N-terminal interaction domain) (PubMed:26673105, PubMed:27773687).
Involved in pre-mRNA splicing as a component of the spliceosome.
Interacts with F-actin (By similarity). Interacts with ANKRD54 (By similarity). Interacts with KBTBD10.
Plays an important role in the regulation of dynamic actin-based, cytoskeletal activities. Agonist-dependent changes in LASP1 phosphorylation may also serve to regulate actin-associated ion transport activities, not only in the parietal cell but also in certain other F-actin-rich secretory epithelial cell types (By similarity).
A report observed N-glycosylation at Asn-235 (PubMed:19139490). However, as the protein is not predicted to localize in an extracellular compartment of the cell, additional evidence is required to confirm this result.
G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions.
Interacts with NHERF1. Interacts with GABARAPL1.
GDP-dissociation inhibitor preventing the GDP to GTP exchange of most Rab proteins. By keeping these small GTPases in their inactive GDP-bound form regulates intracellular membrane trafficking (PubMed:25860027). Negatively regulates protein transport to the cilium and ciliogenesis through the inhibition of RAB8A (PubMed:25860027).
Interacts with RHOH (PubMed:11809807). Interacts with the GDP-bound forms of RAB3A, RAB3B, RAB3C, RAB5A, RAB5B, RAB5C, RAB8B, RAB10, RAB12, RAB35, and RAB43; binds RAB3D to a lesser extent (PubMed:26824392, PubMed:29125462). Interacts with RAB8A (GDP-bound inactive form); prevents RAB8A activation (PubMed:25860027, PubMed:26824392, PubMed:29125462). Interacts with DZIP1; negatively regulates the interaction of GDI2 with GDP-bound RAB8A (PubMed:25860027).
Regulates the GDP/GTP exchange reaction of most RAB proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP.
Directly interacts with KIF14 depending on the activation state (stronger interaction with the kinase-dead form). Homodimer (By similarity). Interacts with TTC3.
Plays a role in cytokinesis. Required for KIF14 localization to the central spindle and midbody. Putative RHO/RAC effector that binds to the GTP-bound forms of RHO and RAC1. It probably binds p21 with a tighter specificity in vivo. Displays serine/threonine protein kinase activity. Plays an important role in the regulation of cytokinesis and the development of the central nervous system. Phosphorylates MYL9/MLC2.
The human genome also contains the UTP14C gene, an autosomal retrotransposed copy of this X-linked gene. Evolution of autosomal retrogenes from X-linked progenitors compensates for X-chromosome silencing during male meiosis.
Converts 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone.
Expressed predominantly in adipose tissue, pancreas and liver.
Biotransformation enzyme that catalyzes the hydrolysis of arene and aliphatic epoxides to less reactive and more water soluble dihydrodiols by the trans addition of water (By similarity). Plays a role in the metabolism of endogenous lipids such as epoxide-containing fatty acids (PubMed:22798687). Metabolizes the abundant endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid (AA) and glycerol (PubMed:24958911).
Biotransformation enzyme that catalyzes the hydrolysis of arene and aliphatic epoxides to less reactive and more water soluble dihydrodiols by the trans addition of water.
In some populations, the high activity haplotype tyr113/his139 is overrepresented among women suffering from pregnancy-induced hypertension (pre-eclampsia) when compared with healthy controls.
Inhibited by 10-hydroxystearamide and methoxy-arachidonyl fluorophosphate.
Variations in EPHX1 gene non-coding regions have been observed in a patient with hypercholanemia. The pathogenicity of these variants has not been confirmed.
Homopentamer. Forms a complex with GCH1 where a GCH1 homodecamer is sandwiched by two GFRP homopentamers (By similarity). Interacts with GCH1.
Mediates tetrahydrobiopterin inhibition of GTP cyclohydrolase 1. This inhibition is reversed by L-phenylalanine.
Belongs to the bZIP family. C/EBP subfamily.
Binds DNA as a homodimer and as a heterodimer (PubMed:26019275). Can form stable heterodimers with CEBPA, CEBPB and CEBPD (By similarity). Interacts with GATA1 and SPI1 (PubMed:26019275). Interacts with SMARCD2 (PubMed:28369036).
Strongest expression occurs in promyelocyte and late-myeloblast-like cell lines.
Transcriptional activator (PubMed:26019275). C/EBP are DNA-binding proteins that recognize two different motifs: the CCAAT homology common to many promoters and the enhanced core homology common to many enhancers. Required for the promyelocyte-myelocyte transition in myeloid differentiation (PubMed:10359588).
Component of chromatin-associated Polycomb (PcG) complexes. Component of a number of PRC1-like complexes; these complexes contain either the polycomb group ring finger protein PCGF1, or PCGF2, or PCGF3, or PCGF4, or PCGF5, or PCGF6 (PubMed:12167701, PubMed:15386022, PubMed:19636380, PubMed:21282530, PubMed:26687479, PubMed:26151332). Part of a complex that contains RNF2, UB2D3 and BMI1; within that complex RNF2 and BMI1 form a tight heterodimer, where UB2D3 interacts only with RNF2 (PubMed:21772249, PubMed:25355358). The complex composed of RNF2, UB2D3 and BMI1 binds nucleosomes, and has activity only with nucleosomal histone H2A (PubMed:21772249). Part of a complex that contains PCGF5, RNF2 and UBE2D3 (PubMed:26151332). Part of a complex that contains AUTS2, PCGF5, RNF2, CSNK2B and RYBP (PubMed:25519132). Interacts with RYBP, PCGF2, CBX4, CBX6, CBX7 and CBX8 (PubMed:19636380, PubMed:21282530, PubMed:19791798, PubMed:20696397). Interacts with RNF1/RING1, BMI1 and PHC2 (PubMed:15386022, PubMed:16714294). Interaction with RYBP and CBX7 is mutually exclusive; both compete for the same binding site on RNF2 (By similarity). Component of repressive BCOR complex containing a Polycomb group subcomplex at least composed of RYBP, PCGF1, BCOR and RING1 (PubMed:16943429). Interacts with CBX2 and PHC1. Interacts with CHTOP. Interacts with AURKB (By similarity). Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EUHMTASE1, RNF1/RING1, RNF2/RING2, MBLR, L3MBTL2 and YAF2 (PubMed:12004135). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975). Interacts with RYBP, HIP2 and TFCP2 (PubMed:11513855, PubMed:11865070, PubMed:20696397). Interacts with NUPR1 (PubMed:28720707).
E3 ubiquitin-protein ligase that mediates monoubiquitination of 'Lys-119' of histone H2A (H2AK119Ub), thereby playing a central role in histone code and gene regulation (PubMed:15386022, PubMed:16359901, PubMed:25519132, PubMed:33864376, PubMed:21772249, PubMed:25355358, PubMed:26151332). H2AK119Ub gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. May be involved in the initiation of both imprinted and random X inactivation (By similarity). Essential component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development (PubMed:16359901, PubMed:26151332). PcG PRC1 complex acts via chromatin remodeling and modification of histones, rendering chromatin heritably changed in its expressibility (PubMed:26151332). E3 ubiquitin-protein ligase activity is enhanced by BMI1/PCGF4 (PubMed:21772249). Acts as the main E3 ubiquitin ligase on histone H2A of the PRC1 complex, while RING1 may rather act as a modulator of RNF2/RING2 activity (Probable). Association with the chromosomal DNA is cell-cycle dependent. In resting B- and T-lymphocytes, interaction with AURKB leads to block its activity, thereby maintaining transcription in resting lymphocytes (By similarity). Also acts as a negative regulator of autophagy by mediating ubiquitination of AMBRA1, leading to its subsequent degradation (By similarity).
Monoubiquitinated, by auto-ubiquitination (By similarity). Polyubiquitinated in the presence of UBE2D3 (in vitro) (PubMed:26151332).
The hPRC-H complex purification reported probably presents a mixture of different PRC1-like complexes.
Belongs to the MPDU1 (TC 2.A.43.3) family.
Required for normal utilization of mannose-dolichol phosphate (Dol-P-Man) in the synthesis of N-linked and O-linked oligosaccharides and GPI anchors.
Acts as an electrogenic sodium (Na(+)) and chloride (Cl-)-dependent sodium-coupled solute transporter, including transport of monocarboxylates (short-chain fatty acids including L-lactate, D-lactate, pyruvate, acetate, propionate, valerate and butyrate), mocarboxylate drugs (nicotinate, benzoate, salicylate and 5-aminosalicylate) and ketone bodies (beta-D-hydroxybutyrate, acetoacetate and alpha-ketoisocaproate), with a Na(+):substrate stoichiometry of between 4:1 and 2:1 (PubMed:14966140, PubMed:15090606, PubMed:17178845, PubMed:16805814, PubMed:16729224, PubMed:17526579, PubMed:17245649, PubMed:20211600, PubMed:30604288). Catalyzes passive carrier mediated diffusion of iodide (PubMed:12107270). Mediates iodide transport from the thyrocyte into the colloid lumen through the apical membrane (PubMed:12107270). May be responsible for the absorption of D-lactate and monocarboxylate drugs from the intestinal tract (PubMed:17245649). Acts as a tumor suppressor, suppressing colony formation in colon cancer, prostate cancer and glioma cell lines (PubMed:12829793, PubMed:15867356, PubMed:18037591). May play a critical role in the entry of L-lactate and ketone bodies into neurons by a process driven by an electrochemical Na(+) gradient and hence contribute to the maintenance of the energy status and function of neurons (PubMed:16805814). Mediates sodium-coupled electrogenic transport of pyroglutamate (5-oxo-L-proline) (PubMed:20211600). Can mediate the transport of chloride, bromide, iodide and nitrate ions when the external concentration of sodium ions is reduced (PubMed:19864324).
Down-regulated in some primary cancers; due to aberrant methylation in primary colon cancers, astrocytomas and oligodendrogliomas as well as in cancers of the colon, prostate and gastric regions, and glial cell lines. Expression reactivated on treatment with a demethylating drug, 5-azacytidine.
Expressed in normal thyroid, localized at the apical pole of thyroid cells facing the colloid lumen, but expression profoundly decreased in thyroid carcinomas. Expressed in normal colon but absent in colon aberrant crypt foci and colon cancers. Present in normal kidney cortex, brain, prostate, gastric mucosa and breast tissue but was significantly down-regulated in primary gliomas, gastric cancer, prostate tumors and breast tumors.
Increase of iodide influx inhibited by addition of perchlorate (NaClO(4)), a competitive inhibitor of iodide uptake catalyzed by sodium iodide symporter (NIS) (PubMed:12107270). Cotransport of monocarboxylates and nicotinate strongly inhibited by probenecid, nonsteroid anti-inflammatory drugs (ibuprofen, fenoprofen, ketprofen, naproxen) in a Na(+)-dependent manner or by prolonged exposure to external concentrations of monocarboxylates (PubMed:15090606, PubMed:16729224).
Interacts (via PDZ-binding motif) with PDZK1 (via PDZ domains 1 and 3); interaction increases nicotinate transport activity of SLC5A8.
Belongs to the nucleobase:cation symporter-2 (NCS2) (TC 2.A.40) family.
Highly expressed in adult small intestine, kidney, thymus, ovary, colon, prostate and liver, and in fetal kidney, liver and thymus.
Sodium:ascorbate cotransporter. Mediates electrogenic uptake of vitamin C, with a stoichiometry of 2 Na(+) for each ascorbate (PubMed:10556483, PubMed:10556521, PubMed:10631088, PubMed:36749388). Has retained some ancestral activity toward nucleobases such as urate, an oxidized purine. Low-affinity high-capacity sodium:urate cotransporter, may regulate serum urate levels by serving as a renal urate re-absorber (PubMed:36749388).
Treatment with the protein kinase C stimulator PMA results in a 10-fold decrease in ascorbate accumulation in transfected cells.
Component of TFIIIB complexes. The TFIIIB complex has two activities, alpha and beta. The TFIIIB-alpha activity complex is composed of TBP, BDP1, and a complex containing both BRF2 and at least four stably associated proteins; this complex inhibits the transcription by pol III via its phosphorylation by CK2; YY1 facilitates the TFIIIB-alpha complex formation. Interacts with TBP; this interaction promotes recruitment of BRF2 to TATA box-containing promoters (PubMed:26638071). Interacts with TBP and the BURE sequence (GC-rich sequence downstream from the TATA box) to form a strong ternary complex which is joined by BDP1; this ternary complex stimulates pol III transcription. Forms a trimeric complex composed of TBP, BRF2 and mini-SNAPc complex (SNAP43, SNAP50, and the N-terminal third of SNAP190) on the promoter. Assembly of the TBP-BRF2 complex is stimulated by SNAP190. Interacts with MAF1 and SNAPC4.
Down-regulated by epigallocatechin gallate (EGCG) treatment.
General activator of RNA polymerase III transcription. Factor exclusively required for RNA polymerase III transcription of genes with promoter elements upstream of the initiation sites (PubMed:11040218, PubMed:11121026, PubMed:11564744, PubMed:26638071). Contributes to the regulation of gene expression; functions as activator in the absence of oxidative stress (PubMed:26638071). Down-regulates expression of target genes in response to oxidative stress (PubMed:26638071). Overexpression protects cells against apoptosis in response to oxidative stress (PubMed:26638071).
In response to oxidative stress, Cys-361 is reversibly oxidized to cysteine sulfenic acid. Oxidation of Cys-361 impairs formation of a ternary complex with TBP and DNA and down-regulates expression of target genes in response to oxidative stress.
Transcription factor that binds GC and GT boxes and displaces Sp1 and Sp3 from these sequences. Modulates dopaminergic transmission in the brain (By similarity).
Has a particular type of basic domain which includes a helix-interrupting proline.
The C-terminal WRPW motif is a transcriptional repression motif which is necessary for interaction with Groucho/TLE family members, transcriptional corepressors recruited to specific target DNA by Hairy-related proteins.
Transcriptional repressor. Represses transcription from both N box- and E box-containing promoters. May with HES1, cooperatively regulate somite formation in the presomitic mesoderm (PSM). May function as a segmentation clock, which is essential for coordinated somite segmentation (By similarity).
Interacts (via SH3 domains) with CACNA1S (PubMed:29078335). Interacts (via SH3 domains) with CACNA1C (PubMed:29078335). Has much lower affinity for CACNA1C than for CACNA1S (PubMed:29078335).
Plays a redundant role in promoting the expression of calcium channel CACNA1S at the cell membrane, and thereby contributes to increased channel activity. Slows down the inactivation rate of the calcium channel CACNA1C.
A synthetic peptide, NIPP-1(330-351), is able to inhibit PP-1. Phosphorylation of Tyr-335 reduces PP-1 inhibition, whereas phosphorylation of Thr-346 or Ser-348 has no effect.
Endoribonuclease function is magnesium-dependent.
Has a basic N- and C-terminal and an acidic central domain.
Inhibitor subunit of the major nuclear protein phosphatase-1 (PP-1). It has RNA-binding activity but does not cleave RNA and may target PP-1 to RNA-associated substrates. May also be involved in pre-mRNA splicing. Binds DNA and might act as a transcriptional repressor. Seems to be required for cell proliferation.
Interacts with phosphorylated CDC5L, SF3B1 and MELK. Interacts with EED, in a nucleic acid-stimulated manner. Part of a complex consisting of PPP1R8, EED, HDAC2 and PP-1. Part of the spliceosome. Interacts with PPP1CA, PPP1CB and PPP1CC.
Isoform Gamma is a site-specific single-strand endoribonuclease that cleaves single strand RNA 3' to purines and pyrimidines in A+U-rich regions. It generates 5'-phosphate termini at the site of cleavage. This isoform does not inhibit PP-1. May be implicated in mRNA splicing.
May be inactivated by phosphorylation on Ser-199 or Ser-204 (By similarity). Phosphorylated by Lyn in vitro on Tyr-264, and also on Tyr-335 in the presence of RNA.
The FHA domain mediates interactions with threonine-phosphorylated MELK.
Ubiquitously expressed, with highest levels in heart and skeletal muscle, followed by brain, placenta, lung, liver and pancreas. Less abundant in kidney. The concentration and ratio between isoforms is cell-type dependent. Isoform Alpha (>90%) and isoform Beta were found in brain, heart and kidney. Isoform Gamma is mainly found in B-cells and T-lymphocytes, and has been found in 293 embryonic kidney cells.
Component of the IFT complex B, at least composed of IFT20, IFT22, IFT25, IFT27, IFT46, IFT52, TRAF3IP1/IFT54, IFT57, IFT74, IFT80, IFT81, and IFT88 (PubMed:23990561). Interacts with IFT74; the interaction is direct: within the IFT complex B, IFT74 and IFT81 mediate the transport of tubulin within the cilium (PubMed:15955805, PubMed:23990561). Interacts with tubulin; the interaction is direct (PubMed:23990561). Interacts with IFT57 and IFT70B (By similarity). Interacts with RABL2/RABL2A; binding is equal in the presence of GTP or GDP (By similarity). Interacts with IFT88 (PubMed:23990561). Interacts (via the IFT74/IFT81 heterodimer) with RABL2B (PubMed:28625565, PubMed:28428259).
Component of the intraflagellar transport (IFT) complex B: together with IFT74, forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium. Binds tubulin via its CH (calponin-homology)-like region (PubMed:23990561). Required for ciliogenesis (PubMed:27666822, PubMed:23990561). Required for proper regulation of SHH signaling (PubMed:27666822). Plays an important role during spermatogenesis by modulating the assembly and elongation of the sperm flagella (By similarity).
Highly expressed in testis, moderately in ovary, heart, liver, skeletal muscle, kidney and pancreas, low in prostate, brain, placenta and lung and not detected in spleen, thymus, small intestine and colon. Isoform CDV-1R is abundantly expressed in testis.
Produced by alternative initiation at Met-570 of isoform CDV-1R.
The CH (calponin-homology)-like region shows high similarity to a CH (calponin-homology) domain and mediated binding to the globular domain of tubulin.
Appears to link the dystrophin/utrophin network with microtubule filaments via the syntrophins. Phosphorylation of DMD or UTRN may modulate their affinities for associated proteins. Functions in a multi-protein complex in spermatid maturation. Regulates lipopolysaccharide-induced IL-12 synthesis in macrophages by forming a complex with TRAF6, resulting in the inhibition of TRAF6 NF-kappa-B activation (By similarity).
Phosphorylated and ubiquitinated. N-terminal ubiquitination leads to degradation of MAST2 by proteasome-mediated proteolysis. N-terminal phosphorylation appears to be a prerequisite for ubiquitination (By similarity).
Belongs to the RNA 3'-terminal cyclase family. Type 1 subfamily.
Catalyzes the conversion of 3'-phosphate to a 2',3'-cyclic phosphodiester at the end of RNA (PubMed:9184239). The mechanism of action of the enzyme occurs in 3 steps: (A) adenylation of the enzyme by ATP; (B) transfer of adenylate to an RNA-N3'P to produce RNA-N3'PP5'A; (C) and attack of the adjacent 2'-hydroxyl on the 3'-phosphorus in the diester linkage to produce the cyclic end product (PubMed:9184239). Likely functions in some aspects of cellular RNA processing (PubMed:9184239, PubMed:25961792). Function plays an important role in regulating axon regeneration by inhibiting central nervous system (CNS) axon regeneration following optic nerve injury (PubMed:25961792).
Belongs to the universal ribosomal protein uL22 family.
Expressed in pancreas, lung, colon, cystic duct, gall bladder, kidney and liver. Expressed at high levels in the well differentiated pancreatic tumor cell lines HPAF, COLO 357 and Capan-1, the moderately differentiated pancreatic tumor cell lines T3M-4, AsPc-1 and BxPc-3, the poorly differentiated pancreatic tumor cell line MIA PaCa-2, and the pancreatic tumor cell lines of undefined differentiation status such as SW979. Expressed at lower levels in the poorly differentiated pancreatic tumor cell lines HCG-25 and PANC-1.
(Microbial infection) Interacts (via SH3 domain) with HEV ORF3 protein.
(Microbial infection) Interacts (via SH3 domain) with HIV-1 Nef and Vif.
Aberrant activation of HCK by HIV-1 protein Nef enhances HIV-1 replication and contributes to HIV-1 pathogenicity.
Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation.
Detected in monocytes and neutrophils (at protein level). Expressed predominantly in cells of the myeloid and B-lymphoid lineages. Highly expressed in granulocytes. Detected in tonsil.
Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). Interacts with VAV1, WAS and RAPGEF1 (By similarity). This interaction stimulates its tyrosine-kinase activity. Interacts with ARRB1 and ARRB2. Interacts with ADAM15. Interacts with FASLG. Interacts with CBL. Interacts with FCGR1A; the interaction may be indirect. Interacts with IL6ST. Interacts (via SH3 domain) with ELMO1. Interacts (via SH3 domain) with TP73. Interacts with YAP1. Interacts with ABL1 and ITGB1, and thereby recruits ABL1 to activated ITGB1. Interacts (via SH3 domain) with WDCP.
Isoform 2 palmitoylation at position 2 requires prior myristoylation. Palmitoylation at position 3 is required for caveolar localization of isoform 2.
Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS.
Phosphorylated on several tyrosine residues. Autophosphorylated. Becomes rapidly phosphorylated upon activation of the immunoglobulin receptors FCGR1A and FCGR2A. Phosphorylation by the BCR-ABL fusion protein mediates activation of HCK. Phosphorylation at Tyr-411 increases kinase activity. Phosphorylation at Tyr-522 inhibits kinase activity. Kinase activity is not required for phosphorylation at Tyr-522, suggesting that this site is a target of other kinases.
Subject to autoinhibition, mediated by intramolecular interactions involving the SH2 and SH3 domains. Kinase activity is also regulated by phosphorylation at regulatory tyrosine residues. Phosphorylation at Tyr-411 is required for optimal activity. Phosphorylation at Tyr-522 inhibits kinase activity. Inhibited by PP1 and A-770041.
The SH3 domain mediates binding to HIV-1 Nef.
Ubiquitinated by CBL, leading to its degradation via the proteasome.
Up-regulated during myeloid cell differentiation. The highest levels are detected in fully differentiated phagocytes. Up-regulated by IL2.
Probable metal transporter. The interaction with the metal ion chaperone COX11 suggests that it may play a role in sensory neuron functions (By similarity). May play a role in biomineralization and retinal function.
Shares weak sequence similarity with the cyclin family, explaining its name. However, it has no cyclin-like function in vivo.
Widely expressed. Highly expressed in heart.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRA4 sub-subfamily.
The alpha4 beta2 gamma 2L receptor is not repressed by diazepam.
Interacts with ITGA2B (via C-terminus cytoplasmic tail region); the interaction is stabilized/increased in a calcium- and magnesium-dependent manner.
The binding of either calcium or magnesium may significantly increases the structural stability of the protein in comparison to apo-CIB (calcium- and magnesium-free form).
Bifunctional enzyme (PubMed:12574510). The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides (PubMed:12869654, PubMed:12574510, PubMed:22798687). Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides (By similarity). Also determines steady-state levels of physiological mediators (PubMed:12869654, PubMed:12574510, PubMed:22798687, PubMed:21217101).
Bifunctional enzyme (PubMed:12574510). The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid and 12-phosphonooxy-octadec-9E-enoic acid (PubMed:12574510). Has phosphatase activity toward lyso-glycerophospholipids with also some lower activity toward lysolipids of sphingolipid and isoprenoid phosphates (PubMed:22217705, PubMed:22387545).
By compounds that cause peroxisome proliferation such as clofibrate, tiadenol and fenofibrate.
Inhibited by 1-(1-acetylpiperidin-4-yl)-3-(4-(trifl uoromethoxy)phenyl)urea (TPAU), 1-cyclohexyl-3-dodecylurea (CDU), 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), 1-((3S, 5S, 7S)-adamantan-1-yl)-3-(5-(2-(2-ethoxyethoxy) ethoxy)pentyl)urea (AEPU), N-adamantyl-N[']-cyclohexyl urea (ACU), 4-(((1S, 4S)-4-(3-((3S, 5S, 7S)-adamantan-1-yl) ureido)cyclohexyl)oxy)benzoic acid (c-AUCB), 4-(((1R, 4R)-4-(3-((3S, 5S, 7S)-adamantan-1-yl)ureido)cyclohexyl)oxy)benzoic acid (t-AUCB), 4-(((1R, 4R)-4-(3-(4(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid (t-TAUCB) and to a lesser extent by 8-(3-((3S, 5S, 7S)-adamantan-1-yl)ureido) octanoic acid (AUOA). Phosphatase activity is inhibited by dodecyl-phosphate, phospholipids such as phospho-lysophosphatidic acids and fatty acids such as palmitic acid and lauric acid (PubMed:22217705, PubMed:22387545).
The N-terminal domain has phosphatase activity. The C-terminal domain has epoxide hydrolase activity.
The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation (Probable).
Expressed by macrophages in various tissues including Kupffer cells. Also found in brain microglia.
Interacts with PTPN6/SHP-1 and PTPN11/SHP-2 upon phosphorylation.
Putative adhesion molecule that mediates sialic-acid dependent binding to cells. Preferentially binds to alpha-2,8-linked sialic acid. The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface. In the immune response, may act as an inhibitory receptor upon ligand induced tyrosine phosphorylation by recruiting cytoplasmic phosphatase(s) via their SH2 domain(s) that block signal transduction through dephosphorylation of signaling molecules.
Binds to myosin; probably involved in interaction with thick myofilaments in the A-band.
Mainly expressed in the skeletal muscle. Slightly expressed in the left atrium and arteria mammaria interna.
Component of the U5 snRNP and the U4/U6-U5 tri-snRNP complex, a building block of the spliceosome (PubMed:26912367, PubMed:16723661). The U4/U6-U5 tri-snRNP complex is composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39 (PubMed:16723661, PubMed:26912367). Component of the pre-catalytic, catalytic and post-catalytic spliceosome complexes (PubMed:28502770, PubMed:28781166, PubMed:28076346, PubMed:29361316, PubMed:30315277, PubMed:29360106, PubMed:29301961, PubMed:30705154). Component of the minor spliceosome, which splices U12-type introns. Within this complex, interacts with CRIPT (PubMed:33509932). Interacts with ERBB4 and PRPF8. Interacts with PIH1D1 (PubMed:24656813). Interacts with RPAP3 and URI1 in a ZNHIT2-dependent manner (PubMed:28561026). Interacts with NRDE2 (PubMed:30538148). Interacts with FAM50A (PubMed:32703943). Interacts with UBL5 (PubMed:25092792).
Required for pre-mRNA splicing as component of the spliceosome, including pre-catalytic, catalytic and post-catalytic spliceosomal complexes (PubMed:28502770, PubMed:28781166, PubMed:28076346, PubMed:29361316, PubMed:30315277, PubMed:29360106, PubMed:29301961, PubMed:30705154, PubMed:25092792). Component of the U5 snRNP and the U4/U6-U5 tri-snRNP complex, a building block of the spliceosome (PubMed:16723661). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
Expressed in omental and subcutaneous adipose tissue (at protein level).
Homodimer (PubMed:19843876). Interacts with CIDEC (PubMed:19843876). Directly interacts with CEBPB (By similarity). Interacts with isoform CLSTN3beta of CLSTN3; inhibiting the lipid transferase activity of CIDEA (By similarity).
In omental and subcutaneous adipose tissue of obese patients matched for BMI, expression levels correlate with insulin sensitivity. Expression is increased 5-6 fold in the group of patients with high insulin sensitivity, compared to the insulin-resistant group. This observation is consistent with the idea that triglyceride storage in adipocytes plays an important role in sequestering triglycerides and fatty acids away from the circulation and peripheral tissues, thus enhancing insulin sensitivity in liver and muscle.
Lipid transferase that promotes unilocular lipid droplet formation by mediating lipid droplet fusion (PubMed:19843876, PubMed:26118629). Lipid droplet fusion promotes their enlargement, restricting lipolysis and favoring lipid storage (PubMed:19843876). Localizes on the lipid droplet surface, at focal contact sites between lipid droplets, and mediates atypical lipid droplet fusion by promoting directional net neutral lipid transfer from the smaller to larger lipid droplets (By similarity). The transfer direction may be driven by the internal pressure difference between the contacting lipid droplet pair and occurs at a lower rate than that promoted by CIDEC (By similarity). May also act as a CEBPB coactivator in epithelial cells to control the expression of a subset of CEBPB downstream target genes, including ID2, IGF1, PRLR, SOCS1, SOCS3, XDH, but not casein (By similarity). By interacting with CEBPB, strengthens the association of CEBPB with the XDH promoter, increases histone acetylation and dissociates HDAC1 from the promoter (By similarity). When overexpressed, induces apoptosis; the physiological significance of its role in apoptosis is unclear (By similarity).
The CIDE-N domain is involved in homodimerization which is crucial for its function in promoting lipid exchange and transfer.
The amphipathic helix mediates embedding into the lipid droplet phospholipid monolayer, promoting phosphatidic acid-binding, thereby facilitating triacylglycerol transfer.
Component of the CIA complex (PubMed:22678361, PubMed:22678362, PubMed:23585563). Component of the MMXD complex, which includes CIAO1, ERCC2, CIAO2B, MMS19 and SLC25A5 (PubMed:20797633). Interacts with CIAO1, ERCC2 and MMS19; the interactions are direct (PubMed:22678362, PubMed:23585563). Interacts with KIF4A; the interaction facilitates the transfer of Fe-S clusters to KIF4A to ensure proper localization of KIF4A to the mitotic machinery (PubMed:29848660). Interacts with CCDC117; the interaction is direct (PubMed:30742009).
Component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into extramitochondrial Fe/S proteins (PubMed:23891004, PubMed:22678362, PubMed:22678361, PubMed:29848660). As a CIA complex component and in collaboration with CIAO1 and MMS19, binds to and facilitates the assembly of most cytosolic-nuclear Fe/S proteins (PubMed:23891004, PubMed:29848660). As part of the mitotic spindle-associated MMXD complex it plays a role in chromosome segregation, probably by facilitating iron-sulfur cluster assembly into ERCC2/XPD (PubMed:20797633). Together with MMS19, facilitates the transfer of Fe-S clusters to the motor protein KIF4A, which ensures proper localization of KIF4A to mitotic machinery components to promote the progression of mitosis (PubMed:29848660).
Binds in vitro to PGBD3-related transposable elements, called MER85s; these non-autonomous 140 bp elements are characterized by the presence of PGBD3 terminal inverted repeats and the absence of internal transposase ORF.
Expressed in heart and oocytes, but not in granulosa cells (at protein level).
PGBD3 gene is located within ERCC6 intron 5.
Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor (PubMed:8690719, PubMed:9295285). Has a broad spectrum of substrates such as apomucin-, MUC5AC-, MUC1- and MUC2-derived peptides (PubMed:9295285).
The ricin B-type lectin domain directs the glycopeptide specificity. It is required in the glycopeptide specificity of enzyme activity but not for activity with naked peptide substrates, suggesting that it triggers the catalytic domain to act on GalNAc-glycopeptide substrates (By similarity).
Widely expressed. Expressed in all tissues tested.
(Microbial infection) Acts as a transcriptional activators in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a Tax-dependent manner. Binds to the DNA sequence 5'-GAACCACCCA-3' which is part of the Tax-responsive element (TRE-2S) regulatory element that augments the Tax-dependent enhancer of HTLV-1 (PubMed:9557682).
Acetylation at Lys-757 inhibits Hh target gene expression, probably by impeding entry into chromatin thus preventing promoter occupancy.
Acts as a transcriptional activator in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a Tax-dependent manner. Binds to the DNA sequence 5'-GAACCACCCA-3' which is part of the Tax-responsive element (TRE-2S) regulatory element that augments the Tax-dependent enhancer of HTLV-1 (PubMed:9557682).
Expressed in breast cancers (at protein level) (PubMed:26565916). Isoform 1 and isoform 4 are expressed in HTLV-1-infected T-cell lines (at protein level) (PubMed:9557682). Isoform 1 and isoform 2 are strongly expressed in HTLV-1-infected T-cell lines (PubMed:9557682). Isoform 3 and isoform 4 are weakly expressed in HTLV-1-infected T-cell lines (PubMed:9557682).
Functions as transcription regulator in the hedgehog (Hh) pathway (PubMed:18455992, PubMed:26565916). Functions as transcriptional activator (PubMed:9557682, PubMed:19878745, PubMed:24311597). May also function as transcriptional repressor (By similarity). Requires STK36 for full transcriptional activator activity. Required for normal embryonic development (PubMed:15994174, PubMed:20685856).
Interaction with ZIC1 and ZIC2 (By similarity). Interacts with STK36 (PubMed:10806483). Interacts with SUFU; this inhibits transcriptional activation mediated by GLI2 (PubMed:24311597). Interacts (via C-terminal internal region) with FOXC1 (via N-terminus); this interaction is direct and increases GLI2 DNA-binding and transcriptional activity through a smoothened (SMO)-independent Hedgehog (Hh) signaling pathway (PubMed:26565916).
Involved in the smoothened (SHH) signaling pathway.
Phosphorylated in vitro by ULK3. Phosphorylated by DYRK2; this inhibits GLI2 transcription factor activity and promotes proteasomal degradation of GLI2.
The N-terminal domain confers transcriptional repressor activity, while the C-terminal domain mediates transcriptional activation.
Binds to the small latent transforming growth factor-beta complex, consisting of the N-terminal TGFB1 latency-associated peptide (LAP) and the mature form of TGFB1, thereby leading to the activation of TGFB1 (PubMed:27389696). The activation of TGFB1 leads to stimulation of naive CD4(+) T-cells to increase FoxP3 expression and to an increase in the number of FoxP3(+) regulatory T-cells (PubMed:27389696). Induces the differentiation of a suppressive CD4(+)LAP(+)FoxP3(-) T-cell subset (PubMed:27389696). Induces the secretion of TGFB1 in macrophages, but not in activated CD4(+) T-cells (PubMed:27389696). May reduce the expression of several pro-inflammatory cytokines and chemokines by CD4(+) T-cells, including IL2 and IL6 (PubMed:27389696).
Interacts with latency-associated peptide; leading to TGFB1 activation.
Belongs to the CND2 (condensin subunit 2) family.
Component of the condensin complex, which contains the SMC2 and SMC4 heterodimer, and three non SMC subunits that probably regulate the complex: NCAPH/BRRN1, NCAPD2/CAPD2 and NCAPG.
Phosphorylated by CDK1. Its phosphorylation, as well as that of NCAPD2 and NCAPG subunits, activates the condensin complex and is required for chromosome condensation (By similarity).
Regulatory subunit of the condensin complex, a complex required for conversion of interphase chromatin into mitotic-like condense chromosomes.
Regulatory subunit of the condensin complex, a complex required for conversion of interphase chromatin into mitotic-like condense chromosomes. The condensin complex probably introduces positive supercoils into relaxed DNA in the presence of type I topoisomerases and converts nicked DNA into positive knotted forms in the presence of type II topoisomerases (PubMed:11136719). Early in neurogenesis, may play an essential role to ensure accurate mitotic chromosome condensation in neuron stem cells, ultimately affecting neuron pool and cortex size (PubMed:27737959).
Widely expressed at low level. Expressed in proliferating cells.
Autoubiquitinated. Autoubiquitination leads to proteasomal degradation and is necessary to control KLHL24 levels.
Expressed in the skin (PubMed:27889062, PubMed:27798626). Found in keratinocytes, dermal fibroblasts, and melanocytes (PubMed:27889062). Basal-layer keratinocytes have lower KLHL24 expression than suprabasal keratinocytes (PubMed:27798626). Expressed in the brain, spinal cord, liver, testis, heart and at higher levels in the skeletal muscle (PubMed:30715372).
Forms homodimers. Interacts with GRIK2 (By similarity). Component of the BCR(KLHL24) E3 ubiquitin ligase complex, composed of CUL3, RBX1 and KLHL24. Interacts with CUL3. Interacts with KRT14 (PubMed:27798626).
Necessary to maintain the balance between intermediate filament stability and degradation, a process that is essential for skin integrity (PubMed:27889062). As part of the BCR(KLHL24) E3 ubiquitin ligase complex, mediates ubiquitination of KRT14 and controls its levels during keratinocytes differentiation (PubMed:27798626). Specifically reduces kainate receptor-mediated currents in hippocampal neurons, most probably by modulating channel properties (By similarity). Has a crucial role in cardiac development and function (PubMed:30715372).
The disease is caused by variants affecting the gene represented in this entry. Gain-of-function mutations that lead to excessive ubiquitination and degradation of KRT14 result in compromised mechanical integrity of basal keratinocytes. Under this pathological condition, trivial mechanical stress can induce blister formation at the basal layer of skin.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-5/CHRNA5 sub-subfamily.
Genetic variations in CHRNA5 have been associated with susceptibility to smoking-related behavioral traits and lung cancer, contributing to the smoking quantitative trait locus 3 (SQTL3) [MIM:612052].
Neuronal AChR seems to be composed of two different type of subunits: alpha and non-alpha (beta). Interacts with LYPD6 (PubMed:27344019).
By various differentiation-inducing agents.
Glomerulus of kidney. Also detected in brain, lung and placenta.
Interacts (phosphorylated form) with FYN and GRB2.
Possesses tyrosine phosphatase activity. Plays a role in regulating the glomerular pressure/filtration rate relationship through an effect on podocyte structure and function (By similarity).
Predominantly expressed in B-lymphoid tissues.
Deubiquitinates monoubiquitinated probes (in vitro). When ubiquitinated, cleaves 'Lys-63'-linked and 'Lys-48'-linked poly-ubiquitin chains (in vitro), hence may act as a deubiquitinating enzyme. May increase macropinocytosis and suppress clathrin- and caveolae-mediated endocytosis. May enhance membrane dynamics and cell motility independently of its catalytic activity.
Monoubiquitinated (By similarity). Ubiquitination activates deubiquitination activity in vitro.
Belongs to the pyrimidine 5'-nucleotidase family.
Isoform 2 is induced by interferon alpha in Raji cells in association with lupus inclusions.
Isoforms 1, 3 and 4 are expressed in reticulocytes. Isoform 4 is hardly detectable in bone marrow and fetal liver.
Nucleotidase which shows specific activity towards cytidine monophosphate (CMP) and 7-methylguanosine monophosphate (m(7)GMP) (PubMed:24603684). CMP seems to be the preferred substrate (PubMed:15968458).
E3 ubiquitin ligase that plays an essential role in the organization of autophagic response and ubiquitination upon lysosomal and phagosomal damages. Plays a role in the stress-induced biogenesis and degradation of protein aggresomes by regulating the p62-KEAP1-NRF2 signaling and particularly by modulating the ubiquitination levels and thus stability of NRF2. Acts as a scaffold protein and facilitates autophagic degradation of protein aggregates by interacting with p62/SQSTM, ATG16L1 and LC3B/MAP1LC3B. In turn, protects the cell against oxidative stress-induced cell death as a consequence of endomembrane damage.
Highest levels found in testis, ovary, small intestine, colon, placenta, heart, skeletal muscle and mammary gland. More highly expressed in the fetus than in the corresponding adult tissues. Expressed in basal keratinocytes.
Homodimerizes via its coiled-coil domain. Heterodimerizes with MID1, TRIM24 and PML. Interacts with Galectin-3/LGALS3 in a ULK1-dependent manner; this interaction mediates autophagy of damage endomembranes. Interacts with BECN1. Interacts with ATG16L1. Interacts with p62/SQSTM and LC3B/MAP1LC3B.
Acts as a corepressor of recombining binding protein suppressor hairless (RBPJ) and inhibits Notch signaling in neural stem cells, thereby opposing their self-renewal and promoting neurogenesis (PubMed:23571214).
Interacts with NCBP1/CBP80; the interaction is direct. Associates with the eukaryotic translation initiation factor 3 (eIF-3) complex.
Specifically required for the pioneer round of mRNA translation mediated by the cap-binding complex (CBC), that takes place during or right after mRNA export via the nuclear pore complex (NPC). Acts via its interaction with the NCBP1/CBP80 component of the CBC complex and recruits the 40S small subunit of the ribosome via eIF3. In contrast, it is not involved in steady state translation, that takes place when the CBC complex is replaced by cytoplasmic cap-binding protein eIF4E. Also required for nonsense-mediated mRNA decay (NMD), the pioneer round of mRNA translation mediated by the cap-binding complex playing a central role in nonsense-mediated mRNA decay (NMD).
Allosteric enzyme that catalyzes the rate-limiting step in glycogen catabolism, the phosphorolytic cleavage of glycogen to produce glucose-1-phosphate, and plays a central role in maintaining cellular and organismal glucose homeostasis.
Allosterically regulated through the non-covalent binding of metabolites, being activated by AMP and inhibited by ATP, ADP, and glucose-6-phosphate. The activity is also controlled by post-translational modifications including phosphorylation.
Homodimer (PubMed:1150650, PubMed:16523484). Homotetramer; to form the enzymatically active phosphorylase A (PubMed:1150650).
Phosphorylation of Ser-15 converts phosphorylase B (unphosphorylated) to phosphorylase A.
Present in the extracellular matrix of human articular cartilage at all ages, although its abundance is far greater in the adult. In the adult cartilage lumican exists predominantly in a glycoprotein form lacking keratan sulfate, whereas the juvenile form of the molecule is a proteoglycan.
Expressed in multiciliated cells (MCCs).
Protein regulator of centriole-deuterosome disengagement and subsequently participates in the ciliogenesis in multiciliated cells (MCCs).
Contains a beta-barrel that binds various ligands in its interior.
Functions as transport protein in the blood stream. Binds various hydrophobic ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability. Appears to function in modulating the activity of the immune system during the acute-phase reaction.
Many different variants of ORM2 are known.
N-glycosylated. N-glycan heterogeneity at Asn-33: Hex5HexNAc4 (minor), Hex6HexNAc5 (major) and dHex1Hex6HexNAc5 (minor).
Synthesis is controlled by glucocorticoids, interleukin-1 and interleukin-6, It increases 5- to 50-fold upon inflammation.
Activated by threonine and tyrosine phosphorylation (PubMed:11875070, PubMed:16336213, PubMed:19166846). Inhibited by dual specificity phosphatases, such as DUSP1 (By similarity). Phosphorylation and activation in response to DNA damaging agents, serum stimulation (PubMed:11875070, PubMed:16336213, PubMed:19166846). Constitutively activated when phosphorylated on Tyr-177. Activity depends on the relative rates of MAPK15 autophosphorylation and dephosphorylation by PTPN1 (PubMed:16336213).
Appears not to be a CSK- and RET-dependent activated kinase.
Atypical MAPK protein that regulates several process such as autophagy, ciliogenesis, protein trafficking/secretion and genome integrity, in a kinase activity-dependent manner (PubMed:22948227, PubMed:24618899, PubMed:29021280, PubMed:21847093, PubMed:20733054). Controls both, basal and starvation-induced autophagy throught its interaction with GABARAP, MAP1LC3B and GABARAPL1 leading to autophagosome formation, SQSTM1 degradation and reduced MAP1LC3B inhibitory phosphorylation (PubMed:22948227). Regulates primary cilium formation and the localization of ciliary proteins involved in cilium structure, transport, and signaling (PubMed:29021280). Prevents the relocation of the sugar-adding enzymes from the Golgi to the endoplasmic reticulum, thereby restricting the production of sugar-coated proteins (PubMed:24618899). Upon amino-acid starvation, mediates transitional endoplasmic reticulum site disassembly and inhibition of secretion (PubMed:21847093). Binds to chromatin leading to MAPK15 activation and interaction with PCNA, that which protects genomic integrity by inhibiting MDM2-mediated degradation of PCNA (PubMed:20733054). Regulates DA transporter (DAT) activity and protein expression via activation of RhoA (PubMed:28842414). In response to H(2)O(2) treatment phosphorylates ELAVL1, thus preventing it from binding to the PDCD4 3'UTR and rendering the PDCD4 mRNA accessible to miR-21 and leading to its degradation and loss of protein expression (PubMed:26595526). Also functions in a kinase activity-independent manner as a negative regulator of growth (By similarity). Phosphorylates in vitro FOS and MBP (PubMed:11875070, PubMed:16484222, PubMed:20638370, PubMed:19166846). During oocyte maturation, plays a key role in the microtubule organization and meiotic cell cycle progression in oocytes, fertilized eggs, and early embryos (By similarity). Interacts with ESRRA promoting its re-localization from the nucleus to the cytoplasm and then prevents its transcriptional activity (PubMed:21190936).
Autophosphorylated on Thr-175 and Tyr-177; activates the enzyme.
Interacts with CSK/c-Src, ABL1, RET and TGFB1I1 (PubMed:11875070, PubMed:16484222, PubMed:16624805). Interacts with GABARAP, MAP1LC3B and GABARAPL1; controls, in a kinase-dependent fashion, both basal and starvation-induced autophagy (PubMed:22948227). Interacts with ESRRA; promotes re-localization of ESRRA to the cytoplasm through a XPO1-dependent mechanism then inhibits ESRRA transcriptional activity (PubMed:21190936). Interacts with PCNA; the interaction is chromatin binding- and kinase activity-dependent and prevents MDM2-mediated PCNA destruction by inhibiting the association of PCNA with MDM2 (PubMed:20733054). Interacts with DVL2 (By similarity). Interacts with CLIC3; MAPK15 does not phosphorylate CLIC3 (By similarity).
The N-terminal region (1-20) is the minimal region necessary for ubiquitination and further proteasomal degradation.
Ubiquitinated (PubMed:19166846). Ubiquitination may allow its tight kinase activity regulation and rapid turnover. May be ubiquitinated by a SCF E3 ligase (By similarity).
Widely expressed with a maximal expression in lung and kidney.
May serve as DNA-binding protein and may be involved in the control of cell-type determination, possibly within the developing nervous system.
Belongs to the peptidase C19 family. USP4 subfamily.
Deubiquitinating enzyme that removes conjugated ubiquitin from target proteins (PubMed:16316627, PubMed:16472766, PubMed:16339847, PubMed:20595234, PubMed:22347420, PubMed:25404403, PubMed:28604766, PubMed:30514904). Deubiquitinates PDPK1 (PubMed:22347420). Deubiquitinates TRIM21 (PubMed:16316627). Deubiquitinates receptor ADORA2A which increases the amount of functional receptor at the cell surface (PubMed:16339847). Deubiquitinates HAS2 (PubMed:28604766). Deubiquitinates RHEB in response to EGF signaling, promoting mTORC1 signaling (PubMed:30514904). May regulate mRNA splicing through deubiquitination of the U4 spliceosomal protein PRPF3 (PubMed:20595234). This may prevent its recognition by the U5 component PRPF8 thereby destabilizing interactions within the U4/U6.U5 snRNP (PubMed:20595234). May also play a role in the regulation of quality control in the ER (PubMed:16339847).
Interacts with RB1 (both dephosphorylated and hypophosphorylated forms) (PubMed:11571652). Interacts with RBL1 and RBL2 (By similarity). Interacts with ADORA2A (via cytoplasmic C-terminus); the interaction is direct (PubMed:16339847). Interacts with SART3; recruits USP4 to its substrate PRPF3 (PubMed:20595234).
Monoubiquitinated by TRIM21. Ubiquitination does not lead to its proteasomal degradation. Autodeubiquitinated.
Overexpressed in small cell tumors and adenocarcinomas of the lung compared to wild-type lung (at protein level). Expressed in the hippocampal neurons.
Phosphorylated at Ser-445 by PKB/AKT1 in response to EGF stimulus, promoting its ability deubiquitinate RHEB.
The DUSP and ubiquitin-like 1 domains promote ubiquitin release and thus enhance USB4 catalytic activity. However, these domains do not bind ubiquitin.
The completion of the deubiquitinase reaction is mediated by the DUSP and ubiquitin-like 1 domains which promotes the release of ubiquitin from the catalytic site enabling subsequent reactions to occur.
The ubiquitin-like domain 2 was thought to interact with the catalytic domain competing with the ubiquitin substrate and thus partially inhibiting USP4 activity (PubMed:21415856). As the results could not be reproduced this work was later retracted (PubMed:24398133). The cristal structure in the paper was correct and was republished later (PubMed:25404403).
By 5-alpha-di-hydrotestosterone and progesterone.
Cleaved into an alpha and beta chain by autocatalysis; this activates the enzyme. The N-terminal residue of the beta subunit is responsible for the nucleophile hydrolase activity.
Expressed in brain, kidney, testis and tissues of the gastrointestinal tract. Present in sperm (at protein level). Over-expressed in uterine, mammary, prostatic and ovarian carcinoma.
Glycine accelerates autocleavage into an alpha and beta chain.
Has both L-asparaginase and beta-aspartyl peptidase activity. May be involved in the production of L-aspartate, which can act as an excitatory neurotransmitter in some brain regions. Is highly active with L-Asp beta-methyl ester. Besides, has catalytic activity toward beta-aspartyl dipeptides and their methyl esters, including beta-L-Asp-L-Phe, beta-L-Asp-L-Phe methyl ester (aspartame), beta-L-Asp-L-Ala, beta-L-Asp-L-Leu and beta-L-Asp-L-Lys. Does not have aspartylglucosaminidase activity and is inactive toward GlcNAc-L-Asn. Likewise, has no activity toward glutamine.
Heterodimer of an alpha and beta chain produced by autocleavage. This heterodimer may then dimerize in turn, giving rise to a heterotetramer.
Belongs to the peptidase C19 family. PAN2 subfamily.
Binds 2 metal cations per subunit in the catalytic exonuclease domain.
Catalytic subunit of the poly(A)-nuclease (PAN) deadenylation complex, one of two cytoplasmic mRNA deadenylases involved in general and miRNA-mediated mRNA turnover. PAN specifically shortens poly(A) tails of RNA and the activity is stimulated by poly(A)-binding protein (PABP). PAN deadenylation is followed by rapid degradation of the shortened mRNA tails by the CCR4-NOT complex. Deadenylated mRNAs are then degraded by two alternative mechanisms, namely exosome-mediated 3'-5' exonucleolytic degradation, or deadenylation-dependent mRNA decaping and subsequent 5'-3' exonucleolytic degradation by XRN1. Also acts as an important regulator of the HIF1A-mediated hypoxic response. Required for HIF1A mRNA stability independent of poly(A) tail length regulation.
Contains a pseudo-UCH domain. This ubiquitin C-terminal hydrolase (UCH)-like or ubiquitin specific protease (USP)-like domain is predicted to be catalytically inactive because it lacks the active site catalytic triad characteristic of thiol proteases, with residues at the equivalent structural positions that are incompatible with catalysis, and it cannot bind ubiquitin. It functions as a structural scaffold for intra- and intermolecular interactions in the complex.
Forms a heterotrimer with an asymmetric homodimer of the regulatory subunit PAN3 to form the poly(A)-nuclease (PAN) deadenylation complex (PubMed:14583602, PubMed:23932717). Interacts with PAN3 isoform 1/Pan3L and isoform 3/Pan3S (PubMed:28559491). Interacts with ZFP36 (By similarity).
Positively regulated by the regulatory subunit PAN3.
The linker, or PAN3 interaction domain (PID), between the WD40 repeats and the pseudo-UCH domain mediates interaction with PAN3.
(Microbial infection) Interacts with L.monocytogenes InlA (PubMed:12526809, PubMed:17540170, PubMed:17715295). The formation of the complex between InlA and cadherin-1 is calcium-dependent (PubMed:12526809).
(Microbial infection) Serves as a receptor for Listeria monocytogenes; internalin A (InlA) binds to this protein and promotes uptake of the bacteria.
Cadherins are calcium-dependent cell adhesion proteins (PubMed:11976333). They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. CDH1 is involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells (PubMed:11976333). Has a potent invasive suppressor role. It is a ligand for integrin alpha-E/beta-7.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Heterozygous CDH1 germline mutations are responsible for familial cases of diffuse gastric cancer. Somatic mutations has also been found in patients with sporadic diffuse gastric cancer and lobular breast cancer.
During apoptosis or with calcium influx, cleaved by a membrane-bound metalloproteinase (ADAM10), PS1/gamma-secretase and caspase-3 (PubMed:11076937, PubMed:11953314, PubMed:10597309). Processing by the metalloproteinase, induced by calcium influx, causes disruption of cell-cell adhesion and the subsequent release of beta-catenin into the cytoplasm (PubMed:10597309). The residual membrane-tethered cleavage product is rapidly degraded via an intracellular proteolytic pathway (PubMed:10597309). Cleavage by caspase-3 releases the cytoplasmic tail resulting in disintegration of the actin microfilament system (PubMed:11076937). The gamma-secretase-mediated cleavage promotes disassembly of adherens junctions (PubMed:11953314). During development of the cochlear organ of Corti, cleavage by ADAM10 at adherens junctions promotes pillar cell separation (By similarity).
E-Cad/CTF2 promotes non-amyloidogenic degradation of Abeta precursors. Has a strong inhibitory effect on APP C99 and C83 production.
Homodimer; disulfide-linked (PubMed:11856755). Component of an E-cadherin/ catenin adhesion complex composed of at least E-cadherin/CDH1, beta-catenin/CTNNB1 or gamma-catenin/JUP, and potentially alpha-catenin/CTNNA1; the complex is located to adherens junctions (PubMed:16126725, PubMed:7982500). Interacts with the TRPV4 and CTNNB1 complex (By similarity). Interacts with CTNND1 (PubMed:15240885). The stable association of CTNNA1 is controversial as CTNNA1 was shown not to bind to F-actin when assembled in the complex (By similarity). Alternatively, the CTNNA1-containing complex may be linked to F-actin by other proteins such as LIMA1 (By similarity). Interaction with PSEN1, cleaves CDH1 resulting in the disassociation of cadherin-based adherens junctions (CAJs) (PubMed:11226248, PubMed:16126725). Interacts with AJAP1 and DLGAP5 (PubMed:14699157, PubMed:14595118). Interacts with TBC1D2 (PubMed:20116244). Interacts with LIMA1 (PubMed:18093941). Interacts with CAV1. Interacts with PIP5K1C (PubMed:17261850). Interacts with RAB8B (By similarity). Interacts with RAPGEF2 (By similarity). Interacts with DDR1; this stabilizes CDH1 at the cell surface and inhibits its internalization (PubMed:20432435). Interacts with KLRG1 (PubMed:19604491). Forms a ternary complex composed of ADAM10, CADH1 and EPHA4; within the complex, CADH1 is cleaved by ADAM10 which disrupts adherens junctions (By similarity). Interacts with SPEF1 (PubMed:31473225). Interacts with CTNNB1 and PKP2 (PubMed:11790773).
N-glycosylation at Asn-637 is essential for expression, folding and trafficking. Addition of bisecting N-acetylglucosamine by MGAT3 modulates its cell membrane location (PubMed:19403558).
O-glycosylated. O-manosylated by TMTC1, TMTC2, TMTC3 or TMTC4. Thr-285 and Thr-509 are O-mannosylated by TMTC2 or TMTC4 but not TMTC1 or TMTC3.
Ubiquitinated by a SCF complex containing SKP2, which requires prior phosphorylation by CK1/CSNK1A1. Ubiquitinated by CBLL1/HAKAI, requires prior phosphorylation at Tyr-754.
Although no clear MSS51 ortholog is encoded in mammalian genomes, the mammalian MSS51/ZMYND17 protein is significantly similar. Considered by a number of resources to be the ortholog of yeast MSS51.
Chemokine that induces chemotaxis of cells expressing CCR5 or CCR1. Inhibits HIV replication in peripheral blood monocytes that express CCR5.
The copy number of the CC4L1 gene varies among individuals; most individuals have 1 to 6 copies in the diploid genome.
Although this protein has been named voltage-gated K channel beta subunit 4.1 in Ref.1 and Ref.2, there is no evidence that it may play a role in ion transport.
Constituent of preproteasomes, but not of mature 20S proteasomes. Within the preproteasome, may directly interact with PSMB1/beta6, PSMB4/beta7, PSMB5/beta5, PSMB6/beta1 and PSMB9/beta1i. Interaction with PSMB8/beta5i has been observed in PubMed:10973495, but not in PubMed:10926487. Forms tetramers.
Molecular chaperone essential for the assembly of standard proteasomes and immunoproteasomes. Degraded after completion of proteasome maturation. Mediates the association of 20S preproteasome with the endoplasmic reticulum.
Strongly expressed from the basal layer to the granular layer of healthy epidermis, whereas in KLICK patients there is a gradual decrease of expression toward the granular layer.
Belongs to the Arg-specific ADP-ribosyltransferase family.
DO is responsible for the Dombrock blood group system [MIM:616060]. The molecular basis of the Do(a)/Do(b) blood group antigen is a single variation in position 265; Asn-265 corresponds to Do(a) and Asp-265 to Do(b). It is also responsible for the antigens Gregory [Gy(a)], Holley [Hy] and Joseph [Jo(a)].
Expressed in B-cell but not T-cell or myeloid cell lines. Highest expression in CD19(+) B-cells, with very low expression in other cell populations.
Involved in B-cell receptor (BCR)-induced Ca(2+) mobilization from intracellular stores. Promotes Lyn-mediated phosphorylation of IP3 receptors 1 and 2.
Phosphorylated on tyrosines upon BCR activation.
(Microbial infection) Interacts with human papillomavirus 16 minor capsid protein L2 (via C-terminus); this interaction mediates the transport of the capsid from the early endosome to the Golgi apparatus.
(Microbial infection) The heterotrimeric retromer cargo-selective complex (CSC) mediates the exit of human papillomavirus from the early endosome and the delivery to the Golgi apparatus.
Acts as component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. The recruitment of the CSC to the endosomal membrane involves RAB7A and SNX3. The CSC seems to associate with the cytoplasmic domain of cargo proteins predominantly via VPS35; however, these interactions seem to be of low affinity and retromer SNX proteins may also contribute to cargo selectivity thus questioning the classical function of the CSC. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX3-retromer mediates the retrograde endosome-to-TGN transport of WLS distinct from the SNX-BAR retromer pathway (PubMed:30213940). The SNX27-retromer is believed to be involved in endosome-to-plasma membrane trafficking and recycling of a broad spectrum of cargo proteins. The CSC seems to act as recruitment hub for other proteins, such as the WASH complex and TBC1D5 (Probable). Required for retrograde transport of lysosomal enzyme receptor IGF2R and SLC11A2. Required to regulate transcytosis of the polymeric immunoglobulin receptor (pIgR-pIgA) (PubMed:15078903, PubMed:15247922, PubMed:20164305). Required for endosomal localization of WASHC2C (PubMed:22070227, PubMed:28892079). Mediates the association of the CSC with the WASH complex via WASHC2 (PubMed:22070227, PubMed:24980502, PubMed:24819384). Required for the endosomal localization of TBC1D5 (PubMed:20923837).
Component of the heterotrimeric retromer cargo-selective complex (CSC), also decribed as vacuolar protein sorting subcomplex (VPS), formed by VPS26 (VPS26A or VPS26B), VPS29 and VPS35 (PubMed:11102511, PubMed:28892079). The CSC has a highly elongated structure with VPS26 and VPS29 binding independently at opposite distal ends of VPS35 as central platform (By similarity). The CSC is believed to associate with variable sorting nexins to form functionally distinct retromer complex variants. The originally described retromer complex (also called SNX-BAR retromer) is a pentamer containing the CSC and a heterodimeric membrane-deforming subcomplex formed between SNX1 or SNX2 and SNX5 or SNX6 (also called SNX-BAR subcomplex); the respective CSC and SNX-BAR subcomplexes associate with low affinity. The CSC associates with SNX3 to form a SNX3-retromer complex. The CSC associates with SNX27, the WASH complex and the SNX-BAR subcomplex to form the SNX27-retromer complex (Probable). Interacts with VPS26A, VPS26B, VPS29, SNX1, SNX2, IGF2R, SNX3, GOLPH3, LRRK2, SLC11A2, WASHC2A, WASHC2C, FKBP15, WASHC1, RAB7A, SNX27, WASHC5, EHD1 (PubMed:11102511, PubMed:15078903, PubMed:17868075, PubMed:22070227, PubMed:19553991, PubMed:21725319, PubMed:22070227, PubMed:22513087, PubMed:23331060, PubMed:23563491, PubMed:23395371, PubMed:24344282, PubMed:24980502, PubMed:17891154, PubMed:19531583, PubMed:30213940). Interacts with MAGEL2; leading to recruitment of the TRIM27:MAGEL2 E3 ubiquitin ligase complex retromer-containing endosomes (PubMed:23452853). Interacts with SORCS2 (By similarity).
Ubiquitous. Highly expressed in heart, brain, placenta, skeletal muscle, spleen, thymus, testis, ovary, small intestine, kidney and colon.
Expressed in a variety of adult and fetal tissues.
A cytochrome P450 monooxygenase that catalyzes the biosynthesis of aldosterone, the main mineralocorticoid in the human body responsible for salt and water homeostasis, thus involved in blood pressure regulation, arterial hypertension, and the development of heart failure (PubMed:1775135, PubMed:1518866, PubMed:9814482, PubMed:15356073, PubMed:12530636, PubMed:22446688, PubMed:11856349, PubMed:23322723, PubMed:1594605, PubMed:9814506). Catalyzes three sequential oxidative reactions of 11-deoxycorticosterone (21-hydroxyprogesterone), namely 11-beta hydroxylation, followed by two successive oxidations at C18 yielding 18-hydroxy and then 18-oxo intermediates (that would not leave the enzyme active site during the consecutive hydroxylation reactions), ending with the formation of aldosterone (PubMed:1775135, PubMed:1518866, PubMed:12530636, PubMed:22446688, PubMed:11856349, PubMed:23322723, PubMed:1594605, PubMed:9814506). Can also produce 18-hydroxycortisol and 18-oxocortisol, derived from successive oxidations of cortisol at C18, normally found at very low levels, but significantly increased in primary aldosteronism, the most common form of secondary hypertension (PubMed:15356073, PubMed:9814482). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate and reducing the second into a water molecule. Two electrons are provided by NADPH via a two-protein mitochondrial transfer system comprising flavoprotein FDXR (adrenodoxin/ferredoxin reductase) and nonheme iron-sulfur protein FDX1 or FDX2 (adrenodoxin/ferredoxin) (PubMed:11856349, PubMed:1594605, PubMed:23322723, PubMed:9814506). Could also be involved in the androgen metabolic pathway (Probable).
Expressed in aldosterone-secreting tumors and in adrenal glands of patients with idiopathic hyperaldosteronism.
Expressed sporadically in the zona glomerulosa (zG) of the adrenal cortex (conventional zonation), as well as in aldosterone-producing cell clusters (APCCs) composed of morphological zG cells in contact with the capsule (variegated zonation).
Expression is induced by angiotensin II, potassium (K+), and also by cAMP.
The disease is caused by variants affecting the gene represented in this entry. The molecular defect causing hyperaldosteronism familial 1 is an anti-Lepore-type fusion of the CYP11B1 and CYP11B2 genes. The hybrid gene has the promoting part of CYP11B1, ACTH-sensitive, and the coding part of CYP11B2.
Abundantly expressed in the thyroid. Also very weakly expressed in brain, spinal cord and placenta. In the thyroid isoform 1 predominates, and isoforms 2 and 6 are also highly expressed. In the placenta isoforms 1 and 2 are expressed equally. In the brain isoform 2 predominates.
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in specific signaling in the thyroid gland.
Inhibited by dipyridimole. Insensitive to selective PDE inhibitors including rolipram and milrinone as well as to the non-selective inhibitor, IBMX. Unaffected by cGMP.
Binds 2 Mg(2+) (PubMed:27284197). Prefers Mg(2+), but can also use Mn(2+) (PubMed:27284197). In vitro, can also utilize other divalent cations such as Ca(2+) (PubMed:27284197).
DNA polymerase specifically involved in the DNA repair by translesion synthesis (TLS) (PubMed:10385124, PubMed:11743006, PubMed:24449906, PubMed:24553286, PubMed:16357261). Due to low processivity on both damaged and normal DNA, cooperates with the heterotetrameric (REV3L, REV7, POLD2 and POLD3) POLZ complex for complete bypass of DNA lesions. Inserts one or 2 nucleotide(s) opposite the lesion, the primer is further extended by the tetrameric POLZ complex. In the case of 1,2-intrastrand d(GpG)-cisplatin cross-link, inserts dCTP opposite the 3' guanine (PubMed:24449906). Particularly important for the repair of UV-induced pyrimidine dimers (PubMed:10385124, PubMed:11743006). Although inserts the correct base, may cause base transitions and transversions depending upon the context. May play a role in hypermutation at immunoglobulin genes (PubMed:11376341, PubMed:14734526). Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have any lyase activity, preventing the release of the 5'-deoxyribose phosphate (5'-dRP) residue. This covalent trapping of the enzyme by the 5'-dRP residue inhibits its DNA synthetic activity during base excision repair, thereby avoiding high incidence of mutagenesis (PubMed:14630940). Targets POLI to replication foci (PubMed:12606586).
Interacts with REV1 (By similarity). Interacts with monoubiquitinated PCNA, but not unmodified PCNA (PubMed:15149598). Interacts with POLI; this interaction targets POLI to the replication machinery (PubMed:12606586). Interacts with PALB2 and BRCA2; the interactions are direct and are required to sustain the recruitment of POLH at blocked replication forks and to stimulate POLH-dependent DNA synthesis on D loop substrates (PubMed:24485656). Interacts (via C-terminus) with TRAIP (PubMed:24553286). Interacts with ubiquitin (PubMed:16357261). Interacts with POLDIP2 (PubMed:20554254).
Monoubiquitinated by RCHY1/PIRH2 (PubMed:20159558, PubMed:21791603). Ubiquitination depends on integrity of the UBZ3-type zinc finger domain and is enhanced by TRAIP (PubMed:24553286, PubMed:16357261). Ubiquitination inhibits the ability of PolH to interact with PCNA and to bypass UV-induced lesions (PubMed:20159558, PubMed:21791603, PubMed:24553286).
The UBZ3-type zinc finger domain and the PIP-box mediate the interaction with ubiquitinated PCNA and are both necessary for the enzymatic activity in translesion synthesis.
The catalytic core consists of fingers, palm and thumb subdomains, but the fingers and thumb subdomains are much smaller than in high-fidelity polymerases; residues from five sequence motifs of the Y-family cluster around an active site cleft that can accommodate DNA and nucleotide substrates with relaxed geometric constraints, with consequently higher rates of misincorporation and low processivity.
The enzyme in complex with the DNA substrate binds a third divalent metal cation (PubMed:27284197). The binding of this third divalent cation, which is coordinated by water molecules and two oxygen atoms from DNA and dNTP, is essential for catalyzing the DNA synthesis (PubMed:27284197).
Brain, spermatozoa, and testis (at protein level). Widely expressed.
Core component of multiple cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. BCR complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the BCR complex depends on the BTB domain-containing protein as the substrate recognition component. BCR(KLHL42) is involved in ubiquitination of KATNA1. BCR(SPOP) is involved in ubiquitination of BMI1/PCGF4, BRMS1, MACROH2A1 and DAXX, GLI2 and GLI3. Can also form a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL; these complexes have lower ubiquitin ligase activity. BCR(KLHL9-KLHL13) controls the dynamic behavior of AURKB on mitotic chromosomes and thereby coordinates faithful mitotic progression and completion of cytokinesis. BCR(KLHL12) is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) acts by mediating monoubiquitination of SEC31 (SEC31A or SEC31B) (PubMed:22358839, PubMed:27716508). BCR(KLHL3) acts as a regulator of ion transport in the distal nephron; by mediating ubiquitination of WNK4 (PubMed:23387299, PubMed:23453970, PubMed:23576762). The BCR(KLHL20) E3 ubiquitin ligase complex is involved in interferon response and anterograde Golgi to endosome transport: it mediates both ubiquitination leading to degradation and 'Lys-33'-linked ubiquitination (PubMed:20389280, PubMed:21840486, PubMed:21670212, PubMed:24768539). The BCR(KLHL21) E3 ubiquitin ligase complex regulates localization of the chromosomal passenger complex (CPC) from chromosomes to the spindle midzone in anaphase and mediates the ubiquitination of AURKB (PubMed:19995937). The BCR(KLHL22) ubiquitin ligase complex mediates monoubiquitination of PLK1, leading to PLK1 dissociation from phosphoreceptor proteins and subsequent removal from kinetochores, allowing silencing of the spindle assembly checkpoint (SAC) and chromosome segregation (PubMed:23455478). The BCR(KLHL22) ubiquitin ligase complex is also responsible for the amino acid-stimulated 'Lys-48' polyubiquitination and proteasomal degradation of DEPDC5. Through the degradation of DEPDC5, releases the GATOR1 complex-mediated inhibition of the TORC1 pathway (PubMed:29769719). The BCR(KLHL25) ubiquitin ligase complex is involved in translational homeostasis by mediating ubiquitination and subsequent degradation of hypophosphorylated EIF4EBP1 (4E-BP1) (PubMed:22578813). The BCR(KLHL25) ubiquitin ligase complex is also involved in lipid synthesis by mediating ubiquitination and degradation of ACLY (PubMed:27664236). The BCR(KBTBD8) complex acts by mediating monoubiquitination of NOLC1 and TCOF1, leading to remodel the translational program of differentiating cells in favor of neural crest specification (PubMed:26399832). Involved in ubiquitination of cyclin E and of cyclin D1 (in vitro) thus involved in regulation of G1/S transition. Involved in the ubiquitination of KEAP1, ENC1 and KLHL41 (PubMed:15983046). In concert with ATF2 and RBX1, promotes degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. The BCR(KCTD17) E3 ubiquitin ligase complex mediates ubiquitination and degradation of TCHP, a down-regulator of cilium assembly, thereby inducing ciliogenesis (PubMed:25270598). The BCR(KLHL24) E3 ubiquitin ligase complex mediates ubiquitination of KRT14, controls KRT14 levels during keratinocytes differentiation, and is essential for skin integrity (PubMed:27798626). The BCR(KLHL18) E3 ubiquitin ligase complex mediates the ubiquitination of AURKA leading to its activation at the centrosome which is required for initiating mitotic entry (PubMed:23213400). The BCR(KEAP1) E3 ubiquitin ligase complex acts as a key sensor of oxidative and electrophilic stress by mediating ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes (PubMed:15601839, PubMed:16006525). As part of the CUL3(KBTBD6/7) E3 ubiquitin ligase complex functions mediates 'Lys-48' ubiquitination and proteasomal degradation of TIAM1 (PubMed:25684205). By controlling the ubiquitination of that RAC1 guanine exchange factors (GEF), regulates RAC1 signal transduction and downstream biological processes including the organization of the cytoskeleton, cell migration and cell proliferation (PubMed:25684205).
Forms neddylation-dependent homodimers. Component of multiple BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes formed of CUL3, RBX1 and a variable BTB domain-containing protein acting as both, adapter to cullin and substrate recognition subunit. The BCR complex may be active as a heterodimeric complex, in which NEDD8, covalently attached to one CUL3 molecule, binds to the C-terminus of a second CUL3 molecule. Interacts with RBX1, RNF7, CYCE and TIP120A/CAND1 (PubMed:10500095, PubMed:10230407, PubMed:12609982). Part of the BCR(SPOP) containing SPOP, and of BCR containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL. Part of the probable BCR(KLHL9-KLHL13) complex with BTB domain proteins KLHL9 and KLHL13. Part of the BCR(KLHL41) complex containing KLHL41. Component of the BCR(KLHL12) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL12 and RBX1. Component of the BCR(KLHL3) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL3 and RBX1 (Probable). Part of the BCR(ENC1) complex containing ENC1. Part of a complex consisting of BMI1/PCGF4, CUL3 and SPOP. Part of a complex consisting of BRMS1, CUL3 and SPOP. Component of the BCR(KLHL21) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL21 and RBX1. Component of the BCR(KLHL22) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL22 and RBX1. Component of the BCR(KLHL25) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL25 and RBX1 (PubMed:22578813, PubMed:27664236). Part of a complex consisting of MACROH2A1, CUL3 and SPOP. Component of the BCR(KLHL42) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL42. Interacts with KLHL42 (via the BTB domain). Interacts with KATNA1; the interaction is enhanced by KLHL42. Component of the BCR(KBTBD8) E3 ubiquitin ligase complex, at least composed of CUL3, KBTBD8 and RBX1 (PubMed:26399832). Interacts with KCTD5, KLHL9, KLHL11, KLHL13, GAN, ZBTB16, KLHL3, KLHL15, KLHL20, KLHL36, GMCL2, BTBD1. Part of a complex that contains CUL3, RBX1 and GAN. Interacts (via BTB domain) with KLHL17; the interaction regulates surface GRIK2 expression. Interacts with KCTD7. Part of the BCR(GAN) complex containing GAN. Part of the BCR(KEAP1) complex containing KEAP1 (PubMed:15983046, PubMed:15601839, PubMed:32341456). Interacts with KLHL10 (By similarity). Interacts with KAT5 and ATF2. Interacts with KCTD17 in the BCR(KCTD17) E3 ubiquitin ligase complex, at least composed of CUL3, KCTD17 and RBX1 (PubMed:25270598). Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1 (PubMed:24076655, PubMed:27565346). Interacts with COPS9 isoform 2 (PubMed:23776465). Interacts with PPP2R5B; this interaction is indirect and mediated through KLHL15-binding and leads to PPP2R5B proteasomal degradation (PubMed:23135275). Interacts with RBBP8/CtIP; this interaction is indirect and mediated through KLHL15-binding and leads to RBBP8 proteasomal degradation (PubMed:27561354). Interacts with KLHL24 in the BCR(KLHL24) E3 ubiquitin ligase complex, composed of CUL3, RBX1 and KLHL24 (PubMed:27798626). Interacts with RHOBTB2 (PubMed:29276004). Interacts with AURKA and KLHL18 (via BTB domain) (PubMed:23213400). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (PubMed:24192928, PubMed:26906416, PubMed:23201271, PubMed:25349211). Component of a BCR3 (BTB-CUL3-RBX1) E3 ubiquitin ligase complex, also named Cul3-RING ubiquitin ligase complex CUL3(KBTBD6/7), composed of CUL3, RBX1, KBTBD6 and KBTBD7 (PubMed:25684205). Component of the BCR(KBTBD2) E3 ubiquitin ligase complex, at least composed of CUL3, KBTBD2 and RBX1. Interacts with KBTBD2 (via the BTB domain) (PubMed:27708159).
Neddylated. Attachment of NEDD8 is required for the E3 ubiquitin-protein ligase activity of the BCR complex. Deneddylated via its interaction with the COP9 signalosome (CSN) complex.
Interacts with TCF3, TCF4 and TCF12. Interacts with CDC20. Efficient DNA-binding and transcription activation require dimerization with another bHLH protein (By similarity).
The C-terminal region is necessary for depolarization-induced and calcium-dependent transcription activation.
Transcriptional regulator implicated in neuronal determination. Mediates calcium-dependent transcription activation by binding to E box-containing promoter. Critical factor essential for the repression of the genetic program for neuronal differentiation; prevents the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. Induces transcription of ZEB1, which in turn represses neuronal differentiation by down-regulating REST expression. Plays a role in the establishment and maturation of thalamocortical connections; involved in the segregation of thalamic afferents into distinct barrel domains within layer VI of the somatosensory cortex. Involved in the development of the cerebellar and hippocampal granular neurons, neurons in the basolateral nucleus of amygdala and the hypothalamic-pituitary axis. Associates with chromatin to the DPYSL3 E box-containing promoter (By similarity).
Tetramer of two catalytic chains and two glycosylated inactive chains.
The 83 kDa subunit binds and stabilizes the catalytic subunit at 37 degrees Celsius and keeps it in circulation. Under some circumstances it may be an allosteric modifier of the catalytic subunit.
Whether or not any Cys residues participate in intrachain bonds is unknown, but they do not form interchain disulfide bonds with the 50 kDa catalytic subunit.
DNA repair enzyme that incises DNA at 8-oxoG residues. Excises 7,8-dihydro-8-oxoguanine and 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine (FAPY) from damaged DNA. Has a beta-lyase activity that nicks DNA 3' to the lesion.
(Microbial infection) Interacts with Staphylococcus aureus protein isdB.
Alpha(0)-thalassemia is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders.
Hemopressin acts as an antagonist peptide of the cannabinoid receptor CNR1 (PubMed:18077343). Hemopressin-binding efficiently blocks cannabinoid receptor CNR1 and subsequent signaling (PubMed:18077343).
Heterotetramer of two alpha chains and two beta chains in adult hemoglobin A (HbA); two alpha chains and two delta chains in adult hemoglobin A2 (HbA2); two alpha chains and two epsilon chains in early embryonic hemoglobin Gower-2; two alpha chains and two gamma chains in fetal hemoglobin F (HbF).
The initiator Met is not cleaved in variant Thionville and is acetylated.
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:9099683, PubMed:11309392, PubMed:22627129). Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes (PubMed:11309392, PubMed:17664281, PubMed:26748701). Within the adrenocorticotropic hormone signaling pathway, produces phosphatidic acid which in turn activates NR5A1 and subsequent steroidogenic gene transcription (PubMed:17664281). Also functions downstream of the nerve growth factor signaling pathway being specifically activated in the nucleus by the growth factor (By similarity). Through its diacylglycerol activity also regulates synaptic vesicle endocytosis (PubMed:26748701).
Interacts with RHOA (constitutively activated, GTP-bound); the interaction inhibits DGKQ (PubMed:11309392, PubMed:15164764). Interacts with PRKCE (PubMed:15632189). Interacts with PRKCH (PubMed:15632189). Interacts with PLCB1 (PubMed:12799190). Interacts with NR5A1; the interaction requires both LXXLL motifs in DGKQ and is required for full phosphatidic acid-mediated activation of NR5A1 (PubMed:17664281).
Phosphorylated by PRKCE and PRKCH in vitro.
The L-X-X-L-L repeats are both required for binding and phosphatidic acid-mediated activation of the nuclear receptor NR5A1.
Cell surface receptor. Plays a functionally redundant role in postnatal brain development and in regulating axon regeneration in the adult central nervous system. Contributes to normal axon migration across the brain midline and normal formation of the corpus callosum. Protects motoneurons against apoptosis; protection against apoptosis is probably mediated by MAG. Plays a role in inhibiting neurite outgrowth and axon regeneration via its binding to neuronal chondroitin sulfate proteoglycans. Binds heparin (By similarity). Like other family members, plays a role in restricting the number dendritic spines and the number of synapses that are formed during brain development (PubMed:22325200). Signaling mediates activation of Rho and downstream reorganization of the actin cytoskeleton (PubMed:22325200).
Identified in a complex that contains RTN4R, RTN4RL1 and NGFR; the interaction depends on the presence of chondroitin sulfate proteoglycans. Does not interact with MAG, OMG and RTN4.
Predominantly expressed in brain. Expressed at lower levels in kidney, lung, mammary gland, placenta, salivary gland, skeletal muscle and spleen.
Guanine nucleotide exchange factor (GEF) which may activate RAB9A and RAB9B. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form. May play a role in late endosomes back to trans-Golgi network/TGN transport.
Expressed in peripheral macrophages and intestinal myeloid-derived cells, is required for optimal PRR (pattern recognition receptor)-induced signaling, cytokine secretion, and bacterial clearance. Upon stimulation of a broad range of PRRs (pattern recognition receptor) such as NOD2 or TLR2, TLR3, TLR4, TLR5, TLR7 and TLR9, associates with YWHAQ/14-3-3T, which in turn leads to the recruitment and activation of MAP kinases and NF-kappa-B signaling complexes that amplifies PRR-induced downstream signals and cytokine secretion (PubMed:28436939). In the intestine, regulates adherens junction stability by regulating the degradation of CYTH1 and CYTH2, probably acting as substrate cofactor for SCF E3 ubiquitin-protein ligase complexes. Stabilizes adherens junctions by limiting CYTH1-dependent ARF6 activation (PubMed:29420262).
Expression is induced by the component of peptidoglycan muramyl dipeptide (PubMed:28436939). Negatively regulated by microRNA-24 (miR-24) (PubMed:28436939).
Highly expressed in intestinal myeloid-derived cells and expressed in monocyte-derived macrophages upon induction by PRR activation.
Interacts with IRAK1, NOD2 and RIPK2; the interaction takes place upon PRR stimulation (PubMed:28436939). Interacts with YWHAQ/14-3-3T; the interaction increases upon PRR stimulation and is required for cellular signaling pathway activation and cytokine secretion (PubMed:28436939). Interacts (via N-terminal domain) with CYTH1 and CYTH2 (via their N-terminal domains) (PubMed:29420262). Interacts with FBXW11 and BTRC; associates with SCF E3 ubiquitin-protein ligase complexes (PubMed:29420262).
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL70.
Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals. The BLOC-1 complex, in association with SNARE proteins, is also proposed to be involved in neurite extension. Plays a role in intracellular vesicle trafficking and synaptic vesicle recycling. May modulate a step between vesicle priming, fusion and calcium-dependent neurotransmitter release through its ability to potentiate the interaction of synaptotagmin with the SNAREs and the plasma-membrane-associated protein SNAP25. Its phosphorylation state influences exocytotic protein interactions and may regulate synaptic vesicle exocytosis. May also have a role in the mechanisms of SNARE-mediated membrane fusion in non-neuronal cells (PubMed:17182842, PubMed:18167355). As part of the BORC complex may play a role in lysosomes movement and localization at the cell periphery. Associated with the cytosolic face of lysosomes, the BORC complex may recruit ARL8B and couple lysosomes to microtubule plus-end-directed kinesin motor (PubMed:25898167).
Component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) composed of BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. Octamer composed of one copy each BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. The BLOC-1 complex associates with the AP-3 protein complex and membrane protein cargos (PubMed:15102850, PubMed:22203680). Component of the BLOC-one-related complex (BORC) which is composed of BLOC1S1, BLOC1S2, BORCS5, BORCS6, BORCS7, BORCS8, KXD1 and SNAPIN (PubMed:25898167). Associates with the SNARE complex. Interacts with CSNK1D, SNAP23 and STX4A but not with STX1A, VAMP2 and SYT1. Interacts with SNAP25; the interaction with SNAP25 is increased by its phosphorylation. Interacts with CNTRL, NANOS1, PUM2 and RGS7 (PubMed:12659861, PubMed:16213214, PubMed:19168546). Interacts with TOR1A; the interaction is direct and associates SNAPIN with the CSN complex (PubMed:18167355, PubMed:21102408).
Expressed in germ cells of 22-week prenatal testis.
Expressed in male germ cells of adult testis (at protein level).
Phosphorylated by CSNK1D/CK1 (By similarity). Phosphorylated by PKD, phosphorylation controls SNAPIN protein stability.
Expressed in fetal and adult brain, leukocytes and fetal fibroblasts.
Interacts with the SH3-containing region of the adapter protein NCK.
(Microbial infection) Involved in post-transcriptional regulation of HIV-1 gene expression.
Induced in proteinuric diseases. Down-regulated in immortalized fibroblasts isolated after a proliferative crisis accompanied with massive cell death.
Phosphorylated on tyrosine residues. Isoform 1 C-terminal region is tyrosine-rich, but isoform 2 lacking this C-terminal region is also tyrosine-phosphorylated.
RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion. Binds preferentially to the 5'-[AU]UAAA-3' motif in vitro. Binds optimally to RNA containing 5'-[AU]UAA-3' as a bipartite motif spaced by more than 15 nucleotides. Binds poly(A). RNA-binding abilities are down-regulated by tyrosine kinase PTK6 (PubMed:10564820, PubMed:19561594, PubMed:26758068). Involved in splice site selection of vascular endothelial growth factor (PubMed:15901763). In vitro regulates CD44 alternative splicing by direct binding to purine-rich exonic enhancer (By similarity). Can regulate alternative splicing of neurexins NRXN1-3 in the laminin G-like domain 6 containing the evolutionary conserved neurexin alternative spliced segment 4 (AS4) involved in neurexin selective targeting to postsynaptic partners such as neuroligins and LRRTM family members (PubMed:26758068). Targeted, cell-type specific splicing regulation of NRXN1 at AS4 is involved in neuronal glutamatergic synapse function and plasticity (By similarity). May regulate expression of KHDRBS2/SLIM-1 in defined brain neuron populations by modifying its alternative splicing (By similarity). Can bind FABP9 mRNA (By similarity). May play a role as a negative regulator of cell growth. Inhibits cell proliferation.
Self-associates to form homooligomers; dimerization increases RNA affinity (PubMed:26758068). Interacts with KHDRBS2/SLM-1 (By similarity). Interacts with KHDRBS1/SAM68; heterooligomer formation of KHDRBS family proteins may modulate RNA substrate specificity (PubMed:10332027). Interacts with the splicing regulatory proteins SFRS9, SAFB and YTHDC1. Interacts with HNRPL (By similarity). Interacts with RBMX, RBMY1A1, p85 subunit of PI3-kinase, SERPINB5 (PubMed:10564820, PubMed:10332027, PubMed:10749975, PubMed:21725612). Interacts with SIAH1 which promotes targeting for degradation (PubMed:15163637).
The proline-rich site binds the SH3 domain of the p85 subunit of PI3-kinase.
Ubiquitous with higher expression in testis, skeletal muscle and brain. Expressed in the kidney only in podocytes, the glomerular epithelial cells of the kidney. Strongly expressed after meiosis.
Catalyzes the 2-hydroxylation of not only racemic phytanoyl-CoA and the isomers of 3-methylhexadecanoyl-CoA, but also a variety of other mono-branched 3-methylacyl-CoA esters (with a chain length of at least seven carbon atoms) and straight-chain acyl-CoA esters (with a chain length longer than four carbon atoms) (PubMed:9326939, PubMed:10744784, PubMed:12031666, PubMed:12923223). Does not hydroxylate long and very long straight chain acyl-CoAs or 2-methyl- and 4-methyl-branched acyl-CoAs (PubMed:10744784, PubMed:12923223).
Expressed in liver, kidney, and T-cells, but not in spleen, brain, heart, lung and skeletal muscle.
Interacts with FKBP52 (PubMed:10051602). Interacts with PHYHIP.
Important for the control of mitochondrial reactive oxygen species homeostasis, apoptosis regulation and cell viability. Possesses a dithiol-reducing activity.
Widely expressed in adult (at protein level) and fetal tissues.
Broadly expressed, with highest levels in heart and skeletal muscle.
Expression is significantly up-regulated by oxidative stress (PubMed:19446606).
Forms homooligomers (PubMed:23625927). Identified in the CTLH complex that contains GID4, RANBP9 and/or RANBP10, MKLN1, MAEA, RMND5A (or alternatively its paralog RMND5B), GID8, ARMC8, WDR26 and YPEL5 (PubMed:29911972). Within this complex, MAEA, RMND5A (or alternatively its paralog RMND5B), GID8, WDR26, and RANBP9 and/or RANBP10 form the catalytic core, while GID4, MKLN1, ARMC8 and YPEL5 have ancillary roles (PubMed:29911972). Interacts with DDB1-CUL4A/B E3 ligase complexes (PubMed:17041588). Forms a complex composed of at least WDR26, a G-beta:gamma unit, and PLCB2 (PubMed:22065575, PubMed:23625927). Interacts with AXIN1 (PubMed:27098453).
G-beta-like protein involved in cell signal transduction (PubMed:15378603, PubMed:19446606, PubMed:22065575, PubMed:23625927, PubMed:27098453, PubMed:26895380). Acts as a negative regulator in MAPK signaling pathway (PubMed:15378603). Functions as a scaffolding protein to promote G beta:gamma-mediated PLCB2 plasma membrane translocation and subsequent activation in leukocytes (PubMed:22065575, PubMed:23625927). Core component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1 (PubMed:29911972). Acts as a negative regulator of the canonical Wnt signaling pathway through preventing ubiquitination of beta-catenin CTNNB1 by the beta-catenin destruction complex, thus negatively regulating CTNNB1 degradation (PubMed:27098453). Serves as a scaffold to coordinate PI3K/AKT pathway-driven cell growth and migration (PubMed:26895380). Protects cells from oxidative stress-induced apoptosis via the down-regulation of AP-1 transcriptional activity as well as by inhibiting cytochrome c release from mitochondria (PubMed:19446606). Protects also cells by promoting hypoxia-mediated autophagy and mitophagy (By similarity).
Interacts (via COMM domain) with COMMD1 (via COMM domain). Interacts with RELA. Interacts with CCDC22, CCDC93, SCNN1B, CUL7.
May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes (PubMed:21778237). Associates with the NF-kappa-B complex and suppresses its transcriptional activity (PubMed:15799966).
Widely expressed with highest expression in lung.
Broadly expressed, with highest levels in brain.
Identified in a complex that contains SEL1L, OS9, FAF2/UBXD8, UBE2J1/UBC6E and AUP1 (PubMed:18711132). Interacts with YOD1 (PubMed:19818707). Interacts (via N-terminus) with UBQLN2 (via C-terminus) (PubMed:24215460). Interacts with PNPLA2 and UBAC2 (PubMed:23297223). Interacts with ZFAND2B; probably through VCP (PubMed:24160817). Interacts with LMBR1L (PubMed:31073040).
Plays an important role in endoplasmic reticulum-associated degradation (ERAD) that mediates ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins (PubMed:18711132, PubMed:24215460). By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333). Involved in inhibition of lipid droplet degradation by binding to phospholipase PNPL2 and inhibiting its activity by promoting dissociation of PNPL2 from its endogenous activator, ABHD5 which inhibits the rate of triacylglycerol hydrolysis (PubMed:23297223). Involved in stress granule disassembly: associates with ubiquitinated G3BP1 in response to heat shock, thereby promoting interaction between ubiquitinated G3BP1 and VCP, followed by G3BP1 extraction from stress granules and stress granule disassembly (PubMed:34739333).
Up-regulated in T-cells and eosinophils from patients with atopic dermatitis.
Acts as a transcriptional regulator. Inhibits myogenesis by sequestrating E proteins, inhibiting trans-activation by MEF2, and inhibiting DNA-binding by MYOD1 through physical interaction. This interaction probably involves the basic domains of both proteins. Also represses expression of pro-inflammatory cytokines such as TNFA and IL1B. Regulates cranial suture patterning and fusion. Activates transcription as a heterodimer with E proteins. Regulates gene expression differentially, depending on dimer composition. Homodimers induce expression of FGFR2 and POSTN while heterodimers repress FGFR2 and POSTN expression and induce THBS1 expression. Heterodimerization is also required for osteoblast differentiation. Represses the activity of the circadian transcriptional activator: NPAS2-BMAL1 heterodimer (By similarity).
Efficient DNA binding requires dimerization with another bHLH protein. Homodimer or heterodimer with E proteins such as TCF3. ID1 binds preferentially to TCF3 but does not interact efficiently with TWIST1 so ID1 levels control the amount of TCF3 available to dimerize with TWIST1 and thus determine the type of dimer formed (By similarity).
Belongs to the class I-like SAM-binding methyltransferase superfamily. EEF2KMT family.
Catalyzes the trimethylation of eukaryotic elongation factor 2 (EEF2) on 'Lys-525'.
Expressed in the brain, neurons and glial cells. Also expressed in highly differentiated cells, such as the serous acini in the parotid gland, distal and proximal tubules of the kidney, tubules of the seminal gland, Kupffer cells and some hepatocytes in the liver, and some cells in the germinal center of lymph nodes (at protein level).
Inactive serine/threonine-protein kinase that plays a role in cell cycle progression and neuronal differentiation.
The truncated protein kinase domain is predicted to be catalytically inactive; has lost the main activatory autophosphorylation site and the conserved key residues involved in phospho-substrate. The C-terminal region (containing the POLO box domain) is sufficient for inducing cell cycle arrest.
Interacts with NOL3; may dephosphorylate NOL3.
Widely expressed. Most abundant in testis, skeletal muscle, and heart.
Found in several complexes of 140-500 kDa. Interacts with YME1L1 (PubMed:26759378). Interacts with COX4I1 (PubMed:26759378). Interacts with COX5A (PubMed:26759378). Interacts with TP53; mediates mitochondrial translocation of TP53 in response to genotoxic stress such as mitomycin C treatment (PubMed:27323408).
Putative mitochondrial ATPase. Plays a role in mitochondrial morphology and mitochondrial protein metabolism. Promotes degradation of excess nuclear-encoded complex IV subunits (COX4I1, COX5A and COX6A1) and normal activity of complexes III and IV of the respiratory chain (PubMed:26759378, PubMed:27323408). Mediates mitochondrial translocation of TP53 and its transcription-independent apoptosis in response to genotoxic stress (PubMed:27323408).
Binds and may modulate the functional properties of nicotinic and muscarinic acetylcholine receptors. May regulate keratinocytes proliferation, differentiation and apoptosis. In vitro moderately inhibits ACh-evoked currents of alpha-3:beta-2-containing nAChRs and strongly these of alpha-4:beta-2-containing nAChRs, modulates alpha-7-containing nAChRs, and inhibits nicotine-induced signaling probably implicating alpha-3:beta-4-containing nAChRs. Proposed to act on alpha-3:beta-2 and alpha-7 nAChRs in an orthosteric, and on mAChRs, such as CHRM1 and CHRM3, in an allosteric manner.
Expressed at highest levels in cervix and esophagus, followed by adult and fetal skin. Expressed at lower levels in brain, lung, stomach, small intestine, colon, rectum, uterus, and thymus. Not detected in spleen nor bone marrow. Up-regulated 3-fold in psoriatic lesional skin (PubMed:12573258). In the epidermis, predominantly produced by keratinocytes of the suprabasal epidermal compartment (at protein level) (PubMed:16575903). In attached gingiva, produced at highest levels by basal cells located in the lowermost epithelial layers (at protein level) (PubMed:16575903). Detected in serum (at protein level) (PubMed:16575903).
Interacts with CHRNA3, CHRNA4, CHRNA5, CHRNA7, CHRNB2 and CHRNB4. Interacts with CHRM1 and CHRM3 probably in an allosteric manner (PubMed:27485575).
Up-regulation by IL22/interleukin-22 is suppressed by IFNG/Interferon gamma (at protein level).
Expressed in placenta, lung, liver, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon, heart, epidermis, esophagus, brain and smooth and skeletal muscle. Expressed strongly in melanoma metastasis lesions and advanced primary tumors.
Found in a mRNA splicing-dependent exon junction complex (EJC). Found in a complex with SR proteins. Found in a mRNP complex with RNPS1. Component of the PSAP complex consisting of RNPS1, SAP18 and PNN. Interacts with PNISR, CTBP1, CTBP2, KRT8, KRT18, KRT19, PS1D/PNO40, PPIG, RNPS1, SFRS4 and SRRM2. Identified in the spliceosome C complex.
Transcriptional activator binding to the E-box 1 core sequence of the E-cadherin promoter gene; the core-binding sequence is 5'CAGGTG-3'. Capable of reversing CTBP1-mediated transcription repression. Auxiliary component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. Participates in the regulation of alternative pre-mRNA splicing. Associates to spliced mRNA within 60 nt upstream of the 5'-splice sites. Component of the PSAP complex which binds RNA in a sequence-independent manner and is proposed to be recruited to the EJC prior to or during the splicing process and to regulate specific excision of introns in specific transcription subsets. Involved in the establishment and maintenance of epithelia cell-cell adhesion. Potential tumor suppressor for renal cell carcinoma.
Antimicrobial activity is decreased when the sodium chloride concentration is increased.
Has antimicrobial activity. Synergistic effects with lysozyme and DEFB103.
High expression in the testis. Gastric antrum exhibited relatively high levels. A lower expression is observed in uterus and neutrophils thyroid gland, lung, and kidney. No detectable expression in other tissues tested.
Autophosphorylated on tyrosine residues. KITLG/SCF binding enhances autophosphorylation. Isoform 1 shows low levels of tyrosine phosphorylation in the absence of added KITLG/SCF (in vitro). Kinase activity is down-regulated by phosphorylation on serine residues by protein kinase C family members. Phosphorylation at Tyr-568 is required for interaction with PTPN11/SHP-2, CRK (isoform Crk-II) and members of the SRC tyrosine-protein kinase family. Phosphorylation at Tyr-570 is required for interaction with PTPN6/SHP-1. Phosphorylation at Tyr-703, Tyr-823 and Tyr-936 is important for interaction with GRB2. Phosphorylation at Tyr-721 is important for interaction with PIK3R1. Phosphorylation at Tyr-823 and Tyr-936 is important for interaction with GRB7.
In testis, detected in spermatogonia in the basal layer and in interstitial Leydig cells but not in Sertoli cells or spermatocytes inside the seminiferous tubules (at protein level) (PubMed:20601678). Expression is maintained in ejaculated spermatozoa (at protein level) (PubMed:20601678).
Monomer in the absence of bound KITLG/SCF. Homodimer in the presence of bound KITLG/SCF, forming a heterotetramer with two KITLG/SCF molecules. Interacts (via phosphorylated tyrosine residues) with the adapter proteins GRB2 and GRB7 (via SH2 domain), and SH2B2/APS. Interacts (via C-terminus) with MPDZ (via the tenth PDZ domain). Interacts (via phosphorylated tyrosine residues) with PIK3R1 and PIK3 catalytic subunit. Interacts (via phosphorylated tyrosine) with CRK (isoform Crk-II), FYN, SHC1 and MATK/CHK (via SH2 domain). Interacts with LYN and FES/FPS. Interacts (via phosphorylated tyrosine residues) with the protein phosphatases PTPN6/SHP-1 (via SH2 domain), PTPN11/SHP-2 (via SH2 domain) and PTPRU. Interacts with PLCG1. Interacts with DOK1 and TEC. Interacts (KITLG/SCF-bound) with IL1RL1. Interacts with IL1RAP (independent of stimulation with KITLG/SCF). A mast cell-specific KITLG/SCF-induced interleukin-33 signaling complex contains IL1RL1, IL1RAP, KIT and MYD88.
Numerous proteins are phosphorylated in response to KIT signaling, but it is not evident to determine which are directly phosphorylated by KIT under in vivo conditions.
Present in an inactive conformation in the absence of bound ligand. KITLG/SCF binding leads to dimerization and activation by autophosphorylation on tyrosine residues. Activity is down-regulated by PRKCA-mediated phosphorylation on serine residues. Inhibited by imatinib/STI-571 (Gleevec) and sunitinib; these compounds maintain the kinase in an inactive conformation.
The gene represented in this entry is involved in disease pathogenesis. Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase.
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.
Ubiquitinated by SOCS6. KIT is rapidly ubiquitinated after autophosphorylation induced by KITLG/SCF binding, leading to internalization and degradation.
Up-regulated by cis-retinoic acid in neuroblastoma cell lines.
E3 SUMO-protein ligase that mediates SUMOylation of TAB2 leading to inhibition of NF-kappa-B and MAPK pathways by suppressing the TRAF6/TAB2/TAK1 complex.
Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EUHMTASE1, RING1, RNF2, MBLR, BAT8 and YAF2.
Putative Polycomb group (PcG) protein. PcG proteins maintain the transcriptionally repressive state of genes, probably via a modification of chromatin, rendering it heritably changed in its expressibility. Its association with a chromatin-remodeling complex suggests that it may contribute to prevent expression of genes that trigger the cell into mitosis. Binds to monomethylated and dimethylated 'Lys-20' on histone H4. Binds histone H3 peptides that are monomethylated or dimethylated on 'Lys-4', 'Lys-9' or 'Lys-27'.
Incorporates a polar amino acid serine into membranes and facilitates the synthesis of two serine-derived lipids, phosphatidylserine and sphingolipids.
(Microbial infection) Acts as a cell surface receptor for Baboon M7 endogenous virus.
(Microbial infection) Acts as a cell surface receptor for Feline endogenous virus RD114.
(Microbial infection) Acts as a cell surface receptor for type D simian retroviruses.
Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A5 subfamily.
Homotrimer (Probable) (PubMed:29872227). Interacts with ERVH48-1/suppressyn; may negatively regulate syncytialization (PubMed:23492904).
Placenta, lung, skeletal muscle, kidney, pancreas, and intestine (PubMed:8702519). Expressed in CD34-positive hematopoietic progenitors (at protein level) (PubMed:24953180).
Regulated by L-cysteine, which can either inhibit substrate influx or trigger substrate efflux without being transported itself.
Sodium-coupled antiporter of neutral amino acids. In a tri-substrate transport cycle, exchanges neutral amino acids between the extracellular and intracellular compartments, coupled to the inward cotransport of at least one sodium ion (PubMed:23756778, PubMed:26492990, PubMed:17094966, PubMed:34741534, PubMed:29872227, PubMed:8702519). The preferred substrate is the essential amino acid L-glutamine, a precursor for biosynthesis of proteins, nucleotides and amine sugars as well as an alternative fuel for mitochondrial oxidative phosphorylation. Exchanges L-glutamine with other neutral amino acids such as L-serine, L-threonine and L-asparagine in a bidirectional way. Provides L-glutamine to proliferating stem and activated cells driving the metabolic switch toward cell differentiation (PubMed:23756778, PubMed:24953180). The transport cycle is usually pH-independent, with the exception of L-glutamate. Transports extracellular L-glutamate coupled to the cotransport of one proton and one sodium ion in exchange for intracellular L-glutamine counter-ion. May provide for L-glutamate uptake in glial cells regulating glutamine/glutamate cycle in the nervous system (PubMed:32733894). Can transport D-amino acids. Mediates D-serine release from the retinal glia potentially affecting NMDA receptor function in retinal neurons (PubMed:17094966). Displays sodium- and amino acid-dependent but uncoupled channel-like anion conductance with a preference SCN(-) >> NO3(-) > I(-) > Cl(-) (By similarity). Through binding of the fusogenic protein syncytin-1/ERVW-1 may mediate trophoblasts syncytialization, the spontaneous fusion of their plasma membranes, an essential process in placental development (PubMed:10708449, PubMed:23492904).
Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Detected in meniscus, bone, tendon, cartilage, synovium, fat and ligaments.
May be cleaved by a furin endopeptidase (By similarity). The precursor is sequentially processed.
Metalloprotease that may play a role in the degradation of COMP.
N-glycosylated. Can be O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS family members. Can also be C-glycosylated with one or two mannose molecules on tryptophan residues within the consensus sequence W-X-X-W of the TPRs. N- and C-glycosylations can also facilitate secretion. O-glycosylated proteoglycan. Contains chondroitin sulfate.
Up-regulated in articular cartilage and synovium from arthritis patients.
Efficient DNA binding requires dimerization with another bHLH protein. Interacts with CSRP3.
Involved in muscle differentiation (myogenic factor). Induces fibroblasts to differentiate into myoblasts. Probable sequence specific DNA-binding protein.
Receptor for a C-C type chemokine. Binds to MIP-1-alpha, MIP-1-delta, RANTES, and MCP-3 and, less efficiently, to MIP-1-beta or MCP-1 and subsequently transduces a signal by increasing the intracellular calcium ions level. Responsible for affecting stem cell proliferation.
Widely expressed in different hematopoietic cells.
Associates with GIRK2, GIRK3 or GIRK4 to form a G-protein activated heteromultimer pore-forming unit. The resulting inward current is much larger (By similarity).
Associates with GIRK2, GIRK3 or GIRK4 to form a G-protein activated heteromultimer pore-forming unit. The resulting inward current is much larger.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ3 subfamily.
This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. This receptor plays a crucial role in regulating the heartbeat.
Interacts with TOR1A, preferentially with the ATP-free form.
Expressed at high levels in the spleen, thymus, and PBMC, at low levels in the prostate, ovary, small intestine, colon (mucosal lining), placenta, lung, and pancreas, and very weakly expressed in the liver and kidney.
Induced at the early stage of T cell activation. Regulated at the transcriptional level during the cell cycle. Induced at a maximum level in the S phase.
May be involved in transcriptional regulation. May be involved in regulation of cell proliferation.
Maximal phosphorylation of Ser-336 correlates with maximal relaxation of aorta in response to acetylcholine.
Plays a role in the regulation of contractile properties of both striated and smooth muscles. When unphosphorylated, may inhibit myosin dephosphorylation. Phosphorylation at Ser-299 reduces this inhibitory activity (By similarity).
Also has weak activity in the presence of Mg(2+) or Ca(2+) ions.
Belongs to the dermatan-sulfate isomerase family.
Converts D-glucuronic acid to L-iduronic acid (IdoUA) residues. Plays an important role in the biosynthesis of the glycosaminoglycan/mucopolysaccharide dermatan sulfate.
N-glycosylated (PubMed:19004833, Ref.7). Glycosylation is important for enzymatic activity (PubMed:19004833).
Ubiquitously expressed with higher expression in kidney and ovary and lower expression in brain, colon and thymus. Also expressed in renal cell carcinomas, brain tumors, and in a part of melanomas and adenocarcinomas from organs other than the breast. Expressed in squamous cell carcinomas (SCC), glioma, and some adenocarcinoma cell lines, but not in breast cancer cell lines or any normal tissues (at protein level).
Belongs to the 2'-deoxynucleoside 5'-phosphate N-hydrolase 1 family.
Catalyzes the cleavage of the N-glycosidic bond of deoxyribonucleoside 5'-monophosphates to yield deoxyribose 5-phosphate and a purine or pyrimidine base. Deoxyribonucleoside 5'-monophosphates containing purine bases are preferred to those containing pyrimidine bases.
Expressed at low levels in brain, colon, lung, peripheral blood leukocytes, placenta, small intestine, and thymus. Expressed at high levels in heart, kidney, liver, skeletal muscle and spleen. Overexpressed in a significant proportion of breast cancers.
(Microbial infection) The CCC complex, in collaboration with the heterotrimeric retriever complex, mediates the exit of human papillomavirus to the cell surface.
Component of the CCC complex, which is involved in the regulation of endosomal recycling of surface proteins, including integrins, signaling receptor and channels. The CCC complex associates with SNX17, retriever and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of numerous cargos such as integrins ITGA5:ITGB1 (PubMed:28892079, PubMed:25355947). Involved in copper-dependent ATP7A trafficking between the trans-Golgi network and vesicles in the cell periphery; the function is proposed to depend on its association within the CCC complex and cooperation with the WASH complex on early endosomes and is dependent on its interaction with WASHC2C (PubMed:25355947).
Interacts with COMMD1, COMMD2 COMMD3, COMMD4, COMMD5, COMMD6, COMMD7, COMMD8, COMMD9, COMMD10, WASHC1. Interacts directly with WASHC2C (PubMed:25355947). Interacts with CCDC93; proposed to be a component of the CCC (COMMD/CCDC22/CCDC93) complex which contains at least COMMD1 (and possibly other COMM domain-containing proteins), CCDC22 and CCDC93; in the complex interacts directly with CCDC22 (Probable). Interacts with VPS35L; associates with the retriever complex (PubMed:25355947). Interacts with SNX17 and SNX31 (PubMed:28892079).
Widely expressed; the highest levels are in prostate, lung and placenta; also detected in kidney, bone marrow, spleen, thymus, spinal cord, adrenal gland, salivary gland, trachea and mammary gland; levels are low in brain, heart, fetal liver, pancreas and testis.
Endoplasmic reticulum ceramidase that catalyzes the hydrolysis of ceramides into sphingosine and free fatty acids at alkaline pH (PubMed:17713573, PubMed:20207939, PubMed:20628055). Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation (PubMed:12783875). Exhibits a strong substrate specificity towards the natural stereoisomer of ceramides with D-erythro-sphingosine as a backbone and has a higher activity towards very long-chain unsaturated fatty acids like the C24:1-ceramide (PubMed:17713573, PubMed:20207939). May also hydrolyze dihydroceramides to produce dihydrosphingosine (PubMed:20207939, PubMed:20628055). ACER1 is a skin-specific ceramidase that regulates the levels of ceramides, sphingosine and sphingosine-1-phosphate in the epidermis, mediates the calcium-induced differentiation of epidermal keratinocytes and more generally plays an important role in skin homeostasis (PubMed:17713573).
Inhibited by sphingosine (By similarity). Activity is Ca(2+)-dependent (PubMed:17713573).
Up-regulated by Ca(2+) (PubMed:17713573). Down-regulated by epidermal growth factor/EGF (PubMed:17713573).
Catalyzes the NADPH-dependent reduction of succinic semialdehyde to gamma-hydroxybutyrate. May have an important role in producing the neuromodulator gamma-hydroxybutyrate (GHB). Has broad substrate specificity. Has NADPH-dependent aldehyde reductase activity towards 2-carboxybenzaldehyde, 2-nitrobenzaldehyde and pyridine-2-aldehyde (in vitro). Can reduce 1,2-naphthoquinone and 9,10-phenanthrenequinone (in vitro). Can reduce the dialdehyde protein-binding form of aflatoxin B1 (AFB1) to the non-binding AFB1 dialcohol. May be involved in protection of liver against the toxic and carcinogenic effects of AFB1, a potent hepatocarcinogen.
Detected in brain, liver, small intestine and testis, and at lower levels in heart, prostate, skeletal muscle and spleen. Detected in kidney proximal and distal tubules, endothelial cells lining the Bowman's capsules and some cysts. Detected at low levels in lung and pancreas (at protein level). Widely expressed.
Expressed primarily in testis and fetal tissues.
Involved in sperm motility. Its absence is associated with genetic background dependent male infertility. Infertility may be due to reduced sperm motility in the female reproductive tract and inability to penetrate the oocyte zona pellucida (By similarity).
Testis. Is selectively expressed in the spermatids of seminiferous tubules.
Was originally thought to be a selenoprotein and was known as sperm mitochondrial capsule selenoprotein.
Transcriptional activator that promotes transcription of muscle-specific target genes and plays a role in muscle differentiation (PubMed:29887215). Together with MYOG and MYOD1, co-occupies muscle-specific gene promoter core region during myogenesis. Induces fibroblasts to differentiate into myoblasts. Probable sequence specific DNA-binding protein.
Can be reprogrammed to form virion-like capsids that deliver engineered cargo mRNAs bearing RNA signals from PEG10 5'- and 3'-UTR into target cells.
Expressed in placenta during the first trimester of gestation (at protein level). In placenta, down-regulated at early hypoxic phase, and highly activated at 11-12 week of gestation.
Expressed in the cytotrophoblast layer but not in the overlying syncytiotrophoblast of the placenta. Expressed in prostate and breast carcinomas but not in normal breast and prostate epithelial cells. Expressed in the Hep-G2 cell line (at protein level). Expressed in brain, liver, spleen, kidney, thymus, lung, ovary, testis, reactive lymph node, skeletal muscle, adipose tissue and placenta. Expressed in pancreatic and hepatocellular carcinomas (HCC).
Expression is directly regulated by E2F1 and E2F4, which bind to its promoter and direct its expression (PubMed:17050006, PubMed:18625225, PubMed:28193232, PubMed:28992046). Up-regulated by MYC (PubMed:16423995). Strongly overepressed in a number of tumors, such has hepatocellular carcinoma (HCC), pancreatic or neuroendocrine prostate cancers (PubMed:20362226, PubMed:26235627, PubMed:28193232).
Homooligomer; homooligomerizes into virion-like capsids (By similarity). Interacts with ACVRL1 (PubMed:15611116). Interacts with SIAH1 and SIAH2 (PubMed:12810624).
In addition to the capsid (CA) and nucleocapsid (NC) subdomains of gag proteins, this isoform contains subdomains of pol, namely a protease (PRO) domain and a predicted reverse transcriptase (RT)-like domain.
Produced by a -1 ribosomal frameshifting due to a slippery site occurring between the codons for Gly-319 and Lys-320 (PubMed:17942406). The ribosomal frameshifting efficiency yield up to 66% of isoform 1 compared to isoform 2 (PubMed:17942406).
Produced by alternative initiation (Probable). Translation initiates from a non-AUG codon (CUG codon) (Probable).
Produced by alternative initiation (PubMed:20084274). Translation initiates from a non-AUG codon (CUG codon) (PubMed:20084274).
Produced by alternative initiation and ribosomal frameshifting (PubMed:20084274). Produced by a -1 ribosomal frameshifting due to a slippery site occurring between the codons for Gly-395 and Lys-396 (PubMed:20084274). Translation initiates from a non-AUG codon (CUG codon) (PubMed:20084274).
Retrotransposon-derived protein that binds its own mRNA and self-assembles into virion-like capsids (PubMed:34413232). Forms virion-like extracellular vesicles that encapsulate their own mRNA and are released from cells, enabling intercellular transfer of PEG10 mRNA (PubMed:34413232). Binds its own mRNA in the 5'-UTR region, in the region near the boundary between the nucleocapsid (NC) and protease (PRO) coding sequences and in the beginning of the 3'-UTR region (PubMed:34413232). Involved in placenta formation: required for trophoblast stem cells differentiation (By similarity). Involved at the immediate early stage of adipocyte differentiation (By similarity). Overexpressed in many cancers and enhances tumor progression: promotes cell proliferation by driving cell cycle progression from G0/G1 (PubMed:12810624, PubMed:16423995, PubMed:26235627, PubMed:28193232). Enhances cancer progression by inhibiting the TGF-beta signaling, possibly via interaction with the TGF-beta receptor ACVRL1 (PubMed:15611116, PubMed:26235627, PubMed:30094509). May bind to the 5'-GCCTGTCTTT-3' DNA sequence of the MB1 domain in the myelin basic protein (MBP) promoter; additional evidences are however required to confirm this result (By similarity).
The PEG10 locus is imprinted, giving rise to paternally expressed proteins.
The protein is evolutionarily related to retrotransposon Gag proteins: it contains the capsid (CA) and nucleocapsid (NC) subdomains of gag.
Was reported to be activated by androgen receptor agonist dihydrotestosterone (DHT) in hepatic cancer cells (HCC), resulting in HCC growth and apoptotic resistance. However, this study was later retracted.
Sodium-independent organic anion transporter, exhibits high specificity for sulfated conjugates of xenobiotics and steroid hormones such as estrone 3-sulfate (E1S) and dehydroepiandrosterone sulfate (DHEAS) (PubMed:17393504, PubMed:26239079, PubMed:28945155). Can transport the statin pravastatin and may contribute to its disposition into the hepatocytes when the function of OATPs is compromised (PubMed:26239079). It is specifically activated by 3 to 5 carbons-containing short-chain fatty acids/SCFAs, including propionate (propanoate), butyrate (butanoate) and valerate (pentanoate) (PubMed:17393504). May operate the exchange of sulfated organic components against short-chain fatty acids/SCFAs, in particular butanoate, at the sinusoidal membrane of hepatocytes (PubMed:17393504).
Specifically expressed in liver (also at protein level).
Functions as guanine nucleotide exchange factor (GEF) with specificity for RAB11A and RAB25 (PubMed:26506309, PubMed:30217979). Inhibits the auto- and transphosphorylation activity of BTK. Plays a negative regulatory role in BTK-related cytoplasmic signaling in B-cells. May be involved in BCR-induced apoptotic cell death.
Highly expressed in testis and ovaries. It is also expressed in a variety of tissues including spleen, lymph node, thymus, bone marrow, fetal liver, colon, small intestine and prostate.
Interacts with BTK (PubMed:9571151, PubMed:10339589). Interacts with all isoforms of MAPK8, MAPK9, MAPK10 and MAPK12 (PubMed:12167088). Interacts with GDP-bound and nucleotide-free forms of RAB11A (PubMed:26506309, PubMed:30217979).
The N-terminal half of the protein mediates interaction with RAB11A and functions as guanine nucleotide exchange factor. Four long alpha-helices (interrupted by a central kink) assemble into coiled coils, giving rise to a 'V' shape.
Acrosomal membrane-anchored protein involved in the process of fertilization and in acrosome biogenesis.
Highly N- and O-glycosylated; contains sialic acid.
Isoform 1 is highly expressed in testis. Isoform 2 is expressed at low levels in skin and blood.
Oligomer composed of two catalytic chains (alpha and beta), an inhibitory chain (gamma) and the delta chain.
Rod-specific cGMP phosphodiesterase that catalyzes the hydrolysis of 3',5'-cyclic GMP (PubMed:20940301). Necessary for the formation of a functional phosphodiesterase holoenzyme (By similarity). Involved in retinal circadian rhythm photoentrainment via modulation of UVA and orange light-induced phase-shift of the retina clock (By similarity). May participate in processes of transmission and amplification of the visual signal (PubMed:8394174).
By retinoic acid and phorbol-12-myristate 13-acetate (PMA).
Controls fundamental aspects of growth and development.
SHOXA is expressed in skeletal muscle, placenta, pancreas, heart and bone marrow fibroblast and SHOXB is highly expressed in bone marrow fibroblast followed by kidney and skeletal muscle. SHOXB is not expressed in brain, kidney, liver and lung. Highly expressed in osteogenic cells.
Belongs to the AVIT (prokineticin) family.
In adult testis, is strongly expressed only in Leydig cells. In testicular tumors, expressed specifically in Leydig cell tumors (at protein level). Expressed from 14 weeks until birth in fetal testis.
Localizes to glandular epithelium, stroma and vascular epithelial cells of first trimester decidua (at protein level). Up-regulated in first trimester decidua when compared with non-pregnant endometrium. Expressed in the steroidogenic glands, ovary, testis, adrenal and placenta.
Potently contracts gastrointestinal (GI) smooth muscle. Induces proliferation, migration and fenestration (the formation of membrane discontinuities) in capillary endothelial cells derived from endocrine glands. Has little or no effect on a variety of other endothelial and non-endothelial cell types. Induces proliferation and differentiation, but not migration, of enteric neural crest cells. Directly influences neuroblastoma progression by promoting the proliferation and migration of neuroblastoma cells. Positively regulates PTGS2 expression and prostaglandin synthesis. May play a role in placentation. May play a role in normal and pathological testis angiogenesis.
Down-regulated in testis from patients with maturation arrest (MA) or Sertoli cell-only syndrome (SCOS).
Interacts with the chaperone complex consisting of HSC70 and SGTA.
Palmitoylated. Palmitoylation is not required for membrane association.
Forms an OPN3-dependent complex with TYR in response to blue light in melanocytes.
Plays a role in melanin biosynthesis (PubMed:33100333). Catalyzes the conversion of L-dopachrome into 5,6-dihydroxyindole-2-carboxylic acid (DHICA).
Expressed at highest levels in skeletal muscle, and at moderate levels in heart, lung and peripheral blood leukocytes.
Heterohexamer (By similarity). Oligomerizes with other LRRC8 proteins (LRRC8A, LRRC8B, LRRC8D and/or LRRC8E) to form a heterohexamer (Probable). Detected in a channel complex that contains LRRC8A, LRRC8C and LRRC8E (PubMed:28193731). In vivo, the subunit composition may depend primarily on expression levels, and heterooligomeric channels containing various proportions of the different LRRC8 proteins may coexist (Probable).
Non-essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes (PubMed:24790029, PubMed:26824658, PubMed:28193731). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24790029, PubMed:26824658, PubMed:28193731). Plays a redundant role in the efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (PubMed:24790029, PubMed:26824658, PubMed:28193731). The VRAC channel also mediates transport of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol (PubMed:33171122). Channel activity requires LRRC8A plus at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (PubMed:24790029, PubMed:26824658, PubMed:28193731).
The cytoplasmic N-terminus preceding the first transmembrane (residues 1-22) regulates volume-regulated anion channel (VRAC) conductance, ion permeability and inactivation gating.
May play a role in the trafficking of a subset of G-protein coupled receptors.
Belongs to the DEAD box helicase family. DDX47/RRP3 subfamily.
Expressed in skin, lung and breast. Also expressed in the brain.
Interacts with AGO1 and AGO2. Interacts with GABARAP. Interacts with NOL8; the interaction is RNA-dependent.
Required for efficient ribosome biogenesis (By similarity). May have a role in mRNA splicing (PubMed:16963496). Involved in apoptosis (PubMed:15977068).
Mitochondrial NAD(+) kinase that phosphorylates NAD(+) to yield NADP(+). Can use both ATP or inorganic polyphosphate as the phosphoryl donor.
Mitochondrial NAD(+) kinase that phosphorylates NAD(+) to yield NADP(+). Can use both ATP or inorganic polyphosphate as the phosphoryl donor. Also has weak NADH kinase activity in vitro; however NADH kinase activity is much weaker than the NAD(+) kinase activity and may not be relevant in vivo.
Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of phospholipids, in particular phosphatidylcholines (PC), from the outer to the inner leaflet of the plasma membrane (PubMed:25315773, PubMed:17948906). May participate in the establishment of the canalicular membrane integrity by ensuring asymmetric distribution of phospholipids in the canicular membrane (By similarity). Thus may have a role in the regulation of bile acids transport into the canaliculus, uptake of bile acids from intestinal contents into intestinal mucosa or both and protect hepatocytes from bile salts (By similarity). Involved in the microvillus formation in polarized epithelial cells; the function seems to be independent from its flippase activity (PubMed:20512993). Participates in correct apical membrane localization of CDC42, CFTR and SLC10A2 (PubMed:25239307, PubMed:27301931). Enables CDC42 clustering at the apical membrane during enterocyte polarization through the interaction between CDC42 polybasic region and negatively charged membrane lipids provided by ATP8B1 (By similarity). Together with TMEM30A is involved in uptake of the synthetic drug alkylphospholipid perifosine (PubMed:20510206). Required for the preservation of cochlear hair cells in the inner ear (By similarity). May act as cardiolipin transporter during inflammatory injury (By similarity).
Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit ATP8B1 and an accessory beta subunit TMEM30A (PubMed:17948906, PubMed:25239307). The flippase ATP8B1:TMEM30A complex can form an intermediate phosphoenzyme in vitro (PubMed:20947505, PubMed:20961850, PubMed:21914794). Also interacts with beta subunit TMEM30B (PubMed:20947505, PubMed:20961850, PubMed:21914794).
Found in most tissues except brain and skeletal muscle. Most abundant in pancreas and small intestine.
Broad specificity glycosidase of the intestinal brush border membrane that hydrolyzes lactose, the main sugar in mammalian milk, to produce D-glucose and D-galactose (PubMed:3929764, PubMed:9762914, PubMed:12594539, PubMed:16400612). The mature protein is composed of two domains that catalyze the hydrolysis of beta-glucopyranosides and beta-galactopyranosides, with a preference for hydrophilic aglycones (in lactose and cellobiose) for one domain and hydrophobic aglycones (in phlorizin and glycosylceramides) for the other (PubMed:3929764, PubMed:9762914, PubMed:12594539).
Specifically expressed in small intestine.
The glycosyl hydrolase-1 3/region III carries the phlorizin hydrolase/glycosylceramidase activities.
The glycosyl hydrolase-1 4/region IV carries the lactase activity.
(Microbial infection) Acts as a receptor for CotH proteins expressed by fungi of the order mucorales, the causative agent of mucormycosis, which plays an important role in epithelial cell invasion by the fungi (PubMed:24355926, PubMed:20484814, PubMed:32487760). Acts as a receptor for R.delemar CotH3 in nasal epithelial cells, which may be an early step in rhinoorbital/cerebral mucormycosis (RCM) disease progression (PubMed:32487760).
(Microbial infection) Interacts with Japanese encephalitis virus envelope protein E.
(Microbial infection) Interacts with R.delemar invasin CotH3 on the surface of nasal epithelial cells (PubMed:32487760, PubMed:24355926). Interacts with R.delemar invasin CotH2 (PubMed:24355926).
(Microbial infection) Plays an important role in viral binding to the host cell membrane and entry for several flaviruses such as Dengue virus, Zika virus and Japanese encephalitis virus (PubMed:33432092, PubMed:15098107, PubMed:28053106). Acts as a component of the cellular receptor for Dengue virus serotype 2/DENV-2 on human liver cells (PubMed:15098107).
AMPylated by FICD (PubMed:25601083). In unstressed cells, AMPylation at Thr-518 by FICD inactivates the chaperome activity: AMPylated form is locked in a relatively inert state and only weakly stimulated by J domain-containing proteins (By similarity). In response to endoplasmic reticulum stress, de-AMPylation by the same protein, FICD, restores the chaperone activity (By similarity).
AMPylation was initially reported to take place at Ser-365 and Thr-366 in vitro, and promote activation of HSPA5/BiP (PubMed:25601083). However, it was later shown that AMPylation takes place at Thr-518 and leads to inactivation of HSPA5/BiP.
Antibodies against the protein protects endothelial cells from invasion by the fungus R.delemar, a causative agent of mucormycosis, and could thus potentially be used to treat mucormycosis disease (PubMed:20484814). Antibodies against the protein also protect a diabetic ketoacidosis mouse model against mucormycosis (PubMed:20484814).
By endoplasmic reticulum stress (PubMed:21289099). Induced in nasal epithelial cells by high free iron levels (PubMed:32487760, PubMed:20484814, PubMed:27159390). Induced in nasal epithelial cells in high glucose (PubMed:32487760, PubMed:20484814, PubMed:27159390). Induced in nasal epithelial cells by 3-hydroxybutyric acid (BHB) (PubMed:32487760, PubMed:27159390).
Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen (PubMed:2294010, PubMed:23769672, PubMed:23990668, PubMed:28332555). Involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10/ERdj5, probably to facilitate the release of DNAJC10/ERdj5 from its substrate (By similarity). Acts as a key repressor of the ERN1/IRE1-mediated unfolded protein response (UPR) (PubMed:1550958, PubMed:19538957). In the unstressed endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating ERN1/IRE1 (By similarity). Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1, allowing homodimerization and subsequent activation of ERN1/IRE1 (By similarity). Plays an auxiliary role in post-translational transport of small presecretory proteins across endoplasmic reticulum (ER). May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel. Appears to specifically regulate translocation of precursors having inhibitory residues in their mature region that weaken channel gating. May also play a role in apoptosis and cell proliferation (PubMed:26045166).
Monomer and homooligomer; homooligomerization via the interdomain linker inactivates the chaperone activity and acts as a storage of HSPA5/BiP molecules (By similarity). Interacts with DNAJC1 (via J domain) (By similarity). Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5 (By similarity). Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX (By similarity). Interacts with TMEM132A and TRIM21 (PubMed:12699405). May form a complex with ERLEC1, OS9, SEL1L and SYVN1 (PubMed:18264092, PubMed:18502753). Interacts with DNAJC10 (PubMed:12411443, PubMed:23769672). Interacts with DNAJB9/ERdj4; leading to recruit HSPA5/BiP to ERN1/IRE1 (By similarity). Interacts with ERN1/IRE1; interaction takes place following interaction with DNAJB9/ERdj4 and leads to inactivate ERN1/IRE1 (By similarity). Interacts with MX1 (By similarity). Interacts with METTL23 (PubMed:23349634). Interacts with CEMIP; the interaction induces calcium leakage from the endoplasmic reticulum and cell migration (PubMed:23990668). Interacts with PCSK4 form; the interaction takes place in the endoplasmic reticulum (PubMed:21080038). Interacts with CIPC (PubMed:26657846). Interacts with CCDC88B (via C-terminus); the interaction opposes ERN1-mediated JNK activation, protecting against apoptosis (PubMed:21289099). Interacts with INPP5K; necessary for INPP5K localization at the endoplasmic reticulum (PubMed:26940976). Interacts with MANF; the interaction is direct (PubMed:22637475). Interacts with LOXL2; leading to activate the ERN1/IRE1-XBP1 pathway of the unfolded protein response (PubMed:28332555). Interacts with CLU under stressed condition; interaction increases CLU protein stability; facilitates its retrotranslocation and redistribution to the mitochondria; cooperatively suppress stress-induced apoptosis by stabilizing mitochondrial membrane integrity (PubMed:22689054). Interacts with CCDC47 (By similarity). Interacts with CLN3 (Probable). Interacts with KIAA1324; may regulate the function of HSPA5 in apoptosis and cell proliferation (PubMed:26045166). Interacts with CASP7 (PubMed:26045166). Interacts with ILDR2; the interaction stabilizes ILDR2 expression (By similarity). Interacts with ADAM7 (By similarity).
The chaperone activity is regulated by ATP-induced allosteric coupling of the nucleotide-binding (NBD) and substrate-binding (SBD) domains. In the ADP-bound and nucleotide-free (apo) states, the two domains have little interaction (PubMed:26655470). In contrast, in the ATP-bound state the two domains are tightly coupled, which results in drastically accelerated kinetics in both binding and release of polypeptide substrates (PubMed:26655470). J domain-containing co-chaperones (DNAJB9/ERdj4 or DNAJC10/ERdj5) stimulate the ATPase activity and are required for efficient substrate recognition by HSPA5/BiP (By similarity). Homooligomerization inactivates participating HSPA5/BiP protomers and probably act as reservoirs to store HSPA5/BiP molecules when they are not needed by the cell (By similarity).
The interdomain linker regulates the chaperone activity by mediating the formation of homooligomers. Homooligomers are formed by engagement of the interdomain linker of one HSPA5/BiP molecule as a typical substrate of an adjacent HSPA5/BiP molecule. HSPA5/BiP oligomerization inactivates participating HSPA5/BiP protomers. HSPA5/BiP oligomers probably act as reservoirs to store HSPA5/BiP molecules when they are not needed by the cell. When the levels of unfolded proteins rise, cells can rapidly break up these oligomers to make active monomers.
Activated by autophosphorylation on Ser-220. Kinase activity is inhibited by SPRED1.
Autophosphorylated on serine and tyrosine residues.
Dual specificity protein kinase activity catalyzing autophosphorylation and phosphorylation of exogenous substrates on both serine/threonine and tyrosine residues (By similarity). Regulates the cellular cytoskeleton by enhancing actin stress fiber formation via phosphorylation of cofilin and by preventing microtubule breakdown via inhibition of TAOK1/MARKK kinase activity (By similarity). Inhibits podocyte motility via regulation of actin cytoskeletal dynamics and phosphorylation of CFL1 (By similarity). Positively regulates integrin-mediated cell spreading, via phosphorylation of cofilin (PubMed:15584898). Suppresses ciliogenesis via multiple pathways; phosphorylation of CFL1, suppression of ciliary vesicle directional trafficking to the ciliary base, and by facilitating YAP1 nuclear localization where it acts as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1 (PubMed:25849865). Probably plays a central role at and after the meiotic phase of spermatogenesis (By similarity).
Expressed in podocytes and renal tubular cells in the kidney (at protein level).
Interacts (via both C- and N-termini) with SPRY4 (via C-terminus); the interaction inhibits TESK1 kinase activity (PubMed:12027893, PubMed:15584898). Interacts with TAOK1; the interaction inhibits TAOK1 kinase activity (By similarity). Interacts (via C-terminus) with SPRED1 (via C-terminus); the interaction inhibits TESK1 kinase activity (PubMed:18216281). Interacts (via C-terminus) with PARVA/PARVIN (via C-terminus); the interaction inhibits TESK1 kinase activity (PubMed:15817463). Interacts with YWHAB/14-3-3 beta; the interaction is dependent on the phosphorylation of TESK1 Ser-437 and inhibits TESK1 kinase activity (PubMed:11555644). Interacts with SPRY1, SPRY3 and SPRED2 (PubMed:17974561). Interacts (via C-terminus) with SPRY2 (via C-terminus); the interaction disrupts SPRY2 interaction with PPP2CA/PP2A-C, possibly by vesicular sequestration of SPRY2 (PubMed:17974561). Therefore dephosphorylation of SPRY2 by the serine/threonine-protein phosphatase 2A (PP2A) holoenzyme is lost, inhibiting its interaction with GRB2 (PubMed:17974561).
The extracatalytic C-terminal part is highly rich in proline residues.
Lipoprotein-associated calcium-independent phospholipase A2 involved in phospholipid catabolism during inflammatory and oxidative stress response (PubMed:7700381, PubMed:8624782, PubMed:2040620, PubMed:16371369, PubMed:17090529, PubMed:10066756). At the lipid-aqueous interface, hydrolyzes the ester bond of fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) (PubMed:2040620, PubMed:10504265). Specifically targets phospholipids with a short-chain fatty acyl group at sn-2 position (PubMed:2040620). Can hydrolyze phospholipids with long fatty acyl chains, only if they carry oxidized functional groups (PubMed:2040620, PubMed:8624782). Hydrolyzes and inactivates platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), a potent pro-inflammatory signaling lipid that acts through PTAFR on various innate immune cells (PubMed:10504265, PubMed:10066756, PubMed:7592717, PubMed:11590221, PubMed:7700381, PubMed:18434304, PubMed:16371369, PubMed:8675689, PubMed:8624782). Hydrolyzes oxidatively truncated phospholipids carrying an aldehyde group at omega position, preventing their accumulation in low-density lipoprotein (LDL) particles and uncontrolled pro-inflammatory effects (PubMed:2040620, PubMed:7700381). As part of high-density lipoprotein (HDL) particles, can hydrolyze phospholipids having long-chain fatty acyl hydroperoxides at sn-2 position and protect against potential accumulation of these oxylipins in the vascular wall (PubMed:17090529). Catalyzes the release from membrane phospholipids of F2-isoprostanes, lipid biomarkers of cellular oxidative damage (PubMed:16371369).
N-glycosylated. Macrophage-derived PLA2G7 carries sialylated complex-type N-glycans that hinder its binding to HDL particles.
Plasma (PubMed:11590221, PubMed:12821559). Secreted by macrophages (at protein level) (PubMed:11590221).
Up-regulated upon monocyte differentiation toward macrophage lineage.
Interacts with RBCK1. Interacts with phosphorylated IRS4 (By similarity). Interacts with PIM3 (By similarity). Interacts with KIT (phosphorylated).
SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. May be a substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (By similarity). Regulates KIT degradation by ubiquitination of the tyrosine-phosphorylated receptor.
Heterodimer; heterodimerizes with EHMT2. Interacts with WIZ and EHMT2. Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EHMT1, RING1, RNF2, MBLR, L3MBTL2 and YAF2. Interacts (via ANK repeats) with RELA (when monomethylated at 'Lys-310') (PubMed:21515635). Interacts with MPHOSPH8. Interacts with CDYL. Interacts with REST only in the presence of CDYL. Part of a complex containing at least CDYL, REST, WIZ, SETB1, EHMT1 and EHMT2. Interacts with BAZ2B (By similarity). Interacts with MSX1 (By similarity).
Histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also weakly methylates 'Lys-27' of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. During G0 phase, it probably contributes to silencing of MYC- and E2F-responsive genes, suggesting a role in G0/G1 transition in cell cycle. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of 'Lys-373' of p53/TP53. Represses the expression of mitochondrial function-related genes, perhaps by occupying their promoter regions, working in concert with probable chromatin reader BAZ2B (By similarity).
Methyltransferase activity is inhibited by BIX-01294. Efficiently inhibited by compound E72, a BIX-01294 derivative in which the diazepane ring and the benzyl are replaced with a 3-dimethylaminopropyl and a 5-aminopentyl group at sites B and C, respectively.
The ANK repeats recognize and bind RELA subunit of NF-kappa-B, when RELA is monomethylated at 'Lys-310' (By similarity). They also specifically recognize and bind H3K9me1 and H3K9me2.
The disease is caused by variants affecting the gene represented in this entry. The syndrome can be either caused by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene or by a submicroscopic 9q34.3 deletion. Although it is not known if and to what extent other genes in the 9q34.3 region contribute to the syndrome observed in deletion cases, EHMT1 seems to be the major determinant of the core disease phenotype (PubMed:19264732).
Acts as a high affinity receptor for both nicotinic acid (also known as niacin) and (D)-beta-hydroxybutyrate and mediates increased adiponectin secretion and decreased lipolysis through G(i)-protein-mediated inhibition of adenylyl cyclase. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet. Mediates nicotinic acid-induced apoptosis in mature neutrophils. Receptor activation by nicotinic acid results in reduced cAMP levels which may affect activity of cAMP-dependent protein kinase A and phosphorylation of target proteins, leading to neutrophil apoptosis. The rank order of potency for the displacement of nicotinic acid binding is 5-methyl pyrazole-3-carboxylic acid = pyridine-3-acetic acid > acifran > 5-methyl nicotinic acid = acipimox >> nicotinuric acid = nicotinamide.
Expression in neutrophils occurs in the late terminal differentiation phase.
Expression largely restricted to adipose tissue and spleen. Expressed on mature neutrophils but not on immature neutrophils or eosinophils.
Chromatin reader component of some histone acetyltransferase (HAT) SAGA-type complexes like the TFTC-HAT, ATAC or STAGA complexes (PubMed:19103755, PubMed:20850016, PubMed:26421618, PubMed:21685874, PubMed:26578293). SGF29 specifically recognizes and binds methylated 'Lys-4' of histone H3 (H3K4me), with a preference for trimethylated form (H3K4me3) (PubMed:20850016, PubMed:26421618, PubMed:21685874, PubMed:26578293). In the SAGA-type complexes, SGF29 is required to recruit complexes to H3K4me (PubMed:20850016). Involved in the response to endoplasmic reticulum (ER) stress by recruiting the SAGA complex to H3K4me, thereby promoting histone H3 acetylation and cell survival (PubMed:23894581). Also binds non-histone proteins that are methylated on Lys residues: specifically recognizes and binds CGAS monomethylated on 'Lys-506' (By similarity).
Interacts with dimethylated and trimethylated 'Lys-4' of histone H3 (H3K4me2 and H3K4me3), with a preference for the trimethylated form (H3K4me3) (PubMed:21685874, PubMed:26578293). Component of some SAGA-type complexes (PubMed:20850016). Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1 (PubMed:19103755). Interacts with (methylated) CGAS (By similarity). Interacts with TADA3L, GCN5L2, SUPT3H and MYC (By similarity).
The SGF29 C-terminal (also named tudor-like) domain mediates binding to methylated 'Lys-4' of histone H3 (H3K4me), with a preference for trimethylated form (H3K4me3).
A phosphoprotein adapter involved in the XPO1-mediated U snRNA export from the nucleus. Bridge components required for U snRNA export, the cap binding complex (CBC)-bound snRNA on the one hand and the GTPase Ran in its active GTP-bound form together with the export receptor XPO1 on the other. Its phosphorylation in the nucleus is required for U snRNA export complex assembly and export, while its dephosphorylation in the cytoplasm causes export complex disassembly. It is recycled back to the nucleus via the importin alpha/beta heterodimeric import receptor. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Its compartmentalized phosphorylation cycle may also contribute to the directionality of export. Binds strongly to m7G-capped U1 and U5 small nuclear RNAs (snRNAs) in a sequence-unspecific manner and phosphorylation-independent manner (By similarity). Also plays a role in the biogenesis of U3 small nucleolar RNA (snoRNA). Involved in the U3 snoRNA transport from nucleoplasm to Cajal bodies. Binds strongly to m7G-capped U3, U8 and U13 precursor snoRNAs and weakly to trimethylated (TMG)-capped U3, U8 and U13 snoRNAs. Binds also to telomerase RNA.
Found in a U snRNA export complex with PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA. Part of a precomplex with PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20 and m7G-capped RNA. Interacts with NCBP1/CBP80 (By similarity). Found in a complex with snoRNA. Interacts with NCBP2/CBP20 (PubMed:26382858).
Phosphorylated in the nucleus. Dephosphorylated in the cytoplasm (By similarity).
Associates with the Nup107-160 subcomplex of the NPC.
Required for the assembly of a functional nuclear pore complex (NPC) on the surface of chromosomes as nuclei form at the end of mitosis. May initiate NPC assembly by binding to chromatin and recruiting the Nup107-160 subcomplex of the NPC. Also required for the localization of the Nup107-160 subcomplex of the NPC to the kinetochore during mitosis and for the completion of cytokinesis.
The N-terminus forms a highly conserved seven-bladed beta propeller decorated with long loops and mediates anchorage to the Nup107-160 subcomplex of the nuclear pore, synergistically with the central alpha domain. The disordered C-terminus is responsible for the interactions with chromatin (By similarity).
Detected in brain and spinal cord. Highly expressed in a number of intrahepatic cholangiocarcinoma tissue biopsies.
Guanine nucleotide exchange factor (GEF) with specificity for RAP2A, KRAS, HRAS, and NRAS (in vitro). Plays a role in cell migration.
Implicated in the suppression of cell death. Interacts with the BCL-2 and adenovirus E1B 19 kDa proteins.
Induced upon stimulation with inflammatory cytokines produced by T-helper 1 cells (IL1A, TNF, IFNG) and T-helper 17 cells (IL17A, IL22).
Interacts with CYSRT1; the interaction is direct.
Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex. The CST complex binds single-stranded DNA with high affinity in a sequence-independent manner, while isolated subunits bind DNA with low affinity by themselves. Initially the CST complex has been proposed to protect telomeres from DNA degradation (PubMed:19854130). However, the CST complex has been shown to be involved in several aspects of telomere replication. The CST complex inhibits telomerase and is involved in telomere length homeostasis; it is proposed to bind to newly telomerase-synthesized 3' overhangs and to terminate telomerase action implicating the association with the ACD:POT1 complex thus interfering with its telomerase stimulation activity. The CST complex is also proposed to be involved in fill-in synthesis of the telomeric C-strand probably implicating recruitment and activation of DNA polymerase alpha (PubMed:22763445). The CST complex facilitates recovery from many forms of exogenous DNA damage; seems to be involved in the re-initiation of DNA replication at repaired forks and/or dormant origins (PubMed:25483097).
Component of the CST complex, composed of TEN1/C17orf106, CTC1/C17orf68 and STN1; in the complex interacts directly with STN1.
It is uncertain whether Met-1 or Met-2 is the initiator. Some orthologous sequences cannot be extended.
Inhibitory effect on stress fiber organization. May down-regulate Rho-like GTPase in hematopoietic cells.
Predominantly in hematopoietic cells (spleen, thymus and leukocytes); low levels in placenta, lung and various fetal tissues.
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including SEM1, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Belongs to the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). Component of the homologous recombination repair (HR) complex composed of ERCC5/XPG, BRCA2, PALB2, DSS1 and RAD51 (PubMed:26833090). Interacts with the C-terminal of BRCA2 (PubMed:10373512, PubMed:21719596).
Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins.
Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair (PubMed:15117943). Component of the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket). TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. Binds and stabilizes BRCA2 and is thus involved in the control of R-loop-associated DNA damage and thus transcription-associated genomic instability. R-loop accumulation increases in SEM1-depleted cells.
Expressed in limb bud, craniofacial primordia and skin.
Due to intron retention. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Homodimer; disulfide-linked, upon oxidation (PubMed:27892488). 5 homodimers assemble to form a ring-like decamer (PubMed:27892488). Interacts with TIPIN (PubMed:17141802).
The enzyme can be inactivated by further oxidation of the cysteine sulfenic acid (C(P)-SOH) to sulphinic acid (C(P)-SO2H) instead of its condensation to a disulfide bond. It can be reactivated by forming a transient disulfide bond with sulfiredoxin SRXN1, which reduces the cysteine sulfinic acid in an ATP- and Mg-dependent manner.
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively.
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides and as sensor of hydrogen peroxide-mediated signaling events. Might participate in the signaling cascades of growth factors and tumor necrosis factor-alpha by regulating the intracellular concentrations of H(2)O(2).
Interacts with EGFR (ubiquitinated); the interaction is direct and may regulate EGFR internalization.
Ubiquitin-binding protein that specifically recognizes and binds 'Lys-63'-linked ubiquitin. Does not bind 'Lys-48'-linked ubiquitin. Positively regulates the internalization of ligand-activated EGFR by binding to the Ub moiety of ubiquitinated EGFR at the cell membrane.
Highly expressed in heart, brain and skeletal muscle. Detected at low levels in placenta.
Identified in the spliceosome C complex (PubMed:11991638). Interacts with FRA10AC1 (PubMed:34694367).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIA3 subfamily.
Homotetramer or heterotetramer of pore-forming glutamate receptor subunits. Tetramers may be formed by the dimerization of dimers. Interacts with PRKCABP, GRIP1 and GRIP2 (By similarity). Found in a complex with GRIA1, GRIA2, GRIA4, CNIH2, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with CACNG5 (By similarity).
Palmitoylated. Depalmitoylated upon glutamate stimulation. Cys-621 palmitoylation leads to Golgi retention and decreased cell surface expression. In contrast, Cys-847 palmitoylation does not affect cell surface expression but regulates stimulation-dependent endocytosis (By similarity).
Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate.
Belongs to the potassium channel family. KQT (TC 1.A.1.15) subfamily. Kv7.4/KCNQ4 sub-subfamily.
Expressed in the outer, but not the inner, sensory hair cells of the cochlea. Slightly expressed in heart, brain and skeletal muscle.
Homotetramer. May form heteromultimers with KCNQ3. Interacts with HSP90AB1; promotes cell surface expression of KCNQ4 (PubMed:23431407).
Mutagenesis experiments were carried out by expressing in Xenopus oocytes KCNQ4 mutants either individually (homomultimers) or in combination with wild-type KCNQ4 (mut/wt homomultimers) in a ratio of 1:1, to mimic the situation in a heterozygous DFNA2 patient.
Probably important in the regulation of neuronal excitability. May underlie a potassium current involved in regulating the excitability of sensory cells of the cochlea. KCNQ4 channels are blocked by linopirdin, XE991 and bepridil, whereas clofilium is without significant effect. Muscarinic agonist oxotremorine-M strongly suppress KCNQ4 current in CHO cells in which cloned KCNQ4 channels were coexpressed with M1 muscarinic receptors.
The A-domain tail carries the major determinants of channel assembly specificity. Its coiled-coil region is Four-stranded.
Embryonic expression pattern: liver, lung, intestine, kidney, urinary tract; adult expression pattern: intestine, colon, testis and thymus.
Expressed in thymus, testis, small intestine, colon followed by ovary. Appears to be expressed only in adult organs containing proliferating/cycling cells or in response to growth factors. Also expressed in epithelial cell lines derived from tumors. Not expressed in resting cells. Isoform 2 is highly expressed in testis.
Induced during liver regeneration and oxidative stress.
Interacts with PINT87aa which is encoded by the circular form of the long non-coding RNA LINC-PINT; the interaction inhibits FOXM1-mediated transcription of PHB2.
Phosphorylated in M (mitotic) phase. Phosphorylation by the checkpoint kinase CHEK2 in response to DNA damage increases the FOXM1 protein stability probably stimulating the transcription of genes involved in DNA repair. Phosphorylated by CDK1 in late S and G2 phases, creating docking sites for the POLO box domains of PLK1. Subsequently, PLK1 binds and phosphorylates FOXM1, leading to activation of transcriptional activity and subsequent enhanced expression of key mitotic regulators.
Transcription factor regulating the expression of cell cycle genes essential for DNA replication and mitosis (PubMed:19160488, PubMed:20360045). Plays a role in the control of cell proliferation (PubMed:19160488). Also plays a role in DNA break repair, participating in the DNA damage checkpoint response (PubMed:17101782). Promotes transcription of PHB2 (PubMed:33754036).
Within the protein there is a domain which acts as a transcriptional activator. Insertion of a splicing sequence within it inactivates this transcriptional activity, as it is the case for isoform 4.
Expressed in the eye, including iris, ciliary body, retinal pigment epithelium, but not lens (protein level).
Regulates maturation of the transmembrane metalloprotease ADAM10.
Expressed exclusively at the outer cell surface of transitional epithelia and the keratinocyte of stratified squamous epithelia.
May act as a specification marker at earliest stage specification of lymphocytes between B- and T-cell development. Marks the earliest stage of B-cell specification.
Forms a complex containing SNAP47, VAMP2 and STX1A (By similarity). Associates with the BLOC-1 complex. Interacts with BLOC1S6.
Plays a role in intracellular membrane fusion.
Expressed under normal conditions, its expression can further be increased after various stress treatments.
Cytokine that inhibits the activity of BMP2 and BMP4 in a dose-dependent manner, and thereby modulates signaling by BMP family members. Contributes to the regulation of embryonic morphogenesis via BMP family members. Antagonizes BMP4-induced suppression of progesterone production in granulosa cells.
Homodimer. Interacts with BMP2, BMP4 and BMP7, but has lower affinity for BMP7 than for BMP2 and BMP4. Binds heparin; this impairs the interaction with BMP2.
Induced by low iron levels, and down-regulated by elevated iron levels.
NAD(H)-dependent dehydrogenase/reductase with a preference for cyclic substrates (PubMed:35150746) (By similarity). Catalyzes stereoselective conversion of 4-oxo-L-proline to cis-4-hydroxy-L-proline, likely a detoxification mechanism for ketoprolines (PubMed:35150746). Mediates the formation of 2,5-dihydroxybenzoate (2,5-DHBA), a siderophore that chelates free cytoplasmic iron and associates with LCN2, thereby regulating iron transport and homeostasis while protecting cells against free radical-induced oxidative stress. The iron-siderophore complex is imported into mitochondria, providing an iron source for mitochondrial metabolic processes in particular heme synthesis (By similarity). May act as a 3-hydroxybutyrate dehydrogenase (PubMed:16380372).
Postulated to act as a 3-hydroxybutyrate dehydrogenase, however its contribution to ketone body formation appears to be physiologically irrelevant since it has very low affinity for the substrate.
Appears to regulate cell growth through interactions with the extracellular matrix and cytokines. Binds calcium and copper, several types of collagen, albumin, thrombospondin, PDGF and cell membranes. There are two calcium binding sites; an acidic domain that binds 5 to 8 Ca(2+) with a low affinity and an EF-hand loop that binds a Ca(2+) ion with a high affinity.
Expressed at high levels in tissues undergoing morphogenesis, remodeling and wound repair.
(Microbial infection) Interacts with Norwalk virus VPg protein (PubMed:12773399).
Defects in EIF3D are associated with some cancers, such as prostate, breast and colon cancers. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Down-regulation inhibits proliferation of cancers (PubMed:25370813, PubMed:25322666, PubMed:25682860, PubMed:26617750, PubMed:26008152, PubMed:26036682, PubMed:27035563).
The RNA gate region regulates mRNA cap recognition to prevent promiscuous mRNA-binding before assembly of EIF3D into the full eukaryotic translation initiation factor 3 (eIF-3) complex.
mRNA cap-binding component of the eukaryotic translation initiation factor 3 (eIF-3) complex, a complex required for several steps in the initiation of protein synthesis of a specialized repertoire of mRNAs (PubMed:27462815). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation (PubMed:18599441, PubMed:25849773). The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression (PubMed:25849773). In the eIF-3 complex, EIF3D specifically recognizes and binds the 7-methylguanosine cap of a subset of mRNAs (PubMed:27462815).
Detected in alveolar macrophages (at protein level).
Interacts with TRAF1, TRAF2, TRAF3 and TRAF5.
Most specific Hodgkin disease associated antigen.
Phosphorylated on serine and tyrosine residues (Probable). Isoform 2 is constitutively phosphorylated (PubMed:8839832).
Receptor for TNFSF8/CD30L (PubMed:8391931). May play a role in the regulation of cellular growth and transformation of activated lymphoblasts. Regulates gene expression through activation of NF-kappa-B (PubMed:8999898).
Was originally thought to be the ubiquinone-binding protein (QP-C).
(Microbial infection) Up-regulated in response to enterovirus 71 (EV71) infection (at protein level).
Detected in all tissues tested: skeletal muscle, heart, aorta, large intestine, small intestine, stomach, esophagus, bladder, adrenal gland, thyroid, pancreas, testis, adipose tissue, kidney, liver, spleen, cerebral cortex, blood serum and cerebrospinal fluid. Highest levels are found in the heart and in tissues composed of striated and smooth muscle.
Homooligomer (PubMed:10383393). Homodimer; becomes monomeric upon activation (PubMed:20178975). Heterooligomer; with HSPB6 (PubMed:23948568). Associates with alpha- and beta-tubulin (PubMed:10777697). Interacts with TGFB1I1 (By similarity). Interacts with CRYAB (PubMed:1560006). Interacts with HSPB8 (PubMed:11342557). Interacts with HSPBAP1 (PubMed:10751411).
Phosphorylated upon exposure to protein kinase C activators and heat shock (PubMed:8325890). Phosphorylation by MAPKAPK2 and MAPKAPK3 in response to stress dissociates HSPB1 from large small heat-shock protein (sHsps) oligomers and impairs its chaperone activity and ability to protect against oxidative stress effectively. Phosphorylation by MAPKAPK5 in response to PKA stimulation induces F-actin rearrangement (PubMed:1332886, PubMed:8093612, PubMed:19166925).
Small heat shock protein which functions as a molecular chaperone probably maintaining denatured proteins in a folding-competent state (PubMed:10383393, PubMed:20178975). Plays a role in stress resistance and actin organization (PubMed:19166925). Through its molecular chaperone activity may regulate numerous biological processes including the phosphorylation and the axonal transport of neurofilament proteins (PubMed:23728742).
Up-regulated in response to environmental stresses such as heat shock (PubMed:8325890). Up-regulated by estrogen stimulation (PubMed:2743305).
Contradictory results have been reported for activation of this receptor by beta-ionone in human and mouse. Beta-ionone does not activate OR51E2 in mouse. This difference may depend on the different methods used for the experiment or may be due to species difference.
Highly expressed in the prostate (PubMed:11707321). Also expressed in spleen, liver, olfactory epithelium, retinal pigment epithelium and medulla oblongata (PubMed:29249973, PubMed:11707321, PubMed:16491480). In the retinal pigment epithelium expression is restricted to the pigment cells and choroid (at protein level) (PubMed:29249973). Expressed in epidermal melanocytes (at protein level) (PubMed:27226631).
Olfactory receptor (PubMed:29249973, PubMed:27226631). Activated by the odorant, beta-ionone, a synthetic terpenoid (PubMed:29249973, PubMed:27226631, PubMed:19389702). The activity of this receptor is probably mediated by G-proteins leading to the elevation of intracellular Ca(2+), cAMP and activation of the protein kinases PKA and MAPK3/MAPK1 (PubMed:27226631, PubMed:29249973). Stimulation of OR51E2 by beta-ionone affects melanocyte proliferation, differentiation, and melanogenesis (PubMed:27226631). Activation of OR51E2 by beta-ionone increases proliferation and migration of primary retinal pigment epithelial (RPE) cells (PubMed:29249973). Activated also by the short-chain fatty acids (SCFA) acetate and propionate. In response to SCFA, may positively regulate renin secretion and increase blood pressure (PubMed:23401498). May also be activated by steroid hormones and regulate cell proliferation (PubMed:19389702). Activated by L-lactate in glomus cells (By similarity).
Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids, phosphatidylserines (PS) and phosphatidylethanolamines (PE), from the outer to the inner leaflet of the plasma membrane (PubMed:25315773, PubMed:32493773, PubMed:24904167, PubMed:26567335). Major PS-flippase in immune cell subsets. In erythrocyte plasma membrane, it is required to maintain PS in the inner leaflet preventing its exposure on the surface. This asymmetric distribution is critical for the survival of erythrocytes in circulation since externalized PS is a phagocytic signal for erythrocyte clearance by splenic macrophages (PubMed:26944472). Required for B cell differentiation past the pro-B cell stage (By similarity). Seems to mediate PS flipping in pro-B cells (By similarity). May be involved in the transport of cholestatic bile acids (By similarity).
Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit ATP11C and an accessory beta subunit TMEM30A.
Phosphorylated at Ser-1116 likely by PRKCA; this creates a functional di-leucine motif that is sufficient for endocytosis.
Proteolytically cleaved by CASP3, CASP6 and CASP7.
The di-leucine motif is required for sorting to clathrin-coated endosomes upon ca(2+)-dependent PRKCA activation.
Belongs to the flavin monoamine oxidase family.
Does not seem to display oxidase activity towards spermidine or N(1)-acetyl-spermine, but this has to be confirmed.
Flavoenzyme which catalyzes the oxidation of spermine to spermidine. Can also use N(1)-acetylspermine and spermidine as substrates, with different affinity depending on the isoform (isozyme) and on the experimental conditions. Plays an important role in the regulation of polyamine intracellular concentration and has the potential to act as a determinant of cellular sensitivity to the antitumor polyamine analogs. May contribute to beta-alanine production via aldehyde dehydrogenase conversion of 3-amino-propanal.
Has the lowest Km values for the different substrates and has the highest affinity for spermidine.
Inhibited at more than 90% by SL-11144, SL-11150 and SL-11158, at concentrations less than 1 uM.
Major isoform. Has the highest affinity for the 3 substrates. Has a greater affinity for spermidine and spermine than for N(1)-acetylspermine.
Substrate specificities and affinities comparable to those of isoform 1.
Widely expressed. Expressed in human tumor cell lines. Isoform 4 is only found in an embryonal kidney cell line.
(Microbial infection) Interacts with M.tuberculosis PtpA, whick blocks TRIM27-promoted JNK/p38 MAPK pathway activation and cell apoptosis.
(Microbial infection) Interacts with herpes simplex virus protein ICP0.
(Microbial infection) Positively regulates hepatitis C virus replication by suppressing type I IFN response during infection.
A chromosomal aberration involving TRIM27/RFP is found in papillary thyroid carcinomas (PTCs). Translocation t(6;10)(p21.3;q11.2) with RET. The translocation generates TRIM27/RET and delta TRIM27/RET oncogenes.
By type I interferons and upon hepatitis C viral infection.
E3 ubiquitin-protein ligase that mediates ubiquitination of various substrates and thereby plays a role in diffent processes including proliferation, innate immunity, apoptosis, immune response or autophagy (PubMed:22829933, PubMed:24144979, PubMed:29688809, PubMed:36111389). Ubiquitinates PIK3C2B and inhibits its activity by mediating the formation of 'Lys-48'-linked polyubiquitin chains; the function inhibits CD4 T-cell activation. Acts as a regulator of retrograde transport: together with MAGEL2, mediates the formation of 'Lys-63'-linked polyubiquitin chains at 'Lys-220' of WASHC1, leading to promote endosomal F-actin assembly (PubMed:23452853). Has a transcriptional repressor activity by cooperating with EPC1. Induces apoptosis by activating Jun N-terminal kinase and p38 kinase and also increases caspase-3-like activity independently of mitochondrial events. May function in male germ cell development. Has DNA-binding activity and preferentially bound to double-stranded DNA. Forms a complex with and ubiquitinates the ubiquitin-specific protease USP7, which in turn deubiquitinates RIPK1 resulting in the positive regulation of TNF-alpha-induced apoptosis (PubMed:24144979). In addition, acts with USP7 or PTPN11 as an inhibitor of the antiviral signaling pathway by promoting kinase TBK1 ubiquitination and degradation (PubMed:26358190, PubMed:29688809). Acts as a negative regulator of NOD2 signaling by mediating ubiquitination of NOD2, promoting its degradation by the proteasome (PubMed:22829933). Alternatively, facilitates mitophagy via stabilization of active TBK1 (PubMed:36111389). Negatively regulates autophagy flux under basal conditions by directly polyubiquitinating ULK1 (PubMed:35670107). During starvation-induced autophagy, catalyzes non-degradative ubiquitination of the kinase STK38L promoting its activation and phosphorylation of ULK1 leading to its ubiquitination and degradation to restrain the amplitude and duration of autophagy (PubMed:35670107).
Expressed in testis namely within the seminiferous tubules.
Homomultimerizes. Part of a complex consisting of TRIM27, USP7 and MAGEL2; directly interacts with USP7 (PubMed:26365382, PubMed:29688809). Interacts with PML, EIF3S6, EPC1, CHD4 and EID1. Interacts with MAGED4, MAGEF1 and MAGEL2. Interacts with PTPN11 (PubMed:26358190). Interacts with autophagy receptor p62/SQSTM1 (PubMed:36111389).
The coiled-coil region mediates interaction with EPC1 and CHD4. The B box and coiled-coil domains mediate interaction with PML. The B box and the distal coiled-coil domains mediate homomultimerisation. The B30.2 domain mediates interaction with EIF3S6.
Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111).
The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN.
The high-resolution electron microscopy structures indicate that the N-terminus is cytoplasmic, followed by two short helices that dip into the membrane, but do not cross it (PubMed:26280335). In contrast, results based on mutagenesis to create N-glycosylation sites indicate that the N-terminus is lumenal (PubMed:12639958, PubMed:30598546, PubMed:30630874). Both studies indicate that the C-terminus is lumenal (PubMed:12639958, PubMed:26280335).
Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain.
Expressed predominantly in the placenta, in syncytiotrophoblasts. Moderate levels in the adrenal gland, low levels in the trachea and very low levels in the bone marrow.
Expressed in a wide variety of cancer types.
Interacts with CHTOP (By similarity). Interacts with DDX39B/UAP56 and NXF1; interaction with DDX39B/UAP56 and NXF1 are mutually exclusive. Interacts with SSRP1; required for its recruitment to mRNAs.
Required for mRNA export from the nucleus to the cytoplasm. Acts as an adapter that uses the DDX39B/UAP56-NFX1 pathway to ensure efficient mRNA export and delivering to the nuclear pore. Associates with spliced and unspliced mRNAs simultaneously with ALYREF/THOC4.
Binding of unsaturated fatty acid molecules (via FZ domain) promotes homodimerization (PubMed:28377511). Interacts with WNT2B (PubMed:12490564). Interacts with WNT7A (PubMed:18230341, PubMed:20530549). Interacts with GOPC (By similarity).
Receptor for Wnt proteins (PubMed:9054360, PubMed:10097073, PubMed:20530549). Can activate WNT2, WNT10B, WNT5A, but not WNT2B or WNT4 (in vitro); the in vivo situation may be different since not all of these are known to be coexpressed (By similarity). In neurons, activation of WNT7A promotes formation of synapses (PubMed:20530549). Functions in the canonical Wnt/beta-catenin signaling pathway. The canonical Wnt/beta-catenin signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes (By similarity). A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues (Probable). Plays a role in yolk sac angiogenesis and in placental vascularization (By similarity).
Ubiquitinated by RNF43 and ZNRF3, leading to its degradation by the proteasome.
Expressed in all tissues examined. Highest level in skeletal muscle.
One of the essential components for the initiation of protein synthesis. Protects formylmethionyl-tRNA from spontaneous hydrolysis and promotes its binding to the 30S ribosomal subunits. Also involved in the hydrolysis of GTP during the formation of the 70S ribosomal complex.
(Microbial infection) Interacts with Hepatitis E virus (HEV) ORF2.
Can form homooligomers (monomers, dimers and tetramers) (PubMed:23969831). Interacts with RAB11A (GDP-bound form); regulates RAB11A (PubMed:17082457). Interacts with FKBP8; may negatively regulate ZFYVE27 phosphorylation (PubMed:17082457, PubMed:18459960). Interacts with VAPA (via MSP domain); may regulate ZFYVE27 retention in the endoplasmic reticulum and its function in cell projections formation (PubMed:19289470, PubMed:21976701). Interacts with VAPB (via MSP domain) (PubMed:19289470, PubMed:21976701). Interacts with REEP1, REEP5 and ATL1 (PubMed:24668814, PubMed:23969831). Interacts with ATL2, ATL3 and SPAST (PubMed:23969831). Interacts with KIF5A and RTN3 (PubMed:21976701). Interacts with RAB11B (GDP-bound form), SURF4, KIF5B and KIF5C (By similarity).
Key regulator of RAB11-dependent vesicular trafficking during neurite extension through polarized membrane transport (PubMed:17082457). Promotes axonal elongation and contributes to the establishment of neuronal cell polarity (By similarity). Involved in nerve growth factor-induced neurite formation in VAPA-dependent manner (PubMed:19289470). Contributes to both the formation and stabilization of the tubular ER network (PubMed:24668814). Involved in ER morphogenesis by regulating the sheet-to-tubule balance and possibly the density of tubule interconnections (PubMed:23969831). Acts as an adapter protein and facilitates the interaction of KIF5A with VAPA, VAPB, SURF4, RAB11A, RAB11B and RTN3 and the ZFYVE27-KIF5A complex contributes to the transport of these proteins in neurons. Can induce formation of neurite-like membrane protrusions in non-neuronal cells in a KIF5A/B-dependent manner (PubMed:21976701).
Phosphorylated. Phosphorylation is induced by NGF through the MAPK/ERK pathway and modulates interaction with RAB11A.
The disease is caused by variants affecting the gene represented in this entry. According to PubMed:18606302, the properties of the variant Val-191 and its frequency in some populations raise doubts on the implication of that gene in the disease.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Cation-independent O-methyltransferase family.
By all-trans-, 9-cis- and 13-cis-retinoic acid and by serum treatment, following starvation, in the retinoblastoma cell line Y79.
Catalyzes the transfer of a methyl group onto N-acetylserotonin, producing melatonin (N-acetyl-5-methoxytryptamine).
Does not show Acetylserotonin O-methyltransferase activity.
Expressed in the pineal gland (at protein level). In the retina, very low expression is found at the mRNA level (PubMed:7989373), and not at the protein level (PubMed:8574683).
By gamma irradiation and chemical mutagens but not by UV irradiation.
Homotetramer. Component of activated, catalytic and post-catalytic spliceosomes (PubMed:28502770, PubMed:28076346, PubMed:29360106, PubMed:29301961, PubMed:30705154). Component of the Prp19 complex/PRP19C/Nineteen complex/NTC and related complexes described as PRP19-CDC5L splicing complex and PSO4 complex. A homotetramer of PRPF19, CDC5L, PLRG1 and BCAS2 constitute the core of those complexes. The interaction with CDC5L, PLRG1 and BCAS2 is direct within this core complex. At least three less stably associated proteins CTNNBL1, CWC15 and HSPA8 are found in the Prp19 complex. The Prp19 complex associates with the spliceosome during its assembly and remodeling recruiting additional proteins. Component of the XAB2 complex, a multimeric protein complex composed of XAB2, PRPF19, AQR, ZNF830, ISY1, and PPIE. Interacts with CWC22 and EIF4A3 in an RNA-independent manner. Interacts with RPA1 and RPA2; the PRP19-CDC5L complex is recruited to the sites of DNA repair where it interacts with the replication protein A complex (RPA). Interacts with SETMAR; required for SETMAR recruitment to site of DNA damage. Interacts with U2AF2; the interaction is direct and recruits the Prp19 complex to RNA polymerase II C-terminal domain (CTD) and the pre-mRNA. Interacts with PRPF3. Interacts with APEX1, DNTT and PSMB4. Interacts with PSMC5 (By similarity). Interacts with KNSTRN (PubMed:24718257). Interacts (via N-terminus) with CDC5L (By similarity). Interacts with KHDC4 (PubMed:19641227). Interacts with USB1 (PubMed:23022480).
The 7 WD repeats are necessary and sufficient to support interaction with the RPA complex.
Ubiquitin-protein ligase which is a core component of several complexes mainly involved pre-mRNA splicing and DNA repair. Required for pre-mRNA splicing as component of the spliceosome (PubMed:28502770, PubMed:28076346, PubMed:29360106, PubMed:29301961, PubMed:30705154). Core component of the PRP19C/Prp19 complex/NTC/Nineteen complex which is part of the spliceosome and participates in its assembly, its remodeling and is required for its activity. During assembly of the spliceosome, mediates 'Lys-63'-linked polyubiquitination of the U4 spliceosomal protein PRPF3. Ubiquitination of PRPF3 allows its recognition by the U5 component PRPF8 and stabilizes the U4/U5/U6 tri-snRNP spliceosomal complex (PubMed:20595234). Recruited to RNA polymerase II C-terminal domain (CTD) and the pre-mRNA, it may also couple the transcriptional and spliceosomal machineries (PubMed:21536736). The XAB2 complex, which contains PRPF19, is also involved in pre-mRNA splicing, transcription and transcription-coupled repair (PubMed:17981804). Beside its role in pre-mRNA splicing PRPF19, as part of the PRP19-CDC5L complex, plays a role in the DNA damage response/DDR. It is recruited to the sites of DNA damage by the RPA complex where PRPF19 directly ubiquitinates RPA1 and RPA2. 'Lys-63'-linked polyubiquitination of the RPA complex allows the recruitment of the ATR-ATRIP complex and the activation of ATR, a master regulator of the DNA damage response (PubMed:24332808). May also play a role in DNA double-strand break (DSB) repair by recruiting the repair factor SETMAR to altered DNA (PubMed:18263876). As part of the PSO4 complex may also be involved in the DNA interstrand cross-links/ICLs repair process (PubMed:16223718). In addition, may also mediate 'Lys-48'-linked polyubiquitination of substrates and play a role in proteasomal degradation (PubMed:11435423). May play a role in the biogenesis of lipid droplets (By similarity). May play a role in neural differentiation possibly through its function as part of the spliceosome (By similarity).
Ubiquitous. Weakly expressed in senescent cells of different tissue origins. Highly expressed in tumor cell lines.
Expressed in immune cells in the lung (at protein level) (PubMed:29686383). The phosphorylated form at Ser-71 is expressed in normal breast tissue cells but not in breast cancer cells.
Interacts with STIL (By similarity). Interacts with KIF20B (PubMed:11470801). Interacts with NEK6 (PubMed:16476580). Interacts (via WW domain) with PRKX (PubMed:19367327). Interacts with BTK (PubMed:16644721). Interacts (via PpiC domain) with DAPK1 (PubMed:21497122). Interacts with the phosphorylated form of RAF1 (PubMed:15664191). Interacts (via WW domain) with ATCAY; upon NGF stimulation (PubMed:18628984). Interacts with PML (isoform PML-4) (PubMed:22033920). Interacts with BCL6 (PubMed:17828269). Interacts with FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Directly interacts with RBBP8/CtIP; this interaction depends upon RBBP8 phosphorylation (PubMed:23623683). Interacts (via WW domain) with IRAK3/IRAK-M (when phosphorylated at 'Ser-110') in response to IL33-mediated (but not TLR4 ligand LPS) dendritic cell stimulation (PubMed:29686383).
Peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr-Pro) motifs (PubMed:21497122, PubMed:23623683, PubMed:29686383). By inducing conformational changes in a subset of phosphorylated proteins, acts as a molecular switch in multiple cellular processes (PubMed:21497122, PubMed:22033920, PubMed:23623683). Displays a preference for acidic residues located N-terminally to the proline bond to be isomerized. Regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Down-regulates kinase activity of BTK (PubMed:16644721). Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation (PubMed:15664191). Binds and targets PML and BCL6 for degradation in a phosphorylation-dependent manner (PubMed:17828269). Acts as a regulator of JNK cascade by binding to phosphorylated FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation: degradation of FBXW7 leads to subsequent stabilization of JUN (PubMed:22608923). May facilitate the ubiquitination and proteasomal degradation of RBBP8/CtIP through CUL3/KLHL15 E3 ubiquitin-protein ligase complex, hence favors DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR) (PubMed:23623683, PubMed:27561354). Upon IL33-induced lung inflammation, catalyzes cis-trans isomerization of phosphorylated IRAK3/IRAK-M, inducing IRAK3 stabilization, nuclear translocation and expression of pro-inflammatory genes in dendritic cells (PubMed:29686383).
Phosphorylation at Ser-71 by DAPK1 results in inhibition of its catalytic activity, nuclear localization, and its ability to induce centrosome amplification, chromosome instability and cell transformation (PubMed:21497122). Ser-71 is dephosphorylated upon IL33-stimulation of dendritic cells (By similarity).
The WW domain is required for the interaction with STIL and KIF20B.
Could play a role in neuronal development.
Autophosphorylated; phosphorylation promotes the assembly of higher order oligomers and enzymatic activity.
Cell cycle-regulated, with maximal activity in the S-phase (PubMed:10523312, PubMed:20016786). Rapidly and transiently inhibited by phosphorylation following the generation of DNA double-stranded breaks during S-phase, probably by CHEK1, possibly at Ser-750 (PubMed:12660173, PubMed:12955071). This inhibition is cell cycle checkpoint- and ATM-dependent (PubMed:12955071).
Detected in placenta, fetal liver, kidney, pancreas, heart and skeletal muscle (PubMed:9427565). Highly expressed in testis (PubMed:9427565, PubMed:9662073). Detected in spleen, thymus, colon, ovary, small intestine, prostate and peripheral blood leukocytes (PubMed:9662073). Almost undetectable in liver and lung (PubMed:9662073).
Monomer (PubMed:29955062). May form homodimers; homodimerization may enhance autophosphoylation and enzymatic activity (PubMed:29955062). Heterodimer with TLK1 (PubMed:10523312, PubMed:29955062, PubMed:33323470). Interacts with YWHAZ; association with 14-3-3 proteins such as YWHAZ regulates subcellular location (PubMed:10455159). May also interact with FEZ1/LZTS1 and FEZ2 (PubMed:16484223). Interacts with CHD7 and CHD8 (PubMed:33323470). Interacts with DYNLL1/LC8 (PubMed:29955062).
Phosphorylated at Ser-750, probably by CHEK1.
Serine/threonine-protein kinase involved in the process of chromatin assembly and probably also DNA replication, transcription, repair, and chromosome segregation (PubMed:9427565, PubMed:10523312, PubMed:11470414, PubMed:12660173, PubMed:12955071, PubMed:29955062, PubMed:33323470). Phosphorylates the chromatin assembly factors ASF1A and ASF1B (PubMed:11470414, PubMed:20016786, PubMed:29955062, PubMed:35136069). Phosphorylation of ASF1A prevents its proteasome-mediated degradation, thereby enhancing chromatin assembly (PubMed:20016786). Negative regulator of amino acid starvation-induced autophagy (PubMed:22354037).
AQP1 is responsible for the Colton blood group system [MIM:110450]. Approximately 92% of Caucasians are Co(A+B-) (Ala-45), approximately 8% are Co(A+B+), and only 0.2% are Co(A-B+) (Val-45). Co(A-B-) which is very rare, is due to a complete absence of AQP1.
Detected in erythrocytes (at protein level). Expressed in a number of tissues including erythrocytes, renal tubules, retinal pigment epithelium, heart, lung, skeletal muscle, kidney and pancreas. Weakly expressed in brain, placenta and liver.
Forms a water-specific channel that provides the plasma membranes of red cells and kidney proximal tubules with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient (PubMed:1373524). Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane (PubMed:35835865).
Homotetramer (PubMed:35835865). Component of the ankyrin-1 complex in the erythrocyte, composed of ANK1, RHCE, RHAG, SLC4A1, EPB42, GYPA, GYPB and AQP1 (PubMed:35835865). Interacts with EPHB2; involved in endolymph production in the inner ear (By similarity). Identified in a complex with STOM (PubMed:23219802). Interacts (via the N-terminal) with ANK1 (via ANK 1-5 repeats) (PubMed:35835865). Interacts (via the C-terminal) with EPB42 (PubMed:35835865).
Pharmacologically inhibited by submillimolar concentrations of mercury.
ATP-binding RNA helicase involved in the biogenesis of 60S ribosomal subunits.
Belongs to the DEAD box helicase family. DDX51/DBP6 subfamily.
Binds NEDD4 (By similarity). Binds BCL3 and CREBBP.
Has 5'-polynucleotide kinase and nicking endonuclease activity. May play a role in DNA repair or recombination.
The Smr domain has nicking endonuclease activity, but no significant double strand cleavage or exonuclease activity.
Ubiquitinated; this targets the protein for degradation by the proteasome.
Acts as a ligand for C-C chemokine receptor CCR2 (PubMed:24442440). Signals through binding and activation of CCR2 and induces a strong chemotactic response and mobilization of intracellular calcium ions (PubMed:24442440). Exhibits a chemotactic activity for monocytes and lymphocytes but not neutrophils (PubMed:24442440).
Detected in prostate epithelium (at protein level) (PubMed:17338636). Detected in trachea and testis (PubMed:17338636). Highly expressed in benign prostatic hyperplasia and in some prostate cancers, and can also be detected in breast tumor tissue (PubMed:17338636, PubMed:24442440).
By 1,25-dihydroxyvitamin D-3 and TGFB1. Down-regulated in response to oxidative stress.
Homodimer; disulfide-linked. Interacts with TXN/thioredoxin through its redox-active site. Interacts with transcriptional repressors ZBTB16, ZBTB32 and HDAC1. Interacts (via C-terminus) with ITCH (via WW domains). Interacts with DDIT4.
May act as an oxidative stress mediator by inhibiting thioredoxin activity or by limiting its bioavailability. Interacts with COPS5 and restores COPS5-induced suppression of CDKN1B stability, blocking the COPS5-mediated translocation of CDKN1B from the nucleus to the cytoplasm. Functions as a transcriptional repressor, possibly by acting as a bridge molecule between transcription factors and corepressor complexes, and over-expression will induce G0/G1 cell cycle arrest. Required for the maturation of natural killer cells. Acts as a suppressor of tumor cell growth. Inhibits the proteasomal degradation of DDIT4, and thereby contributes to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1).
Ubiquitinated; undergoes polyubiquitination catalyzed by ITCH resulting in proteasomal degradation.
Part of an E3 ubiquitin-protein ligase complex with Elongin BC (ELOB and ELOC), RBX1 and CUL5. Component of a probable ECS(LRRC41) complex which contains CUL5, RNF7/RBX2, Elongin BC and LRRC41. Interacts with CUL5, RNF7, ELOB and ELOC.
Probable substrate recognition component of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
The Elongin BC complex binding domain is also known as BC-box with the consensus [APST]-L-x(3)-C-x(3)-[AILV].
Belongs to the ZP domain family. ZPA subfamily.
Can form homopolymers that assemble into long fibers (in vitro). Polymers of ZP2 and ZP3 organized into long filaments cross-linked by ZP1 homodimers (By similarity). Interacts with ZP3 (PubMed:28886344).
Component of the zona pellucida, an extracellular matrix surrounding oocytes which mediates sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy (PubMed:29895852). The zona pellucida is composed of 3 to 4 glycoproteins, ZP1, ZP2, ZP3, and ZP4. ZP2 may act as a secondary sperm receptor (PubMed:29895852).
O-glycosylated; contains sulfate-substituted glycans.
Proteolytically cleaved in the N-terminal part by the metalloendopeptidase ASTL exocytosed from cortical granules after fertilization, yielding a N-terminal peptide of about 30 kDa which remains covalently attached to the C-terminal peptide via disulfide bond(s). This cleavage may play an important role in the post-fertilization block to polyspermy. Additional proteolytically cleavage of the N-terminal peptide of 30 kDa occurs in one-cell and two-cell embryos.
Found Associated with the EvC complex composed of EFCAB7, IQCE, EVC2 and EVC.
Participates positively in the ciliary Hedgehog (Hh) signaling.
Belongs to the snail C2H2-type zinc-finger protein family.
Binds E-box via C2H2-type zinc finger domain.
Seems to inhibit myoblast differentiation. Transcriptional repressor of E-box-dependent transactivation of downstream myogenic bHLHs genes. Binds preferentially to the canonical E-box sequences 5'-CAGGTG-3' and 5'-CACCTG-3' (By similarity).
(Microbial infection) Interacts with HHV-8 MIR1 protein.
(Microbial infection) Polyubiquitinated in a post ER compartment by interaction with human herpesvirus 8 MIR1 protein. This targets the protein for rapid degradation via the ubiquitin system.
Allele A*01:01: Presents a restricted peptide repertoire including viral epitopes derived from IAV NP/nucleoprotein (CTELKLSDY), IAV PB1/polymerase basic protein 1 (VSDGGPNLY), HAdV-11 capsid L3/hexon protein (LTDLGQNLLY), SARS-CoV-2 3a/ORF3a (FTSDYYQLY) as well as tumor peptide antigens including MAGE1 (EADPTGHSY), MAGEA3 (EVDPIGHLY) and WT1 (TSEKRPFMCAY), all having in common a canonical motif with a negatively charged Asp or Glu residue at position 3 and a Tyr anchor residue at the C-terminus (PubMed:1402688, PubMed:7504010, PubMed:17189421, PubMed:20364150, PubMed:25880248, PubMed:30530481, PubMed:19177349, PubMed:24395804, PubMed:26758806, PubMed:32887977). A number of HLA-A*01:01-restricted peptides carry a post-translational modification with oxidation and N-terminal acetylation being the most frequent (PubMed:25880248). Fails to present highly immunogenic peptides from the EBV latent antigens (PubMed:18779413).
Allele A*02:01: A major allele in human populations, presents immunodominant viral epitopes derived from IAV M/matrix protein 1 (GILGFVFTL), HIV-1 env (TLTSCNTSV), HIV-1 gag-pol (ILKEPVHGV), HTLV-1 Tax (LLFGYPVYV), HBV C/core antigen (FLPSDFFPS), HCMV UL83/pp65 (NLVPMVATV) as well as tumor peptide antigens including MAGEA4 (GVYDGREHTV), WT1 (RMFPNAPYL) and CTAG1A/NY-ESO-1 (SLLMWITQC), all having in common hydrophobic amino acids at position 2 and at the C-terminal anchors.
Allele A*03:01 is associated with increased susceptibility to multiple sclerosis (MS), an autoimmune disease of the central nervous system (PubMed:10746785). May contribute to the initiation phase of the disease by presenting myelin PLP1 self-peptide (KLIETYFSK) to autoreactive CD8-positive T cells capable of initiating the first autoimmune attacks (PubMed:18953350).
Allele A*03:01: Presents viral epitopes derived from IAV NP (ILRGSVAHK), HIV-1 nef (QVPLRPMTYK), HIV-1 gag-pol (AIFQSSMTK), SARS-CoV-2 N/nucleoprotein (KTFPPTEPK) as well as tumor peptide antigens including PMEL (LIYRRRLMK), NODAL (HAYIQSLLK), TRP-2 (RMYNMVPFF), all having in common hydrophobic amino acids at position 2 and Lys or Arg anchor residues at the C-terminus (PubMed:7504010, PubMed:7679507, PubMed:9862734, PubMed:19543285, PubMed:21943705, PubMed:2456340, PubMed:32887977). May also display spliced peptides resulting from the ligation of two separate proteasomal cleavage products that are not contiguous in the parental protein (PubMed:27049119).
Allele A*11:01: Presents several immunodominant epitopes derived from HIV-1 gag-pol and HHV-4 EBNA4, containing the peptide motif with Val, Ile, Thr, Leu, Tyr or Phe at position 2 and Lys anchor residue at the C-terminus. Important in the control of HIV-1, EBV and HBV infections (PubMed:10449296). Presents an immunodominant epitope derived from SARS-CoV-2 N/nucleoprotein (KTFPPTEPK) (PubMed:32887977).
Allele A*23:01: Interacts with natural killer (NK) cell receptor KIR3DL1 and may contribute to functional maturation of NK cells and self-nonself discrimination during innate immune response.
Allele A*24:02: Presents viral epitopes derived from HIV-1 nef (RYPLTFGWCF), EBV lytic- and latent-cycle antigens BRLF1 (TYPVLEEMF), BMLF1 (DYNFVKQLF) and LMP2 (IYVLVMLVL), SARS-CoV nucleocapsid/N (QFKDNVILL), as well as tumor peptide antigens including PRAME (LYVDSLFFL), all sharing a common signature motif, namely an aromatic residue Tyr or Phe at position 2 and a nonhydrophobic anchor residue Phe, Leu or Iso at the C-terminus (PubMed:9047241, PubMed:12393434, PubMed:24192765, PubMed:20844028). Interacts with natural killer (NK) cell receptor KIR3DL1 and may contribute to functional maturation of NK cells and self-nonself discrimination during innate immune response (PubMed:17182537, PubMed:18502829).
Allele A*26:01 is associated with increased susceptibility to Behcet disease (BD) in the Northeast Asian population. Especially in the HLA-B*51-negative BD populations, HLA-A*26 is significantly associated with the onset of BD.
Allele A*26:01: Presents several epitopes derived from HIV-1 gag-pol (EVIPMFSAL, ETKLGKAGY) and env (LVSDGGPNLY), carrying as anchor residues preferentially Glu at position 1, Val or Thr at position 2 and Tyr at the C-terminus.
Allele A*29:02 is associated with increased susceptibility to birdshot chorioretinopathy (BSCR). May aberrantly present retinal autoantigens and induce autoimmune uveitis.
Allele A*29:02: Presents peptides having a common motif, namely a Glu residue at position 2 and Tyr or Leu anchor residues at the C-terminus.
Allele A*32:01: Interacts with natural killer (NK) cell receptor KIR3DL1 and may contribute to functional maturation of NK cells and self-nonself discrimination during innate immune response.
Allele A*68:01: Presents viral epitopes derived from IAV NP (KTGGPIYKR) and HIV-1 tat (ITKGLGISYGR), having a common signature motif namely, Val or Thr at position 2 and positively charged residues Arg or Lys at the C-terminal anchor.
Allele A*74:01: Presents immunodominant HIV-1 epitopes derived from gag-pol (GQMVHQAISPR, QIYPGIKVR) and rev (RQIHSISER), carrying an aliphatic residue at position 2 and Arg anchor residue at the C-terminus. May contribute to viral load control in chronic HIV-1 infection.
Alleles A*02:01 and A*24:02 are associated with increased susceptibility to diabetes mellitus, insulin-dependent (IDDM) (PubMed:22245737, PubMed:18802479, PubMed:16731854, PubMed:22522618). In a glucose-dependent way, allele A*02:01 may aberrantly present the signal peptide of preproinsulin (ALWGPDPAAA) on the surface of pancreatic beta cells to autoreactive CD8-positive T cells, potentially driving T-cell mediated cytotoxicity in pancreatic islets (PubMed:22245737, PubMed:18802479). Allele A*24:02 may present the signal peptide of preproinsulin (LWMRLLPLL) and contribute to acute pancreatic beta-cell destruction and early onset of IDDM (PubMed:16731854, PubMed:22522618).
Antigen-presenting major histocompatibility complex class I (MHCI) molecule. In complex with B2M/beta 2 microglobulin displays primarily viral and tumor-derived peptides on antigen-presenting cells for recognition by alpha-beta T cell receptor (TCR) on HLA-A-restricted CD8-positive T cells, guiding antigen-specific T cell immune response to eliminate infected or transformed cells (PubMed:2456340, PubMed:2784196, PubMed:1402688, PubMed:7504010, PubMed:9862734, PubMed:10449296, PubMed:12138174, PubMed:12393434, PubMed:15893615, PubMed:17189421, PubMed:19543285, PubMed:21498667, PubMed:24192765, PubMed:7694806, PubMed:24395804, PubMed:28250417). May also present self-peptides derived from the signal sequence of secreted or membrane proteins, although T cells specific for these peptides are usually inactivated to prevent autoreactivity (PubMed:25880248, PubMed:7506728, PubMed:7679507). Both the peptide and the MHC molecule are recognized by TCR, the peptide is responsible for the fine specificity of antigen recognition and MHC residues account for the MHC restriction of T cells (PubMed:12796775, PubMed:18275829, PubMed:19542454, PubMed:28250417). Typically presents intracellular peptide antigens of 8 to 13 amino acids that arise from cytosolic proteolysis via IFNG-induced immunoproteasome or via endopeptidase IDE/insulin-degrading enzyme (PubMed:17189421, PubMed:20364150, PubMed:17079320, PubMed:26929325, PubMed:27049119). Can bind different peptides containing allele-specific binding motifs, which are mainly defined by anchor residues at position 2 and 9 (PubMed:7504010, PubMed:9862734).
Heterotrimer that consists of an alpha chain HLA-A, a beta chain B2M and a peptide (peptide-HLA-A-B2M) (PubMed:7504010, PubMed:7679507, PubMed:21943705, PubMed:19177349, PubMed:24395804, PubMed:26758806, PubMed:7504010, PubMed:7506728, PubMed:8805302, PubMed:7694806, PubMed:7935798, PubMed:9177355, PubMed:18275829, PubMed:22245737, PubMed:28250417, PubMed:11502003, PubMed:8906788, PubMed:19542454). Early in biogenesis, HLA-A-B2M dimer interacts with the components of the peptide-loading complex composed of TAPBP, TAP1-TAP2, TAPBPL, PDIA3/ERP57 and CALR (PubMed:21263072). Interacts with TAP1-TAP2 transporter via TAPBP; this interaction is obligatory for the loading of peptide epitopes delivered to the ER by TAP1-TAP2 transporter (PubMed:8805302, PubMed:8630735, PubMed:21263072). Interacts with TAPBPL; TAPBPL binds peptide-free HLA-A-B2M complexes or those loaded with low affinity peptides, likely facilitating peptide exchange for higher affinity peptides (PubMed:26869717). Only optimally assembled peptide-HLA-B2M trimer translocates to the surface of antigen-presenting cells, where it interacts with TCR and CD8 coreceptor on the surface of T cells. HLA-A (via polymorphic alpha-1 and alpha-2 domains) interacts with antigen-specific TCR (via CDR3 domains) (PubMed:22245737, PubMed:12796775, PubMed:18275829). One HLA-A molecule (mainly via nonpolymorphic alpha-3 domain) interacts with one CD8A homodimer (via CDR-like loop); this interaction ensures peptide-HLA-A-B2M recognition by CD8-positive T cells only (PubMed:9177355, PubMed:2784196). Alleles A*23:01; A*24:02 and A*32:01 interact (via Bw4 motif) with KIR3DL1 on NK cells; this interaction is direct.
Highly polymorphic. Polymorphic residues encode for alpha-1 and alpha-2 domains of the peptide-binding cleft, where they contribute to variations in peptide binding and TCR recognition among different alleles. The human population is estimated to have millions of HLA-A alleles. But only 11 common HLA-A alleles are considered core alleles, representing all functionally significant variation (polymorphism) in alpha-1 and alpha-2 domains. These are: A*01:01; A*02:01; A*02:05; A*03:01; A*11:01; A*24:02; A*26:01; A*29:02; A*30:01; A*74:01 and A*80:01. Among these, A*02:01; A*11:01; A*24:02 and A*26:01, were likely passed by introgression from archaic to modern humans. Functional alleles of more recent origin (non-core) were derived by recombination (PubMed:28650991). The sequence shown is that of A*03:01. The sequences of core alleles and common representative alleles of serologically distinct allele groups are described as variants of A*03:01 (PubMed:28650991). Allelic variations of HLA-A signal peptide regulate HLA-E recognition by KLRD1-KLRC1 and KLRD1-KLRC2 receptors in viral infection and tumorigenesis by affecting its processing and by changing the affinity of HLA-E-VL9 complex for KLRD1-KLRC1 and KLRD1-KLRC2 receptors (PubMed:37264229). Allele A*31:01 is associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry [MIM:608579] (PubMed:21428769).
The VL9 peptide/epitope (VMAPRT[V/L][L/V/I/F]L) derived from the signal sequence is loaded onto HLA-E and enables HLA-E expression at the plasma membrane. Distinct VL9 peptides presented by HLA-E variably affect its recognition by KLRD1-KLRC1 or KLRD1-KLRC2 receptors on NK cells, setting NK cell activation threshold. Common HLA-A allotypes contain functional VL9 peptides (VMAPRTLLL, VMAPRTLVL and VPAPRTLLL).
The alpha-1 domain is a structural part of the peptide-binding cleft.
The alpha-2 domain is a structural part of the peptide-binding cleft (PubMed:21543847, PubMed:21943705, PubMed:19177349, PubMed:26758806, PubMed:24395804, PubMed:7694806, PubMed:8906788, PubMed:2784196, PubMed:28250417, PubMed:22245737, PubMed:19542454, PubMed:20619457, PubMed:20844028). Mediates the interaction with TAP1-TAP2 complex (PubMed:8805302).
Up-regulated by IFNG, and pro-inflammatory cytokines IL1B and TNF.
Although its physiological function is unclear, it can inhibit neutrophil cathepsin G and mast cell chymase, both of which can convert angiotensin-1 to the active angiotensin-2.
Plasma. Synthesized in the liver. Like the related alpha-1-antitrypsin, its concentration increases in the acute phase of inflammation or infection. Found in the amyloid plaques from the hippocampus of Alzheimer disease brains.
Activity is inhibited by 4,4'-Di-isothiocyanatostilbene-2,2'-disulfonic acid (DIDS - an inhibitor of several anion channels and transporters) (PubMed:18577713). Zinc-binding negatively regulates its activity (Probable).
Activity is inhibited by 4,4'-Di-isothiocyanatostilbene-2,2'-disulfonic acid (DIDS - an inhibitor of several anion channels and transporters).
Expressed in the brain, heart and kidney.
Expressed in the pyramidal cells of the hippocampus (at protein level). Highly expressed in all major regions of the brain, spinal column and in testis, and moderate levels in trachea, thyroid and medulla region of kidney. Low expression levels observed in pancreas and kidney cortex.
Mediates electroneutral sodium- and carbonate-dependent chloride-HCO3(-) exchange with a Na(+):HCO3(-) stoichiometry of 2:1 (PubMed:18577713). Plays a major role in pH regulation in neurons (By similarity). Mediates sodium reabsorption in the renal cortical collecting ducts (By similarity).
Could be a novel TATA-binding protein (TBP) which can function as a basal transcription activator. Can act as a regulator of basal transcription for class II genes (By similarity).
Interacts with ESF1/ABTAP (By similarity). Interacts with IGHMBP2.
A chromosomal aberration involving RUNX1 is found in acute leukemia. Translocation t(11,21)(q13;q22) that forms a MACROD1-RUNX1 fusion protein.
A chromosomal aberration involving RUNX1/AML1 is a cause of M2 type acute myeloid leukemia (AML-M2). Translocation t(8;21)(q22;q22) with RUNX1T1.
A chromosomal aberration involving RUNX1/AML1 is a cause of chronic myelogenous leukemia (CML). Translocation t(3;21)(q26;q22) with EAP or MECOM.
A chromosomal aberration involving RUNX1/AML1 is a cause of chronic myelomonocytic leukemia. Inversion inv(21)(q21;q22) with USP16.
A chromosomal aberration involving RUNX1/AML1 is a cause of therapy-related myelodysplastic syndrome (T-MDS). Translocation t(3;21)(q26;q22) with EAP or MECOM.
A chromosomal aberration involving RUNX1/AML1 is found in acute myeloid leukemia. Translocation t(20;21)(q11;q22) with CBFA2T2.
A chromosomal aberration involving RUNX1/AML1 is found in childhood acute lymphoblastic leukemia (ALL). Translocation t(12;21)(p13;q22) with TEL. The translocation fuses the 3'-end of TEL to the alternate 5'-exon of AML-1H.
A chromosomal aberration involving RUNX1/AML1 is found in therapy-related myeloid malignancies. Translocation t(16;21)(q24;q22) that forms a RUNX1-CBFA2T3 fusion protein.
Expressed in all tissues examined except brain and heart. Highest levels in thymus, bone marrow and peripheral blood.
Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters (Probable). Essential for the development of normal hematopoiesis (PubMed:17431401). Acts synergistically with ELF4 to transactivate the IL-3 promoter and with ELF2 to transactivate the BLK promoter (PubMed:10207087, PubMed:14970218). Inhibits KAT6B-dependent transcriptional activation (By similarity). Involved in lineage commitment of immature T cell precursors. CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation. CBF complexes binding to the transcriptional silencer is essential for recruitment of nuclear protein complexes that catalyze epigenetic modifications to establish epigenetic ZBTB7B silencing (By similarity). Controls the anergy and suppressive function of regulatory T-cells (Treg) by associating with FOXP3. Activates the expression of IL2 and IFNG and down-regulates the expression of TNFRSF18, IL2RA and CTLA4, in conventional T-cells (PubMed:17377532). Positively regulates the expression of RORC in T-helper 17 cells (By similarity).
Heterodimer with CBFB. RUNX1 binds DNA as a monomer and through the Runt domain. DNA-binding is increased by heterodimerization. Isoform AML-1L can neither bind DNA nor heterodimerize. Interacts with TLE1 and ALYREF/THOC4 (PubMed:9119228, PubMed:9751710). Interacts with ELF1, ELF2 and SPI1 (PubMed:10207087). Interacts via its Runt domain with the ELF4 N-terminal region (PubMed:10207087). Interaction with ELF2 isoform 2 (NERF-1a) may act to repress RUNX1-mediated transactivation (PubMed:14970218). Interacts with KAT6A and KAT6B (PubMed:11742995, PubMed:11965546). Interacts with SUV39H1, leading to abrogation of transactivating and DNA-binding properties of RUNX1 (PubMed:12917624, PubMed:16652147). Interacts with YAP1 (PubMed:18280240). Interacts with HIPK2 (By similarity). Interaction with CDK6 prevents myeloid differentiation, reducing its transcription transactivation activity. Found in a complex with PRMT5, RUNX1 and CBFB. Interacts with FOXP3 (PubMed:17377532). Interacts with TBX21 (By similarity). Interacts with DPF2 (PubMed:28533407).
Isoform AML-1G shows higher binding activities for target genes and binds TCR-beta-E2 and RAG-1 target site with threefold higher affinity than other isoforms. It is less effective in the context of neutrophil terminal differentiation.
Isoform AML-1L interferes with the transactivation activity of RUNX1.
Phosphorylated in Ser-249 Thr-273 and Ser-276 by HIPK2 when associated with CBFB and DNA. This phosphorylation promotes subsequent EP300 phosphorylation.
Phosphorylated in its C-terminus upon IL-6 treatment. Phosphorylation enhances interaction with KAT6A.
The fusion of AML1 with EAP in T-MDS induces a change of reading frame in the latter resulting in 17 AA unrelated to those of EAP.
Heteromultimeric cytoplasmic complex with HSP90, HSP70, and FKBP4, in the absence of ligand. After ligand binding, it translocates to the nucleus and binds to DNA as a homodimer and as a heterodimer with NR3C1. May interact with HSD11B2 in the absence of ligand. Binds the coactivators NCOA1, NCOA2, TIF1 and NRIP1.
Lacks steroid-binding activity and acts as ligand-independent transactivator.
Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels.
Ubiquitous. Highly expressed in distal tubules, convoluted tubules and cortical collecting duct in kidney, and in sweat glands. Detected at lower levels in cardiomyocytes, in epidermis and in colon enterocytes.
Belongs to the group II decarboxylase family. Sphingosine-1-phosphate lyase subfamily.
Cleaves phosphorylated sphingoid bases (PSBs), such as sphingosine-1-phosphate, into fatty aldehydes and phosphoethanolamine. Elevates stress-induced ceramide production and apoptosis (PubMed:11018465, PubMed:14570870, PubMed:24809814, PubMed:28165339). Required for global lipid homeostasis in liver and cholesterol homeostasis in fibroblasts. Involved in the regulation of pro-inflammatory response and neutrophil trafficking. Modulates neuronal autophagy via phosphoethanolamine production which regulates accumulation of aggregate-prone proteins such as APP (By similarity). Seems to play a role in establishing neuronal contact sites and axonal maintenance (By similarity).
Ubiquitously expressed (PubMed:11018465, PubMed:28165343). Expressed in fetal and adult adrenal gland (at protein level) (PubMed:28165343).
Caspase-3 cleaves DFF45 at 2 sites to generate an active factor.
Inhibitor of the caspase-activated DNase (DFF40).
Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane (PubMed:23229899, PubMed:24417819). The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (Probable). In the complex, plays a central role in bridging PI4KA to EFR3B and HYCC1, via direct interactions (By similarity).
Component of a phosphatidylinositol 4-kinase (PI4K) complex, composed of PI4KA, EFR3 (EFR3A or EFR3B), TTC7 (TTC7A or TTC7B) and HYCC (HYCC1 or HYCC2) (PubMed:24417819). Interacts with PI4KA (PubMed:34415310). Interaction with PI4KA is direct (By similarity). Interacts with EFR3 (EFR3A or EFR3B), interaction is direct (By similarity). Interacts with HYCC (HYCC1 or HYCC2), interaction is direct (By similarity). Association with the PI4K complex is strongly reduced by TMEM150A (By similarity).
Expressed in epithelial cells of the intestine, thymus, and pancreas (at protein level).
The disease is caused by variants affecting the gene represented in this entry. Phenotypic variations have been observed: the mildest case show intestinal aberrations consisting of bloody diarrhea, apoptotic enterocolitis, and acute graft-versus-host disease- (GVHD)-like symptoms, but no atresias (PubMed:25546680). Other patients show multiple intestinal atresias, some being associated with immunodeficiency syndrome, while other do not show immunodeficiency defects (PubMed:23423984).
Belongs to the universal ribosomal protein uS7 family.
Component of the mitochondrial small ribosomal subunit (mt-SSU), essential for mitochondrial protein synthesis (PubMed:25556185, PubMed:25838379). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (PubMed:25838379).
By p53/TP53, UV irradiation, by hydrogen peroxide treatment or by treatment with a DNA-damaging reagent.
Highly expressed in heart, brain and small intestine. Less abundant in skeletal muscle, spleen, prostate, ovary and colon. A smaller transcript is expressed specifically in the testis.
May play a role in the reorganization of neuronal actin structure.
Belongs to the mitochondrion-specific ribosomal protein mS35 family.
Belongs to the G-protein coupled receptor 1 family. Bradykinin receptor subfamily. BDKRB1 sub-subfamily.
This is a receptor for bradykinin. Could be a factor in chronic pain and inflammation.
Involved in the control of early migration of neurons expressing gonadotropin-releasing hormone (GNRH neurons) (By similarity). May be involved in the maintenance of osteochondroprogenitor cells pool (By similarity).
Mutations in IGSF10 may be a cause of self-limited delayed puberty. This common condition is defined as the absence of testicular enlargement in boys or breast development in girls at an age that is 2-2.5 standard deviations later than the population mean. Self-limited delayed puberty segregates within families, with the majority of families displaying an autosomal dominant pattern of inheritance.
Expressed in heart, placenta, liver, pancreas and with a higher level in skeletal muscle.
In tissues from a six months embryo, highly expressed in heart, testis and skeletal muscle, lower expression levels in kidney, intestines and prostate.
May function as a transcriptional repressor, suppressing transcriptional activities mediated by MAPK signaling pathways.
The KRAB domain is responsible for the transcriptional repressor activity.
Activity with myo-inositol monophosphate and D-galactose 1-phosphate is inhibited by Li(+), Ca(2+) and Mn(2+), but also by Mg(2+) at concentrations above 3 mM.
Responsible for the provision of inositol required for synthesis of phosphatidylinositol and polyphosphoinositides and has been implicated as the pharmacological target for lithium action in brain. Has broad substrate specificity and can use myo-inositol monophosphates, myo-inositol 1,3-diphosphate, myo-inositol 1,4-diphosphate, scyllo-inositol-phosphate, D-galactose 1-phosphate, glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate, beta-glycerophosphate, and 2'-AMP as substrates.
The two loci are in opposite orientation.
Acetylation at lysine residues stabilizes the protein, stimulates interaction with HDAC1 and HDAC3, but not HDAC2, and represses ESR1 and TP53 coactivation activity.
As an RNA helicase, unwinds RNA and alters RNA structures through ATP binding and hydrolysis. Involved in multiple cellular processes, including pre-mRNA splicing, alternative splicing, ribosomal RNA processing and miRNA processing, as well as transcription regulation. Regulates the alternative splicing of exons exhibiting specific features (PubMed:12138182, PubMed:23022728, PubMed:24910439, PubMed:22266867). For instance, promotes the inclusion of AC-rich alternative exons in CD44 transcripts (PubMed:12138182). This function requires the RNA helicase activity (PubMed:12138182, PubMed:23022728, PubMed:24910439, PubMed:22266867). Affects NFAT5 and histone macro-H2A.1/MACROH2A1 alternative splicing in a CDK9-dependent manner (PubMed:26209609, PubMed:22266867). In NFAT5, promotes the introduction of alternative exon 4, which contains 2 stop codons and may target NFAT5 exon 4-containing transcripts to nonsense-mediated mRNA decay, leading to the down-regulation of NFAT5 protein (PubMed:22266867). Affects splicing of mediators of steroid hormone signaling pathway, including kinases that phosphorylates ESR1, such as CDK2, MAPK1 and GSK3B, and transcriptional regulators, such as CREBBP, MED1, NCOR1 and NCOR2. By affecting GSK3B splicing, participates in ESR1 and AR stabilization (PubMed:24275493). In myoblasts and epithelial cells, cooperates with HNRNPH1 to control the splicing of specific subsets of exons (PubMed:24910439). In addition to binding mature mRNAs, also interacts with certain pri-microRNAs, including MIR663/miR-663a, MIR99B/miR-99b, and MIR6087/miR-6087 (PubMed:25126784). Binds pri-microRNAs on the 3' segment flanking the stem loop via the 5'-[ACG]CAUC[ACU]-3' consensus sequence (PubMed:24581491). Required for the production of subsets of microRNAs, including MIR21 and MIR125B1 (PubMed:24581491, PubMed:27478153). May be involved not only in microRNA primary transcript processing, but also stabilization (By similarity). Participates in MYC down-regulation at high cell density through the production of MYC-targeting microRNAs (PubMed:24581491). Along with DDX5, may be involved in the processing of the 32S intermediate into the mature 28S ribosomal RNA (PubMed:17485482). Promoter-specific transcription regulator, functioning as a coactivator or corepressor depending on the context of the promoter and the transcriptional complex in which it exists (PubMed:15298701). Enhances NFAT5 transcriptional activity (PubMed:22266867). Synergizes with TP53 in the activation of the MDM2 promoter; this activity requires acetylation on lysine residues (PubMed:17226766, PubMed:20663877, PubMed:19995069). May also coactivate MDM2 transcription through a TP53-independent pathway (PubMed:17226766). Coactivates MMP7 transcription (PubMed:17226766). Along with CTNNB1, coactivates MYC, JUN, FOSL1 and cyclin D1/CCND1 transcription (PubMed:17699760). Alone or in combination with DDX5 and/or SRA1 non-coding RNA, plays a critical role in promoting the assembly of proteins required for the formation of the transcription initiation complex and chromatin remodeling leading to coactivation of MYOD1-dependent transcription. This helicase-independent activity is required for skeletal muscle cells to properly differentiate into myotubes (PubMed:17011493, PubMed:24910439). During epithelial-to-mesenchymal transition, coregulates SMAD-dependent transcriptional activity, directly controlling key effectors of differentiation, including miRNAs which in turn directly repress its expression (PubMed:24910439). Plays a role in estrogen and testosterone signaling pathway at several levels. Mediates the use of alternative promoters in estrogen-responsive genes and regulates transcription and splicing of a large number of steroid hormone target genes (PubMed:24275493, PubMed:20406972, PubMed:20663877, PubMed:19995069). Contrary to splicing regulation activity, transcriptional coregulation of the estrogen receptor ESR1 is helicase-independent (PubMed:19718048, PubMed:24275493). Plays a role in innate immunity. Specifically restricts bunyavirus infection, including Rift Valley fever virus (RVFV) or La Crosse virus (LACV), but not vesicular stomatitis virus (VSV), in an interferon- and DROSHA-independent manner (PubMed:25126784). Binds to RVFV RNA, likely via structured viral RNA elements (PubMed:25126784). Promotes mRNA degradation mediated by the antiviral zinc-finger protein ZC3HAV1, in an ATPase-dependent manner (PubMed:18334637).
Interacts with DDX5 in an RNA-independent manner (PubMed:12595555, PubMed:19995069). Interacts with CDK9 transcription elongation complex under basal conditions. Following cell stimulation with poly(I:C), a synthetic double-stranded RNA mimicking viral infection, the interaction with CDK9 is decreased (PubMed:26209609). Interacts with ESR1 in an estrogen-independent manner (PubMed:19718048, PubMed:20663877). Interacts with HNRNPH1; this interaction is important for the regulation of alternative splicing on G-quadruplex structures (PubMed:24910439). At high, but not low, cell density, interacts with DROSHA and DGCR8, the core components of the microprocessor complex involved in the maturation of primary microRNAs (pri-miRNAs) into pre-miRNAs. The interaction with DGCR8 is reduced during mitosis (PubMed:24589731, PubMed:24581491). At low, but not high, cell density, interacts with YAP1 and with its paralog, WWTR1/TAZ. Interactions with DROSHA and YAP1 are mutually exclusive (PubMed:24581491). In vitro, the pre-miRNA processing activity of the DDX17-containing microprocessor complex is weaker than that of the DROSHA/DGCR8 microprocessor complex devoid of DDX17 (PubMed:15531877). Interacts with UPF3B (PubMed:23788676). Interacts with NFAT5; this interaction leads to DDX17 recruitment to LNC2 and S100A4 promoters and NFAT5-mediated DDX17-enhanced transactivation (PubMed:22266867). Interacts with HDAC1, HDAC2 and HDAC3; this interaction with HDAC1 and HDAC3, but not HDAC2, depends upon DDX17 acetylation (PubMed:15298701, PubMed:20663877). Interacts with ZC3HAV1 (via N-terminal domain) in an RNA-independent manner. Interacts with EXOSC3/RRP40 and EXOSC5/RRP46; this interaction may be indirect and mediated by ZC3HAV1-binding (PubMed:18334637). Interacts with EP300; this interaction leads to acetylation at lysine residues (PubMed:17226766, PubMed:19995069). Interacts with CREBBP/CBP and KAT2B/P/CAF (PubMed:17226766). Directly interacts with CTNNB1 (PubMed:17699760). Interacts with MYOD1 (PubMed:17011493). Interacts with TP53 (PubMed:15660129). Interacts with DCP1A in an RNA-independent manner. Interacts with DCP2 in an RNA-dependent manner (PubMed:21876179). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts with ERCC6 (PubMed:26030138).
Produced by alternative initiation at Met-80 of isoform 1.
Sumoylation significantly increases stability. It also promotes interaction specifically with HDAC1 (but not HDAC2, nor HDAC3) and strongly stimulates ESR1 and TP53 coactivation.
Was reported to act as a transcriptional coactivator for estrogen receptor ESR1 (PubMed:11250900). Although this publication was retracted because of aberrations in some figures, this function was also described in other publications by different groups and may be real (PubMed:24275493, PubMed:20406972, PubMed:20663877, PubMed:19995069).
Widely expressed (PubMed:8871553). Low expression, if any, in normal colonic epithelial cells (at protein level). Levels tend to increase during colon cancer progression, from very low in benign hyperplastic polyps to very high in tubular and villous adenomas (PubMed:17699760).
Belongs to the DNA mismatch repair MutS family.
Heterooligomer of MSH4 and MSH5. Interacts with HJURP.
Involved in DNA mismatch repair and meiotic recombination processes. Facilitates crossovers between homologs during meiosis (By similarity).
Widely expressed, with high levels in testis and ovary, including granulosa cells (PubMed:9740671, PubMed:28175301). Also expressed in fetal ovary and adrenal gland (PubMed:28175301).
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia and flagellar axoneme (PubMed:36191189). Forms filamentous polymers in the walls of ciliary and flagellar microtubules (By similarity). Contributes to normal sperm motility (By similarity).
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia and flagellar axoneme. Forms filamentous polymers in the walls of ciliary and flagellar microtubules. Required for normal sperm mobility.
Strongly expressed in spermatozoa. Also detected at low levels in pancreas. Expressed in airway epithelial cells (PubMed:36191189).
Mitochondrial protein-lysine N-methyltransferase that trimethylates adenine nucleotide translocases ANT2/SLC25A5 and ANT3/SLC25A6, thereby regulating mitochondrial respiration (PubMed:31213526). Probably also trimethylates ANT1/SLC25A4 (PubMed:31213526).
The pre-methyltransferase (preMT) region is responsible for mitochondrial localization.
Catalytically inactive phosphatase (PubMed:20180778, PubMed:23163895). By binding to G3BP1, inhibits the formation of G3BP1-induced stress granules (PubMed:20180778, PubMed:23163895). Does not act by protecting the dephosphorylation of G3BP1 at 'Ser-149' (PubMed:23163895). Inhibits PTPMT1 phosphatase activity (PubMed:24709986). By inhibiting PTPMT1, positively regulates intrinsic apoptosis (PubMed:21262771). May play a role in the formation of neurites during neuronal development (PubMed:29250526).
Interacts with G3BP1 (PubMed:20180778). Interacts with PTPMT1; the interaction inhibits PTPMT1 catalytic activity (PubMed:24709986).
Lacks the two active site residues His and Cys at position 245 and 246 which are essential for dual-specificity phosphatase activity. Lacks phosphatase activity.
Contains a central domain (substrate domain) containing multiple potential SH2-binding sites and a C-terminal domain containing a divergent helix-loop-helix (HLH) motif. The SH2-binding sites putatively bind CRK, NCK and ABL SH2 domains.
Docking protein which plays a central coordinating role for tyrosine-kinase-based signaling related to cell adhesion. May serve as an activator of SRC and a downstream effector. Interacts with the SH3 domain of FYN and with CRK, SRC, and YES (By similarity).
Phosphorylated on multiple tyrosine residues. Phosphorylated on tyrosines by FYN and SRC (By similarity).
The SH3-binding sites that bind to the SRC SH3 domain are required for interaction with CRK and are implicated in promotion of serum response element (SRE) activation. The SH3 domain interacts with PTK2/FAK1.
The protein has been detected in lung and placenta.
Na(+)/H(+) antiporter. Mediates the electoneutral exchange of intracellular H(+) ions for extracellular Na(+) in 1:1 stoichiometry (PubMed:15522866). Acts as an Na(+)/H(+) exchanger in the trans-Golgi. Contributes to the regulation of pH regulation of Golgi apparatus, and consequently, in protein trafficking and endosomal morphology (PubMed:15522866, PubMed:20719963). In germ cells, plays a crucial role in acrosome biogenesis and sperm development, probably by playing a role in the fusion of the Golgi-derived vesicles that form the acrosomal cap (By similarity). Can also be active at the cell surface of specialized cells. In the small intestine, at the cell membrane, plays a major physiological role in transepithelial absorption of Na(+) and regulates intracellular pH homeostasis of intestinal epithelial cells (PubMed:34288721). Acts as an important regulator of mucosal integrity in the intestine and in the stomach, could mediate the pH fluctuation necessary for mucin exocytosis or assist membrane trafficking of other proteins (By similarity). Plays a role in photoreceptor survival and in the maintenance of intracellular pH homeostasis in retinal pigment epithelium (RPE cells) (By similarity).
Ubiquitous. Strongly expressed in skeletal muscle and kidney (PubMed:15522866). Detected throughout the entire gastrointestinal tract, with high expression detected in stomach, duodenum and ascending colon (PubMed:18209477).
Calcium-dependent phospholipid-binding protein that may play a role in calcium-mediated intracellular processes.
Expressed in the brain, testis, thymus and small intestine (PubMed:10534407, PubMed:12949241).
The C2 domain 1 is not necessary for calcium-mediated translocation and association to the plasma membrane. The C2 domain 2 is necessary for calcium-mediated translocation and association to the plasma membrane.
Defects in LMNA may cause a late-onset cardiocutaneous progeria syndrome characterized by cutaneous manifestations of aging appearing in the third decade of life, cardiac valve calcification and dysfunction, prominent atherosclerosis, and cardiomyopathy, leading to death on average in the fourth decade.
Disease-associated isoform. Polymorphism at codon 608 results in activation of a cryptic splice donor site within exon 11, resulting in a truncated protein product that lacks the site for endoproteolytic cleavage.
Farnesylation of prelamin-A/C facilitates nuclear envelope targeting.
Homodimer of lamin A and lamin C (PubMed:15476822). Interacts with lamin-associated polypeptides IA, IB and TMPO-alpha, RB1 and with emerin (PubMed:12475961). Interacts with SREBF1, SREBF2, SUN2 and TMEM43 (By similarity). Interacts with TMEM201 (By similarity). Proteolytically processed isoform A interacts with NARF (PubMed:10514485). Interacts with SUN1 (PubMed:19933576). Interacts with MLIP (PubMed:21498514). Interacts with DMPK; may regulate nuclear envelope stability (PubMed:21949239). Interacts with SUV39H1; the interaction increases stability of SUV39H1 (PubMed:23695662). Interacts with SYNE2 (PubMed:23977161). Interacts with ITSN1 isoform 2 (PubMed:29599122). Interacts with IFFO1; enables the formation of an interior nucleoskeleton that is recruited to DNA double-strand breaks (PubMed:31548606).
In the arteries, prelamin-A/C accumulation is not observed in young healthy vessels but is prevalent in medial vascular smooth muscle cells (VSMCs) from aged individuals and in atherosclerotic lesions, where it often colocalizes with senescent and degenerate VSMCs. Prelamin-A/C expression increases with age and disease. In normal aging, the accumulation of prelamin-A/C is caused in part by the down-regulation of ZMPSTE24/FACE1 in response to oxidative stress.
Increased phosphorylation of the lamins occurs before envelope disintegration and probably plays a role in regulating lamin associations. Phosphorylation status of S-22 determines its localization between double-strand break (DSB) sites and the nuclear matrix (PubMed:31548606).
Interacts (via C-terminus) with LEMD2 (via N-terminus) (in vitro).
Lamins are components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane, which is thought to provide a framework for the nuclear envelope and may also interact with chromatin (PubMed:10080180, PubMed:10580070, PubMed:10587585, PubMed:10814726, PubMed:11799477, PubMed:12075506, PubMed:12927431, PubMed:15317753, PubMed:18551513, PubMed:18611980, PubMed:22431096, PubMed:23666920, PubMed:31548606). Lamin A and C are present in equal amounts in the lamina of mammals (PubMed:10080180, PubMed:10580070, PubMed:10587585, PubMed:10814726, PubMed:11799477, PubMed:12075506, PubMed:12927431, PubMed:15317753, PubMed:18551513, PubMed:18611980, PubMed:22431096, PubMed:23666920, PubMed:31548606). Recruited by DNA repair proteins XRCC4 and IFFO1 to the DNA double-strand breaks (DSBs) to prevent chromosome translocation by immobilizing broken DNA ends (PubMed:31548606). Plays an important role in nuclear assembly, chromatin organization, nuclear membrane and telomere dynamics. Required for normal development of peripheral nervous system and skeletal muscle and for muscle satellite cell proliferation (PubMed:10080180, PubMed:10814726, PubMed:11799477, PubMed:18551513, PubMed:22431096). Required for osteoblastogenesis and bone formation (PubMed:12075506, PubMed:15317753, PubMed:18611980). Also prevents fat infiltration of muscle and bone marrow, helping to maintain the volume and strength of skeletal muscle and bone (PubMed:10587585). Required for cardiac homeostasis (PubMed:10580070, PubMed:12927431, PubMed:23666920, PubMed:18611980).
Prelamin-A/C can accelerate smooth muscle cell senescence. It acts to disrupt mitosis and induce DNA damage in vascular smooth muscle cells (VSMCs), leading to mitotic failure, genomic instability, and premature senescence.
Proteolytic cleavage of the C-terminal of 18 residues of prelamin-A/C results in the production of lamin-A/C (PubMed:20458013, PubMed:8175923, PubMed:9030603). The prelamin-A/C maturation pathway includes farnesylation of CAAX motif by protein farnesyltransferase (FNTA and FNTB), removal of the last three amino acids (-AAX) by RCE1/FACE2 and/or ZMPSTE24, methylation of the C-terminal cysteine by ICMT and endoproteolytic removal of the last 15 C-terminal amino acids by ZMPSTE24 (PubMed:20458013, PubMed:8175923, PubMed:9030603). Proteolytic cleavage requires prior farnesylation and methylation, and absence of these blocks cleavage (PubMed:20458013, PubMed:8175923, PubMed:9030603).
Sumoylation is necessary for the localization to the nuclear envelope.
The disease is caused by variants affecting the gene represented in this entry. HGPS is caused by the toxic accumulation of a truncated form of lamin-A/C. This mutant protein, called progerin (isoform 6), acts to deregulate mitosis and DNA damage signaling, leading to premature cell death and senescence. The mutant form is mainly generated by a silent or missense mutation at codon 608 of prelamin A that causes activation of a cryptic splice donor site, resulting in production of isoform 6 with a deletion of 50 amino acids near the C terminus. Progerin lacks the conserved ZMPSTE24/FACE1 cleavage site and therefore remains permanently farnesylated. Thus, although it can enter the nucleus and associate with the nuclear envelope, it cannot incorporate normally into the nuclear lamina (PubMed:12714972).
There are three types of lamins in human cells: A, B, and C.
Highly expressed in sinusoidal endothelial cells of liver, spleen and lymph nodes. Also expressed in non SEC-cells such as HMDMs (monocyte-derivedmacrophages), HAMs (T-cell leukemia virus type 1-associated myelopathy), and several macrophage cell line.
Interacts with GULP1 and heparin. Also interacts with alpha-M/beta-2 integrin (ITGAM and ITGB2) and thymosin beta 4 (TMSB4X and/or TMSB4Y).
Phosphatidylserine receptor that enhances the engulfment of apoptotic cells. Hyaluronan receptor that binds to and mediates endocytosis of hyaluronic acid (HA). Acts also, in different species, as a primary systemic scavenger receptor for heparin (Hep), chondroitin sulfate (CS), dermatan sulfate (DS), nonglycosaminoglycan (GAG), acetylated low-density lipoprotein (AcLDL), pro-collagen propeptides and advanced glycation end products (AGE). May serve to maintain tissue integrity by supporting extracellular matrix turnover or it may contribute to maintaining fluidity of bodily liquids by resorption of hyaluronan. Counter receptor which plays an important role in lymphocyte recruitment in the hepatic vasculature. Binds to both Gram-positive and Gram-negative bacteria and may play a role in defense against bacterial infection. The proteolytically processed 190 kDa form also functions as an endocytosis receptor for heparin internalization as well as HA and CS.
Proteolytically processed to yield a 190 kDa protein.
Recognizes phosphatidyl serine via its epidermal growth factor-like domains.
Detected in bronchial epithelial cells (PubMed:21964404). Detected in heart left atrium and left ventricle (PubMed:17478540). Detected in cardiac myocytes (at protein level) (PubMed:21653227). Widely expressed with high levels in heart, brain and kidney, and lower levels in colon, ovary, placenta, lung and liver (PubMed:8605869, PubMed:9362344). Highly expressed in cerebellum, and detected at lower levels in amygdala, caudate nucleus, brain cortex, hippocampus, putamen, substantia nigra, thalamus, dorsal root ganglion, spinal cord, pituitary, heart, kidney, lung, placenta, pancreas, stomach, small intestine, uterus and prostate (PubMed:11165377). Detected in right and left heart ventricle and atrium, and in heart Purkinje fibers (PubMed:17478540). Detected in bronchial epithelial cells (PubMed:21964404).
Homodimer; disulfide-linked (PubMed:8978667, PubMed:22282804). Heterodimer with KCNK2; disulfide-linked (By similarity). In astrocytes, forms mostly heterodimeric potassium channels with KCNK2, with only a minor proportion of functional channels containing homodimeric KCNK1 (By similarity). Interacts with KCNK3 and KCNK9, forming functional heterodimeric channels (PubMed:23169818). Interacts with GNG4 (By similarity). Identified in a complex with PSD and ARF6; interacts only with PSD that is bound to ARF6 (By similarity). Interacts with UBE2I (PubMed:15820677).
Inhibited by Ba(2+) ions and quinidine (PubMed:8605869). Inhibited by quinine (PubMed:8605869, PubMed:21653227). Is slightly inhibited by 10 mM tetraethylammonium (TEA), and only marginally inhibited by 4-aminopyridine, charybdotoxin and dendrotoxin (PubMed:8605869). Lowering the extracellular pH to below 6.5 transiently activates the channel, and then inhibits channel activity (PubMed:15820677, PubMed:22431633). Inhibited when the intracellular pH is decreased down to pH 6.0, but this may be due to indirect effects (PubMed:8605869).
Ion channel that contributes to passive transmembrane potassium transport and to the regulation of the resting membrane potential in brain astrocytes, but also in kidney and in other tissues (PubMed:15820677, PubMed:21653227). Forms dimeric channels through which potassium ions pass in accordance with their electrochemical gradient. The channel is selective for K(+) ions at physiological potassium concentrations and at neutral pH, but becomes permeable to Na(+) at subphysiological K(+) levels and upon acidification of the extracellular medium (PubMed:21653227, PubMed:22431633). The homodimer has very low potassium channel activity, when expressed in heterologous systems, and can function as weakly inward rectifying potassium channel (PubMed:8605869, PubMed:8978667, PubMed:15820677, PubMed:21653227, PubMed:22431633, PubMed:23169818, PubMed:25001086). Channel activity is modulated by activation of serotonin receptors (By similarity). Heterodimeric channels containing KCNK1 and KCNK2 have much higher activity, and may represent the predominant form in astrocytes (By similarity). Heterodimeric channels containing KCNK1 and KCNK3 or KCNK9 have much higher activity (PubMed:23169818). Heterodimeric channels formed by KCNK1 and KCNK9 may contribute to halothane-sensitive currents (PubMed:23169818). Mediates outward rectifying potassium currents in dentate gyrus granule cells and contributes to the regulation of their resting membrane potential (By similarity). Contributes to the regulation of action potential firing in dentate gyrus granule cells and down-regulates their intrinsic excitability (By similarity). In astrocytes, the heterodimer formed by KCNK1 and KCNK2 is required for rapid glutamate release in response to activation of G-protein coupled receptors, such as F2R and CNR1 (By similarity). Required for normal ion and water transport in the kidney (By similarity). Contributes to the regulation of the resting membrane potential of pancreatic beta cells (By similarity). The low channel activity of homodimeric KCNK1 may be due to sumoylation (PubMed:15820677, PubMed:20498050, PubMed:23169818). The low channel activity may be due to rapid internalization from the cell membrane and retention in recycling endosomes (PubMed:19959478).
Sumoylation is controversial. Sumoylated by UBE2I (PubMed:15820677). Not sumoylated when expressed in xenopus oocytes or mammalian cells (PubMed:17693262). Sumoylation inactivates the channel, but does not interfere with expression at the cell membrane (PubMed:15820677). Sumoylation of a single subunit is sufficient to silence the dimeric channel (PubMed:20498050, PubMed:23169818). Sumoylation of KCNK1 is sufficient to silence heterodimeric channels formed by KCNK1 and KCNK3 or KCNK9 (PubMed:23169818). Desumoylated by SENP1; this activates the channel (PubMed:15820677, PubMed:20498050, PubMed:23169818). Desumoylated by SENP1; this strongly increases halothane-mediated activation of heterodimeric channels formed with KCNK9 (PubMed:23169818). SENP1 treatment has no effect (PubMed:17693262).
When the external K(+) concentration is lowered to subphysiological levels, it takes several minutes till the channel has reached a new, stable state characterized by increased Na(+) permeability (PubMed:21653227). Likewise, when the external pH is lowered to values below 6.5, it takes several minutes till the channel has reached a new, stable state characterized by increased Na(+) permeability (PubMed:22431633). When raising the K(+) concentration back to 5 mM, it takes 40 to 70 minutes for the channel to regain its original selectivity for K(+) (PubMed:21653227). Likewise, it takes more that 25 minutes for the channel to regain its original K(+) selectivity when the pH is raised back to 7.4 (PubMed:22431633).
Belongs to the GTP-binding SRP family. SRP54 subfamily.
Component of a signal recognition particle (SRP) complex that consists of a 7SL RNA molecule of 300 nucleotides and six protein subunits: SRP72, SRP68, SRP54, SRP19, SRP14 and SRP9 (PubMed:12244299). Interacts with RNPS1 (PubMed:14729963). Interacts with the SRP receptor subunit SRPRA (PubMed:34020957).
Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER) (PubMed:34020957). As part of the SRP complex, associates with the SRP receptor (SR) component SRPRA to target secretory proteins to the endoplasmic reticulum membrane (PubMed:34020957). Binds to the signal sequence of presecretory proteins when they emerge from the ribosomes (PubMed:34020957). Displays basal GTPase activity, and stimulates reciprocal GTPase activation of the SR subunit SRPRA (PubMed:28972538, PubMed:34020957). Forms a guanosine 5'-triphosphate (GTP)-dependent complex with the SR subunit SRPRA (PubMed:34020957). SR compaction and GTPase mediated rearrangement of SR drive SRP-mediated cotranslational protein translocation into the ER (PubMed:34020957). Requires the presence of SRP9/SRP14 and/or SRP19 to stably interact with RNA (By similarity). Plays a role in proliferation and differentiation of granulocytic cells, neutrophils migration capacity and exocrine pancreas development (PubMed:28972538, PubMed:29914977).
The M domain binds the 7SL RNA in presence of SRP19 and binds the signal sequence of presecretory proteins.
The NG domain, also named G domain, is a special guanosine triphosphatase (GTPase) domain, which binds GTP and forms a guanosine 5'-triphosphate (GTP)-dependent complex with a homologous NG domain in the SRP receptor subunit SRPRA (PubMed:34020957). The two NG domains undergo cooperative rearrangements upon their assembly, which culminate in the reciprocal activation of the GTPase activity of one another (PubMed:34020957). SRP receptor compaction upon binding with cargo-loaded SRP and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER (PubMed:34020957).
up-regulated during granulocytic differentiation.
After synthesis, undergoes cleavage between Leu-3048 and Thr-3049 in the GPS domain. Cleavage at the GPS domain occurs through a cis-autoproteolytic mechanism involving an ester-intermediate via N-O acyl rearrangement. This process takes place in the early secretory pathway, depends on initial N-glycosylation, and requires the REJ domain. There is evidence that cleavage at GPS domain is incomplete. Uncleaved and cleaved products may have different functions in vivo.
Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B (PubMed:27214281). Both PKD1 and PKD2 are required for channel activity (PubMed:27214281). Involved in renal tubulogenesis (PubMed:12482949). Involved in fluid-flow mechanosensation by the primary cilium in renal epithelium (By similarity). Acts as a regulator of cilium length, together with PKD2 (By similarity). The dynamic control of cilium length is essential in the regulation of mechanotransductive signaling (By similarity). The cilium length response creates a negative feedback loop whereby fluid shear-mediated deflection of the primary cilium, which decreases intracellular cAMP, leads to cilium shortening and thus decreases flow-induced signaling (By similarity). May be an ion-channel regulator. Involved in adhesive protein-protein and protein-carbohydrate interactions.
Interacts with PKD2; the interaction is required for ciliary localization (PubMed:20881056). Component of a heterotetrameric channel complex with PKD2; the tetramer contains one PKD1 chain and three PKD2 chains (PubMed:30093605). Interacts with PKD2L1 (By similarity). Interacts with PRKX; involved in differentiation and controlled morphogenesis of the kidney (PubMed:17980165). Interacts (via extracellular domain) with WNT3A, WNT4, WNT5A and WNT9B (PubMed:27214281). Interacts with DVL1 and DVL2 (PubMed:27214281). Interacts with NPHP1 (via SH3 domain) (PubMed:20856870). Interacts with BBS1, BBS4, BBS5 and TTC8 (PubMed:24939912). Interacts with RGS7 (PubMed:10339594).
The LDL-receptor class A domain is atypical; the potential calcium-binding site is missing.
Interacts with MUS81 to form a DNA structure-specific endonuclease with substrate preference for branched DNA structures with a 5'-end at the branch nick. Typical substrates include 3'-flap structures, replication forks and nicked Holliday junctions. May be required in mitosis for the processing of stalled or collapsed replication forks.
May self-associate. Interacts with MUS81.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIA1 subfamily.
Homotetramer or heterotetramer of pore-forming glutamate receptor subunits (By similarity). Tetramers may be formed by the dimerization of dimers (PubMed:23739980). Found in a complex with GRIA2, GRIA3, GRIA4, CNIH2, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8 (By similarity). Interacts with HIP1 and RASGRF2. Interacts with SYNDIG1 and GRIA2 (By similarity). Interacts with DLG1 (via C-terminus). Interacts with LRFN1. Interacts with PRKG2 (By similarity). Interacts with CNIH2 and CACNG2 (PubMed:20805473). Interacts with CACNG5. Interacts (via C-terminus) with PDLIM4 (via LIM domain); this interaction as well as the interaction of PDLIM4 with alpha-actinin is required for their colocalization in early endosomes. Interacts with SNX27 (via PDZ domain); the interaction is required for recycling to the plasma membrane when endocytosed and prevent degradation in lysosomes. Interacts (via PDZ-binding motif) with SHANK3 (via PDZ domain) (By similarity). Interacts with CACNG3; associates GRIA1 with the adapter protein complex 4 (AP-4) to target GRIA1 to the somatodendritic compartment of neurons (By similarity).
Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate.
Palmitoylated. Depalmitoylated upon glutamate stimulation. Cys-603 palmitoylation leads to Golgi retention and decreased cell surface expression. In contrast, Cys-829 palmitoylation does not affect cell surface expression but regulates stimulation-dependent endocytosis (By similarity).
Phosphorylated at Ser-645. Phosphorylated at Ser-710 by PKC. Phosphorylated at Ser-849 by PKC, PKA and CAMK2. Phosphorylated at Ser-863 by PKC, PKA and PRKG2 (By similarity). Phosphorylation of Ser-863 is reduced by induction of long-term depression and increased by induction of long-term potentiation (By similarity).
By TNF, IFNG/IFN-gamma and IFNB1/IFN-beta.
Directly interacts with NEDD8 and PSMD4/S5a, a member of the regulatory subunit of the 26S proteasome. Isoform 1 binds to NEDD8 more efficiently than isoform 2. Interacts with AIPL1. The interaction with UBD via UBA domains facilitates the linking of UBD-conjugated target protein to the proteasome complex and accelerates UBD degradation and that of its conjugates.
Specific down-regulator of the NEDD8 conjugation system. Recruits NEDD8, UBD, and their conjugates to the proteasome for degradation. Isoform 1 promotes the degradation of NEDD8 more efficiently than isoform 2.
Widely expressed with lowest expression in the pancreas for isoform 1 and in leukocytes, liver, prostate and skeletal muscle for isoform 2.
Chromatin-remodeling protein that binds DNA through histones and regulates gene transcription. May specifically recognize and bind trimethylated 'Lys-27' (H3K27me3) and non-methylated 'Lys-4' of histone H3. Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin. Plays a role in the development of the nervous system by activating the expression of genes promoting neuron terminal differentiation. In parallel, it may also positively regulate the trimethylation of histone H3 at 'Lys-27' thereby specifically repressing genes that promote the differentiation into non-neuronal cell lineages. Regulates the expression of genes involved in cell proliferation and differentiation. Downstream activated genes may include CDKN2A that positively regulates the p53/TP53 pathway, which in turn, prevents cell proliferation. In spermatogenesis, it probably regulates histone hyperacetylation and the replacement of histones by transition proteins in chromatin, a crucial step in the condensation of spermatid chromatin and the production of functional spermatozoa.
Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5. The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes. Interacts with HDAC2.
Defects in CHD5 may be a cause of the development of cancers from epithelial, neural and hematopoietic origin. CHD5 is one of the missing genes in the del(1p36), a deletion which is extremely common in this type of cancers. A decrease of its expression, results in increased susceptibility of cells to Ras-mediated transformation in vitro and in vivo (PubMed:17289567).
Preferentially expressed in total brain, fetal brain, and cerebellum. It is also moderately expressed in the adrenal gland and detected in testis.
The PHD domains mediate specific binding to histone H3 unmethylated at 'Lys-4' and may preferentially recruit the protein to transcriptionally inactive genes.
The chromo domains mediate specific binding to histone H3 trimethylated at 'Lys-27' (H3K27me3) and may be required in neuron differentiation for proper gene regulation.
Catalyzes the interconversion of (R)- and (S)-stereoisomers of alpha-methyl-branched-chain fatty acyl-CoA esters (PubMed:7649182, PubMed:10655068, PubMed:11060359). Acts only on coenzyme A thioesters, not on free fatty acids, and accepts as substrates a wide range of alpha-methylacyl-CoAs, including pristanoyl-CoA, trihydroxycoprostanoyl-CoA (an intermediate in bile acid synthesis), and arylpropionic acids like the anti-inflammatory drug ibuprofen (2-(4-isobutylphenyl)propionic acid) but neither 3-methyl-branched nor linear-chain acyl-CoAs (PubMed:7649182, PubMed:10655068, PubMed:11060359).
Expression is elevated in prostate cancer.
Interacts with GABA-A receptor and O-GlcNAc transferase. Interacts with HGS (By similarity). Interacts with RHOT1/Miro-1 and RHOT2/Miro-2.
May regulate endosome-to-lysosome trafficking of membrane cargo, including EGFR.
Widely expressed, with highest expression in heart.
The C-terminus is necessary for localization to the cell membrane (PubMed:26578515).
Widely expressed, with much higher levels in fetal tissues than in adult ones. Up-regulated in certain cancer tissues.
mRNA-binding protein involved in proper cytoplasmic distribution of mitochondria. Specifically binds mRNAs of nuclear-encoded mitochondrial proteins in the cytoplasm and regulates transport or translation of these transcripts close to mitochondria, playing a role in mitochondrial biogenesis.
Based on a readthrough transcript which may produce an INS-IGF2 fusion protein.
Expressed in pancreas, eye and, to a lower extent, in limb.
Associated with severe intellectual disability, microcephaly, and feeding difficulties as well as cerebral atrophy.
Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping. Involved with LARP6 in the stabilization of type I collagen mRNAs for CO1A1 and CO1A2. During cell spreading, plays an important role in cytoskeleton reorganization, focal contacts formation (in the central part but not the margins of spreading cells), and lamellipodial extension; this function is mechanically antagonized by MYH9.
Isoform 1 is expressed in cerebellum and spinal chord. Isoform 2 is expressed in cerebrum and retina. Isoform 3 is expressed in the cerebrum and to a much lower extent in cerebellum.
Myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). Interacts with PLEKHG6 (PubMed:16721066). Interacts with ECPAS (PubMed:20682791). Interacts with KIF26B (By similarity). Interacts with LARP6 (PubMed:20603131). Interacts with MCC (PubMed:22480440). Interacts with CFAP95 (PubMed:28345668).
Represents a conventional non-muscle myosin. This protein should not be confused with the unconventional myosin-10 (MYO10).
By serum response factor SRF and myogenin. SRF binds to the CArG site and MYOG binds to the E-box element on SMYD1 promoter.
Expression seems mostly restricted to heart and skeletal muscle.
Interacts with HDAC1, HDAC2 and HDAC3. Interacts (via MYND-type zinc finger) with NACA isoform skNAC.
Methylates histone H3 at 'Lys-4' (H3K4me), seems able to perform both mono-, di-, and trimethylation. Acts as a transcriptional repressor. Essential for cardiomyocyte differentiation and cardiac morphogenesis.
The SET domain is split between the S-sequence (residues 1-49) and the core SET domain (residues 181-258), however the two segments still come together to form a conserved SET domain fold.
Performs a specialized role during sperm development and maturation.
Proximal caput region of the epididymis. Lower expression in the testis. Within the testis it is localized to the elongating spermatids, whereas within the epididymis it is exclusively synthesized by the proximal caput epithelium.
Catalyzes the deubiquitination of SPDL1 (PubMed:30258100). Plays a role in the repair of UV-induced DNA damage via deubiquitination of ERCC1, promoting its recruitment to DNA damage sites (PubMed:25538220). May be involved in the maintenance of photoreceptor function (PubMed:30573563). May play a role in normal retinal development (By similarity). Plays a role in cell migration (PubMed:30258100).
Interacts with ERCC1 (PubMed:25538220). The catalytically active form interacts with SPDL1 (PubMed:30258100).
Widely expressed. High expression is detected in the cerebellum. In the eye, it is expressed at high levels in the optic nerve, sclera and retina, with relatively low levels in the choroid, lens and retinal pigment epithelium (PubMed:30573563).
Downstream effector molecules involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape.
Phosphorylation by ABL1 promotes lamellipodia formation and cell migration.
Involved in RNA polymerase III-mediated transcription. Integral, tightly associated component of the DNA-binding TFIIIC2 subcomplex that directly binds tRNA and virus-associated RNA promoters.
Part of the TFIIIC subcomplex TFIIIC2, consisting of six subunits, GTF3C1, GTF3C2, GTF3C3, GTF3C4, GTF3C5 and GTF3C6. Interacts with BRF1 and TBP.
Probably involved in thrombopoiesis. Plays a role in the development or secretion of alpha-granules, that contain several growth factors important for platelet biogenesis.
Activated following phosphorylation at Thr-231 by WNK kinases (WNK1, WNK2, WNK3 or WNK4) (PubMed:16832045, PubMed:17190791, PubMed:21321328, PubMed:34289367). Specifically inhibited by YU239252 (YU252) (PubMed:34289367).
Effector serine/threonine-protein kinase component of the WNK-SPAK/OSR1 kinase cascade, which is involved in various processes, such as ion transport, response to hypertonic stress and blood pressure (PubMed:16669787, PubMed:18270262, PubMed:21321328, PubMed:34289367). Specifically recognizes and binds proteins with a RFXV motif (PubMed:16669787, PubMed:21321328). Acts downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4): following activation by WNK kinases, catalyzes phosphorylation of ion cotransporters, such as SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A3/NCC, SLC12A5/KCC2 or SLC12A6/KCC3, regulating their activity (PubMed:21321328). Mediates regulatory volume increase in response to hyperosmotic stress by catalyzing phosphorylation of ion cotransporters SLC12A1/NKCC2, SLC12A2/NKCC1 and SLC12A6/KCC3 downstream of WNK1 and WNK3 kinases (PubMed:12740379, PubMed:16669787, PubMed:21321328). Phosphorylation of Na-K-Cl cotransporters SLC12A2/NKCC1 and SLC12A2/NKCC1 promote their activation and ion influx; simultaneously, phosphorylation of K-Cl cotransporters SLC12A5/KCC2 and SLC12A6/KCC3 inhibit their activity, blocking ion efflux (PubMed:16669787, PubMed:19665974, PubMed:21321328). Acts as a regulator of NaCl reabsorption in the distal nephron by mediating phosphorylation and activation of the thiazide-sensitive Na-Cl cotransporter SLC12A3/NCC in distal convoluted tubule cells of kidney downstream of WNK4 (PubMed:18270262). Mediates the inhibition of SLC4A4, SLC26A6 as well as CFTR activities (By similarity). Phosphorylates RELT (By similarity).
PAPA box (proline-alanine repeats) may target the kinase to a specific subcellular location by facilitating interaction with intracellular proteins such as actin or actin-like proteins.
Phosphorylation at Thr-231 by WNK kinases (WNK1, WNK2, WNK3 or WNK4) is required for activation (PubMed:16832045, PubMed:17190791, PubMed:21321328, PubMed:34289367). Autophosphorylation at Thr-231 positively regulates its activity (By similarity). Phosphorylated at Ser-309 by PRKCQ (PubMed:14988727).
Predominantly expressed in brain and pancreas followed by heart, lung, kidney, skeletal muscle, liver, placenta and testis.
The phosphorylated form forms a complex with WNK2 (By similarity). Interacts with SORL1 (via cytosolic C-terminus) (PubMed:20385770).
E3 ubiquitin ligase that plays a role in several processes including innate immnity, autophagy or inflammation (PubMed:28594402, PubMed:34512673). Negatively regulates miRNAs by modulating the ubiquitination and stability of TNRC6A, a protein involved in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (PubMed:24778252). This ubiquitination results in the suppressed expression of miR-138-5p leading to increased autophagy (PubMed:31160576). Upon enteroviral infection, promotes 'Lys-63'-mediated ubiquitination activation of IFIH1/MDA5 leading to innate signaling cascade (PubMed:28594402). Mechanistically, selectively recognizes MDA5 filaments that occur on dsRNAs (PubMed:33373584). Plays also a role in limitation of inflammation through different mechanisms. First, promotes 'Lys-48'-mediated ubiquitination of VCAM1 leading to its degradation and limitation of LPS-induced lung inflammation (PubMed:31310649). In addition, negatively regulates inflammasome activation by promoting 'lys48'-linked ubiquitination of NLRP3 which is critical for the inhibition of NLRP3 inflammasome activation in resting macrophages (PubMed:34512673).
Homo-multimerizes (PubMed:24778252). Interacts with ARRDC4 (PubMed:28594402).
Belongs to the chloride channel MCLC family.
Expressed in the retina of the eye, with extensive expression in the lamina cribrosa, optic nerve, ganglion cell layer, inner nuclear layer, outer nuclear layer and retinal pigment epithelium.
Interacts with mitochondrial protein PIGBOS1 (via C-terminus); the interaction occurs at the mitochondria-associated endoplasmic reticulum (ER) membrane, a zone of contact between the ER and mitochondrial membranes, but does not appear to play a role in ER-mitochondria tethering and is not affected by ER stress (PubMed:31653868). Interacts with CALR (PubMed:30157172).
Seems to act as a chloride ion channel (PubMed:30157172). Plays a role in retina development (PubMed:30157172).
(Microbial infection) May be involved in hepatitis C virus (HCV) replication and release.
Belongs to the cyclophilin-type PPIase family. PPIase D subfamily.
Identified in ESR1 or NR3C1/GCR steroid receptor-chaperone complexes. Found in HSP90 chaperone complexes with kinase clients LCK or EIF2AK1. Two monomers associate with one HSP90 homodimer. Interacts with HSP90AA1. Interacts with HSP90AB1; PPID and FKBP4 compete for binding to HSP90AB1 and the interaction is mutually exclusive with the PPID:HSPA8 interaction. Interacts with HSPA8; PPID and STIP1 but not FKBP4 compete for binding to HSPA8 and the interaction is mutually exclusive with the PPID:HSP90AB1 interaction. Interacts with S100A1 and S100A2; the interactions dissociate the PPID:HSP90AA1 interaction. Interacts with S100A6. Interacts with MYB, ILF2, XRCC6, RACK1 and RPS3. Interacts with cytoplasmic dynein 1 intermediate chain (DYNC1I1 or DYNC1I2).
Less sensitive to inhibition by cyclosporin A than is CYP-18.
PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding (PubMed:11350175, PubMed:20676357). Proposed to act as a co-chaperone in HSP90 complexes such as in unligated steroid receptors heterocomplexes. Different co-chaperones seem to compete for association with HSP90 thus establishing distinct HSP90-co-chaperone-receptor complexes with the potential to exert tissue-specific receptor activity control. May have a preference for estrogen receptor complexes and is not found in glucocorticoid receptor complexes. May be involved in cytoplasmic dynein-dependent movement of the receptor from the cytoplasm to the nucleus. May regulate MYB by inhibiting its DNA-binding activity. Involved in regulation of AHR signaling by promoting the formation of the AHR:ARNT dimer; the function is independent of HSP90 but requires the chaperone activity. Involved in regulation of UV radiation-induced apoptosis. Promotes cell viability in anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma (ALK+ ALCL) cell lines.
This protein should not be confused with mitochondrial peptidyl-prolyl cis-trans isomerase F (PPIF) which is often referred to as cyclophilin D or CypD.
Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures. Interacts (phosphorylated upon activation by BDNF) with SHC1; mediates SHC1 phosphorylation and activation. Interacts (phosphorylated upon activation by BDNF) with PLCG1 and/or PLCG2; mediates PLCG1 phosphorylation and activation. Interacts with SH2B1 and SH2B2. Interacts with NGFR; may regulate the ligand specificity of the receptor (By similarity). Interacts with SORCS2; this interaction is important for normal targeting to post-synaptic densities in response to high-frequency stimulation (By similarity). Interacts (phosphorylated upon ligand-binding) with SH2D1A; regulates NTRK2. Interacts with SQSTM1 and KIDINS220 (By similarity). Interacts (phosphorylated upon ligand-binding) with FRS2; activates the MAPK signaling pathway (PubMed:10092678). Interacts with APPL1 (By similarity). Interacts with MAPK8IP3/JIP3 and KLC1; interaction with KLC1 is mediated by MAPK8IP3/JIP3 (By similarity). Interacts with SORL1; this interaction facilitates NTRK2 trafficking between synaptic plasma membranes, postsynaptic densities and cell soma, hence positively regulates BDNF signaling (By similarity).
Isoform TrkB is expressed in the central and peripheral nervous system. In the central nervous system (CNS), expression is observed in the cerebral cortex, hippocampus, thalamus, choroid plexus, granular layer of the cerebellum, brain stem, and spinal cord. In the peripheral nervous system, it is expressed in many cranial ganglia, the ophthalmic nerve, the vestibular system, multiple facial structures, the submaxillary glands, and dorsal root ganglia. Isoform TrkB-T1 is mainly expressed in the brain but also detected in other tissues including pancreas, kidney and heart. Isoform TrkB-T-Shc is predominantly expressed in the brain.
Phosphorylated. Undergoes ligand-mediated autophosphorylation that is required for interaction with SHC1 and PLCG1 and other downstream effectors. Isoform TrkB-T-Shc is not phosphorylated.
Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity (By similarity). Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin-4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2 (PubMed:7574684, PubMed:15494731). Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation (PubMed:15494731). Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin-dependent calcium signaling in glial cells and mediate communication between neurons and glia.
The neuronal activity and the influx of calcium positively regulate the kinase activity and the internalization of the receptor which are both important for active signaling. Regulated by NGFR that may control the internalization of the receptor. NGFR may also stimulate the activation by BDNF compared to NTF3 and NTF4. SH2D1A inhibits the autophosphorylation of the receptor, and alters the recruitment and activation of downstream effectors and signaling cascades. The formation of active receptors dimers able to fully transduce the ligand-mediated signal, may be negatively regulated by the formation of inactive heterodimers with the non-catalytic isoforms (By similarity).
Trk also stands for tropomyosin-related kinase since the first Trk was isolated as an oncogenic protein which was the result of a fusion between the tropomyosin gene TPM3 and NTRK1.
Ubiquitinated. Undergoes polyubiquitination upon activation; regulated by NGFR. Ubiquitination regulates the internalization of the receptor (By similarity).
Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance and lamellipodial and filopodial dynamics in migrating cells. ENAH induces the formation of F-actin rich outgrowths in fibroblasts. Acts synergistically with BAIAP2-alpha and downstream of NTN1 to promote filipodia formation (By similarity).
Expressed in myoepithelia of parotid, breast, bronchial glands and sweat glands. Expressed in colon-rectum muscolaris mucosae epithelium, pancreas acinar ductal epithelium, endometrium epithelium, prostate fibromuscolar stroma and placenta vascular media. Overexpressed in a majority of breast cancer cell lines and primary breast tumor lesions.
Expression restricted to invasive cancer cells.
Homotetramer (By similarity). Interacts with APBB1IP, APBB1, PFN1 and ROBO4 (PubMed:12941633, PubMed:15469846, PubMed:17686488). Isoforms, containing the polyproline-rich regions with PPLP motifs, bind the WW domain of APBB1IP (PubMed:15469846). Isoforms, containing the PPSY motif, bind, in vitro, to the WW2 and WW3 domains of NEDD4 and to the WW1 domain of YAP1 (By similarity). Binds the SH3 domain of BAIAP2-alpha but only after the autoinhibitory region of BAIAP2-alpha has been blocked by interaction with CDC42 (PubMed:11696321, PubMed:18158903). Interacts, via the EVH1/WH1 domain, with the Pro-rich domains from VCL, ZYX and Listeria monocytogenes actA and with TES (via LIM domains) (PubMed:9312002, PubMed:18158903, PubMed:21278383). The TES LIM domain and the Pro-rich domains from VCL or ZYX compete for the same binding site (PubMed:9312002). Interaction with ZYX is important for targeting ENAH to focal adhesions and enhances production of actin-rich structures at the apical surface of cells (PubMed:10801818). Interacts, through the Pro-rich region, with the C-terminal SH3 domain of DNMPB (By similarity). Binds GPHN (By similarity). Interacts with FAT1 (via EVH1 domains) (By similarity). Heterotrimer with TES and ACTL7A (PubMed:21278383). Interacts with PRPF40A (By similarity).
NTN1-induced PKA phosphorylation on Ser-265 directly parallels the formation of filopodial protrusions.
Dephosphorylated on Tyr-345 by PTPN18, this event negatively regulates the association of PSTPIP1 with SH2 domain-containing proteins as tyrosine kinase. Phosphorylation of Tyr-345 is probably required for subsequent phosphorylation at other tyrosine residues. Phosphorylation is induced by activation of the EGFR and PDGFR in a ABL1 dependent manner. The phosphorylation regulates the interaction with WAS and with MEFV (By similarity).
Highly expressed in the peripheral blood leukocytes, granulocytes and monocytes, namely in T-cells and natural killer cells, and in spleen. Weakly expressed in the thymus, small intestine, lung and placenta.
Homodimer (PubMed:19584923). Homotrimer (PubMed:17964261). Interacts (via coiled-coil domain) with CD2AP, PTPN12 and PTPN18. Interacts (via SH3 domain) with ABL1 and WAS. Interacts (via SH3 and coiled-coil domains) with MEFV (via B-box zinc finger); the interaction allows binding of MEFV to PYCARD and facilitates formation of PYCARD pyroptosomes. Interacts with CD2, DNM2 and FASLG.
Involved in regulation of the actin cytoskeleton. May regulate WAS actin-bundling activity. Bridges the interaction between ABL1 and PTPN18 leading to ABL1 dephosphorylation. May play a role as a scaffold protein between PTPN12 and WAS and allow PTPN12 to dephosphorylate WAS. Has the potential to physically couple CD2 and CD2AP to WAS. Acts downstream of CD2 and CD2AP to recruit WAS to the T-cell:APC contact site so as to promote the actin polymerization required for synapse induction during T-cell activation (By similarity). Down-regulates CD2-stimulated adhesion through the coupling of PTPN12 to CD2. Also has a role in innate immunity and the inflammatory response. Recruited to inflammasomes by MEFV. Induces formation of pyroptosomes, large supramolecular structures composed of oligomerized PYCARD dimers which form prior to inflammatory apoptosis. Binding to MEFV allows MEFV to bind to PYCARD and facilitates pyroptosome formation. Regulates endocytosis and cell migration in neutrophils.
The F-BAR domain is important for filament formation. The SH3 domain is not required for filament formation or localization to the uropod.
According to PubMed:11992404, the transcription of XAGE1A is regulated by methylation of the CpG island in the promoter, and four alternative RNA splicing variants, XAGE-1a, b, c have been identified.
In normal tissues, highly expressed in testis. Expressed also in many different types of cancers: highly expressed in breast cancer, prostate cancer and many types of lung cancers, including squamous cell carcinoma, small cell carcinoma, non-small cell carcinoma, and adenocarcinoma, as well as in Ewing's cell lines, in some Ewing's sarcoma patient samples, and in one of one alveolar rhabdomyosarcoma patient sample.
PubMed:17335148, examines the translation products of theses four XAGE1A transcripts, and finds that the XAGE-1c transcript is possibly translated to 9- and 17-aa polypeptides and not to a protein consisting of 160 amino acids as shown in PubMed:11992404.
XAGE-1a and XAGE-1b mRNAs are produced by alternative promoter usage. However, for both isoforms, the translation initiator codon remains the same, generating an identical protein. XAGE-1b is the predominant transcript, compared to XAGE-1a.
Belongs to the HAD-like hydrolase superfamily. CbbY/CbbZ/Gph/YieH family.
Dephosphorylates pseudouridine 5'-phosphate, a potential intermediate in rRNA degradation. Pseudouridine is then excreted intact in urine.
Inhibited by low concentrations of calcium.
Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation.
Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin. Facilitates and stabilizes the interaction between dynein and dynactin and activates dynein processivity (the ability to move along a microtubule for a long distance without falling off the track) (PubMed:25814576). Facilitates the binding of RAB6A to the Golgi by stabilizing its GTP-bound form. Regulates coat complex coatomer protein I (COPI)-independent Golgi-endoplasmic reticulum transport via its interaction with RAB6A and recruitment of the dynein-dynactin motor complex (PubMed:25962623). Contributes to nuclear and centrosomal positioning prior to mitotic entry through regulation of both dynein and kinesin-1. During G2 phase of the cell cycle, associates with RANBP2 at the nuclear pores and recruits dynein and dynactin to the nuclear envelope to ensure proper positioning of the nucleus relative to centrosomes prior to the onset of mitosis (By similarity).
Part of a tripartite complex with dynein and dynactin, acts an adapter linking the dynein motor complex and dynactin (PubMed:25814576). Interacts with CPNE4 (via VWFA domain) (By similarity). Interacts with RAB6A (PubMed:23664119). Interacts with NEK9 (PubMed:11864968). Interacts with DNAI1 (PubMed:23664119, PubMed:23664120). Interacts with DYNC1H1 (PubMed:25512093). Interacts with RANBP2 (PubMed:20386726). Binds preferentially to tyrosinated microtubules than to detyrosinated microtubules. Interacts with DYNLL1, DYNC1I2; DCTN1, DCTN2 and KIF5A (By similarity). Interacts with KIF1C (PubMed:24482476).
The fourth coiled coil region is involved in Golgi targeting and in the interaction with DCTN2.
Co-chaperone that facilitates HSP-mediated activation of TSSK6.
Expressed in testis but is absent from mature sperm.
Interacts with HSP70. Associates with HSP90. Interacts with TSSK6; this interaction is direct and recruits TSACC to HSP90.
Belongs to the beta-2-microglobulin family.
Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system. Exogenously applied M.tuberculosis EsxA or EsxA-EsxB (or EsxA expressed in host) binds B2M and decreases its export to the cell surface (total protein levels do not change), probably leading to defects in class I antigen presentation (PubMed:25356553).
Glycation of Ile-21 is observed in long-term hemodialysis patients.
Heterodimer of an alpha chain and a beta chain. Beta-2-microglobulin is the beta-chain of major histocompatibility complex class I molecules. Polymers of beta 2-microglobulin can be found in tissues from patients on long-term hemodialysis. B2M alone (not in complex with HLA-I) interacts with M.tuberculosis EsxA (ESAT-6) and an EsxA-EsxB (CFP-10) complex; the tripartite complex can be detected in the host endoplasmic reticulum (PubMed:25356553). The B2M-EsxA complex can be detected in patients with pleural tuberculosis and is stable from pH 4.0 to 8.0 and in the presence of 2M NaCl (PubMed:25356553). Forms a heterotrimer with HLA-E and a self- or a foreign peptide (PubMed:9427624). Forms a heterotrimer with HLA-G and a self-peptide (PubMed:17056715). Forms a heterotrimer with HLA-F and a self-peptide (PubMed:10605026). Forms a heterotrimer with MR1 and a metabolite antigen.
The disease is caused by variants affecting the gene represented in this entry. Apart from the presence of causative mutations, beta-2-microglobulin may adopt the fibrillar configuration of amyloid when its serum levels are persistently high. High beta(2)-microglobulin serum levels result in amyloidosis in patients on long-term hemodialysis (PubMed:7918443). In contrast to patients with dialysis-related amyloidosis, patients with hereditary amyloidosis have normal circulating concentrations of beta2-microglobulin (PubMed:22693999).
Binds up to 3 Ca(2+) cations per subunit.
Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.
Involved in communication between the T-tubular and junctional sarcoplasmic reticulum (SR) membranes.
Detected in colon, heart, kidney, liver, lung, mammary gland, ovary, spleen and testis (PubMed:17562706). Expressed in melanocytes (at protein level) (PubMed:34310951).
Homodimer. Interacts (via ITIM motif) with PTPN6 (PubMed:17562706). Interacts (via ITIM motif) with PTPN11; this interaction triggers dephosphorylation and activation of PTPN11 (PubMed:17562706, PubMed:34310951).
Inhibitory receptor postulated to negatively regulate immune and non-immune functions (PubMed:17562706, PubMed:34310951). Upon phosphorylation, recruits SH2 domain-containing PTPN6 and PTPN11 phosphatases to its ITIM motif and antagonizes activation signals (PubMed:17562706, PubMed:34310951). Although it inhibits KLRK1/NKG2D-mediated signaling, it does not bind known ligands of KLRK1/NKG2D and therefore is not its inhibitory counterpart (PubMed:17562706). May limit activation of myeloid cell subsets in response to infection or tissue inflammation (PubMed:17562706). May protect target cells against natural killer cell-mediated lysis (PubMed:17562706). May negatively regulate cell cycle and differentiation of melanocytes via inactivation of STAT3 (PubMed:34310951).
Up-regulated upon differentiation of monocytes to macrophages.
Belongs to the histone deacetylase family. HD type 1 subfamily.
Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:10748112, PubMed:10922473, PubMed:10926844, PubMed:14701748, PubMed:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:10748112, PubMed:10922473, PubMed:10926844, PubMed:14701748). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:10748112, PubMed:10922473, PubMed:10926844, PubMed:14701748). Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin (PubMed:22885700). May play a role in smooth muscle cell contractility (PubMed:15772115). In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones (PubMed:28497810).
Interacts with PEPB2-MYH11, a fusion protein consisting of the 165 N-terminal residues of CBF-beta (PEPB2) with the tail region of MYH11 produced by the inversion Inv(16)(p13q22), a translocation associated with acute myeloid leukemia of M4EO subtype (PubMed:12509458). The PEPB2-MYH1 fusion protein also interacts with RUNX1, a well known transcriptional regulator, suggesting that the interaction with HDAC8 may participate in the conversion of RUNX1 into a constitutive transcriptional repressor (PubMed:12509458). Interacts with CBFA2T3 (PubMed:11533236). Interacts with phosphorylated SMG5/EST1B; this interaction protects SMG5 from ubiquitin-mediated degradation (PubMed:16809764). Associates with alpha-SMA (smooth muscle alpha-actin) (PubMed:15772115).
Its activity is inhibited by trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), 3-(1-methyl-4-phenylacetyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide (APHA), 4-dimethylamino-N-(6-hydroxycarbamoyethyl)benzamide-N-hydroxy-7-(4-dimethylaminobenzoyl)aminoheptanamide (MS-344), 5-(4-methyl-benzoylamino)-biphenyl-3,4'-dicarboxylic acid 3-dimethylamide 4'-hydroxyamide (CRA-A) and butyrate.
Phosphorylated by PKA on serine 39. Phosphorylation reduces deacetylase activity observed preferentially on histones H3 and H4.
Weakly expressed in most tissues. Expressed at higher level in heart, brain, kidney and pancreas and also in liver, lung, placenta, prostate and kidney.
Binds directly to helix 1 of the histone fold of histone H4, a region that is not accessible when H4 is in chromatin (PubMed:18571423, PubMed:9427644). Subunit of the type B histone acetyltransferase (HAT) complex, composed of RBBP7 and HAT1 (PubMed:9427644). Subunit of the core histone deacetylase (HDAC) complex, which is composed of HDAC1, HDAC2, RBBP4 and RBBP7. The core HDAC complex associates with SIN3A, ARID4B/SAP180, SAP18, SAP30, SAP130, SUDS3/SAP45 and possibly ARID4A/RBP1 and ING1 to form the SIN3 HDAC complex (PubMed:11118440, PubMed:11784859, PubMed:9150135, PubMed:9651585). Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5 (PubMed:33283408, PubMed:10444591, PubMed:11102443, PubMed:9790534, PubMed:28977666, PubMed:16428440). The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes (PubMed:33283408, PubMed:16428440, PubMed:28977666). The NuRD complex may interact with MBD3L1 (PubMed:15456747). The NuRD complex may interact with MBD3L2 (PubMed:15701600). Subunit of the PRC2/EED-EZH2 complex, which is composed of at least EED, EZH2, RBBP4, RBBP7 and SUZ12 (PubMed:12435631). The PRC2/EED-EZH2 complex may also associate with HDAC1 (PubMed:12435631). Component of the NURF-1 ISWI chromatin remodeling complex (also called the nucleosome-remodeling factor (NURF) complex) at least composed of SMARCA1 (isoform 2), BPTF, RBBP4 and RBBP7 (PubMed:14609955, PubMed:15310751). Within the complex interacts with isoform 2 of SMARCA1 (PubMed:14609955, PubMed:15310751). Component of the BPFT-SMARCA1 complex at least composed of SMARCA1 (isoform 1), BPFT, RBBP4 and RBBP7; the complex is catalytically inactive and does not remodel chromatin (PubMed:15310751). Within the complex interacts with isoform 1 of SMARCA1 (PubMed:15310751). Interacts with BRCA1 (PubMed:10220405). Interacts with CDK2AP1 (PubMed:20523938). Interacts with CENPA (PubMed:25556658). Interacts with CHD3 (PubMed:28977666). Interacts with CHD4 (PubMed:28977666). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP (PubMed:10866654). Interacts with HDAC7 (By similarity). Interacts with MTA1 (PubMed:12920132). Interacts with PWWP2B (By similarity). Interacts with RB1 (via viral protein-binding domain) (PubMed:7503932, PubMed:10220405). Interacts with SUV39H1 (By similarity).
Core histone-binding subunit that may target chromatin remodeling factors, histone acetyltransferases and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the type B histone acetyltransferase (HAT) complex, which is required for chromatin assembly following DNA replication; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; and the PRC2/EED-EZH2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex.
Expressed in cultured endothelial cells and in placenta.
Hydrolyzes bioactive fatty-acid esters of hydroxy-fatty acids (FAHFAs), but not other major classes of lipids (PubMed:27018888). Show a preference for FAHFAs with branching distal from the carboxylate head group of the lipids (PubMed:27018888). Regulates the expression and the cell-associated anticoagulant activity of the inhibitor TFPI in endothelial cells (in vitro) (PubMed:21868574).
Inhibited by N-hydroxyhydantoin carbamate JJH260 and beta-lactone KC01.
Belongs to the universal ribosomal protein uL1 family. Highly divergent.
Down-regulated during cellular senescence.
Expressed at high intensities in the heart, skeletal muscle, and placenta.
Interacts with ING1 (isoform 2). Interacts with KPNA7 and KPNA2 (PubMed:36647821).
Regulates cellular senescence through inhibition of PTEN translation. Acts as a pro-apoptotic regulator in response to DNA damage.
Belongs to the dynein light chain LC1-type family.
Expressed in tissues carrying motile cilia such as respiratory epithelia, ependyma and testis.
Interacts with ZMYND10 (via C-terminus) (PubMed:29601588). Interacts with DNAH5, a outer arm dynein heavy chain (PubMed:15845866, PubMed:21496787). Interacts with tubulin located within the A-tubule of the outer doublets in a ATP-independent manner (PubMed:21496787).
Outer (ODAs) and inner (IDAs) dynein arms contain the molecular motors that generate the force to move cilia by ATP-dependent reactions. There are two mechanosensory systems that monitor and respond to the mechanical state (curvature) of the axoneme. One system involves the central pair microtubule complex and radial spokes and the second system involves the outer dynein arms.
Part of the multisubunit axonemal ATPase complexes that generate the force for cilia motility and govern beat frequency (By similarity). Component of the outer arm dynein (ODA). May be involved in a mechanosensory feedback mechanism controlling ODA activity based on external conformational cues by tethering the outer arm dynein heavy chain (DNAH5) to the microtubule within the axoneme (By similarity). Important for ciliary function in the airways and for the function of the cilia that produce the nodal flow essential for the determination of the left-right asymmetry (PubMed:21496787).
Acts as a suppressor of ciliogenesis, specifically, the initiation of ciliogenesis.
Mainly expressed in trachea and testis. Not detected in bone marrow, bladder, leukocytes. Only weakly detected in tongue, stomach, brain and ovaries.
Expressed in osteogenic cells particularly during phases of active bone remodeling. In adult trabecular bone, expressed in osteocytes and flattened bone-lining cells (inactive osteoblasts).
Following secretion this protein is inactivated by cleavage into a N-terminal fragment and a C-terminal fragment. The processing is effected by proprotein convertases.
Interacts with FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:16597617). Affinity between fibroblast growth factors (FGFs) and their receptors is increased by KL and heparan sulfate glycosaminoglycans that function as coreceptors (By similarity).
O-glycosylated at Thr-171 and Thr-178 by GALNT3 and glycosylation of Thr-178 requires previous glycosylation at Thr171. Glycosylation is necessary for secretion; it blocks processing by proprotein convertases when the O-glycan is alpha 2,6-sialylated. Competition between proprotein convertase cleavage and block of cleavage by O-glycosylation determines the level of secreted active FGF23.
Phosphorylation at Ser-180 mediated by FAM20C slows down glycosylation at Thr-178 notably.
Regulator of phosphate homeostasis (PubMed:11062477). Inhibits renal tubular phosphate transport by reducing SLC34A1 levels (PubMed:11409890). Up-regulates EGR1 expression in the presence of KL (By similarity). Acts directly on the parathyroid to decrease PTH secretion (By similarity). Regulator of vitamin-D metabolism (PubMed:15040831). Negatively regulates osteoblast differentiation and matrix mineralization (PubMed:18282132).
Heterodimer with GPN1 (PubMed:21768307). Binds to RNA polymerase II (RNAPII) (PubMed:20864038, PubMed:21768307). Interacts directly with subunits RPB4 and RPB7 and the CTD of RPB1 (PubMed:21768307).
Small GTPase required for proper localization of RNA polymerase II (RNAPII). May act at an RNAP assembly step prior to nuclear import.
Adapter protein involved in asymmetrical cell division and cell polarization processes. Probably involved in the formation of epithelial tight junctions. Association with PARD3 may prevent the interaction of PARD3 with F11R/JAM1, thereby preventing tight junction assembly. The PARD6-PARD3 complex links GTP-bound Rho small GTPases to atypical protein kinase C proteins (PubMed:10873802). Regulates centrosome organization and function. Essential for the centrosomal recruitment of key proteins that control centrosomal microtubule organization (PubMed:20719959).
Expressed in pancreas, skeletal muscle, brain and heart. Weakly expressed in kidney and placenta.
Interacts with MAP2K5 (By similarity). Interacts with PARD3. Interacts with GTP-bound forms of CDC42, RHOQ/TC10 and RAC1. Interacts with the N-terminal part of PRKCI and PRKCZ. Part of a complex with PARD3, CDC42 or RAC1 and PRKCI or PRKCZ. Part of a complex with LLGL1 and PRKCI (By similarity). Interacts with human T-cell leukemia virus type I TAX protein. Interacts with PALS1 and CRB3. Interacts with TGFBR1; involved in TGF-beta induced epithelial to mesenchymal transition. Interacts with ECT2 ('Thr-359' phosphorylated form) and PRKCI. Interacts with DCTN1 and PCM1 (PubMed:20719959).
Phosphorylated by the TGF-beta receptor.
The PB1 domain mediates interactions with MAP2K5.
The PDZ domain mediates the interaction with CRB3.
Interacts with MTNR1B (PubMed:28827538). Interacts with ARRB1 and ARRB2 in a spontaneous and agonist-independent manner; leading to the internalization of GPR135 in the endosomal compartment (PubMed:28827538).
Orphan receptor. Has spontaneous activity for beta-arrestin recruitment (PubMed:28827538). Shows a reciprocal regulatory interaction with the melatonin receptor MTNR1B most likely through receptor heteromerization (PubMed:28827538).
(Microbial infection) By human cytomegalovirus infection.
(Microbial infection) Required for the efficient production of infectious virion during human cytomegalovirus infection. Mechanistically, participates in the formation of the cytoplasmic viral assembly compartment where tegument acquisition and envelopment occur.
Mediates endoplasmic reticulum to Golgi transport. Together with p115/USO1 and GM130/GOLGA2, involved in vesicle tethering and fusion at the cis-Golgi membrane to maintain the stacked and inter-connected structure of the Golgi apparatus.
Part of a ternary complex containing STX5A, NSFL1C and VCP (By similarity). Identified in a unique SNARE complex composed of the Golgi SNAREs GOSR1, GOSR2, YKT6 and VTI1A (By similarity). Interacts with COG4 (PubMed:19536132). Interacts with GM130/GOLGA2 (By similarity). Interacts (via IxM motif) with SEC24C and SEC24D; mediates STX5 packaging into COPII-coated vesicles (PubMed:18843296). Interacts with VLDLR; this interaction mediates VLDLR translocation from the endoplasmic reticulum to the plasma membrane (PubMed:23701949).
Produced by alternative initiation at Met-55 of isoform 1.
Produced by alternative splicing and alternative initiation.
Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2'-deoxy-N-6-hydroxylaminopurine triphosphate (dHAPTP) and xanthosine 5'-triphosphate (XTP) to their respective monophosphate derivatives. The enzyme does not distinguish between the deoxy- and ribose forms. Probably excludes non-canonical purines from RNA and DNA precursor pools, thus preventing their incorporation into RNA and DNA and avoiding chromosomal lesions.
The disease is caused by variants affecting the gene represented in this entry. Three different human populations have been reported with respect to their ITPase activity: high, mean (25% of high) and low activity. The variant Thr-32 is associated with complete loss of enzyme activity, may be by altering the local secondary structure of the protein. Heterozygotes for this polymorphism have 22.5% of the control activity: this is consistent with a dimeric structure of the enzyme.
Ubiquitous. Highly expressed in heart, liver, sex glands, thyroid and adrenal gland.
Belongs to the potassium channel family. V (TC 1.A.1.2) subfamily. Kv8.1/KCNV1 sub-subfamily.
Heteromultimer with KCNB1 and KCNB2. Interacts with KCNC4 and KCND1.
Potassium channel subunit that does not form functional channels by itself. Modulates KCNB1 and KCNB2 channel activity by shifting the threshold for inactivation to more negative values and by slowing the rate of inactivation. Can down-regulate the channel activity of KCNB1, KCNB2, KCNC4 and KCND1, possibly by trapping them in intracellular membranes.
A chromosomal aberration involving OLIG2 may be a cause of a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(14;21)(q11.2;q22) with TCRA.
By SHH. Also induced by NKX6-1 in the developing spinal cord, but not in the rostral hindbrain (By similarity).
Expressed in the brain, in oligodendrocytes. Strongly expressed in oligodendrogliomas, while expression is weak to moderate in astrocytomas. Expression in glioblastomas highly variable.
Interacts with NKX2-2. Interacts with ZNF488.
Required for oligodendrocyte and motor neuron specification in the spinal cord, as well as for the development of somatic motor neurons in the hindbrain. Functions together with ZNF488 to promote oligodendrocyte differentiation. Cooperates with OLIG1 to establish the pMN domain of the embryonic neural tube. Antagonist of V2 interneuron and of NKX2-2-induced V3 interneuron development.
The bHLH is essential for interaction with NKX2-2.
Found only in very low concentrations in the endoplasmic reticulum, Golgi apparatus and endoplasmic reticulum-Golgi intermediate compartment compared to other members of the EMP24/GP25L family.
Homodimer in endoplasmic reticulum, endoplasmic reticulum-Golgi intermediate compartment and cis-Golgi network. Interacts with IL1RL1 (PubMed:23319592). Interacts with RNF26; this interaction is important to modulate innate immune signaling through the cGAS-STING pathway (PubMed:32614325).
Potential role in vesicular protein trafficking, mainly in the early secretory pathway. May act as a cargo receptor at the lumenal side for incorporation of secretory cargo molecules into transport vesicles and may be involved in vesicle coat formation at the cytoplasmic side. Plays a positive role in IL-33-mediated IL-8 and IL-6 production by interacting with interleukin-33 receptor IL1RL1 (PubMed:23319592). Also plays a role in the modulation of innate immune signaling through the cGAS-STING pathway by interacting with RNF26 (PubMed:32614325).
Highly expressed in thymus, uterus and testis (PubMed:11591158). Detected at lower levels in brain, mammary gland, prostate, salivary gland and fetal spleen (PubMed:11591158). In brain, highest expression in thalamus, hippocampus and amygdala (PubMed:11591158).
Uniporter that mediates the uptake of cationic L-amino acids such as L-arginine, L-lysine and L-ornithine (PubMed:11591158). The transport is sodium ions- and pH-independent, moderately trans-stimulated and is mediated by passive diffusion (PubMed:11591158).
Acts as a transcriptional coactivator for AR-mediated transactivation function. May act as a transcriptional regulator during spermatogenesis and, in particular, during meiotic division.
Acts as a transcriptional corepressor for AR-mediated transactivation function. May act as a transcriptional regulator during spermatogenesis and, in particular, during meiotic division.
Contaminating sequence. Potential poly-A sequence starting in position 1214.
Homodimer. Heterodimer of isoform 1 and isoform 2. Isoform 1 and isoform 2 interact with AR.
Enriched in colonic mucosa. The expression of A4 follows a gradient along the crypto-villus axis with the most abundant message occurring in the lower half of the crypt.
May play a role in cell differentiation in the intestinal epithelium.
Specifically expressed in the CNS and endocrine tissues. Also detected in other tissues including heart, testis and prostate.
Interacts with GABA(A) receptor subunits (PubMed:28978485). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3 (By similarity). Interacts with GABRB3 (By similarity). Interacts with GABRA2 (By similarity). Interacts with GABRG2 (By similarity). Interacts with GABRA1 (PubMed:28978485). Interacts with NLGN2; leading to mutual regulation of protein level and synaptic clustering (By similarity).
Plays a role in the regulation of inhibitory synapse formation and function by being involved in maintening gamma-aminobutyric acid receptors (GABAARs) clustering and their associated scaffold proteins at inhibitory synaptic sites. Acts in concert with NLGN2 to recruit or stabilize GABAARs.
Cytoplasmic potassium channel subunit that modulates the characteristics of the channel-forming alpha-subunits (PubMed:7499366, PubMed:7603988, PubMed:17156368, PubMed:17540341, PubMed:19713757). Modulates action potentials via its effect on the pore-forming alpha subunits (By similarity). Promotes expression of the pore-forming alpha subunits at the cell membrane, and thereby increases channel activity (By similarity). Mediates closure of delayed rectifier potassium channels by physically obstructing the pore via its N-terminal domain and increases the speed of channel closure for other family members (PubMed:9763623). Promotes the closure of KCNA1, KCNA2 and KCNA5 channels (PubMed:7499366, PubMed:7890032, PubMed:7603988, PubMed:7649300, PubMed:8938711, PubMed:12077175, PubMed:12130714, PubMed:15361858, PubMed:17540341, PubMed:19713757). Accelerates KCNA4 channel closure (PubMed:7890032, PubMed:7649300, PubMed:7890764, PubMed:9763623). Accelerates the closure of heteromeric channels formed by KCNA1 and KCNA4 (PubMed:17156368). Accelerates the closure of heteromeric channels formed by KCNA2, KCNA5 and KCNA6 (By similarity). Isoform KvB1.2 has no effect on KCNA1, KCNA2 or KCNB1 (PubMed:7890032, PubMed:7890764). Enhances KCNB1 and KCNB2 channel activity (By similarity). Binds NADPH; this is required for efficient down-regulation of potassium channel activity (PubMed:17540341). Has NADPH-dependent aldoketoreductase activity (By similarity). Oxidation of the bound NADPH strongly decreases N-type inactivation of potassium channel activity (By similarity).
Homotetramer (By similarity). Interaction with tetrameric potassium channel alpha subunits gives rise to a heterooctamer (Probable). Identified in potassium channel complexes containing KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNAB1 and KCNAB2 (By similarity). Interacts with KCNA1 (By similarity). Interacts with the dimer formed by GNB1 and GNG2; this enhances KCNA1 binding (By similarity). Interacts with KCNA4 (PubMed:9763623). Interacts with KCNA5 (PubMed:12130714). Interacts with KCNB2 (By similarity). Interacts with SQSTM1 (By similarity). Part of a complex containing KCNA1, KCNA4 and LGI1; interaction with LGI1 inhibits down-regulation of KCNA1 channel activity (By similarity).
In brain, expression is most prominent in caudate nucleus, hippocampus and thalamus. Significant expression also detected in amygdala and subthalamic nucleus. Also expressed in both healthy and cardiomyopathic heart. Up to four times more abundant in left ventricle than left atrium.
The N-terminal domain of the beta subunit mediates closure of delayed rectifier potassium channels by physically obstructing the pore.
Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits; the complex contains two deadenylase subunits, CNOT6 or CNOT6L, and CNOT7 or CNOT8. In the complex interacts directly with CNOT1. Interacts with BTG1, BTG2 and TOB1. Interacts with BTG4 (By similarity).
Has 3'-5' poly(A) exoribonuclease activity for synthetic poly(A) RNA substrate. Its function seems to be partially redundant with that of CNOT7. Catalytic component of the CCR4-NOT complex which is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. During miRNA-mediated repression the complex seems also to act as translational repressor during translational initiation. Additional complex functions may be a consequence of its influence on mRNA expression. Associates with members of the BTG family such as TOB1 and BTG2 and is required for their anti-proliferative activity.
(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) nucleoprotein; this interaction recruits EIF1AX to the viral replication complex to facilitate viral genomic RNA synthesis and virus production.
Component of the 43S pre-initiation complex (43S PIC), which binds to the mRNA cap-proximal region, scans mRNA 5'-untranslated region, and locates the initiation codon (PubMed:9732867). This protein enhances formation of the cap-proximal complex (PubMed:9732867). Together with EIF1, facilitates scanning, start codon recognition, promotion of the assembly of 48S complex at the initiation codon (43S PIC becomes 48S PIC after the start codon is reached), and dissociation of aberrant complexes (PubMed:9732867). After start codon location, together with EIF5B orients the initiator methionine-tRNA in a conformation that allows 60S ribosomal subunit joining to form the 80S initiation complex (PubMed:35732735). Is released after 80S initiation complex formation, just after GTP hydrolysis by EIF5B, and before release of EIF5B (PubMed:35732735). Its globular part is located in the A site of the 40S ribosomal subunit (PubMed:35732735). Its interaction with EIF5 during scanning contribute to the maintenance of EIF1 within the open 43S PIC (PubMed:24319994). In contrast to yeast orthologs, does not bind EIF1 (PubMed:24319994).
Component of the 43S pre-initiation complex (43S PIC), which is composed of the 40S ribosomal subunit, EIF1, eIF1A (EIF1AX), eIF3 complex, EIF5 and eIF2-GTP-initiator tRNA complex (eIF2 ternary complex). Interacts with EIF5; this interaction contributes to the maintenance of EIF1 within the open 43S PIC (PubMed:24319994). Interacts through its C-terminal domain (CTD) with the CTD of EIF5B; from the location of the start codon by the 43S complex until the formation of the 80S complex (PubMed:12569173, PubMed:30211544, PubMed:35732735).
Interacts with RAB21 (GDP-bound form), VPS29, RAB32 (GTP-bound form), RAB38 (GTP-bound form), VAMP7, KIF5A, KIF5C, GOLGA4. Interacts with low affinity with RAB5. ANKRD27:RAB32 heterodimers can homodimerize to form tetramers. Can interact with RAB38 or RAB32, VPS29 and VAMP7 simultaneously (PubMed:16525121, PubMed:18477474, PubMed:19745841, PubMed:22705394, PubMed:23104059, PubMed:24856514, PubMed:21808068). A decreased interaction with RAB32 seen in the presence of SGSM2 (PubMed:21808068).
May be a guanine exchange factor (GEF) for Rab21, Rab32 and Rab38 and regulate endosome dynamics (PubMed:16525121, PubMed:18477474). May regulate the participation of VAMP7 in membrane fusion events; in vitro inhibits VAMP7-mediated SNARE complex formation by trapping VAMP7 in a closed, fusogenically inactive conformation (PubMed:23104059). Involved in peripheral melanosomal distribution of TYRP1 in melanocytes; the function, which probably is implicating vesicle-trafficking, includes cooperation with Rab32, Rab38 and VAMP7 (By similarity). Involved in the regulation of neurite growth; the function seems to require its GEF activity, probably towards Rab21, and VAMP7 but not Rab32/38 (By similarity). Proposed to be involved in Golgi sorting of VAMP7 and transport of VAMP7 vesicles to the cell surface; the function seems to implicate kinesin heavy chain isoform 5 proteins, GOLGA4, RAB21 and MACF1 (PubMed:22705394). Required for the colocalization of VAMP7 and Rab21, probably on TGN sites (PubMed:19745841). Involved in GLUT1 endosome-to-plasma membrane trafficking; the function is dependent of association with VPS29 (PubMed:24856514). Regulates the proper trafficking of melanogenic enzymes TYR, TYRP1 and DCT/TYRP2 to melanosomes in melanocytes (By similarity).
Transfers an acyl-group from acyl-ACP to the sn-1 position of glycerol-3-phosphate producing a lysophosphatidic acid (LPA), an essential step for the triacylglycerol (TAG) and glycerophospholipids. In vitro also transfers an acyl-group from acyl-ACP to the LPA producing a phosphatidic acid (PA). Prefers arachidonoyl-CoA as the acyl donor. Required for primary processing step during piRNA biosynthesis. Molecular mechanisms by which it promotes piRNA biosynthesis are unclear and do not involve its acyltransferase activity.
Potential regulator of neural basic helix-loop-helix genes.
An autoinhibitory domain is present in the N-terminal region of the protein.
Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Interacts with MARK2, leading to inhibit MARK2 independently of kinase activity. Interacts with RHOD and RHOH.
Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates the proto-oncogene RAF1 and stimulates its kinase activity. Promotes cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Phosphorylates CTNND1, probably to regulate cytoskeletal organization and cell morphology. Keeps microtubules stable through MARK2 inhibition and destabilizes the F-actin network leading to the disappearance of stress fibers and focal adhesions.
Interacts with RAD51D. Part of the BCDX2 complex consisting of RAD51B, RAD51C, RAD51D and XRCC2; the complex has a ring-like structure arranged into a flat disk around a central channel. In the absence of DNA, the BCDX2 subcomplex XRCC2:RAD51D formed a multimeric ring structure; in the presence of single-stranded DNA it formed a filamentous structure with the ssDNA.
Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions. Part of the RAD51 paralog protein complex BCDX2 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, BCDX2 acts downstream of BRCA2 recruitment and upstream of RAD51 recruitment. BCDX2 binds predominantly to the intersection of the four duplex arms of the Holliday junction and to junction of replication forks. The BCDX2 complex was originally reported to bind single-stranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA.
A scaffold protein that connects plasma membrane proteins and regulatory components, regulating their surface expression in epithelial cells apical domains. May be involved in the coordination of a diverse range of regulatory processes for ion transport and second messenger cascades. In complex with NHERF1, may cluster proteins that are functionally dependent in a mutual fashion and modulate the trafficking and the activity of the associated membrane proteins. May play a role in the cellular mechanisms associated with multidrug resistance through its interaction with ABCC2 and PDZK1IP1. May potentiate the CFTR chloride channel activity. Required for normal cell-surface expression of SCARB1. Plays a role in maintaining normal plasma cholesterol levels via its effects on SCARB1. Plays a role in the normal localization and function of the chloride-anion exchanger SLC26A6 to the plasma membrane in the brush border of the proximal tubule of the kidney. May be involved in the regulation of proximal tubular Na(+)-dependent inorganic phosphate cotransport therefore playing an important role in tubule function (By similarity).
Expression is limited to epithelial cells. Expressed in the kidney (brush border of proximal tubule), pancreas, liver, and small intestine. Expressed at a lower level in the adrenal cortex, testis and stomach. Overexpressed in breast, renal and lung carcinomas.
Interaction with the C-terminus of CFTR could be mediated through independent binding of PDZ 1, 3 and 4 domains.
Interacts with PDZK1IP1 and ABCC2. Interacts (via PDZ domains 1 and 3) with SCARB1 (C-terminal domain). Forms a heterodimeric complex with NHERF1. Interacts with AKAP2, BCR, CFTR, SLC22A12, SLC22A4, SLC22A5, NHERF2 and SLC17A1. Component of a complex, composed of PDZK1, SYNGAP1, KLHL17 and NMDA receptors. Interacts (via PDZ1 domain) directly with KLHL17; the interaction is important for integrity of actin cytoskeleton structures in neurons. Interacts (via the first PDZ domain) with PTGIR (via non-isoprenylated C-terminus) (By similarity). Interacts (via C-terminal PDZ domain) with SLC26A6 (via C-terminal domain) (By similarity). Interacts (via C-terminal PDZ domain) with SLC9A3 (via C-terminal domain). Interacts (via PDZ domains 1 and 3) with SLC5A8 (via PDZ-binding motif); interaction increases nicotinate transport activity of SLC5A8 (PubMed:30604288).
The PDZ 1 and 3 domains seem to be involved in the interaction with SLCO1A1.
The PDZ 2 and 3 domains seem to be involved in the interaction with SLC26A3.
The PDZ 2 and 4 domains do not interact with the C-terminal region of SCARB1.
Assembles a suppression complex (suppresome) by tethering SIRT1 and MDM2 to regulate composite modifications of p53/TP53. Confers both deacetylation-mediated functional inactivation, by SIRT1, and ubiquitination-dependent degradation, by MDM2, of p53/TP53, promoting a proliferative and cell survival behaviors (PubMed:29681526). May play a role in the regulation of spermatogenesis (By similarity).
Interacts with MEIG1 (By similarity). Interacts with TP53, MDM2 and SIRT1; the interactions mediate post-transcriptional modifications of TP53 by MDM2 and SIRT1 (PubMed:29681526).
(Microbial infection) Interacts with HCV non-structural protein 4B/NS4B (via C-terminal region); this interaction may promote the recruitment of NS4B in the proximity of lipid droplet.
(Microbial infection) May be involved in the assembly and release stages of hepatitis C virus (HCV) life cycle and thus play a crucial role in HCV propagation.
N(6)-adenine-methyltransferase able to methylate both DNA and long non-coding RNAs. Methylates adenosine residues at the N6 position of some long non-coding RNAs (lncRNAs) (PubMed:34980213). DNA methylation by TMT1A promote osteogenic and odontogenic differentiation by upregulating expression of genes that promote differentiation and survival (PubMed:34226523, PubMed:34790668). Recruits cellular proteins to the lipid droplet for the formation of functional organelles (PubMed:19773358). Acts also as an oncogene in multiple myeloma (PubMed:34790668).
Self-associates (PubMed:18477614). Interacts with SNRNP200; this interaction may promote the odontogenic differentiation (PubMed:34790668).
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:9830018, PubMed:23949095). Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes (Probable). Has probably no preference for any of the diacylglycerols in terms of the acyl chain composition, especially for the acyl chain at the sn-2 position (PubMed:9830018). By controlling the diacylglycerol/DAG-mediated activation of RASGRP3, negatively regulates the Rap1 signaling pathway. May play a role in presynaptic diacylglycerol/DAG signaling and control neurotransmitter release during metabotropic glutamate receptor-dependent long-term depression (By similarity).
Interacts (via PDZ-binding motif) with DLG4; controls the localization of DGKI to the synapse (PubMed:21119615). Interacts (via PDZ-binding motif) with DLG1 (By similarity). Interacts (via PDZ-binding motif) with DLG2 (By similarity). Interacts (via PDZ-binding motif) with DLG3 (By similarity). May interact with RASGRP3; involved in the regulation of RASGRP3 activity (By similarity).
Specifically expressed in brain and retina (PubMed:9830018). In brain, highly expressed in hippocampus, caudate nucleus, occipital pole, cerebral cortex, and cerebellum (PubMed:9830018). Also detected in kidney (PubMed:15894621).
Chromatin binding factor that binds to DNA sequence specific sites. Involved in transcriptional regulation by binding to chromatin insulators and preventing interaction between promoter and nearby enhancers and silencers. Acts as transcriptional repressor binding to promoters of vertebrate MYC gene and BAG1 gene. Also binds to the PLK and PIM1 promoters. Acts as a transcriptional activator of APP. Regulates APOA1/C3/A4/A5 gene cluster and controls MHC class II gene expression. Plays an essential role in oocyte and preimplantation embryo development by activating or repressing transcription. Seems to act as tumor suppressor. Plays a critical role in the epigenetic regulation. Participates in the allele-specific gene expression at the imprinted IGF2/H19 gene locus. On the maternal allele, binding within the H19 imprinting control region (ICR) mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to IGF2. Plays a critical role in gene silencing over considerable distances in the genome. Preferentially interacts with unmethylated DNA, preventing spreading of CpG methylation and maintaining methylation-free zones. Inversely, binding to target sites is prevented by CpG methylation. Plays an important role in chromatin remodeling. Can dimerize when it is bound to different DNA sequences, mediating long-range chromatin looping. Mediates interchromosomal association between IGF2/H19 and WSB1/NF1 and may direct distant DNA segments to a common transcription factory. Causes local loss of histone acetylation and gain of histone methylation in the beta-globin locus, without affecting transcription. When bound to chromatin, it provides an anchor point for nucleosomes positioning. Seems to be essential for homologous X-chromosome pairing. May participate with Tsix in establishing a regulatable epigenetic switch for X chromosome inactivation. May play a role in preventing the propagation of stable methylation at the escape genes from X- inactivation. Involved in sister chromatid cohesion. Associates with both centromeres and chromosomal arms during metaphase and required for cohesin localization to CTCF sites. Regulates asynchronous replication of IGF2/H19. Plays a role in the recruitment of CENPE to the pericentromeric/centromeric regions of the chromosome during mitosis (PubMed:26321640).
Interacts with CHD8 (PubMed:16949368). Interacts with LLPH (By similarity). Interacts with CENPE (PubMed:26321640).
More than 13'00 CTCF-binding sites in potential insulators were identified in the human genome.
Sumoylated on Lys-74 and Lys-689; sumoylation of CTCF contributes to the repressive function of CTCF on the MYC P2 promoter.
The 11 zinc fingers are highly conserved among vertebrates, exhibiting almost identical amino acid sequences. Different subsets or combination of individual zinc fingers gives the ability to CTCF to recognize multiple DNA target sites.
Ubiquitous. Absent in primary spermatocytes.
At Carnagie stage 13 (CS13, after 4 weeks of development) and CS14 CC2D2A is ubiquitously expressed, with a distinct signal in the spinal cord and limb buds. At CS17 CC2D2A continue to be widely expressedin particular throughout the central nervous system (CNS), lung, and digestive tract epithelia. At CS22 expression continues to be intense within the CNS, where strong and specific expression is observed in the eye and in external granular layer of cerebellum. CC2D2A expression is also observed in the costal perichondrium.
Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Required for ciliogenesis and sonic hedgehog/SHH signaling (By similarity).
Strongly expressed in prostate, pancreas, kidney, lung, liver, retina, kidney, fetal brain and fetal kidney. Lower expression in spleen, small intestine, colon, skeletal muscle, ovary, thymus and heart.
Major component of the transverse filaments of synaptonemal complexes, formed between homologous chromosomes during meiotic prophase. Required for normal assembly of the central element of the synaptonemal complexes. Required for normal centromere pairing during meiosis. Required for normal meiotic chromosome synapsis during oocyte and spermatocyte development and for normal male and female fertility.
Structural component of synaptonemal complexes (By similarity). Homotetramer that consists of an N-terminal four-helical bundle that bifurcates into two elongated C-terminal dimeric coiled coils (PubMed:29915389, PubMed:26323297). This tetrameric building block potentially self-assembles into a supramolecular zipper-like lattice to mediate meiotic chromosome synapsis. Self-assembly is likely initiated by local proton density at chromosome axis, which is predicted to trigger antiparallel back to back assembly of adjacent C-terminal ends into tetrameric structures that anchor to chromosomal DNA. Then the N-terminal ends are predicted to undergo cooperative antiparallel head to head assembly at the midline of synaptonemal complexes central element to form a zipper-like lattice between properly aligned homologous chromosomes (PubMed:29915389). The nascent synapsis generated by SYCP1 is stabilized through interaction with central element proteins SYCE1 and SYCE2 (By similarity). Forms a complex with EWSR1, PRDM9, SYCP3 and REC8; complex formation is dependent of phosphorylated form of REC8 and requires PRDM9 bound to hotspot DNA; EWSR1 joins PRDM9 with the chromosomal axis through REC8 (By similarity). Interacts with SPO16 (By similarity).
The molecule is in a coiled coil structure that is formed by 4 polypeptide chains. The N-terminal and C-terminal regions exhibit a prominent seven-residues periodicity.
Found in ovarian granulosa cells, testis, prostate and seminal vesicle tissue. High levels also detected in liver.
May be a signaling adapter molecule involved in NGFR/p75NTR-mediated apoptosis induced by NGF. Plays a role in zinc-triggered neuronal death. In absence of reductive stress, acts as a pseudosubstrate for the CRL2(FEM1B) complex: associates with FEM1B via zinc, thereby preventing association between FEM1B and its substrates.
Self-associates. Binds to the DEATH domain of p75NTR/NGFR. Interacts with 14-3-3 epsilon (YWHAE). Interacts with DIABLO/SMAC.
The histidine cluster (His cluster) and Cys-108 mediate zinc-binding.
The nuclear export signal is required for export from the nucleus and the interactions with itself and NGFR/p75NTR.
Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate.
Overexpressed in several esophageal squamous cell carcinomas (ESCs).
Golgi ceramidase that catalyzes the hydrolysis of ceramides into sphingoid bases like sphingosine and free fatty acids at alkaline pH (PubMed:16940153, PubMed:18945876, PubMed:20207939, PubMed:20089856). Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation (PubMed:20207939). Has a better catalytic efficiency towards unsaturated long-chain ceramides, including C18:1-, C20:1- and C24:1-ceramides (PubMed:16940153, PubMed:18945876, PubMed:20207939, PubMed:20089856). Saturated long-chain ceramides and unsaturated very long-chain ceramides are also good substrates, whereas saturated very long-chain ceramides and short-chain ceramides are poor substrates (PubMed:20089856). Also hydrolyzes dihydroceramides to produce dihydrosphingosine (PubMed:20207939, PubMed:20628055). It is the ceramidase that controls the levels of circulating sphingosine-1-phosphate and dihydrosphingosine-1-phosphate in plasma through their production by hematopoietic cells (By similarity). Regulates cell proliferation, autophagy and apoptosis by the production of sphingosine and sphingosine-1-phosphate (PubMed:16940153, PubMed:26943039, PubMed:28294157, PubMed:29229990). As part of a p53/TP53-dependent pathway, promotes for instance autophagy and apoptosis in response to DNA damage (PubMed:26943039, PubMed:28294157, PubMed:29229990). Through the production of sphingosine, may also regulate the function of the Golgi complex and regulate the glycosylation of proteins (PubMed:18945876).
Specifically activated by lumenal, but not cytosolic Ca(2+). Inhibited by Zn(2+) or Cu(2+). Mg(2+) or Mn(2+) have no effect on ceramidase activity (PubMed:20089856). Inhibited by De-MAPP (PubMed:20207939).
Up-regulated upon serum deprivation (PubMed:16940153). Up-regulated by N-(4-hydroxyphenyl)retinamode/4-HPR (PubMed:20628055). Up-regulated upon DNA damage, in a p53/TP53-dependent manner, resulting in increased levels of sphingosine and sphingosine-1-phosphate (at protein level) (PubMed:26943039, PubMed:28294157, PubMed:29229990).
Could be the product of a pseudogene. The intronless gene encoding this protein has arisen by SVA-mediated retrotransposition of the SLC35G6 gene in the primate lineage. There is no evidence for transcription (PubMed:17101974).
Belongs to the Mediator complex subunit 27 family.
Essential for the generation of mature 18S rRNA, specifically necessary for cleavages at sites A0, 1 and 2 of the 47S precursor. Directly interacts with U3 snoRNA.
Interacts with NF-kappa-B p50/NFKB1 and NF-kappa-B p65/RELA.
Transcription factor essential for neural and some non-neural tissues development, such as retina and lung respectively. Binds to an 11-bp consensus sequence containing the invariant tetranucleotide 5'-ACGC-3'. During development of the central nervous system, is required to specify the amacrine and horizontal cell fates from multipotent retinal progenitors while suppressing the alternative photoreceptor cell fates through activating DLL4-NOTCH signaling. Also acts synergistically with ASCL1/MASH1 to activate DLL4-NOTCH signaling and drive commitment of p2 progenitors to the V2b interneuron fates during spinal cord neurogenesis. In development of non-neural tissues, plays an essential role in the specification of the atrioventricular canal and is indirectly required for patterning the distal airway during lung development (By similarity).
Catalyzes the oxidative decarboxylation of (S)-malate to pyruvate using NADP(+) as a cofactor (PubMed:7818469). Can also reverse the decarboxylation reaction, but only with significantly lower efficiency (PubMed:7818469).
Expressed predominantly in organs with a low-division rate.
Probable mitochondrial acylpyruvase which is able to hydrolyze acetylpyruvate and fumarylpyruvate in vitro (PubMed:15551868, PubMed:21878618). Also has oxaloacetate decarboxylase activity (PubMed:25575590).
Interacts with CIB1; the interaction is direct. Interacts with the chaperone BIP/HSPA5 (PubMed:30224801). Interacts with RIGI (PubMed:36793726).
Interferon-stimulated protein that plays an important role in innate immune response against a wide variety of viruses (PubMed:31142663). Inhibits flavivirus replication by preventing the formation of virus-induced endoplasmic reticulum membrane invaginations, which are double-membrane vesicles that flaviviruses use for their replication (PubMed:30224801). Has an antiviral activity towards hepatitis C virus/HCV by inhibiting the EGFR signaling pathway, whose activation is required for entry of the virus into cells (PubMed:25757571). Within the nucleus, restricts hepatitis B virus/HBV promoter activity leading to substantial reduction of viral replication and gene expression (PubMed:33868257). Plays a role in apoptosis, negatively regulating the intrinsinc apoptotic signaling pathway and TNFSF10-induced apoptosis (PubMed:15685448, PubMed:17823654, PubMed:26244642). However, it has also been shown to have a pro-apoptotic activity (PubMed:27673746). Modulates innate immune response mediated by RIGI by preventing its activation (PubMed:36793726).
Up-regulated by type-I interferon (PubMed:14728724, PubMed:17823654, PubMed:33868257). Up-regulated upon Dengue virus type 2/DENV2 infection (at protein level) (PubMed:26244642).
Acyl-CoA dehydrogenase only active with R- and S-2-methyl-C15-CoA.
Widely expressed with highest expression in fetal brain, followed by heart, muscle, kidney and adult brain. Expression levels varying from isoform to isoform.
Phosphorylation of the protein kinase-like domain is required for full activation by ANP.
Receptor for the atrial natriuretic peptide NPPA/ANP and the brain natriuretic peptide NPPB/BNP which are potent vasoactive hormones playing a key role in cardiovascular homeostasis. Has guanylate cyclase activity upon binding of the ligand.
Transcriptional factor that defines subclasses of motoneurons that segregate into columns in the spinal cord and select distinct axon pathways.
Found in the epidermis and esophageal epithelium.
Interacts with EGF (By similarity). Interacts (via cytoplasmic N-terminus) with FRMD8/iTAP; this interaction leads to mutual protein stabilization (PubMed:29897333, PubMed:29897336). Interacts with ADAM17/TACE (PubMed:29897333, PubMed:29897336).
Antagonizes the transcription repression by isoform 1 by competing for the binding of the NuRD complex. Does not bind DNA.
Interacts with CHD4/Mi-2; the interaction is direct.
Transcription repressor that specifically binds the 5'-GGAG[GA]A[GA]A-3' consensus sequence. Represses transcription by recruiting the chromatin multiprotein complex NuRD to target promoters. Negatively regulates expression of EGFR, a gene involved in cell proliferation, survival and migration. Its ability to repress genes of the EGFR pathway suggest it may act as a tumor suppressor. Able to suppress breast carcinogenesis.
Ubiquitinated in case of infection by HIV-1, leading to its degradation. Ubiquitination is mediated by the CUL4A-RBX1-DDB1-DCAF1/VPRBP complex that is hijacked by HIV-1 via interaction between HIV-1 Vpr and DCAF1/VPRBP.
Belongs to the GMC oxidoreductase family.
Belongs to the UTP23/FCF1 family. FCF1 subfamily.
Belongs to the MMS22 family. MMS22L subfamily.
Component of the MMS22L-TONSL complex, a complex at least composed of MMS22L and TONSL/NFKBIL2 (PubMed:21055983, PubMed:21055984, PubMed:21055985, PubMed:21113133, PubMed:27797818). Interacts with RAD51; interaction is direct (PubMed:27797818).
Component of the MMS22L-TONSL complex, a complex that promotes homologous recombination-mediated repair of double-strand breaks (DSBs) at stalled or collapsed replication forks (PubMed:21055983, PubMed:21055984, PubMed:21055985, PubMed:21113133, PubMed:26527279, PubMed:27338793, PubMed:29478807). The MMS22L-TONSL complex is required to maintain genome integrity during DNA replication (PubMed:21055983, PubMed:21055984, PubMed:21055985, PubMed:27797818). It mediates the assembly of RAD51 filaments on single-stranded DNA (ssDNA): the MMS22L-TONSL complex is recruited to DSBs following histone replacement by histone chaperones and eviction of the replication protein A complex (RPA/RP-A) from DSBs (PubMed:21055983, PubMed:21055984, PubMed:21055985, PubMed:29478807). Following recruitment to DSBs, the TONSL-MMS22L complex promotes recruitment of RAD51 filaments and subsequent homologous recombination (PubMed:27797818, PubMed:29478807). Within the complex, MMS22L acts by binding ssDNA (PubMed:27797818).
Degraded by the ubiquitin-proteasome system upon replication stress.
Acts as a transcriptional activator and repressor required for cardiac development and may have key roles in the maintenance of functional and structural phenotypes in adult heart.
Guanine nucleotide exchange factor for ARF6.
Isoform 2 is expressed in epididymis (at protein level).
May be involved in the trafficking and exocytosis of secretory vesicles in non-neuronal tissues.
Neither C2 domains mediates Ca(2+)-dependent or -independent phospholipid binding.
Abundantly expressed in testis and slightly in pancreas. Mainly present in the interstitial cells of testicular tissues.
Expressed at high level in placenta and pancreas. Also detected in CD11c+ immature dendritic cells. Only expressed in dendritic cells and not in other leukocytes, including monocyte precursors. TLR3 is the TLR that is expressed most strongly in the brain, especially in astrocytes, glia, and neurons.
Heavily N-glycosylated, except on that part of the surface of the ectodomain that is involved in ligand binding.
Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via the adapter TRIF/TICAM1, leading to NF-kappa-B activation, IRF3 nuclear translocation, cytokine secretion and the inflammatory response.
Monomer and homodimer; dimerization is triggered by ligand-binding, the signaling unit is composed of one ds-RNA of around 40 bp and two TLR3 molecules, and lateral clustering of signaling units along the length of the ds-RNA ligand is required for TLR3 signal transduction. Interacts (via transmembrane domain) with UNC93B1; the interaction is required for transport from the ER to the endosomes (PubMed:33432245). Interacts with SRC; upon binding of double-stranded RNA. Interacts with TICAM1 (via the TIR domain) in response to poly(I:C) and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). The tyrosine-phosphorylated form (via TIR domain) interacts with WDFY1 (via WD repeat 2) in response to poly(I:C) (PubMed:25736436).
TLR3 signaling requires a proteolytic cleavage mediated by cathepsins CTSB and CTSH, the cleavage occurs between amino acids 252 and 346. The cleaved form of TLR3 is the predominant form found in endosomes.
The Phe-412 allele (dbSNP:rs3775291) occurs with a frequency of 30% in populations with European and Asian ancestry, and confers some natural resistance to HIV-1 infection.
Ubiquitinated by TRIM3; leading to recognition and sorting of polyubiquitinated TLR3 by the ESCRT complexes (PubMed:32878999). Ubiquitinated by ZNRF1 via 'Lys-63'-linked ubiquitin chains; leading to TLR3 lysosomal trafficking and degradation (PubMed:37158982).
ds-RNA binding is mediated by LRR 1 to 3, and LRR 17 to 18.
(Microbial infection) Interacts with human cytomegalovirus protein UL38.
Ubiquitin-specific protease that regulates cell survival in various contexts through modulating the protein stability of some of its substrates including DDB2, MCL1 or TP53. Plays a positive role on ferritinophagy where ferritin is degraded in lysosomes and releases free iron.
Highly expressed in the retinal pigment epithelium (RPE) and pancreas. Weak expression in heart, liver and muscle.
Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts. They have a role in regulating cell growth and differentiation in specific cell types. SFRP5 may be involved in determining the polarity of photoreceptor, and perhaps, other cells in the retina.
Interacts via LIM domain 1 with ZYX. Interacts (via LIM domain 3) with ENAH and VASP. Interacts with ALKBH4, talin, actin, alpha-actinin, GRIP1 and PXN. Interacts (via LIM domain 2) with ACTL7A (via N-terminus). Heterodimer with ACTL7A; the heterodimer interacts with ENAH to form a heterotrimer.
Scaffold protein that may play a role in cell adhesion, cell spreading and in the reorganization of the actin cytoskeleton. Plays a role in the regulation of cell proliferation. May act as a tumor suppressor. Inhibits tumor cell growth.
The N-terminal and the C-terminal halves of the protein can associate with each other, thereby hindering interactions with ZYX.
Component of splicing factor SF3B complex which is composed of at least eight subunits; SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6, PHF5A and DDX42 (PubMed:12234937, PubMed:12738865, PubMed:16432215, PubMed:27720643, PubMed:28541300). Within the SF3B complex interacts directly with SF3B1 (PubMed:21062891, PubMed:16432215, Ref.20). The SF3B complex composed of SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6 and PHF5A interacts with U2AF2 (PubMed:27720643). Component of the minor spliceosome, which splices U12-type introns (PubMed:15146077, PubMed:33509932).
Involved in pre-mRNA splicing as a component of the splicing factor SF3B complex (PubMed:27720643). SF3B complex is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA (PubMed:12234937). Directly contacts the pre-mRNA branch site adenosine for the first catalytic step of splicing (PubMed:16432215). Enters the spliceosome and associates with the pre-mRNA branch site as part of the 17S U2 or, in the case of the minor spliceosome, as part of the 18S U11/U12 snRNP complex, and thus may facilitate the interaction of these snRNP with the branch sites of U2 and U12 respectively (PubMed:16432215).
Preferentially binds to euchromatin and modulates cellular transcription by counteracting linker histone-mediated chromatin compaction.
Specifically targeted by its C-terminus to nucleosomes in euchromatin.
Involved in the second step of GPI biosynthesis. De-N-acetylation of N-acetylglucosaminyl-phosphatidylinositol.
Expressed in heart, skeletal muscle, thymus, spleen, kidney, liver, placenta and leukocytes.
Binds DNA as a dimer and can form stable heterodimers with CEBPA and CEBPB. Interacts with ZNF638; this interaction increases transcriptional activation.
Transcription factor that binds to the promoter and the enhancer regions of target genes. Binds to the enhancer element PRE-I (positive regulatory element-I) of the IL-4 gene (PubMed:7665092). Binds to the promoter and the enhancer of the immunoglobulin heavy chain. Binds to GPE1, a cis-acting element in the G-CSF gene promoter.
Belongs to the actin family. ARP6 subfamily.
Component of the chromatin-remodeling SRCAP complex composed of at least SRCAP, DMAP1, RUVBL1, RUVBL2, ACTL6A, YEATS4, ACTR6 and ZNHIT1 (PubMed:15647280, PubMed:20473270). Interacts with CBX1, CBX3 and CBX5 (PubMed:16487625).
Required for formation and/or maintenance of proper nucleolar structure and function (PubMed:26164235). Plays a dual role in the regulation of ribosomal DNA (rDNA) transcription (By similarity). In the presence of high glucose, maintains active rDNA transcription through H2A.Z deposition and under glucose starvation, is required for the repression of rDNA transcription, and this function may be independent of H2A.Z (By similarity).
Binds phosphatidylinositol 4,5-bisphosphate (PIP2) via its two PDZ domains. These domains target SDCBP2 to the plasma membranes and nucleoli, two PIP2-rich regions.
Binds phosphatidylinositol 4,5-bisphosphate (PIP2). May play a role in the organization of nuclear PIP2, cell division and cell survival (PubMed:15961997).
Down-regulated by HPV8 E6 papillomavirus (HPV) oncoprotein (at protein level).
Monomer and homodimer (PubMed:11152476, PubMed:23300061). Interacts with SDCBP (PubMed:11152476). Interacts with TM4SF1 (PubMed:11102519).
Preferentially expressed in cells of the digestive tract (PubMed:11102519). Low expression in skeletal muscle and kidney (PubMed:11102519). Detected in differentiated keratinocytes of normal and malignant epithelium (PubMed:22623796). In healthy skin, expression is localized in suprabasal epidermal layers (PubMed:22623796).
The nuclear speckles location of SDCBP2 is under debate. One study shows that in paraformaldehyde fixed cells, SDCBP2 is highly enriched in nuclear speckles (PubMed:15961997). The same authors investigate subcellular location in living cells and fail to detect SDCBP2 in nuclear speckles, and propose that enrichment in nuclear speckles is fixation-dependent (PubMed:23300061).
Adapter protein which modulates coupling of cell surface receptor kinases with specific signaling pathways. Binds to, and suppresses signals from, the activated insulin receptor (INSR). Potent inhibitor of insulin-stimulated MAPK3 phosphorylation. Plays a critical role regulating PDPK1 membrane translocation in response to insulin stimulation and serves as an adapter protein to recruit PDPK1 to activated insulin receptor, thus promoting PKB/AKT1 phosphorylation and transduction of the insulin signal.
Expressed at high levels in the liver, kidney, pancreas, testis, ovary, heart and skeletal muscle.
Interacts with the cytoplasmic domain of the autophosphorylated insulin receptor (INSR), through the SH2 domain (By similarity). Interacts with GRB14 (via BPS domain); this interaction protects the tyrosines in the activation loop on INSR from dephosphorylation. Binds to the ankyrin repeat region of TNKS2 via its N-terminus. Interacts with activated NRAS. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated).
Phosphorylated on serine residues. Phosphorylated on tyrosine residues by TEK/TIE2.
The PH domain binds relatively non-specifically and with low affinity to several phosphoinositides, the best binder being PI(3,4,5)P3.
Involved in the early part of the secretory pathway.
Expression is induced in lung and colon cancer cells.
Seems to be involved in the regulation of proliferation and migration.
Can homomultimerise. Interacts with CACNG2. Interacts (via the SH3-Guanylate kinase-like sub-module) with DLG4/PSD95 and DLGAP1/GKAP. Interacts (via the PDZ domain) with CADM1 (via C-terminus) (By similarity). Interacts with KCNN2/SK2 (via N-terminal domain) (By similarity). Interacts with SRC (PubMed:19665017).
Postsynaptic MAGUK scaffold protein that links CADM1 cell adhesion molecules to core components of the postsynaptic density (By similarity). In CA1 pyramidal neurons, required for synaptic KCNN2-containing channel function and long-term potentiation expression (By similarity). Seems to negatively regulate SRC function in epithelial cells (PubMed:19665017).
Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex (PubMed:22801543, PubMed:17317665, PubMed:24449906). As a component of the trimeric and tetrameric DNA polymerase delta complexes (Pol-delta3 and Pol-delta4, respectively), plays a role in high fidelity genome replication, including in lagging strand synthesis, and repair. Required for optimal Pol-delta activity. Stabilizes the Pol-delta complex and plays a major role in Pol-delta stimulation by PCNA (PubMed:10219083, PubMed:10852724, PubMed:11595739, PubMed:16510448, PubMed:24035200). Pol-delta3 and Pol-delta4 are characterized by the absence or the presence of POLD4. They exhibit differences in catalytic activity. Most notably, Pol-delta3 shows higher proofreading activity than Pol-delta4 (PubMed:19074196, PubMed:20334433). Although both Pol-delta3 and Pol-delta4 process Okazaki fragments in vitro, Pol-delta3 may also be better suited to fulfill this task, exhibiting near-absence of strand displacement activity compared to Pol-delta4 and stalling on encounter with the 5'-blocking oligonucleotides. Pol-delta3 idling process may avoid the formation of a gap, while maintaining a nick that can be readily ligated (PubMed:24035200). Along with DNA polymerase kappa, DNA polymerase delta carries out approximately half of nucleotide excision repair (NER) synthesis following UV irradiation. In this context, POLD3, along with PCNA and RFC1-replication factor C complex, is required to recruit POLD1, the catalytic subunit of the polymerase delta complex, to DNA damage sites (PubMed:20227374). Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR) (PubMed:24310611). Involved in the translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites performed by Pol-delta4, independently of DNA polymerase zeta (REV3L) or eta (POLH). Facilitates abasic site bypass by DNA polymerase delta by promoting extension from the nucleotide inserted opposite the lesion (PubMed:19074196, PubMed:25628356, PubMed:27185888). Also involved in TLS, as a component of the tetrametric DNA polymerase zeta complex. Along with POLD2, dramatically increases the efficiency and processivity of DNA synthesis of the DNA polymerase zeta complex compared to the minimal zeta complex, consisting of only REV3L and REV7 (PubMed:24449906).
Component of both the DNA polymerase delta and DNA polymerase zeta complexes (PubMed:22801543, PubMed:17317665, PubMed:24449906). The tetrameric DNA polymerase delta complex (Pol-delta4), which consists of POLD1/p125, POLD2/p50, POLD3/p66/p68 and POLD4/p12, with POLD1 bearing DNA polymerase and 3' to 5' proofreading exonuclease activities (PubMed:11328591, PubMed:11595739, PubMed:17317665, PubMed:22801543). Within this complex, directly interacts with POLD2 (PubMed:11328591, PubMed:16510448, PubMed:18818516). Following stress caused by DNA damaging agents or by replication stress, POLD4 is degraded and Pol-delta4 is converted into a trimeric form of the complex (Pol-delta3), which consists of POLD1, POLD2 and POLD3. Pol-delta3 is the major form occurring at S phase replication sites, as well as DNA damage sites (PubMed:11595739, PubMed:17317665, PubMed:22801543, PubMed:23913683). Directly interacts with PCNA, as do POLD1 and POLD4; this interaction stimulates Pol-delta polymerase activity (PubMed:11328591, PubMed:11595739, PubMed:12403614, PubMed:16510448, PubMed:22148433). POLD3 phosphorylation at Ser-458 impairs PCNA binding (PubMed:22148433). Component of the DNA polymerase zeta complex (POLZ), which consists of REV3L, MAD2L2, POLD2 and POLD3, with REV3L bearing DNA polymerase catalytic activity (PubMed:24449906). The DNA polymerase delta complex interacts with POLDIP2; this interaction is probably mediated through direct binding to POLD2 (PubMed:12522211).
Expression is cell cycle-dependent, with highest levels in G2/M phase and lowest in G1.
Phosphorylation at Ser-458 is catalyzed in vitro by PKA. It is thought to decrease the affinity for PCNA and Pol-delta4 processivity (PubMed:22148433). Can also be phosphorylated in vitro by CDK1-cyclin-A complex, as well as CDK2-cyclin-A and CDK2-cyclin-E complexes. PCNA interferes with CDK-cyclin phosphorylation (PubMed:11595739).
Ubiquitinated, but not targeted to the proteasome (PubMed:16934752). Sumoylated (PubMed:16934752, PubMed:25218447). Sumoylation with SUMO3 may be predominant (PubMed:16934752).
Although strongly similar to members of the ADAMTS family it lacks the metalloprotease and disintegrin-like domains which are typical of that family.
Glycosylated (By similarity). Can be O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS family members. Can also be C-glycosylated with one or two mannose molecules on tryptophan residues within the consensus sequence W-X-X-W of the TPRs, and N-glycosylated. These other glycosylations can also facilitate secretion (By similarity).
There is a significant increase in total and active TGFB1 in the culture medium as well as nuclear localization of phosphorylated SMAD2 in fibroblasts from individuals with geleophysic dysplasia.
Component of the PR-DUB complex, at least composed of BAP1 and ASXL1 (PubMed:20436459). Interacts with RARA, RXRA and NCOA1 (PubMed:16606617). Interacts with PPARA and PPARG (By similarity).
Contains one Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif, which may be required for an association with nuclear receptors.
Probable Polycomb group (PcG) protein involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor gamma (PPARG) (PubMed:16606617). Acts as coactivator of RARA and RXRA through association with NCOA1 (PubMed:16606617). Acts as corepressor for PPARG and suppresses its adipocyte differentiation-inducing activity (By similarity). Non-catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-119' (H2AK119ub1) (PubMed:20436459). Acts as a sensor of N(6)-methyladenosine methylation on DNA (m6A): recognizes and binds m6A DNA, leading to its ubiquitination and degradation by TRIP12, thereby inactivating the PR-DUB complex and regulating Polycomb silencing (PubMed:30982744).
The HARE HTH-type domain recognizes and binds N(6)-methyladenosine methylated DNA (m6A).
Ubiquitinated by TRIP12, leading to its subsequent degradation following binding N(6)-methyladenosine methylated DNA (m6A).
Was previously reported to interact with KDM1A, CBX1, CBX3 and CBX5. However, this publication has been retracted.
Widely expressed at low level. Expressed in heart, brain, skeletal muscle, placenta, pancreas, spleen, prostate, small intestine, colon, peripheral blood, leukocytes, bone marrow and fetal liver. Highly expressed in testes.
(Microbial infection) Interacts with ebolavirus protein VP24; this interaction activates transcription factor NFE2L2/NRF2 by blocking its interaction with KEAP1.
Auto-ubiquitinated by the BCR(KEAP1) complex (PubMed:15572695, PubMed:15983046). Quinone-induced oxidative stress, but not sulforaphane, increases its ubiquitination (PubMed:15572695, PubMed:15983046). Ubiquitination and subsequent degradation is most pronounced following prolonged exposure of cells to oxidative stress, particularly in glutathione-deficient cells that are highly susceptible to oxidative stress (PubMed:15572695, PubMed:15983046).
Component of the BCR(KEAP1) E3 ubiquitin ligase complex, at least composed of 2 molecules of CUL3, 2 molecules of KEAP1, and RBX1 (PubMed:15572695, PubMed:15983046, PubMed:15601839, PubMed:17127771, PubMed:18251510, PubMed:24896564). Interacts with NFE2L2/NRF2; the interaction is direct (PubMed:15379550, PubMed:15601839, PubMed:16006525, PubMed:18387606, PubMed:16888629). Forms a ternary complex with NFE2L2/NRF2 and PGAM5 (PubMed:17046835). Interacts with (phosphorylated) SQSTM1/p62; the interaction is direct and inactivates the BCR(KEAP1) complex by sequestering it in inclusion bodies, promoting its degradation (PubMed:20495340, PubMed:20452972). Interacts with NFE2L1 (PubMed:16687406). Interacts with BPTF and PTMA (PubMed:15657435). Interacts with MAP1LC3B (PubMed:24089205). Interacts indirectly with ENC1 (PubMed:19424503). Interacts with SESN1 and SESN2 (PubMed:23274085). Interacts with HSP90AA1 and HSP90AB1 (PubMed:26517842).
Degraded via a proteasomal-independent process during selective autophagy: interaction with phosphorylated SQSTM1/p62 sequesters KEAP1 in inclusion bodies, leading to its degradation.
KEAP1 contains reactive cysteine residues that act as sensors for endogenously produced and exogenously encountered small molecules, which react with sulfhydryl groups and modify the cysteine sensors, leading to impair ability of the BCR(KEAP1) complex to ubiquitinate target proteins.
Non-enzymatic covalent modifications of reactive cysteines by electrophile metabolites inactivate the BCR(KEAP1) complex (PubMed:17127771, PubMed:18251510, PubMed:29590092, PubMed:30323285). Accumulation of fumarate promotes the formation of cysteine S-succination (S-(2-succinyl)cysteine), leading to inactivate the BCR(KEAP1) complex and promote NFE2L2/NRF2 nuclear accumulation and activation (By similarity). Nitric oxide-dependent 8-Nitro-cGMP formation promotes cysteine guanylation (S-cGMP-cysteine), leading to NFE2L2/NRF2 nuclear accumulation and activation (By similarity). Itaconate, an anti-inflammatory metabolite generated in response to lipopolysaccharide, alkylates cysteines, activating NFE2L2/NRF2 (PubMed:29590092). Methylglyoxal, a reactive metabolite that accumulates when the glycolytic enzyme PGK1 is inhibited, promotes formation of a methylimidazole cross-link between proximal Cys-151 and Arg-135 on another KEAP1 molecule, resulting in an inactive dimer that inactivates the BCR(KEAP1) complex (PubMed:30323285).
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination (PubMed:14585973, PubMed:15379550, PubMed:15572695, PubMed:15983046, PubMed:15601839). KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes (PubMed:15601839, PubMed:16006525). In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (PubMed:19489739, PubMed:16006525, PubMed:17127771, PubMed:18251510, PubMed:29590092). In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2 (PubMed:20452972). The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation (PubMed:28380357). The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome (PubMed:15379550, PubMed:17046835).
The Kelch repeats mediate interaction with NFE2L2/NRF2, BPTF and PGAM5.
The mechanism of inactivation of the BCR(KEAP1) complex by covalent modifications of reactive cysteines is unclear. Covalent modifications were initially thought to disrupt interaction between KEAP1 and NFE2L2/NRF2 (By similarity). Recent publications suggest that cysteine modifications disrupt the interaction between KEAP1 and CUL3 without affecting the interaction between KEAP1 and NFE2L2/NRF2 (PubMed:16006525, PubMed:17127771, PubMed:18251510, PubMed:24896564).
Ubiquitin ligase activity of the BCR(KEAP1) complex is inhibited by oxidative stress and electrophile metabolites such as sulforaphane (PubMed:15983046, PubMed:17046835, PubMed:29590092, PubMed:30323285). Electrophile metabolites react with reactive cysteine residues in KEAP1 and trigger non-enzymatic covalent modifications of these cysteine residues, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex (PubMed:19489739, PubMed:17127771, PubMed:18251510, PubMed:29590092, PubMed:30323285). Selective autophagy also inactivates the BCR(KEAP1) complex via interaction between KEAP1 and SQSTM1/p62, which sequesters the complex in inclusion bodies and promotes its degradation (PubMed:20495340, PubMed:20452972).
Amyloid-beta peptides are degraded by IDE.
Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Amyloid-beta protein 42 is a more effective reductant than amyloid-beta protein 40. Amyloid-beta peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. APP42-beta may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity. Also binds GPC1 in lipid rafts.
Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain.
Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and, NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Amyloid-beta protein 42 binds CHRNA7 in hippocampal neurons. Amyloid-beta associates with HADH2. Soluble APP binds, via its N-terminal head, to FBLN1. Interacts with CPEB1 and AGER (By similarity). Interacts with ANKS1B and TNFRSF21. Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions (PubMed:25122912). Can form homodimers; this is promoted by heparin binding. Amyloid-beta protein 40 interacts with S100A9. CTF-alpha product of APP interacts with GSAP. Isoform APP695 interacts with SORL1 (via N-terminal ectodomain); this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides (PubMed:16174740, PubMed:16407538, PubMed:17855360, PubMed:24523320). The C99 fragment also interacts with SORL1 (PubMed:16407538). Isoform APP751 interacts with SORL1 (PubMed:16174740). Isoform APP770 interacts with SORL1 (PubMed:16174740). Interacts with PLD3. Interacts with VDAC1 (PubMed:25168729). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (PubMed:11689470). Interacts with SYT7 (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (PubMed:30630874). Interacts with LRRK2 (PubMed:28720718). Interacts (via cytoplasmic domain) with KIF5B (PubMed:23011729). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (PubMed:14527950, PubMed:8855266). Interacts (via intracellular domain) with APBB3 (PubMed:10081969).
Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between amyloid-beta molecules resulting in amyloid-beta-metal aggregates. The affinity for copper is much higher than for other transient metals and is increased under acidic conditions. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding.
Expressed in the brain and in cerebrospinal fluid (at protein level) (PubMed:2649245). Expressed in all fetal tissues examined with highest levels in brain, kidney, heart and spleen. Weak expression in liver. In adult brain, highest expression found in the frontal lobe of the cortex and in the anterior perisylvian cortex-opercular gyri. Moderate expression in the cerebellar cortex, the posterior perisylvian cortex-opercular gyri and the temporal associated cortex. Weak expression found in the striate, extra-striate and motor cortices. Expressed in cerebrospinal fluid, and plasma. Isoform APP695 is the predominant form in neuronal tissue, isoform APP751 and isoform APP770 are widely expressed in non-neuronal cells. Isoform APP751 is the most abundant form in T-lymphocytes. Appican is expressed in astrocytes.
Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond. In vitro, the APP-Cu(+) complex in the presence of hydrogen peroxide results in an increased production of amyloid-beta-containing peptides.
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Interaction between APP molecules on neighboring cells promotes synaptogenesis (PubMed:25122912). Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (PubMed:17062754, PubMed:23011729). Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.
Increased levels during neuronal differentiation.
N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).
N-glycosylated (PubMed:2900137). N- and O-glycosylated (PubMed:2649245). O-glycosylation on Ser and Thr residues with core 1 or possibly core 8 glycans. Partial tyrosine glycosylation (Tyr-681) is found on some minor, short amyloid-beta peptides (amyloid-beta 1-15, 1-16, 1-17, 1-18, 1-19 and 1-20) but not found on amyloid-beta protein 38, amyloid-beta protein 40 nor on amyloid-beta protein 42. Modification on a tyrosine is unusual and is more prevelant in AD patients. Glycans had Neu5AcHex(Neu5Ac)HexNAc-O-Tyr, Neu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr and O-AcNeu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr structures, where O-Ac is O-acetylation of Neu5Ac. Neu5AcNeu5Ac is most likely Neu5Ac 2,8Neu5Ac linked. O-glycosylations in the vicinity of the cleavage sites may influence the proteolytic processing. Appicans are L-APP isoforms with O-linked chondroitin sulfate.
Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific (PubMed:10341243). Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins (PubMed:10341243). Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-beta (PubMed:8131745, PubMed:11146006). The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members (PubMed:11517218). In dopaminergic (DA) neurons, phosphorylation on Thr-743 by LRKK2 promotes the production and the nuclear translocation of the APP intracellular domain (AICD) which induces DA neuron apoptosis (PubMed:28720718). Phosphorylation on Tyr-757 is required for SHC binding (PubMed:11877420). Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP. This phosphorylation is inhibited by heparin (PubMed:8999878).
Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either CASP6, CASP8 or CASP9 results in the production of the neurotoxic C31 peptide and the increased production of amyloid-beta peptides.
Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro) (PubMed:30630874). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE (PubMed:11604391, PubMed:16154999). Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase and all terminating at Gln-686.
The C-terminal region can bind zinc ions; this favors dimerization and formation of higher oligomers.
The GFLD subdomain binds Cu(2+) ions; this promotes homodimerization.
The L-isoforms are referred to as appicans.
The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The YENPXY site is also involved in clathrin-mediated endocytosis.
The OX-2 motif shows some similarity to a region in the N-terminus of CD200/MOX2.
The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells.
The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.
The transmembrane helix undergoes a conformation change and unravels partially when bound to PSEN1, facilitating cleavage by PSEN1.
Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP).
Expressed in testis. Wide expression in various cancer tissues and cancer cell lines.
Belongs to the Mediator complex subunit 12 family.
Contaminating sequence. Sequence of unknown origin in the N-terminal part and potential poly-A sequence.
May be a component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors (By similarity).
May be a component of the Mediator complex, which is known to be composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP (By similarity).
Functions in signal transduction from heterotrimeric G protein-coupled receptors. Binds to membranes containing phosphatidylinositol 4,5-bisphosphate. Can bind DNA (in vitro). May contribute to the regulation of transcription in the nucleus. Could be involved in the hypothalamic regulation of body weight (By similarity). Contribute to stimulation of phagocytosis of apoptotic retinal pigment epithelium (RPE) cells and macrophages.
Interacts with GNAQ. Interacts with TULP1.
May be involved in transcriptional regulation as a repressor. Plays a role in limb development.
Expressed in brain and testis (PubMed:15645143).
Expressed in fetal brain (PubMed:15645143).
Plays a role in neuronal proliferation and differentiation (PubMed:25281927). Plays a role in the accumulation of cellular cholesterol (By similarity). Involved in intracellular lipid droplet formation (PubMed:25281927). May contribute to cholesterol homeostasis in neuronal cells (By similarity).
The SSD (sterol-sensing) domain is necessary for the increase in cellular cholesterol uptake.
Up-regulated by thyroid hormone T3 (PubMed:19179482).
Tumor suppressor. It blocks the growth, invasion, and metastatic properties of mammary tumors. As it does not undergo the S (stressed) to R (relaxed) conformational transition characteristic of active serpins, it exhibits no serine protease inhibitory activity.
Belongs to the transient receptor (TC 1.A.4) family. Polycystin subfamily. MCOLN2 sub-subfamily.
Channel activity is reduced by low extracellular/lumenal pH level (PubMed:19940139).
Forms homooligomeric complexes; probably tetrameric (By similarity). Can heterooligomerize with MCOLN1; heteromeric assemblies have different channel properties as compared to the respective homooligomers and may be tissue-specific (PubMed:19885840). Interacts with TMEM176A (PubMed:25130899).
Nonselective cation channel probably playing a role in the regulation of membrane trafficking events. Acts as Ca(2+)-permeable cation channel with inwardly rectifying activity (PubMed:19940139, PubMed:19885840). May activate ARF6 and be involved in the trafficking of GPI-anchored cargo proteins to the cell surface via the ARF6-regulated recycling pathway (PubMed:17662026). May play a role in immune processes. In adaptive immunity, TRPML2 and TRPML1 may play redundant roles in the function of the specialized lysosomes of B cells (By similarity). In the innate immune response, may play a role in the regulation of chemokine secretion and macrophage migration (By similarity). Through a possible and probably tissue-specific heteromerization with MCOLN1 may be at least in part involved in many lysosome-dependent cellular events (PubMed:19885840).
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. May govern uptake and detoxification of both endogenous compounds and xenobiotics at the testis and brain blood barriers.
Angiopoietin binding leads to receptor dimerization and activation by autophosphorylation at Tyr-992 on the kinase activation loop. Inhibited by staurosporine, K252a, PP2, damnacanthal, SB203580, CEP-11207, CEP-11981 and CE-245677. Inhibited by triazine, thienopyrimidine and thiazolopyrimidine derivatives.
Autophosphorylated on tyrosine residues in response to ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Autophosphorylation occurs in a sequential manner, where Tyr-992 in the kinase activation loop is phosphorylated first, followed by autophosphorylation at Tyr-1108 and at additional tyrosine residues. ANGPT1-induced phosphorylation is impaired during hypoxia, due to increased expression of ANGPT2. Phosphorylation is important for interaction with GRB14, PIK3R1 and PTPN11. Phosphorylation at Tyr-1102 is important for interaction with SHC1, GRB2 and GRB7. Phosphorylation at Tyr-1108 is important for interaction with DOK2 and for coupling to downstream signal transduction pathways in endothelial cells. Dephosphorylated by PTPRB.
Belongs to the protein kinase superfamily. Tyr protein kinase family. Tie subfamily.
Detected in umbilical vein endothelial cells. Proteolytic processing gives rise to a soluble extracellular domain that is detected in blood plasma (at protein level). Predominantly expressed in endothelial cells and their progenitors, the angioblasts. Has been directly found in placenta and lung, with a lower level in umbilical vein endothelial cells, brain and kidney.
Homodimer. Heterodimer with TIE1. Interacts with ANGPT1, ANGPT2 and ANGPT4 (PubMed:9204896, PubMed:15284220, PubMed:32908006). At cell-cell contacts in quiescent cells, forms a signaling complex composed of ANGPT1 plus TEK molecules from two adjoining cells. In the absence of endothelial cell-cell contacts, interaction with ANGPT1 mediates contacts with the extracellular matrix. Interacts with PTPRB; this promotes endothelial cell-cell adhesion. Interacts with DOK2, GRB2, GRB7, GRB14, PIK3R1 and PTPN11/SHP2. Colocalizes with DOK2 at contacts with the extracellular matrix in migrating cells. Interacts (tyrosine phosphorylated) with TNIP2. Interacts (tyrosine phosphorylated) with SHC1 (via SH2 domain).
May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.
Proteolytic processing leads to the shedding of the extracellular domain (soluble TIE-2 alias sTIE-2).
Somatic mutations of TEK are associated with solitary and multiple sporadic venous malformations.
The soluble extracellular domain is functionally active in angiopoietin binding and can modulate the activity of the membrane-bound form by competing for angiopoietins.
Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of pro-inflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1.
Ubiquitinated. The phosphorylated receptor is ubiquitinated and internalized, leading to its degradation.
Host defense peptide that exhibits antibacterial and antifungal activity (PubMed:34481960). Exhibits antimicrobial activity against E.coli, S.aureus and C.albicans (in vitro) (PubMed:34481960). Has high lipopolysaccharide (LPS)-binding affinity, and may thereby be involved in immunoregulation through LPS neutralization (PubMed:34481960).
Probable transcription factor involved in the control of specification of mesoderm and endoderm.
Guanine nucleotide exchange factor (GEF) which may activate RAB39A and/or RAB39B. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form.
Interacts with PABPC1 (PubMed:20573744, Ref.23). Interacts with RACK1 (PubMed:20573744). Associates with polysomes via the 40S ribosomal subunit (PubMed:20573744).
(Microbial infection) During SARS coronavirus-2/SARS-CoV-2 infection, may recognize and internalize the complex formed by AVP/Arg-vasopressin, SARS-CoV-2 spike protein and secreted ACE2 through DNM2/dynamin 2-dependent endocytosis.
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system.
Protease which specifically processes pro-lysyl oxidase. Required for the embryonic development. Predominant protease, which in the development, influences dorsal-ventral patterning and skeletogenesis.
Interacts (via the extracellular domain) with FGF2.
Plays a role in the regulation of chondrocyte maturation and postnatal endochondral ossification. May inhibit cell growth stimulation induced by FGF2.
(Microbial infection) Following infection by hepatitis C virus (HCV), promotes HCV-triggered membrane remodeling, leading to autophagy and Golgi fragmentation, a step required for HCV replication.
Acts as a positive regulator of mitophagy in response to intracellular mycobacteria infection: specifically binds cardiolipin, leading to its translocation to mitochondria, where it promotes affected mitochondrial fission and mitophagy.
Genetic variations in the IRGM promoter determine Mycobacterium tuberculosis susceptibility [MIM:607948] (PubMed:19750224). People that are homozygote for -261C-T (rs9637876) variant, which is located within an Alu sequence in the promoter region, are associated with protection from M.tuberculosis (PubMed:19750224). In contrast, -261T-T allele is significantly associated with protection from pulmonary tuberculosis caused by M.tuberculosis, but not by M.africanum, a strain restricted to West Africa, or M.bovis (PubMed:19750224).
Immunity-related GTPase that plays important roles in innate immunity and inflammatory response (PubMed:16888103, PubMed:19165925, PubMed:25891078). Acts as a dynamin-like protein that binds to intracellular membranes and promotes remodeling and trafficking of those membranes (By similarity). Required for clearance of acute protozoan and bacterial infections by interacting with autophagy and lysosome regulatory proteins, thereby promoting the fusion of phagosomes with lysosomes for efficient degradation of cargo including microbes (PubMed:16888103, PubMed:25891078, PubMed:29420192, PubMed:32939830). Regulates selective autophagy, including xenophagy and mitophagy, both directly and indirectly (PubMed:16888103, PubMed:25891078, PubMed:29420192, PubMed:32939830). Directly regulates autophagy by acting as a molecular adapter that promotes the coassembly of the core autophagy machinery to mediate antimicrobial defense: IRGM (1) activates AMPK, which in turn phosphorylates ULK1 and BECN1 to induce autophagy, (2) promotes the coassembly of ULK1 and BECN1, enhancing BECN1-interacting partners and (3) influences the composition of the BECN1 complex, by competing with the negative regulators BCL2 and RUBCN, to trigger autophagy (PubMed:25891078). Also activates autophagy by promoting recruitment of STX17 to autophagosomes (PubMed:29420192). In collaboration with ATG8 proteins, regulate lysosomal biogenesis, a fundamental process for any autophagic pathway, by promoting TFEB dephosphorylation (PubMed:32753672). Also modulates autophagy by assisting with autophagosome formation and preventing lysosomal deacidification (By similarity). While activating autophagy, acts as a key negative regulator of the inflammatory and interferon responses both by (1) promoting mitophagy and (2) mediating autophagy-dependent degradation of effectors of the inflammatory response (PubMed:30612879, PubMed:32715615, PubMed:36221902). Promotes degradation of damaged and IFNG/IFN-gamma-stressed mitochondria via mitophagy, preventing cytosolic release of ligands that activate inflammation (PubMed:32715615). Acts as a suppressor of inflammation by promoting recruitment of inflammation effectors, such as CGAS, RIGI/RIG-I and NLRP3, to autophagosome membranes, leading to their SQSTM1/p62-dependent autophagic degradation (PubMed:30612879, PubMed:32715615). Also directly inhibits assembly of the NLRP3 inflammasome by preventing the association between NLRP3 and PYCARD (PubMed:30612879). Acts as a negative regulator of antiviral innate immune response by suppressing the RIPK2-dependent pro-inflammatory response: mediates recruitment of RIPosomes, composed of RIPK2 and NOD1 or NOD2, to autophagosome membranes, promoting their SQSTM1/p62-dependent autophagic degradation (PubMed:34467632, PubMed:36221902).
Interacts with ULK1; promoting the coassembly of ULK1 and BECN1 (PubMed:25891078). Interacts with BECN1; enhancing BECN1-interacting partners and influencing the composition of the BECN1 complex (PubMed:25891078). Interacts with ATG16L1 (PubMed:25891078). Interacts with NOD2; promoting IRGM 'Lys-63'-linked polyubiquitination, which is required for interactions with the core autophagy factors (PubMed:25891078). Interacts with STX17; promoting STX17 recruitment to autophagosomes (PubMed:29420192). Interacts with ATG8 proteins (GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B and MAP1LC3C); promoting STX17 recruitment to autophagosomes (PubMed:29420192). Interacts with TFEB; promoting association between TFEB and PPP3CB and TFEB dephosphorylation (PubMed:32753672). Interacts with PPP3CB; promoting association between TFEB and PPP3CB and TFEB dephosphorylation (PubMed:32753672). Interacts with NLRP3; preventing NLRP3 inflammasome assembly and promoting SQSTM1/p62-dependent autophagic degradation of NLRP3 (PubMed:30612879). Interacts with CGAS; promoting SQSTM1/p62-dependent autophagic degradation of CGAS (PubMed:32715615). Interacts with RIGI/RIG-I; promoting SQSTM1/p62-dependent autophagic degradation of RIGI/RIG-I (PubMed:32715615). Interacts with NOD1; promoting SQSTM1/p62-dependent autophagic degradation of RIGI/RIG-I (PubMed:36221902). Interacts with NOD2; promoting SQSTM1/p62-dependent autophagic degradation of RIGI/RIG-I (PubMed:36221902). Interacts with RIPK2; promoting SQSTM1/p62-dependent autophagic degradation of RIGI/RIG-I (PubMed:36221902).
The G5 motif of the IRG-type G domain is missing because the IRGM protein is truncated in anthropoids.
There is a huge difference in terms of sequence and regulation of expression compared to the mouse ortholog and hence, the function might be slightly different.
Ubiquitinated via 'Lys-63'-linked polyubiquitination in a NOD2-dependent process. 'Lys-63'-linked polyubiquitination is required for interactions with the core autophagy factors.
Widely expressed (at protein level) (PubMed:16888103). Expressed in several tissues including colon, small bowel and peripheral blood leukocytes (PubMed:17554261).
Expressed in spleen, thymus, prostate, testis, uterus, small intestine, colon and peripheral blood leukocytes.
Endoplasmic reticulum (ER)-anchored autophagy regulator which exists in an inactive state under basal conditions but is activated following cellular stress (PubMed:34338405). When activated, induces ER fragmentation and mediates ER delivery into lysosomes through sequestration into autophagosomes via interaction with ATG8 family proteins (PubMed:34338405). Required for collagen quality control in a LIR motif-independent manner (By similarity).
Interacts with ATG8 family modifier proteins MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAP, GABARAPL1 and GABARAPL2 (PubMed:26040720, PubMed:34338405, PubMed:34854256). Shows higher affinity for GABARAPL1 than for MAP1LC3B (PubMed:34854256). Interacts with CANX (PubMed:34338405).
Endoplasmic reticulum transmembrane protein involved in vesicle-mediated transport, which is required for neutrophil function. Required for vesicle-mediated transport; it is however unclear whether it is involved in early secretory pathway or intracellular protein transport. Acts as a regulator of neutrophil function, probably via its role in vesicle-mediated transport: required for defense against fungal pathogens and for granulocyte colony-stimulating factor (GM-CSF) signaling pathway; possibly by regulating glycosylation and/or targeting of proteins contributing to the viability and migration of neutrophils.
Experiments in mouse confirm the importance of JAGN1 in neutrophil function with some differences. Mice lacking JAGN1 do not show neutropenia and display increased susceptibility to fungal infections due to defective killing capacity of neutrophil granulocytes.
Forms homooligomers; homo-oligomerization is essential for the roles in membrane tethering and enhancement of SNARE-mediated fusion (PubMed:25686604). Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex I (PI3KC3-C1) in which the core composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 is associated with ATG14 (PubMed:18843052, PubMed:19050071, PubMed:19270696, PubMed:22314358, PubMed:23878393). PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex (PubMed:25490155). PI3KC3-C1 can associate with further regulatory subunits. Interacts with PIK3CB (By similarity). Interacts (via coiled-coil domain) with BECN2 (via coiled-coil domain); this interaction is tighter than BECN2 self-association (PubMed:23954414, PubMed:28218432). Interacts with the STX17-SNAP29 binary t-SNARE complex (PubMed:25686604). Interacts with NRBF2 (By similarity). Interacts with PIK3C3 and BECN1; this interaction is increased in the absence of TMEM39A (PubMed:31806350). Interacts with STEEP1; the interaction is required for trafficking of STING1 from the endoplasmic reticulum (PubMed:32690950).
Required for both basal and inducible autophagy. Determines the localization of the autophagy-specific PI3-kinase complex PI3KC3-C1 (PubMed:18843052, PubMed:19050071). Plays a role in autophagosome formation and MAP1LC3/LC3 conjugation to phosphatidylethanolamine (PubMed:19270696, PubMed:20713597). Promotes BECN1 translocation from the trans-Golgi network to autophagosomes (PubMed:20713597). Enhances PIK3C3 activity in a BECN1-dependent manner. Essential for the autophagy-dependent phosphorylation of BECN1 (PubMed:23878393). Stimulates the phosphorylation of BECN1, but suppresses the phosphorylation PIK3C3 by AMPK (PubMed:23878393). Binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction to promote autophagosome-endolysosome fusion (PubMed:25686604). Modulates the hepatic lipid metabolism (By similarity).
The N-terminal cysteine repeats are required for proper localization to the endoplasmic reticulum.
The coiled-coil domain is required for BECN1- and PIK3C3-binding and for autophagy.
The final 80 residues in the C-terminus define a minimum required region for autophagosome binding called BATS.
Antibodies against normal cellular SSA2 protein are found in sera from patients with systemic lupus erythematosus (SLE).
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Found in a complex with PUF60 and Y5 RNA (PubMed:10668799). Interacts with RAB11FIP5 (PubMed:10545525).
RNA-binding protein that binds to misfolded non-coding RNAs, pre-5S rRNA, and several small cytoplasmic RNA molecules known as Y RNAs (PubMed:18056422, PubMed:26382853). Binds to endogenous Alu retroelements which are induced by type I interferon and stimulate porinflammatory cytokine secretion (PubMed:26382853). Regulates the expression of Alu retroelements as well as inflammatory genes (PubMed:26382853). May play roles in cilia formation and/or maintenance (By similarity).
The MIDAS-like motif in the VWFA-like domain binds divalent metal cations.
The horseshoe-shaped TROVE domain is built with 7 helical HEAT-like repeats, and is closed by the VWFA-like domain giving rise to a ring-shaped monomer. Single-stranded RNA is bound in the positively charged central cavity (By similarity).
Probably acts as target recruitment subunit in an E3 ubiquitin ligase complex ZYGA-CUL2-elongin BC.
Identified in the spliceosome C complex. Found in a pre-mRNA splicing complex with SFRS4, SFRS5, SNRP70, SNRPA1, SRRM1 and SRRM2. Found in a pre-mRNA exonic splicing enhancer (ESE) complex with SNRP70, SNRPA1, SRRM1 and TRA2B/SFRS10. Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932). Found in a mRNA splicing-dependent exon junction complex (EJC) with DEK, PRPF8, NCBP1, RBM8A, RNPS1, SRRM1 and ALYREF/THOC4. Interacts with DDX39B, CPSF1, RBM8A, RNPS1, and ALYREF/THOC4. Seems to be a compound of RNA export complexes that are released from speckles in a ATP-dependent manner.
Part of pre- and post-splicing multiprotein mRNP complexes. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). Involved in numerous pre-mRNA processing events. Promotes constitutive and exonic splicing enhancer (ESE)-dependent splicing activation by bridging together sequence-specific (SR family proteins, SFRS4, SFRS5 and TRA2B/SFRS10) and basal snRNP (SNRP70 and SNRPA1) factors of the spliceosome. Stimulates mRNA 3'-end cleavage independently of the formation of an exon junction complex. Binds both pre-mRNA and spliced mRNA 20-25 nt upstream of exon-exon junctions. Binds RNA and DNA with low sequence specificity and has similar preference for either double- or single-stranded nucleic acid substrates.
Phosphorylated on multiple serine and threonine residues by DYRK3 during the G2-to-M transition, after the nuclear-envelope breakdown (PubMed:29973724). Phosphorylation by DYRK3 promotes disassembly of nuclear speckles (PubMed:29973724).
Binds actin monomers (G actin) and plays a role in multiple processes including the regulation of actin cytoskeleton dynamics, actin stress fibers formation, cell motility and survival, formation of tubules by endothelial cells, and regulation of PPP1CA activity (PubMed:21798305, PubMed:21939755). Involved in the regulation of cortical neuron migration and dendrite arborization (By similarity).
Binds three actin monomers via the three C-terminal RPEL repeats.
Detected in umbilical vein endothelial cells.
Interacts (via RPEL repeats) with ACTA1 and PPP1CA; ACTA1 and PPP1CA compete for the same binding site.
Specifically expressed in brain. Strongly expressed in medulla oblongata and to a lower extent in hippocampus and corpus callosum. Expressed in keratinocytes.
This protein is produced by a bicistronic gene which also produces the C1QTNF5 protein from a non-overlapping reading frame.
Belongs to the NmrA-type oxidoreductase family.
By nitric oxide, cGMP and pro-inflammatory cytokines.
Homodimer. Interacts with ASS1. Interaction is enhanced by low NADPH/NADP(+) ratios, which results in inhibition of ASS1 activity.
Lacks the conserved Tyr residue in the active site triad of Ser-Tyr-Lys necessary for dehydrogenase activity, suggesting that it has no oxidoreductase activity.
Redox sensor protein. Undergoes restructuring and subcellular redistribution in response to changes in intracellular NADPH/NADP(+) levels. At low NADPH concentrations the protein is found mainly as a monomer, and binds argininosuccinate synthase (ASS1), the enzyme involved in nitric oxide synthesis. Association with ASS1 impairs its activity and reduces the production of nitric oxide, which subsecuently prevents apoptosis. Under normal NADPH concentrations, the protein is found as a dimer and hides the binding site for ASS1. The homodimer binds one molecule of NADPH. Has higher affinity for NADPH than for NADP(+). Binding to NADPH is necessary to form a stable dimer.
Reduced levels of NMRAL1 by RNAi increases nitric oxide production and reduces cell viability. Overexpression of NMRAL1 increases cell viability.
Expressed mainly in the testis. Also expressed in the brain where they are enriched at the postsynaptic sites. Expressed at lower levels in the trachea, prostate, bone marrow, spinal cord, colon, fetal brain, heart, thymus, fetal liver, spleen, leukocytes, ovary, small intestine, pancreas and skeletal muscle. Expression is significantly lower in testicular cancer tissues than in normal testicular tissues. Isoform 3 is expressed in the testis, trachea, prostate and bone marrow.
May dephosphorylate receptor tyrosine-protein kinase ERBB4 and inhibits its ligand-induced proteolytic cleavage (PubMed:15219672). May play a role in odontogenesis (PubMed:27843125).
Up-regulated by mibolerone (a synthetic androgen) and dihydrotestosterone (DHT) and is down-regulated by estrogen and progestin.
IGF-binding proteins prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cell culture. They alter the interaction of IGFs with their cell surface receptors. Promotes cell migration.
Phosphorylated; probably by casein kinase II. Phosphorylation alters the affinity of the protein for IGFs. In amniotic fluid, the unmodified protein is the most abundant form, while mono-, bi-, tri- and tetraphosphorylated forms are present in decreasing amounts. The phosphorylation state may influence the propensity to proteolysis.
Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM. This complex may also include HSP70.
Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM. This complex may also include HSP70. The complex is not found in FA patients. Interacts with ZBTB32. Upon IFNG induction, interacts with STAT1. Interacts with CDK1. Interacts with EIF2AK2; interaction between FA variants and EIF2AK2 may lead to augmented EIF2AK2 activation and cell death.
DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function. May be implicated in interstrand DNA cross-link repair and in the maintenance of normal chromosome stability. Upon IFNG induction, may facilitate STAT1 activation by recruiting STAT1 to IFNGR1.
Expression increases during S phase, is maximal at the G2/M transition, and declines during M phase (at protein level).
Expressed at higher level in heart, skeletal muscle, kidney and liver.
The 3'-UTR region of the mRNA encoding this protein contains a motif called CDIR (for cell death inhibiting RNA) that binds HNRPD/AUF1 and HSPB1/HSP27. It is able to inhibit interferon-gamma induced apoptosis.
Component of the RNF20/40 E3 ubiquitin-protein ligase complex that mediates monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1). H2BK120ub1 gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation (H3K4me and H3K79me, respectively). It thereby plays a central role in histone code and gene regulation. The RNF20/40 complex forms a H2B ubiquitin ligase complex in cooperation with the E2 enzyme UBE2A or UBE2B; reports about the cooperation with UBE2E1/UBCH are contradictory. Required for transcriptional activation of Hox genes.
Component of the RNF20/40 complex (also known as BRE1 complex) probably composed of 2 copies of RNF20/BRE1A and 2 copies of RNF40/BRE1B. Interacts with UBE2E1/UBCH6.
Component of the RNF20/40 complex (also known as BRE1 complex) probably composed of 2 copies of RNF20/BRE1A and 2 copies of RNF40/BRE1B. Interacts with UBE2E1/UBCH6. Interacts with RB1 and WAC.
Ubiquitously expressed. Expressed at higher level in testis, heart and pancreas, while it is only weakly expressed in lung, skeletal muscle and small intestine.
Binds RAB27A that has been activated by GTP-binding, and possibly also RAB3A and RAB6A.
May act as Rab effector protein and play a role in vesicle trafficking. Binds phospholipids.
Plays an essential role for normal photoreceptor cell maintenance and vision.
Regulates ADAM10 maturation and trafficking to the cell surface. Promotes ADAM10-mediated cleavage of CD44.
As a co-chaperone for HSPA5 it is required for proper folding, trafficking or degradation of proteins (PubMed:10827079, PubMed:15525676, PubMed:29706351). Binds directly to both unfolded proteins that are substrates for ERAD and nascent unfolded peptide chains, but dissociates from the HSPA5-unfolded protein complex before folding is completed (PubMed:15525676). May help recruiting HSPA5 and other chaperones to the substrate. Stimulates HSPA5 ATPase activity (PubMed:10827079). It is necessary for maturation and correct trafficking of PKD1 (PubMed:29706351).
By endoplasmic reticulum stress-inducing agents such as thapsigargin and tunicamycin.
Contains high-mannose Endo H-sensitive carbohydrates.
Cys-169, Cys-171, Cys-193 and Cys-196 form intramolecular disulfide bonds. The preferential partner for each Cys is not known.
Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX. Binds to denatured substrates in an ATP-independent manner. Interacts via the J domain with HSPA5 in an ATP-dependent manner.
PubMed:11584023 reported a cytosolic, as well as nuclear subcellular location. This result was obtained using an N-terminally GFP-tagged construct which most probably affected signal peptide-driven targeting to the ER. As a consequence, the in vivo revelance of the observed interaction with APOBEC1, a nuclear protein, is dubious. This holds true for the interaction with PWP1.
Thr-188 was reported to be phosphorylated upon DNA damage by ATM or ATR; however as this position has been shown to be in the ER lumen, the in vivo relevance is not proven.
Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:24269233, PubMed:22633490, PubMed:21242590). Preferentially uses palmitoleate, oleate and linoleate (PubMed:24269233). Preferentially activates arachidonate than epoxyeicosatrienoic acids (EETs) or hydroxyeicosatrienoic acids (HETEs) (By similarity).
Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation.
Expressed during the early stages of erythroid development while expression is very low in reticulocytes and young erythrocytes.
Highly expressed in liver, heart, skeletal muscle, kidney and erythroid cells, and to a lesser extent in brain, lung, placenta and pancreas.
Inhibited at high temperature and by arachidonate.
Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. Participates in AID/AICDA-mediated somatic hypermutation (SHM) and class-switch recombination (CSR), 2 processes resulting in the production of high-affinity, mutated isotype-switched antibodies (PubMed:32484799).
Component of the PRP19-CDC5L splicing complex composed of a core complex comprising a homotetramer of PRPF19, CDC5L, PLRG1 and BCAS2, and at least three less stably associated proteins CTNNBL1, CWC15 and HSPA8. Interacts directly with CWC15 and CDC5L in the complex (PubMed:32484799). Interacts with AICDA; the interaction is important for the antibody diversification activity of AICDA (PubMed:18722174, PubMed:21385873). Interacts with PRPF31 (via its NLS). Interacts (via its N-terminal NLS) with KPNA1 and KPNA2.
The surface residues of the concave side of the superhelical ARM repeat region contribute to, but are not essential for NLS binding.
Widely expressed with highest levels in skeletal muscle, placenta, heart, spleen, testis and thyroid.
Belongs to the krueppel C2H2-type zinc-finger protein family. ZFX/ZFY subfamily.
Belongs to the glycerate kinase type-2 family.
During mitosis, may be involved in the condensation of spindle midzone microtubules, leading to the formation of midbody.
Widely expressed in fetal tissues. In adult tissues, expressed in testis and ovary and, at much lower levels, in kidney and pancreas.
A chromosomal aberration involving TLX1 may be a cause of a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(10;14)(q24;q11) with TCRD.
Controls the genesis of the spleen. Binds to the DNA sequence 5'-GGCGGTAAGTGG-3'.
Interacts with MEIS1, MEIS2, PBX1, PBX2 and PBX3.
TLX1 is oriented in a head-to-head manner with TDI. Both genes share the same promoter with robust bidirectional activity.
Seems to be involved in the assembly of the postsynaptic apparatus. May play a role in acetyl-choline receptor (AChR) aggregation in the postsynaptic membrane (By similarity).
Present in fetal hypothalamus at 19 weeks of gestation (at protein level).
Probably involved in the differentiation of hypothalamic neuroendocrine cells.
Belongs to the gamma type-C retroviral envelope protein family. HERV class-I R env subfamily.
Expressed at higher level in adrenal, sebaceous glands and placenta. Expressed at lower level in bone marrow, brain, breast, colon, heart, kidney, liver, lung, ovary, PBL, prostate, skin, spleen, testis, thymus, thyroid, trachea.
HERV-R_7q21.2 genomic and subgenomic RNAs have been observed.
Highly expressed in primitive adrenal cortex and placenta. Expressed at lower level in developing nervous tissues, tongue, heart, gut, kidney, columna vertebralis and liver.
Retroviral envelope proteins mediate receptor recognition and membrane fusion during early infection. Endogenous envelope proteins may have kept, lost or modified their original function during evolution. This endogenous envelope protein has lost its fusogenic properties. It can inhibit cell growth through decrease expression of cyclin B1 and increased expression of p21 in vitro.
Specific enzymatic cleavages in vivo yield the mature SU and TM proteins (By similarity). Has been mainly detected in vivo as an 65 kDa unprocessed polyprotein precursor.
TM anchors the envelope heterodimer to the viral membrane through one transmembrane domain. The other hydrophobic domain, called fusion peptide, mediates fusion of the viral membrane with the target cell membrane (By similarity).
The surface (SU) and transmembrane (TM) proteins form a heterodimer. SU and TM are attached by non-covalent interactions or by a labile interchain disulfide bond (By similarity).
This envelope gene is polymorphic with at least five different alleles. A mutation introducing a premature stop codon instead of amino acid 223 is present in approximately 1% of the Caucasian population (PubMed:9525678).
This provirus is intergenic, the closest flanking genes being ZNF117 and FLJ25037.
Truncated; premature stop codon upstream of the fusion peptide on TM.
CGRP induces vasodilation. It dilates a variety of vessels including the coronary, cerebral and systemic vasculature. Its abundance in the CNS also points toward a neurotransmitter or neuromodulator role.
Functions as a spatial regulator of RAF1 kinase by sequestrating it to the Golgi.
Expressed in unfertilized oocytes (at protein level).
Monomer (PubMed:27309808). Interacts with IZUMO1; the interaction is direct. IZUMO1 and IZUMO1R/JUNO form a complex with 1:1 stoichiometry (PubMed:24739963, PubMed:27309818, PubMed:27309808). Interacts with FCRL3/MAIA; FCRL3/MAIA replaces IZUMO1R/JUNO as IZUMO1 receptor after sperm-egg adhesion, thereby permitting species-specific gamete fusion (PubMed:36070373).
Receptor for IZUMO1 present at the cell surface of oocytes (oolemma), which is essential for species-specific gamete recognition and fertilization. The IZUMO1:IZUMO1R/JUNO interaction is a necessary adhesion event between sperm and egg that is required for fertilization but is not sufficient for cell fusion. The ligand-receptor interaction probably does not act as a membrane 'fusogen'. Does not bind folate.
The protein is rapidly cleaved following fertilization, being only weakly detectable in zona-intact fertilized eggs at telophase II and undetectable at the pronuclear stage. Sheding is probably required to block to polyspermy and ensuring egg fusion with a single sperm.
Belongs to the adipolin/erythroferrone family.
By insulin in subcutaneous adipose tissue.
Homomultimer; disulfide-linked. May interact with ERFE (By similarity).
Insulin-sensitizing adipocyte-secreted protein (adipokine) that regulates glucose metabolism in liver and adipose tissue. Promotes glucose uptake in adipocytes and suppresses de novo glucose production in hepatocytes via the PI3K-Akt signaling pathway. Administration lead to reduction of blood glucose. Able to attenuate inflammation in fat tissue.
Predominantly expressed by adipose tissues.
Processed into Adipolin fC1QTNF12 and Adipolin gC1QTNF12 by FURIN. Insulin enhances endogenous C1QTNF12 cleavage.
Interacts with CHUK/IKKA, inhibiting its kinase activity.
May be involved in inflammation and recognition of cytosolic pathogen-associated molecular patterns (PAMPs) not intercepted by membrane-bound receptors. Acts as a negative regulator of the type I interferon signaling pathway by serving as an adapter to promote DTX4-mediated ubiquitination of activated TBK1, and its subsequent degradation. Suppresses NF-kappaB induction by the cytokines TNFA and IL1B, suggesting that it operates at a point of convergence in these two cytokine signaling pathways.
The pyrin domain is sufficient for suppression of NF-kappaB activity, it adopts a typical death domain fold, but in contrast to several NLRP family pyrin domains it doesn't bind homotypically to the ASC adapter, which supports the observation that NLRP4 has no effect on IL1B activation.
Associated component of the telomerase holoenzyme complex (PubMed:19179534). Component of the vault ribonucleoprotein particle, at least composed of MVP, PARP4 and one or more vault RNAs (vRNAs) (By similarity). Binds to VAULTRC1, VAULTRC2 and VAULTRC4/hvg4 vRNAs (By similarity).
Component of the telomerase ribonucleoprotein complex that is essential for the replication of chromosome termini (PubMed:19179534). Also a component of the ribonucleoprotein vaults particle, a multi-subunit structure involved in nucleo-cytoplasmic transport (By similarity). Responsible for the localizing and stabilizing vault RNA (vRNA) association in the vault ribonucleoprotein particle. Binds to TERC (By similarity).
A stop codon in the gene coding for this protein at position Tyr-27 is responsible for functional diversity thus producing a pseudogene.
Adapter protein which binds TBK1 and IKBKE playing a role in antiviral innate immunity (PubMed:14560022, PubMed:21931631). Activates serine/threonine-protein kinase TBK1 and facilitates its oligomerization (PubMed:14560022, PubMed:21931631). Enhances the phosphorylation of NF-kappa-B p65 subunit RELA by TBK1 (PubMed:14560022, PubMed:21931631). Promotes TBK1-induced as well as TNF-alpha or PMA-induced activation of NF-kappa-B (PubMed:14560022, PubMed:21931631). Participates in IFNB promoter activation via TICAM1 (PubMed:15611223).
Homodimer (By similarity). Interacts with IKBKE (PubMed:14560022, PubMed:17568778). Interacts with TBK1 (PubMed:14560022, PubMed:21931631, PubMed:29251827). Interacts with TICAM1 (PubMed:15611223). Interacts with TAX1BP1 (PubMed:30459273). Interacts with CALCOCO2 (PubMed:30459273).
Ubiquitinated via 'Lys-48'-linked polyubiquitination by TRIM38, leading to its degradation.
Widely expressed (PubMed:14560022). Abundant expression seen in the pancreas and testis (PubMed:14560022).
Uniporter that promotes Zn(2+) import from the extracellular space to the cytoplasm across the cell membrane. The transport activity is temperature dependent. May play a role in neurulation and neurite extension. May play a key role in maintaining intracellular zinc content at levels that reduce the inhibitory effects of rises in oxidative stress on spermatogonia and spermatozoa viability during spermatogenesis.
Expressed in several human brain regions, most prominently in the caudate nucleus.
Interacts with MTOR, RPTOR and NF1 (PubMed:23027611). Interacts with CDK5 (By similarity).
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase. It has a high affinity for tricyclic psychotropic drugs (By similarity). Controls pyramidal neurons migration during corticogenesis, through the regulation of CDK5 activity (By similarity). Is an activator of TOR signaling (PubMed:23027611).
Interacts with TUBGCP2 and TUBGCP3 (PubMed:9566969, PubMed:9566969). Interacts with B9D2 (By similarity). Interacts with CDK5RAP2; the interaction is leading to centrosomal localization of TUBG1 and CDK5RAP2 (PubMed:17959831). Interacts with CIMAP3 (PubMed:20643351). Interacts with SAS6 and NUP62 at the centrosome (PubMed:24107630). Interacts with EML3 (phosphorylated at 'Thr-881') and HAUS8 (PubMed:30723163).
Phosphorylation at Ser-131 by BRSK1 regulates centrosome duplication, possibly by mediating relocation of gamma-tubulin and its associated proteins from the cytoplasm to the centrosome.
Tubulin is the major constituent of microtubules. The gamma chain is found at microtubule organizing centers (MTOC) such as the spindle poles or the centrosome. Pericentriolar matrix component that regulates alpha/beta chain minus-end nucleation, centrosome duplication and spindle formation.
Acetylation at Lys-88 negatively regulates ornithine carbamoyltransferase activity in response to nutrient signals.
Belongs to the aspartate/ornithine carbamoyltransferase superfamily. OTCase family.
Catalyzes the second step of the urea cycle, the condensation of carbamoyl phosphate with L-ornithine to form L-citrulline (PubMed:6372096, PubMed:8112735, PubMed:2556444). The urea cycle ensures the detoxification of ammonia by converting it to urea for excretion (PubMed:2556444).
Mainly expressed in liver and intestinal mucosa.
Negatively regulated by lysine acetylation.
Plasma membrane-associated small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. Causes the formation of thin, actin-rich surface projections called filopodia. Functions cooperatively with CDC42 and Rac to generate additional structures, increasing the diversity of actin-based morphology.
Involved in the interconversion between alpha- and beta-L-fucoses. L-Fucose (6-deoxy-L-galactose) exists as alpha-L-fucose (29.5%) and beta-L-fucose (70.5%), the beta-form is metabolized through the salvage pathway. GDP-L-fucose formed either by the de novo or salvage pathways is transported into the endoplasmic reticulum, where it serves as a substrate for N- and O-glycosylations by fucosyltransferases. Fucosylated structures expressed on cell surfaces or secreted in biological fluids are believed to play a critical role in cell-cell adhesion and recognition processes.
Mainly homodimer, but exists also as homotetramer, homooctamer, and homodecamer. The homodimeric form seems catalytically inactive (By similarity).
(Microbial infection) ADP-riboxanation by C.violaceum CopC blocks CASP9 processing, preventing CASP9 activation and ability to mediate intrinsic apoptosis.
Cleavages at Asp-315 by granzyme B and at Asp-330 by caspase-3 generate the two active subunits. Caspase-8 and -10 can also be involved in these processing events.
Expressed at low levels in fetal heart, at moderate levels in neonate heart, and at high levels in adult heart.
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 35 kDa (p35) and a 10 kDa (p10) subunit. Caspase-9 and APAF1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome C and ATP. Interacts (inactive form) with EFHD2. Interacts with HAX1. Interacts with BIRC2/c-IAP1, XIAP/BIRC4, BIRC5/survivin, BIRC6/bruce and BIRC7/livin. Interacts with ABL1 (via SH3 domain); the interaction is direct and increases in the response of cells to genotoxic stress and ABL1/c-Abl activation. Interacts with BCL2L10 (PubMed:19255499). Interacts with NleF from pathogenic E.coli.
Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis.
Involved in the activation cascade of caspases responsible for apoptosis execution. Binding of caspase-9 to Apaf-1 leads to activation of the protease which then cleaves and activates effector caspases caspase-3 (CASP3) or caspase-7 (CASP7). Promotes DNA damage-induced apoptosis in a ABL1/c-Abl-dependent manner. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP).
Lacks activity is an dominant-negative inhibitor of caspase-9.
May function as an endogenous apoptotic inhibitor, inhibits the BAX-mediated cleavage of procaspase-3.
Phosphorylated at Thr-125 by MAPK1/ERK2. Phosphorylation at Thr-125 is sufficient to block caspase-9 processing and subsequent caspase-3 activation. Phosphorylation on Tyr-153 by ABL1/c-Abl; occurs in the response of cells to DNA damage.
Ubiquitous, with highest expression in the heart, moderate expression in liver, skeletal muscle, and pancreas. Low levels in all other tissues. Within the heart, specifically expressed in myocytes.
A chromosomal aberration involving CDH11 is a common genetic feature of aneurysmal bone cyst, a benign osseous neoplasm. Translocation t(16;17)(q22;p13) with USP6. The translocation generates a fusion gene in which the strong CDH11 promoter is fused to the entire USP6 coding sequence, resulting in USP6 transcriptional up-regulation.
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. Required for proper focal adhesion assembly (PubMed:33811546). Involved in the regulation of cell migration (PubMed:33811546).
Expressed mainly in brain but also found in other tissues. Expressed in neuroblasts. In the embryo from 67 to 72 days of gestation, detected at high levels in facial mesenchyme including the central palatal mesenchyme, dental mesenchyme, the eye and optic muscle, and the tongue (at protein level) (PubMed:33811546).
Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses. May also form heterodimers with other ephrin receptors (By similarity). Interacts with FYN; possible downstream effector of EPHA8 in regulation of cell adhesion. Interacts with PIK3CG; regulates integrin-mediated cell adhesion to substrate. Interacts with TIAM1; regulates clathrin-mediated endocytosis of EPHA8. Interacts with ANKS1A and ANKS1B; EPHA8 kinase activity-independent but stimulated by EPHA8 ubiquitination.
Phosphorylated. Phosphorylation is stimulated upon binding of its ligands including EFNA2, EFNA3 and EFNA5. Autophosphorylation on Tyr-616 is critical for association with FYN. Autophosphorylation on Tyr-839 modulates tyrosine kinase activity (By similarity).
Receptor tyrosine kinase which binds promiscuously GPI-anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. The GPI-anchored ephrin-A EFNA2, EFNA3, and EFNA5 are able to activate EPHA8 through phosphorylation. With EFNA5 may regulate integrin-mediated cell adhesion and migration on fibronectin substrate but also neurite outgrowth. During development of the nervous system also plays a role in axon guidance. Downstream effectors of the EPHA8 signaling pathway include FYN which promotes cell adhesion upon activation by EPHA8 and the MAP kinases in the stimulation of neurite outgrowth (By similarity).
Ubiquitinated. Ubiquitination by CBL regulates the receptor stability and activity through proteasomal degradation. ANKS1A prevents ubiquitination and degradation (By similarity).
A polymorphism 1.2 kb upstream of the MAOA coding sequences consists of a 30-bp repeated sequence present in 3, 3.5, 4, or 5 copies. The polymorphism affect transcriptional activity of the MAOA gene promoter. Alleles with 3.5 or 4 copies of the repeat sequence are transcribed 2 to 10 times more efficiently than those with 3 or 5 copies of the repeat.
Catalyzes the oxidative deamination of primary and some secondary amine such as neurotransmitters, with concomitant reduction of oxygen to hydrogen peroxide and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues (PubMed:20493079, PubMed:8316221, PubMed:18391214, PubMed:24169519). Preferentially oxidizes serotonin (PubMed:20493079, PubMed:24169519). Also catalyzes the oxidative deamination of kynuramine to 3-(2-aminophenyl)-3-oxopropanal that can spontaneously condense to 4-hydroxyquinoline (By similarity).
Heart, liver, duodenum, blood vessels and kidney.
Monomer, homo- or heterodimer (containing two subunits of similar size). Each subunit contains a covalently bound flavin. Enzymatically active as monomer.
Associated component of the WMM complex, a complex that mediates N6-methyladenosine (m6A) methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing (PubMed:24981863, PubMed:29507755). Acts as a key regulator of m6A methylation by promoting m6A methylation of mRNAs in the 3'-UTR near the stop codon: recruits the catalytic core components METTL3 and METTL14, thereby guiding m6A methylation at specific sites (PubMed:29507755). Required for mRNA polyadenylation via its role in selective m6A methylation: m6A methylation of mRNAs in the 3'-UTR near the stop codon correlating with alternative polyadenylation (APA) (PubMed:29507755).
Component of the WMM complex, a N6-methyltransferase complex composed of a catalytic subcomplex, named MAC, and of an associated subcomplex, named MACOM (PubMed:29507755). The MAC subcomplex is composed of METTL3 and METTL14. The MACOM subcomplex is composed of WTAP, ZC3H13, CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B) (PubMed:24981863, PubMed:29507755). Interacts with WTAP (PubMed:24100041). Also a component of a MACOM-like complex, named WTAP complex, composed of WTAP, ZC3H13, CBLL1, VIRMA, RBM15, BCLAF1 and THRAP3 (PubMed:24100041). Interacts with NUDT21 and CPSF6 (PubMed:29507755).
Catalyzes calcium-induced ATP-independent rapid bidirectional and non-specific movement of the phospholipids (lipid scrambling or lipid flip-flop) between the inner and outer membrane of the mitochondria (PubMed:14573790, PubMed:17226776, PubMed:18358005, PubMed:29337693, PubMed:31769662). Plays an important role in mitochondrial respiratory function, morphology, and apoptotic response (PubMed:14573790, PubMed:17226776, PubMed:18358005, PubMed:12649167). Mediates the translocation of cardiolipin from the mitochondrial inner membrane to outer membrane enhancing t-Bid induced cytochrome c release and apoptosis (PubMed:14573790, PubMed:17226776, PubMed:18358005). Enhances TNFSF10-induced apoptosis by regulating the distribution of cardiolipin in the mitochondrial membrane resulting in increased release of apoptogenic factors and consequent amplification of the activity of caspases (PubMed:18491232). Regulates cardiolipin de novo biosynthesis and its resynthesis (PubMed:16939411).
Expressed in heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, uterus, small intestine and peripheral blood lymphocytes. Not detected in testis, brain and liver.
Monomer (PubMed:29337693). Forms homooligomers upon binding to Ca(2+), Pb(2+) and Hg(2+) ions (PubMed:31769662, PubMed:29337693). Interacts with PDCD6 in a calcium-dependent manner (PubMed:18256029). Interacts with PRKCD; interaction is enhanced by UV irradiation (PubMed:12649167).
Palmitoylation regulates its localization to the cell membrane or the nucleus; trafficking to the cell membrane is dependent upon palmitoylation whereas in the absence of palmitoylation, localizes to the nucleus.
Phosphorylation at Thr-21 by PKC/PRKCD upon apoptotic stimuli enhances phospholipid scramblase activity.
A cytochrome P450 monooxygenase that plays a major role in adrenal steroidogenesis. Catalyzes the hydroxylation at C-21 of progesterone and 17alpha-hydroxyprogesterone to respectively form 11-deoxycorticosterone and 11-deoxycortisol, intermediate metabolites in the biosynthetic pathway of mineralocorticoids and glucocorticoids (PubMed:25855791, PubMed:10602386, PubMed:16984992, PubMed:22014889, PubMed:27721825). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:25855791).
Seven non deleterious alleles are known: CYP21A2*1A, CYP21A2*1B, CYP21A2*2, CYP21A2*3, CYP21A2*4, CYP21A2*5 and CYP21A2*6. The sequence shown corresponds to allele CYP21A2*1B. Deleterious alleles are mostly generated by recombinations between CYP21A2 and the pseudogene CYP21A1P through gene conversion. This process consists of recombination events that either delete CYP21A2 or transfer deleterious mutations from CYP21A1P to CYP21A2.
The leucine-rich hydrophobic amino acid N-terminal region probably helps to anchor the protein to the microsomal membrane.
Belongs to the peptidase C78 family. ZUFSP subfamily.
C2H2-type zinc finger 4 is a ubiquitin-binding zinc finger (UBZ) and required for polyubiquitin binding, possibly binding the proximal ubiqutin, and for catalytic activity (PubMed:29576528) (Probable). C2H2-type zinc fingers 1-3 are required for localization to sites of DNA damage (PubMed:29576528).
Deubiquitinase with endodeubiquitinase activity that specifically interacts with and cleaves 'Lys-63'-linked long polyubiquitin chains. Shows only weak activity against 'Lys-11' and 'Lys-48'-linked chains (PubMed:29576528, PubMed:29563501, PubMed:29476094). Plays an important role in genome stability pathways, functioning to prevent spontaneous DNA damage and also promote cellular survival in response to exogenous DNA damage (PubMed:29576528, PubMed:29576527). Modulates the ubiquitination status of replication protein A (RPA) complex proteins in response to replication stress (PubMed:29563501).
The motif interacting with ubiquitin (MIU) and ZUFSP ubiquitin-binding domain (zUBD, also called ZUFSP helical arm ZHA) are responsible for binding the distal (outgoing) ubiquitin units S1 and S2 respectively.
Isolated from prostate cancer cell lines; expression associated with progression to androgen insensitive phenotype. Expressed in normal testis and at lower level in normal placenta.
Acts as a co-chaperone in iron-sulfur cluster assembly in mitochondria (PubMed:20668094). Required for incorporation of iron-sulfur clusters into SDHB, the iron-sulfur protein subunit of succinate dehydrogenase that is involved in complex II of the mitochondrial electron transport chain (PubMed:26749241). Recruited to SDHB by interaction with SDHAF1 which first binds SDHB and then recruits the iron-sulfur transfer complex formed by HSC20, HSPA9 and ISCU through direct binding to HSC20 (PubMed:26749241). Plays an essential role in hematopoiesis (By similarity).
Acts as a co-chaperone in iron-sulfur cluster assembly in the cytoplasm (PubMed:29309586). Also mediates complex formation between components of the cytosolic iron-sulfur biogenesis pathway and the CIA targeting complex composed of CIAO1, DIPK1B/FAM69B and MMS19 by binding directly to the scaffold protein ISCU and to CIAO1 (PubMed:29309586). This facilitates iron-sulfur cluster insertion into a number of cytoplasmic and nuclear proteins including POLD1, ELP3, DPYD and PPAT (PubMed:29309586).
Expressed in lung, brain, stomach, spleen, ovary, testis, liver, muscle and heart.
Homodimer (PubMed:29309586). Interacts with ISCU (cytoplasmic form); this interaction stabilzes the (Fe-S) clusters on ISCU (PubMed:29309586). Interacts with the CIA complex member CIAO1 (via LYR motif) (PubMed:29309586).
Interacts with ISCU and HSPA9 to form an iron-sulfur transfer complex (PubMed:20668094). Interacts with SDHAF1 (via the first LYR motif); the interaction recruits the iron-sulfur transfer complex composed of HSC20, HSPA9 and ISCU and mediates the incorporation of iron-sulfur clusters into SDHB which also interacts with HSC20 (PubMed:26749241). Interacts with the cytoplasmic form of ISCU and with CIA complex member CIAO1 (via LYR motif) (PubMed:29309586).
Expressed in testis. Detected in spermatocytes, spermatids and spermatozoa (at protein level).
PRY has multiple identical or highly similar copies on chromosome Y, some of which might be non functional pseudogenes.
(Microbial infection) May interact with SARS coronavirus-2/SARS-CoV-2; they may form a complex with secreted ACE2.
Has a direct antidiuretic action on the kidney, it also causes vasoconstriction of the peripheral vessels. Acts by binding to vasopressin receptors (V1bR/AVPR1B, V1aR/AVPR1A, and V2R/AVPR2) (PubMed:18174156).
Interacts with vasopressin receptors V1bR/AVPR1B (Ki=85 pM), V1aR/AVPR1A (Ki=0.6 nM) and V2R/AVPR2 (Ki=4.9 nM) (PubMed:18174156). Interacts with oxytocin receptor (OXTR) (Ki=110 nM) (PubMed:18174156).
Contaminating sequence. Presence of complementary strand sequence in the clone.
Interacts with BCL6; the interaction is direct (PubMed:10898795). Forms ternary complexes with BCL6 and SMRT/NCOR2 on selected target genes promoters; potently repress expression (PubMed:23911289, PubMed:18280243). Can interact with HDAC1, HDAC3 and HDAC5 (PubMed:10898795). Interacts with PCGF1; the interaction is direct (PubMed:16943429, PubMed:23523425, PubMed:26687479). Interacts with KDM2B. Component of an approximately 800 kDa repressive BCOR complex at least composed of BCOR, RYBP, PCGF1, RING1, RNF2/RING2, KDM2B and SKP1 (PubMed:16943429). Interacts with CPNE4 (via VWFA domain) (By similarity). Isoform 1 may interact with MLLT3/AF9 (By similarity).
Transcriptional corepressor. May specifically inhibit gene expression when recruited to promoter regions by sequence-specific DNA-binding proteins such as BCL6 and MLLT3. This repression may be mediated at least in part by histone deacetylase activities which can associate with this corepressor. Involved in the repression of TFAP2A; impairs binding of BCL6 and KDM2B to TFAP2A promoter regions. Via repression of TFAP2A acts as a negative regulator of osteo-dentiogenic capacity in adult stem cells; the function implies inhibition of methylation on histone H3 'Lys-4' (H3K4me3) and 'Lys-36' (H3K36me2).
Belongs to the glycosyltransferase 11 family.
Catalyzes the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to the terminal galactose residue of glycoconjugates through an alpha(1,2) linkage leading to H antigen synthesis that is an intermediate substrate in the synthesis of ABO blood group antigens (PubMed:2118655). H antigen is essential for maturation of the glomerular layer of the main olfactory bulb, in cell migration and early cell-cell contacts during tumor associated angiogenesis (PubMed:18205178). Preferentially fucosylates soluble lactose and to a lesser extent fucosylates glycolipids gangliosides GA1 and GM1a (By similarity).
Genetic variations in FUT1 define the H blood group and are responsible for the Bombay and para-Bombay phenotypes [MIM:616754]. Erythrocytes from individuals with the Bombay and para-Bombay blood group phenotypes are deficient in H antigens.
There are two genes (FUT1 and FUT2) which encode galactoside 2-L-fucosyltransferase. They are expressed in a tissue-specific manner with expression restricted to cells of mesodermal or endodermal origin respectively.
Interacts with STYXL1; the interaction inhibits PTPMT1 catalytic activity.
Lipid phosphatase which dephosphorylates phosphatidylglycerophosphate (PGP) to phosphatidylglycerol (PG) (By similarity). PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle (By similarity). Has also been shown to display phosphatase activity toward phosphoprotein substrates, specifically mediates dephosphorylation of mitochondrial proteins, thereby playing an essential role in ATP production (By similarity). Has probably a preference for proteins phosphorylated on Ser and/or Thr residues compared to proteins phosphorylated on Tyr residues (By similarity). Probably involved in regulation of insulin secretion in pancreatic beta cells (By similarity). May prevent intrinsic apoptosis, probably by regulating mitochondrial membrane integrity (PubMed:24709986).
Was originally erroneously termed DUSP23.
Belongs to the PIGG/PIGN/PIGO family. PIGO subfamily.
Ethanolamine phosphate transferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers ethanolamine phosphate to the GPI third mannose which links the GPI-anchor to the C-terminus of the proteins by an amide bond.
Forms a complex with PIGF. PIGF is required to stabilize PIGO (By similarity).
Belongs to the DEAD box helicase family. DEAH subfamily. PRP16 sub-subfamily.
Probable ATP-binding RNA helicase (Probable). Involved in pre-mRNA splicing as component of the spliceosome (PubMed:29301961, PubMed:9524131).
Expressed predominantly in testis and in nasal epithelial cells.
Interacts (via CS domain) with ZMYND10 (via C-terminus).
Involved in dynein arm assembly, is important for expression and transporting outer dynein arm (ODA) proteins from the cytoplasm to the cilia (PubMed:23122589, PubMed:23527195, PubMed:33403504). Acts as a crucial component in the formation and motility of spermatozoal flagella (PubMed:33403504).
Localized in the cytoplasm of early spermatogonia and spermatids of different spermatogenic stages and in the flagella of mature epididymal spermatozoa.
Defects in CAMSAP2 may be a cause of susceptibility to epilepsy in the Chinese population.
Interacts with CAMSAP3 (By similarity). Interacts with KATNA1 and KATNB1; leading to regulate the length of CAMSAP2-decorated microtubule stretches (PubMed:24486153). Interacts with a complex formed by AKAP9 and PDE4DIP isoform 13/MMG8/SMYLE, which recruits CAMSAP2 to the Golgi (PubMed:27666745, PubMed:28814570). Interacts with MAPRE1/EB1 (PubMed:28726242, PubMed:28814570).
Key microtubule-organizing protein that specifically binds the minus-end of non-centrosomal microtubules and regulates their dynamics and organization (PubMed:23169647, PubMed:24486153, PubMed:24706919). Specifically recognizes growing microtubule minus-ends and autonomously decorates and stabilizes microtubule lattice formed by microtubule minus-end polymerization (PubMed:24486153, PubMed:24706919). Acts on free microtubule minus-ends that are not capped by microtubule-nucleating proteins or other factors and protects microtubule minus-ends from depolymerization (PubMed:24486153, PubMed:24706919). In addition, it also reduces the velocity of microtubule polymerization (PubMed:24486153, PubMed:24706919). Through the microtubule cytoskeleton, also regulates the organization of cellular organelles including the Golgi and the early endosomes (PubMed:27666745). Essential for the tethering, but not for nucleation of non-centrosomal microtubules at the Golgi: together with Golgi-associated proteins AKAP9 and PDE4DIP, required to tether non-centrosomal minus-end microtubules to the Golgi, an important step for polarized cell movement (PubMed:27666745). Also acts as a regulator of neuronal polarity and development: localizes to non-centrosomal microtubule minus-ends in neurons and stabilizes non-centrosomal microtubules, which is required for neuronal polarity, axon specification and dendritic branch formation (PubMed:24908486). Through the microtubule cytoskeleton, regulates the autophagosome transport (PubMed:28726242).
The CKK domain binds microtubules and specifically recognizes the minus-end of microtubules (PubMed:24486153).
The MBD (microtubule-binding domain) region can recognize some features of the microtubule lattice, which might contribute to the specific decoration of growing microtubule minus-ends by CAMSAP2.
Expressed at high levels in skeletal muscle and, at much lower levels, in heart, brain and pancreas.
May facilitate the release of atrial natriuretic peptide by cardiomyocytes and hence play a role in the regulation of arterial pressure.
A chromosomal aberration involving NSD2 is a cause of multiple myeloma tumors. Translocation t(4;14)(p16.3;q32.3) with IgH.
Depending on the experimental set up and substrate used, NSD2 has been shown to mono-, di- or tri-methylate 'Lys-27', 'Lys-36' or 'Lys-79' of histone H3 and 'Lys-20' or 'Lys-44' of histone H4 (PubMed:19808676). However, dimethylation of nucleosomal histone H3 at 'Lys-36' (H3K36me2) is likely to be the physiological reaction catalyzed by NSD2 (PubMed:19808676, PubMed:22099308).
Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2) (PubMed:22099308). Methylation of histone H3 at 'Lys-27' is controversial (PubMed:18172012, PubMed:22099308). Mono-, di- or tri-methylates histone H3 at 'Lys-27' (H3K27me, H3K27me2 and H3K27me3) (PubMed:18172012). Does not methylate histone H3 at 'Lys-27' (PubMed:22099308). May act as a transcription regulator that binds DNA and suppresses IL5 transcription through HDAC recruitment (PubMed:11152655, PubMed:18172012).
Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2) (PubMed:27571355, PubMed:22099308, PubMed:19808676, PubMed:29728617, PubMed:33941880). Also monomethylates nucleosomal histone H3 at 'Lys-36' (H3K36me) in vitro (PubMed:22099308). Does not trimethylate nucleosomal histone H3 at 'Lys-36' (H3K36me3) (PubMed:22099308). However, specifically trimethylates histone H3 at 'Lys-36' (H3K36me3) at euchromatic regions in embryonic stem (ES) cells (By similarity). By methylating histone H3 at 'Lys-36', involved in the regulation of gene transcription during various biological processes (PubMed:16115125, PubMed:22099308, PubMed:29728617). In ES cells, associates with developmental transcription factors such as SALL1 and represses inappropriate gene transcription mediated by histone deacetylation (By similarity). During heart development, associates with transcription factor NKX2-5 to repress transcription of NKX2-5 target genes (By similarity). Plays an essential role in adipogenesis, by regulating expression of genes involved in pre-adipocyte differentiation (PubMed:29728617). During T-cell receptor (TCR) and CD28-mediated T-cell activation, promotes the transcription of transcription factor BCL6 which is required for follicular helper T (Tfh) cell differentiation (By similarity). During B-cell development, required for the generation of the B1 lineage (By similarity). During B2 cell activation, may contribute to the control of isotype class switch recombination (CRS), splenic germinal center formation, and the humoral immune response (By similarity). Plays a role in class switch recombination of the immunoglobulin heavy chain (IgH) locus during B-cell activation (By similarity). By regulating the methylation of histone H3 at 'Lys-36' and histone H4 at 'Lys-20' at the IgH locus, involved in TP53BP1 recruitment to the IgH switch region and promotes the transcription of IgA (By similarity).
Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2).
Interacts with HDAC1. Interacts (via PHD-type zinc fingers 1, 2 and 3) with SALL1. Interacts (via PHD-type 1, 2 and 3) with SALL4. Interacts with NANOG. Interacts with OGT. Interacts (via HMG box) with NKX2-5.
NSD2 is located in the Wolf-Hirschhorn syndrome (WHS) critical region. WHS results from by sub-telomeric deletions in the short arm of chromosome 4. NSD2 is deleted in every case, however deletion of linked genes contributes to both the severity of the core characteristics and the presence of the additional syndromic problems.
Widely expressed (PubMed:9618163, PubMed:18172012). Predominantly expressed in thymus and testis (PubMed:9787135, PubMed:18172012).
Associated with DNA polymerase alpha, RFC1 and cyclin A, in multiprotein DNA replication complexes. Also associates with replication origins at the G1/S phase boundary and throughout the S phase in vivo.
By UVC irradiation in quiescent primary fibroblasts. By mitomycin C in human melanoma MeWO cells.
Involved in DNA replication and the cellular response to DNA damage. May participate in DNA replication factories and create a bridge between DNA replication and repair mediated by high molecular weight complexes. May play a role in illegitimate recombination and regulation of gene expression. May participate in mRNA processing. Binds, in vitro, to double-stranded DNA. Also shown to bind preferentially to curved DNA in vitro and in vivo (By similarity). Binds via its C-terminal domain to RNA in vitro.
Recognized by antibodies directed against the RecA protein.
The C-terminal domain (268-393) is organized into 2 subdomains that bear structural similarities to SH3-like domains. Both subdomains adopt a similar 5-stranded beta-barrel-like fold and are connected to each other by a short linker of 5 residues. The 5 beta-sheets are packed at approximately right angles against each other. A highly conserved groove formed at the interface between the 2 subdomains, comprised of Lys residues 302 and 391 and other positively charged residues, may possibly be the site of RNA-binding.
Ubiquitously expressed in all tissues examined, with highest levels in skeletal muscle, heart and testis. Differentially expressed in non-tumorigenic and tumorigenic cell lines. Highly expressed in proliferating epithelial keratinocyte cells in vitro (at protein level).
Blocks nociceptin action in pain transmission by inhibiting nociceptin-induced hyperalgesia and allodynia.
Ligand of the opioid receptor-like receptor OPRL1. It may act as a transmitter in the brain by modulating nociceptive and locomotor behavior. May be involved in neuronal differentiation and development.
Predominantly expressed in the brain and spinal cord. Also expressed and secreted by peripheral blood neutrophils following degranulation.
Specific enzymatic cleavages at paired basic residues probably yield other active peptides besides nociceptin.
Component of E3 ubiquitin ligase complex consisting of FBXO45, MYCBP2 and SKP1 (PubMed:29997255). Functions in substrate recognition but plays also an important role in assembly of the complex (PubMed:29997255). Required for normal neuromuscular synaptogenesis, axon pathfinding and neuronal migration (By similarity). Regulates neuron migration during brain development through interaction with N-cadherin/CDH2 after secretion via a non-classical mechanism (By similarity). Plays a role in the regulation of neurotransmission at mature neurons (By similarity). May control synaptic activity by controlling UNC13A via ubiquitin dependent pathway (By similarity). Specifically recognizes TP73, promoting its ubiquitination and degradation. Polyubiquitinates NMNAT2, an adenylyltransferase that acts as an axon maintenance factor, and regulates its stability and degradation by the proteasome (PubMed:29997255). Acts also by ubiquitinating FBXW7 during prolonged mitotic arrest and promotes FBXW7 proteasomal degradation (PubMed:31285543). Induces subsequently an increase in mitotic slippage and prevents mitotic cell death (PubMed:31285543). In response to influenza infection, mediates interferon-lambda receptor IFNLR1 polyubiquitination and degradation through the ubiquitin-proteasome system by docking with its intracellular receptor domain (PubMed:36379255).
Down-regulated in response to DNA-damage (PubMed:19581926). Induced upon influenza infection (PubMed:36379255).
Forms a complex with MYCBP2 and SKP1 (PubMed:29997255). Interacts with HEY1; leading to FBXO45 nuclear translocation. Interacts (via SPRY domain) with CDH2 (PubMed:32341084).
Expressed in both healthy and inflamed gingival tissue samples at similar levels, with higher expression in the gingival connective tissue compared to gingival epithelium. Strongest expression in testis, followed by leukocytes.
The stop codon in position 277 is polymorphic and is replaced, though at very low frequency, by a Lys codon allowing the translation of a longer protein. It is not clear if the common, shorter variant shown here is functional or not.
Acetylated by p300/CBP, acetylation increases stability. Deacetylated by HDAC1.
Binds the NGFI-B response element (NBRE) as a monomer (PubMed:18690216). Binds the Nur response element (NurRE), consisting of two inverse NBRE-related octanucleotide repeats separated by 6 base-pairs, as a dimer (PubMed:18690216, PubMed:9315652). Interacts (via N-terminus) with NLRP3 (via LRR repeat domain); the interaction is direct, requires binding of NR4A1/Nur77 to NBRE-containing dsDNA and lipopolysaccharide, and leads to non-canonical NLRP3 inflammasome activation (By similarity). Interacts with GADD45GIP1 (PubMed:15459248). Interacts with STK11 (PubMed:22983157). Interacts with IFI27 (PubMed:22427340). Heterodimer (via DNA-binding domain) with RXRA (via C-terminus); DNA-binding of the heterodimer is enhanced by 9-cis retinoic acid (PubMed:17761950, PubMed:15509776). Competes for the RXRA interaction with EP300 and thereby attenuates EP300 mediated acetylation of RXRA (PubMed:17761950). Interacts with NCOA1 (PubMed:18690216). Interacts with NCOA2 (PubMed:18690216). Interacts with NCOA3 (PubMed:18690216).
Fetal muscle and adult liver, brain and thyroid.
In the cytosol, upon its detection of both bacterial lipopolysaccharide (LPS) and NBRE-containing mitochondrial DNA released by GSDMD pores during pyroptosis, it promotes non-canonical NLRP3 inflammasome activation by stimulating association of NLRP3 and NEK7.
Induced by cytosporone B (Csn-B); directly stimulates its own expression (PubMed:18690216). Induced by corticotropin-releasing hormone (CRH) (PubMed:9315652). Induced by growth-stimulating agents (PubMed:1651101).
Its transcription factor activity is activated by binding cytosporone B (Csn-B) via its ligand-binding (NR LBD) domain and stimulates recruitment of coactivators NCOA1 and NCOA2, but not NCOA3, to promoters (PubMed:18690216). Csn-B-binding is also accompanied by its translocation to the mitochondrion (PubMed:18690216). Its transcription factor activity is activated by corticotropin-releasing hormone (CRH) and forskolin (PubMed:9315652). Not activated by binding cytosporone C (Csn-C) (PubMed:18690216).
Orphan nuclear receptor. Binds the NGFI-B response element (NBRE) 5'-AAAGGTCA-3' (PubMed:18690216, PubMed:9315652, PubMed:8121493). Binds 9-cis-retinoic acid outside of its ligand-binding (NR LBD) domain (PubMed:18690216). Participates in energy homeostasis by sequestrating the kinase STK11 in the nucleus, thereby attenuating cytoplasmic AMPK activation (PubMed:22983157). Regulates the inflammatory response in macrophages by regulating metabolic adaptations during inflammation, including repressing the transcription of genes involved in the citric acid cycle (TCA) (By similarity). Inhibits NF-kappa-B signaling by binding to low-affinity NF-kappa-B binding sites, such as at the IL2 promoter (PubMed:15466594). May act concomitantly with NR4A2 in regulating the expression of delayed-early genes during liver regeneration (By similarity). Plays a role in the vascular response to injury (By similarity).
Phosphorylated at Ser-351 by RPS6KA1 and RPS6KA3 in response to mitogenic or stress stimuli.
The NR LBD domain binds the lipid A moiety of lipopolysaccharide (LPS) in the cytosol.
Catalyzes the transfer of a ribitol 5-phosphate from CDP-L-ribitol to the ribitol 5-phosphate previously attached by FKTN/fukutin to the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3-N-acetylglucosamine-beta-4-(phosphate-6-)mannose), a carbohydrate structure present in alpha-dystroglycan (DAG1) (PubMed:26923585, PubMed:29477842, PubMed:31949166, PubMed:27194101). This constitutes the second step in the formation of the ribose 5-phosphate tandem repeat which links the phosphorylated O-mannosyl trisaccharide to the ligand binding moiety composed of repeats of 3-xylosyl-alpha-1,3-glucuronic acid-beta-1 (PubMed:25279699, PubMed:26923585, PubMed:29477842, PubMed:31949166, PubMed:27194101).
Expressed in the retina (at protein level) (PubMed:29416295). Expressed predominantly in skeletal muscle, placenta, and heart and relatively weakly in brain, lung, liver, kidney, and pancreas (PubMed:11592034).
Homodimer; disulfide-linked (PubMed:21886772). Tetramer (PubMed:31949166). Forms a complex composed of FKRP, FKTN/fukutin, and RXYLT1/TMEM5 (PubMed:29477842). Exists also as large multimeric protein complexes (PubMed:25279699). May interact with the dystrophin-glycoprotein complex (DGC) (By similarity).
Encoded in intron of the gene CYFIP2 (opposite strand).
Catalyzes the phosphorylation of various hexoses, such as D-glucose, D-glucosamine, D-fructose, D-mannose and 2-deoxy-D-glucose, to hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, D-fructose 6-phosphate, D-mannose 6-phosphate and 2-deoxy-D-glucose 6-phosphate, respectively) (PubMed:1637300, PubMed:25316723, PubMed:27374331). Does not phosphorylate N-acetyl-D-glucosamine (PubMed:27374331). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (By similarity). Involved in innate immunity and inflammation by acting as a pattern recognition receptor for bacterial peptidoglycan (PubMed:27374331). When released in the cytosol, N-acetyl-D-glucosamine component of bacterial peptidoglycan inhibits the hexokinase activity of HK1 and causes its dissociation from mitochondrial outer membrane, thereby activating the NLRP3 inflammasome (PubMed:27374331).
Hexokinase is an allosteric enzyme inhibited by its product D-glucose 6-phosphate (PubMed:1637300). Hexokinase activity is inhibited by N-acetyl-D-glucosamine (PubMed:27374331).
Hexokinase is known to act as a monomer (PubMed:10686099). It however homodimerizes at elevated protein concentrations used for crystallizations (PubMed:9493266, PubMed:10574795).
Isoform 2: Erythrocyte specific (Ref.6). Isoform 3: Testis-specific (PubMed:10978502). Isoform 4: Testis-specific (PubMed:10978502).
Monomer (PubMed:10686099). Interacts with RABL2/RABL2A; binds preferentially to GTP-bound RABL2 (By similarity). Interacts with VDAC1 (PubMed:22304920). The HK1-VDAC1 complex interacts with ATF2 (PubMed:22304920). Interacts (via N-terminal spermatogenic cell-specific region) with PFKM (via C-terminus) (By similarity). Interacts with SMAD5 (PubMed:28675158).
The N- and C-terminal halves of this hexokinase contain a hexokinase domain (PubMed:9493266, PubMed:9735292, PubMed:10574795). The catalytic activity is associated with the C-terminus while regulatory function is associated with the N-terminus (PubMed:9493266, PubMed:9735292, PubMed:10574795). Each domain can bind a single D-glucose and D-glucose 6-phosphate molecule (PubMed:9493266).
Microtubule-associated formin which regulates both actin and microtubule dynamics. Induces microtubule acetylation and stabilization and actin stress fiber formation (PubMed:18815276). Regulates Golgi ribbon formation (PubMed:26564798). Required for normal cilia assembly. Early in cilia assembly, may assist in the maturation and positioning of the centrosome/basal body, and once cilia assembly has initiated, may also promote cilia elongation by inhibiting disassembly (PubMed:29742020).
The FH2 and MBD domains are essential for its function in regulating Golgi ribbon formation.
(Microbial infection) Interacts with human enterovirus 71/EV-71 capsid protein VP1; the interaction is required for induction of autophagy and the infectivity of EV-71.
(Microbial infection) Involved in human enterovirus 71/EV-71 infection by enhancing the autophagy mechanism during the infection.
Expression increases approximately 3-fold upon entry into G1 phase compared to other phases of the cell cycle. Also induced following inhibition of mitochondrial protein synthesis by thiamphenicol.
In the mitochondria, together with PHB, forms large ring complexes (prohibitin complexes) in the inner mitochondrial membrane (IMM) and functions as chaperone protein that stabilizes mitochondrial respiratory enzymes and maintains mitochondrial integrity in the IMM, which is required for mitochondrial morphogenesis, neuronal survival, and normal lifespan (Probable). The prohibitin complex, with DNAJC19, regulates cardiolipin remodeling and the protein turnover of OMA1 in a cardiolipin-binding manner (By similarity). Also regulates cytochrome-c oxidase assembly (COX) and mitochondrial respiration (PubMed:20959514, PubMed:11302691). Binding to sphingoid 1-phosphate (SPP) modulates its regulator activity (PubMed:20959514, PubMed:11302691). Has a key role of mitophagy receptor involved in targeting mitochondria for autophagic degradation (PubMed:28017329). Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6 (PubMed:31522117).
In the nucleus, serves as transcriptional co-regulator (Probable). Acts as a mediator of transcriptional repression by nuclear hormone receptors via recruitment of histone deacetylases. Functions as an estrogen receptor (ER)-selective coregulator that potentiates the inhibitory activities of antiestrogens and represses the activity of estrogens. Competes with NCOA1 for modulation of ER transcriptional activity (By similarity).
In the plasma membrane, is involved in IGFBP6-induced cell migration (PubMed:24003225). Cooperates with CD86 to mediate CD86-signaling in B lymphocytes that regulates the level of IgG1 produced through the activation of distal signaling intermediates. Upon CD40 engagement, required to activate NF-kappa-B signaling pathway via phospholipase C and protein kinase C activation (By similarity).
LC3-interaction region (LIR) is required for interaction with MAP1LC3B/LC3-II and for Parkin-mediated mitophagy.
Levels of expression in fibroblasts decrease heterogeneously during cellular aging.
Phosphorylated. Tyrosine phosphorylation is indirectly stimulated by IGFBP6.
Protein with pleiotropic attributes mediated in a cell-compartment- and tissue-specific manner, which include the plasma membrane-associated cell signaling functions, mitochondrial chaperone, and transcriptional co-regulator of transcription factors and sex steroid hormones in the nucleus.
The mitochondrial prohibitin complex consists of two subunits (PHB1 and PHB2), assembled into a membrane-associated ring-shaped supercomplex of approximately 1 mDa (PubMed:20959514, PubMed:28017329, PubMed:31522117). Interacts with ESR1, HDAC1 and HDAC5 (By similarity). Interacts with ZNF703 (PubMed:21328542). Interacts with STOML2 (PubMed:21746876). Interacts with ARFGEF3 (PubMed:19496786). Interacts with SPHK2. Interacts with COX4I1; the interaction associates PHB2 with COX (By similarity). Interacts with MAP1LC3B (membrane-bound form LC3-II); the interaction is direct and upon mitochondrial depolarization and proteasome-dependent outer membrane rupture (PubMed:28017329). Interacts with IGFBP6 (via C-terminal domain) (PubMed:24003225). Interacts with CLPB (PubMed:31522117). Interacts with CD86 (via cytoplasmic domain); the interactions increases after priming with CD40 (By similarity). Interacts with AFG3L2 (By similarity). Interacts with DNAJC19 (By similarity).
Expressed primarily in skeletal muscle. Detected at lower levels in heart, prostate and pancreas.
Interacts with ACTN2, ACTN3, FLNA, FLNB, FLNC, LDB3, PPP3CA and TCAP. Interacts via its C-terminal region with MYOT.
Myozenins may serve as intracellular binding proteins involved in linking Z-disk proteins such as alpha-actinin, gamma-filamin, TCAP/telethonin, LDB3/ZASP and localizing calcineurin signaling to the sarcomere. Plays an important role in the modulation of calcineurin signaling. May play a role in myofibrillogenesis.
Expressed specifically in the middle/upper portions of the hair cortex, in the region termed the keratogenous zone.
Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway. May also regulate MDM2 autoubiquitination and degradation and thereby activate p53/TP53.
Homodimer (PubMed:28202711). Interacts with KRT17 and SAMSN1 (By similarity). Found in a complex with XPO7, EIF4A1, ARHGAP1, VPS26A, VPS29 and VPS35. Interacts with GAB2. Interacts with SRPK2. Interacts with COPS6. Interacts with COP1; this interaction leads to proteasomal degradation. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB (PubMed:23572552). Interacts with SLITRK1 (PubMed:19640509). Interacts with LRRK2; this interaction is dependent on LRRK2 phosphorylation (PubMed:28202711).
Present mainly in tissues enriched in stratified squamous keratinizing epithelium.
Ubiquitinated. Ubiquitination by RFFL induces proteasomal degradation and indirectly regulates p53/TP53 activation.
p53-regulated inhibitor of G2/M progression.
Detected in skin fibroblasts (at protein level) (PubMed:8537347).
GTPase-activating protein for Rho family members (PubMed:8537347).
The pG1 pseudoGTPase domain does not bind GTP.
May be involved in the calcium-dependent regulation of rhodopsin phosphorylation.
Probably binds two or three calcium ions.
(Microbial infection) Interacts with HTLV-1 Tax, p30II and HBZ.
(Microbial infection) Interacts with human herpes virus 8/HHV-8 protein vIRF-1; this interaction inhibits CREBBP binding to IRF3.
Acetylates histones, giving a specific tag for transcriptional activation (PubMed:24616510). Also acetylates non-histone proteins, like DDX21, FBL, IRF2, MAFG, NCOA3, POLR1E/PAF53 and FOXO1 (PubMed:10490106, PubMed:11154691, PubMed:12738767, PubMed:12929931, PubMed:9707565, PubMed:24207024, PubMed:28790157, PubMed:30540930, PubMed:35675826). Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-BMAL1 and CLOCK-BMAL1 heterodimers (PubMed:14645221). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates POLR1E/PAF53, leading to decreased association of RNA polymerase I with the rDNA promoter region and coding region (PubMed:24207024). Acetylates DDX21, thereby inhibiting DDX21 helicase activity (PubMed:28790157). Acetylates FBL, preventing methylation of 'Gln-105' of histone H2A (H2AQ104me) (PubMed:30540930). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493).
Autoacetylation is required for binding to protein substrates, such as acetylated histones and acetylated TP53/p53 (PubMed:24616510). Autoacetylation is induced by glucose and fatty acids (PubMed:35675826).
Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with KMT2A/MLL1; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription.
Found in a complex containing NCOA2; NCOA3; IKKA; IKKB and IKBKG. Probably part of a complex with HIF1A and EP300. Interacts with GATA1; the interaction results in acetylation and enhancement of transcriptional activity of GATA1. Interacts with MAF and ZCCHC12. Interacts with DAXX; the interaction is dependent on CBP sumoylation and results in suppression of the transcriptional activity via recruitment of HDAC2 to DAXX (By similarity). Interacts with phosphorylated CREB1. Interacts with CITED4 (C-terminal region). Interacts (via the TAZ-type 1 domain) with HIF1A. Interacts with SRCAP, CARM1, ELF3, MLLT7/FOXO4, N4BP2, NCOA1, NCOA3, NCOA6, PCAF, DDX5, DDX17, PELP1, PML, SMAD1, SMAD2, SMAD3, SPIB and TRERF1. Interacts with KLF1; the interaction results in acetylation of KLF1 and enhancement of its transcriptional activity. Interacts with MTDH. Interacts with NFATC4. Interacts with MAFG; the interaction acetylates MAFG in the basic region and stimulates NFE2 transcriptional activity through increasing its DNA-binding activity. Interacts with IRF2; the interaction acetylates IRF2 and regulates its activity on the H4 promoter. Interacts with IRF3 (when phosphorylated); forming the dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I interferon genes (PubMed:27302953). Interacts (via N-terminus) with SS18L1/CREST (via C-terminus). Interacts with MECOM. Interacts with CITED1 (via C-terminus). Interacts with FOXO1; the interaction acetylates FOXO1 and inhibits its transcriptional activity. Interacts with NPAS2, CLOCK and BMAL1. Interacts with ASF1A and ASF1B; this promotes histone acetylation. Interacts with acetylated TP53/p53 and with the acetylated histones H3 and H4. Interacts (via transactivation domain and C-terminus) with PCNA; the interaction occurs on chromatin in UV-irradiated damaged cells (PubMed:24939902). Interacts with DHX9 (via N-terminus); this interaction mediates association with RNA polymerase II holoenzyme and stimulates CREB-dependent transcriptional activation (PubMed:9323138). Interacts with SMAD4; negatively regulated by ZBTB7A (PubMed:25514493). Interacts with DUX4 (via C-terminus) (PubMed:26951377). Forms a complex with KMT2A and CREB1 (PubMed:23651431). Interacts with DDX3X; this interaction may facilitate HNF4A acetylation (PubMed:28128295). Interacts with MSX1; the interaction may inhibit MSX1 autoinactivation (By similarity).
Methylation of the KIX domain by CARM1 blocks association with CREB. This results in the blockade of CREB signaling, and in activation of apoptotic response (By similarity).
Phosphorylated by CHUK/IKKA at Ser-1382 and Ser-1386; these phosphorylations promote cell growth by switching the binding preference of CREBBP from TP53 to NF-kappa-B.
Sumoylation negatively regulates transcriptional activity via the recruitment of DAAX.
The KIX domain mediates binding to HIV-1 Tat.
Expressed in various tissues including retina, heart, skeletal muscle, prostate, ovary, small intestine, thyroid, adrenal cortex, testis, stomach and spinal cord.
ATP-dependent RNA helicase. Required for mRNA export and translation regulation during spermatid development (By similarity).
Highly expressed in the Leydig and germ cells of the testis and weakly expressed in the pituitary and hypothalamus.
Phosphorylated on threonine residues. The phosphorylated form is found in the cytoplasm but not in the nucleus (By similarity).
Up-regulated at transcriptional level by chorionic gonadotropin via cyclic AMP-induced androgen formation in the Leydig cell.
Binds with and transactivates the corticotropin-releasing hormone (CRH) promoter.
Expressed in neurons of the paraventricular nucleus, thalamus and occipital cortex and in glial cells (at protein level). Predominantly expressed in dendritic cells. Detected in brain and skeletal muscle. Highly expressed in mature dendritic cells and at a lower level in immature dendritic cells. Expressed in paraventricular nucleus, supraoptic nucleus and nucleus basalis of Meynert. Strongly expressed in paraventricular nucleus of depressed patients compared to controls. Not expressed in monocytes and B-cells.
Accessory subunit of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which plays an essential role in the initiation of DNA synthesis (PubMed:9705292). During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, an accessory subunit POLA2 and two primase subunits, the catalytic subunit PRIM1 and the regulatory subunit PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1 (By similarity). The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands (By similarity). These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively (By similarity).
Accessory subunit of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which plays an essential role in the initiation of DNA synthesis.
Belongs to the DNA polymerase alpha subunit B family.
Component of the alpha DNA polymerase complex (also known as the alpha DNA polymerase-primase complex) consisting of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and primase complex subunits PRIM1 and PRIM2 respectively (PubMed:9705292, PubMed:26975377). Within the complex, POLA1 directly interacts with PRIM2/p58 (By similarity).
Phosphorylated in a cell cycle-dependent manner, in G2/M phase.
The N-terminal 240 amino acids are sufficient to mediate complex formation.
Acts as both a transcriptional activator and repressor (PubMed:10359848, PubMed:29739711). Binds to the DNA sequence 5'-ACAAT-3' and shows a preference for guanine residues surrounding this core motif (PubMed:10359848). Binds to its own promoter and activates its own transcription (By similarity). Required to activate the expression of postmeiotic genes involved in spermiogenesis (By similarity). Binds to the promoter region of CTNNB1 and represses its transcription which leads to inhibition of Wnt signaling (PubMed:29739711). Also inhibits Wnt signaling by binding to the CTNNB1 protein, preventing interaction of CTNNB1 with TCF7L2/TCF4 (PubMed:29739711).
Interacts with CTNNB1, competitively inhibiting CTNNB1-TCF7L2/TCF4 interaction.
Component of the PEX2-PEX10-PEX12 retrotranslocation channel, composed of PEX2, PEX10 and PEX12 (PubMed:24662292). Interacts with PEX19 (PubMed:10704444, PubMed:11390669).
E3 ubiquitin-protein ligase component of a retrotranslocation channel required for peroxisome organization by mediating export of the PEX5 receptor from peroxisomes to the cytosol, thereby promoting PEX5 recycling (PubMed:24662292). The retrotranslocation channel is composed of PEX2, PEX10 and PEX12; each subunit contributing transmembrane segments that coassemble into an open channel that specifically allows the passage of PEX5 through the peroxisomal membrane (By similarity). PEX10 also regulates PEX5 recycling by acting as a E3 ubiquitin-protein ligase (PubMed:24662292). When PEX5 recycling is compromised, PEX10 catalyzes polyubiquitination of PEX5 during its passage through the retrotranslocation channel, leading to its degradation (By similarity).
The E3 ubiquitin-protein ligase activity is stimulated by PEX12.
The three subunits of the retrotranslocation channel (PEX2, PEX10 and PEX12) coassemble in the membrane into a channel with an open 10 Angstrom pore (By similarity). The RING-type zinc-fingers that catalyze PEX5 receptor ubiquitination are positioned above the pore on the cytosolic side of the complex (By similarity).
Highly expressed in kidney, weakly expressed in heart, liver, spleen, and small intestine. Not expressed in adult brain or spinal cord.
Component of the uniplex complex, composed of MCU, MCUB, MICU1, MICU2 and EMRE/SMDT1 (PubMed:24231807). Homooligomer (PubMed:21685886, PubMed:26341627). Forms a pentamer (By similarity). Heterooligomer with CCDC109B/MCUB; this inhibits channel activity (By similarity). Interacts with MICU1; MICU1 acts as an essential regulator for MCU (PubMed:21685886, PubMed:23101630, PubMed:23178883, PubMed:24332854, PubMed:26341627). Interacts with MCUR1 (PubMed:23178883, PubMed:26341627, PubMed:27184846, PubMed:26976564). Interacts with CCDC90B (PubMed:27184846). Interactions with MICU1 and MCUR1 are mutually exclusive (PubMed:23178883). Interacts with MICU2 (PubMed:26341627). Interacts with SLC25A23 (PubMed:24430870).
Forms a well-packed pentamer with an overall cylindrical shape. The inner core of the pentamer is formed with the second transmembrane region and the second coiled-coil region: while the transmembrane regions pack into a five-helix bundle having a largely polar pore across the membrane, the coiled-coil outside the membrane forms a pentamer with a hydrophobic core. The inner core is wrapped by the first transmembrane region through contacts between the first and the second transmembrane regions. The second transmembrane is followed by the inner juxtamembrane region (IJMH) that orients at a wide angle relative to the second transmembrane. The two core domains are held together on the periphery by the outer juxtamembrane helix (OJMH).
Inhibited by ruthenium red or its derivative Ru360.
MCU transcripts are down-regulated by microRNA miR-25 (PubMed:23246404). Down-regulation by miR-25 may protect cardiomyocytes against oxidative damage in cardiomyocytes (PubMed:25764156).
Mitochondrial inner membrane calcium uniporter that mediates calcium uptake into mitochondria (PubMed:21685888, PubMed:21685886, PubMed:23101630, PubMed:22904319, PubMed:23178883, PubMed:22829870, PubMed:22822213, PubMed:24332854, PubMed:23755363, PubMed:26341627). Constitutes the pore-forming and calcium-conducting subunit of the uniporter complex (uniplex) (PubMed:23755363). Activity is regulated by MICU1 and MICU2. At low Ca(2+) levels MCU activity is down-regulated by MICU1 and MICU2; at higher Ca(2+) levels MICU1 increases MCU activity (PubMed:24560927, PubMed:26903221). Mitochondrial calcium homeostasis plays key roles in cellular physiology and regulates cell bioenergetics, cytoplasmic calcium signals and activation of cell death pathways. Involved in buffering the amplitude of systolic calcium rises in cardiomyocytes (PubMed:22822213). While dispensable for baseline homeostatic cardiac function, acts as a key regulator of short-term mitochondrial calcium loading underlying a 'fight-or-flight' response during acute stress: acts by mediating a rapid increase of mitochondrial calcium in pacemaker cells (PubMed:25603276). participates in mitochondrial permeability transition during ischemia-reperfusion injury (By similarity). Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake (PubMed:22904319, PubMed:22829870). Mitochondrial calcium uptake in skeletal muscle cells is involved in muscle size in adults (By similarity). Regulates synaptic vesicle endocytosis kinetics in central nerve terminal (By similarity). Involved in antigen processing and presentation (By similarity).
Phosphorylation by CaMK2 in heart leads to increased MCU current (PubMed:23051746, PubMed:25254481). The regulation of MCU by CaMK2 is however subject to discussion: another group was unable to reproduce these results (PubMed:25254480). Phosphorylated on tyrosines by PTK2B/PYK2, promoting oligomerization (PubMed:24800979).
The N-terminal MCU domain is required for efficient Ca(2+) uptake and for interaction with MCUR1. It is not required for targeting to the mitochondria, oligomerization, interaction with MICU1 and MICU2, or assembly of the uniplex complex.
The critical DXXE motif connecting the transmembrane regions forms a pentameric barrel that constitutes the mouth of the pore. Inside the barrel, two acidic residues are in position to form two carboxylate rings. In absence of SMDT1/EMRE regulator, the calcium ions cannot exit the channel, suggesting that SMDT1/EMRE-binding induces conformational rearrangements to allow calcium to exit.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Involved in the formation of glutathione conjugates of both prostaglandin A2 (PGA2) and prostaglandin J2 (PGJ2) (PubMed:9084911). Participates in the formation of novel hepoxilin regioisomers (PubMed:21046276).
There are two alleles; GSTM1A and GSTM1B which differ in position 173. The sequence shown is that of allele GSTM1A.
Detected in spinal cord (PubMed:11133365). Isoform 1 and isoform 2 are found in sciatic nerve and Schwann cells (PubMed:11157804).
Has a remarkable domain of repetitive pentameric units sometimes followed by a tripeptide spacer, it may separate two functional basic and acidic domains.
Homodimer (via PDZ domain) (PubMed:24675079). Interacts with SCN10A. Found in a complex with SCN10A (By similarity). Interacts with DRP2. Identified in a dystroglycan complex that contains at least PRX, DRP2, UTRN, DMD and DAG1 (By similarity). Detected in a complex composed of at least EZR, AHNAK, PPL and PRX (By similarity). Identified in a complex with EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, VIM and spectrin (By similarity).
Scaffolding protein that functions as part of a dystroglycan complex in Schwann cells, and as part of EZR and AHNAK-containing complexes in eye lens fiber cells. Required for the maintenance of the peripheral myelin sheath that is essential for normal transmission of nerve impulses and normal perception of sensory stimuli. Required for normal transport of MBP mRNA from the perinuclear to the paranodal regions. Required for normal remyelination after nerve injury. Required for normal elongation of Schwann cells and normal length of the internodes between the nodes of Ranvier. The demyelinated nodes of Ranvier permit saltatory transmission of nerve impulses; shorter internodes cause slower transmission of nerve impulses. Required for the formation of appositions between the abaxonal surface of the myelin sheath and the Schwann cell plasma membrane; the Schwann cell cytoplasm is restricted to regions between these appositions. Required for the formation of Cajal bands and of Schmidt-Lanterman incisures that correspond to short, cytoplasm-filled regions on myelinated nerves. Recruits DRP2 to the Schwann cell plasma membrane. Required for normal protein composition of the eye lens fiber cell plasma membrane and normal eye lens fiber cell morphology.
The Arg/Lys-rich basic domain functions as a tripartite nuclear localization signal.
The PDZ domain contains the signal for export from the nucleus (PubMed:24633211). The N-terminal region including the PDZ domain is required for the formation of Cajal bands on myelinated nerves.
Contaminating sequence. Due to an insert of 27 undefined residues.
Palmitoylated on at least one of the three cysteine residues present in the C-terminal part.
Receptor for the hormone galanin. The activity of this receptor is mediated by G proteins that inhibit adenylate cyclase activity.
Adipokine secreted by white adipose tissue that plays an important regulatory role in the glucose metabolism of liver, muscle and pancreas (PubMed:27087445, PubMed:30853600). Hormone that targets the liver in response to fasting to increase plasma glucose levels (PubMed:27087445). Binds the olfactory receptor OR4M1 at the surface of hepatocytes and promotes hepatocyte glucose release by activating the protein kinase A activity in the liver, resulting in rapid glucose release into the circulation (PubMed:27087445, PubMed:31230984). May act as a regulator of adaptive thermogenesis by inhibiting browning and energy consumption, while increasing lipid deposition in white adipose tissue (By similarity). Also acts as an orexigenic hormone that increases appetite: crosses the blood brain barrier and exerts effects on the hypothalamus (By similarity). In the arcuate nucleus of the hypothalamus, asprosin directly activates orexigenic AgRP neurons and indirectly inhibits anorexigenic POMC neurons, resulting in appetite stimulation (By similarity). Activates orexigenic AgRP neurons via binding to the olfactory receptor OR4M1 (By similarity). May also play a role in sperm motility in testis via interaction with OR4M1 receptor (By similarity).
Asprosin levels are elevated in patients with type II diabetes and metabolic syndrome (at protein level).
Attractive therapeutic target for type II diabetes and metabolic syndrome.
Cleavage of N- and C-terminus by furin is required for incorporation into the extracellular matrix and assembly into microfibrils (PubMed:27026396). The C-terminus, which corresponds to the Asprosin chain, was initially thought to constitute a propeptide (PubMed:24982166). Fibrillin-1 and Asprosin chains are still linked together during the secretion from cells, but are subsequently separated by furin, an essential step for incorporation of Fibrillin-1 into the nascent microfibrils (PubMed:24982166).
Forms intermolecular disulfide bonds either with other fibrillin-1 molecules or with other components of the microfibrils.
Interacts with COL16A1 (PubMed:15165854). Interacts with integrin alpha-V/beta-3 (PubMed:15062093). Interacts with ADAMTS10; this interaction promotes microfibril assembly (PubMed:21402694). Interacts with THSD4; this interaction promotes fibril formation (By similarity). Interacts (via N-terminal domain) with FBLN2 and FBLN5 (PubMed:15790312, PubMed:17255108). Interacts with ELN (PubMed:15790312). Forms a ternary complex with ELN and FBLN2 or FBLN5 and a significant interaction with ELN seen only in the presence of FBLN2 or FBLN5 (PubMed:17255108). Interacts (via N-terminal domain) with LTBP2 (via C-terminal domain) in a Ca(+2)-dependent manner (PubMed:17293099). Interacts (via N-terminal domain) with LTBP1 (via C-terminal domain) (PubMed:17293099). Interacts with integrins ITGA5:ITGB1, ITGAV:ITGB3 and ITGAV:ITGB6 (PubMed:17158881, PubMed:12807887). Interacts (via N-terminal domain) with BMP2, BMP4, BMP7, BMP10 and GDF5 (PubMed:18339631). Interacts (via N-terminal domain) with MFAP2 and MFAP5 (PubMed:15131124). Interacts with ADAMTSL5 (PubMed:23010571). Interacts with MFAP4 (PubMed:26601954). Interacts (via N-terminal domain) with TNFSF11 in a Ca(+2)-dependent manner (PubMed:24039232). Interacts (via N-terminal domain) with EFEMP2; this interaction inhibits EFEMP2 binding to LOX and ELN (PubMed:17255108, PubMed:19349279, PubMed:19570982).
O-glycosylated on serine residues by POGLUT2 and POGLUT3 which is necessary for efficient protein secretion.
Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues (PubMed:1860873, PubMed:15062093). Fibrillin-1-containing microfibrils provide long-term force bearing structural support (PubMed:27026396). In tissues such as the lung, blood vessels and skin, microfibrils form the periphery of the elastic fiber, acting as a scaffold for the deposition of elastin (PubMed:27026396). In addition, microfibrils can occur as elastin-independent networks in tissues such as the ciliary zonule, tendon, cornea and glomerulus where they provide tensile strength and have anchoring roles (PubMed:27026396). Fibrillin-1 also plays a key role in tissue homeostasis through specific interactions with growth factors, such as the bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and latent transforming growth factor-beta-binding proteins (LTBPs), cell-surface integrins and other extracellular matrix protein and proteoglycan components (PubMed:27026396). Regulates osteoblast maturation by controlling TGF-beta bioavailability and calibrating TGF-beta and BMP levels, respectively (By similarity). Negatively regulates osteoclastogenesis by binding and sequestering an osteoclast differentiation and activation factor TNFSF11 (PubMed:24039232). This leads to disruption of TNFSF11-induced Ca(2+) signaling and impairment of TNFSF11-mediated nuclear translocation and activation of transcription factor NFATC1 which regulates genes important for osteoclast differentiation and function (PubMed:24039232). Mediates cell adhesion via its binding to cell surface receptors integrins ITGAV:ITGB3 and ITGA5:ITGB1 (PubMed:12807887, PubMed:17158881). Binds heparin and this interaction has an important role in the assembly of microfibrils (PubMed:11461921).
The disease is caused by variants affecting the gene represented in this entry. The majority of the more than a thousand mutations in FBN1 currently known are point mutations, the rest are frameshifts and splice site mutations. Marfan syndrome has been suggested in at least 2 historical figures, Abraham Lincoln and Paganini.
Was named after the Greek word for white, because of the reduction in subcutaneous white adipose tissue that is displayed by asprosin-deficient patients.
Involved in the early processing steps of the pre-rRNA in the maturation pathway leading to the 18S rRNA.
(Microbial infection) Functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP-ribosyltransferase.
(Microbial infection) Identified in a complex with RAB1A and EspG from enteropathogenic E.coli.
(Microbial infection) Interacts with EspG from enteropathogenic E.coli.
(Microbial infection) Interacts with the V.cholerae enterotoxin subunit A1; this causes a conformation change so that the toxin can bind NAD and catalyze the ADP-ribosylation of Gs alpha.
Activation is generally mediated by a guanine exchange factor (GEF), while inactivation through hydrolysis of bound GTP is catalyzed by a GTPase activating protein (GAP). Activated by ASAP3. Inactivated by ACAP1 and ACAP2. Activated by NGF via NTRK1 (By similarity).
GTP-binding protein involved in protein trafficking that regulates endocytic recycling and cytoskeleton remodeling (PubMed:11266366, PubMed:21170023, PubMed:16737952, PubMed:7589240, PubMed:18400762, PubMed:32103017). Required for normal completion of mitotic cytokinesis (By similarity). Plays a role in the reorganization of the actin cytoskeleton and the formation of stress fibers (By similarity). Involved in the regulation of dendritic spine development, contributing to the regulation of dendritic branching and filopodia extension (PubMed:14978216). Plays an important role in membrane trafficking, during junctional remodeling and epithelial polarization. Regulates surface levels of adherens junction proteins such as CDH1 (By similarity). Required for NTRK1 sorting to the recycling pathway from early endosomes (By similarity).
GTP-bound form is myristoylated on Lys-3 by NMT1 and NMT2, allowing ARF6 to remain on membranes during the GTPase cycle, thereby promoting its activity (PubMed:32103017). GDP-bound inactive form is demyristoylated on Lys-3 by SIRT2 at early endosomes or endocytic recycling compartment to allow its efficient activation by a guanine exchange factor (GEF) after GDP release (PubMed:32103017).
Interacts (when activated) with GGA1, GGA2 and GGA3; the interaction is required for proper subcellular location of GGA1, GGA2 and GGA3 (PubMed:11950392). Interacts with PIP5K1C (PubMed:12847086). Interacts with USP6 (via Rab-GAP TBC domain) (PubMed:15509780). Interacts with RAB11FIP3 and RAB11FIP4 (PubMed:16148947, PubMed:17030804, PubMed:17628206). Interacts with HERC1 (PubMed:15642342). Interacts with ARHGAP21 (PubMed:15793564). Interacts with ASAP3; the interaction is stabilized by calcium ions (PubMed:16737952, PubMed:20510928). Interacts with NCS1/FREQ at the plasma membrane (PubMed:17555535). Interacts with TBC1D24 (PubMed:20727515). Interacts with ECPAS (PubMed:20682791). Interacts with MICALL1 (PubMed:21951725). Interacts with SPAG9 homodimers, forming heterotetramers (PubMed:19644450). Interacts with CYTH3 (PubMed:23940353). Interacts with ASAP2 (By similarity). Interacts with UACA (By similarity). Interacts with KIF23, forming heterodimers and heterotetramers (By similarity). Interacts with C9orf72 (By similarity). Interacts (GTP-bound form) with TJAP1/PILT (By similarity).
Ubiquitous, with higher levels in heart, substantia nigra, and kidney.
Atypical E2F transcription factor that participates in various processes such as angiogenesis, polyploidization of specialized cells and DNA damage response. Mainly acts as a transcription repressor that binds DNA independently of DP proteins and specifically recognizes the E2 recognition site 5'-TTTC[CG]CGC-3'. Directly represses transcription of classical E2F transcription factors such as E2F1. Acts as a regulator of S-phase by recognizing and binding the E2-related site 5'-TTCCCGCC-3' and mediating repression of G1/S-regulated genes. Plays a key role in polyploidization of cells in placenta and liver by regulating the endocycle, probably by repressing genes promoting cytokinesis and antagonizing action of classical E2F proteins (E2F1, E2F2 and/or E2F3). Required for placental development by promoting polyploidization of trophoblast giant cells. Also involved in DNA damage response: up-regulated by p53/TP53 following genotoxic stress and acts as a downstream effector of p53/TP53-dependent repression by mediating repression of indirect p53/TP53 target genes involved in DNA replication. Acts as a promoter of sprouting angiogenesis, possibly by acting as a transcription activator: associates with HIF1A, recognizes and binds the VEGFA promoter, which is different from canonical E2 recognition site, and activates expression of the VEGFA gene. Acts as a negative regulator of keratinocyte differentiation.
By p53/TP53 following DNA damage: expression is directly activated by p53/TP53 (at protein level).
Homodimer and heterodimer: mainly forms homodimers and, to a lesser extent, heterodimers with E2F8. Dimerization is important for DNA-binding. Interacts with HIF1A. Interacts with MN1 (PubMed:31839203).
In contrast to classical members of the E2F transcription factor, atypical members contain 2 DNA-binding domains and regulate transcription in a DP-independent manner. Both DNA-binding domains are required for DNA-binding and are proposed to form an intramolecular structure that is similar to the winged helix structure of the E2F-DP heterodimer (PubMed:14633988).
Interacts with KIF23 and RBM44. Interacts with CEP55; inhibiting interaction between CEP55 and PDCD6IP/ALIX and TSG101 (By similarity).
Phosphorylated on Thr residues by CDK1 during early phases of mitosis, promoting the interaction with PLK1 and recruitment to kinetochores. Phosphorylated on Ser-437 by PLK1 during late prometaphase promotes the rapid depletion from kinetochores and its subsequent degradation by the APC/C complex.
Required both for the formation of intercellular bridges during meiosis and for kinetochore-microtubule attachment during mitosis. Intercellular bridges are evolutionarily conserved structures that connect differentiating germ cells and are required for spermatogenesis and male fertility. Acts by promoting the conversion of midbodies into intercellular bridges via its interaction with CEP55: interaction with CEP55 inhibits the interaction between CEP55 and PDCD6IP/ALIX and TSG101, blocking cell abscission and leading to transform midbodies into intercellular bridges. Also plays a role during mitosis: recruited to kinetochores by PLK1 during early mitosis and regulates the maturation of the outer kinetochores and microtubule attachment. Has no protein kinase activity in vitro (By similarity).
Ser-376 is present instead of the conserved Asp which is expected to be an active site residue.
The GPPX3Y motif mediates interaction with CEP55.
Binds 2 Ca(2+) ions per subunit. One ion binds at a conserved binding site (GCXCG), whereas the second ion binds at a flexible site and may act as a supplemental electrophile as well as a backup.
Restricted to the brain, heart, lung, and placenta.
Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids (PubMed:10681567, PubMed:11922621, PubMed:28883454). Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity), releasing various unsaturated fatty acids including oleoate, linoleoate, arachidonate, docosahexaenoate and lysophosphatidylethanolamines in preference to lysophosphatidylcholines (PubMed:10681567, PubMed:28883454). In response to high-fat diet, hydrolyzes minor lipoprotein phospholipids including phosphatidylserines, phosphatidylinositols and phosphatidylglycerols, altering lipoprotein composition and fat storage in adipose tissue and liver (By similarity). May act in an autocrine and paracrine manner (PubMed:11922621). Contributes to lipid remodeling of cellular membranes and generation of lipid mediators involved in pathogen clearance. Cleaves sn-2 fatty acyl chains of phosphatidylglycerols and phosphatidylethanolamines, which are major components of membrane phospholipids in bacteria (PubMed:11922621). Acts as a hair follicle phospholipase A2. Selectively releases lysophosphatidylethanolamines (LPE) and various unsaturated fatty acids in skin to regulate hair follicle homeostasis (By similarity). May regulate the inflammatory response by releasing arachidonate, a precursor of prostaglandins and leukotrienes (PubMed:11922621). Upon allergen exposure, may participate in allergic inflammatory response by enhancing leukotriene C4 synthesis and degranulation in mast cells (By similarity).
Up-regulated by inflammatory cytokine IL1B.
First detected at low levels at approximately postnatal day 7. Subsequently, expression increases rapidly during the first month after birth.
Functions as signal transducer for the rod photoreceptor RHO. Required for normal RHO-mediated light perception by the retina (PubMed:22190596). Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs), such as the photoreceptor RHO. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Activated RHO promotes GDP release and GTP binding. Signaling is mediated via downstream effector proteins, such as cGMP-phosphodiesterase (By similarity).
Heterotrimeric G proteins are composed of 3 subunits alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. Interacts with RHO. Interacts with RGS9 and PDE6G (By similarity). Interacts (when myristoylated) with UNC119; interaction is required for localization in sensory neurons (PubMed:21642972).
Rod photoreceptor cells (PubMed:1614872). Predominantly expressed in the retina followed by the ciliary body, iris and retinal pigment epithelium (PubMed:22190596).
Adapter protein involved in protein degradation by interacting with COP1 ubiquitin ligase (PubMed:27041596). The COP1-binding motif is masked by autoinhibitory interactions with the protein kinase domain (PubMed:26455797). Serves to alter COP1 substrate specificity by directing the activity of COP1 toward CEBPA (PubMed:27041596). Binds selectively the recognition sequence of CEBPA (PubMed:26455797). Regulates myeloid cell differentiation by altering the expression of CEBPA in a COP1-dependent manner (By similarity). Controls macrophage, eosinophil and neutrophil differentiation via the COP1-binding domain (By similarity). Interacts with MAPK kinases and regulates activation of MAP kinases, but has no kinase activity (PubMed:15299019, PubMed:26455797).
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. Tribbles subfamily.
Expressed in most human tissues with the highest levels in skeletal muscle, thyroid gland, pancreas, peripheral blood leukocytes, and bone marrow.
Monomer (PubMed:26455797). Interacts (via protein kinase domain) with CEBPA (PubMed:20410507, PubMed:26455797). Interacts with COP1 (PubMed:20410507, PubMed:27041596).
The C-terminus (351-372) is required for interaction with COP1 (PubMed:27041596).
The COP1-binding motif (355-360) is required for regulation activity (By similarity).
The protein kinase active site is incompatible with ATP binding and is inactive (PubMed:26455797).
Single-stranded DNA-binding protein recruited to replication forks to maintain genome stability (PubMed:28735897). Prevents fork collapse by antagonizing the accumulation of RAD51 at forks to ensure the proper balance of fork remodeling and protection without interfering with the capacity of cells to complete homologous recombination of double-strand breaks (PubMed:28735897).
Autophosphorylated; ligand binding stimulates autophosphorylation on tyrosine residues.
Brain, heart, lung, kidney, placenta, pancreas, liver and skeletal muscle. Preferentially expressed in fetal brain.
Heterotetramer upon binding of the ligand (By similarity). The heterotetramer is composed of an ephrin dimer and a receptor dimer (PubMed:17897949). Interacts (via PDZ-binding motif) with GRIP1 and PICK1 (via PDZ domain) (By similarity). Interacts with ARHGEF15; mediates ARHGEF15 phosphorylation, ubiquitination and degradation by the proteasome (By similarity). Interacts with AQP1; involved in endolymph production in the inner ear (By similarity). Interacts with SPSB1 and SPSB4 (PubMed:28931592). The phosphorylated form interacts with RASA1 (via SH2 domain 1) (By similarity). Interacts with EFNA5 (By similarity). Interacts with SH2D3C (By similarity).
Ligand binding induces cleavage by matrix metalloproteinases (MMPs) such as MMP7/MMP9, producing an EphB2/N-terminal fragment (NTF) and a C-terminal long fragment (EphB2-LF). EphB2-LF is further cleaved by MMPs, producing EphB2/CTF1 which is further cleaved by the PS1/gamma-secretase producing EphB2/CTF2.
Polyubiquitinated; ligand binding stimulates ubiquitination (PubMed:28931592). Ubiquitinated by RNF186 at Lys-891, mainly through 'Lys-27'-linked polyubiquitin chains (PubMed:33280498).
Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Functions in axon guidance during development. Involved in the guidance of commissural axons, that form a major interhemispheric connection between the 2 temporal lobes of the cerebral cortex. Also involved in guidance of contralateral inner ear efferent growth cones at the midline and of retinal ganglion cell axons to the optic disk. In addition to axon guidance, also regulates dendritic spines development and maturation and stimulates the formation of excitatory synapses. Upon activation by EFNB1, abolishes the ARHGEF15-mediated negative regulation on excitatory synapse formation. Controls other aspects of development including angiogenesis, palate development and in inner ear development through regulation of endolymph production. Forward and reverse signaling through the EFNB2/EPHB2 complex regulate movement and adhesion of cells that tubularize the urethra and septate the cloaca. May function as a tumor suppressor. May be involved in the regulation of platelet activation and blood coagulation (PubMed:30213874).
The gene represented in this entry may be involved in disease pathogenesis. EPHB2 mutations have been found in a prostate cancer cell line derived from a brain metastasis.
Catalyzes the hydrolysis of ribonucleotide and deoxyribonucleotide monophosphates, releasing inorganic phosphate and the corresponding nucleoside (PubMed:11133996, PubMed:7599155, PubMed:8967393, PubMed:34814800). AMP is the major substrate but can also hydrolyze dCMP and IMP (PubMed:11133996, PubMed:7599155, PubMed:8967393, PubMed:34814800).
Highly expressed in skeletal muscle. Detected at intermediate levels in heart, brain, kidney and pancreas.
Single-stranded nucleic acid binding protein that binds preferentially to oligo dC.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ1 subfamily.
In the kidney and pancreatic islets. Lower levels in skeletal muscle, pancreas, spleen, brain, heart and liver.
In the kidney, probably plays a major role in potassium homeostasis. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. This channel is activated by internal ATP and can be blocked by external barium.
Interacts with SGK1 and SLC9A3R2/NHERF2.
Phosphorylation at Ser-44 by SGK1 is necessary for its expression at the cell membrane.
Expressed in colon, placenta, liver and very weakly in exocervix. Increased expression observed in lymph nodes of breast carcinoma.
Heterotetramer of two type I and two type II keratins. KRT18 associates with KRT8 (PubMed:10852826, PubMed:24940650). Interacts with PLEC isoform 1C, when in a heterodimer with KRT8 (PubMed:24940650). Interacts with the thrombin-antithrombin complex (By similarity). Interacts with PNN and mutated CFTR. Interacts with YWHAE, YWHAH and YWHAZ only when phosphorylated. Interacts with DNAJB6, TCHP and TRADD. Interacts with FAM83H (PubMed:23902688). Interacts with EPPK1 (By similarity). Interacts with PKP1 and PKP2 (PubMed:10852826).
Involved in the uptake of thrombin-antithrombin complexes by hepatic cells (By similarity). When phosphorylated, plays a role in filament reorganization. Involved in the delivery of mutated CFTR to the plasma membrane. Together with KRT8, is involved in interleukin-6 (IL-6)-mediated barrier protection.
O-GlcNAcylation increases solubility, and decreases stability by inducing proteasomal degradation.
Phosphorylation at Ser-34 increases during mitosis. Hyperphosphorylated at Ser-53 in diseased cirrhosis liver. Phosphorylation increases by IL-6.
Proteolytically cleaved by caspases during epithelial cell apoptosis. Cleavage occurs at Asp-238 by either caspase-3, caspase-6 or caspase-7.
Does not function as a ligand for either NMUR1 or NMUR2. Indirectly induces prolactin release although its potency is much lower than that of neuromedin precursor-related peptide 36.
Does not function as a ligand for either NMUR1 or NMUR2. Indirectly induces prolactin release from lactotroph cells in the pituitary gland, probably via the hypothalamic dopaminergic system.
Expressed throughout the enteric nervous system with highest levels being found in the jejunum.
Ligand for receptors NMUR1 and NMUR2 (By similarity). Stimulates muscle contractions of specific regions of the gastrointestinal tract. In humans, NmU stimulates contractions of the ileum and urinary bladder.
Binds with low affinity to interleukin-13 (IL13). Together with IL4RA can form a functional receptor for IL13. Also serves as an alternate accessory protein to the common cytokine receptor gamma chain for interleukin-4 (IL4) signaling, but cannot replace the function of IL2RG in allowing enhanced interleukin-2 (IL2) binding activity.
Interleukin-13 receptor is a complex of IL4R, IL13RA1, and possibly other components. Interacts with TRAF3IP1. Interacts with IL4 (PubMed:18243101).
Ubiquitous. Highest levels in heart, liver, skeletal muscle and ovary; lowest levels in brain, lung and kidney. Also found in B-cells, T-cells and endothelial cells.
Interacts (via central region) with CFAP418 (via N-terminus); the interaction is direct (PubMed:36233334). Interacts (via C-terminus) with microtubules (PubMed:22791751). Interacts with LCA5 (PubMed:22940612). Interacts with CEP290 (PubMed:22940612). Interacts with SDCCAG8 (PubMed:22940612). Interacts with FAM161B (PubMed:22791751). Interacts with POC1B (PubMed:25018096). Interacts with CEP78 (PubMed:27588451).
Isoform 1 and isoform 3 are widely expressed with highest levels in retina and testis, with isoform 1 being the most abundant in all tissues tested.
All three alleles (A, B and C) have similar nucleoside transport activity.
Can also transport the antiviral pyrimidine nucleoside analogs 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC). It may be involved in the intestinal absorption and renal handling of pyrimidine nucleoside analogs used to treat acquired immunodeficiency syndrome (AIDS).
Due to its high apparent affinity but slow transport, adenosine could act as a negative regulator of pyrimidine transport under some conditions.
N-glycosylated. N-glycosylation is required for localization to the plasma membrane and the transporter activity.
Sodium and pyrimidine nucleoside symporter of the plasma membrane that imports uridine, thymidine and cytidine into cells by coupling their transport to the transmembrane sodium electrochemical gradient. Also transports adenosine, an atypical substrate transported with high apparent affinity, but low maximum velocity. Therefore, exhibits the transport characteristics of the nucleoside transport system cit or N2 subtype (N2/cit) (PubMed:9124315, PubMed:10455109, PubMed:14701834, PubMed:15194733, PubMed:21795683, PubMed:21998139, PubMed:32126230, PubMed:30658162). Involved in renal nucleoside (re)absorption (PubMed:30658162).
Auxillary subunit of N-terminal acetyltransferase complexes which display alpha (N-terminal) acetyltransferase (NAT) activity (PubMed:15496142, PubMed:20154145, PubMed:29754825, PubMed:32042062). The NAT activity may be important for vascular, hematopoietic and neuronal growth and development (PubMed:15496142). Required to control retinal neovascularization in adult ocular endothelial cells (PubMed:11687548). In complex with XRCC6 and XRCC5 (Ku80), up-regulates transcription from the osteocalcin promoter (PubMed:12145306).
Cleaved by caspases during apoptosis, resulting in a stable 35 kDa fragment.
Component of the N-terminal acetyltransferase A complex (also called the NatA complex) composed of NAA10 and NAA15 (PubMed:15496142, PubMed:20154145, PubMed:32042062). Within the complex interacts with NAA10 (PubMed:15496142, PubMed:20154145, PubMed:29754825, PubMed:32042062). Component of the N-terminal acetyltransferase A (NatA)/HYPK complex at least composed of NAA10, NAA15 and HYPK, which has N-terminal acetyltransferase activity (PubMed:20154145, PubMed:29754825, PubMed:32042062). In complex with NAA10, interacts with HYPK (PubMed:20154145, PubMed:29754825, PubMed:32042062). Component of the N-terminal acetyltransferase E (NatE) complex at least composed of NAA10, NAA15 and NAA50 (PubMed:29754825, PubMed:32042062). Within the complex interacts with NAA10; the interaction is required for binding to NAA50 (PubMed:29754825, PubMed:32042062). Interacts with NAAT50 (PubMed:16507339, PubMed:29754825, PubMed:32042062). The interaction of the NatA complex with NAA50 reduces the acetylation activity of the NatA complex (PubMed:32042062). Component of the N-terminal acetyltransferase E (NatE)/HYPK complex at least composed of NAA10, NAA15, NAA50 and HYPK (PubMed:32042062). In complex with NAA10 interacts with HYPK; the interaction with HYPK reduces the capacity of the NatA complex to interact with NAA50 (PubMed:20154145, PubMed:29754825, PubMed:32042062). Interacts with NAA11 (PubMed:16638120). Interacts with XRCC6 and XRCC5 (PubMed:12145306, PubMed:29754825, PubMed:16507339).
Expressed at high levels in testis and in ocular endothelial cells. Also found in brain (corpus callosum), heart, colon, bone marrow and at lower levels in most adult tissues, including thyroid, liver, pancreas, mammary and salivary glands, lung, ovary, urogenital system and upper gastrointestinal tract. Overexpressed in gastric cancer, in papillary thyroid carcinomas and in a Burkitt lymphoma cell line (Daudi). Specifically suppressed in abnormal proliferating blood vessels in eyes of patients with proliferative diabetic retinopathy.
Phosphatase that has high activity toward pyridoxal 5'-phosphate (PLP). Also active at much lower level toward pyrophosphate, phosphoethanolamine (PEA), phosphocholine (PCho), phospho-l-tyrosine, fructose-6-phosphate, p-nitrophenyl phosphate, and h-glycerophosphate.
Isoform 2 is expressed in brain and skeletal muscle. Isoform 3 is expressed in excitable cells of brain, retina and skeletal muscle. Isoform 4 is expressed in skeletal muscle.
Mediates the electrogenic exchange of Ca(2+) against Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes. Contributes to cellular Ca(2+) homeostasis in excitable cells, both in muscle and in brain. In a first phase, voltage-gated channels mediate the rapid increase of cytoplasmic Ca(2+) levels due to release of Ca(2+) stores from the endoplasmic reticulum. SLC8A3 mediates the export of Ca(2+) from the cell during the next phase, so that cytoplasmic Ca(2+) levels rapidly return to baseline. Contributes to Ca(2+) transport during excitation-contraction coupling in muscle. In neurons, contributes to the rapid decrease of cytoplasmic Ca(2+) levels back to baseline after neuronal activation, and thereby contributes to modulate synaptic plasticity, learning and memory (By similarity). Required for normal oligodendrocyte differentiation and for normal myelination (PubMed:21959935). Mediates Ca(2+) efflux from mitochondria and contributes to mitochondrial Ca(2+) ion homeostasis (By similarity).
Up-regulated during in vitro differentiation of oligodendrocytes (at protein level). Up-regulated during in vitro differentiation of oligodendrocytes.
Component of the 43S pre-initiation complex (43S PIC), which binds to the mRNA cap-proximal region, scans mRNA 5'-untranslated region, and locates the initiation codon (PubMed:11166181, PubMed:22813744, PubMed:24319994). In this complex, acts as a GTPase-activating protein, by promoting GTP hydrolysis by eIF2G (EIF2S3) (PubMed:11166181). During scanning, interacts with both EIF1 (via its C-terminal domain (CTD)) and EIF1A (via its NTD) (PubMed:22813744). This interaction with EIF1A contributes to the maintenance of EIF1 within the open 43S PIC (PubMed:24319994). When start codon is recognized, EIF5, via its NTD, induces eIF2G (EIF2S3) to hydrolyze the GTP (PubMed:11166181). Start codon recognition also induces a conformational change of the PIC to a closed state (PubMed:22813744). This change increases the affinity of EIF5-CTD for EIF2-beta (EIF2S2), which allows the release, by an indirect mechanism, of EIF1 from the PIC (PubMed:22813744). Finally, EIF5 stabilizes the PIC in its closed conformation (PubMed:22813744).
Component of the 43S pre-initiation complex (43S PIC), which is composed of the 40S ribosomal subunit, EIF1, eIF1A (EIF1AX), eIF3 complex, EIF5 and eIF2-GTP-initiator tRNA complex (eIF2 ternary complex). Interacts with eIF1A (EIF1AX) during scanning (PubMed:24319994). Interacts through its C-terminal domain (CTD) with EIF1 or with eIF2-beta (EIF2S2) (mutually exclusive) through a common binding site (PubMed:21745818, PubMed:22813744). Interacts through its C-terminal domain (CTD) with the CTD of EIF5B (PubMed:30211544). Interacts with FMR1 isoform 6; this interaction occurs in a RNA-dependent manner (PubMed:24658146).
Interacts with TLE4; increases transcriptional repression (By similarity). Interacts with DCAF7 and PHB2. May interact with HSPD1.
Luminal B breast cancers are the clinically more aggressive estrogen receptor-positive tumors. Amplification of a distal 8p12 locus occurs in around one third of the cases and ZNF703 is the single gene within the minimal amplicon. Amplification of the gene correlates with its protein expression in tumor cells. ZNF703 is a classical breast cancer oncogene since it is able to transform non-malignant cells and increase cellular proliferation.
Transcriptional corepressor which does not bind directly to DNA and may regulate transcription through recruitment of histone deacetylases to gene promoters. Regulates cell adhesion, migration and proliferation. May be required for segmental gene expression during hindbrain development.
Contaminating sequence. Potential poly-A sequence starting in position 229.
Present on the surface of mature hematopoietic cells of the monocyte and myeloid lineages (at protein level).
Probably acts as an activating receptor.
Dual specificity protein phosphatase; active with phosphotyrosine, phosphoserine and phosphothreonine residues. The highest relative activity is toward ERK1.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to an N-unsubstituted glucosamine linked to a 2-O-sulfo iduronic acid unit on heparan sulfate. Unlike 3-OST-1, does not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate (By similarity).
Highest expression in endothelial cells. Also detected in vascular smooth muscle, macrophages, lymphocytes, and mast cells.
Interacts with FLNA. Interacts with the 20S proteasome subunit PSMA7.
Regulates endothelial chemotaxis and tube formation. Has a role in angiogenesis and apoptosis via modulation of the actin cytoskeleton and facilitation of proteasomal degradation of the apoptosis inhibitors BIRC3/IAP1 and BIRC2/IAP2.
Involved in the regulation of endocytosis and in several stages of intracellular trafficking (PubMed:32513819). Together with SNX4, involved in autophagosome assembly by regulating trafficking and recycling of phospholipid scramblase ATG9A (PubMed:32513819).
Expressed in the stratified squamous skin epithelium, but not in epithelia of other types (at protein level).
Low affinity receptor for acetylcholine known to be targeted by disease-causing pemphigus vulgaris antibodies in keratinocytes.
Protects cells and enzymes from oxidative damage, by catalyzing the reduction of hydrogen peroxide, lipid peroxides and organic hydroperoxide, by glutathione. May constitute a glutathione peroxidase-like protective system against peroxide damage in sperm membrane lipids.
Activates transcription from class II MHC promoters. Recognizes X-boxes. Mediates cooperative binding between RFX and NF-Y. RFX binds the X1 box of MHC-II promoters.
Homodimer. The RFX heterotetrameric complex consists of 2 molecules of RFX5 and one each of RFXAP and RFX-B/RFXANK; with each subunit representing a separate complementation group. Interacts (via PxLPxI/L motif) with RFXANK (via ankyrin repeats); the interaction is direct. RFX forms cooperative DNA binding complexes with X2BP and CBF/NF-Y. RFX associates with CIITA to form an active transcriptional complex.
The N-terminus is required for dimer formation, association with RFXANK and RFXAP, assembly of the RFX complex, and for binding of this complex to its X box target site in the MHC-II promoter. The C-terminus mediates cooperative binding between the RFX complex and NF-Y.
The PxLPxI/L motif mediates interaction with ankyrin repeats of RFXANK.
Key negative regulator of Shh signaling, which promotes the processing of GLI3 into GLI3R during neural tube development. Recruited by TULP3 and the IFT-A complex to primary cilia and acts as a regulator of the PKA-dependent basal repression machinery in Shh signaling by increasing cAMP levels, leading to promote the PKA-dependent processing of GLI3 into GLI3R and repress the Shh signaling. In presence of SHH, it is removed from primary cilia and is internalized into recycling endosomes, preventing its activity and allowing activation of the Shh signaling. Its ligand is unknown (By similarity).
May play a role in lipid transport protein in Schwann cells. May bind cholesterol.
P2 protein and myelin basic protein together constitute a major fraction of peripheral nervous system myelin protein.
EIF4E-binding protein that regulates translation and stability of mRNAs in processing bodies (P-bodies) (PubMed:16157702, PubMed:24335285, PubMed:27342281, PubMed:32354837). Plays a key role in P-bodies to coordinate the storage of translationally inactive mRNAs in the cytoplasm and prevent their degradation (PubMed:24335285, PubMed:32354837). Acts as a binding platform for multiple RNA-binding proteins: promotes deadenylation of mRNAs via its interaction with the CCR4-NOT complex, and blocks decapping via interaction with eIF4E (EIF4E and EIF4E2), thereby protecting deadenylated and repressed mRNAs from degradation (PubMed:27342281, PubMed:32354837). Component of a multiprotein complex that sequesters and represses translation of proneurogenic factors during neurogenesis (By similarity). Promotes miRNA-mediated translational repression (PubMed:24335285, PubMed:27342281, PubMed:28487484). Required for the formation of P-bodies (PubMed:16157702, PubMed:22966201, PubMed:27342281, PubMed:32354837). Involved in mRNA translational repression mediated by the miRNA effector TNRC6B by protecting TNRC6B-targeted mRNAs from decapping and subsequent decay (PubMed:32354837). Also acts as a nucleoplasmic shuttling protein, which mediates the nuclear import of EIF4E and DDX6 by a piggy-back mechanism (PubMed:10856257, PubMed:28216671).
Interacts (via YXXXXLphi motif) with EIF4E (PubMed:10856257, PubMed:16157702, PubMed:23991149, PubMed:24335285, PubMed:25923732, PubMed:28487484). Interacts (via YXXXXLphi motif) with EIF4E2 (PubMed:23991149, PubMed:28487484). Interacts with DDX6 (PubMed:26027925, PubMed:27342281, PubMed:28216671, PubMed:31422817, PubMed:32354837, PubMed:26489469, PubMed:31439631). Interacts with CSDE1/UNR (PubMed:27342281, PubMed:32354837). Interacts with CNOT1; promoting association with the CCR4-NOT complex (PubMed:26027925, PubMed:27342281, PubMed:32354837, PubMed:26489469). Interacts with LSM14A; promoting EIF4ENIF1 localization to P-bodies (PubMed:26027925, PubMed:32354837, PubMed:29510985). Interacts with PATL1 (PubMed:26027925, PubMed:32354837). Interacts with importin beta only in the presence of importin alpha, suggesting a direct interaction with importin alpha (PubMed:10856257). Interacts with APOBEC3G in an RNA-dependent manner (PubMed:16699599).
Intrinsically disordered protein with multiple low-complexity regions that confer binding to multiple RNA translation, deadenylation and decapping factors.
Phosphorylation by MAPK8/JNK1 and or MAPK9/JNK2 in response to oxidative stress promotes P-body assembly (PubMed:22966201). Phosphorylated during meiotic maturation (By similarity).
The YXXXXLphi motif mediates interaction with eIF4E (EIF4E and EIF4E2).
(Microbial infection) Interacts with Staphylococcus aureus protein SdrD; this interaction increases S.aureus adherence to keratinocytes.
Binds to JUP/plakoglobin (PubMed:19759396). Interacts with PKP2 (PubMed:11790773).
Epidermis, tongue, tonsil and esophagus.
Protein abundance is reduced via proteasomal degradation in response to P.gingivalis infection of gingival epithelial cells.
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 non-structural protein 6 (nsp6); the interaction is independent of PtdIns3P-binding and leads to endoplasmic reticulum (ER) and double membrane vesicles (DMVs) binding to lipid droplets.
(Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 infection, mediates through binding with non-structural protein 6 (nsp6) the replication organelle-lipid droplet association required to sustain viral replication.
Expressed in all tissues examined, including, brain, placenta, lung, liver, skeletal muscle, pancreas and kidney. Highly expressed in heart.
Highly expressed in heart. Also detected in the testis.
Interacts with RAB18 (in GTP-bound form) (PubMed:31293035, PubMed:30970241). Interacts with BSCL2 in a RAB18-dependent manner (PubMed:30970241). Interacts with ZW10 (PubMed:30970241).
Plays a role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis (PubMed:30970241). Regulates the morphology, size and distribution of LDs (PubMed:31293035, PubMed:30970241). Mediates the formation of endoplasmic reticulum-lipid droplets (ER-LD) contacts by forming a complex with RAB18 and ZW10 (PubMed:30970241). Binds to phosphatidylinositol 3-phosphate (PtdIns3P) through FYVE-type zinc finger (PubMed:11739631, PubMed:11256955).
Expressed in gastric parietal cells (at protein level).
The catalytic subunit of the gastric H(+)/K(+) ATPase pump which transports H(+) ions in exchange for K(+) ions across the apical membrane of parietal cells. Uses ATP as an energy source to pump H(+) ions to the gastric lumen while transporting K(+) ion from the lumen into the cell (By similarity). Remarkably generates a million-fold proton gradient across the gastric parietal cell membrane, acidifying the gastric juice down to pH 1 (By similarity). Within a transport cycle, the transfer of a H(+) ion across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing (E1) to outward-facing state (E2). The release of the H(+) ion in the stomach lumen is followed by binding of K(+) ion converting the pump conformation back to the E1 state (By similarity).
The gastric H(+)/K(+) ATPase pump is composed of the catalytic alpha subunit ATP4A and the regulatory beta subunit ATP4B. Interacts (via the P-domain) with ATP4B (via N-terminus); this interaction stabilizes the lumenal-open E2 conformation state and prevents the reverse reaction of the transport cycle.
Down-regulated during megakaryocytic differentiation of K562 cells by 12-O-tetradecanoylphorbol-13-acetate (TPA) (at protein level). Up-regulated in normal PBMCs by mitogens.
Expressed in hematopoietic precursor cells, thyroid and spermatids (at protein level). Expressed in bone marrow, testis, thymus. Expressed in prostate cancer and ovarian cancer. Also expressed in thymus and thyroid tumors, non-Hodgkin lymphoma, various leukemia cell lines, peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) of patients with leukemia.
Regulates the proliferation and differentiation of hematopoietic cells. Overexpression block the TPA-induced megakaryocytic differentiation in the K562 cell model. May also prevent cell apoptosis through the activation of the nuclear factor-kappa B (NF-kB).
Expressed in heart and pancreas, with lower expression in brain and muscle and almost no expression in placenta, lung, liver and kidney.
Homodimer. Interacts with TJP1. Interacts with MAGI1 (via PDZ domain); forms a complex with CTNNB1 and CDH2 and promotes recruitment to the adherens junction and stabilization on the cell surface. Interacts with PSEN1; undergoes a presenilin-dependent gamma-secretase cleavage that releases a Dll1-intracellular form. Interacts with MFAP5. Interacts with MIB1. Interacts with NEURL1B; leads to ubiquitination. Interacts with NEURL1 (By similarity). Interacts with SYNJ2BP; enhances DLL1 protein stability, and promotes Notch signaling in endothelial cells (PubMed:24025447). Interacts with MAGI1, MAGI2, MAGI3 and MPDZ (PubMed:15509766). Interacts (via ubiquitin) with EPN1 (via IUM domain); binding with NOTCH1 attached to neighboring cell, promotes ligand ubiquitination and EPN1 interaction, leading to NECD transendocytosis and Notch signaling. Interacts with NOTCH1 (By similarity) (PubMed:15509766, PubMed:24025447). Interacts with NOTCH2NLB; leading to promote Notch signaling pathway in a cell-autonomous manner through inhibition of cis DLL1-NOTCH2 interactions (PubMed:29856955).
O-fucosylated. Can be elongated to a disaccharide by MFNG.
Phosphorylated in a membrane association-dependent manner. Phosphorylation at Ser-697 requires the presence of Ser-694, whereas phosphorylation at Ser-694 occurs independently of the other site. Phosphorylation is required for full ligand activity in vitro and affects surface presentation, ectodomain shedding, and endocytosis.
Putative Notch ligand involved in the mediation of Notch signaling.
Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner (PubMed:11006133). Following transinteraction, ligand cells produce mechanical force that depends of a clathrin-mediated endocytosis, requiring ligand ubiquitination, EPN1 interaction, and actin polymerisation; these events promote Notch receptor extracellular domain (NECD) transendocytosis and triggers Notch signaling through induction of cleavage, hyperphosphorylation, and nuclear accumulation of the intracellular domain of Notch receptors (NICD) (By similarity). Is required for embryonic development and maintenance of adult stem cells in many different tissues and immune systeme; the DLL1-induced Notch signaling is mediated through an intercellular communication that regulates cell lineage, cell specification, cell patterning and morphogenesis through effects on differentiation and proliferation (PubMed:11581320). Plays a role in brain development at different level, namely by regulating neuronal differentiation of neural precursor cells via cell-cell interaction, most likely through the lateral inhibitory system in an endogenous level dependent-manner. During neocortex development, Dll1-Notch signaling transmission is mediated by dynamic interactions between intermediate neurogenic progenitors and radial glia; the cell-cell interactions are mediated via dynamic and transient elongation processes, likely to reactivate/maintain Notch activity in neighboring progenitors, and coordinate progenitor cell division and differentiation across radial and zonal boundaries. During cerebellar development, regulates Bergmann glial monolayer formation and its morphological maturation through a Notch signaling pathway. At the retina and spinal cord level, regulates neurogenesis by preventing the premature differentiation of neural progenitors and also by maintaining progenitors in spinal cord through Notch signaling pathway. Also controls neurogenesis of the neural tube in a progenitor domain-specific fashion along the dorsoventral axis. Maintains quiescence of neural stem cells and plays a role as a fate determinant that segregates asymmetrically to one daughter cell during neural stem cells mitosis, resulting in neuronal differentiation in Dll1-inheriting cell. Plays a role in immune systeme development, namely the development of all T-cells and marginal zone (MZ) B-cells (By similarity). Blocks the differentiation of progenitor cells into the B-cell lineage while promoting the emergence of a population of cells with the characteristics of a T-cell/NK-cell precursor (PubMed:11581320). Also plays a role during muscle development. During early development, inhibits myoblasts differentiation from the medial dermomyotomal lip and later regulates progenitor cell differentiation. Directly modulates cell adhesion and basal lamina formation in satellite cells through Notch signaling. Maintains myogenic progenitors pool by suppressing differentiation through down-regulation of MYOD1 and is required for satellite cell homing and PAX7 expression. During craniofacial and trunk myogenesis suppresses differentiation of cranial mesoderm-derived and somite-derived muscle via MYOD1 regulation but in cranial mesoderm-derived progenitors, is neither required for satellite cell homing nor for PAX7 expression. Also plays a role during pancreatic cell development. During type B pancreatic cell development, may be involved in the initiation of proximodistal patterning in the early pancreatic epithelium. Stimulates multipotent pancreatic progenitor cells proliferation and pancreatic growth by maintaining HES1 expression and PTF1A protein levels. During fetal stages of development, is required to maintain arterial identity and the responsiveness of arterial endothelial cells for VEGFA through regulation of KDR activation and NRP1 expression. Controls sprouting angiogenesis and subsequent vertical branch formation through regulation on tip cell differentiation. Negatively regulates goblet cell differentiation in intestine and controls secretory fat commitment through lateral inhibition in small intestine. Plays a role during inner ear development; negatively regulates auditory hair cell differentiation. Plays a role during nephron development through Notch signaling pathway. Regulates growth, blood pressure and energy homeostasis (By similarity).
Ubiquitinated by MIB (MIB1 or MIB2), leading to its endocytosis and subsequent degradation (By similarity). Ubiquitinated; promotes recycling back to the plasma membrane and confers a strong affinity for NOTCH1. Multi-ubiquitination of Lys-613 by MIB1 promotes both cis and trans-interaction with NOTCH1, as well as activation of Notch signaling. Ubiquitinated by NEURL1B (By similarity).
Interacts with both mature and propeptide myostatin/MSTN.
Primarily expressed in ovary, testis and brain, but not in liver. In fetal tissues, it is primarily expressed in brain, skeletal muscle, thymus and kidney.
Protease-inhibitor that contains multiple distinct protease inhibitor domains. Probably has serine protease- and metalloprotease-inhibitor activity. Inhibits the biological activity of mature myostatin, but not activin (By similarity).
Belongs to the TDD superfamily. DTWD1 family.
Catalyzes the formation of 3-(3-amino-3-carboxypropyl)uridine (acp3U) at position 20 in the D-loop of several cytoplasmic tRNAs (acp3U(20)).
Activated by binding to the regulatory factor DNMT3L.
Interacts with BAZ2A/TIP5, SUV39H1 and CBX4. Interacts with UHRF1 (By similarity). Interacts with DNMT1 and DNMT3A, SETDB1, UBL1, UBE2I9 and ZHX1. Interacts with the PRC2/EED-EZH2 complex.
Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNA methylation is coordinated with methylation of histones. May preferentially methylates nucleosomal DNA within the nucleosome core region. May function as transcriptional co-repressor by associating with CBX4 and independently of DNA methylation. Seems to be involved in gene silencing (By similarity). In association with DNMT1 and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9. Isoforms 4 and 5 are probably not functional due to the deletion of two conserved methyltransferase motifs. Functions as a transcriptional corepressor by associating with ZHX1. Required for DUX4 silencing in somatic cells (PubMed:27153398).
The PWWP domain is essential for targeting to pericentric heterochromatin.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. DNMT3B mutations lead to DUX4 expression in somatic tissues, including muscle cells, when an haplotype on chromosome 4 is permissive for DUX4 expression. Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death.
Ubiquitous; highly expressed in fetal liver, heart, kidney, placenta, and at lower levels in spleen, colon, brain, liver, small intestine, lung, peripheral blood mononuclear cells, and skeletal muscle. Isoform 1 is expressed in all tissues except brain, skeletal muscle and PBMC, 3 is ubiquitous, 4 is expressed in all tissues except brain, skeletal muscle, lung and prostate and 5 is detectable only in testis and at very low level in brain and prostate.
It is uncertain whether Met-1 or Met-33 is the initiator.
(Microbial infection) Acts as a receptor for Venezuelan equine encephalitis virus.
(Microbial infection) Interacts with Venezuelan equine encephalitis virus/VEEV spike proteins E1 and E2.
Expressed at high levels in brain, lung, skeletal muscle, and pancreas. Expressed at moderate levels in heart, placenta, and kidney but not detected in the liver.
Interacts with APP precursor C-terminus. Interacts directly with ITCH; this interaction promotes ITCH auto-ubiquitination leading to its degradation (PubMed:26854353). Interacts directly with NEDD4; this interaction promotes NEDD4 auto-ubiquitination (PubMed:26854353). Interacts directly with NEDD4L (PubMed:26854353).
May influence APP processing, resulting in a decrease in sAPP-alpha production and increased amyloidogenic P3 peptide production. May regulate ITCH and NEDD4 E3 ligase activity and degradation (PubMed:26854353).
Binds EEA1 (PubMed:10491193). Interacts with RIN2 and RIN3, which probably regulate its pathway, possibly by acting as GEFs (PubMed:11733506). Interacts with GDI1, GDI2, CHML and CHM; phosphorylation at Ser-84 disrupts this interaction (PubMed:29125462).
Phosphorylation of Ser-84 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM, CHML and RAB GDP dissociation inhibitors GDI1 and GDI2.
Protein transport. Probably involved in vesicular traffic.
Contains bound zinc ions after heterologous expression in insect cells, giving rise to a protein that lacks DHICA oxidase activity.
Genetic variants in TYRP1 define the skin/hair/eye pigmentation variation locus 11 (SHEP11) [MIM:612271] and are responsible for variability in hair color linked to chromosome 9p23 in Melanesians. Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification.
Monomer (PubMed:28661582). Interacts with ATP7A (By similarity) (PubMed:28661582). Interacts with SLC45A2 (By similarity).
Plays a role in melanin biosynthesis (PubMed:22556244, PubMed:16704458, PubMed:23504663). Catalyzes the oxidation of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) into indole-5,6-quinone-2-carboxylic acid in the presence of bound Cu(2+) ions, but not in the presence of Zn(2+) (PubMed:28661582). May regulate or influence the type of melanin synthesized (PubMed:22556244, PubMed:16704458). Also to a lower extent, capable of hydroxylating tyrosine and producing melanin (By similarity).
The activity depends critically on the nature of the bound metal ion. Catalyzes the oxidation of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) in the presence of bound Cu(2+) ions, but lacks activity in the presence of bound Zn(2+) ions.
The precise function of this protein in melanin biosynthesis is still under debate. DHICA oxidase activity is controversial (PubMed:9758418, PubMed:28661582). Lacks DHICA oxidase activity (PubMed:9758418). Has DHICA oxidase activity in the presence of Cu(2+), but lacks DHICA oxidase activity with Zn(2+) (PubMed:28661582).
Belongs to the eukaryotic ribosomal protein eL39 family.
Component of the large ribosomal subunit (PubMed:23636399, PubMed:32669547). Interacts with IMPACT (By similarity).
RNA-binding component of the large ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell.
Component of the HAUS augmin-like complex. The complex interacts with the gamma-tubulin ring complex and this interaction is required for spindle assembly (PubMed:19369198, PubMed:19427217). Interacts with PLK1, NEDD1 and gamma-tubulin (PubMed:19029337). Interacts with EML3 (phosphorylated at 'Thr-881') (PubMed:30723163).
Contributes to mitotic spindle assembly, maintenance of centrosome integrity and completion of cytokinesis as part of the HAUS augmin-like complex. Promotes the nucleation of microtubules from the spindle through recruitment of NEDD1 and gamma-tubulin.
(Microbial infection) Interacts with Orthopoxvirus OPG038/M2 protein, inhibiting the interaction with CTLA4/CD152.
(Microbial infection) Interacts with adenovirus subgroup B fiber proteins.
Expressed on activated B-cells, macrophages and dendritic cells.
Homodimer; CD80 dimers on the antigen presenting cells (APCs) bridge CTLA4/CD152 dimers on T-cells in a periodic zipper-like arrangement.
Involved in the costimulatory signal essential for T-lymphocyte activation. T-cell proliferation and cytokine production is induced by the binding of CD28, binding to CTLA-4 has opposite effects and inhibits T-cell activation.
Soluble isoform. Expressed in T-cells activated by ConA, non-activated monocytes and monocytes activated with IFN-c.
Soluble isoform. Expressed in unstimulated B-cells and monocytes, but not T-cells.
Acetyltransferase required for the establishment of sister chromatid cohesion (PubMed:15821733, PubMed:15958495). Couples the processes of cohesion and DNA replication to ensure that only sister chromatids become paired together. In contrast to the structural cohesins, the deposition and establishment factors are required only during the S phase. Acetylates the cohesin component SMC3 (PubMed:21111234).
Cell-cycle regulated. Down-regulated when cells enter M phase. Expression increases again when cells enter S phase of the next cell cycle.
Widely expressed in fetal tissues. In adult, it is expressed in thymus, placenta and small intestine.
Adaptor protein complex 2 (AP-2) is a heterotetramer composed of two large adaptins (alpha-type subunit AP2A1 or AP2A2 and beta-type subunit AP2B1), a medium adaptin (mu-type subunit AP2M1) and a small adaptin (sigma-type subunit AP2S1) (PubMed:12086608, PubMed:19140243). Interacts with EPN1 (PubMed:10944104, PubMed:16516836). Interacts with EPS15; clathrin competes with EPS15 (PubMed:10944104, PubMed:16903783). Interacts with SNAP91; clathrin competes with SNAP91 (PubMed:10944104, PubMed:16516836, PubMed:16903783). Interacts with CLTC; clathrin competes with EPS15, SNAP91 and PIP5K1C (PubMed:10944104). Interacts with LDLRAP1 (PubMed:15728179, PubMed:16516836, PubMed:16903783). Interacts with AMPH and BIN1 (PubMed:16516836, PubMed:16903783). Interacts with ARF6 (GDP-bound) (PubMed:17719203). Interacts (dephosphorylated at Tyr-737) with ARRB1; phosphorylation of AP2B1 at Tyr-737 disrupts the interaction (PubMed:11777907, PubMed:17456551, PubMed:16516836, PubMed:16903783). Interacts with SLC2A8 (PubMed:16723738). Interacts with SCYL1 and SCYL2 (PubMed:16903783). Interacts with TGFBR1 and TGFBR2 (PubMed:12429842). Interacts with PIP5K1C; clathrin competes with PIP5K1C (By similarity). Interacts with DENND1B, but not with DENND1A, nor DENND1C (PubMed:20154091). Interacts with FCHO1 (PubMed:22484487). Interacts with RFTN1 (PubMed:27022195). Interacts with KIAA1107 (PubMed:29262337). Together with AP2A1 or AP2A2 and AP2M1, it interacts with ADAM10; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons (PubMed:23676497).
Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. During long-term potentiation in hippocampal neurons, AP-2 is responsible for the endocytosis of ADAM10 (PubMed:23676497). The AP-2 beta subunit acts via its C-terminal appendage domain as a scaffolding platform for endocytic accessory proteins; at least some clathrin-associated sorting proteins (CLASPs) are recognized by their [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif. The AP-2 beta subunit binds to clathrin heavy chain, promoting clathrin lattice assembly; clathrin displaces at least some CLASPs from AP2B1 which probably then can be positioned for further coat assembly.
Highly expressed in the testis, spleen, thymus, prostate, ovary, blood leukocyte and brain, but not in the heart, placenta, lung, liver, skeletal muscle, kidney and pancreas. Testis expression is restricted to germ cells and is about 3-fold higher in adults than in embryos.
Phosphorylation at Tyr-737 by SRC occurs at the plasma membrane in clathrin-coated vesicles (CCVs).
Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses (By similarity). Interacts with EPHB6; transphosphorylates EPHB6 to form an active signaling complex. Interacts with PICK1 (By similarity). Interacts (through Tyr-594) with NCK1 (via SH2 domain); activates the JUN cascade to regulate cell adhesion (By similarity). The ligand-activated form interacts (through Tyr-928) with GRB7 and GRB10 (via SH2 domains). The ligand-activated form interacts (residues within the catalytic domain) with GRB2 (via SH2 domain). Interacts with GRB2, SHC1 and SRC; activates the MAPK/ERK cascade to regulate cell migration. Interacts with CBL; regulates receptor degradation through ubiquitination. Interacts with ACP1.
Phosphorylated. Autophosphorylation is stimulated by the ligand EFNB1. Required for interaction with SH2 domain-containing interactors, for activation of the MAPK/ERK and JUN signaling cascades and for ubiquitination by CBL.
Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Cognate/functional ephrin ligands for this receptor include EFNB1, EFNB2 and EFNB3. During nervous system development, regulates retinal axon guidance redirecting ipsilaterally ventrotemporal retinal ganglion cells axons at the optic chiasm midline. This probably requires repulsive interaction with EFNB2. In the adult nervous system together with EFNB3, regulates chemotaxis, proliferation and polarity of the hippocampus neural progenitors. In addition to its role in axon guidance also plays an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and synapse formation. May also regulate angiogenesis. More generally, may play a role in targeted cell migration and adhesion. Upon activation by EFNB1 and probably other ephrin-B ligands activates the MAPK/ERK and the JNK signaling cascades to regulate cell migration and adhesion respectively. Involved in the maintenance of the pool of satellite cells (muscle stem cells) by promoting their self-renewal and reducing their activation and differentiation (By similarity).
Ubiquitinated; (EFNB1)ligand-induced poly- and/or multi-ubiquitination by CBL is regulated by SRC and leads to lysosomal degradation.
May function as a motor for intraflagellar retrograde transport. Functions in cilia biogenesis. May play a role in transport between endoplasmic reticulum and Golgi or organization of the Golgi in cells (By similarity).
The cytoplasmic dynein complex 2 is probably composed by a heavy chain DYNC2H1 homodimer and a number of DYNC2LI1 light intermediate chains.
The disease is caused by variants affecting the gene represented in this entry. In some cases DYNC2H1 mutations result in disease phenotype in the presence of mutations in NEK1 indicating digenic inheritance (digenic short rib-polydactyly syndrome 3/6 with polydactyly) (PubMed:21211617).
The PHTF domain was initially defined as an atypical homeodomain, suggesting that this protein could act as a transcription regulator (PubMed:10395808). However, the protein is not found in the nucleus and mainly localizes in the endoplasmic reticulum membrane, suggesting that it does not act as a transcription factor (By similarity).
Seems to play a negative regulatory role in 5-phosphoribose 1-diphosphate synthesis.
Component of the precatalytic spliceosome (spliceosome B complex) (PubMed:28781166). Component of the U4/U6-U5 tri-snRNP complex, a building block of the precatalytic spliceosome (spliceosome B complex) (PubMed:10523320, PubMed:28781166, PubMed:26912367). The U4/U6-U5 tri-snRNP complex is composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39, plus LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 (PubMed:26912367). LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 form a heptameric, ring-shaped subcomplex (the LSM2-8 complex) that is part of the U4/U6-U5 tri-snRNP complex and the precatalytic spliceosome (PubMed:10523320, PubMed:26912367, PubMed:28781166).
LSm subunits form a heteromer with a doughnut shape.
Plays a role in U6 snRNP assembly and function. Binds to the 3' end of U6 snRNA.
Monomer and homodimer. The variant form found in the bladder carcinoma cell line Hu549 does not form homodimers. Interacts with TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6. Interacts with TRAF6 and MAP3K8; the interaction is required for ERK activation.
Receptor for TNFSF5/CD40LG (PubMed:31331973). Transduces TRAF6- and MAP3K8-mediated signals that activate ERK in macrophages and B cells, leading to induction of immunoglobulin secretion (By similarity).
Accelerates GTPase activity of RHOA and CDC42, but not RAC1. Stimulates the hydrolysis of phosphatidylinositol 4,5-bisphosphate by PLCD1.
Binds both the SH2 and PTB domains of TNS1.
Widely expressed with highest levels in kidney, lung and placenta.
Essential for maintaining normal cardiac rhythm in the developing heart and for neonatal survival (By similarity). Inhibits potassium and calcium currents in the cardiomyocytes, this assists in timely action potential repolarization and thereby maintains normal cardiac rhythm (By similarity).
Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability (By similarity).
Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters (By similarity).
Lysine deamination at Lys-5 (H3K4all) to form allysine is mediated by LOXL2. Allysine formation by LOXL2 only takes place on H3K4me3 and results in gene repression (By similarity).
Methylation at Lys-5 (H3K4me), Lys-37 (H3K36me) and Lys-80 (H3K79me) are linked to gene activation. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are linked to gene repression. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication (By similarity).
Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 or isoform M2 of PKM (PKM2) is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin (By similarity).
Serine ADP-ribosylation constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage. Serine ADP-ribosylation at Ser-11 (H3S10ADPr) is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac).
Succinylation at Lys-80 (H3K79succ) by KAT2A takes place with a maximum frequency around the transcription start sites of genes. It gives a specific tag for epigenetic transcription activation. Desuccinylation at Lys-123 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair.
The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Interacts with TONSL; CHAF1A and CHAF1B (PubMed:33857403).
Deubiquitinating enzyme which may play an important role during spermatogenesis.
Expressed predominantly in the intestinal epithelium. Expressed in luminal cells of colonic mucosa. Also expressed in the Merkel cells of keratinized oral mucosa; specifically at the tips of some rete ridges of the gingival mucosa, in the basal layer of the palatal mucosa and in the taste buds of lingual mucosa.
First detected at embryonic week 8 in individual 'converted' simple epithelial cells of the developing intestinal mucosa. In later fetal stages, synthesis extends over most goblet cells and a variable number of villus enterocytes. In the developing gastric and intestinal mucosa, expressed in all enterocytes and goblet cells as well as certain 'low-differentiated' columnar cells, whereas the neuroendocrine and Paneth cells are negative.
Heterotetramer of two type I and two type II keratins. Associates with KRT8.
Hyperphosphorylation at Ser-13 occurs during the early stages of apoptosis but becomes less prominent during the later stages. Phosphorylation at Ser-13 also increases in response to stress brought on by cell injury (By similarity).
Plays a significant role in maintaining keratin filament organization in intestinal epithelia. When phosphorylated, plays a role in the secretion of mucin in the small intestine (By similarity).
Proteolytically cleaved by caspases during apoptosis. Cleavage occurs at Asp-228.
Induced following exposure to ionizing radiation.
Interacts directly with ZFYVE20 (By similarity). Binds EEA1 (By similarity). Interacts (in its GTP-bound form) with RABGEF1 (PubMed:21849477). Interacts (in its GTP-bound form) with RINL (PubMed:21419809).
Plays a role in endocytosis and intracellular protein transport. Mediates trafficking of TF from early endosomes to recycling endosomes (PubMed:16537905). Required for NGF-mediated endocytosis of NTRK1, and subsequent neurite outgrowth (PubMed:21849477). Binds GTP and GDP and has low GTPase activity. Alternates between a GTP-bound active form and a GDP-bound inactive form (PubMed:16537905).
Interacts with MORN4 (PubMed:25822849). Interacts (via C-terminus) with ESPN and ESPNL (By similarity).
Probable actin-based motor with a protein kinase activity. Probably plays a role in vision and hearing (PubMed:12032315). Required for normal cochlear hair bundle development and hearing. Plays an important role in the early steps of cochlear hair bundle morphogenesis. Influences the number and lengths of stereocilia to be produced and limits the growth of microvilli within the forming auditory hair bundles thereby contributing to the architecture of the hair bundle, including its staircase pattern. Involved in the elongation of actin in stereocilia tips by transporting the actin regulatory factor ESPN to the plus ends of actin filaments (By similarity).
Strongest expression in retina, retinal pigment epithelial cells, cochlea and pancreas.
Early expressed in fetal development and was observed in Brunner's glands and pancreatic ducts at 18-19 weeks and in gastric glands at 20 weeks of gestation. Expressed transiently in the nephrogenic zone of the kidney in the early mid-trimester of development. Detected in the epithelium of ureteric buds at 13 weeks and at lower levels from 17 to 23 weeks of gestation.
Expressed in the regenerative zone of gastric antrum, gastric body mucosa and gastric incisura mucosa. Expressed in the deeper mucous glands of gastric antrum. Overexpressed in Helicobacter pylori infected gastric epithelium. Highly expressed in duodenal Brunner's glands, gall bladder, seminal vesicle, pancreatic centroacinar cells and ducts, and periductal glands of the common bile duct.
May provide a mechanism for modulation of the composition of the protective mucus layer related to acid secretion or the presence of bacteria and noxious agents in the lumen. Plays an important role in the cytoprotection of epithelial surfaces and are used as tumor markers in a variety of cancers. May play a role in epithelial organogenesis.
The number of repeats is highly polymorphic and varies among different alleles. These repeats are very similar but not identical.
Up-regulated by NFKB1. Repressed by mithramycin A which is an inhibitor of binding of transcription factors.
A connexon is composed of a hexamer of connexins (By similarity). Interacts with TJP1.
Expressed in vascular smooth muscle cells. Found in heart, colon, and artery (at protein level). Found in cerebral cortex, heart, liver, lung, kidney, spleen and testis.
Acts as an interface between multiple growth factor receptors possessing tyrosine kinase activity, such as insulin receptor, IGF1R and FGFR1, and a complex network of intracellular signaling molecules containing SH2 domains. Involved in the IGF1R mitogenic signaling pathway. Promotes the AKT1 signaling pathway and BAD phosphorylation during insulin stimulation without activation of RPS6KB1 or the inhibition of apoptosis. Interaction with GRB2 enhances insulin-stimulated mitogen-activated protein kinase activity. May be involved in nonreceptor tyrosine kinase signaling in myoblasts. Plays a pivotal role in the proliferation/differentiation of hepatoblastoma cell through EPHB2 activation upon IGF1 stimulation. May play a role in the signal transduction in response to insulin and to a lesser extent in response to IL4 and GH on mitogenesis. Plays a role in growth, reproduction and glucose homeostasis. May act as negative regulators of the IGF1 signaling pathway by suppressing the function of IRS1 and IRS2.
Down-regulated by PPP4C in a phosphatase activity-dependent manner.
Expressed in myoblasts. Expressed in liver and hepatocellular carcinoma.
Interacts with SOCS6 in response to stimulation with either insulin or IGF1 (By similarity). Interacts with CRK and CRKL. Interaction with CRK is stronger than with CRKL. Interacts with CRK via the phosphorylated YXXM motifs. Interacts with GRB2 and PIK3R1. Interacts with PLC-gamma, SHC1, PTK6, PPP4C and NISCH.
Phosphorylated on tyrosine residues in response to both insulin and IGF1 signaling. Phosphorylated on Tyr-921 in response to FGF2 signaling. Phosphorylation of Tyr-921 is required for GRB2, phospholipase C-gamma and phosphatidylinositol 3-kinase interaction.
May play a role in ciliary/flagellar motility by regulating the assembly and the activity of axonemal inner dynein arm.
Abundant expression in the male reproductive tract only. Abundant expressed in testis and the caput region of epididymis, but low in the corpus region.
AP-1 family transcription factor that controls the differentiation of lineage-specific cells in the immune system. Following infection, participates in the differentiation of CD8(+) thymic conventional dendritic cells in the immune system. Acts via the formation of a heterodimer with JUN family proteins that recognizes and binds DNA sequence 5'-TGA[CG]TCA-3' and regulates expression of target genes (By similarity). Selectively suppresses CCN1 transcription and hence blocks the downstream cell proliferation signals produced by CCN1 and inhibits CCN1-induced anchorage-independent growth and invasion in several cancer types, such as breast cancer, malignant glioma and metastatic melanoma. Possibly acts by interfering with AP-1 binding to CCN1 promoter.
By type I interferon. Down-regulated in most hepatocellular carcinoma tumorous tissues (at protein level).
Heterodimer; heterodimerizes with JUN family proteins.
Functions in tethering peripheral heterochromatin to the nuclear lamina during interphase, possibly through the interaction with heterochromatin protein CBX5/HP1 alpha (PubMed:24209742). Might play a role in reattaching heterochromatin to the nuclear lamina at mitotic exit (PubMed:24209742). Promotes myoblast differentiation during skeletal myogenesis, possibly by stimulating transcription factor MyoD activity via binding to CBX5/HP1 alpha (PubMed:25906157). Involved in the positive regulation of the PI3K-Akt-mTOR signaling pathway and in promoting cell proliferation, possibly via binding to GRB2 (PubMed:27041574).
Interacts (via proline-rich region) with GRB2 (via SH3 domain 2) (PubMed:27041574). Interacts (via N-terminus) with CBX5 (PubMed:25906157).
Acts as a receptor for L-lactate and mediates its anti-lipolytic effect through a G(i)-protein-mediated pathway.
Expressed abundantly in brown and white fat. It also detectable at lower levels in liver, kidney, skeletal muscle, brain and pituitary. Not detected in frontal, temporal and occipital lobes of the cortex, basal forebrain, caudate nucleus, nucleus accumbens and hippocampus.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Protein arginine N-methyltransferase family. PRMT8 subfamily.
Homodimer (PubMed:16051612, PubMed:26876602, PubMed:26529540). Tetramer; individual homodimers associates to form a homotetramer (PubMed:26529540). Homooctamer; individual homodimers associates to form a homooctamer and homooligomerization is required for proper localization to the cell membrane (PubMed:26876602). Heterodimer with PRMT1; heterodimerization may recruit PRMT1 activity to the plasma membrane (PubMed:16051612). Interacts with PRMT2 (via the SH3 domain) (PubMed:17925405). Interacts with FYN (via the SH3 domain) (PubMed:17925405). Interacts with EWS; independently of EWS methylation status (PubMed:18320585).
S-adenosyl-L-methionine-dependent and membrane-associated arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and asymmetrical dimethylarginine (aDMA) in proteins such as NIFK, myelin basic protein, histone H4, H2A and H2A/H2B dimer (PubMed:16051612, PubMed:17925405, PubMed:26876602, PubMed:26529540). Able to mono- and dimethylate EWS protein; however its precise role toward EWS remains unclear as it still interacts with fully methylated EWS (PubMed:18320585).
The N-terminal region (1-60) inhibits the arginine N-methyltransferase activity.
The SH3-binding motifs mediate the interaction with SH3 domain-containing proteins such as PRMT2 and FYN, possibly leading to displace the N-terminal domain and activate the protein.
Plays a role in the regulation of microglia polarization.
May be involved in the negative regulation of skeletal muscle differentiation, independently of its glycerophosphocholine phosphodiesterase activity.
Widely expressed, with highest expression in spinal chord.
(Microbial infection) Interacts with and activated by HIV-1 Nef.
Activated by binding small G proteins (By similarity). Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, enables phosphorylation of Thr-402 and allows the kinase domain to adopt an active structure (By similarity). Following caspase cleavage, autophosphorylated PAK-2p34 is constitutively active (PubMed:9786869).
During apoptosis proteolytically cleaved by caspase-3 or caspase-3-like proteases to yield active PAK-2p34.
Full-length PAK2 is autophosphorylated when activated by CDC42/p21. Following cleavage, both peptides, PAK-2p27 and PAK-2p34, become highly autophosphorylated, with PAK-2p27 being phosphorylated on serine and PAK-2p34 on threonine residues, respectively. Autophosphorylation of PAK-2p27 can occur in the absence of any effectors and is dependent on phosphorylation of Thr-402, because PAK-2p27 is acting as an exogenous substrate.
Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1 (PubMed:20696164). Interacts with SH3MD4 (PubMed:16374509). Interacts with SCRIB (PubMed:18716323). Interacts with ARHGEF7 and GIT1 (PubMed:19273597). PAK-2p34 interacts with ARHGAP10 (PubMed:15471851).
Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell motility, cell cycle progression, apoptosis or proliferation (PubMed:7744004, PubMed:19273597, PubMed:19923322, PubMed:9171063, PubMed:12853446, PubMed:16617111, PubMed:33693784). Acts as downstream effector of the small GTPases CDC42 and RAC1 (PubMed:7744004). Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues (PubMed:7744004). Full-length PAK2 stimulates cell survival and cell growth (PubMed:7744004). Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration (PubMed:21317288). Phosphorylates JUN and plays an important role in EGF-induced cell proliferation (PubMed:21177766). Phosphorylates many other substrates including histone H4 to promote assembly of H3.3 and H4 into nucleosomes, BAD, ribosomal protein S6, or MBP (PubMed:21724829). Phosphorylates CASP7, thereby preventing its activity (PubMed:21555521, PubMed:27889207). Additionally, associates with ARHGEF7 and GIT1 to perform kinase-independent functions such as spindle orientation control during mitosis (PubMed:19273597, PubMed:19923322). On the other hand, apoptotic stimuli such as DNA damage lead to caspase-mediated cleavage of PAK2, generating PAK-2p34, an active p34 fragment that translocates to the nucleus and promotes cellular apoptosis involving the JNK signaling pathway (PubMed:9171063, PubMed:12853446, PubMed:16617111). Caspase-activated PAK2 phosphorylates MKNK1 and reduces cellular translation (PubMed:15234964).
Ubiquitously expressed. Higher levels seen in skeletal muscle, ovary, thymus and spleen.
Widely expressed; highly expressed in the uterus, fetal brain and spinal cord, also detected in heart, liver, lung, colon, spleen, thymus, prostate, placenta, adrenal gland, salivary and mammary gland.
(Microbial infection) Interacts with hepatitis C virus (HCV) proteins NS2 and E2 (PubMed:24009510). Interacts with NS2B from Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) (PubMed:29593046).
(Microbial infection) Required for the post-translational processing of proteins involved in virion assembly and secretion from flaviviruses such as West Nile virus (WNV), Japanese encephalitis virus (JEV), Dengue virus type 2 (DENV-2), Yellow Fever virus (YFV), Zika virus (ZIKV) and hepatitis C virus (HCV) (PubMed:24009510, PubMed:27383988, PubMed:29593046). Plays a key role in the post-translational processing of flaviviral structural proteins prM, E, and NS1 (PubMed:27383988, PubMed:29593046). In HCV, it is involved in virion assembly where it promotes the interaction between HCV virus proteins NS2 and E2 (PubMed:24009510).
Component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum (PubMed:34388369). Dispensable for SPC enzymatic activity (By similarity).
Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3 (PubMed:34388369). Component of the signal peptidase complex paralog C (SPC-C) composed of a catalytic subunit SEC11C and three accessory subunits SPCS1, SPCS2 and SPCS3 (PubMed:34388369). Within the complex, interacts with SPCS2 and SPCS3 (PubMed:34388369). The complex induces a local thinning of the ER membrane which is used to measure the length of the signal peptide (SP) h-region of protein substrates (PubMed:34388369). This ensures the selectivity of the complex towards h-regions shorter than 18-20 amino acids (PubMed:34388369).
Expressed in heart, brain, liver, kidney, pancreas and placenta. Not expressed in skeletal muscle and lung.
Expression is decreased in hepatocellular carcinoma samples as compared to adjacent non-cancerous liver tissues from the same patients. Transfection in hepatocellular carcinoma cells and overexpression can inhibit the cell growth.
Binds to membranes enriched in phosphatidylserine or phosphatidylglycerol in a calcium-dependent manner (PubMed:27676605, PubMed:30610115). Half-maximal membrane binding requires about 60 uM calcium. Does not bind to membranes that lack phospholipids with an acidic headgroup (PubMed:27676605).
Binds to membranes enriched in phosphatidylserine or phosphatidylglycerol in a calcium-dependent manner, but requires higher calcium levels for membrane binding than isoform A. Half-maximal membrane binding requires about 320 uM calcium.
Detected in epithelial cells in colon and jejunum (at protein level). Detected in epithelial cells in jejunum.
Highly expressed in normal and neoplastic prostate. Also expressed in cardiac atrium, salivary gland, spleen and selective cells in the CNS.
Calcium-dependent cell-adhesion protein.
Abundantly expressed in testis (PubMed:9741684, PubMed:10026212). Found in other tissues to a lower extent (PubMed:9741684, PubMed:10026212). Expressed in dermal fibroblast and skeletal muscle (PubMed:32403198).
Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins.
Subject to product inhibition by geranylgeranyl diphosphate.
Component of splicing factor SF3B complex which is composed of at least eight subunits; SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6, PHF5A and DDX42 (PubMed:12234937, PubMed:12738865, PubMed:27720643, PubMed:28541300). SF3B associates with the splicing factor SF3A and a 12S RNA unit to form the U2 small nuclear ribonucleoproteins complex (U2 snRNP) (PubMed:12234937). Interacts directly with SF3B2. Found in a complex with PRMT9, SF3B2 and SF3B4 (PubMed:25737013). The SF3B complex composed of SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6 and PHF5A interacts with U2AF2 (PubMed:27720643). Component of the minor spliceosome, which splices U12-type introns (PubMed:15146077, PubMed:33509932).
Involved in pre-mRNA splicing as a component of the splicing factor SF3B complex (PubMed:27720643). SF3B complex is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA (PubMed:12234937). May also be involved in the assembly of the 'E' complex. SF3B4 has been found in complex 'B' and 'C' as well (PubMed:10882114). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (PubMed:15146077).
A soluble form (TMEFF2-ECD) is produced by proteolytic shedding. This shedding can be induced by phorbol ester or pro-inflammatory cytokines such as TNFalpha, and is mediated by ADAM17.
Contaminating sequence. Mitochondrial contamination starting in position 361.
Down-regulated in tumor cell lines in response to a high level of methylation in the 5' region. The CpG island methylation correlates with TMEFF2 silencing in tumor cell lines.
Highly expressed in adult and fetal brain, spinal cord and prostate. Expressed in all brain regions except the pituitary gland, with highest levels in amygdala and corpus callosum. Expressed in the pericryptal myofibroblasts and other stromal cells of normal colonic mucosa. Expressed in prostate carcinoma. Down-regulated in colorectal cancer. Present in Alzheimer disease plaques (at protein level). Isoform 3 is expressed weakly in testis and at high levels in normal and cancerous prostate.
May be a survival factor for hippocampal and mesencephalic neurons. The shedded form up-regulates cancer cell proliferation, probably by promoting ERK1/2 phosphorylation.
O-glycosylated; contains chondroitin sulfate glycosaminoglycans.
Interacts with CNTLN; the interaction recruits CEP68 to the centrosome (PubMed:24554434). Interacts with the SCF(FBXW11) complex which contains SKP1, CUL1 and FBXW11; the interaction is probably mediated by FBXW11 and the complex also contains CDK5RAP2 and PCNT (PubMed:25503564). Also interacts with F-box protein BTRC (PubMed:25704143, PubMed:25503564). Interacts with serine/threonine-protein kinase PLK1; the interaction leads to phosphorylation of CEP68 and its subsequent degradation (PubMed:25503564). Interacts with NEK2; the interaction leads to phosphorylation of CEP68 (PubMed:24554434).
Involved in maintenance of centrosome cohesion, probably as part of a linker structure which prevents centrosome splitting (PubMed:18042621). Required for localization of CDK5RAP2 to the centrosome during interphase (PubMed:24554434, PubMed:25503564). Contributes to CROCC/rootletin filament formation (PubMed:30404835).
Phosphorylation by PLK1 is required for binding to BTRC in prometaphase (PubMed:25503564). Phosphorylated directly or indirectly by NEK2 (PubMed:24554434). NEK2-mediated phosphorylation promotes CEP68 dissociation from the centrosome and its degradation at the onset of mitosis (PubMed:25704143).
Ubiquitinated and targeted for proteasomal degradation in early mitosis by the SCF(BTRC) and/or SCF(FBXW11) E3 ubiquitin-protein ligase complexes (PubMed:25704143, PubMed:25503564). Degradation is complete by prometaphase and is required for removal of CDK5RAP2 from the peripheral pericentriolar material and subsequent centriole separation (PubMed:25503564).
Belongs to the type II malonyltransferase family.
Catalyzes the transfer of a malonyl moiety from malonyl-CoA to the free thiol group of the phosphopantetheine arm of the mitochondrial ACP protein (NDUFAB1). This suggests the existence of the biosynthesis of fatty acids in mitochondria.
Exclusively expressed in proliferating cells from the transition G1/S until the end of cytokinesis.
Expressed in lung carcinoma cell lines but not in normal lung tissues.
Interacts with AURKA (PubMed:14580337, PubMed:18662907, PubMed:18663142). Interacts with importin-alpha; leading to inactivate TPX2 (PubMed:26165940). Interacts with HNRNPU; this interaction recruits HNRNPU to spindle microtubules (MTs) (PubMed:21242313, PubMed:25986610). Interacts with BCL2L10 (By similarity).
Spindle assembly factor required for normal assembly of mitotic spindles. Required for normal assembly of microtubules during apoptosis. Required for chromatin and/or kinetochore dependent microtubule nucleation. Mediates AURKA localization to spindle microtubules (PubMed:18663142, PubMed:19208764). Activates AURKA by promoting its autophosphorylation at 'Thr-288' and protects this residue against dephosphorylation (PubMed:18663142, PubMed:19208764). TPX2 is inactivated upon binding to importin-alpha (PubMed:26165940). At the onset of mitosis, GOLGA2 interacts with importin-alpha, liberating TPX2 from importin-alpha, allowing TPX2 to activates AURKA kinase and stimulates local microtubule nucleation (PubMed:26165940).
A rare heterozygous in-frame DNAI3 deletion encompassing exons 14-17 has been found in a fetus with encephalocele. Overexpression of human DNAI3 RNA lacking exons 14-17 in zebrafish embryos also results in similar brain malformations, suggesting that DNAI3 defects might be involved in encephalocele formation.
Acts as a negative regulator of cell migration, invasion, and metastasis downstream of p53/TP53, through inhibition of Arp2/3 complex-mediated actin polymerization (PubMed:32128961). Via its association with the multisubunit axonemal dynein complex, is potentially involved in the regulation of cilia function (By similarity). May play a role in osteogenesis of dental tissue-derived mesenchymal stem cells (By similarity).
Interacts with ACTR2; this interaction reduces binding of the Arp2/3 complex to the VCA domain of nucleation promoting factors (PubMed:32128961). Part of the multisubunit axonemal dynein complex formed at least of two heavy chains and a number of intermediate and light chains. Found in a associated with the catalytic heavy chain DNAH2, the intermediate chain DNAI4, and the light chain DYNLT1 (By similarity).
Up-regulated at the transcriptional level by TP53.
Detected in resting neutrophils (PubMed:10772777). Detected in peripheral blood T-cells (PubMed:17008549). Detected in extracellular vesicles in blood serum from patients with inflammatory bowel disease, but not in serum from healthy donors (PubMed:25664854). Detected in placenta (at protein level) (PubMed:2532504). Detected in liver.
Functions at least in part by activating the formyl peptide receptors and downstream signaling cascades (PubMed:22879591, PubMed:15187149, PubMed:25664854). Promotes chemotaxis of granulocytes and monocytes via activation of the formyl peptide receptors (PubMed:15187149). Promotes rearrangement of the actin cytoskeleton, cell polarization and cell migration (PubMed:15187149). Promotes resolution of inflammation and wound healing (PubMed:25664854). Acts via neutrophil N-formyl peptide receptors to enhance the release of CXCL2 (PubMed:22879591).
Homodimer; non-covalently linked (By similarity). Homodimer; linked by transglutamylation (PubMed:2532504). Homodimers linked by transglutamylation are observed in placenta, but not in other tissues (PubMed:2532504). Interacts with S100A11 (PubMed:8557678, PubMed:10673436). Heterotetramer, formed by two molecules each of S100A11 and ANXA1 (PubMed:10673436). Interacts with DYSF (By similarity). Interacts with EGFR (By similarity).
Peptides based on the N-terminal sequence might be used for the treatment of inflammation, e.g. in chronic bowel diseases and in rheumatoid arthritis.
Phosphorylated by protein kinase C, EGFR and TRPM7 (PubMed:2457390, PubMed:15485879). Phosphorylated in response to EGF treatment (PubMed:2532504).
Plays important roles in the innate immune response as effector of glucocorticoid-mediated responses and regulator of the inflammatory process. Has anti-inflammatory activity (PubMed:8425544). Plays a role in glucocorticoid-mediated down-regulation of the early phase of the inflammatory response (By similarity). Contributes to the adaptive immune response by enhancing signaling cascades that are triggered by T-cell activation, regulates differentiation and proliferation of activated T-cells (PubMed:17008549). Promotes the differentiation of T-cells into Th1 cells and negatively regulates differentiation into Th2 cells (PubMed:17008549). Has no effect on unstimulated T cells (PubMed:17008549). Negatively regulates hormone exocytosis via activation of the formyl peptide receptors and reorganization of the actin cytoskeleton (PubMed:19625660). Has high affinity for Ca(2+) and can bind up to eight Ca(2+) ions (By similarity). Displays Ca(2+)-dependent binding to phospholipid membranes (PubMed:2532504, PubMed:8557678). Plays a role in the formation of phagocytic cups and phagosomes. Plays a role in phagocytosis by mediating the Ca(2+)-dependent interaction between phagosomes and the actin cytoskeleton (By similarity).
Proteolytically cleaved by cathepsin CTSG to release the active N-terminal peptide Ac2-26.
The full-length protein can bind eight Ca(2+) ions via the annexin repeats. Calcium binding causes a major conformation change that modifies dimer contacts and leads to surface exposure of the N-terminal phosphorylation sites; in the absence of Ca(2+), these sites are buried in the interior of the protein core. The N-terminal region becomes disordered in response to calcium-binding.
Was originally identified as calcium and phospholipid binding protein that displays Ca(2+)-dependent binding to phospholipid membranes and can promote membrane aggregation in vitro. Was initially identified as inhibitor of phospholipase A2 activity (in vitro) (PubMed:2936963, PubMed:8425544). Inhibition of phospholipase activity is mediated via its phospholipid binding activity that limits the access of phospholipase to its substrates.
Produces N-acetylneuraminic acid (Neu5Ac) and 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (KDN) (PubMed:10749855, PubMed:27213289). Can also use N-acetylmannosamine 6-phosphate and mannose 6-phosphate as substrates to generate phosphorylated forms of Neu5Ac and KDN, respectively (PubMed:10749855).
Activated by phosphorylation of Thr-239. Once activated, activity is stimulated by binding target proteins (By similarity).
Catalytic activity is enhanced by phosphorylation of Thr-239.
Directly regulated by p53/TP53. Negatively regulated by miR-126.
Expressed at higher level in the fetal lung, kidney, spleen and heart.
Interacts with NSF; causing NSF dissociation from GRIA2. Interacts with CIB1 (By similarity).
The POLO box domains act as phosphopeptide-binding module that recognize and bind serine-[phosphothreonine/phosphoserine]-(proline/X) motifs. PLK2 recognizes and binds docking proteins that are already phosphorylated on these motifs, and then phosphorylates them (By similarity).
There are indications that PLK2 might act as a tumor suppressor: PLK2 is significantly down-regulated in a wide range of acute myeloid leukemias (AMLs) and B-cell lymphomas due to aberrant cytosine methylation in the CpG island located at the 5' of the PLK2 gene (PubMed:16160013, PubMed:21340720). Moreover, miR-126, a microRNA that negatively regulates PLK2 is up-regulated in AMLs, suggesting that PLK2 down-regulation by miR-126 could also contribute to leukemogenesis (PubMed:18832181).
Tumor suppressor serine/threonine-protein kinase involved in synaptic plasticity, centriole duplication and G1/S phase transition. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates CENPJ, NPM1, RAPGEF2, RASGRF1, SNCA, SIPA1L1 and SYNGAP1. Plays a key role in synaptic plasticity and memory by regulating the Ras and Rap protein signaling: required for overactivity-dependent spine remodeling by phosphorylating the Ras activator RASGRF1 and the Rap inhibitor SIPA1L1 leading to their degradation by the proteasome. Conversely, phosphorylates the Rap activator RAPGEF2 and the Ras inhibitor SYNGAP1, promoting their activity. Also regulates synaptic plasticity independently of kinase activity, via its interaction with NSF that disrupts the interaction between NSF and the GRIA2 subunit of AMPARs, leading to a rapid rundown of AMPAR-mediated current that occludes long term depression. Required for procentriole formation and centriole duplication by phosphorylating CENPJ and NPM1, respectively. Its induction by p53/TP53 suggests that it may participate in the mitotic checkpoint following stress.
Expressed in the oocyte, expression is maintained at least until blastocyst stage.
Transcription regulator required to maintain maternal and paternal gene imprinting, a process by which gene expression is restricted in a parent of origin-specific manner by epigenetic modification of genomic DNA and chromatin, including DNA methylation. Acts by controlling DNA methylation during the earliest multicellular stages of development at multiple imprinting control regions (ICRs) (PubMed:30602440). Acts together with ZFP57, but seems to be the major factor in human early embryonic imprinting maintenance. In contrast, in mice, ZFP57 plays the predominant role in imprinting maintenance (PubMed:30602440).
Isoform 1 is specifically expressed in leukemias and a variety of solid tumor cell lines and is also detected in testis and heart. Isoform 2 is predominantly expressed in testis and weakly expressed in tumor cells.
Isoform 1 is the dominant immunogenic isoform and is capable of eliciting a humoral response in individuals with a variety of solid tumors. Expression of isoform 1 in a wide variety of malignancies as well as the presence of an immunogenic epitope suggest that it may be a suitable target for antigen-specific immunotherapy.
Interacts with SLC16A1, SLC16A6 and SLC16A7.
Plays a role in the outgrowth of motoneurons and in the formation of neuromuscular junctions. Following muscle denervation, promotes nerve terminal sprouting and the formation of additional acetylcholine receptor clusters at synaptic sites without affecting terminal Schwann cell number or morphology. Delays the retraction of terminal sprouts following re-innervation of denervated endplates. May play a role in targeting the monocarboxylate transporters SLC16A1, SLC16A6 and SLC16A7 to the cell membrane (By similarity).
Chimeric cDNA. C-terminal is identical to the product of the WLS gene.
Interacts with HDAC1. Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2.
It is uncertain whether Met-1 or Met-55 is the initiator.
Transcriptional repressor regulating the expression of a number of genes including SP1 target genes. Probably functions through recruitment of HDAC1 a histone deacetylase involved in chromatin silencing.
Ubiquitously expressed, but at very low levels. However, consistent level of expression are observed in heart, testis, thyroid, ovary and adrenal gland. Transcripts are up-regulated in breast carcinoma cell lines and tumor.
Wrong choice of CDS. Probable cloning artifact due to reverse transcription from RNA internal poly-A tracts.
Activated following phosphorylation by WNK kinases (WNK1, WNK2, WNK3 or WNK4).
Effector serine/threonine-protein kinase component of the WNK-SPAK/OSR1 kinase cascade, which is involved in various processes, such as ion transport, response to hypertonic stress and blood pressure (PubMed:16669787, PubMed:18270262, PubMed:21321328, PubMed:34289367). Specifically recognizes and binds proteins with a RFXV motif (PubMed:16669787, PubMed:21321328, PubMed:17721439). Acts downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4): following activation by WNK kinases, catalyzes phosphorylation of ion cotransporters, such as SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A3/NCC, SLC12A5/KCC2 or SLC12A6/KCC3, regulating their activity (PubMed:17721439). Mediates regulatory volume increase in response to hyperosmotic stress by catalyzing phosphorylation of ion cotransporters SLC12A1/NKCC2, SLC12A2/NKCC1 and SLC12A6/KCC3 downstream of WNK1 and WNK3 kinases (PubMed:16669787, PubMed:21321328). Phosphorylation of Na-K-Cl cotransporters SLC12A2/NKCC1 and SLC12A2/NKCC1 promote their activation and ion influx; simultaneously, phosphorylation of K-Cl cotransporters SLC12A5/KCC2 and SLC12A6/KCC3 inhibit their activity, blocking ion efflux (PubMed:16669787, PubMed:19665974, PubMed:21321328). Acts as a regulator of NaCl reabsorption in the distal nephron by mediating phosphorylation and activation of the thiazide-sensitive Na-Cl cotransporter SLC12A3/NCC in distal convoluted tubule cells of kidney downstream of WNK4 (PubMed:18270262). Also acts as a regulator of angiogenesis in endothelial cells downstream of WNK1 (PubMed:23386621, PubMed:25362046). Acts as an activator of inward rectifier potassium channels KCNJ2/Kir2.1 and KCNJ4/Kir2.3 downstream of WNK1: recognizes and binds the RXFXV/I variant motif on KCNJ2/Kir2.1 and KCNJ4/Kir2.3 and regulates their localization to the cell membrane without mediating their phosphorylation (PubMed:29581290). Phosphorylates RELL1, RELL2 and RELT (PubMed:16389068, PubMed:28688764). Phosphorylates PAK1 (PubMed:14707132). Phosphorylates PLSCR1 in the presence of RELT (PubMed:22052202).
Phosphorylation at Thr-185 by WNK kinases (WNK1, WNK2, WNK3 or WNK4) is required for activation (PubMed:16669787, PubMed:16832045, PubMed:17190791, PubMed:21321328, PubMed:22989884, PubMed:29581290). Autophosphorylated; promoting its activity (PubMed:14707132, PubMed:22052202).
Ubiquitously expressed in all tissue examined.
Required for the estrogen-dependent expression of ESR1 target genes. Can act in cooperation with MED1.
Component of the chaperonin-containing T-complex (TRiC), a heterooligomeric complex of about 850 to 900 kDa that forms two stacked rings, 12 to 16 nm in diameter.
Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of proteins upon ATP hydrolysis.
Growth factor that mediates its effects via EGFR, ERBB2 and ERBB4. Required for normal cardiac valve formation and normal heart function. Promotes smooth muscle cell proliferation. May be involved in macrophage-mediated cellular proliferation. It is mitogenic for fibroblasts, but not endothelial cells. It is able to bind EGF receptor/EGFR with higher affinity than EGF itself and is a far more potent mitogen for smooth muscle cells than EGF. Also acts as a diphtheria toxin receptor.
Interacts with FBLN1 (By similarity). Interacts with EGFR and ERBB4.
O-glycosylated with core 1 or possibly core 8 glycans. Thr-47 is a minor glycosylation site compared to Thr-44.
Several N-termini have been identified by direct sequencing. The forms with N-termini 63, 73 and 74 have been tested and found to be biologically active.
Heterohexamer (Probable). Oligomerizes with other LRRC8 proteins (LRRC8A, LRRC8C, LRRC8D and/or LRRC8B) to form a heterohexamer (PubMed:24790029, PubMed:26824658, PubMed:28193731). Detected in a channel complex that contains LRRC8A, LRRC8C and LRRC8E (PubMed:28193731). In vivo, the subunit composition may depend primarily on expression levels, and heterooligomeric channels containing various proportions of the different LRRC8 proteins may coexist (Probable).
Non-essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes (PubMed:24790029, PubMed:26824658, PubMed:28193731). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24790029, PubMed:26824658). Mediates efflux of amino acids, such as aspartate, in response to osmotic stress (PubMed:28193731). The VRAC channel also mediates transport of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol (PubMed:33171122). Channel activity requires LRRC8A plus at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (PubMed:24790029, PubMed:26824658, PubMed:28193731). Also plays a role in lysosome homeostasis by forming functional lysosomal VRAC channels in response to low cytoplasmic ionic strength condition: lysosomal VRAC channels are necessary for the formation of large lysosome-derived vacuoles, which store and then expel excess water to maintain cytosolic water homeostasis (PubMed:33139539).
Adipocyte-secreted protein (adipokine) that acts as a key regulator for white adipose tissue (WAT) thermogenesis and glucose homeostasis at least in part through activation of protein kinase A (PKA).
Mediates pre-mRNA alternative splicing regulation. Acts either as activator or repressor of splicing on specific pre-mRNA targets. Inhibits cardiac troponin-T (TNNT2) pre-mRNA exon inclusion but induces insulin receptor (IR) pre-mRNA exon inclusion in muscle. Antagonizes the alternative splicing activity pattern of CELF proteins. RNA-binding protein that binds to 5'ACACCC-3' core sequence, termed zipcode, within the 3'UTR of ITGA3. Binds to CUG triplet repeat expansion in myotonic dystrophy muscle cells by sequestering the target RNAs. Seems to regulate expression and localization of ITGA3 by transporting it from the nucleus to cytoplasm at adhesion plaques. May play a role in myotonic dystrophy pathophysiology (DM).
Belongs to the nonaspanin (TM9SF) (TC 9.A.2) family.
Expressed in lung, pancreas, kidney, liver, placenta, skeletal muscle, heart and brain. The amount in skeletal muscle, heart and brain were considerably lower than in the other tissues.
Interacts with the RPA1 subunit of RPA complex.
May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be due to an intron retention.
Mediates the import of RPA complex into the nucleus, possibly via some interaction with importin beta. Isoform 2 is sumoylated and mediates the localization of RPA complex into the PML body of the nucleus, thereby participating in RPA function in DNA metabolism.
Sumoylated. Sumoylation is required for localization in the nuclear PML body and transport of RPA complex in PML body. Upon UV irradiation and during S phase, it is desumoylated, releasing RPA complex that is translocated to sites of DNA damage. Sumoylation takes place at different Lys residues. Variant 'Lys-103' adds a sumoylation site and increases total sumoylation levels.
Widely expressed. Expressed in pancreas, kidney, muscle, liver, lung, placenta, brain, heart, leukocytes, colon, intestine, ovary, testis, prostate, thymus and spleen.
Zinc chaperone that directly transfers zinc cofactor to target metalloproteins, thereby activating them. Catalyzes zinc insertion into the active site of methionine aminopeptidase METAP1, which function to cleave the initiator methionine from polypeptides during or after protein translation. Mechanistically, the N-terminal psi-PxLVp motif binds to the C6H2-type zinc finger of inactive form of METAP1. After formation of the docked complex, zinc is transferred from the CXCC motif in the GTPase domain of ZNG1B to the zinc binding site in the peptidase domain of METAP1 in a process requiring GTP hydrolysis. GTP/GDP exchange is required for release of active METAP1.
Associates with the adapter-like complex 4 (AP-4) and may therefore play a role in vesicular trafficking of proteins at the trans-Golgi network.
Interacts with AP4B1 and AP4E1; the interaction is direct and mediates the association of TEPSIN with the adapter-like complex 4 (AP-4), a heterotetramer composed of AP4B1, AP4E1, AP4M1 and AP4S1.
Is responsible for the charging of tRNA(Phe) with phenylalanine in mitochondrial translation. To a lesser extent, also catalyzes direct attachment of m-Tyr (an oxidized version of Phe) to tRNA(Phe), thereby opening the way for delivery of the misacylated tRNA to the ribosome and incorporation of ROS-damaged amino acid into proteins.
A chromosomal aberration involving PDGFB is found in dermatofibrosarcoma protuberans. Translocation t(17;22)(q22;q13) with PDGFB.
Antiparallel homodimer; disulfide-linked. Antiparallel heterodimer with PDGFA; disulfide-linked. The PDGFB homodimer interacts with PDGFRA and PDGFRB homodimers, and with heterodimers formed by PDGFRA and PDGFRB. The heterodimer composed of PDGFA and PDGFB interacts with PDGFRB homodimers, and with heterodimers formed by PDGFRA and PDGFRB. Interacts with XLKD1 (By similarity). Interacts with LRP1 (PubMed:15053742). Interacts with SORL1 (via the N-terminal ectodomain) (PubMed:15053742, PubMed:16393139).
Available under the name Regranex (Ortho-McNeil). Used to promote healing in diabetic neuropathic foot ulcers.
Expressed at high levels in the heart, brain (sustantia nigra), placenta and fetal kidney. Expressed at moderate levels in the brain (hippocampus), skeletal muscle, kidney and lung.
Growth factor that plays an essential role in the regulation of embryonic development, cell proliferation, cell migration, survival and chemotaxis. Potent mitogen for cells of mesenchymal origin (PubMed:26599395). Required for normal proliferation and recruitment of pericytes and vascular smooth muscle cells in the central nervous system, skin, lung, heart and placenta. Required for normal blood vessel development, and for normal development of kidney glomeruli. Plays an important role in wound healing. Signaling is modulated by the formation of heterodimers with PDGFA (By similarity).
It is uncertain whether Met-1 or Met-99 is the initiator.
Acts as a repressor of MYOD-dependent transcription, glucocorticoid receptor-dependent transcription, and muscle differentiation.
Homodimer and heterodimer with EID2. Interacts with HDAC1 and HDAC2.
The C-terminal portion of EID2B is required for nuclear localization.
Belongs to the Dus family. Dus2 subfamily.
Dihydrouridine synthase. Catalyzes the NADPH-dependent synthesis of dihydrouridine, a modified base found in the D-loop of most tRNAs (PubMed:15994936, PubMed:26429968, PubMed:30149704, PubMed:34798057). Negatively regulates the activation of EIF2AK2/PKR (PubMed:18096616).
Efficient dihydrouridine synthesis requires the presence of both the catalytic domain and the C-terminal RNA-binding DRBM domain.
Interacts with EPRS1. Interacts (via DRBM domain) with PRKRA and EIF2AK2/PKR (via DRBM 1 domain).
Weak expression in heart, placenta and skeletal muscle. Up-regulated in most lung cancer cells (at protein level).
3 different light chains, LC1, LC2 and LC3, can associate with MAP1A and MAP1B proteins. LC1 interacts with the amino-terminal region of MAP1B. Interacts with ANP32A and TIAM2. Interacts with the tubulin tyrosine TTL (By similarity). Interacts (via C-terminus) with GAN (via Kelch domains) (PubMed:12147674, PubMed:16227972). Interacts (via N-terminus) with DAPK1 (PubMed:18195017). Interacts with TMEM185A (PubMed:15525354). Interacts with MAP1LC3B (PubMed:24089205). Interacts with KIRREL3 (PubMed:25902260). MAP1 light chain LC1 (via C-terminus): Interacts with ELAVL4; the interaction contributes to the association of ELAVL4 with microtubules (By similarity). MAP1 light chain LC1: Interacts with ELAVL2 and ELAVL3 (By similarity).
Facilitates tyrosination of alpha-tubulin in neuronal microtubules (By similarity). Phosphorylated MAP1B is required for proper microtubule dynamics and plays a role in the cytoskeletal changes that accompany neuronal differentiation and neurite extension (PubMed:33268592). Possibly MAP1B binds to at least two tubulin subunits in the polymer, and this bridging of subunits might be involved in nucleating microtubule polymerization and in stabilizing microtubules. Acts as a positive cofactor in DAPK1-mediated autophagic vesicle formation and membrane blebbing.
Has a highly basic region with many copies of the sequence KKEE and KKEI/V, repeated but not at fixed intervals, which is responsible for the binding of MAP1B to microtubules.
LC1 is generated from MAP1B by proteolytic processing.
S-nitrosylation at Cys-2464 enhances interaction with microtubules, and may act as an effector modification for neuronal nitric oxide synthase control of growth-cone size, growth-cone collapse and axon retraction.
(Microbial infection) Cleaved between Gln-130 and Gly-131 by the Protease 3C from various human enteroviruses and rhinoviruses (EV68, EV71, Coxsackievirus B3, HRV-14 and HRV-16) (PubMed:33093214, PubMed:33410748). This cleavage triggers N-glycine-mediated proteasomal degradation of the autoinhibitory NLRP1 N-terminal fragment via the cullin:ZER1/ZYG11B complex which liberates the activating C-terminal fragment and activates NLRP1 inflammasome (PubMed:33093214).
(Microbial infection) Cleaved between Gln-333 and Gly-334 by the 3C-like proteinase nsp5 from human coronavirus SARS-CoV-2 (PubMed:35594856). This cleavage liberates the activating C-terminal fragment and activates NLRP1 inflammasome, leading to downstream activation of GSDME and lung epithelial cell death (PubMed:35594856).
(Microbial infection) Interacts with human herpes virus 8/HHV-8 proteins ORF45; relieving autoinhibition of the NLRP1 inflammasome.
(Microbial infection) Interacts with vaccinia virus protein F1 (PubMed:16439990).
(Microbial infection) The NLRP1 inflammasome is activated by human herpes virus 8/HHV-8 protein ORF45, which interacts with the N-terminal part of NLRP1 and promotes its translocation into the nucleus, relieving autoinhibition and leading to activation.
Acts as the sensor component of the NLRP1 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis (PubMed:22665479, PubMed:12191486, PubMed:17349957, PubMed:27662089, PubMed:31484767, PubMed:33093214, PubMed:33410748, PubMed:33731929, PubMed:33731932, PubMed:35857590). Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (PubMed:22665479, PubMed:12191486, PubMed:17349957). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as cleavage by some human enteroviruses and rhinoviruses, double-stranded RNA, UV-B irradiation, or Val-boroPro inhibitor, and mediates the formation of the inflammasome polymeric complex composed of NLRP1, CASP1 and PYCARD/ASC (PubMed:22665479, PubMed:12191486, PubMed:17349957, PubMed:25562666, PubMed:30291141, PubMed:30096351, PubMed:33243852, PubMed:33093214, PubMed:33410748, PubMed:35857590). In response to pathogen-associated signals, the N-terminal part of NLRP1 is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1, C-terminus), which polymerizes and associates with PYCARD/ASC to initiate the formation of the inflammasome complex: the NLRP1 inflammasome recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis (PubMed:22665479, PubMed:12191486, PubMed:17349957, PubMed:32051255, PubMed:33093214). In the absence of GSDMD expression, the NLRP1 inflammasome is able to recruit and activate CASP8, leading to activation of gasdermin-E (GSDME) (PubMed:33852854, PubMed:35594856). Activation of NLRP1 inflammasome is also required for HMGB1 secretion; the active cytokines and HMGB1 stimulate inflammatory responses (PubMed:22801494). Binds ATP and shows ATPase activity (PubMed:11113115, PubMed:15212762, PubMed:33243852). Plays an important role in antiviral immunity and inflammation in the human airway epithelium (PubMed:33093214). Specifically recognizes a number of pathogen-associated signals: upon infection by human rhinoviruses 14 and 16 (HRV-14 and HRV-16), NLRP1 is cleaved and activated which triggers NLRP1-dependent inflammasome activation and IL18 secretion (PubMed:33093214). Positive-strand RNA viruses, such as Semliki forest virus and long dsRNA activate the NLRP1 inflammasome, triggering IL1B release in a NLRP1-dependent fashion (PubMed:33243852). Acts as a direct sensor for long dsRNA and thus RNA virus infection (PubMed:33243852). May also be activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, in a NOD2-dependent manner (PubMed:18511561). The NLRP1 inflammasome is also activated in response to UV-B irradiation causing ribosome collisions: ribosome collisions cause phosphorylation and activation of NLRP1 in a MAP3K20-dependent manner, leading to pyroptosis (PubMed:35857590).
Associated with differentiation in stratified epithelia of the skin, esophagus, intestine, and cervix, as well as in the prostate gland. Undetectable in undifferentiated basal cells, but expressed in differentiated luminal secretory cells (PubMed:11113115). Expressed in differentiated macrophages and granulocytes, but not their precursors (at protein level) (PubMed:11113115, PubMed:15285719). In testis, also associated with cell differentiation, with conflicting results. Expressed in spermatogonia and primary spermatocytes, but not in cells from later differentiation stages, including secondary spermatocytes, spermatids, and spermatozoa (at protein level) (PubMed:17164409). Not detected in spermatocytes, nor spermatids, and strongly expressed in spermatozoa (at protein level) (PubMed:11113115).
Autocatalytically cleaved (PubMed:22087307, PubMed:22665479, PubMed:33093214). Autocatalytic cleavage in FIIND region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding (PubMed:22087307, PubMed:22665479, PubMed:33093214). Both N- and C-terminal parts remain associated non-covalently (PubMed:22087307, PubMed:22665479, PubMed:33093214).
Constitutes the active part of the NLRP1 inflammasome (PubMed:33093214, PubMed:33731929, PubMed:33731932). In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, N-terminus), preventing activation of the NLRP1 inflammasome (PubMed:33093214). In response to pathogen-associated signals, the N-terminal part of NLRP1 is degraded by the proteasome, releasing this form, which polymerizes and associates with PYCARD/ASC to form of the NLRP1 inflammasome complex: the NLRP1 inflammasome complex then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and subsequent pyroptosis (PubMed:33093214).
Constitutes the precursor of the NLRP1 inflammasome, which mediates autoproteolytic processing within the FIIND domain to generate the N-terminal and C-terminal parts, which are associated non-covalently in absence of pathogens and other damage-associated signals.
In macrophages and dendritic cells, NLRP1 inflammasome activation of CASP1 and IL1B maturation can be dampened by direct contact with activated effector and memory T-cells. This effect may be mediated by hexameric TNF ligands, such as CD40LG.
Interacts (via LRR repeats) with BCL2 and BCL2L1 (via the loop between motifs BH4 and BH3); these interactions reduce NLRP1 inflammasome-induced CASP1 activation and IL1B release, possibly by impairing NLRP1 interaction with PYCARD (PubMed:17418785). Interacts with NOD2; this interaction is enhanced in the presence of muramyl dipeptide (MDP) and increases IL1B release (PubMed:18511561). Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to danger-associated signals (PubMed:22801494). Interacts with MEFV; this interaction targets NLRP1 to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation (PubMed:17431422, PubMed:26347139). Binds (via LRR domain) to dsDNA and dsRNA (PubMed:33243852). Interacts with DPP9; leading to inhibit activation of the inflammasome (PubMed:30291141, PubMed:31525884, PubMed:33731932). DPP9 acts via formation of a ternary complex, composed of a DPP9 homodimer, one full-length NLRP1 protein, and one cleaved C-terminus of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus) (PubMed:33731932). Interacts with DPP8; leading to inhibit activation of the inflammasome, probably via formation of a ternary complex with DPP8 (PubMed:31525884).
Interacts with the C-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus) in absence of pathogens and other damage-associated signals.
Interacts with the N-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, N-terminus) in absence of pathogens and other damage-associated signals (PubMed:33093214). Homomultimer; forms the NLRP1 inflammasome polymeric complex, a filament composed of homopolymers of this form in response to pathogens and other damage-associated signals (PubMed:33420028, PubMed:33420033). The NLRP1 inflammasome polymeric complex associates with PYCARD/ASC (PubMed:22665479, PubMed:12191486, PubMed:17418785, PubMed:17349957). Interacts (via CARD domain) with PYCARD/ASC (via CARD domain); leading to pro-caspase-1 (proCASP1) recruitment (PubMed:22665479, PubMed:12191486, PubMed:17418785). Pro-caspase-1 (proCASP1) filament formation increases local enzyme concentration, resulting in trans-autocleavage and activation (PubMed:22665479, PubMed:12191486, PubMed:17349957). Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response (PubMed:22665479, PubMed:12191486, PubMed:17349957).
It is unclear whether is involved in inflammasome formation. It is not cleaved within the FIIND domain, does not assemble into specks, nor promote IL1B release (PubMed:22665479). However, in an vitro cell-free system, it has been shown to be activated by MDP (PubMed:17349957).
NLRP1 inflammasome is activated by cleavage by the Protease 3C from various human enteroviruses and rhinoviruses (EV68, EV71, Coxsackievirus B3, HRV-14 and HRV-16): cleavage promotes ubiquitination and degradation of the N-terminal part, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1, C-terminus), which polymerizes and forms the NLRP1 inflammasome (PubMed:33093214, PubMed:33410748). NLRP1 inflammasome is also activated by cleavage by the 3C-like proteinase nsp5 from human coronavirus SARS-CoV-2 (PubMed:35594856). Activated double-stranded RNA: positive-strand RNA viruses such as Semliki forest virus and long dsRNA activate the NLRP1 inflammasome (PubMed:33243852). In contrast to its mouse ortholog, not activated by Bacillus anthracis lethal toxin (PubMed:19651869). NLRP1 inflammasome is inhibited by DPP8 and DPP9, which sequester the C-terminal fragment of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus) in a ternary complex, thereby preventing NLRP1 oligomerization and activation (PubMed:30291141, PubMed:31525884, PubMed:33731929, PubMed:33731932). NLRP1 inflammasome is activated by Val-boroPro (Talabostat, PT-100), an inhibitor of dipeptidyl peptidases DPP8 and DPP9 (PubMed:30291141, PubMed:33731929, PubMed:33731932). Val-boroPro relieves inhibition of DPP8 and/or DPP9 by promoting disruption of the ternary complex, releasing its C-terminal part from autoinhibition (PubMed:33731929, PubMed:33731932). ATPase activity is activated by dsRNA-binding but not dsDNA-binding (PubMed:33243852).
Phosphorylated by MAP3K20 isoform ZAKalpha, MAPK11 and MAPK14 in response to UV-B irradiation and ribosome collisions, promoting activation of the NLRP1 inflammasome and pyroptosis.
Regulatory part that prevents formation of the NLRP1 inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus), preventing activation of the NLRP1 inflammasome (PubMed:33093214). In response to pathogen-associated signals, this part is ubiquitinated and degraded by the proteasome, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the NLRP1 inflammasome (PubMed:33093214).
The C-terminal part of NLRP1 oligomerizes to form the core of the NLRP1 inflammasome filament: in the filament, the CARD domains form a central helical filaments that are promoted by oligomerized, but flexibly linked, UPA regions surrounding the filaments (PubMed:33420028, PubMed:33420033). The UPA region reduces the threshold needed for filament formation and signaling (PubMed:33420028, PubMed:33420033). Must recruit the adapter PYCARD/ASC to facilitate CASP1 interaction and polymerization (PubMed:33420033).
The CARD domain, rather than the pyrin domain, is involved in the interaction with PYCARD, CASP1 and CASP5.
The FIIND (domain with function to find) region is involved in homomerization, but not in CASP1-binding (By similarity). Autocatalytic cleavage in this region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding (PubMed:22665479, PubMed:22087307). Both N- and C-terminal fragments remain associated (PubMed:22665479, PubMed:22087307).
The ZAKalpha motifs are recognized and phosphorylated by isoform ZAKalpha of MAP3K20.
The leucine-rich repeat (LRR) domain may be involved in autoinhibition in the absence of activating signal, possibly through intramolecular interaction with the NACHT domain. Serves as the predominant binding domain for dsRNA and dsDNA (PubMed:33243852).
The pyrin domain mediates an autoinhibitory function, potentially acting as a threshold modulator, which allows NLRP1 to discriminate long from short dsRNA. Inhibits ATPase activity of the NATCH domain.
Ubiquitinated by the cullin:ZER1/ZYG11B complex in response to pathogen-associated signals, leading to its degradation by the proteasome and subsequent release of the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1, C-terminus), which polymerizes and forms the NLRP1 inflammasome.
Up-regulated by ATF4 during endoplasmic reticulum (ER) stress response (PubMed:26086088). Up-regulated in arterial endothelial cells exposed to plasma from patients with peripheral arterial disease, but not to plasma from healthy controls (PubMed:24439873).
Upon dsRNA-binding via its LRR domain, NACHT domain gains ATPase activity which is inhibited by the pyrin domain.
Widely expressed (PubMed:11113115, PubMed:17164409). Abundantly expressed in primary immune cells (isoform 1 and isoform 2), including in neutrophils, monocytes/macrophages, dendritic cells (mostly Langerhans cells), and B- and T-lymphocytes (at protein level) (PubMed:15285719, PubMed:17164409). Strongly expressed in epithelial cells lining the glandular epithelium, such as that of the gastrointestinal tract (stomach, small intestine, colon), the respiratory tract (trachea and bronchi), and the endometrial and endocervical glands, gallbladder, prostate, and breast (at protein level). In testis, expressed in spermatogonia and primary spermatocytes, but not in Sertoli cells (at protein level). In the brain, expressed in neurons, in particular in pyramidal ones and in oligodendrocytes, but not detected in microglia (at protein level) (PubMed:17164409). Expressed in adult and fetal ocular tissues, including in adult and 24-week old fetal choroid, sclera, cornea, and optic nerve, as well as in adult retina and fetal retina/retinal pigment epithelium (PubMed:23349227). Highly expressed in the skin throughout the epidermis and in dermal fibroblasts, in both glabrous skin and plantar skin. It is detected in keratinocytes, but not in melanocytes. Expressed in epidermal appendages such as hair follicles (PubMed:27662089).
By hypoxia and also by 2-deoxyglucose or tunicamycin.
Has a pivotal role in cytoprotective cellular mechanisms triggered by oxygen deprivation. May play a role as a molecular chaperone and participate in protein folding.
Highly expressed in tissues that contain well-developed endoplasmic reticulum and synthesize large amounts of secretory proteins. Highly expressed in liver and pancreas and lower expression in brain and kidney. Also expressed in macrophages within aortic atherosclerotic plaques, and in breast cancers.
Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX.
Belongs to the ELO family. ELOVL3 subfamily.
Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme that exhibits activity toward saturated and unsaturated acyl-CoA substrates with higher activity toward C18 acyl-CoAs, especially C18:0 acyl-CoAs. May participate in the production of saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.
The C-terminal di-lysine motif may confer endoplasmic reticulum localization.
Component of the DRTF1/E2F transcription factor complex. Binds cooperatively with DP-1 to E2F sites. Interaction with retinoblastoma protein RB1 or proteins RBL1 and RBL2 inhibits the E2F transactivation domain. Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2. The complex exists in quiescent cells where it represses cell cycle-dependent genes. It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2.
Transcriptional activator that binds to E2F sites, these sites are present in the promoter of many genes whose products are involved in cell proliferation. May mediate growth factor-initiated signal transduction. It is likely involved in the early responses of resting cells to growth factor stimulation. Specifically required for multiciliate cell differentiation: together with MCIDAS and E2F5, binds and activate genes required for centriole biogenesis.
Belongs to the LU7TM family. TMEM87 subfamily.
May be involved in retrograde transport from endosomes to the trans-Golgi network (TGN) (PubMed:26157166). In one study, shown to be a component of a novel mechanoelectrical transduction pathway which is involved in cell adhesion and migration, and is thought to act either as a mechanically activated ion channel or as an accessory protein which modulates an unidentified mechanically activated ion channel (PubMed:32228863). In another study, neither basal nor mechanically activated channel activity has been observed and, based on structural similarity with WLS, has been suggested to function as a trafficking chaperone for membrane-associated cargo (PubMed:36373655).
Plays a role in positive regulation of melanoma cell migration.
Controls reversibly actin polymerization and depolymerization in a pH-sensitive manner. Its F-actin depolymerization activity is regulated by association with CSPR3 (PubMed:19752190). It has the ability to bind G- and F-actin in a 1:1 ratio of cofilin to actin. It is the major component of intranuclear and cytoplasmic actin rods. Required for muscle maintenance. May play a role during the exchange of alpha-actin forms during the early postnatal remodeling of the sarcomere (By similarity).
Interacts with CSRP3; possibly two molecules of CFL2 can interact with one molecule if CSRP3.
Isoform CFL2b is expressed predominantly in skeletal muscle and heart. Isoform CFL2a is expressed in various tissues.
The phosphorylation of Ser-24 may prevent recognition of the nuclear localization signal.
Acts as a GTPase-activating protein (GAP) toward guanine nucleotide exchange factors like ARL2, ARL3, ARF1 and ARF6, but not for GTPases outside the Arf family.
Actin-binding protein that enhances membrane ruffling and RAC activation. Enhances the actin-bundling activity of LCP1. Binds calcium. Plays a role in RAC signaling and in phagocytosis. May play a role in macrophage activation and function. Promotes the proliferation of vascular smooth muscle cells and of T-lymphocytes. Enhances lymphocyte migration. Plays a role in vascular inflammation.
Detected in T-lymphocytes and peripheral blood mononuclear cells.
Homodimer (Potential). Monomer. Interacts with LCP1.
Component of the pre-catalytic spliceosome B and the catalytic spliceosome C complexes (PubMed:11991638, PubMed:22961380, PubMed:28502770, PubMed:28076346, PubMed:29360106, PubMed:29301961). Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932). Interacts with EIF4A3 and PRPF19 in an RNA-independent manner. Direct interaction with EIF4A3 is mediated by the MIF4G domain (PubMed:24218557). Full interaction with EIF4A3 occurs only when EIF4A3 is not part of the EJC and prevents EIF4A3 binding to RNA.
Required for pre-mRNA splicing as component of the spliceosome (PubMed:12226669, PubMed:11991638, PubMed:22961380, PubMed:28502770, PubMed:28076346, PubMed:29360106, PubMed:29301961). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). Promotes exon-junction complex (EJC) assembly (PubMed:22959432, PubMed:22961380). Hinders EIF4A3 from non-specifically binding RNA and escorts it to the splicing machinery to promote EJC assembly on mature mRNAs. Through its role in EJC assembly, required for nonsense-mediated mRNA decay.
Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. May form part of a tissue-specific acute response to remodeling stimuli. Known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, MMP-14 and MMP-15.
Monomethylation at Lys-86 (K86me1) regulates actin-myosin interaction and actomyosin-dependent processes. Demethylation by ALKBH4 is required for maintaining actomyosin dynamics supporting normal cleavage furrow ingression during cytokinesis and cell migration.
Expressed in breast, ductal and invasive ductal carcinomas of the breast, sporadic colorectal adenomas and carcinomas (at protein level). Expressed in fetal brain. Expressed in lung, amygdala, eye, prostate, pancreatic and prostate cancers, head and neck tumors and embryonal tumor.
Found in a complex with CDC73; CTNNB1 and PYGO1. Interacts with CTNNB1.
Tne C-terminal domain is important for its transactivation activity.
Transcriptional regulator that acts as an activator. Promotes beta-catenin transcriptional activity. Plays a role in tumorigenesis. Enhances the neoplastic transforming activity of CTNNB1 (By similarity).
Transcription factor that may function in dorsoventral specification of the forebrain. Required for axon guidance and major tract formation in the developing forebrain. May contribute to the differentiation of the neuroretina, pigmented epithelium and optic stalk (By similarity).
Expressed in neural tissues, with strongest expression in fetal and adult brain. Expressed in the developing cortical plate and marginal zone of 20-week-old human fetal brain.
Interacts with CDH1 and CDH2 (By similarity). Interacts with ZNF639; recruits CTNNA2 to the nucleus (PubMed:16182284). Interacts with F-actin (PubMed:30013181).
May function as a linker between cadherin adhesion receptors and the cytoskeleton to regulate cell-cell adhesion and differentiation in the nervous system (By similarity). Required for proper regulation of cortical neuronal migration and neurite growth (PubMed:30013181). It acts as negative regulator of Arp2/3 complex activity and Arp2/3-mediated actin polymerization (PubMed:30013181). It thereby suppresses excessive actin branching which would impair neurite growth and stability (PubMed:30013181). Regulates morphological plasticity of synapses and cerebellar and hippocampal lamination during development. Functions in the control of startle modulation (By similarity).
Receptor for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase. It is functionally coupled not only to inhibition of adenylate cyclase, but also to activation of both arachidonate release and mitogen-activated protein (MAP) kinase cascade. Mediates antiproliferative action of somatostatin in tumor cells.
Specifically expressed in fetal and adult brain, lung tissue, stomach, and in lesser quantities in the kidney, pituitary and adrenals.
(Microbial infection) May function as a retroviral receptor as it confers human cells susceptibility to infection to Gibbon Ape Leukemia Virus (GaLV), Simian sarcoma-associated virus (SSAV) and Feline leukemia virus subgroup B (FeLV-B) as well as 10A1 murine leukemia virus (10A1 MLV).
By phosphate deprivation as well as by IL8/interleukin-8 in hypertrophic chondrocytes.
Region A confers human cells susceptibility to infection by Gibbon Ape Leukemia Virus (GaLV) and Feline leukemia virus subgroup B (FeLV-B). Substitution of Human SLC20A1 region A by region A of murine SLC20A1 prevents viral infection.
Sodium-phosphate symporter which preferentially transports the monovalent form of phosphate with a stoichiometry of two sodium ions per phosphate ion (PubMed:11009570, PubMed:7929240, PubMed:8041748, PubMed:19726692, PubMed:17494632, PubMed:16790504). May play a role in extracellular matrix and cartilage calcification as well as in vascular calcification (PubMed:11009570). Essential for cell proliferation but this function is independent of its phosphate transporter activity (PubMed:19726692).
By 12-O-tetradecanoylphorbol-13 acetate (TPA).
Interacts with TRAF1 and TRAF2 as well as with JUN. Forms a multimeric complex with RUNX2 and E3 ubiquitin ligase WWP1 (By similarity).
Phosphorylated on threonine and serine residues.
Plays a role of transcription factor; binds to recognition signal sequences (Rss heptamer) for somatic recombination of immunoglobulin and T-cell receptor gene segments; Binds also to the kappa-B motif of gene such as S100A4, involved in cell progression and differentiation. Kappa-B motif is a gene regulatory element found in promoters and enhancers of genes involved in immunity, inflammation, and growth and that responds to viral antigens, mitogens, and cytokines. Involvement of HIVEP3 in cell growth is strengthened by the fact that its down-regulation promotes cell cycle progression with ultimate formation of multinucleated giant cells. Strongly inhibits TNF-alpha-induced NF-kappa-B activation; Interferes with nuclear factor NF-kappa-B by several mechanisms: as transcription factor, by competing for Kappa-B motif and by repressing transcription in the nucleus; through a non transcriptional process, by inhibiting nuclear translocation of RELA by association with TRAF2, an adapter molecule in the tumor necrosis factor signaling, which blocks the formation of IKK complex. Interaction with TRAF proteins inhibits both NF-Kappa-B-mediated and c-Jun N-terminal kinase/JNK-mediated responses that include apoptosis and pro-inflammatory cytokine gene expression. Positively regulates the expression of IL2 in T-cell. Essential regulator of adult bone formation.
The ZAS2 domain binds DNA as dimers, tetramers, and multiple of tetramers and readily forms highly ordered DNA-protein structures.
Golgi Na(+), K(+)/(H+) antiporter. Mediates the electoneutral influx of Na(+) or K(+) in exchange for H(+). May contribute to the regulation of Golgi apparatus volume and pH.
Inhibited by benzamil and quinine but not by amiloride.
Interacts with SCAMP1, SCAMP2 and SCAMP5; may participate in its shuttling from trans-Golgi network to recycling endosomes.
Available under the names Factrel (Ayerst Labs), Lutrepulse or Lutrelef (Ferring Pharmaceuticals) and Relisorm (Serono). Used in evaluating hypothalamic-pituitary gonadotropic function.
Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.
The 3D-structure was determined for the synthetic analog Triptorelin.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in GNRH1 as well as in other HH-associated genes including PROKR2 and FGFR1 (PubMed:23643382).
The precursor is cleaved by ACE, which removes the Gly-Lys-Arg peptide at the C-terminus, leading to mature hormone (PubMed:10336644, PubMed:7683654). The mature form of Gonadoliberin-1 is also cleaved and degraded by ACE (PubMed:2983326, PubMed:7683654).
Acts as a signaling pathway regulator involved in innate immune system response (PubMed:26342464, PubMed:29038465, PubMed:29350881). In response to interferon IFN-alpha, associates in a complex with signaling pathway regulator NMI to regulate immune response; the complex formation prevents proteasome-mediated degradation of IFI35 and correlates with IFI35 dephosphorylation (PubMed:10779520, PubMed:10950963). In complex with NMI, inhibits virus-triggered type I interferon/IFN-beta production (PubMed:26342464). In complex with NMI, negatively regulates nuclear factor NF-kappa-B signaling by inhibiting the nuclear translocation, activation and transcription of the NF-kappa-B subunit p65/RELA, resulting in the inhibition of endothelial cell proliferation, migration and re-endothelialization of injured arteries (PubMed:29350881). Beside its role as an intracellular signaling pathway regulator, also functions extracellularly as damage-associated molecular patterns (DAMPs) to promote inflammation when actively released by macrophage to the extracellular space during cell injury and pathogen invasion (PubMed:29038465). Macrophage-secreted IFI35 activates NF-kappa-B signaling in adjacent macrophages through Toll-like receptor 4/TLR4 activation, thereby inducing NF-kappa-B translocation from the cytoplasm into the nucleus which promotes the release of pro-inflammatory cytokines (PubMed:29038465).
Due to a polymorphism at the 3'-splice acceptor site of intron 4.
Expressed in a wide range of cell types, including fibroblasts, macrophages, and epithelial cells.
Homodimer (PubMed:8288566, PubMed:10950963). Also interacts with BATF (PubMed:8954125). Interacts with TRIM21 (PubMed:26342464). Interacts with NMI; the interaction is direct and is facilitated by TRIM21 (PubMed:10779520, PubMed:10950963, PubMed:26342464).
Phosphorylated. Dephosphorylation correlates with the formation of a complex with NMI.
The NID domain 1 is involved in the negative regulation of p65/RELA transcription and the negative regulation of NF-kappa-B pathway activation.
Up-regulated by interferons IFN-alpha and IFN-gamma.
(Microbial infection) Interacts with herpes simplex virus 1 protein UL12.
Component of the MRE11-RAD50-NBN (MRN complex) which plays a critical role in the cellular response to DNA damage and the maintenance of chromosome integrity. The complex is involved in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity, cell cycle checkpoint control and meiosis.
Component of the MRE11-RAD50-NBN (MRN complex) which plays a critical role in the cellular response to DNA damage and the maintenance of chromosome integrity. The complex is involved in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity, cell cycle checkpoint control and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. NBN modulate the DNA damage signal sensing by recruiting PI3/PI4-kinase family members ATM, ATR, and probably DNA-PKcs to the DNA damage sites and activating their functions. It can also recruit MRE11 and RAD50 to the proximity of DSBs by an interaction with the histone H2AX. NBN also functions in telomere length maintenance by generating the 3' overhang which serves as a primer for telomerase dependent telomere elongation. NBN is a major player in the control of intra-S-phase checkpoint and there is some evidence that NBN is involved in G1 and G2 checkpoints. The roles of NBS1/MRN encompass DNA damage sensor, signal transducer, and effector, which enable cells to maintain DNA integrity and genomic stability. Forms a complex with RBBP8 to link DNA double-strand break sensing to resection. Enhances AKT1 phosphorylation possibly by association with the mTORC2 complex.
Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (PubMed:26215093, PubMed:9590181, PubMed:9705271, PubMed:11238951). As part of the MRN complex, interacts with MCM9; the interaction recruits the complex to DNA repair sites (PubMed:26215093). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (PubMed:10783165). Interacts with histone H2AX this requires phosphorylation of H2AX on 'Ser-139' (PubMed:12419185). Interacts with HJURP (PubMed:17823411). Interacts with INTS3 (PubMed:19683501). Interacts with KPNA2 (PubMed:16188882). Interacts with TERF2 (PubMed:10888888). Interacts with RBBP8; the interaction links the role of the MRN complex in DNA double-strand break sensing to resection (PubMed:19759395). Interacts with SP100; recruits NBN to PML bodies (PubMed:12470659). Interacts with ATF2 (PubMed:15916964). Interacts with MTOR, MAPKAP1 isoform 2 and RICTOR; indicative for an association with the mTORC2 complex (PubMed:23762398). Interacts with MRNIP (PubMed:27568553). Interacts with UFL1; promoting UFL1 recruitment to double-strand breaks following DNA damage (PubMed:30886146). Interacts with CYREN (via XLF motif) (By similarity).
Contaminating sequence. Potential poly-A sequence starting in position 550.
Defects in NBN might play a role in the pathogenesis of childhood acute lymphoblastic leukemia (ALL).
Phosphorylated by ATM in response of ionizing radiation, and such phosphorylation is responsible intra-S phase checkpoint control and telomere maintenance.
The C-terminal domain contains a MRE11-binding site, and this interaction is required for the nuclear localization of the MRN complex.
The EEXXXDDL motif at the C-terminus is required for the interaction with ATM and its recruitment to sites of DNA damage and promote the phosphorylation of ATM substrates, leading to the events of DNA damage response.
The FHA and BRCT domains are likely to have a crucial role for both binding to histone H2AX and for relocalization of MRE11/RAD50 complex to the vicinity of DNA damage.
Ubiquitous (PubMed:9590180). Expressed at high levels in testis (PubMed:9590180).
Up-regulated by ionizing radiation (IR).
Kinetochore- and microtubule-binding protein that plays a key role in spindle assembly (PubMed:24462186, PubMed:24462187, PubMed:26388440). ZNF207/BuGZ is mainly composed of disordered low-complexity regions and undergoes phase transition or coacervation to form temperature-dependent liquid droplets. Coacervation promotes microtubule bundling and concentrates tubulin, promoting microtubule polymerization and assembly of spindle and spindle matrix by concentrating its building blocks (PubMed:26388440). Also acts as a regulator of mitotic chromosome alignment by mediating the stability and kinetochore loading of BUB3 (PubMed:24462186, PubMed:24462187). Mechanisms by which BUB3 is protected are unclear: according to a first report, ZNF207/BuGZ may act by blocking ubiquitination and proteasomal degradation of BUB3 (PubMed:24462186). According to another report, the stabilization is independent of the proteasome (PubMed:24462187).
Mainly composed of disordered low-complexity regions outside of the C2H2-type zinc fingers. Coacervation depends on hydrophobic and aromatic Phe and Tyr in the disordered low-complexity region, that may promote coacervation by forming intermolecular hydrophobic interactions.
The GLEBS region mediates interaction with BUB3 (PubMed:24462186, PubMed:24462187).
The microtubule-binding region is required for efficient loading of BUB3 onto kinetochores and proper mitosis.
Belongs to the melanin-concentrating hormone family.
Differentially processed in the brain and in peripheral organs producing two neuropeptides; NEI and MCH. A third peptide, NGE, may also be produced. Preferential processing in neurons by prohormone convertase 2 (PC2) generates NEI. MCH is generated in neurons of the lateral hypothalmic area by several prohormone convertases including PC1/3, PC2 and PC5/6.
MCH may act as a neurotransmitter or neuromodulator in a broad array of neuronal functions directed toward the regulation of goal-directed behavior, such as food intake, and general arousal. May also have a role in spermatocyte differentiation.
Predominantly expressed in lateral hypothalamus, also detected in pallidum, neocortex and cerebellum. Also found in thymus, brown adipose tissue, duodenum and testis (spermatogonia, early spermatocytes and Sertoli cells). No expression in peripheral blood. In brain exclusively mature MCH and NEI peptides are present. In peripheral tissues a large product, encompassing the NEI and MCH domains of the precursor, is found predominantly.
Homodimer. Homooligomer. ER stress induces phosphorylation-dependent monomerization (PubMed:27062250). Interacts with BLZF1/Golgin 45 (PubMed:11739401). Identified in a complex with RAB2 and GORASP2 (PubMed:11739401). Interacts with JAM2 and JAM3 (By similarity). Interacts with members of the p24 cargo receptors (PubMed:11739402). Interacts with CNIH1 and the cytoplasmic domain of transmembrane TGFA, prior its transit in the trans-Golgi (PubMed:11101516, PubMed:17607000). Interacts with KCTD5 (PubMed:19361449). Interacts with TMED2 and TMED3 (By similarity). Interacts with SEC16A in response to ER stress (PubMed:28067262). Interacts (via PDZ GRASP-type 1 domain) with core-glycosylated CFTR in response to ER stress (PubMed:21884936).
Key structural protein of the Golgi apparatus (PubMed:33301566). The membrane cisternae of the Golgi apparatus adhere to each other to form stacks, which are aligned side by side to form the Golgi ribbon (PubMed:33301566). Acting in concert with GORASP1/GRASP65, is required for the formation and maintenance of the Golgi ribbon, and may be dispensable for the formation of stacks (PubMed:33301566). However, other studies suggest that GORASP2 plays a role in the assembly and membrane stacking of the Golgi cisternae, and in the process by which Golgi stacks reform after breakdown during mitosis and meiosis (PubMed:10487747, PubMed:21515684, PubMed:22523075). May regulate the intracellular transport and presentation of a defined set of transmembrane proteins, such as transmembrane TGFA (PubMed:11101516). Required for normal acrosome formation during spermiogenesis and normal male fertility, probably by promoting colocalization of JAM2 and JAM3 at contact sites between germ cells and Sertoli cells (By similarity). Mediates ER stress-induced unconventional (ER/Golgi-independent) trafficking of core-glycosylated CFTR to cell membrane (PubMed:21884936, PubMed:27062250, PubMed:28067262).
Myristoylated (PubMed:11101516). Myristoylation is essential for the Golgi targeting (By similarity).
Phosphorylated in mitotic cells (PubMed:11408587). ER stress-induced phosphorylation at Ser-441 induces monomerization and subsequent relocalization from Golgi to ER which is essential for mediating unconventional (ER/Golgi-independent) trafficking of CFTR to the cell membrane (PubMed:21884936, PubMed:27062250).
Interacts with PXN (PubMed:12861019). Interacts with Salmonella typhimurium sopA (PubMed:12861019). Interacts with JKAMP (PubMed:19269966). Interacts with STING1; the interaction of endogenous proteins is dependent on viral infection (PubMed:19285439).
Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins (PubMed:11329381, PubMed:12861019, PubMed:16176924, PubMed:19285439, PubMed:19269966). May function together with E2 ubiquitin-conjugating enzymes UBE2D1/UBCH5A and UBE2D2/UBC4 (PubMed:11329381). Mediates ubiquitination of PXN/paxillin,thereby regulating cell motility and localization of PXN/paxillin (PubMed:12861019). Catalyzes ubiquitination of Salmonella type III secreted protein sopA (PubMed:16176924). Mediates the 'Lys-63'-linked polyubiquitination of JKAMP thereby regulating JKAMP function by decreasing its association with components of the proteasome and ERAD; the ubiquitination appears to involve E2 ubiquitin-conjugating enzyme UBE2N (PubMed:19269966). Mediates the 'Lys-48'-linked polyubiquitination of STING1 at 'Lys-150' leading to its proteasomal degradation; the ubiquitination occurs in mitochondria after viral transfection and regulates antiviral responses (PubMed:19285439). Catalyzes ubiquitination and subsequent degradation of ATG4B, thereby inhibiting autophagy (PubMed:23093945).
The RING-type zinc finger domain is responsible for E3 ligase activity.
Component of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex composed at least by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2 (PubMed:16162815, PubMed:9463366). Interacts with PIGQ (PubMed:9463366).
Increased levels, possibly caused by overexpression, are observed in morphologically abnormal spermatozoa from infertile men, suggesting that it may be used as a marker of aberrant spermatogenesis.
May be required for post-translational modifications of proteins required for acrosomal biogenesis. May act by reducing disulfide bonds within the sperm.
Testis-specific. Only expressed during spermiogenesis, prominently in the Golgi apparatus of pachytene spermatocytes and round and elongated spermatids, with a transient localization in the developing acrosome of round spermatids (at protein level).
Allosterically activated by S-adenosyl-methionine/AdoMet. Activated by S-adenosylhomocysteine/AdoHcy (PubMed:20506325). Binds non-covalently to a heme group that may control the redox sensitivity of the enzyme (PubMed:11483494, PubMed:12173932, PubMed:22738154).
Belongs to the cysteine synthase/cystathionine beta-synthase family.
Hydro-lyase catalyzing the first step of the transsulfuration pathway, where the hydroxyl group of L-serine is displaced by L-homocysteine in a beta-replacement reaction to form L-cystathionine, the precursor of L-cysteine. This catabolic route allows the elimination of L-methionine and the toxic metabolite L-homocysteine (PubMed:23981774, PubMed:20506325, PubMed:23974653). Also involved in the production of hydrogen sulfide, a gasotransmitter with signaling and cytoprotective effects on neurons (By similarity).
In the adult strongly expressed in liver and pancreas, some expression in heart and brain, weak expression in lung and kidney. In the fetus, expressed in brain, liver and kidney.
Down-regulated during the epithelial-to-mesenchymal transition (EMT).
mRNA splicing factor that regulates the formation of epithelial cell-specific isoforms. Specifically regulates the expression of FGFR2-IIIb, an epithelial cell-specific isoform of FGFR2. Also regulates the splicing of CD44, CTNND1, ENAH, 3 transcripts that undergo changes in splicing during the epithelial-to-mesenchymal transition (EMT). Acts by directly binding specific sequences in mRNAs. Binds the GU-rich sequence motifs in the ISE/ISS-3, a cis-element regulatory region present in the mRNA of FGFR2 (PubMed:19285943). Regulates splicing and expression of genes involved in inner ear development, auditory hair cell differentiation, and cell fate specification in the cochlear epithelium (By similarity).
Interacts with components of the ASC-1 complex TRIP4, ASCC1, ASCC2 and ASCC3 (PubMed:31799605). Interact with AHCYL1 and AHCYL2 (PubMed:31799605). Interact with YTHDC2 (PubMed:31799605).
The regulatory loop blocks the catalytic center by bridging the methyltransferase domain and the C-terminal CCHC-type zinc finger, resulting in an autoinhibitory conformation.
rRNA N6-methyltransferase that specifically methylates the adenine in position 4220 of 28S rRNA (PubMed:30531910, PubMed:31328227, PubMed:31799605, PubMed:31695039). N6-methylation of adenine(4220) in 28S rRNA is required for translation (PubMed:30531910, PubMed:31799605).
E3 ubiquitin-protein ligase that mediates E2-dependent, 'Lys-48'- and/or 'Lys-63'-linked polyubiquitination of substrates and may play a role in diverse biological processes. Through their polyubiquitination, may play a role in the endosomal trafficking and degradation of membrane receptors including EGFR, FLT3, MET and CXCR4.
Expressed at extremely low levels in normal breast, prostate, lung, colon. Higher levels of expression are detected in heart, skeletal muscle, testis as well as in breast and prostate cancer cells.
Interacts with RAB7A. Interacts with EGFR and FLT3.
RING-type zinc finger-dependent and E2-dependent autoubiquitination.
Interacts with DRG2. Interacts with androgen receptor (By similarity).
Protects DRG2 from proteolytic degradation.
Component of the IFT complex B. Interacts with IFT46; the interaction is direct.
Component of the intraflagellar transport (IFT) complex B required for transport of proteins in the motile cilium. Required for transport of specific ciliary cargo proteins related to motility, while it is neither required for IFT complex B assembly or motion nor for cilium assembly. Required for efficient coupling between the accumulation of GLI2 and GLI3 at the ciliary tips and their dissociation from the negative regulator SUFU. Plays a key role in maintaining the integrity of the IFT complex B and the proper ciliary localization of the IFT complex B components. Not required for IFT complex A ciliary localization or function. Essential for maintaining proper microtubule organization within the ciliary axoneme.
Interacts (via zinc-finger domains) with RPS2/40S ribosomal protein S2, perhaps as nascent RPS2 is synthesized during translation; the interaction is direct; the interaction is extra-ribosomal (PubMed:30530495). Interaction with RPS2 competes with the binding of RPS2 to protein arginine methyltransferase PRMT3 (PubMed:30530495). Interacts with Polycomb group (PcG) complex protein BMI1 (By similarity). May be part of a complex including at least ZNF277, BMI1 and RNF2/RING2 (By similarity).
Probable transcription factor. Involved in modulation of cellular senescence; represses transcription of the tumor suppressor gene INK4A/ARF, perhaps acting via the Polycomb group (PcG) complex PRC1.
Beta-1,3-N-acetylglucosaminyltransferase involved in the synthesis of poly-N-acetyllactosamine. Has activity for type 2 oligosaccharides (PubMed:11042166). Also acts as a core1-1,3-N-acetylglucosaminyltransferase (Core1-beta3GlcNAcT) to form the 6-sulfo sialyl Lewis x on extended core1 O-glycans (PubMed:11439191).
Expressed in colon, jejunum, stomach, esophagus, placenta and trachea.
Associated component of the proteasome that specifically recognizes acetylated histones and promotes ATP- and ubiquitin-independent degradation of core histones during spermatogenesis and DNA damage response. Recognizes and binds acetylated histones via its bromodomain-like (BRDL) region and activates the proteasome by opening the gated channel for substrate entry. Binds to the core proteasome via its C-terminus, which occupies the same binding sites as the proteasomal ATPases, opening the closed structure of the proteasome via an active gating mechanism. Component of the spermatoproteasome, a form of the proteasome specifically found in testis: binds to acetylated histones and promotes degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. Also involved in DNA damage response in somatic cells, by promoting degradation of histones following DNA double-strand breaks.
Homodimer. Interacts with the 20S and 26S proteasomes. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.
The bromodomain-like (BRDL) region specifically recognizes and binds acetylated histones.
C-mannosylated at Trp-214 in the WSXWS motif, the sugar chain makes extensive hydrogen bonds with Asn-73 sugar, and bridges the two fibronectin domains transforming the V-shaped receptor into an A-frame.
Chromosomal aberrations involving IL21R is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;16)(q27;p11), with BCL6.
Heterodimer with the common gamma subunit. Associates with JAK1.
Selectively expressed in lymphoid tissues. Most highly expressed in thymus and spleen.
Expressed in the blood vessel walls (at protein level).
Expressed in the blood vessel walls (at protein level). Highly expressed in brain, lung, and pancreas; a lower level of expression is detectable in heart, placenta, liver, and kidney, whereas no expression can be observed in skeletal muscle. Isoform 4a is heart-specific.
Neuronal cell surface protein that may be involved in cell recognition and cell adhesion. May mediate intracellular signaling (By similarity).
O-glycosylated; contains heparan sulfate. Heparan sulfate attachment is required for synapse development by mediating interactions with neuroligins.
Proccessed by alpha-secretase leading to the formation of an extracellular soluble protein as well as a C-terminal membrane-embedded fragment (CTF). Proteolysis of these CTFs by gamma-secretase releases intracellular domains (ICDs) and extracellular peptides.
The laminin G-like domain 2 binds to NXPH1 (By similarity). Specific isoforms bind to alpha-dystroglycan (By similarity). The cytoplasmic C-terminal region binds to CASK (By similarity). Specific isoforms bind neuroligins NLGN1, NLGN2 and NLGN3 (By similarity). Interacts with CLSTN3 (By similarity).
Weakly interacts with CBLN1 and CBLN2 (By similarity). Very weak binding, if any, with CBLN4 (By similarity). Specific isoforms bind neuroligins NLGN1, NLGN2 and NLGN3 (By similarity). Interacts with CLSTN3 (By similarity).
Has a key role in phospholipid metabolism, and catalyzes the first step of phosphatidylethanolamine and phosphatidylcholine biosynthesis.
This protein is produced by a bicistronic gene which also produces the CPT1B protein from a non-overlapping reading frame.
Filament-forming cytoskeletal GTPase (By similarity). May play a role in platelet secretion (PubMed:15116257). Seems to participate in the process of SNARE complex formation in synaptic vesicles (By similarity).
KIAA0202a differs from KIAA0202c at the level of the 3'-UTR.
Septins polymerize into heterooligomeric protein complexes that form filaments, and can associate with cellular membranes, actin filaments and microtubules. GTPase activity is required for filament formation (By similarity). Interacts with CDK14 (PubMed:12098780). Interacts with SEPTIN5 (PubMed:12909369). Interacts with SEPTIN7 (By similarity). Interacts with SEPTIN4 (PubMed:15116257). Interacts with VAMP2; the interaction inhibits interaction of VAMP2 with SYP (By similarity). Interacts with STX1A (By similarity).
Stabilizes BACE1 protein levels and promotes the sorting and accumulation of BACE1 to the recycling or endosomal compartments, modulating the beta-amyloidogenic processing of APP.
Widely expressed, including in brain, heart and platelets; most abundant in aorta. Isoform 2 is expressed at low levels in specific brain areas, such as occipital pole, frontal lobe, temporal lobe and putamen. Isoform 1 and 3 are highly expressed in specific brain areas, such as occipital pole, frontal lobe, temporal lobe and putamen. Isoform 2 is highly expressed in prostate, testis and ovary. Isoform 1 and isoform 3 are expressed at low levels in prostate, testis and ovary.
Author states that kinase activity observed in PubMed:11956649 may be due to sample contamination. This protein is predicted to be catalytically inactive.
Homodimer (By similarity). Binds to MLF1, recruiting a serine kinase which phosphorylates both itself and MLF1 (By similarity). Phosphorylated MLF1 binds to YWHAZ and is retained in the cytoplasm (By similarity). Interacts with ELOC/TCEB1, ELOB/TCEB2, TSC22D2 and TSC22D4 (PubMed:22510880). Interacts with the Elongin BC E3 ubiquitin ligase complex via its interaction with ELOB/TCEB2 and ELOC/TCEB1 (PubMed:22510880). Interacts with SALL4 (PubMed:22510880).
May act as a tumor suppressor to decrease tumor incidence and improve survival (PubMed:22510880). Expression levels have also been found to be reduced in a range of tumor types, such as leukemia, lymphoma, colorectal, breast, brain, esophageal, renal cell, prostate and lung (PubMed:22510880).
Required for embryonic development (By similarity). Plays a role in intestinal epithelial cell fate and proliferation, thereby involved in the architectural development of the intestine potentially via the regulation of Wnt-responsive genes (By similarity). May play a role in subcellular trafficking between the endoplasmic reticulum and Golgi apparatus through interactions with the Rho-type GTPases (PubMed:11956649). Binding to the NS3 protein of dengue virus type 2 appears to subvert this activity into the alteration of the intracellular membrane structure associated with flaviviral replication (PubMed:15084397).
Ubiquitously expressed in all tissues examined with high levels in the testis.
Expressed in hematopoietic stem/progenitor cells.
Monomer. Interacts with pre-ribosome complex. May bind to RNA (By similarity). Interacts with NOL8. May interact with SBDS. Interacts with FTSJ3.
Required for proper 34S pre-rRNA processing and 60S ribosome subunit assembly.
Associates with the RNA polymerase (Pol I) complex (PubMed:29065309). Interacts with POLR1E (PubMed:29065309).
Chromatin-associated factor that regulates transcription (PubMed:29065309). Regulates Pol I-mediated rRNA biogenesis and, probably, Pol III-mediated transcription (PubMed:29065309). Regulates the epigenetic status of rDNA (PubMed:29065309).
High levels seen in the placenta, skeletal muscle, kidney and pancreas while lower levels were seen in the heart, brain and lung.
The exocyst complex is composed of SEC3, SEC5, SEC6, SEC8, SEC10, SEC15, EXO70 and EXO84.
Interacts with CPSF6 (PubMed:15169763). Interacts with RBMY1A1 (PubMed:15595951). Interacts with SREK1/SFRS12 (PubMed:10757789). Interacts with NXF1 (PubMed:12667464, PubMed:17036044). Interacts with YTHDC1, leading to recruitment to RNA elements adjacent to m6A sites (PubMed:26876937, PubMed:28984244).
Phosphorylated by CLK1, CLK2, CLK3 and CLK4. Extensively phosphorylated on serine residues in the RS domain.
Splicing factor that specifically promotes exon-inclusion during alternative splicing (PubMed:26876937). Interaction with YTHDC1, a RNA-binding protein that recognizes and binds N6-methyladenosine (m6A)-containing RNAs, promotes recruitment of SRSF3 to its mRNA-binding elements adjacent to m6A sites, leading to exon-inclusion during alternative splicing (PubMed:26876937). Also functions as export adapter involved in mRNA nuclear export (PubMed:11336712, PubMed:18364396, PubMed:28984244). Binds mRNA which is thought to be transferred to the NXF1-NXT1 heterodimer for export (TAP/NXF1 pathway); enhances NXF1-NXT1 RNA-binding activity (PubMed:11336712, PubMed:18364396). Involved in nuclear export of m6A-containing mRNAs via interaction with YTHDC1: interaction with YTHDC1 facilitates m6A-containing mRNA-binding to both SRSF3 and NXF1, promoting mRNA nuclear export (PubMed:28984244). RNA-binding is semi-sequence specific (PubMed:17036044).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRG1 sub-subfamily.
Hyperphosphorylated during the G1/S phase transition.
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Interacts with POLR2J, RB1/RB, RBL1/P107 and RBL2/P130 (PubMed:12450794, PubMed:10783144). Interacts with PAWR and SP1 (PubMed:12847090, PubMed:14627703). May also bind MAPT (PubMed:14697667).
Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797). May function as a general inhibitor of the histone deacetylase HDAC1. Binding to the pocket region of RB1 may displace HDAC1 from RB1/E2F complexes, leading to activation of E2F target genes and cell cycle progression. Conversely, displacement of HDAC1 from SP1 bound to the CDKN1A promoter leads to increased expression of this CDK inhibitor and blocks cell cycle progression. Also antagonizes PAWR mediated induction of aberrant amyloid peptide production in Alzheimer disease (presenile and senile dementia), although the molecular basis for this phenomenon has not been described to date.
Ubiquitously expressed. Expressed at high levels in brain, heart, kidney, placenta and thymus.
Involved in proliferation and apoptosis in myeloid precursor cells.
Probably ubiquitinated leading to its degradation by the proteasome.
Component of the PeBoW complex, composed of BOP1, PES1 and WDR12 (PubMed:16043514, PubMed:16738141, PubMed:17189298, PubMed:17353269). The complex is held together by BOP1, which interacts with PES1 via its N-terminal domain and with WDR12 via a high-affinity interaction between the seven-bladed beta-propeller domains of the 2 proteins. The PeBoW complex associates with the 66S pre-ribosome (By similarity). The PeBoW complex also associates with DDX27, PES1 interacts directly with DDX27 (PubMed:25825154). Interacts with IRS1 and UBTF. May interact with MAP1B (By similarity).
Component of the PeBoW complex, composed of BOP1, PES1 and WDR12. Within the PeBoW complex BOP1 interacts directly with PES1 and WDR12. The PeBoW complex also associates with the 66S pre-ribosome. Interacts with IRS1 and UBTF. May interact with MAP1B.
Significant levels are detected in a variety of cancer cell lines, including glioblastoma, breast carcinoma, colon carcinoma and cervical carcinoma cells. Levels are abnormally elevated in malignant tumors of astrocytic origin.
Serves as a reserve supply of oxygen and facilitates the movement of oxygen within muscles.
(Microbial infection) Acts as a receptor for Semliki Forest virus.
(Microbial infection) Interacts with Semliki Forest virus E2-E1 heterodimer; this interaction mediates viral entry to host cell.
(Microbial infection) Interacts with protein VP1 of the minor-group human rhinoviruses (HRVs) through the second and third LDL-receptor class A domains.
Abundant in heart and skeletal muscle; also ovary and kidney; not in liver.
Homooligomer (PubMed:30873003). Binds to the extracellular matrix protein Reelin/RELN (PubMed:30873003). Interacts with LRP8 (PubMed:30873003). Interacts with LDLRAP1 (By similarity). Interacts with SNX17 (By similarity). Interacts with DAB1. Interacts with PCSK9. Interacts with PAFAH1B3 and PAFAH1B2, the catalytic complex of (PAF-AH (I)) heterotetrameric enzyme; these interactions may modulate the Reelin pathway (PubMed:17330141). Interacts with STX5; this interaction mediates VLDLR translocation from the endoplasmic reticulum to the plasma membrane (PubMed:23701949). Interacts with CLU (PubMed:24381170).
Multifunctional cell surface receptor that binds VLDL and transports it into cells by endocytosis and therefore plays an important role in energy metabolism. Binds also to a wide range of other molecules including Reelin/RELN or apolipoprotein E/APOE-containing ligands as well as clusterin/CLU (PubMed:24381170, PubMed:30873003). In the off-state of the pathway, forms homooligomers or heterooligomers with LRP8 (PubMed:30873003). Upon binding to ligands, homooligomers are rearranged to higher order receptor clusters that transmit the extracellular RELN signal to intracellular signaling processes by binding to DAB1 (PubMed:30873003). This interaction results in phosphorylation of DAB1 leading to the ultimate cell responses required for the correct positioning of newly generated neurons. Later, mediates a stop signal for migrating neurons, preventing them from entering the marginal zone (By similarity).
Ubiquitinated at Lys-839 by MYLIP leading to degradation.
Converts 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone (By similarity). Exhibits high acyl-CoA specificity for polyunsaturated fatty acyl-CoA, especially docosahexaenoyl-CoA (22:6-CoA, DHA-CoA) (By similarity).
Widely expressed with highest levels in skeletal muscle, followed by heart, liver, prostate and thymus.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv11.3/KCNH7 sub-subfamily.
Pore-forming (alpha) subunit of voltage-gated potassium channel. Channel properties may be modulated by cAMP and subunit assembly.
The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming alpha subunits that can associate with modulating beta subunits. Heteromultimer with KCNH2/ERG1 and KCNH6/ERG2 (By similarity).
Major protein of the otoconia, a calcium carbonate structure in the saccule and utricle of the ear. Together with OTOL1, acts as a scaffold for otoconia biomineralization: sequesters calcium and forms interconnecting fibrils between otoconia that are incorporated into the calcium crystal structure. Together with OTOL1, modulates calcite crystal morphology and growth kinetics. It is unlikely that this protein has phospholipase A2 activity.
Activated by phosphorylation on Ser-257 and Thr-261 by MAP kinase kinase kinases (MAP3Ks).
Activated in response to a variety of cellular stresses, including UV and gamma-irradiation, heat shock, hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory cytokines. Also activated by developmental cues. MAP2K4/MKK4 is activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to pro-inflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.
Interacts with SPAG9 (By similarity). Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3.
The D domain (residues 34-52) contains a conserved docking site and is required for the binding to MAPK substrates.
The DVD domain (residues 364-387) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation.
Seems to be a major component of sperm tail outer dense fibers (ODF). ODFs are filamentous structures located on the outside of the axoneme in the midpiece and principal piece of the mammalian sperm tail and may help to maintain the passive elastic structures and elastic recoil of the sperm tail. May have a modulating influence on sperm motility. Functions as a general scaffold protein that is specifically localized at the distal/subdistal appendages of mother centrioles. Component of the centrosome matrix required for the localization of PLK1 and NIN to the centrosomes. Required for the formation and/or maintenance of normal CETN1 assembly.
Self-associates. Associates with microtubules and forms a fibrillar structure partially linked to the microtubule network. Interacts via its C-terminus with PLK1 (PubMed:16966375). Interacts with ODF1 (By similarity). Interacts with MARK4; the interaction is required for localization of ODF2 to centrioles (PubMed:23400999). Interacts with TSSK4 (By similarity). Interacts with AKNA (By similarity). Interacts with QRICH2 (PubMed:30683861). Interacts with CFAP58 (By similarity).
Testis-specific (at protein level). Highly expressed in cytoplasm of step 2 round spermatids. Detected in the middle piece and extends to about half the principal piece of the sperm tails.
Tyrosine phosphorylated. Phosphorylated by TSSK4 on Ser-95.
E3 ubiquitin-protein ligase. Mediates 'Lys-63'-linked polyubiquitination of the innate immune receptor RIGI, this linkage doesn't lead to proteasomal degradation but seems to enhance IFN induction.
Belongs to the YY transcription factor family.
Interacts with YAF2 through the region encompassing the first and second zinc fingers (PubMed:9016636). Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the DBINO domain of INO80 (PubMed:17721549, PubMed:18026119, PubMed:18922472, PubMed:21303910). Interacts with EED and EZH2; the interactions are indicative for an association with the PRC2/EED-EZH2 complex (PubMed:11158321). Interacts with SFMBT2 (PubMed:23385818). Found in a complex with SMAD1 and SMAD4 (PubMed:15329343). Found in a complex with YY1, SIN3A and HDAC1 (By similarity).
Multifunctional transcription factor that exhibits positive and negative control on a large number of cellular and viral genes by binding to sites overlapping the transcription start site (PubMed:15329343, PubMed:17721549, PubMed:24326773, PubMed:25787250). Binds to the consensus sequence 5'-CCGCCATNTT-3'; some genes have been shown to contain a longer binding motif allowing enhanced binding; the initial CG dinucleotide can be methylated greatly reducing the binding affinity (PubMed:15329343, PubMed:17721549, PubMed:24326773, PubMed:25787250). The effect on transcription regulation is depending upon the context in which it binds and diverse mechanisms of action include direct activation or repression, indirect activation or repression via cofactor recruitment, or activation or repression by disruption of binding sites or conformational DNA changes (PubMed:15329343, PubMed:17721549, PubMed:24326773, PubMed:25787250). Its activity is regulated by transcription factors and cytoplasmic proteins that have been shown to abrogate or completely inhibit YY1-mediated activation or repression (PubMed:15329343, PubMed:17721549, PubMed:24326773, PubMed:25787250). For example, it acts as a repressor in absence of adenovirus E1A protein but as an activator in its presence (PubMed:1655281). Acts synergistically with the SMAD1 and SMAD4 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression (PubMed:15329343). Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (PubMed:15329343). May play an important role in development and differentiation. Proposed to recruit the PRC2/EED-EZH2 complex to target genes that are transcriptional repressed (PubMed:11158321). Involved in DNA repair (PubMed:18026119, PubMed:28575647). In vitro, binds to DNA recombination intermediate structures (Holliday junctions). Plays a role in regulating enhancer activation (PubMed:28575647).
Phosphorylation at Ser-118 by CK2 prevents proteolytic cleavage by caspase-7 (CASP7) during apoptosis.
Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair; proposed to target the INO80 complex to YY1-responsive elements.
Proteolytically cleaved by caspase-7 (CASP7) in response to apoptosis (PubMed:22184066). Phosphorylation at Ser-118 protects against proteolytic cleavage (PubMed:22184066).
Transiently poly-ADP-ribosylated by PARP1 upon DNA damage, with the effect of decreasing affinity of YY1 to its cognate DNA binding sites.
Component of a complex composed of PALS1, CRB1 and EPB41L5 (PubMed:17920587). Within the complex, interacts (via FERM domain) with PALS1 (via HOOK domain) and with CRB1 (via intracellular domain) (PubMed:17920587). Interacts with CRB2 (via intracellular domain) (PubMed:17920587). Interacts with CRB3 (via intracellular domain) (PubMed:17920587).
Plays a role in the formation and organization of tight junctions during the establishment of polarity in epithelial cells.
Ethylenediaminetetraacetic acid completely abolishes catalytic activity (PubMed:24415556). Catalytic activity is enhanced by complex formation with SELENOF (PubMed:24415556).
Has no enzymatic activity towards unfolded RNase B or thyroglobulin.
Higher levels in kidney, pancreas, heart, and skeletal muscle.
Interacts with METTL23 (PubMed:23349634). Interacts with SELENOF (PubMed:24415556).
Recognizes glycoproteins with minor folding defects. Reglucosylates single N-glycans near the misfolded part of the protein, thus providing quality control for protein folding in the endoplasmic reticulum. Reglucosylated proteins are recognized by calreticulin for recycling to the endoplasmic reticulum and refolding or degradation.
Homodimer (PubMed:19255245). Heterodimer with MAPRE1 (PubMed:19255245). Binds monomeric and polymerized GTP-bound tubulin (PubMed:10188731, PubMed:34996871). Interacts with APC2 (PubMed:10644998). Interacts with DCTN1 and SRCIN1 (PubMed:14514668, PubMed:19146815). Binds to the C-terminal domain of APC (PubMed:14514668). Interacts (via C-terminus) with CLIP1 (PubMed:17563362). Interacts with SLAIN2 and SLAIN1 (PubMed:21646404). Interacts with AKAP9 (PubMed:28814570). Interacts with PDE4DIP (PubMed:28814570). Interacts with PDE4DIP isoform 13/MMG8/SMYLE; this interaction is required for its recruitment to the Golgi apparatus (PubMed:25217626).
Plus-end tracking protein (+TIP) that binds to the plus-end of microtubules and regulates the dynamics of the microtubule cytoskeleton (PubMed:28814570, PubMed:19255245). Promotes microtubule growth (PubMed:28814570, PubMed:19255245). May be involved in spindle function by stabilizing microtubules and anchoring them at centrosomes (PubMed:28814570, PubMed:19255245). Also acts as a regulator of minus-end microtubule organization: interacts with the complex formed by AKAP9 and PDE4DIP, leading to recruit CAMSAP2 to the Golgi apparatus, thereby tethering non-centrosomal minus-end microtubules to the Golgi, an important step for polarized cell movement (PubMed:28814570). Promotes elongation of CAMSAP2-decorated microtubule stretches on the minus-end of microtubules (PubMed:28814570).
Predominantly expressed in brain and muscle.
Endoribonuclease that specifically cleaves inosine-containing RNAs: cleaves RNA at the second phosphodiester bond 3' to inosine (PubMed:23912683, PubMed:23912718, PubMed:27573237, PubMed:31703097, PubMed:25195743). Active against both single-stranded and double-stranded RNAs (PubMed:31703097, PubMed:25195743). Has strong preference for single-stranded RNAs (ssRNAs) toward double-stranded RNAs (dsRNAs) (PubMed:23912718). Cleaves mRNAs and tRNAs containing inosine (PubMed:23912683, PubMed:31703097). Also able to cleave structure-specific dsRNA substrates containing the specific sites 5'-IIUI-3' and 5'-UIUU-3' (PubMed:23912718, PubMed:27573237). Inosine is present in a number of RNAs following editing; the function of inosine-specific endoribonuclease is still unclear: it could either play a regulatory role in edited RNAs, or be involved in antiviral response by removing the hyperedited long viral dsRNA genome that has undergone A-to-I editing (Probable). Binds branched DNA structures (PubMed:23139746).
Endoribonuclease that specifically cleaves inosine-containing RNAs: cleaves RNA at the second phosphodiester bond 3' to inosine (PubMed:31703097). Active against both single-stranded and double-stranded RNAs (PubMed:31703097). Cleaves tRNAs containing inosine (PubMed:31703097).
Inhibited by normal intracellular concentrations of ATP.
Monomer (PubMed:25195743). Interacts with PABPC1; the interaction is RNA-dependent and stimulates ENDOV activity (PubMed:27573237).
Was initially characterized as an endodeoxyribonuclease involved in DNA repair (PubMed:22664237). While it shows some weak endodeoxyribonuclease activity in vitro, such activity probably does not exist in vivo.
Interacts with TSC2; interaction is inhibited by TSC1. Interacts with PKM, ARF1 and ARF6. Forms a ternary complex with clathrin heavy chain (CLTC) and HSPA1A.
Involved in membrane trafficking via some guanine nucleotide exchange factor (GEF) activity and its ability to bind clathrin. Acts as a GEF for Arf and Rab, by exchanging bound GDP for free GTP. Binds phosphatidylinositol 4,5-bisphosphate, which is required for GEF activity. May also act as a E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
Involved in the positive regulation of starvation-induced autophagy (PubMed:25076851).
Widely expressed. Highly expressed in the pancreas.
Involved in the negative regulation of epithelial-mesenchymal transition, the process by which epithelial cells lose their polarity and adhesion properties to become mesenchymal cells with enhanced migration and invasive properties.
(Microbial infection) Deamidated at Gln-40 by bacterial cyclomodulin Cif produced by enteropathogenic E.coli, Y.pseudotuberculosis or B.pseudomallei, leading to impair NEDD8 ability to activate cullin-RING-based E3 ubiquitin-protein ligase complexes (CRL complexes) (PubMed:20688984, PubMed:21903097, PubMed:23589306, PubMed:26632597, PubMed:23175788). Deamidation occurs on NEDD8-modified cullins (PubMed:20850415, PubMed:21903097). NEDD8 deamidation prevents switching from the inactive to active state by maintaining the 'closed' structure of the CRL complexes (PubMed:23589306, PubMed:26632597). Deamidation may also impair its deconjugation by the COP9 signalosome; However this result needs additional evidences (PubMed:20850415, PubMed:21903097).
Cleavage of precursor form by UCHL3 or SENP8 is necessary for function.
Highly expressed in heart, skeletal muscle, spleen, thymus, prostate, testis, ovary, colon and leukocytes.
Interacts with AHR; interaction is direct (PubMed:12215427). Interacts with NUB1; interaction is direct (PubMed:11259415).
Ubiquitin-like protein which plays an important role in cell cycle control and embryogenesis via its conjugation to a limited number of cellular proteins, such as cullins or p53/TP53 (PubMed:9694792, PubMed:10318914, PubMed:10597293, PubMed:11953428, PubMed:15242646, PubMed:14690597). Attachment of NEDD8 to cullins is critical for the recruitment of E2 to the cullin-RING-based E3 ubiquitin-protein ligase complex, thus facilitating polyubiquitination and proteasomal degradation of cyclins and other regulatory proteins (PubMed:9694792, PubMed:10318914, PubMed:10597293, PubMed:11953428, PubMed:20688984). Attachment of NEDD8 to p53/TP53 inhibits p53/TP53 transcriptional activity (PubMed:15242646). Covalent attachment to its substrates requires prior activation by the E1 complex UBE1C-APPBP1 and linkage to the E2 enzyme UBE2M (PubMed:14690597).
Acts as a ligand for galanin receptors GALR2 and GALR3 (PubMed:17284679, PubMed:24517231). Intracerebroventricular administration of the peptide induces an increase in arterial blood pressure, a decrease in both heart rate and renal excretion and delayed natriuresis. Intraventricular administration of the peptide induces antinociceptive activity. Also induces contraction of muscarinic-like stomach smooth muscles. Intraperitoneal administration of the peptide induces a reduction in food consumption and body weight. Inhibits long chain fatty acid uptake into adipocytes (By similarity).
Down-regulated in omental and subcutaneous fat of obese subjects.
Expressed in the type I glomic cells within the carotid body (at protein level). Expressed predominantly in pancreas, testis, kidney, brain and placenta. Expressed in submucosal layer of esophagus and stomach fundus.
Intracerebroventricular administration of the peptide induces a decrease in heart rate, but no change in arterial pressure, and an increase in urine flow rate. Intraventricular administration of the peptide induces antinociceptive activity (By similarity).
Plays a role as a central modulator of cardiovascular and renal function and nociception. Also plays a role in energy metabolism and storage. Inhibits adrenocortical cell proliferation with minor stimulation on corticosteroid release (By similarity).
Structural component of the gap junctions and the hemichannels.
Detected in thyroid, spleen and testis, and at lower levels in stomach, spinal cord, lymph node, trachea, adrenal gland, prostate, ovary and intestine.
Part of the gamma-tubulin complex. Interacts with TUBG1.
Defects in ARID5B may be a cause of susceptibility to coronary atherosclerosis in the Japanese population.
Methylation at Lys-336 prevents DNA-binding. Demethylation by PHF2 promotes recruitment of the PHF2-ARID5B complex to promoters.
The ARID domain mediates the interaction with DNA.
Transcription coactivator that binds to the 5'-AATA[CT]-3' core sequence and plays a key role in adipogenesis and liver development. Acts by forming a complex with phosphorylated PHF2, which mediates demethylation at Lys-336, leading to target the PHF2-ARID5B complex to target promoters, where PHF2 mediates demethylation of dimethylated 'Lys-9' of histone H3 (H3K9me2), followed by transcription activation of target genes. The PHF2-ARID5B complex acts as a coactivator of HNF4A in liver. Required for adipogenesis: regulates triglyceride metabolism in adipocytes by regulating expression of adipogenic genes. Overexpression leads to induction of smooth muscle marker genes, suggesting that it may also act as a regulator of smooth muscle cell differentiation and proliferation. Represses the cytomegalovirus enhancer.
Localizes to glandular epithelium, stroma and vascular endothelial cells of first trimester decidua (at protein level). Up-regulated in first trimester decidua when compared with non-pregnant endometrium. Expressed in the stomach, throughout the small intestine, colon, rectum, thyroid gland, pituitary gland, salivary gland, adrenal gland, testis, ovary, brain, spleen, prostate and pancreas.
Receptor for prokineticin 1. Exclusively coupled to the G(q) subclass of heteromeric G proteins. Activation leads to mobilization of calcium, stimulation of phosphoinositide turnover and activation of p44/p42 mitogen-activated protein kinase. May play a role during early pregnancy.
Required for the development of soma-targeting inhibitory GABAergic synapses made by parvalbumin-positive basket cells.
Belongs to the AAA ATPase family. RarA/MGS1/WRNIP1 subfamily.
Forms homooligomers (PubMed:18842586), possibly octamers. Directly interacts with POLD1, POLD2 and POLD4 (PubMed:15670210). Interacts with the N-terminal domain of WRN (By similarity). Interacts (via UBZ4-type zinc finger) with monoubiquitin and polyubiquitin (PubMed:17550899, PubMed:18842586). Interacts with TRIM14 and PPP6C; these interactions positively regulate the RIGI signaling pathway (PubMed:29053956).
Functions as a modulator of initiation or reinitiation events during DNA polymerase delta-mediated DNA synthesis. In the presence of ATP, stimulation of DNA polymerase delta-mediated DNA synthesis is decreased. Also plays a role in the innate immune defense against viruses. Stabilizes the RIGI dsRNA interaction and promotes RIGI 'Lys-63'-linked polyubiquitination. In turn, RIGI transmits the signal through mitochondrial MAVS.
The UBZ4-type zinc finger binds ubiquitin.
Autophosphorylated. Binding of FGF family members together with heparan sulfate proteoglycan or heparin promotes receptor dimerization and autophosphorylation on tyrosine residues. Autophosphorylation occurs in trans between the two FGFR molecules present in the dimer. Phosphorylation at Tyr-724 is essential for stimulation of cell proliferation and activation of PIK3R1, STAT1 and MAP kinase signaling. Phosphorylation at Tyr-760 is required for interaction with PIK3R1 and PLCG1.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Somatic mutations can constitutively activate FGFR3.
Expressed in brain, kidney and testis. Very low or no expression in spleen, heart, and muscle. In 20- to 22-week old fetuses it is expressed at high level in kidney, lung, small intestine and brain, and to a lower degree in spleen, liver, and muscle. Isoform 2 is detected in epithelial cells. Isoform 1 is not detected in epithelial cells. Isoform 1 and isoform 2 are detected in fibroblastic cells.
Monomer. Homodimer after ligand binding. Interacts with FGF1, FGF2, FGF4, FGF6; FGF8, FGF9, FGF10, FGF17, FGF18, FGF19, FGF20 and FGF23 (in vitro). Interacts with KLB. Affinity for fibroblast growth factors (FGFs) is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Likewise, KLB increases the affinity for FGF19 and FGF21. Interacts with PIK3R1, PLCG1, SOCS1 and SOCS3. Isoform 3 forms disulfide-linked dimers.
Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by SU5402.
The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving FGFR3 is found in multiple myeloma. Translocation t(4;14)(p16.3;q32.3) with the IgH locus.
The second and third Ig-like domains directly interact with fibroblast growth factors (FGF) and heparan sulfate proteoglycans.
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling.
Ubiquitinated. Is rapidly ubiquitinated after ligand binding and autophosphorylation, leading to receptor internalization and degradation. Subject to both proteasomal and lysosomal degradation.
Interacts with ABI1. Part of a complex that contains SOS1, ABI1 and EPS8L2. Associates with F-actin.
Stimulates guanine exchange activity of SOS1. May play a role in membrane ruffling and remodeling of the actin cytoskeleton. In the cochlea, is required for stereocilia maintenance in adult hair cells (By similarity).
Activated by mannosylphosphoryldolichol and phospholipids such as phosphatidylglycerol and phosphatidylcholine (Probable). Inhibited by natural nucleoside antibiotic tunicamycin, which acts as a structural analog and competitor of UDP-GlcNAc (PubMed:9451016, PubMed:29459785, PubMed:30388443).
Belongs to the glycosyltransferase 4 family.
Catalyzes the initial step of dolichol-linked oligosaccharide biosynthesis in N-linked protein glycosylation pathway: transfers GlcNAc-1-P from UDP-GlcNAc onto the carrier lipid dolichyl phosphate (P-dolichol), yielding GlcNAc-P-P-dolichol.
Broad expression. High expression in thalamus and brain. Significantly expressed in vasculature.
Called SOLO because the encoded protein is related to but shorter than DUO and TRIO.
Interacts (via the spectrin 1 repeat) with TRPC4 and TRPC5 (via CIRB domain). Interacts with CTNNB1.
May act as the primary docking protein directing membrane turnover and assembly of the transient receptor potential channels TRPC4 and TRPC5. Binds phospholipids such as phosphatidylinositol monophosphates, phosphatidylinositol diphosphates (PIP2s) and phosphatidic acid, but not less polar lipids including phosphatidylcholine, phosphatidylserine, and phosphatidylinositol. The binding to PIP2s is calcium dependent. Might be involved in the plasma membrane localization of CTNNB1.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. PIM subfamily.
Detected in various tissues, including the heart, brain, lung, kidney, spleen, placenta, skeletal muscle, and peripheral blood leukocytes. Not found or barely expressed in the normal adult endoderm-derived organs such as colon, thymus, liver, or small intestine. However, expression is augmented in premalignant and malignant lesions of these organs.
Interacts with BAD. Interacts with PPP2CA; this interaction promotes dephosphorylation of PIM3, ubiquitination and proteasomal degradation. Interacts with SOCS6 (By similarity).
Phosphorylated. Interaction with PPP2CA promotes dephosphorylation.
Proto-oncogene with serine/threonine kinase activity that can prevent apoptosis, promote cell survival and protein translation. May contribute to tumorigenesis through: the delivery of survival signaling through phosphorylation of BAD which induces release of the anti-apoptotic protein Bcl-X(L), the regulation of cell cycle progression, protein synthesis and by regulation of MYC transcriptional activity. Additionally to this role on tumorigenesis, can also negatively regulate insulin secretion by inhibiting the activation of MAPK1/3 (ERK1/2), through SOCS6. Involved also in the control of energy metabolism and regulation of AMPK activity in modulating MYC and PPARGC1A protein levels and cell growth.
Expressed in many tumors of several types, such as melanoma, head and neck squamous cell carcinoma, lung carcinoma and breast carcinoma, but not in normal tissues except for testis and placenta.
(Microbial infection) Restricts Epstein-Barr virus (EBV) lytic replication by acting as an inhibitor for transcription factors involved in lytic gene expression (PubMed:29262325). The virus can use apoptotic caspases to antagonize PIAS1-mediated restriction and express its lytic genes (PubMed:29262325).
A paper showing that PRMT1-mediated arginine methylation of PIAS1 regulates STAT1 signaling has been retracted, because some of the data was found to be deliberately falsified.
Expressed in numerous tissues with highest level in testis.
Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. Plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway, the p53 pathway and the steroid hormone signaling pathway. In vitro, binds A/T-rich DNA. The effects of this transcriptional coregulation, transactivation or silencing, may vary depending upon the biological context. Sumoylates PML (at'Lys-65' and 'Lys-160') and PML-RAR and promotes their ubiquitin-mediated degradation. PIAS1-mediated sumoylation of PML promotes its interaction with CSNK2A1/CK2 which in turn promotes PML phosphorylation and degradation (By similarity). Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation. Plays a dynamic role in adipogenesis by promoting the SUMOylation and degradation of CEBPB (By similarity). Mediates the nuclear mobility and localization of MSX1 to the nuclear periphery, whereby MSX1 is brought into the proximity of target myoblast differentiation factor genes (By similarity). Also required for the binding of MSX1 to the core enhancer region in target gene promoter regions, independent of its sumolyation activity (By similarity). Capable of binding to the core enhancer region TAAT box in the MYOD1 gene promoter (By similarity).
Interacts with NCOA2 and AR. Interacts with NR2C1; the interaction promotes its sumoylation (By similarity). Interacts with DDX21, CSRP2, AXIN1, JUN, UBE2I, SUMO1, SATB2, PLAG1, TP53 and STAT1 (dimer), following IFNA1-stimulation. Interacts with SP3 (preferentially when SUMO-modified). Interacts with KLF8; the interaction results in SUMO ligation and repression of KLF8 transcriptional activity and of its cell cycle progression into G(1) phase. Interacts with CHUK/IKKA; this interaction induces PIAS1 phosphorylation. Interacts with PTK2/FAK1; the interaction promotes its sumoylation. Interacts with DDX5. Interacts with PML (By similarity). Interacts with MTA1. Interacts with SUMO1P1/SUMO5 (PubMed:27211601). Interacts with PRDM1/Blimp-1 (PubMed:28842558). Interacts (via N-terminus) with MSX1 (via C-terminus); the interaction is required for the localization of both proteins to the nuclear periphery and specific binding of MSX1 to the core enhancer region in target gene promoters (PubMed:16600910).
The SP-RING-type domain is required for promoting EKLF sumoylation.
Highest expression in the placenta, adipose tissue, stomach and intestine, intermediate levels in the brain, spleen, lung and heart, lowest levels in the kidney.
Receptor for UDP-glucose and other UDP-sugar coupled to G-proteins. Not activated by ATP, ADP, UTP or ATP.
Interacts with RELB and NFKB1/p105 (PubMed:15799966). Interacts with CCDC22, CCDC93, SCNN1B, CUL1 (PubMed:21778237, PubMed:23563313, PubMed:23637203, PubMed:25355947, PubMed:28892079).
Promotes the growth of epithelial cells. May stimulate the phosphorylation of EGFR and mitogen-activated protein kinases.
A chromosomal aberration involving HSPBAP1 has been found in a family with renal carcinoma (PubMed:12939738). Translocation t(2;3)(q35;q21) with the putative pseudogene DIRC3 (PubMed:12939738). Produces a hybrid mRNA encoding a truncated HSPBAP1 lacking the first 36 amino acids (PubMed:12939738).
May play a role in cellular stress response.
G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. Binds NHERF1 (PubMed:12193606). Forms a complex with PECAM1 and BDKRB2 (PubMed:18672896). Interacts with PECAM1. Interacts with GAS2L2 (PubMed:23994616).
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Required for platelet activation. Regulates B-cell selection and survival and is required to prevent B-cell-dependent autoimmunity. Regulates chemotaxis of BM-derived neutrophils and dendritic cells (in vitro) (By similarity). Transduces FFAR4 signaling in response to long-chain fatty acids (LCFAs) (PubMed:27852822). Together with GNA11, required for heart development (By similarity).
Histaminylated at Gln-209 residues by TGM2.
Palmitoylated by ZDHHC3 and ZDHHC7 (PubMed:19001095). Palmitoylation occurs in the Golgi and participates in the localization of GNAQ to the plasma membrane (PubMed:19001095).
Predominantly expressed in ovary, prostate, testis and colon. Down-regulated in the peripheral blood lymphocytes (PBLs) of rheumatoid arthritis patients (at protein level).
Belongs to the NADPH-dependent diflavin oxidoreductase NDOR1 family.
Interacts with CIAPIN1; as part of the cytosolic iron-sulfur (Fe-S) protein assembly (CIA) machinery (By similarity) (PubMed:20802492, PubMed:23596212). Interacts with DCPS (PubMed:16140270).
Low expression in brain, heart, kidney, pancreas, prostate and skeletal muscle. Highest levels in the placenta. Expressed in cancer cell lines including promyelocytic leukemia, HeLaS3, chronic myelagenous leukemia, lymphoblastic leukemia, Burkitt's lymphoma, colorectal adenocarcinoma, lung carcinoma, and melanoma G-361.
NADPH-dependent reductase which is a central component of the cytosolic iron-sulfur (Fe-S) protein assembly (CIA) machinery (PubMed:10625700, PubMed:28648056, PubMed:23596212, PubMed:20802492, PubMed:15900210). Transfers electrons from NADPH via its FAD and FMN prosthetic groups to the [2Fe-2S] cluster of CIAPIN1, another key component of the CIA machinery (PubMed:28648056, PubMed:23596212, PubMed:20802492). In turn, this reduced cluster provides electrons for assembly of cytosolic iron-sulfur cluster proteins (PubMed:23596212, PubMed:20802492). It can also reduce the [2Fe-2S] cluster of CISD1 and activate this protein implicated in Fe/S cluster repair (PubMed:28648056). In vitro can fully activate methionine synthase/MTR in the presence of soluble cytochrome b5/CYB5A (PubMed:12871938).
Interacts with FYN. When phosphorylated, interacts with CSK. Interacts with NHERF1/EBP50. In resting T-cells, part of a PAG1-NHERF1-MSN complex which is disrupted upon TCR activation. Interacts with LYN on plasma membrane lipid rafts. Identified in a complex with LYN and STAT3.
Negatively regulates TCR (T-cell antigen receptor)-mediated signaling in T-cells and FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Promotes CSK activation and recruitment to lipid rafts, which results in LCK inhibition. Inhibits immunological synapse formation by preventing dynamic arrangement of lipid raft proteins. May be involved in cell adhesion signaling.
Phosphorylated by FYN on Tyr-317 in resting T-cells; which promotes interaction with CSK. Dephosphorylated by PTPRC/CD45 upon TCR activation; which leads to CSK dissociation. May also be dephosphorylated by PTPN11. Hyperphosphorylated in mast cells upon FCER1 activation. Phosphorylated by LYN.
Ubiquitously expressed. Present in germinal center B-cells, plasma cells, T-cells, monocytes and platelets (at protein level).
Although related to peptidase S1 family, lacks the conserved active Ser residue in position 192 which is replaced by an Ala, suggesting that it has no protease activity. Lacks also metal binding sites Glu in position 67 which is replaced by Asn and Asn in position 69 which is replaced by Lys.
Patients with unexplained male infertility (UMI) show a decrease in the number of sperm cells compared to fertile men (PubMed:27649891). Sperm exhibit also abnormal activation of the proacrosin/acrosin system and premature proteolysis of ADAM2 (PubMed:27649891).
Plays a role in male fertility (By similarity). May have a role in sperm migration or binding to zona-intact eggs (By similarity). Involved in the activation of the proacrosin/acrosin system (PubMed:27649891).
Testis-specific (PubMed:27649891). Expressed in spermatids (at protein level) (PubMed:27649891).
Associates with SLC3A1 to form a functional transporter complex that mediates the electrogenic exchange between cationic amino acids and neutral amino acids, with a stoichiometry of 1:1 (PubMed:8663357, PubMed:16825196, PubMed:32817565, PubMed:32494597). Has system b(0,+)-like activity with high affinity for extracellular cationic amino acids and L-cystine and lower affinity for intracellular neutral amino acids (PubMed:8663357, PubMed:16825196, PubMed:32494597). Substrate exchange is driven by high concentration of intracellular neutral amino acids and the intracellular reduction of L-cystine to L-cysteine (PubMed:8663357). Required for reabsorption of L-cystine and dibasic amino acids across the brush border membrane in renal proximal tubules.
Disulfide-linked heterodimer composed of the catalytic light chain subunit SLC7A9 and the heavy chain subunit SLC3A1. The heterodimer is the minimal functional unit. Assembles in heterotetramers (dimers of heterodimers) and higher order oligomers; the oligomerization is mediated by SLC3A1 likely to prevent degradation and facilitate heteromer trafficking to the plasma membrane (PubMed:16825196, PubMed:32494597, PubMed:32817565). Interacts with CAV1 (By similarity).
Expressed in the brush border membrane in the kidney (at protein level). Kidney, small intestine, liver and placenta.
Expressed in adult bone marrow, placenta, liver, skeletal muscle and pancreas. Down-regulated in hepatocellular carcinoma.
Homodimer. Interacts with BNIP3L, MYT1, RHBDL4/RHBDD1 and TCTP.
Integral membrane protein that functions as NADPH-dependent ferric-chelate reductase, using NADPH from one side of the membrane to reduce a Fe(3+) chelate that is bound on the other side of the membrane (PubMed:26205815). Mediates sequential transmembrane electron transfer from NADPH to FAD and onto heme, and finally to the Fe(3+) chelate (By similarity). Can also reduce Cu(2+) to Cu(1+) (By similarity). Mediates efficient transferrin-dependent iron uptake in erythroid cells (By similarity). May play a role downstream of p53/TP53 to interface apoptosis and cell cycle progression (By similarity). Indirectly involved in exosome secretion by facilitating the secretion of proteins such as TCTP (PubMed:15319436, PubMed:16651434).
Proteolytically cleaved by RHBDL4/RHBDD1. RHBDL4/RHBDD1-induced cleavage occurs at multiple sites in a glycosylation-independent manner.
Was initially thought to have tumor suppressor function in prostate cancer. However, it was shown that it is probably not the case (PubMed:12866033).
Detected in duodenum mucosal crypts of cholera patients, near Paneth cells (at protein level). Detected in trachea, nasal septal epithelium and lung.
May play a role in innate immunity in mouth, nose and lungs. Binds bacterial lipopolysaccharide (LPS) and modulates the cellular responses to LPS.
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.8/KCNA10 sub-subfamily.
Detected in kidney, in proximal tubules, glomerular endothelium, in vascular endothelium and in smooth muscle cells.
Homotetramer. Interacts with KCN4B/POMP. Interaction with KCN4B/POMP is necessary for the modulation of channel activity by cAMP.
Mediates voltage-dependent potassium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a potassium-selective channel through which potassium ions may pass in accordance with their electrochemical gradient. The channel activity is up-regulated by cAMP.
2 N-termini have been observed in the mature protein: the first at Glu-30, resulting from signal peptide cleavage, the second at Ser-46.
Highly expressed in the pancreas. Also found in the colon, kidney, prostate, small intestine and testis.
Induces apoptosis of alpha and beta cells in a dose- and time-dependent manner.
Belongs to the engrailed homeobox family.
Required for proper formation of the apical ectodermal ridge and correct dorsal-ventral patterning in the limb.
The gene represented in this entry is involved in disease pathogenesis. Homozygous structural variants on chromosome 2 located 300 kb upstream of EN1 result in altered EN1 expression with pathological consequences.
Specifically binds poly(G) RNA homopolymers in vitro.
Expressed in barely detectable amounts in most tissues except brain, highest levels being found in lung, liver and skeletal muscle.
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (p20) and a 10 kDa (p10) subunits (By similarity). Interacts with MEFV (PubMed:17431422). Interacts with SERPINB1; this interaction regulates CASP5 activity (PubMed:30692621).
Produced by alternative initiation at Met-71 of isoform 1.
Thiol protease that acts as a mediator of programmed cell death (PubMed:29898893, PubMed:28314590). Initiates pyroptosis, a programmed lytic cell death pathway through cleavage of Gasdermin-D (GSDMD): cleavage releases the N-terminal gasdermin moiety (Gasdermin-D, N-terminal) that binds to membranes and forms pores, triggering pyroptosis (PubMed:29898893). During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590).
Up-regulated by bacterial lipopolysaccharides (LPS).
As part of the OOEP-KHDC3L scaffold, recruits BLM and TRIM25 to DNA replication forks, thereby promoting the ubiquitination of BLM by TRIM25, enhancing BLM retainment at replication forks and therefore promoting stalled replication fork restart (By similarity). Positively regulates the homologous recombination-mediated DNA double-strand break (DSB) repair pathway by regulating ATM activation and RAD51 recruitment to DSBs in oocytes (By similarity). Thereby contributes to oocyte survival and the resumption and completion of meiosis (By similarity). As a member of the subcortical maternal complex (SCMC), plays an essential role for zygotes to progress beyond the first embryonic cell divisions via regulation of actin dynamics (By similarity). Required for the formation of F-actin cytoplasmic lattices in oocytes which in turn are responsible for symmetric division of zygotes via the regulation of mitotic spindle formation and positioning (By similarity).
Component of the subcortical maternal complex (SCMC), at least composed of NLRP5, KHDC3L, OOEP, and TLE6 isoform 1 (PubMed:26537248, PubMed:25542835). Within the complex, interacts with NLRP5, KHDC3L and TLE6 isoform 1 (PubMed:26537248, PubMed:25542835). As part of the SCMC interacts with the SCMC-associated protein NLRP4F (By similarity). The SCMC may facilitate translocation of its components between the nuclear and cytoplasmic compartments (PubMed:25542835). Forms a scaffold complex with KHDC3L/FILIA, and interacts with BLM and TRIM25 at DNA replication forks (By similarity).
Contains an atypical KH domain with amino acid changes at critical sites, suggesting that it may not bind RNA.
Expressed in oocytes of the fetal ovary (PubMed:25542835). Expressed primarily with other SCMC components in the subcortex of oocytes and early embryos (PubMed:25542835). Expression is excluded from cell-cell contact regions after the 2-cell stage (PubMed:25542835).
May play a role in the regulation of calcium sequestration or release in the SR of skeletal and cardiac muscle.
(Microbial infection) ADP-ribosylated by M.pneumoniae CARDS toxin in vitro.
(Microbial infection) In COVID-19 patient derived macrophages, expression is induced by SARS-CoV-2 spike protein, probably via TLR2 (at protein level).
(Microbial infection) Interacts with M.pneumoniae CARDS toxin, which ADP-ribosylates NLRP3.
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 N protein; the interaction is direct and promotes the binding of NLRP3 with PYCARD/ASC and facilitates NLRP3 inflammasome assembly.
By activators of Toll-like receptors, such as lipoteichoic acid (LTA) (TLR2), polyinosine-polycytidylic acid (poly(I:C), a synthetic analog of dsRNA) (TLR3) and bacterial lipopolysaccharides (LPS) (TLR4), and by TNF (PubMed:14662828). Up-regulated in osteoblasts after exposure to invasive, but not invasion-defective, strains of Salmonella typhimurium (at protein level) (PubMed:17907925). In macrophages, up-regulated by endocannabinoid anandamide/AEA (PubMed:23955712).
Degraded via selective autophagy following interaction with IRGM (PubMed:30612879). IRGM promotes NLRP3 recruitment to autophagosome membranes, promoting its SQSTM1/p62-dependent autophagy-dependent degradation (PubMed:30612879).
Independently of inflammasome activation, regulates the differentiation of T helper 2 (Th2) cells and has a role in Th2 cell-dependent asthma and tumor growth (By similarity). During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription (By similarity). Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3' (By similarity). May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF (By similarity).
Palmitoylation by ZDHHC12 inhibits the NLRP3 inflammasome by promoting NLRP3 degradation by the chaperone-mediated autophagy pathway (PubMed:36586411). Following palmitoylation, HSPA8/HSC70 recognizes and binds the KFERQ-like motifs on NLRP3 and promotes NLRP3 recruitment to lysosomes, where it is degraded via the chaperone-mediated autophagy pathway in a LAMP2-dependent process (PubMed:36586411).
Phosphorylation at Ser-198 by MAPK8/JNK1 increases inflammasome activation by promoting deubiquitination by BRCC3 and NLRP3 homooligomerization (PubMed:28943315). Phosphorylation at Ser-806 by CSNK1A1 prevents inflammasome activation by preventing NEK7 recruitment (PubMed:34615873). Phosphorylation at Ser-5 in the pyrin domain inhibits homomultimerization of NLRP3 and activation of the NLRP3 inflammasome: dephosphorylation by protein phosphatase 2A (PP2A) promotes assembly of the NLRP3 inflammasome (PubMed:28465465). Phosphorylation at Ser-295 by PKD/PRKD1 promotes NLRP3 inflammasome assembly (By similarity). Phosphorylation by ERK1/MAPK3 promotes NLRP3 inflammasome assembly (PubMed:24623131). Phosphorylation by BTK (at Tyr-136, Tyr-140, Tyr-143 and Tyr-168) in the region that mediates binding to phosphatidylinositol phosphate, promotes relocalization of NLRP3 and assembly of the NLRP3 inflammasome (PubMed:34554188). Phosphorylation at Tyr-861 inhibits NLRP3 inflammasome assembly: dephosphorylation by PTPN22 promotes inflammasome activation (PubMed:27043286).
Predominantly expressed in macrophages (PubMed:33231615, PubMed:34133077). Also expressed in dendritic cells, B- and T-cells (at protein level) (PubMed:11786556) (PubMed:17164409). Expressed in LPS-treated granulocytes, but not in resting cells (at protein level) (PubMed:17164409). Expression in monocytes is very weak (at protein level) (PubMed:17164409). Expressed in stratified non-keratinizing squamous epithelium, including oral, esophageal and ectocervical mucosa and in the Hassall's corpuscles in the thymus. Also, detected in the stratified epithelium covering the bladder and ureter (transitional mucosa) (at protein level) (PubMed:17164409). Expressed in lung epithelial cells (at protein level) (PubMed:23229815). Expressed in chondrocytes (PubMed:12032915). Expressed at low levels in resting osteoblasts (PubMed:17907925).
Sensor component of NLRP3 inflammasomes; inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (PubMed:11786556, PubMed:15030775, PubMed:21880711). The core of NLRP3 inflammasomes consists of a signal sensor component (NLRP3), an adapter (PYCARD/ASC), which recruits an effector pro-inflammatory caspase (CASP1 and, possibly, CASP4 and CASP5) (PubMed:11786556, PubMed:15030775, PubMed:21880711). Homodecamer; inactive NLRP3 forms homodecameric double-ring cages that hide pyrin domains within NACHT-LRR rings to avoid premature activation (PubMed:35114687, PubMed:35254907). Interacts (via pyrin domain) with PYCARD/ASC (via pyrin domain); interaction is direct (PubMed:11786556, PubMed:34341353, PubMed:27432880, PubMed:35559676, PubMed:36142182, PubMed:36442502). Interacts (via LRR repeat domain) with NEK7 (via N-terminus); the interaction is required for the formation of the complex NLRP3:PYCARD, oligomerization of PYCARD/ASC and activation of CASP1 (PubMed:31189953, PubMed:36442502). Interacts (via LRR repeat domain) with NR4A1/Nur77 (via N-terminus); the interaction is direct, requires activation of NR4A1 by its ligands NBRE-containing dsDNA and lipopolysaccharide, and stimulates the association of NLRP3 with NEK7 for non-canonical NLRP3 inflammasome activation (By similarity). Interacts with CARD8; leading to inhibit formation of the NLRP3 inflammasome (PubMed:24517500). Interacts with MEFV; this interaction targets NLRP3 to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation (PubMed:17431422, PubMed:26347139). Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to specific stimuli (PubMed:22801494). Interacts with GBP5 (via DAPIN domain); this interaction promotes inflammasome assembly in response to microbial and soluble, but not crystalline, agents (PubMed:22461501). Interacts with PML (isoform PML-1) (via the leucine-rich repeat (LRR) domain); PML-mediated increase in NLRP3 inflammasome activation does not depend upon this interaction (PubMed:23430110). Interacts (via NACHT domain) with DHX33 (via DEAH box); NLRP3 activation in presence of cytosolic dsRNA is mediated by DHX33 (PubMed:23871209). Interacts (via NACHT and LRR domains) with ARRB2; this interaction is direct and inducible by polyunsaturated fatty acids (PUFAs) (PubMed:23809162). Interacts with PYDC5 (PubMed:24531343). Interacts (via NACHT domain) with DDX3X under both LPS-primed and inflammasome-activating conditions (By similarity). Interacts with IRF4 (via the LRR domain); this interaction is direct and is required for optimal IRF4 binding to IL4 promoter and efficient IL4 transactivation during differentiation of Th2 helper T-cells (By similarity). Interacts with MAVS; promoting localization to mitochondria and activation of the NLRP3 inflammasome (PubMed:23582325). Interacts with MARK4; promoting localization of NLRP3 to the microtubule organizing center (MTOC) (PubMed:28656979). Interacts with TRIM50; this interaction promotes also NLRP3 oligomerization and subsequent inflammasome activation (By similarity). Interacts with IRGM; preventing NLRP3 inflammasome assembly and promoting NLRP3 degradation (PubMed:30612879). Interacts (via KFERQ-like motifs) with HSPA8/HSC70; promoting NLRP3 degradation by the chaperone-mediated autophagy pathway (PubMed:36586411).
Sensor component of the NLRP3 inflammasome, which mediates inflammasome activation in response to defects in membrane integrity, leading to secretion of inflammatory cytokines IL1B and IL18 and pyroptosis (PubMed:16407889, PubMed:18604214, PubMed:18403674, PubMed:23582325, PubMed:28847925, PubMed:33231615, PubMed:34133077, PubMed:34341353, PubMed:27929086, PubMed:28656979, PubMed:25686105, PubMed:30487600, PubMed:30612879, PubMed:31086327, PubMed:31086329, PubMed:31189953, PubMed:34512673, PubMed:36442502). In response to pathogens and other damage-associated signals that affect the integrity of membranes, initiates the formation of the inflammasome polymeric complex composed of NLRP3, CASP1 and PYCARD/ASC (PubMed:16407889, PubMed:18403674, PubMed:28847925, PubMed:33231615, PubMed:34133077, PubMed:34341353, PubMed:27432880, PubMed:31189953, PubMed:36142182, PubMed:36442502). Recruitment of pro-caspase-1 (proCASP1) to the NLRP3 inflammasome promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), promoting cytokine secretion and pyroptosis (PubMed:23582325, PubMed:28847925, PubMed:33231615, PubMed:34133077, PubMed:34341353, PubMed:31189953). Activation of NLRP3 inflammasome is also required for HMGB1 secretion; stimulating inflammatory responses (PubMed:22801494). Under resting conditions, ADP-bound NLRP3 is autoinhibited (PubMed:35114687). NLRP3 activation stimuli include extracellular ATP, nigericin, reactive oxygen species, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, such as asbestos, silica, aluminum salts, cytosolic dsRNA, etc (PubMed:16407889, PubMed:18604214, PubMed:18403674, PubMed:19414800, PubMed:23871209). Almost all stimuli trigger intracellular K(+) efflux (By similarity). These stimuli lead to membrane perturbation and activation of NLRP3 (By similarity). Upon activation, NLRP3 is transported to microtubule organizing center (MTOC), where it is unlocked by NEK7, leading to its relocalization to dispersed trans-Golgi network (dTGN) vesicle membranes and formation of an active inflammasome complex (PubMed:36442502). Associates with dTGN vesicle membranes by binding to phosphatidylinositol 4-phosphate (PtdIns4P) (PubMed:30487600, PubMed:34554188). Shows ATPase activity (PubMed:17483456).
The FISNA domain is a critical mediator of NLRP3 conformational during NLRP3 activation (PubMed:34524838, PubMed:36442502). It becomes ordered in its key regions during activation to stabilize the active NACHT conformation and mediate most interactions in the NLRP3 disk (PubMed:36442502).
The KFERQ-like motifs mediate binding to HSPA8/HSC70 following NLRP3 paylmitoylation by ZDHHC12.
The LRR domain mediates the interaction with IRF4, PML, NEK7 and NR4A1/Nur77.
The disulfide bond in the pyrin domain might play a role in reactive oxygen species-mediated activation.
The pyrin domain (also called DAPIN domain or PYD) is involved in PYCARD/ASC-binding.
Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination (PubMed:22948162, PubMed:27929086). Ubiquitination does not lead to degradation, but inhibits inflammasome activation (By similarity). Deubiquitination is catalyzed by BRCC3 and associated with NLRP3 activation and inflammasome assembly (By similarity). This process can be induced by the activation of Toll-like receptors (by LPS), through a non-transcriptional pathway dependent on the mitochondrial production of reactive oxygen species, and by ATP (By similarity). Ubiquitinated by TRIM31 via 'Lys-48'-linked ubiquitination, leading to its degradation by the proteasome (PubMed:27929086). Ubiquitinated at Lys-689 by the SCF(FBXL2) complex, leading to its degradation by the proteasome (PubMed:26037928). Ubiquitinated by TRIM35 via 'lys-48' and 'Lys-63'-linked ubiquitination leading to inhibition of NLRP3 inflammasome activation (PubMed:34512673).
Under resting conditions, NLRP3 binds ADP and is autoinhibited (PubMed:35114687). Inactive NLRP3 forms homodecameric double-ring cages that hide pyrin domains within NACHT-LRR rings to avoid premature activation (PubMed:35114687). NLRP3 activation stimuli include extracellular ATP, nigericin, reactive oxygen species, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, such as asbestos, silica, aluminum salts, cytosolic dsRNA, etc (PubMed:16407889, PubMed:18604214, PubMed:18403674, PubMed:19414800, PubMed:35114687). Activated upon human coronavirus SARS-CoV-2 infection (PubMed:33231615, PubMed:34133077). Almost all stimuli trigger intracellular K(+) efflux (By similarity). These stimuli lead to membrane perturbations that induce activation of NLRP3 (By similarity). Upon activation, NLRP3 is transported to microtubule organizing center (MTOC), where it is unlocked by NEK7, leading to its relocalization to dispersed trans-Golgi network (dTGN) vesicle membranes and recruitment of PYCARD/ASC for the formation of an active inflammasome complex (PubMed:30487600, PubMed:30612879, PubMed:36442502). NEK7-activated NLRP3 forms a disk-shaped inflammasome (PubMed:36442502). NLRP3 and PYCARD/ASC interact via their respective pyrin domains; interaction initiates speck formation (nucleation) which greatly enhances further addition of soluble PYCARD/ASC molecules to the speck in a prion-like polymerization process (PubMed:24630722, PubMed:28465465, PubMed:27432880, PubMed:35559676, PubMed:36142182, PubMed:36442502). Clustered PYCARD/ASC nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization and activation (PubMed:24630722). Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response (PubMed:24630722). NLRP3 inflammasome assembly is inhibited by IRGM, which impedes NLRP3 oligomerization (PubMed:30612879). Specifically inhibited by sulfonylurea MCC950 (also named CP-456,773, CRID3), a potent and specific small-molecule inhibitor of the NLRP3 inflammasome that acts by preventing ATP hydrolysis (PubMed:25686105, PubMed:31086327, PubMed:31086329, PubMed:34687713, PubMed:35114687, PubMed:35254907).
Belongs to the bacterial ribosomal protein bL35 family.
(Microbial infection) Interacts with HCV protein NS5A and NS5B (PubMed:21957124).
Endoplasmic reticulum-anchored protein that mediates the formation of contact sites between the endoplasmic (ER) and late endosomes via interaction with STARD3 (PubMed:33124732). In addition, mediates recruitment of VAPA to plasma membrane sites through OSBPL3 binding (PubMed:25447204). The OSBPL3-VAPA complex stimulates RRAS signaling which in turn attenuates integrin beta-1 (ITGB1) activation at the cell surface (PubMed:25447204). With OSBPL3, may regulate ER morphology (PubMed:16143324). May play a role in vesicle trafficking (PubMed:11511104, PubMed:19289470).
Homodimer; disulfide-linked (PubMed:33124732, PubMed:11511104). Heterodimer with VAPB (PubMed:11511104). Homotetramer (PubMed:33124732). Interacts with VAMP1, VAMP2, STX1A, BET1, SEC22C and with the C-terminal domain of OCLN (PubMed:11511104, PubMed:9657962, PubMed:10523508). Interacts (via MSP domain) with OSBPL1A (via FFAT motif) (PubMed:33124732). Interacts (via MSP domain) with ZFYVE27; may retain ZFYVE27 in the endoplasmic reticulum and regulate its function in cell projections formation (PubMed:19289470, PubMed:21976701). Interacts with OSBP (PubMed:20178991). Interacts (via C-terminus) with RSAD2/viperin (via C-terminus) (PubMed:21957124). Interacts with IFITM3 (PubMed:23601107). Interacts with OSBPL3 (phosphorylated form) (PubMed:16143324, PubMed:25447204). Interacts with KIF5A in a ZFYVE27-dependent manner (PubMed:21976701). Interacts (via MSP domain) with STARD3 (via phosphorylated FFAT motif); this interaction recruits VAPA to the endosome (PubMed:24105263, PubMed:33124732). Interacts with STARD3NL (via FFAT motif) (PubMed:24105263). Interacts with CERT1 (PubMed:16895911). Interacts with PLEKHA3 and SACM1L to form a ternary complex (PubMed:30659099). Interacts with VPS13A (via FFAT motif) (PubMed:30741634). Interacts with RB1CC1 (via phosphorylated FFAT motif), MIGA2 (via phosphorylated FFAT motif), RMDN3 (via phosphorylated FFAT motif), KCNB1 (via phosphorylated FFAT motif) and KCNB2 (via phosphorylated FFAT motif) (PubMed:33124732).
Detected on T-cells, natural killer cells, dendritic cells and macrophages (at protein level). Ubiquitous. Highly expressed in heart, pancreas and lung, Moderately expressed in placenta, liver and muscle.
Plays a role in T-cell activation and in the adaptive immune response. Regulates the proliferation of activated T-cells. Regulates the release of cytokines and IFNG by activated T-cells. Mediates the response of T-cells toward infected and transformed cells that are characterized by high levels of phosphorylated metabolites, such as isopentenyl pyrophosphate.
2 molecules of GDNFR-alpha are thought to form a complex with the disulfide-linked GDNF dimer and with 2 molecules of RET (By similarity). Interacts with RET (PubMed:23333276). Interacts with SORL1, either alone or in complex with GDNF (PubMed:23333276). Interaction between SORL1 and GFRA1 leads to GFRA1 internalization, but not degradation (PubMed:23333276).
Receptor for GDNF. Mediates the GDNF-induced autophosphorylation and activation of the RET receptor (By similarity).
Down-regulates ESR1 protein levels through the ubiquitination-proteasome pathway, regardless of the presence of 17 beta-estradiol. Also involved in 17 beta-estradiol-induced ESR1 degradation. Controls PGR protein levels through a similar mechanism.
Interacts with PGR. Interacts with ESR1 in the presence or absence of 17 beta-estradiol.
May predict the clinical outcome of tamoxifen therapy of breast cancer patients. Patients with tumors that highly express CUEDC2 do not respond to tamoxifen treatment as effectively as those with tumors with low expression.
Significantly up-regulated in breast tumor tissues compared with matched adjacent normal tissues (at protein level). Levels inversely correlate with ESR1 in breast cancers and are lower in low-grade tumors compared to high-grade tumors.
The CUE domain mediates interaction with PGR and ESR1.
Has apparently no steroid dehydrogenase activity.
Catalyzes the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, one of the steps in tyrosine catabolism.
Found in a segmental duplication on p arm of chromosome 16 giving rise to two identical copies of this gene sharing exons with SLX1A and SLX1B. The ORFs of SULT1A3 and SULT1A4 differ with only a single nucleotide change that does not alter the encoded amino acid. It is not possible to determine whether any individual polymorphism is present within SULT1A3 or SULT1A4 (PubMed:15358107).
Liver, colon, kidney, lung, brain, spleen, small intestine, placenta and leukocyte.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of phenolic monoamines (neurotransmitters such as dopamine, norepinephrine and serotonin) and phenolic and catechol drugs.
Belongs to the flagellar radial spoke RSP14 family.
Component of the axonemal radial spoke complex 1 (RS1), at least composed of spoke head proteins RSPH1, RSPH3, RSPH9 and the cilia-specific component RSPH4A or sperm-specific component RSPH6A, spoke stalk proteins RSPH14, DNAJB13, DYDC1, ROPN1L and NME5, and the anchor protein IQUB.
Expressed in adult cerebellum, spinal cord, spleen, skeletal muscle and some/5 out of 9 rhabdoid tumors. Detected in fetal brain, lung, liver and kidney.
A chromosomal aberration involving TFG is found in papillary thyroid carcinomas (PTCs). Translocation t(1;3)(q21;q11) with NTRK1. The TFG sequence is fused to the 3'-end of NTRK1 generating the TRKT3 (TRK-T3) fusion transcript.
Plays a role in the normal dynamic function of the endoplasmic reticulum (ER) and its associated microtubules (PubMed:23479643, PubMed:27813252). Required for secretory cargo traffic from the endoplasmic reticulum to the Golgi apparatus (PubMed:21478858).
Self-associates to form an oligomeric complex (PubMed:23479643). Interacts with PDCD6; promoting localization and polymerization of TFG at endoplasmic reticulum exit site (PubMed:27813252). Interacts with SEC16B (PubMed:21478858).
Can bind protoporphyrin IX and may play a role in the transport of porphyrins and heme (By similarity). Promotes the transport of cholesterol across mitochondrial membranes and may play a role in lipid metabolism (PubMed:24814875), but its precise physiological role is controversial. It is apparently not required for steroid hormone biosynthesis. Was initially identified as peripheral-type benzodiazepine receptor; can also bind isoquinoline carboxamides (PubMed:1847678).
Found in many tissue types. Expressed at the highest levels under normal conditions in tissues that synthesize steroids.
In erythrocytes, expression levels decrease throughout differentiation (PubMed:27641616). Not expressed in mature erythrocytes (PubMed:27641616).
Interacts with TSPOAP1 (By similarity). May interact with STAR (By similarity). Interacts with MOST-1.
Detected in seminal plasma (at protein level).
Plays an important role in the degradation of some oligopeptides.
Associates with SLC3A1/rBAT to form a functional heterodimeric complex that transports anionic and neutral amino acids across the apical plasma membrane of renal epithelium. Preferentially mediates exchange transport, but can also operate via facilitated diffusion. May act as a major transporter for L-cystine in late proximal tubules, ensuring its reabsorption from the luminal fluid in exchange for cytosolic L-glutamate or L-aspartate.
Disulfide-linked heterodimer composed of the catalytic light subunit SLC7A13 and the heavy subunit SLC3A1.
Component of heteromultimeric potassium channels (PubMed:23576435). Identified in potassium channel complexes containing KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (By similarity). Interacts with KCND2 (PubMed:11847232, PubMed:18957440). Interacts with KCND3 (By similarity). Interacts with the C-terminus of PSEN2 and probably PSEN1 (PubMed:11847232).
Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels. Modulates KCND2 channel density, inactivation kinetics and rate of recovery from inactivation in a calcium-dependent and isoform-specific manner (PubMed:11847232, PubMed:18957440, PubMed:23576435). Modulates KCND3/Kv4.3 currents (PubMed:23576435). Isoform 4 does not increase KCND2 expression at the cell membrane (PubMed:18957440). Isoform 4 retains KCND3 in the endoplasmic reticulum and negatively regulates its expression at the cell membrane.
The KIS (K-channel inactivation suppressor) domain is required for converting A-type Kv4 current to a slowly inactivating delayed rectifier potassium current.
Acts as component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NFX1 pathway. The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production. Plays a role in apoptosis negative control involved in brain development.
Component of the THO complex, which is composed of THOC1, THOC2, THOC3, THOC5, THOC6 and THOC7; together with at least ALYREF/THOC4, DDX39B, SARNP/CIP29 and CHTOP, THO forms the transcription/export (TREX) complex which seems to have a dynamic structure involving ATP-dependent remodeling.
Amiloride-sensitive ion current is nearly abolished.
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. SCNN1A subfamily.
Does not give rise to amiloride-sensitive ion current.
Does not give rise to amiloride-sensitive ion current. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Expressed in the female reproductive tract, from the fimbrial end of the fallopian tube to the endometrium (at protein level) (PubMed:22207244). Expressed in kidney (at protein level). In the respiratory tract, expressed in the bronchial epithelium (at protein level). Highly expressed in lung. Detected at intermediate levels in pancreas and liver, and at low levels in heart and placenta (PubMed:22207244). in skin, expressed in keratinocytes, melanocytes and Merkel cells of the epidermal sub-layers, stratum basale, stratum spinosum and stratum granulosum (at protein level) (PubMed:28130590). Expressed in the outer root sheath of the hair follicles (at protein level) (PubMed:28130590). Detected in both peripheral and central cells of the sebaceous gland (at protein level) (PubMed:28130590). Expressed by eccrine sweat glands (at protein level) (PubMed:28130590). In skin, also expressed by arrector pili muscle cells and intradermal adipocytes (PubMed:28130590). Isoform 1 and isoform 2 predominate in all tissues. Expression of isoform 3, isoform 4 and isoform 5 is very low or not detectable, except in lung and heart (PubMed:9575806).
Heterotrimer containing an alpha/SCNN1A, a beta/SCNN1B and a gamma/SCNN1G subunit. An additional delta/SCNN1D subunit exists only in some organisms and can replace the alpha/SCNN1A subunit to form an alternative channel with specific properties (By similarity). Interacts with NEDD4 (via WW domains) (PubMed:11244092, PubMed:11696533, PubMed:12167593, PubMed:23665454). Interacts with NEDD4L (via WW domains) (PubMed:11244092, PubMed:11696533). Interacts with WWP1 (via WW domains) (PubMed:9169421). Interacts with WWP2 (via WW domains) (PubMed:12167593, PubMed:9169421). Interacts with the full-length immature form of PCSK9 (pro-PCSK9) (PubMed:22493497).
Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride. Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells. Plays an essential role in electrolyte and blood pressure homeostasis, but also in airway surface liquid homeostasis, which is important for proper clearance of mucus. Controls the reabsorption of sodium in kidney, colon, lung and eccrine sweat glands. Also plays a role in taste perception.
Activated by micromolar concentrations of calcium and inhibited by calpastatin.
Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction (PubMed:19617626, PubMed:21531719, PubMed:2400579). Proteolytically cleaves CTBP1 at 'Asn-375', 'Gly-387' and 'His-409' (PubMed:23707407). Cleaves and activates caspase-7 (CASP7) (PubMed:19617626).
Forms a heterodimer with a small (regulatory) subunit CAPNS1.
Undergoes calcium-induced successive autoproteolytic cleavages that generate a membrane-bound 78 kDa active form and an intracellular 75 kDa active form. Calpastatin reduces with high efficiency the transition from 78 kDa to 75 kDa calpain forms.
Although the precise topology is not known, experimental data suggest that both the N- and C-termini face the cytosol.
Component of the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins (PubMed:16289116, PubMed:28827405). Could enhance presenilin-mediated amyloid-beta protein 40 generation. Binds to ubiquilins and this interaction is required for efficient degradation of CD3D via the ERAD pathway (PubMed:18307982).
Interacts with PSEN1 and PSEN2 (PubMed:11799129). Interacts with UBXN6 (PubMed:18656546). Interacts with UBQLN1, UBQLN2 and UBQLN4 (PubMed:18307982). Component of the HRD1 complex, which comprises at least SYNV1/HRD1, FAM8A1, HERPUD1/HERP, OS9, SEL1L and UBE2J1. FAM8A1 binding to SYNV1 may promote recruitment of HERPUD1 to the HRD1 complex (PubMed:16289116, PubMed:28827405).
Up-regulated by endoplasmic reticulum stress and CREB3.
Widely expressed; in the brain, expression seems to be restricted to neurons and vascular smooth muscle cells. Present in activated microglia in senile plaques in the brain of patients with Alzheimer disease.
Monomer (By similarity). Interacts with DALRD3 (PubMed:32427860).
S-adenosyl-L-methionine-dependent methyltransferase that mediates N(3)-methylcytidine modification of residue 32 of the tRNA anticodon loop of tRNA(Thr)(UGU) and tRNA(Arg)(CCU).
Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Highly expressed in normal tissue without inflammatory stimuli and infrequently expressed in cancer cell lines. Weakly expressed in monocyte-derived dendritic cells. Not detected in lung or unstimulated peripheral blood lymphocytes.
Potent chemoattractant for neutrophils, and weaker for dendritic cells. Not chemotactic for T-cells, B-cells, monocytes, natural killer cells or granulocytes. Does not inhibit proliferation of myeloid progenitors in colony formation assays.
The destruction box (D-box) acts as a recognition signal for degradation via the ubiquitin-proteasome pathway.
Ubiquitinated, followed by degradation by the proteasome.
Up-regulated in peripheral blood lymphocytes in response to bacterial lipopolysaccharides (LPS).
Belongs to the G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRA1D sub-subfamily.
Interacts with FLNA (via filamin repeat 21); increases PKA-mediated phosphorylation of FLNA.
Palmitoylated. Palmitoylation by ZDHHC21 may increase the expression of the receptor and regulate downstream signaling.
This alpha-adrenergic receptor mediates its effect through the influx of extracellular calcium.
Forms a complex with CASK and APBA1 or CASKIN1 (By similarity). Component of the brain-specific heterotrimeric complex (LIN-10-LIN-2-LIN-7 complex) composed of at least APBA1, CASK, and LIN7, which associates with the motor protein KIF17 to transport vesicles along microtubules (By similarity). Can also interact with other modular proteins containing protein-protein interaction domains like PALS1, PALS2, MPP7, DLG1, DLG2 and DLG3 through its L27 domain. Interacts with DLG4 and GRIN2B as well as CDH1 and CTNNB1, the channels KCNJ12/Kir2.2, KCNJ4/Kir2.3 and probably KCNJ2/Kir2.1 and SLC6A12/BGT-1 via its PDZ domain. The association of LIN7A with cadherin and beta-catenin is calcium-dependent, occurs at synaptic junctions and requires the actin cytoskeleton. Interacts with EGFR, ERBB2, ERBB3 and ERBB4 with both PDZ and KID domains. Associates with KIF17 via APBA1. Interacts with HTR4 (By similarity). Forms a tripartite complex composed of DLG1, MPP7 and LIN7 (LIN7A or LIN7C). Interacts with MAPK12 (By similarity).
(Microbial infection) Interacts with influenza virus PA, PB1 and PB2,leading to inhibition of RdRp complex assembly.
(Microbial infection) Interacts with zika virus capsid protein.
Antiviral interferon-stimulated protein that plays a role in innate immunity and in the suppression of viruses through different mechanisms (PubMed:33147462, PubMed:36594413). Plays a role in the late phase response of TLR-induced immune effector expression (By similarity). During influenza infection, interacts with PB2, PB1, and PA to disrupt the formation of the viral RdRp complex (PubMed:33147462). Inhibits zika virus by interacting with the capsid protein in the nucleolus and reducing its abundance through proteasomal degradation (PubMed:36594413). Strong transcriptional coactivator (PubMed:10982866).
Belongs to the universal ribosomal protein uS11 family.
Centriolar protein required for centriole subdistal appendage assembly and microtubule anchoring in interphase cells (PubMed:28422092). Together with CCDC68, cooperate with subdistal appendage components ODF2, NIN and CEP170 for hierarchical subdistal appendage assembly (PubMed:28422092). Recruits NIN and CEP170 to centrosomes (PubMed:28422092). Also required for neurite growth. Localizes CYTH2 to vesicles to allow its transport along neurites, and subsequent ARF6 activation and neurite growth.
Interacts with NIN and CEP170; leading to recruit them to centrosomes (PubMed:28422092). Directly interacts with CYTH2; this interaction stabilizes CCDC120, possibly by preventing ubiquitination.
Ubiquitinated; interaction with CYTH2 may prevent ubiquitination.
Forms a 24-polypeptide structural core with octahedral symmetry.
Patients with primary biliary cirrhosis (PBC) show autoantibodies against the E2 component of branched-chain alpha-keto acid dehydrogenase complex. PBC is a chronic, progressive cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients serum. It manifests with inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis.
The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3). Within this complex, the catalytic function of this enzyme is to accept, and to transfer to coenzyme A, acyl groups that are generated by the branched-chain alpha-keto acid decarboxylase component.
Belongs to the protoporphyrinogen/coproporphyrinogen oxidase family. Protoporphyrinogen oxidase subfamily.
Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX.
The disease is caused by variants affecting the gene represented in this entry. Mutations leading to severe PPOX deficiency cause the rare homozygous variant form of VP. Missense mutations that preserve 10%-25% of wild-type activity may not cause clinically overt VP in heterozygotes (PubMed:9811936). Mutations with intermediate effect on catalytic activity may cause VP, but with a low clinical penetrance (PubMed:10486317).
Expressed in primitive cells of the kidney, ureter, eye, ear and central nervous system.
Interacts with ELGN3; the interaction targets PAX2 for destruction. Interacts with TLE4.
Mainly in fetal kidney and juvenile nephrogenic rests.
Transcription factor that may have a role in kidney cell differentiation (PubMed:24676634). Has a critical role in the development of the urogenital tract, the eyes, and the CNS.
Expressed in mature metaphase II (MII) stage oocytes (at protein level) (PubMed:36070373). In B-cells, expression increases as a function of differentiation and peaks on memory B-cells.
Genetic variation in FCRL3 may influence susceptibility to autoimmune disorders, including Graves disease or multiple sclerosis. Graves disease is an autoimmune disorder associated with overactivity of the thyroid gland and hyperthyroidism. Multiple sclerosis is an autoimmune/inflammatory neurodegenerative disease which mainly affects young adults and is characterized by destruction of myelin in the central nervous system.
Interacts (via phosphorylated ITIM motifs) with phosphatases INPP5D, PTPN6 and PTPN11. Interacts (via ITIM motifs) SYK and ZAP70. Interacts with IZUMO1R/JUNO (PubMed:36070373). Interacts (via extracellular domain) with IZUMO1; the interaction replaces IZUMO1R/JUNO as IZUMO1 receptor after adhesion between sperm and egg (PubMed:36070373).
Phosphorylated on cytoplasmic tyrosines; required for interaction with protein tyrosine phosphatases and protein tyrosine kinases.
Primarily expressed in secondary lymphoid tissues by mature subsets of B-cells. Low expression on transitional B cells which increases to higher surface expression on mature and memory B-cells with innate-like features (at protein level) (PubMed:23857366). Expressed a low levels in naive and germinal center B-cells but also expressed in NK cells (at protein level) (PubMed:20190142). Expressed in unfertilized oocytes (at protein level) (PubMed:36070373). Expressed in a population of thymically derived naturally occurring regulatory T-cells that exhibits a memory phenotype, specialized in suppressing immune response to self-antigens (PubMed:20190142). Detected in spleen, lymph node, peripheral blood lymphocytes, thymus, bone marrow, kidney, salivary gland, adrenal gland and uterus.
Promotes TLR9-induced B-cell proliferation, activation and survival but inhibits antibody production and suppresses plasma cell differentiation. Enhances activation of NF-kappa-B and MAPK signaling pathways in TLR9 stimulated B-cells (PubMed:23857366). Has inhibitory potentional on B-cell receptor (BCR)-mediated signaling, possibly through association with SH2 domain-containing phosphatases. Inhibits cell tyrosine phosphorylation, calcium mobilization and activation-induced cell death induced through BCR signaling (PubMed:19843936). Regulatory T-cells expressing FCRL3 exhibit a memory phenotype, are relatively nonresponsive to antigenic stimulation in presence of IL2 and have reduced capacity to suppress the proliferation of effector T-cells (PubMed:20190142, PubMed:19494275). Acts as a human-specific epitope on the cell surface of oocytes (oolemma) and plays a role during sperm-egg adhesion and fusion (PubMed:36070373). Interacts with the IZUMO1-IZUMO1R/JUNO sperm-egg complex and replaces IZUMO1R/JUNO as IZUMO1 receptor during fertilization, thereby permitting species-specific gamete fusion (PubMed:36070373).
Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions (PubMed:7826387, PubMed:9041240, PubMed:10787414, PubMed:15337749, PubMed:16115875, PubMed:22554803, PubMed:31511694, PubMed:31126740, PubMed:32276275). Mechanistically, acts as a secondary active transporter, which exports intracellular organic anions down their concentration gradients to facilitate the uptake of its substrates (PubMed:22554803, PubMed:31511694, PubMed:31126740). Has high affinity for N5-methyltetrahydrofolate, the predominant circulating form of folate (PubMed:10787414, PubMed:14609557, PubMed:22554803). Also able to mediate the import of antifolate drug methotrexate (PubMed:7615551, PubMed:7641195, PubMed:9767079, PubMed:22554803). Also acts as an importer of immunoreactive cyclic dinucleotides, such as cyclic GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol, and its linkage isomer 3'-3'-cGAMP, thus playing a role in triggering larger immune responses (PubMed:31511694, PubMed:31126740). 5-amino-4-imidazolecarboxamide riboside (AICAR), when phosphorylated to AICAR monophosphate, can serve as an organic anion for antiporter activity (PubMed:22554803).
Belongs to the reduced folate carrier (RFC) transporter (TC 2.A.48) family.
Placenta, liver, and to a much smaller extent, in lung.
Constitutes the minor histocompatibility antigen HA-2. More generally, minor histocompatibility antigens (mHags) refer to immunogenic peptide which, when complexed with MHC, can generate an immune response after recognition by specific T-cells. The peptides are derived from polymorphic intracellular proteins, which are cleaved by normal pathways of antigen processing. The binding of these peptides to MHC class I or class II molecules and their expression on the cell surface can stimulate T-cell responses and thereby trigger graft rejection or graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation from HLA-identical sibling donor. GVHD is a frequent complication after bone marrow transplantation (BMT), due to mismatch of minor histocompatibility antigen in HLA-matched sibling marrow transplants. HA-2 is restricted to MHC class I HLA-A*0201.
Interacts with calmodulin; via its IQ motifs.
Specifically expressed in hematopoietic cells.
The myosin tail domain mediates binding to phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2), phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) and binds to membranous compartments. It is required for recruitment to Fc-gamma receptor (Fc-gamma-R) phagocytic cups.
Unconventional myosin required during immune response for detection of rare antigen-presenting cells by regulating T-cell migration. Unconventional myosins are actin-based motor molecules with ATPase activity and serve in intracellular movements. Acts as a regulator of T-cell migration by generating membrane tension, enforcing cell-intrinsic meandering search, thereby enhancing detection of rare antigens during lymph-node surveillance, enabling pathogen eradication. Also required in B-cells, where it regulates different membrane/cytoskeleton-dependent processes. Involved in Fc-gamma receptor (Fc-gamma-R) phagocytosis.
Activated by phosphorylation at Ser-218 by PDPK1. Autophosphorylated on Ser-377, as part of the activation process. May be phosphorylated at Thr-356 and Ser-360 by MAPK1/ERK2 and MAPK3/ERK1 (By similarity).
Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells. Transiently dissociates following mitogenic stimulation (By similarity). Interacts with FBXO5; cooperate to induce the metaphase arrest of early blastomeres; increases and stabilizes interaction of FBXO5 with CDC20 (By similarity).
N-terminal myristoylation results in an activated kinase in the absence of added growth factors.
Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of transcription factors, regulates translation, and mediates cellular proliferation, survival, and differentiation. May function as tumor suppressor in epithelial ovarian cancer cells.
Upon extracellular signal or mitogen stimulation, phosphorylated at Thr-570 in the C-terminal kinase domain (CTKD) by MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates Ser-377, allowing binding of PDPK1, which in turn phosphorylates Ser-218 in the N-terminal kinase domain (NTDK) leading to the full activation of the protein and subsequent phosphorylation of the substrates by the NTKD.
Widely expressed with higher expression in lung, skeletal muscle, brain, uterus, ovary, thyroid and prostate.
Interacts (via ARM domain) with MIRO1, MIRO2 and TRAK2. The interaction with Miro is calcium-dependent. Interacts with SOX10.
Regulates mitochondrial aggregation and transport in axons in living neurons. May link mitochondria to the TRAK2-kinesin motor complex via its interaction with Miro and TRAK2. Mitochondrial distribution and dynamics is regulated through ARMCX3 protein degradation, which is promoted by PCK and negatively regulated by WNT1. Enhances the SOX10-mediated transactivation of the neuronal acetylcholine receptor subunit alpha-3 and beta-4 subunit gene promoters.
The polymorphism is not associated with Axenfeld-Reiger syndrome (ARS), iridogoniodysgenesis syndrome (IGDS) or related ocular malformations.
Transcription factor, which is involved in craniofacial development, in odontogenesis and in stomach organogenesis. May have a role in the differentiation of molars from incisors. Plays a role in suppressing endodermal Wnt activity (By similarity). Binds to a regulatory module of the NCAM promoter.
Widely expressed. Expressed at higher levels in testis and heart. Detected in craniofacial tissue and adult iris, but not in lymphocytes, fibroblasts, choroid retina, retinal pigment epithelium, kidney, or fetal liver.
Component of the 2-(3-amino-3-carboxypropyl)histidine synthase complex composed of DPH1, DPH2, DPH3 and a NADH-dependent reductase (By similarity). Interacts with SERGEF (PubMed:14980502).
Required for the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2. DPH1 and DPH2 transfer a 3-amino-3-carboxypropyl (ACP) group from S-adenosyl-L-methionine (SAM) to a histidine residue, the reaction is assisted by a reduction system comprising DPH3 and a NADH-dependent reductase. Acts as an electron donor to reduce the Fe-S cluster in DPH1-DPH2 keeping the [4Fe-4S] clusters in the active and reduced state. Restores iron to DPH1-DPH2 iron-sulfur clusters which have degraded from [4Fe-4S] to [3Fe-4S] by donating an iron atom to reform [4Fe-4S] clusters, in a manner dependent on the presence of elongation factor 2 and SAM. Associates with the elongator complex and is required for tRNA Wobble base modifications mediated by the elongator complex. The elongator complex is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s 2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine).
The DPH-type metal-binding (MB) domain can also bind zinc. However, iron is the physiological binding partner as zinc binding impairs the protein electron donor function.
Widely expressed with highest levels in small intestine, spleen, thymus, heart, liver and lung.
Interacts with COPS5; regulates the phosphorylation of JUN and the transcriptional activity of AP-1 (PubMed:20978819). Interacts with RYBP; may prevent the ubiquitin-mediated proteasomal degradation of FANK1 (PubMed:27060496).
Polyubiquitinated. Polyubiquitination leads to proteasomal degradation.
The fibronectin type-III domain mediates interaction with COPS5 and RYBP.
Through the activation of JUN and AP-1-mediated transcription, may regulate apoptosis.
Belongs to the class I-like SAM-binding methyltransferase superfamily. MenG/UbiE family.
Component of a multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9. Interacts with PYURF; the interaction is direct, stabilizes COQ5 protein and associates PYURF with COQ enzyme complex (PubMed:35614220).
Methyltransferase required for the conversion of 2-polyprenyl-6-methoxy-1,4-benzoquinol (DDMQH2) to 2-polyprenyl-3-methyl-6-methoxy-1,4-benzoquinol (DMQH2).
Widely expressed, with highest levels in liver, lung, placenta and skeletal muscle.
Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism (PubMed:11788823, PubMed:12909640, PubMed:23661675, PubMed:25495645). Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake (By similarity). Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1 (PubMed:12097324, PubMed:19318355, PubMed:20581395). Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids (PubMed:17110602, PubMed:19028676). Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol (PubMed:12565906). Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By similarity). Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity (By similarity).
Expressed principally in liver. Weakly expressed in kidney. Binds to adipocytes. Increased expression and colocalization with activated ITGB3 in glomeruli of patients with nephrotic syndrome showing effaced podocyte foot processes (at protein level).
In part proteolytically cleaved by proprotein convertases; proposed to be involved in activation.
In vitro inhibits LPL activity; not effective on GPIHBP1-stabilized LPL.
Interacts with ANGPTL8. Interacts with ITGB3 (By similarity).
Involved in angiogenesis. Binds to endothelial cells via integrin alpha-V/beta-3 (ITGAV:ITGB3), activates FAK, MAPK and Akt signaling pathways and induces cell adhesion and cell migration (PubMed:11877390). Secreted from podocytes, may modulate properties of glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt signaling (PubMed:18535744). May increase the motility of podocytes. May induce actin filament rearrangements in podocytes implicating integrin alpha-V/beta-3 and Rac1 activation. Binds to hematopoietic stem cells (HSC) and is involved in the regulation of HSC activity probably implicating down-regulation of IKZF1/IKAROS (By similarity).
May be involved in atherosclerosis. Plasma levels are closely associated with arterial wall thickness.
O-glycosylated at Thr-226 by GALNT2; blocks processing and activation by proprotein convertases.
The fibrinogen C-terminal domain is sufficient to mediate endothelial cell adhesion.
Was suggested to inhibit LPL through a direct mechanism; however, the necessary concentration to achieve in vitro inhibition is at least 30-fold higher than ANGPTL3 plasma concentration.
Metallocarboxypeptidase that mediates protein deglutamylation of tubulin and non-tubulin target proteins. Catalyzes the removal of polyglutamate side chains present on the gamma-carboxyl group of glutamate residues within the C-terminal tail of tubulin protein. Specifically cleaves tubulin long-side-chains, while it is not able to remove the branching point glutamate. Also catalyzes the removal of polyglutamate residues from the carboxy-terminus of non-tubulin proteins such as MYLK. Mediates the deglutamylation of nucleotidyltransferase CGAS, leading to CGAS antiviral defense response activation (By similarity). Involved in KLF4 deglutamylation which promotes KLF4 proteasome-mediated degradation, thereby negatively regulating cell pluripotency maintenance and embryogenesis (PubMed:29593216).
Detected in breast, endometrium, colon and biliary tract. Detected in polarized epithelial structures characterized by cell-cell adhesion (at protein level).
May play a role in epithelial cell-cell contacts. May play a role in tumor invasiveness and metastasis formation.
O-glycosylated. The O-glycan is modified with sialic acid residues.
Adds a myristoyl group to the N-terminal glycine residue of certain cellular and viral proteins (PubMed:25255805, PubMed:9506952). Also able to mediate N-terminal lysine myristoylation of proteins: catalyzes myristoylation of ARF6 on both 'Gly-2' and 'Lys-3' (PubMed:32103017). Lysine myristoylation is required to maintain ARF6 on membranes during the GTPase cycle (PubMed:32103017).
Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins.
Sequence AAF36406.2 was incorrectly indicated as originating from bovine.
Acts as a synapse-to-nucleus messenger to promote NMDA receptor-mediated excitotoxicity in neurons in a JUN-dependent manner (By similarity). Inhibits ubiquitination-mediated degradation and promotes phosphorylation and transcriptional activity of transcription factor JUN (PubMed:27458189). Might play a redundant role in the regulation of T cell receptor signaling (PubMed:21460222). Might promote apoptosis in T cells (PubMed:21460222).
Forms a complex with NMDA receptor zeta subunit GRIN1 and epsilon subunit GRIN2B (PubMed:27458189). Interacts with GRIN1 and GRIN2B (PubMed:27458189). The interaction with GRIN1 is reduced upon NMDA receptor activity (By similarity). Found in a postsynaptic membrane complex with DLG4 and GRIN1 (By similarity). Interacts with DLG4 (via PDZ3 domain and to lesser degree via PDZ2 domain) (By similarity). Found in a complex with JUN and FBXW7 (PubMed:27458189). Interacts with JUN and FBXW7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (PubMed:27458189). Interacts with SRC (PubMed:21460222).
Strongly expressed in brain tissue including the hippocampus, and moderately expressed in esophagus, trachea, lung, ovary, cervix, prostate, testes, thyroid, thymus, lymph nodes and peripheral blood lymphocytes.
Tyrosine phosphorylated, possibly by SRC.
Up-regulated in peripheral blood leukocytes in response to T-cell receptor stimulation.
As a component of the GATOR2 complex, functions as an activator of the amino acid-sensing branch of the mTORC1 signaling pathway (PubMed:25457612, PubMed:23723238, PubMed:27487210, PubMed:36528027, PubMed:35831510). The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex (PubMed:23723238, PubMed:27487210, PubMed:36528027, PubMed:35831510). GATOR2 probably acts as a E3 ubiquitin-protein ligase toward GATOR1 (PubMed:36528027). In the presence of abundant amino acids, the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027). In the absence of amino acids, GATOR2 is inhibited, activating the GATOR1 complex (PubMed:25457612, PubMed:26972053, PubMed:27487210). Within the GATOR2 complex, SEC13 and SEH1L are required to stabilize the complex (PubMed:35831510).
At the nuclear pore: component of the Y-shaped Nup107-160 subcomplex of the nuclear pore complex (NPC) (PubMed:14517296, PubMed:18160040, PubMed:36528027, PubMed:35831510). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13 (PubMed:18160040). At the COPII coat complex: interacts with SEC31A and SEC31B (PubMed:16495487, PubMed:16957052). Interacts with SEC16A (PubMed:17428803, PubMed:19638414, PubMed:25201882). Interacts with SEC16B (PubMed:22355596). Component of the GATOR2 subcomplex, composed of MIOS, SEC13, SEH1L, WDR24 and WDR59 (PubMed:23723238). The GATOR2 complex interacts with CASTOR1 and CASTOR2; the interaction is negatively regulated by arginine (PubMed:26972053). The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612).
Functions as a component of the nuclear pore complex (NPC) and the COPII coat (PubMed:8972206). At the endoplasmic reticulum, SEC13 is involved in the biogenesis of COPII-coated vesicles (PubMed:8972206). Required for the exit of adipsin (CFD/ADN), an adipocyte-secreted protein from the endoplasmic reticulum (By similarity).
Expression in colon is increased in Crohn's disease and human ulcerative colitis (at protein level).
Glycosylated. Glycosylation affects the expression levels.
Inhibited by emetine, quinidine and verapamil. The IC(50) of emetine is 4.2 uM. Not inhibited by valproic acid (PubMed:10966938). Transport of (R)-carnitine is stimulated by cholesterol in the plasma membrane (PubMed:33334877).
Intestinal expression is induced by IFNG.
Retained in the ER, unable to perform carnitine uptake.
Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine (PubMed:10454528, PubMed:10525100, PubMed:10966938, PubMed:17509700, PubMed:20722056, PubMed:33124720). Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Relative uptake activity ratio of carnitine to TEA is 11.3 (PubMed:10454528, PubMed:10525100, PubMed:10966938). In intestinal epithelia, transports the quorum-sensing pentapeptide CSF (competence and sporulation factor) from Bacillus Subtilis wich induces cytoprotective heat shock proteins contributing to intestinal homeostasis (PubMed:18005709). May also contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable).
Strongly expressed in kidney, skeletal muscle, heart and placenta (PubMed:10454528). Primarily expressed by surface epithelial cells of the colon (at protein level) (PubMed:18005709). Expressed in CD68 macrophage and CD43 T-cells but not in CD20 B-cells (PubMed:10454528). In testis, localized to Sertoli cell basal membranes, peritubular myoid cells and Leydig cells (PubMed:35307651).
IGF-binding proteins prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cell culture. They alter the interaction of IGFs with their cell surface receptors. Activates the MAPK signaling pathway and induces cell migration (PubMed:24003225).
Interacts (via C-terminal domain) with PHB2.
O-linked glycans consist of hexose (probably Gal), N-acetylhexosamine (probably GalNAc) and sialic acid residues. O-glycosylated with core 1 or possibly core 8 glycans. O-glycosylated on one site only in the region AA 143-168 in cerebrospinal fluid.
(Microbial infection) In case of infection by HIV-1 virus, recruited to HIV-1 RNA and catalyzes 2'-O-methylation of the viral genome, allowing HIV-1 virus to escape the innate immune system (PubMed:30626973). RNA 2'-O-methylation provides a molecular signature for discrimination of self from non-self and is used by HIV-1 to evade innate immune recognition by IFIH1/MDA5 (PubMed:30626973). Mediates methylation of internal residues of HIV-1 RNA, with a strong preference for adenosine (PubMed:30626973). Recruited to HIV-1 RNA via interaction with TARBP2/TRBP (PubMed:30626973).
(Microbial infection) Interacts with TARBP2/TRBP in case of infection by HIV-1; leading to recruitment to HIV-1 TAR RNA (PubMed:30626973). The complex formed with TARBP2/TRBP is independent of DICER (PubMed:30626973).
Belongs to the class I-like SAM-binding methyltransferase superfamily. RNA methyltransferase RlmE family. SPB1 subfamily.
RNA 2'-O-methyltransferase involved in the processing of the 34S pre-rRNA to 18S rRNA and in 40S ribosomal subunit formation.
Substrate-recognition subunit of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1 (Probable) (PubMed:29911972). Binds proteins and peptides with a Pro/N-degron consisting of an unmodified N-terminal Pro followed by a small residue, and has the highest affinity for the peptide Pro-Gly-Leu-Trp (PubMed:29632410). Binds peptides with an N-terminal sequence of the type Pro-[Ala,Gly]-[Leu,Met,Gln,Ser,Tyr]-[Glu,Gly,His,Ser,Val,Trp,Tyr]. Does not bind peptides with an acetylated N-terminal Pro residue (PubMed:29632410).
The first four residues of target peptides with a free N-terminal Pro (a Pro/N-degron) are bound inside a deep and narrow beta-barrel structure.
Widely expressed with highest levels in spinal cord, brain, heart and bone marrow. Also expressed in fetal brain and liver.
Catalyzes the synthesis of lactosylceramide (LacCer) via the transfer of galactose from UDP-galactose to glucosylceramide (GlcCer) (PubMed:3099851, PubMed:1551920, PubMed:24498430). LacCer is the starting point in the biosynthesis of all gangliosides (membrane-bound glycosphingolipids) which play pivotal roles in the CNS including neuronal maturation and axonal and myelin formation (By similarity).
High expression in brain and adrenal gland, lower in liver, lung, colon and peripheral white blood cells.
Oxidizes the CoA esters of the bile acid intermediates di- and tri-hydroxycholestanoic acids (PubMed:27884763). Capable of oxidizing short as well as long chain 2-methyl branched fatty acids (By similarity).
Present in all tissues tested: heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Most abundant in heart, liver and kidney.
Arg-105 is dimethylated, probably to asymmetric dimethylarginine.
Cold-inducible mRNA binding protein that enhances global protein synthesis at both physiological and mild hypothermic temperatures. Reduces the relative abundance of microRNAs, when overexpressed. Enhances phosphorylation of translation initiation factors and active polysome formation (By similarity).
Interacts with RPL4. Associates with the 60S ribosomal subunits in an RNA-independent manner. Associates with ribosomes (By similarity).
Exhibits ester hydrolase activity on the substrate p-nitrophenyl acetate.
Cadherins are calcium-dependent cell adhesion proteins (By similarity). They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types (PubMed:21269602). This cadherin may play a important role in endothelial cell biology through control of the cohesion and organization of the intercellular junctions (By similarity). It associates with alpha-catenin forming a link to the cytoskeleton (PubMed:10861224). Acts in concert with KRIT1 and PALS1 to establish and maintain correct endothelial cell polarity and vascular lumen (By similarity). These effects are mediated by recruitment and activation of the Par polarity complex and RAP1B (PubMed:20332120). Required for activation of PRKCZ and for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction (PubMed:20332120).
Interacts (via cadherin 5 domain) with PTPRB (By similarity). Interacts with TRPC4 (PubMed:19996314). Interacts with KRIT1 (PubMed:20332120). Interacts with PARD3 (By similarity). Interacts with RTN4 (isoform B) (PubMed:21183689). Interacts with PALS1; the interaction promotes PALS1 localization to cell junctions and is required for CDH5-mediated vascular lumen formation and endothelial cell (PubMed:27466317).
Phosphorylated on tyrosine residues by KDR/VEGFR-2. Dephosphorylated by PTPRB (By similarity).
Expressed in heart, adrenal gland, testis, liver, brain and fetal brain. Not expressed in pancreas.
Glycosyltransferase that participates in the transfer of N-acetylglucosamine (GlcNAc) to the core mannose residues of N-linked glycans. Catalyzes the formation of the GlcNAcbeta1-4 branch on the GlcNAcbeta1-2Manalpha1-3 arm of the core structure of N-linked glycans. Essential for the production of tri- and tetra-antennary N-linked sugar chains (By similarity). Does not catalyze the transfer of GlcNAc to the Manalpha1-6 arm to form GlcNAcBeta1-4Manalpha1-6 linkage ('GnT-VI' activity).
Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed to be not involved in catalysis. Required for proper complex I assembly (PubMed:30245030). Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.
Shares weak sequence similarity with the cyclin family, hence its name. However, it has no cyclin-like function in vivo.
Widely expressed. Expressed in adult and fetal heart, brain, lung, liver, skeletal muscle and kidney. Expressed in adult pancreas and placenta and in fetal spleen abd thymus. Expressed at intermediate level in pancreas, placenta and brain but low in skeletal muscle and lung.
Transcription factor that binds specifically to the DRE (dual repressor element) and represses HTR1A gene transcription in neuronal cells.
Widely distributed in brain and peripheral tissues.
Farnesylation mediates presynaptic targeting and is important for function in neurotransmitter release.
Weakly binds to the SNARE core complex containing SNAP25, VAMP2 and STX1A.
A cytochrome P450 monooxygenase that may play a role in retinoid and phospholipid metabolism (PubMed:22591743, PubMed:26936974). Catalyzes the hydroxylation of saturated carbon hydrogen bonds. Hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may regulate atRA clearance. Other retinoids such as all-trans retinol and all-trans retinal are potential endogenous substrates (PubMed:26936974). Catalyzes both epoxidation of double bonds and hydroxylation of carbon hydrogen bonds of the fatty acyl chain of 1-acylphospholipids/2-lysophospholipids. Can metabolize various lysophospholipids classes including lysophosphatidylcholines (LPCs), lysophosphatidylinositols (LPIs), lysophosphatidylserines (LPSs), lysophosphatidylglycerols (LPGs), lysophosphatidylethanolamines (LPEs) and lysophosphatidic acids (LPAs) (PubMed:22591743). Has low or no activity toward 2-acylphospholipids/1-lysophospholipids, diacylphospholipids and free fatty acids (PubMed:26936974, PubMed:22591743). May play a role in tumorigenesis by activating procarcinogens such as aflatoxin B1, polycyclic aromatic hydrocarbon dihydrodiols and aromatic amines (PubMed:20805301, PubMed:16551781, PubMed:24278521). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:22591743, PubMed:26936974).
Very low levels are detected in fetal and adult tissues. Highly expressed in several tumor samples, in particular colon and adrenal tumors.
Detected in placenta, colon, liver and skin. Detected at very low levels in most tissues.
Has no ubiquitin ligase activity on its own. The UBE2V2/UBE2N heterodimer catalyzes the synthesis of non-canonical poly-ubiquitin chains that are linked through 'Lys-63'. This type of poly-ubiquitination does not lead to protein degradation by the proteasome. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage.
Up-regulated in cultured fresh blood cells upon treatment with vitamin D3.
Exhibits weak E3 ubiquitin-protein ligase activity (PubMed:18591963, PubMed:19407830, PubMed:22410793). E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates (PubMed:18591963, PubMed:19407830, PubMed:22410793). Can ubiquitinate AKT1 preferentially at 'Lys-284' involving 'Lys-48'-linked polyubiquitination and seems to be involved in regulation of Akt signaling by targeting phosphorylated Akt to proteasomal degradation (PubMed:22410793). Mediates polyubiquitination of cytoplasmic TP53 at 'Lys-24' which targets TP53 for proteasomal degradation, thus reducing TP53 levels in the cytoplasm and mitochondrion (PubMed:21597459). Proposed to preferentially act as a SUMO E3 ligase at physiological concentrations (PubMed:19407830). Plays a role in the control of mitochondrial morphology by promoting mitochondrial fragmentation, and influences mitochondrial localization (PubMed:19407830, PubMed:18207745, PubMed:18213395). Likely to promote mitochondrial fission through negatively regulating the mitochondrial fusion proteins MFN1 and MFN2, acting in a pathway that is parallel to the PRKN/PINK1 regulatory pathway (PubMed:24898855). May also be involved in the sumoylation of the membrane fission protein DNM1L (PubMed:18207745, PubMed:19407830). Inhibits cell growth (PubMed:18591963, PubMed:22410793). When overexpressed, activates JNK through MAP3K7/TAK1 and induces caspase-dependent apoptosis (PubMed:23399697). Involved in the modulation of innate immune defense against viruses by inhibiting RIGI-dependent antiviral response (PubMed:23399697). Can mediate RIGI sumoylation and disrupt its polyubiquitination (PubMed:23399697).
Homooligomer (PubMed:18591963). Interacts with MAP3K7/TAK1 (PubMed:18591963). Interacts with UBC9 (PubMed:19407830). Interacts with and sumoylates DNM1L (PubMed:19407830). Interacts with MAVS (PubMed:23399697). Interacts with TP53 (via N-terminus); the interaction leads to ubiquitination and proteasomal degradation of TP53 (PubMed:21597459).
The zinc finger domain is required for E3 ligase activity.
Widely expressed with highest levels in the heart, skeletal muscle, placenta, kidney and liver. Barely detectable in colon and thymus.
Cobalamin (vitamin B12) cytosolic chaperone that catalyzes the reductive decyanation of cyanocob(III)alamin (cyanocobalamin, CNCbl) to yield cob(II)alamin and cyanide, using FAD or FMN as cofactors and NADPH as cosubstrate (PubMed:18779575, PubMed:19700356, PubMed:21697092, PubMed:25809485). Cyanocobalamin constitutes the inactive form of vitamin B12 introduced from the diet, and is converted into the active cofactors methylcobalamin (MeCbl) involved in methionine biosynthesis, and 5'-deoxyadenosylcobalamin (AdoCbl) involved in the TCA cycle (PubMed:19801555). Forms a complex with the lysosomal transporter ABCD4 and its chaperone LMBRD1, to transport cobalamin across the lysosomal membrane into the cytosol (PubMed:25535791). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR (methionine synthase) which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (PubMed:21071249, PubMed:27771510). Also acts as a glutathione transferase by catalyzing the dealkylation of the alkylcob(III)alamins MeCbl and AdoCbl, using the thiolate of glutathione for nucleophilic displacement to generate cob(I)alamin and the corresponding glutathione thioether (PubMed:19801555, PubMed:21697092, PubMed:22642810, PubMed:25809485). The conversion of incoming MeCbl or AdoCbl into a common intermediate cob(I)alamin is necessary to meet the cellular needs for both cofactors (PubMed:19801555). Cysteine and homocysteine cannot substitute for glutathione in this reaction (PubMed:19801555).
Monomer in the absence of bound substrate (PubMed:21697092, PubMed:22642810). Homodimer; dimerization is triggered by binding to FMN or adenosylcobalamin (PubMed:22642810). Interacts with LMBRD1 and ABCD4; the interaction ensures the transport of cobalamin from the lysosome to the cytoplasm (PubMed:25535791). Forms a multiprotein complex with MMADHC, MTR and MTRR; the interaction with MTR could modulate MMACHC-dependent processing of cobalamin (PubMed:27771510). Heterodimer with MMADHC; the interaction might play a role in the regulation of the balance between AdoCbl and MeCbl synthesis (PubMed:21071249, PubMed:23415655, PubMed:26483544).
Widely expressed. Expressed at higher level in fetal liver. Also expressed in spleen, lymph node, thymus and bone marrow. Weakly or not expressed in peripheral blood leukocytes.
Widely expressed (PubMed:11401430). Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas (PubMed:11401430).
Zinc phosphodiesterase, which displays some tRNA 3'-processing endonuclease activity (PubMed:12711671, PubMed:32075755). Specifically involved in tRNA repair: acts downstream of the ribosome-associated quality control (RQC) pathway by removing a 2',3'-cyclic phosphate from tRNAs following cleavage by ANKZF1 (PubMed:32075755). tRNAs are then processed by TRNT1 (PubMed:32075755).
Homodimer. Dimerization is mediated by the extracellular domain and is independent of SLIT liganding (PubMed:24673457). Interacts with SLIT1 (By similarity). Interacts with SLIT2 (PubMed:10102268, PubMed:11404413, PubMed:17848514). Interacts with FLRT3 (PubMed:24560577). Interacts with MYO9B (via Rho-GAP domain) (PubMed:26529257).
Maps within a region of overlapping homozygous deletions characterized in both small cell lung cancer cell lines (SCLC) and in a breast cancer cell line. The promoter region of ROBO1 shows complete hypermethylation of CpG sites in the BT-20 breast tumor cell lines, some primary invasive breast carcinomasa and some primary clear cell renal cell carcinomas (CC-RCC).
Receptor for SLIT1 and SLIT2 that mediates cellular responses to molecular guidance cues in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development (PubMed:10102268, PubMed:24560577). Interaction with the intracellular domain of FLRT3 mediates axon attraction towards cells expressing NTN1 (PubMed:24560577). In axon growth cones, the silencing of the attractive effect of NTN1 by SLIT2 may require the formation of a ROBO1-DCC complex (By similarity). Plays a role in the regulation of cell migration via its interaction with MYO9B; inhibits MYO9B-mediated stimulation of RHOA GTPase activity, and thereby leads to increased levels of active, GTP-bound RHOA (PubMed:26529257). May be required for lung development (By similarity).
Ubiquitinated. May be deubiquitinated by USP33.
Widely expressed, with exception of kidney.
Binds medium- and long-chain acyl-CoA esters with very high affinity and may function as an intracellular carrier of acyl-CoA esters. It is also able to displace diazepam from the benzodiazepine (BZD) recognition site located on the GABA type A receptor. It is therefore possible that this protein also acts as a neuropeptide to modulate the action of the GABA receptor.
Isoform 1 is ubiquitous, with a moderate expression level. Isoform 2 is ubiquitous with high level in liver and adipose tissue. Isoform 3 is ubiquitous with strong expression in adipose tissue and heart.
Predominantly expressed in adipose tissue and hippocampus.
Belongs to the liprin family. Liprin-beta subfamily.
Forms homodimers and heterodimers. Interacts with S100A4 in a calcium-dependent mode.
May regulate the disassembly of focal adhesions. Did not bind receptor-like tyrosine phosphatases type 2A.
The N-terminal coiled coil regions mediate homodimerization preferentially and heterodimerization type beta/beta. The C-terminal, non-coiled coil regions mediate heterodimerization type beta/alpha and interaction with S100A4.
Affects the rate of fibrils formation. May have a primary role in collagen fibrillogenesis (By similarity).
Interacts with GORAB. Interacts with COPA, COPB1 and COPB2 (By similarity). Homooligomer. Interacts with AP2B1.
Isoform 6 acts as transcriptional activator. It binds to three different types of GC-rich DNA binding sites (box-A, -B and -C) in the beta-polymerase promoter region. It also binds to the TERT promoter region.
Regulates COPI-mediated retrograde protein traffic at the interface between the Golgi apparatus and the endoplasmic reticulum (PubMed:18556652). Involved in the maintenance of the Golgi apparatus morphology (PubMed:26581903). Has no detectable kinase activity in vitro (PubMed:18556652).
Although transmembrane domains are strongly predicted, they may rather represent hydrophobic globular domains associated with microtubules.
Homodimer. Interacts with ODF1. May associate with microtubules (By similarity). Interacts with SUN3 and SYNE1; suggesting the formation of a spermatogenesis-specific LINC complex; a SUN domain-based heterotrimer with SUN3 may associate with SYNE1 (By similarity). Interacts with SEPT12 and LMNB1; during spermatogenesis (PubMed:25775403).
Involved in spermatogenesis. Required for sperm head formation but not required to establish and maintain general polarity of the sperm head. Required for anchoring and organization of the manchette. Required for targeting of SUN3 and probably SYNE1 through a probable SUN1:SYNE3 LINC complex to the nuclear envelope and involved in accurate posterior sperm head localization of the complex. May anchor SUN3 the nuclear envelope. Involved in maintenance of the nuclear envelope integrity. May assist the organization and assembly of outer dense fibers (ODFs), a specific structure of the sperm tail.
Predominantly epressed in testis. Expressed in ejaculated spermatozoa (at protein level).
P0 forms a pentameric complex by interaction with dimers of P1 and P2 (PubMed:3323886). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Interacts with APEX1 (PubMed:19188445). Interacts with FMR1 isoform 6 (PubMed:24658146).
Ribosomal protein P0 is the functional equivalent of E.coli protein L10.
Ubiquitinated at Lys-264 by RNF14 and RNF25 in response to ribosome collisions (ribosome stalling).
A chromosomal aberration involving COL1A1 is found in dermatofibrosarcoma protuberans. Translocation t(17;22)(q22;q13) with PDGF.
Contains 3-hydroxyproline at a few sites. This modification occurs on the first proline residue in the sequence motif Gly-Pro-Hyp, where Hyp is 4-hydroxyproline.
Contains mostly 4-hydroxyproline. Proline residues at the third position of the tripeptide repeating unit (G-X-Y) are hydroxylated in some or all of the chains.
Forms the fibrils of tendon, ligaments and bones. In bones the fibrils are mineralized with calcium hydroxyapatite.
Lysine residues at the third position of the tripeptide repeating unit (G-X-Y) are 5-hydroxylated in some or all of the chains.
O-glycosylated on hydroxylated lysine residues. The O-linked glycan consists of a Glc-Gal disaccharide.
Trimers of one alpha 2(I) and two alpha 1(I) chains. Interacts with MRC2 (By similarity). Interacts with TRAM2 (PubMed:14749390). Interacts with MFAP4 in a Ca (2+)-dependent manner (By similarity).
Type I collagen is a member of group I collagen (fibrillar forming collagen).
Belongs to the paired-like homeobox family. PEPP subfamily.
Expressed in testis, mainly expressed in germ cells, but also detected in somatic cells such as Sertoli cells, Leydig cells and peritubular cells.
Predominantly expressed in early stage germ cells, type-B spermatogonia and early spermatocytes.
RHOF2 and RHOF2B are arranged in a head-to-head orientation and share high sequence similarity (>99%). They cannot easily be distinguished and are usually analyzed as a single gene.
Transcription factor maybe involved in reproductive processes. Modulates expression of target genes encoding proteins involved in processes relevant to spermatogenesis.
Autoregulated by feedback control of mRNA degradation (PubMed:31727855). In excess of soluble tubulin, TTC5/STRAP cofactor triggers co-translation degradation of tubulin mRNA (PubMed:31727855).
Dimer of alpha and beta chains (PubMed:17563362, PubMed:34996871, PubMed:35482892). A typical microtubule is a hollow water-filled tube with an outer diameter of 25 nm and an inner diameter of 15 nM (PubMed:34996871, PubMed:35482892). Alpha-beta heterodimers associate head-to-tail to form protofilaments running lengthwise along the microtubule wall with the beta-tubulin subunit facing the microtubule plus end conferring a structural polarity (PubMed:34996871, PubMed:35482892). Microtubules usually have 13 protofilaments but different protofilament numbers can be found in some organisms and specialized cells (PubMed:34996871, PubMed:35482892). Nascent tubulin polypeptide interacts (via beta-tubulin MREC motif) with TTC5/STRAP; this interaction may result in tubulin mRNA-targeted degradation (PubMed:31727855).
Nitration of Tyr-451 is irreversible and interferes with normal dynein intracellular distribution.
The MREC motif mediates interaction with TTC5/STRAP and may be critical for tubulin autoregulation.
Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers (PubMed:34996871). Microtubules grow by the addition of GTP-tubulin dimers to the microtubule end, where a stabilizing cap forms (PubMed:34996871). Below the cap, tubulin dimers are in GDP-bound state, owing to GTPase activity of alpha-tubulin (PubMed:34996871).
Highly expressed in liver. Detected at lower levels in colon, ileum and jejunum.
May play a role in protein trafficking. May act as a linker molecule between the submembranous matrix on the luminal side of zymogen granule membrane (ZGM) and aggregated secretory proteins during granule formation in the TGN.
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:7574697, PubMed:15766564, PubMed:19965576). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316).
Alternative splicing has been shown to occur but the shorter forms are believed to be non-functional.
Several alleles are found in the human population, contributing to interindividual variations in the therapeutic efficacy and toxicity of a myriad of drugs such as paclitaxel or amodiaquine. The allele shown here is CYP2C8*1 (PubMed:26427316). CYP2C8 genetic variations are associated with altered drug metabolism and adverse drug effects including acute rhabdomyolysis after cerivastatin use [MIM:618018].
Acetylated mainly by p300/CBP, recruited to the complex by CPSF6. Acetylation decreases interaction with PAPAO. Deacetylated by the class I/II HDACs, HDAC1, HDAC3 and HDAC10, and by the class III HDACs, SIRT1 and SIRT2.
Belongs to the Nudix hydrolase family. CPSF5 subfamily.
Component of the cleavage factor Im (CFIm) complex that functions as an activator of the pre-mRNA 3'-end cleavage and polyadenylation processing required for the maturation of pre-mRNA into functional mRNAs (PubMed:9659921, PubMed:8626397, PubMed:14690600, PubMed:15937220, PubMed:17024186, PubMed:17098938, PubMed:29276085). CFIm contributes to the recruitment of multiprotein complexes on specific sequences on the pre-mRNA 3'-end, so called cleavage and polyadenylation signals (pA signals) (PubMed:9659921, PubMed:8626397, PubMed:14690600, PubMed:17024186). Most pre-mRNAs contain multiple pA signals, resulting in alternative cleavage and polyadenylation (APA) producing mRNAs with variable 3'-end formation (PubMed:17098938, PubMed:23187700, PubMed:29276085). The CFIm complex acts as a key regulator of cleavage and polyadenylation site choice during APA through its binding to 5'-UGUA-3' elements localized in the 3'-untranslated region (UTR) for a huge number of pre-mRNAs (PubMed:17098938, PubMed:20695905, PubMed:29276085). NUDT21/CPSF5 activates indirectly the mRNA 3'-processing machinery by recruiting CPSF6 and/or CPSF7 (PubMed:29276085). Binds to 5'-UGUA-3' elements localized upstream of pA signals that act as enhancers of pre-mRNA 3'-end processing (PubMed:8626397, PubMed:14690600, PubMed:15169763, PubMed:17024186, PubMed:22813749, PubMed:20479262). The homodimer mediates simultaneous sequence-specific recognition of two 5'-UGUA-3' elements within the pre-mRNA (PubMed:20479262, PubMed:21295486). Plays a role in somatic cell fate transitions and pluripotency by regulating widespread changes in gene expression through an APA-dependent function (By similarity). Binds to chromatin (By similarity). Binds to, but does not hydrolyze mono- and di-adenosine nucleotides (PubMed:18445629).
Homodimer (via N- and C-terminus); binds RNA as homodimer (PubMed:20695905, PubMed:18445629, PubMed:20479262). Component of the cleavage factor Im (CFIm) complex which is a heterotetramer composed of two subunits of NUDT21/CPSF5 and two subunits of CPSF6 or CPSF7 or a heterodimer of CPSF6 and CPSF7 (PubMed:9659921, PubMed:8626397, PubMed:14561889, PubMed:20695905, PubMed:23187700, PubMed:21295486). The cleavage factor Im (CFIm) complex associates with the CPSF and CSTF complexes to promote the assembly of the core mRNA 3'-processing machinery (PubMed:29276085). Interacts with CPSF6 (via the RRM domain); this interaction is direct and enhances binding to RNA (PubMed:14561889, PubMed:15169763, PubMed:17172643, PubMed:19864460, PubMed:29276085). Interacts with CPSF7 (PubMed:29276085, Ref.30). Interacts with FIP1L1; this interaction occurs in a RNA sequence-specific manner (PubMed:15937220). Interacts with PABPN1 (PubMed:15169763). Interacts (via N-terminus) with PAPOLA (via C-terminus); this interaction is direct and diminished by acetylation (PubMed:15169763, PubMed:17172643). Interacts with SNRNP70 (PubMed:14561889). Interacts with VIRMA (PubMed:29507755).
Lacks the conserved metal-binding residues in the NUDIX motif and does not have hydrolase activity.
Divalent metal cations; Mn(2+) or Mg(2+). Activity higher in presence of Mn(2+) than of Mg(2+). Binds 1 Mg(2+) or Mn(2+) ion per subunit.
Heterooligomer of subunits alpha (IDH3A), beta (IDH3B), and gamma (IDH3G) in the apparent ratio of 2:1:1. The heterodimer containing one IDH3A and one IDH3B subunit and the heterodimer containing one IDH3A and one IDH3G subunit assemble into a heterotetramer (which contains two subunits of IDH3A, one of IDH3B and one of IDH3G) and further into the heterooctamer.
Regulatory subunit which plays a role in the allosteric regulation of the enzyme catalyzing the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate. The heterodimer composed of the alpha (IDH3A) and beta (IDH3B) subunits and the heterodimer composed of the alpha (IDH3A) and gamma (IDH3G) subunits, have considerable basal activity but the full activity of the heterotetramer (containing two subunits of IDH3A, one of IDH3B and one of IDH3G) requires the assembly and cooperative function of both heterodimers.
The heterotetramer and the heterodimer composed of IDH3A and IDH3G subunits can be allosterically activated by citrate (CIT) or/and ADP, and the two activators can act independently or synergistically. The heterodimer composed of IDH3A and IDH3B subunits cannot be allosterically regulated and the allosteric regulation of the heterotetramer is through the IDH3G subunit and not the IDH3B subunit. The IDH3G subunit contains the allosteric site which consists of a CIT-binding site and an ADP-binding site, and the binding of CIT and ADP causes conformational changes at the allosteric site which are transmitted to the active site in the catalytic subunit (IDH3A) through a cascade of conformational changes at the heterodimer interface, leading to stabilization of the isocitrate-binding at the active site and thus activation of the enzyme. ATP can activate the heterotetramer and the heterodimer composed of IDH3A and IDH3G subunits at low concentrations but inhibits their activities at high concentrations, whereas ATP exhibits only inhibitory effect on the heterodimer composed of IDH3A and IDH3B subunits.
Isoform 1 is expressed at high level in brain, skeletal muscle, testis, bone, calvaria, osteoblasts and leukocytes. Expressed at intermediate level in liver, heart, kidney and spleen. Expressed at low level in lung, pancreas, placenta and ovary. Not detected in thymus, prostate, small intestine, tongue and colon. Isoform 1 and isoform 2 are expressed in kidney at the same level. Isoform 2 is expressed at lower level than isoform 1 in the other tissues.
Receptor activated by multiple ligands, including osteocalcin (BGLAP), basic amino acids, and various cations (PubMed:15576628). Activated by amino acids with a preference for basic amino acids such as L-Lys, L-Arg and L-ornithine but also by small and polar amino acids (PubMed:15576628). The L-alpha amino acids respond is augmented by divalent cations Ca(2+) and Mg(2+) (By similarity). Seems to act through a G(q)/G(11) and G(i)-coupled pathway (By similarity). Regulates testosterone production by acting as a ligand for uncarboxylated osteocalcin hormone: osteocalcin-binding at the surface of Leydig cells initiates a signaling response that promotes the expression of enzymes required for testosterone synthesis in a CREB-dependent manner (By similarity). Mediates the non-genomic effects of androgens in multiple tissue (By similarity). May coordinate nutritional and hormonal anabolic signals through the sensing of extracellular amino acids, osteocalcin, divalent ions and its responsiveness to anabolic steroids (PubMed:20947496).
Component of the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1 (PubMed:26300262). Heterodimer consisting of MSH2-MSH6 (MutS alpha) (PubMed:8942985, PubMed:7604264). Forms a ternary complex with MutL alpha (MLH1-PMS1). Interacts with MCM9 (PubMed:26300262). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex (PubMed:10783165). This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains (PubMed:10783165).
Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs, and recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. After mismatch binding, forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair. Recruited on chromatin in G1 and early S phase via its PWWP domain that specifically binds trimethylated 'Lys-36' of histone H3 (H3K36me3): early recruitment to chromatin to be replicated allowing a quick identification of mismatch repair to initiate the DNA mismatch repair reaction.
Phosphorylated by PRKCZ, which may prevent MutS alpha degradation by the ubiquitin-proteasome pathway.
The PWWP domain specifically recognizes and binds trimethylated 'Lys-36' of histone H3 (H3K36me3).
Detected in natural killer cells (at protein level). Highest level expression seen in spleen and peripheral blood leukocytes and is also expressed at high levels in thymus, colon and placenta, suggesting preferential expression in hematopoietic tissues.
Homodimer. Interacts with BIN1. Interacts with ARHGEF6 (via SH3 domain), ARHGEF7 (via SH3 domain), SH3GL1, SH3GL2 and SH3GL3. Identified in a complex with ARHGEF6 and GIT2.
Promotes cell motility and migration, probably via its interaction with the cell membrane and with podosome proteins that mediate interaction with the cytoskeleton. Modulates membrane curvature and mediates membrane tubulation. Plays a role in podosome formation. Inhibits phagocytosis.
The BAR domain mediates dimerization and interaction with membranes enriched in phosphatidylinositides.
Up-regulated during monocytic differentiation.
Riboflavin transporter localized at the inner mitochondrial membrane of the spermatozoa midpiece, which is required for male fertility (By similarity). SLC22A14-mediated riboflavin transport is essential for spermatozoa energy generation and motility: riboflavin is the precursor of FMN and FAD, which are coenzymes of many enzymes in the TCA cycle (the citric acid cycle) in mitochondria (By similarity). Required for sperm motility and normal sperm flagellar structure (By similarity).
Heterodimer of CALCRL and RAMP3 (By similarity). Heterodimer of CALCRL and RAMP1 or CALCRL and RAMP2.
Predominantly expressed in the lung and heart.
Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3 (By similarity). Receptor for adrenomedullin together with RAMP2 (PubMed:22102369, PubMed:30115739). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase (PubMed:22102369, PubMed:30115739).
Contains 24 transmembrane helices (TM) that form four homologous functional repeats connected by intracellular linkers. Each of the four internal repeats contains five hydrophobic transmembrane segments (S1, S2, S3, S5, S6) and one positively charged transmembrane segment (S4). S4 segments represent the voltage-sensor. S4 transmembrane segments lack some of the charged residues (K and R) found at every third position in the S4s of the NaV, CaV, and KV channels. Pore-forming loops (P loops) between S5 and S6 of each domain form an EEKE sodium- ion selectivity filter a mixture between the EEEE found in the CaVs and the DEKA of NaVs. Voltage-sensing domains (VSDs), formed by S1 to S4 of each domain, detect changes in membrane potential and induce the opening or closing of the ion-conducting pore domain, formed by S5 and S6.
Found in a complex with NALCN, UNC79, UNC80 and NACL1; these auxiliary subunits are indispensable for the function of NALCN channel (PubMed:32494638, PubMed:32698188, PubMed:33203861). Interacts with UNC80; required for the NALCN activation/inhibition by GPCRs in neurons. Found in a complex with NALCN, UNC79 and UNC80; UNC80 bridges NALCN to UNC79 (By similarity). Interacts with CHRM3 (By similarity).
Inhibited by low micromolar concentrations of Gd(3+) and high micromolar concentrations of verapamil. Insensitive to tetrodotoxin (TTX) and potentiated by low external Ca(2+) concentration.
NALCN was also originally reported to be a voltage-independent, cation-nonselective channel which is permeable to sodium, potassium and calcium ions (PubMed:17448995). However, NALCN is recently reported to be selective only for monovalent cations and to be blocked by extracellular divalent cations (PubMed:32494638). Futhemore, coexpression of NALCN, UNC79, UNC80, and NALF1 results in voltage-dependent NALCN currents (PubMed:32494638, PubMed:31409833).
Voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability (PubMed:17448995, PubMed:31409833). NALCN channel functions as a multi-protein complex, which consists at least of NALCN, NALF1, UNC79 and UNC80 (PubMed:32494638, PubMed:33203861). NALCN is the voltage-sensing, pore-forming subunit of the NALCN channel complex (PubMed:17448995). NALCN channel complex is constitutively active and conducts monovalent cations but is blocked by physiological concentrations of extracellular divalent cations (PubMed:32494638). In addition to its role in regulating neuronal excitability, is required for normal respiratory rhythm, systemic osmoregulation by controlling the serum sodium concentration and in the regulation of the intestinal pace-making activity in the interstitial cells of Cajal (By similarity). NALCN channel is also activated by neuropeptides such as neurotensin and substance P (SP) through a SRC family kinases-dependent pathway (By similarity). In addition, NALCN activity is enhanced/modulated by several GPCRs, such as CHRM3 (By similarity).
According to a report, acts as a negative regulator of T-cell activation independently of its enzymatic activity (PubMed:28891065). However, authors of this study only tested enzyme activity via phenylalanine (Phe) deprivation and not via tryptophan (Trp). As IL4I1 immunoregulator activity is mediated via Trp degradation and subsequent activation of the transcription factor AHR, additional experiments are required to confirm this statement (PubMed:32818467, PubMed:32866000).
Belongs to the flavin monoamine oxidase family. FIG1 subfamily.
By IL4/interleukin-4 (PubMed:12031486). Expression is up-regulated in numerous cancer and metastasis: expression is induced by immune checkpoint blockade (PubMed:32818467).
L-amino-acid oxidase activity toward phenylalanine (Phe) is specfically inhibited by a number of Phe derivatives, such as Cp3 (ethyl 3-(2,6-dichlorophenyl)-2-(piperidin-1-yl)propanoate) or Cp2-SO4 (PubMed:31812258). Cp3 is a very potent inhibitor for activity toward phenylalanine but is toxic (PubMed:31812258). In contrast, Cp2-SO4 is less efficient but not toxic and is able to reverse immunosuppressive action of IL4I1 in vitro (PubMed:31812258).
Primarily found in immune tissues, with the highest expression in lymph nodes and spleen (PubMed:12031486, PubMed:12446450). Present in germinal center macrophages and inflammatory myeloid cells and antigen-presenting cells (at protein level) (PubMed:17356132). Also present in spermatozoa (at protein level) (PubMed:25767141). Highly expressed in primary mediastinal large B-cell lymphoma, a specific subtype of diffuse large B-cell lymphoma (PubMed:12446450). Expressed by neoplastic cells of several B-cell lymphomas and by tumor-associated macrophages (PubMed:19436310).
Secreted L-amino-acid oxidase that acts as a key immunoregulator (PubMed:17356132, PubMed:32818467, PubMed:32866000). Has preference for L-aromatic amino acids: converts phenylalanine (Phe), tyrosine (Tyr) and tryptophan (Trp) to phenylpyruvic acid (PP), hydroxyphenylpyruvic acid (HPP), and indole-3-pyruvic acid (I3P), respectively (PubMed:17356132, PubMed:32818467, PubMed:32866000). Also has weak L-arginine oxidase activity (PubMed:26673964). Acts as a negative regulator of anti-tumor immunity by mediating Trp degradation via an indole pyruvate pathway that activates the transcription factor AHR (PubMed:32818467, PubMed:32866000). IL4I1-mediated Trp catabolism generates I3P, giving rise to indole metabolites (indole-3-acetic acid (IAA) and indole-3-aldehyde (I3A)) and kynurenic acid, which act as ligands for AHR, a ligand-activated transcription factor that plays important roles in immunity and cancer (PubMed:32818467, PubMed:32866000). AHR activation by indoles following IL4I1-mediated Trp degradation enhances tumor progression by promoting cancer cell motility and suppressing adaptive immunity (PubMed:32818467). Also has an immunoregulatory function in some immune cells, probably by mediating Trp degradation and promoting downstream AHR activation: inhibits T-cell activation and proliferation, promotes the differentiation of naive CD4(+) T-cells into FOXP3(+) regulatory T-cells (Treg) and regulates the development and function of B-cells (PubMed:17356132, PubMed:25446972, PubMed:25778793, PubMed:28891065). Also regulates M2 macrophage polarization by inhibiting T-cell activation (By similarity). Also has antibacterial properties by inhibiting growth of Gram negative and Gram positive bacteria through the production of NH4(+) and H2O2 (PubMed:23355881).
Uses the promoter of the upstream NUP62 gene and shares the first 2 non-coding exons with NUP62.
Component of the vault ribonucleoprotein particle, at least composed of MVP, PARP4 and one or more vault RNAs (vRNAs) (PubMed:10477748). Interacts with TEP1 (PubMed:10551828, PubMed:15169895).
Was initially thought to mediate to mediate poly-ADP-ribosylation of proteins (PubMed:10477748). However, it was later shown to act as a mono-ADP-ribosyltransferase (PubMed:25043379).
Widely expressed; the highest levels are in the kidney; also detected in heart, placenta, lung, liver, skeletal muscle, spleen, leukocytes and pancreas.
Expressed at high levels in thymus and testis, at low levels in small intestine, the mucosal lining of colon, and placenta, and at very low levels in spleen and ovary; expression is not detected in prostate, peripheral blood Leukocytes, heart, brain, lung, liver, skeletal muscle, kidney or pancreas. Isoform 2 is testis-specific.
In complex with KIF18B, constitutes the major microtubule plus-end depolymerizing activity in mitotic cells (PubMed:21820309). Regulates the turnover of microtubules at the kinetochore and functions in chromosome segregation during mitosis (PubMed:19060894). Plays a role in chromosome congression and is required for the lateral to end-on conversion of the chromosome-microtubule attachment (PubMed:23891108).
Interacts with CENPH. Interacts with MTUS2/TIP150; the interaction is direct. Interacts with MAPRE1; the interaction is direct, regulated by phosphorylation and is probably required for targeting to growing microtubule plus ends. Interacts with KIF18B at microtubule tips; this interaction increases the affinity of both partners for microtubule plus ends and is required for robust microtubule depolymerization. Phosphorylation by AURKA or AURKB strongly reduces KIF18B-binding.
Phosphorylation by AURKB, regulates association with centromeres and kinetochores and the microtubule depolymerization activity.
Belongs to the RNase H2 subunit C family.
The T6 pseudogene located upstream of SRY on chromosome Y is derived from the transcript of this gene.
Interacts with CRMP2 (PubMed:19235893). Interacts with CLN5 (PubMed:19941651). Interacts with CLN3 (PubMed:17237713).
Heterodimer with PSMC3IP/HOP2. MND1-PSMC3IP interacts with DMC1 and RAD51 and binds preferentially to dsDNA.
Required for proper homologous chromosome pairing and efficient cross-over and intragenic recombination during meiosis (By similarity). Stimulates both DMC1- and RAD51-mediated homologous strand assimilation, which is required for the resolution of meiotic double-strand breaks.
Catalyzes the conversion of 17-oxosteroids to 17beta-hydroxysteroids (PubMed:8075637, PubMed:16216911, PubMed:27927697, PubMed:26545797). Favors the reduction of androstenedione to testosterone (PubMed:16216911, PubMed:27927697, PubMed:26545797). Testosterone is the key androgen driving male development and function (PubMed:8075637). Uses NADPH while the two other EDH17B enzymes use NADH (PubMed:26545797, PubMed:8075637, PubMed:16216911). Androgens such as epiandrosterone, dehydroepiandrosterone, androsterone and androstanedione are accepted as substrates and reduced at C-17 (PubMed:16216911). Can reduce 11-ketoandrostenedione as well as 11beta-hydroxyandrostenedione at C-17 to the respective testosterone forms (PubMed:16216911, PubMed:27927697).
Forms homodimers (PubMed:27219064). Associates with microtubules plus ends; binds to beta-tubulin subunits exposed on microtubule outer surface at its distal tip; also associates with microtubule lattice (PubMed:19131341, PubMed:27219064, PubMed:27306797). Associated with the gamma-tubulin complex. Interacts with the head domain of EPB41 (PubMed:11003675). Interacts with LYST (PubMed:11984006). Interacts with CEP152 (via C-terminus) (PubMed:20852615). Interacts with STIL (PubMed:22020124, PubMed:25385835). Forms a complex with STIL and SASS6 (PubMed:22020124).
Phosphorylation at Ser-589 and Ser-595 by PLK2 is required for procentriole formation and centriole elongation. Phosphorylation by PLK2 oscillates during the cell cycle: it increases at G1/S transition and decreases during the exit from mitosis. Phosphorylation at Ser-595 is also mediated by PLK4 but is not a critical step in PLK4 function in procentriole assembly.
Plays an important role in cell division and centrosome function by participating in centriole duplication (PubMed:17681131, PubMed:20531387). Inhibits microtubule nucleation from the centrosome. Involved in the regulation of slow processive growth of centriolar microtubules. Acts as microtubule plus-end tracking protein that stabilizes centriolar microtubules and inhibits microtubule polymerization and extension from the distal ends of centrioles (PubMed:15047868, PubMed:27219064, PubMed:27306797). Required for centriole elongation and for STIL-mediated centriole amplification (PubMed:22020124). Required for the recruitment of CEP295 to the proximal end of new-born centrioles at the centriolar microtubule wall during early S phase in a PLK4-dependent manner (PubMed:27185865). May be involved in the control of centriolar-microtubule growth by acting as a regulator of tubulin release (PubMed:27306797).
Highest levels are found in fetal and adult brain, prostate, testis and spinal cord. Undetectable expression in adrenal gland, skeletal muscle, bone marrow, fetal, and adult liver, heart, salivary gland, and trachea. Detected in the HEK293, HEK293T, LNCaP, MCF-7, T-47D and EVSA-T cell lines (at protein level).
May be involved in the regulation of centrosome duplication and cell cycle progression.
Previously reported to exhibit GTP-binding affinity comparable to that of RAB6A (PubMed:16103095). In contrast (PubMed:20064528) concludes that RAB6C is an inefficient GTP-binding.
Primate-specific retrogene derived from isoform 2 of RAB6A transcript.
Acetylation at Lys-53 inhibits kinase activity. Deacetylated by HDAC6.
Activated by phosphorylation on Thr-175.
Interacts with and phosphorylates TORC2/CRTC2.
Phosphorylated at Thr-175 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39 (PubMed:14976552). Phosphorylated at Thr-484 in response to insulin in adipocytes (PubMed:30586628).
Serine/threonine-protein kinase that plays a role in many biological processes such as fatty acid oxidation, autophagy, immune response or glucose metabolism (PubMed:23322770, PubMed:26983400). Phosphorylates 'Ser-794' of IRS1 in insulin-stimulated adipocytes, potentially modulating the efficiency of insulin signal transduction. Inhibits CREB activity by phosphorylating and repressing TORCs, the CREB-specific coactivators (PubMed:15454081). Phosphorylates EP300 and thus inhibits its histone acetyltransferase activity (PubMed:21084751, PubMed:26983400). In turn, regulates the DNA-binding ability of several transcription factors such as PPARA or MLXIPL (PubMed:21084751, PubMed:26983400). Also plays a role in thymic T-cell development (By similarity).
'Toso' is a Japanese liquor drunk on New Year's day to celebrate long life and eternal youth.
Expressed in lymph nodes, peripheral blood leukocytes, lung, thymus and kidneys. Very weak expression detected in spleen, liver, heart, and salivary gland. Expressed in lymphoid cell lines such as Jurkat, CEM-T4, MOLT-4, HB11;19 and Reh. No expression detected in nonhematopoietic cell lines including Hep-G2, HEK293 and HeLa. Detected at high levels in chronic lymphocytic leukemia cells.
May play a role in the immune system processes. Protects cells from FAS-, TNF alpha- and FADD-induced apoptosis without increasing expression of the inhibitors of apoptosis BCL2 and BCLXL. Seems to activate an inhibitory pathway that prevents CASP8 activation following FAS stimulation, rather than blocking apoptotic signals downstream. May inhibit FAS-induced apoptosis by preventing CASP8 processing through CFLAR up-regulation.
The Ig-like domain is required for the anti-apoptotic ability.
Homotetramer and homodimer (By similarity). Heterotetramer with HNF1A; formed by a dimer of dimers (By similarity). Interacts with HNF1B (via HNF-p1 domain); the interaction increases HNF1B transactivation activity (PubMed:24204001).
Involved in tetrahydrobiopterin biosynthesis (By similarity). Seems to both prevent the formation of 7-pterins and accelerate the formation of quinonoid-BH2. Coactivator for HNF1A-dependent transcription (By similarity). Regulates the dimerization of homeodomain protein HNF1A and enhances its transcriptional activity (By similarity). Also acts as a coactivator for HNF1B-dependent transcription (PubMed:24204001).
Interacts directly with RAD21 in cohesin complex. Cohesin complexes are composed of a heterodimer between a SMC1 protein (SMC1A or SMC1B) and SMC3, which are attached via their hinge domain, and RAD21 which link them at their heads, and one STAG protein (STAG1, STAG2 or STAG3). In cohesin complexes, STAG2 is mutually exclusive with STAG1 and STAG3.
Variants MKMS 743-Trp--Phe-1231 DEL and HPE13 1033-Arg--Phe-1231 DEL were previously described; however, the corresponding paper has been retracted as Case 1's sex was incorrectly reported invalidating the conclusions.
Component of a PRC1-like complex (PubMed:12167701, PubMed:15386022, PubMed:19636380, PubMed:21282530, PubMed:26151332, PubMed:21772249, PubMed:25355358). Identified in a PRC1-like HPRC-H complex with CBX2, CBX4, CBX8, PHC1, PHC2, PHC3 RING1 and RNF2 (PubMed:12167701). Interacts with RNF2/RING2 (PubMed:16714294, PubMed:21772249, PubMed:25355358). Interacts with RING1 (By similarity). Part of a complex that contains RNF2, UB2D3 and BMI1, where RNF2 and BMI1 form a tight heterodimer, and UB2D3 interacts only with RNF2 (PubMed:21772249, PubMed:25355358). The complex composed of RNF2, UB2D3 and BMI1 binds nucleosomes, and has activity only with nucleosomal histone H2A (PubMed:21772249, PubMed:25355358). Interacts with CBX7 and CBX8 (PubMed:19636380). Interacts with SPOP (PubMed:15897469). Part of a complex consisting of BMI1, CUL3 and SPOP (PubMed:15897469). Interacts with E4F1 (PubMed:16882984). Interacts with PHC2 (PubMed:9121482, PubMed:9199346, PubMed:27827373). Interacts with zinc finger protein ZNF277 (By similarity). May be part of a complex including at least ZNF277, BMI1 and RNF2/RING2 (By similarity).
Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:15386022, PubMed:16359901, PubMed:26151332, PubMed:16714294, PubMed:21772249, PubMed:25355358, PubMed:27827373). The complex composed of RNF2, UB2D3 and BMI1 binds nucleosomes, and has activity only with nucleosomal histone H2A (PubMed:21772249, PubMed:25355358). In the PRC1-like complex, regulates the E3 ubiquitin-protein ligase activity of RNF2/RING2 (PubMed:15386022, PubMed:26151332, PubMed:21772249).
Monoubiquitinated (By similarity). May be polyubiquitinated; which does not lead to proteasomal degradation.
Hydrolase that can remove conjugated ubiquitin from proteins and participates in endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins. May act by triming the ubiquitin chain on the associated substrate to facilitate their threading through the VCP/p97 pore. Ubiquitin moieties on substrates may present a steric impediment to the threading process when the substrate is transferred to the VCP pore and threaded through VCP's axial channel. Mediates deubiquitination of 'Lys-27'-, 'Lys-29'- and 'Lys-33'-linked polyubiquitin chains. Also able to hydrolyze 'Lys-11'-linked ubiquitin chains. Cleaves both polyubiquitin and di-ubiquitin. May play a role in macroautophagy, regulating for instance the clearance of damaged lysosomes. May recruit PLAA, UBXN6 and VCP to damaged lysosome membranes decorated with K48-linked ubiquitin chains and remove these chains allowing autophagosome formation (PubMed:27753622).
Interacts with VCP; the interaction is direct. Interacts with FAF2/UBXD8. Interacts with DERL1; however interaction is dependent on the UBAX-like region, suggesting that it may be indirect. Interacts with PLAA, UBXN6 and VCP; may form a complex involved in macroautophagy (PubMed:27753622).
The C2H2-type zinc finger mediates specificity for 'Lys-27'-, 'Lys-29'- and 'Lys-33'-linked polyubiquitin chains but not for 'Lys-11'-linked ubiquitin chains. Selectivity for 'Lys-11'-linked ubiquitin chains is provided by recognition of the sequence surrounding 'Lys-11' in ubiquitin. The S2 site region provides specificity for longer 'Lys-11'-linked ubiquitin chains (PubMed:23827681).
The UBAX-like region mediates the interaction with VCP. According to PubMed:19818707, it corresponds to a UBX domain, which is a hallmark for VCP-associated proteins. However, no canonical UBX is detected by prediction tools such as Pfam or PROSITE.
Interacts with CDC42, in a GTP-dependent manner, and with SEPT7.
Probably involved in the organization of the actin cytoskeleton. May act downstream of CDC42 to induce actin filament assembly leading to cell shape changes. Induces pseudopodia formation in fibroblasts. Inhibits MAPK8 independently of CDC42 binding. Controls septin organization and this effect is negatively regulated by CDC42 (By similarity).
Acts as a GTPase-activating protein for RAB35. Together with RAB35 may be involved in regulation of insulin-induced glucose transporter SLC2A4/GLUT4 translocation to the plasma membrane in adipocytes.
Interacts with RAB1A and RAB10; in a GTP-dependent manner.
Seems to play a role in the correct specification of the left-right axis. May antagonize NODAL and BMP4 signaling. Cystine knot-containing proteins play important roles during development, organogenesis, tissue growth and differentiation (By similarity).
Expressed in germinal center B-cell and in lymphomas derived from germinal center B-cell.
Nuclear GTPase found in germinal center B-cells, where it may inhibit function of the activation-induced cytidine deaminase AICDA (PubMed:19734146). Reduces somatic hypermutation in B-cells which may enhance genome stability (By similarity).
DAZ genes are prone to deletions but also to duplications. In a population of infertile men, DAZ genes deletions are associated with oligozoospermia but an increased number of DAZ genes is not a significant risk factor for spermatogenic failure.
Testis-specific. Expression restricted to premeiotic germ cells, particularly in spermatogonia (at protein level).
ATPase activity is dependent of phosphorylation by PAK1 and presence of DNA.
Essential for epigenetic silencing by the HUSH (human silencing hub) complex. Recruited by HUSH to target site in heterochromatin, the ATPase activity and homodimerization are critical for HUSH-mediated silencing (PubMed:28581500, PubMed:29440755, PubMed:32693025). Represses germ cell-related genes and L1 retrotransposons in collaboration with SETDB1 and the HUSH complex, the silencing is dependent of repressive epigenetic modifications, such as H3K9me3 mark. Silencing events often occur within introns of transcriptionally active genes, and lead to the down-regulation of host gene expression (PubMed:29211708). During DNA damage response, regulates chromatin remodeling through ATP hydrolysis. Upon DNA damage, is phosphorylated by PAK1, both colocalize to chromatin and induce H2AX expression. ATPase activity is required and dependent of phosphorylation by PAK1 and presence of DNA (PubMed:23260667). Recruits histone deacetylases, such as HDAC4, to promoter regions, causing local histone H3 deacetylation and transcriptional repression of genes such as CA9 (PubMed:20225202, PubMed:20110259). Exhibits a cytosolic function in lipogenesis, adipogenic differentiation, and lipid homeostasis by increasing the activity of ACLY, possibly preventing its dephosphorylation (PubMed:24286864).
Highly expressed in smooth muscle, pancreas and testis.
Homodimerizes upon ATP-binding and dissociate upon ATP hydrolysis; homodimerization is required for gene silencing (PubMed:29440755). Interacts with HDAC4 (PubMed:20110259). Interacts with ACLY (PubMed:24286864). Interacts with TASOR and MPHOSPH8; the interactions associate MORC2 with the HUSH complex which recruits MORC2 to heterochromatic loci (PubMed:28581500).
Phosphorylated by PAK1 at Ser-739 upon DNA damage. Phosphorylation is required for ATPase activity and recruitment to damaged chromatin.
Interacts with CABYR. Interacts with ROPN1 and ROPN1L; the interaction increases upon spermatozoa capacitation conditions.
May be involved in the later stages of fibrous sheath biogenesis and spermatozoa capacitation. Inhibits ROPN1 and ROPN1L SUMOylation. Binds calcium.
Phosphorylated by PKA upon spermatozoa capacitation conditions.
RNA-binding protein that binds to AU-rich element (ARE) sequences of target mRNAs, including VEGF mRNA (PubMed:10710437). May also bind poly-A tracts via RRM 3 (By similarity). May be involved in neuronal differentiation and maintenance (By similarity). Plays a role in the stabilization of GAP43 mRNA and in spatial learning (By similarity).
RRM 1 and RRM 2 bind cooperatively to AU-rich sequences in target mRNAs. RRM 3 binds to poly-A mRNA sequences (By similarity).
Testis. Not detected in epididymis nor placenta. In testis, mainly expressed in germ cells, but also detected in somatic cells such as Sertoli cells, Leydig cells and peritubular cells (PubMed:28171660).
Functions in endosome to Golgi retrograde transport. In response to calcium influx, may interact with SNARE fusion receptors and membrane phospholipids to mediate endosome fusion with the trans-Golgi network. By promoting the recycling of secretory vesicle transmembrane proteins, it indirectly controls dense-core secretory vesicle biogenesis, maturation and their ability to mediate the constitutive and regulated secretion of neurotransmitters and hormones. May regulate behavior and food intake by controlling calcium-stimulated exocytosis of neurotransmitters including NPY and serotonin and hormones like insulin (PubMed:28626000). Proposed to play a role in hypothalamic neuronal firing by modulating gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission (By similarity).
Interacts with ADGRB1; this interaction is direct (PubMed:9790924). Interacts with endosomal SNARE proteins VAMP3, VAMP4, STX6 and STX16; this interaction is increased in the presence of calcium (PubMed:28626000).
Predominantly expressed in brain (PubMed:9790924). Also expressed in nonneural tissues such as breast and testes epithelium (PubMed:12498718).
Monomer in the presence of bound GDP and in the absence of bound nucleotide. Homodimer in the presence of bound GTP. Can form linear oligomers. Heterodimer with GIMAP7.
The heterodimer formed by GIMAP2 and GIMAP7 has GTPase activity. In contrast, GIMAP2 has no GTPase activity by itself.
(Microbial infection) Binds to the head and beginning of the coiled stalk of N.meningitidis adhesin A (nadA) variant 3; binding can be abrogated by monoclonal antibodies against the specific regions of NadA. Binding occurs in protein microarrays, in solution and when LOX-1 is expressed on the cell surface.
(Microbial infection) May serve as a receptor for adhesin A variant 3 (nadA) of N.meningitidis.
By inflammatory cytokines such as TNF, IFNG/IFN-gamma, IL6/interleukin-6 and by pathological conditions such as hyperlipidemia, hypertension and diabetes mellitus. Up-regulated in atherosclerotic lesions, by oxLDL, reactive oxygen species and fluid shear stress, suggesting that it may participate in amplification of oxLDL-induced vascular dysfunction.
Expressed at high level in endothelial cells and vascular-rich organs such as placenta, lung, liver and brain, aortic intima, bone marrow, spinal cord and substantia nigra. Also expressed at the surface of dendritic cells. Widely expressed at intermediate and low level.
Homodimer; disulfide-linked. May form a hexamer composed of 3 homodimers. Interacts with HSP70.
Independent association genetic studies have implicated OLR1 gene variants in myocardial infarction susceptibility.
OLR1 may be involved in Alzheimer disease (AD). Involvement in AD is however unclear: according to some authors, variations in OLR1 modify the risk of AD(PubMed:12354387, PubMed:12810610, PubMed:15976314). While according to others they do not (PubMed:15000751, PubMed:15060104).
Receptor that mediates the recognition, internalization and degradation of oxidatively modified low density lipoprotein (oxLDL) by vascular endothelial cells. OxLDL is a marker of atherosclerosis that induces vascular endothelial cell activation and dysfunction, resulting in pro-inflammatory responses, pro-oxidative conditions and apoptosis. Its association with oxLDL induces the activation of NF-kappa-B through an increased production of intracellular reactive oxygen and a variety of pro-atherogenic cellular responses including a reduction of nitric oxide (NO) release, monocyte adhesion and apoptosis. In addition to binding oxLDL, it acts as a receptor for the HSP70 protein involved in antigen cross-presentation to naive T-cells in dendritic cells, thereby participating in cell-mediated antigen cross-presentation. Also involved in inflammatory process, by acting as a leukocyte-adhesion molecule at the vascular interface in endotoxin-induced inflammation. Also acts as a receptor for advanced glycation end (AGE) products, activated platelets, monocytes, apoptotic cells and both Gram-negative and Gram-positive bacteria.
The C-type lectin domain mediates the recognition and binding of oxLDL.
The cytoplasmic region is required for subcellular sorting on the cell surface.
The intrachain disulfide-bonds prevent N-glycosylation at some sites.
Associated with a number of cancers such as colon (PubMed:15480429) and bone cancer (PubMed:17203229). Possibly involved in polycystic kidney diseases (PubMed:15530380).
Expressed in testis, thyroid and trachea and to a lower extent in spinal cord and adrenal gland. Highly expressed in colon cancer and osteosarcoma cell lines.
Interacts with CLU/clusterin (PubMed:15480429). Interacts with UBXN10; the interaction is direct (PubMed:26389662).
Required for cilia biogenesis. Appears to function within the multiple intraflagellar transport complex B (IFT-B). Key regulator of hedgehog signaling.
Expressed in adult heart, brain, placenta, skeletal muscle and pancreas, and in fetal lung, kidney and brain. There is little expression in adult lung, liver and kidney.
Belongs to the PtdIns transfer protein family. PI transfer class IIB subfamily.
Catalyzes the transfer of phosphatidylinositol (PI) and phosphatidic acid (PA) between membranes (PubMed:10531358, PubMed:22822086). Binds PA derived from the phospholipase D signaling pathway and among the cellular PA species, preferably binds to the C16:0/16:1 and C16:1/18:1 PA species (PubMed:22822086).
Catalyzes the transfer of phosphatidylinositol between membranes.
Expressed in mesenchymal cells, including alveolar myofibroblasts, kidney mesangial cells and hepatic stellar cells and vascular and visceral smooth muscle (at protein level).
Heterodimer of an alpha and a beta subunit. The alpha subunit is composed of a heavy and a light chain linked by a disulfide bond. Alpha-8 associates with beta-1.
Integrin alpha-8/beta-1 functions in the genesis of kidney and probably of other organs by regulating the recruitment of mesenchymal cells into epithelial structures. It recognizes the sequence R-G-D in a wide array of ligands including TNC, FN1, SPP1 TGFB1, TGFB3 and VTN. NPNT is probably its functional ligand in kidney genesis. Neuronal receptor for TNC it mediates cell-cell interactions and regulates neurite outgrowth of sensory and motor neurons.
Highest levels found in fetal brain and testis. Detected in the adult intestinal epithelium, specifically in goblet cell at protein level.
Phosphorylation at Ser-462 creates a docking site for 14-3-3, which stabilizes the protein and modulates its ability to bind RNA.
RNA-binding protein. May be involved in post-transcriptional regulatory mechanisms.
Forms homodimers and heterodimers with liprins-alpha and liprins-beta. Interacts with the second PTPase domain of PTPRD, PTPRF and PTPRS. Interacts with GIT1, KIF1A and GRIP1 (By similarity).
May regulate the disassembly of focal adhesions. May localize receptor-like tyrosine phosphatases type 2A at specific sites on the plasma membrane, possibly regulating their interaction with the extracellular environment and their association with substrates.
The N-terminal coiled coil regions mediate homodimerization preferentially and heterodimerization type alpha/alpha. The C-terminal, non-coiled coil regions mediate heterodimerization type alpha/beta and interaction with PTPRD, PTPRF and PTPRS.
As part of the central apparatus of the cilium axoneme may play a role in cilium movement. May play an important role in sperm architecture and function.
Data is conflicting regarding whether it fulfills the criteria of a membrane-bound estrogen receptor (PubMed:15705806, PubMed:17379646). Other reports suggest that it is not (PubMed:16645038, PubMed:18566127).
Data is conflicting regarding whether it is localized either at the cell membrane (PM) (PubMed:15539556, PubMed:21427217, PubMed:21540189, PubMed:21354433, PubMed:21149639, PubMed:23674134). Other reports suggest that it localizes at the endoplasmic reticulum (ER) (PubMed:15705806, PubMed:18566127).
Does not bind estradiol according to PubMed:18566127 and PubMed:16645038.
Expressed in placenta, endothelial and epithelial cells, non laboring and laboring term myometrium, fibroblasts and cancer-associated fibroblasts (CAF), prostate cancer cells and invasive adenocarcinoma (at protein level). Ubiquitously expressed, but is most abundant in placenta. In brain regions, expressed as a 2.8 kb transcript in basal forebrain, frontal cortex, thalamus, hippocampus, caudate and putamen.
G-protein coupled estrogen receptor that binds to 17-beta-estradiol (E2) with high affinity, leading to rapid and transient activation of numerous intracellular signaling pathways. Stimulates cAMP production, calcium mobilization and tyrosine kinase Src inducing the release of heparin-bound epidermal growth factor (HB-EGF) and subsequent transactivation of the epidermal growth factor receptor (EGFR), activating downstream signaling pathways such as PI3K/Akt and ERK/MAPK. Mediates pleiotropic functions among others in the cardiovascular, endocrine, reproductive, immune and central nervous systems. Has a role in cardioprotection by reducing cardiac hypertrophy and perivascular fibrosis in a RAMP3-dependent manner. Regulates arterial blood pressure by stimulating vasodilation and reducing vascular smooth muscle and microvascular endothelial cell proliferation. Plays a role in blood glucose homeostasis contributing to the insulin secretion response by pancreatic beta cells. Triggers mitochondrial apoptosis during pachytene spermatocyte differentiation. Stimulates uterine epithelial cell proliferation. Enhances uterine contractility in response to oxytocin. Contributes to thymic atrophy by inducing apoptosis. Attenuates TNF-mediated endothelial expression of leukocyte adhesion molecules. Promotes neuritogenesis in developing hippocampal neurons. Plays a role in acute neuroprotection against NMDA-induced excitotoxic neuronal death. Increases firing activity and intracellular calcium oscillations in luteinizing hormone-releasing hormone (LHRH) neurons. Inhibits early osteoblast proliferation at growth plate during skeletal development. Inhibits mature adipocyte differentiation and lipid accumulation. Involved in the recruitment of beta-arrestin 2 ARRB2 at the plasma membrane in epithelial cells. Functions also as a receptor for aldosterone mediating rapid regulation of vascular contractibility through the PI3K/ERK signaling pathway. Involved in cancer progression regulation. Stimulates cancer-associated fibroblast (CAF) proliferation by a rapid genomic response through the EGFR/ERK transduction pathway. Associated with EGFR, may act as a transcription factor activating growth regulatory genes (c-fos, cyclin D1). Promotes integrin alpha-5/beta-1 and fibronectin (FN) matrix assembly in breast cancer cells.
Homodimer (Probable). Heterodimer; heterodimerizes with other G-protein-coupled receptor (GPCRs) like CRHR1, HTR1A and PAQR8. Interacts (via C-terminus tail motif) with DLG4 (via N-terminus tandem pair of PDZ domains); the interaction is direct and induces the increase of GPER1 protein levels residing at the plasma membrane surface in a estradiol-independent manner (By similarity). Interacts with RAMP3. Interacts with KRT7 and KRT8. Interacts with EGFR; the interaction increases after agonist-induced stimulation in cancer-associated fibroblasts (CAF). Interacts with EGFR and ESR1.
Ubiquitinated; ubiquitination occurs at the plasma membrane and leads to proteasome-mediated degradation.
Up-regulated by EGF and TGF-alpha in endometrial, ovarian and breast tumor cells. Up-regulated by progestin and by phorbol 12-myristate 13-acetate (PMA) in breast cancer cell lines.
Cell surface of thymocytes, T-lymphocytes, neutrophils, plasma cells and myelomas.
Cleavage by CTSG releases its extracellular domain and triggers its intramembrane proteolysis by gamma-secretase releasing the CD43 cytoplasmic tail chain (CD43-ct) which translocates to the nucleus.
Glycosylated; has a high content of sialic acid and O-linked carbohydrate structures.
Has a high content of sialic acid and O-linked carbohydrate structures.
Monomer (By similarity). Interacts with CTNNB1 (PubMed:15003504). Interacts with RDX (via FERM domain), EZR and MSN (By similarity).
Phosphorylation at Ser-355 is regulated by chemokines, requires its association with ERM proteins (EZR, RDX and MSN) and is essential for its function in the regulation of T-cell trafficking to lymph nodes.
Predominant cell surface sialoprotein of leukocytes which regulates multiple T-cell functions, including T-cell activation, proliferation, differentiation, trafficking and migration. Positively regulates T-cell trafficking to lymph-nodes via its association with ERM proteins (EZR, RDX and MSN) (By similarity). Negatively regulates Th2 cell differentiation and predisposes the differentiation of T-cells towards a Th1 lineage commitment. Promotes the expression of IFN-gamma by T-cells during T-cell receptor (TCR) activation of naive cells and induces the expression of IFN-gamma by CD4(+) T-cells and to a lesser extent by CD8(+) T-cells (PubMed:18036228). Plays a role in preparing T-cells for cytokine sensing and differentiation into effector cells by inducing the expression of cytokine receptors IFNGR and IL4R, promoting IFNGR and IL4R signaling and by mediating the clustering of IFNGR with TCR (PubMed:24328034). Acts as a major E-selectin ligand responsible for Th17 cell rolling on activated vasculature and recruitment during inflammation. Mediates Th17 cells, but not Th1 cells, adhesion to E-selectin. Acts as a T-cell counter-receptor for SIGLEC1 (By similarity).
Protects cells from apoptotic signals, promoting cell survival.
Belongs to the transient receptor (TC 1.A.4) family. TrpV subfamily. TRPV6 sub-subfamily.
Calcium selective cation channel that mediates Ca(2+) uptake in various tissues, including the intestine (PubMed:11097838, PubMed:11278579, PubMed:11248124, PubMed:15184369, PubMed:23612980, PubMed:29258289). Important for normal Ca(2+) ion homeostasis in the body, including bone and skin (By similarity). The channel is activated by low internal calcium level, probably including intracellular calcium store depletion, and the current exhibits an inward rectification (PubMed:15184369). Inactivation includes both a rapid Ca(2+)-dependent and a slower Ca(2+)-calmodulin-dependent mechanism; the latter may be regulated by phosphorylation. In vitro, is slowly inhibited by Mg(2+) in a voltage-independent manner. Heteromeric assembly with TRPV5 seems to modify channel properties. TRPV5-TRPV6 heteromultimeric concatemers exhibit voltage-dependent gating.
Expressed at high levels in the gastrointestinal tract, including esophagus, stomach, duodenum, jejunum, ileum and colon, and in pancreas, placenta, prostate and salivary gland. Expressed at moderate levels in liver, kidney and testis. Expressed in trophoblasts of placenta villus trees (at protein level)(PubMed:23612980). Expressed in locally advanced prostate cancer, metastatic and androgen-insensitive prostatic lesions but not detected in healthy prostate tissue and benign prostatic hyperplasia.
Homotetramer (PubMed:29258289). Probably forms also heterotetramers with TRPV5. Interacts with TRPV5. Interacts with S100A10 and probably with the ANAX2-S100A10 heterotetramer. The interaction with S100A10 is required for the trafficking to the plasma membrane. Interacts with BSPRY (By similarity). Interacts with TCAF1 and TCAF2 isoform 2 (PubMed:25559186). Interacts with calmodulin (PubMed:11248124).
Phosphorylation at Tyr-201 by SRC leads to an increased calcium influx through the channel. Probably dephosphorylated at this site by PTPN1 (By similarity). Phosphorylation by PRKCA at the calmodulin binding site delays channel inactivation (PubMed:11248124).
Unusual initiator. The initiator methionine is coded by a non-canonical ACG threonine codon.
Plays a structural role to facilitate the assembly and ensure the full activity of the enzyme catalyzing the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate. The heterodimer composed of the alpha (IDH3A) and beta (IDH3B) subunits and the heterodimer composed of the alpha (IDH3A) and gamma (IDH3G) subunits, have considerable basal activity but the full activity of the heterotetramer (containing two subunits of IDH3A, one of IDH3B and one of IDH3G) requires the assembly and cooperative function of both heterodimers.
Acetylated on Lys-439 by CREBBP. Acetylated by EP300. Deacetylated by SIRT1 and HDAC3.
Interacts with MYOG (By similarity). Forms a complex with class II HDACs in undifferentiating cells. On myogenic differentiation, HDACs are released into the cytoplasm allowing MEF2s to interact with other proteins for activation. Interacts with HDAC4 (in undifferentiating cells); the interaction translocates MEF2D to nuclear dots. Forms a heterodimer with MEF2A. Interacts with MAPK7; the interaction phosphorylates but does not activate MEF2D (By similarity). Interacts with CCAR2 and HDAC3.
Phosphorylated on Ser-444 by CDK5 is required for Lys-439 sumoylation and inhibits transcriptional activity. In neurons, enhanced CDK5 activity induced by neurotoxins promotes caspase 3-mediated cleavage leading to neuron apoptosis. Phosphorylation on Ser-180 can be enhanced by EGF. Phosphorylated and activated by CaMK4.
Present in myotubes and also in undifferentiated myoblasts.
Proteolytically cleaved in cerebellar granule neurons on several sites by caspase 7 following neurotoxicity. Preferentially cleaves the CDK5-mediated hyperphosphorylated form which leads to neuron apoptosis and transcriptional inactivation (By similarity).
Sumoylated on Lys-439 with SUMO2 but not SUMO1; which inhibits transcriptional activity and myogenic activity. Desumoylated by SENP3.
Transcriptional activator which binds specifically to the MEF2 element, 5'-YTA[AT](4)TAR-3', found in numerous muscle-specific, growth factor- and stress-induced genes. Mediates cellular functions not only in skeletal and cardiac muscle development, but also in neuronal differentiation and survival. Plays diverse roles in the control of cell growth, survival and apoptosis via p38 MAPK signaling in muscle-specific and/or growth factor-related transcription. Plays a critical role in the regulation of neuronal apoptosis (By similarity).
Belongs to the F-actin-capping protein alpha subunit family.
F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike other capping proteins (such as gelsolin and severin), these proteins do not sever actin filaments. May play a role in the formation of epithelial cell junctions (PubMed:22891260). Forms, with CAPZB, the barbed end of the fast growing ends of actin filaments in the dynactin complex and stabilizes dynactin structure. The dynactin multiprotein complex activates the molecular motor dynein for ultra-processive transport along microtubules (By similarity).
Heterodimer of an alpha and a beta subunit. Subunit of dynactin, a multiprotein complex part of a tripartite complex with dynein and a adapter, such as BICDL1, BICD2 or HOOK3. The dynactin complex is built around ACTR1A/ACTB filament and consists of an actin-related filament composed of a shoulder domain, a pointed end and a barbed end. Its length is defined by its flexible shoulder domain. The soulder is composed of 2 DCTN1 subunits, 4 DCTN2 and 2 DCTN3. The 4 DCNT2 (via N-terminus) bind the ACTR1A filament and act as molecular rulers to determine the length. The pointed end is important for binding dynein-dynactin cargo adapters. Consists of 4 subunits: ACTR10, DCNT4, DCTN5 and DCTN6. The barbed end is composed of a CAPZA1:CAPZB heterodimers, which binds ACTR1A/ACTB filament and dynactin and stabilizes dynactin (By similarity). Component of the WASH complex, composed of F-actin-capping protein subunit alpha (CAPZA1, CAPZA2 or CAPZA3), F-actin-capping protein subunit beta (CAPZB), WASH (WASHC1, WASH2P, WASH3P, WASH4P, WASH5P or WASH6P), WASHC2 (WASHC2A or WASHC2C), WASHC3, WASHC4 and WASHC5. Interacts with S100A (By similarity). Interacts with S100B. Interacts with SH3BP1; recruits CAPZA1 to forming cell junctions (PubMed:22891260). Interacts with CD2AP (PubMed:22891260). Directly interacts with CRACD; this interaction decreases binding to actin (PubMed:30361697).
Encoded in intron of the gene GTF2E2 (opposite strand). Confirmed by numerous ESTs.
Component of the MMS22L-TONSL complex, a complex at least composed of MMS22L and TONSL/NFKBIL2 (PubMed:21055983, PubMed:21055984, PubMed:21055985, PubMed:21113133, PubMed:27338793). Interacts with the MCM complex, the FACT complex and the RPA complex (PubMed:21055983, PubMed:21055984, PubMed:26527279). Interacts with MCM5; the interaction is direct (PubMed:26527279). Binds histones, with a strong preference for histone H3.1 (histones H3.1 and H3-4/H3.1t) (PubMed:21055983, PubMed:21055984, PubMed:26527279, PubMed:33857403). Interacts (via ANK repeats) with histone H4; specifically binds histone H4 lacking methylation at 'Lys-20' (H4K20me0) (PubMed:27338793). May interact with DNAJC9; the interaction seems to be histone-dependent (PubMed:33857403).
Component of the MMS22L-TONSL complex, a complex that promotes homologous recombination-mediated repair of double-strand breaks (DSBs) at stalled or collapsed replication forks (PubMed:21055983, PubMed:21055984, PubMed:21055985, PubMed:21113133, PubMed:26527279, PubMed:27797818, PubMed:29478807, PubMed:27338793, PubMed:30773278). The MMS22L-TONSL complex is required to maintain genome integrity during DNA replication (PubMed:21055983, PubMed:21055984, PubMed:21055985). It mediates the assembly of RAD51 filaments on single-stranded DNA (ssDNA): the MMS22L-TONSL complex is recruited to DSBs following histone replacement by histone chaperones and eviction of the replication protein A complex (RPA/RP-A) from DSBs (PubMed:21055983, PubMed:21055984, PubMed:21055985, PubMed:27797818, PubMed:29478807). Following recruitment to DSBs, the TONSL-MMS22L complex promotes recruitment of RAD51 filaments and subsequent homologous recombination (PubMed:27797818, PubMed:29478807). Within the complex, TONSL acts as histone reader, which recognizes and binds newly synthesized histones following their replacement by histone chaperones (PubMed:29478807, PubMed:27338793). Specifically binds histone H4 lacking methylation at 'Lys-20' (H4K20me0) and histone H3.1 (PubMed:27338793).
Expressed in heart, skeletal muscle and tracheal epithelial cells.
The ANK repeats mediate the interaction with the MCM complex and histones, while the LRR repeats mediate the interaction with MMS22L.
Was reported to share sequence similarities with IKBKB and therefore named 'NF-kappa-B inhibitor-like protein 2' (PubMed:7738005). However, the sequence similarity is remote and effects as regulator of NF-kappa-B are probably indirect and require additional evidence (PubMed:9242696).
Facilitative glucose transporter required for the development of the cardiovascular system.
Widely expressed; highest levels in liver and pancreas.
Liver, adrenal and at lower level in the kidney. Is present in human fetus in higher level in the adrenal than the liver and the kidney.
Subject to substrate inhibition. Alternate orientations for binding of steroid substrates to SULT2A1 may play a role in substrate inhibition.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfonation of steroids and bile acids in the liver and adrenal glands. Mediates the sulfation of a wide range of steroids and sterols, including pregnenolone, androsterone, DHEA, bile acids, cholesterol and as well many xenobiotics that contain alcohol and phenol functional groups (PubMed:7678732, PubMed:2268288, PubMed:14573603, PubMed:18042734, PubMed:19589875, PubMed:21187059, PubMed:29671343, PubMed:7854148). Sulfonation increases the water solubility of most compounds, and therefore their renal excretion, but it can also result in bioactivation to form active metabolites. Plays an important role in maintening steroid and lipid homeostasis (PubMed:21187059, PubMed:19589875, PubMed:14573603). Plays a key role in bile acid metabolism (PubMed:2268288). In addition, catalyzes the metabolic activation of potent carcinogenic polycyclic arylmethanols (By similarity).
Activated by DAG and phorbol esters. Phorbol-ester/DAG-type domains 1 and 2 bind both DAG and phorbol ester with high affinity and mediate translocation to the cell membrane. Autophosphorylation of Ser-735 and phosphorylation of Ser-731 by PKC relieves auto-inhibition by the PH domain.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. PKD subfamily.
Converts transient diacylglycerol (DAG) signals into prolonged physiological effects, downstream of PKC. Involved in resistance to oxidative stress (By similarity).
Expressed in all cell stages of spermatogenesis.
Filament-forming cytoskeletal GTPase (Probable). Involved in the migration of cortical neurons and the formation of neuron leading processes during embryonic development (By similarity). Plays a role in sperm head formation during spermiogenesis, potentially via facilitating localization of ACTN4 to cell filaments (PubMed:33228246).
Septins polymerize into heterooligomeric protein complexes that form filaments, and can associate with cellular membranes, actin filaments and microtubules. GTPase activity is required for filament formation. Interacts with ACTN4 (PubMed:33228246). Interacts with SEPTIN9 (PubMed:17922164). Interacts (via C-terminus) with SEPTIN4 (By similarity).
Expression is increased in differentiating erythroid cells (at protein level) (PubMed:26816381). Up-regulated during adipocyte differentiation (PubMed:14701838).
Homodimer (PubMed:9973611). Interacts with BCL6 (By similarity). Interacts with RELA; involved in the control by RELA of the accessibility of target gene promoters (PubMed:29813070). Interacts with AR (via NR LBD domain); the interaction is direct and androgen-dependent (PubMed:20812024). Interacts with NCOR1 (PubMed:20812024). Interacts with NCOR2 (PubMed:20812024). Interacts with SMAD4; the interaction is direct and stimulated by TGFB1 (PubMed:25514493). Interacts with HDAC1 (PubMed:25514493). Interacts with SP1; ZBTB7A prevents the binding to GC-rich motifs in promoters and represses the transcriptional activity of SP1 (PubMed:12004059). Interacts with the DNA-dependent protein kinase complex/DNA-PKc (PubMed:26446488). Interacts with KHDRBS1; negatively regulates KHDRBS1 splicing activity (PubMed:24514149).
Sumoylated. Undergoes sumoylation with SUMO1 that may regulate its transcriptional activity.
The BTB domain mediates the interaction with the androgen receptor/AR and HDAC1 (PubMed:20812024, PubMed:25514493). Also mediates the interaction with SP1 (PubMed:12004059).
Transcription factor that represses the transcription of a wide range of genes involved in cell proliferation and differentiation (PubMed:14701838, PubMed:17595526, PubMed:20812024, PubMed:25514493, PubMed:26455326, PubMed:26816381). Directly and specifically binds to the consensus sequence 5'-[GA][CA]GACCCCCCCCC-3' and represses transcription both by regulating the organization of chromatin and through the direct recruitment of transcription factors to gene regulatory regions (PubMed:12004059, PubMed:17595526, PubMed:20812024, PubMed:25514493, PubMed:26816381). Negatively regulates SMAD4 transcriptional activity in the TGF-beta signaling pathway through these two mechanisms (PubMed:25514493). That is, recruits the chromatin regulator HDAC1 to the SMAD4-DNA complex and in parallel prevents the recruitment of the transcriptional activators CREBBP and EP300 (PubMed:25514493). Collaborates with transcription factors like RELA to modify the accessibility of gene transcription regulatory regions to secondary transcription factors (By similarity). Also directly interacts with transcription factors like SP1 to prevent their binding to DNA (PubMed:12004059). Functions as an androgen receptor/AR transcriptional corepressor by recruiting NCOR1 and NCOR2 to the androgen response elements/ARE on target genes (PubMed:20812024). Thereby, negatively regulates androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024). Involved in the switch between fetal and adult globin expression during erythroid cells maturation (PubMed:26816381). Through its interaction with the NuRD complex regulates chromatin at the fetal globin genes to repress their transcription (PubMed:26816381). Specifically represses the transcription of the tumor suppressor ARF isoform from the CDKN2A gene (By similarity). Efficiently abrogates E2F1-dependent CDKN2A transactivation (By similarity). Regulates chondrogenesis through the transcriptional repression of specific genes via a mechanism that also requires histone deacetylation (By similarity). Regulates cell proliferation through the transcriptional regulation of genes involved in glycolysis (PubMed:26455326). Involved in adipogenesis through the regulation of genes involved in adipocyte differentiation (PubMed:14701838). Plays a key role in the differentiation of lymphoid progenitors into B and T lineages (By similarity). Promotes differentiation towards the B lineage by inhibiting the T-cell instructive Notch signaling pathway through the specific transcriptional repression of Notch downstream target genes (By similarity). Also regulates osteoclast differentiation (By similarity). May also play a role, independently of its transcriptional activity, in double-strand break repair via classical non-homologous end joining/cNHEJ (By similarity). Recruited to double-strand break sites on damage DNA, interacts with the DNA-dependent protein kinase complex and directly regulates its stability and activity in DNA repair (By similarity). May also modulate the splicing activity of KHDRBS1 toward BCL2L1 in a mechanism which is histone deacetylase-dependent and thereby negatively regulates the pro-apoptotic effect of KHDRBS1 (PubMed:24514149).
Widely expressed (PubMed:9927193). In normal thymus, expressed in medullary epithelial cells and Hassle's corpuscles (at protein level) (PubMed:15662416). In tonsil, expressed in squamous epithelium and germinal center lymphocytes (at protein level) (PubMed:15662416). Up-regulated in a subset of lymphomas, as well as in a subset of breast, lung, colon, prostate and bladder carcinomas (at protein level) (PubMed:15662416). Expressed in adipose tissues (PubMed:14701838).
Highest expression in lung and peripheral leukocytes, and minor expression in liver and kidney.
Protamines substitute for histones in the chromatin of sperm during the haploid phase of spermatogenesis. They compact sperm DNA into a highly condensed, stable and inactive complex.
Proteolytic processing into mature chains is required for histone eviction during spermatogenesis. Transition proteins (TNP1 and TNP2) are required for processing.
(Microbial infection) Exhibits antiviral activity against Japanese encephalitis virus (JEV). Ubiquitinates the viral non-structural protein 2 (NS2A) and targets it for proteasome-mediated degradation.
(Microbial infection) Interacts with Japanese encephalitis virus non-structural protein 2 (NS2A); mediates the ubiquitination of NS2A, targeting it for proteasome-mediated degradation.
Arose via a partial duplication of the TRIM41 gene, followed by independent loss or pseudogenization of TRIM52 in multiple mammalian and primate lineages.
Autoubiquitinated (PubMed:27667714). Polyubiquitinated (PubMed:20596523, PubMed:27667714). Undergoes extremely rapid proteolytic degradation by the proteasome (PubMed:31133683).
E3 ubiquitin-protein ligase (PubMed:27667714). Positively regulates the NF-kappa-B signaling pathway (PubMed:27667714, PubMed:28073078).
The RING-type zinc finger domain is essential for its E3 ubiquitin-protein ligase activity, ability to positively regulate the NF-kappa-B signaling pathway and its antiviral activity.
Up-regulated by Golgi stress-inducing agents such nigericin, trichostatin, tetoposide, campothecin and brefeldin A (PubMed:31133683). Up-regulated by IL1B/interleukin-1 beta and TNFA/TNF-alpha (PubMed:28073078).
(Microbial infection) ADP-riboxanation by C.violaceum CopC blocks CASP3 processing, preventing CASP3 activation and ability to recognize and cleave substrates.
Cleavage by granzyme B, caspase-6, caspase-8 and caspase-10 generates the two active subunits (PubMed:7596430, PubMed:8755496, PubMed:35338844, PubMed:35446120). Additional processing of the propeptides is likely due to the autocatalytic activity of the activated protease (PubMed:7596430, PubMed:8755496). Active heterodimers between the small subunit of caspase-7 protease and the large subunit of caspase-3 also occur and vice versa (PubMed:7596430, PubMed:8755496).
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 17 kDa (p17) and a 12 kDa (p12) subunit. Interacts with BIRC6/bruce.
Highly expressed in lung, spleen, heart, liver and kidney. Moderate levels in brain and skeletal muscle, and low in testis. Also found in many cell lines, highest expression in cells of the immune system.
S-nitrosylated on its catalytic site cysteine in unstimulated human cell lines and denitrosylated upon activation of the Fas apoptotic pathway, associated with an increase in intracellular caspase activity. Fas therefore activates caspase-3 not only by inducing the cleavage of the caspase zymogen to its active subunits, but also by stimulating the denitrosylation of its active site thiol.
Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis (PubMed:7596430, PubMed:18723680, PubMed:20566630, PubMed:23650375, PubMed:35338844, PubMed:35446120). Following cleavage and activation by initiator caspases (CASP8, CASP9 and/or CASP10), mediates execution of apoptosis by catalyzing cleavage of many proteins (PubMed:7596430, PubMed:18723680, PubMed:20566630, PubMed:23650375). At the onset of apoptosis, it proteolytically cleaves poly(ADP-ribose) polymerase PARP1 at a '216-Asp-|-Gly-217' bond (PubMed:7774019, PubMed:7596430, PubMed:10497198, PubMed:16374543). Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain (By similarity). Cleaves and activates caspase-6, -7 and -9 (PubMed:7596430). Involved in the cleavage of huntingtin (PubMed:8696339). Triggers cell adhesion in sympathetic neurons through RET cleavage (PubMed:21357690). Cleaves and inhibits serine/threonine-protein kinase AKT1 in response to oxidative stress (PubMed:23152800). Acts as an inhibitor of type I interferon production during virus-induced apoptosis by mediating cleavage of antiviral proteins CGAS, IRF3 and MAVS, thereby preventing cytokine overproduction (PubMed:30878284). Also involved in pyroptosis by mediating cleavage and activation of gasdermin-E (GSDME) (PubMed:35446120, PubMed:35338844). Cleaves XRCC4 and phospholipid scramblase proteins XKR4, XKR8 and XKR9, leading to promote phosphatidylserine exposure on apoptotic cell surface (PubMed:23845944, PubMed:33725486).
Probable transcriptional regulator involved in developmental processes. This is major determinant crucial to palatogenesis.
Forms homodimers and heterodimers with SOX6.
Transcription factor involved in chondrocytes differentiation and cartilage formation. Specifically binds the 5'-AACAAT-3' DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis, including cartilage matrix protein-coding genes, such as COL2A1 and AGC1. Required for overt chondrogenesis when condensed prechondrocytes differentiate into early stage chondrocytes: SOX5 and SOX6 cooperatively bind with SOX9 on active enhancers and super-enhancers associated with cartilage-specific genes, and thereby potentiate SOX9's ability to transactivate. Not involved in precartilaginous condensation, the first step in chondrogenesis, during which skeletal progenitors differentiate into prechondrocytes. Together with SOX6, required to form and maintain a pool of highly proliferating chondroblasts between epiphyses and metaphyses, to form columnar chondroblasts, delay chondrocyte prehypertrophy but promote hypertrophy, and to delay terminal differentiation of chondrocytes on contact with ossification fronts. Binds to the proximal promoter region of the myelin protein MPZ gene.
Component of the RNA exosome complex (PubMed:29906447). Specifically part of the catalytically inactive RNA exosome core (Exo-9) complex which is believed to associate with catalytic subunits EXOSC10, and DIS3 or DIS3L in cytoplasmic- and nuclear-specific RNA exosome complex forms. Exo-9 is formed by a hexameric ring of RNase PH domain-containing subunits specifically containing the heterodimers EXOSC4-EXOSC9, EXOSC5-EXOSC8 and EXOSC6-EXOSC7, and peripheral S1 domain-containing components EXOSC1, EXOSC2 and EXOSC3 located on the top of the ring structure.
Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes.
Cleavage by S.pyogenes SpeB relieves autoinhibition by releasing the N-terminal moiety (Gasdermin-A, N-terminal) that initiates pyroptosis.
Expressed predominantly in the gastrointestinal tract and, at a lower level, in the skin. Also detected in mammary gland. In the gastrointestinal tract, mainly expressed in differentiated cells, including the differentiated cell layer of esophagus and mucus-secreting pit cells of the gastric epithelium. Down-regulated in gastric cancer cells.
Homooligomer; homooligomeric ring-shaped pore complex containing 18-36 subunits when inserted in the membrane.
Intramolecular interactions between N- and C-terminal domains are important for autoinhibition in the absence of activation signal. The intrinsic pyroptosis-inducing activity is carried by the N-terminal domain.
Pore-forming protein that causes membrane permeabilization and pyroptosis (PubMed:17471240, PubMed:27281216, PubMed:35110732, PubMed:35545676). Released upon cleavage by S.pyogenes effector protein SpeB, and binds to membrane inner leaflet lipids (PubMed:27281216, PubMed:35110732, PubMed:35545676). Homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:27281216, PubMed:35110732, PubMed:35545676). Pyroptosis triggers the elimination of the infected skin cell, depriving the pathogen of its protective niche, while inducing an inflammatory response (PubMed:35110732, PubMed:35545676). This ultimately prevents bacterial penetration of the epithelial barrier and a subsequent systemic dissemination of the pathogen (PubMed:35110732, PubMed:35545676). Binds to cardiolipin and other acidic phospholipids, such as phosphatidylserine, which mediate its targeting to the inner leaflet membrane (PubMed:27281216, PubMed:35110732).
The full-length protein before cleavage is inactive: intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of activation signal (By similarity). The intrinsic pyroptosis-inducing activity is carried by the released N-terminal moiety (Gasdermin-A, N-terminal) following cleavage by S.pyogenes effector protein SpeB (PubMed:35110732, PubMed:35545676).
This form constitutes the precursor of the pore-forming protein and acts as a sensor of infection: upon infection by S.pyogenes, specifically cleaved by S.pyogenes effector protein SpeB in epithelial cells, releasing the N-terminal moiety (Gasdermin-A, N-terminal) that binds to membranes and forms pores, triggering pyroptosis.
Expressed in melanocytes (at protein level).
Expressed in the kidney and retinal pigment epithelium.
Expressed in the retinal pigment epithelium, brain, and placenta (PubMed:9647758). Expressed in the kidney (PubMed:9647758, PubMed:10578055).
Homodimer or heterodimer; dimerization is mediated via the coiled coil region (PubMed:24631970). Efficient DNA binding requires dimerization with another bHLH protein (PubMed:14975237). Binds DNA in the form of homodimer or heterodimer with either TFE3, TFEB or TFEC (PubMed:15507434). Interacts with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD); promoting its recruitment to lysosomal membrane in the presence of nutrients (PubMed:23401004, PubMed:36608670). Interacts with KARS1 (PubMed:14975237). Identified in a complex with HINT1 and CTNNB1 (PubMed:22647378). Interacts with VSX2 (By similarity).
The disease is caused by variants affecting the gene represented in this entry. An allelic combination involving at least one dominant-negative mutation, inherited in a recessive manner, represents the underlying molecular mechanism leading to COMMAD syndrome.
The leucine zipper region is part of a larger coiled coil.
Transcription factor that acts as a master regulator of melanocyte survival and differentiation as well as melanosome biogenesis (PubMed:10587587, PubMed:22647378, PubMed:27889061, PubMed:9647758). Binds to M-boxes (5'-TCATGTG-3') and symmetrical DNA sequences (E-boxes) (5'-CACGTG-3') found in the promoter of pigmentation genes, such as tyrosinase (TYR) (PubMed:10587587, PubMed:22647378, PubMed:27889061, PubMed:9647758). Involved in the cellular response to amino acid availability by acting downstream of MTOR: in the presence of nutrients, MITF phosphorylation by MTOR promotes its inactivation (PubMed:36608670). Upon starvation or lysosomal stress, inhibition of MTOR induces MITF dephosphorylation, resulting in transcription factor activity (PubMed:36608670). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1) (PubMed:10587587, PubMed:22647378, PubMed:27889061, PubMed:9647758). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium (PubMed:10587587, PubMed:22647378, PubMed:27889061, PubMed:9647758).
Ubiquitinated by the SCF(BTRC) and SCF(FBXW11) complexes following phosphorylation ar Ser-5 by MTOR, leading to its degradation by the proteasome (PubMed:36608670). Ubiquitinated following phosphorylation at Ser-180, leading to subsequent degradation by the proteasome (PubMed:10673502). Deubiquitinated by USP13, preventing its degradation (PubMed:10673502).
Variations affecting this gene are associated with susceptibility to pheochromocytomas and paragangliomas, rare neural crest-derived tumors with an approximate incidence of 1:300,000/year.
When nutrients are present, phosphorylation by MTOR at Ser-5 via non-canonical mTORC1 pathway promotes ubiquitination by the SCF(BTRC) complex, followed by degradation (PubMed:36608670). Phosphorylation at Ser-405 significantly enhances the ability to bind the tyrosinase promoter (PubMed:10587587). Phosphorylation by MARK3/cTAK1 at Ser-280 promotes association with 14-3-3/YWHA adapters and retention in the cytosol (PubMed:16822840). Phosphorylated at Ser-180 and Ser-516 following KIT signaling, triggering a short live activation: Phosphorylation at Ser-180 and Ser-516 by MAPK and RPS6KA1, respectively, activate the transcription factor activity but also promote ubiquitination and subsequent degradation by the proteasome (PubMed:10673502). Phosphorylated in response to blue light (415nm) (PubMed:28842328).
Binds in a species-specific manner to the zona pellucida of the egg. May be involved in gamete recognition and/or signaling.
During sperm migration through the reproductive tracts, the mucin-like domain might inhibit inappropriate trapping of spermatozoa or promoting adhesion to the oviductal isthmus.
In testis, primarily in haploid spermatids.
The MAM domains probably mediate sperm adhesion to the zona pellucida.
The VWFD domain 2 may mediate covalent oligomerization.
Accumulates according to a robust circadian rhythm.
Belongs to the bZIP family. PAR subfamily.
Binds DNA as a homodimer or a heterodimer. Can form a heterodimer with DBP.
Transcription factor that binds to and transactivates the TSHB promoter. Binds to a minimal DNA-binding sequence 5'-[TC][AG][AG]TTA[TC][AG]-3'.
Glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate. Appears to have a function in striated muscle development and regeneration.
Mammalian enolase is composed of 3 isozyme subunits, alpha, beta and gamma, which can form homodimers or heterodimers which are cell-type and development-specific. Interacts with PNKD.
B30.2 box contains a microtubule-binding site.
Highly expressed in brain tissues, including cerebellum, cerebral cortex, medulla, occipital pole, frontal lobe, temporal lobe and putamen. Lower expression in spinal chord.
May be involved in microtubule organization and stabilization.
Oligomerization is required for binding to microtubules.
Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers.
Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection.
Cytokine that plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of pro-inflammatory chemokines, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone development. Required for normal male and female fertility. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration. Plays a role in lipoprotein clearance.
Homodimer or heterodimer; disulfide-linked (PubMed:1531650, PubMed:3264877, PubMed:8422357). Likely to exist in multiple forms: homodimer consisting of 2 identical 150-200 kDa proteoglycan subunits, heterodimer consisting of a 150-200 kDa proteoglycan subunit and a truncated 43 kDa subunit, and homodimer consisting of 2 identical 43 kDa subunits (PubMed:8051056). Interacts with CSF1R (PubMed:20504948).
O-glycosylated; contains chondroitin sulfate (PubMed:8051056, PubMed:1531650). O-glycosylated with core 1 or possibly core 8 glycans (PubMed:22171320, PubMed:23234360, PubMed:3264877).
Belongs to the potassium channel KCNN family. KCa2.1/KCNN1 subfamily.
Forms a voltage-independent potassium channel activated by intracellular calcium (PubMed:8781233, PubMed:9287325, PubMed:17142458). Activation is followed by membrane hyperpolarization (By similarity). Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization (By similarity).
Heterooligomer. The complex is composed of 4 channel subunits each of which binds to a calmodulin subunit which regulates the channel activity through calcium-binding (By similarity).
Inhibited by bee venom neurotoxin apamin (PubMed:9287325, PubMed:17142458). Inhibited by d-tubocurarine and tetraethylammonium (TEA) (PubMed:9287325, PubMed:17142458).
Has antimicrobial activity against E.coli (By similarity). Plays a role in the defense response in the male reproductive tract, contributing to sperm maturation, storage and protection (By similarity).
Specifically expressed in caput and proximal corpus of epididymis (at protein level) (PubMed:8167223). Present in the epididymal epithelium and on the sperm surface, with a subacrosomal equatorial distribution on the sperm head (at protein level) (PubMed:8167223).
In the testis, expressed mainly in A dark spermatogonia, mid and late spermatocytes and spermatids but not in mitotically active A pale and B spermatogonia.
May be involved in inflammation and spermatogenesis.
Upon heterologous expression, a small proportion of the isolated Pyrin domain forms homodimers and higher oligomers.
Although strongly related to RNA-specific endonuclease proteins, it lacks the HXHXDH motif that binds zinc and participates in the catalytic center. Its function as endonuclease is therefore unsure.
Belongs to the metallo-beta-lactamase superfamily. RNA-metabolizing metallo-beta-lactamase-like family. INTS9 subfamily.
Belongs to the peptidase M67A family. PSMD14 subfamily.
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD4, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD4 interacts with subunit PSMD7 through their respective MPN domain. Interacts with TXNL1 (PubMed:19349277).
Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. The PSMD14 subunit is a metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains within the complex. Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation. Also involved in homologous recombination repair by promoting RAD51 loading.
Widely expressed. Highest levels in heart and skeletal muscle.
Auxiliary protein of the large-conductance, voltage and calcium-activated potassium channel (BK alpha). Required for the conversion of BK alpha channels from a high-voltage to a low-voltage activated channel type in non-excitable cells. These are characterized by negative membrane voltages and constant low levels of calcium.
Isoform 1 is expressed highly in normal prostate and salivary gland, very weakly in colon, pancreas, and intestine, and not at all in other tissues. Isoform 1 is expressed highly in many cancer cell lines and in breast cancer, pancreatic cancer and colon cancer. Isoform 2 is expressed in cancer cell lines.
Translation initiates from a UGC codon. It is unsure whether the initiator amino acid is a modified cysteine or a methionine. Could also be the result of a proteolytic cleavage from a longer precursor.
Expressed in spleen, thymus, lung, brain, tonsil, heart and prostate.
Interacts with CHUK and IKBKB; prevents CHUK and IKBKB phosphorylation and inhibits their kinase activity. Interacts with RIGI and IFIH1; blocks the interaction of MAVS to RIGI.
Probable regulator of the NF-kappa-B and type I interferon signaling pathways. May also regulate the type II interferon signaling pathway. Plays a role in homeostatic control of innate immunity and in antiviral defense mechanisms.
Supposed to contain a CARD domain at the N-terminus (PubMed:20434986). However, this domain is not detected by Pfam, PROSITE or SMART. Has a weak similarity with a DAPIN domain.
A chromosomal aberration involving MLLT10 is associated with acute leukemias. Translocation t(10;11)(p12;q23) with KMT2A/MLL1. The result is a rogue activator protein.
A chromosomal aberration involving MLLT10 is associated with diffuse histiocytic lymphomas. Translocation t(10;11)(p13;q14) with PICALM.
Probably involved in transcriptional regulation. In vitro or as fusion protein with KMT2A/MLL1 has transactivation activity. Binds to cruciform DNA. In cells, binding to unmodified histone H3 regulates DOT1L functions including histone H3 'Lys-79' dimethylation (H3K79me2) and gene activation (PubMed:26439302).
Self-associates. Interacts with FSTL3 isoform 2; the interaction enhances MLLT10 in vitro transcriptional activity and self-association. Interacts with YEATS4. Interacts with SS18. Interacts with DOT1L; this interaction also occurs with the KMT2A/MLL1 fusion protein. Interacts with histone H3; interaction is necessary for MLLT10 binding to nucleosomes; interaction is inhibited by histone H3 'Lys-27' methylations (H3K27me1, H3K27me2 and H3K27me3) amd acetylation; interaction stabilizes association of MLLT10 at chromatin; interaction is essential for histone H3 'Lys-79' dimethylation (H3K79me2) (PubMed:26439302).
Endothelial and bone marrow stromal cells.
Interacts with RHOQ and CDC42, in a GTP-dependent manner.
Probably involved in the organization of the actin cytoskeleton. Induced membrane extensions in fibroblasts.
Cell adhesion protein that mediates homophilic cell adhesion in a calcium-independent manner (By similarity). Plays a role as coinhibitory receptor in immune response, insulin action and functions also as an activator during angiogenesis (PubMed:18424730, PubMed:23696226, PubMed:25363763). Its coinhibitory receptor function is phosphorylation- and PTPN6 -dependent, which in turn, suppress signal transduction of associated receptors by dephosphorylation of their downstream effectors. Plays a role in immune response, of T cells, natural killer (NK) and neutrophils (PubMed:18424730, PubMed:23696226). Upon TCR/CD3 complex stimulation, inhibits TCR-mediated cytotoxicity by blocking granule exocytosis by mediating homophilic binding to adjacent cells, allowing interaction with and phosphorylation by LCK and interaction with the TCR/CD3 complex which recruits PTPN6 resulting in dephosphorylation of CD247 and ZAP70 (PubMed:18424730). Also inhibits T cell proliferation and cytokine production through inhibition of JNK cascade and plays a crucial role in regulating autoimmunity and anti-tumor immunity by inhibiting T cell through its interaction with HAVCR2 (PubMed:25363763). Upon natural killer (NK) cells activation, inhibit KLRK1-mediated cytolysis of CEACAM1-bearing tumor cells by trans-homophilic interactions with CEACAM1 on the target cell and lead to cis-interaction between CEACAM1 and KLRK1, allowing PTPN6 recruitment and then VAV1 dephosphorylation (PubMed:23696226). Upon neutrophils activation negatively regulates IL1B production by recruiting PTPN6 to a SYK-TLR4-CEACAM1 complex, that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome. Down-regulates neutrophil production by acting as a coinhibitory receptor for CSF3R by down-regulating the CSF3R-STAT3 pathway through recruitment of PTPN6 that dephosphorylates CSF3R (By similarity). Also regulates insulin action by promoting INS clearance and regulating lipogenesis in liver through regulating insulin signaling (By similarity). Upon INS stimulation, undergoes phosphorylation by INSR leading to INS clearance by increasing receptor-mediated insulin endocytosis. This inernalization promotes interaction with FASN leading to receptor-mediated insulin degradation and to reduction of FASN activity leading to negative regulation of fatty acid synthesis. INSR-mediated phosphorylation also provokes a down-regulation of cell proliferation through SHC1 interaction resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 and phosphatidylinositol 3-kinase pathways (By similarity). Functions as activator in angiogenesis by promoting blood vessel remodeling through endothelial cell differentiation and migration and in arteriogenesis by increasing the number of collateral arteries and collateral vessel calibers after ischemia. Also regulates vascular permeability through the VEGFR2 signaling pathway resulting in control of nitric oxide production (By similarity). Down-regulates cell growth in response to EGF through its interaction with SHC1 that mediates interaction with EGFR resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 pathway (By similarity). Negatively regulates platelet aggregation by decreasing platelet adhesion on type I collagen through the GPVI-FcRgamma complex (By similarity). Inhibits cell migration and cell scattering through interaction with FLNA; interfers with the interaction of FLNA with RALA (PubMed:16291724). Mediates bile acid transport activity in a phosphorylation dependent manner (By similarity). Negatively regulates osteoclastogenesis (By similarity).
Cell adhesion protein that mediates homophilic cell adhesion in a calcium-independent manner (By similarity). Promotes populations of T cells regulating IgA production and secretion associated with control of the commensal microbiota and resistance to enteropathogens (By similarity).
Expressed in columnar epithelial cells of the colon (at protein level) (PubMed:10436421). The predominant forms expressed by T cells are those containing a long cytoplasmic domain (PubMed:18424730). Expressed in granulocytes and lymphocytes. Leukocytes only express isoforms 6 and isoform 1 (PubMed:11994468).
Ig-like V-type domain mediates trans-homophilic cell adhesion through homodimerization and this active process is regulated by tyrosine kinase, PTPN11 and PTPN6. Ig-like C2-type and/or cytoplasmic domains mediate cis-dimer/oligomer.
Induced in primary T cells by activation with IL-2.
Monomer. Oligomer. Heterodimer. Homodimer (PubMed:26483485). Cis-dimer/oligomer (via Ig-like C2-type and/or via cytoplasmic domains); induced by trans-homophilic cell adhesion through an allosteric mechanism transmitted by the Ig-like V-type domain, and is regulated by intracellular calcium and calmodulin. Interacts (via cytoplasmic domain) with calmodulin in a calcium dependent manner; reduces homophilic cell adhesion through dissociation of dimer (By similarity). Isoform 1 interacts (via cytoplasmic domain) with PTPN11 (preferentially) and PTPN6; cis-homodimer form is preferred; this interaction is decreased by formation of Isoform 1 /Isoform 8 cis-heterodimers and is dependent on the monomer/dimer equilibrium; this interaction is phosphorylation-dependent (PubMed:23696226). Isoform 1 interacts with LYN (By similarity). Isoform 1 interacts (via cytoplasmic domain) with SRC (via SH2 domain); this interaction is regulated by trans-homophilic cell adhesion (PubMed:7478590). Isoform 1 interacts (via cytoplasmic domain) with LCK; mediates phosphorylation at Tyr-493 and Tyr-520 resulting in PTPN6 association. Isoform 1 interacts with PTPN6; this interaction is phosphorylation-dependent and causes a profound decrease in TCR stimulation-induced CD247 and ZAP70 phosphorylation. Isoform 1 interacts with TCR/CD3 complex through TCR beta chain and CD3E; colocalizes at the cell surface and upon stimulation of the TCR/CD3 complex recruits PTPN6 in the TCR/CD3 complex, resulting in dephosphorylation of CD247 and ZAP70 (PubMed:18424730). Isoform 1 interacts (via cytoplasmic domain) with SHC1 (via SH2 domain); SHC1 mediates interaction with INSR or EGFR in a Ser-508 phosphorylation-dependent manner (By similarity). Isoform 1 interacts with EGFR; the interaction is indirect (PubMed:15467833). Isoform 1 interacts with CSF3R; down-regulates the CSF3R-STAT3 pathway through recruitment of PTPN6 that dephosphorylates CSF3R (By similarity). Isoform 1 (phosphorylated form) interacts with TLR4 and SYK; recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, leading to a reduction of the inflammasome activity (By similarity). Isoform 1 interacts with FLNA; inhibits cell migration and cell scattering by interfering with the interaction of FLNA with RALA (PubMed:16291724). Isoform 1 interacts (via cytoplasmic domain) with PXN; the interaction is phosphotyrosyl-dependent (PubMed:11035932). Isoform 1 interacts with KLRK1; recruits PTPN6 that dephosphorylates VAV1 (PubMed:23696226). Isoform 1 interacts with CEACAM8 (PubMed:11994468). Isoform 1 interacts with FASN; this interaction is insulin and phosphorylation-dependent; reduces fatty-acid synthase activity (By similarity). Interacts (via Ig-like V-type) with HAVCR2 (via Ig-like V-type); facilitates the maturation and cell surface expression of HAVCR2 thereby regulating T cell tolerance induction (PubMed:25363763). Isoform 8 interacts (via the cytoplasmic domain) with ANXA2; this interaction is regulated by phosphorylation and appears in the AIIt complex (PubMed:14522961). Interacts (via Lewis X moieties) with CD209 (via C-type lectin domain); this interaction is regulated by the glycosylation pattern of CEACAM1 on cell types and regulates contact between dendritic cells and neutrophils (PubMed:16246332).
Phosphorylated on serine and tyrosine (By similarity). Isoform 1 is phosphorylated on tyrosine by Src family kinases like SRC and LCK and by receptor like CSF3R, EGFR and INSR upon stimulation (PubMed:15467833, PubMed:18424730, PubMed:7478590). Phosphorylated at Ser-508; mediates activity. Phosphorylated at Tyr-493; regulates activity (By similarity). Phosphorylated at Tyr-493 by EGFR and INSR upon stimulation; this phosphorylation is Ser-508-phosphorylation-dependent; mediates cellular internalization; increases interaction with downstream proteins like SHC1 and FASN (By similarity). Phosphorylated at Tyr-493 and Tyr-520 by LCK; mediates PTPN6 association and is regulated by homophilic ligation of CEACAM1 in the absence of T cell activation (PubMed:18424730). Phosphorylated at Tyr-520; mediates interaction with PTPN11 (By similarity).
Pseudophosphorylated double mutant Thr-457->Asp and Ser-459->Asp. The single mutant Ser-459->Asp mutant highly binds with ANXA2.
Expressed in the brain, with highest levels found in the amygdala, nucleus caudatus, thalamus and hippocampus.
Interacts with ATP1B1. Part of a complex containing ATP1B1, TRPV4, AQP4 and HEPACAM.
Regulates the response of astrocytes to hypo-osmosis by promoting calcium influx.
Required for sound encoding at inner hair cells (IHCs) synapses, likely via inhibition of the inactivation of voltage-gated calcium channel of type 1.3 (Cav1.3) in the IHCs (PubMed:28183797). Required for the normal transfer of light signals through the retina (By similarity).
Belongs to the Mediator complex subunit 20 family.
Interacts with PPARG (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.
It is not yet known where COX8C is expressed.
Binds 1 Mg(2+) ions per subunit. Binds 2 divalent metal cations per subunit: site 1 preferentially binds zinc, while site 2 has a preference for magnesium. Binds magnesium less tightly than zinc.
Binds 1 Zn(2+) ion per subunit. Binds 2 divalent metal cations per subunit: site 1 preferentially binds zinc, while site 2 has a preference for magnesium. Tightly binds zinc.
Composed of a C-terminal catalytic domain containing two putative divalent metal sites and an N-terminal regulatory domain which contains two homologous allosteric cGMP-binding regions, A and B.
Expressed in aortic smooth muscle cells, heart, placenta, skeletal muscle and pancreas and, to a much lesser extent, in brain, liver and lung.
Phosphorylation is regulated by binding of cGMP to the two allosteric sites (By similarity). Phosphorylation by PRKG1 leads to its activation.
Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP (PubMed:9714779, PubMed:15489334). Specifically regulates nitric-oxide-generated cGMP (PubMed:15489334).
Sildenafil (Viagra) is a highly selective and potent inhibitor of PDE5A and is effective in the treatment of penile erectile dysfunction. Also inhibited by zaprinast.
Was initially thought to act as a major regulator of cardiac hypertrophy in myocytes and muscle and investigations have been made on selective PDE5A inhibitors that could protect against cardiovascular disease. However, while PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signaling is often depressed by heart disease, limiting its effect. Moreover, clinical trial using PDE5A inhibitors were disappointing.
Divalent metal ions. Mg(2+) is the most effective.
Functions as a pyridoxal phosphate (PLP) phosphatase, which also catalyzes the dephosphorylation of pyridoxine 5'-phosphate (PNP) and pyridoxamine 5'-phosphate (PMP), with order of substrate preference PLP > PNP > PMP and therefore plays a role in vitamin B6 metabolism (PubMed:14522954, PubMed:8132548). Also functions as a protein serine phosphatase that specifically dephosphorylates 'Ser-3' in proteins of the actin-depolymerizing factor (ADF)/cofilin family like CFL1 and DSTN. Thereby, regulates cofilin-dependent actin cytoskeleton reorganization, being required for normal progress through mitosis and normal cytokinesis. Does not dephosphorylate phosphothreonines in LIMK1. Does not dephosphorylate peptides containing phosphotyrosine (PubMed:15580268).
Inhibited by NaF, Zn(2+), Ca(2+), Mn(2+) and EDTA.
Ubiquitously expressed (at protein level) (PubMed:23223568). Highly expressed in all the regions of central nerve system except the spinal cord. Also expressed at high level in liver and testis. In fetus, it is weakly expressed in all organs except brain (PubMed:14522954, PubMed:15580268).
A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with KMT2A/MLL1.
Deacetylation by SIRT1 or SIRT2 stimulates interaction of FOXO3 with SKP2 and facilitates SCF(SKP2)-mediated FOXO3 ubiquitination and proteasomal degradation (PubMed:21841822). Deacetylation by SIRT2 stimulates FOXO3-mediated transcriptional activity in response to oxidative stress (By similarity). Deacetylated by SIRT3 (PubMed:23283301). Deacetylation by SIRT3 stimulates FOXO3-mediated mtDNA transcriptional activity in response to metabolic stress (PubMed:23283301).
Heavily methylated by SET9 which decreases stability, while moderately increasing transcriptional activity. The main methylation site is Lys-271. Methylation doesn't affect subcellular location.
In the presence of survival factors such as IGF-1, phosphorylated on Thr-32 and Ser-253 by AKT1/PKB (PubMed:10102273). This phosphorylated form then interacts with 14-3-3 proteins and is retained in the cytoplasm (PubMed:10102273). Survival factor withdrawal induces dephosphorylation and promotes translocation to the nucleus where the dephosphorylated protein induces transcription of target genes and triggers apoptosis (PubMed:10102273). Although AKT1/PKB doesn't appear to phosphorylate Ser-315 directly, it may activate other kinases that trigger phosphorylation at this residue (PubMed:10102273, PubMed:11154281). Phosphorylated by STK4/MST1 on Ser-209 upon oxidative stress, which leads to dissociation from YWHAB/14-3-3-beta and nuclear translocation (PubMed:16751106). Phosphorylated by PIM1 (PubMed:18593906). Phosphorylation by AMPK leads to the activation of transcriptional activity without affecting subcellular localization (PubMed:17711846). In response to metabolic stress, phosphorylated by AMPK on Ser-30 which mediates FOXO3 mitochondrial translocation (PubMed:29445193). Phosphorylation by MAPKAPK5 promotes nuclear localization and DNA-binding, leading to induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation (PubMed:21329882). Phosphorylated by CHUK/IKKA and IKBKB/IKKB (PubMed:15084260). TNF-induced inactivation of FOXO3 requires its phosphorylation at Ser-644 by IKBKB/IKKB which promotes FOXO3 retention in the cytoplasm, polyubiquitination and ubiquitin-mediated proteasomal degradation (PubMed:15084260). May be dephosphorylated by calcineurin A on Ser-299 which abolishes FOXO3 transcriptional activity (By similarity). In cancer cells, ERK mediated-phosphorylation of Ser-12 is required for mitochondrial translocation of FOXO3 in response to metabolic stress or chemotherapeutic agents (PubMed:29445193). Phosphorylation at Ser-253 promotes its degradation by the proteasome (PubMed:30513302). Dephosphorylation at Ser-253 by protein phosphatase 2A (PPP2CA) promotes its stabilization; interaction with PPP2CA is enhanced by AMBRA1 (PubMed:30513302).
Polyubiquitinated. Ubiquitinated by a SCF complex containing SKP2, leading to proteasomal degradation.
The N-terminus is cleaved following import into the mitochondrion.
Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes, such as apoptosis and autophagy (PubMed:10102273, PubMed:16751106, PubMed:21329882, PubMed:30513302). Acts as a positive regulator of autophagy in skeletal muscle: in starved cells, enters the nucleus following dephosphorylation and binds the promoters of autophagy genes, such as GABARAP1L, MAP1LC3B and ATG12, thereby activating their expression, resulting in proteolysis of skeletal muscle proteins (By similarity). Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress (PubMed:10102273, PubMed:16751106). Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation (PubMed:21329882). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription (PubMed:23283301). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (By similarity). Also acts as a key regulator of regulatory T-cells (Treg) differentiation by activating expression of FOXP3 (PubMed:30513302).
Upon metabolic stress, forms a complex composed of FOXO3, SIRT3 and mitochondrial RNA polymerase POLRMT; the complex is recruited to mtDNA in a SIRT3-dependent manner (PubMed:23283301). Also forms a complex composed of FOXO3, SIRT3, TFAM and POLRMT (PubMed:29445193). Interacts with SIRT2; the interaction occurs independently of SIRT2 deacetylase activity (By similarity). Interacts with YWHAB/14-3-3-beta and YWHAZ/14-3-3-zeta, which are required for cytosolic sequestration (PubMed:16751106). Upon oxidative stress, interacts with STK4/MST1, which disrupts interaction with YWHAB/14-3-3-beta and leads to nuclear translocation (PubMed:16751106). Interacts with PIM1 (PubMed:18593906). Interacts with DDIT3/CHOP (PubMed:22761832). Interacts (deacetylated form) with SKP2 (PubMed:21841822). Interacts with CHUK and IKBKB (PubMed:15084260, PubMed:22313691). Interacts with CAMK2A, CAMK2B and calcineurin A (By similarity). Interacts with NUPR1; this interaction represses FOXO3 transactivation (PubMed:20181828).
Contains 2 Inka boxes (also named iBox or inca box) (PubMed:26607847). The Inka boxes bind and inhibit PAK4 by binding a substrate-like manner (PubMed:26607847).
Inhibitor of the serine/threonine-protein kinase PAK4 (PubMed:26607847). Acts by binding PAK4 in a substrate-like manner, inhibiting the protein kinase activity (PubMed:26607847).
Expressed in fetal brain, heart, kidney, liver, lung, skeletal muscle, spleen and thymus. In dividing cells expression increases during S and G2 phases, peaks at mitosis and subsequently drops as cells enter G1 phase.
Interacts with F-actin (PubMed:10931866). Interacts with CD2AP (PubMed:15800069). May interact with RHOA (PubMed:16357138). Interacts with FZR1/CDH1 during mitotic exit (PubMed:16040610).
Required for cytokinesis (PubMed:16040610). Essential for the structural integrity of the cleavage furrow and for completion of cleavage furrow ingression. Plays a role in bleb assembly during metaphase and anaphase of mitosis (PubMed:23870127). May play a significant role in podocyte cell migration (PubMed:24676636).
Ubiquitinated, and this requires FZR1/CDH1.
Ubiquitously expressed. Present at highest levels in the brain, at high levels in the placenta and testis, at intermediate levels in the intestine, ovary, skeletal muscle and thymus and at lower levels in heart, kidney, liver, lung, pancreas, prostate and spleen. In the kidney, it is widely expressed in tubules, but sparsely expressed in the glomerulus (PubMed:24676636). Expression is significantly increased in renal biopsy specimens from idiopathic FSGS (PubMed:24676636). Overexpressed in many tumor types including breast, colorectal, endometrial, hepatic, kidney, lung, ovarian and pancreatic tumors.
Functions as a negative regulator of MYRF in oligodendrocyte differentiation and myelination. Interacts with the C-terminal of MYRF inhibiting MYRF self-cleavage and N-fragment nuclear translocation. The secreted form promotes differentiation of T helper 1 cells (Th1).
Interacts (via N-terminal region) with MYRF; the interaction inhibits MYRF self-cleavage.
Widely expressed with high expression in the ovary, pancreas and prostate (PubMed:25946230). Expressed in the eye, particularly in corneal endothelium, iris, ciliary body, sclera, optic nerve, optic nerve head, and retina (PubMed:24852644). Expressed by activated peripheral blood mononuclear cells (PubMed:25946230).
Is part of a complex with DLG4/PSD-95 and DLGAP1/GKAP. Interacts with CTTN/cortactin SH3 domain, DLGAP1/GKAP and alpha-latrotoxin receptor 1. Interacts with DNM2, DBNL, GRID2, BAIAP2, SLC9A3, PLCB3 and CFTR. Interacts (via proline-rich region) with PDE4D. Interacts with ABI1 (via SH3 domain).
Isoform 3 is present in epithelial colonic cells (at protein level).
Seems to be an adapter protein in the postsynaptic density (PSD) of excitatory synapses that interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors, and the actin-based cytoskeleton. May play a role in the structural and functional organization of the dendritic spine and synaptic junction.
The PDZ domain is required for interaction with GRID2, PLCB3, CFTR and SLC9A3.
Forms an interface between the RNA polymerase II enzyme and chaperone/scaffolding protein, suggesting that it is required to connect RNA polymerase II to regulators of protein complex formation.
Tightly associated with the RNA polymerase II complex (PubMed:17643375). Component of the R2TP complex composed at least of RUVBL1, RUVBL2, RPAP3 and PIHD1 (PubMed:20864032). Component of the PAQosome complex which is responsible for the biogenesis of several protein complexes and which consists of R2TP complex members RUVBL1, RUVBL2, RPAP3 and PIH1D1, URI complex members PFDN2, PFDN6, PDRG1, UXT and URI1 as well as ASDURF, POLR2E and DNAAF10/WDR92 (PubMed:31738558). Interacts with PIH1D1 (PubMed:21078300). Interacts with TSC1 and TSC2 (PubMed:28561026). Interacts with PRPF8 and EFTUD2 in a ZNHIT2-dependent manner (PubMed:28561026).
Detected in adult an fetal brain. Detected in heart, kidney, skeletal muscle, small intestine, lung, prostate and testis.
Isoform 1 appears to be a stable component of the Pol II(G) complex form of RNA polymerase II (Pol II). Pol II synthesizes mRNA precursors and many functional non-coding RNAs and is the central component of the basal RNA polymerase II transcription machinery. Isoform 1 may play a role in the Mediator complex-dependent regulation of transcription activation. Isoform 1 acts in vitro as a negative regulator of transcriptional activation; this repression is relieved by the Mediator complex, which restores Pol II(G) activator-dependent transcription to a level equivalent to that of Pol II.
Isoform 1 is a component of the Pol II(G) complex, which contains the RNA polymerase II (Pol II) core complex subunits and POLR2M isoform 1. Pol II(G) appears to be an abundant form of Pol II.
May have microtubule-stabilizing activity.
Palmitoylated. Palmitoylation enhances association with microtubules.
Forms homodimers and heterodimers with PHETA. Interacts with OCRL and INPP5B.
Glycosylated. Glycosylation at Asn-113 may occur at a secondary level. Glycosylation is necessary for proper targeting of the transporter to the plasma membrane.
Involved in the renal transport of a variety of drugs with well-known nephrotoxic potential, therefore may play a role in the etiology of the drug-associated nephrotoxicity (PubMed:10462545, PubMed:12538807). Uptakes the diagnostic agent PAH/para-aminohippurate and clinically used drugs (PubMed:9762842, PubMed:9887087, PubMed:10462545, PubMed:12538807, PubMed:15644426, PubMed:17038320, PubMed:17502342, PubMed:23832370, PubMed:26377792, PubMed:15914676). Mediates the pH- and chloride-dependent bidirectional transport of PAH/para-aminohippurate in exchange for 2-oxoglutarate or glutarate as counteranions (PubMed:9950961, PubMed:15644426, PubMed:26377792). Can also mediate PAH/cGMP exchange (PubMed:26377792).
Multiple cysteine residues are necessary for proper targeting to the plasma membrane.
Secondary active transporter that functions as a Na(+)-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate (PubMed:9950961, PubMed:11907186, PubMed:11669456, PubMed:14675047, PubMed:22108572, PubMed:23832370, PubMed:28534121). Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (PubMed:9887087). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186). Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792). Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370). May transport glutamate (PubMed:26377792). Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:11669456, PubMed:14675047). Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792). Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651).
Strongly expressed in kidney (PubMed:9887087, PubMed:9950961, PubMed:10049739, PubMed:10462545, PubMed:10964714). Expressed at lower level in liver, skeletal muscle, brain and placenta (PubMed:9887087, PubMed:9950961, PubMed:10049739, PubMed:10462545). In kidney, found at the basolateral membrane of the proximal tubule (PubMed:9887087). In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed in Leydig cells and vascular endothelial cells (PubMed:35307651).
(Microbial infection) Interacts with HTLV1 Rex protein (via N-terminal nuclear localization signal).
(Microbial infection) Interacts with hepatitis delta virus S-HDAg.
A chromosomal aberration involving NPM1 is a cause of myelodysplastic syndrome (MDS). Translocation t(3;5)(q25.1;q34) with MLF1.
A chromosomal aberration involving NPM1 is found in a form of acute promyelocytic leukemia. Translocation t(5;17)(q32;q11) with RARA.
A chromosomal aberration involving NPM1 is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with ALK. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated.
Acetylated at C-terminal lysine residues, thereby increasing affinity to histones.
Decamer formed by two pentameric rings associated in a head-to-head fashion (By similarity). Disulfide-linked dimers under certain conditions (PubMed:25818168). The SWAP complex consists of NPM1, NCL, PARP1 and SWAP70 (By similarity). Interacts with NSUN2 and SENP3. Interacts with the methylated form of RPS10. Interacts (via N-terminal domain) with APEX1; the interaction is RNA-dependent and decreases in hydrogen peroxide-damaged cells. Interacts with isoform 1 of NEK2. Interacts with ROCK2 and BRCA2. Interacts with RPGR. Interacts with CENPW. Interacts with EIF2AK2/PKR. Interacts with CEBPA (isoform 4) (PubMed:20075868). Interacts with DDX31; this interaction prevents interaction between NPM1 and HDM2 (PubMed:23019224). Interacts with MYC; competitive with NOP53 (PubMed:25956029). Interacts with NOP53; the interaction is direct and competitive with MYC (PubMed:25956029). Interacts with LRRC34 (By similarity). Interacts with RRP1B (PubMed:19710015, PubMed:20926688). Interacts with NPM3 (PubMed:22362753). Interacts with ALKBH2 (PubMed:23972994). Interacts with TTF1 (via C-terminal region) (By similarity).
Defects in NPM1 are associated with acute myelogenous leukemia (AML). Mutations in exon 12 affecting the C-terminus of the protein are associated with an aberrant cytoplasmic location.
Involved in diverse cellular processes such as ribosome biogenesis, centrosome duplication, protein chaperoning, histone assembly, cell proliferation, and regulation of tumor suppressors p53/TP53 and ARF. Binds ribosome presumably to drive ribosome nuclear export. Associated with nucleolar ribonucleoprotein structures and bind single-stranded nucleic acids. Acts as a chaperonin for the core histones H3, H2B and H4. Stimulates APEX1 endonuclease activity on apurinic/apyrimidinic (AP) double-stranded DNA but inhibits APEX1 endonuclease activity on AP single-stranded RNA. May exert a control of APEX1 endonuclease activity within nucleoli devoted to repair AP on rDNA and the removal of oxidized rRNA molecules. In concert with BRCA2, regulates centrosome duplication. Regulates centriole duplication: phosphorylation by PLK2 is able to trigger centriole replication. Negatively regulates the activation of EIF2AK2/PKR and suppresses apoptosis through inhibition of EIF2AK2/PKR autophosphorylation. Antagonizes the inhibitory effect of ATF5 on cell proliferation and relieves ATF5-induced G2/M blockade (PubMed:22528486). In complex with MYC enhances the transcription of MYC target genes (PubMed:25956029). May act as chaperonin or cotransporter in the nucleolar localization of transcription termination factor TTF1 (By similarity).
Phosphorylated at Ser-4 by PLK1 and PLK2. Phosphorylation at Ser-4 by PLK2 in S phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at Ser-4 by PLK1 takes place during mitosis. Phosphorylated by CDK2 at Ser-125 and Thr-199. Phosphorylation at Thr-199 may trigger initiation of centrosome duplication. Phosphorylated by CDK1 at Thr-199, Thr-219, Thr-234 and Thr-237 during cell mitosis. When these four sites are phosphorated, RNA-binding activity seem to be abolished. May be phosphorylated at Ser-70 by NEK2. The Thr-199 phosphorylated form has higher affinity for ROCK2. CDK6 triggers Thr-199 phosphorylation when complexed to Kaposi's sarcoma herpesvirus (KSHV) V-cyclin, leading to viral reactivation by reducing viral LANA levels.
Ubiquitinated. Ubiquitination leads to proteasomal degradation. Deubiquitinated by USP36 (PubMed:19208757).
As part of the central apparatus of the cilium axoneme plays a role in cilium movement.
Expressed in mammary, salivary glands and prostate. Also detected in lung. Mainly expressed in cancer cell lines of breast origin. Highly expressed in lymph node-positive compared with node-negative tumors. Detected in all lymph node containing metastatic cells.
May play a role as marker for the diagnosis of metastatic breast cancer.
The number of repeats varies from 3 to 2 in one variant form which is equally present in breast cancer tumors.
Overexpressed in tumor cells lines with a t(11;14)(q13;q32) translocation.
Interacts with CYTH2. Interacts with KPNA2; the interaction is direct. Does not interact with ARL4A.
Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). GTP-binding protein that does not act as an allosteric activator of the cholera toxin catalytic subunit. Recruits CYTH1, CYTH2, CYTH3 and CYTH4 to the plasma membrane in GDP-bound form.
Expressed in adult testis, prostate, prostate, spleen, thymus, skeletal muscle, fetal kidney and brain.
Component of the THO complex, which is composed of THOC1, THOC2, THOC3, THOC5, THOC6 and THOC7; together with at least ALYREF/THOC4, DDX39B, SARNP/CIP29 and CHTOP, THO forms the transcription/export (TREX) complex which seems to have a dynamic structure involving ATP-dependent remodeling. Interacts with THOC1, POLDIP3 and ZC3H11A.
Expressed in the hippocampus and the cerebral cortex.
Required for efficient export of polyadenylated RNA and spliced mRNA. Acts as component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NFX1 pathway. The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production. THOC2 (and probably the THO complex) is involved in releasing mRNA from nuclear speckle domains. Required for NXF1 localization to the nuclear rim. Plays a role for proper neuronal development.
Kinase that phosphorylates MYL2 in vitro. Promotes sarcomere formation in cardiomyocytes and increases cardiomyocyte contractility (By similarity).
Contains two rhodanese domains with different primary structures but with near identical secondary structure conformations suggesting a common evolutionary origin. Only the C-terminal rhodanese domain contains the catalytic cysteine residue (By similarity).
Formation of iron-sulfur complexes, cyanide detoxification or modification of sulfur-containing enzymes. Other thiol compounds, besides cyanide, can act as sulfur ion acceptors. Also has weak mercaptopyruvate sulfurtransferase (MST) activity (By similarity). Together with MRPL18, acts as a mitochondrial import factor for the cytosolic 5S rRNA. Only the nascent unfolded cytoplasmic form is able to bind to the 5S rRNA.
Binds 'Lys-48'-linked polyubiquitin chains of ubiquitinated proteins (PubMed:24160817). Associates with the proteasome complex; upon exposure to arsenite (By similarity). Interacts (via VIM motif) with VCP; the interaction is direct (PubMed:21896481, PubMed:24160817, PubMed:26337389). Interacts with BAG6 (PubMed:24160817, PubMed:26337389). Interacts with IGF1R (nascent precursor form) (PubMed:26692333). Interacts with DERL1, FAF2, NPLOC4 and UFD1; probably through VCP (PubMed:24160817).
Down-regulated by the miRNA miR-125a-3p in myelo-proliferative neoplasms.
Phosphorylated by MAPK14. Phosphorylation has no effect on association with the proteasome complex.
Plays a role in protein homeostasis by regulating both the translocation and the ubiquitin-mediated proteasomal degradation of nascent proteins at the endoplasmic reticulum. It is involved in the regulation of signal-mediated translocation of proteins into the endoplasmic reticulum. It also plays a role in the ubiquitin-mediated proteasomal degradation of proteins for which signal-mediated translocation to the endoplasmic reticulum has failed. May therefore function in the endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation (By similarity). By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333).
The UIM domains specifically bind 'Lys-48'-linked ubiquitin polymers. The UIM domains mediate interaction with polyubiquitinated proteins.
Catalyzes the formation of diacylglycerol from 2-monoacylglycerol and fatty acyl-CoA. Has a preference toward monoacylglycerols containing unsaturated fatty acids in an order of C18:3 > C18:2 > C18:1 > C18:0. Plays a central role in absorption of dietary fat in the small intestine by catalyzing the resynthesis of triacylglycerol in enterocytes. May play a role in diet-induced obesity. Also able to use 1-monoalkylglycerol (1-MAkG) as an acyl acceptor for the synthesis of monoalkyl-monoacylglycerol (MAMAG) (PubMed:28420705).
Highly expressed in liver, small intestine, colon, stomach and kidney.
Inhibited by oleic acid and sphingosine, while it is stimulated by phosphatidylcholine, phosphatidylserine and phosphatidic acid.
Both CR1 and CR2 regions are required for speckled nuclear localization.
Homooligomer (PubMed:27732854). Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5 (PubMed:33283408, PubMed:28977666, PubMed:16428440). The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes (PubMed:33283408, PubMed:16428440, PubMed:28977666, PubMed:27732854). Interacts with MBD2; this is required for the enhancement of MBD2-mediated repression and for targeting to the chromatin (PubMed:11756549, PubMed:12183469, PubMed:16415179, PubMed:27732854). Interacts with MBD3 (PubMed:11756549, PubMed:12183469, PubMed:27732854). Component of the MeCP1 histone deacetylase complex (PubMed:11756549). Interacts with histone tails, including that of histones H2A, H2B, H3 and H4 (PubMed:16415179). Interacts with ERCC6 (PubMed:26030138).
Transcriptional repressor (PubMed:12183469, PubMed:16415179). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:28977666). Enhances MBD2-mediated repression (PubMed:12183469, PubMed:16415179). Efficient repression requires the presence of GATAD2A (PubMed:16415179). Targets MBD3 to discrete loci in the nucleus (PubMed:11756549). May play a role in synapse development (PubMed:23644463).
E3 ubiquitin-protein ligase that plays a role in the establishment and maintenance of neuronal transmission and plasticity. Ubiquitinates the Na(+)/K(+) ATPase alpha-1 subunit/ATP1A1 and thereby influences its endocytosis and/or degradation (PubMed:22797923). Acts also as a positive regulator of mTORC1 activation by amino acids, which functions upstream of the V-ATPase and of Rag-GTPases (PubMed:27244671). In turn, phosphorylation by mTOR leads to its inhibition via targeting to the cytosol allowing a self-regulating feedback mechanism (PubMed:27244671).
Highly expressed in the brain, with higher expression during development than in adult. Expressed also in mammary glands, testis, colon and kidney.
Interacts with UBE2N (PubMed:16215985). Interacts with ZNRF1 (PubMed:22797923). Interacts (when phosphorylated) with YWHAE (PubMed:22797923).
Phosphorylated; leading to binding to YWHAE (PubMed:22797923). Phosphorylated by MTOR at Ser-145 and dephosphorylated by PP6C. Ser-145 phosphorylation stimulates vesicle-to-cytosol translocation (PubMed:27244671).
The RING-type zinc finger domain is required for E3 ligase activity.
Laminin is a complex glycoprotein, consisting of three different polypeptide chains (alpha, beta, gamma), which are bound to each other by disulfide bonds into a cross-shaped molecule comprising one long and three short arms with globules at each end. Alpha-3 is a subunit of laminin-5 (laminin-332 or epiligrin/kalinin/nicein), laminin-6 (laminin-311 or K-laminin) and laminin-7 (laminin-321 or KS-laminin).
Laminin-5 is thought to be involved in (1) cell adhesion via integrin alpha-3/beta-1 in focal adhesion and integrin alpha-6/beta-4 in hemidesmosomes, (2) signal transduction via tyrosine phosphorylation of pp125-FAK and p80, (3) differentiation of keratinocytes.
Laminin-5 is up-regulated in wound sites of human skin.
Skin; respiratory, urinary, and digestive epithelia and in other specialized tissues with prominent secretory or protective functions. Epithelial basement membrane, and epithelial cell tongue that migrates into a wound bed. A differential and focal expression of the subunit alpha-3 is observed in the CNS.
Asymmetrically dimethylated at arginines, probably by PRMT1, methylation promotes localization to nuclear speckles.
Consists of two polypeptides of p32 and p33. Identified in the spliceosome C complex (PubMed:11991638). Component of a ribonucleoprotein complex containing mRNAs and RNA-binding proteins including DDX5, HNRNPH2 and SRSF1 as well as splicing regulator ARVCF (PubMed:24644279). In vitro, self-associates and binds SRSF2, SNRNP70 and U2AF1 but not U2AF2. Binds SREK1/SFRS12. Interacts with SAFB/SAFB1. Interacts with PSIP1/LEDGF. Interacts with RSRC1 (via Arg/Ser-rich domain). Interacts with ZRSR2/U2AF1-RS2. Interacts with CCDC55 (via C-terminus). Interacts with SRPK1 and a sliding docking interaction is essential for its sequential and processive phosphorylation by SRPK1. Interacts with NXF1. Interacts with CCNL1, CCNL2 and CDK11B (PubMed:18216018). Interacts with RRP1B (PubMed:23604122). Interacts (when phosphorylated in its RS domain) with TNPO3; promoting nuclear import (PubMed:24449914). Interacts with ILDR1 (via C-terminus) and ILDR2 (By similarity).
Phosphorylated by CLK1, CLK2, CLK3 and CLK4. Phosphorylated by SRPK1 at multiple serines in its RS domain via a directional (C-terminal to N-terminal) and a dual-track mechanism incorporating both processive phosphorylation (in which the kinase stays attached to the substrate after each round of phosphorylation) and distributive phosphorylation steps (in which the kinase and substrate dissociate after each phosphorylation event). The RS domain of SRSF1 binds to a docking groove in the large lobe of the kinase domain of SRPK1 and this induces certain structural changes in SRPK1 and/or RRM 2 domain of SRSF1, allowing RRM 2 to bind the kinase and initiate phosphorylation. The cycles continue for several phosphorylation steps in a processive manner (steps 1-8) until the last few phosphorylation steps (approximately steps 9-12). During that time, a mechanical stress induces the unfolding of the beta-4 motif in RRM 2, which then docks at the docking groove of SRPK1. This also signals RRM 2 to begin to dissociate, which facilitates SRSF1 dissociation after phosphorylation is completed.
Plays a role in preventing exon skipping, ensuring the accuracy of splicing and regulating alternative splicing. Interacts with other spliceosomal components, via the RS domains, to form a bridge between the 5'- and 3'-splice site binding components, U1 snRNP and U2AF. Can stimulate binding of U1 snRNP to a 5'-splice site-containing pre-mRNA. Binds to purine-rich RNA sequences, either the octamer, 5'-RGAAGAAC-3' (r=A or G) or the decamers, AGGACAGAGC/AGGACGAAGC. Binds preferentially to the 5'-CGAGGCG-3' motif in vitro. Three copies of the octamer constitute a powerful splicing enhancer in vitro, the ASF/SF2 splicing enhancer (ASE) which can specifically activate ASE-dependent splicing. Isoform ASF-2 and isoform ASF-3 act as splicing repressors. May function as export adapter involved in mRNA nuclear export through the TAP/NXF1 pathway.
The RRM 2 domain plays an important role in governing both the binding mode and the phosphorylation mechanism of the RS domain by SRPK1. RS domain and RRM 2 are uniquely positioned to initiate a highly directional (C-terminus to N-terminus) phosphorylation reaction in which the RS domain slides through an extended electronegative channel separating the docking groove of SRPK1 and the active site. RRM 2 binds toward the periphery of the active site and guides the directional phosphorylation mechanism. Both the RS domain and an RRM domain are required for nucleocytoplasmic shuttling.
Heterodimer with IL20RB and heterodimer with IL10RB.
The IL20RA/IL20RB dimer is a receptor for IL19, IL20 and IL24. The IL20RA/IL10RB dimer is a receptor for IL26.
Widely expressed with highest levels in skin and testis and high levels in brain. Highly expressed in psoriatic skin.
Binds to linker H1 histones but not to core histones (By similarity). Interacts with histones H2A, H2B, H3 and H4 (PubMed:8724350, PubMed:27618665). Interacts with histone H3.3 (PubMed:33857403). Also binds to HSP90 in the cytoplasm. This interaction stimulates binding of NASP to H1-6/H1T (By similarity).
Isoform 1 is testis- and sperm-specific.
Required for DNA replication, normal cell cycle progression and cell proliferation. Forms a cytoplasmic complex with HSP90 and H1 linker histones and stimulates HSP90 ATPase activity. NASP and H1 histone are subsequently released from the complex and translocate to the nucleus where the histone is released for binding to DNA.
Homooligomer and heterooligomer with RASGRF2. Interacts with USP8, thereby regulating its stability (By similarity).
Phosphorylated by PLK2, leading to ubiquitination and degradation by the proteasome.
Phosphorylated by SRC and LCK. Phosphorylation by LCK increases its capacity to stimulate the GDP/GTP exchange on Ras, whereas its phosphorylation by SRC seems not to have an effect on stimulation activity.
The DH (DBL-homology) domain mediates interaction with RASGRF2.
Ubiquitinated and degraded following phosphorylation by PLK2.
(Microbial infection) Interacts with Staphylococcus aureus protein SdrC; this interaction increases S.aureus adherence to cells.
Cell surface protein involved in cell-cell-interactions, exocytosis of secretory granules and regulation of signal transmission. Function is isoform-specific. Alpha-type isoforms have a long N-terminus with six laminin G-like domains and play an important role in synaptic signal transmission. Alpha-type isoforms play a role in the regulation of calcium channel activity and Ca(2+)-triggered neurotransmitter release at synapses and at neuromuscular junctions. They play an important role in Ca(2+)-triggered exocytosis of secretory granules in pituitary gland. They may affect their functions at synapses and in endocrine cells via their interactions with proteins from the exocytotic machinery. Likewise, alpha-type isoforms play a role in regulating the activity of postsynaptic NMDA receptors, a subtype of glutamate-gated ion channels. Both alpha-type and beta-type isoforms may play a role in the formation or maintenance of synaptic junctions via their interactions (via the extracellular domains) with neuroligin family members, CBLN1 or CBLN2. In vitro, triggers the de novo formation of presynaptic structures. May be involved in specification of excitatory synapses. Alpha-type isoforms were first identified as receptors for alpha-latrotoxin from spider venom.
Interacts (via laminin G-like domain 2 and/or laminin G-like domain 6) with NLGN1 forming a heterotetramer, where one NLGN1 dimer interacts with one NRXN1 dimer. Also interacts (via laminin G-like domain 2 and/or laminin G-like domain 6) with NLGN2, NLGN3 and NLGN4L; interactions with NLGN1, NLGN2, NLGN3 and NLGN4L are calcium-dependent. Interacts (via cytoplasmic C-terminal region) with CASK (via the PDZ, SH3 and guanylate kinase-like domains) (By similarity). Interacts (via cytoplasmic C-terminus) with CASKIN1 and APBA1. Interacts (via laminin G-like domain 2) with NXPH1 and NXPH3. Alpha-type isoforms (neurexin-1-alpha) interact (via laminin G-like domain 2 and/or laminin G-like domain 6) with DAG1 (via alpha-dystroglycan chain). Interacts with LRRTM1, LRRTM2, LRRTM3 and LRRTM4 (By similarity). Interacts with SYT13 and SYTL1. Interacts with CBLN1, CBLN2 and, less avidly, with CBLN4 (By similarity). Interacts with CLSTN3 (PubMed:25352602).
Neuronal cell surface protein involved in cell recognition and cell adhesion by forming intracellular junctions through binding to neuroligins. Plays a role in formation of synaptic junctions.
O-glycosylated; contains heparan sulfate. Heparan sulfate attachment is required for synapse development by mediating interactions with neuroligins and LRRTM2.
The cytoplasmic C-terminal region binds to CASK. Binds NLGN1, NLGN2 and NLGN3, DAG1 (alpha-dystroglycan) and alpha-latrotoxin. Binding to neuroligins is calcium-dependent, and the binding preference ranks as follow: NLGN1 > NLGN4 >> NLGN3 > NLGN2 (By similarity). Interacts with CBLN2 and more weakly with CBLN4 (By similarity). Interacts with CBLN1; interaction is CBLN1 hexamer form-dependent; CBLN1-binding is calcium-independent; isoform 1b does not interact with CBLN1 (PubMed:27418511). Interacts with CLSTN3 (By similarity).
May play a role in compacting or stabilizing the myelin sheath, possibly by binding the negatively charged acidic phospholipids of the cytoplasmic membrane.
(Microbial infection) Interacts with HIV-2 and SIV Tat. Does not bind efficiently to the transactivation domain of the HIV-1 Tat (PubMed:10364329).
(Microbial infection) Promotes transcriptional activation of early and late herpes simplex virus 1/HHV-1 promoters.
Interacts with CDK9 to form P-TEFb (PubMed:9499409, PubMed:16331689). Interacts with POLR2A (via the C-terminal domain (CTD)); mediates transcriptional activity (PubMed:15563843). Interacts with HEXIM1; mediates formation of a tripartite complex with KPNA2. Interacts with HEXIM2 (PubMed:19883659). Interacts with PKN1; enhances MYOD1-dependent transcription (PubMed:16331689). P-TEFB complex interacts with RB1; promotes phosphorylation of RB1 (PubMed:12037672). P-TEFB complex interacts with MYOD1; promotes the transcriptional activity of MYOD1 through its CDK9-mediated phosphorylation (By similarity). Interacts with MDFI and MDFIC (PubMed:17289077). Interacts with MON1B; down-regulates CCNT2-mediated activation of viral promoters during herpes simplex virus 1/HHV-1 infection (PubMed:21509660).
Regulatory subunit of the cyclin-dependent kinase pair (CDK9/cyclin T) complex, also called positive transcription elongation factor B (P-TEFB), which is proposed to facilitate the transition from abortive to production elongation by phosphorylating the CTD (carboxy-terminal domain) of the large subunit of RNA polymerase II (RNAP II) (PubMed:9499409, PubMed:15563843). The activity of this complex is regulated by binding with 7SK snRNA (PubMed:11713533). Plays a role during muscle differentiation; P-TEFB complex interacts with MYOD1; this tripartite complex promotes the transcriptional activity of MYOD1 through its CDK9-mediated phosphorylation and binds the chromatin of promoters and enhancers of muscle-specific genes; this event correlates with hyperphosphorylation of the CTD domain of RNA pol II (By similarity). In addition, enhances MYOD1-dependent transcription through interaction with PKN1 (PubMed:16331689). Involved in early embryo development (By similarity).
Belongs to the gluconokinase GntK/GntV family.
Expressed in heart, brain, placenta, liver, pancreas, kidney and skeletal muscle.
A disulfide bond is formed between rather than within filaments and promotes the formation of a keratin filament cage around the nucleus.
Expressed in the corneal epithelium (at protein level) (PubMed:26758872). Detected in the basal layer, lowered within the more apically located layers specifically in the stratum spinosum, stratum granulosum but is not detected in stratum corneum. Strongly expressed in the outer root sheath of anagen follicles but not in the germinative matrix, inner root sheath or hair (PubMed:9457912). Found in keratinocytes surrounding the club hair during telogen (PubMed:9457912).
Heterotetramer of two type I and two type II keratins (By similarity). Forms a disulfide-linked heterodimer (via 2B domains) with KRT5 (via 2B domains) (PubMed:24940650, PubMed:22705788). Forms a heterodimer with KRT1; the interaction is more abundant in the absence of KRT5 (By similarity). Interacts with PLEC isoform 1C, when in a heterodimer with KRT5 (PubMed:24940650). Interacts with TRADD and with keratin filaments (PubMed:11684708). Associates with other type I keratins (PubMed:11724817). Interacts with EPPK1 (By similarity). Interacts with KLHL24 (PubMed:27798626). Interacts with PKP1 (via N-terminus) and PKP2 (PubMed:10852826).
The nonhelical tail domain is involved in promoting KRT5-KRT14 filaments to self-organize into large bundles and enhances the mechanical properties involved in resilience of keratin intermediate filaments in vitro.
Ubiquitinated by the BCR(KLHL24) E3 ubiquitin ligase complex.
Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols. Displays enzymatic activity towards endogenous metabolites such as aromatic and aliphatic aldehydes, ketones, monosaccharides and bile acids, with a preference for negatively charged substrates, such as glucuronate and succinic semialdehyde (PubMed:10510318). Functions as a detoxifiying enzyme by reducing a range of toxic aldehydes. Reduces methylglyoxal and 3-deoxyglucosone, which are present at elevated levels under hyperglycemic conditions and are cytotoxic. Involved also in the detoxification of lipid-derived aldehydes like acrolein (By similarity). Plays a role in the activation of procarcinogens, such as polycyclic aromatic hydrocarbon trans-dihydrodiols, and in the metabolism of various xenobiotics and drugs, including the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN) (PubMed:18276838, PubMed:11306097). Displays no reductase activity towards retinoids (By similarity).
Widely expressed. Highly expressed in kidney, salivary gland and liver. Detected in trachea, stomach, brain, lung, prostate, placenta, mammary gland, small intestine and lung.
Expressed in tuft cells of colon mucosa, as well as in small intestine and thymus (PubMed:35576971).
In the N-terminus, possesses a conserved OCA domain for bivalent binding to class II POU domain-containing transcription factors and to an octamer DNA motif (5'-ATGAAAT-3').
Interacts with POU2F3 (via the POU domain) in a DNA-dependent manner; this interaction recruits POU2AF2 to chromatin and increases POU2F3 transactivation activity.
Transcriptional coactivator of POU2F3 (PubMed:35576971, PubMed:36197978). This complex drives the development of tuft cells, a rare chemosensory cells that coordinate immune and neural functions within mucosal epithelial tissues (PubMed:35576971).
Component of the MCM8-MCM9 complex, a complex involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR) (PubMed:23401855). Required for DNA resection by the MRE11-RAD50-NBN/NBS1 (MRN) complex by recruiting the MRN complex to the repair site and by promoting the complex nuclease activity (PubMed:26215093). Probably by regulating the localization of the MRN complex, indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs (PubMed:23401855). Acts as a helicase in DNA mismatch repair (MMR) following DNA replication errors to unwind the mismatch containing DNA strand (PubMed:26300262). In addition, recruits MLH1, a component of the MMR complex, to chromatin (PubMed:26300262). The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression (PubMed:23401855). Probably by regulating HR, plays a key role during gametogenesis (By similarity).
Component of the MCM8-MCM9 complex, which forms a hexamer composed of MCM8 and MCM9 (PubMed:23401855, PubMed:26300262, PubMed:26215093). Interacts with the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1 (PubMed:26300262). Interacts with MLH1; the interaction recruits MLH1 to chromatin (PubMed:26300262). Interacts with MSH2; the interaction recruits MCM9 to chromatin (PubMed:26300262). Interacts with MSH6 (PubMed:26300262). Interacts with the MRN complex composed of MRE11, RAD50 and NBN/NBS1; the interaction recruits the MRN complex to DNA damage sites (PubMed:26215093). Interacts with RAD51; the interaction recruits RAD51 to DNA damage sites (PubMed:23401855).
The expression of isoform L and isoform M is cell cycle regulated: induced in S-phase, decreases through G2/M, and becomes constant through G1.
GTPase-activating protein that plays a role in the early steps of endocytosis (PubMed:32623794).
Detected in all tissues tested with highest levels of expression in brain and spleen.
Expression is highly regulated during erythroid development with increased expression at the stage of differentiation associated with the onset of global nuclear condensation and reduced cell proliferation.
Homotrimer; via C1q domain (PubMed:25331957). Found in a complex with LRP6, CCNY and CDK14 during G2/M stage; CAPRIN2 functions as a scaffold for the complex by binding to CCNY via its N terminus and to CDK14 via its C terminus (PubMed:27821587). Interacts with LRP5 (PubMed:18762581). Interacts with LRP6 (PubMed:18762581, PubMed:25331957).
Promotes phosphorylation of the Wnt coreceptor LRP6, leading to increased activity of the canonical Wnt signaling pathway (PubMed:18762581). Facilitates constitutive LRP6 phosphorylation by CDK14/CCNY during G2/M stage of the cell cycle, which may potentiate cells for Wnt signaling (PubMed:27821587). May regulate the transport and translation of mRNAs, modulating for instance the expression of proteins involved in synaptic plasticity in neurons (By similarity). Involved in regulation of growth as erythroblasts shift from a highly proliferative state towards their terminal phase of differentiation (PubMed:14593112). May be involved in apoptosis (PubMed:14593112).
The C1q domain is essential for the function in Wnt signaling.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIA4 subfamily.
Homotetramer or heterotetramer of pore-forming glutamate receptor subunits. Tetramers may be formed by the dimerization of dimers. Interacts with EPB41L1 via its C-terminus (By similarity). Found in a complex with GRIA1, GRIA2, GRIA3, CNIH2, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with CACNG5 and PRKCG (By similarity).
Palmitoylated. Depalmitoylated upon glutamate stimulation. Cys-611 palmitoylation leads to Golgi retention and decreased cell surface expression. In contrast, Cys-837 palmitoylation does not affect cell surface expression but regulates stimulation-dependent endocytosis (By similarity).
Phosphorylated at Ser-862 by PRKCG; phosphorylation increases plasma membrane-associated GRI4 expression.
Heterotetramer of two PDHA2 and two PDHB subunits. The heterotetramer interacts with DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules.
Phosphorylation at Ser-291, Ser-293 and Ser-298 by PDK family kinases inactivates the enzyme; for this phosphorylation at a single site is sufficient. Phosphorylation at Ser-293 interferes with access to active site, and thereby inactivates the enzyme. Dephosphorylation at all three sites, i.e. at Ser-291, Ser-293 and Ser-298, is required for reactivation.
Pyruvate dehydrogenase activity is inhibited by phosphorylation of PDHA2; it is reactivated by dephosphorylation.
Testis. Expressed in postmeiotic spermatogenic cells.
Endosome-associated protein that plays a role in membrane receptor sorting, cytokinesis and ciliogenesis (PubMed:23108400, PubMed:25278552, PubMed:27767179). Involved in the endosome-to-plasma membrane trafficking and recycling of SNX27-retromer-dependent cargo proteins, such as GLUT1 (PubMed:25278552). Involved in the regulation of cytokinesis; the function may involve PTPN13 and GIT1 (PubMed:23108400). Plays a role in the formation of cilia (PubMed:27767179). Involved in cargo protein localization, such as PKD2, at primary cilia (PubMed:27767179). Involved in the presentation of the tumor necrosis factor (TNF) receptor TNFRSF1A on the cell surface, and hence in the modulation of the TNF-induced apoptosis (By similarity).
Expressed in the colon (at protein level).
Found in a complex with ENTR1, PTPN13 and GIT1 (PubMed:23108400). Interacts with PTPN13 (via the FERM domain) (PubMed:23108400). Interacts (via N-terminus) with GIT1 (via N- and C-terminus); this interaction is direct (PubMed:23108400). Interacts with NOD2 (PubMed:27812135). Interacts (via N-terminus) with IFT88 (PubMed:27767179). Interacts with VPS35 (PubMed:25278552).
Tne N-terminal domain is necessary and sufficient for basal body localization and ciliogenesis.
Interacts (via the SH3-domain) with PTEN. Interacts with RB1.
Non-receptor tyrosine-protein kinase that negatively regulates cell proliferation. Positively regulates PTEN protein stability through phosphorylation of PTEN on 'Tyr-336', which in turn prevents its ubiquitination and degradation, possibly by reducing its binding to NEDD4. May function as a tumor suppressor.
Predominantly expressed in epithelial derived cell lines and tissues, especially normal liver, kidney, breast and colon.
Autophosphorylated on tyrosine residues. Phosphorylated by MAP kinase. Tyrosine phosphorylation may be required for dimerization.
Dimer. Interacts with DCOHM, MAP2K3/MKK3, RANBP9 and TCF1/HNF1A (PubMed:11980910). Part of a complex consisting of RANBP9, RAN, DYRK1B and COPS5 (PubMed:14500717). Interacts with DCAF7 (PubMed:14593110). Interacts with RNF169 (PubMed:33469661).
Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities. Plays an essential role in ribosomal DNA (rDNA) double-strand break repair and rDNA copy number maintenance (PubMed:33469661). During DNA damage, mediates transcription silencing in part via phosphorylating and enforcing DSB accumulation of the histone methyltransferase EHMT2 (PubMed:32611815). Enhances the transcriptional activity of TCF1/HNF1A and FOXO1. Inhibits epithelial cell migration. Mediates colon carcinoma cell survival in mitogen-poor environments. Inhibits the SHH and WNT1 pathways, thereby enhancing adipogenesis. In addition, promotes expression of the gluconeogenic enzyme glucose-6-phosphatase catalytic subunit 1 (G6PC1).
Highest expression in skeletal muscle, testis, heart and brain with little expression in colon or lung. Expressed in a variety of tumor cell lines.
Component of the ribosome quality control complex (RQC), a ribosome-associated complex that mediates ubiquitination and extraction of incompletely synthesized nascent chains for proteasomal degradation (PubMed:30244831). In the RQC complex, required to promote formation of 'Lys-48'-linked polyubiquitin chains during ubiquitination of incompletely synthesized proteins by LTN1 (PubMed:30244831). Also acts as a transcriptional repressor: represses transcription of SRF in vitro and so may play a role in heart development (PubMed:16574069). May play a role in cell death control (By similarity).
Component of the ribosome quality control complex (RQC), composed of the E3 ubiquitin ligase LTN1, TCF25 and NEMF associated with the 60S ribosomal subunit (PubMed:30244831). Interacts with XIAP (By similarity).
In the embryo, widely expressed with highest levels in brain. In the adult, highest expression is found in the heart.
The C-terminal region mediates transcriptional repression.
(Microbial infection) Interacts with HCV NS5A.
(Microbial infection) Interacts with HIV-1 Nef to activate the Nef associated p21-activated kinase (PAK). This interaction depends on the C-terminus of both proteins and leads to increased production of HIV.
(Microbial infection) Interacts with herpes simplex virus 1 UL46 and varicella virus ORF12; this interaction activates the PI3K/AKT pathway.
(Microbial infection) Interacts with herpes simplex virus 1 UL46; this interaction activates the PI3K/AKT pathway.
Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling (PubMed:17626883, PubMed:19805105, PubMed:7518429). Modulates the cellular response to ER stress by promoting nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement (PubMed:20348923).
Heterodimer of a regulatory subunit PIK3R1 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts (via SH2 domains) with CCDC88A/GIV (tyrosine-phosphorylated form); the interaction enables recruitment of PIK3R1 to the EGFR receptor, enhancing PI3K activity and cell migration (PubMed:21954290). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts with PIK3R2; the interaction is dissociated in an insulin-dependent manner (By similarity). Interacts with XBP1 isoform 2; the interaction is direct and induces translocation of XBP1 isoform 2 into the nucleus in a ER stress- and/or insulin-dependent but PI3K-independent manner (PubMed:20348923). Interacts with FER. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with PTK2/FAK1 (By similarity). Interacts with phosphorylated TOM1L1. Interacts with phosphorylated LIME1 upon TCR and/or BCR activation. Interacts with SOCS7. Interacts with RUFY3. Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts with LYN (via SH3 domain); this enhances enzyme activity (By similarity). Interacts with phosphorylated LAT, LAX1 and TRAT1 upon TCR activation. Interacts with CBLB. The SH2 domains interact with the YTHM motif of phosphorylated INSR in vitro. Also interacts with tyrosine-phosphorylated IGF1R in vitro. Interacts with CD28 and CD3Z upon T-cell activation. Interacts with IRS1 and phosphorylated IRS4, as well as with NISCH and HCST. Interacts with FASLG, KIT and BCR. Interacts with AXL, FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts with FGR and HCK. Interacts with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated). Interacts with ERBB4 (phosphorylated). Interacts with NTRK1 (phosphorylated upon ligand-binding). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467). Interacts with APPL1 and APPL2 (By similarity). Interacts with SRC (PubMed:28903391). Interacts with ALOX5; this interaction bridges ALOX5 with CD40 after CD40 ligation in B cells and leads to the production of reactive oxygen species (ROS) (PubMed:21200133). Interacts with TYK2 (PubMed:10995743). Interacts with nephrin NPHN1; the interaction is reduced by high glucose levels (PubMed:28955049).
In adipose tissue, polyubiquitinated by the BCR(KBTBD2) E3 ubiquitin ligase complex; recognized by KBTBD2 through the SH2 domains, undergoes 'Lys-48'-linked polyubiquitination leading to its degradation.
Isoform 2 is expressed in skeletal muscle and brain, and at lower levels in kidney and cardiac muscle. Isoform 2 and isoform 4 are present in skeletal muscle (at protein level).
Phosphorylated. Tyrosine phosphorylated in response to signaling by FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylated by CSF1R. Phosphorylated by ERBB4. Phosphorylated on tyrosine residues by TEK/TIE2. Dephosphorylated by PTPRJ. Phosphorylated by PIK3CA at Ser-608; phosphorylation is stimulated by insulin and PDGF. The relevance of phosphorylation by PIK3CA is however unclear (By similarity). Phosphorylated in response to KIT and KITLG/SCF. Phosphorylated by FGR.
Polyubiquitinated in T-cells by CBLB; which does not promote proteasomal degradation but impairs association with CD28 and CD3Z upon T-cell activation.
The SH3 domain mediates the binding to CBLB, and to HIV-1 Nef.
May play a role in organizing the actin cytoskeleton.
Associates with the mitochondrial contact site and cristae organizing system (MICOS) complex (PubMed:26168012, PubMed:27390132). May associate with the endoplasmic reticulum membrane protein complex (EMC) (PubMed:27390132).
Transmembrane protein of the mitochondrial outer membrane that controls mitochondrial organization (PubMed:26168012, PubMed:27543974, PubMed:27390132). May regulate the assembly of the MICOS (mitochondrial contact site and cristae organizing system) complex which is essential to the biogenesis and dynamics of mitochondrial cristae, the inwards folds of the inner mitochondrial membrane (PubMed:27390132). Through its interaction with the EMC (endoplasmic reticulum membrane protein complex), could regulate mitochondrial lipid homeostasis and thereby mitochondrial fission (PubMed:27390132).
Catalyzes the attachment of serine to tRNA(Ser). Is also probably able to aminoacylate tRNA(Sec) with serine, to form the misacylated tRNA L-seryl-tRNA(Sec), which will be further converted into selenocysteinyl-tRNA(Sec).
Homodimer. The tRNA molecule probably binds across the dimer.
Detected on round and elongated spermatids (at protein level) (PubMed:15372036). Highest expression in placenta, brain and kidney. Significant expression is detected on platelets. Expressed in intestinal mucosa cells. Expressed in the vascular endothelium. Found in serum (at protein level). Also detected in the synovial fluid of patients with rheumatoid arthritis, psoriatic arthritis or ostearthritis (at protein level).
Interacts with ITGAM (PubMed:12208882, PubMed:15194813). Interacts with GORASP2 (By similarity).
Junctional adhesion protein that mediates heterotypic cell-cell interactions with its cognate receptor JAM2 to regulate different cellular processes (PubMed:11590146, PubMed:11823489). Plays a role in homing and mobilization of hematopoietic stem and progenitor cells within the bone marrow. At the surface of bone marrow stromal cells, it contributes to the retention of the hematopoietic stem and progenitor cells expressing JAM3 (PubMed:11590146, PubMed:24357068). Plays a central role in leukocytes extravasation by facilitating transmigration through the endothelium (By similarity). Plays a role in spermatogenesis where JAM2 and JAM3, which are respectively expressed by Sertoli and germ cells, mediate an interaction between both cell types and play an essential role in the anchorage of germ cells onto Sertoli cells and the assembly of cell polarity complexes during spermatid differentiation (By similarity). Also functions as a counter-receptor for ITGAM, mediating leukocyte-platelet interactions and is involved in the regulation of transepithelial migration of polymorphonuclear neutrophils (PMN) (PubMed:12208882, PubMed:15194813). Plays a role in angiogenesis (PubMed:23255084). Plays a role in the regulation of cell migration (Probable). During myogenesis, it is involved in myocyte fusion (By similarity).
Promotes chemotaxis of vascular endothelial cells and stimulates angiogenesis.
Proteolytically cleaved from endothelial cells surface into a soluble form by ADAM10 and ADAM17; the release of soluble JAM3 is increased by pro-inflammatory factors.
S-palmitoylated by ZDHHC7. S-palmitoylation promotes expression at tight junctions.
The Ig-like V-type domain mediates interaction with JAM2.
Belongs to the nuclear transition protein 2 family.
Expressed by spermatids (at protein level).
Plays a key role in the replacement of histones to protamine in the elongating spermatids of mammals. In condensing spermatids, loaded onto the nucleosomes, where it promotes the recruitment and processing of protamines, which are responsible for histone eviction.
Believed to act as a modulator of nicotinic acetylcholine receptors (nAChRs) activity. In vitro increases receptor desensitization and decreases affinity for ACh of alpha-4:beta-2-containing nAChRs. May play a role in the intracellular trafficking of alpha-4:beta-2 and alpha-7-containing nAChRs and may inhibit their expression at the cell surface. May be involved in the control of anxiety.
Interacts with CHRNA4 and nAChRs containing alpha-4:beta-2 (CHRNA4:CHRNB2) and alpha-7 (CHRNA7) subunits.
Has a role in transport between endoplasmic reticulum and Golgi.
Monomer (By similarity). Heterotrimer composed of RABGGTA, RABGGTB and CHM; within this trimer, RABGGTA and RABGGTB form the catalytic component B, while CHM (component A) mediates Rab protein binding (PubMed:21905166). Can associate with the Rab GGTase dimer (RGGT or component B) prior to Rab protein binding; the association is stabilized by geranylgeranyl pyrophosphate (GGpp). The CHM:RGGT:Rab complex is destabilized by GGpp (PubMed:18532927). Interacts with RAB1A, RAB1B, RAB5A, RAB7A and RAB27A and mediates their prenylation (PubMed:7957092). Interacts with the non-phosphorylated forms of RAB3A, RAB3B, RAB3C, RAB3D, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB35, and RAB43 (PubMed:26824392, PubMed:29125462).
Substrate-binding subunit (component A) of the Rab geranylgeranyltransferase (GGTase) complex. Binds unprenylated Rab proteins and presents the substrate peptide to the catalytic component B. The component A is thought to be regenerated by transferring its prenylated Rab back to the donor membrane.
Substrate-binding subunit of the Rab geranylgeranyltransferase (GGTase) complex. Binds unprenylated Rab proteins and presents the substrate peptide to the catalytic component B composed of RABGGTA and RABGGTB, and remains bound to it after the geranylgeranyl transfer reaction. The component A is thought to be regenerated by transferring its prenylated Rab back to the donor membrane. Besides, a pre-formed complex consisting of CHM and the Rab GGTase dimer (RGGT or component B) can bind to and prenylate Rab proteins; this alternative pathway is proposed to be the predominant pathway for Rab protein geranylgeranylation.
Expressed in the corneal epithelium (at protein level).
Involved in corneal epithelium organization, integrity and corneal keratin expression.
Highly expressed in tonsils, especially in hypertrophic tonsils. Detected at very low levels in fetal liver.
A chromosomal aberration involving FNBP1 is found in acute leukemias. Translocation t(9;11)(q34;q23) with KMT2A/MLL1. The relatively low incidence of the KMT2A/MLL1-FNBP1 fusion protein in acute leukemia may reflect the marginal capacity of this fusion protein to induce cellular transformation.
Interacts specifically with GTP-bound RND2 and CDC42. Interacts with PDE6G and microtubules (By similarity). Homodimerizes, the dimers can polymerize end-to-end to form filamentous structures. Interacts with AKAP9, ARHGAP17, DAAM1, DIAPH1, DIAPH2, DNM1, DNM2, DNM3, FASLG/FASL, SNX2 and WASL/N-WASP. May interact with TNKS.
May act as a link between RND2 signaling and regulation of the actin cytoskeleton (By similarity). Required to coordinate membrane tubulation with reorganization of the actin cytoskeleton during the late stage of clathrin-mediated endocytosis. Binds to lipids such as phosphatidylinositol 4,5-bisphosphate and phosphatidylserine and promotes membrane invagination and the formation of tubules. Also enhances actin polymerization via the recruitment of WASL/N-WASP, which in turn activates the Arp2/3 complex. Actin polymerization may promote the fission of membrane tubules to form endocytic vesicles. May be required for the lysosomal retention of FASLG/FASL.
Very highly expressed in the epithelial cells of the gastrointestinal tract, respiratory, reproductive and urinary systems. Also highly expressed in brown adipose tissue, cardiomyocytes, enteric ganglia and glucagon producing cells of the pancreas. Expressed in germ cells of the testis and all regions of the brain.
Encoded in an intron of the TRPC5 gene (opposite strand). May be a non-coding RNA.
(Microbial infection) Interacts with Chikungunya virus capsid protein; this interaction allows the nuclear import of the viral capsid protein.
(Microbial infection) Interacts with MERS virus protein OF4b; this interaction prevents the translocation of NF-kappa-B complex to the nucleus.
(Microbial infection) Interacts with human adenovirus 5 E1A protein; this interaction allows E1A import into the host nucleus.
Forms a complex with importin subunit beta-1. Interacts with SNAI1. Interacts with TALDO1 isoform 1 (By similarity).
Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS.
Highly expressed in testis, ovary, small intestine, heart, skeletal muscle, lung and pancreas, but barely detectable in kidney, thymus, colon and peripheral blood leukocytes.
Identified in fetal brain, kidney and liver. In adult tissues found primarily in ovary, kidney, liver, lung, placenta, brain and peripheral blood leukocytes. Expressed as well in various cancer cell lines.
Plays a specialized role in the generation of left-right asymmetry during embryogenesis. May act as a negative regulator of the NOTCH-signaling pathway (PubMed:26429889, PubMed:26437028). Cleaves alpha-1-antitrypsin (PubMed:12617721).
Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport. Regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. Required for skeletal homeostasis. Promotes mammary mesenchyme differentiation and bud outgrowth by modulating mesenchymal cell responsiveness to BMPs. Up-regulates BMPR1A expression in the mammary mesenchyme and this increases the sensitivity of these cells to BMPs and allows them to respond to BMP4 in a paracrine and/or autocrine fashion. BMP4 signaling in the mesenchyme, in turn, triggers epithelial outgrowth and augments MSX2 expression, which causes the mammary mesenchyme to inhibit hair follicle formation within the nipple sheath (By similarity). Promotes colon cancer cell migration and invasion in an integrin alpha-6/beta-1-dependent manner through activation of Rac1.
Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport. Regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. Required for skeletal homeostasis. Promotes mammary mesenchyme differentiation and bud outgrowth by modulating mesenchymal cell responsiveness to BMPs. Up-regulates BMPR1A expression in the mammary mesenchyme and this increases the sensitivity of these cells to BMPs and allows them to respond to BMP4 in a paracrine and/or autocrine fashion. BMP4 signaling in the mesenchyme, in turn, triggers epithelial outgrowth and augments MSX2 expression, which causes the mammary mesenchyme to inhibit hair follicle formation within the nipple sheath.
Osteostatin is a potent inhibitor of osteoclastic bone resorption.
PTHrP interacts with PTH1R (via N-terminal extracellular domain).
There are 3 principal secretory forms, called PTHrP[1-36], PTHrP[38-94], and osteostatin (PTHrP[107-139]) arising from endoproteolytic cleavage of the initial translation product. Each of these secretory forms is believed to have one or more of its own receptors that mediates the normal paracrine, autocrine and endocrine actions.
There are several secretory forms, including osteostatin, arising from endoproteolytic cleavage of the initial translation product. Each of these secretory forms is believed to have one or more of its own receptors that mediates the normal paracrine, autocrine and endocrine actions.
Ubiquitous. Also expressed in the mammary gland.
Heterotetramer of 2 alpha/HADHA and 2 beta/HADHB subunits; forms the mitochondrial trifunctional enzyme (PubMed:29915090, PubMed:30850536). Also purified as higher order heterooligomers including a 4 alpha/HADHA and 4 beta/HADHB heterooligomer which physiological significance remains unclear (PubMed:8163672, PubMed:29915090). The mitochondrial trifunctional enzyme interacts with MTLN (PubMed:32243843). Interacts with RSAD2/viperin (PubMed:21527675).
Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway (PubMed:8135828, PubMed:29915090, PubMed:30850536). The mitochondrial beta-oxidation pathway is the major energy-producing process in tissues and is performed through four consecutive reactions breaking down fatty acids into acetyl-CoA (PubMed:29915090). Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids (PubMed:30850536). Mitochondrial trifunctional enzyme is a heterotetrameric complex composed of two proteins, the trifunctional enzyme subunit alpha/HADHA carries the 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities, while the trifunctional enzyme subunit beta/HADHB described here bears the 3-ketoacyl-CoA thiolase activity (PubMed:8135828, PubMed:29915090, PubMed:30850536).
(Microbial infection) Interacts with S.aureus hly; this interaction is necessary for toxin pore formation, disruption of focal adhesions and S.aureus hly-mediated cytotoxicity.
(Microbial infection) Promotes the cytotoxic activity of S.aureus hly by binding to the toxin at zonula adherens and promoting formation of toxin pores.
Catalytically inactive when the propeptide is intact and associated with the mature enzyme (By similarity). The disintegrin and cysteine-rich regions modulate access of substrates to exerts an inhibitory effect on the cleavage of ADAM10 substrates (PubMed:29224781).
Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP) (PubMed:26686862, PubMed:11786905, PubMed:29224781). Contributes to the normal cleavage of the cellular prion protein (PubMed:11477090). Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity (PubMed:12475894). Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis (By similarity). Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form (PubMed:17557115). Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B (PubMed:19114711, PubMed:21288900). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R and IL11RA, leading to the release of secreted forms of IL6R and IL11RA (PubMed:26876177). Enhances the cleavage of CHL1 by BACE1 (By similarity). Cleaves NRCAM (By similarity). Cleaves TREM2, resulting in shedding of the TREM2 ectodomain (PubMed:24990881). Involved in the development and maturation of glomerular and coronary vasculature (By similarity). During development of the cochlear organ of Corti, promotes pillar cell separation by forming a ternary complex with CADH1 and EPHA4 and cleaving CADH1 at adherens junctions (By similarity). May regulate the EFNA5-EPHA3 signaling (PubMed:16239146).
Expressed in the brain (at protein level) (PubMed:23676497). Expressed in spleen, lymph node, thymus, peripheral blood leukocyte, bone marrow, cartilage, chondrocytes and fetal liver (PubMed:11511685, PubMed:9016778).
Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells (PubMed:16239146). Interacts with the clathrin adapter AP2 complex subunits AP2A1, AP2A2, AP2B1, and AP2M1; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons (PubMed:23676497). Interacts (via extracellular domain) with TSPAN33 (via extracellular domain) and (via cytoplasmic domain) with AFDN; interaction with TSPAN33 allows the docking of ADAM10 to zonula adherens through a PDZ11-dependent interaction between TSPAN33 and PLEKHA7 while interaction with AFDN locks ADAM10 at zonula adherens (PubMed:30463011). Forms a ternary complex composed of ADAM10, EPHA4 and CADH1; within the complex, ADAM10 cleaves CADH1 which disrupts adherens junctions (By similarity). Interacts with EPHA2 (By similarity). Interacts with NGF in a divalent cation-dependent manner (PubMed:20164177). Interacts with TSPAN14; the interaction promotes ADAM10 maturation and cell surface expression (PubMed:26686862, PubMed:26668317). Interacts with TSPAN5, TSPAN10, TSPAN15, TSPAN17 and TSPAN33; these interactions regulate ADAM10 substrate specificity (PubMed:26686862). Interacts with DLG1; this interaction recruits ADAM10 to the cell membrane during long-term depression in hippocampal neurons (PubMed:23676497). Interacts (via extracellular domain) with BACE1 (via extracellular domain) (By similarity). Interacts with FAM171A1 (PubMed:30312582).
The Cys-rich region C-terminal to the disintegrin domain functions as a substrate-recognition module, it recognizes the EFNA5-EPHA3 complex but not the individual proteins (By similarity). Both Cys-rich and stalk region are necessary for interaction with TSPAN5, TSPAN10, TSPAN14, TSPAN17, TSPAN33 (PubMed:26668317). Stalk region is sufficient for interaction with TSPAN15 (By similarity).
The precursor is cleaved by furin and PCSK7.
The propeptide keeps the metalloprotease in a latent form via a cysteine switch mechanism. This mechanism may be mediated by a highly conserved cysteine (Cys-173) in the propeptide, which interacts and neutralizes the zinc-coordinating HEXGHXXGXXHD catalytic core of the metalloprotease domain. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.
Expressed in ovarian follicles (from the primordial through to the secondary stage), in mature oocytes, and less frequently in preimplantation embryos.
Germ cells. Expressed in the fetal ovary, but not by a range of other tissues. Expression increases across mid-gestation, rising some 40-fold by the time of primordial follicle formation.
Germline specific transcription factor implicated in postnatal oocyte-specific gene expression. Plays a key regulatory role in the expression of multiple oocyte-specific genes, including those that initiate folliculogenesis and those that encode the zona pellucida (ZP1, ZP2 and ZP3) required for fertilization and early embryonic survival. Essential for oocytes to survive and form primordial follicles. The persistence of FIGLA in adult females suggests that it may regulate additional pathways that are essential for normal ovarian development. Binds to the E-box (5'-CANNTG-3') of the ZPs (ZP1, ZP2, ZP3) promoters.
Brain. Present in neurons within the hippocampus, frontal cortex and temporal cortex (at protein level). Expressed at low levels in most peripheral tissues and at higher levels in colon, kidney, pancreas, placenta, prostate, stomach and trachea. Expressed at low levels in the brain. Found in spinal cord, medulla oblongata, substantia nigra and locus coruleus. Expressed in the ductal epithelium of both normal and malignant prostate.
Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. It has also been shown that it can cleave APP between residues 671 and 672 (PubMed:10591213, PubMed:11083922, PubMed:11423558, PubMed:15857888, PubMed:16816112). Involved in the proteolytic shedding of PMEL at early stages of melanosome biogenesis. Cleaves PMEL within the M-beta fragment to release the amyloidogenic PMEL luminal fragment containing M-alpha and a small portion of M-beta N-terminus. This is a prerequisite step for subsequent processing and assembly of PMEL fibrils into amyloid sheets (PubMed:23754390). Responsible also for the proteolytic processing of CLTRN in pancreatic beta cells (PubMed:21907142).
Up-regulated in primary breast and colon tumors and liver metastasis.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. NR3B/GRIN3B subfamily.
Forms heteromeric channel of a zeta subunit (GRIN1), a epsilon subunit (GRIN2A, GRIN2B, GRIN2C or GRIN2D) and a third subunit (GRIN3A or GRIN3B). Does not form functional homomeric channels. Found in a complex containing GRIN1 and GRIN2A (By similarity).
NMDA receptor subtype of glutamate-gated ion channels with reduced single-channel conductance, low calcium permeability and low voltage-dependent sensitivity to magnesium. Mediated by glycine.
Glycosylated. Interaction with OGT leads to GlcNAcylation.
Interacts with TET2 and OGT; this interaction mediates TET2 O-GlcNAcylation and stability by promoting the interaction between OGT and TET2 (PubMed:34667079). Interacts with KDM6A (PubMed:34667079). Interacts with TET1 (PubMed:34667079).
Mediates OGT interaction with and O-GlcNAcylation of TET2 to control TET2 stabilization at enhancers and CpG islands (CGIs).
Autoacetylation at Lys-432 is required for proper function.
Catalytic subunit of histone acetyltransferase HBO1 complexes, which specifically mediate acetylation of histone H3 at 'Lys-14' (H3K14ac), thereby regulating various processes, such as gene transcription, protein ubiquitination, immune regulation, stem cell pluripotent and self-renewal maintenance and embryonic development (PubMed:16387653, PubMed:21753189, PubMed:24065767, PubMed:26620551, PubMed:31767635, PubMed:31827282). Some complexes also catalyze acetylation of histone H4 at 'Lys-5', 'Lys-8' and 'Lys-12' (H4K5ac, H4K8ac and H4K12ac, respectively), regulating DNA replication initiation, regulating DNA replication initiation (PubMed:10438470, PubMed:19187766, PubMed:20129055, PubMed:24065767). Specificity of the HBO1 complexes is determined by the scaffold subunit: complexes containing BRPF scaffold (BRPF1, BRD1/BRPF2 or BRPF3) direct KAT7/HBO1 specificity towards H3K14ac, while complexes containing JADE (JADE1, JADE2 and JADE3) scaffold direct KAT7/HBO1 specificity towards histone H4 (PubMed:19187766, PubMed:20129055, PubMed:24065767, PubMed:26620551). H3K14ac promotes transcriptional elongation by facilitating the processivity of RNA polymerase II (PubMed:31827282). Acts as a key regulator of hematopoiesis by forming a complex with BRD1/BRPF2, directing KAT7/HBO1 specificity towards H3K14ac and promoting erythroid differentiation (PubMed:21753189). H3K14ac is also required for T-cell development (By similarity). KAT7/HBO1-mediated acetylation facilitates two consecutive steps, licensing and activation, in DNA replication initiation: H3K14ac facilitates the activation of replication origins, and histone H4 acetylation (H4K5ac, H4K8ac and H4K12ac) facilitates chromatin loading of MCM complexes, promoting DNA replication licensing (PubMed:10438470, PubMed:11278932, PubMed:18832067, PubMed:19187766, PubMed:20129055, PubMed:21856198, PubMed:24065767, PubMed:26620551). Acts as a positive regulator of centromeric CENPA assembly: recruited to centromeres and mediates histone acetylation, thereby preventing centromere inactivation mediated by SUV39H1, possibly by increasing histone turnover/exchange (PubMed:27270040). Involved in nucleotide excision repair: phosphorylation by ATR in response to ultraviolet irradiation promotes its localization to DNA damage sites, where it mediates histone acetylation to facilitate recruitment of XPC at the damaged DNA sites (PubMed:28719581). Acts as an inhibitor of NF-kappa-B independently of its histone acetyltransferase activity (PubMed:16997280).
Component of the HBO1 complex composed of KAT7/HBO1, MEAF6, ING4 or ING5, and one scaffold subunit: complexes containing BRPF scaffold (BRPF1, BRD1/BRPF2 or BRPF3) direct KAT7/HBO1 specificity towards H3K14ac, while complexes containing JADE scaffold (JADE1, JADE2 and JADE3) mediate acetylation of histone H4 (PubMed:16387653, PubMed:19187766, PubMed:20129055, PubMed:21753189, PubMed:24065767, PubMed:26620551, PubMed:29382722). Interacts with MCM2 and ORC1 (PubMed:10438470, PubMed:11278932, PubMed:16387653). Interacts with the androgen receptor (AR); in the presence of dihydrotestosterone (PubMed:10930412). Interacts with CDT1 (PubMed:18832067). Interacts with MAP2K1 and CUL1 (By similarity). Interacts with p53/TP53; leading to inhibit histone acetyltransferase activity (PubMed:17954561). Interacts with MIS18BP1 (PubMed:27270040).
Histone acetyltransferase activity is inhibited by GMNN in the context of a complex with CDT1, inhibiting histone H4 acetylation and DNA replication licensing (PubMed:20129055). Selectively inhibited by WM-3835 (N'-(4-fluoro-5-methyl-[1,1'-biphenyl]-3-carbonyl)-3- hydroxybenzenesulfonohydrazide) inhibitor (PubMed:31827282).
Phosphorylated at Ser-50 and Ser-53 by ATR in response to DNA damage, promoting its ubiquitination by the CRL4(DDB2) complex and subsequent degradation (PubMed:26572825). Phosphorylation at Ser-50 and Ser-53 by ATR in response to ultraviolet-induced DNA, promotes localization to DNA damage sites (PubMed:28719581). Phosphorylation at Ser-57 by PLK1 during mitosis seems important for prereplicative complex formation and DNA replication licensing, and requires prior phosphorylation at Thr-85 and Thr-88 by CDK1 (PubMed:18250300). Phosphorylated by MAP2K1, which accelerates its degradation (By similarity).
Plays a central role in the maintenance of leukemia stem cells in acute myeloid leukemia (AML) (PubMed:31827282). Acts by mediating acetylation of histone H3 at 'Lys-14' (H3K14ac), thereby facilitating the processivity of RNA polymerase II to maintain the high expression of key genes, such as HOXA9 and HOXA10 that help to sustain the functional properties of leukemia stem cells (PubMed:31827282).
The C2HC MYST-type zinc finger is required for interaction with MCM2 and ORC1.
The N-terminus is involved in transcriptional repression, while the C-terminus mediates AR-interaction.
Ubiquitinated at Lys-338, leading to proteasomal degradation (PubMed:23319590). Ubiquitinated by the CRL4(DDB2) complex following phosphorylation by ATR, leading to its subsequent degradation (PubMed:26572825).
Available under the name Infuse (Medtronic Sofamor Danek). Used for treating open tibial shaft fractures.
Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis (PubMed:18436533, PubMed:31019025, PubMed:24362451). Induces cartilage and bone formation (PubMed:3201241). Initiates the canonical BMP signaling cascade by associating with type I receptor BMPR1A and type II receptor BMPR2 (PubMed:15064755, PubMed:17295905, PubMed:18436533). Once all three components are bound together in a complex at the cell surface, BMPR2 phosphorylates and activates BMPR1A (PubMed:7791754). In turn, BMPR1A propagates signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act as activators and repressors of transcription of target genes. Also acts to promote expression of HAMP, via the interaction with its receptor BMPR1A/ALK3 (PubMed:31800957). Can also signal through non-canonical pathways such as ERK/MAP kinase signaling cascade that regulates osteoblast differentiation (PubMed:20851880, PubMed:16771708). Also stimulates the differentiation of myoblasts into osteoblasts via the EIF2AK3-EIF2A-ATF4 pathway by stimulating EIF2A phosphorylation which leads to increased expression of ATF4 which plays a central role in osteoblast differentiation (PubMed:24362451). Acts as a positive regulator of odontoblast differentiation during mesenchymal tooth germ formation, expression is repressed during the bell stage by MSX1-mediated inhibition of CTNNB1 signaling (By similarity).
Homodimer; disulfide-linked (PubMed:10074410). Interacts with SOSTDC1 (PubMed:15020244). Interacts with GREM2, RGMA, RGMB and RGMC. Interacts with ASPN (By similarity). Interacts with MAFP5 (By similarity). Interacts with FBN1 (via N-terminal domain) and FBN2 (PubMed:18339631). Interacts with type I receptor BMPR1A (PubMed:15064755). Interacts with type II receptor BMPR2 (PubMed:7791754). Interacts with SCUBE3 (PubMed:33308444). Interacts with TNFAIP6 (primarily via Link domain); this interaction is inhibited by hyaluronan. Interacts with ERFE (PubMed:31800957). Interacts with BMPR1A/ALK3; the interaction may induce HAMP expression (PubMed:31800957). Forms heterodimers with BMP6 in vitro; the heterodimer then binds to its receptor BMPR1A /ALK3 and may induce HAMP expression (PubMed:31800957).
Particularly abundant in lung, spleen and colon and in low but significant levels in heart, brain, placenta, liver, skeletal muscle, kidney, pancreas, prostate, ovary and small intestine.
The gene represented in this entry is involved in disease pathogenesis. Duplications of a cis-regulatory element located approximately 110 kb downstream of BMP2 have been found in BDA2 families. They likely cause altered BMP2 expression with pathological consequences.
Autoubiquitinated in vitro in the presence of UBR5.
Catalyzes the covalent attachment of ubiquitin to other proteins.
This protein specifically binds to the DNA sequence 5'-GGGACTTTCC-3' which is found in the enhancer elements of numerous viral promoters such as those of SV40, CMV, or HIV1. In addition, related sequences are found in the enhancer elements of a number of cellular promoters, including those of the class I MHC, interleukin-2 receptor, somatostatin receptor II, and interferon-beta genes. It may act in T-cell activation.
Although the active site residues are conserved, lacks the conserved Asp/Asn residue which is normally found 7-9 residues after the catalytic His.
Splicing events through non-canonical splice sites.
Catalyzes the activation of fatty acids by CoA to produce an acyl-CoA, the first step in fatty acid metabolism (By similarity). Capable of activating medium-chain fatty acids with a preference for C6-12 fatty acids (By similarity).
A 50 kDa form is created by proteolytic cleavage.
Expressed in inner ear structures; the cochlea and the vestibule.
Monomer (PubMed:22610276). May form homodimer (PubMed:22610276). Interacts with type II collagen (PubMed:22610276). Interacts with SLC44A2 (PubMed:17926100). Interacts with ANXA2 (PubMed:21886777).
Plays a role in the control of cell shape and motility in the trabecular meshwork.
Part of BBSome complex, that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBIP10. Interacts with HDAC6.
The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia. The BBSome complex is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Firstly the BBSome associates with the ciliary membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and promotes docking and fusion of carrier vesicles to the base of the ciliary membrane. Required for primary cilia assembly and BBSome stability. Regulates cytoplasmic microtubule stability and acetylation.
Was previously thought to be non-coding and described as 'non-protein coding RNA 81', abbreviated NCRNA00081.
Acts a an auxiliary subunit of the sensory mechanoelectrical transduction (MET) channel in hair cells (By similarity). Plays a role in regulating hair cell MET channel localization and function (By similarity).
Monomer and homodimer (PubMed:34089643). Interacts with ITGA2B (via C-terminus cytoplasmic tail region); the interaction is stabilized/increased in a calcium and magnesium-dependent manner (PubMed:22779914). Interacts with TMC1 (By similarity).
The binding of either calcium or magnesium significantly increases the structural stability of the protein in comparison to apo-CIB (calcium- and magnesium-free form).
Belongs to the Mediator complex subunit 31 family.
(Microbial infection) Cleaved and inactivated by Protease 3C from Human enterovirus 71 (EV71), preventing GSDMD-mediated pyroptosis.
(Microbial infection) Cleaved and inactivated by the 3C-like proteinase nsp5 from human coronavirus SARS-CoV-2, preventing GSDMD-mediated pyroptosis.
(Microbial infection) Ubiquitinated by S.flexneri IpaH7.8, leading to its degradation by the proteasome.
Cleavage at Asp-275 by CASP1 (mature and uncleaved precursor forms), CASP4, CASP5 or CASP8 relieves autoinhibition and is sufficient to initiate pyroptosis (PubMed:26375003, PubMed:29898893, PubMed:32109412). Cleavage by CASP1 and CASP4 is not strictly dependent on the consensus cleavage site on GSDMD but depends on an exosite interface on CASP1 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32109412). Cleavage by CASP8 takes place following inactivation of MAP3K7/TAK1 by Yersinia toxin YopJ (By similarity). Cleavage at Asp-87 by CASP3 or CAPS7 inactivates the ability to mediate pyroptosis, but generates the Gasdermin-D, p13 chain, which translocates to the nucleus and acts as a transcription regulator (PubMed:28392147, PubMed:28045099, PubMed:37327784). Cleavage by papain allergen generates the Gasdermin-D, p40 chain (PubMed:35794369).
Expressed in the suprabasal cells of esophagus, as well as in the isthmus/neck, pit, and gland of the stomach, suggesting preferential expression in differentiating cells.
Forms a ring-shaped pore complex containing 27-28 subunits that inserts into the membrane (PubMed:33883744). The pore conduit is predominantly negatively charged, facilitating the release of mature interleukin-1 (IL1B and IL18) (PubMed:33883744). In contrast interleukin-1 precursors are not released, due to the presence of an acidic region that is proteolytically removed by CASP1 during maturation (PubMed:33883744).
Homooligomer; homooligomeric ring-shaped pore complex containing 27-28 subunits when inserted in the membrane (PubMed:34289345, PubMed:33883744). Homooligomerization is promoted by the mTORC1 complex in macrophages (PubMed:34289345). In response to a canonical inflammasome stimulus, such as nigericin, recruited to NLRP3 inflammasone with similar kinetics to that of uncleaved CASP1 precursor (By similarity). Although this recruitment is also observed in the absence of PYCARD, it is more efficient in its presence (By similarity).
Intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of cleavage by inflammatory caspases CASP1, CASP4 or CASP5 (PubMed:26375003, PubMed:29898893, PubMed:28928145, PubMed:29576317). The linker helix loop inserts into the N-terminal domain (PubMed:28928145). The intrinsic pyroptosis-inducing activity is carried by Gasdermin-D, N-terminal, that is released upon cleavage by inflammatory caspases (PubMed:26375003).
Precursor of a pore-forming protein that plays a key role in host defense against pathogen infection and danger signals (PubMed:26375003, PubMed:26375259, PubMed:27281216). This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-D, N-terminal) binds to membranes and forms pores, triggering pyroptosis (PubMed:26375003, PubMed:26375259, PubMed:27281216).
Produced by the cleavage by papain allergen (PubMed:35794369). After cleavage, moves to the plasma membrane and homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the specific release of mature interleukin-33 (IL33), promoting type 2 inflammatory immune response (PubMed:35794369).
Promotes pyroptosis in response to microbial infection and danger signals (PubMed:26375003, PubMed:26375259, PubMed:27418190, PubMed:28392147, PubMed:32820063, PubMed:34289345). Produced by the cleavage of gasdermin-D by inflammatory caspases CASP1, CASP4 or CASP5 in response to canonical, as well as non-canonical (such as cytosolic LPS) inflammasome activators (PubMed:26375003, PubMed:26375259, PubMed:27418190). After cleavage, moves to the plasma membrane where it strongly binds to inner leaflet lipids, including monophosphorylated phosphatidylinositols, such as phosphatidylinositol 4-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, as well as phosphatidylinositol (3,4,5)-bisphosphate, and more weakly to phosphatidic acid and phosphatidylserine (PubMed:27281216, PubMed:29898893, PubMed:36227980). Homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the release of mature interleukin-1 (IL1B and IL18) and triggering pyroptosis (PubMed:27418190, PubMed:27281216, PubMed:29898893, PubMed:33883744). Gasdermin pores also allow the release of mature caspase-7 (CASP7) (By similarity). In some, but not all, cells types, pyroptosis is followed by pyroptotic cell death, which is caused by downstream activation of ninjurins (NINJ1 or NINJ2), which mediate membrane rupture (cytolysis) (PubMed:33472215, PubMed:37198476). Also forms pores in the mitochondrial membrane, resulting in release of mitochondrial DNA (mtDNA) into the cytosol (By similarity). Gasdermin-D, N-terminal released from pyroptotic cells into the extracellular milieu rapidly binds to and kills both Gram-negative and Gram-positive bacteria, without harming neighboring mammalian cells, as it does not disrupt the plasma membrane from the outside due to lipid-binding specificity (PubMed:27281216). Under cell culture conditions, also active against intracellular bacteria, such as Listeria monocytogenes (By similarity). Also active in response to MAP3K7/TAK1 inactivation by Yersinia toxin YopJ, which triggers cleavage by CASP8 and subsequent activation (By similarity). Strongly binds to bacterial and mitochondrial lipids, including cardiolipin (PubMed:27281216). Does not bind to unphosphorylated phosphatidylinositol, phosphatidylethanolamine nor phosphatidylcholine (PubMed:27281216).
Succination of Cys-191 by the Krebs cycle intermediate fumarate, which leads to S-(2-succinyl)cysteine residues, inhibits processing by caspases, and ability to initiate pyroptosis (PubMed:32820063). Succination modification is catalyzed by a non-enzymatic reaction caused by an accumulation of fumarate (PubMed:32820063).
The full-length protein before cleavage is inactive: intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of activation signal (PubMed:26375003, PubMed:28928145, PubMed:29576317, PubMed:32109412). The intrinsic pyroptosis-inducing activity is carried by the released N-terminal moiety (Gasdermin-D, N-terminal) following cleavage by caspases CASP1, CASP4, CASP5 or CASP8 (PubMed:26375003, PubMed:26375259, PubMed:27418190, PubMed:29898893, PubMed:32109412). Cleavage at Asp-87 by CASP3 or CAPS7 inactivates the ability to mediate pyroptosis (PubMed:28392147).
Transcription coactivator produced by the cleavage by CASP3 or CASP7 in the upper small intestine in response to dietary antigens (By similarity). Required to maintain food tolerance in small intestine: translocates to the nucleus and acts as a coactivator for STAT1 to induce the transcription of CIITA and MHC class II molecules, which in turn induce type 1 regulatory T (Tr1) cells in upper small intestine (By similarity).
Belongs to the 'GDSL' lipolytic enzyme family. IAH1 subfamily.
Hydrolyzes specifically phosphatidic acid (PA) to produce 2-acyl lysophosphatidic acid (LPA; a potent bioactive lipid mediator) and fatty acid. Does not hydrolyze other phospholipids, like phosphatidylserine (PS), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) or triacylglycerol (TG).
Present in intestine (at protein level). Expressed in colon, prostate, kidney, pancreas, ovary, testis, intestine, lung and pancreas. Expressed at lower level in brain, spleen and heart. In the skin, it is prominently expressed in hair follicles, including the stem cell-rich bulge region and the inner root sheath (PubMed:17095700, PubMed:32336749).
Belongs to the cytochrome c-type heme lyase family.
Lyase that catalyzes the covalent linking of the heme group to the cytochrome C apoprotein to produce the mature functional cytochrome.
Cytokine and cellular adhesion trigger induction. Down-regulated in a majority of lung carcinoma samples.
Expression is cell cycle regulated with a peak in G1 phase.
Interacts (via the POLO-box domain) with CIB1; leading to inhibit PLK3 kinase activity. Interacts with GOLGB1.
Phosphorylated in an ATM-dependent manner following DNA damage. Phosphorylated as cells enter mitosis and dephosphorylated as cells exit mitosis.
Serine/threonine-protein kinase involved in cell cycle regulation, response to stress and Golgi disassembly. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates ATF2, BCL2L1, CDC25A, CDC25C, CHEK2, HIF1A, JUN, p53/TP53, p73/TP73, PTEN, TOP2A and VRK1. Involved in cell cycle regulation: required for entry into S phase and cytokinesis. Phosphorylates BCL2L1, leading to regulate the G2 checkpoint and progression to cytokinesis during mitosis. Plays a key role in response to stress: rapidly activated upon stress stimulation, such as ionizing radiation, reactive oxygen species (ROS), hyperosmotic stress, UV irradiation and hypoxia. Involved in DNA damage response and G1/S transition checkpoint by phosphorylating CDC25A, p53/TP53 and p73/TP73. Phosphorylates p53/TP53 in response to reactive oxygen species (ROS), thereby promoting p53/TP53-mediated apoptosis. Phosphorylates CHEK2 in response to DNA damage, promoting the G2/M transition checkpoint. Phosphorylates the transcription factor p73/TP73 in response to DNA damage, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates HIF1A and JUN is response to hypoxia. Phosphorylates ATF2 following hyperosmotic stress in corneal epithelium. Also involved in Golgi disassembly during the cell cycle: part of a MEK1/MAP2K1-dependent pathway that induces Golgi fragmentation during mitosis by mediating phosphorylation of VRK1. May participate in endomitotic cell cycle, a form of mitosis in which both karyokinesis and cytokinesis are interrupted and is a hallmark of megakaryocyte differentiation, via its interaction with CIB1.
The POLO box domains act as phosphopeptide-binding module that recognize and bind serine-[phosphothreonine/phosphoserine]-(proline/X) motifs. PLK3 recognizes and binds docking proteins that are already phosphorylated on these motifs, and then phosphorylates them (By similarity). The POLO box domains mediates localization to the centrosome.
Transcripts are highly detected in placenta, lung, followed by skeletal muscle, heart, pancreas, ovaries and kidney and weakly detected in liver and brain. May have a short half-live. In cells of hematopoietic origin, strongly and exclusively detected in terminally differentiated macrophages. Transcript expression appears to be down-regulated in primary lung tumor.
Expressed in Paneth cells, at the base of small intestinal crypts.
His-153 variation is a common polymorphism in African populations with a minor allele frequency of 9.2%, it eliminates sulfation at Tyr-154, with no consequences on digestive physiology.
In the ileum, may be involved in defensin processing, including DEFA5.
In some small cell lung carcinoma (SCLC) cell lines, there is an intrachromosomal rearrangements at 1p32 fusing the first exon of the RLF gene with L-myc.
Widely expressed in fetal and adult tissues.
Broadly expressed, with greatest levels in skeletal muscle followed by heart, brain, pancreas and testis.
Interacts with BID and PKD2 (PubMed:15692567, PubMed:15692563). Interacts with SIRT1 (PubMed:29656858). Interacts with HDAC1 (PubMed:29656858). Interacts with TRPV1 (PubMed:29656858). Interacts with WDR37 (PubMed:34642815).
Multifunctional sorting protein that controls the endoplasmic reticulum (ER)-mitochondria communication, including the apposition of mitochondria with the ER and ER homeostasis. In addition, in response to apoptotic inducer, translocates BIB to mitochondria, which initiates a sequence of events including the formation of mitochondrial truncated BID, the release of cytochrome c, the activation of caspase-3 thereby causing cell death. May also be involved in ion channel trafficking, directing acidic cluster-containing ion channels to distinct subcellular compartments.
Highly expressed in testes and pancreas. Low levels found in the heart, lungs, and brain. Very low expression detected in the placenta. No expression seen in skeletal muscle, liver, kidney, thymus, small intestine, colons, spleen, leukocytes, prostate gland, and ovary. In the adult testes, expression was about 6.44-fold higher than in the embryo testes. No expression in testes of patients with Sertoli-cell-only syndrome. In patients with arrest at spermatogonium and primary spermatocyte stages, no expression was detected. In patients with arrest at the spermatid stage, expression level was weak or absent. Variable expression was seen in patients with spermatogenic arrest.
May play a role in testicular development/spermatogenesis and may be an important factor in male infertility.
Down-regulated by bacterial lipopolysaccharides (LPS) in glial cells (PubMed:12388062). Down-regulated upon hypoxia (PubMed:16583402).
Expressed in the cerebral cortex by pyramidal and GABAergic neurons, astrocytes and other non-neuronal cells (at protein level). Expressed in placenta, heart, lung, skeletal muscle, spleen, stomach and testis (PubMed:10891391, PubMed:12388062, PubMed:15054072, PubMed:16148032). Highly expressed in cytotrophoblast cells from term placenta (PubMed:20599747).
Inhibited by alpha-(methylamino)isobutyric acid (MeAIB). Inhibited by lithium, potassium, choline ions, N-methylglucamine. The pH dependence has an allosteric effect on the transport.
N-glycosylation plays an important role in the L-glutamine transport.
Symporter that cotransports short-chain neutral amino acids and sodium ions from the extraccellular to the intracellular side of the cell membrane (PubMed:20599747, PubMed:10891391). The transport is elctrogenic, pH dependent and driven by the Na(+) electrochemical gradient (PubMed:10891391). Participates in the astroglia-derived glutamine transport into GABAergic interneurons for neurotransmitter GABA de novo synthesis (By similarity). May also contributes to amino acid transport in placental trophoblasts (PubMed:20599747). Also regulates synaptic plasticity (PubMed:12388062).
Highly expressed in pancreas, testis, and pituitary and moderately in the kidney, liver, uterus, heart, prostate, and brain, whereas expression is lower in the ovary and colon.
Transports zinc ions across cell and organelle membranes into the cytoplasm and regulates intracellular zinc homeostasis (PubMed:25014355, PubMed:19420709, PubMed:28219737). Participates in the zinc ions efflux out of the secretory compartments (PubMed:19420709). Regulates intracellular zinc level, resulting in the enhancement of AKT1 and MAPK3/MAPK1 (Erk1/2) phosphorylation in response to the BCR activation (PubMed:23505453). Also functions as membrane androgen receptor that mediates, through a G protein, the non-classical androgen signaling pathway, characterized by the activation of MAPK3/MAPK1 (Erk1/2) and transcription factors CREB1 or ATF1 (By similarity). This pathway contributes to CLDN1 and CLDN5 expression and tight junction formation between adjacent Sertoli cells (By similarity). Mediates androgen-induced vascular endothelial cell proliferation through activation of an inhibitory G protein leading to the AKT1 and MAPK3/MAPK1 (Erk1/2) activation which in turn modulate inhibition (phosphorylation) of GSK3B and CCND1 transcription (PubMed:34555425). Moreover, has dual functions as membrane-bound androgen receptor and as an androgen-dependent zinc transporter both of which are mediated through an inhibitory G protein (Gi) that mediates both MAP kinase and zinc signaling leading to the androgen-dependent apoptotic process (PubMed:25014355, PubMed:28219737).
Transports zinc ions across cell and organelle membranes into the cytoplasm and regulates intracellular zinc homeostasis. Participates in the zinc ions efflux out of the secretory compartments. Also functions as membrane androgen receptor that mediates, through a G protein, the non-classical androgen signaling pathway, characterized by the activation of MAPK3/MAPK1 (Erk1/2) and transcription factors CREB1 or ATF1. Moreover, has dual functions as membrane-bound androgen receptor and as an androgen-dependent zinc transporter both of which are mediated through an inhibitory G protein (Gi) that mediates both MAP kinase and zinc signaling leading to the androgen-dependent apoptotic process.
Up-regulated by testosterone in cancer cells.
Efficient DNA binding requires dimerization with another bHLH protein. Heterodimer; forms a heterodimer with ARNT, ARNT2 (By similarity).
Transcriptional factor that may have pleiotropic effects during embryogenesis and in the adult.
Cell surface receptor for SEMA4C, SEMA4D and SEMA4G that plays an important role in cell-cell signaling (By similarity). Plays a role in glutamatergic synapse development and is required for SEMA4A-mediated excitatory synapse development (By similarity). Binding to class 4 semaphorins promotes downstream activation of RHOA and phosphorylation of ERBB2 at 'Tyr-1248' (By similarity). Required for normal differentiation and migration of neuronal cells during brain corticogenesis and for normal embryonic brain development (By similarity). Regulates the migration of cerebellar granule cells in the developing brain (By similarity). Plays a role in RHOA activation and subsequent changes of the actin cytoskeleton (PubMed:12183458). Plays a role in axon guidance, invasive growth and cell migration (PubMed:15184888). May modulate the activity of RAC1 and CDC42 (By similarity).
Monomer, and heterodimer with PLXNB1 (PubMed:12533544). Interacts with SEMA4C, SEMA4D and SEMA4G (By similarity). Interacts with MET (PubMed:15184888). Interacts with ARHGEF11 and ARHGEF12 (PubMed:12183458). May also interact with MST1R (PubMed:15184888).
Interacts with GMNN; the interaction inhibits binding of the MCM complex to origins of replication (PubMed:11125146, PubMed:14672932, PubMed:14993212, PubMed:15257290). Interacts with MCM6 (By similarity). Interacts with CDC6; are mutually dependent on one another for loading MCM complexes onto chromatin (PubMed:14672932). Interacts with PCNA (PubMed:16861906). Interacts with LRWD1 during G1 phase and during mitosis (PubMed:22645314). Interacts with NDC80 subunit of the NDC80 complex; leading to kinetochore localization (PubMed:22581055). Interacts with GRWD1; origin binding of GRWD1 is dependent on CDT1 (PubMed:25990725). Interacts with KAT7 (PubMed:18832067). Interacts with ubiquitin-binding protein FAF1; the interaction is likely to promote CDT1 degradation (PubMed:26842564).
Phosphorylation by cyclin A-dependent kinases at Thr-29 targets CDT1 for ubiquitynation by SCF(SKP2) E3 ubiquitin ligase and subsequent degradation (PubMed:14993212). Phosphorylated at Thr-29 by MAPK8/JNK1, which blocks replication licensing in response to stress (PubMed:21856198). Binding to GMNN is not affected by phosphorylation.
Present during G1 and early S phase of the cell cycle. Degraded during the late S, G2, and M phases.
Required for both DNA replication and mitosis (PubMed:11125146, PubMed:22581055, PubMed:21856198, PubMed:14993212, PubMed:26842564). DNA replication licensing factor, required for pre-replication complex assembly. Cooperates with CDC6 and the origin recognition complex (ORC) during G1 phase of the cell cycle to promote the loading of the mini-chromosome maintenance (MCM) complex onto DNA to generate pre-replication complexes (pre-RC)(PubMed:14672932). Required also for mitosis by promoting stable kinetochore-microtubule attachments (PubMed:22581055). Potential oncogene (By similarity).
Two independent E3 ubiquitin ligase complexes, SCF(SKP2) and the DCX(DTL) complex, mediated CDT1 degradation in S phase. Ubiquitinated by the DCX(DTL) complex, in response to DNA damage, leading to its degradation. Ubiquitination by the DCX(DTL) complex is necessary to ensure proper cell cycle regulation and is PCNA-dependent: interacts with PCNA via its PIP-box, while the presence of the containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to its degradation. Phosphorylation at Thr-29 by CDK2 targets CDT1 for ubiquitination by SCF(SKP2) E3 ubiquitin ligase and subsequent degradation (PubMed:14993212). The interaction with GMNN protects it against ubiquitination. Deubiquitinated by USP37 (PubMed:27296872).
Cyclic nucleotide phosphodiesterase with specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes (PubMed:1315035, PubMed:8695850, PubMed:8155697, PubMed:25961942). Has also activity toward cUMP (PubMed:27975297). Independently of its catalytic activity it is part of an E2/17beta-estradiol-induced pro-apoptotic signaling pathway. E2 stabilizes the PDE3A/SLFN12 complex in the cytosol, promoting the dephosphorylation of SLFN12 and activating its pro-apoptotic ribosomal RNA/rRNA ribonuclease activity. This apoptotic pathway might be relevant in tissues with high concentration of E2 and be for instance involved in placenta remodeling (PubMed:31420216, PubMed:34707099).
Homodimer (PubMed:8155697, PubMed:34272366). Interacts with SLFN12; direct low affinity interaction which is stimulated by binding of 17beta-estradiol/E2 to PDE3A and that positively regulates the ribonuclease activity of SLFN12 (PubMed:31420216, PubMed:35104454, PubMed:34272366, PubMed:34707099).
Inhibited by cGMP (PubMed:8695850, PubMed:8155697). Inhibited by 17beta-estradiol (PubMed:35104454). Inhibited by milrinone (PubMed:27975297).
Component of the CatSper complex or CatSpermasome composed of the core pore-forming members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 as well as auxiliary members CATSPERB, CATSPERG, CATSPERD, CATSPERE, CATSPERZ, C2CD6/CATSPERT, TMEM249, TMEM262 and EFCAB9 (By similarity). HSPA1 may be an additional auxiliary complex member (By similarity). The core complex members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 form a heterotetrameric channel (By similarity). The auxiliary CATSPERB, CATSPERG, CATSPERD and CATSPERE subunits form a pavilion-like structure over the pore which stabilizes the complex through interactions with CATSPER4, CATSPER3, CATSPER1 and CATSPER2 respectively (By similarity). TMEM262/CATSPERH interacts with CATSPERB, further stabilizing the complex. C2CD6/CATSPERT interacts at least with CATSPERD and is required for targeting the CatSper complex in the flagellar membrane (By similarity).
Required for proper cytoplasm removal during spermatogenesis.
The poly-Ala region of SKIDA1 is highly polymorphic and the number of Ala can vary.
Activated by hyperosmotic shock after mannitol treatment.
Acts as an osmosensitive calcium-permeable cation channel (PubMed:24503647). Required for the functional integrity of the kidney glomerular filtration barrier (By similarity).
Expressed in podocytes of kidney glomeruli (PubMed:30900988). Significantly reduced expression in patients with focal segmental glomerulosclerosis (PubMed:30900988).
Interacts with cyclin-dependent kinases such as CDK1, CDK2 and CDK3. Does not interact with CDK4. Interacts (via C-terminus) with phosphorylated CDK2 (via C-terminal helix). Interacts with MS4A3 (via C-terminus); the interaction enhances CDKN3 enzymatic activity.
May play a role in cell cycle regulation. Dual specificity CC phosphatase active toward substrates containing either phosphotyrosine or phosphoserine residues (PubMed:8127873, PubMed:8242750). Dephosphorylates CDK2 at 'Thr-160' in a cyclin-dependent manner (PubMed:7569954).
May play a role in cell cycle regulation. Dual specificity phosphatase active toward substrates containing either phosphotyrosine or phosphoserine residues.
Up-regulated in breast and prostate cancer cells.
According to a report, processing following retrotranslocation is dependent on the proteasome (PubMed:24998528). However, it was later shown that processing takes place in a proteasome-independent manner (PubMed:27676297, PubMed:27676298).
CNC-type bZIP family transcription factor that translocates to the nucleus and regulates expression of target genes in response to various stresses (PubMed:8932385, PubMed:9421508). Heterodimerizes with small-Maf proteins (MAFF, MAFG or MAFK) and binds DNA motifs including the antioxidant response elements (AREs), which regulate expression of genes involved in oxidative stress response (PubMed:8932385, PubMed:9421508). Activates or represses expression of target genes, depending on the context (PubMed:8932385, PubMed:9421508). Plays a key role in cholesterol homeostasis by acting as a sensor of cholesterol excess: in low cholesterol conditions, translocates into the nucleus and represses expression of genes involved in defense against cholesterol excess, such as CD36 (By similarity). In excess cholesterol conditions, the endoplasmic reticulum membrane form of the protein directly binds cholesterol via its CRAC motif, preventing cleavage and release of the transcription factor NRF1, thereby allowing expression of genes promoting cholesterol removal (By similarity). Critical for redox balance in response to oxidative stress: acts by binding the AREs motifs on promoters and mediating activation of oxidative stress response genes, such as GCLC, GCLM, GSS, MT1 and MT2 (By similarity). Plays an essential role during fetal liver hematopoiesis: probably has a protective function against oxidative stress and is involved in lipid homeostasis in the liver (By similarity). Involved in proteasome homeostasis: in response to proteasome inhibition, mediates the 'bounce-back' of proteasome subunits by translocating into the nucleus and activating expression of genes encoding proteasome subunits (PubMed:20932482). Also involved in regulating glucose flux (By similarity). Together with CEBPB; represses expression of DSPP during odontoblast differentiation (PubMed:15308669). In response to ascorbic acid induction, activates expression of SP7/Osterix in osteoblasts.
Cleaved at Leu-104 by the aspartyl protease DDI2 following retrotranslocation, releasing the protein from the endoplasmic reticulum membrane and forming the transcription factor NRF1 that translocates into the nucleus (PubMed:24448410, PubMed:27676297, PubMed:27676298, PubMed:27528193). Ubiquitination is prerequisite for cleavage by aspartyl protease DDI2 (PubMed:27676298).
Endoplasmic reticulum membrane sensor that translocates into the nucleus in response to various stresses to act as a transcription factor (PubMed:20932482, PubMed:24448410). Constitutes a precursor of the transcription factor NRF1 (By similarity). Able to detect various cellular stresses, such as cholesterol excess, oxidative stress or proteasome inhibition (PubMed:20932482). In response to stress, it is released from the endoplasmic reticulum membrane following cleavage by the protease DDI2 and translocates into the nucleus to form the transcription factor NRF1 (By similarity). Acts as a key sensor of cholesterol excess: in excess cholesterol conditions, the endoplasmic reticulum membrane form of the protein directly binds cholesterol via its CRAC motif, preventing cleavage and release of the transcription factor NRF1, thereby allowing expression of genes promoting cholesterol removal, such as CD36 (By similarity). Involved in proteasome homeostasis: in response to proteasome inhibition, it is released from the endoplasmic reticulum membrane, translocates to the nucleus and activates expression of genes encoding proteasome subunits (PubMed:20932482).
Interacts (via CPD region) with FBXW7; leading to its ubiquitination and degradation (By similarity). Interacts with SYVN1/HRD1; leading to its ubiquitination and degradation (By similarity). Interacts (when ubiquitinated) with DDI2; leading to its cleavage (PubMed:27528193).
Interacts (via the bZIP domain) with small MAF protein (MAFF, MAFG or MAFK); required for binding to antioxidant response elements (AREs) on DNA (PubMed:8932385, PubMed:9421508). Interacts (via Destruction motif) with BTRC; leading to its ubiquitination and degradation (By similarity). Interacts with CEBPB; the heterodimer represses expression of DSPP during odontoblast differentiation (PubMed:15308669). Interacts with MOTS-c, a peptide produced by the mitochondrially encoded 12S rRNA MT-RNR1 (PubMed:29983246).
Its topology is subject to discussion. According to some groups, it has a single-pass type II membrane protein in normal conditions and is retrotranslocated into a single-pass type III membrane protein in response to stress (PubMed:24448410). According to other reports, it is integrated into the endoplasmic reticulum membrane via multiple membrane-spanning alpha-helices.
N-glycosylated in normal conditions, when it has a single-pass type II membrane protein topology, with the DNA-binding domain facing the endoplasmic reticulum lumen (PubMed:20932482, PubMed:24998528, PubMed:24448410, PubMed:27528193). Deglycosylated during retrotranslocation to the cytosolic side of the membrane, to have a single-pass type III membrane protein topology with the major part of the protein facing the cytosol (PubMed:20932482, PubMed:24998528, PubMed:24448410).
Phosphorylation by CK2 at Ser-528 inhibits transcription factor activity, possibly by affecting DNA-binding activity (By similarity). Phosphorylation at Ser-599 is required for interaction with CEBPB (PubMed:15308669).
The cholesterol recognition/amino acid consensus (CRAC) region directly binds cholesterol, as well as campesterol and 27-hydroxycholesterol. Has much lower affinity for epicholesterol.
Ubiquitinated by the SCF(BTRC) complex in the nucleus, leading to its degradation by the proteasome.
Ubiquitinated by the SCF(FBXW7) complex and SYVN1/HRD1, leading to its degradation by the proteasome (PubMed:20932482). Ubiquitinated during retrotranslocation to the cytosolic side of the membrane: ubiquitination does not lead to degradation and is required for processing by the aspartyl protease DDI2 and subsequent release from the endoplasmic reticulum membrane (PubMed:24998528, PubMed:27676298).
Was initially thought to activate erythroid-specific, globin gene expression (PubMed:8036168). Knockout experiments in mouse however demonstrated that it is not the case.
(Microbial infection) Binds to HIV-1 Nef through its SH3 domain. This interaction inhibits its tyrosine-kinase activity.
Binds both upstream activators and downstream substrates in multimolecular complexes. Found in a complex with at least BRAF, HRAS, MAP2K1/MEK1, MAPK3 and RGS14 (By similarity). Interacts with ADAM15, ARRB2, CANX, DAPK1 (via death domain), HSF4, IER3, MAP2K1/MEK1, MORG1, NISCH, and SGK1. Interacts with PEA15 and MKNK2 (By similarity). MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation (By similarity). Interacts with TPR. Interacts with CDKN2AIP. Interacts with HSF1 (via D domain and preferentially with hyperphosphorylated form); this interaction occurs upon heat shock (PubMed:10747973). Interacts with CAVIN4 (By similarity). Interacts with GIT1; this interaction is necessary for MAPK3 localization to focal adhesions (By similarity). Interacts with ZNF263 (PubMed:32051553). Interacts with EBF4.
Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-202 and Tyr-204 in response to external stimuli like insulin or NGF. Both phosphorylations are required for activity. This phosphorylation causes dramatic conformational changes, which enable full activation and interaction of MAPK1/ERK2 with its substrates. Dephosphorylated and inactivated by DUSP3, DUSP6 and DUSP9.
Phosphorylated upon KIT and FLT3 signaling (By similarity). Dually phosphorylated on Thr-202 and Tyr-204, which activates the enzyme. Ligand-activated ALK induces tyrosine phosphorylation. Dephosphorylated by PTPRJ at Tyr-204.
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway (PubMed:34497368). MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade also plays a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DEPTOR, FRS2 or GRB10) (PubMed:35216969). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade.
Highly expressed in cardiac, skeletal muscle and during myoblast differentiation. Weakly expressed in other tissues (at protein level). Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Interacts with DDX1 and YBX1. Interacts with HNRNPH1; the interaction in RNA-independent.
Mediates pre-mRNA alternative splicing regulation. Acts either as activator or repressor of splicing on specific pre-mRNA targets. Inhibits cardiac troponin-T (TNNT2) pre-mRNA exon inclusion but induces insulin receptor (IR) pre-mRNA exon inclusion in muscle. Antagonizes the alternative splicing activity pattern of CELF proteins. Regulates the TNNT2 exon 5 skipping through competition with U2AF2. Inhibits the formation of the spliceosome A complex on intron 4 of TNNT2 pre-mRNA. Binds to the stem-loop structure within the polypyrimidine tract of TNNT2 intron 4 during spliceosome assembly. Binds to the 5'-YGCU(U/G)Y-3'consensus sequence. Binds to the IR RNA. Binds to expanded CUG repeat RNA, which folds into a hairpin structure containing GC base pairs and bulged, unpaired U residues.
The protein represented in this entry is involved in disease pathogenesis. In corneal endothelial cells from patients, MBNL1 is sequestered by TCF4 RNAs containing pathogenic CUG triplet repeat expansions. This results in missplicing of essential MBNL1-regulated mRNAs.
The protein represented in this entry may be involved in disease pathogenesis. In muscle cells from patients, MBNL1 is sequestered by DMPK RNAs containing pathogenic CUG triplet repeat expansions. MBNL1 binding is proportional to repeat length consistent with the direct correlation between the length of repeat expansion and disease severity.
Has a dual function in spindle-assembly checkpoint signaling and in promoting the establishment of correct kinetochore-microtubule (K-MT) attachments. Promotes the formation of stable end-on bipolar attachments. Necessary for kinetochore localization of BUB1. Regulates chromosome segregation during oocyte meiosis. The BUB1/BUB3 complex plays a role in the inhibition of anaphase-promoting complex or cyclosome (APC/C) when spindle-assembly checkpoint is activated and inhibits the ubiquitin ligase activity of APC/C by phosphorylating its activator CDC20. This complex can also phosphorylate MAD1L1.
Interacts with BUB1 and BUBR1. The BUB1/BUB3 complex interacts with MAD1L1. Interacts with ZNF207/BuGZ; leading to promote stability and kinetochore loading of BUB3.
Altered GDF9 function may be involved in ovarian disorders and contribute to the likelihood of dizygotic twinning.
Expressed in ovarian granulosa cells. Present in oocytes of primary follicles (at protein level).
Homodimer or heterodimer (Potential). But, in contrast to other members of this family, cannot be disulfide-linked (By similarity).
Homodimer or heterodimer (Potential). But, in contrast to other members of this family, cannot be disulfide-linked.
Ovarian physiology and fertility are controlled by endocrine and paracrine signals. These act in a species-dependent manner and determine the ovulation quota in different mammalian species. While humans, and mammals such as the cow or red deer, normally ovulate only one egg per cycle, other mammals such as mouse and pig can ovulate in excess of ten per cycle. The mechanisms that regulate the species-specific differences in the number of follicles that go onto ovulate during each reproductive cycle are poorly understood. According to PubMed:21970812, mRNA expression levels of GDF9 and BMP15 are tightly coregulated within each species and influence species-specific ovulation-rates.
Phosphorylated; phosphorylation is critical for GDF9 function. In vitro, can be phosphorylated by CK at Ser-325.
Required for ovarian folliculogenesis. Promotes primordial follicle development. Stimulates granulosa cell proliferation. Promotes cell transition from G0/G1 to S and G2/M phases, through an increase of CCND1 and CCNE1 expression, and RB1 phosphorylation. It regulates STAR expression and cAMP-dependent progesterone release in granulosa and thecal cells. Attenuates the suppressive effects of activin A on STAR expression and progesterone production by increasing the expression of inhibin B. It suppresses FST and FSTL3 production in granulosa-lutein cells.
(Microbial infection) Isoform 2 interacts with Epstein-Barr virus EBNA2.
Deubiquitinated by USP37; leading to stabilization.
Interacts with the cohesin complex throughout the cell cycle; interacts with both chromatin-bound and soluble pools of the complex. Interacts with RAD21; the interaction is direct. Interacts with PDS5A; the interaction is direct, cohesin-dependent and competitive with CDCA5/SORORIN. Interacts (via FGF motifs) with PDS5B; the interaction is direct. Interacts with a SMC1 protein (SMC1A or SMC1B) and SMC3.
Isoform 1 is highly expressed in uterine cervix tumor. Isoform 2 is widely expressed with a high level in skeletal muscle and heart.
Regulator of sister chromatid cohesion in mitosis which negatively regulates cohesin association with chromatin (PubMed:26299517). Involved in both sister chromatid cohesion during interphase and sister-chromatid resolution during early stages of mitosis. Couples DNA replication to sister chromatid cohesion. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair.
(Microbial infection) The heterotrimeric retriever complex, in collaboration with the CCC complex, mediates the exit of human papillomavirus to the cell surface.
Acts as component of the retriever complex. The retriever complex is a heterotrimeric complex related to retromer cargo-selective complex (CSC) and essential for retromer-independent retrieval and recycling of numerous cargos such as integrin alpha-5/beta-1 (ITGA5:ITGB1) (PubMed:28892079). The recruitment of the retriever complex to the endosomal membrane involves CCC and WASH complexes (PubMed:28892079). In the endosomes, drives the retriever and recycling of NxxY-motif-containing cargo proteins by coupling to SNX17, a cargo essential for the homeostatic maintenance of numerous cell surface proteins associated with processes that include cell migration, cell adhesion, nutrient supply and cell signaling (PubMed:28892079).
Component of the heterotrimeric retriever complex formed by VPS26C, VPS29 and VPS35L (PubMed:28892079). Interacts with SNX17; the interaction is direct and associates SNX17 with the retriever complex (PubMed:28892079). Interacts with SNX31; the interaction is direct (PubMed:28892079).
Gln-173 is the main determinant for regioselectivity, which segregates between initiases and elongases in all tubulin--tyrosine ligase family. A glutamine residue at this position is found in elongases TTLL6, TTLL9, TTLL11, TTLL13, TTLL10 and favors glutamate-chain elongation, whereas an arginine residue is found in initiases TTLL2, TTLL4, TTLL5, TTLL3, TTLL8 and favors initiation.
Probable tubulin polyglutamylase that generates side chains of glutamate on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of target proteins. Similar to TTLL1, may acquire enzymatic activity only in complex with other proteins as it is most likely lacking domains important for autonomous activity. Mediates tubulin polyglutamylation which induces establishment of microtubule heterogeneity in sperm flagella, thereby playing a role in normal motile flagella axoneme structure and sperm flagella beating pattern.
Catalyzes the formation of diacylglycerol from 2-monoacylglycerol and fatty acyl-CoA. Also able to catalyze the terminal step in triacylglycerol synthesis by using diacylglycerol and fatty acyl-CoA as substrates. Has a preference toward palmitoyl-CoA and oleoyl-CoA. May be involved in absorption of dietary fat in the small intestine by catalyzing the resynthesis of triacylglycerol in enterocytes. Also able to use 1-monoalkylglycerol (1-MAkG) as an acyl acceptor for the synthesis of monoalkyl-monoacylglycerol (MAMAG) (PubMed:28420705).
Selectively expressed in the digestive system. Highly expressed in the ileum, and at lower level in jejunum, duodenum, colon, cecum and the rectum. Not expressed in the stomach and the esophagus and trachea. Expressed at very low level in liver.
Ubiquitinated. Ubiquitination leads to proteasomal degradation.
Belongs to the non-lysosomal glucosylceramidase family.
Inhibited by AMP-DMN/N -((5-adamantane-1-yl-methoxy)pentyl)-deoxynojirimycin (PubMed:11489889, PubMed:30308956). Activated by Mn(2+), Co(2+) and Mg(2+) and inhibited by Zn(2+) (PubMed:11489889). Enzymatic activity is dependent on membrane association and requires the presence of lipids (PubMed:11489889). The membrane-associated enzyme is not inhibited by condutiriol B epoxide and bromocondutiriol B epoxide (PubMed:11489889).
Non-lysosomal glucosylceramidase that catalyzes the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine) to free glucose and ceramides (such as N-acylsphing-4-enine) (PubMed:17105727, PubMed:30308956, PubMed:32144204). GlcCers are membrane glycosphingolipids that have a wide intracellular distribution (By similarity). They are the main precursors of more complex glycosphingolipids that play a role in cellular growth, differentiation, adhesion, signaling, cytoskeletal dynamics and membrane properties (By similarity). Involved in the transglucosylation of cholesterol, transfers glucose from GlcCer to cholesterol, thereby modifying its water solubility and biological properties (PubMed:32144204). Under specific conditions, may catalyze the reverse reaction, transferring glucose from cholesteryl-3-beta-D-glucoside to ceramide (such as N-acylsphing-4-enine) (Probable). May play a role in the metabolism of bile acids (PubMed:11489889, PubMed:9111029, PubMed:17080196). Able to hydrolyze bile acid 3-O-glucosides as well as to produce bile acid-glucose conjugates thanks to a bile acid glucosyl transferase activity (PubMed:11489889, PubMed:9111029, PubMed:17080196). Catalyzes the hydrolysis of galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine), as well as the galactosyl transfer between GalCers and cholesterol in vitro with lower activity compared with their activity against GlcCers (PubMed:32144204).
Widely expressed (PubMed:11489889). Mainly expressed in brain, heart, skeletal muscle, kidney and placenta and expressed at lower levels in liver, spleen, small intestine and lung (PubMed:11489889). Detectable in colon, thymus and peripheral blood leukocytes (PubMed:11489889).
Homodimer (PubMed:31358901). Interacts with A1CF (PubMed:24916387). Interacts with APOBEC1; form an mRNA editing complex (PubMed:24916387).
Single-stranded RNA-binding protein that functions in a variety of RNA processes, including alternative splicing, RNA stabilization, and RNA editing (PubMed:24038582, PubMed:24916387, PubMed:27050523, PubMed:30844405, PubMed:31358901, PubMed:34160127). Functions as an enzyme-substrate adapter for the cytidine deaminase APOBEC1. With APOBEC1 forms an mRNA editing complex involved into cytidine to uridine editing of a variety of mRNA molecules (PubMed:24038582, PubMed:24916387, PubMed:30844405). Through the binding of their 3'UTR, also stabilizes a variety of mRNAs and regulates the expression of genes such as the interferon alpha/beta receptor and interleukin-10 (PubMed:34160127). Also involved in the alternative splicing of several genes including TJP1. Binds the pre-mRNA (U)GCAUG consensus sequences in downstream intronic regions of alternative exons, regulating their exclusion and inclusion into mRNAs (PubMed:31358901, PubMed:27050523). Independently of its RNA-binding activity, could negatively regulate MAVS by promoting its lysosomal degradation (By similarity).
The RRM domains are required for mRNA stabilization.
Acetylation at Lys-425 and Lys-595 by KAT5 in response to fatty acids promotes translocation to the endoplasmic reticulum and synthesis of diacylglycerol.
Acts as a magnesium-dependent phosphatidate phosphatase enzyme which catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride, phosphatidylcholine and phosphatidylethanolamine biosynthesis and therefore controls the metabolism of fatty acids at different levels (PubMed:20231281, PubMed:29765047). Is involved in adipocyte differentiation (By similarity). Acts also as nuclear transcriptional coactivator for PPARGC1A/PPARA regulatory pathway to modulate lipid metabolism gene expression (By similarity). Recruited at the mitochondrion outer membrane and is involved in mitochondrial fission by converting phosphatidic acid to diacylglycerol (By similarity).
Contains 1 Asp-Xaa-Asp-Xaa-Thr (DXDXT) motif, a catalytic motif essential for phosphatidate phosphatase activity.
Contains one Leu-Xaa-Xaa-Ile-Leu (LXXIL), a transcriptional binding motif, which mediates interaction with PPARA.
Interacts (via LXXIL motif) with PPARA (By similarity). Interacts with PPARGC1A. Interaction with PPARA and PPARGC1A leads to the formation of a complex that modulates gene transcription (By similarity). Interacts with MEF2C (By similarity).
May represent a candidate gene for human lipodysytropy syndromes.
Phosphorylated at multiple sites in response to insulin. Phosphorylation is controlled by the mTOR signaling pathway. Phosphorylation is decreased by epinephrine. Phosphorylation may not directly affect the catalytic activity but may regulate the localization. Dephosphorylated by the CTDNEP1-CNEP1R1 complex (By similarity).
Potently inhibited by sphingolipids, in particular, the sphingoid bases sphinganine and sphingosine and ceramide-1-phosphate. Inhibited by concentrations of Mg(2+) and Mn(2+) above their optimums and by Ca(2+), Zn(2+), N-ethylmaleimide and propranolol.
Specifically expressed in skeletal muscle. Also abundant in adipose tissue. Lower levels in some portions of the digestive tract.
Guanine nucleotide exchange factor (GEF) for RAB14. Also has some, lesser GEF activity towards RAB35.
Identified as having similarity to the core DENN family and referred to as DENN6B (PubMed:21330364). Prediction methods do not indicate a DENN domain for this sequence and, the exact role of the DENN or this DENN-like domain in GEF activity needs to be clarified.
Interacts with CLIP2, ERC1, MAPRE1, MAPRE3, microtubules, PHLDB2 and RSN. The interaction with ERC1 may be mediated by PHLDB2. Interacts with GCC2; recruits CLASP1 to Golgi membranes. Interacts with MACF1 (By similarity).
Microtubule plus-end tracking protein that promotes the stabilization of dynamic microtubules. Involved in the nucleation of noncentrosomal microtubules originating from the trans-Golgi network (TGN). Required for the polarization of the cytoplasmic microtubule arrays in migrating cells towards the leading edge of the cell. May act at the cell cortex to enhance the frequency of rescue of depolymerizing microtubules by attaching their plus-ends to cortical platforms composed of ERC1 and PHLDB2. This cortical microtubule stabilizing activity is regulated at least in part by phosphatidylinositol 3-kinase signaling. Also performs a similar stabilizing function at the kinetochore which is essential for the bipolar alignment of chromosomes on the mitotic spindle.
Exists as an octamer composed of four CKMT2 homodimers.
Sarcomere-specific. Found only in heart and skeletal muscles.
Expressed in bone and small intestine (PubMed:31560140). Highly expressed in osteoclasts, and low expressed in osteoblasts and peripheral blood mononuclear cells (PBMCs) (PubMed:31560140).
May be involved in osteoclast differentiation.
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs.
Specifically expressed in kidney and testis.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of thyroxine. Involved in the metabolism of thyroxine (By similarity).
Highly expressed in B-cells, monocytes and tonsil.
In monocytes, down-regulated by the cell-wall fraction of Mycobacterium bovis (BCG-CWS).
M-shaped tetramer of two CD180-LY86 heterodimers.
May cooperate with CD180 and TLR4 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) and cytokine production. Important for efficient CD180 cell surface expression (By similarity).
Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels. Catalyzes the hydrolysis of phytanoyl-CoA and pristanoyl-CoA, two methyl-branched fatty acids derived from phytol, that enter the body via the diet.
Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. May be the terminally assembled subunit of Complex I.
Belongs to the complex I NDUFV3 subunit family.
Complex I is composed of 45 different subunits. This is a component of the flavoprotein-sulfur (FP) fragment of the enzyme.
Binds to the mature mitochondrial complex III dimer, after the incorporation of the Rieske protein UQCRFS1 (PubMed:28673544). Interacts with UQCRC1 and UQCRFS1 (By similarity). Interacts with ZFYVE26 and CHMP4B (PubMed:20208530).
Required for the preservation of the structural and functional integrity of mitochondrial respiratory complex III by allowing the physiological turnover of the Rieske protein UQCRFS1 (PubMed:21278747, PubMed:28673544). Involved in the clearance of UQCRFS1 N-terminal fragments, which are produced upon incorporation of UQCRFS1 into the complex III and whose presence is detrimental for its catalytic activity (PubMed:28673544).
Was reported to be required for the abcission step in cytokinesis, possibly regulating the ESCRT-III complex via its interaction with CHMP4B (PubMed:20208530). According to the same authors, localizes to the centrosome during all stages of the cell cycle and is recruited to the midbody during cytokinesis (PubMed:20208530). However, the midbody localization could not be confirmed by others (PubMed:21278747).
A paper describing ATG4C tissue expression and activity has been retracted, due to concerns of image duplication in some of the figures.
Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins (PubMed:21177865, PubMed:29458288, PubMed:30661429). The protease activity is required for proteolytic activation of ATG8 family proteins: cleaves the C-terminal amino acid of ATG8 proteins MAP1LC3 and GABARAPL2, to reveal a C-terminal glycine (PubMed:21177865). Exposure of the glycine at the C-terminus is essential for ATG8 proteins conjugation to phosphatidylethanolamine (PE) and insertion to membranes, which is necessary for autophagy (By similarity). In addition to the protease activity, also mediates delipidation of ATG8 family proteins (PubMed:29458288, PubMed:33909989). Catalyzes delipidation of PE-conjugated forms of ATG8 proteins during macroautophagy (PubMed:29458288, PubMed:33909989). Compared to ATG4B, the major protein for proteolytic activation of ATG8 proteins, shows weaker ability to cleave the C-terminal amino acid of ATG8 proteins, while it displays stronger delipidation activity (PubMed:29458288). In contrast to other members of the family, weakly or not involved in phagophore growth during mitophagy (PubMed:33773106).
Involved in nuclear movement during fibroblast polarization and migration. Proposed to be involved in actin-dependent nuclear movement via association with transmembrane actin-associated nuclear (TAN) lines which are bound to F-actin cables and couple the nucleus to retrograde actin flow (By similarity). Overexpression can recruit Ran GTPase to the nuclear periphery (PubMed:27541860).
Isoform 2 interacts with EMD (PubMed:21610090). Interacts with SUN2 and LMNA (By similarity). May bind to Ran GTPase; has a greater affinity for Ran-GTP over Ran-GDP.
May define a distinct membrane domain in the vicinity of the mitotic spindle (PubMed:19494128). Involved in the organization of the nuclear envelope implicating EMD, SUN1 and A-type lamina (PubMed:21610090).
Highly expressed in adult liver (at protein level) (PubMed:9677409). Detected in endometrium, liver and foreskin (PubMed:10329026, PubMed:11967490). Detected in the spineous layers of adult skin, and at lower levels in basal and granular skin layers (PubMed:10329026). Detected in fetal liver and lung.
Inhibited by citral, perillyl alcohol, geraniol, farnesol and geranyl geraniol.
Membrane topology is controversial (PubMed:12534290). Membrane topology structure with endoplasmic reticulum lumen orientation of the catalytic domains while the C-terminus is in the cytosol have been suggested (By similarity). Others investigators have argued for a reverse orientation, with a membrane-embedded N-terminal domain but no C-terminal transmembrane segment, and a cytosolic orientation of the catalytic domain (PubMed:12534290). These contradictory results are probably because of differences in the assay systems.
Oxidoreductase with a preference for NAD. Oxidizes all-trans-retinol, 9-cis-retinol, 11-cis-retinol and 13-cis-retinol to the corresponding aldehydes (PubMed:10329026, PubMed:12534290, PubMed:9677409). Has higher activity towards CRBP-bound retinol than with free retinol (PubMed:12534290). Oxidizes also 3-alpha-hydroxysteroids. Oxidizes androstanediol and androsterone to dihydrotestosterone and androstanedione. Can also catalyze the reverse reaction (PubMed:10329026, PubMed:9677409, PubMed:29541409).
The C-terminal region plays a crucial role in controlling the activity of RDH16 and its required for endoplasmic reticulum (ER) retention.
Transiently up-regulated by retinoic acid.
Although the protein is conserved in Drosophila, the gene encoding the orthologous protein is inactive in rodents.
Expressed in retina (at protein level) (PubMed:18976725, PubMed:18836446, PubMed:27737822, PubMed:27846257). Isoform 1: Detected in retina (PubMed:27846257). Isoform 2: Detected in retina (PubMed:27846257). Isoform 3: Strongly expressed in retina and testis (PubMed:27846257). Isoform 4: Strongly expressed in testis, and weakly expressed in retina (PubMed:27846257).
Required to maintain the integrity of photoreceptor cells (PubMed:18836446). Specifically required for normal morphology of the photoreceptor ciliary pocket, and might thus facilitate protein trafficking between the photoreceptor inner and outer segments via the transition zone (By similarity).
Expressed in a wide variety of tissues with strong expression being seen in the heart, brain, kidney, spleen and testis.
Probable guanine nucleotide exchange factor.
Belongs to the protein-tyrosine phosphatase family. Receptor class 5 subfamily.
Contaminating sequence. The N-terminus may be contaminated with vector sequence.
Protein tyrosine phosphatase that negatively regulates oligodendrocyte precursor proliferation in the embryonic spinal cord. Required for normal differentiation of the precursor cells into mature, fully myelinating oligodendrocytes. May play a role in protecting oligondendrocytes against apoptosis. May play a role in the establishment of contextual memory, probably via the dephosphorylation of proteins that are part of important signaling cascades (By similarity).
Specifically expressed in the central nervous system, where it is localized in the Purkinje cell layer of the cerebellum, the dentate gyrus, and the subependymal layer of the anterior horn of the lateral ventricle. Developmentally regulated in the brain.
The carbonic-anhydrase like domain interacts with CNTN1 (contactin) (PubMed:20133774). Interacts with PTN (PubMed:16814777). Interaction with PTN promotes formation of homooligomers; oligomerization impairs phosphatase activity (By similarity). Interacts (via chondroitin sulfate chains) with MDK (via C-terminal); this interaction is inhibited by PTN; this interaction promotes neuronal migration (By similarity).
The human genome was initially thought to contain 2 genes for PTPRZ: PTPRZ1 (on chr 7) and PTPRZ2 (on chr 1). However, PTPRZ2 probably does not exist and corresponds to PTPRZ1.
Was termed (PubMed:8387522, PubMed:2170109) RPTPase beta.
Involved in the regulation of the perinuclear actin network and nuclear shape through interaction with filamins. Plays an essential role in the formation of cartilaginous skeletal elements.
(Microbial infection) ADP-riboxanation by C.violaceum CopC blocks CASP8 processing, preventing CASP8 activation and ability to mediate extrinsic apoptosis.
(Microbial infection) Interacts (via RIP homotypic interaction motif) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RIP homotypic interaction motif); this interaction prevents necroptosis activation.
(Microbial infection) Interacts (via RIP homotypic interaction motif) with herpes simplex virus 2/HHV-2 protein RIR1/ICP10 (via RIP homotypic interaction motif); this interaction prevents necroptosis activation.
(Microbial infection) Interacts with NleF from pathogenic E.coli.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits CASP8 activation.
(Microbial infection) Interacts with molluscum contagiosum virus protein MC160.
(Microbial infection) Proteolytically cleaved by the cowpox virus CRMA death inhibitory protein.
CASP8 activity is restricted by RIPK1 (By similarity). Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis (PubMed:23516580).
Contains a N-terminal extension that is required for interaction with the BCAP31 complex.
Generation of the subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events.
Genetic variations in CASP8 are associated with reduced risk of lung cancer [MIM:211980] in a population of Han Chinese subjects. Genetic variations are also associated with decreased risk of cancer of various other forms including esophageal, gastric, colorectal, cervical, and breast, acting in an allele dose-dependent manner.
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit (PubMed:10508784). Interacts with FADD, CFLAR and PEA15 (PubMed:10442631). Interacts with TNFAIP8L2 (By similarity). Interacts with CASP8AP2 (PubMed:16378960). Interacts with RFFL and RNF34; negatively regulate CASP8 through proteasomal degradation (PubMed:15069192). Interacts with NOL3; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium (PubMed:15509781). Interacts with UBR2ca (PubMed:28602583). Interacts with RIPK1 (By similarity). Interacts with stimulated TNFRSF10B; this interaction is followed by CASP8 proteolytic cleavage and activation (PubMed:18846110). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity).
Interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1.
Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle.
Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex (Probable). Acts as an inhibitor of the caspase cascade (PubMed:12010809).
Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.
Phosphorylation on Ser-387 during mitosis by CDK1 inhibits activation by proteolysis and prevents apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes.
Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood (PubMed:23516580, PubMed:8681376, PubMed:8681377, PubMed:9006941, PubMed:9184224, PubMed:8962078, PubMed:35446120, PubMed:35338844). Initiator protease that induces extrinsic apoptosis by mediating cleavage and activation of effector caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death (PubMed:23516580, PubMed:8681376, PubMed:8681377, PubMed:9006941, PubMed:9184224, PubMed:8962078, PubMed:35446120, PubMed:35338844). Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10 (PubMed:8962078, PubMed:9006941, PubMed:16916640). Binding to the adapter molecule FADD recruits it to either receptor TNFRSF6/FAS mediated or TNFRSF1A (PubMed:8681376, PubMed:8681377). The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation (PubMed:9184224). The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases (PubMed:9184224). Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC (PubMed:9184224). In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-324', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:31827280, PubMed:31827281). Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-C and -D (GSDMC and GSDMD, respectively): gasdermin cleavage promotes release of the N-terminal moiety that binds to membranes and forms pores, triggering pyroptosis (PubMed:32929201, PubMed:34012073). Initiates pyroptosis following inactivation of MAP3K7/TAK1 (By similarity). Also acts as a regulator of innate immunity by mediating cleavage and inactivation of N4BP1 downstream of TLR3 or TLR4, thereby promoting cytokine production (By similarity). May participate in the Granzyme B (GZMB) cell death pathways (PubMed:8755496). Cleaves PARP1 and PARP2 (PubMed:8681376).
Mainly expressed in the small intestine, liver, lung and heart.
By pro-inflammatory cytokines such as TNF and IL1B/interleukin-1 beta.
Disease susceptibility is associated with variants affecting the gene represented in this entry. A nucleotide transition affecting a splice donor site results in the use of an alternative splice site and the production of isoform 3. Individuals expressing isoform 3 have a higher risk for sarcoidosis.
Expressed in brain, heart, kidney, liver, pancreas, ovary, leukocyte, small intestine, testis and thymus.
Negative regulator of T-cell proliferation.
Expressed at highest levels in fetal and adult liver, followed by fetal heart, kidney, and lung, adult heart, and pancreas.
Inhibited by warfarin (coumadin) (PubMed:15879509, PubMed:16270630, PubMed:22923610, PubMed:33154105). Warfarin locks VKORC1 in both redox states into the closed conformation (PubMed:33154105). Inhibited by warfarin analogs phenindione, brodifacoum and chlorophacinone (PubMed:33154105).
Involved in vitamin K metabolism. Catalytic subunit of the vitamin K epoxide reductase (VKOR) complex which reduces inactive vitamin K 2,3-epoxide to active vitamin K. Vitamin K is required for the gamma-carboxylation of various proteins, including clotting factors, and is required for normal blood coagulation, but also for normal bone development.
Partially oxidized VKORC1 forms a cysteine adduct with substrates, vitamin K 2,3-epoxide, inducing a closed conformation, juxtaposing all cysteines (S-S or SH) for unimpeded electron transfer (PubMed:33154105). VKOR becomes fully oxidized with an open conformation that releases reaction products, vitamin K quinone, or hydroquinone (PubMed:33154105). Cys-132 and Cys-135 constitute the catalytic redox-active center (PubMed:33154105). Cys-43 and Cys-51 are the cysteine pair that mediates transfer of reducing equivalents during catalysis (PubMed:33154105).
Brain, heart, kidney, liver, muscle and stomach. Also expressed in a number of cell lines such as carcinoma HeLa cells, hepatoma Hep-G2 cells, and colon carcinoma Caco-2 cells.
Palmitoylated on Cys-331, Cys-332, Cys-343 and Cys-348; which plays an important role in plasma membrane localization.
Sphingomyelin synthase that primarily contributes to sphingomyelin synthesis and homeostasis at the plasma membrane. Catalyzes the reversible transfer of phosphocholine moiety in sphingomyelin biosynthesis: in the forward reaction transfers phosphocholine head group of phosphatidylcholine (PC) on to ceramide (CER) to form ceramide phosphocholine (sphingomyelin, SM) and diacylglycerol (DAG) as by-product, and in the reverse reaction transfers phosphocholine from SM to DAG to form PC and CER. The direction of the reaction appears to depend on the levels of CER and DAG in the plasma membrane (PubMed:14685263, PubMed:17449912, PubMed:17982138, PubMed:18370930). Does not use free phosphorylcholine or CDP-choline as donors (PubMed:14685263). Can also transfer phosphoethanolamine head group of phosphatidylethanolamine (PE) on to ceramide (CER) to form ceramide phosphoethanolamine (CPE) (PubMed:19454763). Regulates receptor-mediated signal transduction via mitogenic DAG and proapoptotic CER, as well as via SM, a structural component of membrane rafts that serve as platforms for signal transduction and protein sorting (PubMed:17449912, PubMed:17982138). To a lesser extent, plays a role in secretory transport via regulation of DAG pool at the Golgi apparatus and its downstream effects on PRKD1 (PubMed:18370930, PubMed:21980337). Required for normal bone matrix mineralization (PubMed:30779713).
Arg-218 is the main determinant for regioselectivity, which segregates between initiases and elongases in all tubulin--tyrosine ligase family. A glutamine residue at this position is found in elongases TTLL6, TTLL9, TTLL11, TTLL13, TTLL10 and favors glutamate-chain elongation, whereas an arginine residue is found in initiases TTLL2, TTLL4, TTLL5, TTLL3, TTLL8 and favors initiation.
Probable tubulin polyglutamylase that generates side chains of glutamate on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of target proteins (By similarity). Similar to TTLL1, may acquire enzymatic activity only in complex with other proteins as it is most likely lacking domains important for autonomous activity (By similarity). Probably involved in the side-chain initiation step of the polyglutamylation reaction rather than the elongation step (By similarity).
(Microbial infection) Acts as a receptor for human JC polyomavirus/JCPyV.
Binds lysergic acid diethylamine (LSD) in the orthosteric pocket (Probable). Bound LSD dissociates extremely slowly, with a residence time of about 221 minutes at 37 degrees Celsius.
Detected in brain cortex (at protein level). Detected in blood platelets.
G-protein coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:1330647, PubMed:18703043, PubMed:19057895). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD) (PubMed:28129538). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors (PubMed:28129538). Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways (PubMed:28129538). Signaling activates phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca(2+) ions from intracellular stores (PubMed:18703043, PubMed:28129538). Affects neural activity, perception, cognition and mood (PubMed:18297054). Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction.
Interacts (via C-terminus) with MPDZ and PATJ (PubMed:11150294, PubMed:14988405). May interact (via C-terminus) with MPP3, PRDX6, DLG4, DLG1, CASK, APBA1 and MAGI2 (PubMed:14988405). Interacts with GRM2 and DRD2; this may affect signaling (PubMed:18297054, PubMed:21645528, PubMed:22300836).
The PDZ domain-binding motif is involved in the interaction with PATJ, CASK, APBA1, DLG1 and DLG4.
(Microbial infection) Interacts with Coxsackievirus A16, enterovirus 71 and poliovirus P2C proteins (PubMed:17182608).
(Microbial infection) Interacts with West Nile virus protein NS4A.
(Microbial infection) Plays a positive role in viral replication and pathogenesis of enteroviruses.
By endoplasmic reticulum stress (at protein level) (PubMed:17191123). Up-regulated and self-aggregates upon RNA viral infection (PubMed:34313226).
Homodimer. Interacts with ATL1 (By similarity). Interacts with RTN4. Isoform 3 interacts with BACE1, BACE2, BCL2 and FADD. Interacts with ATL2. Interacts with TMEM33 (By similarity). Interacts with ZFYVE27 and with KIF5A in a ZFYVE27-dependent manner (PubMed:21976701). Interacts with RIGI (PubMed:34313226). Interacts with TRIM25 (PubMed:34313226).
Isoform 3 is widely expressed, with highest levels in brain, where it is enriched in neuronal cell bodies from gray matter (at protein level). Three times more abundant in macula than in peripheral retina. Isoform 1 is expressed at high levels in brain and at low levels in skeletal muscle. Isoform 2 is only found in melanoma.
May be involved in membrane trafficking in the early secretory pathway. Inhibits BACE1 activity and amyloid precursor protein processing. May induce caspase-8 cascade and apoptosis. May favor BCL2 translocation to the mitochondria upon endoplasmic reticulum stress. Induces the formation of endoplasmic reticulum tubules (PubMed:25612671). Also acts as an inflammation-resolving regulator by interacting with both TRIM25 and RIGI, subsequently impairing RIGI 'Lys-63'-linked polyubiquitination leading to IRF3 and NF-kappa-B inhibition.
Ca(2+)-binding protein that plays a key role in store-operated Ca(2+) entry (SOCE) in T-cells by regulating CRAC channel activation. Acts as a cytoplasmic calcium-sensor that facilitates the clustering of ORAI1 and STIM1 at the junctional regions between the plasma membrane and the endoplasmic reticulum upon low Ca(2+) concentration. It thereby regulates CRAC channel activation, including translocation and clustering of ORAI1 and STIM1. Upon increase of cytoplasmic Ca(2+) resulting from opening of CRAC channels, dissociates from ORAI1 and STIM1, thereby destabilizing the ORAI1-STIM1 complex.
Expressed in endothelial cells (PubMed:25475730). Expressed in Weibel-Palade bodies (which are P-selectin/SELP negative) in endothelial cells (PubMed:31092558). Expressed in the Jurkat T-cell line (PubMed:30814157, PubMed:27016526).
Interacts with DYNC1H1 (PubMed:31092558). Interacts with the dynein-dynactin complex in a Ca(2+)-dependent manner (PubMed:30814157). Interacts with VAV1 (PubMed:27016526).
Interacts with ORAI1 and STIM1; the interaction is direct and takes place in absence of Ca(2+). Forms a complex with ORAI1 and STIM1 at low concentration of Ca(2+), the complex dissociates at elevated Ca(2+) concentrations. Interacts with ORAI2 and ORAI3.
Rab GTPase that mediates the trafficking of Weibel-Palade bodies (WPBs) to microtubule organizing center (MTOC) in endothelial cells in response to acute inflammatory stimuli (PubMed:31092558). During histamine (but not thrombin) stimulation of endothelial cells, the dynein-bound form induces retrograde transport of a subset of WPBs along microtubules to the MTOC in a Ca(2+)-independent manner and its GTPase activity is essential for this function (PubMed:31092558). Ca(2+)-regulated dynein adapter protein that activates dynein-mediated transport and dynein-dynactin motility on microtubules and regulates endosomal trafficking of CD47 (PubMed:30814157). Acts as an intracellular signaling module bridging two important T-cell receptor (TCR) signaling pathways, Ca(2+)-NFAT and JNK, to affect T-cell activation (PubMed:27016526). In resting T-cells, is predominantly localized near TGN network in a GTP-bound form, upon TCR stimulation, localizes at the immunological synapse via interaction with VAV1 to activate downstream Ca(2+)-NFAT and JNK signaling pathways (PubMed:27016526). Plays a role in T-helper 1 (Th1) cell differentiation and T-helper 17 (Th17) cell effector function (PubMed:29987160). Plays a role in store-operated Ca(2+) entry (SOCE) in T-cells by regulating CRAC channel activation (PubMed:27016526).
Alpha-1,6-mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the second mannose to the glycosylphosphatidylinositol during GPI precursor assembly.
Monomer (PubMed:26092730). Part of the core SMN complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP (PubMed:11714716, PubMed:9323129, PubMed:16314521, PubMed:17178713). Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG (PubMed:18984161, PubMed:9323129, PubMed:16314521). Interacts with GEMIN5; the interaction is direct (PubMed:11714716). Interacts (via C-terminus) with SMN1; the interaction is direct (PubMed:21816274, PubMed:26092730, PubMed:10500148, PubMed:31799625, PubMed:17178713, PubMed:22607171, PubMed:23022347). Interacts with GEMIN5; the interaction is direct (PubMed:17178713). Interacts with SNRPD1; the interaction is direct (PubMed:21816274, PubMed:31799625). Interacts with SNRPD2; the interaction is direct (PubMed:21816274, PubMed:31799625). Interacts (via N-terminus) with SNRPF; the interaction is direct (PubMed:21816274, PubMed:31799625). Interacts (via N-terminus) with SNRPE; the interaction is direct (PubMed:21816274, PubMed:31799625). Interacts (via N-terminus) with SNRPG; the interaction is direct (PubMed:21816274).
The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs (PubMed:18984161, PubMed:9323129). Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (Sm core) (PubMed:18984161). In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG (5Sm) are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP (PubMed:18984161). To assemble core snRNPs, the SMN complex accepts the trapped 5Sm proteins from CLNS1A (PubMed:18984161, PubMed:9323129). Binding of snRNA inside 5Sm ultimately triggers eviction of the SMN complex, thereby allowing binding of SNRPD3 and SNRPB to complete assembly of the core snRNP (PubMed:31799625). Within the SMN complex, GEMIN2 constrains the conformation of 5Sm, thereby promoting 5Sm binding to snRNA containing the snRNP code (a nonameric Sm site and a 3'-adjacent stem-loop), thus preventing progression of assembly until a cognate substrate is bound (PubMed:31799625, PubMed:21816274, PubMed:16314521).
May play a role in the wound healing process. May promote epidermal proliferation, remodeling and regeneration. May promote the chemotactic activity of endothelial cells and induce neovascularization. May counteract high-fat diet-induced obesity and related insulin resistance through increased energy expenditure.
Expressed in most embryo-fetal and adult tissues. Abundant in primary chondrocytes, osteoblasts, cerebellum, kidney, lung, stomach, heart, pancreas and fetal brain. Very low or no expression in the spleen, thymus, esophagus, bladder and thyroid gland.
Myristoylated in vitro; myristoylation is not essential for protein targeting to Golgi compartment.
Necessary for correct organization of Golgi apparatus. Involved in bone development.
Acts as component of the GARP complex that is involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN). The GARP complex is required for the maintenance of the cycling of mannose 6-phosphate receptors between the TGN and endosomes, this cycling is necessary for proper lysosomal sorting of acid hydrolases such as CTSD (PubMed:18367545). Within the GARP complex, required to tether the complex to the TGN. Not involved in endocytic recycling (PubMed:25799061).
Component of the Golgi-associated retrograde protein (GARP) complex, also called VFT (VPS fifty-three) complex, composed of VPS51, VPS52, VPS53 and VPS54 (PubMed:15878329, PubMed:25799061, PubMed:27440922). EIPR1 interacts with GARP complex and mediates its recruitment to the trans-Golgi network (PubMed:27440922). Interacts with VPS51 in an EIPR1-independent manner (PubMed:31721635).
Proteolytically cleaved in primary hepatocytes into a C-terminal 80 kDa form (By similarity). Proteolytically cleaved into a C-terminal SOGA 25 kDa form that is detected in plasma.
Regulates autophagy by playing a role in the reduction of glucose production in an adiponectin- and insulin-dependent manner.
The C-terminal 25 kDa form occurs as a monomer.
Up-regulated in the plasma by adiponectin in healthy fasting female.
Acts in vitro to stimulate the secretion of adrenocorticotropic hormone (ACTH) (PubMed:8612563). Binds with high affinity to CRF receptor types 1, 2-alpha, and 2-beta (PubMed:8612563). Plays a role in the establishment of normal hearing thresholds (By similarity). Reduces food intake and regulates ghrelin levels in gastric body and plasma (By similarity).
Interacts with CRHR1 and CRHR2 (via their N-terminal extracellular domain).
Keratinocytes in epidermis and the outer and inner root sheaths of hair follicles, epithelium of sebaceous and sweat glands, erector pili muscle, cutaneous blood vessel walls, cutaneous nerves and dermal mononuclear cells (PubMed:10690896). Detected in plasma cells in the lamia propria in colon mucosa (PubMed:15531481) (at protein level). Expressed in pituitary and adrenal glands (PubMed:10690896). Detected in plasma cells in the lamia propria in colon mucosa (PubMed:15531481).
Positive correlation between increased expression in colonic lamina propria and severity of inflammation in patients with ulcerative colitis.
Expressed in central nervous system, with high level in pituitary, cerebellum and temporal lobe. Widely expressed in breast cancer cell lines.
Interacts with LMO2, possibly leading to regulate the transcriptional activity of a DNA-binding complex containing LMO2 (PubMed:16314316). Interacts with OMP (By similarity).
Regulator of mitochondrial apoptosis and G1 cell cycle in breast cancer (PubMed:19711341). Protects the breast cancer cells against mitochondrial apoptosis and this effect is mediated through the modulation of BCL2 protein family, which involves the positive regulation of anti-apoptotic member BCL2 and the negative regulation of pro-apoptotic members BAD, BAK1 and PUMA (PubMed:19711341). Required for the normal cell cycle progression during G1 in breast cancer cells through the regulation of CCND1 and CDKN1A (PubMed:19711341). Regulates the level of PP2A regulatory subunit B and PP2A phosphatase activity (PubMed:19711341). In absence of reductive stress, acts as a pseudosubstrate for the CRL2(FEM1B) complex: associates with FEM1B via zinc, thereby preventing association between FEM1B and its substrates (By similarity).
The histidine cluster (His cluster) and Cys-125 mediate zinc-binding.
Functions as a RHOA-specific guanine nucleotide exchange factor regulating signaling pathways downstream of integrins and growth factor receptors. Functions in axonal branching, synapse formation and dendritic morphogenesis. Functions also in focal adhesion formation, cell motility and B-lymphocytes activation. May regulate NEFL expression and aggregation and play a role in apoptosis (By similarity).
Homooligomer; forms cytoplasmic aggregates. Forms a complex with MAPK8 and MAPK8IP1. Interacts with RHOA. Interacts with microtubules. Interacts with YWHAE and YWHAH. Interacts with PTK2/FAK1. Interacts with NEFL (By similarity). Interacts with CTNND2; prevents interaction with RHOA.
Phosphorylated on tyrosine upon stimulation of cells by laminin.
Defects in HACE1 are a cause of Wilms tumor (WT). WT is a pediatric malignancy of kidney and one of the most common solid cancers in childhood. HACE1 is epigenetically down-regulated in sporadic Wilms tumor. Moreover, a t(5;6)(q21;q21) translocation that truncates HACE1 has been found in a child with bilateral, young-onset Wilms tumor (PubMed:19948536).
E3 ubiquitin-protein ligase involved in Golgi membrane fusion and regulation of small GTPases. Acts as a regulator of Golgi membrane dynamics during the cell cycle: recruited to Golgi membrane by Rab proteins and regulates postmitotic Golgi membrane fusion. Acts by mediating ubiquitination during mitotic Golgi disassembly, ubiquitination serving as a signal for Golgi reassembly later, after cell division. Specifically interacts with GTP-bound RAC1, mediating ubiquitination and subsequent degradation of active RAC1, thereby playing a role in host defense against pathogens. May also act as a transcription regulator via its interaction with RARB.
Expressed in fetal and pediatric kidney cells.
Expressed in multiple tissues including heart, brain and kidney.
Interacts with RARB (By similarity). Interacts with RAB1 (RAB1A, RAB1B or RAB1C), RAB4 (RAB4A or RAB4B) and RAB11 (RAB11A or RAB11B); in a GTP-dependent manner. Interacts with RAC1; in a GTP-dependent manner. Interacts with the 26S proteasomal complex through the 20S core proteasomal subunit.
Interacts with GNAS. May interact with DNAJB1.
Regulates the expression, localization to the plasma membrane and function of the sodium chloride cotransporters SLC12A1 and SLC12A3, two key components of salt reabsorption in the distal renal tubule.
Widely expressed. In the developing and adult kidney, expressed in the thick ascending limb of the loop of Henle and the distal convoluted tubules outside the loop.
Activated by tyrosine and threonine phosphorylation (By similarity). Activated in response to hyperosmolarity, hydrogen peroxide, and epidermal growth factor (EGF).
Dually phosphorylated on Thr-219 and Tyr-221, which activates the enzyme (By similarity). Autophosphorylated in vitro on threonine and tyrosine residues when the C-terminal part of the kinase, which could have a regulatory role, is absent.
Expressed in many adult tissues. Abundant in heart, placenta, lung, kidney and skeletal muscle. Not detectable in liver.
Interacts with MAP2K5. Forms oligomers (By similarity). Interacts with MEF2A, MEF2C and MEF2D; the interaction phosphorylates the MEF2s and enhances transcriptional activity of MEF2A, MEF2C but not MEF2D (By similarity). Interacts with SGK1. Preferentially interacts with PML isoform PML-4 but shows interaction also with its other isoforms: isoform PML-1, isoform PML-2, isoform PML-3 and isoform PML-6. Interacts (via N-terminal half) with HSP90AB1-CDC37 chaperone complex in resting cells; the interaction is MAP2K5-independent and prevents MAPK7 from ubiquitination and proteasomal degradation (PubMed:23428871).
Plays a role in various cellular processes such as proliferation, differentiation and cell survival. The upstream activator of MAPK7 is the MAPK kinase MAP2K5. Upon activation, it translocates to the nucleus and phosphorylates various downstream targets including MEF2C. EGF activates MAPK7 through a Ras-independent and MAP2K5-dependent pathway. May have a role in muscle cell differentiation. May be important for endothelial function and maintenance of blood vessel integrity. MAP2K5 and MAPK7 interact specifically with one another and not with MEK1/ERK1 or MEK2/ERK2 pathways. Phosphorylates SGK1 at Ser-78 and this is required for growth factor-induced cell cycle progression. Involved in the regulation of p53/TP53 by disrupting the PML-MDM2 interaction.
The second proline-rich region may interact with actin targeting the kinase to a specific location in the cell.
Expressed ubiquitously, with highest levels in lung, placenta, spleen and thymus. Down-regulated in the majority (74%) of breast tumors in comparison with corresponding normal breast epithelial tissues. Expressed in the epidermis, epidermal keratinocytes, dermal fibroblasts and melanocytes (PubMed:23333244, PubMed:26203640).
Interacts with GNAS (PubMed:23333244). Interacts with IQGAP1 (PubMed:23333244). Interacts with TRAF6 (via C-terminus); the interaction is LPS-dependent (PubMed:23776175). Interacts with MAP3K7, CHUK and IKBKB (PubMed:23776175).
Is a positive regulator of NF-kappa-B signaling downstream of TLR4 activation. It acts as a scaffold molecule to assemble a molecular complex that includes TRAF6, MAP3K7, CHUK and IKBKB, thereby facilitating NF-kappa-B signaling activation (PubMed:23776175). Regulates TRAF6 and MAP3K7 ubiquitination (PubMed:23776175). Involved in the regulation of cell mobility (PubMed:23333244, PubMed:23776175, PubMed:25315659). Regulates lipolysaccharide (LPS)-induced endothelial cell migration (PubMed:23776175). Is involved in the regulation of skin pigmentation through the control of melanocyte migration in the epidermis (PubMed:23333244).
Heterotetramer of two alpha and two beta subunits. The C-terminal is necessary for the formation of a heterotetrameric GABP-alpha-2/beta-2 complex, and also facilitates homotypic dimerization. Interacts with ADGRB2.
May function as transcription factor capable of interacting with purine rich repeats (GA repeats).
GTPase-activating protein for the ADP ribosylation factor family.
PH domain binds phospholipids including phosphatidic acid, phosphatidylinositol 3-phosphate, phosphatidylinositol 3,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). May mediate protein binding to PIP2 or PIP3 containing membranes.
Belongs to the mitochondrion-specific ribosomal protein mL43 family.
High relative levels in skeletal muscle and testis. Lower levels of expression in the heart, brain, placenta, lung, liver, kidney, pancreas, spleen, thymus, prostate, ovary, small intestine, colon and leukocytes. Expression is coregulated with TWNK.
Belongs to the adenylosuccinate synthetase family.
Inhibited competitively by AMP and IMP and non-competitively by fructose 1,6-bisphosphate.
Plays an important role in the de novo pathway and in the salvage pathway of purine nucleotide biosynthesis. Catalyzes the first commited step in the biosynthesis of AMP from IMP.
Plays an important role in the de novo pathway and in the salvage pathway of purine nucleotide biosynthesis. Catalyzes the first committed step in the biosynthesis of AMP from IMP.
Plays an important role in the de novo pathway of purine nucleotide biosynthesis.
An older version of this entry represented the conceptual translation of what was thought to be HNRNPA3 but which was in fact a pseudogene (HNRPA3P1/FBRNP) located on chromosome 10.
Plays a role in cytoplasmic trafficking of RNA. Binds to the cis-acting response element, A2RE. May be involved in pre-mRNA splicing.
Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle.
Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation. Thr-277 is likely to be the main autophosphorylation site. Phosphorylation of Ser-555 and Ser-556 is induced by CDC42.
Expressed in a wide variety of normal and neoplastic tissues including fetal lung, liver, heart and kidney, and adult lung, liver, heart, kidney, placenta, skeletal muscle, pancreas and brain.
Homodimer; undergoes dimerization during activation (PubMed:9829970). Interacts with MAP2K4/MKK4 (By similarity). Interacts with MAP2K7/MKK7 (PubMed:9003778). Found in a complex with SH3RF1, RAC1, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK8/JNK1 (By similarity).
Ciliary dysfunction leads to a broad spectrum of disorders, collectively termed ciliopathies. Overlapping clinical features include retinal degeneration, renal cystic disease, skeletal abnormalities, fibrosis of various organ, and a complex range of anatomical and functional defects of the central and peripheral nervous system. The ciliopathy range of diseases includes Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, nephronophtisis, Senior-Loken syndrome, and Jeune asphyxiating thoracic dystrophy among others. Single-locus allelism is insufficient to explain the variable penetrance and expressivity of such disorders, leading to the suggestion that variations across multiple sites of the ciliary proteome, including NPHP4, influence the clinical outcome (PubMed:21258341).
Expressed in kidney, skeletal muscle, heart and liver, and to a lesser extent in brain and lung.
Interacts with NPHP1 (PubMed:15661758). Interacts with NPHP1 and RPGRIP1L/NPHP8; NPHP1, NPHP4 and RPGRIP1L are proposed to form a functional NPHP1-4-8 module localized to cell-cell contacts and the ciliary transition zone; NPHP4 mediates the interaction between NPHP1 and RPGRIP1L. Interacts with IQCB1/NPHP5; the interaction likely requires additional interactors (By similarity). Interacts with RPGRIP1, CEP164, JADE1, PALS1, INADL, PARD6A, INVS, DVL2, LATS1. Interacts with INTU; INTU mediates the interaction between NPHP4 and DAAM1 (PubMed:26644512). Interacts with SPATA7 (By similarity).
Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module (PubMed:19755384, PubMed:21565611). Does not seem to be strictly required for ciliogenesis (PubMed:21565611). Required for building functional cilia. Involved in the organization of the subapical actin network in multiciliated epithelial cells. Seems to recruit INT to basal bodies of motile cilia which subsequently interacts with actin-modifying proteins such as DAAM1 (By similarity). In cooperation with INVS may down-regulate the canonical Wnt pathway and promote the Wnt-PCP pathway by regulating expression and subcellular location of disheveled proteins. Stabilizes protein levels of JADE1 and promotes its translocation to the nucleus leading to cooperative inhibition of canonical Wnt signaling (PubMed:21498478, PubMed:22654112). Acts as negative regulator of the hippo pathway by association with LATS1 and modifying LATS1-dependent phosphorylation and localization of WWTR1/TAZ (PubMed:21555462).
May be involved in cardiac laterality defects and heterotaxy.
May be involved in male infertility. Homozygosity for a frameshift truncating mutation are associated with markedly abnormal sperm morphology.
A linker region between the coiled-coil and PDZ region holds the protein in an inactive state (PubMed:27071417).
Acts as a scaffolding protein that can activate the inflammatory transcription factor NF-kappa-B and p38/JNK MAP kinase signaling pathways. Forms a signaling complex with BCL10 and MALT1, and activates MALT1 proteolytic activity and inflammatory gene expression. MALT1 is indispensable for CARD14-induced activation of NF-kappa-B and p38/JNK MAP kinases (PubMed:11278692, PubMed:21302310, PubMed:27113748, PubMed:27071417). May play a role in signaling mediated by TRAF2, TRAF3 and TRAF6 and protects cells against apoptosis.
Interacts (via CARD domain) with BCL10 (via CARD domain) (PubMed:21302310). Forms a complex with MALT1 and BCL10; resulting in the formation of a CBM (CARD14-BLC10-MALT1) complex (PubMed:27113748, PubMed:27071417). Interacts with TRAF2, TRAF3 and TRAF6 (PubMed:21302310).
Isoform 1 is detected in placenta and epidermal keratinocytes (PubMed:22521418). Isoform 2 is detected in leukocytes and fetal brain (PubMed:22521418).
Not able to activate the inflammatory transcription factor NF-kappa-B and may function as a dominant negative regulator (PubMed:21302310, PubMed:26358359).
Supposed to contain a SH3 domain which is not detected by PROSITE, Pfam or SMART.
Belongs to the small G protein signaling modulator family.
Interacts with GJA1. Interaction with GJA1 induces its degradation (By similarity). Interacts via its RUN domain with the C-terminal region of NF2. Interacts with RAB3A, RAB4A, RAB5A, RAB8A, RAB11A, RAP1A, RAP1B, RAP2A, RAP2B and PDCD6IP. No interaction with RAB27A.
May play a cooperative role in NF2-mediated growth suppression of cells.
As a component of the coat protein complex II (COPII), may function in vesicle budding and cargo export from the endoplasmic reticulum.
COPII is composed of at least 5 proteins: the SEC23/24 complex, the SEC13/31 complex and SAR1. SEC13 and SEC31 make a 2:2 tetramer that forms the edge element of the COPII outer coat. The tetramer self-assembles in multiple copies to form the complete polyhedral cage. Interacts (via WD 8) with SEC13 (By similarity). Interacts with SEC31A.
Monoubiquitinated by the BCR(KLHL12) E3 ubiquitin ligase complex, leading to regulate the size of COPII coats.
Ubiquitously expressed at low levels with specific expression in thymus and testis. Expressed in testis by Sertoli cells, Leydig cells and spermatogonia and in cerebellum more prominently by Purkinje and granular cells (at protein level).
Functions as a GTPase-activating protein (GAP) for RAC1 and CDC42. Required for cell spreading, polarized lamellipodia formation and cell migration.
Interacts with ITSN1, which inhibits GAP activity. Interacts with PARVA (By similarity). Interacts with GTP-loaded RHOU.
Mainly expressed in fetal heart and muscle.
Phosphorylation on Thr-789 reduces GAP activity.
Has been described as GLUT10 in literature, but this gene name has already been used for SLC2A10.
Belongs to the amidase family. GatA subfamily.
Catalytic subunit of glucosidase II that cleaves sequentially the 2 innermost alpha-1,3-linked glucose residues from the Glc(2)Man(9)GlcNAc(2) oligosaccharide precursor of immature glycoproteins (PubMed:10929008). Required for PKD1/Polycystin-1 and PKD2/Polycystin-2 maturation and localization to the cell surface and cilia (PubMed:27259053).
Detected in placenta (PubMed:3881423). Isoform 1 and isoform 2 are expressed in the kidney and liver (PubMed:27259053).
GANAB variations may act as a disease modifier in autosomal dominant polycystic liver disease in patients who have causative mutations in other genes, such as PKHD1 or ALG8.
F-actin-binding protein which plays a role in cross-linking actin to other cytoskeletal proteins and also binds to microtubules (PubMed:15265687, PubMed:20937854). Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854). Acts as a positive regulator of Wnt receptor signaling pathway and is involved in the translocation of AXIN1 and its associated complex (composed of APC, CTNNB1 and GSK3B) from the cytoplasm to the cell membrane (By similarity). Has actin-regulated ATPase activity and is essential for controlling focal adhesions (FAs) assembly and dynamics (By similarity). Interaction with CAMSAP3 at the minus ends of non-centrosomal microtubules tethers microtubules minus-ends to actin filaments, regulating focal adhesion size and cell migration (PubMed:27693509). May play role in delivery of transport vesicles containing GPI-linked proteins from the trans-Golgi network through its interaction with GOLGA4 (PubMed:15265687). Plays a key role in wound healing and epidermal cell migration (By similarity). Required for efficient upward migration of bulge cells in response to wounding and this function is primarily rooted in its ability to coordinate microtubule dynamics and polarize hair follicle stem cells (By similarity). As a regulator of actin and microtubule arrangement and stabilization, it plays an essential role in neurite outgrowth, branching and spine formation during brain development (By similarity).
Isoform 2: Interacts with MAPRE1, CLASP1, CLASP2, AXIN1 and LRP6 (By similarity). Isoform 2: Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (By similarity). Isoform 2: Interacts with GOLGA4 (PubMed:15265687). Isoform 2: Interacts with CAMSAP3 (PubMed:27693509, PubMed:27802168).
Isoform 2: Ubiquitously expressed. Isoform 1: Expressed in cell lines NCI-H460, A-549 and HaCaT. Isoform 4: Expressed in heart, lung, pituitary and placenta, not found in brain, kidney, liver, pancreas or skeletal muscle.
Phosphorylated on serine residues in the C-terminal tail by GSK3B. Phosphorylation inhibits microtubule-binding and this plays a critical role in bulge stem cell migration and skin wound repair. Wnt-signaling can repress phosphorylation (By similarity).
The C-terminal tail is required for phosphorylation by GSK3B and for microtubule-binding.
Catalyzes the aldol cleavage of fructose 1,6-biphosphate to form two triosephosphates dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in glycolysis as well as the reverse stereospecific aldol addition reaction in gluconeogenesis. In fructolysis, metabolizes fructose 1-phosphate derived from the phosphorylation of dietary fructose by fructokinase into dihydroxyacetone phosphate and D-glyceraldehyde (PubMed:10970798, PubMed:12205126, PubMed:20848650). Acts as an adapter independently of its enzymatic activity, exerts a tumor suppressor role by stabilizing the ternary complex with G6PD and TP53 to inhibit G6PD activity and keep oxidative pentose phosphate metabolism in check (PubMed:35122041).
Homotetramer. Interacts with BBS1, BBS2, BBS4 and BBS7 (PubMed:18000879). Forms a ternary complex with G6PD and TP53; this interaction is direct (PubMed:35122041).
In vertebrates, 3 forms of this ubiquitous glycolytic enzyme are found, aldolase A in muscle, aldolase B in liver and aldolase C in brain.
Interacts with GNAO1 (By similarity). Interacts with GNAI3.
Regulates G protein-coupled receptor signaling cascades, including signaling via muscarinic acetylcholine receptor CHRM2 and dopamine receptor DRD2 (By similarity). Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form (PubMed:18434541). Modulates the activity of potassium channels that are activated in response to DRD2 and CHRM2 signaling (By similarity).
Acts as a regulator of programmed cell death, mediating both autophagy and apoptosis.
Expressed in lung, kidney, liver, pancreas, placenta, but not in heart and skeletal muscle.
Drastically down-regulated in response to PDGF-BB or cell injury, that promote smooth muscle cell proliferation and dedifferentiation. Seems to play a role in the development of the embryonic vascular system.
Highly expressed in the aorta, but not in heart and skeletal muscle.
Interacts with KAT14. The LIM domain 1 is necessary and sufficient for this interaction. Interacts with GLRX3 (By similarity).
Possible role in EGF receptor signaling.
Abundantly expressed in kidney, liver and lung. Lower levels in heart, placenta and pancreas. Expressed in colonic epithelial cells. Up-regulated in colonic tumors.
Phosphorylation at Tyr-55 by SRC is required for enhancement of lysophosphatidic acid-induced cell migration. Tyr-55 is dephosphorylated by PTPN13.
Relays signals from the cell surface to the nucleus to weaken adherens junction and promote actin cytoskeleton reorganization and cell invasiveness. Involved in lysophosphatidic acid-induced cell adhesion and migration. Acts as a transcriptional coactivator for NF-kappa-B and JUN, and mediates the transrepression of these transcription factors induced by glucocorticoid receptor.
Specifically interacts with the ligand binding domain of the thyroid receptor (TR) in the presence of thyroid hormone (PubMed:14688263). Interacts (via the third LIM domain and C-terminus) with PTPN13 (via the second PDZ domain) (PubMed:10400701, PubMed:17591779, PubMed:19017743, PubMed:10826496). Interacts (via the second LIM domain or via the third LIM domain plus C-terminus) with PDLIM4 (via PDZ domain) (PubMed:10826496). Found in a complex with PTPN13 and PDLIM4 (By similarity). Interacts with SVIL isoform 2 (PubMed:16880273). Interacts with LPAR2 but not other LPA receptors (PubMed:14688263). Interacts with PRKAA2 (PubMed:16624523). Interacts with MAGI1 (PubMed:19017743). Interacts with SCRIB (PubMed:16137684). In case of infection, interacts with S.typhimurium protein sseI (PubMed:17095609).
The LIM zinc-binding domains mediate interaction with LPAR2 and with S.typhimurium protein sseI.
Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion.
Mast cells in lung, heart, skin and placenta. Expressed in both normal skin and in urticaria pigmentosa lesions.
Disease susceptibility is associated with variants affecting the gene represented in this entry. An increased risk for developing amyotrophic lateral sclerosis seems to be conferred by CAG repeat intermediate expansions greater than 23 but below the threshold for developing spinocerebellar ataxia.
Expressed in the brain, heart, liver, skeletal muscle, pancreas and placenta. Isoform 1 is predominant in the brain and spinal cord. Isoform 4 is more abundant in the cerebellum. In the brain, broadly expressed in the amygdala, caudate nucleus, corpus callosum, hippocampus, hypothalamus, substantia nigra, subthalamic nucleus and thalamus.
Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
Monomer (By similarity). Can also form homodimers (By similarity). Interacts with TARDBP; the interaction is RNA-dependent (PubMed:20740007). Interacts with RBFOX1 (PubMed:10814712). Interacts with polyribosomes (PubMed:16835262). Interacts with SH3GL2 and SH3GL3 (PubMed:18602463). Interacts with SH3KBP1 and CBL (By similarity). Interacts with EGFR (PubMed:18602463). Interacts with ATXN2L (PubMed:23209657).
The disease is caused by variants affecting the gene represented in this entry. SCA2 is caused by expansion of a CAG repeat resulting in about 36 to 52 repeats in some patients. Longer expansions result in earlier the expansion, onset of the disease.
The poly-Gln region of ATXN2 is polymorphic: 17 to 29 repeats are found in the normal population. Higher numbers of repeats result in different disease phenotypes depending on the length of the expansion.
Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER) (PubMed:34020957). The SRP complex interacts with the signal sequence in nascent secretory and membrane proteins and directs them to the membrane of the ER (PubMed:34020957). The SRP complex targets the ribosome-nascent chain complex to the SRP receptor (SR), which is anchored in the ER, where SR compaction and GTPase rearrangement drive cotranslational protein translocation into the ER (PubMed:34020957). Binds the signal recognition particle RNA (7SL RNA), SRP72 binds to this complex subsequently (PubMed:16672232, PubMed:27899666). The SRP complex possibly participates in the elongation arrest function (By similarity).
Heterodimer with SRP72 (PubMed:16672232, PubMed:28369529, PubMed:27899666). SRP68/SRP72 heterodimer formation is stabilized by the presence of 7SL RNA (By similarity). Component of a signal recognition particle (SRP) complex that consists of a 7SL RNA molecule of 300 nucleotides and six protein subunits: SRP72, SRP68, SRP54, SRP19, SRP14 and SRP9 (By similarity). Within the SRP complex, interacts (via C-terminus) with SRP72 (via N-terminus) (PubMed:16672232, PubMed:28369529, PubMed:27899666).
The N-terminus is required for RNA-binding.
Expressed in monocytes/macrophages (at protein level).
Glycosylated. Genetic variations that affect N-glycosylation sites reduce activity, but enzymatic deglycosylation has no effect.
Hydrolyzes DNA under acidic conditions with a preference for double-stranded DNA. Plays a major role in the clearance of nucleic acids generated through apoptosis, hence preventing autoinflammation (PubMed:29259162, PubMed:31775019). Necessary for proper fetal development and for definitive erythropoiesis in fetal liver and bone marrow, where it degrades nuclear DNA expelled from erythroid precursor cells (PubMed:29259162).
The disease is caused by variants affecting the gene represented in this entry. The genetic variation producing the missense variant p.G116A, associated with AIPCS, has been shown to predominantly affect splicing, leading to in-frame deletion of exon 4, encoding amino acids 116 to 171. The protein resulting from this aberrant splicing may be unstable.
Highly expressed in non-small-cell lung carcinoma (NSCLC) tissue, with increased expression correlating with advanced disease, lymph node metastases and poor prognosis, as such may be a candidate prognostic marker (PubMed:28418919). May act as an oncogene and promote tumor growth via positive regulation of cell cycle progression at G1/S phase transition (PubMed:28418919). May promote invasion and metastasis via activation of the AKT/GSK-3 beta signaling pathway (PubMed:28418919). Expressed in the cytoplasm in NSCLC tissue (PubMed:28418919).
Weakly expressed in the lung (at protein level).
Autoubiquitinated. MTA1 destabilizes it by promoting its autoubiquitination.
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Involved in JUN ubiquitination and degradation. Directly involved in p53 (TP53) ubiquitination and degradation, thereby abolishing p53-dependent transcription and apoptosis. Ubiquitinates p53 independently of MDM2 or RCHY1. Probably mediates E3 ubiquitin ligase activity by functioning as the essential RING domain subunit of larger E3 complexes. In contrast, it does not constitute the catalytic RING subunit in the DCX DET1-COP1 complex that negatively regulates JUN, the ubiquitin ligase activity being mediated by RBX1. Involved in 14-3-3 protein sigma/SFN ubiquitination and proteasomal degradation, leading to AKT activation and promotion of cell survival. Ubiquitinates MTA1 leading to its proteasomal degradation. Upon binding to TRIB1, ubiquitinates CEBPA, which lacks a canonical COP1-binding motif (Probable).
Homodimer. Homodimerization is mediated by the coiled coil domain. Component of the DCX DET1-COP1 ubiquitin ligase complex at least composed of RBX1, DET1, DDB1, CUL4A and COP1. Isoform 2 does not interact with CUL4A but still binds to RBX1, suggesting that the interaction may be mediated by another cullin protein. Isoform 1 and isoform 2 interact with CUL5 but not with CUL1, CUL2 not CUL3. Interacts with bZIP transcription factors JUN, JUNB and JUND but not with FOS, ATF2 nor XBP1. Interacts with p53 (TP53). Interacts with COPS6; this interaction stabilizes RFWD2 through reducing its auto-ubiquitination and decelerating its turnover rate. Interacts with SFN; this interaction leads to SFN degradation. Isoform 4 forms heterodimers with isoform 1, preventing its association with DET1. Interacts with p53/TP53 and MTA1. Interacts with TRIB1 (via C-terminus) and TRIB2 (PubMed:20410507, PubMed:27041596).
TRIB1 competes with substrates for RFWD2 binding.
The RING finger domain, in addition to its role in ubiquitination, functions as a structural scaffold to bring two clusters of positive-charged residues within spatial proximity to mimic a bipartite nuclear localization signal (NLS) (By similarity).
The WD40 domain (386-731) is necessary and sufficient for TRIB1 binding (PubMed:27041596).
Ubiquitously expressed at low level. Expressed at higher level in testis, placenta, skeletal muscle and heart.
Unable to associate with other components of the CRL complex. Acts as a dominant-negative.
Chromatin regulator which modulates histone acetylation and gene expression in neural precursor cells (By similarity). May recruit histone deacetylases (HDACs) to the p160 coactivators/nuclear receptor complex to inhibit ligand-dependent transactivation (PubMed:15184363). Has a role in proliferation and development of cortical neural precursors (PubMed:25556659). May also regulate bone homeostasis (By similarity).
Expression levels are regulated during the cell cycle, reaching maximal levels at M phase and then rapidly declining after late M phase.
Interacts with the PAS region of the p160 coactivators.
Subject to proteasomal degradation which is probably essential to regulate its activity.
Interacts with CDK20, which promotes CDK20 stability and function (By similarity). Interacts with FAM149B1; may play a role in cilium assembly.
Required for high-level Shh responses in the developing neural tube. Together with CDK20, controls the structure of the primary cilium by coordinating assembly of the ciliary membrane and axoneme, allowing GLI2 to be properly activated in response to Shh signaling (By similarity).
The Rab-GAP TBC domain appears to be inactive, probably due to a lack of the essential Arg and Gln in the catalytic finger motifs.
Acts as a MHC class II receptor (PubMed:20519654). When stimulated on its own, does not play a role in cytokine production or the release of cytotoxic granules by NK cells and cytotoxic CD8(+) T cells (PubMed:17213291, PubMed:18991291). Does not act as an Fc receptor (PubMed:18991291).
Contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). The phosphorylated ITIM motif is involved in PTPN11 binding.
Down-regulated upon stimulation with mitogen phytohaemagglutinin (PHA) or concavalin A in peripheral blood mononuclear cells (PBMCs).
Expressed by cytolytic cells including NK cells, effector and effector-memory CD8(+) T-cells, and a subset of NKT cells (at protein level) (PubMed:17213291, PubMed:18991291, PubMed:20933011). Also expressed in gamma delta T cells and in a rare subset of effector CD4(+) T-cells (at protein level) (PubMed:18991291). Expressed in spleen, skin, peripheral blood leukocytes, liver, lung, bone marrow, small intestine and placenta (PubMed:20933011). Expression among T-cells is greatly expanded in HIV-1 infected individuals, and includes not only effector and effector-memory CD8(+) T-cells but also populations of CD4(+) T-cells (PubMed:17213291, PubMed:20933011). Expression among CD8(+) T-cells and NK cells is expanded in individuals with chronic lymphocytic leukemia (CLL) but is reduced in PBMCs from patients with acute (AML), chronic myeloid leukemia (CML) and non-Hodgkin's lymphoma (PubMed:18991291, PubMed:20933011). Expression is higher in PBMCs and/or CD3(+) cells of patients with autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and idiopathic thrombocytopenia purpura (ITP) (PubMed:20933011). In contrast, expression in CD3(+) cells from patients with lupus anticoagulans (LA) is higher (PubMed:20933011).
Interacts (tyrosine phosphorylated) with PTPN11 (PubMed:17213291, PubMed:20933011). Interacts (tyrosine phosphorylated) with PTPN6, INPP5D, INPPL1 and GRB2 (PubMed:20933011). Interacts with class II MHC HLA-DR when the alpha chain is associated with a beta-1, beta-4 or a beta-5 but not a beta-3 chain (PubMed:20519654).
Phosphorylated on Tyr residues. Tyrosine phosphorylation induces association with phosphatase PTPN11, PTPN6, INPP5D, INPPL1 and GRB2.
Microtubule-associated protein that is involved in the formation of parallel microtubule bundles linked by cross-bridges in the proximal axon. Required for the uniform orientation and maintenance of the parallel microtubule fascicles, which are important for efficient cargo delivery and trafficking in axons. Thereby also required for proper axon specification, the establishment of neuronal polarity and proper neuronal migration.
Widely expressed. Expressed in adult and fetal brain, fetal eyes, adult lens, kidney, liver and intestine.
May be involved in tuning the metabolism, energy expenditure, and excretion processes.
Component of the ER membrane protein complex (EMC) (PubMed:22119785, PubMed:29242231, PubMed:32459176). EMC8 and EMC9 are mutually exclusive subunits of the EMC complex (PubMed:32459176).
Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins (PubMed:30415835, PubMed:29809151, PubMed:29242231, PubMed:32459176). Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues (PubMed:30415835, PubMed:29809151, PubMed:29242231). Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices (PubMed:30415835, PubMed:29809151). It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes (PubMed:29809151, PubMed:29242231). By mediating the proper cotranslational insertion of N-terminal transmembrane domains in an N-exo topology, with translocated N-terminus in the lumen of the ER, controls the topology of multi-pass membrane proteins like the G protein-coupled receptors (PubMed:30415835). By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes (Probable).
Gamma-tubulin complex is composed of gamma-tubulin, TUBGCP2, TUBGCP3, TUBGCP4, TUBGCP5 and TUBGCP6.
Binds predominantly GDP, and also GTP (PubMed:17448446). Acts as a dynein adapter protein that activates dynein-mediated transport and dynein-dynactin motility on microtubules (PubMed:30814157).
Down-regulated in cutaneous melanoma cells but not in breast cancer cells.
Homodimer (PubMed:17448446). Interacts with the dynein-dynactin complex (PubMed:30814157).
Effector of small Rab GTPases which is involved in junctional complexes assembly through the regulation of cell adhesion molecules transport to the plasma membrane and actin cytoskeleton reorganization. Regulates the endocytic recycling of occludins, claudins and E-cadherin to the plasma membrane and may thereby regulate the establishment of tight junctions and adherens junctions. In parallel, may regulate actin cytoskeleton reorganization directly through interaction with F-actin or indirectly through actinins and filamins. Most probably involved in the processes of epithelial cell differentiation, cell spreading and neurite outgrowth (By similarity).
Interacts with RAB13 (GTP-bound form); competes with RAB8A and is involved in tight junctions assembly. Interacts with RAB8A; competes with RAB13 and is involved in E-cadherin endocytic recycling (By similarity). Interacts with RAB8B (By similarity). Interacts (preferentially in opened conformation) with ACTN1 and ACTN4; stimulated by RAB13 activation (By similarity). Interacts (via calponin-homology (CH) domain) with the filamins FLNA, FLNB and FLNC (via actin-binding domain).
Probably exists in a closed and an opened conformation due to interaction of the C-terminal coiled-coil domain with an N-terminal region including the calponin-homology (CH) and the LIM zinc-binding domain. The conformational change is regulated by RAB13 (By similarity).
C-, N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans.
Constituent of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells. C7 serves as a membrane anchor.
Monomer or dimer; as a C5b-7 complex it can also form multimeric rosettes. MAC assembly is initiated by proteolytic cleavage of C5 into C5a and C5b. C5b binds sequentially C6, C7, C8 and multiple copies of the pore-forming subunit C9.
Autoantibodies against MIA2 are present in several cancer types, including benign meningioma and cutaneous T-cell lymphoma (CTCL).
Highly expressed in liver and weakly in testis. Expression was higher in patients with severe fibrosis or inflammation and chronic hepatitis (PubMed:12586826). Isoform 1 is specifically expressed in lung, testis, small intestine, colon, pancreas, kidney, liver and prostate (PubMed:27138255). Isoform 8 is expressed only in testis (at the protein level). Isoform 8 (at protein level) and isoform 9 are expressed in cutaneous T-cell lymphoma (CTCL) cell lines, colorectal carcinomas, breast carcinomas and melanoma. Isoform 9, but not isoform 5A, is expressed in head and neck squamous cell carcinoma (PubMed:12839582).
Interacts with MIA3 (PubMed:21525241, PubMed:25202031, PubMed:27138255, PubMed:27170179). Interacts with the COPII coat subunits SEC23A, SEC23B and maybe SEC24C (PubMed:21525241, PubMed:27551091). Interacts with PREB; recruits PREB to endoplasmic reticulum exit sites (PubMed:25202031, PubMed:27170179). Interacts with APOB (PubMed:27138255).
Plays a role in the transport of cargos that are too large to fit into COPII-coated vesicles and require specific mechanisms to be incorporated into membrane-bound carriers and exported from the endoplasmic reticulum (PubMed:27138255, PubMed:21525241, PubMed:25202031, PubMed:27170179). Plays a role in the secretion of lipoproteins, pre-chylomicrons and pre-VLDLs, by participating in their export from the endoplasmic reticulum (PubMed:27138255). Thereby, may play a role in cholesterol and triglyceride homeostasis (By similarity). Required for collagen VII (COL7A1) secretion by loading COL7A1 into transport carriers and recruiting PREB/SEC12 at the endoplasmic reticulum exit sites (PubMed:21525241, PubMed:25202031, PubMed:27170179).
Readthrough transcript producing a functional fusion protein MIA2-CTAGE5 with similarity to MIA3.
The proline-rich domain (PRD) contains repeated PPP motifs. A single PPP motif is necessary and sufficient to mediate interaction with the COPII coat subunits SEC23A and SEC23B (PubMed:21525241, PubMed:27551091). The coiled coil domains mediate interaction with MIA3 (PubMed:21525241). The first coiled coil domain mediates interaction with PREB (PubMed:25202031).
Highly expressed in prostate and testis, and at slightly lower levels in spleen, thymus, uterus, small intestine and colon.
Interacts with KATNB1. Also interacts with CTNNB1, gamma-tubulin and KIF23.
Negative regulator of katanin-mediated microtubule severing and release from the centrosome. Required for central spindle formation and the completion of cytokinesis. May negatively regulate axonal outgrowth by preventing the formation of microtubule bundles that are necessary for transport within the elongating axon. Negative regulator of the Wnt signaling pathway. Represses beta-catenin-mediated transcriptional activation by promoting the nuclear exclusion of beta-catenin.
Atypical E3 ubiquitin-protein ligase that mediates 'Lys-63'-linked ubiquitination of MAP3K14/NIK, leading to stabilize and activate MAP3K14/NIK. It thereby acts as an activator of the non-canonical NF-kappa-B2/NFKB2 pathway. May also play an important role in cell proliferation and/or anti-apoptosis.
Expressed ubiquitously, particularly at high level in testis. Isoform 2 is testis specific.
In contrast to other E3 ubiquitin-protein ligase, does not contain any domain (RING-type zinc finger or HECT domain) known to mediate E3 ligase activity.
Belongs to the complex I 75 kDa subunit family.
Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits (PubMed:12611891). This is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme (By similarity). Complex I associates with ubiquinol-cytochrome reductase complex (Complex III) to form supercomplexes (PubMed:30879903, PubMed:31557978). Interacts with MDM2 (PubMed:30879903). Interacts with AKAP1 (By similarity).
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:30879903, PubMed:31557978). Essential for catalysing the entry and efficient transfer of electrons within complex I (PubMed:31557978). Plays a key role in the assembly and stability of complex I and participates in the association of complex I with ubiquinol-cytochrome reductase complex (Complex III) to form supercomplexes (PubMed:30879903, PubMed:31557978).
Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analogs at neutral pH. Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release.
Expressed in placenta and hematopoietic cells. Expression is increased in malignant tissues.
Highly Expressed in keyhole limpet hemocyanin-stimulated dendritic cell (DC) and weakly expressed in unstimulated mature and immature DC (PubMed:11444830). Highly expressed in kidney and liver (PubMed:11444830). Moderately expressed in heart, skeletal muscle, and placenta (PubMed:11444830). Weakly expressed in the small intestine (PubMed:11444830).
Interacts with CAMK2A and CAMK2B in the presence of Ca(2+)/calmodulin or after autophosphorylation.
Potent and specific cellular inhibitor of CaM-kinase II (CAMK2) (PubMed:11444830). Traps Ca(2+)/calmodulin on CAMK2 (By similarity).
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1F subfamily.
Expression in skeletal muscle and retina (PubMed:10873387). Isoform 4 is expressed in retina (PubMed:27226626).
Interacts with CABP4; suppresses robust calcium-dependent inactivation of channel without enhancing the hyperpolarized voltage-dependent activation (PubMed:27226626).
Voltage-dependent L-type calcium channel activates at more hyperpolarized voltages and exhibits a robust calcium-dependent inactivation (CDI), due to incoming calcium ions, during depolarizations.
Voltage-dependent calcium channels are multisubunit complexes, consisting of alpha-1, alpha-2, beta and delta subunits in a 1:1:1:1 ratio. The channel activity is directed by the pore-forming and voltage-sensitive alpha-1 subunit. In many cases, this subunit is sufficient to generate voltage-sensitive calcium channel activity. The auxiliary subunits beta and alpha-2/delta linked by a disulfide bridge regulate the channel activity. Interacts (via IQ domain) with CABP4; in a calcium independent manner (By similarity).
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1F gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, and by benzothiazepines. Activates at more negative voltages and does not undergo calcium-dependent inactivation (CDI), due to incoming calcium ions, during depolarization.
By p53/TP53 and p63/TP63. Directly activated by p53/TP53.
Interacts (via coiled-coil domains) with BNIP3L (via BH3 domain). Interacts (via coiled-coil domains) with BNIP3 (via BH3 domain).
Key regulator of mitochondrial quality that mediates the repairing or degradation of unhealthy mitochondria in response to mitochondrial damage. Mediator of mitochondrial protein catabolic process (also named MALM) by mediating the degradation of damaged proteins inside mitochondria by promoting the accumulation in the mitochondrial matrix of hydrolases that are characteristic of the lysosomal lumen. Also involved in mitochondrion degradation of damaged mitochondria by promoting the formation of vacuole-like structures (named MIV), which engulf and degrade unhealthy mitochondria by accumulating lysosomes. The physical interaction of SPATA18/MIEAP, BNIP3 and BNIP3L/NIX at the mitochondrial outer membrane regulates the opening of a pore in the mitochondrial double membrane in order to mediate the translocation of lysosomal proteins from the cytoplasm to the mitochondrial matrix.
In BCR signaling, appears to function as a docking protein acting downstream of TEC and participates in a positive feedback loop by increasing the activity of TEC.
Interacts with KIT and CSF1R (By similarity). Interacts with URI1; the interaction is phosphorylation-dependent and occurs in a growth-dependent manner.
Phosphorylated on tyrosine by TEC. Phosphorylated on tyrosine by KIT (By similarity).
Expressed preferentially in dendritic cells.
Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. May play a role in changing or maintaining the spatial distribution of cytoskeletal structures (By similarity).
Homodimer (By similarity). The cytoplasmic dynein 1 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits which present intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs); the composition seems to vary in respect to the IC, LIC and LC composition (By similarity). The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits (By similarity). Dynein ICs and LICs bind directly to the HC dimer and the LCs assemble on the IC dimer (By similarity). Interacts with DYNC1I1 (By similarity). Interacts with BMF (By similarity). Component of the myosin V motor complex (By similarity). Interacts with BCAS1 (By similarity). Interacts with Basson/BSN (PubMed:19380881). Interacts with AMBRA1 (via TQT motifs); tethering AMBRA1 to the cytoskeleton (PubMed:20921139). Interacts with IQUB (By similarity).
Part of the nuclear protein complex gamma-globin promoter and enhancer binding factor (gamma-PE) composed at least by SATB1 and HOXB2.
Catalyzes the hydrolysis of the vinyl ether bond of choline or ethanolamine lysoplasmalogens, forming fatty aldehyde and glycerophosphocholine or glycerophosphoethanolamine, respectively and is specific for the sn-2-deacylated (lyso) form of plasmalogen.
Competitively inhibited by lysophosphatidic acid.
Belongs to the glycosyltransferase 16 (GT16) protein family.
Plays an essential role in protein N-glycosylation. Catalyzes the transfer of N-acetylglucosamine (GlcNAc) onto the free terminal mannose moiety in the core structure of the nascent N-linked glycan chain, giving rise to the second branch in complex glycans.
Interacts with RIGI; this interaction is GTP-dependent and induced upon viral infection; this interaction suppresses the RNA sensing activity of RIGI.
May suppress the RNA sensing activity of RIGI in a GTP-dependent.
Highly expressed in heart, ovary, testis, liver, and kidney, at lower levels in spleen, prostate, brain, skeletal muscle, pancreas, small intestine and colon, and undetected in peripheral blood leukocytes, thymus, lung and placenta. AIG1 expression is higher in hair follicles from males than from females.
Hydrolyzes bioactive fatty-acid esters of hydroxy-fatty acids (FAHFAs), but not other major classes of lipids (PubMed:27018888). Show a preference for FAHFAs with branching distal from the carboxylate head group of the lipids (PubMed:27018888).
Functions as a component of the PCAF complex. The PCAF complex is capable of efficiently acetylating histones in a nucleosomal context. The PCAF complex could be considered as the human version of the yeast SAGA complex (Probable). With TAF6L, acts as an epigenetic regulator essential for somatic reprogramming. Regulates target genes through H3K9ac deposition and MYC recruitment which trigger MYC regulatory network to orchestrate gene expression programs to control embryonic stem cell state (By similarity).
The PCAF complex is composed of a number of TBP-associated factors (TAFS), such as TAF5, TAF5L, TAF6, TAF6L, TAF9, TAF10 and TAF12, PCAF, and also PCAF-associated factors (PAFs), such as TADA2L/ADA2, TADA3L/ADA3 and SPT3. Component of the STAGA transcription coactivator-HAT complex, at least composed of SUPT3H, GCN5L2, TAF5L, TAF6L, SUPT7L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9.
Belongs to the acetyltransferase family. AANAT subfamily.
Controls the night/day rhythm of melatonin production in the pineal gland. Catalyzes the N-acetylation of serotonin into N-acetylserotonin, the penultimate step in the synthesis of melatonin.
Highly expressed in pineal gland and at lower levels in the retina. Weak expression in several brain regions and in the pituitary gland.
Monomer (By similarity). Interacts with several 14-3-3 proteins, including YWHAB, YWHAE, YWHAG and YWHAZ, preferentially when phosphorylated at Thr-31. Phosphorylation on Ser-205 also allows binding to YWHAZ, but with lower affinity. The interaction with YWHAZ considerably increases affinity for arylalkylamines and acetyl-CoA and protects the enzyme from dephosphorylation and proteasomal degradation (By similarity). It may also prevent thiol-dependent inactivation (By similarity).
cAMP-dependent phosphorylation on both N-terminal Thr-31 and C-terminal Ser-205 regulates AANAT activity by promoting interaction with 14-3-3 proteins.
Detected in low levels in discrete regions within the central nervous system and in several peripheral tissues. Moderately expressed in stomach. Low levels in amygdala, kidney, and lung, and small intestine. Trace amounts in cerebellum, dorsal root ganglia, hippocampus, hypothalamus, liver, medulla, pancreas, pituitary, pontine reticular formation, prostate, skeletal muscle and spleen.
Receptor for trace amines, including beta-phenylethylamine (b-PEA), p-tyramine (p-TYR), octopamine and tryptamine, with highest affinity for b-PEA and p-TYR. Unresponsive to classical biogenic amines, such as epinephrine and histamine and only partially activated by dopamine and serotonin. Trace amines are biogenic amines present in very low levels in mammalian tissues. Although some trace amines have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative. Trace amines are likely to be involved in a variety of physiological functions that have yet to be fully understood. The signal transduced by this receptor is mediated by the G(s)-class of G-proteins which activate adenylate cyclase.
Belongs to the class-II aminoacyl-tRNA synthetase family. Phe-tRNA synthetase alpha subunit type 2 subfamily.
Heterotetramer; dimer of two heterodimers formed by FARSA and FARSB.
Citrullination at Arg-58 (H1R54ci) by PADI4 takes place within the DNA-binding site of H1 and results in its displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance.
Testis-specific histone H1 that forms less compacted chromatin compared to other H1 histone subtypes (PubMed:26757249). Formation of more relaxed chromatin may be required to promote chromatin architecture required for proper chromosome regulation during meiosis, such as homologous recombination (PubMed:26757249). Histones H1 act as linkers that bind to nucleosomes and compact polynucleosomes into a higher-order chromatin configuration (Probable).
This histone is a testis-specific H1 variant that appears during meiosis in spermatogenesis.
GTF2IRD1 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of GTF2IRD1 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.
Highly expressed in adult skeletal muscle, heart, fibroblast, bone and fetal tissues. Expressed at lower levels in all other tissues tested.
Highly expressed in developing and regenerating muscles, at the time of myofiber diversification.
Interacts with the retinoblastoma protein (RB1) via its C-terminus.
May be a transcription regulator involved in cell-cycle progression and skeletal muscle differentiation. May repress GTF2I transcriptional functions, by preventing its nuclear residency, or by inhibiting its transcriptional activation. May contribute to slow-twitch fiber type specificity during myogenesis and in regenerating muscles. Binds troponin I slow-muscle fiber enhancer (USE B1). Binds specifically and with high affinity to the EFG sequences derived from the early enhancer of HOXC8 (By similarity).
The N-terminal half may have an activating activity.
Antiporter specific for GDP-l-fucose and depending on the concomitant reverse transport of GMP. Involved in GDP-fucose import from the cytoplasm into the Golgi lumen.
Belongs to the TPT transporter family. SLC35C subfamily.
Abundantly expressed in the chondrocyte extracellular matrix, and is also found in bone, tendon, ligament and synovium and blood vessels. Increased amounts are produced during late stages of osteoarthritis in the area adjacent to the main defect.
Each of the eight TSP type-3 repeats binds two calcium ions. The TSP C-terminal domain binds three calcium ions.
Pentamer; disulfide-linked (PubMed:32686688). Exists in a more compact conformation in the presence of calcium and shows a more extended conformation in the absence of calcium (PubMed:19276170). Interacts with ITGB3, ITGA5 and FN1. Binding to FN1 requires the presence of divalent cations (Ca(2+), Mg(2+) or Mn(2+)). The greatest amount of binding is seen in the presence of Mn(2+) (PubMed:16051604, PubMed:12225811). Interacts with MATN1, MATN3, MATN4 and ACAN (PubMed:15075323, PubMed:17588949). Binds heparin, heparan sulfate and chondroitin sulfate. EDTA dimishes significantly its binding to ACAN and abolishes its binding to MATN3, MATN4 and chondroitin sulfate (PubMed:17588949). Interacts with collagen I, II and IX, and interaction with these collagens is dependent on the presence of zinc ions (PubMed:11084047). Interacts with ADAMTS12 (PubMed:16611630). Interacts with ITGA7 (By similarity).
Plays a role in the structural integrity of cartilage via its interaction with other extracellular matrix proteins such as the collagens and fibronectin. Can mediate the interaction of chondrocytes with the cartilage extracellular matrix through interaction with cell surface integrin receptors (PubMed:16542502, PubMed:16051604). Could play a role in the pathogenesis of osteoarthritis (PubMed:16542502). Potent suppressor of apoptosis in both primary chondrocytes and transformed cells. Suppresses apoptosis by blocking the activation of caspase-3 and by inducing the IAP family of survival proteins (BIRC3, BIRC2, BIRC5 and XIAP) (PubMed:17993464). Essential for maintaining a vascular smooth muscle cells (VSMCs) contractile/differentiated phenotype under physiological and pathological stimuli. Maintains this phenotype of VSMCs by interacting with ITGA7 (By similarity).
Present during the earliest stages of limb maturation and is later found in regions where the joints develop.
The TSP C-terminal domain mediates interaction with FN1 and ACAN.
The cell attachment motif mediates the attachment to chondrocytes. It mediates the induction of both the IAP family of survival proteins and the antiapoptotic response.
Expressed exclusively in tissues containing a high content of terminally differentiated epithelial cells including mammary gland, colon, trachea, kidney, prostate, uterus, stomach and skin.
Interacts with TBP. Interacts with CREBBP and EP300; these act as transcriptional coactivators of ELF3 and positively modulate its function. Interacts with XRCC5/KU86 and XRCC6/KU70; these inhibit the ability of ELF3 to bind DNA and negatively modulate its transcriptional activity. Associated with CLND7 and POU2F3. Interacts with ZNF768 (PubMed:30476274).
Transcriptional activator that binds and transactivates ETS sequences containing the consensus nucleotide core sequence GGA[AT]. Acts synergistically with POU2F3 to transactivate the SPRR2A promoter and with RUNX1 to transactivate the ANGPT1 promoter. Also transactivates collagenase, CCL20, CLND7, FLG, KRT8, NOS2, PTGS2, SPRR2B, TGFBR2 and TGM3 promoters. Represses KRT4 promoter activity. Involved in mediating vascular inflammation. May play an important role in epithelial cell differentiation and tumorigenesis. May be a critical downstream effector of the ERBB2 signaling pathway. May be associated with mammary gland development and involution. Plays an important role in the regulation of transcription with TATA-less promoters in preimplantation embryos, which is essential in preimplantation development (By similarity).
Transcriptionally regulated by ERBB2 receptor signaling in breast cancer epithelial cells. Up-regulated by phorbol 12-myristate 13-acetate (PMA) in bronchial epithelial cells. By retinoic acid in MCF-7 mammary epithelial cells (at protein level).
Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane (PubMed:26571211). The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (PubMed:26571211). HYCC1 plays a key role in oligodendrocytes formation, a cell type with expanded plasma membrane that requires generation of PtdIns(4)P (PubMed:26571211). Its role in oligodendrocytes formation probably explains its importance in myelination of the central and peripheral nervous system (PubMed:26571211, PubMed:16951682). May also have a role in the beta-catenin/Lef signaling pathway (Probable).
Component of a phosphatidylinositol 4-kinase (PI4K) complex, composed of PI4KA, EFR3 (EFR3A or EFR3B), TTC7 (TTC7A or TTC7B) and HYCC (HYCC1 or HYCC2) (PubMed:26571211). Interacts with TTC7 (TTC7A or TTC7B), interaction is direct (PubMed:26571211).
Widely expressed. Highest levels in heart, brain, placenta, spleen and testis.
Expressed at highest levels in brain, testis, colon and kidney. Expressed at medium levels in heart and liver, small intestine and stomach. Expressed at low levels in peripheral leukocytes, bone marrow, skeletal muscle and aorta. Expressed in adipose tissue (PubMed:24269233, PubMed:9878842). Expressed in brain gray matter (PubMed:21395585).
Mediates the levels of long-chain fatty acids (LCFA) in the cell by facilitating their transport across cell membranes (PubMed:10518211, PubMed:12556534, PubMed:20448275, PubMed:21395585, PubMed:22022213). Appears to be the principal fatty acid transporter in small intestinal enterocytes (PubMed:20448275). Also functions as an acyl-CoA ligase catalyzing the ATP-dependent formation of fatty acyl-CoA using LCFA and very-long-chain fatty acids (VLCFA) as substrates, which prevents fatty acid efflux from cells and might drive more fatty acid uptake (PubMed:22022213, PubMed:24269233). Plays a role in the formation of the epidermal barrier. Required for fat absorption in early embryogenesis (By similarity). Probably involved in fatty acid transport across the blood barrier (PubMed:21395585). Indirectly inhibits RPE65 via substrate competition and via production of VLCFA derivatives like lignoceroyl-CoA. Prevents light-induced degeneration of rods and cones (By similarity).
SLC27A4/FATP4-mediated fatty acid uptake is associated to paramaters related to insulin resistance, which is associated with disturbed fatty acid metabolism and homeostasis, such as obesity. SLC27A4/FATP4 expression is positively correlated with acquired obesity.
May play a role in protection or detoxification.
Forms a ternary complex with IGFR1 and ITGAV:ITGB3 (PubMed:19578119). Forms a ternary complex with IGFR1 and ITGA6:ITGB4 (PubMed:22351760, PubMed:23696648). Interacts with SH2D3C isoform 2 (PubMed:20881139).
The insulin-like growth factors, isolated from plasma, are structurally and functionally related to insulin but have a much higher growth-promoting activity. May be a physiological regulator of [1-14C]-2-deoxy-D-glucose (2DG) transport and glycogen synthesis in osteoblasts. Stimulates glucose transport in bone-derived osteoblastic (PyMS) cells and is effective at much lower concentrations than insulin, not only regarding glycogen and DNA synthesis but also with regard to enhancing glucose uptake. May play a role in synapse maturation (PubMed:21076856, PubMed:24132240). Ca(2+)-dependent exocytosis of IGF1 is required for sensory perception of smell in the olfactory bulb (By similarity). Acts as a ligand for IGF1R. Binds to the alpha subunit of IGF1R, leading to the activation of the intrinsic tyrosine kinase activity which autophosphorylates tyrosine residues in the beta subunit thus initiatiating a cascade of down-stream signaling events leading to activation of the PI3K-AKT/PKB and the Ras-MAPK pathways. Binds to integrins ITGAV:ITGB3 and ITGA6:ITGB4. Its binding to integrins and subsequent ternary complex formation with integrins and IGFR1 are essential for IGF1 signaling. Induces the phosphorylation and activation of IGFR1, MAPK3/ERK1, MAPK1/ERK2 and AKT1 (PubMed:19578119, PubMed:22351760, PubMed:23696648, PubMed:23243309).
Potential trans-activating factor that could play an important role in the transcription of genes required for the later stages of cell cycle progression.
Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals. The BLOC-1 complex, in association with SNARE proteins, is also proposed to be involved in neurite extension. Plays a role in intracellular vesicle trafficking.
Interacts with BLOC1S5 and BLOC1S6 (By similarity). Component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) composed of BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. Octamer composed of one copy each BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. The BLOC-1 complex associates with the AP-3 protein complex and membrane protein cargos.
A cleavage occurs, separating the extracellular domain from the transmembrane segment. This process called 'ectodomain shedding' is thought to be involved in receptor desensitization, signal transduction and/or membrane localization.
Can bidirectionally induce pre- and post-synaptic differentiation of neurons by mediating interaction with IL1RAP and IL1RAPL1 trans-synaptically. Involved in pre-synaptic differentiation through interaction with SLITRK2.
Interacts with PPFIA1, PPFIA2 and PPFIA3 (PubMed:9624153). Interacts (via extracellular domain) with SLITRK4 (via LRR 1 and 2 repeats). Interacts with SLITRK2; induces presynaptic differentiation. Interacts (via the second immunoglobilin domain) with IL1RAPL1 (via the first immunoglobilin domain); induces pre- and postsynaptic differentiation of neurons and synapse formation. Interacts (via the third immunoglobilin domain) with IL1RAP (via the first immunoglobilin domain); induces pre- and postsynaptic differentiation of neurons (By similarity).
Binds acetylated histones H3 and H4 (PubMed:22464331, PubMed:26365797). Binds butyrylated histone H4 (PubMed:26365797). Component of the multiprotein chromatin-remodeling subcomplex SWI/SNF called GBAF, which includes at least BICRA or BICRAL (mutually exclusive), BRD9, SS18, the core BAF subunits, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, SMARCC1/BAF155, and SMARCD1/BAF60A (PubMed:29374058). Interacts (via N-terminal bromodomain) with acteylated RAD54 (PubMed:32457312). Interacts (via C-terminus) with RAD51 (PubMed:32457312).
Plays a role in chromatin remodeling and regulation of transcription (PubMed:22464331, PubMed:26365797). Acts as a chromatin reader that recognizes and binds acylated histones: binds histones that are acetylated and/or butyrylated (PubMed:26365797). Component of SWI/SNF chromatin remodeling subcomplex GBAF that carries out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner (PubMed:29374058). Orchestrates also the RAD51-RAD54 complex formation and thereby plays a role in homologous recombination (HR) (PubMed:32457312).
The Bromo domain mediates interaction with histones that have acetylated lysine residues at specific positions (PubMed:22464331). Also recognizes and binds histones that are butyrylated (PubMed:26365797).
Disease susceptibility may be associated with variants affecting the gene represented in this entry. A copy number variation (CNV) resulting in BHLHA9 duplications is a necessary but not sufficient susceptibility factor for Split-hand/foot malformation with long bone deficiency, a highly variable phenotype with reduced penetrance, particularly in females (PubMed:22147889).
Heterodimer (PubMed:25466284). Efficient DNA binding requires dimerization with another bHLH protein. Interacts with TCF3, TCF4, and TCF12 (PubMed:25466284).
Transcription factor, which play a role in limb development. Is an essential player in the regulatory network governing transcription of genes implicated in limb morphogenesis.
Forms a complex, named COMB/coordinator of mitochondrial CYTB biogenesis, composed of UQCC1, UQCC2, UQCC4, UQCC5 and UQCC6; stabilizes nascent cytochrome b/MT-CYB and promotes its membrane insertion. Forms a complex, named COMA, composed of UQCC1, UQCC2 and UQCC4; activates MT-CYB translation. Forms a complex, named COMC, composed of UQCC1, UQCC2; UQCC3 and UQCC4; mediates MT-CYB hemylation and association with the first nuclear-encoded complex III subunit UQCRQ. Complexes COMA and COMB are bound to the mitochondrion inner membrane by UQCC4.
Required for the assembly and stability of the mitochondrial ubiquinol-cytochrome c reductase complex (complex III (CIII) or cytochrome b-c1 complex), a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain (ETC) which drives oxidative phosphorylation.
Deubiquitination at Lys-191 and Lys-194 by USP32.
Small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins playing a key role in the regulation of endo-lysosomal trafficking. Governs early-to-late endosomal maturation, microtubule minus-end as well as plus-end directed endosomal migration and positioning, and endosome-lysosome transport through different protein-protein interaction cascades. Plays a central role, not only in endosomal traffic, but also in many other cellular and physiological events, such as growth-factor-mediated cell signaling, nutrient-transportor mediated nutrient uptake, neurotrophin transport in the axons of neurons and lipid metabolism. Also involved in regulation of some specialized endosomal membrane trafficking, such as maturation of melanosomes, pathogen-induced phagosomes (or vacuoles) and autophagosomes. Plays a role in the maturation and acidification of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis. Plays a role in the fusion of phagosomes with lysosomes. Plays important roles in microbial pathogen infection and survival, as well as in participating in the life cycle of viruses. Microbial pathogens possess survival strategies governed by RAB7A, sometimes by employing RAB7A function (e.g. Salmonella) and sometimes by excluding RAB7A function (e.g. Mycobacterium). In concert with RAC1, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts. Controls the endosomal trafficking and neurite outgrowth signaling of NTRK1/TRKA (PubMed:11179213, PubMed:12944476, PubMed:14617358, PubMed:20028791, PubMed:21255211). Regulates the endocytic trafficking of the EGF-EGFR complex by regulating its lysosomal degradation. Involved in the ADRB2-stimulated lipolysis through lipophagy, a cytosolic lipase-independent autophagic pathway (By similarity). Required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413). Required for vesicular trafficking and cell surface expression of ACE2 (PubMed:33147445). May play a role in PRPH neuronal intermediate filament assembly (By similarity).
The GTP-bound form interacts with RAC1 (By similarity). Interacts with NTRK1/TRKA (By similarity). Interacts with C9orf72 (By similarity). Interacts with CHM, the substrate-binding subunit of the Rab geranylgeranyltransferase complex (By similarity). Interacts with RILP (PubMed:11179213, PubMed:14668488, PubMed:15933719, PubMed:20028791, PubMed:22431521). Interacts with PSMA7 (PubMed:14998988). Interacts with RNF115 (PubMed:16925951). Interacts with FYCO1 (PubMed:20100911). Interacts with the PIK3C3/VPS34-PIK3R4 complex (PubMed:14617358). The GTP-bound form interacts with OSBPL1A (PubMed:16176980). Interacts with CLN3 (PubMed:22261744). Does not interact with HPS4 and the BLOC-3 complex (heterodimer of HPS1 and HPS4) (PubMed:20048159). Interacts with CLN5 (PubMed:22431521). Interacts with PLEKHM1 (via N- and C-terminus) (PubMed:28325809). Interacts with RUFY4 (PubMed:26416964). Interacts with PRPH; the interaction is direct (PubMed:23179371). Interacts with VPS13A (PubMed:30709847). The GDP-bound form interacts with RIMOC1 (PubMed:34432599). Interacts with the MON1A-CCZ1B complex and this interaction is enhanced in the presence of RIMOC1 (PubMed:34432599).
Widely expressed; high expression found in skeletal muscle.
Expression is highest in the periphery, particularly in the stomach, but also in the kidney, liver, pancreas, and prostate. In brain, levels of expression are generally lower than in the periphery, with the exception of cerebellum, spinal cord, and dorsal root ganglia (DRG).
This retinoic acid-inducible G-protein coupled receptor provide evidence for a possible interaction between retinoid and G-protein signaling pathways.
Acts as a sulfur carrier required for molybdopterin biosynthesis. Component of the molybdopterin synthase complex that catalyzes the conversion of precursor Z into molybdopterin by mediating the incorporation of 2 sulfur atoms into precursor Z to generate a dithiolene group. In the complex, serves as sulfur donor by being thiocarboxylated (-COSH) at its C-terminus by MOCS3. After interaction with MOCS2B, the sulfur is then transferred to precursor Z to form molybdopterin.
Belongs to the MoaD family. MOCS2A subfamily.
Belongs to the MoaE family. MOCS2B subfamily.
C-terminal thiocarboxylation occurs in 2 steps, it is first acyl-adenylated (-COAMP) via the hesA/moeB/thiF part of MOCS3, then thiocarboxylated (-COSH) via the rhodanese domain of MOCS3.
Catalytic subunit of the molybdopterin synthase complex, a complex that catalyzes the conversion of precursor Z into molybdopterin. Acts by mediating the incorporation of 2 sulfur atoms from thiocarboxylated MOCS2A into precursor Z to generate a dithiolene group.
Heterotetramer; composed of 2 small (MOCS2A) and 2 large (MOCS2B) subunits.
Highest levels are found in heart and skeletal muscle. Lower levels are present in brain, kidney and pancreas. Very low levels are found in lung and peripheral blood leukocytes.
This protein is produced by a bicistronic gene which also produces the large subunit (MOCS2B) from an overlapping reading frame. Expression of these 2 proteins are related since a mutation that removes the start codon of the small subunit (MOCS2A) also impairs expression of the large subunit (MOCS2B).
This protein is produced by a bicistronic gene which also produces the small subunit (MOCS2A) from an overlapping reading frame. Expression of these 2 proteins are related since a mutation that removes the start codon of the small subunit (MOCS2A) also impairs expression of the large subunit (MOCS2B).
Widely expressed. Highest levels are found in heart and skeletal muscle. Lower levels are present in brain, kidney and pancreas. Very low levels are found in lung and peripheral blood leukocytes.
Catalyzes both the synthesis and degradation of fructose 2,6-bisphosphate.
Homodimer (PubMed:16316985). Forms a heterodimer with PFKFB2 (PubMed:36402789).
Low expression in testis, ovary and thymus. Expressed in embryonic stem and carcinoma cells. Highly expressed in testicular germ cell tumors.
Mediates binding to H3K9me2 via N-terminal region, while ability to exclude TET3 from the maternal pronucleus requires the C-terminal part.
Primordial germ cell (PGCs)-specific protein involved in epigenetic chromatin reprogramming in the zygote following fertilization (PubMed:35314832). In zygotes, DNA demethylation occurs selectively in the paternal pronucleus before the first cell division, while the adjacent maternal pronucleus and certain paternally-imprinted loci are protected from this process (By similarity). Participates in protection of DNA methylation in the maternal pronucleus by preventing conversion of 5mC to 5hmC: specifically recognizes and binds histone H3 dimethylated at 'Lys-9' (H3K9me2) on maternal genome, and protects maternal genome from TET3-mediated conversion to 5hmC and subsequent DNA demethylation (By similarity). Does not bind paternal chromatin, which is mainly packed into protamine and does not contain much H3K9me2 mark (By similarity). Also protects imprinted loci that are marked with H3K9me2 in mature sperm from DNA demethylation in early embryogenesis (By similarity). May be important for the totipotent/pluripotent states continuing through preimplantation development (By similarity). Also involved in chromatin condensation in oocytogenesis (By similarity).
Calcium-dependent phospholipase A2 that selectively hydrolyzes glycerophospholipids in the sn-2 position (PubMed:14709560). Has a preference for linoleic acid at the sn-2 position (PubMed:14709560).
Expressed in stratified squamous epithelia, such as those in skin and cervix, but not in other tissues (PubMed:14709560). Strongly expressed in the upper spinous layer of the psoriatic epidermis, expressed weakly and discontinuously in atopic dermatitis and mycosis fungoides, and not detected in the epidermis of normal skin (PubMed:14709560).
The N-terminal C2 domain mediates the association with lipid membranes upon calcium binding (Probable). An additional second C2 domain may stand in between the C2 domain and the PLA2c domain (Probable).
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is composed of 13 subunits: EIF3A, EIF3B, EIF3C, EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L and EIF3M. The eIF-3 complex appears to include 3 stable modules: module A is composed of EIF3A, EIF3B, EIF3G and EIF3I; module B is composed of EIF3F, EIF3H, and EIF3M; and module C is composed of EIF3C, EIF3D, EIF3E, EIF3K and EIF3L. EIF3C of module C binds EIF3B of module A and EIF3H of module B, thereby linking the three modules. EIF3J is a labile subunit that binds to the eIF-3 complex via EIF3B. The eIF-3 complex interacts with RPS6KB1 under conditions of nutrient depletion. Mitogenic stimulation leads to binding and activation of a complex composed of MTOR and RPTOR, leading to phosphorylation and release of RPS6KB1 and binding of EIF4B to eIF-3. Interacts with CCND3, but not with CCND1 and CCND2.
Ubiquitous, with the highest levels of expression in brain, testis and kidney.
Highly expressed in brain, bone marrow, small intestine, muscle, spleen and pancreas. Moderate expression was seen in lung, liver and kidney.
Expressed in many tissues. Strong expression in the photoreceptor cells of the retina, with a punctate pattern of labeling over the nuclei and inner segments with less expression along the other segments and outer plexiform layer.
A palmitoylation site was proposed at Cys-77, but it was later shown that this cysteine is engaged in a disulfide bond (PubMed:24292069).
Disulfide bonds have critical and distinct roles in secretion and activity. Loss of each conserved cysteine in WNT3A results in high molecular weight oxidized Wnt oligomers, which are formed through inter-Wnt disulfide bonding.
Forms a soluble 1:1 complex with AFM; this prevents oligomerization and is required for prolonged biological activity (PubMed:26902720). The complex with AFM may represent the physiological form in body fluids (PubMed:26902720). Homooligomer; disulfide-linked, leading to inactivation (By similarity). Interacts with PORCN (PubMed:20826466). Interacts with APCDD1 and WLS (PubMed:16678095, PubMed:20393562). Component of the Wnt-Fzd-LRP5-LRP6 signaling complex that contains a WNT protein, a FZD protein and LRP5 or LRP6. Interacts directly in the complex with LRP6 (PubMed:20093360). Interacts with glypican GPC3 (PubMed:16227623). Interacts with PKD1 (via extracellular domain) (PubMed:27214281).
Ligand for members of the frizzled family of seven transmembrane receptors (Probable). Functions in the canonical Wnt signaling pathway that results in activation of transcription factors of the TCF/LEF family (PubMed:20093360, PubMed:21244856, PubMed:24841207, PubMed:26902720). Required for normal embryonic mesoderm development and formation of caudal somites. Required for normal morphogenesis of the developing neural tube (By similarity). Mediates self-renewal of the stem cells at the bottom on intestinal crypts (in vitro) (PubMed:26902720).
Moderately expressed in placenta and at low levels in adult lung, spleen, and prostate.
Palmitoleoylation by PORCN is required for efficient binding to frizzled receptors. Palmitoleoylation is required for proper trafficking to cell surface, vacuolar acidification is critical to release palmitoleoylated WNT3A from WLS in secretory vesicles (PubMed:20826466, PubMed:21244856, PubMed:24292069). Depalmitoleoylated by NOTUM, leading to inhibit Wnt signaling pathway, possibly by promoting disulfide bond formation and oligomerization (PubMed:25731175).
Proteolytic processing by TIKI1 and TIKI2 promotes oxidation and formation of large disulfide-bond oligomers, leading to inactivation of WNT3A.
Enhances the transcriptional activity of estrogen receptors ESR1 and ESR2.
Enhances the transcriptional activity of the estrogen receptor ESR2 only (PubMed:15199063). Mediates cell death induced by a combination of interferon-beta and retinoic acid (PubMed:9774665).
Expressed predominantly in Leydig cells (at protein level). Also expressed in ovary, spleen, heart, liver, kidney and pancreas and in a number of cancer cell lines.
Homodimer (PubMed:17512005, PubMed:8577704). Interacts with HERC5.
Induced by a combination of interferon-beta and retinoic acid (at protein level).
Induced by estradiol or testosterone in HeLa cells.
Induces actin and tubulin polymerization, leading to formation of cell membrane protrusions.
Major isoform. The N-terminus of the sequence is processed into a mature form that lacks residues Met-151 and Asn-152 at the N-terminus.
Reduces disulfideprotein thioredoxin (Trx) to its dithiol-containing form (PubMed:8577704). Homodimeric flavoprotein involved in the regulation of cellular redox reactions, growth and differentiation. Contains a selenocysteine residue at the C-terminal active site that is essential for catalysis (Probable). Also has reductase activity on hydrogen peroxide (H2O2) (PubMed:10849437).
The N-terminal glutaredoxin domain does not contain the C-P-Y-C redox-active motif normally found in glutaredoxins and has been found to be inactive in classical glutaredoxin assays.
The thioredoxin reductase active site is a redox-active disulfide bond. The selenocysteine residue is also essential for catalytic activity.
Widely expressed with highest levels in kidney, testis, uterus, ovary, prostate, placenta and fetal liver.
Major protein kinase C substrate of platelets.
Belongs to the AAA ATPase family. Katanin p60 subunit A1 subfamily.
Can homooligomerize into hexameric rings, which may be promoted by interaction with microtubules. Interacts with KATNB1, which may serve as a targeting subunit (PubMed:10751153). Interacts with ASPM; the katanin complex formation KATNA1:KATNB1 is required for the association of ASPM (By similarity). Interacts with dynein and NDEL1. Associates with the E3 ligase complex containing DYRK2, EDD/UBR5, DDB1 and DCAF1 proteins (EDVP complex) (PubMed:19287380). Interacts with KLHL42 (via the kelch domains). Interacts with CUL3; the interaction is enhanced by KLHL42 (PubMed:19261606). Interacts with KATNB1 and KATNBL1 (PubMed:26929214). Interacts with CAMSAP2 and CAMSAP3; leading to regulate the length of CAMSAP-decorated microtubule stretches (PubMed:24486153, PubMed:28386021).
Acetylated on Lys-19 by coactivators in response to TGF-beta signaling, which increases transcriptional activity. Isoform short: Acetylation increases DNA binding activity in vitro and enhances its association with target promoters in vivo. Acetylation in the nucleus by EP300 is enhanced by TGF-beta.
Expressed at high levels in skeletal muscle, endothelial cells, heart and placenta.
In response to TGF-beta, ubiquitinated by NEDD4L; which promotes its degradation. Monoubiquitinated, leading to prevent DNA-binding (By similarity). Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082). Ubiquitinated by RNF111, leading to its degradation: only SMAD2 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD2 and regulating its turnover (By similarity).
Monomer; in the absence of TGF-beta (PubMed:9670020). Heterodimer; in the presence of TGF-beta (PubMed:9670020). Forms a heterodimer with co-SMAD, SMAD4, in the nucleus to form the transactivation complex SMAD2/SMAD4 (PubMed:9670020, PubMed:24324267, PubMed:15350224). Found in a complex with SMAD3 and TRIM33 upon addition of TGF-beta (PubMed:16751102). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts (via the MH2 domain) with ZFYVE9; may form trimers with the SMAD4 co-SMAD (PubMed:10615055). Interacts with TAZ/WWRT1 (PubMed:18568018). Interacts with FOXH1 (PubMed:9702198). Interacts with SNW1 (PubMed:11278756). Interacts with CREB-binding protein (CBP) and EP300 (PubMed:16862174). Interacts with SNON (PubMed:11389444). Interacts with ALK4/ACVR1B (PubMed:9892009, PubMed:10615055). Interacts with SKOR1 (PubMed:17292623). Interacts with SKOR2 (PubMed:16200078). Interacts with PRDM16 (PubMed:19049980). Interacts (via MH2 domain) with LEMD3 (PubMed:15601644, PubMed:15647271). Interacts with RBPMS (PubMed:17099224). Interacts with WWP1. Interacts (dephosphorylated form, via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling (PubMed:19289081). Interacts with PDPK1 (via PH domain) (PubMed:17327236). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation (PubMed:11387212). Interacts with USP15 (PubMed:21947082). Interacts with PPP5C (PubMed:22781750). Interacts with LDLRAD4 (via the SMAD interaction motif) (PubMed:24627487). Interacts (via MH2 domain) with PMEPA1 (via the SMAD interaction motif) (PubMed:20129061). Interacts with ZFHX3 (PubMed:25105025). Interacts with ZNF451 (PubMed:24324267). Interacts with SMURF2 when phosphorylated on Ser-465/467 (PubMed:11389444). Interacts with PPM1A (PubMed:16751101). Interacts with TGF-beta (PubMed:8980228). Interacts with TGFBR1 (PubMed:9865696). Interacts with TGIF (PubMed:10835638). Interacts with SMAD3 and TRIM33 (PubMed:16751102). Interacts with ZNF580 (PubMed:21599657). Interacts with NEDD4L in response to TGF-beta (By similarity). Interacts with HGS (By similarity). Interacts with AIP1 (By similarity). Interacts with WWP1 (By similarity). Interacts with PML (By similarity). Interacts weakly with ZNF8 (By similarity). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD2 inhibitors (By similarity). Interacts with YAP1 (when phosphorylated at 'Ser-127') (By similarity). Interacts when phosphorylated with IPO7; the interaction facilitates translocation of SMAD2 to the nucleus (By similarity).
Phosphorylated on one or several of Thr-220, Ser-245, Ser-250, and Ser-255. In response to TGF-beta, phosphorylated on Ser-465/467 by TGF-beta and activin type 1 receptor kinases. TGF-beta-induced Ser-465/467 phosphorylation declines progressively in a KMT5A-dependent manner. Able to interact with SMURF2 when phosphorylated on Ser-465/467, recruiting other proteins, such as SNON, for degradation. In response to decorin, the naturally occurring inhibitor of TGF-beta signaling, phosphorylated on Ser-240 by CaMK2. Phosphorylated by MAPK3 upon EGF stimulation; which increases transcriptional activity and stability, and is blocked by calmodulin. Phosphorylated by PDPK1.
Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD2/SMAD4 complex, activates transcription. Promotes TGFB1-mediated transcription of odontoblastic differentiation genes in dental papilla cells (By similarity). Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. May act as a tumor suppressor in colorectal carcinoma (PubMed:8752209).
Cytokine with immunomodulatory activity. Alone, does not induce cytokine production, but reduces IL22 and IL17A production by T-cells in response to heat-killed Candida albicans. Reduces IL36G-induced production of IL8 by peripheral blood mononuclear cells. Increases IL6 production by dendritic cells stimulated by bacterial lipopolysaccharides (LPS). Ligand for IL-36R/IL1RL2.
Expressed in fetal skin, spleen and tonsil. Expressed mostly in the basal epithelia of skin and in proliferating B-cells of the tonsil.
Expressed in liver, skeletal muscle, prostate, uterus, rectum, stomach, and bladder and to a lower extent in brain, kidney, pancreas, and bone marrow. Expressed in mononuclear leukocytes and megakaryocytes.
Palmitoylated. Palmitoylation is required for association with recycling endosome membranes and activation of TNIK.
Small GTP-binding protein which cycles between a GDP-bound inactive and a GTP-bound active form. May play a role in cytoskeletal rearrangements and regulate cell spreading through activation of the effector TNIK. May play a role in SRE-mediated gene transcription.
Belongs to the ATPase gamma chain family.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). CF(0) has three main subunits: a, b and c.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). CF(0) has three main subunits: a, b and c. Component of an ATP synthase complex composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5PD, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and ATP5MJ (By similarity). Interacts with FLVCR2; this interaction occurs in the absence of heme and is disrupted upon heme binding.
Isoform Heart is expressed specifically in the heart and skeletal muscle, which require rapid energy supply. Isoform Liver is expressed in the brain, liver and kidney. Isoform Heart and Isoform Liver are expressed in the skin, intestine, stomach and aorta.
Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(1) domain and the central stalk which is part of the complex rotary element. The gamma subunit protrudes into the catalytic domain formed of alpha(3)beta(3). Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits.
Associates with the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOOL/MIC27, IMMT/MIC60, APOO/MIC23/MIC26 and QIL1/MIC13. This complex was also known under the names MINOS or MitOS complex. The MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1, MTX2 and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9. Interacts with IMMT/MIC60.
Plays a role in mitochondrial morphogenesis.
A cytochrome P450 monooxygenase involved in the metabolism of endogenous oxysterols and steroid hormones, including neurosteroids (PubMed:10588945, PubMed:24491228). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:10588945, PubMed:24491228). Catalyzes the hydroxylation of carbon hydrogen bonds of steroids with a preference for 7-alpha position (PubMed:10588945, PubMed:24491228). Usually metabolizes steroids carrying a hydroxy group at position 3, functioning as a 3-hydroxy steroid 7-alpha hydroxylase (PubMed:24491228). Hydroxylates oxysterols, including 25-hydroxycholesterol and (25R)-cholest-5-ene-3beta,26-diol toward 7-alpha hydroxy derivatives, which may be transported to the liver and converted to bile acids (PubMed:9802883, PubMed:10588945). Via its product 7-alpha,25-dihydroxycholesterol, a ligand for the chemotactic G protein-coupled receptor GPR183/EBI2, regulates B cell migration in germinal centers of lymphoid organs, thus guiding efficient maturation of plasma B cells and overall antigen-specific humoral immune response (By similarity). 7-alpha hydroxylates neurosteroids, including 3beta-hydroxyandrost-5-en-17-one (dehydroepiandrosterone) and pregnenolone, both involved in hippocampus-associated memory and learning (PubMed:24491228). Metabolizes androstanoids toward 6- or 7-alpha hydroxy derivatives (PubMed:24491228).
Inhibited by drugs voriconazole and metyrapone.
Widely expressed. Expressed in brain, testis, ovary, prostate, liver, colon, kidney, small intestine, thymus and spleen.
Belongs to the glycosyltransferase 68 family.
Catalyzes the reaction that attaches fucose through an O-glycosidic linkage to a conserved serine or threonine residue in the consensus sequence C1-X-X-S/T-C2 of thrombospondin type I repeats (TSRs) where C1 and C2 are the first and second cysteines of the repeat, respectively (PubMed:22588082). O-fucosylates members of several protein families including the ADAMTS, the thrombospondin (TSP) and spondin families (Probable) (PubMed:17395588). Required for the proper secretion of ADAMTS family members such as ADAMTSL1 and ADAMTS13 (PubMed:17395589, PubMed:17395588). The O-fucosylation of TSRs is also required for restricting epithelial to mesenchymal transition (EMT), maintaining the correct patterning of mesoderm and localization of the definite endoderm (By similarity).
Isoform A is expressed in fetal liver and peripheral blood lymphocytes. Isoform B is expressed in spleen, lung, testis, bone marrow, thymus, pancreas, prostate, fetal brain, fetal liver and fetal kidney. Isoform C is expressed in brain, heart, spleen, liver, lung, stomach, testis, placenta, skin, thymus, pancreas, mammary gland, prostate, fetal brain, fetal liver and fetal heart.
Calcium may be bound by the cadherin-like repeats.
Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. May contribute to epidermal cell positioning (stratification) by mediating differential adhesiveness between cells that express different isoforms.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. NR2D/GRIN2D subfamily.
Component of NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:9489750, PubMed:27616483, PubMed:26875626, PubMed:28126851). Sensitivity to glutamate and channel kinetics depend on the subunit composition (PubMed:9489750).
Heterotetramer. Forms heterotetrameric channels composed of two zeta subunits (GRIN1), and two epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) (in vitro) (PubMed:9489750, PubMed:26875626, PubMed:28126851). In vivo, the subunit composition may depend on the expression levels of the different subunits (Probable). Interacts with PDZ domains of PATJ and DLG4 (By similarity).
Activated in response to hyperosmotic stress: cell shrinkage promotes formation of a membraneless compartment that concentrates WNK1 with its substrates, OXSR1/OSR1 and STK39/SPAK (PubMed:36318922). Activation requires autophosphorylation of Ser-382 and, to a lower extent, Ser-378 (PubMed:15883153, PubMed:16263722, PubMed:16832045, PubMed:17190791, PubMed:31656913, PubMed:34289367). Autophosphorylation and subsequent activation is inhibited by increases in intracellular ionic strength: Cl(-) potently inhibits WNK1 kinase activity via direct binding (By similarity). Also inhibited by K(+) ions (By similarity). Inhibited by small compounds staurosporine, tyrphostin 47, as well as Src tyrosine kinase inhibitors PP1 and PP2 (PubMed:19739668).
Autophosphorylated at Ser-378 and Ser-382, promoting its activity (PubMed:15883153, PubMed:16263722, PubMed:16832045, PubMed:17190791, PubMed:31656913, PubMed:34289367). Autophosphorylation at Ser-382 is inhibited by intracellular calcium (By similarity). Phosphorylation at Thr-60 increases ability to activate SGK1 (By similarity).
Contains the nervous system-specific exon HSN2. Produced by alternative splicing.
Disordered regions undergo liquid-liquid phase separation (LLPS) for the formation of a cytoplasmic membraneless compartment that concentrates WNK1 with its substrates, OXSR1/OSR1 and STK39/SPAK.
HSN2 was originally thought to be an intronless gene lying within a WNK1 gene intron. It has been shown to be a nervous system-specific exon of WNK1 included in isoform 4 and isoform 5 (PubMed:18521183).
Interacts with WNK3 (By similarity). Interacts with WNK4; inhibiting the activity of WNK4 (By similarity). Interacts with SGK1; promoting its activation (PubMed:36373794). Associates with the mTORC2 complex (PubMed:36373794). Interacts with UVRAG (PubMed:27911840). Interacts (via amphipathic alpha-helix region) with EMC2; promoting the ER membrane protein complex assembly (PubMed:33964204).
Interacts with isoform 1; inhibiting isoform 1 activity.
It is uncertain whether Met-1 or Met-214 is the initiator in isoform 4 and isoform 5.
Kinase-defective isoform specifically expressed in kidney, which acts as a dominant-negative regulator of the longer isoform 1 (PubMed:14645531). Does not directly inhibit WNK4 and has no direct effect on sodium and chloride ion transport (By similarity). Down-regulates sodium-chloride cotransporter activity indirectly by inhibiting isoform 1, it associates with isoform 1 and attenuates its kinase activity (By similarity). In kidney, may play an important role regulating sodium and potassium balance (By similarity).
Serine/threonine-protein kinase component of the WNK1-SPAK/OSR1 kinase cascade, which acts as a key regulator of blood pressure and regulatory volume increase by promoting ion influx (PubMed:15883153, PubMed:17190791, PubMed:31656913, PubMed:34289367, PubMed:36318922). WNK1 mediates regulatory volume increase in response to hyperosmotic stress by acting as a molecular crowding sensor, which senses cell shrinkage and mediates formation of a membraneless compartment by undergoing liquid-liquid phase separation (PubMed:36318922). The membraneless compartment concentrates WNK1 with its substrates, OXSR1/OSR1 and STK39/SPAK, promoting WNK1-dependent phosphorylation and activation of downstream kinases OXSR1/OSR1 and STK39/SPAK (PubMed:15883153, PubMed:16263722, PubMed:17190791, PubMed:19739668, PubMed:21321328, PubMed:22989884, PubMed:25477473, PubMed:34289367, PubMed:36318922). Following activation, OXSR1/OSR1 and STK39/SPAK catalyze phosphorylation of ion cotransporters SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A5/KCC2 and SLC12A6/KCC3, regulating their activity (PubMed:16263722, PubMed:21321328). Phosphorylation of Na-K-Cl cotransporters SLC12A2/NKCC1 and SLC12A2/NKCC1 promote their activation and ion influx; simultaneously, phosphorylation of K-Cl cotransporters SLC12A5/KCC2 and SLC12A6/KCC3 inhibit their activity, blocking ion efflux (PubMed:19665974, PubMed:21321328). Also acts as a regulator of angiogenesis in endothelial cells via activation of OXSR1/OSR1 and STK39/SPAK: activation of OXSR1/OSR1 regulates chemotaxis and invasion, while STK39/SPAK regulates endothelial cell proliferation (PubMed:25362046). Also acts independently of the WNK1-SPAK/OSR1 kinase cascade by catalyzing phosphorylation of other substrates, such as SYT2, PCF11 and NEDD4L (PubMed:29196535). Mediates phosphorylation of SYT2, regulating SYT2 association with phospholipids and membrane-binding (By similarity). Regulates mRNA export in the nucleus by mediating phosphorylation of PCF11, thereby decreasing the association between PCF11 and POLR2A/RNA polymerase II and promoting mRNA export to the cytoplasm (PubMed:29196535). Acts as a negative regulator of autophagy (PubMed:27911840). Required for the abscission step during mitosis, independently of the WNK1-SPAK/OSR1 kinase cascade (PubMed:21220314). May also play a role in actin cytoskeletal reorganization (PubMed:10660600). Also acts as a scaffold protein independently of its protein kinase activity: negatively regulates cell membrane localization of various transporters and channels, such as SLC4A4, SLC26A6, SLC26A9, TRPV4 and CFTR (By similarity). Involved in the regulation of epithelial Na(+) channel (ENaC) by promoting activation of SGK1 in a kinase-independent manner: probably acts as a scaffold protein that promotes the recruitment of SGK1 to the mTORC2 complex in response to chloride, leading to mTORC2-dependent phosphorylation and activation of SGK1 (PubMed:36373794). Acts as an assembly factor for the ER membrane protein complex independently of its protein kinase activity: associates with EMC2 in the cytoplasm via its amphipathic alpha-helix, and prevents EMC2 ubiquitination and subsequent degradation, thereby promoting EMC2 stabilization (PubMed:33964204).
Strong expression in dorsal root ganglia and spinal cord.
The RFXV motifs mediate recognition with downstream kinases OXSR1/OSR1 and STK39/SPAK.
This isoform is kidney-specific and specifically expressed in the distal convoluted tubule (DCT) and connecting tubule (CNT) of the nephron.
Ubiquitinated by the BCR(KLHL3) complex, leading to its degradation (PubMed:23576762, PubMed:23387299). Also ubiquitinated by the BCR(KLHL2) complex (PubMed:23838290).
Widely expressed, with highest levels observed in the testis, heart, kidney and skeletal muscle.
Detected in brain and pancreas. Detected in pancreatic beta cells.
G-protein coupled receptor for medium and long chain saturated and unsaturated fatty acids that plays an important role in glucose homeostasis. Fatty acid binding increases glucose-stimulated insulin secretion, and may also enhance the secretion of glucagon-like peptide 1 (GLP-1). May also play a role in bone homeostasis; receptor signaling activates pathways that inhibit osteoclast differentiation (By similarity). Ligand binding leads to a conformation change that triggers signaling via G-proteins that activate phospholipase C, leading to an increase of the intracellular calcium concentration. Seems to act through a G(q) and G(i)-mediated pathway. Mediates the anti-inflammatory effects of omega-3 polyunsaturated fatty acids (PUFAs) via inhibition of NLRP3 inflammasome activation.
The receptor is strongly activated by gamma-linolenic acid, while myristate gives a lower response. It is also activated by phytanic acid and pristanic acid (PubMed:21570468). Is also activated by synthetic agonists, such as TAK-875 (fasiglifam); this compound is a partial agonist and potentiates the activity of the endogenous ligand gamma-linolenic acid (PubMed:24130766).
Defects in PNPLA4 may play a role in mitochondrial disorders characterized by complex IV deficiency.
Expressed in all tissues examined, including heart, brain, placenta, lung, liver, muscle, kidney, pancreas and spleen.
Has abundant triacylglycerol lipase activity (PubMed:15364929, PubMed:16150821, PubMed:17603008). Transfers fatty acid from triglyceride to retinol, hydrolyzes retinylesters, and generates 1,3-diacylglycerol from triglycerides (PubMed:17603008). Additionally possesses acylglycerol transacylase and phospholipase A2 activities (PubMed:15364929, PubMed:17603008).
Expressed at low abundance in various brain tissues, as well as in fetal liver, but not in the cerebellum or placenta. In the brain, comparable levels of expression in basal ganglia, frontal cortex, substantia nigra, amygdala and hippocampus, highest expression in hippocampus and lowest expression in basal ganglia.
Acts as an adapter for myotubularin-related phosphatases (PubMed:19038970, PubMed:22647598). Increases lipid phosphatase MTMR6 catalytic activity, specifically towards phosphatidylinositol 3,5-bisphosphate and MTMR6 binding affinity for phosphorylated phosphatidylinositols (PubMed:19038970, PubMed:22647598). Positively regulates lipid phosphatase MTMR7 catalytic activity (By similarity). Increases MTMR8 catalytic activity towards phosphatidylinositol 3-phosphate (PubMed:22647598). The formation of the MTMR6-MTMR9 complex, stabilizes both MTMR6 and MTMR9 protein levels (PubMed:19038970). Stabilizes MTMR8 protein levels (PubMed:22647598). Plays a role in the late stages of macropinocytosis possibly by regulating MTMR6-mediated dephosphorylation of phosphatidylinositol 3-phosphate in membrane ruffles (PubMed:24591580). Negatively regulates autophagy, in part via its association with MTMR8 (PubMed:22647598). Negatively regulates DNA damage-induced apoptosis, in part via its association with MTMR6 (PubMed:19038970, PubMed:22647598). Does not bind mono-, di- and tri-phosphorylated phosphatidylinositols, phosphatidic acid and phosphatidylserine (PubMed:19038970).
Although it belongs to the non-receptor class myotubularin subfamily, lacks the conserved active site cysteine residue at position 333 in the dsPTPase catalytic loop, suggesting that it has no phosphatase activity.
Homodimer (PubMed:19038970). Heterodimer (via C-terminus) with lipid phosphatase MTMR6 (via C-terminus) (PubMed:16787938, PubMed:12890864, PubMed:19038970, PubMed:23188820). Heterodimer (via coiled coil domain) with lipid phosphatase MTMR7 (via C-terminus) (By similarity). Heterodimer with lipid phosphatase MTMR8 (PubMed:22647598, PubMed:16787938).
The GRAM domain is required for cell membrane localization.
The coiled coil domain mediates interaction with MTMR9.
Carries out a dual function: signal transduction and activation of transcription (PubMed:29844444). Mediates cellular responses to the cytokine KITLG/SCF and other growth factors. Binds to the GAS element and activates PRL-induced transcription. Positively regulates hematopoietic/erythroid differentiation.
Tyrosine phosphorylated in response to signaling via activated KIT, resulting in translocation to the nucleus. Tyrosine phosphorylated in response to signaling via activated FLT3; wild-type FLT3 results in much weaker phosphorylation than constitutively activated mutant FLT3. Alternatively, can be phosphorylated by JAK2. Phosphorylation at Tyr-699 by PTK6 or HCK leads to an increase of its transcriptional activity.
Upon activation, forms homodimers (PubMed:29844444). Forms also heterodimers with related family members. Binds NR3C1 (By similarity). Interacts with NCOA1 (PubMed:12954634). Interacts with NMI (PubMed:9989503). Interacts with SOCS7 (PubMed:15677474). Interacts (via SH2 domain) with INSR (PubMed:9428692). Interacts with CPEB3; this inhibits STAT5B-mediated transcriptional activation (PubMed:20639532).
Transcriptional repressor that contribute to growth arrest during terminal macrophage differentiation by repressing target genes involved in Ras-dependent proliferation. Represses MMP1 promoter activity.
Trimethylated at Lys-165 by EEF1AKMT3 (PubMed:28108655). Mono-, di-, and trimethylated at Lys-36 by EEF1AKMT4; trimethylated form is predominant. Methylation by EEF1AKMT4 contributes to the fine-tuning of translation rates for a subset of tRNAs (PubMed:28520920). Trimethylated at the N-terminus by METTL13 (PubMed:30143613). Mono- and dimethylated at Lys-55 by METTL13; dimethylated form is predominant (PubMed:30143613, PubMed:30612740).
Component of the TFIID basal transcription factor complex, composed of TATA-box-binding protein TBP, and a number of TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473, PubMed:10594036). Component of the TFTC-HAT complex, at least composed of TAF5L, TAF6L, TADA3L, SUPT3H, TAF2, TAF4, TAF5, GCN5L2/GCN5, TAF10, TAF12 and TRRAP (PubMed:10373431, PubMed:12601814). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975). Interacts with ATF7; the interaction inhibits ATF7-mediated tranactivation (PubMed:15735663).
The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription (PubMed:33795473). TFIID recognizes and binds promoters with or without a TATA box via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC) (PubMed:33795473). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473, PubMed:10594036, PubMed:8942982). TAF4 may maintain an association between the TFIID and TFIIA complexes, while bound to the promoter, together with TBP, during PIC assembly (PubMed:33795473). Potentiates transcriptional activation by the AF-2S of the retinoic acid, vitamin D3 and thyroid hormone (PubMed:9192867).
Interacts (via C-terminus) with SHANK3 (via PDZ domain). Interacts (via coiled coil) with SIPA1L1. Can form homooligomers.
May be involved in promoting the maturation of dendritic spines, probably via regulating SIPA1L1 levels at the postsynaptic density of synapses.
Cell death receptor specific for IGFBP3, may mediate caspase-8-dependent apoptosis upon ligand binding.
Interacts with IGFBP3. Interacts with CASP8.
Widely expressed in normal tissues but suppressed in prostate and breast tumor.
Contains a tandem atypical propeller in EMLs (TAPE) domain. The N-terminal beta-propeller is formed by canonical WD repeats; in contrast, the second beta-propeller contains one blade that is formed by discontinuous parts of the polypeptide chain (By similarity).
Homotrimer; self-association is mediated by the N-terminal coiled coil.
Interacts with GRID2 and may also interact with GRID1 (By similarity). Interacts with EML3 (PubMed:25740311). Binds unpolymerized tubulins via its WD repeat region (PubMed:11694528, PubMed:24706829).
Tubulin binding protein that inhibits microtubule nucleation and growth, resulting in shorter microtubules.
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids and their oxygenated derivatives (oxylipins) (PubMed:7679927, PubMed:1739747, PubMed:8914854, PubMed:10553002, PubMed:10660572, PubMed:15611369). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:7679927, PubMed:1739747, PubMed:8914854, PubMed:10553002, PubMed:10660572, PubMed:15611369). Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of saturated and unsaturated fatty acids, the catalytic efficiency decreasing in the following order: dodecanoic > tetradecanoic > (9Z)-octadecenoic > (9Z,12Z)-octadecadienoic > hexadecanoic acid (PubMed:10553002, PubMed:10660572). Acts as a major omega-hydroxylase for dodecanoic (lauric) acid in liver (PubMed:7679927, PubMed:1739747, PubMed:8914854, PubMed:15611369). Participates in omega-hydroxylation of (5Z,8Z,11Z,14Z)-eicosatetraenoic acid (arachidonate) to 20-hydroxyeicosatetraenoic acid (20-HETE), a signaling molecule acting both as vasoconstrictive and natriuretic with overall effect on arterial blood pressure (PubMed:10620324, PubMed:10660572, PubMed:15611369). Can also catalyze the oxidation of the penultimate carbon (omega-1 oxidation) of fatty acids with lower efficiency (PubMed:7679927). May contribute to the degradation of saturated very long-chain fatty acids (VLCFAs) such as docosanoic acid, by catalyzing successive omega-oxidations to the corresponding dicarboxylic acid, thereby initiating chain shortening (PubMed:18182499). Omega-hydroxylates (9R,10S)-epoxy-octadecanoate stereoisomer (PubMed:15145985). Plays a minor role in omega-oxidation of long-chain 3-hydroxy fatty acids (PubMed:18065749). Has little activity toward prostaglandins A1 and E1 (PubMed:7679927).
CYP4A11v seems to be a rare allelic variant of CYP4A11, it seems to be unstable and not to metabolize lauric acid.
Expressed in liver (PubMed:7679927). Expressed in S2 and S3 segments of proximal tubules in cortex and outer medulla of kidney (PubMed:7679927, PubMed:10660572).
(Microbial infection) Interacts with HIV-1 Nef; this interaction up-regulates the expression of the Fas ligand (FASLG) at the cell surface.
(Microbial infection) Interacts with HIV-2 Nef protein; this interaction induces down-regulation of cell surface TCR/CD3 complexes.
CD3Z is expressed in normal lymphoid tissue and in peripheral blood mononuclear cells (PBMCs) (PubMed:11722641).
Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways (PubMed:2470098, PubMed:7509083). CD3Z ITAMs phosphorylation creates multiple docking sites for the protein kinase ZAP70 leading to ZAP70 phosphorylation and its conversion into a catalytically active enzyme (PubMed:7509083). Plays an important role in intrathymic T-cell differentiation. Additionally, participates in the activity-dependent synapse formation of retinal ganglion cells (RGCs) in both the retina and dorsal lateral geniculate nucleus (dLGN) (By similarity).
The ITAM domains mediate interaction with SHB.
The TCR-CD3 complex is composed of a CD3D/CD3E and a CD3G/CD3E heterodimers that preferentially associate with TCRalpha and TCRbeta, respectively, to form TCRalpha/CD3E/CD3G and TCRbeta/CD3G/CD3E trimers. In turn, the hexamer interacts with CD3Z homodimer to form the TCR-CD3 complex. Alternatively, TCRalpha and TCRbeta can be replaced by TCRgamma and TCRdelta (PubMed:17055436). Interacts with SLA (PubMed:10449770). Interacts with TRAT1 (PubMed:11390434). Interacts with DOCK2 (PubMed:12176041). Interacts with SLA2. Interacts with SHB (PubMed:9484780). Interacts with ZAP70 (PubMed:26783323, PubMed:7659156). Interacts (tyrosine phosphorylated) with SHC1 (via SH2 domain) (PubMed:7544002). Interacts with PTPRC (PubMed:15684325). Interacts with CRK; this interaction regulates CD3Z phosphorylation (PubMed:28465009). Interacts (on T cell side) with CD81, ICAM1 and CD9 at immunological synapses between antigen-presenting cells and T cells (PubMed:23858057). Interacts with CD160 (PubMed:11978774). Interacts with LY6E (By similarity). The signaling subunit of immunoglobulin gamma (IgG) Fc receptor complex. As a homodimer or a heterodimer with FCER1G, associates with the ligand binding subunit FCGR3A (via transmembrane domain); this interaction is a prerequisite for Fc receptor complex expression on the cell surface.
Infection by L.monocytogenes induces increases in mucin secretion and MUC4 and MUC12 transcription. This may constitute a host cell defense response that inhibits the entry of listeria monocytogenes in the cell.
Involved in epithelial cell protection, adhesion modulation, and signaling. May be involved in epithelial cell growth regulation. Stimulated by both cytokine TNF-alpha and TGF-beta in intestinal epithelium.
The proteolytic cleavage occurs within the SEA domain. This domain is not interchangeable, suggesting that it is insufficient to mediate efficient cleavage.
Ubiquitous, with higher expression in colon. Down-regulated in colorectal cancer as well as in the colon of patients with ulcerative colitis (UC) and Crohn's disease (CD).
Belongs to the class I-like SAM-binding methyltransferase superfamily. rRNA adenine N(6)-methyltransferase family. KsgA subfamily.
By the nuclear respiratory factors NRF1 and NRF2/GABPB2 and PGC-1 coactivators.
Homodimer (PubMed:29149603). Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT (PubMed:29149603). In this complex TFAM recruits POLRMT to the promoter whereas TFB2M induces structural changes in POLRMT to enable promoter opening and trapping of the DNA non-template strand (PubMed:29149603). Interacts with mitochondrial RNA polymerase POLRMT (PubMed:12068295). Interacts with TFAM (PubMed:12897151).
S-adenosyl-L-methionine-dependent rRNA methyltransferase which may methylate two specific adjacent adenosines in the loop of a conserved hairpin near the 3'-end of 12S mitochondrial rRNA (Probable). Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT that is required for basal transcription of mitochondrial DNA (PubMed:29149603, PubMed:12068295, PubMed:20410300, PubMed:15526033). In this complex, TFAM recruits POLRMT to a specific promoter whereas TFB2M induces structural changes in POLRMT to enable promoter opening and trapping of the DNA non-template strand (PubMed:29149603, PubMed:15526033). Stimulates transcription independently of the methyltransferase activity (PubMed:12897151).
Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. Plays a role in the regulation of skeletogenesis, through a mechanism that involves integrin-mediated signaling and PTK2B/PYK2 (PubMed:33242826).
Domain G is globular and is part of the major cell-binding site located in the long arm of the laminin heterotrimer.
Expressed in heart, lung, kidney, skeletal muscle, pancreas, retina and placenta. Little or no expression in brain and liver. Expressed in muscle, ligaments, periosteum, trabecular bone and throughout the cartilage, particularly in the growth plate and in articular chondrocytes (PubMed:33242826).
Laminin is a complex glycoprotein, consisting of three different polypeptide chains (alpha, beta, gamma), which are bound to each other by disulfide bonds into a cross-shaped molecule comprising one long and three short arms with globules at each end. Alpha-5 is a subunit of laminin-10 (laminin-511), laminin-11 (laminin-521) and laminin-15 (laminin-523).
AMPylation at Tyr-77 by L.pneumophila DrrA occurs in the switch 2 region and leads to moderate inactivation of the GTPase activity. It appears to prolong the lifetime of the GTP state of RAB1B by restricting access of GTPase effectors to switch 2 and blocking effector-stimulated GTP hydrolysis, thereby rendering RAB35 constitutively active.
Interacts with DENND1A and DENND1B; in a nucleotide-dependent manner (PubMed:20154091, PubMed:22065758). Interacts with DENND1C; weak interaction which is nucleotide-independent (PubMed:20154091). Interacts (GTP-bound form) with ACAP2 and MICALL1; the interaction is direct and probably recruits ACAP2 and MICALL1 to membranes (PubMed:21951725). Interacts with EHD1; the interaction is indirect through MICALL1 and probably recruits EHD1 to membranes (By similarity). Interacts with GDI1, GDI2, CHM and CHML; phosphorylation at Thr-72 disrupts these interactions (PubMed:29125462).
Phosphocholinated by L.pneumophila AnkX. Both GDP-bound and GTP-bound forms can be phosphocholinated. Phosphocholination inhibits the GEF activity of DENND1A.
Rab activation is generally mediated by a guanine exchange factor (GEF), while inactivation through hydrolysis of bound GTP is catalyzed by a GTPase activating protein (GAP) (PubMed:20154091). That Rab is activated by the guanine exchange factors DENND1A, DENND1B and DENND1C (PubMed:20154091).
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. That Rab is involved in the process of endocytosis and is an essential rate-limiting regulator of the fast recycling pathway back to the plasma membrane. During cytokinesis, required for the postfurrowing terminal steps, namely for intercellular bridge stability and abscission, possibly by controlling phosphatidylinositol 4,5-bis phosphate (PIP2) and SEPT2 localization at the intercellular bridge. May indirectly regulate neurite outgrowth. Together with TBC1D13 may be involved in regulation of insulin-induced glucose transporter SLC2A4/GLUT4 translocation to the plasma membrane in adipocytes.
Removes ADP-ribose from aspartate and glutamate residues in proteins bearing a single ADP-ribose moiety (PubMed:23474714, PubMed:23474712). Inactive towards proteins bearing poly-ADP-ribose (PubMed:23474714, PubMed:23474712). Deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins (PubMed:21257746).
Subject to product inhibition by ADP-ribose.
Homodimer; disulfide-linked in response to retinal illumination (By similarity). Interacts with CXCR4; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and modulates the calcium ion mobilization activity of CXCR4 (PubMed:20048153).
Inner and outer segments, and the inner plexiform regions of the retina.
May play a role in an as yet undefined retina-specific signal transduction. Could bind to photoactivated-phosphorylated red/green opsins.
Precursors of the cornified envelope of the stratum.
Component of the HAUS augmin-like complex. The complex interacts with the gamma-tubulin ring complex and this interaction is required for spindle assembly. Associates with microtubules. The interaction with microtubules is strong during mitosis, while it is weak or absent during interphase. It is unclear whether this interaction is direct or indirect. Interacts with EML3 (phosphorylated at 'Thr-881') and TUBG1 (PubMed:30723163).
Binds very efficiently to importin subunit beta-1/KPNB1 via the IBB domain; this complex dissociates in the presence of RAN-GTP. Shows a limited binding to the RB1 nuclear localization signal (NLS), but not to the SV40, nor NPM1 NLSs. Interacts with RSL1D1 (PubMed:36647821).
3-hydroxykynurenine, an oxidized tryptophan metabolite that is common in biological fluids, reacts with Cys-53, Lys-111, Lys-137, and Lys-149 to form heterogeneous polycyclic chromophores including hydroxanthommatin. The reaction by alpha-1-microglobulin is autocatalytic; the human protein forms chromophore even when expressed in insect and bacterial cells. The chromophore can react with accessible cysteines forming non-reducible thioether cross-links with other molecules of alpha-1-microglobulin or with other proteins such as Ig alpha-1 chain C region 'Cys-352'.
Antioxidant and tissue repair protein with reductase, heme-binding and radical-scavenging activities. Removes and protects against harmful oxidants and repairs macromolecules in intravascular and extravascular spaces and in intracellular compartments (PubMed:11877257, PubMed:15683711, PubMed:22096585, PubMed:23157686, PubMed:23642167, PubMed:25698971, PubMed:32823731, PubMed:32092412). Intravascularly, plays a regulatory role in red cell homeostasis by preventing heme- and reactive oxygen species-induced cell damage. Binds and degrades free heme to protect fetal and adult red blood cells from hemolysis (PubMed:11877257, PubMed:32092412). Reduces extracellular methemoglobin, a Fe3+ (ferric) form of hemoglobin that cannot bind oxygen, back to the Fe2+ (ferrous) form deoxyhemoglobin, which has oxygen-carrying potential (PubMed:15683711). Upon acute inflammation, inhibits oxidation of low-density lipoprotein particles by MPO and limits vascular damage (PubMed:25698971). Extravascularly, protects from oxidation products formed on extracellular matrix structures and cell membranes. Catalyzes the reduction of carbonyl groups on oxidized collagen fibers and preserves cellular and extracellular matrix ultrastructures (PubMed:23642167, PubMed:22096585). Importantly, counteracts the oxidative damage at blood-placenta interface, preventing leakage of free fetal hemoglobin into the maternal circulation (PubMed:21356557). Intracellularly, has a role in maintaining mitochondrial redox homeostasis. Bound to complex I of the respiratory chain of mitochondria, may scavenge free radicals and preserve mitochondrial ATP synthesis. Protects renal tubule epithelial cells from heme-induced oxidative damage to mitochondria (PubMed:23157686, PubMed:32823731). Reduces cytochrome c from Fe3+ (ferric) to the Fe2+ (ferrous) state through formation of superoxide anion radicals in the presence of ascorbate or NADH/NADPH electron donor cofactors, ascorbate being the preferred cofactor (PubMed:15683711). Has a chaperone role in facilitating the correct folding of bikunin in the endoplasmic reticulum compartment (By similarity).
Detected in placenta (at protein level) (PubMed:32337544). Detected in cerebrospinal fluid, plasma and urine (at protein level) (PubMed:25326458, PubMed:36213313). Expressed in airway epithelium and submucosal gland (at protein level). Colocalizes with TNFAIP6 at the ciliary border. Present in bronchoalveolar lavage fluid (at protein level).
Expressed by the liver and secreted in plasma. Occurs in many physiological fluids including plasma, urine, and cerebrospinal fluid (PubMed:11877257). Expressed in epidermal keratinocytes, in dermis and epidermal-dermal junction (at protein level) (PubMed:22096585). Expressed in red blood cells (at protein level) (PubMed:32092412). Expressed in placenta (PubMed:21356557).
Heavy chains are interlinked with bikunin via a chondroitin 4-sulfate bridge to the C-terminal aspartate.
I-alpha-I plasma protease inhibitors are assembled from one or two heavy chains (HC) and one light chain, bikunin. Inter-alpha-inhibitor (I-alpha-I) is composed of ITIH1/HC1, ITIH2/HC2 and bikunin, and pre-alpha-inhibitor (P-alpha-I) of ITIH3/HC3 and bikunin (PubMed:2476436, PubMed:16873769). Interacts with TNFAIP6 (via Link domain) (PubMed:15917224).
In the N-terminal section; belongs to the calycin superfamily. Lipocalin family.
In vitro, the first twelve residues of the amino end of the inhibitor appear to have a reactive site capable of inhibiting the activity of a number of enzymes. Its in vivo function is not known.
Kunitz-type serine protease inhibitor and structural component of extracellular matrix with a role in extracellular space remodeling and cell adhesion (PubMed:25301953, PubMed:20463016). Among others, has antiprotease activity toward kallikrein, a protease involved in airway inflammation; inhibits GZMK/granzyme, a granule-stored serine protease involved in NK and T cell cytotoxic responses; and inhibits PLG/plasmin, a protease required for activation of matrix metalloproteinases (PubMed:16873769, PubMed:10480954, PubMed:15917224). As part of I-alpha-I complex, provides for the heavy chains to be transferred from I-alpha-I complex to hyaluronan in the presence of TNFAIP6, in a dynamic process that releases free bikunin and remodels extracellular matrix proteoglycan structures. Free bikunin, but not its heavy chain-bound form, acts as potent protease inhibitor in airway secretions (PubMed:16873769). Part of hyaluronan-rich extracellular matrix that surrounds oocyte during cumulus oophorus expansion, an indispensable process for proper ovulation (By similarity). Also inhibits calcium oxalate crystallization (PubMed:7676539).
Kunitz-type serine protease inhibitor. Has high catalytic efficiency for F10/blood coagulation factor Xa and may act as an anticoagulant by inhibiting prothrombin activation. Inhibits trypsin and mast cell CMA1/chymase and tryptase proteases.
Monomer (PubMed:22512701, PubMed:9183005). Homodimer (PubMed:9183005). In plasma, it occurs as a monomer or dimer and in covalently-linked complexes with immunoglobulin A (IgA), ALB/albumin and F2/prothrombin (PubMed:9183005). Chromophore-bound alpha-1-microglobulin interacts with the constant region of immunoglobulin A (PubMed:9183005). Chromophore-bound alpha-1-microglobulin interacts with ALB with molar ratio 2:1 and 1:1; this interaction does not prevent fatty acid binding to ALB (PubMed:9183005). Interacts with F2/prothrombin (via N-terminus) with molar ratio 2:1 and 1:1; this interaction does not prevent the activation of prothrombin to thrombin (PubMed:9183005). Interacts with NDUFAB1, a subunit of mitochondrial complex I (PubMed:23157686). Interacts with FN1 (By similarity).
Monomer. Also occurs as a complex with tryptase in mast cells.
N-glycosylated. N-glycan heterogeneity at Asn-115: Hex5HexNAc4 (major), Hex6HexNAc5 (minor) and dHex1Hex6HexNAc5 (minor). N-glycan at Asn-250: Hex5HexNAc4.
O-glycosylated. O-linkage of the glycosaminoglycan, chondroitin sulfate, at Ser-215 allows cross-linking between the three polypeptide chains.
Proteolytically cleaved by PRSS3 at Kunitz domain 2.
Proteolytically cleaved in the presence of oxyhemoglobin or MPO (PubMed:11877257, PubMed:25698971). The cleaved form t-alpha-1-microglobulin lacks the C-terminal tetrapeptide LIPR and is released from IgA-alpha-1-microglobulin complex as well as from free alpha-1-microglobulin when exposed to oxyhemoglobin or erythrocyte membranes. The cleavage of IgA-alpha-1-microglobulin complex is associated with the reduction of the covalent bond between IgA and alpha-1-microglobulin, yielding an intact IgA molecule (PubMed:11877257). The cleavage by MPO is associated with the transfer of heme group from MPO to t-alpha-1-microglobulin (PubMed:25698971). t-alpha-1-microglobulin has higher reductase activity when compared with full length protein (PubMed:15683711).
The Kunitz domains 1 and 2 serve as protease inhibitor domains.
The precursor is proteolytically processed into separately functioning proteins.
Up-regulated by TNFAIP6. In a transesterification reaction, TNFAIP6 cleaves the ester bond between the heavy chain and the chondroitin sulfate chain in I-alpha-I complex and potentiates the antiprotease function of I-alpha-I complex through release of free bikunin.
Up-regulated in airway epithelium and submucosal gland in response to inflammatory cytokine TNF.
Up-regulated upon oxidative stress (PubMed:23642167, PubMed:22096585, PubMed:21356557). Up-regulated in keratinocytes upon exposure to heme and reactive oxygen species (PubMed:22096585). Up-regulated in hemoglobin-perfused placenta (PubMed:21356557).
Interacts with CYTH2; the interaction is direct and ARL4D GTP-dependent. Does not interact with ARL4D.
(Microbial infection) Interacts with SV40 Large T antigen; this interaction induces activation of a DNA damage response and promotes p53/TP53 stabilization and phosphorylation.
(Microbial infection) Interacts with herpes virus 8 protein LANA1.
Autophosphorylated when the cells enters mitosis.
BUB1 N-terminal domain directs kinetochore localization and binding to BUB3.
High expression in testis and thymus, less in colon, spleen, lung and small intestine. Expressed in fetal thymus, bone marrow, heart, liver, spleen and thymus. Expression is associated with cells/tissues with a high mitotic index.
Inhibited by phorbol 12-myristate 13-acetate (PMA).
Interacts with BUB3 and KNL1. Interacts (when phosphorylated) with PLK1. The BUB1-BUB3 complex interacts with MAD1L1.
Serine/threonine-protein kinase that performs 2 crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Has a key role in the assembly of checkpoint proteins at the kinetochore, being required for the subsequent localization of CENPF, BUB1B, CENPE and MAD2L1. Required for the kinetochore localization of PLK1. Required for centromeric enrichment of AUKRB in prometaphase. Plays an important role in defining SGO1 localization and thereby affects sister chromatid cohesion. Promotes the centromeric localization of TOP2A (PubMed:35044816). Acts as a substrate for anaphase-promoting complex or cyclosome (APC/C) in complex with its activator CDH1 (APC/C-Cdh1). Necessary for ensuring proper chromosome segregation and binding to BUB3 is essential for this function. Can regulate chromosome segregation in a kinetochore-independent manner. Can phosphorylate BUB3. The BUB1-BUB3 complex plays a role in the inhibition of APC/C when spindle-assembly checkpoint is activated and inhibits the ubiquitin ligase activity of APC/C by phosphorylating its activator CDC20. This complex can also phosphorylate MAD1L1. Kinase activity is essential for inhibition of APC/CCDC20 and for chromosome alignment but does not play a major role in the spindle-assembly checkpoint activity. Mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis.
The KEN box is required for its ubiquitination and degradation.
Ubiquitinated and degraded during mitotic exit by APC/C-Cdh1.
Upon spindle-assembly checkpoint activation it is hyperphosphorylated and its kinase activity toward CDC20 is stimulated. Phosphorylation at Thr-609 is required for interaction with PLK1, phosphorylation at this site probably creates a binding site for the POLO-box domain of PLK1, thus enhancing the PLK1-BUB1 interaction.
Ammonium transporter involved in the maintenance of acid-base homeostasis. Transports ammonium and its related derivative methylammonium across the basolateral plasma membrane of epithelial cells likely contributing to renal transepithelial ammonia transport and ammonia metabolism. May transport either NH4(+) or NH3 ammonia species predominantly mediating an electrogenic NH4(+) transport (PubMed:15284342, PubMed:15929723, PubMed:24077989). May act as a CO2 channel providing for renal acid secretion (PubMed:24077989).
Fetally expressed by kidney and to a lower extent in liver.
Interacts (via C-terminus) with ANK2 and ANK3; required for targeting to the basolateral membrane.
Specifically expressed in kidney. Also detected in liver and ovary.
Can form homooligomers. Interacts with PARsylated AXIN1, AXIN2, BLZF1, CASC3, H1-2, IPO7, LIG3, NCL, PARP1, XRCC1, XRCC5 and XRCC6. Interacts with DDB1, DHX15, IQGAP1, LRPPRC, PARP2, PRKDC, RUVBL2, TNKS1 and TNKS2. Binding often leads to interactor ubiquitination, in the presence of the appropriate E1 and E2 enzymes, and proteasomal degradation.
Defects in RNF146 are a cause of susceptibility to breast cancer.
E3 ubiquitin-protein ligase that specifically binds poly-ADP-ribosylated (PARsylated) proteins and mediates their ubiquitination and subsequent degradation (PubMed:21478859, PubMed:21799911, PubMed:22267412). May regulate many important biological processes, such as cell survival and DNA damage response (PubMed:21825151, PubMed:22267412). Acts as an activator of the Wnt signaling pathway by mediating the ubiquitination of PARsylated AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex (PubMed:21478859, PubMed:21799911). Acts in cooperation with tankyrase proteins (TNKS and TNKS2), which mediate PARsylation of target proteins AXIN1, AXIN2, BLZF1, CASC3, TNKS and TNKS2 (PubMed:21799911). Recognizes and binds tankyrase-dependent PARsylated proteins via its WWE domain and mediates their ubiquitination, leading to their degradation (PubMed:21799911). Different ubiquitin linkage types have been observed: TNKS2 undergoes ubiquitination at 'Lys-48' and 'Lys-63', while AXIN1 is only ubiquitinated at 'Lys-48' (PubMed:21799911). May regulate TNKS and TNKS2 subcellular location, preventing aggregation at a centrosomal location (PubMed:21799911). Neuroprotective protein (PubMed:21602803). Protects the brain against N-methyl-D-aspartate (NMDA) receptor-mediated glutamate excitotoxicity and ischemia, by interfering with PAR-induced cell death, called parthanatos (By similarity). Prevents nuclear translocation of AIFM1 in a PAR-binding dependent manner (By similarity). Does not affect PARP1 activation (By similarity). Protects against cell death induced by DNA damaging agents, such as N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and rescues cells from G1 arrest (By similarity). Promotes cell survival after gamma-irradiation (PubMed:21825151). Facilitates DNA repair (PubMed:21825151).
The WWE domain mediates non-covalent PAR-binding.
Ubiquitinated; autoubiquitinated. Polyubiquitinated in the presence of UBE2D1, UBE2D2 and UBE2D3. Multimonoubiquitinated in the presence of UBE2E1. Not ubiquitinated in the presence of UBE2H, CDC34, UBE2L3, UBE2L6, nor UBE2C. In the absence of PAR, autoubiquitination occurs on Lys-85, Lys-95 and Lys-176 via 'Lys-11' and 'Lys-48' ubiquitin linkages. In the presence of PAR, Lys-131 and Lys-176 are ubiquitinated via 'Lys-6', 'Lys-33' and 'Lys-48' ubiquitin linkages. Autoubiquitination is enhanced upon PAR-binding.
Ubiquitously expressed. Up-regulated in brains from patients with Alzheimer disease.
Was named dactylidin after the Greek term 'daktylidi' for ring, 'the thing around the finger' (PubMed:15813938). Was named Iduna after the Norse goddess of protection and eternal youth (PubMed:21602803).
Short-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation, an aerobic process breaking down fatty acids into acetyl-CoA and allowing the production of energy from fats (By similarity). The first step of fatty acid beta-oxidation consists in the removal of one hydrogen from C-2 and C-3 of the straight-chain fatty acyl-CoA thioester, resulting in the formation of trans-2-enoyl-CoA (By similarity). Among the different mitochondrial acyl-CoA dehydrogenases, short-chain specific acyl-CoA dehydrogenase acts specifically on acyl-CoAs with saturated 4 to 6 carbons long primary chains (PubMed:21237683, PubMed:11134486).
Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly, possibly in combination with membrane fission (PubMed:18687924). Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413).
Proposed to be monomeric or homodimeric in nucleotide-free form and to oligomerize upon binding to ATP to form two stacked hexameric or heptameric rings with a central pore through which ESCRT-III substrates are translocated in an ATP-dependent manner. In vitro, associates on the inside of a helical tubular structure formed by a CHMP2A-CHMP3 polymer. Interacts with CHMP1A, CHMP1B, CHMP2A, CHMP4B and CHMP6. Interacts with VPS4A; the interaction suggests a heteromeric assembly with VPS4A. Interacts with VTA1.
Polyubiquitinated by ZNF598 via 'Lys-63'-linked ubiquitin chains when a ribosome has stalled, initiating the ribosome quality control (RQC) pathway to degrade the potentially detrimental aberrant nascent polypeptide (PubMed:28065601, PubMed:28132843, PubMed:28685749, PubMed:32011234, PubMed:36302773). Deubiquitinated by OTUD3 and USP21, antagonizing ZNF598 activity (PubMed:32011234).
Catalyzes the synthesis of acetyl-CoA from short-chain fatty acids (PubMed:16788062). Acetate is the preferred substrate (PubMed:16788062). Can also utilize propionate with a much lower affinity (By similarity). Provides acetyl-CoA that is utilized mainly for oxidation under ketogenic conditions (By similarity). Involved in thermogenesis under ketogenic conditions, using acetate as a vital fuel when carbohydrate availability is insufficient (By similarity).
Inhibited by acetylation at Lys-642 and activated by deacetylation mediated by the deacetylase SIRT3.
Reversibly acetylated on Lys-642 (PubMed:16788062). The acetyl-CoA synthase activity is inhibited by acetylation and activated by deacetylation mediated by the deacetylase SIRT3.
Antibodies against AMPH are detected in patients with stiff-man syndrome, a rare disease of the central nervous system characterized by progressive rigidity of the body musculature with superimposed painful spasms.
Heterodimer with BIN1 (By similarity). Binds SH3GLB1 (By similarity). Interacts with REPS1 and SGIP1(PubMed:20946875). Binds AP2A2 (PubMed:12057195). Interacts with AP2B1 (PubMed:16903783). Interacts with DNM1 and SYNJ1 (By similarity).
May participate in mechanisms of regulated exocytosis in synapses and certain endocrine cell types. May control the properties of the membrane associated cytoskeleton.
Neurons, certain endocrine cell types and spermatocytes.
Increases the transcriptional activity of NFKB1 by facilitating its nuclear translocation, DNA-binding and associated apoptotic response, when overexpressed (PubMed:15735698). May sequester WWOX in lysosomal vesicles and thereby regulate WWOX role as tumor suppressor (PubMed:30285739).
Widely expressed with highest levels in thymus and ovary.
Enhances bone morphogenetic protein (BMP) signaling in a paracrine manner. In contrast, it inhibits both the activin-A and TGFB1-mediated signaling pathways (By similarity).
Interacts with BMP7 and, by doing so, enhances binding to the type I receptors that contains cytoplasmic serine/threonine protein kinase domains. Also able to interact with activin-A and TGFB1 (By similarity).
Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class V subfamily.
Kidney, heart, liver, pancreas and vascular smooth muscle cells. Also detected in aortic intima (at protein level).
Negatively regulates cell proliferation and cell migration.
May have a potential role in hypercalcemia of malignancy.
Belongs to the PF07175/osteoregulin family.
Cleaved by CTSB/cathepsin B; the cleavage is blocked by metalloprotease PHEX.
Expressed by osteoblasts (PubMed:10945470, PubMed:11414762, PubMed:15108058). Expressed by stem cells in dental pulp (PubMed:15153459). Expressed by mesenchymal cells in dental papilla and dental pulp (PubMed:18547474, PubMed:22341070). Expressed in teeth, specifically in decidious dentin (PubMed:20581062). Expressed in ondotoblasts (PubMed:12489176). Expressed in salivary glands (PubMed:15329369). Secreted from oncogenic hypophosphatemic tumors (PubMed:11414762).
Interacts (via the ASARM motif) with PHEX; the interaction is zinc-dependent.
Phosphorylated on serine residues in the ASARM motif (in vitro) by FAM20C; the phosphorylation is important for the inhibition of bone mineralization (PubMed:19998030, PubMed:22582013).
Promotes renal phosphate excretion and inhibits intestinal phosphate absorption (PubMed:14962809, PubMed:19005008). Promotes bone mineralization by osteoblasts and cartilage mineralization by chondrocytes (PubMed:18162525, PubMed:19998030, PubMed:22766095). Regulates the mineralization of the extracellular matrix of the craniofacial complex, such as teeth, bone and cartilage (By similarity). Promotes dental pulp stem cell proliferation and differentiation (PubMed:22341070).
The acidic serine aspartate-rich MEPE-associated (ASARM) motif is sufficient when phosphorylated to inhibit bone mineralization by osteoblasts and cartilage mineralization by chondrocytes by binding hydroxyapatite crystals during the mineralization stage (PubMed:15664000, PubMed:18162525, PubMed:18597632, PubMed:19998030, PubMed:22766095). It can also inhibit dentin mineralization (PubMed:20581062).
The dentonin region is sufficient to promote dental pulp stem cell proliferation (PubMed:15153459). It can also stimulate bone formation, osteoblast differentiation, and activate integrin signaling pathways (PubMed:15040834).
Dual phosphorylation of Thr-250 and Thr-255 activates the kinase. Phosphorylation of Thr-385 activates the kinase. MAPK3/ERK1 is one of the kinases which activate MKNK1/MNK1. Phosphorylation by PAK2 leads to a reduced phosphorylation of EIF4G1.
Interacts with the C-terminal regions of EIF4G1 and EIF4G2. Also binds to dephosphorylated ERK1 and ERK2, and to the p38 kinases.
May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap.
Phosphorylated and activated by the p38 kinases and kinases in the Erk pathway.
Interacts with IFT88 (By similarity). Interacts with IFT57 (By similarity). Interacts with RABL2/RABL2A; binds preferentially to GDP-bound RABL2 (By similarity).
Required for the maintenance and formation of cilia. Plays an indirect role in hedgehog (Hh) signaling, cilia being required for all activity of the hedgehog pathway (By similarity).
Found in a cytosolic complex with ASF1 (ASF1A or ASF1B) and histones H3 and H4.
Nuclear transport receptor that mediates nuclear import of proteins, such as histones, RPS3A, TNP2 and VDR (PubMed:11823430, PubMed:16207705, PubMed:17682055, PubMed:21454524). Serves as receptor for nuclear localization signals (NLS) in cargo substrates (PubMed:11823430, PubMed:16207705). Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism (PubMed:11823430, PubMed:16207705). At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran (PubMed:11823430). The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus (PubMed:11823430). Mediates the nuclear import of the histone H3-H4 dimer when in complex with ASF1 (ASF1A or ASF1B) (PubMed:21454524, PubMed:29408485). Mediates the ligand-independent nuclear import of vitamin D receptor (VDR) (PubMed:16207705). In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS (PubMed:12610148).
Overexpressed in glioblastoma multiforme (GBM) patients.
Plays a key role in maintaining the cardiac electrical stability by modulating cell surface expression of SCN5A (PubMed:32175648). May play a role in the modulation of anxiety behavior by regulating GABAergic neuronal system in the nucleus accumbens (By similarity).
Expressed in the developing and adult retina. Also expressed in the hypothalamic and the pituitary regions.
Interacts with DLG4 (By similarity). Interacts (via LRR repeats) with NTNG2. Forms a complex with DLG4 and with NMDA receptors.
Synaptic adhesion protein. Regulates the formation of exitatory synapses through the recruitment of pre-and-postsynaptic proteins. Organize the lamina/pathway-specific differentiation of dendrites. Plays an important role for auditory synaptic responses. Involved in the suppression of glioma (By similarity).
AQP3 is responsible for the GIL blood group system. Isoform 2 is detected in GIL-negative individuals that lack functional AQP3.
Due to a polymorphism at the 5'-splice donor site of intron 5, leading to exon 5 skipping and premature termination of translation. This is the molecular basis of the GIL blood group.
Water channel required to promote glycerol permeability and water transport across cell membranes (PubMed:12239222, PubMed:30420639). Acts as a glycerol transporter in skin and plays an important role in regulating SC (stratum corneum) and epidermal glycerol content. Involved in skin hydration, wound healing, and tumorigenesis. Provides kidney medullary collecting duct with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient. Slightly permeable to urea and may function as a water and urea exit mechanism in antidiuresis in collecting duct cells. It may play an important role in gastrointestinal tract water transport and in glycerol metabolism (By similarity).
Widely expressed in epithelial cells of kidney (collecting ducts) and airways, in keratinocytes, immature dendritic cells and erythrocytes. Isoform 2 is not detectable in erythrocytes at the protein level.
Constitutively phosphorylated. Phosphorylated on tyrosine residues in C-terminal region by ABL1. Phosphorylated on tyrosine residues within the YXXM motifs by BTK and SYK (By similarity). Isoform 1 and isoform 2 are phosphorylated on tyrosine residues, most likely within the YXXM motifs, via CD19 activation (By similarity). Toll-like receptor activation induces appearance of a phosphorylated form associated with membranes (By similarity).
Homooligomer (By similarity). Interacts (phosphorylated on tyrosine residues within YXXM motifs) with PIK3R1 (via SH2 domain); required for BCR- and TLR-mediated activation of phosphoinositide 3-kinase. Interacts (via polyproline C-terminal region) with ABI1 (via SH3 domain); the interaction promotes phosphorylation of PIK3AP1 by ABL1. May interact with MYD88 and TIRAP (By similarity).
Signaling adapter that contributes to B-cell development by linking B-cell receptor (BCR) signaling to the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway. Has a complementary role to the BCR coreceptor CD19, coupling BCR and PI3K activation by providing a docking site for the PI3K subunit PIK3R1. Alternatively, links Toll-like receptor (TLR) signaling to PI3K activation, a process preventing excessive inflammatory cytokine production. Also involved in the activation of PI3K in natural killer cells. May be involved in the survival of mature B-cells via activation of REL.
The DBB domain is required for dimerization.
Belongs to the Mediator complex subunit 1 family.
Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors (PubMed:10406464, PubMed:11867769, PubMed:12037571, PubMed:12218053, PubMed:12556447, PubMed:14636573, PubMed:15340084, PubMed:15471764, PubMed:15989967, PubMed:16574658, PubMed:9653119). Acts as a coactivator for GATA1-mediated transcriptional activation during erythroid differentiation of K562 erythroleukemia cells (PubMed:24245781).
Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. This subunit specifically interacts with a number of nuclear receptors in a ligand-dependent fashion including AR, ESR1, ESR2, PPARA, PPARG, RORA, RXRA, RXRG, THRA, THRB and VDR. Interacts with CTNNB1, GABPA, GLI3, PPARGC1A and TP53. Interacts with YWHAH. Interacts with CLOCK; this interaction requires the presence of THRAP3 (By similarity). Interacts with GATA1 and CCAR1. Interacts with NR4A3 (By similarity). Interacts (via IBM motif) with PSIP1 (via IBD domain); phosphorylation increases its affinity for PSIP1 (PubMed:29997176).
Phosphorylated by MAPK1 or MAPK3 during G2/M phase which may enhance protein stability and promote entry into the nucleolus (PubMed:16314496). Phosphorylation increases its interaction with PSIP1 (PubMed:29997176).
Interacts with HAND1; the interaction enhances HAND1-induced differentiation of trophoblast giant cells (By similarity). Interacts with POU5F1 (OCT3/4); binds synergistically with POU5F1 to DNA (By similarity). Interacts with FHL3; the interaction recruits the transcriptional coactivator FHL3 to the FOXK1 promoter (By similarity).
Transcription factor that binds to DNA at the 5'-AACAATG-3' consensus sequence (By similarity). Acts as a transcriptional activator and repressor (By similarity). Binds synergistically with POU5F1 (OCT3/4) to gene promoters (By similarity). Binds to the FOXK1 promoter and recruits FHL3, resulting in transcriptional activation of FOXK1 which leads to myoblast proliferation (By similarity). Acts as an inhibitor of myoblast differentiation via transcriptional repression which leads to down-regulation of the muscle-specific genes MYOD and MYOG (By similarity). Involved in trophoblast giant cell differentiation via enhancement of HAND1 transcriptional activity (By similarity). Regulates transcription of HRC via binding to it proximal enhancer region (By similarity). Involved in skeletal muscle regeneration (By similarity). Also plays a role in the development of myogenic precursor cells (By similarity).
Widely expressed in fetal and adult tissues examined, highest level found in fetal spinal cord and adult brain and testis.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ4 subfamily.
Heart, skeletal muscle, and several different brain regions including the hippocampus.
Homomultimeric and heteromultimeric association with KCNJ2 and KCNJ12. Association, via its PDZ-recognition domain, with LIN7A, LIN7B, LIN7C, DLG1, CASK and APBA1 plays a key role in its localization and trafficking (By similarity). Interacts with TAX1BP3. TAX1BP3 competes with LIN7 family members for KCNJ4 binding.
Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium and cesium (By similarity).
The Val/Gly/Ala/Pro stretch may have a functional role in the conductance or permeation properties.
Protein disulfide isomerase of the endoplasmic reticulum lumen involved in the formation of disulfide bonds in proteins. Can reduce insulin disulfide bonds.
May play a role in sperm acrosome biogenesis.
The primate lineage appears to have undergone gene duplication of FAM209, such that humans contain FAM209A and FAM209B.
Expressed in many tissues. High levels of expression in brain, liver, thymus and peripheral blood leukocytes and low levels of expression in heart, kidney, testis and colon.
Belongs to the SRP receptor beta subunit family.
Component of the signal recognition particle (SRP) complex receptor (SR) (By similarity). Ensures, in conjunction with the SRP complex, the correct targeting of the nascent secretory proteins to the endoplasmic reticulum membrane system (By similarity). May mediate the membrane association of SR (By similarity).
Belongs to the DeoC/FbaB aldolase family. DeoC type 2 subfamily.
Catalyzes a reversible aldol reaction between acetaldehyde and D-glyceraldehyde 3-phosphate to generate 2-deoxy-D-ribose 5-phosphate. Participates in stress granule (SG) assembly. May allow ATP production from extracellular deoxyinosine in conditions of energy deprivation.
Mainly expressed in liver, lung and colon.
(Microbial infection) Interacts with vaccinia virus protein C9L.
Belongs to the CSN7/EIF3M family. CSN7 subfamily.
Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, JUN, I-kappa-B-alpha/NFKBIA, ITPK1 and IRF8/ICSBP, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively.
Component of the CSN complex, composed of COPS1/GPS1, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7 (COPS7A or COPS7B), COPS8 and COPS9 isoform 1 (PubMed:11337588, PubMed:18850735, PubMed:26456823). In the complex, it probably interacts directly with COPS1, COPS2, COPS4, COPS5, COPS6 and COPS8 (PubMed:11337588, PubMed:18850735). Interacts with EIF3S6 (PubMed:12220626).
Expression is regulated by the phosphatidylinositol (PI) 3-kinase pathway.
Involved in the mitochondrial division probably by regulating membrane fission. Loss-of-function induces the release of cytochrome c, which activates the caspase cascade and leads to apoptosis.
Interacts with RNA polymerase II and the DRB sensitivity-inducing factor complex (DSIF complex), which is composed of SUPT5H and SUPT4H1. Interacts with KDM6A (By similarity). Interacts (via SH2 domain) with SETD1A (By similarity). Interacts (via SH2 domain) with POLR2A phosphorylated at 'Ser-2'. Interacts with IWS1, AICDA and PAAF1. Interacts with histone H2B and H3. Interacts with WDR43 (By similarity).
Transcription elongation factor which binds histone H3 and plays a key role in the regulation of transcription elongation and mRNA processing. Enhances the transcription elongation by RNA polymerase II (RNAPII) and is also required for the efficient activation of transcriptional elongation by the HIV-1 nuclear transcriptional activator, Tat. Besides chaperoning histones in transcription, acts to transport and splice mRNA by forming a complex with IWS1 and the C-terminal domain (CTD) of the RNAPII subunit RPB1 (POLR2A). The SUPT6H:IWS1:CTD complex recruits mRNA export factors (ALYREF/THOC4, EXOSC10) as well as histone modifying enzymes (such as SETD2), to ensure proper mRNA splicing, efficient mRNA export and elongation-coupled H3K36 methylation, a signature chromatin mark of active transcription. SUPT6H via its association with SETD1A, regulates both class-switch recombination and somatic hypermutation through formation of H3K4me3 epigenetic marks on activation-induced cytidine deaminase (AICDA) target loci. Promotes the activation of the myogenic gene program by entailing erasure of the repressive H3K27me3 epigenetic mark through stabilization of the chromatin interaction of the H3K27 demethylase KDM6A.
A chromosomal aberration involving WDCP is found in one subject with colorectal cancer. Translocation t(2;2)(p23.3;p23.1). A 5 million base pair tandem duplication generates an in-frame WDCP-ALK gene fusion.
Oligomer. Interacts with HCK (via SH3 domain).
Phosphorylated on Tyr when associated with HCK.
Expressed at low levels. Expressed in B-lymphocytes. Detected in tonsil, lung, kidney, spleen and placenta. Expressed by a small subset of germinal center B-cells in tonsils and by melanocytes (at protein level).
Component of the Golgi-associated retrograde protein (GARP) complex, also called VFT (VPS fifty-three) complex, composed of VPS51, VPS52, VPS53 and VPS54 (PubMed:27440922, PubMed:15878329, PubMed:20685960). Component of the endosome-associated retrograde protein (EARP) complex, composed of VPS51, VPS52, VPS53 and VPS50/Syndetin (PubMed:25799061, PubMed:27440922). EIPR1 interacts with both EARP and GARP complexes and mediates the recruitment of the GARP complex to the trans-Golgi network (PubMed:27440922). Interacts with RAB6A and STX10 (PubMed:15878329, PubMed:20685960). Interacts with BLTP3B (PubMed:20163565).
Component of the SNARE complex composed of STX4, SNAP23 and VAMP7 that interacts with SYT7 during lysosomal exocytosis. Found in a complex with VAMP8 and SNAP23. Detected in a complex with SNAP23 and STXBP4. Interacts with VAMP2. Interacts with SNAP23 and SNAPIN. Interacts with LLGL1. Interacts (via C-terminus) with CENPF. Interacts with DOC2B. Interacts with STXBP6. Interacts with STXBP3; excludes interaction with DOC2B and SNAP25. Interacts with STXBP4; excludes interaction with VAMP2 (By similarity). Interacts with STXBP5L (By similarity).
Expressed in neutrophils and neutrophil-differentiated HL-60 cells. Expression in neutrophils increases with differentiation.
Plasma membrane t-SNARE that mediates docking of transport vesicles (By similarity). Necessary for the translocation of SLC2A4 from intracellular vesicles to the plasma membrane (By similarity). In neurons, recruited at neurite tips to membrane domains rich in the phospholipid 1-oleoyl-2-palmitoyl-PC (OPPC) which promotes neurite tip surface expression of the dopamine transporter SLC6A3/DAT by facilitating fusion of SLC6A3-containing transport vesicles with the plasma membrane (By similarity). Together with STXB3 and VAMP2, may also play a role in docking/fusion of intracellular GLUT4-containing vesicles with the cell surface in adipocytes and in docking of synaptic vesicles at presynaptic active zones (By similarity).
Autophosphorylated on Ser/Thr. Phosphorylated in cytosol under basal conditions and dephosphorylated when membrane-associated (By similarity).
Homodimer (By similarity). Interacts with MBIP (PubMed:10801814).
Interacts with MBIP through the leucine-zipper motif.
Part of a non-canonical MAPK signaling pathway (PubMed:28111074). Activated by APOE, enhances the AP-1-mediated transcription of APP, via a MAP kinase signal transduction pathway composed of MAP2K7 and MAPK1/ERK2 and MAPK3/ERK1 (PubMed:28111074). May be an activator of the JNK/SAPK pathway.
The activity of MAP3K12 can be regulated through its proteasomal degradation. APOE, through a receptor-mediated mechanism, activates MAP3K12 by preventing its proteasomal degradation.
Detected in fetal erythrocytes (at protein level).
Detected in the yolk sac of the early embryo and in erythrocytes from fetal umbilical cord blood. Detected at low levels after 10 weeks of gestation. Hemoglobin Portland levels are increased in fetuses with homozygous alpha-thalassemia, but it constitutes only a minor proportion of total hemoglobin and its levels decrease steadily after 10 weeks of gestation. Hemoglobin Portland-2 is detected in blood from still-born neoneates with homozygous alpha-thalassemia (at protein level).
Heterotetramer of two zeta chains and two epsilon chains in early embryonic hemoglobin Gower-1; two zeta chains and two gamma chains in fetal hemoglobin Portland-1. Heterotetramer of two zeta chains and two beta chains in hemoglobin Portland-2, detected in fetuses and neonates with homozygous alpha-thalassemia.
The zeta chain is an alpha-type chain of mammalian embryonic hemoglobin.
Cell adhesion molecule that plays a role in neuronal self-avoidance. Promotes repulsion between specific neuronal processes of either the same cell or the same subtype of cells. Mediates within retinal amacrine and ganglion cell subtypes both isoneuronal self-avoidance for creating an orderly dendritic arborization and heteroneuronal self-avoidance to maintain the mosaic spacing between amacrine and ganglion cell bodies (PubMed:10925149). Receptor for netrin required for axon guidance independently of and in collaboration with the receptor DCC. Might also collaborate with UNC5C in NTN1-mediated axon repulsion independently of DCC (By similarity). In spinal cord development plays a role in guiding commissural axons projection and pathfinding across the ventral midline to reach the floor plate upon ligand binding (PubMed:18585357, PubMed:19196994). Mediates intracellular signaling by stimulating the activation of MAPK8 and MAP kinase p38 (PubMed:18585357, PubMed:19196994). Adhesion molecule that promotes lamina-specific synaptic connections in the retina: expressed in specific subsets of interneurons and retinal ganglion cells (RGCs) and promotes synaptic connectivity via homophilic interactions (By similarity).
Has been reported to enhance netrin-induced phosphorylation of PAK1 and FYN; and the interaction between DSCAM, PAK1 and RAC1 has been described. This article has been withdrawn by the authors.
Homodimer; mediates homophilic interactions to promote cell adhesion (By similarity). Interacts with DCC; the interaction is abolished in response to NTN1 (By similarity). Interacts (via extracellular domain) with NTN1 (PubMed:19196994). Interacts (via extracellular domain) with UNC5C (via Ig-like C2-type domain) (PubMed:22685302). Interacts with PTK2 (By similarity). Interacts with FYN (By similarity).
Ig-like C2-type domains 7 to 9 are sufficient for interaction with NTN1 and commissural axon outgrowth. The transmembrane domain is necessary for interaction with DCC (By similarity).
Phosphorylated at tyrosine residues. Phosphorylation is enhanced by NTN1.
Belongs to the polyprenol kinase family.
Catalyzes CTP-mediated phosphorylation of dolichol, the terminal step in de novo dolichyl monophosphate (Dol-P) biosynthesis (PubMed:12213788, PubMed:16923818, PubMed:17273964). Dol-P is a lipid carrier essential for the synthesis of N-linked and O-linked oligosaccharides and for GPI anchors (PubMed:12213788).
Complements the defects in growth, dolichol kinase activity and protein N-glycosylation at the restrictive temperature in yeast sec59 mutant cells.
Binds DNA as a homodimer. Interacts with MEIS1, MEIS2 and MEIS3 (By similarity).
Sequence-specific, AT-rich binding transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.
Interacts with ESR1 and ESR2 in the presence of estradiol. Interacts with CTBP1, HDAC3 and HDAC6. Component of a large corepressor complex that contains about 20 proteins, including CTBP1, CTBP2, HDAC1 and HDAC2.
May act as transcription activator that binds DNA elements with the sequence 5'-CCCTATCGATCGATCTCTACCT-3' (By similarity). Repressor of ligand-dependent transcription activation by target nuclear receptors. Repressor of ligand-dependent transcription activation by ESR1, ESR2, NR3C1, PGR, RARA, RARB, RARG, RXRA and VDR.
Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. NuA4 may also play a direct role in DNA repair when directly recruited to sites of DNA damage. Also a component of the mSin3A complex which acts to repress transcription by deacetylation of nucleosomal histones. Required for homologous recombination repair (HRR) and resistance to mitomycin C (MMC). Involved in the localization of PALB2, BRCA2 and RAD51, but not BRCA1, to DNA-damage foci.
Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6. The NuA4 complex interacts with MYC and the adenovirus E1A protein. MORF4L1 may also participate in the formation of NuA4 related complexes which lack the KAT5/TIP60 catalytic subunit, but which include the SWI/SNF related protein SRCAP. Component of the mSin3A histone deacetylase complex, which includes SIN3A, HDAC2, ARID4B, MORF4L1, RBBP4/RbAp48, and RBBP7/RbAp46. Interacts with RB1 and KAT8. May also interact with PHF12 and one or more as yet undefined members of the TLE (transducin-like enhancer of split) family of transcriptional repressors. Interacts with the N-terminus of MRFAP1. Found in a complex composed of MORF4L1, MRFAP1 and RB1. Interacts with the entire BRCA complex, which contains BRCA1, PALB2, BRCA2 and RAD51. Interacts with PALB2. Forms a complex with MSL1 and NUPR1.
Thiol protease. Key protease responsible for the removal of the invariant chain from MHC class II molecules and MHC class II antigen presentation (PubMed:30612035). The bond-specificity of this proteinase is in part similar to the specificities of cathepsin L.
CCNL1 is amplified in several HNSCC. May play a critical role in the formation of loco-regional metastases and an unfavorable clinical outcome of HNSCC.
Contains a RS region (arginine-serine dipeptide repeat) within the C-terminal domain which is the hallmark of the SR family of splicing factors. This region probably plays a role in protein-protein interactions.
Interacts with POLR2A via its hyperphosphorylated C-terminal domain (CTD) (By similarity). Interacts with CDK11A, CDK12 and CDK13 (PubMed:11980906, PubMed:18216018). Isoforms 1 and 2, but not isoform 3, interact with CDK11B. May form a ternary complex with CDK11B and casein kinase II (CKII) (PubMed:18216018). Interacts with pre-mRNA-splicing factors, including at least SRSF1, SRSF2 and SRSF7/SLU7 (PubMed:11980906, PubMed:18216018).
Involved in pre-mRNA splicing. Functions in association with cyclin-dependent kinases (CDKs) (PubMed:18216018). Inhibited by the CDK-specific inhibitor CDKN1A/p21 (PubMed:11980906). May play a role in the regulation of RNA polymerase II (pol II). May be a candidate proto-oncogene in head and neck squamous cell carcinomas (HNSCC) (PubMed:12414649, PubMed:15700036).
Widely expressed. Overexpression in primary tumors of head and neck squamous cell carcinomas (HNSCC).
(Microbial infection) Interacts with herpes virus HSV-1 ICP0 protein; the interaction leads to the disruption of the BHC complex, thereby preventing the BHC complex from repressing transcription of viral genes.
Essential component of the BHC complex, a corepressor complex that represses transcription of neuron-specific genes in non-neuronal cells. The BHC complex is recruited at RE1/NRSE sites by REST and acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier. In the BHC complex, it serves as a molecular beacon for the recruitment of molecular machinery, including MeCP2 and SUV39H1, that imposes silencing across a chromosomal interval. Plays a central role in demethylation of Lys-4 of histone H3 by promoting demethylase activity of KDM1A on core histones and nucleosomal substrates. It also protects KDM1A from the proteasome. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development and controls hematopoietic differentiation.
Interacts directly with GFI1 and GFI1B in a RCOR/GFI/KDM1A/HDAC complex. Interacts with INMS1 (By similarity). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST and PHF21A/BHC80. The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I. Interacts with REST. Interacts with the SMARCE1/BAF57, suggesting that the BHC complex may recruit the ATP-dependent chromatin-remodeling SWI-SNF complex. Interacts with SOX2 (By similarity).
Phosphorylated by HSV-1 protein kinases in case of infection.
The SANT domains may bridge the nucleosomal substrates and the demethylase KDM1A.
Homotrimer when in free form. Directly interacts with WASF2. Component of the WAVE1 complex composed of ABI2, CYFIP1 or CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Within the complex, a heterodimer containing NCKAP1 and CYFIP1 interacts with a heterotrimer formed by WAVE1, ABI2 and BRK1.
Involved in regulation of actin and microtubule organization. Part of a WAVE complex that activates the Arp2/3 complex. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes (By similarity).
Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels (PubMed:16940157, PubMed:10944470). Displays higher activity toward long chain acyl CoAs (C14-C20) (PubMed:16940157, PubMed:10944470). The enzyme is involved in enhancing the hepatic fatty acid oxidation in mitochondria (By similarity).
Strongest expression in heart, liver, muscle and kidney. Weak in placenta and pancreas.
Was originally (PubMed:10944470) thought to be peroxisomal but was later shown (PubMed:16940157) to be mitochondrial.
Acetylated by EP300; acetylation positively regulates the transcriptional activity of XBP1 isoform 2 (PubMed:20955178). Isoform 2 is deacetylated by SIRT1; deacetylation negatively regulates the transcriptional activity of XBP1 isoform 2 (PubMed:20955178).
Expressed in plasma cells in rheumatoid synovium (PubMed:11460154). Over-expressed in primary breast cancer and metastatic breast cancer cells (PubMed:25280941). Isoform 1 and isoform 2 are expressed at higher level in proliferating as compared to confluent quiescent endothelial cells (PubMed:19416856).
Functions as a stress-inducible potent transcriptional activator during endoplasmic reticulum (ER) stress by inducing unfolded protein response (UPR) target genes via binding to the UPR element (UPRE). Up-regulates target genes encoding ER chaperones and ER-associated degradation (ERAD) components to enhance the capacity of productive folding and degradation mechanism, respectively, in order to maintain the homeostasis of the ER under ER stress (PubMed:11779464, PubMed:25239945). Plays a role in the production of immunoglobulins and interleukin-6 in the presence of stimuli required for plasma cell differentiation (By similarity). Induces phospholipid biosynthesis and ER expansion (PubMed:15466483). Contributes to the VEGF-induced endothelial cell (EC) growth and proliferation in a Akt/GSK-dependent and/or -independent signaling pathway, respectively, leading to beta-catenin nuclear translocation and E2F2 gene expression (PubMed:23529610). Promotes umbilical vein EC apoptosis and atherosclerotisis development in a caspase-dependent signaling pathway, and contributes to VEGF-induced EC proliferation and angiogenesis in adult tissues under ischemic conditions (PubMed:19416856, PubMed:23529610). Involved in the regulation of endostatin-induced autophagy in EC through BECN1 transcriptional activation (PubMed:23184933). Plays a role as an oncogene by promoting tumor progression: stimulates zinc finger protein SNAI1 transcription to induce epithelial-to-mesenchymal (EMT) transition, cell migration and invasion of breast cancer cells (PubMed:25280941). Involved in adipocyte differentiation by regulating lipogenic gene expression during lactation. Plays a role in the survival of both dopaminergic neurons of the substantia nigra pars compacta (SNpc), by maintaining protein homeostasis and of myeloma cells. Increases insulin sensitivity in the liver as a response to a high carbohydrate diet, resulting in improved glucose tolerance. Improves also glucose homeostasis in an ER stress- and/or insulin-independent manner through both binding and proteasome-induced degradation of the transcription factor FOXO1, hence resulting in suppression of gluconeogenic genes expression and in a reduction of blood glucose levels. Controls the induction of de novo fatty acid synthesis in hepatocytes by regulating the expression of a subset of lipogenic genes in an ER stress- and UPR-independent manner (By similarity). Associates preferentially to the HDAC3 gene promoter region in a disturbed flow-dependent manner (PubMed:25190803). Binds to the BECN1 gene promoter region (PubMed:23184933). Binds to the CDH5/VE-cadherin gene promoter region (PubMed:19416856). Binds to the ER stress response element (ERSE) upon ER stress (PubMed:11779464). Binds to the 5'-CCACG-3' motif in the PPARG promoter (By similarity).
Functions as a transcription factor during endoplasmic reticulum (ER) stress by regulating the unfolded protein response (UPR). Required for cardiac myogenesis and hepatogenesis during embryonic development, and the development of secretory tissues such as exocrine pancreas and salivary gland (By similarity). Involved in terminal differentiation of B lymphocytes to plasma cells and production of immunoglobulins (PubMed:11460154). Modulates the cellular response to ER stress in a PIK3R-dependent manner (PubMed:20348923). Binds to the cis-acting X box present in the promoter regions of major histocompatibility complex class II genes (PubMed:8349596). Involved in VEGF-induced endothelial cell (EC) proliferation and retinal blood vessel formation during embryonic development but also for angiogenesis in adult tissues under ischemic conditions. Functions also as a major regulator of the UPR in obesity-induced insulin resistance and type 2 diabetes for the management of obesity and diabetes prevention (By similarity).
Isoform 1 and isoform 2 N-terminus domains are necessary for nuclear localization targeting. Isoform 1 C-terminus domain confers localization to the cytoplasm and is sufficient to impose rapid degradation (By similarity). Isoform 1 transmembrane signal-anchor domain is necessary for its own mRNA to be recruited to the endoplasmic reticulum (ER) which will undergo unconventional ERN1-dependent splicing in response to ER stress (PubMed:19394296, PubMed:21233347). Isoform 1 N-terminus and C-terminus regions are necessary for DNA-binding and weak transcriptional activity, respectively. Isoform 2 N-terminus and C-terminus regions are necessary for DNA-binding and strong transcriptional activity upon ER stress, respectively (PubMed:11779464, PubMed:8657566). Isoform 2 C-terminus region contains a nuclear exclusion signal (NES) at positions 186 through 208. Isoform 2 C-terminus region contains a degradation domain at positions 209 through 261 (PubMed:16461360).
Isoform 1 is up-regulated at the recovery phase of the endoplasmic reticulum (ER) stress response and isoform 2 is up-regulated early during the ER stress response and gradually decreased at later phase of ER stress (PubMed:16461360). Isoform 1 and isoform 2 are down-regulated by laminar flow but up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (at protein level) (PubMed:19416856). Down-regulated by the B-cell-specific transcription factor PAX5 (PubMed:8627152). Up-regulated by interleukin IL-6 in myeloma cells (PubMed:10375612). Up-regulated during plasma-cell differentiation, either through the CD40 receptor signaling pathway or mitogens such as lipopolysaccharide (LPS) (PubMed:11460154). Isoform 1 and isoform 2 are down-regulated by laminar flow but up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (PubMed:25190803). Isoform 2 is up-regulated early during the ER stress response in a ATF6-dependent manner (PubMed:11779464, PubMed:17110785, PubMed:16461360). Isoform 2 is up-regulated by endostatin in a ERN1-dependent manner (PubMed:23184933). Isoform 2 is transiently up-regulated by the mitogenic vascular endothelial growth factor (VEGF) in endothelial cells (PubMed:23529610).
Isoform 2 interacts with SIRT1. Isoform 2 interacts with PIK3R1 and PIK3R2; the interactions are direct and induce translocation of XBP1 isoform 2 into the nucleus and the unfolded protein response (UPR) XBP1-dependent target genes activation in a ER stress- and/or insulin-dependent but PI3K-independent manner. Isoform 2 interacts with FOXO1; the interaction is direct and leads to FOXO1 ubiquitination and degradation via the proteasome pathway in hepatocytes (By similarity). Isoform 1 interacts with HM13 (PubMed:25239945). Isoform 1 interacts with RNF139; the interaction induces ubiquitination and degradation of isoform 1 (PubMed:25239945). Isoform 1 interacts (via luminal domain) with DERL1; the interaction obviates the need for ectodomain shedding prior HM13/SPP-mediated XBP1 isoform 1 cleavage (PubMed:25239945). Isoform 1 interacts with isoform 2; the interaction sequesters isoform 2 from the nucleus and enhances isoform 2 degradation in the cytoplasm (PubMed:16461360, PubMed:25239945). Isoform 1 interacts with HDAC3 and AKT1; the interactions occur in endothelial cell (EC) under disturbed flow (PubMed:25190803). Isoform 1 interacts with the oncoprotein FOS (PubMed:1903538). Isoform 2 interacts with ATF6; the interaction occurs in a ER stress-dependent manner and is required for DNA binding to the unfolded protein response element (UPRE) (PubMed:17765680). Isoform 2 interacts with PIK3R1; the interaction is direct and induces translocation of XBP1 isoform 2 into the nucleus and the unfolded protein response (UPR) XBP1-dependent target genes activation in a ER stress- and/or insulin-dependent but PI3K-independent manner (PubMed:20348923).
Plays a role in the unconventional cytoplasmic splicing processing of its own mRNA triggered by the endoplasmic reticulum (ER) transmembrane endoribonuclease ERN1: upon ER stress, the emerging XBP1 polypeptide chain, as part of a mRNA-ribosome-nascent chain (R-RNC) complex, cotranslationally recruits its own unprocessed mRNA through transient docking to the ER membrane and translational pausing, therefore facilitating efficient IRE1-mediated XBP1 mRNA isoform 2 production (PubMed:19394296, PubMed:21233347). In endothelial cells (EC), associated with KDR, promotes IRE1-mediated XBP1 mRNA isoform 2 productions in a vascular endothelial growth factor (VEGF)-dependent manner, leading to EC proliferation and angiogenesis (PubMed:23529610). Functions as a negative feed-back regulator of the potent transcription factor XBP1 isoform 2 protein levels through proteasome-mediated degradation, thus preventing the constitutive activation of the ER stress response signaling pathway (PubMed:16461360, PubMed:25239945). Inhibits the transactivation activity of XBP1 isoform 2 in myeloma cells (By similarity). Acts as a weak transcriptional factor (PubMed:8657566). Together with HDAC3, contributes to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to EC survival under disturbed flow/oxidative stress (PubMed:25190803). Binds to the ER stress response element (ERSE) upon ER stress (PubMed:11779464). Binds to the consensus 5'-GATGACGTG[TG]N(3)[AT]T-3' sequence related to cAMP responsive element (CRE)-like sequences (PubMed:8657566). Binds the Tax-responsive element (TRE) present in the long terminal repeat (LTR) of T-cell leukemia virus type 1 (HTLV-I) and to the TPA response elements (TRE) (PubMed:2321018, PubMed:2196176, PubMed:1903538, PubMed:8657566). Associates preferentially to the HDAC3 gene promoter region in a static flow-dependent manner (PubMed:25190803). Binds to the CDH5/VE-cadherin gene promoter region (PubMed:19416856).
Potent transcriptional activator. Induced by unconventional ERN1-dependent splicing in response to endoplasmic reticulum stress (PubMed:11779464, PubMed:19622636, PubMed:19394296). ERN1 cleaves a 26-bp fragment causing a frameshift of the mRNA transcript (PubMed:11779464).
Ubiquitinated, leading to proteasome-mediated degradation in response to ER stress (PubMed:11779464, PubMed:16461360, PubMed:25239945).
X-box-binding protein 1, cytoplasmic form and luminal form are produced by intramembrane proteolytic cleavage of ER membrane-anchored isoform 1 triggered by HM13/SPP in a DERL1-RNF139-dependent and VCP/p97-independent manner. X-box-binding protein 1, luminal form is ubiquitinated leading to proteasomal degradation (PubMed:25239945).
Allosterically activated by benzodiazepines (PubMed:2538761, PubMed:29950725). Activated by pentobarbitol (By similarity). Inhibited by the antagonist bicuculline (PubMed:29950725). Inhibited by zinc ions (PubMed:27864268).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRG2 sub-subfamily.
Heteropentamer, formed by a combination of alpha, beta, gamma, delta and rho chains (PubMed:2538761, PubMed:29950725). Interacts with GABARAP (PubMed:9892355). Interacts with KIF21B (By similarity). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3 (By similarity). Interacts with LHFPL4 (By similarity). Interacts with SHISA7; interaction leads to the regulation of GABA(A) receptor trafficking, channel deactivation kinetics and pharmacology (By similarity).
Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:2538761, PubMed:29950725). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (PubMed:23909897, PubMed:25489750, PubMed:27864268). The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the synaptogenic effect of this subunit is influenced by the type of alpha and beta subunits present in the receptor pentamer (By similarity). The alpha1/beta2/gamma2 receptor and the alpha1/beta3/gamma2 receptor exhibit synaptogenic activity (PubMed:23909897, PubMed:25489750). The alpha2/beta2/gamma2 receptor exhibits synatogenic activity whereas the alpha2/beta3/gamma2 receptor shows very little or no synaptogenic activity (By similarity). Functions also as histamine receptor and mediates cellular responses to histamine (By similarity).
Palmitoylated by ZDHHC3/GODZ; required for the accumulation of GABA(A) receptors at the postsynaptic membrane of inhibitory GABAergic synapses.
Inhibited by both FK506 and rapamycin, but not by cyclosporin A.
Interacts with TMPO-beta, TSG101 and TFDP2 (By similarity). Interacts with EMD.
Possible function in spermatogenesis. Enhances the degradation of MDM2 and increases the amount of p53 probably by modulating the nucleocytoplasmic transport (By similarity).
Associates with the precursor of the 40S ribosome subunit. Interacts (via its N-terminus) with PRMT5 (via its N-terminus) (PubMed:22072790, PubMed:21081503). Interacts with WDR77 (PubMed:22072790). Found in a PRMT5 complex composed of PRMT5, WDR77 and RIOK1 (PubMed:21081503). Interacts (via its C-terminus) with NCL; this interaction targets NCL for PRTM5 methylation (PubMed:21081503).
Involved in the final steps of cytoplasmic maturation of the 40S ribosomal subunit. Involved in processing of 18S-E pre-rRNA to the mature 18S rRNA. Required for the recycling of NOB1 and PNO1 from the late 40S precursor (PubMed:22072790). The association with the very late 40S subunit intermediate may involve a translation-like checkpoint point cycle preceeding the binding to the 60S ribosomal subunit (By similarity). Despite the protein kinase domain is proposed to act predominantly as an ATPase (By similarity). The catalytic activity regulates its dynamic association with the 40S subunit (By similarity). In addition to its role in ribosomal biogenesis acts as an adapter protein by recruiting NCL/nucleolin the to PRMT5 complex for its symmetrical methylation (PubMed:21081503).
Catalyzes the oxidation of cis-isomers of retinol, including 11-cis-, 9-cis-, and 13-cis-retinol in an NAD-dependent manner (PubMed:11675386, PubMed:10588954, PubMed:9931293, PubMed:9115228). Has no activity towards all-trans retinal (By similarity). Plays a significant role in 11-cis retinol oxidation in the retinal pigment epithelium cells (RPE). Also recognizes steroids (androsterone, androstanediol) as its substrates (PubMed:9931293, PubMed:29541409).
Inhibited by 9-cis-, 13-cis- and all-trans-retinoic acids, with the most potent inhibitor being 13-cis-retinoic acid. Weakly inhibited by oleic acid.
The last 8 amino acids of the C-terminal tail are important for a proper localization as well as for the in vivo enzymatic activity.
Widely expressed. In the eye, abundant in the retinal pigment epithelium.
Accessory component of the DNA polymerase epsilon complex (PubMed:10801849). Participates in DNA repair and in chromosomal DNA replication (By similarity).
Belongs to the DNA polymerase epsilon subunit B family.
Component of the DNA polymerase epsilon complex consisting of four subunits: the catalytic subunit POLE and the accessory subunits POLE2, POLE3 and POLE4.
E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as ECSIT, IKBKG, IRAK1, AKT1 and AKT2 (PubMed:31620128, PubMed:11057907, PubMed:18347055, PubMed:19713527, PubMed:19465916). Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation (PubMed:19675569). Leads to the activation of NF-kappa-B and JUN (PubMed:16378096, PubMed:17135271, PubMed:17703191). Seems to also play a role in dendritic cells (DCs) maturation and/or activation (By similarity). Represses c-Myb-mediated transactivation, in B-lymphocytes (PubMed:18093978, PubMed:18758450). Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor (PubMed:8837778, PubMed:19825828, PubMed:12140561). Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation (By similarity). Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production (By similarity). Participates also in the TCR signaling by ubiquitinating LAT (PubMed:25907557, PubMed:23514740).
Homotrimer. Homooligomer. N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK2, IRAK3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ (By similarity). Interacts with PELI2 and PELI3. Binds UBE2V1. Interacts with TAX1BP1; this interaction mediates deubiquitination of TRAF6 and inhibition of NF-kappa-B activation (PubMed:10920205, PubMed:17703191). Interacts with ZNF675. Interacts with ARRB1 and ARRB2. Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal). Interacts with RBCK1. Interacts with LIMD1 (via LIM domains) (By similarity). Interacts with RSAD2/viperin (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with ZFAND5. Interacts with IL1RL1. Interacts with TRAFD1. Interacts with AJUBA. Interacts with MAVS/IPS1. Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with IFIT3 (via N-terminus). Interacts with TICAM2. Interacts with CARD14. Interacts with CD40 and MAP3K8; the interaction is required for ERK activation (By similarity). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (PubMed:25861989). Interacts with WDFY3 (By similarity). Interacts with TRIM13 (PubMed:28087809). Interacts with GPS2 (By similarity). Interacts (via C-terminus) with SASH1 (PubMed:23776175). Interacts with LRRC19 (PubMed:25026888). Interacts with IL17RA and TRAF3IP2. Interacts with TOMM70 (PubMed:20628368). Interacts with AMBRA1; interaction is required to mediate 'Lys-63'-linked ubiquitination of ULK1 (PubMed:23524951). Interacts with CRBN; this interaction inhibits TLR4-mediated signaling by preventing TRAF6-mediated ubiquitination of ECSIT (PubMed:31620128).
Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (PubMed:19825828). Polyubiquitinated on Lys-124; after cell stimulation with IL1B or TGFB. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappaB signaling upon DNA damage (PubMed:25861989). LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888). Ubiquitinated at Lys-319 by the SCF(FBXL2) complex, leading to its degradation by the proteasome (By similarity).
Sumoylated on Lys-124, Lys-142 and Lys-453 with SUMO1.
Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family.
Serine/threonine kinase that acts as a key regulator of ciliogenesis: controls the initiation of ciliogenesis by binding to the distal end of the basal body and promoting the removal of CCP110, which caps the mother centriole, leading to the recruitment of IFT proteins, which build the ciliary axoneme. Has some substrate preference for proteins that are already phosphorylated on a Tyr residue at the +2 position relative to the phosphorylation site. Able to phosphorylate tau on serines in vitro (PubMed:23141541). Phosphorylates MPHOSPH9 which promotes its ubiquitination and proteasomal degradation, loss of MPHOSPH9 facilitates the removal of the CP110-CEP97 complex (a negative regulator of ciliogenesis) from the mother centrioles, promoting the initiation of ciliogenesis (PubMed:30375385).
Interacts with LRGUK (via guanylate kinase-like domain). Interacts (via C-terminus) with HOOK1 (via coiled-coil region).
Probable component of the manchette, a microtubule-based structure which plays a key role in sperm head morphogenesis during late stages of sperm development.
Activates both Ras-dependent and Ras-independent migratory pathways in melanomas. Contributes to the early phases of agrin-induced tyrosine phosphorylation of CHRNB1.
Interacts (via PID domain) with phosphorylated MUSK (via NPXY motif); undergoes tyrosine phosphorylation downstream of activated MUSK. Interacts with GRB2; the interaction is dependent of Tyr-424 phosphorylation and increased by EGF.
Only expressed in melanomas. Weakly expressed in normal melanocytes and benign nevi. Highly expressed at the transition from radial growth phase to vertical growth phase and metastatic melanomas, when tumor cells acquire migratory competence and invasive potential.
Phosphorylated; the phosphorylation is enhanced by EGF. Phosphorylation at Tyr-424 is required for the interaction with GRB2.
Highly expressed in the heart, skeletal muscle, placenta and lung. Weakly expressed in the thymus, spleen, kidney and liver. Expressed on activated T- and B-cells, dendritic cells, keratinocytes and monocytes.
Interacts with PDCD1 (PubMed:11015443, PubMed:18287011, PubMed:26602187). Interacts (via transmembrane domain) with CMTM4 and CMTM6 (PubMed:28813417, PubMed:28813410). Interacts with (phosphorylated) STAT3; promoting nuclear translocation (PubMed:32929201).
Plays a critical role in induction and maintenance of immune tolerance to self (PubMed:11015443, PubMed:28813417, PubMed:28813410). As a ligand for the inhibitory receptor PDCD1/PD-1, modulates the activation threshold of T-cells and limits T-cell effector response (PubMed:11015443, PubMed:28813417, PubMed:28813410). Through a yet unknown activating receptor, may costimulate T-cell subsets that predominantly produce interleukin-10 (IL10) (PubMed:10581077). Can also act as a transcription coactivator: in response to hypoxia, translocates into the nucleus via its interaction with phosphorylated STAT3 and promotes transcription of GSDMC, leading to pyroptosis (PubMed:32929201).
The PDCD1-mediated inhibitory pathway is exploited by tumors to attenuate anti-tumor immunity and escape destruction by the immune system, thereby facilitating tumor survival (PubMed:28813417, PubMed:28813410). The interaction with PDCD1/PD-1 inhibits cytotoxic T lymphocytes (CTLs) effector function (By similarity). The blockage of the PDCD1-mediated pathway results in the reversal of the exhausted T-cell phenotype and the normalization of the anti-tumor response, providing a rationale for cancer immunotherapy (By similarity).
Truncation of the 3'-untranslated (3'-UTR) region of CD274 transcripts leads to elevated expression of CD274 in multiple cancers including T-cell leukemia, diffuse large B-cell lymphoma and stomach adenocarcinoma (PubMed:27281199). Disruption of 3'-UTR region is caused by structural variants that stabilize CD274 transcripts, leading to overexpression (PubMed:27281199). Increased expression in tumors promotes immune evasion and tumor cell growth by allowing malignant cells to escape destruction by the immune system (PubMed:27281199).
Ubiquitinated; STUB1 likely mediates polyubiquitination of PD-L1/CD274 triggering its degradation (PubMed:28813410). Ubiquitinated by MARCHF8; leading to degradation (PubMed:34183449).
Up-regulated on T- and B-cells, dendritic cells, keratinocytes and monocytes after LPS and IFNG activation. Up-regulated in B-cells activated by surface Ig cross-linking.
Widely expressed, highest in lung, liver and pituitary and in various peripheral blood cells, including neutrophils and some subtypes of lymphoid and myeloid cells.
Belongs to the Dus family. Dus4 subfamily.
Accessory subunit of neuronal kainate-sensitive glutamate receptors, GRIK2 and GRIK3. Increases kainate-receptor channel activity, slowing the decay kinetics of the receptors, without affecting their expression at the cell surface, and increasing the open probability of the receptor channels. Modulates the agonist sensitivity of kainate receptors. Slows the decay of kainate receptor-mediated excitatory postsynaptic currents (EPSCs), thus directly influencing synaptic transmission (By similarity).
Interacts with GRIK2 and GRIK3, but neither with AMPA-nor with NMDA-sensitive glutamate receptors.
Actin-bundling protein. In the inner ear, it is required for stereocilia formation. Mediates liquid packing of actin filaments that is necessary for stereocilia to grow to their proper dimensions.
In small intestine, colon, and kidney; relatively lower levels of expression are detected in the lung and stomach.
DQ0602 (heterodimer of DQA1*01:02/DQB1*06:02) confers dominant protection against type 1 diabetes (T1D) and strong susceptibility to narcolepsy. DQB1*06:02 has been found to be present in most of the narcolepsy patients. As well 98% of the patients with an HCRT deficiency are positive for DQB1*06:02.
DQ2 (heterodimer of DQA1*05:01/DQB1*02:01) is associated with more than 90% of celiac disease patients. A minority displays DQ8 (heterodimer of DQA1*03/DQB1*03:02).
Anchors the extracellular matrix to the cytoskeleton via F-actin. Ligand for dystroglycan. Component of the dystrophin-associated glycoprotein complex which accumulates at the neuromuscular junction (NMJ) and at a variety of synapses in the peripheral and central nervous systems and has a structural function in stabilizing the sarcolemma. Also implicated in signaling events and synaptic transmission.
Expressed in muscle fibers accumulating in the costameres of myoplasm at the sarcolemma. Expressed in brain, muscle, kidney, lung and testis. Most tissues contain transcripts of multiple isoforms. Isoform 15: Only isoform to be detected in heart and liver and is also expressed in brain, testis and hepatoma cells.
Interacts with SYNM (By similarity). Interacts with the syntrophins SNTA1, SNTB1, SNTB2, SNTG1 and SNTG2 (PubMed:7844150, PubMed:8576247). Interacts with KRT19 (PubMed:16000376). Component of the dystrophin-associated glycoprotein complex which is composed of three subcomplexes: a cytoplasmic complex comprised of DMD (or UTRN), DTNA and a number of syntrophins, such as SNTB1, SNTB2, SNTG1 and SNTG2, the transmembrane dystroglycan complex, and the sarcoglycan-sarcospan complex. Interacts with DAG1 (betaDAG1) with DMD; the interaction is inhibited by phosphorylation on the PPXY motif of DAG1 (PubMed:7592992, PubMed:11495720, PubMed:10932245). Interacts with CMYA5 (By similarity). Directly interacts with ANK2 and ANK3; these interactions do not interfere with betaDAG1-binding and are necessary for proper localization in muscle cells (By similarity). Identified in a dystroglycan complex that contains at least PRX, DRP2, UTRN, DMD and DAG1 (By similarity). Interacts with DTNB (By similarity). Interacts with PGM5; the interaction is direct (By similarity). Interacts with NOS1; localizes NOS1 to sarcolemma in muscle cells (By similarity).
Isoform 15: Expressed in embryonic neural tissue from the sixth week of development. Isoform 16: Detected in all embryonic tissues examined.
Produced by alternative splicing of isoform 12.
Produced by alternative splicing of isoform 4.
The DMD gene is the largest known gene in humans. It is 2.4 million base-pairs in size, comprises 79 exons and takes over 16 hours to be transcribed and cotranscriptionally spliced.
Belongs to the NAD-dependent glycerol-3-phosphate dehydrogenase family.
Has glycerol-3-phosphate dehydrogenase activity.
Belongs to the metallophosphoesterase superfamily. Purple acid phosphatase family.
Antibodies against POLR3C have been found in the sera of patients with systemic sclerosis (SSc).
Belongs to the eukaryotic RPC3/POLR3C RNA polymerase subunit family.
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits (By similarity). RPC3/POLR3C, RPC6/POLR3F and RPC7/POLR3G form a Pol III subcomplex (PubMed:9171375, PubMed:12391170). Directly interacts with POLR3G and POLR3GL (PubMed:24107381, PubMed:21358628, PubMed:26394183). Directly interacts with POLR3F/RPC39 (PubMed:26394183). Interacts with GTF3C4 (PubMed:10523658). As part of the RNA polymerase III (Pol III) complex, interacts with PKP2 (PubMed:11416169).
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Specific core component of RNA polymerase III which synthesizes small RNAs, such as 5S rRNA and tRNAs. May direct with other members of the subcomplex RNA Pol III binding to the TFIIIB-DNA complex via the interactions between TFIIIB and POLR3F. May be involved either in the recruitment and stabilization of the subcomplex within RNA polymerase III, or in stimulating catalytic functions of other subunits during initiation. Plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF- Kappa-B through the RIG-I pathway. Preferentially binds single-stranded DNA (ssDNA) in a sequence-independent manner (PubMed:21358628).
Highest levels are present in fetal heart and adult lung. Intermediate levels in peripheral leukocytes, placenta, and spinal cord and low expression in fetal brain, spleen, thymus, and lung and in adult heart, aorta, testis, bone marrow, small intestine, thymus, lymph node, and appendix.
Homotrimer associated through a moderately stable interaction of the C-terminal globular C1q domains, allowing the nucleation of the triple helix and then a further quaternary assembly to higher-order polymers via intermolecular disulfide bonds (By similarity). Interacts with EMILIN1.
May be responsible for anchoring smooth muscle cells to elastic fibers, and may be involved not only in the formation of the elastic fiber, but also in the processes that regulate vessel assembly. Has cell adhesive capacity.
(Microbial infection) Interacts with human herpesvirus 8/HHV-8 protein vOX2/K14.
CD200 and CD200R1 interact via their respective N-terminal Ig-like domains (By similarity). Interacts with Human herpesvirus 8 vOX2 protein.
Expressed in granulocytes, monocytes, most T-cells, neutrophils, basophils and a subset of NK, NKT and B-cells (at protein level). Expressed in bone marrow, lymph nodes, spleen, lung, liver, spinal cord, kidney. Expressed in monocyte-derived dendritic and mast cells.
Inhibitory receptor for the CD200/OX2 cell surface glycoprotein. Limits inflammation by inhibiting the expression of pro-inflammatory molecules including TNF-alpha, interferons, and inducible nitric oxide synthase (iNOS) in response to selected stimuli. Also binds to HHV-8 K14 viral CD200 homolog with identical affinity and kinetics as the host CD200.
Accepts the ubiquitin-like protein NEDD8 from the UBA3-NAE1 E1 complex and catalyzes its covalent attachment to other proteins. The specific interaction with the E3 ubiquitin ligase RBX2, but not RBX1, suggests that the RBX2-UBE2F complex neddylates specific target proteins, such as CUL5.
Belongs to the ubiquitin-conjugating enzyme family. UBE2F subfamily.
Interacts with UBA3 and RBX2 (PubMed:19250909). Interacts (N-terminally acetylated form) with (via DCUN1 domain) DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5 (PubMed:23201271).
The acetylation of Met-1 increases affinity for DCUN1D3 by about 2 orders of magnitude and is crucial for NEDD8 transfer to cullins.
May form homomultimers or heteromultimers in combination with an as yet unidentified subunits.
May have a central role in fertilization. May generate a Ca(2+) transporting channel directly involved in initiating the acrosome reaction of the sperm.
Belongs to the complex I subunit 2 family.
Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. Interacts with TMEM242 (PubMed:33753518).
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:16996290). Essential for the catalytic activity and assembly of complex I (PubMed:16996290).
(Microbial infection) Promotes influenza virus infection by inhibiting viral nucleoprotein NP binding to PLSCR1 and thereby PLSCR1-mediated antiviral activity.
Homooligomer (PubMed:15381095). Interacts with MARVELD2 and OCLN; the interaction is required to recruit MARVELD2 to tricellular contacts (PubMed:23239027). Interacts (via C-terminus) with TRA2A, TRA2B and SRSF1 (By similarity). Interacts with PLSCR1 (PubMed:35595813).
Mainly expressed in prostate and to a lower extent in testis, pancreas, kidney, heart and liver.
Maintains epithelial barrier function by recruiting MARVELD2/tricellulin to tricellular tight junctions (tTJs) (PubMed:23239027). Crucial for normal hearing by maintaining the structural and functional integrity of tTJs, which are critical for the survival of auditory neurosensory HCs. Mediates fatty acids and lipoproteins-stimulated CCK/cholecystokinin secretion in the small intestine. In the inner ear, may regulate alternative pre-mRNA splicing via binding to TRA2A, TRA2B and SRSF1 (By similarity).
Homodimer (PubMed:20826455). Heterodimer with PEX11G (PubMed:20826455). Probably interacts with COPB2 and COPA (By similarity). Interacts with PEX19 (PubMed:10704444). Interacts with FIS1 (PubMed:20826455).
May be involved in peroxisomal proliferation and may regulate peroxisomes division (PubMed:9792670). May mediate binding of coatomer proteins to the peroxisomal membrane (By similarity). Promotes membrane protrusion and elongation on the peroxisomal surface (PubMed:20826455).
A signal sequence is predicted but has been shown not to be cleaved in the reticulum endoplasmic.
Homooligomer. Homooligomerization is necessary for enzyme activity.
Intralysosomal proteolytic cleavage is faster and enzymatic activity higher than isoform 2.
Lysosomal acetyltransferase that acetylates the non-reducing terminal alpha-glucosamine residue of intralysosomal heparin or heparan sulfate, converting it into a substrate for luminal alpha-N-acetyl glucosaminidase.
Undergoes intralysosomal proteolytic cleavage; occurs within the end of the first and/or the beginning of the second luminal domain and is essential for the activation of the enzyme.
Widely expressed, with highest level in leukocytes, heart, liver, skeletal muscle, lung, placenta and liver.
Belongs to the DEAD box helicase family. DDX54/DBP10 subfamily.
Expressed in the fallopian tube, cervix and uterus. Also expressed in the brain.
Has RNA-dependent ATPase activity. Represses the transcriptional activity of nuclear receptors.
Interacts in a hormone-dependent manner with nuclear receptors.
Copy-number variation of UGT2B17 defines the bone mineral density quantitative trait locus 12 (BMND12) [MIM:612560]. Variance in bone mineral density is a susceptibility factor for osteoporotic fractures.
Expressed in various tissues including the liver, kidney, testis, uterus, placenta, mammary gland, adrenal gland, skin and prostate.
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:8798464, PubMed:16595710, PubMed:18719240, PubMed:19022937, PubMed:23288867). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (epitestosterone, androsterone) and estrogens (estradiol, epiestradiol) (PubMed:8798464, PubMed:16595710, PubMed:18719240, PubMed:19022937, PubMed:23288867).
Belongs to the monovalent cation:proton antiporter 2 (CPA2) transporter (TC 2.A.37) family.
Expressed in the cornea, lens capsule and choroid-retinal pigment epithelium (at protein level).
Expressed both developing and adult tissues (PubMed:15289879). In adults, significant expression is seen in tumors of the brain, colon and lymph node (PubMed:15289879).
Interacts with SIN3A and SIN3B (via PAH2) to form a complex which represses transcription (By similarity). Component of SIN3A-, but not SIN3B-, containing multiprotein complexes (By similarity). Interacts with FOXO4 and MEF2C; both interactions inhibit FOXO4 and MEF2C transactivation activity (By similarity). Interacts (when phosphorylated) with YWHAE/14-3-3-epsilon; promotes sequestration in the cytoplasm and leads to impaired ability to bind DNA (By similarity). Interacts with FHL2 (By similarity). Interacts with SRF (PubMed:17670796). Interacts with DVL2 and DVL3; the interaction induces DVL2 nuclear translocation (PubMed:25805136). Interacts with BAP1 (when phosphorylated) (PubMed:25451922).
Phosphorylation by GSK3 (GSK3A or GSK3B) promotes interaction with YWHAE/14-3-3-epsilon and retention in the cytoplasm. In response to mTORC1 signaling, phosphorylation by GSK3 is prevented, leading to translocation to the nucleus.
Transcriptional regulator involved in different processes such as glucose metabolism, aerobic glycolysis, muscle cell differentiation and autophagy (By similarity). Recognizes and binds the forkhead DNA sequence motif (5'-GTAAACA-3') and can both act as a transcription activator or repressor, depending on the context (PubMed:17670796). Together with FOXK2, acts as a key regulator of metabolic reprogramming towards aerobic glycolysis, a process in which glucose is converted to lactate in the presence of oxygen (By similarity). Acts by promoting expression of enzymes for glycolysis (such as hexokinase-2 (HK2), phosphofructokinase, pyruvate kinase (PKLR) and lactate dehydrogenase), while suppressing further oxidation of pyruvate in the mitochondria by up-regulating pyruvate dehydrogenase kinases PDK1 and PDK4 (By similarity). Probably plays a role in gluconeogenesis during overnight fasting, when lactate from white adipose tissue and muscle is the main substrate (By similarity). Involved in mTORC1-mediated metabolic reprogramming: in response to mTORC1 signaling, translocates into the nucleus and regulates the expression of genes associated with glycolysis and downstream anabolic pathways, such as HIF1A, thereby regulating glucose metabolism (By similarity). Together with FOXK2, acts as a negative regulator of autophagy in skeletal muscle: in response to starvation, enters the nucleus, binds the promoters of autophagy genes and represses their expression, preventing proteolysis of skeletal muscle proteins (By similarity). Acts as a transcriptional regulator of the myogenic progenitor cell population in skeletal muscle (By similarity). Binds to the upstream enhancer region (CCAC box) of myoglobin (MB) gene, regulating the myogenic progenitor cell population (By similarity). Promotes muscle progenitor cell proliferation by repressing the transcriptional activity of FOXO4, thereby inhibiting myogenic differentiation (By similarity). Involved in remodeling processes of adult muscles that occur in response to physiological stimuli (By similarity). Required to correct temporal orchestration of molecular and cellular events necessary for muscle repair (By similarity). Represses myogenic differentiation by inhibiting MEFC activity (By similarity). Positively regulates Wnt/beta-catenin signaling by translocating DVL into the nucleus (PubMed:25805136). Reduces virus replication, probably by binding the interferon stimulated response element (ISRE) to promote antiviral gene expression (PubMed:25852164).
By CSF3/G-CSF (PubMed:7510105). Up-regulated in CD4(+) T-cells from peripheral blood mononuclear cells of patients with visceral leishmaniasis (PubMed:32839608).
Expressed in activated T-cells, in kidney, liver, lung and pancreas. Not expressed in brain, heart, or skeletal muscle. Expressed at high levels in TCR gamma delta-expressing CTL clones, and in some TCR alpha beta-expressing CTL clones (both CD4+ and CD8+), but is not expressed in other TCR alpha beta-expressing CTL clones and in cell lines representing B-cells, monocytes, and myeloid cells.
Regulates cytotoxic granule exocytosis in effector lymphocytes, thus acting as a critical mediator of inflammation in a broad range of infectious and non-infectious diseases (By similarity). Essential for cytotoxic degranulation of natural killer (NK) cells and CD8(+) T-cells and for the activation of CD4(+) T-cells following infection (By similarity). Plays a critical role in CD8(+) T-cell and NK cell-mediated cytolysis of target cells and contributes to the cytolytic activity via the perforin/granzyme pathway by enhancing exocytosis of LAMP1-carrying lytic granules (By similarity). Contributes to NK cell-mediated control of cancer metastasis (By similarity).
Belongs to the glycosyl hydrolase 59 family.
Detected in urine. Detected in testis, brain and placenta (at protein level). Detected in kidney and liver.
Hydrolyzes the galactose ester bonds of glycolipids such as galactosylceramide and galactosylsphingosine (PubMed:8281145, PubMed:8399327). Enzyme with very low activity responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon (PubMed:8281145, PubMed:8399327).
Polymorphic amino-acid changes are responsible for the wide range of catalytic activities found in the general population.
A chromosomal aberration involving EVI5 is found is a patient with stage 4S neuroblastoma. Translocation t(1;10)(p22;q21) that forms a EVI5-TRNG10 fusion protein. TRNG10 is a probable structural transcript which is normally not translated.
Depletion of EVI5 by RNAi causes cell cycle arrest and mitotic abnormalities.
Dimeric and monomeric. Interacts with alpha- and gamma-tubulin. Interacts with FBXO5. Interacts with the chromosome passenger complex (CPC) which is at least composed of AURKB/aurora-B, BIRC5/survivin, CDCA8/borealin and INCENP.
Down-regulated during mitosis through proteasomal degradation.
Expressed in various cell lines (at protein level). Expressed in a wide range of tissues including brain and adrenal.
Functions as a regulator of cell cycle progression by stabilizing the FBXO5 protein and promoting cyclin-A accumulation during interphase. May play a role in cytokinesis.
Probably phosphorylated by PLK1; may be required for degradation during mitosis.
Ubiquitinated. Degradation during prophase is ubiquitin-dependent.
A retroviral element acts as an alternative tissue-specific promoter for this gene. The LTR of an HERV-E element enhances the expression in placenta and embryonic kidney.
Has E3 ubiquitin ligase activity towards IGBP1, promoting its monoubiquitination, which results in deprotection of the catalytic subunit of protein phosphatase PP2A, and its subsequent degradation by polyubiquitination.
Homodimer or heterodimer with MID2. Interacts with IGBP1. Interacts with TRIM16.
In the fetus, highest expression found in kidney, followed by brain and lung. Expressed at low levels in fetal liver. In the adult, most abundant in heart, placenta and brain.
The disease is caused by variants affecting the gene represented in this entry. MID1 mutations produce proteins with a decreased affinity for microtubules.
Belongs to the G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRB2 sub-subfamily.
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine.
Binds NHERF1 and GPRASP1. Interacts with ARRB1 and ARRB2. Interacts with SRC (PubMed:9924018). Interacts with USP20 and USP33 (PubMed:19424180, PubMed:23166351). Interacts with VHL; the interaction, which is increased on hydroxylation of ADRB2, ubiquitinates ADRB2 leading to its degradation. Interacts with EGLN3; the interaction hydroxylates ADRB2 facilitating VHL-E3 ligase-mediated ubiquitination. Interacts (via PDZ-binding motif) with SNX27 (via PDZ domain); the interaction is required when endocytosed to prevent degradation in lysosomes and promote recycling to the plasma membrane. Interacts with CNIH4 (PubMed:24405750). Interacts with ARRDC3 (PubMed:20559325, PubMed:25220262). Interacts with NEDD4 (PubMed:23166351). Interacts with MARCHF2 (PubMed:23166351).
Hydroxylation by EGLN3 occurs only under normoxia and increases the interaction with VHL and the subsequent ubiquitination and degradation of ADRB2.
Palmitoylated (PubMed:2540197, PubMed:11146000, PubMed:27481942, PubMed:17962520, PubMed:18547522). Mainly palmitoylated at Cys-341 (PubMed:2540197, PubMed:17962520, PubMed:18547522). Palmitoylation may reduce accessibility of phosphorylation sites by anchoring the receptor to the plasma membrane. Agonist stimulation promotes depalmitoylation and further allows Ser-345 and Ser-346 phosphorylation (PubMed:11146000). Also undergoes transient, ligand-induced palmitoylation at Cys-265 probably by ZDHHC9, ZDHHC14 and ZDHHC18 within the Golgi (PubMed:27481942). Palmitoylation at Cys-265 requires phosphorylation by PKA and receptor internalization and stabilizes the receptor (PubMed:27481942). Could be depalmitoylated by LYPLA1 at the plasma membrane (PubMed:27481942).
Phosphorylated by PKA and BARK upon agonist stimulation, which mediates homologous desensitization of the receptor. PKA-mediated phosphorylation seems to facilitate phosphorylation by BARK.
Phosphorylation of Tyr-141 is induced by insulin and leads to supersensitization of the receptor.
Polyubiquitinated (PubMed:23166351). Agonist-induced ubiquitination leads to sort internalized receptors to the lysosomes for degradation (PubMed:19424180, PubMed:20559325, PubMed:23166351). Deubiquitination by USP20 and USP33, leads to ADRB2 recycling and resensitization after prolonged agonist stimulation. USP20 and USP33 are constitutively associated and are dissociated immediately after agonist stimulation. Ubiquitination by the VHL-E3 ligase complex is oxygen-dependent.
The Gly-16 allele is overrepresented in individuals affected by nocturnal asthma as compared to controls, and appears to be an important genetic factor in the expression of this asthmatic phenotype.
Belongs to the uracil-DNA glycosylase (UDG) superfamily. SMUG1 family.
Recognizes base lesions in the genome and initiates base excision DNA repair. Acts as a monofunctional DNA glycosylase specific for uracil (U) residues in DNA with a preference for single-stranded DNA substrates. The activity is greater toward mismatches (U/G) compared to matches (U/A). Excises uracil (U), 5-formyluracil (fU) and uracil derivatives bearing an oxidized group at C5 [5-hydroxyuracil (hoU) and 5-hydroxymethyluracil (hmU)] in ssDNA and dsDNA, but not analogous cytosine derivatives (5-hydroxycytosine and 5-formylcytosine), nor other oxidized bases. The activity is damage-specific and salt-dependent. The substrate preference is the following: ssDNA > dsDNA (G pair) = dsDNA (A pair) at low salt concentration, and dsDNA (G pair) > dsDNA (A pair) > ssDNA at high salt concentration.
Associates with GIRK1 to form a G-protein-activated heteromultimer pore-forming unit. Interacts (via PDZ-binding motif) with SNX27 (via PDZ domain); the interaction is required when endocytosed to prevent degradation in lysosomes and promote recycling to the plasma membrane (By similarity).
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ9 subfamily.
The PDZ-binding motif specifically binds the PDZ domain of SNX27: the specificity for SNX27 is provided by the 2 residues located upstream (Glu-388 and Ser-389) of the PDZ-binding motif.
This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium (By similarity).
May be up-regulated in malignant colon cancers, compared to normal colon and colon adenomas. Expression is also elevated in other common cancer types, including breast, lung, uterus, and ovary.
May play a role in the regulation of cellular reactive oxygen species metabolism. May participate in cell growth regulation.
Up-regulated in peripheral blood mononuclear cells following Epstein-Barr virus (EBV) infection or following transfection with EBV LMP1 protein.
Acts as an adapter protein that plays a role in intracellular signaling cascades triggered either by the cell surface activated epidermal growth factor receptor and/or cytoplasmic protein tyrosine kinases. Promotes activation of the MAPK/ERK signaling pathway. Plays a role in the regulation of cell proliferation.
Isoform 1 interacts with EGFR. Isoform 1 interacts (via proline-rich domain and phosphorylated at Tyr-105 and Tyr-453) with GRB2 (via SH3 domains); the interaction occurs upon EGF stimulation. Isoform 1 interacts (phosphorylated at Tyr-453) with PTPN11; the interaction increases MAPK/ERK activity and does not affect the GRB2/SOS complex formation. Isoform 2 does not interact with GRB2.
On EGF stimulation, phosphorylated on Tyr-105 and Tyr-453.
ADP-ribosylated on Ser-104 in response to DNA damage.
Both the unedited and the RNA edited versions are induced by butyrate (at protein level). Only RNA edited version is induced by DTT, vinblastine or TNF (at protein level).
Histones H1 are necessary for the condensation of nucleosome chains into higher-order structures. The histones H1.0 are found in cells that are in terminal stages of differentiation or that have low rates of cell division.
Partially edited. In approximately 3.6% of the mRNA molecules, a new initiator methionine is created by a single uridine insertion in the 5'-UTR, causing an N-terminal extension of 99 amino acids. The existence of the RNA edited version is supported by direct protein sequencing by MS/MS of the following peptides specific to that version: 12-21; 22-33; 37-47; 48-67; 68-83; 84-94 and 97-113. The RNA edited version is called ET-H1.0.
Phosphorylated on Ser-17 in RNA edited version.
(Microbial infection) Acts as a receptor for Lassa virus glycoprotein (PubMed:24970085, PubMed:25972533, PubMed:27605678, PubMed:28448640). Promotes also fusion of the virus with host membrane in less acidic endosomes (PubMed:29295909).
(Microbial infection) Interacts with Lassa virus protein glycoprotein.
(Microbial infection) The glycosylation of Asn-76 is essential for Lassa virus entry into cells.
Interacts with ABCB9; this interaction strongly stabilizes ABCB9 and protects ABCB9 against lysosomal degradation (PubMed:22641697). Interacts with FURIN (PubMed:32295904). Interacts with TMEM175; inhibiting the proton channel activity of TMEM175 (PubMed:37390818).
Lysosomal membrane glycoprotein which plays an important role in lysosome biogenesis, lysosomal pH regulation, autophagy and cholesterol homeostasis (PubMed:37390818). Acts as an important regulator of lysosomal lumen pH regulation by acting as a direct inhibitor of the proton channel TMEM175, facilitating lysosomal acidification for optimal hydrolase activity (PubMed:37390818). Also plays an important role in NK-cells cytotoxicity (PubMed:2022921, PubMed:23632890). Mechanistically, participates in cytotoxic granule movement to the cell surface and perforin trafficking to the lytic granule (PubMed:23632890). In addition, protects NK-cells from degranulation-associated damage induced by their own cytotoxic granule content (PubMed:23847195). Presents carbohydrate ligands to selectins (PubMed:7685349).
O- and N-glycosylated; some of the 18 N-linked glycans are polylactosaminoglycans.
Associates with the 60S ribosomal subunit of the 80S translational complex.
Belongs to the peptidase M24A family. Methionine aminopeptidase type 1 subfamily.
Binds 2 divalent metal cations per subunit. Has a high-affinity and a low affinity metal-binding site. The true nature of the physiological cofactor is under debate. The enzyme is active with zinc, cobalt, manganese or divalent iron ions. Has high activity with zinc; zinc cofactor is transferred into the active site region by the ZNG1 zinc chaperone.
Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). Required for normal progression through the cell cycle.
Monomer; monomeric form has weak exonuclease activity. Homodimer; homodimeric form is unsure but has much higher exonuclease activity, suggesting that it could homodimerize upon DNA-binding. Interacts with the replication protein A (RPA) complex.
Single-stranded DNA (ssDNA) bidirectional exonuclease involved in DNA repair. Probably involved in DNA repair following ultraviolet (UV) irradiation and interstrand cross-links (ICLs) damage. Has both 5'-3' and 3'-5' exonuclease activities with a strong preference for 5'-ends. Acts as a sliding exonuclease that loads at ssDNA ends and then slides along the ssDNA prior to cutting; however the sliding and the 3'-5' exonuclease activities are abolished upon binding to the replication protein A (RPA) complex that enforces 5'-directionality activity.
Brain and spinal cord. Isoform 2 is expressed in testis and brain, but not detected in lung, liver or spleen.
Composed of an N-terminal domain that binds Munc18-1 and LIN-2/CASK, a middle phosphotyrosine-binding domain (PID/PTB) that mediates binding with the cytoplasmic domain of the amyloid-beta precursor protein, and two C-terminal PDZ domains thought to attach proteins to the plasma membrane.
Part of a multimeric complex containing STXBP1 and STX1A. Interacts with STXBP1 (By similarity). Also part of the brain-specific heterotrimeric complex LIN-10/X11-alpha, LIN-2/CASK, and LIN7. Component of the brain-specific heterotrimeric complex (LIN-10-LIN-2-LIN-7 complex) composed of at least APBA1, CASK, and LIN7, which associates with the motor protein KIF17 to transport vesicles along microtubules (By similarity). Within the complex, interacts (via PDZ domain) with the motor protein KIF17; the interaction is direct and is required for association of KIF17 with the cargo that is to be transported (By similarity). Both isoform 1 and isoform 2 bind to the cytoplasmic domain of amyloid protein (APP). Interacts (via PDZ 1 and 2 domains) with FSPB. Isoform 2, but not isoform 1, interacts (via its truncated PID domain) with active, GTP-bound RAB6A and RAB6B.
Putative function in synaptic vesicle exocytosis by binding to Munc18-1, an essential component of the synaptic vesicle exocytotic machinery. May modulate processing of the amyloid-beta precursor protein (APP) and hence formation of APP-beta. Component of the LIN-10-LIN-2-LIN-7 complex, which associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules (By similarity).
The PID domain, truncated by 11 amino acids, as observed in isoform 2, but not full-length, mediates the interaction with RAB6A and RAB6B.
The autoinhibitory helix linker occludes the APP binding site.
This isoform interacts with RAB6 GTPases.
Probably involved in membrane protein trafficking.
Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. May contribute to epidermal cell positioning (stratification) by mediating differential adhesiveness between cells that express different isoforms. Linked to the keratinization of epithelial tissues.
Strongly expressed in epidermis, less in lymph node and tongue.
Detected in bone marrow, thymus and spleen.
Interacts with RHOA (PubMed:20400958). Interacts with RAC1 (PubMed:7512369). Interacts with RAC2 (PubMed:10655614). Interacts with CDC42 (PubMed:7512369).
Regulates the GDP/GTP exchange reaction of the Rho proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them (PubMed:8356058, PubMed:7512369). Regulates reorganization of the actin cytoskeleton mediated by Rho family members (PubMed:8262133).
Interacts with members of the heat shock protein 70 families; these proteins may possibly be methylation substrates for the enzyme.
Cilium- and flagellum-specific protein that plays a role in axonemal structure organization and motility. May play a role in outer and inner dynein arm assembly.
GTPase activating protein that acts on ARF1. Can also activate ARF6 (in vitro). May play a role in clathrin-dependent retrograde transport from early endosomes to the trans-Golgi network (By similarity).
Interacts with ARF1. Interacts with PICALM and clathrin heavy chains (By similarity).
Serine protease inhibitor with activity toward thrombin, trypsin, and urokinase. Promotes neurite extension by inhibiting thrombin. Binds heparin.
Interacts with NOTCH4. Interacts (via N-terminal DSL and MNNL domains) with NOTCH1 (via EGF-like domains).
Involved in the Notch signaling pathway as Notch ligand (PubMed:11134954). Activates NOTCH1 and NOTCH4. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting (PubMed:20616313). Essential for retinal progenitor proliferation. Required for suppressing rod fates in late retinal progenitors as well as for proper generation of other retinal cell types (By similarity). During spinal cord neurogenesis, inhibits V2a interneuron fate (PubMed:17728344).
The Delta-Serrate-Lag2 (DSL) domain is required for binding to the Notch receptor.
Homodimer (By similarity). Can also form heterodimers (By similarity). Interacts with SYT1 (By similarity).
Phosphorylation of Ser-97 is required for mossy-fiber long-term potentiation.
Synaptic vesicle phosphoprotein that enhances spontaneous neurotransmitter release but does not effect induced neurotransmitter release (By similarity). Unlike other synaptotagmins, it does not bind Ca(2+) or phospholipids (By similarity). Essential for mossy-fiber long-term potentiation in the hippocampus (By similarity).
Interacts with ASTN1; the interaction is not calcium-dependent.
Mediates recycling of the neuronal cell adhesion molecule ASTN1 to the anterior pole of the cell membrane in migrating neurons. Promotes ASTN1 internalization and intracellular transport of endocytosed ASTN1 (By similarity). Selectively binds inositol-4,5-bisphosphate, inositol-3,4,5-trisphosphate and inositol-1,3,4,5-tetrakisphosphate, suggesting it is recruited to membranes that contain lipids with a phosphoinositide headgroup (Ref.6).
The C-terminal region after the fibronectin type-III domain presents structural similarity to annexin domains and binds calcium ions.
Component of the mitochondrial small ribosomal subunit (mt-SSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (PubMed:25838379). Interacts with METTL17 (By similarity).
(Microbial infection) Interacts (via C-terminus) with human cytomegalovirus/HHV-5 protein UL69.
(Microbial infection) Interacts (via C-terminus) with human respiratory syncytial virus (HRSV) M2-1 protein.
(Microbial infection) Positively regulates the replication of dengue virus (DENV).
Binds the poly(A) tail of mRNA, including that of its own transcript, and regulates processes of mRNA metabolism such as pre-mRNA splicing and mRNA stability (PubMed:11051545, PubMed:17212783, PubMed:25480299). Its function in translational initiation regulation can either be enhanced by PAIP1 or repressed by PAIP2 (PubMed:11051545, PubMed:20573744). Can probably bind to cytoplasmic RNA sequences other than poly(A) in vivo. Binds to N6-methyladenosine (m6A)-containing mRNAs and contributes to MYC stability by binding to m6A-containing MYC mRNAs (PubMed:32245947). Involved in translationally coupled mRNA turnover (PubMed:11051545). Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain (PubMed:11051545). Involved in regulation of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons; for the recognition of premature termination codons (PTC) and initiation of NMD a competitive interaction between UPF1 and PABPC1 with the ribosome-bound release factors is proposed (PubMed:18447585). By binding to long poly(A) tails, may protect them from uridylation by ZCCHC6/ZCCHC11 and hence contribute to mRNA stability (PubMed:25480299).
Many viruses shutoff host mRNA translational machinery by inhibiting cellular PABPC1 activity using different mechanisms. Picornaviruses, caliciviruses or lentiviruses encode proteases that cleave PABPC1 at several defined sites in the proline-rich linker region between RRMs and the C-terminal domain. Rotaviruses, gammherpesviruses and bunyamwera virus relocalize PABPC1 from the cytoplasm to the nucleus thus altering its function. Many of these viruses translate their mRNA in a PABPC1-independent manner and are unaffected by host PABPC1 inhibition.
May form homodimers. Component of a multisubunit autoregulatory ribonucleoprotein complex (ARC), at least composed of IGF2BP1, PABPC1 and CSDE1 (PubMed:16356927). Directly interacts with IGF2BP1; the interaction is enhanced by SEPIN14P20 peptide RBPR (PubMed:32245947, PubMed:29476152). Part of a complex associated with the FOS mCRD domain and consisting of HNRPD, SYNCRIP, PAIP1 and CSDE1/UNR (PubMed:11051545). Interacts with the PABPC1-interacting motif-1 (PAM1) and -2 (PAM2) of PAIP1 and PAIP2 (PubMed:9548260, PubMed:11172725, PubMed:11438674, PubMed:11997512, PubMed:11287632, PubMed:20096703, PubMed:33876849). Interacts with PAIP1 with a 1:1 stoichiometry and with PAIP2 with a 1:2 stoichiometry. The interaction with CSDE1 is direct and RNA-independent. Found in a mRNP complex with YBX2 (By similarity). Interacts with TENT2/GLD2 (By similarity). Identified in the spliceosome C complex (PubMed:11991638). Identified in a mRNP complex, at least composed of DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1. The interaction with DDX3X is direct and RNA-independent (PubMed:18596238, PubMed:21883093, PubMed:22872150). This interaction increases in stressed cells and decreases during cell recovery (PubMed:21883093). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with NXF1/TAP (PubMed:17267499, PubMed:18596238). Interacts with PIWIL1 (By similarity). Interacts with AGO1, AGO2, GSPT1 and GSPT2 (PubMed:17932509, PubMed:18447585, Ref.63). Interacts with LARP4B (Ref.65). Interacts (via the second and third RRM domains and the C-terminus) with PAIP2B (via central acidic portion and C-terminus) (PubMed:16804161, PubMed:11287632). Forms a complex with LARP1 and SHFL (PubMed:20430826, PubMed:24532714, PubMed:25940091, PubMed:26735137). Interacts with LARP4 (PubMed:21098120). Interacts with ZFC3H1 in a RNase-sensitive manner (PubMed:27871484). Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner (PubMed:23125361). Interacts with TENT5C; the interaction has no effect on TENT5C poly(A) polymerase function (PubMed:28931820). Interacts with G3BP1 and G3BP2 (PubMed:23279204). Interacts with ENDOV; the interaction is RNA-dependent and stimulates ENDOV activity (PubMed:27573237). Interacts with UPF1; the interaction is RNA-dependent (PubMed:25220460). Interacts with IGF2BP2 and IGF2BP3 (PubMed:29476152). May interact with SETX (PubMed:21700224). Interacts with RBM46 (By similarity). Interacts with PAN3 isoform 1/Pan3L and isoform 3/Pan3S (via N-terminus); interaction with isoform 1 is less efficient than with isoform 3 (PubMed:28559491).
Methylated by CARM1. Arg-493 is dimethylated, probably to asymmetric dimethylarginine.
The RNA-binding domains RRM1 and RRM2 and the C-terminus (last 138 amino acids) regions interact with the PABPC1-interacting motif-1 (PAM1) and -2 (PAM2) of PAIP1, respectively.
The RNA-binding domains RRM2 and RRM3 and the C-terminus (last 138 amino acids) regions interact with the PABPC1-interacting motif-1 (PAM1) and -2 (PAM2) of PAIP2, respectively.
Was termed (Ref.5) polyadenylate binding protein II.
Orphan receptor with constitutive G(s) signaling activity that activate cyclic AMP. Promotes neurite outgrowth and blocks myelin inhibition in neurons (By similarity).
Was originally (PubMed:12220620) thought to be a receptor for sphingosine 1-phosphate. It has been demonstrated that it is not the case (PubMed:19286662).
(Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein Tax; this interaction inhibits the host nonsense-mediated mRNA decay (NMD).
Found in a post-splicing messenger ribonucleoprotein (mRNP) complex (PubMed:21419344). Associates with the exon junction complex (EJC) (PubMed:11546874, PubMed:16452507). Associates with the SGM1C complex; is phosphorylated by the complex kinase component SGM1 (PubMed:19417104). Part of a complex composed of SMG1, DHX34 and UPF1; within the complex DHX34 acts as a scaffolding protein to facilitate SMG1 phosphorylation of UPF1 (PubMed:26841701). Interacts with UPF2 (PubMed:11163187, PubMed:11073994, PubMed:11113196, PubMed:19556969). Interacts with UPF3A and UPF3B (PubMed:11163187). Interacts with EST1A (PubMed:12554878). Interacts with SLBP (PubMed:16086026). Interacts (when hyperphosphorylated) with PNRC2 (PubMed:19150429). Interacts with AGO1 and AGO2 (PubMed:17932509). Interacts with GSPT2 (PubMed:18447585). Interacts with isoform 1 and isoform 5 of ADAR/ADAR1 (PubMed:18362360). Interacts with SMG7 (PubMed:15721257). Interacts with ZC3H12A; this interaction occurs in a mRNA translationally active- and termination-dependent manner and is essential for ZC3H12A-mediated degradation of target mRNAs (PubMed:26000482). Interacts with CPSF6 (PubMed:19864460). Interacts with MOV10; the interaction is direct and RNA-dependent (PubMed:24726324). Interacts with SHFL; the interaction increases in the presence of RNA (PubMed:27974568). Interacts with UPF2 and DDX4; interactions are mediated by TDRD6 (PubMed:25220460). Interacts with DHX34 and PABPC1/PABP1; the interactions are RNA-independent (PubMed:25220460). Interacts with RBM46 (By similarity).
Phosphorylated by SMG1; required for formation of mRNA surveillance complexes.
RNA-dependent helicase required for nonsense-mediated decay (NMD) of aberrant mRNAs containing premature stop codons and modulates the expression level of normal mRNAs (PubMed:11163187, PubMed:16086026, PubMed:18172165, PubMed:21145460, PubMed:21419344, PubMed:24726324). Is recruited to mRNAs upon translation termination and undergoes a cycle of phosphorylation and dephosphorylation; its phosphorylation appears to be a key step in NMD (PubMed:11544179, PubMed:25220460). Recruited by release factors to stalled ribosomes together with the SMG1C protein kinase complex to form the transient SURF (SMG1-UPF1-eRF1-eRF3) complex (PubMed:19417104). In EJC-dependent NMD, the SURF complex associates with the exon junction complex (EJC) (located 50-55 or more nucleotides downstream from the termination codon) through UPF2 and allows the formation of an UPF1-UPF2-UPF3 surveillance complex which is believed to activate NMD (PubMed:21419344). Phosphorylated UPF1 is recognized by EST1B/SMG5, SMG6 and SMG7 which are thought to provide a link to the mRNA degradation machinery involving exonucleolytic and endonucleolytic pathways, and to serve as adapters to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation and allowing the recycling of NMD factors (PubMed:12554878). UPF1 can also activate NMD without UPF2 or UPF3, and in the absence of the NMD-enhancing downstream EJC indicative for alternative NMD pathways (PubMed:18447585). Plays a role in replication-dependent histone mRNA degradation at the end of phase S; the function is independent of UPF2 (PubMed:16086026, PubMed:18172165). For the recognition of premature termination codons (PTC) and initiation of NMD a competitive interaction between UPF1 and PABPC1 with the ribosome-bound release factors is proposed (PubMed:18447585, PubMed:25220460). The ATPase activity of UPF1 is required for disassembly of mRNPs undergoing NMD (PubMed:21145460). Together with UPF2 and dependent on TDRD6, mediates the degradation of mRNA harboring long 3'UTR by inducing the NMD machinery (By similarity). Also capable of unwinding double-stranded DNA and translocating on single-stranded DNA (PubMed:30218034).
The [ST]-Q motif constitutes a recognition sequence for kinases from the PI3/PI4-kinase family.
5' to 3' helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction (PubMed:19158098, PubMed:30218034, PubMed:22999958). Specific to 5'-phosphorylated single-stranded guanine-rich sequences (PubMed:8349627, PubMed:22999958). May play a role in RNA metabolism, ribosome biogenesis or initiation of translation (PubMed:19299493, PubMed:19158098). May play a role in regulation of transcription (By similarity). Interacts with tRNA-Tyr (PubMed:19299493).
Expressed in all tissues examined. Expressed in the developing and adult human brain, with highest expression in the cerebellum. Moderately expressed in fibroblasts.
Homooligomer (PubMed:19299493). Interacts with RUVBL1 (PubMed:19299493). Interacts with RUVBL2 (PubMed:19299493). Interacts with GTF3C1 (PubMed:19299493). Interacts with ABT1 (PubMed:19299493). Interacts with ribosomes (PubMed:19158098).
The R3H domain recognizes phosphorylated 5'-ends of single-stranded nucleic acids which promotes binding of nucleic acids and stimulates ATPase activity.
Can form homodimers. Interacts (via C-terminus) with MAP1LC3B. Interacts with RAB7A; the interaction with RAB7A induces FYCO1 recruitment to late endosomal/lysosomal compartments. Interacts with MAP1LC3B (By similarity).
May mediate microtubule plus end-directed vesicle transport.
The disease is caused by variants affecting the gene represented in this entry. Pathogenic mutations in FYCO1 can affect intracellular transport of autophagocytic vesicles from the perinuclear area to the periphery, leading to an accumulation of large numbers of vesicles and hence loss of lens transparency (PubMed:21636066).
E3 ubiquitin-protein ligase that regulates several biological processes through the ubiquitin-mediated proteasomal degradation of various target proteins. Ubiquitinates the caspases CASP8 and CASP10, promoting their proteasomal degradation, to negatively regulate cell death downstream of death domain receptors in the extrinsic pathway of apoptosis (PubMed:15069192). May mediate 'Lys-48'-linked polyubiquitination of RIPK1 and its subsequent proteasomal degradation thereby indirectly regulating the tumor necrosis factor-mediated signaling pathway (Ref.13). Negatively regulates p53/TP53 through its direct ubiquitination and targeting to proteasomal degradation (PubMed:17121812). Indirectly, may also negatively regulate p53/TP53 through ubiquitination and degradation of SFN (PubMed:18382127). Mediates PPARGC1A proteasomal degradation probably through ubiquitination thereby indirectly regulating the metabolism of brown fat cells (PubMed:22064484). Possibly involved in innate immunity, through 'Lys-48'-linked polyubiquitination of NOD1 and its subsequent proteasomal degradation (PubMed:25012219).
Interacts with CASP8 and CASP10. Interacts (via RING-type zinc finger) with PPARGC1A. Interacts with NOD1. Interacts with p53/TP53; involved in p53/TP53 ubiquitination. Interacts (via RING-type zinc finger) with MDM2; the interaction stabilizes MDM2.
Proteolytically cleaved by caspases upon induction of apoptosis by TNF.
The FYVE-type zinc finger domain is required for localization and may confer affinity for cellular compartments enriched in phosphatidylinositol 5-phosphate and phosphatidylinositol 3-phosphate phospholipids.
The RING-type zinc finger is required for the ubiquitination of target proteins.
Ubiquitous. Detected in heart, brain, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, colon and leukocytes.
E3 ubiquitin protein ligase that is part of an apoptotic signaling pathway activated by endoplasmic reticulum stress (PubMed:23896122). Stimulates the expression of proteins specific of the unfolded protein response (UPR), ubiquitinates BNIP1 and regulates its localization to the mitochondrion and induces calcium release from the endoplasmic reticulum that ultimately leads to cell apoptosis (PubMed:23896122). Plays a role in the maintenance of intestinal homeostasis and clearance of enteric pathogens. Upon NOD2 stimulation, ubiquitinates the ER stress sensor activating transcription factor 6/ATF6 and promotes the unfolded protein response UPR (PubMed:34623328). Participates in basal level of autophagy maintenance by regulating the ubiquitination of EPHB2 and EPHB3. Upon stimulation by ligand EFNB1, ubiquitinates EPHB2 and further recruits MAP1LC3B for autophagy induction (PubMed:33280498). Controls nutrient sensing by ubiquitinating Sestrin-2/SESN2, which is an intracellular sensor of cytosolic leucine and inhibitor of mTORC1 activity (PubMed:31586034).
Polyubiquitinated. 'Lys-29'-linked autoubiquitination leads to proteasomal degradation.
The RING-type domain is required for ubiquitination.
Catalyzes the hydrolysis of S-adenosyl-L-homocysteine to form adenosine and homocysteine (PubMed:10933798). Binds copper ions (By similarity).
Homotetramer (PubMed:9586999, PubMed:28647132, PubMed:19177456). Interaction with AHCYL1 (PubMed:28647132).
Identified in the spliceosome A complex; remains associated with the spliceosome throughout the splicing process (PubMed:10490618). Component of the spliceosome B complex (PubMed:28781166). Identified in the spliceosome C complex (PubMed:11991638). Identified in the spliceosome E complex (PubMed:10882114). Component of the minor spliceosome, also called U12-type spliceosome (PubMed:15146077, PubMed:33509932). Within this complex, interacts with SCNM1 (PubMed:33509932). Component of splicing factor SF3B complex which is composed of at least eight subunits; SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6, PHF5A and DDX42 (PubMed:12234937, PubMed:12738865, PubMed:28541300, PubMed:27720643). SF3B associates with the splicing factor SF3A and a 12S RNA unit to form the U2 small nuclear ribonucleoproteins complex (U2 snRNP). Interaction between SF3B3 and SF3B1 is tighter than the interaction between SF3B3 and SF3B2 (PubMed:12234937). Within the SF3B complex interacts directly with SF3B1 (via HEAT domain), SF3B5 and PHF5A (PubMed:27720643). The SF3B complex composed of SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6 and PHF5A interacts with U2AF2 (PubMed:27720643). Associates with the STAGA transcription coactivator-HAT complex. Interacts with SUPT3H (PubMed:11564863). Interacts with TAF3 (PubMed:11438666).
Involved in pre-mRNA splicing as a component of the splicing factor SF3B complex, a constituent of the spliceosome (PubMed:10490618, PubMed:10882114, PubMed:27720643, PubMed:28781166). SF3B complex is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA (PubMed:12234937). May also be involved in the assembly of the 'E' complex (PubMed:10882114). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (PubMed:15146077) (Probable).
The core of the protein consists of three beta-propeller domains.
Cell adhesion molecule which is required for leukocyte transendothelial migration (TEM) under most inflammatory conditions (PubMed:19342684, PubMed:17580308). Tyr-690 plays a critical role in TEM and is required for efficient trafficking of PECAM1 to and from the lateral border recycling compartment (LBRC) and is also essential for the LBRC membrane to be targeted around migrating leukocytes (PubMed:19342684). Trans-homophilic interaction may play a role in endothelial cell-cell adhesion via cell junctions (PubMed:27958302). Heterophilic interaction with CD177 plays a role in transendothelial migration of neutrophils (PubMed:17580308). Homophilic ligation of PECAM1 prevents macrophage-mediated phagocytosis of neighboring viable leukocytes by transmitting a detachment signal (PubMed:12110892). Promotes macrophage-mediated phagocytosis of apoptotic leukocytes by tethering them to the phagocytic cells; PECAM1-mediated detachment signal appears to be disabled in apoptotic leukocytes (PubMed:12110892). Modulates bradykinin receptor BDKRB2 activation (PubMed:18672896). Regulates bradykinin- and hyperosmotic shock-induced ERK1/2 activation in endothelial cells (PubMed:18672896). Induces susceptibility to atherosclerosis (By similarity).
Expressed on platelets and leukocytes and is primarily concentrated at the borders between endothelial cells (PubMed:18388311, PubMed:21464369). Expressed in human umbilical vein endothelial cells (HUVECs) (at protein level) (PubMed:19342684, PubMed:17580308). Expressed on neutrophils (at protein level) (PubMed:17580308). Isoform Long predominates in all tissues examined (PubMed:12433657). Isoform Delta12 is detected only in trachea (PubMed:12433657). Isoform Delta14-15 is only detected in lung (PubMed:12433657). Isoform Delta14 is detected in all tissues examined with the strongest expression in heart (PubMed:12433657). Isoform Delta15 is expressed in brain, testis, ovary, cell surface of platelets, human umbilical vein endothelial cells (HUVECs), Jurkat T-cell leukemia, human erythroleukemia (HEL) and U-937 histiocytic lymphoma cell lines (at protein level) (PubMed:12433657, PubMed:18388311).
Palmitoylation by ZDHHC21 is necessary for cell surface expression in endothelial cells and enrichment in membrane rafts.
Phosphorylated on Ser and Tyr residues after cellular activation by src kinases (PubMed:21464369, PubMed:9298995, PubMed:19342684, PubMed:18710921). Upon activation, phosphorylated on Ser-729 which probably initiates the dissociation of the membrane-interaction segment (residues 709-729) from the cell membrane allowing the sequential phosphorylation of Tyr-713 and Tyr-690 (PubMed:21464369). Constitutively phosphorylated on Ser-734 in resting platelets (PubMed:21464369). Phosphorylated on tyrosine residues by FER and FES in response to FCER1 activation (By similarity). In endothelial cells Fyn mediates mechanical-force (stretch or pull) induced tyrosine phosphorylation (PubMed:18710921).
The Ig-like C2-type domains 2 and 3 contribute to formation of the complex with BDKRB2 and in regulation of its activity.
Trans-homodimer (via Ig-like C2-type 1 and Ig-like C2-type 2 domains); trans-homodimerization is required for cell-cell interaction (PubMed:26702061, PubMed:27958302). Forms a complex with BDKRB2 and GNAQ (PubMed:18672896). Interacts with BDKRB2 and GNAQ (PubMed:18672896).Interacts with PTPN11; Tyr-713 is critical for PTPN11 recruitment (PubMed:18388311, PubMed:19342684). Interacts with FER (By similarity). Interacts (via Ig-like C2-type domain 6) with CD177; the interaction is Ca(2+)-dependent; the interaction is direct (PubMed:17580308).
Histone methyltransferase that specifically trimethylates 'Lys-20' of histone H4 to form trimethylated histone H4 lysine 20 (H4K20me3) which represents a specific tag for epigenetic transcriptional repression (By similarity). In association with the NCoR corepressor complex, is involved in the repression of toll-like receptor 4 (TLR4)-target inflammatory genes in macrophages by catalyzing the formation of H4K20me3 at the gene promoters (By similarity). Plays an important role in embryonic stem (ES) cell self-renewal and differentiation (By similarity). Promotes ES cell maintenance by silencing differentiation genes through deposition of H4K20me3 marks (By similarity). Maintains genome stability of ES cells during differentiation through regulation of heterochromatin formation and repression of endogenous repetitive DNA elements by depositing H4K20me3 marks (PubMed:28951459).
Interacts with the N-CoR complex (By similarity). Interacts with EHMT2 and CBX5 (By similarity).
Interacts with SKI. Interacts (via LRR repeat) with CDC42BPA (via AGC-kinase C-terminal domain), CDC42BPB (via AGC-kinase C-terminal domain) and LIMK1 (via LIM zinc-binding domains). Forms a tripartite complex with CDC42BPA, CDC42BPB and LIMK1.
Negatively regulates TGF-beta-induced signaling; in cooperation with SKI prevents the translocation of SMAD2 from the nucleus to the cytoplasm in response to TGF-beta. Acts as an adapter that mediates the specific recognition of LIMK1 by CDC42BPA and CDC42BPB in the lamellipodia. LRAP25-mediated CDC42BPA/CDC42BPB targeting to LIMK1 and the lamellipodium results in LIMK1 activation and the subsequent phosphorylation of CFL1 which is important for lamellipodial F-actin regulation.
Potential role in vesicular protein trafficking, mainly in the early secretory pathway. Required for the maintenance of the Golgi apparatus; involved in protein exchange between Golgi stacks during assembly. Probably not required for COPI-vesicle-mediated retrograde transport.
Belongs to the EGF-CFC (Cripto-1/FRL1/Cryptic) family.
This gene differs from CFC1 by only one residue at position 78:R -> W. R78W is also thought to be a CFC1 polymorphism.
A chromosomal aberration involving BCAS3 has been found in some breast carcinoma cell lines. Translocation t(17;20)(q23;q13) with BCAS4.
Expressed in stomach, liver, lung, kidney, prostate, testis, thyroid gland, adrenal gland, brain, heart, skeletal muscle, colon, spleen, small intestine, placenta, blood leukocyte and mammary epithelial cells. Expressed in undifferentiated ES cells. Expressed in blood islands and nascent blood vessels derived from differentiated ES cells into embryoid bodies (BD). Expressed in endothelial cells. Not detected in brain. Expressed in brain tumors (at protein level). Expressed in brain. Highly expressed in breast cancers and in glioma cell lines.
Has been proposed to contain 7 WD repeats. This prediction could not be reproduced.
Interacts with histone H3, ESR1, KAT2B and PELP1; the interactions occur in a estrogen-dependent manner. Interacts with beta-tubulin and VIM. Interacts (via C-terminal) with PHAF1; the interaction is requrired for the association with the phagophore (PubMed:33499712).
Plays a role in angiogenesis. Participates in the regulation of cell polarity and directional endothelial cell migration by mediating both the activation and recruitment of CDC42 and the reorganization of the actin cytoskeleton at the cell leading edge. Promotes filipodia formation (By similarity). Functions synergistically with PELP1 as a transcriptional coactivator of estrogen receptor-responsive genes. Stimulates histone acetyltransferase activity. Binds to chromatin. Plays a regulatory role in autophagic activity. In complex with PHAF1, associates with the preautophagosomal structure during both non-selective and selective autophagy (PubMed:33499712). Probably binds phosphatidylinositol 3-phosphate (PtdIns3P) which would mediate the recruitment preautophagosomal structures (PubMed:33499712).
Component of heteromultimeric potassium channels. Identified in potassium channel complexes containing KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (By similarity). Part of a heterooctamer composed of the tetrameric channel and four KCNIP1 chains. Interacts with KCND3 and the N-terminal domain of KCND2. Probably part of a complex consisting of KCNIP1, KCNIP2 isoform 3 and KCND2. Self-associates to form homodimers and homotetramers. Interacts with KCNIP2 isoform 3 in a calcium-dependent manner. Interacts with Naja atra venom CTX3.
Isoform 1 and isoform 2 are expressed in brain and kidney. Isoform 1 is also expressed in liver, pancreas, skeletal muscle, small intestine and testis. Isoform 2 is also expressed in lung, pancreas, leukocytes, prostate and thymus.
Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels. Regulates channel density, inactivation kinetics and rate of recovery from inactivation in a calcium-dependent and isoform-specific manner. In vitro, modulates KCND1/Kv4.1 and KCND2/Kv4.2 currents. Increases the presence of KCND2 at the cell surface.
Expressed in colon, prostate, spleen, testis, ovary, thymus and small intestine. Weakly expressed in leukocytes.
Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. Bind to single-stranded DNA (ssDNA) and has DNA-dependent ATPase activity. Part of the RAD51 paralog protein complex BCDX2 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, BCDX2 acts downstream of BRCA2 recruitment and upstream of RAD51 recruitment. BCDX2 binds predominantly to the intersection of the four duplex arms of the Holliday junction and to junction of replication forks. The BCDX2 complex was originally reported to bind single-stranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA. Involved in telomere maintenance. The BCDX2 subcomplex XRCC2:RAD51D can stimulate Holliday junction resolution by BLM.
Part of the BCDX2 complex consisting of RAD51B, RAD51C, RAD51D and XRCC2; the complex has a ring-like structure arranged into a flat disc around a central channel. In the absence of DNA, the BCDX2 subcomplex XRCC2:RAD51D formed a multimeric ring structure; in the presence of single-stranded DNA it formed a filamentous structure with the ssDNA. Interacts with SWSAP1 and ZSWIM7; involved in homologous recombination repair. Interacts with BLM; required for stimulation of BLM activity by the BCDX2 subcomplex XRCC2:RAD51D.
Functions as a calcium-regulated nucleotide exchange factor activating both Ras and RAC1 through the exchange of bound GDP for GTP. Preferentially activates HRAS in vivo compared to RRAS based on their different types of prenylation. Functions in synaptic plasticity by contributing to the induction of long term potentiation.
Homooligomer and heterooligomer with RASGRF1. Interacts with Ras and RAC1. Interacts in a calcium-dependent manner with calmodulin (By similarity). Interacts with CDK5R1 and EPB49. Interacts with the AMPA receptor through GRIA1 (By similarity). Interacts with microtubules (By similarity).
Phosphorylated by CDK5; down-regulates RASGRF2-mediated RAC1 activation.
The DH (DBL-homology) domain mediates interaction with RASGRF1 and EPB49 and is required for RAC1 activation.
The IQ domain mediates the calcium-dependent interaction with calmodulin but is dispensable for the Ras-GEF activity.
The Ras-GEF domain and the N-terminal Ras-GEF domain form a Ras-binding site and mediate Ras activation.
Ubiquitinated upon interaction with Ras. Ubiquitination leads to degradation through the 26S proteasome (By similarity).
Widely expressed with higher expression in brain, followed by heart, lung, pancreas and kidney. Detected in placenta. Expressed in brain and lung (at protein level).
Functions in endoplasmic reticulum to Golgi vesicle-mediated transport and regulates the proper organization of the endoplasmic reticulum and the Golgi (By similarity). Plays a key role in targeting to neuronal dendrites receptors such as HTR1A (By similarity). Plays also a role in primary cilium and sperm flagellum assembly probably through protein transport to these compartments (PubMed:33103737).
Interacts with HTR1A (via C-terminus). Interacts with ABCB9 (via TMD0); this interaction allows (but is not essential) the ER-to-Golgi trafficking and strongly depends on a salt bridge within TMD0 (PubMed:30877195).
Interacts with guanylate kinase-like domain of DLG1, DLG2, DLG3, DLG4 and AIP1. Interacts with the PDZ domain of SHANK1, SHANK2 and SHANK3. Found in a complex with DLG4 and SHANK1, SHANK2 or SHANK3. Found in a complex with DLG4 and BEGAIN. Interacts with DYL2 and LRFN1 (By similarity). Interacts with MPP2 (via the SH3-Guanylate kinase-like sub-module) (By similarity).
Part of the postsynaptic scaffold in neuronal cells.
Ubiquitinated by TRIM3; leading to proteasomal degradation.
Belongs to the class V-like SAM-binding methyltransferase superfamily. SETD3 actin-histidine methyltransferase family.
Phosphorylated by GSK3B, which is required for recognition by the SCF(FBXW7) complex and subsequent degradation.
Protein levels peak in S phase and are lowest during M phase (at protein level).
Protein-histidine N-methyltransferase that specifically mediates 3-methylhistidine (tele-methylhistidine) methylation of actin at 'His-73' (PubMed:30526847, PubMed:30626964, PubMed:30785395, PubMed:31388018, PubMed:31993215). Histidine methylation of actin is required for smooth muscle contraction of the laboring uterus during delivery (PubMed:30626964). Does not have protein-lysine N-methyltransferase activity and probably only catalyzes histidine methylation of actin (PubMed:30626964, PubMed:30785395, PubMed:31388018).
Shows protein-methionine methyltransferase activity in vitro on an actin mutant with a Met instead of a His residue at position 73.
The SET domain specifically recognizes and binds actin, suggesting that it does not accommodate substrates diverging from actin.
Ubiquitinated by the SCF(FBXW7) complex following phosphorylation by GSK3B, leading to its degradation by the proteasome.
Was initially reported to have histone methyltransferase activity and methylate 'Lys-4' and 'Lys-36' of histone H3 (H3K4me and H3K36me) (By similarity). However, this conclusion was based on mass spectrometry data wherin mass shifts were inconsistent with a bona fide methylation event (PubMed:30626964). In vitro, the protein-lysine methyltransferase activity is weak compared to the protein-histidine methyltransferase activity (PubMed:30526847).
Autophosphorylated (By similarity). Phosphorylated by ATM in response to DNA damage. Phosphorylated by LRRK2.
Highly expressed in the testis, and to a lower extent also expressed in brain, placenta, colon and skeletal muscle.
Proteolytically processed by caspase-3 (CASP3).
Self-associates. Interacts with MAP2K3 (By similarity). Interacts with SPRED1 (By similarity). Interacts with TESK1; the interaction inhibits TAOK1 kinase activity (By similarity). Interacts with MAP3K7.
Serine/threonine-protein kinase activity is inhibited by SPRED1.
Serine/threonine-protein kinase involved in various processes such as p38/MAPK14 stress-activated MAPK cascade, DNA damage response and regulation of cytoskeleton stability. Phosphorylates MAP2K3, MAP2K6 and MARK2. Acts as an activator of the p38/MAPK14 stress-activated MAPK cascade by mediating phosphorylation and subsequent activation of the upstream MAP2K3 and MAP2K6 kinases. Involved in G-protein coupled receptor signaling to p38/MAPK14. In response to DNA damage, involved in the G2/M transition DNA damage checkpoint by activating the p38/MAPK14 stress-activated MAPK cascade, probably by mediating phosphorylation of MAP2K3 and MAP2K6. Acts as a regulator of cytoskeleton stability by phosphorylating 'Thr-208' of MARK2, leading to activate MARK2 kinase activity and subsequent phosphorylation and detachment of MAPT/TAU from microtubules. Also acts as a regulator of apoptosis: regulates apoptotic morphological changes, including cell contraction, membrane blebbing and apoptotic bodies formation via activation of the MAPK8/JNK cascade. Plays an essential role in the regulation of neuronal development in the central nervous system (PubMed:33565190). Also plays a role in the regulation of neuronal migration to the cortical plate (By similarity).
Was initially thought to play a role in the spindle checkpoint (PubMed:17417629). However, it was later shown that it is not the case and that phenotypes initially observed are the cause of the siRNA used that has an off-target effect resulting in MAD2L1 inhibition (PubMed:19904549, PubMed:20162290).
Expressed in the heart, placenta, lung and pancreas.
Heterotetramer of two alpha-2 chains and two beta chains (P4HB) (the beta chain is the multi-functional PDI), where P4HB plays the role of a structural subunit; this tetramer catalyzes the formation of 4-hydroxyproline in collagen.
Inhibited by poly(L-proline) only at very high concentrations.
Interacts with IL9R. Interacts with IL2RG.
Multifunctional cytokine secreted mainly by T-helper 2 lymphocytes and also mast cells or NKT cells that plays important roles in the immune response against parasites (PubMed:29742432). Affects intestinal epithelial permeability and adaptive immunity (PubMed:29742432). In addition, induces the differentiation of specific T-cell subsets such as IL-17 producing helper T-cells (TH17) and also proliferation and differentiation of mast cells. Mechanistically, exerts its biological effects through a receptor composed of IL9R subunit and a signal transducing subunit IL2RG. Receptor stimulation results in the rapid activation of JAK1 and JAK3 kinase activities leading to STAT1, STAT3 and STAT5-mediated transcriptional programs. Induction of differentiation genes seems to be mediated by STAT1 alone, while protection of cells from apoptosis depends on STAT3 and STAT5.
Interacts with the C-terminal transactivation domain of PAX2 (By similarity). Forms a constitutive complex with PAGR1 independently of the MLL2/MLL3 complex (By similarity). Interacts with TP53BP1 (when phosphorylated at the N-terminus by ATM) (PubMed:15456759, PubMed:17690115, PubMed:23727112). Interacts with HLTF (PubMed:19723507). Component of the KMT2 family MLL2/MLL3 complex (also named ASCOM complex), at least composed of the HMTs KMT2D and/or KMT2C, the common subunits ASH2L, RBBP5, WDR5 and DPY30, and the complex type-specific subunits PAXIP1/PTIP, PAGR1, NCOA6 and KDM6A; required for the association of PAGR1 with the MLL2/MLL3 complex (PubMed:17178841, PubMed:17500065, PubMed:17761849, PubMed:17925232). Interacts with NUPR1; this interaction prevents PAXIP1 inhibition of PAX2 transcription factor activity (PubMed:11940591).
Involved in DNA damage response and in transcriptional regulation through histone methyltransferase (HMT) complexes. Plays a role in early development. In DNA damage response is required for cell survival after ionizing radiation. In vitro shown to be involved in the homologous recombination mechanism for the repair of double-strand breaks (DSBs). Its localization to DNA damage foci requires RNF8 and UBE2N. Recruits TP53BP1 to DNA damage foci and, at least in particular repair processes, effective DNA damage response appears to require the association with TP53BP1 phosphorylated by ATM at 'Ser-25'. Together with TP53BP1 regulates ATM association. Proposed to recruit PAGR1 to sites of DNA damage and the PAGR1:PAXIP1 complex is required for cell survival in response to DNA damage; the function is probably independent of MLL-containing histone methyltransferase (HMT) complexes. However, this function has been questioned (By similarity). Promotes ubiquitination of PCNA following UV irradiation and may regulate recruitment of polymerase eta and RAD51 to chromatin after DNA damage. Proposed to be involved in transcriptional regulation by linking MLL-containing histone methyltransferase (HMT) complexes to gene promoters by interacting with promoter-bound transcription factors such as PAX2. Associates with gene promoters that are known to be regulated by KMT2D/MLL2. During immunoglobulin class switching in activated B-cells is involved in trimethylation of histone H3 at 'Lys-4' and in transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus; this function appears to involve the recruitment of MLL-containing HMT complexes. Conflictingly, its function in transcriptional regulation during immunoglobulin class switching is reported to be independent of the MLL2/MLL3 complex (By similarity).
The BRCT 1 and 2 domains mediate the interaction with PAGR1A.
The BRCT 5 and 6 domains mediate the association with the MLL2/MLL3 complex (By similarity). The BRCT 5 and 6 domains function as a single module and are necessary and sufficient for in vitro phospho-specific binding (substrates phosphorylated by the kinases ataxia telangiectasia-mutated (ATM), ataxia telangiectasia and RAD3-related (ATR) in response to gamma irradiation). In contrast, in vivo two pairs of BRCT domains (3-6) bind to phosphorylated TP53BP1 much more efficiently.
Appeared to be synthesized preferentially in liver, placenta, testis, colon and intestine. Substantial amounts are also detected in pancreas, kidney, lung, heart and skeletal muscle.
Endopeptidase that degrades various components of the extracellular matrix. May activate progelatinase A.
NAD-dependent mitochondrial malic enzyme that catalyzes the oxidative decarboxylation of malate to pyruvate.
Subject to allosteric activation by fumarate.
This isoenzyme can also use NADP(+) but is more effective with NAD(+).
Expressed in cancer cell lines and glioblastoma tissue.
Interacts with CABLES1 and CABLES2 (By similarity). Interacts with ATF1. Binding to CCNC/cyclin-C promotes RB1 phosphorylation.
Serine/threonine-protein kinase that plays a critical role in the control of the eukaryotic cell cycle; involved in G0-G1 and G1-S cell cycle transitions. Interacts with CCNC/cyclin-C during interphase. Phosphorylates histone H1, ATF1, RB1 and CABLES1. ATF1 phosphorylation triggers ATF1 transactivation and transcriptional activities, and promotes cell proliferation and transformation. CDK3/cyclin-C mediated RB1 phosphorylation is required for G0-G1 transition. Promotes G1-S transition probably by contributing to the activation of E2F1, E2F2 and E2F3 in a RB1-independent manner.
Coordinated expression with SEPTIN2 and SEPTIN6.
Filament-forming cytoskeletal GTPase. Required for normal organization of the actin cytoskeleton. Required for normal progress through mitosis. Involved in cytokinesis. Required for normal association of CENPE with the kinetochore. Plays a role in ciliogenesis and collective cell movements. Forms a filamentous structure with SEPTIN12, SEPTIN6, SEPTIN2 and probably SEPTIN4 at the sperm annulus which is required for the structural integrity and motility of the sperm tail during postmeiotic differentiation (PubMed:25588830).
Septins polymerize into heterooligomeric protein complexes that form filaments, and associate with cellular membranes, actin filaments and microtubules. GTPase activity is required for filament formation. Filaments are assembled from asymmetrical heterotrimers, composed of SEPTIN2, SEPTIN6 and SEPTIN7 that associate head-to-head to form a hexameric unit. Within the trimer, directly interacts with SEPTIN6, while interaction with SEPTIN2 seems indirect. In the absence of SEPTIN6, forms homodimers. Interacts directly with CENPE and links CENPE to septin filaments composed of SEPTIN2, SEPTIN6 and SEPTIN7. Interacts with SEPTIN5 and SEPTIN8 (By similarity). Interacts with SEPTIN9 and SEPTIN11. Component of a septin core octameric complex consisting of SEPTIN12, SEPTIN7, SEPTIN6 and SEPTIN2 or SEPTIN4 in the order 12-7-6-2-2-6-7-12 or 12-7-6-4-4-6-7-12 and located in the sperm annulus; the SEPTIN12:SEPTIN7 association is mediated by the respective GTP-binding domains (PubMed:25588830).
Highly expressed in bone (PubMed:11746498, PubMed:17827158). Abundantly expressed in articular cartilage and chondrocytes and is increased in osteoarthritis (OA) (PubMed:11746498, PubMed:17827158). Colocalizes with ASPN in chondrocytes within OA lesions of articular cartilage (PubMed:17827158).
Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Interacts with TGF-beta receptors (TGFBR1 and TGFBR2), leading to signal transduction (PubMed:20207738).
Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Interacts with the serine proteases, HTRA1 and HTRA3: the interaction with either inhibits TGFB1-mediated signaling and the HTRA protease activity is required for this inhibition (By similarity). May interact with THSD4; this interaction may lead to sequestration by FBN1 microfibril assembly and attenuation of TGFB signaling (By similarity). Interacts with CD109, DPT and ASPN (PubMed:9895299, PubMed:16754747, PubMed:17827158). Interacts with EFEMP2 (PubMed:27339457). Interacts with TSKU; the interaction contributes to regulation of the hair cycle (By similarity).
Homodimer; disulfide-linked (PubMed:28117447, PubMed:29109152). Interacts with transforming growth factor beta-1 (TGF-beta-1) chain; interaction is non-covalent and maintains TGF-beta-1 in a latent state; each latency-associated peptide (LAP) monomer interacts with TGF-beta-1 in the other monomer (PubMed:29109152). Interacts with LTBP1; leading to regulation of TGF-beta-1 activation (PubMed:2022183, PubMed:8617200, PubMed:8939931). Interacts with LRRC32/GARP; leading to regulation of TGF-beta-1 activation on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:22278742, PubMed:19651619). Interacts with LRRC33/NRROS; leading to regulation of TGF-beta-1 in macrophages and microglia (Probable). Interacts (via cell attachment site) with integrins ITGAV and ITGB6 (ITGAV:ITGB6), leading to release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Interacts with NREP; the interaction results in a decrease in TGFB1 autoinduction (By similarity). Interacts with HSP90AB1; inhibits latent TGFB1 activation (PubMed:20599762). Interact with PSG9; leading to TGFB1 activation (PubMed:27389696).
In post-menopausal Japanese women, the frequency of Leu-10 is higher in subjects with osteoporosis than in controls.
Multifunctional protein that regulates the growth and differentiation of various cell types and is involved in various processes, such as normal development, immune function, microglia function and responses to neurodegeneration (By similarity). Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains remain non-covalently linked rendering TGF-beta-1 inactive during storage in extracellular matrix (PubMed:29109152). At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS that control activation of TGF-beta-1 and maintain it in a latent state during storage in extracellular milieus (PubMed:2022183, PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). TGF-beta-1 is released from LAP by integrins (ITGAV:ITGB6 or ITGAV:ITGB8): integrin-binding to LAP stabilizes an alternative conformation of the LAP bowtie tail and results in distortion of the LAP chain and subsequent release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Once activated following release of LAP, TGF-beta-1 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (PubMed:20207738). While expressed by many cells types, TGF-beta-1 only has a very localized range of action within cell environment thanks to fine regulation of its activation by Latency-associated peptide chain (LAP) and 'milieu molecules' (By similarity). Plays an important role in bone remodeling: acts as a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts (By similarity). Can promote either T-helper 17 cells (Th17) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner (By similarity). At high concentrations, leads to FOXP3-mediated suppression of RORC and down-regulation of IL-17 expression, favoring Treg cell development (By similarity). At low concentrations in concert with IL-6 and IL-21, leads to expression of the IL-17 and IL-23 receptors, favoring differentiation to Th17 cells (By similarity). Stimulates sustained production of collagen through the activation of CREB3L1 by regulated intramembrane proteolysis (RIP) (PubMed:25310401). Mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus (PubMed:25893292, PubMed:29483653, PubMed:30696809). Positively regulates odontoblastic differentiation in dental papilla cells, via promotion of IPO7-mediated translocation of phosphorylated SMAD2 to the nucleus and subsequent transcription of target genes (By similarity). Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (PubMed:25893292, PubMed:30696809).
N-glycosylated (PubMed:3162913, PubMed:2493139, PubMed:28117447). Deglycosylation leads to activation of Transforming growth factor beta-1 (TGF-beta-1); mechanisms triggering deglycosylation-driven activation of TGF-beta-1 are however unclear (PubMed:2493139).
Required to maintain the Transforming growth factor beta-1 (TGF-beta-1) chain in a latent state during storage in extracellular matrix (PubMed:28117447). Associates non-covalently with TGF-beta-1 and regulates its activation via interaction with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS, that control activation of TGF-beta-1 (PubMed:2022183, PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). Interaction with LRRC33/NRROS regulates activation of TGF-beta-1 in macrophages and microglia (Probable). Interaction with LRRC32/GARP controls activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:22278742, PubMed:19651619). Interaction with integrins (ITGAV:ITGB6 or ITGAV:ITGB8) results in distortion of the Latency-associated peptide chain and subsequent release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447).
TGF-beta-1 is inactivated by fresolimumab (also named GC1008), a monoclonal-neutralizing antibody.
The 'straitjacket' and 'arm' domains encircle the Transforming growth factor beta-1 (TGF-beta-1) monomers and are fastened together by strong bonding between Lys-56 and Tyr-103/Tyr-104.
The cell attachment site motif mediates binding to integrins (ITGAV:ITGB6 or ITGAV:ITGB8) (PubMed:28117447). The motif locates to a long loop in the arm domain called the bowtie tail (PubMed:28117447). Integrin-binding stabilizes an alternative conformation of the bowtie tail (PubMed:28117447). Activation by integrin requires force application by the actin cytoskeleton, which is resisted by the 'milieu molecules' (such as LTBP1, LRRC32/GARP and/or LRRC33/NRROS), resulting in distortion of the prodomain and release of the active TGF-beta-1 (PubMed:28117447).
Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively.
Transforming growth factor beta-1 proprotein: The precursor proprotein is cleaved in the Golgi apparatus by FURIN to form Transforming growth factor beta-1 (TGF-beta-1) and Latency-associated peptide (LAP) chains, which remain non-covalently linked, rendering TGF-beta-1 inactive.
Acts as a acyl-protein thioesterase hydrolyzing fatty acids from S-acylated cysteine residues in proteins such as trimeric G alpha proteins, GAP43, ZDHHC6 or HRAS (PubMed:21152083, PubMed:28826475). Deacylates GAP43 (PubMed:21152083). Mediates depalmitoylation of ZDHHC6 (PubMed:28826475). Has lysophospholipase activity (PubMed:25301951). Hydrolyzes prostaglandin glycerol esters (PG-Gs) in the following order prostaglandin D2-glycerol ester (PGD2-G) > prostaglandin E2 glycerol ester (PGE2-G) > prostaglandin F2-alpha-glycerol ester (PGF2-alpha-G) (PubMed:25301951). Hydrolyzes 1-arachidonoylglycerol but not 2-arachidonoylglycerol or arachidonoylethanolamide (PubMed:25301951).
Expressed in various breast cancer cell lines.
Inhibited by compound 1 or (5,5-Dioxido-4H-thieno[3,2-c]thiochromen-2-yl)(4-(4-methoxyphenyl)piperazin-1-yl)methanone.
Interacts with CLN5 (PubMed:19941651). Interacts with ATP5F1A and ATP5F1B (By similarity).
Removes thioester-linked fatty acyl groups such as palmitate from modified cysteine residues in proteins or peptides during lysosomal degradation. Prefers acyl chain lengths of 14 to 18 carbons (PubMed:8816748).
Expressed ubiquitously. Expression is highest in heart, skeletal muscle, kidney and liver, intermediate in brain, non-mucosal colon, spleen and placenta, and lowest in small intestine, thymus, lung and peripheral blood leukocytes.
Interacts with CECR2, HEBP2, MAP1S and UXT. Interacts with PPARGC1A. Interacts with FOXO1 (By similarity). Component of mRNP complexes associated with HNRPA1. Interacts (via N-terminus) with EIF4E; the interaction promotes association of EIF4E with 4ESE-containing mRNAs (PubMed:19262567, PubMed:28325843). Interacts with exportin XPO1/CRM1; interacts both alone and in complex with EIF4E and 4ESE-containing mRNAs to form an EIF4E-dependent mRNA export complex (PubMed:28325843). Interacts with importin IPO8; the interaction occurs when LRPPRC is in its RNA-free form and returns LRPPRC to the nucleus for further export rounds (PubMed:28325843).
May play a role in RNA metabolism in both nuclei and mitochondria. In the nucleus binds to HNRPA1-associated poly(A) mRNAs and is part of nmRNP complexes at late stages of mRNA maturation which are possibly associated with nuclear mRNA export. Positively modulates nuclear export of mRNAs containing the EIF4E sensitivity element (4ESE) by binding simultaneously to both EIF4E and the 4ESE and acting as a platform for assembly for the RNA export complex (PubMed:19262567, PubMed:28325843). Also binds to exportin XPO1/CRM1 to engage the nuclear pore and traffic the bound mRNAs to the cytoplasm (PubMed:28325843). May bind mature mRNA in the nucleus outer membrane. In mitochondria binds to poly(A) mRNA. Plays a role in translation or stability of mitochondrially encoded cytochrome c oxidase (COX) subunits. May be involved in transcription regulation. Cooperates with PPARGC1A to regulate certain mitochondrially encoded genes and gluconeogenic genes and may regulate docking of PPARGC1A to transcription factors. Seems to be involved in the transcription regulation of the multidrug-related genes MDR1 and MVP. Part of a nuclear factor that binds to the invMED1 element of MDR1 and MVP gene promoters. Binds single-stranded DNA (By similarity).
Component of the BCR(KLHL20) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL20 and RBX1. Interacts with PDZ-RhoGEF/ARHGEF11, DAPK1, PML and CORO7. Interacts with F-actin. Interacts with IFN-gamma (IFNG). Interacts (via kelch repeats) with IVNS1ABP (via kelch repeats); this interaction blocks the assembly of CUL3-KLHL20 complex (PubMed:25619834).
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex involved in interferon response and anterograde Golgi to endosome transport. The BCR(KLHL20) E3 ubiquitin ligase complex mediates the ubiquitination of DAPK1, leading to its degradation by the proteasome, thereby acting as a negative regulator of apoptosis (PubMed:20389280). The BCR(KLHL20) E3 ubiquitin ligase complex also specifically mediates 'Lys-33'-linked ubiquitination (PubMed:24768539). Involved in anterograde Golgi to endosome transport by mediating 'Lys-33'-linked ubiquitination of CORO7, promoting interaction between CORO7 and EPS15, thereby facilitating actin polymerization and post-Golgi trafficking (PubMed:24768539). Also acts as a regulator of endothelial migration during angiogenesis by controlling the activation of Rho GTPases. The BCR(KLHL20) E3 ubiquitin ligase complex acts as a regulator of neurite outgrowth by mediating ubiquitination and degradation of PDZ-RhoGEF/ARHGEF11 (PubMed:21670212). In case of tumor, the BCR(KLHL20) E3 ubiquitin ligase complex is involved in tumor hypoxia: following hypoxia, the BCR(KLHL20)complex mediates ubiquitination and degradation of PML, potentiating HIF-1 signaling and cancer progression (PubMed:21840486).
Microtubule plus-end-directed kinetochore motor which plays an important role in chromosome congression, microtubule-kinetochore conjugation and spindle assembly checkpoint activation. Drives chromosome congression (alignment of chromosomes at the spindle equator resulting in the formation of the metaphase plate) by mediating the lateral sliding of polar chromosomes along spindle microtubules towards the spindle equator and by aiding the establishment and maintenance of connections between kinetochores and spindle microtubules (PubMed:7889940, PubMed:23891108, PubMed:25395579). The transport of pole-proximal chromosomes towards the spindle equator is favored by microtubule tracks that are detyrosinated (PubMed:25908662). Acts as a processive bi-directional tracker of dynamic microtubule tips; after chromosomes have congressed, continues to play an active role at kinetochores, enhancing their links with dynamic microtubule ends (PubMed:23955301). Suppresses chromosome congression in NDC80-depleted cells and contributes positively to congression only when microtubules are stabilized (PubMed:25743205). Plays an important role in the formation of stable attachments between kinetochores and spindle microtubules (PubMed:17535814) The stabilization of kinetochore-microtubule attachment also requires CENPE-dependent localization of other proteins to the kinetochore including BUB1B, MAD1 and MAD2. Plays a role in spindle assembly checkpoint activation (SAC) via its interaction with BUB1B resulting in the activation of its kinase activity, which is important for activating SAC. Necessary for the mitotic checkpoint signal at individual kinetochores to prevent aneuploidy due to single chromosome loss (By similarity).
Monomer (PubMed:15236970). Interacts with CENPF (PubMed:9763420). Interacts with BUB1B (PubMed:9763420, PubMed:19625775). Interacts with SEPT7 (PubMed:18460473). Interacts with KIF18A (PubMed:19625775). Interacts with PRC1 (PubMed:15297875). Interacts with NUF2; this interaction determines kinetochore localization (PubMed:17535814). Interacts with SKAP; this interaction greatly favors SKAP binding to microtubules (PubMed:22110139). Interacts with TRAPPC12 (PubMed:25918224). Interacts with CTCF (PubMed:25395579).
Sumoylated with SUMO2 and SUMO3. The sumoylation mediates the association to the kinetochore.
The C-terminal inhibitory domain is phosphorylated. Phosphorylation relieves autoinhibition of the kinetochore motor (By similarity).
The protein is composed of a N-terminal kinesin-motor domain involved in the chromosome movements, a long coil-coiled region involved in the homodimerization and an inhibitory C-tail involved in autoinhibition of the N-terminal catalytic part.
Detected on neurons in the caudate region (PubMed:28469074). Detected on neurons in the hippocampus (at protein level) (PubMed:30840898). Highly expressed in brain and kidney. Detected at low levels in heart, liver, small intestine, skeletal muscle and thymus (PubMed:11499680).
Does not promote Schwann cell apoptosis in response to proBDNF.
Expression is decreased in the brains of Huntington disease (HD) patients after the onset of symptoms.
Homodimer (in vitro) (By similarity). Heterodimer with NGFR. The extracellular domains of the heterodimer bind the precursor form of NGF (proNGF) (PubMed:22155786, PubMed:24908487). Has much higher affinity for proNGF than for mature NGF (PubMed:24908487). Can also bind mature NGF and BDNF (By similarity). Each chain in the receptor dimer interacts (via extracellular domain) with an NGF dimer (in vitro) (By similarity). Interacts with the precursor forms of BDNF (proBDNF) and NTF3 (proNT3) (PubMed:24908487). The cytoplasmic region of the heterodimer formed by NGFR and SORCS2 binds TRIO. ProNGF binding mediates dissociation of TRIO from the receptor complex (PubMed:22155786). Interacts with SLC1A1. Interacts with VPS35. Interacts (via extracellular domain) with NTRK2 (via extracellular domain). Interacts with VPS35. Interacts (via extracellular domain) with GRIN2A (By similarity).
Proteolytic cleavage removes a propeptide, giving rise to a 122 kDa chain that includes a cytoplasmic tail. Further cleavage gives rise to a 104 kDa chain that lacks the cytoplasmic tail, and a membrane-bound 18 kDa chain. The 104 kDa chain remains bound to the 18 kDa chain.
SorCS2 104 kDa chain and SorCS2 18 kDa chain together promote Schwann cell apoptosis in response to proBDNF.
The N-terminus of the protein was constructed in analogy to that of the mouse ortholog using the sequence of chromosome 4.
The heterodimer formed by NGFR and SORCS2 functions as receptor for the precursor forms of NGF (proNGF) and BDNF (proBDNF) (PubMed:22155786, PubMed:24908487). ProNGF and proBDNF binding both promote axon growth cone collapse (in vitro) (PubMed:22155786, PubMed:24908487). Plays a role in the regulation of dendritic spine density in hippocampus neurons (By similarity). Required for normal neurite branching and extension in response to BDNF (PubMed:27457814). Plays a role in BDNF-dependent hippocampal synaptic plasticity. Together with NGFR and NTRK2, is required both for BDNF-mediated synaptic long-term depression and long-term potentiation (PubMed:27457814). ProNGF binding promotes dissociation of TRIO from the heterodimer, which leads to inactivation of RAC1 and/or RAC2 and subsequent reorganization of the actin cytoskeleton (PubMed:22155786). Together with the retromer complex subunit VPS35, required for normal expression of GRIN2A at synapses and dendritic cell membranes. Required for normal expression of the amino acid transporter SLC1A1 at the cell membrane, and thereby contributes to protect cells against oxidative stress (By similarity).
Expressed in lymphoid tissues and activated T cells.
Receptor for the C-X-C chemokine CXCL16. Used as a coreceptor by SIVs and by strains of HIV-2 and m-tropic HIV-1.
Component of the oligosaccharyltransferase (OST) complex.
Specific component of the STT3A-containing form of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation (PubMed:31831667). N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity. May be involved in N-glycosylation of APP (amyloid-beta precursor protein). Can modulate gamma-secretase cleavage of APP by enhancing endoprotelysis of PSEN1.
Specific component of the STT3A-containing form of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation. N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity. May be involved in N-glycosylation of APP (amyloid-beta precursor protein). Can modulate gamma-secretase cleavage of APP by enhancing endoprotelysis of PSEN1.
Specific component of the STT3A-containing form of the oligosaccharyltransferase (OST) complex (PubMed:31831667). OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits (PubMed:21768116, PubMed:31831667). STT3A complex assembly occurs through the formation of 3 subcomplexes. Subcomplex 1 contains RPN1 and TMEM258, subcomplex 2 contains the STT3A-specific subunits STT3A, DC2/OSTC, and KCP2 as well as the core subunit OST4, and subcomplex 3 contains RPN2, DAD1, and OST48. The STT3A complex can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes (By similarity). Interacts with PSEN1 and NCSTN; indicative for an association with the gamma-secretase complex (PubMed:21768116).
Composed of an N-terminal domain that binds STXBP1, a middle phosphotyrosine-binding domain (PID/PTB) that mediates binding with the cytoplasmic domain of the amyloid-beta precursor protein, and two C-terminal PDZ domains thought to attach proteins to the plasma membrane.
Part of a multimeric complex containing STXBP1 and syntaxin-1. Binds to the cytoplasmic domain of amyloid-beta protein, and to the nuclear factor NF-kappa-B/p65 via its PDZ domain. Interacts with the N-terminal domain of NECAB3.
Putative function in synaptic vesicle exocytosis by binding to STXBP1, an essential component of the synaptic vesicle exocytotic machinery. May modulate processing of the amyloid-beta precursor protein (APP) and hence formation of APP-beta.
Activates ubiquitin by first adenylating with ATP its C-terminal glycine residue and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a ubiquitin-E1 thioester and free AMP. Catalyzes the ISGylation of influenza A virus NS1 protein.
Expressed in a variety of normal and tumor cell types, but is reduced in lung cancer cell lines.
Monomer (By similarity). Binds and is involved in the conjugation of G1P2/ISG15.
Found during embryonic development and in early differentiated states.
Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. The binding of Met-tRNA(I) occurs after the AUG codon finds its position in the P-site of 40S ribosomes, the situation that takes place during initiation complex formation on some specific RNAs. Its activity in tRNA binding with 40S subunits does not require the presence of the aminoacyl moiety. Possesses the unique ability to deliver non-Met (elongator) tRNAs into the P-site of the 40S subunit. In addition to its role in initiation, can promote release of deacylated tRNA and mRNA from recycled 40S subunits following ABCE1-mediated dissociation of post-termination ribosomal complexes into subunits.
Was previously erroneously called ligatin, a trafficking receptor for phosphoglycoproteins, while ligatin is actually a distinct 10 kDa filamentous membrane protein encoded by a still unidentified gene.
It is unclear whether this protein requires a metal cofactor for catalysis. It was originally proposed to be a Zn(2+)-dependent metalloenzyme based on structural similarities to bacterial aminopeptidases and the observation that it can bind Zn(2+) ions, typically in a 1:1 stoichiometry (PubMed:18072935, PubMed:21288892). However, a recent study suggests a Zn(2+)-independent catalytic mechanism (By similarity).
Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue. Also catalyzes N-terminal pyroglutamate formation. In vitro, catalyzes pyroglutamate formation of N-terminally truncated form of APP amyloid-beta peptides [Glu-3]-amyloid-beta. May be involved in the N-terminal pyroglutamate formation of several amyloid-related plaque-forming peptides.
Cells silencing ZNF365 display delayed mitotic progression and exit, due to increased replication stress, and ultimately leading to cytokinesis failure, re-duplication of centrosomes and increased aneuploidy.
Homodimer. Interacts with NDE1 and NDEL1. Does not interact with TUBG1. Interacts with DISC1 (PubMed:17389905). Interacts with PARP1 (PubMed:23966166).
Induced by gamma irradiation and zeocin.
Involved in the regulation of neurogenesis. Negatively regulates neurite outgrowth (PubMed:17389905). Involved in the morphogenesis of basket cells in the somatosensory cortex during embryogenesis. Involved in the positive regulation of oligodendrocyte differentiation during postnatal growth. Involved in dendritic arborization, morphogenesis of spine density dendrite, and establishment of postsynaptic dendrite density in cortical pyramidal neurons (By similarity). Involved in homologous recombination (HR) repair pathway. Required for proper resolution of DNA double-strand breaks (DSBs) by HR. Is required for recovery of stalled replication forks, and directly contributes to genomic stability. Interacts with PARP1 and mediates MRE11-dependent DNA end resection during replication fork recovery (PubMed:23966166). Contributes to genomic stability by preventing telomere dysfunction (PubMed:23776040).
Isoform 1 is expressed in brain. Isoform 2 is expressed in placenta and at low level in lung and liver. Isoform 3 is expressed in kidney and pancreas. Isoform 1 is expressed exclusively in brain (PubMed:17389905).
Heterodimer with MEIS1 (PubMed:26550823). Interacts with IPO7; the interaction facilitates nuclear translocation of DLX3 in dental papilla cells (By similarity).
Transcriptional activator (By similarity). Activates transcription of GNRHR, via binding to the downstream activin regulatory element (DARE) in the gene promoter (By similarity).
Interacts with NHERF1, HGS and AGAP2. Interacts with LAYN (By similarity). Interacts with SGSM3. Interacts (via FERM domain) with MPP1. Interacts with WWC1. Interacts with the CUL4A-RBX1-DDB1-VprBP/DCAF1 E3 ubiquitin-protein ligase complex. The unphosphorylated form interacts (via FERM domain) with VPRBP/DCAF1. Interacts (via FERM domain) with NOP53; the interaction is direct (PubMed:21167305). Interacts with SCHIP1; the interaction is direct (PubMed:10669747).
Phosphorylation of Ser-518 inhibits nuclear localization by disrupting the intramolecular association of the FERM domain with the C-terminal tail (PubMed:20178741). The dephosphorylation of Ser-518 favors the interaction with NOP53 (PubMed:21167305).
Probable regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in tumor suppression by restricting proliferation and promoting apoptosis. Along with WWC1 can synergistically induce the phosphorylation of LATS1 and LATS2 and can probably function in the regulation of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway. May act as a membrane stabilizing protein. May inhibit PI3 kinase by binding to AGAP2 and impairing its stimulating activity. Suppresses cell proliferation and tumorigenesis by inhibiting the CUL4A-RBX1-DDB1-VprBP/DCAF1 E3 ubiquitin-protein ligase complex.
Ubiquitinated by the CUL4A-RBX1-DDB1-DCAF1/VprBP E3 ubiquitin-protein ligase complex for ubiquitination and subsequent proteasome-dependent degradation.
Widely expressed. Isoform 1 and isoform 3 are predominant. Isoform 4, isoform 5 and isoform 6 are expressed moderately. Isoform 8 is found at low frequency. Isoform 7, isoform 9 and isoform 10 are not expressed in adult tissues, with the exception of adult retina expressing isoform 10. Isoform 9 is faintly expressed in fetal brain, heart, lung, skeletal muscle and spleen. Fetal thymus expresses isoforms 1, 7, 9 and 10 at similar levels.
Exhibits arylsulfatase activity and highly specific endoglucosamine-6-sulfatase activity (PubMed:12368295, PubMed:30788513, PubMed:35294879). It can remove sulfate from the C-6 position of glucosamine within specific subregions of intact heparin (PubMed:12368295, PubMed:30788513, PubMed:35294879).
Expressed at highest levels in the ovary, skeletal muscle, stomach, brain, uterus, heart, kidney and placenta.
Glycosylation at Ser-583 negatively regulates its N-acetylglucosamine-6-sulfatase and arylsulfatase activities.
Transcription factor required for the proper patterning of the epidermis, which plays a key role in early epithelial morphogenesis (PubMed:35585237). Directly binds promoter and enhancer regions and acts by maintaining local enhancer-promoter chromatin architecture (PubMed:35585237). Interacts with many sequence-specific zinc-finger transcription factors and methyl-CpG-binding proteins to regulate the expression of mesoderm genes that wire surface ectoderm stratification (PubMed:35585237).
Associated with the mammalian reproductive process. Catalyzes the cross-linking of proteins and the conjugation of polyamines to specific proteins in the seminal tract.
Detected in T-cell leukemia bearing a t(X;14) translocation. Plays a key role in T-cell prolymphocytic leukemia.
Not found at a significant level in any tissue.
Shares a non-coding 5' exon with isoform 1 which is spliced to a different set of 3' exons encoding an unrelated protein.
(Microbial infection) Acts as a receptor for herpes simplex virus 1/HHV-1, herpes simplex virus 2/HHV-2, and pseudorabies virus/PRV.
(Microbial infection) Interacts with herpes simplex virus 1/HHV-1, herpes simplex virus 2/HHV-2, and pseudorabies virus/PRV envelope glycoprotein D (PubMed:21980294, PubMed:22146396, PubMed:9696799, PubMed:9657005).
Ig-like C2-type 2 mediates neurite outgrowth through binding, induction of phosphorylation, and activation of FGFR.
Interacts (via Ig-like C2-type domain 2) with FGFR1, FGFR2 and FGFR3 (By similarity). Cis- and trans-homodimer. Can form trans-heterodimers with NECTIN3 and with NECTIN4. Interaction between NECTIN1 and NECTIN3 on the pre- and postsynaptic sites, respectively, initiates the formation of puncta adherentia junctions between axons and dendrites. Interacts (via cytoplasmic domain) with AFDN (via PDZ domain); this interaction recruits NECTIN1 to cadherin-based adherens junctions and provides a connection with the actin cytoskeleton. Interacts with integrin alphaV/beta3.
Promotes cell-cell contacts by forming homophilic or heterophilic trans-dimers. Heterophilic interactions have been detected between NECTIN1 and NECTIN3 and between NECTIN1 and NECTIN4. Has some neurite outgrowth-promoting activity.
Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of cathecolamines, dopamine, noradrenaline, and adrenaline. Uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to L-Dopa (PubMed:17391063, PubMed:1680128, PubMed:15287903, PubMed:8528210, Ref.18, PubMed:34922205, PubMed:24753243). In addition to tyrosine, is able to catalyze the hydroxylation of phenylalanine and tryptophan with lower specificity (By similarity). Positively regulates the regression of retinal hyaloid vessels during postnatal development (By similarity).
Homotetramer (Ref.18, PubMed:24947669). Interacts (when phosphorylated at Ser-19) with YWHAG; one YWHAG dimer bounds to one TH tetramer, this interaction may influence the phosphorylation and dephosphorylation of other sites (PubMed:24947669).
Inhibited in feedback fashion by the catecholamine neurotransmitters, especially by dopamine in competition with tetrahydrobiopterin (PubMed:15287903). Phosphorylation of several Ser/Thr residues in the N-terminus regulates the catalytic activity (PubMed:1680128, PubMed:7901013). Ser-62 and Ser-71 are readily phosphorylated to activate the catalytic activity (PubMed:1680128, PubMed:7901013). A Cysteine modification induced by N-ethylmaleimide (NEM), inhibits tyrosine 3-monooxygenase activity through the modification of the Cys-207 (PubMed:34922205).
Mainly expressed in the brain and adrenal glands.
May play a role in the pathogenesis of Parkinson disease (PD). A genome-wide copy number variation analysis has identified a 34 kilobase deletion over the TH gene in a PD patient but not in any controls.
Phosphorylated on Ser-19, Ser-62 and Ser-71 by several protein kinases with different site specificities. Phosphorylation at Ser-62 and Ser-71 leads to an increase of TH activity (PubMed:7901013). Phosphorylation at Ser-71 activates the enzyme and also counteracts the feedback inhibition of TH by catecholamines (PubMed:15287903). Phosphorylation of Ser-19 and Ser-62 triggers the proteasomal degradation of TH through the ubiquitin-proteasome pathway (By similarity). Phosphorylation at Ser-62 facilitates transport of TH from the soma to the nerve terminals via the microtubule network (PubMed:28637871). Phosphorylation at Ser-19 induces the high-affinity binding to the 14-3-3 protein YWHAG; this interaction may influence the phosphorylation and dephosphorylation of other sites (PubMed:24947669). Ser-19 increases the phosphorylation at Ser-71 in a hierarchical manner, leading to increased activity (By similarity).
Catalyzes the activation of fatty acids by CoA to produce an acyl-CoA, the first step in fatty acid metabolism.
Interacts with DDI2; probably also interacts with DDI1.
Replication termination factor which is a component of the elongating replisome (Probable). Required for ATR pathway signaling upon DNA damage and has a positive activity during DNA replication. Might function to facilitate fork pausing at replication fork barriers like the rDNA. May be globally required to stimulate ATR signaling after the fork stalls or encounters a lesion (Probable). Interacts with nascent DNA (PubMed:29290612).
Undergoes proteasomal degradation, via DDI1 and DDI2. Removal from stalled replisomes and degradation are required for genome stability.
Belongs to the PNRC family. PNRC2 subfamily.
Expressed in heart, lung, muscle and brain.
Interacts with UPF1/RENT1; preferentially interacts with hyperphosphorylated form (PubMed:19150429, PubMed:25775514). Interacts with DCP1A (PubMed:19150429, PubMed:25775514). Interacts with many nuclear receptors including ESR1, ESRRA, ESRRG, NR3C1/GR, NR5A1, PGR, TR, RAR and RXR (PubMed:11574675, PubMed:14651967, PubMed:25775514).
Involved in nonsense-mediated mRNA decay (NMD) by acting as a bridge between the mRNA decapping complex and the NMD machinery (PubMed:19150429). May act by targeting the NMD machinery to the P-body and recruiting the decapping machinery to aberrant mRNAs (PubMed:19150429). Required for UPF1/RENT1 localization to the P-body (PubMed:19150429). Plays a role in glucocorticoid receptor-mediated mRNA degradation by interacting with the glucocorticoid receptor NR3C1 in a ligand-dependent manner when it is bound to the 5' UTR of target mRNAs and recruiting the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay (PubMed:25775514). Also acts as a nuclear receptor coactivator (PubMed:11574675). May play a role in controlling the energy balance between energy storage and energy expenditure (By similarity).
The interaction between PNRC2 and nuclear receptors is dependent on the SH3 binding motif.
Expressed strongly in the exocrine pancreas.
Required for cis-Golgi integrity and efficient ER to Golgi transport. Involved in the maintenance of the integrity of the cis-Golgi, possibly via its interaction with GOLGA2/GM130.
The B box-type and RING-type zinc fingers although degenerate play a central role in function of the protein.
Cytokine that binds to LTBR/TNFRSF3. May play a specific role in immune response regulation. Provides the membrane anchor for the attachment of the heterotrimeric complex to the cell surface. Isoform 2 is probably non-functional.
Heterotrimer of either two LTB and one LTA subunits or (less prevalent) one LTB and two LTA subunits.
Involved in the regulation of mitochondrial distribution and morphology (PubMed:17349998, PubMed:28554942, PubMed:28544275). Required for mitochondrial fusion and mitochondrial network formation (PubMed:28554942, PubMed:28544275).
Present in all cell lines tested (at protein level). Widely expressed.
Expressed in cornea, skin, vagina, esophagus, and larynx (at protein level). Expressed in trachea and mammary gland. Weakly expressed in testis and kidney. Highly expressed in corneal epithelium, colon and trachea. Moderately expressed in brain, urogenital organs, bladder, uterus and prostate. Highly expressed in tissues containing stratified epithelium including cornea, esophagus, larynx, skin and vagina than those tissues which contain only epithelial monolayers. Expressed in normal breast epithelium but not in breast cancer. Highly expressed during epithelial stratification. Expressed in endothelial cells of lung. Expressed selectively in endothelia of small pulmonary arteries, arterioles, and subpleural and interlobular venules.
Plays a role in modulating chloride current across the plasma membrane in a calcium-dependent manner, and cell adhesion. Involved in basal cell adhesion and/or stratification of squamous epithelia. May act as a tumor suppressor in breast and colorectal cancer. Plays a key role for cell adhesion in the beginning stages of lung metastasis via the binding to ITGB4.
Significantly down-regulated in breast and colorectal cancer.
The 141 kDa mature form is autoproteolytically cleaved by the metalloprotease domain, producing a 109 kDa form and a 35 kDa form. The cleavage is necessary for calcium-activated chloride channel (CaCC) activation activity.
Component of the tRNA-splicing ligase complex required to facilitate the enzymatic turnover of catalytic subunit RTCB. Together with DDX1, acts by facilitating the guanylylation of RTCB, a key intermediate step in tRNA ligation.
Genetic variants in DENND1A may play a role in susceptibility to polycystic ovary syndrome (PCOS), the most common endocrine disease among premenopausal women. PCOS is a complex disorder characterized by infertility, hirsutism, obesity, various menstrual disturbances, and enlarged ovaries studded with atretic follicles.
Guanine nucleotide exchange factor (GEF) regulating clathrin-mediated endocytosis through RAB35 activation. Promotes the exchange of GDP to GTP, converting inactive GDP-bound RAB35 into its active GTP-bound form. Regulates clathrin-mediated endocytosis of synaptic vesicles and mediates exit from early endosomes (PubMed:20154091, PubMed:20937701). Binds phosphatidylinositol-phosphates (PtdInsPs), with some preference for PtdIns(3)P (By similarity).
Interacts with RAB35 (PubMed:20154091). Interacts with clathrin and with the adapter protein complex 2, AP-2 (PubMed:20154091, PubMed:20937701). Interacts with ITSN1 and SH3GL2 (By similarity). Interacts (when phosphorylated) with YWHAE (PubMed:26055712).
Phosphorylated on serine and/or threonine in an Akt-dependent manner. Phosphorylation probably regulates the guanine nucleotide exchange factor (GEF) activity, possibly by disrupting an intramolecular interaction between the DENN domain and the C-terminus of the protein, thereby relieving the autoinhibition.
The guanine nucleotide exchange factor (GEF) activity is autoinhibited. Autoinhibition may be the result of intramolecular interaction between the DENN domain and the C-terminus, which is disrupted upon phosphorylation. Activation is regulated by Akt activation.
May modulate the activity of casein kinase-1. Inhibits CSNK1D autophosphorylation (in vitro).
Monomer. Interacts with CSNK1D and CSNK1E.
Pituitary, ovary, testis, breast and prostate but not in liver and spleen.
Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This receptor mediates its action by association with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Isoform 2 may act as an inhibitor of GnRH-R signaling.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in GNRHR as well as in other HH-associated genes including FGFR1 (PubMed:23643382).
A central region that included the first H15 (linker histone H1/H5 globular) domain binds at the entry/exit site of the nucleosomal DNA.
Component of heterochromatin that maintains heterochromatin integrity during G1/S progression and regulates the duration of G1 phase to critically influence cell proliferative capacity (PubMed:24830416). Mediates chromatin condensation during hypoxia, leading to increased tumor cell viability, radio-resistance, chemo-resistance and self-renewal(PubMed:25100860).
Interacts (via PxVxL motif) with CBX5 (via Trp-174).
May play a role in cell growth and maintenance of cell morphology.
Bifunctional iron sensor that switches between 2 activities depending on iron availability (PubMed:1946430, PubMed:1281544, PubMed:8041788). Iron deprivation, promotes its mRNA binding activity through which it regulates the expression of genes involved in iron uptake, sequestration and utilization (PubMed:1946430, PubMed:1281544, PubMed:8041788, PubMed:23891004). Binds to iron-responsive elements (IRES) in the untranslated region of target mRNAs preventing for instance the translation of ferritin and aminolevulinic acid synthase and stabilizing the transferrin receptor mRNA (PubMed:1946430, PubMed:1281544, PubMed:8041788, PubMed:23891004).
Conversely, when cellular iron levels are high, binds a 4Fe-4S cluster which precludes RNA binding activity and promotes the aconitase activity, the isomerization of citrate to isocitrate via cis-aconitate.
Interacts (when associated with the 4Fe-4S) with FBXL5. Interacts with frataxin(81-210).
Involved in the synthesis of sialyl-paragloboside, a precursor of sialyl-Lewis X determinant. Has a alpha-2,3-sialyltransferase activity toward Gal-beta1,4-GlcNAc structure on glycoproteins and glycolipids. Has a restricted substrate specificity, it utilizes Gal-beta1,4-GlcNAc on glycoproteins, and neolactotetraosylceramide and neolactohexaosylceramide, but not lactotetraosylceramide, lactosylceramide or asialo-GM1.
Probable assembly factor of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complexes that promotes the exchange of the substrate-recognition F-box subunit in SCF complexes, thereby playing a key role in the cellular repertoire of SCF complexes.
Ubiquitinated and targeted for proteasomal degradation.
Directly cleaved by HTRA2 to produce active form.
Disease susceptibility is associated with variants affecting the gene represented in this entry. A polymorphism in the MMP3 promoter region is associated with the risk of coronary heart disease and myocardial infarction, due to lower MMP3 proteolytic activity and higher extracellular matrix deposition in atherosclerotic lesions.
Enzymatic activity is activated by HTRA2 in dopaminergic cells upon mitochondrial stress.
Metalloproteinase with a rather broad substrate specificity that can degrade fibronectin, laminin, gelatins of type I, III, IV, and V; collagens III, IV, X, and IX, and cartilage proteoglycans. Activates different molecules including growth factors, plasminogen or other matrix metalloproteinases such as MMP9 (PubMed:11029580, PubMed:1371271). Once released into the extracellular matrix (ECM), the inactive pro-enzyme is activated by the plasmin cascade signaling pathway (PubMed:2383557). Acts also intracellularly (PubMed:22265821). For example, in dopaminergic neurons, gets activated by the serine protease HTRA2 upon stress and plays a pivotal role in DA neuronal degeneration by mediating microglial activation and alpha-synuclein/SNCA cleavage (PubMed:21330369). In addition, plays a role in immune response and possesses antiviral activity against various viruses such as vesicular stomatitis virus, influenza A virus (H1N1) and human herpes virus 1 (PubMed:35940311). Mechanistically, translocates from the cytoplasm into the cell nucleus upon virus infection to influence NF-kappa-B activities (PubMed:35940311).
Low or absent expression in normal pancreas and stronger expression in 15 of 18 exocrine pancreatic adenocarcinomas (at protein level).
Plays a role in apical endocytosis/recycling. Plays a role in the maturation and acidification of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis. Plays a role in the fusion of phagosomes with lysosomes.
Activity is inhibited by 4,4'-Di-isothiocyanatostilbene-2,2'-disulfonic acid (DIDS - an inhibitor of several anion channels and transporters) and gluconate.
Antiporter that mediates the exchange of sulfate and oxalate against chloride ions across a membrane (PubMed:11834742, PubMed:11278976). Stimulates anion transport activity of CFTR (PubMed:22121115, PubMed:23582645). May cooperate with CFTR in the regulation of chloride and bicarbonate ions fluxes required for activation of the ADCY10/PKA pathway during sperm motility and sperm capacitation (By similarity). May play a role in sperm tail differentiation and motility and hence male fertility (By similarity).
Expression observed exclusively in testis, restricted to the meiotic phase of the germ cell (PubMed:11834742). Abundant expression located in the seminiferous tubules, concentrated on the luminal side of the tubuli harboring the spermatocytes and spermatids (PubMed:11834742, PubMed:11278976).
Incorrectly indicated as originating from mouse.
Interacts with RACGAP1 (PubMed:11278976). Interacts with CFTR; stimulates anion transport activity of CFTR (PubMed:22121115, PubMed:23582645).
Repressed by tunicamycin, an inhibitor of N-glycosylation.
May mediate cell differentiation events during embryonic development.
This protein is produced by a bicistronic gene which also produces the CERS1 protein from a non-overlapping reading frame.
Mitochondrial proton-coupled zinc ion antiporter mediating the export of zinc from the mitochondria and involved in zinc homeostasis, zinc mobilization as well as mitochondrial morphology and health (PubMed:28334855, PubMed:34397090, PubMed:35614220, PubMed:34433664). In nucleus, functions as a secondary coactivator for nuclear receptors by cooperating with p160 coactivators subtypes. Plays a role in transcriptional activation of Wnt-responsive genes (By similarity).
Ubiquitously expressed in fetal and adult tissues and cancer cell lines.
Expressed at late stages of melanosome differentiation.
Genetic variants in SLC45A2 define the skin/hair/eye pigmentation variation locus 5 (SHEP5) [MIM:227240]. Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair.
Proton-associated glucose and sucrose transporter (By similarity). May be able to transport also fructose (By similarity). Expressed at a late melanosome maturation stage where functions as proton/glucose exporter which increase lumenal pH by decreasing glycolysis (PubMed:32966160, PubMed:35469906). Regulates melanogenesis by maintaining melanosome neutralization that is initially initiated by transient OCA2 and required for a proper function of the tyrosinase TYR (PubMed:32966160, PubMed:35469906).
(Microbial infection) Binds to HIV-1 gp120, thereby allowing the virus to enter GALT, which is thought to be the major trigger of AIDS disease. Interaction would involve a tripeptide L-D-I in HIV-1 gp120.
(Microbial infection) May interact with HIV-1 gp120.
Expressed in a variety of leukocyte lines.
Heterodimer of an alpha and a beta subunit (PubMed:1542691). ITGB7/beta-7 associates with either ITGA4/alpha-4 or ITGAE/alpha-E (PubMed:1542691). Integrin ITGA4/ITGB7 interacts with MADCAM1 (PubMed:10837471). Integrin ITGA4/ITGB7 interacts with VCAM1 and fibronectin (Probable). Interacts with FLNA (via filamin repeats 4, 9, 12, 17, 19, 21, and 23) (PubMed:19828450).
Integrin ITGA4/ITGB7 (alpha-4/beta-7) (Peyer patches-specific homing receptor LPAM-1) is an adhesion molecule that mediates lymphocyte migration and homing to gut-associated lymphoid tissue (GALT) (Probable). Integrin ITGA4/ITGB7 interacts with the cell surface adhesion molecules MADCAM1 which is normally expressed by the vascular endothelium of the gastrointestinal tract (PubMed:10837471, PubMed:14608374). Interacts also with VCAM1 and fibronectin, an extracellular matrix component (Probable). It recognizes one or more domains within the alternatively spliced CS-1 region of fibronectin (Probable). Interactions involve the tripeptide L-D-T in MADCAM1, and L-D-V in fibronectin (Probable). Integrin ITGAE/ITGB7 (alpha-E/beta-7, HML-1) is a receptor for E-cadherin (PubMed:10837471).
The VWFA domain (or beta I domain) contains three cation-binding sites: the ligand-associated metal ion-binding site (LIMBS or SyMBS), the metal ion-dependent adhesion site (MIDAS), and the adjacent MIDAS site (ADMIDAS) (PubMed:14608374). This domain is also part of the ligand-binding site (PubMed:14608374). The MIDAS site is required for both rolling and adhesion (PubMed:14608374). The ADMIDAS site is required for rolling and mediates the negative regulatory effects of higher Ca(2+) concentration on ligand binding (PubMed:14608374). The LIMBS site is required for adhesion and mediates the positive regulatory effects of low Ca(2+) concentrations on ligand binding (PubMed:14608374).
Actin-bundling protein found in intestinal microvilli, hair cell stereocilia, and fibroblast filopodia. May play a role in the regulation of bone development.
Expressed in a variety of organs, including muscle, brain, uterus and esophagus.
Genetic variations in PLS3 define the bone mineral density quantitative trait locus 18 (BMND18) [MIM:300910]. Variance in bone mineral density influences bone mass, contributes to size determination in the general population, and is a susceptibility factor for osteoporotic fractures.
Forms protease inhibiting heterodimer with TMPRSS7.
Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade (PubMed:15853774, PubMed:15140129). AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa (PubMed:15140129). Its inhibitory activity is greatly enhanced in the presence of heparin.
Expressed in testis (germ cells), but not in liver, kidney, prostate and small intestine. Expressed in airway epithelial cells (PubMed:36191189).
Interacts with FHL5 (via second LIM domain) (By similarity). Interacts with RANBP9 (PubMed:15014887).
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (PubMed:36191189). Plays a role in spermatogenesis by enhancing the binding of CREM isoform tau to its coactivator FHL5 and increasing the FHL5-regulated transcriptional activation of CREM isoform tau (By similarity). Involved in the acrosome reaction and in binding of sperm to the zona pellucida (By similarity). Plays a role in regulation of the cell cycle by controlling progression through the G2/M phase, possibly by delaying the activation of CDK1 which is required for entry into mitosis (PubMed:19548270). May play a role in fertility and microtubule formation through interaction with RANBP9 (PubMed:10500252).
IF-3 binds to the 28S ribosomal subunit and shifts the equilibrum between 55S ribosomes and their 39S and 28S subunits in favor of the free subunits, thus enhancing the availability of 28S subunits on which protein synthesis initiation begins.
Interacts with the C-terminal half of SNRNP70, the Arg/Ser-rich domain of AKAP17A as well as with U2AF1 and CLK1.
Isoform 2 is phosphorylated on Ser-310 upon DNA damage, probably by ATM or ATR.
Splice factor required for alternative splicing of TRA2B/SFRS10 transcripts. May interfere with constitutive 5'-splice site selection.
The RanBP2-type zinc fingers mediate binding to RNA.
G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity (By similarity). Signaling stimulates TRPM1 channel activity and Ca(2+) uptake. Required for normal vision.
Homodimer (PubMed:17405131). Interacts with GPR179 (By similarity).
Interacts (via the DH domain) with BVES (via the C-terminus cytoplasmic tail) (By similarity). Interacts with activated GNAQ and GNA11. Interacts with RHOA, CDC42 and RAC1.
Isoform 1 and isoform 2 are highly expressed in excitable tissues, such as brain, heart and muscle. Also detected in kidney and liver.
May play a role in actin cytoskeleton reorganization in different tissues since its activation induces formation of actin stress fibers. It works as a guanine nucleotide exchange factor for Rho family of small GTPases. Links specifically G alpha q/11-coupled receptors to RHOA activation. May be an important regulator of processes involved in axon and dendrite formation. In neurons seems to be an exchange factor primarily for RAC1. Involved in skeletal myogenesis (By similarity).
The guanine nucleotide exchange activity is autoinhibited by the PH domain.
Expressed in colon and colon cancer tissue.
Plays an important role in the organization of the cytoskeleton. Binds to and sequesters actin monomers (G actin) and therefore inhibits actin polymerization (By similarity). May be involved in cell migration (PubMed:19296525).
Plays an important role in the organization of the cytoskeleton. Binds to and sequesters actin monomers (G-actin) and therefore inhibits actin polymerization.
Interacts with AGO2. Found in a complex, composed of AGO2, CHD7 and FAM172A.
Plays a role in the regulation of alternative splicing, by interacting with AGO2 and CHD7. Seems to be required for stabilizing protein-protein interactions at the chromatin-spliceosome interface. May have hydrolase activity.
Acts as a negative regulator of SRC by activating CSK which inhibits SRC activity and downstream signaling, leading to impaired cell spreading and migration. Regulates dendritic spine morphology. Involved in calcium-dependent exocytosis. May play a role in neurotransmitter release or synapse maintenance.
Expressed in some primary breast carcinomas where its presence is significantly associated with increased tumor size. Not detected in normal breast tissue.
Interacts with the N-terminal coiled-coil region of SNAP25 (By similarity). Interacts with BCAR1/p130Cas and SRC through its C-terminal domain. Interacts with CSK, CTTN, SORBS3/vinexin, SYP and MAPRE3/EB3.
Tyrosine-phosphorylated in response to EGF and to cell adhesion to integrin ligands.
Antiparallel disulfide-linked heterodimer of an alpha chain and a beta chain (PubMed:12047389, PubMed:1491011, PubMed:1551440, PubMed:2780565, PubMed:2387851, PubMed:8328966). Self-associates and forms higher oligomers (PubMed:1903064). Interacts with a broad range of misfolded proteins, including APP, APOC2 and LYZ (PubMed:17407782, PubMed:8328966, PubMed:17412999). Slightly acidic pH promotes interaction with misfolded proteins (PubMed:12176985). Forms high-molecular weight oligomers upon interaction with misfolded proteins (PubMed:19535339). Interacts with APOA1, LRP2, CLUAP1 and PON1 (PubMed:15480429, PubMed:17260971, PubMed:1742316, PubMed:8292612, PubMed:1903064). Interacts with the complement complex (PubMed:2601725). Interacts (via alpha chain) with XRCC6 (By similarity). Interacts with SYVN1, COMMD1, BTRC, CUL1 and with ubiquitin and SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes (PubMed:17451556, PubMed:20068069). Interacts (via alpha chain) with BAX in stressed cells, where BAX undergoes a conformation change leading to association with the mitochondrial membrane (PubMed:16113678). Does not interact with BAX in unstressed cells (PubMed:16113678). Found in a complex with LTF, CLU, EPPIN and SEMG1 (PubMed:17567961). Interacts (immaturely glycosylated pre-secreted form) with HSPA5; this interaction promotes CLU stability and facilitates stress-induced CLU retrotranslocation from the secretory pathway to the mitochondria, thereby reducing stress-induced apoptosis by stabilizing mitochondrial membrane integrity (PubMed:22689054). Interacts (isoform 4) with BCL2L1; this interaction releases and activates BAX and promotes cell death (PubMed:21567405). Interacts with TGFBR2 and ACVR1 (PubMed:8555189). Interacts (secreted form) with STMN3; this interaction may act as an important modulator during neuronal differentiation (By similarity). Interacts with VLDLR and LRP8 (PubMed:24381170).
Detected in blood plasma, cerebrospinal fluid, milk, seminal plasma and colon mucosa. Detected in the germinal center of colon lymphoid nodules and in colon parasympathetic ganglia of the Auerbach plexus (at protein level). Ubiquitous. Detected in brain, testis, ovary, liver and pancreas, and at lower levels in kidney, heart, spleen and lung.
Does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity (PubMed:24073260). Promotes cell death through interaction with BCL2L1 that releases and activates BAX (PubMed:21567405).
Does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity.
Extensively glycosylated with sulfated N-linked carbohydrates (PubMed:17260971, PubMed:2387851). About 30% of the protein mass is comprised of complex N-linked carbohydrate (PubMed:2387851). Endoplasmic reticulum (ER) stress induces changes in glycosylation status and increases level of hypoglycosylated forms (PubMed:22689054). Core carbohydrates are essential for chaperone activity (PubMed:25402950). Non-secreted forms are hypoglycosylated or unglycosylated (PubMed:24073260).
Functions as extracellular chaperone that prevents aggregation of non native proteins (PubMed:11123922, PubMed:19535339). Prevents stress-induced aggregation of blood plasma proteins (PubMed:11123922, PubMed:12176985, PubMed:17260971, PubMed:19996109). Inhibits formation of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA and aggregation-prone LYZ variants (in vitro) (PubMed:12047389, PubMed:17412999, PubMed:17407782). Does not require ATP (PubMed:11123922). Maintains partially unfolded proteins in a state appropriate for subsequent refolding by other chaperones, such as HSPA8/HSC70 (PubMed:11123922). Does not refold proteins by itself (PubMed:11123922). Binding to cell surface receptors triggers internalization of the chaperone-client complex and subsequent lysosomal or proteasomal degradation (PubMed:21505792). Protects cells against apoptosis and against cytolysis by complement (PubMed:2780565). Intracellular forms interact with ubiquitin and SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes and promote the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:20068069). Promotes proteasomal degradation of COMMD1 and IKBKB (PubMed:20068069). Modulates NF-kappa-B transcriptional activity (PubMed:12882985). A mitochondrial form suppresses BAX-dependent release of cytochrome c into the cytoplasm and inhibit apoptosis (PubMed:16113678, PubMed:17689225). Plays a role in the regulation of cell proliferation (PubMed:19137541). An intracellular form suppresses stress-induced apoptosis by stabilizing mitochondrial membrane integrity through interaction with HSPA5 (PubMed:22689054). Secreted form does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity (PubMed:24073260). Secreted form act as an important modulator during neuronal differentiation through interaction with STMN3 (By similarity). Plays a role in the clearance of immune complexes that arise during cell injury (By similarity).
Isoform 4 has been previously detected in cytosol and in the nuclei of apoptotic cells and promoted apoptosis following irradiation (PubMed:12551933). However the nuclear localization and apoptosis promotion has not been confirmed in other cell types (PubMed:24073260).
Major isoform. Major isoform. Detectable at protein level in stressed and unstressed cells (PubMed:24073260).
Minor isoform that has been detected in a breast cancer cell line, but not in any other tissues or cell lines (PubMed:12551933). Not glycosylated. Not detected in unstressed cells. Detectable at low level in stressed cells (PubMed:24073260).
Polyubiquitinated, leading to proteasomal degradation (PubMed:17451556, PubMed:19137541). Under cellular stress, the intracellular level of cleaved form is reduced due to proteasomal degradation (PubMed:17451556).
Proteolytically cleaved on its way through the secretory system, probably within the Golgi lumen (PubMed:2387851). Proteolytic cleavage is not necessary for its chaperone activity (PubMed:25402950). All non-secreted forms are not proteolytically cleaved (PubMed:24073260). Chaperone activity of uncleaved forms is dependent on a non-reducing environment (PubMed:25402950).
Translated from an unconventional translation initiation site CTG (PubMed:24073260). Not glycosylated (PubMed:24073260). Not detected in unstressed cells. Detectable at low level in stressed cells (PubMed:24073260).
Up-regulated in response to enterovirus 71 (EV71) infection (at protein level) (PubMed:16548883). Up-regulated by agents that induce apoptosis, both at mRNA and protein level (PubMed:17689225). Isoform 1 is up-regulated by androgen (PubMed:17148459). Isoform 2 is down-regulated by androgen (PubMed:17148459).
A genetic variation in the IFNGR1 gene is associated with susceptibility to Helicobacter pylori infection [MIM:600263].
Monomer (PubMed:9367779). Heterodimer with IFNGR2, to form the IFNG receptor complex (PubMed:7615558). Interacts with JAK1 (PubMed:7615558). Interacts (when phosphorylated) with STAT1 (PubMed:8156998). Interacts with SOCS1 (By similarity).
Phosphorylated at Ser/Thr residues. Phosphorylation of Tyr-457 is required for IFNG receptor signal transduction (PubMed:8156998). Influenza virus infection leads to phosphorylation in a CSNK1A1-dependent manner (PubMed:29343571).
Receptor subunit for interferon gamma/INFG that plays crucial roles in antimicrobial, antiviral, and antitumor responses by activating effector immune cells and enhancing antigen presentation (PubMed:20015550). Associates with transmembrane accessory factor IFNGR2 to form a functional receptor (PubMed:7615558, PubMed:2971451, PubMed:7617032, PubMed:10986460, PubMed:7673114). Upon ligand binding, the intracellular domain of IFNGR1 opens out to allow association of downstream signaling components JAK1 and JAK2. In turn, activated JAK1 phosphorylates IFNGR1 to form a docking site for STAT1. Subsequent phosphorylation of STAT1 leads to dimerization, translocation to the nucleus, and stimulation of target gene transcription (PubMed:28883123). STAT3 can also be activated in a similar manner although activation seems weaker. IFNGR1 intracellular domain phosphorylation also provides a docking site for SOCS1 that regulates the JAK-STAT pathway by competing with STAT1 binding to IFNGR1 (By similarity).
Ubiquitinated after phosphorylation in a CSNK1A1-dependent manner, leading to the lysosome-dependent degradation (PubMed:29343571). Proteasomally degraded through 'Lys-48'-mediated ubiquitination (PubMed:28883123). Ubiquitination is necessary for efficient IFNGR1 signaling (PubMed:28883123).
Interacts with histones H2A, H2B, H3 and H4 (PubMed:11823430, PubMed:30855230). The binding is coupled to RanGTP cycles (PubMed:11823430). Interacts with AKIRIN2; promoting association with pre-assembled proteasomes (PubMed:34711951). Associates with pre-assembled proteasomes; interaction is indirect and mediated via interaction with AKIRIN2 (PubMed:34711951). Interacts with PPP2R1A and PPP2R1B (PubMed:12670497).
Nuclear transport receptor that mediates nuclear import of proteins, such as histones, proteasome and actin (PubMed:11823430, PubMed:34711951, PubMed:30855230). Serves as receptor for nuclear localization signals (NLS) in cargo substrates (PubMed:11823430). Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism (PubMed:11823430). At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran (PubMed:11823430). The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus (PubMed:11823430). Mediates the import of pre-assembled proteasomes into the nucleus; AKIRIN2 acts as a molecular bridge between IPO9 and the proteasome complex (PubMed:11823430, PubMed:34711951). Mediates the nuclear import of histones H2A, H2B, H4 and H4 (PubMed:11823430, PubMed:30855230). In addition to nuclear import, also acts as a chaperone for histones by preventing inappropriate non-nucleosomal interactions (PubMed:30855230). Mediates the nuclear import of actin (By similarity).
(Microbial infection) The Legionella effector RavZ is a deconjugating enzyme that hydrolyzes the amide bond between the C-terminal glycine residue and an adjacent aromatic residue in ATG8 proteins conjugated to phosphatidylethanolamine (PE), producing an ATG8 protein that is resistant to reconjugation by the host machinery due to the cleavage of the reactive C-terminal glycine (PubMed:31722778). RavZ is also able to mediate delipidation of ATG8 proteins conjugated to phosphatidylserine (PS) (PubMed:33909989).
Heart, brain, placenta, liver, skeletal muscle, kidney and pancreas.
Interacts with GPHN and NSF (By similarity). Interacts with ATG3, ATG7, ATG13 (PubMed:11096062, PubMed:11825910, PubMed:12507496, PubMed:23043107). Interacts with alpha- and beta-tubulin (PubMed:9892355, PubMed:11729197). Interacts with GABRG2 (PubMed:9892355, PubMed:11729197). Interacts with RB1CC1 (PubMed:23043107). Interacts with ULK1 (PubMed:11146101, PubMed:23043107). Interacts with CALR (PubMed:19154346). Interacts with DDX47 (PubMed:15977068). Interacts with TP53INP1 and TP53INP2 (PubMed:19056683, PubMed:22421968, PubMed:22470510). Interacts with TBC1D5 and TBC1D25 (PubMed:21383079, PubMed:22354992). Directly interacts with SQSTM1 (PubMed:17580304, PubMed:24668264). Interacts with MAPK15 (PubMed:22948227). Interacts with TECPR2 (PubMed:20562859). Interacts with PCM1 (PubMed:24089205). Interacts with TRIM5 and TRIM21 (PubMed:25127057, PubMed:26347139). Interacts with MEFV (PubMed:26347139). Interacts with KIF21B (By similarity). Interacts with WDFY3; this interaction is required for WDFY3 recruitment to MAP1LC3B-positive p62/SQSTM1 bodies (PubMed:24668264). Interacts with the reticulophagy receptor TEX264 (PubMed:31006538). Interacts with UBA5 (PubMed:26929408). Interacts with FLCN; interaction regulates autophagy (PubMed:25126726). Interacts with KBTBD6 and KBTBD7; the interaction is direct and required for the ubiquitination of TIAM1 (PubMed:25684205). Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3 (PubMed:34338405). Interacts with IRGM (PubMed:29420192). Interacts with STX17 (PubMed:29420192). Interacts with CT55; this interaction may be important for GABARAP protein stability (PubMed:36481789).
The precursor molecule is cleaved by ATG4 (ATG4A, ATG4B, ATG4C or ATG4D) to expose the glycine at the C-terminus and form the cytosolic form, GABARAP-I (PubMed:15169837, PubMed:20818167, PubMed:30661429). The processed form is then activated by APG7L/ATG7, transferred to ATG3 and conjugated to phosphatidylethanolamine (PE) phospholipid to form the membrane-bound form, GABARAP-II (PubMed:15169837). During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid (PubMed:33909989). ATG4 proteins also mediate the delipidation of PE-conjugated forms (PubMed:33909989). In addition, ATG4B and ATG4D mediate delipidation of ATG8 proteins conjugated to PS during non-canonical autophagy (PubMed:33909989). ATG4B constitutes the major protein for proteolytic activation (PubMed:30661429). ATG4D is the main enzyme for delipidation activity (By similarity).
Ubiquitin-like modifier that plays a role in intracellular transport of GABA(A) receptors and its interaction with the cytoskeleton (PubMed:9892355). Involved in autophagy: while LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation (PubMed:15169837, PubMed:20562859, PubMed:22948227). Through its interaction with the reticulophagy receptor TEX264, participates in the remodeling of subdomains of the endoplasmic reticulum into autophagosomes upon nutrient stress, which then fuse with lysosomes for endoplasmic reticulum turnover (PubMed:31006538). Also required for the local activation of the CUL3(KBTBD6/7) E3 ubiquitin ligase complex, regulating ubiquitination and degradation of TIAM1, a guanyl-nucleotide exchange factor (GEF) that activates RAC1 and downstream signal transduction (PubMed:25684205). Thereby, regulates different biological processes including the organization of the cytoskeleton, cell migration and proliferation (PubMed:25684205). Involved in apoptosis (PubMed:15977068).
Controls osteoclast survival and size (By similarity). As a dimer with JUN, activates LIF transcription (By similarity). Activates CEBPB transcription in PGE2-activated osteoblasts (By similarity).
Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala) (PubMed:27622773, PubMed:27911835, PubMed:28493438, PubMed:33909043). Also edits incorrectly charged tRNA(Ala) via its editing domain (PubMed:27622773, PubMed:27911835, PubMed:28493438).
Monomer (PubMed:27911835). Interacts with ANKRD16; the interaction is direct (By similarity).
The C-terminal C-Ala domain (residues 756 to 968) is not required for catalytic activity and can bind DNA (in vitro) (PubMed:27911835). The C-terminal C-Ala domain (residues 756 to 968), along with tRNA(Ala), serves as a bridge to cooperatively bring together the editing and aminoacylation centers thus stimulating deacylation of misacylated tRNAs. The human domain can be used in vitro to replace the corresponding domain in E.coli (PubMed:19661429).
Degrades casein, gelatins of types I, III, IV, and V, and fibronectin. Activates procollagenase.
Forms homomultimers. Multimerization appears to be important for presynaptic targeting. Interacts with BSN.
Phosphorylated. Phosphorylation promotes association with synaptic vesicle membranes.
Presynaptic protein involved in the synaptic transmission tuning. Regulates synaptic release probability by decreasing the calcium sensitivity of release.
Amidohydrolase that hydrolyzes specifically one of the carboamide linkages in D-pantetheine thus recycling pantothenic acid (vitamin B5) and releasing cysteamine.
By Th17/Th1 type cytokines, but not by Th2-type.
Widely expressed with higher expression in spleen, kidney and blood. Overexpressed in lesional psoriatic skin.
Acylated; primarily with C14, C16 and C18 fatty acids.
Phosphorylation at Tyr-232 by isoform 1 of CHKA (CHKalpha2) promotes dissociation from lipid droplets: dissociation is followed by recruitment of autophagosome machinery to lipid droplets and subsequent lipid droplet lipolysis.
Structural component of lipid droplets, which is required for the formation and maintenance of lipid storage droplets.
Glycosylation at Asn-75 and/or Asn-79 is required for interaction with VIP36 while glycosylation at Asn-345 and Asn-402 modulates ligand-mediated GUCY2C activation.
Guanylyl cyclase that catalyzes synthesis of cyclic GMP (cGMP) from GTP (PubMed:1718270, PubMed:11950846, PubMed:23269669, PubMed:22521417, PubMed:22436048). Receptor for the E.coli heat-stable enterotoxin; E.coli enterotoxin markedly stimulates the accumulation of cGMP in mammalian cells expressing GUCY2C (PubMed:1718270, PubMed:1680854). Also activated by the endogenous peptides guanylin and uroguanylin (PubMed:8381596).
Homotrimer (PubMed:11123935). Interacts via its C-terminal region with NHERF4 (PubMed:11950846). Interacts with the lectin chaperone VIP36 (PubMed:23269669).
Found in articular chondrocytes. Expressed in a variety of tissues.
Necessary for efficient 3-hydroxylation of fibrillar collagen prolyl residues.
(Microbial infection) Interacts with S.flexneri E3 ubiquitin-protein ligases IpaH1.4 and IpaH2.5, leading to its ubiquitination.
(Microbial infection) Ubiquitinated by S.flexneri E3 ubiquitin-protein ligases IpaH1.4 and IpaH2.5, leading to its degradation by the proteasome, thereby preventing formation of the bacterial ubiquitin coat and activation of innate immunity.
Autoubiquitinated (PubMed:24726323). Interaction with OTULIN is required to suppress formation of 'Met-1'-linked polyubiquitin chains and prevent subsequent inactivation of the LUBAC complex (PubMed:24726323).
Component of the LUBAC complex (linear ubiquitin chain assembly complex) which consists of SHARPIN, RBCK1 and RNF31 (PubMed:17006537, PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:28481331). LUBAC has a MW of approximately 600 kDa suggesting a heteromultimeric assembly of its subunits (PubMed:17006537, PubMed:21455173, PubMed:21455180, PubMed:21455181). Associates with the TNF-R1 signaling complex (TNF-RSC) in a stimulation-dependent manner (PubMed:20005846). Interacts (via the PUB domain) with OTULIN (via the PIM motif); the interaction is direct (PubMed:23708998, PubMed:24726323, PubMed:24726327). Interacts (via the PUB domain) with VCP (via the PIM motif) (PubMed:24726327). Interacts (via the PUB domain) with SPATA2 (via the PIM motif); interaction is direct and bridges RNF31 and CYLD (PubMed:27458237, PubMed:27545878, PubMed:28189684, PubMed:27591049). Interacts with CYLD; the interaction is indirect and is mediated via SPATA2 (PubMed:27458237, PubMed:27545878, PubMed:26997266). Interacts with MUSK (By similarity). Interacts with CARD11, promoting linear ubiquitination of BCL10 (PubMed:27777308).
E3 ubiquitin-protein ligase component of the LUBAC complex which conjugates linear ('Met-1'-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation (PubMed:17006537, PubMed:19136968, PubMed:20005846, PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:22863777, PubMed:28481331, PubMed:28189684). LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways (PubMed:17006537, PubMed:19136968, PubMed:20005846, PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:22863777, PubMed:28189684). Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation (PubMed:21455173, PubMed:28189684). LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex (PubMed:20005846, PubMed:27458237). The LUBAC complex is also involved in innate immunity by conjugating linear polyubiquitin chains at the surface of bacteria invading the cytosol to form the ubiquitin coat surrounding bacteria (PubMed:28481331, PubMed:34012115). LUBAC is not able to initiate formation of the bacterial ubiquitin coat, and can only promote formation of linear polyubiquitins on pre-existing ubiquitin (PubMed:28481331). Recruited to the surface of bacteria by RNF213, which initiates the bacterial ubiquitin coat (PubMed:34012115). The bacterial ubiquitin coat acts as an 'eat-me' signal for xenophagy and promotes NF-kappa-B activation (PubMed:28481331, PubMed:34012115). Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis (PubMed:23708998). RNF31 is required for linear ubiquitination of BCL10, thereby promoting TCR-induced NF-kappa-B activation (PubMed:27777308). Binds polyubiquitin of different linkage types (PubMed:23708998).
Expressed in both normal and transformed breast epithelial cell lines.
RING 1 and IBR zinc-fingers catalyze the first step transfer of ubiquitin from the E2 onto RING 2, to transiently form a HECT-like covalent thioester intermediate.
The PUB domain mediates interaction with the PIM motifs of VCP and RNF31, with a strong preference for RNF31.
The RanBP2-type zinc fingers mediate the specific interaction with ubiquitin.
The UBA domain mediates association with RBCK1/HOIL1 via interaction with its UBL domain.
The linear ubiquitin chain determining domain (LDD) mediates the final transfer of ubiquitin from RING 2 onto the N-terminus of a target ubiquitin.
(Microbial infection) Interacts with human papillomavirus 4/HPV4 protein E8, human papillomavirus 5/HPV5 protein E1, and human papillomavirus 16/HPV16 proteins E2 and E5.
(Microbial infection) Involved in keratinocyte-intrinsic immunity to human beta-papillomaviruses (HPVs).
Calcium-binding protein that plays a role in the regulation of numerous cellular processes, such as cell differentiation, cell division, cell proliferation, cell migration, thrombosis, angiogenesis, cardiac hypertrophy and apoptosis. Involved in bone marrow megakaryocyte differentiation by negatively regulating thrombopoietin-mediated signaling pathway. Participates in the endomitotic cell cycle of megakaryocyte, a form of mitosis in which both karyokinesis and cytokinesis are interrupted. Plays a role in integrin signaling by negatively regulating alpha-IIb/beta3 activation in thrombin-stimulated megakaryocytes preventing platelet aggregation. Up-regulates PTK2/FAK1 activity, and is also needed for the recruitment of PTK2/FAK1 to focal adhesions; it thus appears to play an important role in focal adhesion formation. Positively regulates cell migration on fibronectin in a CDC42-dependent manner, the effect being negatively regulated by PAK1. Functions as a negative regulator of stress activated MAP kinase (MAPK) signaling pathways. Down-regulates inositol 1,4,5-trisphosphate receptor-dependent calcium signaling. Involved in sphingosine kinase SPHK1 translocation to the plasma membrane in a N-myristoylation-dependent manner preventing TNF-alpha-induced apoptosis. Regulates serine/threonine-protein kinase PLK3 activity for proper completion of cell division progression. Plays a role in microtubule (MT) dynamics during neuronal development; disrupts the MT depolymerization activity of STMN2 attenuating NGF-induced neurite outgrowth and the MT reorganization at the edge of lamellipodia. Promotes cardiomyocyte hypertrophy via activation of the calcineurin/NFAT signaling pathway. Stimulates calcineurin PPP3R1 activity by mediating its anchoring to the sarcolemma. In ischemia-induced (pathological or adaptive) angiogenesis, stimulates endothelial cell proliferation, migration and microvessel formation by activating the PAK1 and ERK1/ERK2 signaling pathway. Promotes also cancer cell survival and proliferation. May regulate cell cycle and differentiation of spermatogenic germ cells, and/or differentiation of supporting Sertoli cells.
Monomer. Interacts with MYO1C. Interacts (via C-terminal region) with PPP3R1 and CACNA1C; the interactions increase upon cardiomyocytes hypertrophy (By similarity). Interacts with the heterodimeric integrin alpha-IIb/beta3 (ITGA2B-ITGB3). Interacts with ITGA2B (via cytoplasmic domain); the interaction is direct and calcium-dependent. Interacts with the protein kinases PLK2/SNK and PRKDC (via the region immediately upstream of the kinase domain). Interacts with PLK3; the interaction inhibits PLK3 kinase activity. Interacts with PSEN2. Interacts (via C-terminus) with F8. Interacts with NBR1 (via C-terminus). Interacts with FEZ1 (via C-terminus). Interacts with UBR5 (via C-terminus); the interaction is sensitive to DNA damage, and may target CIB1 for ubiquitin-mediated degradation. Interacts with IFI6; the interaction is direct (PubMed:15685448). Interacts with BCL2 (PubMed:15685448). Interacts with ITPR3; the interaction occurs in a calcium-dependent manner. Interacts with PTK2/FAK1. Interacts with MAP3K5; the interaction inhibits MAP3K5 activation by phosphorylation, and its subsequent interaction with TRAF2. Isoform 2 interacts with PRKD2 (via N-terminal AP-rich region), PTK2/FAK1 and PAK1. Interacts with TAS1R2 (via C-terminus); the interaction is independent of the myristoylation state of CIB1. Interacts (via C-terminal region) with STMN2 (via the N-terminal region); the interaction is direct, occurs in a calcium-dependent manner and attenuates the STMN2-induced neurite outgrowth inhibition. Interacts with SPHK1, the interaction occurs in a calcium-dependent manner. Interacts with ITGA2B (via C-terminal cytoplasmic tail); the interaction occurs upon platelet aggregation and is stabilized/increased in a calcium and magnesium-dependent manner. Interacts with PAK1 (via N-terminal region); the interaction is direct and occurs in a calcium-dependent manner. Interacts with RAC3 (via C-terminal region); the interaction induces their association with the cytoskeleton upon alpha-IIb/beta3 integrin-mediated adhesion. Interacts with ITGA5 and ITGAV. Interacts and forms a complex with TMC6 and TMC8 (PubMed:30068544).
Phosphorylation of isoform 2 at Ser-118 by PRKD2 increases its ability to stimulate tumor angiogenesis.
Plays a regulatory role in angiogenesis and tumor growth by mediating PKD/PRKD2-induced vascular endothelial growth factor A (VEGFA) secretion.
The EF-hands may also bind magnesium ions in the presence of high Mg(2+) levels and low Ca(2+) levels.
Ubiquitously expressed. Expressed in the epidermis, hair follicles and keratinocytes (PubMed:30068544). Detected in platelets and in cell lines of megakaryocytic and erythrocytic lineages. Both isoform 1 and isoform 2 are detected in various cancer cell lines, with isoform 2 being the predominant form (at protein level).
Up-regulated during breast cancer progression.
Belongs to the SMC family. SMC4 subfamily.
Forms a heterodimer with SMC2. Component of the condensin complex, which contains the SMC2 and SMC4 heterodimer, and three non SMC subunits that probably regulate the complex: BRRN1/CAPH, CNAP1/CAPD2 and CAPG.
The SMC hinge domain, which separates the large intramolecular coiled coil regions, allows the heterodimerization with SMC2, forming a V-shaped heterodimer.
Widely expressed. Higher expression in testis, colon, thymus.
Interacts with the C-terminus of CACNA1E (PubMed:15258581). Interacts with alpha-tubulin (PubMed:19734894).
Microtubule-associated protein which regulates cell division and neuronal migration during cortical development. Necessary for mitotic spindle organization (PubMed:19734894, PubMed:28370826). Necessary for radial and tangential cell migration during brain development, possibly acting as a regulator of cell morphology and process formation during migration (PubMed:22926142). May enhance calcium influx through CACNA1E and stimulate programmed cell death (PubMed:15258581, PubMed:19734894, PubMed:22926142, PubMed:28370826). Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (PubMed:36191189).
Mutation Leu-229 may be a cause of intractable epilepsy of infancy. Affected individuals have seizures of multiple type, manifested as tonic, clonic, and myoclonic seizures in the neonatal period, and as tonic seizures activated frequently by sleep, and repeated frequent myoclonic seizures in later infancy. The seizures are unresponsive to numerous antiepileptic drugs, and infants die in the first years of life. Although heterozygosity for Leu-229 has been associated with relatively benign forms of epilepsy in adolescence, homozygosity for the same mutation has much more severe consequences.
Widely expressed. Not detected in lymphocytes.
Detected in heart muscle (at protein level). Isoform 1 and isoform 2 are ubiquitous with highest levels in brain and thymus.
Has the potential to contribute to the immunosuppressive and toxic effects of FK506 and rapamycin. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
Identified in a complex composed of RYR2, FKBP1B, PKA catalytic subunit, PRKAR2A, AKAP6, and the protein phosphatases PP2A and PP1. Interacts directly with RYR2.
Catalyzes the oxidative ring opening of 3-hydroxyanthranilate to 2-amino-3-carboxymuconate semialdehyde, which spontaneously cyclizes to quinolinate.
Chondroitin sulfate- and hyaluronan-binding proteoglycan involved in the organization of interphotoreceptor matrix; may participate in the maturation and maintenance of the light-sensitive photoreceptor outer segment. Binds heparin.
Expressed in the retina (at protein level) (PubMed:10702256, PubMed:29777959). Expressed by photoreceptors of the interphotoreceptor matrix (IPM) surrounding both rods and cones (at protein level) (PubMed:10542133, PubMed:29777959). IPM occupies the subretinal space between the apices of the retinal pigment epithelium and the neural retina (PubMed:10542133). Expressed in the pineal gland (at protein level) (PubMed:10702256).
Expressed in the retina 17 weeks post-conception (at protein level) (PubMed:29777959). Expressed in the outer neuroblastic zone and retinal pigment epithelium (at protein level) (PubMed:29777959).
Expressed abundantly in pancreas, heart and brain with low levels of expression in lung, kidney, liver and thyroid.
May play a role in neurotransmitter secretion.
Homomer (Probable). Does not interact with MEGF10.
May regulate the mosaic spacing of specific neuron subtypes in the retina through homotypic retinal neuron repulsion. Mosaics provide a mechanism to distribute each cell type evenly across the retina, ensuring that all parts of the visual field have access to a full set of processing elements (By similarity).
Although related to peptidase S1 family, lacks the conserved active Ser residue in position 346 which is replaced by a Thr, suggesting that it has no protease activity.
Highly expressed in testis where it is primarily localised in spermatids (at protein level).
In round spermatids, acts as a scaffold protein supporting FREY1 in IZUMO1 recruitment at the endoplasmic reticulum membrane and coordination of IZUMO1 complex assembly. Stabilizes FREY1 at the endoplasmic reticulum membrane through interaction. May recruit IZUMO1 interaction partners.
Interacts (via active sites) with FREY; the interaction stabilizes FREY1 protein and inhibits SPPL2C proteolytic activity.
Sperm-specific intramembrane-cleaving aspartic protease (I-CLiP) that cleaves distinct tail-anchored proteins and SNARE proteins (PubMed:30733281). In elongated spermatids, modulates intracellular Ca(2+) homeostasis by controlling PLN abundance through proteolytic cleavage (By similarity). During spermatogenesis, processes SNARE proteins and impacts vesicular trafficking which supports compartmental reorganization in maturating spermatids and may play a role in formation of the acrosome (PubMed:30733281).
The PAL motif is required for normal active site conformation. The catalytic domains embedded in the membrane are in the opposite orientation to that of the presenilin protein family; therefore, it is predicted to cleave type II-oriented substrate peptides like the prototypic protease SPP.
Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane (By similarity).
Binds 3 Ca(2+) ions per subunit. Two of the Ca(2+) ions are bound to the C2 domain.
Binds 5 Ca(2+) ions per subunit. Two of the Ca(2+) ions are bound to the C2 domain.
Strongly expressed in lung, liver and heart. Also expressed at least in pancreas, kidney, skeletal muscle, placenta and brain.
The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes (PubMed:9188725). Essential for trophoblast and placental development (By similarity). Binds phosphatidylinositol 4,5-bisphosphate (PubMed:7890667, PubMed:9188725).
(Microbial infection) Cellular cofactor of human T-cell leukemia virus type I (HTLV-1) Rex protein and of human immunodeficiency virus type 1 (HIV-1) Rev protein, essential for mRNA export of retroviral transcripts.
Acetylated by PCAF/KAT2B, regulating its subcellular localization (PubMed:19379712, PubMed:22771473). Deacetylated by SIRT2 (PubMed:22771473).
Binds to 80S ribosomes (PubMed:27115996). Actively translating ribosomes show mutually exclusive binding of eIF5a (EIF5A or EIF5A2) and EEF2/eEF2 (PubMed:27115996). Interacts with DAPL1; interaction takes place at the polypeptide exit tunnel of hibernating ribosomes and prevents translation (By similarity). Interacts with DHPS (PubMed:10229683). Interacts with SDCBP (PubMed:15371445). Interacts with DOHH (PubMed:17213197).
Expressed in umbilical vein endothelial cells and several cancer cell lines (at protein level).
Mature eIF5A-1 may be used as an in situ diagnostic marker for aberrant proliferation in intraepithelial neoplasia of the vulva.
Translation factor that promotes translation elongation and termination, particularly upon ribosome stalling at specific amino acid sequence contexts (PubMed:33547280). Binds between the exit (E) and peptidyl (P) site of the ribosome and promotes rescue of stalled ribosome: specifically required for efficient translation of polyproline-containing peptides as well as other motifs that stall the ribosome (By similarity). Acts as ribosome quality control (RQC) cofactor by joining the RQC complex to facilitate peptidyl transfer during CAT tailing step (By similarity). Also involved in actin dynamics and cell cycle progression, mRNA decay and probably in a pathway involved in stress response and maintenance of cell wall integrity (PubMed:16987817). With syntenin SDCBP, functions as a regulator of p53/TP53 and p53/TP53-dependent apoptosis (PubMed:15371445). Regulates also TNF-alpha-mediated apoptosis (PubMed:15452064, PubMed:17187778). Mediates effects of polyamines on neuronal process extension and survival (PubMed:17360499).
Homohexamer. Interacts with TOR1A; the interaction may be specific of neural tissues. Interacts with TOR1AIP1; TOR1AIP1 is required for TOR1B location on the nuclear membrane. Interacts (ATP-bound) with TOR1AIP2; important for endoplasmic reticulum integrity.
May serve as a molecular chaperone assisting in the proper folding of secreted and/or membrane proteins. Plays a role in non-neural cells nuclear envelope and endoplasmic reticulum integrity. May have a redundant function with TOR1A in non-neural tissues.
Widely expressed with low levels in brain.
GTPase-activating protein (GAP) for ADP ribosylation factor 1 (ARF1). Implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Hydrolysis of ARF1-bound GTP may lead to dissociation of coatomer from Golgi-derived membranes to allow fusion with target membranes.
Interacts with the coatomer complex. Interacts with the C-terminal appendage domain of COPG1.
Vero cells overexpressing truncated ARFGAP2 show accumulation of cholera toxin A subunit in the Golgi complex rather than the endoplasmic reticulum.
Homodimer. Interacts with DLG4; the interaction possibly being prevented by the association between NOS1 and CAPON. Forms a ternary complex with CAPON and RASD1. Forms a ternary complex with CAPON and SYN1. Interacts with ZDHHC23. Interacts with NOSIP; which may impair its synaptic location (By similarity). Interacts with HTR4 (By similarity). Interacts with SLC6A4. Interacts with VAC14 (By similarity). Interacts (via N-terminal domain) with DLG4 (via N-terminal tandem pair of PDZ domains). Interacts with SLC6A4. Forms a complex with ASL, ASS1 and SLC7A1; the complex regulates cell-autonomous L-arginine synthesis and citrulline recycling while channeling extracellular L-arginine to nitric oxide synthesis pathway (By similarity). Interacts with DMD; localizes NOS1 to sarcolemma in muscle cells (By similarity). Interacts with DYNLL1; inhibits the nitric oxide synthase activity (By similarity).
Isoform 1 is ubiquitously expressed: detected in skeletal muscle and brain, also in testis, lung and kidney, and at low levels in heart, adrenal gland and retina. Not detected in the platelets. Isoform 3 is expressed only in testis. Isoform 4 is detected in testis, skeletal muscle, lung, and kidney, at low levels in the brain, but not in the heart and adrenal gland.
Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body.
Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR.
Stimulated by calcium/calmodulin. Inhibited by DYNLL1 that prevents the dimerization of the protein. Inhibited by NOSIP.
The PDZ domain participates in protein-protein interaction, and is responsible for targeting nNos to synaptic membranes. Mediates interaction with VAC14.
Ubiquitinated; mediated by STUB1/CHIP in the presence of Hsp70 and Hsp40 (in vitro).
Belongs to the dihydrofolate reductase family.
Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFR2.
Widely expressed in fetal and adult tissues, including throughout the fetal and adult brains and whole blood. Expression is higher in the adult brain than in the fetal brain.
Acts as an electroneutral and low-affinity sodium (Na(+))-dependent sodium-coupled solute transporter (PubMed:17692818). Catalyzes the transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, nicotinate, propionate, butyrate and beta-D-hydroxybutyrate (By similarity). May be responsible for the first step of reabsorption of monocarboxylates from the lumen of the proximal tubule of the kidney and the small intestine. May play also a role in monocarboxylates transport in the retina (By similarity).
Cotransport of monocarboxylates and nicotinate strongly inhibited by ibuprofen, fenoprofen and ketoprofen.
Expressed in placenta, testis and leukocytes. Expressed in neuroblastoma. Present in K-562 erythrocytic leukemia cell line (at protein level).
Heterodimer with ARID3A. Interacts with unphosphorylated RB1.
Transcription factor which may be involved in neuroblastoma growth and malignant transformation. Favors nuclear targeting of ARID3A.
Expressed in hair follicles and in the dermis (at protein level).
Expressed in skin fibroblasts and retinal pigment epithelium (RPE) cells.
Has been shown in one study to play a role in cleavage furrow maturation during cytokinesis. However, other studies have shown no role in this process.
Induced by high glucose levels and transforming growth factor beta (at protein level).
Involved in transforming growth factor beta-mediated rearrangement of the podocyte cytoskeleton which includes reduction of F-actin fibers and broadening, flattening and elongation of podocytes (PubMed:29488390). Plays a role in basement membrane organization (By similarity). May promote cleavage furrow maturation during cytokinesis in preimplantation embryos (By similarity). May play a role in the architecture of adhesive and flexible epithelial cell junctions (By similarity). May play a role during myocardial remodeling by imparting an effect on cardiac fibroblast migration (By similarity).
Belongs to the bacterial ribosomal protein bL28 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25278503, PubMed:11551941). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (PubMed:11551941, PubMed:25278503). Interacts with OXA1L.
Found in a variety of normal tissues including spleen, testes, thymus, liver, kidney, brain, adrenal, lung and retinal tissue.
Potentially represents an important therapeutic reagent for HLA-A24 patients. This antigen is recognized by tumor-infiltrating lymphocyte (TIL) 1290 in the context of HLA-A24.
Detected in all the examined tissues with highest expression in liver, followed by heart, stomach, kidney, skeletal muscle, placenta, and pancreas.
Involved in the regulation of cell cycle progression, this activity is related to the inhibition of apoptosis following the removal of essential growth factors (PubMed:12145692). Exhibits H3K4me3-binding activity (PubMed:29061846).
Overexpression in murine myeloid cell line 32Dcl3 causes G2/M arrest.
(Microbial infection) In alveolar cells and fibroblasts, expression is induced by Sars-CoV-2 infection.
(Microbial infection) Interacts with human coronavirus SARS-CoV-2 spike protein (via RBD domain); the interaction is direct and sequesters virions at the cell surface.
(Microbial infection) Interacts with human coronavirus SARS-CoV-2 spike protein (via RBD domain); the interaction is direct.
(Microbial infection) Modulates the ability of SARS-CoV-2 to infect host cells through interaction with the spike protein (PubMed:36735681, PubMed:36757924, PubMed:36228039). Does not act as a SARS-CoV-2 entry receptor but sequesters virions and antagonizes in trans SARS-CoV-2 infection of ACE2(+) cells when expressed on nearby cells (PubMed:36757924, PubMed:36228039).
Expressed in brain and placenta (PubMed:11785964). Expressed in lung fibroblasts (PubMed:36757924, PubMed:36228039). Expressed in chodrocytes (PubMed:34702854).
In fiboblasts, expression is strongly induced by TGFB1 (PubMed:36735681, PubMed:36757924). In chodrocytes, expression is induced by IL1B (PubMed:34702854).
Involved in cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility. Acts in association with DOCK1 and CRK. Was initially proposed to be required in complex with DOCK1 to activate Rac Rho small GTPases. May enhance the guanine nucleotide exchange factor (GEF) activity of DOCK1 (By similarity).
Probably interacts directly with the SH3-domain of DOCK1 via its SH3-binding site. Part of a complex with DOCK1 and RAC1 (By similarity). Interacts with ADGRB3 (PubMed:24567399).
Catalytic subunit of the phosphorylase b kinase (PHK), which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase. In vitro, phosphorylates PYGM, TNNI3, MAPT/TAU, GAP43 and NRGN/RC3 (By similarity).
The two calmodulin-binding domains appear to act in concert to bind a single molecule of calmodulin and are pseudosubstrate/autoinhibitory domains.
Able to isomerize both 3-cis and 3-trans double bonds into the 2-trans form in a range of enoyl-CoA species.
Belongs to the radical SAM superfamily. Lipoyl synthase family.
Binds 2 [4Fe-4S] clusters per subunit. One cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.
Catalyzes the radical-mediated insertion of two sulfur atoms into the C-6 and C-8 positions of the octanoyl moiety bound to the lipoyl domains of lipoate-dependent enzymes, thereby converting the octanoylated domains into lipoylated derivatives.
Belongs to the acetyltransferase family. NAA40 subfamily.
Down-regulated in hepatocellular carcinoma tissues.
N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A (PubMed:21935442, PubMed:25619998). In contrast to other N-alpha-acetyltransferase, has a very specific selectivity for histones H4 and H2A N-terminus and specifically recognizes the 'Ser-Gly-Arg-Gly sequence' (PubMed:21935442, PubMed:25619998). Acts as a negative regulator of apoptosis (PubMed:26666750). May play a role in hepatic lipid metabolism (By similarity).
Widely expressed; with the highest expression level in liver and the lowest expression in brain (at protein level).
Detected in various tissues with highest expression in lung.
Low affinity receptor for N-formyl-methionyl peptides, which are powerful neutrophils chemotactic factors. Binding of FMLP to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. Acts as a receptor for humanin (PubMed:15465011).
Expressed in endothelial cells (PubMed:2430793, PubMed:3097076). Found in plasma, platelets, and hepatoma and fibrosarcoma cells.
Forms a heterodimer with TMPRSS7 (PubMed:15853774). Interacts with VTN (PubMed:7522053). Binds LRP1B; binding is followed by internalization and degradation (PubMed:11384978). Interacts with PPP1CB (PubMed:28296156). In complex with PLAU/uPA, interacts with PLAUR/uPAR (PubMed:15053742). Interacts with SORL1 and LRP1, either alone or in complex with PLAU; these interactions are abolished in the presence of LRPAP1/RAP (PubMed:15053742). The ternary complex composed of PLAUR-PLAU-PAI1 also interacts with SORL1 (PubMed:15053742). Also interacts with SORL1, when complexed to PLAT/tPA (PubMed:15053742).
Inactivated by proteolytic attack of the urokinase-type (u-PA) and the tissue-type (TPA), cleaving the 369-Arg-|-Met-370 bond.
Serine protease inhibitor. Inhibits TMPRSS7 (PubMed:15853774). Is a primary inhibitor of tissue-type plasminogen activator (PLAT) and urokinase-type plasminogen activator (PLAU). As PLAT inhibitor, it is required for fibrinolysis down-regulation and is responsible for the controlled degradation of blood clots (PubMed:8481516, PubMed:9207454, PubMed:17912461). As PLAU inhibitor, it is involved in the regulation of cell adhesion and spreading (PubMed:9175705). Acts as a regulator of cell migration, independently of its role as protease inhibitor (PubMed:15001579, PubMed:9168821). It is required for stimulation of keratinocyte migration during cutaneous injury repair (PubMed:18386027). It is involved in cellular and replicative senescence (PubMed:16862142). Plays a role in alveolar type 2 cells senescence in the lung (By similarity). Is involved in the regulation of cementogenic differentiation of periodontal ligament stem cells, and regulates odontoblast differentiation and dentin formation during odontogenesis (PubMed:25808697, PubMed:27046084).
The disease is caused by variants affecting the gene represented in this entry. A rare PAI-1D mutation resulting in a frameshift and protein truncation has been found in an Old Order Amish community. Homozygous mutation carriers suffer from episodes of major hemorrhage, while heterozygous carriers do not manifest abnormal bleeding (PubMed:9207454). Heterozygosity for the mutation is associated with longer leukocyte telomere length, lower fasting insulin levels, lower prevalence of diabetes mellitus, and a longer life span (PubMed:29152572).
Putative regulatory subunit of serine/threonine-protein phosphatase 4.
Serine/threonine-protein phosphatase 4 (PP4) occurs in different assemblies of the catalytic and one or more regulatory subunits. Component of the PP4 complex PPP4C-PPP4R4.
A paper describing a role for this protein in IRAK1-independent activation of the MAPK/ERK pathway in response to IL1 has been retracted, because some of the experimental data could not be reproduced.
Autophosphorylated (PubMed:8226782, PubMed:1833717). Isoform 1 undergoes phosphorylation mainly on Ser residues, and isoform 2 on both Ser and Thr residues (PubMed:8226782). Phosphorylated on Thr-290; the phosphorylation is necessary but not sufficient for full kinase activity in vitro and for the dissociation of isoform 1 from NFKB1, leading to its degradation (PubMed:15466476, PubMed:15699325). Phosphorylated on Ser-400 by IKBKB; the phosphorylation is required for LPS-stimulated activation of the MAPK/ERK pathway in macrophages (PubMed:17472361, PubMed:22988300).
Can be converted to an oncogenic protein by proviral activation, leading to a C-terminally truncated protein with transforming activity.
Expressed in several normal tissues and human tumor-derived cell lines.
Forms a ternary complex with NFKB1/p105 and TNIP2. Interacts with NFKB1; the interaction increases the stability of MAP3K8 but inhibits its MEK phosphorylation activity, whereas loss of interaction following LPS stimulation leads to its degradation. Interacts with CD40 and TRAF6; the interaction is required for ERK activation. Interacts with KSR2; the interaction inhibits ERK and NF-kappa-B activation.
Isoform 1 is activated specifically during the S and G2/M phases of the cell cycle.
Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the pro-inflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant.
Up-regulated by IL12 in T-lymphocytes. Up-regulated in subcutaneous adipose tissue of obese individuals.
Homodimer. Interacts with polycystin-2/PKD2 and GM130. Interacts with the C-terminal region of CTNNB1 (PubMed:12712206, PubMed:16424001). Interacts (C-terminus) with TCIM (C-terminus), TCIM competes with CTNNB1 for the interaction with CBY1 (PubMed:16424001). Interacts with FAM92A; this interaction facilitates targeting of FAM92A to cilium basal body (PubMed:27528616, PubMed:30395363). Interacts with CIBAR2 (PubMed:27528616).
Inhibits the Wnt/Wingless pathway by binding to CTNNB1/beta-catenin and inhibiting beta-catenin-mediated transcriptional activation through competition with TCF/LEF transcription factors. Has also been shown to play a role in regulating the intracellular trafficking of polycystin-2/PKD2 and possibly of other intracellular proteins. Promotes adipocyte and cardiomyocyte differentiation.
Widely expressed. Expressed at higher levels in heart, skeletal muscle, kidney and placenta. Also found in brain, lung, liver and testis. Significantly down-regulated in thyroid and metastatic uterine tumors.
Enzyme that cleaves 2',5'-phosphodiester bond linking adenosines of the 5'-triphosphorylated oligoadenylates, triphosphorylated oligoadenylates referred as 2-5A modulates the 2-5A system. Degrades triphosphorylated 2-5A to produce AMP and ATP (PubMed:26055709). Also cleaves 3',5'-phosphodiester bond of oligoadenylates (PubMed:21666256, PubMed:30389976, PubMed:26055709). Plays a role as a negative regulator of the 2-5A system that is one of the major pathways for antiviral and antitumor functions induced by interferons (IFNs). Suppression of this enzyme increases cellular 2-5A levels and decreases viral replication in cultured small-airway epithelial cells and Hela cells (PubMed:26055709).
COPII is composed of at least five proteins: the Sec23/24 complex, the Sec13/31 complex and Sar1 (By similarity). Interacts with SAR1A (PubMed:26522472).
Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules for their transport to the Golgi complex.
Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules.
(Microbial infection) Interacts with varicella-zoster virus IE63 protein.
Component of the TFIID-containing RNA polymerase II pre-initiation complex that is composed of TBP and at least GTF2A1, GTF2A2, GTF2E1, GTF2E2, GTF2F1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2B, TCEA1, ERCC2 and ERCC3 (PubMed:27193682). Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription (PubMed:9852112, PubMed:11319235). Interacts with XPB, XPD, GTF2H1 and GTF2H3 (PubMed:11319235).
Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. The N-terminus of GTF2H2 interacts with and regulates XPD whereas an intact C-terminus is required for a successful escape of RNAP II form the promoter.
Widely expressed, with higher expression in skeletal muscle.
Acetylation on Lys-403 activates transcriptional activity. Acetylated by p300 on several sites in diffentiating myocytes. Acetylation on Lys-4 increases DNA binding and transactivation (By similarity). Hyperacetylation by p300 leads to enhanced cardiac myocyte growth and heart failure.
Binds DNA as a homo- or heterodimer. Dimerizes with MEF2D. Interacts with HDAC7 (By similarity). Interacts with PIAS1; the interaction enhances sumoylation. Interacts with HDAC4, HDAC9 and SLC2A4RG. Interacts (via the N-terminal) with MAPK7; the interaction results in the phosphorylation and transcriptional activity of MEF2A.
Constitutive phosphorylation on Ser-408 promotes Lys-403 sumoylation thus preventing acetylation at this site. Dephosphorylation on Ser-408 by PPP3CA upon neuron depolarization promotes a switch from sumoylation to acetylation on residue Lys-403 leading to inhibition of dendrite claw differentiation. Phosphorylation on Thr-312 and Thr-319 are the main sites involved in p38 MAPK signaling and activate transcription. Phosphorylated on these sites by MAPK14/p38alpha and MAPK11/p38beta, but not by MAPK13/p38delta nor by MAPK12/p38gamma. Phosphorylation on Ser-408 by CDK5 induced by neurotoxicity inhibits MEF2A transcriptional activation leading to apoptosis of cortical neurons. Phosphorylation on Thr-312, Thr-319 and Ser-355 can be induced by EGF.
Isoform MEF2 and isoform MEFA are expressed only in skeletal and cardiac muscle and in the brain. Isoform RSRFC4 and isoform RSRFC9 are expressed in all tissues examined.
Proteolytically cleaved in cerebellar granule neurons on several sites by caspase 3 and caspase 7 following neurotoxicity. Preferentially cleaves the CDK5-mediated hyperphosphorylated form which leads to neuron apoptosis and transcriptional inactivation.
Sumoylation on Lys-403 is enhanced by PIAS1 and represses transcriptional activity. Phosphorylation on Ser-408 is required for sumoylation. Has no effect on nuclear location nor on DNA binding. Sumoylated with SUMO1 and, to a lesser extent with SUMO2 and SUMO3. PIASx facilitates sumoylation in postsynaptic dendrites in the cerebellar cortex and promotes their morphogenesis (By similarity).
Transcriptional activator which binds specifically to the MEF2 element, 5'-YTA[AT](4)TAR-3', found in numerous muscle-specific genes. Also involved in the activation of numerous growth factor- and stress-induced genes. Mediates cellular functions not only in skeletal and cardiac muscle development, but also in neuronal differentiation and survival. Plays diverse roles in the control of cell growth, survival and apoptosis via p38 MAPK signaling in muscle-specific and/or growth factor-related transcription. In cerebellar granule neurons, phosphorylated and sumoylated MEF2A represses transcription of NUR77 promoting synaptic differentiation. Associates with chromatin to the ZNF16 promoter.
Forms a ternary complex with IL18 and IL18RAP (PubMed:14528293, PubMed:25500532). Within this complex, IL18R1 is involved in ligand-binding and IL18RAP in signaling leading to NF-kappa-B and JNK activation (Probable). Interacts with SLC12A3 in peritoneal macrophages; this interaction is increased by IL18 treatment (By similarity).
Highly expressed in leukocytes, spleen, lung. Also expressed, but at lower levels, in liver, small intestine, colon, prostate, thymus, placenta, and heart. Specifically coexpressed with IL18R1 in Th1 cells (PubMed:10925275, PubMed:11046021, PubMed:10653850).
Induced by IL12/interleukin-12 in T-cells. Proposed to be a phenotypic marker for T-helper 1 (Th1) cells.
N-glycosylated. N-linked glycosyl chains contribute to ligand recognition and intra-receptor interactions required for formation of an active ternary receptor complex.
Within the IL18 receptor complex, responsible for the binding of the pro-inflammatory cytokine IL18, but not IL1A nor IL1B (PubMed:8626725, PubMed:14528293, PubMed:25261253, PubMed:25500532). Involved in IL18-mediated IFNG synthesis from T-helper 1 (Th1) cells (PubMed:10653850). Contributes to IL18-induced cytokine production, either independently of SLC12A3, or as a complex with SLC12A3 (By similarity).
Expressed in eosinophils, dendritic cells and/or monocytes (at protein level) (PubMed:29686383). Expressed predominantly in peripheral blood lymphocytes (PubMed:10383454).
Monomer (PubMed:33238146). Homodimer; disulfide-linked (PubMed:33238146). May interact with IRAK4 (when phosphorylated) (PubMed:33238146). Interacts (when phosphorylated at Ser-110) with PIN1 (via WW domain) in response to IL33-mediated (but not TLR4 ligand LPS) dendritic cell stimulation (PubMed:29686383).
Putative inactive protein kinase which regulates signaling downstream of immune receptors including IL1R and Toll-like receptors (PubMed:10383454, PubMed:29686383). Inhibits dissociation of IRAK1 and IRAK4 from the Toll-like receptor signaling complex by either inhibiting the phosphorylation of IRAK1 and IRAK4 or stabilizing the receptor complex (By similarity). Upon IL33-induced lung inflammation, positively regulates expression of IL6, CSF3, CXCL2 and CCL5 mRNAs in dendritic cells (PubMed:29686383).
Ser-293 is present instead of the conserved Asp which is expected to be an active site residue. Low level autophosphorylation activity has been reported in PubMed:10383454, while other authors describe this as an inactive kinase.
The nucleotide binding domain binds ATP with low affinity.
The form A (78 kDa) is processed by internal peptidase cleavage to a 32 kDa N-terminal species (form B) and a 48 kDa C-terminal species.
By EGF, VEGF, FGF2 and phorbol myristate acetate (PMA).
Forms functional homodimers and homooligomers that are not required for substrate recognition and catalytic activity (PubMed:14725715). Can also form heterooligomers with other PLPP2 and PLPP3 (PubMed:18215144). Interacts with CTNND1; negatively regulates the PLPP3-mediated stabilization of beta-catenin/CTNNB1 (PubMed:20123964).
Independently of this phosphatase activity may also function in the Wnt signaling pathway and the stabilization of beta-catenin/CTNNB1, thereby regulating cell proliferation, migration and differentiation in angiogenesis or yet in tumor growth (PubMed:20123964, PubMed:21569306). Also plays a role in integrin-mediated cell-cell adhesion in angiogenesis (PubMed:12660161, PubMed:16099422).
Magnesium-independent phospholipid phosphatase (PubMed:9705349). Insensitive to N-ethylmaleimide (PubMed:9705349). Inhibited by sphingosine, zinc ions and modestly by propanolol (PubMed:9705349).
Magnesium-independent phospholipid phosphatase of the plasma membrane that catalyzes the dephosphorylation of a variety of glycerolipid and sphingolipid phosphate esters including phosphatidate/PA, lysophosphatidate/LPA, diacylglycerol pyrophosphate/DGPP, sphingosine 1-phosphate/S1P and ceramide 1-phosphate/C1P (PubMed:9705349, PubMed:9607309, PubMed:27694435). Also acts on N-oleoyl ethanolamine phosphate/N-(9Z-octadecenoyl)-ethanolamine phosphate, a potential physiological compound (PubMed:9607309). Has both an extracellular and an intracellular phosphatase activity, allowing the hydrolysis and the cellular uptake of these bioactive lipid mediators from the milieu, regulating signal transduction in different cellular processes (PubMed:9607309, PubMed:23591818, PubMed:27694435). Through the dephosphorylation of extracellular sphingosine-1-phosphate and the regulation of its extra- and intracellular availability, plays a role in vascular homeostasis, regulating endothelial cell migration, adhesion, survival, proliferation and the production of pro-inflammatory cytokines (PubMed:27694435). By maintaining the appropriate levels of this lipid in the cerebellum, also ensure its proper development and function (By similarity). Through its intracellular lipid phosphatase activity may act in early compartments of the secretory pathway, regulating the formation of Golgi to endoplasmic reticulum retrograde transport carriers (PubMed:23591818).
N-glycosylated (PubMed:9705349). Contains high-mannose oligosaccharides (PubMed:9705349).
The dityrosine basolateral targeting motif mediates localization to the basolateral membrane in polarized cells.
The integrin-binding motif mediates the binding to integrin alpha-5/beta-1 (ITGA5:ITGB1) and integrin alpha-V/beta-3 (ITGAV:ITGB3) and is required for the function in integrin-mediated cell-cell adhesion.
Ubiquitously expressed (PubMed:9305923, PubMed:12660161). Highly expressed in heart and placenta (PubMed:9305923).
Inorganic ion transporter that transports phosphate or copper ions across the mitochondrial inner membrane into the matrix compartment (By similarity) (PubMed:17273968, PubMed:29237729). Mediates proton-coupled symport of phosphate ions necessary for mitochondrial oxidative phosphorylation of ADP to ATP (By similarity) (PubMed:17273968). Transports copper ions probably in the form of anionic copper(I) complexes to maintain mitochondrial matrix copper pool and to supply copper for cytochrome C oxidase complex assembly (PubMed:29237729). May also play a role in regulation of the mitochondrial permeability transition pore (mPTP) (By similarity).
Interacts with PPIF; the interaction is impaired by CsA.
Interacts with PRX; this enhances phosphorylation. Identified in a dystroglycan complex that contains at least PRX, DRP2, UTRN, DMD and DAG1.
Required for normal myelination and for normal organization of the cytoplasm and the formation of Cajal bands in myelinating Schwann cells. Required for normal PRX location at appositions between the abaxonal surface of the myelin sheath and the Schwann cell plasma membrane. Possibly involved in membrane-cytoskeleton interactions of the central nervous system.
(Microbial infection) Acts as a receptor for Ebolavirus.
(Microbial infection) Acts as a receptor for Japanese encephalitis virus.
(Microbial infection) Acts as a receptor for Lassa virus and Lymphocytic choriomeningitis virus glycoprotein (PubMed:22156524, PubMed:22673088).
(Microbial infection) Acts as a receptor for SARS-CoV.
(Microbial infection) Interacts with lassa virus and Lymphocytic choriomeningitis virus glycoprotein (PubMed:22156524, PubMed:22673088).
Binds mannose, N-acetylglucosamine (GlcNAc) and fucose, but not galactose, in a Ca(2+)-dependent manner, in vitro.
Expressed exclusively in fetal and adult liver and in lymph nodes. Specifically expressed by endothelial cells lining lymph node and liver sinuses (at protein level).
Acetylated at Lys-253, Lys-253 and Lys-254 under high glucose condition. Acetylation increases catalytic activity. Under glucose restriction SIRT1 levels dramatically increase and it deacetylates the enzyme.
Catalyzes the interconversion of 2-phosphoglycerate and 3-phosphoglyceratea crucial step in glycolysis, by using 2,3-bisphosphoglycerate (PubMed:23653202). Also catalyzes the interconversion of (2R)-2,3-bisphosphoglycerate and (2R)-3-phospho-glyceroyl phosphate (PubMed:23653202).
Expressed in the liver and brain. Not found in the muscle.
Belongs to the AB hydrolase superfamily. AB hydrolase 4 family.
Interacts with PDE3B; this interaction regulates PDE3B's stability and expression and, thereby, impacts the antilipolytic action of insulin.
May regulate adipocyte lipolysis and liver lipid accumulation.
May act as a specific coactivator for the mammalian TEFs.
Acetylation by EP300 and CREBBP destabilizes ITPK1, and down-regulates enzymatic activity. Deacetylated by SIRT1.
Expressed in brain > heart > skeletal muscle = kidney = pancreas = liver = placenta > lung. In brain, it is expressed in cerebellum, cerebral cortex, medulla, spinal cord, occipital lobe, frontal lobe, temporal lobe and putamen.
Kinase that can phosphorylate various inositol polyphosphate such as Ins(3,4,5,6)P4 or Ins(1,3,4)P3 (PubMed:11042108, PubMed:8662638). Phosphorylates Ins(3,4,5,6)P4 at position 1 to form Ins(1,3,4,5,6)P5 (PubMed:11042108). This reaction is thought to have regulatory importance, since Ins(3,4,5,6)P4 is an inhibitor of plasma membrane Ca(2+)-activated Cl(-) channels, while Ins(1,3,4,5,6)P5 is not. Also phosphorylates Ins(1,3,4)P3 on O-5 and O-6 to form Ins(1,3,4,6)P4, an essential molecule in the hexakisphosphate (InsP6) pathway (PubMed:11042108, PubMed:8662638). Also acts as an inositol polyphosphate phosphatase that dephosphorylates Ins(1,3,4,5)P4 and Ins(1,3,4,6)P4 to Ins(1,3,4)P3, and Ins(1,3,4,5,6)P5 to Ins(3,4,5,6)P4 (PubMed:17616525, PubMed:11909533). May also act as an isomerase that interconverts the inositol tetrakisphosphate isomers Ins(1,3,4,5)P4 and Ins(1,3,4,6)P4 in the presence of ADP and magnesium (PubMed:11909533). Probably acts as the rate-limiting enzyme of the InsP6 pathway. Modifies TNF-alpha-induced apoptosis by interfering with the activation of TNFRSF1A-associated death domain (PubMed:11909533, PubMed:12925536, PubMed:17616525). Plays an important role in MLKL-mediated necroptosis. Produces highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which bind to MLKL mediating the release of an N-terminal auto-inhibitory region leading to its activation. Essential for activated phospho-MLKL to oligomerize and localize to the cell membrane during necroptosis (PubMed:17616525).
PubMed:11533064 detected some protein kinase activity and ability to phosphorylate transcription factors c-jun/JUN and ATF2. However, PubMed:15762844 showed that it does not have protein kinase activity.
Phosphorylation of Thr-321 impairs interaction with DLG1 and DLG4.
Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits. Thought to stabilize the calcium channel in an inactivated (closed) state.
The L-type calcium channel is composed of five subunits: alpha-1, alpha-2/delta, beta and gamma. Interacts with the PDZ domains of DLG4/PSD-95 and DLG1/SAP97. May interact with GOPC (By similarity). Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CNIH2, CNIH3, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8 (By similarity). Interacts with GRIA1 and GRIA2 (PubMed:20805473). Interacts with MPP2 (By similarity).
May play a role in the immune response to viral infection.
Catalyzes the N-acetylation of the amino acid thialysine (S-(2-aminoethyl)-L-cysteine), a L-lysine analog with the 4-methylene group substituted with a sulfur (PubMed:15283699). May also catalyze acetylation of polyamines, such as norspermidine, spermidine or spermine (PubMed:12803540). However, ability to acetylate polyamines is weak, suggesting that it does not act as a diamine acetyltransferase in vivo (PubMed:15283699).
Diamine acetyltransferase activity is unclear (PubMed:15283699, PubMed:12803540). According to a report, mediates acetylation of polyamines, such as norspermidine, spermidine or spermine (PubMed:12803540). However, another publication showed that such activity is weak compared to thialysine acetyltransferase activity, suggesting that polyamines are not substrates in vivo (PubMed:15283699).
Widely expressed (PubMed:15283699, PubMed:12803540). Under physiological conditions, SSAT2 is expressed at lower level that SSAT1 (SSAT). Many tissues express only SSAT1, several tissues express both SSAT1 and SSAT2, and bone, cervix, ovary and pineal gland expressed only SSAT2 (PubMed:12803540).
Could also function as a primary ATP-dependent active transporter for glutathione conjugates of electrophiles. May also actively catalyze the efflux of a wide range of substrates including xenobiotics like doxorubicin (DOX) contributing to cell multidrug resistance.
Expressed ubiquitously but at low levels. Shows a strong expression in the erythrocytes.
Interacts with the GTP-bound form of RALA (via effector domain); during mitosis, recruits RALBP1 to the mitochondrion where it promotes DNM1L phosphorylation and mitochondrial fission (PubMed:7673236, PubMed:21822277). Interacts with DNM1L; mediates its mitotic kinase cyclin B-CDK1-mediated phosphorylation during mitosis to promote mitochondrial fission (PubMed:21822277). Interacts with the mitotic kinase cyclin B-CDK1 during mitosis (PubMed:12775724, PubMed:21822277). Interacts with the GTP-bound form of RALB (via effector domain) (PubMed:7673236, PubMed:20696399). Interacts with REPS1; the interaction is direct and does not affect RALA-binding nor GTPase activator activity of RALBP1 (By similarity). Interacts with REPS2; the interaction is direct and does not affect RALA-binding nor GTPase activator activity of RALBP1 (PubMed:9422736). Interacts with EPN1, NUMB and TFAP2A during interphase and mitosis (PubMed:12775724). Interacts with AP2M1; as part of the AP2 complex (PubMed:10910768). Interacts with CDC42 (Probable). Interacts with RAC1 (PubMed:7673236).
May undergo proteolytic cleavage to give peptides which reassemble to form a transporter complex.
Multifunctional protein that functions as a downstream effector of RALA and RALB (PubMed:7673236). As a GTPase-activating protein/GAP can inactivate CDC42 and RAC1 by stimulating their GTPase activity (PubMed:7673236). As part of the Ral signaling pathway, may also regulate ligand-dependent EGF and insulin receptors-mediated endocytosis (PubMed:10910768, PubMed:12775724). During mitosis, may act as a scaffold protein in the phosphorylation of EPSIN/EPN1 by the mitotic kinase cyclin B-CDK1, preventing endocytosis during that phase of the cell cycle (PubMed:12775724). During mitosis, also controls mitochondrial fission as an effector of RALA (PubMed:21822277). Recruited to mitochondrion by RALA, acts as a scaffold to foster the mitotic kinase cyclin B-CDK1-mediated phosphorylation and activation of DNM1L (PubMed:21822277).
Originally designated as dinitrophenyl S-glutathione (DNP-SG) ATPase due to its ability to stimulate ATP hydrolysis in the presence of DNP-SG.
The Rho-GAP domain mediates the GTPase activator activity toward CDC42.
Tyrosine-phosphorylated upon stimulation of cells with EGF.
Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6 (PubMed:22000856). DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease (PubMed:17143291). Inhibits the pro-apoptotic function of KREMEN1 in a Wnt-independent manner, and has anti-apoptotic activity (By similarity).
Interacts with LRP6 (PubMed:11448771, PubMed:17804805, PubMed:20093360, PubMed:22000856). Interacts (via the C-termianl Cys-rich domain) with LRP5 (via beta-propeller regions 3 and 4); the interaction, enhanced by MESD and or KREMEN, antagonizes Wnt-mediated signaling (PubMed:19746449). Forms a ternary complex with LRP6 and KREM1 (PubMed:27524201). Interacts with KREM1 (PubMed:17804805).
Cell type-specific subunit of the general transcription factor TFIID that may function as a gene-selective coactivator in certain cells. TFIID is a multimeric protein complex that plays a central role in mediating promoter responses to various activators and repressors. TAF4B is a transcriptional coactivator of the p65/RELA NF-kappa-B subunit. Involved in the activation of a subset of antiapoptotic genes including TNFAIP3. May be involved in regulating folliculogenesis. Through interaction with OCBA/POU2AF1, acts as a coactivator of B-cell-specific transcription. Plays a role in spermiogenesis and oogenesis.
May be due to exon inclusion. Unphosphorylated form.
Preferentially expressed in ovarian granulosa cells (at protein level). Highly expressed in B-cells.
TFIID is composed of TATA binding protein (TBP) and a number of TBP-associated factors (TAFs) (PubMed:15601843). Heterodimerizes with TAF12/TFII20 via the C-terminal H2A-like histone-fold domain (PubMed:15601843). This heterodimer forms a histone-like octamer with the TAF6/TAFII70-TAF9/TAFII31 heterodimer (PubMed:15601843). Interacts with P65/RELA homodimers and P65/RELA-REL heterodimers (PubMed:10849440). Interaction with POU2AF1, via its C-terminal activation domain, is required for octamer-dependent transcription (PubMed:10828057). Interacts with ZNF628 (By similarity).
Under stimulation by forskolin, Isoform 1 is phosphorylated by protein kinase A (PKA).
Depletion of ARHGAP21 induces cell spreading and accumulation of F-actin stress fibers.
Functions as a GTPase-activating protein (GAP) for RHOA and CDC42. Downstream partner of ARF1 which may control Golgi apparatus structure and function. Also required for CTNNA1 recruitment to adherens junctions.
Interacts with GTP-bound ARF1 and ARF6. Interacts with CTNNA1.
Required for In1A-dependent entry of Listeria monocytogenes into cells.
Sumoylated with SUMO2 and SUMO3 in proliferating lymphocytes.
Widely expressed with higher expression in brain, heart, skeletal muscle and placenta.
Does not interact with nucleosides, nucleobases or nucleotides, other than a moderate activity for adenosine (PubMed:15448143, PubMed:17393420, PubMed:20592246). Mediates the uptake of neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) (PubMed:15448143, PubMed:16099839, PubMed:17018840, PubMed:17121826, PubMed:20592246, PubMed:20858707, PubMed:23255610).
Electrogenic voltage-dependent transporter that mediates the transport of a variety of endogenous bioactive amines, cationic xenobiotics and drugs (PubMed:15448143, PubMed:16099839, PubMed:16873718, PubMed:17018840, PubMed:17121826, PubMed:20592246, PubMed:20858707, PubMed:22396231, PubMed:31537831). Utilizes the physiologic inside-negative membrane potential as a driving force to facilitate cellular uptake of organic cations (PubMed:15448143, PubMed:20592246, PubMed:22396231). Functions as a Na(+)- and Cl(-)-independent bidirectional transporter (PubMed:15448143, PubMed:16099839, PubMed:22396231, PubMed:31537831). Substrate transport is pH-dependent and enhanced under acidic condition, which is most likely the result of allosteric changes in the transporter structure (PubMed:16873718, PubMed:17018840, PubMed:20592246, PubMed:22396231, PubMed:31537831). Implicated in monoamine neurotransmitters uptake such as serotonin, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, histamine and tyramine, thereby supporting a role in homeostatic regulation of aminergic neurotransmission in the central nervous system (PubMed:15448143, PubMed:16099839, PubMed:17018840, PubMed:17121826, PubMed:20858707, PubMed:22396231). Also responsible for the uptake of bioactive amines and drugs through the blood-cerebrospinal fluid (CSF) barrier, from the CSF into choroid plexus epithelial cells, thereby playing a significant role in the clearance of cationic neurotoxins, xenobiotics and metabolic waste in the brain (By similarity). Involved in bidirectional transport of the purine nucleoside adenosine and plays a role in the regulation of extracellular adenosine concentrations in cardiac tissues, in particular during ischemia (PubMed:16873718, PubMed:20592246, PubMed:31537831). May be involved in organic cation uptake from the tubular lumen into renal tubular cells, thereby contributing to organic cation reabsorption in the kidney (PubMed:17018840). Also transports guanidine (PubMed:16099839).
Glu-206 is essential for cation selectivity and may function as the charge sensor for cationic substrates.
Mainly expressed in brain and skeletal muscle (PubMed:15448143, PubMed:16873718, PubMed:20592246, PubMed:20858707). In brain, expressed in cerebellum, cerebral cortex, medulla oblongata, occipital pole, frontal and temporal lobes putamen, spinal cord, substancia nigra, hippocampus, caudate nucleus, nucleus accumbens, pons and choroid plexus (PubMed:15448143, PubMed:16873718, PubMed:20858707, PubMed:23255610). Expressed in heart, in both cardiomyocytes and vascular endothelial cells (PubMed:15448143, PubMed:20858707, PubMed:16873718). Also expressed in adrenal gland, small intestine, pancreas, kidney, liver, bone marrow, lymph node (PubMed:15448143, PubMed:16873718, PubMed:17018840, PubMed:20858707). Located in endometrial stroma, where the expression is high in the proliferative phase, decreases during the secretory phase, and is no longer detectable in the menstrual phase (PubMed:17393420).
Unlike mouse protein, not able to transport adenine nucleotide in acidic condition.
Expressed in normal gastrointestinal epithelium and in 95% of colon cancers.
May play a role in cell-cell recognition and signaling.
N-glycosylated, contains approximately 8 kDa of N-linked carbohydrate.
Acetylated by KAT5/TIP60 under autophagy induction, promoting protein kinase activity.
Acetylation by KAT5/TIP60 stimulates the protein kinase activity (By similarity). The protein kinase activity is activated by unanchored 'Lys-63'-linked polyubiquitin chains: unanchored 'Lys-63'-linked polyubiquitin chains are catalyzed by TRIM32 in an AMBRA1-dependent manner (PubMed:31123703).
Autophosphorylated. Phosphorylated under nutrient-rich conditions; dephosphorylated during starvation or following treatment with rapamycin. Under nutrient sufficiency, phosphorylated by MTOR/mTOR, disrupting the interaction with AMPK and preventing activation of ULK1 (By similarity). In response to nutrient limitation, phosphorylated and activated by AMPK, leading to activate autophagy (PubMed:21205641, PubMed:25891078).
Interacts with GABARAP and GABARAPL2 (PubMed:11146101). Interacts (via C-terminus) with ATG13 (PubMed:18936157). Part of a complex consisting of ATG13, ATG101, ULK1 and RB1CC1 (PubMed:19287211). Associates with the mammalian target of rapamycin complex 1 (mTORC1) through an interaction with RPTOR; the association depends on nutrient conditions and is reduced during starvation (PubMed:19211835, PubMed:21795849). Interacts with FEZ1; SCOC interferes with FEZ1-binding (PubMed:22354037). Interacts with TBC1D14 (PubMed:22613832). Interacts (phosphorylated form) with TRIM5 (PubMed:25127057). When phosphorylated at Ser-317, interacts with MEFV and BECN1 simultaneously (PubMed:26347139). Interacts with TRIM21 and IRF3, in the presence of TRIM21 (PubMed:26347139). Interacts with SESN2 (PubMed:25040165). Interacts with SQSTM1 (PubMed:25040165). Interacts with C9orf72 (PubMed:27334615). Interacts with WDR45 (PubMed:28561066). Interacts with ATG13; this interaction is increased in the absence of TMEM39A (PubMed:31806350). Interacts with WIPI2 (PubMed:28890335). Interacts with ATP2A2 (PubMed:28890335). Interacts with AMBRA1 (PubMed:25438055, PubMed:31123703). Interacts with IRGM; promoting the coassembly of ULK1 and BECN1 (PubMed:25891078).
Serine/threonine-protein kinase involved in autophagy in response to starvation (PubMed:18936157, PubMed:21460634, PubMed:21795849, PubMed:23524951, PubMed:25040165, PubMed:31123703, PubMed:29487085). Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes (PubMed:18936157, PubMed:21460634, PubMed:21795849, PubMed:25040165). Part of regulatory feedback loops in autophagy: acts both as a downstream effector and negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR (PubMed:21795849). Activated via phosphorylation by AMPK and also acts as a regulator of AMPK by mediating phosphorylation of AMPK subunits PRKAA1, PRKAB2 and PRKAG1, leading to negatively regulate AMPK activity (PubMed:21460634). May phosphorylate ATG13/KIAA0652 and RPTOR; however such data need additional evidences (PubMed:18936157). Plays a role early in neuronal differentiation and is required for granule cell axon formation (PubMed:11146101). May also phosphorylate SESN2 and SQSTM1 to regulate autophagy (PubMed:25040165). Phosphorylates FLCN, promoting autophagy (PubMed:25126726). Phosphorylates AMBRA1 in response to autophagy induction, releasing AMBRA1 from the cytoskeletal docking site to induce autophagosome nucleation (PubMed:20921139). Phosphorylates ATG4B, leading to inhibit autophagy by decreasing both proteolytic activation and delipidation activities of ATG4B (PubMed:28821708).
Ubiquitinated via 'Lys-63'-linkage by a complex composed of AMBRA1 and TRAF6 following autophagy induction, promoting ULK1 stability and kinase activity. Deubiquitinated by USP20; leading to ULK1 stability and autophagy initiation (PubMed:29487085).
Ubiquitously expressed. Detected in the following adult tissues: skeletal muscle, heart, pancreas, brain, placenta, liver, kidney, and lung.
Acts as a negative regulator of heterotrimeric G proteins assembly by trapping the preloaded G beta subunits inside the CCT chaperonin.
Acts as a positive regulator of hedgehog signaling and regulates ciliary function.
Expressed ubiquitously, highest levels are found in neural tissues amounting to 10% of total PDCL mRNA.
Forms a complex with the beta and gamma subunits of the GTP-binding protein, transducin. Interacts with the CCT chaperonin complex.
Functions as a co-chaperone for CCT in the assembly of heterotrimeric G protein complexes, facilitates the assembly of both Gbeta-Ggamma and RGS-Gbeta5 heterodimers.
Autoubiquitinated as part of the enzymatic reaction.
Directly interacts with ITGA2B and, as a result, with integrin ITGA2B/ITGB3 (PubMed:18331836). There is no evidence that integrin ITGA2B/ITGB3 is an endogenous substrate for RNF181-directed ubiquitination (PubMed:18331836).
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:18331836). Catalyzes monoubiquitination of 26S proteasome subunit PSMC2/RPT1 (PubMed:24811749).
Widely expressed, with highest levels in liver and heart and lowest levels in brain and skeletal muscle. Expressed in platelets (at protein level).
Homodimer. May also form higher-order oligomers (PubMed:12835319). Interacts (when phosphorylated) with ARRB1 and ARRB2; the interaction is associated with internalization of C5aR (PubMed:12464600). Interacts (via N-terminal domain) with S.aureus chemotaxis inhibitory protein (CHIPS); the interaction blocks the receptor and may thus inhibit the immune response (PubMed:15153520, PubMed:15542591, PubMed:21706042).
Phosphorylated on serine residues in response to C5a binding, resulting in internalization of the receptor and short-term desensitization to the ligand. The key residues involved in this process are Ser-334 and Ser-338.
Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a (PubMed:1847994, PubMed:8182049, PubMed:7622471, PubMed:9553099, PubMed:10636859, PubMed:15153520, PubMed:29300009). The ligand interacts with at least two sites on the receptor: a high-affinity site on the extracellular N-terminus, and a second site in the transmembrane region which activates downstream signaling events (PubMed:8182049, PubMed:7622471, PubMed:9553099). Receptor activation stimulates chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production (PubMed:10636859, PubMed:15153520).
Sulfation plays a critical role in the association of C5aR with C5a, but no significant role in the ability of the receptor to transduce a signal and mobilize calcium in response to a small a small peptide agonist (PubMed:11342590). Sulfation at Tyr-14 is important for CHIPS binding (PubMed:21706042).
(Microbial infection) Interacts with the N-terminal domain of Kaposi's sarcoma-associated herpesvirus latent nuclear antigen (LNA).
Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres. Plays an important role in the correct PLK1 localization to the mitotic kinetochores. A scaffold protein responsible for the initial recruitment and maintenance of the kinetochore PLK1 population until its degradation. Involved in transcriptional repression.
Component of the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU. The CENPA-NAC complex interacts with the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. Interacts with MLF1. Interacts with PLK1.
Expressed at high levels in the testis, fetal liver, thymus, bone marrow and at lower levels in the lymph nodes, placenta, colon and spleen. Present in all cell lines examined, including B-cells, T-cells, epithelial cells and fibroblast cells. Expressed at high levels in glioblastoma cell lines.
Phosphorylated by PLK1 at Thr-78, creating a self-tethering site that specifically interacts with the polo-box domain of PLK1.
Absence of residues from position 133 within an exon that change the frame which is not the result of an alternative splicing.
Atypical Ras-like protein that acts as a potent regulator of NF-kappa-B activity by preventing the degradation of NF-kappa-B inhibitor beta (NFKBIB) by most signals, explaining why NFKBIB is more resistant to degradation. May act by blocking phosphorylation of NFKBIB and nuclear localization of p65/RELA NF-kappa-B subunit. It is unclear whether it acts as a GTPase. Both GTP- and GDP-bound forms block phosphorylation of NFKBIB (By similarity).
Belongs to the small GTPase superfamily. Ras family. KappaB-Ras subfamily.
In contrast to other members of the Ras family, the members of the KappaB-Ras subfamily do not contain the conserved Gly and Gln residues in positions 13 and 65, which are replaced by Ala and Leu residues, respectively, and are therefore similar to the constitutively active forms of oncogenic forms of Ras. This suggests that members of this family are clearly different from other small GTPases proteins.
Interacts with both NF-kappa-B inhibitor alpha (NFKBIA) and beta (NFKBIB) in vitro. However, it probably only interacts with NFKBIB in vivo.
Adult pituitary gland, heart, small intestine, adrenal gland, cerebellum and fetal hypothalamus. No expression in fetal or adult kidney, liver, pancreas, uterus, spleen, lung, thyroid or ovary.
Heterodimer with SSTR2. Heterodimerization with SSTR2 increases cell growth inhibition activity of SSTR2.
Palmitoylated by ZDHHC5, but not ZDHHC3, nor ZDHHC8. Palmitoylation creates an additional intracellular loop which is thought to be important for efficient coupling to G-proteins and may target the protein to lipid rafts.
Receptor for somatostatin 28 and to a lesser extent for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. Increases cell growth inhibition activity of SSTR2 following heterodimerization.
Glycosylation at Asn-628 is necessary both for surface expression and neutral endopeptidase activity.
Important cell surface marker in the diagnostic of human acute lymphocytic leukemia.
Inhibited in a dose dependent manner by opiorphin (PubMed:17101991). Activated by K49-P1-20, a twenty-residue synthetic peptide shortened from the snake B.asper myotoxin II (PubMed:26931059).
Myristoylation is a determinant of membrane targeting.
Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids (PubMed:6349683, PubMed:6208535, PubMed:15283675, PubMed:8168535). Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond (PubMed:6349683, PubMed:17101991). Catalyzes cleavage of bradykinin, substance P and neurotensin peptides (PubMed:6208535). Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9 (PubMed:6349683, PubMed:15283675). Involved in the degradation of atrial natriuretic factor (ANF) and brain natriuretic factor (BNP(1-32)) (PubMed:2531377, PubMed:2972276, PubMed:16254193). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers (PubMed:20876573).
Activated by phosphorylation on Ser-52 and Ser-588.
Associates with U4/U6-U5 tri-small nuclear ribonucleoproteins (U4/U6-U5 tri-snRNPs) (PubMed:18425142). Interacts with PKB/AKT1 in a phosphorylation-dependent manner (PubMed:19592491). The phosphorylated form (by PKB/AKT1) interacts with YWHAB and YWHAE (PubMed:19592491). Interaction with YWHAB suppresses its cleavage by caspases and inhibits the release of its N-terminal pro-apoptotic fragment (PubMed:19592491). Interacts with SFN (PubMed:19592491). Interacts with ACIN1 (PubMed:18559500). Interacts with POLR2A/RNA polymerase II; the interaction occurs during the co-transcriptional formation of inappropriate R-loops (PubMed:28076779).
Highly expressed in brain, moderately expressed in heart and skeletal muscle and at low levels in lung, liver, and kidney.
Phosphorylation at Thr-492 by PKB/AKT1 enhances its stimulatory activity in triggering cyclin-D1 (CCND1) expression and promoting apoptosis in neurons, which can be blocked by YWHAB. It also enhances its protein kinase activity toward ACIN1 and SRSF2, promotes its nuclear translocation and prevents its proteolytic cleavage.
Proteolytically cleaved at Asp-139 and Asp-403 by caspase-3 during apoptotic cell death. Cleavage at Asp-139 which is the major site of cleavage, produces a small N-terminal fragment that translocates into nucleus and promotes VP16-induced apoptosis.
Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing (PubMed:9472028, PubMed:18559500, PubMed:21056976). Promotes neuronal apoptosis by up-regulating cyclin-D1 (CCND1) expression (PubMed:19592491). This is done by the phosphorylation of SRSF2, leading to the suppression of p53/TP53 phosphorylation thereby relieving the repressive effect of p53/TP53 on cyclin-D1 (CCND1) expression (PubMed:21205200). Phosphorylates ACIN1, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not cyclin A2 up-regulation (PubMed:18559500). Plays an essential role in spliceosomal B complex formation via the phosphorylation of DDX23/PRP28 (PubMed:18425142). Probably by phosphorylating DDX23, leads to the suppression of incorrect R-loops formed during transcription; R-loops are composed of a DNA:RNA hybrid and the associated non-template single-stranded DNA (PubMed:28076779). Can mediate hepatitis B virus (HBV) core protein phosphorylation (PubMed:12134018). Plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles (PubMed:16122776).
The cDNA appears to contain a duplicated region.
Necessary for collagen type I synthesis. May couple the activity of the ER Ca(2+) pump SERCA2B with the activity of the translocon. This coupling may increase the local Ca(2+) concentration at the site of collagen synthesis, and a high Ca(2+) concentration may be necessary for the function of molecular chaperones involved in collagen folding. Required for proper insertion of the first transmembrane helix N-terminus of TM4SF20 into the ER lumen, may act as a ceramide sensor for regulated alternative translocation (RAT) (PubMed:27499293).
Can form homotypic interactions (PubMed:10196196). Interacts with IRF4/Pip (PubMed:10196196). Interacts with JUN (PubMed:10196196). Interacts with TBP (PubMed:10196196). May also interact with CREBBP and EP300 (PubMed:11864910). Interacts with NONO/p54(nrb) (By similarity).
Expressed in plasmacytoid dendritic cells (pDCs) and B-cells, not expressed in T-cells or granulocytes. May also be enriched in stem cell populations of the liver.
Sequence specific transcriptional activator which binds to the PU-box, a purine-rich DNA sequence (5'-GAGGAA-3') that can act as a lymphoid-specific enhancer. Promotes development of plasmacytoid dendritic cells (pDCs), also known as type 2 DC precursors (pre-DC2) or natural interferon (IFN)-producing cells. These cells have the capacity to produce large amounts of interferon and block viral replication. May be required for B-cell receptor (BCR) signaling, which is necessary for normal B-cell development and antigenic stimulation.
The protein contains a weakly acidic N-terminal transactivation domain (TAD) followed by a second TAD rich in proline, serine and threonine. Each of these domains may be required for transcriptional activation of a subset of target genes.
(Microbial infection) Essential for infection by muliple viruses, including SARS-CoV-2, that utilize activated cathepsins for entry after M6P-dependent lysosomal transport.
Interacts with GNPTAB; this interaction is important for proper localization of GNPTAB in Golgi stacks (PubMed:36074821, PubMed:36096887). Interacts with MBTPS1 (PubMed:36096887).
Required for mannose-6-phosphate-dependent trafficking of lysosomal enzymes (PubMed:36074822, PubMed:36096887, PubMed:36074821). LYSET bridges GlcNAc-1-phosphate transferase (GNPTAB), to the membrane-bound transcription factor site-1 protease (MBTPS1), thus allowing proteolytic activation of the GNPTAB. GNPTAB is involved in the regulation of M6P-dependent Golgi-to-lysosome trafficking of lysosomal enzymes (PubMed:36096887, PubMed:36074822, PubMed:36074821). LYSET is thus an essential factor for maturation and delivery of lysosomal hydrolases (PubMed:36074822).
Atypical PKCs (PRKCI and PRKCZ) exhibit an elevated basal enzymatic activity (that may be due to the interaction with SMG1 or SQSTM1) and are not regulated by diacylglycerol, phosphatidylserine, phorbol esters or calcium ions. Two specific sites, Thr-412 (activation loop of the kinase domain) and Thr-564 (turn motif), need to be phosphorylated for its full activation (By similarity). Might also be a target for novel lipid activators that are elevated during nutrient-stimulated insulin secretion.
Calcium- and diacylglycerol-independent serine/ threonine-protein kinase that plays a general protective role against apoptotic stimuli, is involved in NF-kappa-B activation, cell survival, differentiation and polarity, and contributes to the regulation of microtubule dynamics in the early secretory pathway. Is necessary for BCR-ABL oncogene-mediated resistance to apoptotic drug in leukemia cells, protecting leukemia cells against drug-induced apoptosis. In cultured neurons, prevents amyloid beta protein-induced apoptosis by interrupting cell death process at a very early step. In glioblastoma cells, may function downstream of phosphatidylinositol 3-kinase (PI(3)K) and PDPK1 in the promotion of cell survival by phosphorylating and inhibiting the pro-apoptotic factor BAD. Can form a protein complex in non-small cell lung cancer (NSCLC) cells with PARD6A and ECT2 and regulate ECT2 oncogenic activity by phosphorylation, which in turn promotes transformed growth and invasion. In response to nerve growth factor (NGF), acts downstream of SRC to phosphorylate and activate IRAK1, allowing the subsequent activation of NF-kappa-B and neuronal cell survival. Functions in the organization of the apical domain in epithelial cells by phosphorylating EZR. This step is crucial for activation and normal distribution of EZR at the early stages of intestinal epithelial cell differentiation. Forms a protein complex with LLGL1 and PARD6B independently of PARD3 to regulate epithelial cell polarity. Plays a role in microtubule dynamics in the early secretory pathway through interaction with RAB2A and GAPDH and recruitment to vesicular tubular clusters (VTCs). In human coronary artery endothelial cells (HCAEC), is activated by saturated fatty acids and mediates lipid-induced apoptosis. Involved in early synaptic long term potentiation phase in CA1 hippocampal cells and short term memory formation (By similarity).
Forms a complex with SQSTM1 and MP2K5 (By similarity). Interacts directly with SQSTM1 (Probable). Interacts with IKBKB. Interacts with PARD6A, PARD6B and PARD6G. Part of a quaternary complex containing aPKC, PARD3, a PARD6 protein (PARD6A, PARD6B or PARD6G) and a GTPase protein (CDC42 or RAC1). Part of a complex with LLGL1 and PARD6B. Interacts with ADAP1/CENTA1. Interaction with SMG1, through the ZN-finger domain, activates the kinase activity. Interacts with CDK7. Forms a complex with RAB2A and GAPDH involved in recruitment onto the membrane of vesicular tubular clusters (VTCs). Interacts with ECT2 ('Thr-359' phosphorylated form). Interacts with VAMP2 (PubMed:17313651). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529).
Phosphorylation at Thr-412 in the activation loop is not mandatory for activation (By similarity). Upon neuronal growth factor (NGF) stimulation, phosphorylated by SRC at Tyr-265, Tyr-280 and Tyr-334 (PubMed:11713277, PubMed:16452474). Phosphorylation at Tyr-265 facilitates binding to KPNB1/importin-beta regulating entry of PRKCI into the nucleus (PubMed:11891849). Phosphorylation on Tyr-334 is important for NF-kappa-B stimulation (PubMed:11713277). Phosphorylated at Thr-564 during the initial phase of long term potentiation (By similarity).
Predominantly expressed in lung and brain, but also expressed at lower levels in many tissues including pancreatic islets. Highly expressed in non-small cell lung cancers.
The C1 zinc finger does not bind diacylglycerol (DAG).
The pseudosubstrate motif resembles the sequence around sites phosphorylated on target proteins, except the presence of a non-phosphorylatable residue in place of Ser, it modulates activity by competing with substrates.
Component of the BCR(KBTBD2) E3 ubiquitin ligase complex, at least composed of CUL3, KBTBD2 and RBX1 (PubMed:27708159). Interacts (via the BTB domain) with CUL3 (By similarity).
Recognizes the BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex substrate, PIK3R1, through the 4 tandem C-terminal Kelch domains.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of the insulin signaling pathway, modulating insulin sensitivity by limiting PIK3R1/p85alpha abundance in adipocytes. Targets PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), for 'Lys-48'-linked polyubiquitination and proteasome-mediated degradation.
RNA-binding factor that positively regulates gene expression by prohibiting miRNA-mediated gene suppression. Relieves miRNA repression in germline cells (By similarity). Prohibits the function of several miRNAs by blocking the accessibility of target mRNAs. Sequence-specific RNA-binding factor that binds specifically to U-rich regions (URRs) in the 3' untranslated region (3'-UTR) of several mRNAs. Does not bind to miRNAs. May play a role during primordial germ cell (PGC) survival (By similarity). However, does not seem to be essential for PGC migration (By similarity).
Highly expressed in marrow from patients with pre-B ALL associated with the t(1;19) translocation. Strongly expressed in brain and testis. Expressed in fetal brain. Isoform 4 is highly expressed in brain (at protein level). Isoform 6 is expressed in brain and several cancer cell lines.
Isoform 2 may participate in the regulation of nucleoplasmic coilin protein interactions in neuronal and transformed cells.
Isoform 3 can regulate global protein synthesis by altering nucleolar numbers.
Isoform 3 interacts with DLG4 (By similarity). Interacts with EPHA8. Isoform 2 interacts with COIL. Isoform 4 interacts with APP and EPHA8. Isoform 6 interacts with EPHA8.
Isoform 3 nuclear translocation requires an NMDAR-dependent proteolytic cleavage.
Isoform 4 may play a role as a modulator of APP processing. Overexpression can down-regulate APP processing.
Transcriptionally up-regulated in t(1:19) pre-B cell acute lymphocytic leukemia by the chimeric TCF3-PBX1. Not expressed in pre-B cell that lack this translocation.
(Microbial infection) Promotes herpes simplex virus type 2/HHV-2 infection in vaginal epithelial cells by decreasing the nuclear localization of IRF3, the primary mediator of type I interferon activation.
Autoubiquitinates upon viral infection. In turn, autoubiquitinated TRIM26 recruits NEMO and bridges TBK1-NEMO interaction.
By cytokine TGF-beta and binding of activated SMAD3 to the TRIM26 promoter (PubMed:29203640). Upon herpes simplex virus type 2/HHV-2 infection (PubMed:33419081). By type I interferon (PubMed:35872575).
E3 ubiquitin-protein ligase which regulates the IFN-beta production and antiviral response downstream of various DNA-encoded pattern-recognition receptors (PRRs). Plays also a central role in determining the response to different forms of oxidative stress by controlling levels of DNA glycosylases NEIL1, NEIL3 and NTH1 that are involved in repair of damaged DNA (PubMed:29610152, PubMed:36232914). Promotes nuclear IRF3 ubiquitination and proteasomal degradation (PubMed:25763818). Bridges together TBK1 and NEMO during the innate response to viral infection leading to the activation of TBK1. Positively regulates LPS-mediated inflammatory innate immune response by catalyzing the 'Lys-11'-linked polyubiquitination of TAB1 to enhance its activation and subsequent NF-kappa-B and MAPK signaling (PubMed:34017102). In a manner independent of its catalytic activity, inhibits WWP2, a SOX2-directed E3 ubiquitin ligase, and thus protects SOX2 from polyubiquitination and proteasomal degradation (PubMed:34732716). Ubiquitinates the histone acetyltransferase protein complex component PHF20 and thereby triggers its degradation in the nucleus after its recruitment by the histone demethylase KDM6B, serving as a scaffold protein (PubMed:23452852). Upon induction by TGF-beta, ubiquitinates the TFIID component TAF7 for proteasomal degradation (PubMed:29203640). Induces ferroptosis by ubiquitinating SLC7A11, a critical protein for lipid reactive oxygen species (ROS) scavenging (By similarity). Inhibits directly hepatitis B virus replication by mediating HBX ubiquitination and subsequent degradation (PubMed:35872575).
Interacts with TBK1; this interaction bridges together TBK1 and NEMO in order to activate TBK1 (PubMed:26611359). Interacts with INCA1 (PubMed:21750715).
Expressed in adrenal tissue, JEG-3, NCI-H295A, Hep-G2 and HeLa cell lines.
Functions as a transcriptional activator in a promoter context-dependent manner. Modulates the placental expression of CYP11A1. Involved in regulation of the alpha-globin gene in erythroid cells. Activation of the alpha-globin promoter in erythroid cells is via synergistic interaction with TFCP2 (By similarity). Involved in regulation of the alpha-globin gene in erythroid cells. Binds strongly to sequences around the HIV-1 initiation site and weakly over the TATA-box. Represses HIV-1 transcription by inhibiting the binding of TFIID to the TATA-box.
Interacts with TFCP2. Interacts with PIAS1, and is probably part of a complex containing TFCP2, UBP1 and PIAS1 (By similarity).
May be involved in cell-adhesion. May function as a trans-neural growth-promoting factor in regenerative axon sprouting in the mammalian brain (By similarity).
Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain.
Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code (PubMed:26741168). Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively.
Interacts with histone deacetylase proteins HDAC1, HDAC2 and HDAC3. Interacts with RB and NCOR1.
Several specific inhibitors are being developed and tested.
The 2 Tudor domains recognize and bind methylated histone H3 'Lys-4' residue (H3K4me). Double Tudor domain has an interdigitated structure and the unusual fold is required for its ability to bind methylated histone tails. Trimethylated H3 'Lys-4' (H3K4me3) is bound in a cage of 3 aromatic residues, 2 of which are from the Tudor domain 2, while the binding specificity is determined by side-chain interactions involving residues from the Tudor domain 1. The Tudor domains are also able to bind trimethylated histone H3 'Lys-9' (H3K9me3), di- and trimethylated H4 'Lys-20' (H4K20me2 and H4K20me3). Has high affinity for H4K20me2, blocking recruitment of proteins such as TP53BP1.
Ubiquitinated by RNF8 and RNF168 following DNA damage, leading to its degradation. Degradation promotes accessibility of H4K20me2 mark for DNA repair protein TP53BP1, which is then recruited.
Negatively regulates TSP1 expression at the level of transcription. This down-regulation was shown to reduce taxane-induced apoptosis.
May play a role in growth-suppressive activity and cell death (PubMed:24652652). May be involved in the production of chemokine molecules in umbilical vein endothelial cells (HUVECs) cultured in THP1 monocyte LPS-induced medium (PubMed:20236627). Plays a role in preventing tumor onset (By similarity).
Up-regulated by chemotherapeutic DNA-damaging agents and by p53/TP53 and/or by p73/TP73 in response to cytotoxic insults (PubMed:24652652). Up-regulated by lipopolysaccharide (LPS) in monocytic THP1 cells (PubMed:20236627). Up-regulated in umbilical vein endothelial cells (HUVECs) cultured in THP1 monocyte LPS-induced medium.
Coactivates PAX5-dependent transcription together with either SMARCA4 or GCN5L2.
Interacts with GCN5L2, SMARCA4, SMARCE1 and PAX5. Component of the TFTC-HAT complex.
Binds PTPN11 when tyrosine-phosphorylated, except in macrophages, where it primarily binds PTPN6. Binds GRB2 in vitro. Binds FGR (By similarity). Binds JAK2 irrespective of its phosphorylation status and forms a stable complex. Binds SCAP1 and/or SCAP2. The resulting complex recruits FYB1. Binds PTK2B. Interacts with TRIM2 (By similarity).
Immunoglobulin-like cell surface receptor for CD47. Acts as docking protein and induces translocation of PTPN6, PTPN11 and other binding partners from the cytosol to the plasma membrane. Supports adhesion of cerebellar neurons, neurite outgrowth and glial cell attachment. May play a key role in intracellular signaling during synaptogenesis and in synaptic function (By similarity). Involved in the negative regulation of receptor tyrosine kinase-coupled cellular responses induced by cell adhesion, growth factors or insulin. Mediates negative regulation of phagocytosis, mast cell activation and dendritic cell activation. CD47 binding prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells. Plays a role in antiviral immunity and limits new world arenavirus infection by decreasing virus internalization (By similarity). Receptor for THBS1 (PubMed:24511121). Interaction with THBS1 stimulates phosphorylation of SIRPA (By similarity). In response to THBS1, involved in ROS signaling in non-phagocytic cells, stimulating NADPH oxidase-derived ROS production (PubMed:24511121).
Phosphorylated on tyrosine residues in response to stimulation with EGF, growth hormone, insulin and PDGF. Dephosphorylated by PTPN11.
Ubiquitous. Highly expressed in brain. Detected on myeloid cells, but not T-cells. Detected at lower levels in heart, placenta, lung, testis, ovary, colon, liver, small intestine, prostate, spleen, kidney, skeletal muscle and pancreas.
Represents a conventional myosin. This protein should not be confused with the unconventional myosin-1 (MYO1).
Expressed in some epidermal sweat gland ducts (at protein level) and in exocervix, esophagus and placenta.
O-glycosylated; glycans consist of single N-acetylglucosamine residues.
Type 1 keratin (Probable). Maintains postnatal tongue mucosal cell homeostasis and tissue organization in response to mechanical stress, potentially via regulation of the G1/S phase cyclins CCNE1 and CCNE2 (By similarity).
Detected in fetal brain, and at lower levels in fetal kidney. Detected in adult brain and pancreas, and at lower levels in kidney and lung. Expressed in spiral ganglion cells and the organ of Corti of fetal cochlea (PubMed:31972369).
Expected to bind 2 Fe(2+) ions per subunit.
Stearoyl-CoA desaturase that utilizes O(2) and electrons from reduced cytochrome b5 to introduce the first double bond into saturated fatty acyl-CoA substrates. Catalyzes the insertion of a cis double bond at the delta-9 position into fatty acyl-CoA substrates including palmitoyl-CoA and stearoyl-CoA (PubMed:15610069, PubMed:15907797, PubMed:22745828). Gives rise to a mixture of 16:1 and 18:1 unsaturated fatty acids (PubMed:15610069, PubMed:15907797). Involved in neuronal cell proliferation and differentiation through down-regulation of EGFR/AKT/MAPK and Wnt signaling pathways (PubMed:22745828).
This protein has no ortholog in rodents.
May be involved in transcriptional regulation. May play a role in neuronal function; perhaps involved in protection of brain tissues from oxidative stress. May be involved in erythroid differentiation (By similarity).
COPII is composed of at least five proteins: the Sec23/24 complex, the Sec13/31 complex and Sar1 (PubMed:17499046, PubMed:27551091). Interacts with TMED2 and TMED10 (PubMed:20427317). Interacts with CNIH4 (PubMed:24405750). Interacts with GOSR2 (via IxM motif) and STX5 (via IxM motif); recruits GOSR2 and STX5 into COPII-coated vesicles (PubMed:18843296).
Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules for their transport to the Golgi complex (PubMed:17499046, PubMed:20427317, PubMed:18843296). Plays a central role in cargo selection within the COPII complex and together with SEC24C may have a different specificity compared to SEC24A and SEC24B (PubMed:17499046, PubMed:20427317, PubMed:18843296). May more specifically package GPI-anchored proteins through the cargo receptor TMED10 (PubMed:20427317). May also be specific for IxM motif-containing cargos like the SNAREs GOSR2 and STX5 (PubMed:18843296).
Ubiquitously expressed, with higher amounts in placenta, pancreas, heart and liver.
Binds 1 magnesium or manganese ion per subunit.
In the C-terminal section; belongs to the GART family.
In the N-terminal section; belongs to the GARS family.
In the central section; belongs to the AIR synthase family.
The C-terminal GART domain carries the phosphoribosylglycinamide formyltransferase activity.
The N-terminal ATP-grasp domain carries the phosphoribosylamine--glycine ligase activity.
The central AIRS domain carries the phosphoribosylformylglycinamidine cyclo-ligase activity.
Trifunctional enzyme that catalyzes three distinct reactions as part of the 'de novo' inosine monophosphate biosynthetic pathway.
Part of cGMP kinase signaling complex at least composed of ACTA2/alpha-actin, CNN1/calponin H1, PLN/phospholamban, PRKG1 and ITPR1.
Smooth muscle, and tissues containing significant amounts of smooth muscle.
Thin filament-associated protein that is implicated in the regulation and modulation of smooth muscle contraction. It is capable of binding to actin, calmodulin and tropomyosin. The interaction of calponin with actin inhibits the actomyosin Mg-ATPase activity (By similarity).
Thin filament-associated protein that is implicated in the regulation and modulation of smooth muscle contraction. It is capable of binding to actin, calmodulin and tropomyosin. The interaction of calponin with actin inhibits the actomyosin Mg-ATPase activity.
Expressed predominantly in skeletal muscle (at protein level) (PubMed:10882522, PubMed:31610034). Also detected in heart (PubMed:10882522).
May play a role in the maintenance of heart function mediated, at least in part, through cAMP-binding. May play a role in the regulation of KCNK2/TREK-1-mediated current amplitude (PubMed:31610034).
Autophosphorylation at Thr-219 is required for targeting to the TCR and cellular function of PRKCQ upon antigen receptor ligation. Following TCR stimulation, phosphorylated at Tyr-90 and Ser-685.
Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non-redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates in the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non-canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylates CCDC88A/GIV and inhibits its guanine nucleotide exchange factor activity (PubMed:23509302).
Expressed in skeletal muscle, T-cells, megakaryoblastic cells and platelets.
Novel PKCs (PRKCD, PRKCE, PRKCH and PRKCQ) are calcium-insensitive, but activated by diacylglycerol (DAG) and phosphatidylserine. Three specific sites; Thr-538 (activation loop of the kinase domain), Ser-676 (turn motif) and Ser-695 (hydrophobic region), need to be phosphorylated for its full activation. Inhibited by PRKCH upstream open reading frame 2 (PubMed:34593629).
Part of a lipid raft complex composed at least of BCL10, CARD11, MALT1 and IKBKB (PubMed:16356855). Interacts with GLRX3 (via N-terminus) (PubMed:10636891). Interacts with ECT2 (PubMed:15254234). Interacts with CCDC88A/GIV; the interaction leads to phosphorylation of CCDC88A and inhibition of its guanine nucleotide exchange factor activity (PubMed:23509302). Interacts with PRKCH upstream open reading frame 2; the interaction leads to inhibition of kinase activity (PubMed:34593629).
The C1 domain, containing the phorbol ester/DAG-type region 1 (C1A) and 2 (C1B), is the diacylglycerol sensor and the C2 domain is a non-calcium binding domain.
Interacts with HNRNPDL (PubMed:15190078). Interacts with the 5FMC complex; the interaction requires association with CHTOP. Interacts with CAVIN1 (By similarity).
Involved in transcriptional regulation. Represses the transcription of a number of genes including gastrin, stromelysin and enolase. Binds to the G-rich box in the enhancer region of these genes.
Sumoylated with SUMO2. Desumoylated by SENP3, resulting in the stimulation of transcription of its target genes (By similarity).
Expressed in airway epithelial cells (at protein level). Not detected in spermatozoa (at protein level).
Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Required for structural and functional integrity of the cilia of ependymal cells lining the brain ventricles.
Interacts with DNAL1 (PubMed:21496787). Consists of at least two heavy chains and a number of intermediate and light chains.
Interacts with USP25 (isoform USP25m only); the interaction prevents proteasomal degradation of MYBPC1.
Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands. Slow skeletal protein that binds to both myosin and actin (PubMed:31264822, PubMed:31025394). In vitro, binds to native thin filaments and modifies the activity of actin-activated myosin ATPase. May modulate muscle contraction or may play a more structural role.
Belongs to the glutaredoxin family. Monothiol subfamily.
Homodimer (PubMed:21029046). Interacts with ISCU (PubMed:26100117). Interacts with BOLA1 (PubMed:27532773, PubMed:27532772).
Monothiol glutaredoxin involved in mitochondrial iron-sulfur (Fe/S) cluster transfer (PubMed:20364084, PubMed:23615440). Receives 2Fe/2S clusters from scaffold protein ISCU and mediates their transfer to apoproteins, to the 4Fe/FS cluster biosynthesis machinery, or export from mitochondrion (PubMed:20364084, PubMed:23615440, PubMed:24334290). Required for normal regulation of hemoglobin synthesis by the iron-sulfur protein ACO1 (PubMed:20364084).
May play a role in tumorigenesis of colorectal carcinomas with high microsatellite instability (MSI-H).
PCNXL2 is characterized by high mutational frequencies and biallelic mutations in MSI-H colorectal tumors, and is thus likely to be a target gene in these tumors.
Belongs to the complex I NDUFA10 subunit family.
Complex I is composed of 45 different subunits. This a component of the hydrophobic protein fraction.
Phosphorylation at Ser-250 by PINK1 is required for the binding and/or reduction of the complex I substrate ubiquinone.
Allele GC*1S is O-glycosylated at Thr-436 (PubMed:20079467). The trisaccharide sugar moiety can be modified by the successive removal of neuraminic acid and galactose leaving an O-mceeN-acetyl-galactosamine. This conversion is thought to produce a macrophage-activating factor (Gc-MAF). Only a minor proportion of plasma GC is O-glycosylated (PubMed:17360250). The potential N-glycosylation site predicted at Asn-288 is thought to be nonglycosylated.
Associates with membrane-bound immunoglobulin on the surface of B-lymphocytes and with IgG Fc receptor on the membranes of T-lymphocytes. Interacts with LRP2; the interaction is required for renal uptake of GC in complex with 25-hydroxyvitamin D3 (By similarity).
Expressed in the liver. Found in plasma, ascites, cerebrospinal fluid and urine.
Involved in vitamin D transport and storage, scavenging of extracellular G-actin, enhancement of the chemotactic activity of C5 alpha for neutrophils in inflammation and macrophage activation.
Over 80 variants of human DBP have been identified. The three most common alleles are called GC*1F, GC*1S, and GC*2. The sequence shown is that of the GC*1A1 allele.
About 40% of plasma transthyretin circulates in a tight protein-protein complex with the plasma retinol-binding protein (RBP). The formation of the complex with RBP stabilizes the binding of retinol to RBP and decreases the glomerular filtration and renal catabolism of the relatively small RBP molecule. There is evidence for 2 binding sites for RBP, one possibly being a region that includes Ile-104, located on the outer surface of the transthyretin molecule.
Detected in serum and cerebrospinal fluid (at protein level). Highly expressed in choroid plexus epithelial cells. Detected in retina pigment epithelium and liver.
Each monomer has two 4-stranded beta sheets and the shape of a prolate ellipsoid. Antiparallel beta-sheet interactions link monomers into dimers. A short loop from each monomer forms the main dimer-dimer interaction. These two pairs of loops separate the opposed, convex beta-sheets of the dimers to form an internal channel.
Homotetramer. Dimer of dimers. In the homotetramer, subunits assemble around a central channel that can accommodate two ligand molecules. Interacts with RBP4.
Not glycosylated under normal conditions. Following unfolding, caused for example by variant AMYL-TTR 'Gly-38', the cryptic Asn-118 site is exposed and glycosylated by STT3B-containing OST complex, leading to its degradation by the ER-associated degradation (ERAD) pathway.
Sulfonation of the reactive cysteine Cys-30 enhances the stability of the native conformation of TTR, avoiding misassembly of the protein leading to amyloid formation.
Tetramer dissociation and partial unfolding leads to the formation of aggregates and amyloid fibrils. Small molecules that occupy at least one of the thyroid hormone binding sites stabilize the tetramer, and thereby stabilize the native state and protect against misfolding and the formation of amyloid fibrils.
Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.
Two binding sites for thyroxine are located in the channel. Less than 1% of plasma prealbumin molecules are normally involved in thyroxine transport. L-thyroxine binds to the transthyretin by an order of magnitude stronger than does the triiodo-L-thyronine. Thyroxine-binding globulin is the major carrier protein for thyroid hormones in man.
Bifunctional inositol kinase that acts in concert with the IP6K kinases IP6K1, IP6K2 and IP6K3 to synthesize the diphosphate group-containing inositol pyrophosphates diphosphoinositol pentakisphosphate, PP-InsP5, and bis-diphosphoinositol tetrakisphosphate, (PP)2-InsP4 (PubMed:17690096, PubMed:17702752, PubMed:21222653, PubMed:29590114). PP-InsP5 and (PP)2-InsP4, also respectively called InsP7 and InsP8, regulate a variety of cellular processes, including apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, insulin signaling and neutrophil activation (PubMed:17690096, PubMed:17702752, PubMed:21222653, PubMed:29590114). Phosphorylates inositol hexakisphosphate (InsP6) at position 1 to produce PP-InsP5 which is in turn phosphorylated by IP6Ks to produce (PP)2-InsP4 (PubMed:17690096, PubMed:17702752). Alternatively, phosphorylates PP-InsP5 at position 1, produced by IP6Ks from InsP6, to produce (PP)2-InsP4 (PubMed:17690096, PubMed:17702752). Required for normal hearing (PubMed:29590114).
Bifunctional inositol kinase that acts in concert with the IP6K kinases to synthesize the diphosphate group-containing inositol pyrophosphates diphosphoinositol pentakisphosphate, PP-InsP5, and bis-diphosphoinositol tetrakisphosphate, (PP)2-InsP4. PP-InsP5 and (PP)2-InsP4, also respectively called InsP7 and InsP8, may regulate a variety of cellular processes, including apoptosis, vesicle trafficking, cytoskeletal dynamics, and exocytosis. Phosphorylates inositol hexakisphosphate (InsP6).
Interacts with ADAM10; the interaction influences ADAM10 substrate specificity.
Regulates maturation and trafficking of the transmembrane metalloprotease ADAM10 (PubMed:26686862, PubMed:30463011). Promotes ADAM10-mediated cleavage of CDH2 (By similarity). Negatively regulates ligand-induced Notch activity probably by regulating ADAM10 activity (PubMed:26686862).
Homodimer; disulfide-linked. Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5 (By similarity). Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX. Interacts with AIMP1; regulates its retention in the endoplasmic reticulum. Interacts with OS9. Interacts with CNPY3. This interaction is disrupted in the presence of ATP (By similarity). Interacts with TLR4 and TLR9, but not with TLR3. Interacts with MZB1 in a calcium-dependent manner (By similarity). Interacts with METTL23. Interacts with IL1B; the interaction facilitates cargo translocation into the ERGIC (PubMed:32272059).
Molecular chaperone that functions in the processing and transport of secreted proteins (By similarity). When associated with CNPY3, required for proper folding of Toll-like receptors (By similarity). Functions in endoplasmic reticulum associated degradation (ERAD) (PubMed:18264092). Has ATPase activity (By similarity). May participate in the unfolding of cytosolic leaderless cargos (lacking the secretion signal sequence) such as the interleukin 1/IL-1 to facilitate their translocation into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and secretion; the translocation process is mediated by the cargo receptor TMED10 (PubMed:32272059).
Expressed in brain and to a lower extent in lung. In brain, it is found in cerebrum, cerebellum and spinal cord. In embryo expressed in the notochord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome.
The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by calcium-activated phosphatidylinositol-specific phospholipase C enzymes.
(Microbial infection) Activated by SARS coronavirus-2/SARS-CoV-2 spike protein.
(Microbial infection) Expression is induced by SARS coronavirus-2/SARS-CoV-2 spike protein.
(Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 infection, is activated by spike protein which increases the amplitude of spontaneous Ca(2+) signals and is required for spike-mediated syncytia.
Exhibits synergistic gating by Ca(2+) and voltage (By similarity). Inhibited by some non-specific cation channel blockers such as: ruthenium red, 2-aminoethyl diphenylborinate (2APB), gadolinium and cadmium ions (By similarity).
Expressed in embryonic stem cell, fetal liver, retina, chronic myologenous leukemia and intestinal cancer.
Small-conductance calcium-activated nonselective cation (SCAN) channel which acts as a regulator of phospholipid scrambling in platelets and osteoblasts. Phospholipid scrambling results in surface exposure of phosphatidylserine which in platelets is essential to trigger the clotting system whereas in osteoblasts is essential for the deposition of hydroxyapatite during bone mineralization. Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide (By similarity). Can generate outwardly rectifying chloride channel currents in airway epithelial cells and Jurkat T lymphocytes.
It is uncertain whether Met-1 or Met-46 is the initiator.
Detected in heart, skeletal muscle, spleen, kidney, liver, placenta, lung, peripheral blood leukocytes, adrenal gland, bone marrow, brain, lymph node, mammary gland, prostate, spinal cord, stomach, thyroid and trachea.
Phosphatidylinositol 3,4,5-trisphosphate-dependent GTPase-activating protein that modulates actin cytoskeleton remodeling by regulating ARF and RHO family members. Is activated by phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) binding. Can be activated by phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4,5)P2) binding, albeit with lower efficiency. Has a preference for ARF1 and ARF5 (By similarity).
Highly expressed in lymph node, brain, heart, lung, skeletal muscle, ovary, small intestine, and colon, with lower levels in placenta, pancreas, testis, spleen, and thymus, and no expression in kidney, liver, and peripheral blood leukocytes.
Calcium-sensitive protein which reversibly blocks the barbed ends of actin filaments but does not sever preformed actin filaments. May play an important role in macrophage function. May play a role in regulating cytoplasmic and/or nuclear structures through potential interactions with actin. May bind DNA.
Interacts with NUP62 (PubMed:18266911). Interacts with NUTF2 and RAN; involved in CAPG nuclear import (PubMed:18266911).
This protein was originally thought to be a DNA-binding protein with a helix-loop-helix domain.
(Microbial infection) Mediates the nuclear export of adenovirus VA1 dsRNA.
Component of a nuclear export receptor complex composed of XPO5, RAN, dsRNA-binding proteins and dsRNA. Found in a nuclear export complex with XPO5, RAN, EEF1A1, and aminoacylated tRNA. Found in a nuclear export complex with XPO5, RAN, ILF3 and dsRNA. Found in a nuclear export complex with XPO5, RAN and pre-miRNA (PubMed:19965479). Found in a nuclear export complex with XPO5, RAN, ILF3 and minihelix VA1 dsRNA. Found in a nuclear export complex with XPO5, RAN, ILF3, ZNF346 and dsRNA. Interacts with EEF1A1, ILF3, NUP153, NUP214 and ZNF346. Interacts with RAN and cargo proteins in a GTP-dependent manner. Interacts with isoform 5 of ADAR/ADAR1 (via DRBM domains). Interacts with SMAD4; mediates nuclear export of SMAD4 (PubMed:26878725). Interacts with RAN (GTP-bound form) (PubMed:19965479).
Expressed in heart, brain, placenta, lung, skeletal muscle, kidney and pancreas.
Mediates the nuclear export of micro-RNA precursors, which form short hairpins (PubMed:14681208, PubMed:14631048, PubMed:15613540). Also mediates the nuclear export of synthetic short hairpin RNAs used for RNA interference. In some circumstances can also mediate the nuclear export of deacylated and aminoacylated tRNAs. Specifically recognizes dsRNAs that lack a 5'-overhang in a sequence-independent manner, have only a short 3'-overhang, and that have a double-stranded length of at least 15 base-pairs (PubMed:19965479). Binding is dependent on Ran-GTP (PubMed:19965479).
Mediates the nuclear export of proteins bearing a double-stranded RNA binding domain (dsRBD) and double-stranded RNAs (cargos). XPO5 in the nucleus binds cooperatively to the RNA and to the GTPase Ran in its active GTP-bound form. Proteins containing dsRBDs can associate with this trimeric complex through the RNA. Docking of this complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause disassembly of the complex and release of the cargo from the export receptor. XPO5 then returns to the nuclear compartment by diffusion through the nuclear pore complex, to mediate another round of transport. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Overexpression may in some circumstances enhance RNA-mediated gene silencing (RNAi). Mediates nuclear export of isoform 5 of ADAR/ADAR1 in a RanGTP-dependent manner.
Detected in retina and retinal derived Y-79 retinoblastoma cells. Also found in fetal brain.
May have a role in the recovery or adaptation response of photoreceptors. May have a role in development.
Sialate:O-sulfotransferase which catalyzes 8-O-sulfation at the Sia-glycan level using 3'-phosphoadenosine 5'-phosphosulfate (PAPS) as a donor, forming 8-O-sulfated Sia (Sia8S)-glycans.
Interacts with CXXC4. Interacts (via PDZ domain) with NXN (By similarity). Interacts with BRD7 and INVS. Interacts (via PDZ domain) with VANGL1 and VANGL2 (via C-terminus). Interacts with ARRB1; the interaction is enhanced by phosphorylation of DVL1. Interacts with CYLD (By similarity). Interacts (via PDZ domain) with RYK. Self-associates (via DIX domain) and forms higher homooligomers. Interacts (via PDZ domain) with DACT1 and FZD7, where DACT1 and FZD7 compete for the same binding site (By similarity). Interacts (via DEP domain) with MUSK; the interaction is direct and mediates the formation a DVL1, MUSK and PAK1 ternary complex involved in AChR clustering (By similarity). Interacts (via PDZ domain) with TMEM88. Interacts with DCDC2. Interacts with FOXK2 (PubMed:25805136). Interacts with PKD1 (via extracellular domain) (PubMed:27214281). Interacts (via PDZ domain) with CCDC88C/DAPLE; competes with CCDC88C for binding to frizzled receptor FZD7 and dissociates from CCDC88C following initiation of non-canonical Wnt signaling when CCDC88C displaces DVL1 from ligand-activated FZD7 (PubMed:26126266, PubMed:14750955).
Participates in Wnt signaling by binding to the cytoplasmic C-terminus of frizzled family members and transducing the Wnt signal to down-stream effectors. Plays a role both in canonical and non-canonical Wnt signaling. Plays a role in the signal transduction pathways mediated by multiple Wnt genes. Required for LEF1 activation upon WNT1 and WNT3A signaling. DVL1 and PAK1 form a ternary complex with MUSK which is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ).
The DEP domain mediates interaction with the cell membrane.
The DIX domain promotes homooligomerization.
Ubiquitinated; undergoes both 'Lys-48'-linked ubiquitination, leading to its subsequent degradation by the ubiquitin-proteasome pathway, and 'Lys-63'-linked ubiquitination. The interaction with INVS is required for ubiquitination. Deubiquitinated by CYLD, which acts on 'Lys-63'-linked ubiquitin chains (By similarity).
Gustducin-coupled strychnine receptor implicated in the perception of bitter compounds in the oral cavity and the gastrointestinal tract. Signals through PLCB2 and the calcium-regulated cation channel TRPM5.
Belongs to the adaptor complexes medium subunit family. Delta-COP subfamily.
Component of the coatomer, a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. The coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. In mammals, the coatomer can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins; the complex also influences the Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors (By similarity).
Oligomeric complex that consists of at least the alpha, beta, beta', gamma, delta, epsilon and zeta subunits.
The disease is caused by variants affecting the gene represented in this entry. the skeletal phenotype, that characterizes this disorder, may be due to defective type I collagen transport and reduction of collagen secretion.
Belongs to the cyclophilin-type PPIase family. PPIase H subfamily.
Interacts directly with PRPF4. Part of a heteromeric complex containing PPIH, PRPF3 and PRPF4 that is stable in the absence of RNA. Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39. Heterodimer with PRPF18.
PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding (PubMed:20676357). Participates in pre-mRNA splicing. May play a role in the assembly of the U4/U5/U6 tri-snRNP complex, one of the building blocks of the spliceosome. May act as a chaperone.
ADF augments the expression of the interleukin-2 receptor TAC (IL2R/P55).
Causes an allergic reaction in human (PubMed:17182577, PubMed:19032234, PubMed:21489611). Recombinant protein binds to IgE in atopic eczema-suffering patients allergic to opportunistic skin-colonizing yeast M.sympodialis. Intermediate cross-reactivity is detected between the recombinant thioredoxin from M.sympodialis (Mala s 13) and recombinant form of this protein. Skin-prick test (SPT) and atopy patch test (APT) with 5 patients confirm cross-reactivity between the two proteins (PubMed:17182577). Recombinant protein binds to IgE of patients suffering from allergic bronchopulmonary aspergillosis (ABPA) and cross-reacts extensively with recombinant thioredoxin proteins from A.fumigatus (Asp f 28 and Asp f 29) and Mala s 13. Causes a positive skin reaction and induces proliferation of the human peripheral blood mononuclear cells in ABPA patients allergic to this protein. Acts as an IgE-binding self-antigen in ABPA patients allergic to fungal thioredoxin (PubMed:19032234). In atopic dermatitis (AD)-suffering patients allergic to M.sympodialis, a cross-reactivity between Mala s 13 and this protein can be detected in T-cells of the peripheral blood and skin. Keratinocytes stimulated by interferon (IFN)-alpha and tumor necrosis factor (TNF)-alpha release thioredoxin, which then becomes available for cross-reactivity with Mala s 13-specific T cells. The autoreactive T cells identified include T-helper 1 (Th1), T-helper 2 (Th2), T-helper 17 (Th17) and T-helper 22 (Th22) phenotypes. Skinhoming T cells autoreactive to this protein may be relevant for cutaneous inflammation in patients with AD (PubMed:21489611).
Homodimer; disulfide-linked (PubMed:9369469, PubMed:17260951). Interacts with TXNIP through the redox-active site (PubMed:17260951). Interacts with MAP3K5 and CASP3 (PubMed:15246877). In case of infection, interacts with S.typhimurium protein slrP (PubMed:19690162). Interacts with APEX1; the interaction stimulates the FOS/JUN AP-1 DNA-binding activity in a redox-dependent manner (PubMed:9108029).
In case of infection, ubiquitinated by S.typhimurium protein slrP, leading to its degradation.
In the fully reduced protein, both Cys-69 and Cys-73 are nitrosylated in response to nitric oxide (NO). When two disulfide bonds are present in the protein, only Cys-73 is nitrosylated. Cys-73 can serve as donor for nitrosylation of target proteins.
Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions (PubMed:2176490, PubMed:17182577, PubMed:19032234). Plays a role in the reversible S-nitrosylation of cysteine residues in target proteins, and thereby contributes to the response to intracellular nitric oxide. Nitrosylates the active site Cys of CASP3 in response to nitric oxide (NO), and thereby inhibits caspase-3 activity (PubMed:16408020, PubMed:17606900). Induces the FOS/JUN AP-1 DNA-binding activity in ionizing radiation (IR) cells through its oxidation/reduction status and stimulates AP-1 transcriptional activity (PubMed:9108029, PubMed:11118054).
Unlike human OOSP2, mouse OOSP2 seems not participate in folliculogenesis and oocyte maturation.
Can functionally substitute for CWC12 in yeast.
Component of pre-catalytic, catalytic and post-catalytic spliceosome complexes (PubMed:11991638, PubMed:28502770, PubMed:28076346, PubMed:29361316, PubMed:29360106, PubMed:29301961, PubMed:30705154). Found in a pre-mRNA splicing complex with SFRS4, SFRS5, SNRP70, SNRPA1, SRRM1 and SRRM2 (PubMed:9531537). Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932). Interacts with DHX8 (PubMed:28062851). Interacts with CACTIN (PubMed:28062851).
Expressed in liver, placenta, and white blood cells.
Required for pre-mRNA splicing as component of the spliceosome. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
Component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1 (PubMed:29911972). Required for internalization of the GABA receptor GABRA1 from the cell membrane via endosomes and subsequent GABRA1 degradation (By similarity). Acts as a mediator of cell spreading and cytoskeletal responses to the extracellular matrix component THBS1 (PubMed:18710924).
Homodimer; may form higher oligomers (By similarity). Identified in the CTLH complex that contains GID4, RANBP9 and/or RANBP10, MKLN1, MAEA, RMND5A (or alternatively its paralog RMND5B), GID8, ARMC8, WDR26 and YPEL5 (PubMed:17467196, PubMed:29911972). Within this complex, MAEA, RMND5A (or alternatively its paralog RMND5B), GID8, WDR26, and RANBP9 and/or RANBP10 form the catalytic core, while GID4, MKLN1, ARMC8 and YPEL5 have ancillary roles (PubMed:29911972). Interacts with RANBP9 (PubMed:18710924). Part of a complex consisting of RANBP9, MKLN1 and GID8 (PubMed:12559565). Interacts with GABRA1. Interacts with the C-terminal tail of PTGER3 (By similarity).
The LisH mediates head to tail dimerization.
Auto-ubiquitinated; requires the RING-type zinc finger. Auto-polyubiquitination leads to proteasomal degradation.
Endoplasmic reticulum (ER) membrane anchored E3 ligase involved in the retrotranslocation and turnover of membrane and secretory proteins from the ER through a set of processes named ER-associated degradation (ERAD). This process acts on misfolded proteins as well as in the regulated degradation of correctly folded proteins. Enhances ionizing radiation-induced p53/TP53 stability and apoptosis via ubiquitinating MDM2 and AKT1 and decreasing AKT1 kinase activity through MDM2 and AKT1 proteasomal degradation. Regulates ER stress-induced autophagy, and may act as a tumor suppressor (PubMed:22178386). Also plays a role in innate immune response by stimulating NF-kappa-B activity in the TLR2 signaling pathway. Ubiquitinates TRAF6 via the 'Lys-29'-linked polyubiquitination chain resulting in NF-kappa-B activation (PubMed:28087809). Participates as well in T-cell receptor-mediated NF-kappa-B activation (PubMed:25088585). In the presence of TNF, modulates the IKK complex by regulating IKBKG/NEMO ubiquitination leading to the repression of NF-kappa-B (PubMed:25152375).
Interacts (via C-terminal domain) with VCP. Interacts with AKT1; the interaction ubiquitinates AKT1 and leads to its proteasomal degradation. Interacts with MDM2; the interaction ubiquitinates AKT1 and leads to its proteasomal degradation. Interacts with p62/SQSTM1. Interacts with TRAF6 (PubMed:28087809). Interacts with IKBKG/NEMO (PubMed:25152375).
Located on chromosome 13 within the minimal deletion region for B-cell chronic lymphocytic leukemia.
The C-terminal domain transmembrane domain is indispensable for the localization to the ER.
The RING-type zinc finger is required for auto-polyubiquitination.
The coiled-coil domain is required for the induction of autophagy during endoplasmic reticulum (ER) stress.
The TPR repeats are six to seven residues longer than a canonical TPR motif.
Belongs to the succinate/malate CoA ligase alpha subunit family.
Heterodimer of an alpha and a beta subunit. Different beta subunits determine nucleotide specificity. Together with the ATP-specific beta subunit SUCLA2, forms an ADP-forming succinyl-CoA synthetase (A-SCS). Together with the GTP-specific beta subunit SUCLG2 forms a GDP-forming succinyl-CoA synthetase (G-SCS).
Succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of either ATP or GTP and thus represents the only step of substrate-level phosphorylation in the TCA. The alpha subunit of the enzyme binds the substrates coenzyme A and phosphate, while succinate binding and specificity for either ATP or GTP is provided by different beta subunits.
ATP- and membrane-binding protein that probably controls membrane reorganization/tubulation upon ATP hydrolysis. Plays a role in early endosomal transport.
Homooligomer, and heterooligomer with EHD1, EHD2 and EHD3.
As part of the MLL1/MLL complex, involved in the methylation of histone H3 at 'Lys-4', particularly trimethylation. Histone H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. May play some role in histone H3 acetylation. In a teratocarcinoma cell, plays a crucial role in retinoic acid-induced differentiation along the neural lineage, regulating gene induction and H3 'Lys-4' methylation at key developmental loci. May also play an indirect or direct role in endosomal transport.
Homodimer. Core component of several methyltransferase-containing complexes including MLL1/MLL, MLL2/3 (also named ASCOM complex) and MLL4/WBP7. Each complex is at least composed of ASH2L, RBBP5, WDR5, DPY30, one or more specific histone methyltransferases (KMT2A/MLL1, KMT2D/MLL2, KMT2C/MLL3 and KMT2B/MLL4), and the facultative components MEN1, HCFC1, HCFC2, NCOA6, KDM6A, PAXIP1/PTIP, PAGR1 and alpha- and beta-tubulin (By similarity). Interacts with ASH2L; the interaction is direct. Interacts with ARFGEF1. Component of the SET1 complex, at least composed of the catalytic subunit (SETD1A or SETD1B), WDR5, WDR82, RBBP5, ASH2L/ASH2, CXXC1/CFP1, HCFC1 and DPY30.
Mitochondrial electroneutral antiporter that exports citrate from the mitochondria into the cytosol in exchange for malate (PubMed:29031613, PubMed:29238895). Also able to mediate the exchange of citrate for isocitrate, phosphoenolpyruvate, cis-aconitate and to a lesser extend cis-aconitate, maleate and succinate (PubMed:29031613). In the cytoplasm citrate is important in the regulation of glycolysis through a feedback mechanism and in the production of acetyl-CoA which is needed for the synthesis of fatty acids, sterols, prostaglandins, dolichol and coenzyme Q (CoQ). Required for proper neuromuscular junction formation (Probable).
Possesses a short cleavable presequence, which, however, is found to be dispensable both for targeting to mitochondria and insertion into the inner membrane. However, the presequence is required to keep SLC25A1 in a soluble state and thus in an import-competent state. Mature SLC25A1 lacking the presequence is prone to aggregation.
Activation by cleavage is down-regulated upon activation of SIRT3-dependent PRKAA1/AMPK-alpha signaling cascade which leads to inhibition of ATP-consuming lipogenesis to restore cellular energy balance.
Efficient DNA binding of the soluble transcription factor fragment requires dimerization with another bHLH protein (PubMed:8402897). Interacts with CEBPA, the interaction produces a transcriptional synergy (By similarity). Interacts with LMNA (By similarity).
Expressed in a wide variety of tissues, most abundant in liver and adrenal gland (PubMed:8402897). In fetal tissues lung and liver shows highest expression (PubMed:8402897).
Forms a tight complex with SCAP, the SCAP-SREBP complex, in the endoplasmic reticulum membrane.
Isoform expressed only in select tissues, which has higher transcriptional activity compared to SREBP-1C (By similarity). Able to stimulate both lipogenic and cholesterogenic gene expression (PubMed:12177166, PubMed:32497488). Has a role in the nutritional regulation of fatty acids and triglycerides in lipogenic organs such as the liver (By similarity). Required for innate immune response in macrophages by regulating lipid metabolism (By similarity).
Key transcription factor that regulates expression of genes involved in cholesterol biosynthesis and lipid homeostasis (PubMed:8402897, PubMed:12177166, PubMed:32322062). Binds to the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3'). Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3') (PubMed:8402897, PubMed:12177166). Regulates the promoters of genes involved in cholesterol biosynthesis and the LDL receptor (LDLR) pathway of sterol regulation (PubMed:8402897, PubMed:12177166, PubMed:32322062).
Phosphorylated by AMPK, leading to suppress protein processing and nuclear translocation, and repress target gene expression (By similarity). Phosphorylation at Ser-402 by SIK1 represses activity possibly by inhibiting DNA-binding (By similarity).
Precursor of the transcription factor form (Processed sterol regulatory element-binding protein 1), which is embedded in the endoplasmic reticulum membrane (PubMed:32322062). Low sterol concentrations promote processing of this form, releasing the transcription factor form that translocates into the nucleus and activates transcription of genes involved in cholesterol biosynthesis and lipid homeostasis (By similarity).
Predominant isoform expressed in most tissues, which has weaker transcriptional activity compared to isoform SREBP-1A (By similarity). Primarily controls expression of lipogenic gene (PubMed:12177166). Strongly activates global lipid synthesis in rapidly growing cells (By similarity).
Predominantly expressed in liver and adipose tissues (PubMed:8402897). Also expressed in kidney, brain, white fat, and muscle (PubMed:8402897).
Predominates in hepatoma cell lines (PubMed:8402897). Also expressed in kidney, brain, white fat, and muscle (PubMed:8402897).
Processed in the Golgi apparatus, releasing the protein from the membrane (PubMed:8626610, PubMed:32322062). At low cholesterol the SCAP-SREBP complex is recruited into COPII vesicles for export from the endoplasmic reticulum (PubMed:8626610, PubMed:32322062). In the Golgi, complex SREBPs are cleaved sequentially by site-1 (MBTPS1, S1P) and site-2 (MBTPS2, S2P) protease (PubMed:8626610, PubMed:32322062). The first cleavage by site-1 protease occurs within the luminal loop, the second cleavage by site-2 protease occurs within the first transmembrane domain, releasing the transcription factor from the Golgi membrane (PubMed:32322062).
The absence of Golgi proteolytic processing requirement makes this isoform constitutively active in transactivation of lipogenic gene promoters.
Ubiquitinated; the nuclear form has a rapid turnover and is rapidly ubiquitinated and degraded by the proteasome in the nucleus.
Catalytic subunit of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis.
Component of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex composed at least by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2 (PubMed:16162815, PubMed:9463366). Interacts with PIGC, PIGH, PIGP, PIGQ and DPM2 (PubMed:16162815). Interacts directly with PIGY; this interaction regulates glycosylphosphatidylinositol-N-acetylglucosaminyltransferase activity (PubMed:16162815). Interacts with PIGQ (PubMed:9463366).
The disease is caused by variants affecting the gene represented in this entry. PIGA deficiency causes disruption of iron homeostasis, due to failure to attach GPI anchors to hemojuvelin (HJV), a BMP coreceptor that regulates hepcidin (HAMP) expression. HAMP is an essential regulator of iron absorption and distribution across tissues. PIGA-deficient cells lack hemojuvelin surface expression and show significantly lower HAMP mRNA levels compared to control cells.
Expressed in testis and in acute myeloid leukemia (AML) patients.
Expressed only in testis on the round spermatids of stage I, II and II. Absent in spermatogonia and spermatocyte.
Homodimer (PubMed:19644450). The homodimer interacts with ARF6, forming a heterotetramer (PubMed:19644450). Homooligomer (PubMed:19644450). Interacts with MAX, MAPK14, MAP3K3, MYC, KNS2 and MAP2K4 (By similarity). Interaction with KNS2 is important in the formation of ternary complex with MAPK8 (By similarity). Interacts with NFKB1 (PubMed:14743216). Interacts with PIP4P1 (PubMed:29146937). Interacts with PIKFYVE (By similarity).
Increased in systemic sclerosis fibroblasts.
May play a role in spermatozoa-egg-interaction.
The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module (PubMed:14743216). Regulates lysosomal positioning by acting as an adapter protein which links PIP4P1-positive lysosomes to the dynein-dynactin complex (PubMed:29146937). Assists PIKFYVE selective functionality in microtubule-based endosome-to-TGN trafficking (By similarity).
Basal layers of epidermis (at protein level). Not expressed in the pancreas.
In spite of its original name 'Pancreatic elastase 1', CELA1 is not detected in the pancreas. Elastase activity described in the pancreas may be in fact due to CELA2A (PubMed:10620133).
Serine proteases that hydrolyze many proteins in addition to elastin.
Cell surface receptor for PLXNB1, PLXNB2, PLXNB3 and PLXND1 that plays an important role in cell-cell signaling (By similarity). Regulates glutamatergic and GABAergic synapse development (By similarity). Promotes the development of inhibitory synapses in a PLXNB1-dependent manner and promotes the development of excitatory synapses in a PLXNB2-dependent manner (By similarity). Plays a role in priming antigen-specific T-cells, promotes differentiation of Th1 T-helper cells, and thereby contributes to adaptive immunity (By similarity). Promotes phosphorylation of TIMD2 (By similarity). Inhibits angiogenesis (By similarity). Promotes axon growth cone collapse (By similarity). Inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons (By similarity).
Interacts with PLXNB1, PLXNB2, PLXNB3, PLXND1 and TIMD2 (By similarity).
Exhibits lysophospholipase, transacylase, PAF acetylhydrolase and asparaginase activities (By similarity). Can catalyze three types of transacylation reactions: (1) acyl transfer from 1-acyl-sn-glycero-3-phosphocholine (1-acyl-GPC) to the sn-1(3) positions of glycerol and 2-acylglycerol (sn-1 to -1(3) transfer), (2) acyl transfer from 1-acyl-GPC to the sn-2 positions of 1-acyl-GPC, 1-acyl-sn-glycero-3-phosphoethanolamine (1-acyl-GPE), and other lysophospholipids (sn-1 to -2 transfer) and (3) acyl transfer from 2-acyl-GPC to the sn-1 position of 2-acyl-GPC and 2-acyl-GPE (sn-2 to -1 transfer) (By similarity). Mediates the synthesis of 1-arachidonoyl species of phospholipids by transferring the arachidonoyl residue from 2-arachidonoyl lysophospholipid to the sn-1 position of 2-acyl lysophospholipid (By similarity).
In the N-terminal section; belongs to the asparaginase 1 family.
Probable RNA-binding protein, which may be required during spermatogenesis. May act by binding to the 3'-UTR of mRNAs and regulating their translation (By similarity).
Testis specific. Not expressed in early embryos, primordial germ cells and spermatogonial cells. First expressed in the cytoplasm of spermatocytes and then persists through meiosis.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A8 subfamily.
Creatine:sodium symporter which mediates the uptake of creatine (PubMed:7953292, PubMed:7945388, PubMed:9882430, PubMed:17465020, PubMed:22644605, PubMed:25861866). Plays an important role in supplying creatine to the brain via the blood-brain barrier (By similarity).
Predominantly expressed in skeletal muscle and kidney. Also found in brain, heart, colon, testis and prostate.
Homomultimer. Interacts with NTRK1/TrkA (By similarity).
Required for axon extension during neural development.
Essential sperm cell-surface protein required for fertilization by acting as a ligand for IZUMO1R/JUNO receptor on egg. The IZUMO1:IZUMO1R/JUNO interaction is a necessary adhesion event between sperm and egg that is required for fertilization but is not sufficient for cell fusion. The ligand-receptor interaction probably does not act as a membrane 'fusogen'. Acts a ligand for the human-specific oolemma epitope FCRL3/MAIA during fertilization (PubMed:36070373). FCRL3/MAIA replaces IZUMO1R/JUNO as IZUMO1 receptor after sperm-egg adhesion, which permits species-specific gamete fusion (PubMed:36070373).
Izumo is the name of a Japanese shrine to marriage.
Monomer (PubMed:27309808, PubMed:27309818). Monomer, homodimer and homooligomer; depending on the context (By similarity). Interacts with IZUMO1R/JUNO. IZUMO1 and IZUMO1R/JUNO form a complex with 1:1 stoichiometry (PubMed:27309808, PubMed:27309818). In gamete recognition, IZUMO1R/JUNO first binds to monomeric IZUMO1 (By similarity). The weak, but specific interaction with IZUMO1R/JUNO induces IZUMO1 homodimerization (By similarity). The process follows a tight binding phase where IZUMO1 bends the entire structure towards the sperm membrane side through a thiol-disulfide exchange reaction (By similarity). The molecule no longer binds to IZUMO1R/JUNO and instead binds to a putative second oocyte receptor (By similarity). Interacts with ACE3 (By similarity). Part of a oolemmal binding multimeric complex (IZUMO1 complex) composed at least of IZUMO1 and GLIPR1L1; the complex assemblage is influenced by the maturation status of the male germ cell. Interacts with GLIPR1L1. Interacts with FREY; the interaction retains IZUMO1 at the endoplasmic reticulum membrane and coordinates IZUMO1 complex assembly (By similarity). Interacts with FCRL3/MAIA (via extracellular domain); the interaction replaces IZUMO1R/JUNO as IZUMO1 receptor after sperm-egg adhesion (PubMed:36070373).
N-glycosylated. Glycosylation is not essential for fusion and for proper protein trafficking in sperm.
Phosphorylated. The cytoplasmic C-terminus is phosphorylated and undergoes phosphorylation changes during epididymal transit.
Sperm-specific (at protein level) (PubMed:15759005, PubMed:36070373). Detectable on sperm surface only after the acrosome reaction (PubMed:15759005, PubMed:36070373).
The cytoplasmic C-terminus region is not essential for fertilization. It is however required for protein stability.
The extracellular domain assumes a distinct boomerang shape when not bound to IZUMO1R/JUNO (PubMed:27309818). Interaction with IZUMO1R/JUNO triggers a conformation change, so that the IZUMO1 extracellular domain assumes an upright conformation (PubMed:27309818).
Highly expressed in heart, brain, placenta, liver, skeletal muscle and pancreas.
Interacts with RP9, SNW1, SFRS1, SFRS2,U2AF1, RBPJ, SAP30, HDAC2 NKAP and NEK6. Interacts with Epstein-Barr virus RPMS1. Component of the histone deacetylase complex. Component of the Notch corepressor complex. Interacts with NKAPL (By similarity).
May modulate splice site selection during alternative splicing of pre-mRNAs (By similarity). Regulates transcription and acts as corepressor for RBPJ. Recruits RBPJ to the Sin3-histone deacetylase complex (HDAC). Required for RBPJ-mediated repression of transcription.
Acts as a GTPase-activating protein (GAP) for ARL2 with low specific activity.
Both isoform 1 and isoform 6 are widely expressed.
Expressed in the somitic mesoderm, the central nervous system, the kidney, the heart, nasal epithelium, and limbs.
Self-associates. Interacts with HES1 and HEYL. Interacts with HDAC1, NCOR1 and SIN3A. Interacts with GATA4 and GATA6. Interacts with CCDC89/BOIP.
Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGTG-3' (PubMed:11095750). Downstream effector of Notch signaling required for cardiovascular development. Specifically required for the Notch-induced endocardial epithelial to mesenchymal transition, which is itself criticial for cardiac valve and septum development. May be required in conjunction with HEY2 to specify arterial cell fate or identity. Promotes maintenance of neuronal precursor cells and glial versus neuronal fate specification. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6 and by the neuronal bHLH factors ASCL1/MASH1 and NEUROD4/MATH3 (PubMed:15485867). Involved in the regulation of liver cancer cells self-renewal (PubMed:25985737).
Belongs to the complex I 20 kDa subunit family.
Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits (PubMed:12611891). This is a component of the iron-sulfur (IP) fragment of the enzyme (By similarity).
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:17275378). Essential for the catalytic activity of complex I (PubMed:17275378).
Hydroxylated ar Arg-111 by NDUFAF5 early in the pathway of assembly of complex I, before the formation of the juncture between peripheral and membrane arms.
Prolactin acts primarily on the mammary gland by promoting lactation.
Canstatin, a cleavage product corresponding to the collagen alpha 2(IV) NC1 domain, possesses both anti-angiogenic and anti-tumor cell activity. It inhibits proliferation and migration of endothelial cells, reduces mitochondrial membrane potential, and induces apoptosis. Specifically induces Fas-dependent apoptosis and activates procaspase-8 and -9 activity. Ligand for alphavbeta3 and alphavbeta5 integrins.
Proteolytic processing produces the C-terminal NC1 peptide, canstatin.
There are six type IV collagen isoforms, alpha 1(IV)-alpha 6(IV), each of which can form a triple helix structure with 2 other chains to generate type IV collagen network. Interacts with EFEMP2 (By similarity).
A fraction undergoes proteolytic cleavage of the extracellular domain at the cell membrane to generate a cytoplasmic tail fragment. This is internalized into the early endosome from where it trafficks in an LDLRAP1/ARH-dependent manner to the endocytic recycling compartment (ERC). In the ERC, it is further cleaved by gamma-secretase to release a fragment which translocates to the nucleus and mediates transcriptional repression.
Binds plasminogen, extracellular matrix components, plasminogen activator-plasminogen activator inhibitor type I complex, apolipoprotein E-enriched beta-VLDL, lipoprotein lipase, lactoferrin, CLU/clusterin and calcium (PubMed:7768901). Forms a multimeric complex together with LRPAP1 (PubMed:1400426). Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats) (By similarity). Interacts with LRP2BP (PubMed:12508107). Interacts (via NPXY motif) with DAB2; the interaction is not affected by tyrosine phosphorylation of the NPXY motif (PubMed:10769163, PubMed:15134832). Interacts with MB (By similarity). Interacts with BMP4 (By similarity). Interacts with the Sonic hedgehog protein N-product which is the active product of SHH (By similarity). Interacts with CST3 in a calcium-dependent manner (PubMed:17462596). Interacts with the vitamin-D binding protein GC/DBP (By similarity). Interacts with sex hormone-binding protein SHBG (PubMed:16143106). Interacts with angiotensin-2 (By similarity). Also interacts with angiotensin 1-7 (By similarity). Interacts with APOM (By similarity). Interacts with selenoprotein SEPP1 (By similarity). Interacts with LEP (By similarity). Interacts with ALB (By similarity). Interacts with the antiapoptotic protein BIRC5/survivin (PubMed:23825075). Interacts with matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (By similarity). In neurons, forms a trimeric complex with APP and APPB1/FE65 (By similarity). Interacts with LDLRAP1/ARH; mediates trafficking of LRP2 to the endocytic recycling compartment (By similarity). Does not interact with beta-amyloid protein 40 alone but interacts with the complex composed of beta-amyloid protein 40 and CLU/APOJ (By similarity). Interacts with MDK (By similarity).
Expressed in first and third trimester cytotrophoblasts in the placenta (at protein level) (PubMed:27798286). Absorptive epithelia, including renal proximal tubules.
Expression in the choroid plexus of the brain is markedly reduced in aging subjects when compared with younger adults.
Multiligand endocytic receptor (By similarity). Acts together with CUBN to mediate endocytosis of high-density lipoproteins (By similarity). Mediates receptor-mediated uptake of polybasic drugs such as aprotinin, aminoglycosides and polymyxin B (By similarity). In the kidney, mediates the tubular uptake and clearance of leptin (By similarity). Also mediates transport of leptin across the blood-brain barrier through endocytosis at the choroid plexus epithelium (By similarity). Endocytosis of leptin in neuronal cells is required for hypothalamic leptin signaling and leptin-mediated regulation of feeding and body weight (By similarity). Mediates endocytosis and subsequent lysosomal degradation of CST3 in kidney proximal tubule cells (By similarity). Mediates renal uptake of 25-hydroxyvitamin D3 in complex with the vitamin D3 transporter GC/DBP (By similarity). Mediates renal uptake of metallothionein-bound heavy metals (PubMed:15126248). Together with CUBN, mediates renal reabsorption of myoglobin (By similarity). Mediates renal uptake and subsequent lysosomal degradation of APOM (By similarity). Plays a role in kidney selenium homeostasis by mediating renal endocytosis of selenoprotein SEPP1 (By similarity). Mediates renal uptake of the antiapoptotic protein BIRC5/survivin which may be important for functional integrity of the kidney (PubMed:23825075). Mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (By similarity). Mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH (By similarity). Also mediates ShhN transcytosis (By similarity). In the embryonic neuroepithelium, mediates endocytic uptake and degradation of BMP4, is required for correct SHH localization in the ventral neural tube and plays a role in patterning of the ventral telencephalon (By similarity). Required at the onset of neurulation to sequester SHH on the apical surface of neuroepithelial cells of the rostral diencephalon ventral midline and to control PTCH1-dependent uptake and intracellular trafficking of SHH (By similarity). During neurulation, required in neuroepithelial cells for uptake of folate bound to the folate receptor FOLR1 which is necessary for neural tube closure (By similarity). In the adult brain, negatively regulates BMP signaling in the subependymal zone which enables neurogenesis to proceed (By similarity). In astrocytes, mediates endocytosis of ALB which is required for the synthesis of the neurotrophic factor oleic acid (By similarity). Involved in neurite branching (By similarity). During optic nerve development, required for SHH-mediated migration and proliferation of oligodendrocyte precursor cells (By similarity). Mediates endocytic uptake and clearance of SHH in the retinal margin which protects retinal progenitor cells from mitogenic stimuli and keeps them quiescent (By similarity). Plays a role in reproductive organ development by mediating uptake in reproductive tissues of androgen and estrogen bound to the sex hormone binding protein SHBG (By similarity). Mediates endocytosis of angiotensin-2 (By similarity). Also mediates endocytosis of angiotensis 1-7 (By similarity). Binds to the complex composed of beta-amyloid protein 40 and CLU/APOJ and mediates its endocytosis and lysosomal degradation (By similarity). Required for embryonic heart development (By similarity). Required for normal hearing, possibly through interaction with estrogen in the inner ear (By similarity).
N-glycosylation is required for ligand binding.
The cytoplasmic domain is required for sorting to the apical cell membrane.
Two overlapping PxLPxI/L motifs mediate interaction with ankyrin repeats of ANKRA2.
Cytokine that may play a role in anterior neural induction and somite formation during embryogenesis in part through a BMP-inhibitory mechanism. Can regulate Nodal signaling during gastrulation as well as the formation and patterning of the primitive streak (By similarity).
Forms monomers and predominantly dimers.
Calcium-binding protein that modulates excitation-contraction coupling in the heart. Contributes to calcium homeostasis in the heart sarcoplasmic reticulum. Modulates the activity of RYR2 calcium channels.
Homodimer. Interacts with GCA, RYR2 and ANXA7.
This protein has been shown to bind calcium with high affinity.
This protein is encoded by an amplified gene in multidrug-resistant cells.
Highly expressed in pancreas and selectively expressed in brain, lung, liver, skeletal muscle and kidney.
Interacts with the FxxxFxxxF motif of DRD1 via its C-terminal domain.
Regulates the export of target proteins, such as DRD1, from the endoplasmic reticulum to the cell surface.
Expression is up-regulated by dexamethasone.
Has a role in the formation and organization of the extracellular matrix. In the eye, it functions as a mediator of dexamethasone-induced matrix deposition in the trabecular meshwork, the tissue responsible for the outflow of the ocular aqueous humor and for the maintenance of intraocular pressure (PubMed:21199193). Is a negative regulator of angiogenesis in the cornea, and plays a major role in maintaining corneal avascularity and transparency (PubMed:25622036).
Highly expressed in the cornea (at protein level) (PubMed:11682471). Expression is restricted to the stromal layer (PubMed:11682471). Also detected at the junction between the corneal stromal layer and the conjuctiva. Not detected in the sclera (PubMed:11682471).
Arg-982 is dimethylated, probably to asymmetric dimethylarginine.
Component of the oxidative stress-induced survival signaling. May regulate the activation of SRC family protein kinases (PubMed:19015244). May act as a scaffolding protein enabling SRC family protein kinases to phosphorylate and activate PI3-kinase (PubMed:19015244). Binds IGF2 RNA and promotes the production of IGF2 protein (PubMed:19015244).
Interacts with PURA (By similarity). Interacts with SRC family protein kinases YES1, SRC and FYN (PubMed:19015244). Upon tyrosine phosphorylation, interacts with PIK3R1 (PubMed:19015244). Interacts with IGF2BP1/IMP-1 in an RNA-dependent manner (PubMed:19015244).
May play a role in the progression of scirrhous-type gastric cancer by supporting cancer cell survival during oxidative stress.
Phosphorylated on tyrosine by SRC family protein kinases upon oxidative stress, for instance following UV irradiation.
Widely expressed (PubMed:14585507). In gastric mucosa, detected in the bottom region of the foveolar epithelium (at protein level) (PubMed:19015244).
Interacts with GPSM1 (PubMed:18566450). Interacts with GPSM2 (via TPR repeat region) (PubMed:23318951).
Stabilizes membrane-bound GPSM1, and thereby promotes its interaction with GNAI1.
Expressed predominantly in brain; concentrated in presynaptic nerve terminals.
Non-amyloid component of senile plaques found in Alzheimer disease. Could act as a regulator of SNCA aggregation process. Protects neurons from staurosporine and 6-hydroxy dopamine (6OHDA)-stimulated caspase activation in a p53/TP53-dependent manner. Contributes to restore the SNCA anti-apoptotic function abolished by 6OHDA. Not found in the Lewy bodies associated with Parkinson disease.
Phosphorylated. Phosphorylation by G-protein coupled receptor kinases (GRK) is more efficient than phosphorylation by CK1, CK2 and CaM-kinase II.
Widely expressed, with highest levels in kidney, liver and pancreas. Down-regulated in tumors.
Component of mRNA stress granules. Interacts with FMR1, FXR1, FXR2, EWSR1, FUS, SERBP1, EEF1A1 and DDX3X or DDX3Y, and with the small nuclear ribonucleoprotein-associated proteins SNRPB and SNRPN. Interacts with 'Lys-48'-linked tetra-ubiquitin, but not with monoubiquitin or 'Lys-63'-linked ubiquitin chains. May interact with the exon junction complex (EJC) composed at least of CASC3, EIF4A3, MAGOH and RBM8A. Interacts with POLR2A (via the C-terminal domain (CTD)).
Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Probably cleaved by enteroviral 2A proteinase.
Scaffolding protein that specifically recognizes and binds dimethylarginine-containing proteins (PubMed:15955813). Plays a role in the regulation of translation of target mRNAs by binding Arg/Gly-rich motifs (GAR) in dimethylarginine-containing proteins. In nucleus, acts as a coactivator: recognizes and binds asymmetric dimethylation on the core histone tails associated with transcriptional activation (H3R17me2a and H4R3me2a) and recruits proteins at these arginine-methylated loci (PubMed:21172665). In cytoplasm, acts as an antiviral factor that participates in the assembly of stress granules together with G3BP1 (PubMed:35085371).
The Tudor domain specifically recognizes and binds asymmetric dimethylation of histone H3 'Arg-17' (H3R17me2a) and histones H4 'Arg-3', 2 tags for epigenetic transcriptional activation.
Brain specific (PubMed:16044242, PubMed:23763432). Highly expressed in the hypothalamus, also expressed in forebrain, amygdala, corpus callosum and spinal cord (PubMed:23161870).
Plasma membrane progesterone (P4) receptor coupled to G proteins (PubMed:23763432, PubMed:23161870). Seems to act through a G(s) mediated pathway (PubMed:23161870). Involved in neurosteroid inhibition of apoptosis (PubMed:23161870). May be involved in regulating rapid P4 signaling in the nervous system (PubMed:23763432). Also binds dehydroepiandrosterone (DHEA), pregnanolone, pregnenolone and allopregnanolone (PubMed:23763432, PubMed:23161870).
Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1. In the complex, it probably interacts directly with KAT2A, KAT14 and WDR5.
Inhibits the MAP3K12 activity to induce the activation of the JNK/SAPK pathway. Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4.
Ubiquitous. High expression seen in the heart and lung.
Induces bone formation in conjunction with TGF-beta-1 or TGF-beta-2.
Autoantibodies against THSD7A have been detected in serum and glomeruli from patients with idiopathic membranous nephropathy (PubMed:25394321). The majority of the autoantibodies react with the two most N-terminal TSP type-1 domains (PubMed:29555830).
Detected on kidney podocytes along the glomerular capillary wall (at protein level).
Plays a role in actin cytoskeleton rearrangement.
Proteolytic cleavage in the extracellular region generates a 210 kDa soluble form.
Sequence analysis combined with the expression of constructs corresponding each to two or three adjacent TSP type-1 domains suggests the presence of 21 TSP type-1 domains; not all of these are detected by standard bioinformatic tools.
The soluble form promotes endothelial cell migration and filopodia formation during sprouting angiogenesis via a FAK-dependent mechanism.
Acts as a transcriptional coactivator for PPARA and possibly other nuclear receptors. Proposed to be a ATP-dependent chromatin remodeling protein. Has DNA-dependent ATPase activity and binds to A/T-rich DNA. Associates with A/T-rich regulatory regions in promoters of genes that participate in the differentiation of progenitors during osteogenesis (By similarity).
Interacts with PPARA. Probably interacts with ESR1 and NR1I3.
Phosphorylated on serine and tyrosine residues.
Widely expressed at low levels. In bone marrow, expression is restricted to osteoprogenitor cells adjacent to mature osteoblasts.
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. PB-cadherins may have a role in the morphological organization of pituitary gland and brain tissues (By similarity).
Has chemorepulsive activities for sympathetic axons. Ligand of NRP2 (By similarity).
Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules (PubMed:16461343, PubMed:18056643). Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue (PubMed:21719704). Dephosphorylates ZAP70 at its activating 'Tyr-493' residue (PubMed:16461343). Dephosphorylates the immune system activator SKAP2 (PubMed:21719704). Positively regulates toll-like receptor (TLR)-induced type 1 interferon production (PubMed:23871208). Promotes host antiviral responses mediated by type 1 interferon (By similarity). Regulates NOD2-induced pro-inflammatory cytokine secretion and autophagy (PubMed:23991106). Acts as an activator of NLRP3 inflammasome assembly by mediating dephosphorylation of 'Tyr-861' of NLRP3 (PubMed:27043286). Dephosphorylates phospho-anandamide (p-AEA), an endocannabinoid to anandamide (also called N-arachidonoylethanolamide) (By similarity).
By muramyl-dipeptide and lipopolysaccharide.
Expressed in bone marrow, B and T-cells, PBMCs, natural killer cells, monocytes, dendritic cells and neutrophils (PubMed:15208781). Both isoform 1 and 4 are predominantly expressed in lymphoid tissues and cells. Isoform 1 is expressed in thymocytes and both mature B and T-cells.
Interacts with CSK (PubMed:15208781). Interacts with LPXN (By similarity). Interacts with CBL (PubMed:10068674). Interacts with TRAF3 (via MATH domain); the interaction promotes TRAF3 polyubiquitination (PubMed:23871208).
Lacks most of the phosphatase domain and functions as a dominant negative isoform of the full length PTPN22.
Phosphorylation on Ser-35 by PKC/PRKCD abrogates its ability to dephosphorylate and inactivate the SRC family kinases.
Acts as a ligand for C-C chemokine receptor CCR6. Signals through binding and activation of CCR6 and induces a strong chemotactic response and mobilization of intracellular calcium ions (PubMed:11352563, PubMed:11035086, PubMed:20068036). The ligand-receptor pair CCL20-CCR6 is responsible for the chemotaxis of dendritic cells (DC), effector/memory T-cells and B-cells and plays an important role at skin and mucosal surfaces under homeostatic and inflammatory conditions, as well as in pathology, including cancer and various autoimmune diseases (PubMed:21376174). CCL20 acts as a chemotactic factor that attracts lymphocytes and, slightly, neutrophils, but not monocytes (PubMed:9038201, PubMed:11352563). Involved in the recruitment of both the pro-inflammatory IL17 producing helper T-cells (Th17) and the regulatory T-cells (Treg) to sites of inflammation. Required for optimal migration of thymic natural regulatory T cells (nTregs) and DN1 early thymocyte progenitor cells (By similarity). C-terminal processed forms have been shown to be equally chemotactically active for leukocytes (PubMed:11035086). Positively regulates sperm motility and chemotaxis via its binding to CCR6 which triggers Ca2+ mobilization in the sperm which is important for its motility (PubMed:23765988, PubMed:25122636). Inhibits proliferation of myeloid progenitors in colony formation assays (PubMed:9129037). May be involved in formation and function of the mucosal lymphoid tissues by attracting lymphocytes and dendritic cells towards epithelial cells (By similarity). Possesses antibacterial activity towards E.coli ATCC 25922 and S.aureus ATCC 29213 (PubMed:12149255).
By bacterial lipopolysaccharides (LPS), TNF and IFNG/IFN-gamma. Induced by phorbol myristate acetate (PMA) in U-937 cell line and bowes melanoma. Repressed by IL10/interleukin-10.
C-terminal processed forms which lack 1, 3 or 6 amino acids are produced by proteolytic cleavage after secretion from peripheral blood monocytes.
Expressed in the seminal plasma, endometrial fluid and follicular fluid (at protein level). Expressed predominantly in the liver, lymph nodes, appendix, peripheral blood lymphocytes, and fetal lung. Low levels seen in thymus, prostate, testis, small intestine and colon.
This protein is an anticoagulant protein that acts as an indirect inhibitor of the thromboplastin-specific complex, which is involved in the blood coagulation cascade.
Belongs to the sirtuin family. Class III subfamily.
In contrast to class I sirtuins, class III sirtuins have only weak deacetylase activity. Difference in substrate specificity is probably due to a larger hydrophobic pocket with 2 residues (Tyr-102 and Arg-105) that bind to malonylated and succinylated substrates and define the specificity (PubMed:22076378).
Inhibited by suramin. NAD-dependent lysine desuccinylase activity is inhibited by physiological nicotinamide concentrations, while deacetylase activity is not. In contrast, resveratrol activates deacetylase activity, while inhibiting desuccinylase activity.
Interacts with CPS1 (By similarity). Interacts with PCCA (PubMed:23438705). Monomer (PubMed:17355872). Homodimer (PubMed:17355872). Forms homodimers upon suramin binding (PubMed:17355872).
NAD-dependent lysine demalonylase, desuccinylase and deglutarylase that specifically removes malonyl, succinyl and glutaryl groups on target proteins (PubMed:21908771, PubMed:22076378, PubMed:24703693, PubMed:29180469). Activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting: acts by mediating desuccinylation and deglutarylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting (PubMed:22076378, PubMed:24703693). Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species (PubMed:24140062). Activates SHMT2 by mediating its desuccinylation (PubMed:29180469). Modulates ketogenesis through the desuccinylation and activation of HMGCS2 (By similarity). Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo. Can deacetylate cytochrome c (CYCS) and a number of other proteins in vitro such as UOX.
The mechanism of demalonylation and desuccinylation involves the presence of a 1',2'-cyclic intermediate, suggesting that sirtuins use the ADP-ribose-peptidylamidate mechanism to remove acyl groups from substrate lysine residues.
E3 ubiquitin-protein ligase that mediates polyubiquitination of CD4. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. May play a role in ubuquitin-dependent protein sorting in developmenting spermatids.
Interacts (YXXL motif) with AP1M1. Interacts (via PDZ-binding motif) with LIN7A. Interacts with unidentified fucose glycoproteins.
Antizyme inhibitor (AZI) protein that positively regulates ornithine decarboxylase (ODC) activity and polyamine uptake. AZI is an enzymatically inactive ODC homolog that counteracts the negative effect of ODC antizymes (AZs) OAZ1, OAZ2 and OAZ3 on ODC activity by competing with ODC for antizyme-binding (PubMed:17900240, PubMed:26305948). Inhibits antizyme-dependent ODC degradation and releases ODC monomers from their inactive complex with antizymes, leading to formation of the catalytically active ODC homodimer and restoring polyamine production (PubMed:17900240).
Belongs to the Orn/Lys/Arg decarboxylase class-II family.
Monomer (PubMed:26305948). Interacts with OAZ1 and OAZ3; this interaction disrupts the interaction between the antizyme and ODC1 (Probable).
Ubiquitinated, leading to its proteasomal degradation; a process that is reduced in presence of antizyme OAZ1.
Forms part of the preprotein translocase of the outer mitochondrial membrane (TOM complex) containing TOMM22, TOMM40, TOMM40L and TOMM70. Interacts with mitochondrial targeting sequences (By similarity).
Potential channel-forming protein implicated in import of protein precursors into mitochondria.
May serve as a predictive marker for renal cell carcinoma.
Negatively regulates T-cell-mediated immune response by inhibiting T-cell activation, proliferation, cytokine production and development of cytotoxicity. When expressed on the cell surface of tumor macrophages, plays an important role, together with regulatory T-cells (Treg), in the suppression of tumor-associated antigen-specific T-cell immunity. Involved in promoting epithelial cell transformation.
Overexpressed in breast, ovarian, endometrial, renal cell (RCC) and non-small-cell lung cancers (NSCLC). Expressed on activated T- and B-cells, monocytes and dendritic cells, but not expressed in most normal tissues (at protein level). Widely expressed, including in kidney, liver, lung, ovary, placenta, spleen and testis.
The mouse ortholog has been shown to be a GPI-anchored protein but the Gly residue which is predicted to be the modified site in mouse and rat is not conserved in human.
Up-regulated by IL6/interleukin-6 and IL10/interleukin-10 and inhibited by CSF2/GM-CSF and IL4/interleukin-4 on antigen-presenting cells (APCs).
Component of the probable ECS(SPSB1) E3 ubiquitin-protein ligase complex which contains CUL5, RNF7/RBX2, Elongin BC complex and SPSB1 (PubMed:15601820). Interacts with CUL5, RNF7, ELOB and ELOC (PubMed:15601820). Directly interacts with MET tyrosine kinase domain in the presence and in the absence of HGF, however HGF treatment has a positive effect on this interaction (PubMed:15713673). When phosphorylated, interacts with RASA1 without affecting its stability (PubMed:15713673). Interacts (via B30.2/SPRY domain) with PAWR; this interaction is direct and occurs in association with the Elongin BC complex (PubMed:17189197, PubMed:20561531). Interacts with NOS2 (PubMed:21199876). Interacts with EPHB2 (PubMed:28931592).
The B30.2/SPRY domain is involved in MET and PAWR binding (PubMed:15713673, PubMed:20561531).
May be neddylated. Neddylation may be required for E3 ligase activity (By similarity).
Part of a SCF (SKP1-cullin-F-box) protein ligase complex. Interacts with SKP1, CUL1 and RBX1/ROC1 (By similarity).
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Required for muscle atrophy following denervation.
Autophosphorylated. Phosphorylation at Ser-324 by ATM following DNA damage is required for activation of the p38/MAPK14 stress-activated MAPK cascade. Phosphorylated by LRRK2.
Self-associates. Interacts with ERN1 and TRAF2. Interaction with TRAF2 is facilitated under ER stress conditions, such as treatment with tunicamycin, and may promote TRAF2 phosphorylation.
Serine/threonine-protein kinase that acts as a regulator of the p38/MAPK14 stress-activated MAPK cascade and of the MAPK8/JNK cascade. Acts as an activator of the p38/MAPK14 stress-activated MAPK cascade. In response to DNA damage, involved in the G2/M transition DNA damage checkpoint by activating the p38/MAPK14 stress-activated MAPK cascade, probably by mediating phosphorylation of upstream MAP2K3 and MAP2K6 kinases. Inhibits basal activity of MAPK8/JNK cascade and diminishes its activation in response epidermal growth factor (EGF).
Ubiquitously expressed at a low level, and highly expressed in peripheral blood leukocytes (PBLs), thymus, spleen, kidney, skeletal muscle, heart and liver.
Interacts with DYSF; the interaction is direct and Ca(2+)-independent.
May be required for neuronal cell differentiation.
Acts as a component of endosomal retrieval machinery that is involved in protein transport from early endosomes to either recycling endosomes or the trans-Golgi network (PubMed:27440922). Mediates the recruitment of Golgi-associated retrograde protein (GARP) complex to the trans-Golgi network and controls early endosome-to-Golgi transport of internalized protein(PubMed:27440922). Promotes the recycling of internalized transferrin receptor (TFRC) to the plasma membrane through interaction with endosome-associated recycling protein (EARP) complex (PubMed:27440922). Controls proper insulin distribution and secretion, and retention of cargo in mature dense core vesicles (By similarity). Required for the stability of the endosome-associated retrograde protein (EARP) complex subunits and for proper localization and association of EARP with membranes (By similarity).
Interacts with two multisubunit tethering complexes: EARP composed of VPS50, VPS51, VPS52 and VPS53 subunits and GARP complex composed of VPS51, VPS52, VPS53 and VPS54 subunits. Interacts with SNAP29.
Expressed in placenta and several fetal tissues.
Homodimer. May undergo minor heretodimerization with DIO1 and DIO2.
Responsible for the deiodination of T4 (3,5,3',5'-tetraiodothyronine) into RT3 (3,3',5'-triiodothyronine) and of T3 (3,5,3'-triiodothyronine) into T2 (3,3'-diiodothyronine). RT3 and T2 are inactive metabolites. May play a role in preventing premature exposure of developing fetal tissues to adult levels of thyroid hormones. Can regulate circulating fetal thyroid hormone concentrations throughout gestation. Essential role for regulation of thyroid hormone inactivation during embryological development.
Dimer of a heavy chain and a light chain cross-linked by a disulfide bond. Interacts with SRPX2. Directly interacts with SHKBP1 (PubMed:16733801).
Expressed in the stratum spinosum of the epidermis. Weak expression is detected in the stratum granulosum.
The gene represented in this entry is involved in disease pathogenesis. Tandem duplications in a non-coding genomic region containing an active enhancer element for CTSB result in CTSB abnormal expression with pathological consequences.
Thiol protease which is believed to participate in intracellular degradation and turnover of proteins (PubMed:12220505). Cleaves matrix extracellular phosphoglycoprotein MEPE (PubMed:12220505). Involved in the solubilization of cross-linked TG/thyroglobulin in the thyroid follicle lumen (By similarity). Has also been implicated in tumor invasion and metastasis (PubMed:3972105).
Mediates B-cell B-cell interactions. May be involved in the localization of B-cells in lymphoid tissues. Binds sialylated glycoproteins; one of which is CD45. Preferentially binds to alpha-2,6-linked sialic acid. The sialic acid recognition site can be masked by cis interactions with sialic acids on the same cell surface. Upon ligand induced tyrosine phosphorylation in the immune response seems to be involved in regulation of B-cell antigen receptor signaling. Plays a role in positive regulation through interaction with Src family tyrosine kinases and may also act as an inhibitory receptor by recruiting cytoplasmic phosphatases via their SH2 domains that block signal transduction through dephosphorylation of signaling molecules.
Phosphorylated on tyrosine residues by LYN.
Phosphorylation of Tyr-762, Tyr-807 and Tyr-822 are involved in binding to SYK, GRB2 and SYK, respectively. Phosphorylation of Tyr-842 is involved in binding to SYK, PLCG2 and PIK3R1/PIK3R2.
Predominantly monomer of isoform CD22-beta. Also found as heterodimer of isoform CD22-beta and a shorter isoform. Interacts with PTPN6/SHP-1, LYN, SYK, PIK3R1/PIK3R2 and PLCG1 upon phosphorylation. Interacts with GRB2, INPP5D and SHC1 upon phosphorylation (By similarity). May form a complex with INPP5D/SHIP, GRB2 and SHC1.
ADP-ribosylation by PARP1 increases protein half-life and may be involved in TGFB-induced SNAI1 up-regulation.
Expressed in a variety of tissues with the highest expression in kidney. Expressed in mesenchymal and epithelial cell lines.
Induced by TPA maximally by 2.5-fold at 4 hours, in HepG2 cells (at protein level).
Interacts with FBXL14 and GSK3B. Interacts with BTRC; interaction occurs when it is phosphorylated on the destruction motif. Interacts (via SNAG domain) with WTIP (via LIM domains) (By similarity). Interacts (via SNAG domain) with LIMD1 (via LIM domains), and AJUBA (via LIM domains). Interacts with LOXL2 and LOXL3. Interacts (via N-terminal region) with CSNK2A1. Interacts with EGR1 upon TPA induction. Interacts (via N-terminal region) with LATS2; the interaction is dependent on LATS2 kinase activity but independent of SNAI1 Thr-203 phosphorylation. Interacts (via zinc fingers) with KPNB1 and TNPO1; the interactions mediate nuclear import. Interacts (via zinc fingers) with KPNA1; the interaction disrupts the transport complex with KPNB1 and prevents nuclear import increasing SNAI1 degradation in the cytoplasm. Interacts (via zinc fingers) with KPNA2; the interaction, in combination with KPNB1, mediates nuclear import. Interacts with KPNA4; this interaction mediates nuclear import. May interact (via zinc fingers) with IPO7. Interacts (via zinc fingers) with PARP1; the interaction requires SNAI1 to be poly-ADP-ribosylated and non-phosphorylated (active) by GSK3B. Interacts (via SNAG domain) with KDM1A (PubMed:20389281, PubMed:20562920, PubMed:21300290, PubMed:23721412). Interaction with KDM1A is necessary for the down-regulation of dimethylated H3K4 mark and promoter activity of E-cadherin/CDH1, CDN7 and KRT8 (PubMed:20389281, PubMed:20562920). Interacts with TP53/p53 and (via zinc fingers) with NOTCH1 (via intracellular domain); the interactions induce SNAI1 degradation via MDM2-mediated ubiquitination and inhibit SNAI1-induced cell invasion. Interacts with MDM2; the interaction promotes SNAI1 ubiquitination. Interacts (via zinc fingers) with CSNK1E. Interacts with PAK1 (PubMed:15833848).
Involved in induction of the epithelial to mesenchymal transition (EMT), formation and maintenance of embryonic mesoderm, growth arrest, survival and cell migration. Binds to 3 E-boxes of the E-cadherin/CDH1 gene promoter and to the promoters of CLDN7 and KRT8 and, in association with histone demethylase KDM1A which it recruits to the promoters, causes a decrease in dimethylated H3K4 levels and represses transcription (PubMed:20389281, PubMed:20562920). The N-terminal SNAG domain competes with histone H3 for the same binding site on the histone demethylase complex formed by KDM1A and RCOR1, and thereby inhibits demethylation of histone H3 at 'Lys-4' (in vitro) (PubMed:20389281, PubMed:21300290, PubMed:23721412). During EMT, involved with LOXL2 in negatively regulating pericentromeric heterochromatin transcription (By similarity). SNAI1 recruits LOXL2 to pericentromeric regions to oxidize histone H3 and repress transcription which leads to release of heterochromatin component CBX5/HP1A, enabling chromatin reorganization and acquisition of mesenchymal traits (By similarity). Associates with EGR1 and SP1 to mediate tetradecanoyl phorbol acetate (TPA)-induced up-regulation of CDKN2B, possibly by binding to the CDKN2B promoter region 5'-TCACA-3. In addition, may also activate the CDKN2B promoter by itself.
O-GlcNAcylation at Ser-112 is enhanced in hyperglycaemic conditions, it opposes phosphorylation by GSK3B, and stabilizes the protein.
Phosphorylated by GSK3B. Once phosphorylated, it becomes a target for BTRC ubiquitination. Phosphorylation by CSNK1E, probably at Ser-104, provides the priming site for the subsequent phosphorylation by GSK3B, probably at Ser-100 and Ser-96. Phosphorylation by PAK1 may modulate its transcriptional activity by promoting increased accumulation in the nucleus. Phosphorylation at Ser-11 and Ser-92 positively regulates its functions in induction of EMT and cell survival, respectively. Phosphorylation by LATS2, upon mitotic stress, oncogenic stress or Hippo pathway activation, occurs in the nucleus and promotes nuclear retention and stabilization of total cellular protein level (PubMed:24157836).
The interaction with mouse KPNA2 may prevent SNAI1 nuclear import.
Ubiquitinated on Lys-98, Lys-137 and Lys-146 by FBXL14 and BTRC leading to degradation (PubMed:19955572). BTRC-triggered ubiquitination requires previous GSK3B-mediated SNAI1 phosphorylation. Ubiquitination induced upon interaction with NOTCH1 or TP53/p53 is mediated by MDM2 (PubMed:20385133). Ubiquitinated in a FBXL5-dependent manner; preventing interaction with DNA and promoting its degradation (PubMed:24157836). Deubiquitinated by USP37; leading to stabilization (PubMed:31911859).
(Microbial infection) Interacts with influenza A virus NS1 blocks processing of pre-mRNAs, thereby preventing nuclear export of host cell mRNAs.
Component of the cleavage and polyadenylation specificity factor (CPSF) complex that play a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. CPSF4 binds RNA polymers with a preference for poly(U).
Component of the cleavage and polyadenylation specificity factor (CPSF) complex, composed of CPSF1, CPSF2, CPSF3, CPSF4 and FIP1L1. Interacts with FIP1L1.
Component of the cleavage and polyadenylation specificity factor (CPSF) complex.
Heterophilic interaction with SREC2 via its extracellular domain. The heterophilic interaction is suppressed by the presence of ligand such as Ac-LDL. Interacts with AVIL (By similarity).
Mediates the binding and degradation of acetylated low density lipoprotein (Ac-LDL). Mediates heterophilic interactions, suggesting a function as adhesion protein. Plays a role in the regulation of neurite-like outgrowth (By similarity).
Homodimer (By similarity). Interacts with SCN10A (By similarity). Interacts with DIP2A; DIP2A may act as a cell surface receptor for FSTL1 (PubMed:20860622, PubMed:20054002). Interacts with BMP4 (PubMed:29212066). Interacts with CD14; this interaction promotes TL4-mediated signaling cascade (PubMed:22265692).
Overexpressed in synovial tissues from rheumatoid arthritis (PubMed:15638044).
Secreted glycoprotein that is involved in various physiological processes, such as angiogenesis, regulation of the immune response, cell proliferation and differentiation (PubMed:29212066, PubMed:22265692). Plays a role in the development of the central nervous system, skeletal system, lungs, and ureter (By similarity). Promotes endothelial cell survival, migration and differentiation into network structures in an AKT-dependent manner. Also promotes survival of cardiac myocytes (By similarity). Initiates various signaling cascades by activating different receptors on the cell surface such as DIP2A, TLR4 or BMP receptors (PubMed:20054002, PubMed:22265692).
Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a heterodimer with MAD1, MAD4, MNT, WBSCR14 and MLXIP. Can also bind DNA as a homodimer.
Expressed in all tissues tested, including spleen, thymus, prostate, ovary, intestine, colon, peripheral blood leukocyte, heart, liver, skeletal muscle and kidney. Lower levels of expression in testis, brain, placenta and lung.
Transcription regulator. Forms a sequence-specific DNA-binding protein complex with MAD1, MAD4, MNT, WBSCR14 and MLXIP which recognizes the core sequence 5'-CACGTG-3'. The TCFL4-MAD1, TCFL4-MAD4, TCFL4-WBSCR14 complexes are transcriptional repressors. Plays a role in transcriptional activation of glycolytic target genes. Involved in glucose-responsive gene regulation.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of catecholamines, phenolic drugs and neurotransmitters. Is also responsible for the sulfonation and activation of minoxidil. Mediates the metabolic activation of carcinogenic N-hydroxyarylamines to DNA binding products and could so participate as modulating factor of cancer risk.
Highly expressed in colorectal and lung cancer tissues.
Induced by UV irradiation. Expression starts to increase in early S phase and is steady high until late S phase in both cancer and normal cells.
May be an anti-apoptotic protein involved in DNA repair or cell survival.
Autoproteolytic processing of the proenzyme produces the active enzyme composed on the heavy and the light chain held together by a disulfide bond. Isoform 1 but not isoform 2 is activated through autoproteolytic processing.
Functions in the lectin pathway of complement, which performs a key role in innate immunity by recognizing pathogens through patterns of sugar moieties and neutralizing them. The lectin pathway is triggered upon binding of mannan-binding lectin (MBL) and ficolins to sugar moieties which leads to activation of the associated proteases MASP1 and MASP2. Functions as an endopeptidase and may activate MASP2 or C2 or directly activate C3 the key component of complement reaction. Isoform 2 may have an inhibitory effect on the activation of the lectin pathway of complement or may cleave IGFBP5. Also plays a role in development (PubMed:21258343).
Homodimer. Interacts with the oligomeric lectins MBL2, FCN2 and FCN3; triggers the lectin pathway of complement through activation of C3. Interacts with SERPING1. Interacts with COLEC11; probably triggers the lectin pathway of complement (PubMed:20956340).
N-glycosylated. Some N-linked glycan are of the complex-type (By similarity).
Protein of the plasma which is primarily expressed by liver.
(Microbial infection) In case of HIV or SIV infections, binds to the transactivation domain of the viral nuclear transcriptional activator, Tat, thereby increasing Tat's affinity for the transactivating response RNA element (TAR RNA). Serves as an essential cofactor for Tat, by promoting RNA Pol II activation, allowing transcription of viral genes.
(Microbial infection) Interacts with the transactivation region of HIV-1, HIV-2 and SIV Tat.
ADP-ribosylation on serine residues by PARP1 in response to DNA damage disrupts the phase separation activity of CCNT1, thereby preventing activation of CDK9.
Cyclin-T1 is the predominant cyclin that associates with CDK9 to form a heterodimer called P-TEFb (PubMed:9499409, PubMed:35393539, PubMed:30134174). P-TEFb forms a complex with AFF4/AF5Q31 (PubMed:12065898). Component of a complex which is at least composed of HTATSF1/Tat-SF1, P-TEFb complex, RNA pol II, SUPT5H, and NCL/nucleolin (PubMed:10393184). Component of the 7SK snRNP complex at least composed of P-TEFb (composed of CDK9 and CCNT1/cyclin-T1), HEXIM1, HEXIM2, BCDIN3, SART3 proteins and 7SK and U6 snRNAs (PubMed:17643375). Interacts (via central region) with ZMYND8 (via N-terminus); the interaction is direct and the association appears to occur between homodimeric ZMYND8 and the activated form of the P-TEFb complex (PubMed:30134174). Interacts with BRD4, targets chromatin binding (PubMed:16109376, PubMed:16109377, PubMed:24360279). Interacts with JMJD6 (PubMed:24360279). Interacts with MDFIC (PubMed:12944466). Interacts with HSF1 (PubMed:27189267). Interacts with HTATSF1 (PubMed:10913173). Interacts with TBX21 (PubMed:27292648).
Regulatory subunit of the cyclin-dependent kinase pair (CDK9/cyclin-T1) complex, also called positive transcription elongation factor B (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNA Pol II) (PubMed:16109376, PubMed:16109377, PubMed:35393539, PubMed:30134174). Required to activate the protein kinase activity of CDK9: acts by mediating formation of liquid-liquid phase separation (LLPS) that enhances binding of P-TEFb to the CTD of RNA Pol II (PubMed:29849146, PubMed:35393539).
The histidine-rich domain (HRD) region is intrinsically disordered and promotes the formation of phase-separated liquid droplets that enhance binding of the P-TEFb complex to the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNA Pol II).
(Microbial infection) Interacts with herpes virus 8/HHV-8 protein LANA1; this interaction regulates the MLL1 histone methyltransferase activity on viral DNA.
A chromosomal aberration involving KMT2A may be a cause of chronic neutrophilic leukemia. Translocation t(4;11)(q21;q23) with SEPT11.
Auto-methylated at Cys-3882: auto-methylation is inhibited by the WRAD complex and unmodified histone H3.
Chromosomal aberrations involving KMT2A are a cause of acute leukemias. Translocation t(1;11)(q21;q23) with MLLT11/AF1Q; translocation t(3;11)(p21;q23) with NCKIPSD/AF3p21; translocation t(3,11)(q25,q23) with GMPS; translocation t(4;11)(q21;q23) with AFF1/MLLT2/AF4; insertion ins(5;11)(q31;q13q23) with AFF4/AF5Q31; translocation t(5;11)(q12;q23) with AF5-alpha/CENPK; translocation t(6;11)(q27;q23) with AFDN; translocation t(9;11)(p22;q23) with MLLT3/AF9; translocation t(10;11)(p11.2;q23) with ABI1; translocation t(10;11)(p12;q23) with MLLT10/AF10; t(11;15)(q23;q14) with KNL1 and ZFYVE19; translocation t(11;17)(q23;q21) with MLLT6/AF17; translocation t(11;19)(q23;p13.3) with ELL; translocation t(11;19)(q23;p13.3) with MLLT1/ENL; translocation t(11;19)(q23;p23) with GAS7; translocation t(X;11)(q13;q23) with FOXO4/AFX1. Translocation t(3;11)(q28;q23) with LPP. Translocation t(10;11)(q22;q23) with TET1. Translocation t(9;11)(q34;q23) with DAB2IP. Translocation t(4;11)(p12;q23) with FRYL. Fusion proteins KMT2A-MLLT1, KMT2A-MLLT3 and KMT2A-ELL interact with PPP1R15A and, on the contrary to unfused KMT2A, inhibit PPP1R15A-induced apoptosis. Fusion protein KMT2A-MLLT3 interacts with MEN1 and PSIP1 (PubMed:22936661, PubMed:25305204).
Heart, lung, brain and T- and B-lymphocytes.
Histone methyltransferase that plays an essential role in early development and hematopoiesis (PubMed:15960975, PubMed:12453419, PubMed:15960975, PubMed:19556245, PubMed:19187761, PubMed:20677832, PubMed:21220120, PubMed:26886794). Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac) (PubMed:15960975, PubMed:12453419, PubMed:15960975, PubMed:19556245, PubMed:24235145, PubMed:19187761, PubMed:20677832, PubMed:21220120, PubMed:26886794). Catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4) via a non-processive mechanism. Part of chromatin remodeling machinery predominantly forms H3K4me1 and H3K4me2 methylation marks at active chromatin sites where transcription and DNA repair take place (PubMed:25561738, PubMed:15960975, PubMed:12453419, PubMed:15960975, PubMed:19556245, PubMed:19187761, PubMed:20677832, PubMed:21220120, PubMed:26886794). Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity (PubMed:19187761, PubMed:26886794). Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9' (PubMed:19187761). Binds to unmethylated CpG elements in the promoter of target genes and helps maintain them in the nonmethylated state (PubMed:20010842). Required for transcriptional activation of HOXA9 (PubMed:12453419, PubMed:20677832, PubMed:20010842). Promotes PPP1R15A-induced apoptosis (PubMed:10490642). Plays a critical role in the control of circadian gene expression and is essential for the transcriptional activation mediated by the CLOCK-BMAL1 heterodimer (By similarity). Establishes a permissive chromatin state for circadian transcription by mediating a rhythmic methylation of 'Lys-4' of histone H3 (H3K4me) and this histone modification directs the circadian acetylation at H3K9 and H3K14 allowing the recruitment of CLOCK-BMAL1 to chromatin (By similarity). Also has auto-methylation activity on Cys-3882 in absence of histone H3 substrate (PubMed:24235145).
MLL cleavage product N320 heterodimerizes with MLL cleavage product C180 (via SET and FYRC domains). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, HCFC2, WDR5, DPY30 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MEN1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15199122, PubMed:15960975, PubMed:17500065, PubMed:19556245, PubMed:23508102, PubMed:19187761, PubMed:26886794). Forms a core complex with the evolutionary conserved subcomplex WRAD composed of WDR5, RBBP5, ASH2L/ASH2 and DPY30 subunits; WRAD differentially stimulates the methyltransferase activity (PubMed:25561738). Interacts (via WIN motif) with WDR5; the interaction is direct (PubMed:19556245, PubMed:18829459, PubMed:22665483, PubMed:18840606). Interaction with WDR5 is required for stable interaction with ASH2L and RBBP5, and thereby also for optimal histone methyltransferase activity (PubMed:26886794). Interacts with KAT8/MOF; the interaction is direct (PubMed:15960975). Interacts with SBF1 and PPP1R15A (PubMed:9537414, PubMed:10490642). Interacts with ZNF335 (PubMed:23178126). Interacts with CLOCK and BMAL1 in a circadian manner (By similarity). Interacts with PPIE; this results in decreased histone H3 methyltransferase activity (PubMed:20677832, PubMed:20541251). Interacts with CREBBP (PubMed:16253272). Interacts with the WRAD complex composed of WDR5, RBBP5, ASH2L and DPY30 (PubMed:22665483). Interacts (via MBM motif) with MEN1 (PubMed:22936661, PubMed:22327296, PubMed:25305204). Interacts (via IBM motifs) with PSIP1 (via IBD domain) with moderate affinity whereas the KMT2A-MEN1 complex interacts with a greater affinity; MEN1 enhances interaction of KMT2A with PSIP1 (PubMed:22327296, PubMed:25305204, PubMed:25082813, PubMed:29997176). Phosphorylation increases its affinity for PSIP1 (PubMed:29997176). Forms a complex with CREBBP and CREB1 (PubMed:23651431).
Proteolytic cleavage by TASP1 generates MLL cleavage product N320 and MLL cleavage product C180, which reassemble through a non-covalent association. 2 cleavage sites exist, cleavage site 1 (CS1) and cleavage site 2 (CS2), to generate MLL cleavage products N320 and C180. CS2 is the major site.
The CXXC-type zinc finger binds to DNA sequence elements containing unnmethylated CpG dinucleotides.
The SET domain structure is atypical and is not in an optimal position to have methyltransferase activity. It requires other components of the MLL1/MLL complex, such as ASH2L or RBBP5, to order the active site and obtain optimal histone methyltransferase activity.
The third PHD-type zinc-finger binds both trimethylated histone H3K4me3 and PPIE; histone and PPIE bind to distinct surfaces (PubMed:20677832, PubMed:20541251). Nevertheless, PPIE binding and histone binding are mutually inhibitory (PubMed:20677832). Isomerization of a peptidylproline bond in the linker between the third PHD-type zinc-finger and the bromo domain disrupts the interaction between the bromo domain and the third PHD-type zinc-finger, and thereby facilitates interaction with PPIE (PubMed:20541251).
Expressed in testis and placenta, and in a significant fraction of tumors of various histologic types.
Part of a specialized transcription system that mediates the transcription of most ribosomal proteins through the 5'-TCT-3' motif which is a core promoter element at these genes. Seems to also mediate the transcription of NF1. Does not bind the TATA box.
Ubiquitously expressed, with highest levels in the testis and ovary.
Receptor for prostaglandin D2 (PGD2). Coupled to the G(i)-protein. Receptor activation may result in pertussis toxin-sensitive decreases in cAMP levels and Ca(2+) mobilization. PI3K signaling is also implicated in mediating PTGDR2 effects. PGD2 induced receptor internalization. CRTH2 internalization can be regulated by diverse kinases such as, PKC, PKA, GRK2, GPRK5/GRK5 and GRK6. Receptor activation is responsible, at least in part, in immune regulation and allergic/inflammation responses.
The 330-DSEL-333 motif is involved in the recycling of PTGDR2 to the cell surface after agonist-induced internalization. This motif seems to be required for GRK2 and GPRK5/GRK5 to promote agonist-induced internalization. Thr-347 is a major site for PKC-induced internalization of the receptor.
Widespread expression. High expression in stomach, small intestine, heart and thymus. Intermediate expression in colon, spinal cord and peripheral blood and low expression in brain, skeletal muscle and spleen. Expressed also on Th2- and Tc2- type cells, eosinophils and basophils.
Monomer; active form. Homodimer; inactive form (Probable). Interacts with CNTN3, CNTN4, CNTN5 and CNTN6.
Possesses tyrosine phosphatase activity.
Activated by magnesium and inorganic phosphate. Competitively or non-competitively inhibited by ADP, 2,3-bisphosphoglyceride or GDP.
Homodimer. The active form is probably a hexamer composed of 3 homodimers.
ATPase that regulates mitochondrial ABC transporters ABCB7, ABCB8/MITOSUR and ABCB10 (PubMed:25063848). Regulates mitochondrial ferric concentration and heme biosynthesis and plays a role in the maintenance of mitochondrial homeostasis and cell survival (PubMed:25063848).
Homodimer (PubMed:25063848). Interacts with ABCB7, ABCB8/MITOSUR and ABCB10 (PubMed:25063848).
Expressed in the central nervous system, muscle cells (heart and skeletal muscle), pancreas, prostate and lung.
Microtubule-dependent motor protein required for spindle pole assembly during mitosis. Required to stabilize the pericentriolar material (PCM).
Belongs to the PPP phosphatase family. PP-6 (PP-V) subfamily.
Catalytic subunit of protein phosphatase 6 (PP6) (PubMed:17079228, PubMed:29053956, PubMed:32474700). PP6 is a component of a signaling pathway regulating cell cycle progression in response to IL2 receptor stimulation (PubMed:10227379). N-terminal domain restricts G1 to S phase progression in cancer cells, in part through control of cyclin D1 (PubMed:17568194). During mitosis, regulates spindle positioning (PubMed:27335426). Down-regulates MAP3K7 kinase activation of the IL1 signaling pathway by dephosphorylation of MAP3K7 (PubMed:17079228). Participates also in the innate immune defense against viruses by desphosphorylating RIGI, an essential step that triggers RIGI-mediated signaling activation (PubMed:29053956). Also regulates innate immunity by acting as a negative regulator of the cGAS-STING pathway: mediates dephosphorylation and inactivation of CGAS and STING1 (PubMed:32753499, PubMed:32474700). CGAS dephosphorylation at 'Ser-435' impairs its ability to bind GTP, thereby inactivating it (PubMed:32474700).
Protein phosphatase 6 (PP6) holoenzyme is proposed to be a heterotrimeric complex formed by the catalytic subunit, a SAPS domain-containing subunit (PP6R) and an ankyrin repeat-domain containing regulatory subunit (ARS) (PubMed:18186651). Interacts with subunits PPP6R1, PPP6R2 and PPP6R3 (PubMed:16769727, PubMed:18186651). Interacts with subunit ANKRD28 (PubMed:18186651). Interacts with IGBP1 (PubMed:9647778). Interacts with MAP3K7 (PubMed:17079228). Interacts with NFKBIE (PubMed:16769727). Interacts with TRIM14 and WRNIP1; these interactions positively regulate the RIG-I signaling pathway (PubMed:29053956).
Regulated by IL2/interleukin-2 in peripheral blood T cells.
Ubiquitously expressed in all tissues tested with highest expression levels in testis, heart, kidney, brain, stomach, liver and skeletal muscle and lowest in placenta, lung colon and spleen.
Dubious isoform. The N-terminus appears to be derived from exons of the CEP43 locus which is located on the opposing strand of chromosome 6 at a distance of several Mb.
May function as a GTPase-activating protein and may play important roles during T-cell activation.
Binds hydroxyproline-rich sequence motifs in fibrillar, glycosylated collagen, such as the GQOGVMGFO motif, where O stands for hydroxyproline. Interacts with SRC. Interacts (tyrosine phosphorylated) with SHC1.
Detected in osteocytes, osteoblastic cells in subchondral bone, bone lining cells, tibia and cartilage (at protein level). Detected at high levels in heart and lung, and at low levels in brain, placenta, liver, skeletal muscle, pancreas, and kidney.
Present in an inactive state in the absence of collagen binding and phosphorylation by SRC. Tyrosine phosphorylation enhances the affinity for ATP and the catalytic activity.
Tyrosine kinase involved in the regulation of tissues remodeling (PubMed:30449416). It functions as cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing.
Tyrosine phosphorylated in response to collagen binding. Phosphorylated by SRC; this is required for activation and subsequent autophosphorylation on additional tyrosine residues.
Up-regulated during osteoblast differentiation (in vitro). Up-regulated in cartilage from osteoarthritis patients.
Interacts with SPAG5 (PubMed:24424245). Interacts with NUP62 (PubMed:21698267).
Lipid transporter involved in lipid countertransport between the endoplasmic reticulum and the plasma membrane: specifically exchanges phosphatidylserine with phosphatidylinositol 4-phosphate (PI4P), delivering phosphatidylserine to the plasma membrane in exchange for PI4P, which is degraded by the SAC1/SACM1L phosphatase in the endoplasmic reticulum. Binds phosphatidylserine and PI4P in a mutually exclusive manner (PubMed:26206935). Binds oxysterol, 25-hydroxycholesterol and cholesterol (PubMed:17428193, PubMed:17991739, PubMed:21698267).
Widely expressed (PubMed:11735225). Expressed at higher level in macrophages (PubMed:17991739).
Autophosphorylation at Ser-1070 negatively regulates the phosphatidylinositol-4,5-bisphosphate 3-kinase activity.
Heterodimer of a catalytic subunit PIK3CB and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interaction with PIK3R2 is required for nuclear localization and nuclear export. Part of a complex with PIK3R1 and PTEN. Binding to PTEN may antagonize the lipid kinase activity under normal growth conditions. Part of a complex involved in autophagosome formation composed of PIK3C3 and PIK3R4 (By similarity). Interacts with BECN1, ATG14 and RAB5A (By similarity).
Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors. Has also a protein kinase activity showing autophosphorylation (PubMed:12502714).
The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1; the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1; and the PI3K/PI4K kinase domain with the cSH2 (C-terminal SH2) region of PIK3R1. The inhibitory interaction between the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1 is weak. The nuclear localization signal (NLS) is required for its function in cell survival.
The B chain of factor XIII is not catalytically active, but is thought to stabilize the A subunits and regulate the rate of transglutaminase formation by thrombin.
Belongs to the flagellar radial spoke RSP4/6 family.
Component of the axonemal radial spoke 1 (RS1) and 2 (RS2) complexes, at least composed of spoke head proteins RSPH1, RSPH3, RSPH9 and the cilia-specific component RSPH4A or sperm-specific component RSPH6A, spoke stalk proteins RSPH14, DNAJB13, DYDC1, ROPN1L and NME5, and the RS1 complex-specific anchor protein IQUB. Interacts with RSPH1. Interacts with RSPH3B. Interacts with RSPH4A. Interacts with RSPH9. Interacts with RSPH10B.
Functions as part of radial spoke complexes in the axoneme of sperm flagella that play an important part in motility. The triple radial spokes (RS1, RS2 and RS3) are required to modulate beating of the sperm flagellum.
Phosphorylated by PKA. Phosphorylation increases in capacitated sperm.
Belongs to the chloride channel (TC 2.A.49) family.
Belongs to the chloride channel (TC 2.A.49) family. CLCNKB subfamily.
Compared with CLCNKA/BSND, CLCNKB/BSND is more sensitive to pH and less responsive to Ca(2+).
Interacts with BSND. Forms heteromers with BSND in the thick ascending limb of Henle and more distal segments (By similarity).
Component of the menin-associated histone methyltransferase complex, at least composed of KMT2B/MLL4, ASH2L, RBBP5, WDR5, DPY30, MEN1; the complex interacts with POLR2A and POLR2B via MEN1 (PubMed:14992727, PubMed:23508102). Interacts with NFE2 (PubMed:17707229). Interacts with KDM6B (PubMed:17825402). Interacts (via WIN motif) with WDR5 (PubMed:22665483, PubMed:22266653, PubMed:18840606). Interacts (via MBM motif) with MEN1 (PubMed:22327296). Forms a core complex with the evolutionary conserved subcomplex WRAD composed of WDR5, RBBP5, ASH2L/ASH2 and DPY30 subunits; WRAD differentially stimulates the methyltransferase activity (PubMed:25561738).
Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4) via a non-processive mechanism. Part of chromatin remodeling machinery predominantly forms H3K4me1 and H3K4me2 methylation marks at active chromatin sites where transcription and DNA repair take place (PubMed:25561738, PubMed:17707229). Likely plays a redundant role with KMT2C in enriching H3K4me1 marks on primed and active enhancer elements (PubMed:24081332). Plays a central role in beta-globin locus transcription regulation by being recruited by NFE2 (PubMed:17707229). Plays an important role in controlling bulk H3K4me during oocyte growth and preimplantation development (By similarity). Required during the transcriptionally active period of oocyte growth for the establishment and/or maintenance of bulk H3K4 trimethylation (H3K4me3), global transcriptional silencing that preceeds resumption of meiosis, oocyte survival and normal zygotic genome activation (By similarity).
This protein was first named MLL2 by PubMed:10637508 and PubMed:10409430. MLL2 corresponds to another protein located on chromosome 12 (see AC O14686). Thus, KMT2B/MLL4 is often referred to as MLL2 and vice versa in the literature.
Widely expressed. Highest levels in testis. Also found in brain with higher expression in the cerebellum than in any other region, bone marrow, heart, muscle, kidney, placenta, spleen, thymus, prostate, ovary, intestine, colon, peripheral blood lymphocytes and pancreas. Often amplified in pancreatic carcinomas.
Dehydrogenase that converts trans-4-L-hydroxyproline to delta-1-pyrroline-3-hydroxy-5-carboxylate (Hyp) using ubiquinone-10 as the terminal electron acceptor. Can also use proline as a substrate but with a very much lower efficiency. Does not react with other diastereomers of Hyp: trans-4-D-hydroxyproline and cis-4-L-hydroxyproline. Ubiquininone analogs such as menadione, duroquinone and ubiquinone-1 react more efficiently than oxygen as the terminal electron acceptor during catalysis.
Hydroproxyproline dehydrogenase activity is inhibited by THFA,(1R,3R)3-OH-cyclopentane-COOH and 5-OH-1H-pyrazole-3-COOH.
By TNF, IL1A/interleukin-1 alpha and parthenolide.
Interacts with YBX1 (By similarity). Interacts with TTN/titin.
Mainly expressed in activated vascular endothelial cells. To a lower extent, also expressed in hepatoma cells.
May play an important role in endothelial cell activation. May act as a nuclear transcription factor that negatively regulates the expression of cardiac genes. Induction seems to be correlated with apoptotic cell death in hepatoma cells.
Expressed in melanocytes (PubMed:23999003). Expressed in brain. Within brain, expression is highest in hippocampus, with substantial levels also detected in amygdala and thalamus (PubMed:23999003).
Interacts with KIF1A; the interaction increases in presence of calcium and decreases when SYT4 is phosphorylated at Ser-135.
Phosphorylation at Ser-135 by MAPK8/JNK1 reduces interaction with KIF1A and neuronal dense core vesicles mobility.
Synaptotagmin family member which does not bind Ca(2+) (PubMed:23999003) (By similarity). Involved in neuronal dense core vesicles (DCVs) mobility through its interaction with KIF1A. Upon increased neuronal activity, phosphorylation by MAPK8/JNK1 destabilizes the interaction with KIF1A and captures DCVs to synapses (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003).
Unlike in other synaptotagmin family members, the first C2 domain/C2A does not bind Ca(2+) neither mediates Ca(2+)-dependent phospholipid binding. An aspartate-to-serine substitution in this domain inactivates Ca(2+)/phospho-lipid binding.
May play a role as an activator of transcription of OPRM1. Overexpression of SOX21 can up-regulate the OPRM1 distal promoter activity in mor-expressing neuronal cells. May play a role in ameloblast differentiation.
Interacts with KATNA1 and KATNAL1; these interactions are competed by KATNB1 which has a higher affinity for them.
Regulates microtubule-severing activity of KATNAL1 in a concentration-dependent manner in vitro.
Component of the spliceosome B complex (PubMed:9724750, PubMed:28781166). Associated with U2 snRNPs (PubMed:9724750, PubMed:28781166). Binds splicing factors SNRPB, SNRPC and SF1 (PubMed:9724750). Interacts via the WW domains with the Pro-rich domains of KHDRBS1/SAM68 (By similarity). Interacts via the WW domains with the Pro-rich domains of WBP11 (PubMed:19592703). Interacts with SNRNP200 (PubMed:35241646).
Involved in pre-mRNA splicing as a component of the spliceosome (PubMed:9724750, PubMed:19592703, PubMed:28781166). May play a role in cross-intron bridging of U1 and U2 snRNPs in the mammalian A complex (PubMed:9724750).
The WW domain recognizes the proline, glycine and methionine-rich (PGM) motif present in the splicing factors, as well as the Arg/Gly-rich-flanked Pro-rich domains found in several WW domain-binding proteins.
Found in a complex with KDM8 (PubMed:24981860). Interacts (via N-terminus) with KDM8 (via N-terminus)(PubMed:24981860, PubMed:28455245).
Plays a role in transcriptional repression of satellite repeats, possibly by regulating H3K36 methylation levels in centromeric regions together with KDM8 (PubMed:24981860). Possibly together with KDM8, is involved in proper mitotic spindle organization and chromosome segregation (PubMed:24981860). Plays a role in regulating alpha-tubulin deacetylation and cytoskeletal microtubule stability, thereby promoting cell migration and TGF-beta-induced epithelial to mesenchymal transition (EMT), potentially through the inhibition of KDM8 (PubMed:28455245).
Postulated to regulate KDM8 histone demethylase activity on di- and trimethylated 'Lys-36' (H3K36me2/me3) of histone H3 (PubMed:24981860). However the demethylase activity of JMJD5 is controversial, as it was later shown to rather act as an endopeptidase that cleaves monomethylated and dimethylated arginine residues of histones H2, H3 and H4. In several studies, JMJD5 was shown not to display any demethylase activity toward methylated H3K36 nor toward other methyllysines in the N-terminal tails of H3 and H4 in vitro (PubMed:28982940).
Specifically hydroxylated (with R stereochemistry) at C-3 of ARG-141 by KDM8.
Down-regulated in gastric cancer tissues.
It is uncertain whether Met-1 or Met-49 is the initiator.
May regulate certain MYC target genes, MYC seems to be a direct upstream transcriptional activator. Does not seem to significantly affect growth cell capacity. Overexpression seems to mediate many of the known phenotypic features associated with MYC, including promotion of apoptosis, alteration of morphology, enhancement of anchorage-independent growth, tumorigenic conversion, promotion of genomic instability, and inhibition of hematopoietic differentiation (By similarity).
Interacts with PI4KB (PubMed:23572552). Interacts with GBF1 (PubMed:31519766).
Involved in GBF1 recruitment, Golgi maintenance and protein secretion.
May be involved in transcriptional regulation. Essential for Golgi structural integrity (PubMed:29851555).
Receptor for TNFRSF25 and TNFRSF6B. Mediates activation of NF-kappa-B. Inhibits vascular endothelial growth and angiogenesis (in vitro). Promotes activation of caspases and apoptosis.
Specifically expressed in endothelial cells. Detected in monocytes, placenta, lung, liver, kidney, skeletal muscle, pancreas, spleen, prostate, small intestine and colon.
Up-regulated by IL1A/interleukin-1 alpha and TNF.
Belongs to the cyclophilin-type PPIase family. PPIase E subfamily.
Enzyme activity is inhibited by cyclosporin A.
Found in all the examined tissues including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Identified in the spliceosome C complex (PubMed:11991638, PubMed:28076346). Component of the XAB2 complex, a multimeric protein complex composed of XAB2, PRPF19, AQR, ZNF830, ISY1, and PPIE (PubMed:17981804). Identified in a pentameric intron-binding (IB) complex composed of AQR, XAB2, ISY1, ZNF830 and PPIE that is incorporated into the spliceosome as a preassembled complex (PubMed:25599396). The IB complex does not contain PRPF19 (PubMed:25599396). Interacts (via RNA-binding domain) with KMT2A (via the third PHD-type zinc-finger) (PubMed:20677832, PubMed:20541251, PubMed:20460131).
Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28076346). Combines RNA-binding and PPIase activities (PubMed:8977107, PubMed:18258190, PubMed:20677832, PubMed:20460131). Binds mRNA and has a preference for single-stranded RNA molecules with poly-A and poly-U stretches, suggesting it binds to the poly(A)-region in the 3'-UTR of mRNA molecules (PubMed:8977107, PubMed:18258190, PubMed:20460131). Catalyzes the cis-trans isomerization of proline imidic peptide bonds in proteins (PubMed:8977107, PubMed:18258190, PubMed:20677832, PubMed:20541251). Inhibits KMT2A activity; this requires proline isomerase activity (PubMed:20677832, PubMed:20541251, PubMed:20460131).
The RRM domain mediates both interaction with RNA and with KMT2A (via the third PHD-type zinc-finger), but has much higher affinity for the KMT2A PHD-type zinc-finger.
A stop codon at position Arg-172 in the gene coding for this protein is responsible for functional diversity thus producing a pseudogene. The stop codon is more frequent in non-Africans than in African-Americans.
Belongs to the complex I 51 kDa subunit family.
Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits (PubMed:12611891). This is a component of the flavoprotein-sulfur (FP) fragment of the enzyme (PubMed:12611891). Interacts with RAB5IF (PubMed:31536960).
Plays a role as a mediator in the endoplasmic reticulum (ER) cholesterol and bile acid homeostasis (PubMed:11063737, PubMed:12145310, PubMed:20663892). Participates in sterol transport out of the ER and distribution into plasma membranes (PubMed:20663892).
Ubiquitous. Highly expressed in liver and adipose.
When transfected in S.cerevisiae, it can complement the absence of yeast of ARV1 protein, suggesting a conserved role in sphingolipid metabolism.
Constituent of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells. C8A inserts into the target membrane, but does not form pores by itself.
Heterotrimer of 3 chains: alpha, beta and gamma. The alpha and gamma chains are disulfide bonded. Component of the membrane attack complex (MAC). MAC assembly is initiated by proteolytic cleavage of C5 into C5a and C5b. C5b sequentially binds C6, C7, C8 and multiple copies of the pore-forming subunit C9.
Actin cross-linking/gelling protein (By similarity). Involved in calcium interactions and contractile properties of the cell that may contribute to replicative senescence.
Overexpressed in senescent human fibroblasts.
By GATA1 which binds to GFI1B promoter in cooperation with the transcription factor NFYA. Target gene of transcription factor E2-alpha/TCF3 that promotes growth arrest and apoptosis in lymphomas.
Component of a RCOR-GFI-KDM1A-HDAC complex. Interacts directly with RCOR1, KDM1A and HDAC2 (By similarity). Forms a complex with GATA1. Interacts with histone methyltransferases EHMT2 and SUV39H1. Interacts with ARIH2 (via RING-type 2). Interacts with RUNX1T1.
Essential for erythroid differentiation. Binds to target gene promoters and associates with the LSD1-CoREST repressor complex more efficiently than the major isoform 1.
Essential proto-oncogenic transcriptional regulator necessary for development and differentiation of erythroid and megakaryocytic lineages. Component of a RCOR-GFI-KDM1A-HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development and controls hematopoietic differentiation. Transcriptional repressor or activator depending on both promoter and cell type context; represses promoter activity of SOCS1 and SOCS3 and thus, may regulate cytokine signaling pathways. Cooperates with GATA1 to repress target gene transcription, such as the apoptosis regulator BCL2L1; GFI1B silencing in leukemic cell lines markedly increase apoptosis rate. Inhibits down-regulation of MYC and MYB as well as the cyclin-dependent kinase inhibitor CDKN1A/P21WAF1 in IL6-treated myelomonocytic cells. Represses expression of GATA3 in T-cell lymphomas and inhibits GATA1-mediated transcription; as GATA1 also mediates erythroid GFI1B transcription, both GATA1 and GFI1B participate in a feedback regulatory pathway controlling the expression of GFI1B gene in erythroid cells. Suppresses GATA1-mediated stimulation of GFI1B promoter through protein interaction. Binds to gamma-satellite DNA and to its own promoter, auto-repressing its own expression. Alters histone methylation by recruiting histone methyltransferase to target genes promoters. Plays a role in heterochromatin formation.
Expressed in bone marrow and fetal liver, but also detectable in fetal spleen, fetal thymus, and testes. Detected in hematopoietic stem cells, erythroblasts, and megakaryocytes. Overexpressed in bone marrow of patients with erythroleukemia and megakaryocytic leukemia as well as in their corresponding leukemic cell lines, and markedly repressed in severe aplastic anemia (SAA).
Methylation at Lys-8 in the SNAG domain seems required for the recruitment of the corepressor complex.
The SNAG domain of GFIs is required for nuclear location and for interaction with some corepressors.
The zinc finger domains are essential for erythroid expansion and acts as an activation domain whereas non finger domain serves as repression domain.
In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling (PubMed:25514493). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.
Monomer; in the absence of TGF-beta activation (PubMed:9670020). Heterotrimer; on TGF-beta activation (PubMed:15799969). Heterotrimer composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex (PubMed:15799969, PubMed:15350224). Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Found in a complex with SMAD1 and YY1 (By similarity). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Interacts with CITED1 and CITED2. Interacts with PDPK1 (via PH domain) (By similarity). Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. Interacts (via MH2 domain) with ZNF451 (via N-terminal zinc-finger domains) (PubMed:24324267). Interacts with ZC3H3 (By similarity). Interacts weakly with ZNF8 (PubMed:12370310). Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (PubMed:26878725). Interacts with CREB3L1, the interaction takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator to induce the expression of genes involved in the assembly of collagen extracellular matrix (PubMed:25310401). Interacts with DLX1 (PubMed:14671321). Interacts with ZBTB7A; the interaction is direct and stimulated by TGFB1 (PubMed:25514493). Interacts with CREBBP; the recruitment of this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with EP300; the interaction with this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with HDAC1 (PubMed:25514493). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850). Interacts (via N-terminus) with TSC22D1 (PubMed:15881652).
Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination by USP9X restores its competence to mediate TGF-beta signaling.
SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.
The MH1 domain is required for DNA binding.
Monoubiquitination at Lys-87 prevents binding to phosphatidylinositol 3-phosphate (PI3P) and localization to early endosome membranes.
Negative regulator of epidermal growth factor receptor (EGFR) signaling. Acts by promoting EGFR degradation in endosomes when not monoubiquitinated.
The FYVE-type zinc finger mediates the interaction with phosphatidylinositol 3-phosphate (PI3P) and localization to early endosome membranes when not monoubiquitinated at Lys-87.
Activated by monovalent cations, such as potassium, rubidium or ammonium.
Catalyzes the activation of fatty acids by CoA to produce an acyl-CoA, the first step in fatty acid metabolism (PubMed:10434065, PubMed:12616642). Capable of activating medium-chain fatty acids (e.g. butyric (C4) to decanoic (C10) acids), and certain carboxylate-containing xenobiotics, e.g. benzoate (PubMed:10434065, PubMed:12616642).
Expressed in kidney, prostate, lung, liver, thymus, colon, pancreas, and skeletal muscle, and low levels in placenta. Not detected in heart, brain, spleen, testis, ovary, small intestine and leukocyte.
Interacts (in GTP-bound form) with GARIN4 (via N-terminus) (PubMed:26209634). Interacts (in GTP-bound form) with GARIN5A. Interacts (in GTP-bound form) with GARIN1B (By similarity).
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between active GTP-bound and inactive GDP-bound states. In their active state, drive transport of vesicular carriers from donor organelles to acceptor organelles to regulate the membrane traffic that maintains organelle identity and morphology. Regulates the compacted morphology of the Golgi (Probable). Promotes cytosolic DNA-induced innate immune responses. Regulates IFN responses against DNA viruses by regulating the CGAS-STING signaling axis (By similarity).
Homodimer; disulfide-linked. Interacts with PDGFB and IGFBP3. Forms a transient ternary complex with PDGFB and PDGFRB in TGN (By similarity).
Ligand-specific transporter trafficking between intracellular organelles (TGN) and the plasma membrane. Plays a role in autocrine regulation of cell growth mediated by growth regulators containing cell surface retention sequence binding (CRS). May act as a hyaluronan (HA) transporter, either mediating its uptake for catabolism within lymphatic endothelial cells themselves, or its transport into the lumen of afferent lymphatic vessels for subsequent re-uptake and degradation in lymph nodes (PubMed:10037799). Binds to pericelluar hyaluronan matrices deposited on the surface of leukocytes and facilitates cell adhesion and migration through lymphatic endothelium (PubMed:26823460).
Mainly expressed in endothelial cells lining lymphatic vessels.
Acyl-CoA dehydrogenase, that exhibits maximal activity towards saturated C22-CoA (PubMed:21237683). Probably participates in beta-oxydation and energy production but could also play a role in the metabolism of specific fatty acids to control fatty acids composition of cellular lipids in brain (Probable).
Widely expressed with highest levels in brain followed by liver, heart and kidney.
Interacts with HOMER1. Interacts with AMPA receptor complexes. Interacts with SH3GL2 (endophilin-A1) (By similarity). Interacts (via C-terminus) with NR1D1 (By similarity).
Stimulates GTP hydrolysis of members of the Rho family. Its action on RHOA activity and signaling is implicated in growth and stabilization of dendritic spines, and therefore in synaptic function. Critical for the stabilization of AMPA receptors at postsynaptic sites. Critical for the regulation of synaptic vesicle endocytosis at presynaptic terminals. Required for the localization of NR1D1 to dendrites, can suppress its repressor activity and protect it from proteasomal degradation (By similarity).
Detected in kidney, hippocampus and lung carcinoma.
Phosphorylated, leading to STXBP5L increased turnover and subsequent de-repression of insulin secretion (By similarity). Phosphorylated on serine residues in response to glucose or phorbol esters (By similarity).
Plays a role in vesicle trafficking and exocytosis inhibition. In pancreatic beta-cells, inhibits insulin secretion probably by interacting with and regulating STX1A and STX4, key t-SNARE proteins involved in the fusion of insulin granules to the plasma membrane. Also plays a role in neurotransmitter release by inhibiting basal acetylcholine release from axon terminals and by preventing synaptic fatigue upon repetitive stimulation (By similarity). Promotes as well axonal outgrowth (PubMed:25504045).
Ubiquitinated by the E3 ligase SYVN1, leading to STXBP5L proteasomal degradation.
Highly expressed in hair follicles from scalp. In hair, it is specifically present in the inner root sheath (IRS) of the hair follicle. Present in the IRS cuticle, but not in Henle or Huxley layers of the IRS. In the IRS cuticle, it is expressed between the lowermost bulb region of the cuticle and the region where Henle cells undergo abrupt terminal differentiation. Detected up to the uppermost cortex region where cuticle cells terminally differentiate (at protein level).
Component of clathrin-coated vesicles (PubMed:15758025). Component of the aftiphilin/p200/gamma-synergin complex, which plays roles in AP1G1/AP-1-mediated protein trafficking including the trafficking of transferrin from early to recycling endosomes, and the membrane trafficking of furin and the lysosomal enzyme cathepsin D between the trans-Golgi network (TGN) and endosomes (PubMed:15758025).
Self-associates (PubMed:15758025). Interacts with GGA1 (via GAE domain) (PubMed:14665628, PubMed:15758025). Interacts with GGA3 (via GAE domain), AP1G1 (via GAE domain) and AP1G2 (via GAE domain) (PubMed:14665628). Component of the aftiphilin/p200/gamma-synergin complex, at least composed of AFTPH/aftiphilin, HEATR5B/p200a and SYNRG/gamma-synergin, which plays a role in the AP1G1/AP-1-mediated protein trafficking from early to recycling endosomes (PubMed:15758025). Within the complex interacts with HEATR5B/p200a and SYNRG/gamma-synergin; the interactions are direct (PubMed:15758025). Interacts with AP1G1/AP-1; the interaction is required to recruit AFTPH/aftiphilin to the perinuclear region of the cell (PubMed:15758025). Interacts with CLTCL1/Clathrin (PubMed:15758025).
The WXXF motifs mediate binding of accessory proteins to the ear-domain of AP-1, GGAs and AP-2 through hydrophobic interactions. Selective binding to the GAE domains of AP-1 or to the alpha-ear domain of AP-2 is tuned by the acidic context surrounding the motif and the properties of the second residue of the motif itself (By similarity).
Hydrolyzes lysoglycerophospholipids to produce lysophosphatidic acid (LPA) and the corresponding amines (PubMed:27637550). Shows a preference for 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF), lysophosphatidylcholine (lyso-PC) and N-acylethanolamine lysophospholipids (PubMed:27637550). Does not display glycerophosphodiester phosphodiesterase activity, since it cannot hydrolyze either glycerophosphoinositol or glycerophosphocholine.
Lysophospholipase D activity is stimulated by calcium. Loss of lysophospholipase D activity in presence of EDTA.
Widely expressed, with high level in kidney and ovary.
Catalyzes the formation of mannose 6-phosphate (M6P) markers on high mannose type oligosaccharides in the Golgi apparatus. M6P residues are required to bind to the M6P receptors (MPR), which mediate the vesicular transport of lysosomal enzymes to the endosomal/prelysosomal compartment.
Due to the low pH in the endosomal/prelysosomal compartment, the lysosomal enzyme-MPR complex dissociates and then the enzyme is delivered to the lysosome. Between 5% and 20% of newly synthesized lysosomal enzymes escape the binding to the MPR in the Golgi apparatus and are secreted.
Expressed in the heart, whole brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Genetic variations in GNPTAB have been suggested to play a role in susceptibility to persistent stuttering. Stuttering is a common speech disorder characterized by repetitions, prolongations, and interruptions in the flow of speech.
Hexamer of two alpha, two beta and two gamma (GNPTG) subunits; disulfide-linked. The alpha and/or the beta subunits of the enzyme constitute the catalytic subunits (PubMed:19955174). Interacts with LYSET; facilitates proper localization of GNPTAB (PubMed:36074821).
Stealth proteins are part of a protein family that is conserved from bacteria to higher eukaryotes. Family members were first identified in microbes as proteins that help pathogens to elude the host innate immune system. Microbial stealth proteins are most likely involved in the biosynthesis of exopolysaccharides. Stealth proteins are predicted to function as hexose-1-phosphoryltransferases.
The DMAP1-binding domain mediates substrate recognition. It specifically recognizes a conformation-dependent protein determinant present in acid hydrolases (PubMed:23733939).
The alpha- and beta-subunits are generated by a proteolytic cleavage by MBTPS1 protease at the Lys-928-Asp-929 bond.
Highly expressed in prostate, rectum, and distal colon, and weakly expressed in bladder. Expressed in prostate cancer cell lines.
Acetylated on lysine residues by KAT8 upon ionizing radiation-induced DNA damage; deacetylated by HDAC3.
According to a report, mainly mediates demethylation of N(6),2'-O-dimethyladenosine cap (m6A(m)), by demethylating the N(6)-methyladenosine adjacent to mRNA cap, whereas it has low activity toward internal N(6)-methyladenosine (m6A) in mRNAs (PubMed:28002401). According to a second report, has strong activity toward internal N(6)-methyladenosine (m6A) in mRNAs and is able to demethylate different RNA species, such as tRNA, mRNA or small nuclear RNA (snRNA), depending on the context and subcellular location (PubMed:30197295).
Activated by ascorbate (By similarity). Inhibited by N-oxalylglycine, fumarate and succinate (By similarity). RNA N(6)-methyladenosine demethylase activity is inhibited by fluorescein derivatives (PubMed:26457839). RNA N(6)-methyladenosine demethylase activity is selectively inhibited by meclofenamic acid; inhibition is specific to FTO and meclofenamic acid does not inhibit ALKBH5 (PubMed:25452335). Specifically inhibited by R-2-hydroxyglutarate (R-2HG), an oncometabolite that also exerts a broad antileukemic activity (PubMed:29249359). Inhibition by R-2HG leads to increased level of N(6)-methyladenosine-containing transcripts, leading to down-regulate expression of MYC and CEBPA transcripts (PubMed:29249359).
Disease susceptibility is associated with variants affecting the gene represented in this entry. It is unclear whether variations associated with obesity directly affect FTO function or alter the expression of adjacent genes such as IRX3, rather than FTO itself (PubMed:24646999, PubMed:26287746). A pathogenic intronic FTO variation (rs1421085) disrupts an evolutionarily conserved motif for ARID5B binding (PubMed:26287746). Loss of ARID5B binding results in overexpression of two genes distal to FTO, IRX3 and IRX5. IRX3 and IRX5 overexpression shifts pre-adipocytes differentiation from brown to white fat cells, resulting in increased lipid storage and loss of mitochondrial thermogenesis (PubMed:26287746).
Genetic variations at the FTO locus define the body mass index quantitative trait locus 14 (BMIQ14) [MIM:612460]. Variance in body mass index is a susceptibility factor for obesity.
Monomer (By similarity). May also exist as homodimer (By similarity).
RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis (PubMed:22002720, PubMed:26458103, PubMed:28002401, PubMed:30197295, PubMed:26457839, PubMed:25452335). Specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes (PubMed:22002720, PubMed:26458103, PubMed:30197295, PubMed:26457839, PubMed:25452335). M6A demethylation by FTO affects mRNA expression and stability (PubMed:30197295). Also able to demethylate m6A in U6 small nuclear RNA (snRNA) (PubMed:30197295). Mediates demethylation of N(6),2'-O-dimethyladenosine cap (m6A(m)), by demethylating the N(6)-methyladenosine at the second transcribed position of mRNAs and U6 snRNA (PubMed:28002401, PubMed:30197295). Demethylation of m6A(m) in the 5'-cap by FTO affects mRNA stability by promoting susceptibility to decapping (PubMed:28002401). Also acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs (PubMed:30197295). Has no activity towards 1-methylguanine (PubMed:20376003). Has no detectable activity towards double-stranded DNA (PubMed:20376003). Also able to repair alkylated DNA and RNA by oxidative demethylation: demethylates single-stranded RNA containing 3-methyluracil, single-stranded DNA containing 3-methylthymine and has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine (PubMed:18775698, PubMed:20376003). Ability to repair alkylated DNA and RNA is however unsure in vivo (PubMed:18775698, PubMed:20376003). Involved in the regulation of fat mass, adipogenesis and body weight, thereby contributing to the regulation of body size and body fat accumulation (PubMed:18775698, PubMed:20376003). Involved in the regulation of thermogenesis and the control of adipocyte differentiation into brown or white fat cells (PubMed:26287746). Regulates activity of the dopaminergic midbrain circuitry via its ability to demethylate m6A in mRNAs (By similarity). Plays an oncogenic role in a number of acute myeloid leukemias by enhancing leukemic oncogene-mediated cell transformation: acts by mediating m6A demethylation of target transcripts such as MYC, CEBPA, ASB2 and RARA, leading to promote their expression (PubMed:28017614, PubMed:29249359).
The 3D-structure of the Fe2OG dioxygenase domain is similar to that of the Fe2OG dioxygenase domain found in the bacterial DNA repair dioxygenase alkB and its mammalian orthologs, but sequence similarity is very low. As a consequence, the domain is not detected by protein signature databases.
Ubiquitously expressed, with relatively high expression in adrenal glands and brain; especially in hypothalamus and pituitary (PubMed:17434869, PubMed:17496892). Highly expressed in highly expressed in acute myeloid leukemias (AML) with t(11;11)(q23;23) with KMT2A/MLL1 rearrangements, t(15;17)(q21;q21)/PML-RARA, FLT3-ITD, and/or NPM1 mutations (PubMed:28017614).
Binds to type I and II regulatory subunits of protein kinase A and anchors them to the cytoplasmic face of the mitochondrial outer membrane (By similarity). Involved in mitochondrial-mediated antiviral innate immunity (PubMed:31522117). Promotes translocation of NDUFS1 into mitochondria to regulate mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) activity (By similarity).
Interacts with SLC8A3 (By similarity). Interacts with CFAP91 (PubMed:12223483). Interacts with CLPB (PubMed:31522117). Interacts with NDUFS1 (By similarity).
Isoform 1 is detected in thymus, prostate, testis, ovary, colon and small intestine (PubMed:8769136). Isoform 2 is highly expressed in testis and detected at much lower levels in kidney, pancreas, liver, lung and brain (PubMed:7499250).
Ca(2+) sensor involved in Ca(2+)-dependent exocytosis of secretory and synaptic vesicles through Ca(2+) and phospholipid binding to the C2 domain (By similarity). Ca(2+) induces binding of the C2-domains to phospholipid membranes and to assembled SNARE-complexes; both actions contribute to triggering exocytosis (By similarity). SYT7 binds Ca(2+) with high affinity and slow kinetics compared to other synaptotagmins (By similarity). Involved in Ca(2+)-triggered lysosomal exocytosis, a major component of the plasma membrane repair (PubMed:11342594). Ca(2+)-regulated delivery of lysosomal membranes to the cell surface is also involved in the phagocytic uptake of particles by macrophages (By similarity). Ca(2+)-triggered lysosomal exocytosis also plays a role in bone remodeling by regulating secretory pathways in osteoclasts and osteoblasts (By similarity). In case of infection, involved in participates cell invasion by Trypanosoma cruzi via Ca(2+)-triggered lysosomal exocytosis (PubMed:11342594, PubMed:15811535). Involved in cholesterol transport from lysosome to peroxisome by promoting membrane contacts between lysosomes and peroxisomes: probably acts by promoting vesicle fusion by binding phosphatidylinositol-4,5-bisphosphate on peroxisomal membranes (By similarity). Acts as a key mediator of synaptic facilitation, a process also named short-term synaptic potentiation: synaptic facilitation takes place at synapses with a low initial release probability and is caused by influx of Ca(2+) into the axon terminal after spike generation, increasing the release probability of neurotransmitters (By similarity). Probably mediates synaptic facilitation by directly increasing the probability of release (By similarity). May also contribute to synaptic facilitation by regulating synaptic vesicle replenishment, a process required to ensure that synaptic vesicles are ready for the arrival of the next action potential: SYT7 is required for synaptic vesicle replenishment by acting as a sensor for Ca(2+) and by forming a complex with calmodulin (By similarity). Also acts as a regulator of Ca(2+)-dependent insulin and glucagon secretion in beta-cells (By similarity). Triggers exocytosis by promoting fusion pore opening and fusion pore expansion in chromaffin cells (By similarity). Also regulates the secretion of some non-synaptic secretory granules of specialized cells (By similarity).
Homodimer. Can also form heterodimers with SYT6, SYT9 and SYT10. Interacts with calmodulin (CALM1, CALM2 or CALM3). Interacts with CD63; required for localization to lysosomes. Interacts with APP (By similarity).
Palmitoylated at its vesicular N-terminus; palmitoylation is required for localization to lysosome and phagocytosis in macrophages.
The C2 domains bind Ca(2+) and membranes. Binding to membranes involves Ca(2+)-dependent phospholipid binding. Compared to other members of the family, the C2 domains of SYT7 dock and insert into cellular membranes in response to intracellular Ca(2+) concentrations that are lower than those required for other synaptotagmins (PubMed:22966849). The two C2 domains bind independently to planar membranes, without interdomain cooperativity (PubMed:25437758). Moreover, SYT7 C2 domains insert more deeply into membranes compared to other synaptotagmins (PubMed:26322740, PubMed:26333120).
Expressed in brain. The mRNA was broadly distributed with higher levels in gray matter zones and lower levels in regions rich in white matter. Not detected in fetal sample but its expression increases linearly with age.
P450 monooxygenase that plays a major role in cholesterol homeostasis in the brain. Primarily catalyzes the hydroxylation (with S stereochemistry) at C-24 of cholesterol side chain, triggering cholesterol diffusion out of neurons and its further degradation (PubMed:10377398, PubMed:14640697, PubMed:25017465, PubMed:18621681). By promoting constant cholesterol elimination in neurons, may activate the mevalonate pathway and coordinate the synthesis of new cholesterol and nonsterol isoprenoids involved in synaptic activity and learning (By similarity). Further hydroxylates cholesterol derivatives and hormone steroids on both the ring and side chain of these molecules, converting them into active oxysterols involved in lipid signaling and biosynthesis (PubMed:12077124, PubMed:14640697, PubMed:28190002). Acts as an epoxidase converting cholesta-5,24-dien-3beta-ol/desmosterol into (24S),25-epoxycholesterol, an abundant lipid ligand of nuclear NR1H2 and NR1H3 receptors shown to promote neurogenesis in developing brain (PubMed:25017465). May also catalyze the oxidative metabolism of xenobiotics, such as clotrimazole (PubMed:20667828).
(Microbial infection) During SARS coronavirus-2/SARS-CoV-2 infection, it is able to recognize and internalize the complex formed by secreted ACE2 and SARS-CoV-2 spike protein through DNM2/dynamin 2-dependent endocytosis.
Interacts with MAS1 (PubMed:15809376). Interacts with ARRB1 (By similarity). Interacts with FLNA (via filamin repeat 21); increases PKA-mediated phosphorylation of FLNA (PubMed:26460884).
Liver, lung, adrenal and adrenocortical adenomas.
Receptor for angiotensin II, a vasoconstricting peptide, which acts as a key regulator of blood pressure and sodium retention by the kidney (PubMed:1567413, PubMed:8987975, PubMed:15611106, PubMed:25913193, PubMed:26420482, PubMed:30639100, PubMed:32079768). The activated receptor in turn couples to G-alpha proteins G(q) (GNAQ, GNA11, GNA14 or GNA15) and thus activates phospholipase C and increases the cytosolic Ca(2+) concentrations, which in turn triggers cellular responses such as stimulation of protein kinase C (PubMed:15611106).
Receptor for angiotensin II, a vasoconstricting peptide, which acts as a key regulator of blood pressure and sodium retention by the kidney. The activated receptor in turn couples to G-alpha proteins G(q) and thus activates phospholipase C and increases the cytosolic Ca(2+) concentrations, which in turn triggers cellular responses such as stimulation of protein kinase C.
Strongly inhibited by anti-hypertensive drugs losartan, candesartan, valsartan, irbesartan, telmisartan, eprosartan, olmesartan and azilsartan, most of which share a common biphenyl-tetrazole scaffold.
Plays a role in spermatogenesis, where it is important for normal sperm head morphology. Also required for the acrosome reaction and thus normal male fertility.
Interacts (when S-nitrosylated) with GAPDH (By similarity). Interacts with RAB8A; interaction is dependent on the phosphorylation of 'Thr-72' of RAB8A (PubMed:29125462, PubMed:30398148). Interacts with RAB10 and RAB12; the interaction is dependent on the phosphorylation of 'Thr-73' of RAB10, and 'Ser-105' of RAB12 (PubMed:29125462, PubMed:30398148).
Plays a role in the regulation of cell shape and polarity (By similarity). Plays a role in cellular protein transport, including protein transport away from primary cilia (By similarity). Neuroprotective protein, which acts by sequestring GAPDH in the cytosol and prevent the apoptotic function of GAPDH in the nucleus (By similarity). Competes with SIAH1 for binding GAPDH (By similarity). Does not regulate lysosomal morphology and distribution (PubMed:14668488). Binds to RAB10 following LRRK2-mediated RAB10 phosphorylation which leads to inhibition of ciliogenesis (PubMed:30398148).
S-nitrosylation is required for the interaction with GAPDH.
The disease is caused by variants affecting the gene represented in this entry. The causative mutation is a heterozygous trinucleotide repeat expansion (CGG) in the 5-prime untranslated region of the gene. The expansion ranges from 139 to 197 repeats in individuals with OPDM, and 9 to 1 repeats in controls.
Widely expressed. Expressed at lower level in liver and kidney.
The sequence shown is that of allele KAP1.3.
Expressed in a very restricted set of primarily hormone-regulated epithelial tissues with particularly high expression in the prostate gland. Significantly lower expression is seen in other hormone regulated tissues such as mammary gland, salivary gland, and ovary. Expressed in prostate carcinoma cells.
Interacts with the DNA-binding domain of the androgen receptor. Interacts with NKX3-1.
May function as an androgen-independent transactivator of the prostate-specific antigen (PSA) promoter. Binds to 5'-GGAT-3' DNA sequences. May play a role in the regulation of the prostate gland and/or prostate cancer development. Acts as a transcriptional activator for SERPINB5 promoter.
Expressed in all tissues examined except for placenta. Highest levels in colon, kidney, lung, testis, spleen, and brain.
Mitochondrial transporter mediating uptake of thiamine diphosphate into mitochondria. It is not clear if the antiporter activity is affected by the membrane potential or by the proton electrochemical gradient.
Previously identified as the mitochondrial deoxyribonucleotide carrier (PubMed:11226231). However other experiments later demonstrated that SLC25A19 is a thiamine diphosphate transporter and not a mitochondrial deoxyribonucleotide carrier (PubMed:15539640, PubMed:18280798).
Expressed in hair root and not in skin. Expressed also in liver and skeletal muscle.
Has transcriptional repression activity, partially through the recruitment of the corepressor TRIM28 but has also repression activity independently of this interaction. Essential during embryonic development, where it acts as direct repressor of a placental-specific transcript of IGF2 in early development and regulates convergent extension movements required for axis elongation and tissue morphogenesis in all germ layers. Also important for normal morphogenesis of extraembryonic tissues including the yolk sac, extraembryonic mesoderm and placenta. May enhance proliferation or maintenance of neural stem cells.
Isoform 3 is highly polymorphic with three major alleles: H, C1 and C1. The H allele is found at higher frequencies in Japanese (0.71) and Taiwan Chinese (0.72) populations compared to European (0.45) and African (0.39) populations. The H allele may be associated with smaller head size in infants.
Widely expressed. The highest expression is observed in the brain.
As the sensor component of the NLRP9 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens, including rotavirus, initiates the formation of the inflammasome polymeric complex, made of NLRP9, PYCARD and CASP1. Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and release in the extracellular milieu. The active cytokines stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death. NLRP9 inflammasome activation may be initiated by DHX9 interaction with viral double-stranded RNA (dsRNA), preferentially to short dsRNA segments.
Expressed in ileum intestinal epithelial cells. Not detected in peripheral blood mononuclear cells (PubMed:28636595). Expressed in cerebral endothelial cells and, at much lower levels, in brain pericytes (PubMed:28432035).
In brain pericytes, up-regulated at the mRNA level in response to oxidative stress.
Sensor component of NLRP9 inflammasomes. Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens, such as rotavirus, and play critical roles in innate immunity and inflammation. The core of NLRP9 inflammasomes consists of a signal sensor component (NLRP9), an adapter (ASC/PYCARD), which recruits an effector pro-inflammatory caspase (CASP1). Within the complex, NLRP9 and PYCARD interact via their respective DAPIN/pyrin domains. This interaction initiates speck formation (nucleation) which greatly enhances further addition of soluble PYCARD molecules to the speck in a prion-like polymerization process. Clustered PYCARD nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization. CASP1 filament formation increases local enzyme concentration, resulting in trans-autocleavage and activation. Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response (PubMed:28636595). Interacts with DHX9 upon rotavirus infection; this interaction may trigger inflammasome activation and inflammatory response (PubMed:28636595).
Interacts with DAG1 alpha-dystroglycan. Interacts with GPR158 and GPR179; transsynaptic interaction is required for synaptic organization of photoreceptor cells.
Involved in both the retinal photoreceptor ribbon synapse formation and physiological functions of visual perception. Plays a key role in the synaptic organization of photoreceptors by mediating transsynaptic interaction between alpha-dystroglycan and GPR179 on the postsynaptic membrane. Necessary for proper bipolar dendritic tip apposition to the photoreceptor ribbon synapse. Promotes matrix assembly and cell adhesiveness.
In the epidermis, expressed predominantly in the granular layer at the apical edge of keratinocytes (at protein level). Also detected in placenta, testis and thymus but not in epithelia of kidney, lung, small intestine or colon.
Is able to inhibit all four classes of proteinases by a unique 'trapping' mechanism. This protein has a peptide stretch, called the 'bait region' which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein which traps the proteinase. The entrapped enzyme remains active against low molecular weight substrates (activity against high molecular weight substrates is greatly reduced). Following cleavage in the bait region a thioester bond is hydrolyzed and mediates the covalent binding of the protein to the proteinase (By similarity). Displays inhibitory activity against chymotrypsin, papain, thermolysin, subtilisin A and, to a lesser extent, elastase but not trypsin. May play an important role during desquamation by inhibiting extracellular proteases.
Abundantly expressed in thymus, spleen and peripheral blood Leukocytes and lymph nodes. Lower expression in bone marrow and small intestine.
Chromosomal aberrations involving IKZF1 are a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;7)(q27;p12), with BCL6.
Defects in IKZF1 are frequent occurrences (28.6%) in acute lymphoblasic leukemia (ALL). Such alterations or deletions lead to poor prognosis for ALL.
Heterodimer formed by the various isoforms; this modulates transcription regulator activity (PubMed:17135265, PubMed:17934067). Heterodimer with other IKAROS family members. Interacts with IKZF4 AND IKZF5 (PubMed:10978333). Component of the chromatin-remodeling NuRD repressor complex which includes at least HDAC1, HDAC2, RBBP4, RBBP7, IKZF1, MTA2, MBD2, MBD3, MTA1L1, CHD3 and CHD4. Interacts directly with the CHD4 component of the NuRD complex. Interacts directly with SMARCA4; the interaction associates IKFZ1 with the BAF complex (PubMed:10204490). Interacts with SUMO1; the interaction sumoylates IKAROS, promoted by PIAS2 and PIAS3. Interacts with PIAS2 (isoform alpha); the interaction promotes sumoylation and reduces transcription repression. Interacts, to a lesser extent, with PIAS3. Interacts with PPP1CC; the interaction targets PPP1CC to pericentromeric heterochromatin, dephosphorylates IKAROS, stabilizes it and prevents it from degradation. Interacts with IKZF3 (By similarity).
Phosphorylation controls cell-cycle progression from late G(1) stage to S stage. Hyperphosphorylated during G2/M phase. Dephosphorylated state during late G(1) phase. Phosphorylation on Thr-140 is required for DNA and pericentromeric location during mitosis. CK2 is the main kinase, in vitro. GSK3 and CDK may also contribute to phosphorylation of the C-terminal serine and threonine residues. Phosphorylation on these C-terminal residues reduces the DNA-binding ability. Phosphorylation/dephosphorylation events on Ser-13 and Ser-295 regulate TDT expression during thymocyte differentiation. Dephosphorylation by protein phosphatase 1 regulates stability and pericentromeric heterochromatin location. Phosphorylated in both lymphoid and non-lymphoid tissues (By similarity). Phosphorylation at Ser-361 and Ser-364 downstream of SYK induces nuclear translocation.
Sumoylated. Simultaneous sumoylation on the 2 sites results in a loss of both HDAC-dependent and HDAC-independent repression. Has no effect on pericentromeric heterochromatin location. Desumoylated by SENP1 (By similarity).
The C-terminal zinc-finger domain is required for dimerization.
The N-terminal zinc-fingers 2 and 3 are required for DNA binding as well as for targeting IKFZ1 to pericentromeric heterochromatin.
Transcription regulator of hematopoietic cell differentiation (PubMed:17934067). Binds gamma-satellite DNA (PubMed:17135265, PubMed:19141594). Plays a role in the development of lymphocytes, B- and T-cells. Binds and activates the enhancer (delta-A element) of the CD3-delta gene. Repressor of the TDT (fikzfterminal deoxynucleotidyltransferase) gene during thymocyte differentiation. Regulates transcription through association with both HDAC-dependent and HDAC-independent complexes. Targets the 2 chromatin-remodeling complexes, NuRD and BAF (SWI/SNF), in a single complex (PYR complex), to the beta-globin locus in adult erythrocytes. Increases normal apoptosis in adult erythroid cells. Confers early temporal competence to retinal progenitor cells (RPCs) (By similarity). Function is isoform-specific and is modulated by dominant-negative inactive isoforms (PubMed:17135265, PubMed:17934067).
Widely expressed; the highest levels are found in lung, thymus, pancreas, placenta, adult brain and prostate; also detected in spleen, liver, kidney, colon, small intestine, uterus, spinal cord, adrenal gland, salivary gland, trachea, mammary gland, skeletal muscle, testis and fetal brain and liver.
Activated by guanosine analogs including deoxyguanosine, 7-thia-8-oxoguanosine or 7-deazaguanosine in a RNA-independent manner. Activated by imiquimod (PubMed:32706371).
Contains two binding domains, first site for small ligands and second site for ssRNA.
Detected in brain, placenta, spleen, stomach, small intestine, lung and in plasmacytoid pre-dendritic cells. Expressed in peripheral mononuclear blood cells (PubMed:32706371).
Endosomal receptor that plays a key role in innate and adaptive immunity (PubMed:14976261, PubMed:32433612). Controls host immune response against pathogens through recognition of uridine-containing single strand RNAs (ssRNAs) of viral origin or guanosine analogs (PubMed:31608988, PubMed:27742543, PubMed:12738885, PubMed:32706371, PubMed:35477763). Upon binding to agonists, undergoes dimerization that brings TIR domains from the two molecules into direct contact, leading to the recruitment of TIR-containing downstream adapter MYD88 through homotypic interaction (PubMed:27742543). In turn, the Myddosome signaling complex is formed involving IRAK4, IRAK1, TRAF6, TRAF3 leading to activation of downstream transcription factors NF-kappa-B and IRF7 to induce pro-inflammatory cytokines and interferons, respectively (PubMed:27742543, PubMed:32706371).
Homodimer (PubMed:27742543). Interacts with MYD88 via their respective TIR domains (Probable). Interacts with UNC93B1 (PubMed:33432245). Interacts with SMPDL3B (By similarity).
Component of the PEX2-PEX10-PEX12 retrotranslocation channel, composed of PEX2, PEX10 and PEX12.
E3 ubiquitin-protein ligase component of a retrotranslocation channel required for peroxisome organization by mediating export of the PEX5 receptor from peroxisomes to the cytosol, thereby promoting PEX5 recycling (PubMed:24662292). The retrotranslocation channel is composed of PEX2, PEX10 and PEX12; each subunit contributing transmembrane segments that coassemble into an open channel that specifically allows the passage of PEX5 through the peroxisomal membrane (By similarity). PEX2 also regulates peroxisome organization by acting as a E3 ubiquitin-protein ligase (By similarity). PEX2 ubiquitinates PEX5 during its passage through the retrotranslocation channel: catalyzes monoubiquitination of PEX5 at 'Cys-11', a modification that acts as a signal for PEX5 extraction into the cytosol (By similarity). Required for pexophagy in response to starvation by mediating ubiquitination of peroxisomal proteins, such as PEX5 and ABCD3/PMP70 (PubMed:27597759). Also involved in the response to reactive oxygen species (ROS) by mediating 'Lys-48'-linked polyubiquitination and subsequent degradation of PNPLA2/ATGL, thereby regulating lipolysis (PubMed:34903883).
Forms intramolecular and intermolecular disulfide bonds in response to reactive oxygen species (ROS), promoting higher stability.
Phosphorylated (PubMed:26980729). Phosphorylation of the protein kinase-like domain is required for full activation by CNP (By similarity).
Receptor for the C-type natriuretic peptide NPPC/CNP hormone. Has guanylate cyclase activity upon binding of its ligand. May play a role in the regulation of skeletal growth.
Activated by phosphorylation on Thr-211. Inhibited by phosphorylation on Thr-564.
Interacts with MAPT/TAU (PubMed:23666762). Interacts with DLG5 (via coiled-coil domain). Interacts with STK3/MST2 and STK4/MST1 in the presence of DLG5 (PubMed:28087714). Interacts with YWHAB, YWHAG, YWHAQ and YWHAZ (PubMed:16959763). Interacts with PKP2 (via N-terminus) (PubMed:12941695). Interacts with CDC25C (PubMed:12941695). Interacts with KSR1 (PubMed:12941695).
Phosphorylated at Thr-211 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39 (PubMed:14976552). Phosphorylation at Thr-564 by PRKCZ/aPKC inhibits the kinase activity (PubMed:15084291).
Serine/threonine-protein kinase (PubMed:16822840, PubMed:16980613, PubMed:23666762). Involved in the specific phosphorylation of microtubule-associated proteins for MAP2 and MAP4. Phosphorylates the microtubule-associated protein MAPT/TAU (PubMed:23666762). Phosphorylates CDC25C on 'Ser-216' (PubMed:12941695). Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus (PubMed:16980613). Regulates localization and activity of MITF by mediating its phosphorylation, promoting subsequent interaction between MITF and 14-3-3 and retention in the cytosol (PubMed:16822840). Negatively regulates the Hippo signaling pathway and antagonizes the phosphorylation of LATS1. Cooperates with DLG5 to inhibit the kinase activity of STK3/MST2 toward LATS1 (PubMed:28087714). Phosphorylates PKP2 and KSR1 (PubMed:12941695).
Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. EZ subfamily.
Component of the PRC2/EED-EZH1 complex, which includes EED, EZH1, SUZ12, RBBP4 and AEBP2 (PubMed:19026781). The PRC2/EED-EZH1 is less abundant than the PRC2/EED-EZH2 complex, has weak methyltransferase activity and compacts chromatin in the absence of the methyltransferase cofactor S-adenosyl-L-methionine (SAM) (PubMed:19026781). Interacts with EZHIP; the interaction blocks EZH1 methyltransferase activity (PubMed:31451685).
Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH1 complex, which methylates 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Required for embryonic stem cell derivation and self-renewal, suggesting that it is involved in safeguarding embryonic stem cell identity. Compared to EZH2-containing complexes, it is less abundant in embryonic stem cells, has weak methyltransferase activity and plays a less critical role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation.
DSP may be an important factor in dentinogenesis. DPP may bind high amount of calcium and facilitate initial mineralization of dentin matrix collagen as well as regulate the size and shape of the crystals.
Expressed in teeth. DPP is synthesized by odontoblast and transiently expressed by pre-ameloblasts.
The disease is caused by variants affecting the gene represented in this entry. DSPP defects causing dentin abnormalities act in a dominant negative manner and include missense, splice-site, frameshift mutations. 5' frameshift mutations cause dentin dysplasia while frameshift mutations at the 3' end cause the more severe dentinogenesis imperfecta phenotype (PubMed:18521831, PubMed:22392858).
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family.
Synaptic vesicle transporter with apparent selectivity for neutral amino acids. The transport is sodium-coupled but chloride-independent, likely driven by the proton electrochemical gradient generated by vacuolar H(+)-ATPase in an overall electrogenic mechanism. May contribute to the synaptic uptake of neurotransmitter precursors in a process coupled in part to vesicle exocytosis.
Phosphoinositide-binding protein involved in protein sorting and membrane trafficking in endosomes.
Degraded via selective autophagy following interaction with IRGM (PubMed:36221902). IRGM promotes NOD1-RIPK2 RIPosome recruitment to autophagosome membranes, promoting their SQSTM1/p62-dependent autophagic degradation (PubMed:36221902).
Highly expressed in adult heart, skeletal muscle, pancreas, spleen and ovary (PubMed:10224040). Also detected in placenta, lung, liver, kidney, thymus, testis, small intestine and colon (PubMed:10224040).
Homooligomer: homooligomerizes following ligand-binding, promoting RIPK2 recruitment (PubMed:10880512). Interacts (via CARD domain) with RIPK2 (via CARD domain) (PubMed:10880512, PubMed:30478312, PubMed:23300079, PubMed:17054981). Following RIPK2 recruitment, RIPK2 homooligomerizes via its CARD domain and forms long filaments named RIPosomes (PubMed:30478312). Interacts with ARHGEF2 (PubMed:19043560). Interacts (via CARD domain) with ubiquitin; inhibiting interaction with RIPK2 (PubMed:23300079, PubMed:25127239). Interacts with NLRP10 and recruits it to the cell membrane following invasive bacterial infection (PubMed:22672233). Interacts with IFIH1; this interaction promotes transcription of antiviral genes and inhibition of viral replication (PubMed:32169843). Interacts with IRGM; promoting NOD1 degradation (PubMed:36221902). Interacts with ATG16L1 (By similarity).
Human and mouse NOD1 bind gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP) in a different context (PubMed:16211083). do not detect the same muropeptide from bacterial peptidoglycan: while human NOD1 detects a tripeptide-containing muropeptide (MurNAc-TriDAP or TriDAP), mouse Nod1 needs a tetrapeptide structure for efficient sensing (MurNAc-tetraDAP or TetraDAP) (PubMed:16211083).
In contrast to isoform 1, does not efficiently recognize and bind gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP) ligand.
Palmitoylated. Palmitoylation is required for proper recruitment to the bacterial entry site and hence for proper signaling upon cognate peptidoglycan detection.
Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and thus participates in both innate and adaptive immune responses (PubMed:11058605, PubMed:12796777, PubMed:12791997, PubMed:15044951, PubMed:16172124, PubMed:19043560, PubMed:22672233, PubMed:27099311). Specifically recognizes and binds gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP), a dipeptide present in peptidoglycan of Gram-negative bacteria (PubMed:12871942, PubMed:12796777, PubMed:12791997, PubMed:16211083, PubMed:16172124). Preferentially binds iE-DAP in tripeptide-containing muropeptides (MurNAc-TriDAP or TriDAP) (PubMed:16211083). Ligand binding triggers oligomerization that facilitates the binding and subsequent activation of the proximal adapter receptor-interacting RIPK2 (PubMed:12796777, PubMed:12791997, PubMed:17054981). Following recruitment, RIPK2 undergoes 'Met-1'- (linear) and 'Lys-63'-linked polyubiquitination by E3 ubiquitin-protein ligases XIAP, BIRC2, BIRC3 and the LUBAC complex, becoming a scaffolding protein for downstream effectors, triggering activation of the NF-kappa-B and MAP kinases signaling (PubMed:10880512, PubMed:12791997, PubMed:19043560). This in turn leads to the transcriptional activation of hundreds of genes involved in immune response (PubMed:10880512, PubMed:19043560). Also acts as a regulator of antiviral response elicited by dsRNA and the expression of RLR pathway members by targeting IFIH1 and TRAF3 to modulate the formation of IFIH1-MAVS and TRAF3-MAVS complexes leading to increased transcription of type I IFNs (PubMed:32169843). Also acts as a regulator of autophagy via its interaction with ATG16L1, possibly by recruiting ATG16L1 at the site of bacterial entry (By similarity). Besides recognizing pathogens, also involved in the endoplasmic reticulum stress response: acts by sensing and binding to the cytosolic metabolite sphingosine-1-phosphate generated in response to endoplasmic reticulum stress, initiating an inflammation process that leads to activation of the NF-kappa-B and MAP kinases signaling (PubMed:27007849, PubMed:33942347). In addition, plays a role in insulin trafficking in beta cells in a cell-autonomous manner (By similarity). Mechanistically, upon recognizing cognate ligands, NOD1 and RIPK2 localize to insulin vesicles where they recruit RAB1A to direct insulin trafficking through the cytoplasm (By similarity).
The LRR repeats recognize and bind gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP).
Ubiquitinated. 'Lys-48'-linked polyubiquitination by RNF34 promotes proteasomal degradation and thereby negatively regulates NOD1 for instance in NF-kappa-B activation.
ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes (PubMed:11581266, PubMed:15083066, PubMed:10359813). Transports glucuronide conjugates such as bilirubin diglucuronide, estradiol-17-beta-o-glucuronide and GSH conjugates such as leukotriene C4 (LTC4) (PubMed:15083066, PubMed:11581266). Transports also various bile salts (taurocholate, glycocholate, taurochenodeoxycholate-3-sulfate, taurolithocholate- 3-sulfate) (By similarity). Does not contribute substantially to bile salt physiology but provides an alternative route for the export of bile acids and glucuronides from cholestatic hepatocytes (By similarity). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can confer resistance to various anticancer drugs, methotrexate, tenoposide and etoposide, by decreasing accumulation of these drugs in cells (PubMed:11581266, PubMed:10359813).
Mainly expressed in the liver. Also expressed in small intestine, colon, prostate, testis, brain and at a lower level in the kidney. In testis, localized to peritubular myoid cells, Leydig cells, along the basal membrane of Sertoli cells and moderately in the adluminal compartment of the seminiferous tubules (PubMed:35307651).
Strongly up-regulated under conditions of MRP2 deficiency.
Binds a calmodulin chain via each of the two IQ domains. IQ domain 1 mediates interaction with calmodulin both in the presence and in the absence of Ca(2+). IQ domain 2 mediates interaction with calmodulin in the presence of Ca(2+).
Contrary to the situation in zebrafish, xenopus and drosophila, mammalian MYO1D defects have no effects on left-right body asymmetry.
Expressed in many tissues. Highest levels in brain, followed by lung and ovary; expression is lowest in spleen.
Interacts (via the two IQ motifs) with calmodulin. Binds an additional calmodulin chain via a third, C-terminal region. Interacts with F-actin.
The TH1 domain is required for activity in complementing zebrafish defects in Kupffer's vesicle lumen size.
Unconventional myosin that functions as actin-based motor protein with ATPase activity (By similarity). Plays a role in endosomal protein trafficking, and especially in the transfer of cargo proteins from early to recycling endosomes (By similarity). Required for normal planar cell polarity in ciliated tracheal cells, for normal rotational polarity of cilia, and for coordinated, unidirectional ciliary movement in the trachea. Required for normal, polarized cilia organization in brain ependymal epithelial cells (By similarity).
Essential regulator of neutrophil polarity. Regulates neutrophil polarization by regulating AKT1 phosphorylation through a mechanism that is independent of PIK3CG activity (By similarity).
Essential regulator of neutrophil polarity. Regulates neutrophil polarization by regulating AKT1 phosphorylation through a mechanism that is independent of PIK3CG activity.
Heterodimer with PALS1. Interacts with DLG5 and NF2. Interacts (via guanylate kinase-like domain) with WHRN (via third PDZ domain).
Thought to be palmitoylated by ZDHHC17 (PubMed:22496366). This work was later retracted due to image manipulation (PubMed:29475958).
Chromatin reader protein that recognizes and binds histone H3 trimethylated at 'Lys-9', dimethylated at 'Lys-27' and trimethylated at 'Lys-27' (H3K9me3, H3K27me2 and H3K27me3, respectively) (PubMed:19808672, PubMed:28402439). Part of multimeric repressive chromatin complexes, where it is required for transmission and restoration of repressive histone marks, thereby preserving the epigenetic landscape (PubMed:28402439). Required for chromatin targeting and maximal enzymatic activity of Polycomb repressive complex 2 (PRC2); acts as a positive regulator of PRC2 activity by bridging the pre-existing histone H3K27me3 and newly recruited PRC2 on neighboring nucleosomes (PubMed:22009739). Acts as a corepressor for REST by facilitating histone-lysine N-methyltransferase EHMT2 recruitment and H3K9 dimethylation at REST target genes for repression (PubMed:19061646). Involved in X chromosome inactivation in females: recruited to Xist RNA-coated X chromosome and facilitates propagation of H3K9me2 by anchoring EHMT2 (By similarity). Promotes EZH2 accumulation and H3K27me3 methylation at DNA double strand breaks (DSBs), thereby facilitating transcriptional repression at sites of DNA damage and homology-directed repair of DSBs (PubMed:29177481). Required for neuronal migration during brain development by repressing expression of RHOA (By similarity). By repressing the expression of SCN8A, contributes to the inhibition of intrinsic neuronal excitability and epileptogenesis (By similarity). In addition to acting as a chromatin reader, acts as a hydro-lyase (PubMed:28803779). Shows crotonyl-coA hydratase activity by mediating the conversion of crotonyl-CoA ((2E)-butenoyl-CoA) to beta-hydroxybutyryl-CoA (3-hydroxybutanoyl-CoA), thereby acting as a negative regulator of histone crotonylation (PubMed:28803779). Histone crotonylation is required during spermatogenesis; down-regulation of histone crotonylation by CDYL regulates the reactivation of sex chromosome-linked genes in round spermatids and histone replacement in elongating spermatids (By similarity). By regulating histone crotonylation and trimethylation of H3K27, may be involved in stress-induced depression-like behaviors, possibly by regulating VGF expression (By similarity).
Expressed in the hippocampus with reduced expression in epileptic tissue compared to normal adjacent tissue (at protein level) (PubMed:28842554). Ubiquitous (PubMed:19808672). Expressed at moderate levels in all tissues examined (PubMed:19808672). Isoform 2: Most abundantly expressed isoform (PubMed:19808672).
Forms multimers and multimerization is required for stable binding to chromatin (PubMed:19808672). Interacts with HDAC1 and HDAC2 via its C-terminal acetyl-CoA-binding domain (By similarity). Interacts with EZH2, EED, SUZ12, REST, EHMT1 and EHMT2 (PubMed:19061646). Part of a complex containing at least CDYL, REST, WIZ, SETB1, EHMT1 and EHMT2. Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2 (PubMed:22009739). Interacts with CHAF1A and CHAF1B; bridging the CAF-1 complex to the MCM2-7 (MCM) complex (PubMed:28402439). Interacts with MCM3 and MCM5; bridging the CAF-1 complex to the MCM2-7 (MCM) complex (PubMed:28402439). Recruited to Xist RNA-coated X chromosome (By similarity). Interacts with EHMT2 and PRDM9; interaction only takes place when PRDM9 is bound to hotspot DNA (By similarity).
Not able to recognize and bind histone H3K9me3, histone H3K27me2 and histone H3K27me3, due to the absence of the chromo domain (PubMed:19808672). Acts as a negative regulator of isoform 2 by displacing isoform 2 from chromatin.
Not able to recognize and bind histone H3K9me3, histone H3K27me2 and histone H3K27me3, due to the presence of a N-terminal extension that inactivates the chromo domain (PubMed:19808672).
The acetyl-CoA-binding domain mediates crotonyl-coA hydratase activity (PubMed:28803779). The acetyl-CoA-binding domain is required for recruitment to sites of DNA double strand breaks and for binding to poly (ADP ribose) moieties (PubMed:29177481).
The chromo domain recognizes and binds histone H3K9me3, histone H3K27me2 and histone H3K27me3.
Was initially reported to display histone acetyltransferase activity, with a preference for histone H4 (PubMed:12072557). Such activity is however unsure in vivo. Histone acetyltransferase activity would be in contradiction with the function of the protein in corepressor complexes (PubMed:19061646, PubMed:22009739). Moreover, crystallographic studies demonstrated that it does not share any similarity with other acetyltransferases and instead forms a crotonase-like fold (PubMed:19507244).
Widely expressed. Detected in fetal and adult kidney, heart, liver, lung and skeletal muscle.
ATP-binding RNA helicase involved in translation initiation. Part of the 43S pre-initiation complex that is required for efficient initiation on mRNAs of higher eukaryotes with structured 5'-UTRs by promoting efficient NTPase-dependent 48S complex formation. Specifically binds to the 40S ribosome near the mRNA entrance. Does not possess a processive helicase activity.
Part of the 43S pre-initiation complex (PIC) that contains at least Met-tRNA, EIF1, EIF1A (EIF1AX or EIF1AY), EIF2S1, EIF2S2, EIF2S3, EIF3A, EIF3B, EIF3C, EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L, EIF3M, DHX29 and the 40S ribosomal subunit.
By expression of E2F1, E2F2, E2F3 and E2F4. Expression is reduced in response to radiation-induced DNA damage.
Chimeric cDNA. A chimeric cDNA originating from chromosomes 11 and 4.
Expressed throughout the cell cycle. Expression peaks at the G1/S phase boundary and declines during S phase.
Interacts with the cylin/CDK complexes CCNE1/CDK2 and CCNA1/CDK2. Interacts with BZW1, CASP8AP2, CREBBP, MIZF and YY1. Interacts with the RUVBL1, RUVBL2 and TRRAP subunits of the NuA4 complex. May also interact with GAPDH, NME1, NME2 and STIP1.
Phosphorylated at Ser-775, Ser-779, Ser-1100, Thr-1270 and Thr-1350 by CCNE1/CDK2 at G1-S transition and until prophase, which promotes association with histone gene clusters and stimulates activation of histone transcription. Also phosphorylated by CCNA1/CDK2 in vitro.
Required for progression through the G1 and S phases of the cell cycle and for S phase entry. Activates transcription of the histone H2A, histone H2B, histone H3 and histone H4 genes in conjunction with MIZF. Also positively regulates the ATM, MIZF and PRKDC promoters. Transcriptional activation may be accomplished at least in part by the recruitment of the NuA4 histone acetyltransferase (HAT) complex to target gene promoters.
The LisH domain is required for the activation of histone gene transcription.
Histone chaperone that facilitates histone deposition and histone exchange and removal during nucleosome assembly and disassembly (PubMed:10759893, PubMed:11897662, PubMed:12842904, PubMed:14718166, PubMed:15664198, PubMed:16151251, PubMed:21454524). Cooperates with chromatin assembly factor 1 (CAF-1) to promote replication-dependent chromatin assembly and with HIRA to promote replication-independent chromatin assembly (PubMed:11897662, PubMed:14718166, PubMed:15664198). Promotes homologous recombination-mediated repair of double-strand breaks (DSBs) at stalled or collapsed replication forks: acts by mediating histone replacement at DSBs, leading to recruitment of the MMS22L-TONSL complex and subsequent loading of RAD51 (PubMed:29478807). Also involved in the nuclear import of the histone H3-H4 dimer together with importin-4 (IPO4): specifically recognizes and binds newly synthesized histones with the monomethylation of H3 'Lys-9' and acetylation at 'Lys-14' (H3K9me1K14ac) marks, and diacetylation at 'Lys-5' and 'Lys-12' of H4 (H4K5K12ac) marks in the cytosol (PubMed:21454524, PubMed:29408485). Required for the formation of senescence-associated heterochromatin foci (SAHF) and efficient senescence-associated cell cycle exit (PubMed:15621527).
Interacts with histone H3 (including both histone H3.1 and H3.3) and histone H4 (PubMed:10759893, PubMed:12842904, PubMed:14718166, PubMed:15664198, PubMed:33857403, PubMed:15840725). Interacts with the CHAF1A, CHAF1B and RBBP4 subunits of the CAF-1 complex (PubMed:11897662, PubMed:16980972). Interacts with CABIN1, HAT1, HIRA, NASP, TAF1 and UBN1 (PubMed:12093919, PubMed:14680630, PubMed:14718166, PubMed:15621527, PubMed:16980972, PubMed:19029251). Interacts with CDAN1 (PubMed:22407294). Found in a cytosolic complex with IPO4 and histones H3 and H4 (PubMed:21454524, PubMed:22407294). Interacts with CREBBP (PubMed:24616510).
Phosphorylated by TLK1 and TLK2 (PubMed:11470414, PubMed:20016786, PubMed:35136069). Highly phosphorylated in S-phase and at lower levels in M-phase (PubMed:11470414). TLK2-mediated phosphorylation at Ser-192 prevents proteasome-dependent degradation (PubMed:20016786). Phosphorylation at Ser-192 by PRKDC in response to DNA damage promotes the histone chaperone activity and ability to replace histones at double-strand breaks (DSBs) at stalled or collapsed replication forks, leading to RAD51 recruitment (PubMed:29478807).
(Microbial infection) Interacts (via cap-binding region) with potato virus Y VPg; this interaction mediates the translation of the VPg-viral RNA conjugates and interferes with the cellular EIF4E-dependent mRNA export and translation.
(Microbial infection) Interacts with Lassa virus Z protein.
(Microbial infection) Interacts with Lymphocytic choriomeningitis virus (LCMV) Z protein (via RING-type zinc finger); the interaction results in conformational changes of both interacting proteins and reduces EIF4E affinity for the m7G mRNA cap structure.
A chromosomal aberration involving EIF4E has been found in a patient with classic autism. Translocation t(45)(q23q31.3). The breakpoint on chromosome 4 is located 56 kb downstream of EIF4E (PubMed:19556253).
Acts in the cytoplasm to initiate and regulate protein synthesis and is required in the nucleus for export of a subset of mRNAs from the nucleus to the cytoplasm which promotes processes such as RNA capping, processing and splicing (PubMed:11606200, PubMed:24335285, PubMed:29987188, PubMed:22684010, PubMed:22578813). Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome (By similarity). This protein recognizes and binds the 7-methylguanosine (m7G)-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures (PubMed:16271312, PubMed:22578813). Together with EIF4G1, antagonizes the scanning promoted by EIF1-EIF4G1 and is required for TISU translation, a process where the TISU element recognition makes scanning unnecessary (PubMed:29987188). In addition to its role in translation initiation, also acts as a regulator of translation and stability in the cytoplasm (PubMed:24335285). Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression: in the complex, EIF4E mediates the binding to the mRNA cap (By similarity). Component of a multiprotein complex that sequesters and represses translation of proneurogenic factors during neurogenesis (By similarity). In P-bodies, component of a complex that mediates the storage of translationally inactive mRNAs in the cytoplasm and prevents their degradation (PubMed:24335285). May play an important role in spermatogenesis through translational regulation of stage-specific mRNAs during germ cell development (By similarity). As well as its roles in translation, also involved in mRNA nucleocytoplasmic transport (By similarity). Its role in mRNA export from the nucleus to the cytoplasm relies on its ability to bind the m7G cap of RNAs and on the presence of the 50-nucleotide EIF4E sensitivity element (4ESE) in the 3'UTR of sensitive transcripts (By similarity). Interaction with the 4ESE is mediated by LRPPRC which binds simultaneously to both EIF4E and the 4ESE, thereby acting as a platform for assembly for the RNA export complex (By similarity). EIF4E-dependent mRNA export is independent of ongoing protein or RNA synthesis and is also NFX1-independent but is XPO1-dependent with LRPPRC interacting with XPO1 to form an EIF4E-dependent mRNA export complex (By similarity). Alters the composition of the cytoplasmic face of the nuclear pore to promote RNA export by reducing RANBP2 expression, relocalizing nucleoporin NUP214 and increasing expression of RANBP1 and RNA export factors DDX19 and GLE1 (By similarity). Promotes the nuclear export of cyclin CCND1 mRNA (By similarity). Promotes the nuclear export of NOS2/iNOS mRNA (PubMed:23471078). Promotes the nuclear export of MDM2 mRNA (PubMed:22684010). Promotes the export of additional mRNAs, including others involved in the cell cycle (By similarity). In the nucleus, binds to capped splice factor-encoding mRNAs and stimulates their nuclear export to enhance splice factor production by increasing their cytoplasmic availability to the translation machinery (By similarity). May also regulate splicing through interaction with the spliceosome in an RNA and m7G cap-dependent manner (By similarity). Also binds to some pre-mRNAs and may play a role in their recruitment to the spliceosome (By similarity). Promotes steady-state capping of a subset of coding and non-coding RNAs by mediating nuclear export of capping machinery mRNAs including RNMT, RNGTT and RAMAC to enhance their translation (By similarity). Stimulates mRNA 3'-end processing by promoting the expression of several core cleavage complex factors required for mRNA cleavage and polyadenylation, and may also have a direct effect through its interaction with the CPSF3 cleavage enzyme (By similarity). Rescues cells from apoptosis by promoting activation of serine/threonine-protein kinase AKT1 through mRNA export of NBS1 which potentiates AKT1 phosphorylation and also through mRNA export of AKT1 effectors, allowing for increased production of these proteins (By similarity).
Disease susceptibility is associated with variants affecting the gene represented in this entry. A heterozygous single-nucleotide insertion has been found in families affected by autism. The variant results in increased promoter activity and is involved in disease pathogenesis through EIF4E deregulation (PubMed:19556253).
Phosphorylation increases the ability of the protein to bind to mRNA caps and to form the eIF4F complex (PubMed:11154262, PubMed:3112145, PubMed:7590282, PubMed:7665584, PubMed:7782323, PubMed:8505316, PubMed:9878069). Phosphorylation also enhances its mRNA transport function (By similarity). Phosphorylation at Ser-209 is not essential for protein synthesis (PubMed:11606200, PubMed:12138083).
The antiviral drug ribavirin relocalizes nuclear EIF4E to the cytoplasm and reduces the elevated EIF4E levels found in acute myeloid leukemia patients, suggesting its potential use as a therapeutic agent (PubMed:19433856). Ribavirin suppresses EIF4E-mediated oncogenic transformation by binding to EIF4E at the functional site used by the m7G mRNA cap and competing with the mRNA cap for binding to EIF4E which leads to relocalization of the majority of EIF4E to the cytoplasm and inhibition of nucleocytoplasmic mRNA transport (PubMed:15601771).
Was originally thought to be phosphorylated on Ser-53 (PubMed:3112145); this was later shown to be wrong (PubMed:7665584).
eIF4F is a multi-subunit complex, the composition of which varies with external and internal environmental conditions (PubMed:11408474, PubMed:11879179, PubMed:16271312, PubMed:17631896). It is composed of at least EIF4A, EIF4E and EIF4G1/EIF4G3 (PubMed:8521827, PubMed:11408474, PubMed:29987188, PubMed:11879179, PubMed:12975586). EIF4E is also known to interact with other partners (PubMed:8521827, PubMed:11408474, PubMed:11879179, PubMed:12975586). Interacts with EIF4ENIF1/4E-T; promotes recruitment to P-bodies and import into the nucleus (PubMed:10856257, PubMed:16157702, PubMed:23991149, PubMed:24335285, PubMed:28487484). Hypophosphorylated EIF4EBP1, EIF4EBP2 and EIF4EBP3 compete with EIF4G1/EIF4G3 to interact with EIF4E; insulin stimulated MAP-kinase (MAPK1 and MAPK3) phosphorylation of EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation (PubMed:8521827, PubMed:16271312, PubMed:21661078, PubMed:24207126, PubMed:25533957, PubMed:25702871). Interacts mutually exclusive with EIF4A1 or EIF4A2 (PubMed:11408474). Interacts with NGDN and PIWIL2 (By similarity). Component of the CYFIP1-EIF4E-FMR1 complex composed of CYFIP, EIF4E and FMR1 (By similarity). Interacts directly with CYFIP1 (By similarity). Interacts with CLOCK (By similarity). Binds to MKNK2 in nucleus (PubMed:12897141). Interacts with LIMD1, WTIP and AJUBA (PubMed:20616046). Interacts with APOBEC3G in an RNA-dependent manner (PubMed:16699599). Interacts with LARP1 (PubMed:20430826). Interacts with METTL3 (PubMed:27117702). Interacts with RBM24; this interaction prevents EIF4E from binding to p53/TP53 mRNA and inhibits the assembly of translation initiation complex (PubMed:29358667). Interacts with DDX3X; interaction is direct and in an RNA-independent manner; this interaction enhances EIF4E cap-binding ability and is required for the repression of cap-dependent translation and the increase of IRES-mediated translation (PubMed:17667941, PubMed:21883093, PubMed:28733330). DDX3X competes with EIF4G1 for interaction with EIF4E (PubMed:17667941, PubMed:21883093). Interacts with EIF4G1; which in a mutual exclusive interaction associates either with EIF1 or with EIF4E on a common binding site (PubMed:29987188). Interacts with BTG4 and CNOT7 (By similarity). Interacts with LRPPRC (via N-terminus); the interaction promotes association of EIF4E with 4ESE-containing mRNAs (PubMed:19262567, PubMed:28325843). Interacts with mRNA cleavage enzyme CPSF3 and its cofactor CPSF1 (PubMed:31042468). Interacts (via RING-type zinc finger) with PML; the interaction results in conformational changes of both interacting proteins and reduces EIF4E affinity for the 5' m7G cap of mRNA, thus reducing EIF4E-mediated mRNA nuclear export (PubMed:11500381, PubMed:11575918). Interacts with homeobox protein HHEX/PRH; the interaction inhibits EIF4E-mediated mRNA nuclear export (PubMed:12554669). Interacts with homeobox protein HOXA9; the interaction positively regulates EIF4E-mediated mRNA nuclear export (By similarity). Interacts with homeobox protein EMX2 (By similarity).
Associates (via C-terminus) with F-actin (PubMed:15096633, PubMed:29058690). Interacts with SCARF1 (By similarity). Interacts with PLCE1 (PubMed:29058690). Interacts with ACTR2 and ACTR3; associates with the ARP2/3 complex (PubMed:29058690).
Ca(2+)-regulated actin-binding protein which plays an important role in actin bundling (PubMed:29058690). May have a unique function in the morphogenesis of neuronal cells which form ganglia. Required for SREC1-mediated regulation of neurite-like outgrowth. Plays a role in regenerative sensory axon outgrowth and remodeling processes after peripheral injury in neonates. Involved in the formation of long fine actin-containing filopodia-like structures in fibroblast. Plays a role in ciliogenesis. In podocytes, controls lamellipodia formation through the regulation of EGF-induced diacylglycerol generation by PLCE1 and ARP2/3 complex assembly (PubMed:29058690).
Most highly expressed in the small intestine and colonic lining. Weaker expression also detected in the thymus, prostate, testes and uterus (PubMed:12034507). Expressed in podocytes (at protein level) (PubMed:29058690).
Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase type II family.
Hydrolyzes phosphatidylinositol 4,5-bisphosphate (PtIns(4,5)P2) and the signaling molecule phosphatidylinositol 1,4,5-trisphosphate (PtIns(1,4,5)P3), and thereby modulates cellular signaling events.
Interacts with APPL1, FAM109A and FAM109B (PubMed:20133602, PubMed:21233288). Interacts with several Rab GTPases, at least RAB1A, RAB2A, RAB5A, RAB6A, RAB8A, RAB9A and RAB33B; these interactions may play a dual role in targeting INPP5B to the specific membranes and stimulating its phosphatase activity (PubMed:17956944, PubMed:26824392, Ref.12). Interacts preferentially with non-phosphorylated RAB8A; phosphorylation of RAB8A on 'Thr-72' disrupts this interaction (PubMed:26824392). Interacts with INPP5F (PubMed:25869668).
Isoprenylation at Cys-990 may be required for localization at the membrane.
May be proteolytically cleaved after Lys-320 as inferred from N-terminal protein sequence of the 75 kda form.
The ASH (ASPM-SPD2-Hydin) and RhoGAP (Rho GTPase activating) domains form a single folding module. The ASH domain has an immunoglobulin-like fold, the Rho-GAP domain lacks the catalytic arginine and is catalytically inactive. The ASH-RhoGAP module regulates the majority of the protein-protein interactions currently described. The ASH domain mediates association with membrane-targeting Rab GTPases. The Rho-GAP domain interacts with the endocytic adapter APPL1, which is then displaced by FAM109A and FAM109B as endosomes mature, all three interactions rely on F&H motifs, an approximately 12-13 amino-acid sequence centered around Phe and His residues essential for binding (By similarity).
Belongs to the peptidase M16 family. UQCRC1/QCR1 subfamily.
Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits. The complex is composed of 3 respiratory subunits cytochrome b, cytochrome c1 and Rieske protein UQCRFS1, 2 core protein subunits UQCRC1/QCR1 and UQCRC2/QCR2, and 6 low-molecular weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, UQCR10/QCR9, UQCR11/QCR10 and subunit 9, the cleavage product of Rieske protein UQCRFS1 (By similarity). The complex exists as an obligatory dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and cytochrome c oxidase (complex IV, CIV), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with UQCC6 (PubMed:32161263). Interacts with STMP1 (By similarity).
Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. The cytochrome b-c1 complex catalyzes electron transfer from ubiquinol to cytochrome c, linking this redox reaction to translocation of protons across the mitochondrial inner membrane, with protons being carried across the membrane as hydrogens on the quinol. In the process called Q cycle, 2 protons are consumed from the matrix, 4 protons are released into the intermembrane space and 2 electrons are passed to cytochrome c (By similarity). The 2 core subunits UQCRC1/QCR1 and UQCRC2/QCR2 are homologous to the 2 mitochondrial-processing peptidase (MPP) subunits beta-MPP and alpha-MPP respectively, and they seem to have preserved their MPP processing properties (By similarity). May be involved in the in situ processing of UQCRFS1 into the mature Rieske protein and its mitochondrial targeting sequence (MTS)/subunit 9 when incorporated into complex III (Probable). Seems to play an important role in the maintenance of proper mitochondrial function in nigral dopaminergic neurons (PubMed:33141179).
Expressed in brain, including substantia nigra, striatum, cortex and cerebellum, and in spinal cord, heart, kidney, liver and muscle.
Belongs to the V-ATPase D subunit family.
Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:33065002). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (By similarity). May play a role in cilium biogenesis through regulation of the transport and the localization of proteins to the cilium (PubMed:21844891).
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex (PubMed:33065002). The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H (PubMed:33065002). The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR (PubMed:33065002). Interacts with SNX10 (PubMed:21844891).
Interacts with NPHP1 and INVS/NPHP2. Interacts (when myristoylated) with UNC119 and UNC119B; interaction is required for localization to cilium. Interacts with CEP164. Component of a complex containing at least ANKS6, INVS, NEK8 and NPHP3. ANKS6 may organize complex assembly by linking INVS and NPHP3 to NEK8 and INVS may target the complex to the proximal ciliary axoneme.
Required for normal ciliary development and function. Inhibits disheveled-1-induced canonical Wnt-signaling activity and may also play a role in the control of non-canonical Wnt signaling which regulates planar cell polarity. Probably acts as a molecular switch between different Wnt signaling pathways. Required for proper convergent extension cell movements.
Widely expressed at low level. Expressed in heart, placenta, liver, skeletal muscle, kidney and pancreas. Expressed at very low level in brain and lung.
Down-regulated in keratinocytes upon UVB irradiation.
Expressed in male germ cells of adult testis (at protein level). Highly expressed in testis and ovary. Predominantly expressed in stem cells and germ cells. Expressed at lower level in brain, heart, kidney, liver, muscle, placenta, intestine and stomach Expressed in cerebellum, corpus callosum, caudate nucleus, hippocampus, medulla oblongata and putamen. Expressed in all fetal tissues tested.
Homodimer; homodimerizes in vitro. Interacts with DAZ1, DAZL and NANOS1 via its pumilio repeats. Interacts with NANOS3 (By similarity). Interacts with SNAPIN. Recruits the CCR4-POP2-NOT deadenylase leading to translational inhibition and mRNA degradation. Interacts with DDX20. In case of viral infection, interacts with DHX58 (PubMed:25340845). Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner (PubMed:23125361).
Sequence-specific RNA-binding protein that acts as a post-transcriptional repressor by binding the 3'-UTR of mRNA targets. Binds to an RNA consensus sequence, the Pumilio Response Element (PRE), 5'-UGUANAUA-3', that is related to the Nanos Response Element (NRE) (, PubMed:21397187). Mediates post-transcriptional repression of transcripts via different mechanisms: acts via direct recruitment of the CCR4-POP2-NOT deadenylase leading to translational inhibition and mRNA degradation (PubMed:22955276). Also mediates deadenylation-independent repression by promoting accessibility of miRNAs (PubMed:18776931, PubMed:22345517). Acts as a post-transcriptional repressor of E2F3 mRNAs by binding to its 3'-UTR and facilitating miRNA regulation (PubMed:22345517). Plays a role in cytoplasmic sensing of viral infection (PubMed:25340845). Represses a program of genes necessary to maintain genomic stability such as key mitotic, DNA repair and DNA replication factors. Its ability to repress those target mRNAs is regulated by the lncRNA NORAD (non-coding RNA activated by DNA damage) which, due to its high abundance and multitude of PUMILIO binding sites, is able to sequester a significant fraction of PUM1 and PUM2 in the cytoplasm (PubMed:26724866). May regulate DCUN1D3 mRNA levels (PubMed:25349211). May support proliferation and self-renewal of stem cells. Binds specifically to miRNA MIR199A precursor, with PUM1, regulates miRNA MIR199A expression at a postranscriptional level (PubMed:28431233).
The pumilio repeats mediate the association with RNA by packing together to form a right-handed superhelix that approximates a half donut. RNA-binding occurs on the concave side of the surface (PubMed:21397187). PUM2 is composed of 8 pumilio repeats of 36 residues; each repeat binds a single nucleotide in its RNA target. Residues at positions 12 and 16 of the pumilio repeat bind each RNA base via hydrogen bonding or van der Waals contacts with the Watson-Crick edge, while the amino acid at position 13 makes a stacking interaction. The recognition of RNA by pumilio repeats is base specific: cysteine and glutamine at position 12 and 16, respectively, bind adenine; asparagine and glutamine bind uracil; and serine and glutamate bind guanine.
At 17 weeks of gestation, strongly expressed in hepatic erythroblasts. At that stage, also expressed in fetal splenic plasma cells and in lymphatic vessel of fetal peritoneum. In vitro, up-regulated during the erythroid differentiation of CD34+ cells from healthy donors (at protein level).
Down-regulated by phosphatidylserines exposed on the cell surface.
Expressed in numerous tissues. In normal brain, expressed exclusively in neurons, not in astrocytes. In Alzheimer disease brains, expressed in about half of the activated astrocytes located around classical senile plaques. In Parkinson disease substantia nigra, not detected in melanin-containing neurons nor in activated astrocytes. Expressed in erythrocytes (at protein level). Expressed in myoblasts (at protein level).
Homotrimer. Interacts with PKD2. Interacts with STOML3.
PIEZO1 is responsible for the Er blood group system (ER) [MIM:620207]. At least five antigens have been identified: Er(a), Er(b), Er(3), Er(4), and Er(5). The molecular basis of the Er(a)/Er(b) polymorphism is a single variation at position 2394; Gly-2394 corresponds to Er(a) and Ser-2394 to Er(b), while the Er(3) antigen is recognized by antibodies produced by Er(a-b-) individuals. The Er(4) and Er(5) antigens are defined by Glu-2407 and Arg-2245, respectively. Alloantibodies against Er(4) and Er(5) are associated with hemolytic disease of the fetus and newborn.
Pore-forming subunit of a mechanosensitive non-specific cation channel (PubMed:23479567, PubMed:23695678). Generates currents characterized by a linear current-voltage relationship that are sensitive to ruthenium red and gadolinium. Plays a key role in epithelial cell adhesion by maintaining integrin activation through R-Ras recruitment to the ER, most probably in its activated state, and subsequent stimulation of calpain signaling (PubMed:20016066). In the kidney, may contribute to the detection of intraluminal pressure changes and to urine flow sensing. Acts as shear-stress sensor that promotes endothelial cell organization and alignment in the direction of blood flow through calpain activation (PubMed:25119035). Plays a key role in blood vessel formation and vascular structure in both development and adult physiology (By similarity). Acts as sensor of phosphatidylserine (PS) flipping at the plasma membrane and governs morphogenesis of muscle cells. In myoblasts, flippase-mediated PS enrichment at the inner leaflet of plasma membrane triggers channel activation and Ca2+ influx followed by Rho GTPases signal transduction, leading to assembly of cortical actomyosin fibers and myotube formation.
The disease is caused by variants affecting the gene represented in this entry. All disease-causing mutations characterized so far produce a gain-of-function phenotype, mutated channels exhibiting increased cation transport in erythroid cells, that could be due to slower channel inactivation rate compared to the wild-type protein.
Distinct domains of TAF5/TAFII100 are required for functional interaction with transcription factor TFIIFB (RAP30) and incorporation into the TFIID complex.
Homodimer (PubMed:17227857). Component of the TFIID basal transcription factor complex, composed of TATA-box-binding protein TBP, and a number of TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:10373431, PubMed:33795473). The TFIID complex structure can be divided into 3 modules TFIID-A, TFIID-B, and TFIID-C (PubMed:33795473). TAF5 forms the TFIID-A module together with TAF3 and TBP, and in TFIID-B with TAF8 (PubMed:33795473). Component of the TFTC-HAT complex, at least composed of TAF5L, TAF6L, TADA3L, SUPT3H/SPT3, TAF2, TAF4, TAF5, GCN5L2/GCN5, TAF10 and TRRAP (PubMed:10373431, PubMed:12601814, PubMed:17227857). TBP is not part of the TFTC-HAT complex (PubMed:10373431, PubMed:12601814). Interacts strongly with the histone H4-related TAF6 and the histone H3-related TAF9, as well as a stable complex comprised of both TAF6 and TAF9 (PubMed:9045704). Apparently weaker interactions with TBP, TAF1, TAF11, and TAF12, but not TAF7, also have been observed (PubMed:8758937, PubMed:9045704).
The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription (PubMed:33795473). TFIID recognizes and binds promoters with or without a TATA box via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC) (PubMed:33795473). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473, PubMed:8758937, PubMed:8942982, PubMed:9045704). The TFIID complex structure can be divided into 3 modules TFIID-A, TFIID-B, and TFIID-C (PubMed:33795473). TAF5 is involved in two modules of TFIID, in TFIID-A together with TAF3 and TBP, and in TFIID-B with TAF8 (PubMed:33795473). Involved in contacts between TFIID and TFIIF in the PIC (PubMed:33795473).
Forms a tight complex with SCAP, the SCAP-SREBP complex, in the endoplasmic reticulum membrane (PubMed:19706601, PubMed:32322062). Interacts (via C-terminal domain) with RNF139 (PubMed:19706601).
Homodimer; efficient DNA binding of the soluble transcription factor fragment requires dimerization with another bHLH protein (By similarity). Interacts with LMNA (By similarity).
Key transcription factor that regulates expression of genes involved in cholesterol biosynthesis (PubMed:12177166, PubMed:32322062). Binds to the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3'). Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3') (PubMed:7903453, PubMed:12177166). Regulates transcription of genes related to cholesterol synthesis pathway (PubMed:12177166, PubMed:32322062).
Phosphorylated by AMPK, leading to suppress protein processing and nuclear translocation, and repress target gene expression.
Precursor of the transcription factor form (Processed sterol regulatory element-binding protein 2), which is embedded in the endoplasmic reticulum membrane (PubMed:32322062). Low sterol concentrations promote processing of this form, releasing the transcription factor form that translocates into the nucleus and activates transcription of genes involved in cholesterol biosynthesis (PubMed:32322062).
Processed in the Golgi apparatus, releasing the protein from the membrane (PubMed:8626610, PubMed:32322062, PubMed:9651382, PubMed:10805775). At low cholesterol the SCAP-SREBP complex is recruited into COPII vesicles for export from the endoplasmic reticulum (PubMed:8626610, PubMed:32322062, PubMed:9651382, PubMed:10805775). In the Golgi, complex SREBPs are cleaved sequentially by site-1 (MBTPS1, S1P) and site-2 (MBTPS2, S2P) protease (PubMed:8626610, PubMed:9651382, PubMed:10805775, PubMed:32322062). The first cleavage by site-1 protease occurs within the luminal loop, the second cleavage by site-2 protease occurs within the first transmembrane domain, releasing the transcription factor from the Golgi membrane (PubMed:9651382, PubMed:10805775). Apoptosis triggers cleavage by the cysteine proteases caspase-3 and caspase-7. Cleavage and activation is induced by mediated cholesterol efflux (PubMed:8643593).
Ubiquitously expressed in adult and fetal tissues.
Adapter protein that interacts with EDAR DEATH domain and couples the receptor to EDA signaling pathway during morphogenesis of ectodermal organs. Mediates the activation of NF-kappa-B.
Detected in adult pancreas, placenta and fetal skin, and at lower levels in lung, thymus, prostate and testis.
Self-associates and binds EDAR, TRAF1, TRAF2 and TRAF3.
A chromosomal aberration involving BIRC3 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(11;18)(q21;q21) with MALT1. This translocation is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphoma.
Auto-ubiquitinated and degraded by the proteasome in apoptotic cells.
Highly expressed in fetal lung, and kidney. In the adult, expression is mainly seen in lymphoid tissues, including spleen, thymus and peripheral blood lymphocytes.
Interacts with PRSS25; interaction inhibits apoptotic suppressor activity. The BIR motifs region interacts with TNF receptor associated factors 1 and 2 (TRAF1 and TRAF2) to form a heteromeric complex, which is then recruited to the tumor necrosis factor receptor 2 (TNFR2). Interaction with TRAF2 is required for ubiquitination of IKBKE, degradation of NFKBIA and activation of NF-kappa-B. Interacts with RIP1, RIP2, RIP3, RIP4 and USP19.
Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, mitogenic kinase signaling and cell proliferation, as well as cell invasion and metastasis. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and regulates both canonical and non-canonical NF-kappa-B signaling by acting in opposite directions: acts as a positive regulator of the canonical pathway and suppresses constitutive activation of non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, IKBKE, TRAF1, and BCL10. Acts as an important regulator of innate immune signaling via regulation of Toll-like receptors (TLRs), Nodlike receptors (NLRs) and RIG-I like receptors (RLRs), collectively referred to as pattern recognition receptors (PRRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8.
USP19 regulates the stability of BIRC3/c-IAP2 by preventing its ubiquitination.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of the N-acetylgalactosamine (GalNAc) residue of chondroitin (PubMed:9714738, PubMed:9883891, PubMed:15215498). Chondroitin sulfate constitutes the predominant proteoglycan present in cartilage and is distributed on the surfaces of many cells and extracellular matrices (PubMed:9714738). Catalyzes with a lower efficiency the sulfation of Gal residues of keratan sulfate, another glycosaminoglycan (PubMed:9714738). Can also catalyze the sulfation of the Gal residues in sialyl N-acetyllactosamine (sialyl LacNAc) oligosaccharides (By similarity). May play a role in the maintenance of naive T-lymphocytes in the spleen (By similarity).
Widely expressed in adult tissues. Expressed in heart, placenta, skeletal muscle and pancreas. Also expressed in various immune tissues such as spleen, lymph node, thymus and appendix.
Interacts with NKX2-5 (By similarity). Isoform 1 and isoform 3 interact with FERMT2, FLNA, FLNB and FLNC. Isoform 2 interacts with FLNB.
Isoform 1 and isoform 3 are expressed in heart, kidney, lung, pancreas, placenta and platelets. Isoform 2 is expressed in brain, heart, kidney, lung, pancreas, placenta, skeletal muscle and platelets.
Serves as an anchoring site for cell-ECM adhesion proteins and filamin-containing actin filaments. Is implicated in cell shape modulation (spreading) and motility. May participate in the regulation of filamin-mediated cross-linking and stabilization of actin filaments. May also regulate the assembly of filamin-containing signaling complexes that control actin assembly. Promotes dissociation of FLNA from ITGB3 and ITGB7. Promotes activation of integrins and regulates integrin-mediated cell-cell adhesion.
The N-terminal region is intrinsically disordered.
Component of the IFT complex B, at least composed of IFT20, IFT22, IFT25, IFT27, IFT46, IFT52, TRAF3IP1/IFT54, IFT57, IFT74, IFT80, IFT81, and IFT88. Interacts with IFT88 (By similarity).
Small GTPase-like component of the intraflagellar transport (IFT) complex B.
In some cases of acute leukemia, a translocation results in the formation of a KMT2A/MLL1-EEN fusion gene.
Interacts with ARC (By similarity). Interacts with SYNJ1 and DNM1. Interacts with PDCD6IP. Interacts with BIN2.
Ubiquitous. Higher expression in pancreas, placenta, prostate, testis and uterus.
DNA helicase that acts as a tension sensor that associates with catenated DNA which is stretched under tension until it is resolved during anaphase (PubMed:17218258, PubMed:23973328). Functions as ATP-dependent DNA translocase (PubMed:23973328, PubMed:28977671). Can promote Holliday junction branch migration (in vitro) (PubMed:23973328).
Interacts with PLK1, which phosphorylates it (PubMed:17218258, PubMed:17671160, PubMed:28977671). Both proteins are mutually dependent on each other for correct subcellular localization (PubMed:17218258, PubMed:17671160). Interacts (via N-terminal TPR repeat) with BEND3 (via BEN domains 1 and 3); the interaction is direct (PubMed:28977671).
Phosphorylation by PLK1 prevents the association with chromosome arms and restricts its localization to the kinetochore-centromere region.
Was initially thought to play a role in the spindle checkpoint. However, it was later shown that phenotypes initially observed are due to off-target effects of the siRNA used which results in MAD2L1 down-regulation and mis-localization.
(Microbial infection) Acts as coreceptor with CD4 for HIV-1 virus envelope protein (PubMed:14607932). May have more potent HIV-1 coreceptor activity than isoform 1 (PubMed:14607932).
(Microbial infection) Acts as coreceptor with CD4 for HIV-1 virus envelope protein (PubMed:14607932). May have more potent HIV-1 coreceptothr activity than isoform 1 (PubMed:14607932).
(Microbial infection) Acts as coreceptor with CD4 for HIV-1 virus envelope protein.
(Microbial infection) Interacts with HIV-1 envelope polyprotein gp160.
(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein G; this interaction modulates host immune response.
Expressed in lymphoid and neural tissues (PubMed:7590284). Expressed in lymphocyte subsets, such as natural killer (NK) cells, gamma-delta T-cells and terminally differentiated CD8(+) T-cells (PubMed:12055230). Expressed in smooth muscle cells in atherosclerotic plaques (PubMed:14581400).
Expression is down-regulated by miR-27a-5p microRNA in natural killer (NK) cell lymphocytes in response to TGF-beta1.
Found in a ternary complex with CX3CL1 and ITGAV:ITGB3 or ITGA4:ITGB1.
Receptor for the C-X3-C chemokine fractalkine (CX3CL1) present on many early leukocyte cells; CX3CR1-CX3CL1 signaling exerts distinct functions in different tissue compartments, such as immune response, inflammation, cell adhesion and chemotaxis (PubMed:9390561, PubMed:9782118, PubMed:12055230, PubMed:23125415). CX3CR1-CX3CL1 signaling mediates cell migratory functions (By similarity). Responsible for the recruitment of natural killer (NK) cells to inflamed tissues (By similarity). Acts as a regulator of inflammation process leading to atherogenesis by mediating macrophage and monocyte recruitment to inflamed atherosclerotic plaques, promoting cell survival (By similarity). Involved in airway inflammation by promoting interleukin 2-producing T helper (Th2) cell survival in inflamed lung (By similarity). Involved in the migration of circulating monocytes to non-inflamed tissues, where they differentiate into macrophages and dendritic cells (By similarity). Acts as a negative regulator of angiogenesis, probably by promoting macrophage chemotaxis (PubMed:14581400, PubMed:18971423). Plays a key role in brain microglia by regulating inflammatory response in the central nervous system (CNS) and regulating synapse maturation (By similarity). Required to restrain the microglial inflammatory response in the CNS and the resulting parenchymal damage in response to pathological stimuli (By similarity). Involved in brain development by participating in synaptic pruning, a natural process during which brain microglia eliminates extra synapses during postnatal development (By similarity). Synaptic pruning by microglia is required to promote the maturation of circuit connectivity during brain development (By similarity). Acts as an important regulator of the gut microbiota by controlling immunity to intestinal bacteria and fungi (By similarity). Expressed in lamina propria dendritic cells in the small intestine, which form transepithelial dendrites capable of taking up bacteria in order to provide defense against pathogenic bacteria (By similarity). Required to initiate innate and adaptive immune responses against dissemination of commensal fungi (mycobiota) component of the gut: expressed in mononuclear phagocytes (MNPs) and acts by promoting induction of antifungal IgG antibodies response to confer protection against disseminated C.albicans or C.auris infection (PubMed:29326275). Also acts as a receptor for C-C motif chemokine CCL26, inducing cell chemotaxis (PubMed:20974991).
This protein is not N-glycosylated which is unusual for G-protein-coupled receptors.
Variations in CX3CR1 are associated with rapid progression to AIDS [MIM:609423]. Increased susceptibility to HIV infection and rapid progression to AIDS are associated with the Ile-249/Met-280 haplotype.
Required for neurogenesis in the neural plate and retina. Strongly cooperates with neural bHLH factors to promote neurogenesis.
Interacts with SNCA; this interaction promotes the aggregation of SNCA.
Isoform Long is predominantly expressed in heart, brain and skeletal muscle. Isoform Short and Isoform Long are expressed throughout the central nervous system, including spinal cord.
Positive regulator of amyloid protein aggregation and proteotoxicity (PubMed:20723760, PubMed:22854022, PubMed:31034892). Induces conformational changes in amyloid proteins, such as APP, HTT, and SNCA, driving them into compact formations preceding the formation of aggregates (PubMed:20723760, PubMed:22854022, PubMed:31034892).
Retinol dehydrogenase with a clear preference for NADP. Displays high activity towards 9-cis, 11-cis and all-trans-retinol. Shows a very weak activity towards 13-cis-retinol. Has no activity towards steroid.
Shows clear specificity for the pro-S hydrogen on C4 of NADPH and the pro-R hydrogen on C15 of retinols.
Belongs to the eukaryotic ribosomal protein eL42 family.
Expressed in testis, spermatocytes and spermatids (at protein level). Expressed in spermatocytes, spermatids, prostate, skeletal muscle, ovary, small intestine, heart, brain and pancreas.
Interacts with the ELOC-ELOB/Elongin BC complex. Part of an E3 ubiquitin ligase complex including ZER1, CUL2 and Elongin BC.
Serves as substrate adapter subunit in the E3 ubiquitin ligase complex ZYG11B-CUL2-Elongin BC (PubMed:17304241, PubMed:31273098). Acts to target substrates bearing N-terminal degrons for proteasomal degradation with the first four residues of substrates being the key recognition elements (PubMed:33093214, PubMed:34214466, PubMed:36496439). Involved in the clearance of proteolytic fragments generated by caspase cleavage during apoptosis since N-terminal glycine degrons are strongly enriched at caspase cleavage sites. Also important in the quality control of protein N-myristoylation in which N-terminal glycine degrons are conditionally exposed after a failure of N-myristoylation (PubMed:31273098).
Associated with nonmuscle myosin II heavy chain. Interacts with PRKCI/aPKC, PARD6B/Par-6 and PARD6A. Interacts with STX4A (By similarity). Interacts with RAB10 (GDP-bound form); the interaction is direct and promotes RAB10 association with membranes and activation through competition with the Rab inhibitor GDI1 (By similarity). Interacts with DCAF1.
Cortical cytoskeleton protein found in a complex involved in maintaining cell polarity and epithelial integrity. Involved in the regulation of mitotic spindle orientation, proliferation, differentiation and tissue organization of neuroepithelial cells. Involved in axonogenesis through RAB10 activation thereby regulating vesicular membrane trafficking toward the axonal plasma membrane.
Down-regulation of LLGL1 is associated with the progression of colorectal cancer and melanoma. Located within the Smith-Magenis syndrome region on chromosome 17; deleted in patients with this syndrome.
Expressed in brain, kidney, and muscle but is barely seen in heart and placenta. Down-regulated or lost in all cell lines and in most of the tumor samples analyzed. Loss was associated with advanced stage of the disease.
Expression increases cell adhesion and decreases cell migration. Substitutes for Drosophila l(2)gl tumor suppressor function in vivo.
Phosphorylated at least at Ser-663 by PRKCI.
Component of the BRF-1 ISWI chromatin remodeling complex, at least composed of SMARCA1 and BAZ2B, which regulates the spacing of histone octamers on the DNA template to facilitate access to DNA (PubMed:28801535). Within the BRF-1 ISWI chromatin remodeling complex interacts with SMARCA1; the interaction is direct (PubMed:28801535). Component of the BRF-5 ISWI chromatin remodeling complex, at least composed of SMARCA5/SNF2H and BAZ2B, which regulates the spacing of histone octamers on the DNA template to facilitate access to DNA (PubMed:28801535). Within the BRF-5 ISWI chromatin remodeling complex interacts with SMARCA5/SNF2H; the interaction is direct (PubMed:28801535). Interacts with acetylated lysine residues on histone H1.4, H2A, H2B, H3 and H4 (in vitro). Interacts with EHMT1 (By similarity).
Expressed at varying levels in several tissues, whereas a smaller transcript was expressed specifically in testis.
Regulatory subunit of the ATP-dependent BRF-1 and BRF-5 ISWI chromatin remodeling complexes, which form ordered nucleosome arrays on chromatin and facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair (PubMed:28801535). Both complexes regulate the spacing of nucleosomes along the chromatin and have the ability to slide mononucleosomes to the center of a DNA template (PubMed:28801535). The BRF-1 ISWI chromatin remodeling complex has a lower ATP hydrolysis rate than the BRF-5 ISWI chromatin remodeling complex (PubMed:28801535). Chromatin reader protein, which may play a role in transcriptional regulation via interaction with ISWI (By similarity) (PubMed:10662543). Involved in positively modulating the rate of age-related behavioral deterioration (By similarity). Represses the expression of mitochondrial function-related genes, perhaps by occupying their promoter regions, working in concert with histone methyltransferase EHMT1 (By similarity).
Expressed in the cerebellum (at protein level).
Has a dual branch-promoting and guidance activity, which may play an important role in the patterning of mitral and tufted cell collaterals to the olfactory cortex (By similarity). Chemoattractant for fetal olfactory epithelial cells.
Interacts with FGFR1; this interaction does not interfere with FGF2-binding to FGFR1. Binds heparin. Heparin may promote or interfere with ANOS1-FGFR1-FGF2 complex formation depending on the sequential order of its binding to the various constituents. For instance, heparin-ANOS1 interaction favors subsequent binding to pre-existing binary FGFR1-FGF2 complex, while heparin-FGF2 complex does not interact with ANOS1-FGFR1.
May be proteolytically cleaved at the cell surface and released from the cell surface.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in ANOS1 as well as in other HH-associated genes including FGFR1 and TACR3 (PubMed:23643382).
Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane. The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis. In the complex, plays a central role in bridging PI4KA to EFR3B and HYCC1, via direct interactions (PubMed:26571211).
Component of a phosphatidylinositol 4-kinase (PI4K) complex, composed of PI4KA, EFR3 (EFR3A or EFR3B), TTC7 (TTC7A or TTC7B) and HYCC (HYCC1 or HYCC2) (PubMed:23229899). Interacts with PI4KA, interaction is direct (PubMed:26571211). Interacts with EFR3 (EFR3A or EFR3B), interaction is direct (PubMed:26571211). Interacts with HYCC (HYCC1 or HYCC2), interaction is direct (PubMed:26571211). Association with the PI4K complex is strongly reduced by TMEM150A (PubMed:25608530).
Binds DNA and may function as a transcriptional repressor.
Interacts with ABCB1, ABCB4 and ABCB11 (By similarity). Directly associates with HCLS1/HS1, through binding to its N-terminal region (PubMed:9058808). Interacts with CTTN (By similarity). Interacts with PKD2 (PubMed:10760273). Interacts with GNA13 (PubMed:15339924). Interacts with CASP9 (PubMed:16857965). Interacts with ITGB6 (PubMed:17545607). Interacts with PLN and ATP2A2; these interactions are inhibited by calcium (PubMed:17241641, PubMed:18971376). Interacts with GRB7 (PubMed:20665473). Interacts (via C-terminus) with XIAP/BIRC4 (via BIR 2 domain and BIR 3 domain) and this interaction blocks ubiquitination of XIAP/BIRC4 (PubMed:20171186). Interacts with TPC2 (PubMed:24188827). Interacts with KCNC3 (PubMed:26997484). Interacts with XPO1 (PubMed:23164465). Interacts with RNF217 (PubMed:25298122). Interacts with UCP3; the interaction is direct and calcium-dependent (PubMed:26915802).
Proteolytically cleaved by caspase-3 during apoptosis.
Recruits the Arp2/3 complex to the cell cortex and regulates reorganization of the cortical actin cytoskeleton via its interaction with KCNC3 and the Arp2/3 complex (PubMed:26997484). Slows down the rate of inactivation of KCNC3 channels (PubMed:26997484). Promotes GNA13-mediated cell migration. Involved in the clathrin-mediated endocytosis pathway. May be involved in internalization of ABC transporters such as ABCB11. May inhibit CASP9 and CASP3. Promotes cell survival. May regulate intracellular calcium pools.
The disease is caused by variants affecting the gene represented in this entry. The clinical phenotype due to HAX1 deficiency appears to depend on the localization of the mutations and their influence on the transcript variants. Mutations affecting exclusively isoform 1 are associated with isolated congenital neutropenia, whereas mutations affecting both isoform 1 and isoform 5 are associated with additional neurologic symptoms (PubMed:18337561).
Ubiquitous. Up-regulated in oral cancers.
Disease susceptibility is associated with variants affecting the gene represented in this entry. RABL3 variants have been found in families with a history of pancreatic ductal adenocarcinoma and multiple other occurrences of cancer, including melanoma, breast cancer, prostate cancer, and colon cancer.
Homodimer (By similarity). Interacts with GPR89; the interaction stabilizes GPR89 (By similarity). Interacts with RAP1GDS1 (PubMed:31406347).
Required for KRAS signaling regulation and modulation of cell proliferation (PubMed:31406347). Regulator of KRAS prenylation, and probably prenylation of other small GTPases (PubMed:31406347). Required for lymphocyte development and function (By similarity). Not required for myeloid cell development (By similarity).
Interacts with SYCP2. Interacts with PBXIP1; may prevent interaction between PBXIP1 and ESR2 (By similarity). Interacts with SHOC1 (PubMed:29742103).
Regulator of crossing-over during meiosis. Involved in initiation and/or maintenance of chromosome synapsis and formation of crossovers.
Testis-specific. Not expressed in adult ovaries.
DNA-binding helicase that specifically binds to the promoter of target genes, leading to chromatin remodeling, possibly by promoting deposition of histone H3.3. Involved in myogenesis via interaction with MYOD1: binds to myogenic gene regulatory sequences and mediates incorporation of histone H3.3 prior to the onset of myogenic gene expression, promoting their expression (By similarity).
Interacts with MYOD1. Interacts with histone H3.3 (By similarity).
The CHD1 helical C-terminal domain (CHCT) may bind DNA and nucleosomes.
A soluble form (sCD163) is produced by proteolytic shedding which can be induced by lipopolysaccharide, phorbol ester and Fc region of immunoglobulin gamma. This cleavage is dependent on protein kinase C and tyrosine kinases and can be blocked by protease inhibitors. The shedding is inhibited by the tissue inhibitor of metalloproteinase TIMP3, and thus probably induced by membrane-bound metalloproteinases ADAMs.
Acute phase-regulated receptor involved in clearance and endocytosis of hemoglobin/haptoglobin complexes by macrophages and may thereby protect tissues from free hemoglobin-mediated oxidative damage. May play a role in the uptake and recycling of iron, via endocytosis of hemoglobin/haptoglobin and subsequent breakdown of heme. Binds hemoglobin/haptoglobin complexes in a calcium-dependent and pH-dependent manner. Exhibits a higher affinity for complexes of hemoglobin and multimeric haptoglobin of HP*1F phenotype than for complexes of hemoglobin and dimeric haptoglobin of HP*1S phenotype. Induces a cascade of intracellular signals that involves tyrosine kinase-dependent calcium mobilization, inositol triphosphate production and secretion of IL6 and CSF1. Isoform 3 exhibits the higher capacity for ligand endocytosis and the more pronounced surface expression when expressed in cells.
After shedding, the soluble form (sCD163) may play an anti-inflammatory role, and may be a valuable diagnostic parameter for monitoring macrophage activation in inflammatory conditions.
Expressed in monocytes and mature macrophages such as Kupffer cells in the liver, red pulp macrophages in the spleen, cortical macrophages in the thymus, resident bone marrow macrophages and meningeal macrophages of the central nervous system. Expressed also in blood. Isoform 1 is the lowest abundant in the blood. Isoform 2 is the lowest abundant in the liver and the spleen. Isoform 3 is the predominant isoform detected in the blood.
Induced by anti-inflammatory mediators such as glucocorticoids, interleukin-6/IL6 and interleukin-10/IL10; suppressed by pro-inflammatory mediators like bacterial lipopolysaccharides (LPS), IFNG/IFN-gamma and TNF.
Intravenous lipopolysaccharide (LPS) produces a rapid rise of sCD163 in plasma of patient as it induces metalloproteinase-mediated shedding from monocytes surface. Long-term LPS infusion finally increases expression of the membrane-bound form on circulating monocytes.
The SRCR domain 3 mediates calcium-sensitive interaction with hemoglobin/haptoglobin complexes.
The soluble form (sCD163) in plasma is a novel parameter in diseases affecting macrophage function and monocyte/macrophage load in the body. The concentration of sCD163 is probably reflecting the number of macrophages of the 'alternative macrophage activation' phenotype with a high CD163 expression playing a major role in dampening the inflammatory response and scavenging components of damaged cells. This has initiated a number of clinical studies for evaluation of sCD163 as a disease marker in inflammatory conditions e.g. infection, autoimmune disease, transplantation, atherosclerosis and cancer.
Able to phosphorylate several exogenous substrates and to undergo autophosphorylation. Negatively regulates cilium length in a cAMP and mTORC1 signaling-dependent manner.
Expressed in heart, brain, lung, kidney, and pancreas, and at very low levels in placenta, liver and skeletal muscle. Detected in retina.
Phosphorylation appears to increase the enzymatic activity.
Binds phosphatidylinositol 3-phosphate (PtdIns-(3)P) and phosphatidylinositol 3,5-bisphosphate (PtdIns-(3,5)P2) in liposome-based assays. Can bind PtdIns(3,4,5)P3 in protein:lipid overlay assays, but not in liposome-based assays.
Involved in several stages of intracellular trafficking. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) or phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) (PubMed:12198132). Acts in part as component of the retromer membrane-deforming SNX-BAR subcomplex. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX-BAR subcomplex functions to deform the donor membrane into a tubular profile called endosome-to-TGN transport carrier (ETC) (Probable). Can sense membrane curvature and has in vitro vesicle-to-membrane remodeling activity (PubMed:19816406, PubMed:23085988). Involved in retrograde endosome-to-TGN transport of lysosomal enzyme receptors (IGF2R, M6PR and SORT1) and Shiginella dysenteria toxin stxB. Plays a role in targeting ligand-activated EGFR to the lysosomes for degradation after endocytosis from the cell surface and release from the Golgi (PubMed:12198132, PubMed:15498486, PubMed:17550970, PubMed:17101778, PubMed:18088323, PubMed:21040701). Involvement in retromer-independent endocytic trafficking of P2RY1 and lysosomal degradation of protease-activated receptor-1/F2R (PubMed:16407403, PubMed:20070609). Promotes KALRN- and RHOG-dependent but retromer-independent membrane remodeling such as lamellipodium formation; the function is dependent on GEF activity of KALRN (PubMed:20604901). Required for endocytosis of DRD5 upon agonist stimulation but not for basal receptor trafficking (PubMed:23152498).
Predominantly forms heterodimers with BAR domain-containing sorting nexins SNX5, SNX6 and SNX32; can self-associate to form homodimers (PubMed:23085988). The heterodimers are proposed to self-assemble into helical arrays on the membrane to stabilize and expand local membrane curvature underlying endosomal tubule formation. Thought to be a component of the originally described retromer complex (also called SNX-BAR retromer) which is a pentamer containing the heterotrimeric retromer cargo-selective complex (CSC), also described as vacuolar protein sorting subcomplex (VPS) and a heterodimeric membrane-deforming subcomplex formed between SNX1 or SNX2 and SNX5 or SNX6 (also called SNX-BAR subcomplex); the respective CSC and SNX-BAR subcomplexes associate with low affinity (Probable). Interacts with SNX5, SNX6, SNX32, VPS26A, VPS29, VPS35, DRD5, DENND5A, KALRN, RHOG (GDP-bound form) (PubMed:9819414, PubMed:11102511, PubMed:19619496, PubMed:19935774, PubMed:19619496, PubMed:20604901, PubMed:23085988, PubMed:23152498). The interaction with SNX2 is reported controversially (PubMed:9819414, PubMed:11997453, PubMed:19619496, PubMed:23085988). Interacts with DNAJC13; prevented by presence of HGS (PubMed:19874558). Interacts with HGS (By similarity).
The BAR domain is able to sense membrane curvature upon dimerization (PubMed:19816406). Membrane remodeling seems to implicate insertion of a N-terminal amphipathic helix (AH) in the membrane (Probable).
In addition to its expression in the developing eyelid, it is transcribed very early in somatic cells of the developing gonad (before sex determination) and its expression persists in the follicular cells of the adult ovary.
In granulosa-like cells, up-regulated at transcript and protein levels under oxidative stress and heat-shock conditions. Down-regulated by SIRT1.
Interacts with ESR1 (By similarity). Interacts with SMAD3 (By similarity). Interacts with DDX20. Interacts with UBE2I/UBC9.
Sumoylated with SUMO1; sumoylation is required for transcriptional repression activity.
The disease is caused by variants affecting the gene represented in this entry. There is a mutational hotspot in the region coding for the poly-Ala domain, since 30% of all mutations in the ORF lead to poly-Ala expansions, resulting mainly in BPES type II.
Transcriptional regulator. Critical factor essential for ovary differentiation and maintenance, and repression of the genetic program for somatic testis determination. Prevents trans-differentiation of ovary to testis through transcriptional repression of the Sertoli cell-promoting gene SOX9 (By similarity). Has apoptotic activity in ovarian cells. Suppresses ESR1-mediated transcription of PTGS2/COX2 stimulated by tamoxifen (By similarity). Is a regulator of CYP19 expression (By similarity). Participates in SMAD3-dependent transcription of FST via the intronic SMAD-binding element (By similarity). Is a transcriptional repressor of STAR. Activates SIRT1 transcription under cellular stress conditions. Activates transcription of OSR2.
(Microbial infection) Glycosylated at Arg-18 by enteropathogenic E.coli protein NleB1: arginine GlcNAcylation enhances transcription factor activity and impairs glucose metabolism.
(Microbial infection) In monocytes, human coronavirus SARS-CoV-2 increases HIF1A levels and activity which promotes a pro-inflammatory state.
(Microbial infection) Upon infection by human coronavirus SARS-CoV-2, is required for induction of glycolysis in monocytes and the consequent pro-inflammatory state (PubMed:32697943). In monocytes, induces expression of ACE2 and cytokines such as IL1B, TNF, IL6, and interferons (PubMed:32697943). Promotes human coronavirus SARS-CoV-2 replication and monocyte inflammatory response (PubMed:32697943).
Acetylation of Lys-532 by ARD1 increases interaction with VHL and stimulates subsequent proteasomal degradation (PubMed:12464182). Deacetylation of Lys-709 by SIRT2 increases its interaction with and hydroxylation by EGLN1 thereby inactivating HIF1A activity by inducing its proteasomal degradation (PubMed:24681946).
Contains two independent C-terminal transactivation domains, NTAD and CTAD, which function synergistically. Their transcriptional activity is repressed by an intervening inhibitory domain (ID).
Expressed in most tissues with highest levels in kidney and heart. Overexpressed in the majority of common human cancers and their metastases, due to the presence of intratumoral hypoxia and as a result of mutations in genes encoding oncoproteins and tumor suppressors. A higher level expression seen in pituitary tumors as compared to the pituitary gland.
Functions as a master transcriptional regulator of the adaptive response to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:18658046, PubMed:20624928, PubMed:22009797, PubMed:9887100, PubMed:30125331). Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:20624928, PubMed:22009797, PubMed:9887100, PubMed:30125331). Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease (PubMed:22009797). Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300 (PubMed:9887100, PubMed:16543236). Activity is enhanced by interaction with NCOA1 and/or NCOA2 (PubMed:10594042). Interaction with redox regulatory protein APEX1 seems to activate CTAD and potentiates activation by NCOA1 and CREBBP (PubMed:10202154, PubMed:10594042). Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia (PubMed:19528298).
In normoxia, is hydroxylated on Pro-402 and Pro-564 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1 (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). EGLN3/PHD3 has also been shown to hydroxylate Pro-564 (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). Deubiquitinated by USP20 (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). In normoxia, is hydroxylated on Asn-803 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation (PubMed:12080085). This hydroxylation is inhibited by the Cu/Zn-chelator, Clioquinol (PubMed:12080085). Repressed by iron ion, via Fe(2+) prolyl hydroxylase (PHD) enzymes-mediated hydroxylation and subsequent proteasomal degradation (PubMed:28296633).
Induced by reactive oxygen species (ROS).
Interacts with the ARNT; forms a heterodimer that binds core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (PubMed:10944113, PubMed:20699359). Interacts with COPS5; the interaction increases the transcriptional activity of HIF1A through increased stability (By similarity). Interacts with EP300 (via TAZ-type 1 domains); the interaction is stimulated in response to hypoxia and inhibited by CITED2 (PubMed:8917528, PubMed:9887100, PubMed:12778114, PubMed:16543236, PubMed:16973622, PubMed:11959990). Interacts with CREBBP (via TAZ-type 1 domains) (PubMed:8917528, PubMed:11959977). Interacts with NCOA1, NCOA2, APEX1 and HSP90 (PubMed:10594042, PubMed:10202154). Interacts (hydroxylated within the ODD domain) with VHLL (via beta domain); the interaction, leads to polyubiquitination and subsequent HIF1A proteasomal degradation (PubMed:14757845). During hypoxia, sumoylated HIF1A also binds VHL; the interaction promotes the ubiquitination of HIF1A (PubMed:11006129, PubMed:10944113, PubMed:16862177, PubMed:12004076, PubMed:12050673). Interacts with SENP1; the interaction desumoylates HIF1A resulting in stabilization and activation of transcription (By similarity). Interacts (via the ODD domain) with NAA10; the interaction appears not to acetylate HIF1A nor have any affect on protein stability, during hypoxia (PubMed:12464182, PubMed:16288748). Interacts with RWDD3; the interaction enhances HIF1A sumoylation (PubMed:17956732, PubMed:23469069). Interacts with TSGA10 (By similarity). Interacts with HIF3A (By similarity). Interacts with RORA (via the DNA binding domain); the interaction enhances HIF1A transcription under hypoxia through increasing protein stability (PubMed:18658046). Interaction with PSMA7 inhibits the transactivation activity of HIF1A under both normoxic and hypoxia-mimicking conditions (PubMed:11389899). Interacts with USP20 (PubMed:15776016). Interacts with RACK1; promotes HIF1A ubiquitination and proteasome-mediated degradation (PubMed:17244529). Interacts (via N-terminus) with USP19 (PubMed:22128162). Interacts with SIRT2 (PubMed:24681946). Interacts (deacetylated form) with EGLN1 (PubMed:24681946). Interacts with CBFA2T3 (PubMed:25974097). Interacts with HSP90AA1 and HSP90AB1 (PubMed:26517842). Interacts with DCUN1D1; this interaction increases the interaction between VHL and DCUN1D1 (PubMed:23401859). Interacts with HIF1AN (PubMed:12446723).
Polyubiquitinated; in normoxia, following hydroxylation and interaction with VHL. Lys-532 appears to be the principal site of ubiquitination. Clioquinol, the Cu/Zn-chelator, inhibits ubiquitination through preventing hydroxylation at Asn-803. Ubiquitinated by E3 ligase VHL (PubMed:25615526). Deubiquitinated by UCHL1 (PubMed:25615526).
Requires phosphorylation for DNA-binding. Phosphorylation at Ser-247 by CSNK1D/CK1 represses kinase activity and impairs ARNT binding (PubMed:20699359, PubMed:20889502). Phosphorylation by GSK3-beta and PLK3 promote degradation by the proteasome (By similarity).
S-nitrosylation of Cys-800 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex.
Sumoylated; with SUMO1 under hypoxia (PubMed:15465032, PubMed:15776016, PubMed:17610843). Sumoylation is enhanced through interaction with RWDD3 (PubMed:17956732). Both sumoylation and desumoylation seem to be involved in the regulation of its stability during hypoxia (PubMed:15465032, PubMed:15776016, PubMed:17610843). Sumoylation can promote either its stabilization or its VHL-dependent degradation by promoting hydroxyproline-independent HIF1A-VHL complex binding, thus leading to HIF1A ubiquitination and proteasomal degradation (PubMed:15465032, PubMed:15776016, PubMed:17610843). Desumoylation by SENP1 increases its stability amd transcriptional activity (By similarity). There is a disaccord between various publications on the effect of sumoylation and desumoylation on its stability and transcriptional activity (Probable).
The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.
Under reduced oxygen tension. Induced also by various receptor-mediated factors such as growth factors, cytokines, and circulatory factors such as PDGF, EGF, FGF2, IGF2, TGFB1, HGF, TNF, IL1B/interleukin-1 beta, angiotensin-2 and thrombin. However, this induction is less intense than that stimulated by hypoxia. Repressed by HIPK2 and LIMD1.
Up-regulated in peripheral T-lymphocytes after T-cell receptor stimulation. Highest expression in peripheral blood leukocytes and thymus.
Binds to EDARADD. Associates with TRAF1, TRAF2, TRAF3 and NIK.
Detected in fetal kidney, lung, skin and cultured neonatal epidermal keratinocytes. Not detected in lymphoblast and fibroblast cell lines.
Found in craniofacial tissues from embryonic day 42-53. Expressed in fetal skin 11 and 15 weeks after gestation.
Genetic variation in EDAR is associated with variations in head hair thickness and defines the hair morphology locus 1 (HRM1) [MIM:612630]. Besides skin color and facial features, hair morphology is one of the most distinctive traits among human populations, and classical classification of human population is based on such visible traits.
Receptor for EDA isoform A1, but not for EDA isoform A2. Mediates the activation of NF-kappa-B and JNK. May promote caspase-independent cell death.
Homodimer. Part of a copper-dependent multiprotein complex containing S100A13, FGF1 and SYT1. Interacts with FGF1 and SYT1 (By similarity). Interacts with IL1A (PubMed:21270123).
Plays a role in the export of proteins that lack a signal peptide and are secreted by an alternative pathway. Binds two calcium ions per subunit. Binds one copper ion. Binding of one copper ion does not interfere with calcium binding. Required for the copper-dependent stress-induced export of IL1A and FGF1. The calcium-free protein binds to lipid vesicles containing phosphatidylserine, but not to vesicles containing phosphatidylcholine (By similarity).
Belongs to the cyclophilin-type PPIase family. PPIL3 subfamily.
PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. May be involved in pre-mRNA splicing.
Divalent metal cations. Mg(2+) or Mn(2+).
Highly expressed in metastasis-suppressed chromosome 6 melanoma hybrids.
NAD(P)H pyrophosphatase that hydrolyzes NADH into NMNH and AMP, and NADPH into NMNH and 2',5'-ADP. Has a marked preference for the reduced pyridine nucleotides. Does not show activity toward NAD-capped RNAs; the NAD-cap is an atypical cap present at the 5'-end of some RNAs.
Component of the RNA exosome complex (PubMed:20531389, PubMed:26166824, PubMed:29906447). The catalytically inactive RNA exosome core (Exo-9) complex is believed to associate with catalytic subunits EXOSC10, and DIS3 or DIS3L in cytoplasmic- and nuclear-specific RNA exosome complex forms (PubMed:20531389). Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Interacts with C1D and MPHOSPH6 (PubMed:17412707). Interacts with ALYREF/THOC4 (PubMed:17234882). Interacts with MTREX; the interaction mediates the association of MTREX with nuclear RNA exosomes (PubMed:26166824). Interacts with DHX36; this interaction occurs in a RNase-insensitive manner (PubMed:14731398). Interacts with NRDE2 (PubMed:30538148).
Putative catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797). The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. EXOSC10 is required for nucleolar localization of C1D and probably mediates the association of MTREX, C1D and MPHOSPH6 with the RNA exosome involved in the maturation of 5.8S rRNA.
Binding to heparin is much weaker than in the close homolog PF4/CXCL4.
Inhibitor of angiogenesis. Inhibitor of endothelial cell chemotaxis (in vitro).
The N-terminal processed forms of platelet factor 4 variant seems to be produced by proteolytic cleavage. The most abundant form is Platelet factor 4 variant(5-74).
Autophosphorylated on serine and threonine residues; this autophosphorylation represses activity. Reactivated by phosphatase-mediated dephosphorylation. May be dephosphorylated by PP1.
Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. In balance with PP1, determines the circadian period length through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. Controls PER1 and PER2 nuclear transport and degradation. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. Phosphorylates NEDD9/HEF1 (By similarity). EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate.
Exhibits substrate-dependent heparin activation. Drug-mediated inhibition leads to a delay of the oscillations with the magnitude of this effect dependent upon the timing of drug administration. Inhibited by phosphorylation. Repressed by 3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261), N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide (CKI-7), 4-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide (D4476), 3,4-diaryl-isoxazoles and -imidazoles, and 4-(3-cyclohexyl-5-(4-fluoro-phenyl)-3H-imidazol-4-yl) pyrimidin-2-ylamine (PF670462, PF670).
Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. However, kinase activity is not uniform, with highest kinase activity in splenocytes. In blood, highly expressed in hemopoietic cells and mature granulocytes. Also found in monocytes and lymphocytes.
Highly present in extravillous trophoblast cells, which are present at the placenta implantation site and invade the decidua and decidual vessels.
May be involved in Alzheimer disease by phosphorylating MAPT/TAU.
Monomer (PubMed:22168824, PubMed:23106386). Component of the circadian core oscillator, which includes the CRY proteins, CLOCK, or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins (By similarity). Interacts with DNMT1 and MAP1A (By similarity). Interacts directly with PER1 and PER2 which may lead to their degradation (PubMed:11165242). Interacts with MAPT/TAU (PubMed:14761950). Interacts with SNAPIN (By similarity). Interacts with DBNDD2 (PubMed:16618118). Interacts with AKAP9/AKAP450; this interaction promotes centrosomal subcellular location (PubMed:12270714). Binds to tubulins in mitotic cells upon DNA damage (PubMed:10826492). Interacts with GJA1 (PubMed:12270943). Interacts with DDX3X; this interaction enhances CSNK1D kinase activity in vitro, but it is unclear whether this interaction is physiologically relevant (PubMed:29222110).
Was shown to phosphorylate and activate DCK in vitro but probably not in vivo.
Catalyzes the covalent attachment of ubiquitin to other proteins (PubMed:22496338). May be involved in hormonal homeostasis in females. Involved in regulation of B4GALT1 cell surface expression, B4GALT1-mediated cell adhesion to laminin and embryoid body formation (By similarity).
Monomer and homodimer. Only the homodimer is linked to ubiquitin through thiolester activation. Interacts (via N-terminus) with B4GALT1 (via N-terminal cytoplasmic domain). The interaction is direct.
Found in a complex with TMIE and PCDH15. Interacts with PCDH15; this interaction is required for efficient localization to hair bundles. Interacts with TOMT.
In the inner ear, may be a component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel. Regulates transducer channel conductance and is required for fast channel adaptation (By similarity).
Expressed in monocyte-derived macrophages. Up-regulated in invasive melanoma and breast carcinoma cell lines.
Hydrolyzes 2-acetyl monoalkylglycerol ether (1-O-alkyl-2-acetyl-sn-glycerol), the penultimate precursor of the pathway for de novo synthesis of platelet-activating factor (PubMed:17052608). May be responsible for the hydrolysis of cholesterol esters (such as cholesteryl (9Z-octadecenoate)) in macrophages (By similarity). Also involved in organ detoxification by hydrolyzing exogenous organophosphorus compounds (By similarity). May contribute to cancer pathogenesis by promoting tumor cell migration (PubMed:17052608).
Acts as a guanine-nucleotide exchange factor (GEF). Promotes guanine-nucleotide exchange on ARF1, ARF3 and ARF6. Activates ARF factors through replacement of GDP with GTP (By similarity). The cell membrane form, in association with ARL4 proteins, recruits ARF6 to the plasma membrane (PubMed:17398095). Involved in neurite growth (By similarity).
Binds via its PH domain to the inositol head group of phosphatidylinositol 3,4,5-trisphosphate. The PH domain is necessary and sufficient for plasma membrane relocalization.
Heteromer. Composed of TAMALIN, CYTH2 and at least one GRM1 (By similarity). Interacts with ARRB1 (PubMed:17623778, PubMed:17398095). Interacts with ARL4D; the interaction is direct (PubMed:17398095). Directly interacts with CCDC120 through the coiled coil domain; this interaction stabilizes CCDC120, possibly by preventing its ubiquitination, and is required for neurite growth in neuroblastoma cells (PubMed:25326380). Interacts with ARF1 (PubMed:14654833). Interacts with FRMD4A (By similarity). Interacts (via N-terminal domain) with INAVA (via N-terminal domain) (PubMed:29420262).
The coiled coil domain is involved in interaction with CCDC120.
(Microbial infection) Interacts with Hepatitis C virus (HCV) non-structural protein 5A; this interaction may promote the association of NS5A and other viral replicase components with lipid droplets.
Interacts (in GTP-bound form) with ZFYVE1 (PubMed:31293035, PubMed:30970241). Interacts with ZW10 and this interaction is enhanced in the presence of ZFYVE1 (PubMed:30970241). Interacts with BSCL2 (PubMed:30970241).
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes (PubMed:24891604, PubMed:30970241). Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (PubMed:24891604, PubMed:30970241). Required for the localization of ZFYVE1 to lipid droplets and for its function in mediating the formation of endoplasmic reticulum-lipid droplets (ER-LD) contacts (PubMed:30970241). Also required for maintaining endoplasmic reticulum structure (PubMed:24891604). Plays a role in apical endocytosis/recycling (By similarity). Plays a key role in eye and brain development and neurodegeneration (PubMed:21473985).
Interacts with the PDZ domains of MAGI3, SDCBP and SNTA1. The interaction with SDCBP, is required for the targeting to the cell surface. In the endoplasmic reticulum, in its immature form (i.e. with a prosegment and lacking full N-glycosylation), interacts with CNIH. In the Golgi apparatus, may form a complex with CNIH and GORASP2. Interacts (via cytoplasmic C-terminal domain) with NKD2.
Isoform 1, isoform 3 and isoform 4 are expressed in keratinocytes and tumor-derived cell lines.
TGF alpha is a mitogenic polypeptide that is able to bind to the EGF receptor/EGFR and to act synergistically with TGF beta to promote anchorage-independent cell proliferation in soft agar.
Broad specificity oxidoreductase that catalyzes the NADPH-dependent reduction of a variety of flavins, such as riboflavin, FAD or FMN, biliverdins, methemoglobin and PQQ (pyrroloquinoline quinone). Contributes to heme catabolism and metabolizes linear tetrapyrroles. Can also reduce the complexed Fe(3+) iron to Fe(2+) in the presence of FMN and NADPH. In the liver, converts biliverdin to bilirubin.
Mesobiliverdin acts as competitve inhibitor for flavin reduction, indicating that flavin and tetrapyrrole substrates compete for the same site.
Predominantly expressed in liver and erythrocytes. At lower levels in heart, lung, adrenal gland and cerebrum.
Belongs to the AB hydrolase superfamily. ABHD16 family.
Inhibited by beta-lactone-based lipid inhibitors, such as beta-lactone palmostatin-B.
Phosphatidylserine (PS) lipase that mediates the hydrolysis of phosphatidylserine to generate lysophosphatidylserine (LPS) (By similarity). LPS constitutes a class of signaling lipids that regulates immunological and neurological processes (By similarity). Has no activity towards diacylglycerol, triacylglycerol or lysophosphatidylserine lipase (PubMed:25290914). Also has monoacylglycerol lipase activity, with preference for 1-(9Z,12Z-octadecadienoyl)-glycerol (1-LG) and 2-glyceryl-15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ(2)-G) (PubMed:25290914).
Expressed in brain; detected in the basal forebrain, frontal cortex, caudate, putamen, thalamus and hippocampus.
Homodimers (By similarity). Forms heterodimer with MTNR1B (PubMed:28827538). Interacts with ARRB1 and ARRB2 in a spontaneous and agonist-independent manner; leading to the internalization of GPR62 in the endosomal compartment (PubMed:28827538).
Lacks the conserved DRY and BBXXB motifs. The restoration of these motifs affects its constitutive activity.
Orphan G-protein coupled receptor. Constitutively activates the G(q/11)/inositol phosphate and the G(s)-alpha/cAMP signaling pathways (PubMed:28827538). Has spontaneous activity for beta-arrestin recruitment (PubMed:28827538). Shows a reciprocal modulation of signaling functions with the melatonin receptor MTNR1B most likely through receptor heteromerization (PubMed:28827538).
Expression is induced by interleukin-2 (IL2), interleukin-7 (IL7) and interleukin-12 (IL12A and IL12B) on activated T-cells.
Interacts with MHC class II (MHC-II); selectively recognizes stable complexes of peptide and MHC-II (PubMed:1692078, PubMed:7589152, PubMed:8647185, PubMed:9159144). Interacts with FGL1 (via the Fibrinogen C-terminal domain) (PubMed:30580966).
Lymphocyte activation gene 3 protein: Inhibitory receptor on antigen activated T-cells (PubMed:7805750, PubMed:8647185, PubMed:20421648). Delivers inhibitory signals upon binding to ligands, such as FGL1 (By similarity). FGL1 constitutes a major ligand of LAG3 and is responsible for LAG3 T-cell inhibitory function (By similarity). Following TCR engagement, LAG3 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation (By similarity). May inhibit antigen-specific T-cell activation in synergy with PDCD1/PD-1, possibly by acting as a coreceptor for PDCD1/PD-1 (By similarity). Negatively regulates the proliferation, activation, effector function and homeostasis of both CD8(+) and CD4(+) T-cells (PubMed:7805750, PubMed:8647185, PubMed:20421648). Also mediates immune tolerance: constitutively expressed on a subset of regulatory T-cells (Tregs) and contributes to their suppressive function (By similarity). Also acts as a negative regulator of plasmacytoid dendritic cell (pDCs) activation (By similarity). Binds MHC class II (MHC-II); the precise role of MHC-II-binding is however unclear (PubMed:8647185).
May function as a ligand for MHC class II (MHC-II) on antigen-presenting cells (APC), promoting APC activation/maturation and driving Th1 immune response.
Primarily expressed in activated T-cells and a subset of natural killer (NK) cells.
Proteolytically cleaved by ADAM10 and ADAM17 within the connecting peptide region, leading to release of Secreted lymphocyte activation gene 3 protein (sLAG-3). ADAM10 mediates constitutive cleavage, but cleavage increases following T-cell activation, whereas shedding by ADAM17 is induced by TCR signaling in a PRKCQ-dependent manner.
The KIEELE motif is required for interaction with downstream signaling molecules.
Midbrain; expressed at significantly higher levels outside the brain (up to 30-fold), particularly in the kidney, bone marrow and prostate.
Cell-cycle-regulated enzyme of importance in nucleotide metabolism (PubMed:9575153). Catalyzes the first enzymatic step in the salvage pathway converting thymidine into thymidine monophosphate (PubMed:22385435). Transcriptional regulation limits expression to the S phase of the cell cycle and transient expression coincides with the oscillation in the intracellular dTTP concentration (Probable). Also important for the activation of anticancer and antiviral nucleoside analog prodrugs such as 1-b-d-arabinofuranosylcytosine (AraC) and 3c-azido-3c-deoxythymidine (AZT) (PubMed:22385435).
Homotetramer (PubMed:15611477, PubMed:15733844, PubMed:17407781, PubMed:22385435, PubMed:14697231). Tetramerization from dimerization is induced by ATP and increases catalytic efficiency due to a high affinity for thymidine (PubMed:14697231). Tetramerization is inhibited by phosphorylation at Ser-13 (PubMed:14697231). Interacts (via the KEN box) with FZR1 (PubMed:14701726).
KEN box sequence located in the C-terminal region is required for its mitotic degradation by the APC/C-FZR1 ubiquitin ligase and interaction capability with FZR1.
Phosphorylated on Ser-13 in mitosis. Phosphorylation of Ser-13 by CDK1 during mitosis reduces homotetramerization and catalytic efficiency when DNA replication is complete and intracellular TK1 is still present at a high level (PubMed:9575153, PubMed:14697231).
Polyubiquitinated. Postmitosis, ubiquitination leads to proteasomal degradation. The KEN box sequence located at the C-terminal region targets for degradation by the anaphase promoting complex (APC/C) activated and rate-limited by FZR1.
Significantly increased in the cells during progression to the S and M phases, and becomes barely detectable in the early G(1) phase by a proteolytic control during mitotic exit.
Two forms have been identified in animal cells, one in cytosol and one in mitochondria. Activity of the cytosolic enzyme is high in proliferating cells and peaks during the S-phase of the cell cycle; it is very low in resting cells.
Interacts (via N-terminal region) with PABPC1 (PubMed:27615744, PubMed:21098120). Interacts with RACK1 (PubMed:21098120).
RNA binding protein that binds to the poly-A tract of mRNA molecules (PubMed:21098120). Associates with the 40S ribosomal subunit and with polysomes (PubMed:21098120). Plays a role in the regulation of mRNA translation (PubMed:21098120). Plays a role in the regulation of cell morphology and cytoskeletal organization (PubMed:21834987, PubMed:27615744).
Catalyzes the transfer of a dimethylallyl group onto the adenine at position 37 of both cytosolic and mitochondrial tRNAs, leading to the formation of N6-(dimethylallyl)adenosine (i6A37) (PubMed:11111046, PubMed:24126054, PubMed:24901367, PubMed:34774131). Mediates modification of a limited subset of tRNAs: tRNA(Ser)(AGA), tRNA(Ser)(CGA), tRNA(Ser)(UGA), as well as partial modification of the selenocysteine tRNA(Ser)(UCA) (PubMed:24126054). TRIT1 is therefore required for selenoprotein expression (PubMed:24126054).
Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors.
Can form heterodimers with PROP1 in binding to DNA (By similarity). Interacts with TLE1.
Required for the normal development of the forebrain, eyes and other anterior structures such as the olfactory placodes and pituitary gland. Possible transcriptional repressor. Binds to the palindromic PIII sequence, 5'-AGCTTGAGTCTAATTGAATTAACTGTAC-3'. HESX1 and PROP1 bind as heterodimers on this palindromic site, and, in vitro, HESX1 can antagonize PROP1 activation.
Strongly expressed in Rathke pouch in seven-week-old embryo.
Heparin blocks kallistatin's complex formation with tissue kallikrein and abolishes its inhibitory effect on tissue kallikrein's activity.
Inhibits human amidolytic and kininogenase activities of tissue kallikrein. Inhibition is achieved by formation of an equimolar, heat- and SDS-stable complex between the inhibitor and the enzyme, and generation of a small C-terminal fragment of the inhibitor due to cleavage at the reactive site by tissue kallikrein.
Component of the BCR(KLHL21) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL21 and RBX1.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for efficient chromosome alignment and cytokinesis. The BCR(KLHL21) E3 ubiquitin ligase complex regulates localization of the chromosomal passenger complex (CPC) from chromosomes to the spindle midzone in anaphase and mediates the ubiquitination of AURKB. Ubiquitination of AURKB by BCR(KLHL21) E3 ubiquitin ligase complex may not lead to its degradation by the proteasome.
(Microbial infection) Interacts with Epstein-Barr virus BRLF1/Rta protein, leading to the regulation of host genes in Epstein-Barr virus-infected cells.
Detected at low levels in breast, lung and stomach; highly up-regulated in the corresponding cancerous tissues (at protein level).
Interacts with MBD1; the interaction is enhanced when MBD1 is sumoylated (PubMed:12665582, PubMed:16757475). Interacts with SETDB1; the interaction protects SETDB1 from proteasomal degradation and is required to stimulate histone methyltransferase activity and facilitate the conversion of dimethylated to trimethylated H3 'Lys-9' (PubMed:14536086, PubMed:15691849, PubMed:27732843). Interacts with SUMO ubiquitin-like proteins (SUMO1, SUNO2 and SUMO3), with a preference for SUMO2 and SUMO3 (PubMed:16757475, PubMed:18842587). Interacts with SP1, ATF7 and ZHX1 (PubMed:10976766, PubMed:12659632, PubMed:19106100). Interacts with the general transcription machinery, including ERCC2, ERCC3, GTF2E1, GTF2E2 and POLR2A (PubMed:19106100).
Recruiter that couples transcriptional factors to general transcription apparatus and thereby modulates transcription regulation and chromatin formation. Can both act as an activator or a repressor depending on the context. Required for HUSH-mediated heterochromatin formation and gene silencing (PubMed:27732843). Mediates MBD1-dependent transcriptional repression, probably by recruiting complexes containing SETDB1 (PubMed:12665582). Stabilizes SETDB1, is required to stimulate histone methyltransferase activity of SETDB1 and facilitates the conversion of dimethylated to trimethylated H3 'Lys-9' (H3K9me3). The complex formed with MBD1 and SETDB1 represses transcription and couples DNA methylation and histone H3 'Lys-9' trimethylation (H3K9me3) (PubMed:14536086, PubMed:27732843). Facilitates telomerase TERT and TERC gene expression by SP1 in cancer cells (PubMed:19106100).
Expressed in lung, thymus and small intestine. Detected in cutaneous dendritic cells, activated T-cells, monocytes and granulocytes as well as with epithelial cells with dendritic morphology. Expressed in some leukemic cells, the CD4(+) CD56(+) blastic tumor cells, as well as in Langerhans cells from LCH (Langerhans cell histiocytosis) patients.
Plays a role as inhibitor of T-cells proliferation induced by CD3. Inhibits expression of IL2RA on activated T-cells and secretion of IL2. Inhibits tyrosine kinases that are required for IL2 production and cellular proliferation. Inhibits phospholipase C-gamma-1/PLCG1 phosphorylation and subsequent CD3-induced changes in intracellular free calcium. Prevents nuclear translocation of nuclear factor of activated T-cell to the nucleus. Plays a role in the inhibition of T-cell proliferation via IL10 secretion by cutaneous dendritic cells. May be a marker of CD4(+) CD56(+) leukemic tumor cells.
Belongs to the eukaryotic ribosomal protein eS12 family.
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Subunit of the 40S ribosomal complex (By similarity).
Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797). Subunit of the 40S ribosomal complex (By similarity).
Belongs to the adrenodoxin/putidaredoxin family.
Essential for the synthesis of various steroid hormones (PubMed:20547883, PubMed:21636783). Participates in the reduction of mitochondrial cytochrome P450 for steroidogenesis (PubMed:20547883, PubMed:21636783). Transfers electrons from adrenodoxin reductase to CYP11A1, a cytochrome P450 that catalyzes cholesterol side-chain cleavage (PubMed:20547883, PubMed:21636783). Does not form a ternary complex with adrenodoxin reductase and CYP11A1 but shuttles between the two enzymes to transfer electrons (By similarity).
Highest levels in the adrenal gland (at protein level). Also detected in kidney and testis (at protein level).
Binds STRN4 (By similarity). Interacts with DNM1 and EPS15 (By similarity). Interacts with nucleoside diphosphate kinase (By similarity). Binds STRN and STRN3. Part of a ternary complex containing MOB4/PHOCN, STRN and/or STRN3 and PPA2. Interacts with CTTNBP2 (By similarity). Interacts with CTTNBP2NL.
May play a role in membrane trafficking, specifically in membrane budding reactions.
Binds 2 divalent metal cations per subunit. Has a high-affinity and a low affinity metal-binding site. The true nature of the physiological cofactor is under debate. The enzyme is active with cobalt, zinc, manganese or divalent iron ions. Most likely, methionine aminopeptidases function as mononuclear Fe(2+)-metalloproteases under physiological conditions, and the catalytically relevant metal-binding site has been assigned to the histidine-containing high-affinity site.
It is uncertain whether Met-1 or a Met upstream of this sequence is the initiator.
Overexpressed in colon cancer cell lines and colon tumors as compared to normal tissues (at protein level).
Removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). Requires deformylation of the N(alpha)-formylated initiator methionine before it can be hydrolyzed (By similarity). May play a role in colon tumorigenesis.
Core component of the SNX27-retromer, a multiprotein complex composed of SNX27, the WASH complex and the retromer complex. Interacts (via PDZ domain) with a number of target transmembrane proteins (via PDZ-binding motif): ABCC4, ADRB2, ARHGEF7, GRIA1, GRIA2, GRIN1, GRIN2A GRIN2C, KCNJ6, KCNJ9 and SLC2A1/GLUT1. Interacts (via the FERM-like regions) with the WASH complex. Interacts with SNX1. Interacts with CYTIP. Isoform 1 and isoform 2 directly interact with DGKZ. Isoform 1 and isoform 2 interact with HT4R isoform 5-HTA(A). Interacts with MCC. Interacts (via PDZ domains) with SLC9A3; directs SLC9A3 membrane insertion from early endosomes to the plasma membrane (PubMed:25851603).
Involved in the retrograde transport from endosome to plasma membrane, a trafficking pathway that promotes the recycling of internalized transmembrane proteins. Following internalization, endocytosed transmembrane proteins are delivered to early endosomes and recycled to the plasma membrane instead of being degraded in lysosomes. SNX27 specifically binds and directs sorting of a subset of transmembrane proteins containing a PDZ-binding motif at the C-terminus: following interaction with target transmembrane proteins, associates with the retromer complex, preventing entry into the lysosomal pathway, and promotes retromer-tubule based plasma membrane recycling. SNX27 also binds with the WASH complex. Interacts with membranes containing phosphatidylinositol-3-phosphate (PtdIns(3P)). May participate in establishment of natural killer cell polarity. Recruits CYTIP to early endosomes.
The PDZ domain mediates binding to a subset of proteins containing a PDZ-binding motif at the C-terminus: the specificity for PDZ-binding motif is provided by the 2 residues located upstream of the canonical PDZ-binding motif (By similarity). The PDZ domain also mediates binding to the retromer complex via direct interaction with VPS26 (VPS26A or VPS26B) (PubMed:23563491).
The PX domain mediates binding to phosphatidylinositol 3-phosphate (PtdIns(3P)) and localization to early endosome membranes.
Widely expressed. Expressed in cells of hematopoietic origin (at protein level).
Component of the GPI transamidase complex, necessary for transfer of GPI to proteins (PubMed:34576938). Essential for GPI-anchoring of precursor proteins but not for GPI synthesis. Acts before or during formation of the carbonyl intermediate.
Forms a complex with PIGK/GPI8, PIGT, PIGU and PIGS.
Ubiquitously expressed in fetal and adult tissues. Expressed at higher levels in fetal tissues than adult tissues.
Detected in testis and prostate. Detected at lower levels in peripheral blood leukocytes and spleen.
Interacts with PCGF1, forming heterodimers (PubMed:23523425, PubMed:27568929). The PCGF1-BCORL1 heterodimeric complex interacts with the KDM2B-SKP1 heterodimeric complex to form a homotetrameric polycomb repression complex 1 (PRC1.1) (PubMed:27568929). Interacts with CTBP1, HDAC4, HDAC5 and HDAC7 (PubMed:17379597).
Transcriptional corepressor. May specifically inhibit gene expression when recruited to promoter regions by sequence-specific DNA-binding proteins such as BCL6. This repression may be mediated at least in part by histone deacetylase activities which can associate with this corepressor.
Stimulates guanine exchange activity of SOS1. May play a role in membrane ruffling and remodeling of the actin cytoskeleton.
Belongs to the AB hydrolase superfamily. ABHD17 family.
Hydrolyzes fatty acids from S-acylated cysteine residues in proteins (PubMed:26701913). Has depalmitoylating activity towards NRAS (PubMed:26701913). Has depalmitoylating activity towards DLG4/PSD95 (PubMed:26701913). May have depalmitoylating activity towards MAP6 (By similarity).
Palmitoylated on cysteine residues located in a cysteine cluster at the N-terminus which promotes membrane localization (PubMed:26701913). Palmitoylation is required for post-synaptic localization and for depalmitoylating activity towards DLG4/PSD95 (By similarity).
Acts as component of the STAGA transcription coactivator-HAT complex (PubMed:15932940, PubMed:18206972). Mediates the interaction of STAGA complex with the CRX and is involved in CRX-dependent gene activation (PubMed:15932940, PubMed:18206972). Necessary for microtubule cytoskeleton stabilization (PubMed:22100762).
Component of the STAGA transcription coactivator-HAT complex, at least composed of SUPT3H, GCN5L2, TAF5L, TAF6L, SUPT7L, TADA3L, TAD1L, TAF10, TAF12, TRRAP, TAF9 and ATXN7 (PubMed:15932940, PubMed:18206972). The STAGA core complex is associated with a subcomplex required for histone deubiquitination composed of ATXN7L3, ENY2 and USP22 (PubMed:15932940, PubMed:18206972). Interacts with SORBS1, PSMC1 and CRX (PubMed:11371513, PubMed:11734547). Interacts with TRRAP, GCN5L2 and TAF10 (PubMed:15115762). Interacts with alpha tubulin (PubMed:22100762).
Isoform a is expressed in CNS, but is expressed predominantly in the peripherical tissues.
Isoform b is expressed in CNS (PubMed:12533095). Also highly expressed in the frontal lobe, skeletal muscle and spinal cord and is expressed at a lower level in the lung, lymphoblast and intestine (PubMed:12533095).
Proteolytically cleaved by caspase-7 (CASP7) (PubMed:17646170). The cleavage may be involved in SCA7 degeneration: the isoform fragments may exert distinct toxic influences that could contribute to selective neurodegeneration (PubMed:17646170).
Sumoylation decreases the aggregation propensity and cellular toxicity of forms with an expanded poly-Gln region but has no effect on subcellular location or interaction with components of the STAGA complex.
The poly-Gln region of ATXN7 is highly polymorphic (4 to 18 repeats) in the normal population and is expanded to about 38-130 repeats in SCA7 patients. Intermediate alleles with 28 to 35 repeats are prone to further expansion.
Homotrimer; trimerization probably requires binding to phosphatidylinositol 4,5-bisphosphate (PIP2).
Monovalent cation channel required for maintenance of rapid intracellular calcium release. May act as a potassium counter-ion channel that functions in synchronization with calcium release from intracellular stores.
Integral component of the ORC complex. Directly interacts with CDT1, GMNN and ORC2. Interacts with ORC2 only when non-ubiquitinated; this interaction prevents LRWD1 ubiquitination and degradation. Some of these interactions are regulated in a cell-cycle dependent manner. Interaction with ORC1 occurs predominantly during G1. Association with phosphorylated ORC1 during mitosis is not efficient. Interaction with CDT1 occurs during G1 phase, as well as during mitosis with phosphorylated CDT1. Interaction with GMNN occurs from G1/S to mitosis. Interaction with ORC2 is observed throughout the cell cycle. The stoichiometry of the ORCA/ORC/CDT1/GMNN complex is 1:1:1:2. Interacts with CUL4A and DDB1; this interaction may lead to ubiquitination.
Regulated in a cell-cycle dependent manner. Highest expression in G1 phase. Expression decreases during S phase, rises again during G2 and drops during mitosis (at protein level). In contrast to protein levels, transcript levels do not show any significant variation during different stages of the cell cycle (PubMed:22935713).
Required for G1/S transition. Recruits and stabilizes the origin recognition complex (ORC) onto chromatin during G1 to establish pre-replication complex (preRC) and to heterochromatic sites in post-replicated cells. Binds a combination of DNA and histone methylation repressive marks on heterochromatin. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3 in a cooperative manner with DNA methylation. Required for silencing of major satellite repeats. May be important ORC2, ORC3 and ORC4 stability.
Testis-specific. Drastically down-regulated in testis from patients with Sertoli cell-only syndrome (SCOS).
The entire WD repeat region is required for the interaction with ORC, CDT1 and GMNN, as well as for association with chromatin and for binding to histone H3 and H4 trimethylation marks H3K9me3 and H4K20me3.
Ubiquitinated; undergoes 'Lys-48'-linked polyubiquitination leading to proteasomal degradation. Ubiquitination occurs within the WD repeats at the end of the G1 phase. Ubiquitination may be catalyzed by the CUL4-DDB1 E3 ubiquitin-protein ligase complex and other E3 ligases.
Co-chaperone that binds to numerous kinases and promotes their interaction with the Hsp90 complex, resulting in stabilization and promotion of their activity (PubMed:8666233). Inhibits HSP90AA1 ATPase activity (PubMed:23569206).
Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Forms a complex with Hsp90/HSP90AB1 and CDK6 (PubMed:9482106). Interacts with HSP90AA1 (PubMed:23569206, PubMed:27353360). Interacts with AR, CDK4, CDK6 and EIF2AK1 (PubMed:11036079, PubMed:11085988, PubMed:9150368, PubMed:9482106). Interacts with RB1 (By similarity). Interacts with KSR1 (PubMed:10409742). Interacts with FLCN, FNIP1 and FNIP2 (PubMed:27353360).
Belongs to the pyridoxamine 5'-phosphate oxidase family.
Catalyzes the oxidation of either pyridoxine 5'-phosphate (PNP) or pyridoxamine 5'-phosphate (PMP) into pyridoxal 5'-phosphate (PLP).
Ubiquitous. Expressed in liver, brain, lung, prostate and stomach (at protein level).
Expressed in the pituitary, testis, and heart and at lower levels in the brain.
May be capable of activating GPR83 via the GNAQ signaling pathway.
The active form requires C-terminal amidation and disulfide bond formation.
Displays arylsulfatase activity at acidic pH towards artificial substrates, such as p-nitrocatechol sulfate and also, but with a lower activity towards p-nitrophenyl sulfate and 4-methylumbelliferyl sulfate (PubMed:18283100, PubMed:29300381). Catalyzes the hydrolysis of the 3-sulfate groups of the N-sulfo-D-glucosamine 3-O-sulfate units of heparin (PubMed:22689975).
N-glycosylated (PubMed:18283100). N-glycosylated with both high mannose and complex type sugars (By similarity).
The 63-kDa precursor undergoes proteolytic processing in two steps, yielding two fragments in the first step (apparent molecular masses of 44 and 18 kDa) (PubMed:25135642). In the second step, the 44-kDa fragment is processed further to the 34- and 10-kDa chains. The 10-kDa chain is a cleavage product of the 44-kDa fragment but linked to the 18-kDa chain through a disulfide bridge (PubMed:25135642).
Widely expressed, with very low expression in brain, lung, heart and skeletal muscle.
Binds to DNA preferentially in the vicinity of transcriptional start sites. Interacts with MSH2 and TRIM28. Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2. Interacts with PCNA.
DNA helicase that possesses intrinsic ATP-dependent nucleosome-remodeling activity and is both required for DNA repair and heterochromatin organization. Promotes DNA end resection of double-strand breaks (DSBs) following DNA damage: probably acts by weakening histone DNA interactions in nucleosomes flanking DSBs. Required for the restoration of heterochromatin organization after replication. Acts at replication sites to facilitate the maintenance of heterochromatin by directing H3 and H4 histones deacetylation, H3 'Lys-9' trimethylation (H3K9me3) and restoration of silencing.
Isoform 1 is expressed ubiquitously. Isoform 3 is expressed mainly in skin and esophagus. Expressed in fibroblasts and keratinocytes (at protein level) (PubMed:29409814).
The disease is caused by variants affecting the gene represented in this entry. Splice site mutations causing aberrant splicing of skin-specific isoform 3 are likely to exert a loss-of-function effect and are involved in ADERM.
The disease is caused by variants affecting the gene represented in this entry. Splice site mutations causing aberrant splicing of skin-specific isoform 3 are likely to exert a loss-of-function effect and are involved in BSNS.
Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.
Highly expressed in the central nervous system. Also found in skeletal muscle and at low levels in pancreas.
The J domain is functional and is shown to stimulate E.coli dnaK ATPase activity.
The ubiquitin-like domain mediates interaction with the proteasome.
Activates HECT domain-containing E3 ubiquitin-protein ligases, including NEDD4 and ITCH, and consequently modulates the stability of their targets. As a result, controls many cellular processes. Prevents chronic T-helper cell-mediated inflammation by activating ITCH and thus controlling JUNB degradation (By similarity). Promotes pancreatic beta cell death through degradation of JUNB and inhibition of the unfolded protein response, leading to reduction of insulin secretion (PubMed:26319551). Restricts the production of pro-inflammatory cytokines in effector Th17 T-cells by promoting ITCH-mediated ubiquitination and degradation of RORC (By similarity). Together with NDFIP2, limits the cytokine signaling and expansion of effector Th2 T-cells by promoting degradation of JAK1, probably by ITCH- and NEDD4L-mediated ubiquitination (By similarity). Regulates peripheral T-cell tolerance to self and foreign antigens, forcing the exit of naive CD4+ T-cells from the cell cycle before they become effector T-cells (By similarity). Negatively regulates RLR-mediated antiviral response by promoting SMURF1-mediated ubiquitination and subsequent degradation of MAVS (PubMed:23087404). Negatively regulates KCNH2 potassium channel activity by decreasing its cell-surface expression and interfering with channel maturation through recruitment of NEDD4L to the Golgi apparatus where it mediates KCNH2 degradation (PubMed:26363003). In cortical neurons, mediates the ubiquitination of the divalent metal transporter SLC11A2/DMT1 by NEDD4L, leading to its down-regulation and protection of the cells from cobalt and iron toxicity (PubMed:19706893). Important for normal development of dendrites and dendritic spines in cortex (By similarity). Enhances the ubiquitination of BRAT1 mediated by: NEDD4, NEDD4L and ITCH and is required for the nuclear localization of ubiquitinated BRAT1 (PubMed:25631046). Enhances the ITCH-mediated ubiquitination of MAP3K7 by recruiting E2 ubiquitin-conjugating enzyme UBE2L3 to ITCH (By similarity). Modulates EGFR signaling through multiple pathways. In particular, may regulate the ratio of AKT1-to-MAPK8 signaling in response to EGF, acting on AKT1 probably through PTEN destabilization and on MAPK8 through ITCH-dependent MAP2K4 inactivation. As a result, may control cell growth rate (PubMed:20534535). Inhibits cell proliferation by promoting PTEN nuclear localization and changing its signaling specificity (PubMed:25801959).
Forms heterodimers with NDFIP2 (PubMed:20534535). Interacts with several E3 ubiquitin-protein ligases, including ITCH, NEDD4, NEDD4L and WWP2 (PubMed:18776082, PubMed:19706893, PubMed:26363003). The interaction with NEDD4, NEDD4L and ITCH leads to relocalization of these proteins to exosomes and eventually to exosomal secretion (By similarity). Interacts with U2SURP (By similarity). Interacts with SLC11A2/DMT1 (PubMed:18776082, PubMed:19706893). Interacts with PTEN (PubMed:20534535, PubMed:25801959). May interact with phosphorylated EGFR (PubMed:20534535). Interacts with BRAT1 (PubMed:25631046). Interacts with KCNH2 (PubMed:26363003). Interacts with MAVS (PubMed:23087404). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (By similarity). Interacts (via N-terminus) with UBE2L3; the interaction mediates recruitment of UBE2L3 to ITCH (PubMed:25632008).
Increased protein expression in neuronal cells in response to Co(2+) or Fe(2+) ions.
The PPxY motifs are required for E3 ubiquitin-protein ligase binding and activation and for ubiquitination.
Ubiquitinated by NEDD4 and ITCH; mono-, di- and polyubiquitinated forms are detected. Ubiquitination regulates its degradation.
Undergoes transient tyrosine phosphorylation following EGF stimulation, most probably by catalyzed by SRC. Phosphorylation SRC is enhanced in the presence of NDFIP2 which may act as a scaffold to recruit SRC to NDFIP1.
Widely expressed. Higher levels are detected in cerebellum, pituitary, thalamus, kidney, liver, testis, salivary glands and placenta. Also expressed in fetal brain, kidney and lung.
Binds the type 2 receptor protein ACVR2A.
Present in pancreas, heart, colon, small intestine, ovary and the hippocampus, medulla oblongata and putamen of the brain. Isoform 1, isoform 2, isoform 3 and isoform 4 are all expressed in the placenta throughout pregnancy.
Serine/threonine protein kinase which forms a receptor complex on ligand binding. The receptor complex consisting of 2 type II and 2 type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators, SMAD2 and SMAD3. Receptor for activin AB, activin B and NODAL. Plays a role in cell differentiation, growth arrest and apoptosis.
Mainly expressed in the cerebellum (PubMed:25165868). Also expressed in cerebral cortex, skeletal muscle and thyroid, but at much lower levels (PubMed:25165868).
The transmembrane segment S4 functions as voltage-sensor and is characterized by a series of positively charged amino acids at every third position (PubMed:30810529). Transplantation of the transmembrane segment S4 into HVCN1, generates a functional voltage-activated proton channel (PubMed:30810529).
Voltage-sensor protein present on the post-synaptic side of glutamatergic mossy fibers and granule cells in the cerebellum (PubMed:25165868, PubMed:30810529). Despite the presence of a voltage-sensor segment, does not form a functional ion channel and its precise role remains unclear (PubMed:25165868, PubMed:30810529). Undergoes both rapid and slow structural rearrangements in response to changes in voltage (PubMed:30810529). Contains a zinc-binding site that can regulate the slow conformational transition (PubMed:30810529).
Expressed in placenta, pancreatic cancer, colon cancer with RER, cervical cancer, and in head and neck tumors.
Transcriptional repressor of genes that require a bHLH protein for their transcription.
(Microbial infection) In case of herpes simplex virus 1/HHV-1 infection, forms heteromeric amyloid structures with HHV-1 protein RIR1/ICP6 which may inhibit RIPK3-mediated necroptosis, thereby preventing host cell death pathway and allowing viral evasion.
(Microbial infection) Interacts (via RIP homotypic interaction motif/RHIM) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RHIM); this interaction may induce heteromeric amyloid assemblies and prevent necroptosis activation.
(Microbial infection) Interacts (via RIP homotypic interaction motif/RHIM) with herpes simplex virus 2/HHV-2 protein RIR1/ICP10 (via RHIM); this interaction prevents necroptosis activation.
(Microbial infection) Proteolytically cleaved by S.flexneri OspD3 within the RIP homotypic interaction motif (RHIM), leading to its degradation and inhibition of necroptosis.
(Microbial infection) The RIP homotypic interaction motif/RHIM mediates interaction with the RHIM motif of the herpes simplex virus 1/HHV-1 protein RIR1/ICP6 to form heteromeric amyloid structures.
Activity is stimulated by ZBP1, which senses double-stranded Z-RNA structures (By similarity). RIPK3-dependent necroptosis is inhibited by RIPK1: RIPK1 prevents the ZBP1-induced activation of RIPK3 via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis (By similarity).
Expression is significantly increased in colon and lung cancers.
Highly expressed in the pancreas. Detected at lower levels in heart, placenta, lung and kidney.
Interacts (via RIP homotypic interaction motif) with RIPK1 (via RIP homotypic interaction motif); this interaction induces RIPK1 phosphorylation and formation of a RIPK1-RIPK3 necrosis-inducing complex (PubMed:10339433, PubMed:11734559, PubMed:19524512, PubMed:29681455). Interacts with MLKL; the interaction is direct and triggers necroptosis (PubMed:22265413, PubMed:22421439). Interacts with ZBP1 (via RIP homotypic interaction motif); interaction with ZBP1 activates RIPK3, triggering necroptosis (By similarity). Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity (PubMed:22265413, PubMed:22265414, PubMed:22421439). Binds TRAF2 and is recruited to the TNFR-1 signaling complex (PubMed:29883609). Interacts with PYGL, GLUL and GLUD1; these interactions result in activation of these metabolic enzymes (PubMed:19498109). Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4 (PubMed:21931591). Interacts with ARHGEF2 (PubMed:21887730). Interacts with PELI1 (via atypical FHA domain); the phosphorylated form at Thr-182 binds preferentially to PELI1 (PubMed:29883609). Interacts with BUB1B, TRAF2 and STUB1 (PubMed:29883609). Interacts with CASP6 (PubMed:32298652). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity).
Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B (PubMed:21931591). Polyubiquitinated with 'Lys-48'-linked chains by PELI1 leading to its subsequent proteasome-dependent degradation. Ubiquitinated by STUB1 leading to its subsequent proteasome-dependent degradation (PubMed:29883609).
RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:19524513). Autophosphorylated following interaction with ZBP1 (By similarity). Phosphorylation of Ser-199 plays a role in the necroptotic function of RIPK3 (PubMed:11734559, PubMed:19524512). Autophosphorylates at Ser-227 following activation by ZBP1: phosphorylation at these sites is a hallmark of necroptosis and is required for binding MLKL (PubMed:22265413). Phosphorylation at Thr-182 is important for its kinase activity, interaction with PELI1 and PELI1-mediated 'Lys-48'-linked polyubiquitination and for its ability to mediate TNF-induced necroptosis (PubMed:29883609).
Serine/threonine-protein kinase that activates necroptosis and apoptosis, two parallel forms of cell death (PubMed:19524512, PubMed:19524513, PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:29883609, PubMed:32657447). Necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members, is triggered by RIPK3 following activation by ZBP1 (PubMed:19524512, PubMed:19524513, PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:29883609, PubMed:32298652). Activated RIPK3 forms a necrosis-inducing complex and mediates phosphorylation of MLKL, promoting MLKL localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage (PubMed:19524512, PubMed:19524513, PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:25316792, PubMed:29883609). In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following ZBP1 activation, which senses double-stranded Z-RNA structures, nuclear RIPK3 catalyzes phosphorylation and activation of MLKL, promoting disruption of the nuclear envelope and leakage of cellular DNA into the cytosol (By similarity). Also regulates apoptosis: apoptosis depends on RIPK1, FADD and CASP8, and is independent of MLKL and RIPK3 kinase activity (By similarity). Phosphorylates RIPK1: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:19524513). In some cell types, also able to restrict viral replication by promoting cell death-independent responses (By similarity). In response to Zika virus infection in neurons, promotes a cell death-independent pathway that restricts viral replication: together with ZBP1, promotes a death-independent transcriptional program that modifies the cellular metabolism via up-regulation expression of the enzyme ACOD1/IRG1 and production of the metabolite itaconate (By similarity). Itaconate inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (By similarity). RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL (PubMed:19498109). These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production (PubMed:19498109).
The RIP homotypic interaction motif/RHIM mediates interaction with the RHIM motif of RIPK1. Both motifs form a hetero-amyloid serpentine fold, stabilized by hydrophobic packing and featuring an unusual Cys-Ser ladder of alternating Ser (from RIPK1) and Cys (from RIPK3).
Involved in T-cell adhesion processes and in spontaneous rosette formation with erythrocytes. Plays a role in a late step of leukocyte extravasation helping leukocytes to overcome the endothelial basement membrane. Acts at the same site as, but independently of, PECAM1. Involved in T-cell adhesion processes (By similarity).
Expressed at low levels in the pituitary, liver, spleen, prostate, testis, ovary, small intestine and colon. Also expressed in various pituitary, testicular, liver and ovarian tumors.
Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids, phosphatidylserines (PS) and phosphatidylethanolamines (PE), from the outer to the inner leaflet of intracellular membranes (PubMed:30018401). May contribute to the maintenance of membrane lipid asymmetry in endosome compartment (PubMed:30018401).
Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit ATP11B and an accessory beta subunit TMEM30A.
The ATPase activity is up-regulated by aminophospholipids PS and PE.
A cleavage occurs, separating the extracellular domain from the transmembrane segment. This process called 'ectodomain shedding' is thought to be involved in receptor desensitization, signal transduction and/or membrane localization (By similarity).
Binding to large heparan sulfate proteoglycan structures promotes oligomerization. Binding to chondroitin sulfate proteoglycan does not lead to oligomerization (By similarity). Interacts (via Ig-like domains) with NTRK3 (PubMed:25385546). Interacts (via Ig-like domains) with NTRK1, but does not form detectable complexes with NTRK2 (By similarity). Interacts with PPFIA1, PPFIA2 and PPFIA3 (PubMed:8524829, PubMed:9624153).
Cell surface receptor that binds to glycosaminoglycans, including chondroitin sulfate proteoglycans and heparan sulfate proteoglycan (PubMed:21454754). Binding to chondroitin sulfate and heparan sulfate proteoglycans has opposite effects on PTPRS oligomerization and regulation of neurite outgrowth. Contributes to the inhibition of neurite and axonal outgrowth by chondroitin sulfate proteoglycans, also after nerve transection. Plays a role in stimulating neurite outgrowth in response to the heparan sulfate proteoglycan GPC2. Required for normal brain development, especially for normal development of the pituitary gland and the olfactory bulb. Functions as tyrosine phosphatase (PubMed:8524829). Mediates dephosphorylation of NTRK1, NTRK2 and NTRK3 (By similarity). Plays a role in down-regulation of signaling cascades that lead to the activation of Akt and MAP kinases (By similarity). Down-regulates TLR9-mediated activation of NF-kappa-B, as well as production of TNF, interferon alpha and interferon beta (PubMed:26231120).
Detected in peripheral blood plasmacytoid dendritic cells (at protein level) (PubMed:26231120). Detected in all tissues tested except for placenta and liver (PubMed:8524829, PubMed:8992885). Detected in peripheral blood plasmacytoid dendritic cells (PubMed:26231120).
Regulates cell proliferation through the inhibition of cell cycle arrest at the G1 phase (PubMed:22842486). Also negatively regulates p53-mediated apoptosis (PubMed:22842486).
Belongs to the cyclophilin-type PPIase family. PPIL2 subfamily.
Component of the minor spliceosome, which splices U12-type introns. Within this complex, interacts with PRPF8/PRP8, EFTUD2/SNU114 and PLRG1 (PubMed:33509932). Interacts with isoform 2 of BSG (PubMed:15946952). Interacts (via the PPIase cyclophilin-type domain) with CRNKL1; they may form a trimeric complex with HSP90.
Despite the fact that it belongs to the cyclophilin-type PPIase family, a report has shown that it has probably no peptidyl-prolyl cis-trans isomerase activity due to the presence of a tyrosine instead of a tryptophan at position 389.
Has a ubiquitin-protein ligase activity acting as an E3 ubiquitin protein ligase or as an ubiquitin-ubiquitin ligase promoting elongation of ubiquitin chains on substrates. By mediating 'Lys-48'-linked polyubiquitination of proteins could target them for proteasomal degradation (PubMed:11435423). May also function as a chaperone, playing a role in transport to the cell membrane of BSG/Basigin for instance (PubMed:15946952). Probable inactive PPIase with no peptidyl-prolyl cis-trans isomerase activity (PubMed:20676357). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
Highest expression in thymus, pancreas and testis. Also detected in heart, placenta, lung, liver, skeletal muscle, kidney, spleen, prostate, ovary, small intestine and colon. Poorly detected in brain and leukocytes. Strong protein expression in lymph node (cortical, paracortical and medullar regions), thyroid (follicular epithelial cells), testis (developing spermatozoa), stomach (cells lining the gastric pit), pancreas, kidney (proximal and distal-tubule cells and collecting duct cells but not in glomeruli), endometrium and colon (goblet cells). Moderate protein expression in spleen, prostate (epithelium and squamous cell carcinomas), placenta and adrenal gland. Weak protein expression in liver, heart, breast, ovary, and lung. No protein expression in brain and bladder. High protein expression in most lymphomas and melanomas.
A region including the PH domain and partially overlapping with the Rho-GAP domain mediates interaction with phosphoinositides.
GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state. Has a substantial GAP activity toward CDC42 and RAC1 and less toward RHOA. Has a role in regulating adhesion of hematopoietic cells to the extracellular matrix. Binds phosphoinositides, and has the highest affinity for phosphatidylinositol 3,4,5-trisphosphate, followed by phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 4,5-bisphosphate.
Predominantly expressed in peripheral blood leukocytes, spleen, and thymus.
Strongly expressed in skin and scalp, and weak expression observed in thymus and tongue. In the hair follicle, expression is restricted to the mid- to upper inner root sheath cuticle, being present slightly above the apex of the dermal papilla (at protein level).
Could induce apoptosis in a BH3 domain-dependent manner. The direct interaction network of Bcl-2 family members may play a key role in modulation RTL10/BOP intrinsic apoptotic signaling activity.
Interacts (via BH3 domain) with VDAC1. Interacts with pro-survival Bcl-2 family members, BCL2, BCL2L1 isoform Bcl-X(L), MCL1, BCL2A1 and BCL2L2. Interacts with BAX and BAK1.
The BH3 motif is required for pro-apoptotic activity and for interaction with pro-survival Bcl-2 family members.
Plays a critical role in the regulation of cDC1-mediated cross-presentation of viral and tumor antigens in dendritic cells. Mechanistically, acts near the plasma membrane and interacts with endosomal membranes to promote endosomal-to-cytosol antigen trafficking. Also plays a role in B-cell survival through regulation of autophagy.
Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade (PubMed:18497260, PubMed:20381137, PubMed:23723238, PubMed:24095279). Forms heterodimeric Rag complexes with RagC/RRAGC or RagD/RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form: RagB/RRAGB is in its active form when GTP-bound RagB/RRAGB forms a complex with GDP-bound RagC/RRAGC (or RagD/RRAGD) and in an inactive form when GDP-bound RagB/RRAGB heterodimerizes with GTP-bound RagC/RRAGC (or RagD/RRAGD) (PubMed:18497260, PubMed:20381137, PubMed:23723238, PubMed:24095279). In its GTP-bound active form, promotes the recruitment of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB (PubMed:18497260, PubMed:20381137, PubMed:23723238). Involved in the RCC1/Ran-GTPase pathway (PubMed:9394008).
Interacts with RRAGC and RRAGD; heterodimerization stabilizes RRAG proteins (PubMed:11073942). The GTP-bound form of RRAGB (in complex with the GDP-bound form of RRAGC or RRAGD) interacts with RPTOR, thereby promoting recruitment of mTORC1 to the lysosomes (PubMed:18497260). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator (By similarity). Interacts with SH3BP4; the interaction with this negative regulator is most probably direct, preferentially occurs with the inactive GDP-bound form of RRAGB, is negatively regulated by amino acids and prevents interaction with RPTOR (PubMed:22575674). Interacts with the GATOR1 complex; inactivates RRAGB (PubMed:23723238). The Rag heterodimer interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Interacts with SESN1, SESN2 and SESN3 (PubMed:25259925).
The activation of GTP-binding proteins is generally mediated by a guanine exchange factor (GEF), while inactivation through hydrolysis of bound GTP is catalyzed by a GTPase activating protein (GAP) (PubMed:22980980, PubMed:23723238). The Ragulator complex functions as a GEF and promotes the active GTP-bound form (PubMed:22980980). The GATOR1 complex functions as a GAP and stimulates RRAGB GTPase activity to turn it into its inactive GDP-bound form, preventing mTORC1 recruitment and activation (PubMed:23723238).
(Microbial infection) Interacts with SARS-CoV translation inhibitor nsp1; this interaction may disrupt nuclear pore function.
Belongs to the nucleoporin interacting component (NIC) family.
Part of the nuclear pore complex (NPC) (PubMed:9348540, PubMed:15229283, PubMed:15703211). Component of the p62 complex, a complex composed of NUP62 and NUP54 (PubMed:9348540). Forms a complex with NUP35, NUP155, NUP205 and lamin B; the interaction with NUP35 is direct (PubMed:15703211). Does not interact with TPR (PubMed:12802065, PubMed:15229283). Interacts with SMAD4 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (PubMed:26878725).
Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance (PubMed:9348540). May anchor nucleoporins, but not NUP153 and TPR, to the NPC. During renal development, regulates podocyte migration and proliferation through SMAD4 signaling (PubMed:26878725).
Constitutively expressed in all tissues.
Has peptide-independent ATPase activity.
Found within the stromal cells in close contact to the vascular structure of placental villi, yolk sac, fetal liver, adrenal cortex and pancreas and in the beta cells of the islets of Langerhans in the adult pancreas. Found also in some forms of neuroendocrine lung tumor tissue.
May have a role in neuroendocrine differentiation.
Monomer. Interacts with SH3RF2 (By similarity).
Expressed mostly in tissues of the hematopoietic system, including bone marrow, spleen, lymph node and peripheral leukocytes. Among leukocytes, monocytes and neutrophils express the highest level. Expressed in CD14+ monocytes, but not in T-cells, B-cells or natural killer (NK) cells (at protein level).
May play a role in triggering innate immune responses. Does not seem to play a role for any class I MHC antigen recognition.
Binds SREK1/SFRS12. Interacts with DYRK1A.
Extensively phosphorylated on serine residues in the RS domain. Phosphorylated by DYRK1A, probably in the RS domain. Phosphorylation by DYRK1A modulates alternative splice site selection and inhibits the expression of MAPT/Tau exon 10.
Plays a role in constitutive splicing and modulates the selection of alternative splice sites. Plays a role in the alternative splicing of MAPT/Tau exon 10. Binds to alternative exons of TNC pre-mRNA and promotes the expression of alternatively spliced TNC. Plays a role in wound healing and in the regulation of keratinocyte differentiation and proliferation via its role in alternative splicing.
Widely expressed. Not detected in thymus.
Expressed in airway epithelial cells, renal tubular cells, pancreatic acinar cells and epithelial cells of the stomach, duodenum, and gallbladder (at protein level).
Expression increases in the cilia of the embryonic lung from 14 weeks of gestation.
Defects in MASTL may play a role in the pathogenesis of thrombocytopenia, a disorder defined by reduced number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting.
Phosphorylation at Thr-741 by CDK1 during M phase activates its kinase activity (By similarity). Maximum phosphorylation occurs in prometaphase.
Reduced levels of MASTL by RNAi causes mitotic abnormalities that consist of delay in G(2) phase and slow chromosome condensation. Cells that enter and progress through mitosis often fail to completely separate their sister chromatids in anaphase leading to the formation of 4N G(1) cells subsequent to failure of cytokinesis (PubMed:20818157, PubMed:20538976).
Serine/threonine kinase that plays a key role in M phase by acting as a regulator of mitosis entry and maintenance. Acts by promoting the inactivation of protein phosphatase 2A (PP2A) during M phase: does not directly inhibit PP2A but acts by mediating phosphorylation and subsequent activation of ARPP19 and ENSA at 'Ser-62' and 'Ser-67', respectively. ARPP19 and ENSA are phosphatase inhibitors that specifically inhibit the PPP2R2D (PR55-delta) subunit of PP2A. Inactivation of PP2A during M phase is essential to keep cyclin-B1-CDK1 activity high. Following DNA damage, it is also involved in checkpoint recovery by being inhibited. Phosphorylates histone protein in vitro; however such activity is unsure in vivo. May be involved in megakaryocyte differentiation.
Interacts with RIMS1, RIMS2, CACNA1D and CACNA1B, and potentially with other Ca(2+) channel alpha-1 isoforms.
Plays a role in the synaptic transmission as bifunctional linker that interacts simultaneously with RIMS1, RIMS2, CACNA1D and CACNA1B.
The SH3 domains mediate binding to a proline-rich motif in RIMS1, RIMS2, CACNA1D and CACNA1B.
Insulin-independent facilitative glucose transporter.
Predominantly expressed in skeletal muscle, heart and prostate, with lower levels in brain, placenta and kidney.
Belongs to the methyltransferase superfamily. RRP8 family.
Component of the eNoSC complex, composed of SIRT1, SUV39H1 and RRP8.
Essential component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. In the complex, RRP8 binds to H3K9me2 and probably acts as a methyltransferase. Its substrates are however unknown.
Homodimer. Binds SFRS1, SFRS2, SFRS3 and SFRS6. Interacts with the spliceosome (By similarity). Interacts with SREK1IP1.
Participates in the regulation of alternative splicing by modulating the activity of other splice facors. Inhibits the splicing activity of SFRS1, SFRS2 and SFRS6. Augments the splicing activity of SFRS3 (By similarity).
Interacts with PIP5K1A; the interaction inhibits PIP5K1A kinase activity.
Phosphatidylinositol 5-phosphate 4-kinase with low enzymatic activity. May be a GTP sensor, has higher GTP-dependent kinase activity than ATP-dependent kinase activity. PIP4Ks negatively regulate insulin signaling through a catalytic-independent mechanism. They interact with PIP5Ks and suppress PIP5K-mediated PtdIns(4,5)P2 synthesis and insulin-dependent conversion to PtdIns(3,4,5)P3 (PubMed:31091439).
Phosphorylated, phosphorylation is induced by EGF.
Disease susceptibility is associated with variants affecting the gene represented in this entry. A polymorphism at position 244 strongly influences susceptibility to multiple sclerosis. Overtransmission of the major 'C' allele coding for Thr-244 is detected in offspring affected with multiple sclerosis. In vitro analysis of transcripts from minigenes containing either 'C' allele (Thr-244) or 'T' allele (Ile-244) shows that the 'C' allele results in an approximately two-fold increase in the skipping of exon 6, leading to increased production of a soluble form of IL7R. Thus, the multiple sclerosis associated 'C' risk allele of IL7R would probably decrease membrane-bound expression of IL7R. As this risk allele is common in the general population, some additional triggers are probably required for the development and progression of MS.
N-glycosylated IL-7Ralpha binds IL7 300-fold more tightly than the unglycosylated form.
Receptor for interleukin-7. Also acts as a receptor for thymic stromal lymphopoietin (TSLP).
The IL7 receptor is a heterodimer of IL7R and IL2RG. The TSLP receptor is a heterodimer of CRLF2 and IL7R.
Defects in UHRF1 may be a cause of cancers. Overexpressed in many different forms of human cancers, including bladder, breast, cervical, colorectal and prostate cancers, as well as pancreatic adenocarcinomas, rhabdomyosarcomas and gliomas. Plays an important role in the correlation of histone modification and gene silencing in cancer progression. Expression is associated with a poor prognosis in patients with various cancers, suggesting that it participates in cancer progression.
Expressed in fetal thymus, liver and kidney.
Expressed in thymus, bone marrow, testis, lung and heart. Overexpressed in breast cancer.
Interacts with DNMT3A and DNMT3B (By similarity). Interacts with DNMT1; the interaction is direct. Interacts with USP7; leading to its deubiquitination. Interacts with histone H3. Interacts with HDAC1, but not with HDAC2. Interacts with BLTP3A. Interacts with PML. Interacts with EHMT2. Binds hemimethylated CpG containing oligonucleotides. Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (PubMed:32051553). Interacts with UHRF2 (PubMed:30335751). Interacts with FANCD2 (PubMed:30335751). Interacts with TET1 isoform 2; this interaction induces the recruitment of TET1 isoform 2 to replicating heterochromatin (By similarity).
Multi domain E3 ubiquitin ligase that also plays a role in DNA methylation and histone modifications.
Multidomain protein that acts as a key epigenetic regulator by bridging DNA methylation and chromatin modification. Specifically recognizes and binds hemimethylated DNA at replication forks via its YDG domain and recruits DNMT1 methyltransferase to ensure faithful propagation of the DNA methylation patterns through DNA replication. In addition to its role in maintenance of DNA methylation, also plays a key role in chromatin modification: through its tudor-like regions and PHD-type zinc fingers, specifically recognizes and binds histone H3 trimethylated at 'Lys-9' (H3K9me3) and unmethylated at 'Arg-2' (H3R2me0), respectively, and recruits chromatin proteins. Enriched in pericentric heterochromatin where it recruits different chromatin modifiers required for this chromatin replication. Also localizes to euchromatic regions where it negatively regulates transcription possibly by impacting DNA methylation and histone modifications. Has E3 ubiquitin-protein ligase activity by mediating the ubiquitination of target proteins such as histone H3 and PML. It is still unclear how E3 ubiquitin-protein ligase activity is related to its role in chromatin in vivo. Plays a role in DNA repair by cooperating with UHRF1 to ensure recruitment of FANCD2 to interstrand cross-links (ICLs) leading to FANCD2 activation.
Phosphorylation at Ser-298 of the linker region decreases the binding to H3K9me3. Phosphorylation at Ser-639 by CDK1 during M phase impairs interaction with USP7, preventing deubiquitination and leading to degradation by the proteasome.
The YDG domain (also named SRA domain) specifically recognizes and binds hemimethylated DNA at replication forks (DNA that is only methylated on the mother strand of replicating DNA) (PubMed:17673620). It contains a binding pocket that accommodates the 5-methylcytosine that is flipped out of the duplex DNA. 2 specialized loops reach through the resulting gap in the DNA from both the major and the minor grooves to read the other 3 bases of the CpG duplex. The major groove loop confers both specificity for the CpG dinucleotide and discrimination against methylation of deoxycytidine of the complementary strand (PubMed:18772889). The YDG domain also recognizes and binds 5-hydroxymethylcytosine (5hmC) (PubMed:21731699).
The YDG domain mediates the interaction with histone H3.
The tudor-like regions specifically recognize and bind histone H3 unmethylated at 'Arg-2' (H3R2me0), while the PHD-type zinc finger specifically recognizes and binds histone H3 trimethylated at 'Lys-9' (H3K9me3).
The tudor-like regions specifically recognize and bind histone H3 unmethylated at 'Arg-2' (H3R2me0), while the PHD-type zinc finger specifically recognizes and binds histone H3 trimethylated at 'Lys-9' (H3K9me3). The tudor-like regions simultaneously recognizes H3K9me3 through a conserved aromatic cage in the first tudor-like subdomain and unmodified H3K4 (H3K4me0) within a groove between the tandem subdomains (PubMed:21489993, PubMed:21777816, PubMed:22100450). The linker region plays a role in the formation of a histone H3-binding hole between the reader modules formed by the tudor-like regions and the PHD-type zinc finger by making extended contacts with the tandem tudor-like regions (PubMed:22837395).
Ubiquitinated; which leads to proteasomal degradation. Autoubiquitinated; interaction with USP7 leads to deubiquitination and prevents degradation. Ubiquitination and degradation takes place during M phase, when phosphorylation at Ser-639 prevents interaction with USP7 and subsequent deubiquitination. Polyubiquitination may be stimulated by DNA damage.
Up-regulated in proliferating cells, and down-regulated in quiescent cells. Down-regulated upon adriamycin-induced DNA damage, in a p53/TP53 and CDKN1A-dependent way. Induced by E2F1 transcription factor.
(Microbial infection) Interacts with HHV-1 ICP27 protein; this interaction recruits ALYREF to viral replication compartments and probably directs viral mRNA to the TAP/NFX1 pathway.
(Microbial infection) Interacts with human Kaposi's sarcoma-associated herpesvirus (HHV-8) ORF57 protein; this interaction allows efficient export of HHV-8 early and late intronless transcripts.
Acts as chaperone and promotes the dimerization of transcription factors containing basic leucine zipper (bZIP) domains and thereby promotes transcriptional activation.
Antibodies against ALYREF/THOC4 are found in sera of patients with systemic lupus erythematosus (SLE).
Arg-204 is dimethylated, probably to asymmetric dimethylarginine. Arginine methylation reduces RNA binding.
Export adapter involved in nuclear export of spliced and unspliced mRNA. Binds mRNA which is thought to be transferred to the NXF1-NXT1 heterodimer for export (TAP/NFX1 pathway) (PubMed:15833825, PubMed:15998806, PubMed:17190602, PubMed:11707413, PubMed:11675789, PubMed:11979277, PubMed:18364396, PubMed:22144908, PubMed:22893130, PubMed:23222130, PubMed:25662211). Component of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and specifically associates with spliced mRNA and not with unspliced pre-mRNA (PubMed:15833825, PubMed:15998806, PubMed:17190602). TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm (PubMed:15833825, PubMed:15998806, PubMed:17190602). TREX recruitment occurs via an interaction between ALYREF/THOC4 and the cap-binding protein NCBP1 (PubMed:15833825, PubMed:15998806, PubMed:17190602). The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production; ALYREF/THOC4 mediates the recruitment of the TREX complex to the intronless viral mRNA (PubMed:18974867). Required for TREX complex assembly and for linking DDX39B to the cap-binding complex (CBC) (PubMed:15998806, PubMed:17984224). In conjunction with THOC5 functions in NXF1-NXT1 mediated nuclear export of HSP70 mRNA; both proteins enhance the RNA binding activity of NXF1 and are required for NXF1 localization to the nuclear rim (PubMed:19165146). Involved in the nuclear export of intronless mRNA; proposed to be recruited to intronless mRNA by ATP-bound DDX39B. Involved in transcription elongation and genome stability (PubMed:12438613, PubMed:17984224). Involved in mRNA export of C5-methylcytosine (m5C)-containing mRNAs: specifically recognizes and binds m5C mRNAs and mediates their nucleo-cytoplasmic shuttling (PubMed:28418038).
Homomultimer. Is part of several complexes involved in mRNA processing and export. Component of the transcription/export (TREX) complex at least composed of ALYREF/THOC4, DDX39B, SARNP/CIP29, CHTOP and the THO subcomplex; TREX seems to have a dynamic structure involving ATP-dependent remodeling; in the complex interacts (via C-terminus) directly with DDX39B and interacts directly with THOC1 and THOC2. Found in mRNA splicing-dependent exon junction complexes (EJC). Identified in the spliceosome C complex. Found in a mRNP complex with UPF3A and UPF3B. Interacts with RBM8A, NCBP1, THOC5, LEF1, RUNX1, EIF4A3, RNPS1, SRRM1, IWS1 and EXOSC1. Interacts with RBM15B (PubMed:19586903). Interacts with NXF1; the interaction is direct.
Cornea (at protein level) (PubMed:10802664, PubMed:11683372). Increased expression in the stroma of keratoconus corneas (PubMed:11683372). Also detected in trachea, and in low levels, in intestine, skeletal muscle, ovary, lung and putamen (PubMed:10802664).
May be important in developing and maintaining corneal transparency and for the structure of the stromal matrix.
Acts as a receptor for kynurenic acid, an intermediate in the tryptophan metabolic pathway. The activity of this receptor is mediated by G-proteins that elicit calcium mobilization and inositol phosphate production through G(qi/o) proteins.
Predominantly expressed in immune and gastrointestinal tissues.
Acetylation at Lys-472 activates malonyl-CoA decarboxylase activity. Deacetylation at Lys-472 by SIRT4 represses activity, leading to promote lipogenesis (By similarity).
Catalyzes the conversion of malonyl-CoA to acetyl-CoA. In the fatty acid biosynthesis MCD selectively removes malonyl-CoA and thus assures that methyl-malonyl-CoA is the only chain elongating substrate for fatty acid synthase and that fatty acids with multiple methyl side chains are produced. In peroxisomes it may be involved in degrading intraperoxisomal malonyl-CoA, which is generated by the peroxisomal beta-oxidation of odd chain-length dicarboxylic fatty acids. Plays a role in the metabolic balance between glucose and lipid oxidation in muscle independent of alterations in insulin signaling. May play a role in controlling the extent of ischemic injury by promoting glucose oxidation.
Expressed in fibroblasts and hepatoblastoma cells (at protein level). Expressed strongly in heart, liver, skeletal muscle, kidney and pancreas. Expressed in myotubes. Expressed weakly in brain, placenta, spleen, thymus, testis, ovary and small intestine.
Homotetramer. Dimer of dimers. The two subunits within a dimer display conformational differences suggesting that at any given moment, only one of the two subunits is competent for malonyl-CoA binding and catalytic activity. Under oxidizing conditions, can form disulfide-linked homotetramers (in vitro). Associates with the peroxisomal targeting signal receptor PEX5.
Interchain disulfide bonds may form in peroxisomes (Potential). Interchain disulfide bonds are not expected to form in the reducing environment of the cytoplasm and mitochondria.
Malonyl-CoA decarboxylase activity does not require any cofactors or divalent metal ions. Formation of interchain disulfide bonds leads to positive cooperativity between active sites and increases the affinity for malonyl-CoA and the catalytic efficiency (in vitro).
May be produced by alternative initiation at Met-40 of isoform mitochondrial. Alternatively, represents a proteolytic processed form of the mitochondrial form.
Component of the transition zone in primary cilia. Required for ciliogenesis.
Probable serine/threonine-protein kinase.
Product of a dubious gene prediction. The corresponding gene is on a region of chromosome 21 that is known to be an artifactual duplication of another chromosome 21 region in the GRCh38 assembly. This entry may represent an artifactual copy of AC P57059.
C-termini of isoform 1 and isoform 2 are sufficient to interact with and to repress the activity of CLOCK-BMAL1 (PubMed:25936801).
Functions as a suppressor of the biological clock that drives the daily circadian rhythms of cells throughout the body (PubMed:25936801). Acts as a nuclear repressor of the CLOCK-BMAL1 heterodimer-mediated transcriptional activation of the core clock components (PubMed:25936801). Inhibits circadian clock function in cancer cells, when overexpressed (PubMed:25936801).
Interacts with the CLOCK-BMAL1 heterodimer; this interaction inhibits CLOCK-BMAL1 transcriptional activation and suppress circadian timekeeping (PubMed:25936801). Interacts with BMAL1 (PubMed:25936801).
Testis-specific (PubMed:25936801). Expressed in a broad range of cancer cells, including melanoma, lung cancer, and breast cancer (at protein level). Testis-specific (PubMed:15162151). Found in histologically normal tissues from patients with uterus, lung and small intestine cancers. Widespread expression seen in solid tumors and diffuse large B-cell lymphoma (DLBCL)-derived cell lines. Isoform 2 is expressed in all DLBCL-derived cell lines, while isoform 1 is preferentially expressed in cell lines derived from non-germinal center DLBCL (PubMed:15162151).
Interacts with EGFR, ERBB2 and ERBB4 (in vitro).
May play a role in craniofacial and inner ear morphogenesis during embryonic development. May act within the otic vesicle epithelium to control formation of the lateral semicircular canal in the inner ear, possibly by restricting the expression of NTN1 (By similarity).
Catalyzes the conversion of gamma-aminobutyrate and L-beta-aminoisobutyrate to succinate semialdehyde and methylmalonate semialdehyde, respectively (PubMed:10407778, PubMed:15528998). Can also convert delta-aminovalerate and beta-alanine (By similarity).
Liver > pancreas > brain > kidney > heart > placenta.
Belongs to the methyltransferase superfamily. METTL18 family.
Interacts with GRWD1 and members of the heat shock protein 90 and 70 families; these proteins may possibly be methylation substrates for the enzyme.
Monomethylated at His-154 through automethylation (PubMed:33693809). Automethylation at His-154 positively regulates the methyltransferase activity toward RPL3 (PubMed:33693809). Probably methylated on other residues (PubMed:33693809).
Protein-L-histidine N-tele-methyltransferase that specifically monomethylates RPL3, thereby regulating translation elongation (PubMed:23349634, PubMed:33693809, PubMed:35674491). Histidine methylation of RPL3 regulates translation elongation by slowing ribosome traversal on tyrosine codons: slower elongation provides enough time for proper folding of synthesized proteins and prevents cellular aggregation of tyrosine-rich proteins (PubMed:35674491).
Extracellular matrix protein which may play a role in cell adhesion.
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins.
Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules (PubMed:10935626). Modulates NOTCH1 activity by modifying O-fucose residues at specific EGF-like domains resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1 (By similarity).
Acts as a tumor suppressor. Inhibits DNA synthesis. Its ability to inhibit oncogenic transformation is mediated through its association with RB1. Plays a role in the expression of genes required for the G1/S transition.
Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2. The complex exists in quiescent cells where it represses cell cycle-dependent genes. It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2. Interacts with RB1.
Expressed in testis, ovary, liver, spleen, brain, kidney, prostate, lung, liver, and heart.
Ubiquitinated by the CRL2(APPBP2) complex, which recognizes the Arg-Xaa-Xaa-Gly sequence at the C-terminus, leading to its degradation.
Associates with proteins harboring glycine-rich transmembrane domains and ensures their efficient localization to the cell surface (PubMed:25999474). Regulates the assembly and activity of V-ATPase in colon cancer cells via its interaction with V-type proton ATPase subunit H (ATP6V1H) and contributes to V-ATPase-mediated pH alterations in cancer cells which play an important role in drug resistance and invasiveness of colon cancer cells (PubMed:25659576). Plays an important role in an atypical phagocytic activity of metastatic melanoma cells called cannibalism and is involved in the pH regulation of the intracellular vesicles in tumor cells (PubMed:19893578).
Highly expressed in metastatic melanoma cells whereas it is undetectable in primary melanoma cells, healthy skin tissues and peripheral blood lymphocytes. Expressed in CD34(+) hematopoietic progenitor cells and during monocyte and granulocyte differentiation. Overexpressed in acute myeloid leukemia, in particular in those displaying granulocytic differentiation (at protein level).
Interacts with ATP6V1H in colon cancer cells (PubMed:25659576).
Transcriptionally repressed following hypoxia by HIF1A in leukemic cells.
A functional Walker motif (consensus sequence G-X-X-G-X-G-K-[ST]-T) is expected to bind ATP. The essential Lys in this region is not conserved in ABCG8 (G-S-S-G-C-R-A-S) and is not required for transport activity mediated by the heterodimer with ABCG5.
ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane. Plays an essential role in the selective transport of the dietary cholesterol in and out of the enterocytes and in the selective sterol excretion by the liver into bile (PubMed:11099417, PubMed:11452359, PubMed:27144356, PubMed:15054092). Required for normal sterol homeostasis (PubMed:11099417, PubMed:11452359, PubMed:15054092). The heterodimer with ABCG5 has ATPase activity (PubMed:16893193, PubMed:20210363, PubMed:27144356).
Minor form detected in approximately 10% of the cDNA clones.
Predominantly expressed in the liver (PubMed:11099417, PubMed:11452359). Low expression levels in the small intestine and colon (PubMed:11099417). Very low levels in other tissues, including brain, heart and spleen (PubMed:11452359).
Seems to have a defective ATP-binding region.
The ATPase activity of the heterodimer is stimulated by cholate. Taurocholate, glycocholate, taurochenodeoxycholate, glycochenodeoxycholate and taurodeoxycholate also stimulate ATPase activity, but to a lower degree. Glycodeoxycholate has no significant effect on ATPase activity. ATPase activity is inhibited by vanadate and by berillium fluoride.
The poly-Gly region is polymorphic and the number of Gly varies in the population (from 9 to 12).
Abundant in the brain (PubMed:11294880). Expressed at low levels in the aorta, uterus and intestine (PubMed:11294880).
Belongs to the Ca(2+):cation antiporter (CaCA) (TC 2.A.19) family. SLC24A subfamily.
Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+).
(Microbial infection) Interacts with human cytomegalovirus protein UL13; this interaction alters cristae architecture.
Belongs to the MICOS complex subunit Mic60 family.
Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane. Plays an important role in the maintenance of the MICOS complex stability and the mitochondrial cristae morphology (PubMed:22114354, PubMed:25781180).
Component of the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOOL/MIC27, IMMT/MIC60, APOO/MIC23/MIC26 and MICOS13/MIC13 (PubMed:25764979, PubMed:25781180). This complex was also known under the names MINOS or MitOS complex. The MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1 and MTX2 (together described as components of the mitochondrial outer membrane sorting assembly machinery (SAM) complex) and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9 (PubMed:25764979, PubMed:25781180). The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both membranes termed the mitochondrial intermembrane space bridging (MIB) complex (PubMed:22252321). Interacts with HSPA1A/HSPA1B and OPA1, preferentially with the soluble OPA1 form (By similarity). Interacts with MICOS13/MIC13, MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, SAMM50 and TMEM11 (PubMed:25997101). Interacts with APOO/MIC23/MIC26 and APOOL/MIC27 (PubMed:25764979, PubMed:25781180). Interacts with ARMC1 (PubMed:31644573). Interacts with ARMC12 (By similarity). Interacts with mitochondrial microprotein SHMOOSE (PubMed:36127429).
Negatively regulates aortic matrix metalloproteinase-9 (MMP9) production and may play a protective role in vascular remodeling.
Calcium-dependent cell-adhesion protein (By similarity). May play a role in activity-induced synaptic reorganization underlying long term memory (By similarity). Could be involved in CDH2 internalization through TAOK2/p38 MAPK pathway. In hippocampal neurons, may play a role in the down-regulation of dendritic spines, maybe through its action on CDH2 endocytosis (By similarity).
The N-terminal extracellular domain forms homophilic interactions; these interactions activate p38 MAPK via TAOK2 and trigger endocytosis. Interacts with CDH2; this interaction may lead to CDH2 cointernalization. Interacts with CDH11. Interacts with TAOK2.
A chromosomal aberration involving CBFA2T3 is found in therapy-related myeloid malignancies. Translocation t(16;21)(q24;q22) that forms a RUNX1-CBFA2T3 fusion protein.
Down-regulated by all-trans retinoic acid (ATRA).
Homooligomer. Homotetramerization is mediated by nervy homology region 2 (NRH2) (By similarity). Can interact with RUNX1T1 and CBFA2T2; heterotetramerization between members of the CBFA2T family is proposed (PubMed:12242670). Component of a TAL-1 complex composed at least of CBFA2T3, LDB1, TAL1 and TCF3 (By similarity). Interacts with ERBB4, HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, NCOR1, NCOR2, and ZNF652. According to PubMed:12242670, may not interact with HDAC6. Interacts with PLXNA1, PLXNA3 and PRKAR1A. Isoform 2 interacts with PRKAR2A, PDE7A and probably PDE4A. Interacts with ZBTB4, ZBTB38 and ZBTB33. Interacts with HIF1A and EGLN1. Interacts with the AML1-MTG8/ETO fusion protein.
Isoform 2 functions as an A-kinase-anchoring protein (PubMed:11823486).
Transcriptional corepressor which facilitates transcriptional repression via its association with DNA-binding transcription factors and recruitment of other corepressors and histone-modifying enzymes (PubMed:12559562, PubMed:15203199). Can repress the expression of MMP7 in a ZBTB33-dependent manner (PubMed:23251453). Reduces the protein levels and stability of the transcriptinal regulator HIF1A; interacts with EGLN1 and promotes the HIF1A prolyl hydroxylation-dependent ubiquitination and proteasomal degradation pathway (PubMed:25974097). Contributes to inhibition of glycolysis and stimulation of mitochondrial respiration by down-regulating the expression of glycolytic genes including PFKFB3, PFKFB4, PDK1, PFKP, LDHA and HK1 which are direct targets of HIF1A (PubMed:23840896, PubMed:25974097). Regulates the proliferation and the differentiation of erythroid progenitors by repressing the expression of TAL1 target genes (By similarity). Plays a role in granulocyte differentiation (PubMed:15231665).
Widely expressed with higher expression in heart, pancreas, skeletal muscle, spleen, thymus and peripheral blood leukocytes. Expressed in hematopoietic cells (at protein level).
Belongs to the Cob(I)alamin adenosyltransferase family.
Converts cob(I)alamin to adenosylcobalamin (adenosylcob(III)alamin), a coenzyme for methylmalonyl-CoA mutase, therefore participates in the final step of the vitamin B12 conversion (PubMed:12514191). Generates adenosylcobalamin (AdoCbl) and directly delivers the cofactor to MUT in a transfer that is stimulated by ATP-binding to MMAB and gated by MMAA (Probable).
Expressed from early embryogenesis through to adulthood.
Expressed ubiquitously at low levels. High levels of expression are confined to hematopoietic tissues including peripheral blood leukocytes, thymus and spleen.
Plays a role in ribosome biogenesis and in nuclear import of the 60S ribosomal protein L5/large ribosomal subunit protein uL18 (RPL5) (PubMed:35213692). Required for proper erythrocyte maturation (PubMed:35213692).
Expressed in liver and kidney and at reduced levels in the brain, heart, and skeletal muscle.
Homotetramer (By similarity). May interact with PRNP.
Involved in the regulation of homocysteine metabolism. Converts homocysteine to methionine using S-methylmethionine (SMM) as a methyl donor.
Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Component of the STAGA transcription coactivator-HAT complex, at least composed of SUPT3H, SUPT7L, GCN5L2, TAF5L, TAF6L, TADA3L, TAD1L, TAF10, TAF12 and TAF9.
Expressed at high levels in adenocarcinomas and gliomas and low in esophageal cancers and malignant hematological disease. Also expressed at high level in the thymus, low in peripheral blood mononuclear cells, and lowest in the stomach, small intestine, and skeletal muscle.
(Microbial infection) Acts as an entry co-receptor for herpes simplex virus 1.
(Microbial infection) Interacts with herpes simplex virus 1 glycoprotein B.
According to PubMed:10660620, N- and O-glycosylated. According to PubMed:10903717, only N-glycosylated.
Contains 2 copies of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases. PTPN6 seems to bind predominantly to the first ITIM motif.
Monomer. Interacts with PTPN6/SHP-1 and PTPN11/SHP-2 upon tyrosine phosphorylation.
Paired receptors consist of highly related activating and inhibitory receptors and are widely involved in the regulation of the immune system. PILRA is thought to act as a cellular signaling inhibitory receptor by recruiting cytoplasmic phosphatases like PTPN6/SHP-1 and PTPN11/SHP-2 via their SH2 domains that block signal transduction through dephosphorylation of signaling molecules. Receptor for PIANP.
Predominantly detected in hemopoietic tissues and is expressed by monocytes, macrophages, and granulocytes, but not by lymphocytes. Also strongly expressed by dendritic cells (DC); preferentially by CD14+/CD1a- DC derived from CD34+ progenitors. Also expressed by CD11c+ blood and tonsil DC, but not by CD11c- DC precursors.
Catalyzes the phosphorylation of sphingosine to form sphingosine-1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-dihydrosphingosine, D-erythro-sphingosine and L-threo-dihydrosphingosine. Binds phosphoinositides (PubMed:19168031, PubMed:12954646). In contrast to prosurvival SPHK1, has a positive effect on intracellular ceramide levels, inhibits cells growth and enhances apoptosis (PubMed:16118219). In mitochondria, is important for cytochrome-c oxidase assembly and mitochondrial respiration. The SPP produced in mitochondria binds PHB2 and modulates the regulation via PHB2 of complex IV assembly and respiration (PubMed:20959514). In nucleus, plays a role in epigenetic regulation of gene expression. Interacts with HDAC1 and HDAC2 and, through SPP production, inhibits their enzymatic activity, preventing the removal of acetyl groups from lysine residues with histones. Up-regulates acetylation of histone H3-K9, histone H4-K5 and histone H2B-K12 (PubMed:19729656). In nucleus, may have an inhibitory effect on DNA synthesis and cell cycle (PubMed:12954646, PubMed:16103110). In mast cells, is the main regulator of SPP production which mediates calcium influx, NF-kappa-B activation, cytokine production, such as TNF and IL6, and degranulation of mast cells (By similarity). In dopaminergic neurons, is involved in promoting mitochondrial functions regulating ATP and ROS levels (By similarity). Also involved in the regulation of glucose and lipid metabolism (By similarity).
Cleaved by CASP1 in apoptotic cells. The truncated form is released from cells.
In patients with Alzheimer's disease brains, may be preferentially localized in the nucleus. Cytosolic expression decrease correlates with the density of amyloid deposits.
Inhibited by sulfatide (PubMed:19168031). Kinase activity is increased by phosphorylation by MAPK2 upon PMA or EGF treatments (PubMed:17311928).
Interacts with histone H3 (PubMed:19729656). Interacts with HDAC1, HDAC2, MBD2 and SIN3A (PubMed:19729656). Interacts with EEF1A1; the interaction enhances SPHK2 kinase activity (PubMed:18263879). Interacts with PHB2 (By similarity).
Mainly expressed in adult kidney, liver, and brain (PubMed:10751414). Expressed in cerebral cortex and hippocampus (at protein level) (PubMed:29615132). Isoform 1 is the predominant form expressed in most tissues (PubMed:16103110).
Phosphorylated by PKD on Ser-419 and Ser-421 upon PMA treatment. Phosphorylation induces export from the nucleus to the cytoplasm (PubMed:17635916). Phosphorylated by MAPK1 and MAPK2 at Ser-387 and Thr-614, phosphorylation is induced by agonists such as EGF and PMA and increases kinase activity (PubMed:17311928).
Acts as a regulator of the Hippo signaling pathway (PubMed:28087714, PubMed:28169360). Negatively regulates the Hippo signaling pathway by mediating the interaction of MARK3 with STK3/4, bringing them together to promote MARK3-dependent hyperphosphorylation and inactivation of STK3 kinase activity toward LATS1 (PubMed:28087714). Positively regulates the Hippo signaling pathway by mediating the interaction of SCRIB with STK4/MST1 and LATS1 which is important for the activation of the Hippo signaling pathway. Involved in regulating cell proliferation, maintenance of epithelial polarity, epithelial-mesenchymal transition (EMT), cell migration and invasion (PubMed:28169360). Plays an important role in dendritic spine formation and synaptogenesis in cortical neurons; regulates synaptogenesis by enhancing the cell surface localization of N-cadherin. Acts as a positive regulator of hedgehog (Hh) signaling pathway. Plays a critical role in the early point of the SMO activity cycle by interacting with SMO at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation (By similarity).
Highly expressed in normal breast tissues and low-grade breast cancer tissues (at protein level) (PubMed:28169360). Highly expressed in the placenta and prostate. Expressed at a lower level in the thyroid, spinal cord, trachea, adrenal gland, skeletal muscle, pancreas, heart, brain, liver and kidney. A short splice product shows more limited expression, being absent from at least the brain.
Interacts with MPP1 (PubMed:9738934). Interacts with CTNNB1 and with the third SH3 domain of SORBS3 to form a ternary complex (PubMed:12657639). Interacts (via coiled-coil domain) with MARK3. Interacts (via PDZ domain 3) with STK3/MST2 and STK4/MST1 (PubMed:28087714). Interacts with SCRIB (PubMed:28169360). Interacts with CTNB1, SMO and (via PDZ4 or guanylate kinase-like domain) with KIF7 (By similarity).
The guanylate kinase-like domain interacts with the SH3 domain.
According to a report, ubiquitin-binding is dispensable for function (PubMed:22396592). However, such data are not confirmed by PubMed:22705371.
Component of the Fanconi anemia (FA) complex required to recruit the FA complex to DNA interstrand cross-links (ICLs) and promote ICLs repair. Following DNA damage recognizes and binds 'Lys-63'-linked ubiquitin generated by RNF8 at ICLs and recruits other components of the FA complex. Promotes translesion synthesis via interaction with REV1.
Component of the Fanconi anemia (FA) complex. Interacts with FANCA; interaction is direct. Interacts with REV1. Reported to bind monoubiquitinated REV1; however it binds better to non-ubiquitinated REV1 (PubMed:22266823).
The UBZ2-type zinc finger binds both 'Lys-48'- and 'Lys-63'-linked polyubiquitin with preference for 'Lys-63'-linked polyubiquitin.
In adult tissues, expressed only in skeletal muscle.
Expressed in lung, spleen, thymus and peripheral blood leukocytes.
Neuroendocrine protein of the granin family that regulates the biogenesis of secretory granules.
Detected in peripheral blood mononuclear cells and in T-cells (at protein level). Detected in spleen and lymphocytes.
Plays a role in T-cell responses in the adaptive immune response.
Phosphorylated when associated with the catalytic subunit (PRKAA1 or PRKAA2). Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK.
The glycogen-binding domain may target AMPK to glycogen so that other factors like glycogen-bound debranching enzyme or protein phosphatases can directly affect AMPK activity.
Cross-linked by interchain disulfide bonds around the DNA-helix.
Highest expression in brain, prostate and testis, and moderate expression in kidney, small intestine and ovary.
Microtubule-associated force-producing protein that may play a role in organelle transport. Has ATPase activity (By similarity). Involved in synaptic transmission (PubMed:24812067). Mediates dendritic trafficking of mRNAs (By similarity). Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation (By similarity).
Oligomer composed of two heavy chains and two light chains. Interacts with GRIP1 and KLC3 (By similarity). Interacts with TRAK1 (PubMed:15644324). Interacts with ZFYVE27 (By similarity).
Belongs to the TRAFAC class YlqF/YawG GTPase family. NOA1 subfamily.
Homodimer or multimer (By similarity). Interacts with mitochondrial complex I, DAP3, MRPL12 and MRPS27.
Involved in regulation of mitochondrial protein translation and respiration. Plays a role in mitochondria-mediated cell death. May act as a scaffolding protein or stabilizer of respiratory chain supercomplexes. Binds GTP.
Detected at the highest levels in peripheral blood leukocytes and breast cancer cell lines. Found in leukocytes of the myeloid lineage, with the strongest expression observed in granulocytes and no detectable expression in lymphocytes. Expressed in thymic epithelial cells and fibroblasts.
Belongs to the GST superfamily. Kappa family.
Glutathione S-transferase that catalyzes the conjugation of glutathione to exogenous and endogenous compounds (PubMed:14709161, PubMed:14742434). Significant glutathione conjugating activity is found only with the model substrate, 1-chloro-2,4-dinitrobenzene (CDNB) (PubMed:14709161).
Interacts with PRKAR1A and PRKAR2A. Interacts with ENO4.
Major structural component of sperm fibrous sheath. Plays a role in sperm motility.
RI-alpha binding site, predicted to form an amphipathic helix, could participate in protein-protein interactions with a complementary surface on the R-subunit dimer.
Testis specific; only expressed in round spermatids.
Hydrolyzes oligopeptides such as neurotensin, bradykinin and dynorphin A (By similarity). Acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin, an antagonist peptide of the cannabinoid receptor CNR1 (By similarity).
Detected in placenta, kidney, lung, pancreas and at very low level in other tissues.
Glycoprotein which is a component of the gelatinous extracellular matrix in the cupulae of the vestibular organ.
Proteolytically cleaved before the transmembrane segment to yield the secreted form found in the extracellular matrix of the cupula.
(Microbial infection) Interacts (via C-terminus) with SARS coronaviru/SARS-CoV and SARS coronavirus-2/SARS-CoV-2 virus protein ORF9b.
(Microbial infection) Interacts with parasite T.gondii RH strain MAF1b1; the interaction impairs TOMM70 import activity, enables the parasite to associate with the host mitochondria and facilitates the association of MAF1b1 with MIB complex component SAMM50, promoting the formation of SPOTs (structures positive for outer mitochondrial membrane (OMM)); the interaction is probably indirect.
Acts as receptor of the preprotein translocase complex of the outer mitochondrial membrane (TOM complex) (PubMed:12526792). Recognizes and mediates the translocation of mitochondrial preproteins from the cytosol into the mitochondria in a chaperone dependent manner (PubMed:12526792, PubMed:35025629). Mediates TBK1 and IRF3 activation induced by MAVS in response to Sendai virus infection and promotes host antiviral responses during virus infection (PubMed:20628368, PubMed:25609812, PubMed:32728199). Upon Sendai virus infection, recruits HSP90AA1:IRF3:BAX in mitochondrion and the complex induces apoptosis (PubMed:25609812).
Forms part of the preprotein translocase complex of the outer mitochondrial membrane (TOM complex) which consists of at least 7 different proteins (TOMM5, TOMM6, TOMM7, TOMM20, TOMM22, TOMM40 and TOMM70) (PubMed:18331822). Interacts with CAPN8 (By similarity). Interacts with TRADD, TRAF6 and STING (PubMed:20628368). Interacts with MAVS; the interaction is enhanced by Sendai virus infection (PubMed:20628368). Interacts with HSPA8 and HSP90AA1; both interactions are required for preprotein mitochondrial import (PubMed:12526792). The interaction with HSP90AA1 is direct and mediates the association of TOMM70 with IRF3 and TBK1 (PubMed:20628368, PubMed:25609812).
Catalyzes the adenylation of flavin mononucleotide (FMN) to form flavin adenine dinucleotide (FAD) coenzyme.
In the C-terminal section; belongs to the PAPS reductase family. FAD1 subfamily.
The molybdenum cofactor biosynthesis protein-like region may not be functional.
May function as a ubiquitin-protein or polyubiquitin hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. May therefore play an important regulatory role at the level of protein turnover by preventing degradation of proteins through the removal of conjugated ubiquitin. Essential component of TGF-beta/BMP signaling cascade. Deubiquitinates monoubiquitinated SMAD4, opposing the activity of E3 ubiquitin-protein ligase TRIM33. Monoubiquitination of SMAD4 hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination of SMAD4 by USP9X re-empowers its competence to mediate TGF-beta signaling (By similarity).
The disease may be caused by variants affecting the gene represented in this entry. The role of USP9Y in spermatogenesis failure is uncertain (PubMed:19246359). A 4-bp deletion in a splice-donor site, causing exon skipping and protein truncation has been observed in non-obstructive azoospermia (PubMed:10581029). However, complete USP9Y deletion has been detected in individuals with no spermatogenic defects (PubMed:19246359).
USP9Y is located in the 'azoospermia factor a' (AZFa) region on chromosome Y which is deleted in Sertoli cell-only syndrome. This is an infertility disorder in which no germ cells are visible in seminiferous tubules leading to azoospermia. However, AZFa deletions resulting in complete loss of USP9Y have also been found in normospermic men (PubMed:19246359).
(Microbial infection) Inhibits Epstein-Barr virus EBNA2-mediated transcriptional activation and host cell proliferation, through direct interaction.
(Microbial infection) Interacts (via MYND-type zinc finger) with Epstein-Barr virus EBNA2 protein (via PXLXP motif) (PubMed:11733528, PubMed:26845565). Interacts with Epstein-Barr virus-derived protein LMP1; leading to negatively regulate NF-kappa-B activation by Epstein-Barr virus-derived protein LMP1 (PubMed:12181323, PubMed:16382137, PubMed:19379743, PubMed:20138174).
(Microbial infection) Interacts (via MYND-type zinc finger) with human adenovirus early E1A protein (via PXLXP motif); this interaction inhibits E1A mediated transactivation.
A chromosomal aberration involving ZMYND11 is a cause of acute poorly differentiated myeloid leukemia. Translocation (10;17)(p15;q21) with MBTD1.
Chromatin reader that specifically recognizes and binds histone H3.3 trimethylated at 'Lys-36' (H3.3K36me3) and regulates RNA polymerase II elongation. Does not bind other histone H3 subtypes (H3.1 or H3.2) (By similarity). Colocalizes with highly expressed genes and functions as a transcription corepressor by modulating RNA polymerase II at the elongation stage. Binds non-specifically to dsDNA (PubMed:24675531). Acts as a tumor-suppressor by repressing a transcriptional program essential for tumor cell growth.
Down-regulated in breast cancer patients with poor prognosis.
Homooligomer; forms homooligomers via its C-terminus (PubMed:26845565). Interacts with histone H3.3 trimethylated at 'Lys-36' (H3.3K36me3) (PubMed:24675531, PubMed:26655721). Interacts (via MYND-type zinc finger) with NCOR1 (PubMed:10734313). Interacts (via MYND-type zinc finger) with MGA protein (via PXLXP motif) (PubMed:23372760). Interacts (via MYND-type zinc finger) with EZH2 (PubMed:16565076). Interacts with EMSY and E2F6 (PubMed:15947784, PubMed:16565076). Interacts with PIAS1 and UBE2I (PubMed:19766626).
Sumoylated following its interaction with PIAS1 and UBE2I.
The PWWP domain specifically recognizes and binds histone H3.3 trimethylated at 'Lys-36' (H3.3K36me3) and adopts a five-bladed beta-barrel fold with an extended C-terminal alpha-helix, with a conserved H3.3K36me3-binding aromatic cage formed by Phe-291 and Trp-294 of the beta1-beta2 loop and Phe-310 of the beta3-beta4 loop. Specific recognition of H3.3 histone is mediated by the encapsulation of the H3.3-specific 'Ser 31' residue in a composite pocket formed by the tandem bromo-PWWP domains.
Expressed in testis. Up-regulated in bladder cancer cells (at protein level).
Isoform 2 and isoform 5 can form homodimers and heterodimers. Interacts with ZNF224.
May be involved in transcriptional regulation as a transcriptional corepressor. The DEPDC1A-ZNF224 complex may play a critical role in bladder carcinogenesis by repressing the transcription of the A20 gene, leading to transport of NF-KB protein into the nucleus, resulting in suppression of apoptosis of bladder cancer cells.
Antigen recognized by serum from scleroderma patient.
Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates the ubiquitination of target proteins, leading most often to their proteasomal degradation. In complex with CUL3, involved in ubiquitination and proteasomal degradation of BRMS1, DAXX, PDX1/IPF1, GLI2 and GLI3. In complex with CUL3, involved in ubiquitination of MACROH2A1 and BMI1; this does not lead to their proteasomal degradation. Inhibits transcriptional activation of PDX1/IPF1 targets, such as insulin, by promoting PDX1/IPF1 degradation. The cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing homodimeric SPOP has higher ubiquitin ligase activity than the complex that contains the heterodimer formed by SPOP and SPOPL. Involved in the regulation of bromodomain and extra-terminal motif (BET) proteins BRD2, BRD3, BRD4 stability (PubMed:32109420).
Interacts with GLI2 and GLI3 (By similarity). Homodimer and homooligomer. Heterodimer with SPOPL. Each dimer interacts with two CUL3 molecules. Part of cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes that contain CUL3 and homodimeric SPOP, or the heterodimer formed by SPOP and SPOPL, plus a target protein, such as MACROH2A1, PDX1/IPF1, BMI1, BRMS1 and DAXX.
The BTB (POZ) domain mediates dimerization and interaction with CUL3.
The MATH domain mediates interaction with protein-ubiquitin ligase substrates, such as MACROH2A1 and BMI1.
Broadly expressed, with highest levels in skeletal muscle, heart and kidney.
Part of the mechanistic target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8 and RPTOR (PubMed:12718876, PubMed:12408816, PubMed:15268862, PubMed:17510057, PubMed:23636326, PubMed:27909983, PubMed:26678875, PubMed:31601764, PubMed:24403073, PubMed:29236692, PubMed:34519268, PubMed:34519269, PubMed:36697823). mTORC1 associates with AKT1S1/PRAS40, which inhibits its activity (PubMed:31601764). mTORC1 binds to and is inhibited by FKBP12-rapamycin (PubMed:12408816). Within mTORC1, interacts directly with MTOR and RPTOR (PubMed:12718876). Part of the mechanistic target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR (PubMed:15268862, PubMed:15467718, PubMed:17461779, PubMed:17510057, PubMed:23636326, PubMed:26678875, PubMed:34519268). Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin (PubMed:12408816). mTORC1 and mTORC2 associate with DEPTOR, which regulates its activity (PubMed:34519268, PubMed:34519269). Interacts with RHEB (PubMed:15854902). Interacts with MEAK7 (PubMed:29750193). Interacts with SIK3 (PubMed:30232230). Interacts with SLC38A7; this interaction promotes the recruitment of mTORC1 to the lysosome and its subsequent activation (PubMed:35561222).
Phosphorylation at Thr-51 by CDK1 promotes ubiquitination by the SCF(FBXW7) complex, followed by degradation.
Subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals (PubMed:12718876, PubMed:15268862, PubMed:15467718, PubMed:24403073). mTORC1 is activated in response to growth factors or amino acids (PubMed:12718876, PubMed:15268862, PubMed:15467718, PubMed:24403073). In response to nutrients, mTORC1 is recruited to the lysosome membrane and promotes protein, lipid and nucleotide synthesis by phosphorylating several substrates, such as ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) (PubMed:12718876, PubMed:15268862, PubMed:15467718, PubMed:24403073). In the same time, it inhibits catabolic pathways by phosphorylating the autophagy initiation components ULK1 and ATG13, as well as transcription factor TFEB, a master regulators of lysosomal biogenesis and autophagy (PubMed:24403073). The mTORC1 complex is inhibited in response to starvation and amino acid depletion (PubMed:24403073). Within mTORC1, LST8 interacts directly with MTOR and enhances its kinase activity (PubMed:12718876). In nutrient-poor conditions, stabilizes the MTOR-RPTOR interaction and favors RPTOR-mediated inhibition of MTOR activity (PubMed:12718876). mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive (PubMed:15467718). mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors (PubMed:15467718). mTORC2 promotes the serum-induced formation of stress-fibers or F-actin (PubMed:15467718). mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation (PubMed:15467718). mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed:15467718). mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657' (PubMed:15467718).
Ubiquitination by the SCF(FBXW7) and SCF(FBXW11) complexes following phosphorylation at Thr-51 by CDK1, leads to its degradation by the proteasome.
Expressed in umbilical vein endothelial cells and in several highly vascularized tissues such as kidney, colon, skeletal muscle, heart and small intestine. Highly expressed in ductal epithelial cells of salivary glands, seminal vesicles and the collecting tubules of the kidney. Isoform 1 is also highly expressed in both fetal and adult brain, pituitary, tonsils, spleen, adenoids, fetal kidney, liver, testes and ovary. Isoform 1 is also expressed at moderate levels in primary aortic endothelial cells and adrenal medulla, and at low levels in adrenal cortex. Isoform 4 is specifically and highly expressed in pituitary, fetal brain and umbilical vein endothelial cells.
Feedback inhibitor of fibroblast growth factor mediated Ras-MAPK signaling and ERK activation (PubMed:12958313, PubMed:12807873). Regulates the nuclear ERK signaling pathway by spatially blocking nuclear translocation of activated ERK without inhibiting cytoplasmic phosphorylation of ERK (PubMed:15239952). Mediates JNK activation and may be involved in apoptosis (By similarity). May inhibit FGF-induced FGFR1 tyrosine phosphorylation (By similarity). Might have a role in the early stages of fate specification of GnRH-secreting neurons (By similarity). Inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells (By similarity).
Interacts with MAP3K7 (By similarity). Self-associates. Interacts with FGFR1, FGFR2 and phosphorylated MAP2K1 or MAP2K2. Associates with a MAP2K1/2-MAPK1/3 complex.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in IL17RD also have a heterozygous mutation in another HH-associated gene including FGFR1 and KISS1R (PubMed:23643382).
Highly expressed in the CNS, the highest expression is seen in the amygdala, hippocampus and thalamus. Weak expression is detected in testis. Down-regulated in glioblastoma.
One of the 8 copies of RANBP2 clustered close to the chromosome 2 centromere.
Metalloprotease which may be important for placentation by regulating biological activity of key peptides at the embryo-maternal interface. On synthetic substrates it shows a marked preference for Leu-4-methylcoumaryl-7-amide (Leu-MCA) over Met-MCA, Arg-LCA and Lys-LCA. Cleaves the N-terminal amino acid of several peptides such as angiotensin-3, kisspeptin-10 and endokinin C.
Specifically expressed in placenta and not in other tissues. Mainly found at the cell surface region of the extravillous trophoblasts. Detected on extravillous trophoblasts in the outer layer of the chorion laeve in the fetal membrane Not detected on either fetal amnionic epithelial cells or maternal decidual cells. Also detected in the migrating extravillous trophoblasts in the maternal decidual tissues (at protein level).
A tripeptide motif (ECD) within disintegrin-like domain could be involved in the binding to egg integrin receptor and thus could mediate sperm/egg binding.
Sperm surface membrane protein that may be involved in spermatogenesis and fertilization. This is a non catalytic metalloprotease-like protein (By similarity).
The prodomain and the metalloprotease-like domain are cleaved during the epididymal maturation of the spermatozoa.
Heterodimer; heterodimerizes with SNX7 or SNX30 (PubMed:32513819). Interacts with WWC1/KIBRA (PubMed:17994011). Identified in a complex with WWC1/KIBRA and dynein components DYNLL1 and DYNC1I2 (PubMed:17994011). Interacts with BIN1 (PubMed:12668730).
Involved in the regulation of endocytosis and in several stages of intracellular trafficking (PubMed:12668730, PubMed:17994011, PubMed:32513819, PubMed:33468622). Plays a role in recycling endocytosed transferrin receptor and prevent its degradation (PubMed:17994011). Involved in autophagosome assembly by regulating trafficking and recycling of phospholipid scramblase ATG9A (PubMed:32513819, PubMed:33468622).
The PX domain binds phosphatidylinositol 3-phosphate which is necessary for peripheral membrane localization.
Capable of hydrolyzing lactones and a number of aromatic carboxylic acid esters. Has antioxidant activity. Is not associated with high density lipoprotein. Prevents LDL lipid peroxidation, reverses the oxidation of mildly oxidized LDL, and inhibits the ability of MM-LDL to induce monocyte chemotaxis.
Ser-311 is associated with an increased risk of cornary heart disease.
Widely expressed with highest expression in liver, lung, placenta, testis and heart.
Probable guanine nucleotide exchange factor. Putative effector of Ras and/or Rap. Associates with the GTP-bound form of Rap 1A and H-Ras in vitro (By similarity).
Binds ROCK1 and ROCK2 (By similarity). Also binds PKN1/PRK1 (PubMed:9478917). Interacts with ARGGEF3 (PubMed:12221096). Interacts with RTKN (By similarity). Interacts with AKAP13 (PubMed:11546812). Interacts with RIPOR1 (PubMed:27807006).
Mediates apoptosis in neoplastically transformed cells after DNA damage. Not essential for development but affects cell adhesion and growth factor signaling in transformed cells. Plays a negative role in tumorigenesis as deletion causes tumor formation. Involved in intracellular protein trafficking of a number of proteins. Targets PKN1 to endosomes and is involved in trafficking of the EGF receptor from late endosomes to lysosomes. Also required for stability and nuclear trafficking of AKT1/AKT which promotes endothelial cell survival during vascular development. Serves as a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Required for genotoxic stress-induced cell death in breast cancer cells.
Prenylation specifies the subcellular location of RHOB. The farnesylated form is localized to the plasma membrane while the geranylgeranylated form is localized to the endosome.
RHOB is one of the targets of farnesyltransferase inhibitors which are currently under investigation as cancer therapeutics. These elevate the levels of geranylgeranylated RHOB and cause mislocalization, leading to apoptosis and antineoplastic effects.
Up-regulated by DNA damaging agents like H(2)O(2) or ionizing radiation (IR).
May play a role in neuronal cell development.
Lipase with broad substrate specificity, catalyzing the hydrolysis of triacylglycerols (TAGs), diacylglycerols (DAGs), monoacylglycerols (MAGs), cholesteryl esters and retinyl esters (PubMed:8812477, PubMed:15955102, PubMed:15716583, PubMed:19800417). Shows a preferential hydrolysis of DAGs over TAGs and MAGs and preferentially hydrolyzes the fatty acid (FA) esters at the sn-3 position of the glycerol backbone in DAGs (PubMed:19800417). Preferentially hydrolyzes FA esters at the sn-1 and sn-2 positions of the glycerol backbone in TAGs (By similarity). Catalyzes the hydrolysis of 2-arachidonoylglycerol, an endocannabinoid and of 2-acetyl monoalkylglycerol ether, the penultimate precursor of the pathway for de novo synthesis of platelet-activating factor (By similarity). In adipose tissue and heart, it primarily hydrolyzes stored triglycerides to free fatty acids, while in steroidogenic tissues, it principally converts cholesteryl esters to free cholesterol for steroid hormone production (By similarity).
Monomer and homodimer (By similarity). Interacts with CAVIN1 in the adipocyte cytoplasm (PubMed:17026959). Interacts with PLIN5 (By similarity).
Phosphorylation by AMPK reduces its translocation towards the lipid droplets.
Retinyl ester hydrolase is inhibited by bis-p-nitrophenyl phosphate.
Dual specificity phosphatase able to dephosphorylate phosphotyrosine, phosphoserine and phosphothreonine residues within the same substrate, with a preference for phosphotyrosine as a substrate (PubMed:17498703). Involved in the modulation of intracellular signaling cascades. In skeletal muscle regulates systemic glucose homeostasis by activating, AMPK, an energy sensor protein kinase (By similarity). Affects MAP kinase signaling though modulation of the MAPK1/2 cascade in skeletal muscle promoting muscle cell differentiation, development and atrophy (By similarity).
Homodimer (PubMed:21543850). Interacts with PRKAA2 (By similarity).
(Microbial infection) Interacts (via KSSR motif) with Epstein-Barr virus EBNA1; the interaction requires phosphorylation of EBNA1, is independent and simultaneous to EBNA1 interaction with USP7 as well as necessary for PML nuclear bodies disruption by EBNA1. EBNA1, USP7 and CSNK2B form a ternary complex.
(Microbial infection) Upon infection with Epstein-Barr virus (EBV), the interaction with viral EBNA1 increases the association of CK2 with PML proteins, which increases PML phosphorylation by CK2, triggering the polyubiquitylation and degradation of PML (PubMed:20719947, PubMed:24216761). Seems to also suppress EBV reactivation by mediating ARK2N and JUN at the Z promoter which inhibits BZLF1 transcrition (PubMed:31341047).
Belongs to the casein kinase 2 subunit beta family.
Casein kinase II/CK2 is a tetramer composed of an alpha subunit, an alpha' subunit and two beta subunits. The beta subunit dimerization is mediated by zinc ions. Interacts with DYNLT2 (By similarity). Interacts with CD163. Also a component of a CK2-SPT16-SSRP1 complex composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B, the complex associating following UV irradiation. Interacts with MUSK; mediates phosphorylation of MUSK by CK2. Interacts with FGF1; this interaction is increased in the presence of FIBP, suggesting a possible cooperative interaction between CSNKB and FIBP in binding to FGF1. Interacts (via KSSR motif) with ARK2N (PubMed:24216761). Interacts with JUN and ARK2N; mediates the interaction between ARK2N and JUN (PubMed:31341047).
Regulatory subunit of casein kinase II/CK2. As part of the kinase complex regulates the basal catalytic activity of the alpha subunit a constitutively active serine/threonine-protein kinase that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine (PubMed:11239457, PubMed:16818610). Participates in Wnt signaling (By similarity).
Regulatory subunit of casein kinase II/CK2. As part of the kinase complex regulates the basal catalytic activity of the alpha subunit a constitutively active serine/threonine-protein kinase that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Participates in Wnt signaling.
Tetramer of two alpha and two beta subunits.
The KSSR motif is part of a protein interaction pocket that mediates interaction with cellular and viral proteins.
Transcription factor required during cardiovascular development (PubMed:23289003). Plays an important role in the transcriptional program(s) that underlies smooth muscle cell diversity (By similarity). Binds to the functionally important CEF-1 nuclear protein binding site in the cardiac-specific slow/cardiac troponin C transcriptional enhancer (PubMed:25543888).
Catalyzes the transfer of a sulfate group to position 3 of non-reducing beta-galactosyl residues in glycerolipids and sphingolipids, therefore participates in the biosynthesis of sulfoglycolipids (PubMed:9030544, PubMed:8830034). Catalyzes the synthesis of galactosylceramide sulfate (sulfatide), a major lipid component of the myelin sheath and of monogalactosylalkylacylglycerol sulfate (seminolipid), present in spermatocytes (PubMed:8830034). Seems to prefer beta-glycosides at the non-reducing termini of sugar chains attached to a lipid moiety (PubMed:8830034). Also acts on lactosylceramide, galactosyl 1-alkyl-2-sn-glycerol and galactosyl diacylglycerol (in vitro) (PubMed:8830034).
Expressed in kidney proximal tubule, gastric mucosa and adenocarcinoma (PubMed:9030544, PubMed:10785389). Highly expressed in renal cell carcinoma cell lines (PubMed:9030544, PubMed:8830034).
Interacts (via PDZ-binding motif) with DLG4/SAP90 (via PDZ domain 2); this interaction may promote translocation of DLG4/SAP90 to the membrane.
Probable cell surface receptor that regulates oligodendroglial precursor cell migration (By similarity). Might also regulate differentiation of oligodendroglial precursor cells (By similarity). Has growth cone collapse activity against retinal ganglion-cell axons (By similarity).
Amino acids 60-89 in isoform 2 are necessary for interaction with COPS5, CUL1, CUL3.
Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8/ICSBP, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. Plays a role in cell proliferation.
Component of the CSN complex, composed of COPS1/GPS1, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7 (COPS7A or COPS7B), COPS8 and COPS9 isoform 1. In the complex, it interacts directly with COPS3, COPS5 and COPS6 (PubMed:26456823). Isoform 2 associates with CSN complex (PubMed:23776465). Isoform 2 interacts with COPS5, CUL1, CUL3 and RPL11 (PubMed:23776465). According to PubMed:26456823, does not associate with CSN complex.
Negatively regulates neddylation of proteins, including ribosoaml protein RPL11.
The Phe/Asp-rich domain at the C-terminus is necessary for its incorporation into the CSN complex.
Endothelial sialomucin, also called endomucin or mucin-like sialoglycoprotein, which interferes with the assembly of focal adhesion complexes and inhibits interaction between cells and the extracellular matrix.
Highly O-glycosylated. Sialic acid-rich glycoprotein.
Activated following phosphorylation by p38-alpha/MAPK14 following various stresses. Inhibited following sumoylation. Specifically inhibited by pyrrolopyridine inhibitors.
Heterodimer with p38-alpha/MAPK14; this heterodimer forms a stable complex: molecules are positioned 'face to face' so that the ATP-binding sites of both kinases are at the heterodimer interface (PubMed:12171911, PubMed:17576063, PubMed:17255097, PubMed:17480064, PubMed:17449059, PubMed:17395714). Interacts with PHC2 (PubMed:15094067). Interacts with HSF1 (PubMed:16278218).
Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at Thr-222, Ser-272 and Thr-334.
Stress-activated serine/threonine-protein kinase involved in cytokine production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, CEP131, ELAVL1, HNRNPA0, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Phosphorylates HSF1; leading to the interaction with HSP90 proteins and inhibiting HSF1 homotrimerization, DNA-binding and transactivation activities (PubMed:16278218). Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to the dissociation of HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impairment of their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to the regulation of the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity, leading to inhibition of dependent degradation of ARE-containing transcripts. Phosphorylates CEP131 in response to cellular stress induced by ultraviolet irradiation which promotes binding of CEP131 to 14-3-3 proteins and inhibits formation of novel centriolar satellites (PubMed:26616734). Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilization of GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3.
Sumoylation inhibits the protein kinase activity.
Expressed in kidney and brain. In the kidney, expressed in glomeruli, most probably in podocytes, and in tubules (at protein level). In the brain, expressed in the cerebellum, with high levels in Purkinje cells and their projecting axons, in the deep cerebellar nuclei and in pyramidal neurons of the cerebral cortex (at protein level). In the white matter, mainly present in astrocytes, but not in oligodendrocytes (at protein level). Also highly expressed in endothelial cells of cerebral capillaries (at protein level).
In fetal kidney (25 weeks of gestation), expressed in immature podocytes from the S-shaped-body stage to the capillary loop stage. Expression decreases along glomerular maturation (at protein level). In mature glomeruli, expressed at the periphery of the glomerular tuft, most probably in the cell body of mature podocytes. Also detected in mature tubules (at protein level).
May play a role in the regulation of microtubule organization and dynamics (PubMed:25466283).
Interacts with SEC61B, SEC61A1 and the SEC61 complex. Interacts with CANX (By similarity).
Interacts with target proteins during their translocation into the lumen of the endoplasmic reticulum. Protects unfolded target proteins against degradation during ER stress. May facilitate glycosylation of target proteins after termination of ER stress. May modulate the use of N-glycosylation sites on target proteins (By similarity).
Constitutes an important route for the delivery of antifolate drugs, such as methotrexate and pemetrexed, in cancer chemotherapy (PubMed:18524888, PubMed:34040256). Ubiquitously expressed in solid tumors to which it delivers antifolates: within the acid microenvironment of cancer cells, antifolate drugs uptake mediated by SLC46A1/PCFT is increased (PubMed:18524888, PubMed:34040256).
Expressed at highest level in the upper half of the small intestine (duodenum and jejunum), expression decreases downwardly in the subsequent quarter and is undetectable in the last quarter (the lowest ileum) (PubMed:17129779, PubMed:19762432). Also expressed in kidney, liver, placenta, spleen, retina and retinal pigment epithelium (PubMed:17129779, PubMed:17335806). Lower levels found in testis (PubMed:17129779). Very low levels in brain, lung, stomach, heart and muscle (PubMed:17129779).
Inactive isoform which is not able to mediate proton-coupled folate transport.
Proton-coupled folate symporter that mediates folate absorption using an H(+) gradient as a driving force (PubMed:17129779, PubMed:17446347, PubMed:17475902, PubMed:19389703, PubMed:19762432, PubMed:25504888, PubMed:30858177, PubMed:31792273, PubMed:34619546, PubMed:29344585, PubMed:31494288, PubMed:32893190). Involved in the intestinal absorption of folates at the brush-border membrane of the proximal jejunum, and the transport from blood to cerebrospinal fluid across the choroid plexus (PubMed:17129779, PubMed:17446347, PubMed:17475902, PubMed:19389703, PubMed:25504888, PubMed:30858177, PubMed:29344585, PubMed:31494288, PubMed:32893190). Functions at acidic pH via alternate outward- and inward-open conformation states (PubMed:34040256, PubMed:32893190). Protonation of residues in the outward open state primes the protein for transport (PubMed:34040256). Binding of folate promotes breaking of salt bridge network and subsequent closure of the extracellular gate, leading to the inward-open state and release of protons and folate (PubMed:34040256). Also able to transport antifolate drugs, such as methotrexate and pemetrexed, which are established treatments for cancer and autoimmune diseases (PubMed:18524888, PubMed:19762432, PubMed:25608532, PubMed:28802835, PubMed:29326243, PubMed:34619546, PubMed:34040256, PubMed:22345511). Involved in FOLR1-mediated endocytosis by serving as a route of export of folates from acidified endosomes (PubMed:19074442). Also acts as a lower-affinity, pH-independent heme carrier protein and constitutes the main importer of heme in the intestine (PubMed:17156779). Imports heme in the retina and retinal pigment epithelium, in neurons of the hippocampus, in hepatocytes and in the renal epithelial cells (PubMed:32621820). Hence, participates in the trafficking of heme and increases intracellular iron content (PubMed:32621820).
Expressed in gastrointestinal and immune tissue, as well as prostate, testis and ovary. Expressed in lamina propria and eosinophils but not in epithelial cells. Expression is greater in benign adjacent tissues than in colon tumors.
Interacts with BAD, BAK1, BAX, BCL2, BCL2L1/Bcl-xL and BCL2L11/BimEL (PubMed:16509771). The interaction with BAX is increased, when cells initiate apoptosis upon IL2 withdrawal (PubMed:16509771). Also interacts with BCL2 (By similarity). Forms a complex with BCL2L1 or MCL1 and HSPA8/HSC70; the interaction between HSPA8 and BCL2L1 or MCL1 is impaired in the absence of GIMAP5 (By similarity). May interact (via N-terminus) with microtubules (By similarity).
Plays a role in T lymphocyte development and the optimal generation of CD4/CD8 double-positive thymocytes (By similarity). Inhibitor of GSK3A, possibly by sequestering GSK3A in cytoplasmic vesicles and impairing its translocation to the nucleus. Consequently, impairs GSK3A-dependent transcriptional program and regulation of the DNA damage response occurring during T cells proliferation (PubMed:29382851). Required for the survival of peripheral T cells, natural killer (NK) and NK T-cell development and the maintenance of normal liver function (By similarity). May promote the survival of mature T lymphocytes upon cytokine withdrawal (By similarity). May regulate Ca(2+) homeostasis by modulating lysosomal Ca(2+) stores, preventing its accumulation in the absence of T cell activation (By similarity). May play a role in mitochondrial DNA segregation in hematopoietic tissues (By similarity). Is a regulator of liver endothelial cell homeostasis (By similarity).
Widely expressed with high levels in lymph node and spleen (PubMed:14724691). High expression found in T lymphocytes, including CD4 and CD8-positive T-cells, and monocytes (PubMed:14724691, PubMed:29382851). Very low expression levels in B-lymphocytes (PubMed:14724691).
Belongs to the glycosyltransferase group 1 family. Glycosyltransferase 33 subfamily.
Catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation.
Cis-aconitate decarboxylase that catalyzes production of itaconate and is involved in the inhibition of the inflammatory response (PubMed:23609450, PubMed:23610393, PubMed:31548418, PubMed:35662396). Acts as a negative regulator of the Toll-like receptors (TLRs)-mediated inflammatory innate response by stimulating the tumor necrosis factor alpha-induced protein TNFAIP3 expression via reactive oxygen species (ROS) in LPS-tolerized macrophages (PubMed:23609450). Involved in antimicrobial response of innate immune cells; ACOD1-mediated itaconic acid production contributes to the antimicrobial activity of macrophages by generating itaconate, leading to alkylation of proteins, such as TFEB (PubMed:23610393, PubMed:35662396). Involved in antiviral response following infection by flavivirus in neurons: ACOD1-mediated itaconate production inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (By similarity). Plays a role in the embryo implantation (By similarity).
Expressed in LPS-tolerized macrophages (at protein level). Expressed in peripheral blood mononuclear cells (PBMCs), microglia and macrophage cells.
Up-regulated after lipopolysaccharide (LPS) stimulation. Up-regulated in LPS-tolerized macrophage by LPS. Up-regulated in peripheral blood mononuclear cells (PBMC) of patient after acute sepsis.
Expressed in kidney, liver, spleen and testis but not in colon.
Functions as a multifunctional transcription factor that may exhibit positive and negative control on a large number of genes. May antagonize YY1 and function in development and differentiation.
The gene encoding this protein appears to have arisen by retrotransposition of the YY1 gene in placental mammals. It is encoded by a single exon found in an intron of the gene MBTPS2.
Expressed in brain, to a lesser extent in testis, and poorly in all the other tissues.
Responsible for the transport of glutamate from the cytosol into the mitochondrial matrix with the concomitant import of a proton (symport system).
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. ROCO subfamily.
Binding of GTP stimulates kinase activity.
Homodimer (PubMed:22952686). Interacts with CSK (PubMed:23526378).
Plays a role in the negative regulation of bone mass, acting through the maturation of osteoclasts.
The cDNA contains a duplication of exon 3.
Highly expressed in the testis and olfactory bulb.
Olfactory receptor that acts as a receptor of Asprosin hormone, potentially at the surface of hepatocytes and may help to promote hepatocyte glucose release.
The human olfactory receptor 4M1 (Q8NGD0) is not the one to one ortholog of mouse Or4m1 (Q8VFT4).
Exhibits a coumarin 7-hydroxylase activity. Active in the metabolic activation of hexamethylphosphoramide, N,N-dimethylaniline, 2'-methoxyacetophenone, N-nitrosomethylphenylamine, and the tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Possesses phenacetin O-deethylation activity.
Expressed in liver and a number of extrahepatic tissues, including nasal mucosa, lung, trachea, brain, mammary gland, prostate, testis, and uterus, but not in heart, kidney, bone marrow, colon, small intestine, spleen, stomach, thymus, or skeletal muscle.
The frequencies of the Cys-257 allele in white, black, Hispanic, and Asian individuals are 1.9%, 14.4%, 5.8%, and 7.7%, respectively. The Cys-257 variant is 37 to 56% less active than the wild-type Arg-257 protein toward all substrates tested.
Interacts with AFG2A, AFG2B and CINP (PubMed:35354024). Does not associate with pre-60S ribosomal particles (PubMed:35354024).
Involved in the cytoplasmic maturation steps of pre-60S ribosomal particles by promoting the release of shuttling protein RSL24D1/RLP24 from the pre-ribosomal particles (PubMed:35354024). Acts together with AFG2A, AFG2B and CINP (PubMed:35354024).
Phosphorylated on serines by CK2 kinase.
A truncated MFN1 construct containing the GTPase domain and the associated helix bundle is a monomer in the absence of bound GTP and a homodimer in the GTP-bound form; GDP cannot replace GTP and induce dimerization.
Detected in kidney and heart (at protein level) (PubMed:12759376). Ubiquitous (PubMed:11950885, PubMed:12759376). Expressed at slightly higher level in kidney and heart (PubMed:12759376). Isoform 2 may be overexpressed in some tumors, such as lung cancers (PubMed:11751411).
Homodimer, also in the absence of bound GTP (PubMed:27920125, PubMed:28114303). Forms higher oligomers in the presence of a transition state GTP analog (PubMed:28114303). Forms homomultimers and heteromultimers with MFN2 (By similarity). Oligomerization is essential for mitochondrion fusion (PubMed:27920125, PubMed:28114303). Component of a high molecular weight multiprotein complex (PubMed:12759376). Interacts with VAT1 (By similarity). Interacts with THG1L; THG1L probably functions as a guanyl-nucleotide exchange factor/GEF, activating MFN1.
Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion (PubMed:12475957, PubMed:12759376, PubMed:27920125, PubMed:28114303). Membrane clustering requires GTPase activity (PubMed:27920125). It may involve a major rearrangement of the coiled coil domains (PubMed:27920125, PubMed:28114303). Mitochondria are highly dynamic organelles, and their morphology is determined by the equilibrium between mitochondrial fusion and fission events (PubMed:12475957, PubMed:12759376). Overexpression induces the formation of mitochondrial networks (in vitro) (PubMed:12759376). Has low GTPase activity (PubMed:27920125, PubMed:28114303).
Ubiquitinated by non-degradative ubiquitin by PRKN (PubMed:23933751). Deubiquitination by USP30 inhibits mitochondrial fusion (By similarity). Ubiquitinated by MARCHF5 (PubMed:20103533). When mitochondria are depolarized and dysfunctional, it is ubiquitinated by a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that contains FBXO7 and PRKN (PubMed:23933751).
Bifunctional enzyme that catalyzes the first two steps in lysine degradation.
Expressed in all 16 tissues examined with highest expression in the liver.
In the C-terminal section; belongs to the saccharopine dehydrogenase family.
The N-terminal and the C-terminal domains contain respectively the lysine ketoglutarate reductase and saccharopine dehydrogenase activity.
The disease is caused by variants affecting the gene represented in this entry. In hyperlysinemia 1, both enzymatic functions of AASS are defective and patients have increased serum lysine and possibly increased saccharopine. Some individuals, however, retain significant amounts of lysine-ketoglutarate reductase and present with saccharopinuria, a metabolic condition with few, if any, clinical manifestations.
Positively regulates Toll-like receptor TLR7 signaling in macrophages.
Postsynaptic density scaffolding protein. Binds and cross-links cytoplasmic regions of GRM1, GRM5, ITPR1, DNM3, RYR1, RYR2, SHANK1 and SHANK3. By physically linking GRM1 and GRM5 with ER-associated ITPR1 receptors, it aids the coupling of surface receptors to intracellular calcium release. May also couple GRM1 to PI3 kinase through its interaction with AGAP2. Isoform 1 regulates the trafficking and surface expression of GRM5. Isoform 3 acts as a natural dominant negative, in dynamic competition with constitutively expressed isoform 1 to regulate synaptic metabotropic glutamate function. Isoform 3, may be involved in the structural changes that occur at synapses during long-lasting neuronal plasticity and development. Forms a high-order complex with SHANK1, which in turn is necessary for the structural and functional integrity of dendritic spines (By similarity). Negatively regulates T cell activation by inhibiting the calcineurin-NFAT pathway. Acts by competing with calcineurin/PPP3CA for NFAT protein binding, hence preventing NFAT activation by PPP3CA (PubMed:18218901).
Tetramer; this tetrameric structure is critical for forming the high-order complex with SHANK1, which in turn is necessary for the structural and functional integrity of dendritic spines (By similarity). Interacts with GRM1, GRM5, ITPR1, DNM3, RYR1, RYR2 and SHANK3 (PubMed:10464340). Interacts with IFT57 and OPHN1 (By similarity). Isoform 1 encodes a coiled-coil structure that mediates homo- and heteromultimerization (By similarity). Interacts with SHANK1; forms high-order polymerized complex with a mesh-like network structure, at least composed of SHANK1, HOMER1 and DLGAP1; the complex formation is SHANK1 multimerization dependent (By similarity).Interacts with SHANK1; forms high-order polymerized complex with a mesh-like network structure, at least composed of SHANK1, HOMER1 and DLGAP1; the complex formation is SHANK1 multimerization dependent (By similarity). Interacts with NFATC4 (PubMed:18218901). Interacts with DAGLA (via PPXXF motif); this interaction is required for the cell membrane localization of DAGLA (By similarity). Interacts with SRGAP2 (By similarity).
The WH1 domain interacts with the PPXXF motif in GRM1, GRM5, RYR1, RYR2, ITPR1, SHANK 1 and SHANK3. The coiled-Coil domain forms an antiparallel tetrameric arrangement (By similarity).
May be involved in N-linked oligosaccharide assembly. May participate in the translocation of oligosaccharide from the cytoplasmic side to the lumenal side of the endoplasmic reticulum membrane.
Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in epigenetic chromatin reprogramming in the zygote following fertilization (PubMed:31928709). Also mediates subsequent conversion of 5hmC into 5-formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC probably constitutes the first step in cytosine demethylation (By similarity). Selectively binds to the promoter region of target genes and contributes to regulate the expression of numerous developmental genes (PubMed:23217707). In zygotes, DNA demethylation occurs selectively in the paternal pronucleus before the first cell division, while the adjacent maternal pronucleus and certain paternally-imprinted loci are protected from this process. Participates in DNA demethylation in the paternal pronucleus by mediating conversion of 5mC into 5hmC, 5fC and 5caC. Does not mediate DNA demethylation of maternal pronucleus because of the presence of DPPA3/PGC7 on maternal chromatin that prevents TET3-binding to chromatin (By similarity). In addition to its role in DNA demethylation, also involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT (PubMed:23353889). Binds preferentially to DNA containing cytidine-phosphate-guanosine (CpG) dinucleotides over CpH (H=A, T, and C), hemimethylated-CpG and hemimethylated-hydroxymethyl-CpG (PubMed:29276034).
Expressed in colon, muscle, adrenal gland and peripheral blood lymphocytes.
Expressed in fetal brain but not adult brain.
Interacts with HCFC1 (PubMed:23353889). Interacts with OGT (PubMed:23353889, PubMed:23222540). Directly interacts (via C-terminus) with the DCAF1 component of the CRL4(VprBP) E3 ubiquitin-protein ligase complex (PubMed:24357321, PubMed:25557551).
Monoubiquitinated at Lys-994 by the DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex called CRL4(VprBP) or CUL4A-RBX1-DDB1-DCAF1/VPRBP complex; this modification promotes binding to DNA.
Subsequent steps in cytosine demethylation are subject to discussion. According to a first model cytosine demethylation occurs through deamination of 5hmC into 5-hydroxymethyluracil (5hmU) and subsequent replacement by unmethylated cytosine by the base excision repair system. According to another model, cytosine demethylation is rather mediated via conversion of 5hmC into 5fC and 5caC, followed by excision by TDG.
The CXXC zinc finger mediates binding to CpG-DNA (PubMed:29276034). It mediates binding to DNA sequences containing unmethylated cytosine or 5-carboxylcytosine in 5'-CCG-3' DNA sequence motifs (By similarity).
Antibodies against EEA1 are found in sera from patients with subacute cutaneous lupus erythematosus and other autoimmune diseases.
Binds phospholipid vesicles containing phosphatidylinositol 3-phosphate and participates in endosomal trafficking.
Homodimer. Binds STX6. Binds RAB5A, RAB5B, RAB5C and RAB22A that have been activated by GTP-binding. Interacts with RAB31. Interacts with ERBB2. Interacts with SAMD9 and SAMD9L (PubMed:24029230). May interact with PLEKHF2.
Belongs to the sodium channel (TC 1.A.1.10) family.
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.3/SCN3A subfamily.
Expressed in enterochromaffin cells in both colon and small bowel (at protein level).
Heterooligomer of a large alpha subunit and 2-3 smaller beta subunits. Heterooligomer with SCN2B or SCN4B; disulfide-linked. Interacts with NEDD4L (PubMed:15548568). Interacts with the conotoxin GVIIJ (PubMed:24497506).
May be ubiquitinated by NEDD4L; which would promote its endocytosis.
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:24157691, PubMed:28235671, PubMed:29466837). May contribute to the regulation of serotonin/5-hydroxytryptamine release by enterochromaffin cells (By similarity). In pancreatic endocrine cells, required for both glucagon and glucose-induced insulin secretion (By similarity).
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient.
Phosphorylation at Ser-1501 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents.
Interacts with TOR1A and TOR1B (ATP-bound).
Required for endoplasmic reticulum integrity. Regulates the distribution of TOR1A between the endoplasmic reticulum and the nuclear envelope as well as induces TOR1A, TOR1B and TOR3A ATPase activity.
Homodimer. Interacts with lysosomal protein GLMP (via lumenal domain); the interaction starts while both proteins are still in the endoplasmic reticulum and is required for stability and lysosomal localization of MFSD1.
Lysosomal transporter which is essential for liver homeostasis. Required to maintain stability and lysosomal localization of GLMP.
The dileucine internalization motif is required for lysosomal localization.
Forms a homo/heterooligomeric complex with EXT1. Interacts with GALNT5. Interacts with NDST1.
Belongs to the potassium channel family. C (Shaw) (TC 1.A.1.2) subfamily. Kv3.3/KCNC3 sub-subfamily.
Homotetramer. Heterotetramer with KCNC1 (PubMed:23734863). Interacts (via C-terminus) with HAX1 (PubMed:26997484). Identified in a complex with ACTR3, a subunit of the Arp2/3 complex; this interaction is indirect and depends on the presence of HAX1 (PubMed:26997484). Interaction with HAX1 modulates channel gating (PubMed:26997484).
The C-terminal cytoplasmic tail contributes to the regulation of channel inactivation and to the interaction with HAX1 and the Arp2/3 complex.
The cytoplasmic N-terminus mediates N-type inactivation.
Voltage-gated potassium channel that plays an important role in the rapid repolarization of fast-firing brain neurons. The channel opens in response to the voltage difference across the membrane, forming a potassium-selective channel through which potassium ions pass in accordance with their electrochemical gradient. The channel displays rapid activation and inactivation kinetics (PubMed:10712820, PubMed:26997484, PubMed:22289912, PubMed:23734863, PubMed:16501573, PubMed:19953606, PubMed:21479265, PubMed:25756792). It plays a role in the regulation of the frequency, shape and duration of action potentials in Purkinje cells. Required for normal survival of cerebellar neurons, probably via its role in regulating the duration and frequency of action potentials that in turn regulate the activity of voltage-gated Ca(2+) channels and cellular Ca(2+) homeostasis (By similarity). Required for normal motor function (PubMed:23734863, PubMed:16501573, PubMed:19953606, PubMed:21479265, PubMed:25756792). Plays a role in the reorganization of the cortical actin cytoskeleton and the formation of actin veil structures in neuronal growth cones via its interaction with HAX1 and the Arp2/3 complex (PubMed:26997484).
Acts as an activator of both rRNA/tRNA and protein methyltransferases (PubMed:25851604, PubMed:18539146, PubMed:20308323, PubMed:25851604, PubMed:31328227, PubMed:31636962, PubMed:31061526). Together with methyltransferase BUD23, methylates the N(7) position of a guanine in 18S rRNA (PubMed:25851604). The heterodimer with N6AMT1/HEMK2 catalyzes N5-methylation of ETF1 on 'Gln-185', using S-adenosyl L-methionine as methyl donor (PubMed:18539146, PubMed:31636962, PubMed:31061526). The heterodimer with N6AMT1/HEMK2 also monomethylates 'Lys-12' of histone H4 (H4K12me1) (PubMed:31061526). The heterodimer with ALKBH8 catalyzes the methylation of 5-carboxymethyl uridine to 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in target tRNA species (PubMed:20308323). Together with methyltransferase THUMPD3, catalyzes the formation of N(2)-methylguanosine at position 6 in a broad range of tRNA substrates and at position 7 of tRNA(Trp) (PubMed:34669960). Involved in the pre-rRNA processing steps leading to small-subunit rRNA production (PubMed:25851604). Together with methyltransferase METTL5, specifically methylates the 6th position of adenine in position 1832 of 18S rRNA (PubMed:33428944, PubMed:35033535, PubMed:31328227).
Heterodimer with BUD23/WBSCR22; this heterodimerization is necessary for the metabolic stability and activity of the catalytic subunit BUD23 (PubMed:25851604, PubMed:34948388). Heterodimer with N6AMT1/HEMK2; this heterodimerization is necessary for S-adenosyl-L-methionine-binding to N6AMT1/HEMK2 (PubMed:20308323, PubMed:25851604, PubMed:31632689, PubMed:31636962, PubMed:31061526, PubMed:34948388, PubMed:32969463). Heterodimer with ALKBH8 (PubMed:20308323, PubMed:34948388). Heterodimer with METTL5; this heterodimerization is necessary for the stability of the catalytic subunit METTL5 (PubMed:34948388, PubMed:32217665, PubMed:33428944, PubMed:35033535, PubMed:31328227). Interacts with THUMPD3; the interaction is direct and is required for THUMPD3 methyltransferase activity (PubMed:34948388, PubMed:34669960). Interacts with THUMPD2 (PubMed:34948388). Interacts with TRMT11 (PubMed:34948388).
Citrullination by PADI4 within the nuclear localization signal disrupts the interaction with p53 and increases susceptibility to degradation.
Component of HBO1 complexes, which specifically mediate acetylation of histone H3 at 'Lys-14' (H3K14ac), and have reduced activity toward histone H4 (PubMed:16387653). Through chromatin acetylation it may function in DNA replication (PubMed:16387653). May inhibit tumor progression by modulating the transcriptional output of signaling pathways which regulate cell proliferation (PubMed:15251430, PubMed:15528276). Can suppress brain tumor angiogenesis through transcriptional repression of RELA/NFKB3 target genes when complexed with RELA (PubMed:15029197). May also specifically suppress loss of contact inhibition elicited by activated oncogenes such as MYC (PubMed:15029197). Represses hypoxia inducible factor's (HIF) activity by interacting with HIF prolyl hydroxylase 2 (EGLN1) (PubMed:15897452). Can enhance apoptosis induced by serum starvation in mammary epithelial cell line HC11 (By similarity).
Homodimer (PubMed:19187765, PubMed:22334692). Component of the HBO1 complex composed of KAT7/HBO1, MEAF6, ING4 or ING5, and one scaffold subunit: complexes containing BRPF scaffold (BRPF1, BRD1/BRPF2 or BRPF3) direct KAT7/HBO1 specificity towards H3K14ac, while complexes containing JADE scaffold (JADE1, JADE2 and JADE3) mediate acetylation of histone H4 (PubMed:16387653). Interacts with H3K4me3 and to a lesser extent with H3K4me2, the interaction augments KAT7/HBO1 acetylation activity on H3 tails (PubMed:16728974, PubMed:18381289). Interacts with EP300, RELA and TP53; these interactions may be indirect (PubMed:12750254, PubMed:15029197). Interacts with EGLN1 (PubMed:15897452). Interacts with BCL2A1 (By similarity).
Lacks the nuclear localization signal (NLS), resulting in increased cytoplasmic localization.
The N-terminal coiled-coil domain mediates homodimerization.
Interacts with SETDB1 and TRIM28/KAP1. Interacts with ATRX. Forms a complex with ATRX, SETDB1 and TRIM28 (PubMed:27029610).
Probable transcription repressor. Specifically binds to the 3'-end of zinc-finger coding genes and recruiting chromatin-modifying proteins such as SETDB1 and TRIM28/KAP1, leading to transcription repression. The SETDB1-TRIM28-ZNF274 complex may play a role in recruiting ATRX to the 3'-exons of zinc-finger coding genes with atypical chromatin signatures to establish or maintain/protect H3K9me3 at these transcriptionally active regions (PubMed:27029610).
Found in a mRNP complex (i.e. messenger ribonucleoproteins which correspond to mRNA with bound proteins), at least composed of TDRD1, TDRD6, TDRD7 and DDX4. Found in a complex, at least composed of PIWIL1, PIWIL2, DDX4 and TDRD6. Interacts with Tex19.1 and probably Tex19.2. Interacts with PRMT5. Interacts with SNRPB (when methylated); to trigger spliceosome formation.
The tudor domains recognize and bind to proteins with dimethylated arginine residues.
Tudor domain-containing protein involved in germ cell development, more specifically the formation of chromatoid body (during spermiogenesis), Balbiani body (during oogenesis), germ plasm (upon fertilization), and for proper miRNA expression and spliceosome maturation (By similarity). Essential for RNA-dependent helicase UPF1 localization to chromatoid body, for UPF1-UPF2 and UPF1-DDX4 interactions which are required for mRNA degradation, using the extended 3' UTR-triggered nonsense-mediated mRNA decay (NMD) pathway. Involved in spliceosome maturation and mRNA splicing in prophase I spermatocytes through interaction with arginine N-methyltransferase PRMT5 and symmetrically arginine dimethylated SNRPB (small nuclear ribonucleoprotein-associated protein) (By similarity).
Undergoes proteolytic cleavage near the C-terminal by an unknown protease during the transition from meiosis I to meiosis II in primary spermatocytes.
Binds DNA via bZIP domain; DNA-binding is under control of cellular redox homeostasis (in vitro) (PubMed:28981703). To enable DNA binding, the bZIP domain must undergo a conformational rearrangement which requires the reduction of the interchain disulfide bond between FosB and JunD (in vitro) (PubMed:28981703).
Heterodimer; binds DNA as a heterodimer (PubMed:28981703). Component of an AP-1 transcription factor complex composed of JUN-FOS heterodimers (By similarity). As part of the AP-1 transcription factor complex, forms heterodimers with FOS proteins, thereby binding to the AP-1 consensus sequence and stimulating transcription (By similarity). Forms heterodimers with FOSB; thereby binding to the AP-1 consensus sequence (PubMed:28981703). Interacts (via MBM motif) with MEN1; this interaction represses transcriptional activation (PubMed:9989505, PubMed:22327296). Interacts with MAPK10; this interaction is inhibited in the presence of MEN1 (PubMed:22327296).
Phosphorylated by MAP kinases MAPK8 and MAPK10; phosphorylation is inhibited in the presence of MEN1.
Transcription factor binding AP-1 sites (PubMed:9989505). Heterodimerizes with proteins of the FOS family to form an AP-1 transcription factor complex, thereby enhancing their DNA binding activity to an AP-1 consensus sequence 3'-TGA[GC]TCA-5' and enhancing their transcriptional activity (PubMed:9989505, PubMed:28981703).
(Microbial infection) Necessary for the expression of the Adenovirus E4 gene.
Acetylated by EP300/p300. Deacetylated by SIRT7, promoting heterotetramerization and activity.
Heterotetramer of two alpha and two beta subunits (PubMed:7799916). Interacts with HCFC1, causing repression of transcriptional activity (PubMed:10675337).
Transcription factor capable of interacting with purine rich repeats (GA repeats) (PubMed:8441384, PubMed:10675337, PubMed:8816484). Acts as a a master regulator of nuclear-encoded mitochondrial genes (By similarity).
RAB2B effector protein required for accurate acrosome formation and normal male fertility. In complex with RAB2A/RAB2B, seems to suppress excessive vesicle trafficking during acrosome formation.
Involved in the proliferation of osteoblasts during bone formation and bone regeneration. Promotes matrix assembly (By similarity).
Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. This small subunit may act as a tissue-specific chaperone of the large subunit, possibly by helping it fold into its correct conformation for activity.
Heterodimer of a large (catalytic) and a small (regulatory) subunit.
Pseudouridine synthase that catalyzes pseudouridylation of mRNAs.
Binds specifically to calcyclin in a calcium-dependent manner (By similarity). Required for midbody formation and completion of the terminal phase of cytokinesis.
Interacts with S100A6 (PubMed:28469040). Interacts with PDCD6 in a calcium-dependent manner. Interacts with KIF23 during cytokinesis.
Expressed in liver (PubMed:3365415). Expressed in kidney and epithelial cells of both benign and malignant prostate tissue. Expressed in epididymis (at protein level).
Inhibited by CP-166,572, an inhibitor that is competitive with fructose (PubMed:12962626). Also competitively inhibited by phenanthroline and 4-methylpyrazole in vitro (PubMed:3365415).
Polyol dehydrogenase that catalyzes the reversible NAD(+)-dependent oxidation of various sugar alcohols. Is mostly active with D-sorbitol (D-glucitol), L-threitol, xylitol and ribitol as substrates, leading to the C2-oxidized products D-fructose, L-erythrulose, D-xylulose, and D-ribulose, respectively (PubMed:3365415). Is a key enzyme in the polyol pathway that interconverts glucose and fructose via sorbitol, which constitutes an important alternate route for glucose metabolism. The polyol pathway is believed to be involved in the etiology of diabetic complications, such as diabetic neuropathy and retinopathy, induced by hyperglycemia (PubMed:12962626, PubMed:29966615, PubMed:25105142). May play a role in sperm motility by using sorbitol as an alternative energy source for sperm motility (PubMed:16278369). May have a more general function in the metabolism of secondary alcohols since it also catalyzes the stereospecific oxidation of (2R,3R)-2,3-butanediol. To a lesser extent, can also oxidize L-arabinitol, galactitol and D-mannitol and glycerol in vitro. Oxidizes neither ethanol nor other primary alcohols. Cannot use NADP(+) as the electron acceptor (PubMed:3365415).
Up-regulated by androgens and down-regulated by castration.
Receptor for thyrotropin-releasing hormone (TRH). Upon ligand binding, this G-protein-coupled receptor triggers activation of the phosphatidylinositol (IP3)-calcium-protein kinase C (PKC) pathway.
Homodimer. Dimerization does not affect PPP2R5B-binding, but is required for its proteasomal degradation (PubMed:23135275). Interacts with CUL3 (PubMed:27561354, PubMed:14528312, PubMed:23135275). Directly interacts with PPP2R5B; this interaction leads to PPP2R5B proteasomal degradation (PubMed:23135275). Interacts with RBBP8/CtIP; this interaction leads to RBBP8 proteasomal degradation (PubMed:27561354). Interacts with PACMP micropeptide; interaction prevents ubiquitination and degradation of RBBP8/CtIP (PubMed:35219381).
Substrate-specific adapter for CUL3 E3 ubiquitin-protein ligase complex (PubMed:27561354, PubMed:14528312, PubMed:35219381). Acts as an adapter for CUL3 to target the serine/threonine-protein phosphatase 2A (PP2A) subunit PPP2R5B for ubiquitination and subsequent proteasomal degradation, thus promoting exchange with other regulatory subunits (PubMed:23135275). Acts as an adapter for CUL3 to target the DNA-end resection factor RBBP8/CtIP for ubiquitination and subsequent proteasomal degradation (PubMed:27561354, PubMed:35219381). Through the regulation of RBBP8/CtIP protein turnover, plays a key role in DNA damage response, favoring DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR) (PubMed:27561354, PubMed:35219381).
Forms a complex with NDFIP1 and NEDD4L, in cortical neurons, in response to iron and cobalt exposure; this interaction leads to SLC11A2 ubiquitination by NEDD4L and proteasome-dependent degradation (PubMed:19706893). Interacts with NDFIP1, NDFIP2 and WWP2; this interaction leads to SLC11A2 ubiquitination by WWP2 and subsequent proteasome-dependent degradation (By similarity). Interacts with COX2 and TOM6 at the outer mitochondrion membrane (PubMed:24448823). Interacts with ARRDC1; this interaction regulates the incorporation of SLC11A2 into extracellular vesicles through an ubiquitination-dependent mechanism (PubMed:27462458). Interacts with ARRDC4; controls the incorporation of SLC11A2 into extracellular vesicles through an ubiquitination-dependent mechanism (PubMed:27462458).
NRAMP2-mediated iron uptake is markedly stimulated by nifedipine in a concentration-dependent manner.
Proton-coupled metal ion symporter operating with a proton to metal ion stoichiometry of 1:1 (PubMed:17109629, PubMed:22736759, PubMed:25491917, PubMed:17293870, PubMed:25326704). Selectively transports various divalent metal cations, in decreasing affinity: Cd(2+) > Fe(2+) > Co(2+), Mn(2+) >> Zn(2+), Ni(2+), VO(2+) (PubMed:17109629, PubMed:22736759, PubMed:25491917, PubMed:17293870, PubMed:25326704). Essential for maintenance of iron homeostasis by modulating intestinal absorption of dietary Fe(2+) and TF-associated endosomal Fe(2+) transport in erythroid precursors and other cells (By similarity). Enables Fe(2+) and Mn(2+) ion entry into mitochondria, and is thus expected to promote mitochondrial heme synthesis, iron-sulfur cluster biogenesis and antioxidant defense (PubMed:24448823) (By similarity). Can mediate uncoupled fluxes of either protons or metal ions.
The capacity to transport copper ions remains controversial.
Ubiquitously expressed. Expressed in erythroid progenitors.
Up-regulated under iron-depletion conditions. Down-regulated in response to high extracellular iron levels.
Higher expression in adult small intestine and to a much lesser extent in fetal kidney.
Both the O-glycan-rich domain of the extracellular domain and the C-terminus PDZ-binding motif (DTHL) in the cytoplasmic tail harbor an apical sorting signal. The cytoplasmic domain is necessary for the apical membrane targeting and renal tubulogenesis. The cytoplasmic C-terminus PDZ-binding motif (DTHL) is essential for interaction with NHERF1 and for targeting NHERF1 to the apical cell membrane. The extracellular domain is necessary for microvillus formation (By similarity). The large highly anionic extracellular domain allows to maintain open filtration pathways between neighboring podocyte foot processes.
Involved in the regulation of both adhesion and cell morphology and cancer progression. Functions as an anti-adhesive molecule that maintains an open filtration pathway between neighboring foot processes in the podocyte by charge repulsion. Acts as a pro-adhesive molecule, enhancing the adherence of cells to immobilized ligands, increasing the rate of migration and cell-cell contacts in an integrin-dependent manner. Induces the formation of apical actin-dependent microvilli. Involved in the formation of a preapical plasma membrane subdomain to set up initial epithelial polarization and the apical lumen formation during renal tubulogenesis. Plays a role in cancer development and aggressiveness by inducing cell migration and invasion through its interaction with the actin-binding protein EZR. Affects EZR-dependent signaling events, leading to increased activities of the MAPK and PI3K pathways in cancer cells.
Monomer; when associated with the membrane raft. Oligomer; when integrated in the apical membrane. Interacts (via the C-terminal PDZ-binding motif DTHL) with NHERF1 (via the PDZ domains); the interaction is not detected in glomerular epithelium cells, take place early in the secretory pathway and is necessary for its apical membrane sorting. Found in a complex with EZR, PODXL and NHERF2. Associates with the actin cytoskeleton through complex formation with EZR and NHERF2. Interacts (via the C-terminal PDZ-binding motif DTHL) with NHERF2 (via the PDZ 1 domain); interaction is detected in glomerular epithelium cells (By similarity). Interacts with EZR.
N- and O-linked glycosylated. Sialoglycoprotein (By similarity).
May be involved in several stages of intracellular trafficking. May play a role in intracellular protein transport from early endosomes to the trans-Golgi network.
Belongs to the FAM175 family. Abraxas subfamily.
Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. In the complex, interacts directly with UIMC1/RAP80, BRCC3/BRCC36 and BABAM2. Interacts directly (when phosphorylated at Ser-406) with BRCA1. Homodimer. The homodimer interacts directly (when phosphorylated at Ser-404 and Ser-406) with two BRCA1 chains, giving rise to a heterotetramer. Binds polyubiquitin.
Involved in DNA damage response and double-strand break (DSB) repair. Component of the BRCA1-A complex, acting as a central scaffold protein that assembles the various components of the complex and mediates the recruitment of BRCA1. The BRCA1-A complex specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesion sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at DSBs. This complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX.
Phosphorylation of Ser-406 of the pSXXF motif by ATM or ATR constitutes a specific recognition motif for the BRCT domain of BRCA1 (PubMed:17643121, PubMed:17525340, PubMed:17643122). Ionizing radiation promotes rapid phosphorylation at Ser-404 and Ser-406 by ATM; this promotes recruitment of BRCA1 to sites of DNA damage (PubMed:26778126).
Interacts with F-actin; the interaction disrupts the F-actin structures and leads to marked changes of neuronal morphology. Component of a complex, composed of PDZK1, SYNGAP1, KLHL17 and NMDA receptors. Interacts directly with PDZK1 (via PDZ1 domain); the interaction is important for integrity of actin cytoskeleton structures in neurons. Interacts with DLG4 and SYNGAP1. Interacts (via kelch repeats) with GRIK2 (via C-terminus); the interaction targets GRIK2 for degradation via ubiquitin-proteasome pathway. Interacts with GRIK1. Interacts with (via BTB domain) CUL3; the interaction regulates surface GRIK2 expression (By similarity).
Substrate-recognition component of some cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes. The BCR(KLHL17) complex mediates the ubiquitination and subsequent degradation of GLUR6. May play a role in the actin-based neuronal function (By similarity).
Highly expressed in testis, ovary, thymus, prostate, spleen, small intestine, colon, heart, skeletal muscle, liver, kidney and pancreas.
Protects against apoptosis mediated by Apaf-1.
Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B) and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific (Probable). Component of the BAF complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C (PubMed:18765789). In muscle cells, the BAF complex also contains DPF3. Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin. Interacts with PHF10/BAF45A (By similarity). Interacts with CEBPB (when not methylated)(PubMed:20111005). Interacts with TOPBP1 (PubMed:15075294). Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Interacts with DPF2 (PubMed:20460684). Interacts with ERCC6 (PubMed:26030138).
During apoptosis, cleaved by cathepsin CTSG to produce a 160 kDa cleavage product which localizes to the cytosol.
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Binds DNA non-specifically (PubMed:22952240, PubMed:26601204). Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity).
Interacts with DIO2. Component of the probable ECS(WSB1) E3 ubiquitin ligase complex which contains CUL5, RNF7/RBX2, Elongin BC complex and WSB1. Component of a probable ECS-like E3 ubiquitin-protein ligase complex which contains CUL5, RBX1, Elongin BC complex and WSB1. Interacts with CUL5, RNF7, ELOB and ELOC. Binds to HIPK2 through WD40 repeats.
Probable substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes type II iodothyronine deiodinase/DIO2. Confers constitutive instability to HIPK2 through proteasomal degradation.
Homodimer. Heterodimer with MID1IP1 (By similarity). Interacts with THRB and PLAGL1.
Mainly expressed in tissues that synthesize triglycerides.
Plays a role in the regulation of lipogenesis, especially in lactating mammary gland. Important for the biosynthesis of triglycerides with medium-length fatty acid chains. May modulate lipogenesis by interacting with MID1IP1 and preventing its interaction with ACACA (By similarity). May function as transcriptional coactivator. May modulate the transcription factor activity of THRB.
Homooligomer (By similarity). Does not interact MYO18; differs from GOLPH3 by its inability to interact with MYO18. May interact with ARF1.
Phosphatidylinositol-4-phosphate-binding protein that may antagonize the action of GOLPH3 which is required for the process of vesicle budding at the Golgi and anterograde transport to the plasma membrane.
Broadly expressed, with lowest levels in brain, skeletal muscle and intestine. Up-regulated in substantia nigra neurons from Parkinson disease patients (at protein level).
Monomer. Interacts with BTRC. Identified in a complex with CUL4A, DDB1 and BTRC. Interacts with TXNIP; this inhibits the proteasomal degradation of DDIT4.
Phosphorylated by GSK3B; this promotes proteasomal degradation.
Polyubiquitinated by a DCX (DDB1-CUL4A-RBX1) E3 ubiquitin-protein ligase complex with BTRC as substrate-recognition component, leading to its proteasomal degradation.
Regulates cell growth, proliferation and survival via inhibition of the activity of the mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 is mediated by a pathway that involves DDIT4/REDD1, AKT1, the TSC1-TSC2 complex and the GTPase RHEB. Plays an important role in responses to cellular energy levels and cellular stress, including responses to hypoxia and DNA damage. Regulates p53/TP53-mediated apoptosis in response to DNA damage via its effect on mTORC1 activity. Its role in the response to hypoxia depends on the cell type; it mediates mTORC1 inhibition in fibroblasts and thymocytes, but not in hepatocytes (By similarity). Required for mTORC1-mediated defense against viral protein synthesis and virus replication (By similarity). Inhibits neuronal differentiation and neurite outgrowth mediated by NGF via its effect on mTORC1 activity. Required for normal neuron migration during embryonic brain development. Plays a role in neuronal cell death.
Up-regulated in fibroblasts upon ionizing radiation, via a TP53-dependent pathway. Up-regulated by TP63 in primary keratinocytes, and down-regulated during keratinocyte differentiation. Up-regulated upon DNA alkylation. Up-regulated by amyloid beta-peptide and retinoic acid. Up-regulated by hypoxia, via a PI3K and HIF1A-dependent but TP53/TP63-independent mechanism (at protein level).
Component of some SCF complex, composed of CUL1, SKP1, RBX1 and FBXO42. Interacts (via the kelch domain) with p53/TP53; interaction is direct.
Substrate-recognition component of some SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Specifically recognizes p53/TP53, promoting its ubiquitination and degradation.
Forms a complex with PIGG and PIGO. PIGF is required to stabilize PIGG and PIGO.
Involved in GPI-anchor biosynthesis (PubMed:33386993). It acts through the transfer of ethanolamine phosphate to the third mannose of GPI.
Calcium-binding protein. May be involved in the control of sperm flagellar movement.
(Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human parvovirus B19.
(Microbial infection) Integrin ITGA5:ITGB1 acts as a receptor for Human metapneumovirus.
(Microbial infection) Integrin ITGA5:ITGB1 interacts with human metapneumovirus fusion protein.
(Microbial infection) Integrin ITGA5:ITGB1 interacts with human parvovirus B19 capsid proteins.
Expressed in placenta (at protein level).
Heterodimer of an alpha and a beta subunit. The alpha subunit is composed of a heavy and a light chain linked by a disulfide bond. ITGA5/Alpha-5 associates with ITGB1/beta-1 (PubMed:33962943). Interacts with NISCH (PubMed:11912194). Interacts with HPS5 (PubMed:10094488). Interacts with RAB21 and COMP. Interacts with CIB1. ITGA5:ITGB1 interacts with CCN3. ITGA5:ITGB1 interacts with FBN1 (PubMed:12807887, PubMed:17158881). ITGA5:ITGB1 interacts with IL1B (PubMed:29030430). ITGA5:ITGB1 interacts with ACE2 (PubMed:33102950). Interacts with ANGPT2 (PubMed:32908006).
Integrin alpha-5/beta-1 (ITGA5:ITGB1) is a receptor for fibronectin and fibrinogen. It recognizes the sequence R-G-D in its ligands. ITGA5:ITGB1 binds to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1 (PubMed:18635536, PubMed:25398877). ITGA5:ITGB1 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (PubMed:12807887, PubMed:17158881). ITGA5:ITGB1 acts as a receptor for fibronectin (FN1) and mediates R-G-D-dependent cell adhesion to FN1 (PubMed:33962943). ITGA5:ITGB1 is a receptor for IL1B and binding is essential for IL1B signaling (PubMed:29030430). ITGA5:ITGB3 is a receptor for soluble CD40LG and is required for CD40/CD40LG signaling (PubMed:31331973).
Proteolytic cleavage by PCSK5 mediates activation of the precursor.
Binds ubiquitin-conjugating enzymes (E2s). In vitro, interacts with the ubiquitin-conjugating enzyme, UBE2D2. The phosphorylated form interacts with PRKAR1A, PRKAR2A and PRKAR2B. Binds the catalytic subunits of cAMP-dependent protein kinase. Interacts with MFHAS1 (PubMed:28471450). Interacts with TBC1D31; the interaction is direct and recruits PJA2 to centrosomes (PubMed:33934390).
Has E2-dependent E3 ubiquitin-protein ligase activity (PubMed:12036302, PubMed:21423175). Responsible for ubiquitination of cAMP-dependent protein kinase type I and type II-alpha/beta regulatory subunits and for targeting them for proteasomal degradation. Essential for PKA-mediated long-term memory processes (PubMed:21423175). Through the ubiquitination of MFHAS1, positively regulates the TLR2 signaling pathway that leads to the activation of the downstream p38 and JNK MAP kinases and promotes the polarization of macrophages toward the pro-inflammatory M1 phenotype (PubMed:28471450). Plays a role in ciliogenesis by ubiquitinating OFD1 (PubMed:33934390).
Belongs to the bacterial ribosomal protein bS21 family.
Disease susceptibility is associated with variants affecting the gene represented in this entry. The lifetime risk of being diagnosed with sick sinus syndrome is higher for carriers of variant p.Arg721Trp than for non-carriers.
Represents a conventional myosin. This protein should not be confused with the unconventional myosin-6 (MYO6).
Interacts (via C-terminus) with DLG1, DLG2, DLG3 and DLG4/PSD95. Interacts (via N-terminus) with ARHGEF7; the interaction is mediated by the PDZ domain (PubMed:19118189). Interacts with GPSM2 (via TPR repeat region) (PubMed:25664792).
Positive regulator of dendritic spine morphogenesis and density. Required for the maintenance of excitatory synaptic transmission. Binds phosphatidylinositol 4,5-bisphosphate.
The FERM domain mediates the interaction with phosphatidylinositol 4,5-bisphosphate.
Belongs to the sodium channel auxiliary subunit SCN4B (TC 8.A.17) family.
Contains an interchain disulfide bond with SCN2A.
Expressed at a high level in dorsal root ganglia, at a lower level in brain, spinal cord, skeletal muscle and heart. Expressed in the atrium.
Modulates channel gating kinetics. Causes negative shifts in the voltage dependence of activation of certain alpha sodium channels, but does not affect the voltage dependence of inactivation. Modulates the susceptibility of the sodium channel to inhibition by toxic peptides from spider, scorpion, wasp and sea anemone venom.
The voltage-sensitive sodium channel consists of an ion conducting pore forming alpha-subunit (SCN2A) regulated by one or more beta subunits (SCN1B, SCN2B, SCN3B and SCN4B). SCN1B and SCN3B are non-covalently associated with SCN2A. SCN2B and SCN4B are disulfide-linked to SCN2A (PubMed:24297919).
Component of the ACF-1 ISWI chromatin remodeling complex at least composed of SMARCA1 and BAZ1A, which regulates the spacing of histone octamers on the DNA template to facilitate access to DNA (PubMed:28801535). Within the ACF-1 ISWI chromatin remodeling complex interacts with SMARCA1; the interaction is direct (PubMed:28801535). Component of the ACF-5 ISWI chromatin remodeling complex (also called the ACF complex) at least composed of BAZ1A and SMARCA5/SNF2H, which regulates the spacing of histone octamers on the DNA template to facilitate access to DNA (PubMed:10880450, PubMed:12198550, PubMed:28801535). Within the ACF-5 ISWI chromatin remodeling complex interacts with SMARCA5/SNF2H; the interaction is direct (PubMed:10880450, PubMed:12198550, PubMed:28801535). Component of the CHRAC ISWI chromatin remodeling complex at least composed of SMARCA5/SNF2H, BAZ1A/ACF1, CHRAC1 and POLE3; the complex preferentially binds DNA through the CHRAC1-POLE3 heterodimer and possesses ATP-dependent nucleosome-remodeling activity (PubMed:10880450, PubMed:12434153, PubMed:14759371). Within the complex interacts (via N-terminus) with POLE3-CHRAC1 heterodimer; the interaction is direct and is required for the complex to preferentially bind to DNA (PubMed:10880450, PubMed:12434153, PubMed:14759371). Within the complex interacts with SMARCA5/SNF2H; the interaction is direct and promotes the interaction with the POLE3-CHRAC1 heterodimer (PubMed:10880450, PubMed:12434153, PubMed:14759371). Interacts with NCOR1 (via its RD1 domain); the interaction corepresses a number of NCOR1-regulated genes (PubMed:17519354).
Highly expressed in testis and at low or undetectable levels in other tissues analyzed.
Regulatory subunit of the ATP-dependent ACF-1 and ACF-5 ISWI chromatin remodeling complexes, which form ordered nucleosome arrays on chromatin and slide edge- and center-positioned histone octamers away from their original location on the DNA template to facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair (PubMed:17099699, PubMed:28801535). Both complexes regulate the spacing of nucleosomes along the chromatin and have the ability to slide mononucleosomes to the center of a DNA template in an ATP-dependent manner (PubMed:14759371, PubMed:17099699, PubMed:28801535). The ACF-1 ISWI chromatin remodeling complex has a lower ATP hydrolysis rate than the ACF-5 ISWI chromatin remodeling complex (PubMed:28801535). Has a role in sensing the length of DNA which flank nucleosomes, which modulates the nucleosome spacing activity of the ACF-5 ISWI chromatin remodeling complex (PubMed:17099699). Involved in DNA replication and together with SMARCA5/SNF2H is required for replication of pericentric heterochromatin in S-phase (PubMed:12434153). May have a role in nuclear receptor-mediated transcription repression (PubMed:17519354).
Stimulated by double-stranded DNA and nucleosomal DNA.
Abundantly expressed in placenta but also detected in kidney, liver, lung, pancreas, skeletal muscle and heart. Expressed in primitive and myeloid, but not lymphoid, hematopoietic cells. Also observed in cell lines derived from liver, breast, colon, lung, melanocyte and cervix.
Expressed in fetal heart, lung, liver and to a lower extent in brain. Not expressed in adult brain.
Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses (By similarity). Interacts with RASA1; the interaction depends on EPHB4 tyrosine-phosphorylation (PubMed:30578106).
Phosphorylated; autophosphorylation is stimulated by EFNB2.
Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Together with its cognate ligand/functional ligand EFNB2 it is involved in the regulation of cell adhesion and migration, and plays a central role in heart morphogenesis, angiogenesis and blood vessel remodeling and permeability. EPHB4-mediated forward signaling controls cellular repulsion and segregation from EFNB2-expressing cells.
(Microbial infection) By regulating clathrin-mediated endocytosis, AAK1 plays a role in the entry of hepatitis C virus as well as for the lifecycle of other viruses such as Ebola and Dengue.
By regulating the entry of hepatitis C virus as well as the lifecycle of other viruses such as Ebola and Dengue, AAK1 is a potential drug target for developing antiviral therapies.
Detected in brain, heart and liver. Isoform 1 is the predominant isoform in brain.
Interacts (via CBD domain) with clathrin (PubMed:17494869, PubMed:14617351). Interacts with AP-2 complex (PubMed:17494869, PubMed:12952931, PubMed:14617351). Interacts with NUMB (PubMed:18657069). Interacts with alpha-adaptin (By similarity). Interacts with EPS15 isoform 2 (PubMed:21464124). Interacts with membrane-bound activated NOTCH1 but not with the inactive full-length form of NOTCH1 (PubMed:21464124). Preferentially interacts with monoubiquitinated activated NOTCH1 compared to the non-ubiquitinated form (PubMed:21464124).
Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis (PubMed:17494869, PubMed:11877457, PubMed:11877461, PubMed:12952931, PubMed:14617351, PubMed:25653444). Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1 (PubMed:17494869). Preferentially, may phosphorylate substrates on threonine residues (PubMed:11877457, PubMed:18657069). Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes (PubMed:12952931). Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes (PubMed:18657069). Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity (PubMed:21464124).
Functions as a voltage-gated monoatomic cation channel permeable to both potassium and calcium (By similarity). Plays a role in the cellular response to DNA damage (PubMed:23542032).
Homooligomer (By similarity). Interacts with CRYAB; in the cellular response to DNA damage (PubMed:23542032).
Belongs to the thymidine/pyrimidine-nucleoside phosphorylase family.
Catalyzes the reversible phosphorolysis of thymidine. The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis.
May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in vitro.
Belongs to the FAD-dependent oxidoreductase 2 family. FRD/SDH subfamily.
Component of complex II composed of four subunits: the flavoprotein (FP) SDHA, iron-sulfur protein (IP) SDHB, and a cytochrome b560 composed of SDHC and SDHD (By similarity). Interacts with SDHAF2/SDH5; interaction is required for FAD attachment (PubMed:19628817). Interacts with TRAP1 (PubMed:23747254). Interacts with LACC1 (PubMed:28593945).
Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q) (PubMed:24781757). Can act as a tumor suppressor (PubMed:20484225).
Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
Phosphorylation at Tyr-215 is important for efficient electron transfer in complex II and the prevention of ROS generation.
(Microbial infection) Interacts with viral proteins that contain a late-budding motif P-P-P-Y. This interaction is essential for viral particle budding of many retroviruses, like HTLV-1 Gag and MLV Gag. Interacts with Herpes simplex virus 2 (HHV-2) protein UL56; this interaction induces NEDD4 degradation (PubMed:18353951). Interacts with Ebola virus protein VP40 (PubMed:12559917).
(Microbial infection) Involved in the ubiquitination of Ebola virus protein VP40 which plays a role in viral budding.
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Specifically ubiquitinates 'Lys-63' in target proteins (PubMed:23644597, PubMed:21399620, PubMed:19920177). Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes (By similarity). Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes (PubMed:21765395). Promotes ubiquitination of RAPGEF2 (PubMed:11598133). According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD (By similarity). Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development (By similarity). Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2 (PubMed:20086093). Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). Ubiquitinates DAZAP2, leading to its proteasomal degradation (PubMed:11342538). Ubiquitinates POLR2A (PubMed:19920177). Functions as a platform to recruit USP13 to form an NEDD4-USP13 deubiquitination complex that plays a critical role in cleaving the 'Lys-48'-linked ubiquitin chains of VPS34 and then stabilizing VPS34, thus promoting the formation of autophagosomes (PubMed:32101753).
Interacts with UBE2D2. Binds SCNN1A, SCNN1B and SCNN1G. Binds, in vitro, through the WW2 and WW3 domains, to neural isoforms of ENAH that contain the PPSY motif. Interacts with BEAN1, LITAF, RNF11, WBP1, WBP2, PMEPAI and PRRG2 (By similarity). Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes (By similarity). Interaction with PTEN is questionable according to PubMed:18562292. Interacts (via C2 domain) with GRB10 (via SH2 domain). Interacts with ERBB4 (By similarity). Interacts with TNIK; the interaction is direct, allows the TNIK-dependent recruitment of RAP2A and its ubiquitination by NEDD4. Interacts (via WW3 domain) with TNK2; EGF promotes this interaction. Interacts (via WW3 domain) with FGFR1 (via C-terminus). Interacts with OTUD7B. Interacts with ISG15. Interacts (via WW domain) with RAPGEF2; this interaction leads to ubiquitination and degradation via the proteasome pathway. Interacts (via WW domains) with ARRDC3 (via PPXY motifs) (PubMed:20559325, PubMed:24379409). Interacts with LAPTM4B; may play a role in the lysosomal sorting of LAPTM4B (PubMed:22096579). Interacts (via WW domains) with ARRDC1, ARRDC2 and ARRDC3 (PubMed:21191027). Interacts with ZBTB7B (By similarity). Interacts with PRRG4 (via cytoplasmic domain) (PubMed:23873930). Interacts directly with LDLRAD3; this interaction promotes NEDD4 auto-ubiquitination. Interacts with ADRB2 (PubMed:23166351). Interacts (via WW domains) with DAZAP2 (via PPAY motif) (PubMed:11342538). Interacts with USP13 (PubMed:32101753).
The WW domains mediate interaction with PPxY motif-containing proteins (PubMed:21191027). The WW domains mediate interaction with LITAF, RNF11, WBP1, WBP2, PMEPAI, NDFIP1 and PRRG2 (By similarity).
Undergoes 'Lys-29'-linked auto-ubiquitination at Lys-1279 and serves as a scaffold for recruiting USP13 to form an NEDD4-USP13 deubiquitination complex.
Expressed in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas. Not found in the brain.
Interacts with NEUROD1 (PubMed:12482979). Interacts with AR (PubMed:17550981).
Transcription factor that binds specifically to the RAS-responsive elements (RRE) of gene promoters (PubMed:9305772, PubMed:15067362, PubMed:8816445, PubMed:10390538, PubMed:17550981). Represses the angiotensinogen gene (PubMed:15067362). Negatively regulates the transcriptional activity of AR (PubMed:17550981). Potentiates the transcriptional activity of NEUROD1 (PubMed:12482979). Promotes brown adipocyte differentiation (By similarity). May be involved in Ras/Raf-mediated cell differentiation by enhancing calcitonin expression (PubMed:8816445).
Expressed in macrophage and/or dendritic cells of spleen and lymph nodes.
As part of the NSL complex it is involved in acetylation of nucleosomal histone H4 on several lysine residues and therefore may be involved in the regulation of transcription.
Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1.
Controls the flux of glucose into the hexosamine pathway. Most likely involved in regulating the availability of precursors for N- and O-linked glycosylation of proteins.
Highest levels of expression in heart, placenta, and spinal cord.
Catalyzes the hydrolysis of endogenous amidated lipids like the sleep-inducing lipid oleamide ((9Z)-octadecenamide), the endocannabinoid anandamide (N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine), as well as other fatty amides, to their corresponding fatty acids, thereby regulating the signaling functions of these molecules (PubMed:17015445, PubMed:19926788). Hydrolyzes monounsaturated substrate anandamide preferentially as compared to polyunsaturated substrates.
Expressed in kidney, liver, lung, prostate, heart and ovary.
Inhibited by O-aryl carbamates and alpha-keto heterocytes.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ8 subfamily.
Defects in KCNJ8 may be associated with susceptibility to J-wave syndromes, a group of heart disorders characterized by early repolarization events as indicated by abnormal J-wave manifestation on electrocardiogram (ECG). The J point denotes the junction of the QRS complex and the ST segment on the ECG, marking the end of depolarization and the beginning of repolarization. An abnormal J wave is a deflection with a dome or hump morphology immediately following the QRS complex of the surface ECG. Examples of J-wave disorders are arrhythmias associated with an early repolarization pattern in the inferior or mid to lateral precordial leads, Brugada syndrome, some cases of idiopathic ventricular fibrillation (VF) with an early repolarization pattern in the inferior, inferolateral or global leads, as well as arrhythmias associated with hypothermia.
Predominantly detected in fetal and adult heart.
This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by external barium (By similarity).
Widely expressed. Isoform 2 and isoform 4 are predominantly expressed in brain.
Catalyzes the decomposition of L-selenocysteine to L-alanine and elemental selenium.
Up-regulated in acute glomerulonephritis. Regulated by JUN/AP-1.
May have S-adenosyl-L-methionine-dependent methyl-transferase activity.
2 major forms (42 and 36 kDa) and 2 minors (32 and 27 kDa) may be processed by proteolytic cleavage (PubMed:16488400). The largest form (42 kDa) seems to be secreted and the other major form (63 kDa) seems to accumulate within the cells or pericellular milieu (PubMed:16488400). Polypeptide consisting of Met-77 to Arg-318 may correspond to the 27 kDa form and that consisting of Met-77 to Val-365 may correspond to the 36 kDa form (PubMed:16488400).
Belongs to the transglutaminase-like superfamily. Vasohibin family.
Interacts with SVBP; interaction enhances VASH1 tyrosine carboxypeptidase activity.
Preferentially expressed in endothelial cells (PubMed:15467828, PubMed:16707096). Highly expressed in fetal organs (PubMed:15467828). Expressed in brain and placenta, and at lower level in heart and kidney (PubMed:15467828). Highly detected in microvessels endothelial cells of atherosclerotic lesions (PubMed:16707096).
Tyrosine carboxypeptidase that removes the C-terminal tyrosine residue of alpha-tubulin, thereby regulating microtubule dynamics and function (PubMed:29146869, PubMed:31270470, PubMed:31235910, PubMed:31171830, PubMed:31235911). Critical for spindle function and accurate chromosome segregation during mitosis since microtubule detyronisation regulates mitotic spindle length and postioning (PubMed:31171830). Acts as an angiogenesis inhibitor: inhibits migration, proliferation and network formation by endothelial cells as well as angiogenesis (PubMed:15467828, PubMed:16488400, PubMed:16707096, PubMed:19204325). This inhibitory effect is selective to endothelial cells as it does not affect the migration of smooth muscle cells or fibroblasts (PubMed:15467828, PubMed:16488400, PubMed:16707096).
Autophosphorylated on Thr-1161 and Thr-1165. Autophosphorylation is activated by phospholipids.
Protein kinase activity is inhibited by the first PAS domain: binding of an unidentified ligand desinhibits the protein kinase activity. May be activated by autophosphorylation on Thr-1161 and Thr-1165 (PubMed:11459942). The activating role of autophosphorylation at Thr-1161 is unclear: according to a report, autophosphorylation at Thr-1161 does not play a major role in activation (PubMed:20943661). Autophosphorylation is enhanced upon phosphatidylinositol monophosphate (phosphatidylinositol 4-phosphate) binding and inhibited upon phosphatidylinositol bi- and tri-phosphate binding. In contrast, phosphorylation of target proteins is inhibited upon all phosphatidylinositol-binding (phosphatidylinositol mono- bi- and tri-phosphate).
Serine/threonine-protein kinase involved in energy homeostasis and protein translation. Phosphorylates EEF1A1, GYS1, PDX1 and RPS6. Probably plays a role under changing environmental conditions (oxygen, glucose, nutrition), rather than under standard conditions. Acts as a sensor involved in energy homeostasis: regulates glycogen synthase synthesis by mediating phosphorylation of GYS1, leading to GYS1 inactivation. May be involved in glucose-stimulated insulin production in pancreas and regulation of glucagon secretion by glucose in alpha cells; however such data require additional evidences. May play a role in regulation of protein translation by phosphorylating EEF1A1, leading to increase translation efficiency. May also participate in respiratory regulation.
The protein kinase domain mediates binding to phosphatidylinositol.
Ubiquitously expressed, with slightly higher expression in brain, prostate and testis. Reduced expression was found in placenta. Present in germ cells of testis and in the midpiece of sperm tails (at protein level).
May serve as a scaffold protein for MADD and RAB3GA on synaptic vesicles (PubMed:11809763). Plays a role in the brain as a key controller of neuronal and endocrine homeostatic processes (By similarity).
Belongs to the transferase hexapeptide repeat family.
Catalyzes the formation of GDP-mannose, an essential precursor of glycan moieties of glycoproteins and glycolipids.
Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation. pH-dependent Ca(2+) sensor required to activate the CatSper channel. Sperm cell hyperactivation is needed for sperm motility which is essential late in the preparation of sperm for fertilization. Associates with the CatSper complex via direct interaction with CATSPERZ, and senses intracellular Ca(2+). Together with CATSPERZ, associates with the CatSper channel pore and is required for the two-row structure of each single CatSper channel.
Component of the CatSper complex or CatSpermasome composed of the core pore-forming members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 as well as auxiliary members CATSPERB, CATSPERG, CATSPERD, CATSPERE, CATSPERZ, C2CD6/CATSPERT, TMEM249, TMEM262 and EFCAB9 (By similarity). HSPA1 may be an additional auxiliary complex member (By similarity). The core complex members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 form a heterotetrameric channel (By similarity). The auxiliary CATSPERB, CATSPERG, CATSPERD and CATSPERE subunits form a pavilion-like structure over the pore which stabilizes the complex through interactions with CATSPER4, CATSPER3, CATSPER1 and CATSPER2 respectively (By similarity). TMEM262/CATSPERH interacts with CATSPERB, further stabilizing the complex. C2CD6/CATSPERT interacts at least with CATSPERD and is required for targeting the CatSper complex in the flagellar membrane (By similarity). Interacts with CATSPERZ; the interaction is direct, Ca(2+)-dependent and connects EFCAB9 with the CatSper complex (By similarity). Dissociates from CATSPERZ at elevated pH (By similarity).
Component of the EvC complex composed of EFCAB7, IQCE, EVC2 and EVC; built from two subcomplexes, EVC2:EVC and EFCAB7:IQCE. Interacts (via N-terminus) with EFCAB7 (via EF-hands 1 and 2); this interaction anchors the EVC-EVC2 complex in a signaling microdomain at the base of cilia and stimulates the Hedgehog (Hh) pathway. Interacts with EVC2 (via N-terminal end). Interacts with EVC.
Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling (By similarity). Required for proper limb morphogenesis (PubMed:28488682).
Contaminating sequence. Potential poly-A sequence starting in position 563.
Component of the SIN3-repressing complex. Enhances the ability of SIN3-HDAC1-mediated transcriptional repression. When tethered to the promoter, it can direct the formation of a repressive complex to core histone proteins. Auxiliary component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. Component of the ASAP and PSAP complexes which bind RNA in a sequence-independent manner and are proposed to be recruited to the EJC prior to or during the splicing process and to regulate specific excision of introns in specific transcription subsets. The ASAP complex can inhibit mRNA processing during in vitro splicing reactions. The ASAP complex promotes apoptosis and is disassembled after induction of apoptosis. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits the formation of proapoptotic isoforms such as Bcl-X(S); the activity is different from the established EJC assembly and function.
Found in a mRNA splicing-dependent exon junction complex (EJC). Component of the heterotrimeric ASAP (apoptosis- and splicing-associated protein) and PSAP complexes consisting of RNPS1, SAP18 and either ACIN1 or PNN, respectively; the ASAP and PSAP complexes probably are formed mutually exclusive. For the ASAP complex, the association of SAP18 seems to require a preformed RNPS1:ACIN1 complex. Forms a complex with SIN3A and HDAC1. Interacts with SUFU.
Overexpressed in hepatocellular carcinoma.
Belongs to the class I-like SAM-binding methyltransferase superfamily. EFM5 family.
Protein N-lysine methyltransferase that selectively catalyzes the trimethylation of EEF1A at 'Lys-79'.
Protein-lysine methyltransferase that selectively catalyzes the trimethylation of EEF1A at 'Lys-79'.
Was originally thought to be an N(6)-adenine-specific DNA methyltransferase based on primary sequence and predicted secondary structure.
Clathrin is the major protein of the polyhedral coat of coated pits and vesicles. Two different adapter protein complexes link the clathrin lattice either to the plasma membrane or to the trans-Golgi network. Acts as component of the TACC3/ch-TOG/clathrin complex proposed to contribute to stabilization of kinetochore fibers of the mitotic spindle by acting as inter-microtubule bridge (PubMed:15858577, PubMed:16968737, PubMed:21297582). The TACC3/ch-TOG/clathrin complex is required for the maintenance of kinetochore fiber tension (PubMed:23532825). Plays a role in early autophagosome formation (PubMed:20639872).
Clathrin triskelions, composed of 3 heavy chains and 3 light chains, are the basic subunits of the clathrin coat (PubMed:16968737). In the presence of light chains, hub assembly is influenced by both the pH and the concentration of calcium. Interacts with HIP1 (PubMed:11532990). Interacts with DENND1A, DENND1B and DENND1C (By similarity). May interact with OCRL (By similarity). Interacts with ERBB2 (PubMed:16314522). Interacts with FKBP6 (PubMed:18529014). Interacts with CKAP5 and TACC3 forming the TACC3/ch-TOG/clathrin complex located at spindle inter-microtubules bridges; the complex implicates clathrin triskelions; TACC3 and CLTC are proposed to form a composite microtubule interaction surface (PubMed:21297582). Interacts with ATG16L1 (via N-terminus) (PubMed:20639872). Interacts with RFTN1; the interaction occurs in response to pathogens (PubMed:27022195, PubMed:21266579). Interacts with USP2 isoform 4 (PubMed:26756164). Interacts with TMEM106B (via N-terminus) (PubMed:25066864).
The N-terminal seven-bladed beta-propeller is formed by WD40-like repeats, and projects inward from the polyhedral outer clathrin coat. It constitutes a major protein-protein interaction node.
Interferon-induced dynamin-like GTPase with potent antiviral activity against human immunodeficiency virus type 1 (HIV-1). Acts by targeting the viral capsid and affects the nuclear uptake and/or stability of the HIV-1 replication complex and the subsequent chromosomal integration of the proviral DNA. Exhibits antiviral activity also against simian immunodeficiency virus (SIV-mnd). May play a role in regulating nucleocytoplasmic transport and cell-cycle progression.
Binds to the purine-rich region in HTLV-I LTR.
May play metabolic roles in sperm maturation or fertilization (By similarity). Phospholipid transfer protein that preferentially selects lipid species containing a palmitoyl or stearoyl chain on the sn-1 and an unsaturated fatty acyl chain (18:1 or 18:2) on the sn-2 position. Able to transfer phosphatidylcholine (PC) and phosphatidyetanolamline (PE) between membranes.
Phosphorylation at Ser-284 by CK2 negatively regulates lipid transfer activity, possibly by decreasing membrane association.
Various sequencing problems as well as a translation in a wrong frame.
Detected in monocytes, CD11c+ immature dendritic cells, plasmacytoid pre-dendritic cells and dermal microvessel endothelial cells.
Homodimer (via cytoplasmic TIR domain) (PubMed:25088687). Heterodimer with TLR2 via their respective extracellular domains (PubMed:16880211). Binds MYD88 via their respective TIR domains (Probable). Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR4. The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4:TLR6 heterodimerization and signal initiation (PubMed:20037584). The heterodimer TLR2:TLR6 interacts with CD14 and CD36 in response to triacylated lipopeptides (PubMed:16880211).
Participates in the innate immune response to Gram-positive bacteria and fungi. Specifically recognizes diacylated and, to a lesser extent, triacylated lipopeptides (PubMed:20037584). In response to diacylated lipopeptides, forms the activation cluster TLR2:TLR6:CD14:CD36, this cluster triggers signaling from the cell surface and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR2 (PubMed:11441107). In complex with TLR4, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion (PubMed:11441107, PubMed:20037584).
Inhibits neuronal cell proliferation by negative regulation of the cell cycle transition. Promotes pituitary gonadotrope cell proliferation, migration and invasion, when overexpressed. May play a role in cell pituitary tumor development.
Strongly expressed in oral keratinocytes compared to the weak expression in tongue squamous cell carcinoma (SCC). Expressed in endothelial and aortic smooth muscle cells. Overexpressed in gonadotropinomas compared to normal pituitarie tissues.
Does not possess sterol isomerase activity and does not bind sigma ligands.
Widely expressed with highest levels in liver, lung and kidney.
Acceptor splice site between exons 4 and 5 is non-canonical but conserved through species for that particular gene.
Acts as a non-receptor guanine nucleotide exchange factor which binds to and activates guanine nucleotide-binding protein (G-protein) alpha subunit GNAI3.
Highly expressed in skeletal muscle and kidney tissues, and at moderate level in intestinal tissue. Expressed in corneal epithelial cells.
Hydrolyzes the phosphatidylinositol 4,5-bisphosphate (PIP2) to generate 2 second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG mediates the activation of protein kinase C (PKC), while IP3 releases Ca(2+) from intracellular stores. Required for acrosome reaction in sperm during fertilization, probably by acting as an important enzyme for intracellular Ca(2+) mobilization in the zona pellucida-induced acrosome reaction. May play a role in cell growth. Modulates the liver regeneration in cooperation with nuclear PKC. Overexpression up-regulates the Erk signaling pathway and proliferation.
Interacts (via GBA motif) with guanine nucleotide-binding protein G(i) alpha subunit GNAI3 (inactive GDP-bound form); high-affinity interaction (PubMed:30194280).
Interacts (via GBA motif) with guanine nucleotide-binding protein G(i) alpha subunit GNAI3 (inactive GDP-bound form); low-affinity interaction (PubMed:30194280).
The C2 domain mediates pre-localization to the membrane prior to Ca(2+) import and non-selective Ca(2+)-mediated targeting to various cellular membranes.
The PDZ-binding motif mediates the interaction with GRIP1.
The PH domain is not a critical determinant of the membrane localization.
Expressed at the highest levels in the adult cerebellum.
Individuals with blood hypertension and a SLC35F3 risk allele T/T homozygosity (intronic variant rs17514104) show a significant reduction in blood thiamine content.
Acts as a GTPase-activating protein (GAP) toward guanine nucleotide exchange factors like ARL2, ARL3, ARF1 and ARF6, but not for GTPases outside the Arf family. Regulates IFN-related antiviral responses.
Alveolar cells (morphologically type II cells) and alveolar macrophages (at protein level). Expressed in brain, colon, heart, kidney, liver, lung, muscle, placenta, small intestine, spleen, stomach and testis. In lung it is expressed in alveolar macrophages and alveolar walls.
It is unsure whether Met-1 or an upstream Met is the initiator as the upstream Met corresponds to polymorphism rs1879326.
Main constituent of aortic medial amyloid.
Mammary epithelial cell surfaces and aortic media. Overexpressed in several carcinomas.
Medin has a ragged N-terminus with minor species starting at Pro-264 and Gly-273.
Plays an important role in the maintenance of intestinal epithelial homeostasis and the promotion of mucosal healing. Promotes VEGF-dependent neovascularization (By similarity). Contributes to phagocytic removal of apoptotic cells in many tissues. Specific ligand for the alpha-v/beta-3 and alpha-v/beta-5 receptors. Also binds to phosphatidylserine-enriched cell surfaces in a receptor-independent manner. Zona pellucida-binding protein which may play a role in gamete interaction.
The F5/8 type C 2 domain mediates high-affinity binding to phosphatidylserine-containing membranes.
During normal pregnancy, the production is continuously increasing until the 37th gestational week and is followed by a sharp decrease after the 41st week of gestation. In pathological pregnancies, urinary levels fail to increase. Candidate for the diagnosis of threatened premature pregnancy termination.
Expressed at highest levels in testis. Moderate expression is detected in spleen, thymus, prostate, ovary, small intestine, and colon (PubMed:11935316). Expressed in the first trimester pregnancy decidua (PubMed:12516630). Localized to extravillous cytotrophoblast (at protein level). Also found in syncytiotrophoblast and part of the villous cytotrophoblast. Isoform 1 is expressed in first trimester and term villous trophoblast; trophoblast cells can additionally express other isoforms (PubMed:18817979). Overexpressed in solid tumors from stomach and uterus and in cells from ovary, cervical, breast, lymphoma and leukemia cancer (PubMed:25218441).
Isoform 1 interacts with PCM1, BBS4 and CEP63 (PubMed:21224392, PubMed:23110211, PubMed:26297806). Interacts with IL4R (PubMed:25218441).
Pericentriolar protein required to maintain mitotic spindle pole integrity (PubMed:21224392). Required for the centrosomal accumulation of PCM1 and the recruitment of centriolar satellite proteins such as BBS4. Via association with PCM1 may be involved in primary cilia formation (PubMed:23110211). Required for CEP63 centrosomal localization and its interaction with WDR62. Together with CEP63 promotes centriole duplication. Promotes the centrosomal localization of CDK2 (PubMed:26297806).
The secreted form is a mediator of progesterone that by acting on the phospholipase A2 enzyme interferes with arachidonic acid metabolism, induces a Th2 biased immune response, and by controlling decidual naturakl killer cells (NK) activity exerts an anti-abortive effect (PubMed:14634107, PubMed:3863495, PubMed:12516630). Increases the production of Th2-type cytokines by signaling via the JAK/STAT pathway. Activates STAT6 and inhibits STAT4 phosphorylation. Signaling via a not identified receptor seems to implicate IL4R and a GPI-anchored protein (PubMed:16393965, PubMed:25218441).
May be involved in the regulation of spermatogenesis and sperm maturation.
Expressed in retina and less in brain and hippocampus.
Interacts with GPR61, GPR62 and GPR135 (PubMed:28827538).
Arginine methyltransferase that methylates the guanidino nitrogens of arginyl residues in proteins such as STAT3, FBL, histone H4. Acts as a coactivator (with NCOA2) of the androgen receptor (AR)-mediated transactivation. Acts as a coactivator (with estrogen) of estrogen receptor (ER)-mediated transactivation. Enhances PGR, PPARG, RARA-mediated transactivation. May inhibit NF-kappa-B transcription and promote apoptosis. Represses E2F1 transcriptional activity (in a RB1-dependent manner). May be involved in growth regulation.
Higher expression in breast cancer tissues.
Higher expression in breast cancer tissues. Doesn't interact with ESR1.
Self-associates. Interacts with RB1 and E2F1 (By similarity). Interacts with NCOA6 coactivator. Interacts (via SH3 domain) with PRMT8. Interacts with AR. Interacts with NFKBIA. Interacts with ESR1, ESR2, PGR, PPARG, RARA, RXRA and THRB. Interacts with HNRNPUL1.
Widely expressed. Highly expressed in androgen target organs such as heart, prostate, skeletal muscle, ovary and spinal cord.
A cytochrome P450 monooxygenase involved in the metabolism of endogenous cholesterol and its oxygenated derivatives (oxysterols) (PubMed:11013305, PubMed:12077124, PubMed:19965590, PubMed:2384150, PubMed:21813643). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:2384150, PubMed:11013305, PubMed:12077124, PubMed:19965590, PubMed:21813643). Functions as a critical regulatory enzyme of bile acid biosynthesis and cholesterol homeostasis. Catalyzes the hydroxylation of carbon hydrogen bond at 7-alpha position of cholesterol, a rate-limiting step in cholesterol catabolism and bile acid biosynthesis (PubMed:12077124, PubMed:19965590, PubMed:2384150). 7-alpha hydroxylates several oxysterols, including 4beta-hydroxycholesterol and 24-hydroxycholesterol (PubMed:11013305, PubMed:12077124). Catalyzes the oxidation of the 7,8 double bond of 7-dehydrocholesterol and lathosterol with direct and predominant formation of the 7-keto derivatives (PubMed:21813643).
Up-regulated by glucose and by cholestyramine. Down-regulated by chenodeoxycholic acid.
May function as a tumor suppressor, inhibiting colony formation, causing G1 arrest and ultimately inducing apoptosis in homozygous 3p21.3 120-kb region-deficient cells.
Myristoylation is required for tumor suppressor activity.
Strong expression in heart, lung, skeletal muscle, kidney, and pancreas, followed by brain and liver, lowest levels in placenta.
Expressed in fetal and adult skeletal muscle.
Myosin regulatory subunit that plays an essential role to maintain muscle integrity during early development (By similarity). Plays a role in muscle contraction (By similarity).
Essential role in pre-mRNA splicing. Required in cell cycle progression for S/G(2) transition.
Homodimer. Interacts with the U5-102 kDa protein subunit of the spliceosome.
Belongs to the lyase 1 family. Adenylosuccinate lyase subfamily.
Catalyzes two non-sequential steps in de novo AMP synthesis: converts (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido)succinate (SAICAR) to fumarate plus 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide, and thereby also contributes to de novo IMP synthesis, and converts succinyladenosine monophosphate (SAMP) to AMP and fumarate.
Homotetramer. Residues from neighboring subunits contribute catalytic and substrate-binding residues to each active site.
The enzyme reaction kinetics indicate cooperativity between subunits.
Ubiquitously expressed. Both isoforms are produced by all tissues. Isoform 2 is 10-fold less abundant than isoform 1.
BCL7B is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of BCL7B may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.
Positive regulator of apoptosis. Plays a role in the Wnt signaling pathway, negatively regulating the expression of Wnt signaling components CTNNB1 and HMGA1 (PubMed:25569233). Involved in cell cycle progression, maintenance of the nuclear structure and stem cell differentiation (PubMed:25569233). May play a role in lung tumor development or progression (By similarity).
DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK4 functions in RET-mediated neurite outgrowth and plays a positive role in activation of the MAP kinase pathway (By similarity). Putative link with downstream effectors of RET in neuronal differentiation. May be involved in the regulation of the immune response induced by T-cells.
Interacts with RET and TEK/TIE2. Interaction with RET is mediated through the PTB domain and requires phosphorylation of RET 'Tyr-1062' (By similarity).
Phosphorylated on tyrosine residues in response to insulin, IGF1 or RET stimulation.
Widely expressed. High expression in skeletal muscle, heart, kidney and liver. Weaker expression in spleen, lung and small intestine, brain, heart and. Expressed in both resting and activated peripheral blood T-cells.
The two common alleles; HOX1B*A and HOX1B*B have a frequency of 78.8% and 21.2% respectively.
Defects in PRPH2 are found in different retinal diseases including cone-rod dystrophy, retinitis pigmentosa, macular degeneration. The mutations underlying autosomal dominant retinitis pigmentosa and severe macular degeneration are largely missense or small in-frame deletions in a large intradiscal loop between the third and fourth transmembrane domains. In contrast, those associated with the milder pattern phenotypes or with digenic RP are scattered more evenly through the gene and are often nonsense mutations. This observation correlates with the hypothesis that the large loop is an important site of interaction between PRPH2 molecules and other protein components in the disk.
Essential for retina photoreceptor outer segment disk morphogenesis, may also play a role with ROM1 in the maintenance of outer segment disk structure (By similarity). Required for the maintenance of retinal outer nuclear layer thickness (By similarity). Required for the correct development and organization of the photoreceptor inner segment (By similarity).
Homodimer; disulfide-linked (By similarity). Forms a homotetramer (By similarity). Forms a heterotetramer with ROM1 (By similarity). Homotetramer and heterotetramer core complexes go on to form higher order complexes by formation of intermolecular disulfide bonds (By similarity). Interacts with MREG (By similarity). Interacts with STX3 (By similarity). Interacts with SNAP25 (By similarity).
Retina (photoreceptor). In rim region of ROS (rod outer segment) disks.
Interacts with SNAP2; the interaction is direct. Interacts with STX1; the interaction is direct. Interacts with RAB8B (By similarity).
Isoform 1 and isoform 3 are found in adult brain. Isoform 2 is expressed in the fetus and in adult brain, heart, placenta, skeletal muscle and kidney.
Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion and in the control of neurotransmitter release at these output synapses. Interacts in a calcium-dependent manner to the presynaptic SNARE proteins at ribbon synapses of cochlear inner hair cells (IHCs) to trigger exocytosis of neurotransmitter. Also essential to synaptic exocytosis in immature outer hair cells (OHCs). May also play a role within the recycling of endosomes (By similarity).
The N-terminal first 124 residues can be classified as C2 domain, based on their 3D-structure. They are not sufficient for calcium ion or phospholipid binding (By similarity).
May have a role in proliferation and/or differentiation.
Homodimer; disulfide-linked. Associates with CD5. Interacts (tyrosine phosphorylated) with PTPN6/SHP-1 (By similarity).
Phosphorylated upon engagement of the B-cell receptor, probably by LYN or SYK. Phosphorylation at Tyr-7 is important for interaction with PTPN6/SHP-1 (By similarity).
Plays a role in B-cell proliferation and differentiation.
Pre-B-cells and B-cells but not terminally differentiated plasma cells.
Expressed most abundantly in testis with lower levels in heart, brain, pancreas, prostate and ovary.
Increases ligand-dependent transcriptional activity of AR and other nuclear hormone receptors.
Interacts with AR, SMARCA4/BRG1 and SMARCE1/BAF57. Interaction with either SMARCA4 and SMARCE1 enhances AR-mediated transcription.
Component of the THO complex, which is composed of THOC1, THOC2, THOC3, THOC5, THOC6 and THOC7; together with at least ALYREF/THOC4, DDX39B, SARNP/CIP29 and CHTOP, THO forms the transcription/export (TREX) complex which seems to have a dynamic structure involving ATP-dependent remodeling. Interacts with NIF3L1 and THOC5.
Required for efficient export of polyadenylated RNA. Acts as component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NFX1 pathway.
The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production.
Detected in peripheral blood B-cells (at protein level). Detected in spleen, liver and peripheral blood.
Interacts with FASLG. Interacts with phosphotyrosine containing proteins. Interacts (via SH3 domain) with CTTN. Interacts (phosphorylated at Ser-23) with YWHAB, YWHAE, YWHAG, YWHAH, YWHAZ and SFN. Interacts directly with SAP30 and HDAC1. Identified in a complex with SAP30 and HDAC1 (By similarity).
Negative regulator of B-cell activation. Down-regulates cell proliferation (in vitro). Promotes RAC1-dependent membrane ruffle formation and reorganization of the actin cytoskeleton. Regulates cell spreading and cell polarization. Stimulates HDAC1 activity. Regulates LYN activity by modulating its tyrosine phosphorylation (By similarity).
Up-regulated in peripheral blood B-cells by IL4, IL13 and by CD40 stimulation.
Belongs to the DNA polymerase type-A family.
DNA polymerase with very low fidelity that catalyzes considerable misincorporation by inserting dTTP opposite a G template, and dGTP opposite a T template (PubMed:16787914, PubMed:17118716). Is the least accurate of the DNA polymerase A family (i.e. POLG, POLN and POLQ) (PubMed:17118716). Can perform accurate translesion DNA synthesis (TLS) past a 5S-thymine glycol. Can perform efficient strand displacement past a nick or a gap and gives rise to an amount of product similar to that on non-damaged template. Has no exonuclease activity (PubMed:16787914). Error-prone DNA polymerase that preferentially misincorporates dT regardless of template sequence (PubMed:25775266). May play a role in TLS during interstrand cross-link (ICL) repair (PubMed:19908865). May be involved in TLS when genomic replication is blocked by extremely large major groove DNA lesions. May function in the bypass of some DNA-protein and DNA-DNA cross-links. May have a role in cellular tolerance to DNA cross-linking agents (PubMed:20102227). Involved in the repair of DNA cross-links and double-strand break (DSB) resistance. Participates in FANCD2-mediated repair. Forms a complex with HELQ helicase that participates in homologous recombination (HR) repair and is essential for cellular protection against DNA cross-links (PubMed:19995904).
Highly expressed in testis and heart. Weakly expressed in skeletal muscle.
Interacts with FANCD2, FANCI, PCNA, RAD51 and HELQ.
Arachidonic acid release is markedly increased by glypican, a glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan.
By IL1B/interleukin-1 beta and TNF in microvascular endothelial cells (at protein level).
Expressed in kidney, heart, liver, and skeletal muscle. Also present in placenta and peripheral blood leukocytes. Not detected in colon, thymus, spleen and small intestine. In lung, expressed in bronchial epithelial cells and alveolar macrophages, but scarcely detected in alveolar epithelium, arterial walls and interstitial fibroblasts (at protein level). In joints of osteoarthritis and rheumatoid arthritis, expressed in endothelial cells (at protein level). In normal heart, detected in some vessels. In myocardial tissues with acute infarction, expressed in vascular endothelial cells adjacent to cardiomyocytes and those in lesions with granulation. Expression in cardiomyocytes is scarce (at protein level). In uterus, breast and colon cancers, detected in tumor cells and neighboring microvascular endothelium, but not in normal glandular tissues (at protein level) (PubMed:15863501). Expressed in dermal resting mast cells (at protein level) and pulmonary mast cells (PubMed:23624557). Expressed in neuronal fibers (at protein level) (PubMed:17868035). Highly expressed in dorsal root ganglia neurons (at protein level) (PubMed:17868035). Expressed in Purkinje cells in cerebellum (at protein level) (PubMed:17868035). In stomach is preferentially expressed in neuronal fibers and in microvascular endothelium (PubMed:17868035). Sparsely expressed in normal aorta (at protein level). Highly expressed in macrophages and smooth muscle cells in aorta with atheroma (PubMed:18801741).
In several cell types, the N- and C-termini are cleaved off.
N-glycosylation does not affect the catalytic activity, but is required for proper secretion. A nonglycosylated form is observed in several cell types.
Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids. Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids without apparent head group selectivity (PubMed:12522102, PubMed:18801741, PubMed:15863501, PubMed:28947740). Contributes to phospholipid remodeling of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles. Hydrolyzes LDL phospholipids releasing unsaturated fatty acids that regulate macrophage differentiation toward foam cells (PubMed:18801741). May act in an autocrine and paracrine manner (PubMed:23624557). Secreted by immature mast cells, acts on nearby fibroblasts upstream to PTDGS to synthesize prostaglandin D2 (PGD2), which in turn promotes mast cell maturation and degranulation via PTGDR (PubMed:23624557). Secreted by epididymal epithelium, acts on immature sperm cells within the duct, modulating the degree of unsaturation of the fatty acyl components of phosphatidylcholines required for acrosome assembly and sperm cell motility. Facilitates the replacement of fatty acyl chains in phosphatidylcholines in sperm membranes from omega-6 and omega-9 to omega-3 polyunsaturated fatty acids (PUFAs). Coupled to lipoxygenase pathway, may process omega-6 PUFAs to generate oxygenated lipid mediators in the male reproductive tract (By similarity). At pericentrosomal preciliary compartment, negatively regulates ciliogenesis likely by regulating endocytotic recycling of ciliary membrane protein (PubMed:20393563). Coupled to cyclooxygenase pathway provides arachidonate to generate prostaglandin E2 (PGE2), a potent immunomodulatory lipid in inflammation and tumorigenesis (PubMed:12522102, PubMed:15863501). At colonic epithelial barrier, preferentially hydrolyzes phospholipids having arachidonate and docosahexaenoate at sn-2 position, contributing to the generation of oxygenated metabolites involved in colonic stem cell homeostasis (PubMed:28947740). Releases C16:0 and C18:0 lysophosphatidylcholine subclasses from neuron plasma membranes and promotes neurite outgrowth and neuron survival (PubMed:17868035).
The phospholipase A2-like domain represents the fully processed form after N- and C-termini are cleaved off. It is the secreted mature form found in biological fluids.
Does not associate with the C1 complex. According to PubMed:15385675, doesn't cleave the proform of complement C1s.
Highly expressed in placenta, liver, kidney, pancreas, moderately in lung, spleen, prostate, ovary, colon, and PBL, and weakly in heart, skeletal muscle, thymus, testis, and small intestine. Expressed in PC-3 (prostate adenocarcinoma) and SK-OV-3 (ovary adenocarcinoma) cells, but not in LoVo and HT-29 (colon adenocarcinoma), SMMC7721 (hepatocellular carcinoma), CaoV-3 (ovary adenocarcinoma), HeLa (cervix epithelioid carcinoma), MCF-7 (breast adenocarcinoma), U-251MG (glioma) or A-549 (lung carcinoma) cells. Widely expressed in myeloid leukemia cell lines, including K-562 (chronic myelogenous leukemia), THP-1 (myelomonocytic leukemia), HL-60 and NB4 (promyelocytic leukemia), and KG-1 (acute myelogenous leukemia) cells. Expressed mainly in the liver and in serum (at protein level).
Mediates the proteolytic cleavage of HP/haptoglobin in the endoplasmic reticulum.
Up-regulated in monocytes and dendritic cells (DC) undergoing maturation or activation.
As part of the intermicrovillar adhesion complex/IMAC plays a role in epithelial brush border differentiation, controlling microvilli organization and length. Plays a role in assembly of the complex (PubMed:26812018). May play a role in cellular response to endoplasmic reticulum stress (By similarity).
Expressed in kidney and small intestine.
Part of the IMAC/intermicrovillar adhesion complex/intermicrovillar tip-link complex composed of ANKS4B, MYO7B, USH1C, CDHR2 and CDHR5 (PubMed:26812018). Interacts with USH1C; the interaction is direct and is required for ANKS4B localization to the tip of microvilli (PubMed:26812017, PubMed:26812018). Interacts with MYO7B; the interaction is direct (PubMed:26812018). May interact with HSPA5 (By similarity).
Belongs to the complex I NDUFB4 subunit family.
Abundantly expressed in heart and skeletal muscle, and at lower levels in placenta, lung, liver and pancreas. Also expressed in HeLaS3 and MOLT-4 cell lines.
Involved in regulating cell migration through association with the actin cytoskeleton. Has an essential role in the maintenance of Z line and sarcomere integrity.
Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a homodimer or a heterodimer (USF1/USF2). Interacts with varicella-zoster virus IE62 protein.
Transcription factor that binds to a symmetrical DNA sequence (E-boxes) (5'-CACGTG-3') that is found in a variety of viral and cellular promoters.
Core component of at least two putative endosomal tethering complexes, the homotypic fusion and vacuole protein sorting (HOPS) complex and the class C core vacuole/endosome tethering (CORVET) complex. Their common core is composed of the class C Vps proteins VPS11, VPS16, VPS18 and VPS33A, which in HOPS further associates with VPS39 and VPS41 and in CORVET with VPS8 and TGFBRAP1 (PubMed:23351085, PubMed:25783203, PubMed:25266290, PubMed:23901104, PubMed:28013294). Interacts with RAB5C (By similarity). Interacts with UVRAG, STX17, MON1A and MON1B (PubMed:18552835, PubMed:20434987, PubMed:24554770, PubMed:28013294). Interacts with VIPAS39; however, this interaction is debated (PubMed:19109425, PubMed:23901104). Associates with adaptor protein complex 3 (AP-3) and clathrin (PubMed:21411634). Interacts with PLEKHM1 (PubMed:28325809).
Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Believed to act as a core component of the putative HOPS and CORVET endosomal tethering complexes which are proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The HOPS complex is proposed to be recruited to Rab7 on the late endosomal membrane and to regulate late endocytic, phagocytic and autophagic traffic towards lysosomes. The CORVET complex is proposed to function as a Rab5 effector to mediate early endosome fusion probably in specific endosome subpopulations (PubMed:23351085, PubMed:24554770, PubMed:25266290, PubMed:25783203). Required for fusion of endosomes and autophagosomes with lysosomes; the function is dependent on its association with VPS16 but not VIPAS39 (PubMed:25783203). The function in autophagosome-lysosome fusion implicates STX17 but not UVRAG (PubMed:24554770).
Catalytic component of P4-ATPase flippase complex, which catalyzes the hydrolysis of ATP coupled to the transport of phosphatidylcholine (PC) from the outer to the inner leaflet of the plasma membrane. May contribute to the maintenance of membrane lipid asymmetry.
Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit ATP8B2 and an accessory beta subunit TMEM30A or TMEM30B.
Isoform 3 is ubiquitous, with highest expression in aorta, cerebellum and uterus.
Protein insertase that mediates insertion of transmembrane proteins into the mitochondrial outer membrane (PubMed:36264797). Catalyzes insertion of proteins with alpha-helical transmembrane regions, such as signal-anchored, tail-anchored and multi-pass membrane proteins (PubMed:36264797). Does not mediate insertion of beta-barrel transmembrane proteins (PubMed:36264797). Also acts as a receptor for the truncated form of pro-apoptotic BH3-interacting domain death agonist (p15 BID) and has therefore a critical function in apoptosis (By similarity). Regulates the quiescence/cycling of hematopoietic stem cells (HSCs) (By similarity). Acts as a regulator of mitochondrial fusion, essential for the naive-to-primed interconversion of embryonic stem cells (ESCs) (By similarity). Acts as a regulator of lipid homeostasis and has a regulatory role in adipocyte differentiation and biology (By similarity).
Belongs to the POU transcription factor family. Class-6 subfamily.
Expressed only within the CNS, where its expression is restricted to the medical habenulla, to a dispersed population of neurons in the dorsal hypothalamus, and to subsets of ganglion and amacrine cells in the retina.
Probable transcription factor likely to be involved in early steps in the differentiation of amacrine and ganglion cells. Recognizes and binds to the DNA sequence 5'-ATGCAAAT-3'. Isoform 1 does not bind DNA.
Acetylated at Lys-33 (PubMed:32538779). Deacetylation at Lys-33 by SIRT1 promotes homomultimerization and binding to double-strand breaks (DSBs) sites (PubMed:32538779).
Compared to the defatty-acylase activity, the protein deacetylase activity is weak in vitro, and requires activation (PubMed:24052263, PubMed:23892288, PubMed:21362626, PubMed:23552949). The histone deacetylase activity is strongly activated upon binding to nucleosomes and chromatin in vivo (PubMed:23892288, PubMed:27043296, PubMed:33067423). Two molecules of SIRT6 associate with the acidic patch of one nucleosome, while the C-terminal disordered region of SIRT6 associates with nucleosomal DNA, leading to efficient histone deacetylation (PubMed:33067423). The protein-lysine deacetylase activity is also activated by long-chain free fatty-acids (PubMed:24052263). The histone deacetylase activity is specifically repressed by long non-coding RNA lncPRESS1, which binds to SIRT6 and prevents chromatin-binding, thereby promoting stem cell pluripotency (PubMed:27912097). Due to its essential role as tumor suppressor and involvement in DNA repair and life span, extensive research is made for the identification of small compound regulators of SIRT6 (PubMed:27990725, PubMed:30395713, PubMed:30374165, PubMed:31844103, PubMed:33214841, PubMed:33649599, PubMed:33649600). Nitro-fatty acids (nitro-oleic acid and nitro-conjugated linoleic acid) strongly stimulate the protein-lysine deacetylase activity by forming a covalent Michael adduct formation with Cys-18 (PubMed:33122195). Activated by UBCS039 (4-(pyridin-3-yl)-4,5- dihydropyrrolo[1,2-a]quinoxaline) (PubMed:27990725). Inhibited by non-selective hydroxamate trichostatin A inhibitor (PubMed:30395713). Deacetylase activity is activated by fluvastatin and quercetin-based compounds (PubMed:31844103, PubMed:33214841). The protein-lysine deacetylase activity, but not the defatty-acylase activity, is specifically activated by MDL-800 and MDL-801 activators in vivo, enhancing the histone deacetylase and tumor suppressor activities (PubMed:30374165, PubMed:33649599, PubMed:33649600). MDL-800 and MDL-801 selectively activate SIRT6 and not other members of the sirtuin family (PubMed:30374165). The binding-mode of MDL-801 is however subject to discussion (PubMed:30374165, PubMed:33649599, PubMed:33649600).
Down-regulated in a number of cancers, such as pancreatic cancer or colon carcinomas (PubMed:23217706). Post-transcriptionally regulated by miR-766 (PubMed:23653361). Expression is post-transcriptionally repressed by miR-122 (PubMed:26748705).
Homodimer; binds to nucleosomes and DNA ends as a homodimer (PubMed:31995034, PubMed:32538779). Interacts with RELA; interferes with RELA binding to target DNA (PubMed:19135889). Interacts with SMARCA5; promoting recruitment of SMARCA5/SNF2H to double-strand breaks (DSBs) sites (PubMed:23911928). Interacts with the mTORC2 complex; preventing the ability of SIRT6 to deacetylate FOXO1. Interacts with the CLOCK-BMAL1 complex; recruited by the CLOCK-BMAL1 complex to regulate expression of clock-controlled genes. Interacts with CSNK2A2; preventing CSNK2A2 localization to the nucleus (By similarity).
Monoubiquitinated at Lys-170 by STUB1/CHIP, preventing its degradation by the proteasome.
NAD-dependent protein deacetylase, deacylase and mono-ADP-ribosyltransferase that plays an essential role in DNA damage repair, telomere maintenance, metabolic homeostasis, inflammation, tumorigenesis and aging (PubMed:18337721, PubMed:19135889, PubMed:19625767, PubMed:21680843, PubMed:23217706, PubMed:23653361, PubMed:24052263, PubMed:27322069, PubMed:27180906, PubMed:21362626, PubMed:23552949, PubMed:30374165, PubMed:29555651). Displays protein-lysine deacetylase or defatty-acylase (demyristoylase and depalmitoylase) activity, depending on the context (PubMed:24052263, PubMed:27322069, PubMed:23552949). Acts as a key histone deacetylase by catalyzing deacetylation of histone H3 at 'Lys-9', 'Lys-18' and 'Lys-56' (H3K9ac, H3K18ac and H3K56ac, respectively), suppressing target gene expression of several transcription factors, including NF-kappa-B (PubMed:19625767, PubMed:24012758, PubMed:23892288, PubMed:23911928, PubMed:27043296, PubMed:26898756, PubMed:27180906, PubMed:33067423, PubMed:21362626, PubMed:30374165, PubMed:26456828). Acts as an inhibitor of transcription elongation by mediating deacetylation of H3K9ac and H3K56ac, preventing release of NELFE from chromatin and causing transcriptional pausing (By similarity). Involved in DNA repair by promoting double-strand break (DSB) repair: acts as a DSB sensor by recognizing and binding DSB sites, leading to (1) recruitment of DNA repair proteins, such as SMARCA5/SNF2H, and (2) deacetylation of histone H3K9ac and H3K56ac (PubMed:23911928, PubMed:31995034, PubMed:32538779). SIRT6 participation to DSB repair is probably involved in extension of life span (By similarity). Also promotes DNA repair by deacetylating non-histone proteins, such as DDB2 and p53/TP53 (PubMed:32789493, PubMed:29474172). Specifically deacetylates H3K18ac at pericentric heterochromatin, thereby maintaining pericentric heterochromatin silencing at centromeres and protecting against genomic instability and cellular senescence (PubMed:27043296). Involved in telomere maintenance by catalyzing deacetylation of histone H3 in telomeric chromatin, regulating telomere position effect and telomere movement in response to DNA damage (PubMed:18337721, PubMed:19625767, PubMed:21847107). Required for embryonic stem cell differentiation by mediating histone deacetylation of H3K9ac (PubMed:25915124, PubMed:29555651). Plays a major role in metabolism by regulating processes such as glycolysis, gluconeogenesis, insulin secretion and lipid metabolism (PubMed:24012758, PubMed:26787900). Inhibits glycolysis via histone deacetylase activity and by acting as a corepressor of the transcription factor HIF1A, thereby controlling the expression of multiple glycolytic genes (By similarity). Has tumor suppressor activity by repressing glycolysis, thereby inhibiting the Warburg effect (PubMed:23217706). Also regulates glycolysis and tumorigenesis by mediating deacetylation and nuclear export of non-histone proteins, such as isoform M2 of PKM (PKM2) (PubMed:26787900). Acts as a negative regulator of gluconeogenesis by mediating deacetylation of non-histone proteins, such as FOXO1 and KAT2A/GCN5 (PubMed:23142079, PubMed:25009184). Promotes beta-oxidation of fatty acids during fasting by catalyzing deacetylation of NCOA2, inducing coactivation of PPARA (By similarity). Acts as a regulator of lipid catabolism in brown adipocytes, both by catalyzing deacetylation of histones and non-histone proteins, such as FOXO1 (By similarity). Also acts as a regulator of circadian rhythms, both by regulating expression of clock-controlled genes involved in lipid and carbohydrate metabolism, and by catalyzing deacetylation of PER2 (By similarity). The defatty-acylase activity is specifically involved in regulation of protein secretion (PubMed:24052263, PubMed:23552949, PubMed:27322069, PubMed:28406396). Has high activity toward long-chain fatty acyl groups and mediates protein-lysine demyristoylation and depalmitoylation of target proteins, such as RRAS2 and TNF, thereby regulating their secretion (PubMed:23552949, PubMed:28406396). Also acts as a mono-ADP-ribosyltransferase by mediating mono-ADP-ribosylation of PARP1, TRIM28/KAP1 or SMARCC2/BAF170 (PubMed:21680843, PubMed:22753495, PubMed:27568560, PubMed:27322069). Mono-ADP-ribosyltransferase activity is involved in DNA repair, cellular senescence, repression of LINE-1 retrotransposon elements and regulation of transcription (PubMed:21680843, PubMed:22753495, PubMed:27568560).
Phosphorylation at Ser-10 by MAPK8/JNK1 in response to oxidative stress stimulates the mono-ADP-ribosyltransferase activity on PARP1, leading to PARP1 recruitment to double-strand breaks (DSBs).
Sumoylated, leading to specifically decrease ability to deacetylate histone H3 at 'Lys-56' (H3K56ac).
The C-terminal disordered region mediates non-specific DNA-binding.
The binding-mode of MDL-801 selective activator is subject to discussion (PubMed:30374165, PubMed:33649599, PubMed:33649600). According to a group, MDL-801 binds around the acyl channel exit and acts as an allosteric activator (PubMed:30374165, PubMed:33649600). According to another group, the binding mode of MDL-801 remains undefined (PubMed:33649599).
Upon DNA damage, was reported to promote DNA end resection via deacetylation of RBBP8. However, this study was later retracted.
Variability among SIRT6 alleles may account for variations in life span (PubMed:25541994). A minor allele (rs107251) is associated with a decreased life span of 5.5 and 5.9 years when homozygous (TT); when compared to the major allele homozygous (CC) and heterozygous (CT) genotypes, respectively (PubMed:25541994).
Expressed in respiratory cells and in sperm (at protein level) (PubMed:33139725). Expressed in nasopharyngeal epithelium and trachea (PubMed:10524255).
Interacts with AK8; dimerization with AK8 may create a cavity at the interface of the dimer that can accommodate AMP (PubMed:33139725). Interacts with CFAP52 (PubMed:33139725). Interacts with ENKUR (PubMed:33139725). Directly interacts with DNALI1 (PubMed:33139725). Interacts with DNAH11 (PubMed:33139725). Interacts with DNAI1 (PubMed:33139725).
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (PubMed:36191189). It is an AMP-binding protein that may facilitate dynein ATPase-dependent ciliary and flagellar beating via adenine nucleotide homeostasis. May function as a donor of AMP to AK8 and hence promote ADP production (PubMed:33139725).
Expressed in a wide range of tissues including ovary, testis, placenta, uterus and bladder.
Plasma membrane progesterone (P4) receptor coupled to G proteins (PubMed:23763432). Seems to act through a G(i) mediated pathway (PubMed:23763432). May be involved in oocyte maturation (PubMed:12601167). Involved in neurosteroid inhibition of apoptosis (PubMed:23161870). Also binds dehydroepiandrosterone (DHEA), pregnanolone, pregnenolone and allopregnanolone (PubMed:23161870).
Docking protein that plays a role in tyrosine kinase-based signaling related to cell adhesion and cell spreading. Regulates PTK2/FAK1 activity, focal adhesion integrity, and cell spreading.
Expressed abundantly in lung and spleen. Also highly expressed in ovarian and leukemia cell lines.
Interacts (via SH3 domain) with PTK2/FAK1 (via C-terminus).
ATP-dependent chaperone, which plays an essential role in the cytoplasmic maturation steps of pre-60S ribosomal particles by promoting the release of shuttling protein RSL24D1/RLP24 from the pre-ribosomal particles (PubMed:35354024). Acts together with AFG2A, AIRIM and CINP (PubMed:35354024).
Associates with pre-60S ribosomal particles (PubMed:35354024). Interacts with AIRIM (PubMed:35354024).
Belongs to the AAA ATPase family. AFG2 subfamily.
Expressed in both neurons and glia during embryonic and adult stages of brain development.
Binds to actin. Binds to the cytoplasmic domain of receptor protein tyrosine phosphatase delta.
Expressed in many tissues, including spleen, thymus, prostate, testis, uterus, colon, and peripheral blood.
May be related to cancer progression or tumor metastasis in a variety of organ sites, most likely through an interaction with the actin cytoskeleton.
The WH2 motif at the C-terminus binds to actin monomers.
The gene for this protein is either identical to or adjacent to that of MEF2B. Some mRNAs that encode this protein also include MEF2B.
Acetylation at Lys-220 by KAT2B/PCAF promotes dynamic kinetochore-microtubule interactions in early mitosis.
Crotonylated by KAT5 during mitosis, promoting astral microtubule plasticity and dynamic connection between astral microtubules and the cortex during mitotic chromosome segregation, thereby ensuring accurate spindle positioning in mitosis (PubMed:34608293). Decrotonylated by HDAC3 (PubMed:34608293).
Homodimer (PubMed:15616574). Heterodimer with MAPRE3 (PubMed:19255245). Interacts with DCTN1, DCTN2, TERF1 and dynein intermediate chain (PubMed:10226031, PubMed:11943150, PubMed:12388762, PubMed:14514668, PubMed:23874158, PubMed:16109370, PubMed:16949363). Interaction with DIAPH1 and DIAPH2 (By similarity). Interacts (via C-terminal residues 206-211) with APC (via C-terminal residues 2674-2843); the interaction inhibits association with and bundling of F-actin (PubMed:17293347). Interacts with CLASP2, DST, KIF2C and STIM1; probably required for their targeting to the growing microtubule plus ends (PubMed:7606712, PubMed:12388762, PubMed:14514668, PubMed:15631994, PubMed:19543227, PubMed:15616574, PubMed:19632184). Interacts with MTUS2; interaction is direct and probably targets MTUS2 to microtubules (PubMed:19543227). Interacts with APC2 (PubMed:10644998). Interacts with CLASP1 (PubMed:15631994). Interacts with CDK5RAP2 (PubMed:19553473). Interacts with MACF1 (By similarity). Interacts with RABL2/RABL2A; binds preferentially to GTP-bound RABL2 (By similarity). Interacts with KCNAB2 (By similarity). Interacts (via C-terminus) with CLIP1 (PubMed:17563362, PubMed:21646404). Interacts with SLAIN2 and SLAIN1 (PubMed:21646404). Interacts with KIF18B; this interaction is required for efficient accumulation of KIF18B at microtubule plus ends (PubMed:21820309). Interacts with MISP (PubMed:23509069). Interacts with KNSTRN (PubMed:23035123). Interacts with NCKAP5L (PubMed:26485573). Interacts with CAMSAP2 (PubMed:28726242). Interacts with PDE4DIP isoform 13/MMG8/SMYLE; this interaction is required for its recruitment to the Golgi apparatus (PubMed:25217626, PubMed:28814570). Forms a pericentrosomal complex with AKAP9, CDK5RAP2 and PDE4DIP isoform 13/MMG8/SMYLE; within this complex, MAPRE1 binding to CDK5RAP2 may be mediated by PDE4DIP (PubMed:29162697). Interacts with AKNA (By similarity). Interacts with GAS2L1, GAS2L2, and GAS2L3 (PubMed:24706950). Interacts with RARRES1 and AGBL2 (PubMed:21303978).
Plus-end tracking protein (+TIP) that binds to the plus-end of microtubules and regulates the dynamics of the microtubule cytoskeleton (PubMed:12388762, PubMed:16109370, PubMed:19632184, PubMed:21646404, PubMed:23001180, PubMed:28726242, PubMed:28814570, PubMed:34608293). Promotes cytoplasmic microtubule nucleation and elongation (PubMed:12388762, PubMed:16109370, PubMed:19632184, PubMed:21646404, PubMed:28726242, PubMed:28814570). Involved in mitotic spindle positioning by stabilizing microtubules and promoting dynamic connection between astral microtubules and the cortex during mitotic chromosome segregation (PubMed:12388762, PubMed:34608293). Also acts as a regulator of minus-end microtubule organization: interacts with the complex formed by AKAP9 and PDE4DIP, leading to recruit CAMSAP2 to the Golgi apparatus, thereby tethering non-centrosomal minus-end microtubules to the Golgi, an important step for polarized cell movement (PubMed:28814570). Promotes elongation of CAMSAP2-decorated microtubule stretches on the minus-end of microtubules (PubMed:28814570). Acts as a regulator of autophagosome transport via interaction with CAMSAP2 (PubMed:28726242). Functions downstream of Rho GTPases and DIAPH1 in stable microtubule formation (By similarity). May play a role in cell migration (By similarity).
Acts as an endogenous negative regulator of isoform 1.
Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Binds to G(i)-alpha and G(o)-alpha, but not to G(s)-alpha (By similarity).
Positively regulates TNFSF11-induced osteoclast differentiation. Acts as a regulator of TNFSF11-mediated Ca(2+) signaling pathways via its interaction with SERCA2 which is critical for the TNFSF11-induced CREB1 activation and mitochondrial ROS generation necessary for proper osteoclast generation. Association between TMEM64 and SERCA2 in the ER leads to cytosolic Ca (2+) spiking for activation of NFATC1 and production of mitochondrial ROS, thereby triggering Ca (2+) signaling cascades that promote osteoclast differentiation and activation. Negatively regulates osteoblast differentiation and positively regulates adipocyte differentiation via modulation of the canonical Wnt signaling pathway. Mediates the switch in lineage commitment to osteogenesis rather than to adipogenesis in mesenchymal stem cells by negatively regulating the expression, activity and nuclear localization of CTNNB1.
Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). Interacts with SERPINB2 (PubMed:14732874). Interacts with RFPL4A (By similarity).
(Microbial infection) Interacts with human papillomavirus/HPV type 16, 18 and 31 proteins E6.
A chromosomal aberration involving FBLN1 is found in a complex type of synpolydactyly referred to as 3/3-prime/4 synpolydactyly associated with metacarpal and metatarsal synostoses. Reciprocal translocation t(12;22)(p11.2;q13.3) with RASSF8. Fibroblasts derived from a patient with synpolydactyly displayed alterations in the level of isoform D splice variant incorporated into the ECM and secreted into the conditioned culture medium. By contrast, the expression of isoform C was not perturbed in the patients fibroblasts. Furthermore, no aberrant polypeptides were detected in extracts of cultured patients fibroblasts. The translocation t(12;22) may result in haploinsufficiency of the isoform D splice variant, which could lead to the observed limb malformation.
Elevated expression and altered processing of FBLN1 protein is associated with human breast cancer.
Expression increased by estrogen in ovarian cancer cells.
Homomultimerizes and interacts with various extracellular matrix components such as FN1, LAMA1, LAMA2, NID, ACAN, CSPG2 and type IV collagen. Interacts also with APP and FGB. Interacts with FBLN7 (By similarity). Interacts with CCN3 (PubMed:9927660).
Homomultimerizes and interacts with various extracellular matrix components.
Incorporated into fibronectin-containing matrix fibers. May play a role in cell adhesion and migration along protein fibers within the extracellular matrix (ECM). Could be important for certain developmental processes and contribute to the supramolecular organization of ECM architecture, in particular to those of basement membranes.
Incorporated into fibronectin-containing matrix fibers. May play a role in cell adhesion and migration along protein fibers within the extracellular matrix (ECM). Could be important for certain developmental processes and contribute to the supramolecular organization of ECM architecture, in particular to those of basement membranes. Has been implicated in a role in cellular transformation and tumor invasion, it appears to be a tumor suppressor. May play a role in haemostasis and thrombosis owing to its ability to bind fibrinogen and incorporate into clots. Could play a significant role in modulating the neurotrophic activities of APP, particularly soluble APP.
Isoform A and isoform B are only expressed in placenta. Isoform C and isoform D are expressed in a variety of tissues and cultured cells.
Widely expressed during embryonic development. Prominent in the matrix of the leptomeningeal anlage, in basement membranes of the neuroepithelium and the perineurium of peripheral nerves. In embryos of gestational week (gw) 4, staining was observed in the early mesenchymal bone anlagen. In gw 6.5 and 8, all perichondrial structures showed expression but the chondrocytes themselves showed no staining. In gw 10, expression is prominent in the interterritorial matrix surrounding the hypertrophic chondrocytes.
Expressed in several cell lines tested, including primary and transformed cell lines.
Expressed in bone marrow, lymph nodes, T lymphocytes, spleen, thymus and tonsil. Overexpressed in tumor cell lines.
Farnesylated. Farnesylation is required for membrane targeting. Unfarnesylated forms are shifted into the nucleus.
Homotrimer. Interacts with ATF5 (By similarity). Interacts with tubulin.
Protein tyrosine phosphatase which stimulates progression from G1 into S phase during mitosis. May play a role in the development and maintenance of differentiating epithelial tissues. Enhances cell proliferation, cell motility and invasive activity, and promotes cancer metastasis.
Strongly down-regulated upon tetrodotoxin treatment.
Interacts with DISC1. Interacts preferentially with phosphorylated forms of myosin regulatory light chain (MRLC) (By similarity). Interacts (via the N-terminal region) with HDAC6; inhibits the deacetylase activity of HDAC6 (By similarity). Interacts with KIBRA (via the C-terminal region); retains AMPAR in the cytosol after internalization (By similarity).
Phosphorylation at Thr-91 by PLK1 affects CCDC141 degradation.
Plays a critical role in cortical radial and GnRH neurons migration during brain development. Regulates cortical radial migration by negatively controlling the activity of histone deacetylase 6 (HDAC6) and promotes centrosome maturation. CAMDI is required for dilation formation of cortical neurons during radial migration. Plays a critical role in learning and memory performance through regulation of AMPA-selective glutamate receptors (AMPARs) cell surface expression in competition with KIBRA.
Ubiquitinated and degradated by the CDC20-APC/C pathway. During brain development, CDC20-APC/C complex degrades CCDC141 after centrosome translocation into the dilated area. CCDC141 is restabilized in the dilation until the centrosome enters the dilation, at which point it is once again immediately destabilized by CDC20-APC/C complex. The oscillatory regulation of CCDC141 protein is needed for proper cortical migration.
Catalyzes the conversion of the nucleoside breakdown products ribose-1-phosphate and deoxyribose-1-phosphate to the corresponding 5-phosphopentoses. Catalyzes the interconversion of glucose-1-phosphate into glucose-6-phosphate but with a lower catalytic efficiency (PubMed:17804405). In vitro, has also a low glucose 1,6-bisphosphate synthase activity which is most probably not physiologically relevant (PubMed:17804405, PubMed:18927083).
The phosphomutase activity is stimulated by glucose 1,6-bisphosphate.
ATP-dependent transporter of the ATP-binding cassette (ABC) family that may be involved in the cellular efflux of sterols, in particular cholesterol and desmosterol (a cholesterol precursor), to high-density lipoprotein (HDL) (PubMed:15240127, PubMed:33141061). May play an important role in the removal of amyloid-beta peptides from brain, in a process that can be antagonized by desmosterol. However it is unclear whether ABCG4 can directly transport amyloid-beta peptides or whether peptide export may be facilitated due to changes in the membrane lipid environment (By similarity). Induces apoptosis in various cells (PubMed:27228027).
Expressed specifically in the brain and the eye.
Half-transporter that forms a functional transporter via homo- or heterodimerization. Homodimer (PubMed:27228027). Heterodimers with ABCG1 (Probable) (PubMed:27228027).
Protein expression is stabilized by cellular cholesterol status and cholesterol synthesis intermediates desmosterol, lathosterol and lanosterol.
Whether ABCG4 is an LXR target gene, is still under debate. Studies performed in monocytes, and in one astrocyte cell line indicated that ABCG4 expression could be up-regulated by oxysterols and other LXR ligands (PubMed:11606068, PubMed:33141061). However, subsequent observations in a number of different cell types (primary mouse cells, oligodendrocytes and neuron-like cell lines) have not confirmed this observation (By similarity) (PubMed:33141061).
Electrogenic antiporter that exchanges one cholinergic neurotransmitter, acetylcholine or choline, with two intravesicular protons across the membrane of synaptic vesicles. Uses the electrochemical proton gradient established by the V-type proton-pump ATPase to store neurotransmitters inside the vesicles prior to their release via exocytosis (PubMed:8910293, PubMed:20225888) (By similarity). Determines cholinergic vesicular quantal size at presynaptic nerve terminals in developing neuro-muscular junctions with an impact on motor neuron differentiation and innervation pattern (By similarity). Part of forebrain cholinergic system, regulates hippocampal synapse transmissions that underlie spatial memory formation (By similarity). Can transport serotonin.
Peripheral and central cholinergic nervous systems.
Potently inhibited by L-vesamicol, reserpine and tetrabenazine.
Has been termed C11orf5, but is not the official C11orf5 as defined by HGNC.
Identified in the spliceosome C complex (PubMed:28502770, PubMed:28076346). Component of the PRP19-CDC5L splicing complex composed of a core complex comprising a homotetramer of PRPF19, CDC5L, PLRG1 and BCAS2, and at least three less stably associated proteins CTNNBL1, CWC15 and HSPA8 (PubMed:20176811). Interacts directly with CTNNBL1 in the complex (PubMed:20176811). Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932).
Involved in pre-mRNA splicing as component of the spliceosome (PubMed:28502770, PubMed:28076346). Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
Binds calmodulin via its IQ domains. Interacts with APC2. Interacts with alpha-, beta-, and gamma-catenin. Interacts with N-cadherin (CDH2). Interacts with microtubules (By similarity). Interacts with NPHP1. Interacts with DVL1, PRICKLE (PRICKLE1 or PRICKLE2) and Strabismus (VANGL1 or VANGL2). Interacts with IQCB1; the interaction likely requires additional interactors. Component of a complex containing at least ANKS6, INVS, NEK8 and NPHP3. ANKS6 may organize complex assembly by linking INVS and NPHP3 to NEK8 and INVS may target the complex to the proximal ciliary axoneme.
Hydroxylated at Asn-75, most probably by HIF1AN.
May be ubiquitinated via its interaction with APC2.
Required for normal renal development and establishment of left-right axis. Probably acts as a molecular switch between different Wnt signaling pathways. Inhibits the canonical Wnt pathway by targeting cytoplasmic disheveled (DVL1) for degradation by the ubiquitin-proteasome. This suggests that it is required in renal development to oppose the repression of terminal differentiation of tubular epithelial cells by Wnt signaling. Involved in the organization of apical junctions in kidney cells together with NPHP1, NPHP4 and RPGRIP1L/NPHP8 (By similarity). Does not seem to be strictly required for ciliogenesis (By similarity).
The D-box 1 (destruction box 1) mediates the interaction with APC2, and may act as a recognition signal for degradation via the ubiquitin-proteasome pathway.
Widely expressed. Strongly expressed in the primary cilia of renal tubular cells.
Belongs to the Antp homeobox family. Deformed subfamily.
Expressed at high levels in placenta (cyto- and syncytiotrophoblastic cells) and at lower levels in spleen, peripheral blood leukocytes (predominantly B-cells) and small intestine.
Putative adhesion molecule that mediates sialic-acid dependent binding to cells. Binds to alpha-2,6-linked sialic acid. The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface.
Should not be confused with SIGLEC5 which has been called CD33L2.
Interacts with the DNA-binding domain of the nuclear receptors NR3C1/GR, ESR2/ER-beta, THRB and RXRA (By similarity). Forms a stable heterodimer with MND1. Interacts with PSMC3/TBP1.
Overexpressed in leiomyomas compared to myometrium.
PTM: Phosphorylated by PKA, PKC and MAPK.
Plays an important role in meiotic recombination. Stimulates DMC1-mediated strand exchange required for pairing homologous chromosomes during meiosis. The complex PSMC3IP/MND1 binds DNA, stimulates the recombinase activity of DMC1 as well as DMC1 D-loop formation from double-strand DNA. This complex stabilizes presynaptic RAD51 and DMC1 filaments formed on single strand DNA to capture double-strand DNA. This complex stimulates both synaptic and presynaptic critical steps in RAD51 and DMC1-promoted homologous pairing. May inhibit HIV-1 viral protein TAT activity and modulate the activity of proteasomes through association with PSMC3. Acts as a tissue specific coactivator of hormone-dependent transcription mediated by nuclear receptors.
Interacts with RIMS1, RIMS2, RPH3A and RPH3AL (By similarity). Interacts with GDI2, CHM and CHML; phosphorylation at Thr-94 disrupts these interactions (PubMed:29125462). Interacts with MADD (via uDENN domain); the GTP-bound form is preferred for interaction (By similarity).
Phosphorylation of Thr-94 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM, CHML and RAB GDP dissociation inhibitor GDI2.
Chimeric cDNA. The in vivo relevance of this transcript of the STON1 and GTF2A1L (AC Q9UNN4) genes creating a chimeric protein of 1182 residues is uncertain.
In contrast to other members of the family, it does not contain NPF (Asn-Pro-Phe) sites and thereby does not interact with EPS15, EPS15R and ITSN1.
May be involved in the endocytic machinery.
Activated by 1,2-diacyl-sn-glycero-3-phosphate/phosphatidic acid irrespective of its acyl chain composition.
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:9159104, PubMed:15544348, PubMed:18004883, PubMed:19744926, PubMed:22108654, PubMed:22627129, PubMed:23949095). Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes (PubMed:9159104, PubMed:15544348, PubMed:18004883, PubMed:19744926, PubMed:22108654, PubMed:22627129, PubMed:23949095). Also plays an important role in the biosynthesis of complex lipids (Probable). Does not exhibit an acyl chain-dependent substrate specificity among diacylglycerol species (PubMed:9159104, PubMed:19744926, PubMed:22108654). Can also phosphorylate 1-alkyl-2-acylglycerol in vitro but less efficiently and with a preference for alkylacylglycerols containing an arachidonoyl group (PubMed:15544348, PubMed:19744926, PubMed:22627129). The biological processes it is involved in include T cell activation since it negatively regulates T-cell receptor signaling which is in part mediated by diacylglycerol (By similarity). By generating phosphatidic acid, stimulates PIP5KIA activity which regulates actin polymerization (PubMed:15157668). Through the same mechanism could also positively regulate insulin-induced translocation of SLC2A4 to the cell membrane (By similarity).
Forms a signaling complex with RASGRP1 and HRAS.
Highest levels in brain, and substantial levels in skeletal muscle, heart, and pancreas.
Interacts (via PDZ-binding motif) with the PDZ domain of the syntrophin SNTG1 and that of SNX27 (PubMed:11352924, PubMed:17351151). Interacts with IRS1 in the absence of insulin; insulin stimulation decreases this interaction (By similarity). Found in a ternary complex with IRS1 and PIP5K1A in the absence of insulin (By similarity). Interacts with PIP5K1A (PubMed:15157668).
Phosphorylation of the MARCKS homology domain by PKC reduces nuclear accumulation of DGK-zeta.
The PDZ-binding motif mediates interaction with PDZ domain-containing proteins like SNTG1 and SNX27.
May associate with CD21. May regulate the release of Ca(2+) from intracellular stores.
Phosphorylated in response to growth factor stimulation.
Seems to bind one calcium ion with high affinity.
Cleavage of p35 to p25 may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative diseases. The p25 form accumulates in neurons in the brain of patients with Alzheimer disease, but not in normal brain. This accumulation correlates with an increase in CDK5 kinase activity. Application of amyloid beta peptide A-beta(1-42) induced the conversion of p35 to p25 in primary cortical neurons. Expression of the p25/Cdk5 complex in cultured primary neurons induces cytoskeletal disruption, morphological degeneration and apoptosis.
Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1 (p25) and macromolecular complex composed of at least CDK5, CDK5R1 (p35) and CDK5RAP1 or CDK5RAP2 or CDK5RAP3 (PubMed:16039528, PubMed:17671990, PubMed:15689152). Only the heterodimer shows kinase activity (PubMed:16039528, PubMed:17671990, PubMed:15689152). Interacts with EPHA4 and NGEF; may mediate the activation of NGEF by EPHA4 (By similarity). Interacts with RASGRF2 (PubMed:15128856). The complex p35/CDK5 interacts with CLOCK (PubMed:24235147).
Myristoylated. A proper myristoylation signal is essential for the proper distribution of p35.
Phosphorylation at Ser-8 and Thr-138 by CDK5 prevents calpain-mediated proteolysis.
The p35 form is proteolytically cleaved by calpain, giving rise to the p25 form. P35 has a 5 to 10 fold shorter half-life compared to p25. The conversion results in deregulation of the CDK5 kinase: p25/CDK5 kinase displays an increased and altered tau phosphorylation in comparison to the p35/CDK5 kinase in vivo (By similarity).
Ubiquitinated, leading to its degradation: degradation of p35 by proteasome results in down-regulation of CDK5 activity (PubMed:12393264). During this process, CDK5 phosphorylates p35 and induces its ubiquitination and subsequent degradation (PubMed:12393264). Ubiquitinated by the CRL2(FEM1B) complex, which recognizes the -Gly-Leu-Asp-Arg C-degron at the C-terminus, leading to its degradation (PubMed:33398170, PubMed:33398168).
p35 is a neuron specific activator of CDK5. The complex p35/CDK5 is required for neurite outgrowth and cortical lamination. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. Activator of TPKII. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-BMAL1 heterodimer in association with altered stability and subcellular distribution.
A chromosomal aberration involving BCL10 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(1;14)(p22;q32). Although the BCL10/IgH translocation leaves the coding region of BCL10 intact, frequent BCL10 mutations could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.
Homomultimer; homooligomerized following recruitment by CARD domain-containing proteins that form a nucleating helical template that recruits BCL10 via CARD-CARD interaction (PubMed:24074955). Self-associates by CARD-CARD interaction and interacts with other CARD-proteins such as CARD9, CARD10, CARD11 and CARD14 (PubMed:26488816, PubMed:27113748, PubMed:27777308, PubMed:28628108, PubMed:31296852, PubMed:24074955). Forms a complex with CARD14 and MALT1; resulting in the formation of a CBM (CARD14-BCL10-MALT1) complex (PubMed:27113748). Forms a complex with CARD11 and MALT1; resulting in the formation of a CBM (CARD11-BCL10-MALT1) complex (PubMed:28628108, PubMed:24074955). Forms a complex with CARD9 and MALT1; resulting in the formation of a CBM (CARD9-BCL10-MALT1) complex (By similarity). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (PubMed:17287217). Binds caspase-9 with its C-terminal domain (PubMed:10187815). Interacts with TRAF2 and BIRC2/c-IAP2 (PubMed:11466612). Interacts with PELI2 and SOCS3; these interactions may be mutually exclusive (By similarity).
Phosphorylated. Phosphorylation results in dissociation from TRAF2 and binding to BIRC2/c-IAP2 (PubMed:11466612). Phosphorylated by IKBKB/IKKB (PubMed:17213322).
Plays a key role in both adaptive and innate immune signaling by bridging CARD domain-containing proteins to immune activation (PubMed:10187770, PubMed:10364242, PubMed:10400625, PubMed:25365219, PubMed:24074955). Acts by channeling adaptive and innate immune signaling downstream of CARD domain-containing proteins CARD9, CARD11 and CARD14 to activate NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:24074955). Recruited by activated CARD domain-containing proteins: homooligomerized CARD domain-containing proteins form a nucleating helical template that recruits BCL10 via CARD-CARD interaction, thereby promoting polymerization of BCL10, subsequent recruitment of MALT1 and formation of a CBM complex (PubMed:24074955). This leads to activation of NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:18287044, PubMed:27777308, PubMed:24074955). Activated by CARD9 downstream of C-type lectin receptors; CARD9-mediated signals are essential for antifungal immunity (PubMed:26488816). Activated by CARD11 downstream of T-cell receptor (TCR) and B-cell receptor (BCR) (PubMed:18264101, PubMed:18287044, PubMed:27777308, PubMed:24074955). Promotes apoptosis, pro-caspase-9 maturation and activation of NF-kappa-B via NIK and IKK (PubMed:10187815).
Proteolytically cleaved by MALT1; required for T-cell activation.
Ubiquitinated via both 'Lys-63'-linked and linear ('Met-1'-linked) polyubiquitin chains in response to T-cell receptor (TCR) activation (PubMed:18287044, PubMed:27777308). Ubiquitination is recognized by IKBKG/NEMO, the regulatory subunit of I-kappa-B kinase (IKK), and is required for TCR-induced NF-kappa-B activation (PubMed:18287044, PubMed:27777308). Linear ubiquitination at Lys-17, Lys-31 and Lys-63 is mediated by RNF31/HOIP; linear ubiquitination is recognized with much higher affinity than 'Lys-63'-linked ubiquitin by IKBKG/NEMO (PubMed:27777308). CARD11 is required for linear ubiquitination by HOIP by promoting the targeting of BCL10 to RNF31/HOIP (PubMed:27777308).
Expressed in macrophages and in malignant cells. Expressed by the liver and secreted in plasma (at protein level).
Interacts (via the HRR domain) with TPM1; the interaction appears to contribute to the antiangiogenic properties of the HRR domain. Interacts with THBS2; the interaction blocks the antiangiogenic effect of THBS2 with CD36 (By similarity). Interacts with THBS1 (via the TSP type I repeats); the interaction blocks the antiangiogenic effect of THBS1 with CD3. Interacts with PLG (via its Kringle domains); the interaction tethers PLG to the cell surface and enhances its activation. Interacts with HPSE; the interaction is enhanced at acidic pH, partially inhibits binding of HPSE to cell surface receptors and modulates its enzymatic activity. Interacts (via the HRR domain) with TMP1; the interaction partially mediates the antiangiogenic properties of HRG. Interacts with kappa and lambda light chains of IgG molecules. Interacts with ATP5F1A; the interaction occurs on the surface of T-cells and alters their cell morphology in concert with CONA. Binds IgG molecules containing kappa and lambda light chains and inhibits the formation of insoluble immunoglobulin complexes. Interacts with F12; the interaction, which is enhanced in the presence of zinc ions and inhibited by heparin-binding to HRG, inhibits factor XII autoactivation and contact-initiated coagulation.
Plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, and divalent metal ions. Binds heparin and heparin/glycosaminoglycans in a zinc-dependent manner. Binds heparan sulfate on the surface of liver, lung, kidney and heart endothelial cells. Binds to N-sulfated polysaccharide chains on the surface of liver endothelial cells. Inhibits rosette formation. Acts as an adapter protein and is implicated in regulating many processes such as immune complex and pathogen clearance, cell chemotaxis, cell adhesion, angiogenesis, coagulation and fibrinolysis. Mediates clearance of necrotic cells through enhancing the phagocytosis of necrotic cells in a heparan sulfate-dependent pathway. This process can be regulated by the presence of certain HRG ligands such as heparin and zinc ions. Binds to IgG subclasses of immunoglobins containing kappa and lambda light chains with different affinities regulating their clearance and inhibiting the formation of insoluble immune complexes. Tethers plasminogen to the cell surface. Binds T-cells and alters the cell morphology. Modulates angiogenesis by blocking the CD6-mediated antiangiongenic effect of thrombospondins, THBS1 and THBS2. Acts as a regulator of the vascular endothelial growth factor (VEGF) signaling pathway; inhibits endothelial cell motility by reducing VEGF-induced complex formation between PXN/paxillin and ILK/integrin-linked protein kinase and by promoting inhibition of VEGF-induced tyrosine phosphorylation of focal adhesion kinases and alpha-actinins in endothelial cells. Also plays a role in the regulation of tumor angiogenesis and tumor immune surveillance. Normalizes tumor vessels and promotes antitumor immunity by polarizing tumor-associated macrophages, leading to decreased tumor growth and metastasis.
Proteolytic cleavage produces several HRG fragments which are mostly disulfide-linked and, therefore, not released. Cleavage by plasmin is inhibited in the presence of heparin, zinc ions or in an acidic environment. Cleavage reduces binding of HRG to heparan sulfate, but enhances the ability of HRG to bind and tether plasminogen to the cell surface. On platelet activation, releases a 33 kDa antiangiogenic peptide which encompasses the HRR. Also cleaved in the C-terminal by plasmin.
The His/Pro-rich (HRR) region contains approximately 12 tandem internal repeats of the 5-residue G[H/P][H/P]PH consensus sequence. HRR binds heparan sulfate and possesses antiangiogenic, antibacterial and antifungal properties through binding Candida cells, and preferentially lysing the ergosterol-containing liposomes at low pH. The tandem repeats also bind divalent metal ions and heme.
The cystatin domains can also bind heparan sulfate. Binding is enhanced in the presence of zinc ions.
ATP-dependent RNA helicase (PubMed:16170325). Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:22961380, PubMed:28502770, PubMed:28076346, PubMed:29301961). Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs (PubMed:16209946, PubMed:16170325, PubMed:16314458, PubMed:16923391, PubMed:16931718, PubMed:19033377, PubMed:20479275). The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). Its RNA-dependent ATPase and RNA-helicase activities are induced by CASC3, but abolished in presence of the MAGOH-RBM8A heterodimer, thereby trapping the ATP-bound EJC core onto spliced mRNA in a stable conformation. The inhibition of ATPase activity by the MAGOH-RBM8A heterodimer increases the RNA-binding affinity of the EJC. Involved in translational enhancement of spliced mRNAs after formation of the 80S ribosome complex. Binds spliced mRNA in sequence-independent manner, 20-24 nucleotides upstream of mRNA exon-exon junctions. Shows higher affinity for single-stranded RNA in an ATP-bound core EJC complex than after the ATP is hydrolyzed. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly (PubMed:22203037). Involved in craniofacial development (PubMed:24360810).
Identified in the spliceosome C complex (PubMed:11991638, PubMed:22961380, PubMed:28502770, PubMed:28076346, PubMed:29301961). Core component of the mRNA splicing-dependent exon junction complex (EJC); the core complex contains CASC3, EIF4A3, MAGOH or MAGOHB, and RBM8A (PubMed:15034551, PubMed:14730019, PubMed:16170325, PubMed:16314458, PubMed:23917022, PubMed:16923391, PubMed:16931718, PubMed:19033377, PubMed:20479275). Interacts with CASC3, MAGOH, NXF1, RBM8A and ALYREF/THOC4 (PubMed:14730019, PubMed:16170325, PubMed:16495234, PubMed:22961380). May interact with NOM1. Interacts with POLDIP3 (PubMed:18423201). Interacts with CWC22 and PRPF19 in an RNA-independent manner (PubMed:22959432, PubMed:22961380, PubMed:23236153, PubMed:24218557). Direct interaction with CWC22 is mediated by the helicase C-terminal domain (PubMed:22959432, PubMed:24218557). Full interaction with CWC22 occurs only when EIF4A3 is not part of the EJC and prevents EIF4A3 binding to RNA. Identified in a complex composed of the EJC core, UPF3B and UPF2. The EJC core can also interact with UPF3A (in vitro) (PubMed:20479275). Interacts with NCBP3 (PubMed:26382858). Interacts with NRDE2 (PubMed:30538148). Interacts with DHX34; the interaction is RNA-independent (PubMed:25220460).
The ATPase activity is increased some 4-fold in the presence of RNA.
The disease is caused by variants affecting the gene represented in this entry. EIF4A3 mutations resulting in Richieri-Costa-Pereira syndrome include a repeat expansion of 18 or 20 nucleotides in the 5' untranslated region. Affected individuals have 14 to 16 repeats, while healthy individuals have 3 to 12 repeats (PubMed:24360810).
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.7/SCN9A subfamily.
Expressed strongly in dorsal root ganglion, with only minor levels elsewhere in the body, smooth muscle cells, MTC cell line and C-cell carcinoma. Also expressed in vagus nerves within the head and neck region (PubMed:31647222). Isoform 1 is expressed preferentially in the central and peripheral nervous system. Isoform 2 is expressed preferentially in the dorsal root ganglion.
Inhibited by tetrodotoxin (PubMed:23077250). Weakly inhibited by saxitoxin (PubMed:23077250).
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:7720699, PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It is a tetrodotoxin-sensitive Na(+) channel isoform (PubMed:7720699). Plays a role in pain mechanisms, especially in the development of inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487, PubMed:24311784).
Phosphorylation at Ser-1490 by PKC in a highly conserved cytoplasmic loop increases peak sodium currents.
SCN9A has been originally reported to be involved in generalized epilepsy with febrile seizures plus (GEFS+)(PubMed:19763161). However, it has later been shown that SCN9A variants are not a likely cause of autosomal dominant febrile seizures/febrile seizures plus and other monogenic seizure phenotypes (PubMed:33216760).
The sodium channel complex consists of a large, channel-forming alpha subunit (SCN9A) regulated by one or more beta subunits (SCN1B, SCN2B, SCN3B and SCN4B) (PubMed:7720699, PubMed:17167479, PubMed:25240195). SCN1B and SCN3B are non-covalently associated with SCN2A. SCN2B and SCN4B are disulfide-linked to SCN2A. Interacts with NEDD4 and NEDD4L (By similarity). Interacts with the scorpion alpha-toxin CvIV4 (PubMed:21887265). Interacts with the conotoxin GVIIJ (PubMed:24497506). Interacts with the spider huwentoxin-IV (through the extracellular loop S3-S4 of repeat II) (PubMed:20855463, PubMed:21659528, PubMed:30661758, PubMed:30765606). Interacts with the spider protoxin-II (through the extracellular loop S3-S4 of repeats II and IV) (PubMed:20855463, PubMed:21659528, PubMed:30661758, PubMed:30765606). Interacts with the spider beta/delta-theraphotoxin-Pre1a (PubMed:28428547).
Ubiquitinated by NEDD4L; which may promote its endocytosis. Does not seem to be ubiquitinated by NEDD4.
Activated by phosphorylation on Thr-214.
Expressed at all stages of the mitotic cell cycle.
Interacts with MAPT/TAU (PubMed:23666762). Interacts with gamma-tubulin (PubMed:14594945). Interacts with ODF2 (PubMed:23400999). Interacts with USP9X (PubMed:18254724). Interacts with YWHAQ (PubMed:16959763). Interacts with NLRP3; promoting NLRP3 recruitment to microtubule organizing center (MTOC) (PubMed:28656979).
Phosphorylated at Thr-214 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39 (PubMed:14976552). Phosphorylated throughout the cell cycle (PubMed:25123532).
Serine/threonine-protein kinase (PubMed:15009667, PubMed:14594945, PubMed:23666762, PubMed:23184942). Phosphorylates the microtubule-associated protein MAPT/TAU (PubMed:14594945, PubMed:23666762). Also phosphorylates the microtubule-associated proteins MAP2 and MAP4 (PubMed:14594945). Involved in regulation of the microtubule network, causing reorganization of microtubules into bundles (PubMed:14594945, PubMed:25123532). Required for the initiation of axoneme extension during cilium assembly (PubMed:23400999). Regulates the centrosomal location of ODF2 and phosphorylates ODF2 in vitro (PubMed:23400999). Plays a role in cell cycle progression, specifically in the G1/S checkpoint (PubMed:25123532). Reduces neuronal cell survival (PubMed:15009667). Plays a role in energy homeostasis by regulating satiety and metabolic rate (By similarity). Promotes adipogenesis by activating JNK1 and inhibiting the p38MAPK pathway, and triggers apoptosis by activating the JNK1 pathway (By similarity). Phosphorylates mTORC1 complex member RPTOR and acts as a negative regulator of the mTORC1 complex, probably due to disruption of the interaction between phosphorylated RPTOR and the RRAGA/RRAGC heterodimer which is required for mTORC1 activation (PubMed:23184942). Involved in NLRP3 positioning along microtubules by mediating NLRP3 recruitment to microtubule organizing center (MTOC) upon inflammasome activation (PubMed:28656979).
Ubiquitinated with 'Lys-29'- and 'Lys-33'-linked polyubiquitins which appear to impede LKB1-mediated phosphorylation. Deubiquitinated by USP9X.
Ubiquitous. Isoform 2 is brain-specific (PubMed:11326310). Expressed at highest levels in brain and testis. Also expressed in heart, lung, liver, muscle, kidney and spleen (PubMed:14594945).
Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Has activity toward EA2 peptide substrate, but has a weak activity toward Muc2 or Muc1b substrates (By similarity).
Interacts with EXT2. Does not interact with EXT1, EXTL1 or EXTL3.
Expressed at very low levels in many tissues, with strongest expression in cerebellum, spinal cord, stomach, pituitary gland, liver, pancreas, salivary gland, kidney, bladder, and heart.
Probably associates with an alpha chain. Interacts (via C-terminus) with TRPC4.
During thymocyte development, may play a role in the regulation of apoptosis (By similarity). GTPase which exhibits a higher affinity for GDP than for GTP.
Highly expressed in spleen and peripheral blood leukocytes that contain mostly T- and B-lymphocytes. Expressed specifically in resting T- and B-lymphocytes and expression significantly decreases during B- or T-lymphocyte activation. Expressed at lower levels in thymus, ovary, colon and small intestine.
May interact (via IQ domain) with calmodulin/CALM1 only in the absence of Ca(2+) (By similarity). Interacts with BAX, but not with other Bcl-2 family members (By similarity).
Phosphorylated at very low levels in resting splenocytes. Rapidly and transiently phosphorylated in response to splenocyte activation.
Activated by phosphorylation on tyrosine residues.
Interacts with AGAP2 via its SH3 domain. Interacts (via SH2 domain) with RET. Interacts with FLT1 (tyrosine-phosphorylated) (By similarity). Interacts (via SH2 domain) with FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts with LAT (phosphorylated) upon TCR activation. Interacts (via SH3 domain) with the Pro-rich domain of TNK1. Associates with BLNK, VAV1, GRB2 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with CBLB in activated T-cells; which inhibits phosphorylation. Interacts with SHB. Interacts (via SH3 domain) with the Arg/Gly-rich-flanked Pro-rich domains of KHDRBS1/SAM68. This interaction is selectively regulated by arginine methylation of KHDRBS1/SAM68. Interacts with INPP5D/SHIP1, THEMIS and CLNK (By similarity). Interacts with AXL, FLT4 and KIT. Interacts with RALGPS1. Interacts (via the SH2 domains) with VIL1 (phosphorylated at C-terminus tyrosine phosphorylation sites). Interacts (via SH2 domain) with PDGFRA and PDGFRB (tyrosine phosphorylated). Interacts with PIP5K1C (By similarity). Interacts with NTRK1 and NTRK2 (phosphorylated upon ligand-binding). Interacts with SYK; activates PLCG1. Interacts with GRB2, LAT and THEMIS upon TCR activation in thymocytes (By similarity). Interacts with TESPA1; the association is increased with prolonged stimulation of the TCR and may facilitate the assembly of the LAT signalosome.
Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Plays an important role in the regulation of intracellular signaling cascades. Becomes activated in response to ligand-mediated activation of receptor-type tyrosine kinases, such as PDGFRA, PDGFRB, EGFR, FGFR1, FGFR2, FGFR3 and FGFR4 (By similarity). Plays a role in actin reorganization and cell migration (PubMed:17229814).
The SH3 domain mediates interaction with CLNK (By similarity). The SH3 domain also mediates interaction with RALGPS1 (PubMed:10747847).
Tyrosine phosphorylated in response to signaling via activated FLT3, KIT and PDGFRA (By similarity). Tyrosine phosphorylated by activated FGFR1, FGFR2, FGFR3 and FGFR4. Tyrosine phosphorylated by activated FLT1 and KDR. Tyrosine phosphorylated by activated PDGFRB. The receptor-mediated activation of PLCG1 involves its phosphorylation by tyrosine kinases, in response to ligation of a variety of growth factor receptors and immune system receptors. For instance, SYK phosphorylates and activates PLCG1 in response to ligation of the B-cell receptor. May be dephosphorylated by PTPRJ. Phosphorylated by ITK and TXK on Tyr-783 upon TCR activation in T-cells.
Ubiquitinated by CBLB in activated T-cells.
Defects in LZTS1 are found in many types of tumors.
Highly expressed in testis, prostate, spleen, thymus, ovary and brain. Detected at lower levels in heart, placenta, small intestine, colon, liver, kidney, skeletal muscle and pancreas. Not detectable in primary tumors from breast and prostate and in many cancer cell lines.
Involved in the regulation of cell growth. May stabilize the active CDC2-cyclin B1 complex and thereby contribute to the regulation of the cell cycle and the prevention of uncontrolled cell proliferation. May act as a tumor suppressor.
Phosphorylated on serine residues. Hyperphosphorylated by the cAMP-dependent kinase PKA during cell-cycle progression.
A stop codon at position Ala-40 in the gene coding for this protein is responsible for functional diversity thus producing a pseudogene. The stop codon is more frequent in non-Africans than in African-Americans.
Negatively regulates Wnt/beta-catenin signaling during development.
Cell surface receptor that plays a functionally redundant role in the inhibition of neurite outgrowth mediated by MAG (By similarity). Plays a functionally redundant role in postnatal brain development. Contributes to normal axon migration across the brain midline and normal formation of the corpus callosum. Does not seem to play a significant role in regulating axon regeneration in the adult central nervous system. Protects motoneurons against apoptosis; protection against apoptosis is probably mediated by MAG (By similarity). Like other family members, plays a role in restricting the number dendritic spines and the number of synapses that are formed during brain development (PubMed:22325200). Signaling mediates activation of Rho and downstream reorganization of the actin cytoskeleton (PubMed:22325200).
Highly expressed in brain and liver. Expressed at lower levels in kidney, mammary gland, placenta, skeletal muscle, spleen and thyroid.
Interaction with MAG is controversial, and may be indirect (Probable). Does not interact with MAG, OMG and RTN4 (PubMed:12839991). Interacts with MAG (By similarity).
Undergoes zinc metalloproteinase-mediated ectodomain shedding in neuroblastoma cells; is released both as a full-length ectodomain and an N-terminal fragment containing the leucine-rich repeat (LRR) region of the protein.
Catalyzes the transfer of sialic acid from a CMP-linked sialic acid donor onto the terminal sialic acid of an acceptor through alpha-2,8-linkages. Is active with alpha-2,3-linked, alpha-2,6-linked and alpha-2,8-linked sialic acid of N-linked oligosaccharides of glycoproteins and glycolipids. Displays preference for substrates with alpha-2,3-linked terminal sialic acid. It can form polysialic acid in vitro directly on alpha-2,3-, alpha-2,6-, or alpha-2,8-linked sialic acid.
Expressed in fetal and adult brain and fetal liver.
Protein that plays a role in the inhibition of canonical Wnt signaling pathway (PubMed:25557784). May be involved in neuronal migration during development of the cerebral neocortex (By similarity). Involved in the control of ciliogenesis and ciliary length (PubMed:25601850, PubMed:27319779).
Ubiquitously expressed. In brain, highly expressed in the entorhinal cortex, inferior temporal cortex, medial temporal cortex, hypothalamus, amygdala and hippocampus (PubMed:10601354, PubMed:16278297). Expressed in liver by cholangiocytes, the epithelial cells of the bile ducts (at protein level) (PubMed:27319779).
GTPase signaling protein that binds to and hydrolyzes GTP. Regulates signaling pathways involving G-proteins-coupled receptor and heterotrimeric proteins such as GNB1, GNB2 and GNB3. May be involved in selected striatal competencies, mainly locomotor activity and motor coordination.
Monomer (Potential). Interacts with PIK3CA and UBE2I (By similarity). Interacts with GNB1, GNB2 and GNB3. Interacts with HTT; interacts with mutant HTT (mHTT) with a much higher affinity than wild type HTT.
Pancreatic endocrine cells (islets of Langerhans).
Reduces cell survival in striatal cells with Huntington disease by binding to mutant Huntington disease protein (mHTT; poly-Gln region with 82 repeats) and inducing sumoylation of mHTT.
Interacts with epithelial sodium channel ENaC. Interacts directly with SCNN1A (ENaC subunit alpha) and SCNN1B (ENaC subunit beta) C-terminal tails. Interacts with ENaC regulatory proteins NEDD4L, RAF1 and SGK1.
Involved in transepithelial sodium transport. Regulates aldosterone-induced and epithelial sodium channel (ENaC)-mediated sodium transport through regulation of ENaC cell surface expression. Acts as a scaffold protein coordinating the assembly of an ENaC-regulatory complex (ERC).
The PDZ domain is required for interaction with ENaC and SGK1, but not for interaction with NEDDL4 and RAF1.
The gene name MAGI1, shown in this entry as a synonym, is an obsolete human gene nomenclature committee-approved name. It should be noted that MAGI1 currently is the official name for the unrelated membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1.
Up-regulated by aldosterone (at protein level).
Detected in brain, eye, nerve tissue, kidney and lung.
Transposase-derived protein that may have nuclease activity (Potential). Does not have transposase activity.
May be involved in the regulation of neurotransmitter release and synaptogenesis.
Neuron specific. Detected predominantly in brain.
Phosphorylation at Ser-9 dissociates synapsins from synaptic vesicles.
Regulated by calcium. Calcium inhibits ATP binding to the C-domain.
Receptor for ADP. Coupled to G(i)-proteins. May play a role in hematopoiesis and the immune system.
Stimulation by ADP in stably transfected CHO cells resulted in inhibition of adenylyl cyclase and the phosphorylation of the MAP kinases MAPK3 and MAPK1 in a pertussis toxin-sensitive way. Inhibition of adenylyl cyclase and phosphorylation of the MAP kinases are transduction mechanisms that involve G(i) proteins.
Strong expression in spleen and adult brain. Lower expression in placenta, lung, liver, spinal cord, thymus, small intestine, uterus, stomach, testis, fetal brain, and adrenal gland. Not detected in pancreas, heart, kidney, skeletal muscle, ovary or fetal aorta. Clearly detected in lymph node and bone marrow, weakly detected in peripheral blood mononuclear cells (PBMC) and in peripheral blood leukocytes (PBL), but not detected in polymorphonuclear cells (PMN). In the brain, detected in all brain regions examined.
Belongs to the GTP cyclohydrolase I type 2/NIF3 family.
Homodimer (PubMed:12951069). Interacts with COPS2 (By similarity). Interacts with THOC7 (PubMed:12951069).
May function as a transcriptional corepressor through its interaction with COPS2, negatively regulating the expression of genes involved in neuronal differentiation.
Belongs to the universal ribosomal protein uS4 family.
Component of the small ribosomal subunit (PubMed:23636399). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797).
Homodimer. The CSTF complex is composed of CSTF1 (50 kDa subunit), CSTF2 (64 kDa subunit) and CSTF3 (77 kDa subunit). CSTF3 directly interacts with CSTF1 and CSTF2. Interacts with FIP1L1.
One of the multiple factors required for polyadenylation and 3'-end cleavage of mammalian pre-mRNAs.
Detected at very low levels in normal tonsils, and at higher levels in hypertrophic tonsils.
May be involved in sperm maturation and/or fertilization.
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:32669547). Homodimer (PubMed:12962325). Interacts with DHX33 (PubMed:26100019).
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:32669547). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:12962325, PubMed:23636399, PubMed:32669547). Binds to G-rich structures in 28S rRNA and in mRNAs (PubMed:12962325). Plays a regulatory role in the translation apparatus; inhibits cell-free translation of mRNAs (PubMed:12962325).
Detected in a natural killer (NK) cells.
Plays an essential role in total transketolase activity and cell proliferation in cancer cells; after transfection with anti-TKTL1 siRNA, total transketolase activity dramatically decreases and proliferation was significantly inhibited in cancer cells. Plays a pivotal role in carcinogenesis.
Essential bifunctional enzyme that catalyzes both the N-deacetylation and the N-sulfation of glucosamine (GlcNAc) of the glycosaminoglycan in heparan sulfate (PubMed:9230113, PubMed:9744796, PubMed:35137078). Modifies the GlcNAc-GlcA disaccharide repeating sugar backbone to make N-sulfated heparosan, a prerequisite substrate for later modifications in heparin biosynthesis (PubMed:9230113). Plays a role in determining the extent and pattern of sulfation of heparan sulfate. Participates in biosynthesis of heparan sulfate that can ultimately serve as L-selectin ligands, thereby playing a role in inflammatory response (By similarity). Required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413).
Interacts with heparan sulfate co-polymerase subunits EXT1 and EXT2. Interacts with NDST1 isoform 1.
Interacts with heparan sulfate co-polymerase subunits EXT1 and EXT2. Interacts with NDST1 isoform 3.
Lacks both N-deacetylase and N-sulfotransferase activities. Acts as a dominant negative on isoform 1, likely by changing the composition of enzyme complexes responsible for elongation and modification of heparan sulfates.
The increased expression in several types of cancer is associated with shorter survival.
Widely expressed. Expression is most abundant in heart, liver and pancreas.
Protein-lysine methyltransferase that efficiently catalyzes three successive methylations on 'Lys-36' in eukaryotic translation elongation factor 1 alpha (EEF1A1 or EEF1A2).
A chromosomal aberration involving FOXP1 is found in acute lymphoblastic leukemia. Translocation t(9;3)(p13;p14.1) with PAX5.
By androgen in an isoform-specific manner; expression of isoform 4 is greatly induced.
Forms homodimers and heterodimers with FOXP2 and FOXP4 (PubMed:25027557). Dimerization is required for DNA-binding. Self-associates (PubMed:26647308). Interacts with CTBP1 (By similarity). Interacts with NCOR2 and AR (PubMed:18347093, PubMed:18640093). Interacts with FOXP2 (PubMed:26647308). Interacts with TBR1 (PubMed:30250039). Interacts with AURKA; this interaction facilitates the phosphorylation of FOXP1, which suppresses the expression of FBXL7 (PubMed:28218735). Interacts with ZMYM2 (PubMed:32891193).
Involved in transcriptional regulation in embryonic stem cells (ESCs). Stimulates expression of transcription factors that are required for pluripotency and decreases expression of differentiation-associated genes. Has distinct DNA-binding specifities as compared to the canonical form and preferentially binds DNA with the sequence 5'-CGATACAA-3' (or closely related sequences) (PubMed:21924763). Promotes ESC self-renewal and pluripotency (By similarity).
Isoform 8 is specifically expressed in embryonic stem cells.
Transcriptional repressor (PubMed:18347093, PubMed:26647308). Can act with CTBP1 to synergistically repress transcription but CTPBP1 is not essential (By similarity). Plays an important role in the specification and differentiation of lung epithelium. Acts cooperatively with FOXP4 to regulate lung secretory epithelial cell fate and regeneration by restricting the goblet cell lineage program; the function may involve regulation of AGR2. Essential transcriptional regulator of B-cell development. Involved in regulation of cardiac muscle cell proliferation. Involved in the columnar organization of spinal motor neurons. Promotes the formation of the lateral motor neuron column (LMC) and the preganglionic motor column (PGC) and is required for respective appropriate motor axon projections. The segment-appropriate generation of spinal cord motor columns requires cooperation with other Hox proteins. Can regulate PITX3 promoter activity; may promote midbrain identity in embryonic stem cell-derived dopamine neurons by regulating PITX3. Negatively regulates the differentiation of T follicular helper cells T(FH)s. Involved in maintenance of hair follicle stem cell quiescence; the function probably involves regulation of FGF18 (By similarity). Represses transcription of various pro-apoptotic genes and cooperates with NF-kappa B-signaling in promoting B-cell expansion by inhibition of caspase-dependent apoptosis (PubMed:25267198). Binds to CSF1R promoter elements and is involved in regulation of monocyte differentiation and macrophage functions; repression of CSF1R in monocytes seems to involve NCOR2 as corepressor (PubMed:15286807, PubMed:18799727, PubMed:18347093). Involved in endothelial cell proliferation, tube formation and migration indicative for a role in angiogenesis; the role in neovascularization seems to implicate suppression of SEMA5B (PubMed:24023716). Can negatively regulate androgen receptor signaling (PubMed:18640093). Acts as a transcriptional activator of the FBXL7 promoter; this activity is regulated by AURKA (PubMed:28218735).
Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5 (PubMed:33283408, PubMed:28977666, PubMed:16428440). The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes (PubMed:33283408, PubMed:16428440, PubMed:28977666). Interacts with CHD3 (PubMed:28977666). Interacts with CHD4 (PubMed:28977666). Interacts with GATAD2A (PubMed:33283408). Interacts with HDAC7 (By similarity). Interacts with MBD3 (By similarity). Interacts with p53/TP53 (PubMed:11099047). Interacts with MINT (PubMed:11331609). Interacts with PIMREG (PubMed:18757745). Interacts with NACC2 (PubMed:22926524). Interacts with ERCC6 (PubMed:26030138). Interacts with PWWP2B (By similarity).
May function as a transcriptional coregulator (PubMed:16428440, PubMed:28977666). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:28977666).
Homodimer. Interacts with clathrin. Interacts with GDP-bound ARF6, but not with GTP-bound ARF6. Part of a complex composed of GULP1, ACAP1 and ARF6. Interacts with ACAP1, LRP1, MEGF10 and STAB2.
May function as an adapter protein. Required for efficient phagocytosis of apoptotic cells. Modulates cellular glycosphingolipid and cholesterol transport. May play a role in the internalization and endosomal trafficking of various LRP1 ligands, such as PSAP. Increases cellular levels of GTP-bound ARF6.
Widely expressed. Detected in macrophages, pancreas, kidney, skeletal muscle, heart, colon, intestine, lung, placenta and ovary.
Inositol 5-phosphatase, which converts inositol 1,4,5-trisphosphate to inositol 1,4-bisphosphate. Also converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate and inositol 1,3,4,5-tetrakisphosphate to inositol 1,3,4-trisphosphate in vitro. May be involved in modulation of the function of inositol and phosphatidylinositol polyphosphate-binding proteins that are present at membranes ruffles.
The 5 Arg-Ser-Xaa-Ser-Xaa-Xaa (RSXSXX) motifs may constitute binding sites for the 14-3-3 protein.
Adapter protein complex 2 (AP-2) is a heterotetramer composed of two large adaptins (alpha-type subunit AP2A1 or AP2A2 and beta-type subunit AP2B1), a medium adaptin (mu-type subunit AP2M1) and a small adaptin (sigma-type subunit AP2S1) (By similarity). Interacts with ATP6V1H and MEGF10 (PubMed:12032142, PubMed:17643423). Interacts with EGFR and TTGN1 (By similarity). Interacts with F2R (PubMed:16581796). Interacts with PIP5K1C; tyrosine phosphorylation of PIP5K1C weakens the interaction (By similarity). Interacts with KIAA0319; required for clathrin-mediated endocytosis of KIAA0319 (PubMed:19419997). Interacts with DVL2 (via DEP domain) (By similarity). Interacts with KCNQ1; mediates estrogen-induced internalization via clathrin-coated vesicles (PubMed:23529131). Interacts with P2RX4 (via internalization motif) (By similarity). Together with AP2A1 or AP2A2 and AP2B1, it interacts with ADAM10; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons (PubMed:23676497). Probably interacts with ACE2 (via endocytic sorting signal motif); the interaction is inhibited by ACE2 phosphorylation (PubMed:33436498). Interacts with RALBP1; the interaction is direct (PubMed:10910768). Interacts with TMEM106B (via N-terminus) (PubMed:25066864).
Component of the adaptor protein complex 2 (AP-2) (PubMed:12694563, PubMed:12952941, PubMed:14745134, PubMed:14985334, PubMed:15473838, PubMed:31104773). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways (PubMed:12694563, PubMed:12952941, PubMed:14745134, PubMed:14985334, PubMed:15473838, PubMed:31104773). Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation (PubMed:12694563, PubMed:12952941, PubMed:14745134, PubMed:14985334, PubMed:15473838, PubMed:31104773). AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome (PubMed:12694563, PubMed:12952941, PubMed:14745134, PubMed:14985334, PubMed:15473838, PubMed:31104773). The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components (PubMed:12694563, PubMed:12952941, PubMed:14745134, PubMed:14985334, PubMed:15473838, PubMed:31104773). Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation (PubMed:12694563, PubMed:12952941, PubMed:14745134, PubMed:14985334, PubMed:15473838, PubMed:31104773). AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis (PubMed:16581796). AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface (PubMed:12694563, PubMed:12952941, PubMed:14745134, PubMed:14985334, PubMed:15473838, PubMed:31104773). AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules (By similarity). AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway (PubMed:19033387). During long-term potentiation in hippocampal neurons, AP-2 is responsible for the endocytosis of ADAM10 (PubMed:23676497). The AP-2 mu subunit binds to transmembrane cargo proteins; it recognizes the Y-X-X-Phi motifs (By similarity). The surface region interacting with to the Y-X-X-Phi motif is inaccessible in cytosolic AP-2, but becomes accessible through a conformational change following phosphorylation of AP-2 mu subunit at Thr-156 in membrane-associated AP-2 (PubMed:11877457). The membrane-specific phosphorylation event appears to involve assembled clathrin which activates the AP-2 mu kinase AAK1 (PubMed:11877457). Plays a role in endocytosis of frizzled family members upon Wnt signaling (By similarity).
Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules.
Phosphorylation at Thr-156 increases the affinity of the AP-2 complex for cargo membrane proteins during the initial stages of endocytosis.
(Microbial infection) In case of infection, required for translation and replication of hepatitis C virus (HCV).
Interacts (via region A) with DDX6/RCK (PubMed:20543818, PubMed:20584987, PubMed:31422817, PubMed:31439631). Interacts (via region H and region C) with LSM1 and LSM4 (PubMed:20584987, PubMed:20852261). Interacts (via region N) with DCP1A, DCP2, EDC3, EDC4 and XRN1 (PubMed:20584987, PubMed:20543818). Interacts with the CCR4-NOT complex (PubMed:20584987). Interacts with the Lsm-containing SMN-Sm protein complex (PubMed:20543818). Interacts with EIF4ENIF1/4E-T (PubMed:26027925, PubMed:32354837).
RNA-binding protein involved in deadenylation-dependent decapping of mRNAs, leading to the degradation of mRNAs (PubMed:17936923, PubMed:20543818, PubMed:20584987, PubMed:20852261). Acts as a scaffold protein that connects deadenylation and decapping machinery (PubMed:17936923, PubMed:20543818, PubMed:20584987, PubMed:20852261). Required for cytoplasmic mRNA processing body (P-body) assembly (PubMed:17936923, PubMed:20543818, PubMed:20584987, PubMed:20852261).
The region A, also named N-term, mediates the interaction with DDX6/RCK and is required for cytoplasmic mRNA processing body assembly.
The region C, also named Pat-C, is required for RNA-binding and mediates the binding with the Lsm-containing SMN-Sm protein complex and the decapping machinery. It folds into an alpha-alpha superhelix, exposing conserved and basic residues on one side of the domain.
Can form homodimers. Interacts with SGO1. Interacts with FGF1.
Required for nuclear import of FGF1, but not that of FGF2. Might regulate nuclear import of exogenous FGF1 by facilitating interaction with the nuclear import machinery and by transporting cytosolic FGF1 to, and possibly through, the nuclear pores.
Interacts (via C-terminus) with APP (via C-terminus) (PubMed:8855266, PubMed:14527950). Interacts with APLP2 (via cytoplasmic domain) (PubMed:8855266).
Plays a role in the maintenance of lens transparency, and may also play a role in muscle cell strength (By similarity). Involved in hippocampal neurite branching and neuromuscular junction formation, as a result plays a role in spatial memory functioning (By similarity). Activates transcription of APP (PubMed:14527950).
Calcium-regulated non-lysosomal thiol-protease. Involved in membrane trafficking in the gastric surface mucus cells (pit cells) and may involve the membrane trafficking of mucus cells via interactions with coat protein. Proteolytically cleaves the beta-subunit of coatomer complex (By similarity).
Monomer and homooligomer. Interacts with COPS1/GPS1, COPB1, EYA2, NME2, NME4 and TOMM70 (By similarity).
The domain III mediates oligomerization.
Undergoes autolytic cleavage between Ala-5 and Ala-6 which gives rise to fragments extending from Ala-6 to the C-terminus, Ala-6 to the EF-hand 2 domain and from Ala-6 to the beginning of domain III.
Alternative splice donor/acceptor on exon 5 and lacks exon 10.
Alternative splice donor/acceptor on exon 5.
Alternative splice donor/acceptor on exon 7 and lacks exon 10.
Alternative splice donor/acceptor on exon 7.
CD44 is responsible for the Indian blood group system. The molecular basis of the In(A)=In1/In(B)=In2 blood group antigens is a single variation in position 46; In(B), the most frequent allele, has Arg-46.
Cell-surface receptor that plays a role in cell-cell interactions, cell adhesion and migration, helping them to sense and respond to changes in the tissue microenvironment (PubMed:16541107, PubMed:19703720, PubMed:22726066). Participates thereby in a wide variety of cellular functions including the activation, recirculation and homing of T-lymphocytes, hematopoiesis, inflammation and response to bacterial infection (PubMed:7528188). Engages, through its ectodomain, extracellular matrix components such as hyaluronan/HA, collagen, growth factors, cytokines or proteases and serves as a platform for signal transduction by assembling, via its cytoplasmic domain, protein complexes containing receptor kinases and membrane proteases (PubMed:18757307, PubMed:23589287). Such effectors include PKN2, the RhoGTPases RAC1 and RHOA, Rho-kinases and phospholipase C that coordinate signaling pathways promoting calcium mobilization and actin-mediated cytoskeleton reorganization essential for cell migration and adhesion (PubMed:15123640).
Detected in fibroblasts and urine (at protein level) (PubMed:25326458, PubMed:36213313). Detected in placenta (at protein level) (PubMed:32337544). Isoform 10 (epithelial isoform) is expressed by cells of epithelium and highly expressed by carcinomas. Expression is repressed in neuroblastoma cells.
Expressed in the developing retina between 16 and 19 weeks post-conception, specifically in the outer neuroblastic zone, inner neuroblastic zone, interphotoreceptor zone and the retinal pigment epithelium (at protein level).
Interacts with PKN2 (PubMed:15123640). Interacts with TIAM1 and TIAM2 (By similarity). Interacts with HA, as well as other glycosaminoglycans, collagen, laminin, and fibronectin via its N-terminal segment (PubMed:14992719, PubMed:17085435, PubMed:25195884). Interacts with UNC119 (PubMed:19381274). Interacts with PDPN (via extracellular domain); this interaction is required for PDPN-mediated directional migration and regulation of lamellipodia extension/stabilization during cell spreading and migration (PubMed:20962267). Interacts with RDX, EZR and MSN (By similarity). Interacts with EGFR (PubMed:18757307, PubMed:23589287). Interacts with CD74; this complex is essential for the MIF-induced signaling cascade that results in B cell survival (By similarity).
O-glycosylated; contains chondroitin sulfate glycans which can be more or less sulfated and whose number may affect the accessibility of specific proteinases to their cleavage site(s). It is uncertain if O-glycosylation occurs on Thr-637 or Thr-638.
Phosphorylated; activation of PKC results in the dephosphorylation of Ser-706 (constitutive phosphorylation site), and the phosphorylation of Ser-672.
Proteolytically cleaved in the extracellular matrix by specific proteinases (possibly MMPs) in several cell lines and tumors.
Soluble isoform, has enhanced hyaluronan binding.
The lectin-like LINK domain is responsible for hyaluronan binding.
Plays a role in cell adhesion, and thereby in cell motility which requires repeated formation and disassembly of focal adhesions. Regulates microtubule-induced PTK2/FAK1 dephosphorylation, an event important for focal adhesion disassembly, as well as integrin beta-1/ITGB1 cell surface expression.
The C-terminal region exhibits a structure similar to canonical PH domains, but lacks a positively charged interface to bind phosphatidylinositol phosphate.
The FYVE-type zinc finger mediates interaction with PTK2/FAK1, and also interaction with PI(3)P and association with endosomes.
Highly expressed in testis (PubMed:9299235, PubMed:33437391). Also expressed in the ovary (PubMed:9299235).
Involved in meiotic recombination. Required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis.
Alpha-(1,4) exo-glucosidase involved in breakdown of dietary starch oligosaccharides in small intestine. Cleaves the non-reducing alpha-(1,4)-linked glucose residue in linear dextrins with retention of anomeric center stereochemistry (PubMed:12547908, PubMed:18356321, PubMed:27480812, PubMed:18036614, PubMed:22058037). Mainly hydrolyzes short length oligomaltoses having two to seven glucose residues (PubMed:12547908, PubMed:18356321, PubMed:27480812, PubMed:18036614, PubMed:22058037). Can cleave alpha-(1,2), alpha-(1,3) and alpha-(1,6) glycosidic linkages with lower efficiency, whereas beta glycosidic linkages are usually not hydrolyzed (PubMed:27480812).
Broadly expressed. Highly expressed in small intestine. Expressed in granulocytes.
Does not undergo intracellular or extracellular proteolytic cleavage.
Down-regulated at high oligomaltose concentration as it occurs during the mealtime (PubMed:18356321). Down-regulated by anti-diabetic drug acarbose (PubMed:18036614, PubMed:22058037).
The C-terminal glucoamylase domain (ctMGAM) acts on longer maltoside substrates having four to seven glucose residues.
The N-terminal maltase domain (ntMGAM) mainly hydrolyzes short length oligomaltoses having two to four glucose residues.
The displayed isoform 2 sequence is inferred based on alignments, homology, conservation, expression and longest protein. RNA-seq transcriptomic analysis supports all introns in a single sample. No single full-size mRNA sequence supports this isoform yet, however it is clearly identified by mass spectrometry analysis.
Most abundant in kidney and liver. Also highly expressed in brain, spleen, testis and placenta. Overexpressed in several colorectal tumors.
Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Binds directly to MTOR and RICTOR within the TORC2 complex.
Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. PRR5 plays an important role in regulation of PDGFRB expression and in modulation of platelet-derived growth factor signaling. May act as a tumor suppressor in breast cancer.
Expressed in many tissues, in particular the brain especially in the cortex and hippocampus.
Transmembrane reductase that uses ascorbate as an electron donor in the cytoplasm and transfers electrons across membranes to reduce monodehydro-L-ascorbate radical in the lumen of secretory vesicles. It is therefore involved the regeneration and homeostasis within secretory vesicles of ascorbate which in turn provides reducing equivalents needed to support the activity of intravesicular enzymes.
Belongs to the chloride channel CLIC family.
Can insert into membranes and form poorly selective ion channels that may also transport chloride ions. Channel activity depends on the pH. Membrane insertion seems to be redox-regulated and may occur only under oxydizing conditions. Promotes cell-surface expression of HRH3. Has alternate cellular functions like a potential role in angiogenesis or in maintaining apical-basolateral membrane polarity during mitosis and cytokinesis. Could also promote endothelial cell proliferation and regulate endothelial morphogenesis (tubulogenesis).
Component of a multimeric complex consisting of several cytoskeletal proteins, including actin, ezrin, alpha-actinin, gelsolin, IQGAP1 and CLIC5A. Binds directly to brain dynamin I in a complex containing actin, tubulin and 14-3-3 isoforms. Monomer. Interacts with HRH3. Interacts with AKAP9.
Detected in epithelial cells from colon, esophagus and kidney (at protein level). Expression is prominent in heart, kidney, placenta and skeletal muscle.
Members of this family may change from a globular, soluble state to a state where the N-terminal domain is inserted into the membrane and functions as chloride channel. A conformation change of the N-terminal domain is thought to expose hydrophobic surfaces that trigger membrane insertion.
Up-regulated by calcium ions in differentiating keratinocytes. Up-regulated in myofibroblasts.
Component of the U11/U12 snRNPs that are part of the U12-type spliceosome. Not found in the major spliceosome.
Associates with microtubules in a manner that is dependent on the C-terminal B30.2 domain.
E3 ubiquitin ligase that plays a role in microtubule stabilization. Mediates the 'Lys-48'-linked polyubiquitination of LRRK2 to drive its localization to microtubules and its proteasomal degradation in neurons. This ubiquitination inhibits LRRK2 kinase activation by RAB29 (PubMed:35266954).
Homodimer or heterodimer with MID1. Interacts with IGBP1.
Low level in fetal kidney and lung, and in adult prostate, ovary and small intestine.
The tripartite motif (RBCC; RING- and B box-type zinc fingers and coiled coil domains) mediates dimerization.
Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors. This subunit may specifically regulate transcription of targets of the Wnt signaling pathway and SHH signaling pathway.
Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Also interacts with CTNNB1 and GLI3.
Binds 1 zinc ion per subunit. In the homodimer, two zinc ions are bound between subunits.
Catalyzes the conversion of hemimercaptal, formed from methylglyoxal and glutathione, to S-lactoylglutathione (PubMed:20454679, PubMed:9705294, PubMed:23122816). Involved in the regulation of TNF-induced transcriptional activity of NF-kappa-B (PubMed:19199007). Required for normal osteoclastogenesis (By similarity).
Catalyzes the conversion of hemimercaptal, formed from methylglyoxal and glutathione, to S-lactoylglutathione.
Exists in a nitric oxide (NO)-modified form. The exact nature of the modification is unknown, but it suppresses the TNF-induced transcriptional activity of NF-kappa-B.
Exists in three separable isoforms which originate from two alleles in the genome. These correspond to two homodimers and one heterodimer composed of two subunits showing different electrophoretic properties.
Glutathionylation at Cys-139 inhibits enzyme activity.
Phosphorylated at Thr-107 in the presence of CaMK2. However, this is a consensus site for phosphorylation by CK2 so phosphorylation may be mediated by CK2 rather than CaMK2. Phosphorylation is induced by TNF and suppresses the TNF-induced transcriptional activity of NF-kappa-B.
Regulated by oxidation of Cys-139 in response to the redox state of the cell. Results in the alternative formation of cystine or glutathione-bound cysteine, the latter modification leading to reduced enzyme activity.
Specific growth arrest protein involved in growth suppression. Blocks entry to S phase. Prevents cycling of normal and transformed cells.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Cation-dependent O-methyltransferase family.
Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones (By similarity). Required for auditory function (PubMed:18794526). Component of the cochlear hair cell's mechanotransduction (MET) machinery. Involved in the assembly of the asymmetric tip-link MET complex. Required for transportation of TMC1 and TMC2 proteins into the mechanically sensitive stereocilia of the hair cells. The function in MET is independent of the enzymatic activity (By similarity).
Interacts with LHFPL5, PCDH15, TMC1, TMC2 and TMIE. Interacts directly with TMC1. The interaction of TOMT with TMC1 and TMC2 is required for the transportation of TMC1/2 into the stereocilia of hair cells.
LRRC51 and TOMT were originally considered as alternative reading frames, LRTOMT1 and LRTOMT2 of the same LRTOMT gene in primates.
A chromosomal aberration involving RAD51B is found in pulmonary chondroid hamartoma. Translocation t(6;14)(p21;q23-24) with HMGA1.
A chromosomal aberration involving RAD51B is found in uterine leiomyoma. Translocation t(12;14)(q15;q23-24) with HMGA2.
Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. May promote the assembly of presynaptic RAD51 nucleoprotein filaments. Binds single-stranded DNA and double-stranded DNA and has DNA-dependent ATPase activity. Part of the RAD51 paralog protein complex BCDX2 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, BCDX2 acts downstream of BRCA2 recruitment and upstream of RAD51 recruitment. BCDX2 binds predominantly to the intersection of the four duplex arms of the Holliday junction and to junction of replication forks. The BCDX2 complex was originally reported to bind single-stranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA. The BCDX2 subcomplex RAD51B:RAD51C exhibits single-stranded DNA-dependent ATPase activity suggesting an involvement in early stages of the HR pathway.
Part of the BCDX2 complex consisting of RAD51B, RAD51C, RAD51D and XRCC2; the complex has a ring-like structure arranged into a flat disc around a central channel (PubMed:11744692, PubMed:11751635, PubMed:11751636, PubMed:11842112, PubMed:11842113, PubMed:12427746, PubMed:14704354). The BCDX2 subcomplex RAD51B:RAD51C interacts with RAD51 (PubMed:11744692, PubMed:11751635, PubMed:11751636, PubMed:11842112, PubMed:11842113, PubMed:12427746, PubMed:14704354). Interacts with SWSAP1; involved in homologous recombination repair (PubMed:21965664). Interacts with HELQ (PubMed:24005041).
Phosphorylated on tyrosine residues by BCR-ABL.
Expressed in a subset of NK cells predominantly in intestinal epithelium and liver. Detected in peripheral blood T-cells and preferentially in adult T-cells with a memory antigenic phenotype.
Homodimer; disulfide-linked. Interacts with acid sphingomyelinase/SMPD1.
Plays an inhibitory role on natural killer (NK) cells cytotoxicity. Activation results in specific acid sphingomyelinase/SMPD1 stimulation with subsequent marked elevation of intracellular ceramide. Activation also leads to AKT1/PKB and RPS6KA1/RSK1 kinases stimulation as well as markedly enhanced T-cell proliferation induced by anti-CD3. Acts as a lectin that binds to the terminal carbohydrate Gal-alpha(1,3)Gal epitope as well as to the N-acetyllactosamine epitope. Binds also to CLEC2D/LLT1 as a ligand and inhibits NK cell-mediated cytotoxicity as well as interferon-gamma secretion in target cells.
Expressed specifically in dorsal root ganglion and trigeminal ganglion neurons. Detected at low levels in spinal cord.
In contrast to its mouse ortholog, it is not regulated by extracellular protons.
Interacts with calcineurin. Interacts with YWHAH, in a phosphorylation-dependent manner.
Outward rectifying potassium channel. Produces rapidly activating outward rectifier K(+) currents. May function as background potassium channel that sets the resting membrane potential. Channel activity is directly activated by calcium signal. Activated by the G(q)-protein coupled receptor pathway. The calcium signal robustly activates the channel via calcineurin, whereas the anchoring of 14-3-3/YWHAH interferes with the return of the current to the resting state after activation. Inhibited also by arachidonic acid and other naturally occurring unsaturated free fatty acids. Channel activity is also enhanced by volatile anesthetics, such as isoflurane. Appears to be the primary target of hydroxy-alpha-sanshool, an ingredient of Schezuan pepper. May be involved in the somatosensory function with special respect to pain sensation (By similarity).
Phosphorylation of Ser-252 is required for the binding of 14-3-3eta/YWHAH. Calcineurin-mediated dephosphorylation of Ser-264 enhances channel activity (By similarity).
The disease is caused by variants affecting the gene represented in this entry. Susceptibility to migraine has been shown to be conferred by a frameshift mutation that segregates with the disorder in a large multigenerational family. Migraine was associated with sensitivity to lights, sounds, and smells, as well as nausea and occasional vomiting. Triggers included fatigue, alcohol and bright lights. Mutations in KCNK18 are a rare cause of migraine.
Phospholipase that may play a role in phospholipids remodeling. May selectively cleave myristate (C14)-containing phosphatidylcholines through its predominant phospholipase 1 activity, cleaving preferentially acyl groups in sn1 position. In parallel, may have a minor phospholipase 2 activity acting on acyl groups in position sn2. In addition to (C14)-containing phosphatidylcholines, may also act on other medium-chain-containing and oxidatively truncated phospholipids.
(Microbial infection) Interacts with Mumps virus protein SH.
Defects in UBQLN4 are the cause of the UBQLN4 deficiency syndrome (UBDS) (PubMed:30612738). Patients display intellectual impairment, growth retardation, microcephaly, facial dysmorphism, hearing loss, ataxia and anemia (PubMed:30612738). Cells display genomic instability characterized by hypersensitivity to genotoxic agents, leading to enhanced apoptotic cell death in response to DNA damage (PubMed:30612738).
Highly expressed in pancreas, kidney, skeletal muscle, heart and throughout the brain, and at lower levels in placenta, lung and liver.
Homooligomer (PubMed:15280365, PubMed:30612738). Binds signal sequences of proteins that are targeted to the endoplasmic reticulum (By similarity). Interacts (via UBA domain) with GJA1 (not ubiquitinated) and with ubiquitin; both compete for the same binding site (By similarity). Interacts (via UBA domain) with ubiquitin and with polyubiquitin chains (By similarity). Interacts (via ubiquitin-like domain) with PSMD2 and PSMD4, regulatory subunits of the 26S proteasome (PubMed:15280365). Interacts with ATXN1/SCA1; interaction with ATXN1 inhibits polyubiquitination of UBQLN4 and interferes with PSMD4 binding (PubMed:11001934, PubMed:15280365). Interacts with HERPUD1 (PubMed:18307982). Interacts (via ubiquitin-like domain) with UBQLN1 (via UBA domain) (PubMed:23459205). Interacts with UBQLN2 (PubMed:23459205). Interacts (via STI1 1 and 2 domains) with MAP1LC3A/B/C (PubMed:23459205). Interacts with BAG6 (PubMed:27113755). Interacts with MRE11 (when ubiquitinated); interaction with ubiquitinated MRE11 leads to MRE11 removal from chromatin (PubMed:30612738). Interacts with DESI1/POST; leading to nuclear export (PubMed:29666234). Interacts with BCL2A1 and BCL2L10 (PubMed:34245648).
May be a potential prognostic marker in cancer patients.
Phosphorylated by ATM at Ser-318 in response to DNA damage, leading to localization in the nucleus and recruitment to sites of DNA damage.
Regulator of protein degradation that mediates the proteasomal targeting of misfolded, mislocalized or accumulated proteins (PubMed:15280365, PubMed:27113755, PubMed:29666234, PubMed:30612738). Acts by binding polyubiquitin chains of target proteins via its UBA domain and by interacting with subunits of the proteasome via its ubiquitin-like domain (PubMed:15280365, PubMed:27113755, PubMed:30612738). Key regulator of DNA repair that represses homologous recombination repair: in response to DNA damage, recruited to sites of DNA damage following phosphorylation by ATM and acts by binding and removing ubiquitinated MRE11 from damaged chromatin, leading to MRE11 degradation by the proteasome (PubMed:30612738). MRE11 degradation prevents homologous recombination repair, redirecting double-strand break repair toward non-homologous end joining (NHEJ) (PubMed:30612738). Specifically recognizes and binds mislocalized transmembrane-containing proteins and targets them to proteasomal degradation (PubMed:27113755). Collaborates with DESI1/POST in the export of ubiquitinated proteins from the nucleus to the cytoplasm (PubMed:29666234). Also plays a role in the regulation of the proteasomal degradation of non-ubiquitinated GJA1 (By similarity). Acts as an adapter protein that recruits UBQLN1 to the autophagy machinery (PubMed:23459205). Mediates the association of UBQLN1 with autophagosomes and the autophagy-related protein LC3 (MAP1LC3A/B/C) and may assist in the maturation of autophagosomes to autolysosomes by mediating autophagosome-lysosome fusion (PubMed:23459205).
Ubiquitinated; this does not lead to proteasomal degradation (PubMed:15280365). May undergo both 'Lys-48'- and 'Lys-63'-linked polyubiquitination (PubMed:15280365).
Up-regulated in aggressive tumors: expression is significantly increased in stage 3 and 4 neuroblastomas, compared to stage 1 disease.
Bifunctional enzyme with both ATP sulfurylase and APS kinase activity, which mediates two steps in the sulfate activation pathway. The first step is the transfer of a sulfate group to ATP to yield adenosine 5'-phosphosulfate (APS), and the second step is the transfer of a phosphate group from ATP to APS yielding 3'-phosphoadenylylsulfate (PAPS: activated sulfate donor used by sulfotransferase). In mammals, PAPS is the sole source of sulfate; APS appears to be only an intermediate in the sulfate-activation pathway (PubMed:9576487, PubMed:9668121, PubMed:9648242, PubMed:14747722). Required for normal biosynthesis of sulfated L-selectin ligands in endothelial cells (PubMed:9576487).
Expressed in testis, pancreas, kidney, thymus, prostate, ovary, small intestine, colon, leukocytes and liver. Also expressed in high endothelial venules (HEV) cells and in cartilage.
Inhibited by chlorate (PubMed:9576487). The kinase activity is subject to inhibition by the substrate adenylyl sulfate (PubMed:17540769).
The N-terminal first 50 residues are required for inhibition by the substrate adenylyl sulfate.
Catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate in the presence of divalent cations and probably participates in glycogen synthesis from carbohydrate precursors, such as lactate.
Homotetramer. Interacts with ALDOA; the interaction blocks inhibition by physiological concentrations of AMP and reduces inhibition by Ca(2+). Interacts with alpha-actinin and F-actin.
Specific for the alpha-anomer of the substrate (PubMed:22120740). The Arg-33 mutant form has been shown to act on the beta-anomer (PubMed:24086250).
Subject to complex allosteric regulation. The enzyme can assume an active R-state, or an inactive T-state. Intermediate conformations may exist. AMP acts as allosteric inhibitor (PubMed:33977262). Fructose 2,6-bisphosphate acts as competitive inhibitor. Strongly inhibited by Ca(2+).
Localized to the kidney (PubMed:31553721). Highly specific expression pattern in the nephron, localized to segment 3 of the proximal tubule (PubMed:31553721).
Presence of two potential AG acceptor sites at the splice junction between exons 9 and 10, thus resulting in two different splice variants.
Renal transmembrane organic anion/dicarboxylate exchanger that participates in the reabsorption of conjugated steroids including estradiol-17beta-D-glucuronide (or 17beta-estradiol 17-O-(beta-D-glucuronate)), androstanediol glucuronide (or 5alpha-androstane-3alpha,17beta-diol 3-O-(beta-D-glucuronate)), and estrone 3-sulfate, as well as bile acids taurocholate and glycocholate, driven by an outward gradient of dicarboxylates such as glutarate or succinate.
Transport is chloride sensitive and transtimulated by glutaric acid (PubMed:31553721). Transport is inhibited by anionic compounds from different chemical classes (PubMed:31553721).
Widely expressed, especially in adult heart, brain, prostate, testes, peripherical blood leukocytes and fetal brain.
At rest, the N- and C-terminal domains interact, as part of a larger autoinhibitory complex, with calmodulin pre-associated at the N-terminal domain. Upon a calcium rise, calmodulin becomes calcium-saturated and subsequently binds to the C-terminal domain. Fully calcium-saturated calmodulin then leaves the N-terminal domain, binding solely to the C-terminal domain, and the whole autoinhibitory complex dissociates, resulting in activation of adenylate cyclase. As local calcium concentrations decrease, the calmodulin becomes calcium free and binds once more to the N-terminal domain, whereupon the whole system returns to rest with the re-association of the autoinhibitory complex. In non-excitable cells, activated by capacitative calcium entry (CCE) through store-operated channels, namely through interaction with ORAI1 and STIM1; membrane raft and caveolae localization and membrane integrity are indispensable. CCE-mediated adenylate cyclase activity is decreased by AKAP5 and AKAP7. CCE-mediated adenylate cyclase activity is up-regulated by AKAP9 and the mitochondrially targeted AKAP1. In excitable cells, activated during membrane depolarization through L-type voltage-gated calcium channels (VGCC), leading to calcium entry; the L-type alpha subunit is sufficient. Activated via stimulation of the GLP1R. Synergistically activated by calcium/calmodulin and GNAS. Stimulated by forskolin. Inhibited by PKA directly bound to AKAP5 at membrane raft. Inhibition by acute activation of OPRM1 and activation by chronic activation of OPRM1 is mediated by pertussis toxin-sensitive G(i) and G(o) G alpha proteins and G beta-gamma dimer. Activity is inhibited by G beta-gamma dimer.
Catalyzes the formation of cAMP in response to calcium entry leadings to cAMP signaling activation that affect processes suche as synaptic plasticity and insulin secretion. Plays a role in many brain functions, such as learning, memory, drug addiction, and anxiety modulation through regulation of synaptic plasticity by modulating long-term memory and long-term potentiation (LTP) through CREB transcription factor activity modulation. Plays a central role in insulin secretion by controlling glucose homeostasis through glucagon-like peptide 1 and glucose signaling pathway and maintains insulin secretion through calcium-dependent PKA activation leading to vesicle pool replenishment. Also, allows PTGER3 to induce potentiation of PTGER4-mediated PLA2 secretion by switching from a negative to a positive regulation, during the IL1B induced-dedifferentiation of smooth muscle cells.
Detected in brain cortex (PubMed:1715695). Expressed in islet (PubMed:25403481).
Homodimer; via transmembrane domain. Monomer. Heterodimer. Oligemer; via transmembrane domain. Interacts with PRKAR2A and AKAP5; inhibits adenylate cyclase activity through PKA phosphorylation. Interacts with PPP2CA and PPP2R1A; does not mediate the inhibitory effects of PKA on adenylate cyclase activity; interaction is dependent of catalytically active PPP2CA; antagonizes interaction with calmodulin. Interacts with AKAP5 (palmitoylated form); promotes the phosphorylation of ADCY8 after store-operated calcium entry (SOCE) stimulation at membrane raft. Interacts with ORAI1; interaction is calcium store depletion independent; interaction occurs in membrane raft; interaction increases markedly after store depletion; positively regulates SOCE-induced adenylate cyclase activity; contributes to the targeting of ADCY8 to discrete regions of the plasma membrane that are shielded from other calcium events. Interacts with STIM1. Interacts with actin; interaction is calcium independent; interaction is affected by calcium-calmodulin; interaction controls the distribution and regulation of ADCY8. Interacts with calmodulin; at rest, interacts via N-terminal domain; upon a calcium rise, calmodulin becomes calcium-saturated and subsequently binds to the C-terminal domain forming an autoinhibitory complex; fully calcium-saturated calmodulin leaves the N-terminal domain, binding solely to the C-terminal domain leading to dissociation of autoinhibitory complex and resulting in activation of adenylate cyclase; antagonizes interaction with PPP2CA; interaction is calcium dependent. Interacts with PPP2R5D.
N-glycosylated; N-glycosylation is responsible for raft-targeting; is not necessary for CCE-stimulated adenylate cyclase activity.
Phosphorylated by PKA; mediates inhibition of adenylate cyclase activity at membrane raft; does not influence either CALM1 or PPP2CA interaction with ADCY8.
The protein contains two modules with six transmembrane helices each; both are required for catalytic activity. Isolated N-terminal or C-terminal guanylate cyclase domains have no catalytic activity, but when they are brought together, enzyme activity is restored. The active site is at the interface of the two domains. Both contribute substrate-binding residues, but the catalytic metal ions are bound exclusively via the N-terminal guanylate cyclase domain. The two transmembrane clusters are necessary and suficient for the plasma membrane targeting and oligomers assembly. The N-terminal and C-terminal domains interact at rest as part of a larger autoinhibitory complex, with calmodulin pre-associated at the N-terminal domain; the binding is specifically inhibited by fully calcium-saturated calmodulin, resulting in activation of AC8.
Expressed preferentially at high level in the brain.
Modulates the O-glycosylation and complex N-glycosylation steps occurring during the Golgi maturation of APP. Inhibits APP transport to the cell surface and further shedding.
Moderate to high levels of expression in thyroid, ovary, stomach, heart, pancreas, skeletal muscle, kidney and liver. Also detected in epithelial cells.
Rab GTPase effector involved in the late steps of regulated exocytosis, both in endocrine and exocrine cells (By similarity). Acts as a potential RAB3B effector protein in epithelial cells.
Recruited to dense-core vesicles through specific interaction with RAB27A in endocrine cells. Interacts with RAB3A, RAB3B, RAB3C and RAB3D. Interacts with ZYX (By similarity).
The N-terminus of the RabBD domain is necessary and sufficient for interaction with RAB27A.
Belongs to the actin family. ARP8 subfamily.
Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the DBINO domain of INO80. Interacts with ACTR5; the interaction is observed in asynchronous (interphase) cells but not in metaphase-arrested cells indicative for a possible dissociation of the INO80 complex in mitotic cells. Exists as monomers and dimers, but the dimer is most probably the biologically relevant form required for stable interactions with histones that exploits the twofold symmetry of the nucleosome core.
Plays an important role in the functional organization of mitotic chromosomes. Exhibits low basal ATPase activity, and unable to polymerize.
Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair. Required for the recruitment of INO80 (and probably the INO80 complex) to sites of DNA damage. Strongly prefer nucleosomes and H3-H4 tetramers over H2A-H2B dimers, suggesting it may act as a nucleosome recognition module within the complex.
(Microbial infection) Incorporated into Ebola virus-like particles, where its phospholipid scramblase activity is required to promote phosphatidylserine exposure on the surface of viral particles (PubMed:29338048). Externalization of phosphatidylserine on the surface of viral particles is required for uptake by host cells (PubMed:29338048).
Activated upon caspase cleavage to generate the XK-related protein 8, processed form (PubMed:23845944). Does not act prior the onset of apoptosis (PubMed:23845944).
Expression is repressed in PLB-985 leukemia and Raji lymphoma cells due to CpG methylation near the transcription start site of XKR8 gene, possibly explaining the inability of PLB-985 leukemia and Raji lymphoma cells to expose phosphatidylserine during apoptosis.
Interacts with BSG and NPTN; which act as chaperones to localize XKR8 at the cell membrane.
Phospholipid scramblase that promotes phosphatidylserine exposure on apoptotic cell surface (PubMed:23845944, PubMed:25231987). Phosphatidylserine is a specific marker only present at the surface of apoptotic cells and acts as a specific signal for engulfment (PubMed:23845944). Required for the clearance of apoptotic cells, such as engulfment of apoptotic germ cells by Sertoli cells, clearance of senescent neutrophils or regulation of bipolar cell numbers in the retina (By similarity). Has no effect on calcium-induced exposure of phosphatidylserine (PubMed:23845944). Promotes myoblast differentiation and survival (PubMed:28881496).
Phosphorylation at Thr-375 activates the phospholipid scramblase activity.
Undergoes proteolytic processing by caspase-3 (CASP3) to generate the XK-related protein 8, processed form, leading to its activation.
Interacts with FGFR1 and FGFR2. Interacts with FGFBP1.
Plays an important role in the regulation of embryonic development, cell proliferation and cell differentiation. Required for normal branching morphogenesis. May play a role in wound healing.
GPI-anchored cell membrane protein involved in Nodal signaling. Cell-associated CRIPTO acts as a Nodal coreceptor in cis. Shedding of CRIPTO by TMEM8A modulates Nodal signaling by allowing soluble CRIPTO to act as a Nodal coreceptor on other cells (PubMed:27881714). Could play a role in the determination of the epiblastic cells that subsequently give rise to the mesoderm (PubMed:11909953).
Interacts with the activin type-1 receptor ACVR1B.
Preferentially expressed in gastric and colorectal carcinomas than in their normal counterparts. Expressed in breast and lung.
The GPI-anchor is attached to the protein in the endoplasmic reticulum and serves to target the protein to the cell surface. There, it is processed by GPI processing phospholipase A2 (TMEM8A), removing an acyl-chain at the sn-2 position of GPI and releasing CRIPTO as a lysophosphatidylinositol-bearing form, which is further cleaved by phospholipase D (GPLD1) into a soluble form.
E3 ubiquitin-protein ligase involved in DNA damage response by promoting DNA resection and homologous recombination (PubMed:26502055, PubMed:26502057). Recruited to sites of double-strand breaks following DNA damage and specifically promotes double-strand break repair via homologous recombination (PubMed:26502055, PubMed:26502057). Two different, non-exclusive, mechanisms have been proposed. According to a report, regulates the choice of double-strand break repair by favoring homologous recombination over non-homologous end joining (NHEJ): acts by mediating ubiquitination of XRCC5/Ku80, leading to remove the Ku complex from DNA breaks, thereby promoting homologous recombination (PubMed:26502055). According to another report, cooperates with UBE2Ds E2 ubiquitin ligases (UBE2D1, UBE2D2, UBE2D3 or UBE2D4) to promote homologous recombination by mediating ubiquitination of RBBP8/CtIP (PubMed:26502057). Together with NLK, involved in the ubiquitination and degradation of TCF/LEF (PubMed:16714285). Also exhibits auto-ubiquitination activity in combination with UBE2K (PubMed:16714285). May act as a negative regulator in the Wnt/beta-catenin-mediated signaling pathway (PubMed:16714285).
Interacts with NLK (PubMed:16714285). Interacts with XRCC5/Ku80 (PubMed:26502055). Interacts with RBBP8/CtIP (PubMed:26502057).
The zinc finger domains (C2H2-type and C2HC-type zinc fingers) bind DNA and mediate recruitment to double-strand break sites. They show strong preference for DNA with 5'- or 3'-single-stranded overhangs, while they do not bind blunt-ended double-stranded DNA or poly(ADP-ribose) (PAR) polymers.
Involved in the inactivation of MAP kinases. Dephosphorylates ERK, JNK and p38 MAP-kinases. Plays a negative role in TCR signaling by dephosphorylating MAP3K7 adapter TAB1 leading to its inactivation (PubMed:24403530).
Interacts with BRD3 (By similarity). Interacts with AR and CCAR1. Interacts with MDFIC (By similarity).
Transcriptional activator which regulates endothelin-1 gene expression in endothelial cells. Binds to the consensus sequence 5'-AGATAG-3'.
Belongs to the eukaryotic-type N-acetylglucosamine kinase family.
Converts endogenous N-acetylglucosamine (GlcNAc), a major component of complex carbohydrates, from lysosomal degradation or nutritional sources into GlcNAc 6-phosphate (PubMed:22692205). Involved in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway: although human is not able to catalyze formation of Neu5Gc due to the inactive CMAHP enzyme, Neu5Gc is present in food and must be degraded (PubMed:22692205). Also has N-acetylmannosamine (ManNAc) kinase activity (By similarity). Also involved in innate immunity by promoting detection of bacterial peptidoglycan by NOD2: acts by catalyzing phosphorylation of muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, to generate 6-O-phospho-muramyl dipeptide, which acts as a direct ligand for NOD2 (PubMed:36002575).
Centrosomal protein which may be required for microtubule attachment to centrosomes. May act by forming ring-like structures around microtubules. Mediates nuclear translocation and mitogenic activity of the internalized growth factor FGF2, but that of FGF1.
Homodimer and homooligomer. Interacts with microtubules. Interacts with FGF2 and RAP80. Does not interact with FGF1 or FGF2 isoform 24 kDa.
The C-terminal region mediates the interaction with microtubules and is able to nucleate and bundles microtubules in vitro.
The centrosome localization domain (CLD) region mediates the localization to centrosomes and homooligomerization.
Expressed in retina, testis and, at a lower level, brain.
Important for recycling the chief excitatory neurotransmitter, glutamate, during neurotransmission.
Stoichiometry shows that ADP-ribosylation occurs in one subunit per catalytically active homohexamer.
Palmitoylated; which is required for presynaptic clustering.
Phosphorylated; which does not affect kinetic parameters or subcellular location.
Belongs to the pseudouridine synthase TruD family.
Pseudouridylate synthase that catalyzes pseudouridylation of RNAs (PubMed:28073919, PubMed:29628141, PubMed:30778726, PubMed:31477916, PubMed:35051350, PubMed:34718722). Acts as a regulator of protein synthesis in embryonic stem cells by mediating pseudouridylation of RNA fragments derived from tRNAs (tRFs): pseudouridylated tRFs inhibit translation by targeting the translation initiation complex (PubMed:29628141). Also catalyzes pseudouridylation of mRNAs: mediates pseudouridylation of mRNAs with the consensus sequence 5'-UGUAG-3' (PubMed:28073919, PubMed:31477916, PubMed:35051350). Acts as a regulator of pre-mRNA splicing by mediating pseudouridylation of pre-mRNAs at locations associated with alternatively spliced regions (PubMed:35051350). Pseudouridylation of pre-mRNAs near splice sites directly regulates mRNA splicing and mRNA 3'-end processing (PubMed:35051350). In addition to mRNAs and tRNAs, binds other types of RNAs, such as snRNAs, Y RNAs and vault RNAs, suggesting that it can catalyze pseudouridylation of many RNA types (PubMed:29628141).
Detected in skin eccrine sweat glands, at the apical cell membrane and at intercellular canaliculi (at protein level).
Forms a water-specific channel (PubMed:8621489, PubMed:18768791). Plays an important role in fluid secretion in salivary glands (By similarity). Required for TRPV4 activation by hypotonicity. Together with TRPV4, controls regulatory volume decrease in salivary epithelial cells (PubMed:16571723). Seems to play a redundant role in water transport in the eye, lung and in sweat glands (By similarity).
Homotetramer (PubMed:18768791, PubMed:26569106). Interacts with TRPV4; the interaction is probably indirect and regulates TRPV4 activation by hypotonicity.
Expressed from early in development through adulthood.
Isoform 1 expression is specific to nervous system. Expressed in nerve terminal and cell body, and is associated with nerve-terminal vesicles. Expression seen in Purkinje cells, cortical neurons, neuroectodermal tumors and graded in cerebral cortex (deeper layers exhibit stronger expression) (PubMed:1851215). Isoform 2 is expressed at high levels in brain and testis (PubMed:17453999).
Available under the names Neupogen or Granulokine (Amgen/Roche) and Granocyte (Rhone-Poulenc). Used to treat neutropenia (a disorder characterized by an extremely low number of neutrophils in blood).
Granulocyte/macrophage colony-stimulating factors are cytokines that act in hematopoiesis by controlling the production, differentiation, and function of 2 related white cell populations of the blood, the granulocytes and the monocytes-macrophages. This CSF induces granulocytes.
O-glycan consists of Gal-GalNAc disaccharide which can be modified with up to two sialic acid residues (done in recombinantly expressed G-CSF from CHO cells).
PubMed:2420009 misquotes the gene name as 'CSF1'.
Enhancer-binding elongation factor that specifically binds enhancers in embryonic stem cells (ES cells), marks them, and is required for their future activation during stem cell specification. Does not only bind to enhancer regions of active genes, but also marks the enhancers that are in a poised or inactive state in ES cells and is required for establishing proper RNA polymerase II occupancy at developmentally regulated genes in a cohesin-dependent manner. Probably required for priming developmentally regulated genes for later recruitment of the super elongation complex (SEC), for transcriptional activation during differentiation. Required for recruitment of P-TEFb within SEC during differentiation. Probably preloaded on germ cell chromatin, suggesting that it may prime gene activation by marking enhancers as early as in the germ cells. Promoting epithelial-mesenchymal transition (EMT) (By similarity). Elongation factor component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. Component of the little elongation complex (LEC), a complex required to regulate small nuclear RNA (snRNA) gene transcription by RNA polymerase II and III (PubMed:22195968).
Interacts with AFF4 (By similarity). Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3). Component of the little elongation complex (LEC), at least composed of ELL (ELL, ELL2 or ELL3), ZC3H8, ICE1 and ICE2.
Component of the PCAF complex, at least composed of TADA2L/ADA2, SUPT3H, TADA3L/ADA3, TAF5L/PAF65-beta, TAF6L/PAF65-alpha, TAF10/TAFII30, TAF12/TAFII20, TAF9/TAFII31 and TRRAP. Associates with TAFII31 and GCN5L2. Component of the TFTC-HAT complex, at least composed of TAF5L, TAF6L, TADA3L, SUPT3H/SPT3, TAF2/TAFII150, TAF4/TAFII135, TAF5/TAFII100, GCN5L2/GCN5, TAF10 and TRRAP. Component of the STAGA transcription coactivator-HAT complex, at least composed of SUPT3H, GCN5L2, TAF5L, TAF6L, SUPT7L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9. The STAGA core complex is associated with a subcomplex required for histone deubiquitination composed of ATXN7L3, ENY2 and USP22.
Expressed in all tissues tested including pancreas, kidney, skeletal muscle, liver, lung, placenta, brain and heart.
Enzyme activity is tightly regulated to prevent the accumulation of reactive oxygen species in the endoplasmic reticulum. Reversibly down-regulated by the formation of disulfide bonds between the active site Cys-94 and Cys-131, and between Cys-99 and Cys-104. Glutathione may be required to regulate its activity in the endoplasmic reticulum.
Oxidoreductase involved in disulfide bond formation in the endoplasmic reticulum. Efficiently reoxidizes P4HB/PDI, the enzyme catalyzing protein disulfide formation, in order to allow P4HB to sustain additional rounds of disulfide formation. Following P4HB reoxidation, passes its electrons to molecular oxygen via FAD, leading to the production of reactive oxygen species (ROS) in the cell. Required for the proper folding of immunoglobulins (PubMed:29858230). Plays an important role in ER stress-induced, CHOP-dependent apoptosis by activating the inositol 1,4,5-trisphosphate receptor IP3R1. Involved in the release of the unfolded cholera toxin from reduced P4HB/PDI in case of infection by V.cholerae, thereby playing a role in retrotranslocation of the toxin.
Phosphorylated on Ser-145 by FAM20C in the Golgi which increases its enzymatic activity (PubMed:29858230). Phosphorylation is induced by lactation (By similarity). It is also induced by hypoxia and reductive stress (PubMed:29858230).
Predominantly monomer. May function both as a monomer and a homodimer. Interacts with PDILT (PubMed:15475357). Interacts with ERP44; the interaction results in retention of ERO1A in the endoplasmic reticulum (PubMed:29858230, PubMed:11847130).
Stimulated by hypoxia; suggesting that it is regulated via the HIF-pathway.
The Cys-94/Cys-99 and Cys-394/Cys-397 disulfide bonds constitute the redox-active center. The Cys-94/Cys-99 disulfide bond may accept electron from P4HB and funnel them to the active site disulfide Cys-394/Cys-397 (By similarity). The regulatory Cys-99/Cys-104 disulfide bond stabilizes the other regulatory bond Cys-94/Cys-131 (PubMed:23027870).
Widely expressed at low level. Expressed at high level in upper digestive tract. Highly expressed in esophagus. Weakly expressed in stomach and duodenum.
(Microbial infection) Acts as a receptor for human coronavirus MERS-CoV-2.
(Microbial infection) Interacts with MERS coronavirus/MERS-CoV spike protein.
Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation (PubMed:10951221, PubMed:10900005, PubMed:11772392, PubMed:17287217). Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC (PubMed:10951221, PubMed:10900005, PubMed:11772392, PubMed:14691230). Its binding to CAV1 and CARD11 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner (PubMed:17287217). Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion (PubMed:11772392). In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM (PubMed:16651416, PubMed:10593948). May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation (PubMed:18708048). When overexpressed, enhanced cell proliferation, a process inhibited by GPC3 (PubMed:17549790). Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones such as brain natriuretic peptide 32 (PubMed:16254193, PubMed:10570924). Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline (PubMed:10593948).
Expressed specifically in lymphatic vessels but not in blood vessels in the skin, small intestine, esophagus, ovary, breast and prostate glands. Not detected in lymphatic vessels in the lung, kidney, uterus, liver and stomach (at protein level). Expressed in the poorly differentiated crypt cells of the small intestine as well as in the mature villous cells. Expressed at very low levels in the colon.
Level of plasma concentrations of the soluble form (SDPP) can be managed as a colon carcinoma diagnostic and prognostic marker.
Monomer. Homodimer (PubMed:12832764, PubMed:15448155, PubMed:17287217, PubMed:12646248, PubMed:12483204, PubMed:12906826). Heterodimer with Seprase (FAP) (PubMed:16651416). Requires homodimerization for optimal dipeptidyl peptidase activity and T-cell costimulation. Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (PubMed:17287217). Associates with collagen (PubMed:8526932). Interacts with PTPRC; the interaction is enhanced in an interleukin-12-dependent manner in activated lymphocytes (PubMed:12676959). Interacts (via extracellular domain) with ADA; does not inhibit its dipeptidyl peptidase activity (PubMed:15016824, PubMed:10951221, PubMed:14691230, PubMed:7907293, PubMed:8101391). Interacts with CAV1 (via the N-terminus); the interaction is direct (PubMed:17287217). Interacts (via cytoplasmic tail) with CARD11 (via PDZ domain); its homodimerization is necessary for interaction with CARD11 (PubMed:17287217). Interacts with IGF2R; the interaction is direct (PubMed:10900005). Interacts with GPC3 (PubMed:17549790). Interacts with human coronavirus-EMC spike protein and acts as a receptor for this virus (PubMed:23486063).
Phosphorylated. Mannose 6-phosphate residues in the carbohydrate moiety are necessary for interaction with IGF2R in activated T-cells. Mannose 6-phosphorylation is induced during T-cell activation.
The extracellular cysteine-rich region is necessary for association with collagen, dimer formation and optimal dipeptidyl peptidase activity.
The soluble form (Dipeptidyl peptidase 4 soluble form also named SDPP) derives from the membrane form (Dipeptidyl peptidase 4 membrane form also named MDPP) by proteolytic processing.
Up-regulated by IL12/interleukin-12 on activated T-cells. IL12-activated cells expressed enhanced levels of DPP4 but not mRNAs. Down-regulated by TNF. Up-regulated in migratory endothelial cells and in the invasive endothelial cells in tumors. Induced by hypoxia (PubMed:16670267).
A monovalent cation. K(+) is most effective, followed by NH4(+) and Rb(+). Na(+), Li(+) and Cs(+) are ineffective.
Belongs to the folylpolyglutamate synthase family.
Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfer reactions involved in purine, pyrimidine and amino acid synthesis. Unsubstituted reduced folates are the preferred substrates. Metabolizes methotrexate (MTX) to polyglutamates.
Produced by alternative initiation at Met-43 of isoform 1.
A short stretch of the intracellular domain (AA 8-14) proximal to the transmembrane domain is required for association with Fc receptor gamma chain.
Associated with FCER1G (By similarity). Heterodimer with CLEC4D; this heterodimer forms a pattern recognition receptor (PRR) against fungal infection (PubMed:23911656).
Calcium-dependent lectin that acts as a pattern recognition receptor (PRR) of the innate immune system: specifically recognizes and binds alpha-mannans on C.albicans hypheas (PubMed:23911656, PubMed:28652405). Binding of C.albicans alpha-mannans to this receptor complex leads to phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of FCER1G, triggering activation of SYK, CARD9 and NF-kappa-B, consequently driving maturation of antigen-presenting cells and shaping antigen-specific priming of T-cells toward effector T-helper 1 and T-helper 17 cell subtypes (By similarity). Recognizes also, in a mannose-dependent manner, allergens from house dust mite and fungi, by promoting cysteinyl leukotriene production (By similarity). Recognizes soluble elements from the eggs of Shistosoma mansoni altering adaptive immune responses (By similarity).
Expressed in lung, spleen, lymph node, leukocytes, bone marrow, tonsils and dendritic cells. Strongly expressed in purified monocytes and weakly in B-cells. In peripheral blood cells, preferentially expressed in plasmacytoids rather than myeloids.
Up-regulated by granulocyte-macrophage colony-stimulating factor (GM-CSF), TGF-beta 1, TNF-alpha and down-regulated by IL-4, IL-10 or UVB in CD14+ monocytes.
A chromosomal aberration involving HIP1 is found in a form of chronic myelomonocytic leukemia (CMML). Translocation t(5;7)(q33;q11.2) with PDGFRB (PubMed:9616134). The chimeric HIP1-PDGFRB transcript results from an in-frame fusion of the two genes (PubMed:9616134). The reciprocal PDGFRB-HIP1 transcript is not expressed (PubMed:9616134).
Binds F-actin via the talin-like I/LWEQ domain.
Homodimer. Binds actin. Binds HTT (via N-terminus). This interaction is restricted to the brain. Binds to IFT57. In normal conditions, it poorly interacts with IFT57, HIP1 being strongly associated with HTT. However, in mutant HTT proteins with a long poly-Gln region, interaction between HTT and HIP1 is inhibited, promoting the interaction between HIP1 and IFT57. Interacts with CLTB (via N-terminus). Interacts (via coiled coil domain) with AR. Interacts with AP2A1, AP2A2, CLTC and HIP1R. Interacts with GRIA1, GRIN2A and GRIN2B.
Plays a role in clathrin-mediated endocytosis and trafficking (PubMed:11532990, PubMed:11577110, PubMed:11889126). Involved in regulating AMPA receptor trafficking in the central nervous system in an NMDA-dependent manner (By similarity). Regulates presynaptic nerve terminal activity (By similarity). Enhances androgen receptor (AR)-mediated transcription (PubMed:16027218). May act as a proapoptotic protein that induces cell death by acting through the intrinsic apoptosis pathway (PubMed:11007801). Binds 3-phosphoinositides (via ENTH domain) (PubMed:14732715). May act through the ENTH domain to promote cell survival by stabilizing receptor tyrosine kinases following ligand-induced endocytosis (PubMed:14732715). May play a functional role in the cell filament networks (PubMed:18790740). May be required for differentiation, proliferation, and/or survival of somatic and germline progenitors (PubMed:11007801, PubMed:12163454).
The affinity of the huntingtin protein-HIP1 interaction is inversely correlated to the length of the polyglutamine tract added to the huntingtin protein in Huntington disease.
The pseudo DED region (pDED) mediates the interaction with IFT57.
Ubiquitously expressed with the highest level in brain. Expression is up-regulated in prostate and colon cancer.
Component of the heterodimeric RalGAP1 complex with RALGAPA1 and of the heterodimeric RalGAP2 complex with RALGAPA2. Heterodimerization is required for activity (By similarity).
Highly expressed in brain, mostly in amygdala.
Non-catalytic subunit of the heterodimeric RalGAP1 and RalGAP2 complexes which act as GTPase activators for the Ras-like small GTPases RALA and RALB.
Splicing acceptor site is not canonical.
Expressed at low level in different cell lines.
Found in the major hispocompatibility complex class III region. May be implicated in susceptibility to lung tumors.
Dubious isoform. Could be a cloning artifact.
May play an important role in mediating p53/TP53-dependent apoptosis.
Binds TFR through the extracellular domain in a pH-dependent manner.
Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Iron overload due to HFE variants is a precipitating or exacerbating factor in variegate porphyria.
Expressed in all tissues tested except brain.
Genetic variations in HFE define the transferrin serum level quantitative trait locus 2 (TFQTL2) [MIM:614193]. Iron is essential for biochemical functions such as oxygen transport and oxidative phosphorylation. Excessive iron can cause iron-overload-related liver diseases, whereas iron deficiency can lead to anemia. Iron status can be assessed by measuring the levels of serum iron, serum transferrin, transferrin saturation with iron, and serum ferritin.
Arg-224 is found in the MHC 7.1 haplotype (HLA-A3,B7,DR15) population.
Detected in different cell types including monocytes, T-cells, B-cells and hepatocytes.
Interacts with CACTIN (via N-terminal domain); the interaction occurs in a proinflammatory-independent manner.
Involved in the regulation of innate immune response. Acts as negative regulator of Toll-like receptor and interferon-regulatory factor (IRF) signaling pathways. Contributes to the negative regulation of transcriptional activation of NF-kappa-B target genes in response to endogenous proinflammatory stimuli.
According to a report, the spliced A3GALT2 mRNA is not detected in human tissues (PubMed:18630988). The functional activity of human A3GALT2 tested by expressing a chimeric protein containing the catalytic domain of human A3GALT2 is unable to synthesize isogloboside 3 (iGb3). Futhermore mutagenesis experiments in rat, show that the mutant 'Asn-253' of human A3GALT2 completely eliminates alpha-1,3-galactosyltransferase activity (PubMed:18630988).
Expressed in thymus and monocyte derived dendritic cells.
Synthesizes the galactose-alpha(1,3)-galactose group on the glycosphingolipid isoglobotrihexosylceramide or isogloboside 3 (iGb3) by catalyzing the transfer of galactose from UDP-Galactose to its acceptor molecule Gal-beta-1,4-Glc-ceramide. Can also catalyze the addition of galactose to iGb3 itself to form polygalactose structures.
As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport. According to PubMed:18395520, it may play a role in cell death.
Expressed in various tumor cell lines including Jurkat, Hep-G2 and HeLa.
Probably part of the adaptor protein complex 5 (AP-5) a tetramer composed of AP5B1, AP5M1, AP5S1 and AP5Z1.
Component of the chaperonin-containing T-complex (TRiC), a heterooligomeric complex of about 850 to 900 kDa that forms two stacked rings, 12 to 16 nm in diameter (PubMed:25467444). Interacts with PACRG (PubMed:14532270).
Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of proteins upon ATP hydrolysis (PubMed:25467444). The TRiC complex mediates the folding of WRAP53/TCAB1, thereby regulating telomere maintenance (PubMed:25467444). The TRiC complex plays a role in the folding of actin and tubulin (Probable).
Displays an antiviral effect against flaviviruses such as west Nile virus (WNV) in the presence of OAS1B.
Expressed in spermatocytes and elongating spermatids inside the seminiferous tubules (at protein level) (PubMed:24557841). Testis-specific (PubMed:11318611, PubMed:24557841).
Interacts with HSPA2; this interaction may promote the recruitment of HSPA2 to the spindle.
Testis-specific spindle-associated factor that plays a role in spermatogenesis. In association with HSPA2, participates in the maintenance of spindle integrity during meiosis in male germ cells.
Binds the second PAH repeat of SIN3A (Probable). Binds TCF4 (PubMed:11500377). Binds RB1 (PubMed:10958660).
Transcriptional repressor that binds to the promoter region of target genes. Plays a role in the regulation of the cell cycle and of the Wnt pathway. Binds preferentially to the sequence 5'-TTCATTCATTCA-3'. Binding to the histone H1.0 promoter is enhanced by interaction with RB1. Disrupts the interaction between DNA and TCF4.
Ubiquitinated by the CTLH E3 ubiquitin-protein ligase complex, leading to subsequent proteasomal degradation.
Binds to MLF1 and retains it in the nucleus.
Acts as a negative regulator of osteoclast differentiation in basal and inflammatory conditions by regulating TNFSF11-induced Ca (2+) fluxes, thereby controlling the induction of NFATC1.
Clathrin coats are formed from molecules containing 3 heavy chains and 3 light chains. Interacts with CALY; the interaction stimulates clathrin self-assembly and clathrin-mediated endocytosis. Interacts with CKAP5 and TACC3 forming the TACC3/ch-TOG/clathrin complex located at spindle inter-microtubules bridges; the complex implicates clathrin triskelions.
Clathrin is the major protein of the polyhedral coat of coated pits and vesicles. Acts as component of the TACC3/ch-TOG/clathrin complex proposed to contribute to stabilization of kinetochore fibers of the mitotic spindle by acting as inter-microtubule bridge (PubMed:15858577, PubMed:21297582).
Interacts with SKOR1 which acts as a transcriptional corepressor.
Transcription factor required for the development of GABAergic interneurons in the dorsal horn of the spinal cord and migration and further development of hypaxial muscle precursor cells for limb muscles, diaphragm and hypoglossal cord.
Actin-binding protein (PubMed:16636079, PubMed:17294403, PubMed:28493397). Plays a role in the activation of T-cells in response to costimulation through TCR/CD3 and CD2 or CD28 (PubMed:17294403). Modulates the cell surface expression of IL2RA/CD25 and CD69 (PubMed:17294403).
Chromosomal aberrations involving LCP1 is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;13)(q27;q14), with BCL6.
Defects in LCP1 has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea.
Detected in intestinal microvilli, hair cell stereocilia, and fibroblast filopodia, in spleen and other lymph node-containing organs. Expressed in peripheral blood T-lymphocytes, neutrophils, monocytes, B-lymphocytes, and myeloid cells.
Monomer. Interacts with AIF1 (By similarity). Interacts with actin (PubMed:28493397).
Phosphorylated on a serine residue in response to costimulation through TCR/CD3 and CD2 or CD28. Serine phosphorylation promotes association with the actin cytoskeleton and targeting to peripheral cell projections.
Highly expressed in kidney, lung, placenta, stomach, skeletal muscle, colon and small intestine. Isoform A is prevalently expressed in the lung, testis, placenta, stomach and colon. Isoform B is more abundant in the brain, kidney and the liver. Isoform C is not detected in brain, heart, liver, kidney and skeletal muscle. Expressed on T-cells in fibrotic liver; at protein level. Overexpressed in fibrotic and cirrhotic liver.
Interacts with MYD88, IRAK1, IRAK4, and TRAF6. Bound to its ligand IL-33, interacts with IL1RAP to form the minimal interleukin-33 signaling complex with a 1:1:1 stoichiometry. Interacts with KIT (bound to KITLG/SCF). A mast cell-specific KITLG/SCF-induced interleukin-33 signaling complex contains IL1RL1, IL1RAP, KIT and MYD88. Interacts with TMED1 (PubMed:23319592).
Receptor for interleukin-33 (IL-33) which plays crucial roles in innate and adaptive immunity, contributing to tissue homeostasis and responses to environmental stresses together with coreceptor IL1RAP (PubMed:35238669). Its stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of MAPK3/ERK1 and/or MAPK1/ERK2, MAPK14, and MAPK8. Possibly involved in helper T-cell function (PubMed:16286016) (Probable). Upon tissue injury, induces UCP2-dependent mitochondrial rewiring that attenuates the generation of reactive oxygen species and preserves the integrity of Krebs cycle required for persistent production of itaconate and subsequent GATA3-dependent differentiation of inflammation-resolving alternatively activated macrophages (By similarity).
Ubiquitinated at Lys-321 in a FBXL19-mediated manner; leading to proteasomal degradation. Ubiquitination by TRAF6 via 'Lys-27'-linked polyubiquitination and deubiquitination by USP38 serves as a critical regulatory mechanism for fine-tuning IL1RL1-mediated inflammatory response (PubMed:35238669).
Forms heterodimers with BAR domain-containing sorting nexins SNX1 and SNX2; does not homodimerize (PubMed:23085988). The heterodimers are proposed to self-assemble into helical arrays on the membrane to stabilize and expand local membrane curvature underlying endosomal tubule formation. Thought to be a component of the originally described retromer complex (also called SNX-BAR retromer) which is a pentamer containing the heterotrimeric retromer cargo-selective complex (CSC), also described as vacuolar protein sorting subcomplex (VPS), and a heterodimeric membrane-deforming subcomplex formed between SNX1 or SNX2 and SNX5 or SNX6 (also called SNX-BAR subcomplex); the respective CSC and SNX-BAR subcomplexes associate with low affinity (Probable). Interacts with SNX1, SNX2, VPS26A, VPS29, VPS35, DCTN1, DOCK1, MIB1, PIP5K1C isoform 3. Interacts with HGS; increased by PIP5K1C isoform 3 kinase activity and by PtdIns(3P) and/or PtdIns(3,4)P2 (PubMed:16857196, PubMed:16968745, PubMed:19619496, PubMed:23085988, PubMed:18596235, PubMed:23602387, PubMed:24610942).
Involved in several stages of intracellular trafficking. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) or phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) (PubMed:15561769). Acts in part as component of the retromer membrane-deforming SNX-BAR subcomplex. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX-BAR subcomplex functions to deform the donor membrane into a tubular profile called endosome-to-TGN transport carrier (ETC) (Probable). Does not have in vitro vesicle-to-membrane remodeling activity (PubMed:23085988). Involved in retrograde transport of lysosomal enzyme receptor IGF2R (PubMed:17148574, PubMed:18596235). May function as link between endosomal transport vesicles and dynactin (Probable). Plays a role in the internalization of EGFR after EGF stimulation (Probable). Involved in EGFR endosomal sorting and degradation; the function involves PIP5K1C isoform 3 and is retromer-independent (PubMed:23602387). Together with PIP5K1C isoform 3 facilitates HGS interaction with ubiquitinated EGFR, which initiates EGFR sorting to intraluminal vesicles (ILVs) of the multivesicular body for subsequent lysosomal degradation (Probable). Involved in E-cadherin sorting and degradation; inhibits PIP5K1C isoform 3-mediated E-cadherin degradation (PubMed:24610942). Plays a role in macropinocytosis (PubMed:18854019, PubMed:21048941).
The selectivity for particular phosphatidylinositol lipids is under debate. According to one report (PubMed:19553671), the rat protein binds exclusively to phosphatidylinositol 4,5-bisphosphate, while the human protein has been reported (PubMed:15561769) to bind to phosphatidylinositol 3,4-bisphosphate and also to phosphatidylinositol 3-phosphate.
Promotes LRP6 phosphorylation by casein kinases and thereby plays a role in Wnt signaling. May be a membrane scaffold protein involved in the self-aggregation of LRP6 to further enhance its activity.
Expressed by malignant and fetal tissue at very low levels.
Constitutively expressed in most human cells; is induced to higher levels upon serum stimulation in untransformed and transformed cells.
Homodimer; disulfide-linked, upon oxidation. 5 homodimers assemble to form a ring-like decamer (PubMed:18172504). Interacts with GDPD5; forms a mixed-disulfide with GDPD5 (By similarity). Interacts with SESN1 and SESN2 (PubMed:15105503). Interacts with FAM107A (PubMed:21969592).
Phosphorylated on Thr-90 during the M-phase, which leads to a more than 80% decrease in enzymatic activity.
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides and as sensor of hydrogen peroxide-mediated signaling events. Might participate in the signaling cascades of growth factors and tumor necrosis factor-alpha by regulating the intracellular concentrations of H(2)O(2) (PubMed:9497357). Reduces an intramolecular disulfide bond in GDPD5 that gates the ability to GDPD5 to drive postmitotic motor neuron differentiation (By similarity).
Interacts with HLA-F; this interaction is direct.
Receptor on natural killer (NK) cells for HLA-C alleles. Does not inhibit the activity of NK cells.
Putative metalloprotease with an atypical HExxxH zinc-binding motif instead of HExxH, which interrupts the active site-containing helix without affecting the integrity of the catalytic site arrangement.
Detected in brain cortex and hippocampus pyramidal neurons (at protein level) (PubMed:17040209). Detected in cerebrospinal fluid (at protein level) (PubMed:25326458). Predominantly expressed in the brain (PubMed:9070919).
Monomer. Has a tendency to form large polymers already at 41 and 45 degrees Celsius (in vitro).
Serine protease inhibitor that inhibits plasminogen activators and plasmin but not thrombin (PubMed:9442076, PubMed:26329378, PubMed:19265707, PubMed:19285087, PubMed:11880376). May be involved in the formation or reorganization of synaptic connections as well as for synaptic plasticity in the adult nervous system. May protect neurons from cell damage by tissue-type plasminogen activator (Probable).
Lipid transporter that specifically mediates export of sphingosine-1-phosphate (sphing-4-enine 1-phosphate, S1P) and sphinganine-1-phosphate in the lymph, thereby playing a role in lymphocyte trafficking (PubMed:19074308, PubMed:23180825, PubMed:21084291). S1P is a bioactive signaling molecule that regulates many physiological processes important for the development and for the immune system (PubMed:19074308, PubMed:23180825). Regulates levels of S1P and the S1P gradient that exists between the high circulating concentrations of S1P and low tissue levels that control lymphocyte trafficking (PubMed:19074308, PubMed:23180825). Required for the egress of T-cells from lymph nodes during an immune response by mediating S1P secretion, which generates a gradient that enables activated T-cells to access lymph (By similarity). Also required for the egress of immature B-cells from the bone marrow (By similarity). In contrast, not involved in S1P release from red blood cells (By similarity). Involved in auditory function (PubMed:30973865). S1P release in the inner ear is required for maintenance of the endocochlear potential in the cochlea (By similarity). In addition to export, also able to mediate S1P import (By similarity).
Interacts with DAXX to form the chromatin remodeling complex ATRX:DAXX. Probably binds EZH2. Binds annexin V in a calcium and phosphatidylcholine/phosphatidylserine-dependent manner. Interacts directly with CBX5 via the PxVxL motif. Interacts with RAD50, MRE11 and NBN; indicative for an association with the MRN complex. Interacts with histone MACROH2A1. Interacts with histone H3 peptides methylated at 'Lys-10' with preferences H3K9me3 > H3K9me2 > H3K9me1. Interacts with histone H3 peptides unmethylated at 'Lys-5' (H3K4me0). Interacts with MECP2, SMC1 and SMC3. Interacts with SETDB1, TRIM28 and ZNF274 (PubMed:27029610).
Involved in transcriptional regulation and chromatin remodeling. Facilitates DNA replication in multiple cellular environments and is required for efficient replication of a subset of genomic loci. Binds to DNA tandem repeat sequences in both telomeres and euchromatin and in vitro binds DNA quadruplex structures. May help stabilizing G-rich regions into regular chromatin structures by remodeling G4 DNA and incorporating H3.3-containing nucleosomes. Catalytic component of the chromatin remodeling complex ATRX:DAXX which has ATP-dependent DNA translocase activity and catalyzes the replication-independent deposition of histone H3.3 in pericentric DNA repeats outside S-phase and telomeres, and the in vitro remodeling of H3.3-containing nucleosomes. Its heterochromatin targeting is proposed to involve a combinatorial readout of histone H3 modifications (specifically methylation states of H3K9 and H3K4) and association with CBX5. Involved in maintaining telomere structural integrity in embryonic stem cells which probably implies recruitment of CBX5 to telomeres. Reports on the involvement in transcriptional regulation of telomeric repeat-containing RNA (TERRA) are conflicting; according to a report, it is not sufficient to decrease chromatin condensation at telomeres nor to increase expression of telomeric RNA in fibroblasts (PubMed:24500201). May be involved in telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines. Acts as negative regulator of chromatin incorporation of transcriptionally repressive histone MACROH2A1, particularily at telomeres and the alpha-globin cluster in erythroleukemic cells. Participates in the allele-specific gene expression at the imprinted IGF2/H19 gene locus. On the maternal allele, required for the chromatin occupancy of SMC1 and CTCTF within the H19 imprinting control region (ICR) and involved in esatblishment of histone tails modifications in the ICR. May be involved in brain development and facial morphogenesis. Binds to zinc-finger coding genes with atypical chromatin signatures and regulates its H3K9me3 levels. Forms a complex with ZNF274, TRIM28 and SETDB1 to facilitate the deposition and maintenance of H3K9me3 at the 3' exons of zinc-finger genes (PubMed:27029610).
Phosphorylated at serine residues during mitose. Phosphorylation may promote the release from the nuclear matrix and progression to mitosis.
The ADD domain predominantly interacts with histone H3 trimethylated at 'Lys-10'(H3K9me3) (and to a lesser extent H3 mono- or dimethylated at 'Lys-10') and simultanously to histone H3 unmethylated at 'Lys-5' (H3K4me0). The interaction with H3K9me3 is disrupted by the presence of H3K4me3 suggesting a readout of the combined histone H3 methylation state.
C8 is a constituent of the membrane attack complex. C8 binds to the C5B-7 complex, forming the C5B-8 complex. C5-B8 binds C9 and acts as a catalyst in the polymerization of C9. The gamma subunit seems to be able to bind retinol.
C8 is composed of three chains: alpha, beta and gamma. The alpha and gamma chains are disulfide bonded.
Expressed in brain. Detected in the anterior part of the neural fetal retina (at protein level).
Probably plays a role in the development of the brain and the sense organs. Can bind to the BCD target sequence (BTS): 5'-TCTAATCCC-3'.
Expressed in thymus, small intestine, spleen, prostate, ovary, colon and testis.
Component of the DRTF1/E2F transcription factor complex. Forms heterodimers with DP family members. The E2F2 complex binds specifically hypophosphorylated retinoblastoma protein RB1. During the cell cycle, RB1 becomes phosphorylated in mid-to-late G1 phase, detaches from the DRTF1/E2F complex, rendering E2F transcriptionally active. Viral oncoproteins, notably E1A, T-antigen and HPV E7, are capable of sequestering RB1, thus releasing the active complex. Binds EAPP.
Highest level of expression is found in placenta, low levels are found in lung. Found as well in many immortalized cell lines derived from tumor samples.
Phosphorylated by CDK2 and cyclin A-CDK2 in the S-phase.
Transcription activator that binds DNA cooperatively with DP proteins through the E2 recognition site, 5'-TTTC[CG]CGC-3' found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication. The DRTF1/E2F complex functions in the control of cell-cycle progression from g1 to s phase. E2F2 binds specifically to RB1 in a cell-cycle dependent manner.
(Microbial infection) Interacts with herpes simplex virus 1 VP22.
A chromosomal aberration involving SET is found in some cases of acute undifferentiated leukemia (AUL). Translocation t(6;9)(q21;q34.1) with NUP214/CAN.
A long alpha helix in the N-terminus mediates dimerization, while the earmuff domain is responsible for core histone and dsDNA binding. The C-terminal acidic domain mediates the inhibition of histone acetyltransferases and is required for the DNA replication stimulatory activity.
Cleaved after Lys-176 by GZMA. The cleavage inhibits its nucleosome assembly activity and disrupts the inhibition on NME1.
Headphone-shaped homodimer. Isoforms 1 and 2 interact directly with each other and with ANP32A within the tripartite INHAT (inhibitor of acetyltransferases) complex. Isoform 1 and isoform 2 interact also with histones. Isoform 2 is a component of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and TREX1, but not NME2 or TREX2. Within this complex, directly interacts with ANP32A, NME1, HMGB2 and TREX1; the interaction with ANP32A is enhanced after cleavage. Interacts with APBB1, CHTOP, SETBP1, SGO1.
Isoform 2 is phosphorylated on Ser-15 and Ser-24.
Multitasking protein, involved in apoptosis, transcription, nucleosome assembly and histone chaperoning. Isoform 2 anti-apoptotic activity is mediated by inhibition of the GZMA-activated DNase, NME1. In the course of cytotoxic T-lymphocyte (CTL)-induced apoptosis, GZMA cleaves SET, disrupting its binding to NME1 and releasing NME1 inhibition. Isoform 1 and isoform 2 are potent inhibitors of protein phosphatase 2A. Isoform 1 and isoform 2 inhibit EP300/CREBBP and PCAF-mediated acetylation of histones (HAT) and nucleosomes, most probably by masking the accessibility of lysines of histones to the acetylases. The predominant target for inhibition is histone H4. HAT inhibition leads to silencing of HAT-dependent transcription and prevents active demethylation of DNA. Both isoforms stimulate DNA replication of the adenovirus genome complexed with viral core proteins; however, isoform 2 specific activity is higher.
N-terminus of isoform 1 is methylated by METTL11A/NTM1. Mainly trimethylated (By similarity).
Widely expressed. Low levels in quiescent cells during serum starvation, contact inhibition or differentiation. Highly expressed in Wilms' tumor.
Oxidizes the CoA-esters of 2-methyl-branched fatty acids.
Acts as a ribosome receptor and mediates interaction between the ribosome and the endoplasmic reticulum membrane.
Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation (By similarity). The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres (By similarity). Part of a nucleosome-associated complex that binds specifically to histone H3-containing nucleosomes at the centromere, as opposed to nucleosomes containing CENPA. Component of the heterotetrameric CENP-T-W-S-X complex that binds and supercoils DNA, and plays an important role in kinetochore assembly. CENPW has a fundamental role in kinetochore assembly and function. It is one of the inner kinetochore proteins, with most further proteins binding downstream. Required for normal chromosome organization and normal progress through mitosis.
Heterodimer with CENPT; this dimer coassembles with CENPS-CENPX heterodimers at centromeres to form the tetrameric CENP-T-W-S-X complex, which is a subcomplex of the large constitutive centromere-associated network (CCAN, also known as the interphase centromere complex or ICEN) (PubMed:19070575, PubMed:19533040, PubMed:21695110, PubMed:22304917). Interacts with NPM1 (PubMed:22002061).
Highly expressed in ovary, liver, lung and pancreas and to a lower extent in breast and gastrointestinal tract cancers; such as those of the colon, rectum and stomach. Overexpressed in high grade breast invasive tumors. Expressed in many cancer cell types.
Constitutively potentiates the superoxide-generating activity of NOX1 and NOX3 and is required for the biogenesis of otoconia/otolith, which are crystalline structures of the inner ear involved in the perception of gravity. Isoform 3 is more potent than isoform 1 in activating NOX3. Together with NOXA1, may also substitute to NCF1/p47phox and NCF2/p67phox in supporting the phagocyte NOX2/gp91phox superoxide-generating activity.
Expressed in testis, small and large intestines, liver, kidney and pancreas. Isoform 3 is mainly expressed in colon. Isoform 1 is preferentially expressed in testis.
Interacts with NOX1, NOXA1, CYBA/p22phox and NCF2/p67phox. Interacts with SH3PXD2A and SH3PXD2B.
The PX domain mediates lipid-binding, localization to the plasma membrane and is required for NOX1 activation.
The SH3 domains mediate interaction with CYBA/p22phox. Also mediates intramolecular interaction with the proline-rich region.
Calcium-dependent lectin that acts as a pattern recognition receptor (PRR) of the innate immune system: recognizes damage-associated molecular patterns (DAMPs) of pathogen-associated molecular patterns (PAMPs) of bacteria and fungi (PubMed:23602766, PubMed:23911656). The PAMPs include alpha-mannans on C.albicans hypheas and mycobacterial trehalose 6,6'-dimycolate (TDM) (PubMed:23602766, PubMed:23911656). Interacts with signaling adapter Fc receptor gamma chain/FCER1G, likely via CLEC4E, to form a functional complex in myeloid cells (By similarity). Binding of mycobacterial TDM or C.albicans alpha-mannans to this receptor complex leads to phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of FCER1G, triggering activation of SYK, CARD9 and NF-kappa-B, consequently driving maturation of antigen-presenting cells and shaping antigen-specific priming of T-cells toward effector T-helper 1 and T-helper 17 cell subtypes (PubMed:23602766, PubMed:23911656). The heterodimer formed with CLEC6A is active against fungal infection (PubMed:23911656). Functions as an endocytic receptor (PubMed:14971047). May be involved in antigen uptake at the site of infection, either for clearance of the antigen, or for processing and further presentation to T-cells (PubMed:14971047).
Expressed weakly in peripheral blood leukocytes, bone marrow and spleen. Expression is confined mostly in monocytes and macrophage and seems to be up-regulated by IL-6, IL-10, TNF-alpha and IFN-gamma.
Heterodimer with CLEC4E; disulfide-linked (By similarity). CLEC4E acts as a bridge for interaction between CLEC4D and FCER1G to form a functional complex (By similarity). Heterodimer with CLEC6A; this heterodimer forms a pattern recognition receptor (PRR) against fungal infection (PubMed:23911656).
Expressed in the brain, adrenal gland and corneal endothelium (CE). Expressed in steroid-producing cells of the ovary and testis (at protein level). Expressed in steroid-producing cells of the ovary and testis. Weakly expressed in placenta. Expressed in corneal endothelial cells.
Interacts with RHOT1/Miro-1, TRAK1/OIP106 and TRAK2/GRIF1 (By similarity). Interacts with RHOT2/Miro-2.
Plays a role in the trafficking of mitochondria along microtubules. Regulates the kinesin-mediated axonal transport of mitochondria to nerve terminals along microtubules during hypoxia. Participates in the translocation of TRAK2/GRIF1 from the cytoplasm to the mitochondrion. Also plays a role in steroidogenesis through maintenance of mitochondrial abundance and morphology (By similarity). Plays an inhibitory role during neocortex development by regulating mitochondrial morphology, distribution and motility in neocortical neurons (By similarity).
Interacts with TRPM8 (via N-terminus and C-terminus domains); the interaction inhibits TRPM8 channel activity. Interacts with TRPV6.
Isoform 2 is expressed in the prostate and strongly expressed in cancerous prostate samples.
Positively regulates the plasma membrane cation channel TRPM8 activity. Involved in the recruitment of TRPM8 to the cell surface. Promotes prostate cancer cell migration inhibition in a TRPM8-dependent manner.
The C-terminal region is necessary for the channel activity stimulation.
Expression is undetectable in all tissues tested except for differentiating myoblasts of FSHD patients, which display low, yet distinct levels of expression, partly from FRG2, but predominantly originating from its homolog on chromosome 10.
DNA polymerase that promotes microhomology-mediated end-joining (MMEJ), an alternative non-homologous end-joining (NHEJ) machinery triggered in response to double-strand breaks in DNA (PubMed:25642963, PubMed:25643323). MMEJ is an error-prone repair pathway that produces deletions of sequences from the strand being repaired and promotes genomic rearrangements, such as telomere fusions, some of them leading to cellular transformation (PubMed:25642963, PubMed:25643323). POLQ acts as an inhibitor of homology-recombination repair (HR) pathway by limiting RAD51 accumulation at resected ends (PubMed:25642963). POLQ-mediated MMEJ may be required to promote the survival of cells with a compromised HR repair pathway, thereby preventing genomic havoc by resolving unrepaired lesions (By similarity). The polymerase acts by binding directly the 2 ends of resected double-strand breaks, allowing microhomologous sequences in the overhangs to form base pairs. It then extends each strand from the base-paired region using the opposing overhang as a template. Requires partially resected DNA containing 2 to 6 base pairs of microhomology to perform MMEJ (PubMed:25643323). The polymerase activity is highly promiscuous: unlike most polymerases, promotes extension of ssDNA and partial ssDNA (pssDNA) substrates (PubMed:18503084, PubMed:21050863, PubMed:22135286). Also exhibits low-fidelity DNA synthesis, translesion synthesis and lyase activity, and it is implicated in interstrand-cross-link repair, base excision repair and DNA end-joining (PubMed:14576298, PubMed:18503084, PubMed:19188258, PubMed:24648516). Involved in somatic hypermutation of immunoglobulin genes, a process that requires the activity of DNA polymerases to ultimately introduce mutations at both A/T and C/G base pairs (By similarity).
Homomultimer; forms dimers and multimers (PubMed:25643323). Interacts with RAD51 (PubMed:25642963). Interacts with ORC2 and ORC4 (PubMed:24989122).
The loop 2 region is involved in the binding of the 2 ends of resected double-strand breaks and homomultimerization.
Was wrongly named DNA polymerase eta (POLH) somne authors (Ref.4). This protein corresponds to DNA polymerase theta (POLQ) and should not be confused with DNA polymerase eta (POLH) (AC Q9Y253).
Expressed abundantly in placenta, and non-pregnant mammary gland with low expression in the kidney, fetal brain and pancreas.
Metalloproteinase which specifically cleaves insulin-like growth factor binding protein (IGFBP)-5 at the '163-Ser-|-Lys-164' bond. Shows limited proteolysis toward IGFBP-3.
E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins (By similarity). Promotes the polyubiquitination and proteasome-dependent degradation of RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation and negatively regulating inflammatory responses (By similarity). Plays a role in the regulation of spermiation and in male fertility (By similarity).
Expressed in sperm, with significantly reduced expression in sperm of patients with oligoasthenoteratozoospermia (at protein level) (PubMed:28008940). Widely expressed with expression in testis, ovary, small intestine, colon, peripheral blood leukocytes, fetal liver, bone marrow, thymus, lymph node and spleen (PubMed:11597136).
Interacts with PDLIM2 (via LIM zinc-binding domain) (By similarity). Interacts with RELA (By similarity).
Partially overlaps and is antisense to the RAF1 proto-oncogene.
Belongs to the potassium channel KCNN family. KCa2.2/KCNN2 subfamily.
Expressed in atrial myocytes (at protein level). Widely expressed.
Forms a voltage-independent potassium channel activated by intracellular calcium (PubMed:10991935, PubMed:9287325, PubMed:33242881). Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization.
Inhibited by bee venom neurotoxin apamin (PubMed:10991935, PubMed:9287325). Inhibited by UCL 1684 and tetraethylammonium (TEA) (By similarity).
Probably binds and transports small hydrophobic volatile molecules.
Strongly expressed in genital sphere organs such as the prostate and mammary glands.
Activity of the CRL2(FEM1B) complex toward FNIP1 is inhibited by BEX family proteins (BEX1, BEX2, BEX3, BEX4 and/or BEX5) in absence of reductive stress. Mechanistically, BEX proteins act as pseudosubstrate inhibitors that associate with FEM1B via zinc in absence of reductive stress, thereby preventing association between FEM1B and FNIP1.
Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter FEM1B (PubMed:15601820, PubMed:29779948). Homooligomer (PubMed:10542291). Interacts with PPM1F and PHTF1 (PubMed:11559703). Interacts with the death domain of FAS/TNFRSF6 and TNFRSF1A (PubMed:10542291). Interacts with CHEK1 (PubMed:19330022). Interacts with NKX3-1 (By similarity).
Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:33398170, PubMed:33398168). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (PubMed:29779948, PubMed:33398170, PubMed:33398168). The CRL2(FEM1B) complex specifically recognizes proteins ending with -Gly-Leu-Asp-Arg, such as CDK5R1, leading to their ubiquitination and degradation (PubMed:33398170, PubMed:33398168). Also acts as a regulator of the reductive stress response by mediating ubiquitination of reduced FNIP1: in response to reductive stress, the CRL2(FEM1B) complex specifically recognizes a conserved Cys degron in FNIP1 when this degron is reduced, leading to FNIP1 degradation and subsequent activation of mitochondria to recalibrate reactive oxygen species (ROS) (By similarity). Mechanistically, recognizes and binds reduced FNIP1 through two interface zinc ions, which act as a molecular glue that recruit reduced FNIP1 to FEM1B (By similarity). Promotes ubiquitination of GLI1, suppressing GLI1 transcriptional activator activity (PubMed:24076122). Promotes ubiquitination and degradation of ANKRD37 (By similarity). Promotes ubiquitination and degradation of SLBP (PubMed:28118078). Involved in apoptosis by acting as a death receptor-associated protein that mediates apoptosis (PubMed:10542291). Also involved in glucose homeostasis in pancreatic islet (By similarity). May also act as an adapter/mediator in replication stress-induced signaling that leads to the activation of CHEK1 (PubMed:19330022).
Widely expressed (PubMed:10542291). Highly expressed in testis (PubMed:10542291). Weakly expressed in other tissues (PubMed:10542291).
Binds long-chain acyl-coenzyme A molecules with a strong preference for unsaturated C18:1-CoA, lower affinity for unsaturated C20:4-CoA, and very weak affinity for saturated C16:0-CoA. Does not bind fatty acids.
Detected in placenta and spleen (at protein level). Detected in placenta, umbilical cord blood, CD34-positive hematopoietic progenitor cells and bone marrow.
Autoubiquitinated in vitro in the presence of UBE2D1 and UBE2E1.
E3 ubiquitin-protein ligase that acts as a regulator of the TORC1 signaling pathway (PubMed:35114100, PubMed:33594058). Positively regulates the TORC1 signaling pathway independently of arginine levels: acts by catalyzing 'Lys-29'-polyubiquitination and degradation of CASTOR1, releasing the GATOR2 complex from CASTOR1 (PubMed:33594058). Also negatively regulates the TORC1 signaling pathway in response to leucine deprivation: acts by mediating 'Lys-63'-linked polyubiquitination of SESN2, promoting SESN2-interaction with the GATOR2 complex (PubMed:35114100). Also involved in protein trafficking and localization (PubMed:23129617, PubMed:23353890, PubMed:24387786, PubMed:27808481, PubMed:32409562). Acts as a regulator of synaptic transmission by mediating ubiquitination and degradation of AMPAR receptor GluA2/GRIA2 (PubMed:23129617, PubMed:33650289). Does not catalyze ubiquitination of GluA1/GRIA1 (PubMed:23129617). Also acts as a regulator of the recycling endosome pathway by mediating ubiquitination of VAMP3 (PubMed:23353890). Regulates lysosome positioning by catalyzing ubiquitination and degradation of ARL8B (PubMed:27808481). Plays a role in growth regulation involved in G1/S transition by mediating, possibly by mediating ubiquitination of SLC22A18 (PubMed:16314844). Acts with a limited set of E2 enzymes, such as UBE2D1 and UBE2N (PubMed:33650289).
Widely expressed (PubMed:23129617). Strongly expressed in the kidney, pancreas, testis and liver (at protein level) (PubMed:16314844, PubMed:23129617).
Involved in ribosomal large subunit assembly. May regulate the localization of the 5S RNP/5S ribonucleoprotein particle to the nucleolus.
Interacts directly with activated KRAS in a GTP-dependent manner. Interacts (via SARAH domain) with STK3/MST2 and STK4/MST1.
Phosphorylated by STK3/MST2 and STK4/MST1.
Potential tumor suppressor. Acts as a KRAS-specific effector protein. May promote apoptosis and cell cycle arrest. Stabilizes STK3/MST2 by protecting it from proteasomal degradation.
Widely expressed with highest levels in brain, placenta, peripheral blood and lung. Frequently down-regulated in lung tumor cell lines.
Epidermolysis bullosa acquisita (EBA) is an autoimmune acquired blistering skin disease resulting from autoantibodies to type VII collagen.
Homotrimer. Interacts with MIA3/TANGO1; facilitating its loading into transport carriers and subsequent secretion.
Stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV collagen.
Involved in the inhibition of cytokine-induced death of pancreatic beta cells. Involved in the promotion of insulin secretion from pancreatic beta cells (PubMed:21853325). Is a downstream transcriptional target of p53/TP53, and acts as a pro-survival homeostatic factor that attenuates the development of cellular stress. Maintains protein homeostasis and promotes cell survival through attenuation of endoplasmic reticulum (ER) stress and the subsequent induction of unfolded protein response (UPR) (PubMed:27740623).
Widely expressed. Highly expressed in kidney and pancreas.
Chaperone protein which promotes assembly of the 20S proteasome as part of a heterodimer with PSMG1. The PSMG1-PSMG2 heterodimer binds to the PSMA5 and PSMA7 proteasome subunits, promotes assembly of the proteasome alpha subunits into the heteroheptameric alpha ring and prevents alpha ring dimerization.
Degraded by the proteasome upon completion of 20S proteasome maturation.
Forms a heterodimer with PSMG1. The PSMG1-PSMG2 heterodimer interacts directly with the PSMA5 and PSMA7 proteasome alpha subunits.
Widely expressed with highest levels in lung, brain and colon. Moderately expressed in muscle, stomach, spleen and heart. Weakly expressed in small intestine, pancreas and liver. Highly expressed in hepatocellular carcinomas with low levels in surrounding liver tissue.
Binds DNA as a dimer. Can form homodimers or heterodimers with other AP-2 family members (By similarity).
Highly expressed in brain, placenta, skeletal muscle, thymus, small intestine, and prostate, and expressed at lower levels in leukocyte, spleen, testis, ovary and colon. Barely detectable in heart, kidney, liver, lung or pancreas.
Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes. AP-2 factors bind to the consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development. They also suppress a number of genes including MCAM/MUC18, C/EBP alpha and MYC (By similarity).
Seems to be associated with spermiogenesis but is not essential for sperm development and male fertility.
A chromosomal aberration involving ZMYM2 may be a cause of stem cell leukemia lymphoma syndrome (SCLL). Translocation t(8;13)(p11;q12) with FGFR1. SCLL usually presents as lymphoblastic lymphoma in association with a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow.
Can form homodimers (PubMed:32891193). May be a component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST, PHF21A/BHC80, ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I. Interacts with FOXP1 and FOXP2 (PubMed:32891193).
Involved in the negative regulation of transcription.
Component of the poly(A) tail exosome targeting (PAXT) complex made of accessory factors, such as PABPN1, ZFC3H1 and MTREX, and which directs a subset of long and polyadenylated poly(A) RNAs for exosomal degradation (PubMed:27871484). Co-localizes with component of the CBC-ARS2 (CBCA) complex. Binds to RNA exosome components. Interacts with NCBP1/CBP80, ZC3H18, MTREX and PABPN1 in a RNase-insensitive manner, and with PABPC4, PABPC1 and ZC3H14 in a RNase-sensitive manner (PubMed:27871484).
Subunit of the trimeric poly(A) tail exosome targeting (PAXT) complex, a complex that directs a subset of long and polyadenylated poly(A) RNAs for exosomal degradation. The RNA exosome is fundamental for the degradation of RNA in eukaryotic nuclei. Substrate targeting is facilitated by its cofactor MTREX, which links to RNA-binding protein adapters.
Expressed at relatively high levels in peripheral blood leukocytes and, to lesser extent, in spleen.
G protein-coupled receptor that is activated by a major product of dietary fiber digestion, the short chain fatty acids (SCFAs), and that plays a role in the regulation of whole-body energy homeostasis and in intestinal immunity. In omnivorous mammals, the short chain fatty acids acetate, propionate and butyrate are produced primarily by the gut microbiome that metabolizes dietary fibers. SCFAs serve as a source of energy but also act as signaling molecules. That G protein-coupled receptor is probably coupled to the pertussis toxin-sensitive, G(i/o)-alpha family of G proteins but also to the Gq family (PubMed:12496283, PubMed:12711604, PubMed:23589301). Its activation results in the formation of inositol 1,4,5-trisphosphate, the mobilization of intracellular calcium, the phosphorylation of the MAPK3/ERK1 and MAPK1/ERK2 kinases and the inhibition of intracellular cAMP accumulation. May play a role in glucose homeostasis by regulating the secretion of GLP-1, in response to short-chain fatty acids accumulating in the intestine. May also regulate the production of LEP/Leptin, a hormone acting on the central nervous system to inhibit food intake. Finally, may also regulate whole-body energy homeostasis through adipogenesis regulating both differentiation and lipid storage of adipocytes. In parallel to its role in energy homeostasis, may also mediate the activation of the inflammatory and immune responses by SCFA in the intestine, regulating the rapid production of chemokines and cytokines. May also play a role in the resolution of the inflammatory response and control chemotaxis in neutrophils. In addition to SCFAs, may also be activated by the extracellular lectin FCN1 in a process leading to activation of monocytes and inducing the secretion of interleukin-8/IL-8 in response to the presence of microbes (PubMed:21037097). Among SCFAs, the fatty acids containing less than 6 carbons, the most potent activators are probably acetate, propionate and butyrate (PubMed:12496283, PubMed:12711604). Exhibits a SCFA-independent constitutive G protein-coupled receptor activity (PubMed:23066016).
Interacts with FCN1 (via Fibrinogen C-terminal domain).
Metallocarboxypeptidase that mediates protein deglutamylation of tubulin and non-tubulin target proteins (PubMed:22170066, PubMed:24022482, PubMed:30420557). Catalyzes the removal of polyglutamate side chains present on the gamma-carboxyl group of glutamate residues within the C-terminal tail of alpha- and beta-tubulin (PubMed:22170066, PubMed:24022482, PubMed:30420557). Specifically cleaves tubulin long-side-chains, while it is not able to remove the branching point glutamate (PubMed:24022482). Also catalyzes the removal of polyglutamate residues from the carboxy-terminus of alpha-tubulin as well as non-tubulin proteins such as MYLK (PubMed:22170066). Involved in KLF4 deglutamylation which promotes KLF4 proteasome-mediated degradation, thereby negatively regulating cell pluripotency maintenance and embryogenesis (PubMed:29593216).
Hydrolyzes the polyglutamate sidechains of pteroylpolyglutamates. Progressively removes gamma-glutamyl residues from pteroylpoly-gamma-glutamate to yield pteroyl-alpha-glutamate (folic acid) and free glutamate (PubMed:11005824, PubMed:8816764). May play an important role in the bioavailability of dietary pteroylpolyglutamates and in the metabolism of pteroylpolyglutamates and antifolates.
B-FABP could be involved in the transport of a so far unknown hydrophobic ligand with potential morphogenic activity during CNS development. It is required for the establishment of the radial glial fiber system in developing brain, a system that is necessary for the migration of immature neurons to establish cortical layers (By similarity).
Expressed in brain and other neural tissues.
Chromosomal aberrations involving CENPK are a cause of acute leukemias. Translocation t(5;11)(q12;q23) with KMT2A/MLL1.
Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex. Acts in coordination with KNL1 to recruit the NDC80 complex to the outer kinetochore.
Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex interacts with the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU. Interacts directly with CENPH.
Detected in several fetal organs with highest levels in fetal liver. In adults, it is weakly expressed in lung and placenta.
Acetylated at Lys-29 by EP300, the acetylation enhances the interaction with CEBPB, DNA-binding and transactivation activity.
Binds DNA as a dimer. Interacts with PTP4A1/PRL-1 (By similarity). Interacts with CCND3, but not with CCND1 or CCND2 (PubMed:15358120). Interacts with HSPA1A or HSPA1B; the interaction protects ATF5 from degradation via proteasome-dependent and caspase-dependent processes. Interacts (via C-terminal region) with NPM1 (via C-terminal region); the interaction leads to loss of association between HSPA1A or HSPA1B and ATF5 and promotes ATF5 degradation via proteasome-dependent and caspase-dependent processes (PubMed:22528486, PubMed:24379400). Interacts with NLK; the interaction stabilizes ATF5 at the protein level in a kinase-independent manner (PubMed:25512613). Interacts with alpha-tubulin, gamma-tubulin members TUBGCP2 and TUBGCP4, PCNT; the ATF5:PCNT:polyglutamylated tubulin (PGT) tripartite unites the mother centriole and the pericentriolar material (PCM) in the centrosome (PubMed:26213385). Interacts with CEBPB and EP300; EP300 is required for ATF5 and CEBPB interaction and DNA binding (By similarity).
Down-regulated by pro-apoptotic stimuli (PubMed:21212266). However, the pro-apoptotic cisplatin increases protein levels by inhibiting polyubiquitination (PubMed:18458088). IL1B increases protein levels through protein stabilization and increase of translation efficiency (PubMed:24379400).
Phosphorylated by NLK, probably at Ser-92, Thr-94, Ser-126 and Ser-190.
Transcription factor that either stimulates or represses gene transcription through binding of different DNA regulatory elements such as cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), ATF5-specific response element (ARE) (consensus: 5'-C[CT]TCT[CT]CCTT[AT]-3') but also the amino acid response element (AARE), present in many viral and cellular promoters. Critically involved, often in a cell type-dependent manner, in cell survival, proliferation, and differentiation (PubMed:10373550, PubMed:15358120, PubMed:21212266, PubMed:20654631). Its transcriptional activity is enhanced by CCND3 and slightly inhibited by CDK4 (PubMed:15358120). Important regulator of the cerebral cortex formation, functions in cerebral cortical neuroprogenitor cells to maintain proliferation and to block differentiation into neurons. Must be down-regulated in order for such cells to exit the cycle and differentiate (By similarity). Participates in the pathways by which SHH promotes cerebellar granule neuron progenitor cells proliferation (By similarity). Critical for survival of mature olfactory sensory neurons (OSN), directs expression of OSN-specific genes (By similarity). May be involved in osteogenic differentiation (PubMed:22442021). Promotes cell proliferation and survival by inducing the expression of EGR1 sinergistically with ELK1. Once acetylated by EP300, binds to ARE sequences on target genes promoters, such as BCL2 and EGR1 (PubMed:21791614). Plays an anti-apoptotic role through the transcriptional regulation of BCL2, this function seems to be cell type-dependent (By similarity). Cooperates with NR1I3/CAR in the transcriptional activation of CYP2B6 in liver (PubMed:18332083). In hepatic cells, represses CRE-dependent transcription and inhibits proliferation by blocking at G2/M phase (PubMed:22528486, PubMed:18701499). May act as a negative regulator of IL1B transduction pathway in liver (PubMed:24379400). Upon IL1B stimulus, cooperates with NLK to activate the transactivation activity of C/EBP subfamily members (PubMed:25512613). Besides its function of transcription factor, acts as a cofactor of CEBPB to activate CEBPA and promote adipocyte differentiation (PubMed:24216764). Regulates centrosome dynamics in a cell-cycle- and centriole-age-dependent manner. Forms 9-foci symmetrical ring scaffold around the mother centriole to control centrosome function and the interaction between centrioles and pericentriolar material (PubMed:26213385).
Ubiquitinated by CDC34 and UBE2B in order to be degraded by the proteasome. Cisplatin inhibits ubiquitination and proteasome-mediated degradation by inhibiting the interaction with CDC34 (PubMed:18458088). Ubiquitination and degradation by the proteasome are inhibited by NLK in a kinase-independent manner (PubMed:25512613).
Widely expressed with higher expression levels in liver.
Adaptor protein complex 1 (AP-1) is a heterotetramer composed of two large adaptins (gamma-type subunit AP1G1 and beta-type subunit AP1B1), a medium adaptin (mu-type subunit AP1M1 or AP1M2) and a small adaptin (sigma-type subunit AP1S1 or AP1S2 or AP1S3) (PubMed:34102099). Interacts (via GAE domain) with RABEP1 (PubMed:12773381, PubMed:14665628, PubMed:12042876). Interacts with SYNRG/gamma-synergin (PubMed:12042876). Interacts with EPS15 (By similarity). Interacts (via GAE domain) with AP1AR (via coiled-coil domain) (PubMed:15775984). Interacts with CLN3 (via dileucine motif); this interaction facilitates lysosomal targeting (PubMed:15598649). Interacts (via GAE domain) with AFTPH/aftiphilin; the interaction is required to recruit AFTPH/aftiphilin to the perinuclear region of the cell (PubMed:14665628, PubMed:15758025).
Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. In association with AFTPH/aftiphilin in the aftiphilin/p200/gamma-synergin complex, involved in the trafficking of transferrin from early to recycling endosomes, and the membrane trafficking of furin and the lysosomal enzyme cathepsin D between the trans-Golgi network (TGN) and endosomes (PubMed:15758025).
Myosin regulatory subunit that plays an important role in regulation of both smooth muscle and nonmuscle cell contractile activity via its phosphorylation. Implicated in cytokinesis, receptor capping, and cell locomotion (PubMed:11942626, PubMed:2526655). In myoblasts, may regulate PIEZO1-dependent cortical actomyosin assembly involved in myotube formation (By similarity).
Phosphorylation increases the actin-activated myosin ATPase activity and thereby regulates the contractile activity. It is required to generate the driving force in the migration of the cells but not necessary for localization of myosin-2 at the leading edge. Phosphorylation is required for myotube formation.
Smooth muscle tissues and in some, but not all, nonmuscle cells.
A chromosomal aberration involving TAF15/TAF2N is found in a form of extraskeletal myxoid chondrosarcomas (EMC). Translocation t(9;17)(q22;q11) with NR4A3.
ADP-ribosylated during genotoxic stress.
Belongs to the RNA polymerase II (Pol II) transcriptional multiprotein complex, together with the TATA-binding protein (TBP) and other TBP-associated factors (TAF(II)s). Binds SF1.
Dimethylated by PRMT1 at Arg-206 to asymmetric dimethylarginine. The methylation may favor nuclear localization and positive regulation of TAF15 transcriptional activity.
RNA and ssDNA-binding protein that may play specific roles during transcription initiation at distinct promoters. Can enter the preinitiation complex together with the RNA polymerase II (Pol II).
Ubiquitous. Observed in all fetal and adult tissues.
Restricted to cells of the myeloid series.
The N- and C-terminal barrels adopt an identical fold despite having only 13% of conserved residues.
The N-terminal region may be exposed to the interior of the granule, whereas the C-terminal portion may be embedded in the membrane. During phagocytosis and degranulation, proteases may be released and activated and cleave BPI at the junction of the N- and C-terminal portions of the molecule, providing controlled release of the N-terminal antibacterial fragment when bacteria are ingested.
The cytotoxic action of BPI is limited to many species of Gram-negative bacteria; this specificity may be explained by a strong affinity of the very basic N-terminal half for the negatively charged lipopolysaccharides that are unique to the Gram-negative bacterial outer envelope. Has antibacterial activity against the Gram-negative bacterium P.aeruginosa, this activity is inhibited by LPS from P.aeruginosa.
Catalyzes ATP-dependent efflux of cholesterol and taurocholate (PubMed:29300488). Interaction with ABCA1 potentiates cholesterol efflux to lipid-free APOA1, which regulates high-density lipoprotein cholesterol levels (PubMed:28882873).
Catalyzes ATP-dependent import of organic anions such as taurocholate and estrone sulfate (PubMed:12379217). In vitro, also imports ochratoxin A (PubMed:12379217). Also mediates cholesterol efflux independent of apolipoprotein, and plays a role in sphingomyelin production in oligodendrocytes (PubMed:23560799).
Cholesterol efflux is increased by extracellularly applied taurocholate.
Dofequidar (MS-209) and ochratoxin A inhibited the 17beta-estradiol 17-O-(beta-D-glucuronate) influx.
Interacts with ABCA1; this interaction potentiates cholesterol efflux.
Widely expressed with higher expression in heart, skeletal muscle and liver (PubMed:12379217, PubMed:28882873, PubMed:29300488). Highly expressed in the superior frontal white matter and inferior temporal white matter (PubMed:12379217).
Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes and Peyer's patches. Required for the generation of LTi (lymphoid tissue inducer) cells. Regulates thymocyte survival through DNA-binding on ROREs of target gene promoter regions and recruitment of coactivaros via the AF-2. Also plays a key role, downstream of IL6 and TGFB and synergistically with RORA, for lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. May also play a role in the pre-TCR activation cascade leading to the maturation of alpha/beta T-cells and may participate in the regulation of DNA accessibility in the TCR-J(alpha) locus.
Interacts (via AF-2 motif) with the coactivator NCOA2 (via LXXLL motif) (PubMed:20211758). Interacts with the corepressor NCOR1 (By similarity). Interacts with CRY1 (PubMed:22170608). Interacts (via AF-2 motif) with the coactivators NCOA1 and PPARGC1A (via LXXLL motif) (By similarity). Interacts (via AF-2 motif) with PROX1 (By similarity). Interacts with FOXP3 (PubMed:18368049). Interacts with NR0B2 (By similarity).
Isoform 1 is widely expressed in many tissues, including liver and adipose, and highly expressed in skeletal muscle. Isoform 2 is primarily expressed in immature thymocytes.
Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of cellular differentiation, immunity, peripheral circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism (PubMed:19381306, PubMed:19965867, PubMed:22789990, PubMed:26160376, PubMed:20203100). Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively (PubMed:19965867, PubMed:22789990). Recruits distinct combinations of cofactors to target gene regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates the circadian expression of clock genes such as CRY1, BMAL1 and NR1D1 in peripheral tissues and in a tissue-selective manner. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORC-mediated activation of the expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Involved in the regulation of the rhythmic expression of genes involved in glucose and lipid metabolism, including PLIN2 and AVPR1A (PubMed:19965867). Negative regulator of adipocyte differentiation through the regulation of early phase genes expression, such as MMP3. Controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. In liver, has specific and redundant functions with RORA as positive or negative modulator of expression of genes encoding phase I and Phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as SULT1E1. Also plays a role in the regulation of hepatocyte glucose metabolism through the regulation of G6PC1 and PCK1 (PubMed:19965867). Regulates the rhythmic expression of PROX1 and promotes its nuclear localization (PubMed:19381306, PubMed:19965867, PubMed:22789990, PubMed:26160376, PubMed:20203100). Plays an indispensable role in the induction of IFN-gamma dependent anti-mycobacterial systemic immunity (PubMed:26160376).
The AF-2 (activation function-2) motif is required for recruiting coregulators containing LXXLL motifs such as NCOA1 and NCOA2.
Expressed in fetal kidney, and also in adult pancreas and placenta. Not expressed in intestine, peripheral blood lymphocytes and ovary.
Putative transcription factor. Involved in hair formation and spermatogenesis. May function in the differentiation and/or maintenance of the urogenital system (By similarity).
Belongs to the PPP phosphatase family. PP-4 (PP-X) subfamily.
Methylation at the C-terminal Leu-307 is critical for interactions with regulatory subunits and functions in DNA repair.
Protein phosphatase that is involved in many processes such as microtubule organization at centrosomes, maturation of spliceosomal snRNPs, apoptosis, DNA repair, tumor necrosis factor (TNF)-alpha signaling, activation of c-Jun N-terminal kinase MAPK8, regulation of histone acetylation, DNA damage checkpoint signaling, NF-kappa-B activation and cell migration. The PPP4C-PPP4R1 PP4 complex may play a role in dephosphorylation and regulation of HDAC3. The PPP4C-PPP4R2-PPP4R3A PP4 complex specifically dephosphorylates H2AX phosphorylated on Ser-140 (gamma-H2AX) generated during DNA replication and required for DNA double strand break repair. Dephosphorylates NDEL1 at CDK1 phosphorylation sites and negatively regulates CDK1 activity in interphase (By similarity). In response to DNA damage, catalyzes RPA2 dephosphorylation, an essential step for DNA repair since it allows the efficient RPA2-mediated recruitment of RAD51 to chromatin.
Serine/threonine-protein phosphatase 4 (PP4) occurs in different assemblies of the catalytic and one or more regulatory subunits (PubMed:12668731, PubMed:18715871, PubMed:16085932, PubMed:18614045). Component of the PP4 complexes PPP4C-PPP4R1, PPP4C-PPP4R2, PPP4C-PPP4R2-PPP4R3A, PPP4C-PPP4R2-PPP4R3B and PPP4C-PPP4R4 (PubMed:12668731, PubMed:18715871, PubMed:16085932, PubMed:18614045). The PPP4C-PPP4R2 complex appears to be a tetramer composed of 2 molecules of PPP4C and 2 molecules of PPP4R2 (PubMed:12668731). Interacts with REL, NFKB1/p50 and RELA (PubMed:1336397). Interacts with SMN1 and GEMIN4 (PubMed:12668731). Interacts with IRS4 (phosphorylated) (PubMed:15331607). Interacts with SMEK1/PPP4R3A; the interaction requires PP4R2 (PubMed:16085932). Interacts with HDAC3 (PubMed:15805470).
Contains an N-terminal autoinhibitory domain. Activated by phosphorylation at Thr-812, inhibited by phosphorylation at Ser-924 and Ser-994 (By similarity).
Isoform 2 and isoform 3 are widely expressed. Isoform 2 highest levels are observed in fetal brain, and isoform 3 highest levels in pancreas, peripheral blood leukocytes, fetal brain and spleen.
Serine/threonine kinase which acts as a component of the MAP kinase signal transduction pathway (PubMed:20362554, PubMed:26732173). Once activated, acts as an upstream activator of the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases (PubMed:20362554, PubMed:26732173). May function in a signal transduction pathway that is activated by various cell stresses and leads to apoptosis (PubMed:20362554). Involved in phosphorylation of WNK4 in response to osmotic stress or hypotonic low-chloride stimulation via the p38 MAPK signal transduction cascade (PubMed:26732173).
Belongs to the class I-like SAM-binding methyltransferase superfamily. RNA methyltransferase RlmE family. TRM7 subfamily.
Found in fetal brain, lung, liver and kidney (PubMed:15162322). Widely expressed in adult tissue; with high expression in heart and liver, lower expression in skeletal muscle, kidney, and pancreas and also lowly expressed in brain and lung (PubMed:15342698). In the adult brain, expressed in amygdala, caudate nucleus, corpus callosum, hippocampus and thalamus (PubMed:15162322).
Inhibited by 2,6-diaminopurine (DAP); inhibition promotes UGA stop-codon readthrough during translation by misincorporation of tRNA(Trp) in the nascent polypeptide.
Interacts with WDR6; the interaction is direct, and required for 2'-O-methylation of position 34 in substrate tRNAs.
Methylates the 2'-O-ribose of nucleotides at positions 32 and 34 of the tRNA anticodon loop of substrate tRNAs (PubMed:25404562, PubMed:32558197, PubMed:32198346, PubMed:33771871, PubMed:26310293, PubMed:36720500). Requisite for faithful cytoplasmic translation (PubMed:32393790). Requires THADA for methylation of the nucleotide at position 32 of the anticodon loop of substrate tRNAs (PubMed:26310293, PubMed:25404562). Requires WDR6 for methylation of the nucleotide at position 34 of the anticodon loop of substrate tRNAs (PubMed:32558197, PubMed:33771871). Promotes translation efficiency of the UUU codon (PubMed:32558197). Plays a role in neurogenesis (PubMed:36720500). Required for expression of genes involved in neurogenesis, mitochondrial translation and energy generation, and lipid biosynthesis (PubMed:36720500, PubMed:33771871). Requisite for RNA-mediated gene silencing (PubMed:36720500). May modify position 32 in tRNA(Arg(ACG)), tRNA(Arg(CCG)), tRNA(Arg(UCG)), tRNA(Cys(GCA)), tRNA(Cys(ACA)), tRNA(Gln(CUG)), tRNA(Gln(UUG)), tRNA(Gly(CCC)), tRNA(Leu(CAG))/tRNA(Leu(CAA)), tRNA(Leu(A/IAG)), tRNA(Leu(UAG)), tRNA(Phe(GAA)), tRNA(Pro(AGG))/tRNA(Pro(CGG))/tRNA(Pro(UGG)) and tRNA(Trp(CCA)), and position 34 in tRNA(Phe(GAA)), tRNA(Leu(CAA)), tRNA(Sec(UCA)), and tRNA(Trp(CCA)) (PubMed:32558197, PubMed:32198346, PubMed:33771871, PubMed:26310293, PubMed:36720500).
Methylates the 2'-O-ribose of nucleotides at positions 32 and 34 of the tRNA anticodon loop of substrate tRNAs.
Beta-1,3-N-acetylglucosaminyltransferase involved in the synthesis of poly-N-acetyllactosamine. Catalyzes the initiation and elongation of poly-N-acetyllactosamine chains. Shows a marked preference for Gal(beta1-4)Glc(NAc)-based acceptors (PubMed:9892646). Probably constitutes the main polylactosamine synthase.
Interacts with B3GNT8; this interaction greatly increases B3GNT2 catalytic activity, independently of B3GNT8 enzymatic activity.
Was indicated as B3Gal-T6 in submitted DNA entries.
Autophosphorylated, Ser-21 is a minor site of autophosphorylation compared to Ser-491 and Thr-492 (By similarity). Phosphorylation at Ser-21 is regulated by light and activated by cAMP.
Farnesylation is required for full activity.
Inhibited by RCVRN, which prevents the interaction between GRK1 and RHO (By similarity). Inhibition is calcium-dependent (By similarity). Inhibited by phosphorylation of Ser-21.
Interacts (via N-terminus) with RCVRN (via C-terminus); the interaction is Ca(2+)-dependent (By similarity). Interacts (when prenylated) with PDE6D; this promotes release from membranes (By similarity). May form a complex composed of RHO, GRK1 and RCVRN in a Ca(2+)-dependent manner; RCVRN prevents the interaction between GRK1 and RHO (By similarity).
Retina-specific kinase involved in the signal turnoff via phosphorylation of rhodopsin (RHO), the G protein- coupled receptor that initiates the phototransduction cascade (PubMed:15946941). This rapid desensitization is essential for scotopic vision and permits rapid adaptation to changes in illumination (By similarity). May play a role in the maintenance of the outer nuclear layer in the retina (By similarity).
Retinal-specific. Expressed in rods and cones cells.
A chromosomal aberration involving MN1 may be a cause of acute myeloid leukemia (AML). Translocation t(12;22)(p13;q11) with ETV6.
Defects in MN1 involved in the development of meningiomas, slowly growing benign tumors derived from the arachnoidal cap cells of the leptomeninges, the soft coverings of the brain and spinal cord. Meningiomas are believed to be the most common primary tumors of the central nervous system in man.
Interacts with PBX1, PKNOX1, ZBTB24, E2F7, RING1.
Transcriptional activator which specifically regulates expression of TBX22 in the posterior region of the developing palate. Required during later stages of palate development for growth and medial fusion of the palatal shelves. Promotes maturation and normal function of calvarial osteoblasts, including expression of the osteoclastogenic cytokine TNFSF11/RANKL. Necessary for normal development of the membranous bones of the skull (By similarity). May play a role in tumor suppression (Probable).
Widely expressed in fetal and adult tissues. Highest expression is observed in fetal brain and skeletal muscle, and adult skeletal muscle.
Involved in the differentiation of haploid spermatids.
A chromosomal aberration involving BRWD3 can be found in patients with B-cell chronic lymphocytic leukemia (B-CLL). Translocation t(X;11)(q21;q23) with ARHGAP20 does not result in fusion transcripts but disrupts both genes.
Found in most adult tissues. Down-regulated in a majority of the B-CLL cases examined.
Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape.
The translocation involving this gene was originally published as t(X;11)(q13;23), but BRWD3 is localized to Xq21 and not to Xq13.
Although predicted to be a GTP-binding protein because of the presence of a Rho-like region, binds and hydrolyzes ATP. In contrast to Rho-like proteins, the conserved Asp residue in position 138 in the G4 region is replaced by an Asn, decreasing the ability to bind GTP.
Interacts with RAB9A and RAB9B (at lower level compared to RAB9A-binding). Interacts with M6PRBP1/TIP47.
Rab9-regulated ATPase required for endosome to Golgi transport. Involved in transport vesicle docking at the Golgi complex, possibly by participating in release M6PRBP1/TIP47 from vesicles to permit their efficient docking and fusion at the Golgi. Specifically binds Rab9, but not other Rab proteins. Has low intrinsic ATPase activity due to autoinhibition, which is relieved by Rab9.
Ubiquitous. Highly expressed in neural and cardiac tissues, pancreas, placenta and testis.
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:16210324, PubMed:23949095). Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes (Probable).
Expressed in testis, and to a lesser extent in placenta.
Phosphorylated at Tyr-78 by some member of the SRC family in response to H(2)O(2).
Expressed at higher level in adult thymus, brain and lung, than in corresponding fetal tissues. Expressed at lower level in spleen, heart, kidney and liver during development.
GAP activity stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2).
GTPase-activating protein (GAP) for ADP ribosylation factor 1 (ARF1). Hydrolysis of ARF1-bound GTP may lead to dissociation of coatomer from Golgi-derived membranes to allow fusion with target membranes.
Widely expressed. Highest expression in endocrine glands (pancreas, pituitary gland, salivary gland, and prostate) and testis with a much higher expression in the testis than in the ovary.
Although related to peptidase S1 family, the active site residues characteristic of serine proteases appear to be absent from this protein, which may therefore lack protease activity.
Belongs to the peptidase S1 family. Plasminogen subfamily.
Cleaved after Arg-483, probably by HPN/Hepsin, to yield the active form consisting of two disulfide-linked chains.
Dimer of an alpha chain and a beta chain linked by a disulfide bond. Interacts (via beta chain) with MST1R (via SEMA domain).
MST1 variant Cys-689 may be associated with inflammatory bowel disease (IBD), a chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is unsure whether Cys-689 itself or a variation in linkage disequilibrium with Cys-689 is responsible for the association with IBD.
Autophosphorylated, but autophosphorylation is not required for catalytic activity.
Interacts with Nkx1-2. Interacts with FAS and DAXX. Probably part of a complex consisting of HIPK3, FAS and FADD. Interacts with and stabilizes ligand-bound androgen receptor (AR) (By similarity). Interacts with UBL1/SUMO-1. Binds to NR5A1/SF1, SPEN/MINT and RUNX2.
Overexpressed in multidrug resistant cells. Highly expressed in heart and skeletal muscle, and at lower levels in placenta, pancreas, brain, spleen, prostate, thymus, testis, small intestine, colon and leukocytes. Not found in liver and lung.
Serine/threonine-protein kinase involved in transcription regulation, apoptosis and steroidogenic gene expression. Phosphorylates JUN and RUNX2. Seems to negatively regulate apoptosis by promoting FADD phosphorylation. Enhances androgen receptor-mediated transcription. May act as a transcriptional corepressor for NK homeodomain transcription factors. The phosphorylation of NR5A1 activates SF1 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. In osteoblasts, supports transcription activation: phosphorylates RUNX2 that synergizes with SPEN/MINT to enhance FGFR2-mediated activation of the osteocalcin FGF-responsive element (OCFRE).
Expressed in spleen, prostate, testis, uterus, small intestine, colon, peripheral blood leukocytes, heart, placenta, lung, liver, skeletal muscle, and pancreas Isoform 2 is ubiquitously expressed (at lower levels than isoform 1).
Functions as sorting adapter in different signaling pathways to facilitate downstream signaling leading to type I interferon induction (PubMed:16603631, PubMed:16757566, PubMed:25385819, PubMed:25825441). In TLR4 signaling, physically bridges TLR4 and TICAM1 and functionally transmits signal to TICAM1 in early endosomes after endocytosis of TLR4. In TLR2 signaling, physically bridges TLR2 and MYD88 and is required for the TLR2-dependent movement of MYD88 to endosomes following ligand engagement (PubMed:25385819). Involved in IL-18 signaling and is proposed to function as a sorting adapter for MYD88 in IL-18 signaling during adaptive immune response (PubMed:22685567). Forms a complex with RAB11FIP2 that is recruited to the phagosomes to promote the activation of the actin-regulatory GTPases RAC1 and CDC42 and subsequent phagocytosis of Gram-negative bacteria (PubMed:30883606).
Homodimer. Interacts with TLR4, TICAM1, IRF3 and IRF7 in response to LPS. Interacts with IL1R1, IL1RAP, IRAK2, IRAK3 and TRAF6. Interacts with protein kinase-inactive mutants of IRAK1 and IRAK4. Isoform 1 interacts with isoform 2; the interaction occurs in late endosomes and disrupts the interaction between isoform 1 and TICAM1. Interacts with MYD88; the interaction decreases after IL-18 stimulation in a time-dependent manner. Interacts with IL18R1 and IL18RAP. Interacts with TLR2 (PubMed:25385819). Interacts with RAB11FIP2 (PubMed:30883606).
Isoform 1 is myristoylated. Required for membrane association which is critical for its ability to initiate efficient signaling.
Phosphorylated by PRKCE in response to LPS. Phosphorylation is essential for its function. It is depleted from the membrane upon phosphorylation. Tyrosine phosphorylation is inhibited by phosphatase PTPN4.
Proposed to inhibit LPS-TLR4 signaling at the late endosome by interaction with isoform 1 thereby disrupting the association of isoform 1 with TICAM1. May be involved in TLR4 degradation in late endosomes.
The TIR domain mediates the interaction with TRAF6 and MYD88.
Belongs to the actin-binding proteins ADF family. GMF subfamily.
Phosphorylated; stimulated by phorbol ester.
This protein causes differentiation of brain cells, stimulation of neural regeneration, and inhibition of proliferation of tumor cells.
Belongs to the chibby family. SPERT subfamily.
Homodimer. Binds to NEK1 (By similarity).
Homotetramer (PubMed:24698160, PubMed:25619277, PubMed:9753690). Identified in complex with ABRAXAS2 and the other subunits of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985).
Inhibited by tetrahydrofolate concentrations above 40 uM.
Interconversion of serine and glycine (PubMed:8505317, PubMed:24698160).
Interacts with the Fc portion of IgG and with MUC2.
Mainly expressed in placenta and colon epithelium. Expressed in thyroid, and down-regulated in thyroid carcinomas. Present in serum, with higher levels in patients with various autoimmune diseases (at protein level).
May be involved in the maintenance of the mucosal structure as a gel-like component of the mucosa.
The N-terminal IgGFc-binding region is primate-specific.
Acts as a hormone in response to different stimuli like anti-inflammatory signals, such as IL17A, or gut microbiome. Is secreted by different cell types to activate its receptor EXTL3 and induce cell specific signaling pathways. Induced by IL17A in keratinocytes, regulates keratinocyte proliferation and differentiation after skin injury. In parallel, inhibits skin inflammation through the inhibition of inflammatory cytokines such as IL6 and TNF. Induced by IL22 in lung epithelial cells, inhibits cytokine production and regulates allergic airway inflammation. Induced in small intestine by inulin-enriched diet and Lactobacillus gasseri enriched microbiome, plays a role in the improvement of gut barrier function, the regulation of energy balance and glucose levels. Modulates microbiota composition in duodenal contents. Produced by nociceptor in response to endotoxins, prevents endotoxic death by targeting kynurenine pathway in microglia.
Bactericidal C-type lectin which acts exclusively against Gram-positive bacteria and mediates bacterial killing by binding to surface-exposed carbohydrate moieties of peptidoglycan. Restricts bacterial colonization of the intestinal epithelial surface and consequently limits activation of adaptive immune responses by the microbiota.
Forms a hexameric membrane-permeabilizing oligomeric pore on membrane phospholipids. The hexamer is formed by three dimers related by helical symmetry. Forms filaments, filamentation traps pore complexes and limits damage to host cells. Interacts with EXTL3.
Has bactericidal activity against L.monocytogenes and methicillin-resistant S.aureus.
Lipopolysaccharide inhibits pore-forming activity, explaining why is bactericidal for Gram-positive but not Gram-negative bacteria.
Predominantly expressed in pancreas, where it may be restricted to exocrine pancreas. Moderate expression levels in testis and weak in heart, kidney and placenta.
Proteolytic processing by trypsin removes an inhibitory N-terminal propeptide and is essential for peptidoglycan binding and antibacterial activity.
The EPN motif is essential for recognition of the peptidoglycan carbohydrate backbone and for efficient bacterial killing with Glu-114 playing a key role in peptidoglycan binding and bactericidal activity.
Expressed at low levels in adult lung, brain and duodenum with moderate levels in testis. Highly expressed in fetal cochlea.
May play a role in actin filament architecture in developing stereocilia of sensory cells.
Interacts with CGAS (PubMed:30135424). Interacts with RIGI (PubMed:30193849). Interacts with IFIH1/MDA5 (PubMed:30193849).
Nucleic acid-binding protein involved in innate immune response to DNA and RNA viruses (PubMed:30193849, PubMed:30135424). Binds DNA and RNA in the cytoplasm and acts by promoting recognition of viral nucleic acids by virus sensors, such as RIGI, IFIH1/MDA5 and CGAS (PubMed:30193849, PubMed:30135424). Acts as a co-sensor for recognition of double-stranded DNA (dsDNA) by cGAS in the cytoplasm, thereby playing a role in innate immune response to cytosolic dsDNA and DNA virus (PubMed:30135424). Binds dsDNA and probably acts by promoting sensing of dsDNA by CGAS, leading to enhance CGAS oligomerization and activation (PubMed:30135424). Promotes sensing of viral RNA by RIGI-like receptors proteins RIGI and IFIH1/MDA5 via two mechanisms: binds double-stranded RNA (dsRNA), enhancing the binding of RIGI and IFIH1/MDA5 to dsRNA and promotes 'Lys-63'-linked ubiquitination and subsequent activation of RIGI and IFIH1/MDA5 (PubMed:30193849).
Interacts with RAB11FIP5 and STXBP6. Interacts with SGSM1, SGSM2 and SGSM3 (By similarity). Interacts with EXOC6 in a GTP-dependent manner (By similarity). Interacts with RAB11FIP1, RAB11FIP2, RAB11FIP3 (via its C-terminus) and RAB11FIP4. Forms a complex with RAB11FIP3 and dynein intermediate chain DYNC1LI1; the interaction between RAB11A1 and RAB11FIP3 is direct; the complex regulates endocytic trafficking (PubMed:20026645). Interacts with EVI5; EVI5 and RAB11FIP3 may be mutually exclusive and compete for binding RAB11A. Interacts with RAB11FIP5 (By similarity). Interacts with STXBP6 (By similarity). Interacts with VIPAS39. Interacts with MYO5B. Found in a complex with MYO5B and CFTR. Interacts with NPC1L1. Interacts (GDP-bound form) with ZFYVE27 (PubMed:21976701, PubMed:17082457). Interacts with BIRC6/bruce. May interact with TBC1D14. Interacts with UNC119; in a cell cycle-dependent manner. GDP-bound and nucleotide-free forms interact with SH3BP5 (PubMed:26506309, PubMed:30217979). Interacts (GDP-bound form) with KIF5A in a ZFYVE27-dependent manner (PubMed:21976701). Interacts (GDP-bound form) with RELCH (By similarity). Found in a complex composed of RELCH, OSBP1 and RAB11A (By similarity). Interacts with TBC1D12 (PubMed:28384198). Interacts with DEF6 (PubMed:31308374). Interacts with VPS33B (PubMed:28017832). Interacts with ATP9A (PubMed:36604604). Forms a heterotetramer with RAB11FIP3; the GTP-bound form is preferred for binding (PubMed:26258637). Forms a complex with Rabin8/RAB3IP and RAB11FIP3, probably a heterohexamer with two of each protein subunit, where Rabin8/RAB3IP and RAB11FIP3 simultaneously bind to RAB11A; the complex promotes preciliary trafficking and cilia growth (PubMed:26258637, PubMed:31204173). Forms a complex containing RAB11A, ASAP1, Rabin8/RAB3IP, RAP11FIP3 and ARF4; the complex promotes preciliary trafficking; the complex binds to RHO in photoreceptor cells and promotes RHO ciliary transport (PubMed:25673879, PubMed:26258637). Interacts (GTP-bound form) with WDR44; the interaction prevents RAB11A-RAB3IP-RAB11FIP3 complex formation (PubMed:10077598, PubMed:31204173, PubMed:32344433).
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. The small Rab GTPase RAB11A regulates endocytic recycling (PubMed:20026645). Forms a functional Rab11/FIP3/dynein complex that regulates the movement of peripheral sorting endosomes (SE) along microtubule tracks toward the microtubule organizing center/centrosome, generating the endosomal recycling compartment (ERC) (PubMed:20026645). Acts as a major regulator of membrane delivery during cytokinesis (PubMed:15601896). Together with MYO5B and RAB8A participates in epithelial cell polarization. Together with RAB3IP, RAB8A, the exocyst complex, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis. Together with MYO5B participates in CFTR trafficking to the plasma membrane and TF (Transferrin) recycling in nonpolarized cells. Required in a complex with MYO5B and RAB11FIP2 for the transport of NPC1L1 to the plasma membrane. Participates in the sorting and basolateral transport of CDH1 from the Golgi apparatus to the plasma membrane. Regulates the recycling of FCGRT (receptor of Fc region of monomeric Ig G) to basolateral membranes. May also play a role in melanosome transport and release from melanocytes. Promotes Rabin8/RAB3IP preciliary vesicular trafficking to mother centriole by forming a ciliary targeting complex containing Rab11, ASAP1, Rabin8/RAB3IP, RAB11FIP3 and ARF4, thereby regulating ciliogenesis initiation (PubMed:25673879, PubMed:31204173). On the contrary, upon LPAR1 receptor signaling pathway activation, interaction with phosphorylated WDR44 prevents Rab11-RAB3IP-RAB11FIP3 complex formation and cilia growth (PubMed:31204173). Participates in the export of a subset of neosynthesized proteins through a Rab8-Rab10-Rab11-endososomal dependent export route via interaction with WDR44 (PubMed:32344433).
Decreases the sensitivity of PDP1 to magnesium ions, and this inhibition is reversed by the polyamine spermine.
According to some authors, 4 of the identified SERPIN11 transcripts contained coding sequences that could be distinguished by different combinations of single nucleotide polymorphisms (designated SERPINB11a, SERPINB11b, SERPINB11c, and SERPINB11d), and one contained a nonsense mutation introducing a premature stop codon in position 90 identified in the official genome sequence (SERPINB11f) (PubMed:17562709). The sequence displayed here corresponds to SERPINB11a.
Detected in a restricted number of tissues, including lung, placenta, prostate, and tonsil.
Has no serine protease inhibitory activity, probably due to mutations in the scaffold impairing conformational change.
Mutations in the scaffold leading to either a stop codon instead of a Glu at position 90, an Arg instead of the well conserved Trp at position 188, or a Pro instead of Ser at position 303 lead to the loss of inhibitory activity.
Mitochondrial membrane carrier protein that mediates the import of NAD(+) into mitochondria (PubMed:32906142, PubMed:33262325, PubMed:33087354). Mitochondrial NAD(+) is required for glycolysis and mitochondrial respiration (PubMed:32906142, PubMed:33262325, PubMed:33087354). Compared to SLC25A52, SLC25A51-mediated transport is essential for the import of NAD(+) in mitochondria (PubMed:32906142). The transport mechanism, uniport or antiport, its electrogenicity and substrate selectivity, remain to be elucidated.
Present in scalp but not in hairless skin. Abundantly expressed in the differentiating cortex of growing (anagen) hair. Expression is restricted to the keratinocytes of the hair cortex and is absent from inner root sheath and medulla.
Detected in photoreceptor outer segments in the retina (at protein level).
Retinol dehydrogenase with a clear preference for NADP. Converts all-trans-retinal to all-trans-retinol. May play a role in the regeneration of visual pigment at high light intensity (By similarity).
Retinol dehydrogenase with a clear preference for NADP. Converts all-trans-retinal to all-trans-retinol. May play a role in the regeneration of visual pigment at high light intensity.
Belongs to the eukaryotic ATPase epsilon family.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). CF(0) seems to have nine subunits: a, b, c, d, e, f, g, F6 and 8 (or A6L). Component of an ATP synthase complex composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5PD, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and ATP5MJ (By similarity).
Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(1) domain and of the central stalk which is part of the complex rotary element. Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits (By similarity).
Highly expressed in testis, colon and stomach. Weakly expressed in other tissues.
Transfers N-acetylgalactosamine (GalNAc) from UDP-GalNAc to N-acetylglucosamine-beta-benzyl with a beta-1,4-linkage to form N,N'-diacetyllactosediamine, GalNAc-beta-1,4-GlcNAc structures in N-linked glycans and probably O-linked glycans. Mediates the N,N'-diacetyllactosediamine formation on gastric mucosa.
Belongs to the DapA family. NanA subfamily.
Catalyzes the cleavage of N-acetylneuraminic acid (sialic acid) to form pyruvate and N-acetylmannosamine via a Schiff base intermediate (PubMed:33895133). It prevents sialic acids from being recycled and returning to the cell surface (PubMed:33895133). Involved in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway (PubMed:22692205, PubMed:33895133). Although human is not able to catalyze formation of Neu5Gc due to the inactive CMAHP enzyme, Neu5Gc is present in food and must be degraded (Probable).
Isoform 2 is expressed in placenta, liver, kidney, pancreas, spleen, thymus, ovary, small intestine and peripheral blood leukocyte.
BRCT domains are necessary for its targeting to ionizing radiation-induced nuclear foci.
Interacts (via N-terminus) with SLF2; this interaction links RAD18 to the SMC5-SMC6 complex (PubMed:25931565, PubMed:36373674). Interacts (via BRCT domains) with RAD18; this interaction occurs in a SLF2-independent manner (PubMed:25931565). Interacts with SMC6 (PubMed:25931565). Interacts (via BRCT domains) with RAD18 (via C-terminus and phosphorylated form); this interaction is required for efficient repair of UV-induced DNA damage (By similarity).
Plays a role in the DNA damage response (DDR) pathway by regulating postreplication repair of UV-damaged DNA and genomic stability maintenance (PubMed:25931565). The SLF1-SLF2 complex acts to link RAD18 with the SMC5-SMC6 complex at replication-coupled interstrand cross-links (ICL) and DNA double-strand breaks (DSBs) sites on chromatin during DNA repair in response to stalled replication forks (PubMed:25931565). Promotes the recruitment of SLF2 and the SMC5-SMC6 complex to DNA lesions (PubMed:25931565, PubMed:36373674).
Highly expressed in kidney, and to a lower extent in ovary.
Associates with the PRC2 complex, which consists of the core components EED, EZH1 or EZH2, SUZ12, and RBBP4, and various combinations of accessory subunits including AEBP2, JARID2, PHF19, MTF2 and EPOP (PubMed:29499137, PubMed:31959557). Found in a monomeric PRC2.2 (class 2) complex consisting of at least SUZ12, RBBP4, AEBP2 and JARID2 (PubMed:29499137). Facilitates nucleosome binding of the PRC2 complex (PubMed:29499137). Interacts with SUZ12 (via C2H2-type zinc finger domain); the interaction is direct; competes with EPOP for SUZ12 binding (PubMed:29499137). Interacts with histone methyltransferases EHMT1/GLP1 and EHMT2/G9a (By similarity). Interacts with GATA4 (via the N-terminal region) (By similarity). Interacts with NKX2-5 (via the C-terminal region) (By similarity). Interacts with RB1 (By similarity). Interacts with ZNF496 (By similarity). Interacts with ESRRB (By similarity).
During embryogenesis, predominantly expressed in neurons and particularly in dorsal root ganglion cells.
Regulator of histone methyltransferase complexes that plays an essential role in embryonic development, including heart and liver development, neural tube fusion process and hematopoiesis (PubMed:20075857). Acts as an accessory subunit for the core PRC2 (Polycomb repressive complex 2) complex, which mediates histone H3K27 (H3K27me3) trimethylation on chromatin (PubMed:20075857, PubMed:29499137, PubMed:31959557). Binds DNA and mediates the recruitment of the PRC2 complex to target genes in embryonic stem cells, thereby playing a key role in stem cell differentiation and normal embryonic development (PubMed:20075857). In cardiac cells, it is required to repress expression of cyclin-D1 (CCND1) by activating methylation of 'Lys-9' of histone H3 (H3K9me) by the GLP1/EHMT1 and G9a/EHMT2 histone methyltransferases (By similarity). Also acts as a transcriptional repressor of ANF via its interaction with GATA4 and NKX2-5 (By similarity). Participates in the negative regulation of cell proliferation signaling (By similarity). Does not have histone demethylase activity (By similarity).
The ARID domain is required to target the PRC2 complex to its target genes.
The GSGFP motif is required for the interaction with SUZ12.
Forms a heterotetramer with XRCC4 (PubMed:31548606). The interaction with XRCC4 is direct, involves LIG4-free XRCC4 and leads to relocalization of IFFO1 at the double-strand break (DSB) sites (PubMed:31548606). Interacts with LMNA; the interaction forms an interior nucleoskeleton and the recruitment to DNA double-strand breaks (PubMed:31548606).
Nuclear matrix protein involved in the immobilization of broken DNA ends and the suppression of chromosome translocation during DNA double-strand breaks (DSBs) (PubMed:31548606). Interacts with the nuclear lamina component LMNA, resulting in the formation of a nucleoskeleton that relocalizes to the DSB sites in a XRCC4-dependent manner and promotes the immobilization of the broken ends, thereby preventing chromosome translocation (PubMed:31548606). Acts as a scaffold that allows the DNA repair protein XRCC4 and LMNA to assemble into a complex at the DSB sites (PubMed:31548606).
Expressed in columnar and transitional epithelia, mononuclear cells, and ganglion cells (at protein level). Widely expressed, with highest levels in thymus and placenta and lowest in peripheral blood, skeletal muscle and kidney.
Part of a complex with ERBB2 and EGFR. Part of a complex with phosphorylated EGFR and GRB2. Interacts with phosphorylated EGFR and PDGFR, maybe indirectly. Interacts with GRB2.
Phosphorylates PtdIns and PtdIns4P with a preference for PtdIns (PubMed:10805725, PubMed:9830063, PubMed:11533253). Does not phosphorylate PtdIns(4,5)P2 (PubMed:9830063). May be involved in EGF and PDGF signaling cascades (PubMed:10805725).
Interacts (via cytoplasmic C-terminal domain) with USP4; the interaction is direct (PubMed:16339847). May interact with DRD4 (PubMed:18832607). Interacts with NECAB2 (PubMed:17689978). Interacts (via cytoplasmic C-terminal domain) with GAS2L2; interaction enhances receptor-mediated adenylyl cyclase activity (By similarity).
Receptor for adenosine (By similarity). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase (By similarity).
The cytoplasmic C-terminal domain is necessary for targeting the non-ubiquitinated form of this protein to the cell surface.
Ubiquitinated. Deubiquitinated by USP4; leading to stabilization and expression at the cell surface.
Constitutively phosphorylated by PKC on serine/threonine in A431 cells.
Expressed in placenta, prostate and thymus.
Interacts with VIM and HINT1 (PubMed:7644499). Interacts with IKBKG/NEMO (PubMed:27695001). Interacts with STING1 (PubMed:29038422).
Plays a crucial role in the regulation of macrophage activation in response to viral or bacterial infections within the respiratory tract. Mechanistically, TRIM29 interacts with IKBKG/NEMO in the lysosome where it induces its 'Lys-48' ubiquitination and subsequent degradation. In turn, the expression of type I interferons and the production of pro-inflammatory cytokines are inhibited. Additionally, induces the 'Lys-48' ubiquitination of STING1 in a similar way, leading to its degradation.
Down-regulated in response to toll-like receptor ligand.
Interacts with IKBKB; disrupts IKBKB-IKBKG interaction preventing I-kappa-B-kinase (IKK) core complex formation and leading to a decrease of IKBKB phosphorylation and NF-kappaB activation (PubMed:27426725). Interacts with CHUK (PubMed:27426725).
Negatively regulates Toll-like receptor-mediated NF-kappa-B signaling by disrupting IKK core complex formation through interaction with IKBKB.
Autophosphorylated on Tyr-749, Tyr-753 and Tyr-754 in the activation loop allowing full activity. Autophosphorylated on Tyr-872 leading to recruitment of downstream partners of the signaling cascade such as PLCG2 (By similarity).
Interacts (upon activation) with TNK2; stimulates TNK2 autophosphorylation. Interacts (via N-terminus) with extracellular ligands LGALS3, TUB, TULP1 and GAS6 (By similarity). Interacts with VAV1 in a phosphotyrosine-independent manner. Interacts with TIMD4; this interaction enhances TIMD4-mediated efferocytosis (PubMed:32640697).
Not expressed in normal B- and T-lymphocytes but is expressed in numerous neoplastic B- and T-cell lines. Highly expressed in testis, ovary, prostate, lung, and kidney, with lower expression in spleen, small intestine, colon, and liver.
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment (PubMed:32640697). Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Also plays an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3.
Component of a calcium channel complex consisting of a pore-forming alpha subunit (CACNA1C) and the ancillary subunits CACNB3 and CACNA2D1 (PubMed:29742403). The channel complex contains alpha, beta, gamma and delta subunits in a 1:1:1:1 ratio (Probable). Interacts with CACNA2D4 (PubMed:12181424). Interacts with FASLG (PubMed:19807924). Interacts with CBARP; prevents the interaction of CACNB3 with the alpha subunit CACNA1C thereby negatively regulating the activity of the corresponding calcium channel (By similarity).
Expressed mostly in brain, colon and ovary.
Regulatory subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:8119293). Increases CACNA1B peak calcium current and shifts the voltage dependencies of channel activation and inactivation (By similarity). Increases CACNA1C peak calcium current and shifts the voltage dependencies of channel activation and inactivation (By similarity).
Despite its name, it does not contain a R3H domain.
3 different light chains, LC1, LC2 and LC3, can associate with MAP1A and MAP1B proteins. Interacts with TIAM2. Interacts with guanylate kinase-like domain of DLG1, DLG2, DLG4. Binds to CSNK1D (By similarity). MAP1 light chain LC2: Interacts with ELAVL4 (By similarity).
LC2 is generated from MAP1A by proteolytic processing.
Structural protein involved in the filamentous cross-bridging between microtubules and other skeletal elements.
The basic region containing the repeats may be responsible for the binding of MAP1A to microtubules.
(Microbial infection) Interacts (via SH3 domains) with Chikungunya virus non-structural protein 3 (via C-terminus); this interaction plays a role in initiation of viral replication.
Adapter protein involved in regulating diverse signal transduction pathways. Involved in the regulation of endocytosis and lysosomal degradation of ligand-induced receptor tyrosine kinases, including EGFR and MET/hepatocyte growth factor receptor, through an association with CBL and endophilins. The association with CBL, and thus the receptor internalization, may be inhibited by an interaction with PDCD6IP and/or SPRY2. Involved in regulation of ligand-dependent endocytosis of the IgE receptor. Attenuates phosphatidylinositol 3-kinase activity by interaction with its regulatory subunit (By similarity). May be involved in regulation of cell adhesion; promotes the interaction between TTK2B and PDCD6IP. May be involved in the regulation of cellular stress response via the MAPK pathways through its interaction with MAP3K4. Is involved in modulation of tumor necrosis factor mediated apoptosis. Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape and migration. Has an essential role in the stimulation of B cell activation (PubMed:29636373).
Can self-associate and form homotetramers. Interacts with CD2, F-actin capping protein, PIK3R3, GRB2, EGFR, MET, BLNK, MAP3K4, PDCD6IP, SPRY2, ARHGAP17, ARHGAP27, MAGI2, CRK, BCAR1, SOS1, ASAP1, ARAP3, HIP1R, SYNJ2, INPP5D and STAP1. Interacts with CBL and CBLB, but does not interact with CBLC. Two molecules of SH3KBP1 seem to bind through their respective SH3 1 domain to one molecule of CBLB. The interaction with CBL or CBLB and EGFR is increased upon EGF stimulation. The interaction with CBL is attenuated by PDCD6IP. Interacts through its proline-rich region with the SH3 domain of endophilins SH3GL1, SH3GL2 and SH3GL3. The SH3KBP1-endophilin complex seems to associate with a complex containing the phosphorylated receptor (EGFR or MET) and phosphorylated CBL. Probably associates with ASAP1 and phosphorylated EGFR. Probably part of a complex consisting of at least SH3KBP1, ASAP1 and ARAP3. Interacts with focal adhesion kinases PTK2/FAK1 and PTK2B/PYK2, probably as a dimer. Interacts with DAB2 and probably associates with chathrin through its interaction with DAB2. Part of a complex consisting of SH3KBP1, DAB2, and clathrin heavy chain. DAB2 and clathrin dissociate from SH3KBP1 following growth factor treatment, enabling interaction with CBL. Interacts with DDN and probably associates with MAGI2 through its interaction with DDN. Interacts with the SH3 domains of SRC tyrosine-protein kinases SRC, LCK, LYN, FGR, FYN and HCK. Interacts with TRADD, BIRC2, TRAF1, TRAF2 and TNFR1, and the association with a TNFR1-associated complex upon stimulation with TNF-alpha seems to be mediated by SRC. Interacts (via SH3 domains) with SHKBP1 (via PXXXPR motifs) (By similarity). Interaction with CBL is abolished in the presence of SHKBP1 (By similarity). Interacts (via SH3 domains) with ZFP36 (via extreme C-terminal region) (PubMed:20221403). Interacts with MAP3K4; this interaction enhances the association with ZFP36 (PubMed:20221403).
Interacts with CD2 cytoplasmic tail and does not interact with F-actin.
Monoubiquitinated by CBL and CBLB after EGF stimulation; probably on its C-terminus.
Ubiquitously expressed. Also expressed in some cancer cell lines.
Belongs to the complex I 30 kDa subunit family.
Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits (PubMed:12611891). Interacts with NDUFAF3 (PubMed:19463981). Interacts with RAB5IF (PubMed:31536960). Found in subcomplexes containing subunits NDUFS2, MT-ND1 and NDUFA13 (PubMed:17209039, PubMed:18826940).
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:14729820, PubMed:30140060). Essential for the catalytic activity and assembly of complex I (PubMed:14729820, PubMed:24028823, PubMed:30140060).
Expressed in brain. Expressed in the spinal dorsal horn with especially strong expression in lamina IIi; found in excitory synaptic boutons and in ependymal cells (at protein level).
Interacts (calcium-dependent) with ADORA2A and GRM5.
May act as a signaling scaffold protein that senses intracellular calcium. Can modulate ligand-induced internalization of ADORA2A and coupling efficiency of mGluR5/GRM5; for both receptors may regulate signaling activity such as promoting MAPK1/3 (ERK1/2) activation.
Homotrimer (By similarity). Interacts with MYO18A (PubMed:25965346).
Isoform I, isoform II and isoform III are expressed in monocyte-derived macrophages. Isoform I and isoform II are expressed in the liver, placenta and brain.
Membrane glycoproteins implicated in the pathologic deposition of cholesterol in arterial walls during atherogenesis. Two types of receptor subunits exist. These receptors mediate the endocytosis of a diverse group of macromolecules, including modified low density lipoproteins (LDL) (PubMed:2251254). Isoform III does not internalize acetylated LDL (PubMed:9548586).
The disease may be caused by variants affecting the gene represented in this entry. Genetic variants in MSR1 have been found in individuals with Barrett esophagus and are thought to contribute to disease susceptibility.
The disease may be caused by variants affecting the gene represented in this entry. MSR1 variants may play a role in susceptibility to prostate cancer. MSR1 variants have been found in individuals with prostate cancer and co-segregate with the disease in some families.
E3 ubiquitin-protein ligase that plays a role in different processes including cell differentiation, receptor recycling or regulation of inflammation (PubMed:28593998, PubMed:33996800, PubMed:37158982). Mediates the ubiquitination of AKT1 and GLUL, thereby playing a role in neuron cells differentiation. Plays a role in the establishment and maintenance of neuronal transmission and plasticity. Regulates Schwann cells differentiation by mediating ubiquitination of GLUL. Promotes neurodegeneration by mediating 'Lys-48'-linked polyubiquitination and subsequent degradation of AKT1 in axons: degradation of AKT1 prevents AKT1-mediated phosphorylation of GSK3B, leading to GSK3B activation and phosphorylation of DPYSL2/CRMP2 followed by destabilization of microtubule assembly in axons. Ubiquitinates the Na(+)/K(+) ATPase alpha-1 subunit/ATP1A1 and thereby influences its endocytosis and/or degradation (PubMed:22797923). Controls ligand-induced EGFR signaling via mediating receptor ubiquitination and recruitment of the ESCRT machinery (PubMed:33996800). Acts as a negative feedback mechanism controlling TLR3 trafficking by mediating TLR3 'Lys-63'-linked polyubiquitination to reduce type I IFN production (PubMed:37158982). Modulates inflammation by promoting caveolin-1/CAV1 ubiquitination and degradation to regulate TLR4-activated immune response (PubMed:28593998).
Expressed primarily in the nervous system, with expression higher in developing brain relative to adult. Expressed at low levels in testis and thymus.
Interacts with AKT1, GLUL and TUBB2A (By similarity). Interacts with ZNRF2 (PubMed:22797923). Interacts (via its RING domain) with UBE2N (PubMed:29626159). Interacts (when phosphorylated) with YWHAE (PubMed:22797923).
N-myristoylation targets ZNRF1 to intracellular membranes.
Phosophorylated by SRC at Tyr-103; leading to 'Lys-63'-linked ubiquitination of TLR3, lysosomal trafficking and degradation.
Abundantly expressed in testis, but is also present in several tissues at a much lower level.
Acts as a regulator of tubulin stability.
Involved in spermatozoa motility (PubMed:30122540, PubMed:30122541). May also regulate cilium motility through its role in the assembly of the axonemal radial spokes (By similarity).
Isoform 1 is highly expressed in testis and, at lower levels, in lung. Very low levels are detected in kidney and brain (PubMed:30122540). In testis, expressed in spermatozoa (at protein level) (PubMed:30122540, PubMed:30122541). Isoform 2 is not detected in testis, lung, kidney, nor in brain (PubMed:30122540).
Expressed in colon, prostate, small intestine, testis and spleen, with lower expression in thymus, ovary, and peripheral blood leukocytes. Up-regulated expression in prostate, breast, and bladder cancer, but not in lung and colon cancer.
Epidermis-specific type I keratin involved in wound healing. Involved in the activation of follicular keratinocytes after wounding, while it does not play a major role in keratinocyte proliferation or migration. Participates in the regulation of epithelial migration by inhibiting the activity of SRC during wound repair.
Heterodimer of a type I and a type II keratin. KRT6 isomers associate with KRT16 and/or KRT17 (By similarity). Interacts with TCHP (PubMed:15731013).
There are at least six isoforms of human type II keratin-6 (K6), K6A being the most abundant representing about 77% of all forms found in epithelia.
Acts as a negative regulator of apoptosis.
Acts as a positive regulator of apoptosis.
Expressed at higher levels in the embryonic lung, liver and kidney than in the heart and brain. In adults, higher level expression is seen in the placenta, lung, kidney, and pancreas than in the heart, brain, liver and skeletal muscle.
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a p18 subunit and a p12 subunit (PubMed:12920126). Forms a complex named the PIDDosome with PIDD1 and CRADD (PubMed:9044836, PubMed:8985253, PubMed:15073321, PubMed:16652156). Interacts with NOL3 (via CARD domain); inhibits CASP2 activity in a phosphorylation-dependent manner (PubMed:9560245).
Involved in the activation cascade of caspases responsible for apoptosis execution. Might function by either activating some proteins required for cell death or inactivating proteins necessary for cell survival (PubMed:15073321). Associates with PIDD1 and CRADD to form the PIDDosome, a complex that activates CASP2 and triggers apoptosis in response to genotoxic stress (PubMed:15073321).
May function as an endogenous apoptosis inhibitor that antagonizes caspase activation and cell death.
The CARD domain mediates a direct interaction with CRADD.
The mature protease can process its own propeptide, but not that of other caspases.
Genetic variants in SERPINA7 influence the serum levels of thyroxine-binding globulin and define the thyroxine-binding globulin quantitative trait locus (TBGQTL) [MIM:300932]. Individuals with low or high serum levels of thyroxine-binding globulin show, respectively, reduced or elevated protein-bound iodine but are euthyroid and do not manifest major metabolic alterations (PubMed:1294376, PubMed:1515456, PubMed:1901689, PubMed:1906047, PubMed:2155256, PubMed:2501669). Two qualitative TBG variants occur in particular populations. TBG-A is found in 40% of Australian aborigines, it has reduced affinity for thyroxine and triiodothyroxine and increased susceptibility to inactivation by heat or acid (PubMed:2495303). TBG-S ('s' for slow shift on isoelectic focusing) is found in blacks, Eskimos, Melanesians, Polynesians and Indonesians, but not in Caucasians; TBG-S is slightly more thermolabile (PubMed:2115061).
Major thyroid hormone transport protein in serum.
Belongs to the transglutaminase-like superfamily.
Probable cytoskeleton-associated protease required for normal muscle growth. Involved in function, maturation and stabilization of the neuromuscular junction. May act by cleaving muscle-specific proteins such as FLNC (By similarity).
Monomer; predominantly monomeric at low salt concentrations. Homooligomer; predominantly homooligomeric at high salt concentrations. Homodimer. Homotetramer. Interacts with MRPL13, MRPL20, MRPL28, MRPL48, MRPL49 and MRPL51. Associates preferentially as a dimer with the large ribosomal subunit 39S of the mitochondrial ribosome.
Required for the insertion of integral membrane proteins into the mitochondrial inner membrane. Essential for the activity and assembly of cytochrome oxidase. Required for the correct biogenesis of ATP synthase and complex I in mitochondria.
Exhibits both long-chain fatty acids (LCFA) transport activity and acyl CoA synthetase towards very long-chain fatty acids (PubMed:21768100, PubMed:10198260). Shows a preference for generating CoA derivatives of n-3 fatty acids, which are preferentially trafficked into phosphatidylinositol (PubMed:21768100).
Exhibits long-chain fatty acids (LCFA) transport activity but lacks acyl CoA synthetase towards very long-chain fatty acids.
Expressed in liver, kidney, placenta, intestine, brain, heart, and colon (PubMed:10198260, PubMed:21768100, PubMed:24269233). Predominantly expressed in liver (PubMed:20530735).
Expressed in liver, placenta, and intestine, but much lower relative to isoform 1.
Mediates the import of long-chain fatty acids (LCFA) into the cell by facilitating their transport across cell membranes, playing an important role in hepatic fatty acid uptake (PubMed:20530735, PubMed:22022213, PubMed:24269233, PubMed:10198260, PubMed:10749848, PubMed:11980911). Also functions as an acyl-CoA ligase catalyzing the ATP-dependent formation of fatty acyl-CoA using LCFA and very-long-chain fatty acids (VLCFA) as substrates, which prevents fatty acid efflux from cells and might drive more fatty acid uptake (PubMed:20530735, PubMed:22022213, PubMed:24269233, PubMed:10198260, PubMed:10749848, PubMed:11980911). Plays a pivotal role in regulating available LCFA substrates from exogenous sources in tissues undergoing high levels of beta-oxidation or triglyceride synthesis (PubMed:20530735). Can also activate branched-chain fatty acids such as phytanic acid and pristanic acid (PubMed:10198260). May contribute to the synthesis of sphingosine-1-phosphate (PubMed:24269233). Does not activate C24 bile acids, cholate and chenodeoxycholate (PubMed:11980911). In vitro, activates 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholestanate (THCA), the C27 precursor of cholic acid deriving from the de novo synthesis from cholesterol (PubMed:11980911). However, it is not critical for THCA activation and bile synthesis in vivo (PubMed:20530735).
Early expression in the hair follicle, mainly found in supramatricial cells and lowermost cortical cells of the hair bulb.
Heterotetrameric enzyme that catalyzes the condensation of farnesyl diphosphate (FPP), which acts as a primer, and isopentenyl diphosphate (IPP) to produce prenyl diphosphates of varying chain lengths and participates in the determination of the side chain of ubiquinone (PubMed:16262699). Supplies nona and decaprenyl diphosphate, the precursors for the side chain of the isoprenoid quinones ubiquinone-9 (Q9)and ubiquinone-10 (Q10) respectively (PubMed:16262699). The enzyme adds isopentenyl diphosphate molecules sequentially to farnesyl diphosphate with trans stereochemistry (PubMed:16262699).
Activity is strongly reduced in seminal plasma of infertile men.
Belongs to the glycosyltransferase 14 family. XylT subfamily.
Catalyzes the first step in the biosynthesis of chondroitin sulfate and dermatan sulfate proteoglycans, such as DCN. Transfers D-xylose from UDP-D-xylose to specific serine residues of the core protein (PubMed:15461586, PubMed:17189265, PubMed:24581741, PubMed:23982343). Required for normal embryonic and postnatal skeleton development, especially of the long bones (PubMed:24581741, PubMed:23982343). Required for normal maturation of chondrocytes during bone development, and normal onset of ossification (By similarity).
Widely expressed. Expressed at higher level in placenta, kidney and pancreas. Weakly expressed in skeletal muscle.
Predominantly expressed in the heart and skeletal muscle.
Adapter protein involved in invadopodia and podosome formation and extracellular matrix degradation. Binds matrix metalloproteinases (ADAMs), NADPH oxidases (NOXs) and phosphoinositides. Acts as an organizer protein that allows NOX1- or NOX3-dependent reactive oxygen species (ROS) generation and ROS localization. Plays a role in mitotic clonal expansion during the immediate early stage of adipocyte differentiation (By similarity).
Interacts with ADAM15 (By similarity). Interacts with NOXO1. Interacts (via SH3 domains) with NOXA1; the interaction is direct. Interacts with FASLG.
Phosphorylated in SRC-transformed cells.
At 6 weeks post-conception (WPC) expressed in the hyaloid artery and lens capsule (at protein level) (PubMed:29777959). Expressed between 6 and 19 WPC in the choroid and Bruch's membrane with faint expression in the retinal pigment epithelium, outer neuroblastic zone, inner plexiform layer, and the inner neuroblastic zone (at protein level) (PubMed:29777959).
Expressed in Bruch's membrane, outer plexiform layer, inner nuclear layer, inner plexiform layer, ganglion cell layer, inner limiting membrane and around the blood vessels of the retina (at protein level) (PubMed:29777959). Alpha 3 and alpha 4 type IV collagens are colocalized and present in kidney, eye, basement membranes of lens capsule, cochlea, lung, skeletal muscle, aorta, synaptic fibers, fetal kidney and fetal lung. PubMed:8083201 reports similar levels of expression of alpha 3 and alpha 4 type IV collagens in kidney, but PubMed:7523402 reports that in kidney levels of alpha 3 type IV collagen are significantly lower than those of alpha 4 type IV collagen. Highest levels of expression of alpha 4 type IV collagen are detected in kidney, calvaria, neuroretina and cardiac muscle. Lower levels of expression are observed in brain, lung and thymus, and no expression is detected in choroid plexus, liver, adrenal, pancreas, ileum or skin.
There are six type IV collagen isoforms, alpha 1(IV)-alpha 6(IV), each of which can form a triple helix structure with 2 other chains to generate type IV collagen network. The alpha 3(IV) chain forms a triple helical protomer with alpha 4(IV) and alpha 5(IV); this triple helical structure dimerizes through NC1-NC1 domain interactions such that the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains of one protomer connect with the alpha 5(IV), alpha 4(IV) and alpha 3(IV) chains of the opposite protomer, respectively. Associates with LAMB2 at the neuromuscular junction and in GBM (By similarity).
Expressed in synovial fibroblasts and synovial membranes.
Has hexosaminidase activity. Responsible for the cleavage of the monosaccharides N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) from cellular substrates. Has a preference for galactosaminide over glucosaminide substrates (PubMed:27149221).
Inhibited by O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino N-phenylcarbamate (PUGNAc) (By similarity). Inhibited by galacto-NAG-thiazoline (PubMed:27149221).
Guanine-nucleotide releasing factor that promotes the exchange of Ran-bound GDP by GTP, and thereby plays an important role in RAN-mediated functions in nuclear import and mitosis (PubMed:1944575, PubMed:17435751, PubMed:20668449, PubMed:22215983, PubMed:11336674). Contributes to the generation of high levels of chromosome-associated, GTP-bound RAN, which is important for mitotic spindle assembly and normal progress through mitosis (PubMed:12194828, PubMed:17435751, PubMed:22215983). Via its role in maintaining high levels of GTP-bound RAN in the nucleus, contributes to the release of cargo proteins from importins after nuclear import (PubMed:22215983). Involved in the regulation of onset of chromosome condensation in the S phase (PubMed:3678831). Binds both to the nucleosomes and double-stranded DNA (PubMed:17435751, PubMed:18762580).
Interacts with RAN (PubMed:17435751, PubMed:18762580, PubMed:29040603, PubMed:11336674). Interacts with KPNA3 (PubMed:34564892). Interacts (via N-terminus and RCC1 repeats) with KPNA4 (PubMed:29042532). Interacts with ARRB2; the interaction is detected in the nucleus upon OR1D2 stimulation (PubMed:16820410).
N-terminal methylation by METTL11A/NTM1 is required for binding double-stranded DNA and stable chromatin association. Di- and trimethylation produce a permanent positive charge on the amino group, which facilitates electrostatic binding to the phosphate groups on DNA, while inhibiting histone-binding. Methylated tail helps retain RCC1 on chromosomes during nucleotide exchange on Ran.
Patients with Raynaud disease produce antibodies that bind to RCC1.
(Microbial infection) Interacts with HIV-1 capsid protein P24 and nucleocapsid protein P7 (in vitro); the interaction may promote the integration of the virus in the host nucleus (in vitro).
(Microbial infection) Interacts with HIV-1 capsid protein P24 and nucleocapsid protein P7 and may thereby promote the integration of the virus in the host nucleus (in vitro) (PubMed:23523133). Binding affinity to HIV-1 CA-NC complexes bearing the capsid change Asn-74-Asp is reduced (in vitro) (PubMed:23523133).
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 ORF6 protein; the interaction blocks STAT1 nuclear translocation, antagonizes interferon signaling and blocks mRNA nuclear export (ex vivo).
(Microbial infection) Interacts with SARS coronavirus/SARS-CoV ORF6 protein.
(Microbial infection) Interacts with vesicular stomatitis virus protein M (PubMed:11106761).
A chromosomal aberration involving NUP98 has been found in M0 type acute myeloid leukemia. Translocation t(4;11)(q23;p15) with RAP1GDS1.
A chromosomal aberration involving NUP98 has been found in M5 type acute myeloid leukemia. Translocation t(11;12)(p15;p13) with KDM5A.
A chromosomal aberration involving NUP98 has been found in T-cell acute lymphocytic leukemia. Translocation t(4;11)(q23;p15) with RAP1GDS1.
A chromosomal aberration involving NUP98 has been identified in acute leukemias. Translocation t(6;11)(q24.1;p15.5) with CCDC28A. The chimeric transcript is an in-frame fusion of NUP98 exon 13 to CCDC28A exon 2. Ectopic expression of NUP98-CCDC28A in mouse promotes the proliferative capacity and self-renewal potential of hematopoietic progenitors and rapidly induced fatal myeloproliferative neoplasms and defects in the differentiation of the erythro-megakaryocytic lineage.
A chromosomal aberration involving NUP98 is associated with pediatric acute myeloid leukemia (AML) with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes. Translocation t(9;11)(p22;p15) with PSIP1/LEDGF. The chimeric transcript is an in-frame fusion of NUP98 exon 8 to PSIP1/LEDGF exon 4.
A chromosomal aberration involving NUP98 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(3;11)(q12.2;p15.4) with LNP1.
A chromosomal aberration involving NUP98 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with TOP1.
Chromosomal aberrations involving NUP98 have been found in M7 type childhood acute myeloid leukemia. Translocation t(11;12)(p15;p13) with KDM5A.
Chromosomal aberrations involving NUP98 have been found in acute myeloid leukemia. Translocation t(7;11)(p15;p15) with HOXA9 (PubMed:8563753). The chimera includes NUP98 intrinsic disordered regions which contribute to aberrant liquid-liquid phase separation puncta of the chimera in the nucleus. This phase-separation enhances the chimera genomic targeting and induces organization of aberrant three-dimensional chromatin structures leading to tumorous transformation (PubMed:34163069). Translocation t(11;17)(p15;p13) with PHF23 (PubMed:17287853).
Chromosomal aberrations involving NUP98 have been found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NSD1. Translocation t(8;11)(p11.2;p15) with WHSC1L1.
Contains G-L-F-G repeats. The FG repeat domains in Nup98 have a direct role in the transport.
Isoform 1 to isoform 4 are autoproteolytically cleaved to yield Nup98 and Nup96 or Nup98 only, respectively (PubMed:10087256, PubMed:20407419, PubMed:12191480, PubMed:18287282). Cleaved Nup98 is necessary for the targeting of Nup98 to the nuclear pore and the interaction with Nup96 (PubMed:20407419, PubMed:12191480).
Part of the nuclear pore complex (NPC) (PubMed:15229283, PubMed:18287282). Interacts directly with NUP96 (PubMed:12191480). Part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and NUP96; this complex plays a role in RNA export and in tethering NUP98 and NUP153 to the nucleus (PubMed:11684705). Interacts with RAE1 (PubMed:10209021, PubMed:20498086). Does not interact with TPR (PubMed:11684705). Interacts with NUP88 (PubMed:30543681). Interacts directly with NUP88 and NUP214, subunits of the cytoplasmic filaments of the NPC (By similarity). Interacts (via N-terminus) with DHX9 (via DRBM, OB-fold and RGG domains); this interaction occurs in a RNA-dependent manner and stimulates DHX9-mediated ATPase activity (PubMed:28221134).
Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance. NUP98 and NUP96 are involved in the bidirectional transport across the NPC (PubMed:33097660). May anchor NUP153 and TPR to the NPC. In cooperation with DHX9, plays a role in transcription and alternative splicing activation of a subset of genes (PubMed:28221134). Involved in the localization of DHX9 in discrete intranuclear foci (GLFG-body) (PubMed:28221134).
Binds trophinin, tastin and cytokeratins.
Found in the placenta from the sixth week of pregnancy. Was localized in the cytoplasm of the syncytiotrophoblast in the chorionic villi and in endometrial decidual cells at the uteroplacental interface. After week 10, the level decreased and then disappeared from placental villi.
HeLa cells lacking BYSL show a delay in the processing of the 18S rRNA component of the 40S ribosomal subunit. HT-H cells lacking BYSL show trophinin-independent signaling through ERBB4.
Required for processing of 20S pre-rRNA precursor and biogenesis of 40S ribosomal subunits. May be required for trophinin-dependent regulation of cell adhesion during implantation of human embryos.
Binds promoter DNA and regulates initiation of transcription (PubMed:17662942). Required for normal mitochondrial transcription and translation, and for normal assembly of mitochondrial respiratory complexes. Required for normal mitochondrial function (By similarity). Maintains 16S rRNA levels and functions in mitochondrial ribosome assembly by regulating the biogenesis of the 39S ribosomal subunit (By similarity).
Contains seven structural repeats of about 35 residues, where each repeat contains three helices. The repeats form a superhelical structure with a solenoid shape.
Highly expressed in heart, liver, kidney and testis. Detected at lower levels in brain, spleen and lung.
Specifically expressed in testis. Not detected in other tissues tested.
Belongs to the glycosyltransferase 90 family.
Dual specificity glycosyltransferase that catalyzes the transfer of glucose and xylose from UDP-glucose and UDP-xylose, respectively, to a serine residue found in the consensus sequence of C-X-S-X-P-C (PubMed:21081508, PubMed:21490058, PubMed:21949356, PubMed:27807076, PubMed:28775322). Specifically targets extracellular EGF repeats of protein such as CRB2, F7, F9 and NOTCH2 (PubMed:21081508, PubMed:21490058, PubMed:21949356, PubMed:27807076, PubMed:28775322). Acts as a positive regulator of Notch signaling by mediating O-glucosylation of Notch, leading to regulate muscle development (PubMed:27807076). Notch glucosylation does not affect Notch ligand binding (PubMed:21490058). Required during early development to promote gastrulation: acts by mediating O-glucosylation of CRB2, which is required for CRB2 localization to the cell membrane (By similarity).
Expressed in most adult tissues at different intensities. Abundantly expressed in liver. Expressed also in brain, heart, skeletal muscle, spleen, kidney, placenta, lung and peripheral blood leukocyte. Not detectable in colon, thymus and small intestine. Expressed in the epidermis, especially in the upper parts, stratum spinosum and stratum granulosum (at protein level).
A polymorphism in position 149 is associated with a higher risk of coronary artery disease (CAD). A significantly higher mutation frequency (Arg-149) is observed in patients with angiographically proven severe atherosclerosis compared with an unselected population (Ser-149).
Cell-surface glycoprotein having a role in immunoadhesion. Mediates in the adhesion of blood neutrophils in cytokine-activated endothelium through interaction with SELPLG/PSGL1. May have a role in capillary morphogenesis.
Interacts with SELPLG/PSGL1 and PODXL2 through the sialyl Lewis X epitope. SELPLG sulfation appears not to be required for this interaction.
Belongs to the eukaryotic ribosomal protein eL30 family.
Expressed in the retina. Expressed in the rod and cone photoreceptors, extending from the inner segments (IS), through the outer nuclear layer (ONL) and into the synapses in the outer plexiform layer (OPL). Strongly expressed to the photoreceptor connecting cilium at the tips of the IS (at protein level).
Tubulin-folding protein; involved in the final step of the tubulin folding pathway.
Arg-727 is the main determinant for regioselectivity, which segregates between initiases and elongases in all tubulin--tyrosine ligase family. A glutamine residue at this position is found in elongases TTLL6, TTLL9, TTLL11, TTLL13, TTLL10 and favors glutamate-chain elongation, whereas an arginine residue is found in initiases TTLL2, TTLL4, TTLL5, TTLL3, TTLL8 and favors initiation.
Monoglutamylase which modifies both tubulin and non-tubulin proteins, adding a single glutamate on the gamma-carboxyl group of specific glutamate residues of target proteins. Involved in the side-chain initiation step of the polyglutamylation reaction but not in the elongation step. Preferentially modifies beta-tail tubulin over the alpha-tubulin. Monoglutamylates nucleosome assembly proteins NAP1L1 and NAP1L4. Monoglutamylates nucleotidyltransferase CGAS, leading to inhibition of CGAS catalytic activity, thereby preventing antiviral defense function. Involved in KLF4 glutamylation which impedes its ubiquitination, thereby leading to somatic cell reprogramming, pluripotency maintenance and embryogenesis.
Identified in a complex with ZNF541, HDAC1 and HSPA2. Identified in a complex with ZNF541 and HDAC1. Identified in a complex with HDAC1, HDAC2, DNTTIP1 and ZNF541.
Transcription regulator which is essential for male fertility and for the completion of meiotic prophase in spermatocytes. Regulates progression of the pachytene stage of meiotic prophase and promotes the transcriptional activation activity ZNF541. Required for the organization of chromosomes during metaphase I.
Probable ligand of the IGFLR1 cell membrane receptor.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv11.1/KCNH2 sub-subfamily.
Has no channel activity by itself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation.
Highly expressed in heart and brain. Isoforms USO are frequently overexpressed in cancer cells.
Phosphorylated on serine and threonine residues. Phosphorylation by PKA inhibits ion conduction.
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr) (PubMed:18559421, PubMed:26363003, PubMed:27916661).
Primate-specific. Lacks a domain that is crucial for slow channel deactivation.
The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming alpha subunits that can associate with modulating beta subunits (PubMed:27916661). Interacts with DNAJB12 and DNAJB14; chaperones DNAJB12 and DNAJB14 promote tetramerization (PubMed:27916661). Heteromultimer with KCNH6/ERG2 and KCNH7/ERG3 (By similarity). Interacts with ALG10B (By similarity). Heteromultimer with KCNE1 and KCNE2 (PubMed:9230439, PubMed:10219239). Interacts with CANX (PubMed:16361248). The core-glycosylated, but not the fully glycosylated form interacts with RNF207 (PubMed:25281747). Interacts with NDFIP1 and NDFIP2 (PubMed:26363003).
Twice more abundant than isoform 1 in heart.
Up-regulated by RNF207 (at protein level).
Interacts (in its GTP-bound form) with CEP19 (via residues 121-150); this interaction is required for its localization to the mother centriole and cilium basal body. Interacts (in its GTP-bound form) with the intraflagellar transport (IFT) complex B (via the IFT74-IFT81 heterodimer) (PubMed:28625565, PubMed:28428259). Binding to CEP19 and the IFT74-IFT81 heterodimer is mutually exclusive (PubMed:28428259).
Small GTPase required for ciliation. Activated in a guanine nucleotide exchange factor (GEF)-independent manner via its intrinsic GDP for GTP nucleotide exchange ability (PubMed:28625565). Involved in ciliary assembly by binding the intraflagellar transport (IFT) complex B from the large pool pre-docked at the base of the cilium and thus triggers its entry into the cilia (PubMed:28625565, PubMed:28428259).
Tyr-334 is present instead of the conserved His which is expected to be an active site residue suggesting that this protein has lost its catalytic activity.
A chromosomal aberration involving PRCC is found in patients with papillary renal cell carcinoma. Translocation t(X;1)(p11.2;q21.2) with TFE3.
Interacts with MAD2L2; the interaction is direct.
May regulate cell cycle progression through interaction with MAD2L2.
Constitutively interacts with CASP4; required for the localization of procaspase 4 to the ER.
Critical mediator, in cooperation with CASP4, of endoplasmic reticulum-stress induced apoptosis. Required or the activation of CASP4 following endoplasmic reticulum stress.
A polymorphism in the promoter region (5-HTT gene-linked polymorphic region, 5-HTTLPR) is located approximately 1 kb upstream of the transcription initiation site and is composed of 16 repeat elements. The polymorphism consists of a 44-bp insertion or deletion involving repeat elements 6 to 8. The short allele is associated with lower transcriptional efficiency of the promoter compared with the long allele. Over half of the Caucasian population has a short allele. Individuals with one or two copies of the short allele exhibit more depressive symptoms, diagnosable depression and suicidality in relation to stressful life events than individuals homozygous for the long allele.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A4 subfamily.
Expressed in platelets (at protein level).
Genetic variations in SLC6A4 determine the genetic susceptibility to alcoholism [MIM:103780].
Monomer or homooligomer (By similarity). Interacts with TGFB1I1 (PubMed:16803896). Interacts with SEC23A, SEC24C and PATJ. Interacts with NOS1; the interaction may diminish the cell surface localization of SERT in the brain and, correspondingly, reduce serotonin reuptake. Interacts with filamentous actin and STX1A (By similarity). Interacts (via the N-terminus) with STX1A (via the H3 domain); this interaction regulates SLC4A6 channel conductance (By similarity). Interacts (via C-terminus) with SCAMP2; the interaction is direct and retains transporter molecules intracellularly (PubMed:16870614). Interacts with ITGAV:ITGB3 (PubMed:18317590). Interacts (via C-terminus) with ITGB3; this interaction regulates SLC6A4 trafficking (PubMed:18317590).
Phosphorylation at Thr-276 increases 5-HT uptake and is required for cGMP-mediated SERT regulation.
Polymorphisms that alter SLC6A4 expression or function may increase the susceptibility to autism.
Serotonin transporter that cotransports serotonin with one Na(+) ion in exchange for one K(+) ion and possibly one proton in an overall electroneutral transport cycle. Transports serotonin across the plasma membrane from the extracellular compartment to the cytosol thus limiting serotonin intercellular signaling (PubMed:27756841, PubMed:34851672, PubMed:21730057, PubMed:10407194, PubMed:27049939, PubMed:12869649). Essential for serotonin homeostasis in the central nervous system. In the developing somatosensory cortex, acts in glutamatergic neurons to control serotonin uptake and its trophic functions accounting for proper spatial organization of cortical neurons and elaboration of sensory circuits. In the mature cortex, acts primarily in brainstem raphe neurons to mediate serotonin uptake from the synaptic cleft back into the pre-synaptic terminal thus terminating serotonin signaling at the synapse (By similarity). Modulates mucosal serotonin levels in the gastrointestinal tract through uptake and clearance of serotonin in enterocytes. Required for enteric neurogenesis and gastrointestinal reflexes (By similarity). Regulates blood serotonin levels by ensuring rapid high affinity uptake of serotonin from plasma to platelets, where it is further stored in dense granules via vesicular monoamine transporters and then released upon stimulation (PubMed:17506858, PubMed:18317590). Mechanistically, the transport cycle starts with an outward-open conformation having Na1(+) and Cl(-) sites occupied. The binding of a second extracellular Na2(+) ion and serotonin substrate leads to structural changes to outward-occluded to inward-occluded to inward-open, where the Na2(+) ion and serotonin are released into the cytosol. Binding of intracellular K(+) ion induces conformational transitions to inward-occluded to outward-open and completes the cycle by releasing K(+) possibly together with a proton bound to Asp-98 into the extracellular compartment. Na1(+) and Cl(-) ions remain bound throughout the transport cycle (PubMed:27756841, PubMed:34851672, PubMed:21730057, PubMed:10407194, PubMed:27049939, PubMed:12869649). Additionally, displays serotonin-induced channel-like conductance for monovalent cations, mainly Na(+) ions. The channel activity is uncoupled from the transport cycle and may contribute to the membrane resting potential or excitability (By similarity).
The 5-HTTLPR polymorphism may influence susceptibility to anxiety [MIM:607834].
The polymorphism Val-425 seems to be linked to a susceptibility to obsessive-compulsive disorder (OCD) [MIM:164230].
This protein is the target of psychomotor stimulants such as amphetamines or cocaine.
Was reported to interact with RAB4 and to be induced by serotonin, however the paper was retracted as some results and conclusions are not reliable.
Was reported to interact with VIM, however the paper was retracted as some results and conclusions are not reliable.
Detected in fetal brain (at protein level). Ubiquitous. Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, prostate, spleen, thymus, prostate, testis, ovary, small intestine and colon.
Has omega-amidase activity (PubMed:22674578, PubMed:19595734). The role of omega-amidase is to remove potentially toxic intermediates by converting 2-oxoglutaramate and 2-oxosuccinamate to biologically useful 2-oxoglutarate and oxaloacetate, respectively (PubMed:19595734).
Antibodies against TCFL5 are present in sera from patients with Chagas disease (also called American Trypanosomiasis), a disease caused by Trypanosoma cruzi. Two different epitopes that mimic Trypanosoma cruzi antigens have been identified: R1 and R3 epitopes, which are recognized by T- and B-cells, respectively.
Isoform 3 is specifically expressed in primary spermatocytes at the pachytene stage, but not those at leptonema stage. Not expressed in other testicular cells, including spermatogonia located in the basal compartment of the seminiferous tubule or spermatids.
Isoform 3 is testis specific. Isoform 2 is pancreas specific.
Putative transcription factor. Isoform 3 may play a role in early spermatogenesis.
Able to isomerize both 3-cis and 3-trans double bonds into the 2-trans form in a range of enoyl-CoA species. Has a preference for 3-trans substrates.
Abundant in heart, skeletal muscle and liver. Expressed in CD34(+) T-cells and CD34(+) bone marrow cells.
In the C-terminal section; belongs to the enoyl-CoA hydratase/isomerase family.
Expressed in T-cells and some myeloid cell lines. Expressed in Th1/Th0 cells with IFN-gamma-producing potential.
Interacts with PARP1 and EEF1A1 (PubMed:17177976). Interacts with SH2D2A (By similarity). Interacts with FYN (By similarity).
Non-receptor tyrosine kinase that plays a redundant role with ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation leads to the recruitment of TXK to the cell membrane, where it is phosphorylated at Tyr-420. Phosphorylation leads to TXK full activation. Contributes also to signaling from many receptors and participates in multiple downstream pathways, including regulation of the actin cytoskeleton. Like ITK, can phosphorylate PLCG1, leading to its localization in lipid rafts and activation, followed by subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Plays a role in the positive regulation of IFNG transcription in T-helper 1 cells as part of an IFNG promoter-binding complex with PARP1 and EEF1A1 (PubMed:11859127, PubMed:17177976). Within the complex, phosphorylates both PARP1 and EEF1A1 (PubMed:17177976). Phosphorylates also key sites in LCP2 leading to the up-regulation of Th1 preferred cytokine IL-2. Phosphorylates 'Tyr-201' of CTLA4 which leads to the association of PI-3 kinase with the CTLA4 receptor.
Phosphorylated at Tyr-420 by FYN. Autophosphorylation at Tyr-91 is critical for the activation of TXK, leading to the up-regulation of IFN-gamma gene transcription.
The cysteine string at the N-terminus is palmitoylated and required for the proper subcellular location.
Unlike the other TEC subfamily members, TXK is activated independently of the activity of phosphatidylinositol 3-kinase, consistent with its lack of a PH domain. Membrane association is performed through palmitoylation at the N-terminus.
Beta-1,3-galactosyltransferase that transfers galactose from UDP-alpha-D-galactose to substrates with a terminal beta-N-acetylglucosamine (beta-GlcNAc) residue. Involved in the biosynthesis of the carbohydrate moieties of glycolipids and glycoproteins. Inactive towards substrates with terminal alpha-N-acetylglucosamine (alpha-GlcNAc) or alpha-N-acetylgalactosamine (alpha-GalNAc) residues.
Detected in brain and colon mucosa and to a lesser extent in colon adenocarcinoma cells.
Modulates leading keratinocyte migration and cellular adhesion to matrix proteins during a wound-healing response and promotes wound repair. May play a role during trichilemmal differentiation of the hair follicle (By similarity).
Forms a heterodimer with RXR. Interacts with CCAR2 (via N-terminus) in a ligand-independent manner (PubMed:25661920). Interacts (when sumoylated) with GPS2; interaction with GPS2 onto hepatic acute phase protein promoters prevents N-Cor corepressor complex dissociation (PubMed:20159957). Interacts with ABCA12 and ABCA1; this interaction is required for ABCA1 localization to the cell surface and is necessary for its normal activity and stability (PubMed:23931754).
Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity (PubMed:25661920). Binds preferentially to double-stranded oligonucleotide direct repeats having the consensus half-site sequence 5'-AGGTCA-3' and 4-nt spacing (DR-4). Regulates cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8; DLDLR and LRP8. Interplays functionally with RORA for the regulation of genes involved in liver metabolism (By similarity). Induces LPCAT3-dependent phospholipid remodeling in endoplasmic reticulum (ER) membranes of hepatocytes, driving SREBF1 processing and lipogenesis (By similarity). Via LPCAT3, triggers the incorporation of arachidonate into phosphatidylcholines of ER membranes, increasing membrane dynamics and enabling triacylglycerols transfer to nascent very low-density lipoprotein (VLDL) particles (By similarity). Via LPCAT3 also counteracts lipid-induced ER stress response and inflammation, likely by modulating SRC kinase membrane compartmentalization and limiting the synthesis of lipid inflammatory mediators (By similarity). Plays an anti-inflammatory role during the hepatic acute phase response by acting as a corepressor: inhibits the hepatic acute phase response by preventing dissociation of the N-Cor corepressor complex (PubMed:20159957).
Sumoylated by SUMO2 at Lys-409 and Lys-447 during the hepatic acute phase response, leading to promote interaction with GPS2 and prevent N-Cor corepressor complex dissociation.
Belongs to the aminoglycoside phosphotransferase family.
Catalyzes the GTP-dependent phosphorylation of 5-hydroxy-L-lysine.
Belongs to the RBR family. RNF14 subfamily.
E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway, a pathway that takes place when a ribosome has stalled during translation, and which promotes ubiquitination and degradation of translation factors on stalled ribosomes (PubMed:36638793). Recruited to stalled ribosomes by the ribosome collision sensor GCN1 and mediates ubiquitination of EEF1A1/eEF1A, leading to its degradation (PubMed:36638793). In addition to EEF1A1/eEF1A, RNF14 catalyzes ubiquitination of other translation factors on stalled ribosomes: mediates ubiquitination and degradation of ETF1/eRF1 and ubiquitination of ribosomal proteins RPL0, RPL1, RPL12, RPS13 and RPS17 (PubMed:36638793). Independently of its function in the response to stalled ribosomes, acts as a regulator of transcription in Wnt signaling via its interaction with TCF transcription factors (TCF7/TCF1, TCF7L1/TCF3 and TCF7L2/TCF4) (PubMed:23449499). May also play a role as a coactivator for androgen- and, to a lesser extent, progesterone-dependent transcription (PubMed:19345326).
Interacts with GCN1; interaction takes place in response to ribosome collisions and is required for ubiquitination of EEF1A1/eEF1A (PubMed:36638793). Interacts with the ubiquitin-conjugating enzymes UBE2E1 and UBE2E2 (PubMed:11322894). Interacts with AR/androgen receptor (PubMed:10085091, PubMed:19345326). Interacts with TCF7/TCF1, TCF7L1/TCF3 and TCF7L2/TCF4; promoting Wnt signaling (PubMed:23449499).
RING-type zinc finger-dependent and UBE2E2-dependent autoubiquitination.
Heterohexamer (PubMed:32415200). Oligomerizes with other LRRC8 proteins (LRRC8A, LRRC8B, LRRC8C and/or LRRC8E) to form a heterohexamer (PubMed:24782309, PubMed:26530471, PubMed:28193731, PubMed:26824658). In vivo, the subunit composition may depend primarily on expression levels, and heterooligomeric channels containing various proportions of the different LRRC8 proteins may coexist (Probable).
Non-essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes (PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731, PubMed:32415200). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24790029, PubMed:26824658, PubMed:28193731). Plays a redundant role in the efflux of amino acids, such as aspartate, in response to osmotic stress (PubMed:28193731). LRRC8A and LRRC8D are required for the uptake of the drug cisplatin (PubMed:26530471). Channel activity requires LRRC8A plus at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (PubMed:24782309, PubMed:24790029, PubMed:26824658, PubMed:28193731). Also acts as a regulator of glucose-sensing in pancreatic beta cells: VRAC currents, generated in response to hypotonicity- or glucose-induced beta cell swelling, depolarize cells, thereby causing electrical excitation, leading to increase glucose sensitivity and insulin secretion (By similarity). VRAC channels containing LRRC8D inhibit transport of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol (PubMed:33171122). Mediates the import of the antibiotic blasticidin-S into the cell (PubMed:24782309).
Interacts with PXN, PRLR, VAV1 and VAV2 and this interaction is prolactin-dependent.
Phosphorylation at Thr-479 regulates its catalytic activity.
Protein kinase which influences neuronal morphogenesis and polarity through effects on microtubules. Regulates microtubule acetylation in neurons. Contributes to prolactin-mediated phosphorylation of PXN and VAV2. Implicated in prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells through mechanisms involving RAC1 activation and phosphorylation of PXN and VAV2.
Up-regulated in malignant versus normal breast tissue. Isoform 2 shows a high level of expression in testis, ovary and brain.
In pregnancy, the expression of NKB is confined to the outer syncytiotrophoblast of the placenta, significant concentrations of NKB can be detected in plasma as early as week 9, and plasma concentrations of NKB are grossly elevated in pregnancy-induced hypertension and pre-eclampsia.
Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles (By similarity). Is a critical central regulator of gonadal function.
Able to form dimers stabilized by noncovalent forces.
This is an intracellular thiol proteinase inhibitor. Tightly binding reversible inhibitor of cathepsins L, H and B.
A chromosomal aberration involving ZNF320 is found in a form of glioblastoma. Translocation t(10;19)(q26;q13.3) with BRWD2/WDR11.
Expressed at high levels in placenta, pancreas, kidney and heart, and at lower levels in liver, skeletal muscle and brain.
Acetylated. Acetylation oscillates throughout the cell cycle, and the acetylation state at Lys-31 is regulated by the deacetylase SIRT1 and the acetyltransferase NAT10. Deacetylated CENATAC is responsible for its centrosome targeting, and acetylated CENATAC promotes SASS6 degradation by enhancing the binding affinity of SASS6 for APC/C E3 ubiquitin-protein ligase complex/FZR1.
Component of the minor spliceosome that promotes splicing of a specific, rare minor intron subtype (PubMed:34009673). Negative regulator of centrosome duplication (PubMed:31722219). Constrains centriole number by modulating the degradation of the centrosome-duplication-associated protein SASS6 in an acetylation-dependent manner. SIRT1 deacetylates CENATAC in G1 phase, allowing for SASS6 accumulation on the centrosome and subsequent procentriole assembly. The CENATAC acetylation level is restored in mitosis by NAT10, promoting SASS6 proteasome degradation by facilitating SASS6 binding to APC/C E3 ubiquitin-protein ligase complex/FZR1 (PubMed:31722219).
Interacts with SASS6; the interaction increases with CENATAC acetylation.
(Microbial infection) Acts as a receptor for C.difficile toxin TcdB in the colonic epithelium.
(Microbial infection) Interacts with C.difficile toxin TcdB; frizzled receptors constitute the major host receptors for TcdB in the colonic epithelium.
High expression in adult skeletal muscle and fetal kidney, followed by fetal lung, adult heart, brain, and placenta. Specifically expressed in squamous cell esophageal carcinomas.
Interacts with MAGI3 (By similarity). Interacts with DVL1 (By similarity). Interacts with CCDC88C/DAPLE; the interaction displaces DVL1 from FZD7, leading to inhibition of canonical Wnt signaling and triggering of non-canonical Wnt responses (PubMed:26126266). Interacts with MYOC (PubMed:19188438). Binds to SDCBP; this interaction is increased by inositol trisphosphate (IP3) (PubMed:27386966). Interacts with glypican GPC3 (PubMed:24496449).
Receptor for Wnt proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. Activation by WNT8 induces expression of beta-catenin target genes (By similarity). Following ligand activation, binds to CCDC88C/DAPLE which displaces DVL1 from FZD7 and leads to inhibition of canonical Wnt signaling, activation of G-proteins by CCDC88C and triggering of non-canonical Wnt responses (PubMed:26126266). May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues.
Sumoylated with SUMO1 and SUMO2/3 and by UBC9. Sumoylation at Lys-236 inhibits enzymatic activity. Sumoylation at the C-terminal lysine cluster plays an essential role in nuclear trafficking.
A chromosomal aberration involving TRIM24/TIF1 is found in papillary thyroid carcinomas (PTCs). Translocation t(7;10)(q32;q11) with RET. The translocation generates the TRIM24/RET (PTC6) oncogene.
Interacts with CARM1, NCOA2/GRIP1, PML, KAT5/TIP60, BRD7, CBX1, CBX3 and CBX5. Part of a coactivator complex containing TRIM24, NCOA2 and CARM1 (By similarity). Interacts with NR3C2/MCR. Interacts with the ligand-binding domain of estrogen receptors (in vitro). Interaction with DNA-bound estrogen receptors requires the presence of estradiol. Interacts with AR and p53/TP53. Interacts (via bromo domain) with histone H3 (via N-terminus), provided that it is not methylated at 'Lys-4' (H3K4me0). Does not interact with histone H3 that is methylated at 'Lys-4' (H3K4me1, H3K4me2 or H3K4me3). Interacts (via bromo domain) with histone H3 (via N-terminus) that is acetylated at 'Lys-23' (H3K23ac). Has the highest affinity for histone H3 that is both unmodified at 'Lys-4' (H3K4me0) and acetylated at 'Lys-23' (H3K23ac). Has very low affinity for histone H3 that is methylated at 'Lys-9' (H3K9me), or acetylated at both 'Lys-9' (H3K9ac) and 'Lys-14' (H3K14ac), or acetylated at 'Lys-27' (H3K27ac) (in vitro). Interacts with TRIM16.
Phosphorylated at Ser-768 by ATM kinase induces ubiquitination and degradation during DNA damage.
Transcriptional coactivator that interacts with numerous nuclear receptors and coactivators and modulates the transcription of target genes. Interacts with chromatin depending on histone H3 modifications, having the highest affinity for histone H3 that is both unmodified at 'Lys-4' (H3K4me0) and acetylated at 'Lys-23' (H3K23ac). Has E3 protein-ubiquitin ligase activity. During the DNA damage response, participates in an autoregulatory feedback loop with TP53. Early in response to DNA damage, ATM kinase phosphorylates TRIM24 leading to its ubiquitination and degradation. After sufficient DNA repair has occurred, TP53 activates TRIM24 transcription, ultimately leading to TRIM24-mediated TP53 ubiquitination and degradation (PubMed:24820418). Plays a role in the regulation of cell proliferation and apoptosis, at least in part via its effects on p53/TP53 levels. Up-regulates ligand-dependent transcription activation by AR, GCR/NR3C1, thyroid hormone receptor (TR) and ESR1. Modulates transcription activation by retinoic acid (RA) receptors, including RARA. Plays a role in regulating retinoic acid-dependent proliferation of hepatocytes (By similarity). Participates also in innate immunity by mediating the specific 'Lys-63'-linked ubiquitination of TRAF3 leading to activation of downstream signal transduction of the type I IFN pathway (PubMed:32324863). Additionally, negatively regulates NLRP3/CASP1/IL-1beta-mediated pyroptosis and cell migration probably by ubiquitinating NLRP3 (PubMed:33724611).
Undergoes ubiquitination-mediated degradation in response to DNA damage.
Up-regulated in some cases of breast cancer (PubMed:21164480). Expression is induced by damage-activated TP53 (PubMed:24820418).
Exerts its effect at some terminal stage of cytochrome c oxidase synthesis, probably by being involved in the insertion of the copper B into subunit I.
Interacts with CNNM4/ACDP4. Interacts with RANBP2 (PubMed:34400285).
Binds nucleotide much more tightly and catalyzes nucleotide insertion much more efficiently in the presence of Mg(2+) than in the presence of Mn(2+).
Error-prone DNA polymerase specifically involved in DNA repair (PubMed:11013228, PubMed:11387224). Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls (PubMed:11013228, PubMed:11387224, PubMed:14630940, PubMed:15199127). Favors Hoogsteen base-pairing in the active site (PubMed:15254543). Inserts the correct base with high-fidelity opposite an adenosine template (PubMed:15254543). Exhibits low fidelity and efficiency opposite a thymidine template, where it will preferentially insert guanosine (PubMed:11013228). May play a role in hypermutation of immunoglobulin genes (PubMed:12410315). Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but may not have lyase activity (PubMed:11251121, PubMed:14630940).
Interacts with POLH (PubMed:12606586). Interacts with REV1 (By similarity). Interacts with ubiquitin (By similarity).
Monoubiquitinated. Protein monoubiquitination prevents POLI binding to ubiquitin via the ubiquitin-binding motif 1 and ubiquitin-binding motif 2.
Ubiquitin-binding motif 1 and ubiquitin-binding motif 2 regulate POLI protein monoubiquitination and localization to nuclear foci after UV-induced DNA damage.
Homodimer (By similarity). Interacts with PTPNS1. Part of a complex consisting of SKAP2, FYB1 and PTPNS1. Part of a complex consisting of SKAP2, FYB1 and LILRB3. May interact with actin (By similarity). Interacts with FYB1, which is required for SKAP2 protein stability. Interacts with LAT, GRB2, PTK2B and PRAM1. May interact with FYN, HCK and LYN. Interacts with FASLG.
May be involved in B-cell and macrophage adhesion processes. In B-cells, may act by coupling the B-cell receptor (BCR) to integrin activation. May play a role in src signaling pathway.
Phosphorylated in resting platelets. Phosphorylated by FYN on Tyr-261 upon T-cell activation (Probable). Dephosphorylated on Tyr-75 by PTPN22.
The SH3 domain interacts with FYB1 and PTK2B.
Ubiquitously expressed. Present in platelets (at protein level).
Belongs to the IspD/TarI cytidylyltransferase family. IspD subfamily.
Cytidylyltransferase required for protein O-linked mannosylation (PubMed:22522420, PubMed:27130732, PubMed:27601598, PubMed:26687144, PubMed:22522421, PubMed:26923585). Catalyzes the formation of CDP-ribitol nucleotide sugar from D-ribitol 5-phosphate (PubMed:27130732, PubMed:26687144, PubMed:26923585). CDP-ribitol is a substrate of FKTN during the biosynthesis of the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3-N-acetylglucosamine-beta-4-(phosphate-6-)mannose), a carbohydrate structure present in alpha-dystroglycan (DAG1), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity (PubMed:27130732, PubMed:26687144, PubMed:26923585). Shows activity toward other pentose phosphate sugars and mediates formation of CDP-ribulose or CDP-ribose using CTP and ribulose-5-phosphate or ribose-5-phosphate, respectively (PubMed:26687144). Not Involved in dolichol production (PubMed:26687144).
Ubiquitously expressed, with high expression in brain.
Detected in placenta (at protein level) (PubMed:32337544). Detected in cerebrospinal fluid and fibroblasts (at protein level) (PubMed:25326458, PubMed:36213313). Highly expressed in kidney, also detected on liver and spleen (PubMed:27599751). Expressed by proximal tubular cells of the kidney (at protein level) (PubMed:27599751). Expression highly increases during chronic kidney disease and autosomal dominant polycystic kidney disease, where is detected in cysts (PubMed:27599751).
Expression is induced by TGFB1, in kidney tubular cells. This induction is inhibited by the vitamin D receptor activator paricalcitol (at protein level).
In kidney, has anti-inflammatory and anti-fibrotic properties by limiting the induction of chemokines, fibronectin and collagen expression in response to TGB1 and pro-inflammatory stimuli.
Over-expressed in centenarians. Expression is reduced from young to old but increased from old to centenarians.
Expressed mainly in epithelial cells. Expressed in the central nervous system (CNS), in the ileum and within the brain in the frontal and occipital lobe.
Homodimer. Interacts with CREB1; the interaction is not depolarization dependent. Interacts with CREBBP (via C-terminus) (By similarity). Interacts (via HGM box) with CITED1 (via C-terminus); the interaction increases estrogen-response element (ERE)-dependent transcription and protection against cell death. Interacts with CREB1 (phosphorylated form).
The N-terminus is absolutely necessary for transactivation activity.
Transcriptional coactivator of the p300/CBP-mediated transcription complex. Activates transactivation through cAMP response element (CRE) sites. Protects against cell death by inducing antiapoptotic and repressing pro-apoptotic transcripts. Stimulates transcription from the estrogen-responsive or BCL-2 promoters. Required for depolarization-induced transcription activation of the C-FOS promoter in neurons. Associates with chromatin to the estrogen-responsive C3 promoter region.
the C-terminus is required for calcium responsiveness but not for transactivation activity.
Antibodies against TRIB2 are present in sera from patients with autoimmune uveitis.
Highly expressed in peripheral blood leukocytes.
Interacts with MAPK kinases and regulates activation of MAP kinases. Does not display kinase activity (By similarity).
Lipid-binding protein that transports phosphatidylinositol, the precursor of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), from its site of synthesis in the endoplasmic reticulum to the cell membrane (PubMed:28209843). It thereby maintains the pool of cell membrane phosphoinositides, which are degraded during phospholipase C (PLC) signaling (PubMed:28209843). Plays a key role in the coordination of Ca(2+) and phosphoinositide signaling: localizes to sites of contact between the endoplasmic reticulum and the cell membrane, where it tethers the two bilayers (PubMed:28209843). In response to elevation of cytosolic Ca(2+), it is phosphorylated at its C-terminus and dissociates from the cell membrane, abolishing phosphatidylinositol transport to the cell membrane (PubMed:28209843). Positively regulates insulin secretion in response to glucose: phosphatidylinositol transfer to the cell membrane allows replenishment of PI(4,5)P2 pools and calcium channel opening, priming a new population of insulin granules (PubMed:28209843).
Phosphorylation at the C-terminus acidifies the protein and leads to disassociation from the acidic cell membrane. Reassociates with the cell membrane upon dephosphorylation.
The SMP-LBD domain is a lipid transport module, which binds glycerolipids with a preference for phosphatidylinositol (PI).
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits (By similarity). Interacts with POLR3D/RPC4.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Specific peripheric component of RNA polymerase III which synthesizes small RNAs, such as 5S rRNA and tRNAs. Essential for efficient transcription from both the type 2 VAI and type 3 U6 RNA polymerase III promoters. Plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF- Kappa-B through the RIG-I pathway (By similarity).
Catalyzes the NAD-dependent oxidation of the highly active 17beta-hydroxysteroids, such as estradiol (E2), testosterone (T), and dihydrotestosterone (DHT), to their less active forms and thus regulates the biological potency of these steroids. Oxidizes estradiol to estrone, testosterone to androstenedione, and dihydrotestosterone to 5alpha-androstan-3,17-dione. Also has 20-alpha-HSD activity.
Expressed primarily in trachea and testis, 2 tissues containing axonemal structures. Also expressed in lung.
Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Involved in sperm motility; implicated in sperm flagellar assembly (By similarity).
Highly expressed in placenta and lung, followed by brain, heart, kidney, liver, pancreas and skeletal muscle. Expressed by B-lymphocytes, but not T-lymphocytes or nonhematopoietic cells.
Interacts with PtdIns(3,4,5)P3 and PLCG2. In vitro, interacts with PtdIns(3,4)P2.
May act as a B-cell-associated adapter that regulates B-cell antigen receptor (BCR)-signaling downstream of PI3K.
Deubiquitinase that plays a role in the regulation of several processes such as maintenance of synaptic function, cardiac function, inflammatory response or osteoclastogenesis (PubMed:22212137, PubMed:23359680). Abrogates the ubiquitination of multiple proteins including WWTR1/TAZ, EGFR, HIF1A and beta-site amyloid precursor protein cleaving enzyme 1/BACE1 (PubMed:22212137, PubMed:25615526). In addition, recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin to maintain a stable pool of monoubiquitin that is a key requirement for the ubiquitin-proteasome and the autophagy-lysosome pathways (PubMed:9774100, PubMed:8639624, PubMed:12408865). Regulates amyloid precursor protein/APP processing by promoting BACE1 degradation resulting in decreased amyloid beta production (PubMed:22212137). Plays a role in the immune response by regulating the ability of MHC I molecules to reach cross-presentation compartments competent for generating Ag-MHC I complexes (By similarity). Mediates the 'Lys-48'-linked deubiquitination of the transcriptional coactivator WWTR1/TAZ leading to its stabilization and inhibition of osteoclastogenesis (By similarity). Deubiquitinates and stabilizes epidermal growth factor receptor EGFR to prevent its degradation and to activate its downstream mediators (By similarity). Modulates oxidative activity in skeletal muscle by regulating key mitochondrial oxidative proteins (By similarity). Enhances the activity of hypoxia-inducible factor 1-alpha/HIF1A by abrogateing its VHL E3 ligase-mediated ubiquitination and consequently inhibiting its degradation (PubMed:25615526).
Found in neuronal cell bodies and processes throughout the neocortex (at protein level). Expressed in neurons and cells of the diffuse neuroendocrine system and their tumors. Weakly expressed in ovary. Down-regulated in brains from Parkinson disease and Alzheimer disease patients.
Monomer. Homodimer. Interacts with SNCA (By similarity). Interacts with COPS5.
Oxidation of Met-1, Met-6, Met-12, Met-124 and Met-179 to methionine sulfoxide, and oxidation of Cys-220 to cysteine sulfonic acid have been observed in brains from Alzheimer disease (AD) and Parkinson disease (PD) patients. In AD, UCHL1 was found to be associated with neurofibrillary tangles. In contrast to UCHL3, does not hydrolyze a peptide bond at the C-terminal glycine of NEDD8.
PubMed:9774100 reports the association of mutation Ile93Met with Parkinson disease. However, according to PubMed:16450370 this association is uncertain and UCHL1 is not a susceptibility gene for Parkinson disease.
The homodimer may have ATP-independent ubiquitin ligase activity (PubMed:12408865). However, in another study, UCHL1 was shown to lack ubiquitin ligase activity (PubMed:23359680).
The oxidation forms of Met-1, Met-6, Met-12, Met-124, Met-179 and Cys-220 are subject of controversy and could be the artifactual results of sample handling.
Bifunctional axonal guidance cue regulated by sulfated proteoglycans; attractive effects result from interactions with heparan sulfate proteoglycans (HSPGs), while the inhibitory effects depend on interactions with chondroitin sulfate proteoglycans (CSPGs) (By similarity). Ligand for receptor PLXNB3. In glioma cells, SEMA5A stimulation of PLXNB3 results in the disassembly of F-actin stress fibers, disruption of focal adhesions and cellular collapse as well as inhibition of cell migration and invasion through ARHGDIA-mediated inactivation of RAC1. May promote angiogenesis by increasing endothelial cell proliferation and migration and inhibiting apoptosis.
Although initially described as a cell membrane glycoprotein, ADRM1 is intracellular and non-glycosylated, and has probably no direct role in cell adhesion.
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:16990800). Interacts with the proteasomal scaffolding protein PSMD1 (PubMed:16990800, PubMed:16815440, PubMed:16906146, PubMed:20471946). Interacts with deubiquitinase UCHL5; this interaction activates the auto-inhibited UCHL5 by deoligomerizing it (PubMed:17139257, PubMed:24752541, PubMed:25702870, PubMed:25702872). Interacts with UBQLN2 and ubiquitin (PubMed:27396824).
Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins (PubMed:16815440, PubMed:16906146, PubMed:16990800, PubMed:17139257, PubMed:18497817, PubMed:24752541, PubMed:25702870, PubMed:25702872). This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required (PubMed:16815440, PubMed:16906146, PubMed:16990800, PubMed:17139257, PubMed:18497817, PubMed:24752541, PubMed:25702870, PubMed:25702872). Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair (PubMed:16815440, PubMed:16906146, PubMed:16990800, PubMed:17139257, PubMed:18497817, PubMed:24752541, PubMed:25702870, PubMed:25702872). Within the complex, functions as a proteasomal ubiquitin receptor (PubMed:18497817). Engages and activates 19S-associated deubiquitinases UCHL5 and PSMD14 during protein degradation (PubMed:16906146, PubMed:16990800, PubMed:17139257, PubMed:24752541). UCHL5 reversibly associate with the 19S regulatory particle whereas PSMD14 is an intrinsic subunit of the proteasome lid subcomplex (PubMed:16906146, PubMed:16990800, PubMed:17139257, PubMed:24752541).
The Pru (pleckstrin-like receptor for ubiquitin) domain mediates interactions with PSMD1 and ubiquitin. Preferential binding to the proximal subunit of 'Lys-48'-linked diubiquitin allows UCHL5 access to the distal subunit.
Ubiquitinated by UBE3C in response to proteotoxic stress.
Belongs to the eukaryotic ribosomal protein eL41 family.
Component of the large ribosomal subunit (PubMed:23636399). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399). Interacts with the beta subunit of protein kinase CKII and stimulates phosphorylation of DNA topoisomerase II alpha by CKII (PubMed:9299532).
There are multiple pseudogenes of this gene dispersed through the genome.
Activity is enhanced by binding to the pyruvate dehydrogenase subunit DLAT. Inhibited by AZD7545; this compound interferes with DLAT binding and thereby inhibits kinase activity. Inhibited by dichloroacetate and radicicol.
Exposure of cancer cells to severe hypoxia induces translocation of AKT to the mitochondrion, leading to AKT-mediated phosphorylation of PDK1 at Thr-346 which supports tumor cell survival and proliferation during hypoxia.
Expressed predominantly in the heart. Detected at lower levels in liver, skeletal muscle and pancreas.
Homodimer, and heterodimer with PDK2. Interacts with the pyruvate dehydrogenase complex subunit DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3).
Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress.
Phosphorylated by constitutively activated ABL1, FGFR1, FLT3 and JAK2 (in vitro), and this may also occur in cancer cells that express constitutively activated ABL1, FGFR1, FLT3 and JAK2. Phosphorylation at Tyr-243 and Tyr-244 strongly increases kinase activity, while phosphorylation at Tyr-136 has a lesser effect.
Up-regulated via the HIF1A signaling pathway in response to hypoxia.
7-dehydrocholesterol reductase of the cholesterol biosynthetic pathway reducing the C7-C8 double bond of cholesta-5,7-dien-3beta-ol (7-dehydrocholesterol/7-DHC) and cholesta-5,7,24-trien-3beta-ol, two intermediates in that pathway.
Interacts with DHCR24; this interaction regulates DHCR7 activity (PubMed:25637936). Interacts with TMEM147 (PubMed:25637936).
Widely expressed. Most abundant in adrenal gland, liver, testis, and brain.
Expression is stimulated and enhanced by IFNG/IFN-gamma.
Heterodimer with SLC3A2, that functions as an antiporter which operates as an efflux route by exporting cationic amino acids from inside the cells in exchange with neutral amino acids plus sodium ions and may participate in nitric oxide synthesis via the transport of L-arginine (PubMed:9878049, PubMed:9829974, PubMed:17329401, PubMed:10080182, PubMed:10655553, PubMed:15756301, PubMed:15776427, PubMed:14603368). Also mediates arginine transport in non-polarized cells, such as monocytes, and is essential for the correct function of these cells (PubMed:15280038, PubMed:31705628). The transport mechanism is electroneutral and operates with a stoichiometry of 1:1 (By similarity). In vitro, Na(+) and Li(+), but also H(+), are cotransported with the neutral amino acids (By similarity).
Highest expression in kidney and peripheral blood leukocytes (PubMed:9829974). Weaker expression is observed in lung, heart, placenta, spleen, testis and small intestine (PubMed:9829974). Expressed in normal fibroblasts and those from LPI patients (PubMed:10080183, PubMed:11078698). Also expressed in HUVECs, monocytes, retinal pigment epithelial cells, and various carcinoma cell lines, with highest expression in a colon-carcinoma cell line (PubMed:11742806, PubMed:15280038, PubMed:17197568, PubMed:17329401).
Belongs to the ETF alpha-subunit/FixB family.
Domain I shares an identical polypeptide fold with the beta subunit ETFB though there is no sequence similarity.
Heterodimer composed of ETFA and ETFB (PubMed:8962055, PubMed:15159392, PubMed:15975918, PubMed:9334218). Identified in a complex that contains ETFA, ETFB and ETFRF1 (PubMed:27499296). Interaction with ETFRF1 promotes dissociation of the bound FAD and loss of electron transfer activity (PubMed:27499296). Interacts with TASOR (By similarity).
Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase (PubMed:27499296, PubMed:15159392, PubMed:15975918, PubMed:9334218, PubMed:10356313). It transfers the electrons to the main mitochondrial respiratory chain via ETF-ubiquinone oxidoreductase (ETF dehydrogenase) (PubMed:9334218). Required for normal mitochondrial fatty acid oxidation and normal amino acid metabolism (PubMed:12815589, PubMed:1882842, PubMed:1430199).
Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells (PubMed:23851396, PubMed:23934049, PubMed:2527252, PubMed:8033114, PubMed:8567728, PubMed:19074442). Has high affinity for folate and folic acid analogs at neutral pH (PubMed:23851396, PubMed:23934049, PubMed:2527252, PubMed:8033114, PubMed:8567728). Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release (PubMed:8567728). Required for normal embryonic development and normal cell proliferation (By similarity).
Primarily expressed in tissues of epithelial origin. Expression is increased in malignant tissues. Expressed in kidney, lung and cerebellum. Detected in placenta and thymus epithelium.
The secreted form is derived from the membrane-bound form either by cleavage of the GPI anchor, or/and by proteolysis catalyzed by a metalloprotease.
Belongs to the methyltransferase superfamily. Rsm22 family.
Interacts with mitochondrial small ribosomal subunit (mt-SSU) subunits MRPS15 and MRPS27.
Probable S-adenosyl-L-methionine-dependent RNA methyltransferase required to stabilize the mitochondrial small ribosomal subunit (mt-SSU). Required for protein translation in mitochondria.
Also promotes endoribonucleolytic cleavage of some transcripts by promoting recruitment of the ribonuclease P/MRP complex (PubMed:8973653, PubMed:30930054). Acts by bridging YTHDF2 and the ribonuclease P/MRP complex (PubMed:30930054). RIDA/HRSP12 binds to N6-methyladenosine (m6A)-containing mRNAs containing a 5'-GGUUC-3' motif: cooperative binding of RIDA/HRSP12 and YTHDF2 to such transcripts lead to recruitment of the ribonuclease P/MRP complex and subsequent endoribonucleolytic cleavage (PubMed:30930054).
Catalyzes the hydrolytic deamination of enamine/imine intermediates that form during the course of normal metabolism. May facilitate the release of ammonia from these potentially toxic reactive metabolites, reducing their impact on cellular components. It may act on enamine/imine intermediates formed by several types of pyridoxal-5'-phosphate-dependent dehydratases including L-threonine dehydratase.
Expressed predominantly in liver and kidney. Lower levels in lung and brain.
Homotrimer (PubMed:14997576). Interacts with YTHDF2 (PubMed:30930054).
Up-regulated during cellular differentiation.
Acts as an adapter for the XPO1/CRM1-mediated export of the 60S ribosomal subunit.
Found in a 60S ribosomal subunit export complex with RAN and XPO1 (PubMed:12724356). Interacts with XPO1. Associates with pre-60S ribosomal particles (PubMed:12724356, PubMed:32669547).
As part of the exocyst, may play a role in regulated exocytosis of insulin granules.
Interacts with EXOC2, EXOC4 and EXOC5; may be part of the exocyst.
(Microbial infection) Interacts with Epstein-Barr virus EBNA6; this interaction upregulates and stabilizes PIM1 and induces cell proliferation by inhibiting the growth suppressive properties of p21.
Autophosphorylated on both serine/threonine and tyrosine residues. Phosphorylated. Interaction with PPP2CA promotes dephosphorylation.
Expressed primarily in cells of the hematopoietic and germline lineages. Isoform 1 and isoform 2 are both expressed in prostate cancer cell lines.
Interacts with RP9 (By similarity). Interacts with HSP90AA1, this interaction stabilizes PIM1 protein levels (PubMed:15798097). Interacts (ubiquitinated form) with HSP70 and promotes its proteasomal degradation (PubMed:15798097).
Isoform 1 is isolated as a monomer whereas isoform 2 complexes with other proteins.
Isoform 2, but not isoform 1, binds BMX.
Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis (PubMed:15528381, PubMed:1825810, PubMed:31548394). Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3) (PubMed:18593906). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity (By similarity). The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis (By similarity). Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1 (By similarity). Phosphorylation of MAP3K5, another proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis (PubMed:19749799). Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C (PubMed:16356754). Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability (PubMed:12431783). Promotes cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels (PubMed:18593906). Phosphorylation of CDKN1B, induces 14-3-3 proteins binding, nuclear export and proteasome-dependent degradation (PubMed:18593906). May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3 (PubMed:10664448). Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis (By similarity). Acts as a positive regulator of mTORC1 signaling by mediating phosphorylation and inhibition of DEPDC5 component of the GATOR1 complex (PubMed:31548394). Also phosphorylates and activates the ATP-binding cassette transporter ABCG2, allowing resistance to drugs through their excretion from cells (PubMed:18056989). Promotes brown adipocyte differentiation (By similarity).
Strongly induced in leukocytes by the JAK/STAT pathway in response to cytokines. Induced by different cellular stresses, heat shock and cytotoxic agents.
Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. EngB GTPase family.
The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry. A rare GJA5 genotype has been detected in combination with a mutation in SCN5A in a large family with atrial standstill.
Heterohexamer; composed of 3 copies of TIMM8 (TIMM8A or TIMM8B) and 3 copies of TIMM13, named soluble 70 kDa complex. Associates with the TIM22 complex, whose core is composed of TIMM22.
Mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane. Also required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. Acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space. The TIMM8-TIMM13 complex mediates the import of proteins such as TIMM23, SLC25A12/ARALAR1 and SLC25A13/ARALAR2, while the predominant TIMM9-TIMM10 70 kDa complex mediates the import of much more proteins.
The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space. However, during the transit of TIMM13 from cytoplasm into mitochondrion, the Cys residues probably coordinate zinc, thereby preventing folding and allowing its transfer across mitochondrial outer membrane (By similarity).
Interacts with HIRA. Weak interaction with histones H2B and H3. Interacts with CK2.
May play a role in chromatin function and histone metabolism via its interaction with HIRA and histones.
Widely expressed. Isoform 1 is predominant in skeletal muscle. Isoform 2 is predominant in liver and heart.
A number of papers have reported some protein lysine acetyltransferase activity in vitro (PubMed:14592445, PubMed:17631499, PubMed:19303003, PubMed:26882543, PubMed:27993683, PubMed:30165671). However, most experiments have been performed in vitro using a protein construct lacking the RNA-binding region at the terminus (PubMed:14592445, PubMed:17631499, PubMed:19303003). Recent evidence suggests that NAT10 mainly acts as a RNA cytidine acetyltransferase in vivo (PubMed:30449621).
Acetylation at Lys-426 is required to activation of rRNA transcription (PubMed:27993683). May be autoacetylated; however ability to autoacetylate in vivo requires additional evidences (PubMed:27993683).
Belongs to the RNA cytidine acetyltransferase family. NAT10 subfamily.
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Interacts with THUMPD1 (PubMed:25653167). Interacts with SUN1 (via N-terminus) (PubMed:17631499). Interacts with TERT (PubMed:18082603).
RNA cytidine acetyltransferase that catalyzes the formation of N(4)-acetylcytidine (ac4C) modification on mRNAs, 18S rRNA and tRNAs (PubMed:25411247, PubMed:25653167, PubMed:30449621). Catalyzes ac4C modification of a broad range of mRNAs, enhancing mRNA stability and translation (PubMed:30449621). mRNA ac4C modification is frequently present within wobble cytidine sites and promotes translation efficiency (PubMed:30449621). Mediates the formation of ac4C at position 1842 in 18S rRNA (PubMed:25411247). May also catalyze the formation of ac4C at position 1337 in 18S rRNA (By similarity). Required for early nucleolar cleavages of precursor rRNA at sites A0, A1 and A2 during 18S rRNA synthesis (PubMed:25411247, PubMed:25653167). Catalyzes the formation of ac4C in serine and leucine tRNAs (By similarity). Requires the tRNA-binding adapter protein THUMPD1 for full tRNA acetyltransferase activity but not for 18S rRNA acetylation (PubMed:25653167). In addition to RNA acetyltransferase activity, also able to acetylate lysine residues of proteins, such as histones, microtubules, p53/TP53 and MDM2, in vitro (PubMed:14592445, PubMed:17631499, PubMed:19303003, PubMed:26882543, PubMed:27993683, PubMed:30165671). The relevance of the protein lysine acetyltransferase activity is however unsure in vivo (PubMed:30449621). Activates telomerase activity by stimulating the transcription of TERT, and may also regulate telomerase function by affecting the balance of telomerase subunit assembly, disassembly, and localization (PubMed:14592445, PubMed:18082603). Involved in the regulation of centrosome duplication by acetylating CENATAC during mitosis, promoting SASS6 proteasome degradation (PubMed:31722219). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Specifically inhibited by remodelin (4-[2-(2-cyclopentylidenehydrazinyl)-4-thiazolyl]-benzonitrile, monohydrobromide), a hydrobromide salt molecule (PubMed:24786082). Remodelin can improve nuclear architecture, chromatin organization and fitness of cells from patients suffering from Hutchinson-Gilford progeria syndrome (HGPS); molecular mechanisms explaining the relation between NAT10 activity and nuclear architecture are however unclear (PubMed:24786082).
Transcriptionally activated by genotoxic agents; possible role in DNA damage and induction of cellular resistance to genotoxic agents.
Escape from X chromosome inactivation results in an increased expression in females (PubMed:31092820, PubMed:31001245). In monocytes and B cells, induced by type I and type II interferons as well as LPS (PubMed:31092820).
Highly expressed in immune cell types such as B-cells, neutrophils, dendritic cells and monocytes, the expression levels are two-three-fold higher in female cells compared to male cells (at protein level) (PubMed:31092820, PubMed:31001245). Expressed at low levels in T-cells and NK cells (PubMed:31001245).
Innate immune adapter that mediates the recruitment and activation of IRF5 downstream of endolysosomal toll-like receptors TLR7, TLR8 and TLR9 (PubMed:32433612). Following recruitment to endolysosome by SLC15A4 downstream of TLR7, TLR8 and TLR9, specifically recruits IRF5 transcription factor via its pLxIS motif, leading to IRF5 activation and subsequent expression of type I interferons (PubMed:32433612). Plays a role in the regulation of endolysosomal pH in immune cells such as B-cells, dendritic cells and monocytes (PubMed:31001245).
Interacts (via pLxIS motif) with IRF5; leading to IRF5 activation (PubMed:32433612). Interacts with SLC15A4; leading to its recruitment to endolysosome (PubMed:32433612).
Some alleles may be associated with systemic lupus erythematosus (SLE); a chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. Because it evades X-chromosome inactivation, its expression is increased in female immune cells which may be involved to SLE striking sex imbalance towards females.
The pLxIS motif constitutes an IRF5-binding motif: following phosphorylation, the phosphorylated pLxIS motif of TASL recruits IRF5.
The phosphorylated pLxIS motif constitutes an IRF5-binding motif, leading to recruitment of the transcription factor IRF5 to induce type-I interferons and other cytokines.
Detected in brain, gastric carcinoma, lung, ovary, skeletal muscle, umbilical cord blood and a cell line derived from kidney proximal tubule epithelium.
Hydrolyzes inorganic pyrophosphate (PubMed:27523597). This activity is essential for correct regulation of mitochondrial membrane potential, and mitochondrial organization and function (PubMed:27523598).
(Microbial infection) Plays a role during influenza virus infection in lungs cells ex vivo. Acts at the level of virus entering host cytoplasm from late endosome.
Expressed predominantly in natural killer cells, and in cytotoxic T cells.
May have a specific function in the mechanism or regulation of T-cell cytolytic activity.
(Microbial infection) Interacts with HTLV-1 protein p40tax.
(Microbial infection) Interacts with hepatitis B virus/HBV protein X.
Belongs to the chaperonin (HSP60) family.
Chaperonin implicated in mitochondrial protein import and macromolecular assembly. Together with Hsp10, facilitates the correct folding of imported proteins. May also prevent misfolding and promote the refolding and proper assembly of unfolded polypeptides generated under stress conditions in the mitochondrial matrix (PubMed:1346131, PubMed:11422376). The functional units of these chaperonins consist of heptameric rings of the large subunit Hsp60, which function as a back-to-back double ring. In a cyclic reaction, Hsp60 ring complexes bind one unfolded substrate protein per ring, followed by the binding of ATP and association with 2 heptameric rings of the co-chaperonin Hsp10. This leads to sequestration of the substrate protein in the inner cavity of Hsp60 where, for a certain period of time, it can fold undisturbed by other cell components. Synchronous hydrolysis of ATP in all Hsp60 subunits results in the dissociation of the chaperonin rings and the release of ADP and the folded substrate protein (Probable).
Homoheptamer arranged in a ring structure (PubMed:1346131, PubMed:11422376, PubMed:25918392). The functional units of these chaperonins consist of heptameric rings of the large subunit Hsp60, which function as a back-to-back double ring. Interacts with 2 heptameric Hsp10 rings to form the symmetrical football complex (PubMed:25918392). Interacts with HRAS (By similarity). Interacts with ATAD3A (PubMed:22664726). Interacts with ETFBKMT and EEF1AKMT3 (PubMed:23349634). Interacts with MFHAS1 (PubMed:24286120).
(Microbial infection) Interacts with C.botulinum neurotoxin type A1 and type A2 (BoNT/A, botA) (PubMed:29649119). Interaction is improved by glycosylation of SV2 (PubMed:29649119).
(Microbial infection) Possible receptor for C.botulinum neurotoxin type D (BoNT/D, botD); note that type D does not usually infect humans.
(Microbial infection) Receptor for C.botulinum neurotoxin type A (BoNT/A, botA); the toxin probably binds via extracellular loop 4 (PubMed:27313224). Recognition by BoNT/A relies on both protein-protein and protein-N-glycosylation; glycosylation of Asn-559 increases its affinity for BoNT/A (PubMed:27313224). Also serves as a receptor for the closely related C.botulinum neurotoxin type A2; glycosylation is not essential but enhances the interaction (PubMed:29649119).
Interacts with SYT1 in a calcium-dependent manner.
N-glycosylated. Upon expression in a kidney cell line the most abundant glycan on Asn-534 is GlcNAc(3)Hex(5), while on Asn-559 and Asn-565 the most abundant glycan is GlcNAc2Fuc1Man3GlcNAc3Gal3. Both Asn-559 and Asn-565 have a high degree of glycan heterogeneity (PubMed:27313224).
Plays a role in the control of regulated secretion in neural and endocrine cells, enhancing selectively low-frequency neurotransmission. Positively regulates vesicle fusion by maintaining the readily releasable pool of secretory vesicles.
Expressed at low level in several tissues including fetal cartilage.
It is uncertain whether Met-1 or Met-34 is the initiator. Orthologous sequences start at a downstream Met.
Interacts with CAMK2B; the presence of Ca(2+)/calmodulin increases the interaction but is not essential (By similarity). Interacts with CAMK2A; this interaction requires CAMK2A activation by Ca(2+) (By similarity).
Potent and specific inhibitor of CaM-kinase II (CAMK2) (By similarity). Plays a role in the maintenance of long-term retrieval-induced memory in response to contextual fear (By similarity). Modulates blood pressure and vascular reactivity via regulation of CAMK2 activity in addition to regulation of left ventricular mass (By similarity). Mediates the NLRP3 inflammasome in cardiomyocytes via acting as an inhibitor of the MAPK14/p38 and MAPK8/JNK pathways, thereby regulating ventricular remodeling and cardiac rhythm post-myocardial infarction (By similarity). Negatively effects insulin sensitivity and promotes lipid formation in adipose tissues independent of CAMK2 signaling (By similarity).
There was previous evidence showing expression across a broad range of tissues. However this paper was retracted as immunoblot data was viewed as unreliable.
(Microbial infection) interacts with Rift valley fever virus NSs (via OmegaXaV motif).
Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription. Interacts with PUF60.
Component of the TFIID basal transcription factor complex, composed of TATA-box-binding protein TBP, and a number of TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473). Component of the TATA-binding protein-free TAF complex (TFTC), the PCAF histone acetylase complex and the STAGA transcription coactivator-HAT complex (PubMed:11564863, PubMed:9885574, PubMed:10373431, PubMed:12601814, PubMed:18206972). The PCAF complex consists at least of TADA2L/ADA2, TADA3L/ADA3, SUPT3H, TAF5L TAF6L, TAF9, TAF10, TAF12 and TRRAP (PubMed:9885574). The TFTC-HAT complex consists at least of TAF5L, TAF6L, TADA3L, SUPT3H, TAF2, TAF4, TAF5, GCN5L2/GCN5, TAF10 and TRRAP (PubMed:10373431, PubMed:12601814). The STAGA transcription coactivator-HAT complex consists at least of SUPT3H, GCN5L2, TAF5L, TAF6L, SUPT7L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9 (PubMed:11564863, PubMed:18206972). The STAGA core complex is associated with a subcomplex required for histone deubiquitination composed of ATXN7L3, ENY2 and USP22 (PubMed:18206972). Interacts with TAF3 (PubMed:11438666). Interacts with LOXL2 (PubMed:25959397). Interacts with TAF12 isoform TAFII20; the interaction is direct (PubMed:7729427).
Lysine deamination at Lys-189 to form allysine is mediated by LOXL2. Allysine formation by LOXL2 results in release of TAF10 from promoters, leading to inhibition of TFIID-dependent transcription.
Monomethylated at Lys-189 by SETD7, leading to increased affinity for RNA polymerase II.
The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription (PubMed:33795473). TFIID recognizes and binds promoters with or without a TATA box via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC) (PubMed:33795473). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473). TAF10 is also component of the PCAF histone acetylase complex, the TATA-binding protein-free TAF complex (TFTC) and the STAGA transcription coactivator-HAT complex (PubMed:18206972, PubMed:11564863, PubMed:9885574, PubMed:10373431, PubMed:12601814). May regulate cyclin E expression (By similarity).
The [KR]-[STA]-K motif is specifically recognized by the SETD7 methyltransferase.
Expressed in testis, ovary, heart and skeletal muscle (PubMed:12213202). Expressed in the cornea, but absent from the corneal endothelium (PubMed:26749309).
Interacts (via zinc-finger domains) with CEBPA (via bZIP domain); the interaction inhibits the transcription factor activity of CEBPA and is required to repress adipogenesis.
The disease is caused by variants affecting the gene represented in this entry. Disease-causing mutations in the OVOL2 promoter alter promoter activity, dysregulate OVOL2 expression, and probably induce OVOL2 ectopic expression in the corneal endothelium.
Zinc-finger transcription repressor factor (PubMed:19700410). Plays a critical role in maintaining the identity of epithelial lineages by suppressing epithelial-to mesenchymal transition (EMT) mainly through the repression of ZEB1, an EMT inducer (By similarity). Positively regulates neuronal differentiation (By similarity). Suppresses cell cycling and terminal differentiation of keratinocytes by directly repressing MYC and NOTCH1 (PubMed:19700410). Important for the correct development of primordial germ cells in embryos (By similarity). Plays dual functions in thermogenesis and adipogenesis to maintain energy balance. Essential for brown/beige adipose tissue-mediated thermogenesis, is necessary for the development of brown adipocytes. In white adipose tissues, limits adipogenesis by blocking CEBPA binding to its transcriptional targets and inhibiting its transcription factor activity (By similarity).
Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.
Belongs to the complex I NDUFB1 subunit family.
Belongs to the G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRB1 sub-subfamily.
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately equal affinity. Mediates Ras activation through G(s)-alpha- and cAMP-mediated signaling. Involved in the regulation of sleep/wake behaviors (PubMed:31473062).
Genetic variations in ADRB1 are associated with inter-individual variability in the resting heart rate. This quantitative trait has been significantly correlated with cardiovascular morbidity and mortality [MIM:607276].
Genetic variations in ADRB1 are associated with the familial natural short sleep 2 (FNSS2) phenotype, an autosomal dominant trait [MIM:618591]. Individuals with this trait require less sleep in any 24-hour period than is typical for their age group.
Homologous desensitization of the receptor is mediated by its phosphorylation by beta-adrenergic receptor kinase.
Interacts (via C-terminus PDZ motif) with RAPGEF2; the interaction is direct. Interacts with GOPC, MAGI3 and DLG4.
The PDZ domain-binding motif mediates competitive interactions with GOPC, MAGI3 and DLG4 and plays a role in subcellular location of the receptor.
Export adapter involved in mRNA nuclear export in cancer cells. Binds and enhances the RNA-binding activity of the nuclear RNA export factor NXF1. Can restore mRNA export function in cells compromised by loss of mRNA export adapters (PubMed:25662211).
Expressed specifically in testis. Also expressed in a wide variety of cancer types, but particularly high levels of expression observed in melanoma cells.
Interacts with NXF1, NXF2, THOC1, THOC5, DDX39B/UAP56 and SRRT.
Belongs to the D-glucuronyl C5-epimerase family.
Converts D-glucuronic acid residues adjacent to N-sulfate sugar residues to L-iduronic acid residues, both in maturing heparan sulfate (HS) and heparin chains. This is important for further modifications that determine the specificity of interactions between these glycosaminoglycans and proteins.
Homodimer (PubMed:30872481). Interacts with HS2ST1.
(Microbial infection) Interacts with human cytomegalovirus protein UL7.
Autophosphorylated on several tyrosine residues in response to FLT3LG binding. FLT3LG binding also increases phosphorylation of mutant kinases that are constitutively activated. Dephosphorylated by PTPRJ/DEP-1, PTPN1, PTPN6/SHP-1, and to a lesser degree by PTPN12. Dephosphorylation is important for export from the endoplasmic reticulum and location at the cell membrane.
Can be used as diagnostic tool to establish the exact cause of acute myeloid leukemia, and to determine the optimal therapy.
Detected in bone marrow, in hematopoietic stem cells, in myeloid progenitor cells and in granulocyte/macrophage progenitor cells (at protein level). Detected in bone marrow, liver, thymus, spleen and lymph node, and at low levels in kidney and pancreas. Highly expressed in T-cell leukemia.
Monomer in the absence of bound FLT3LG. Homodimer in the presence of bound FLT3LG. Interacts with FIZ1 following ligand activation (By similarity). Interacts with FES, FER, LYN, FGR, HCK, SRC and GRB2. Interacts with PTPRJ/DEP-1 and PTPN11/SHP2. Interacts with RNF115 and RNF126 (By similarity).
N-glycosylated, contains complex N-glycans with sialic acid.
Present in an inactive conformation in the absence of bound ligand. FLT3LG binding leads to dimerization and activation by autophosphorylation.
Rapidly ubiquitinated by UBE2L6 and the E3 ubiquitin-protein ligase SIAH1 after autophosphorylation, leading to its proteasomal degradation.
The gene represented in this entry may be involved in disease pathogenesis. Somatic mutations that lead to constitutive activation of FLT3 are frequent in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the activation loop of the kinase domain can result in a constitutively activated kinase.
The juxtamembrane autoregulatory region is important for normal regulation of the kinase activity and for maintaining the kinase in an inactive state in the absence of bound ligand. Upon tyrosine phosphorylation, it mediates interaction with the SH2 domains of numerous signaling partners. In-frame internal tandem duplications (ITDs) result in constitutive activation of the kinase. The activity of the mutant kinase can be stimulated further by FLT3LG binding.
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways.
Activity is increased by the procollagen C-endopeptidase enhancer protein.
Interacts with POSTN, the interaction promotes deposition on the extracellular matrix.
Metalloprotease that plays key roles in regulating the formation of the extracellular matrix (ECM) via processing of various precursor proteins into mature functional enzymes or structural proteins (PubMed:33206546). Thereby participates in several developmental and physiological processes such as cartilage and bone formation, muscle growth and homeostasis, wound healing and tissue repair (PubMed:33169406, PubMed:32636307). Roles in ECM formation include cleavage of the C-terminal propeptides from procollagens such as procollagen I, II and III or the proteolytic activation of the enzyme lysyl oxidase LOX, necessary to formation of covalent cross-links in collagen and elastic fibers (PubMed:31152061, PubMed:33206546). Additional substrates include matricellular thrombospondin-1/THBS1 whose cleavage leads to cell adhesion disruption and TGF-beta activation (PubMed:32636307).
Plays an important role in bone repair by acting as a coactivator of BMP7.
Proteolytically activated in the trans-Golgi network by furin-like/paired basic proprotein convertases, cleavage is not required for secretion.
Belongs to the glycosyltransferase 49 family.
Beta-1,4-glucuronyltransferase involved in O-mannosylation of alpha-dystroglycan (DAG1) (PubMed:19587235, PubMed:23359570, PubMed:25279699, PubMed:25279697). Transfers a glucuronic acid (GlcA) residue onto a xylose (Xyl) acceptor to produce the glucuronyl-beta-1,4-xylose-beta disaccharide primer, which is further elongated by LARGE1, during synthesis of phosphorylated O-mannosyl glycan (PubMed:25279699, PubMed:25279697). Phosphorylated O-mannosyl glycan is a carbohydrate structure present in alpha-dystroglycan (DAG1), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity (PubMed:25279699, PubMed:25279697). Required for axon guidance; via its function in O-mannosylation of alpha-dystroglycan (DAG1) (By similarity).
In the adult, highly expressed in heart, brain, skeletal muscle and kidney and to a lesser extent in placenta, pancreas, spleen, prostate, testis, ovary, small intestine and colon. Very weak expression in lung, liver, thymus and peripheral blood leukocytes. In fetal highly expressed in brain and kidney and to a lesser extent in lung and liver.
Was initially characterized as a beta-1,3-N-acetylglucosaminyltransferase involved in the synthesis of poly-N-acetyllactosamine, able to initiate the synthesis or the elongation of the linear poly-N-acetyllactosaminoglycans (PubMed:9405606). However, it was later shown that it acts as a beta-1,4-glucuronyltransferase (PubMed:25279699, PubMed:25279697).
Cell surface receptor for PLXNB1 and PLXNB2 that plays an important role in cell-cell signaling (PubMed:20877282). Regulates GABAergic synapse development (By similarity). Promotes the development of inhibitory synapses in a PLXNB1-dependent manner (By similarity). Modulates the complexity and arborization of developing neurites in hippocampal neurons by activating PLXNB1 and interaction with PLXNB1 mediates activation of RHOA (PubMed:19788569). Promotes the migration of cerebellar granule cells (PubMed:16055703). Plays a role in the immune system; induces B-cells to aggregate and improves their viability (in vitro) (PubMed:8876214). Induces endothelial cell migration through the activation of PTK2B/PYK2, SRC, and the phosphatidylinositol 3-kinase-AKT pathway (PubMed:16055703).
Homodimer (PubMed:20877282). Interacts with PLXNB2 (By similarity). Interacts with PLXNB1 (PubMed:10520995).
Strongly expressed in skeletal muscle, peripheral blood lymphocytes, spleen, and thymus and also expressed at lower levels in testes, brain, kidney, small intestine, prostate, heart, placenta, lung and pancreas, but not in colon and liver.
Interacts with C-terminus of the glutamate receptor GRID2 via PDZ domain.
Postsynaptic scaffolding protein at the parallel fiber-Purkinje cell synapse, where it may serve to link GRID2 with actin cytoskeleton and various signaling molecules.
Acts as a central player within a network of stress response pathways promoting cellular adaptability. The E3 ligase HUWE1 assists HAPSTR1 in controlling stress signaling and in turn, HUWE1 feeds back to promote the degradation of HAPSTR1. HAPSTR1 represents a central coordination mechanism for stress response programs (PubMed:35776542). Functions as a negative regulator of TP53/P53 in the cellular response to telomere erosion and probably also DNA damage (PubMed:33660365). May attenuate p53/TP53 activation through the E3 ubiquitin ligase HUWE1 (PubMed:33660365).
Homooligomer (PubMed:35776542). Heterooligomer with HAPSTR2; the interaction is direct and stabilizes HAPSTR1 (PubMed:36631436). Interacts with HUWE1 (PubMed:35776542).
Induced by specific types of stressors like DNA damage, cellular starvation and proteotoxicity.
Ubiquitinated by HUWE1. Promotes HAPSTR1 degradation through polyubiquitination.
Down-regulated in the occipital lobe of an early stage Alzheimer disease patients.
Potential NADPH-dependent oxidoreductase. May be involved in the regulation of neuronal survival, differentiation and axonal outgrowth.
Expressed in fetal heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas.
Highly expressed in heart, skeletal muscle, and brain. Lower expression in liver, lung, kidney, pancreas and placenta.
The KRAB domain is required for transcriptional repression.
Transcriptional repressor. Regulator of transcriptional factor complexes and may suppress SRE and AP-1 transcription activities mediated by growth factor signaling pathways.
(Microbial infection) The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the budding of enveloped viruses (HIV-1 and other lentiviruses). Via its interaction with PDCD6IP involved in HIV-1 p6- and p9-dependent virus release.
ISGylated. Isgylation weakens its interaction with VPS4A.
Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released (PubMed:12860994, PubMed:18209100). The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis (PubMed:21310966). Together with SPAST, the ESCRT-III complex promotes nuclear envelope sealing and mitotic spindle disassembly during late anaphase (PubMed:26040712). Plays a role in the endosomal sorting pathway. ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. When overexpressed, membrane-assembled circular arrays of CHMP4B filaments can promote or stabilize negative curvature and outward budding. CHMP4A/B/C are required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413).
Probable core component of the endosomal sorting required for transport complex III (ESCRT-III). ESCRT-III components are thought to multimerize to form a flat lattice on the perimeter membrane of the endosome. Several assembly forms of ESCRT-III may exist that interact and act sequentially. Interacts with CHMP6 and CHMP4C. Interacts with PDCD6IP; the interaction is direct. Interacts with VPS4A; the interaction is direct. Interacts with VPS4B; the interaction is direct. Interacts with CHMP7. Interacts with CFTR; the interaction requires misfolded CFTR. Interacts with PTPN23.
Widely expressed. Expressed at higher level in heart and skeletal muscle. Also expressed in brain, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung and peripheral blood lymphocytes.
A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) in the cardiovascular system (PubMed:8631948, PubMed:19965576). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:8631948, PubMed:19965576). Catalyzes the epoxidation of double bonds of PUFA (PubMed:8631948, PubMed:19965576). Converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EpETrE), likely playing a major role in the epoxidation of endogenous cardiac arachidonic acid pools (PubMed:8631948). In endothelial cells, participates in eicosanoids metabolism by converting hydroperoxide species into hydroxy epoxy metabolites. In combination with 15-lipoxygenase metabolizes arachidonic acid and converts hydroperoxyicosatetraenoates (HpETEs) into hydroxy epoxy eicosatrienoates (HEETs), which are precursors of vasodilatory trihydroxyicosatrienoic acids (THETAs). This hydroperoxide isomerase activity is NADPH- and O2-independent (PubMed:19737933). Catalyzes the monooxygenation of a various xenobiotics, such as danazol, amiodarone, terfenadine, astemizole, thioridazine, tamoxifen, cyclosporin A and nabumetone (PubMed:19923256). Catalyzes hydroxylation of the anthelmintics albendazole and fenbendazole (PubMed:23959307). Catalyzes the sulfoxidation of fenbedazole (PubMed:19923256).
Highly expressed in heart, present at lower levels in liver, kidney and skeletal muscle (at protein level).
Expressed at highest levels in heart, kidney, placenta and lung, and at lowest levels in brain, thymus and spleen. Present in vascular endothelial cells and placenta. Over-expressed in placenta from women with pre-eclampsia (at protein level).
Homotrimer. Interacts with DAB2 (By similarity). Interacts with NOS3, DNM2, WASL and CAV1.
May negatively regulate transcription of the NOSTRIN gene.
Multivalent adapter protein which may decrease NOS3 activity by inducing its translocation away from the plasma membrane.
The F-BAR domain is necessary for membrane targeting.
The SH3 domain mediates interaction with NOS3, DNM2 and WASL.
Endoplasmic reticulum (ER)-shaping membrane protein that plays a role in determining ER morphology (PubMed:30032983). Involved in the stabilization of nascent three-way ER tubular junctions within the ER network (PubMed:24223779, PubMed:25404289, PubMed:25548161, PubMed:27619977). May also play a role as a curvature-stabilizing protein within the three-way ER tubular junction network (PubMed:25404289). May be involved in limb development (By similarity). Is involved in central nervous system development (PubMed:30032983).
Expressed in neural precursor cells, where it is detected at the growth-cone-like structure and branching sites of neurite-like processes.
Homodimer; homodimerization requires the C4-type zinc finger motif and decreases during mitosis in a phosphorylation-dependent manner (PubMed:27619977).
Homodimer; homodimerization requires the C4-type zinc finger motif and decreases during mitosis in a phosphorylation-dependent manner.
Myristoylated; myristoylation is necessary for the endoplasmic reticulum (ER) three-way ER tubular junction formation, but is not required neither for membrane translocation, membrane topology formation, nor for the specific localization to ER membranes (PubMed:24223779).
Phosphorylated. Phosphorylation occurs at Ser-177, Ser-182, Ser-217, Ser-227, Ser-321 and Ser-384 during interphase (PubMed:27619977). Phosphorylation occurs at Ser-114, Ser-153, Ser-194, Thr-211 and Ser-353 during mitosis; these phosphorylations reduce both its homodimerization and the ER three-way tubular junction formation (PubMed:27619977).
Plays a role in determining ER morphology.
Subject to proteasomal degradation following phosphorylation during mitosis (PubMed:27619977).
The C4-type zinc finger motif is necessary both for its ER three-way tubular junction localization and formation.
The transmembrane domain 1 and 2 function as a signal-anchor and stop-transfer sequence, respectively, generating a double-spanning integral membrane protein with a N- and C-terminal cytoplasmic orientation (PubMed:24223779). Transmembrane domain 1 and 2 are probably sufficient to mediate membrane translocation and topology formation in a N-myristoylation-independent manner (PubMed:24223779). Transmembrane domain 2 is sufficient to block the protein secretion pathway (PubMed:24223779). The two coiled-coil domains are necessary for its endoplasmic reticulum (ER) three-way tubular junction localization (PubMed:27619977). The C4-type zinc finger motif is necessary both for its ER three-way tubular junction localization and formation (PubMed:24223779, PubMed:27619977).
Contains a GTPase activator for the Rho-type GTPases (RhoGAP) domain that would be able to negatively regulate the actin cytoskeleton as well as cell spreading. However, also contains N-terminally a BAR-domin which is able to play an autoinhibitory effect on this RhoGAP activity.
Expressed on cells of the hematopoietic lineage. Detected in dendritic cells and epidermal Langerhans cells. Expressed in peripheral blood mononuclear cells, in all leukemia/lymphoma cell lines. Detected also in some solid tumors and tissues such as cancerous and non-cancerous tissue.
HA-1 forms a complex with MHC class I HLA-A*0201.
Infusion of lymphocyte from mHag HA-1-negative donors results in a durable remission in mHag HA-1-positive patients with leukemia or multiple myeloma.
Precursor of the histocompatibility antigen HA-1. More generally, minor histocompatibility antigens (mHags) refer to immunogenic peptide which, when complexed with MHC, can generate an immune response after recognition by specific T-cells. The peptides are derived from polymorphic intracellular proteins, which are cleaved by normal pathways of antigen processing. The binding of these peptides to MHC class I or class II molecules and its expression on the cell surface can stimulate T-cell responses and thereby trigger graft rejection or graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation from HLA-identical sibling donor. GVHD is a frequent complication after bone marrow transplantation (BMT), due to mismatch of minor histocompatibility antigen in HLA-matched sibling marrow transplants. Specifically, mismatching for mHag HA-1 which is recognized as immunodominant, is shown to be associated with the development of severe GVHD after HLA-identical BMT. HA-1 is presented to the cell surface by MHC class I HLA-A*0201, but also by other HLA-A alleles. This complex specifically elicits donor-cytotoxic T-lymphocyte (CTL) reactivity against hematologic malignancies after treatment by HLA-identical allogenic BMT. It induces cell recognition and lysis by CTL.
Rho-GAP domain is able to regulate RhoGTPase activity, actin cytoskeleton and cell spreading. However N-terminally BAR domain plays an autoinhibitory role.
The HA-1H allele is presented on the cell surface and recognized by CTL, whereas the HA-1R allele is poorly represented by HLA-A and non-immunogenic, although HA-1R allelic frequency is the highest (PubMed:9820595, PubMed:16399573).
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A16 subfamily.
Highly expressed in peripheral tissues, particularly in testis, pancreas, and prostate.
Converts glycerol-3-phosphate to 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) by incorporating an acyl moiety at the sn-1 position of the glycerol backbone (PubMed:18238778). Active against both saturated and unsaturated long-chain fatty acyl-CoAs (PubMed:18238778). Protects cells against lipotoxicity (PubMed:30846318).
Ubiquitous. High levels in testis. Relatively high level of expression in skeletal muscle and heart. Relatively low level of expression in lung.
Component of a ribonucleoprotein (RNP) complex (By similarity). Interacts with DDX6 (PubMed:31422817).
Required for oocyte meiotic maturation. May be involved in the storage of translationally inactive mRNAs and protect them from degradation (By similarity). Plays a role in control of mRNA translation (By similarity).
Calcium-regulated non-lysosomal thiol-protease. Proteolytically cleaves CTBP1 at 'His-409'. Mediates, with UTP25, the proteasome-independent degradation of p53/TP53 (PubMed:23357851, PubMed:27657329).
Homodimer; via EF-hand domain 4 (PubMed:24846670). Interacts with TTN/titin (PubMed:14583192). Interacts with CMYA5; this interaction, which results in CMYA5 proteolysis, may protect CAPN3 from autolysis (PubMed:20634290). Interacts with SIMC1 (PubMed:23707407). Interacts with UTP25; the interaction is required for CAPN3 translocation to the nucleolus (PubMed:23357851, PubMed:27657329).
By viral infection, upon exposure to double-stranded RNA, or upon treatment with either interferon-gamma or interferon-beta.
Expressed in keratinocytes, monocytes and in resting dendritic cells.
May play a role in the regulation of immune cell function. Cytokine that imparts cellular protection against viral infection in a species-specific manner. Activates the interferon-stimulated response element signaling pathway. It is able to directly modulate cytokine release from monocytes and dendritic cells. Binds heparin.
(Microbial infection) Interacts with human adenovirus 5 E1A protein (PubMed:23864635).
Autophosphorylated on numerous tyrosine residues. Can also autophosphorylate on serine and threonine residues (in vitro).
Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities (PubMed:21127067, PubMed:8769099, PubMed:30773093, PubMed:20981014, PubMed:23665168). Exhibits a substrate preference for proline at position P+1 and arginine at position P-3 (PubMed:23665168). Plays an important role in double-strand breaks (DSBs) repair following DNA damage (PubMed:31024071). Mechanistically, phosphorylates RNF169 and increases its ability to block accumulation of TP53BP1 at the DSB sites thereby promoting homologous recombination repair (HRR) (PubMed:30773093). Also acts as a positive regulator of transcription by acting as a CTD kinase that mediates phosphorylation of the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A (PubMed:25620562, PubMed:29849146). May play a role in a signaling pathway regulating nuclear functions of cell proliferation (PubMed:14500717). Modulates alternative splicing by phosphorylating the splice factor SRSF6 (By similarity). Has pro-survival function and negatively regulates the apoptotic process (By similarity). Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1 (By similarity). This in turn inhibits p53/TP53 activity and apoptosis (By similarity). Phosphorylates SEPTIN4, SEPTIN5 and SF3B1 at 'Thr-434' (By similarity).
Expressed in the developing central nervous system. Overexpressed 1.5-fold in fetal Down syndrome brain.
Inhibited by RANBP9 (PubMed:14500717). Inhibited by harmine, leucettamine B and leucettine L41 (PubMed:22998443).
Interacts with RAD54L2/ARIP4 (By similarity). Interacts with CRY2 (By similarity). Interacts with RANBP9 (PubMed:14500717). Interacts with WDR68 (PubMed:14593110). Interacts with SIRT1 (By similarity).
The histidine-rich domain (HRD) region is intrinsically disordered and promotes the formation of phase-separated liquid droplets that enhance its ability to phosphorylate the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNA Pol II).
The polyhistidine repeats act as targeting signals to nuclear speckles.
Ubiquitous. Highest levels in skeletal muscle, testis, fetal lung and fetal kidney.
Hydrolyzes UDP-glucose to glucose 1-phosphate and UMP and ADP-ribose to ribose 5-phosphate and AMP. The physiological substrate is probably UDP-glucose. Poor activity on other substrates such as ADP-glucose, CDP-glucose, GDP-glucose and GDP-mannose.
Homodimer (PubMed:16709157). Interacts (via the MENTAL domain) with STARD3NL (PubMed:16709157). Interacts (via FFAT motif) with VAPA. Interacts (via FFAT motif) with VAPB (PubMed:24105263). Interacts (via FFAT motif) with MOSPD2 (via MSP domain) (PubMed:29858488).
Tethering protein that creates contact site between the endoplasmic reticulum and late endosomes: localizes to late endosome membranes and contacts the endoplasmic reticulum via interaction with VAPA and VAPB (PubMed:24105263).
The MENTAL domain anchors the protein in endosome membranes and exposes the START domain in the cytosol (By similarity). It binds cholesterol and mediates homotypic as well as heterotypic interactions between STARD3 and STARD3NL (PubMed:15718238, PubMed:16709157).
Electroneutral Cl(-)/HCO3(-) antiporter that favors chloride ion entry and efflux of hydrogencarbonate and sodium ion across the basolateral membrane and may participate in salivary secretion (PubMed:27114614). Also mediates Cl(-)/HCO3(-) exchange activity in the presence of K(+) as well as Cs(+), Li(+), and Rb(+) (By similarity). Does not contribute to Cl(-)/HCO3(-) exchanger in the apical membrane of the upper villous epithelium (By similarity).
(Microbial infection) Interacts with human cytomegalovirus UL27.
Acetylation at the major site Lys-195 is important for oligomerization and ability to degrade its target substrates. Deacetylated by SIRT1.
Homoheptamer; the stability of the heptamer is essential for the specific activation of the trypsine-like subunit and inhibition of the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits of the proteasome. Interacts with p53/TP53 and MDM2. Interacts with MAP3K3 (By similarity). Associates with the proteasome. Interacts with CCAR2. Interacts with PSME3IP1 (via C-terminus); the interaction is direct and promotes the association of PSME3 with the 20S proteasome (PubMed:29934401). Interacts with COIL; the interaction is inhibited by PSME3IP1 (PubMed:29934401).
Phosphorylated by MAP3K3 (By similarity). Phosphorylation at Ser-247 promotes its association with CCAR2.
Subunit of the 11S REG-gamma (also called PA28-gamma) proteasome regulator, a doughnut-shaped homoheptamer which associates with the proteasome. 11S REG-gamma activates the trypsin-like catalytic subunit of the proteasome but inhibits the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits. Facilitates the MDM2-p53/TP53 interaction which promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53/TP53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. May also be involved in cell cycle regulation. Mediates CCAR2 and CHEK2-dependent SIRT1 inhibition (PubMed:25361978).
The C-terminal sequences affect heptamer stability and proteasome affinity.
Up-regulated in thyroid carcinoma cells.
Expressed in late erythroblast differentiation stages (PubMed:26968549). Underexpressed in ovarian cancer epithelia cells compared with normal human ovarian surface epithelia (PubMed:28594398).
Plays a role in erythroid differentiation (PubMed:26968549). Involved in cell proliferation and tumor cell growth suppression (PubMed:28594398). Involved in the metabolic reprogramming of cancer cells in a PDK4-dependent manner (PubMed:28594398).
Up-regulated by the erythroid transcription factor GATA1 (PubMed:26968549).
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins (PubMed:15247280, PubMed:15496420, PubMed:18284575, PubMed:20061386, PubMed:21532592). In vitro catalyzes 'Lys-11'-, as well as 'Lys-48'-linked polyubiquitination (PubMed:15247280, PubMed:15496420, PubMed:18284575, PubMed:20061386, PubMed:21532592). Cooperates with the E2 CDC34 and the SCF(FBXW11) E3 ligase complex for the polyubiquitination of NFKBIA leading to its subsequent proteasomal degradation (PubMed:20347421). Acts as an initiator E2, priming the phosphorylated NFKBIA target at positions 'Lys-21' and/or 'Lys-22' with a monoubiquitin (PubMed:10329681). Ubiquitin chain elongation is then performed by CDC34, building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin (PubMed:10329681). Acts also as an initiator E2, in conjunction with RNF8, for the priming of PCNA (PubMed:18948756). Monoubiquitination of PCNA, and its subsequent polyubiquitination, are essential events in the operation of the DNA damage tolerance (DDT) pathway that is activated after DNA damage caused by UV or chemical agents during S-phase (PubMed:18948756). Associates with the BRCA1/BARD1 E3 ligase complex to perform ubiquitination at DNA damage sites following ionizing radiation leading to DNA repair (PubMed:16628214). Targets DAPK3 for ubiquitination which influences promyelocytic leukemia protein nuclear body (PML-NB) formation in the nucleus (PubMed:18515077). In conjunction with the MDM2 and TOPORS E3 ligases, functions ubiquitination of p53/TP53 (PubMed:12646252, PubMed:15280377). In conjunction with the CBL E3 ligase, targets EGFR for polyubiquitination at the plasma membrane as well as during its internalization and transport on endosomes (PubMed:18508924). In conjunction with the STUB1 E3 quality control E3 ligase, ubiquitinates unfolded proteins to catalyze their immediate destruction (PubMed:11743028). Together with RNF135, catalyzes the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIGI to activate the downstream signaling pathway that leads to interferon beta production (PubMed:28469175). Together with ZNF598, catalyzes ubiquitination of 40S ribosomal proteins in response to ribosome collisions (PubMed:28685749). In cooperation with the GATOR2 complex, catalyzes 'Lys-6'-linked ubiquitination of NPRL2 (PubMed:36528027).
Interacts with SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex; when Cullin is neddylated, the interaction between the E2 and the SCF complex is strengthened. Interacts with DAPK3. Interacts with BRCA1; the DNA damage checkpoint promotes the association with BRCA1 after ionizing radiation. Interacts non-covalently with ubiquitin. Interacts with E3 ubiquitin-protein ligase CBLC. Interacts with UBTD1 (PubMed:24211586). Interacts with RIGI and RNF135; involved in RIGI ubiquitination and activation (PubMed:28469175).
Alpha N-methyltransferase that methylates the N-terminus of target proteins containing the N-terminal motif [Ala/Pro/Ser]-Pro-Lys when the initiator Met is cleaved. Specifically catalyzes monomethylation of exposed alpha-amino group of Ala or Ser residue in the [Ala/Ser]-Pro-Lys motif and Pro in the Pro-Pro-Lys motif (PubMed:24090352, PubMed:30417120). Predominantly functions as a mono-methyltransferase but is also able to di-/tri-methylate the GPKRIA peptide and di-methylate the PPKRIA peptide (in vitro) (PubMed:30417120). May activate NTMT1 by priming its substrates for trimethylation (PubMed:24090352).
Belongs to the methyltransferase superfamily. NTM1 family.
Expressed specifically in testis during spermatogenesis.
Iron-sulfur cluster scaffold protein which can assemble [4Fe-4S] clusters and deliver them to target proteins.
Monomer and homohexamer; the apo-NFU1 is a monomer, while the holo-NFU1 is a hexamer composed of a trimer of dimer that is probably linked by some 4Fe-4S cluster (PubMed:27818104). Interacts with HIRA and EPM2A/laforin (PubMed:12915448). Interacts with BOLA3 (PubMed:27532772). Interacts with HSPA9 (PubMed:26702583).
Ubiquitous. Expression in adult lung is weak compared to fetal lung.
Homodimer; disulfide-linked. When phosphorylated, interacts with PTPN11/SHP2, GRB2 and CSK.
In contrast to its orthologs it harbors a signal sequence.
Negatively regulates TCR (T-cell antigen receptor)-mediated signaling in T-cells. Involved in positive selection of T-cells.
Phosphorylated on tyrosines by LCK, FYN or ZAP70 upon TCR activation; which leads to the recruitment of PTPN11, GRB2 and CSK.
Specifically expressed in T- and B-cells. Present in plasma cells but not in germinal center B-cells (at protein level). Expressed in T- and B-cell lymphoma.
Expressed chiefly in non-neuronal tissues. Particularly abundant in epithelial and glandular tissues including pancreas, prostate, mammary, stomach, colon and lung.
May be involved in transferrin trafficking. Likely to power actin-based membrane trafficking in many physiologically crucial tissues.
Activated by autophosphorylation. Prior phosphorylation at Tyr-523 by SRC inhibits ulterior autophosphorylation at Tyr-412. Activated by phorbol myristate acetate, phosphatidic acid and poly-Lys. Binding (via SH2 domain) of HCLS1 that is already phosphorylated by SYK strongly increases kinase activity.
Detected in neutrophils, monocytes and natural killer cells (at protein level). Detected in monocytes and large lymphocytes.
Interacts with ITGB1, ITGB2, MS4A2/FCER1B, FCER1G, FCGR2A and/or FCGR2B. Interacts (via SH2 domain) with SYK (tyrosine phosphorylated). Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). Interacts with PTK2/FAK1. Interacts (via SH2 domain) with HCLS1 (tyrosine phosphorylated by SYK). Interacts with SIRPA and PTPNS1. Interacts (not phosphorylated on tyrosine residues) with CBL; FGR tyrosine phosphorylation promotes dissociation. Interacts with PIK3R1 and FASLG (By similarity). Interacts with CLNK (By similarity).
Mutations that cause aberrant kinase activation can confer oncogene activity and promote aberrant cell proliferation.
Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors devoid of kinase activity and contributes to the regulation of immune responses, including neutrophil, monocyte, macrophage and mast cell functions, cytoskeleton remodeling in response to extracellular stimuli, phagocytosis, cell adhesion and migration. Promotes mast cell degranulation, release of inflammatory cytokines and IgE-mediated anaphylaxis. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as MS4A2/FCER1B, FCGR2A and/or FCGR2B. Acts downstream of ITGB1 and ITGB2, and regulates actin cytoskeleton reorganization, cell spreading and adhesion. Depending on the context, activates or inhibits cellular responses. Functions as negative regulator of ITGB2 signaling, phagocytosis and SYK activity in monocytes. Required for normal ITGB1 and ITGB2 signaling, normal cell spreading and adhesion in neutrophils and macrophages. Functions as positive regulator of cell migration and regulates cytoskeleton reorganization via RAC1 activation. Phosphorylates SYK (in vitro) and promotes SYK-dependent activation of AKT1 and MAP kinase signaling. Phosphorylates PLD2 in antigen-stimulated mast cells, leading to PLD2 activation and the production of the signaling molecules lysophosphatidic acid and diacylglycerol. Promotes activation of PIK3R1. Phosphorylates FASLG, and thereby regulates its ubiquitination and subsequent internalization. Phosphorylates ABL1. Promotes phosphorylation of CBL, CTTN, PIK3R1, PTK2/FAK1, PTK2B/PYK2 and VAV2. Phosphorylates HCLS1 that has already been phosphorylated by SYK, but not unphosphorylated HCLS1. Together with CLNK, it acts as a negative regulator of natural killer cell-activating receptors and inhibits interferon-gamma production (By similarity).
Phosphorylated. Autophosphorylated on tyrosine residues. Becomes phosphorylated in response to FCGR2A and/or FCGR2B engagement, cell adhesion and signaling by ITGB2. Prior phosphorylation at Tyr-523 by SRC inhibits ulterior autophosphorylation at Tyr-412.
Ubiquitinated. Becomes ubiquitinated in response to ITGB2 signaling; this does not lead to degradation.
Associates with HSF2 (PubMed:9651507). The interaction seems to occur between the trimerization domain of HSF2 and the N-terminal hydrophilic region of HSF2BP (PubMed:9651507). Interacts (via C-terminus) with BNC1 (By similarity). Interacts (via N-terminus) with BRCA2 and BRME1; the interactions are direct and allow the formation of a ternary complex. The complex BRME1:HSF2BP:BRCA2 interacts with SPATA22, MEIOB and RAD51 (By similarity) (PubMed:31242413).
Meiotic recombination factor component of recombination bridges involved in meiotic double-strand break repair. Modulates the localization of recombinases DMC1:RAD51 to meiotic double-strand break (DSB) sites through the interaction with BRCA2 and its recruitment during meiotic recombination (By similarity) (PubMed:31242413). Indispensable for the DSB repair, homologous synapsis, and crossover formation that are needed for progression past metaphase I, is essential for spermatogenesis and male fertility (By similarity). Required for proper recombinase recruitment in female meiosis (By similarity). Inhibits BNC1 transcriptional activity during spermatogenesis, probably by sequestering it in the cytoplasm (By similarity). May be involved in modulating HSF2 activation in testis (PubMed:9651507).
Testis specific. Overexpressed in some tumors (PubMed:31242413).
Ubiquitous; strongly expressed in testis and some cancer cell lines.
(Microbial infection) Interacts with SV40 VP1.
(Microbial infection) Interacts with human herpes virus 1 (HHV-1) transcriptional regulator ICP22; this interaction recruits HSPA8/HSP40 to discrete nuclear foci.
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with PACRG. Interacts with HSPH1/HSP105. Interacts with IRAK1BP1 and BAG1. Interacts with DNAJC7. Interacts with DNAJB12 (via J domain) (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661). Interacts with DNAJB14 (via J domain) (PubMed:23018488, PubMed:24732912, PubMed:27916661). Interacts (via C-terminus) with the E3 ligase CHIP forming a 210 kDa complex of one CHIP and two HSPA8 molecules. Interacts with CITED1 (via N-terminus); the interaction suppresses the association of CITED1 to p300/CBP and Smad-mediated transcription transactivation. Component of the PRP19-CDC5L splicing complex composed of a core complex comprising a homotetramer of PRPF19, CDC5L, PLRG1 and BCAS2, and at least three less stably associated proteins CTNNBL1, CWC15 and HSPA8. Interacts with TRIM5. Part of a complex composed at least of ASH2L, EMSY, HCFC1, HSPA8, CCAR2, MATR3, MKI67, RBBP5, TUBB2A, WDR5 and ZNF335; this complex may have a histone H3-specific methyltransferase activity. Interacts with METTL21A. Following LPS binding, may form a complex with CXCR4, GDF5 and HSP90AA1. Interacts with PRKN. Interacts with FOXP3. Interacts with DNAJC9 (via J domain) (PubMed:17182002). Interacts with MLLT11 (PubMed:24880125). Interacts with RNF207 (PubMed:25281747). Interacts with DNAJC21 (PubMed:27346687). Interacts with DNAJB2 (PubMed:15936278). Interacts with TTC1 (via TPR repeats) (PubMed:15708368). Interacts with SGTA (via TPR repeats) (By similarity). Interacts with HSF1 (via transactivation domain) (PubMed:9499401). Interacts with HOPX, HSP40 and HSP90 (PubMed:27708256). Interacts with STUB1 (PubMed:27708256). Interacts with BAG2 (PubMed:24318877). Interacts with BAG3 (PubMed:27474739, PubMed:24318877). Interacts with DNAJC12 (PubMed:24122553). Interacts with ZMYND10 (PubMed:29601588). Interacts with HSPC138 (PubMed:25760597). Interacts with BCL2L1, GIMAP5 and MCL1; the interaction with BCL2L1 or MCL1 is impaired in the absence of GIMAP5 (By similarity). Interacts with NLPR12 (PubMed:17947705). Interacts with TTC4 (PubMed:18320024). Interacts with TOMM70; the interaction is required for preprotein mitochondrial import (PubMed:12526792). May interact with DNJC9; the interaction seems to be histone-dependent (PubMed:33857403). Interacts with BAG5 and JPH2; the interaction with JPH2 is increased in the presence of BAG5 (PubMed:35044787).
Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, chaperone-mediated autophagy, activation of proteolysis of misfolded proteins and the formation and dissociation of protein complexes. Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation (PubMed:2799391, PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488, PubMed:36586411). This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488, PubMed:12526792). The co-chaperones have been shown to not only regulate different steps of the ATPase cycle of HSP70, but they also have an individual specificity such that one co-chaperone may promote folding of a substrate while another may promote degradation (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488, PubMed:12526792). The affinity of HSP70 for polypeptides is regulated by its nucleotide bound state. In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. HSP70 goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release. The HSP70-associated co-chaperones are of three types: J-domain co-chaperones HSP40s (stimulate ATPase hydrolysis by HSP70), the nucleotide exchange factors (NEF) such as BAG1/2/3 (facilitate conversion of HSP70 from the ADP-bound to the ATP-bound state thereby promoting substrate release), and the TPR domain chaperones such as HOPX and STUB1 (PubMed:24318877, PubMed:27474739, PubMed:24121476, PubMed:26865365). Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70 (PubMed:12526792). Acts as a repressor of transcriptional activation. Inhibits the transcriptional coactivator activity of CITED1 on Smad-mediated transcription. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. May have a scaffolding role in the spliceosome assembly as it contacts all other components of the core complex. Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:10722728, PubMed:11276205). Substrate recognition component in chaperone-mediated autophagy (CMA), a selective protein degradation process that mediates degradation of proteins with a -KFERQ motif: HSPA8/HSC70 specifically recognizes and binds cytosolic proteins bearing a -KFERQ motif and promotes their recruitment to the surface of the lysosome where they bind to lysosomal protein LAMP2 (PubMed:2799391, PubMed:11559757, PubMed:36586411). KFERQ motif-containing proteins are eventually transported into the lysosomal lumen where they are degraded (PubMed:2799391, PubMed:11559757, PubMed:36586411). Participates in the ER-associated degradation (ERAD) quality control pathway in conjunction with J domain-containing co-chaperones and the E3 ligase STUB1 (PubMed:23990462). Interacts with VGF-derived peptide TLQP-21 (PubMed:28934328).
Trimethylation at Lys-561 reduces fibrillar SNCA binding.
Involved in the regulation of endothelial cell proliferation and migration. Mediates H(2)O(2)-induced leukocyte chemotaxis by elevating interleukin-8 production and may play a role in inflammation. May be involved in transcriptional regulation.
Up-regulated in presence of reactive oxygen species (ROS), like H(2)O(2), through the NF-kappaB signaling pathway. Up-regulated by sphingosine-1-phosphate (SP1) through the p38 MAPK signaling pathway (at protein level).
May be involved in the ribosome maturation process. Complements an ObgE(CgtA) function in E.coli ribosome maturation. Plays a role of GTPase in vitro. When missing, disorganization of the nucleolar architecture is observed.
An homozygous frameshift variant in the second exon of PYURF have been found in a patient with profound metabolic acidosis and clinical features including muscle hypotonia, failure to thrive, developmental delay, optic atrophy, persistently elevated lactate levels in the blood and cerebrospinal fluid, and abnormal cerebellar white matter and cerebellar atrophy on magnetic resonance imaging.
In mitochondria, S-adenosylmethionine-dependent methyltransferase chaperone that supports both coenzyme Q biosynthesis, by stabilizing its components, such as COQ5, and NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) assembly, by stabilizing complex I assembly factors, such as NDUFAF5.
Interacts (via TRM112 domain) with NDUFAF5; the interaction is direct and stabilizes NDUFAF5 protein (PubMed:35614220). Interacts with COQ5; the interaction is direct, stabilizes COQ5 protein and associates PYURF with COQ enzyme complex (PubMed:35614220).
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.2/KCNA2 sub-subfamily.
Detected in brain cortex (PubMed:16473933). Detected in peroneal nerve in the juxtaparanodal regions of the node of Ranvier; expression is decreased in patients with diabetes mellitus that suffer from axonal neuropathy (PubMed:22649228). Detected in paranodal and juxtanodal zones in myelinated spinal cord (at protein level) (PubMed:11086297).
Homotetramer and heterotetramer with other channel-forming alpha subunits, such as KCNA1, KCNA4, KCNA5, KCNA6 and KCNA7. Channel activity is regulated by interaction with the beta subunits, including KCNAB1 and KCNAB2. Identified in a complex with KCNA1 and KCNAB2 (PubMed:11086297). Identified in a complex with KCNA5 and KCNAB1 (By similarity). Identified in a complex with KCNA4 and FYN (By similarity). Interacts with the beta subunit KCNAB1 (PubMed:19713757). Interacts with PTK2B (By similarity). Interacts (via C-terminus) with CTTN (By similarity). Interacts (via N-terminal cytoplasmic domain) with RHOA (GTP-bound form); this regulates channel activity by reducing location at the cell surface in response to CHRM1 activation (By similarity). Interacts with DRD2 (By similarity). Interacts with SIGMAR1; cocaine consumption leads to increased interaction (By similarity). Interacts with ADAM22 (By similarity). Interacts (via C-terminus) with the PDZ domains of DLG1, DLG2 and DLG4 (By similarity). Interacts with CNTNAP2 (PubMed:10624965). Interacts with ADAM11 (By similarity).
Inhibited by 4-aminopyridine (4-AP) and charybdotoxin (CTX), but not by tetraethylammonium (TEA) (PubMed:19912772). Inhibited by dendrotoxin (DTX) (By similarity). Inhibited by tityustoxin-K alpha (TsTX-Kalpha), a toxin that is highly specific for KCNA2 (By similarity). Inhibited by maurotoxin (By similarity). Inhibited by kappaM conotoxins kappaM-RIIIJ and kappaM-RIIIK; kappaM-RIIIJ has much higher affinity for channels containing KCNA2 than kappaM-RIIIK, with the exception of heterodimers formed by KCNA2 and KCNA7 where the opposite is true (PubMed:20220134).
N-glycosylated, with complex, sialylated N-glycans.
Phosphorylated on tyrosine residues; phosphorylation increases in response to ischemia (By similarity). Phosphorylated on tyrosine residues by activated PTK2B/PYK2 (By similarity). Phosphorylation on tyrosine residues suppresses ion channel activity (By similarity). Phosphorylated on tyrosine residues in response to CHRM1 activation; this abolishes interaction with CTTN. This is probably due to endocytosis of the phosphorylated channel subunits (By similarity). Phosphorylated on serine residues in response to increased cAMP levels; phosphorylation is apparently not catalyzed by PKA (By similarity).
The cytoplasmic N-terminus is important for tetramerization. Interactions between the different subunits modulate the gating characteristics (By similarity). Besides, the cytoplasmic N-terminal domain mediates interaction with RHOA and thus is required for RHOA-mediated endocytosis (By similarity).
The delay or D-type current observed in hippocampus pyramidal neurons is probably mediated by potassium channels containing KCNA2 plus KCNA1 or other family members. It is activated at about -50 mV, i.e. below the action potential threshold, and is characterized by slow inactivation, extremely slow recovery from inactivation, sensitivity to dendrotoxin (DTX) and to 4-aminopyridine (4-AP).
Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the cardiovascular system. Prevents aberrant action potential firing and regulates neuronal output. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:19912772, PubMed:8495559, PubMed:11211111, PubMed:23769686). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNA7, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:8495559, PubMed:20220134). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation of delayed rectifier potassium channels. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Homotetrameric KCNA2 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure (PubMed:19912772, PubMed:23769686). In contrast, a heteromultimer formed by KCNA2 and KCNA4 shows rapid inactivation (PubMed:8495559). Regulates neuronal excitability and plays a role as pacemaker in the regulation of neuronal action potentials (By similarity). KCNA2-containing channels play a presynaptic role and prevent hyperexcitability and aberrant action potential firing (By similarity). Response to toxins that are selective for KCNA2-containing potassium channels suggests that in Purkinje cells, dendritic subthreshold KCNA2-containing potassium channels prevent random spontaneous calcium spikes, suppressing dendritic hyperexcitability without hindering the generation of somatic action potentials, and thereby play an important role in motor coordination (By similarity). Plays a role in the induction of long-term potentiation of neuron excitability in the CA3 layer of the hippocampus (By similarity). May function as down-stream effector for G protein-coupled receptors and inhibit GABAergic inputs to basolateral amygdala neurons (By similarity). May contribute to the regulation of neurotransmitter release, such as gamma-aminobutyric acid (GABA) (By similarity). Contributes to the regulation of the axonal release of the neurotransmitter dopamine (By similarity). Reduced KCNA2 expression plays a role in the perception of neuropathic pain after peripheral nerve injury, but not acute pain (By similarity). Plays a role in the regulation of the time spent in non-rapid eye movement (NREM) sleep (By similarity).
Growth factor active in angiogenesis, lymphangiogenesis and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels. May function in the formation of the venous and lymphatic vascular systems during embryogenesis, and also in the maintenance of differentiated lymphatic endothelium in adults. Binds and activates VEGFR-2 (KDR/FLK1) and VEGFR-3 (FLT4) receptors.
Highly expressed in lung, heart, small intestine and fetal lung, and at lower levels in skeletal muscle, colon, and pancreas.
Homodimer; non-covalent and antiparallel.
Undergoes a complex proteolytic maturation which generates a variety of processed secreted forms with increased activity toward VEGFR-3 and VEGFR-2. VEGF-D first form an antiparallel homodimer linked by disulfide bonds before secretion. The fully processed VEGF-D is composed mostly of two VEGF homology domains (VHDs) bound by non-covalent interactions.
Exchange factor for GTP-binding proteins RhoA, RhoG and, to a lesser extent, Rac1. Binds physically to the nucleotide-free states of those GTPases. Plays an important role in angiogenesis. Its recruitment by phosphorylated EPHA2 is critical for EFNA1-induced RAC1 GTPase activation and vascular endothelial cell migration and assembly (By similarity). May be important for integrin-mediated signaling, at least in some cell types. In osteoclasts, along with SYK tyrosine kinase, required for signaling through integrin alpha-v/beta-1 (ITAGV-ITGB1), a crucial event for osteoclast proper cytoskeleton organization and function. This signaling pathway involves RAC1, but not RHO, activation. Necessary for proper wound healing. In the course of wound healing, required for the phagocytotic cup formation preceding macrophage phagocytosis of apoptotic neutrophils. Responsible for integrin beta-2 (ITGB2)-mediated macrophage adhesion and, to a lesser extent, contributes to beta-3 (ITGB3)-mediated adhesion. Does not affect integrin beta-1 (ITGB1)-mediated adhesion (By similarity).
Interacts with the PH domain of SH2B2. Interacts (via SH2 domains) with the phosphorylated form of EPHA2. Interacts with ROS1; constitutive interaction that mediates VAV3 phosphorylation.
Isoform 1 and isoform 3 are widely expressed; both are expressed at very low levels in skeletal muscle. In keratinocytes, isoform 1 is less abundant than isoform 3. Isoform 3 is detected at very low levels, if any, in adrenal gland, bone marrow, spleen, fetal brain and spinal chord; in these tissues, isoform 1 is readily detectable.
Phosphorylated. Phosphorylation can be mediated by ROS1. In osteoclasts, undergoes tyrosine phosphorylation in response to CSF1 (By similarity).
Probable component of the multiprotein Integrator (INT) complex.
Can degrade fibrillar type I, II, and III collagens.
Cannot be activated without removal of the activation peptide.
Chromosomal aberrations involving CDKL5 are found in patients manifesting early-onset seizures and spams and psychomotor impairment. Translocation t(X;6)(p22.3;q14); translocation t(X;7)(p22.3;p15).
Expressed in brain, lung, kidney, prostate, ovary, placenta, pancreas and testis.
Mediates phosphorylation of MECP2 (PubMed:15917271, PubMed:16935860). May regulate ciliogenesis (PubMed:29420175).
Functions as a ubiquitin ligase protein in vivo, mediating ubiquitination and promoting degradation of MEKK1, suggesting that it may regulate the Notch pathway via some ubiquitin ligase activity (By similarity). Regulator of Notch signaling, a signaling pathway involved in cell-cell communications that regulates a broad spectrum of cell-fate determinations. Mainly acts as a positive regulator of Notch, but it also acts as a negative regulator, depending on the developmental and cell context. Mediates the antineural activity of Notch, possibly by inhibiting the transcriptional activation mediated by MATCH1. Involved in neurogenesis, lymphogenesis and myogenesis, and may also be involved in MZB (Marginal zone B) cell differentiation. Promotes B-cell development at the expense of T-cell development, suggesting that it can antagonize NOTCH1.
Homodimer. May form a heterodimer with other members of the Deltex family. Interacts with NOTCH1 via its N-terminal region and EIF3F, the interaction is required for NOTCH1 deubiquitination. Interacts with EP300. Forms a heterodimer with BBAP; the heterodimerization leading to an increase of in vitro ubiquitin ligase activity. Interacts with ITCH.
Ubiquitinated; undergoes 'Lys-29'-linked polyubiquitination catalyzed by ITCH.
Widely expressed. Strongly expressed in blood vessel. Also expressed in embryonic nervous system, pancreas, lung, adrenal gland, digestive tube and muscles. Expressed in MZB cells and developing B- and T-cells.
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. ASIC3 subfamily.
Cation channel with high affinity for sodium, which is gated by extracellular protons and inhibited by the diuretic amiloride. Generates a biphasic current with a fast inactivating and a slow sustained phase. In sensory neurons is proposed to mediate the pain induced by acidosis that occurs in ischemic, damaged or inflamed tissue. May be involved in hyperalgesia. May play a role in mechanoreception. Heteromeric channel assembly seems to modulate channel properties.
Expressed by sensory neurons. Strongly expressed in brain, spinal chord, lung, lymph nodes, kidney, pituitary, heart and testis.
Expressed in fetal tissues, expression increases in lung and kidney adult tissues.
Homotrimer or heterotrimer with other ASIC proteins (By similarity). Interacts with STOM; this regulates channel activity. Interacts with DLG4 (By similarity). Interacts with LIN7B, MAGI1/BAIAP1, GOPC and ASIC2.
Phosphorylated by PKA. Phosphorylated by PKC. In vitro, PRKCABP/PICK-1 is necessary for PKC phosphorylation and activation of a ASIC3/ACCN3-ASIC2/ASIC2b channel, but does not activate a homomeric ASIC3 channel (By similarity).
Potentiated by FMRFamide-related neuropeptides. Sensitized and potentiated by NPSF. Regulated by lactate and Ca(2+). Inhibited by anti-inflammatory drugs, like salicylic acid (By similarity). Sensitized and potentiated by NPFF.
The PDZ domain-binding motif is involved in interaction with LIN7A, GOPC and MAGI1.
Encoded by one of two nearly identical genes: FCGR3A and FCGR3B (Shown here) which are expressed in a tissue-specific manner. The 'Phe-203' in FCGR3A determines the transmembrane domains whereas the Ser-203 in FCGR3B determines the GPI-anchoring.
Expressed specifically by polymorphonuclear leukocytes (neutrophils). Also expressed by stimulated eosinophils.
Glycosylated. Glycosylation plays an inhibitory role in the interaction with IgG3.
Monomer. Interacts with INPP5D/SHIP1 (By similarity).
Receptor for the Fc region of immunoglobulins gamma. Low affinity receptor. Binds complexed or aggregated IgG and also monomeric IgG. Contrary to III-A, is not capable to mediate antibody-dependent cytotoxicity and phagocytosis. May serve as a trap for immune complexes in the peripheral circulation which does not activate neutrophils.
The soluble form is produced by a proteolytic cleavage.
There are three allelic forms of FCGR3B: FCGR3B*01 (NA-1), FCGR3B*02 (HNA-1b, NA-2) (shown here) and SH. FCGR3B*01 and FCGR3B*02 are detectable with antibodies against the biallelic neutrophil-specific antigen system NA. The more active FCGR3B*01 allele has been associated with severe renal disease in certain systemic vasculitides.
Highly abundant in skeletal muscle. Also detected in testis.
Catalyzes the reversible conversion of beta-D-fructose 1,6-bisphosphate (FBP) into two triose phosphate and plays a key role in glycolysis and gluconeogenesis (PubMed:14766013). In addition, may also function as scaffolding protein (By similarity).
Homotetramer. Interacts with SNX9 and WAS (By similarity). Interacts with FBP2; the interaction blocks FBP2 inhibition by physiological concentrations of AMP and reduces inhibition by Ca(2+).
Binds DNA as a dimer; homodimer and heterodimer with RXRA. Interacts with the coactivators NCOA1/SRC1, NCOA2/GRIP1, NCOA7 and MED1/TRAP220 in a ligand-inducible manner. Interacts with the corepressor NCOR1 in absence of ligand. Interacts with C1D (By similarity). Interacts with NR2F6; the interaction impairs the binding of the THRB homodimer and THRB:RXRB heterodimer to T3 response elements. Interacts with PRMT2 and THRSP. Interacts with TACC1; this interaction is decreased in the presence of thyroid hormone T3 (PubMed:20078863).
Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine.
Appears to function in the signal transduction from Ras activation to actin cytoskeletal remodeling. Suppresses insulin-induced promoter activities through AP1 and SRE. Mediates Rap1-induced adhesion.
Interacts, through the N-terminal Pro-rich region, with the WW domain of APBB1. Interacts with RAP1A, PFN1, TLN1, VASP, VCL and ENAH.
The two Pro-rich regions are required for the suppression of AP1 transcription activity.
Widely expressed with high expression in thymus, spleen, lymph node, bone marrow and peripheral leukocytes.
Belongs to the bacterial ribosomal protein bL34 family.
Probable transcriptional activator. Binds to the consensus sequence 5'-AGGCCY-3'.
The binding of ZFY to DNA is mediated by the interaction of the GGCC core base pairs with zinc fingers 12 and 13.
Was originally thought to be the testis determining factor (TDF).
Available under the name Endostar (Jiangsu Simcere Pharmaceutical) for the treatment of non-small-cell lung cancer.
Belongs to the multiplexin collagen family.
Circulating endostatins are found as sialoglycoprotein and asialoglycoprotein structures.
Detected in placenta (at protein level) (PubMed:32337544). Present in multiple organs with highest levels in liver, lung and kidney.
Forms homotrimers (PubMed:11257123). Recombinant non-collagenous domain 1 has stronger affinity to NID1, HSPG2 and laminin-1:NID1 complex and lower affinity to FBLN1 and FBLN2 than endostatin (By similarity).
May regulate extracellular matrix-dependent motility and morphogenesis of endothelial and non-endothelial cells; the function requires homotrimerization and implicates MAPK signaling.
Monomeric (PubMed:11257123). Interacts with KDR/VEGFR2. Interacts with the ITGA5:ITGB1 complex. Interacts with NID1, HSPG2, laminin-1:NID1 complex, FBLN1 and FBLN2 (By similarity).
Non-collagenous domain 1 seems to be the predominant tissue form from which endostatin is cleaved. However, the proteolytic cleavage site to generate non-collagenous domain 1 is not known. Soluble recombinant non-collagenous domain 1 amenable to biochemical studies has been used instead.
Potently inhibits endothelial cell proliferation and angiogenesis (PubMed:9459295). May inhibit angiogenesis by binding to the heparan sulfate proteoglycans involved in growth factor signaling (By similarity). Inhibits VEGFA-induced endothelial cell proliferation and migration. Seems to inhibit VEGFA-mediated signaling by blocking the interaction of VEGFA to its receptor KDR/VEGFR2. Modulates endothelial cell migration in an integrin-dependent manner implicating integrin ITGA5:ITGB1 and to a lesser extent ITGAV:ITGB3 and ITGAV:ITGB5 (By similarity). May negatively regulate the activity of homotrimeric non-collagenous domain 1 (PubMed:11257123).
Probably plays a major role in determining the retinal structure as well as in the closure of the neural tube.
Prolines at the third position of the tripeptide repeating unit (G-X-Y) of the triple-helical regions are hydroxylated.
There is an association between a polymorphism in position 1675 and prostate cancer. Heterozygous Asn-1675 individuals have a 2.5 times increased chance of developing prostate cancer as compared with homozygous Asp-1675 individuals.
Undergoes proteolytic processing by CTSL/cathepsin-L and elastase-like proteases to generate both non-collagenous domain 1 trimers and endostatin monomers (PubMed:10626789). In tissue extracts (brain, skeletal muscle, heart, kidney, testis and liver) predominantly bands of approximately 38 kDa are detected; recombinant non-collagenous domain 1 shows similar mobility. In vitro, several proteolytic cleavage sites in the non-collagenous domain 1 hinge region generating different endostatin-like peptides are reported (By similarity).
Cilium-specific protein required to control the microtubule-based, ciliary axoneme structure. May act by maintaining the association between IFT subcomplexes A and B. Binds GTP but is not able to hydrolyze it; the GTPase activity remains unclear. Required to pattern the neural tube. Involved in cerebral cortex development: required for the initial formation of a polarized radial glial scaffold, the first step in the construction of the cerebral cortex, by regulating ciliary signaling. Regulates the migration and placement of postmitotic interneurons in the developing cerebral cortex. May regulate endocytic recycling traffic; however, additional evidence is required to confirm these data.
Monomer (By similarity). Interacts with CIMAP3. Interacts with IFT complex B components IFT46 and IFT74 (By similarity) (PubMed:20643351, PubMed:24339792). Interacts with EXOC2; regulates ARL13B localization to the cilium membrane.
Sumoylation is required for PKD2 entry into cilium.
Used as a ciliary marker because of its specific localization to microtubule doublets of the ciliary axoneme.
Was initially thought to form a homodimer (PubMed:18554500). However, 3D structure of C.reinhardtii ortholog showed that it is probably not the case.
May play a role in anteroposterior axis elongation.
Forms homooligomers, independently of the DNA-binding domain.
Transcription repressor. Sequence-specific ssDNA and dsDNA binding protein, with preference for GCT end CTG repeats. Cell migration modulator which enhances the glioma-specific migration ability of neural stem cells (NSC) and neural precursor cells (NPC).
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodiun ions.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Beta-2/CHRNB2 sub-subfamily.
Neuronal AChR is composed of two different types of subunits: alpha and beta. Beta-2 subunit can be combined to alpha-2, alpha-3 or alpha-4 to give rise to functional receptors, complexes with beta-2 may be heteropentamers. Alpha-2/4:beta-2 nAChR complexes are proposed to exist in two subtypes: LS (low agonist sensitivity) with a (alpha-2/4)3:(beta-2)2 and HS (high agonist sensitivity) with a (alpha-2/4)2:(beta-2)3 stoichiometry; the subtypes differ in their subunit binding interfaces which are involved in ligand binding (PubMed:27493220, PubMed:22361591). Interacts with RIC3; which is required for proper folding and assembly (PubMed:16120769). Interacts with LYPD6 (PubMed:27344019). The heteropentamer alpha-3-beta-2 interacts with alpha-conotoxins BuIA, MII, PnIA and GID (By similarity). The heteropentamer alpha-3-beta-2 interacts with the alpha-conotoxins ImI and ImII (PubMed:15609996). The heteropentamer alpha-4-beta-2 interacts with the alpha-conotoxins PnIA, GID and MII (By similarity).
Acts as a regulator of myogenesis in cooperation with HDGFL2 (PubMed:32459350). Mediates the interaction of HDGFL2 with the BAF complex (PubMed:32459350). HDGFL2-DPF3a activate myogenic genes by increasing chromatin accessibility through recruitment of SMARCA4/BRG1/BAF190A (ATPase subunit of the BAF complex) to myogenic gene promoters (PubMed:32459350).
Belongs to the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a post-mitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to post-mitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Muscle-specific component of the BAF complex, a multiprotein complex involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Specifically binds acetylated lysines on histone 3 and 4 (H3K14ac, H3K9ac, H4K5ac, H4K8ac, H4K12ac, H4K16ac). In the complex, it acts as a tissue-specific anchor between histone acetylations and methylations and chromatin remodeling. It thereby probably plays an essential role in heart and skeletal muscle development.
Component of the BAF complex, which includes at least actin (ACTB), ARID1A, ARID1B/BAF250, SMARCA2, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more of SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C (PubMed:18765789). In muscle cells, the BAF complex also contains DPF3 (PubMed:18765789). Interacts with acetylated histones H3 and H4 (PubMed:18765789). Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin (By similarity).
Interacts with HDGFL2, SMARCA4/BRG1/BAF190A, SMARCC1/BAF155 and SMARCD1/BAF60A.
Lacks PHD-type zinc fingers and does not bind to acetylated histones H3 and H4.
Phosphorylation at Ser-323 enhances its interaction with HDGFL2.
The PHD-type zinc fingers mediate the binding to acetylated histones.
Homodimer (PubMed:22427660). Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5 (PubMed:33283408, PubMed:28977666, PubMed:16428440). The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes (PubMed:33283408, PubMed:28977666, PubMed:16428440). Interacts with monomeric unphosphorylated CDK2 (By similarity). Interacts with CDK2AP2 (PubMed:14985111). Interacts with GATAD2A (PubMed:33283408). Interacts with HDAC1 (PubMed:20523938). Interacts with HDAC2 (PubMed:20523938). Interacts with MBD2 (PubMed:20523938). Interacts with MBD3 (PubMed:20523938). Interacts with RBBP4 (PubMed:20523938). Interacts with RBBP7 (PubMed:20523938).
Inhibitor of cyclin-dependent kinase CDK2 (By similarity). Also acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:20523938, PubMed:16428440, PubMed:28977666).
Phosphorylated in vitro by IKBKE at Ser-46.
Binds calcium via its EF-hands (By similarity). Isoform 5 binds calcium.
Isoform 5 interacts with STXBP1; the interaction is enhanced in presence of calcium. Isoform 5 interacts with STX3.
Isoform 5 may be involved in the exocytosis of zymogens by pancreatic acini.
Ubiquitous. Isoform 5 is expressed in pancreas.
Expressed in esophageal squamous cell carcinomas.
Exists either as monomer or, after proteolytic processing, as a dimer of two chains linked by disulfide bond(s).
Involved in osteopontin/bone sialoprotein dephosphorylation. Its expression seems to increase in certain pathological states such as Gaucher and Hodgkin diseases, the hairy cell, the B-cell, and the T-cell leukemias.
The disease is caused by variants affecting the gene represented in this entry. ACP5 inactivating mutations result in a functional excess of phosphorylated osteopontin causing deregulation of osteopontin signaling and consequential autoimmune disease.
Can dephosphorylate single and diphosphorylated synthetic MAPK peptides, with preference for the phosphotyrosine and diphosphorylated forms over phosphothreonine.
Belongs to the cytidine and deoxycytidylate deaminase family. ADAT2 subfamily.
Probably participates in deamination of adenosine-34 to inosine in many tRNAs.
(Microbial infection) Interacts with HCV NS5A; the interaction stimulates RNA-binding ability of NS5A and is dependent on the peptidyl-prolyl cis-trans isomerase activity of PPIA/CYPA.
(Microbial infection) Interacts with HIV-1 capsid protein (PubMed:20364129, PubMed:8513493).
(Microbial infection) Interacts with human SARS coronavirus nucleoprotein.
(Microbial infection) Interacts with measles virus nucleoprotein.
(Microbial infection) May act as a mediator between human SARS coronavirus nucleoprotein and BSG/CD147 in the process of invasion of host cells by the virus (PubMed:15688292).
(Microbial infection) Stimulates RNA-binding ability of HCV NS5A in a peptidyl-prolyl cis-trans isomerase activity-dependent manner.
Acetylation at Lys-125 markedly inhibits catalysis of cis to trans isomerization and stabilizes cis rather than trans forms of the HIV-1 capsid. PPIA acetylation also antagonizes the immunosuppressive effects of cyclosporine by inhibiting the sequential steps of cyclosporine binding and calcineurin inhibition (PubMed:20364129, Ref.12). Acetylation at Lys-125 favors its interaction with TARDBP (PubMed:25678563).
Binds cyclosporin A (CsA). CsA mediates some of its effects via an inhibitory action on PPIase.
Catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides (PubMed:2001362, PubMed:20676357, PubMed:21245143, PubMed:25678563, PubMed:21593166). Exerts a strong chemotactic effect on leukocytes partly through activation of one of its membrane receptors BSG/CD147, initiating a signaling cascade that culminates in MAPK/ERK activation (PubMed:11943775, PubMed:21245143). Activates endothelial cells (ECs) in a pro-inflammatory manner by stimulating activation of NF-kappa-B and ERK, JNK and p38 MAP-kinases and by inducing expression of adhesion molecules including SELE and VCAM1 (PubMed:15130913). Induces apoptosis in ECs by promoting the FOXO1-dependent expression of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis (PubMed:31063815). In response to oxidative stress, initiates proapoptotic and antiapoptotic signaling in ECs via activation of NF-kappa-B and AKT1 and up-regulation of antiapoptotic protein BCL2 (PubMed:23180369). Negatively regulates MAP3K5/ASK1 kinase activity, autophosphorylation and oxidative stress-induced apoptosis mediated by MAP3K5/ASK1 (PubMed:26095851). Necessary for the assembly of TARDBP in heterogeneous nuclear ribonucleoprotein (hnRNP) complexes and regulates TARDBP binding to RNA UG repeats and TARDBP-dependent expression of HDAC6, ATG7 and VCP which are involved in clearance of protein aggregates (PubMed:25678563). Plays an important role in platelet activation and aggregation (By similarity). Regulates calcium mobilization and integrin ITGA2B:ITGB3 bidirectional signaling via increased ROS production as well as by facilitating the interaction between integrin and the cell cytoskeleton (By similarity). Binds heparan sulfate glycosaminoglycans (PubMed:11943775). Inhibits replication of influenza A virus (IAV) (PubMed:19207730). Inhibits ITCH/AIP4-mediated ubiquitination of matrix protein 1 (M1) of IAV by impairing the interaction of ITCH/AIP4 with M1, followed by the suppression of the nuclear export of M1, and finally reduction of the replication of IAV (PubMed:30328013, PubMed:22347431).
Interacts with protein phosphatase PPP3CA/calcineurin A (PubMed:12218175, PubMed:12357034). Interacts with PRPF19 isoform 2 (via N-terminus) (By similarity). Interacts with isoform 2 of BSG/CD147 (PubMed:15688292, PubMed:11353871, PubMed:11943775, PubMed:21245143). Interacts with FOXO1; the interaction promotes FOXO1 dephosphorylation, nuclear accumulation and transcriptional activity (PubMed:31063815). Interacts with integrin ITGA2B:ITGB3; the interaction is ROS and peptidyl-prolyl cis-trans isomerase (PPIase) activity-dependent and is increased in the presence of thrombin (By similarity). Interacts with MAP3K5 (PubMed:26095851). Interacts with TARDBP; the interaction is dependent on the RNA-binding activity of TARDBP and the PPIase activity of PPIA/CYPA and the acetylation of PPIA/CYPA at Lys-125 favors the interaction (PubMed:25678563). Interacts with HNRNPA1, HNRNPA2B1, HNRNPC, RBMX, HNRNPK and HNRNPM (PubMed:25678563).
Required for proper function of the olfactory system. May be involved in establishing the acuity of olfactory sensory signaling (By similarity).
PubMed:11087666 sequence was originally thought to originate from mouse.
Transcription factor (PubMed:9748269, PubMed:10207080). Activates the epsilon- and gamma-globin gene promoters and, to a much lower degree, the beta-globin gene and represses promoters containing SP1-like binding inhibiting cell growth (PubMed:9748269, PubMed:10207080, PubMed:16131492). Represses transcription of SMAD7 which enhances TGF-beta signaling (By similarity). Induces apoptosis (By similarity).
Ubiquitous. Higher expression in erythroid cells.
Interacts with the SNARE proteins SNAP-23 and VAMP.
SNARE that acts to regulate protein transport between late endosomes and the trans-Golgi network.
Interacts with UTP4. Interacts with FBL/fibrillarin in a transcription-dependent manner (PubMed:22916032). May associate with the proposed t-UTP subcomplex of the SSU processome containing at least UTP4, WDR43, HEATR1, UTP15, WDR75.
Is the likely candidate for being the functional analog of yeast Utp8.
Ribosome biogenesis factor. May be required for both optimal rDNA transcription and small subunit (SSU) pre-rRNA processing at sites A', A0, 1 and 2b.
Binds to plexin family members and plays an important role in the regulation of developmental processes. Required for normal cardiovascular development during embryogenesis. Functions as attractant for growing axons, and thereby plays an important role in axon growth and axon guidance (By similarity).
Expressed intensely in the heart, skeletal muscle, colon, small intestine, ovary, testis, and prostate. Faint expression ubiquitously among other organs, including brain.
Homodimer; disulfide-linked (By similarity). Heterodimer with SORCS2. The extracellular domains of the heterodimer bind NGF (PubMed:22155786, PubMed:24908487). The cytoplasmic region of the heterodimer binds TRIO. NGF binding mediates dissociation of TRIO from the receptor complex (PubMed:22155786). Interacts with RTN4R (PubMed:19052207). Interacts with TRAF2, TRAF4, TRAF6, PTPN13 and RANBP9 (PubMed:10514511, PubMed:9915784, PubMed:10544233, PubMed:12963025). Interacts through TRAF6 with SQSTM1 which bridges NGFR to NTRK1 (PubMed:11244088). Interacts with BEX1 (By similarity). Interacts with BEX3 (By similarity). Interacts with KIDINS220 and NTRK1. Can form a ternary complex with NTRK1 and KIDINS220 and this complex is affected by the expression levels of KIDINS220. An increase in KIDINS220 expression leads to a decreased association of NGFR and NTRK1. Interacts with NTRK2; may regulate the ligand specificity of the NTRK2 receptor (By similarity). Interacts (via death domain) with RAB31 (By similarity). Interacts with LINGO1 (PubMed:14966521). Interacts with NRADD (By similarity). Interacts with MAGED1; the interaction antagonizes the association NGFR:NTRK1 (By similarity). Interacts (via death domain) with ARHGDIA and RIPK2 (PubMed:26646181).
Low affinity receptor which can bind to NGF, BDNF, NTF3, and NTF4. Forms a heterodimeric receptor with SORCS2 that binds the precursor forms of NGF, BDNF and NTF3 with high affinity, and has much lower affinity for mature NGF and BDNF (PubMed:24908487). Plays an important role in differentiation and survival of specific neuronal populations during development (By similarity). Can mediate cell survival as well as cell death of neural cells. Plays a role in the inactivation of RHOA (PubMed:26646181). Plays a role in the regulation of the translocation of GLUT4 to the cell surface in adipocytes and skeletal muscle cells in response to insulin, probably by regulating RAB31 activity, and thereby contributes to the regulation of insulin-dependent glucose uptake (By similarity). Necessary for the circadian oscillation of the clock genes BMAL1, PER1, PER2 and NR1D1 in the suprachiasmatic nucleus (SCmgetaN) of the brain and in liver and of the genes involved in glucose and lipid metabolism in the liver (PubMed:23785138).
O-linked glycans consist of Gal(1-3)GalNAc core elongated by 1 or 2 NeuNAc.
The death domain mediates interaction with RANBP9 (By similarity). It also mediates interaction with ARHGDIA and RIPK2 (PubMed:26646181).
The extracellular domain is responsible for interaction with NTRK1.
Expressed in fetal brain and in various regions of the adult central nervous system including the spinal cord, the thalamus, and the cerebellum.
Plays an essential role in the regulation of neuronal differentiation and migration during development of the central nervous system.
Expressed in placenta, prostate and testis.
Catalyzes the transfer of phosphatidylinositol (PI) and phosphatidylcholine (PC) between membranes (PubMed:10531358, PubMed:22822086, PubMed:15522822, PubMed:18636990, PubMed:14962392). Shows a preference for PI and PC containing shorter saturated or monosaturated acyl chains at the sn-1 and sn-2 positions (PubMed:15522822, PubMed:22822086). Preference order for PC is C16:1 > C16:0 > C18:1 > C18:0 > C20:4 and for PI is C16:1 > C16:0 > C18:1 > C18:0 > C20:4 > C20:3 (PubMed:22822086).
Adds a myristoyl group to the N-terminal glycine residue of certain cellular and viral proteins (PubMed:22865860, PubMed:32686708, PubMed:34999170, PubMed:25255805, PubMed:9353336, PubMed:9506952). Also able to mediate N-terminal lysine myristoylation of proteins: catalyzes myristoylation of ARF6 on both 'Gly-2' and 'Lys-3' (PubMed:32103017, PubMed:32111831). Lysine myristoylation is required to maintain ARF6 on membranes during the GTPase cycle (PubMed:32103017).
Belongs to the Prospero homeodomain family.
The Prospero-type homeodomain and the adjacent Prospero domain act as a single structural unit, the Homeo-Prospero domain.
Transcription regulator. Does not seem to be essential for embryonic development and postnatal survival (By similarity).
GTPase-activating protein for the ADP ribosylation factor family (Potential). Binds phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3) and inositol 1,3,4,5-tetrakisphosphate (InsP4). Possesses a stoichiometry of two binding sites for InsP4 with identical affinity.
Highly expressed in placenta, spleen, kidney, skeletal muscle and adrenal gland. Weakly expressed in thyroid, liver, heart, lung, small intestine, peripheral blood leukocytes. Not detected in spinal cord, brain, stomach, trachea, colon, lymph node and bone marrow.
Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates and be involved in a variety of cellular processes (PubMed:22399288). Catalyzes the palmitoylation of KCNMA1, regulating localization of KCNMA1 to the plasma membrane (PubMed:22399288). Might also mediate palmitoylation of CNN3 (By similarity).
Interacts with FGFR1. Interacts (via extracellular domain) with ADGRL1/LPHN1 and ADGRL3 (via olfactomedin-like domain).
Phosphorylated in response to FGFR1 signaling, but is not a direct substrate of FGFR1 or SRC. A mutant where the Tyr phosphorylation sites have been replaced by Phe displays constitutive FGFR1-dependent activation of downstream MAP kinases.
Plays a role in fibroblast growth factor-mediated signaling cascades that lead to the activation of MAP kinases. Promotes neurite outgrowth via FGFR1-mediated activation of downstream MAP kinases. Promotes an increase both in neurite number and in neurite length. May play a role in cell-cell adhesion and cell guidance via its interaction with ADGRL1/LPHN1 and ADGRL3.
Proteolytic cleavage in the juxtamembrane region gives rise to a soluble ectodomain.
(Microbial infection) Interacts with influenza A virus non-structural protein 1/NS (PubMed:9696811).
(Microbial infection) Involved in the alternative splicing of influenza A virus M1 mRNA through interaction with HNRNPK, thereby facilitating the generation of viral M2 protein.
Homodimer; through the BTB domain (By similarity). Interacts with AHR/Aryl hydrocarbon receptor (PubMed:16582008). Interacts with HNRNPK (PubMed:23825951). Interacts (via kelch repeats) with KLHL20 (via kelch repeats); this interaction blocks the assembly of Cul3-KLHL20 complex (PubMed:25619834).
Involved in many cell functions, including pre-mRNA splicing, the aryl hydrocarbon receptor (AHR) pathway, F-actin organization and protein ubiquitination. Plays a role in the dynamic organization of the actin skeleton as a stabilizer of actin filaments by association with F-actin through Kelch repeats (By similarity). Protects cells from cell death induced by actin destabilization (By similarity). Functions as modifier of the AHR/Aryl hydrocarbon receptor pathway increasing the concentration of AHR available to activate transcription (PubMed:16582008). In addition, functions as a negative regulator of BCR(KLHL20) E3 ubiquitin ligase complex to prevent ubiquitin-mediated proteolysis of PML and DAPK1, two tumor suppressors (PubMed:25619834). Inhibits pre-mRNA splicing (in vitro) (PubMed:9696811).
When the BTB domain is lacking, AHR signaling induction promoted by IVNS1ABP is massively increased; Thus, the BTB domain inhibits AHR signaling induced by IVNS1ABP.
Focadhesin is predicted to contain three transmembrane domains. However, experimental data indicate that it does not localize to organelles with bilayered lipid membranes, challenging the presence of the transmembrane domains.
Required for the maintenance of SKIC2 and SKIC3 proteostatic levels in the liver. May be involved in the regulation of RNA degradation by the exosome complex (PubMed:35864190). Potential tumor suppressor in gliomas.
Ubiquitous. High expression in brain followed by testis, muscle, pancreas, heart, ovary, small intestine, placenta, prostate, thymus, kidney, colon, liver, lung, spleen and leukocytes. Expression is reduced in most glioblastomas and all glioblastoma cell lines.
Component of a multisubunit histone acetyltransferase complex (MSL) at least composed of the KAT8/MOF/MYST1, MSL1/hampin, MSL2 and MSL3 (PubMed:16227571, PubMed:16543150). Forms a MSL heterotetrameric core with MSL2 (PubMed:16227571). Interacts with KAT8 and MSL3; both interactions are direct (PubMed:22547026, PubMed:21217699, PubMed:30224647). Directly interacts with NUPR1 (PubMed:19650074). Interacts with TP53BP1; this interaction may be required for MSL1 DNA repair activity, but not for histone acetyltransferase activity (PubMed:19650074). Interacts with TTC4, ECM2 and PIHD1 (By similarity).
Component of histone acetyltransferase complex responsible for the majority of histone H4 acetylation at 'Lys-16' (H4K16ac) which is implicated in the formation of higher-order chromatin structure (PubMed:16227571). Greatly enhances MSL2 E3 ubiquitin ligase activity, promoting monoubiquitination of histone H2B at 'Lys-34' (H2BK34Ub) (PubMed:21726816). This modification in turn stimulates histone H3 methylation at 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) and leads to gene activation, including that of HOXA9 and MEIS1 (PubMed:21726816). In the MSL complex, acts as a scaffold to tether MSL3 and KAT8 together for enzymatic activity regulation (PubMed:22547026).
The coiled coil is formed by helices from two subunits in the MSL1 homodimer.
N-glycosylated; N-glycans are probably of the complex type and modified by sialic acid residues.
O-glycosylated; modified by sialic acid residues.
Phosphorylated probably by c-AMP-dependent kinases in its lumenal part.
Plays a role in endosome to Golgi protein trafficking; mediates protein transport along the late endosome-bypass pathway from the early endosome to the Golgi.
Expressed predominantly in thymus and brain. Expression is down-regulated in 28 of 95 tested cancer cell lines.
Interacts with SMYD2 (By similarity). Interacts with POLR2A. Interacts with SMYD3; the interaction may bridge SMYD3 and RNA polymerase II.
May act as a helicase that plays a role in RNA metabolism in multiple tissues and organs within the developing embryo.
Differences in regional receptor expression in the brain as well as differences in social behavior may result from a highly variable repetitive sequence in the 5' flanking region of AVPR1A. One such allelic variant has been linked to autism.
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system. Has been involved in social behaviors, including affiliation and attachment.
Asymmetrically methylated by PRMT1 (PubMed:25284789). Symmetrically methylated by PRMT5 (By similarity).
Expressed in an erythroid progenitor cell line derived from peripheral blood. Expressed in glioblastoma cells (PubMed:25284789).
Interacts with PRMT1 and PRMT5 (PubMed:25284789). Interacts with the 5FMC complex; the interaction is methylation-dependent. Interacts with FYTTD1, SET and PRC1 complex members CBX4, RNF2 and PHC2; the interactions are methylation-independent. Interacts with ZNF148 (By similarity). Component of the transcription/export (TREX) complex at least composed of ALYREF/THOC4, DDX39B, SARNP/CIP29, CHTOP and the THO subcomplex; TREX seems to have dynamic structure involving ATP-dependent remodeling; in the complex interacts (methylated) with ALYREF/THOC4 and with DDX39B in a methylation-independent manner. Interacts (methylated) with NXF1; the interaction is mutually exclusive with the NXF1:THOC5 interaction (PubMed:23299939, PubMed:23826332). Interacts with WDR77 and ERH (PubMed:25284789).
Plays an important role in the ligand-dependent activation of estrogen receptor target genes (PubMed:19858291). May play a role in the silencing of fetal globin genes (PubMed:20688955). Recruits the 5FMC complex to ZNF148, leading to desumoylation of ZNF148 and subsequent transactivation of ZNF148 target genes (By similarity). Plays an important role in the tumorigenicity of glioblastoma cells. Binds to 5-hydroxymethylcytosine (5hmC) and associates with the methylosome complex containing PRMT1, PRMT5, MEP50 and ERH. The CHTOP-methylosome complex associated with 5hmC is recruited to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of genes involved in glioblastomagenesis (PubMed:25284789).
Required for effective mRNA nuclear export and is a component of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NFX1 pathway. The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production. Stimulates DDX39B ATPase and helicase activities. In cooperation with ALYREF/THOC4 enhances NXF1 RNA binding activity (PubMed:23299939).
Core component of a Cul9-RING ubiquitin-protein ligase complex, a complex that mediates ubiquitination and subsequent degradation of BIRC5 and is required to maintain microtubule dynamics and genome integrity. Acts downstream of the 3M complex, which inhibits CUL9 activity, leading to prevent ubiquitination of BIRC5 (PubMed:24793696). Cytoplasmic anchor protein in p53/TP53-associated protein complex. Regulates the subcellular localization of p53/TP53 and subsequent function (PubMed:12526791, PubMed:17332328).
In vitro, self-ubiquitination in the presence of E1, E2 and ubiquitin.
Part of a Cul9-RING complex at least composed of CUL9 and RBX1. Interacts with CUL7: interaction with CUL7 component of the 3M complex leads to inhibition of CUL9 activity. The CUL7-CUL9 heterodimer seems to interact specifically with TP53. Forms a complex with p53/TP53 in the cytoplasm of unstressed cells. Interacts with UBCH7 and UBCH8.
The IBR domain is required for interaction with UBCH7 and UBCH8.
Ubiquitously expressed in all tissues with highest expression in testis brain and kidney.
Expressed in several tissues, including heart, brain, thymus, skeletal muscle, small intestine, testis, kidney, placenta, peripheral blood cells and adult and fetal liver.
Might function as an inhibitor of Lys-specific proteases. Might influence the maturation of megakaryocytes via its action as a serpin.
Predominantly expressed in mesangial cells. Expressed in the epidermis of the whole body.
E3 ubiquitin-protein ligase. Modulates cyclin B levels and participates in the regulation of cell cycle progression through the G2 phase. Overexpression causes delayed entry into mitosis.
Highly expressed in heart. Detected at intermediate levels in liver and kidney, and at low levels in placenta, brain and lung.
Phosphorylated by CDK1 on serine or threonine residues (in vitro).
Ubiquitin E3 ligase that acts as a limiting factor for crossing-over during meiosis: required during zygonema to limit the colocalization of RNF212 with MutS-gamma-associated recombination sites and thereby establish early differentiation of crossover and non-crossover sites. Later, it is directed by MutL-gamma to stably accumulate at designated crossover sites. Probably promotes the dissociation of RNF212 and MutS-gamma to allow the progression of recombination and the implementation of the final steps of crossing over (By similarity). Modulates cyclin-B levels and participates in the regulation of cell cycle progression through the G2 phase. Overexpression causes delayed entry into mitosis.
Composed of a globular head, an elongated tail (coiled-coil) and a highly acidic C-terminal domain.
General vesicular transport factor required for intercisternal transport in the Golgi stack; it is required for transcytotic fusion and/or subsequent binding of the vesicles to the target membrane. May well act as a vesicular anchor by interacting with the target membrane and holding the vesicular and target membranes in proximity.
Homodimer. Dimerizes by parallel association of the tails, resulting in an elongated structure with two globular head domains side by side, and a long rod-like tail structure (Probable). Interacts with MIF.
Phosphorylated in a cell cycle-specific manner; phosphorylated in interphase but not in mitotic cells. Dephosphorylated protein associates with the Golgi membrane; phosphorylation promotes dissociation.
Activated by phosphorylation on Thr-524.
Component of a protein kinase signal transduction cascade. Regulates the JNK and ERK5 pathways by phosphorylating and activating MAP2K5 and MAP2K7 (By similarity). Plays a role in caveolae kiss-and-run dynamics.
Interacts with PKN2; the interaction activates PKN2 kinase activity in a MAP3K2-independent kinase activity (By similarity). Self-associates. Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts (via the kinase catalytic domain) with STK38. Interacts with XIAP/BIRC4.
Ubiquitination by XIAP/BIRC4 does not lead to proteasomal degradation.
Plays a role in neurogenesis. Prevents motor neuron cell body migration out of the neural tube.
Couples NMDA-sensitive glutamate receptor signaling to the nucleus and triggers long-lasting changes in the cytoarchitecture of dendrites and spine synapse processes. Part of the cAMP response element-binding protein (CREB) shut-off signaling pathway. Stimulates outgrowth of olfactory axons and migration of gonadotropin-releasing hormone (GnRH) and luteinizing-hormone-releasing hormone (LHRH) neuronal cells.
Highly expressed in adult and fetal brain. Weakly expressed in heart, liver, spleen, testis, small intestine, skeletal muscle, peripheral white blood cells and kidney.
Interacts with KPNA1; the interaction occurs in a calcium-independent manner after synaptic NMDA receptor stimulation and is required for nuclear import of NSMF but is competed by CABP1. Interacts (via the central NLS-containing motif region) with CABP1 (via EF-hands 1 and 2); the interaction occurs in a calcium-dependent manner after synaptic NMDA receptor stimulation and prevents the nuclear import of NSMF. Cannot be competed by calmodulin (By similarity).
NSMF mRNAs expressed in the hippocampus exhibit a prominent dendritic localization which is mediated by a dendritic targeting element (DTE) residing in the 3'-untranslated region (3'UTR). Transport from dendrites to the nucleus is induced by NMDA receptor activation and results in a rapid stripping of synaptic contacts and a reduction of dendritic complexity (By similarity).
Proteolytically processed after NMDA receptor activation. Cleaved in a calcium-dependent and calpain-sensitive manner. Calpain cleavage is essential for the translocation process from dendrites to the nucleus (By similarity).
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in NSMF as well as in other HH-associated genes including FGFR1 (PubMed:23643382).
Found in a complex with CDC20, CDC27 and TUBG1. Interacts with CDC20 (By similarity).
Core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (PubMed:11991638, PubMed:19325628, PubMed:21516107, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Most spliceosomal snRNPs contain a common set of Sm proteins, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (PubMed:19325628, PubMed:21516107, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Component of the U1 snRNP (PubMed:19325628, PubMed:25555158). The U1 snRNP is composed of the U1 snRNA and the 7 core Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG, and at least three U1 snRNP-specific proteins SNRNP70/U1-70K, SNRPA/U1-A and SNRPC/U1-C (PubMed:19325628, PubMed:25555158). Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39, plus LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 (PubMed:26912367). Component of the U7 snRNP complex, or U7 Sm protein core complex, that is composed of the U7 snRNA and at least LSM10, LSM11, SNRPB, SNRPD3, SNRPE, SNRPF and SNRPG; the complex does not contain SNRPD1 and SNRPD2 (PubMed:11574479). Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932, PubMed:15146077). Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG; catalyzes core snRNPs assembly (PubMed:18984161, PubMed:16314521). Forms a 6S pICln-Sm complex composed of CLNS1A/pICln, SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG; ring-like structure where CLNS1A/pICln mimics additional Sm proteins and which is unable to assemble into the core snRNP (PubMed:18984161, PubMed:23333303). Interacts with GEMIN2 (via N-terminus); the interaction is direct (PubMed:21816274, PubMed:31799625). Interacts with SNRPD2; the interaction is direct (PubMed:21816274, PubMed:31799625). Interacts with SNRPE; the interaction is direct (PubMed:21816274, PubMed:31799625).
Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6. May also participate in the formation of NuA4 related complexes which lack the KAT5/TIP60 catalytic subunit, but which include the SWI/SNF related protein SRCAP. The NuA4 complex interacts with MYC and the adenovirus E1A protein. EP400 interacts with TRRAP, RUVBL1 and RUVBL2. Component of a SWR1-like complex. Interacts with ZNF42. Interacts with PHF5A. Interacts with human cytomegalovirus UL27. Interacts with human adenovirus 5 E1A protein; this interaction stabilizes MYC (PubMed:18413597).
Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. May be required for transcriptional activation of E2F1 and MYC target genes during cellular proliferation. The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. May regulate ZNF42 transcription activity. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome.
A chromosomal aberration involving FGFR1OP2 may be a cause of stem cell myeloproliferative disorder (MPD). Insertion ins(12;8)(p11;p11p22) with FGFR1. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion protein FGFR1OP2-FGFR1 may exhibit constitutive kinase activity and be responsible for the transforming activity.
May be involved in wound healing pathway.
Acts as a negative growth regulator via p53-mediated apoptosis pathway. Regulates formation of degradative autolysosomes during autophagy (By similarity).
EI24 is on a chromosomal region frequently deleted in solid tumors, and it is thought to play a role in breast and cervical cancer. Particularly, expression analysis of EI24 in cancerous tissues shows that EI24 loss is associated with tumor invasiveness.
Widely expressed, with highest levels in skeletal muscle. Expressed throughout the central nervous system, including in the cerebellum and cerebellar vermis, with higher expression in the substantia nigra. Widely expressed in fetal tissues.
Functions as a proapoptotic molecule through the caspase-dependent mitochondrial pathway of cell death.
Heart, placenta, skeletal muscle, kidney, lung and pancreas.
Interacts with MFAP4 (PubMed:26601954). Interacts (via propeptide) with EFEMP2; this interaction is strong and facilitates formation of ternary complexes with ELN during elastic fiber assembly; this interaction limits interaction of EFEMP2 with FBLN5 (PubMed:19855011).
Mediates the post-translational oxidative deamination of lysine residues on target proteins leading to the formation of deaminated lysine (allysine).
Proteolytically cleaved by BMP1 which removes the propeptide (PubMed:31152061). Also proteolytically cleaved by ADAMTS2 and ADAMTS14, but not by ADAMTS3, at an additional cleavage site downstream of the BMP1 cleavage site (PubMed:31152061). The propeptide plays a role in directing the deposition of this enzyme to elastic fibers, via interaction with tropoelastin (By similarity). Cleavage by BMP1 to remove the propeptide does not increase enzymatic activity but increases binding to collagen (PubMed:31152061). Cleavage by ADAMTS2 produces a form with reduced collagen-binding activity (PubMed:31152061).
Responsible for the post-translational oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin (PubMed:26838787). Regulator of Ras expression. May play a role in tumor suppression. Plays a role in the aortic wall architecture (By similarity).
Sulfated at Tyr-187 and also at either Tyr-183 or Tyr-184 which enhances binding to collagen.
Polymerase that creates the 3' poly(A) tail of mitochondrial transcripts. Can use all four nucleotides, but has higher activity with ATP and UTP (in vitro). Plays a role in replication-dependent histone mRNA degradation. May be involved in the terminal uridylation of mature histone mRNAs before their degradation is initiated. Might be responsible for the creation of some UAA stop codons which are not encoded in mtDNA.
The disease is caused by variants affecting the gene represented in this entry. MTPAP mutations result in a defect of mitochondrial mRNA maturation. Affected individuals exhibit a drastic decrease in poly(A) tail length of mitochondrial mRNA transcripts, including COX1 and RNA14 (PubMed:20970105).
Ubiquitous, with stronger expression in tissues with high energy requirements: heart, brain, and skeletal muscle.
Dubious isoform. Probable cloning artifact lacking polyadenylation evidence.
Essential for normal male fertility and for progressive motility of spermatozoa.
Part of the SNAPc complex composed of 5 subunits: SNAPC1, SNAPC2, SNAPC3, SNAPC4 and SNAPC5. SNAPC4 interacts with SNAPC1, SNAPC2, SNAPC5, BRF2 and TBP.
Required for postnatal maturation of the hair bundle and long-term survival of hair cells and spiral ganglion.
Widely expressed in adult and fetal tissues. Highest levels are found in jejunum, lymph node, parietal lobe, fetal spleen and fetal thymus. Expressed in cervical, melanoma, chronic myelogenous and gastric cancer cell lines.
Binds to the SECIS element in the 3'-UTR of some mRNAs encoding selenoproteins. Binding is stimulated by SELB.
Contains a transit peptide at positions 1-15.
Catalyzes the phosphorylation of pantothenate to generate 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis.
Detected at much lower levels in kidney, liver, brain and testis and not detected in heart or skeletal muscle.
Expressed at high levels in brain, heart, kidney, liver, skeletal muscle and testis.
Induced by bezafibrate, a hypolipidemic drug which acts as an agonist of peroxisome proliferator activator receptor alpha (PPARA), while isoform 2 levels decrease slightly.
Regulated by feedback inhibition by CoA and its thioesters.
The N-terminal extension, may be the regulatory domain.
Required for gamma-tubulin complex recruitment to the centrosome.
Interacts (via N-terminus) with MAGOH and RBM8A; the interaction is direct. Associates (eIF2A-like region) with the 40S ribosomal subunit and the 48S preinitiation complex.
Key regulator of the exon junction complex (EJC), a multiprotein complex that associates immediately upstream of the exon-exon junction on mRNAs and serves as a positional landmark for the intron exon structure of genes and directs post-transcriptional processes in the cytoplasm such as mRNA export, nonsense-mediated mRNA decay (NMD) or translation. Acts as an EJC disassembly factor, allowing translation-dependent EJC removal and recycling by disrupting mature EJC from spliced mRNAs. Its association with the 40S ribosomal subunit probably prevents a translation-independent disassembly of the EJC from spliced mRNAs, by restricting its activity to mRNAs that have been translated. Interferes with NMD and enhances translation of spliced mRNAs, probably by antagonizing EJC functions. May bind RNA; the relevance of RNA-binding remains unclear in vivo, RNA-binding was detected by PubMed:14968132, while PubMed:19410547 did not detect RNA-binding activity independently of the EJC.
The eIF2A-like region shares sequence similarity with eIF2A and mediates the interaction with the 40S ribosomal subunit and the 48S preinitiation complex.
Activated by ligand-binding, leading to homodimerization and autophosphorylation.
Expressed in non-hematopoietic cell lines and T- and B-cell lines.
Genetic variations in LTK that cause up-regulation of the PI3K pathway may possibly contribute to susceptibility to abnormal proliferation of self-reactive B-cells and, therefore, to systemic lupus erythematosus (SLE) (PubMed:14695357). SLE is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue, thought to represent a failure of the regulatory mechanisms of the autoimmune system (PubMed:14695357).
Homodimer; homodimerizes following ligand-binding (PubMed:34646012). Part of a complex including LTK, TNK2 and GRB2, in which GRB2 promotes LTK recruitment by TNK2 (PubMed:19815557).
Receptor with a tyrosine-protein kinase activity (PubMed:10445845, PubMed:20548102, PubMed:30061385). Following activation by ALKAL1 or ALKAL2 ligands at the cell surface, transduces an extracellular signal into an intracellular response (PubMed:30061385, PubMed:34646012). Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway (PubMed:20548102). Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif (By similarity). The exact function of this protein is not known; studies with chimeric proteins demonstrate its ability to promote growth and specifically neurite outgrowth, and cell survival (PubMed:9223670, PubMed:18849880). Involved in regulation of the secretory pathway involving endoplasmic reticulum (ER) export sites (ERESs) and ER to Golgi transport (PubMed:20548102).
Binds to the N-terminus of tropomyosin and to actin.
Blocks the elongation and depolymerization of the actin filaments at the pointed end. The Tmod/TM complex contributes to the formation of the short actin protofilament, which in turn defines the geometry of the membrane skeleton (By similarity).
Called DUO because the encoded protein is closely related to but shorter than TRIO.
Interacts with the C-terminal of peptidylglycine alpha-amidating monooxygenase (PAM) and with the huntingtin-associated protein 1 (HAP1) (By similarity). Interacts with FASLG.
Isoform 2 is brain specific. Highly expressed in cerebral cortex, putamen, amygdala, hippocampus and caudate nucleus. Weakly expressed in brain stem and cerebellum. Isoform 4 is expressed in skeletal muscle.
Promotes the exchange of GDP by GTP. Activates specific Rho GTPase family members, thereby inducing various signaling mechanisms that regulate neuronal shape, growth, and plasticity, through their effects on the actin cytoskeleton. Induces lamellipodia independent of its GEF activity.
The two GEF domains catalyze nucleotide exchange for RAC1 and RhoA which are bound by DH1 and DH2 respectively. The two GEF domains appear to play differing roles in neuronal development and axonal outgrowth. SH3 1 binds to the first GEF domain inhibiting GEF activity only when in the presence of a PXXP peptide, suggesting that the SH3 domain/peptide interaction mediates binding to GEF1. CRK1 SH3 domain binds to and inhibits GEF1 activity (By similarity).
CASK and LIN7 form two mutually exclusive tripartite complexes with APBA1 or CASKIN1 (By similarity). Component of the brain-specific heterotrimeric complex (LIN-10-LIN-2-LIN-7 complex) composed of at least APBA1, CASK, and LIN7, which associates with the motor protein KIF17 to transport vesicles along microtubules (By similarity). Forms a heterotrimeric complex with DLG1 and LIN7B via their L27 domains (By similarity). Identified in a complex with ACTN4, IQGAP1, MAGI2, NPHS1, SPTAN1 and SPTBN1 (By similarity). Part of a complex containing CASK, TBR1 and TSPYL2 (By similarity). Interacts with WHRN (By similarity). Interacts (via the PDZ, SH3 and guanylate kinase-like domains) with NRXN1 (via C-terminus) (By similarity). Interacts with CASKIN1, APBA1, LIN7(A/B/C) and L27 domain of DLG1 and isoform 2 of DLG4 (By similarity). Interacts with FCHSD2 (By similarity). Interacts with KIRREL3 (PubMed:19012874). Interacts with TBR1 (By similarity). Interacts with TSPYL2 (By similarity).
Differs from archetypal CaMK members in that the kinase domain exhibits a constitutively active conformation and the autoinhibitory region does not engage in direct contact with the ATP-binding cleft, although it still binds Ca(2+)/CAM.
In the N-terminal section; belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily.
Multidomain scaffolding Mg(2+)-independent protein kinase that catalyzes the phosphotransfer from ATP to proteins such as NRXN1, and plays a role in synaptic transmembrane protein anchoring and ion channel trafficking (PubMed:18423203). Contributes to neural development and regulation of gene expression via interaction with the transcription factor TBR1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1. Component of the LIN-10-LIN-2-LIN-7 complex, which associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules (By similarity).
The first L27 domain binds DLG1 and the second L27 domain probably binds LIN7.
The protein kinase domain mediates the interaction with FCHSD2.
Ubiquitous. Expression is significantly greater in brain relative to kidney, lung, and liver and in fetal brain and kidney relative to lung and liver.
Unlike other protein kinases, does not require a divalent cation such as magnesium for catalytic activity.
Catalyzes the final step of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway, the ATP-dependent amidation of deamido-NAD using L-glutamine as a nitrogen source.
In the C-terminal section; belongs to the NAD synthetase family.
Interacts with EIF4B, IMP8, PRMT5, TNRC6A and TNRC6B (PubMed:19167051). Interacts with ZFP36 (PubMed:15766526).
Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) and represses the translation of mRNAs which are complementary to them. Lacks endonuclease activity and does not appear to cleave target mRNAs. Also required for RNA-directed transcription and replication of the human hapatitis delta virus (HDV).
Ubiquitinated on surface-exposed lysines by a SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 during target-directed microRNA degradation (TDMD), a process that mediates degradation of microRNAs (miRNAs). Ubiquitination by the SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 leads to its subsequent degradation, thereby exposing miRNAs for degradation. ZSWIM8 recognizes and binds AGO4 when it is engaged with a TDMD target.
Belongs to the PC-esterase family. CASD1 subfamily.
Highly expressed in peripheral B lymphocytes.
O-acetyltransferase that catalyzes 9-O-acetylation of sialic acids (PubMed:20947662, PubMed:26169044). Sialic acids are sugars at the reducing end of glycoproteins and glycolipids, and are involved in various processes such as cell-cell interactions, host-pathogen recognition (PubMed:20947662, PubMed:26169044).
Can form homodimers or heterodimers with ETV6/TEL1.
Located on a fragment of chromosome 11 flanked on the centromeric side by the acute lymphoblastic leukemia-associated t(4;11)(q21;q23) translocation breakpoint and on the telomeric side by the Ewing- and neuroepithelioma-associated t(11;22) (q24;q12) breakpoint.
Sequence-specific transcriptional activator (PubMed:24100448, PubMed:26316623, PubMed:28255014). Recognizes the DNA sequence 5'-C[CA]GGAAGT-3'.
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving FLI1 is found in patients with Erwing sarcoma. Translocation t(11;22)(q24;q12) with EWSR1.
Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine (PubMed:8452534, PubMed:16670267, PubMed:23193172, PubMed:9361033, PubMed:26166670). Plays an important role in purine metabolism and in adenosine homeostasis. Modulates signaling by extracellular adenosine, and so contributes indirectly to cellular signaling events. Acts as a positive regulator of T-cell coactivation, by binding DPP4 (PubMed:20959412). Its interaction with DPP4 regulates lymphocyte-epithelial cell adhesion (PubMed:11772392). Enhances dendritic cell immunogenicity by affecting dendritic cell costimulatory molecule expression and cytokines and chemokines secretion (By similarity). Enhances CD4+ T-cell differentiation and proliferation (PubMed:20959412). Acts as a positive modulator of adenosine receptors ADORA1 and ADORA2A, by enhancing their ligand affinity via conformational change (PubMed:23193172). Stimulates plasminogen activation (PubMed:15016824). Plays a role in male fertility (PubMed:21919946, PubMed:26166670). Plays a protective role in early postimplantation embryonic development (By similarity).
Found in all tissues, occurs in large amounts in T-lymphocytes (PubMed:20959412). Expressed at the time of weaning in gastrointestinal tissues.
Inhibited by Cu(2+) and Hg(2+), coformycin, deoxycoformycin (dCF), 2-deoxyadenosine, 6-methylaminopurine riboside, 2-3-iso-propylidene-adenosine and erythro-9-(2-hydroxy-3-nonyl)adenine.
Interacts with DPP4 (via extracellular domain) (PubMed:10951221, PubMed:14691230, PubMed:7907293, PubMed:8101391, PubMed:15016824). Interacts with PLG (via Kringle 4 domain); the interaction stimulates PLG activation when in complex with DPP4 (PubMed:15016824).
There is a common allele, ADA*2, also known as the ADA 2 allozyme. It is associated with the reduced metabolism of adenosine to inosine. It specifically enhances deep sleep and slow-wave activity (SWA) during sleep.
Inhibits neuronal cell proliferation by negative regulation of the cell cycle transition.
(Microbial infection) Interacts with Zika virus protein NS3; this interaction promotes viral NS3 degradation.
(Microbial infection) Interacts with the human dengue virus DENV proteins NS3 and NS4A.
Inhibits programmed -1 ribosomal frameshifting (-1PRF) of a variety of mRNAs from viruses, such as HIV1, and cellular genes, such as PEG10. Interacts with the -1PRF signal of target mRNA and translating ribosomes and causes premature translation termination at the frameshifting site (PubMed:30682371). Regulates HIV1 GAG-POL expression by inhibiting -1PRF (PubMed:30682371). Exhibits antiviral activity against dengue virus (DENV) and can inhibit the replication of all DENV serotypes. May block the protein translation of DENV RNA via its association with cellular mRNA-binding proteins and viral RNA. Interrupts also Zika virus replication by promoting viral NS3 degradation via a lysosome-dependent pathway (PubMed:32150556). Can also limit the replication of hepatitis C virus (HCV) by restricting formation of viral replication organelle, West Nile virus (WNV), Chikungunya virus (CHIKV), herpes simplex virus type 1 (HHV-1), herpes virus type 8 (HHV-8) and human adenovirus (PubMed:26735137, PubMed:27974568, PubMed:30944177, PubMed:32294532). Binds nucleic acids with a higher affinity for ssRNA and ssDNA than for dsDNA (PubMed:27974568).
Interacts with PABPC1 (PubMed:26735137). Found in a complex with PABPC1 and LARP1 (PubMed:26735137). Interacts with ELAV1, MOV10 and UPF1; the interactions increase in presence of RNA (PubMed:27974568). Binds to ribosomes (PubMed:30682371). Interacts with GSPT1 (PubMed:30682371).
Isoform 4 does not inhibit programmed ribosomal frameshifting (-1PRF). Does not bind to ribosomes.
Up-regulated by interferon (IFN) treatment (PubMed:26735137, PubMed:27974568, PubMed:30682371, PubMed:32294532). Expression increases in response to DENV infection in an IFN-dependent manner (PubMed:27974568).
By poly(RI), poly(RC) and Newcastle disease virus.
Widely expressed, with highest levels in liver, kidney, pancreas, thymus, and small intestine.
Acts as a sodium-dependent hypoxanthine transporter (PubMed:35094660). May show xanthine-hypoxanthine exchange activity (PubMed:35094660).
Belongs to the CND3 (condensin subunit 3) family.
Overexpressed in some cancer lines and some tumor cells.
Phosphorylated by CDK1. Its phosphorylation, as well as that of NCAPD2 and NCAPH subunits, activates the condensin complex and is required for chromosome condensation (By similarity).
Regulatory subunit of the condensin complex, a complex required for conversion of interphase chromatin into mitotic-like condense chromosomes. The condensin complex probably introduces positive supercoils into relaxed DNA in the presence of type I topoisomerases and converts nicked DNA into positive knotted forms in the presence of type II topoisomerases.
Expressed in heart, brain, cerebellum, testis, lung, thyroid, spoleen and liver (PubMed:16971491). In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed within the tubules (PubMed:35307651, PubMed:16971491). In testis, also present in spermatogonia at different stages. In brain, expressed in the choroid plexus epithelium, at the apical membrane as well as in the subapical intracellular vesicular compartments. In brain, also associated with neuronal bodies and axons in both the gray and the white matters of the frontal cortex (PubMed:16971491).
Expressed in placental trophoblasts (PubMed:10873595, PubMed:12409283). Expressed in pancreas, kidney, liver, lung, brain, heart, cerebellum, peripheral blood leukocyte, colon, small intestine, ovary, testis, prostate, thyroid, thymus and spleen (PubMed:10873595, PubMed:16971491, PubMed:14631946). Expressed in fetal brain, heart, kidney, liver, lung, skeletal muscle, spleen and pancreas (PubMed:10873595). In testis, detected in spermatogonia at different stages and absent from Sertoli cells. Expressed in the choroid plexus epithelium, at the basolateral membrane. In brain, also very abundant in the gray matter of the frontal cortex, but not associated with neuronal cell bodies. Not detected in the white matter (PubMed:16971491).
Generally the expression of isoform 1 is higher than that of isoform 2.
Putative organic anion antiporter with apparent broad substrate specificity. Recognizes various substrates including thyroid hormone L-thyroxine, prostanoids such as prostaglandin E1 and E2, bile acids such as taurocholate, glycolate and glycochenodeoxycholate and peptide hormones such as L-arginine vasopressin, likely operating in a tissue-specific manner (PubMed:10873595, PubMed:14631946, PubMed:16971491, PubMed:19129463, PubMed:30063921). The transport mechanism, its electrogenicity and potential tissue-specific counterions remain to be elucidated (Probable).
Transcriptionally up-regulated by SP1 and RELA in response to FGF19.
Guanine nucleotide exchange factor that specifically activates the small GTPase SAR1B. Mediates the recruitment of SAR1B and other COPII coat components to endoplasmic reticulum membranes and is therefore required for the formation of COPII transport vesicles from the ER.
Interacts with SAR1B (GDP-bound form) (By similarity). Interacts with MIA2; recruits PREB to endoplasmic reticulum exit sites (PubMed:25202031, PubMed:27170179). Interacts with CIDEB; facilitating loading of SCAP-SREBP into COPII vesicles (By similarity).
Interacts with SAR1B (GDP-bound form). Interacts with MIA2; recruits PREB to endoplasmic reticulum exit sites.
Was first identified based on its probable role in the regulation of pituitary gene transcription. Binds to the prolactin gene (PRL) promoter and seems to activate transcription.
Expressed in kidney, lung, heart, placenta, liver, small intestine and colon. No expression in brain, skeletal muscle, pancreas, spleen, thymus, prostate, testis and ovary.
Inhibited by apstatin and the chelating agent 1,10-phenanthroline. Also inhibited by high concentrations of Zn(2+). Not significantly inhibited by bestatin or phosphoramidon.
Membrane-bound metalloprotease which catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Arg-Pro-Pro. May play a role in the metabolism of the vasodilator bradykinin.
Isoform Wnt-16b is expressed in peripheral lymphoid organs such as spleen, appendix, and lymph nodes, in kidney but not in bone marrow. Isoform Wnt-16a is expressed at significant levels only in the pancreas.
Both Ser-745 and Ser-756 become phosphorylated when T-cells are exposed to phorbol esters (PubMed:11700305). Phosphorylation on Thr-758 (but not on Ser-756) allows interaction with 14-3-3 proteins (PubMed:11700305, PubMed:16301335).
Heterodimer of an alpha and a beta subunit (PubMed:20033057). The ITGB2 beta subunit associates with the ITGAL, ITGAM, ITGAX or ITGAD alpha subunits. Found in a complex with CD177 and ITGAM/CD11b (PubMed:21193407, PubMed:28807980). Interacts with FGR (By similarity). Interacts with COPS5 and RANBP9 (PubMed:10766246, PubMed:14722085). Interacts with FLNA (via filamin repeats 4, 9, 12, 17, 19, 21, and 23) (PubMed:19828450). Interacts with THBD (PubMed:27055590).
Integrin ITGAL/ITGB2 is a receptor for ICAM1, ICAM2, ICAM3 and ICAM4. Integrin ITGAL/ITGB2 is also a receptor for the secreted form of ubiquitin-like protein ISG15; the interaction is mediated by ITGAL (PubMed:29100055). Integrins ITGAM/ITGB2 and ITGAX/ITGB2 are receptors for the iC3b fragment of the third complement component and for fibrinogen. Integrin ITGAX/ITGB2 recognizes the sequence G-P-R in fibrinogen alpha-chain. Integrin ITGAM/ITGB2 recognizes P1 and P2 peptides of fibrinogen gamma chain. Integrin ITGAM/ITGB2 is also a receptor for factor X. Integrin ITGAD/ITGB2 is a receptor for ICAM3 and VCAM1. Contributes to natural killer cell cytotoxicity (PubMed:15356110). Involved in leukocyte adhesion and transmigration of leukocytes including T-cells and neutrophils (PubMed:11812992, PubMed:28807980). Triggers neutrophil transmigration during lung injury through PTK2B/PYK2-mediated activation (PubMed:18587400). Integrin ITGAL/ITGB2 in association with ICAM3, contributes to apoptotic neutrophil phagocytosis by macrophages (PubMed:23775590). In association with alpha subunit ITGAM/CD11b, required for CD177-PRTN3-mediated activation of TNF primed neutrophils (PubMed:21193407).
Leukocytes (PubMed:23775590). Expressed in neutrophils (at protein level) (PubMed:21193407, PubMed:28807980).
Belongs to the AAA ATPase family. MSP1 subfamily.
Interacts with GRIA2 and GRIP1 in an ATP-dependent manner (By similarity). ATAD1-catalyzed ATP hydrolysis disrupts not only its binding to GRIA2 and GRIP1, but also interaction between GRIP1 and GRIA2, leading to AMPAR complex disassembly (By similarity).
Outer mitochondrial translocase required to remove mislocalized tail-anchored transmembrane proteins on mitochondria (PubMed:24843043). Specifically recognizes and binds tail-anchored transmembrane proteins: acts as a dislocase that mediates the ATP-dependent extraction of mistargeted tail-anchored transmembrane proteins from the mitochondrion outer membrane (By similarity). Also plays a critical role in regulating the surface expression of AMPA receptors (AMPAR), thereby regulating synaptic plasticity and learning and memory (By similarity). Required for NMDA-stimulated AMPAR internalization and inhibition of GRIA1 and GRIA2 recycling back to the plasma membrane; these activities are ATPase-dependent (By similarity).
Activated by TLR ligands such as LPS, bacterial DNA and peptidoglycan.
Expressed in renal collecting duct epithelial cells.
Pathogen-recognition receptor which mediates the activation of TRAF2- and TRAF6 NF-kappa-B signaling pathways and induces the expression of pro-inflammatory cytokines (PubMed:19679103, PubMed:25026888). In kidney, prevents infection by uropathogenic bacteria by inducing the production of cytokines, chemokines and antimicrobial substances. In gut, involved in host-microbiota interactions, plays a critical role in promoting the recruitment of immune cells and intestinal inflammation (By similarity).
Amino acid residues between 299-311 are important for both protein expression and enzymatic activity. The minimal catalytic domain is located between positions 299-651. Single amino acid substitutions in the stem domain from MEB patients abolished the activity of the membrane-bound form but not the soluble form. This suggests that the stem domain of the soluble form is unnecessary for activity, but that some amino acids play a crucial role in the membrane-bound form.
Belongs to the glycosyltransferase 13 family.
Constitutively expressed. An additional weaker band is also detected in spinal cord, lymph node, and trachea. Expressed especially in astrocytes. Also expressed in immature and mature neurons.
Initiates complex N-linked carbohydrate formation. Essential for the conversion of high-mannose to hybrid and complex N-glycans.
Interacts with DAG1 (via O-linked mannose moiety) (PubMed:27493216). Interacts (via transmembrane domain) with FKTN; the interaction is direct and is required for normal location in Golgi membranes (PubMed:17034757).
Participates in O-mannosyl glycosylation by catalyzing the addition of N-acetylglucosamine to O-linked mannose on glycoproteins (PubMed:11709191, PubMed:27493216, PubMed:28512129). Catalyzes the synthesis of the GlcNAc(beta1-2)Man(alpha1-)O-Ser/Thr moiety on alpha-dystroglycan and other O-mannosylated proteins, providing the necessary basis for the addition of further carbohydrate moieties (PubMed:11709191, PubMed:27493216). Is specific for alpha linked terminal mannose and does not have MGAT3, MGAT4, MGAT5, MGAT7 or MGAT8 activity.
Participates in O-mannosyl glycosylation by catalyzing the addition of N-acetylglucosamine to O-linked mannose on glycoproteins. Catalyzes the synthesis of the GlcNAc(beta1-2)Man(alpha1-)O-Ser/Thr moiety on alpha-dystroglycan and other O-mannosylated proteins, providing the necessary basis for the addition of further carbohydrate moieties. Is specific for alpha linked terminal mannose.
The GG-type lectin domain is known as the stem domain in POMGnT1. It mediates specific interaction with beta-linked N-acetylglucosamine moieties of O-glycosylated proteins. It also interacts with its product, N-acetyl-beta-D-glucosaminyl-(1->2)-O-alpha-D-mannosylprotein.
The cofactor is mostly bound to the substrate.
The manganese ion interacts primarily with the substrate UDP-N-acetylglucosamine.
The stem domain mediates specific interaction with beta-linked N-acetylglucosamine moieties of O-glycosylated proteins. It also interacts with its product, N-acetyl-beta-D-glucosaminyl-(1->2)-O-alpha-D-mannosylprotein.
(Microbial infection) Interacts with Herpes simplex virus 1 (HHV-1) protein ICP22; this interaction relocalizes the FACT complex to viral genomes in infected cells.
Autoantibodies against SSRP1 are present in sera from patients with systemic lupus erythematosus, but not other rheumatic diseases.
Component of the FACT complex, a general chromatin factor that acts to reorganize nucleosomes. The FACT complex is involved in multiple processes that require DNA as a template such as mRNA elongation, DNA replication and DNA repair. During transcription elongation the FACT complex acts as a histone chaperone that both destabilizes and restores nucleosomal structure. It facilitates the passage of RNA polymerase II and transcription by promoting the dissociation of one histone H2A-H2B dimer from the nucleosome, then subsequently promotes the reestablishment of the nucleosome following the passage of RNA polymerase II. The FACT complex is probably also involved in phosphorylation of 'Ser-392' of p53/TP53 via its association with CK2 (casein kinase II). Binds specifically to double-stranded DNA and at low levels to DNA modified by the antitumor agent cisplatin. May potentiate cisplatin-induced cell death by blocking replication and repair of modified DNA. Also acts as a transcriptional coactivator for p63/TP63.
Interacts with MYOG (via C-terminal region) (By similarity). Component of the FACT complex, a stable heterodimer of SSRP1 and SUPT16H (PubMed:10421373). Also a component of a CK2-SPT16-SSRP1 complex which forms following UV irradiation, composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B (PubMed:11239457, PubMed:12393879). Binds to histone H3-H4 tetramers, but not to intact nucleosomes. Identified in a centromere complex containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:27499292). Interacts with isoform gamma of TP63 (PubMed:12374749). Interacts with FYTTD1/UIF (PubMed:19836239). Interacts with SRF (By similarity). Interacts with NEK9 (PubMed:14660563).
Phosphorylated by CK2 following UV but not gamma irradiation. Phosphorylation inhibits its DNA-binding activity.
The HMG box DNA-binding domain mediates DNA-binding. It has both affinity and specificity for DNA damaged globally with cisplatin.
Ubiquitinated. Polyubiquitinated following caspase cleavage resulting in degradation of the N-terminal ubiquitinated part of the cleaved protein.
Acts as a synaptic organizer in specific subsets of neurons in the brain (By similarity). Essential for the formation and maintenance of inhibitory GABAergic synapses (By similarity). Promotes the development of dendrite-targeting inhibitory GABAergic synapses made by somatostatin-positive interneurons (By similarity). May contribute to the function of ventral medial habenula region of the brain implicated in the regulation of anxiety-related behaviors (By similarity). May play a role in CBLN3 export from the endoplasmic reticulum and secretion (By similarity).
Homohexamer; disulfide-linked homotrimers. The trimers are assembled via the globular C1q domains. The trimers associate via N-terminal cysteine residues to form disulfide-linked hexamers (By similarity). May form oligomers with CBLN1, CBLN2 and CBLN3 prior to secretion (By similarity). Strongly interacts with DCC in a NTN1-displaceable fashion (By similarity). Weakly binds to NRXN1 and NRXN2 long and short isoforms produced by alternative promoter usage. Interaction with NRXN3 short isoform is hardly detectable; no interaction at all with NRXN3 long isoform (By similarity).
Homodimer. Interacts (via the BTB domain) with HDAC1 and NCOR2.
Negatively regulates class switch recombination or isotype switching in splenic B-cells.
The BTB domain is important for homodimerization and for its function in negative regulation of class switch recombination.
May play a role in prolonged long term-potentiation (LTP) maintenance.
Acts as a negative regulator of hedgehog signaling probably by promoting internalization and subsequent degradation of smoothened protein (SMO) present in the ciliary membrane. Plays a role in sonic hedgehog (SHH)-induced spinal neural progenitor cells differentiation.
Gate loop 1 and gate loop 2 regions are adjacent to the S-adenosyl-L-homocysteine-binding site and display large conformational changes upon ligand-binding. They may play an important role in adenosine recognition. The interface loop contributes to the heterodimer interaction.
Heterodimer; heterodimerizes with METTL14 to form an antiparallel heterodimer that constitutes an active methyltransferase (PubMed:27627798, PubMed:27373337, PubMed:27281194). Component of the WMM complex, a N6-methyltransferase complex composed of a catalytic subcomplex, named MAC, and of an associated subcomplex, named MACOM (PubMed:24407421, PubMed:24981863, PubMed:27602518, PubMed:29507755, PubMed:29506078, PubMed:29348140). The MAC subcomplex is composed of METTL3 and METTL14 (PubMed:24407421, PubMed:24981863, PubMed:27602518, PubMed:29507755). The MACOM subcomplex is composed of WTAP, ZC3H13, CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B) (PubMed:27602518, PubMed:29507755). Interacts with NCBP1/CBP80 (PubMed:27117702). Interacts with EIF4E (PubMed:27117702). Interacts with EIF3B (PubMed:27117702).
Methyltransferase activity is regulated by miRNAs via a sequence pairing mechanism (By similarity). Methyltransferase activity is inhibited by sumoylation (PubMed:29506078).
Overexpressed in a number of cancer tissues, such as lung adenocarcinoma and colon adenocarcinoma (PubMed:27117702).
Sumoylation inhibits the N6-adenosine-methyltransferase activity. Sumoylation does not affect subcellular location or interaction with METTL14. Desumoylated by SENP1.
The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N(6) position of some RNAs and regulates various processes such as the circadian clock, differentiation of embryonic and hematopoietic stem cells, cortical neurogenesis, response to DNA damage, differentiation of T-cells and primary miRNA processing (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:27627798, PubMed:27373337, PubMed:27281194, PubMed:28297716, PubMed:30428350, PubMed:29506078, PubMed:29348140, PubMed:9409616). In the heterodimer formed with METTL14, METTL3 constitutes the catalytic core (PubMed:27627798, PubMed:27373337, PubMed:27281194). N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in mRNA stability, processing, translation efficiency and editing (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:28297716, PubMed:9409616). M6A acts as a key regulator of mRNA stability: methylation is completed upon the release of mRNA into the nucleoplasm and promotes mRNA destabilization and degradation (PubMed:28637692). In embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A regulates the length of the circadian clock: acts as an early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A also regulates circadian regulation of hepatic lipid metabolism (PubMed:30428350). M6A regulates spermatogonial differentiation and meiosis and is essential for male fertility and spermatogenesis (By similarity). Also required for oogenesis (By similarity). Involved in the response to DNA damage: in response to ultraviolet irradiation, METTL3 rapidly catalyzes the formation of m6A on poly(A) transcripts at DNA damage sites, leading to the recruitment of POLK to DNA damage sites (PubMed:28297716). M6A is also required for T-cell homeostasis and differentiation: m6A methylation of transcripts of SOCS family members (SOCS1, SOCS3 and CISH) in naive T-cells promotes mRNA destabilization and degradation, promoting T-cell differentiation (By similarity). Inhibits the type I interferon response by mediating m6A methylation of IFNB (PubMed:30559377). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates m6A methylation of Xist RNA, thereby participating in random X inactivation: m6A methylation of Xist leads to target YTHDC1 reader on Xist and promote transcription repression activity of Xist (PubMed:27602518). M6A also regulates cortical neurogenesis: m6A methylation of transcripts related to transcription factors, neural stem cells, the cell cycle and neuronal differentiation during brain development promotes their destabilization and decay, promoting differentiation of radial glial cells (By similarity). METTL3 mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998). Acts as a positive regulator of mRNA translation independently of the methyltransferase activity: promotes translation by interacting with the translation initiation machinery in the cytoplasm (PubMed:27117702). Its overexpression in a number of cancer cells suggests that it may participate in cancer cell proliferation by promoting mRNA translation (PubMed:27117702). During human coronorivus SARS-CoV-2 infection, adds m6A modifications in SARS-CoV-2 RNA leading to decreased RIGI binding and subsequently dampening the sensing and activation of innate immune responses (PubMed:33961823).
Widely expressed at low level. Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes.
Cell adhesion molecule contributing to the interactive process required for myelination in the central nervous system.
Do not confuse oligodendrocyte-myelin glycoprotein (OMG) with myelin-oligodendrocyte glycoprotein (MOG).
O-glycosylated in its Ser/Thr-rich repeat domain.
Oligodendrocytes and myelin of the central nervous system.
Accepts electrons from ETF and reduces ubiquinone.
Interacts (via KH domains) with ANKS6 (via SAM domain) in an RNA-dependent manner (By similarity). Interacts with ANKS3 (By similarity).
Putative RNA-binding protein. Acts as a negative regulator of Wnt signaling. May be involved in regulating gene expression during embryonic development.
Expressed predominantly in the pancreas.
Expressed in diffuse large B-cell lymphoma (DLBCL) and several germinal center (GC)-like lymphoma cell lines (at protein level). Highly expressed in normal GC lymphocytes and GC-derived malignancies. Expressed in thymus and spleen.
Interacts with ACTB and MYH2; the interaction with MYH2 is increased by IL6-induced phosphorylation. Interacts (via C-terminus) with ARHGEF11 (via DH domain). Interacts with ARHGEF12. Interacts with SYK; the interaction increases after B-cell receptor stimulation, resulting in enhanced SYK autophosphorylation and activity.
Involved in the negative regulation of lymphocyte motility. It mediates the migration-inhibitory effects of IL6. Serves as a positive regulator of the RhoA signaling pathway. Enhancement of RhoA activation results in inhibition of lymphocyte and lymphoma cell motility by activation of its downstream effector ROCK. Is a regulator of B-cell receptor signaling, that acts through SYK kinase activation.
Phosphorylation on tyrosine residues can be induced by IL6. Phosphorylation is mediated by LYN.
Targeted by the ubiquitin E3 ligase subunit FBXO10 to mediate its ubiquitination and degradation.
Component of the PRC2/EED-EZH2 complex, which includes EED, EZH2, SUZ12, RBBP4 and RBBP7 and possibly AEBP2. The minimum components required for methyltransferase activity of the PRC2/EED-EZH2 complex are EED, EZH2 and SUZ12. The PRC2 complex may also interact with DNMT1, DNMT3A, DNMT3B and PHF1 via the EZH2 subunit and with SIRT1 via the SUZ12 subunit. Interacts with HDAC1 and HDAC2. Binds ATRX via the SET domain (Probable). Interacts with PRAME. Interacts with CDYL. Interacts with CLOCK, BMAL1 and CRY1 (By similarity). Interacts with DNMT3L; the interaction is direct (By similarity). Interacts with EZHIP; the interaction blocks EZH2 methyltransferase activity (PubMed:30923826, PubMed:31086175, PubMed:31451685). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (PubMed:32051553). Interacts with ARMC12 (PubMed:30026490). Interacts with ZMYND8; the interaction is dependent on the presence of chromatin (PubMed:36064715, PubMed:33323928).
Expression decreases during senescence of embryonic fibroblasts (HEFs). Expression peaks at the G1/S phase boundary.
Expression is induced by E2F1, E2F2 and E2F3. Expression is reduced in cells subject to numerous types of stress including UV-, IR- and bleomycin-induced DNA damage and by activation of p53/TP53.
Glycosylated: O-GlcNAcylation at Ser-75 by OGT increases stability of EZH2 and facilitates the formation of H3K27me3 by the PRC2/EED-EZH2 complex.
In the ovary, expressed in primordial follicles and oocytes and also in external follicle cells (at protein level) (PubMed:31451685). Expressed in many tissues (PubMed:14532106). Overexpressed in numerous tumor types including carcinomas of the breast, colon, larynx, lymphoma and testis (PubMed:14532106).
Phosphorylated by AKT1. Phosphorylation by AKT1 reduces methyltransferase activity. Phosphorylation at Thr-345 by CDK1 and CDK2 promotes maintenance of H3K27me3 levels at EZH2-target loci, thus leading to epigenetic gene silencing.
Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Displays a preference for substrates with less methylation, loses activity when progressively more methyl groups are incorporated into H3K27, H3K27me0 > H3K27me1 > H3K27me2 (PubMed:22323599, PubMed:30923826). Compared to EZH1-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. Regulates the circadian clock via histone methylation at the promoter of the circadian genes. Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription.
Two variants of the PRC2 complex have been described, termed PRC3 and PRC4. Each of the three complexes may include a different complement of EED isoforms, although the precise sequences of the isoforms in each complex have not been determined. The PRC2 and PRC4 complexes may also methylate 'Lys-26' of histone H1 in addition to 'Lys-27' of histone H3 (PubMed:15099518, PubMed:15684044). In contrast, other studies have demonstrated no methylation of 'Lys-26' of histone H1 by PRC2 (PubMed:16431907).
ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell (PubMed:21586654, PubMed:27693233). Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane (By similarity). In addition to its ADP:ATP antiporter activity, also involved in mitochondrial uncoupling and mitochondrial permeability transition pore (mPTP) activity (PubMed:31883789). Plays a role in mitochondrial uncoupling by acting as a proton transporter: proton transport uncouples the proton flows via the electron transport chain and ATP synthase to reduce the efficiency of ATP production and cause mitochondrial thermogenesis (By similarity). Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A4/ANT1 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity) (By similarity). Proton transporter activity requires free fatty acids as cofactor, but does not transport it (By similarity). Also plays a key role in mPTP opening, a non-specific pore that enables free passage of the mitochondrial membranes to solutes of up to 1.5 kDa, and which contributes to cell death (PubMed:31883789). It is however unclear if SLC25A4/ANT1 constitutes a pore-forming component of mPTP or regulates it (By similarity). Acts as a regulator of mitophagy independently of ADP:ATP antiporter activity: promotes mitophagy via interaction with TIMM44, leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (By similarity).
Monomer (By similarity). Found in a complex with ARL2, ARL2BP and SLC25A4/ANT1 (By similarity). Interacts with ARL2BP (By similarity). Interacts with ARHGAP11B, thereby inhibiting the mitochondrial permeability transition pore (mPTP) (PubMed:31883789). Interacts with TIMM44; leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (By similarity).
The matrix-open state (m-state) is inhibited by the membrane-permeable bongkrekic acid (BKA) (By similarity). The cytoplasmic-open state (c-state) is inhibited by the membrane-impermeable toxic inhibitor carboxyatractyloside (CATR) (PubMed:21586654). Proton transporter activity is inhibited by ADP:ATP antiporter activity (By similarity).
Under cell death induction, transglutaminated by TGM2. Transglutamination leads to formation of covalent cross-links between a glutamine and the epsilon-amino group of a lysine residue, forming polymers.
Polymorphisms dbSNP:rs37972 and dbSNP:rs37973, located in GLCCI1 promoter region, are associated with a decreased response to glucorticoid treatment [MIM:614400] in asthma patients (PubMed:21991891), as well as in chronic obstructive pulmonary disease patients (PubMed:22187997). The mean increase in forced expiratory volume in 1 second in glucorticoid treated subjects who are homozygous for the mutant (G) rs37973 allele is only about one-third of that seen in similarly treated subjects who are homozygous for the wild-type allele (A) (PubMed:21991891). These polymorphisms affect GLCCI1 transcription level.
Predominantly expressed in lung, spleen, thymus and testis and, at lower levels, in brain, bone marrow, peripheral leukocytes, skin and trachea.
(Microbial infection) Interacts with Epstein-Barr virus (EBV) tegument protein BGLF2; this interaction participates in the inhibition of type I IFN signaling by the virus.
(Microbial infection) Interacts with Epstein-Barr virus protein LMP1; this interaction inhibits TYK2-mediated interferon signaling.
(Microbial infection) Interacts with papillomavirus-18 protein E6; this interaction impairs JAK-STAT activation by interferon-alpha.
Interacts (via FERM domain) with JAKMIP1 (PubMed:15277531, PubMed:20478313). Interacts with PIK3R1; this interaction is important for cell migration (PubMed:10995743).
Observed in all cell lines analyzed. Expressed in a variety of lymphoid and non-lymphoid cell lines.
Phosphorylated (PubMed:7638186). Phosphorylation by JAK1 at Tyr-1054 and Tyr-1055 induces kinase activation (PubMed:8232552, PubMed:8702790).
The protein kinase 1 domain (also termed pseudokinase domain) mediates autoinhibition of the TYK2 kinase domain.
Tyrosine kinase of the non-receptor type involved in numerous cytokines and interferons signaling, which regulates cell growth, development, cell migration, innate and adaptive immunity (PubMed:8232552, PubMed:7813427, PubMed:7657660, PubMed:10995743, PubMed:10542297). Plays both structural and catalytic roles in numerous interleukins and interferons (IFN-alpha/beta) signaling (PubMed:10542297). Associates with heterodimeric cytokine receptor complexes and activates STAT family members including STAT1, STAT3, STAT4 or STAT6 (PubMed:10542297, PubMed:7638186). The heterodimeric cytokine receptor complexes are composed of (1) a TYK2-associated receptor chain (IFNAR1, IL12RB1, IL10RB or IL13RA1), and (2) a second receptor chain associated either with JAK1 or JAK2 (PubMed:7813427, PubMed:10542297, PubMed:7526154, PubMed:25762719). In response to cytokine-binding to receptors, phosphorylates and activates receptors (IFNAR1, IL12RB1, IL10RB or IL13RA1), creating docking sites for STAT members (PubMed:7526154, PubMed:7657660). In turn, recruited STATs are phosphorylated by TYK2 (or JAK1/JAK2 on the second receptor chain), form homo- and heterodimers, translocate to the nucleus, and regulate cytokine/growth factor responsive genes (PubMed:7657660, PubMed:10542297, PubMed:25762719). Negatively regulates STAT3 activity by promototing phosphorylation at a specific tyrosine that differs from the site used for signaling (PubMed:29162862).
Based on a naturally occurring readthrough transcript which produces a PALM2-AKAP2 fusion protein.
Binds to regulatory subunit (RII) of protein kinase A. May be involved in establishing polarity in signaling systems or in integrating PKA-RII isoforms with downstream effectors to capture, amplify and focus diffuse, trans-cellular signals carried by cAMP. Binds to and modulates the structure of the actin cytoskeleton.
Expressed in infantile heart and muscle, and fibroblasts.
The RII-alpha binding site, predicted to form an amphipathic helix, could participate in protein-protein interactions with a complementary surface on the R-subunit dimer.
Belongs to the potassium channel family. V (TC 1.A.1.2) subfamily. Kv8.2/KCNV2 sub-subfamily.
Detected in lung, liver, kidney, pancreas, spleen, thymus, prostate, testis, ovary and colon.
Heteromultimer with KCNB1, KCNC1 and KCNF1. Does not form homomultimers.
Potassium channel subunit. Modulates channel activity by shifting the threshold and the half-maximal activation to more negative values.
Expressed in the brain, heart, stomach, spleen, lymph node and testis (PubMed:12949241). Expressed in melanocytes (PubMed:23999003).
Expressed in different tissues. Highest levels are detected in adult placenta, liver and pancreas.
Positive regulator of neurite outgrowth by stabilizing myosin regulatory light chain (MRLC). It prevents MIR-mediated MRLC ubiquitination and its subsequent proteasomal degradation.
Acetylated within its nuclear localization sequence, which impacts subcellular localization.
Cytokine constitutively present intracellularly in nearly all resting non-hematopoietic cells that plays an important role in inflammation and bridges the innate and adaptive immune systems (PubMed:26439902). After binding to its receptor IL1R1 together with its accessory protein IL1RAP, forms the high affinity interleukin-1 receptor complex (PubMed:2950091, PubMed:17507369). Signaling involves the recruitment of adapter molecules such as MYD88, IRAK1 or IRAK4 (PubMed:17507369). In turn, mediates the activation of NF-kappa-B and the three MAPK pathways p38, p42/p44 and JNK pathways (PubMed:14687581). Within the cell, acts as an alarmin and cell death results in its liberation in the extracellular space after disruption of the cell membrane to induce inflammation and alert the host to injury or damage (PubMed:15679580). In addition to its role as a danger signal, which occurs when the cytokine is passively released by cell necrosis, directly senses DNA damage and acts as signal for genotoxic stress without loss of cell integrity (PubMed:26439902).
Monomer. Interacts with TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion (PubMed:32272059). Interacts with IL1R1 (PubMed:2950091). Interacts with S100A13; this interaction is the first step in the export of IL1A, followed by direct translocation of this complex across the plasma membrane (PubMed:21270123).
Phosphorylated. Phosphorylation greatly enhances susceptibility to digestion and promotes the conversion of pre-IL1A alpha to the biologically active IL1A.
Proteolytic processed by CAPN1 in a calcium-dependent manner. Cleavage from 31 kDa precursor to 18 kDa biologically active molecules.
The similarity among the IL-1 precursors suggests that the amino ends of these proteins serve some as yet undefined function.
Required for male fertility through its role in axonemal doublet stabilization which is essential for sperm motility and fertilization.
Homodimer. Interacts with lamin-associated polypeptides IA, IB and 2. Interacts with SPAG4 and SEPT12.
Aspartate aminotransferase activity found to be increased in cerebral spinal fluid (CSF) of patients with Alzheimer disease (PubMed:16039064). Fetal serum levels of the enzyme in the umbilical artery and vein are found to be significantly higher than maternal serum levels (PubMed:22633534).
Biosynthesis of L-glutamate from L-aspartate or L-cysteine (PubMed:21900944). Important regulator of levels of glutamate, the major excitatory neurotransmitter of the vertebrate central nervous system. Acts as a scavenger of glutamate in brain neuroprotection. The aspartate aminotransferase activity is involved in hepatic glucose synthesis during development and in adipocyte glyceroneogenesis. Using L-cysteine as substrate, regulates levels of mercaptopyruvate, an important source of hydrogen sulfide. Mercaptopyruvate is converted into H(2)S via the action of 3-mercaptopyruvate sulfurtransferase (3MST). Hydrogen sulfide is an important synaptic modulator and neuroprotectant in the brain. In addition, catalyzes (2S)-2-aminobutanoate, a by-product in the cysteine biosynthesis pathway (PubMed:27827456).
Genetic variations in GOT1 are associated with low serum aspartate aminotransferase and define the aspartate aminotransferase serum level quantitative trait locus 1 (ASTQTL1) [MIM:614419].
Interacts with SUPT6H; binds preferentially to the POLR2A-bound SUPT6H. Interacts with ALYREF/THOC4, SETD2 and PRMT5. Interacts with HDGFRP2. Interacts (via IBM motif) with PSIP1 (via IBD domain); phosphorylation increases its affinity for PSIP1 (PubMed:29997176).
Transcription factor which plays a key role in defining the composition of the RNA polymerase II (RNAPII) elongation complex and in modulating the production of mature mRNA transcripts. Acts as an assembly factor to recruit various factors to the RNAPII elongation complex and is recruited to the complex via binding to the transcription elongation factor SUPT6H bound to the C-terminal domain (CTD) of the RNAPII subunit RPB1 (POLR2A). The SUPT6H:IWS1:CTD complex recruits mRNA export factors (ALYREF/THOC4, EXOSC10) as well as histone modifying enzymes (such as SETD2) to ensure proper mRNA splicing, efficient mRNA export and elongation-coupled H3K36 methylation, a signature chromatin mark of active transcription.
Lipid-binding protein involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration. Binds a phospholipid of at least 10 carbons in each acyl group. May be required to present its bound-lipid to COQ7.
Structurally similar to the bacterial FadR protein (fatty acid metabolism regulator protein).
Homodimer; disulfide-linked. Heterodimer of 2 chains generated by proteolytic processing; the large extracellular N-terminal fragment and the membrane-bound C-terminal fragment predominantly remain associated and non-covalently linked. Fragment generates by the processing enzyme furin remains attached to the extracellular N-terminal fragment. Interacts (via N-terminal extracellular domain) with SFTPD.
Proteolytically cleaved at multiple sites: one in the GPS domain (S1 site) and the other in the SEA domain (S2 site). The proteolytic cleavage at S1 site generates an extracellular subunit and a seven-transmembrane subunit. The proteolytic cleavage at S2 site generates a fragment that undergoes proteolytic cleavage by the processing enzyme furin.
Receptor that plays a critical role in lung surfactant homeostasis. May play a role in controlling adipocyte function.
Homodimer. Interacts with SIVA1 and TRAF2.
Receptor for CD70/CD27L. May play a role in survival of activated T-cells. May play a role in apoptosis through association with SIVA1.
Inhibited by phorbol 12-myristate 13-acetate (PMA). TASK-3 current is strongly decreased in the presence of an extracellular pH inferior to 7.0.
Mainly found in the cerebellum. Also found in adrenal gland, kidney and lung.
Overexpressed in a high proportion of breast cancers. May confer resistance to growth factor deprivation and hypoxia, thereby promoting tumor cell survival in poorly oxygenated areas of solid tumors.
pH-dependent, voltage-insensitive, background potassium channel protein.
A chromosomal aberration involving CCDC34 is found in a patient with hamartoma of the retinal pigment epithelium and retina. Translocation t(11;18) (p13;p11.2).
Antigen recognized by autologous antibody in patients with renal-cell carcinoma.
Involved in spermatogenesis. Has a probable role in anterograde intraflagellar transport which is essential for the formation of sperm flagella.
Expressed in the brain but not in the melanoma cells.
Receptor for MSH (alpha, beta and gamma) and ACTH. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. This receptor is a possible mediator of the immunomodulation properties of melanocortins.
A homozygous transition at position 1 of intron 3 of APOA2 results in deficiency of apolipoprotein A-II, without significant influence either on lipid and lipoprotein profiles or on the occurrence of coronary artery disease [MIM:107670].
A paper describing the crystal structure of this protein has been retracted due to evidence of fabricated data (see also US Office of Research Integrity Notice 2018-07782).
Belongs to the apolipoprotein A2 family.
May stabilize HDL (high density lipoprotein) structure by its association with lipids, and affect the HDL metabolism.
Monomer. Homodimer; disulfide-linked. Also forms a disulfide-linked heterodimer with APOD (PubMed:7918467). Interacts with NAXE and NDRG1.
Plasma; synthesized in the liver and intestine.
Belongs to the peroxiredoxin family. Prx6 subfamily.
Homodimer (PubMed:9587003, PubMed:27353378). Interacts with GSTP1; mediates PRDX6 glutathionylation and regeneration (By similarity). Interacts with APEX1 (PubMed:19188445). Interacts with STH (PubMed:16186110). May interact with FAM168B (PubMed:20716133). May interact with HTR2A (By similarity).
Irreversibly inactivated by overoxidation of Cys-47 to sulfinic acid (Cys-SO(2)H) and sulfonic acid (Cys-SO(3)H) forms upon oxidative stress.
MJ33 or lithium;[(2R)-1-hexadecoxy-3-(2,2,2-trifluoroethoxy)propan-2-yl] methyl phosphate inhibits its phospholipase A2 activity (PubMed:26830860). CI-976 or 2,2-Dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide inhibits its lysophosphatidylcholine acyltransferase activity (PubMed:26830860).
Phosphorylation at Thr-177 by MAP kinases increases the phospholipase activity of the enzyme (By similarity). The phosphorylated form exhibits a greater lysophosphatidylcholine acyltransferase activity compared to the non-phosphorylated form (PubMed:26830860).
The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this 1-Cys peroxiredoxin, no C(R) is present and C(P) instead forms a disulfide with a cysteine from another protein or with a small thiol molecule. C(P) is reactivated by glutathionylation mediated by glutathione S-transferase Pi, followed by spontaneous reduction of the enzyme with glutathione.
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively (PubMed:9497358, PubMed:10893423). Can reduce H(2)O(2) and short chain organic, fatty acid, and phospholipid hydroperoxides (PubMed:10893423). Also has phospholipase activity, can therefore either reduce the oxidized sn-2 fatty acyl group of phospholipids (peroxidase activity) or hydrolyze the sn-2 ester bond of phospholipids (phospholipase activity) (PubMed:10893423, PubMed:26830860). These activities are dependent on binding to phospholipids at acidic pH and to oxidized phospholipds at cytosolic pH (PubMed:10893423). Plays a role in cell protection against oxidative stress by detoxifying peroxides and in phospholipid homeostasis (PubMed:10893423). Exhibits acyl-CoA-dependent lysophospholipid acyltransferase which mediates the conversion of lysophosphatidylcholine (1-acyl-sn-glycero-3-phosphocholine or LPC) into phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine or PC) (PubMed:26830860). Shows a clear preference for LPC as the lysophospholipid and for palmitoyl CoA as the fatty acyl substrate (PubMed:26830860).
Actin-binding protein which may have an oncogenic function and regulates cell proliferation, migration and invasion in cancer cells.
May homodimerize. Interacts with F-actin.
A chromosomal aberration disrupting KLHDC8B has been found in a family with the nodular sclerosis type of Hodgkin lymphoma. Translocation t(2,3)(q11.2;p21.31).
Disease susceptibility is associated with variants affecting the gene represented in this entry. A variant in the 5'-UTR of KLHDC8B, responsible for decreasing its expression, is associated with classic Hodgkin lymphoma and segregates with the disease in some families (PubMed:19706467).
Involved in pinching off the separated nuclei at the cleavage furrow and in cytokinesis (PubMed:20107318). Required for mitotic integrity and maintenance of chromosomal stability. Protects cells against mitotic errors, centrosomal amplification, micronucleus formation and aneuploidy. Plays a key role of midbody function involving abscission of the daughter cells during cytokinesis and appropriate chromosomal and nuclear segregation into the daughter cells (PubMed:22988245, PubMed:23713010).
Transcribed predominantly during S phase, translated exclusively during mitosis and cytokinesis and rapidly degraded after cell division.
Deubiquitinating enzyme that removes conjugated ubiquitin from specific proteins to regulate different cellular processes. Regulates cell proliferation by deubiquitinating and inhibiting RCE1 thereby controlling the small GTPases NRAS and HRAS localization and activation. In parallel, mediates deubiquitination of CDC25A, preventing CDC25A degradation by the proteasome during the G1/S and G2/M phases promoting cell-cycle progression. Also regulates cell proliferation and apoptosis through deubiquitination of SUDS3 a regulator of histone deacetylation. Through activation of the Rho family GTPases RAC1A, CDC42 and RHOA, regulates cell migration. Through the cleavage of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains of the cytoplasmic innate immune receptors RIGI and IFIH1 stimulates the cellular response to viral infection.
Interacts with SUDS3; the interaction is direct.
Overexpressed in a subset of human breast cancers, overexpression leading to an abnormally high level of CDC25A, which arrests cells through replication stress or premature mitosis, the latter occurring when CDK1 is activated inappropriately.
The RS447 megasatellite DNA is a highly polymorphic conserved tandem repetitive sequence which contains a copy of the USP17 gene. It is present with an interindividual variation in copy number, ranging from 20 to 103, and can be found in the genome both on chromosome 4 and chromosome 8. USP17 is also frequently named DUB3 in the literature. The high similarity between the UPS17-like genes makes impossible to clearly assign data to one of the genes of the family. Oligonucleotides designed in RNAi experiments are for instance not specific of a given UPS17-like gene.
Up-regulated by IL4/interleukin-4, IL6/interleukin-6 and chemokines including CXCL8 and CXCL12 (at protein level). Up-regulated during the G1/S transition of the cell cycle.
Interacts with PNPLA2; this interaction stimulates the phospholipase A2 activity of PNPLA2.
Neurotrophic protein; induces extensive neuronal differentiation in retinoblastoma cells. Potent inhibitor of angiogenesis. As it does not undergo the S (stressed) to R (relaxed) conformational transition characteristic of active serpins, it exhibits no serine protease inhibitory activity.
Retinal pigment epithelial cells and blood plasma.
The N-terminal (AA 44-121) exhibits neurite outgrowth-inducing activity. The C-terminal exposed loop (AA 382-418) is essential for serpin activity.
The N-terminus is blocked. Extracellular phosphorylation enhances antiangiogenic activity.
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:20702771, PubMed:19965576, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:2732228, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:21576599, PubMed:21490593). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:14559847, PubMed:12865317). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:2732228, PubMed:15373842, PubMed:15764715, PubMed:22773874). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:2732228, PubMed:15373842, PubMed:15764715). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981).
Chimeric transcripts, characterized by CYP3A43 exon 1 joined at canonical splice sites to distinct sets of CYP3A4 exons, have been detected. All are possibly produced by trans-splicing. The chimeric transcripts exist in 3 different combinations: CYP3A43 exon 1 joined in frame to CYP3A4 exons 2-13, CYP3A43 exon 1 joined in frame to CYP3A4 exons 4-13 and CYP3A43 exon 1 joined in frame to CYP3A4 exon 7-13. The longest chimeric isoform (CYP3A43 exon 1 joined to CYP3A4 exons 2-13) exhibits 6-beta-hydroxylase activity, while a shorter isoform (CYP3A43 exon 1 joined to CYP3A4 exons 4-13) does not. All chimeric transcripts are expressed at very low levels in the liver (PubMed:11726664).
Expressed in prostate and liver. According to some authors, it is not expressed in brain (PubMed:19094056). According to others, weak levels of expression are measured in some brain locations (PubMed:19359404, PubMed:18545703). Also expressed in epithelium of the small intestine and large intestine, bile duct, nasal mucosa, kidney, adrenal cortex, epithelium of the gastric mucosa with intestinal metaplasia, gallbladder, intercalated ducts of the pancreas, chief cells of the parathyroid and the corpus luteum of the ovary (at protein level).
Interacts with PGRMC1; the interaction requires PGRMC1 homodimerization.
Polyubiquitinated in the presence of AMFR and UBE2G1 and also STUB1/CHIP and UBE2D1 (in vitro).
Important for normal spermatogenesis and male fertility. Specifically required for progression to the post-meiotic stages of spermatocyte development. Seems to be necessary for normal expression levels of a number of testis-expressed gene transcripts, although its role in this process is unclear.
Activated by phosphorylation on Thr-530.
Binds both upstream activators and downstream substrates in multimolecular complexes. Part of a complex with MAP2K3, RAC1 and CCM2. Interacts with MAP2K5 and SPAG9.
Component of a protein kinase signal transduction cascade. Mediates activation of the NF-kappa-B, AP1 and DDIT3 transcriptional regulators.
Phosphorylation at Ser-166 and Ser-337 by SGK1 inhibits its activity.
Catalyzes the conversion of GTP to GDP through hydrolysis of the gamma-phosphate bond in GTP. When hydroxylated at C-3 of 'Lys-21' by JMJD7, may bind to RNA and play a role in translation.
Highest levels in skeletal muscle, heart and kidney. Low levels in colon, thymus, spleen, small intestine, lung and Leukocytes.
Hydroxylated (with S stereochemistry) at C-3 of Lys-21 by JMJD7; this modification hinders trypsin-catalyzed proteolysis in vitro.
Interacts with RWDD1; this interaction confers protection to polyubiquitination and proteolytic degradation (By similarity). Interacts with JMJD7; this interaction is direct (PubMed:29915238).
Homodimer (PubMed:27486783). Component of the axonemal radial spoke complex 1 (RS1), at least composed of spoke head proteins RSPH1, RSPH3, RSPH9 and the cilia-specific component RSPH4A or sperm-specific component RSPH6A, spoke stalk proteins RSPH14, DNAJB13, DYDC1, ROPN1L and NME5, and the anchor protein IQUB (By similarity). Interacts with SUN5 (By similarity). Interacts with IQUB (By similarity).
Specifically expressed in testis and trachea.
Has phosphatase activity with the synthetic substrate 6,8-difluoro-4-methylumbelliferyl phosphate (in vitro) (PubMed:24531476, PubMed:29121083). Has almost no detectable activity with phosphotyrosine, even less activity with phosphothreonine and displays complete lack of activity with phosphoserine (PubMed:29121083). The poor activity with phosphotyrosine may be due to steric hindrance by bulky amino acid sidechains that obstruct access to the active site (PubMed:29121083).
Belongs to the small GTPase superfamily. SAR1 family.
Expressed in many tissues including small intestine, liver, muscle and brain.
GTP-binding protein involved in transport from the endoplasmic reticulum to the Golgi apparatus (By similarity). Activated by the guanine nucleotide exchange factor PREB (By similarity). Involved in the selection of the protein cargo and the assembly of the COPII coat complex (By similarity). Synergizes with the cargo receptor SURF4 to mediate the export of lipoproteins from the endoplasmic reticulum, thereby regulating lipoprotein delivery and the maintenance of lipid homeostasis (PubMed:33186557).
Homodimer (By similarity). Binds PREB (By similarity). Part of the COPII coat complex (By similarity). Binds to the cytoplasmic tails of target proteins in the endoplasmic reticulum (By similarity). Interacts with SURF4 (PubMed:33186557).
Binds 2 Mg(2+) or Mg(2+) ions per subunit.
Catalytic component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3 (PubMed:18984158).
Catalytic ribonuclease component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3, which cleaves tRNA molecules in their 5'-ends (PubMed:18984158, PubMed:25953853, PubMed:34715011). The presence of TRMT10C/MRPP1, HSD17B10/MRPP2 is required to catalyze tRNA molecules in their 5'-ends (PubMed:25953853).
Degraded by LONP1 following mitochondrial unfolded protein response, probably leading to inhibit translation in mitochondrion.
Displays a distorted and non-productive active site that probably switches to a fully productive state only upon association with TRMT10C/MRPP1, HSD17B10/MRPP2 and pre-tRNA substrate.
Down-regulated following mitochondrial unfolded protein response.
Part of the neuronal tubulin polyglutamylase complex which contains TPGS1, TPGS2, TTLL1, LRRC49 and NICN1 (Probable). Interacts with CSTPP1 and LRRC49 (PubMed:34782749).
Subunit of the tubulin polyglutamylase complex (TPGC). The complex mediates cilia and flagella polyglutamylation which is essential for their biogenesis and motility.
Widely expressed. Expressed at higher level in heart and spleen.
Expressed in brain. Also expressed in glioblastoma cells.
Increased expression in glioblastomas and on wounding, in basal keratinocytes. This expression is calcium ion-dependent.
Possesses ATPase activity (By similarity). Plays a part in calcium-regulated keratinocyte activation in epidermal repair mechanisms. Has no effect on cell proliferation. Negatively regulates mitochondrial fusion in cooperation with mitofusin proteins (MFN1-2).
Binds to RTN4R (PubMed:19052207). Interacts with ATL1 (PubMed:19665976). Interacts with TMEM170A (PubMed:19665976, PubMed:26906412). Interacts with RTN4IP1 (By similarity).
Developmental neurite growth regulatory factor with a role as a negative regulator of axon-axon adhesion and growth, and as a facilitator of neurite branching. Regulates neurite fasciculation, branching and extension in the developing nervous system. Involved in down-regulation of growth, stabilization of wiring and restriction of plasticity in the adult CNS (PubMed:10667797, PubMed:11201742). Regulates the radial migration of cortical neurons via an RTN4R-LINGO1 containing receptor complex (By similarity). Acts as a negative regulator of central nervous system angiogenesis. Inhibits spreading, migration and sprouting of primary brain microvascular endothelial cells (MVECs). Also induces the retraction of MVECs lamellipodia and filopodia in a ROCK pathway-dependent manner (By similarity).
Homodimer (PubMed:27786289). Interacts with BAD/Bcl-xl and BCL2. Interact with RTN3 (PubMed:12811824, PubMed:16979658). Interacts with NGBR (PubMed:16835300). Interacts with SPTLC1 (By similarity). Interacts with GRAMD4 (By similarity). Interacts with CDH5 (PubMed:21183689). Interacts with BACE1 and BACE2 (PubMed:15286784, PubMed:16965550). Interacts with REEP5 (PubMed:32075961). Interacts with RETREG3 (PubMed:33826365).
Interacts in trans with CNTNAP1 (By similarity). Interacts with REEP5 (PubMed:32075961).
Interacts with BACE1 and BACE2 (PubMed:15286784, PubMed:16965550). Interacts with TMEM33 (PubMed:25612671).
Isoform A: is specifically expressed in brain and testis and weakly in heart and skeletal muscle. Isoform B: widely expressed except for the liver. Highly expressed in endothelial cells and vascular smooth muscle cells, including blood vessels and mesenteric arteries (PubMed:15034570, PubMed:21183689). Isoform C: is expressed in brain, skeletal muscle and adipocytes. Isoform D is testis-specific.
Mainly function in endothelial cells and vascular smooth muscle cells, is also involved in immune system regulation (Probable). Modulator of vascular remodeling, promotes the migration of endothelial cells but inhibits the migration of vascular smooth muscle cells. Regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure. Inhibits serine palmitoyltransferase, SPTLC1, the rate-limiting enzyme of the novo sphingolipid biosynthetic pathway, thereby controlling production of endothelial sphingosine-1-phosphate (S1P). Required to promote macrophage homing and functions such as cytokine/chemokine gene expression involved in angiogenesis, arteriogenesis and tissue repair. Mediates ICAM1 induced transendothelial migration of leukocytes such as monocytes and neutrophils and acute inflammation. Necessary for immune responses triggered by nucleic acid sensing TLRs, such as TLR9, is required for proper TLR9 location to endolysosomes. Also involved in immune response to LPS. Plays a role in liver regeneration through the modulation of hepatocytes proliferation (By similarity). Reduces the anti-apoptotic activity of Bcl-xl and Bcl-2. This is likely consecutive to their change in subcellular location, from the mitochondria to the endoplasmic reticulum, after binding and sequestration (PubMed:11126360). With isoform C, inhibits BACE1 activity and amyloid precursor protein processing (PubMed:16965550).
N-terminal part, called Am-Nogo-B(1-200), is the functional domain for RTN4B-mediated signaling in endothelial and vascular smooth muscle cells.
Regulates cardiomyocyte apoptosis upon hypoxic conditions (By similarity). With isoform B, inhibits BACE1 activity and amyloid precursor protein processing (PubMed:16965550).
Required to induce the formation and stabilization of endoplasmic reticulum (ER) tubules (PubMed:27619977, PubMed:25612671, PubMed:24262037). They regulate membrane morphogenesis in the ER by promoting tubular ER production (PubMed:27619977, PubMed:25612671, PubMed:24262037, PubMed:27786289). They influence nuclear envelope expansion, nuclear pore complex formation and proper localization of inner nuclear membrane proteins (PubMed:26906412). However each isoform have specific functions mainly depending on their tissue expression specificities (Probable).
Three regions, residues 59-172, 544-725 and the loop 66 amino acids, between the two transmembrane domains, known as Nogo-66 loop, appear to be responsible for the inhibitory effect on neurite outgrowth and the spreading of neurons. This Nogo-66 loop, mediates also the binding of RTN4 to its receptor (By similarity).
Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter KLHDC3.
Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:29775578). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (PubMed:29779948, PubMed:29775578). The CRL2(KLHDC3) complex specifically recognizes proteins with a glycine (Gly) at the C-terminus, leading to their ubiquitination and degradation: recognizes the C-terminal -Arg-(Xaa)n-Arg-Gly, -Arg-(Xaa)n-Lys-Gly, and -Arg-(Xaa)n-Gln-Gly degrons (PubMed:29779948, PubMed:29775578). The CRL2(KLHDC3) complex mediates ubiquitination and degradation of truncated SELENOV and SEPHS2 selenoproteins produced by failed UGA/Sec decoding, which end with a glycine (PubMed:26138980). May be involved in meiotic recombination process (PubMed:12606021).
(Microbial infection) Interacts with herpes simplex virus 2 ICP4.
(Microbial infection) Interacts with human adenovirus E1A protein; this interaction probably disrupts the TBP-TATA complex.
Binds DNA as monomer (PubMed:2194289, PubMed:2374612). Component of the TFIID basal transcription factor complex, composed of TATA-box-binding protein TBP, and a number of TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:9836642, PubMed:27007846, PubMed:33795473). Part of a TFIID-containing RNA polymerase II pre-initiation complex that is composed of TBP and at least GTF2A1, GTF2A2, GTF2E1, GTF2E2, GTF2F1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2B, TCEA1, ERCC2, ERCC3, TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:27007846, PubMed:33795473). Component of the transcription factor SL1/TIF-IB complex, composed of TBP and at least TAF1A, TAF1B, TAF1C and TAF1D (PubMed:7801123). Association of TBP to form either TFIID or SL1/TIF-IB appears to be mutually exclusive (PubMed:7801123). Interacts with TAF1A, TAF1B and TAF1C (PubMed:7801123). Interacts with TFIIB, NCOA6, DRAP1, DR1 and ELF3 (PubMed:11461703, PubMed:10391676, PubMed:10567404). Interacts with SPIB, SNAPC1, SNAPC2 and SNAPC4 (PubMed:12621023, PubMed:10196196). Interacts with UTF1 (PubMed:9748258). Interacts with BRF2; this interaction promotes recruitment of BRF2 to TATA box-containing promoters (PubMed:11564744, PubMed:26638071). Interacts with UBTFD (PubMed:7982918). Interacts with GPBP1D (By similarity). Interacts with CITED2 (By similarity). Interacts with ATF7IP (Probable). Interacts with LLPH (By similarity). Interacts with HSF1 (via transactivation domain) (PubMed:11005381). Interacts with GTF2B (via C-terminus); this interaction with promoter-bound TBP guides RNA polymerase II into the pre-initiation complex (PIC) (PubMed:8504927). Interacts with PAX5 (PubMed:10197586). Interacts with MSX1; the interaction may inhibit MSX1 autoinactivation (By similarity).
The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription (PubMed:33795473). TFIID recognizes and binds promoters with or without a TATA box via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC) (PubMed:33795473, PubMed:27193682, PubMed:2194289, PubMed:2363050, PubMed:2374612). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473, PubMed:27007846). The TFIID complex structure can be divided into 3 modules TFIID-A, TFIID-B, and TFIID-C (PubMed:33795473). TBP forms the TFIID-A module together with TAF3 and TAF5 (PubMed:33795473). TBP is a general transcription factor that functions at the core of the TFIID complex (PubMed:33795473, PubMed:27193682, PubMed:2194289, PubMed:2363050, PubMed:2374612, PubMed:9836642). During assembly of the core PIC on the promoter, as part of TFIID, TBP binds to and also bends promoter DNA, irrespective of whether the promoter contains a TATA box (PubMed:33795473). Component of a BRF2-containing transcription factor complex that regulates transcription mediated by RNA polymerase III (PubMed:26638071). Component of the transcription factor SL1/TIF-IB complex, which is involved in the assembly of the PIC during RNA polymerase I-dependent transcription (PubMed:15970593). The rate of PIC formation probably is primarily dependent on the rate of association of SL1 with the rDNA promoter (PubMed:15970593). SL1 is involved in stabilization of nucleolar transcription factor 1/UBTF on rDNA (PubMed:15970593).
The poly-Gln region of TBP is highly polymorphic (25 to 42 repeats) in normal individuals and is expanded to about 47-63 repeats in spinocerebellar ataxia 17 (SCA17) patients.
Widely expressed, with levels highest in the testis and ovary.
Contains at least 2 actin-binding sites per coiled-coil dimer.
Expressed in fetal brain, retina and cochlea but is not detectable in the other tissues.
Insoluble aggregates is found in the brain of schizophrenia patients.
Isoform 1 forms aggregates (PubMed:28438837, PubMed:25333879). Isoform 1 binds to TRIO and F-actin (PubMed:11148140, PubMed:28438837). Isoform 1 may also interact with myosin II (PubMed:11148140). Interacts with HECTD3 (PubMed:18194665). Interacts with PJVK (By similarity). Interacts with TERF1; mediates TERF1 localization to the centrosome (PubMed:24692559).
Phosphorylation at Thr-457 by PLK1 ensures mitotic progression and is essential for accurate chromosome segregation (PubMed:22820163). Phosphorylation at residues Thr-221 and Thr-457 by kinase NEK2A and PLK1 coordinates TERF1 translocation from telomere to spindle pole (PubMed:24692559).
Plays a pivotal role in the formation of stereocilia rootlets.
Regulates actin cytoskeletal organization, cell spreading and cell contraction by directly binding and stabilizing filamentous F-actin and prevents its depolymerization (PubMed:18194665, PubMed:28438837). May also serve as a linker protein to recruit proteins required for F-actin formation and turnover (PubMed:18194665). Essential for correct mitotic progression (PubMed:24692559, PubMed:22820163).
Ubiquitinated by HECTD3, leading to its degradation by the proteasome.
Widely expressed. Highly expressed in heart and placenta.
Expressed in different cell lines (at protein level).
Interacts (via middle region) with microtubules.
Microtubule-associated protein (MAP) that plays a role in the regulation of cell division; promotes microtubule stability and participates in the organization of the spindle midzone and normal progress of cytokinesis.
Bifunctional zinc metalloenzyme that comprises both epoxide hydrolase (EH) and aminopeptidase activities. Acts as an epoxide hydrolase to catalyze the conversion of LTA4 to the pro-inflammatory mediator leukotriene B4 (LTB4) (PubMed:11917124, PubMed:12207002, PubMed:15078870, PubMed:18804029, PubMed:1897988, PubMed:1975494, PubMed:2244921). Has also aminopeptidase activity, with high affinity for N-terminal arginines of various synthetic tripeptides (PubMed:20813919, PubMed:18804029). In addition to its pro-inflammatory EH activity, may also counteract inflammation by its aminopeptidase activity, which inactivates by cleavage another neutrophil attractant, the tripeptide Pro-Gly-Pro (PGP), a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP9) and prolylendopeptidase (PREPL) (PubMed:20813919, PubMed:24591641). Involved also in the biosynthesis of resolvin E1 and 18S-resolvin E1 from eicosapentaenoic acid, two lipid mediators that show potent anti-inflammatory and pro-resolving actions (PubMed:21206090).
Inhibited by bestatin (PubMed:11175901). The epoxide hydrolase activity is restrained by suicide inactivation that involves binding of LTA4 to Tyr-379 (PubMed:7667299). 4-(4-benzylphenyl)thiazol-2-amine (ARM1) selectively inhibits the epoxide hydrolase activity (PubMed:24591641).
Isoform 1 and isoform 2 are expressed in monocytes, lymphocytes, neutrophils, reticulocytes, platelets and fibroblasts.
Phosphorylation at Ser-416 inhibits leukotriene-A4 hydrolase activity.
Belongs to the peptidase M16 family. UQCRC2/QCR2 subfamily.
Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits. The complex is composed of 3 respiratory subunits cytochrome b, cytochrome c1 and Rieske protein UQCRFS1, 2 core protein subunits UQCRC1/QCR1 and UQCRC2/QCR2, and 6 low-molecular weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, UQCR10/QCR9, UQCR11/QCR10 and subunit 9, the cleavage product of Rieske protein UQCRFS1 (By similarity). The complex exists as an obligatory dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and cytochrome c oxidase (complex IV, CIV), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with RAB5IF (PubMed:31536960). Interacts with STMP1 (By similarity).
Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. The cytochrome b-c1 complex catalyzes electron transfer from ubiquinol to cytochrome c, linking this redox reaction to translocation of protons across the mitochondrial inner membrane, with protons being carried across the membrane as hydrogens on the quinol. In the process called Q cycle, 2 protons are consumed from the matrix, 4 protons are released into the intermembrane space and 2 electrons are passed to cytochrome c (By similarity). The 2 core subunits UQCRC1/QCR1 and UQCRC2/QCR2 are homologous to the 2 mitochondrial-processing peptidase (MPP) subunits beta-MPP and alpha-MPP respectively, and they seem to have preserved their MPP processing properties (By similarity). May be involved in the in situ processing of UQCRFS1 into the mature Rieske protein and its mitochondrial targeting sequence (MTS)/subunit 9 when incorporated into complex III (Probable).
Heterodimer of CDKN2B with CDK4 or CDK6. Isoform 2 does not interact with CDK4 nor CDK6.
Interacts strongly with CDK4 and CDK6. Potent inhibitor. Potential effector of TGF-beta induced cell cycle arrest.
Isoform 2 is expressed in normal (keratinocytes, fibroblasts) and tumor cell lines.
May function as 2-oxoglutarate-dependent dioxygenase.
Expressed in adipose tissue (at protein level). Highly expressed in omental and subcutaneous adipose tissues. Expressed in heart, cornea, liver, kidney and spleen.
Plays a role in fat cell development; promotes adipogenic differentiation and stimulates transcription initiation of master adipogenesis factors like PPARG and CEBPA at early stages of preadipocyte differentiation. Its overexpression confers resistance to the anticancer chemotherapeutic drug cisplatin.
Up-regulated during pre-adipocyte differentiation. Up-regulated following DNA damage induced by UV irradiation.
Homodimer (By similarity). Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins (By similarity). Interacts directly with TIMELESS, PER2, PER3, CRY1 and CRY2 (By similarity). Interacts with BMAL1 and CLOCK (By similarity). Interacts with GPRASP1 (By similarity). Interacts (phosphorylated) with BTRC and FBXW11; the interactions trigger proteasomal degradation (PubMed:15917222). Interacts with NONO, WDR5 and SFPQ (By similarity). Interacts with USP2 (By similarity). Interacts with HNF4A (PubMed:30530698).
Phosphorylated on serine residues by CSNK1D, CSNK1E and probably also by CSNK1G2. Phosphorylation by CSNK1D or CSNK1E promotes nuclear location of PER proteins as well as ubiquitination and subsequent degradation. May be dephosphorylated by PP1.
Serum-induced levels in fibroblasts show circadian oscillations. Maximum levels after 1 hour stimulation, minimum levels after 12 hours. Another peak is then observed after 20 hours. Protein levels show maximum levels at 6 hours, decrease to reach minimum levels at 20 hours, and increase again to reach a second peak after 26 hours. Levels then decrease slightly and then increase to maximum levels at 32 hours. Levels of phosphorylated form increase between 3 hours and 12 hours.
Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. Regulates circadian target genes expression at post-transcriptional levels, but may not be required for the repression at transcriptional level. Controls PER2 protein decay. Represses CRY2 preventing its repression on CLOCK/BMAL1 target genes such as FXYD5 and SCNN1A in kidney and PPARA in liver. Besides its involvement in the maintenance of the circadian clock, has an important function in the regulation of several processes. Participates in the repression of glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) by BMAL1:CLOCK. Plays a role in the modulation of the neuroinflammatory state via the regulation of inflammatory mediators release, such as CCL2 and IL6. In spinal astrocytes, negatively regulates the MAPK14/p38 and MAPK8/JNK MAPK cascades as well as the subsequent activation of NFkappaB. Coordinately regulates the expression of multiple genes that are involved in the regulation of renal sodium reabsorption. Can act as gene expression activator in a gene and tissue specific manner, in kidney enhances WNK1 and SLC12A3 expression in collaboration with CLOCK. Modulates hair follicle cycling. Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1.
Ubiquitinated; requires phosphorylation by CSNK1E and interaction with BTRC and FBXW11. Deubiquitinated by USP2 (By similarity).
Widely expressed. Expressed in hair follicles (at protein level).Found in heart, brain, placenta, lung, liver, skeletal muscle, pancreas, kidney, spleen, thymus, prostate, testis, ovary and small intestine. Highest level in skeletal muscle.
IAPP is the peptide subunit of amyloid found in pancreatic islets of type 2 diabetic patients and in insulinomas.
Interacts with IDE and INS. Can form homodimers. Interaction with INS inhibits homodimerization and fibril formation.
Selectively inhibits insulin-stimulated glucose utilization and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism.
The mature protein is largely unstructured in the absence of a cognate ligand, and has a strong tendency to form fibrillar aggregates. Homodimerization may be the first step of amyloid formation.
Relatively widely expressed in a range of tissues.
Interacts with RAC1. Binds to F-actin. Interacts with FASLG. Interacts (via SH3 domain) with E.coli effector protein EspF(U) (via PXXP motifs). Identified in a complex containing at least WASL, BAIAP2L1 and E.coli EspF(U). Interacts with E.coli intimin receptor Tir.
May function as adapter protein. Involved in the formation of clusters of actin bundles. Plays a role in the reorganization of the actin cytoskeleton in response to bacterial infection.
Phosphorylated on tyrosine in response to insulin.
The IMD domain is predicted to have a helical structure. It may induce actin bundling and filopodia formation (By similarity).
(Microbial infection) Plays a role in fluid-phase endocytosis, a process exploited by vaccinia intracellular mature virus (IMV) to enter cells. As a result, may facilitate the penetration of IMV into cells.
Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fission of tubules that serve as transport intermediates during endosome sorting. Mediates the recruitment of the WASH core complex to endosome membranes via binding to phospholipids and VPS35 of the retromer CSC. Mediates the recruitment of the F-actin-capping protein dimer to the WASH core complex probably promoting localized F-actin polymerization needed for vesicle scission (PubMed:19922874, PubMed:20498093, PubMed:22513087, PubMed:23331060). Via its C-terminus binds various phospholipids, most strongly phosphatidylinositol 4-phosphate (PtdIns-(4)P), phosphatidylinositol 5-phosphate (PtdIns-(5)P) and phosphatidylinositol 3,5-bisphosphate (PtdIns-(3,5)P2). Involved in the endosome-to-plasma membrane trafficking and recycling of SNX27-retromer-dependent cargo proteins, such as GLUT1 (PubMed:25278552). Required for the association of DNAJC13, ENTR1, ANKRD50 with retromer CSC subunit VPS35 (PubMed:24980502). Required for the endosomal recruitment of CCC and retriever complexes subunits COMMD1 and CCDC93 as well as the retrievere complex subunit VPS35L (PubMed:25355947, PubMed:28892079).
Component of the WASH core complex also described as WASH regulatory complex (SHRC) composed of WASH (WASHC1, WASH2P or WASH3P), WASHC2 (WASHC2A or WASHC2C), WASHC3, WASHC4 and WASHC5; in the complex interacts (via N-terminus) directly with WASHC1. The WASH core complex associates via WASHC2 with the F-actin-capping protein dimer (formed by CAPZA1, CAPZA2 or CAPZA3 and CAPZB) in a transient or substoichiometric manner which was initially described as WASH complex (PubMed:19922875, PubMed:20498093). Interacts with VPS35; mediates the association with the retromer CSC complex. Interacts with FKBP15. Interacts with CCDC93, CCDC22, VPS35L; indicative for an association of the WASH core complex with the CCC and retriever complexes. May directly interact with TBC1D23 (Probable).
Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development. On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. May bind activin as well.
Homodimer (By similarity). Heterodimer with a RAR molecule (PubMed:28167758). Binds DNA preferentially as a RAR/RXR heterodimer (PubMed:28167758). Interacts with RARA (PubMed:28167758).
Homodimer. Heterodimer; with a rar molecule.
Receptor for retinoic acid that acts as a transcription factor. Forms homo- or heterodimers with retinoic acid receptors (rars) and binds to target response elements in response to their ligands, all-trans or 9-cis retinoic acid, to regulate gene expression in various biological processes.
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid (By similarity).
Expressed in the ovary, specifically in granulosa cells of follicles that have passed the primary stage and in oocytes (at protein level) (PubMed:30933929). Expressed at high levels in brain. Lower levels in small intestine. In brain regions, detected in all regions tested. Highest levels in the cerebellum and cerebral cortex.
Is a receptor for the SMIM20 derived peptides Phoenixin-14 and Phoenixin-20 (By similarity). It mediates the Phoenixin-14 and Phoenixin-20 augmentation of gonadotropin-releasing hormone (GNRH) signaling in the hypothalamus and pituitary gland (By similarity). In the ovary, it mediates the effects of Phoenixin-14 and Phoenixin-20 induced granulosa cell proliferation during follicular growth (PubMed:30933929).
By MYC overexpression in a concentration dependent manner in neuroblastoma cell line.
Cells lacking CDCA7L display a reduction of 25-30% of colony formation in medulloblastoma cell lines. CDCA7L overexpression induces colony formation.
Interacts with MYC (PubMed:15994933, PubMed:16829576). Interacts (via IBM motifs) with PSIP1 (via IBD domain); phosphorylation increases its affinity for PSIP1 (PubMed:16735438, PubMed:25082813, PubMed:29997176).
Plays a role in transcriptional regulation as a repressor that inhibits monoamine oxidase A (MAOA) activity and gene expression by binding to the promoter. Plays an important oncogenic role in mediating the full transforming effect of MYC in medulloblastoma cells. Involved in apoptotic signaling pathways; May act downstream of P38-kinase and BCL-2, but upstream of CASP3/caspase-3 as well as CCND1/cyclin D1 and E2F1.
Ubiquitous. Overexpressed in medulloblastoma.
By silencing of the transcription factor BTF3.
Expressed in the colon, rectum, and cultured colonic smooth muscle. Detected in various cancer cell lines.
Part of cGMP kinase signaling complex at least composed of ACTA2/alpha-actin, CNN1/calponin H1, PLN/phospholamban, PRKG1 and ITPR1 (By similarity). Interacts with PRKG1/cGKI-beta and ITPR1/IP3R type I.
Phosphorylated by PRKG1/cGKI-beta; Ser-386 showed constitutive phosphorylation in platelets whereas Ser-676 is only phosphorylated in presence of cGMP and nitric oxide (NO); Ser-689 is phosphorylated in resting platelets but increases in presence of cGMP and NO. PRKG1 inhibitor prevents phosphorylation of Ser-676 and Ser-689 in response to NO and cGMP.
Plays a role as NO/PRKG1-dependent regulator of IP3-induced calcium release; its phosphorylation by PRKG1 inhibits bradykinin and IP3-induced calcium release from intracellular stores. Recruits PRKG1 to the endoplasmic reticulum and may mediate the assembly of PRKG1 and ITPR1 in a macrocomplex. Involved in PRKG1 signaling cascade leading to inhibition of platelet activation and aggregation. Mediates also NO-dependent inhibition of calcium signaling in gastrointestinal smooth muscle contributing to NO-dependent relaxation.
Highly expressed in pancreas. Detected at intermediate levels in heart, placenta and kidney, and at low levels in brain, liver and skeletal muscle. Not detected in normal lung.
Interacts with GGT7 isoform 3 and SLC3A2.
(Microbial infection) Interacts with ebolavirus transcriptional activator VP30; this interaction prevents TARBP2/TRBP binding to DICER1 and thus allows the virus to counteract host RNA silencing.
(Microbial infection) Interacts with ebolavirus transcriptional activator VP35; this interaction prevents TARBP2/TRBP binding to DICER1 and thus allows the virus to counteract host RNA silencing.
Belongs to the helicase family. Dicer subfamily.
Component of the RISC loading complex (RLC), or micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, AGO2 and TARBP2; DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto AGO2. Note that the trimeric RLC/miRLC is also referred to as RISC. Interacts with DHX9, AGO1, PIWIL1 and PRKRA. Associates with the 60S ribosome. Interacts with BCDIN3D. Interacts with AGO2, TARBP2, EIF6, MOV10 and RPL7A (60S ribosome subunit); they form a large RNA-induced silencing complex (RISC) (PubMed:17507929). Interacts (via Dicer dsRNA-binding fold domain) with ALOX5 (via PLAT domain); this interaction enhances arachidonate 5-lipoxygenase activity and modifies the miRNA precursor processing activity of DICER1 (PubMed:19022417).
DICER1 mutations have been found in uterine cervix embryonal rhabdomyosarcoma, primitive neuroectodermal tumor, Wilms tumor, pulmonary sequestration and juvenile intestinal polyp (PubMed:21882293). Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in non-epithelial ovarian tumors. These mutations do not abolish DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic (PubMed:22187960).
Double-stranded RNA (dsRNA) endoribonuclease playing a central role in short dsRNA-mediated post-transcriptional gene silencing. Cleaves naturally occurring long dsRNAs and short hairpin pre-microRNAs (miRNA) into fragments of twenty-one to twenty-three nucleotides with 3' overhang of two nucleotides, producing respectively short interfering RNAs (siRNA) and mature microRNAs. SiRNAs and miRNAs serve as guide to direct the RNA-induced silencing complex (RISC) to complementary RNAs to degrade them or prevent their translation. Gene silencing mediated by siRNAs, also called RNA interference, controls the elimination of transcripts from mobile and repetitive DNA elements of the genome but also the degradation of exogenous RNA of viral origin for instance. The miRNA pathway on the other side is a mean to specifically regulate the expression of target genes.
Acts as a transcriptional coregulator, that can have both coactivator and corepressor functions. Inhibits the DCSTAMP-repressive activity of TAL1, hence enhancing the access of the transcription factor MITF to the DC-STAMP promoter in osteoclast. Plays a role in bone homeostasis; required as a positive regulator in TNFSF11//RANKL-mediated osteoclast fusion via a DCSTAMP-dependent pathway. May also be required in the regulation of osteoblast differentiation (By similarity). Involved in the transcriptional corepression of NF-kappaB in macrophages (PubMed:18025162). Plays a role as a regulator in the pro-inflammatory cascade (PubMed:18025162).
Detected in macrophages. IL10 regulates expression in a STAT3-dependent way.
Interacts with TAL1; this interaction inhibits TAL1 occupancy of the DCSTAMP promoter, leading to the activation of the DCSTAMP promoter by the transcription factor MITF.
Up-regulated by interleukin IL6 and soluble interleukin receptor IL6R in astrocytes (PubMed:25903009).
Activated by Ca(2+)/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows phosphorylation of Thr-180 within the activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-180 results in several fold increase in total activity. Unlike CaMK4, may be unable to exhibit autonomous activity after Ca(2+)/calmodulin activation.
Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, activates CREB-dependent gene transcription, regulates calcium-mediated granulocyte function and respiratory burst and promotes basal dendritic growth of hippocampal neurons. In neutrophil cells, required for cytokine-induced proliferative responses and activation of the respiratory burst. Activates the transcription factor CREB1 in hippocampal neuron nuclei. May play a role in apoptosis of erythroleukemia cells. In vitro, phosphorylates transcription factor CREM isoform Beta.
Expressed during hippocampal formation with high expression in the pyramidal cell layers.
Expression increases upon treatment of EC cells with DMSO and retinoic acid. Induced by KCL in PC12 cells.
Widely expressed. Highly and mostly expressed in polymorphonuclear leukocytes (neutrophilic and eosinophilic granulocytes) while little or no expression is observed in monocytes and lymphocytes.
Di- and tri-sumoylated in developing retina. PIAS3-mediated sumoylation promotes repression of cone-specific gene expression and activation of rod-specific genes. Sumoylation on Lys-185 appears to be the main site (By similarity).
Eye specific; found solely in the outer nuclear layer of the adult neurosensory retina, where the nuclei of cone and rod photoreceptors reside.
Homodimer. Interacts with PIAS3; the interaction sumoylates NR2E3 and promotes repression of cone-specific gene transcription and activation of rod-specific genes (By similarity). Component of a complex that includes NR2E3, PIAS3, NRL, CRX and/or NR1D1. Binds NR1D1. Binds directly in the complex with CRX, PIAS3 and NR1D1 (By similarity). Interacts (via the DNA-binding domain) with CRX (via its DNA binding domain); the interaction represses S- and M-cone opsin expression.
Orphan nuclear receptor of retinal photoreceptor cells. Transcriptional factor that is an activator of rod development and repressor of cone development. Binds the promoter region of a number of rod- and cone-specific genes, including rhodopsin, M- and S-opsin and rod-specific phosphodiesterase beta subunit. Enhances rhodopsin expression. Represses M- and S-cone opsin expression.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:11279069). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (PubMed:25278503).
Belongs to the peptidase C19 family. UBP8 subfamily.
Component of some SAGA transcription coactivator-HAT complexes, at least composed of ATXN7, ATXN7L3, ENY2, GCN5L2, SUPT3H, TAF10, TRRAP and USP22. Within the SAGA complex, ATXN7L3, ENY2 and USP22 form a subcomplex required for histone deubiquitination (PubMed:18206972, PubMed:27601583). Interacts directly with ATXN7L3; leading to its recruitment to the SAGA complex (PubMed:18206972). Interacts with ATXN7L3 and weakly with ATXN7L3B (PubMed:27601583).
Histone deubiquitinating component of the transcription regulatory histone acetylation (HAT) complex SAGA. Catalyzes the deubiquitination of both histones H2A and H2B, thereby acting as a coactivator. Recruited to specific gene promoters by activators such as MYC, where it is required for transcription. Required for nuclear receptor-mediated transactivation and cell cycle progression.
Moderately expressed in various tissues including heart and skeletal muscle, and weakly expressed in lung and liver.
DNA-binding protein that binds to the to a 5'-TGTACAGTGT-3' core sequence. May function as a transcriptional transactivator and transcriptional repressor. Probably exerts its repressor effect by preventing GATA3 from binding to DNA. May play a role in regulating the differentiation and activation of helper T-cells (By similarity).
Homodimer (via PTB domain). Interacts with the N-terminal of FANCC. Interacts with ZBTB16. Interacts with GATA3 (By similarity).
Predominantly expressed in testis. Some isoforms are ubiquitously expressed.
The BTB (POZ) domain possesses repressor activity.
The C-terminal zinc finger domain functions as a transcriptional transactivator.
Axoneme-binding protein that plays a role in the regulation of ciliary motility and cilium length.
The conserved TPR domains are dispensable for ciliary targeting. The N-terminal half is important for cilary localization and/or binding to the axoneme.
Adapter protein that binds to and probably organizes the subcellular localization of a variety of membrane proteins. May link various receptors to the actin cytoskeleton and the extracellular matrix via the dystrophin glycoprotein complex. Plays an important role in synapse formation and in the organization of UTRN and acetylcholine receptors at the neuromuscular synapse. Binds to phosphatidylinositol 4,5-bisphosphate (By similarity).
High expression in skeletal muscle and heart. Low expression in brain, pancreas, liver, kidney and lung. Not detected in placenta.
Monomer and homodimer. Interacts with the other members of the syntrophin family SNTB1 and SNTB2; SGCG and SGCA of the dystrophin glycoprotein complex; NOS1; GRB2; the sodium channel proteins SCN4A and SCN5A; F-actin and calmodulin (By similarity). Interacts with dystrophin protein DMD and related proteins DTNA and UTRN and with MAPK12, TGFA and GA. Interacts with MYOC; regulates muscle hypertrophy (By similarity). Interacts with DTNB (By similarity).
Phosphorylated by CaM-kinase II. Phosphorylation may inhibit the interaction with DMD (By similarity).
The PH 1 domain mediates the oligomerization in a calcium dependent manner, and the association with the phosphatidylinositol 4,5-bisphosphate.
Catalyzes the oxidation of hydrogen sulfide with the help of a quinone, such as ubiquinone-10, giving rise to thiosulfate and ultimately to sulfane (molecular sulfur) atoms. Requires an additional electron acceptor; can use sulfite, sulfide or cyanide (in vitro) (PubMed:22852582). It is believed the in vivo electron acceptor is glutathione (PubMed:25225291, PubMed:29715001).
Highly expressed in brain, heart, pancreas, skeletal muscle and kidney. Detected at lower levels in placenta, lung and liver.
Homodimer. Binds TNFRSF1A (PubMed:9038203). Interacts with PIP4K2A; the interaction suppresses ubiquitination by the SPOP/CUL3 complex (PubMed:20583997).
Participates in the biosynthesis of phosphatidylinositol 4,5-bisphosphate (PubMed:9038203, PubMed:26774281). Preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation and its activity reflects changes in direct proportion to the physiological GTP concentration (PubMed:26774281). Its GTP-sensing activity is critical for metabolic adaptation (PubMed:26774281). PIP4Ks negatively regulate insulin signaling through a catalytic-independent mechanism. They interact with PIP5Ks and suppress PIP5K-mediated PtdIns(4,5)P2 synthesis and insulin-dependent conversion to PtdIns(3,4,5)P3 (PubMed:31091439).
Ubiquitinated by the SPOP/CUL3 complex. Ubiquitination is stimulated by PtdIns5P levels.
Directly interacts with LMNA (By similarity). Interacts with ISL1 (via N-terminal domain); the interaction represses ISL1 transactivator activity (By similarity). Interactions of ISL1 with MLIP1 and GCN5/KAT2A may be mutually exclusive (By similarity).
Predominantly expressed in the heart and skeletal muscle (PubMed:21498514, PubMed:26436652, PubMed:34581780). Also detected in liver (PubMed:21498514).
Required for myoblast differentiation into myotubes, possibly acting as a transcriptional regulator of the myogenic program (By similarity). Required for cardiac adaptation to stress through integrated regulation of the AKT/mTOR pathways and FOXO1. Regulates cardiac homeostasis and plays a role in the protection against cardiac hypertrophy (By similarity). Binds chromatin (By similarity). May act as a transcriptional cofactor for ISL1, repressing its transcriptional activity (By similarity). May also repress MYOCD transcriptional activity (By similarity).
The disease is caused by variants affecting the gene represented in this entry. In a patient homozygous for the variant p.Gln762Ter, it has been shown that skeletal muscles display a clear alteration of the alternative splicing isoform expression pattern. While the variant transcript likely undergoes nonsense-mediated mRNA decay, cells may attempt to compensate for truncated MLIP proteins by expressing alternative transcripts; this partial escape mechanism may account for the relatively mild phenotype in this individual, who did not develop significant symptoms until around 50 years of age.
Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5, CEP68 and probably NFKB2 (PubMed:25704143). SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of cyclin E, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO11) directs ubiquitination of BCL6 and DTL but does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(CCNF) directs ubiquitination of CCP110. SCF(FBXL3) and SCF(FBXL21) direct ubiquitination of CRY1 and CRY2. SCF(FBXO9) directs ubiquitination of TTI1 and TELO2. SCF(FBXO10) directs ubiquitination of BCL2.
Interacts with KDM2B, forming heterodimers (PubMed:27568929). The KDM2B-SKP1 heterodimeric complex interacts with the PCGF1-BCORL heterodimeric complex to form a homotetrameric polycomb repression complex 1 (PRC1.1) (PubMed:27568929). Component of multiple SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complexes formed of CUL1, SKP1, RBX1 and a variable F-box domain-containing protein as substrate-specific subunit. Component of the SCF(FBXW11) complex containing FBXW11. Component of the SCF(SKP2) complex containing SKP2, in which it interacts directly with SKP1, SKP2 and RBX1. Component of the SCF(FBXW2) complex containing FBXw2. Component of the SCF(FBXO32) complex containing FBXO32. Component of the probable SCF(FBXO7) complex containing FBXO7. Component of the SCF(FBXO10) complex containing FBXO10. Component of the SCF(FBXO11) complex containing FBXO11. Component of the SCF(FBXO25) complex containing FBXO25. Component of the SCF(FBXO33) complex containing FBXO33. Component of the probable SCF(FBXO4) complex containing FBXO4. Component of the SCF(FBXO44) complex, composed of SKP1, CUL1 and FBXO44. Component of the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC. This complex binds phosphorylated NFKBIA. Part of a SCF complex consisting of CUL1, RBX1, SKP1 and FBXO2. Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Component of the SCF(FBXO17) complex, composed of SKP1, CUL1 and FBXO17. Component of the SCF(FBXO27) complex, composed of SKP1, CUL1 and FBXO27. Component of the SCF(CCNF) complex consisting of CUL1, RBX1, SKP1 and CCNF. Component of the SCF(FBXL3) complex composed of CUL1, SKP1, RBX1 and FBXL3. Component of the SCF(FBXL21) complex composed of CUL1, SKP1, RBX1 and FBXL21. Component of the SCF(FBXO9) composed of CUL1, SKP1, RBX1 and FBXO9. Component of the SCF(FBXW7) composed of CUL1, SKP1, RBX1 and FBXW7 (PubMed:28727686). Interacts with CEP68 (PubMed:25503564). Interacts with NOTCH2 (PubMed:29149593). Interacts with FBXW15 (By similarity). The SKP1-KDM2A and SKP1-KDM2B complexes interact with UBB (PubMed:30033217).
Expressed in all tissues examined with high levels in brain, placenta and pancreas.
Interacts with the GTP-bound form of Ras proteins (NRAS, HRAS and KRAS). This interaction prevents the association between RAF1 and Ras. Interacts with 14-3-3 proteins YWHAB, YWHAE and YWHAZ when phosphorylated on Ser-351. Interacts with the SH3 domain of ABL1 and ABL2. Interacts with RAB5A. The interaction with Ras is probably regulated and antagonized by the interaction with 14-3-3 proteins. The interaction with 14-3-3 proteins is regulated by phosphorylation on Ser-351.
Phosphorylated on tyrosine residues by ABL1 and ABL2. Phosphorylation at Ser-351 by PRKD1 induces interaction with 14-3-3 proteins.
Ras effector protein, which may serve as an inhibitory modulator of neuronal plasticity in aversive memory formation. Can affect Ras signaling at different levels. First, by competing with RAF1 protein for binding to activated Ras. Second, by enhancing signaling from ABL1 and ABL2, which regulate cytoskeletal remodeling. Third, by activating RAB5A, possibly by functioning as a guanine nucleotide exchange factor (GEF) for RAB5A, by exchanging bound GDP for free GTP, and facilitating Ras-activated receptor endocytosis.
Shows reduced ability to bind to Ras and 14-3-3 proteins.
Expression does not increase during promyelocyte differentiation.
Heterodimer composed of XRCC5/Ku80 and XRCC6/Ku70 (PubMed:11493912). Component of the core long-range non-homologous end joining (NHEJ) complex (also named DNA-PK complex) composed of PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF (PubMed:12509254, PubMed:9742108, PubMed:12547193, PubMed:25941166, PubMed:25670504, PubMed:33854234). Additional component of the NHEJ complex includes PAXX (PubMed:25574025, PubMed:27601299, PubMed:27705800). Following autophosphorylation, PRKDC dissociates from DNA, leading to formation of the short-range NHEJ complex, composed of LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF (PubMed:33854234). The XRCC5-XRCC6 dimer also associates with NAA15, and this complex binds to the osteocalcin promoter and activates osteocalcin expression (PubMed:12145306). In addition, XRCC6 interacts with the osteoblast-specific transcription factors MSX2, RUNX2 and DLX5 (PubMed:12145306). Interacts with ELF3 (PubMed:15075319). Interacts with ATP23 (PubMed:10219089). The XRCC5-XRRC6 dimer associates in a DNA-dependent manner with APEX1 (PubMed:8621488). Binds to CDK9 isoform 2 (PubMed:20493174). Identified in a complex with DEAF1 and XRCC5 (PubMed:22442688). Interacts with DEAF1 (via the SAND domain); the interaction is direct and may be inhibited by DNA-binding (PubMed:22442688). Interacts with CLU (By similarity). Interacts with NR4A3; the DNA-dependent protein kinase complex DNA-PK phosphorylates and activates NR4A3 and prevents NR4A3 ubiquitinylation and degradation (PubMed:25852083). Interacts with CYREN isoform 1 (CYREN-1) and isoform 4 (CYREN-2) (via KBM motif) (PubMed:27063109, PubMed:24610814, PubMed:28959974). Interacts (via N-terminus) with HSF1 (via N-terminus); this interaction is direct and prevents XRCC5/XRCC6 heterodimeric binding and non-homologous end joining (NHEJ) repair activities induced by ionizing radiation (IR) (PubMed:26359349). Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA (PubMed:28712728). Interacts with HMBOX1 (PubMed:23685356). Interacts with ATF7 (PubMed:29490055). Interacts with APLF (via KBM motif) (PubMed:23689425, PubMed:27063109). Interacts with WRN (via KBM motif) (PubMed:27063109). The XRCC5-XRCC6 dimer associates with ALKBH2.
Individuals with systemic lupus erythematosus (SLE) and related disorders produce extremely large amounts of autoantibodies to XRCC5 and XRCC6. Existence of a major autoantigenic epitope or epitopes on the C-terminal 190 amino acids of XRCC6 containing the leucine repeat. The majority of autoantibodies to XRCC6 in most sera from patients with SLE seem to be reactive with this region.
Phosphorylation by PRKDC may enhance helicase activity. Phosphorylation of Ser-51 does not affect DNA repair.
Single-stranded DNA-dependent ATP-dependent helicase that plays a key role in DNA non-homologous end joining (NHEJ) by recruiting DNA-PK to DNA (PubMed:7957065, PubMed:8621488, PubMed:12145306, PubMed:11493912, PubMed:20493174, PubMed:2466842, PubMed:9742108). Required for double-strand break repair and V(D)J recombination (PubMed:7957065, PubMed:8621488, PubMed:12145306, PubMed:11493912, PubMed:20493174, PubMed:2466842, PubMed:9742108). Also has a role in chromosome translocation (PubMed:7957065, PubMed:8621488, PubMed:12145306, PubMed:11493912, PubMed:20493174, PubMed:2466842, PubMed:9742108). Has a role in chromosome translocation (PubMed:7957065, PubMed:20493174, PubMed:2466842, PubMed:9742108, PubMed:8621488, PubMed:12145306, PubMed:11493912). The DNA helicase II complex binds preferentially to fork-like ends of double-stranded DNA in a cell cycle-dependent manner (PubMed:7957065, PubMed:8621488, PubMed:20493174, PubMed:2466842, PubMed:9742108, PubMed:12145306, PubMed:11493912). It works in the 3'-5' direction (PubMed:20493174, PubMed:2466842, PubMed:9742108, PubMed:7957065, PubMed:8621488, PubMed:12145306, PubMed:11493912). During NHEJ, the XRCC5-XRRC6 dimer performs the recognition step: it recognizes and binds to the broken ends of the DNA and protects them from further resection (PubMed:7957065, PubMed:8621488, PubMed:20493174, PubMed:2466842, PubMed:9742108, PubMed:12145306, PubMed:11493912). Binding to DNA may be mediated by XRCC6 (PubMed:20493174, PubMed:2466842, PubMed:9742108, PubMed:7957065, PubMed:8621488, PubMed:12145306, PubMed:11493912). The XRCC5-XRRC6 dimer acts as regulatory subunit of the DNA-dependent protein kinase complex DNA-PK by increasing the affinity of the catalytic subunit PRKDC to DNA by 100-fold (PubMed:7957065, PubMed:8621488, PubMed:12145306, PubMed:11493912, PubMed:20493174, PubMed:2466842, PubMed:9742108). The XRCC5-XRRC6 dimer is probably involved in stabilizing broken DNA ends and bringing them together (PubMed:7957065, PubMed:8621488, PubMed:12145306, PubMed:11493912, PubMed:20493174, PubMed:2466842, PubMed:9742108). The assembly of the DNA-PK complex to DNA ends is required for the NHEJ ligation step (PubMed:7957065, PubMed:8621488, PubMed:12145306, PubMed:11493912, PubMed:20493174, PubMed:2466842, PubMed:9742108). Probably also acts as a 5'-deoxyribose-5-phosphate lyase (5'-dRP lyase), by catalyzing the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site near double-strand breaks (PubMed:20383123). 5'-dRP lyase activity allows to 'clean' the termini of abasic sites, a class of nucleotide damage commonly associated with strand breaks, before such broken ends can be joined (PubMed:20383123). The XRCC5-XRRC6 dimer together with APEX1 acts as a negative regulator of transcription (PubMed:8621488). In association with NAA15, the XRCC5-XRRC6 dimer binds to the osteocalcin promoter and activates osteocalcin expression (PubMed:12145306). Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728).
Belongs to the DEAD box helicase family. DDX10/DBP4 subfamily.
Belongs to the centromere protein F family.
Gradually accumulates during the cell cycle, reaching peak levels in G2 and M phase, and is rapidly degraded upon completion of mitosis.
Interacts with and STX4 (via C-terminus) (By similarity). Interacts (via N-terminus) with RBL1, RBL2 and SNAP25 (By similarity). Self-associates. Interacts with CENP-E and BUBR1 (via C-terminus). Interacts (via C-terminus) with NDE1, NDEL1 and RB1.
Required for kinetochore function and chromosome segregation in mitosis. Required for kinetochore localization of dynein, LIS1, NDE1 and NDEL1. Regulates recycling of the plasma membrane by acting as a link between recycling vesicles and the microtubule network though its association with STX4 and SNAP25. Acts as a potential inhibitor of pocket protein-mediated cellular processes during development by regulating the activity of RB proteins during cell division and proliferation. May play a regulatory or permissive role in the normal embryonic cardiomyocyte cell cycle and in promoting continued mitosis in transformed, abnormally dividing neonatal cardiomyocytes. Interaction with RB directs embryonic stem cells toward a cardiac lineage. Involved in the regulation of DNA synthesis and hence cell cycle progression, via its C-terminus. Has a potential role regulating skeletal myogenesis and in cell differentiation in embryogenesis. Involved in dendritic cell regulation of T-cell immunity against chlamydia.
Arginine methylation may function as a switch in regulation of function in Wnt signaling.
Interacts (via the PDZ domain) with the C-terminal regions of VANGL1 and VANGL2 (By similarity). Interacts (via the region containing both the PDZ and DEP domains) with LRRFIP2; the DIX domain may inhibit this interaction. Interacts with CYLD, CEP164 and DAB2. Interacts with DCDC2. Interacts with FOXK1 and FOXK2 (PubMed:25805136). Interacts with DAAM2 (By similarity).
Involved in the signal transduction pathway mediated by multiple Wnt genes.
Ubiquitinated. Deubiquitinated by CYLD, which acts on 'Lys-63'-linked ubiquitin chains.
The Rab-GAP TBC domain is short and lacks the C-terminal part. It is therefore unclear whether the protein has GTPase-activating activity.
Induced by oxidative stress and DNA damage. Isoform 4 is induced by hypoxia (through transactivation by HIF1A and SP1), but not isoform 1.
Monomer. Interacts (via the DNA-binding domain) with HIF1A; the interaction enhances HIF1A transcription under hypoxia through increasing protein stability. Interacts with CEBPB; the interaction disrupts the interaction CEBPB:EP300. Interacts with the coactivators NCOA2, PPARGC1A (via LXXLL motif), EP300 and MED1. Interacts with the corepressor NCOR1. Interacts with MAGED1 and CTNNB1. Interacts with CRY1 and PER2. Interacts (via AF-2 motif) with PROX1 (By similarity). Interacts with NRIP1. Isoform 4 interacts (via AF-2 motif) with isoform 1 of FOXP3 (via LXXLL motif).
Monomethylated at Lys-38 by EZH2, this creates a degron recognized by a DCX (DDB1-DCAF1/VPRBP-CUL4A-RBX1) E3 ubiquitin ligase complex.
Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development (PubMed:29656859). Regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium-mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC1 and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti-inflammatory role by inducing CHUK expression and inhibiting NF-kappa-B signaling.
Phosphorylation by conventional PKCs in neurons inhibits transcriptional activity. Phosphorylated on Thr-183 by MAPK1/ERK1 in vitro.
Produced by alternative promoter usage. Region from 23 to 71 inhibits DNA-binding and transactivation activity.
Sumoylated by SENP1 and SENP2. Sumoylation, promoted by PIAS2, PIAS3, PIAS4 but not PIAS1, enhances the transcriptional activity. Desumoylated by SENP1.
The AF-2 (activation function-2) motif is required for recruiting coregulators containing LXXLL motifs.
Ubiquitinated, leading to its degradation by the proteasome. Proteasomal degradation is required for efficient transcriptional activity and is prevented by HR.
Widely expressed in a number of tissues. Expressed in both regulatory T-cells (Treg) and effector T-cells (Teff) (PubMed:18354202, PubMed:7916608). Isoform 4: Highly expressed in the central nervous system, including in the cerebellum (PubMed:29656859).
Autoantigen in insulin-dependent diabetes mellitus (IDDM).
Belongs to the protein-tyrosine phosphatase family. Receptor class 8 subfamily.
Does not possess catalytic activity due to replacement of highly conserved residues in tyrosine-protein phosphatase domain.
Expression is restricted to neuroendocrine cells. Found in pancreas, brain and pituitary.
Homodimer; shown for the unprocessed protein (proICA512) in the endoplasmic reticulum and resolved during protein maturation as ICA512-TMF seems to be predominantly monomeric in secretory granules; however, ICA512-CCF interacts with ICA512-TMF disrupting the ICA512-TMF:SNTB2 complex. The isolated lumenal RESP18 homology domain has been shown to form disulfide-linked homooligomers (PubMed:25561468, PubMed:18824546, PubMed:26836020). Interacts (via cytoplasmic domain) with phosphorylated SNTB2; this protects PTPRN against cleavage by CAPN1 to produce ICA512-CCF. Dephosphorylation of SNTB2 upon insulin stimulation disrupts the interaction and results in PTPRN cleavage (PubMed:11483505). Interacts with SNX19 (PubMed:16273344). ICA512-CCF interacts with PIAS4; in the nucleus (PubMed:15596545). Interacts with STAT5B (phosphorylated); down-regulated by ICA512-CCF sumoylation; ICA512-CCF prevents STAT5B dephosphorylation; ICA512-CCF mediates interaction of STAT5B with PIAS4 (PubMed:15596545, PubMed:16622421). Interacts (via RESP18 homology domain) with insulin and proinsulin (PubMed:26836020). Interacts with PTPRN2, PTPRA and PTPRE (By similarity).
ICA512-CCF translocated to the nucleus promotes expression of insulin and other granule-related genes; the function implicates binding to and regulating activity of STAT5B probably by preventing its dephosphorylation and potentially by inducing its sumoylation by recruiting PIAS4 (PubMed:15596545, PubMed:16622421, PubMed:18178618). Enhances pancreatic beta-cell proliferation by converging with signaling by STAT5B and STAT3 (PubMed:15596545, PubMed:16622421, PubMed:18178618). ICA512-CCF located in the cytoplasm regulates dynamics and exocytosis of insulin secretory granules (SGs) by dimerizing with ICA512-TMF and displacing SNTB2 thus enhancing SGs mobility and exocytosis (PubMed:18824546, PubMed:20886068).
ICA512-TMF regulates dynamics and exocytosis of insulin secretory granules (SGs); binding of ICA512-TMF to SNTB2/beta-2-syntrophin is proposed to restrain SGs mobility and exocytosis by tethering them to the actin cytoskeleton depending on UTRN; the function is inhibited by cytoplasmic ICA512-CFF dimerizing with ICA512-TMF and displacing SNTB2.
Plays a role in vesicle-mediated secretory processes (PubMed:24843546). Required for normal accumulation of secretory vesicles in hippocampus, pituitary and pancreatic islets (By similarity). Required for the accumulation of normal levels of insulin-containing vesicles and preventing their degradation (PubMed:24843546). Plays a role in insulin secretion in response to glucose stimuli (PubMed:24843546). Required for normal accumulation of the neurotransmitters norepinephrine, dopamine and serotonin in the brain (By similarity). In females, but not in males, required for normal accumulation and secretion of pituitary hormones, such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (By similarity). Required to maintain normal levels of renin expression and renin release (By similarity). Seems to lack intrinsic enzyme activity (By similarity). May regulate catalytic active protein-tyrosine phosphatases such as PTPRA through dimerization (By similarity).
Subject to proteolytic cleavage at multiple sites (PubMed:11483505). Subject to cleavage on a pair of basic residues (By similarity). On exocytosis of secretory granules in pancreatic beta-cells ICA512-TMF is transiently inserted in the plasma-membrane and cleaved by mu-type calpain CPN1 to yield ICA512-CCF (By similarity).
Sumoylated at two sites including Lys-754. Sumoylation decreases interaction with STAT5.
The RESP18 homology domain is sufficient for targeting proICA512 to secretory granules.
Isoform 1 is widely expressed, with highest expression in skeletal muscle, thymus, brain and lung. Isoform 3 is less abundant than isoform 1 and predominantly expressed in kidney, pancreas, liver, lung and thymus.
Expressed in brain, ovary, testis, salivary gland, trachea and lung.
Serine protease which preferentially hydrolyzes peptides with Arg at the P1 position.
Binding to PMPCA is required for catalytic activity.
Catalytic subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins (PubMed:29576218) (Probable). Preferentially, cleaves after an arginine at position P2 (By similarity). Required for PINK1 turnover by coupling PINK1 mitochondrial import and cleavage, which results in subsequent PINK1 proteolysis (PubMed:22354088).
Expressed in heart, gut and gut-derived tissues. Expressed in skin upper pilosebaceous unit. Expression is decreased or lost in acne lesions (PubMed:33082341).
In sebocytes, expression is up-regulated by Cutibacterium acnes.
Produced by alternative initiation at Met-147 of isoform 1.
Rare variants in GATA6 may be a cause of susceptibility to atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure.
The GATA-type zinc fingers mediate interaction with LMCD1.
The disease is caused by variants affecting the gene represented in this entry. GATA6 mutations have been found in patients with non-syndromic persistent truncus arteriosus (PubMed:19666519).
Transcriptional activator (PubMed:19666519, PubMed:27756709, PubMed:22750565, PubMed:22824924). Regulates SEMA3C and PLXNA2 (PubMed:19666519). Involved in gene regulation specifically in the gastric epithelium (PubMed:9315713). May regulate genes that protect epithelial cells from bacterial infection (PubMed:16968778). Involved in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression (By similarity). Binds to BMP response element (BMPRE) DNA sequences within cardiac activating regions (By similarity). In human skin, controls several physiological processes contributing to homeostasis of the upper pilosebaceous unit. Triggers ductal and sebaceous differentiation as well as limits cell proliferation and lipid production to prevent hyperseborrhoea. Mediates the effects of retinoic acid on sebocyte proliferation, differentiation and lipid production. Also contributes to immune regulation of sebocytes and antimicrobial responses by modulating the expression of anti-inflammatory genes such as IL10 and pro-inflammatory genes such as IL6, TLR2, TLR4, and IFNG. Activates TGFB1 signaling which controls the interfollicular epidermis fate (PubMed:33082341).
Binds only to the receptor EDAR, while isoform 3 binds exclusively to the receptor EDA2R.
Cytokine which is involved in epithelial-mesenchymal signaling during morphogenesis of ectodermal organs. Functions as a ligand activating the DEATH-domain containing receptors EDAR and EDA2R (PubMed:8696334, PubMed:11039935, PubMed:27144394, PubMed:34582123). May also play a role in cell adhesion (By similarity).
Homotrimer. The homotrimers may then dimerize and form higher-order oligomers.
Not abundant; expressed in specific cell types of ectodermal (but not mesodermal) origin of keratinocytes, hair follicles, sweat glands. Also in adult heart, liver, muscle, pancreas, prostate, fetal liver, uterus, small intestine and umbilical chord.
Cleaved during mitotis which leads to removal of CDK5RAP2 from the centrosome and promotes centriole disengagement and subsequent centriole separation (PubMed:22722493, PubMed:25503564). The C-terminal fragment is rapidly degraded following cleavage (PubMed:22722493).
Composed of a coiled-coil central region flanked by non-helical N- and C-terminals.
Expressed in all tissues tested, including placenta, liver, kidney and thymus.
Integral component of the filamentous matrix of the centrosome involved in the initial establishment of organized microtubule arrays in both mitosis and meiosis. Plays a role, together with DISC1, in the microtubule network formation. Is an integral component of the pericentriolar material (PCM). May play an important role in preventing premature centrosome splitting during interphase by inhibiting NEK2 kinase activity at the centrosome.
Interacts with CHD3. Interacts with CHD4; the interaction regulates centrosome integrity (By similarity). Interacts with DISC1 and PCM1. Binds calmodulin. Interacts with CDK5RAP2; the interaction is leading to centrosomal localization of PCNT and CDK5RAP2. Interacts with isoform 1 of NEK2. Interacts with CEP131. Interacts with CCDC13 (PubMed:24816561). Interacts with CEP68 (PubMed:25503564). Interacts with ATF5; the ATF5:PCNT:polyglutamylated tubulin (PGT) tripartite unites the mother centriole and the pericentriolar material (PCM) in the centrosome (PubMed:26213385).
Ubiquitinated by TRIM43; leading to proteasomal degradation.
Defects in EPS8 are associated with some cancers, such as pancreatic, oral squamous cell carcinomas or pituitary cancers. Contributes to cell transformation in response to growth factor treatment and is overexpressed in a number of tumors, indicating that EPS8 levels must be tightly regulated.
Expressed in all tissues analyzed, including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Expressed in all epithelial and fibroblastic lines examined and in some, but not all, hematopoietic cells.
Homodimer. Part of a complex consisting of ABI1, EPS8 and SOS1. Interacts with MYO15A and WHRN. Interacts with LANCL1 (By similarity). Interacts with EGFR; mediates EPS8 phosphorylation (By similarity). Interacts with BAIAP2. Interacts with SHB.
Phosphorylation at Ser-625 and Thr-629 by MAPK following BDNF treatment promotes removal from actin and filopodia formation (By similarity). Phosphorylated by several receptor tyrosine kinases.
Signaling adapter that controls various cellular protrusions by regulating actin cytoskeleton dynamics and architecture. Depending on its association with other signal transducers, can regulate different processes. Together with SOS1 and ABI1, forms a trimeric complex that participates in transduction of signals from Ras to Rac by activating the Rac-specific guanine nucleotide exchange factor (GEF) activity. Acts as a direct regulator of actin dynamics by binding actin filaments and has both barbed-end actin filament capping and actin bundling activities depending on the context. Displays barbed-end actin capping activity when associated with ABI1, thereby regulating actin-based motility process: capping activity is auto-inhibited and inhibition is relieved upon ABI1 interaction. Also shows actin bundling activity when associated with BAIAP2, enhancing BAIAP2-dependent membrane extensions and promoting filopodial protrusions. Involved in the regulation of processes such as axonal filopodia growth, stereocilia length, dendritic cell migration and cancer cell migration and invasion. Acts as a regulator of axonal filopodia formation in neurons: in the absence of neurotrophic factors, negatively regulates axonal filopodia formation via actin-capping activity. In contrast, it is phosphorylated in the presence of BDNF leading to inhibition of its actin-capping activity and stimulation of filopodia formation. Component of a complex with WHRN and MYO15A that localizes at stereocilia tips and is required for elongation of the stereocilia actin core. Indirectly involved in cell cycle progression; its degradation following ubiquitination being required during G2 phase to promote cell shape changes.
The SH3 domain mediates interaction with SHB.
The effector region is required for activating the Rac-specific guanine nucleotide exchange factor (GEF) activity. It mediates both barbed-end actin capping and actin bundling activities. The capping activity is mediated by an amphipathic helix that binds within the hydrophobic pocket at the barbed ends of actin blocking further addition of actin monomers, while the bundling activity is mediated by a compact 4 helix bundle, which contacts 3 actin subunits along the filament (By similarity).
Ubiquitinated by the SCF(FBXW5) E3 ubiquitin-protein ligase complex during G2 phase, leading to its transient degradation and subsequent cell shape changes required to allow mitotic progression. Reappears at the midzone of dividing cells (By similarity).
At least 30 of the 32 cysteine residues are in the reduced form.
Forms high-affinity heterodimers with RNASE1, ANG and RNASE2.
Ribonuclease inhibitor which inhibits RNASE1, RNASE2 and ANG. May play a role in redox homeostasis.
The LRR domain forms a horseshoe-shaped structure that interacts tightly with target RNases via a large protein interaction surface on its interior side.
E3 ubiquitin ligase that catalyzes 'Lys-63'-linked polyubiquitination of target protein, enhancing protein-protein interaction and cell signaling (PubMed:19825828). Transfers ubiquitin from E2 ubiquitin-conjugating enzyme UBE2V1-UBE2N to substrate protein (PubMed:19825828). Essential adapter molecule in IL17A-mediated signaling (PubMed:19825828, PubMed:24120361). Upon IL17A stimulation, interacts with IL17RA and IL17RC receptor chains through SEFIR domains and catalyzes 'Lys-63'-linked polyubiquitination of TRAF6, leading to TRAF6-mediated activation of NF-kappa-B and MAPkinase pathways (PubMed:19825828).
Interacts with IKBKG/NF-kappa B essential modulator, with CHUK/IKK-alpha and with IKBKB/IKK-beta (PubMed:12459498). Interacts with TRAF6; this interaction is direct (PubMed:12459498, PubMed:19825828). Interacts with IL17RA and IL17RC (PubMed:19825828, PubMed:24120361, PubMed:33723527). Interacts with IL17RB (PubMed:24120361).
The presence of U-box domain is not predicted by SMART and SWISS-MODEL tools.
Plays a role in the regulation of centrosome and Golgi apparatus positioning, with consequences on cell shape and cell migration.
Inhibited by quercetin, rutenin and its derivatives.
NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol (PubMed:18449627, PubMed:15799708, PubMed:17912391, PubMed:7005231, PubMed:1921984, PubMed:17344335, PubMed:18826943). Can convert prostaglandin E to prostaglandin F2-alpha (By similarity). Can bind glutathione, which explains its higher affinity for glutathione-conjugated substrates. Catalyzes the reduction of S-nitrosoglutathione (PubMed:18826943, PubMed:17344335). In addition, participates in the glucocorticoid metabolism by catalyzing the NADPH-dependent cortisol/corticosterone into 20beta-dihydrocortisol (20b-DHF) or 20beta-corticosterone (20b-DHB), which are weak agonists of NR3C1 and NR3C2 in adipose tissue (PubMed:28878267).
Expressed in the brain, kidney, testis, placenta, uterus, ovary, adrenal, prostate, skin and heart. Not detected in spleen.
Receptor for relaxins. The activity of this receptor is mediated by G proteins leading to stimulation of adenylate cyclase and an increase of cAMP. Binding of the ligand may also activate a tyrosine kinase pathway that inhibits the activity of a phosphodiesterase that degrades cAMP.
Interacts with CPNE1 and CPNE4 (By similarity). Interacts with COMMD1, COMMD2 COMMD3, COMMD4, COMMD5, COMMD6, COMMD7, COMMD8, COMMD9, COMMD10 (PubMed:25355947). Interacts with CUL1, CUL2, CUL3, SKP1, BTRC (PubMed:23563313). Interacts with CCDC93; proposed to be a component of the CCC (COMMD/CCDC22/CCDC93) complex which contains at least COMMD1 (and possibly other COMM domain-containing proteins), CCDC22 and CCDC93; in the complex interacts directly with CCDC93 (PubMed:25355947). Interacts with VPS35L; associates with the retriever complex (PubMed:25355947, PubMed:28892079). Interacts with SNX17 and SNX31 (PubMed:28892079).
Involved in regulation of NF-kappa-B signaling. Promotes ubiquitination of I-kappa-B-kinase subunit IKBKB and its subsequent proteasomal degradation leading to NF-kappa-B activation; the function may involve association with COMMD8 and a CUL1-dependent E3 ubiquitin ligase complex. May down-regulate NF-kappa-B activity via association with COMMD1 and involving a CUL2-dependent E3 ubiquitin ligase complex. Regulates the cellular localization of COMM domain-containing proteins, such as COMMD1 and COMMD10 (PubMed:23563313). Component of the CCC complex, which is involved in the regulation of endosomal recycling of surface proteins, including integrins, signaling receptor and channels. The CCC complex associates with SNX17, retriever and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of numerous cargos such as integrins ITGA5:ITGB1 (PubMed:28892079, PubMed:25355947). Plays a role in copper ion homeostasis. Involved in copper-dependent ATP7A trafficking between the trans-Golgi network and vesicles in the cell periphery; the function is proposed to depend on its association within the CCC complex and cooperation with the WASH complex on early endosomes (PubMed:25355947).
Widely expressed in adult tissues and in fetal liver and brain, with highest levels in prostate and lowest in skeletal muscle.
Antibodies against CIP2A are present in sera from many patients with gastric or prostate cancer, suggesting that it may act as a marker for such cancers.
Expressed at low levels in most of the tissues. Overexpressed in head-and-neck squamous cell carcinomas (HNSCC). Present in liver cancer cells (at protein level).
Homodimer (PubMed:28174209). Interacts with MYC (PubMed:17632056). Interacts with PPP2R5C; this interaction stabilizes CIP2A (PubMed:28174209). Interacts with PPP2R1A; this interaction stabilizes CIP2A (PubMed:28174209).
Oncoprotein that inhibits PP2A and stabilizes MYC in human malignancies. Promotes anchorage-independent cell growth and tumor formation.
Homodimer. Can only homodimerize with isoform 1. Interacts directly with COMMD1 (via COMM domain). Interacts with RELA, RELB, NFKB1/p105. Does not interact with NFKBIB. Interacts with CCDC22, CCDC93, SCNN1B, CUL4A.
May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes (PubMed:21778237). Down-regulates activation of NF-kappa-B. Inhibits TNF-induced NFKB1 activation.
Ubiquitous. Expressed in brain, heart, skeletal muscle, lung, pancreas, liver, kidney, small intestine and placenta.
E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway, a pathway that takes place when a ribosome has stalled during translation, and which promotes ubiquitination and degradation of translation factors on stalled ribosomes (PubMed:36638793). Catalyzes ubiquitination of RPS27A in response to ribosome collisions, promoting activation of RNF14 (PubMed:36638793). RNF25 catalyzes ubiquitination of other ribosomal proteins on stalled ribosomes, such as RPL0, RPL1, RPL12, RPS13 and RPS17 (PubMed:36638793). Also involved in ubiquitination and degradation of stalled ETF1/eRF1 (PubMed:36638793). Independently of its function in the response to stalled ribosomes, mediates ubiquitination and subsequent proteasomal degradation of NKD2 (By similarity). May also stimulate transcription mediated by NF-kappa-B via its interaction with RELA/p65 (PubMed:12748188).
Interacts with UBE2D2, and may also interact with UBE2E1 and UBE2E3 (PubMed:26475854). Interacts with RELA/p65 (PubMed:12748188).
Can bind to DNA as a heterodimer with PAX3. Interacts with PAXBP1; the interaction links PAX7 to a WDR5-containing histone methyltransferase complex (By similarity). Interacts with DAXX (PubMed:10393185).
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving PAX7 is found in rhabdomyosarcoma. Translocation t(1;13)(p36;q14) with FOXO1. The resulting protein is a transcriptional activator.
Transcription factor that is involved in the regulation of muscle stem cells proliferation, playing a role in myogenesis and muscle regeneration.
Expressed exclusively in testis and sperm. Highest expression is found in the neck region of ejaculated sperm with lower levels found in the tail and postacrosome region.
F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike other capping proteins (such as gelsolin and severin), these proteins do not sever actin filaments. May play a role in the morphogenesis of spermatid (By similarity).
Heterodimer of an alpha and a beta subunit (By similarity). Component of the WASH complex, composed of F-actin-capping protein subunit alpha (CAPZA1, CAPZA2 or CAPZA3), F-actin-capping protein subunit beta (CAPZB), WASH (WASHC1, WASH2P, WASH3P, WASH4P, WASH5P or WASH6P), WASHC2 (WASHC2A or WASHC2C), WASHC3, WASHC4 and WASHC5.
Degraded following binding to N(6)-methyladenosine methylated DNA (m6A).
Probable protease (By similarity). Acts as a sensor of N(6)-methyladenosine methylation on DNA (m6A): recognizes and binds m6A DNA, leading to its degradation (PubMed:30982744).
The RAMA domain recognizes and binds N(6)-methyladenosine methylation on DNA (m6A).
Homodimer; and heterodimer with alpha-lactalbumin to form lactose synthase. Interacts (via N-terminal cytoplasmic domain) with UBE2Q1 (via N-terminus); the interaction is direct (By similarity).
The Golgi complex form catalyzes the production of lactose in the lactating mammary gland and could also be responsible for the synthesis of complex-type N-linked oligosaccharides in many glycoproteins as well as the carbohydrate moieties of glycolipids.
The cell surface form functions as a recognition molecule during a variety of cell to cell and cell to matrix interactions, as those occurring during development and egg fertilization, by binding to specific oligosaccharide ligands on opposing cells or in the extracellular matrix.
The soluble form derives from the membrane forms by proteolytic processing.
Ubiquitously expressed, but at very low levels in fetal and adult brain.
Expressed in brain, colon, pancreas, placenta and kidney. Isoform 1 is expressed in lung and tonsil. Isoform 2 is prostate-specific.
GRHL genes (GRHL1, GRHL2 and GRHL3) show a paradoxical lack of redundancy despite their extensive sequence identity in the DNA-binding and protein dimerization domains and the fact that the core consensus DNA binding sites are identical. They have related, but remarkably different functions during embryogenesis because of their differential spatiotemporal expression patterns during development.
Homodimer, also forms heterodimers with GRHL1 and GRHL2 (PubMed:12549979). Interacts with LMO4 (By similarity).
Transcription factor playing important roles in primary neurulation and in the differentiation of stratified epithelia of both ectodermal and endodermal origin (By similarity). Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' acting as an activator and repressor on distinct target genes (PubMed:21081122, PubMed:25347468). xhibits functional redundancy with GRHL2 in epidermal morphogenetic events and epidermal wound repair (By similarity). Exhibits functional redundancy with GRHL2 in epidermal morphogenetic events and epidermal wound repair but is essential to form the epidermal barrier with TGM3 as critical direct target gene among others. Despite being dispensable during normal epidermal homeostasis in the adulthood, is again required for barrier repair after immune-mediated epidermal damage, regulates distinct gene batteries in embryonic epidermal differentiation and adult epidermal barrier reformation after injury. Plays unique and cooperative roles with GRHL2 in establishing distinct zones of primary neurulation. Essential for spinal closure, functions cooperatively with GRHL2 in closure 2 (forebrain/midbrain boundary) and posterior neuropore closure (By similarity). Also required for proper development of the oral periderm (PubMed:24360809). No genetic interaction with GRHL3, no functional cooperativity due to diverse target gene selectivity (PubMed:21081122).
'Akiraka ni suru' means 'making things clear' in Japanese. The name is given based on the presence of the clear nuclear localization signal.
Molecular adapter that acts as a bridge between proteins, and which is involved skeletal muscle development (By similarity). Functions as signal transducer for MSTN during skeletal muscle regeneration and myogenesis (By similarity). May regulate chemotaxis of both macrophages and myoblasts by reorganising actin cytoskeleton, leading to more efficient lamellipodia formation via a PI3 kinase dependent pathway (By similarity). In contrast to AKIRIN2, not involved in nuclear import of proteasomes (PubMed:34711951).
Widely expressed with the highest expression in heart, liver, placenta and peripheral blood leukocytes.
Deubiquitinating enzyme that plays a role in many cellular processes including autophagy, cellular antiviral response or membrane protein biogenesis (PubMed:27801882, PubMed:29487085). Attenuates TLR4-mediated NF-kappa-B signaling by cooperating with beta-arrestin-2/ARRB2 and inhibiting TRAF6 autoubiquitination (PubMed:26839314). Promotes cellular antiviral responses by deconjugating 'Lys-33' and 'Lys-48'-linked ubiquitination of STING1 leading to its stabilization (PubMed:27801882). Plays an essential role in autophagy induction by regulating the ULK1 stability through deubiquitination of ULK1 (PubMed:29487085). Acts as a positive regulator for NF-kappa-B activation by TNF-alpha through deubiquitinating 'Lys-48'-linked polyubiquitination of SQSTM1, leading to its increased stability (PubMed:32354117). Acts as a regulator of G-protein coupled receptor (GPCR) signaling by mediating the deubiquitination beta-2 adrenergic receptor (ADRB2)(PubMed:19424180). Plays a central role in ADRB2 recycling and resensitization after prolonged agonist stimulation by constitutively binding ADRB2, mediating deubiquitination of ADRB2 and inhibiting lysosomal trafficking of ADRB2. Upon dissociation, it is probably transferred to the translocated beta-arrestins, possibly leading to beta-arrestins deubiquitination and disengagement from ADRB2 (PubMed:19424180). This suggests the existence of a dynamic exchange between the ADRB2 and beta-arrestins. Deubiquitinates DIO2, thereby regulating thyroid hormone regulation. Deubiquitinates HIF1A, leading to stabilize HIF1A and enhance HIF1A-mediated activity (PubMed:15776016). Deubiquitinates MCL1, a pivotal member of the anti-apoptotic Bcl-2 protein family to regulate its stability (PubMed:35063767). Within the endoplasmic reticulum, participates with USP33 in the rescue of post-translationally targeted membrane proteins that are inappropriately ubiquitinated by the cytosolic protein quality control in the cytosol (PubMed:33792613).
Interacts with VHL, leading to its ubiquitination and subsequent degradation (PubMed:12056827). Interacts with CCP110 (PubMed:23486064). Interacts with DIO2 (PubMed:12865408). Interacts with HIF1A (PubMed:15776016). Interacts with ADRB2 (PubMed:19424180, PubMed:23166351). Interacts with USP18 (PubMed:27801882).
The UBP-type zinc finger binds 3 zinc ions. However, it does not bind ubiquitin, probably because the conserved Arg in position 55 is replaced by a Glu residue (By similarity).
(Microbial infection) Interacts with HCMV protein UL141; this interaction prevents TNFRSF10A cell surface expression.
Monomer (PubMed:26457518). Homooligomers and heterooligomers with TNFRSF10B (PubMed:19090789). Three TNFRSF10A molecules interact with the TNFSF10 homotrimer (PubMed:26457518). Can interact with TRADD and RIPK1. Interacts with ARAP1. In the absence of stimulation, interacts with BIRC2, DDX3X and GSK3B. The interaction with BIRC2 and DDX3X is further enhanced upon receptor stimulation and accompanied by DDX3X and BIRC2 cleavage (PubMed:18846110). Interacts with ZDHHC3 (PubMed:22240897).
Palmitoylated (PubMed:19090789). Palmitoylation of TNFRSF10A is required for its association with lipid rafts, oligomerization and function in TRAIL-induced cell death (PubMed:19090789). Palmitoylated by ZDHHC3 (Probable).
Receptor for the cytotoxic ligand TNFSF10/TRAIL (PubMed:26457518). The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis (PubMed:19090789). Promotes the activation of NF-kappa-B (PubMed:9430227).
Widely expressed. High levels are found in spleen, peripheral blood leukocytes, small intestine and thymus, but also in K-562 erythroleukemia cells, MCF-7 breast carcinoma cells and activated T-cells.
Homodimer and homotetramer. Interacts with CREBBP. Interacts preferentially with histone H3 that is not methylated at 'Lys-4'. Binds with lower affinity to histone H3 that is monomethylated at 'Lys-4'. Trimethylation of histone H3 at 'Lys-4' or phosphorylation at 'Thr-3' abolish the interaction. Binds with lower affinity to histone H3 that is acetylated at 'Lys-4', or that is acetylated at 'Lys-9' or trimethylated at 'Lys-9'. Binds histone H3 that is dimethylated at 'Arg-2' with very low affinity.
Interacts via the first PHD domain with the N-terminus of histone H3 that is not methylated at 'Lys-4'. Disruption of the first PHD domain has been shown to lead to reduced transcriptional activity and to localization of the protein mainly in the cytoplasm in small granules. While the PHD zinc fingers are necessary for the transactivation capacity of the protein, other regions also modulate this function.
Phosphorylated. Phosphorylation could trigger oligomerization.
The HSR domain is required for localization on tubular structures (N-terminal part) and for homodimerization.
The L-X-X-L-L repeats may be implicated in binding to nuclear receptors.
The disease is caused by variants affecting the gene represented in this entry. Most of the mutations alter the nucleus-cytoplasm distribution of AIRE and disturb its association with nuclear dots and cytoplasmic filaments. Most of the mutations also decrease transactivation of the protein. The HSR domain is responsible for the homomultimerization activity of AIRE. All the missense mutations of the HSR and the SAND domains decrease this activity, but those in other domains do not. The AIRE protein is present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturb the formation of these complexes (PubMed:14974083). Heterozygous mutations within the PHD1 domain have dominant-negative effects and cause organ-specific autoimmune diseases (PubMed:26084028). Patients harbor extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines such as type I interferons which could protect them from some types of autoimmune diseases, like type I diabetes (PubMed:27426947).
Transcription factor playing an essential role to promote self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery, called tissue restricted antigens (TRA) (PubMed:26084028). Binds to G-doublets in an A/T-rich environment; the preferred motif is a tandem repeat of 5'-ATTGGTTA-3' combined with a 5'-TTATTA-3' box. Binds to nucleosomes (By similarity). Binds to chromatin and interacts selectively with histone H3 that is not methylated at 'Lys-4', not phosphorylated at 'Thr-3' and not methylated at 'Arg-2'. Functions as a sensor of histone H3 modifications that are important for the epigenetic regulation of gene expression. Mainly expressed by medullary thymic epithelial cells (mTECs), induces the expression of thousands of tissue-restricted proteins, which are presented on major histocompatibility complex class I (MHC-I) and MHC-II molecules to developing T-cells percolating through the thymic medulla (PubMed:26084028). Also induces self-tolerance through other mechanisms such as the regulation of the mTEC differentiation program. Controls the medullary accumulation of thymic dendritic cells and the development of regulatory T-cell through the regulation of XCL1 expression. Regulates the production of CCR4 and CCR7 ligands in medullary thymic epithelial cells and alters the coordinated maturation and migration of thymocytes. In thimic B-cells, allows the presentation of licensing-dependent endogenous self-anitgen for negative selection. In secondary lymphoid organs, induces functional inactivation of CD4(+) T-cells. Expressed by a distinct bone marrow-derived population, induces self-tolerance through a mechanism that does not require regulatory T-cells and is resitant to innate inflammatory stimuli (By similarity).
Widely expressed. Expressed at higher level in thymus (medullary epithelial cells and monocyte-dendritic cells), pancreas, adrenal cortex and testis. Expressed at lower level in the spleen, fetal liver and lymph nodes. In secondary lymphoid organs, expressed in a discrete population of bone marrow-derived toleregenic antigen presenting cells (APCs) called extrathymic AIRE expressing cells (eTAC)(at protein level) (PubMed:23993652). Isoform 2 and isoform 3 seem to be less frequently expressed than isoform 1, if at all.
Expression is increased in differentiated thyroid carcinomas compared to normal thyroid tissue and anaplastic thyroid tumors where expression is low or undetectable. Expression is found in thyrocytes but not in stromal cells (at protein level) (PubMed:15735754). Detected in neonate heart and lung (PubMed:8288227).
Forms a soluble 1:1 complex with AFM; this prevents oligomerization and is required for prolonged biological activity (PubMed:26902720). The complex with AFM may represent the physiological form in body fluids (PubMed:26902720). Homooligomer; disulfide-linked, leading to inactivation (in vitro). Interacts with PORCN. Interacts with WLS (By similarity). Interacts with glypican GCP3 (PubMed:14610063). Interacts with PKD1 (via extracellular domain) (PubMed:27214281). Interacts with TMEM67 (PubMed:34731008).
Glycosylation is necessary for secretion but not for activity.
Ligand for members of the frizzled family of seven transmembrane receptors. Can activate or inhibit canonical Wnt signaling, depending on receptor context. In the presence of FZD4, activates beta-catenin signaling. In the presence of ROR2, inhibits the canonical Wnt pathway by promoting beta-catenin degradation through a GSK3-independent pathway which involves down-regulation of beta-catenin-induced reporter gene expression (By similarity). Suppression of the canonical pathway allows chondrogenesis to occur and inhibits tumor formation. Stimulates cell migration. Decreases proliferation, migration, invasiveness and clonogenicity of carcinoma cells and may act as a tumor suppressor (PubMed:15735754). Mediates motility of melanoma cells (PubMed:17426020). Required during embryogenesis for extension of the primary anterior-posterior axis and for outgrowth of limbs and the genital tubercle. Inhibits type II collagen expression in chondrocytes (By similarity).
Proteolytic processing by TIKI1 and TIKI2 promotes oxidation and formation of large disulfide-bond oligomers, leading to inactivation of WNT5A.
Binds and transports small hydrophobic volatile molecules with a higher affinity for aldehydes and large fatty acids, including undecanal, palmitic acid, efficient aldehydes, benzenic aldehydes, heterocyclic aldehydes and aliphatic acids.
Strongly expressed in the nasal structures, salivary and lachrymal glands, and lung (PubMed:10607840). Expressed in the liver (PubMed:27827363).
RNA-binding protein that functions as regulator of alternative splicing for multiple target mRNAs, including PTPRC/CD45 and STAT5A. Required for alternative splicing of PTPRC.
Widely expressed. Detected in bone marrow stroma cells, skeletal muscle, heart, placenta, pancreas, kidney and lung.
Highly expressed in brain. Weakly expressed in heart, lung, skeletal muscle, kidney, thymus, prostate, testis and small intestine.
Plays a role in neurogenesis and brain development (By similarity). May suppress cell cycle progression in postmitotic neurons by inhibiting G1/S transition (PubMed:11420708).
Silenced by methylation in 50% of bladder cancer cell lines.
Expressed specifically in testis and sperm. Weakly expressed in pancreatic-duct cells. Up-regulated in pancreatic-duct cells from patients with cystic fibrosis.
Interacts via its C2 domain with PtdIns(3)P and, to a lesser extent, PtdIns(5)P in vitro.
The EF-hand and C2 domains are essential for triggering Ca(2+) oscillating activity and the regulation of PLCZ1 enzyme activity.
The X-Y linker region between PI-PLC X-box and Y-box domains may be a target for proteolysis and may play an important regulatory role during fertilization.
The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. In vitro, hydrolyzes PtdIns(4,5)P2 in a Ca(2+)-dependent manner. Triggers intracellular Ca(2+) oscillations in oocytes solely during M phase and is involved in inducing oocyte activation and initiating embryonic development up to the blastocyst stage. Is therefore a strong candidate for the egg-activating soluble sperm factor that is transferred from the sperm into the egg cytoplasm following gamete membrane fusion. May exert an inhibitory effect on phospholipase-C-coupled processes that depend on calcium ions and protein kinase C, including CFTR trafficking and function.
Abundantly expressed in skeletal muscle. Very low levels in heart.
Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells. Provides a structural foundation for functional cross-talk between the cell surface and intracellular calcium release channels. JPH1 contributes to the construction of the skeletal muscle triad by linking the t-tubule (transverse-tubule) and SR (sarcoplasmic reticulum) membranes.
A microdeletion of chromosome 10q23 involving BMPR1A and PTEN is a cause of chromosome 10q23 deletion syndrome, which shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome.
Interacts with low affinity with GDF5; positively regulates chondrocyte differentiation (PubMed:24098149). Interacts with BMP4 (PubMed:8006002). Interacts with SCUBE3 (PubMed:33308444). Interacts with TSC22D1/TSC-22 (PubMed:21791611). Interacts with BMP2; the interaction may induce HAMP expression (PubMed:31800957, PubMed:10881198, PubMed:15064755, PubMed:17295905, PubMed:18937504). Interacts with BMP6 (PubMed:31800957). Interacts with heterodimers composed of BMP2 and BMP6 in vitro; the interaction may induce HAMP expression (PubMed:31800957).
On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP2, BMP4, GDF5 and GDF6. Positively regulates chondrocyte differentiation through GDF5 interaction. Mediates induction of adipogenesis by GDF6. May promote the expression of HAMP, potentially via its interaction with BMP2 (By similarity).
Activated by cAMP. cAMP binding causes a conformation change that leads to the assembly of an active tetramer and channel opening.
Highly expressed in thalamus, testis and in heart, both in ventricle and atrium. Detected at much lower levels in amygdala, substantia nigra, cerebellum and hippocampus.
Homotetramer. The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming subunits.
Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) that regulate the rhythm of heart beat. May contribute to the native pacemaker currents in neurons (Ih). May mediate responses to sour stimuli.
Plays a role in the regulation of the cell surface expression of TLR4.
Although it contains a rhodanese domain, does not display phosphatase activity, suggesting that the protein is enzymatically inactive.
Genetic variations in CEP41 may be associated with susceptibility to autism (PubMed:21438139).
Required during ciliogenesis for tubulin glutamylation in cilium. Probably acts by participating in the transport of TTLL6, a tubulin polyglutamylase, between the basal body and the cilium.
Associated with the NPC, however it may not be a stable component of the NPC complex since it shuttles between the nucleus and the cytoplasm. Interacts with nuclear pore complex proteins NUP155 and NUP42. Isoform 2 does not interact with NUP42. Able to form a heterotrimer with NUP155 and NUP42 in vitro.
Required for the export of mRNAs containing poly(A) tails from the nucleus into the cytoplasm. May be involved in the terminal step of the mRNA transport through the nuclear pore complex (NPC).
Belongs to the complex I 49 kDa subunit family.
Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. Component of the iron-sulfur (IP) fragment of the enzyme (PubMed:12611891). Interacts with NDUFAF3 (PubMed:19463981). Interacts with NDUFAF7 (PubMed:20406883, PubMed:24089531). Interacts with CERS2 (By similarity).
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:30922174, PubMed:22036843). Essential for the catalytic activity of complex I (PubMed:30922174, PubMed:22036843). Essential for the assembly of complex I (By similarity). Redox-sensitive, critical component of the oxygen-sensing pathway in the pulmonary vasculature which plays a key role in acute pulmonary oxygen-sensing and hypoxic pulmonary vasoconstriction (PubMed:30922174). Plays an important role in carotid body sensing of hypoxia (By similarity). Essential for glia-like neural stem and progenitor cell proliferation, differentiation and subsequent oligodendrocyte or neuronal maturation (By similarity).
Dimethylation at Arg-118 by NDUFAF7 takes place after NDUFS2 assembles into the complex I, leading to stabilize the early intermediate complex (PubMed:24089531, PubMed:24838397).
Functions as a GTPase-activating protein (GAP) with a broad specificity.
Atypical E3 ubiquitin-protein ligase which ubiquitinates TLR2 at 'Lys-754' leading to its degradation by the proteasome. Plays a role in regulating inflammatory cytokine release and gram-positive bacterial clearance by functioning, in part, through the ubiquitination and degradation of TLR2 (PubMed:27805901). Inhibitor of protein phosphatase 1 (PubMed:9843442).
(Microbial infection) Interacts (via C-terminus) with the Herpes simplex virus activator VP16; this interaction stimulates RNA Pol II transcription by increasing the extent of pre-initiation complex assembly.
(Microbial infection) Interacts with Herpes simplex virus 1 protein ICP4.
Acetylated (PubMed:24441171). Autoacetylated; autoacetylation at Lys-238 stimulates transcription activation (PubMed:12931194).
Expressed in the inner cell mass forming the embryoblast (PubMed:24441171). Not detected in cells from the outer thin layer trophoblast (at protein level) (PubMed:24441171).
Found in a ternary complex with TATA box-bound TBP (PubMed:8413225, PubMed:8515820, PubMed:8516311, PubMed:8516312, PubMed:10619841, PubMed:29158257). Part of a TFIID-containing RNA polymerase II pre-initiation complex (PIC) that is composed of TBP and at least GTF2A1, GTF2A2, GTF2E1, GTF2E2, GTF2F1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2B, TCEA1, ERCC2, ERCC3, TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:27193682). Associates with TFIID-TFIIA (DA complex) to form TFIID-TFIIA-TFIIB (DAB complex), which is then recognized by RNA polymerase II (Pol II) (PubMed:1876184, PubMed:2247058). Found in a RNA polymerase II initiation complex (PubMed:3818643, PubMed:3029109, PubMed:8413225, PubMed:8516312, PubMed:7601352). Interacts (via C-terminus) with TBP; this interaction with TATA box-bound TBP guides Pol II into the PIC (PubMed:8504927, PubMed:10619841). Interacts (via N-terminus) with Pol II (PubMed:8504927, PubMed:8413225). Interacts (via C-terminus) with SSU72; this interaction is inhibited by SYMPK (PubMed:29158257). Interacts with NR2F1; this interaction is direct (PubMed:1517211). Interacts with PGR (PubMed:1517211). Interacts with ESR1 (PubMed:1517211). Interacts with GTF2F1 (via C-terminus and preferentially via acetylated form); this interaction prevents binding of GTF2B to GTF2F2 (PubMed:8662660, PubMed:12931194). Interacts with GTF2F2 (via N-terminus); this interaction is inhibited in presence of GTF2F1 (PubMed:8504927, PubMed:8662660). Interacts with the transcription elongation factor TCEA2 (PubMed:8566795). Interacts with HSF1 (via transactivation domain) (PubMed:11005381). Interacts with GPBP1 (By similarity).
General transcription factor that plays a role in transcription initiation by RNA polymerase II (Pol II). Involved in the pre-initiation complex (PIC) formation and Pol II recruitment at promoter DNA (PubMed:1876184, PubMed:1946368, PubMed:1517211, PubMed:3818643, PubMed:3029109, PubMed:8413225, PubMed:8515820, PubMed:8516311, PubMed:8516312, PubMed:7601352, PubMed:9420329, PubMed:12931194, PubMed:27193682). Together with the TATA box-bound TBP forms the core initiation complex and provides a bridge between TBP and the Pol II-TFIIF complex (PubMed:8504927, PubMed:8413225, PubMed:8515820, PubMed:8516311, PubMed:8516312). Released from the PIC early following the onset of transcription during the initiation and elongation transition and reassociates with TBP during the next transcription cycle (PubMed:7601352). Associates with chromatin to core promoter-specific regions (PubMed:12931194, PubMed:24441171). Binds to two distinct DNA core promoter consensus sequence elements in a TBP-independent manner; these IIB-recognition elements (BREs) are localized immediately upstream (BREu), 5'-[GC][GC][GA]CGCC-3', and downstream (BREd), 5'-[GA]T[TGA][TG][GT][TG][TG]-3', of the TATA box element (PubMed:9420329, PubMed:16230532, PubMed:7675079, PubMed:10619841). Modulates transcription start site selection (PubMed:10318856). Exhibits also autoacetyltransferase activity that contributes to the activated transcription (PubMed:12931194).
The TFIIB-type zinc-binding domain is necessary for the interaction and recruitment of RNA polymerase II to the core promoter, the formation of a fully competent pre-initiation complex (PIC) assembly and basal transcription initiation (PubMed:8515820, PubMed:8516311, PubMed:8516312, PubMed:8413225). The C-terminus is necessary and sufficient for interaction with the TATA box-bound TBP complex and for the formation of PIC (PubMed:8515820, PubMed:8516311, PubMed:8413225).
Activated by phosphorylation on Ser-356 by an unknown kinase (may be mTORC2 but not confirmed), transforming it into a substrate for PDPK1 which then phosphorylates it on Thr-193.
Highly expressed in liver, kidney and pancreas, and at lower levels in brain.
Not regulated by serum or glucocorticoids.
Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, survival and proliferation. Up-regulates Na(+) channels: SCNN1A/ENAC, K(+) channels: KCNA3/Kv1.3, KCNE1 and KCNQ1, amino acid transporter: SLC6A19, glutamate transporter: SLC1A6/EAAT4, glutamate receptors: GRIA1/GLUR1 and GRIK2/GLUR6, Na(+)/H(+) exchanger: SLC9A3/NHE3, and the Na(+)/K(+) ATPase.
Two specific sites, one in the kinase domain (Thr-193) and the other in the C-terminal regulatory region (Ser-356), need to be phosphorylated for its full activation.
Involved in cognitive function in the brain, possibly via the noradrenergic system.
RTL4 is one of at least 11 genes called Mar or Mart related to long terminal repeat retrotransposons. They do not correspond to functional retrotransposons, but rather to neofunctionalized retrotransposons genes.
Guanine nucleotide exchange factor (GEF) for Rap1A, Rap2A and M-Ras GTPases. Does not interact with cAMP.
Interacts with the second PDZ domain of human PTP1e.
Isoform 3 has highest expression levels in the brain, heart, liver, lung and placenta and is barely detectable in skeletal muscle, kidney and pancreas.
Highly expressed in endometrial epithelial cells in proliferative phase of the menstrual cycle. Levels decrease approximately 10-fold in the secretory phase. Virtually undetectable in samples from postmenopausal women.
Type I interferon required for maintaining basal levels of IFN-regulated genes, including 2'-5'-oligoadenylate synthetase, IRF7 and ISG15, in the female reproductive tract. Directly mediates protection against viral and bacterial genital infections (By similarity).
Only one single gene encoding glyoxalase II has been identified in vertebrates. In yeast and higher plants, separate genes encode the cytosolic and mitochondrial forms of glyoxalase II.
Produced by alternative splicing. Also produced by alternative initiation at Met-49 of isoform 1.
Thiolesterase that catalyzes the hydrolysis of S-D-lactoyl-glutathione to form glutathione and D-lactic acid.
The SSX2IP:WRAP73 complex is proposed to act as regulator of spindle anchoring at the mitotic centrosome. Required for the centrosomal localization of SSX2IP and normal mitotic bipolar spindle morphology (PubMed:26545777). Required for the targeting of centriole satellite proteins to centrosomes such as of PCM1, SSX2IP, CEP290 and PIBF1/CEP90. Required for ciliogenesis and involved in the removal of the CEP97:CCP110 complex from the mother centriole. Involved in ciliary vesicle formation at the mother centriole and required for the docking of vesicles to the basal body during ciliogenesis; may promote docking of RAB8A- and ARL13B-containing vesicles (PubMed:26675238).
Ubiquitous. Predominant expression in heart, brain, liver, thymus, prostate, and testis, and barely detectable expression in lung.
Interacts with PKN1 (By similarity). Interacts with TRAF2. Interacts with mono- and polyubiquitin. Interacts with PEX6. Interacts with PEX5 (Cys-linked ubiquitinated) (By similarity).
Involved in regulation of TNF-alpha induced NF-kappa-B activation and apoptosis. Involved in modulation of 'Lys-48'-linked polyubiquitination status of TRAF2 and decreases association of TRAF2 with RIPK1. Required for PTS1 target sequence-dependent protein import into peroxisomes and PEX5 stability; may cooperate with PEX6. In vitro involved in PEX5 export from the cytosol to peroxisomes (By similarity).
The A20-type zinc finger domain mediates regulation of NF-kappa-B activity.
The AN1-type zinc finger domain mediates association with TRAF2.
Widely expressed with high level in heart, skeletal muscle, liver, kidney and placenta.
Heterohexamer of two PFD-alpha type and four PFD-beta type subunits.
Heterohexamer of two PFD-alpha type and four PFD-beta type subunits. Binds to the C-terminal part of VHL.
Interacts with corepressor CtBP2. Interacts with PIAS1, PIAS2, and PIAS4; the interaction with each ligase sumoylates KLF8.
Sumoylation at Lys-67 represses transcriptional activity and reduces cell cycle progression into the G(1) phase. Has no effect on subcellular location.
The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. In KLF8, the motif is inactive.
Transcriptional repressor and activator. Binds to CACCC-boxes promoter elements. Also binds the GT-box of cyclin D1 promoter and mediates cell cycle progression at G(1) phase as a downstream target of focal adhesion kinase (FAK).
Detected in adult testis, and in fetal brain and kidney.
17q23 region is one of the most commonly amplified regions in breast cancer and therefore may harbor genes important for breast cancer development and progression.
Amplified in breast cancer cell lines MCF-7 and BT-474.
Interacts with STX1 (PubMed:12044471). May interact with CPNE6 (PubMed:12044471).
GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state. Has strong activity toward RHOA, and weaker activity toward RAC1 and CDC42. May act as a specific effector of RAP2A to regulate Rho. In concert with RASIP1, suppresses RhoA signaling and dampens ROCK and MYH9 activities in endothelial cells and plays an essential role in blood vessel tubulogenesis.
Interacts with PTPN13/PTPL1. Interacts with RAP2A via its coiled coil domain. Interacts with RASIP1 (By similarity).
Strongly down-regulated in mantle-cell lymphomas. Up-regulated in migrating glioma cells.
Widely expressed. Highly expressed in skeletal muscle and heart. Expressed at intermediate level in placenta, liver and pancreas. Weakly expressed in brain, lung and kidney.
Inhibited by thiorphan and phosphoramidon.
Metalloprotease involved in sperm function, possibly by modulating the processes of fertilization and early embryonic development. Degrades a broad variety of small peptides with a preference for peptides shorter than 3 kDa containing neutral bulky aliphatic or aromatic amino acid residues. Shares the same substrate specificity with MME and cleaves peptides at the same amide bond (By similarity).
Predominantly expressed in testis. Weakly expressed in brain, kidney and heart.
Homodimer; in the catalytically active form (PubMed:11371164, PubMed:12054796, PubMed:12777791). Monomer in the secreted form (PubMed:11371164, PubMed:12054796, PubMed:12777791).
In the cytoplasm, catalyzes the conversion of glucose-6-phosphate to fructose-6-phosphate, the second step in glycolysis, and the reverse reaction during gluconeogenesis (PubMed:28803808). Besides it's role as a glycolytic enzyme, also acts as a secreted cytokine: acts as an angiogenic factor (AMF) that stimulates endothelial cell motility (PubMed:11437381). Acts as a neurotrophic factor, neuroleukin, for spinal and sensory neurons (PubMed:3352745, PubMed:11004567). It is secreted by lectin-stimulated T-cells and induces immunoglobulin secretion (PubMed:3352745, PubMed:11004567).
Phosphorylation at Ser-185 by CK2 has been shown to decrease enzymatic activity and may contribute to secretion by a non-classical secretory pathway.
Strongly inhibited by erythrose 4-phosphate.
A cell surface antigen recognized in lymophocytes by multiple mAbs.
ATP inhibits the cADPR hydrolyzing activity.
Belongs to the ADP-ribosyl cyclase family.
Expressed at high levels in pancreas, liver, kidney, brain, testis, ovary, placenta, malignant lymphoma and neuroblastoma.
Preferentially expressed at both early and late stages of the B and T-cell maturation. It is also detected on erythroid and myeloid progenitors in bone marrow, where the level of surface expression was shown to decrease during differentiation of blast-forming unit E to colony-forming unit E.
Synthesizes cyclic ADP-ribose (cADPR), a second messenger for glucose-induced insulin secretion (PubMed:8253715, PubMed:7961800). Synthesizes the Ca(2+) mobilizer nicotinate-adenine dinucleotide phosphate, NAADP(+), from 2'-phospho-cADPR and nicotinic acid, as well as from NADP(+) and nicotinic acid. At both pH 5.0 and pH 7.4 preferentially transforms 2'-phospho-cADPR into NAADP(+), while preferentially cleaving NADP(+) to cADPR and ADPRP rather than into NADDP(+) (PubMed:16690024). Has cADPR hydrolase activity (PubMed:8253715, PubMed:7961800).
After cleavage, the post-translationally modified ChM-I is secreted as a glycoprotein.
Bifunctional growth regulator that stimulates the growth of cultured chondrocytes in the presence of basic fibroblast growth factor (FGF) but inhibits the growth of cultured vascular endothelial cells. May contribute to the rapid growth of cartilage and vascular invasion prior to the replacement of cartilage by bone during endochondral bone development. Inhibits in vitro tube formation and mobilization of endothelial cells. Plays a role as antiangiogenic factor in cardiac valves to suppress neovascularization.
Detected in cartilage and cardiac valves (at protein level). Detected in the laminae fibrosa, spongiosa and ventricularis layers of normal cardiac valves (at protein level). Expression is decreased cardiac valves of patients with valvular heart disease (at protein level). Weakly expressed in chondrosarcoma.
Expressed at 9 weeks in developing cartilagenous bone rudiments.
By E2F and p53/TP53 in apoptotic neurons (PubMed:11389439). Translation is inhibited by HNRPA1, which binds to the IRES of APAF1 mRNAs (PubMed:31498791).
Monomer. Oligomerizes to a heptameric ring, known as the apoptosome, upon binding of cytochrome c and dATP. Oligomeric Apaf-1 and pro-caspase-9 bind to each other via their respective NH2-terminal CARD domains and consecutively mature caspase-9 is released from the complex. Pro-caspase-3 is recruited into the Apaf-1-pro-caspase-9 complex via interaction with pro-caspase-9. Interacts with APIP. Interacts (via CARD and NACHT domains) with NAIP/BIRC1 (via NACHT domain). Interacts with CIAO2A (PubMed:25716227).
Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis.
Physiological concentrations of calcium ions negatively affect the assembly of apoptosome by inhibiting nucleotide exchange in the monomeric form.
The CARD domain mediates interaction with APIP.
The monomeric form is autoinhibited in a closed conformation through a bound ADP at the nucleotide binding site. Exchange of ADP for ATP and binding of cytochrome c trigger a large conformational change where the first WD repeat region swings out, allowing the NB-ARC domain to rotate and expose the contact areas for oligomerization (By similarity).
Ubiquitous. Highest levels of expression in adult spleen and peripheral blood leukocytes, and in fetal brain, kidney and lung. Isoform 1 is expressed in heart, kidney and liver.
Interacts with IFT27, IFT81, IFT172, ATP6V1E1, HK1, LDHC, MAPRE1 and HSPA2.
Plays an essential role in male fertility, sperm intra-flagellar transport, and tail assembly. Binds, in a GTP-regulated manner, to a specific set of effector proteins including key proteins involved in cilia development and function and delivers them into the growing sperm tail.
Highest level in lung. High level in ovary, moderate levels in heart, kidney, placenta, skeletal muscle and spleen (at protein level). Pancreas and spleen express a shorter isoform (at protein level).
Osteosarcoma cells (U2OS) lacking KIF2B show disorganised often monopolar mitotic spindles, severely reduced velocity of chromosome movement and blocked cytokinesis. Bipolar mitotic spindles can be restored by simultaneous depletion of KIF2B, KIFC1 and NUMA1.
Phosphorylation at Thr-125 by PLK1 is required for activity in the correction of kinetochore-microtubules attachment errors, while phosphorylation at Ser-204 also by PLK1 is required for the kinetochore localization and activity in prometaphase.
Plus end-directed microtubule-dependent motor required for spindle assembly and chromosome movement. Has microtubule depolymerization activity (PubMed:17538014). Plays a role in chromosome congression (PubMed:23891108).
Interacts with BRI3BP (PubMed:17943721). Interacts (via C-terminal) with SMARCA4; the interaction regulates transcriptional expression of thermogenic genes in brown adipose tissue (By similarity).
Kidney, liver, skeletal muscle, heart and brain. Overexpressed in various tumors including leukemia, lymphoma, and carcinomas of the breast, kidney, ovary, stomach, colon and uterine cervix.
Plays an essential role for mitochondrial structure and function, as well as thermogenesis of brown adipocytes. In brown adipose tissue also localizes in the nucleus where it interacts with the chromatin remodeler SMARCA4 to regulate thermogenic genes expression, such as UCP1 (By similarity). May regulate phagocytosis and inflammatory responses to lipopolysaccharide in macrophages (PubMed:31980577). Involved in tumorigenesis and may function as a negative regulator of the p53/TP53 (PubMed:12879013).
Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter KLHDC10 (PubMed:23102700, PubMed:29779948, PubMed:33909987). Interacts (via the 6 Kelch repeats) with PPP5C (PubMed:23102700).
Expressed in fetal brain, liver, lung, kidney and placenta.
Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:33909987). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (PubMed:29779948, PubMed:33909987). The CRL2(KLHDC10) complex specifically recognizes proteins with a proline-glycine (Pro-Gly) or an alanine tail (CAT tail) at the C-terminus, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:33909987). The CRL2(KLHDC10) complex is involved in the ribosome-associated quality control (RQC) pathway, which mediates the extraction of incompletely synthesized nascent chains from stalled ribosomes: CRL2(KLHDC10) acts downstream of NEMF and recognizes CAT tails associated with stalled nascent chains, leading to their ubiquitination and degradation (PubMed:33909987). Participates in the oxidative stress-induced cell death through MAP3K5 activation (PubMed:23102700). Inhibits PPP5C phosphatase activity on MAP3K5 (PubMed:23102700). Acts as a regulator of necroptosis (By similarity).
Expressed in testis, heart, lung, and weakly expressed in brain, liver, muscle, placenta and small intestine (PubMed:19369242). Expressed in the retina, found in the cone photoreceptors, Mueller cells, cone pedicles and in the innermost retinal layer (PubMed:19369242).
Homodimer; via C-terminus (PubMed:17209048). Interacts with MYH9 (PubMed:22693546). Interacts with SAFB/SAFB1 (PubMed:22693546).
Transcriptional regulator that binds to poly-guanine tracts in gene promoters and activates transcription (By similarity). Able to bind single- and double-stranded DNA and RNA (By similarity).
Binds polysaccharides in a Ca(2+)-independent manner (By similarity).
Binds DNA as a monomer (PubMed:30322619, PubMed:30540931). Interacts (via C-terminus) with EP300 and CREBBP (PubMed:26951377).
DUX genes are present in 3.3-kilobase elements, a tandem repeat family scattered in the genome found on the short arms of all acrocentric chromosomes as well as on several other chromosomes.
Isoform 1: Detected in embryos at the 4-cell stage. Not detected in embryos at the 2-cell stage, or at the 8-cell stage (at protein level). Detected in embryos at the 4-cell stage. Not detected in embryos at the 2-cell stage, or at the 8-cell stage (PubMed:28459457). Detected in induced pluripotent (iPS) cells, but expression is suppressed upon differentiation to embryoid bodies. Isoform 2: Detected in embryoid bodies derived from induced pluripotent (iPS) cells, but not in the induced pluripotent (iPS) cells themselves (PubMed:21060811).
Isoform 1: Does not seem to be expressed in normal muscle, but is detected in muscle of individuals with FSHD, and also in testis (at protein level) (PubMed:21060811, PubMed:17984056). Isoform 1: Does not seem to be expressed in normal muscle, but in muscle of individuals with FSHD, where it may be toxic to cells (PubMed:21060811, PubMed:17984056). Isoform 2: Detected in skeletal muscle, fibroblasts and testis from healthy individuals (PubMed:21060811).
Probably inactive as a transcriptional activator, due to the absence of the C-terminal region that is important for transcriptional activation. Can inhibit transcriptional activation mediated by isoform 1. Heterologous expression of isoform 2 has no deleterious effect on cell survival.
The C-terminal region is required for efficient activation of transcription from target promoters (PubMed:26951377, PubMed:29618456). It mediates interaction with EP300 and CREBBP (PubMed:26951377).
The gene represented in this entry is involved in disease pathogenesis. The disease is caused by deletion of an integral number of units of a 3.3-kb tandem repeats, termed D4Z4 macrosatellite, located on chromosome 4q35. In unaffected subjects, the D4Z4 array consists of 11-150 repeats, while in FSHD1 patients, the array is reduced to 1-10 repeats (PubMed:19320656). DUX4 is located in D4Z4 macrosatellite which is epigenetically repressed in somatic tissues. D4Z4 chromatin relaxation in FSHD1 results in inefficient epigenetic repression of DUX4 and a variegated pattern of DUX4 protein expression in a subset of skeletal muscle nuclei. Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death.
The two homeobox domains are arranged in a head-to-head orientation when bound to double-stranded DNA, each domain binding to one of the two DNA strands. Together, the homeobox domains can be considered to bind DNA with the consensus sequence 5'-TAATCTAATCA-3', but due to the head-to-head orientation of the DNA-bound domains, the first homeobox domain binds to the consensus sequence 5'-TAAT-3', and the second homeobox domain binds DNA on the opposite strand, with the consensus sequence 5'-TGAT-3' (PubMed:30322619, PubMed:30540931). Both homeobox domains confer nuclear targeting (PubMed:15709750).
Transcription factor that is selectively and transiently expressed in cleavage-stage embryos (PubMed:28459457). Binds to double-stranded DNA elements with the consensus sequence 5'-TAATCTAATCA-3' (PubMed:28459457, PubMed:28459454, PubMed:29572508, PubMed:30540931, PubMed:30315230). Binds to chromatin containing histone H3 acetylated at 'Lys-27' (H3K27ac) and promotes deacetylation of H3K27ac. In parallel, binds to chromatin that lacks histone H3 acetylation at 'Lys-27' (H3K27ac) and recruits EP300 and CREBBP to promote acetylation of histone H3 at 'Lys-27' at new sites (PubMed:26951377). Involved in transcriptional regulation of numerous genes, primarily as transcriptional activator, but mediates also repression of a set of target genes (PubMed:17984056, PubMed:27378237, PubMed:26951377, PubMed:28459457, PubMed:28459454, PubMed:29618456, PubMed:30540931, PubMed:29572508). Promotes expression of ZSCAN4 and KDM4E, two proteins with essential roles during early embryogenesis (PubMed:27378237, PubMed:26951377, PubMed:28459457, PubMed:29618456). Heterologous expression in cultured embryonic stem cells mediates also transcription of HERVL retrotransposons and transcripts derived from ACRO1 and HSATII satellite repeats (PubMed:28459457). May activate expression of PITX1 (PubMed:17984056). May regulate microRNA (miRNA) expression (PubMed:24145033). Inappropriate expression can inhibit myogenesis and promote apoptosis (PubMed:26951377, PubMed:28935672, PubMed:29618456).
Available under the names Glucagon (Eli Lilly) and GlucaGen or Glucagon Novo Nordisk (Novo Nordisk). Used to treat severe hypoglycemia in insulin-dependent diabetics.
In the glucagon antagonist, His-53 and Phe-58 are missing. This antagonist has been successfully utilized to reduce glucose concentration in vivo.
Induced in response to nutrient ingestion.
May modulate gastric acid secretion and the gastro-pyloro-duodenal activity. May play an important role in intestinal mucosal growth in the early period of life.
Plays a key role in glucose metabolism and homeostasis. Regulates blood glucose by increasing gluconeogenesis and decreasing glycolysis. A counterregulatory hormone of insulin, raises plasma glucose levels in response to insulin-induced hypoglycemia. Plays an important role in initiating and maintaining hyperglycemic conditions in diabetes.
Potent stimulator of glucose-dependent insulin release. Also stimulates insulin release in response to IL6 (PubMed:22037645). Plays important roles on gastric motility and the suppression of plasma glucagon levels. May be involved in the suppression of satiety and stimulation of glucose disposal in peripheral tissues, independent of the actions of insulin. Has growth-promoting activities on intestinal epithelium. May also regulate the hypothalamic pituitary axis (HPA) via effects on LH, TSH, CRH, oxytocin, and vasopressin secretion. Increases islet mass through stimulation of islet neogenesis and pancreatic beta cell proliferation. Inhibits beta cell apoptosis (Probable).
Production by islet alpha cell is increased by IL6.
Proglucagon is post-translationally processed in a tissue-specific manner in pancreatic A cells and intestinal L cells. In pancreatic A cells, the major bioactive hormone is glucagon cleaved by PCSK2/PC2. In the intestinal L cells PCSK1/PC1 liberates GLP-1, GLP-2, glicentin and oxyntomodulin. GLP-1 is further N-terminally truncated by post-translational processing in the intestinal L cells resulting in GLP-1(7-37) GLP-1-(7-36)amide. The C-terminal amidation is neither important for the metabolism of GLP-1 nor for its effects on the endocrine pancreas.
Release is stimulated by hypoglycemia and inhibited by hyperglycemia, insulin, and somatostatin.
Secreted from enteroendocrine cells throughout the gastrointestinal tract.
Secreted from enteroendocrine cells throughout the gastrointestinal tract. Also secreted in selected neurons in the brain.
Secreted in the A cells of the islets of Langerhans (PubMed:22037645). Secreted from enteroendocrine L cells throughout the gastrointestinal tract (PubMed:22037645). Also secreted in selected neurons in the brain.
Secreted in the A cells of the islets of Langerhans.
Significantly reduces food intake. Inhibits gastric emptying in humans. Suppression of gastric emptying may lead to increased gastric distension, which may contribute to satiety by causing a sensation of fullness.
Stimulates intestinal growth and up-regulates villus height in the small intestine, concomitant with increased crypt cell proliferation and decreased enterocyte apoptosis. The gastrointestinal tract, from the stomach to the colon is the principal target for GLP-2 action. Plays a key role in nutrient homeostasis, enhancing nutrient assimilation through enhanced gastrointestinal function, as well as increasing nutrient disposal. Stimulates intestinal glucose transport and decreases mucosal permeability.
Inhibits CBL-SH3KBP1 complex mediated down-regulation of EGFR signaling by sequestration of SH3KBP1. Binds to SH3KBP1 and prevents its interaction with CBL and inhibits translocation of SH3KBP1 to EGFR containing vesicles upon EGF stimulation.
Monomer (PubMed:28963344). Interacts with CUL3; interaction is direct and forms a 5:5 heterodecamer (PubMed:28963344). Interacts (via PXXXPR motifs) with SH3KBP1 (via SH3 domains) (By similarity). Directly interacts with cathepsin B/CTSB (PubMed:16733801).
Belongs to the potassium channel family. G (TC 1.A.1.2) subfamily. Kv6.3/KCNG3 sub-subfamily.
Expressed in the brain, liver, testis, small intestine, colon, thymus and adrenal gland (PubMed:11852086, PubMed:12060745).
Heterotetramer with KCNB1 (PubMed:11852086, PubMed:12060745, PubMed:19074135). Does not form homomultimers (PubMed:12060745).
Potassium channel subunit that does not form functional channels by itself (PubMed:11852086). Can form functional heterotetrameric channels with KCNB1; this promotes a reduction in the rate of activation and inactivation of the delayed rectifier voltage-gated potassium channel KCNB1 (PubMed:11852086, PubMed:19074135).
May activate the lysosomal degradation of sphingolipids.
Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalosomes. Cell-surface coreceptor of Wnt/beta-catenin signaling, which plays a pivotal role in bone formation. The Wnt-induced Fzd/LRP6 coreceptor complex recruits DVL1 polymers to the plasma membrane which, in turn, recruits the AXIN1/GSK3B-complex to the cell surface promoting the formation of signalosomes and inhibiting AXIN1/GSK3-mediated phosphorylation and destruction of beta-catenin. Required for posterior patterning of the epiblast during gastrulation (By similarity).
Dual phosphorylation of cytoplasmic PPPSP motifs sequentially by GSK3 and CK1 is required for AXIN1-binding, and subsequent stabilization and activation of beta-catenin via preventing GSK3-mediated phosphorylation of beta-catenin. Phosphorylated, in vitro, by GRK5/6 within and outside the PPPSP motifs. Phosphorylation at Ser-1490 by CDK14 during G2/M phase leads to regulation of the Wnt signaling pathway during the cell cycle. Phosphorylation by GSK3B is induced by RPSO1 binding and inhibited by DKK1. Phosphorylated, in vitro, by casein kinase I on Thr-1479.
Homodimer; disulfide-linked. Forms phosphorylated oligomer aggregates on Wnt-signaling. Forms a WNT-signaling complex formed of a WNT protein, a FZD protein and LRP5 or LRP6. Interacts (via the extracellular domain) with WNT1; the interaction is enhanced by prior formation of the Wnt/Fzd complex. Interacts (via the beta-propeller regions 3 and 4) with WNT3A. Interacts (via the beta-propeller regions 1 and 2) with WNT9B. Interacts with FZD5; the interaction forms a coreceptor complex for Wnt signaling and is inhibited by DKK1 and DRAXIN. Interacts (via beta propeller region) with DKK1; the interaction inhibits FZD5/LRP6 complex formation. Interacts with DKK2. Interacts with C1orf187/DRAXIN; the interaction inhibits Wnt signaling (By similarity). Interacts (via the phosphorylated PPPSP motifs) with AXIN1; the interaction recruits the AXIN1/GSK3B complex to cell surface LRP6 signalosomes. Interacts with GRB10; the interaction prevents AXIN1 binding, thus negatively regulating the Wnt signaling pathway (By similarity). Interacts (via the extracellular domain) with RSPO1; the interaction activates Wnt/beta-catenin signaling. Interacts (via the extracellular domain) with RSPO3 (via the cysteine rich domain); the interaction activates Wnt/beta-catenin signaling. Interacts (via the beta-propeller regions 1 and 2) with SOST; the interaction competes with DKK1 for binding for inhibiting beta-catenin signaling. Interacts with MESD; the interaction prevents the formation of LRP6 aggregates and targets LRP6 to the plasma membrane (By similarity). Interacts (via the cytoplasmic domain) with CSNKIE; the interaction phosphorylates LRP6, binds AXIN1 and inhibits AXIN1/GSK3B-mediated phosphorylation of beta-catenin. Interacts with MACF1. Interacts with DAB2; the interaction involves LRP6 phosphorylation by CK2 and sequesters LRP6 towards clathrin-mediated endocytosis. Interacts with TMEM198. Interacts with CAPRIN2; the interaction promotes LRP6 phosphorylation at Ser-1490 (PubMed:18762581, PubMed:25331957). Found in a complex with CAPRIN2, CCNY and CDK14 during G2/M stage; CAPRIN2 functions as a scaffold for the complex by binding to CCNY via its N terminus and to CDK14 via its C terminus (PubMed:27821587). Interacts with LYPD6 (via NxI motif) (PubMed:23987510, PubMed:30069874). Forms a ternary complex with DKK1 and KREM1 (PubMed:27524201). Interacts with KREM1 in a DKK1-dependent manner (PubMed:17804805). Interacts with MDK: this interaction is calcium dependent (By similarity). Interacts with LMBR1L (PubMed:31073040).
Mono-ubiquitinated which retains LRP6 in the endoplasmic reticulum. Ubiquitinated by ZNRF3, leading to its degradation by the proteasome.
N-glycosylation is required for cell surface location.
Palmitoylation on the two sites near the transmembrane domain leads to release of LRP6 from the endoplasmic reticulum.
The PPPSP motifs play a central role in signal transduction by being phosphorylated, leading to activate the Wnt signaling pathway.
The YWTD-EGF-like domains 1 and 2 are required for the interaction with Wnt-frizzled complex. The YWTD-EGF-like domains 3 and 4 are required for the interaction with DKK1.
Undergoes gamma-secretase-dependent regulated intramembrane proteolysis (RIP). The extracellular domain is first released by shedding, and then, through the action of gamma-secretase, the intracellular domain (ICD) is released into the cytoplasm where it is free to bind to GSK3B and to activate canonical Wnt signaling.
Widely coexpressed with LRP5 during embryogenesis and in adult tissues.
Expressed in many tissues. Most abundant in adult thymus and fetal liver.
Has two structurally independent, non-interacting domains: LEM-like (also called LAP2-N or LEM-D) and LEM (also called LAP2-C or LEM-B). LEM-like binds DNA while LEM interacts with BANF1.
Interacts with LMNA, BANF1 and RB1 and with chromosomes. Associates directly or indirectly with lamins at specific cell-cycle stages. Interacts with CMTM6 (PubMed:28813417).
Interacts with LMNB1, LMNB2, BANF1, AKAP8L, GMCL and chromosomes (By similarity). Isoform Zeta interacts with BANF1/BAF and may sequester it in the cytoplasm.
May be involved in the structural organization of the nucleus and in the post-mitotic nuclear assembly. Plays an important role, together with LMNA, in the nuclear anchorage of RB1.
May help direct the assembly of the nuclear lamina and thereby help maintain the structural organization of the nuclear envelope. Possible receptor for attachment of lamin filaments to the inner nuclear membrane. May be involved in the control of initiation of DNA replication through its interaction with NAKAP95.
Mitosis-specific phosphorylation specifically abolishes its binding to lamin B and chromosomes.
Phosphorylated in a mitose-specific manner.
TP and TP5 may play a role in T-cell development and function. TP5 is an immunomodulating pentapeptide.
TP5 is available under the names Timunox (Cilag), Sintomodulina (Italofarmaco) and Mepentil (Recordati). Used in primary and secondary immune deficiencies, autoimmunity, infections and cancer.
The C-terminal domain forms a four-stranded coiled coil.
The N-terminal part contains two structurally independent, non-interacting domains: LEM-like (also called LAP2-N or LEM-D) and LEM (also called LAP2-C or LEM-B). LEM-like binds DNA while LEM interacts with BANF1.
Thymopoietin (TP) and Thymopentin (TP5) may play a role in T-cell development and function. TP5 is an immunomodulating pentapeptide.
Secreted proximal epididymal protein required for post-testicular sperm maturation and male fertility. May be involved in sperm adhesion to the egg zona pellucida. Does not have ribonuclease activity (By similarity).
The N-terminus is blocked. Glycosylated (By similarity).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. 5-hydroxytryptamine receptor (TC 1.A.9.2) subfamily. HTR3C sub-subfamily.
Expressed in many tissues including adult brain, colon, intestine, lung, muscle and stomach as well as fetal colon and kidney.
The HA-stretch region of HTR3C seems to confer increased conductance to HTR3A/HTR3C heteropentamers compared to that of HTR3A homopentamers.
Involved in specifying the paraxial, but not dorsal, mesoderm. May regulate the expression of T-box transcription factors required for mesoderm formation and differentiation (By similarity).
Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition (By similarity). May be involved in apoptosis regulation. Necessary for signal transduction through the sonic hedgehog (Shh) signaling pathway.
The disease is caused by variants affecting the gene represented in this entry. TCTN3-mutated fibroblasts from JBTS18 patients fail to respond to Shh agonists suggesting that at least some of the defects in affected individuals may be secondary to reduced Shh signaling (PubMed:22883145).
An excellent marker of acinar cell differentiation in the pancreas.
Component of the pancreas transcription factor 1 complex (PTF1) which is composed of TCF3/p75, TCF12/p64 and PTF1A/p48. TCF3 is responsible for the nuclear import of the p48/p64 complex. Interacts with TCF3 and RBPSUH/RBP-Jkappa (By similarity).
Pancreas-specific (at protein level). Loss of expression is seen in ductal type pancreas cancers.
The disease is caused by variants affecting the gene represented in this entry. In some families with pancreatic agenesis, disease causing mutations affect the sequence and activity of an enhancer region of 400-bp located 25 kb downstream of PTF1A (PubMed:24212882).
Transcription factor implicated in the cell fate determination in various organs. Binds to the E-box consensus sequence 5'-CANNTG-3'. Plays a role in early and late pancreas development and differentiation. Important for determining whether cells allocated to the pancreatic buds continue towards pancreatic organogenesis or revert back to duodenal fates. May be involved in the maintenance of exocrine pancreas-specific gene expression including ELA1 and amylase. Required for the formation of pancreatic acinar and ductal cells. Plays an important role in cerebellar development. Directly regulated by FOXN4 and RORC during retinal development, FOXN4-PTF1A pathway plays a central role in directing the differentiation of retinal progenitors towards horizontal and amacrine fates.
Belongs to the membrane-bound acyltransferase family. Porcupine subfamily.
Interacts with WNT1, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A and WNT7B.
Isoform 1 is expressed in fetal brain, brain, amygdala, caudate nucleus, cerebellum, hippocampus, pituitary, thalamus, heart, skeletal muscle and testis. Isoform 4 is expressed in amygdala, corpus callosum, hippocampus, spinal cord, kidney, liver, lung, spleen, uterus, testis. Isoform 2 and isoform 3 are expressed in substantia negra, spinal cord, heart and lung.
Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins. Serine palmitoleoylation of WNT proteins is required for efficient binding to frizzled receptors.
The sequence differs from that shown upstream of position 63 for unknown reasons.
Was initially thought to mediate palmitoylation of Wnt proteins (PubMed:24292069). It was later shown that instead it acts as a serine O-palmitoleoyltransferase that mediates the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1), to Wnt proteins.
Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates (PubMed:36586411). Has a palmitoyltransferase activity toward gephyrin/GPHN, regulating its clustering at synapses and its function in gamma-aminobutyric acid receptor clustering (By similarity). Thereby, indirectly regulates GABAergic synaptic transmission (By similarity). Acts as an inhibitor of the NLRP3 inflammasome by mediating palmitoylation of NLRP3, thereby promoting NLRP3 degradation by the chaperone-mediated autophagy (CMA) process (PubMed:36586411).
Proton-sensing G-protein coupled receptor couples to multiple intracellular signaling pathways, including GNAS/cAMP, GNAQ/phospholipase C (PLC), and GNA12/GNA13/Rho pathways (PubMed:12955148, PubMed:17462861, PubMed:22110680, PubMed:20211729). Acidosis-induced GPR4 activation increases paracellular gap formation and permeability of vascular endothelial cells through the GNA12/GNA13/Rho GTPase signaling pathway (PubMed:32058960). In the brain may mediate central respiratory sensitivity to CO(2)H(+) (By similarity).
Was originally thought to be a receptor for sphingosylphosphorylcholine and lysophosphatidylcholine (PubMed:11535583). However, this work has been retracted.
Belongs to the peroxiredoxin-like PRXL2 family. PRXL2C subfamily.
May regulate positively ERK1/2 signaling and AKT1 activation leading to HIF1A up-regulation with an increased expression of glycolysis genes and enhanced glycolysis.
Interacts (via C-terminus) with TESK1 (via both C- and N-termini); the interaction inhibits TESK1 kinase activity (PubMed:12027893, PubMed:15584898). Interacts with RAF1 (PubMed:12717443). Interacts with CAV1 (via C-terminus) (By similarity).
Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras (PubMed:12027893). Probably impairs the formation of GTP-Ras (PubMed:12027893). Inhibits Ras-independent, but not Ras-dependent, activation of RAF1 (PubMed:12717443). Represses integrin-mediated cell spreading via inhibition of TESK1-mediated phosphorylation of cofilin (PubMed:15584898).
The Cys-rich domain is responsible for the localization of the protein to the membrane ruffles.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in SPRY4 also have a heterozygous mutation in another HH-associated gene including DUSP6 and FGFR1 (PubMed:23643382).
A chromosomal aberration involving FBXO25 is a cause of X-linked intellectual disability (XLID). Translocation t(X;8)(p11.22;p23.3) with SHROOM4.
Part of a SCF (SKP1-cullin-F-box) protein ligase complex consisting of FBXO25, SKP1, CUL1 and RBX1. Interacts directly with SKP1 and CUL1. Interacts (via C-terminus) with beta-actin (via N-terminus).
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. May play a role in accumulation of expanded polyglutamine (polyQ) protein huntingtin (HTT) (By similarity).
The F-box is necessary for the interaction with SKP1.
Expressed in the excretory system, thyroid gland and Wilms tumors.
In developing excretory system, during thyroid differentiation and in adult thyroid.
Transcription factor for the thyroid-specific expression of the genes exclusively expressed in the thyroid cell type, maintaining the functional differentiation of such cells.
Homodecamer; composed of 5 homodimers (PubMed:16730026, Ref.18). Interacts with LTO1 (PubMed:24930674).
Housekeeping enzyme that catalyzes the last step in proline biosynthesis. Can utilize both NAD and NADP, but has higher affinity for NAD. Involved in the cellular response to oxidative stress.
Subject to competitive inhibition by the reaction product proline. Subject to competitive inhibition by stearoyl coenzyme A.
Encoded in an intron of the ZNF512B gene (opposite strand).
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. LepA subfamily.
Promotes mitochondrial protein synthesis. May act as a fidelity factor of the translation reaction, by catalyzing a one-codon backward translocation of tRNAs on improperly translocated ribosomes. Binds to mitochondrial ribosomes in a GTP-dependent manner.
Interacts with ULK1 (PubMed:22613832). May interact with RAB11A and RAB11B, but does not exhibit any GTPase-activating activity toward these proteins (PubMed:22613832). Interacts with TRAPPC8 (PubMed:26711178).
Plays a role in the regulation of starvation-induced autophagosome formation (PubMed:22613832). Together with the TRAPPIII complex, regulates a constitutive trafficking step from peripheral recycling endosomes to the early Golgi, maintaining the cycling pool of ATG9 required for initiation of autophagy.
Gamma-tubulin complex is composed of gamma-tubulin, TUBGCP2, TUBGCP3, TUBGCP4, TUBGCP5 and TUBGCP6. Interacts with NINL. Interacts with ATF5; the ATF5:PCNT:polyglutamylated tubulin (PGT) tripartite unites the mother centriole and the pericentriolar material (PCM) in the centrosome (PubMed:26213385).
May interact with target proteins during translocation into the lumen of the endoplasmic reticulum. May protect unfolded target proteins against degradation and facilitate correct glycosylation (Potential).
A chromosomal aberration involving LHX4 may be a cause of acute lymphoblastic leukemia. Translocation t(1;14)(q25;q32) with IGHG1.
May play a critical role in the development of respiratory control mechanisms and in the normal growth and maturation of the lung. Binds preferentially to methylated DNA (PubMed:28473536).
Heterodimer of an alpha and a beta subunit (PubMed:1918072). Beta-8 (ITGB8) associates with alpha-V (ITGAV) to form ITGAV:ITGB8 (PubMed:1918072, PubMed:22278742). ITGAV:ITGB8 interacts with TGFB1 (PubMed:22278742).
Integrin alpha-V:beta-8 (ITGAV:ITGB8) is a receptor for fibronectin (PubMed:1918072). It recognizes the sequence R-G-D in its ligands (PubMed:1918072). Integrin alpha-V:beta-6 (ITGAV:ITGB6) mediates R-G-D-dependent release of transforming growth factor beta-1 (TGF-beta-1) from regulatory Latency-associated peptide (LAP), thereby playing a key role in TGF-beta-1 activation on the surface of activated regulatory T-cells (Tregs) (Probable). Required during vasculogenesis (By similarity).
Placenta, kidney, brain, ovary, uterus and in several transformed cells. Transiently expressed in 293 human embryonic kidney cells.
The VWFA domain (or beta I domain) contains two cation-binding sites: the ligand-associated metal ion-binding site (LIMBS or SyMBS) and the metal ion-dependent adhesion site (MIDAS) (PubMed:31792290). Unlike in the other beta integrins, the cation-binding site adjacent MIDAS site (ADMIDAS) in ITGB8 is not functional due to the presence of two Asn residues instead of 2 Asp residues (PubMed:31792290). This domain is also part of the ligand-binding site (PubMed:31792290).
Interacts (via C-terminus) with CPNE6 (via second C2 domain); this interaction occurs in a calcium-dependent manner in vitro (By similarity). Component of the HRD1 complex, which comprises at least SYNV1/HRD1, DERL1/2, FAM8A1, HERPUD1/HERP, OS9, SEL1L and UBE2J1. FAM8A1 is stabilized by interaction with SYNV1, which prevents its proteasomal degradation. OS9 and UBE2J1 recruitment to the complex may be mediated by SEL1L (PubMed:18502753, PubMed:18264092, PubMed:19084021, PubMed:28827405). Through this complex, may interact with ERLEC1 and HSPA5 (PubMed:18502753). Interacts with HSP90B1 (PubMed:18264092). Interacts with CREB3 (PubMed:20546900).
Lectin which functions in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD). May bind terminally misfolded non-glycosylated proteins as well as improperly folded glycoproteins, retain them in the ER, and possibly transfer them to the ubiquitination machinery and promote their degradation. Possible targets include TRPV4.
Ubiquitously expressed. Found as well in all tumor cell lines analyzed, amplified in sarcomas. Highly expressed in osteosarcoma SJSA-1 and rhabdomyosarcoma Rh30 cell lines. Isoform 2 is the major isoform detected in all cell types examined.
Up-regulated in response to endoplasmic reticulum stress (at protein level).
Catalyzes the cleavage of L-kynurenine (L-Kyn) and L-3-hydroxykynurenine (L-3OHKyn) into anthranilic acid (AA) and 3-hydroxyanthranilic acid (3-OHAA), respectively. Has a preference for the L-3-hydroxy form. Also has cysteine-conjugate-beta-lyase activity.
Expressed in all tissues tested (heart, brain placenta, lung, liver, skeletal muscle, kidney and pancreas). Highest levels found in placenta, liver and lung. Expressed in all brain regions.
Increased levels in several cerebral and systemic inflammatory conditions.
Inhibited by o-methoxybenzoylalanine (OMBA).
It has been reported that this enzyme possesses no measurable activity against L-kynurenine and is subject to inhibition by both L-kynurenine and D-kynurenine at pH 7.9.
Expressed in Paneth cells of the small intestine (at protein level).
Homodimer (PubMed:17088326, PubMed:27076903). Self-assembles into higher-order oligomers termed nanonets, fibril-like structures that entrap microbes (PubMed:22722251). Self-assembly into nanonets seems to protect against proteolytic digestion in duodenal fluid (PubMed:30808760). Interacts with Y.enterocolitica invasin and S.typhimurium fliC/flagellin; the interaction creates an anchoring site for progressive DEFA6 self-assembly into nanonets (PubMed:22722251).
Host-defense peptide that contributes to intestinal innate immunity and mediates homeostasis at mucosal surfaces by forming higher-order oligomers that capture bacteria and prevent microbial invasion of the epithelium (PubMed:15616305, PubMed:25158166, PubMed:25354318, PubMed:28026958, PubMed:17088326). After binding to bacterial surface proteins, undergoes ordered self-assembly to form fibril-like nanonets that surround and entangle bacteria and thereby prevent bacterial invasion across the epithelial barrier (PubMed:22722251). Entangles and agglutinates Gram-negative bacteria, such as E.coli, S.typhimurium and Y.enterocolitica, and Gram-positive bacteria such as L.monocytogenes, thereby protecting the intestine against invasion by enteric bacterial pathogens (PubMed:27076903, PubMed:25158166, PubMed:22722251). Blocks adhesion of C.albicans to intestinal epithelial cells and thereby suppresses fungal invasion of epithelial cells and biofilm formation (PubMed:28026958). Under reducing conditions and in an acidic environment similar to the intestinal milieu, exhibits inhibitory activity against anaerobic bacteria such as B.adolescentis, L.acidophilus and B.breve, as well as B.longum and S.thermophilus, possibly by leading to alterations in bacterial cell envelope structures (PubMed:25354318). The disulfide-linked oxidized form exhibits negligible antimicrobial activity against Gram-negative and Gram-positive bacteria, as compared to the enteric defensin DEFA5 (PubMed:15616305, PubMed:17088326).
Proteolytically cleaved by trypsin at Arg-68; the propeptide is stored in the tissue of the small intestine and the mature peptide is found in the luminal fluid; cleavage may occur during or after release into the lumen (PubMed:27076903). The N-terminal propeptide region suppresses self-assembly and renders DEFA6 propeptide unable to agglutinate bacteria and protect human epithelial cells from bacterial invasion (PubMed:27076903).
Under reducing conditions, naturally present in the gut owing to the low redox potential or enzymatically generated by the thioredoxin system, the disulfide bridges are opened leading to a conformational change of DEF6, thereby changing its antimicrobial spectrum (PubMed:25354318). The reduced form exhibits inhibitory activity against anaerobic bacteria, in contrast to the minimal antimicrobial activity of the disulfide-linked oxidized form (PubMed:15616305, PubMed:25354318, PubMed:17088326). The formation of higher-order nanonets and bacterial entrapment is independent of the redox state (PubMed:30808760).
Homodimer. Heterodimer with a RXR molecule. Binds DNA preferentially as a RAR/RXR heterodimer. Forms a complex with PUS1 and the SRA1 RNA in the nucleus.
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. Required for limb bud development. In concert with RARA or RARB, required for skeletal growth, matrix homeostasis and growth plate function (By similarity).
Found in lymphocytes; preferentially expressed in CD8+ cells.
Interacts with CASP9; with inactive form.
May regulate B-cell receptor (BCR)-induced immature and primary B-cell apoptosis. Plays a role as negative regulator of the canonical NF-kappa-B-activating branch. Controls spontaneous apoptosis through the regulation of BCL2L1 abundance.
Calcium-dependent phospholipid-binding protein that plays a role in ERBB2-mediated tumor cell migration in response to growth factor heregulin stimulation (PubMed:20010870).
Expressed in breast and weakly in prostate and ovarian tissues (PubMed:20010870). Expressed in neutrophils (at protein level) (PubMed:12949241). Widely expressed (PubMed:11041869). Expressed in the brain. Expressed in neutrophil precursors from the bone marrow and peripheral blood (PubMed:12949241). Expressed in primary breast tumors and ovarian endometrioid adenocarcinoma (PubMed:20010870).
Monomer (PubMed:12949241). Interacts with ERBB2 (preferentially with the tyrosine phosphorylated form); this interaction occurs at the cell membrane and is increased in a growth factor heregulin-dependent manner (PubMed:20010870). Interacts with SHC1; this interaction may mediate the binding of CPNE3 with ERBB2 (PubMed:20010870). Interacts with RACK1 (PubMed:20010870).
Phosphorylated on serine and threonine residues (PubMed:11041869).
Was reported to have a protein kinase activity.
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts with BIRC6/bruce (PubMed:18329369). Interacts with MYRIP (By similarity). Interacts with SH3BP1; required for the localization of both SH3BP1 and the exocyst to the leading edge of migrating cells (PubMed:21658605). Interacts with SLC6A9 (By similarity).
May recruit HDACs to the p160 coactivators/nuclear receptor complex to inhibit ligand-dependent transactivation.
Belongs to the 'GDSL' lipolytic enzyme family. Phospholipase B1 subfamily.
Calcium-independent membrane-associated phospholipase that catalyzes complete diacylation of phospholipids by hydrolyzing both sn-1 and sn-2 fatty acyl chains attached to the glycerol backbone (phospholipase B activity) (By similarity). Has dual phospholipase and lysophospholipase activities toward diacylphospholipids. Preferentially cleaves sn-2 ester bonds over sn-1 bonds. Acts as a lipase toward glycerolipid substrates (By similarity). Hydrolyzes fatty acyl chains of diacylglycerols with preference for the sn-2 position and of triacylglycerols with not positional selectivity (By similarity). May also hydrolyze long chain retinyl esters such as retinyl palmitate (By similarity). May contribute to digestion of dietary phospholipids, glycerolipids and retinoids, facilitating lipid absorption at the brush border (By similarity).
Expressed in the epidermis (at protein level).
Undergoes proteolytic cleavage in the ileum.
Interacts with ARMC12 (By similarity). Interacts with PLD6 (PubMed:28852571).
Key enzyme in the regulation of glycerol uptake and metabolism. Essential for male fertility and sperm mitochondrial sheath formation (By similarity). Required for proper arrangement of crescent-like mitochondria to form the mitochondrial sheath during spermatogenesis (By similarity). Can induce mitochondrial clustering through interactions with PLD6 and up-regulation of phosphatidic acid synthesis in the mitochondria (PubMed:28852571).
Testis-specific (PubMed:33536340). Expressed in the midpiece of spermatozoa (PubMed:28852571).
Autoantibodies to NARS1, are often detected in sera from patients with interstitial lung disease (ILD).
Catalyzes the attachment of asparagine to tRNA(Asn) in a two-step reaction: asparagine is first activated by ATP to form Asn-AMP and then transferred to the acceptor end of tRNA(Asn) (PubMed:9421509, PubMed:32738225, PubMed:32788587). In addition to its essential role in protein synthesis, acts as a signaling molecule that induced migration of CCR3-expressing cells (PubMed:30171954, PubMed:12235211). Has an essential role in the development of the cerebral cortex, being required for proper proliferation of radial glial cells (PubMed:32788587).
The N-terminal domain (1-77) recruits and activates specific immune cells by interacting with CCR3-expressing cells.
ASAH2B/ASAH2L is a partial paralog of ASAH2, resulting from a partial duplication of ASAH2 on chromosome 10. It has a polymorphic start codon with a single nucleotide change of the original ASAH2 sequence plus other putative translation start site that might lead to several potential ORFs.
Belongs to the neutral ceramidase family.
In contrast to other members of the family, ASAH2B has no predicted transmembrane domain, and lacks the active site, suggesting that it may be catalytically inactive.
Ubiquitous. Expression is reduced with increasing age and in late-onset Alzheimer disease (LOAD) patients. This reduction is even more pronounced in patients with an affected mother.
Apical polarity protein that plays a central role during the epithelial-to-mesenchymal transition (EMT) at gastrulation, when newly specified mesodermal cells move inside the embryo (By similarity). Acts by promoting cell ingression, the process by which cells leave the epithelial epiblast and move inside the embryo to form a new tissue layer (By similarity). The anisotropic distribution of CRB2 and MYH10/myosin-IIB at cell edges define which cells will ingress: cells with high apical CRB2 are probably extruded from the epiblast by neighboring cells with high levels of apical MYH10/myosin-IIB (By similarity). Plays a role in the maintenance of retinal neuroepithelium organization, structural integrity, adhesion, photoreceptor polarity and retinal photoreceptor layer thickness (By similarity). May play a role in determining the length of cone photoreceptor outer segments and proliferation of late-born progenitor cells (By similarity). Also required for maintenance of the apical polarity complex during development of the cortex (By similarity). Inhibits gamma-secretase-dependent cleavage of APP and secretion of amyloid-beta peptide 40 and amyloid-beta peptide 42, and thereby inhibits gamma-secretase-dependent Notch transcription (PubMed:20299451).
Associates with the gamma-secretase complex via interaction (via the transmembrane domain) with PSEN1/PS1 (PubMed:20299451). Interacts (via intracellular domain) with EPB41L5 (PubMed:17920587). Interacts with PALS1 (By similarity).
Expressed in glomeruli, podocytes of the glomerular capillary loops, and parietal glomerular epithelial cells in the kidney (at protein level) (PubMed:29473663, PubMed:27942854). Expressed in retina, fetal eye and brain (PubMed:15851977). Also expressed in kidney, RPE/choroid, and at low levels in lung, placenta, and heart (PubMed:15851977).
O-glucosylated by POGLUT1 at Ser-267; consists of an O-glucose trisaccharide, in which the O-glucose is elongated by the addition of two xylose residues. O-glucosylation is required for localization at the plasma membrane.
Heterodimerizes with MAU2/SCC4 to form the cohesin loading complex (PubMed:16682347, PubMed:16802858, PubMed:21934712, PubMed:28167679, PubMed:22628566). The NIPBL-MAU2 heterodimer interacts with the cohesin complex composed of SMC1A/B and SMC3 heterodimer, RAD21 and STAG1/SA1 (PubMed:22628566). NIPBL directly contacts all members of the complex, RAD21, SMC1A/B, SMC3 and STAG1 (PubMed:32409525). Interacts directly (via PxVxL motif) with CBX5 (PubMed:15882967, PubMed:20562864). Interacts with ZNF609 (via N-terminus) (By similarity). Interacts with the multiprotein complex Integrator (By similarity). Interacts (via PxVxL motif) with CBX3 (PubMed:28167679).
In embryos, it is expressed in developing limbs and later in cartilage primordia of the ulna and of various hand bones. Sites of craniofacial expression include the cartilage primordium of the basioccipital and basisphenoid skull bones and elsewhere in the head and face, including a region encompassing the mesenchyme adjacent to the cochlear canal. Also expressed in the spinal column, notochord and surface ectoderm sclerotome and what seem to be migrating myoblasts. Expressed in the developing heart in the atrial and ventricular myocardium and in the ventricular tubeculae but absent in the endocardial cushions. Also expressed in the developing esophagus, trachea and midgut loops, in the bronchi of the lung and in the tubules of the metanephros. Expression in organs and tissues not typically affected in CDL (e.g. the developing trachea, bronchi, esophagus, heart and kidney) may reflect a bias towards underreporting of more subtle aspects of the phenotype or problems that typically present later in life. Expressed in the mesenchyme surrounding the cochlear canal possibly reflecting the hearing impairment commonly found. Weakly or not expressed in embryonic brain.
Plays an important role in the loading of the cohesin complex on to DNA. Forms a heterodimeric complex (also known as cohesin loading complex) with MAU2/SCC4 which mediates the loading of the cohesin complex onto chromatin (PubMed:22628566, PubMed:28914604). Plays a role in cohesin loading at sites of DNA damage. Its recruitment to double-strand breaks (DSBs) sites occurs in a CBX3-, RNF8- and RNF168-dependent manner whereas its recruitment to UV irradiation-induced DNA damage sites occurs in a ATM-, ATR-, RNF8- and RNF168-dependent manner (PubMed:28167679). Along with ZNF609, promotes cortical neuron migration during brain development by regulating the transcription of crucial genes in this process. Preferentially binds promoters containing paused RNA polymerase II. Up-regulates the expression of SEMA3A, NRP1, PLXND1 and GABBR2 genes, among others (By similarity).
The C-terminal region containing HEAT repeats and Pro-Xaa-Val-Xaa-Leu (PxVxL) motif are involved in the recruitment of NIPBL to sites of DNA damage.
Widely expressed. Highly expressed in heart, skeletal muscle, fetal and adult liver, fetal and adult kidney. Expressed at intermediates level in thymus, placenta, peripheral leukocyte and small intestine. Weakly or not expressed in brain, colon, spleen and lung.
Directly regulates filament dynamics and has been implicated in a number of complex developmental and morphological processes, including mRNA localization and the establishment of cell polarity.
Binding to ERLEC1 is mediated by the oligosaccharides linked to the kringle domain.
Interacts with ERLEC1. Forms a ternary complex with DKK1 and LRP6.
Receptor for Dickkopf proteins. Cooperates with DKK1/2 to inhibit Wnt/beta-catenin signaling by promoting the endocytosis of Wnt receptors LRP5 and LRP6. Plays a role in limb development; attenuates Wnt signaling in the developing limb to allow normal limb patterning and can also negatively regulate bone formation.
Can be divided into a N-terminal globular domain, a proline-rich P-domain forming an elongated arm-like structure and a C-terminal acidic domain. The P-domain binds one molecule of calcium with high affinity, whereas the acidic C-domain binds multiple calcium ions with low affinity (By similarity).
Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5.
During spermatogenesis, may act as a lectin-independent chaperone for specific client proteins such as ADAM3. Required for sperm fertility (By similarity). CALR3 capacity for calcium-binding may be absent or much lower than that of CALR.
The interaction with glycans occurs through a binding site in the globular lectin domain.
The zinc binding sites are localized to the N-domain.
Increased expression in the majority of primary lung cancers and lung-cell lines tested.
May contribute to specialized endoplasmic reticulum functions in neurons.
May serve as a prognostic marker for lung cancers.
Receptor for the chemokine CCL1/SCYA1/I-309. May regulate monocyte chemotaxis and thymic cell line apoptosis. Alternative coreceptor with CD4 for HIV-1 infection.
Was originally thought to be a receptor for SCYA3 and SCYA17.
Could be a guanine-nucleotide releasing factor. Plays a role in ciliogenesis. Probably regulates cilia formation by regulating actin stress filaments and cell contractility. Plays an important role in photoreceptor integrity. May play a critical role in spermatogenesis and in intraflagellar transport processes (By similarity). May be involved in microtubule organization and regulation of transport in primary cilia.
Heart, brain, placenta, lung, liver, muscle, kidney, retina, pancreas and fetal retinal pigment epithelium. Isoform 3 is found only in the retina. Colocalizes with RPGRIP1 in the outer segment of rod photoreceptors and cone outer segments.
Interacts with SPATA7 (By similarity). Interacts with CEP290 (By similarity). Interacts with WHRN (By similarity). Interacts with PDE6D (PubMed:9990021, PubMed:23559067, PubMed:24981858). Interacts with RPGRIP1 (PubMed:10958648, PubMed:24981858). Interacts with RPGRIP1L (PubMed:19430481, PubMed:24981858). PDE6D, RPGRIP1 and RPGRIP1L may compete for the same binding sites (PubMed:24981858). Isoform 6 interacts with NPM1 (via C-terminus) (PubMed:15772089). Isoform 6 interacts with SMC1A and SMC3 (PubMed:16043481).
The RCC1 repeat region mediates interactions with RPGRIP1.
Interacts with TEFs. Binds to TEAD1/TEF1.
May act as a specific coactivator for the mammalian TEFs. May play a role in the development of skeletal muscles.
Interacts with CFAP53, ODAD1 and ODAD3; the interactions link the outer dynein arms docking complex (ODA-DC) to the internal microtubule inner proteins (MIP) in cilium axoneme.
May be up-regulated during progression from G1 to S phase of the cell cycle. Maximal expression in S or G2 phase.
Microtubule inner protein involved in the attachment of outer dynein arms (ODAs) to dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (PubMed:36191189). Functions at the initial step of left-right asymmetry specification of the visceral organs.
Histone demethylase that specifically demethylates 'Lys-36' of histone H3, thereby playing a central role in histone code. Preferentially demethylates dimethylated H3 'Lys-36' residue while it has weak or no activity for mono- and tri-methylated H3 'Lys-36'. May also recognize and bind to some phosphorylated proteins and promote their ubiquitination and degradation. Required to maintain the heterochromatic state. Associates with centromeres and represses transcription of small non-coding RNAs that are encoded by the clusters of satellite repeats at the centromere. Required to sustain centromeric integrity and genomic stability, particularly during mitosis. Regulates circadian gene expression by repressing the transcriptional activator activity of CLOCK-BMAL1 heterodimer and RORA in a catalytically-independent manner (PubMed:26037310).
Interacts with CBX5/HP1A; the interaction promotes CBX5 localization to chromatin (PubMed:19001877). The SKP1-KDM2A complex interacts with UBB (PubMed:30033217). Part of a SCF (SKP1-cullin-F-box) protein ligase complex (PubMed:30033217).
Mono-ADP-ribosylated at Arg-1020 in response to DNA damage, leading to displacement from chromatin, resulting in increased dimethylation of histone H3 at 'Lys-36'.
The CXXC zinc finger preferentially recognizes nonmethylated CpG DNA, and binding is blocked when the CpG DNA is methylated (PubMed:20417597). It is essential for its ability to repress the transcriptional activator activity of CLOCK-BMAL1 heterodimer (PubMed:26037310).
The JmjC domain mediates demethylation activity and is required for satellite silencing.
Widely expressed, with highest levels in brain, testis and ovary, followed by lung.
Interacts with CTTNBP2; this interaction may regulate dendritic spine distribution of STRN4. Activation of glutamate receptors weakens the interaction with CTTNBP2 (By similarity). Interacts with CTTNBP2NL.
The name 'Zinedin' probably originates from the name of the famous soccer player from Marseille (Zinedine Zidane).
Antigen-presenting molecule specialized in displaying microbial pyrimidine-based metabolites to alpha-beta T cell receptors (TCR) on innate-type mucosal-associated invariant T (MAIT) cells (PubMed:23051753, PubMed:26795251, PubMed:12794138, PubMed:19416870, PubMed:22692454, PubMed:23846752). In complex with B2M preferentially presents riboflavin-derived metabolites to semi-invariant TRAV1-2 TCRs on MAIT cells, guiding immune surveillance of the microbial metabolome at mucosal epithelial barriers (PubMed:26795251, PubMed:24695216, PubMed:20581831). Signature pyrimidine-based microbial antigens are generated via non-enzymatic condensation of metabolite intermediates of the riboflavin pathway with by-products arising from other metabolic pathways such as glycolysis. Typical potent antigenic metabolites are 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OE-RU) and 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), products of condensation of 5-amino-6-D-ribityaminouracil (5-A-RU) with glyoxal or methylglyoxal by-products, respectively (PubMed:24695216). May present microbial antigens to various TRAV1-2-negative MAIT cell subsets, providing for unique recognition of diverse microbes, including pathogens that do not synthesize riboflavin (PubMed:27527800, PubMed:31113973). Upon antigen recognition, elicits rapid innate-type MAIT cell activation to eliminate pathogenic microbes by directly killing infected cells (PubMed:24695216, PubMed:27527800, PubMed:23846752). During T cell development, drives thymic selection and post-thymic terminal differentiation of MAIT cells in a process dependent on commensal microflora (By similarity). Acts as an immune sensor of cancer cell metabolome (PubMed:31959982). May present a tumor-specific or -associated metabolite essential for cancer cell survival to a pan-cancer TCR consisting of TRAV38.2-DV8*TRAJ31 alpha chain paired with a TRBV25.1*TRBJ2.3 beta chain on a non-MAIT CD8-positive T cell clone (MC.7.G5), triggering T cell-mediated killing of a wide range of cancer cell types (PubMed:31959982).
Heterotrimer that consists of MR1, B2M and a metabolite antigen (PubMed:27043408, PubMed:23051753, PubMed:23846752, PubMed:24695216). Forms reversible covalent Schiff base complexes with the microbial metabolite, which serves as a molecular switch triggering complete folding, stable association with B2M and translocation of the ternary complex from endoplasmic reticulum to the plasma membrane (PubMed:27043408, PubMed:23051753, PubMed:23846752, PubMed:24695216). On antigen-presenting cells, the ternary complex interacts with TCR on CD8-positive T cells (PubMed:23846752, PubMed:24695216, PubMed:26795251). The molecular machinery involved in antigen processing remains unknown, but appears to be TAP1-TAP2 and proteasome-independent. Structurally, MR1-B2M heterodimer adopts a topology similar to classical MHC class I molecules, with alpha-1 and alpha-2 domains of MR1 forming the antigen-binding cleft composed of two alpha-helices resting on a floor of 7-stranded anti-parallel beta-pleated sheet (PubMed:23846752, PubMed:24695216, PubMed:26795251). The ribityl moiety of pyrimidine-based antigens is recognized by Tyr-95 residue in the CDR3 alpha loop of the invariant TRAV1-2 TCR (PubMed:23846752, PubMed:24695216, PubMed:26795251).
Homodimerizes and does not associate with B2M.
Reported to be associated with components of the peptide-loading complex, TAPBP, CALR, CANX and PDIA3 (PubMed:23457030, PubMed:12794138). This association in primary cells and its functional relevance is disputable, given that antigen presentation and MAIT cell activation is shown to be TAP1-TAP2 and proteasome-independent.
Several individuals from different ethnic background were analyzed for polymorphism. MR1 was identical in all individuals analyzed, except one. MR1 is not polymorphic.
The alpha-1 domain is a structural part of antigen-binding cleft.
The alpha-2 domain is a structural part of antigen-binding cleft.
Ubiquitous (PubMed:7624800, PubMed:9780177). Low expression is detected in peripheral blood B cells, T cells, monocytes and in bronchial epithelial cells (at protein level) (PubMed:27043408). Expressed in plasmablasts or plasma B cells in the lamina propria of ileum, appendix and colon (at protein level) (PubMed:19760593). Highly expressed on a subset of CD45-positive CD3-positive thymocytes (at protein level) (PubMed:22692454).
Usually inhibited by pterin-based metabolites such as 6-formylpterin (6-FP, a product of folic acid photodegradation). 6-FP competitively inhibits MAIT cell activation by 5-OP-RU (PubMed:28166217). Modulated by commonly prescribed anti-inflammatory drug metabolites. Inhibited by salicilates such as 3-formylsalicylic and 5-formylsalicylic acids. Activated by diclofenac and/or its hydroxy metabolites (PubMed:28166217).
Belongs to the TFIIE beta subunit family.
Recruits TFIIH to the initiation complex and stimulates the RNA polymerase II C-terminal domain kinase and DNA-dependent ATPase activities of TFIIH. Both TFIIH and TFIIE are required for promoter clearance by RNA polymerase.
Tetramer of two alpha and two beta chains (PubMed:1956398). Interacts with FACT subunit SUPT16H (PubMed:10792464). Interacts with ATF7IP (PubMed:19106100). Interacts with SND1 (PubMed:7651391).
Expression levels are tightly regulated during the cell cycle. Strongly up-regulated during late G2 phase and M phase of the mitotic cell cycle. Down-regulated at the G1-S phase transition of the cell cycle.
Interacts with histone H3 that is trimethylated at 'Lys-4' (H3K4me3). Interacts with GSK3B.
Modulates chromatin structure. Required for normal chromosome condensation during the early stages of mitosis. Required for normal chromosome separation during mitosis.
Subject to proteasomal degradation. Stable when bound to chromatin. The soluble form is rapidly degraded.
Common types of chronic kidney disease are associated with tubulointerstitial up-regulation of FAT10. FAT10 may mediate NF-kappa-B activation and may promote tubulointerstitial inflammation in chronic kidney diseases.
Constitutively expressed in mature dendritic cells and B-cells. Mostly expressed in the reticuloendothelial system (e.g. thymus, spleen), the gastrointestinal system, kidney, lung and prostate gland.
Interacts directly with the 26S proteasome. The interaction with NUB1 via the N-terminal ubiquitin domain facilitates the linking of UBD-conjugated target protein to the proteasome complex and accelerates its own degradation and that of its conjugates. Interacts (via ubiquitin-like 1 domain) with the spindle checkpoint protein MAD2L1 during mitosis. Present in aggresomes of proteasome inhibited cells. Interacts with HDAC6 under proteasome impairment conditions. Forms a thioester with UBA6 in cells stimulated with tumor necrosis factor-alpha (TNFa) and interferon-gamma (IFNg). Interacts with SQSTM1 and TP53/p53 (PubMed:25422469).
Rapidly degraded by the proteasome. Cell-cycle regulation with highest expression during the S-phase (at protein level). Induced during dendritic cell maturation. Negatively regulated by p53/TP53. High levels in various gastrointestinal and gynecological cancer cells. Induced in RTECs in common renal diseases including diabetic nephropathy (DN), IgA nephropathy (IgAN), and hypertensive nephrosclerosis (HN), as well as in hepatocellular carcinoma (HCC) and during HIVAN. Inducible by the pro-inflammatory cytokines IFNG/IFN-gamma and TNF in cancers of liver and colon. Repressed by NUB1 (at protein level).
Ubiquitin-like protein modifier which can be covalently attached to target protein and subsequently leads to their degradation by the 26S proteasome, in a NUB1-dependent manner. Probably functions as a survival factor. Conjugation ability activated by UBA6. Promotes the expression of the proteasome subunit beta type-9 (PSMB9/LMP2). Regulates TNF-alpha-induced and LPS-mediated activation of the central mediator of innate immunity NF-kappa-B by promoting TNF-alpha-mediated proteasomal degradation of ubiquitinated-I-kappa-B-alpha. Required for TNF-alpha-induced p65 nuclear translocation in renal tubular epithelial cells (RTECs). May be involved in dendritic cell (DC) maturation, the process by which immature dendritic cells differentiate into fully competent antigen-presenting cells that initiate T-cell responses. Mediates mitotic non-disjunction and chromosome instability, in long-term in vitro culture and cancers, by abbreviating mitotic phase and impairing the kinetochore localization of MAD2L1 during the prometaphase stage of the cell cycle. May be involved in the formation of aggresomes when proteasome is saturated or impaired. Mediates apoptosis in a caspase-dependent manner, especially in renal epithelium and tubular cells during renal diseases such as polycystic kidney disease and Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN).
Belongs to the sodium channel (TC 1.A.1.10) family. SCN7A subfamily.
Lacks the cysteine which covalently binds the conotoxin GVIIJ. This cysteine (position 656) is speculated in other sodium channel subunits alpha to be implied in covalent binding with the sodium channel subunit beta-2 or beta-4.
Belongs to the delta-EF1/ZFH-1 C2H2-type zinc-finger family.
Binds activated SMAD1, activated SMAD2 and activated SMAD3; binding with SMAD4 is not detected (By similarity). Interacts with CBX4 and CTBP1.
Down-regulated by microRNA-221 (miR-221).
Sumoylation on Lys-391 and Lys-866 is promoted by the E3 SUMO-protein ligase CBX4, and impairs interaction with CTBP1 and transcription repression activity.
Transcriptional inhibitor that binds to DNA sequence 5'-CACCT-3' in different promoters (PubMed:16061479, PubMed:20516212). Represses transcription of E-cadherin (PubMed:16061479). Represses expression of MEOX2 (PubMed:20516212).
Acts as a bona fide target gene of p53/TP53. May play a role in the TP53-dependent growth regulatory pathway. May contribute to TP53-mediated apoptosis by regulation of TP53 expression and translocation to the nucleus and nucleolus.
By DNA damage in a p53/TP53-dependent manner. Up-regulated following ionizing radiation in primary squamous cell carcinoma of the lung and in various colon cancer cell lines.
Highly expressed in adult brain, and moderately in adult kidney and testis. Not detected in fetal brain, heart, pancreas, adrenal gland, liver or small intestine.
Widely expressed. Higher expression seen in heart and skeletal muscle.
Loss of OSGIN1 protein disturbs the balance between cell growth, differentiation, and cell death in normal tissue, resulting in uncontrolled growth and formation of tumors.
Regulates the differentiation and proliferation through the regulation of cell death.
Ubiquitous. Highest expression in the ovary, testis, kidney, skeletal muscle and liver (PubMed:11459809, PubMed:14570898, PubMed:15569677). Weakly expressed in spleen, heart, kidney, and pancreas (PubMed:15569677). Highly expressed in tumor cells (at protein level) (PubMed:15569677).
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts with EXOC3L1 (By similarity).
Expressed in the glioblastoma cell line U-87MG, the embryonic kidney cell line HEK293, the pancreatic carcinoma cell line PANC-1, the breast carcinoma cell line MCF-7, the lung cancer cell line NCI-H460, and the chronic myelogenous leukemia cell line K-562.
Plays a role into cellular response to oxidative stress. Decreases cell proliferation.
E3 ubiquitin-protein ligase (PubMed:22529100). May facilitate apoptosis by inhibiting APC/C-Cdh1-mediated poly-ubiquitination and subsequent proteasome-mediated degradation of the pro-apoptotic protein MOAP1 (PubMed:19100260, PubMed:22529100). Regulates the G1/S transition of the cell cycle and DNA damage-induced G2 arrest by stabilizing CDKN1A/p21 (PubMed:23213251). Positively regulates CDKN1A/p21 stability by competing with DTL for CDKN1A/p21 binding, therefore disrupting DCX(DTL) E3 ubiquitin ligase complex-mediated CDKN1A/p21 ubiquitination and degradation (PubMed:23213251).
Isoform 1 interacts with MOAP1 (PubMed:19100260). Isoform 1 and isoform 2 interact with CDKN1A (PubMed:23213251). Isoform 2 interacts (via domain B box-type) with CACTIN (PubMed:26363554).
Regulates the G1/S transition of the cell cycle and DNA damage-induced G2 arrest by stabilizing CDKN1A/p21 (PubMed:23213251). Positively regulates CDKN1A/p21 stability by competing with DTL for CDKN1A/p21 binding, therefore disrupting DCX(DTL) E3 ubiquitin ligase complex-mediated CDKN1A/p21 ubiquitination and degradation (PubMed:23213251). Negatively regulates the canonical NF-kappa-B signaling pathway via stabilization of CACTIN in an ubiquitination-independent manner (PubMed:26363554).
Ubiquitous; highly expressed in brain, heart, kidney, liver, skeletal muscle, spleen and testis.
May be involved in inflammatory process. May regulate cell architecture and adhesion.
Specifically expressed in endothelial cells.
Up-regulated by pro-inflammatory cytokines.
Can form homodimers (via C-terminus) (PubMed:23341463). Interacts (via C-terminus) with WDR62 (via C-terminus) (PubMed:23341463, PubMed:28089251). Interacts with MAPK9 (PubMed:28089251). Interacts (via N-terminus) with NOD2; the interaction is enhanced in presence of muramyl dipeptide (MDP) (PubMed:22700971). Interacts with MAPK10 (By similarity).
Expressed in intestinal mucosa, where it is detected in epithelial cells, endothelial cells, smooth muscle cells and immune cells, such as lymphocytes (PubMed:22700971). Expressed in kidney (PubMed:28089251).
Negative regulator of NOD2 function. It down-regulates NOD2-induced processes such as activation of NF-kappa-B signaling, IL8 secretion and antibacterial response (PubMed:22700971). Involved in JNK signaling pathway (By similarity).
The N-terminal WD40 domain is necessary for the interaction with NOD2 and down-regulation of NOD2 function.
Homodimers and homomultimers. The multimers form ring-like structures with a diameter of 30-40 nm. Binds LGALS1 and LGALS3. Binds ITGB1, COL4A1, COL5A1, COL6A1, FN1 and NID. Interacts with the gamma-tubulin ring complex (gamma-TuRC), composed of gamma-tubulin, TUBGCP2, TUBGCP3, TUBGCP4, TUBGCP5 and TUBGCP6 (PubMed:29162697). The unglycosylated form interacts with PDE4DIP isoform 13/MMG8/SMYLE; this interaction may connect a pericentrosomal complex, made of AKAP9, CDK5RAP2, EB1/MAPRE1 and PDE4DIP, to the gamma-tubulin ring complex (gamma-TuRC) to promote microtubule assembly and acetylation (PubMed:29162697).
Promotes integrin-mediated cell adhesion. May stimulate host defense against viruses and tumor cells.
Ubiquitous. Detected in body fluids such as semen, milk, serum, tears, saliva and urine. Expressed by keratinocytes and fibroblasts.
At 7 and 8 weeks of development, it is highly abundant in the rapidly dividing cells of the central and peripheral nervous systems, the mesenchyme of the frontonasal and mandibular processes and the dermamyotome, and it is expressed in the endodermal derivatives of the foregut, midgut, and hindgut, as well as in the liver, lung, esophagus, and trachea. During midterm fetal stages, 18 and 23 weeks of development, increased expression is observed in the intestinal crypts. Midterm liver and kidney tissues strongly express CLMP in the parenchyma of the lobules and cortex, respectively.
May be involved in the cell-cell adhesion. May play a role in adipocyte differentiation and development of obesity. Is required for normal small intestine development.
Predominantly expressed in epithelial cells within different tissues and in the white adipose tissue. Expressed at high levels in small intestine and placenta, at intermediate levels in the heart, skeletal muscle, colon, spleen, kidney and lung and at low levels in the liver and peripheral blood leukocytes. Highly abundant in the intestine during embryo and fetal development (at protein level).
Up-regulated in mature adipocytes and adipocyte tissue of obese individuals.
Acts as a regulator of Wnt signaling pathway by regulating beta-catenin (CTNNB1) nuclear localization.
Detected in skeletal muscle, kidney, spleen, thyroid, testis, ovary, small intestine, colon and peripheral blood.
As part of a ribonucleoprotein complex composed at least of HNRNPK, HNRNPL and the circular RNA circZNF827 that nucleates the complex on chromatin, may negatively regulate the transcription of genes involved in neuronal differentiation (PubMed:33174841). Could also recruit the nucleosome remodeling and histone deacetylase/NuRD complex to telomeric regions of chromosomes to regulate chromatin remodeling as part of telomere maintenance (PubMed:25150861).
Part of a transcription inhibitory ribonucleoprotein complex composed at least of the circular RNA circZNF827, HNRNPK and HNRNPL (PubMed:33174841). Interacts with the nucleosome remodeling and histone deacetylase/NuRD complex (PubMed:25150861). Interacts with RBBP4; the interaction is direct and recruits RBBP4, a component of the NuRD complex, to telomeres (PubMed:30045876).
The function in telomere maintenance is inferred from experiments in cells displaying alternative lengthening of telomeres/ALT a process specific of cancer cells.
Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase. Interacts with DBF4 (By similarity).
Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Does not bind histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3.
Identified in a complex composed of ACTA1, COBL, GSN AND TMSB4X. Interacts (via WH2 domains) with actin monomers. Interacts with both PACSIN1 and DBNL. Identified in a complex composed of COBL, PACSIN1 and WASL. Interacts with PACSIN1, PACSIN2 and PACSIN3 (By similarity).
Plays an important role in the reorganization of the actin cytoskeleton. Regulates neuron morphogenesis and increases branching of axons and dendrites. Regulates dendrite branching in Purkinje cells (By similarity). Binds to and sequesters actin monomers (G actin). Nucleates actin polymerization by assembling three actin monomers in cross-filament orientation and thereby promotes growth of actin filaments at the barbed end. Can also mediate actin depolymerization at barbed ends and severing of actin filaments. Promotes formation of cell ruffles.
Directly interacts with MDM2; this interaction occurs in the nucleus and does not target DHRS2 to degradation.
NADPH-dependent oxidoreductase which catalyzes the reduction of dicarbonyl compounds. Displays reductase activity in vitro with 3,4-hexanedione, 2,3-heptanedione and 1-phenyl-1,2-propanedione as substrates (PubMed:16685466). May function as a dicarbonyl reductase in the enzymatic inactivation of reactive carbonyls involved in covalent modification of cellular components (PubMed:16685466). Also displays a minor hydroxysteroid dehydrogenase activity toward bile acids such as ursodeoxycholic acid (UDCA) and isoursodeoxycholic acid (isoUDCA), which makes it unlikely to control hormone levels (PubMed:16685466). Doesn't show any activity in vitro with retinoids and sugars as substrates (PubMed:16685466). Attenuates MDM2-mediated p53/TP53 degradation, leading to p53/TP53 stabilization and increased transcription activity, resulting in the accumulation of MDM2 and CDKN1A/p21 (PubMed:20547751). Reduces proliferation, migration and invasion of cancer cells and well as the production of ROS in cancer (PubMed:29106393).
Up-regulated by IL4 and CSF2 in monocytes/macrophages. Down-regulated by bacterial lipopolysaccharides (LPS) and TNF in monocytice-derived dendritic cells. Up-regulated by MYB.
Widely expressed, with highest levels in liver and kidney, followed by heart, spleen, skeletal muscle and placenta. In hemopoietic cells, expressed in dendritic cells, but not in monocytes, macrophages, granulocytes, nor in B and T lymphocytes.
All isoforms except isoform 4 can be incorporated into the mechanistic target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR (PubMed:16962653, PubMed:16919458, PubMed:33378666, PubMed:34519268). Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Interacts with ATF2, MAP3K2 and MAPK8. Interacts with GTP-bound HRAS and KRAS. Interacts with IFNAR2 and SGK1. Isoform 2 interacts with NBN. Isoform 1 interacts with CCDC28B.
Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Within mTORC2, MAPKAP1 is required for complex formation and mTORC2 kinase activity. MAPKAP1 inhibits MAP3K2 by preventing its dimerization and autophosphorylation. Inhibits HRAS and KRAS signaling. Enhances osmotic stress-induced phosphorylation of ATF2 and ATF2-mediated transcription. Involved in ciliogenesis, regulates cilia length through its interaction with CCDC28B independently of mTORC2 complex.
Ubiquitously expressed, with highest levels in heart and skeletal muscle.
Catalyzes the formation of 25-hydroxycholesterol from cholesterol, leading to repress cholesterol biosynthetic enzymes (PubMed:9852097). Plays a key role in cell positioning and movement in lymphoid tissues: 25-hydroxycholesterol is an intermediate in biosynthesis of 7-alpha,25-dihydroxycholesterol (7-alpha,25-OHC), an oxysterol that acts as a ligand for the G protein-coupled receptor GPR183/EBI2, a chemotactic receptor for a number of lymphoid cells (By similarity). May play an important role in regulating lipid metabolism by synthesizing a corepressor that blocks sterol regulatory element binding protein (SREBP) processing (PubMed:9852097). As an interferon-stimulated gene, has broad antiviral activities against a wide range of enveloped viruses, such as vesicular stomatitis virus (VSV) and SARS coronavirus-2 (SARS-CoV-2). Its product, 25-hydroxycholesterol, activates the ER-localized enzyme ACAT to induce internalization of accessible cholesterol on the plasma membrane and restricts SARS-CoV-2 S protein-mediated fusion which inhibits virus replication (PubMed:33239446, PubMed:32944968). In testis, production of 25-hydroxycholesterol by macrophages plays a role in Leydig cell differentiation (By similarity). Required to restrain inflammation in macrophages: production of 25-hydroxycholesterol protects macrophages from cholesterol overload, thereby preventing mitochondrial DNA release and subsequent activation of the AIM2 inflammasome (By similarity).
Induced by interferon (IFN) upon infection by virus like SARS-CoV-2.
Isoform long is highly expressed in osteoclastomas. Isoform short is highly expressed in thymus.
Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (By similarity). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (By similarity). Seems to be directly involved in T-cell activation (PubMed:10329006).
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex (By similarity). The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H (By similarity). The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR (By similarity).
Plays a role as an inducible effector molecule that mediates Fas resistance produced by surface Ig engagement in B cells.
Expressed in both non-smooth muscle tissues as well as smooth muscle tissues.
Microtubule inner protein involved in the attachment of outer dynein arms (ODAs) to dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.
Accumulates in individuals with asthma (at protein levels). Induced by tumor necrosis factor (TNF). Repressed by androgens (e.g. R1881).
Acetylated at Lys-608 by NAA10/ARD1 via a calcium-dependent signaling; this acetylation represses kinase activity and reduces tumor cell migration.
All isoforms including Telokin bind calmodulin. Interacts with SVIL (By similarity). Interacts with CTTN; this interaction is reduced during thrombin-induced endothelial cell (EC) contraction but is promoted by the barrier-protective agonist sphingosine 1-phosphate (S1P) within lamellipodia. A complex made of ABL1, CTTN and MYLK regulates cortical actin-based cytoskeletal rearrangement critical to sphingosine 1-phosphate (S1P)-mediated endothelial cell (EC) barrier enhancement. Binds to NAA10/ARD1 and PTK2B/PYK2.
Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC). Also regulates actin-myosin interaction through a non-kinase activity. Phosphorylates PTK2B/PYK2 and myosin light-chains. Involved in the inflammatory response (e.g. apoptosis, vascular permeability, leukocyte diapedesis), cell motility and morphology, airway hyperreactivity and other activities relevant to asthma. Required for tonic airway smooth muscle contraction that is necessary for physiological and asthmatic airway resistance. Necessary for gastrointestinal motility. Implicated in the regulation of endothelial as well as vascular permeability, probably via the regulation of cytoskeletal rearrangements. In the nervous system it has been shown to control the growth initiation of astrocytic processes in culture and to participate in transmitter release at synapses formed between cultured sympathetic ganglion cells. Critical participant in signaling sequences that result in fibroblast apoptosis. Plays a role in the regulation of epithelial cell survival. Required for epithelial wound healing, especially during actomyosin ring contraction during purse-string wound closure. Mediates RhoA-dependent membrane blebbing. Triggers TRPC5 channel activity in a calcium-dependent signaling, by inducing its subcellular localization at the plasma membrane. Promotes cell migration (including tumor cells) and tumor metastasis. PTK2B/PYK2 activation by phosphorylation mediates ITGB2 activation and is thus essential to trigger neutrophil transmigration during acute lung injury (ALI). May regulate optic nerve head astrocyte migration. Probably involved in mitotic cytoskeletal regulation. Regulates tight junction probably by modulating ZO-1 exchange in the perijunctional actomyosin ring. Mediates burn-induced microvascular barrier injury; triggers endothelial contraction in the development of microvascular hyperpermeability by phosphorylating MLC. Essential for intestinal barrier dysfunction. Mediates Giardia spp.-mediated reduced epithelial barrier function during giardiasis intestinal infection via reorganization of cytoskeletal F-actin and tight junctional ZO-1. Necessary for hypotonicity-induced Ca(2+) entry and subsequent activation of volume-sensitive organic osmolyte/anion channels (VSOAC) in cervical cancer cells. Responsible for high proliferative ability of breast cancer cells through anti-apoptosis.
Can probably be down-regulated by phosphorylation. Tyrosine phosphorylation by ABL1 increases kinase activity, reverses MLCK-mediated inhibition of Arp2/3-mediated actin polymerization, and enhances CTTN-binding. Phosphorylation by SRC at Tyr-464 and Tyr-471 promotes CTTN binding.
In asthmatic patients, overexpression promotes actin filament propulsion, thus contributing to airway hyperresponsiveness. Some MYLK variants may contribute to acute lung injury (ALI) susceptibility. Potential therapeutic target in the treatment of burn edema.
Isoform 1 is activated by phosphorylation on Tyr-464 and Tyr-471. Isoforms which lack these tyrosine residues are not regulated in this way. All catalytically active isoforms require binding to calcium and calmodulin for activation. Repressed by organometallic pyridylnaphthalimide complexes, wortmannin, ML-7 (a synthetic naphthalenesulphonyl derivative that inhibits the binding of ATP to MLCK) and ML-9.
Smooth muscle and non-muscle isozymes are expressed in a wide variety of adult and fetal tissues and in cultured endothelium with qualitative expression appearing to be neither tissue- nor development-specific. Non-muscle isoform 2 is the dominant splice variant expressed in various tissues. Telokin has been found in a wide variety of adult and fetal tissues. Accumulates in well differentiated enterocytes of the intestinal epithelium in response to tumor necrosis factor (TNF).
The C-terminus is deglutamylated by AGTPBP1/CCP1, AGBL1/CCP4 and AGBL4/CCP6, leading to the formation of Myosin light chain kinase, smooth muscle, deglutamylated form. The consequences of C-terminal deglutamylation are unknown (By similarity).
Transcribed from an alternative promoter resulting in the usage of Met-1761 as initiator codon. Has no catalytic activity. Initiator Met is removed.
Transcribed from an alternative promoter resulting in the usage of Met-1761 as initiator codon. Initiator Met is removed.
Transcribed from an alternative promoter resulting in the usage of Met-923 as initiator codon.
A chromosomal aberration involving HMGA2 is associated with a subclass of benign mesenchymal tumors known as lipomas. Translocation t(3;12)(q27-q28;q13-q15) with LPP is shown in lipomas. HMGA2 is also fused with a number of other genes in lipomas.
A chromosomal aberration involving HMGA2 is associated with parosteal lipomas. Translocation t(3;12)(q28;q14) with LPP is also shown in one parosteal lipoma.
A chromosomal aberration involving HMGA2 is associated with pulmonary chondroid hamartomas. Translocation t(3;12)(q27-q28;q14-q15) with LPP is detected in pulmonary chondroid hamartomas.
A chromosomal aberration involving HMGA2 is found in uterine leiomyoma. Translocation t(12;14)(q15;q23-24) with RAD51B. Chromosomal rearrangements involving HMGA2 do not seem to be the principle pathobiological mechanism in uterine leiomyoma.
Expressed predominantly during embryogenesis.
Functions as a transcriptional regulator. Functions in cell cycle regulation through CCNA2. Plays an important role in chromosome condensation during the meiotic G2/M transition of spermatocytes. Plays a role in postnatal myogenesis, is involved in satellite cell activation (By similarity). Positively regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner (PubMed:28796236).
Genetic variations in HMGA2 define the stature quantitative trait locus 9 (STQTL9) [MIM:611547]. Human height is a classic, highly heritable quantitative trait.
Interacts with E4F1 (PubMed:14645522). Interacts with NEK2 (By similarity).
Regulated by cell cycle-dependent phosphorylation which alters its DNA binding affinity. Phosphorylated by NEK2 (By similarity).
E3 ubiquitin-protein ligase that plays an important role in neuronal differentiation, including neurogenesis and gliogenesis, during brain development. During embryonic development initiates neuronal differentiation by inducing cell cycle arrest at the G0/G1 phase through up-regulation of cell-cycle regulatory proteins (PubMed:28684796). Plays a role not only in the fetal period during the development of the nervous system, but also in the adult brain, where it is involved in the maintenance of neural functions and protection of the nervous tissue cells from oxidative stress-induced damage. Exhibits GTPase and E3 ubiquitin-protein ligase activities. Regulates dendritic spine density and synaptic neurotransmission; its ability to hydrolyze GTP is involved in the maintenance of dendritic spine density (By similarity).
Predominantly expressed in brain (PubMed:10574464). Decreased expression in glioma brain tumors as compared to normal brains (at protein level) (PubMed:28684796).
Self-associates. Interacts with SP1 in an oxidative stress-regulated manner. Interacts with SIGMAR1 in an oxidative stress-regulated manner. Interacts with ZBTB16 (via C2H2-type zinc finger domains 1 and 2).
Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9, FANCM and FAAP24. Interacts with FANCM.
Plays a role in DNA repair through recruitment of the FA core complex to damaged DNA. Regulates FANCD2 monoubiquitination upon DNA damage. Induces chromosomal instability as well as hypersensitivity to DNA cross-linking agents, when repressed. Targets FANCM/FAAP24 complex to the DNA, preferentially to single strand DNA.
The C-terminal region is distantly related to RuvA domain 2, a DNA-binding domain.
Interacts with claudin-11/CLDN11 and integrins.
Regulates the proliferation and migration of oligodendrocytes, a process essential for normal myelination and repair.
Component of the small ribosomal subunit (PubMed:23636399). Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661).
Component of the small ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Interacts with actin, ACTL6A, NCOA2, CARM1 and MYD88. Interacts with LRRFIP1 and LRRFIP2. Upon LPS stimulation, LRRFIP2 competes for MYD88-binding. LRRFIP1 constitutively blocks the interaction with MyD88, even in the absence of LPS. Interacts with the nuclear receptors ESR1 and THRB. Interacts with SGK3.
May play a role as coactivator in transcriptional activation by hormone-activated nuclear receptors (NR) and acts in cooperation with NCOA2 and CARM1. Involved in estrogen hormone signaling. Involved in early embryonic development (By similarity). May play a role in regulation of cytoskeletal rearrangements involved in cytokinesis and cell migration, by inhibiting Rac1-dependent paxillin phosphorylation.
Strongest expression in skeletal muscle with high expression also in the heart and lung.
For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.
Phosphorylated at Ser-65 by PINK1 during mitophagy. Phosphorylated ubiquitin specifically binds and activates parkin (PRKN), triggering mitophagy (PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25527291). Phosphorylation does not affect E1-mediated E2 charging of ubiquitin but affects discharging of E2 enzymes to form polyubiquitin chains. It also affects deubiquitination by deubiquitinase enzymes such as USP30 (PubMed:25527291).
Brain; predominant in neural and sensory tissues.
Interacts with RHOH (PubMed:11809807). Interacts with the non-phosphorylated forms of RAB1A, RAB3A, RAB5A, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB35, and RAB43 (PubMed:19570034, PubMed:23815289, PubMed:26824392, PubMed:29125462).
Regulates the GDP/GTP exchange reaction of most Rab proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them. Promotes the dissociation of GDP-bound Rab proteins from the membrane and inhibits their activation. Promotes the dissociation of RAB1A, RAB3A, RAB5A and RAB10 from membranes.
Contains nine structural repeats of about 35 residues, where each repeat contains three helices. The repeats form a left-handed superhelical assembly with a solenoid structure that wraps itself around DNA.
Phosphoprotein with mostly four phosphate groups. While the DNA-binding activity is unaffected by the phosphorylation state, only the phosphorylated form of the protein is active for termination activity. Functioning seems to be regulated by phosphorylation.
Transcription termination factor. Binds to a 28 bp region within the tRNA(Leu(uur)) gene at a position immediately adjacent to and downstream of the 16S rRNA gene; this region comprises a tridecamer sequence critical for directing accurate termination. Binds DNA along the major grove and promotes DNA bending and partial unwinding. Promotes base flipping. Transcription termination activity appears to be polarized with highest specificity for transcripts initiated on the light strand.
Detected in brain and ovary, and at lower levels in heart, small intestine, lung, kidney, skeletal muscle, stomach and spleen (at protein level) (PubMed:18070604). Ubiquitous; expressed in all tissues tested with highest levels in testis (PubMed:14680513).
Functions as transcription repressor, probably via its interaction with histone deacetylase complexes (PubMed:16820529, PubMed:18070604). Involved in the functional recruitment of the class 1 Sin3-histone deacetylase complex (HDAC) to the nucleolus (PubMed:16820529). Binds DNA, apparently without sequence-specificity, and bends bound double-stranded DNA (PubMed:19015240). Binds phosphoinositol phosphates (phosphoinositol 3-phosphate, phosphoinositol 4-phosphate and phosphoinositol 5-phosphate) via the same basic sequence motif that mediates DNA binding and nuclear import (PubMed:19015240, PubMed:26609676).
Functions as transcription repressor; isoform 2 has lower transcription repressor activity than isoform 1 and isoform 3.
Functions as transcription repressor; its activity is marginally lower than that of isoform 1.
Interacts with components of the histone deacetylase complex SIN3A, HDAC1 and HDAC2 (PubMed:16820529). Binds histones and nucleosomes (PubMed:19015240). Interacts with FEZ1 (PubMed:16484223).
The zinc-finger domain mediates direct interaction with DNA and phosphoinositol phosphates (phosphoinositol 3-phosphate, phosphoinositol 4-phosphate and phosphoinositol 5-phosphate) (PubMed:26609676). In vitro oxydation causes reversible disulfide bond formation between Cys residues in the zinc-finger domain and reversible loss of zinc ion binding (PubMed:26609676).
May play an important role in the cellular response to tissue hypoxia. May be either a GDP-fucose transporter that competes with SLC35C1 for GDP-fucose, or a factor that otherwise enhances the fucosylation of Notch and is required for optimal Notch signaling in mammalian cells.
Ubiquitously expressed although the level of expression is tissue dependent. Overexpressed in ovarian cancer.
ADP-ribosylated. ADP-ribosylation by PARP1 is induced by genotoxic stress and correlates with dissociation of FACT from chromatin.
Although related to the peptidase M24 family, this protein lacks conserved active site residues suggesting that it may lack peptidase activity.
Belongs to the peptidase M24 family. SPT16 subfamily.
Component of the FACT complex, a general chromatin factor that acts to reorganize nucleosomes. The FACT complex is involved in multiple processes that require DNA as a template such as mRNA elongation, DNA replication and DNA repair. During transcription elongation the FACT complex acts as a histone chaperone that both destabilizes and restores nucleosomal structure. It facilitates the passage of RNA polymerase II and transcription by promoting the dissociation of one histone H2A-H2B dimer from the nucleosome, then subsequently promotes the reestablishment of the nucleosome following the passage of RNA polymerase II. The FACT complex is probably also involved in phosphorylation of 'Ser-392' of p53/TP53 via its association with CK2 (casein kinase II).
Interacts with MYOG (via C-terminal region) (By similarity). Component of the FACT complex, a stable heterodimer of SSRP1 and SUPT16H (PubMed:10421373). Also a component of a CK2-SPT16-SSRP1 complex which forms following UV irradiation, composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B (PubMed:11239457, PubMed:12393879). Interacts with NEK9 (PubMed:14660563). Binds to histone H2A-H2B (PubMed:10421373). Identified in a centromere complex containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:27499292). Interacts with GTF2E2 (PubMed:10792464).
The C-terminal Glu-rich acidic region is essential for FACT activity.
May be involved in the regulation of feeding, neuroendocrine system, memory, learning and in the afferent pain pathway.
Widely expressed in the central nervous system. High levels are found in substantia nigra, hypothalamus, hippocampus, spinal cord, placenta and fetal brain; lower levels are found in testis, uterus and ovary. Also detected at high levels in colorectal adenocarcinoma.
Belongs to the FARP (FMRFamide related peptide) family.
Morphine modulating peptides. Have wide-ranging physiologic effects, including the modulation of morphine-induced analgesia, elevation of arterial blood pressure, and increased somatostatin secretion from the pancreas. Neuropeptide FF potentiates and sensitizes ASIC1 and ASIC3 channels.
Low-affinity receptor for leukotrienes including leukotriene B4. Mediates chemotaxis of granulocytes and macrophages. The response is mediated via G-proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinities for the leukotrienes is LTB4 > 12-epi-LTB4 > LTB5 > LTB3.
Although UNC93A gene is located in a region of the genome frequently associated with ovarian cancer, no evidence have been found for a tumor suppressor function.
Expressed in testis, small intestine, spleen, prostate and ovary.
May be produced by joining exon 1 to exon 7 thereby eliminating the T-box.
Transcriptional repressor involved in developmental processes (PubMed:10468588). Binds to the palindromic T site 5'-TTCACACCTAGGTGTGAA-3' DNA sequence, or a half-site, which are present in the regulatory region of several genes (PubMed:12000749). Probably plays a role in limb pattern formation (PubMed:10468588). Required for mammary placode induction, and maintenance of the mammary buds during development (By similarity). Involved in branching morphogenesis in both developing lungs and adult mammary glands, via negative modulation of target genes; acting redundantly with TBX2 (By similarity). Required, together with TBX2, to maintain cell proliferation in the embryonic lung mesenchyme; perhaps acting downstream of SHH, BMP and TGFbeta signaling (By similarity). Involved in modulating early inner ear development, acting independently of, and also redundantly with, TBX2 in different subregions of the developing ear (By similarity). Acts as a negative regulator of PML function in cellular senescence (PubMed:22002537).
Induction by cold exposure in brown adipose tissues.
Mitochondrial solute transporter which transports branched-chain amino acid (BCAA; valine, leucine and isoleucine) into mitochondria in brown adipose tissue (BAT) (By similarity). BAT is involved in BCAA catabolism and actively utilizes BCAA in the mitochondria for thermogenesis (PubMed:31435015).
Associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome (PubMed:16951688, PubMed:24316379). Once phosphorylated, IRAK4 dissociates from the receptor complex and then associates with the TNF receptor-associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate complex is required for subsequent NF-kappa-B activation (PubMed:11960013, PubMed:12496252, PubMed:16951688). Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression (PubMed:16951688). Interacts with IL1RL1 (PubMed:16286016). Interacts (when phosphorylated) with IRAK1 (PubMed:33238146). May interact (when phosphorylated) with IRAK3 (PubMed:33238146).
Associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome.
Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens.
Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.
ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Transports a range of endogenous molecules that have a key role in cellular communication and signaling, including cyclic nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile acids, steroid conjugates, urate, and prostaglandins (PubMed:11856762, PubMed:12883481, PubMed:12523936, PubMed:12835412, PubMed:15364914, PubMed:15454390, PubMed:16282361, PubMed:17959747, PubMed:18300232, PubMed:26721430). Mediates the ATP-dependent efflux of glutathione conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4) too. The presence of GSH is necessary for the ATP-dependent transport of LTB4, whereas GSH is not required for the transport of LTC4 (PubMed:17959747). Mediates the cotransport of bile acids with reduced glutathione (GSH) (PubMed:12883481, PubMed:12523936, PubMed:16282361). Transports a wide range of drugs and their metabolites, including anticancer, antiviral and antibiotics molecules (PubMed:11856762, PubMed:12105214, PubMed:15454390, PubMed:18300232, PubMed:17344354). Confers resistance to anticancer agents such as methotrexate (PubMed:11106685).
GSH stimulates the transport of MRP4 (PubMed:17959747). Urate inhibits methotrexate transport but stimulates cGMP transport (PubMed:15454390). Nonsteroidal anti-inflammatory drugs (NSAIDs) strongly suppress the transport of MRP4 substrates (PubMed:12835412).
Interacts (via PDZ-binding motif) with SNX27 (via PDZ domain); this interaction accelerates MRP4 internalization.
N-glycosylated; leading to substrate-selective effects on its transport activity.
Widely expressed, with particularly high levels in prostate, but is barely detectable in liver. sinusoidal membrane of hepatocytes.
Catalyzes the hydrolysis of the 4-position phosphate of phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) (PubMed:20463662, PubMed:15716355). Catalyzes also inositol 1,3,4-trisphosphate and inositol 1,4-bisphosphate (By similarity). Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival (PubMed:30071275) (By similarity). May protect neurons from excitotoxic cell death by regulating the synaptic localization of cell surface N-methyl-D-aspartate-type glutamate receptors (NMDARs) and NMDAR-mediated excitatory postsynaptic current (By similarity).
Displays no 4-phosphatase activity for PtdIns(3,4)P2, Ins(3,4)P2, or Ins(1,3,4)P3.
Isoform 1 is expressed in the platelets, MEG-01 megakaryocytes and Jurkat T-cells. Isoform 2 is expressed in the brain.
Inositol 5-phosphatase which acts on inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate, phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate (PubMed:10753883, PubMed:16824732). Has 6-fold higher affinity for phosphatidylinositol 4,5-bisphosphate than for inositol 1,4,5-trisphosphate (PubMed:10753883). Negatively regulates assembly of the actin cytoskeleton. Controls insulin-dependent glucose uptake among inositol 3,4,5-trisphosphate phosphatases; therefore, is the specific regulator for insulin signaling in skeletal muscle (By similarity).
Interacts with GPR78; necessary for INPP5K localization at the endoplasmic reticulum. Interacts with PAK1; competes with GPR78.
Ubiquitously expressed with highest levels in skeletal muscle, heart and kidney.
Interacts with PCNA and POLD2 (PubMed:12522211). Interacts with SSBP1 (PubMed:16428295). Interacts with PRIMPOL; leading to enhance DNA polymerase activity of PRIMPOL (PubMed:26984527). Interacts with POLH (PubMed:20554254). Interacts with POLD1; leading to stimulate DNA polymerase activity of POLD1 (PubMed:24191025).
Involved in DNA damage tolerance by regulating translesion synthesis (TLS) of templates carrying DNA damage lesions such as 8oxoG and abasic sites (PubMed:24191025). May act by stimulating activity of DNA polymerases involved in TLS, such as PRIMPOL and polymerase delta (POLD1) (PubMed:24191025, PubMed:26984527).
Expressed at high levels in brain and spinal cord and at detectable levels in retinal pigment epithelium. In situ hybridization of adult eye sections localized transcripts only to the perivascular cells, surrounding retinal arterioles, in the ganglion cell/nerve fiber layer. Also expressed by islet cells (at protein level).
G protein-coupled receptor that is activated by the chemokine CCL5/RANTES. Probably coupled to heterotrimeric Gq proteins, it stimulates inositol trisphosphate production and calcium mobilization upon activation. Together with CCL5/RANTES, may play a role in neuron survival through activation of a downstream signaling pathway involving the PI3, Akt and MAP kinases. CCL5/RANTES may also regulate insulin secretion by pancreatic islet cells through activation of this receptor.
Forms a ternary complex of about 140 to 150 kDa with IGF-I or IGF-II and IGFBP-3.
Involved in protein-protein interactions that result in protein complexes, receptor-ligand binding or cell adhesion.
5'-3' DNA helicase involved in DNA damage response by acting as an inhibitor of DNA end resection (PubMed:25617833, PubMed:26774285). Recruitment to single-stranded DNA (ssDNA) following DNA damage leads to inhibit the nucleases catalyzing resection, such as EXO1, BLM and DNA2, possibly via the 5'-3' ssDNA translocase activity of HELB (PubMed:26774285). As cells approach S phase, DNA end resection is promoted by the nuclear export of HELB following phosphorylation (PubMed:26774285). Acts independently of TP53BP1 (PubMed:26774285). Unwinds duplex DNA with 5'-3' polarity. Has single-strand DNA-dependent ATPase and DNA helicase activities. Prefers ATP and dATP as substrates (PubMed:12181327). During S phase, may facilitate cellular recovery from replication stress (PubMed:22194613).
Belongs to the RecD family. HELB subfamily.
Binds to RPA1; this interaction promotes HELB recruitment to chromatin following DNA damage (PubMed:12181327, PubMed:22194613, PubMed:26774285). Interacts with at least two subunits of the DNA polymerase alpha complex (PubMed:12181327): Interacts with CDC45 (PubMed:25933514). Interacts with TOPB1 (PubMed:25933514).
Highly expressed in testis and thymus and weakly in liver, spleen, kidney and brain.
Inhibited by salt concentration greater than 100 mM. Uses either magnesium or manganese ions to support helicase activity. Binds strongly to single-stranded DNA in the absence of ATP but dissociates readily in the presence of 1 mM ATP.
Phosphorylated at Ser-967 by CDK2 during the G1/S transition, resulting in its nuclear export into the cytoplasm (PubMed:15146062, PubMed:26774285). As S phase progresses, its exclusion from the nucleus promotes the activation of long-range resection (PubMed:26774285).
Component of the nuclear pore complex, a complex required for the trafficking across the nuclear membrane.
Component of the p62 complex, a complex composed of NUP62, NUP54, and the isoform p58 and isoform p45 of NUP58. Interacts with NUTF2.
Bri23 peptide prevents aggregation of APP amyloid-beta protein 42 into toxic oligomers.
Glycosylation at Asn-170 is important for cell surface localization, but doesn't affect furin- and ADAM10-induced proteolytic processing.
Homodimer; disulfide-linked. Interacts with SPPL2A and SPPL2B. Interacts with APP. Mature BRI2 (mBRI2) interacts with the APP amyloid-beta A4 protein; the interaction occurs at the cell surface and in the endocytic compartments and enable alpha- and beta-secretase-induced APP cleavage inhibition. Mature BRI2 (mBRI2) interacts with the APP C99; the interaction occurs in the endocytic compartments and enable gamma-secretase-induced C99 cleavage inhibition. May form heterodimers with Bri23 peptide and APP amyloid-beta protein 40. Interacts with ADAM7 in sperm; the interaction increases following capacitation (By similarity).
Mature BRI2 (mBRI2) functions as a modulator of the amyloid-beta A4 precursor protein (APP) processing leading to a strong reduction in the secretion of secretase-processed amyloid-beta protein 40 and amyloid-beta protein 42.
Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition. Plays a role in the induction of neurite outgrowth. Functions as a protease inhibitor by blocking access of secretases to APP cleavage sites.
The disease is caused by variants affecting the gene represented in this entry. A decamer duplication in the 3' region of ITM2B results in the production of the ADan amyloidogenic peptide (PubMed:10781099). ADan is generated by cleavage of the mutated precursor at the normal furin processing site. ADan accumulates in the brain and produces amyloid fibrils responsible for neuronal dysfunction and dementia.
The disease is caused by variants affecting the gene represented in this entry. A single base substitution at the stop codon of ITM2B generates a 277-residue precursor that is cleaved at the normal furin processing site to generate the ABri amyloidogenic peptide (PubMed:10391242). ABri accumulates in the brain and produces amyloid fibrils responsible for neuronal dysfunction and dementia. ABri peptide variant forms fibrils in vitro (PubMed:10526337).
The ectodomain C-terminal part of the imBRI2 is processed by furin producing a secreted Bri23 peptide and a mature BRI2, membrane form (mBRI2). The remaining part of the ectodomain of mBRI2 containing the BRICHOS domain is cleaved by ADAM10 and is secreted (BRI2C, soluble form). The membrane-bound N-terminal fragment (BRI2C, membrane form) is further proteolytically processed by SPPL2A and SPPL2B through regulated intramembrane proteolysis producing a secreted C-peptide and a BRI2 intracellular domain (BRI2 ICD) released in the cytosol. Shedding by ADAM10 facilitates intramembrane cleavage but is not absolutely required for BRI2 ICD generation.
Lactose synthase (LS) is a heterodimer of a catalytic component, beta1,4-galactosyltransferase (beta4Gal-T1) and a regulatory component, alpha-lactalbumin (LA).
Regulatory subunit of lactose synthase, changes the substrate specificity of galactosyltransferase in the mammary gland making glucose a good acceptor substrate for this enzyme. This enables LS to synthesize lactose, the major carbohydrate component of milk. In other tissues, galactosyltransferase transfers galactose onto the N-acetylglucosamine of the oligosaccharide chains in glycoproteins.
Cell adhesion molecule that plays a role in neuronal self-avoidance (PubMed:11453658). Promotes repulsion between specific neuronal processes of either the same cell or the same subtype of cells. Promotes both isoneuronal self-avoidance for creating an orderly neurite arborization in retinal rod bipolar cells and heteroneuronal self-avoidance to maintain mosaic spacing between AII amacrine cells (By similarity). Adhesion molecule that promotes lamina-specific synaptic connections in the retina: expressed in specific subsets of interneurons and retinal ganglion cells (RGCs) and promotes synaptic connectivity via homophilic interactions (By similarity).
Detected in heart, liver, pancreas, skeletal muscle, kidney and in brain, in particular in the amygdala, caudate nucleus, corpus callosum, hippocampus, substantia nigra, thalamus and subthalamus.
Expressed in lung cancer cells, lacks the kinase domain and is most probably secreted.
Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses (By similarity). Interacts (via PDZ-binding motif) with GRIP1 and PICK1 (via PDZ domain) (By similarity).
Receptor tyrosine kinase which binds promiscuously GPI-anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Among GPI-anchored ephrin-A ligands, EFNA5 is a cognate/functional ligand for EPHA7 and their interaction regulates brain development modulating cell-cell adhesion and repulsion. Has a repellent activity on axons and is for instance involved in the guidance of corticothalamic axons and in the proper topographic mapping of retinal axons to the colliculus. May also regulate brain development through a caspase(CASP3)-dependent proapoptotic activity. Forward signaling may result in activation of components of the ERK signaling pathway including MAP2K1, MAP2K2, MAPK1 and MAPK3 which are phosphorylated upon activation of EPHA7.
Interacts with 'R7' family proteins RGS6, RGS7, RGS9 and RGS11. Component of some R7-Gbeta5 complex composed of some R7 protein (RGS6, RGS7, RGS9 or RGS11), Gbeta5 (GNB5) and RGS7BP.
Palmitoylated. Undergoes rapid palmitoylation turnover. De novo and turnover palmitoylation are both mediated by ZDHHC2. Palmitoylation regulates the cell membrane and nuclear shuttling and the regulation of GPCR signaling. Upon depalmitoylation, it is targeted from the plasma membrane into the nucleus. GPCR signaling inhibits depalmitoylation and promotes localization to the plasma membrane.
Regulator of G protein-coupled receptor (GPCR) signaling. Regulatory subunit of the R7-Gbeta5 complexes that acts by controlling the subcellular location of the R7-Gbeta5 complexes. When palmitoylated, it targets the R7-Gbeta5 complexes to the plasma membrane, leading to inhibit G protein alpha subunits. When it is unpalmitoylated, the R7-Gbeta5 complexes undergo a nuclear/cytoplasmic shuttling. May also act by controlling the proteolytic stability of R7 proteins, probably by protecting them from degradation.
The nuclear localization signal is both required for nuclear localization and palmitoylation.
Cell membrane-cytoskeleton-associated protein that plays a role in the regulation of actin polymerization at the barbed end of actin filaments. Prevents F-actin heterodimeric capping protein (CP) activity at the leading edges of migrating cells, and hence generates uncapped barbed ends and enhances actin polymerization, however, seems unable to nucleate filaments (PubMed:16054028). Plays a role in lamellipodial protrusion formations and cell migration (PubMed:19846667).
Expressed in lung, placenta, small intestine, liver, thymus, colon, skeletal muscle, heart and brain. Higher expression in kidney.
Homodimer (PubMed:19846667). Interacts (via C-terminus) with heterodimer capping protein (CP); this interaction uncaps barbed ends capped by CP, enhances barbed-end actin polymerization and promotes lamellipodial formation and cell migration (By similarity). Interacts with heterodimer capping protein (CP) (PubMed:19846667). Interacts with MYO1E (PubMed:19846667). Interacts with TRIO (PubMed:19846667).
Stimulates the autophosphorylation and kinase activity of STK38 and STK38L.
Interacts with CDC42EP4 in a GTP-dependent manner. Interacts with ARHGAP33/TCGAP (By similarity). Interacts with CDC42EP1, CDC42EP2, CDC42EP3, PARD6A, PARD6G (and probably PARD6B) in a GTP-dependent manner. Part of a quaternary complex containing PARD3, some PARD6 protein (PARD6A, PARD6B or PARD6G) and some atypical PKC protein (PRKCI or PRKCZ). Interacts with EXO70 in a GTP-dependent manner. Interacts with GOPC.
May be post-translationally modified by both palmitoylation and polyisoprenylation.
Plasma membrane-associated small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses. Involved in epithelial cell polarization processes. May play a role in CFTR trafficking to the plasma membrane. Causes the formation of thin, actin-rich surface projections called filopodia.
Although it belongs to the peptidase M24 family, it does not contain metal cofactors and lacks aminopeptidase activity.
In cancer cells, isoform 2 is polyubiquitinated leading to its proteasomal degradation and phosphorylation by PKC/PRKCD enhances polyubiquitination.
Isoform 2 interacts with the cytoplasmic domain of non-phosphorylated ERBB3; the interaction requires PKC activity. Interacts with AR. Treatment with HRG leads to dissociation from ERBB3 and increases association with AR. Interacts with NCL/nucleolin. Component of a ribonucleoprotein complex containing at least PA2G4, NCL, TOP1, PABPC2, RPLP0, acetylated histone H1 (HIST1H1A or H1F1), histone H1 2/4, RPL4, RPL8, RPL15, RPL18, RPL18A, RPL21, RPL11, RPL12, RPL28, RPL27, RPLP2 and RPL24. Interacts with HDAC2. Interacts with RB1; the interaction is enhanced upon PA2G4 dephosphorylation. Interacts with AKT1 (By similarity). Isoform 1 and isoform 2 interact with RNF20. Isoform 2 interacts with HUWE1. Interacts with DNAJC21 (PubMed:27346687).
Isoform 2 is undetectable whereas isoform 1 is strongly expressed in cancer cells (at protein level). Isoform 1 and isoform 2 are widely expressed, including heart, brain, lung, pancreas, skeletal muscle, kidney, placenta and liver.
May play a role in a ERBB3-regulated signal transduction pathway. Seems be involved in growth regulation. Acts a corepressor of the androgen receptor (AR) and is regulated by the ERBB3 ligand neuregulin-1/heregulin (HRG). Inhibits transcription of some E2F1-regulated promoters, probably by recruiting histone acetylase (HAT) activity. Binds RNA. Associates with 28S, 18S and 5.8S mature rRNAs, several rRNA precursors and probably U3 small nucleolar RNA. May be involved in regulation of intermediate and late steps of rRNA processing. May be involved in ribosome assembly. Mediates cap-independent translation of specific viral IRESs (internal ribosomal entry site) (By similarity). Regulates cell proliferation, differentiation, and survival. Isoform 1 suppresses apoptosis whereas isoform 2 promotes cell differentiation (By similarity).
Phosphorylated on serine and threonine residues. Phosphorylation is enhanced by HRG treatment. Basal phosphorylation is PKC-dependent and HRG-induced phosphorylation is predominantly PKC-independent. Phosphorylation at Ser-361 by PKC/PRKCD regulates its nucleolar localization.
Binds poly(A) and poly(U) oligoribonucleotides.
Expressed in fetal brain, fetal lung, fetal liver, heart, brain, placenta, lung, liver, muscle, kidney and pancreas.
Expressed in adult liver, kidney, prostate, testis and colon. Much weaker expression in other tissues.
Hydrolyzes nucleoside diphosphates with a preference for GDP, IDP and UDP compared to ADP and CDP (PubMed:15698960, PubMed:10400613). In the lumen of the endoplasmic reticulum, hydrolyzes UDP that acts as an end-product feedback inhibitor of the UDP-Glc:glycoprotein glucosyltransferases. UMP can be transported back by an UDP-sugar antiporter to the cytosol where it is consumed to regenerate UDP-glucose. Therefore, it positively regulates protein reglucosylation by clearing UDP from the ER lumen and by promoting the regeneration of UDP-glucose. Protein reglucosylation is essential to proper glycoprotein folding and quality control in the ER (By similarity).
May mediate some of the cancer-related phenotypes associated with AKT1 activation: its up-regulation by AKT1 leads to the elevation of aerobic glycolysis seen in tumor cells, a phenomenon known as the Warburg effect.
Monomer; active form (PubMed:12508121). Homodimer; disulfide-linked. Homodimers are enzymatically inactive.
N-glycosylated; high-mannose type (By similarity). Glycosylation is not essential for enzymatic activity.
Up-regulated in cell lines and primary tumor samples with active AKT1.
Antibodies against SPAG1 interfere with fertilization.
May play a role in the cytoplasmic assembly of the ciliary dynein arms (By similarity). May play a role in fertilization. Binds GTP and has GTPase activity.
Present in most tissues, including lung, with the strongest expression in brain, colon, kidney, and testis. In sperm and testis, detected in particular in pachytene primary spermatocytes. Up-regulated in pancreatic tumor tissues and not in normal pancreatic tissue.
May play a role in translational regulation of stored mRNAs in transcriptionally inactive haploid spermatids. Binds to poly(U) RNA oligomers (By similarity). Required for cell cycle progression, specifically for the transition from metaphase to anaphase (PubMed:26398195).
N-glycosylated. Glycosylation is required for the growth inhibitory effect.
Regulates the adhesive and proliferative status of intestinal epithelial cells. Can mediate density-dependent cell proliferation.
Expressed in many tissues (PubMed:11139402). Abundant in testis and kidney (PubMed:11139402).
Mitochondrial transporter required for glutathione import into mitochondria (PubMed:34707288, PubMed:35513392). Glutathione, which plays key roles in oxidative metabolism, is produced exclusively in the cytosol and is imported in many organelles (PubMed:34707288). Mitochondrial glutathione is required for the activity and stability of proteins containing iron-sulfur clusters, as well as erythropoiesis (PubMed:34707288).
Mitochondrial transporter required for glutathione import into mitochondria. Glutathione, which plays key roles in oxidative metabolism, is produced exclusively in the cytosol and is imported in many organelles. Mitochondrial glutathione is required for the activity and stability of proteins containing iron-sulfur clusters, as well as erythropoiesis.
Acetylation by KAT2A and KAT2B impairs kinase activity by shifting the kinase to an inactive conformation.
Cryptic POLO box 1 (CPB1) and Cryptic POLO box 2 (CPB2) domains can simultaneously bind to both TENT5C and CEP192.
Down-regulated in HCT 116 colorectal cancer cells, leading to aberrant centrioles composed of disorganized cylindrical microtubules and displaced appendages. Down-regulated by p53/TP53.
Homodimer (By similarity). Interacts with CEP152 (via N-terminus). Interacts with CEP78; this interaction may be important for proper PLK4 localization to the centriole and PLK4-induced overduplication of centrioles (PubMed:27246242). Interacts with CEP131 (PubMed:30804208). Interacts simultaneously with TENT5C and CEP192 (PubMed:32433990). Interacts with TENT5C; this interaction leads to the TENT5C recruitment in the centrosome (PubMed:32433990).
Serine/threonine-protein kinase that plays a central role in centriole duplication. Able to trigger procentriole formation on the surface of the parental centriole cylinder, leading to the recruitment of centriole biogenesis proteins such as SASS6, CENPJ/CPAP, CCP110, CEP135 and gamma-tubulin. When overexpressed, it is able to induce centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole during S phase. Phosphorylates 'Ser-151' of FBXW5 during the G1/S transition, leading to inhibit FBXW5 ability to ubiquitinate SASS6. Its central role in centriole replication suggests a possible role in tumorigenesis, centrosome aberrations being frequently observed in tumors. Also involved in deuterosome-mediated centriole amplification in multiciliated that can generate more than 100 centrioles. Also involved in trophoblast differentiation by phosphorylating HAND1, leading to disrupt the interaction between HAND1 and MDFIC and activate HAND1. Phosphorylates CDC25C and CHEK2. Required for the recruitment of STIL to the centriole and for STIL-mediated centriole amplification (PubMed:22020124). Phosphorylates CEP131 at 'Ser-78' and PCM1 at 'Ser-372' which is essential for proper organization and integrity of centriolar satellites (PubMed:30804208).
Ubiquitinated; leading to its degradation by the proteasome.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins (PubMed:20061386). In vitro catalyzes 'Lys-48'-linked polyubiquitination (PubMed:20061386). Involved in endoplasmic reticulum-associated degradation (ERAD) (PubMed:22607976). Required for sterol-induced ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase and its subsequent proteasomal degradation (PubMed:23223569).
Interacts with AUP1 (via C-terminus); the interaction recruits UBE2G2 to lipid droplets (PubMed:21127063, PubMed:21857022, PubMed:23223569). Interacts with ubiquitin ligases AMFR/gp78 and RNF139/TRC8; recruitment to lipid droplets by AUP1 facilitates interaction of UBE2G2 with AMFR and RNF139, leading to sterol-induced ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase and its subsequent proteasomal degradation (PubMed:23223569).
Forms PANX1/PANX2-heteromeric intercellular channels on coexpression in paired Xenopus oocytes. Does not form homomeric channels (By similarity).
A disulfide bond locks the enzyme in the closed conformation preventing substrate entry into the catalytic chamber.
Belongs to the peptidase M16 family. PreP subfamily.
Mainly exists in a closed and catalytically competent conformation but a closed-to-open switch allows substrate entry into the catalytic chamber (PubMed:24931469). Substrate binding induces closure and dimerization (PubMed:24931469). A disulfide bond may lock the enzyme in a closed conformation preventing substrate entry into the catalytic chamber, participating in redox regulation of the enzyme (Probable). Inhibited by metal-chelating agents (PubMed:10360838). Inhibited by nickel and zinc excess, and slightly activated by manganese (PubMed:19196155).
Metalloendopeptidase of the mitochondrial matrix that functions in peptide cleavage and degradation rather than in protein processing (PubMed:10360838, PubMed:16849325, PubMed:19196155, PubMed:24931469). Has an ATP-independent activity (PubMed:16849325). Specifically cleaves peptides in the range of 5 to 65 residues (PubMed:19196155). Shows a preference for cleavage after small polar residues and before basic residues, but without any positional preference (PubMed:10360838, PubMed:19196155, PubMed:24931469). Degrades the transit peptides of mitochondrial proteins after their cleavage (PubMed:19196155). Also degrades other unstructured peptides (PubMed:19196155). It is also able to degrade amyloid-beta protein 40, one of the peptides produced by APP processing, when it accumulates in mitochondrion (PubMed:16849325, PubMed:24931469, PubMed:26697887). It is a highly efficient protease, at least toward amyloid-beta protein 40 (PubMed:24931469, PubMed:29764912, PubMed:29383861). Cleaves that peptide at a specific position and is probably not processive, releasing digested peptides intermediates that can be further cleaved subsequently (PubMed:24931469). It is also able to degrade amyloid-beta protein 42 (PubMed:29764912).
Monomer and homodimer; homodimerization is induced by binding of the substrate.
Widely expressed. Expressed at higher level in muscle and heart compared to brain, pancreas, liver, lung and placenta.
Activity increases about 2-fold over 72 hours of hypoxia compared with normoxia (PubMed:16234850). Activity increases in the presence of phenobarbital, chenodeoxycholic and NR1H4/FXR-specific agonist GW4064 (PubMed:17975826).
Catalyzes the pyridoxal 5'-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products.
Homodimer (By similarity). Interacts (hydroxylated form) with VHL (PubMed:16234850).
In normoxia, is hydroxylated at Pro-576, promoting interaction with VHL, initiating ubiquitination and subsequent degradation via the proteasome.
Ubiquitinated; in normoxia following hydroxylation and interaction with VHL, leading to its subsequent degradation via the proteasome.
Up-regulated by bile acids; chenodeoxycholic acid, ursodeoxycholic acid and lithocholic acid and by the NR1H4/FXR-specific agonist GW4064.
Highest levels in heart, skeletal muscle, and kidney.
Regulator of endoplasmic reticulum secretion that acts as a key determinant of brain size (PubMed:33122427). Required for secretion of extracellular matrix proteins (PubMed:33122427). Required for correct brain development by depositing sufficient extracellular matrix proteins for tissue integrity and the proliferation of neural progenitors (PubMed:33122427). Acts as a regulator of the unfolded protein response (UPR) (By similarity).
Expressed in mature oligodendrocytes. Detected in the brain, lung, pancreas and testis.
May serve as a cell-surface marker for oligodendrocyte differentiation.
Acts as a glycogen-targeting subunit for PP1 and regulates its activity. Activates glycogen synthase, reduces glycogen phosphorylase activity and limits glycogen breakdown. Dramatically increases basal and insulin-stimulated glycogen synthesis upon overexpression in a variety of cell types.
Interacts with PPP1CC catalytic subunit of PP1 and associates with glycogen. Forms complexes with glycogen phosphorylase, glycogen synthase and phosphorylase kinase which is necessary for its regulation of PP1 activity. Also interacts with EPM2A/laforin.
The N-terminal region is required for binding to PP1, the central region is required for binding to glycogen and the C-terminal region is required for binding to glycogen phosphorylase, glycogen synthase and phosphorylase kinase.
Ubiquitinated by NHLRC1/malin in a EPM2A/laforin-dependent manner.
Auxiliary component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. Component of the ASAP complexes which bind RNA in a sequence-independent manner and are proposed to be recruited to the EJC prior to or during the splicing process and to regulate specific excision of introns in specific transcription subsets; ACIN1 confers RNA-binding to the complex. The ASAP complex can inhibit RNA processing during in vitro splicing reactions. The ASAP complex promotes apoptosis and is disassembled after induction of apoptosis. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the activity is different from the established EJC assembly and function. Induces apoptotic chromatin condensation after activation by CASP3. Regulates cyclin A1, but not cyclin A2, expression in leukemia cells.
Found in a mRNA splicing-dependent exon junction complex (EJC). Component of the heterotrimeric ASAP (apoptosis- and splicing-associated protein) complexes consisting of RNPS1, SAP18 and different isoforms of ACIN1; the association of SAP18 seems to require a preformed RNPS1:ACIN1 complex. Interacts with API5. Interacts with SRPK2 in a phosphorylation-dependent manner.
Phosphorylation on Ser-1180 by SRPK2 up-regulates its stimulatory effect on cyclin A1.
Structural and functional studies of the ASAP complex have been conducted with a chimeric complex involving a conserved fragment of Drosophila melanogaster Acinus/hkl.
Ubiquitous. The Ser-1180 phosphorylated form (by SRPK2) is highly expressed and phosphorylated in patients with myeloid hematologic malignancies.
Undergoes proteolytic cleavage; the processed form is active, contrary to the uncleaved form.
Ubiquitous. Maximal expression in breast and lung, where it represents around 10% of all beta-tubulins. Largely decreased expression in most cancerous tissues.
Directly interacts with DMD and betaDAG1. This interaction does not interfere with binding between DMD and betaDAG1. It is also required for DMD and betaDAG1 retention at costameres (By similarity). Interacts (via N-terminal ANK repeats) with SCHIP1 isoform 5 (via C-terminus); this interaction is required for the localization at axon initial segments (AISs) and nodes of Ranvier (NRs) (By similarity). May be a constituent of a NFASC/NRCAM/ankyrin G complex. Interacts with RHBG (PubMed:15611082). Interacts with PLEC and FLNC (PubMed:21223964). Interacts with KCNA1; this inhibits channel activity (PubMed:23903368). Interacts (via ANK repeats) with IQCJ-SCHIP1; required for IQCJ-SCHIP1 localization at axon initial segments (AIS) and nodes of Ranvier (PubMed:25950943). Interacts with SCHIP1 (PubMed:25950943). Interacts with SCN5A (PubMed:15579534).
Expressed in brain, neurons, muscles and other tissues.
Genetic variations in ANK3 may be associated with autism spectrum disorders susceptibility.
In skeletal muscle, required for costamere localization of DMD and betaDAG1 (By similarity). Membrane-cytoskeleton linker. May participate in the maintenance/targeting of ion channels and cell adhesion molecules at the nodes of Ranvier and axonal initial segments. Regulates KCNA1 channel activity in function of dietary Mg(2+) levels, and thereby contributes to the regulation of renal Mg(2+) reabsorption (PubMed:23903368).
May be part of a Golgi-specific membrane cytoskeleton in association with beta-spectrin.
The disease is caused by variants affecting the gene represented in this entry. A homozygous deletion in ANK3 predicted to result in frameshift and premature truncation, has been shown to be the cause of moderate intellectual disability, an ADHD-like phenotype and behavioral problems in a consanguineous family (PubMed:23390136).
Up-regulated during muscle cell differentiation.
Highly expressed in testis. Detected at intermediate levels in spleen, thymus, prostate, small intestine, colon and peripheral blood leukocytes.
Interacts with CALM1, CETN2, CEP76, CEP104, CEP290 and TALPID3. Interacts with CEP97. Seems to associate with discrete CETN2, CEP97 and CEP290-containing complexes. Interacts with NEURL4 and CCNF; these interactions are not mutually exclusive and both lead to CCP110 ubiquitination and proteasome-dependent degradation. Via its interaction with NEURL4, may indirectly interact with HERC2. Interacts with KIF24, leading to its recruitment to centrioles. Interacts with USP20 and USP33 (PubMed:23486064). Interacts with MPHOSPH9 (PubMed:30375385). Interacts (via N-terminal region) with ENKD1 (via central region); ENKD1 competes with CEP97 for binding to CCP110, destabilizing the interaction between CP110 and CEP97 which promotes the removal of CCP110 and CEP97 from the mother centriole and allows the initiation of ciliogenesis (By similarity).
Necessary for centrosome duplication at different stages of procentriole formation. Acts as a key negative regulator of ciliogenesis in collaboration with CEP97 by capping the mother centriole thereby preventing cilia formation (PubMed:17719545, PubMed:17681131, PubMed:23486064, PubMed:30375385, PubMed:35301795). Also involved in promoting ciliogenesis. May play a role in the assembly of the mother centriole subdistal appendages (SDA) thereby effecting the fusion of recycling endosomes to basal bodies during cilia formation (By similarity). Required for correct spindle formation and has a role in regulating cytokinesis and genome stability via cooperation with CALM1 and CETN2 (PubMed:16760425).
Ubiquitinated by the SCF(CCNF) during G2 phase, leading to its degradation by the proteasome and preventing centrosome reduplication. Deubiquitinated by USP33 in S and G2/M phase, leading to stabilize CCP110 during the period which centrioles duplicate and elongate.
Up-regulated during the transition from G1 to S phase of the cell cycle. The highest levels are observed in S phase, after which the levels decrease markedly.
Component of the TTT complex composed of TELO2, TTI1 and TTI2. Interacts with TELO2 and TTI1 (PubMed:20801936, PubMed:20810650). Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014).
Regulator of the DNA damage response (DDR). Part of the TTT complex that is required to stabilize protein levels of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins. The TTT complex is involved in the cellular resistance to DNA damage stresses, like ionizing radiation (IR), ultraviolet (UV) and mitomycin C (MMC). Together with the TTT complex and HSP90 may participate in the proper folding of newly synthesized PIKKs.
Acts as an actin bundling protein. May play a pivotal role in photoreceptor cell-specific events, such as disk morphogenesis.
Localized specifically in the outer and inner segments of the photoreceptor cells in the retina.
Component of a trimeric complex composed of STK11/LKB1, STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta): the complex tethers STK11/LKB1 in the cytoplasm and stimulates its catalytic activity. Interacts with BIRC4/XIAP. These two proteins are likely to coexist in a complex with TAK1, TRAF6, TAB1 and TAB2.
Highly expressed in heart, skeletal muscle, testis, liver and colon.
Pseudokinase which, in complex with CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta), binds to and activates STK11/LKB1. Adopts a closed conformation typical of active protein kinases and binds STK11/LKB1 as a pseudosubstrate, promoting conformational change of STK11/LKB1 in an active conformation (By similarity).
Ser-184 is present instead of the conserved Asp which is expected to be an active site residue.
Highly enriched in the brain. Much weaker expression in heart, lung and muscle.
Protein with a unique structure having two opposing regulatory activities toward small GTP-binding proteins. The C-terminus is a GTPase-activating protein domain which stimulates GTP hydrolysis by RAC1, RAC2 and CDC42. Accelerates the intrinsic rate of GTP hydrolysis of RAC1 or CDC42, leading to down-regulation of the active GTP-bound form (PubMed:7479768, PubMed:17116687). The central Dbl homology (DH) domain functions as guanine nucleotide exchange factor (GEF) that modulates the GTPases CDC42, RHOA and RAC1. Promotes the conversion of CDC42, RHOA and RAC1 from the GDP-bound to the GTP-bound form (PubMed:7479768). Functions as an important negative regulator of neuronal RAC1 activity (By similarity). Regulates macrophage functions such as CSF-1 directed motility and phagocytosis through the modulation of RAC1 activity (By similarity).
The central Dbl homology (DH) domain functions as guanine nucleotide exchange factor (GEF) that modulates the GTPases CDC42, RHOA and RAC1. Promotes the conversion of CDC42, RHOA and RAC1 from the GDP-bound to the GTP-bound form. The C-terminus is a Rho-GAP domain which stimulates GTP hydrolysis by RAC1, RAC2 and CDC42. The protein has a unique structure having two opposing regulatory activities toward small GTP-binding proteins.
Alternative splicing in the laminin G-like domain regulates binding to alpha-dystroglycan.
Interacts (via cytoplasmic C-terminal region) with CASK (By similarity). Specific isoforms bind alpha-dystroglycan and neuroligins NLGN1, NLGN2 and NLGN3 (By similarity). Interacts with CBLN1, CBLN2 and, less avidly, with CBLN4 (By similarity). Interacts with CLSTN3 (By similarity).
Neuronal cell surface protein that may be involved in cell recognition and cell adhesion.
Neuronal cell surface protein that may be involved in cell recognition and cell adhesion. May mediate intracellular signaling.
The laminin G-like domain 1 binds to NXPH1. Interacts with PATJ (By similarity). Interacts with CBLN1, CBLN2 and, less avidly, with CBLN4 (By similarity). Specific isoforms bind neuroligins NLGN1, NLGN2 and NLGN3 (By similarity). Specific isoforms bind to alpha-dystroglycan (By similarity). Interacts (via Laminin G-like 1 domain) with IGSF21 (Ig-like 1 domain) in a trans-interaction manner (By similarity). Interacts with CLSTN3 (By similarity).
AA 66-79 are essential for peroxisome localization.
Monomer (PubMed:30204880). Isoform 1 and isoform 2 interact with PEX7 (PubMed:30204880). Isoform 2 interacts with isoform 1 of PEX5 in a PEX7-dependent manner (PubMed:30204880).
Cytokine that acts as a physiological ligand for receptor tyrosine kinases LTK and ALK, leading to their activation (PubMed:26418745, PubMed:26630010, PubMed:30061385, PubMed:33411331, PubMed:34646012, PubMed:34819673). Cytokine-binding is sufficient to activate LTK (PubMed:34646012). In contrast, ALKAL2-driven activation of ALK is coupled with heparin-binding to ALK (PubMed:34646012). Stimulation of ALK signaling is involved in neural development and regulation of energy expenditure (PubMed:34646012, PubMed:34819673).
Homodimer; interchain disulfide bond is not required for homodimerization.
It is unclear whether it activates ALK as a homodimer or a monomer (PubMed:34646012, PubMed:34819673). According to a report, homodimeric ALKAL2 activates ALK (PubMed:34819673). According to a second publication, monomeric ALKAL2 binds and activates ALK (PubMed:34646012).
Widely expressed with highest levels in adrenal gland and modest levels in pancreas, testis and uterus.
AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. AMPK also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. The AMPK gamma3 subunit is a non-catalytic subunit with a regulatory role in muscle energy metabolism (PubMed:17878938). It mediates binding to AMP, ADP and ATP, leading to AMPK activation or inhibition: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive.
AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2 (By similarity).
Genetic variation in PRKAG3 defines the skeletal muscle glycogen content and metabolism quantitative trait locus (SMGMQTL) [MIM:619030]. Muscle fibers from carriers of variant Trp-225 have approximately 90% more muscle glycogen content than controls and decreased levels of intramuscular triglyceride.
Skeletal muscle, with weak expression in heart and pancreas.
Catalyzes the second of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of two carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme has a 3-ketoacyl-CoA reductase activity, reducing 3-ketoacyl-CoA to 3-hydroxyacyl-CoA, within each cycle of fatty acid elongation. Thereby, it may participate in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. May also catalyze the transformation of estrone (E1) into estradiol (E2) and play a role in estrogen formation.
Expressed in most tissues tested. Highly expressed in the ovary and mammary. Expressed in platelets.
Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase (PubMed:12909626, PubMed:17716973). Interacts with DBF4 (By similarity). Interacts with MCM10 (PubMed:11095689). Interacts with LRWD1 throughout the cell cycle; this interaction, wich occurs only with non-ubiquitinated form of LRWD1, prevents LRWD1 ubiquitination and hence stabilizes the protein (PubMed:22645314). Interacts with POLQ (PubMed:24989122).
Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K20me3 and H4K27me3. Stabilizes LRWD1, by protecting it from ubiquitin-mediated proteasomal degradation. Also stabilizes ORC3.
Although the protein is present in a diversity of vertebrates ranging from bony fish to mammals, the mouse and rat orthologous proteins do not exist.
Autophosphorylated in vitro at Ser-490. Phosphorylation at Ser-36 is regulated by light and activated by cAMP.
Interacts (when prenylated) with PDE6D; this promotes release from membranes.
Retina-specific kinase involved in the shutoff of the photoresponse and adaptation to changing light conditions via cone opsin phosphorylation, including rhodopsin (RHO).
Retinal cones, outer and inner segments.
Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. Can bind to fibrinogen, fibronectin, laminin and type V collagen.
Highly expressed in spleen, thymus and peripheral blood leukocytes. Highly expressed also in T-cell and monocytic cell lines, expressed at lower level in B-cell lines. Not detected in fibroblast or neuroblastoma cell lines.
Interacts with SLA. Interacts with CBLB (By similarity). Interacts with GRB2 (PubMed:7706237). Interacts with SHB (PubMed:12084069). Interacts with PRAM1 (PubMed:11301322). Interacts (via SH2 domain) with CD6 (via tyrosine phosphorylated C-terminus) (PubMed:16914752, PubMed:24584089). Interacts with FYB1 and the phosphorylated form of FYB2 (PubMed:27335501).
Involved in T-cell antigen receptor mediated signaling.
Phosphorylated after T-cell receptor activation by ZAP70, ITK and TXK, which leads to the up-regulation of Th1 preferred cytokine IL-2. SYK-dependent phosphorylation is required for recruitment of PI3K signaling components.
The SH2 domain mediates interaction with phosphorylated CD6 (PubMed:16914752). The SH2 domain mediates interaction with SHB (PubMed:12084069).
Component of the epidermal cornified cell envelopes.
Expressed in cornified epidermis, psoriatic and regenerating skin after wounding. Found in the upper granular layer and in the entire cornified layer of epidermis.
Forms covalent cross-links mediated by transglutaminase TGM3, between glutamine and the epsilon-amino group of lysine residues (in vitro).
In the N-terminal section; belongs to the S-100 family.
Processed during the process of epidermal differentiation.
Catalyzes the reversible transfer of acyl groups from carnitine to coenzyme A (CoA) and regulates the acyl-CoA/CoA ratio. Also plays a crucial role in the transport of fatty acids for beta-oxidation (PubMed:15099582, PubMed:29395073). Responsible for the synthesis of short- and branched-chain acylcarnitines (PubMed:23485643). Active towards some branched-chain amino acid oxidation pathway (BCAAO) intermediates (PubMed:23485643). Trans-2-enoyl-CoAs and 2-methylacyl-CoAs are poor substrates (PubMed:23485643).
Mostly in skeletal muscle, less in heart, liver and pancreas, only weakly detectable in brain, placenta, lung and kidney.
Active peptidase. Contains a nuclear localization signal at positions 2-9.
Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2 (PubMed:12662155, PubMed:16475979, PubMed:19667070, PubMed:29382749, PubMed:30291141, PubMed:33731929). Acts as a key inhibitor of caspase-1-dependent monocyte and macrophage pyroptosis in resting cells by preventing activation of NLRP1 and CARD8 (PubMed:27820798, PubMed:29967349, PubMed:30291141, PubMed:31525884, PubMed:32796818, PubMed:36357533). Sequesters the cleaved C-terminal part of NLRP1 and CARD8, which respectively constitute the active part of the NLRP1 and CARD8 inflammasomes, in a ternary complex, thereby preventing their oligomerization and activation (PubMed:34019797, PubMed:33731929, PubMed:33731932). The dipeptidyl peptidase activity is required to suppress NLRP1 and CARD8; however, neither NLRP1 nor CARD8 are bona fide substrates of DPP9, suggesting the existence of substrate(s) required for NLRP1 and CARD8 inhibition (PubMed:33731929).
Homodimer (PubMed:16475979, PubMed:29382749). Forms a ternary complex with NLRP1, composed of a DPP9 homodimer, one full-length NLRP1 protein, and one cleaved C-terminus of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus) (PubMed:33731929, PubMed:33731932). Forms a ternary complex with CARD8, composed of a DPP9 homodimer, one full-length NLRP1 protein, and one cleaved C-terminus of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus) (PubMed:33731929, PubMed:34019797). In the ternary complex, only one subunit of the DPP9 homodimer is bound to NLRP1 or CARD8 (PubMed:34019797, PubMed:33731932).
Inhibited by the serine proteinase inhibitor 4-(2-aminoethyl)benzenesulphonyl fluoride (AEBSF), and by di-isopropylfluorophosphate (PubMed:12662155). Inhibited by Val-boroPro (Talabostat, PT-100), a non-selective inhibitor, which triggers pyroptosis in monocytes and macrophages (PubMed:27820798, PubMed:29967349, PubMed:32796818, PubMed:33731932, PubMed:36357533). Val-boroPro inhibits activity by binding to the active site, mimicking a substrate-bound state, thereby displacing the C-terminal fragment of NLRP1, leading to activation of the NLRP1 inflammasome (PubMed:34019797, PubMed:33731932, PubMed:36357533). In contrast, Val-boroPro does not directly displaces CARD8: it acts by promoting degradation of the N-terminal part of CARD8, leading to indirect disruption of the ternary complex (PubMed:34019797). Chemical inhibition of DPP9 by Val-boroPro in HIV-1-infected cells activates the CARD8 inflammasome, triggering cell death, offering a promising strategy for the elimination of HIV-1 reservoirs in people living with HIV-1 (PubMed:36357533).
Ubiquitously expressed, with highest levels in liver, heart and muscle, and lowest levels in brain.
Homodimer (Ref.16). Interacts (via PTS2-type peroxisomal targeting signal region) with PEX7; leading to its translocation into peroxisomes (PubMed:22057399, PubMed:25538232).
Peroxisomal thiolase is markedly induced (at the level of transcription) by various hypolipidemic compounds in parallel with the other two enzymes of the peroxisomal beta-oxidation system.
Responsible for the thiolytic cleavage of straight chain 3-keto fatty acyl-CoAs (3-oxoacyl-CoAs) (PubMed:2882519, PubMed:11734571). Plays an important role in fatty acid peroxisomal beta-oxidation (PubMed:2882519, PubMed:11734571). Catalyzes the cleavage of short, medium, long, and very long straight chain 3-oxoacyl-CoAs (PubMed:2882519, PubMed:11734571).
The PTS2-type peroxisomal targeting signal, which mediates interaction with PEX7 and localization to peroxisomes, is cleaved following import into peroxisomes.
Mainly expressed in brain. In brain, it is expressed in hippocampus.
Prion-like protein that has PrP(C)-like neuroprotective activity. May act as a modulator for the biological actions of normal and abnormal PrP (By similarity).
Belongs to the gamma type-C retroviral envelope protein family. HERV class-I F(c)1 env subfamily.
Low expression in skin, testis and trachea.
Orthologs in P.troglodytes and G.gorilla (truncated).
Retroviral envelope proteins mediate receptor recognition and membrane fusion during early infection. Endogenous envelope proteins may have kept, lost or modified their original function during evolution. This endogenous envelope protein has lost its original fusogenic properties.
The CKS-17 immunosuppressive domain is present in many retroviral envelope proteins. As a synthetic peptide, it inhibits immune function in vitro and in vivo (By similarity).
The CXXC motif is highly conserved across a broad range of retroviral envelope proteins. It is thought to participate in the formation of a labile disulfide bond possibly with the CX6CC motif present in the transmembrane protein (By similarity).
The surface (SU) and transmembrane (TM) proteins form a heterodimer. SU and TM are attached by noncovalent interactions or by a labile interchain disulfide bond (By similarity).
By Epstein-Barr virus (EBV) resulting in the stimulation of the EBV EBER genes.
Component of TFIIIB complex. The TFIIIB complex has two activities, alpha and beta. The TFIIIB-alpha and TFIIIB-beta activities are required for transcription of genes with TFIIIC-bound internal promoters and PSE transcription factor-bound external promoters, respectively. The TFIIIB-alpha activity complex is composed of TBP, BDP1, and a complex containing both BRF2 and at least four stably associated proteins; YY1 facilitates the formation of TFIIIB-alpha activity complex. The TFIIIB-beta activity complex is composed of TBP, BDP1, and BRF1. Interacts with BRF1; this interaction diminishes during mitosis resulting in the release of BDP1 from chromosomal templates. Component of TFIIIC complex. The TFIIIC complex has two activities, C1 and C2. The TFIIIC2 activity complex is only required for transcription of the 'classical' pol III genes whereas the TFIIIC1 activity complex is required for transcription of all pol III genes. The TFIIIC1 activity complex is composed at least of BDP1. Interacts with ZBTB43.
General activator of RNA polymerase III transcription. Requires for transcription from all three types of polymerase III promoters. Requires for transcription of genes with internal promoter elements and with promoter elements upstream of the initiation site.
Isoform 2 is highly expressed in cerebellum.
Phosphorylated by CSNK2A1 during mitosis, resulting in its release from chromatin and suppression of polymerase III transcription.
Negative regulator of the canonical Wnt signaling pathway involved in neuroectodermal patterning. Acts by specifically binding phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), translocating to the cell membrane and interacting with key regulators of the canonical Wnt signaling pathway, such as components of the beta-catenin destruction complex.
Interacts with the GTP-bound form of RAB15.
Regulates transferrin receptor recycling from the endocytic recycling compartment.
Expressed at higher levels in first trimester trophoblasts than at term of gestation.
Most highly expressed in the pancreas, placenta and spinal cord, with lower-level of expression in peripheral blood leukocytes, kidney, lung, fetal liver, stomach, small intestine, testes, spleen, thymus, adrenal glands and lymph nodes. In the adult brain, expressed in the superior frontal gyrus, putamen, caudate nucleus, cingulate gyrus, nucleus accumbens, hippocampus, pons and amygdala, as well as the hypothalamus and pituitary. Expression levels are higher in early (7-9 weeks) than term placentas. Expression levels were increased in both early placentas and molar pregnancies and were reduced in choriocarcinoma cells. Expressed at higher levels in first trimester trophoblasts than at term of gestation. Also found in the extravillous trophoblast suggesting endocrine/paracrine activation mechanism.
Receptor for metastin (kisspeptin-54 or kp-54), a C-terminally amidated peptide of KiSS1. KiSS1 is a metastasis suppressor protein that suppresses metastases in malignant melanomas and in some breast carcinomas without affecting tumorigenicity. The metastasis suppressor properties may be mediated in part by cell cycle arrest and induction of apoptosis in malignant cells. The receptor is essential for normal gonadotropin-released hormone physiology and for puberty. The hypothalamic KiSS1/KISS1R system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood. The receptor is also probably involved in the regulation and fine-tuning of trophoblast invasion generated by the trophoblast itself. Analysis of the transduction pathways activated by the receptor identifies coupling to phospholipase C and intracellular calcium release through pertussis toxin-insensitive G(q) proteins.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in KISS1R as well as in other HH-associated genes including FGFR1 and IL17RD (PubMed:23643382).
Functions as an adapter recruiting ubiquitin-protein ligases to their specific substrates (PubMed:23886940, PubMed:27462458). Through an ubiquitination-dependent mechanism plays for instance a role in the incorporation of SLC11A2 into extracellular vesicles (PubMed:27462458). More generally, plays a role in the extracellular transport of proteins between cells through the release in the extracellular space of microvesicles (PubMed:22315426). By participating in the ITCH-mediated ubiquitination and subsequent degradation of NOTCH1, negatively regulates the NOTCH signaling pathway (PubMed:23886940).
Interacts (via PPxY motifs) with ITCH (via WW domains); the interaction is direct and participates in the recruitment of the ubiquitin-protein ligase ITCH to the NOTCH1 receptor (PubMed:21191027, PubMed:23886940). Interacts with ARRB1 and ARRB2; the interaction is direct (PubMed:23886940). Interacts with TSG101; may recruit TSG101 to the plasma membrane (PubMed:21191027, PubMed:22315426). Interacts (via PPxY motifs) with WWP2 (via WW domains); ubiquitinates ARRDC1 (PubMed:21191027, PubMed:22315426). Interacts with SLC11A2; controls the incorporation of SLC11A2 into extracellular vesicles through an ubiquitination-dependent mechanism (PubMed:27462458). Interacts with WWP1 (via WW domains) (PubMed:21191027). Interacts with NEDD4 (via WW domains) (PubMed:21191027). Interacts with PDCD6IP (PubMed:21191027).
The PPxY motifs mediate interaction with WW domain-containing ubiquitin-protein ligases.
Ubiquitinated (PubMed:21191027, PubMed:22315426). Ubiquitination by WWP2; promotes localization to extracellular microvesicles (PubMed:22315426). Ubiquitinated by WWP1 (PubMed:21191027).
(Microbial infection) Stimulates the activity of Human Immunodeficiency Virus 1/HIV-1 pre-integration complex.
Expressed during neurogenesis in differentiating human embryonic stem cells and in the developing human neocortex.
(Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human rotavirus A.
(Microbial infection) Integrin ITGA2:ITGB1 interacts (via ITAG2 I-domain) with rotavirus A VP4 protein.
Heterodimer of an alpha and a beta subunit. Alpha-2 associates with beta-1. Interacts with HPS5 and RAB21.
Integrin alpha-2/beta-1 is a receptor for laminin, collagen, collagen C-propeptides, fibronectin and E-cadherin. It recognizes the proline-hydroxylated sequence G-F-P-G-E-R in collagen. It is responsible for adhesion of platelets and other cells to collagens, modulation of collagen and collagenase gene expression, force generation and organization of newly synthesized extracellular matrix.
Position 534 is associated with platelet-specific alloantigen HPA-5 (Br). HPA-5B/Br(a) has Lys-534 and HPA-5A/Br(b) has Glu-534. HPA-5B is involved in neonatal alloimmune thrombocytopenia (NAIT or NATP). The Lys-534-Glu polymorphism may play a role in coronary artery disease (CAD).
Component of the Par polarity complex, composed of at least phosphorylated PRKCZ, PARD3 and TIAM1. Interacts with NTRK2; mediates the activation of RAC1 by BDNF. Interacts with MAPK8IP2 and CD44 (By similarity). Interacts with BAIAP2. Interacts with EPHA8; regulates clathrin-mediated endocytosis of EPHA8. Interacts with PARD3. Interacts (via PDZ domain) with CNTNAP4, SDC1 and SDC3 (via C-terminus).
Found in virtually all analyzed tumor cell lines including B- and T-lymphomas, neuroblastomas, melanomas and carcinomas.
Guanyl-nucleotide exchange factor that activates RHO-like proteins and connects extracellular signals to cytoskeletal activities. Activates RAC1, CDC42, and to a lesser extent RHOA and their downstream signaling to regulate processes like cell adhesion and cell migration.
The first PH domain mediates interaction with membranes enriched in phosphoinositides.
Ubiquitinated. Undergoes 'Lys-48' ubiquitination at Lys-1404 and Lys-1420 by a CUL3(KBTBD6/7) E3 ubiquitin ligase complex composed of CUL3, RBX1, KBTBD6 and KBTBD7. 'Lys-48' ubiquitination at Lys-1404 and Lys-1420 triggers proteasomal degradation (PubMed:25684205). Ubiquitination at Lys-1404 and Lys-1420 by CUL3(KBTBD6/7) also requires the membrane-associated protein GABARAP and may therefore be spatially restricted within the cell (PubMed:25684205).
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1B subfamily.
Is specifically blocked by omega-conotoxin GVIA (By similarity). Is specifically blocked by omega-conotoxin MVIIA (ziconotide) (PubMed:34234349). Is insensitive to dihydropyridines (DHP).
Isoform Alpha-1b-1 and isoform Alpha-1b-2 are expressed in the central nervous system, but not in skeletal muscle or aorta. Expressed in the cerebral white matter, cortex, hippocampus, basal ganglia, and cerebellum (PubMed:30982612).
Multisubunit complex consisting of alpha-1, alpha-2, beta and delta subunits in a 1:1:1:1 ratio. The channel activity is directed by the pore-forming and voltage-sensitive alpha-1 subunit. In many cases, this subunit is sufficient to generate voltage-sensitive calcium channel activity. The auxiliary subunits beta and alpha-2/delta linked by a disulfide bridge regulate the channel activity. Interacts with RIMS1. Interacts with FMR1 (via C-terminus); this interaction induces a decrease in the number of presynaptic functional CACNA1B channels at the cell surface.
Phosphorylated in vitro by CaM-kinase II, PKA, PKC and CGPK.
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. This alpha-1B subunit gives rise to N-type calcium currents. N-type calcium channels belong to the 'high-voltage activated' (HVA) group. They are involved in pain signaling. Calcium channels containing alpha-1B subunit may play a role in directed migration of immature neurons. Mediates Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals (By similarity).
(Microbial infection) Interacts (via the ULD domain) with HIV-1 Tat.
Cleaved at Asp-254 by caspase-3 and caspase-6 during T-cell apoptosis in thymus and during B-cell stimulation. The cleaved forms cannot dimerize and lose transcription regulation function because of impaired DNA and chromatin association.
Crucial silencing factor contributing to the initiation of X inactivation mediated by Xist RNA that occurs during embryogenesis and in lymphoma (By similarity). Binds to DNA at special AT-rich sequences, the consensus SATB1-binding sequence (CSBS), at nuclear matrix- or scaffold-associated regions. Thought to recognize the sugar-phosphate structure of double-stranded DNA. Transcriptional repressor controlling nuclear and viral gene expression in a phosphorylated and acetylated status-dependent manner, by binding to matrix attachment regions (MARs) of DNA and inducing a local chromatin-loop remodeling. Acts as a docking site for several chromatin remodeling enzymes (e.g. PML at the MHC-I locus) and also by recruiting corepressors (HDACs) or coactivators (HATs) directly to promoters and enhancers. Modulates genes that are essential in the maturation of the immune T-cell CD8SP from thymocytes. Required for the switching of fetal globin species, and beta- and gamma-globin genes regulation during erythroid differentiation. Plays a role in chromatin organization and nuclear architecture during apoptosis. Interacts with the unique region (UR) of cytomegalovirus (CMV). Alu-like motifs and SATB1-binding sites provide a unique chromatin context which seems preferentially targeted by the HIV-1 integration machinery. Moreover, HIV-1 Tat may overcome SATB1-mediated repression of IL2 and IL2RA (interleukin) in T-cells by binding to the same domain than HDAC1. Delineates specific epigenetic modifications at target gene loci, directly up-regulating metastasis-associated genes while down-regulating tumor-suppressor genes. Reprograms chromatin organization and the transcription profiles of breast tumors to promote growth and metastasis. Promotes neuronal differentiation of neural stem/progenitor cells in the adult subventricular zone, possibly by positively regulating the expression of NEUROD1 (By similarity).
Interacts with CUX1 (via DNA-binding domains); the interaction inhibits the attachment of both proteins to DNA (By similarity). Homodimer. Part of the nuclear protein complex gamma-globin promoter and enhancer binding factor (gamma-PE) composed at least of SATB1 and HOXB2. Interaction with CtBP1 when not acetylated stabalizes attachment to DNA and promotes transcription repression. Interacts with PCAF. Interacts with sumoylated PML and HDAC1 via the ULD domain. Interacts also with DYNLT3 and POLR2J2. Binds to EP300.
Phosphorylated by PKC. Acetylated by PCAF. Phosphorylated form interacts with HDAC1, but unphosphorylated form interacts with PCAF. DNA binding properties are activated by phosphorylation and inactivated by acetylation. In opposition, gene expression is down-regulated by phosphorylation but up-regulated by acetylation.
Sumoylated. Sumoylation promotes cleavage by caspases.
Homodimer (PubMed:25064856). Interacts with EEF2 (PubMed:25064856).
RNA-binding protein involved in the regulation of smooth muscle cell differentiation and proliferation in the gastrointestinal system (PubMed:25064856). Binds NOG mRNA, the major inhibitor of the bone morphogenetic protein (BMP) pathway. Mediates an increase of NOG mRNA levels, thereby contributing to the negative regulation of BMP signaling pathway and promoting reversible dedifferentiation and proliferation of smooth muscle cells (By similarity).
Interacts with CSF2RB; this interaction occurs preferentially in the absence of CSF2.
Selectively involved in CSF2 deprivation-induced apoptosis via a mitochondria-dependent pathway.
Predominantly expressed in thymus, spleen, and testis. Expressed at lower levels in brain, lung, kidney, and ovary.
Up-regulated by IFNG/IFN-gamma in human monocytic cell line THP-1.
Endo/exonuclease with nicking activity towards supercoiled DNA, a preference for single-stranded DNA and 5'-3' exonuclease activity.
Probably inactive since it lacks the active site.
The active site contains 1 hydrated divalent metal cation that has only 1 direct interaction with the protein; all other interactions are via water molecules.
Expressed in the temporal lobe, frontal lobe, parietal lobe, hippocampus, and cerebellum. Also found in kidney, lung, liver, heart, skeletal muscle, placenta.
G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis (PubMed:7759551, PubMed:8702647, PubMed:8636323, PubMed:8878438, PubMed:17555508, PubMed:19789209, PubMed:21566075, PubMed:22114145, PubMed:23966241, PubMed:25292184, PubMed:25104082, PubMed:26386835, PubMed:25766501, PubMed:22789683). Senses fluctuations in the circulating calcium concentration and modulates the production of parathyroid hormone (PTH) in parathyroid glands (By similarity). The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system (PubMed:7759551). The G-protein-coupled receptor activity is activated by a co-agonist mechanism: aromatic amino acids, such as Trp or Phe, act concertedly with divalent cations, such as calcium or magnesium, to achieve full receptor activation (PubMed:27434672, PubMed:27386547).
Homodimer; disulfide-linked (PubMed:27434672, PubMed:27386547, PubMed:16740594). Interacts with VCP and RNF19A (PubMed:16513638). Interacts with ARRB1 (By similarity).
In resting state, adopts an open conformation, anion-binding promoting the inactive configuration (PubMed:27434672). Upon aromatic amino acid-binding, the groove in the extracellular venus flytrap module is closed, thereby inducing the formation of a novel homodimer interface between subunits (PubMed:27434672, PubMed:27386547). Calcium ions stabilize the active state by enhancing homodimer interactions between membrane-proximal domains to fully activate the receptor (PubMed:27434672, PubMed:27386547). Activated by AMG 416, a D-amino acid-containing peptide agonist that is being evaluated for the treatment of secondary hyperparathyroidism in chronic kidney disease patients receiving hemodialysis (PubMed:26290606). AMG 416 agonist acts by forming a disulfide bond with Cys-482 (PubMed:26290606).
The extracellular regions of the homodimer interact in a side-by-side fashion while facing opposite directions (PubMed:27434672, PubMed:27386547). Each extracellular region consists of three domains, LB1 (ligand-binding 1), LB2 and CR (cysteine-rich) (PubMed:17360426). The two lobe-shaped domains LB1 and LB2 form a venus flytrap module (PubMed:27434672, PubMed:27386547). In the inactive configuration, the venus flytrap modules of both protomers are in the open conformation associated with the resting state (open-open) and the interdomain cleft is empty (PubMed:27434672). In addition, each protomer contains three anions, which reinforce the inactive conformation, and one calcium ion (PubMed:27434672). In the active configuration, both protomers of extracellular regions have the closed conformation associated with agonist-binding (closed-closed) (PubMed:27434672, PubMed:27386547). The ligand-binding cleft of each protomer is solely occupied by an aromatic amino-acid (PubMed:27434672, PubMed:27386547). Calcium is bound at four novel sites, including one at the homodimer interface (PubMed:27434672, PubMed:27386547). Agonist-binding induces large conformational changes within the extracellular region homodimer: first, the venus flytrap module of each protomer undergoes domain closure (PubMed:27434672, PubMed:27386547). Second, the LB2 regions of the two protomers approach each other, resulting in an expansion of the homodimer interactions involving LB2 domains (PubMed:27434672, PubMed:27386547). Third, the CR regions of the two subunits interact to form a large homodimer interface that is unique to the active state (PubMed:27434672, PubMed:27386547). The CR regions are brought into close contact by the motion involving LB2 since the two domains are rigidly associated within each subunit (PubMed:27434672, PubMed:27386547).
Ubiquitinated by RNF19A; which induces proteasomal degradation.
Interacts with MXD1, MXD3, MXD4, MXI1 and PIWIL1. Self-associates (By similarity).
Seems to be involved in regulation of transcriptional activity of MYC. In vitro, inhibits DNA-binding activity of Mad-MAX heterodimers. Can recruit Mad transcriptional repressors (MXD1, MXD3, MXD4 and MXI1) to the cytoplasm. May be involved in spermiogenesis (By similarity).
Expressed at embryonic stages 10 to 11 in the nondifferentiated mesodermal cells at the venous and arterial poles, as well as cells of the dorsal coelomic wall and ruptured mesocardium (at protein level) (PubMed:21403123). Expressed by all myocardial cells at embryonic stages 10 to 11 (at protein level) (PubMed:21403123).
Homodimer (via the homeobox); binds DNA as homodimer (PubMed:22849347). Interacts (via the homeobox) with TBX5 (via the T-box); this complex binds DNA (PubMed:26926761). Interacts with HIPK1 and HIPK2, but not HIPK3. Interacts with the C-terminal zinc finger of GATA4 through its homeobox domain. Also interacts with JARID2 which represses its ability to activate transcription of ANF. Interacts with FBLIM1. Interacts with TBX18 (By similarity). Interacts with histone methyltransferase NSD2 (via HMG box) (By similarity). Interacts with NEDD9 (PubMed:29899023). Interacts with TBX1 (By similarity).
The homeobox domain binds to double-stranded DNA (PubMed:22849347).
Transcription factor required for the development of the heart and the spleen (PubMed:22560297). During heart development, acts as a transcriptional activator of NPPA/ANF in cooperation with GATA4 (By similarity). May cooperate with TBX2 to negatively modulate expression of NPPA/ANF in the atrioventricular canal (By similarity). Binds to the core DNA motif of NPPA promoter (PubMed:22849347, PubMed:26926761). Together with PBX1, required for spleen development through a mechanism that involves CDKN2B repression (PubMed:22560297). Positively regulates transcription of genes such as COL3A1 and MMP2, resulting in increased pulmonary endothelial fibrosis in response to hypoxia (PubMed:29899023).
Expressed in the digestive system. Expressed in the epidermis of skin keratinocytes. Strongly expressed in the granular layer. Expressed in the upper epidermis and eccrine sweat glands of the dermis and in the region of keratin filament bundles, which is more pronounced in upper epidermal layers and in the lower cornified layers.
Omega-hydroxyceramide transacylase involved in the synthesis of omega-O-acylceramides (esterified omega-hydroxyacyl-sphingosine; EOS), which are extremely hydrophobic lipids involved in skin barrier formation (PubMed:27751867, PubMed:28248318). Catalyzes the last step of the synthesis of omega-O-acylceramides by transferring linoleic acid from triglycerides to an omega-hydroxyceramide (PubMed:27751867, PubMed:28248318). Omega-O-acylceramides, are required for the biogenesis of lipid lamellae in the stratum corneum and the formation of the cornified lipid envelope which are essential for the epidermis barrier function (PubMed:22246504, PubMed:27751867, PubMed:28248318). These lipids also play a role in keratinocyte differentiation (By similarity). May also act on omega-hydroxylated ultra-long chain fatty acids (omega-OH ULCFA) and acylglucosylceramides (GlcEOS) (By similarity).
Up-regulated upon induced differentiation of keratinocytes.
Heterodimer of a type I and a type II keratin. Associates with KRT16 and/or KRT17 (By similarity).
Highly expressed in hair follicles from scalp. Specifically expressed in the inner root sheath (IRS) of the hair follicle. Present in the all 3 IRS layers: the cuticle, the Henle and the Huxley layers. Also detected in the pseudopods of specialized Huxley cells, termed Fluegelzellen, along the area of differentiated Henle cells (at protein level).
In all 3 IRS layers, expression begins simultaneously in adjacent cells of the lowermost bulb above the germinative cell pool and terminated higher up in the follicle with the asynchronous terminal differentiation of each cell layer (at protein level).
Plays a central role in hair formation. Essential component of keratin intermediate filaments in the inner root sheath (IRS) of the hair follicle.
Autophosphorylated on tyrosine residues between pH 7.9 and pH 10.5.
Probable tetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains contribute to the formation of the ligand-binding domain, while the beta chains carry the kinase domain.
Receptor with tyrosine-protein kinase activity. Functions as a pH sensing receptor which is activated by increased extracellular pH. Activates an intracellular signaling pathway that involves IRS1 and AKT1/PKB.
The extracellular domain is required for sensing alterations in external pH.
Abundantly expressed in pancreas and kidney and to a lower level in brain, testis, colon, and small intestine. Isoform b is strongly expressed in kidney (primarily in the proximal tubule) and pancreas, whereas isoform c is abundantly expressed in brain.
Outward rectifying potassium channel. Produces rapidly activating and non-inactivating outward rectifier K(+) currents. Activated by arachidonic acid and other naturally occurring unsaturated free fatty acids.
Confers bitter perception of salicin to non-taster mice.
Expressed in a subset of gustducin-positive taste receptor cells of the tongue. Expressed in circumvallate papillae and testis (PubMed:16720576).
Genetic variation in TAS2R16 influences sensitivity to beta-glucopyranoside tasting (BGLPT) [MIM:617956]. Variant Asn-172 results in greater receptor activation in response to bitter beta-glucopyranoside compounds including salicin, arbutin and amygdalin compared to Lys-172 (PubMed:16051168). Variant Lys-172 may influence risk of alcohol dependence (PubMed:16385453).
Homodimer. Interacts with F-actin, PKD2, NPHS1 and NPHS2. Interacts with WTIP. Interacts with DDN; interaction is direct. Interacts (via SH3 2 domain) with CBL (via phosphorylated C-terminus). Interacts with BCAR1/p130Cas (via SH3 domain). Interacts with MVB12A and ARHGAP17. Interacts with ANLN, CD2 and CBLB. Interacts with PDCD6IP and TSG101. Interacts with RIN3. Interacts directly with RET (inactive) and CBLC; upon RET activation by GDNF suggested to dissociate from RET as CBLC:CD2AP complex (Probable) (PubMed:10339567, PubMed:11067845, PubMed:15800069, PubMed:16678097, PubMed:16895919, PubMed:17020880, PubMed:17853893, PubMed:18753381, Ref.30). Interacts with CGNL1 and SH3BP1; probably part of a complex at cell junctions (PubMed:22891260). Interacts with CAPZA1 (PubMed:22891260).
Phosphorylated on tyrosine residues; probably by c-Abl, Fyn and c-Src.
Potential homodimerization is mediated by the coiled coil domain.
Seems to act as an adapter protein between membrane proteins and the actin cytoskeleton (PubMed:10339567). In collaboration with CBLC, modulates the rate of RET turnover and may act as regulatory checkpoint that limits the potency of GDNF on neuronal survival. Controls CBLC function, converting it from an inhibitor to a promoter of RET degradation (By similarity). May play a role in receptor clustering and cytoskeletal polarity in the junction between T-cell and antigen-presenting cell (By similarity). May anchor the podocyte slit diaphragm to the actin cytoskeleton in renal glomerolus. Also required for cytokinesis (PubMed:15800069). Plays a role in epithelial cell junctions formation (PubMed:22891260).
The Pro-rich domain may mediate binding to SH3 domains.
Binding to NEK9 stimulates its activity by releasing the autoinhibitory function of Tyr-97.
Displays an autoinhibited conformation: Tyr-97 side chain points into the active site, interacts with the activation loop, and blocks the alphaC helix. The autoinhibitory conformation is released upon binding with NEK9.
Highly expressed in lung, muscle, testis, brain, heart, liver, leukocyte and spleen. Lower expression in ovary, prostate and kidney. No expression seen in small intestine.
Monomer (PubMed:21320329). Interacts with NEK9; interaction takes place during mitosis; it relieves NEK7 autoinhibition and prevents interaction with NLRP3 (PubMed:19414596, PubMed:19941817, PubMed:26522158). Interacts with ANKS3; this interaction alters the subcellular distribution of NEK7 by preventing its nuclear translocation (PubMed:26188091). Interacts (via N-terminus) with NLRP3 (via LRR repeat domain); the interaction is required for the formation of the complex NLRP3:PYCARD, oligomerization of PYCARD and activation of CASP1 (PubMed:31189953, PubMed:36442502).
Phosphorylation at Ser-195 required for its activation.
Protein kinase which plays an important role in mitotic cell cycle progression (PubMed:17101132, PubMed:31409757, PubMed:19941817). Required for microtubule nucleation activity of the centrosome, robust mitotic spindle formation and cytokinesis (PubMed:17586473, PubMed:19414596, PubMed:31409757, PubMed:19941817, PubMed:26522158). Phosphorylates EML4 at 'Ser-146', promoting its dissociation from microtubules during mitosis which is required for efficient chromosome congression (PubMed:31409757). Phosphorylates RPS6KB1 (By similarity). Acts as an essential activator of the NLRP3 inflammasome assembly independently of its kinase activity (PubMed:26642356, PubMed:36442502). Acts by unlocking NLRP3 following NLRP3 tranlocation into the microtubule organizing center (MTOC), relieving NLRP3 autoinhibition and promoting formation of the NLRP3:PYCARD complex, and activation of CASP1 (PubMed:26642356, PubMed:31189953, PubMed:36442502). Serves as a cellular switch that enforces mutual exclusivity of the inflammasome response and cell division: interaction with NEK9 prevents interaction with NLRP3 and activation of the inflammasome during mitosis (PubMed:26642356, PubMed:31189953).
The NTE (N-terminal extension) motif is a structural component of the catalytic domain and thus contributes to activity.
Expressed in the ileocecum, thyroid gland, pituitary gland, salivary gland, adrenal gland, testis, ovary and brain.
Receptor for prokineticin 2. Exclusively coupled to the G(q) subclass of heteromeric G proteins. Activation leads to mobilization of calcium, stimulation of phosphoinositide turnover and activation of p44/p42 mitogen-activated protein kinase.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in PROKR2 as well as in other HH-associated genes including KAL1, SEMA3A, PROK2, GNRH1 and FGFR1 (PubMed:17054399, PubMed:22927827, PubMed:23643382).
Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation.
Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments (PubMed:18039658). Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation (PubMed:18799458, PubMed:17461796, PubMed:18197702, PubMed:22074827). Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway (PubMed:18660751). Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.
Expressed in neuro-epithelioma, colon carcinoma, hepatic and pancreatic cell lines, and in Schwann cells.
Genetic variations in PCSK9 define the low density lipoprotein cholesterol level quantitative trait locus 1 (LDLCQ1) [MIM:603776].
Its proteolytic activity is autoinhibited by the non-covalent binding of the propeptide to the catalytic domain. Inhibited by EGTA.
Monomer. Can self-associate to form dimers and higher multimers which may have increased LDLR degrading activity. The precursor protein but not the mature protein may form multimers. Interacts with APOB, VLDLR, LRP8/APOER2 and BACE1. The full-length immature form (pro-PCSK9) interacts with SCNN1A, SCNN1B and SCNN1G. The pro-PCSK9 form (via C-terminal domain) interacts with LDLR. Interacts (via the C-terminal domain) with ANXA2 (via repeat Annexin 1); the interaction inhibits the degradation of LDLR (PubMed:18799458).
Phosphorylation protects the propeptide against proteolysis.
The C-terminal domain (CRD) is essential for the LDLR-binding and degrading activities.
The catalytic domain is responsible for mediating its self-association.
Undergoes autocatalytic cleavage in the endoplasmic reticulum to release the propeptide from the N-terminus and the cleavage of the propeptide is strictly required for its maturation and activation. The cleaved propeptide however remains associated with the catalytic domain through non-covalent interactions, preventing potential substrates from accessing its active site. As a result, it is secreted from cells as a propeptide-containing, enzymatically inactive protein.
Variant Leu-23 ins polymorphism in PCSK9 might have a modifier effect on LDLR mutation and familial hypercholesterolemia.
Catalyzes the interconversion of L-lactate and pyruvate with nicotinamide adenine dinucleotide NAD(+) as a coenzyme (PubMed:18351441). Significantly increases the transcriptional activity of JUN, when overexpressed.
Although it belongs to the protein phosphatase 2C family, it lacks some of the conserved residues that bind manganese, suggesting it has no phosphatase activity.
5'-3' exonuclease that plays a central role in telomere maintenance and protection during S-phase. Participates in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair, thereby ensuring that telomeres do not fuse. Plays a key role in telomeric loop (T loop) formation by being recruited by TERF2 at the leading end telomeres and by processing leading-end telomeres immediately after their replication via its exonuclease activity: generates 3' single-stranded overhang at the leading end telomeres avoiding blunt leading-end telomeres that are vulnerable to end-joining reactions and expose the telomere end in a manner that activates the DNA repair pathways. Together with TERF2, required to protect telomeres from replicative damage during replication by controlling the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Also involved in response to DNA damage: plays a role in response to DNA interstrand cross-links (ICLs) by facilitating double-strand break formation. In case of spindle stress, involved in prophase checkpoint. Possesses beta-lactamase activity, catalyzing the hydrolysis of penicillin G and nitrocefin (PubMed:31434986). Exhibits no activity towards other beta-lactam antibiotic classes including cephalosporins (cefotaxime) and carbapenems (imipenem) (PubMed:31434986).
Belongs to the DNA repair metallo-beta-lactamase (DRMBL) family.
Interacts with TERF2; the interaction is direct (PubMed:16730176, PubMed:16606622, PubMed:16730175, PubMed:18468965, PubMed:18593705, PubMed:20655466, PubMed:35007328). Interacts with MUS81, MRE11 and FANCD2 (PubMed:18469862). Interacts with HSPA2, HSPA8 and HSPA14 (PubMed:19411856). Interacts with SPAG5 (PubMed:19197158).
The TBM domain mediates interaction with TERF2.
The disease is caused by variants affecting the gene represented in this entry. In addition to missense and stop-gain variants, an aberrant splice variant of DCLRE1B, designated Apollo-Delta, has been found in a patient with severe dyskeratosis congenita and features of Hoyeraal-Hreidarsson syndrome (PubMed:20479256). Apollo-Delta hampers the proper replication of telomeres, leading to major telomeric dysfunction and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome.
Ubiquitinated, leading to its degradation. Interaction with TERF2 protects it from ubiquitination.
Was named 'Apollo' in reference to the twin brother of 'Artemis' in Greek mythology (PubMed:16730175, PubMed:16730176). Artemis/DCLRE1C is a related nuclease.
A disulfide bond is seen in the crystal structure of the human protein, but the Cys residues are not conserved in rodents.
Autoproteolytic cleavage at pH 4.5 gives rise to the alpha and beta subunit (PubMed:15655246, PubMed:22040171, PubMed:17980170, PubMed:18793752, PubMed:30301806). Cleavage gives rise to a conformation change that activates the enzyme (PubMed:17980170, PubMed:18793752, PubMed:30301806, PubMed:22040171). The same catalytic Cys residue mediates the autoproteolytic cleavage and subsequent hydrolysis of lipid substrates (PubMed:17980170, PubMed:18793752) (Probable).
Degrades bioactive fatty acid amides to their corresponding acids, with the following preference: N-palmitoylethanolamine > N-myristoylethanolamine > N-lauroylethanolamine = N-stearoylethanolamine > N-arachidonoylethanolamine > N-oleoylethanolamine (PubMed:15655246, PubMed:17980170, PubMed:18793752, PubMed:30301806, PubMed:22825852). Also exhibits weak hydrolytic activity against the ceramides N-lauroylsphingosine and N-palmitoylsphingosine (PubMed:15655246).
Expressed in numerous tissues, with highest levels in liver and kidney, followed by pancreas.
Heterodimer of an alpha and a beta subunit, produced by autocatalytic cleavage.
N-glycosylated (PubMed:17980170, PubMed:18793752, PubMed:30301806). Tunicamycin treatment causes a reduction in specific activity against N-palmitoylethanolamine.
Detected in dendritic cells. Highly expressed in tumor cell lines, but not detectable in most tissues.
Belongs to the SMC family. SMC1 subfamily.
Forms a heterodimer with SMC3 in cohesin complexes (PubMed:22628566). Cohesin complexes are composed of the SMC1 (SMC1A or SMC1B) and SMC3 heterodimer attached via their SMC hinge domain, RAD21 which link them, and one STAG protein (STAG1, STAG2 or STAG3), which interacts with RAD21 (PubMed:11076961, PubMed:22628566, PubMed:32409525). In germ cell cohesin complexes, SMC1A is mutually exclusive with SMC1B (By similarity). Interacts with BRCA1 (PubMed:11877377). Found in a complex with CDCA5, SMC3 and RAD21, PDS5A/SCC-112 and PDS5B/APRIN (PubMed:15837422). Interacts with NDC80 (PubMed:9295362, PubMed:10409732). Interacts with BRAT1 (PubMed:22977523). Found in a complex containing POLE and SMC3. Interacts with RPGR, STAG3 and SYCP2 (By similarity). The cohesin complex interacts with the cohesin loading complex subunits NIPBL/Scc2 (via HEAT repeats) and MAU2/Scc4 (PubMed:22628566). NIPBL directly contacts all members of the complex, RAD21, SMC1A/B, SMC3 and STAG1 (PubMed:22628566, PubMed:32409525).
Involved in chromosome cohesion during cell cycle and in DNA repair. Central component of cohesin complex. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis. Involved in DNA repair via its interaction with BRCA1 and its related phosphorylation by ATM, or via its phosphorylation by ATR. Works as a downstream effector both in the ATM/NBS1 branch and in the ATR/MSH2 branch of S-phase checkpoint.
Mutated Cornelia de Lange cell lines display genomic instability and sensitivity to ionizing radiation and interstrand cross-linking agents.
Phosphorylated by ATM upon ionizing radiation in a NBS1-dependent manner. Phosphorylated by ATR upon DNA methylation in a MSH2/MSH6-dependent manner. Phosphorylation of Ser-957 and Ser-966 activates it and is required for S-phase checkpoint activation.
The flexible SMC hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC3, forming a V-shaped heterodimer. The two heads of the heterodimer are then connected by different ends of the cleavable RAD21 protein, forming a ring structure (By similarity).
Ubiquitinated by the DCX(DCAF15) complex, leading to its degradation.
Golgi-localized palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates (PubMed:19001095, PubMed:21926431, PubMed:22240897, PubMed:23034182, PubMed:22314500). Has no stringent fatty acid selectivity and in addition to palmitate can also transfer onto target proteins myristate from tetradecanoyl-CoA and stearate from octadecanoyl-CoA (By similarity). Plays an important role in G protein-coupled receptor signaling pathways involving GNAQ and potentially other heterotrimeric G proteins by regulating their dynamic association with the plasma membrane (PubMed:19001095). Palmitoylates ITGA6 and ITGB4, thereby regulating the alpha-6/beta-4 integrin localization, expression and function in cell adhesion to laminin (PubMed:22314500). Plays a role in the TRAIL-activated apoptotic signaling pathway most probably through the palmitoylation and localization to the plasma membrane of TNFRSF10A (PubMed:22240897). In the brain, by palmitoylating the gamma subunit GABRG2 of GABA(A) receptors and regulating their postsynaptic accumulation, plays a role in synaptic GABAergic inhibitory function and GABAergic innervation (By similarity). Palmitoylates the neuronal protein GAP43 which is also involved in the formation of GABAergic synapses (By similarity). Palmitoylates NCDN thereby regulating its association with endosome membranes (By similarity). Probably palmitoylates PRCD and is involved in its proper localization within the photoreceptor (By similarity). Could mediate the palmitoylation of NCAM1 and regulate neurite outgrowth (By similarity). Could palmitoylate DNAJC5 and regulate its localization to Golgi membranes (By similarity). Also constitutively palmitoylates DLG4 (By similarity). May also palmitoylate SNAP25 (By similarity). Could palmitoylate the glutamate receptors GRIA1 and GRIA2 but this has not been confirmed in vivo (By similarity). Could also palmitoylate the D(2) dopamine receptor DRD2 (PubMed:26535572). May also palmitoylate LAMTOR1, promoting its localization to lysosomal membranes (PubMed:35893977).
May also function as a calcium transporter.
Monomer. Homooligomers. The monomeric form has a higher catalytic activity. Forms heterooligomers with ZDHHC7 (By similarity). Interacts with TNFRSF10A (PubMed:22240897).
Phosphorylation by FGFR1 and SRC probably regulates the palmitoyltransferase activity.
Widely expressed with significant expression in heart, lung, liver, skeletal muscle, kidney, testis, thymus, small intestine and leukocyte.
Acts as a negative coregulator of ESR1-mediated transcription in breast cancer cells.
Binds to the LIM domain of a wide variety of LIM domain-containing transcription factors. May regulate the transcriptional activity of LIM-containing proteins by determining specific partner interactions. Plays a role in the development of interneurons and motor neurons in cooperation with LHX3 and ISL1. Acts synergistically with LHX1/LIM1 in axis formation and activation of gene expression. Acts with LMO2 in the regulation of red blood cell development, maintaining erythroid precursors in an immature state.
Due to intron retention. Lacks LIM-binding domain.
Expressed in a wide range of adult tissues including brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, lung and peripheral blood leukocytes.
Interacts with ESR1 (PubMed:19117995). Forms homodimers and heterodimers. Interacts with and activates LHX1/LIM1. Interacts with the LIM domains of ISL1 and LMO2. Can assemble in a complex with LMO2 and TAL1/SCL but does not interact with TAL1/SCL directly. Strongly interacts with the LIM2 domain of LMX1A and more weakly with the LIM1 domain. Homodimerization is not required for, and does not effect, LMX1A-binding. Component of a nuclear TAL-1 complex composed at least of CBFA2T3, LDB1, TAL1 and TCF3. Interacts with LHX6 and LHX9. At neuronal promoters, forms a complex with LHX3 involved in the specification of interneurons, in motor neurons, it is displaced by ISL1 to form a ternary complex in which ISL1 contacts both LHX3 and LDB1. Interacts with SLK; leading to negatively regulate SLK kinase activity (By similarity). Interacts with YWHAZ. Interacts with PRDM1/BLIMP1 (PubMed:32417234). Interacts with LMO4. Interacts with RLIM/RNF12; the interaction inhibits the ubiquitination of LMO proteins (By similarity).
The dimerization domain is located in the N-terminus.
Ubiquitinated by RLIM/RNF12, leading to its degradation by the proteasome.
Binds cholesterol in a hydrophobic pocket; there are no hydrogen bonds between the sterol and the protein.
Detected in gallbladder bile (PubMed:21315718). Detected in fibroblasts, kidney, liver, spleen, small intestine, placenta and testis (at protein level) (PubMed:11125141). Epididymis.
Down-regulated in response to enterovirus 71 (EV71) infection.
Interacts with NPC1 (via the second lumenal domain) in a cholestrol-dependent manner (PubMed:18772377, PubMed:27238017, PubMed:27551080). Interacts with NUS1/NgBR, the interaction stabilizes NCP2 and regulates cholesterol trafficking (PubMed:19723497). Interacts with DHDDS (PubMed:15110773). Interacts with NEDD4L (via C2 domain) (PubMed:19664597). Interacts with NPC1L1 (PubMed:22095670).
Intracellular cholesterol transporter which acts in concert with NPC1 and plays an important role in the egress of cholesterol from the lysosomal compartment (PubMed:17018531, PubMed:11125141, PubMed:18772377, PubMed:29580834, PubMed:15937921). Unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes is transferred by NPC2 to the cholesterol-binding pocket in the N-terminal domain of NPC1 (PubMed:17018531, PubMed:18772377, PubMed:27238017). May bind and mobilize cholesterol that is associated with membranes (PubMed:18823126). NPC2 binds cholesterol with a 1:1 stoichiometry (PubMed:17018531). Can bind a variety of sterols, including lathosterol, desmosterol and the plant sterols stigmasterol and beta-sitosterol (PubMed:17018531). The secreted form of NCP2 regulates biliary cholesterol secretion via stimulation of ABCG5/ABCG8-mediated cholesterol transport (By similarity).
Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway. The secreted form behaves both as a cytokine with immunomodulating properties and an adipokine with anti-diabetic properties, it has no enzymatic activity, partly because of lack of activation by ATP, which has a low level in extracellular space and plasma. Plays a role in the modulation of circadian clock function. NAMPT-dependent oscillatory production of NAD regulates oscillation of clock target gene expression by releasing the core clock component: CLOCK-BMAL1 heterodimer from NAD-dependent SIRT1-mediated suppression (By similarity).
Expressed in large amounts in bone marrow, liver tissue, and muscle. Also present in heart, placenta, lung, and kidney tissues.
Inhibited by FK866. FK866 competes for the same binding site as nicotinamide, but due to its very low dissociation rate, it is essentially an irreversible inhibitor.
Highest level in brain, particularly in the frontal cortex and hypothalamus, lower levels in the liver and heart.
It is uncertain whether Met-1, Met-6 or Met-70 is the initiator.
Receptor for melanin-concentrating hormone, coupled to both G proteins that inhibit adenylyl cyclase and G proteins that activate phosphoinositide hydrolysis.
May down-regulate transcription mediated by NF-kappa-B and the serum response element.
A short helical region is required and sufficient for Cu(2+) binding.
Expressed in testis, in Sertoli cells, ejaculated spermatozoa and in seminal fluid (at protein level).
N-glycosylated. N-glycosylated at two distinct sites.
Required for normal acrosome reaction and for normal male fertility (By similarity). Can bind Cu(2+) (PubMed:15218028, PubMed:20411530).
Acts as component of the EARP complex that is involved in endocytic recycling. The EARP complex associates with Rab4-positive endosomes and promotes recycling of internalized transferrin receptor (TFRC) to the plasma membrane. Within the EARP complex, required to tether the complex to recycling endosomes. Not involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN).
Component of the endosome-associated retrograde protein (EARP) complex, composed of VPS51, VPS52, VPS53 and VPS50/Syndetin (PubMed:25799061, PubMed:27440922). The EARP complex interacts with EIPR1 (PubMed:27440922). Interacts with VPS51 and VPS53 in an EIPR1-independent manner (PubMed:31721635).
Ubiquitous, with higher expression in brain and skeletal muscle.
Was named 'syndetin' after the Greek 'syndeo', which means 'connect' or 'tether'.
Exon 1 splicing donor site is not canonical.
Forms a ternary complex with DKK1 and LRP6 (PubMed:27524201). Interacts with LRP6 in a DKK1-dependent manner. Interacts with DKK1 and RSPO1 (via FU repeats) (PubMed:17804805).
Receptor for Dickkopf proteins. Cooperates with DKK1/2 to inhibit Wnt/beta-catenin signaling by promoting the endocytosis of Wnt receptors LRP5 and LRP6. In the absence of DKK1, potentiates Wnt-beta-catenin signaling by maintaining LRP5 or LRP6 at the cell membrane. Can trigger apoptosis in a Wnt-independent manner and this apoptotic activity is inhibited upon binding of the ligand DKK1. Plays a role in limb development; attenuates Wnt signaling in the developing limb to allow normal limb patterning and can also negatively regulate bone formation. Modulates cell fate decisions in the developing cochlea with an inhibitory role in hair cell fate specification.
Although highly related to the Ras family, lacks the conserved prenylation motif at the C-terminus, which serves to target Ras proteins to membrane compartments.
Down-regulated during development of THP-1 monocytes into macrophages.
Regulator of rDNA transcription. Acts in cooperation UBF/UBTF and positively regulates RNA polymerase I transcription (By similarity).
Widely expressed. Down-regulated in prostate tumors compared to normal prostate tissue. High levels found in colon tumor and normal colon tissue followed by small intestine, liver, jejunum, ileum, bladder and aorta. Lowest levels observed in endothelial cells.
Interacts with CEP43; this interaction is required for its localization to the mother centriole (PubMed:28625565, PubMed:28428259, PubMed:28659385). Interacts (via residues 121-150) with RABL2B (PubMed:28625565, PubMed:28428259). Interacts (via C-terminus) with CEP350; this interaction is required for its localization to the mother centriole (PubMed:28659385).
Required for ciliation (PubMed:28625565, PubMed:28428259, PubMed:28659385). Recruits the RABL2B GTPase to the ciliary base to initiate ciliation. After specifically capturing the activated GTP-bound RABL2B, the CEP19-RABL2B complex binds intraflagellar transport (IFT) complex B from the large pool pre-docked at the base of the cilium and thus triggers its entry into the cilia (PubMed:28625565, PubMed:28428259). Involved in the early steps in cilia formation by recruiting the ciliary vesicles (CVs) to the distal end of the mother centriole where they fuse to initiate cilium assembly. Involved in microtubule (MT) anchoring to the centrosomes (PubMed:28659385).
The region that interacts with CEP43 is conflicting: According to a report, interacts via N-terminus (PubMed:28428259). According to another report, interacts via C-terminus (PubMed:28659385).
Deubiquitinating enzyme that plays a role in various cellular processes, including DNA repair, cell cycle regulation, and immune response (PubMed:22689415, PubMed:30497519, PubMed:31874856, PubMed:35238669). Plays a role in the inhibition of type I interferon signaling by mediating the 'Lys-33' to 'Lys-48' ubiquitination transition of TBK1 leading to its degradation (PubMed:27692986). Cleaves the ubiquitin chain from the histone demethylase LSD1/KDM1A and prevents it from degradation by the 26S proteasome, thus maintaining LSD1 protein level in cells (PubMed:30497519). Plays a role in the DNA damage response by regulating the deacetylase activity of HDAC1 (PubMed:31874856). Mechanistically, removes the 'Lys-63'-linked ubiquitin chain promoting the deacetylase activity of HDAC1 in response to DNA damage (PubMed:31874856). Acts also as a specific deubiquitinase of histone deacetylase 3/HDAC3 and cleaves its 'Lys-63'-linked ubiquitin chains to lower its histone deacetylase activity (PubMed:32404892). Regulates MYC levels and cell proliferation via antagonizing ubiquitin E3 ligase FBXW7 thereby preventing MYC 'Lys-48'-linked ubiquitination and degradation (PubMed:34102342). Participates in antiviral response by removing both 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of Zika virus envelope protein E (PubMed:34696459). Constitutively associated with IL-33R/IL1RL1, deconjugates its 'Lys-27'-linked polyubiquitination resulting in its autophagic degradation (PubMed:35238669).
Highly expressed in skeletal muscle. Expressed in adrenal gland.
Interacts with isoform 1 of FBXW7; this interaction prevents FBXW7-mediated degradation of MYC.
The absence of the residues from Tyr-840 to Ser-871 is not the result of an alternative splicing.
Receptor for Slit proteins, at least for SLIT2, and seems to be involved in angiogenesis and vascular patterning. May mediate the inhibition of primary endothelial cell migration by Slit proteins (By similarity). Involved in the maintenance of endothelial barrier organization and function (PubMed:30455415).
Specifically expressed in endothelial cells. Expressed in endothelial and intimal cells of the ascending aorta (PubMed:30455415).
Can form homooligomers. Homodimer formation at the N-terminus may be regulated by ATP and is required for the interaction with the inner surface of the mitochondrial outer membrane and correct mitochondrial homeostasis. Interacts with components of the mitochondrial ribosome and with other proteins involved in mitochondrial RNA metabolism. May also interact with protein involved in lipid metabolism, including STARD9. May interact with FAM210A. Interacts with GADD45GIP1. Interacts with S100B in a Ca(+2)- and Zn(+2)-dependent manner; this interaction probably occurs in the cytosol prior to mitochondrial targeting. S100B could assist ATAD3A cytoplasmic processing, preventing aggregation and favoring mitochondrial localization. Interacts with HSP60/HSPD1. Forms heterooligomers with ATAD3B; this interaction may affect ATAD3A activity. Interacts with CLPB (PubMed:31522117).
Essential for mitochondrial network organization, mitochondrial metabolism and cell growth at organism and cellular level. May play an important role in mitochondrial protein synthesis. May also participate in mitochondrial DNA replication. May bind to mitochondrial DNA D-loops and contribute to nucleoid stability. Required for enhanced channeling of cholesterol for hormone-dependent steroidogenesis. Involved in mitochondrial-mediated antiviral innate immunity (PubMed:31522117).
Overexpressed in lung adenocarcinomas (at protein level).
The transmembrane domain and a C-terminal adjacent region contain all information necessary for mitochondrial targeting.
A publication reports an opposite topology (PubMed:26774479). However, 3 different articles, 2 in human and one in mouse, confirm the topology shown in this entry (PubMed:27099988, PubMed:27642048).
Component of the uniplex complex, composed of MCU, MCUB, MICU1, MICU2 and EMRE/SMDT1 (PubMed:24231807). Interacts (via the transmembrane region) with MCU (via the first transmembrane region); the interaction is direct (PubMed:27099988). Interacts (via the poly-Asp region) with MICU1 (via polybasic region); the interaction is direct (PubMed:27099988). Interacts (via its C-terminal poly-Asp tail) with MCUR1; the interaction is direct (PubMed:27184846). Unprocessed form interacts (via transit peptide) with MAIP1 (PubMed:27642048).
Essential regulatory subunit of the mitochondrial calcium uniporter complex (uniplex), a complex that mediates calcium uptake into mitochondria (PubMed:24231807, PubMed:26774479, PubMed:27099988). Required to bridge the calcium-sensing proteins MICU1 and MICU2 with the calcium-conducting subunit MCU (PubMed:24231807). Plays a central role in regulating the uniplex complex response to intracellular calcium signaling (PubMed:27099988). Acts by mediating activation of MCU and retention of MICU1 to the MCU pore, in order to ensure tight regulation of the uniplex complex and appropriate responses to intracellular calcium signaling (PubMed:27099988).
The GXXXX[G/A/S] motif at the C-terminal part of the transmembrane region mediates interaction with MCU and is required to activate the calcium-conducting pore in the uniporter complex.
The poly-Asp region at the C-terminus mediates interaction with the polybasic region of MICU1.
Undergoes proteolytic degradation in neurons: degraded by AFG3L2 before SMDT1/EMRE assembly with the uniporter complex, limiting the availability of SMDT1/EMRE for MCU assembly and promoting efficient assembly of gatekeeper subunits with MCU (PubMed:27642048).
Endothelial cells are unique in synthesizing thrombomodulin.
Extracellular region (481-515) contains a binding side for alpha-L/beta-2 and alpha-M/beta-2 integrin.
The disease may be caused by variants affecting the gene represented in this entry. The role of thrombomodulin in thrombosis is controversial. It is likely that genetic or environmental risk factors in addition to THBD variation are involved in the pathogenesis of venous thrombosis.
Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated.
Expression is restricted to the hematopoietic tissues with the exception of liver. Expressed in fetal liver, spleen and thymus. Preferentially expressed by mature leukocytes (at protein level).
Homodimer; active form in leukocyte-endothelial cell adhesion. Interacts (homodimeric form) with CXADR. Interacts (via cytoplasmic domain) with the PI3 kinase; upon CXADR-binding. Interacts with ITGA4 and ITGB1; integrin alpha-4/beta-1 may regulate leukocyte to endothelial cells adhesion by controlling JAML homodimerization.
The Ig-like V-type domain 1 mediates interaction with CXADR (By similarity). The Ig-like V-type domain 2 may also play a role in the interaction (PubMed:15800062).
Transmembrane protein of the plasma membrane of leukocytes that control their migration and activation through interaction with CXADR, a plasma membrane receptor found on adjacent epithelial and endothelial cells. The interaction between both receptors mediates the activation of gamma-delta T-cells, a subpopulation of T-cells residing in epithelia and involved in tissue homeostasis and repair. Upon epithelial CXADR-binding, JAML induces downstream cell signaling events in gamma-delta T-cells through PI3-kinase and MAP kinases. It results in proliferation and production of cytokines and growth factors by T-cells that in turn stimulate epithelial tissues repair. It also controls the transmigration of leukocytes within epithelial and endothelial tissues through adhesive interactions with epithelial and endothelial CXADR.
Up-regulated upon retinoic acid, Me2SO and PMA treatment in differentiating myeloid leukemia cells.
C2 domain 1 is involved in binding calcium and phospholipids. C2 domain 2 may also play a role in the calcium-dependent targeting to membranes (By similarity).
Calcium sensor which positively regulates SNARE-dependent fusion of vesicles with membranes. Binds phospholipids in a calcium-dependent manner and may act at the priming stage of fusion by modifying membrane curvature to stimulate fusion. Involved in calcium-triggered exocytosis in chromaffin cells and calcium-dependent spontaneous release of neurotransmitter in absence of action potentials in neuronal cells. Involved both in glucose-stimulated insulin secretion in pancreatic cells and insulin-dependent GLUT4 transport to the plasma membrane in adipocytes (By similarity).
Interacts with the SNARE (soluble N-ethylmaleimide-sensitive factor attached protein receptor) complex composed of SNAP25, STX1A and VAMP2; the interaction is calcium-dependent and competitive with SYT1. Interacts with STX4; the interaction is calcium-dependent, increased by insulin and glucose, and mediates vesicle fusion with plasma membrane in pancreatic cells and adipocytes. Interacts with STXBP3; the interaction is direct, occurs at the cell membrane and regulates glucose-stimulated insulin secretion. May interact with UNC13A; the interaction mediates targeting to the plasma membrane (By similarity). Interacts with cytoplasmic dynein light chain DYNLT1.
Widely expressed with highest levels in brain and kidney. Expressed in pancreatic islet cells (at protein level).
Calcium- and integrin-binding protein that plays a role in intracellular calcium homeostasis (By similarity). Acts as a auxiliary subunit of the sensory mechanoelectrical transduction (MET) channel in hair cells (By similarity). Essential for mechanoelectrical transduction (MET) currents in auditory hair cells and thereby required for hearing (By similarity). Regulates the function of hair cell mechanotransduction by controlling the distribution of transmembrane channel-like proteins TMC1 and TMC2, and by regulating the function of the MET channels in hair cells (By similarity). Required for the maintenance of auditory hair cell stereocilia bundle morphology and function and for hair-cell survival in the cochlea (By similarity). Critical for proper photoreceptor cell maintenance and function (By similarity). Plays a role in intracellular calcium homeostasis by decreasing ATP-induced calcium release (PubMed:23023331, PubMed:26173970, PubMed:26426422).
Monomer (PubMed:31636333). Homodimer (PubMed:23023331). Interacts with WHRN and MYO7A (PubMed:23023331, PubMed:26426422). Interacts with ITGA2B (via C-terminus cytoplasmic tail region); the interactions are stabilized/increased in a calcium and magnesium-dependent manner (PubMed:22779914). Interacts with ITGA7 (via C-terminus cytoplasmic tail region); the interactions are stabilized/increased in a calcium and magnesium-dependent manner (PubMed:22779914). Interacts with TMC1 (PubMed:28663585, PubMed:34089643). Interacts with TMC2 (PubMed:28663585).
The binding of either calcium or magnesium significantly increases the structural stability of the protein in comparison to apo-CIB (calcium- and magnesium-free form) (PubMed:22779914).
Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82 and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1R10/PNUTS (PubMed:20516061). Interacts with FOXO1 and CREB1 (increased by cAMP); FOXO1 and CREB1 are required for full induction of TOX4-dependent activity and the interactions are inhibited by insulin (By similarity).
Expression is highly induced in diabetic liver.
In liver, recruited to target gene promoters following treatment with dexamethasone and cAMP. Binding is decreased in presence of insulin.
Transcription factor that modulates cell fate reprogramming from the somatic state to the pluripotent and neuronal fate (By similarity). Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase (PubMed:20516061). In liver, controls the expression of hormone-regulated gluconeogenic genes such as G6PC1 and PCK1. This regulation is independent of the insulin receptor activation (By similarity).
Highly expressed in testis, skeletal muscle, brain, heart, placenta, kidney and liver and weakly expressed in thymus, small intestine, lung and colon.
Instead of Lys-820, Arg-820 is found at the binding site.
Interacts with SPHK1 and phosphatidylinositol 3-phosphate (PubMed:12077123). Interacts (via PX domain) with PRDX3 (PubMed:15750338).
May be involved in transmitting sphingosine-1 phosphate (SPP)-mediated signaling into the cell (PubMed:12077123). Plays a role in the recruitment of PRDX3 to early endosomes (PubMed:15750338).
The PX domain is essential for its localization to the early endosomes.
The first protein kinase domain appears to be a pseudokinase domain as it does not contain the classical characteristics, such as the ATP-binding motif, ATP-binding site and active site.
A Gly-cisPro motif from one monomer fits into the active site of the other monomer to allow specific chiral rejection of L-amino acids.
An aminoacyl-tRNA editing enzyme that deacylates mischarged D-aminoacyl-tRNAs. Also deacylates mischarged glycyl-tRNA(Ala), protecting cells against glycine mischarging by AlaRS. Acts via tRNA-based rather than protein-based catalysis; rejects L-amino acids rather than detecting D-amino acids in the active site. By recycling D-aminoacyl-tRNA to D-amino acids and free tRNA molecules, this enzyme counteracts the toxicity associated with the formation of D-aminoacyl-tRNA entities in vivo and helps enforce protein L-homochirality.
Expressed in many adult and fetal tissues. Highest levels in testis, ovary, spleen and in adult and fetal brain.
Homodimer (PubMed:15653697). Interacts with CDC45 and TOPBP1 (PubMed:20065034).
Possible ATPase (PubMed:15653697) involved in DNA replication, may facilitate loading of CDC45 onto pre-replication complexes (PubMed:20065034).
Preferentially phosphorylated in cells arrested early in S phase (PubMed:15653697). Phosphorylation in the C-terminus weakens the interaction with CDC45 (PubMed:20065034).
Component of the chaperonin-containing T-complex (TRiC), a heterooligomeric complex of about 850 to 900 kDa that forms two stacked rings, 12 to 16 nm in diameter (PubMed:25467444). Interacts with PACRG (PubMed:14532270). Interacts with DLEC1 (PubMed:33144677).
Expressed highly in the small intestine and appendix, moderately in lymph node, mucosal lining of the colon, thymus, spleen and very weakly in the bone marrow. Predominantly expressed in dendritic cells (DC) of the germinal center. Weakly expressed in monocyte and highly expressed in macrophage. Absent in immature DC.
Induced during DC maturation and up-regulated in response to T-cell signals. In macrophage up-regulated by bacterial lipopolysaccharides (LPS). Up-regulated by 1-alpha,25-dihydroxyvitamin D3 during differentiation of primary monocyte into macrophage.
May play an important role in the control of the immune response and during pregnancy.
Oligomeric complex that consists of at least the alpha, beta, beta', gamma, delta, epsilon and zeta subunits (By similarity). Probably interacts with PEX11A (By similarity). Interacts with SCYL1 (By similarity). Interacts with JAGN1 (PubMed:25129144). Interacts with TMEM41B (PubMed:30352685).
Uniformly expressed in a wide range of adult and fetal tissues. Xenin is found in gastric, duodenal and jejunal mucosa. Circulates in the blood. Seems to be confined to specific endocrine cells.
Xenin is released into the circulation after a meal.
Xenin stimulates exocrine pancreatic secretion. It inhibits pentagastrin-stimulated secretion of acid, to induce exocrine pancreatic secretion and to affect small and large intestinal motility. In the gut, xenin interacts with the neurotensin receptor.
Widely expressed, but at low level, except in the airway epithelial cells. Detected in brain, heart, kidney, liver, lung, spleen, testis and trachea.
High-affinity epithelial cell surface receptor for the FZD8-related low molecular weight sialoglycopeptide APF/antiproliferative factor. Mediates the APF antiproliferative signaling within cells.
Increased phosphorylation during mitosis prevents binding to microtubules.
Mediates the anchoring of the endoplasmic reticulum to microtubules.
Reversibly palmitoylated. Palmitoylation at Cys-100 by ZDHHC2 is required for its trafficking from the ER to the plasma membrane and for its perinuclear localization. Palmitoylation by ZDHHC2 is also required for its function in APF-mediated antiproliferative signaling (PubMed:19144824).
In case of Herpes simplex virus (HSVI)-binding to cells.
Interacts with ARL6 (By similarity). Interacts with ZCCHC17. Interacts with SRSF2.
Involved in modulating alternative pre-mRNA splicing with either 5' distal site activation or preferential use of 3' proximal site. In case of infection by Herpes simplex virus (HSVI), may act as a splicing inhibitor of HSVI pre-mRNA.
Isoforms 3 and 7 were identified in brain, pancreas, prostate, and testis, but little or no message could be detected in other tissues.
Partially edited. In the brain, edited at about 68%.
(Microbial infection) Acetylation of Thr-179 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B signaling pathway.
(Microbial infection) Interacts with InlC of Listeria monocytogenes.
Activated when phosphorylated and inactivated when dephosphorylated.
Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits (PubMed:32935379). The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:10195894, PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Directly interacts with TRPC4AP (By similarity). May interact with TRAF2 (PubMed:19150425). Interacts with NALP2 (PubMed:15456791). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with NLRC5; prevents CHUK phosphorylation and kinase activity (PubMed:20434986). Interacts with PIAS1; this interaction induces PIAS1 phosphorylation (PubMed:17540171). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with FOXO3 (PubMed:15084260). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14 (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Directly interacts with DDX3X after the physiological activation of the TLR7 and TLR8 pathways; this interaction enhances CHUK autophosphorylation (PubMed:30341167).
Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.
Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576, PubMed:35952808). These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11) (PubMed:21765415). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes (PubMed:20501937). In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities (PubMed:17434128). Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP (PubMed:12789342). Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:15084260). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates AMBRA1 following mitophagy induction, promoting AMBRA1 interaction with ATG8 family proteins and its mitophagic activity (PubMed:30217973).
Ubiquitinated by TRIM56 via 'Lys-63'-linked ubiquitination, promoting activation of CHUK/IKKA.
A chromosomal aberration involving PAX3 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with NCOA1 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children.
Can bind to DNA as a homodimer or a heterodimer with PAX7. Interacts with PAXBP1; the interaction links PAX3 to a WDR5-containing histone methyltransferase complex. Interacts with DAXX. Interacts with TBX18. Interacts with SOX10 (PubMed:21965087).
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving PAX3 is found in rhabdomyosarcoma. Translocation (2;13)(q35;q14) with FOXO1. The resulting protein is a transcriptional activator.
Transcription factor that may regulate cell proliferation, migration and apoptosis. Involved in neural development and myogenesis. Transcriptional activator of MITF, acting synergistically with SOX10 (PubMed:21965087).
Acetylated on Lys-6 and Lys-7. Acetylation is increased by the transcriptional coactivator EP300 acetyltransferase, genotoxic agents like H(2)O(2) and methyl methanesulfonate (MMS). Acetylation increases its binding affinity to the negative calcium response element (nCaRE) DNA promoter. The acetylated form induces a stronger binding of YBX1 to the Y-box sequence in the MDR1 promoter than the unacetylated form. Deacetylated on lysines. Lys-6 and Lys-7 are deacetylated by SIRT1.
Belongs to the DNA repair enzymes AP/ExoA family.
Cleaved at Lys-31 by granzyme A to create the mitochondrial form; leading in reduction of binding to DNA, AP endodeoxynuclease activity, redox activation of transcription factors and to enhanced cell death. Cleaved by granzyme K; leading to intracellular ROS accumulation and enhanced cell death after oxidative stress.
Cys-65 and Cys-93 are nitrosylated in response to nitric oxide (NO) and lead to the exposure of the nuclear export signal (NES).
Extract of mitochondria, but not of nuclei or cytosol, cleaves recombinant APEX1 to generate a mitochondrial APEX1-sized product (By similarity). The specific activity of the cleaved mitochondrial endodeoxyribonuclease appeared to be about 3-fold higher than that of the full-length form.
Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends.
Monomer. Homodimer; disulfide-linked. Component of the SET complex, composed of at least APEX1, SET, ANP32A, HMGB2, NME1 and TREX1. Associates with the dimer XRCC5/XRCC6 in a DNA-dependent manner. Interacts with SIRT1; the interaction is increased in the context of genotoxic stress. Interacts with HDAC1, HDAC2 and HDAC3; the interactions are not dependent on the APEX1 acetylation status. Interacts with XRCC1; the interaction is induced by SIRT1 and increased with the APEX1 acetylated form. Interacts with NPM1 (via N-terminal domain); the interaction is RNA-dependent and decreases in hydrogen peroxide-damaged cells. Interacts (via N-terminus) with YBX1 (via C-terminus); the interaction is increased in presence of APEX1 acetylated at Lys-6 and Lys-7. Interacts with HNRNPL; the interaction is DNA-dependent. Interacts (via N-terminus) with KPNA1 and KPNA2. Interacts with TXN; the interaction stimulates the FOS/JUN AP-1 complex DNA-binding activity in a redox-dependent manner. Interacts with GZMA, KRT8, MDM2, PRDX6, PRPF19, RPLP0, TOMM20 and WDR77. Interacts with POLB (PubMed:9207062, PubMed:26760506). Binds to CDK5.
Multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APEX1 are DNA repair and redox regulation of transcriptional factors. Functions as a apurinic/apyrimidinic (AP) endodeoxyribonuclease in the DNA base excision repair (BER) pathway of DNA lesions induced by oxidative and alkylating agents. Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends. Does also incise at AP sites in the DNA strand of DNA/RNA hybrids, single-stranded DNA regions of R-loop structures, and single-stranded RNA molecules. Has a 3'-5' exoribonuclease activity on mismatched deoxyribonucleotides at the 3' termini of nicked or gapped DNA molecules during short-patch BER. Possesses a DNA 3' phosphodiesterase activity capable of removing lesions (such as phosphoglycolate) blocking the 3' side of DNA strand breaks. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation. Acts as a loading factor for POLB onto non-incised AP sites in DNA and stimulates the 5'-terminal deoxyribose 5'-phosphate (dRp) excision activity of POLB. Plays a role in the protection from granzymes-mediated cellular repair leading to cell death. Also involved in the DNA cleavage step of class switch recombination (CSR). On the other hand, APEX1 also exerts reversible nuclear redox activity to regulate DNA binding affinity and transcriptional activity of transcriptional factors by controlling the redox status of their DNA-binding domain, such as the FOS/JUN AP-1 complex after exposure to IR. Involved in calcium-dependent down-regulation of parathyroid hormone (PTH) expression by binding to negative calcium response elements (nCaREs). Together with HNRNPL or the dimer XRCC5/XRCC6, associates with nCaRE, acting as an activator of transcriptional repression. Stimulates the YBX1-mediated MDR1 promoter activity, when acetylated at Lys-6 and Lys-7, leading to drug resistance. Acts also as an endoribonuclease involved in the control of single-stranded RNA metabolism. Plays a role in regulating MYC mRNA turnover by preferentially cleaving in between UA and CA dinucleotides of the MYC coding region determinant (CRD). In association with NMD1, plays a role in the rRNA quality control process during cell cycle progression. Associates, together with YBX1, on the MDR1 promoter. Together with NPM1, associates with rRNA. Binds DNA and RNA.
NPM1 stimulates endodeoxyribonuclease activity on double-stranded DNA with AP sites, but inhibits endoribonuclease activity on single-stranded RNA containing AP sites.
Phosphorylated. Phosphorylation by kinase PKC or casein kinase CK2 results in enhanced redox activity that stimulates binding of the FOS/JUN AP-1 complex to its cognate binding site. AP-endodeoxyribonuclease activity is not affected by CK2-mediated phosphorylation. Phosphorylation of Thr-233 by CDK5 reduces AP-endodeoxyribonuclease activity resulting in accumulation of DNA damage and contributing to neuronal death.
Probably binds two magnesium or manganese ions per subunit.
The N-terminus contains the redox activity while the C-terminus exerts the DNA AP-endodeoxyribonuclease activity; both function are independent in their actions. An unconventional mitochondrial targeting sequence (MTS) is harbored within the C-terminus, that appears to be masked by the N-terminal sequence containing the nuclear localization signal (NLS), that probably blocks the interaction between the MTS and Tom proteins.
Ubiquitinated by MDM2; leading to translocation to the cytoplasm and proteasomal degradation.
Up-regulated in presence of reactive oxygen species (ROS), like bleomycin, H(2)O(2) and phenazine methosulfate.
Amidohydrolase that hydrolyzes specifically one of the carboamide linkages in D-pantetheine thus recycling pantothenic acid (vitamin B5) and releasing cysteamine (PubMed:11491533). Involved in the thymus homing of bone marrow cells. May regulate beta-2 integrin-mediated cell adhesion, migration and motility of neutrophil.
Widely expressed with higher expression in spleen and blood.
Highly and selectively expressed by undifferentiated rather than differentiated embryonic stem cells (ESC). Levels rapidly diminish as soon as ESC's differentiate (at protein levels). Expressed in almost all epithelial cell membranes but not on mesodermal or neural cell membranes. Found on the surface of adenocarcinoma.
Hyperglycosylated in carcinoma tissue as compared with autologous normal epithelia. Glycosylation at Asn-198 is crucial for protein stability.
May act as a physical homophilic interaction molecule between intestinal epithelial cells (IECs) and intraepithelial lymphocytes (IELs) at the mucosal epithelium for providing immunological barrier as a first line of defense against mucosal infection. Plays a role in embryonic stem cells proliferation and differentiation. Up-regulates the expression of FABP5, MYC and cyclins A and E.
Monomer. Interacts with phosphorylated CLDN7.
The disease is caused by variants affecting the gene represented in this entry. LYNCH8 results from heterozygous deletion of 3-prime exons of EPCAM and intergenic regions directly upstream of MSH2, resulting in transcriptional read-through and epigenetic silencing of MSH2 in tissues expressing EPCAM.
(Microbial infection) In case of infection by polyomavirus, involved in the virus endoplasmic reticulum membrane penetration and infection (PubMed:25631089). Regulates the recruitment of DNAJB12:DNAJB14 into SV40-induced foci and all cooperate to guide SV40 across the endoplasmic reticulum membrane. The foci represent the site from which SV40 penetrates into the cytosol (PubMed:25631089).
Guanine nucleotide exchange factor for the small GTPase RALA. May be involved in cytoskeletal organization. May also be involved in the stimulation of transcription in a Ras-independent fashion (By similarity).
Interacts with the SH3 domains of GRB2 and PLCG1. Interacts with RALA.
RALGPS2 is a potential candidate gene for susceptibility to Alzheimer disease linked to 1q24.
The PH domain mediates binding to phosphatidylinositol 4,5-bisphosphate.
Acetylated by EP300 and KAT2B. HDAC6 drives TRIM50 deacetylation. Acetylation antagonizes with TRIM50 ubiquitination.
Can form dimers and trimers. Interacts with several E2 ubiquitin-conjugating enzymes, including UBE2L6, UBE2E1, UBE2E3. No interaction with UBE2H. Interacts with BECN1. Interacts with SQSTM1. Interacts with NLRP3 (By similarity).
E3 ubiquitin-protein ligase that ubiquitinates Beclin-1/BECN1 in a 'Lys-63'-dependent manner enhancing its binding to ULK1 (PubMed:29604308). In turn, promotes starvation-induced autophagy activation. Interacts also with p62/SQSTM1 protein and thereby induces the formation and the autophagy clearance of aggresome-associated polyubiquitinated proteins through HDAC6 interaction (PubMed:22792322). Promotes also NLRP3 inflammasome activation by directly inducing NLRP3 oligomerization independent of its E3 ligase function (By similarity).
A redox disulfide bond regulates the heme pocket coordination and the rate of nitrite reduction to NO.
Involved in oxygen transport in the brain. Hexacoordinate globin, displaying competitive binding of oxygen or the distal His residue to the iron atom. Not capable of penetrating cell membranes. The deoxygenated form exhibits nitrite reductase activity inhibiting cellular respiration via NO-binding to cytochrome c oxidase. Involved in neuroprotection during oxidative stress. May exert its anti-apoptotic activity by acting to reset the trigger level of mitochondrial cytochrome c release necessary to commit the cells to apoptosis.
Monomer. Homodimer and homotetramer; disulfide-linked (By similarity). Interacts with 14-3-3.
Phosphorylated in vitro by ERK1, ERK2 and PKA, and in vivo during hypoxia. Phosphorylation increases nitrite reductase activity.
Predominantly expressed in brain, the strongest expression is seen in the frontal lobe, the subthalamic nucleus and the thalamus.
(Microbial infection) Interacts with Kaposi's sarcoma-associated herpesvirus/HHV-8 protein ORF34; this interaction results in increased stability of EPAS1 and thus activation of its transcriptional activity.
Expressed in most tissues, with highest levels in placenta, lung and heart. Selectively expressed in endothelial cells.
In normoxia, is hydroxylated on Asn-847 by HIF1AN thus probably abrogating interaction with CREBBP and EP300 and preventing transcriptional activation.
In normoxia, is probably hydroxylated on Pro-405 and Pro-531 by EGLN1/PHD1, EGLN2/PHD2 and/or EGLN3/PHD3. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization (By similarity).
Interacts with HIF3A (By similarity). Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (PubMed:16181639). Interacts with CREBBP (By similarity). Interacts with EGLN1. Interacts with VHL (PubMed:19208626).
Phosphorylated on multiple sites in the CTAD.
Several EPAS1 intronic variants have been identified, forming a unique haplotype in Tibetans, which has been proposed to allow them to thrive in a low-oxygen environment. The high-altitude adaptive haplotype is thought to have originated from Denisovans.
Transcription factor involved in the induction of oxygen regulated genes. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBBP and probably EP300. Interaction with redox regulatory protein APEX1 seems to activate CTAD (By similarity).
Belongs to the G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRA1A sub-subfamily.
Expressed in heart, brain, liver and prostate, but not in kidney, lung, adrenal, aorta and pituitary. Within the prostate, expressed in the apex, base, periurethral and lateral lobe. Isoform 4 is the most abundant isoform expressed in the prostate with high levels also detected in liver and heart.
Homo- and heterooligomer. Heterooligomerizes with ADRA1B homooligomers in cardiac myocytes (PubMed:22120526). Interacts with CAVIN4 (PubMed:24567387).
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine(PE)-stimulated ERK signaling in cardiac myocytes.
Phosphorylated on tyrosine. Tyr-250 may be important for interaction with kinases. Phosphorylated by PTK6 at Tyr-250 modulates PTK6-mediated STAT3 activation. Tyr-22 and Tyr-322 appears to be phosphorylated by SRC.
Substrate of protein kinase PTK6. May play a regulatory role in the acute-phase response in systemic inflammation and may modulate STAT3 activity.
Expressed most strongly in kidney and prostate, much less strongly in the brain, skeletal muscle, placenta, lung, mammary gland, macrophage, uterus, testis and gut, but apparently not in the liver, heart and pancreas. Expressed in activated T cells (PubMed:27745970).
May play a role in the regulation of extra-urea cycle arginine metabolism and also in down-regulation of nitric oxide synthesis. Extrahepatic arginase functions to regulate L-arginine bioavailability to nitric oxid synthase (NOS). Arginine metabolism is a critical regulator of innate and adaptive immune responses. Seems to be involved in negative regulation of the survival capacity of activated CD4(+) and CD8(+) T cells (PubMed:27745970). May suppress inflammation-related signaling in asthmatic airway epithelium (PubMed:27214549). May contribute to the immune evasion of H.pylori by restricting M1 macrophage activation and polyamine metabolism (By similarity). In fetal dendritic cells may play a role in promoting immune suppression and T cell TNF-alpha production during gestation (PubMed:28614294). Regulates RPS6KB1 signaling, which promotes endothelial cell senescence and inflammation and implicates NOS3/eNOS dysfunction (PubMed:22928666). Can inhibit endothelial autophagy independently of its enzymatic activity implicating mTORC2 signaling (PubMed:25484082). Involved in vascular smooth muscle cell senescence and apoptosis independently of its enzymatic activity (PubMed:23832324). Since NOS is found in the penile corpus cavernosum smooth muscle, the clitoral corpus cavernosum and the vagina, arginase-2 plays a role in both male and female sexual arousal (PubMed:12859189).
Belongs to the XRCC4-XLF family. PAXX subfamily.
Homodimer (PubMed:25574025). Interacts with the DNA-bound XRCC5/Ku80 and XRCC6/Ku70 heterodimer (Ku complex); the interaction is direct (PubMed:27601299, PubMed:27705800, PubMed:25574025). Associated component of the non-homologous end joining (NHEJ) complex, composed of the core proteins PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF (PubMed:25670504, PubMed:25941166). Interacts with POLL (DNA polymerase lambda); promoting POLL recruitment to double-strand breaks (DSBs) and stimulation of the end-filling activity of POLL (PubMed:30250067).
Non-essential DNA repair protein involved in DNA non-homologous end joining (NHEJ); participates in double-strand break (DSB) repair and V(D)J recombination (PubMed:25574025, PubMed:25670504, PubMed:25941166, PubMed:27705800). May act as a scaffold required for accumulation of the Ku heterodimer, composed of XRCC5/Ku80 and XRCC6/Ku70, at double-strand break sites and promote the assembly and/or stability of the NHEJ machinery (PubMed:25574025, PubMed:25670504, PubMed:25941166). Involved in NHEJ by promoting the ligation of blunt-ended DNA ends (PubMed:27703001). Together with NHEJ1/XLF, collaborates with DNA polymerase lambda (POLL) to promote joining of non-cohesive DNA ends (PubMed:30250067, PubMed:25670504). Constitutes a non-essential component of classical NHEJ: has a complementary but distinct function with NHEJ1/XLF in DNA repair (PubMed:27705800). Able to restrict infection by herpesvirus 1 (HSV-1) via an unknown mechanism (PubMed:29144403).
Phosphorylation may inhibit interaction with the DNA-bound XRCC5/Ku80 and XRCC6/Ku70 heterodimer (Ku complex).
The N-terminus (residues 1-113) forms a head domain that is structurally related to those of XRCC4, XLF/NHEJ1, and SASS6.
Catalyzes the transfer of a geranylgeranyl moiety from geranylgeranyl diphosphate to both cysteines of proteins with the C-terminal sequence -XXCC, -XCXC and -CCXX.
Heterotrimer composed of RABGGTA, RABGGTB and CHM; within this trimer, RABGGTA and RABGGTB form the catalytic component B, while CHM (component A) mediates peptide substrate binding (PubMed:18532927). The Rab GGTase dimer (RGGT) interacts with CHM (component A) prior to Rab protein binding; the association is stabilized by geranylgeranyl pyrophosphate (GGpp) (PubMed:18532927). The CHM:RGGT:Rab complex is destabilized by GGpp (PubMed:18532927). Interaction of RABGGTB with prenylated PTP4A2 precludes its association with RABGGTA and inhibits enzyme activity (PubMed:11447212). Interacts with CHODL (By similarity). Interacts with non-phosphorylated form of RAB8A; phosphorylation of RAB8A at 'Thr-72' disrupts this interaction (PubMed:26824392).
The enzymatic reaction requires the aid of a Rab escort protein (also called component A).
Expressed in both skeletal and cardiac muscle.
Homodimer; antiparallel. Also forms heterodimers with ACTN3. Interacts with ADAM12, MYOZ1, MYOZ2 and MYOZ3. Interacts via its C-terminal region with the LDB3 PDZ domain. Interacts with XIRP2. Interacts with DST isoform 1 (via N-terminus). Interacts with PARVB. Interacts with SYNPO2.
Component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF) (PubMed:11741539, PubMed:9230079). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility (PubMed:11741539, PubMed:9230079). In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA (PubMed:29925947). The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs) (PubMed:29925947).
Functions as component of the Arp2/3 complex which is involved in regulation of actin polymerization and together with an activating nucleation-promoting factor (NPF) mediates the formation of branched actin networks.
Detected in heart (PubMed:19502560, PubMed:21195082). Detected in brain and muscle (at protein level) (PubMed:19502560). Highly expressed in the heart. Also found in brain and skeletal muscle (PubMed:19502560, PubMed:21195082).
Has sequence-specific DNA-binding activity and can function as transcriptional repressor (in vitro) (PubMed:21110952). May be a regulator of cell cycle: THAP5 overexpression in human cell lines causes cell cycle arrest at G2/M phase (PubMed:19502560).
Interacts with HTRA2; under apoptotic conditions (PubMed:19502560). Interacts with ABRAXAS2 (PubMed:21195082).
Up-regulated both in response to UV light treatment and cisplatin, agents that cause DNA damage (at protein level).
Interacts with SRSF2/SFRS2, U2AF2 and SNRNP70.
Plays a role in pre-mRNA alternative splicing by regulating spliceosome assembly.
Class I metallothioneins contain 2 metal-binding domains: four divalent ions are chelated within cluster A of the alpha domain and are coordinated via cysteinyl thiolate bridges to 11 cysteine ligands. Cluster B, the corresponding region within the beta domain, can ligate three divalent ions to 9 cysteines (By similarity).
Encoded by an expressed retrotransposed copy of the MT1H locus.
Contributes to the epidermal integrity and skin barrier function. Plays a role in the lamellar granule (LG) secretory system and in the stratum corneum (SC) epithelial cell formation (By similarity).
Defects in TMEM79 may be associated with susceptibility to atopic dermatitis. Atopic dermatitis is a complex, inflammatory disease with multiple alleles at several loci thought to be involved in the pathogenesis. It commonly begins in infancy or early childhood and is characterized by a chronic relapsing form of skin inflammation, a disturbance of epidermal barrier function that culminates in dry skin, and IgE-mediated sensitization to food and environmental allergens. It is manifested by lichenification, excoriation, and crusting, mainly on the flexural surfaces of the elbow and knee.
Expressed in the epidermis of the skin. Expressed in epithelial cells of the outermost layer of the stratum granulosum (SG) and hair follicles (at protein level).
Belongs to the dynactin subunits 5/6 family. Dynactin subunit 5 subfamily.
Subunit of dynactin, a multiprotein complex part of a tripartite complex with dynein and a adapter, such as BICDL1, BICD2 or HOOK3 (PubMed:23455152). The dynactin complex is built around ACTR1A/ACTB filament and consists of an actin-related filament composed of a shoulder domain, a pointed end and a barbed end. Its length is defined by its flexible shoulder domain. The soulder is composed of 2 DCTN1 subunits, 4 DCTN2 and 2 DCTN3. The 4 DCNT2 (via N-terminus) bind the ACTR1A filament and act as molecular rulers to determine the length. The pointed end is important for binding dynein-dynactin cargo adapters. Consists of 4 subunits: ACTR10, DCNT4, DCTN5 and DCTN6. Within the complex DCTN6 forms a heterodimer with DCTN5 (PubMed:23455152). The barbed end is composed of a CAPZA1:CAPZB heterodimers, which binds ACTR1A/ACTB filament and dynactin and stabilizes dynactin (By similarity).
Contains 2 copies of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). The phosphorylated ITIM motif bind the SH2 domain of PTPN6.
Expressed in the secondary lymphoid organs, spleen and lymph node. Expression is limited to the mature B-cell lines. Highly expressed in CD19 and within the mantle zones of the tonsil tissue. Isoform 2 is expressed in the spleen, peripheral blood and bone marrow. Isoform 2 and isoform 4 are expressed in B-cell lines. Preferentially expressed in memory B-cells (at protein level).
Isoform 2 is N- and O-glycosylated, and phosphorylated.
May have an regulatory role in normal and neoplastic B cell development.
The tyrosine-phosphorylated isoform 2 interacts with PTPN6.
Interacts with C-terminal domain of actin-binding protein 280.
Isoform 1 is highly expressed in adult and fetal heart, skeletal muscle, and at a much lower levels in adipose tissue and in aorta. Undetectable in other tissues. Isoform 2 and isoform 3 are poorly detected in heart.
Component of the IFT complex B, at least composed of IFT20, IFT22, IFT25, IFT27, IFT46, IFT52, TRAF3IP1/IFT54, IFT57, IFT74, IFT80, IFT81, and IFT88 (By similarity). Interacts with IFT20, IFT22, IFT25, IFT27, IFT52, TRAF3IP1, IFT74, IFT80 and IFT81 (By similarity). Interacts with IFT172 (By similarity). Interacts with IFT57 (By similarity). Interacts with IFT46 (By similarity). Interacts with IFT70B (By similarity). Interacts with C2CD3 (By similarity). Interacts with ENTR1 (via N-terminus) (PubMed:27767179). Interacts with LRRC56 (PubMed:30388400). Interacts with DZIP1 (By similarity).
Expressed in the heart, brain, liver, lung, kidney, skeletal muscle and pancreas.
Positively regulates primary cilium biogenesis (PubMed:17604723). Also involved in autophagy since it is required for trafficking of ATG16L and the expansion of the autophagic compartment.
Activates STAT3 and possibly STAT1 and STAT5 through the IL31 heterodimeric receptor composed of IL31RA and OSMR (PubMed:15184896). May function in skin immunity (PubMed:15184896). Enhances myeloid progenitor cell survival in vitro (By similarity). Induces RETNLA and serum amyloid A protein expression in macrophages (By similarity).
Detected at low levels in testis, bone marrow, skeletal muscle, kidney, colon, thymus, small intestine and trachea.
Up-regulated in skin homing T-cells of patients with atopic dermatitis (AD) and in activated circulating T-cells. Up-regulated in lesional biopsies of patients with allergic contact dermatitis (ACD).
Expressed in heart, kidney, liver, lung, pancreas, and placenta, but not in skeletal muscle.
Chemoattractant for blood monocytes, memory T-helper cells and eosinophils. Causes the release of histamine from basophils and activates eosinophils. May activate several chemokine receptors including CCR1, CCR3, CCR4 and CCR5. One of the major HIV-suppressive factors produced by CD8+ T-cells. Recombinant RANTES protein induces a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). The processed form RANTES(3-68) acts as a natural chemotaxis inhibitor and is a more potent inhibitor of HIV-1-infection. The second processed form RANTES(4-68) exhibits reduced chemotactic and HIV-suppressive activity compared with RANTES(1-68) and RANTES(3-68) (PubMed:16791620, PubMed:1380064, PubMed:8525373, PubMed:9516414, PubMed:15923218). May also be an agonist of the G protein-coupled receptor GPR75, stimulating inositol trisphosphate production and calcium mobilization through its activation. Together with GPR75, may play a role in neuron survival through activation of a downstream signaling pathway involving the PI3, Akt and MAP kinases. By activating GPR75 may also play a role in insulin secretion by islet cells (PubMed:23979485).
Expressed in the follicular fluid (at protein level). T-cell and macrophage specific.
Homo and heterooligomers with other chemokines. Interacts with the brown dog tick evasin-4.
N-terminal processed form RANTES(3-68) is produced by proteolytic cleavage, probably by DPP4, after secretion from peripheral blood leukocytes and cultured sarcoma cells.
N-terminal processed form RANTES(4-68) is produced by proteolytic cleavage by cathepsin CTSG.
The identity of the O-linked saccharides at Ser-27 and Ser-28 are not reported in PubMed:1380064. They are assigned by similarity.
Binds 2 magnesium ions per subunit. Has high activity with manganese and zinc ions (in vitro).
Monomer, and homooligomer (PubMed:11863428, PubMed:18596042, PubMed:20159463). May exist as homodimer, homotrimer, homotetramer and/or homohexamer (PubMed:11863428, PubMed:18596042, PubMed:20159463). Homotetramer, or homohexamer, when bound to DNA (PubMed:11863428, PubMed:18596042, PubMed:20159463). Interacts via its N-terminal domain with WRNIP1 (By similarity). Interacts with EXO1, PCNA and SUPV3L1 (PubMed:12704184, PubMed:17961633). Interacts with PML (isoform PML-4) (PubMed:21639834). Interacts (via KBM motif) with XRCC5 and XRCC6; promoting recruitment to DNA damage sites (PubMed:27063109). Interacts with RECQL5; this interaction stimulates WRN helicase activity on DNA fork duplexes (PubMed:23180761).
Multifunctional enzyme that has both magnesium and ATP-dependent DNA-helicase activity and 3'->5' exonuclease activity towards double-stranded DNA with a 5'-overhang. Has no nuclease activity towards single-stranded DNA or blunt-ended double-stranded DNA. Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Important for genomic integrity. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A (By similarity). Plays a role in double-strand break repair after gamma-irradiation.
The KBM 2 (Ku-binding motif 2) and XLM (XLF-like motif) mediate cooperative interaction with XRCC5/Ku80 and XRCC6/Ku70 and recruitment to DNA damage sites.
A C-terminal ubiquitin-binding domain (UBD) is essential for transcription-coupled nucleotide excision repair activity, interaction with RNA polymerase II, association with chromatin after UV irradiation and for mediating the UV-induced translocation of ERRC8 to the nuclear matrix.
Essential factor involved in transcription-coupled nucleotide excision repair which allows RNA polymerase II-blocking lesions to be rapidly removed from the transcribed strand of active genes (PubMed:20541997, PubMed:26620705, PubMed:16246722). Upon DNA-binding, it locally modifies DNA conformation by wrapping the DNA around itself, thereby modifying the interface between stalled RNA polymerase II and DNA (PubMed:15548521). It is required for transcription-coupled repair complex formation (PubMed:16916636). It recruits the CSA complex (DCX(ERCC8) complex), nucleotide excision repair proteins and EP300 to the sites of RNA polymerase II-blocking lesions (PubMed:16916636). Plays an important role in regulating the choice of the DNA double-strand breaks (DSBs) repair pathway and G2/M checkpoint activation; DNA-dependent ATPase activity is essential for this function (PubMed:25820262). Regulates the DNA repair pathway choice by inhibiting non-homologous end joining (NHEJ), thereby promoting the homologous recombination (HR)-mediated repair of DSBs during the S/G2 phases of the cell cycle (PubMed:25820262). Mediates the activation of the ATM- and CHEK2-dependent DNA damage responses thus preventing premature entry of cells into mitosis following the induction of DNA DSBs (PubMed:25820262). Acts as a chromatin remodeler at DSBs; DNA-dependent ATPase-dependent activity is essential for this function. Remodels chromatin by evicting histones from chromatin flanking DSBs, limiting RIF1 accumulation at DSBs thereby promoting BRCA1-mediated HR (PubMed:29203878). Required for stable recruitment of ELOA and CUL5 to DNA damage sites (PubMed:28292928). Involved in UV-induced translocation of ERCC8 to the nuclear matrix (PubMed:26620705). Essential for neuronal differentiation and neuritogenesis; regulates transcription and chromatin remodeling activities required during neurogenesis (PubMed:24874740).
Homodimer (PubMed:16128801, PubMed:15548521). Binds DNA (PubMed:15548521). Interacts with ERCC8 (PubMed:16751180). Interacts with RNA polymerase II; interaction is enhanced by UV irradiation (PubMed:26620705, PubMed:32142649). Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21 (PubMed:16603771). Interacts with KIAA1530/UVSSA (PubMed:22466612). Interacts with ELOA and CUL5; the interaction is induced by DNA damaging agents or by inhibitors of RNA polymerase II elongation (PubMed:28292928). Interacts (via WHD region) with RIF1 (PubMed:29203878). Interacts with SMARCC2/BAF170, SMARCB1/BAF47 and the neuron-specific chromatin remodeling complex (nBAF complex)(PubMed:24874740). Interacts with ERCC5/XPG (via C-terminus); the interaction stimulates ERCC6/CSB binding to the DNA repair bubble and ERCC6/CSB ATPase activity (PubMed:16246722). May form a complex composed of RNA polymerase II, ERCC6/CSB and ERCC5/XPG which associates with the DNA repair bubble during transcription-coupled nucleotide excision repair (PubMed:16246722). Interacts with CAND1, CSTF1, DDX3X, DDX5, DDX17, DDX23, DHX36, HDAC1, HNRNPU, MTA2, PRPF3, PSMD3, RBBP4, SFPQ, SMARCA1, SMARCA2, TOP1, USP7, XRCC5, COPS3, COPS4, COPS6, DDX1, DDX41, GATAD2A, GATAD2B, PRPF4, PSMC5, SF3B2, CTR9, NONO, PSMD12 and TOP2A (PubMed:26030138).
Involved in repair of DNA damage following UV irradiation, acting either in the absence of ERCC6 or synergistically with ERCC6. Involved in the regulation of gene expression. In the absence of ERCC6, induces the expression of genes characteristic of interferon-like antiviral responses. This response is almost completely suppressed in the presence of ERCC6. In the presence of ERCC6, regulates the expression of genes involved in metabolism regulation, including IGFBP5 and IGFBP7. In vitro binds to PGBD3-related transposable elements, called MER85s; these non-autonomous 140 bp elements are characterized by the presence of PGBD3 terminal inverted repeats and the absence of internal transposase ORF.
Phosphorylated in a cell cycle-dependent manner at Ser-158 by cyclin A-CDK2 and at Ser-10 by ATM in response to DNA damage (PubMed:29203878). Phosphorylation at these two sites promotes the intramolecular interaction of the N-terminal domain with the helicase ATP-binding domain, thereby probably releasing the inhibitory effect of the N-terminal domain on its ATPase activity (PubMed:29203878). Phosphorylation is essential for its chromatin remodeling activity (PubMed:29203878).
Produced by an alternative splicing event that joins the first 5 exons of ERCC6 gene in frame to the entire PGBD3 coding region, which is located within ERCC6 intron 5. The resulting chimeric protein consists of the N-terminal 465 residues of ERCC6 tethered to the entire PGBD3 sequence.
Sumoylation at Lys-205 in an UV-radiation-dependent manner is essential for its transcription-coupled nucleotide excision repair activity.
The N-terminal domain exerts an inhibitory effect on the helicase ATP-binding domain in such a manner that its ATPase activity is restricted (PubMed:29203878). Phosphorylation at Ser-10 and Ser-158 promotes the intramolecular interaction of the N-terminal domain with the helicase ATP-binding domain, thereby probably releasing the inhibitory effect of the N-terminal domain on its ATPase activity (PubMed:29203878).
The protein represented in this entry is involved in disease pathogenesis. Disease-causing variants affect isoform CSB-PGBD3, which is a chimeric protein between ERCC6 N-terminus and the entire PGBD3 sequence.
Ubiquitinated at the C-terminus. Ubiquitination by the CSA complex leads to ERCC6 proteasomal degradation in a UV-dependent manner. Stabilized following interaction with KIAA1530/UVSSA, which promotes recruitment of deubiquitinating enzyme USP7, leading to deubiquitination of ERCC6 thereby preventing UV-induced degradation of ERCC6 by the proteasome.
Homotetramer. The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming subunits. Interacts with KCTD3 and PEX5L.
Hyperpolarization-activated potassium channel. May also facilitate the permeation of sodium ions.
Inhibited by Cs(1+) and ZD7288. Is apparently not activated by cAMP.
ATP-dependent RNA helicase involved in mRNA export from the nucleus (PubMed:10428971). Rather than unwinding RNA duplexes, DDX19B functions as a remodeler of ribonucleoprotein particles, whereby proteins bound to nuclear mRNA are dissociated and replaced by cytoplasmic mRNA binding proteins (PubMed:10428971).
Associates with the nuclear pore complex via interaction with NUP214 (PubMed:10428971, PubMed:19208808, PubMed:19219046). Interacts with NUP214 or RNA in a mutually exclusive manner (PubMed:19208808, PubMed:19219046, PubMed:19244245).
Transcription factor required for the formation of correct projections from nociceptive sensory neurons to the dorsal horn of the spinal cord and normal perception of pain.
DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Depending on the context, it inserts the correct base, but causes frequent base transitions, transversions and frameshifts. Lacks 3'-5' proofreading exonuclease activity. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity.
Detected at low levels in testis, spleen, prostate and ovary. Detected at very low levels in kidney, colon, brain, heart, liver, lung, placenta, pancreas and peripheral blood leukocytes.
Divalent metal cations. Prefers Mg(2+), but can also use Mn(2+).
Interacts with REV1 (By similarity). Interacts with PCNA (PubMed:11784855).
Interacts with CCP110 and CEP97. Interacts with ARMC9, TOGARAM1, CCDC66 and CSPP1 (PubMed:32453716).
Required for ciliogenesis and for structural integrity at the ciliary tip.
Detected in placenta (at protein level) (PubMed:32337544). Found in several connective tissues, especially in articular cartilages.
Homodimer. Forms a ternary complex with MFAP2 and ELN (By similarity).
May be involved in collagen fiber assembly.
The two attached glycosaminoglycan chains can be either chondroitin sulfate or dermatan sulfate.
Homodimer (PubMed:7744965). Interacts with RAN (GDP-bound form); the interaction is direct and regulates RAN nuclear import (PubMed:10679025). Interacts with the nucleoporins NUP54, NUP58 and NUP62 (via FG repeats); recruits NUTF2 to the nuclear pore complex a step required for NUTF2-mediated GDP-bound RAN nuclear import (PubMed:7744965). Interacts with CAPG; mediates its nuclear import (PubMed:18266911).
Mediates the import of GDP-bound RAN from the cytoplasm into the nucleus which is essential for the function of RAN in cargo receptor-mediated nucleocytoplasmic transport. Thereby, plays indirectly a more general role in cargo receptor-mediated nucleocytoplasmic transport. Interacts with GDP-bound RAN in the cytosol, recruits it to the nuclear pore complex via its interaction with nucleoporins and promotes its nuclear import.
Belongs to the PNP/MTAP phosphorylase family. MTAP subfamily.
Catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S-adenosylmethionine. Has broad substrate specificity with 6-aminopurine nucleosides as preferred substrates.
Inhibited by 5'-methylthiotubercin and 5'-chloroformycin.
Loss of MTAP activity may play a role in human cancer. MTAP loss has been reported in a number of cancers, including osteosarcoma, malignant melanoma and gastric cancer.
The disease is caused by variants affecting the gene represented in this entry. DMSMFH causing mutations found in MTAP exon 9 result in exon skipping and dysregulated alternative splicing of all MTAP isoforms (PubMed:22464254).
Associates with GIRK1 or GIRK4 to form a G-protein-activated heteromultimer pore-forming unit. The resulting inward current is much larger. Interacts (via PDZ-binding motif) with SNX27 (via PDZ domain); the interaction is required when endocytosed to prevent degradation in lysosomes and promote recycling to the plasma membrane (By similarity).
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ6 subfamily.
Most abundant in cerebellum, and to a lesser degree in islets and exocrine pancreas.
This potassium channel may be involved in the regulation of insulin secretion by glucose and/or neurotransmitters acting through G-protein-coupled receptors. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium.
Catalytic subunit of the enzyme which catalyzes the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate. The heterodimer composed of the alpha (IDH3A) and beta (IDH3B) subunits and the heterodimer composed of the alpha (IDH3A) and gamma (IDH3G) subunits, have considerable basal activity but the full activity of the heterotetramer (containing two subunits of IDH3A, one of IDH3B and one of IDH3G) requires the assembly and cooperative function of both heterodimers.
Regulatory subunit of serine/threonine-protein phosphatase 4. May play a role in regulation of cell division in renal glomeruli. The PPP4C-PPP4R1 PP4 complex may play a role in dephosphorylation and regulation of HDAC3.
Serine/threonine-protein phosphatase 4 (PP4) occurs in different assemblies of the catalytic and one or more regulatory subunits. Component of the PP4 complex PPP4C-PPP4R1. Interacts with HDAC3.
Widely expressed with high expression in cultured mesangial cells. Isoform 1 and isoform 2 are expressed in renal tissues.
Acts as guanine nucleotide exchange factor (GEF) for RhoA and RhoB GTPases.
Widely expressed. Highest levels are found in adult brain and skeletal muscle. Lower levels are found in heart and kidney.
Has most probably no lipid phosphatase activity (By similarity). Critical residues that support the reaction mechanism in active members of that protein family, including the residues of the active site acting respectively as proton donor and nucleophile, are not conserved.
Induces filopodia formation and promotes neurite growth in a CDC42-independent manner; impedes neurite growth inhibitory-mediated axonal retraction.
Isoform 1 is expressed in brain, lung, kidney and colon. Isoform 2 is expressed in placenta, skeletal muscle and kidney.
(Microbial infection) Interacts with hepatitis C virus protein E1; this interaction prevents E1 interaction with E2 and subsequently inhibits viral infection.
E3 ubiquitin-protein ligase that plays a role in various biological processes such as lung development or innate immunity (PubMed:30111563). Seems to utilize UBE2E1. Promotes innate antiviral response by catalyzing 'Lys-63'-linked ubiquitination of IRF7 (PubMed:35792897). Inhibits also hepatitis C virus assembly by directly binding to viral E1 envelope glycoprotein to disrupt its interaction with E2 (PubMed:30111563).
Highly expressed in granulocytes of peripheral blood. Constitutively expressed at low levels in all hematopoietic cell lines investigated.
Interacts with RIMS1, RIMS2, RPH3A, RPH3AL and RAB3IP (By similarity). Interacts with CHM and CHML; phosphorylation at Thr-86 disrupts these interactions (PubMed:29125462). Interacts with MADD (via uDENN domain); the GTP-bound form is preferred for interaction (By similarity).
Phosphorylation of Thr-86 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM and CHML.
Protein transport. Probably involved in regulated exocytosis (By similarity).
Homozygous deletion comprising CEP89 and SLC7A9 genes has been reported in a patient with isolated complex IV deficiency, intellectual disability and multisystemic problems that include cystinuria, cataract, broad based walking pattern and deafness.
Required for ciliogenesis. Also plays a role in mitochondrial metabolism where it may modulate complex IV activity.
Interacts with DNTTIP1 (PubMed:21573134, PubMed:25653165). Identified in a histone deacetylase complex that contains DNTTIP1, HDAC1 and MIDEAS; this complex assembles into a tetramer that contains four copies of each protein chain (PubMed:25653165).
Acts as a transcriptional repressor (PubMed:23468431).
Binds GDP/GTP and possesses intrinsic GTPase activity. Has higher affinity for GDP than for GTP. In cell lines overexpression leads to a reduction in the rate of proliferation, colony formation and in tumorigenic potential.
Detected in heart, brain, placenta, lung, liver, skin, kidney and pancreas. Detected in estrogen receptor-positive breast-derived cell lines, but not in estrogen receptor-negative cell lines. Expression is decreased or lost in a significant proportion of primary breast tumors with poor clinical prognosis.
Up-regulated by estradiol. Down-regulated by tamoxifen.
Essential for the proper assembly of type I and type II keratin protein complexes and formation of keratin intermediate filaments in the inner root sheath (irs).
Heterotetramer of two type I and two type II keratins. Interacts with KRT6A to form filaments (By similarity).
Strongly expressed in skin and scalp. In the hair follicle, expressed in Henle layer, Huxley layer and in the inner root sheath cuticle of the hair follicle. Expression extends from the bulb region up to the point of differentiation into the three layers. Also present in the medulla of beard hair (at protein level).
Predominantly expressed in the pancreas, especially in the islets.
Receptor for the endogenous fatty-acid ethanolamide oleoylethanolamide (OEA) and lysophosphatidylcholine (LPC). Functions as a glucose-dependent insulinotropic receptor. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Seems to act through a G(s) mediated pathway.
Catalyzes the hydrolysis of queuosine 5'-phosphate, releasing the nucleobase queuine (q). Is required for salvage of queuine from exogenous queuosine (Q) that is imported and then converted to queuosine 5'-phosphate intracellularly.
Catalyzes the hydrolysis of queuosine 5'-phosphate, releasing the nucleobase queuine (q). Is required for salvage of queuine from exogenous queuosine (Q) that is imported and then converted to queuosine 5'-phosphate intracellularly. In vitro, can also catalyze the release of the q base directly from Q as substrate; however, it was shown that Q is not the biologically relevant substrate. Shows a very low activity on queuosine 3',5'-diphosphate, and cannot release q from queuosine 3'-phosphate and from the 5'-nucleotides AMP, UMP, CMP or GMP, indicating specificity for the queuine base (PubMed:36610787). Can complement the yeast mutant SPAC589.05c, restoring Q incorporation into tRNA (PubMed:24911101).
Eukaryotes lack the canonical genes for de novo biosynthesis of queuosine (Q), present in most bacteria. Therefore, this molecule must be sourced from ingested food and/or the gut microbiota, and metabolized to its corresponding nucleobase, queuine (q), before incorporation into cytoplasmic and mitochondrial tRNAs. Incorporation of q into the anticodon of some tRNAs contributes to translational efficiency and accuracy.
Belongs to the queuine tRNA-ribosyltransferase family.
Catalytic subunit of the queuine tRNA-ribosyltransferase (TGT) that catalyzes the base-exchange of a guanine (G) residue with queuine (Q) at position 34 (anticodon wobble position) in tRNAs with GU(N) anticodons (tRNA-Asp, -Asn, -His and -Tyr), resulting in the hypermodified nucleoside queuosine (7-(((4,5-cis-dihydroxy-2-cyclopenten-1-yl)amino)methyl)-7-deazaguanosine) (PubMed:11255023, PubMed:20354154). Catalysis occurs through a double-displacement mechanism. The nucleophile active site attacks the C1' of nucleotide 34 to detach the guanine base from the RNA, forming a covalent enzyme-RNA intermediate. The proton acceptor active site deprotonates the incoming queuine, allowing a nucleophilic attack on the C1' of the ribose to form the product (By similarity).
Heterodimer of a catalytic subunit QTRT1 and an accessory subunit QTRT2.
A chromosomal aberration involving MEAF6 may be a cause of endometrial stromal tumors. Translocation t(1;6)(p34;p21) with PHF1.
Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5 and the subunits EP400, TRRAP, BRD8, EPC1, DMAP1, RUVBL1, RUVBL2, ING3, actin, ACTL6A, MORF4L1, MORF4L2, MRGBP, YEATS4, VPS72 and MEAF6 (PubMed:12963728, PubMed:14966270, PubMed:15647280). Component of the HBO1 complex composed of KAT7/HBO1, MEAF6, ING4 or ING5, and one scaffold subunit: complexes containing BRPF scaffold (BRPF1, BRD1/BRPF2 or BRPF3) direct KAT7/HBO1 specificity towards H3K14ac, while complexes containing JADE scaffold (JADE1, JADE2 and JADE3) mediate acetylation of histone H4 (PubMed:16387653, PubMed:24065767). Component of the MOZ/MORF complex composed at least of ING5, KAT6A, KAT6B, MEAF6 and one of BRPF1, BRD1/BRPF2 and BRPF3 (PubMed:18794358).
Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histone H4 and H2A (PubMed:14966270). This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription (PubMed:14966270). Component of HBO1 complexes, which specifically mediate acetylation of histone H3 at 'Lys-14' (H3K14ac), and have reduced activity toward histone H4 (PubMed:16387653, PubMed:24065767). Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity (PubMed:18794358).
Belongs to the protein-tyrosine phosphatase family. Non-receptor class PTPDC1 subfamily.
May play roles in cilia formation and/or maintenance.
Isoform 1 is expressed in peripheral blood mononuclear cells and kidney. Lower expression in brain and liver. Expression is down-regulated in activated cells. Isoform 2 is expressed in lymphocyte precursors, however, expression shuts down during maturation and differentiation in thymus and fetal liver.
Plays a role in T-cell signaling pathway. Isoform 2 may play a role in T-helper 2 (Th2) signaling pathway and seems to represent the first proximal signaling protein that links T-cell receptor-mediated signal to the activation of c-Maf Th2 specific factor.
(Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry.
(Microbial infection) Interacts with severe fever with thrombocytopenia syndrome virus (SFTSV) NSs; this interaction is inclusion body dependent, it inhibits the formation and nuclear import of the cyclin B1-CDK1 complex and leads to cell cycle arrest.
As a key regulator of the cell cycle, CDK1 is a potent therapeutic target for inhibitors in cancer treatment.
Follows a cyclic expression; during interphase, accumulates gradually following G1, S to reach a critical threshold at the end of G2, which promotes self-activation and triggers onset of mitosis. Induced transiently by TGFB1 at an early phase of TGFB1-mediated apoptosis, but later repressed. Triggered by CKS1B during mitotic entry in breast cancer cells. Down-regulated under genotoxic stresses triggered by PKR/EIF2AK2-mediated phosphorylation.
Forms a stable but non-covalent complex with a regulatory subunit and with a cyclin. Interacts with cyclins-B (CCNB1, CCNB2 and CCNB3) to form a serine/threonine kinase holoenzyme complex also known as maturation promoting factor (MPF). The cyclin subunit imparts substrate specificity to the complex. Can also form CDK1-cylin-D and CDK1-cyclin-E complexes that phosphorylate RB1 in vitro. Binds to RB1 and other transcription factors such as FOXO1 and RUNX2. Promotes G2-M transition when in complex with a cyclin-B. Interacts with DLGAP5. Binds to the CDK inhibitors CDKN1A/p21 and CDKN1B/p27. Isoform 2 is unable to complex with cyclin-B1 and also fails to bind to CDKN1A/p21. Interacts with catalytically active CCNB1 and RALBP1 during mitosis to form an endocytotic complex during interphase. Associates with cyclins-A and B1 during S-phase in regenerating hepatocytes. Interacts with FANCC. Interacts with CEP63; this interaction recruits CDK1 to centrosomes. Interacts with CENPA (PubMed:25556658). Interacts with NR1D1 (PubMed:27238018). Interacts with proteasome subunit PSMA8; to participate in meiosis progression during spermatogenesis (By similarity).
Isoform 2 is found in breast cancer tissues.
Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-161 activates it. Activated through a multistep process; binding to cyclin-B is required for relocation of cyclin-kinase complexes to the nucleus, activated by CAK/CDK7-mediated phosphorylation on Thr-161, and CDC25-mediated dephosphorylation of inhibitory phosphorylation on Thr-14 and Tyr-15. Inhibited by flavopiridol and derivatives, pyrimidine derivatives, pyridine derivatives, purine derivatives, staurosporine, paullones, oxoindoles, indazole analogs, indolin-2-ones, pyrazolo[3,4-b]pyridines, imidazo[1,2-a]pyridine (AZ703), thiazolinone analogs(RO-3306), thiazol urea, macrocyclic quinoxalin-2-one, pyrrolo[2,3-a]carbazole, pyrazolo[1,5-a]-1,3,5-triazine, pyrazolo[1,5-a]pyrimidine (Dinaciclib, SCH 727965), 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine), olomoucine, AG-024322, AT-7519, P276-00, R547/Ro-4584820 and SNS-032/BMS-387032. Repressed by the CDK inhibitors CDKN1A/p21 and CDKN1B/p27 during the G1 phase and by CDKN1A/p21 at the G1-S checkpoint upon DNA damage. Transient activation by rapid and transient dephosphorylation at Tyr-15 triggered by TGFB1.
Phosphorylation at Thr-161 by CAK/CDK7 activates kinase activity. Phosphorylation at Thr-14 and Tyr-15 by PKMYT1 prevents nuclear translocation. Phosphorylation at Tyr-15 by WEE1 and WEE2 inhibits the protein kinase activity and acts as a negative regulator of entry into mitosis (G2 to M transition). Phosphorylation by PKMYT1 and WEE1 takes place during mitosis to keep CDK1-cyclin-B complexes inactive until the end of G2. By the end of G2, PKMYT1 and WEE1 are inactivated, but CDC25A and CDC25B are activated. Dephosphorylation by active CDC25A and CDC25B at Thr-14 and Tyr-15, leads to CDK1 activation at the G2-M transition. Phosphorylation at Tyr-15 by WEE2 during oogenesis is required to maintain meiotic arrest in oocytes during the germinal vesicle (GV) stage, a long period of quiescence at dictyate prophase I, leading to prevent meiotic reentry. Phosphorylation by WEE2 is also required for metaphase II exit during egg activation to ensure exit from meiosis in oocytes and promote pronuclear formation. Phosphorylated at Tyr-4 by PKR/EIF2AK2 upon genotoxic stress. This phosphorylation triggers CDK1 polyubiquitination and subsequent proteolysis, thus leading to G2 arrest. In response to UV irradiation, phosphorylation at Tyr-15 by PRKCD activates the G2/M DNA damage checkpoint.
Plays a key role in the control of the eukaryotic cell cycle by modulating the centrosome cycle as well as mitotic onset; promotes G2-M transition via association with multiple interphase cyclins (PubMed:16407259, PubMed:17459720, PubMed:16933150, PubMed:18356527, PubMed:19509060, PubMed:20171170, PubMed:19917720, PubMed:20937773, PubMed:20935635, PubMed:21063390, PubMed:23355470, PubMed:23601106, PubMed:23602554, PubMed:25556658, PubMed:26829474, PubMed:30704899). Phosphorylates PARVA/actopaxin, APC, AMPH, APC, BARD1, Bcl-xL/BCL2L1, BRCA2, CALD1, CASP8, CDC7, CDC20, CDC25A, CDC25C, CC2D1A, CENPA, CSNK2 proteins/CKII, FZR1/CDH1, CDK7, CEBPB, CHAMP1, DMD/dystrophin, EEF1 proteins/EF-1, EZH2, KIF11/EG5, EGFR, FANCG, FOS, GFAP, GOLGA2/GM130, GRASP1, UBE2A/hHR6A, HIST1H1 proteins/histone H1, HMGA1, HIVEP3/KRC, KAT5, LMNA, LMNB, LMNC, LBR, LATS1, MAP1B, MAP4, MARCKS, MCM2, MCM4, MKLP1, MLST8, MYB, NEFH, NFIC, NPC/nuclear pore complex, PITPNM1/NIR2, NPM1, NCL, NUCKS1, NPM1/numatrin, ORC1, PRKAR2A, EEF1E1/p18, EIF3F/p47, p53/TP53, NONO/p54NRB, PAPOLA, PLEC/plectin, RB1, TPPP, UL40/R2, RAB4A, RAP1GAP, RCC1, RPS6KB1/S6K1, KHDRBS1/SAM68, ESPL1, SKI, BIRC5/survivin, STIP1, TEX14, beta-tubulins, MAPT/TAU, NEDD1, VIM/vimentin, TK1, FOXO1, RUNX1/AML1, SAMHD1, SIRT2, CGAS and RUNX2 (PubMed:16407259, PubMed:17459720, PubMed:16933150, PubMed:18356527, PubMed:19509060, PubMed:20171170, PubMed:19917720, PubMed:20937773, PubMed:20935635, PubMed:21063390, PubMed:23355470, PubMed:23601106, PubMed:23602554, PubMed:25556658, PubMed:32351706, PubMed:26829474, PubMed:30704899, PubMed:34741373). CDK1/CDC2-cyclin-B controls pronuclear union in interphase fertilized eggs (PubMed:18480403, PubMed:20360007). Essential for early stages of embryonic development (PubMed:18480403, PubMed:20360007). During G2 and early mitosis, CDC25A/B/C-mediated dephosphorylation activates CDK1/cyclin complexes which phosphorylate several substrates that trigger at least centrosome separation, Golgi dynamics, nuclear envelope breakdown and chromosome condensation (PubMed:18480403, PubMed:20360007). Once chromosomes are condensed and aligned at the metaphase plate, CDK1 activity is switched off by WEE1- and PKMYT1-mediated phosphorylation to allow sister chromatid separation, chromosome decondensation, reformation of the nuclear envelope and cytokinesis (PubMed:18480403, PubMed:20360007). Phosphorylates KRT5 during prometaphase and metaphase (By similarity). Inactivated by PKR/EIF2AK2- and WEE1-mediated phosphorylation upon DNA damage to stop cell cycle and genome replication at the G2 checkpoint thus facilitating DNA repair (PubMed:20360007). Reactivated after successful DNA repair through WIP1-dependent signaling leading to CDC25A/B/C-mediated dephosphorylation and restoring cell cycle progression (PubMed:20395957). In proliferating cells, CDK1-mediated FOXO1 phosphorylation at the G2-M phase represses FOXO1 interaction with 14-3-3 proteins and thereby promotes FOXO1 nuclear accumulation and transcription factor activity, leading to cell death of postmitotic neurons (PubMed:18356527). The phosphorylation of beta-tubulins regulates microtubule dynamics during mitosis (PubMed:16371510). NEDD1 phosphorylation promotes PLK1-mediated NEDD1 phosphorylation and subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation (PubMed:19509060). In addition, CC2D1A phosphorylation regulates CC2D1A spindle pole localization and association with SCC1/RAD21 and centriole cohesion during mitosis (PubMed:20171170). The phosphorylation of Bcl-xL/BCL2L1 after prolongated G2 arrest upon DNA damage triggers apoptosis (PubMed:19917720). In contrast, CASP8 phosphorylation during mitosis prevents its activation by proteolysis and subsequent apoptosis (PubMed:20937773). This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes (PubMed:20937773). EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing (PubMed:20935635). CALD1 phosphorylation promotes Schwann cell migration during peripheral nerve regeneration (By similarity). CDK1-cyclin-B complex phosphorylates NCKAP5L and mediates its dissociation from centrosomes during mitosis (PubMed:26549230). Regulates the amplitude of the cyclic expression of the core clock gene BMAL1 by phosphorylating its transcriptional repressor NR1D1, and this phosphorylation is necessary for SCF(FBXW7)-mediated ubiquitination and proteasomal degradation of NR1D1 (PubMed:27238018). Phosphorylates EML3 at 'Thr-881' which is essential for its interaction with HAUS augmin-like complex and TUBG1 (PubMed:30723163). Phosphorylates CGAS during mitosis, leading to its inhibition, thereby preventing CGAS activation by self DNA during mitosis (PubMed:32351706).
Polyubiquitinated upon genotoxic stress.
Catalyzes the NADPH-dependent reduction of a variety of carbonyl substrates, like aromatic aldehydes, alkenals, ketones and alpha-dicarbonyl compounds (PubMed:26222439, PubMed:21276782). In addition, catalyzes the reduction of androgens and estrogens with high positional selectivity (shows 17-beta-hydroxysteroid dehydrogenase activity) as well as 3-keto-acyl-CoAs (PubMed:25577493). Displays strong enzymatic activity toward all-trans-retinal and 9-cis-retinal (PubMed:26222439). May play a physiological role in retinoid metabolism (PubMed:26222439).
No oxidoreductase activity observed with the tested substrates.
Widely expressed. Expressed at highest levels in steroid-sensitive tissues, such as placenta, testis and adipose tissue.
Detected in skeletal muscle, fetal and adult heart, brain, placenta, kidney, spleen, thymus, pancreas and lung. Isoform 3 and isoform 4 are heart specific.
PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, and one or several targeting or regulatory subunits. PPP1R12B mediates binding to myosin. Isoform 3 and isoform 4 bind PPP1R12A, but not isoform 1 of PPP1R12B itself. Binds IL16.
Regulates myosin phosphatase activity. Augments Ca(2+) sensitivity of the contractile apparatus.
Cytosolic 10-formyltetrahydrofolate dehydrogenase that catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide (PubMed:19933275, PubMed:21238436). May also have an NADP(+)-dependent aldehyde dehydrogenase activity towards formaldehyde, acetaldehyde, propionaldehyde, and benzaldehyde (By similarity).
Highly expressed in liver, pancreas and kidney.
In the C-terminal section; belongs to the aldehyde dehydrogenase family. ALDH1L subfamily.
In the N-terminal section; belongs to the GART family.
Phosphopantetheinylation at Ser-354 by AASDHPPT is required for the formyltetrahydrofolate dehydrogenase activity.
The C-terminal aldehyde dehydrogenase domain has an NADP-dependent dehydrogenase activity. It catalyzes the oxidation of formate, released by the hydrolysis of formyltetrahydrofolate, into CO2.
The N-terminal hydrolase domain has an NADP-independent formyltetrahydrofolate hydrolase activity, releasing formate and tetrahydrofolate.
The carrier domain is phosphopantetheinylated and uses the 4'-phosphopantetheine/4'-PP swinging arm to transfer the formyl group released by the N-terminal formyltetrahydrofolate hydrolase activity to the C-terminal aldehyde dehydrogenase domain that catalyzes its NADP-dependent oxidation into CO2. The overall NADP-dependent physiological reaction requires the 3 domains (N-terminal hydrolase, C-terminal aldehyde dehydrogenase and carrier domains) to convert formyltetrahydrofolate into tetrahydrofolate and CO2.
DNA polymerase that functions in several pathways of DNA repair (PubMed:11457865, PubMed:19806195, PubMed:20693240, PubMed:30250067). Involved in base excision repair (BER) responsible for repair of lesions that give rise to abasic (AP) sites in DNA (PubMed:11457865, PubMed:19806195). Also contributes to DNA double-strand break repair by non-homologous end joining and homologous recombination (PubMed:19806195, PubMed:20693240, PubMed:30250067). Has both template-dependent and template-independent (terminal transferase) DNA polymerase activities (PubMed:10982892, PubMed:10887191, PubMed:12809503, PubMed:14627824, PubMed:15537631, PubMed:19806195). Has also a 5'-deoxyribose-5-phosphate lyase (dRP lyase) activity (PubMed:11457865, PubMed:19806195).
DNA polymerase that functions in several pathways of DNA repair. Involved in base excision repair (BER) responsible for repair of lesions that give rise to abasic (AP) sites in DNA. Also contributes to DNA double-strand break repair by non-homologous end joining and homologous recombination. Has both template-dependent and template-independent (terminal transferase) DNA polymerase activities. Has also a 5'-deoxyribose-5-phosphate lyase (dRP lyase) activity.
Expressed in a number of tissues. Abundant in testis.
Interacts with PCNA (PubMed:14992725). Interacts with PAXX; promoting POLL recruitment to double-strand breaks (DSBs) and stimulation of the end-filling activity of POLL (PubMed:30250067). Interacts with XRCC4; promoting POLL recruitment to double-strand breaks (DSBs) and stimulation of the end-filling activity of POLL (PubMed:30250067). Interacts with NHEJ1/XLF; promoting POLL recruitment to double-strand breaks (DSBs) and stimulation of the end-filling activity of POLL (PubMed:30250067).
Binds 1 [4Fe-4S] cluster (PubMed:29848660). In the presence of oxygen, the [4Fe-4S] cluster may be converted to [2Fe-2S] (PubMed:29848660).
Highly expressed in hematopoietic tissues, fetal liver, spleen, thymus and adult thymus and bone marrow. Lower levels are found in heart, testis, kidney, colon and lung.
Interacts with the cytosolic iron-sulfur protein assembly (CIA) complex components CIAO2B and MMS19; the interactions facilitate the transfer of Fe-S clusters to KIF4A to ensure proper localization of KIF4A to mitotic machinery components (PubMed:29848660). Interacts (via C-terminus) with unphosphorylated PRC1 (via N-terminus); the interaction is required for the progression of mitosis (PubMed:15297875, PubMed:15625105, PubMed:29848660).
Iron-sulfur (Fe-S) cluster binding motor protein that has a role in chromosome segregation during mitosis (PubMed:29848660). Translocates PRC1 to the plus ends of interdigitating spindle microtubules during the metaphase to anaphase transition, an essential step for the formation of an organized central spindle midzone and midbody and for successful cytokinesis (PubMed:15297875, PubMed:15625105). May play a role in mitotic chromosomal positioning and bipolar spindle stabilization (By similarity).
(Microbial infection) Cleavage by Coxsackievirus B3 protease 3C after site Gln-60. This non-phosphorylated cleavage product retains its ability to interact with TFEB, TFE3 or MITF and presents impaired transcriptional activity, resulting in disruption of lysosomal functions and increased viral infection.
Alkylated via a non-enzymatic covalent modification (PubMed:35662396). Itaconate, an anti-inflammatory metabolite generated in response to lipopolysaccharide, alkylates Cys-212, preventing association with 14-3-3/YWHA adapters, thereby promoting nuclear translocation and activity (PubMed:35662396).
Homodimer and heterodimer; with TFE3 or MITF (PubMed:15507434, PubMed:1748288). Interacts (when phosphorylated by MTOR) with YWHAZ; promoting retention in the cytosol (PubMed:35662396). Interacts with IRGM; promoting association between TFEB and PPP3CB and dephosphorylation (PubMed:32753672). Interacts with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD); promoting its recruitment to lysosomal membrane in the presence of nutrients (PubMed:23401004).
Inhibited by eltrombopag drug, which binds to the bHLH domain and disrupts DNA-binding.
Phosphorylation at Ser-211 by MTOR via non-canonical mTORC1 pathway regulates its subcellular location and activity (PubMed:21617040, PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:23401004, PubMed:24081491, PubMed:25720963, PubMed:30120233, PubMed:32612235, PubMed:32753672, PubMed:35662396, PubMed:36697823). When nutrients are present, phosphorylation by MTOR promotes association with 14-3-3/YWHA adapters and retention in the cytosol (PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:23401004, PubMed:25720963, PubMed:32612235, PubMed:32753672, PubMed:35662396). Inhibition of mTORC1, starvation and lysosomal disruption, promotes dephosphorylation by calcineurin PPP3CB and translocation to the nucleus (PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:25720963, PubMed:32753672). Dephosphorylated by calcineurin PPP3CB in response to lysosomal Ca(2+) release (PubMed:25720963). IRGM promotes dephosphorylation by calcineurin PPP3CB, resulting in TFEB nuclear translocation and stimulation of lysosomal biogenesis (PubMed:32753672). Dephosphorylated by phosphatase PPP3CA following Coxsackievirus B3 infection, leading to nuclear translocation (PubMed:33691586). Exported from the nucleus in a mTORC1-dependent manner in response to nutrient availability (PubMed:30120233).
Sumoylated; does not affect dimerization with MITF.
The leucine zipper region is essential for homo- or heterodimerization and high-affinity DNA binding. DNA binding is mediated by the basic region.
Transcription factor that acts as a master regulator of lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid catabolism, energy metabolism and immune response (PubMed:21617040, PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:25720963, PubMed:30120233, PubMed:31672913, PubMed:32612235, PubMed:32753672, PubMed:35662396, PubMed:36697823, PubMed:36749723, PubMed:37079666). Specifically recognizes and binds E-box sequences (5'-CANNTG-3'); efficient DNA-binding requires dimerization with itself or with another MiT/TFE family member such as TFE3 or MITF (PubMed:1748288, PubMed:19556463, PubMed:29146937). Involved in the cellular response to amino acid availability by acting downstream of MTOR: in the presence of nutrients, TFEB phosphorylation by MTOR promotes its cytosolic retention and subsequent inactivation (PubMed:21617040, PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:25720963, PubMed:32612235, PubMed:32753672, PubMed:35662396, PubMed:36697823). Upon starvation or lysosomal stress, inhibition of MTOR induces TFEB dephosphorylation, resulting in nuclear localization and transcription factor activity (PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:25720963, PubMed:32612235, PubMed:32753672, PubMed:35662396, PubMed:36697823). Specifically recognizes and binds the CLEAR-box sequence (5'-GTCACGTGAC-3') present in the regulatory region of many lysosomal genes, leading to activate their expression, thereby playing a central role in expression of lysosomal genes (PubMed:19556463, PubMed:22692423). Regulates lysosomal positioning in response to nutrient deprivation by promoting the expression of PIP4P1 (PubMed:29146937). Acts as a positive regulator of autophagy by promoting expression of genes involved in autophagy (PubMed:21617040, PubMed:22576015, PubMed:23434374, PubMed:27278822). In association with TFE3, activates the expression of CD40L in T-cells, thereby playing a role in T-cell-dependent antibody responses in activated CD4(+) T-cells and thymus-dependent humoral immunity (By similarity). Specifically recognizes the gamma-E3 box, a subset of E-boxes, present in the heavy-chain immunoglobulin enhancer (PubMed:2115126). Plays a role in the signal transduction processes required for normal vascularization of the placenta (By similarity). Involved in the immune response to infection by the bacteria S.aureus, S.typhimurium or S.enterica: infection promotes itaconate production, leading to alkylation, resulting in nuclear localization and transcription factor activity (PubMed:35662396). Itaconate-mediated alkylation activates TFEB-dependent lysosomal biogenesis, facilitating the bacteria clearance during the antibacterial innate immune response (PubMed:35662396).
May play a role in cell-cell recognition and in neuronal membrane signaling. Seems to be important for the achievement of the necessary balance between dendrite elongation and branching during the elaboration of a complex dendritic arbor. Involved in the development of appropriate excitatory synaptic connectivity (By similarity).
(Microbial infection) Interacts with adenovirus 2 E1A; the interaction enhances the ATF7-mediated viral transactivation activity which requires the zinc-binding domains of both E1A and ATF7.
Acts as a dominant repressor of the E-selectin/NF-ELAM1/delta-A promoter.
Acts as a negative regulator, inhibiting both ATF2 and ATF7 transcriptional activities. It may exert these effects by sequestrating in the cytoplasm the Thr-53 phosphorylating kinase, preventing activation.
Expressed in various tissues including heart, brain, placenta, lung and skeletal muscle. Highest levels in skeletal muscle. Lowest in lung and placenta.
Homodimer; binds DNA as homodimer. Heterodimer; heterodimerizes with other members of ATF family and with JUN family members. Interacts with JNK2; the interaction does not phosphorylate ATF7 but acts as a docking site for other ATF-associated partners such as JUN family members. Interacts (via its transactivation domain) with TAF12 (isoforms TAFII15 and TAFII20); the interaction potentiates the transactivation activity (isoform TAFII20 only) and is inhibited by ATF7 sumoylation. Interacts with TAF4; the interaction inhibits the TAF12-dependent transactivation. Interacts with MAPK9; the interaction does not phosphorylate ATF7 but acts as a docking site for ATF7-associated partners such as JUN. Interacts with Ku complex components XRCC6 and XRCC7 (PubMed:29490055). Interacts with TERT (PubMed:29490055).
On EGF stimulation, phosphorylated first on Thr-53 allowing subsequent phosphorylation on Thr-51. This latter phosphorylation prevents sumoylation, increases binding to TAF12 and enhances transcriptional activity (PubMed:18950637). Social isolation stress as well as TNF-alpha also induce the phosphorylation of ATF7 (PubMed:29490055). Phosphorylated in proliferating colonic and small intestinal epithelial cells (By similarity).
On EGF stimulation, phosphorylated first on Thr-53 allowing subsequent phosphorylation on Thr-51. This latter phosphorylation prevents sumoylation, increases binding to TAF12 and enhances transcriptional activity.
Stress-responsive chromatin regulator that plays a role in various biological processes including innate immunological memory, adipocyte differentiation or telomerase regulation (PubMed:29490055). In absence of stress, contributes to the formation of heterochromatin and heterochromatin-like structure by recruiting histone H3K9 tri- and di-methyltransferases thus silencing the transcription of target genes such as STAT1 in adipocytes, or genes involved in innate immunity in macrophages and adipocytes (By similarity). Stress induces ATF7 phosphorylation that disrupts interactions with histone methyltransferase and enhances the association with coactivators containing histone acetyltransferase and/or histone demethylase, leading to disruption of the heterochromatin-like structure and subsequently transcriptional activation (By similarity). In response to TNF-alpha, which is induced by various stresses, phosphorylated ATF7 and telomerase are released from telomeres leading to telomere shortening (PubMed:29490055). Also plays a role in maintaining epithelial regenerative capacity and protecting against cell death during intestinal epithelial damage and repair (By similarity).
Strongly expressed in skeletal muscle. Also expressed at lower levels in heart and lung.
Sumoylation delays nuclear localization and inhibits transactivation activity through preventing binding to TAF12. RANBP2 appears to be the specific E3 ligase.
Interacts with CANX and DDOST (PubMed:29765154). Interacts with SQLE; this interaction modulates lipid droplet formation (PubMed:29765154).
May modulate lipid droplet formation throught interaction with SQLE.
Epidermis-specific type I keratin that plays a key role in skin. Acts as a regulator of innate immunity in response to skin barrier breach: required for some inflammatory checkpoint for the skin barrier maintenance.
Heterodimer of a type I and a type II keratin. KRT16 associates with KRT6 isomers (KRT6A or KRT6B) (By similarity). Interacts with TCHP (PubMed:15731013). Interacts with TRADD (By similarity).
KRT16 and KRT17 are coexpressed only in pathological situations such as metaplasias and carcinomas of the uterine cervix and in psoriasis vulgaris.
Acts as a modulator of macrophage activation through control of glucose metabolism.
Strongly expressed in liver, kidney and pancreas. Expressed at lower levels in placenta and heart. Very weakly expressed in lung and brain.
Plays a role in acrosome expansion and establishment of normal sperm morphology during spermatogenesis (By similarity). Important for male fertility (PubMed:11870081).
Histone chaperone that stabilizes pre-existing histone tetramers and regulates replication-independent histone exchange on chromatin (PubMed:26109053). Required for normal chromatin refolding in the coding region of transcribed genes, and for the suppression of spurious transcription (PubMed:26109053). Binds DNA and histones and promotes nucleosome assembly (in vitro) (PubMed:23378026, PubMed:26109053). Facilitates formation of tetrameric histone complexes containing histone H3 and H4 (PubMed:26109053). Modulates RNA polymerase 1-mediated transcription (By similarity). Binds DNA, with a preference for branched DNA species, such as Y-form DNA and Holliday junction DNA (PubMed:23378026).
Interacts with histones (PubMed:23378026). Interacts with a heterotetrameric complex formed by histone H3 and H4, especially when the histone tetramer is not bound to DNA (PubMed:26109053). Interacts with histone H3.3 (PubMed:33857403).
The acidic C-terminal domain mediates interaction with histone H3/H4 complexes.
The histone binding domain can functionally complement the yeast ortholog in regulating histone exchange and suppression of spurious transcription.
Belongs to the eukaryotic ribosomal protein eS21 family.
(Microbial infection) Interacts with human cytomegalovirus/HCMV UL84.
(Microbial infection) Interacts with the venezuelan equine encephalitis virus protease nsP2; this interaction probably allows the active transport of protease nsP2 into the host nucleus.
Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS.
Heterodimer; with KPNB1 (PubMed:7604027). Interacts with ANP32E (By similarity). Interacts with ZIC3 (By similarity). Interacts with NSMF; the interaction occurs in a calcium-independent manner after synaptic NMDA receptor stimulation and is required for nuclear import of NSMF but is competed by CABP1 (By similarity). Interacts with APEX1 (PubMed:15942031). Interacts with RAG1 (PubMed:8052633). Interacts with CTNNBL1 (via its N-terminal) (PubMed:21385873). Interacts with AICDA (via its NLS) (PubMed:21385873). Interacts with SNAI1 (via zinc fingers) (PubMed:21454664). Interacts with DCAF8 (PubMed:22500989). Interacts with ITSN1 isoform 2 (PubMed:29599122). Interacts with TALDO1 isoform 1 (By similarity).
Polyubiquitinated in the presence of RAG1 (in vitro).
(Microbial infection) In CMV-infected cells, interacts with the viral glycoprotein UL16 and UL142; this interaction causes ULBP3 retention in the endoplasmic reticulum and cis-Golgi and prevents binding to and activation of KLRK1/NKG2D, providing CMV with an immune evasion mechanism.
Interacts with KLRK1/NKG2D (PubMed:11491531, PubMed:11777960, PubMed:11754823). Does not bind to beta2-microglobulin (By similarity).
Actin- and myosin-binding protein implicated in the regulation of actomyosin interactions in smooth muscle and nonmuscle cells (could act as a bridge between myosin and actin filaments). Stimulates actin binding of tropomyosin which increases the stabilization of actin filament structure. In muscle tissues, inhibits the actomyosin ATPase by binding to F-actin. This inhibition is attenuated by calcium-calmodulin and is potentiated by tropomyosin. Interacts with actin, myosin, two molecules of tropomyosin and with calmodulin. Also plays an essential role during cellular mitosis and receptor capping. Involved in Schwann cell migration during peripheral nerve regeneration (By similarity).
High-molecular-weight caldesmon (isoform 1) is predominantly expressed in smooth muscles, whereas low-molecular-weight caldesmon (isoforms 2, 3, 4 and 5) are widely distributed in non-muscle tissues and cells. Not expressed in skeletal muscle or heart.
In non-muscle cells, phosphorylation by CDK1 during mitosis causes caldesmon to dissociate from microfilaments. Phosphorylation reduces caldesmon binding to actin, myosin, and calmodulin as well as its inhibition of actomyosin ATPase activity. Phosphorylation also occurs in both quiescent and dividing smooth muscle cells with similar effects on the interaction with actin and calmodulin and on microfilaments reorganization. CDK1-mediated phosphorylation promotes Schwann cell migration during peripheral nerve regeneration (By similarity).
The N-terminal part seems to be a myosin/calmodulin-binding domain, and the C-terminal a tropomyosin/actin/calmodulin-binding domain. These two domains are separated by a central helical region in the smooth-muscle form.
Enriched in neocortical regions of the developing cerebral cortex (PubMed:27830782). Not expressed in other compartments of the neocortical wall or in brain regions such as the hippocampus, striatum, mediodorsal nucleus of the thalamus and cerebellum (PubMed:27830782). Also expressed in bone (PubMed:14523025). In developing neonatal rib bone, present at high level in osteoblasts on bone-forming surfaces, in newly incorporated osteocytes and in some late hypertrophic chondrocytes (at protein level) (PubMed:15923362). In adult bone, localizes specifically to osteoblasts and young osteocytes at bone-forming sites (at protein level) (PubMed:15923362).
Expression in the developing cerebral cortex increases during the course of fetal development and peaks around the late-mid fetal stage, concurrent with the onset of synaptogenesis in the cortical plate (PubMed:27830782).
Expression is induced in the developing cerebral cortex in response to neuronal activity in neurons: expression is driven by the presence of a enhancer sequence only present in primates that binds the MEF2 transcription factors (PubMed:27830782).
Hormone that acts as a regulator of dendritic growth in the developing cerebral cortex in response to sensory experience (PubMed:27830782). Induced in the brain following membrane depolarization and inhibits dendritic branching in neurons of the developing cortex (PubMed:27830782). Probably acts by binding to natriuretic peptide receptor NPR3/NPR-C, thereby preventing binding between NPR3/NPR-C and natriuretic peptides, leading to increase cGMP production (By similarity).
This protein-coding gene has been repurposed in primates, with the presence of a new enhancer sequence that drives expression in brain in response to sensory experience, leading to restrict dendritic growth in the developing cortex (PubMed:27830782).
Caput, corpus, and cauda regions of the epididymis, the ductus deferens, sperm and seminal plasma.
May have a role in sperm-egg fusion and maturation.
Facilitates ubiquitin-independent proteasomal degradation of polycomb protein CBX4. Plays a role in inhibiting the activity of glucokinase GCK and both glucose-induced and basal insulin secretion.
Interacts with GCK; the interaction occurs preferentially at low glucose levels.
Represents a conventional myosin. This protein should not be confused with the unconventional myosin-15 (MYO15).
Amplified and overexpressed in some osteosarcomas (OS), suggesting that it may participate in TP53 degradation in OS.
Component of the CSN complex, composed of COPS1/GPS1, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7 (COPS7A or COPS7B), COPS8 and COPS9 isoform 1 (PubMed:18850735, PubMed:26456823). In the complex, it probably interacts directly with COPS1, COPS4, COPS8 and COPS9 isoform 1 (PubMed:18850735, PubMed:26456823). Interacts with CK2 and PKD (PubMed:12628923). Interacts with the translation initiation factor EIF3S6 and IKBKG (PubMed:11418127, PubMed:12220626). Interacts with ERCC6 (PubMed:26030138).
Widely expressed. Expressed at high level in heart and skeletal muscle.
Induced by cytotoxic agents, it is also increased during premature senescence. the induction seems to be mediated by TP53.
May be involved in the regulation of cellular senescence through a positive feedback loop with TP53. Is a TP53 downstream target gene that increases the stability of TP53 protein by promoting the ubiquitination and degradation of MDM2.
Antiparallel heterodimer with CDH23. Found in a complex with TMIE and LHFPL5. Interacts with LHFPL5/TMHS; this interaction is required for efficient localization to hair bundles. Interacts with MYO7A. Interacts with USH1G; this interaction may recruit USH1G to the plasma membrane. Interacts with TOMT. Isoforms CD1 and CD3 interact with TMC1 (via N-terminus) and TMC2 (via N-terminus).
Cadherin repeats 1 and 2 mediate calcium-dependent heterophilic interaction with CDH23.
Calcium-dependent cell-adhesion protein. Essential for maintenance of normal retinal and cochlear function.
Expressed in brain, lung, kidney, spleen and testis. Found also in the inner and outer synaptic layers, and the nerve fiber layer in adult and fetal retinas. Found in the supporting cells, outer sulcus cells and spiral ganglion of fetal cochlea. Expressed in cytotoxic tumor-derived T- and NK-cell lines as well as biopsies of nasal NK/T-cell lymphomas. Not detected in normal or in vitro activated peripheral blood cells, CD4 or CD8 lymphocytes or NK cells. Isoform 3 is expressed in brain, heart, cerebellum and kidney. CD1 isoforms, such as isoform 1, have a limited pattern of expression and is detected in testis, retina and cochlea. CD2 isoforms, such as isoforms 4 and 5, are expressed in heart, kidney, thymus, spleen, testis, retina and cochlea. CD3 isoforms, such as isoform 6, are widely expressed.
Heterodimer of an alpha chain (DOA) and a beta chain (DOB). Forms a heterotetrameric complex with an HLA-DM molecule during intracellular transport in endosomal/lysosomal compartments in B-cells.
Important modulator in the HLA class II restricted antigen presentation pathway by interaction with the HLA-DM molecule in B-cells. Modifies peptide exchange activity of HLA-DM.
The following alleles of DOA are known: DOA*01:01, DOA*01:02 and DOA*01:03. The sequence shown is that of DOA*01:01.
E3 ubiquitin-protein ligase that acts as a negative regulator of NOD2 signaling by mediating ubiquitination and degradation of RIPK2 (PubMed:28656966). Also catalyzes ubiquitination and proteasomal degradation of CANX within the endoplasmic reticulum (PubMed:21205830). Could have a role in spermatogenesis (By similarity).
The RING-type zinc finger is involved in CANX ubiquitination and degradation, but is not required for interaction with CANX.
A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:21289075, PubMed:12865317). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:21289075, PubMed:12865317). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850).
Allele 2B6*9: Has low affinity for anandamide and can only produce 11,12 EpETrE-EAs.
Expressed in liver, lung and heart right ventricle.
Phosphorylation is accompanied by a decrease in enzyme activity.
Variability among CYP2B6 alleles may account for differential metabolism of endogenous steroids and endocannabinoids among individuals. For 16-alpha hydroxylation of testosterone, Vmax/Km values between alleles decrease in the following order: 2B6*1 > 2B6*6 > 2B6*9 > 2B7*4. For 16-beta hydroxylation of testosterone, 2B6*6 has the highest catalytic efficiency. For anandamide metabolism, 2B6*6 and 2B6*9 alleles show significantly lower rates of epoxidation (PubMed:21289075). Genetic variations in CYP2B6 are responsible for poor metabolism of efavirenz and, therefore, susceptibility to efavirenz toxicity in the central nervous system [MIM:614546]. Efavirenz is a non-nucleoside reverse transcriptase inhibitor frequently prescribed with 2 nucleoside reverse transcriptase inhibitors as initial therapy for human immunodeficiency virus (HIV) infection. Up to half of patients treated with efavirenz, experience side effects in the central nervous system, including dizziness, insomnia, impaired concentration, somnolence, and abnormal dreams. Severe depression, aggressive behavior, and paranoid or manic reactions may also occur, depending on efavirenz concentration in the plasma. Patients homozygous for 2B6*6 have significantly higher plasma efavirenz levels when compared to 2B6*6 heterozygous ones (PubMed:15622315, PubMed:15194512, PubMed:20639527).
Expressed in adult spermatocytes and spermatids (at protein level).
Interacts (via N-terminus) with RAB2B (in GTP-bound form) (By similarity). Interacts with FRG1 (PubMed:17103222).
Associates with the organic matrix of bone and cartilage. Thought to act as an inhibitor of bone formation.
Requires vitamin K-dependent gamma-carboxylation for its function.
Although this protein contains a RING domain, intrinsic E3 ligase activity has not been proven.
Isoform 4 (C-terminal) interacts with the GTP-bound form of RAC1. Isoform 4 (C-terminal) interacts with SMARCD2/BAF60b.
Isoform 4 is ubiquitinated in the C-terminal. Ubiquitination is enhanced by activated RAC1. The presence of the RING finger domain is not essential for ubiquitination to occur.
May participate in a protein complex showing an E3 ligase activity regulated by RAC1. Ubiquitination is directed towards itself and possibly other substrates, such as SMARCD2/BAF60b. Intrinsic E3 ligase activity has not been proven.
Splice site between exons 6 and 7 is non-canonical.
Retinoids dehydrogenase/reductase with a clear preference for NADP. Displays high activity towards 9-cis, 11-cis and all-trans-retinal. Shows very weak activity towards 13-cis-retinol (PubMed:15865448, PubMed:12226107). Also exhibits activity, albeit with lower affinity than for retinaldehydes, towards lipid peroxidation products (C9 aldehydes) such as 4-hydroxynonenal and trans-2-nonenal (PubMed:19686838, PubMed:15865448). May play an important function in photoreceptor cells to detoxify 4-hydroxynonenal and potentially other toxic aldehyde products resulting from lipid peroxidation (PubMed:19686838). Has no dehydrogenase activity towards steroids (PubMed:15865448, PubMed:12226107).
Widely expressed, mostly in retina, kidney, brain, skeletal muscle, pancreas and stomach.
=Produced by alternative promoter usage.
Actin binding affinity is primarily determined by CH domain 1.
Homodimer. Interacts with the syntrophins SNTA1; SNTB1 and SNTB2. Interacts with SYNM. Interacts (via its WWW and ZZ domains) with DAG1 (via the PPXY motif of betaDAG1); the interaction is inhibited by the tyrosine phosphorylation of the PPXY motif of DAG1. Interacts with DTNB (By similarity). Interacts with PGM5 (By similarity).
Isoform 1 has high expression in muscle. Isoforms Up70 and Up140 were found in all the adult and fetal tissues tested and relatively abundant in lung and kidney.
May play a role in anchoring the cytoskeleton to the plasma membrane.
Component of centriolar satellites contributing to primary cilium formation.
A chromosomal aberration involving CCND1 may be a cause of B-lymphocytic malignancy, particularly mantle-cell lymphoma (MCL). Translocation t(11;14)(q13;q32) with immunoglobulin gene regions. Activation of CCND1 may be oncogenic by directly altering progression through the cell cycle.
A chromosomal aberration involving CCND1 may be a cause of parathyroid adenomas. Translocation t(11;11)(q13;p15) with the parathyroid hormone (PTH) enhancer.
Belongs to the cyclin family. Cyclin D subfamily.
Interacts with either CDK4 or CDK6 protein kinase to form a serine/threonine kinase holoenzyme complex (PubMed:8114739, PubMed:19237565). The cyclin subunit imparts substrate specificity to the complex (PubMed:20399237, PubMed:19237565, PubMed:8302605, PubMed:9106657). Component of the ternary complex CCND1/CDK4/CDKN1B required for nuclear translocation and modulation of CDK4-mediated kinase activity (PubMed:9106657). Interacts directly with CDKN1B (By similarity). Can form similar complexes with either CDKN1A or CDKN2A (By similarity). Interacts with FBXO4 (By similarity). Interacts with UHRF2; the interaction ubiquitinates CCND1 and appears to occur independently of phosphorylation (PubMed:21952639). Interacts with USP2 (PubMed:19917254). Interacts (via cyclin N-terminal domain) with INSM1 (via N-terminal region); the interaction competes with the binding of CCND1 to CDK4 during cell cycle progression and inhibits CDK4 activity (PubMed:16569215, PubMed:18417529, PubMed:19124461). Interacts with CDK4; the interaction is prevented with the binding of CCND1 to INSM1 during cell cycle progression (PubMed:19124461).
Phosphorylation at Thr-286 by MAP kinases is required for ubiquitination and degradation by the DCX(AMBRA1) complex (PubMed:10766840, PubMed:33854232, PubMed:33854235, PubMed:33854239). It also plays an essential role for recognition by the FBXO31 component of SCF (SKP1-cullin-F-box) protein ligase complex following DNA damage (PubMed:19412162).
Regulatory component of the cyclin D1-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition (PubMed:1833066, PubMed:1827756, PubMed:8114739, PubMed:8302605, PubMed:19412162, PubMed:33854235). Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complex and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase (PubMed:1833066, PubMed:1827756, PubMed:8114739, PubMed:8302605, PubMed:19412162). Hypophosphorylates RB1 in early G(1) phase (PubMed:1833066, PubMed:1827756, PubMed:8114739, PubMed:8302605, PubMed:19412162). Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals (PubMed:1833066, PubMed:1827756, PubMed:8302605, PubMed:19412162). Also a substrate for SMAD3, phosphorylating SMAD3 in a cell-cycle-dependent manner and repressing its transcriptional activity (PubMed:15241418). Component of the ternary complex, cyclin D1/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex (PubMed:9106657). Exhibits transcriptional corepressor activity with INSM1 on the NEUROD1 and INS promoters in a cell cycle-independent manner (PubMed:16569215, PubMed:18417529).
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving CCND1 is found in multiple myeloma. Translocation t(11;14)(q13;q32) with the IgH locus.
Ubiquitinated at Lys-269 by the DCX(AMBRA1) complex during the transition from G1 to S cell phase, leading to its degradation: ubiquitination is dependent on Thr-286 phosphorylation (PubMed:33854232, PubMed:33854235, PubMed:33854239). The DCX(AMBRA1) complex represents the major regulator of CCND1 stability during the G1/S transition (PubMed:33854232, PubMed:33854235, PubMed:33854239). Also ubiquitinated by a SCF (SKP1-CUL1-F-box protein) ubiquitin-protein ligase complex containing FBXO4 and CRYAB (By similarity). Following DNA damage it is ubiquitinated by some SCF (SKP1-cullin-F-box) protein ligase complex containing FBXO31 (PubMed:19412162). SCF-type ubiquitination is dependent on Thr-286 phosphorylation (PubMed:10766840, PubMed:19412162). Ubiquitinated also by UHRF2 apparently in a phosphorylation-independent manner (PubMed:21952639). Ubiquitination leads to its degradation and G1 arrest. Deubiquitinated by USP2; leading to its stabilization (PubMed:19917254).
Forms homodimers or heterodimers with TAS1R1 and TAS1R2.
Putative taste receptor. TAS1R1/TAS1R3 responds to the umami taste stimulus (the taste of monosodium glutamate). TAS1R2/TAS1R3 recognizes diverse natural and synthetic sweeteners. TAS1R3 is essential for the recognition and response to the disaccharide trehalose (By similarity). Sequence differences within and between species can significantly influence the selectivity and specificity of taste responses.
Homooligomer (By similarity). Interacts with SHOC, SYCP1 and SYCE3 (By similarity).
Plays a key role in reinforcing the integrity of the central element of the synaptonemal complex (SC) thereby stabilizing SC, ensuring progression of meiotic prophase I in male and female germ cells (By similarity). Promotes homologous recombination and crossing-over in meiotic prophase I via its association with SHOC1 (By similarity). Required for the localization of TEX11 and MSH4 to recombination intermediates (By similarity).
Serine protease inhibitor which specifically inhibits KLK5. May contribute to the regulation of the desquamation process in skin by inhibiting KLK5.
Skin. Highly expressed at sites of hyperkeratosis. Also detected in thymus, tonsils, testis, pancreas, liver, placenta and brain. Expressed at stratum granulosum and stratum corneum at palmar and plantar sites (at protein level).
Isoform 1 and isoform 2 are expressed in prostate and testis. Isoform 2 is expressed in male and female brain at equivalent levels, in particular in cerebellum, cerebral cortex, corpus callosum, occipital, parrietal and temporal lobes, and pons, but not in amygdala, cerebral peduncle, hippocampus and thalamus.
Contains one Leu-Xaa-Xaa-Ile-Leu (LXXIL) motif, which is essential for the association with nuclear receptors.
Contains one Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif, a motif known to be important for the association with nuclear receptors. Such motif, which is required for an efficient association with nuclear receptors, is however not essential.
Homodimer; mediated by the coiled coil domain. Isoform 3, but not other isoforms, interacts with the cytoplasmic tail of integrin ITGB3. The relevance of the interaction with ITGB3 is however uncertain, since isoform 3 is mainly nuclear. Interacts with CCNA2 and MTA1. Interacts with NFKB1 NF-kappa-B subunit. Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex interacts with the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU. Interacts with TASOR (By similarity).
The DD1 domain (also called RepD1 domain) mediates the corepressor function and is essential in the triggering of apoptosis.
Transcription coregulator that can have both coactivator and corepressor functions. Isoform 1, but not other isoforms, is involved in the coactivation of nuclear receptors for retinoid X (RXRs) and thyroid hormone (TRs) in a ligand-dependent fashion. In contrast, it does not coactivate nuclear receptors for retinoic acid, vitamin D, progesterone receptor, nor glucocorticoid. Acts as a coactivator for estrogen receptor alpha. Acts as a transcriptional corepressor via its interaction with the NFKB1 NF-kappa-B subunit, possibly by interfering with the transactivation domain of NFKB1. Induces apoptosis in breast cancer cells, but not in other cancer cells, via a caspase-2 mediated pathway that involves mitochondrial membrane permeabilization but does not require other caspases. May also act as an inhibitor of cyclin A-associated kinase. Also acts a component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex.
Widely expressed. Expressed in spleen, thymus, prostate, ovary, small intestine and white blood cells. Highly expressed in testis and colon. Isoform 4 is expressed in platelets, lymphocytes and granulocytes.
Expressed in brain, lung, skeletal muscle, heart, pancreas and kidney but not liver or placenta. Also expressed in aorta, ovary, pituitary, small intestine, fetal brain, fetal kidney and, within the adult brain, in the substantia nigra, medulla, amygdala, thalamus and cerebellum.
Homodimer (By similarity). Interacts with EBF1 (By similarity). Interacts with SMAD1 and SMAD4. Interacts with PARP1. Interacts with CEP290.
Transcription factor that can both act as an activator or a repressor depending on the context. Plays a central role in BMP signaling and olfactory neurogenesis. Associates with SMADs in response to BMP2 leading to activate transcription of BMP target genes. Acts as a transcriptional repressor via its interaction with EBF1, a transcription factor involved in terminal olfactory receptor neurons differentiation; this interaction preventing EBF1 to bind DNA and activate olfactory-specific genes. Involved in olfactory neurogenesis by participating in a developmental switch that regulates the transition from differentiation to maturation in olfactory receptor neurons. Controls proliferation and differentiation of neural precursors in cerebellar vermis formation.
Uses different DNA- and protein-binding zinc fingers to regulate the distinct BMP-Smad and Olf signaling pathways. C2H2-type zinc fingers 14-19 mediate the interaction with SMAD1 and SMAD4, while zinc fingers 28-30 mediate the interaction with EBF1. zinc fingers 2-8 bind the 5'-CCGCCC-3' DNA sequence in concert with EBF1, while zinc fingers 9-13 bind BMP target gene promoters in concert with SMADs.
Interacts with ACTN2 (By similarity). Forms a heterodimer with PDLIM4 (via LIM domain) (By similarity).
Isoform 1 is highly expressed in differentiated skeletal muscle. Isoform 2 is heart-specific.
May play a role in the organization of actin filament arrays within muscle cells.
(Microbial infection) Acts as a receptor for malaria parasite Plasmodium vivax (Thai isolate) in immature red blood cells.
(Microbial infection) Interacts with hepatitis C virus/HCV envelope glycoprotein E2; the interaction may facilitate viral entry into host cell.
(Microbial infection) Up-regulated upon hepatitis C virus/HCV infection via NS3-A4 viral protein complex; the up-regulation is mediated by oxidative stress (PubMed:30341327). Up-regulation of the complex formed by SLC3A2 and SLC7A5/LAT1 upon hepatitis C virus/HCV infection (PubMed:30341327).
Acts as a chaperone that facilitates biogenesis and trafficking of functional transporters heterodimers to the plasma membrane. Forms heterodimer with SLC7 family transporters (SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A10 and SLC7A11), a group of amino-acid antiporters (PubMed:11557028, PubMed:9829974, PubMed:9751058, PubMed:9878049, PubMed:10574970, PubMed:10903140, PubMed:30867591, PubMed:33298890, PubMed:33758168, PubMed:34880232). Heterodimers function as amino acids exchangers, the specificity of the substrate depending on the SLC7A subunit. Heterodimers SLC3A2/SLC7A6 or SLC3A2/SLC7A7 mediate the uptake of dibasic amino acids (PubMed:9829974, PubMed:10903140). Heterodimer SLC3A2/SLC7A11 functions as an antiporter by mediating the exchange of extracellular anionic L-cystine and intracellular L-glutamate across the cellular plasma membrane (PubMed:34880232). SLC3A2/SLC7A10 translocates small neutral L- and D-amino acids across the plasma membrane (By similarity). SLC3A2/SLC75 or SLC3A2/SLC7A8 translocates neutral amino acids with broad specificity, thyroid hormones and L-DOPA (PubMed:11557028, PubMed:10574970, PubMed:11389679, PubMed:11564694, PubMed:11742812, PubMed:12117417, PubMed:12225859, PubMed:15980244, PubMed:12716892, PubMed:33298890, PubMed:33758168, PubMed:30867591). SLC3A2 is essential for plasma membrane localization, stability, and the transport activity of SLC7A5 and SLC7A8 (PubMed:10391915, PubMed:10574970, PubMed:11311135, PubMed:15769744, PubMed:33066406). When associated with LAPTM4B, the heterodimer SLC7A5 is recruited to lysosomes to promote leucine uptake into these organelles, and thereby mediates mTORC1 activation (PubMed:25998567). Modulates integrin-related signaling and is essential for integrin-dependent cell spreading, migration and tumor progression (PubMed:15625115, PubMed:11121428).
Belongs to the SLC3A transporter family.
Disulfide-linked heterodimer with a non-glycosylated catalytic light subunit (SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A10 or SLC7A11) (PubMed:11557028, PubMed:9829974, PubMed:9751058, PubMed:10574970, PubMed:10903140, PubMed:11311135, PubMed:30867591, PubMed:9751058, PubMed:12225859, PubMed:12117417, PubMed:15769744, PubMed:33298890, PubMed:33758168, PubMed:34880232, PubMed:35352032). Interacts with TLCD3A/CT120 (PubMed:12270127). Interacts with ICAM1 (PubMed:12716892). Constitutively and specifically associates with beta-1 integrins (alpha-2/beta-1, alpha-3/beta-1, alpha-5/beta-1 and alpha-6/beta-1), but minimally with alpha-4/beta-1 (PubMed:11696247). Interacts with LAPTM4B; recruits SLC3A2 and SLC7A5/LAT1 to lysosomes to promote leucine uptake into these organelles and is required for mTORC1 activation (PubMed:25998567).
Expressed ubiquitously in all tissues tested with highest levels detected in kidney, placenta and testis and weakest level in thymus. During gestation, expression in the placenta was significantly stronger at full-term than at the mid-trimester stage. Expressed in HUVECS and at low levels in resting peripheral blood T-lymphocytes and quiescent fibroblasts. Also expressed in fetal liver and in the astrocytic process of primary astrocytic gliomas. Expressed in retinal endothelial cells and in the intestinal epithelial cell line C2BBe1.
Expression is induced in resting peripheral blood T-lymphocytes following PHA stimulation. Expression increases at the time of maximal DNA synthesis, in fibroblasts stimulated to divide. Expression and the uptake of leucine is stimulated in mononuclear, cytotrophoblast-like choriocarcinoma cells by combined treatment with PMA and calcium ionophore. Up-regulated in response to hydrogen peroxide (PubMed:30341327). Highly expressed in various cancer types (PubMed:23116296, PubMed:28350098, PubMed:19292886).
N-glycosylated; N-glycosylation is crucial for trafficking and stability of SLC3A2 to the plasma membrane.
Phosphorylation on Ser-406; Ser-408 or Ser-410 and on Ser-527 or Ser-531 by ecto-protein kinases favors heterotypic cell-cell interactions.
Acts as proto-oncogene. Retains ability to bind CDK4, but unable to catalyze efficiently RB phosphorylation and inactivation.
Interacts with either CDK4 or CDK6 protein kinase to form a serine/threonine kinase holoenzyme complex (PubMed:8114739, PubMed:18827403). The cyclin subunit imparts substrate specificity to the complex (PubMed:8114739, PubMed:18827403).
Phosphorylation at Thr-280 by MAP kinases is required for ubiquitination and degradation by the DCX(AMBRA1) complex.
Regulatory component of the cyclin D2-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition (PubMed:8114739, PubMed:18827403). Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complex and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase (PubMed:8114739, PubMed:18827403). Hypophosphorylates RB1 in early G(1) phase (PubMed:8114739, PubMed:18827403). Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals (PubMed:8114739, PubMed:18827403).
Ubiquitinated by the DCX(AMBRA1) complex during the transition from G1 to S cell phase, leading to its degradation: ubiquitination is dependent on Thr-280 phosphorylation (PubMed:33854235, PubMed:33854239). The DCX(AMBRA1) complex represents the major regulator of CCND2 stability during the G1/S transition (PubMed:33854235, PubMed:33854239). Polyubiquitinated by the SCF(FBXL2) complex, leading to proteasomal degradation (PubMed:22323446).
Component of the SWI5-SFR1 complex, a complex required for double-strand break repair via homologous recombination.
Component of the SWI5-SFR1 complex. Interacts with RAD51.
By prolactin and androgen; inhibited by estrogen.
Expressed in pathological conditions of the mammary gland and in several exocrine tissues, such as the lacrimal, salivary, and sweat glands.
Calcium also binds, with stronger affinity to another site, beyond the GLA domain. This GLA-independent binding site is necessary for the recognition of the thrombin-thrombomodulin complex.
May be phosphorylated on a Ser or Thr in a region (AA 25-30) of the propeptide.
N- and O-glycosylated. Partial (70%) N-glycosylation of Asn-371 with an atypical N-X-C site produces a higher molecular weight form referred to as alpha. The lower molecular weight form, not N-glycosylated at Asn-371, is beta. O-glycosylated with core 1 or possibly core 8 glycans.
Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids (PubMed:25618265). Exerts a protective effect on the endothelial cell barrier function (PubMed:25651845).
Synthesized as a single chain precursor, which is cleaved into a light chain and a heavy chain held together by a disulfide bond. The enzyme is then activated by thrombin, which cleaves a tetradecapeptide from the amino end of the heavy chain; this reaction, which occurs at the surface of endothelial cells, is strongly promoted by thrombomodulin.
The vitamin K-dependent, enzymatic carboxylation of some Glu residues allows the modified protein to bind calcium.
By all-trans retinoic acid (ATRA), TNF and IL13/interleukin-13. Strongly down-regulated in colorectal cancer.
Glycosyltransferase that can synthesize all known mucin beta 6 N-acetylglucosaminides. Mediates core 2 and core 4 O-glycan branching, 2 important steps in mucin-type biosynthesis. Has also I-branching enzyme activity by converting linear into branched poly-N-acetyllactosaminoglycans, leading to introduce the blood group I antigen during embryonic development.
Primarily expressed in mucus-secreting tissues. Expressed in colon, kidney, small intestine, trachea, and stomach, where mucin is produced.
Exhibits outward rectification in a physiological K(+) gradient and mild inward rectification in symmetrical K(+) conditions.
Inhibited by internal acidification and, to a small degree, by zinc. Not inhibited by quinine, quinidine or barium.
Widespread expression, detected in all tissues tested except for skeletal muscle. Strongest expression in placenta, pancreas, heart, colon and spleen, lower levels detected in peripheral blood leukocytes, lung, liver, kidney and thymus. Lowest expression detected in brain.
Expressed in the testis, in spermatozoa (at protein level) (PubMed:11179690, PubMed:28905369). Expressed in actively dividing fetal tissues, including sternum, intestine, limb, kidney and stomach (PubMed:14585816).
Plays a role in spermatogenesis (PubMed:28905369). When overexpressed, prevents nuclear localization of HIF1A (By similarity).
Processed into N-terminal 27-kDa and C-terminal 55-kDa fragments.
RNA-binding protein that acts as a nuclear receptor corepressor. Probably acts by binding the SRA RNA, and repressing the SRA-mediated nuclear receptor coactivation. Binds the STR7 loop of SRA RNA. Also able to repress glucocorticoid (GR), androgen (AR), thyroid (TR) and VDR-mediated transactivation.
Ubiquitously expressed, with highest level in heart, liver, skeletal muscle and testis.
Component of the ESCRT-0 complex composed of STAM or STAM2 and HGS. Part of a complex at least composed of HSG, STAM2 and EPS15. Interacts with JAK2 and JAK3. Interacts with ubiquitinated proteins and the deubiquitinating enzyme USP8/UBPY (By similarity). Interacts (via the via the PxVxL motif) with CBX5; the interaction is direct. Interacts with VPS37C. Interacts with ubiquitin; the interaction is direct. Interacts (via UIM domain) with UBQLN1 (via ubiquitin-like domain) (By similarity).
Involved in intracellular signal transduction mediated by cytokines and growth factors. Upon IL-2 and GM-CSL stimulation, it plays a role in signaling leading to DNA synthesis and MYC induction. May also play a role in T-cell development. Involved in down-regulation of receptor tyrosine kinase via multivesicular body (MVBs) when complexed with HGS (ESCRT-0 complex). The ESCRT-0 complex binds ubiquitin and acts as sorting machinery that recognizes ubiquitinated receptors and transfers them to further sequential lysosomal sorting/trafficking processes (By similarity).
Phosphorylated in response to IL-2, GM-CSF, EGF and PDGF.
The SH3 domain mediates the interaction with USP8.
The VHS and UIM domains mediate the interaction with ubiquitinated proteins.
Belongs to the PNP/MTAP phosphorylase family.
Catalyzes the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate (PubMed:9305964, PubMed:23438750). Preferentially acts on 6-oxopurine nucleosides including inosine and guanosine (PubMed:9305964).
Expressed in red blood cells; overexpressed in red blood cells (cytoplasm) of patients with hereditary non-spherocytic hemolytic anemia of unknown etiology.
Inhibited by 5'-deaza-1'-aza-2c-deoxy-1'-(9-methylene)-Immucilin-G (DADMe-ImmG).
The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate.
Antigen that is the basis for a widely used serum assay for the monitoring of patients with ovarian epithelial cancer. Due to lack of sensitivity for stage I disease and lack of specificity, it is of little value in the detection of early ovarian cancer. Due to its similarly elevated levels in some nonmalignant conditions, it is not specific enough to be used for population screening.
Binds to MSLN. Binding to MSLN mediates heterotypic cell adhesion. This may contribute to the metastasis of ovarian cancer to the peritoneum by initiating cell attachment to the mesothelial epithelium via binding to MSLN.
Composed of three domains, a Ser-, Thr-rich N-terminal domain, a repeated domain containing between 12 and 60 partially conserved tandem repeats of 156 amino acids and a C-terminal transmembrane contain domain with a short cytoplasmic tail.
Expressed in corneal and conjunctival epithelia (at protein level). Overexpressed in ovarian carcinomas and ovarian low malignant potential (LMP) tumors as compared to the expression in normal ovarian tissue and ovarian adenomas.
Heavily N-glycosylated; expresses primarily high mannose and complex bisecting type N-linked glycans.
Heavily O-glycosylated; expresses both type 1 and type 2 core glycans.
May be phosphorylated. Phosphorylation of the intracellular C-terminal domain may induce proteolytic cleavage and the liberation of the extracellular domain into the extracellular space.
May contain numerous disulfide bridges. Association of several molecules of the secreted form may occur through interchain disulfide bridges providing an extraordinarily large gel-like matrix in the extracellular space or in the lumen of secretory ducts.
The number of repeats is highly polymorphic and can be composed between 12 and 60 extracellular mucin repeats.
Thought to provide a protective, lubricating barrier against particles and infectious agents at mucosal surfaces.
Cys-414 near TM10 is a major determinant of nucleobase transport activity.
Expressed in testis at the blood-testis barrier (at protein level) (PubMed:23639800). Detected in erythrocytes (at protein level) (PubMed:23219802, PubMed:11584005). Expressed at relatively high levels in cerebral cortex, particularly the frontal and parietal lobes, and the thalamus and basal ganglia (at protein level) (PubMed:11311901). In the midbrain expressed at moderate levels, whereas in the other areas of the brainstem, namely medulla and pons, cerebellum and the hippocampus expressed at lower amounts when compared to the other brain regions (at protein level) (PubMed:11311901). Expressed in Langerhans cells and lymphocytes in the pancreas (at protein level) (PubMed:15501974). Expressed in kidney, in polarized renal epithelial cells (PubMed:12527552). Expressed in adipose tissues (PubMed:35790189). Expressed in placenta (PubMed:8986748). Expressed in small intestine (PubMed:10755314).
The absence of the protein in tumor cells is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma.
Transporter activity is sensitive to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR) (PubMed:10722669, PubMed:21795683, PubMed:8986748, PubMed:27995448, PubMed:26406980, PubMed:15037197, PubMed:14759222, PubMed:17379602). Inhibited by dilazep (PubMed:14759222, PubMed:15037197, PubMed:17379602). Inhibited by dipyridamole (PubMed:14759222, PubMed:15037197, PubMed:17379602). Inhibited by hypoxanthine (PubMed:15037197). Inhibited by azidothymidine (AZT) (PubMed:15037197). Inhibited by dideoxycytidine (ddC) (PubMed:15037197). Inhibited by dideoxyinosine (ddI) (PubMed:15037197). Inhibited by azidothymidine (AZT) (PubMed:15037197). Inhibited by draflazine (PubMed:17379602). Inhibited by soluflazine (PubMed:17379602). Inhibited by cladribine (PubMed:27995448). Inhibited by capecitabine (PubMed:27995448). Inhibited by clofarabine (PubMed:27995448). Inhibited by ribavirin (PubMed:27995448). Modestly inhibited by acyclovir (PubMed:27995448). Modestly inhibited by 5-fluorouracil (PubMed:27995448).
Uniporter involved in the facilitative transport of nucleosides and nucleobases, and contributes to maintaining their cellular homeostasis (PubMed:8986748, PubMed:10755314, PubMed:12527552, PubMed:10722669, PubMed:21795683, PubMed:35790189, PubMed:27995448, PubMed:17379602, PubMed:14759222, PubMed:15037197, PubMed:26406980). Functions as a Na(+)-independent transporter (PubMed:8986748). Involved in the transport of nucleosides such as adenosine, guanosine, inosine, uridine, thymidine and cytidine (PubMed:8986748, PubMed:10755314, PubMed:12527552, PubMed:10722669, PubMed:17379602, PubMed:14759222, PubMed:15037197, PubMed:26406980). Also transports purine nucleobases (hypoxanthine, adenine, guanine) and pyrimidine nucleobases (thymine, uracil) (PubMed:21795683, PubMed:27995448). Mediates basolateral nucleoside uptake into Sertoli cells, thereby regulating the transport of nucleosides in testis across the blood-testis barrier (By similarity). Regulates inosine levels in brown adipocytes tissues (BAT) and extracellular inosine levels, which controls BAT-dependent energy expenditure (PubMed:35790189).
A cytochrome P450 monooxygenase involved in primary bile acid biosynthesis. Catalyzes the 12alpha-hydroxylation of 7alpha-hydroxy-4-cholesten-3-one, an intermediate metabolite in cholic acid biosynthesis (PubMed:10051404). Controls biliary balance of cholic acid and chenodeoxycholic acid, ultimately regulating the intestinal absorption of dietary lipids (By similarity). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH--hemoprotein reductase) (By similarity).
Guanine nucleotide exchange factor activating the small GTPase RHOA, which, in turn, induces myosin filament formation. Also activates RHOG. Does not activate RAC1, or to a much lower extent than RHOA and RHOG. Part of a functional unit, involving PLEKHG6, MYH10 and RHOA, at the cleavage furrow to advance furrow ingression during cytokinesis. In epithelial cells, required for the formation of microvilli and membrane ruffles on the apical pole. Along with EZR, required for normal macropinocytosis.
Highest expression in the placenta. Low levels in small intestine, lung, liver, kidney, thymus and heart.
Interacts with MYH10. Interacts with ELMO1 and EZR (in an open conformation). Interacts with CSPP1.
Binds to DNA motifs with the sequence 5'-GCG(T/G)GGGCG-3' via its C2H2-type zinc fingers (PubMed:25258363, PubMed:25999311). The first, most N-terminal zinc finger binds to the 3'-GCG motif, the middle zinc finger interacts with the central TGG motif, and the C-terminal zinc finger binds to the 5'-GCG motif. Binds double-stranded target DNA, irrespective of the cytosine methylation status. Has reduced affinity for target DNA where the cytosines have been oxidized to 5-hydroxymethylcytosine. Does not bind target DNA where the cytosines have been oxidized to 5-formylcytosine or 5-carboxylcytosine (PubMed:25258363).
Interacts with SNAI1 and SP1 upon 12-O-tetradecanoylphorbol-13-acetate (TPA) induction.
Transcriptional regulator (PubMed:20121949). Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3'(EGR-site) in the promoter region of target genes (By similarity). Binds double-stranded target DNA, irrespective of the cytosine methylation status (PubMed:25258363, PubMed:25999311). Regulates the transcription of numerous target genes, and thereby plays an important role in regulating the response to growth factors, DNA damage, and ischemia. Plays a role in the regulation of cell survival, proliferation and cell death. Activates expression of p53/TP53 and TGFB1, and thereby helps prevent tumor formation. Required for normal progress through mitosis and normal proliferation of hepatocytes after partial hepatectomy. Mediates responses to ischemia and hypoxia; regulates the expression of proteins such as IL1B and CXCL2 that are involved in inflammatory processes and development of tissue damage after ischemia. Regulates biosynthesis of luteinizing hormone (LHB) in the pituitary (By similarity). Regulates the amplitude of the expression rhythms of clock genes: BMAL1, PER2 and NR1D1 in the liver via the activation of PER1 (clock repressor) transcription. Regulates the rhythmic expression of core-clock gene BMAL1 in the suprachiasmatic nucleus (SCN) (By similarity).
Transcriptional regulator. Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3'(EGR-site) in the promoter region of target genes. Binds double-stranded target DNA, irrespective of the cytosine methylation status. Regulates the transcription of numerous target genes, and thereby plays an important role in regulating the response to growth factors, DNA damage, and ischemia. Plays a role in the regulation of cell survival, proliferation and cell death.
Belongs to the ABC transporter superfamily. ABCB family. Mitochondrial peptide exporter (TC 3.A.1.212) subfamily.
Catalyzes the export of an unknown physiological substrate from the mitochondrial matrix to the cytosol in an ATP-dependent manner (PubMed:33253225). May also transport the heme analog Zn (II) mesoporphyrin (ZnMP) in an ATP dependent manner but can't export the heme precursor 5-aminolevulinic acid (ALA) from mitochondria (PubMed:33253225). Plays a role in the early step of the heme biosynthetic process during insertion of iron into protoporphyrin IX (PPIX). In turn participates in hemoglobin synthesis and also protects against oxidative stress (PubMed:28808058, PubMed:22085049). In addition may be involved in mitochondrial unfolded protein response (UPRmt) signaling pathway, although ABCB10 probably does not participate in peptide export from mitochondria (PubMed:28315685).
Homodimer or homooligomer (PubMed:23716676, PubMed:30765471). Interacts with PAAT (PubMed:25063848). Interacts with SLC25A37; this interaction stabilizes SLC25A37 and enhances the function of SLC25A37 to import mitochondrial iron during erythroid differentiation (By similarity). Interacts with FECH; this interaction may allow the formation of an oligomeric complex with SLC25A37 (By similarity). Forms a complex with ABCB7 and FECH, where a dimeric FECH bridges ABCB7 and ABCB10 homodimers; this complex may be required for cellular iron homeostasis, mitochondrial function and heme biosynthesis (PubMed:30765471). Interacts with FECH (PubMed:30765471).
Ubiquitous. Highly expressed in bone marrow, expressed at intermediate to high levels in skeletal muscle, small intestine, thyroid, heart, brain, placenta, liver, pancreas, prostate, testis, ovary, leukocyte, stomach, spinal cord, lymph node, trachea and adrenal gland, and low levels are found in lung, kidney, spleen, thymus and colon.
Belongs to the glycosyltransferase 41 family. O-GlcNAc transferase subfamily.
Catalyzes the transfer of a single N-acetylglucosamine from UDP-GlcNAc to a serine or threonine residue in cytoplasmic and nuclear proteins resulting in their modification with a beta-linked N-acetylglucosamine (O-GlcNAc) (PubMed:26678539, PubMed:26369908, PubMed:23103939, PubMed:21240259, PubMed:21285374, PubMed:15361863). Glycosylates a large and diverse number of proteins including histone H2B, AKT1, ATG4B, EZH2, PFKL, KMT2E/MLL5, MAPT/TAU, NOD2 and HCFC1 (PubMed:19451179, PubMed:20200153, PubMed:21285374, PubMed:22923583, PubMed:23353889, PubMed:24474760, PubMed:26678539, PubMed:26369908, PubMed:27527864, PubMed:34074792). Can regulate their cellular processes via cross-talk between glycosylation and phosphorylation or by affecting proteolytic processing (PubMed:21285374). Probably by glycosylating KMT2E/MLL5, stabilizes KMT2E/MLL5 by preventing its ubiquitination (PubMed:26678539). Involved in insulin resistance in muscle and adipocyte cells via glycosylating insulin signaling components and inhibiting the 'Thr-308' phosphorylation of AKT1, enhancing IRS1 phosphorylation and attenuating insulin signaling (By similarity). Involved in glycolysis regulation by mediating glycosylation of 6-phosphofructokinase PFKL, inhibiting its activity (PubMed:22923583). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1. Plays a key role in chromatin structure by mediating O-GlcNAcylation of 'Ser-112' of histone H2B: recruited to CpG-rich transcription start sites of active genes via its interaction with TET proteins (TET1, TET2 or TET3) (PubMed:22121020, PubMed:23353889). As part of the NSL complex indirectly involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852). O-GlcNAcylation of 'Ser-75' of EZH2 increases its stability, and facilitating the formation of H3K27me3 by the PRC2/EED-EZH2 complex (PubMed:24474760). Regulates circadian oscillation of the clock genes and glucose homeostasis in the liver. Stabilizes clock proteins BMAL1 and CLOCK through O-glycosylation, which prevents their ubiquitination and subsequent degradation. Promotes the CLOCK-BMAL1-mediated transcription of genes in the negative loop of the circadian clock such as PER1/2 and CRY1/2 (PubMed:12150998, PubMed:19451179, PubMed:20018868, PubMed:20200153, PubMed:21285374, PubMed:15361863). O-glycosylates HCFC1 and regulates its proteolytic processing and transcriptional activity (PubMed:21285374, PubMed:28584052, PubMed:28302723). Regulates mitochondrial motility in neurons by mediating glycosylation of TRAK1 (By similarity). Glycosylates HOXA1 (By similarity). O-glycosylates FNIP1 (PubMed:30699359). Promotes autophagy by mediating O-glycosylation of ATG4B (PubMed:27527864).
Highly expressed in pancreas and to a lesser extent in skeletal muscle, heart, brain and placenta. Present in trace amounts in lung and liver.
Induction of the nucleocytoplasmic OGT (ncOGT) isoform in the liver on glucose deprivation is mediated by the decreased hexosamine biosynthesis pathway (HBP) flux.
Monomer; may exist in different oligomerization states in cells (PubMed:21240259). Homotrimer, oligomerizes via TPR repeats 6 and 7. Trimerization is not necessary for activity in vitro, however it increases affinity for UDP-GlcNAc (By similarity). Component of a THAP1/THAP3-HCFC1-OGT complex (PubMed:20200153). Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1 (PubMed:20018852). Interacts directly with HCFC1; the interaction O-glycosylates HCFC1, regulates its proteolytic processing and transcriptional activity and, in turn, stabilizes OGT in the nucleus (PubMed:12670868, PubMed:20200153, PubMed:21285374, PubMed:23353889). Interacts (via TPRs 1-6) with SIN3A; the interaction mediates transcriptional repression in parallel with histone deacetylase (PubMed:12150998). Interacts (via TPR 5-6) with TET1, TET2 and TET3 (PubMed:23353889, PubMed:23222540). Interacts (via TPR repeats 6 and 7) with ATXN10 (By similarity). Interacts with histone H2B (PubMed:22121020). Interacts with BMAL1. Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1. Interacts with SINHCAF (By similarity). Component of a complex composed of KMT2E/MLL5 (isoform 3), OGT (isoform 1) and USP7; the complex stabilizes KMT2E/MLL5, preventing KMT2E/MLL5 ubiquitination and proteasomal-mediated degradation (PubMed:26678539). Isoform 1 interacts (via TRP repeats) with isoform 3 KMT2E/MLL5 (via N-terminus) (PubMed:26678539, PubMed:23629655). Isoform 1 interacts with USP7 (PubMed:26678539). Interacts with TRAK1; this interaction is not required for glycosylation of TRAK1 by this protein. Found in a complex with KIF5B, RHOT1, RHOT2 and TRAK1 (PubMed:24995978). Interacts (via TPR repeats domain) with HOXA1; the interaction takes place mainly in the nucleus (By similarity). Interacts with NSD2 (By similarity). Interacts with PROSER1; this interaction mediates TET2 O-GlcNAcylation and stability by promoting the interaction between OGT and TET2 (PubMed:34667079).
Phosphorylation on Ser-3 or Ser-4 by GSK3-beta positively regulates its activity.
Regulation of OGT activity and altered O-GlcNAcylations are implicated in diabetes and Alzheimer disease. O-GlcNAcylation of AKT1 affects insulin signaling and, possibly diabetes. Reduced O-GlcNAcylations and resulting increased phosphorylations of MAPT/TAU are observed in Alzheimer disease (AD) brain cerebrum.
The TPR repeat domain is required for substrate binding and oligomerization.
The mitochondrial isoform (mOGT) is cytotoxic and triggers apoptosis in several cell types including INS1, an insulinoma cell line.
Not known, though may play a role tumor transformation or progression. In vitro promotes cell viability in melanoma cell lines.
In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system.
Phosphorylation at sites in the second and third cytoplasmic loops independently contribute to agonist-induced receptor down-regulation.
Homooligomer (PubMed:24998259). Interacts (via SAM domain) with ANKS6 (via SAM domain) (PubMed:24998259). Interacts with BICC1 (By similarity). Interacts with NPHP1 (By similarity). Interacts with NEK8 (By similarity). Interacts with HIF1AN (By similarity). Interacts with NEK7; this interaction alters the subcellular distribution of NEK7 by preventing its nuclear translocation (PubMed:26188091).
Hydroxylated at Asn-96, most probably by HIF1AN.
May be involved in vasopressin signaling in the kidney.
Phosphorylations at Ser-5, Ser-225, Thr-319, Ser-320, Ser-368 and Ser-371 occur in a NEK7-dependent manner.
Actin-binding protein that is involved in actin cytoskeleton assembly and reorganization (PubMed:22330775, PubMed:21730168). Acts as an actin nucleation factor and promotes assembly of actin filaments together with SPIRE1 and SPIRE2 (PubMed:22330775, PubMed:21730168). Involved in intracellular vesicle transport along actin fibers, providing a novel link between actin cytoskeleton dynamics and intracellular transport (By similarity). Required for asymmetric spindle positioning, asymmetric oocyte division and polar body extrusion during female germ cell meiosis (By similarity). Plays a role in responses to DNA damage, cellular stress and hypoxia by protecting CDKN1A against degradation, and thereby plays a role in stress-induced cell cycle arrest (PubMed:23375502). Also acts in the nucleus: together with SPIRE1 and SPIRE2, promotes assembly of nuclear actin filaments in response to DNA damage in order to facilitate movement of chromatin and repair factors after DNA damage (PubMed:26287480). Protects cells against apoptosis by protecting CDKN1A against degradation (PubMed:23375502).
Belongs to the formin homology family. Cappuccino subfamily.
Expressed almost exclusively in the developing and mature central nervous system.
Interacts with SPIRE1 (PubMed:21705804, PubMed:21730168). Binds actin (PubMed:20082305). Interacts with CDKN1A (PubMed:23375502).
Up-regulated in response to cellular stress, hypoxia and DNA damage via NF-kappa-B.
Possible tumor suppressor which may play a role in cell growth.
Widely expressed with higher expression in lung, kidney, spleen, pancreas, thymus, prostate, testis, ovary, small intestine and thyroid.
Does not bind lactose, and may not bind carbohydrates.
Most of the residues in the galectin domain that have been shown to be critical for carbohydrate-binding in other galectins are not conserved.
Highly expressed in beta-cells of the pancreatic islets.
Homodimer. Interacts with NPHS2/podocin (via the C-terminus). Interacts with NPHS1 (via the Ig-like domains). Interacts with FYN.
The extracellular domain is cleaved leading to the generation of a soluble fragment and a membrane-bound C-terminal fragment, which is further cleaved by gamma-secretase.
Component of the PI(3,5)P2 regulatory complex/PAS complex, at least composed of PIKFYVE, FIG4 and VAC14. VAC14 nucleates the assembly of the complex and serves as a scaffold by pentamerizing into a star-shaped structure, which can bind a single copy each of PIKFYVE and FIG4 and coordinates their activities.
Dual specificity phosphatase component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) (PubMed:17556371, PubMed:33098764). Catalyzes the dephosphorylation of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) to form phosphatidylinositol 3-phosphate (PubMed:33098764). Has serine-protein phosphatase activity acting on PIKfyve to stimulate its lipid kinase activity, its catalytically activity being required for maximal PI(3,5)P2 production (PubMed:33098764). In vitro, hydrolyzes all three D5-phosphorylated polyphosphoinositide and although displaying preferences for PtdIns(3,5)P2, it is capable of hydrolyzing PtdIns(3,4,5)P3 and PtdIns(4,5)P2, at least in vitro (PubMed:17556371).
Inhibits cell growth by regulating the TOR signaling pathway upstream of the TSC1-TSC2 complex and downstream of AKT1.
Up-regulated by oxidized LDL and hypoxia in macrophages.
Up-regulated in atherosclerotic plaques relative to healthy segments of the same artery.
Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits. The complex is composed of 3 respiratory subunits cytochrome b, cytochrome c1 and Rieske protein UQCRFS1, 2 core protein subunits UQCRC1/QCR1 and UQCRC2/QCR2, and 6 low-molecular weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, UQCR10/QCR9, UQCR11/QCR10 and subunit 9, the cleavage product of Rieske protein UQCRFS1 (By similarity). The complex exists as an obligatory dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and cytochrome c oxidase (complex IV, CIV), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with FLVCR2; this interaction occurs in the absence of heme and is disrupted upon heme binding.
Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. The cytochrome b-c1 complex catalyzes electron transfer from ubiquinol to cytochrome c, linking this redox reaction to translocation of protons across the mitochondrial inner membrane, with protons being carried across the membrane as hydrogens on the quinol. In the process called Q cycle, 2 protons are consumed from the matrix, 4 protons are released into the intermembrane space and 2 electrons are passed to cytochrome c. Cytochrome c1 is a catalytic core subunit containing a c-type heme. It transfers electrons from the [2Fe-2S] iron-sulfur cluster of the Rieske protein to cytochrome c.
Catalyzes alpha(1->3) linkage of fucosyl moiety transferred from GDP-beta-L-fucose to N-acetyl glucosamine (GlcNAc) within type 2 lactosamine (LacNAc, Gal-beta(1->4)GlcNAc) glycan attached to N- or O-linked glycoproteins (PubMed:29593094, PubMed:1702034, PubMed:1716630). Robustly fucosylates nonsialylated distal LacNAc unit of the polylactosamine chain to form Lewis X antigen (CD15), a glycan determinant known to mediate important cellular functions in development and immunity. Fucosylates with lower efficiency sialylated LacNAc acceptors to form sialyl Lewis X and 6-sulfo sialyl Lewis X determinants that serve as recognition epitopes for C-type lectins (PubMed:29593094, PubMed:1716630). Together with FUT7 contributes to SELE, SELL and SELP selectin ligand biosynthesis and selectin-dependent lymphocyte homing, leukocyte migration and blood leukocyte homeostasis (By similarity). In a cell type specific manner, may also fucosylate the internal LacNAc unit of the polylactosamine chain to form VIM-2 antigen that serves as recognition epitope for SELE (PubMed:1716630, PubMed:11278338).
Expressed at low levels in bone marrow-derived mesenchymal stem cells.
Expressed in cord blood immature promyelocytes and in peripheral blood myeloid and lymphoid cell populations.
Transmembrane reductase that may use ascorbate as an electron donor in the cytoplasm and transfer electrons across endoplasmic reticulum membranes to reduce monodehydro-L-ascorbate radical and iron cations Fe(3+) in the lumen of that compartment.
Highly expressed in brain, kidney, pancreas, and liver, and at lower levels in lung and placenta.
Probably plays an important role in neuronal membrane skeleton.
Could be proteolytically cleaved to release a smaller active fragment.
Could function as an adhesive molecule and its matrix bound and soluble fragments may play a critical role in vascular biology.
Detected in endothelial cells. Highly expressed in platelets. Stored in platelet alpha granules, and transferred to the cell surface upon activation and aggregation. A smaller form, probably produced by limited proteolysis, after being released from the storage granules, is associated with thrombus and localized with the subendothelial matrices in atherosclerotic plaques.
Down-regulated by inflammatory cytokines.
Forms homooligomers. Forms heterooligomers with SCUBE2. Forms heterooligomers with SCUBE3 (PubMed:33308444).
Expressed in testis (PubMed:22965910). Expressed in the breast (PubMed:8890751).
Interacts with ANKRD26 (PubMed:22666460). Interacts with DYNLL1 (PubMed:22965910). Interacts with FAM83D/CHICA (PubMed:22965910).
Receptor for hyaluronic acid (HA) (By similarity). Involved in cell motility (By similarity). When hyaluronan binds to HMMR, the phosphorylation of a number of proteins, including PTK2/FAK1 occurs. May also be involved in cellular transformation and metastasis formation, and in regulating extracellular-regulated kinase (ERK) activity. May act as a regulator of adipogenisis (By similarity).
MARCKS is the most prominent cellular substrate for protein kinase C. This protein binds calmodulin, actin, and synapsin. MARCKS is a filamentous (F) actin cross-linking protein.
Phosphorylation by PKC displaces MARCKS from the membrane. It also inhibits the F-actin cross-linking activity.
Component of the Sin3/HDAC1 corepressor complex at least composed of BRMS1, BRMS1L and ING2/ING1L. Interacts with HDAC and SIN3A.
Involved in the histone deacetylase (HDAC1)-dependent transcriptional repression activity. When overexpressed in lung cancer cell line that lacks p53/TP53 expression, inhibits cell growth.
Detected in heart, brain, lung, liver, kidney, pancreas and testis.
Inhibited by bis-peroxovanadates and hydrogen peroxide.
Interacts with TMEM39A (PubMed:31806350). Interacts with SEC23A and SEC24A; this interaction is reduced in the absence of TMEM39A (PubMed:31806350). Interacts with PLEKHA3 and VAPA and/or VAPB to form a ternary complex (PubMed:30659099).
Phosphoinositide phosphatase which catalyzes the hydrolysis of phosphatidylinositol 4-phosphate (PtdIns(4)P) (PubMed:24209621, PubMed:27044890, PubMed:29461204, PubMed:30659099). Can also catalyze the hydrolysis of phosphatidylinositol 3-phosphate (PtdIns(3)P) and has low activity towards phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2) (By similarity). Shows a very robust PtdIns(4)P phosphatase activity when it binds PtdIns(4)P in a 'cis' configuration in the cellular environment, with much less activity seen when it binds PtdIns(4)P in 'trans' configuration (PubMed:29461204, PubMed:24209621, PubMed:30659099). PtdIns(4)P phosphatase activity (when it binds PtdIns(4)P in 'trans' configuration) is enhanced in the presence of PLEKHA3 (PubMed:30659099).
Acts as an activator of serum response factor (SRF)-dependent transcription possibly by inducing nuclear translocation of MKL1 or MKL2 and through a mechanism requiring Rho-actin signaling.
Binds F-actin and ABLIM1, ABLIM2 and ABLIM3. Interaction with ABLIM2 and ABLIM3 enhances activity (By similarity).
The actin-binding domain 1 (ABD1) is intrinsically disordered, and binds to F-actin with higher affinity than ABD2.
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). Interacts with CPEB1 and EIF4E (By similarity).
Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. Its dissociation from the complex determines the transition from state pre-A1 to state pre-A1* (PubMed:34516797). Inhibits mRNA translation in a cytoplasmic polyadenylation element (CPE)-dependent manner (By similarity).
Activated by phosphorylation at Ser-189.
Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK3/MAPK6 is phosphorylated at Ser-189 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6. May promote entry in the cell cycle (By similarity).
Heterodimer with ERK4/MAPK4. Interacts with (via FRIEDE motif) MAPKAPK5 (By similarity). Interacts with UBE3A; this interaction may be indirect and mediated by HERC2, possibly via HERC2 interaction with NEURL4.
Highest expression in the skeletal muscle, followed by the brain. Also found in heart, placenta, lung, liver, pancreas, kidney and skin fibroblasts.
In contrast to classical MAPKs, the TXY motif within the activation loop is replaced by the SEG motif, whose phosphorylation activates the MAP kinases.
Phosphorylated at Ser-189 by PAK1, PAK2 and PAK3 resulting in catalytic activation. Phosphorylated by MAPKAPK5 at other sites.
Ubiquitination at Met-1 leads to degradation by the proteasome pathway.
Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6 (PubMed:11714725, PubMed:11818576, PubMed:22854966, PubMed:25960406). Interacts with STAT3 and JAKs (By similarity).
Folds into a two seven-bladed beta-propeller structure which is required for elongator complex assembly.
Component of a complex that binds and activates STK11/LKB1. In the complex, required to stabilize the interaction between CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta) and STK11/LKB1 (By similarity).
Found in serum of 50% of patients with acute monocytic leukemia.
Expressed in many adult tissues, with highest levels in kidney, pancreas and thalamus. Relatively high expression was also detected in fetal kidney and heart.
Involved in extracellular matrix organization (By similarity). Required for the regulation of epidermal-basement membrane adhesion responsible for proper organogenesis during embryonic development (By similarity). Involved in brain organization and function (By similarity).
Filament-forming cytoskeletal GTPase. May play a role in cytokinesis (Potential).
Proteolytically cleaved in vitro in a calmodulin-dependent manner.
Septins polymerize into heterooligomeric protein complexes that form filaments, and can associate with cellular membranes, actin filaments and microtubules. GTPase activity is required for filament formation (By similarity). Interacts with ADGB (By similarity).
Widely expressed. Abundantly expressed in heart and kidney, placenta, skeletal muscles, liver and lung, as well as various tumor cell lines.
Plays a role in the regulation of cell morphology and cytoskeletal organization. May be involved in transcriptional regulation.
Detected in thyroid, lymph node, trachea, adrenal gland, bone marrow, spleen, thymus, prostate, and peripheral blood leukocyte. Detected at lower levels in stomach, testis and spinal cord.
During the cell cycle, expression is increased during S phase and G2/M phase.
Acts as a marker of stem-like cells (CSC) in a number of malignancies (PubMed:24934811). Associated with clinical drug resistance, tumor progression and disease recurrence in malignant melanoma and acute leukemias. Responsible for the resistance to doxorubicin of a subset of malignant melanomas. ABCB5-expressing cells selectively survive when exposed to dacarbazine drug, the reference treatment of metastatic melanoma, vemurafenib and other various chemotherapeutic drugs, suggesting that anti-melanoma chemotherapy participates in the chemoresistance acquisition by selecting tumor cell subpopulations expressing ABCB5 (PubMed:22784549, PubMed:22044138, PubMed:22675422, PubMed:23770371, PubMed:24934811). Present in melanoma-initiating cells that acts as an enhancer of tumor growth by promoting CSC maintenance and tumor growth by controlling IL-1beta (IL1B) secretion to maintain slow-cycling, chemoresistant cells through an IL-1beta (IL1B)/IL8/CXCR1 cytokine signaling circuit (PubMed:24934811).
Energy-dependent efflux transporter responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:12960149, PubMed:22306008, PubMed:15899824, PubMed:15205344). Specifically present in limbal stem cells, where it plays a key role in corneal development and repair (By similarity).
Expressed by CD133-expressing progenitor cells among epidermal melanocytes (at protein level). Widely expressed with specific expression in pigment cells. Highly expressed in several malignant tissues: highly expressed in clinical melanomas, with low expression in normal skin. In melanoma, marks malignant melanoma-initiating cells (MMIC), in which clinical virulence resides as a consequence of unlimited self-renewal capacity, resulting in inexorable tumor progression and metastasis. Also highly expressed in a number of leukemia cells. Expressed in basal limbal epithelium.
Constitutively expressed in cytotoxic T-cells.
May play a role in physiologic lymphocyte functions at mucosal sites.
Cell surface pattern recognition receptor that senses endogenous stress signals with a broad ligand repertoire including advanced glycation end products, S100 proteins, high-mobility group box 1 protein/HMGB1, amyloid beta/APP oligomers, nucleic acids, phospholipids and glycosaminoglycans (PubMed:27572515, PubMed:28515150, PubMed:34743181). Advanced glycosylation end products are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes (PubMed:21565706). These ligands accumulate at inflammatory sites during the pathogenesis of various diseases, including diabetes, vascular complications, neurodegenerative disorders, and cancers and RAGE transduces their binding into pro-inflammatory responses. Upon ligand binding, uses TIRAP and MYD88 as adapters to transduce the signal ultimately leading to the induction or inflammatory cytokines IL6, IL8 and TNFalpha through activation of NF-kappa-B (PubMed:21829704). Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key pro-inflammatory mediators (PubMed:19386136). Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons (PubMed:19906677). ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space. Participates in endothelial albumin transcytosis together with HMGB1 through the RAGE/SRC/Caveolin-1 pathway, leading to endothelial hyperpermeability (PubMed:27572515). Mediates the loading of HMGB1 in extracellular vesicles (EVs) that shuttle HMGB1 to hepatocytes by transferrin-mediated endocytosis and subsequently promote hepatocyte pyroptosis by activating the NLRP3 inflammasome (PubMed:34743181). Promotes also extracellular hypomethylated DNA (CpG DNA) uptake by cells via the endosomal route to activate inflammatory responses (PubMed:24081950, PubMed:28515150).
Constitutive homodimer; disulfide-linked (PubMed:24081950). Forms homooligomers (PubMed:24081950). Interacts with S100A1 and APP (By similarity). Interacts with S100B, S100A12 and S100A14. Interacts with TIRAP (PubMed:21829704). Interacts with HMGB1 (PubMed:34743181).
Detected in lung, brain, heart and kidney.
Phosphorylated on its cytoplasmic domain by PKCzeta/PRKCZ upon ligand binding.
Belongs to the cyclic nucleotide-gated cation channel (TC 1.A.1.5) family. CNGA2 subfamily.
Heterotetramer composed of two subunits of CNGA2, one of CNGA4 and one of CNGB1b. The complex forms the cyclic nucleotide-gated (CNG) channel of olfactory sensory neurons (By similarity).
Odorant signal transduction is probably mediated by a G-protein coupled cascade using cAMP as second messenger. The olfactory channel can be shown to be activated by cyclic nucleotides which leads to a depolarization of olfactory sensory neurons.
The C-terminal coiled-coil domain mediates trimerization of CNGA subunits.
Cell surface receptor that plays a role in immune response and controls the production and differentiation of hematopoietic progenitor cells into lineage-restricted cells. Acts by forming an heterodimeric receptor through interaction with different partners such as IL3RA, IL5RA or CSF2RA (PubMed:1495999). In turn, participates in various signaling pathways including interleukin-3, interleukin-5 and granulocyte-macrophage colony-stimulating factor/CSF2 pathways. In unstimulated conditions, interacts constitutively with JAK1 and ligand binding leads to JAK1 stimulation and subsequent activation of the JAK-STAT pathway (PubMed:9516124).
Heterodimer of an alpha and a beta subunit. The beta subunit is common to the IL3, IL5 and GM-CSF receptors (PubMed:1495999). The signaling GM-CSF receptor complex is a dodecamer of two head-to-head hexamers of two alpha, two beta, and two ligand subunits. Interacts with TMEM102; this interaction occurs preferentially in the absence of CSF2. Interacts with FCER1G; this interaction is direct. Interacts with LYN. Interacts with JAK1 (PubMed:9516124).
Expression is restricted to the gastrointestinal tract (PubMed:16319059). Highly expressed in goblet cells (PubMed:35303419). Also expressed in various tumor cells (PubMed:16319059).
Inflammatory bowel disease (PubMed:35303419). A chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology (PubMed:35303419). It is subdivided into Crohn disease and ulcerative colitis phenotypes (PubMed:35303419). Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon (PubMed:35303419). Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas (PubMed:35303419). In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed (PubMed:35303419). Both diseases include extraintestinal inflammation of the skin, eyes, or joints (PubMed:35303419). Disease susceptibility is associated with variants affecting the gene represented in this entry (PubMed:35303419).
Protein sialyltransferase specifically expressed in goblet cells that plays a key role in intestinal host-commensal homeostasis (PubMed:35303419). Conjugates sialic acid with an alpha-2-6 linkage to N-acetylgalactosamine (GalNAc) glycan chains linked to serine or threonine in glycoproteins (PubMed:16319059, PubMed:35303419). Catalyzes the formation of the sialyl-Tn (S-Tn) antigen, an antigen found in intestinal goblet cells, as well as ulcerative colitis (UC) and various cancers (PubMed:16319059, PubMed:35303419). Protein sialylation in globlet cells is essential for mucus integrity and is required to protect the intestinal mucus against excessive bacterial proteolytic degradation (PubMed:35303419).
Calcium/phospholipid-binding protein which promotes membrane fusion and is involved in exocytosis.
Isoform 1 is expressed in brain, heart and skeletal muscle. Isoform 2 is more abundant in liver, lung, kidney, spleen, fibroblasts and placenta.
G-protein coupled receptor for neuropeptide S (NPS) (PubMed:16790440). Promotes mobilization of intracellular Ca(2+) stores (PubMed:16790440). Inhibits cell growth in response to NPS binding (PubMed:15947423). Involved in pathogenesis of asthma and other IgE-mediated diseases.
Isoform 4 is ubiquitous; it is detected in glandular epithelia of bronchus, stomach, small intestine, colon, uterus, esophagus, spleen, kidney, pancreas, prostate and breast. Isoform 1 is detected in uterus, colon and prostate, and in the smooth muscle cell layer in bronchial and arterial walls (at protein level) (PubMed:15947423). Isoform 1 is predominantly expressed in smooth muscle. Isoform 4 is predominantly expressed in epithelial cells. In bronchial biopsies, it is expressed in smooth muscle cells of asthma patients, but not in control patients; whereas in epithelial cells, its expression is consistently stronger in asthma patients.
Only isoforms with 7 transmembrane topology (isoform 1, isoform 3 and isoform 4) are transported into the plasma membrane in transfected cells, while the truncated ones retain intracellular compartments.
ADP-binding promotes an inactive closed conformation.
Acts as a pattern recognition receptor (PRR); able to activate NF-kappa-B.
Can activate NF-kappa-B in a muramyl dipeptide (MDP)-independent manner.
Degraded via selective autophagy following interaction with IRGM (PubMed:35066577, PubMed:36221902). IRGM promotes NOD2-RIPK2 RIPosome recruitment to autophagosome membranes, promoting their SQSTM1/p62-dependent autophagic degradation (PubMed:36221902).
Expressed at higher level in leukocytes.
Expressed in monocytes, macrophages, dendritic cells, hepatocytes, preadipocytes, epithelial cells of oral cavity, lung and intestine, with higher expression in ileal Paneth cells and in intestinal stem cells.
Homooligomer: homooligomerizes following muramyl dipeptide (MDP)-binding, promoting RIPK2 recruitment (PubMed:11087742, PubMed:22700971). Interacts (via CARD domain) with RIPK2 (via CARD domain) (PubMed:11087742, PubMed:15044951, PubMed:17355968, PubMed:19592251, PubMed:27812135, PubMed:30279485, PubMed:30478312). Following RIPK2 recruitment, RIPK2 homooligomerizes via its CARD domain and forms long filaments named RIPosomes (PubMed:30279485, PubMed:30478312). Interacts (via CARD domain) with ubiquitin; inhibiting interaction with RIPK2 (PubMed:23300079). Component of a signaling complex consisting of ARHGEF2, NOD2 and RIPK2 (PubMed:21887730). Interacts with ANKRD17 (via N-terminus) (PubMed:23711367). Interacts with HSPA1A; the interaction enhances NOD2 stability (PubMed:24790089). Interacts (via both CARD domains) with HSP90; the interaction enhances NOD2 stability (PubMed:23019338). Interacts (via CARD domain) with SOCS3; the interaction promotes NOD2 degradation (PubMed:23019338). Interacts (via CARD domain) with ERBIN; the interaction inhibits activation of NOD2 (PubMed:16203728). Interacts with MAPKBP1; the interaction is enhanced in the presence of muramyl dipeptide (MDP) and inhibits NOD2 homooligomerization and activation (PubMed:22700971). Interacts with INAVA; the interaction takes place upon Pattern recognition receptor (PRR) stimulation (PubMed:28436939). Interacts (via NACHT domain) with CARD9 (PubMed:24960071). Interacts (via CARD domain) with CASP1; this interaction leads to IL1B processing (PubMed:18511561). Also interacts with CASP4 (PubMed:18511561). Interacts with NLRP1; this interaction is enhanced in the presence of muramyl dipeptide (MDP) and leads to increased IL1B release (PubMed:18511561). Interacts with NLRP12; this interaction promotes degradation of NOD2 through the ubiquitin-proteasome pathway (PubMed:30559449). Interacts with ANKHD1, C10orf67, CHMP5, DOCK7, ENTR1, KRT15, LDOC1, PPP1R12C, PPP2R3B, TRIM41 and VIM (PubMed:27812135). Interacts with MAVS; interaction takes place following single-stranded RNA (ssRNA)-binding (PubMed:19701189). Interacts with ATG16L1 (PubMed:20637199, PubMed:23376921). Interacts with IRGM; promoting IRGM 'Lys-63'-linked polyubiquitination, which is required for interactions with the core autophagy factors (PubMed:25891078, PubMed:36221902).
Intramolecular interactions between the N-terminal moiety and the leucine-rich repeats (LRR) may be important for autoinhibition in the absence of activating signal.
O-glycosylated by OGT, O-GlcNAcylation increases protein stability.
Palmitoylated by ZDHHC5; palmitoylation is required for proper recruitment to the bacterial entry site and hence for proper signaling upon cognate peptidoglycan detection (PubMed:31649195, PubMed:34293401, PubMed:35066577). Palmitoylation promotes localization to the cell membrane (PubMed:34293401). Palmitoylation protects from SQSTM1/p62-dependent autophagic degradation (PubMed:35066577).
Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and plays an important role in gastrointestinal immunity (PubMed:12514169, PubMed:12527755, PubMed:12626759, PubMed:15044951, PubMed:15998797, PubMed:27283905, PubMed:27748583, PubMed:31649195). Specifically activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan found in every bacterial peptidoglycan type (PubMed:12514169, PubMed:12871942, PubMed:12527755, PubMed:12626759, PubMed:15044951, PubMed:15998797, PubMed:22857257, PubMed:23322906, PubMed:27748583, PubMed:36002575, PubMed:15198989). NOD2 specifically recognizes and binds 6-O-phospho-MDP, the phosphorylated form of MDP, which is generated by NAGK (PubMed:36002575). 6-O-phospho-MDP-binding triggers oligomerization that facilitates the binding and subsequent activation of the proximal adapter receptor-interacting RIPK2 (PubMed:11087742, PubMed:17355968, PubMed:21887730, PubMed:23806334, PubMed:28436939). Following recruitment, RIPK2 undergoes 'Met-1'- (linear) and 'Lys-63'-linked polyubiquitination by E3 ubiquitin-protein ligases XIAP, BIRC2, BIRC3 and the LUBAC complex, becoming a scaffolding protein for downstream effectors, triggering activation of the NF-kappa-B and MAP kinases signaling (PubMed:11087742, PubMed:12514169, PubMed:12626759, PubMed:21887730, PubMed:23806334, PubMed:23322906, PubMed:28436939, PubMed:15198989). This in turn leads to the transcriptional activation of hundreds of genes involved in immune response (PubMed:15198989). Its ability to detect bacterial MDP plays a central role in maintaining the equilibrium between intestinal microbiota and host immune responses to control inflammation (By similarity). An imbalance in this relationship results in dysbiosis, whereby pathogenic bacteria prevail on commensals, causing damage in the intestinal epithelial barrier as well as allowing bacterial invasion and inflammation (By similarity). Acts as a regulator of appetite by sensing MDP in a subset of brain neurons: microbiota-derived MDP reach the brain, where they bind and activate NOD2 in inhibitory hypothalamic neurons, decreasing neuronal activity, thereby regulating satiety and body temperature (By similarity). NOD2-dependent MDP-sensing of bacterial cell walls in the intestinal epithelial compartment contributes to sustained postnatal growth upon undernutrition (By similarity). Also plays a role in antiviral response by acting as a sensor of single-stranded RNA (ssRNA) from viruses: upon ssRNA-binding, interacts with MAVS, leading to activation of interferon regulatory factor-3/IRF3 and expression of type I interferon (PubMed:19701189). Also acts as a regulator of autophagy in dendritic cells via its interaction with ATG16L1, possibly by recruiting ATG16L1 at the site of bacterial entry (PubMed:20637199). NOD2 activation in the small intestine crypt also contributes to intestinal stem cells survival and function: acts by promoting mitophagy via its association with ATG16L1 (By similarity). In addition to its main role in innate immunity, also regulates the adaptive immune system by acting as regulator of helper T-cell and regulatory T-cells (Tregs) (By similarity). Besides recognizing pathogens, also involved in the endoplasmic reticulum stress response: acts by sensing and binding to the cytosolic metabolite sphingosine-1-phosphate generated in response to endoplasmic reticulum stress, initiating an inflammation process that leads to activation of the NF-kappa-B and MAP kinases signaling (PubMed:27007849, PubMed:33942347). May also be involved in NLRP1 activation following activation by MDP, leading to CASP1 activation and IL1B release in macrophages (PubMed:18511561).
Polyubiquitinated by TRIM27, leading to proteasome-mediated degradation (PubMed:22829933). Polyubiquitinated and degraded following muramyl dipeptide (MDP) stimulation, conferring MDP tolerance and preventing septic shock (PubMed:23019338).
The LRR repeats recognize and bind muramyl dipeptide (MDP).
The NACHT domain recognizes and binds sphingosine-1-phosphate in response to endoplasmic reticulum stress.
Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21 (PubMed:16603771). Identified in the spliceosome C complex (PubMed:11991638). Component of the U11/U12 snRNPs that are part of the U12-type spliceosome (PubMed:15146077). Component of splicing factor SF3B complex which is composed of at least eight subunits; SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6, PHF5A and DDX42 (PubMed:12234937, PubMed:12738865, PubMed:28541300, PubMed:27720643). SF3B associates with the splicing factor SF3A and a 12S RNA unit to form the U2 small nuclear ribonucleoproteins complex (U2 snRNP). Interacts directly with the splicing factor U2AF (PubMed:12234937). Within the SF3B complex interacts directly (via HEAT domain) with SF3B3, SF3B5 and (via HEAT domain) with PHF5A (PubMed:27720643). Interacts directly with SF3B6 (PubMed:16432215, Ref.38, PubMed:21062891). The SF3B complex composed of SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6 and PHF5A interacts with U2AF2 (PubMed:27720643). Phosphorylated form interacts with PPP1R8 (PubMed:12105215). Interacts with PQBP1 (PubMed:23512658). Interacts with RBM17 (PubMed:17589525). Interacts with RBM39 (PubMed:24795046). Interacts with SETX (PubMed:21700224). Interacts with RBM15 (PubMed:26575292). Interacts with USH1G (PubMed:34023904). Interacts with SDE2 (PubMed:34365507). Interacts with U2AF1 (PubMed:34365507). Interacts with CACTIN (PubMed:34365507). Component of the minor spliceosome (PubMed:15146077, PubMed:33509932). Within this complex, interacts with SCNM1 and CRIPT (PubMed:33509932).
Involved in pre-mRNA splicing as a component of the splicing factor SF3B complex (PubMed:27720643). SF3B complex is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA (PubMed:12234937). Together with other U2 snRNP complex components may also play a role in the selective processing of microRNAs (miRNAs) from the long primary miRNA transcript, pri-miR-17-92 (By similarity). May also be involved in the assembly of the 'E' complex (PubMed:10882114). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (PubMed:15146077) (Probable).
Phosphorylated. Phosphorylation occurs concomitantly with the splicing catalytic steps. Phosphorylation on Thr-244, Thr-248 and Thr-313 by cyclin-dependent kinases promotes interaction with PPP1R8 during mitosis.
AOX genes evolved from a xanthine oxidoreductase ancestral precursor via a series of gene duplication and suppression/deletion events. Different animal species contain a different complement of AOX genes encoding an equivalent number of AOX isoenzymes. In mammals, the two extremes are represented by certain rodents such as mice and rats, which are endowed with 4 AOX genes, and by humans, whose genome is characterized by a single active gene (PubMed:22335465).
Abundant in liver, expressed in adipose tissue and at lower levels in lung, skeletal muscle, pancreas. In contrast to mice, no significant gender difference in AOX1 expression level (at protein level).
Belongs to the xanthine dehydrogenase family.
In liver, is down-regulated by adiponectin and by the PPARA agonist, fenofibric acid.
Is very potently inhibited by raloxifene (PubMed:26842593). Also inhibited by estradiol, ethinyl estradiol, hydralazine, menadione, isovanillin and thioridazine. Not inhibited by allopurinol, a xanthine dehydrogenase potent inhibitor (PubMed:22031625, PubMed:22522748, PubMed:22996261, PubMed:9224775, PubMed:26322824).
Not detected in preadipocytes but strongly induced in mature adipocytes.
Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide, N-methylphthalazinium and phthalazine, as well as aldehydes, such as benzaldehyde, retinal, pyridoxal, and vanillin. Plays a key role in the metabolism of xenobiotics and drugs containing aromatic azaheterocyclic substituents. Participates in the bioactivation of prodrugs such as famciclovir, catalyzing the oxidation step from 6-deoxypenciclovir to penciclovir, which is a potent antiviral agent. Is probably involved in the regulation of reactive oxygen species homeostasis. May be a prominent source of superoxide generation via the one-electron reduction of molecular oxygen. May also catalyze nitric oxide (NO) production via the reduction of nitrite to NO with NADH or aldehyde as electron donor. May play a role in adipogenesis.
Was originally thought to be a xanthine dehydrogenase.
Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST and PHF21A/BHC80. The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I. In the complex, it interacts directly with HDAC1, HDAC2, HMG20B/BRAF35, KDM1A and RCOR1/CoREST.
Component of the BHC complex, a corepressor complex that represses transcription of neuron-specific genes in non-neuronal cells. The BHC complex is recruited at RE1/NRSE sites by REST and acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier. In the BHC complex, it may act as a scaffold. Inhibits KDM1A-mediated demethylation of 'Lys-4' of histone H3 in vitro, suggesting a role in demethylation regulation.
Highly expressed in brain (PubMed:31649809). Expressed at lower level in other tissues, including heart, kidney, liver, lung and skeletal muscle (PubMed:31649809). Abundantly expressed in fetal brain (PubMed:31649809).
Originally identified as neuronal protein that specifically associates with HTT/huntingtin and the binding is enhanced by an expanded polyglutamine repeat within HTT possibly affecting HAP1 interaction properties. Both HTT and HAP1 are involved in intracellular trafficking and HAP1 is proposed to link HTT to motor proteins and/or transport cargos. Seems to play a role in vesicular transport within neurons and axons such as from early endosomes to late endocytic compartments and to promote neurite outgrowth. The vesicular transport function via association with microtubule-dependent transporters can be attenuated by association with mutant HTT. Involved in the axonal transport of BDNF and its activity-dependent secretion; the function seems to involve HTT, DCTN1 and a complex with SORT1. Involved in APP trafficking and seems to facilitate APP anterograde transport and membrane insertion thereby possibly reducing processing into amyloid beta. Involved in delivery of gamma-aminobutyric acid (GABA(A)) receptors to synapses; the function is dependent on kinesin motor protein KIF5 and is disrupted by HTT with expanded polyglutamine repeat. Involved in regulation of autophagosome motility by promoting efficient retrograde axonal transport. Seems to be involved in regulation of membrane receptor recycling and degradation, and respective signal transduction, including GABA(A) receptors, tyrosine kinase receptors, EGFR, IP3 receptor and androgen receptor. Among others suggested to be involved in control of feeding behavior (involving hypothalamic GABA(A) receptors), cerebellar and brainstem development (involving AHI1 and NTRK1/TrkA), postnatal neurogenesis (involving hypothalamic NTRK2/TrkB), and ITPR1/InsP3R1-mediated Ca(2+) release (involving HTT and possibly the effect of mutant HTT). Via association with DCTN1/dynactin p150-glued and HTT/huntingtin involved in cytoplasmic retention of REST in neurons. May be involved in ciliogenesis. Involved in regulation of exocytosis. Seems to be involved in formation of cytoplasmic inclusion bodies (STBs). In case of anomalous expression of TBP, can sequester a subset of TBP into STBs; sequestration is enhanced by an expanded polyglutamine repeat within TBP. HAP1-containing STBs have been proposed to play a protective role against neurodegeneration in Huntigton disease (HD) and spinocerebellar ataxia 17 (SCA17).
Predominantly expressed in brain. Selectively expressed in neurons.
Self-associates. Interacts with HTT/huntingtin; enhanced by an expanded polyglutamine repeat within HTT. Interacts with DCTN1; decreased in presence of HTT with expanded polyglutamine repeat. Interacts with KLC2. Interacts with ITPR1 and APP. Interacts with AR; decreased by an expanded polyglutamine repeat within AR. Interacts with YWHAZ. Interacts with BDNF and SORT1; probably forming a complex involved in proBDNF trafficking, degradation and processing. Interacts with TBP, AHI1, HGS and KALRN. Interacts with KIF5A, KIF5B, KIF5C and GABRB3; indicative for an HAP1:KIF5 complex transporting a GABA(A) receptor as cargo. Interacts with ATXN3; in STBs with ATXN3 poly-Gln region with 27 repeats (normal population) and 79 repeats (spinocerebellar ataxia 3 (SCA3) patients) associating in the same strength. Interacts with NTRK2; HAP1 stabilizes association of NTRK2 with SORT1 preventing NTRK2 degradation. Interacts with CCDC113.
Was not found in huntingtin-containing aggregates in huntigton disease (HD) tissue.
Catalyzes the peptide bond hydrolysis in dipeptides having basic amino acids lysine, ornithine or arginine at C-terminus. Postulated to function in a metabolite repair mechanism by eliminating alternate dipeptide by-products formed during carnosine synthesis.
Belongs to the bacterial ribosomal protein bS18 family. Mitochondrion-specific ribosomal protein mL66 subfamily.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379, PubMed:25278503). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. mL66 forms a zinc-binding site with uL10m.
There are 3 mitochondrial isoforms of bS18 in mammalia, localizing to 3 distinct sites in the mitoribosome. bS18m (bs18c) binds to the same site as bacterial bS18, mS40 (bS18b) binds to a novel location of the 28S small subunit, and mL66 (bS18a, this protein) binds to the 39S large subunit.
Exclusively expressed in skeletal and heart muscle.
Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains. Phosphorylates the SR splicing factor SRSF1 and the lamin-B receptor (LBR) in vitro. Required for normal muscle development (By similarity).
Binds DNA as a monomer or a homodimer. Interacts (via the AF2 domain) with coactivator PPARGC1A (via the L3 motif); the interaction greatly enhances transcriptional activity of genes involved in energy metabolism. Interacts with PIAS4; the interaction enhances sumoylation. Interacts with MAPK15; promotes re-localization of ESRRA to the cytoplasm through a XPO1-dependent mechanism then inhibits ESRRA transcriptional activity.
Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Induces the expression of PERM1 in the skeletal muscle.
Induced by PGC1alpha in a number of specific cell types including heart, kidney and muscle.
Phosphorylation on Ser-19 enhances sumoylation on Lys-14 increasing repression of transcriptional activity.
Reversibly acetylated. Acetylation by PCAF/KAT2 at Lys-129, Lys-138, Lys-160 and Lys-162 and PCAF/KAT2 decreases transcriptional activity probably by inhibiting DNA-binding activity; deacetylation involves SIRT1 and HDAC8 and increases DNA-binding.
Sumoylated with SUMO2. Main site is Lys-14 which is enhanced by phosphorylation on Ser-19, cofactor activation, and by interaction with PIAS4. Sumoylation enhances repression of transcriptional activity, but has no effect on subcellular location nor on DNA binding.
During adipocyte differentiation, levels are elevated two-fold (at protein level).
Plays a role in regulating ADIPOQ and FABP4 levels in differentiating adipocytes and is also involved in regulation of adipocyte triglyceride storage (PubMed:23028956). Weakly binds 25-hydroxycholesterol (PubMed:17428193).
Present at highest levels in ovary, testis, kidney, liver, stomach, brain, and adipose tissue. Strong expression (at protein level) in epithelial cells of kidney tubules, testicular tubules, caecum, and skin (PubMed:20599956). Present at low levels in subcutaneous and visceral adipose tissue (at protein level)(PubMed:23028956).
Covalently binds all-trans- and 11-cis-retinal.
Preferentially expressed at high levels in the retinal pigment epithelium (RPE) and Mueller cells of the neural retina.
Receptor for all-trans- and 11-cis-retinal. Binds preferentially to the former and may catalyze the isomerization of the chromophore by a retinochrome-like mechanism.
Interacts with repression-mediating E2 binding site P2 of human papillomavirus type 8 (HPV8).
Plays a role in papillomavirus genes transcription.
Expressed in most tissues tested. Highly expressed in skeletal muscle.
Involved in both the production of very long-chain fatty acids for sphingolipid synthesis and the degradation of the sphingosine moiety in sphingolipids through the sphingosine 1-phosphate metabolic pathway (PubMed:25049234). Catalyzes the last of the four reactions of the long-chain fatty acids elongation cycle (PubMed:12482854). This endoplasmic reticulum-bound enzymatic process, allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle (PubMed:12482854). This enzyme reduces the trans-2,3-enoyl-CoA fatty acid intermediate to an acyl-CoA that can be further elongated by entering a new cycle of elongation (PubMed:12482854). Thereby, it participates in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators (PubMed:12482854). Catalyzes the saturation step of the sphingosine 1-phosphate metabolic pathway, the conversion of trans-2-hexadecenoyl-CoA to palmitoyl-CoA (PubMed:25049234).
Binds specifically to GTP-Rho. May function in a Rho pathway to limit stress fiber formation and/or increase the turnover of F-actin structures in the absence of high levels of RhoA activity.
By thyrotropin (TSH). Regulated by the cAMP pathway.
Interacts with GTP-bound RhoA and RhoB. Interacts with both GTP- and GDP-bound RhoA. According to PubMed:12473120, it does not interact with RhoA. Interacts with KRT18.
Widely expressed. Highly expressed in prostate, trachea, stomach, colon, thyroid and pancreas. Expressed at lower level in brain, spinal cord, kidney, placenta and liver.
DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK3 is a negative regulator of JNK signaling in B-cells through interaction with INPP5D/SHIP1. May modulate ABL1 function (By similarity).
On IL2 stimulation, phosphorylated on C-terminal tyrosine residues possibly by Src kinases. Can also be phosphorylated by ABL1 kinase (By similarity).
On tyrosine phosphorylation, interacts with CSK and INPP5D/SHIP1 via their SH2 domains. Both Tyr-381 and Tyr-398 are required for interaction with INPP5D. Only Tyr-381 is required for interaction with CSK. Binds ABL1 through the PTB domain and in a kinase-dependent manner. Does not interact with RasGAP (By similarity).
Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1.
Interacts through its N-terminal region with the ankyrin repeat region of the Notch proteins NOTCH1, NOTCH2, NOTCH3 and NOTCH4. Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa.
The C-terminal domain is required for transcriptional activation.
Interacts with VANGL2 via its C-terminus (By similarity). The VANGL2-dependent membrane recruitment of PRICKLE3 is a prerequisite for its polarization (By similarity). Interacts with WTIP. WTIP is involved in the recruitment of PRICKLE3 to the basal body (By similarity). Interacts with MT-ATP8, a component of the mitochondrial complex V (PubMed:32516135).
Involved in the planar cell polarity (PCP) pathway that is essential for the polarization of epithelial cells during morphogenetic processes, including gastrulation and neurulation (By similarity). PCP is maintained by two molecular modules, the global and the core modules, PRICKLE3 being part of the core module (By similarity). Distinct complexes of the core module segregate to opposite sides of the cell, where they interact with the opposite complex in the neighboring cell at or near the adherents junctions (By similarity). Involved in the organization of the basal body (By similarity). Involved in cilia growth and positioning (By similarity). Required for proper assembly, stability, and function of mitochondrial membrane ATP synthase (mitochondrial complex V) (PubMed:32516135).
Acts both as a GTPase-activating protein (GAP) and a guanine nucleotide exchange factor (GEF), and participates in various processes such as endocytosis, insulin receptor internalization or LC2A4/GLUT4 trafficking. Acts as a GEF for the Ras-related protein RAB31 by exchanging bound GDP for free GTP, leading to regulate LC2A4/GLUT4 trafficking. In the absence of insulin, it maintains RAB31 in an active state and promotes a futile cycle between LC2A4/GLUT4 storage vesicles and early endosomes, retaining LC2A4/GLUT4 inside the cells. Upon insulin stimulation, it is translocated to the plasma membrane, releasing LC2A4/GLUT4 from intracellular storage vesicles. Also involved in EGFR trafficking and degradation, possibly by promoting EGFR ubiquitination and subsequent degradation by the proteasome. Has GEF activity for Rab5 and GAP activity for Ras.
Interacts with TRIP10/CIP4 (By similarity). Interacts with RAB5A.
Belongs to the dynactin subunits 5/6 family. Dynactin subunit 6 subfamily.
Phosphorylation at Thr-186 by CDK1 during mitotic prometaphase creates a binding site for PLK1 that facilitates its recruitment to kinetochores.
Subunit of dynactin, a multiprotein complex part of a tripartite complex with dynein and a adapter, such as BICDL1, BICD2 or HOOK3. The dynactin complex is built around ACTR1A/ACTB filament and consists of an actin-related filament composed of a shoulder domain, a pointed end and a barbed end (PubMed:23455152). Its length is defined by its flexible shoulder domain. The soulder is composed of 2 DCTN1 subunits, 4 DCTN2 and 2 DCTN3. The 4 DCNT2 (via N-terminus) bind the ACTR1A filament and act as molecular rulers to determine the length. The pointed end is important for binding dynein-dynactin cargo adapters. Consists of 4 subunits: ACTR10, DCNT4, DCTN5 and DCTN6. Within the complex DCTN6 forms a heterodimer with DCTN5 (PubMed:23455152). The barbed end is composed of a CAPZA1:CAPZB heterodimers, which binds ACTR1A/ACTB filament and dynactin and stabilizes dynactin (By similarity). Interacts with PLK1 (PubMed:23455152).
Homooligomer (By similarity). Interacts with RAN-GTP (By similarity). Interacts with EMD (PubMed:32923640).
Phosphorylation may regulate its interaction with RAN-GTP.
The transmembrane domains are required and sufficient for its oligomerization.
Together with EMD, contributes to nuclear envelope stiffness in germ cells (PubMed:32923640). Required for female fertility (By similarity).
Strong expression in heart and skeletal muscle. No expression in liver and kidney.
This protein is produced by a bicistronic gene which also produces the CHKB protein from a non-overlapping reading frame.
The L-type calcium channel is composed of five subunits: alpha-1, alpha-2/delta, beta and gamma.
Thought to stabilize the calcium channel in an inactivated (closed) state. Modulates calcium current when coexpressed with CACNA1G (By similarity).
Homodimer or homooligomer. Homodimerization and homooligomerization do not depend on Ca(2+). Interacts with SYNCRIP isoform 2 C-terminus. Binds inositol 1,3,4,5-tetrakisphosphate (IP4). Binds to AP2 in a Ca(2+)-independent manner. Interacts with STX1A, STX1B and STX2; the interaction is Ca(2+)-dependent.
Involved in the trafficking and exocytosis of secretory vesicles in non-neuronal tissues. Mediates Ca(2+)-regulation of exocytosis acrosomal reaction in sperm. May mediate Ca(2+)-regulation of exocytosis in insulin secreted cells.
The first C2 domain/C2A does not mediate Ca(2+)-dependent phospholipid binding.
The second C2 domain/C2B is responsible for SYNCRIP and inositol 1,3,4,5-tetrakisphosphate (IP4)-binding.
The sequence differs from that shown because it is a pre-mRNA.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(0) seems to have nine subunits: a, b, c, d, e, f, g, F6 and 8 (or A6L). Component of an ATP synthase complex composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5H, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and ATP5MJ (By similarity).
Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates and be involved in a variety of cellular processes (Probable). Palmitoyltransferase that mediates palmitoylation of KCNMA1, regulating localization of KCNMA1 to the plasma membrane. May be involved in NOS1 regulation and targeting to the synaptic membrane.
Highly expressed in lung, and brain and also in primary chondrocytes.
Inhibitor of bone morphogenetic protein (BMP) function, it may regulate BMP responsiveness of osteoblasts and chondrocytes.
ATPase activity is strongly stimulated by single-stranded DNA (PubMed:11751861). Presence of ATP and Mg cofactor are required for helicase activity allowing to unwind duplex oligonucleotides up to 60-70-mer (PubMed:11751861). This helicase activity is stimulated by replication protein A (RPA/RP-A) complex that binds to unwound regions and inhibits re-annealing (PubMed:11751861).
Homodimer (PubMed:34316696). Interacts with POLN (PubMed:19995904). Interacts with RAD51B and RAD51C; promoting association with the BCDX2 complex (PubMed:24005041). Interacts with the replication protein A (RPA/RP-A) complex (PubMed:34316696, PubMed:34937945). Interacts with RAD51; stimulating HELQ DNA helicase activity and ability to unwing DNA (PubMed:34937945).
Single-stranded 3'-5' DNA helicase that plays a key role in homology-driven double-strand break (DSB) repair (PubMed:11751861, PubMed:19995904, PubMed:21398521, PubMed:24005041, PubMed:24005565, PubMed:34316696, PubMed:34937945). Involved in different DSB repair mechanisms that are guided by annealing of extensive stretches of complementary bases at break ends, such as microhomology-mediated end-joining (MMEJ), single-strand annealing (SSA) or synthesis-dependent strand annealing (SDSA) (PubMed:34937945). Possesses both DNA unwinding and annealing activities (PubMed:34937945). Forms a complex with RAD51, stimulating HELQ DNA helicase activity and ability to unwing DNA (PubMed:34937945). Efficiently unwinds substrates containing 3' overhangs or a D-loop (PubMed:21398521, PubMed:34937945). In contrast, interaction with the replication protein A (RPA/RP-A) complex inhibits DNA unwinding by HELQ but strongly stimulates DNA strand annealing (PubMed:34937945). Triggers displacement of RPA from single-stranded DNA to facilitate annealing of complementary sequences (PubMed:34316696, PubMed:34937945).
(Microbial infection) Promotes Chikungunya virus (CHIKV) replication by mediating viral nsp1 palmitoylation.
Palmitoyltransferase that mediates palmitoylation of RRAS, leading to increased cell viability.
Was shown to mediate palmitoylation of STAT3, leading to homodimerization and transcriptional activation of STAT3. However, this study was later retracted.
Acts as component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. The recruitment of the CSC to the endosomal membrane involves RAB7A and SNX3. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX3-retromer mediates the retrograde endosome-to-TGN transport of WLS distinct from the SNX-BAR retromer pathway. The SNX27-retromer is believed to be involved in endosome-to-plasma membrane trafficking and recycling of a broad spectrum of cargo proteins (Probable). The CSC seems to act as recruitment hub for other proteins, such as the WASH complex and TBC1D5 (Probable). Required for retrograde transport of lysosomal enzyme receptor IGF2R (PubMed:15078902, PubMed:15078903). Required to regulate transcytosis of the polymeric immunoglobulin receptor (pIgR-pIgA) (PubMed:15247922). Required for the endosomal localization of WASHC2A (indicative for the WASH complex) (PubMed:22070227). Required for the endosomal localization of TBC1D5 (PubMed:20923837). Mediates retromer cargo recognition of SORL1 and is involved in trafficking of SORL1 implicated in sorting and processing of APP (PubMed:22279231). Involved in retromer-independent lysosomal sorting of F2R (PubMed:16407403). Involved in recycling of ADRB2 (PubMed:21602791). Enhances the affinity of SNX27 for PDZ-binding motifs in cargo proteins (By similarity).
Component of the heterotrimeric retromer cargo-selective complex (CSC), also described as vacuolar protein sorting subcomplex (VPS), formed by VPS26 (VPS26A or VPS26B), VPS29 and VPS35 (PubMed:11102511, PubMed:28892079). The CSC has a highly elongated structure with VPS26 and VPS29 binding independently at opposite distal ends of VPS35 as central platform (By similarity). The CSC is believed to associate with variable sorting nexins to form functionally distinct retromer complex variants. The originally described retromer complex (also called SNX-BAR retromer) is a pentamer containing the CSC and a heterodimeric membrane-deforming subcomplex formed between SNX1 or SNX2 and SNX5 or SNX6 (also called SNX-BAR subcomplex); the respective CSC and SNX-BAR subcomplexes associate with low affinity. The CSC associates with SNX3 to form a SNX3-retromer complex. The CSC associates with SNX27, the WASH complex and the SNX-BAR subcomplex to form the SNX27-retromer complex (Probable). Interacts with VPS29, VPS35, SNX1, SNX2, SNX5, SNX6, SNX3, SNX27, RAB7A, ECPAS, EHD1, WASHC5, SORL1 (PubMed:11102511, PubMed:16190980, PubMed:19619496, PubMed:17868075, PubMed:19531583, PubMed:20682791, PubMed:20923837, PubMed:21725319, PubMed:22279231, PubMed:24344282, PubMed:16732284, PubMed:28892079, PubMed:30213940).
Down-regulated in Alzheimer disease. No polymorphism or variant is however associated with Alzheimer disease for VPS26A.
Homodimer and homotetramer via the coiled coil regions. Interacts tightly with GTP-bound but not GDP-bound CDC42 (By similarity).
Maintained in an inactive, closed conformation by an interaction between the kinase domain and the negative autoregulatory C-terminal coiled-coil region. Agonist binding to the phorbol ester binding site disrupts this, releasing the kinase domain to allow N-terminus-mediated dimerization and kinase activation by transautophosphorylation (By similarity).
May act as a downstream effector of CDC42 in cytoskeletal reorganization. Contributes to the actomyosin contractility required for cell invasion, through the regulation of MYPT1 and thus MLC2 phosphorylation (By similarity).
Allosterically activated by N-acetylglucosamine-6-phosphate (GlcNAc6P).
Belongs to the glucosamine/galactosamine-6-phosphate isomerase family.
Catalyzes the reversible conversion of alpha-D-glucosamine 6-phosphate (GlcN-6P) into beta-D-fructose 6-phosphate (Fru-6P) and ammonium ion, a regulatory reaction step in de novo uridine diphosphate-N-acetyl-alpha-D-glucosamine (UDP-GlcNAc) biosynthesis via hexosamine pathway. Deamination is coupled to aldo-keto isomerization mediating the metabolic flux from UDP-GlcNAc toward Fru-6P. At high ammonium level can drive amination and isomerization of Fru-6P toward hexosamines and UDP-GlcNAc synthesis. Has a role in fine tuning the metabolic fluctuations of cytosolic UDP-GlcNAc and their effects on hyaluronan synthesis that occur during tissue remodeling.
Ubiquitous, with highest expression detected in testis, ovary, placenta, and heart.
Chimera. There is an inclusion of DNA from another gene in position 141.
Required for several aspects of embryonic development including normal development of the eye.
Expressed in placenta and testis. Expressed in testicular germ cell tumors.
May coordinately regulate cell cycle progression and transcription during spermatogenesis. Inhibits degradation of polyubiquitinated cyclin A and cyclin B1 and thereby arrests the cell cycle at early M phase. ESXR1-N acts as a transcriptional repressor. Binds to the sequence 5'-TAATGTTATTA-3' which is present within the first intron of the KRAS gene and inhibits its expression. ESXR1-C has the ability to inhibit cyclin turnover.
Undergoes proteolytic cleavage; produces a 45 kDa N-terminal homeodomain-containing fragment (ESXR1-N) and a 20 kDa C-terminal fragment (ESXR1-C).
Interacts with the thyroid hormone receptor/TR (via the ligand-binding domain); this interaction requires the presence of thyroid hormone (PubMed:10454579). Interacts with the androgen receptor/AR; in an androgen, testosterone and dihydrotestosterone-dependent manner (PubMed:12390891). Interacts with ESR1 (estrogen ligand-bound); competes with UFSP2 (PubMed:10454579, PubMed:25219498). Interacts with UFSP2; competes with ligand-bound ESR1 (PubMed:25219498). Interacts with DDRGK1 and UFL1; the interaction with DDRGK1 is direct (PubMed:25219498). Interacts with NCOA1 (PubMed:25219498). Interacts with EP300 (PubMed:25219498). Part of the ASC-1 complex, that contains TRIP4, ASCC1, ASCC2 and ASCC3 (PubMed:12077347). Identified in the RQT (ribosome quality control trigger) complex, that contains ASCC2, ASCC3 and TRIP4 (PubMed:32099016, PubMed:32579943, PubMed:36302773). Interacts with NEK6 (PubMed:20873783). Interacts with CSRP1 (PubMed:26924529). Interacts with ZCCHC4 (PubMed:31799605).
Polyufmylated by the UFM1-conjugating system composed of the enzymes UBA5, UFC1 and UFL1. Deufmylated by the protease UFSP2. Ufmylation of TRIP4 is promoted by ligand-bound nuclear receptors that compete with UFSP2 for interaction with TRIP4. Nuclear receptors-induced ufmylation promotes the recruitment of additional transcriptional coactivators like EP300 and NCOA1 and therefore the assembly of a coactivator complex facilitating nuclear receptor-mediated transcription.
The C4-type zinc finger mediates a competitive interaction with UFSP2 and ligand-bound nuclear receptors. It also mediates interaction with the transcriptional coactivators and the basal transcription machinery.
Transcription coactivator which associates with nuclear receptors, transcriptional coactivators including EP300, CREBBP and NCOA1, and basal transcription factors like TBP and TFIIA to facilitate nuclear receptors-mediated transcription (PubMed:10454579, PubMed:25219498). May thereby play an important role in establishing distinct coactivator complexes under different cellular conditions (PubMed:10454579, PubMed:25219498). Plays a role in thyroid hormone receptor and estrogen receptor transactivation (PubMed:10454579, PubMed:25219498). Also involved in androgen receptor transactivation (By similarity). Plays a pivotal role in the transactivation of NF-kappa-B, SRF and AP1 (PubMed:12077347). Acts as a mediator of transrepression between nuclear receptor and either AP1 or NF-kappa-B (PubMed:12077347). May play a role in the development of neuromuscular junction (PubMed:26924529). May play a role in late myogenic differentiation (By similarity). Also functions as part of the RQC trigger (RQT) complex that activates the ribosome quality control (RQC) pathway, a pathway that degrades nascent peptide chains during problematic translation (PubMed:32099016, PubMed:32579943, PubMed:36302773).
May act as a positive axonal guidance cue.
Binds F-actin (PubMed:12377779, PubMed:22364218). Interacts with RCC2 (PubMed:25074804). Interacts preferentially with nucleotide-free and GDP-bound RAC1 (PubMed:25074804). Interacts with VIM (via head domain) (By similarity). Isoform 1 and isoform 2 appear as homotrimers, while isoform 3 seems to exist as monomers (PubMed:19651142). Interacts with MICAL2; this interaction recruits MICAL2 to the actin filaments (PubMed:34106209).
Exclusively expressed in well-differentiated myoblasts as well as in mature skeletal muscle.
Plays a role in directed cell migration by regulating the activation and subcellular location of RAC1 (PubMed:25074804, PubMed:25925950). Increases the presence of activated RAC1 at the leading edge of migrating cells (PubMed:25074804, PubMed:25925950). Required for normal organization of the cytoskeleton, including the actin cytoskeleton, microtubules and the vimentin intermediate filaments (By similarity). Plays a role in endoplasmic reticulum-associated endosome fission: localizes to endosome membrane tubules and promotes recruitment of TMCC1, leading to recruitment of the endoplasmic reticulum to endosome tubules for fission (PubMed:30220460). Endosome membrane fission of early and late endosomes is essential to separate regions destined for lysosomal degradation from carriers to be recycled to the plasma membrane (PubMed:30220460). Required for normal cell proliferation, cell migration, and normal formation of lamellipodia (By similarity). Required for normal distribution of mitochondria within cells (By similarity).
The C-terminal coiled-coil domain is essential for cortical membrane localization and oligomerization.
Detected in fibroblasts and urine (at protein level) (PubMed:25326458, PubMed:36213313). Detected in placenta (at protein level) (PubMed:32337544). Expressed predominantly in internal organs such as adrenal gland, pancreas and kidney.
O-glycosylated; with core 1 or possibly core 8 glycans. Contains chondroitin sulfate.
Structural protein that stabilizes microvessels and muscle cells, both in heart and in skeletal muscle.
The name restin has also been used for CAP-Gly domain-containing linker protein 1 the product of the CLIP1 gene.
Forms a ternary complex with MAGI2 and SH3KBP1; recruits DDN to the cytoplasm. Interacts with MAGI1. Interacts with ACTN1 and may interact with WWC1. Interacts with the podocyte slit diaphragm proteins CD2AP, NPHS1 and NPHS2; the interaction with CD2AP and NPHS1 is direct (By similarity).
Promotes apoptosis of kidney glomerular podocytes. Podocytes are highly specialized cells essential to the ultrafiltration of blood, resulting in the extraction of urine and the retention of protein (By similarity).
Specifically expressed in brain and kidney. Expressed in kidney glomerular capillary loops (at protein level).
Binds with low affinity to dsDNA and ssRNA, and with high affinity to dsRNA, with no detectable sequence specificity (PubMed:24521053). May bind to specific miRNA hairpins (PubMed:28431233).
Forms a heteromeric complex with XPO5 and ILF3. Found in a nuclear export complex with XPO5, RAN, ILF3, ZNF346 and double-stranded RNA. Interacts with XPO5. Interacts with ILF3 in an RNA-independent manner.
The zinc-finger domains are required for binding to dsRNA, and also for nuclear localization.
Component of the AP2-containing clathrin coat that may regulate clathrin-dependent trafficking at plasma membrane, TGN and endosomal system (Probable). A possible serine/threonine-protein kinase toward the beta2-subunit of the plasma membrane adapter complex AP2 and other proteins in presence of poly-L-lysine has not been confirmed (PubMed:15809293, PubMed:16914521). By regulating the expression of excitatory receptors at synapses, plays an essential role in neuronal function and signaling and in brain development (By similarity).
Could autophosphorylate in presence of poly-L-lysine.
Interacts with clathrin and AP2B1; the interaction mediates the association with the AP-2 complex.
Heterotetramer of two alpha and two beta subunits.
In spleen mRNA levels are higher in adult than in fetal tissue.
Transcription factor capable of interacting with purine rich repeats (GA repeats). Positively regulates transcription of transcriptional repressor RHIT/ZNF205 (PubMed:22306510).
(Microbial infection) Acts as a receptor for enterovirus 71.
(Microbial infection) Interacts with enterovirus 71 capsid proteins VP1 and VP2.
Acts as a lysosomal receptor for glucosylceramidase (GBA1) targeting.
Genetic variants in SCARB2 can act as modifier of the phenotypic expression and severity of Gaucher disease.
Interacts with WRD11 (via the N-terminal and the central portion of the protein); the interaction associates EMX1 with GLI3.
Transcription factor, which in cooperation with EMX2, acts to generate the boundary between the roof and archipallium in the developing brain. May function in combinations with OTX1/2 to specify cell fates in the developing central nervous system.
When overexpressed, acts as a general inhibitor of transcription that eventually leads to apoptosis.
E3 ubiquitin ligase induced during late erythropoiesis. Directly binds and ubiquitinates the intermediate chain of the microtubule motor dynein (DYNC1LI1/DYNC1LI2), stimulating the degradation of the dynein holoprotein complex. May participate in the erythroblast enucleation process through regulation of nuclear polarization.
Located in the cells of the submucosal serous glands of the bronchi and trachea.
May play some biological role in the host defense system on the mucous membrane independently of or in cooperation with other substances in airway mucous or bronchial secretions. Plays a role in the proteolytic processing of ACE2. Proteolytically cleaves and activates the human coronavirus 229E (HCoV-229E) spike glycoprotein which facilitate virus-cell membrane fusions; spike proteins are synthesized and maintained in precursor intermediate folding states and proteolysis permits the refolding and energy release required to create stable virus-cell linkages and membrane coalescence. Preferentially cleaves the C-terminal side of arginine residues at the P1 position of certain peptides, cleaving Boc-Phe-Ser-Arg-4-methylcoumaryl-7-amide most efficiently and having an optimum pH of 8.6 with this substrate.
Strongly inhibited by diisopropyl fluorophosphate, leupeptin, antipain, aprotinin, and soybean trypsin inhibitor, but hardly inhibited by secretory leukocyte protease inhibitor at 10 microM.
Has both beta-1,3-glucuronic acid and beta-1,4-N-acetylgalactosamine transferase activity. Transfers glucuronic acid (GlcUA) from UDP-GlcUA and N-acetylgalactosamine (GalNAc) from UDP-GalNAc to the non-reducing end of the elongating chondroitin polymer. Involved in the negative control of osteogenesis likely through the modulation of NOTCH signaling.
Ubiquitous, with the highest levels in placenta. Detected at low levels in brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, adrenal gland, mammary gland, stomach, small intestine, lung and peripheral blood leukocytes.
Alternative splice sites (AA 1053-1054) represent a non-canonical GA-AG donor-acceptor pair, but are well-supported by all available human transcripts, and by homologous transcripts in mouse, rat and cow.
Homotetramer (By similarity). Interacts with TRPC4 (By similarity). The PPXXF motif binds HOM1, HOM2 and HOM3. Interacts with RYR1, RYR2, ITPR1, SHANK1 and SHANK3. Interacts with ERP44 in a pH-, redox state- and calcium-dependent manner which results in the inhibition the calcium channel activity. The strength of this interaction inversely correlates with calcium concentration. Part of cGMP kinase signaling complex at least composed of ACTA2/alpha-actin, CNN1/calponin H1, PLN/phospholamban, PRKG1 and ITPR1. Interacts with IRAG1 (PubMed:16990611). Interacts with CABP1 (via N-terminus) (PubMed:12032348, PubMed:14685260). Interacts with TESPA1. Interacts (when not phosphorylated) with AHCYL1 (when phosphorylated); the interaction suppresses inositol 1,4,5-trisphosphate binding to ITPR1 and is increased in the presence of BCL2L10 (PubMed:16793548, PubMed:27995898). Interacts with AHCYL2 (with lower affinity than with AHCYL1) (PubMed:19220705). Interacts with BCL2L10; the interaction is increased in the presence of AHCLY1 (PubMed:27995898). Interacts with BOK (via BH4 domain); protects ITPR1 from proteolysis by CASP3 during apoptosis (PubMed:23884412).
Intracellular channel that mediates calcium release from the endoplasmic reticulum following stimulation by inositol 1,4,5-trisphosphate (PubMed:27108797). Involved in the regulation of epithelial secretion of electrolytes and fluid through the interaction with AHCYL1 (By similarity). Plays a role in ER stress-induced apoptosis. Cytoplasmic calcium released from the ER triggers apoptosis by the activation of CaM kinase II, eventually leading to the activation of downstream apoptosis pathways (By similarity).
Palmitoylated by ZDHHC6 in immune cells, leading to regulation of ITPR1 stability and function.
Phosphorylated by cAMP kinase (PKA). Phosphorylation prevents the ligand-induced opening of the calcium channels. Phosphorylation by PKA increases the interaction with inositol 1,4,5-trisphosphate and decreases the interaction with AHCYL1.
Receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium.
Ubiquitination at multiple lysines targets ITPR1 for proteasomal degradation. Approximately 40% of the ITPR1-associated ubiquitin is monoubiquitin, and polyubiquitins are both 'Lys-48'- and 'Lys-63'-linked (By similarity).
Enhances the incorporation of serine into phosphatidylserine and sphingolipids.
The poly-Ala stretch (positions 24 to 31) may be polymorphic and varies from 6 to 8 Ala residues.
Acts as a feedback negative regulator of signaling by receptor tyrosine kinases, through a mechanism that involves enhancement of receptor ubiquitination and accelerated intracellular degradation.
Contains LRR and Ig-domains that can mediate low-affinity interaction with EGFR (PubMed:25765764). The LRRs and the Ig-domains are each sufficient for EGFR/ERBB1 binding. This interaction is abolished only when both the LRRs and the Ig-domains are deleted (PubMed:15282549).
Interacts (via extracellular LRR and Ig-like domains) with EGFR/ERBB1, ERBB2, ERBB3 and ERBB4 (via extracellular domain) (PubMed:15282549). The physiological relevance of the interaction is controversial; LRIG1 may have low affinity for EGFR, and interaction may occur only when high levels of both proteins are present (PubMed:25765764).
Component of the RSF-1 ISWI chromatin-remodeling complex at least composed of SMARCA1 and RSF1 (PubMed:28801535). Within the RSF-1 ISWI chromatin-remodeling complex interacts with SMARCA1 (PubMed:28801535). Component of the RSF-5 ISWI chromatin-remodeling complex (also called the RSF complex) at least composed of SMARCA5/SNF2H and RSF1 (PubMed:12972596, PubMed:28801535). Within the RSF-5 ISWI chromatin-remodeling complex interacts with SMARCA5/SNF2H; the interaction is direct (PubMed:12972596, PubMed:28801535). Identified in a centromere complex containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:27499292). Also binds the HBV pX/HBx protein, which is required to activate transcription of the viral genome (PubMed:11944984, PubMed:11788598).
Regulatory subunit of the ATP-dependent RSF-1 and RSF-5 ISWI chromatin-remodeling complexes, which form ordered nucleosome arrays on chromatin and facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair (PubMed:12972596, PubMed:28801535). Binds to core histones together with SMARCA5, and is required for the assembly of regular nucleosome arrays by the RSF-5 ISWI chromatin-remodeling complex (PubMed:12972596). Directly stimulates the ATPase activity of SMARCA1 and SMARCA5 in the RSF-1 and RSF-5 ISWI chromatin-remodeling complexes, respectively (PubMed:28801535). The RSF-1 ISWI chromatin remodeling complex has a lower ATP hydrolysis rate than the RSF-5 ISWI chromatin-remodeling complex (PubMed:28801535). The complexes do not have the ability to slide mononucleosomes to the center of a DNA template (PubMed:28801535). Facilitates transcription of hepatitis B virus (HBV) genes by the pX transcription activator. In case of infection by HBV, together with pX, it represses TNF-alpha induced NF-kappa-B transcription activation. Represses transcription when artificially recruited to chromatin by fusion to a heterogeneous DNA binding domain (PubMed:11944984, PubMed:11788598).
Ubiquitously expressed. Highly expressed in the heart, skeletal muscle, kidney and placenta (PubMed:12972596). Expressed at low levels in the brain and colon (PubMed:12972596).
According to PubMed:14630949, expressed in heart, skeletal muscle, liver, kidney and pancreas; undetectable in lung, placenta or brain. According to PubMed:14625278, ubiquitously expressed, with lowest expression in brain and ileum.
Transcription factor involved in SLC2A4 and HD gene transactivation. Binds to the consensus sequence 5'-GCCGGCG-3'.
ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair and the maintenance of genomic stability. Acts as an anti-recombinase to counteract toxic recombination and limit crossover during meiosis. Regulates meiotic recombination and crossover homeostasis by physically dissociating strand invasion events and thereby promotes noncrossover repair by meiotic synthesis dependent strand annealing (SDSA) as well as disassembly of D loop recombination intermediates. Also disassembles T loops and prevents telomere fragility by counteracting telomeric G4-DNA structures, which together ensure the dynamics and stability of the telomere.
Belongs to the helicase family. RAD3/XPD subfamily.
Interacts with TERF1. Interacts (via PIP-box) with PCNA; the interaction is direct and essential for suppressing telomere fragility. Interacts with MMS19; the interaction mediates the association of RTEL1 with the cytosolic iron-sulfur protein assembly (CIA) complex.
The PIP-box (PCNA interacting peptide) motif mediates the interaction with PCNA and localization to replication foci.
The disease is caused by variants affecting the gene represented in this entry. RTEL1 mutations have also been found in patients with a dyskeratosis congenita-like phenotype consisting of one feature of dyskeratosis congenita and short telomeres, in the absence of the typical DKC diagnostic triad (PubMed:23329068).
Variant in position: 1264:R->H (in DKCB5), abolishes activity.
A chromosomal aberration involving EWSR1 has been found in extraskeletal myxoid chondrosarcoma. Translocation t(9;22)(q22-31;q11-12) with NR4A3.
A chromosomal aberration involving EWSR1 is associated with desmoplastic small round cell tumor (DSRCT). Translocation t(11;22)(p13;q12) with WT1.
A chromosomal aberration involving EWSR1 is associated with malignant melanoma of soft parts (MMSP). Translocation t(12;22)(q13;q12) with ATF1. Malignant melanoma of soft parts, also known as soft tissue clear cell sarcoma, is a rare tumor developing in tendons and aponeuroses.
A chromosomal aberration involving EWSR1 is associated with small round cell sarcoma. Translocation t(11;22)(p36.1;q12) with PATZ1.
Binds POLR2C, SF1, calmodulin and RNA. Interacts with PTK2B/FAK2 and TDRD3. Binds calmodulin in the presence, but not in the absence, of calcium ion. Forms a complex with REC8, PRDM9, SYCP3 and SYCP1; complex formation is dependent of phosphorylated form of REC8 and requires PRDM9 bound to hotspot DNA; EWSR1 joins PRDM9 with the chromosomal axis through REC8 (By similarity).
EFPS arise due to chromosomal translocations in which EWSR1 is fused to a variety of cellular transcription factors. EFPS are very potent transcriptional activators dependent on the EAD and a C-terminal DNA-binding domain contributed by the fusion partner. The spectrum of malignancies associated with EFPS are thought to arise via EFP-induced transcriptional deregulation, with the tumor phenotype specified by the EWSR1 fusion partner and cell type. Transcriptional repression of the transforming growth factor beta type II receptor (TGF beta RII) is an important target of the EWS-FLI1, EWS-ERG, or EWS-ETV1 oncogene.
EWS activation domain (EAD) functions as a potent activation domain in EFPS. EWSR1 binds POLR2C but not POLR2E or POLR2G, whereas the isolated EAD binds POLR2E and POLR2G but not POLR2C. Cis-linked RNA-binding domain (RBD) can strongly and specifically repress trans-activation by the EAD.
Highly methylated on arginine residues. Methylation is mediated by PRMT1 and, at lower level by PRMT8.
Might normally function as a transcriptional repressor. EWS-fusion-proteins (EFPS) may play a role in the tumorigenic process. They may disturb gene expression by mimicking, or interfering with the normal function of CTD-POLII within the transcription initiation complex. They may also contribute to an aberrant activation of the fusion protein target genes.
Phosphorylated; calmodulin-binding inhibits phosphorylation of Ser-266.
The gene represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving EWSR1 are found in patients with angiomatoid fibrous histiocytoma. Translocation t(12;22)(q13;q12) with ATF1 generates a chimeric EWSR1/ATF1 protein (PubMed:15884099). Translocation t(2;22)(q33;q12) with CREB1 generates a EWSR1/CREB1 fusion gene that is most common genetic abnormality in this tumor type (PubMed:17724745).
The protein represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving EWSR1 are found in patients with Ewing sarcoma. Translocation t(11;22)(q24;q12) with FLI1 (PubMed:1522903, PubMed:15044653). Translocation t(7;22)(p22;q12) with ETV1 (PubMed:7700648). Translocation t(21;22)(q22;q21) with ERG (PubMed:15044653). Translocation t(2;21;22)(q23;q22;q12) that forms a EWSR1-FEV fusion protein with potential oncogenic activity (PubMed:9121764).
Brain, heart, kidney, pancreas, and liver, but not in lung or placenta.
Component of clathrin-coated pits and vesicles, that may link the endocytic machinery to the actin cytoskeleton. Binds 3-phosphoinositides (via ENTH domain). May act through the ENTH domain to promote cell survival by stabilizing receptor tyrosine kinases following ligand-induced endocytosis.
Homodimer (By similarity). Interacts with actin; homodimerization promotes actin binding (PubMed:16415883). Interacts with CLTB (PubMed:11889126, PubMed:15533940). Interacts with HIP1 (PubMed:11889126). Interacts (via ENTH and I/LWEQ domains) with BCL2L10 (PubMed:19255499).
Expressed in the distal convoluted tubule in the kidney. Found on basolateral membranes of nephron epithelial cells.
Expressed in fetal liver (at protein level) (PubMed:10605026). Expressed in placenta villous mesenchyme, cytotrophoblast, syncytiotrophoblast and invasive extravillous trophoblast (at protein level) (PubMed:28185362).
Expressed in resting B cells (at protein level). Expressed in secondary lymphoid organs rich in B and T cells such as the tonsils, spleen, and thymus (at protein level) (PubMed:10605026, PubMed:11169396). Expressed in the endothelial cells of the tonsils (PubMed:11169396). Expressed on activated lymphoid cells including B cells, NK cells, CD4+ T cells and memory T cells (at protein level) (PubMed:27455421, PubMed:20865824). Expressed in motor neurons of spinal cord (PubMed:26928464).
Forms a heterotrimer with B2M and a self-peptide (PubMed:28636952). Binds a diverse number of peptides ranging from 7 to more than 30 amino acids (PubMed:28636952). Peptide-bound HLA-F-B2M interacts with LILRB1 and LILRB2 but not with KIR3DS1 or KIR3DL2; this interaction is direct (PubMed:28636952, PubMed:11169396). The OC form interacts with KIR3DS1, KIR2DS4 and KIR3DL2; this interaction is direct (PubMed:28636952, PubMed:27455421, PubMed:24018270). Interacts with TAP1-TAP2 complex and CALR; this interaction is required for appropriate folding and peptide loading (PubMed:10605026, PubMed:11169396). Interacts with the coat protein complex II and 14-3-3 proteins; these interactions likely control the anterograde ER-to-Golgi transport of HLA-F (PubMed:16709803). HLA-F-B2M complex interacts with the heavy chain of other MHC class I molecules including HLA-A and HLA-E; this interaction may regulate the intracellular trafficking and the stability of peptide-free MHC class I OCs (PubMed:20483783).
Non-classical major histocompatibility class Ib molecule postulated to play a role in immune surveillance, immune tolerance and inflammation. Functions in two forms, as a heterotrimeric complex with B2M/beta-2 microglobulin and a peptide (peptide-bound HLA-F-B2M) and as an open conformer (OC) devoid of peptide and B2M (peptide-free OC). In complex with B2M, presents non-canonical self-peptides carrying post-translational modifications, particularly phosphorylated self-peptides. Peptide-bound HLA-F-B2M acts as a ligand for LILRB1 inhibitory receptor, a major player in maternal-fetal tolerance. Peptide-free OC acts as a ligand for KIR3DS1 and KIR3DL2 receptors (PubMed:28636952). Upon interaction with activating KIR3DS1 receptor on NK cells, triggers NK cell degranulation and anti-viral cytokine production (PubMed:27455421). Through interaction with KIR3DL2 receptor, inhibits NK and T cell effector functions (PubMed:24018270). May interact with other MHC class I OCs to cross-present exogenous viral, tumor or minor histompatibility antigens to cytotoxic CD8+ T cells, triggering effector and memory responses (PubMed:23851683). May play a role in inflammatory responses in the peripheral nervous system. Through interaction with KIR3DL2, may protect motor neurons from astrocyte-induced toxicity (PubMed:26928464).
Up-regulated in CD4+ T cells upon stimulation via TCR and upon HIV-1 infection.
Compared to the genome, the sequence lacks 6 bp for unexplained reasons.
Detected in prostate, testis, and pancreas.
Activated by manganese or magnesium ions (PubMed:12609998, PubMed:24616449). In the presence of magnesium ions, the enzyme is activated by bicarbonate (PubMed:12609998, PubMed:15659711, PubMed:24567411). In the presence of manganese ions, the enzyme is inhibited by bicarbonate (PubMed:15659711). In the absence of magnesium and bicarbonate, the enzyme is weakly activated by calcium (PubMed:15659711). Calcium mildly increases the enzyme activity, also in the presence of magnesium ions (PubMed:15659711, PubMed:25040695).
Binds 2 magnesium ions per subunit (PubMed:25040695). Is also active with manganese (in vitro) (PubMed:12609998, PubMed:15659711, PubMed:24616449).
Catalyzes the formation of the signaling molecule cAMP (PubMed:12609998, PubMed:15659711, PubMed:24616449, PubMed:25040695, PubMed:24567411). May function as sensor that mediates responses to changes in cellular bicarbonate and CO(2) levels (PubMed:15659711, PubMed:17591988). Has a critical role in mammalian spermatogenesis by producing the cAMP which regulates cAMP-responsive nuclear factors indispensable for sperm maturation in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization (By similarity). Involved in ciliary beat regulation (PubMed:17591988).
Catalyzes the formation of the signaling molecule cAMP. May function as sensor that mediates responses to changes in cellular bicarbonate and CO(2) levels. Has a critical role in mammalian spermatogenesis by producing the cAMP which regulates cAMP-responsive nuclear factors indispensable for sperm maturation in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization. Involved in ciliary beat regulation.
Cleavage may occur to generate the active 48 kDa form.
Detected in airway epithelial cells and testis (at protein level) (PubMed:17591988). Weakly expressed in multiple tissues. Expressed in brain, heart, kidney, liver, lung, pancreas, peripheral blood leukocytes, placenta, skeletal muscle, stomach, thymus, airway epithelial cells, duodenum, jejunum and ileum. Very low level of expression in bone.
The N-terminal guanylate cyclase domains are required for enzyme activity. Fragments or isoforms containing the first 470 amino acid residues are fully active.
Contains a N-terminal dileucine motif (DE)XXXL(LI) important for endosomal/lysosomal and mitochondrial subcellular localization.
Transports nucleoside analog drugs such as cladribine, cordycepin, tubercidin and idovudine (PubMed:15701636, PubMed:19164483). Also involved in the uptake of diabetes treatment medicine metformin, neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)), and ribavirin (PubMed:19164483). Transport activity is insensitive to nanomolar concentrations of the inhibitors nitrobenzylmercaptopurine riboside, dipyridamole and dilazep, and inhibited by higher concentrations (PubMed:15701636). Does not transport hypoxanthine (PubMed:15701636, PubMed:19164483). A truncated version of SLC29A3/hENT3 in which the N-terminal 36 amino acids are deleted, enables cell-surface localization of an otherwise intracellular transporter, and is utilized to investigate the transporter activity (PubMed:15701636, PubMed:19164483, PubMed:20595384, PubMed:28729424).
Uniporter that mediates the facilitative transport of nucleoside across lysosomal and mitochondrial membranes (PubMed:15701636, PubMed:19164483, PubMed:20595384, PubMed:28729424). Functions as a non-electrogenic Na(+)-independent transporter (PubMed:15701636, PubMed:19164483, PubMed:28729424). Substrate transport is pH-dependent and enhanced under acidic condition, probably reflecting the location of the transporter in acidic intracellular compartments (PubMed:15701636, PubMed:19164483, PubMed:28729424). Proton is not a cotransporting ion but most likely change the ionization state of the transporter which dictates transport-permissible/impermissible conformation for nucleoside translocation (PubMed:28729424). May direct the nucleoside transport from lysosomes to cytosol or cytosol to mitochondria to facilitate the fundamental function of salvage synthesis of nucleic acids (PubMed:28729424). Involved in the transport of nucleosides (adenosine, guanosine, uridine, thymidine, cytidine and inosine) and deoxynucleosides (deoxyadenosine, deoxycytidine) (PubMed:15701636, PubMed:19164483, PubMed:20595384, PubMed:28729424). Also mediates transport of purine nucleobases (adenine, guanine) and pyrimidine nucleobases (uracil) (PubMed:15701636, PubMed:19164483). Also able to transport monoamine neurotransmitters dopamine, serotonin, noradrenaline and tyramine (PubMed:19164483). Capable of transporting ATP (PubMed:19164483). Mediates nucleoside export from lysosomes in macrophages, which regulates macrophage functions and numbers (By similarity).
Widely expressed in both adult and fetal tissues (PubMed:15701636). Highest levels in placenta, uterus, ovary, spleen, lymph node and bone marrow (PubMed:15701636). Expressed in liver (PubMed:19164483). Lowest levels in brain and heart (PubMed:15701636). Expressed in macrophages (PubMed:22174130).
Homodimer; disulfide-linked (By similarity). Interacts with MGAT4D (By similarity).
Exhibits both phospholipase A1/2 and acyltransferase activities (PubMed:22825852, PubMed:26503625). Shows phospholipase A1 (PLA1) and A2 (PLA2) activity, catalyzing the calcium-independent release of fatty acids from the sn-1 or sn-2 position of glycerophospholipids (PubMed:22825852). Shows N-acyltransferase activity, catalyzing the calcium-independent transfer of a fatty acyl group at the sn-1 position of phosphatidylcholine (PC) and other glycerophospholipids to the primary amine of phosphatidylethanolamine (PE), forming N-acylphosphatidylethanolamine (NAPE), which serves as precursor for N-acylethanolamines (NAEs) (PubMed:19000777, PubMed:22825852).
Highest expression level in testis and pancreas.
Liver, lung, adrenal, brain, platelets and skin.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of a wide variety of acceptor molecules bearing a hydroxyl or an amine groupe. Sulfonation increases the water solubility of most compounds, and therefore their renal excretion, but it can also result in bioactivation to form active metabolites. Displays broad substrate specificity for small phenolic compounds. Plays an important role in the sulfonation of endogenous molecules such as steroid hormones and 3,3'-diiodothyronin (PubMed:16221673, PubMed:12471039, PubMed:22069470, PubMed:21723874, PubMed:10199779, PubMed:7834621). Mediates the sulfate conjugation of a variety of xenobiotics, including the drugs acetaminophen and minoxidil (By similarity). Mediates also the metabolic activation of carcinogenic N-hydroxyarylamines leading to highly reactive intermediates capable of forming DNA adducts, potentially resulting in mutagenesis (PubMed:7834621). May play a role in gut microbiota-host metabolic interaction. O-sulfonates 4-ethylphenol (4-EP), a dietary tyrosine-derived metabolite produced by gut bacteria. The product 4-EPS crosses the blood-brain barrier and may negatively regulate oligodendrocyte maturation and myelination, affecting the functional connectivity of different brain regions associated with the limbic system.
There are several alleles. The sequence shown is that of allele SULT1A1*3.
Heteromer of p110, p125, p140 and p200 subunits; disulfide-linked. Interacts with VEGFA.
Inhibits endothelial cells motility and acts as a negative regulator of angiogenesis; it down-regulates KDR activation by binding VEGFA.
May protect the cells against DNA damage caused by exposure to the cold-warming stress and facilitates tissue damage repair during the recovery phase.
Component of the distal appendage region of the centriole involved in the initiation of primary cilium assembly. May collaborate with IFT20 in the trafficking of ciliary membrane proteins from the Golgi complex to the cilium during the initiation of primary cilium assembly.
By endoplasmic reticulum stress (PubMed:18561914, PubMed:22637475, PubMed:29497057). By hypoxia (PubMed:29497057).
Interacts with HSPA5; the interaction is direct (PubMed:22637475). Component of a complex containing at least CRELD2, MANF, MATN3 and PDIA4 (By similarity).
Selectively promotes the survival of dopaminergic neurons of the ventral mid-brain (PubMed:12794311). Modulates GABAergic transmission to the dopaminergic neurons of the substantia nigra (By similarity). Enhances spontaneous, as well as evoked, GABAergic inhibitory postsynaptic currents in dopaminergic neurons (By similarity). Inhibits cell proliferation and endoplasmic reticulum (ER) stress-induced cell death (PubMed:18561914, PubMed:22637475, PubMed:29497057). Retained in the ER/sarcoplasmic reticulum (SR) through association with the endoplasmic reticulum chaperone protein HSPA5 under normal conditions (PubMed:22637475). Up-regulated and secreted by the ER/SR in response to ER stress and hypoxia (PubMed:22637475). Following secretion by the ER/SR, directly binds to 3-O-sulfogalactosylceramide, a lipid sulfatide in the outer cell membrane of target cells (PubMed:29497057). Sulfatide binding promotes its cellular uptake by endocytosis, and is required for its role in alleviating ER stress and cell toxicity under hypoxic and ER stress conditions (PubMed:29497057).
The N-terminal region may be required for lipid sulfatide binding.
The N-terminal region may be responsible for neurotrophic activity while the C-terminal region may play a role in the ER stress response.
Was originally (PubMed:8649854, PubMed:8971156, PubMed:9174057) thought to be much longer and included an arginine-rich region thought to be the target of cancer-causing mutations. All these mutations are in what is now thought to be the 5'-UTR of the mRNA.
Catalyzes the dehydration of the S-form of NAD(P)HX at the expense of ATP, which is converted to ADP. Together with NAD(P)HX epimerase, which catalyzes the epimerization of the S- and R-forms, the enzyme allows the repair of both epimers of NAD(P)HX, a damaged form of NAD(P)H that is a result of enzymatic or heat-dependent hydration.
Homodimer (PubMed:17897942). Interacts (via PDZ2 domain) with TJP1/ZO1 (via PDZ2 domain) (PubMed:17897942). Interacts with OCLN (By similarity). Interacts with UBN1 (PubMed:18823282). Interacts with SAFB in the nucleus (By similarity). Interacts with SCRIB (PubMed:15975580). Interacts with USP53 (via the C-terminal region) (By similarity). Interacts with claudins, including CLDN1, CLDN2, CLDN3, CLDN5 and CLDN7 (PubMed:12704386). Interacts with CLDN18 (By similarity). Interacts (via N-terminus) with CTNNA1 (By similarity).
Plays a role in tight junctions and adherens junctions (By similarity). Acts as a positive regulator of RANKL-induced osteoclast differentiation, potentially via mediating downstream transcriptional activity (By similarity).
Produced by alternative splicing of isoform A1.
Produced by alternative splicing of isoform C1.
This protein is found in epithelial cell junctions. Isoform A1 is abundant in the heart and brain. Detected in brain and skeletal muscle. It is present almost exclusively in normal tissues. Isoform C1 is expressed at high level in the kidney, pancreas, heart and placenta. Not detected in brain and skeletal muscle. Found in normal as well as in most neoplastic tissues.
Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane.
Belongs to the XPG/RAD2 endonuclease family. GEN subfamily.
Endonuclease which resolves Holliday junctions (HJs) by the introduction of symmetrically related cuts across the junction point, to produce nicked duplex products in which the nicks can be readily ligated. Four-way DNA intermediates, also known as Holliday junctions, are formed during homologous recombination and DNA repair, and their resolution is necessary for proper chromosome segregation (PubMed:19020614, PubMed:26682650). Cleaves HJs by a nick and counter-nick mechanism involving dual coordinated incisions that lead to the formation of ligatable nicked duplex products. Cleavage of the first strand is rate limiting, while second strand cleavage is rapid. Largely monomeric, dimerizes on the HJ and the first nick occurs upon dimerization at the junction (PubMed:26578604). Efficiently cleaves both single and double HJs contained within large recombination intermediates. Exhibits a weak sequence preference for incision between two G residues that reside in a T-rich region of DNA (PubMed:28049850). Has also endonuclease activity on 5'-flap and replication fork (RF) DNA substrates (PubMed:26578604).
Largely monomeric, dimerizes on the Holliday junction and the first nick occurs upon dimerization at the junction.
XPG-N, XPG-I,5'-3' exonuclease domains interact with DNA. Contains a chromodomain that acts as additional DNA interaction site and is required for efficient DNA recognition and cleavage.
By hypoxia, TNF, and by nutrient starvation. Expression is PI 3-kinase and/or NF-kappa-B-dependent. Induced by ER stress via ATF4-DDIT3/CHOP pathway and can down-regulate its own induction by repression of ATF4-DDIT3/CHOP functions.
Highest expression in liver, pancreas, peripheral blood leukocytes and bone marrow. Also highly expressed in a number of primary lung, colon and breast tumors. Expressed in spleen, thymus, and prostate and is undetectable in other examined tissues, including testis, ovary, small intestine, colon, leukocyte, heart, brain, placenta, lung, skeletal muscle, and kidney.
Inactive protein kinase which acts as a regulator of the integrated stress response (ISR), a process for adaptation to various stress (PubMed:15781252, PubMed:15775988). Inhibits the transcriptional activity of DDIT3/CHOP and is involved in DDIT3/CHOP-dependent cell death during ER stress (PubMed:15781252, PubMed:15775988). May play a role in programmed neuronal cell death but does not appear to affect non-neuronal cells (PubMed:15781252, PubMed:15775988). Acts as a negative feedback regulator of the ATF4-dependent transcription during the ISR: while TRIB3 expression is promoted by ATF4, TRIB3 protein interacts with ATF4 and inhibits ATF4 transcription activity (By similarity). Disrupts insulin signaling by binding directly to Akt kinases and blocking their activation (By similarity). May bind directly to and mask the 'Thr-308' phosphorylation site in AKT1 (By similarity). Interacts with the NF-kappa-B transactivator p65 RELA and inhibits its phosphorylation and thus its transcriptional activation activity (PubMed:12736262). Interacts with MAPK kinases and regulates activation of MAP kinases (PubMed:15299019). Can inhibit APOBEC3A editing of nuclear DNA (PubMed:22977230).
Interacts with AKT1, AKT2, MAP2K1 and MAP2K7 (PubMed:15299019). Interacts with ATF4 (PubMed:12743605). Interacts with DDIT3/CHOP and inhibits its interaction with EP300/P300 (PubMed:15775988, PubMed:17872950). Interacts with APOBEC3C (PubMed:22977230). Interacts (via N-terminus) with APOBEC3A (PubMed:22977230). Interacts with RELA (PubMed:12736262).
The role of this protein in Akt activation has been demonstrated by Du et al (PubMed:12791994) for the mouse ortholog but Iynedjian (PubMed:15469416) has not been able to reproduce the result in rat hepatocytes.
Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH). Associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal. Seems to have a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis.
Glycosylation is necessary for SHH binding.
In the absence of Hh ligands, ubiquitination by ITCH at Lys-1426 promotes endocytosis and both proteasomal and lysosomal degradation.
In the adult, expressed in brain, lung, liver, heart, placenta, skeletal muscle, pancreas and kidney. Expressed in tumor cells but not in normal skin.
In the embryo, found in all major target tissues of sonic hedgehog, such as the ventral neural tube, somites, and tissues surrounding the zone of polarizing activity of the limb bud.
Interacts with SNX17 (PubMed:15769472). Interacts with IHH (PubMed:21537345). Interacts with G-protein coupled receptor GPR37L1 (By similarity).
Plays a role in neuronal plasticity and the proteolytic action may subserve structural reorganizations associated with learning and memory operations.
Inhibits papain and cathepsin L but with affinities lower than other cystatins. May play a role in immune regulation through inhibition of a unique target in the hematopoietic system.
Primarily expressed in peripheral blood cells and spleen.
Heterodimer with other family members, including GBP1, GBP2 and GBP5 (PubMed:21151871). Dimerization regulates subcellular location (PubMed:21151871). Interacts with IRF7; preventing interaction between TRAF6 and IRF7, resulting in impaired TRAF6-mediated IRF7 ubiquitination (By similarity).
Interferon (IFN)-inducible GTPase that plays important roles in innate immunity against a diverse range of bacterial, viral and protozoan pathogens (By similarity). Negatively regulates the antiviral response by inhibiting activation of IRF7 transcription factor (By similarity).
Interacts with RIMS1 and RIMS2 (By similarity). Interacts with Rabphilin-3A/RPH3A and Rab effector Noc2/RPH3AL (By similarity). Interacts with SYTL4 (By similarity). Interacts with RAB3IP (By similarity). Interacts with SGSM1 and SGSM3 (By similarity). Interacts with SYT1 (By similarity). Interacts with MYH9; this interaction is essential for lysosome exocytosis and plasma membrane repair (PubMed:27325790). Interacts with STXBP1; this interaction promotes RAB3A dissociation from the vesicle membrane (By similarity). Interacts with SNCA (PubMed:15207266). Interacts with GDI1, GDI2, CHM and CHML; phosphorylation at Thr-86 disrupts these interactions (PubMed:29125462).
Phosphorylation of Thr-86 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM, CHML and RAB GDP dissociation inhibitors GDI1 and GDI2.
Small GTP-binding protein that plays a central role in regulated exocytosis and secretion. Controls the recruitment, tethering and docking of secretory vesicles to the plasma membrane (By similarity). Upon stimulation, switches to its active GTP-bound form, cycles to vesicles and recruits effectors such as RIMS1, RIMS2, Rabphilin-3A/RPH3A, RPH3AL or SYTL4 to help the docking of vesicules onto the plasma membrane (By similarity). Upon GTP hydrolysis by GTPase-activating protein, dissociates from the vesicle membrane allowing the exocytosis to proceed (By similarity). Stimulates insulin secretion through interaction with RIMS2 or RPH3AL effectors in pancreatic beta cells (By similarity). Regulates calcium-dependent lysosome exocytosis and plasma membrane repair (PMR) via the interaction with 2 effectors, SYTL4 and myosin-9/MYH9 (PubMed:27325790). Acts as a positive regulator of acrosome content secretion in sperm cells by interacting with RIMS1 (PubMed:22248876, PubMed:30599141). Also plays a role in the regulation of dopamine release by interacting with synaptotagmin I/SYT (By similarity). Interacts with MADD (via uDENN domain); the GTP-bound form is preferred for interaction (By similarity).
Expressed at very low levels in all tissues tested.
Inhibited by chloride channel blockers 4,4'-diisothiocyano-2,2'-stilbenedisulfonate (DIDS), niflumic acid (NFA), and 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB).
Outward-rectifying chloride channel involved in endolysosomal chloride homeostasis, membrane fusion and function. Conducts chloride currents up to hundreds of picoamperes. Regulates lysosomal calcium content by reducing the lysosomal membrane potential, thereby activating TRPML1 channel and further release of lysosomal calcium ions. Regulates the pH in endolysosomal compartments and may contribute to progressive acidification from endosome to lysosome. Permeable to other halides such as iodide and fluoride ions.
Interacts with TRPV5 and TRPV6. Interacts with YWHAZ/14-3-3 protein zeta (By similarity).
May regulate epithelial calcium transport by inhibiting TRPV5 activity.
Activated by phosphorylation at Tyr-493 in the activation loop. Inhibited by staurosporine.
Composed of 2 N-terminal SH2 domains and a C-terminal kinase domain. The tandem SH2 domains bind to the doubly phosphorylated tyrosine-based activation motif (ITAM) of CD247/CD3Z and the non-canonical phosphorylated tyrosine-based activation motif (TAM) of RHOH (By similarity). The interdomain B located between the second SH2 and the kinase domain contains 3 tyrosines (Tyr-292, Tyr-315, Tyr-319) that are phosphorylated following TCR activation. These sites have been implicated in binding to other signaling molecules including CBL or VAV1. Thus, ZAP70 can also function as a scaffold by recruiting additional factors to the stimulated TCR complex.
Expressed in T- and natural killer cells. Also present in early thymocytes and pro/pre B-cells.
Interacts with CD247/CD3Z; this interaction docks ZAP70 at the stimulated TCR (PubMed:1423621, PubMed:7659156, PubMed:26783323). Interacts with NFAM1 (PubMed:15143214). Interacts with adapter protein SLA; this interaction negatively regulates T-cell receptor signaling (PubMed:10449770). Interacts with FCRL3 (PubMed:12051764, PubMed:19843936). Interacts with VAV1 (PubMed:9151714). Interacts with CBL; this interaction promotes ubiquitination, internalization and subsequent degradation of CD247/CD3Z (PubMed:10449770, PubMed:10078535). Identified in a complex with CBL and UBE2L3 (PubMed:10966114). Interacts with SHB (PubMed:12084069). Interacts with adapter protein SLA2; this interaction negatively regulates T-cell receptor signaling. Interacts with CBLB. Interacts (via SH2 domains) with RHOH; this interaction regulates ZAP70 subcellular localization. Interacts with DEF6 (By similarity). Interacts (ubiquitinated form) with OTUD7B and UBASH3B (PubMed:26903241).
Phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation. Phosphorylation of Tyr-315 and Tyr-319 are essential for ZAP70 positive function on T-lymphocyte activation whereas Tyr-292 has a negative regulatory role. Within the C-terminal kinase domain, Tyr-492 and Tyr-493 are phosphorylated after TCR induction, Tyr-492 playing a negative regulatory role and Tyr-493 a positive. Tyr-493 is dephosphorylated by PTN22.
Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR).
Ubiquitinated in response to T cell activation. Deubiquitinated by OTUD7B.
Expressed in heart, spleen, testis and, to a lower extent, in thymus and peripheral blood leukocytes. Weakly expressed in lung, placenta, colon and small intestine.
Homodimer; the homodimer is independent of 2Fe-2S clusters (PubMed:27519415). Heterotrimer; forms a heterotrimeric complex composed by two BOLA2 molecules and one GLRX3 molecule; linked by [2Fe-2S] clusters (PubMed:22309771, PubMed:26613676, PubMed:27519415). Interacts (via N-terminus) with PRKCQ/PKC-theta (PubMed:10636891). Interacts (via C-terminus) with CSRP3 (By similarity). Interacts with CSRP2 (By similarity).
Silencing of Grx3 in HeLa cells decreases the activities of several cytosolic Fe/S proteins, such as ACO1, a major component of post-transcriptional iron regulation. As a consequence, Grx3-depleted cells show decreased levels of ferritin and increased levels of transferrin receptor, features characteristic of cellular iron starvation (PubMed:23615448).
The thioredoxin domain lacks the two redox-active cysteines. This strongly suggests that it lacks thioredoxin activity.
Together with BOLA2, acts as a cytosolic iron-sulfur (Fe-S) cluster assembly factor that facilitates [2Fe-2S] cluster insertion into a subset of cytosolic proteins (PubMed:26613676, PubMed:27519415). Acts as a critical negative regulator of cardiac hypertrophy and a positive inotropic regulator (By similarity). Required for hemoglobin maturation (PubMed:23615448). Does not possess any thyoredoxin activity since it lacks the conserved motif that is essential for catalytic activity.
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. Together with SUFU, prevents nuclear import of GLI1, and thereby inhibits GLI1 transcription factor activity. Regulates GLI1 in differentiating chondrocytes. Likewise, regulates GLI3 proteolytic processing and modulates GLI2 and GLI3 transcription factor activity. Plays a role in autophagic vacuole assembly, and mediates defense against pathogens, such as S.aureus, by promoting their capture by autophagosomes that then merge with lysosomes.
Expressed in all tissues tested, including pancreas, heart, muscle, kidney, liver, lung and brain. Highest levels in pancreas.
Inhibited by apstatin and the metal ion chelators EDTA and 1,10-phenanthroline (PubMed:11106490). Partially inhibited by dithiothreitol. Not inhibited by enalaprilat or amastatin (PubMed:11106490). Specifically inhibited by the pseudodipeptide CQ31 (PubMed:35165443). Inhibition by CQ31 indirectly activates the CARD8 inflammasome: dipeptide accumulation following PEPD inactivation weaky inhibit dipeptidyl peptidases DDP8 and DPP9, relieving DPP8- and/or DPP9-mediated inhibition of CARD8 (PubMed:35165443).
Metalloaminopeptidase that catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Arg-Pro-Pro (PubMed:11106490, PubMed:35165443, PubMed:18515364). Contributes to the degradation of bradykinin (PubMed:11106490).
Component of the ribosome quality control complex (RQC), composed of the E3 ubiquitin ligase LTN1, TCF25 and NEMF associated with the 60S ribosomal subunit (PubMed:25578875). The complex probably also contains VCP/p97 and its ubiquitin-binding cofactors (By similarity).
E3 ubiquitin-protein ligase component of the ribosome quality control complex (RQC), a ribosome-associated complex that mediates ubiquitination and extraction of incompletely synthesized nascent chains for proteasomal degradation (PubMed:23685075, PubMed:25132172, PubMed:25578875, PubMed:28757607). Within the RQC complex, LTN1 is recruited to stalled 60S ribosomal subunits by NEMF and mediates ubiquitination of stalled nascent chains (PubMed:25578875). Ubiquitination leads to VCP/p97 recruitment for extraction and degradation of the incomplete translation product (By similarity).
Interacts with VCP (By similarity). Part of a SCF (SKP1-cullin-F-box) protein ligase complex. Interacts with CHEK1 and CUL1.
Substrate-recognition component of some SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complexes. Involved in endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins by recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation. Able to recognize and bind denatured glycoproteins, which are modified with not only high-mannose but also complex-type oligosaccharides. Also recognizes sulfated glycans. Also involved in DNA damage response by specifically recognizing activated CHEK1 (phosphorylated on 'Ser-345'), promoting its ubiquitination and degradation. Ubiquitination of CHEK1 is required to ensure that activated CHEK1 does not accumulate as cells progress through S phase, or when replication forks encounter transient impediments during normal DNA replication.
Protein phosphatase 6 (PP6) holoenzyme is proposed to be a heterotrimeric complex formed by the catalytic subunit, a SAPS domain-containing subunit (PP6R) and an ankyrin repeat-domain containing regulatory subunit (ARS). Interacts with PPP1C and HNRPK. Interacts with PPP6C, PPP6R1 and PPP6R3.
Putative regulatory subunit of protein phosphatase 6 (PP6) that may be involved in the recognition of phosphoprotein substrates. Involved in the PP6-mediated dephosphorylation of NFKBIE opposing its degradation in response to TNF-alpha. Selectively inhibits the phosphatase activity of PPP1C. Targets PPP1C to modulate HNRPK phosphorylation.
Expressed in breast cancer cell lines (at protein level).
Results from the insertion of a beta-actin fragment at the C-terminus in the POTEE paralog gene leading to the formation of a new functional chimeric protein. This insertion occured before the divergence of the Old World monkeys and apes.
A stop codon at position Trp-66 in the gene coding for this protein is responsible for functional diversity thus producing a pseudogene. The stop codon is more frequent in African-Americans than in non-Africans.
(Microbial infection) Monomeric actin is cross-linked by V.cholerae toxins RtxA and VgrG1 in case of infection: bacterial toxins mediate the cross-link between Lys-51 of one monomer and Glu-271 of another actin monomer, resulting in formation of highly toxic actin oligomers that cause cell rounding (PubMed:19015515). The toxin can be highly efficient at very low concentrations by acting on formin homology family proteins: toxic actin oligomers bind with high affinity to formins and adversely affect both nucleation and elongation abilities of formins, causing their potent inhibition in both profilin-dependent and independent manners (PubMed:26228148).
In the intestine, abundantly expressed in smooth muscle cells of muscularis mucosa and muscularis propria. Also detected in intestinal vascular smooth muscle cells.
Monomethylation at Lys-85 (K84me1) regulates actin-myosin interaction and actomyosin-dependent processes. Demethylation by ALKBH4 is required for maintaining actomyosin dynamics supporting normal cleavage furrow ingression during cytokinesis and cell migration.
Oxidation of Met-45 and Met-48 by MICALs (MICAL1, MICAL2 or MICAL3) to form methionine sulfoxide promotes actin filament depolymerization. MICAL1 and MICAL2 produce the (R)-S-oxide form. The (R)-S-oxide form is reverted by MSRB1 and MSRB2, which promotes actin repolymerization.
Deubiquitinase that plays a role in different processes including cell cycle regulation, mitophagy or endoplasmic reticulum stress (PubMed:26348204, PubMed:29449677, PubMed:37004621). Inhibits TNFalpha-induced NF-kappa-B activation through stabilizing TNIP2 protein via deubiquitination (PubMed:26348204). Plays an essential role during mitosis by deubiquitinating and thereby regulating the levels of Aurora B/AURKB protein (PubMed:29449677). In addition, regulates the protein levels of other key component of the chromosomal passenger complex (CPC) such as survivin/BIRC5 or Borealin/CDCA8 by enhancing their stability (PubMed:34438346). Regulates the degradation of mitochondria through the process of autophagy termed mitophagy (PubMed:25915564).
Expressed in testis, pancreas and skeletal muscle.
Homodimer (via C-terminal region). Interacts with HSP90AA1.
Ubiquitinated by CHIP/STUB1 in an HSP90-dependent manner; leading to proteasomal degradation. This ubiquitination can be reversed through auto-deubiquitinating activity.
Down-regulated by gonadotropin suppression sufficient to cause marked suppression of spermatogenesis and additionally progestogen treatment.
Expressed in testis. Expressed in undifferentiated embryonic stem cells.
Interacts with UBR2; does not lead to TEX19 degradation and stabilizes it. Interacts with piRNA-associated proteins DDX4, EDC4, MAEL, PIWIL1, PIWIL2, RANBP9 and TDRD6 (By similarity). Interacts with L1RE1 (PubMed:28806172).
Required during spermatogenesis and placenta development, participating in the repression of retrotransposable elements and prevent their mobilization. Collaborates with the Piwi-interacting RNA (piRNA) pathway, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins. Interacts with Piwi proteins and directly binds piRNAs, a class of 24 to 30 nucleotide RNAs that are generated by a Dicer-independent mechanism and are primarily derived from transposons and other repeated sequence elements. Also during spermatogenesis, promotes, with UBR2, SPO11-dependent recombination foci to accumulate and drive robust homologous chromosome synapsis (By similarity). Interacts with LINE-1 retrotransposon encoded LIRE1, stimulates LIRE1 polyubiquitination, mediated by UBR2, and degradation, inhibiting LINE-1 retrotransposon mobilization (PubMed:28806172).
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cGMP subfamily.
Binding of cGMP results in enzyme activation.
Crucial regulator of intestinal secretion and bone growth. Phosphorylates and activates CFTR on the plasma membrane. Plays a key role in intestinal secretion by regulating cGMP-dependent translocation of CFTR in jejunum (PubMed:33106379). Acts downstream of NMDAR to activate the plasma membrane accumulation of GRIA1/GLUR1 in synapse and increase synaptic plasticity. Phosphorylates GRIA1/GLUR1 at Ser-863 (By similarity). Acts as regulator of gene expression and activator of the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2 in mechanically stimulated osteoblasts. Under fluid shear stress, mediates ERK activation and subsequent induction of FOS, FOSL1/FRA1, FOSL2/FRA2 and FOSB that play a key role in the osteoblast anabolic response to mechanical stimulation (By similarity).
Highly concentrated in brain, lung and intestinal mucosa.
Myristoylation mediates membrane localization.
Interacts (GTP-bound form) with SGSM1; the GDP-bound form has much lower affinity for SGSM1 (PubMed:22637480). The GTP-bound form but not the GDP-bound form interacts with HPS4 and the BLOC-3 complex (heterodimer of HPS1 and HPS4) but does not interact with HPS1 alone (PubMed:20048159).
Involved in the transport of proteins between the endosomes and the trans Golgi network.
Functions as an activator of the E3 ubiquitin protein ligase ITCH in the ubiquitination of the CXCL12-activated CXCR4 receptor. Thereby, triggers CXCR4 endocytosis and desensitization, negatively regulating the CXCL12/CXCR4 signaling pathway.
Interacts with ITCH; enhances the ubiquitination of CXCR4 by ITCH and the subsequent endocytosis and desensitization of the receptor (PubMed:34927784). Interacts with EPN1 (PubMed:34927784).
Monoubiquitinated at Lys-274, Lys-329 and Lys-365 by ITCH.
The cytoplasmic PPxY motifs mediate interaction with the WW domains of ITCH.
Belongs to the adenylate kinase family. AK6 subfamily.
Broad-specificity nucleoside monophosphate (NMP) kinase that catalyzes the reversible transfer of the terminal phosphate group between nucleoside triphosphates and monophosphates. AMP and dAMP are the preferred substrates, but CMP and dCMP are also good substrates. IMP is phosphorylated to a much lesser extent. All nucleoside triphosphates ATP, GTP, UTP, CTP, dATP, dCTP, dGTP, and TTP are accepted as phosphate donors. CTP is the best phosphate donor, followed by UTP, ATP, GTP and dCTP. May have a role in nuclear energy homeostasis. Has also ATPase activity. May be involved in regulation of Cajal body (CB) formation.
Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, chorionic villi and the central nervous system.
Monomer and homodimer (By similarity). Interacts with COIL (via C-terminus).
Plays a role in acrosome compaction and sperm morphogenesis (PubMed:21911476). Is implicated in sperm-oocyte interaction during fertilization (By similarity).
Functions as a coactivator for aryl hydrocarbon and nuclear receptors (NR). Recruited to promoters through its contact with the N-terminal basic helix-loop-helix-Per-Arnt-Sim (PAS) domain of transcription factors or coactivators, such as NCOA2. During ER-activation acts synergistically in combination with other NCOA2-binding proteins, such as EP300, CREBBP and CARM1. Involved in the transcriptional activation of target genes in the Wnt/CTNNB1 pathway. Functions as a secondary coactivator in LEF1-mediated transcriptional activation via its interaction with CTNNB1. Coactivator function for nuclear receptors and LEF1/CTNNB1 involves differential utilization of two different activation regions (By similarity). In association with CCAR1 enhances GATA1- and MED1-mediated transcriptional activation from the gamma-globin promoter during erythroid differentiation of K562 erythroleukemia cells (PubMed:24245781).
Part of a calphoglin complex consisting of CALCOCO1, PPA1 and PGM (Ref.1). Interacts with the bHLH-PAS domains of GRIP1, AHR and ARNT. Interacts with CTNNB1 via both its N- and C-terminal regions. Interacts with EP300. Interacts with CCAR1 (via N-terminus) and GATA1 (By similarity).
Recruitment by nuclear receptors is accomplished by the interaction of the coiled-coiled domain with p160 coactivators.
Seems to enhance inorganic pyrophosphatase thus activating phosphogluomutase (PMG). Probably functions as component of the calphoglin complex, which is involved in linking cellular metabolism (phosphate and glucose metabolism) with other core functions including protein synthesis and degradation, calcium signaling and cell growth.
The C-terminal activation region (AD) is used for downstream signaling. Seems to be essential for coactivator function with nuclear receptors and with the aryl hydrocarbon receptor (By similarity).
The N-terminal activation region (AD) is necessary and sufficient for synergistic activation of LEF1-mediated transcription by CTNNB1. Contains a EP3000 binding region which is important for synergistic cooperation (By similarity).
The inactive holoenzyme is composed of two regulatory chains and two catalytic chains. Activation by cAMP releases the two active catalytic monomers and the regulatory dimer. Interacts with PRKACA and PRKACB (PubMed:33058759). PRKAR1A also interacts with RFC2; the complex may be involved in cell survival. Interacts with AKAP4. Interacts with RARA; the interaction occurs in the presence of cAMP or FSH and regulates RARA transcriptional activity. Interacts with the phosphorylated form of PJA2. Interacts with CBFA2T3 (By similarity). Interacts with PRKX; regulates this cAMP-dependent protein kinase. Interacts with C2orf88/smAKAP; this interaction may target PRKAR1A to the plasma membrane. Interacts with AICDA.
By IFN-alpha and by IL1B/interleukin-1 beta. Up-regulated in articular cartilage and synovium from arthritis patients. Up-regulared in chondrocytes.
Metalloprotease that may play a role in the degradation of COMP. Cleaves also alpha-2 macroglobulin and aggregan. Has anti-tumorigenic properties.
Subjected to an intracellular maturation process yielding a 120 kDa N-terminal fragment containing the metalloproteinase, disintegrin, one TSP type-1 and the Cys-rich domains and a 83 kDa C-terminal fragment containing the spacer 2 and four TSP type-1 domains.
The C-terminal four TSP1-like repeats are necessary and sufficient for binding COMP.
Was reported to be expressed in adult skeletal muscle and fat, in fetal lung, and in gastric carcinomas and cancer cells of diverse origin (PubMed:11279086). However, this paper has been retracted because data in one figure has been falsified (PubMed:30808000).
Binds to and activates the CDH5 promoter, hence plays a role in the transcriptional regulation of genes expressed in the hemogenic endothelium and blocks further differentiation into blood precursors (By similarity). May be required for the survival of both hematopoietic and endothelial precursors during specification (By similarity). Competes with GATA4 for binding and activation of the FGF3 promoter (By similarity). Represses Wnt/beta-catenin-stimulated transcription, probably by targeting CTNNB1 to proteasomal degradation. Binds the DNA sequence 5'-AACAAT-3'.
In 8 week-old embryo, expressed in brain, tongue, heart, liver, lung and vertebrae.
Interacts with CTNNB1/beta-catenin; this interaction may lead to the proteasomal degradation of active CTNNB1 and thus inhibition of Wnt/beta-catenin-stimulated transcription.
Widely expressed in adult and fetal tissues. Present both in mesenchymal and epithelial cells in some adult tissues, including colon. Tends to be down-regulated in prostate adenocarcinomas and colorectal tumors due to promoter hypermethylation.
Interacts with ENG/endoglin, TGFBR2 and TGFBR3 (PubMed:16982625). Interacts with PPP1CC (PubMed:23789093).
Ubiquitously expressed (PubMed:16982625). Expressed in testis (at protein level) (PubMed:23789093).
Binds to the promoter region of genes encoding proteolipid proteins of the central nervous system. May play a role in the development of neurons and oligodendroglia in the CNS. May regulate a critical transition point in oligodendrocyte lineage development by modulating oligodendrocyte progenitor proliferation relative to terminal differentiation and up-regulation of myelin gene transcription.
Contains 7 zinc fingers of the C2HC class arranged in two widely separated clusters. These two domains of DNA binding can function independently and recognize the same DNA sequence.
Mostly in developing nervous system. Expressed in neural progenitors and oligodendrocyte lineage cells. More highly expressed in oligodendrocyte progenitors than in differentiated oligodendrocytes.
Expressed at high level in brain, testis, spleen and thymus. Expressed at intermediate level in kidney, liver, mammary gland and skin.
Interacts with MSX2 and HIPK3 (By similarity). Interacts with NCOR2, HDAC1, HDAC2, RBBP4, MBD3 and MTA1L1. Interacts with RBPSUH; this interaction may prevent the interaction between RBPSUH and NOTCH1. Interacts with the nuclear receptors RAR and PPARD. Interacts with RAR in absence of ligand. Binds to the steroid receptor RNA coactivator SRA.
May serve as a nuclear matrix platform that organizes and integrates transcriptional responses. In osteoblasts, supports transcription activation: synergizes with RUNX2 to enhance FGFR2-mediated activation of the osteocalcin FGF-responsive element (OCFRE) (By similarity). Has also been shown to be an essential corepressor protein, which probably regulates different key pathways such as the Notch pathway. Negative regulator of the Notch pathway via its interaction with RBPSUH, which prevents the association between NOTCH1 and RBPSUH, and therefore suppresses the transactivation activity of Notch signaling. Blocks the differentiation of precursor B-cells into marginal zone B-cells. Probably represses transcription via the recruitment of large complexes containing histone deacetylase proteins. May bind both to DNA and RNA.
The RID domain mediates the interaction with nuclear receptors.
The SPOC domain, which mediates the interaction with NCOR2, is essential for the repressive activity.
Lysosomal acid phosphatase has been shown to be deficient in cultured fibroblasts from patients manifesting intermittent vomiting, hypotonia, lethargy, opisthotonos, terminal bleeding and death in early infancy.
N-glycosylated. The intermediates formed during enzymatic deglycosylation suggest that all eight predicted N-glycosylation sites are used.
The membrane-bound form is converted to the soluble form by sequential proteolytic processing. First, the C-terminal cytoplasmic tail is removed. Cleavage by a lysosomal protease releases the soluble form in the lysosome lumen.
Human saliva appears to contain several cysteine proteinase inhibitors that are immunologically related to cystatin S but that differ in their specificity due to amino acid sequence differences. Cystatin SN, with a pI of 7.5, is a much better inhibitor of papain and dipeptidyl peptidase I than is cystatin S, although both inhibit ficin equally well.
Asymmetric arginine dimethylation by PRMT3 occurs at multiple sites in the Arg/Gly-rich region.
Citrullinated by PADI4 in the Arg/Gly-rich region.
Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399). The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules (PubMed:23636399). The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain (PubMed:23636399). The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel (PubMed:23636399). Plays a role in the assembly and function of the 40S ribosomal subunit (By similarity). Mutations in this protein affects the control of translational fidelity (By similarity). Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly (By similarity).
Component of the small ribosomal subunit (PubMed:23636399). Interacts with zinc finger protein ZNF277 (via zinc-finger domains); the interaction is direct; the interaction is extra-ribosomal (PubMed:30530495). Interaction with ZNF277 competes with the binding of RPS2 to protein arginine methyltransferase PRMT3 (PubMed:30530495).
Monoubiquitinated at Lys-54 and Lys-58 by RNF10 when a ribosome has stalled during translation, leading to its degradation by the proteasome (PubMed:34348161, PubMed:34469731). Deubiquitinated at Lys-54 and Lys-58 by USP10, preventing degradation by the proteasome and promoting 40S ribosome subunit recycling following ribosome dissociation (PubMed:31981475).
Belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM3 sub-subfamily.
Calcium channel mediating constitutive calcium ion entry. Its activity is increased by reduction in extracellular osmolarity, by store depletion and muscarinic receptor activation. In addition, forms heteromultimeric ion channels with TRPM1 which are permeable for calcium and zinc ions (PubMed:21278253).
Expressed primarily in the kidney and, at lower levels, in brain, testis, ovary, pancreas and spinal cord. Expression in the brain and kidney was determined at protein level. In the kidney, expressed predominantly in the collecting tubular epithelium in the medulla, medullary rays, and periglomerular regions; in the brain, highest levels are found in the cerebellum, choroid plexus, the locus coeruleus, the posterior thalamus and the substantia nigra. Down-regulated in renal tumors compared to normal kidney. Expressed in the lens (PubMed:25090642).
Interacts with TRPM1; the interaction results in the formation of a heteromultimeric cation channel complex.
Highly expressed in hematopoietic tissues, in leukemic and lymphoma cell lines, testis, small intestine, colon and colorectal adenocarcinoma cells. Weakly expressed in normal liver, but highly expressed in hepatocellular carcinoma tissues.
Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression, the regulation of cap-dependent protein translation and through survival signaling by phosphorylation of a pro-apoptotic protein, BAD. Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase transcriptional activity. The stabilization of MYC exerted by PIM2 might explain partly the strong synergism between these 2 oncogenes in tumorigenesis. Regulates cap-dependent protein translation in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner and in parallel to the PI3K-Akt pathway. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Promotes cell survival in response to a variety of proliferative signals via positive regulation of the I-kappa-B kinase/NF-kappa-B cascade; this process requires phosphorylation of MAP3K8/COT. Promotes growth factor-independent proliferation by phosphorylation of cell cycle factors such as CDKN1A and CDKN1B. Involved in the positive regulation of chondrocyte survival and autophagy in the epiphyseal growth plate.
Part of a SCF (SKP1-cullin-F-box) protein ligase complex. According to PubMed:34595750 interaction with SKP1 does not occur. Interacts with ANAPC2; the interaction is direct, ANAPC4, CDC16, CDC23; the interaction is direct, ANAPC10; the interaction is direct and CDC26, during spermatogenesis (PubMed:34595750). May interact with CDC20 (By similarity).
Phosphorylated on Ser-76, Thr-234 and Ser-334 in response to calcium, which is a prerequisite for ubiquitination and proteasomal degradation.
Required to establish and maintain the arrest of oocytes at the second meiotic metaphase until fertilization. Acts by inhibiting the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase. Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation (PubMed:34052850, PubMed:34595750). Plays a vital role in modulating the ubiquitilation of CCNB1 and CDK1 during gametogenesis.
Ubiquitinated in response to calcium, which promotes proteasomal degradation.
Expressed in brain, hippocampus, prefrontal cortex, cerebellum, spinal cord, testis, mammary gland, spleen and kidney. Also expressed in fetal brain.
Tissue-specific splicing factor with potential implication in the regulation of alternative splicing during neuron and germ cell differentiation. Antagonizes SRSF1-mediated BCL-X splicing. May affect the choice of alternative 5' splice sites by binding to specific sequences in exons and antagonizing the SR protein SRSF1.
Highly expressed in estrogen receptor-positive breast tumors.
May play a role in breast tumorigenesis by promoting estrogen-dependent cell proliferation, cell-cell interactions and migration.
Up-regulated upon treatment with estradiol in MCF-7 cells.
Detected in brain, placenta, ovary, testis and trachea (at protein level) (PubMed:10331944). Widely expressed (PubMed:10331944). Highly expressed in testis and in proliferating cells (PubMed:7479798, PubMed:10331944).
Export receptor for importin-alpha. Mediates importin-alpha re-export from the nucleus to the cytoplasm after import substrates (cargos) have been released into the nucleoplasm. In the nucleus binds cooperatively to importin-alpha and to the GTPase Ran in its active GTP-bound form. Docking of this trimeric complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the importin-alpha from the export receptor. CSE1L/XPO2 then return to the nuclear compartment and mediate another round of transport. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus.
Found in a complex with CSE1L/XPO2, Ran and KPNA2 (PubMed:9323134, PubMed:9786944). Binds with high affinity to importin-alpha only in the presence of RanGTP. The complex is dissociated by the combined action of RanBP1 and RanGAP1 (PubMed:9323134). Interacts with CFTR (PubMed:20933420).
Phosphorylated on Ser-99 by PKB/AKT2 after insulin treatment. Phosphorylation on Ser-99 abolishes the interaction with STX4A (By similarity).
Plays a role in the translocation of transport vesicles from the cytoplasm to the plasma membrane. Inhibits the translocation of SLC2A4 from intracellular vesicles to the plasma membrane by STX4A binding and preventing the interaction between STX4A and VAMP2. Stimulation with insulin disrupts the interaction with STX4A, leading to increased levels of SLC2A4 at the plasma membrane. May also play a role in the regulation of insulin release by pancreatic beta cells after stimulation by glucose (By similarity).
DNA binding protein that function as transcriptional activator. Is essential for normal postnatal growth and nursing. Is an essential factor for neuronal neuropeptide Y and agouti-related peptide function and locomotory behavior in the control of energy balance (By similarity).
Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation (PubMed:28561066). Binds phosphatidylinositol 3-phosphate (PtdIns3P), and other phosphoinositides including PtdIns(3,5)P2, forming on membranes of the endoplasmic reticulum upon activation of the upstream ULK1 and PI3 kinases and is recruited at phagophore assembly sites where it regulates the elongation of nascent phagophores downstream of WIPI2 (PubMed:28561066, PubMed:30797857). In the cellular response to starvation, may also function together with the TSC1-TSC2 complex and RB1CC1 in the inhibition of the mTORC1 signaling pathway (PubMed:28503735).
Interacts with the TSC1-TSC2 complex; stimulated upon starvation (PubMed:28561066). Interacts with RB1CC1 (PubMed:28561066). Interacts with ATG2A (PubMed:32483132).
Ubiquitously expressed. Highly expressed in heart, skeletal muscle and pancreas. Up-regulated in a variety of tumor tissues including ovarian and uterine cancers.
(Microbial infection) Interacts with human adenovirus 5 protein 100K; this interaction promotes translational shunt in presence of polysomes containing viral tripartite leader mRNAs.
(Microbial infection) Interacts with rotavirus A NSP3; in this interaction, NSP3 takes the place of PABPC1 thereby inducing shutoff of host protein synthesis.
Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome (PubMed:29987188). Exists in two complexes, either with EIF1 or with EIF4E (mutually exclusive) (PubMed:29987188). Together with EIF1, is required for leaky scanning, in particular for avoiding cap-proximal start codon (PubMed:29987188). Together with EIF4E, antagonizes the scanning promoted by EIF1-EIF4G1 and locates the start codon (through a TISU element) without scanning (PubMed:29987188). As a member of the eIF4F complex, required for endoplasmic reticulum stress-induced ATF4 mRNA translation (PubMed:29062139).
Phosphorylated at multiple sites in vivo. Phosphorylation at Ser-1185 by PRKCA induces binding to MKNK1.
Produced by alternative initiation at Met-165 of isoform A.
Produced by alternative initiation at Met-197 of isoform A.
Produced by alternative initiation at Met-41 of isoform A.
Produced by alternative initiation at Met-88 of isoform A.
eIF4F is a multi-subunit complex, the composition of which varies with external and internal environmental conditions. It is composed of at least EIF4A, EIF4E (cap-binding) and EIF4G1/EIF4G3 (PubMed:9372926, PubMed:7651417, PubMed:7935836). Interacts with eIF3 complex, mutually exclusive with EIF4A1 or EIF4A2, EIF4E and through its N-terminus with PABPC1 (PubMed:9857202, PubMed:9372926, PubMed:7651417, PubMed:7935836, PubMed:10996799, PubMed:10970864, PubMed:12086624, PubMed:16698552). Interacts with EIF4E or with EIF1 (mutually exclusive) through a common binding site (PubMed:29987188). Interacts through its C-terminus with the serine/threonine kinases MKNK1, and with MKNK2 (PubMed:9878069, PubMed:11154262). Appears to act as a scaffold protein, holding these enzymes in place to phosphorylate EIF4E (PubMed:9878069, PubMed:11154262). Non-phosphorylated EIF4EBP1 competes with EIF4G1/EIF4G3 to interact with EIF4E; insulin stimulated MAP-kinase (MAPK1 and MAPK3) phosphorylation of EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation (PubMed:8521827). EIF4G1/EIF4G3 interacts with PABPC1 to bring about circularization of the mRNA (PubMed:9857202, PubMed:10996799, PubMed:10970864, PubMed:12086624). Interacts with EIF4E3 (By similarity). Interacts with CIRBP and MIF4GD (PubMed:10996799, PubMed:10970864, PubMed:16513844, PubMed:18025107). Interacts with RBM4 (PubMed:17284590). Interacts with HNRNPD/AUF1; the interaction requires RNA (PubMed:24423872). Interacts with DDX3X; the interaction requires RNA (PubMed:22872150). Interacts with DAZAP2 (PubMed:17984221).
Activated by an increase in cytosolic calcium levels that induce a conformational change of the N-terminal regulatory domain, uncapping the channel and allowing transport (PubMed:22015608, PubMed:24332718, PubMed:26164100). Inhibited by bathophenanthroline, mersalyl, p-hydroxymercuribenzoate, bromcresol purple and tannic acid (PubMed:15123600).
Electroneutral antiporter that mediates the transport of adenyl nucleotides through the inner mitochondrial membrane. Originally identified as an ATP-magnesium/inorganic phosphate antiporter, it also acts as a broad specificity adenyl nucleotide antiporter. By regulating the mitochondrial matrix adenyl nucleotide pool could adapt to changing cellular energetic demands and indirectly regulate adenyl nucleotide-dependent metabolic pathways (PubMed:15123600, PubMed:22015608). In vitro, a low activity is also observed with guanyl and pyrimidine nucleotides (PubMed:15123600). May play a role in protecting cells against oxidative stress-induced cell death, by buffering calcium levels in the mitochondrial matrix through the formation of calcium-phosphate precipitates (PubMed:22015608, PubMed:29100093).
Expressed in all tissues tested. Highly expressed in testis, expressed at intermediate level in small intestine and pancreas, and weakly expressed in kidney, spleen, liver, skeletal muscle and heart.
The regulatory N-terminal domain/NTD formed of two pairs of fused calcium-binding EF-hands, binds calcium in the mitochondrial intermembrane space and regulates the antiporter activity of the transmembrane domain/TMD. In absence of calcium, the apo form of the N-terminal domain is intrinsically disordered and binds to the transmembrane domain, inhibiting the transporter activity. Binding of calcium leads to a major conformational change and abolishes the interaction with the transmembrane domain and the inhibition of the transporter activity (PubMed:24332718).
Acetylated by KAT5/TIP60 under autophagy induction, promoting autophagosome maturation and lipid metabolism (PubMed:30704899). Acetylation is prevented by phosphorylation by MTOR (PubMed:30704899). Lys-483 and Lys-573 constitute the key sites for tuning function in autophagy (PubMed:30704899).
Expressed weakly in cervical carcinoma cell lines.
Interacts with UVRAG; the interaction is direct and promotes association with the PI3K/PI3KC3 and HOPS complexes (PubMed:28306502). Interacts with STX17 (PubMed:28306502, PubMed:30704899).
Phosphorylated by MTOR at Ser-157 under nutrient-rich conditions (PubMed:30704899). Phosphorylation prevents acetylation by KAT5/TIP60 and impairs RUBCNL/PACER function and autophagosome maturation (PubMed:30704899). Under autophagy induction, Phosphorylation by MTOR is repressed, enabling acetylation by KAT5/TIP60 (PubMed:30704899).
Regulator of autophagy that promotes autophagosome maturation by facilitating the biogenesis of phosphatidylinositol 3-phosphate (PtdIns(3)P) in late steps of autophagy (PubMed:28306502, PubMed:30704899). Acts by antagonizing RUBCN, thereby stimulating phosphatidylinositol 3-kinase activity of the PI3K/PI3KC3 complex (PubMed:28306502). Following anchorage to the autophagosomal SNARE STX17, promotes the recruitment of PI3K/PI3KC3 and HOPS complexes to the autophagosome to regulate the fusion specificity of autophagosomes with late endosomes/lysosomes (PubMed:28306502). Binds phosphoinositides phosphatidylinositol 3-phosphate (PtdIns(3)P), 4-phosphate (PtdIns(4)P) and 5-phosphate (PtdIns(5)P) (PubMed:28306502). In addition to its role in autophagy, acts as a regulator of lipid and glycogen homeostasis (By similarity). May act as a tumor suppressor (Probable).
Up-regulated by epigenetic drugs, such as azacitidine, and artificial transcription factors (ATFs)-induced treatments in cervical carcinoma cell lines.
Transcription factor involved in erythroid differentiation. Involved in transcriptional activation of the globin gene.
A chromosomal aberration involving RERE is found in the neuroblastoma cell line NGP. Translocation t(1;15)(p36.2;q24).
Interacts with HDAC1 (By similarity). Interacts with ATN1. Interaction with ATN1 is improved when the poly-Gln region of ATN1 is extended. Interacts with FAT1.
Plays a role as a transcriptional repressor during development. May play a role in the control of cell survival. Overexpression of RERE recruits BAX to the nucleus particularly to POD and triggers caspase-3 activation, leading to cell death.
The interaction with ATN1 is mediated by the coiled coil domain.
Widely expressed. Expressed in tumor cell lines.
May promote the activation of caspase-3 and apoptosis.
Ubiquitous, with the highest levels of expression in heart, placenta and pancreas.
Responsible for the disassembly of ribosomes from messenger RNA at the termination of mitochondrial protein biosynthesis (PubMed:19716793, PubMed:33878294). Acts in collaboration with GFM2 (PubMed:33878294). Promotes mitochondrial ribosome recycling by dissolution of intersubunit contacts (PubMed:33878294).
Actin cytoskeleton-organizing protein that plays a role in the formation of cell projections (PubMed:20215400). Required for actin polymerization at immunological synapses (IS) and for the recruitment of the chemokine receptor CXCR4 to IS (PubMed:20215400). Plays a role in dendritic spine morphogenesis and organization, including the localization of the dopamine receptor DRD1 to the dendritic spines (By similarity). Involved in memory-related synaptic plasticity in the hippocampus (By similarity).
Expressed in the brain, with expression in the molecular layer of the dentate gyrus, stratum pyramidale, and stratum radiatum of the hippocampus (at protein level) (PubMed:8838578). Also expressed in the terminal varicosities distributed along dendritic trees of pyramidal cells in CA4 and CA3 of the hippocampus (at protein level) (PubMed:8838578). Expressed in pyramidal cells in CA2, CA1 and the subiculum of the hippocampus (at protein level) (PubMed:8838578). Expressed in peripheral blood lymphocytes, including T-cells (at protein level) (PubMed:20215400). Expressed in the brain (PubMed:8216329, Ref.2). Expressed in the heart, placenta, lung, skeletal muscle, kidney, pancreas, skin fibroblasts, gingival fibroblasts and bone-derived cells (Ref.2).
Interacts with RUFY3 (By similarity). Interacts with CXCR4; this interaction is enhanced by antigenic stimulation (PubMed:20215400). Interacts (via ADF-H domain) with ZMYND8 (via N-terminus); the interaction leads to sequestering of ZMYND8 in the cytoplasm (PubMed:28966017, PubMed:35916866).
The protein represented in this entry may be involved in disease pathogenesis. In brains of patients with AD, decreased expression and absence from dystrophic neurites in amyloid plaques. Disappearance of debrin from the hippocampus may contribute to the pathogenesis of memory disturbance in AD.
Binding partner of the GTPase-activating protein FLCN: involved in the cellular response to amino acid availability by regulating the non-canonical mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:18663353, PubMed:31672913, PubMed:36103527). Required to promote FLCN recruitment to lysosomes and interaction with Rag GTPases, leading to activation of the non-canonical mTORC1 signaling (By similarity). In low-amino acid conditions, component of the lysosomal folliculin complex (LFC) on the membrane of lysosomes, which inhibits the GTPase-activating activity of FLCN, thereby inactivating mTORC1 and promoting nuclear translocation of TFEB and TFE3 (PubMed:31672913, PubMed:36103527). Upon amino acid restimulation, disassembly of the LFC complex liberates the GTPase-activating activity of FLCN, leading to activation of mTORC1 and subsequent inactivation of TFEB and TFE3 (PubMed:31672913). Together with FLCN, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy (PubMed:25126726). In addition to its role in mTORC1 signaling, also acts as a co-chaperone of HSP90AA1/Hsp90: inhibits the ATPase activity of HSP90AA1/Hsp90, leading to activate both kinase and non-kinase client proteins of HSP90AA1/Hsp90 (PubMed:18403135). Acts as a scaffold to load client protein FLCN onto HSP90AA1/Hsp90 (PubMed:18403135). Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (PubMed:18403135). May play a role in the signal transduction pathway of apoptosis induced by O6-methylguanine-mispaired lesions (By similarity).
Homodimer and homomultimer (PubMed:18403135, PubMed:27353360). Heterodimer and heteromultimer with FNIP1 (PubMed:18403135, PubMed:27353360). Interacts (via C-terminus) with FLCN (via C-terminus) (PubMed:18403135, PubMed:18663353, PubMed:27353360, PubMed:36103527). Phosphorylated FLCN is preferentially bound (PubMed:18663353). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913, PubMed:36103527). Interacts with PRKAA1, PRKAB1 and PRKAG1 subunits of 5'-AMP-activated protein kinase (PubMed:18403135, PubMed:27353360). Interacts with HSP70, HSP90AA1, STIP1, PTGES3, CDC37, BRAF, GCR and CDK4 (PubMed:27353360).
Widely expressed with highest levels in muscle, nasal mucosa, salivary gland, uvula, fat, liver, heart, placenta and pancreas (PubMed:18403135, PubMed:18663353, PubMed:27353360). Moderately expressed in the lung, small intestine, kidney and brain. Lower levels detected in renal cell carcinoma than in normal kidney tissue (PubMed:18403135). Higher levels detected in oncocytoma tumors than in normal kidney. Higher levels detected in renal cell carcinoma tumors than in normal kidney tissue (PubMed:27353360).
Interacts (preferentially in its GTP-bound form) with GCC2 (via its GRIP domain) (PubMed:18243103, PubMed:16885419). Interacts (GTP-bound form) with SGSM1; the GDP-bound form has much lower affinity for SGSM1 (PubMed:22637480). Interacts with SGSM2 (PubMed:21808068). The GTP-bound form but not the GDP-bound form interacts with HPS4 and BLOC-3 complex (heterodimer of HPS1 and HPS4) but does not interact with HPS1 alone (PubMed:20048159).
Involved in the transport of proteins between the endosomes and the trans Golgi network. Involved in the recruitment of SGSM2 to melanosomes and is required for the proper trafficking of melanogenic enzymes TYR, TYRP1 and DCT/TYRP2 to melanosomes in melanocytes.
Mediates cellular uptake of transferrin-bound iron in a non-iron dependent manner. May be involved in iron metabolism, hepatocyte function and erythrocyte differentiation.
Predominantly expressed in liver. While the alpha form is also expressed in spleen, lung, muscle, prostate and peripheral blood mononuclear cells, the beta form is expressed in all tissues tested, albeit weakly.
The variant Lys-172 found in hereditary hemochromatosis type III affects the putative initiation codon of the beta isoform thus preventing its translation.
Activated by at least two different proteolytic cleavages producing a 56 kDa and a 50 kDa form.
Autoinhibited. In the autoinhibited state, the TPR domain interacts with the catalytic region and prevents substrate access to the catalytic pocket. Allosterically activated by various polyunsaturated fatty acids, free long-chain fatty-acids and long-chain fatty acyl-CoA esters, arachidonic acid being the most effective activator. HSP90A and probably RAC1, GNA12 and GNA13 can also release the autoinhibition by the TPR repeat. Activation by RAC1, GNA12 and GNA13 is synergistic with the one produced by fatty acids binding. Inhibited by okadaic acid.
Belongs to the PPP phosphatase family. PP-5 (PP-T) subfamily.
Binds 2 Mg(2+) or Mn(2+) cations per subunit.
Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Part of a complex with HSP90/HSP90AA1 and steroid receptors (By similarity). Interacts (via TPR repeats) with HSP90AA1 (via TPR repeat-binding motif) or HSPA1A/HSPA1B; the interaction is direct and activates the phosphatase activity (PubMed:15383005, PubMed:15577939, PubMed:16531226). Dissociates from HSPA1A/HSPA1B and HSP90AA1 in response to arachidonic acid (PubMed:15383005). Interacts with CPNE1 (via VWFA domain) (By similarity). Interacts with CDC16, CDC27 (PubMed:9405394). Interacts with KLHDC10 (via the 6 Kelch repeats); inhibits the phosphatase activity on MAP3K5 (PubMed:23102700). Interacts with ATM and ATR; both interactions are induced by DNA damage and enhance ATM and ATR kinase activity (PubMed:14871926). Interacts with RAD17; reduced by DNA damage (PubMed:14871926). Interacts with nuclear receptors such as NR3C1/GCR and PPARG (activated by agonist); regulates their transactivation activities (By similarity). Interacts (via TPR repeats) with S100 proteins S100A1, S100A2, S100A6, S100B and S100P; the interactions are calcium-dependent, strongly activate PPP5C phosphatase activity and compete with HSP90AA1 and MAP3K5 interactions (PubMed:22399290). Interacts with SMAD2 and SMAD3 but not with SMAD1; decreases SMAD3 phosphorylation and protein levels (PubMed:22781750). Interacts (via TPR repeats) with CRY1 and CRY2; the interaction with CRY2 down-regulates the phosphatase activity on CSNK1E (PubMed:16790549). Interacts (via TPR repeats) with the active form of RAC1, GNA12 or GNA13; these interactions activate the phosphatase activity and translocate PPP5C to the cell membrane (PubMed:19948726). Interacts with FLCN (PubMed:27353360).
Serine/threonine-protein phosphatase that dephosphorylates a myriad of proteins involved in different signaling pathways including the kinases CSNK1E, ASK1/MAP3K5, PRKDC and RAF1, the nuclear receptors NR3C1, PPARG, ESR1 and ESR2, SMAD proteins and TAU/MAPT (PubMed:14734805, PubMed:14764652, PubMed:14871926, PubMed:15383005, PubMed:15546861, PubMed:16260606, PubMed:16790549, PubMed:16892053, PubMed:19176521, PubMed:19948726, PubMed:21144835, PubMed:22399290, PubMed:22781750, PubMed:23102700, PubMed:9000529, PubMed:30699359). Implicated in wide ranging cellular processes, including apoptosis, differentiation, DNA damage response, cell survival, regulation of ion channels or circadian rhythms, in response to steroid and thyroid hormones, calcium, fatty acids, TGF-beta as well as oxidative and genotoxic stresses (PubMed:14734805, PubMed:14764652, PubMed:14871926, PubMed:15383005, PubMed:15546861, PubMed:16260606, PubMed:16790549, PubMed:16892053, PubMed:19176521, PubMed:19948726, PubMed:21144835, PubMed:22399290, PubMed:22781750, PubMed:23102700, PubMed:9000529, PubMed:30699359). Participates in the control of DNA damage response mechanisms such as checkpoint activation and DNA damage repair through, for instance, the regulation ATM/ATR-signaling and dephosphorylation of PRKDC and TP53BP1 (PubMed:14871926, PubMed:16260606, PubMed:21144835). Inhibits ASK1/MAP3K5-mediated apoptosis induced by oxidative stress (PubMed:23102700). Plays a positive role in adipogenesis, mainly through the dephosphorylation and activation of PPARG transactivation function (By similarity). Also dephosphorylates and inhibits the anti-adipogenic effect of NR3C1 (By similarity). Regulates the circadian rhythms, through the dephosphorylation and activation of CSNK1E (PubMed:16790549). May modulate TGF-beta signaling pathway by the regulation of SMAD3 phosphorylation and protein expression levels (PubMed:22781750). Dephosphorylates and may play a role in the regulation of TAU/MAPT (PubMed:15546861). Through their dephosphorylation, may play a role in the regulation of ions channels such as KCNH2 (By similarity). Dephosphorylate FNIP1, disrupting interaction with HSP90AA1/Hsp90 (PubMed:30699359).
Moderately expressed in tissues and specific brain regions examined.
Regulatory subunit of serine/threonine-protein phosphatase 4 (PP4). May regulate the activity of PPP4C at centrosomal microtubule organizing centers.
Serine/threonine-protein phosphatase 4 (PP4) occurs in different assemblies of the catalytic and one or more regulatory subunits. Component of the PP4 complex PPP4C-PPP4R2-PPP4R3B.
Highly expressed in testis, less abundant in ovary.
GTPase-activating protein for ADP ribosylation factor family members, including ARF1.
May form heterooligomers with GIT1 (By similarity). Directly interacts with protein Piccolo/PCLO (By similarity). Interacts with PPFIA1 and PPFIA2 (By similarity). Interacts with ARHGEF7 (PubMed:10896954). Identified in a complex with ARHGEF6 and BIN2 (PubMed:23285027). Interacts with PAK3 (PubMed:10896954). Interacts with PXN/paxillin (PubMed:11251077). Interacts with TGFB1I1 (By similarity). Forms a complex with EFNB1 and GRB4/NCK2 (By similarity).
Widely expressed. Expressed in adipose tissue and at high levels in testis and pancreas. Expressed at lower levels in tissues such as heart, brain, placenta, kidney, lung, spleen, thymus, prostate, ovary, intestine, colon, leukocyte and liver.
AP-1 family transcription factor that controls the differentiation of CD8(+) thymic conventional dendritic cells in the immune system. Required for development of CD8-alpha(+) classical dendritic cells (cDCs) and related CD103(+) dendritic cells that cross-present antigens to CD8 T-cells and produce interleukin-12 (IL12) in response to pathogens (By similarity). Acts via the formation of a heterodimer with JUN family proteins that recognizes and binds DNA sequence 5'-TGA[CG]TCA-3' and regulates expression of target genes.
Heterodimer; heterodimerizes with JUN family proteins. Interacts with JUN.
EF-1 is composed of four subunits: alpha, beta, delta, and gamma.
Highly expressed in pancreatic tumor tissue and to a lesser extent in normal kidney, intestine, pancreas, stomach, lung, brain, spleen and liver.
Probably plays a role in anchoring the complex to other cellular components.
Plays an important role in the regulation of embryonic development, cell proliferation, and cell differentiation. Required for normal ear development.
HeLa cells lacking SH3GLB1 show dissociation of outer and inner mitochondrial membrane as well as abnormal mitochondrial morphology. Cells overexpressing SH3GLB1 lacking an N-terminal amphipathic helix show a similar phenotype.
Highly expressed in heart, skeletal muscle, kidney and placenta. Detected at lower levels in brain, colon, thymus, spleen, liver, small intestine, lung and peripheral blood leukocytes.
Homodimer, and heterodimer with SH3GLB2 (PubMed:11161816). Binds BAX; induction of apoptosis augments BAX binding (PubMed:11161816, PubMed:11259440). Binds DNM1, HTT, AMPH, BIN1 and ARFGAP1 (By similarity). Interacts with UVRAG; UVRAG bridges the interaction to BECN1 indicative for an association with the PI3K complex II (PI3KC3-C2) (PubMed:17891140, PubMed:20643123).
May be required for normal outer mitochondrial membrane dynamics (PubMed:15452144). Required for coatomer-mediated retrograde transport in certain cells (By similarity). May recruit other proteins to membranes with high curvature. May promote membrane fusion (PubMed:11604418). Involved in activation of caspase-dependent apoptosis by promoting BAX/BAK1 activation (PubMed:16227588). Isoform 1 acts proapoptotic in fibroblasts (By similarity). Involved in caspase-independent apoptosis during nutrition starvation and involved in the regulation of autophagy. Activates lipid kinase activity of PIK3C3 during autophagy probably by associating with the PI3K complex II (PI3KC3-C2) (PubMed:17891140). Associated with PI3KC3-C2 during autophagy may regulate the trafficking of ATG9A from the Golgi complex to the peripheral cytoplasm for the formation of autophagosomes by inducing Golgi membrane tubulation and fragmentation (PubMed:21068542). Involved in regulation of degradative endocytic trafficking and cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20643123). Isoform 2 acts antiapoptotic in neuronal cells; involved in maintenance of mitochondrial morphology and promotes neuronal viability (By similarity).
Phosphorylated at Thr-145 by CDK5; this phosphorylation is required for autophagy induction in starved neurons and facilitates homodimerization.
SH3GLB1 binds liposomes and induces formation of tubules from liposomes. SH3GLB1 lacking the N-terminal amphipathic helix fails to induce liposome tubulation.
The SH3 domain is required and sufficient for the interaction with UVRAG.
Was originally thought to have lysophosphatidic acid acyltransferase activity, but by homology with SH3GL2/endophilin A1 is unlikely to have this activity.
Isoform 1 is widely expressed. Isoform 2 is testis-specific.
Phosphorylated by MELK, leading to inhibit its pro-apoptotic function.
Belongs to the acireductone dioxygenase (ARD) family.
Binds either 1 Fe or Ni cation per monomer. Iron-binding promotes an acireductone dioxygenase reaction producing 2-keto-4-methylthiobutyrate, while nickel-binding promotes an acireductone dioxygenase reaction producing 3-(methylsulfanyl)propanoate.
Catalyzes 2 different reactions between oxygen and the acireductone 1,2-dihydroxy-3-keto-5-methylthiopentene (DHK-MTPene) depending upon the metal bound in the active site (By similarity). Fe-containing acireductone dioxygenase (Fe-ARD) produces formate and 2-keto-4-methylthiobutyrate (KMTB), the alpha-ketoacid precursor of methionine in the methionine recycle pathway (PubMed:15938715). Ni-containing acireductone dioxygenase (Ni-ARD) produces methylthiopropionate, carbon monoxide and formate, and does not lie on the methionine recycle pathway (By similarity). Also down-regulates cell migration mediated by MMP14 (PubMed:14718544). Necessary for hepatitis C virus replication in an otherwise non-permissive cell line (PubMed:11602742).
Detected in heart, colon, lung, stomach, brain, spleen, liver, skeletal muscle and kidney.
Monomer (By similarity). Interacts with MMP14.
Mitochondrial NAD(+) transporter that acts as a 'metabolic gate' in hepatic lipogenesis. Provides NAD(+) substrate to mitochondrial SIRT3 deacetylase and enables its NAD(+)-dependent activities in mitochondrial energy metabolism. This triggers downstream activation of PRKAA1/AMPK-alpha signaling cascade that negatively regulates sterol regulatory element-binding protein (SREBP) transcriptional activities and ATP-consuming lipogenesis to restore cellular energy balance. May transport other mitochondrial metabolites having an aromatic nucleotide and phosphate groups, such as acetyl-CoA. Does not transport amino acids. The transport mechanism remains to be elucidated.
RNA-binding protein involved in the regulation of pre-mRNA alternative splicing. Mediates exon inclusion and/or exclusion in pre-mRNA that are subject to tissue-specific and developmentally regulated alternative splicing. Specifically activates exon 5 inclusion of cardiac isoforms of TNNT2 during heart remodeling at the juvenile to adult transition. Activates the splicing of MAPT/Tau exon 10. Binds to muscle-specific splicing enhancer (MSE) intronic sites flanking the alternative exon 5 of TNNT2 pre-mRNA.
The poly-Gln tract in AAK07474 may be polymorphic.
Component of the IFT complex B, at least composed of IFT20, IFT22, IFT25, IFT27, IFT46, IFT52, TRAF3IP1/IFT54, IFT57, IFT74, IFT80, IFT81, and IFT88 (PubMed:23990561, PubMed:33531668). Interacts with IFT81; the interaction is direct (PubMed:15955805, PubMed:23990561, PubMed:33531668). Within the IFT complex B, IFT74 and IFT81 mediate the transport of tubulin within the cilium (PubMed:15955805, PubMed:23990561). Interacts (via basic region) with beta-tubulin (via acidic region); interaction is direct (PubMed:23990561). Interacts with ARL13B and IFT88 (PubMed:24339792). Interacts (via the IFT74/IFT81 heterodimer) with RABL2B (PubMed:28428259, PubMed:28625565). Interacts with IFT57 and IFT70B (By similarity).
Component of the intraflagellar transport (IFT) complex B: together with IFT81, forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium (PubMed:23990561). Binds beta-tubulin via its basic region (PubMed:23990561). Required for ciliogenesis (PubMed:23990561). Essential for flagellogenesis during spermatogenesis (PubMed:33689014).
Highly expressed in adult and fetal kidney and expressed at lower level in adult heart, placenta, lung, liver and pancreas, and in fetal heart, lung and liver. Little to no expression was detected in adult brain and skeletal muscle or in fetal brain, thymus and spleen (PubMed:11683410). Detected in sperm (at protein level) (PubMed:33689014).
The disease is caused by variants affecting the gene represented in this entry. A homozygous variant at codon 86 has been identified in 2 unrelated affected individuals. In addition to encoding a missense, this variant also affects splicing, predominantly through the induction of an in-frame deletion of 10 amino acids within exon 3. Other minor transcripts can be detected in patient's sperm that use cryptic donor sites present in intron 3, leading either to the retention of 18 bp of intron 3 and an in-frame insertion of 6 amino acids, or to the retention of 108 bp of intron 3, which induces a frameshift and a truncated protein.
Interacts with TOMT. The interaction of TMC1 and TMC2 with TOMT is required for the transportation of TMC1/2 into the stereocilia of hair cells. Interacts (via N-terminus) with both isoforms CD1 and CD3 of PCDH15. Interacts with CIB2 (By similarity).
Probable ion channel required for the normal function of cochlear hair cells (PubMed:11850618). Component of the hair cell's mechanotransduction (MET) machinery. Involved in mechanosensitive responses of the hair cells (By similarity).
Dispensable for normal development and fertility.
It is uncertain whether Met-1 or Met-15 is the initiator.
Expressed at significant levels only in a single epithelial cell population, the proximal tubular epithelial cells of the kidney. Diffusely expressed in various carcinomas originating from kidney, colon, lung and breast.
Interacts with PDZK1 (PubMed:9461128). Forms a heterodimer with SLC5A2; this interaction enhances SLC5A2 transporter activity over a hundred-fold (PubMed:34880493).
May play an important role in tumor biology.
NADH-cytochrome b5 reductase involved in endoplasmic reticulum stress response pathway. Plays a critical role in protecting pancreatic beta-cells against oxidant stress, possibly by protecting the cell from excess buildup of reactive oxygen species (ROS). Reduces a variety of substrates in vitro, such as cytochrome c, feericyanide and methemoglobin.
Variants Arg-187 and Arg-223 do not influence the pathogenesis of non-autoimmune diabetes.
By bacterial lipopolysaccharides (LPS) and IL1B/interleukin-1 beta in peripheral blood mononuclear cells.
Expressed in numerous tissues including uterus and ovary, with low levels in heart and brain. Not detected in skeletal muscle.
Inhibits CASP1/caspase-1-dependent IL1B secretion.
Belongs to the potassium channel family. S (TC 1.A.1.2) subfamily. Kv9.3/KCNS3 sub-subfamily.
Detected in whole normal term placental and placental chorionic plate arteries and veins. Detected in syncytiotrophoblast and in blood vessel endothelium within intermediate villi and chorionic plate (at protein level) (PubMed:22943705). Detected in most tissues, but not in peripheral blood lymphocytes. The highest levels of expression are in lung (PubMed:10484328).
Heterotetramer with KCNB1 (PubMed:10484328). Does not form homomultimers (PubMed:10484328).
Potassium channel subunit that does not form functional channels by itself. Can form functional heterotetrameric channels with KCNB1; modulates the delayed rectifier voltage-gated potassium channel activation and deactivation rates of KCNB1 (PubMed:10484328). Heterotetrameric channel activity formed with KCNB1 show increased current amplitude with the threshold for action potential activation shifted towards more negative values in hypoxic-treated pulmonary artery smooth muscle cells (By similarity).
May act at junctions between the membrane and the cytoskeleton.
May act at junctions between the membrane and the cytoskeleton. Possesses tyrosine phosphatase activity.
Belongs to the cyclophilin-type PPIase family. PPIL1 subfamily.
PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding (PubMed:20676357). May be involved in pre-mRNA splicing (PubMed:11991638).
Phosphorylated. Fully dephosphorylated in mitosis and partially dephosphorylated on heat shock.
Splicing factor that in its dephosphorylated form acts as a general repressor of pre-mRNA splicing (PubMed:11684676, PubMed:12419250, PubMed:14765198). Seems to interfere with the U1 snRNP 5'-splice recognition of SNRNP70 (PubMed:14765198). Required for splicing repression in M-phase cells and after heat shock (PubMed:14765198). Also acts as a splicing factor that specifically promotes exon skipping during alternative splicing (PubMed:26876937). Interaction with YTHDC1, a RNA-binding protein that recognizes and binds N6-methyladenosine (m6A)-containing RNAs, prevents SRSF10 from binding to its mRNA-binding sites close to m6A-containing regions, leading to inhibit exon skipping during alternative splicing (PubMed:26876937). May be involved in regulation of alternative splicing in neurons, with isoform 1 acting as a positive and isoform 3 as a negative regulator (PubMed:12419250).
The phosphorylated but not the dephosphorylated form interacts with TRA2B/SFRS10 (PubMed:14765198). The dephosphorylated form interacts with SNRNP70 (PubMed:14765198). Isoform 1 interacts with FUS C-terminus (PubMed:9774382). Isoform 3 interacts with FUS C-terminus (PubMed:9774382). Interacts with YTHDC1, leading to inhibit RNA-binding activity of SRSF10 (PubMed:26876937).
Belongs to the rod/cone cGMP-PDE gamma subunit family.
Participates in processes of transmission and amplification of the visual signal. cGMP-PDEs are the effector molecules in G-protein-mediated phototransduction in vertebrate rods and cones.
Brain. Expression restricted to astrocytes.
Functions to regulate alternative splicing in neurons by binding pre-mRNA in a sequence-specific manner to activate exon inclusion or exclusion (PubMed:32197073). It binds specifically to the sequences 5'-YCAY-3' and regulates splicing in only a subset of regulated exons (PubMed:10811881). Binding to an exonic 5'-YCAY-3' cluster changes the protein complexes assembled on pre-mRNA, blocking U1 snRNP binding and exon inclusion, whereas binding to an intronic 5'-YCAY-3' cluster enhances spliceosome assembly and exon inclusion. With NOVA1, they perform unique biological functions in different brain areas and cell types. Uniquely regulates alternative splicing events of a series of axon guidance related genes during cortical development, being essential for central nervous system development by regulating neural networks wiring. Regulates differentially alternative splicing on the same transcripts expressed in different neurons. This includes functional differences in transcripts expressed in cortical and cerebellar excitatory versus inhibitory neurons where is required for, respectively, development of laminar structure and motor coordination and synapse formation. Also the regulation the regulation of intron retention can sequester the trans-acting splicing factor PTBP2, acting as a variable cis-acting scaffolding platform for PTBP2 across various natural conditions (By similarity).
Interacts with PTBP2; the interaction is direct.
The third KH domain (KH3) recognizes specifically 5'-YCAY-3'.
(Microbial infection) Acts as a receptor for new-world arenaviruses: Guanarito, Junin and Machupo virus.
(Microbial infection) Interacts with Guanarito, Junin and Machupo arenavirus glycoprotein complex (PubMed:17287727, PubMed:18268337).
Canine and feline parvoviruses bind human and feline transferrin receptors and use these receptors to enter and infect cells.
Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes (PubMed:26214738). Endosomal acidification leads to iron release. The apotransferrin-receptor complex is then recycled to the cell surface with a return to neutral pH and the concomitant loss of affinity of apotransferrin for its receptor. Transferrin receptor is necessary for development of erythrocytes and the nervous system (By similarity). A second ligand, the heditary hemochromatosis protein HFE, competes for binding with transferrin for an overlapping C-terminal binding site. Positively regulates T and B cell proliferation through iron uptake (PubMed:26642240). Acts as a lipid sensor that regulates mitochondrial fusion by regulating activation of the JNK pathway (PubMed:26214738). When dietary levels of stearate (C18:0) are low, promotes activation of the JNK pathway, resulting in HUWE1-mediated ubiquitination and subsequent degradation of the mitofusin MFN2 and inhibition of mitochondrial fusion (PubMed:26214738). When dietary levels of stearate (C18:0) are high, TFRC stearoylation inhibits activation of the JNK pathway and thus degradation of the mitofusin MFN2 (PubMed:26214738).
Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes. Endosomal acidification leads to iron release. The apotransferrin-receptor complex is then recycled to the cell surface with a return to neutral pH and the concomitant loss of affinity of apotransferrin for its receptor. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Acts as a lipid sensor that regulates mitochondrial fusion by regulating activation of the JNK pathway.
Homodimer; disulfide-linked. Binds one transferrin or HFE molecule per subunit. Binds the HLA class II histocompatibility antigen, DR1. Interacts with SH3BP3. Interacts with STEAP3; facilitates TFRC endocytosis in erythroid precursor cells (PubMed:26642240).
N- and O-glycosylated, phosphorylated and palmitoylated. The serum form is only glycosylated.
Palmitoylated on both Cys-62 and Cys-67. Cys-62 seems to be the major site of palmitoylation.
Proteolytically cleaved on Arg-100 to produce the soluble serum form (sTfR).
Regulated by cellular iron levels through binding of the iron regulatory proteins, IRP1 and IRP2, to iron-responsive elements in the 3'-UTR. Up-regulated upon mitogenic stimulation.
Serum transferrin receptor (sTfR) is used as a means of detecting erythropoietin (EPO) misuse by athletes and as a diagnostic test for anemia resulting from a number of conditions including rheumatoid arthritis, pregnancy, irritable bowel syndrome and in HIV patients.
Stearoylated by ZDHHC6 which inhibits TFRC-mediated activation of the JNK pathway and promotes mitochondrial fragmentation (PubMed:26214738). Stearoylation does not affect iron uptake (PubMed:26214738).
Homodimer or homotetramer. Interacts (via actin-binding domain) with SYNE3. Interacts (via calponin-homology (CH) 1 domain) with VIM (via rod region) (By similarity). Interacts (via N-terminus) with DST isoform 2 (via N-terminus) (PubMed:19932097). Interacts with FER. Interacts with TOR1A (PubMed:18827015). Interacts with ANK3 (PubMed:21223964). Identified in complexes that contain VIM, EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, PRX and spectrin (By similarity). Interacts with COL17A1 (PubMed:12482924).
Interacts with KRT14, heterodimers consisting of KRT8 and KRT18, heterodimers consisting of KRT5 and KRT14, heterodimers consisting of KRT14 and KRT15, and heterodimers consisting of KRT1 and KRT10 (PubMed:24940650). Interacts with DES and VIM (PubMed:24940650).
Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes. Could also bind muscle proteins such as actin to membrane complexes in muscle. May be involved not only in the filaments network, but also in the regulation of their dynamics. Structural component of muscle. Isoform 9 plays a major role in the maintenance of myofiber integrity.
Phosphorylated by CDK1; regulates dissociation from intermediate filaments during mitosis.
The N-terminus interacts with actin, the C-terminus with vimentin, desmin, GFAP, cytokeratins, lamin B; whereas both the N- and the C-terminus can bind integrin beta-4.
The disease is caused by variants affecting the gene represented in this entry. A 9 bp deletion containing the initiation codon in exon 1f of PLEC have been found in limb-girdle muscular dystrophy patients. The mutation results in deficient expression of isoform 9 and disorganization of the myofibers, without any effect on the skin.
Widely expressed with highest levels in muscle, heart, placenta and spinal cord.
Belongs to the EF-1-beta/EF-1-delta family.
EF-1 is composed of 4 subunits: alpha, beta, delta, and gamma.
EF-1-beta and EF-1-delta stimulate the exchange of GDP bound to EF-1-alpha to GTP.
Phosphorylation affects the GDP/GTP exchange rate.
In the intracellular compartments, may function as a channel or small molecule transporter.
Ubiquitously expressed. Especially abundant in pancreas, highly expressed in kidney, lower levels in heart, brain, skeletal muscle and placenta. Lowest expression in lung and liver.
Expressed in aortic smooth muscle (at protein level) (PubMed:25298399). In the fetus, expressed in the brain and ocular tissues including lens vesicle and optic cup (PubMed:27844144).
Involved in transforming growth factor beta (TGF-beta)-induced smooth muscle differentiation. TGF-beta induces expression and translocation of OLFM2 to the nucleus where it binds to SRF, causing its dissociation from the transcriptional repressor HEY2/HERP1 and facilitating binding of SRF to target genes (PubMed:25298399). Plays a role in AMPAR complex organization (By similarity). Is a regulator of vascular smooth-muscle cell (SMC) phenotypic switching, that acts by promoting RUNX2 and inhibiting MYOCD binding to SRF. SMC phenotypic switching is the process through which vascular SMCs undergo transition between a quiescent contractile phenotype and a proliferative synthetic phenotype in response to pathological stimuli. SMC phenotypic plasticity is essential for vascular development and remodeling (By similarity).
Peripherally associated with AMPAR complex. AMPAR complex consists of an inner core made of 4 pore-forming GluA/GRIA proteins (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged in a twofold symmetry. One of the two pairs of distinct binding sites is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR complex is complemented by outer core constituents binding directly to the GluA/GRIA proteins at sites distinct from the interaction sites of the inner core constituents. Outer core constituents include at least PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the inner and outer core serve as a platform for other, more peripherally associated AMPAR constituents, including OLFM2. Alone or in combination, these auxiliary subunits control the gating and pharmacology of the AMPAR complex and profoundly impact their biogenesis and protein processing. Interacts with GRIA2 (By similarity). Interacts with OLFM1 and OLFM3 (PubMed:21228389). Interacts with SRF; the interaction promotes dissociation of SRF from the transcriptional repressor HEY2 (PubMed:25298399). Interacts with RUNX2 (By similarity).
Belongs to the peroxiredoxin family. Prx5 subfamily.
S-palmitoylated (PubMed:31740833). Depalmitoylated by ABHD10 (PubMed:31740833).
S-palmitoylated (PubMed:31740833). Palmitoylation occurs on the active site, inhibiting its reactivity; therefore PRDX5 palmitoylation status determines its antioxidant capacity (PubMed:31740833).
The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this atypical 2-Cys Prx, C(R) is present in the same subunit to form an intramolecular disulfide. The disulfide is subsequently reduced by thioredoxin.
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides and as sensor of hydrogen peroxide-mediated signaling events.
Belongs to the RNA 3'-terminal cyclase family. Type 2 subfamily.
Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797). Does not have cyclase activity (By similarity).
Autophosphorylated. Phosphorylated on Thr-508 by ROCK1 and PAK1, resulting in activation. Phosphorylated by PAK4 which increases the ability of LIMK1 to phosphorylate cofilin. Phosphorylated at Ser-323 by MAPKAPK2 during activation of VEGFA-induced signaling, which results in activation of LIMK1 and promotion of actin reorganization, cell migration, and tubule formation of endothelial cells. Dephosphorylated and inactivated by SSH1. Phosphorylated by CDC42BP.
Has a dominant negative effect on actin cytoskeletal changes. Required for atypical chemokine receptor ACKR2-induced phosphorylation of cofilin (CFL1).
Highest expression in both adult and fetal nervous system. Detected ubiquitously throughout the different regions of adult brain, with highest levels in the cerebral cortex. Expressed to a lesser extent in heart and skeletal muscle.
Interacts (via LIM domain) with the cytoplasmic domain of NRG1. Interacts with NISCH. Interacts with RLIM and RNF6 (By similarity). Self-associates to form homodimers (PubMed:10196227). Interacts with HSP90AA1; this interaction promotes LIMK1 dimerization and subsequent transphosphorylation (PubMed:16641196). Interacts with CDKN1C (PubMed:14530263). Interacts with SSH1 (PubMed:15660133). Interacts with ROCK1 (PubMed:10436159, PubMed:10652353). Interacts (via LIM zinc-binding domains) with FAM89B/LRAP25 (via LRR repeat). Forms a tripartite complex with CDC42BPA, CDC42BPB and FAM89B/LRAP25 (By similarity).
LIMK1 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region.
Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways (PubMed:10436159, PubMed:11832213, PubMed:12807904, PubMed:15660133, PubMed:16230460, PubMed:18028908, PubMed:22328514, PubMed:23633677). Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop (PubMed:10436159). LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin-2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton (PubMed:11832213, PubMed:15660133, PubMed:16230460, PubMed:23633677). In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation (PubMed:11832213, PubMed:15660133, PubMed:16230460, PubMed:23633677). Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly (PubMed:18028908). Stimulates axonal outgrowth and may be involved in brain development (PubMed:18028908).
Ubiquitinated. 'Lys-48'-linked polyubiquitination by RNF6 leads to proteasomal degradation through the 26S proteasome, modulating LIMK1 levels in the growth cone and its effect on axonal outgrowth. Also polyubiquitinated by RLIM (By similarity).
Contributes to the regulation of axonal growth in the embryonic and adult central nervous system by inhibiting interactions between RTN4R and LINGO1. Inhibits RTN4R-mediated axon growth cone collapse (By similarity). May play an important role in regulating the production of neural crest cells by the neural tube (By similarity). May be required for normal responses to olfactory stimuli (By similarity).
Homotetramer; disulfide-linked. Dimer of dimers, giving rise to a V-shaped homotretramer. Isoform 1 and isoform 3 interact with RTN4R. Identified in a complex with RTN4R and LINGO1. Peripherally associated with AMPAR complex. AMPAR complex consists of an inner core made of 4 pore-forming GluA/GRIA proteins (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged in a twofold symmetry. One of the two pairs of distinct binding sites is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR complex is complemented by outer core constituents binding directly to the GluA/GRIA proteins at sites distinct from the interaction sites of the inner core constituents. Outer core constituents include at least PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the inner and outer core serve as a platform for other, more peripherally associated AMPAR constituents, including OLFM1. Alone or in combination, these auxiliary subunits control the gating and pharmacology of the AMPAR complex and profoundly impact their biogenesis and protein processing (By similarity). Interacts with OLFM2 (PubMed:21228389).
The protein contains a globular N-terminal tetramerization domain, a long stalk formed by the coiled coil region and a C-terminal olfactomedin-like domain. Interactions between dimers are mediated by the coiled coil region. The dimers interact mostly via the N-terminal tetramerization domain, giving rise to a V-shaped overall architecture of the tetramer.
Detected in cerebrospinal fluid (at protein level).
Inhibits catecholamine release from chromaffin cells and noradrenergic neurons by acting as a non-competitive nicotinic cholinergic antagonist (PubMed:15326220). Displays antibacterial activity against Gram-positive bacteria S.aureus and M.luteus, and Gram-negative bacteria E.coli and P.aeruginosa (PubMed:15723172, PubMed:24723458). Can induce mast cell migration, degranulation and production of cytokines and chemokines (PubMed:21214543). Acts as a potent scavenger of free radicals in vitro (PubMed:24723458). May play a role in the regulation of cardiac function and blood pressure (PubMed:18541522).
O-glycosylated with core 1 or possibly core 8 glycans (PubMed:9852066, PubMed:19838169, PubMed:23234360). Contains chondroitin sulfate (CS); CS attachment is pH-dependent, being observed at mildly acidic conditions of pH 5 but not at neutral pH, and promotes self-assembly in vitro (PubMed:25326458).
Proteolytic processing gives rise to an additional longer form of catestatin (residues 358-390) which displays a less potent catecholamine release-inhibitory activity (PubMed:10781584). Plasmin-mediated proteolytic processing can give rise to additional shorter and longer forms of catestatin peptides (PubMed:17991725).
Regulates granule biogenesis in endocrine cells by up-regulating the transcription of protease nexin 1 (SERPINE2) via a cAMP-PKA-SP1 pathway. This leads to inhibition of granule protein degradation in the Golgi complex which in turn promotes granule formation.
Self-interacts; self-assembly is promoted in vitro by chondroitin sulfate attachment which occurs at mildly acidic pH conditions (PubMed:25326458). Interacts with SCG3 (By similarity).
Strongly inhibits glucose induced insulin release from the pancreas.
Sulfated on tyrosine residues and/or contains sulfated glycans.
Contaminating sequence. At the N-terminus.
Depletion of MAP1S by RNAi causes mitotic abnormalities that consist of failure to form a stable metaphase plate, premature sister chromatid separation, lagging chromosomes, and multipolar spindles.
Expressed in neurons (at protein level). Expressed in spermatocytes, spermatids and spermatozoa. Expressed in the cerebral cortex. Highly expressed in testis. Moderately expressed in the brain, colon, heart, kidney, liver, lung, placenta, small intestine, spleen and stomach. Weakly expressed in muscle.
Heterodimer of a heavy and a light chain. Interacts with microtubules and actin. Both MAP1S heavy and light chains interact with microtubules. MAP1S light chain interacts with actin. Interacts (via C-terminus) with GAN (via Kelch domains) (By similarity). Interacts with ESR1, LRPPRC, RASSF1 isoform A and isoform C, microtubules and VCY2. Interacts with WDR47 (via N-terminus of light chain).
Microtubule-associated protein that mediates aggregation of mitochondria resulting in cell death and genomic destruction (MAGD). Plays a role in anchoring the microtubule organizing center to the centrosomes. Binds to DNA. Plays a role in apoptosis. Involved in the formation of microtubule bundles (By similarity).
The N-terminus of the heavy chain associates with the C-terminus of the light chain to form the heterodimer complex (By similarity). Its C-terminal part of the heavy chain interacts with ESR1.
(Microbial infection) Interacts with Epstein-Barr virus protein BMLF1.
(Microbial infection) Interacts with HTLV-1 Rex.
(Microbial infection) Interacts with SARS-CoV virus protein ORF9b; this interaction mediates protein ORF9b export out of the nucleus.
(Microbial infection) Interacts with influenza A nucleoprotein.
(Microbial infection) Mediates the export of unspliced or incompletely spliced RNAs out of the nucleus from different viruses including HIV-1, HTLV-1 and influenza A. Interacts with, and mediates the nuclear export of HIV-1 Rev and HTLV-1 Rex proteins. Involved in HTLV-1 Rex multimerization.
Cellular target of leptomycin B (LMB), a XPO1/CRM1 nuclear export inhibitor.
Expressed in heart, brain, placenta, lung, liver, skeletal muscle, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes. Not expressed in the kidney.
Found in a U snRNA export complex with PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA (By similarity). Component of a nuclear export receptor complex composed of KPNB1, RAN, SNUPN and XPO1. Found in a trimeric export complex with SNUPN, RAN and XPO1. Found in a nuclear export complex with RANBP3 and RAN. Found in a 60S ribosomal subunit export complex with NMD3, RAN, XPO1. Interacts with DDX3X, NMD3, NUP42, NUP88, NUP214, RANBP3 and TERT. Interacts with NEMF (via its N-terminus). Interacts with the monomeric form of BIRC5/survivin deacetylated at 'Lys-129'. Interacts with DTNBP1 and SERTAD2; the interactions translocate DTNBP1 and SERTAD2 out of the nucleus. Interacts with ATF2. Interacts with SLC35G1 and STIM1. Interacts with DCAF8. Interacts with CPEB3 (PubMed:22730302). Interacts with HAX1 (PubMed:23164465). Interacts with BOK; translocates to the cytoplasm (PubMed:16302269). Interacts with HSP90AB1 (PubMed:22022502). Interacts with LRPPRC; interacts with LRPPRC alone and also when LRPPRC is in complex with EIF4E and with EIF4E sensitivity element (4ESE)-containing mRNAs to form an EIF4E-dependent mRNA export complex (PubMed:28325843).
Mediates the nuclear export of cellular proteins (cargos) bearing a leucine-rich nuclear export signal (NES) and of RNAs. In the nucleus, in association with RANBP3, binds cooperatively to the NES on its target protein and to the GTPase RAN in its active GTP-bound form (Ran-GTP). Docking of this complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the cargo from the export receptor. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Involved in U3 snoRNA transport from Cajal bodies to nucleoli. Binds to late precursor U3 snoRNA bearing a TMG cap.
Catalyzes the exchange of an acyl for a long-chain alkyl group and the formation of the ether bond in the biosynthesis of ether phospholipids.
Catalyzes the exchange of the acyl chain in acyl-dihydroxyacetonephosphate (acyl-DHAP) for a long chain fatty alcohol, yielding the first ether linked intermediate, i.e. alkyl-dihydroxyacetonephosphate (alkyl-DHAP), in the pathway of ether lipid biosynthesis.
Expressed predominantly in secondary lymphoid tissues, such as lymph node, spleen, small intestine, stomach, colon, appendix and trachea. The lymphocyte population is responsible for expression of this protein in these tissues. Isoform 2 is expressed preferentially in spleen.
May play a role in the adhesive and proteolytic events that occur during lymphocyte emigration or may function in ectodomain shedding of lymphocyte surface target proteins, such as FASL and CD40L. May be involved in sperm maturation.
Pro-domain removal and maturation may be, at least in part, autocatalytic.
Detected in cAMP-treated chondrocytes, but not in untreated chondrocytes. Detected in fetal brain, heart and spleen, and in adult testis, kidney and lung.
Functions as guanine nucleotide exchange factor for RAC1. May play a role in semaphorin signaling. Plays a role in the assembly and disassembly of dendritic filopodia, the formation of dendritic spines, regulation of dendrite length and ultimately the formation of synapses (By similarity).
Interacts with CADM1. Interacts with RAC1 (By similarity).
Up-regulated in response to cAMP in cultured embryonic chondrocytes.
Expressed in B-cells (at protein level) (PubMed:12805216). Expressed in dendritic cells and macrophages (PubMed:27022195, PubMed:21266579).
Interacts with TLR4; the interaction occurs in response to lipopolysaccharide stimulation (PubMed:27022195). Interacts with CLTC; the interaction occurs in response to pathogens (PubMed:27022195, PubMed:21266579). Interacts with AP2A1 and AP2B1 (PubMed:27022195).
Involved in protein trafficking via association with clathrin and AP2 complex (PubMed:27022195, PubMed:21266579). Upon bacterial lipopolysaccharide stimulation, mediates internalization of TLR4 to endosomes in dendritic cells and macrophages; and internalization of poly(I:C) to TLR3-positive endosomes in myeloid dendritic cells and epithelial cells; resulting in activation of TICAM1-mediated signaling and subsequent IFNB1 production (PubMed:27022195, PubMed:21266579). Involved in T-cell antigen receptor-mediated signaling by regulating tyrosine kinase LCK localization, T-cell dependent antibody production and cytokine secretion (By similarity). May regulate B-cell antigen receptor-mediated signaling (PubMed:12805216). May play a pivotal role in the formation and/or maintenance of lipid rafts (PubMed:12805216).
At protein level, three alleles are known: CYP3A43*1, CYP3A43*2 and CYP3A43*3. The sequence shown is that of CYP3A43*1, which is the most frequent allele. The allele CYP3A43*2 is likely to be non-functional.
Chimeric transcripts, characterized by CYP3A43 exon 1 joined at canonical splice sites to distinct sets of CYP3A4 or CYP3A5 exons, have been detected. All are possibly produced by trans-splicing. CYP3A43-CYP3A4 chimeric transcripts exist in 3 different combinations: CYP3A43 exon 1 joined in frame to CYP3A4 exons 2-13, CYP3A43 exon 1 joined in frame to CYP3A4 exons 4-13 and CYP3A43 exon 1 joined in frame to CYP3A4 exon 7-13. The longest chimeric isoform (CYP3A43 exon 1 joined to CYP3A4 exons 2-13) exhibits 6-beta-hydroxylase activity, while a shorter isoform (CYP3A43 exon 1 joined to CYP3A4 exons 4-13) does not. CYP3A43-CYP3A5 chimeric transcripts exist in 2 different combinations: CYP3A43 exon 1 joined in frame to CYP3A5 exon 11-13 and CYP3A43 exon 1 joined in frame to CYP3A5 exon 12-13. All chimeric transcripts are expressed at very low levels in the liver (PubMed:11726664).
Exhibits low testosterone 6-beta-hydroxylase activity.
Highest expression level in prostate. Also expressed in liver, kidney, pancreas, fetal liver and fetal skeletal muscle.
E3 ubiquitin-protein ligase involved in the regulation of Fas-, DR3- and DR4-mediated apoptosis. Functions in conjunction with the UBE2D1, UBE2D3 and UBE2E1 E2 ubiquitin-conjugating enzymes.
Polyubiquitinated. Polyubiquitination is followed by degradation via the proteasome (By similarity).
The SWIM-type zinc finger is required for ubiquitination activity.
May suppress myogenic differentiation by modulating MYOG expression and Erk1/2 signaling.
Belongs to the class I-like SAM-binding methyltransferase superfamily. RsmB/NOP family. TRM4 subfamily.
Expressed in adult and fetal brain and in lymphoblastoid cells.
Interacts with NPM1 and NCL during interphase; interaction is disrupted following phosphorylation at Ser-139.
Phosphorylated at Ser-139 by AURKB during mitosis, leading to abolish methyltransferase activity and the interaction with NPM1.
RNA cytosine C(5)-methyltransferase that methylates cytosine to 5-methylcytosine (m5C) in various RNAs, such as tRNAs, mRNAs and some long non-coding RNAs (lncRNAs) (PubMed:17071714, PubMed:22995836, PubMed:31358969, PubMed:31199786). Involved in various processes, such as epidermal stem cell differentiation, testis differentiation and maternal to zygotic transition during early development: acts by increasing protein synthesis; cytosine C(5)-methylation promoting tRNA stability and preventing mRNA decay (PubMed:31199786). Methylates cytosine to 5-methylcytosine (m5C) at positions 34 and 48 of intron-containing tRNA(Leu)(CAA) precursors, and at positions 48, 49 and 50 of tRNA(Gly)(GCC) precursors (PubMed:17071714, PubMed:22995836, PubMed:31199786). tRNA methylation is required generation of RNA fragments derived from tRNAs (tRFs) (PubMed:31199786). Also mediates C(5)-methylation of mitochondrial tRNAs (PubMed:31276587). Catalyzes cytosine C(5)-methylation of mRNAs, leading to stabilize them and prevent mRNA decay: mRNA stabilization involves YBX1 that specifically recognizes and binds m5C-modified transcripts (PubMed:22395603, PubMed:31358969, PubMed:34556860). Cytosine C(5)-methylation of mRNAs also regulates mRNA export: methylated transcripts are specifically recognized by THOC4/ALYREF, which mediates mRNA nucleo-cytoplasmic shuttling (PubMed:28418038). Also mediates cytosine C(5)-methylation of non-coding RNAs, such as vault RNAs (vtRNAs), promoting their processing into regulatory small RNAs (PubMed:23871666). Cytosine C(5)-methylation of vtRNA VTRNA1.1 promotes its processing into small-vault RNA4 (svRNA4) and regulates epidermal differentiation (PubMed:31186410). May act downstream of Myc to regulate epidermal cell growth and proliferation (By similarity). Required for proper spindle assembly and chromosome segregation, independently of its methyltransferase activity (PubMed:19596847).
In contrast to other members of the family, it lacks the conserved active sites, suggesting that it has no phospholipase activity.
Activator of ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases that acts as a as repressor of autophagy (PubMed:20864041, PubMed:31267705). May enhance ubiquitin ligase activity of TRIM28 and stimulate p53/TP53 ubiquitination by TRIM28. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex (PubMed:17942928, PubMed:20864041). May play a role in embryonal development and tumor transformation or aspects of tumor progression (PubMed:17942928, PubMed:20864041). In vitro promotes cell viability in melanoma cell lines (PubMed:17942928). Antigen recognized on a melanoma by autologous cytolytic T-lymphocytes (PubMed:8113684).
Expressed in many tumors of several types, such as melanoma, head and neck squamous cell carcinoma, lung carcinoma and breast carcinoma, but not in normal tissues except for testes and placenta. Never expressed in kidney tumors, Leukemias and lymphomas.
Expressed in most tissues but at significantly lower levels in placenta, lung, liver, and kidney.
Interacts with NEDD4 (By similarity). Binds to the WW domain of YAP1, WWP1 and WWP2. Interacts with WWOX.
The PPxY motif 2 mediates interaction with WWOX. Both PPxY motifs mediate interaction with NEDD4 (By similarity).
As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores.
Binds two moles of calcium per mole of protein.
Involved in global genome nucleotide excision repair (GG-NER) by acting as component of the XPC complex. Cooperatively with RAD23B appears to stabilize XPC. In vitro, stimulates DNA binding of the XPC:RAD23B dimer.
Monomer. Homooligomer (PubMed:15356003). Interacts with SFI1 (PubMed:16956364). Interacts with CCP110 (PubMed:16760425). Component of the XPC complex composed of XPC, RAD23B and CETN2 (PubMed:11279143, PubMed:15964821, PubMed:16533048, PubMed:16627479). Component of the nuclear pore complex (NPC)-associated TREX-2 complex (transcription and export complex 2), composed of at least GANP, 2 copies of ENY2, PCID2, SEM1/DSS1, and either centrin CETN2 or centrin CETN3. The TREX-2 complex also associates with ALYREF/ALY and with the nucleoporin NUP153 (PubMed:22307388, PubMed:23591820).
Plays a fundamental role in microtubule organizing center structure and function. Required for centriole duplication and correct spindle formation. Has a role in regulating cytokinesis and genome stability via cooperation with CALM1 and CCP110.
The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex. The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single-stranded overhangs. The orientation of XPC complex binding appears to be crucial for inducing a productive NER. XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery. Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair.
It is uncertain whether Met-1 or Met-35 is the initiator.
Present on the surface of monocytes, neutrophils, a proportion of peripheral blood T- and B-lymphocytes and lymphocytic cell lines.
G proteins are composed of 3 units, alpha, beta and gamma. Interacts with RASD2.
ADP-ribosylated by TNKS at the onset of mitosis; ADP-ribosylation is not required for its localization to spindle poles (PubMed:16076287).
Also known as nuclear matrix protein-22/NMP-22/NMP22, an antigen used in diagnostic tests of bladder cancer.
Homodimer (PubMed:10075938). Also forms multiarm oligomers by association of C-terminal tail domains, oligomers may further assemble to form a hexagonal nuclear lattice-like network (PubMed:10075938). Associates with the dynein-dynactin complex; this association promotes the transport and accumulation of NUMA1 at the mitotic spindle poles that is inhibited by the BRISC complex in a PLK1-dependent manner (PubMed:10811826, PubMed:17172455, PubMed:23027904, PubMed:22327364, PubMed:26195665). Part of a spindle orientation complex at least composed of GNAI1, GPSM2 and NUMA1 (PubMed:26766442). Interacts (via C-terminus) with microtubules (MTs); this interaction is direct and promotes both MT bundle formation and stability in a dynein-dynactin complex- and CDK1-independent manner (PubMed:12445386, PubMed:11956313, PubMed:26765568). Interacts with EPB41 and EPB41L2; these interactions are negatively regulated by CDK1 during metaphase and are important for anaphase-specific localization of NUMA1 in symmetrically dividing cells (PubMed:23870127, PubMed:24996901). Interacts (via C-terminus) with GPSM2 (via TPR repeats); this interaction is direct, prevented by competitive binding of INSC, is inhibited in a PLK1-dependent manner, blocks the association of NUMA1 with MTs and inhibits NUMA1-induced MT bundle formation, prevents the association of NUMA1 with SPAG5, induces mitotic spindle pole localization of GPSM2, both metaphase cell cortex localization of NUMA1 and mitotic spindle organization (PubMed:11781568, PubMed:12445386, PubMed:22327364, PubMed:24109598, PubMed:27462074, PubMed:21816348). Does not interact with GPSM2 during anaphase (PubMed:23870127). Interacts (via C-terminus) with the nuclear importin alpha/importin beta receptor; this interaction is inhibited by RanGTP (PubMed:11163243). Interacts (via C-terminus) with KPNB1; this interaction is inhibited by RanGTP and the BRISC complex (PubMed:11229403, PubMed:26195665). Interacts with ABRAXAS2 and the BRISC complex; these interactions regulate mitotic spindle assembly (PubMed:26195665). Interacts (via N-terminal end of the coiled-coil domain) with RAE1; this interaction promotes mitotic spindle formation (PubMed:17172455). Interacts (via C-terminus) with SPAG5 (via C-terminus); this interaction promotes the recruitment of SPAG5 to the MTs at spindle poles in a dynein-dynactin-dependent manner and regulates mitotic spindle organization and proper chromosome alignment during mitosis (PubMed:27462074). Interacts with TNKS; this interaction occurs at the onset of mitosis (PubMed:12080061, PubMed:16076287). Interacts with TNKS2 (PubMed:12080061). Interacts with tubulin (PubMed:11956313). Interacts with KHDC3L (via C-terminus) (By similarity).
Microtubule (MT)-binding protein that plays a role in the formation and maintenance of the spindle poles and the alignement and the segregation of chromosomes during mitotic cell division (PubMed:7769006, PubMed:17172455, PubMed:19255246, PubMed:24996901, PubMed:26195665, PubMed:27462074). Functions to tether the minus ends of MTs at the spindle poles, which is critical for the establishment and maintenance of the spindle poles (PubMed:12445386, PubMed:11956313). Plays a role in the establishment of the mitotic spindle orientation during metaphase and elongation during anaphase in a dynein-dynactin-dependent manner (PubMed:23870127, PubMed:24109598, PubMed:24996901, PubMed:26765568). In metaphase, part of a ternary complex composed of GPSM2 and G(i) alpha proteins, that regulates the recruitment and anchorage of the dynein-dynactin complex in the mitotic cell cortex regions situated above the two spindle poles, and hence regulates the correct oritentation of the mitotic spindle (PubMed:23027904, PubMed:22327364, PubMed:23921553). During anaphase, mediates the recruitment and accumulation of the dynein-dynactin complex at the cell membrane of the polar cortical region through direct association with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), and hence participates in the regulation of the spindle elongation and chromosome segregation (PubMed:22327364, PubMed:23921553, PubMed:24996901, PubMed:24371089). Binds also to other polyanionic phosphoinositides, such as phosphatidylinositol 3-phosphate (PIP), lysophosphatidic acid (LPA) and phosphatidylinositol triphosphate (PIP3), in vitro (PubMed:24996901, PubMed:24371089). Also required for proper orientation of the mitotic spindle during asymmetric cell divisions (PubMed:21816348). Plays a role in mitotic MT aster assembly (PubMed:11163243, PubMed:11229403, PubMed:12445386). Involved in anastral spindle assembly (PubMed:25657325). Positively regulates TNKS protein localization to spindle poles in mitosis (PubMed:16076287). Highly abundant component of the nuclear matrix where it may serve a non-mitotic structural role, occupies the majority of the nuclear volume (PubMed:10075938). Required for epidermal differentiation and hair follicle morphogenesis (By similarity).
O-glycosylated during cytokinesis at sites identical or close to phosphorylation sites, this interferes with the phosphorylation status (PubMed:20068230).
Phosphorylation and dephosphorylation on Thr-2055 regulates the extent of cortical NUMA1 and the dynein-dynactin complex localization during mitotic metaphase and anaphase (PubMed:23921553). In metaphase, phosphorylation on Thr-2055 occurs in a kinase CDK1-dependent manner; this phosphorylation maintains low levels of cortical dynein-dynactin complex at metaphase, and hence proper spindle positioning (PubMed:7769006, PubMed:23921553, PubMed:24371089). In anaphase, dephosphorylated on Thr-2055 by phosphatase PPP2CA; this dephosphorylation stimulates its membrane association and with the dynein-dynactin complex its enrichment at the cell cortex, and hence robust spindle elongation (PubMed:23921553, PubMed:24371089). Probably also phosphorylated on Thr-2015 and Ser-2087 by CDK1; these phosphorylations may regulate its cell cortex recruitment during metaphase and anaphase (PubMed:23870127). Phosphorylated on Thr-1047, Ser-1769, Ser-1772, Ser-1789 and Ser-1834 by PLK1; these phosphorylations induce cortical dynein-dynactin complex dissociation from the NUMA1-GPSM2 complex and negatively regulates cortical dynein-dynactin complex localization (PubMed:22327364).
The C-terminal tubulin-binding domain mediates direct binding to microtubules, independently of dynein-dynactin complex, and induces their bundling and stabilization (PubMed:11956313). The 4.1-binding domain is necessary for its cortical stability and spindle orientation (PubMed:24109598).
Ubiquitinated with 'Lys-63'-linked polyubiquitin chains. Deubiquitination by the BRISC complex is important for the incorporation of NUMA1 into mitotic spindle poles and normal spindle pole function, probably by modulating interactions between NUMA1, dynein-dynactin complex and importin-beta.
Component of the RNF20/40 E3 ubiquitin-protein ligase complex that mediates monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1). H2BK120ub1 gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation (H3K4me and H3K79me, respectively). It thereby plays a central role inb histone code and gene regulation. The RNF20/40 complex forms a H2B ubiquitin ligase complex in cooperation with the E2 enzyme UBE2A or UBE2B; reports about the cooperation with UBE2E1/UBCH are contradictory. Required for transcriptional activation of Hox genes. Recruited to the MDM2 promoter, probably by being recruited by p53/TP53, and thereby acts as a transcriptional coactivator. Mediates the polyubiquitination of isoform 2 of PA2G4 in cancer cells leading to its proteasome-mediated degradation.
Component of the RNF20/40 complex (also known as BRE1 complex) probably composed of 2 copies of RNF20/BRE1A and 2 copies of RNF40/BRE1B. Interacts with UBE2E1/UBCH6. Interacts with p53/TP53 and WAC. Interacts with PAF1; the interaction mediates the association of the PAF1 and RNF20/40 complexes which is a prerequsite for recruitment of UBE2A/B. Interacts with isoform 1 and isoform 2 of PA2G4. Interacts with FBXL19 (By similarity).
Expressed in the normal brain and also in malignant gliomas (at protein level).
Acyltransferase that catalyzes the formation of ester bonds between fatty alcohols and fatty acyl-CoAs to form wax monoesters (PubMed:15671038). Shows a strong preference for decyl alcohol (C10), with less activity towards C16 and C18 alcohols (PubMed:15671038). Shows a strong preference for saturated acyl-CoAs (PubMed:15671038).
Predominantly expressed in skin, where it is limited to the sebaceous gland. Expressed in more mature, centrally located cells just before their rupture and sebum release. Also expressed in all tissues except spleen. Expressed at higher level in thymus, prostate and testis.
Expressed in peripheral tissues (at protein level).
Interacts with REEP5 and RTN3 (PubMed:19665976). Interacts with ZFYVE27 (PubMed:23969831).
A paralogous gene encoding an identical protein appears to have arisen by retrotransposition of a cDNA from this locus and to have acquired a promoter and non-coding 5' UTR from the ZNF547 gene.
Belongs to the TRAPP small subunits family. Sedlin subfamily.
Can homodimerize (By similarity). Part of the multisubunit TRAPP (transport protein particle) complex (PubMed:11805826). Interacts with ENO1 and TRAPPC2L (PubMed:11134351, PubMed:19416478). Interacts with PITX1, SF1 and TRAPPC3 (By similarity).
Can homodimerize. Component of the multisubunit TRAPP (transport protein particle) complex, which includes TRAPPC2, TRAPPC2L, TRAPPC3, TRAPPC3L, TRAPPC4, TRAPPC5, TRAPPC8, TRAPPC9, TRAPPC10, TRAPPC11 and TRAPPC12. Interacts with ENO1, PITX1 and SF1.
Expressed in brain, heart, kidney, liver, lung, pancreas, placenta, skeletal muscle, fetal cartilage, fibroblasts, placenta and lymphocytes.
Prevents transcriptional repression and induction of cell death by ENO1 (By similarity). May play a role in vesicular transport from endoplasmic reticulum to Golgi.
Prevents transcriptional repression and induction of cell death by ENO1. May play a role in vesicular transport from endoplasmic reticulum to Golgi.
The gene encoding this protein appears to have arisen by retrotransposition of a cDNA from the X-linked locus TRAPPC2. The site of integration of this retrotransposed cDNA appears to lie within an intron of the ZNF547 gene, which provides a promoter and non-coding 5' exon. TRAPPC2 and this protein are indistinguishable at protein level, and both proteins have been identified and functionally characterized.
Component of the chaperonin-containing T-complex (TRiC), a heterooligomeric complex of about 850 to 900 kDa that forms two stacked rings, 12 to 16 nm in diameter (PubMed:20080638, PubMed:25467444). Interacts with PACRG (PubMed:14532270). Interacts with DNAAF4 (By similarity). Interacts with DLEC1 (PubMed:33144677). Interacts with SPMAP2 (By similarity).
E3 ubiquitin-protein ligase which may be involved in endosomal trafficking. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates.
Interacts with NOTCH2; this interaction increases MINAR1 stability (PubMed:29329397). Interacts (via N-terminus) with DEPTOR (via PDZ domain); this interaction may stabilize DEPTOR protein by impairing its ubiquitination (PubMed:30080879).
Intrinsically disordered protein which may negatively regulate mTOR signaling pathway by stabilizing the mTOR complex component DEPTOR (PubMed:30080879). Negatively regulates angiogenesis (PubMed:29329397). Negatively regulates cell growth (PubMed:29329397, PubMed:30080879). Negatively regulates neurite outgrowth in hippocampal neurons (By similarity).
MINAR1 topology is a matter of debate, some authors think the N-terminus is extracellular, while preliminary experimental results suggest a cytosolic location.
Widely expressed, including in breast epithelial cells and endothelial cells (at protein level). Expression is down-regulated in advanced breast tumors (at protein level).
Belongs to the TGF-beta family. GDNF subfamily.
Expressed during embryogenesis. High level expression seen in fetal kidney and lung while a low level expression seen in the fetal brain.
Homodimer; disulfide-linked. Binds to RET (By similarity).
Ligand for the GFR-alpha-3-RET receptor complex but can also activate the GFR-alpha-1-RET receptor complex. Supports the survival of sensory and sympathetic peripheral neurons in culture and also supports the survival of dopaminergic neurons of the ventral mid-brain. Strong attractant of gut hematopoietic cells thus promoting the formation Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue.
Ubiquitous. Expressed at high levels in peripheral tissues including prostate, placenta, pancreas, heart, kidney, pituitary gland, lung and testis. Expressed at low levels in the brain.
Can bind ESR1 and ESR2. This interaction is abrogated by estrogen and augmented by tamoxifen treatment.
Forms homooligomers. Interacts with ADGRB3. Interacts with C1QL2 and C1QL4, when proteins are coexpressed; this interaction does not occur after secretion.
Highly expressed in adipose tissue, with expression levels at least 2 orders of magnitude higher than in other tissues, including brain and kidney.
May regulate the number of excitatory synapses that are formed on hippocampus neurons. Has no effect on inhibitory synapses (By similarity). Plays a role in glucose homeostasis. Via AMPK signaling pathway, stimulates glucose uptake in adipocytes, myotubes and hepatocytes and enhances insulin-stimulated glucose uptake. In a hepatoma cell line, reduces the expression of gluconeogenic enzymes G6PC1 and PCK1 and hence decreases de novo glucose production (By similarity).
Belongs to the glyceraldehyde-3-phosphate dehydrogenase family.
Homotetramer. Interacts with ARRB2; the interaction is detected in the nucleus upon OR1D2 stimulation.
May play an important role in regulating the switch between different pathways for energy production during spermiogenesis and in the spermatozoon. Required for sperm motility and male fertility (By similarity).
The testis-specific N-terminal extension mediates tight association with the cytoskeletal fibrous sheath of the spermatozoa flagellum, possibly via interchain disulfide-bonding of Cys-21 with sheath components.
Couples the p55 TNF-receptor (TNF-R55 / TNFR1) to neutral sphingomyelinase (N-SMASE). Specifically binds to the N-smase activation domain of TNF-R55. May regulate ceramide production by N-SMASE.
A heterodimeric complex, composed of a mucin-4 alpha chain and a cysteine-rich transmembrane mucin-4 beta chain. Mucin-4 beta chain interacts with ERBB2 via the EGF-like domain 1. In nonpolarized cells, associates with ERBB2 and ERBB3.
Essentially composed of an array of serine- and threonine-rich tandem repeats which is highly polymorphic, the variable number of tandem repeats (VNTR) region.
Expressed early in the primitive gut before respiratory and digestive epithelial cells have acquired their tissue and cell specificity. Expressed at the basal surface of the epithelium from week 14 to 26 weeks and then predominantly localized in only parietal cells. Immediately before birth, found in the cytoplasm of the mucous columnar epithelial cells. In the embryo expressed in skin, then disappears late in gestation.
Expressed in the thymus, thyroid, lung, trachea, esophagus, stomach, small intestine, colon, testis, prostate, ovary, uterus, placenta, and mammary and salivary glands. Expressed in carcinomas arising from some of these epithelia, such as lung cancers, squamous cell carcinomas of the upper aerodigestive tract, mammary carcinomas, biliary tract, colon, and cervix cancers. Minimally or not expressed in the normal pancreas or chronic pancreatitis, but is highly expressed in pancreatic tumors and pancreatic tumor cell lines.
Expression is a very useful predictor of poor prognosis in patients with invasive ductal carcinoma and intrahepatic cholangiocarcinoma, mass forming type (IDC,ICC-MF). Patients with IDC or ICC-MF who have high MUC4 expression had a worse survival rate than those with low MUC4 expression.
May be derived from an intron translation.
May be preferentially expressed in tumor tissues.
Membrane-bound mucin, a family of highly glycosylated proteins that constitute the major component of the mucus, the slimy and viscous secretion covering epithelial surfaces (PubMed:10880978). These glycoproteins play important roles in the protection of the epithelium and are implicated in epithelial renewal and differentiation (PubMed:10880978). Regulates cellular behavior through both anti-adhesive effects on cell-cell and cell-extracellular matrix interactions and its ability to act as an intramembrane ligand for ERBB2. Plays an important role in proliferation and differentiation of epithelial cells by inducing specific phosphorylation of ERBB2. In polarized epithelial cells, segregates ERBB2 and other ERBB receptors and prevents ERBB2 from acting as a coreceptor. The interaction with ERBB2 leads to enhanced expression of CDKN1B. The formation of a MUC4-ERBB2-ERBB3-NRG1 complex leads to down-regulation of CDKN1B, resulting in repression of apoptosis and stimulation of proliferation. Its ability to promote tumor growth may be mainly due to repression of apoptosis as opposed to proliferation.
Proteolytically cleaved into 2 chains, mucin-4 alpha chain and mucin-4 beta chain.
The variable number of tandem repeats (VNTR) region, an array of serine- and threonine-rich tandem repeats, is encoded by a single exon (exon 2) which is highly polymorphic.
Supercomplex made of cofactors A to E. Cofactors A and D function by capturing and stabilizing tubulin in a quasi-native conformation. Cofactor E binds to the cofactor D-tubulin complex; interaction with cofactor C then causes the release of tubulin polypeptides that are committed to the native state. Cofactors B and E can form a heterodimer which binds to alpha-tubulin and enhances their ability to dissociate tubulin heterodimers (By similarity). Interacts with TBCD (PubMed:27666374).
Tubulin-folding protein; involved in the second step of the tubulin folding pathway and in the regulation of tubulin heterodimer dissociation. Required for correct organization of microtubule cytoskeleton and mitotic splindle, and maintenance of the neuronal microtubule network.
Associates with NXF1, NXF2, NXF3 and NXF5.
Regulator of protein export for NES-containing proteins. Also plays a role in mRNA nuclear export.
May activate CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. May play a role in regulating the actin cytoskeleton and cell shape (By similarity).
Expressed at low levels in a number of tissues.
Abundantly expressed in placenta and weakly expressed in small intestine.
Expressed in most tissues examined. Expressed in kidney glomeruli (PubMed:33232676).
Interacts with DVL3. Interacts with INF2 (PubMed:33232676).
Key regulator of the Wnt signaling pathway, which is required for various processes during development, such as dorsal patterning, determination of left/right symmetry or myelination in the central nervous system. Acts downstream of Wnt ligands and upstream of beta-catenin (CTNNB1). Required for canonical Wnt signaling pathway during patterning in the dorsal spinal cord by promoting the aggregation of Disheveled (Dvl) complexes, thereby clustering and formation of Wnt receptor signalosomes and potentiating Wnt activity. During dorsal patterning of the spinal cord, inhibits oligodendrocytes differentiation via interaction with PIP5K1A. Also regulates non-canonical Wnt signaling pathway. Acts downstream of PITX2 in the developing gut and is required for left/right asymmetry within dorsal mesentery: affects mesenchymal condensation by lengthening cadherin-based junctions through WNT5A and non-canonical Wnt signaling, inducing polarized condensation in the left dorsal mesentery necessary to initiate gut rotation. Together with DAAM1, required for myocardial maturation and sarcomere assembly. Is a regulator of actin nucleation and elongation, filopodia formation and podocyte migration (PubMed:33232676).
The DAD domain regulates activation via an autoinhibitory interaction with the GBD/FH3 domain. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments (By similarity).
Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins (PubMed:30415835, PubMed:29809151, PubMed:29242231, PubMed:32459176, PubMed:32439656). Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues (PubMed:30415835, PubMed:29809151, PubMed:29242231). Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices (PubMed:30415835, PubMed:29809151). It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes (PubMed:29809151, PubMed:29242231). By mediating the proper cotranslational insertion of N-terminal transmembrane domains in an N-exo topology, with translocated N-terminus in the lumen of the ER, controls the topology of multi-pass membrane proteins like the G protein-coupled receptors (PubMed:30415835). By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes (Probable). Promotes angiogenesis and tissue repair in the heart after myocardial infarction. Stimulates cardiac endothelial cell migration and outgrowth via the activation of p38 MAPK, PAK and MAPK2 signaling pathways (PubMed:28931551).
Present in serum (at protein level). Increased expression seen in the left ventrice after myocardial infarction (at protein level). Expressed in the pituitary gland. Expressed in brain (PubMed:33531666).
H1 histones are progressively phosphorylated during the cell cycle, becoming maximally phosphorylated during late G2 phase and M phase, and being dephosphorylated sharply thereafter (By similarity). Phosphorylated at Thr-11 by GSK3B during mitosis in prometaphase and dephosphorylated in telophase.
Ubiquitous. Expressed in the majority of the cell lines tested and in testis.
Genetic variations in PSCA may influence susceptibility to some cancers. A polymorphism gives rise to an upstream methionine which produces a longer protein of 123 residues associated with various cancers including diffuse-type gastric cancer and urinary bladder cancer.
Highly expressed in prostate (basal, secretory and neuroendocrine epithelium cells). Also found in bladder (transitional epithelium), placenta (trophoblasts), stomach (neuroendocrine cells), colon (neuroendocrine cells) and kidney (collecting ducts). Overexpressed in prostate cancers and expression is correlated with tumor stage, grade and androgen-independence. Highly expressed in prostate cancer bone metastases. Expressed in gastric epithelial cells, mainly in the isthmus (at protein level). Not detected in normal intestinal epithelium (at protein level). Expressed in brain cortex; expression is significantly increased in the front cortex of Alzheimer disease patients.
May act as a modulator of nicotinic acetylcholine receptors (nAChRs) activity. In vitro inhibits nicotine-induced signaling probably implicating alpha-3:beta-2- or alpha-7-containing nAChRs.
May be involved in the regulation of cell proliferation. Has a cell-proliferation inhibition activity in vitro.
Belongs to the bacterial ribosomal protein bS1 family.
Component of the mitochondrial small ribosomal subunit (mt-SSU) (PubMed:30566640). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins.
Available under the name Nesiritide (Scios). Used for the treatment of heart failure.
Cardiac hormone that plays a key role in mediating cardio-renal homeostasis (PubMed:9458824, PubMed:1672777, PubMed:1914098, PubMed:17372040). May also function as a paracrine antifibrotic factor in the heart (By similarity). Acts by specifically binding and stimulating NPR1 to produce cGMP, which in turn activates effector proteins that drive various biological responses (PubMed:9458824, PubMed:1672777, PubMed:17372040, PubMed:21098034, PubMed:17349887, PubMed:25339504). Involved in regulating the extracellular fluid volume and maintaining the fluid-electrolyte balance through natriuresis, diuresis, vasorelaxation, and inhibition of renin and aldosterone secretion (PubMed:9458824, PubMed:1914098). Binds the clearance receptor NPR3 (PubMed:16870210).
Detected in the cardiac atria (at protein level) (PubMed:2138890, PubMed:2136732). Detected in the kidney distal tubular cells (at protein level) (PubMed:9794555).
May affect cardio-renal homeostasis (PubMed:17372040). Able to promote the production of cGMP although its potency is very low compared to brain natriuretic peptide 32 (PubMed:17372040).
May have a role in cardio-renal homeostasis (PubMed:17372040). Able to promote the production of cGMP (PubMed:17372040).
O-glycosylated on at least seven residues (PubMed:20489134, PubMed:21763278, PubMed:16750161, PubMed:17349887, PubMed:21482747). In cardiomyocytes, glycosylation at Thr-97 is essential for the stability and processing of the extracellular natriuretic peptides B (PubMed:21482747). Glycosylation, especially at Thr-97, may also be important for brain natriuretic peptide 32 stability and/or extracellular distribution (PubMed:21763278). Glycosylation at Thr-97 appears to inhibit FURIN- or CORIN-mediated proteolytic processing, at least in HEK293 cells (PubMed:20489134, PubMed:21763278).
Plasma levels of natriuretic peptides B, brain natriuretic peptide 32 and NT-proBNP are widely used for screening and diagnosis of heart failure (HF), as these markers are typically higher in patients with severe HF.
The precursor molecule is proteolytically cleaved by the endoproteases FURIN or CORIN at Arg-102 to produce brain natriuretic peptide 32 and NT-proBNP (PubMed:21314817, PubMed:10880574, PubMed:21763278, PubMed:20489134, PubMed:21482747). This likely occurs after it has been secreted into the blood, either during circulation or in the target cells (PubMed:21482747). CORIN also cleaves the precursor molecule at additional residues including Arg-99 and possibly Lys-105 (PubMed:20489134, PubMed:21763278). In patients with heart failure, processing and degradation of natriuretic peptides B occurs but is delayed, possibly due to a decrease in enzyme level or activity of CORIN and DPP4 (PubMed:25339504).
Undergoes further proteolytic cleavage by various proteases such as DPP4, MME and possibly FAP, to give rise to a variety of shorter peptides (PubMed:16254193, PubMed:19808300, PubMed:21314817, PubMed:21098034). Cleaved at Pro-104 by the prolyl endopeptidase FAP (seprase) activity (in vitro) (PubMed:21314817). Degraded by IDE (PubMed:21098034). During IDE degradation, the resulting products initially increase the activation of NPR1 and can also stimulate NPR2 to produce cGMP before the fragments are completely degraded and inactivated by IDE (in vitro) (PubMed:21098034).
Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-122 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability (By similarity).
Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. Hominid-specific H3.5/H3F3C preferentially colocalizes with euchromatin, and it is associated with actively transcribed genes.
Methylation at Lys-5 (H3K4me) is linked to gene activation. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are linked to gene repression. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) requires preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-56 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication (By similarity).
Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 or isoform M2 of PKM (PKM2) is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Tyr-41 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin (By similarity).
Specifically expressed in the seminiferous tubules of testis.
Succinylated. Desuccinylation at Lys-122 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair.
May play a role in motor coordination and exploratory behavior.
(Microbial infection) Inactivated by S.flexneri OspC1 and OspC3 proteins, which specifically bind the apo-form of calmodulin, thereby preventing calcium-binding and activity.
(Microbial infection) Interacts with C.violaceum CopC (PubMed:35446120, PubMed:35338844, PubMed:36423631). C.violaceum CopC interacts specifically with the apo form of calmodulin (PubMed:35446120, PubMed:36423631).
(Microbial infection) Interacts with Legionella pneumophila glutamylase SidJ.
(Microbial infection) Interacts with Rubella virus protease/methyltransferase p150.
(Microbial infection) Interacts with S.flexneri OspC1 and OspC3 (PubMed:35568036). S.flexneri OspC1 and OspC3 interact specifically with the apo form of calmodulin and prevents calcium-binding (PubMed:35568036).
(Microbial infection) Required for C.violaceum CopC arginine ADP-riboxanase activity.
(Microbial infection) Required for Legionella pneumophila SidJ glutamylase activity.
Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding (PubMed:16760425, PubMed:23893133, PubMed:26969752, PubMed:27165696, PubMed:28890335, PubMed:31454269, PubMed:35568036). Calcium-binding is required for the activation of calmodulin (PubMed:16760425, PubMed:23893133, PubMed:26969752, PubMed:27165696, PubMed:28890335, PubMed:31454269, PubMed:35568036). Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases, such as myosin light-chain kinases and calmodulin-dependent protein kinase type II (CaMK2), and phosphatases (PubMed:16760425, PubMed:23893133, PubMed:26969752, PubMed:27165696, PubMed:28890335, PubMed:31454269, PubMed:35568036). Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Is a regulator of voltage-dependent L-type calcium channels (PubMed:31454269). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696). Forms a potassium channel complex with KCNQ1 and regulates electrophysiological activity of the channel via calcium-binding (PubMed:25441029). Acts as a sensor to modulate the endoplasmic reticulum contacts with other organelles mediated by VMP1:ATP2A2 (PubMed:28890335).
Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding (PubMed:16760425, PubMed:26969752, PubMed:27165696). Calcium-binding is required for the activation of calmodulin (PubMed:16760425, PubMed:35568036, PubMed:26969752, PubMed:27165696). Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases, such as myosin light-chain kinases and calmodulin-dependent protein kinase type II (CaMK2), and phosphatases (PubMed:16760425, PubMed:35568036, PubMed:26969752, PubMed:27165696). Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).
Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding (PubMed:16760425, PubMed:31454269). Calcium-binding is required for the activation of calmodulin (PubMed:35568036, PubMed:16760425, PubMed:31454269). Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases, such as myosin light-chain kinases and calmodulin-dependent protein kinase type II (CaMK2), and phosphatases (PubMed:16760425, PubMed:35568036). Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425).
Interacts with MYO1C, MYO5A and RRAD. Interacts with MYO10 (By similarity). Interacts with CEP97, CCP110, TTN/titin and SRY (PubMed:9804419, PubMed:12871148, PubMed:15746192, PubMed:16760425, PubMed:17719545). Interacts with USP6; the interaction is calcium dependent (PubMed:16127172). Interacts with CDK5RAP2 (PubMed:20466722). Interacts with SCN5A (By similarity). Interacts with RYR1 (PubMed:18650434). Interacts with FCHO1 (PubMed:22484487). Interacts with MIP in a 1:2 stoichiometry; the interaction with the cytoplasmic domains from two MIP subunits promotes MIP water channel closure (By similarity). Interacts with ORAI1; this may play a role in the regulation of ORAI1-mediated calcium transport (By similarity). Interacts with IQCF1 (By similarity). Interacts with SYT7 (By similarity). Interacts with CEACAM1 (via cytoplasmic domain); this interaction is in a calcium dependent manner and reduces homophilic cell adhesion through dissociation of dimer (By similarity). Interacts with RYR2; regulates RYR2 calcium-release channel activity (PubMed:27516456, PubMed:18650434). Interacts with PCP4; regulates calmodulin calcium-binding (PubMed:27876793). Interacts with the heterotetrameric KCNQ2 and KCNQ3 channel; the interaction is calcium-independent, constitutive and participates in the proper assembly of a functional heterotetrameric M channel (PubMed:27564677).
Interacts with MYO1C, MYO5A and RRAD. Interacts with MYO10 (By similarity). Interacts with CEP97, CCP110, TTN/titin and SRY (PubMed:9804419, PubMed:12871148, PubMed:15746192, PubMed:16760425, PubMed:17719545). Interacts with USP6; the interaction is calcium dependent (PubMed:16127172). Interacts with CDK5RAP2 (PubMed:20466722). Interacts with SCN5A (By similarity). Interacts with RYR1 (PubMed:18650434). Interacts with FCHO1 (PubMed:22484487). Interacts with MIP in a 1:2 stoichiometry; the interaction with the cytoplasmic domains from two MIP subunits promotes MIP water channel closure (By similarity). Interacts with ORAI1; this may play a role in the regulation of ORAI1-mediated calcium transport (By similarity). Interacts with IQCF1 (By similarity). Interacts with SYT7 (By similarity). Interacts with CEACAM1 (via cytoplasmic domain); this interaction is in a calcium dependent manner and reduces homophilic cell adhesion through dissociation of dimer (By similarity). Interacts with RYR2; regulates RYR2 calcium-release channel activity (PubMed:27516456, PubMed:18650434, PubMed:26164367). Interacts with PCP4; regulates calmodulin calcium-binding (PubMed:27876793). Interacts with the heterotetrameric KCNQ2 and KCNQ3 channel; the interaction is calcium-independent, constitutive and participates in the proper assembly of a functional heterotetrameric M channel (PubMed:27564677).
Interacts with MYO1C, MYO5A and RRAD. Interacts with MYO10 (By similarity). Interacts with CEP97, CCP110, TTN/titin and SRY (PubMed:9804419, PubMed:12871148, PubMed:15746192, PubMed:16760425, PubMed:17719545). Interacts with USP6; the interaction is calcium dependent (PubMed:16127172). Interacts with CDK5RAP2 (PubMed:20466722). Interacts with SCN5A (PubMed:21167176). Interacts with RYR1 (PubMed:18650434). Interacts with FCHO1 (PubMed:22484487). Interacts with MIP in a 1:2 stoichiometry; the interaction with the cytoplasmic domains from two MIP subunits promotes MIP water channel closure (PubMed:23893133). Interacts with ORAI1; this may play a role in the regulation of ORAI1-mediated calcium transport (By similarity). Interacts with IQCF1 (By similarity). Interacts with SYT7 (By similarity). Interacts with CEACAM1 (via cytoplasmic domain); this interaction is in a calcium dependent manner and reduces homophilic cell adhesion through dissociation of dimer (By similarity). Interacts with RYR2; regulates RYR2 calcium-release channel activity (PubMed:27516456, PubMed:18650434, PubMed:26164367). Interacts with PCP4; regulates calmodulin calcium-binding (PubMed:27876793). Interacts with the heterotetrameric KCNQ2 and KCNQ3 channel; the interaction is calcium-independent, constitutive and participates in the proper assembly of a functional heterotetrameric M channel (PubMed:27564677). Interacts with alpha-synuclein/SNCA (PubMed:23607618). Interacts with SLC9A1 in a calcium-dependent manner (PubMed:30287853). In the absence of Ca(+2), interacts with GIMAP4 (via IQ domain) (By similarity). Interacts with SCN8A; the interaction modulates the inactivation rate of SCN8A (By similarity). Interaction with KIF1A; the interaction is increased in presence of calcium and increases neuronal dense core vesicles motility (PubMed:30021165). Interacts with KCNN3 (PubMed:31155282). Interacts with KCNQ1 (via C-terminus); forms a heterooctameric structure (with 4:4 KCNQ1:CALM stoichiometry) in a calcium-independent manner (PubMed:18165683, PubMed:25441029). Interacts with PIK3C3; the interaction modulates PIK3C3 kinase activity (PubMed:28890335). Interacts with HINT1; interaction increases in the presence of calcium ions (By similarity). Interacts with HINT3 (By similarity). Interacts with GARIN2; in mature sperm flagella (By similarity). Interacts with IQUB (By similarity). Interacts with SLC26A5 (via STAS domain); this interaction is calcium-dependent and the STAS domain interacts with only one lobe of CALM which is an elongated conformation (PubMed:33667636).
Phosphorylation results in a decreased activity.
The N-terminal and C-terminal lobes of CALM bind to the C-terminus of KCNQ1 in a clamp-like conformation. Binding of CALM C-terminus to KCNQ1 is calcium-independent but is essential for assembly of the structure. Binding of CALM N-terminus to KCNQ1 is calcium-dependent and regulates electrophysiological activity of the channel.
The disease is caused by variants affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4.
The disease is caused by variants affecting the gene represented in this entry. Mutations in CALM2 are the cause of LQT15.
Ubiquitination results in a strongly decreased activity.
Although it belongs to the ADP-ribosylglycohydrolase family, lacks the metal-binding and substrate-binding residues, suggesting that it has no hydrolase activity.
Required for myofibril assembly and outgrowth of the cardiac chambers in the developing heart (By similarity). Appears to be catalytically inactive, showing no activity against O-acetyl-ADP-ribose (By similarity).
Available under the names Groliberin (Pharmacia) or Somatrel (Ferring). Also available under the name Geref (Serono). Geref is a synthetic acetylated form of residues 1 to 29 of GHRH. Used for the treatment of growth hormone deficiency.
Can be used for targeted secretion inhibition. A construct with this protein's ligand domain inserted between the C.botulinum neurotoxin type D (BoNT/D, botD) light chain and translocation domains, when injected into rats, leads to decreased growth hormone production. The GHRH ligand domain binds to the GHRH receptor on somatotrophs where it is taken up into endosomes. There the translocation domain inserts into the membrane, releasing the light chain which cleaves synaptobrevin and inhibits growth hormone exocytosis (PubMed:24029240, PubMed:26324071).
GRF is released by the hypothalamus and acts on the adenohypophyse to stimulate the secretion of growth hormone.
The repeat encompassing Pro-495 to Glu-507 may be polymorphic.
May play a role in photoreceptor development.
May be proteolytically processed at the boundary between the N-terminal non-conserved and the central conserved domain in neuron-like cells.
May be signaling molecules that resemble neuropeptides. Ligand for alpha-neurexins (By similarity).
Component of the SKA1 complex, a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation (PubMed:17093495, PubMed:19289083, PubMed:23085020). Required for timely anaphase onset during mitosis, when chromosomes undergo bipolar attachment on spindle microtubules leading to silencing of the spindle checkpoint (PubMed:17093495). The SKA1 complex is a direct component of the kinetochore-microtubule interface and directly associates with microtubules as oligomeric assemblies (PubMed:19289083). The complex facilitates the processive movement of microspheres along a microtubule in a depolymerization-coupled manner (PubMed:19289083). Affinity for microtubules is synergistically enhanced in the presence of the ndc-80 complex and may allow the ndc-80 complex to track depolymerizing microtubules (PubMed:23085020). In the complex, it mediates the interaction with microtubules (PubMed:19289083, PubMed:23085020).
Component of the SKA1 complex, composed of SKA1, SKA2 and SKA3 (PubMed:17093495). Forms a heterodimer with SKA2; the heterodimer interacting with SKA3 (PubMed:17093495, PubMed:19289083, PubMed:23085020). The core SKA1 complex is composed of 2 SKA1-SKA2 heterodimers, each heterodimer interacting with a molecule of the SKA3 homodimer (PubMed:19289083). The core SKA1 complex associates with microtubules and forms oligomeric assemblies (PubMed:17093495, PubMed:19289083). Interacts with microtubules; the interaction is direct (PubMed:19289083, PubMed:23085020). Interacts with SKA2 (PubMed:19289083). Interacts with SKA3 (PubMed:19289083, PubMed:23085020).
By IFN-alpha, IFNB1/IFN-beta and IFNG/IFN-gamma. Down-regulated by p53/TP53.
IFN-induced antiviral protein which inhibits the entry of viruses to the host cell cytoplasm, permitting endocytosis, but preventing subsequent viral fusion and release of viral contents into the cytosol (PubMed:33563656, PubMed:26354436). Active against multiple viruses, including influenza A virus, SARS coronaviruses (SARS-CoV and SARS-CoV-2), Marburg virus (MARV), Ebola virus (EBOV), Dengue virus (DNV), West Nile virus (WNV), human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV) and vesicular stomatitis virus (VSV) (PubMed:33563656, PubMed:26354436, PubMed:33270927, PubMed:33239446). Can inhibit: influenza virus hemagglutinin protein-mediated viral entry, MARV and EBOV GP1,2-mediated viral entry, SARS-CoV and SARS-CoV-2 S protein-mediated viral entry and VSV G protein-mediated viral entry (PubMed:33563656). Induces cell cycle arrest and mediates apoptosis by caspase activation and in p53-independent manner. In hepatocytes, IFITM proteins act in a coordinated manner to restrict HCV infection by targeting the endocytosed HCV virion for lysosomal degradation (PubMed:26354436). IFITM2 and IFITM3 display anti-HCV activity that may complement the anti-HCV activity of IFITM1 by inhibiting the late stages of HCV entry, possibly in a coordinated manner by trapping the virion in the endosomal pathway and targeting it for degradation at the lysosome (PubMed:26354436).
Palmitoylation on membrane-proximal cysteines controls clustering in membrane compartments and antiviral activity.
Phosphorylation at Tyr-19 is required for endosomal and lysosomal location.
May interact with NGFR (By similarity). Interacts with RPN1, RPN2 and CANX (By similarity).
Molecular chaperone which mediates the proper assembly and functional expression of the nicotinic acetylcholine receptors (nAChRs) throughout the brain (PubMed:26875622, PubMed:27789755, PubMed:28445721, PubMed:32204458, PubMed:32783947). Essential for the proper folding, assembly, function and surface trafficking of alpha-7 (CHRNA7), alpha-4-beta-2, alpha-3-beta-2 and alpha-3-beta-4 receptors (PubMed:26875622, PubMed:27789755, PubMed:28445721, PubMed:32204458, PubMed:32783947). Stably associates with ribophorin-1 (RPN1) and ribophorin-2 (RPN2) (components of the oligosaccharyl transferase (OST) complex) and with calnexin (CANX), both of which are critical for NACHO-mediated effects on CHRNA7 assembly and function (By similarity). Facilitates the proper folding and assembly of alpha-6-beta-2 and alpha-6-beta-2-beta-3 receptors and acts at early stages of the nAChRs subunit assembly (PubMed:28445721). Promotes the expression of the alpha-4(2):beta-2(3) stoichiometric form over the alpha-4(3):beta-2(2) form (PubMed:32676916).
Expressed in testis, brain, pituitary, colon, heart, nerves, prostate, esophagus, lung liver and small intestine (PubMed:29431694). Highly expressed in macrophages, also expressed in monocytes and at low levels in NK and NKT cells (at protein level) (PubMed:29431694).
Expression is up-regulated following differentiation of monocytes to macrophages.
Interacts with MARVELD2 and OCLN. Interacts with P4HB AND HSPA5; the interaction with HSPA5 stabilizes ILDR2 expression. Interacts (via C-terminus) with TRA2A, TRA2B and SRSF1.
May be involved in ER stress pathways with effects on lipid homeostasis and insulin secretion. With ILDR1 and LSR, involved in the maintain of the epithelial barrier function through the recruitment of MARVELD2/tricellulin to tricellular tight junctions (By similarity). Also functions as a B7-like protein family member expressed on immune cells and inflamed tissue and with T-cell inhibitory activity (PubMed:29431694). In the inner ear, may regulate alternative pre-mRNA splicing via binding to TRA2A, TRA2B and SRSF1 (By similarity).
By forskolin (at protein level). By thyrotropin and the Th2-specific cytokines IL-4 and IL-13.
Expressed in thyrocytes and tracheal surface epithelial cells (at protein level). Expressed in thyroid, trachea, bronchium, and to a lower extent, in placenta, testis, prostate, pancreas and heart.
Generates hydrogen peroxide which is required for the activity of thyroid peroxidase/TPO and lactoperoxidase/LPO. Plays a role in thyroid hormones synthesis and lactoperoxidase-mediated antimicrobial defense at the surface of mucosa. May have its own peroxidase activity through its N-terminal peroxidase-like domain.
In the N-terminal section; belongs to the peroxidase family.
The NADPH oxidase activity is calcium-dependent. Peroxidase activity is inhibited by aminobenzohydrazide.
Detected in heart, liver, lung and liver (at protein level). Detected in fetal heart, lung, liver and kidney. Detected in adult heart, placenta, lung, liver, skeletal muscle, kidney and pancreas.
GTP-binding protein that recruits several effectors, such as golgins, arfaptins and Arf-GEFs to the trans-Golgi network, and modulates their functions at the Golgi complex (PubMed:9624189, PubMed:21239483, PubMed:27436755, PubMed:22679020, PubMed:27373159). Plays thereby a role in a wide range of fundamental cellular processes, including cell polarity, innate immunity, or protein secretion mediated by arfaptins, which were shown to play a role in maintaining insulin secretion from pancreatic beta cells (PubMed:22981988).
The GTP-bound form interacts with GOLGA1 (By similarity). The GTP-bound form interacts with GOLGA4 and RGPD8. The GTP-bound form directly interacts with ARFIP2 (PubMed:11303027, PubMed:21239483, PubMed:22679020). Binds to SCOC, preferentially in its GTP-bound form. May interact with UNC119 (PubMed:11303027, PubMed:14580338). Interacts with ARFIP1; this interaction directs ARFIP1 to the trans-Golgi membranes (PubMed:21239483, PubMed:22981988). Interacts with ARFGEF1 (via N-terminus) (PubMed:27436755, PubMed:27373159).
Highly expressed in placenta, lung, pancreas. Lower levels in heart, brain, liver, skeletal muscle and kidney.
Interacts with CHP1; the interaction induces CHP1 to translocate from the Golgi to the nucleus.
Phosphorylates myosin light chains (By similarity). Acts as a positive regulator of apoptosis.
Expression is slightly increased in naive B-cells after the first dividion. By contrast, expression on memory B-cells decreased with each successive division.
Homodimer; via its extracellular domain. Forms a head to tail dimer with a CD48 molecule from another cell. Interacts with SH2 domain-containing proteins SH2D1A/SAP and SH2D1B/EAT-2. Interacts with tyrosine-protein phosphatases PTPN6/SHP-1 and PTPN11//SHP-2 via its phosphorylated cytoplasmic domain, and this interaction is blocked by SH2D1A. Interacts (via phosphorylated ITSM 1 and 2) with INPP5D/SHIP1.
Phosphorylated by tyrosine-protein kinase LCK on tyrosine residues following ligation induced by agonist monoclonal antibody. The association with SH2D1A is dependent of tyrosine phosphorylation of its cytoplasmic domain. Phosphorylated on Tyr-296 and Tyr-316 following platelet aggregation. Phosphorylated on tyrosine residues upon high affinity immunoglobulin epsilon receptor aggregation in mast cells.
Predominantly expressed in hematopoietic tissues, such as lymph node, spleen and peripheral leukocytes. Expressed in macrophages, B-cells, monocytes, platelets, thymocytes, T-cells and dendritic cells. Highly expressed in memory T-cells. Expressed in mast cells.
Self-ligand receptor of the signaling lymphocytic activation molecule (SLAM) family. SLAM receptors triggered by homo- or heterotypic cell-cell interactions are modulating the activation and differentiation of a wide variety of immune cells and thus are involved in the regulation and interconnection of both innate and adaptive immune response. Activities are controlled by presence or absence of small cytoplasmic adapter proteins, SH2D1A/SAP and/or SH2D1B/EAT-2. Can mediate natural killer (NK) cell cytotoxicity dependent on SH2D1A and SH2D1B (By similarity). Increases proliferative responses of activated T-cells and SH2D1A/SAP does not seem be required for this process. Homophilic interactions enhance interferon gamma/IFNG secretion in lymphocytes and induce platelet stimulation via a SH2D1A-dependent pathway. May serve as a marker for hematopoietic progenitor cells (PubMed:11564780, PubMed:12115647, PubMed:12928397, PubMed:12962726, PubMed:16037392) Required for a prolonged T-cell:B-cell contact, optimal T follicular helper function, and germinal center formation. In germinal centers involved in maintaining B-cell tolerance and in preventing autoimmunity (By similarity). In mast cells negatively regulates high affinity immunoglobulin epsilon receptor signaling; independent of SH2D1A and SH2D1B but implicating FES and PTPN6/SHP-1 (PubMed:22068234). In macrophages enhances LPS-induced MAPK phosphorylation and NF-kappaB activation and modulates LPS-induced cytokine secretion; involving ITSM 2 (By similarity). Positively regulates macroautophagy in primary dendritic cells via stabilization of IRF8; inhibits TRIM21-mediated proteasomal degradation of IRF8 (PubMed:29434592).
The ITSMs (immunoreceptor tyrosine-based switch motifs) with the consensus sequence T-X-Y-X-X-[VI] present in SLAM family receptors have overlapping specificity for activating and inhibitory SH2 domain-containingbinding partners. Especially they mediate the interaction with the SH2 domain of SH2D1A and SH2D1B. A 'three-pronged' mechanism is proposed involving threonine (position -2), phosphorylated tyrosine (position 0) and valine/isoleucine (position +3).
Adapter protein that plays a role in endocytosis via clathrin-coated pits. Contributes to the internalization of cell surface receptors, such as integrin ITGB1 and transferrin receptor (PubMed:29887380). Promotes endocytosis of EGFR in cancer cells, and thereby contributes to the down-regulation of EGFR signaling (PubMed:30249660). Recruited to clathrin-coated pits during a mid-to-late stage of assembly, where it is required for normal progress from U-shaped intermediate stage pits to terminal, omega-shaped pits (PubMed:29887380). Binds to membranes enriched in phosphatidylinositol 3,4-bisphosphate or phosphatidylinositol 3,4,5-trisphosphate (PubMed:29887380). When bound to membranes, promotes actin polymerization via its interaction with WAS and/or WASL which leads to the activation of the Arp2/3 complex. Does not promote actin polymerisation in the absence of membranes (PubMed:29887380).
Homodimer (PubMed:29887380). Interacts (via SH3 domain 2) with ITSN1 (via SH3 domain 4). Recruited to clathrin-coated pits during a mid-to-late stage of assembly via interaction with ITSN1. Interacts (via SH3 domain 1) with WASL (PubMed:29887380). Interacts with WAS (By similarity). Interacts with CASK and MAGI1. CASK inhibits interaction with MAGI1 (PubMed:14627983).
Liver, brain, heart, placenta, skeletal muscle, pancreas, lung and kidney.
Phosphorylated. Phosphorylation on a Ser residue is important for recruitment to the cell membrane and for its role in promoting endocytosis.
Recruited to clathrin-coated pits via SH3 domain 2.
The F-BAR domain has an atypical, flat shape and binds preferentially to flat membranes. Upon heterologous expression, the isolated F-BAR domain is localized at the cell membrane, and causes the formation of cellular protrusions.
The function in endocytosis may depend on the cell type. Plays a role in EGFR endocytosis via clathrin-coated pits in cancer cells, but apparently not in normal cells (PubMed:30249660). A later study used both HeLa cells and BSC1 cells (a C.aethiops kidney cell line), and did not mention any cell-type specific effects (PubMed:29887380).
The two SH3 domains cooperate to maintain the protein in an autoinhibited conformation that prevents promiscuous membrane binding.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ13 subfamily.
Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. KCNJ13 has a very low single channel conductance, low sensitivity to block by external barium and cesium, and no dependence of its inward rectification properties on the internal blocking particle magnesium.
Phosphorylation at Ser-201 by PKC strongly inhibits ionic currents, while phosphorylation at Ser-287 by PKA increases them.
Predominantly expressed in small intestine. Expression is also detected in stomach, kidney, and all central nervous system regions tested with the exception of spinal cord.
Found only in the eye, where it is localized to the retinal pigment epithelium (RPE). In the RPE, it is localized to the microvilli that surround the photoreceptor outer segments.
May play a role in rpe physiology either by detecting light directly or by monitoring the concentration of retinoids or other photoreceptor-derived compounds.
GTPase-activating protein (GAP) for ADP ribosylation factor 6 (ARF6).
Interacts with RAB35 (GTP-bound form); the interaction is direct and probably recruits ACAP2 to membranes. Interacts with MICALL1; the interaction is indirect through RAB35 (By similarity).
Widely expressed. Highest level in lung.
Transcriptional repressor; binds to the DNA sequence 5'-CCGGAAGT-3'. Isoform A does not seem to have a repressor activity. Isoform C does not seem to have a repressor activity.
Expressed in brain, cervix, heart, liver, ovary, kidney, prostate and testis.
Inhibits translation of capped and polyadenylated mRNAs by displacing PABPC1 from the poly(A) tail.
Interacts (via central acidic portion and C-terminus) with PABPC1 (via the second and third RRM domains and the C-terminus).
Transcription factor. Binds to the iroquois binding site (IBS) motif of target genes to regulate gene expression; functions as a transcriptional activator or repressor. Modulates expression of RCVRN, VSX1, BHLHE22/BHLHB5 and TACR3/Nk3r. Required downstream of retinal bipolar cell specification for the terminal differentiation of type 2, type 3a and possibly type 6 bipolar cells.
Ca(2+)-dependent actin filament-severing protein that has a regulatory function in exocytosis by affecting the organization of the microfilament network underneath the plasma membrane (PubMed:8547642, PubMed:26365202). Severing activity is inhibited by phosphatidylinositol 4,5-bis-phosphate (PIP2) (By similarity). In vitro, also has barbed end capping and nucleating activities in the presence of Ca(2+). Required for megakaryocyte differentiation, maturation, polyploidization and apoptosis with the release of platelet-like particles (PubMed:11568009). Plays a role in osteoclastogenesis (OCG) and actin cytoskeletal organization in osteoclasts (By similarity). Regulates chondrocyte proliferation and differentiation (By similarity). Inhibits cell proliferation and tumorigenesis. Signaling is mediated by MAPK, p38 and JNK pathways (PubMed:11568009).
Scinderin comes from the latine world 'scincere', meaning 'to cut'.
Highly expressed in brain. Highest expression is observed in the putamen and the thalamus.
Homopentamer; forms an closed pentamer (PubMed:28963344). Interacts with CUL3; interaction is direct and forms a 5:5 heterodecamer (PubMed:28963344). Interacts with TCHP (PubMed:25270598). Interacts with CUL3, as part of the BCR(KCTD17) E3 ubiquitin ligase complex, at least composed of CUL3, KCTD17 and RBX1 (PubMed:25270598).
Is a positive regulator of ciliogenesis, playing a crucial role in the initial steps of axoneme extension. It acts as a substrate-adapter for CUL3-RING ubiquitin ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of TCHP, a protein involved in ciliogenesis down-regulation (PubMed:25270598). May be involved in endoplasmic reticulum calcium ion homeostasis (PubMed:25983243).
The sequence differs in the N-terminus for unknown reasons.
Expressed in kidney, stomach, spleen, bone marrow, uterus, testis, placenta, skeletal muscle, mammary gland, lung, fetal liver, and fetal kidney, but not detected in small intestine, brain, and thymus. Expressed in low-metastatic lung adenocarcinoma cells but not in high-metastatic ones.
May play a role in the suppression of metastatic potential in lung adenoma carcinoma cells.
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:12810723, PubMed:23949095). Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes (Probable) (PubMed:12810723, PubMed:23949095). Plays a key role in promoting cell growth (PubMed:19710016). Activates the Ras/B-Raf/C-Raf/MEK/ERK signaling pathway induced by EGF (PubMed:19710016). Regulates the recruitment of RAF1 and BRAF from cytoplasm to membranes and their heterodimerization (PubMed:19710016).
Expressed only in testis, kidney and colon.
Homooligomers (PubMed:12810723). Heterooligomers (PubMed:12810723). Oligomerization through the SAM domain inhibits the diacylglycerol kinase activity (PubMed:12810723). Heterooligomerizes with SAM domain-containing isoforms of DGKD (PubMed:12810723).
Phosphorylated. Phosphorylation does not inhibit catalytic activity.
Belongs to the Integrator subunit 7 family.
Belongs to the multiprotein complex Integrator, at least composed of INTS1, INTS2, INTS3, INTS4, INTS5, INTS6, INTS7, INTS8, INTS9/RC74, INTS10, INTS11/CPSF3L and INTS12. Interacts with NABP2.
Component of the Integrator (INT) complex, a complex involved in the small nuclear RNAs (snRNA) U1 and U2 transcription and in their 3'-box-dependent processing. The Integrator complex is associated with the C-terminal domain (CTD) of RNA polymerase II largest subunit (POLR2A) and is recruited to the U1 and U2 snRNAs genes (Probable). Plays a role in DNA damage response (DDR) signaling during the S phase (PubMed:21659603). May be not involved in the recruitment of cytoplasmic dynein to the nuclear envelope by different components of the INT complex (PubMed:23904267).
Component of the back of Sec61 (BOS) complex, composed of NCLN/Nicalin, NOMO (NOMO1, NOMO2 or NOMO3) and TMEM147 (PubMed:20538592, PubMed:36261522). The BOS complex is part of the multi-pass translocon (MPT) complex, composed of three subcomplexes, the GEL complex (composed of RAB5IF/OPTI and TMCO1), the BOS complex (composed of NCLN/Nicalin, NOMO and TMEM147) and the PAT complex (composed of WDR83OS/Asterix and CCDC47) (PubMed:36261522, PubMed:32820719). The MPT complex associates with the SEC61 complex (PubMed:32820719, PubMed:36261522). Due to the strong similarity between NOMO1, NOMO2 and NOMO3, similar interaction pattern probably occur for the three gene copies (PubMed:20538592, PubMed:32820719).
Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes (PubMed:36261522, PubMed:32820719). The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions (PubMed:36261522).
Highly expressed in pancreas and skeletal muscle and, at lower levels, in heart.
There are 3 copies of the NOMO gene on chromosome 16p12-p13: NOMO1 (AC Q15155), NOMO2 and NOMO3 (AC P69849). All 3 are extremely similar, which makes their individual characterization difficult. Thus, most experiments probably do not discriminate between the different members. The results reported in other entries may therefore apply for this protein.
Acts as a sequence specific DNA binding transcriptional activator or repressor. The isoforms contain a varying set of transactivation and auto-regulating transactivation inhibiting domains thus showing an isoform specific activity. Isoform 2 activates RIPK4 transcription. May be required in conjunction with TP73/p73 for initiation of p53/TP53 dependent apoptosis in response to genotoxic insults and the presence of activated oncogenes. Involved in Notch signaling by probably inducing JAG1 and JAG2. Plays a role in the regulation of epithelial morphogenesis. The ratio of DeltaN-type and TA*-type isoforms may govern the maintenance of epithelial stem cell compartments and regulate the initiation of epithelial stratification from the undifferentiated embryonal ectoderm. Required for limb formation from the apical ectodermal ridge. Activates transcription of the p21 promoter.
Acts as a sequence specific DNA binding transcriptional activator or repressor. The isoforms contain a varying set of transactivation and auto-regulating transactivation inhibiting domains thus showing an isoform specific activity. May be required in conjunction with TP73/p73 for initiation of p53/TP53 dependent apoptosis in response to genotoxic insults and the presence of activated oncogenes.
Binds DNA as a homotetramer. Isoform composition of the tetramer may determine transactivation activity.
Binds DNA as a homotetramer. Isoform composition of the tetramer may determine transactivation activity. Isoforms Alpha and Gamma interact with HIPK2. Interacts with SSRP1, leading to stimulate coactivator activity. Isoform 1 and isoform 2 interact with WWP1. Interacts with PDS5A. Isoform 5 (via activation domain) interacts with NOC2L.
The disease is caused by variants affecting the gene represented in this entry. Gain-of-function variants located in the transactivation inhibition domain are responsible for premature ovarian failure by inducing accelerated oocyte loss, as shown in mutant mice carrying the pathogenic variant p.Arg647Cys.
The transactivation inhibitory domain (TID) can interact with, and inhibit the activity of the N-terminal transcriptional activation domain of TA*-type isoforms.
Ubiquitinated. Polyubiquitination involves WWP1 and leads to proteasomal degradation of this protein.
Widely expressed, notably in heart, kidney, placenta, prostate, skeletal muscle, testis and thymus, although the precise isoform varies according to tissue type. Progenitor cell layers of skin, breast, eye and prostate express high levels of DeltaN-type isoforms. Isoform 10 is predominantly expressed in skin squamous cell carcinomas, but not in normal skin tissues.
Interacts with CTNNBL1; the interaction is important for the immunoglobulin switch activity of AICDA (PubMed:18722174, PubMed:21385873, PubMed:32484799). Interacts (via its NLS) with KPNA1. Interacts with PKA/PRKACA and PRKAR1A/PKR1 (PubMed:16387847). Interacts with TRIM28 and NCL (By similarity). Interacts with SUPT6H (PubMed:21518874). Interacts with RNF126 (PubMed:23277564). Directly interacts with MCM3AP; this interaction may favor AICDA recruitment to immunoglobulin variable region genes, hence promoting somatic hypermutations (PubMed:20507984).
Negatively regulated by microRNA-155 (miR-155).
Probably monoubiquitinated on several residues by RNF126.
Ser-38 is the major site whereas Thr-27 is the minor site of phosphorylation. Phosphorylation regulates its class-switch recombination activity.
Single-stranded DNA-specific cytidine deaminase. Involved in somatic hypermutation (SHM), gene conversion, and class-switch recombination (CSR) in B-lymphocytes by deaminating C to U during transcription of Ig-variable (V) and Ig-switch (S) region DNA. Required for several crucial steps of B-cell terminal differentiation necessary for efficient antibody responses (PubMed:18722174, PubMed:21385873, PubMed:21518874, PubMed:27716525). May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation (PubMed:21496894).
Strongly expressed in lymph nodes and tonsils.
Contains 2 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif, which are usually required for the association with nuclear receptors.
Interacts with hepatocyte nuclear factor 4-alpha/HNF4A, Sterol regulatory binding transcription factor 1/SREBF1, PPAR-alpha/PPARA, thyroid hormone receptor beta/THRB and host cell factor/HCFC1. Interacts with estrogen-related receptor gamma/ESRRG and alpha/ESRRA. Interacts with PRDM16 (By similarity). Interacts with estrogen receptor alpha/ESR1.
Lacks LXXLL motif 1 and has a reduced ability to enhance the hormone-dependent activity of estrogen receptor alpha.
Plays a role of stimulator of transcription factors and nuclear receptors activities. Activates transcriptional activity of estrogen receptor alpha, nuclear respiratory factor 1 (NRF1) and glucocorticoid receptor in the presence of glucocorticoids. May play a role in constitutive non-adrenergic-mediated mitochondrial biogenesis as suggested by increased basal oxygen consumption and mitochondrial number when overexpressed. May be involved in fat oxidation and non-oxidative glucose metabolism and in the regulation of energy expenditure. Induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner.
Repressed by saturated fatty acids such as palmitate and stearate in skeletal muscle cells. Induced by insulin and reduced by aging in skeletal muscle biopsies. Down-regulated in type 2 diabetes mellitus subjects as well as in pre-diabetics.
Ubiquitous with higher expression in heart, brain and skeletal muscle.
Variation of PPARGC1B may contribute to the pathogenesis of obesity, with a widespread Ala-203 allele being a risk factor for the development of this common disorders.
Expressed in prostate, brain, lung, aorta and kidney.
Specifically deubiquitinates 'Lys-14' (H2AK13Ub) and 'Lys-16'(H2AK15Ub) of histone H2A regulating the DNA damage response at double-strand breaks (DSBs) (PubMed:27083998). USP51 is recruited to chromatin after DNA damage and regulates the dynamic assembly/disassembly of TP53BP1 and BRCA1. Exhibits also activity for 'Lys-27' or 'Lys-63'-linked di-ubiquitin (PubMed:27083998).
May regulate nociceptor function and/or development, including the sensation or modulation of pain. Functions as a specific membrane receptor for beta-alanine. Beta-alanine at micromolar doses specifically evoked Ca(2+) influx in cells expressing the receptor. Beta-alanine decreases forskolin-stimulated cAMP production in cells expressing the receptor, suggesting that the receptor couples with G-protein G(q) and G(i).
Interacts with ZNF638 and TTN/titin (PubMed:11813260, PubMed:12432079). Interacts with E4F1 (PubMed:16652157). Interacts with GRB7 (PubMed:18853468). Interacts with SIRT1 and FOXO1 (PubMed:15692560). Interacts with CEFIP (PubMed:28717008). Interacts with calcineurin (By similarity). Interacts with FOXK1 (By similarity).
May function as a molecular transmitter linking various signaling pathways to transcriptional regulation. Negatively regulates the transcriptional repressor E4F1 and may function in cell growth. Inhibits the transcriptional activity of FOXO1 and its apoptotic function by enhancing the interaction of FOXO1 with SIRT1 and FOXO1 deacetylation. Negatively regulates the calcineurin/NFAT signaling pathway in cardiomyocytes (PubMed:28717008).
The third LIM zinc-binding mediates interaction with E4F1.
Belongs to the peptidase C19 family. USP44 subfamily.
Deubiquitinase that plays a key regulatory role in the spindle assembly checkpoint or mitotic checkpoint by preventing premature anaphase onset. Acts by specifically mediating deubiquitination of CDC20, a negative regulator of the anaphase promoting complex/cyclosome (APC/C) (PubMed:17443180). Deubiquitination of CDC20 leads to stabilize the MAD2L1-CDC20-APC/C ternary complex (also named mitotic checkpoint complex), thereby preventing premature activation of the APC/C (PubMed:17443180). Promotes association of MAD2L1 with CDC20 and reinforces the spindle assembly checkpoint (PubMed:17443180). Promotes also the deubiquitination of histone H2A and H2B (PubMed:23615962, PubMed:27880911). Recruited to RNF8/RNF168-ubiquitinated chromatin surrounding double stranded breaks (DSBs), promotes hydrolysis of such ubiquitin conjugates, thus negatively regulating protein recruitment to damaged chromatin (PubMed:23615962). Participates in nucleotide excision repair (NER) pathway by deubiquitinating DDB2 to prevent its premature degradation so it can remain on damaged chromatin (By similarity). Promotes FOXP3 stabilization through 'Lys-48'-linked deubiquitination leading to increased stability and increased regulatory T-cell lineage stability (PubMed:32644293). Plays also a positive role in innate immune response to DNA viruses by deubiquitinating STING1, selectively removing its 'Lys-48'-linked polyubiquitin chains and stabilizing it (PubMed:31968013).
Elevated in mitosis; levels increase in mitotic cells and rapidly decrease once cells have completed chromosome attachment and exit from mitosis.
Expressed in testis. Expressed at high levels in T-cell acute lymphoblastic leukemia.
Interacts with the N-CoR components TBL1X and TBL1XR1.
Transcriptionally regulated by POU5F1/OCT4 in embryonic stem cells and embryonal carcinoma cells. Induced by TGF-beta during regulatory T-cells differentiation (PubMed:32644293).
Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination and is degraded by the proteasome.
Aberrant splicing in the N-terminal part.
Widely expressed; detected in testis, lung, small intestine, breast, brain, heart, bone marrow, placenta, colon, fetal brain, liver, fetal liver, thymus, salivary gland, spinal cord, spleen, trachea and adrenal gland.
ATP-dependent chaperone, which plays an essential role in the cytoplasmic maturation steps of pre-60S ribosomal particles by promoting the release of shuttling protein RSL24D1/RLP24 from the pre-ribosomal particles (PubMed:35354024). Acts together with AFG2B, AIRIM and CINP (PubMed:35354024). May be involved in morphological and functional mitochondrial transformations during spermatogenesis (By similarity).
The first ATP-binding region binds ATP with low affinity whereas the second ATP-binding region binds ATP with high affinity.
Homodimer. Interacts with RHPN1 (By similarity). May interact with SPA17 (By similarity). Interacts with AKAP3 (PubMed:11278869). Interacts with FSCB; the interaction increases upon spermatozoa capacitation conditions (By similarity).
As part of the Fanconi anemia (FA) complex functions in DNA cross-links repair. Required for the nuclear accumulation of FANCC and provides a critical bridge between the FA complex and FANCD2.
Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM. The complex is not found in FA patients. Interacts with FANCC and FANCD2.
Phosphorylated. Phosphorylation by CHEK1 at Thr-346 and Ser-374 regulates its function in DNA cross-links repair.
Ubiquitinated. Phosphorylation by CHEK1 induces polyubiquitination and degradation.
Its interaction with PHYH suggests a role in the development of the central system.
Highly expressed at the leading edges of cells, on filopodia.
Component of the ER membrane protein complex (EMC) (PubMed:22119785, PubMed:29242231). EMC8 and EMC9 are mutually exclusive subunits of the EMC complex (PubMed:32459176, PubMed:32439656).
Expressed in liver, pancreas, heart, lung, kidney, brain, skeletal muscle, and placenta. Expression levels are highest in pancreas and moderate in heart, skeletal muscle, and placenta.
Detected in mammary epithelia (at protein level).
Down-regulated in some breast cancer subtypes and breast cancer cell lines.
Homodimer; disulfide-linked (By similarity). Interacts with FBN1 (via N-terminal domain) and FBN2 (PubMed:18339631). Interacts with ENG (PubMed:21737454).
Required for maintaining the proliferative activity of embryonic cardiomyocytes by preventing premature activation of the negative cell cycle regulator CDKN1C/p57KIP and maintaining the required expression levels of cardiogenic factors such as MEF2C and NKX2-5. Acts as a ligand for ACVRL1/ALK1, BMPR1A/ALK3 and BMPR1B/ALK6, leading to activation of SMAD1, SMAD5 and SMAD8 transcription factors. Inhibits endothelial cell migration and growth. May reduce cell migration and cell matrix adhesion in breast cancer cell lines.
Detected within the Kolliker's organ, the outer sulcus, Reissner's membrane and the spiral ligament in the fetal inner ear at gestational weeks 12-14. Transient expression is observed in the stria vascularis at gestational week 14. At gestational week 15, it is also expressed in the vestibular system, particularly the saccular macula and ampulla, the periotic mesenchyme, the neuronal cell bodies of the Scarpa's ganglion and the epithelial cells of the semicircular canals.
Recognizes and hydrolyzes the peptide bond at the C-terminal Gly of ubiquitin. Involved in the processing of poly-ubiquitin precursors as well as that of ubiquitinated proteins (PubMed:16214042, PubMed:34059922). May be involved in the regulation of NF-kappa-B activation by TNF receptor superfamily via its interactions with RELA and TRAF2. May also play a regulatory role at postsynaptic sites.
Was termed (PubMed:15354349, PubMed:17081983) USP31.
Widely expressed. Expressed in the fetal inner ear (PubMed:34059922).
May bind integrin alpha-8/beta-1 and play a role in hair follicle morphogenesis. Promotes matrix assembly (By similarity).
A variant causing a frameshift predicted to result in a premature termination codon has been found in a patient with globozoospermia.
May play a role in acrosome formation and nucleus shaping during spermiogenesis.
Interacts with EIF3E (PubMed:21745818). Interacts with EIF2S2 (PubMed:21745818, PubMed:25147208, PubMed:34260931). Interacts with EIF3C (PubMed:34260931).
Translation initiation regulator which represses non-AUG initiated translation and repeat-associated non-AUG (RAN) initiated translation by acting as a competitive inhibitor of eukaryotic translation initiation factor 5 (EIF5) function (PubMed:21745818, PubMed:28981728, PubMed:34260931, PubMed:29470543). Increases the accuracy of translation initiation by impeding EIF5-dependent translation from non-AUG codons by competing with it for interaction with EIF2S2 within the 43S pre-initiation complex (PIC) in an EIF3C-binding dependent manner (PubMed:21745818, PubMed:28981728, PubMed:34260931).
A chromosomal aberration involving NSD3 is found in childhood acute myeloid leukemia. Translocation t(8;11)(p11.2;p15) with NUP98.
Defects in NSD3 may be involved in non small cell lung carcinomas (NSCLC). Amplified or overexpressed in NSCLC.
Highly expressed in brain, heart and skeletal muscle. Expressed at lower level in liver and lung.
Histone methyltransferase. Preferentially dimethylates 'Lys-4' and 'Lys-27' of histone H3 forming H3K2me2 and H3K27me2. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation, while 'Lys-27' is a mark for transcriptional repression.
Expressed in fetal kidney, skeletal muscle, liver, placenta and heart. Also expressed in tumor cell lines derived from lung and colon adenocarcinomas.
Inhibited by serine proteinase inhibitor 4-(2-aminoethyl)-benzenesulfonyl fluoride, but not with EDTA or E-64.
Serine protease. Hydrolyzes the peptides N-t-Boc-Gln-Ala-Arg-AMC and N-t-Boc-Gln-Gly-Arg-AMC and, to a lesser extent, N-t-Boc-Ala-Phe-Lys-AMC and N-t-Boc-Val-Leu-Lys-AMC. Has a preference for substrates with an Arg instead of a Lys residue in position P1.
The 3 protease domains are not proteolytically cleaved.
The first serine protease domain is catalytically active, whereas the second domain lacks the essential His residue of the catalytic triad at position 363, and the third domain lacks the essential Asp residue of the catalytic triad at position 679. The second and third domains are therefore predicted to be inactive (By similarity).
Belongs to the class I-like SAM-binding methyltransferase superfamily. RNA methyltransferase RlmE family.
S-adenosyl-L-methionine-dependent 2'-O-ribose methyltransferase that catalyzes the formation of 2'-O-methyluridine at position 1369 (Um1369) in the 16S mitochondrial large subunit ribosomal RNA (mtLSU rRNA), a universally conserved modification in the peptidyl transferase domain of the mtLSU rRNA.
Widely expressed, with highest expression in muscle, placenta, and heart.
Detected in brain. Expressed at constant levels throughout the cell cycle in neuroblastoma cell lines.
Transcription activator. May act as tumor suppressor.
Expressed mainly in stomach, placenta, small intestine and colon, as well as in normal mucosa of esophagus. Down-regulated in esophageal squamous cell carcinoma.
Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation (PubMed:15602573, PubMed:20114074, PubMed:20484055, PubMed:20639694, PubMed:23088497, PubMed:28561066, PubMed:31271352). Plays an important role in starvation- and calcium-mediated autophagy, as well as in mitophagy (PubMed:28561066). Functions downstream of the ULK1 and PI3-kinases that produce phosphatidylinositol 3-phosphate (PtdIns3P) on membranes of the endoplasmic reticulum once activated (PubMed:28561066). Binds phosphatidylinositol 3-phosphate (PtdIns3P), and maybe other phosphoinositides including PtdIns3,5P2 and PtdIns5P, and is recruited to phagophore assembly sites at the endoplasmic reticulum membranes (PubMed:28561066, PubMed:31271352, PubMed:33499712). There, it assists WIPI2 in the recruitment of ATG12-ATG5-ATG16L1, a complex that directly controls the elongation of the nascent autophagosomal membrane (PubMed:28561066). Together with WDR45/WIPI4, promotes ATG2 (ATG2A or ATG2B)-mediated lipid transfer by enhancing ATG2-association with phosphatidylinositol 3-monophosphate (PI3P)-containing membranes (PubMed:31271352). Involved in xenophagy of Staphylococcus aureus (PubMed:22829830). Invading S.aureus cells become entrapped in autophagosome-like WIPI1 positive vesicles targeted for lysosomal degradation (PubMed:22829830). Also plays a distinct role in controlling the transcription of melanogenic enzymes and melanosome maturation, a process that is distinct from starvation-induced autophagy (PubMed:21317285). May also regulate the trafficking of proteins involved in the mannose-6-phosphate receptor (MPR) recycling pathway (PubMed:15020712).
Interacts with androgen receptor (AR) and the estrogen receptors ESR1 and ESR2 (PubMed:15602573). Interacts with WIPI2 (PubMed:28561066). Interacts with WDR45 (PubMed:28561066). Interacts with ATG16L1 (PubMed:28561066). May interact with NUDC (PubMed:28561066).
The N-terminus might form a beta-propeller domain involved in specific binding to phosphatidylinositol 3,5-bisphosphate (PIP2), leading to the association of the protein to the membrane. Association to the membrane can also occur through binding to phosphatidylinositol 3-monophosphate (PI3P).
Ubiquitously expressed. Highly expressed in skeletal muscle, heart, testis, pancreas and placenta. Highly expressed in G361, Sk-mel-28, Sk-mel-13, WM852 and WM451 cells. Up-regulated in a variety of tumor tissues.
Expressed in brain, lung, kidney, and testis.
GTPase-activating protein for RhoA and Cdc42 small GTPases. Together with CDC42 seems to be involved in the pathway mediating the repulsive signaling of Robo and Slit proteins in neuronal migration. SLIT2, probably through interaction with ROBO1, increases the interaction of SRGAP1 with ROBO1 and inactivates CDC42.
Homodimer (Probable). Forms a heterooligomer with SRGAP2 and SRGAP3 through its F-BAR domain. Interacts with ROBO1, CDC42 and RHOA. Interacts with FASLG.
The F-BAR domain mediates oligomerization, binds membranes, and constrains plasma membrane protrusions.
Binds DNA. Interacts with GATA4 (By similarity).
Transcription factor that acts as a cardiac regulator and an effector of alpha1-adrenergic signaling. Binds to PE response elements (PERE) present in the promoter of genes such as ANF/NPPA and acts as a direct transcriptional activator of NPPA. Also acts as a cofactor with GATA4, a key cardiac regulator (By similarity).
Up-regulated by activation of alpha1-adrenergic receptors.
Activates ubiquitin by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a ubiquitin-E1 thioester and free AMP. Specific for ubiquitin, does not activate ubiquitin-like peptides. Differs from UBE1 in its specificity for substrate E2 charging. Does not charge cell cycle E2s, such as CDC34. Essential for embryonic development. Required for UBD/FAT10 conjugation. Isoform 2 may play a key role in ubiquitin system and may influence spermatogenesis and male fertility.
Forms a thioester with UBD in cells stimulated with tumor necrosis factor-alpha (TNFa) and interferon-gamma (IFNg) (PubMed:17889673, PubMed:25422469).
Widely expressed. Isoform 2 is predominantly expressed in testis with higher expression in adult testis than in fetal testis.
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:9435160, PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:9435160, PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable).
By nicotine, omeprazole, phenobarbital, primidone and rifampicin.
The CYP1A2*1F allele which is quite common (40 to 50%) is due to a substitution of a base in the non-coding region of the CYP1A2 gene and has the effect of decreasing the enzyme inducibility. Individuals who are homozygous for the CYP1A2*1F allele are 'slow' caffeine metabolizers. Thus for these individual increased intake of caffeine seems to be associated with a concomitant increase in the risk of non-fatal myocardial infraction (MI).
Belongs to the complex I subunit 3 family.
Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits (PubMed:12611891). Interacts with TMEM186 (PubMed:32320651). Interacts with TMEM242 (PubMed:33753518).
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (PubMed:25118196). Essential for the catalytic activity of complex I (PubMed:25118196).
Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. Essential for the catalytic activity of complex I.
Available under the name Neumega (Wyeth). Used for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusion following myelosuppressive chemotherapy.
Cytokine that stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte maturation resulting in increased platelet production (PubMed:2145578). Also promotes the proliferation of hepatocytes in response to liver damage. Binding to its receptor formed by IL6ST and IL11RA activates a signaling cascade that promotes cell proliferation (PubMed:12919066). Signaling leads to the activation of intracellular protein kinases and the phosphorylation of STAT3. The interaction with the membrane-bound IL11RA and IL6ST stimulates 'classic signaling', whereas the binding of IL11 and soluble IL11RA to IL6ST stimulates 'trans-signaling' (PubMed:30279168).
Interacts with IL11RA to associate with IL6ST, giving rise to a multimeric signaling complex.
Expressed in fetal life in CD34+ progenitors present in the liver at 18 weeks of gestation but is absent in CD34+ precursors from fetal bone marrow at any developmental stage up to 22 weeks.
Expressed in immature but not mature T-cells. Also found in CD34+ cells from peripheral blood, CD34+ precursors from umbilical cord blood and adult bone marrow.
Heterodimer with TCRB; disulfide linked. This heterodimer assembles with CD3 proteins into a signaling-competent pre-T-cell receptor complex. Interacts with RHBDD1.
The pre-T-cell receptor complex (composed of PTCRA, TCRB and the CD3 complex) regulates early T-cell development.
(Microbial infection) Interacts with Epstein-Barr virus lytic switch protein BZLF1; this interaction induces G1 cell cycle arrest.
Binds DNA as a homodimer and as a heterodimer. Can form stable heterodimers with CEBPB, CEBPD, CEBPE and CEBPG (By similarity). Interacts with PRDM16 (By similarity). Interacts with UBN1 (PubMed:10725330). Interacts with ZNF638; this interaction increases transcriptional activation (By similarity). Interacts with the complex TFDP2:E2F1; the interaction prevents CEBPA binding to target gene promoters and represses its transcriptional activity (PubMed:20176812). Interacts with RB1 (PubMed:15107404). Interacts (when phosphorylated at Ser-190) with CDK2, CDK4, E2F4 and SMARCA2 (PubMed:15107404). Interacts with SREBPF1 (By similarity). Interacts with FOXO1 (via the Fork-head domain); the interaction increases when FOXO1 is deacetylated (By similarity). Interacts with SIX1 (PubMed:27923061). Interacts (via recognition sequence) with TRIB1 (PubMed:20410507, PubMed:26455797). Interacts (via bZIP domain) with OVOL2 (via zinc-finger domains); the interaction inhibits the transcription factor activity of CEBPA and is required to repress adipogenesis (By similarity).
Can act as dominant-negative. Binds DNA and have transctivation activity, even if much less efficiently than isoform 2. Does not inhibit cell proliferation (PubMed:14660596).
Directly and specifically enhances ribosomal DNA transcription interacting with RNA polymerase I-specific cofactors and inducing histone acetylation.
Interacts with TAF1A and UBTF (PubMed:20075868). Interacts with NPM1 (PubMed:20075868).
Phosphorylation at Ser-190 is required for interaction with CDK2, CDK4 and SWI/SNF complex leading to cell cycle inhibition. Dephosphorylated at Ser-190 by protein phosphatase 2A (PP2A) through PI3K/AKT signaling pathway regulation (PubMed:15107404). Phosphorylation at Thr-226 and Thr-230 by GSK3 is constitutive in adipose tissue and lung. In liver, both Thr-226 and Thr-230 are phosphorylated only during feeding but not during fasting. Phosphorylation of the GSK3 consensus sites selectively decreases transactivation activity on IRE-controlled promoters.
Sumoylated, sumoylation blocks the inhibitory effect on cell proliferation by disrupting the interaction with SMARCA2.
The recognition sequence (54-72) is required for interaction with TRIB1.
Transcription factor that coordinates proliferation arrest and the differentiation of myeloid progenitors, adipocytes, hepatocytes, and cells of the lung and the placenta. Binds directly to the consensus DNA sequence 5'-T[TG]NNGNAA[TG]-3' acting as an activator on distinct target genes (PubMed:11242107). During early embryogenesis, plays essential and redundant functions with CEBPB. Essential for the transition from common myeloid progenitors (CMP) to granulocyte/monocyte progenitors (GMP). Critical for the proper development of the liver and the lung (By similarity). Necessary for terminal adipocyte differentiation, is required for postnatal maintenance of systemic energy homeostasis and lipid storage (By similarity). To regulate these different processes at the proper moment and tissue, interplays with other transcription factors and modulators. Down-regulates the expression of genes that maintain cells in an undifferentiated and proliferative state through E2F1 repression, which is critical for its ability to induce adipocyte and granulocyte terminal differentiation. Reciprocally E2F1 blocks adipocyte differentiation by binding to specific promoters and repressing CEBPA binding to its target gene promoters. Proliferation arrest also depends on a functional binding to SWI/SNF complex (PubMed:14660596). In liver, regulates gluconeogenesis and lipogenesis through different mechanisms. To regulate gluconeogenesis, functionally cooperates with FOXO1 binding to IRE-controlled promoters and regulating the expression of target genes such as PCK1 or G6PC1. To modulate lipogenesis, interacts and transcriptionally synergizes with SREBF1 in promoter activation of specific lipogenic target genes such as ACAS2. In adipose tissue, seems to act as FOXO1 coactivator accessing to ADIPOQ promoter through FOXO1 binding sites (By similarity).
Ubiquitinated by COP1 upon interaction with TRIB1.
Expressed in cervical gland, cervical squamous epithelium, endometrium, stomach, kidney distal convoluted tubule, spermatogenic cells in testis, mammary gland, liver and striated muscle (at protein level) (PubMed:18087676, PubMed:23070808). Also detected in placenta (PubMed:18087676). Highest expression in testis relative to other tissues (PubMed:18087676). Detected in T cells and dendritic cells; highly expressed in activated CD8(+) T cells, and also expressed at lower levels in CD4(+) T cells (PubMed:25125657).
In extracellular secreted form, promotes proliferation and activation of CD8(+) T cells, suggesting a cytokine-like function (PubMed:25125657). Enhances cytotoxic anti-tumor activity of CD8(+) T cells (PubMed:25125657). May inhibit ERK and JNK signaling activity (PubMed:18087676, PubMed:23070808). May suppress cell migration and invasion activity, via its effects on ERK and JNK signaling (PubMed:23070808). Has a critical role in the regulation of osteogenesis and bone development (PubMed:32181939).
In the nucleus, enhances stability of the PCAF histone acetyltransferase (HAT) complex member TADA2A and thus promotes PCAF-mediated H3K14 and H4K8 HAT activity. May inhibit TADA2A-mediated TP53/p53 'Lys-321' acetylation, leading to reduced TP53 stability and transcriptional activity. May also promote TADA2A-mediated XRCC6 acetylation thus facilitating cell apoptosis in response to DNA damage.
Interacts with TADA2A. Associates with the PCAF complex via TADA2A binding.
O-glycosylated, with additional sialic acid modifications.
The disease is caused by variants affecting the gene represented in this entry. A recurrent variant in the initiation codon has been found in multiple OI22 patients (PubMed:32181939, PubMed:35019224). The variant results in absence of CCDC134 protein in patient fibroblasts and osteoblasts, increased ERK1/2 phosphorylation, decreased OPN and COL1A1 expression and reduced mineralization (PubMed:32181939).
Activated by phosphorylation on Ser/Thr by MAP kinase kinase kinases.
Acts as a scaffold for the formation of a ternary MAP3K2/MAP3K3-MAP3K5-MAPK7 signaling complex. Activation of this pathway appears to play a critical role in protecting cells from stress-induced apoptosis, neuronal survival and cardiac development and angiogenesis.
Binds MAP3K2/MAP3K3 and MAPK7 via non-overlapping residues of the PB1 domain. This domain also mediates interactions with SQSTM1 and PARD6A (By similarity).
Expressed in many adult tissues. Abundant in heart and skeletal muscle.
Interacts with PARD6A, MAP3K3 and MAPK7. Forms a complex with SQSTM1 and PRKCZ or PRKCI (By similarity).
Interacts with RPGRIP1L. Interacts with PSMA3. Interacts with RACK1; the interaction regulates TBXA2R cell surface expression.
Receptor for thromboxane A2 (TXA2), a potent stimulator of platelet aggregation. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. In the kidney, the binding of TXA2 to glomerular TP receptors causes intense vasoconstriction. Activates phospholipase C.
Expressed in the endothelial cells of the stroma but not in the endothelial cells of normal colonic tissue.
Highest expression in the thyroid gland. Also expressed in the prostate, salivary, and adrenal glands and in the colon testis and kidney.
Protease whose physiological substrate is not yet known.
Functions as a guanine exchange factor (GEF) for RAB26 and thus regulates autophagy of synaptic vesicles in axon terminal of motoneurons (By similarity). Involved in the control of neuronal cell differentiation (PubMed:11704860). Plays a role in angiogenesis through regulation of endothelial cells chemotaxis. Affects also the migration, adhesion, and matrix/bone degradation in macrophages and osteoclasts (PubMed:23777631).
Predominantly expressed in the peripheral nervous system and brain. Highest expression is observed in heart, lung, kidney, testis and moderate expression is present in spleen, pancreas, skeletal muscle, ovary and liver. Weakly expressed in glioblastoma (GBM) cell lines.
Expressed in both the aorta, the coronary artery and umbilical vein endothelial cells (HUVECs) (at protein level).
Olfactory receptor. Activated by the synthetic floral odorant, lyral, and by alpha-cedrene, a sesquiterpene constituent of cedarwood oil. Its activation increases intracellular Ca(2+) (PubMed:25791473, PubMed:28842679). Acts as a key regulator of myogenesis through its actions on cell migration and adhesion by activating the Ca(2+)-dependent AKT signal transduction pathway (By similarity). Acts also as a regulator of angiogenesis (PubMed:25791473). Moreover, plays a role in the regulation of lipid accumulation in hepatocytes via the cAMP-PKA pathway (PubMed:28842679). May be involved in sperm chemotaxis and motility (By similarity).
Diglyceride acyltransferase that uses fatty acyl-CoA as substrate (PubMed:15671038). Particularly active with oleate as a substrate (PubMed:15671038). Has no wax synthase activity to produce wax esters (PubMed:15671038). Able to use 1-monoalkylglycerol (1-MAkG) as an acyl acceptor for the synthesis of monoalkyl-monoacylglycerol (MAMAG) (PubMed:28420705).
Expressed in all tissues tested except pancreas.
Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR3 subfamily.
Brain, skeletal muscle, placenta and possibly liver and kidney. In brain, highest levels are found in the cerebellum, hippocampus, caudate nucleus and amygdala, with lower levels in the corpus callosum, substantia nigra and thalamus.
Channel activity is modulated by the alkaloid ryanodine that binds to the open calcium-release channel with high affinity. At low concentrations, ryanodine maintains the channel in an open conformation. High ryanodine concentrations inhibit channel activity. Channel activity is regulated by calmodulin (CALM). The calcium release is activated by elevated cytoplasmic calcium levels in the micromolar range, by caffeine and adenine nucleotides, such as AMP and ATP. Inhibited by Mg(2+) and ruthenium red.
Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm in muscle and thereby plays a role in triggering muscle contraction (PubMed:12354756, PubMed:9395096). May regulate Ca(2+) release by other calcium channels. Calcium channel that mediates Ca(2+)-induced Ca(2+) release from the endoplasmic reticulum in non-muscle cells. Contributes to cellular calcium ion homeostasis (By similarity). Plays a role in cellular calcium signaling.
Homotetramer. Heterotetramer with RYR2. Interacts with CALM (By similarity). Interacts with FKBP1A. Interacts with SELENON (By similarity).
Overexpressed in multiple myeloma leading to constitutive activation of the PI(3)K/mTORC2/Akt pathway to promote survival.
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO9) composed of CUL1, SKP1, RBX1 and FBXO9. Interacts with TTI1 and TELO2; when TTI1 and TELO2 are phosphorylated by CK2.
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins and plays a role in several biological processes such as cell cycle, cell proliferation, or maintenance of chromosome stability (PubMed:34480022, PubMed:23263282). Ubiquitinates mTORC1-bound TTI1 and TELO2 when they are phosphorylated by CK2 following growth factor deprivation, leading to their degradation. In contrast, does not mediate ubiquitination of TTI1 and TELO2 when they are part of the mTORC2 complex. As a consequence, mTORC1 is inactivated to restrain cell growth and protein translation, while mTORC2 is the activated due to the relief of feedback inhibition by mTORC1 (PubMed:23263282). Plays a role in maintaining epithelial cell survival by regulating the turn-over of chromatin modulator PRMT4 through ubiquitination and degradation by the proteasomal pathway (PubMed:34480022). Regulates also PPARgamma stability by facilitating PPARgamma/PPARG ubiquitination and thereby plays a role in adipocyte differentiation (By similarity).
Isoform 1 can form heterodimers with isoform 5 (and probably other isoforms).
Receptor for prostaglandin F2-alpha (PGF2-alpha). The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. Initiates luteolysis in the corpus luteum (By similarity). Isoforms 2 to 7 do not bind PGF2-alpha but are proposed to modulate signaling by participating in variant receptor complexes; heterodimers between isoform 1 and isoform 5 are proposed to be a receptor for prostamides including the synthetic analog bimatoprost.
Belongs to the Mediator complex subunit 8 family.
Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. May play a role as a target recruitment subunit in E3 ubiquitin-protein ligase complexes and thus in ubiquitination and subsequent proteasomal degradation of target proteins.
Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. May be part of a multisubunit E3 ubiquitin-protein ligase complex with the elongin BC complex (ELOB and ELOC), CUL2 and RBX1.
Interacts with CLOCK. Forms a ternary complex with the CLOCK-BMAL1 heterodimer. Interacts with CAD and HSPA5 (PubMed:26657846).
Transcriptional repressor which may act as a negative-feedback regulator of CLOCK-BMAL1 transcriptional activity in the circadian-clock mechanism. May stimulate BMAL1-dependent phosphorylation of CLOCK. However, the physiogical relevance of these observations is unsure, since experiments in an animal model showed that CIPC is not critially required for basic circadian clock.
Myosins are actin-based motor molecules with ATPase activity. Their highly divergent tails are presumed to bind to membranous compartments, which would be moved relative to actin filaments. As part of the intermicrovillar adhesion complex/IMAC plays a role in epithelial brush border differentiation, controlling microvilli organization and length. May link the complex to the actin core bundle of microvilli (Probable).
Part of the IMAC/intermicrovillar adhesion complex/intermicrovillar tip-link complex composed of ANKS4B, MYO7B, USH1C, CDHR2 and CDHR5 (PubMed:24725409, PubMed:26812018). Interacts with CDHR2 (PubMed:24725409). Interacts with CDHR5 (PubMed:24725409). Interacts with USH1C (PubMed:24725409, PubMed:26812017, PubMed:26812018). Interacts with ANKS4B; requires initial interaction with USH1C (PubMed:26812018).
'Taube nuss' means 'empty nut' in German.
Component of the TFIID basal transcription factor complex, composed of TATA-box-binding protein TBP, and a number of TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473). Interacts with TBP, TAF1, TAF6, TAF10, TAF11 and TAF13 (PubMed:14580349, PubMed:17375202, PubMed:15870280). Component also of a small TAF complex (SMAT) containing TAF8, TAF10 and SUPT7L (PubMed:17375202). Forms a heterodimer with TAF10 (PubMed:17375202). Interaction with TAF10 is mediated mainly via its histone fold domain while interaction with SUPT7L is via its C-terminal region (PubMed:15870280).
Ectopic expression of the histone fold domain acts as a dominant-negative mutant resulting in differentiation inhibition.
The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription (PubMed:33795473). TFIID recognizes and binds promoters with or without a TATA box via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC) (PubMed:33795473). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473). The TFIID complex structure can be divided into 3 modules TFIID-A, TFIID-B, and TFIID-C (PubMed:33795473). TAF8 is involved in forming the TFIID-B module, together with TAF5 (PubMed:33795473). Mediates both basal and activator-dependent transcription (PubMed:14580349). Plays a role in the differentiation of preadipocyte fibroblasts to adipocytes, however, does not seem to play a role in differentiation of myoblasts (PubMed:14580349). Required for the integration of TAF10 in the TAF complex (PubMed:14580349). May be important for survival of cells of the inner cell mass which constitute the pluripotent cell population of the early embryo (By similarity).
Expression is induced by sodium butyrate, an inhibitor of colon cancer cell proliferation.
Expression may increase during differentiation.
Interacts with CCND1 and GRAP2. May also interact with COPS5, RPLP0, SIRT6, SYF2 and TCF3.
May negatively regulate cell cycle progression. May act at least in part via inhibition of the cyclin-D1/CDK4 complex, thereby preventing phosphorylation of RB1 and blocking E2F-dependent transcription.
Ubiquitously expressed. Expression is down-regulated in a variety of tumor types including breast, colon, prostate and rectal tumors, and is up-regulated in certain hepatic carcinomas.
Forms a heterodimer with SMC3. Component of a meiosis-specific cohesin complex, probably composed of the SMC1B and SMC3 heterodimer attached via their SMC hinge domain, RAD21 (or its meiosis-specific related protein REC8), which link them, and STAG3, which interacts with RAD21 or REC8 (By similarity). The cohesin complex interacts with the cohesin loading complex subunits NIPBL/Scc2 (via HEAT repeats) and MAU2/Scc4. NIPBL directly contacts all members of the complex, RAD21, SMC1A/B, SMC3 and STAG1 (By similarity).
Meiosis-specific component of cohesin complex. Required for the maintenance of meiotic cohesion, but not, or only to a minor extent, for its establishment. Contributes to axial element (AE) formation and the organization of chromatin loops along the AE. Plays a key role in synapsis, recombination and chromosome movements. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The meiosis-specific cohesin complex probably replaces mitosis specific cohesin complex when it dissociates from chromatin during prophase I (By similarity).
The flexible SMC hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC3, forming a V-shaped heterodimer. The two heads of the heterodimer are then connected by different ends of the cleavable RAD21 or REC8 protein, forming a ring structure (By similarity).
Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation in response to H(2)O(2) is mediated by a process that requires SRC and PRKCD activity. Phosphorylation at Tyr-1068 is required for autophosphorylation at additional tyrosine residues. Phosphorylation at Tyr-1063 and Tyr-1337 is important for interaction with CRK and subsequent activation of MAPK8. Phosphorylation at Tyr-1230, Tyr-1231 and Tyr-1337 is important for interaction with GRB2 and subsequent activation of the AKT1 and MAPK1/ERK2 and/or MAPK3/ERK1 signaling pathways. In response to endothelial cell adhesion onto collagen, can also be phosphorylated in the absence of FLT4 kinase activity by SRC at Tyr-830, Tyr-833, Tyr-853, Tyr-1063, Tyr-1333, and Tyr-1337.
Detected in endothelial cells (at protein level). Widely expressed. Detected in fetal spleen, lung and brain. Detected in adult liver, muscle, thymus, placenta, lung, testis, ovary, prostate, heart, and kidney.
Interacts with VEGFC and VEGFD. Monomer in the absence of bound VEGFC or VEGFD. Homodimer in the presence of bound VEGFC or VEGFD. Can also form a heterodimer with KDR. Interacts with PTPN14; the interaction is enhanced by stimulation with VEGFC. Interacts with CRK, GRB2, PTK2/FAK1, SHC1, PIK3R1 and PTPN11/SHP-2. Identified in a complex with SRC and ITGB1.
Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.
Present in an inactive conformation in the absence of bound ligand. Binding of VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by MAZ51.
The first and second Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFC binding (PubMed:23878260). The fourth and fifth Ig-like C2-type domains are sufficient for homodimerization (PubMed:23878260). The fifth and seventh Ig-like C2-type domains are required for autophosphorylation and further activation (PubMed:23878260).
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'.
Efficient DNA binding requires dimerization with another bHLH protein. Interacts with ARNT; forms a heterodimer that binds core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) leading to a transcriptional repressor on its target gene TH (By similarity).
May control regulatory pathways relevant to schizophrenia and to psychotic illness. May play a role in late central nervous system development by modulating EPO expression in response to cellular oxygen level (By similarity). Forms a heterodimer that binds core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) leading to transcriptional repression on its target gene TH (By similarity).
Multifunctional cytokine mainly produced by T-cells that plays a regulatory role in immune response, tissue homeostasis, host defense, and oncogenesis (PubMed:25168428, PubMed:27687232). Possesses antiviral functions and induces the type I intereferon response during influenza infection (PubMed:27687232). Signals through two receptor complexes IL20RA/IL20RB or IL20RB/IL22RA1 (PubMed:11706020, PubMed:30111632). In turn, stimulates the JAK1-STAT3 and MAPK pathways and promotes the secretion of pro-inflammatory mediators including IL8 and MMP1 (PubMed:25168428). Intracellularly, maintains endoplasmic reticulum homeostasis by restricting the eIF2alpha-CHOP pathway-mediated stress signal (By similarity). In addition, acts as a quality control mechanism for the ubiquitin proteasome system by alerting the cell to proteasome dysfunction through activation of PKR/EIF2AK2 (By similarity).
Ubiquitination at Lys-122 promotes proteasomal degradation.
Up-regulated in melanoma cells induced to terminally differentiate.
Catalytic subunit of the DNA primase complex and component of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex - primosome/replisome) which play an essential role in the initiation of DNA synthesis (PubMed:9268648, PubMed:9705292, PubMed:17893144, PubMed:24043831, PubMed:26975377, PubMed:25550159, PubMed:31479243, PubMed:33060134). During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, an accessory subunit POLA2 and two primase subunits, the catalytic subunit PRIM1 and the regulatory subunit PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1 (By similarity). The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands (PubMed:17893144). These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively (By similarity). In the primase complex, both subunits are necessary for the initial di-nucleotide formation, but the extension of the primer depends only on the catalytic subunit (PubMed:17893144). Synthesizes 9-mer RNA primers (also known as the 'unit length' RNA primers). Incorporates only ribonucleotides in the presence of ribo- and deoxy-nucleotide triphosphates (rNTPs, dNTPs) (PubMed:26975377). Requires template thymine or cytidine to start the RNA primer synthesis, with an adenine or guanine at its 5'-end (PubMed:25550159, PubMed:26975377). Binds single stranded DNA (By similarity).
Heterodimer of a catalytic subunit PRIM1 and a regulatory subunit PRIM2, also known as the DNA primase complex (PubMed:9705292, PubMed:17893144). Interacts with PRIM2 (via C-terminus) (PubMed:17893144). Component of the alpha DNA polymerase complex (also known as the alpha DNA polymerase-primase complex) consisting of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and the primase complex subunits PRIM1 and PRIM2 respectively (PubMed:9705292, PubMed:26975377, PubMed:24043831). Within the complex, POLA1 directly interacts with PRIM2 (By similarity).
The bound zinc ion is not a cofactor. It is bound to a zinc knuckle motif that may be involved in sequence recognition and the binding of ssDNA (By similarity).
The catalytic domain (residues 1-190 and 303-408) adopts a typical 'prim' fold structure formed by two three strand beta-sheets that line the inside of the lower and upper parts, each surrounded by alpha-helices on the outside (PubMed:24043831, PubMed:24239947). It comprises a highly conserved catalytic triad, a structural zinc-binding motif and the nucleotide-binding motifs. The Asp-109, Asp-111 and Asp-306 catalytic triad binds two Mn2+ or Mg2+ ions which activate for nucleophilic attack the 3'-hydroxyl of the growing RNA primer or of the first NTP bound at the initiation site (PubMed:24043831, PubMed:24239947, PubMed:25550159, PubMed:26975377). The nucleotide-binding motifs coordinate the phosphates, the ribose and the base of a NTP molecule (PubMed:24043831). The interaction between O2' of the initiating NTP and Asp-306 stabilizes the ribose during the di-nucleotide synthesis (PubMed:26975377). It is proposed that the first nucleotide binds to the elongation site, followed by binding to the initiation site of a second NTP, which will become the 5'-terminal nucleotide of the primer (PubMed:26975377).
The presence of the regulatory subunit PRIM2/p58 accelerates the kinetics of initiation and primer extension (By similarity). Inhibited by arabinose nucleoside derivatives such as fludarabine and vidarabine (PubMed:31479243).
Forms a complex with TRIAP1 in the mitochondrion intermembrane space. Interacts with OPA1 and AIFM1.
Highly expressed in fetal liver; less expressed in fetal brain, lung, and kidney. At the adult stage, expression is drastically reduced in the liver but highly expressed in the spleen, brain, lung, lymph nodes and peripheral blood leukocytes.
Involved in the modulation of the mitochondrial apoptotic pathway by ensuring the accumulation of cardiolipin (CL) in mitochondrial membranes. In vitro, the TRIAP1:PRELID1 complex mediates the transfer of phosphatidic acid (PA) between liposomes and probably functions as a PA transporter across the mitochondrion intermembrane space to provide PA for CL synthesis in the inner membrane. Regulates the mitochondrial apoptotic pathway in primary Th cells. Regulates Th cell differentiation by down-regulating STAT6 thereby reducing IL-4-induced Th2 cell number. May be important for the development of vital and immunocompetent organs.
Up-regulated in response to activation in primary T helper cells.
A chromosomal aberration involving PHF1 may be a cause of endometrial stromal tumors. Translocation t(6;7)(p21;p22) with JAZF1. Translocation t(1;6)(p34;p21) with MEAF6.
Highest levels in heart, skeletal muscle, and pancreas, lower levels in brain, placenta, lung, liver and kidney.
Interacts with CHMP1 (By similarity). Associated component of the PRC2 complex. Interacts with p53/TP53.
Polycomb group (PcG) that specifically binds histone H3 trimethylated at 'Lys-36' (H3K36me3) and recruits the PRC2 complex. Involved in DNA damage response and is recruited at double-strand breaks (DSBs). Acts by binding to H3K36me3, a mark for transcriptional activation, and recruiting the PRC2 complex: it is however unclear whether recruitment of the PRC2 complex to H3K36me3 leads to enhance or inhibit H3K27me3 methylation mediated by the PRC2 complex. According to some reports, PRC2 recruitment by PHF1 promotes H3K27me3 and subsequent gene silencing by inducing spreading of PRC2 and H3K27me3 into H3K36me3 loci (PubMed:18285464, PubMed:23273982). According to another report, PHF1 recruits the PRC2 complex at double-strand breaks (DSBs) and inhibits the activity of PRC2 (PubMed:23142980). Regulates p53/TP53 stability and prolonges its turnover: may act by specifically binding to a methylated from of p53/TP53.
The Tudor domain recognizes and binds H3K36me3 (PubMed:23228662, PubMed:23273982, PubMed:23142980).
Interacts with CENPC. Interacts with PLK1; required for recruitment of PLK1 at kinetochores.
Key regulator of kinetochore function during meiosis I: required both for mono-orientation of kinetochores on sister chromosomes and protection of centromeric cohesin from separase-mediated cleavage. Acts by facilitating kinetochore mono-orientation during meiosis I, when kinetochores on sister chromosomes face the same direction and are thus captured and pulled by spindle fibers from the same pole. Also required to prevent cleavage of cohesin at centromeres during meiosis I, possibly by acting as a regulator of the shugoshin-dependent protection pathway. Acts in collaboration with PLK1: required for PLK1 enrichment to kinetochores. Not required during meiosis II or mitosis.
May function as a chaperone that inhibits aggregation of misfolded proteins (PubMed:12204115). Negatively regulates the unfolded protein response (UPR) through binding to UPR sensors such as ERN1, which in turn inactivates ERN1 signaling (PubMed:24508390). May also regulate the UPR via the EIF2AK3 UPR sensor (PubMed:24508390). Plays a role in platelet aggregation and activation by agonists such as convulxin, collagen and thrombin (PubMed:15466936).
Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX (PubMed:12475965). Interacts with MICA on the surface of tumor cells, leading to MICA disulfide bond reduction which is required for its release from tumor cells (PubMed:17495932). Interacts with ITGB3 following platelet stimulation (PubMed:15466936). Interacts with ERN1; the interaction is direct (PubMed:24508390). Interacts with EIF2AK3 (PubMed:24508390).
Adds a GMP to the 5'-end of tRNA(His) after transcription and RNase P cleavage. This step is essential for proper recognition of the tRNA and for the fidelity of protein synthesis (Probable). Also functions as a guanyl-nucleotide exchange factor/GEF for the MFN1 and MFN2 mitofusins thereby regulating mitochondrial fusion (PubMed:25008184, PubMed:27307223). By regulating both mitochondrial dynamics and bioenergetic function, it contributes to cell survival following oxidative stress (PubMed:25008184, PubMed:27307223).
Belongs to the tRNA(His) guanylyltransferase family.
Homotetramer (PubMed:21059936). Interacts with MFN1 and MFN2; functions as a guanyl-nucleotide exchange factor/GEF for MFN2 and also probably MFN1 (PubMed:25008184).
Cell cycle-regulated processing produces four isoforms: p115, p105, p65, and p55. Isoform p115 arises from p105 phosphorylation and appears later in the cell cycle. Isoform p55 arises from p105 as a result of cleavage at a caspase cleavage-related site and it appears specifically at mitosis. The p65 isoform is poorly detected.
Contains a central domain containing multiple potential SH2-binding sites and a C-terminal domain containing a divergent helix-loop-helix (HLH) motif (PubMed:10502414). The SH2-binding sites putatively bind CRKL SH2 domains (PubMed:9020138). The HLH motif confers specific interaction with the HLH protein ID2 (PubMed:10502414). It is absolutely required for the induction of pseudohyphal growth in yeast and mediates homodimerization and heterodimerization with BCAR1/p130cas (PubMed:8668148, PubMed:10502414).
Expressed in B-cells (at protein level) (PubMed:9020138). Expressed in the respiratory epithelium of the main bronchi to the bronchioles in the lungs (at protein level) (PubMed:9584194). High levels detected in kidney, lung, and placenta (PubMed:9584194). Expressed in lymphocytes (PubMed:9497377).
Homodimer (PubMed:9584194, PubMed:10502414). Forms heterodimers with BCAR1/p130cas (PubMed:10502414). Forms complexes with PTK2B/RAFTK, adapter protein CRKL and LYN kinase (PubMed:9020138). Part of a complex composed of NEDD9, AURKA and CTTN; within the complex NEDD9 acts as a scaffold protein and is required for complex formation (PubMed:24574519). Part of a ternary complex composed of SMAD3, ITCH/AIP4 and NEDD9/HEF1; within the complex NEDD9/HEF1 interacts (via N-terminus) with ITCH/AIP4 (via WW domains); the complex mediates ubiquitination and proteasomal degradation of NEDD9/HEF1 (PubMed:15051726). Interacts with SMAD3; the interaction promotes NEDD9 ubiquitination and proteasomal degradation (PubMed:24574519). Interacts with ID2 (PubMed:10502414). Interacts with CTTN (via N-terminus) (PubMed:24574519). Interacts with MICAL (PubMed:11827972). Interacts with TXNL4/DIM1 (PubMed:11054566). Interacts with BCAR3 (via Ras-GEF domain) (PubMed:19103205). Interacts with SH2D3C isoform 1 and isoform 2 (By similarity). Interacts with ECT2 (PubMed:16394104). Interacts with PTPN11/SHP-2 (via SH2 domains); the interaction is enhanced when NEDD9/CAS-L is tyrosine phosphorylated (PubMed:19275884). Interacts (via C-terminus) with PLK1 (via polo box domains) (PubMed:29191835). Interacts with NKX2-5 (PubMed:29899023). Interacts with SMAD3; the interaction is inhibited by oxidation of NEDD9 (PubMed:15051726, PubMed:29899023). Interacts with NEDD9/HEF1; interaction is induced by CXCL12 promotion of ABL-mediated phosphorylation of NEDD9/HEF1 (PubMed:22810897). Interacts (via SH3 domain) with PTK2/FAK (PubMed:8668148, PubMed:8879209, PubMed:9360983). Interacts with FYN; in the presence of PTK2 (PubMed:9360983). Interacts with INPPL1/SHIP2 (By similarity).
Induced by oxidant stress in pulmonary artery endothelial cells.
PTK2/FAK1 phosphorylates the protein at the YDYVHL motif (conserved among all cas proteins) following integrin stimulation (PubMed:9360983). The SRC family kinases (FYN, SRC, LCK and CRK) are recruited to the phosphorylated sites and can phosphorylate other tyrosine residues (PubMed:9020138). Ligation of either integrin beta-1 or B-cell antigen receptor on tonsillar B-cells and B-cell lines promotes tyrosine phosphorylation and both integrin and BCR-mediated tyrosine phosphorylation requires an intact actin network (PubMed:9020138). Phosphorylation is required to recruit NEDD9 to T-cell receptor microclusters at the periphery of newly formed immunological synapses (By similarity). In fibroblasts transformation with oncogene v-ABL results in an increase in tyrosine phosphorylation. Transiently phosphorylated following CD3 cross-linking and this phosphorylated form binds to CRKL and C3G (PubMed:9497377). A mutant lacking the SH3 domain is phosphorylated upon CD3 cross-linking but not upon integrin beta-1 cross-linking (PubMed:9497377). Tyrosine phosphorylation occurs upon stimulation of the G-protein coupled C1a calcitonin receptor. Calcitonin-stimulated tyrosine phosphorylation is mediated by calcium- and protein kinase C-dependent mechanisms and requires the integrity of the actin cytoskeleton. Phosphorylation at Ser-369 induces proteasomal degradation (PubMed:19539609). Phosphorylated by LYN (PubMed:9020138). Phosphorylation at Ser-780 by CSNK1D or CSNK1E, or phosphorylation of Thr-804 by CSNK1E enhances the interaction of NEDD9 with PLK1 (PubMed:29191835).
Polyubiquitinated by ITCH/AIP4, leading to proteasomal degradation.
Scaffolding protein which plays a central coordinating role for tyrosine-kinase-based signaling related to cell adhesion (PubMed:24574519). As a focal adhesion protein, plays a role in embryonic fibroblast migration (By similarity). May play an important role in integrin beta-1 or B cell antigen receptor (BCR) mediated signaling in B- and T-cells. Integrin beta-1 stimulation leads to recruitment of various proteins including CRKL and SHPTP2 to the tyrosine phosphorylated form (PubMed:9020138). Promotes adhesion and migration of lymphocytes; as a result required for the correct migration of lymphocytes to the spleen and other secondary lymphoid organs (PubMed:17174122). Plays a role in the organization of T-cell F-actin cortical cytoskeleton and the centralization of T-cell receptor microclusters at the immunological synapse (By similarity). Negatively regulates cilia outgrowth in polarized cysts (By similarity). Modulates cilia disassembly via activation of AURKA-mediated phosphorylation of HDAC6 and subsequent deacetylation of alpha-tubulin (PubMed:17604723). Positively regulates RANKL-induced osteoclastogenesis (By similarity). Required for the maintenance of hippocampal dendritic spines in the dentate gyrus and CA1 regions, thereby involved in spatial learning and memory (By similarity).
initially expressed in the fetus (at protein level).
E3 ubiquitin-protein ligase that plays a role in the limitation of the innate immune response (PubMed:21474709, PubMed:29117565). Mediates inhibition of the RLR signaling pathway by ubiquitinating RIGI and IFIH1 receptors, leading to their proteasomal degradation (PubMed:21474709). Promotes also the neddylation of IKBKG/NEMO, stabilizing NFKBIA, and thereby inhibiting of NF-kappa-B nuclear translocation and activation (PubMed:21474709).
Highly expressed in normal gastrointestinal epithelia but that is down-regulated in gastrointestinal carcinomas and chronic inflammatory lesions of the gastrointestinal tract.
Contaminating sequence. Potential poly-A sequence starting in position 422.
Contaminating sequence. Potential poly-A sequence starting in position 611.
Contaminating sequence. Potential poly-A sequence starting in position 614.
Mediates apoptosis and actin stress fiber dissolution.
Ubiquitously expressed. Highest expression is found in heart and in skeletal muscle.
Gamma-tubulin complex is composed of gamma-tubulin, TUBGCP2, TUBGCP3, TUBGCP4, TUBGCP5 and TUBGCP6. Interacts with CDK5RAP2; the interaction is leading to centrosomal localization of TUBGCP3 and CDK5RAP2. Interacts with NIN (via N-terminus); the interaction may promote recruitment of the gamma-tubulin ring complex to the centrosome (By similarity).
Interacts with MTX2/metaxin-2. Associates with the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOOL/MIC27, IMMT/MIC60, APOO/MIC23/MIC26 and QIL1/MIC13. This complex was also known under the names MINOS or MitOS complex. The MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1 and MTX2 (together described as components of the mitochondrial outer membrane sorting assembly machinery (SAM) complex) and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9. The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both membranes termed the mitochondrial intermembrane space bridging (MIB) complex. Interacts with ARMC1 (PubMed:31644573).
Involved in transport of proteins into the mitochondrion. Essential for embryonic development (By similarity).
(Microbial infection) Interacts (via LIM domain 1) with Chikungunya virus non-structural protein 3 (via C-terminus); this interaction is required for viral RNA replication.
Elevated levels during postnatal muscle growth.
Isoform 1 is highly expressed in skeletal muscle and to a lesser extent in heart, placenta, ovary, prostate, testis, small intestine, colon and spleen. Expression is barely detectable in brain, lung, liver, kidney, pancreas, thymus and peripheral blood leukocytes. Isoform 2 is expressed in brain, skeletal muscle and to a lesser extent in heart, colon, prostate and small intestine. Isoform 3 is expressed in testis, heart and skeletal muscle.
May have an involvement in muscle development or hypertrophy.
Expressed in the fetal brain, lung, liver, and kidney.
Expressed most abundantly in the CNS (PubMed:9215677). Expressed in the heart, pancreas, thymus, testis and ovary (PubMed:9215677). Weakly expressed in brain, placenta, lung, liver, skeletal muscle, kidney, spleen, prostate, small intestine, colon, and peripheral blood lymphocytes (PubMed:9215677).
Transcription factor that binds to DNA at the consensus sequence 5'-ACCAAAG-3' (By similarity). Acts as a transcriptional activator (By similarity). Binds cooperatively with POU3F2/BRN2 or POU3F1/OCT6 to gene promoters, which enhances transcriptional activation (By similarity). Involved in the differentiation of naive CD4-positive T-cells into peripherally induced regulatory T (pT reg) cells under inflammatory conditions (By similarity). Binds to the promoter region of the FOXP3 gene and promotes its transcription, and might thereby contribute to pT reg cell differentiation in the spleen and lymph nodes during inflammation (By similarity). Plays a redundant role with SOX4 and SOX11 in cell survival of developing tissues such as the neural tube, branchial arches and somites, thereby contributing to organogenesis (By similarity).
All cysteine residues are assumed to be cross-linked to one another. Individual modules containing an even number of conserved cysteine residues are supposed to have disulfide linkages only within the same module.
Component of the membrane attack complex (MAC). MAC assembly is initiated by proteolytic cleavage of C5 into C5a and C5b. C5b binds sequentially C6, C7, C8 and 12-14 copies of the pore-forming subunit C9.
Constituent of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells.
The sequence shown is that of allotype C6 B.
Putative transcriptional activator involved in the hypothalamo-pituitary-gonadal system.
Expressed predominantly in the cerebral cortex of the brain but also at low levels in the spinal cord and medulla.
Detected in erythrocytes (at protein level). Widely expressed.
Homodimer and higher order homooligomer (PubMed:9642292). The homodimer is banana-shaped (PubMed:9642292). Interacts with ASIC1, ASIC2 and ASIC3 (By similarity). Interacts with LANCL1 (PubMed:9512664). Interacts with SLC2A1 (PubMed:23219802). Interacts with SLC4A1; this interaction positively regulates SLC4A1 activity (PubMed:23219802, PubMed:28387307). Identified in large complexes with SLC40A1, SLC14A1, SLC29A1 and AQP1 (PubMed:23219802). Interacts with STOML1; may redistribute STOM from the plasma membrane to late endosomes (PubMed:19696025).
Regulates ion channel activity and transmembrane ion transport. Regulates ASIC2 and ASIC3 channel activity.
Binds lactose with high affinity. Strong inducer of T-cell apoptosis.
Predominantly and highly expressed in the placenta where it is localized mainly in the syncytiotrophoblast and in the endothelia of fetal vessels. Also detected in the amnion and chorionic trophoblasts in fetal membranes.
Golgi-localized palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates and therefore functions in several unrelated biological processes (PubMed:22031296, PubMed:27380321, PubMed:28196865). Has no stringent fatty acid selectivity and in addition to palmitate can also transfer onto target proteins myristate from tetradecanoyl-CoA and stearate from octadecanoyl-CoA (By similarity). Palmitoylates sex steroid hormone receptors, including ESR1, PGR and AR, thereby regulating their targeting to the plasma membrane and their function in rapid intracellular signaling upon binding of sex hormones (PubMed:22031296). Palmitoylates GNAQ, a heterotrimeric G protein, regulating its dynamic localization at the plasma membrane and is thereby involved in GNAQ-dependent G protein-coupled receptor signaling pathways (PubMed:19001095). Functions also in ligand-induced cell death by regulating the FAS signaling pathway through the palmitoylation and stabilization of the receptor at the plasma membrane (PubMed:25301068). In epithelial cells, palmitoylates SCRIB and regulates its localization to the plasma membrane, regulating indirectly cell polarity and differentiation (PubMed:27380321). Also palmitoylates JAM3 and promotes its expression at tight junctions and regulates its function in cell migration (PubMed:28196865). Palmitoylates the glucose transporter GLUT4/SLC2A4 and controls the insulin-dependent translocation of GLUT4 to the plasma membrane (By similarity). In brain, could also palmitoylate SNAP25 and DLG4/PSD95 (By similarity). Could also palmitoylate DNAJC5 and regulate its localization to the Golgi membrane (By similarity). Could also palmitoylate NCDN (By similarity). May play a role in follicle stimulation hormone (FSH) activation of testicular Sertoli cells (By similarity).
Homooligomers. Heterooligomers with ZDHHC3.
Localized to the upper cortex of the hair shaft.
Catalyzes the phosphorylation of 1D-myo-inositol 1,4,5-trisphosphate (InsP3) into 1D-myo-inositol 1,3,4,5-tetrakisphosphate and participates to the regulation of calcium homeostasis.
Expressed in brain and striated muscle (at protein level) (PubMed:14593528). Widely expressed (PubMed:11735225). Expressed in skeletal muscle (PubMed:14593528).
Homodimer (By similarity). Interacts with OSBPL3 (By similarity).
Regulates cellular transport and efflux of cholesterol (PubMed:26941018). Plays a role in phosphatidylinositol-4-phophate (PI4P) turnover at the neuronal membrane (By similarity). Binds via its PH domain PI4P, phosphatidylinositol-4,5-diphosphate, phosphatidylinositol-3,4,5-triphosphate, and phosphatidic acid (By similarity). Weakly binds 25-hydroxycholesterol (PubMed:17428193).
Belongs to the Mediator complex subunit 7 family.
Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery.
Expressed at low levels on peripheral T-cells and is strongly up-regulated after activation, peaking 6 to 9 days after the activating stimulus.
Expressed on normal T-cell lines and clones, and some transformed T-cells, but no other cultured cell lines tested. It is expressed at very low levels on activated B-cells.
Homodimer; disulfide-linked. Interacts with PVR.
May be involved in adhesive interactions of activated T and NK cells during the late phase of the immune response. Promotes NK cell-target adhesion by interacting with PVR present on target cells. May function at a time after T and NK cells have penetrated the endothelium using integrins and selectins, when they are actively engaging diseased cells and moving within areas of inflammation.
The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving CD96 has been found in a patient with C syndrome. Translocation t(3;18)(q13.13;q12.1). CD96 gene was located at the 3q13.13 breakpoint. Precise structural analysis around the breakpoint showed that the gene was disrupted by the translocation in exon 5, probably leading to premature termination or loss of expression of CD96 protein. No gene was detected at the chromosome 18 breakpoint.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379, PubMed:25278503). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins. Interacts with MIEF1 upstream open reading frame protein (PubMed:30215512).
Disease susceptibility is associated with variants affecting the gene represented in this entry. Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.
Factor B which is part of the alternate pathway of the complement system is cleaved by factor D into 2 fragments: Ba and Bb. Bb, a serine protease, then combines with complement factor 3b to generate the C3 or C5 convertase. It has also been implicated in proliferation and differentiation of preactivated B-lymphocytes, rapid spreading of peripheral blood monocytes, stimulation of lymphocyte blastogenesis and lysis of erythrocytes. Ba inhibits the proliferation of preactivated B-lymphocytes.
Monomer (PubMed:19574954). Part of the C3-convertase enzyme complex comprised of Complement C3 beta chain (C3b) and Complement factor B Bb fragment (Bb) and CFP (PubMed:28264884, PubMed:31507604). Interacts to C3b; this interaction is dependent on the presence of Mg2+ (PubMed:28264884, PubMed:31507604). Interacts to CFP; this interaction contributes to the stabilization of the active C3-convertase enzyme complex (PubMed:31507604).
The unliganded VWA domain has an inactive 'locked' conformation whereby the scissile Arg-259|Lys-260 bond is protected from proteolytic activation.
Two major variants, F and S, and 2 minor variants, as well as at least 14 very rare variants, have been identified.
Expressed in kidney (PubMed:7756356). Not detected in intestine (PubMed:7756356). Highly expressed in macrophages (PubMed:20406817).
Proton-coupled amino-acid transporter that transports oligopeptides of 2 to 4 amino acids with a preference for dipeptides (PubMed:7756356, PubMed:18367661, PubMed:16434549). Transports neutral and anionic dipeptides with a proton to peptide stoichiometry of 2:1 or 3:1 (By similarity). In kidney, involved in the absorption of circulating di- and tripeptides from the glomerular filtrate (PubMed:7756356). Can also transport beta-lactam antibiotics, such as the aminocephalosporin cefadroxil, and other antiviral and anticancer drugs (PubMed:16434549). Transports the dipeptide-like aminopeptidase inhibitor bestatin (By similarity). Also able to transport carnosine (PubMed:31073693). Involved in innate immunity by promoting the detection of microbial pathogens by NOD-like receptors (NLRs) (By similarity). Mediates transport of bacterial peptidoglycans across the plasma membrane or, in macrophages, the phagosome membrane: catalyzes the transport of certain bacterial peptidoglycans, such as muramyl dipeptide (MDP), the NOD2 ligand (PubMed:20406817).
SLC15A2 is polymmorphic and has two main variants that differ in three amino acid positions, hPEPT2*1 and hPEPT2*2. They are distributed evenly among the population and don't show functional differences.
Alternative splicing. Incomplete sequence.
Associates with RNA polymerase II, the TCR-specific proteins CKN1/CSA and ERCC6/CSB, and XPA (PubMed:10944529). Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:28076346). Component of the XAB2 complex, a multimeric protein complex composed of XAB2, PRPF19, AQR, ZNF830, ISY1, and PPIE (PubMed:17981804). Identified in a pentameric intron-binding (IB) complex composed of AQR, XAB2, ISY1, ZNF830 and PPIE that is incorporated into the spliceosome as a preassembled complex (PubMed:25599396). The IB complex does not contain PRPF19 (PubMed:25599396).
Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28502770, PubMed:28076346). Involved in transcription-coupled repair (TCR), transcription and pre-mRNA splicing (PubMed:10944529, PubMed:17981804).
(Microbial infection) Interact with Rift valley fever virus NSs (via omegaXaV motif); this interaction is important for EIF2AK2/PKR degradation.
(Microbial infection) Target of human immunodeficiency virus type 1 (HIV-1) protein VPU to polyubiquitinate and deplete BST2 from cells and antagonize its antiviral action.
Expression is negatively regulated by Wnt/beta-catenin pathway.
In the embryo, it is expressed in the developing eye, limbs and brain (PubMed:31402090). Expression is observed in the lens, retina, lips of the optic fissure closure and regions of the conjunctiva at Carnegie stages (CS) between CS15 and CS21. As eye development progresses, the stronger signal observed in the retina progressively shifts from the inner toward the outer retinal layers (PubMed:31402090). In the developing hand, expression is strong at CS15. At CS19 and CS21, after the digits have begun to form, strong expression is seen in the mesenchyme surrounding the developing cartilage (PubMed:31402090). In the brain, it is expressed in the primitive ventricles at CS17 and CS19, hypothalamus and medulla at CS17, and metencephalon at CS19 (PubMed:31402090). Strong expression is also observed in the pharyngeal arches, including the mandibular process and tongue at CS17 (PubMed:31402090).
Self-associates (PubMed:10644755). Component of the SCF(FBXW11) complex formed of CUL1, SKP1, RBX1 and a FBXW11 dimer (PubMed:10066435, PubMed:10437795, PubMed:20347421, PubMed:22017875, PubMed:22017876, PubMed:36608670). Interacts with BST2 and USP47 (PubMed:19730691, PubMed:19966869). Interacts with TRIM21 (PubMed:16880511). Interacts with PER3 (PubMed:15917222). Interacts with INAVA (PubMed:29420262). Interacts with REST (PubMed:18354482).
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:10437795, PubMed:11158290, PubMed:10648623, PubMed:20347421, PubMed:19966869, PubMed:22017875, PubMed:22017876, PubMed:36608670). Probably recognizes and binds to phosphorylated target proteins: the interaction with substrates requires the phosphorylation of the two serine residues in the substrates' destruction motif D-S-G-X(2,3,4)-S (PubMed:10437795, PubMed:10648623, PubMed:20347421, PubMed:19966869, PubMed:22017875, PubMed:22017876, PubMed:36608670). SCF(FBXW11) mediates the ubiquitination of phosphorylated CTNNB1 and participates in Wnt signaling regulation (PubMed:10321728). SCF(FBXW11) plays a key role in NF-kappa-B activation by mediating ubiquitination of phosphorylated NFKBIA, leading to its degradation by the proteasome, thereby allowing the associated NF-kappa-B complex to translocate into the nucleus and to activate transcription (PubMed:10321728, PubMed:10644755, PubMed:10437795, PubMed:20347421). The SCF(FBXW11) complex also regulates NF-kappa-B by mediating ubiquitination of phosphorylated NFKB1: specifically ubiquitinates the p105 form of NFKB1, leading to its degradation (PubMed:11158290). SCF(FBXW11) mediates the ubiquitination of IFNAR1 (PubMed:14532120, PubMed:15337770). SCF(FBXW11) mediates the ubiquitination of CEP68; this is required for centriole separation during mitosis (PubMed:25503564). Involved in the oxidative stress-induced a ubiquitin-mediated decrease in RCAN1 (PubMed:18575781). Mediates the degradation of CDC25A induced by ionizing radiation in cells progressing through S phase and thus may function in the intra-S-phase checkpoint (PubMed:14603323). Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and phosphorylated PER2 (PubMed:15917222). SCF(FBXW11) mediates the ubiquitination of CYTH1, and probably CYTH2 (PubMed:29420262). SCF(FBXW11) acts as a regulator of mTORC1 signaling pathway by catalyzing ubiquitination and subsequent proteasomal degradation of phosphorylated DEPTOR, TFE3 and MITF (PubMed:22017875, PubMed:22017876, PubMed:36608670).
Homodimer (PubMed:10669729). The CSTF complex is composed of CSTF1 (50 kDa subunit), CSTF2 (64 kDa subunit) and CSTF3 (77 kDa subunit) (PubMed:10669729). Interacts (via repeats WD) directly with CSTF3 (PubMed:10669729). Interacts (via repeat WD6) with BARD1 (PubMed:10477523). Interacts with ERCC6 (PubMed:26030138).
One of the multiple factors required for polyadenylation and 3'-end cleavage of mammalian pre-mRNAs (PubMed:10669729). May be responsible for the interaction of CSTF with other factors to form a stable complex on the pre-mRNA (PubMed:10669729).
Bifunctional enzyme localized in the lumen of the endoplasmic reticulum that catalyzes the first two steps of the oxidative branch of the pentose phosphate pathway/shunt, an alternative to glycolysis and a major source of reducing power and metabolic intermediates for biosynthetic processes (By similarity). Has a hexose-6-phosphate dehydrogenase activity, with broad substrate specificity compared to glucose-6-phosphate 1-dehydrogenase/G6PD, and catalyzes the first step of the pentose phosphate pathway (PubMed:12858176, PubMed:18628520, PubMed:23132696). In addition, acts as a 6-phosphogluconolactonase and catalyzes the second step of the pentose phosphate pathway (By similarity). May have a dehydrogenase activity for alternative substrates including glucosamine 6-phosphate and glucose 6-sulfate (By similarity). The main function of this enzyme is to provide reducing equivalents such as NADPH to maintain the adequate levels of reductive cofactors in the oxidizing environment of the endoplasmic reticulum (PubMed:12858176, PubMed:18628520, PubMed:23132696). By producing NADPH that is needed by reductases of the lumen of the endoplasmic reticulum like corticosteroid 11-beta-dehydrogenase isozyme 1/HSD11B1, indirectly regulates their activity (PubMed:18628520).
In the C-terminal section; belongs to the glucosamine/galactosamine-6-phosphate isomerase family. 6-phosphogluconolactonase subfamily.
In the N-terminal section; belongs to the glucose-6-phosphate dehydrogenase family.
Present in most tissues examined, strongest in liver.
Part of the TFIIIC subcomplex TFIIIC2, consisting of six subunits, GTF3C1, GTF3C2, GTF3C3, GTF3C4, GTF3C5 and GTF3C6.
Required for RNA polymerase III-mediated transcription. Component of TFIIIC that initiates transcription complex assembly on tRNA and is required for transcription of 5S rRNA and other stable nuclear and cytoplasmic RNAs. May play a direct role in stabilizing interactions of TFIIIC2 with TFIIIC1.
Down-regulated in many primary skin melanomas. Treatment with a demethylating agent, 5'-aza-2-deoxycytidine, restores expression, suggesting that down-regulation is the result of methylation of the gene.
E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors.
Expressed in skeletal muscle, and to a lesser extent in heart, brain and kidney.
Ubiquitinated. Possibly via autoubiquitination (By similarity).
Homooligomer or heterooligomer (probably pentamer) with neuronal pentraxin receptor (NPTXR).
In the embryo, expressed exclusively in the developing brain, whereas in the adult its expression is restricted to brain, heart, skeletal muscle and lung. In the brain, the highest expression levels are found in specific cell layers of the cortex, the olfactory bulb, the hippocampus and the cerebellum.
Transcription factor that binds preferentially to a variant of the octamer motif (5'-ATGATAAT-3').
Cells expressing STN1 mutants defective for dimerization with TEN1 display elongated telomeres and telomere defects associated with telomere uncapping.
Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex. The CST complex binds single-stranded DNA with high affinity in a sequence-independent manner, while isolated subunits bind DNA with low affinity by themselves. Initially the CST complex has been proposed to protect telomeres from DNA degradation (PubMed:19854130). However, the CST complex has been shown to be involved in several aspects of telomere replication. The CST complex inhibits telomerase and is involved in telomere length homeostasis; it is proposed to bind to newly telomerase-synthesized 3' overhangs and to terminate telomerase action implicating the association with the ACD:POT1 complex thus interfering with its telomerase stimulation activity. The CST complex is also proposed to be involved in fill-in synthesis of the telomeric C-strand probably implicating recruitment and activation of DNA polymerase alpha (PubMed:22964711, PubMed:22763445). The CST complex facilitates recovery from many forms of exogenous DNA damage; seems to be involved in the re-initiation of DNA replication at repaired forks and/or dormant origins (PubMed:25483097). Required for efficicient replication of the duplex region of the telomere. Promotes efficient replication of lagging-strand telomeres (PubMed:22863775, PubMed:22964711). Promotes general replication start following replication-fork stalling implicating new origin firing (PubMed:22863775). May be in involved in C-strand fill-in during late S/G2 phase independent of its role in telomere duplex replication (PubMed:23142664).
Component of the CST complex, a complex that binds to single-stranded DNA and is required to protect telomeres from DNA degradation. The CST complex binds single-stranded DNA with high affinity in a sequence-independent manner, while isolated subunits bind DNA with low affinity by themselves. In addition to telomere protection, the CST complex has probably a more general role in DNA metabolism at non-telomeric sites.
Component of the CST complex, composed of TEN1/C17orf106, CTC1/C17orf68 and STN1; in the complex interacts directly with TEN1 and CTC1. Interacts with ACD/TPP1, POT1 and POLA1.
(Microbial infection) [Isoform 1]: Interacts with ebolavirus VP30.
(Microbial infection) [Isoform 1]: Restricts ebolavirus replication probably by impairing the vp30-NP interaction, and thus viral transcription.
Contains a N-terminus DWNN domain, a zinc-finger domain and a C4C4 zinc-binding RING finger domain (PubMed:22130672). The ring finger may indeed be a U-box domain (PubMed:22130672).
E3 ubiquitin-protein ligase which promotes ubiquitination of YBX1, leading to its degradation by the proteasome (PubMed:18851979). May play a role as a scaffold protein to promote the assembly of the p53/TP53-MDM2 complex, resulting in increase of MDM2-mediated ubiquitination and degradation of p53/TP53; may function as negative regulator of p53/TP53, leading to both apoptosis and cell growth (By similarity). Regulates DNA-replication and the stability of chromosomal common fragile sites (CFSs) in a ZBTB38- and MCM10-dependent manner. Controls ZBTB38 protein stability and abundance via ubiquitination and proteasomal degradation, and ZBTB38 in turn negatively regulates the expression of MCM10 which plays an important role in DNA-replication (PubMed:24726359).
Highly expressed in the placenta and testis. Expressed at lower levels in the brain, heart, kidney, liver and lung. Overexpressed in esophageal cancer.
Interacts with p53/TP53 and RB1 (By similarity). Interacts also with MDM2 and YBX1 (PubMed:17470788). Interacts also with MDM2 and YBX1 (PubMed:18851979). Interacts with NEK6 (PubMed:20873783). Interacts with ZBTB38 (PubMed:24726359).
(Microbial infection) Glycosylated at Arg-603 by enteropathogenic E.coli protein NleB1: arginine GlcNAcylation prevents homotypic/heterotypic death domain interactions.
(Microbial infection) Interacts with Murid herpesvirus 1 protein RIR1.
Deubiquitinated by USP7; this modification is required for TNF-alpha-induced apoptosis.
Homodimer (PubMed:29440439, PubMed:29681455). Interacts (via RIP homotypic interaction motif) with RIPK3 (via RIP homotypic interaction motif); this interaction induces RIPK1 phosphorylation and formation of a RIPK1-RIPK3 necroptosis-inducing complex (PubMed:11734559, PubMed:29883609, PubMed:19524512, PubMed:10358032, PubMed:29681455). Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity (PubMed:22265414). Interacts (via the death domain) with TNFRSF6 (via the death domain) and TRADD (via the death domain) (PubMed:8612133). Is recruited by TRADD to TNFRSF1A in a TNF-dependent process (PubMed:24130170). Binds RNF216, EGFR, IKBKG, TRAF1, TRAF2 and TRAF3 (PubMed:8612133, PubMed:9927690, PubMed:11854271, PubMed:11116146). Interacts with BNLF1 (PubMed:10409763). Interacts with SQSTM1 upon TNF-alpha stimulation (PubMed:10356400). May interact with MAVS/IPS1 (PubMed:16127453). Interacts with ZFAND5 (PubMed:14754897). Interacts with RBCK1 (PubMed:17449468). Interacts with ZBP1 (By similarity). Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4 (PubMed:21931591). Interacts (via kinase domain) with DAB2IP (via Ras-GAP domain); the interaction occurs in a TNF-alpha-dependent manner (PubMed:17389591, PubMed:15310755). Interacts with ARHGEF2 (PubMed:21887730). Interacts (via protein kinase domain) with RFFL; involved in RIPK1 ubiquitination (PubMed:18450452). Interacts with RNF34; involved in RIPK1 ubiquitination (Ref.35). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with PELI1 (PubMed:29883609). Interacts (via death domain) with CRADD (via death domain); the interaction is direct (PubMed:9044836). Component of complex IIa composed of at least RIPK1, FADD and CASP8 (By similarity). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity). Interacts with MAP3K7, CFLAR, CASP8, FADD and NEMO (By similarity). Interacts with TAX1BP1; this interaction negatively regulates RIPK1 ubiquitination (PubMed:17703191).
Proteolytically cleaved by CASP8 at Asp-324 (PubMed:10521396, PubMed:31827281, PubMed:31827280). Cleavage is crucial for limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:31827281, PubMed:31827280). Cleavage abolishes NF-kappa-B activation and enhances the interaction of TRADD with FADD (PubMed:10521396). Proteolytically cleaved by CASP6 during intrinsic apoptosis (PubMed:22858542).
RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:18408713, PubMed:19524513, PubMed:31827280). Phosphorylation of Ser-161 by RIPK3 is necessary for the formation of the necroptosis-inducing complex (PubMed:18408713). Phosphorylation at Ser-25 represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (PubMed:30988283). Phosphorylated at Ser-320 by MAP3K7 which requires prior ubiquitination with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 (By similarity). This phosphorylation positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (By similarity).
Serine-threonine kinase activity is inhibited by linear polyubiquitination ('Met-1'-linked) by the LUBAC complex (By similarity). Inhibited by necrostatins, including necrostatin-1, necrostatin-3 and necrostatin-4 (PubMed:23473668).
Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways (PubMed:32657447, PubMed:31827280, PubMed:31827281, PubMed:17703191, PubMed:24144979). Exhibits kinase activity-dependent functions that regulate cell death and kinase-independent scaffold functions regulating inflammatory signaling and cell survival (PubMed:11101870, PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Has kinase-independent scaffold functions: upon binding of TNF to TNFR1, RIPK1 is recruited to the TNF-R1 signaling complex (TNF-RSC also known as complex I) where it acts as a scaffold protein promoting cell survival, in part, by activating the canonical NF-kappa-B pathway (By similarity). Kinase activity is essential to regulate necroptosis and apoptosis, two parallel forms of cell death: upon activation of its protein kinase activity, regulates assembly of two death-inducing complexes, namely complex IIa (RIPK1-FADD-CASP8), which drives apoptosis, and the complex IIb (RIPK1-RIPK3-MLKL), which drives necroptosis (By similarity). RIPK1 is required to limit CASP8-dependent TNFR1-induced apoptosis (By similarity). In normal conditions, RIPK1 acts as an inhibitor of RIPK3-dependent necroptosis, a process mediated by RIPK3 component of complex IIb, which catalyzes phosphorylation of MLKL upon induction by ZBP1 (PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Inhibits RIPK3-mediated necroptosis via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis (PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Required to inhibit apoptosis and necroptosis during embryonic development: acts by preventing the interaction of TRADD with FADD thereby limiting aberrant activation of CASP8 (By similarity). In addition to apoptosis and necroptosis, also involved in inflammatory response by promoting transcriptional production of pro-inflammatory cytokines, such as interleukin-6 (IL6) (PubMed:31827280, PubMed:31827281). Phosphorylates RIPK3: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:19524513). Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (PubMed:17389591, PubMed:15310755). Required for ZBP1-induced NF-kappa-B activation in response to DNA damage (By similarity).
The RIP homotypic interaction motif (RHIM) mediates interaction with the RHIM motif of RIPK1. Both motifs form a hetero-amyloid serpentine fold, stabilized by hydrophobic packing and featuring an unusual Cys-Ser ladder of alternating Ser (from RIPK1) and Cys (from RIPK3).
The death domain mediates dimerization and activation of its kinase activity during necroptosis and apoptosis (PubMed:29440439). It engages other DD-containing proteins as well as a central (intermediate) region important for NF-kB activation and RHIM-dependent signaling (PubMed:10356400).
The disease is caused by variants affecting the gene represented in this entry. RIPK1-deficient immune cells from IMD57 patients have impaired proinflammatory signaling leading to dysregulated cytokine secretion and are prone to necroptosis.
Ubiquitinated with 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin (PubMed:15258597, PubMed:16603398, PubMed:18450452, PubMed:21455173, PubMed:21931591, PubMed:29883609, Ref.35, PubMed:17703191). Polyubiquitination with 'Lys-63'-linked chains by TRAF2 induces association with the IKK complex (PubMed:15258597). Deubiquitination of 'Lys-63'-linked chains and polyubiquitination with 'Lys-48'-linked chains by TNFAIP3 leads to RIPK1 proteasomal degradation and consequently down-regulates TNF-alpha-induced NF-kappa-B signaling (PubMed:15258597). 'Lys-48'-linked polyubiquitination by RFFL or RNF34 also promotes proteasomal degradation and negatively regulates TNF-alpha-induced NF-kappa-B signaling (PubMed:18450452, Ref.35). Linear polyubiquitinated; the head-to-tail linear polyubiquitination ('Met-1'-linked) is mediated by the LUBAC complex and decreases protein kinase activity (PubMed:21455173). Deubiquitination of linear polyubiquitin by CYLD promotes the kinase activity (By similarity). Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B (PubMed:21931591). Ubiquitinated with 'Lys-63'-linked chains by PELI1 (PubMed:29883609). Ubiquitination at Lys-377 with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 is essential for its phosphorylation at Ser-320 mediated by MAP3K7 (By similarity). This ubiquitination is required for NF-kB activation, suppresses RIPK1 kinase activity and plays a critical role in preventing cell death during embryonic development (By similarity).
Key enzyme for ketone body catabolism. Transfers the CoA moiety from succinate to acetoacetate. Formation of the enzyme-CoA intermediate proceeds via an unstable anhydride species formed between the carboxylate groups of the enzyme and substrate (By similarity).
E3 ubiquitin-protein ligase which may specifically enhance the E2 activity of HIP2. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates (PubMed:16868077). May be involved in T-cell proliferation by regulating LIF secretion (By similarity). May play a role in lysosome homeostasis (PubMed:31270356).
(Microbial infection) Interacts with HBV major surface antigen L. Interacts with HBV core protein C in a ubiquitin-dependent manner.
(Microbial infection) Involved in MVB-assisted maturation of hepatitis B virus (HBV).
Does not appear to be a subunit of the clathrin-associated adaptor protein complex 1 (AP-1).
Expressed in all but one (skeletal muscle) tissues examined.
May function in protein sorting in late endosomes or multivesucular bodies (MVBs).
May interact with AP1S1/Sigma1A-adaptin and AP1S2/Sigma1B-adaptin (PubMed:9733768). Probably does not interact with APB1 (PubMed:9733768). Interacts (via GAE domain) with RABEP1, NECAP1, CLINT1 and AFTPH/aftiphilin (PubMed:14665628).
Expressed in skin. Isoforms 1 and 3 are expressed in kidney and liver. Isoform 1 but not isoform 2 is expressed in colon, esophagus and small intestine.
Isoform 1 interacts with isoform 3/i2 suggesting that oligomerization is involved in negative regulation of transferase activity by isoform 3. Isoform 1 also interacts with respective i2 isoforms of UGT1A1, UGT1A3, UGT1A4, UGT1A7, UGT1A8, UGT1A9 and UGT1A10.
Polymorphisms in the UGT1A6 gene define four common haplotypes: UGT1A6*1, UGT1A6*2, UGT1A6*3 and UGT1A6*4. Liver tissue samples that were homozygous for UGT1A6*2 exhibited a high rate of glucuronidation relative to tissues with other genotypes. Biochemical kinetic studies indicate that the UGT1A6*2 allozyme, expressed homozygously, had almost two-fold greater activity toward p-nitrophenol than UGT1A6*1 and when expressed heterozygously (UGT1A6*1/*2) it is associated with low enzyme activity. Common genetic variation in UGT1A6 confers functionally significant differences in biochemical phenotype. This genetic variation might impact clinical efficacy or toxicity of drugs metabolized by UGT1A6.
The gene is part of the UGT1A complex locus which displays alternative use of promoters, first exons and terminal exons. The locus is defined by 13 first exons, which are alternatively spliced to 3 other common exons and 2 alternative terminal exons 5. From the 27 possible mRNA isoforms, 9 produce functionally active polypeptides (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9 and 1A10) called isoforms 1 (i1). Use of an alternative exon 5 (5b) as terminal exon is leading to 9 additional alternatively spliced products termed isoforms i2 and which lack transferase activity.
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 3 lacks transferase activity but acts as a negative regulator of isoform 1 (By similarity).
Interacts with RAB1B, RAB8A, RAB10, RAB13 and RAB15 (in their GTP-bound forms); binding to RAB1B is of low affinity compared to other Rab proteins; at least in case of RAB8A can bind 2 molecules of RAB8A simultaneously through a high and a low affinity binding site, respectively. Interacts with ERC1 and RAB8A; may bridge ERC1 with RAB8A. Interacts with KIF23 and ERC1; enhances the interaction between KIF23 and ERC1. Interacts with NINL isoform 2.
Monooxygenase that promotes depolymerization of F-actin by mediating oxidation of specific methionine residues on actin to form methionine-sulfoxide, resulting in actin filament disassembly and preventing repolymerization. In the absence of actin, it also functions as a NADPH oxidase producing H(2)O(2). Seems to act as Rab effector protein and plays a role in vesicle trafficking. Involved in exocytic vesicles tethering and fusion: the monooxygenase activity is required for this process and implicates RAB8A associated with exocytotic vesicles. Required for cytokinesis. Contributes to stabilization and/or maturation of the intercellular bridge independently of its monooxygenase activity. Promotes recruitment of Rab8 and ERC1 to the intercellular bridge, and together these proteins are proposed to function in timely abscission.
The bivalent Mical/EHBP Rab binding (bMERB) domain, mediates binding to predominantly Rab8, Rab10, Rab10, Rab13 and Rab15 (in their GTP-bound forms).
Formation of pseudouridine at position 39 in the anticodon stem and loop of transfer RNAs.
Serine protease inhibitor which displays weak inhibitory activity against trypsin (PubMed:8882727). May play a role in facial patterning during embryonic development (By similarity).
Weakly expressed. Expressed at low level in prostate, mammary gland, salivary gland and thyroid gland.
Restriction factor required to restrict infectivity of lentiviruses, such as HIV-1: acts by inhibiting an early step of viral infection. Impairs the penetration of the viral particle into the cytoplasm (PubMed:26416733, PubMed:26416734).
Ubiquitous. Expression levels were increased fourfold to tenfold in lung tumor tissues compared with normal pulmonary tissues.
Expressed in pancreas, kidney, skeletal muscle, lung, placenta, brain, heart, spleen, liver and small intestine. Expressed in blood vessels (at protein level).
May play a role in CNS development by interacting with growth factors implicated in motor neuron differentiation and survival. May play a role in capillary formation and maintenance during angiogenesis. Modulates BMP activity by affecting its processing and delivery to the cell surface.
Catalyzes the pyridoxal-phosphate-dependent breakdown of phosphoethanolamine, converting it to ammonia, inorganic phosphate and acetaldehyde.
Does not seem to possess aminotransferase activity.
E3 ubiquitin-protein ligase that regulates cell proliferation (PubMed:18794910, PubMed:23378536, PubMed:30595371). Involved in apoptosis regulation (PubMed:23378536, PubMed:30595371). Mediates ER stress-induced activation of JNK signaling pathway and apoptosis by promoting ERN1 activation and splicing of XBP1 mRNA (PubMed:23378536, PubMed:30595371). Also involved in protein trafficking and localization (PubMed:24387786).
The RING-type zinc finger domain is required for E3 ligase activity and for promoting ER stress-induced JNK activation and apoptosis.
Widely expressed (at protein level). In normal pancreas, expressed in islets, but not in ducts, nor in acini (at protein level).
A connexon is composed of a hexamer of connexins. Interacts with CNST.
The gene represented in this entry may act as a disease modifier.
Probable component of the Arp2/3 complex in which it may replace ARPC1B (Probable). In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA (By similarity).
Probably functions as component of the Arp2/3 complex which is involved in regulation of actin polymerization and together with an activating nucleation-promoting factor (NPF) mediates the formation of branched actin networks.
Functions as a dominant-negative VHL to serve as a protector of HIFalpha.
Has little or no E3 ubiquitin ligase activity as it lacks the alpha domain required for nucleating the multiprotein E3 ubiquitin ligase complex.
Interacts via the beta domain with the ODD domain of HIF1A. This interaction is independent of prolyl hydroxylation of HIF1A.
Expressed in synovial fibroblasts and articular chondrocytes. Expressed in keratinocytes and monocyte-derived dendritic cells. Expressed in monocytes and myeloid dendritic cells; at protein level.
Interacts with IL1RAP; the association is enhanced by IL36B indicative for an functional signaling complex and inhibited by IL36RN (By similarity).
Receptor for interleukin-36 (IL36A, IL36B and IL36G). After binding to interleukin-36 associates with the coreceptor IL1RAP to form the interleukin-36 receptor complex which mediates interleukin-36-dependent activation of NF-kappa-B, MAPK and other pathways (By similarity). The IL-36 signaling system is thought to be present in epithelial barriers and to take part in local inflammatory response; it is similar to the IL-1 system. Seems to be involved in skin inflammatory response by induction of the IL-23/IL-17/IL-22 pathway.
Cytochrome P450 monooxygenase that catalyzes regio- and stereospecific hydroxylation of cholesterol and its derivatives. Hydroxylates (with R stereochemistry) the terminal methyl group of cholesterol side-chain in a three step reaction to yield at first a C26 alcohol, then a C26 aldehyde and finally a C26 acid (PubMed:9660774, PubMed:12077124, PubMed:21411718, PubMed:28190002). Regulates cholesterol homeostasis by catalyzing the conversion of excess cholesterol to bile acids via both the 'neutral' (classic) and the 'acid' (alternative) pathways (PubMed:9660774, PubMed:1708392, PubMed:11412116, PubMed:2019602, PubMed:7915755, PubMed:9186905, PubMed:9790667). May also regulate cholesterol homeostasis via generation of active oxysterols, which act as ligands for NR1H2 and NR1H3 nuclear receptors, modulating the transcription of genes involved in lipid metabolism (PubMed:9660774, PubMed:12077124). Plays a role in cholestanol metabolism in the cerebellum. Similarly to cholesterol, hydroxylates cholestanol and may facilitate sterol diffusion through the blood-brain barrier to the systemic circulation for further degradation (PubMed:28190002). Also hydroxylates retinal 7-ketocholesterol, a noxious oxysterol with pro-inflammatory and pro-apoptotic effects, and may play a role in its elimination from the retinal pigment epithelium (PubMed:21411718). May play a redundant role in vitamin D biosynthesis. Catalyzes 25-hydroxylation of vitamin D3 that is required for its conversion to a functionally active form (PubMed:15465040).
Expressed in the neural retina and underlying retinal pigment epithelium (at protein level) (PubMed:21411718). Expressed in the gray and white matter of cerebellum (at protein level) (PubMed:28190002).
Interacts with HSP70; this interaction is required for initial targeting to mitochondria.
High expression in heart, lung, liver, skeletal muscle, kidney, pancreas, spleen, testis, ovary, subthalamic nucleus and fetal liver. Weak expression in other tissues tested.
Component of the chaperonin-containing T-complex (TRiC), a heterooligomeric complex of about 850 to 900 kDa that forms two stacked rings, 12 to 16 nm in diameter (PubMed:20080638, PubMed:25467444). Interacts with PACRG (PubMed:14532270). Interacts with DNAAF4 (By similarity).
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The channel is blocked by alpha-bungarotoxin.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-7/CHRNA7 sub-subfamily.
Glycosylations at Asn-46, Asn-90 and Asn-133 are essential for TMEM35A/NACHO-mediated proper subunit assembly and trafficking to the cell membrane.
Homopentamer (By similarity). Interacts with RIC3; which is required for proper folding and assembly (PubMed:15504725, PubMed:16120769). Interacts with LYPD6 (PubMed:27344019). Interacts with the alpha-conotoxin RgIA (By similarity). Interacts with alpha-conotoxins ImI and ImII (PubMed:15609996). Interacts with CANX (PubMed:32783947).
This protein is encoded by a hybrid gene consisting of a duplication of exons 5 through 10 of the CHRNA7 gene fused 3-prime to a copy of the FAM7A gene (exons A through E). The CHRFAM7A gene is in the opposite orientation to the CHRNA7 gene. It seems not to be represented on every human chromosome 15 and it is not clear whether the transcript is actually translated.
Component of the 9-1-1 cell-cycle checkpoint response complex that plays a major role in DNA repair (PubMed:10846170, PubMed:10884395). The 9-1-1 complex is recruited to DNA lesion upon damage by the RAD17-replication factor C (RFC) clamp loader complex (PubMed:12578958). Acts then as a sliding clamp platform on DNA for several proteins involved in long-patch base excision repair (LP-BER) (PubMed:15871698). The 9-1-1 complex stimulates DNA polymerase beta (POLB) activity by increasing its affinity for the 3'-OH end of the primer-template and stabilizes POLB to those sites where LP-BER proceeds; endonuclease FEN1 cleavage activity on substrates with double, nick, or gap flaps of distinct sequences and lengths; and DNA ligase I (LIG1) on long-patch base excision repair substrates (PubMed:15314187, PubMed:15556996, PubMed:15871698). The 9-1-1 complex is necessary for the recruitment of RHNO1 to sites of double-stranded breaks (DSB) occurring during the S phase (PubMed:21659603). Isoform 1 possesses 3'->5' double stranded DNA exonuclease activity (PubMed:9660799).
Component of the toroidal 9-1-1 (RAD9-RAD1-HUS1) complex, composed of RAD9A, RAD1 and HUS1 (PubMed:10846170, PubMed:10884395). The 9-1-1 complex associates with LIG1, POLB, FEN1, RAD17, HDAC1, RPA1 and RPA2 (PubMed:10846170, PubMed:10884395, PubMed:15314187, PubMed:15556996, PubMed:15871698, PubMed:15897895, PubMed:16216273). The 9-1-1 complex associates with the RAD17-RFC complex (PubMed:12578958). RAD1 interacts with POLB, FEN1, HUS1, HUS1B, RAD9A and RAD9B (PubMed:10359610, PubMed:10777662, PubMed:11944979, PubMed:14500360, PubMed:14611806, PubMed:15314187, PubMed:15556996, PubMed:16216273). Interacts with DNAJC7 (PubMed:11573955).
Expressed in testis, uterus, bladder, spleen, ovaries, lung, brain and muscle (at protein level).
Acts as a ligand for FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:8663044). Also acts as an integrin ligand which is required for FGF2 signaling (PubMed:28302677). Binds to integrin ITGAV:ITGB3 (PubMed:28302677). Plays an important role in the regulation of cell survival, cell division, cell differentiation and cell migration (PubMed:8663044, PubMed:28302677). Functions as a potent mitogen in vitro (PubMed:1721615, PubMed:3964259, PubMed:3732516). Can induce angiogenesis (PubMed:23469107, PubMed:28302677). Mediates phosphorylation of ERK1/2 and thereby promotes retinal lens fiber differentiation (PubMed:29501879).
Expressed in granulosa and cumulus cells. Expressed in hepatocellular carcinoma cells, but not in non-cancerous liver tissue.
Monomer. Homodimer. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Interacts with CSPG4, FGFBP1 and TEC. Found in a complex with FGFBP1, FGF1 and FGF2. Interacts with FGFBP3 (PubMed:18669637). Interacts with integrin ITGAV:ITGB3; the interaction is required for FGF2 signaling (PubMed:28302677). Interacts with SNORC (via the extracellular domain) (By similarity). Interacts with glypican GPC3 (By similarity).
Phosphorylation at Tyr-215 regulates FGF2 unconventional secretion.
Several N-termini starting at positions 94, 125, 126, 132, 143 and 162 have been identified by direct sequencing.
This protein binds heparin more strongly than does aFGF.
Belongs to the eukaryotic release factor 1 family. Pelota subfamily.
Component of the Pelota-HBS1L complex, a complex that recognizes stalled ribosomes and triggers the No-Go Decay (NGD) pathway (PubMed:21448132, PubMed:23667253, PubMed:27543824, PubMed:27863242). In the Pelota-HBS1L complex, PELO recognizes ribosomes stalled at the 3' end of an mRNA and engages stalled ribosomes by destabilizing mRNA in the mRNA channel (PubMed:27543824, PubMed:27863242). Following mRNA extraction from stalled ribosomes by the SKI complex, the Pelota-HBS1L complex promotes recruitment of ABCE1, which drives the disassembly of stalled ribosomes, followed by degradation of damaged mRNAs as part of the NGD pathway (PubMed:21448132, PubMed:32006463). As part of the PINK1-regulated signaling, upon mitochondrial damage is recruited to the ribosome/mRNA-ribonucleoprotein complex associated to mitochondrial outer membrane thereby enabling the recruitment of autophagy receptors and induction of mitophagy (PubMed:29861391).
Component of the Pelota-HBS1L complex, also named Dom34-Hbs1 complex, composed of PELO and HBS1L (PubMed:27863242). Interacts with PINK1 (PubMed:29861391). Interacts with ABCE1 (PubMed:29861391). Interacts with CNOT4 (PubMed:29861391).
Inhibited by the proteinase inhibitors amprenavir, indinavir, lopinavir, isovaleryl pepstatin, ritonavir and saquinavir.
Probable aspartic protease (Probable). Seems to act as a proteasomal shuttle which links the proteasome and replication fork proteins like RTF2 (Probable). Required, with DDI2, for cellular survival following replication stress. Together or redudantly with DDI2, removes RTF2 from stalled forks to allow cell cycle progression after replication stress and maintains genome integrity (PubMed:29290612).
A chromosomal aberration involving TGFB2 is found in a family with Peters anomaly. Translocation t(1;7)(q41;p21) with HDAC9.
Defects in TGFB2 may be a cause of non-syndromic aortic disease (NSAD). NSAD is a frequently asymptomatic but potentially lethal disease characterized by thoracic aortic aneurysms and dissections without additional syndromic features.
Homodimer; disulfide-linked (PubMed:1631557, PubMed:1641027). Interacts with TGF-beta receptors (TGFBR1 and TGFBR2), leading to signal transduction (By similarity).
In contrast to other members of the family, does not contain a R-G-D cell attachment site motif that mediates binding to integrins and promotes release of Latency-associated peptide (LAP) chain from TGF-beta-2.
Interacts with Transforming growth factor beta-2 (TGF-beta-2) chain; interaction is non-covalent and maintains (TGF-beta-2) in a latent state (By similarity). Interacts with LRRC32/GARP; leading to regulate activation of TGF-beta-2 (PubMed:19651619). Interacts with NREP; the interaction results in a decrease in TGFB2 autoinduction (By similarity).
Interacts with the serine proteases, HTRA1 and HTRA3 (By similarity). Interacts with ASPN (PubMed:17827158). Interacts with MFAP5 (By similarity).
Multifunctional protein that regulates various processes such as angiogenesis and heart development (PubMed:22772371, PubMed:22772368). Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-2 (TGF-beta-2) chains remain non-covalently linked rendering TGF-beta-2 inactive during storage in extracellular matrix (By similarity). At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1 and LRRC32/GARP, that control activation of TGF-beta-2 and maintain it in a latent state during storage in extracellular milieus (By similarity). Once activated following release of LAP, TGF-beta-2 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (By similarity).
Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-2 (TGF-beta-2) chains, which constitute the regulatory and active subunit of TGF-beta-2, respectively.
Required to maintain the Transforming growth factor beta-2 (TGF-beta-2) chain in a latent state during storage in extracellular matrix (By similarity). Associates non-covalently with TGF-beta-2 and regulates its activation via interaction with 'milieu molecules', such as LTBP1 and LRRC32/GARP, that control activation of TGF-beta-2 (By similarity).
The precursor proprotein is cleaved in the Golgi apparatus to form Transforming growth factor beta-2 (TGF-beta-2) and Latency-associated peptide (LAP) chains, which remain non-covalently linked, rendering TGF-beta-2 inactive.
Functions in L-arginine homeostasis in nonhepatic tissues characterized by the competition between nitric oxide synthase (NOS) and arginase for the available intracellular substrate arginine. Arginine metabolism is a critical regulator of innate and adaptive immune responses. Involved in an antimicrobial effector pathway in polymorphonuclear granulocytes (PMN). Upon PMN cell death is liberated from the phagolysosome and depletes arginine in the microenvironment leading to suppressed T cell and natural killer (NK) cell proliferation and cytokine secretion (PubMed:15546957, PubMed:16709924, PubMed:19380772). In group 2 innate lymphoid cells (ILC2s) promotes acute type 2 inflammation in the lung and is involved in optimal ILC2 proliferation but not survival (By similarity). In humans, the immunological role in the monocytic/macrophage/dendritic cell (DC) lineage is unsure.
Key element of the urea cycle converting L-arginine to urea and L-ornithine, which is further metabolized into metabolites proline and polyamides that drive collagen synthesis and bioenergetic pathways critical for cell proliferation, respectively; the urea cycle takes place primarily in the liver and, to a lesser extent, in the kidneys.
Within the immune system initially reported to be selectively expressed in granulocytes (polymorphonuclear leukocytes [PMNs]) (PubMed:15546957). Also detected in macrophages mycobacterial granulomas (PubMed:23749634). Expressed in group2 innate lymphoid cells (ILC2s) during lung disease (PubMed:27043409).
Expressed in testis, small intestine, prostate, adrenal gland, spleen, lung, bladder, breast and ovary. Expressed in ciliated epithelial cells (PubMed:28176794).
Interacts with HSPA1A/B and HSP90AA1 (By similarity). Interacts with DNAAF2 and DNAAF4 (PubMed:28041644). Interacts wuth DNAI2 (PubMed:28176794).
Plays a role in cytoplasmic pre-assembly of axonemal dynein.
Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:16762839, PubMed:17704056, PubMed:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:16762839, PubMed:17704056). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:16762839, PubMed:17704056). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:28977666). Also functions as deacetylase for non-histone targets, such as NR1D2, RELA, SP1, SP3 and TSHZ3 (PubMed:12837748, PubMed:16478997, PubMed:17996965, PubMed:19343227). Deacetylates SP proteins, SP1 and SP3, and regulates their function (PubMed:12837748, PubMed:16478997). Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons (PubMed:19081374). Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation (PubMed:19081374). Deacetylates TSHZ3 and regulates its transcriptional repressor activity (PubMed:19343227). Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B (PubMed:17000776). Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity (PubMed:17996965). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (By similarity). Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-BMAL1 heterodimer (By similarity). Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation (By similarity). In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones (PubMed:28497810).
Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7, the core complex associates with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex (PubMed:12493763, PubMed:12724404, PubMed:19061646). Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5 (PubMed:33283408, PubMed:11102443, PubMed:28977666, PubMed:16428440). The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes (PubMed:33283408, PubMed:16428440, PubMed:28977666). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST and PHF21A/BHC80 (PubMed:12493763). The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (PubMed:12493763). Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3/SAP45, ARID4B/SAP180, HDAC1 and HDAC2 (PubMed:12724404). Found in a trimeric complex with APBB1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3 (PubMed:19343227). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC2 (PubMed:19433865). Component of a RCOR/GFI/KDM1A/HDAC complex (By similarity). Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (PubMed:17704056). Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2 (PubMed:19061646). The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A (By similarity). Associates with the 9-1-1 complex; interacts with HUS1 (PubMed:10846170). Found in a complex with DNMT3A and HDAC7 (By similarity). Found in a complex with YY1, SIN3A and GON4L (By similarity). Identified in a histone deacetylase complex that contains DNTTIP1, HDAC1 and MIDEAS; this complex assembles into a tetramer that contains four copies of each protein chain (PubMed:25653165). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (By similarity). Interacts with GFI1; the interaction is direct (By similarity). Interacts directly with GFI1B (By similarity). Interacts with TSHZ3 (via N-terminus); the interaction is direct (PubMed:19343227). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1 (PubMed:14633989). Interacts with BANP (PubMed:16166625). Interacts with BAZ2A/TIP5 (By similarity). Interacts with BCL6 (PubMed:15454082). Interacts with BCOR (PubMed:10898795). Interacts with BHLHE40/DEC1 (PubMed:21829689). Interacts with BRCC3; this interaction is enhanced in the presence of PWWP2B (By similarity). Interacts with BRMS1 (PubMed:17000776). Interacts with BRMS1L (PubMed:15451426). Interacts with C10orf90/FATS (via its N-terminal); the interaction prevents binding of HDAC1 to CDKN1A/p21 and facilitates the acetylation and stabilization of CDKN1A/p21 (By similarity). Interacts with CBFA2T3 (PubMed:11533236). Interacts with CCAR2 (PubMed:21030595). Interacts with CDK2AP1 (PubMed:20523938). Interacts with CHD3 (PubMed:28977666). Interacts with CHD4 (PubMed:27616479, PubMed:25593309, PubMed:36064715, PubMed:28977666). Interacts with CHFR (PubMed:19182791). Interacts with CIART (By similarity). Interacts with CDKN1A/p21 (By similarity). Interacts with CDK5 complexed to CDK5R1 (p25) (By similarity). Interacts with CRY1 (By similarity). Interacts with DAXX (PubMed:10669754). Interacts with DDIT3/CHOP (PubMed:17872950). Interacts with DDX5 (PubMed:17369852). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts with DNMT1 (By similarity). Interacts with DNTTIP1 (PubMed:25653165). Interacts with E4F1 (PubMed:12730668). Interacts with EP300 (PubMed:16762839). Interacts with ERCC6 (PubMed:26030138). Interacts with GATAD2A (PubMed:33283408). Interacts with HCFC1 (PubMed:12670868). Interacts with HDAC9 (PubMed:10655483, PubMed:10487760). Interacts with HUS1 (PubMed:10846170). Interacts with INSM1 (PubMed:16569215). Interacts with KDM4A (PubMed:15927959). Interacts with KDM5A; this interaction impairs histone deacetylation (By similarity). Interacts with KDM5B (PubMed:17373667). Interacts with KLF1 (By similarity). Interacts with MBD3L2 (PubMed:15701600). Interacts with MIER1 (PubMed:12482978). Interacts with NFE4 (PubMed:15273251). Interacts with NR4A2/NURR1 (By similarity). Interacts with NR1D2 (via C-terminus) (PubMed:17996965). Interacts with NRIP1 (PubMed:11006275). Interacts with NSD2 (By similarity). Interacts with PACS2 (PubMed:29656858). Interacts with PHB2 (By similarity). Interacts with PPHLN1 (PubMed:17963697). Interacts with PRDM6 (By similarity). Interacts with PRDM16 (PubMed:19049980). Interacts with PWWP2A in a MTA1-dependent manner (By similarity). Interacts with PWWP2B (By similarity). Interacts with RB1 (PubMed:19081374). Interacts with RERE (By similarity). Interacts with SANBR (via the BTB domain) (By similarity). Interacts with SAMSN1 (By similarity). Interacts with SAP30L (PubMed:16820529). Interacts with SETDB1 (By similarity). Interacts with SIN3A (By similarity). Interacts with SMAD3 (PubMed:19049980). Interacts with SMAD4; positively regulated by ZBTB7A (PubMed:25514493). Interacts with SMARCAD1 (PubMed:21549307). Interacts with SMARCA4/BRG1 (PubMed:19081374). Interacts with SMYD2 (By similarity). Interacts with SMYD4 (via MYND-type zinc finger) (PubMed:30110327). Interacts with SP1; the interaction deacetylates SP1 and regulates its transcriptional activity (PubMed:16478997). Interacts with SP3; the interaction deacetylates SP3 and regulates its transcriptional activity (PubMed:12837748, PubMed:17548428). In vitro, C(18) ceramides increase this interaction and the subsequent SP3 deacetylation and SP3-mediated repression of the TERT promoter (PubMed:12837748, PubMed:17548428). Interacts with SPEN/MINT (PubMed:11331609). Interacts with SPHK2 (PubMed:19729656). Interacts with SUV39H1 (By similarity). Interacts with TGIF (PubMed:11427533). Interacts with TGIF2 (PubMed:11427533). Interacts with TRAF6 (PubMed:18093978). Interacts with TRIM28; the interaction recruits HDAC1 to E2F1 and inhibits its acetylation (PubMed:17704056). Interacts with TSC22D3 isoform 1; this interaction affects HDAC1 activity on MYOG promoter and thus inhibits MYOD1 transcriptional activity (By similarity). Interacts with UHRF1 (PubMed:15361834). Interacts with UHRF2 (PubMed:15361834). Interacts with ZBTB7A (PubMed:25514493). Interacts with ZMYND8 (PubMed:25593309, PubMed:36064715). Interacts with ZMYND15 (By similarity). Interacts with ZNF431 (By similarity). Interacts with ZNF516; this interaction is enhanced in the presence of PWWP2B (By similarity). Interacts with ZNF541 (By similarity). Interacts with ZNF638 (PubMed:30487602). Interacts with ZNHIT1 (By similarity). Interacts with the non-histone region of MACROH2A1 (By similarity). Identified in a complex with HDAC2, KCTD19, DNTTIP1 and ZNF541 (By similarity).
Phosphorylation on Ser-421 and Ser-423 promotes enzymatic activity and interactions with NuRD and SIN3 complexes. Phosphorylated by CDK5.
Sumoylated on Lys-444 and Lys-476; which promotes enzymatic activity. Desumoylated by SENP1.
Ubiquitinated by CHFR, leading to its degradation by the proteasome. Ubiquitinated by KCTD11, leading to proteasomal degradation.
Ubiquitous, with higher levels in heart, pancreas and testis, and lower levels in kidney and brain.
Expressed in the epithelial layer of the intestine (at protein level).
Phosphoinositides-binding protein that induces the formation of planar or gently curved membrane structures. Binds to phosphoinositides, including to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) headgroups. There seems to be no clear preference for a specific phosphoinositide (By similarity).
The IMD domain consisting of an antiparallel dimer of three-helix bundles, featuring on one side a positively charged. The N-terminal alpha-helix inserts into the lipid bilayer. Also forms homodimers and homooligomers. The residue Trp-141 is essential for oligomer formation (By similarity).
Phosphorylated by the activated catalytic chain.
Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Type II regulatory chains mediate membrane association by binding to anchoring proteins, including the MAP2 kinase.
The inactive form of the enzyme is composed of two regulatory chains and two catalytic chains. Activation by cAMP produces two active catalytic monomers and a regulatory dimer that binds four cAMP molecules. Interacts with PRKACA and PRKACB (PubMed:33058759). Interacts with the phosphorylated form of PJA2. Forms a complex composed of PRKAR2B, GSK3B and GSKIP through GSKIP interaction; facilitates PKA-induced phosphorylation and regulates GSK3B activity (PubMed:25920809).
Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2.
Belongs to the high motility group (HMG) box superfamily.
Expressed in NK cells (PubMed:21126536). Highly expressed in tumor-infiltrating CD8-positive T cells (at protein level) (PubMed:31207604).
Interacts with HBO1 complex composed at least of KAT7/HBO1, ING4, MEAF6, and JADE2; this complex is involved in histone acetylation. Interacts with DNMT1, LEO1, PAF1, SAP130 and SIN3A; these interactors regulate chromatin remodeling. Interacts with an array of proteins involved in RNA processing and translation and DNA replication.
Transcriptional regulator with a major role in neural stem cell commitment and corticogenesis as well as in lymphoid cell development and lymphoid tissue organogenesis (By similarity). Binds to GC-rich DNA sequences in the proximity of transcription start sites and may alter chromatin structure, modifying access of transcription factors to DNA. During cortical development, controls the neural stem cell pool by inhibiting the switch from proliferative to differentiating progenitors. Beyond progenitor cells, promotes neurite outgrowth in newborn neurons migrating to reach the cortical plate. May activate or repress critical genes for neural stem cell fate such as SOX2, EOMES and ROBO2 (By similarity). Plays an essential role in the development of lymphoid tissue-inducer (LTi) cells, a subset necessary for the formation of secondary lymphoid organs: peripheral lymph nodes and Peyer's patches. Acts as a developmental checkpoint and regulates thymocyte positive selection toward T cell lineage commitment. Required for the development of various T cell subsets, including CD4-positive helper T cells, CD8-positive cytotoxic T cells, regulatory T cells and CD1D-dependent natural killer T (NKT) cells. Required for the differentiation of common lymphoid progenitors (CMP) to innate lymphoid cells (ILC) (By similarity). May regulate the NOTCH-mediated gene program, promoting differentiation of the ILC lineage. Required at the progenitor phase of NK cell development in the bone marrow to specify NK cell lineage commitment (PubMed:21126536) (By similarity). Upon chronic antigen stimulation, diverts T cell development by promoting the generation of exhaustive T cells, while suppressing effector and memory T cell programming. May regulate the expression of genes encoding inhibitory receptors such as PDCD1 and induce the exhaustion program, to prevent the overstimulation of T cells and activation-induced cell death (By similarity).
Up-regulated during differentiation of NK cells from CD34-positive hematopoietic cells in the presence of IL15. Down-regulated in mature NK cells.
(Microbial infection) Acetylated at Lys-55 by the M.tuberculosis Eis protein; this leads to the inhibition of JNK-dependent autophagy, phagosome maturation, and ROS (reactive oxygen species) generation for enhanced intracellular survival of M.tuberculosis.
Dual specificity protein phosphatase involved in the inactivation of MAP kinases. Dephosphorylates MAPK10 bound to ARRB2.
Phosphorylated at Ser-446 by MAPK1/ERK2, which prevents its degradation, and thereby stabilizes it and blocks JNK MAPK activity.
Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I) at early stages. May play a role in the biogenesis of complex I subunit MT-ND1.
The disease is caused by variants affecting the gene represented in this entry. A homozygous disease-causing variant located in intron 2 leads to aberrant splicing and altered isoform synthesis. Kidney and lung tissues from affected individuals show specific loss of mitochondrial isoform 1. Patient cells show defects in mitochondrial complex I assembly and altered mitochondrial respiration.
Widely expressed. A lower expression is observed in lung and kidney compared to heart, muscle and liver (PubMed:27466185). In the kidney, expression is high in the basal zone of the proximal tubular cells (PubMed:27466185).
Acetylated by CREBBP and p300/EP300; preferentially acetylated by CREBBP on Lys-80, Lys-13 and Lys-14 and on Lys-77 by p300/EP300 upon loading on chromatin in response to UV irradiation (PubMed:24939902, PubMed:19419956). Lysine acetylation disrupts association with chromatin, hence promoting PCNA ubiquitination and proteasomal degradation in response to UV damage in a CREBBP- and EP300-dependent manner (PubMed:24939902). Acetylation disrupts interaction with NUDT15 and promotes degradation (PubMed:19419956).
Antibodies against PCNA are present in sera from patients with systemic lupus erythematosus.
Auxiliary protein of DNA polymerase delta and epsilon, is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand (PubMed:35585232). Induces a robust stimulatory effect on the 3'-5' exonuclease and 3'-phosphodiesterase, but not apurinic-apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways (PubMed:24939902). Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion (PubMed:24695737).
Homotrimer (PubMed:24939902). Interacts with p300/EP300; the interaction occurs on chromatin in UV-irradiated damaged cells (PubMed:24939902). Interacts with CREBBP (via transactivation domain and C-terminus); the interaction occurs on chromatin in UV-irradiated damaged cells (PubMed:24939902). Directly interacts with POLD1, POLD3 and POLD4 subunits of the DNA polymerase delta complex, POLD3 being the major interacting partner; the interaction with POLD3 is inhibited by CDKN1A/p21(CIP1) (PubMed:11595739, PubMed:16510448, PubMed:22148433, PubMed:24939902). Forms a complex with activator 1 heteropentamer in the presence of ATP. Interacts with EXO1, POLH, POLK, DNMT1, ERCC5, FEN1, CDC6 and POLDIP2 (PubMed:9305916, PubMed:9302295, PubMed:9566895, PubMed:11784855, PubMed:12522211, PubMed:15225546, PubMed:15149598, PubMed:24911150, PubMed:15616578, PubMed:26760506). Interacts with POLB (PubMed:19336415, PubMed:26760506). Interacts with APEX2; this interaction is triggered by reactive oxygen species and increased by misincorporation of uracil in nuclear DNA (PubMed:11376153, PubMed:19443450). Forms a ternary complex with DNTTIP2 and core histone (PubMed:12786946). Interacts with KCTD10 and PPP1R15A (By similarity). Interacts with SMARCA5/SNF2H (PubMed:15543136). Interacts with BAZ1B/WSTF; the interaction is direct and is required for BAZ1B/WSTF binding to replication foci during S phase (PubMed:15543136). Interacts with HLTF and SHPRH (PubMed:17130289, PubMed:18316726, PubMed:18719106). Interacts with NUDT15; this interaction is disrupted in response to UV irradiation and acetylation (PubMed:19419956). Interacts with CDKN1A/p21(CIP1) and CDT1; interacts via their PIP-box which also recruits the DCX(DTL) complex. The interaction with CDKN1A inhibits POLD3 binding (PubMed:11595739, PubMed:16949367, PubMed:18794347, PubMed:18703516). Interacts with DDX11 (PubMed:18499658). Interacts with EGFR; positively regulates PCNA (PubMed:17115032). Interacts with PARPBP (PubMed:22153967). Interacts (when ubiquitinated) with SPRTN; leading to enhance RAD18-mediated PCNA ubiquitination (PubMed:22681887, PubMed:27084448). Interacts (when polyubiquitinated) with ZRANB3 (PubMed:22704558, PubMed:22705370, PubMed:22759634). Interacts with SMARCAD1 (PubMed:21549307). Interacts with CDKN1C (PubMed:22634751). Interacts with PCLAF (via PIP-box) (PubMed:21628590, PubMed:23000965). Interacts with RTEL1 (via PIP-box); the interaction is direct and essential for the suppression of telomere fragility (PubMed:24115439). Interacts with FAM111A (via PIP-box); the interaction is direct and required for PCNA loading on chromatin binding (PubMed:24561620). Interacts with LIG1 (PubMed:24911150). Interacts with SETMAR (PubMed:20457750). Interacts with ANKRD17 (PubMed:23711367). Interacts with FBXO18/FBH1 (via PIP-box); the interaction recruits the DCX(DTL) complex and promotes ubiquitination and degradation of FBXO18/FBH1 (PubMed:23677613). Interacts with POLN (PubMed:19995904). Interacts with SDE2 (via PIP-box); the interaction is direct and prevents ultraviolet light induced monoubiquitination (PubMed:27906959). Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR; interaction at least with PCNA occurs during DNA replication (PubMed:28191891). Interacts with MAPK15; the interaction is chromatin binding dependent and prevents MDM2-mediated PCNA destruction by inhibiting the association of PCNA with MDM2 (PubMed:20733054). Interacts with PARP10 (via PIP-box) (PubMed:24695737). Interacts with DDI2 (PubMed:29290612). Interacts with HMCES (via PIP-box) (PubMed:30554877). Interacts with TRAIP (via PIP-box) (PubMed:27462463, PubMed:26711499). Interacts with UHRF2 (PubMed:28951215). Interacts with ALKBH2; this interaction is enhanced during the S-phase of the cell cycle. Interacts with ATAD5; the interaction promotes USP1-mediated PCNA deubiquitination (PubMed:20147293).
Methylated on glutamate residues by ARMT1/C6orf211.
Phosphorylated. Phosphorylation at Tyr-211 by EGFR stabilizes chromatin-associated PCNA.
Ubiquitinated (PubMed:24939902, PubMed:20227374). Following DNA damage, can be either monoubiquitinated to stimulate direct bypass of DNA lesions by specialized DNA polymerases or polyubiquitinated to promote recombination-dependent DNA synthesis across DNA lesions by template switching mechanisms. Following induction of replication stress, monoubiquitinated by the UBE2B-RAD18 complex on Lys-164, leading to recruit translesion (TLS) polymerases, which are able to synthesize across DNA lesions in a potentially error-prone manner. An error-free pathway also exists and requires non-canonical polyubiquitination on Lys-164 through 'Lys-63' linkage of ubiquitin moieties by the E2 complex UBE2N-UBE2V2 and the E3 ligases, HLTF, RNF8 and SHPRH. This error-free pathway, also known as template switching, employs recombination mechanisms to synthesize across the lesion, using as a template the undamaged, newly synthesized strand of the sister chromatid. Monoubiquitination at Lys-164 also takes place in undamaged proliferating cells, and is mediated by the DCX(DTL) complex, leading to enhance PCNA-dependent translesion DNA synthesis. Sumoylated during S phase.
Does not function as a copper(1+) importer in vivo (By similarity). However, in vitro functions as low-affinity copper(1+) importer (PubMed:17944601, PubMed:17617060). Regulator of SLC31A1 which facilitates the cleavage of the SLC31A1 ecto-domain or which stabilizes the truncated form of SLC31A1 (Truncated CTR1 form), thereby drives the SLC31A1 truncated form-dependent endosomal copper export and modulates the copper and cisplatin accumulation via SLC31A1 (By similarity).
Oligomer (PubMed:17617060). Interacts with SLC31A1; this interaction stabilizes SLC31A2 and protects it from ubiquitination and the subsequent degradation (PubMed:26205368).
The N-terminal domain may be involved in Cu(2+) acquisition from potential degradation products of proteins in the lysosome.
Ubiquitinated; ubiquitination and the subsequent proteasomal degradation are prevent by SLC31A1 that stabilizes it.
Ubiquitous with high expression in placenta and heart.
Probable transcriptional regulator involved in the development of the skeleton of the limb, vertebral column and head. Acts by controlling the number of mesenchymal precursor cells and chondrocytes (By similarity).
Belongs to the hcp beta-lactamase family.
Interacts with CHCHD4/MIA40 through transient intermolecular disulfide bonds.
Required for assembly of mitochondrial respiratory chain complex I and complex IV.
Component of the RNA exosome complex (PubMed:29906447). Specifically part of the catalytically inactive RNA exosome core (Exo-9) complex which is believed to associate with catalytic subunits EXOSC10, and DIS3 or DIS3L in cytoplasmic- and nuclear-specific RNA exosome complex forms. Exo-9 is formed by a hexameric ring of RNase PH domain-containing subunits specifically containing the heterodimers EXOSC4-EXOSC9, EXOSC5-EXOSC8 and EXOSC6-EXOSC7, and peripheral S1 domain-containing components EXOSC1, EXOSC2 and EXOSC3 located on the top of the ring structure. Interacts with EXOSC5, EXOSC7 and EXOSC10. Interacts with DDX60.
Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC1 as peripheral part of the Exo-9 complex stabilizes the hexameric ring of RNase PH-domain subunits through contacts with EXOSC6 and EXOSC8.
Acts as a scavenger receptor on macrophages, which specifically binds to OxLDL (oxidized low density lipoprotein), suggesting that it may be involved in pathophysiology such as atherogenesis (By similarity). Induces a strong chemotactic response. Induces calcium mobilization. Binds to CXCR6/Bonzo.
Expressed in T-cell areas. Expressed in spleen, lymph nodes, lung, kidney, small intestine and thymus. Weak expression in heart and liver and no expression in brain and bone marrow.
Component of the 7SK snRNP complex at least composed of P-TEFb (composed of CDK9 and CCNT1/cyclin-T1), HEXIM1, HEXIM2, BCDIN3, SART3 proteins and 7SK and U6 snRNAs (PubMed:17643375). Interacts with AGO1 and AGO2 (PubMed:17932509). Interacts with PRPF3 and USP4; the interaction with PRPF3 is direct and recruits USP4 to its substrate PRPF3 (PubMed:15314151, PubMed:20595234). Interacts with USP15; the interaction is direct (PubMed:24526689). Interacts with HIV-1 Tat (PubMed:11959860).
May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Inactive in U4/U6 snRNP recycling.
Regulates Tat transactivation activity through direct interaction. May be a cellular factor for HIV-1 gene expression and viral replication.
U6 snRNP-binding protein that functions as a recycling factor of the splicing machinery. Promotes the initial reassembly of U4 and U6 snRNPs following their ejection from the spliceosome during its maturation (PubMed:12032085). Also binds U6atac snRNPs and may function as a recycling factor for U4atac/U6atac spliceosomal snRNP, an initial step in the assembly of U12-type spliceosomal complex. The U12-type spliceosomal complex plays a role in the splicing of introns with non-canonical splice sites (PubMed:14749385). May also function as a substrate-targeting factor for deubiquitinases like USP4 and USP15. Recruits USP4 to ubiquitinated PRPF3 within the U4/U5/U6 tri-snRNP complex, promoting PRPF3 deubiquitination and thereby regulating the spliceosome U4/U5/U6 tri-snRNP spliceosomal complex disassembly (PubMed:20595234). May also recruit the deubiquitinase USP15 to histone H2B and mediate histone deubiquitination, thereby regulating gene expression and/or DNA repair (PubMed:24526689). May play a role in hematopoiesis probably through transcription regulation of specific genes including MYC (By similarity).
Modulates arousal and anxiety. May play an important anorexigenic role (By similarity). Binds to its receptor NPSR1 with nanomolar affinity to increase intracellular calcium concentrations (PubMed:15312648, PubMed:16790440).
Belongs to the SLAIN motif-containing family.
Binds to the plus end of microtubules and regulates microtubule dynamics and microtubule organization. Promotes cytoplasmic microtubule nucleation and elongation. Required for normal structure of the microtubule cytoskeleton during interphase.
Interacts with CLIP1, CLIP2, CKAP5, CLASP1, MAPRE1 and MAPRE3.
Is highly phosphorylated during mitosis, but not during interphase. The highly phosphorylated form does not localize at microtubule plus ends and does not interact with MAPRE1 or CKAP5.
The N-terminus forms a two-stranded coiled coil.
Widely expressed with highest levels in adult liver, testis and ovary, and lowest levels in adult pancreas and spleen and in fetal brain.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(0) seems to have nine subunits: a, b, c, d, e, f, g, F6 and 8 (or A6L). Component of an ATP synthase complex composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5PD, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and ATP5MJ (By similarity).
Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(0) domain. Minor subunit located with subunit a in the membrane.
Highly expressed in a variety of hematopoietic and epithelial tumor cell lines, but not in normal hematopoietic tissues or other normal tissue, with the exception of testis.
Homodimer (PubMed:20660080). Component of the RNA exosome complex (PubMed:20660080, PubMed:29906447). Specifically part of the catalytically inactive RNA exosome core (Exo-9) complex which is believed to associate with catalytic subunits EXOSC10, and DIS3 or DIS3L in cytoplasmic- and nuclear-specific RNA exosome complex forms. Exo-9 is formed by a hexameric ring of RNase PH domain-containing subunits specifically containing the heterodimers EXOSC4-EXOSC9, EXOSC5-EXOSC8 and EXOSC6-EXOSC7, and peripheral S1 domain-containing components EXOSC1, EXOSC2 and EXOSC3 located on the top of the ring structure. Interacts with EXOSC1. Interacts with GTPBP1. Interacts with ZC3HAV1. Interacts with DDX17 only in the presence of ZC3HAV1 in an RNA-independent manner.
Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes (PubMed:11782436, PubMed:21269460). In vitro, EXOSC5 does not bind or digest single-stranded RNA and binds to double-stranded DNA without detectable DNase activity (PubMed:20660080).
Guanine nucleotide exchange factor (GEF) for the small GTPase RALA. May be involved in cytoskeletal organization (By similarity). Guanine nucleotide exchange factor for.
Interacts with the SH3 domains of GRB2, NCK1, PLCG1 and SRC.
The PH domain mediates binding to membranes. It is required for efficient GEF activity.
Widely expressed (at protein level). Isoform 2 is expressed in brain, colon, kidney, pancreas, prostate, skeletal muscle, small intestine, testis, thymus and uterus. Isoform 1 is expressed at high levels in heart and testis and at lower levels in brain, pancreas, skeletal muscle, small intestine and thymus.
A chromosomal aberration involving ZNF521 is found in acute lymphoblastic leukemia. Translocation t(9;18)(p13;q11.2) with PAX5. The translocation generates the PAX5-ZNF521 oncogene consisting of the N-terminus part of PAX5 and the C-terminus part of ZNF521.
Interacts with EBF1. Interacts with SMAD1 and SMAD4.
Predominantly expressed in hematopoietic cells. Present in organs and tissues that contain stem and progenitor cells, myeloid and/or lymphoid: placenta, spleen, lymph nodes, thymus, bone marrow and fetal liver. Within the hematopoietic system, it is abundant in CD34(+) cells but undetectable in mature peripheral blood leukocytes, and its levels rapidly decrease during the differentiation of CD34(+) cells in response to hemopoietins.
Transcription factor that can both act as an activator or a repressor depending on the context. Involved in BMP signaling and in the regulation of the immature compartment of the hematopoietic system. Associates with SMADs in response to BMP2 leading to activate transcription of BMP target genes. Acts as a transcriptional repressor via its interaction with EBF1, a transcription factor involved specification of B-cell lineage; this interaction preventing EBF1 to bind DNA and activate target genes.
Uses different DNA- and protein-binding zinc fingers to regulate the distinct BMP-Smad and hematopoietic system.
Essential component of the vacuolar proton pump (V-ATPase), a multimeric enzyme that catalyzes the translocation of protons across the membranes. Required for assembly and activity of the V-ATPase.
Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that transports protons across cellular membranes. V-ATPase is responsible for the acidification of various organelles, such as lysosomes, endosomes, the trans-Golgi network, and secretory granules, including synaptic vesicles (PubMed:33065002, PubMed:34909687, PubMed:33833240). In certain cell types, can be exported to the plasma membrane, where it is involved in the acidification of the extracellular environment (By similarity). Required for assembly and activity of the vacuolar ATPase (By similarity). Through its action on compartment acidification, plays an essential role in neuronal development in terms of integrity and connectivity of neurons (PubMed:33833240).
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex (PubMed:33065002). The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H (PubMed:33065002). The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR (PubMed:33065002). Interacts with SPAAR (PubMed:28024296).
Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (By similarity).
Based on a readthrough transcript which may produce a NDUFC2-KCTD14 fusion protein.
Belongs to the complex I NDUFC2 subunit family.
Belongs to the glycosyltransferase 22 family. PIGZ subfamily.
It is uncertain whether Met-1 or Met-32 is the initiator.
Mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers a fourth mannose to some trimannosyl-GPIs during GPI precursor assembly. The presence of a fourth mannose in GPI is facultative and only scarcely detected, suggesting that it only exists in some tissues.
Widely expressed at low level, with highest level in brain and colon.
Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:20562859, PubMed:27193190, PubMed:27103069, PubMed:27559131, PubMed:27617292, PubMed:28195531, PubMed:32303654). In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PubMed:20562859, PubMed:27103069, PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex also acts as a negative regulator of autophagy initiation by interacting with the ULK1/ATG1 kinase complex and inhibiting its protein kinase activity (PubMed:27617292, PubMed:28195531). As part of the C9orf72-SMCR8 complex, stimulates RAB8A and RAB11A GTPase activity in vitro (PubMed:32303654). Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates (PubMed:27559131, PubMed:28195531). In addition to its activity in the cytoplasm within the C9orf72-SMCR8 complex, SMCR8 also localizes in the nucleus, where it associates with chromatin and negatively regulates expression of suppresses ULK1 and WIPI2 genes (PubMed:28195531).
Component of the C9orf72-SMCR8 complex, at least composed of C9orf72, SMCR8 and WDR41 (PubMed:27193190, PubMed:27103069, PubMed:27559131, PubMed:27617292, PubMed:28195531). The complex is formed of two protomers, each individually consisting of one molecule each of C9orf72, SMCR8 and WDR41 (PubMed:32303654). The protomers homodimerize via an interaction between C9orf72 (via C-terminus) and SMCR8 (via N-terminus) (PubMed:32303654). Within each protomer SMCR8 (via DENN domain) acts as a bridging protein between WDR41 (via C-terminus and N-terminus) and C9orf72 (via C-terminus) (PubMed:32303654). The C9orf72-SMCR8 complex associates with the ULK1/ATG1 kinase complex (PubMed:28195531). Interacts with C9orf72; the interaction is direct (PubMed:27559131, PubMed:27617292, PubMed:32303654). Interacts with DLG4/PSD-95 (By similarity).
Phosphorylation by TBK1 is required to promote autophagosome maturation (PubMed:27103069). Phosphorylated by ULK1 (PubMed:27103069).
A 90 degree bend between Pumilio repeats 3 and 4 gives rise to a L-shaped protein.
Inhibits the poly(ADP-ribosyl)ation activity of PARP1 and the degradation of PARP1 by CASP3 following genotoxic stress (PubMed:21266351). Binds to double-stranded RNA or DNA without sequence specificity (PubMed:25512524). Involved in development of the eye and of primordial germ cells (By similarity).
Interacts with PARP1 (via catalytic domain).
The HA-8 region can be cleaved and exposed at the cell surface where it plays a role as a minor histocompatibility HLA-A*0201-restricted antigen.
The following alleles of HA-8 are known: HA-8R, HA-8P, HA-8PL, of which only HA-8R leads to specific cytotoxic T lymphocyte (CTL) recognition. The lack of CTL recognition of cells expressing HA-8P may be due to impaired transport associated with antigen processing. The sequence shown is that of HA-8R.
Although the final Cys may be farnesylated, the terminal tripeptide is probably not removed, and the C-terminus is not methylated.
Belongs to the phosphorylase b kinase regulatory chain family.
By phosphorylation of various serine residues and by calcium.
Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I. The alpha chain may bind calmodulin.
Predominantly expressed in liver and other non-muscle tissues.
Platelet activation apparently involves disruption of the macromolecular complex of GP-Ib with the platelet glycoprotein IX (GP-IX) and dissociation of GP-Ib from the actin-binding protein.
The GPIb-V-IX complex functions as the vWF receptor and mediates vWF-dependent platelet adhesion to blood vessels. The adhesion of platelets to injured vascular surfaces in the arterial circulation is a critical initiating event in hemostasis. GP-IX may provide for membrane insertion and orientation of GP-Ib.
Two GP-Ib beta are disulfide-linked to one GP-Ib alpha. GP-IX is complexed with the GP-Ib heterodimer via a non covalent linkage.
Probable transcription factor involved in embryogenesis and somatogenesis.
Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocyte, heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas.
Interacts with FMR1 (PubMed:10556305). Interacts with ZNHIT3 (PubMed:28335020).
Likely acts as a modulator of nicotinic acetylcholine receptors (nAChRs) activity (PubMed:34631692, PubMed:26586467). In vitro acts on nAChRs in a subtype- and stoichiometry-dependent manner (PubMed:26586467). Modulates specifically alpha-3(3):beta-4(2) nAChRs by enhancing the sensitivity to ACh, decreasing ACh-induced maximal current response and increasing the rate of desensitization to ACh; has no effect on alpha-7 homomeric nAChRs; modulates alpha-3(2):alpha-5:beta-4(2) nAChRs in the context of CHRNA5/alpha-5 variant Asn-398 but not its wild-type sequence (PubMed:26586467). However, according to another report in vitro it can weakly inhibits alpha-7 nAChRs (PubMed:34631692).
Acts as an activator of the phospholipid scramblase activity of XKR4 (PubMed:33725486). This form, which is generated upon caspase-3 (CASP3) cleavage, translocates into the cytoplasm and interacts with XKR4, thereby promoting phosphatidylserine scramblase activity of XKR4 and leading to phosphatidylserine exposure on apoptotic cell surface (PubMed:33725486).
Belongs to the XRCC4-XLF family. XRCC4 subfamily.
DNA non-homologous end joining (NHEJ) core factor, required for double-strand break repair and V(D)J recombination (PubMed:10757784, PubMed:10854421, PubMed:17124166, PubMed:16412978, PubMed:8548796, PubMed:25742519, PubMed:12517771, PubMed:17290226, PubMed:22228831, PubMed:25597996, PubMed:25934149, PubMed:26100018, PubMed:26774286). Acts as a scaffold protein that regulates recruitment of other proteins to DNA double-strand breaks (DSBs) (PubMed:15385968, PubMed:20852255, PubMed:26774286, PubMed:27437582). Associates with NHEJ1/XLF to form alternating helical filaments that bridge DNA and act like a bandage, holding together the broken DNA until it is repaired (PubMed:26100018, PubMed:27437582, PubMed:28500754, PubMed:21775435, PubMed:22287571, PubMed:21768349). The XRCC4-NHEJ1/XLF subcomplex binds to the DNA fragments of a DSB in a highly diffusive manner and robustly bridges two independent DNA molecules, holding the broken DNA fragments in close proximity to one other (PubMed:27437582). The mobility of the bridges ensures that the ends remain accessible for further processing by other repair factors (PubMed:27437582). Plays a key role in the NHEJ ligation step of the broken DNA during DSB repair via direct interaction with DNA ligase IV (LIG4): the LIG4-XRCC4 subcomplex reseals the DNA breaks after the gap filling is completed (PubMed:9242410, PubMed:10757784, PubMed:10854421, PubMed:12517771, PubMed:17290226, PubMed:19837014). XRCC4 stabilizes LIG4, regulates its subcellular localization and enhances LIG4's joining activity (PubMed:9242410, PubMed:10757784, PubMed:10854421, PubMed:12517771, PubMed:17290226, PubMed:21982441, PubMed:22228831). Binding of the LIG4-XRCC4 subcomplex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends (PubMed:10757784, PubMed:10854421). Promotes displacement of PNKP from processed strand break termini (PubMed:20852255, PubMed:28453785).
Homodimer and homotetramer in solution (PubMed:25574025, PubMed:25670504, PubMed:25941166, PubMed:31548606, PubMed:11080143). Interacts with NHEJ1/XLF; the interaction is direct and is mediated via a head-to-head interaction between N-terminal head regions (PubMed:16439205, PubMed:18158905, PubMed:20558749, PubMed:22228831, PubMed:26100018, PubMed:27437582, PubMed:21936820, PubMed:21775435, PubMed:22287571, PubMed:21768349). Interacts with LIG4; the LIG4-XRCC4 subcomplex has a 1:2 stoichiometry and XRCC4 is required for LIG4 stability (PubMed:9259561, PubMed:12517771, PubMed:17290226, PubMed:21982441, PubMed:24984242, PubMed:25934149, PubMed:11702069, PubMed:19332554, PubMed:9242410). Component of the core long-range non-homologous end joining (NHEJ) complex (also named DNA-PK complex) composed of PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF (PubMed:10757784, PubMed:10854421, PubMed:17124166, PubMed:12547193, PubMed:26774286, PubMed:33854234). Additional component of the NHEJ complex includes PAXX (PubMed:16439205). Following autophosphorylation, PRKDC dissociates from DNA, leading to formation of the short-range NHEJ complex, composed of LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF (PubMed:33854234). Interacts with PRKDC; the interaction is direct (PubMed:12509254). Interacts with XRCC6/Ku70; the interaction is direct (PubMed:17124166). Interacts with APTX and APLF (PubMed:15380105, PubMed:17396150, PubMed:17353262, PubMed:18077224). Forms a heterotetramer with IFFO1; the interaction involves LIG4-free XRCC4 and leads to the relocalization of IFFO1 to the sites of DNA damage (PubMed:31548606). Interacts with PNKP; mainly interacts with PNKP when phosphorylated at Thr-233, but is also able to interact at much lower level with PNKP when not unphosphorylated (PubMed:15385968, PubMed:20852255, PubMed:28453785). Interacts with POLL (DNA polymerase lambda) (PubMed:30250067).
Interacts with XKR4; interacts with the processed form of XKR4, which is cleaved by caspase.
Phosphorylated by PRKDC at the C-terminus in response to DNA damage; Ser-260 and Ser-320 constitute the main phosphorylation sites (PubMed:9430729, PubMed:15177042, PubMed:14599745, PubMed:12547193, PubMed:26666690, PubMed:28500754, PubMed:30247612). Phosphorylations by PRKDC at the C-terminus of XRCC4 and NHEJ1/XLF are highly redundant and regulate ability of the XRCC4-NHEJ1/XLF subcomplex to bridge DNA (PubMed:22228831, PubMed:28500754). Phosphorylation by PRKDC does not prevent interaction with NHEJ1/XLF but disrupts ability to bridge DNA and promotes detachment from DNA (PubMed:22228831, PubMed:28500754). Phosphorylation at Ser-327 and Ser-328 by PRKDC promotes recognition by the SCF(FBXW7) complex and subsequent ubiquitination via 'Lys-63'-linked ubiquitin (PubMed:26774286). Phosphorylation at Thr-233 by CK2 promotes interaction with PNKP; regulating PNKP activity and localization to DNA damage sites (PubMed:15385968, PubMed:20852255, PubMed:28453785). Phosphorylation by CK2 promotes interaction with APTX (PubMed:15380105).
Sumoylation at Lys-210 was initially reported to regulate nuclear localization and recombination efficiency of XRCC4 (PubMed:16478998). This result is however not confirmed by another study (PubMed:25934149).
Ubiquitinated at Lys-296 by the SCF(FBXW7) complex via 'Lys-63'-linked ubiquitination, thereby promoting double-strand break repair: the SCF(FBXW7) complex specifically recognizes XRCC4 when phosphorylated at Ser-327 and Ser-328 by PRKDC, and 'Lys-63'-linked ubiquitination facilitates DNA non-homologous end joining (NHEJ) by enhancing association with XRCC5/Ku80 and XRCC6/Ku70 (PubMed:26774286). Monoubiquitinated (PubMed:16412978).
Undergoes proteolytic processing by caspase-3 (CASP3) (Probable) (PubMed:33725486). This generates the protein XRCC4, C-terminus (XRCC4/C), which translocates to the cytoplasm and activates phospholipid scramblase activity of XKR4, thereby promoting phosphatidylserine exposure on apoptotic cell surface (PubMed:33725486).
Although it belongs to the glycosyl hydrolase 31 family, it lacks one active site residue, thus suggesting it may lack some enzyme activity.
Interacts with HAX1; the interaction is direct and calcium-dependent.
Only in skeletal muscle and heart (PubMed:9305858). Also expressed in white and brown adipose tissues (PubMed:9305858). Is more expressed in glycolytic than in oxidative skeletal muscles.
Putative transmembrane transporter that plays a role in mitochondrial metabolism via an as yet unclear mechanism (PubMed:21775425, PubMed:36114012). Originally, this mitochondrial protein was thought to act as a proton transmembrane transporter from the mitochondrial intermembrane space into the matrix, causing proton leaks through the inner mitochondrial membrane, thereby uncoupling mitochondrial membrane potential generation from ATP synthesis (PubMed:9305858, PubMed:11171965, PubMed:12670931, PubMed:12734183). However, this function is controversial and uncoupling may not be the function, or at least not the main function, but rather a consequence of more conventional metabolite transporter activity (PubMed:11707458).
The proton transporter activity is activated by fatty acids (in vitro) (PubMed:11171965). The proton transporter activity is inhibited by ATP and ADP (in vitro) (PubMed:11171965). The effect of Ubiquinone/coenzyme Q10 on the proton transporter activity in reconstituted membranes is unclear (in vitro) (PubMed:11171965, PubMed:12734183).
Up-regulated by beta3-adrenergic stimulation, starvation, glucocorticoids and leptin.
Expressed in heart, skeletal muscle, eye and brain, and at much lower levels in some other tissues.
Heat-shock transcription factor that specifically binds heat shock promoter elements (HSE) (PubMed:22587838, PubMed:23507146). Required for denucleation and organelle rupture and degradation that occur during eye lens terminal differentiation, when fiber cells that compose the lens degrade all membrane-bound organelles in order to provide lens with transparency to allow the passage of light (By similarity). In this process, may regulate denucleation of lens fiber cells in part by activating DNASE2B transcription (By similarity). May be involved in DNA repair through the transcriptional regulation of RAD51 (PubMed:22587838). May up-regulate p53/TP53 protein in eye lens fiber cells, possibly through protein stabilization (PubMed:28981088). In the eye lens, controls the expression of alpha-crystallin B chain/CRYAB and consequently may be involved in the regulation of lysosomal acidification (By similarity).
Homotrimer (By similarity). Exhibits constitutive DNA binding and forms trimers even in the absence of stress (By similarity). Interacts with ALKBH4, DUSP26, MAPK1, MAPK2, MAPK8 and MAP kinase p38 (PubMed:16581800, PubMed:23145062).
Isoform HSF4B is constitutively sumoylated. Sumoylation represses the transcriptional activity and is promoted by phosphorylation on Ser-298. HSFA is not sumoylated.
Phosphorylated mainly on serine residues. Phosphorylation on Ser-298 promotes sumoylation on Lys-293.
Binds to purified microtubules via its C-terminus.
Constitutively expressed during the cell cycle.
Involved in organization of the bipolar mitotic spindle. Required for bipolar spindle assembly, mitosis progression and cytokinesis. May act by stabilizing interphase microtubules.
Histone methyltransferase specifically trimethylating 'Lys-36' of histone H3 forming H3K36me3 (PubMed:21239497). Also monomethylates 'Lys-9' of histone H3 (H3K9me1) in vitro (By similarity). The physiological significance of the H3K9me1 activity is unclear (By similarity).
Widely expressed, with highest level in brain, heart and kidney.
Defects in L1CAM are associated with a wide phenotypic spectrum which varies from severe hydrocephalus and prenatal death (HYCX) to a milder phenotype (MASA). These variations may even occur within the same family. Due to the overlap of phenotypes between HYCX and MASA, many authors use the general concept of L1 syndrome which covers both ends of the spectrum.
Defects in L1CAM may contribute to Hirschsprung disease by modifying the effects of Hirschsprung disease-associated genes to cause intestinal aganglionosis.
Interacts with SHTN1; the interaction occurs in axonal growth cones (By similarity). Interacts with isoform 2 of BSG (By similarity).
Neural cell adhesion molecule involved in the dynamics of cell adhesion and in the generation of transmembrane signals at tyrosine kinase receptors. During brain development, critical in multiple processes, including neuronal migration, axonal growth and fasciculation, and synaptogenesis. In the mature brain, plays a role in the dynamics of neuronal structure and function, including synaptic plasticity.
The disease is caused by variants affecting the gene represented in this entry. L1CAM mutations have also been found in few patients affected by hydrocephalus with Hirschsprung disease, suggesting a role of this gene acting either in a direct or indirect way in the pathogenesis of Hirschsprung disease (PubMed:22344793).
Acts as a positive regulator of ciliary hedgehog signaling. Required for centriole stability (By similarity). May play a role in counteracting perturbation of actin filaments, such as after treatment with the actin depolymerizing microbial metabolite Chivosazole F (PubMed:28796488).
Interacts with TEDC2. Found in a complex with TEDC1, TEDC2, TUBE1 and TUBD1.
Disease susceptibility may be associated with variants affecting the gene represented in this entry. Valine at position 55 results in greater NFKB1 transcriptional activity and IL12B expression and may be associated with susceptibility to insulin-dependent diabetes mellitus.
Expressed mainly in adult and embryonic kidney. Expressed at various levels in immune tissues, with the highest expression in the lymph node and spleen.
In contrast to SUMO1, SUMO2 and SUMO3, seems to be insensitive to sentrin-specific proteases due to the presence of Pro-90. This may impair processing to mature form and conjugation to substrates.
Interacts with SAE2. Covalently attached to a number of proteins (Probable).
Ubiquitin-like protein which can be covalently attached to target lysines as a monomer. Does not seem to be involved in protein degradation and may modulate protein subcellular localization, stability or activity. Upon oxidative stress, conjugates to various anti-oxidant enzymes, chaperones, and stress defense proteins. May also conjugate to NFKBIA, TFAP2A and FOS, negatively regulating their transcriptional activity, and to NR3C1, positively regulating its transcriptional activity. Covalent attachment to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I.
Detected in heart, breast, prostate, skeletal muscle, testis, uterus, bone marrow, colon, small intestine, stomach and thymus.
Exonuclease with a preference for double-stranded DNA with mismatched 3' termini. May play a role in DNA repair.
Only supported by readthrough transcripts formed via the splicing of exons from UCHL5IP and TREX2 genes.
Belongs to the mannose-6-phosphate isomerase type 1 family.
Expressed in all tissues, but more abundant in heart, brain and skeletal muscle.
Interacts with USP12 (PubMed:20147737, PubMed:27373336). Component of the USP12/WDR20/WDR48 deubiquitinating complex (PubMed:20147737, PubMed:27373336). Interacts with USP46 (PubMed:20147737).
Regulator of deubiquitinating complexes. Activates deubiquitinating activity of complexes containing USP12 (PubMed:20147737, PubMed:27373336). Anchors at the base of the ubiquitin-contacting loop of USP12 and remotely modulates the catalytic center of the enzyme (PubMed:27373336).
(Microbial infection) Autoubiquitinated; promoted by Epstein-Barr virus protein BPLF1.
(Microbial infection) Interacts (via SPRY domain) with human respiratory syncytial virus (HRSV) non-structural protein 1; this interaction suppresses RIGI ubiquitination and results in decreased interaction between RIGI and MAVS.
(Microbial infection) Interacts (via coiled coil) with influenza A virus NS1 protein; this interaction specifically inhibits TRIM25 multimerization and TRIM25-mediated RIGI CARD ubiquitination, thereby suppressing RIGI signal transduction.
(Microbial infection) Interacts with Epstein-Barr virus protein BPLF1 and YWHAZ; leading to inhibition of the type-I IFN response.
(Microbial infection) Interacts with JC virus small t antigen; this interaction suppresses RIGI ubiquitination thereby suppressing RIGI signal transduction.
(Microbial infection) Interacts with Severe fever with thrombocytopenia virus (SFTSV) NSs; this interaction this interaction sequesters TRIM25 in NSs-induced cytoplasmic inclusion bodies thereby inhibiting the IFN responses.
(Microbial infection) Interacts with human metapneumovirus protein M2-2; this interaction suppresses RIGI ubiquitination thereby suppressing RIGI signal transduction.
Expressed in breast tumors (at protein level). Ubiquitous.
Forms homodimers (PubMed:27425606, PubMed:27154206, PubMed:29357390, PubMed:31710640). Interacts (via SPRY domain) with RIGI (via CARD domain). Interacts with ZFHX3. Interacts with NLRP12; this interaction reduces the E3 ubiquitin ligase TRIM25-mediated 'Lys-63'-linked RIGI activation. Interacts with the KHDC3L/FILIA-OOEP/FLOPED scaffold complex and BLM at DNA replication forks (By similarity). Interacts with RTN3; this interaction prevents RIGI ubiquitination (PubMed:34313226).
Functions as a ubiquitin E3 ligase and as an ISG15 E3 ligase (PubMed:16352599). Involved in innate immune defense against viruses by mediating ubiquitination of RIGI and IFIH1 (PubMed:17392790, PubMed:30193849, PubMed:33849980, PubMed:29357390, PubMed:31710640, PubMed:36045682). Mediates 'Lys-63'-linked polyubiquitination of the RIGI N-terminal CARD-like region and may play a role in signal transduction that leads to the production of interferons in response to viral infection (PubMed:17392790, PubMed:23950712). Mediates 'Lys-63'-linked polyubiquitination of IFIH1 (PubMed:30193849). Promotes ISGylation of 14-3-3 sigma (SFN), an adapter protein implicated in the regulation of a large spectrum signaling pathway (PubMed:16352599, PubMed:17069755). Mediates estrogen action in various target organs (PubMed:22452784). Mediates the ubiquitination and subsequent proteasomal degradation of ZFHX3 (PubMed:22452784). Plays a role in promoting the restart of stalled replication forks via interaction with the KHDC3L-OOEP scaffold and subsequent ubiquitination of BLM, resulting in the recruitment and retainment of BLM at DNA replication forks (By similarity). Plays an essential role in the antiviral activity of ZAP/ZC3HAV1; an antiviral protein which inhibits the replication of certain viruses. Mechanistically, mediates 'Lys-63'-linked polyubiquitination of ZAP/ZC3HAV1 that is required for its optimal binding to target mRNA (PubMed:28202764, PubMed:28060952). Mediates also the ubiquitination of various substrates implicated in stress granule formation, nonsense-mediated mRNA decay, nucleoside synthesis and mRNA translation and stability (PubMed:36067236).
RING domain dimerization is required for catalysis, TRIM25-mediated RIG-I ubiquitination, interferon induction, and antiviral activity.
The C-terminal B30.2/SPRY domain interacts with the first N-terminal CARD domain of RIGI.
The RING-type zinc finger is important for ISG15 E3 ligase activity and autoISGylation. AutoISGylation negatively regulates ISG15 E3 ligase activity.
A cytochrome P450 monooxygenase involved in the metabolism of endogenous polyunsaturated fatty acids (PUFAs). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase). Catalyzes the hydroxylation of carbon hydrogen bonds, with preference for omega-2 position. Metabolizes (5Z,8Z,11Z,14Z)-eicosatetraenoic acid (arachidonate) toward 18-hydroxy arachidonate (PubMed:11162607). Catalyzes the epoxidation of double bonds of PUFAs such as docosapentaenoic and docosahexaenoic acids (PubMed:16112640). Has low omega-hydroxylase activity toward leukotriene B4 and arachidonate (PubMed:11162645). Involved in the metabolism of xenobiotics. Catalyzes the hydroxylation of the antihistamine drug ebastine (PubMed:11162645).
Expressed in small intestine, liver, colon and heart.
According to PubMed:16322216, another protein (SRG) is encoded on the 3'-UTR of the CASZ1 gene. The existence of this protein that may play a role in apoptosis is extremely dubious despite the fact it was localized in the cytoplasm with the help of a polyclonal antibody.
Endothelial cells depleted in CASZ1 by siRNAs display dramatic alterations in adhesion, morphology and sprouting; normal behavior can be rescued by restoration of EGFL7 expression. The defects are in part due to diminished RhoA expression and impaired focal adhesion localization.
Expressed in heart, lung, skeletal muscle, pancreas, testis, small intestine, and stomach, but it is not detectable in the adult brain.
Transcriptional activator (PubMed:23639441, PubMed:27693370). Involved in vascular assembly and morphogenesis through direct transcriptional regulation of EGFL7 (PubMed:23639441).
Salivary protein that stabilizes saliva supersaturated with calcium salts by inhibiting the precipitation of calcium phosphate salts. It also modulates hydroxyapatite crystal formation on the tooth surface.
Secreted by parotid and submandibular glands.
Substrate for transglutaminase-2. More than 95% of the cyclized peptide is cyclo-statherin Q-37, and less than 5% is cyclo-statherin Q-39. Cyclized forms account for about 1% of total statherin in saliva.
E3 ubiquitin ligase which accepts ubiquitin and transfers it to substrates thereby promoting their degradation by the endoplasmic reticulum-associated degradation (ERAD) pathway which is a pathway involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins (By similarity). May regulate the unfolded protein response to reduce endoplasmic reticulum stress (By similarity).
Belongs to the nuclear transition protein 1 family.
Associated component of the MCM complex that acts as a regulator of DNA replication. Binds to the MCM complex during late S phase and promotes the disassembly of the MCM complex from chromatin, thereby acting as a key regulator of pre-replication complex (pre-RC) unloading from replicated DNA. Can dissociate the MCM complex without addition of ATP; probably acts by destabilizing interactions of each individual subunits of the MCM complex. Required for sister chromatid cohesion.
Interacts with the MCM complex: associates with the MCM3-7 complex which lacks MCM2, while it does not interact with the MCM complex when MCM2 is present (MCM2-7 complex). Interacts with the RPA complex, when composed of all RPA1, RPA2 and RPA3 components, but not with RPA1 or RPA2 alone.
Able to homodimerize (PubMed:25504471, PubMed:25026078, PubMed:25697406). Interacts with DDX6 and EDC4 (By similarity). Interacts with CCR4-NOT deadenylase complex (PubMed:31636267). Interacts with RC3H1; the interaction is RNA independent (PubMed:25697406).
Post-transcriptional repressor of mRNAs containing a conserved stem loop motif, called constitutive decay element (CDE), which is often located in the 3'-UTR, as in HMGXB3, ICOS, IER3, NFKBID, NFKBIZ, PPP1R10, TNF, TNFRSF4 and in many more mRNAs (PubMed:25026078, PubMed:31636267). Cleaves translationally inactive mRNAs harboring a stem-loop (SL), often located in their 3'-UTRs, during the early phase of inflammation in a helicase UPF1-independent manner (By similarity). Binds to CDE and promotes mRNA deadenylation and degradation. This process does not involve miRNAs (By similarity). In follicular helper T (Tfh) cells, represses of ICOS and TNFRSF4 expression, thus preventing spontaneous Tfh cell differentiation, germinal center B-cell differentiation in the absence of immunization and autoimmunity (By similarity). In resting or LPS-stimulated macrophages, controls inflammation by suppressing TNF expression (By similarity). Also recognizes CDE in its own mRNA and in that of paralogous RC3H2, possibly leading to feedback loop regulation (By similarity). Recognizes and binds mRNAs containing a hexaloop stem-loop motif, called alternative decay element (ADE) (By similarity). Together with ZC3H12A, destabilizes TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in its 3'UTR (By similarity). Able to interact with double-stranded RNA (dsRNA) (PubMed:25504471, PubMed:25026078). miRNA-binding protein that regulates microRNA homeostasis. Enhances DICER-mediated processing of pre-MIR146a but reduces mature MIR146a levels through an increase of 3' end uridylation. Both inhibits ICOS mRNA expression and they may act together to exert the suppression (PubMed:25697406, PubMed:31636267). Acts as a ubiquitin E3 ligase. Pairs with E2 enzymes UBE2A, UBE2B, UBE2D2, UBE2F, UBE2G1, UBE2G2 and UBE2L3 and produces polyubiquitin chains (PubMed:26489670). Shows the strongest activity when paired with UBE2N:UBE2V1 or UBE2N:UBE2V2 E2 complexes and generate both short and long polyubiquitin chains (PubMed:26489670).
Proteolytically cleaved after Arg-510 and Arg-579 by MALT1 in activated CD4(+) T cells; cleavage at Arg-510 and Arg-579 is critical for promoting RC3H1 degradation in response to T-cell receptor (TCR) stimulation, and hence is necessary for prolonging the stability of a set of mRNAs controlling Th17 cell differentiation.
The ROQ region is required for CDE RNA-binding (PubMed:25504471, PubMed:25026078). Has 2 separate RNA-binding sites, one for CDE RNA and the other for dsRNA, both sites are important for mRNA decay (PubMed:25026078). ADE RNA-binding involves an extended binding surface on the ROQ region with a number of additional residues compared with the CDE RNA (By similarity). It may also be involved in localization to stress granules (By similarity).
Widely expressed. Expressed at higher level in cerebellum, spleen, ovary and liver.
I-alpha-I plasma protease inhibitors are assembled from one or two heavy chains (HC) and one light chain, bikunin. Inter-alpha-inhibitor (I-alpha-I) is composed of ITIH1/HC1, ITIH2/HC2 and bikunin.
Homooligomer and heterooligomer with HEXIM2; probably dimeric (PubMed:15713661, PubMed:15965233, PubMed:16377779). Core component of the 7SK RNP complex, at least composed of 7SK RNA, LARP7, MEPCE, HEXIM1 (or HEXIM2) and P-TEFb (composed of CDK9 and CCNT1/cyclin-T1) (PubMed:12832472, PubMed:15201869, PubMed:15169877, PubMed:16362050, PubMed:15713661, PubMed:15855166, PubMed:16377779, PubMed:17643375, PubMed:17724342, PubMed:30134174). Interacts with the N-CoR complex through NCOR1 (PubMed:17452463). Interacts with ESR1 and NR3C1 (PubMed:15940264, PubMed:15941832). May interact with NF-kappa-B through RELA (PubMed:12581153). Interacts with CCNT2; mediates formation of a tripartite complex with KPNA2 (PubMed:19883659). Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 non-coding RNA (PubMed:28712728).
Inhibits Tat activity which is required for HIV-1 transcription.
Transcriptional regulator which functions as a general RNA polymerase II transcription inhibitor (PubMed:14580347, PubMed:15713661, PubMed:15201869). Core component of the 7SK RNP complex: in cooperation with 7SK snRNA sequesters P-TEFb in a large inactive 7SK snRNP complex preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation (PubMed:12832472, PubMed:14580347, PubMed:15713661, PubMed:15201869). May also regulate NF-kappa-B, ESR1, NR3C1 and CIITA-dependent transcriptional activity (PubMed:15940264, PubMed:15941832, PubMed:17088550). Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728).
Ubiquitously expressed with higher expression in placenta. HEXIM1 and HEXIM2 are differentially expressed. Expressed in endocrine tissues.
Up-regulated by HMBA (hexamethylene bisacetamide) (at protein level). Down-regulated by estrogen.
Bifunctional modulator of guanine nucleotide-binding proteins (G proteins) (PubMed:19211784, PubMed:27621449). Acts as a non-receptor guanine nucleotide exchange factor which binds to and activates guanine nucleotide-binding protein G(i) alpha subunits (PubMed:19211784, PubMed:21954290, PubMed:23509302, PubMed:25187647). Also acts as a guanine nucleotide dissociation inhibitor for guanine nucleotide-binding protein G(s) subunit alpha GNAS (PubMed:27621449). Essential for cell migration (PubMed:20462955, PubMed:16139227, PubMed:19211784, PubMed:21954290). Interacts in complex with G(i) alpha subunits with the EGFR receptor, retaining EGFR at the cell membrane following ligand stimulation and promoting EGFR signaling which triggers cell migration (PubMed:20462955). Binding to Gi-alpha subunits displaces the beta and gamma subunits from the heterotrimeric G-protein complex which enhances phosphoinositide 3-kinase (PI3K)-dependent phosphorylation and kinase activity of AKT1/PKB (PubMed:19211784). Phosphorylation of AKT1/PKB induces the phosphorylation of downstream effectors GSK3 and FOXO1/FKHR, and regulates DNA replication and cell proliferation (By similarity). Binds in its tyrosine-phosphorylated form to the phosphatidylinositol 3-kinase (PI3K) regulatory subunit PIK3R1 which enables recruitment of PIK3R1 to the EGFR receptor, enhancing PI3K activity and cell migration (PubMed:21954290). Plays a role as a key modulator of the AKT-mTOR signaling pathway, controlling the tempo of the process of newborn neuron integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Inhibition of G(s) subunit alpha GNAS leads to reduced cellular levels of cAMP and suppression of cell proliferation (PubMed:27621449). Essential for the integrity of the actin cytoskeleton (PubMed:16139227, PubMed:19211784). Required for formation of actin stress fibers and lamellipodia (PubMed:15882442). May be involved in membrane sorting in the early endosome (PubMed:15882442). Plays a role in ciliogenesis and cilium morphology and positioning and this may partly be through regulation of the localization of scaffolding protein CROCC/Rootletin (PubMed:27623382).
Homodimer (PubMed:16139227). Interacts (via GBA motif) with guanine nucleotide-binding protein G(i) alpha subunits GNAI1, GNAI2 and GNAI3 (PubMed:19211784, PubMed:21954290, PubMed:23509302, PubMed:27621449, PubMed:31363053). Also interacts (via GNA motif) with guanine nucleotide-binding protein G(s) alpha subunit GNAS (PubMed:27621449). Interaction with G(i) alpha subunits occurs before interaction with GNAS and is regulated by phosphorylation; phosphorylation at Ser-1675 enhances binding to G(i) alpha subunits while phosphorylation at Ser-1690 abolishes G(i) alpha subunit binding, promoting binding to GNAS (PubMed:27621449). Interacts (via C-terminal SH2-like region) with growth factor receptors EGFR, INSR and KDR/VEGFR2 (via their autophosphorylated cytoplasmic tails) (PubMed:25187647). Forms a complex with EGFR and GNAI3 which leads to enhanced EGFR signaling and triggering of cell migration; ligand stimulation is required for recruitment of GNAI3 to the complex (PubMed:20462955, PubMed:25187647). Interacts (tyrosine-phosphorylated form) with phosphatidylinositol 3-kinase (PI3K) regulatory subunit PIK3R1/p85a (via SH2 domains); the interaction enables recruitment of PIK3R1 to the EGFR receptor, enhancing PI3K activity and cell migration (PubMed:21954290). Interacts with serine/threonine-protein kinase PRKCQ; the interaction leads to phosphorylation of CCDC88A and inhibition of its guanine nucleotide exchange factor activity (PubMed:23509302). Interacts (via C-terminus) with DISC1; the interaction is direct (By similarity). Interacts with AKT proteins; the interaction is inhibited in the presence of DISC1 (By similarity). Interacts with AKT1/PKB (via C-terminus) (PubMed:16139227). The non-phosphorylated form interacts with phosphatidylinositol 4-phosphate [PI(4)P] and weakly with phosphatidylinositol 3-phosphate [PI(3)P] (PubMed:16139227). Interacts with microtubules (By similarity). Interacts with actin (PubMed:16139227).
In the presence of tyrosine-autophosphorylated growth factor receptors, the C-terminus folds into an SH2-like region which promotes the stable recruitment of CCDC88A to the growth factor receptors. The SH2-like region is phosphorylated by the growth factor receptors prior to completion of folding.
Phosphorylation is induced by epidermal growth factor (EGF) in a phosphoinositide 3-kinase (PI3K)-dependent manner (PubMed:16139227). Phosphorylation by AKT1/PKB is necessary for delocalization from the cell membrane and for cell migration (PubMed:16139227). Phosphorylated on tyrosine residues which promotes binding to phosphatidylinositol 3-kinase (PI3K) regulatory subunit PIK3R1/p85a and enhances PI3K activity (PubMed:21954290). Tyrosine-phosphorylated by both receptor and non-receptor tyrosine kinases in vitro (PubMed:21954290). Tyrosine phosphorylation is required for AKT1-dependent phosphorylation of Ser-1417 (PubMed:21954290). Phosphorylation at Ser-1690 by PRKCQ disrupts interaction with GNAI3 and inhibits guanine nucleotide exchange factor activity (PubMed:23509302).
Abundant in placenta, moderate in liver and heart, whereas fairly weak in other tissues examined. On term placenta, mainly localized extracellularly surrounding the syncytiotrophoblastic cells and very rarely expressed in the maternal decidua layer.
Secreted scaffold protein that plays an essential role in dorsoventral patterning during early development. Stabilizes axial formation by restricting chordin (CHRD) activity on the dorsal side. Acts by facilitating the association between the tolloid proteases and their substrate chordin (CHRD), leading to enhance chordin (CHRD) degradation (By similarity). May have matrix-related function involved in placental and embryonic development, or play a similar role in other physiological processes.
Component of the proposed t-UTP subcomplex of the ribosomal small subunit (SSU) processome. SSU processome is composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:17699751, PubMed:22916032).
Ribosome biogenesis factor. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. Involved in nucleolar processing of pre-18S ribosomal RNA. Required for optimal pre-ribosomal RNA transcription by RNA polymerase I.
Belongs to the glycosyl hydrolase 63 family.
Cleaves the distal alpha 1,2-linked glucose residue from the Glc(3)Man(9)GlcNAc(2) oligosaccharide precursor in a highly specific manner.
Cleaves the distal alpha 1,2-linked glucose residue from the Glc(3)Man(9)GlcNAc(2) oligosaccharide precursor.
Widespread tissue expression; highest levels in the heart.
Expressed in the kidney, in epithelial cells in both proximal tubules and distal convoluted tubules.
Component of the ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, a VPS37 protein (VPS37A to -D) and MVB12A or MVB12B in a 1:1:1:1 stoichiometry. Interacts with TSG101; the association appears to be mediated by the TSG101-VPS37 binary subcomplex. Interacts with VPS28. Interacts with VPS37B; the association appears to be mediated by the TSG101-VPS37 binary subcomplex. Interacts with VPS37C; the association appears to be mediated by the TSG101-VPS37 binary subcomplex.
Component of the ESCRT-I complex, a regulator of vesicular trafficking process. Required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies.
A chromosomal aberration involving ABL1 has been found in patients with chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
A chromosomal aberration involving ABL1 is found in a form of acute lymphoblastic leukemia (PubMed:15361874). Translocation t(9;9)(q34;q34) with NUP214 (PubMed:15361874).
Acetylated at Lys-711 by EP300 which promotes the cytoplasmic translocation.
Interacts with SORBS1 following insulin stimulation. Found in a trimolecular complex containing CDK5 and CABLES1. Interacts with CABLES1 and PSTPIP1. Interacts with ZDHHC16, ITGB1 and HCK (By similarity). Interacts with STX17; probably phosphorylates STX17. Interacts with INPPL1/SHIP2. Interacts with the 14-3-3 proteins, YWHAB, YWHAE, YWHAG, YWHAH, SFN and YWHAZ; the interaction with 14-3-3 proteins requires phosphorylation on Thr-735 and, sequesters ABL1 into the cytoplasm. Interacts with ABI1, ABI2, BCR, CRK, FGR, FYN, HCK, LYN, PSMA7 RAD9A, RAD51, RAD52, TP73 and WASF3. A complex made of ABL1, CTTN and MYLK regulates cortical actin-based cytoskeletal rearrangement critical to sphingosine 1-phosphate (S1P)-mediated endothelial cell (EC) barrier enhancement. Interacts (via SH3 domain) with CASP9; the interaction is direct and increases in the response of cells to genotoxic stress and ABL1/c-Abl activation. Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases. Interacts with TBX21 (By similarity). Interacts with NEDD9/HEF1; interaction is induced by CXCL12 promotion of ABL-mediated phosphorylation of NEDD9/HEF1 (PubMed:22810897).
Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9 (PubMed:22810897). Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. In response to oxidative stress, phosphorylates serine/threonine kinase PRKD2 at 'Tyr-717' (PubMed:28428613). ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. Regulates T-cell differentiation in a TBX21-dependent manner (By similarity). Positively regulates chemokine-mediated T-cell migration, polarization, and homing to lymph nodes and immune-challenged tissues, potentially via activation of NEDD9/HEF1 and RAP1 (By similarity). Phosphorylates TBX21 on tyrosine residues leading to an enhancement of its transcriptional activator activity (By similarity).
Phosphorylation at Tyr-70 by members of the SRC family of kinases disrupts SH3 domain-based autoinhibitory interactions and intermolecular associations, such as that with ABI1, and also enhances kinase activity. Phosphorylation at Tyr-226 and Tyr-393 correlate with increased activity. DNA damage-induced activation of ABL1 requires the function of ATM and Ser-446 phosphorylation (By similarity). Phosphorylation at Ser-569 has been attributed to a CDC2-associated kinase and is coupled to cell division (By similarity). Phosphorylation at Ser-618 and Ser-619 by PAK2 increases binding to CRK and reduces binding to ABI1. Phosphorylation on Thr-735 is required for binding 14-3-3 proteins for cytoplasmic translocation. Phosphorylated by PRKDC (By similarity).
Polyubiquitinated. Polyubiquitination of ABL1 leads to degradation.
Stabilized in the inactive form by an association between the SH3 domain and the SH2-TK linker region, interactions of the N-terminal cap, and contributions from an N-terminal myristoyl group and phospholipids. Activated by autophosphorylation as well as by SRC-family kinase-mediated phosphorylation. Activated by RIN1 binding to the SH2 and SH3 domains. Also stimulated by cell death inducers and DNA-damage. Phosphatidylinositol 4,5-bisphosphate (PIP2), a highly abundant phosphoinositide known to regulate cytoskeletal and membrane proteins, inhibits also the tyrosine kinase activity (By similarity). Activated by 5-(1,3-diaryl-1H-pyrazol-4-yl)hydantoin, 5-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-2,4-imidazolidinedione (DPH) (PubMed:28428613). Inhibited by ABI1, whose activity is controlled by ABL1 itself through tyrosine phosphorylation. Also inhibited by imatinib mesylate (Gleevec) which is used for the treatment of chronic myeloid leukemia (CML), and by VX-680, an inhibitor that acts also on imatinib-resistant mutants (PubMed:28428613).
Interacts with EPS15, AGFG1/HRB and AGFG2/HRBL. Associates with the clathrin-associated adapter protein complex 2 (AP-2) (By similarity). Interacts with FCHO1. Interacts with FCHO2. Interacts (via EH domains) with DAB2. Interacts with UBQLN1 (via ubiquitin-like domain). Interacts with CAVIN3 (via leucine-zipper domain) (PubMed:19262564). Interacts with REPS2 (PubMed:10393179).
Phosphorylated on tyrosine residues by EGFR.
Seems to be a constitutive component of clathrin-coated pits that is required for receptor-mediated endocytosis. Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR); internalization of ITGB1 as DAB2-dependent cargo but not TFR seems to require association with DAB2.
Studies in clathrin-mediated endocytosis used a siRNA mixture of EPS15 and EPS15L1.
Expressed in testis, including in Leydig cells and in the seminiferous epithelium, in differentiating cells from the spermatogonia to mature spermatozoa stages and round spermatids (at protein level). Expressed in 99.2% of spermatozoa from healthy individuals, but only in 28.6% of macrocephalic spermatozoa from infertile patients (at protein level).
G proteins are composed of 3 units; alpha, beta and gamma (PubMed:12399457). The alpha chain contains the guanine nucleotide binding site (By similarity). Interacts with UBXD5 (PubMed:16202387). Interacts with HAX1 (PubMed:15339924). Interacts (in GTP-bound form) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane. Interacts with RGS22 (PubMed:18703424). Interacts (in GTP-bound form) with ARHGEF1 (PubMed:10747909). Interacts (in GTP-bound form) with ARHGEF11 (via RGS domain) (PubMed:10026210). Interacts (in GTP-bound form) with ARHGEF12 (via RGS domain) (PubMed:11094164). Interacts with CTNND1 (PubMed:15240885). Interacts with GASL2L2 (PubMed:23994616).
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems (PubMed:15240885, PubMed:16787920, PubMed:16705036, PubMed:27084452). Activates effector molecule RhoA by binding and activating RhoGEFs (ARHGEF1/p115RhoGEF, ARHGEF11/PDZ-RhoGEF and ARHGEF12/LARG) (PubMed:15240885, PubMed:12515866). GNA13-dependent Rho signaling subsequently regulates transcription factor AP-1 (activating protein-1) (By similarity). Promotes tumor cell invasion and metastasis by activating RhoA/ROCK signaling pathway (PubMed:16787920, PubMed:16705036, PubMed:27084452). Inhibits CDH1-mediated cell adhesion in process independent from Rho activation (PubMed:11976333).
Palmitoylation is critical for proper membrane localization and signaling.
Phosphorylation on Thr-203 by PKA destabilizes the heterotrimer of alpha, beta and gamma, and inhibits Rho activation.
Adds the third glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation. Transfers glucose from dolichyl phosphate glucose (Dol-P-Glc) onto the lipid-linked oligosaccharide Glc(2)Man(9)GlcNAc(2)-PP-Dol.
Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3 (PubMed:34388369). Within the complex, interacts with SPCS2 and SPCS3 (PubMed:34388369). The complex induces a local thinning of the ER membrane which is used to measure the length of the signal peptide (SP) h-region of protein substrates (PubMed:34388369). This ensures the selectivity of the complex towards h-regions shorter than 18-20 amino acids (PubMed:34388369).
Catalyzes the formation of phosphoribosylamine from phosphoribosylpyrophosphate (PRPP) and glutamine.
In the C-terminal section; belongs to the purine/pyrimidine phosphoribosyltransferase family.
Found in a complex with LRP6, CCNY and CAPRIN2 during G2/M stage; CAPRIN2 functions as a scaffold for the complex by binding to CCNY via its N terminus and to CDK14 via its C terminus (PubMed:27821587). Interacts with CCNY; CCNY mediates its recruitment to the plasma membrane and promotes phosphorylation of LRP6 (PubMed:20059949, PubMed:19524571). Interacts with CCDN3 and CDKN1A (PubMed:17517622). Interacts with SEPT8 (PubMed:12098780). Interacts with 14-3-3 proteina YWHAB, YWHAE, YWHAH and YWHAQ (PubMed:16775625).
Highly expressed in brain, pancreas, kidney, heart, testis and ovary. Also detected at lower levels in other tissues except in spleen and thymus where expression is barely detected.
Serine/threonine-protein kinase activity is promoted by associated cyclins CCDN3 and CCNY and repressed by CDKN1A.
Serine/threonine-protein kinase involved in the control of the eukaryotic cell cycle, whose activity is controlled by an associated cyclin. Acts as a cell-cycle regulator of Wnt signaling pathway during G2/M phase by mediating the phosphorylation of LRP6 at 'Ser-1490', leading to the activation of the Wnt signaling pathway. Acts as a regulator of cell cycle progression and cell proliferation via its interaction with CCDN3. Phosphorylates RB1 in vitro, however the relevance of such result remains to be confirmed in vivo. May also play a role in meiosis, neuron differentiation and may indirectly act as a negative regulator of insulin-responsive glucose transport.
Homodimer (PubMed:9461620, PubMed:18227065, PubMed:9599005, PubMed:17374501). Homodimerizes after import into the mitochondrion (PubMed:9599005).
Predominantly expressed in heart and skeletal muscle (at protein level). Also detected in kidney and liver (at protein level).
S-nitrosylation at Cys-237 in liver improves catalytic efficiency.
Very long-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation, an aerobic process breaking down fatty acids into acetyl-CoA and allowing the production of energy from fats (PubMed:7668252, PubMed:9461620, PubMed:18227065, PubMed:9839948, PubMed:9599005). The first step of fatty acid beta-oxidation consists in the removal of one hydrogen from C-2 and C-3 of the straight-chain fatty acyl-CoA thioester, resulting in the formation of trans-2-enoyl-CoA (PubMed:7668252, PubMed:9461620, PubMed:18227065, PubMed:9839948). Among the different mitochondrial acyl-CoA dehydrogenases, very long-chain specific acyl-CoA dehydrogenase acts specifically on acyl-CoAs with saturated 12 to 24 carbons long primary chains (PubMed:21237683, PubMed:9839948).
Mutations in CHCHD2 are rare, and might vary by ethnic origin.
Transcription factor. Binds to the oxygen responsive element of COX4I2 and activates its transcription under hypoxia conditions (4% oxygen), as well as normoxia conditions (20% oxygen) (PubMed:23303788).
Up-regulated by hypoxia (4% oxygen) (at protein level).
Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A6 subfamily.
Brain, mainly in the cerebellum (PubMed:7791878). Expressed densely and selectively in cell bodies of Purkinje cells.
Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:7791878, PubMed:26690923). Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion. Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport (PubMed:7791878). Plays a redundant role in the rapid removal of released glutamate from the synaptic cleft, which is essential for terminating the postsynaptic action of glutamate (Probable).
Acts as a dominant-negative for isoform c-ETS-1A.
Autoinhibited by a module composed of four alpha helices (HI-1, HI-2, H4, and H5) that flank the DNA-binding ETS domain, reducing the affinity for DNA. Phosphorylation by CaMK2/CaMKII in response to calcium signaling decreases affinity for DNA.
Binds DNA as a homodimer; homodimerization is required for transcription activation (PubMed:18566588). Interacts with MAF and MAFB (By similarity). Interacts with PAX5; the interaction alters DNA-binding properties (By similarity). Interacts with DAXX (PubMed:10698492). Interacts with UBE2I (PubMed:9333025). Interacts with SP100; the interaction is direct and modulates ETS1 transcriptional activity (PubMed:11909962, PubMed:15247905).
Highly expressed within lymphoid cells. Isoforms c-ETS-1A and Ets-1 p27 are both detected in all fetal tissues tested, but vary with tissue type in adult tissues. None is detected in brain or kidney.
Phosphorylation at Ser-251, Ser-282 and Ser-285 by CaMK2/CaMKII in response to calcium signaling decreases affinity for DNA: an increasing number of phosphoserines causes DNA-binding to become progressively weaker.
Sumoylated on Lys-15 and Lys-227, preferentially with SUMO2; which inhibits transcriptional activity.
Transcription factor (PubMed:10698492, PubMed:11909962). Directly controls the expression of cytokine and chemokine genes in a wide variety of different cellular contexts (PubMed:20378371). May control the differentiation, survival and proliferation of lymphoid cells (PubMed:20378371). May also regulate angiogenesis through regulation of expression of genes controlling endothelial cell migration and invasion (PubMed:15247905, PubMed:15592518).
Ubiquitinated; which induces proteasomal degradation.
Up-regulated by retinoic acid, VEGF, TNF-alpha/TNFA, lipopolysaccharide and in response to hypoxia (at protein level).
Activated in breast and prostate cancer cells. Activated by actinomycin-D induced DNA damage.
High levels in skeletal muscle, ovary, kidney and colon.
May play a role in growth regulation. Is associated with G2/M phase arrest in response to DNA damage. May be an intermediate by which p53 mediates its role as an inhibitor of cellular proliferation (By similarity).
Very low levels in normal cells during G1 phase, which increase as cells enter the S phase and stay high throughout the S and G2/M phases. In breast cancer cells consistent high levels are found throughout the cell cycle.
Protein insertase that mediates insertion of transmembrane proteins into the mitochondrial outer membrane (PubMed:36264797). Catalyzes insertion of proteins with alpha-helical transmembrane regions, such as signal-anchored, tail-anchored and multi-pass membrane proteins (By similarity). Does not mediate insertion of beta-barrel transmembrane proteins (By similarity). May play a role in apoptosis (PubMed:12377771).
Widely expressed with a predominant expression in brain.
Associates with the mitochondrial ribosome large subunit; the association occurs in a GTP-dependent manner (PubMed:23396448).
Belongs to the TRAFAC class YlqF/YawG GTPase family. MTG1 subfamily.
Plays a role in the regulation of the mitochondrial ribosome assembly and of translational activity. Displays mitochondrial GTPase activity.
Binds three calcium ions (via EF-hands 2, 3 and 4) when calcium levels are high. Binds Mg(2+) when calcium levels are low.
In the retina, it is expressed in rod and cone photoreceptors.
Stimulates retinal guanylyl cyclase when free calcium ions concentration is low and inhibits guanylyl cyclase when free calcium ions concentration is elevated (PubMed:19459154, PubMed:30622141, PubMed:18706439, PubMed:30184081). This Ca(2+)-sensitive regulation of retinal guanylyl cyclase is a key event in recovery of the dark state of rod photoreceptors following light exposure (By similarity). May be involved in cone photoreceptor light response and recovery of response in bright light (By similarity).
Expressed specifically in testis and skeletal muscle.
NACAL arose from a recent (40-63 million-year-old), anthropoid primate-specific retroduplication of NACA.
Part of the nascent polypeptide-associated complex (NAC), consisting of NACA and BTF3. NAC associates with ribosomes through the BTF3 subunit. Both subunits can contact nascent polypeptide chains (By similarity).
Prevents inappropriate targeting of non-secretory polypeptides to the endoplasmic reticulum (ER). Binds to nascent polypeptide chains as they emerge from the ribosome and blocks their interaction with the signal recognition particle (SRP), which normally targets nascent secretory peptides to the ER. Also reduces the inherent affinity of ribosomes for protein translocation sites in the ER membrane (M sites) (By similarity).
Genetic variations in IFITM3 are responsible for susceptibility to severe influenza virus infection [MIM:614680].
IFN-induced antiviral protein which disrupts intracellular cholesterol homeostasis. Inhibits the entry of viruses to the host cell cytoplasm by preventing viral fusion with cholesterol depleted endosomes. May inactivate new enveloped viruses which buds out of the infected cell, by letting them go out with a cholesterol depleted membrane. Active against multiple viruses, including influenza A virus, SARS coronaviruses (SARS-CoV and SARS-CoV-2), Marburg virus (MARV), Ebola virus (EBOV), Dengue virus (DNV), West Nile virus (WNV), human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV) and vesicular stomatitis virus (VSV) (PubMed:26354436, PubMed:33270927, PubMed:33239446). Can inhibit: influenza virus hemagglutinin protein-mediated viral entry, MARV and EBOV GP1,2-mediated viral entry, SARS-CoV and SARS-CoV-2 S protein-mediated viral entry and VSV G protein-mediated viral entry (PubMed:33270927). Plays a critical role in the structural stability and function of vacuolar ATPase (v-ATPase). Establishes physical contact with the v-ATPase of endosomes which is critical for proper clathrin localization and is also required for the function of the v-ATPase to lower the pH in phagocytic endosomes thus establishing an antiviral state. In hepatocytes, IFITM proteins act in a coordinated manner to restrict HCV infection by targeting the endocytosed HCV virion for lysosomal degradation (PubMed:26354436). IFITM2 and IFITM3 display anti-HCV activity that may complement the anti-HCV activity of IFITM1 by inhibiting the late stages of HCV entry, possibly in a coordinated manner by trapping the virion in the endosomal pathway and targeting it for degradation at the lysosome (PubMed:26354436). Exerts opposing activities on SARS-CoV-2, including amphipathicity-dependent restriction of virus at endosomes and amphipathicity-independent enhancement of infection at the plasma membrane (PubMed:33270927).
Interacts with ATP6V0B (By similarity). Interacts with CD81 (By similarity). Interacts with SPP1; the interaction reduces OPN expression (PubMed:19901966). Interacts with VAPA (PubMed:23601107). Interacts with BRI3 (isoforms 1 and 2); the interaction with isoform 2 is weaker than with isoform 1 (PubMed:30983867).
Palmitoylation on membrane-proximal cysteines controls clustering in membrane compartments and antiviral activity against influenza virus and hepatitis C virus (HCV). Has no effect on anti-SARS-CoV-2 activity.
Phosphorylation at Tyr-20 is required for endosomal and lysosomal location.
Polyubiquitinated with both 'Lys-48' and 'Lys-63' linkages. Ubiquitination negatively regulates antiviral activity. Lys-24 is the most prevalent ubiquitination site.
Lacks one Cys residue in the IBR-type zinc finger domain that is one of the conserved features of the family.
Might act as an E3 ubiquitin-protein ligase, or as part of E3 complex, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes and then transfers it to substrates.
Binds DNA as a dimer (PubMed:11111039, PubMed:22095455). Interacts with DSCR6 (By similarity). Interacts with NKX2-5 (By similarity).
Haploinsufficiency of the TBX1 gene is responsible for most of the physical malformations present in DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). DGS is characterized by the association of several malformations: hypoplastic thymus and parathyroid glands, congenital conotruncal cardiopathy, and a subtle but characteristic facial dysmorphology. VCFS is marked by the association of congenital conotruncal heart defects, cleft palate or velar insufficiency, facial dysmorpholgy and learning difficulties. It is now accepted that these two syndromes represent two forms of clinical expression of the same entity manifesting at different stages of life.
Transcription factor that plays a key role in cardiovascular development by promoting pharyngeal arch segmentation during embryonic development (By similarity). Also involved in craniofacial muscle development (By similarity). Together with NKX2-5, acts as a regulator of asymmetric cardiac morphogenesis by promoting expression of PITX2 (By similarity). Acts upstream of TBX1 for the formation of the thymus and parathyroid glands from the third pharyngeal pouch (By similarity). Required for hair follicle stem cell self-renewal (By similarity). Binds to the palindromic T site 5'-TTCACACCTAGGTGTGAA-3' DNA sequence (PubMed:11111039, PubMed:22095455).
Highly expressed in pancreas and testis and to a lower extent in prostate, ovary, heart, thymus, small intestine and spleen.
Required for bone modeling during late embryogenesis. Regulates type I collagen synthesis in osteoblasts during their postnatal maturation (By similarity).
Expressed in peripheral blood lymphocytes and fetal liver. Expressed preferentially in reproductive and/or developmentally important cells, such as testis, placenta, bone marrow and fetal tissues.
Homodimer, and heterodimer of GMEB1 and GMEB2. GMEB1 and GMEB2 form the parvovirus initiator complex (PIF). Interacts with the glucocorticoid receptor (NR3C1). May interact with CREB-binding protein (CBP).
(Microbial infection) Interacts with E.coli effector protein EspF(U).
Binds the Arp2/3 complex (PubMed:12769847). Interacts with CDC42, RAC, NCK, HCK, FYN, SRC kinase FGR, BTK, ABL1, PSTPIP1, WIP, and to the p85 subunit of PLC-gamma (PubMed:8643625, PubMed:9405671, PubMed:12235133, PubMed:10360578, PubMed:15235593). Interacts (via C-terminus) with ALDOA (PubMed:17329259). Interacts with NCK1 (via SH3 domains) (By similarity). Interacts with FCHSD2 (By similarity).
Effector protein for Rho-type GTPases that regulates actin filament reorganization via its interaction with the Arp2/3 complex (PubMed:12235133, PubMed:12769847, PubMed:16275905). Important for efficient actin polymerization (PubMed:8625410, PubMed:12235133, PubMed:16275905). Possible regulator of lymphocyte and platelet function (PubMed:9405671). Mediates actin filament reorganization and the formation of actin pedestals upon infection by pathogenic bacteria (PubMed:18650809). In addition to its role in the cytoplasmic cytoskeleton, also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA (PubMed:20574068). Promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs) (PubMed:29925947).
Expressed predominantly in the thymus. Also found, to a much lesser extent, in the spleen.
Phosphorylated at Tyr-291 by FYN and HCK, inducing WAS effector activity after TCR engagement. Phosphorylation at Tyr-291 enhances WAS activity in promoting actin polymerization and filopodia formation.
The CRIB (Cdc42/Rac-interactive-binding) region binds to the C-terminal WH2 domain in the autoinhibited state of the protein. Binding of Rho-type GTPases to the CRIB induces a conformation change and leads to activation.
The WH1 (Wasp homology 1) domain may bind a Pro-rich ligand.
(Microbial infection) Binds to OspC on the surface of B.burgdorferi cells, possibly conferring an extracellular protease activity on the bacteria that allows it to traverse host tissue.
(Microbial infection) ENO/enoloase from parasite P.falciparum (strain NF54) interacts with PLG present in the mosquito blood meal to promote the invasion of the mosquito midgut by the parasite ookinete (PubMed:21949403). The catalytic active form, plasmin, is essential for the invasion of the mosquito midgut (PubMed:21949403).
(Microbial infection) Interacts with B.burgdorferi OspC.
(Microbial infection) Interacts with C.albicans GPD2; the interaction is direct and provides active plasmin on the surface of fungal cells.
(Microbial infection) Interacts with P.falciparum (strain NF54) enolase ENO (via DKSLVK motif); the interaction occurs at the ookinete cell surface and is required for ookinete invasion of the mosquito midgut.
(Microbial infection) Interacts with Staphylococcus aureus protein FnbB; this interaction provides active plasmin on the surface of bacterial cells.
Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo.
Converted into plasmin by plasminogen activators, both plasminogen and its activator being bound to fibrin. Activated with catalytic amounts of streptokinase. Plasmin activity inhibited by SERPINE2.
In the presence of the inhibitor, the activation involves only cleavage after Arg-580, yielding two chains held together by two disulfide bonds. In the absence of the inhibitor, the activation involves additionally the removal of the activation peptide.
Interacts (both mature PLG and the angiostatin peptide) with CSPG4 and AMOT (PubMed:10889192, PubMed:16043488). Interacts (via the Kringle domains) with HRG; the interaction tethers PLG to the cell surface and enhances its activation (PubMed:9102401, PubMed:19712047). Interacts (via Kringle 4 domain) with ADA; the interaction stimulates PLG activation when in complex with DPP4 (PubMed:15016824). Angiostatin: Interacts with ATP5F1A; the interaction inhibits most of the angiogenic effects of angiostatin (PubMed:10077593).
Kringle domains mediate interaction with CSPG4.
N-linked glycan contains N-acetyllactosamine and sialic acid. O-linked glycans consist of Gal-GalNAc disaccharide modified with up to 2 sialic acid residues (microheterogeneity).
Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells.
Plasmin is inactivated by alpha-2-antiplasmin immediately after dissociation from the clot.
Present in plasma and many other extracellular fluids. It is synthesized in the liver.
Involved in autophagy. May play a role in a late step of autophagy, such as clearance of autophagosomal cargo. Plays a key role in innate and adaptive immune response triggered by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides from pathogens, and mediated by the nucleotide-sensing receptor TLR9. It is necessary for the translocation of CpG dinucleotides from early endosomes to late endosomes and lysosomes, where TLR9 is located (PubMed:29130391).
The disease is caused by variants affecting the gene represented in this entry. Affected individuals show homozygosity or compound heterozygosity for truncating mutations, aberrant splicing and/or missense mutations. Parental studies suggest recessive inheritance with no carrier manifestation (PubMed:23222957).
Belongs to the mitochondrial carrier (TC 2.A.29) family. SLC25A38 subfamily.
Mitochondrial glycine transporter that imports glycine into the mitochondrial matrix. Plays an important role in providing glycine for the first enzymatic step in heme biosynthesis, the condensation of glycine with succinyl-CoA to produce 5-aminolevulinate (ALA) in the mitochondrial matrix. Required during erythropoiesis.
Plays a role as pro-apoptotic protein that induces caspase-dependent apoptosis.
Preferentially expressed in erythroid cells.
Up-regulated in the brains of patients with Alzheimer's disease.
Expressed prominently in the placenta and is not detected in any other tissues examined.
Catalyzes the cleavage of 2'-deoxyuridine 5'-triphosphate (dUTP) into 2'-deoxyuridine 5'-monophosphate (dUMP) and inorganic pyrophosphate and through its action efficiently prevents uracil misincorporation into DNA and at the same time provides dUMP, the substrate for de novo thymidylate biosynthesis (PubMed:17880943, PubMed:8631816, PubMed:8805593). Inhibits peroxisome proliferator-activated receptor (PPAR) activity by binding of its N-terminal to PPAR, preventing the latter's dimerization with retinoid X receptor (By similarity). Essential for embryonic development (By similarity).
Each trimer binds three substrate molecules. The ligands are bound between subunits, and for each substrate molecule, residues from adjacent subunits contribute to the binding interactions.
Found in a variety of tissues. Isoform 3 expression is constitutive, while isoform 2 expression correlates with the onset of DNA replication (at protein level). Isoform 2 degradation coincides with the cessation of nuclear DNA replication (at protein level).
Involved in nucleotide metabolism via production of dUMP, the immediate precursor of thymidine nucleotides, and decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.
Nuclear isoform 2 is phosphorylated in vivo on Ser-11, a reaction that can be catalyzed in vitro by CDC2. Phosphorylation in mature T-cells occurs in a cell cycle-dependent manner. Isoform 3 is not phosphorylated.
Phosphorylation is necessary for activity.
Endonuclease that catalyzes the cleavage of RNA on the 3' side of pyrimidine nucleotides. Acts on single-stranded and double-stranded RNA.
Monomer. Interacts with and forms tight 1:1 complexes with RNH1. Dimerization of two such complexes may occur. Interaction with RNH1 inhibits this protein.
Pancreas and other tissues and body fluids (indicating it may have other physiological functions besides its role in digestion).
Belongs to the bacterial ribosomal protein bL17 family.
Detected in adrenal gland, mammary gland and adipose tissue.
(Microbial infection) Interacts (via C-terminus) with vaccinia virus protein K7/OPG41; this interaction prevents innate immune signaling activation.
Acts as an actin nucleation factor, remains associated with the slow-growing pointed end of the new filament (PubMed:11747823, PubMed:21620703). Involved in intracellular vesicle transport along actin fibers, providing a novel link between actin cytoskeleton dynamics and intracellular transport (PubMed:11747823). Required for asymmetric spindle positioning and asymmetric cell division during meiosis (PubMed:21620703). Required for normal formation of the cleavage furrow and for polar body extrusion during female germ cell meiosis (PubMed:21620703). Also acts in the nucleus: together with FMN2, promotes assembly of nuclear actin filaments in response to DNA damage in order to facilitate movement of chromatin and repair factors after DNA damage (PubMed:26287480). In addition, promotes innate immune signaling downstream of dsRNA sensing (PubMed:35148361). Mechanistically, contributes to IRF3 phosphorylation and activation downstream of MAVS and upstream of TBK1 (PubMed:35148361).
Autophagy factor required for autophagosome formation and mitophagy. Target of the TOR kinase signaling pathway that regulates autophagy through the control of the phosphorylation status of ATG13 and ULK1, and the regulation of the ATG13-ULK1-RB1CC1 complex. Through its regulation of ULK1 activity, plays a role in the regulation of the kinase activity of mTORC1 and cell proliferation.
Belongs to the ATG13 family. Metazoan subfamily.
Part of a complex consisting of ATG13, ULK1 and RB1CC1 (PubMed:19597335, PubMed:19211835, PubMed:19225151, PubMed:24290141). Interacts with ATG101 (PubMed:19597335, PubMed:19287211, PubMed:26299944). Interacts with ULK1 (via C-terminus); this interaction is increased in the absence of TMEM39A (PubMed:19287211, PubMed:21855797, PubMed:18936157, PubMed:31806350). Interacts with ULK2 (via C-terminus) (PubMed:19225151, PubMed:18936157). Interacts (via the LIR motif) with GABARAP, GABARAPL, GABARAPL2 (PubMed:23043107). Interacts (via the LIR motif) with MAP1LC3A, MAP1LC3B and MAP1LC3C (PubMed:24290141). Interacts with TAB2 and TAB3 (PubMed:21976705). Interacts with C9orf72 (PubMed:27334615). Interacts with RB1CC1; this interaction is increased in the absence of TMEM39A (PubMed:31806350).
Phosphorylated by ULK1, ULK2 and mTOR. Phosphorylation status depends on nutrient-rich conditions; dephosphorylated during starvation or following treatment with rapamycin. ULK1-mediated phosphorylation of ATG13 at Ser-355 is required for efficient clearance of depolarized mitochondria.
The LIR motif (LC3-interacting region) is required for the interaction with the ATG8 family proteins GABARAP, GABARAPL, GABARAPL2, and MAP1LC3A.
Glycosylated at Asn-454. Glycosylation is crucial for recognition by the activin receptor type I/ACVR1.
Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes including cartilage and bone formation (PubMed:31019025). Also plays an important role in the regulation of HAMP/hepcidin expression and iron metabolism by acting as a ligand for hemojuvelin/HJV (PubMed:26582087). Also acts to promote expression of HAMP, potentially via the interaction with its receptor BMPR1A/ALK3 (PubMed:30097509, PubMed:31800957). Initiates the canonical BMP signaling cascade by associating with type I receptor ACVR1 and type II receptor ACVR2B (PubMed:18070108). In turn, ACVR1 propagates signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act as activators and repressors of transcription of target. Can also signal through non-canonical pathway such as TAZ-Hippo signaling cascade to modulate VEGF signaling by regulating VEGFR2 expression (PubMed:33021694).
Interacts with SOSTDC1 (By similarity). Interacts (when glycosylated) with type I receptor ACVR1; the interaction may induce HAMP expression (PubMed:31800957, PubMed:18070108). Interacts with type II receptor ACVR2B (PubMed:18070108). Interacts with Hemojuvelin/HJV (By similarity). Interacts with ERFE; the interaction inhibits BMP-induced transcription of HAMP (PubMed:30097509, PubMed:31800957). Interacts with BMPR1A/ALK3 (PubMed:31800957). Forms heterodimers with BMP2 in vitro; the heterodimer then binds to its receptor BMPR1A /ALK3 and may induce HAMP expression (PubMed:31800957).
Acts upstream of PAK1 to regulate the actin cytoskeleton, adhesion turnover and increase cell migration. Stimulates quiescent cells to reenter the cell cycle. Has no detectable GTPase activity but its high intrinsic guanine nucleotide exchange activity suggests it is constitutively GTP-bound. Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape.
Interacts with PAK3. Interacts with ARHGAP30 in a GTP-independent manner. In its GTP-loaded conformation, interacts with ARHGAP31. Interacts with PTK2B/PYK2.
Tyrosine phosphorylated by SRC in response to PTK2B/PYK2 activation.
Ubiquitously expressed in all tissues examined. Expressed at high levels in the stomach, small intestine, brain, skeletal muscle and placenta.
Expressed in thymus, prostate, testis, ovary, small intestine, colon, mucosa, colon and renal cancer tumors.
Homodimer (By similarity). Interacts with OFD1; the interaction is direct (PubMed:20835237). Interacts with FAM161A (PubMed:22940612). Interacts with RABEP2, ERC1 and CEP131 (PubMed:27224062).
Plays a role in the establishment of cell polarity and epithelial lumen formation (By similarity). Also plays an essential role in ciliogenesis and subsequent Hedgehog signaling pathway that requires the presence of intact primary cilia for pathway activation. Mechanistically, interacts with and mediates RABEP2 centrosomal localization which is critical for ciliogenesis (PubMed:27224062).
Phosphorylates Ins(1,3,4,5,6)P5 at position 2 to form Ins(1,2,3,4,5,6)P6 (InsP6 or phytate). InsP6 is involved in many processes such as mRNA export, non-homologous end-joining, endocytosis, ion channel regulation. It also protects cells from TNF-alpha-induced apoptosis.
The EXKPK motif is conserved in inositol-pentakisphosphate 2-kinases of both family 1 and 2.
Ubiquitously expressed, with high expression in heart, brain, testis and placenta.
Adapter protein that plays a role in intracellular signaling cascades triggered by activated receptor-type kinases. Plays a role in FGFR1 signaling. Probably involved in signaling by the epidermal growth factor receptor (EGFR) and the insulin receptor (INSR). Involved in the MET/HGF-signaling pathway (PubMed:29408807).
Identified in a complex containing FRS2, GRB2, GAB1, PIK3R1 and SOS1 (By similarity). Forms a tripartite complex containing GAB1, METTL13 and SPRY2 (PubMed:29408807). Within the complex interacts with METTL13 (PubMed:29408807). Interacts with GRB2 and with other SH2-containing proteins (PubMed:15010462). Interacts with phosphorylated LAT2 (PubMed:12486104). Interacts with PTPRJ (PubMed:12475979). Interacts (phosphorylated) with PTPN11 (PubMed:15010462). Interacts with HCK (PubMed:15010462).
Phosphorylated in response to FGFR1 activation. Phosphorylated on tyrosine residue(s) by the epidermal growth factor receptor (EGFR) and the insulin receptor (INSR). Tyrosine phosphorylation of GAB1 mediates interaction with several proteins that contain SH2 domains. Phosphorylated on tyrosine residues by HCK upon IL6 signaling.
Choline-specific phosphodiesterase that hydrolyzes sphingomyelin releasing the ceramide and phosphocholine and therefore is involved in sphingomyelin digestion, ceramide formation, and fatty acid (FA) absorption in the gastrointestinal tract (PubMed:12885774, PubMed:12671034, PubMed:15205117, PubMed:16255717, PubMed:28292932). Has also phospholipase C activity and can also cleave phosphocholine from palmitoyl lyso-phosphatidylcholine and platelet-activating factor (PAF) leading to its inactivation (PubMed:16255717, PubMed:12885774). Does not have nucleotide pyrophosphatase activity (PubMed:12885774). May promote cholesterol absorption by affecting the levels of sphingomyelin derived from either diet or endogenous sources, in the intestinal lumen (By similarity).
Decreased levels of alkaline sphingomyelin phosphodiesterase may be associated with colon cancer.
Detected in the colon (at protein level). Expressed in the duodenum, jejunum and liver and at low levels in the ileum. Expression was very low in the esophagus, stomach and colon.
Inhibited in a dose dependent manner by ATP, imidazole, orthovanadate and zinc ion. Not inhibited by ADP, AMP and EDTA.
N-glycosylated; required for activity and transport to the plasma membrane.
Down-regulated in gastric cancer tissue and in gastric cell lines of differentiated and poorly differentiated types.
Belongs to the Mrp/NBP35 ATP-binding proteins family. NUBP1/NBP35 subfamily.
Component of the cytosolic iron-sulfur (Fe/S) protein assembly (CIA) machinery (PubMed:18573874). Required for maturation of extramitochondrial Fe-S proteins (PubMed:18573874). The NUBP1-NUBP2 heterotetramer forms a Fe-S scaffold complex, mediating the de novo assembly of an Fe-S cluster and its transfer to target apoproteins (PubMed:18573874). Implicated in the regulation of centrosome duplication (By similarity). Negatively regulates cilium formation and structure (By similarity).
Heterotetramer of 2 NUBP1 and 2 NUBP2 chains (By similarity). Interacts with KIFC1 (By similarity). Interacts with NUBP2 (PubMed:18573874). Interacts with the BBS/CCT complex subunit CCT1 (By similarity).
Phosphatase that acts on lipids with a phosphoinositol headgroup (PubMed:11676921). Has phosphatase activity towards phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate (PubMed:11676921). May also dephosphorylate proteins phosphorylated on Ser, Thr, and Tyr residues (PubMed:10733931).
At a late stage of fiber differentiation.
(Microbial infection) Acts as a receptor for Epstein-Barr virus.
(Microbial infection) Interacts with Epstein-Barr virus gp350 protein.
Interacts (via Sushi domain 1 and 2) with C3 (PubMed:11387479, PubMed:21527715). Interacts with CD19 (PubMed:1702139). Part of a complex composed of CD19, CR2/CD21, CD81 and IFITM1/CD225 in the membrane of mature B-cells (PubMed:1383329). Interacts (via Sushi domain 1 and 2) with FCER2 (via the C-terminus).
Mature B-lymphocytes, T-lymphocytes, pharyngeal epithelial cells, astrocytes and follicular dendritic cells of the spleen.
Receptor for complement C3, for the Epstein-Barr virus on human B-cells and T-cells and for HNRNPU (PubMed:7753047). Participates in B lymphocytes activation (PubMed:7753047).
Belongs to the MICOS complex subunit Mic19 family. Metazoan Mic19 subfamily.
Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane. Has also been shown to function as a transcription factor which binds to the BAG1 promoter and represses BAG1 transcription. Plays an important role in the maintenance of the MICOS complex stability and the mitochondrial cristae morphology (PubMed:25781180).
Component of the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOOL/MIC27, IMMT/MIC60, APOO/MIC23/MIC26 and MICOS13/MIC13 (PubMed:21081504, PubMed:22114354, PubMed:22228767, PubMed:25997101). This complex was also known under the names MINOS or MitOS complex. The MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1 and MTX2 (together described as components of the mitochondrial outer membrane sorting assembly machinery (SAM) complex) and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9 (PubMed:21081504, PubMed:22114354, PubMed:22228767, PubMed:25997101). The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both membranes termed the mitochondrial intermembrane space bridging (MIB) complex. Interacts with HSPA1A/HSPA1B and OPA1, preferentially with the soluble OPA1 form (By similarity). Interacts with IMMT/MIC60.
Detected at low levels in brain, placenta, lung, liver, kidney and pancreas with increased levels in heart and skeletal muscle. Higher expression in primary lung cancers than in normal lung tissue.
Calcium sensor that plays a key role in processes such as endoplasmic reticulum (ER)-Golgi vesicular transport, endosomal biogenesis or membrane repair. Acts as an adapter that bridges unrelated proteins or stabilizes weak protein-protein complexes in response to calcium: calcium-binding triggers exposure of apolar surface, promoting interaction with different sets of proteins thanks to 3 different hydrophobic pockets, leading to translocation to membranes (PubMed:20691033, PubMed:25667979). Involved in ER-Golgi transport by promoting the association between PDCD6IP and TSG101, thereby bridging together the ESCRT-III and ESCRT-I complexes (PubMed:19520058). Together with PEF1, acts as calcium-dependent adapter for the BCR(KLHL12) complex, a complex involved in ER-Golgi transport by regulating the size of COPII coats (PubMed:27716508). In response to cytosolic calcium increase, the heterodimer formed with PEF1 interacts with, and bridges together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export, which is required for neural crest specification (PubMed:27716508). Involved in the regulation of the distribution and function of MCOLN1 in the endosomal pathway (PubMed:19864416). Promotes localization and polymerization of TFG at endoplasmic reticulum exit site (PubMed:27813252). Required for T-cell receptor-, Fas-, and glucocorticoid-induced apoptosis (By similarity). May mediate Ca(2+)-regulated signals along the death pathway: interaction with DAPK1 can accelerate apoptotic cell death by increasing caspase-3 activity (PubMed:16132846). Its role in apoptosis may however be indirect, as suggested by knockout experiments (By similarity). May inhibit KDR/VEGFR2-dependent angiogenesis; the function involves inhibition of VEGF-induced phosphorylation of the Akt signaling pathway (PubMed:21893193). In case of infection by HIV-1 virus, indirectly inhibits HIV-1 production by affecting viral Gag expression and distribution (PubMed:27784779).
EF-hand 1 (EF1) and 3 (EF3) are the high-affinity calcium-binding sites, while EF-hand 5 (EF5) binds calcium with low-affinity (PubMed:18940611, PubMed:20691033). A one-residue insertion in the EF5-binding loop prevents the glutamyl residue at the C-terminal end of the loop from serving as the canonical bidentate calcium ligand (PubMed:18940611, PubMed:20691033). EF5 acts as a high-affinity magnesium-binding domain instead (By similarity). Magnesium, may affect dimerization (By similarity). EF5 may bind either calcium or magnesium depending on the context (By similarity).
Has a lower Ca(2+) affinity than isoform 1 (By similarity).
Homodimer and heterodimer; heterodimerizes (via the EF-hand 5) with PEF1 (PubMed:11278427, PubMed:11883899, PubMed:27784779). Isoform 1 and isoform 2 self-associate; probably forming homodimers. Interacts with CPNE4 (via VWFA domain) (By similarity). Interacts with PDCD6IP; the interaction is calcium-dependent (PubMed:16957052, PubMed:18256029, PubMed:18940611, PubMed:20691033, PubMed:25667979). Interacts with RBM22 (PubMed:17045351). Interacts with PLSCR4 (PubMed:18256029). Interacts with ANXA7 and TSG101 (PubMed:18256029, PubMed:20691033). Interacts with DAPK1 (PubMed:16132846). Interacts with SEC31A; the interaction is calcium-dependent and promotes monoubiquitination of SEC31A (PubMed:16957052, PubMed:18256029, PubMed:27716508, PubMed:25667979). Interacts with ANXA11 (via N-terminus); the interaction is calcium-dependent (PubMed:11883939, PubMed:18256029, PubMed:18940611). Interacts with PLSCR3 (via N-terminus); the interaction is calcium-dependent (PubMed:18256029). Interacts with MCOLN1; the interaction is calcium-dependent (PubMed:19864416). Interacts with KDR; the interaction is calcium-dependent (PubMed:21893193). Interacts with HEBP2; the interaction is calcium-dependent (PubMed:27784779). Interacts with TFG (PubMed:27813252). Isoform 1: Interacts with SHISA5, leading to stabilize it (PubMed:17889823). Isoform 2: Does not interact with SHISA5 (PubMed:17889823). Isoform 2: Does not interact with PDCD6IP, TSG101, ANXA7 and ANXA11 (PubMed:18256029, PubMed:20691033).
Interacts with different set of proteins thanks to 3 different hydrophobic pockets (PubMed:20691033, PubMed:25667979). Hydrophobic pockets 1 and 2, which mediate interaction with PDCD6IP, are largely formed by residues from EF-hand 3 (EF3) to 5 (EF5), as well as by Tyr-180 (EF5) of a dimerizing molecule (Pocket 1) and from EF-hand (EF2) to 4 (EF4) (Pocket 2) (PubMed:20691033). Hydrophobic pocket 3, which mediates interaction with SEC31A, is mainly formed by residues from EF-hand 1 (EF1) to 3 (EF3) (PubMed:25667979).
Acetylation by CLOCK reduces its binding to glucocorticoid response elements and its transcriptional activity.
Acts as a dominant negative inhibitor of isoform Alpha (PubMed:7769088, PubMed:8621628, PubMed:20484466). Has intrinsic transcriptional activity independent of isoform Alpha when both isoforms are coexpressed (PubMed:19248771, PubMed:26711253). Loses this transcription modulator function on its own (PubMed:20484466). Has no hormone-binding activity (PubMed:8621628). May play a role in controlling glucose metabolism by maintaining insulin sensitivity (By similarity). Reduces hepatic gluconeogenesis through down-regulation of PEPCK in an isoform Alpha-dependent manner (PubMed:26711253). Directly regulates STAT1 expression in isoform Alpha-independent manner (PubMed:26711253).
Can up- or down-modulate aggregation and nuclear localization of expanded polyglutamine polypeptides derived from AR and HD through specific regulation of gene expression. Aggregation and nuclear localization of expanded polyglutamine proteins are regulated cellular processes that can be modulated by this receptor, a well-characterized transcriptional regulator.
Carriers of the 22-Glu-Lys-23 allele are relatively more resistant to the effects of GCs with respect to the sensitivity of the adrenal feedback mechanism than non-carriers, resulting in a better metabolic health profile. Carriers have a better survival than non-carriers, as well as lower serum CRP levels. The 22-Glu-Lys-23 polymorphism is associated with a sex-specific, beneficial body composition at young-adult age, as well as greater muscle strength in males.
Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain (PubMed:3841189). The ligand-binding domain is required for correct chromosome segregation during mitosis although ligand binding is not required (PubMed:25847991).
Encoded by exons 2-7 plus several basepairs from the subsequent intron region. Lacks the ligand binding domain. Accounts for up to 10-20% of mRNAs.
Has highest transcriptional activation activity of all isoforms created by alternative initiation (PubMed:15866175, PubMed:23820903). Has transcriptional repression activity (PubMed:23303127). Mediates glucocorticoid-induced apoptosis (PubMed:23303127, PubMed:23820903).
Has lower transcriptional activation activity than isoform Alpha. Exerts a dominant negative effect on isoform Alpha trans-repression mechanism (PubMed:20484466).
Has lowest transcriptional activation activity of all isoforms created by alternative initiation (PubMed:15866175, PubMed:23820903). Has transcriptional repression activity (PubMed:23303127).
Has transcriptional activation activity.
Has transcriptional activation and repression activity (PubMed:15866175, PubMed:19248771, PubMed:20484466, PubMed:23820903, PubMed:11435610, PubMed:15769988, PubMed:17635946, PubMed:19141540, PubMed:21664385). Mediates glucocorticoid-induced apoptosis (PubMed:23303127). Promotes accurate chromosome segregation during mitosis (PubMed:25847991). May act as a tumor suppressor (PubMed:25847991). May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic gene expression (By similarity).
Heteromultimeric cytoplasmic complex with HSP90AA1, HSPA1A/HSPA1B, and FKBP5 or another immunophilin such as PPID, STIP1, or the immunophilin homolog PPP5C (PubMed:21730050). Upon ligand binding FKBP5 dissociates from the complex and FKBP4 takes its place, thereby linking the complex to dynein and mediating transport to the nucleus, where the complex dissociates (By similarity). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Directly interacts with UNC45A (PubMed:16478993). Binds to DNA as a homodimer, and as heterodimer with NR3C2 or the retinoid X receptor. Binds STAT5A and STAT5B homodimers and heterodimers (By similarity). Interacts with NRIP1, POU2F1, POU2F2 and TRIM28 (By similarity). Interacts with several coactivator complexes, including the SMARCA4 complex, CREBBP/EP300, TADA2L (Ada complex) and p160 coactivators such as NCOA2 and NCOA6 (PubMed:10866662, PubMed:12151000, PubMed:12686538, PubMed:9154805, PubMed:9590696). Interaction with BAG1 inhibits transactivation (PubMed:10477749). Interacts with HEXIM1 and TGFB1I1 (PubMed:12415108, PubMed:15211577, PubMed:15941832). Interacts with NCOA1 (PubMed:9590696). Interacts with NCOA3, SMARCA4, SMARCC1, SMARCD1, and SMARCE1 (By similarity). Interacts with CLOCK, CRY1 and CRY2 in a ligand-dependent fashion (PubMed:19141540, PubMed:21980503, PubMed:22170608). Interacts with CIART (By similarity). Interacts with RWDD3 (By similarity). Interacts with UBE2I/UBC9 and this interaction is enhanced in the presence of RWDD3 (By similarity). Interacts with GRIP1 (PubMed:15769988, PubMed:17635946). Interacts with NR4A3 (via nuclear receptor DNA-binding domain), represses transcription activity of NR4A3 on the POMC promoter Nur response element (NurRE) (PubMed:15591535). Directly interacts with PNRC2 to attract and form a complex with UPF1 and DCP1A; the interaction leads to rapid mRNA degradation (PubMed:25775514). Interacts with GSK3B (PubMed:18838540). Interacts with FNIP1 and FNIP2 (PubMed:27353360). Interacts (via C-terminus) with HNRNPU (via C-terminus) (PubMed:9353307). Interacts with MCM3AP (PubMed:16914116). Interacts (via domain NR LBD) with HSP90AA1 and HSP90AB1 (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863). Interacts (via NR LBD domain) with ZNF764 (via KRAB domain); the interaction regulates transcription factor activity of NR3C1 by directing its actions toward certain biologic pathways (PubMed:28139699).
High constitutive expression by neutrophils may provide a mechanism by which these cells escape glucocorticoid-induced cell death and up-regulation by pro-inflammatory cytokines such as IL8 further enhances their survival in the presence of glucocorticoids during inflammation.
Increased proteasome-mediated degradation in response to glucocorticoids (PubMed:11555652). Isoform Alpha-B appears to be more susceptible to proteolytic degradation than isoform Alpha (PubMed:11435610).
Induced by TNF and becomes the predominant isoform which may lead to glucocorticoid resistance (at protein level).
Lacks exons 5, 6 and 7. Found in glucocorticoid-resistant myeloma patients.
More effective than isoform Alpha in transcriptional activation, but not repression activity.
Phosphorylated in the absence of hormone; becomes hyperphosphorylated in the presence of glucocorticoid. The Ser-203, Ser-226 and Ser-404-phosphorylated forms are mainly cytoplasmic, and the Ser-211-phosphorylated form is nuclear (PubMed:12000743, PubMed:18838540). Phosphorylation at Ser-211 increases transcriptional activity (PubMed:12000743, PubMed:18483179). Phosphorylation at Ser-203, Ser-226 and Ser-404 decreases signaling capacity (PubMed:12000743, PubMed:18483179, PubMed:18838540). Phosphorylation at Ser-404 may protect from glucocorticoid-induced apoptosis (PubMed:18838540). Phosphorylation at Ser-203 and Ser-211 is not required in regulation of chromosome segregation (PubMed:25847991). May be dephosphorylated by PPP5C, attenuates NR3C1 action (By similarity).
Produced by alternative initiation at Met-27 of isoform Alpha.
Produced by alternative initiation at Met-27 of isoform Beta.
Produced by alternative initiation at Met-316 of isoform Alpha.
Produced by alternative initiation at Met-331 of isoform Alpha.
Produced by alternative initiation at Met-336 of isoform Alpha.
Produced by alternative initiation at Met-86 of isoform Alpha.
Produced by alternative initiation at Met-90 of isoform Alpha.
Produced by alternative initiation at Met-98 of isoform Alpha.
Receptor for glucocorticoids (GC) (PubMed:27120390). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors (PubMed:28139699). Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Involved in chromatin remodeling (PubMed:9590696). Plays a role in rapid mRNA degradation by binding to the 5' UTR of target mRNAs and interacting with PNRC2 in a ligand-dependent manner which recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay (PubMed:25775514). Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth (By similarity).
Sumoylation at Lys-277 and Lys-293 negatively regulates its transcriptional activity (PubMed:12144530). Sumoylation at Lys-703 positively regulates its transcriptional activity in the presence of RWDD3 (By similarity). Sumoylation at Lys-277 and Lys-293 is dispensable whereas sumoylation at Lys-703 is critical for the stimulatory effect of RWDD3 on its transcriptional activity (By similarity). Heat shock increases sumoylation in a RWDD3-dependent manner (By similarity).
Ubiquitinated; restricts glucocorticoid-mediated transcriptional signaling.
Widely expressed including bone, stomach, lung, liver, colon, breast, ovary, pancreas and kidney (PubMed:25847991). In the heart, detected in left and right atria, left and right ventricles, aorta, apex, intraventricular septum, and atrioventricular node as well as whole adult and fetal heart (PubMed:10902803).
Widely expressed including brain, bone marrow, thymus, spleen, liver, kidney, pancreas, lung, fat, skeletal muscle, heart, placenta and blood leukocytes.
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Mediates the polyubiquitination and proteasomal degradation of CAMK1 leading to disruption of cyclin D1/CDK4 complex assembly which results in G1 cell cycle arrest in lung epithelia.
Component of the DCX(DTL) E3 ubiquitin ligase complex (also called CRL4(CDT2)), at least composed of CUL4 (CUL4A or CUL4B), DDB1, DTL/CDT2 and RBX1 (PubMed:16861906, PubMed:17085480, PubMed:16949367, PubMed:17041588, PubMed:18794347, PubMed:18794348, PubMed:23478441). Interacts with CDKN1A (PubMed:23213251). Interacts with DDB1 (PubMed:16949367, PubMed:23478445). Interacts with FBXO11; SCF(FBXWO11) controls DTL stability but DCX(DTL) does not control FBXO11 stability (PubMed:23478445, PubMed:23478441). Interacts with CRY1 (PubMed:26431207).
Expressed in all fetal tissues examined, included brain, lung, liver, and kidney. Protein levels peak at G1 and decrease through S-phase.
Expressed in placenta and testis, very low expression seen in skeletal muscle. Detected in all hematopoietic tissues examined, with highest expression in thymus and bone marrow. A low level detected in the spleen and lymph node, and barely detectable level in the peripheral leukocytes. RA treatment down-regulated the expression in NT2 cell.
Induced by TGF-beta, the up-regulation is immediate and transient.
Phosphorylated at Thr-464 by CDK1/Cyclin-B and CDK2/Cyclin-A but not by CDK2/Cyclin-E, MAPK1 or PLK1. Phosphorylation at Thr-464 inhibits the interaction with FBXO11 and decreases upon cell cycle exit induced by TGF-beta or serum starvation.
Substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control, DNA damage response and translesion DNA synthesis. The DCX(DTL) complex, also named CRL4(CDT2) complex, mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1), FBH1, KMT5A and SDE2 (PubMed:16861906, PubMed:16949367, PubMed:16964240, PubMed:17085480, PubMed:18703516, PubMed:18794347, PubMed:18794348, PubMed:19332548, PubMed:20129063, PubMed:23478441, PubMed:23478445, PubMed:23677613, PubMed:27906959). CDT1 degradation in response to DNA damage is necessary to ensure proper cell cycle regulation of DNA replication (PubMed:16861906, PubMed:16949367, PubMed:17085480). CDKN1A/p21(CIP1) degradation during S phase or following UV irradiation is essential to control replication licensing (PubMed:18794348, PubMed:19332548). KMT5A degradation is also important for a proper regulation of mechanisms such as TGF-beta signaling, cell cycle progression, DNA repair and cell migration (PubMed:23478445). Most substrates require their interaction with PCNA for their polyubiquitination: substrates interact with PCNA via their PIP-box, and those containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to their degradation. In undamaged proliferating cells, the DCX(DTL) complex also promotes the 'Lys-164' monoubiquitination of PCNA, thereby being involved in PCNA-dependent translesion DNA synthesis (PubMed:20129063, PubMed:23478441, PubMed:23478445, PubMed:23677613). The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1 (PubMed:26431207).
Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C). Autoubiquitinated through 'Lys-48'-polyubiquitin chains in a PCNA-independent reaction, allowing proteasomal turnover. Polyubiquitinated by SCF(FBXO11) when not phosphorylated, leading to its degradation. A tight regulation of the polyubiquitination by SCF(FBXO11) is involved in the control of different processes such as TGF-beta signaling, cell cycle progression and exit.
Catalyzes the final step of de novo phosphatidylcholine (PC) synthesis, i.e. the transfer of choline phosphate from CDP-choline to the free hydroxyl of a diacylglycerol (DAG), producing a PC. It thereby plays a central role in the formation and maintenance of vesicular membranes.
Highly expressed in testis, colon, small intestine, heart, prostate and spleen. Also detected in kidney, skeletal muscle, pancreas, leukocytes, ovary and thymus. Weakly expressed in the brain, placenta and lung. Overexpressed in cancerous breast epithelial cell lines.
Microtubule-binding protein which stabilizes dynamic microtubules by slowing growth and shrinkage at both plus and minus ends and serves as a sensor of microtubule damage, protecting microtubules from the microtubule-severing enzyme SPAST (PubMed:34970964). Induces microtubule branching which is mediated by the formation of long SSNA1 fibrils which guide microtubule protofilaments to split apart from the mother microtubule and form daughter microtubules (By similarity). Plays a role in axon outgrowth and branching (PubMed:25390646). Required for cell division (PubMed:25390646).
Self-associates to form fibrils (PubMed:22008182, PubMed:34970964). Also forms dimers as well as monomers (PubMed:22008182). Interacts with SPAST (PubMed:15269182, PubMed:25390646).
It is uncertain whether Met-1 or Met-28 is the initiator. Some orthologous sequences cannot be extended.
Expressed in a variety of tissues including brain, colon, gingiva, heart, kidney, liver, lung, placenta, small intestine, spleen and thymus.
TFIIA is a component of the transcription machinery of RNA polymerase II and plays an important role in transcriptional activation. TFIIA in a complex with TBP mediates transcriptional activity.
TFIIA is a heterodimer of the large unprocessed subunit 1 and a small subunit gamma. It was originally believed to be a heterotrimer of an alpha (p35), a beta (p19) and a gamma subunit (p12). TFIIA forms a complex with TBP.
The alpha and beta subunits are postranslationally produced from the precursor form by TASP1. The cleavage promotes proteasomal degradation.
Belongs to the Mediator complex subunit 26 family.
Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors.
Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with CEBPB (when not methylated)(PubMed:20111005).
Among the sulfation sites Tyr-174 is essential for binding of C3a anaphylatoxin.
Interacts with VGF-derived peptide TLQP-21 (By similarity).
Interacts with VGF-derived peptide TLQP-21.
Receptor for the chemotactic and inflammatory peptide anaphylatoxin C3a. This receptor stimulates chemotaxis, granule enzyme release and superoxide anion production.
Widely expressed in several differentiated hematopoietic cell lines, in the lung, spleen, ovary, placenta, small intestine, throughout the brain, heart, and endothelial cells. Mostly expressed in lymphoid tissues.
Expressed in brain in the thalamus, in fetal and adult lung and in placenta.
Ligand for members of the frizzled family of seven transmembrane receptors. Functions in the canonical Wnt signaling pathway that results in activation of transcription factors of the TCF/LEF family (PubMed:20018874). Functions as upstream regulator of FGF10 expression. Plays an important role in embryonic lung development. May contribute to embryonic brain development by regulating the proliferation of dopaminergic precursors and neurons (By similarity).
Expressed at higher level in brain and testis and at lower levels in heart, ovary, spleen and peripheral blood leukocytes. Up-regulated in 13 of 16 renal cell carcinoma samples examined. Up-regulated in colon carcinoma.
Probable large-conductance Ca(2+)-activated chloride channel. May play a role in Ca(2+) signal transduction. May be involved in cell proliferation and cell aggregation.
Involved in the regulation of endocytosis and in several stages of intracellular trafficking (PubMed:32513819). Together with SNX4, involved in autophagosome assembly (PubMed:32513819).
Enhancer of SUMO conjugation. Via its interaction with UBE2I/UBC9, increases SUMO conjugation to proteins by promoting the binding of E1 and E2 enzymes, thioester linkage between SUMO and UBE2I/UBC9 and transfer of SUMO to specific target proteins which include HIF1A, PIAS, NFKBIA, NR3C1 and TOP1. Isoform 1 and isoform 2 positively regulate the NF-kappa-B signaling pathway by enhancing the sumoylation of NF-kappa-B inhibitor alpha (NFKBIA), promoting its stabilization which consequently leads to an increased inhibition of NF-kappa-B transcriptional activity. Isoform 1 and isoform 2 negatively regulate the hypoxia-inducible factor-1 alpha (HIF1A) signaling pathway by increasing the sumoylation of HIF1A, promoting its stabilization, transcriptional activity and the expression of its target gene VEGFA during hypoxia. Isoform 2 promotes the sumoylation and transcriptional activity of the glucocorticoid receptor NR3C1 and enhances the interaction of SUMO1 and NR3C1 with UBE2I/UBC9. Has no effect on ubiquitination.
Isoform 1 and isoform 2 are expressed in glioma tumors (at protein level). Expressed in a wide number of tissues with highest expression in cerebellum, pituitary, heart, kidney, liver, stomach, pancreas, prostate and spleen. Low levels in thalamus, spinal cord, esophagus, thymus, lung and peripheral blood leukocytes. A higher level expression seen in pituitary tumors as compared to the pituitary gland.
Isoform 1 and isoform 2 interact with UBE2I/UBC9 (PubMed:17956732, PubMed:23469069, PubMed:25918163). Isoform 1 shows a greater interaction with NFKBIA and HIF1A as compared to isoform 2 (PubMed:17956732, PubMed:23469069). Isoform 2 interacts with NCOA2 and NR3C1 (PubMed:23508108).
The RWD domain is required for the sumoylation enhancement activity.
Lipid transporter that specifically mediates export of sphingosine-1-phosphate in red blood cells and platelets (PubMed:29045386). Sphingosine-1-phosphate is a signaling sphingolipid and its export from red blood cells into in the plasma is required for red blood cell morphology (By similarity). Sphingosine-1-phosphate export from platelets is required for platelet aggregation and thrombus formation (By similarity). Mediates the export of different sphingosine-1-phosphate (S1P) species, including S1P(d18:0) (sphinganine 1-phosphate), S1P (d18:1) (sphing-4-enine 1-phosphate) and S1P (d18:2) (sphinga-4E,14Z-dienine-1-phosphate) (Probable). Release of sphingosine-1-phosphate is facilitated by a proton gradient (By similarity). In contrast, cations, such as sodium, are not required to drive sphingosine-1-phosphate transport (Probable). In addition to export, also able to mediate S1P import (By similarity). Does not transport lysophosphatidylcholine (LPC) (Probable).
Deoxyglucose transport is inhibit by D-glucose, D-galactose and maltose (PubMed:8457197). Galactose transport is inhibited by D-glucose and maltose (PubMed:8457197).
Facilitative glucose transporter (PubMed:9477959, PubMed:26176916). Can also mediate the uptake of various other monosaccharides across the cell membrane (PubMed:9477959, PubMed:26176916). Mediates the uptake of glucose, 2-deoxyglucose, galactose, mannose, xylose and fucose, and probably also dehydroascorbate (PubMed:9477959, PubMed:26176916). Does not mediate fructose transport (PubMed:9477959, PubMed:26176916). Required for mesendoderm differentiation (By similarity).
Highly expressed in brain (PubMed:8457197). Expressed in many tissues.
Interacts with SMIM43; the interaction may promote SLC2A3-mediated glucose transport to meet the energy needs of mesendoderm differentiation.
Transport is mediated via a series of conformation changes, switching between a conformation where the substrate-binding cavity is accessible from the outside, and a another conformation where it is accessible from the cytoplasm.
(Microbial infection) Down-regulated by BCRF1/viral IL10.
(Microbial infection) Interacts with Epstein-Barr virus BNLF2a.
ABC transporter associated with antigen processing. In complex with TAP2 mediates unidirectional translocation of peptide antigens from cytosol to endoplasmic reticulum (ER) for loading onto MHC class I (MHCI) molecules (PubMed:25656091, PubMed:25377891). Uses the chemical energy of ATP to export peptides against the concentration gradient (PubMed:25377891). During the transport cycle alternates between 'inward-facing' state with peptide binding site facing the cytosol to 'outward-facing' state with peptide binding site facing the ER lumen. Peptide antigen binding to ATP-loaded TAP1-TAP2 induces a switch to hydrolysis-competent 'outward-facing' conformation ready for peptide loading onto nascent MHCI molecules. Subsequently ATP hydrolysis resets the transporter to the 'inward facing' state for a new cycle (PubMed:25377891, PubMed:25656091, PubMed:11274390). Typically transports intracellular peptide antigens of 8 to 13 amino acids that arise from cytosolic proteolysis via IFNG-induced immunoproteasome. Binds peptides with free N- and C-termini, the first three and the C-terminal residues being critical. Preferentially selects peptides having a highly hydrophobic residue at position 3 and hydrophobic or charged residues at the C-terminal anchor. Proline at position 2 has the most destabilizing effect (PubMed:7500034, PubMed:9256420, PubMed:11274390). As a component of the peptide loading complex (PLC), acts as a molecular scaffold essential for peptide-MHCI assembly and antigen presentation (PubMed:26611325, PubMed:1538751, PubMed:25377891).
Heterodimer of TAP1 and TAP2 (TAP1-TAP2) (PubMed:1538751). A component of the peptide loading complex (PLC), interacts via TAPBP with MHCI heterodimer; this interaction mediates peptide-MHCI assembly (PubMed:26611325). Recruits TAPBP in a 1:1 stoichiometry (PubMed:22638925). Interacts with classical MHCI such as HLA-A*02-B2M; this interaction is obligatory for the loading of peptide epitopes (PubMed:8805302, PubMed:8630735). Interacts with non-classical MHCI molecules including HLA-E-B2M and HLA-F-B2M as well as PLC component CALR before the peptide loading (PubMed:9427624, PubMed:10605026). Interacts with PSMB5 and PSMB8 (PubMed:15488952).
Highly expressed in professional APCs monocytes and dendritic cells as well as in lymphocyte subsets T cells, B cells and NK cells.
There are five common alleles; TAP1*01:01 (PSF1A), TAP1*02:01 (PSF1B), TAP1*03:01 (PSF1C), TAP1*01:04 and TAP1*x. The sequence of TAP1*01:01 is shown here.
Up-regulated by IFNG (PubMed:1946428). Down-regulated by IL10 (PubMed:9310490).
Involved in control of cellular proliferation. Onconcogenic modifier contributing to the tumor suppressor function of DNMT3B.
Consists of two domains: the transglutaminase substrate domain (cementoin moiety) and the elastase inhibitor domain. The transglutaminase substrate domain serves as an anchor to localize elafin covalently to specific sites on extracellular matrix proteins.
Neutrophil and pancreatic elastase-specific inhibitor of skin. It may prevent elastase-mediated tissue proteolysis. Has been shown to inhibit the alpha-4-beta-2/CHRNA2-CHRNB2 nicotinic acetylcholine receptor and to produce a weak inhibition on Kv11.1/KCNH2/ERG1 and on the transient receptor potential cation channel subfamily V member 1 (TRPV1) (PubMed:29483648).
Almost absent from liver, thymus and peripheral blood lymphocytes.
Interacts with TAMALIN (By similarity). Interacts with ARF6 (PubMed:23940353). Interacts with FRMD4A (By similarity). Interacts with FRMD4B (By similarity).
Promotes guanine-nucleotide exchange on ARF1 and ARF6. Promotes the activation of ARF factors through replacement of GDP with GTP. Plays a role in the epithelial polarization (By similarity).
Highly expressed in testis and ovary, and to a lesser extent in the lung, spleen and the heart (at protein level).
Plays a role in promoting the proliferation of synovial fibroblasts in response to pro-inflammatory stimuli.
Component of the SMG1C complex composed of SMG1, SMG8 and SMG9; the recruitment of SMG8 to SMG1 N-terminus induces a large conformational change in the SMG1 C-terminal head domain containing the catalytic domain (PubMed:33205750). Forms heterodimers with SMG9; this assembly form may represent a SMG1C intermediate form.
Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Is recruited by release factors to stalled ribosomes together with SMG1 and SMG9 (forming the SMG1C protein kinase complex) and, in the SMG1C complex, is required to mediate the recruitment of SMG1 to the ribosome:SURF complex and to suppress SMG1 kinase activity until the ribosome:SURF complex locates the exon junction complex (EJC). Acts as a regulator of kinase activity.
Ceruloplasmin is a blue, copper-binding (6-7 atoms per molecule) glycoprotein. It has ferroxidase activity oxidizing Fe(2+) to Fe(3+) without releasing radical oxygen species. It is involved in iron transport across the cell membrane. Provides Cu(2+) ions for the ascorbate-mediated deaminase degradation of the heparan sulfate chains of GPC1. May also play a role in fetal lung development or pulmonary antioxidant defense (By similarity).
Ceruloplasmin levels are decreased in Wilson disease, in which copper cannot be incorporated into ceruloplasmin in liver because of defects in the copper-transporting ATPase 2.
Efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with TCF3 and binds the E box (5'-CANNTG-3').
Involved in epithelial-mesenchymal interactions in kidney and lung morphogenesis that include epithelial differentiation and branching morphogenesis. May play a role in the specification or differentiation of one or more subsets of epicardial cell types.
Binds glycerophospholipids in a barrel-like domain and may play a role in cellular lipid transport (By similarity). Tethers the endoplasmic reticulum to the cell membrane and promotes the formation of appositions between the endoplasmic reticulum and the cell membrane.
The C2 domains mediate lipid and calcium binding. The N-terminal C2 domain binds calcium ions and is important for calcium-dependent lipid binding and interaction with membranes. Two calcium ions are bound at a high-affinity site and a third calcium ion is bound with lower affinity. May bind up to four calcium ions. In contrast, the second C2 domain apparently does not bind calcium (By similarity). The third C2 domain mediates interaction with membranes enriched in phosphatidylinositol 4,5-bisphosphate and is required for location at the cell membrane (PubMed:23791178).
The SMP-LTD domain is a barrel-like domain that binds glycerophospholipids in its interior (By similarity).
Widely expressed with high level in cerebellum and skin.
Polyubiquitinated by RNF128 with 'Lys-63'-linked chains, leading to proteasomal degradation.
Component of the axonemal radial spoke head which plays an important role in ciliary motility (PubMed:19200523). Essential for triplet radial spokes (RS1, RS2 and RS3) head assembly in the motile cilia (By similarity).
Expressed in trachea, lungs, and testes (PubMed:23993197). Very strong expression is detected in nasal brushings (PubMed:19200523).
Atypical Ras-like protein that acts as a potent regulator of NF-kappa-B activity by preventing the degradation of NF-kappa-B inhibitor beta (NFKBIB) by most signals, explaining why NFKBIB is more resistant to degradation. May act by blocking phosphorylation of NFKBIB and mediating cytoplasmic retention of p65/RELA NF-kappa-B subunit. It is unclear whether it acts as a GTPase. Both GTP- and GDP-bound forms block phosphorylation of NFKBIB.
In contrast to other members of the Ras family, the members of the KappaB-Ras subfamily do not contain the conserved Gly and Gln residues in positions 13 and 65, which are replaced by Leu residues, and are therefore similar to the constitutively active forms of oncogenic forms of Ras. This suggests that members of this family are clearly different from other small GTPases proteins.
Interacts with both NF-kappa-B inhibitor alpha (NFKBIA) and beta (NFKBIB) in vitro. However, it probably only interacts with NFKBIB in vivo. Forms a complex with NFKBIB and NF-kappa-B heterodimer (p50/NFKB1 and p65/RELA). Also interacts with c-Rel (REL).
Strong transcriptional activator (By similarity). Plays an important role in spermatogenesis; essential for the progression of meiotic prophase I in spermatocytes (By similarity).
Acts as component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. The recruitment of the CSC to the endosomal membrane involves RAB7A and SNX3. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX3-retromer mediates the retrograde transport of WLS distinct from the SNX-BAR retromer pathway. The SNX27-retromer is believed to be involved in endosome-to-plasma membrane trafficking and recycling of a broad spectrum of cargo proteins. The CSC seems to act as recruitment hub for other proteins, such as the WASH complex and TBC1D5. May be involved in retrograde transport of SORT1 but not of IGF2R. Acts redundantly with VSP26A in SNX-27 mediated endocytic recycling of SLC2A1/GLUT1 (By similarity).
Component of the heterotrimeric retromer cargo-selective complex (CSC), also described as vacuolar protein sorting VPS subcomplex (VPS,) formed by VPS26 (VPS26A or VPS26B), VPS29 and VPS35. The CSC has a highly elongated structure with VPS26 and VPS29 binding independently at opposite distal ends of VPS35 as central platform. The CSC is believed to associate with variable sorting nexins to form functionally distinct retromer complex variants. The originally described retromer complex (also called SNX-BAR retromer) is a pentamer containing the CSC and a heterodimeric membrane-deforming subcomplex formed between SNX1 or SNX2 and SNX5 or SNX6 (also called SNX-BAR subcomplex); the respective CSC and SNX-BAR subcomplexes associate with low affinity. The CSC associates with SNX3 to form a SNX3-retromer complex. The CSC associates with SNX27, the WASH complex and the SNX-BAR subcomplex to form the SNX27-retromer complex. Interacts with VPS29, VPS35, TBC1D5, GOLPH3, SNX27 (By similarity).
Acts as an adapter protein downstream of several growth factor receptors to promote cell proliferation, migration, and redistribution of actin fibers (PubMed:24216110). Specifically involved in INS/insulin signaling pathway by mediating MAPK1/ERK2-MAPK3/ERK1 activation and DNA synthesis (PubMed:24216110). Promotes insulin-mediated membrane ruffling (By similarity). In response to vasoconstrictor peptide EDN1, involved in the activation of RAP1 downstream of PTK2B via interaction with phosphorylated BCAR1 (PubMed:19086031). Inhibits cell migration and invasion via regulation of TGFB-mediated matrix digestion, actin filament rearrangement, and inhibition of invadopodia activity (By similarity). May inhibit TGFB-SMAD signaling, via facilitating BCAR1 and SMAD2 and/or SMAD3 interaction (By similarity). Regulates EGF-induced DNA synthesis (PubMed:18722344). Required for the maintenance of ocular lens morphology and structural integrity, potentially via regulation of focal adhesion complex signaling (By similarity). Acts upstream of PTPRA to regulate the localization of BCAR1 and PTPRA to focal adhesions, via regulation of SRC-mediated phosphorylation of PTPRA (By similarity). Positively regulates integrin-induced tyrosine phosphorylation of BCAR1 (By similarity). Acts as a guanine nucleotide exchange factor (GEF) for small GTPases RALA, RAP1A and RRAS (By similarity). However, in a contrasting study, lacks GEF activity towards RAP1 (PubMed:22081014).
Overexpression confers anti-estrogen resistance via RRAS-independent activation of the PI3K pathway, and activation of the cyclin D1 promoter in breast cancer cell lines (PubMed:9582273). Plays a role in insulin-mediated ERK activation and DNA synthesis in breast cancer cells (PubMed:24216110).
Part of a complex comprised of PTPRA, BCAR1, BCAR3 (via SH2 domain) and SRC; the formation of the complex is dependent on integrin mediated-tyrosine phosphorylation of PTPRA (PubMed:22801373). Within the complex, interacts (via SH2 domain) with PTPRA (when phosphorylated on 'Tyr-798') (PubMed:22801373). Interacts (via Ras-GEF domain) with BCAR1 (PubMed:18722344, PubMed:19086031, PubMed:22081014). Interacts (via Ras-GEF domain) with NEDD9 (PubMed:19103205). Interacts with PTK2/FAK1 (By similarity). Interacts with PTPN1. Interacts (via SH2 domain) with EGFR (when tyrosine-phosphorylated) (PubMed:18722344).
The Ras-GEF domain appears to adopt a closed conformation rendering it incapable of carrying out canonical exchange factor function, this closed conformation is probably required for interaction with BCAR1.
The SH2 domain mediates interaction with tyrosine-phosphorylated proteins (PubMed:18722344). However, not involved in the binding to phosphorylated BCAR1 (PubMed:18722344). Required for cell cycle progression in response to INS/insulin (PubMed:24216110). Required for regulation of EFR-induced DNA synthesis (PubMed:18722344).
The guanine nucleotide exchange factor (GEF) activity is controversial. One study showed GEF activity towards RALA, RAP1A and RRAS (By similarity). However, in another study, a construct containing only the Ras-GEF domain lacks GEF activity towards RAP1 (PubMed:22081014).
Ubiquitously expressed. Found in several cancer cell lines, but not in nonmalignant breast tissue.
Expressed in testis. Expressed exclusively at the connecting piece of the sperm.
Interacts with heparin with a high affinity.
Detected only in the testis and, to a lesser extent, in the prostate.
Autoproteolytically processed at the GPS domain; this cleavage modulates receptor activity. Additionally, furin is involved in the cleavage at another site, in the middle of the extracellular domain, generating a soluble fragment.
Detected in cerebrospinal fluid (at protein level) (PubMed:25326458). Strongly expressed in brain. Also detected in heart, thymus, skeletal muscle, and different cell lines.
Heterodimer of 2 chains generated by proteolytic processing; the large extracellular N-terminal fragment and the membrane-bound C-terminal fragment predominantly remain associated and non-covalently linked. Interacts with GABPB2 (By similarity). Interacts (via carboxy-terminus) with TAX1BP3 (PubMed:21787750). Interacts with GNAZ (PubMed:28891236). Interacts with SH3GL2 (PubMed:28891236).
Orphan G-protein coupled receptor involved in cell adhesion and probably in cell-cell interactions. Activates NFAT-signaling pathway, a transcription factor, via the G-protein GNAZ (PubMed:20367554, PubMed:28891236). Involved in angiogenesis inhibition (By similarity).
Receptor activity is regulated by proteolytic processing. The long N-terminal has a an inhibitory effect on the constitutive signaling activity. Removal of the N-terminal region induces an increase of the receptor activity.
Belongs to the CNF-like-inhibitor family.
During embryonic development, interferes with neural crest formation (By similarity). Inhibits AP2 transcriptional activity by interaction with its activation domain.
Interacts with TFAP2A; this interaction inhibits TFAP2A transcriptional activation.
Activated by growth factors and cytokine receptors through a tyrosine-kinase-dependent mechanism. Activated by RAS. IC87114 inhibits lipid kinase activity and is selective in cells at doses up to 5-10 uM. IC87114 blocks T-cell receptor signaling in naive and memory T-cells and reduces cytokine production by memory T-cells.
Autophosphorylation on Ser-1039 results in the almost complete inactivation of the lipid kinase activity.
Heterodimer of a catalytic subunit PIK3CD and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interacts with ERAS (By similarity). Interacts with HRAS.
IC87114 inhibitor reduces passive cutaneous anaphylaxis, attenuates allergic airway inflammation and hyperresponsiveness and allergen induced rhinitis response. Inhibitors may have therapeutic potential for the treatment of immune system-mediated diseases such as auto-immune diseases, inflammation and allergy (PubMed:20940048, PubMed:17290298).
In humans, the highest levels of expression are seen in peripheral blood mononuclear cells, spleen, and thymus, and low levels of expression in testes, uterus, colon, and small intestine but not in other tissues examined including prostate, heart, brain, and liver (PubMed:9235916). Isoform 2 is expressed in normal thymus, lung and spleen tissues, and is detected at low levels in normal lysates from colon and ovarian biopsies, at elevated levels in lysates from colorectal tumors and is abundantly expressed in some ovarian tumors (at protein level). Both isoform 1 and isoform 2 are widely expressed. Isoform 1 is expressed predominantly in leukocytes.
Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:9235916). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Plays a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Plays important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function. Isoform 2 may be involved in stabilizing total RAS levels, resulting in increased ERK phosphorylation and increased PI3K activity.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Caused by the simultaneous occurrence of homozygous mutations in PIK3CD and KNSTRN.
Abundantly expressed in smooth muscle. Low levels of expression in most other tissues. Within the brain, relatively high levels found in hippocampus and corpus callosum.
Belongs to the KCNMB (TC 8.A.14.1) family. KCNMB1 subfamily.
Genetic variation in KCNMB1 can influence the severity of diastolic hypertension (PubMed:15057310).
Interacts with KCNMA1 tetramer. There are probably 4 molecules of KCMNB1 per KCNMA1 tetramer.
Regulatory subunit of the calcium activated potassium KCNMA1 (maxiK) channel. Modulates the calcium sensitivity and gating kinetics of KCNMA1, thereby contributing to KCNMA1 channel diversity. Increases the apparent Ca(2+)/voltage sensitivity of the KCNMA1 channel. It also modifies KCNMA1 channel kinetics and alters its pharmacological properties. It slows down the activation and the deactivation kinetics of the channel. Acts as a negative regulator of smooth muscle contraction by enhancing the calcium sensitivity to KCNMA1. Its presence is also a requirement for internal binding of the KCNMA1 channel opener dehydrosoyasaponin I (DHS-1) triterpene glycoside and for external binding of the agonist hormone 17-beta-estradiol (E2). Increases the binding activity of charybdotoxin (CTX) toxin to KCNMA1 peptide blocker by increasing the CTX association rate and decreasing the dissociation rate.
Cardiac and slow-twitch skeletal muscles. Isoform 2 is expressed in striated muscle. Isoform 2 is specifically expressed at higher levels in patients with neuromuscular diseases, such as limb-girdle muscular dystrophy 2A (LGMD2A), Duchenne muscular dystrophy (DMD) and dermatomyositis (PubMed:24860983).
LIM zinc-binding domain 1 is required for self-association. LIM zinc-binding domain 1 and LIM zinc-binding domain 2 both are required for optimal actin-bundling activity (PubMed:24934443). LIM zinc-binding domain 1 mediates binding to MYOD1. LIM zinc-binding domain 2 mediates binding to SPTB (By similarity).
May play a role in early sarcomere organization. Overexpression in myotubes negatively regulates myotube differentiation. By association with isoform 1 and thus changing the CSRP3 isoform 1:CFL2 stoichiometry is proposed to down-regulate CFL2-mediated F-actin depolymerization.
Positive regulator of myogenesis. Acts as cofactor for myogenic bHLH transcription factors such as MYOD1, and probably MYOG and MYF6. Enhances the DNA-binding activity of the MYOD1:TCF3 isoform E47 complex and may promote formation of a functional MYOD1:TCF3 isoform E47:MEF2A complex involved in myogenesis (By similarity). Plays a crucial and specific role in the organization of cytosolic structures in cardiomyocytes. Could play a role in mechanical stretch sensing. May be a scaffold protein that promotes the assembly of interacting proteins at Z-line structures. It is essential for calcineurin anchorage to the Z line. Required for stress-induced calcineurin-NFAT activation (By similarity). The role in regulation of cytoskeleton dynamics by association with CFL2 is reported conflictingly: Shown to enhance CFL2-mediated F-actin depolymerization dependent on the CSRP3:CFL2 molecular ratio, and also shown to reduce the ability of CLF1 and CFL2 to enhance actin depolymerization (PubMed:19752190, PubMed:24934443). Proposed to contribute to the maintenance of muscle cell integrity through an actin-based mechanism. Can directly bind to actin filaments, cross-link actin filaments into bundles without polarity selectivity and protect them from dilution- and cofilin-mediated depolymerization; the function seems to involve its self-association (PubMed:24934443). In vitro can inhibit PKC/PRKCA activity (PubMed:27353086). Proposed to be involved in cardiac stress signaling by down-regulating excessive PKC/PRKCA signaling (By similarity).
Self-associates. Oligomeric in the cytoplasm and monomeric in the nucleus (By similarity). Homooligomers preferentially form along the actin cytoskeleton. Isoform 2 interacts with isoform 1 (PubMed:24934443, PubMed:24860983). Isoform 1 but not isoform 2 interacts with MYOD1 and MYOG. Isoform 1 interacts with TCAP, ACTN2 and NRAP. Isoform 2 interacts with TCAP and alpha-actinin (PubMed:24860983, PubMed:15582318, PubMed:15205937, PubMed:12507422). Interacts with LDHD. Interacts (via N-terminus)with GLRX3 (via C-terminus) and PPP3CA; GLRX3 and calcineurin compete for interaction with CSRP3. Interacts with MYF6 (By similarity). Interacts with CFL2; the stoichiometry influences F-actin depolymerization and possibly two molecules of CFL2 can interact with one molecule of CSRP3 resulting in the highest functional impact; the interaction is stronger with phosphorylated CFL2 (PubMed:19752190).
Apoptosis-inducing protein that modulates the tumor suppressor function of CDKN2A/p14ARF. Enhances the stability of CDKN2A/p14ARF protein by protecting it from degradation. May act as a tumor suppressor (PubMed:22094112).
Belongs to the TALE/TGIF homeobox family.
Binds to a retinoid X receptor (RXR) responsive element from the cellular retinol-binding protein II promoter (CRBPII-RXRE). Inhibits the 9-cis-retinoic acid-dependent RXR alpha transcription activation of the retinoic acid responsive element. Active transcriptional corepressor of SMAD2. Links the nodal signaling pathway to the bifurcation of the forebrain and the establishment of ventral midline structures. May participate in the transmission of nuclear signals during development and in the adult, as illustrated by the down-modulation of the RXR alpha activities.
Interacts with SMAD2 (PubMed:10835638). Interacts with CTBP, SMAD3 and HDAC1.
Involved in maintaining the homeostasis of cellular nucleotides by catalyzing the interconversion of nucleoside phosphates. Has both nucleoside monophosphate and diphosphate kinase activities. Catalyzes the phosphorylation of AMP, dAMP, CMP and dCMP with ATP as phosphate donor and of CMP with GTP as phosphate donor. Also catalyzes the production of ATP, CTP, GTP, UTP, dATP, dCTP, dGTP and TTP from the corresponding diphosphate substrates with either ATP or GTP as phosphate donor. Shows substrate preference of CDP > UDP > ADP > GDP > TDP.
Has no tyrosine-protein phosphatase activity at mild acidic conditions (pH 5.5). The in vivo relevance of the low PPase activity at acidic conditions (pH 4.5) is questioned. This catalytic activity seems to be affected by the replacement of a highly conserved residue in the tyrosine-protein phosphatase domain.
Highest levels in brain and pancreas (PubMed:8954911, PubMed:8798755). Lower levels in trachea, prostate, stomach and spinal cord (PubMed:8798755).
Plays a role in vesicle-mediated secretory processes. Required for normal accumulation of secretory vesicles in hippocampus, pituitary and pancreatic islets. Required for the accumulation of normal levels of insulin-containing vesicles and preventing their degradation. Plays a role in insulin secretion in response to glucose stimuli. Required for normal accumulation of the neurotransmitters norepinephrine, dopamine and serotonin in the brain. In females, but not in males, required for normal accumulation and secretion of pituitary hormones, such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (By similarity). Required to maintain normal levels of renin expression and renin release (By similarity). May regulate catalytic active protein-tyrosine phosphatases such as PTPRA through dimerization (By similarity). Has phosphatidylinositol phosphatase activity; the PIPase activity is involved in its ability to regulate insulin secretion. Can dephosphorylate phosphatidylinositol 4,5-biphosphate (PI(4,5)P2), phosphatidylinositol 5-phosphate and phosphatidylinositol 3-phosphate (By similarity). Regulates PI(4,5)P2 level in the plasma membrane and localization of cofilin at the plasma membrane and thus is indirectly involved in regulation of actin dynamics related to cell migration and metastasis; upon hydrolyzation of PI(4,5)P2 cofilin is released from the plasma membrane and acts in the cytoplasm in severing F-actin filaments (PubMed:26620550).
Self-associates. Interacts (via cytoplasmic domain) with PTPRN (via cytoplasmic domain). Interacts (precursor form) with CPE. Interacts with HAP1. Interacts with AP2A1 or AP2A2 and AP1G1; indicative for an association with adaptor protein complex 2 (AP-2) and adaptor protein complex 1 (AP-1) (By similarity). Interacts with AP2M1; indicative for an association with adaptor protein complex 2 (AP-2). Interacts with MYO5A (By similarity).
Subject to proteolytic cleavage at multiple sites.
The cytoplasmic domain appears to contain the autoantigenic epitopes.
The leucine-based sorting signal is proposed to function in trafficking at the plasma membrane.
The tyrosine-based internalization signal is proposed to function at the level of clathrin-mediated endocytosis and recycling.
Binds to WAS within the N-terminal region 170, at a site distinct from the CDC42-binding site.
Binds to WAS, profilin and actin. Binds to WASL (By similarity). Interacts with DBNL. Interacts with FNBP1L (via the SH3 domain) (PubMed:19798448).
Highly expressed in peripheral blood mononuclear cells, spleen, placenta, small intestine, colon and thymus. Lower expression in ovary, heart, brain, lung, liver, skeletal muscle, kidney, pancreas, prostate and testis.
Plays a role in the reorganization of the actin cytoskeleton. Contributes with NCK1 and GRB2 in the recruitment and activation of WASL. May participate in regulating the subcellular localization of WASL, resulting in the disassembly of stress fibers in favor of filopodia formation. Plays a role in the formation of cell ruffles (By similarity). Plays an important role in the intracellular motility of vaccinia virus by functioning as an adapter for recruiting WASL to vaccinia virus.
Recruited to PIP5K-induced vesicle surfaces in the absence of functional WASL.
Belongs to the glycogen debranching enzyme family.
Liver, kidney and lymphoblastoid cells express predominantly isoform 1; whereas muscle and heart express not only isoform 1, but also muscle-specific isoform mRNAs (isoforms 2, 3 and 4). Isoforms 5 and 6 are present in both liver and muscle.
Multifunctional enzyme acting as 1,4-alpha-D-glucan:1,4-alpha-D-glucan 4-alpha-D-glycosyltransferase and amylo-1,6-glucosidase in glycogen degradation.
The products of the mRNAs termed isoforms 1 to 4 are identical.
Involved in the post-translational conjugation of arginine to the N-terminal aspartate or glutamate of a protein. This arginylation is required for degradation of the protein via the ubiquitin pathway.
Involved in the post-translational conjugation of arginine to the N-terminal aspartate or glutamate of a protein. This arginylation is required for degradation of the protein via the ubiquitin pathway. Does not arginylate cysteine residues.
Monomer. Interacts with LIAT1; LIAT1 is not a substrate of ATE1, the interaction takes place in the cytoplasm and seems to increase ATE1 arginyltransferase activity.
Interacts with GRAP2 and GRB2 (PubMed:21179510). Interacts with UBAP1 (PubMed:21757351, PubMed:27839950). Interacts with CHMP4B (PubMed:18434552).
Plays a role in sorting of endocytic ubiquitinated cargos into multivesicular bodies (MVBs) via its interaction with the ESCRT-I complex (endosomal sorting complex required for transport I), and possibly also other ESCRT complexes (PubMed:18434552, PubMed:21757351). May act as a negative regulator of Ras-mediated mitogenic activity (PubMed:18434552). Plays a role in ciliogenesis (PubMed:20393563).
Has ADP-ribosyltransferase activity toward GLP1R.
Acts as a regulator of autophagy in response to S.aureus infection by promoting activation of LC3 (MAP1LC3A, MAP1LC3B or MAP1LC3C). Acts by interacting with ATG16L1, leading to promote a functional complex between LC3 and ATG16L1 and promoting LC3 lipidation and subsequent activation of autophagy (PubMed:27273576, PubMed:23376921). Modulates the O-glycosylation and complex N-glycosylation steps occurring during the Golgi maturation of several proteins such as APP, BACE1, SEAP or PRNP (PubMed:20427278). Inhibits APP transport to the cell surface and further shedding (PubMed:20427278).
Interacts with ATG16L1 (via WD repeats).
The ATG16L1-binding motif mediates interaction with ATG16L1 and promotes autophagy.
Acts as a transcriptional repressor. Involved in the early stages of mesenchymal stem cell (MSC) osteogenic differentiation. Is a regulator of podocyte gene expression during primary glomerula disease. Binds to promoter DNA.
Homodimer (via homeobox domain 1) (PubMed:12659632, PubMed:14659886). Heterodimer with ZHX1 (via homeobox domain 1) (PubMed:12659632). Heterodimer with ZHX2 (via homeobox domain 1) (PubMed:14659886). Heterodimerization with ZHX1 is a prerequisite for repressor activity (PubMed:12659632). Interacts with NFYA (PubMed:12659632).
Up-regulated during osteogenic differentiation of mesenchymal stem cells.
Widely expressed. High expression in kidney. Expressed during osteogenic differentiation.
5,6-dichloro-1-b-D-ribofuranosylbenzimidazole (DRB) inhibits autophosphorylation. TG003 inhibits its kinase activity and affects the regulation of alternative splicing mediated by phosphorylation of SR proteins (By similarity).
Autophosphorylates on all three types of residues. Phosphorylation on Ser-34 and Thr-127 by AKT1 is induced by ionizing radiation or insulin. Phosphorylation plays a critical role in cell proliferation following low dose radiation and prevents cell death following high dose radiation. Phosphorylation at Thr-344 by PKB/AKT2 induces its kinase activity which is required for its stability. The phosphorylation status at Ser-142 influences its subnuclear localization; inhibition of phosphorylation at Ser-142 results in accumulation in the nuclear speckle.
Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Acts as a suppressor of hepatic gluconeogenesis and glucose output by repressing PPARGC1A transcriptional activity on gluconeogenic genes via its phosphorylation. Phosphorylates PPP2R5B thereby stimulating the assembly of PP2A phosphatase with the PPP2R5B-AKT1 complex leading to dephosphorylation of AKT1. Phosphorylates: PTPN1, SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Phosphorylates PAGE4 at several serine and threonine residues and this phosphorylation attenuates the ability of PAGE4 to potentiate the transcriptional activator activity of JUN (PubMed:28289210).
Endothelial cells (PubMed:19168442). Expressed in androgen-dependent prostate cancer cells (PubMed:28289210).
Interacts with RBMX. Interacts with AKT1 and UBL5.
Interacts with RAB8A, RAB10, RAB13 and RAB15 (in their GTP-bound forms); at least in case of RAB8A can bind 2 molecules of RAB8A simultaneously; ternary complex formation of RAB8A, RAB13 and EHBP1L1 is possible.
May act as Rab effector protein and play a role in vesicle trafficking.
Active at low pH (under pH 4.6): proton channel activity is activated by luminal side protons (PubMed:35750034). Polyunsaturated fatty acids, such as arachidonic acid, also activate the channel activity (PubMed:35750034). Proton channel activity is directly inhibited by LAMP1 or LAMP2, facilitating lysosomal acidification (PubMed:37390818). Channel activity is activated following interaction with AKT (AKT1, AKT2 or AKT3): interaction promotes activation from closed to an open state (PubMed:33505021). Activation by AKT is independent of AKT serine/threonine-protein kinase activity (PubMed:33505021).
Composed of two modules of six transmembranes, forming a homodimer with a tetrameric architecture (PubMed:28723891, PubMed:32228865). The six transmembrane regions of each module are tightly packed within each subunit without undergoing domain swapping (PubMed:32228865). Forms a central ion-conduction pore lined by the side chains of the pore-lining helices (PubMed:32228865). Conserved isoleucine residues (Ile-46 in the first module and Ile-271 in the second module) in the center of the pore serve as the gate in the closed conformation (PubMed:32228865). In the widened channel in the open conformation, Ser-45 and Ile-46 in the first module (and Thr-274 and Ile-271 in the second module), establish a constriction essential for potassium selectivity (PubMed:32228865).
Disease susceptibility may be associated with variants affecting the gene represented in this entry. TMEM175 defects result in unstable lysosomal pH, leading to decreased lysosomal catalytic activity, decreased glucocerebrosidase activity, impaired autophagosome clearance by the lysosome and decreased mitochondrial respiration (PubMed:28193887).
Homodimer (PubMed:28723891, PubMed:32228865, PubMed:35608336). Interacts with AKT (AKT1, AKT2 or AKT3); leading to formation of the lysoK(GF) complex, which activates the channel (PubMed:33505021). Interacts with LAMP1; inhibiting the proton channel activity of TMEM175 (PubMed:37390818). Interacts with LAMP2; inhibiting the proton channel activity of TMEM175 (PubMed:37390818).
Proton-activated proton channel that catalyzes proton efflux from endosomes and lysosomes to maintain a steady-state pH (PubMed:35750034, PubMed:35333573, PubMed:37390818). Activated at low pH (under pH 4.6) by luminal side protons: selectively mediates lysosomal proton release from lysosomes, eliciting a proton leak that balances V-ATPase activity to maintain pH homeostasis (PubMed:35750034). Regulation of lumenal pH stability is required for autophagosome-lysosome fusion (PubMed:26317472, PubMed:32267231). May also act as a potassium channel at higher pH, regulating potassium conductance in endosomes and lysosomes (PubMed:26317472, PubMed:28723891, PubMed:32228865, PubMed:32267231, PubMed:33505021). The potassium channel activity is however unclear as it was tested in non-physiological conditions for a lysosomal channel (PubMed:35750034). Constitutes the pore-forming subunit of the lysoK(GF) complex, a complex activated by extracellular growth factors (PubMed:33505021). The lysoK(GF) complex is composed of TMEM175 and AKT (AKT1, AKT2 or AKT3), a major target of growth factor receptors: in the complex, TMEM175 channel is opened by conformational changes by AKT, leading to its activation (PubMed:33505021). The lysoK(GF) complex is required to protect neurons against stress-induced damage (PubMed:33505021).
The potassium channel activity in endosomes and lysosomes is unclear in vivo (PubMed:35750034). Potassium transport was initially measured with a luminal side pH above 7.0, which is non-physiological for lysosomal channels (PubMed:26317472, PubMed:28723891, PubMed:32228865, PubMed:32267231, PubMed:33505021). Under the normal lysosomal pH (4.5- 5.0), TMEM175 is much more permeable to protons than to potassium or sodium (PubMed:35750034).
Belongs to the cyclophilin-type PPIase family. PPIase B subfamily.
Interacts with DYM. Interacts with CALR, CLGN and CANX. Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX (PubMed:12475965).
PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding.
Acyltransferase required to remodel newly synthesized phospholipid cardiolipin (1',3'-bis-[1,2-diacyl-sn-glycero-3-phospho]-glycerol or CL), a key component of the mitochondrial inner membrane, with tissue specific acyl chains necessary for adequate mitochondrial function (PubMed:12930833, PubMed:19700766, PubMed:19164547, PubMed:26908608, PubMed:33096711). Its role in cellular physiology is to improve mitochondrial performance (PubMed:32234310). CL is critical for the coassembly of lipids and proteins in mitochondrial membranes, for instance, remodeling of the acyl groups of CL in the mitochondrial inner membrane affects the assembly and stability of respiratory chain complex IV and its supercomplex forms (By similarity). Catalyzes the transacylation between phospholipids and lysophospholipids, with the highest rate being between phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine or PC) and CL. Catalyzes both 1-acyl-sn-glycero-3-phosphocholine (lysophosphatidylcholine or LPC) reacylation and PC-CL transacylation, that means, it exchanges acyl groups between CL and PC by a combination of forward and reverse transacylations. Also catalyzes transacylations between other phospholipids such as phosphatidylethanolamine (1,2-diacyl-sn-glycero-3-phosphoethanolamine or PE) and CL, between PC and PE, and between PC and phosphatidate (1,2-diacyl-sn-glycero-3-phosphate or PA), although at lower rate. Not regiospecific, it transfers acyl groups into any of the sn-1 and sn-2 positions of the monolysocardiolipin (MLCL), which is an important prerequisite for uniformity and symmetry in CL acyl distribution. Cannot transacylate dilysocardiolipin (DLCL), thus, the role of MLCL is limited to that of an acyl acceptor. CoA-independent, it can reshuffle molecular species within a single phospholipid class. Redistributes fatty acids between MLCL, CL, and other lipids, which prolongs the half-life of CL. Its action is completely reversible, which allows for cyclic changes, such as fission and fusion or bending and flattening of the membrane. Hence, by contributing to the flexibility of the lipid composition, it plays an important role in the dynamics of mitochondria membranes. Essential for the final stage of spermatogenesis, spermatid individualization (By similarity). Required for the initiation of mitophagy (PubMed:33096711). Required to ensure progression of spermatocytes through meiosis (By similarity). Exon 7 of human tafazzin is essential for catalysis (PubMed:19700766).
Acyltransferase which is required to remodel newly synthesized phospholipid cardiolipin, a key component of the mitochondrial inner membrane. Required for the initiation of mitophagy. Required to ensure progression of spermatocytes through meiosis.
Associates with multiple protein complexes.
Catalyzes the transacylation between lysophosphatidate (such as 1-acyl-sn-glycero-3-phosphate) and phosphatidylglycerol (1,2-diacyl-sn-glycero-3-phospho-(1'-sn-glycerol)) (PubMed:19700766). Contributes to cardiolipin (1',3'-bis-[1,2-diacyl-sn-glycero-3-phospho]-glycerol or CL) remodeling (PubMed:12930833, PubMed:19700766).
Catalyzes the transacylation between lysophospholipids and phospholipids, and plays a fundamental role in cardiolipin (1',3'-bis-[1,2-diacyl-sn-glycero-3-phospho]-glycerol or CL) metabolism and remodeling.
High levels in cardiac and skeletal muscle. Up to 10 isoforms can be present in different amounts in different tissues. Most isoforms are ubiquitous. Isoforms that lack the N-terminus are found in leukocytes and fibroblasts, but not in heart and skeletal muscle. Some forms appear restricted to cardiac and skeletal muscle or to leukocytes.
The enzyme was named after a masochistic character Tafazzi, once popular on Italian television, apparently due to the difficulty encountered for its identification and characterization.
(Microbial infection) Binds M.pneumoniae CARDS toxin, probably serves as one receptor for this pathogen. When ANXA2 is down-regulated by siRNA, less toxin binds to human cells and less vacuolization (a symptom of M.pneumoniae infection) is seen.
(Microbial infection) Interacts with M.pneumoniae CARDS toxin; CARDS probably uses this protein as a receptor. A portion of internalized CARDS remains associated with intracellular annexin 2.
(Microbial infection) Interacts with human cytomegalovirus (HCMV).
Calcium-regulated membrane-binding protein whose affinity for calcium is greatly enhanced by anionic phospholipids. It binds two calcium ions with high affinity. May be involved in heat-stress response. Inhibits PCSK9-enhanced LDLR degradation, probably reduces PCSK9 protein levels via a translational mechanism but also competes with LDLR for binding with PCSK9 (PubMed:18799458, PubMed:24808179, PubMed:22848640).
Heterotetramer containing 2 light chains of S100A10/p11 and 2 heavy chains of ANXA2/p36 (By similarity). Interacts with ATP1B1 (By similarity). Interacts with DYSF (By similarity). Interacts with COCH (PubMed:21886777). Interacts (via repeat Annexin 1) with PCSK9 (via the C-terminal domain); the interaction inhibits the degradation of LDLR (PubMed:18799458). Interacts with CEACAM1 (via the cytoplasmic domain); this interaction is regulated by phosphorylation of CEACAM1 (PubMed:14522961). Interacts with APPL2 and APPL1; targets APPL2 to endosomes and acting in parallel to RAB5A (By similarity). Interacts with S100A4 (PubMed:28669632). May interact with UBAP2 (PubMed:27121050).
Increased expression of ANXA2 is associated with hepatocellular carcinoma tumor progression.
It may cross-link plasma membrane phospholipids with actin and the cytoskeleton and be involved with exocytosis.
Phosphorylation of Tyr-24 enhances heat stress-induced translocation to the cell surface.
Component of the SWI5-SFR1 complex, a complex required for double-strand break repair via homologous recombination (PubMed:21252223). Acts as a transcriptional modulator for ESR1 (PubMed:23874500).
Component of the SWI5-SFR1 complex. Interacts with RAD51; the interaction is weak (PubMed:21252223). Interacts with ESR1 in the ligand-independent and ligand-dependent manner (PubMed:23874500).
High levels in amygdala, corpus callosum, hippocampus and subthalamic nucleus. Also detectable in caudate nucleus, hypothalamus and substantia nigra.
Receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is PYY > NPY > PYY (3-36) > NPY (2-36) > [Ile-31, Gln-34] PP > [Leu-31, Pro-34] NPY > PP, [Pro-34] PYY and NPY free acid.
Expressed at highest levels in cartilage, bone (osteosarcoma) and gut (small intestine and colon), whereas moderate expression is seen in trachea and brain. Expressed in visceral mesoderm and embryonic skeleton.
Transcriptional repressor that acts as a negative regulator of chondrocyte maturation. PLays a role in distal stomach development; required for proper antral-pyloric morphogenesis and development of antral-type epithelium. In concert with GSC, defines the structural components of the middle ear; required for tympanic ring and gonium development and in the regulation of the width of the malleus (By similarity).
In fetal tissues, highly expressed in brain, detectable in lung and liver, but not in kidney. In adult tissues, expressed ubiquitously in the brain, detectable in the heart, liver, spleen, thymus, prostate, testis, ovary, small intestine and colon. The type A isoforms seem to be expressed predominantly in fetal brain whereas type B isoforms are expressed abundantly in both fetal and adult brain.
Probable kinase that may be involved in a calcium-signaling pathway controlling neuronal migration in the developing brain. May also participate in functions of the mature nervous system.
Catalyzes the phosphorylation of the ketose sugar fructose to fructose-1-phosphate.
More widely distributed but with a low expression level. KM=7 mM for D-fructose (at 25 degrees Celsius). KM=036 mM for Mg-ATP (at 25 degrees Celsius). kcat is 6.9 sec(-1).
Most abundant in liver, kidney, gut, spleen and pancreas. Low levels also found in adrenal, muscle, brain and eye.
A short soluble form is also released from the membrane by proteolysis (PubMed:26876177). The sIL11RA is formed either by limited proteolysis of membrane-bound receptors, a process referred to as ectodomain shedding, or directly secreted from the cells after alternative mRNA splicing (PubMed:26876177). mIL11RA is cleaved by the proteases ADAM10, ELANE and PRTN3 (PubMed:26876177).
Expressed in a number of cell lines, including the myelogenous leukemia cell line K-562, the megakaryocytic leukemia cell line M-07e, the erythroleukemia cell line TF-1, and the osteosarcoma cell lines, MG-63 and SaOS-2 (PubMed:7670098). Also expressed in normal and malignant prostate epithelial cell lines. Expression levels are increased in prostate carcinoma.
On IL11 binding, forms a multimer complex with IL6ST/gp130.
Receptor for interleukin-11 (IL11). The receptor systems for IL6, LIF, OSM, CNTF, IL11 and CT1 can utilize IL6ST for initiating signal transmission. The IL11/IL11RA/IL6ST complex may be involved in the control of proliferation and/or differentiation of skeletogenic progenitor or other mesenchymal cells (Probable). Essential for the normal development of craniofacial bones and teeth. Restricts suture fusion and tooth number.
Soluble form of IL11 receptor (sIL11RA) that acts as an agonist of IL11 activity (PubMed:30279168, PubMed:26876177). The IL11:sIL11RA complex binds to IL6ST/gp130 on cell surfaces and induces signaling also on cells that do not express membrane-bound IL11RA in a process called IL11 trans-signaling (PubMed:30279168, PubMed:26876177).
Plays a role in the fasting response, glucose homeostasis, lipolysis and lipogenesis. Can stimulate cell proliferation (in vitro). May be involved in hair development.
Activated by N-ethylmaleimide (NEM). Inhibited by furosemide, DIDS and bumetanide. The inhibition is much stronger in the presence of 50 mM K(+) in the uptake medium. Inhibited by DIOA. Inhibited by WNK3.
Detected in muscle, brain, lung, heart and kidney.
Homomultimer and heteromultimer with other K-Cl cotransporters.
Mediates electroneutral potassium-chloride cotransport when activated by cell swelling (PubMed:10913127). May mediate K(+) uptake into Deiters' cells in the cochlea and contribute to K(+) recycling in the inner ear. Important for the survival of cochlear outer and inner hair cells and the maintenance of the organ of Corti. May be required for basolateral Cl(-) extrusion in the kidney and contribute to renal acidification (By similarity).
Chromosomal aberrations involving MSI2 may contribute to disease progression in chronic myeloid leukemia. Translocation t(7;17)(p15;q23) with HOXA9; translocation t(7;17)(q32-34;q23).
RNA binding protein that regulates the expression of target mRNAs at the translation level. May play a role in the proliferation and maintenance of stem cells in the central nervous system (By similarity).
Up-regulated in astrocytes after brain injury.
May play a role in mitochondrial aerobic respiration essentially in the testis. Can also promote mitochondrial fission (By similarity).
Binds DNA as a homodimer and as a heterodimer (PubMed:1741402). Can form stable heterodimers with CEBPB (PubMed:1741402). Can form stable heterodimers with CEBPA and CEBPE. Directly interacts with SPI1/PU.1; this interaction does not affect DNA-binding properties of each partner. Interacts with PRDM16.
Transcription activator that recognizes two different DNA motifs: the CCAAT homology common to many promoters and the enhanced core homology common to many enhancers (PubMed:16397300). Important transcription factor regulating the expression of genes involved in immune and inflammatory responses (PubMed:1741402, PubMed:16397300). Transcriptional activator that enhances IL6 transcription alone and as heterodimer with CEBPB (PubMed:1741402).
The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1.
Component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into extramitochondrial Fe/S proteins. Seems to negatively regulate the level of HIF1A expression, although this effect could be indirect.
External component of the CIA complex (PubMed:22678361, PubMed:22678362, PubMed:23585563). In the CIA complex, interacts directly with CIAO1 and MMS19 (PubMed:23585563).
Mainly expressed in brain although also detected in other tissues like heart and skeletal muscle. Isoform 1 and isoform 2 are specifically expressed in neuronal tissues. Isoform 3 and isoform 4 are expressed in non-neuronal tissues. Isoform 5 and isoform 6 are truncated forms expressed in non-neuronal tissues.
Monomer. Interacts with NOVA1; the interaction is direct. Identified in a mRNP complex, at least composed of DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1. Part of a ternary complex containing KHSRP and HNRPH1 (PubMed:11003644, PubMed:19029303). Interacts with NOVA2; the interaction is direct (By similarity).
RNA-binding protein which binds to intronic polypyrimidine tracts and mediates negative regulation of exons splicing. May antagonize in a tissue-specific manner the ability of NOVA1 to activate exon selection. In addition to its function in pre-mRNA splicing, plays also a role in the regulation of translation.
Belongs to the eukaryotic mitochondrial porin family.
Consists mainly of a membrane-spanning beta-barrel formed by 19 beta-strands (PubMed:18832158, PubMed:18755977). The helical N-terminus folds back into the pore opening and plays a role in voltage-gated channel activity (PubMed:18832158, PubMed:18755977).
Expressed in erythrocytes (at protein level) (PubMed:27641616). Expressed in heart, liver and skeletal muscle (PubMed:8420959).
Forms a channel through the mitochondrial outer membrane and also the plasma membrane. The channel at the outer mitochondrial membrane allows diffusion of small hydrophilic molecules; in the plasma membrane it is involved in cell volume regulation and apoptosis. It adopts an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV. The open state has a weak anion selectivity whereas the closed state is cation-selective (PubMed:11845315, PubMed:18755977, PubMed:20230784, PubMed:8420959). Binds various signaling molecules, including the sphingolipid ceramide, the phospholipid phosphatidylcholine, and the sterol cholesterol (PubMed:31015432). In depolarized mitochondria, acts downstream of PRKN and PINK1 to promote mitophagy or prevent apoptosis; polyubiquitination by PRKN promotes mitophagy, while monoubiquitination by PRKN decreases mitochondrial calcium influx which ultimately inhibits apoptosis (PubMed:32047033). May participate in the formation of the permeability transition pore complex (PTPC) responsible for the release of mitochondrial products that triggers apoptosis (PubMed:15033708, PubMed:25296756). May mediate ATP export from cells (PubMed:30061676).
Homodimer and homotrimer; in response to cyclic AMP or calcium (PubMed:30061676). Interacts with hexokinases including HK1 (PubMed:8420959, PubMed:22304920). The HK1-VDAC1 complex interacts with ATF2 (PubMed:22304920). Interacts with BCL2L1 (PubMed:18755977, PubMed:25296756). Interacts with BAK1 (PubMed:25296756). Interacts with RTL10/BOP (via BH3 domain) (PubMed:23055042). Interacts with amyloid-beta and APP; induces VDAC1 dephosphorylation (PubMed:25168729). Component of the mitochondrial permeability transition pore complex (mPTPC), at least composed of SPG7, VDAC1 and PPIF (PubMed:26387735). Interacts with SPG7, NIPSNAP2 and SLC25A30 (PubMed:26387735). Interacts with TMEM41B (PubMed:30352685). Interacts with BCAP31 (PubMed:31206022).
Phosphorylation at Ser-193 by NEK1 promotes the open conformational state preventing excessive mitochondrial membrane permeability and subsequent apoptotic cell death after injury. Phosphorylation by the AKT-GSK3B axis stabilizes the protein probably by preventing ubiquitin-mediated proteasomal degradation.
Ubiquitinated (PubMed:25621951, PubMed:32047033). Undergoes monoubiquitination and polyubiquitination by PRKN; monoubiquitination at Lys-274 inhibits apoptosis, whereas polyubiquitination leads to its degradation and promotes mitophagy (PubMed:25621951, PubMed:32047033). Deubiquitinated by USP30 (PubMed:25621951).
Belongs to the eukaryotic cobalamin transport proteins family.
Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum. After interaction with CUBN, the CBLIF-cobalamin complex is internalized via receptor-mediated endocytosis.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRQ sub-subfamily.
Generally pentameric. This subunit coassembles with alpha-2, beta-1 and gamma-1.
May play a role in the apoptotic pathway or cell-cycle regulation induced by p53/TP53 after DNA damage.
Acts as a transcriptional repressor. Inhibits interleukin-2 (IL-2) gene expression. Enhances or represses the promoter activity of the ATP1A1 gene depending on the quantity of cDNA and on the cell type. Represses E-cadherin promoter and induces an epithelial-mesenchymal transition (EMT) by recruiting SMARCA4/BRG1. Represses BCL6 transcription in the presence of the corepressor CTBP1. Positively regulates neuronal differentiation. Represses RCOR1 transcription activation during neurogenesis. Represses transcription by binding to the E box (5'-CANNTG-3'). In the absence of TGFB1, acts as a repressor of COL1A2 transcription via binding to the E-box in the upstream enhancer region (By similarity).
Colocalizes with SMARCA4/BRG1 in E-cadherin-negative cells from established lines, and stroma of normal colon as well as in de-differentiated epithelial cells at the invasion front of colorectal carcinomas (at protein level). Expressed in heart and skeletal muscle, but not in liver, spleen, or pancreas.
Interacts (via N-terminus) with SMARCA4/BRG1.
Regulator of the canonical Wnt signaling pathway. Acts by specifically binding phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), translocating to the cell membrane (By similarity).
Belongs to the U1 small nuclear ribonucleoprotein C family.
Component of the U1 snRNP (PubMed:2136774). The U1 snRNP is composed of the U1 snRNA and the 7 core Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP, and at least 3 U1 snRNP-specific proteins SNRNP70/U1-70K, SNRPA/U1-A and SNRPC/U1-C. SNRPC/U1-C interacts with U1 snRNA and the 5' splice-site region of the pre-mRNA. Interacts (via N-terminus) with TIA1 (via C-terminus); thereby promoting spliceosomal U1 snRNP recruitment to 5' splice sites (PubMed:12486009).
Component of the spliceosomal U1 snRNP, which is essential for recognition of the pre-mRNA 5' splice-site and the subsequent assembly of the spliceosome. SNRPC/U1-C is directly involved in initial 5' splice-site recognition for both constitutive and regulated alternative splicing. The interaction with the 5' splice-site seems to precede base-pairing between the pre-mRNA and the U1 snRNA. Stimulates commitment or early (E) complex formation by stabilizing the base pairing of the 5' end of the U1 snRNA and the 5' splice-site region.
Component of the spliceosomal U1 snRNP, which is essential for recognition of the pre-mRNA 5' splice-site and the subsequent assembly of the spliceosome. snrpc/U1-C is directly involved in initial 5' splice-site recognition for both constitutive and regulated alternative splicing. The interaction with the 5' splice-site seems to precede base-pairing between the pre-mRNA and the U1 snRNA. Stimulates E complex formation by stabilizing the base pairing of the 5' end of the U1 snRNA and the 5' splice-site region.
U1 snRNP is composed of the 7 core Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP, and at least 3 U1 snRNP-specific proteins SNRNP70/U1-70K, SNRPA/U1-A and SNRPC/U1-C. SNRPC/U1-C interacts with U1 snRNA and the 5' splice-site region of the pre-mRNA.
By CSF2/GM-CSF, IL5/interleukin-5 and n-butyrate.
Expressed in the placenta, lung, left and right heart ventricles, heart atrium, leukocytes and differentiated HL-60 granulocytes.
Receptor for platelet activating factor, a chemotactic phospholipid mediator that possesses potent inflammatory, smooth-muscle contractile and hypotensive activity. Seems to mediate its action via a G protein that activates a phosphatidylinositol-calcium second messenger system.
Interacts (via KRAB domain) with HDAC2; the interaction is direct. Interacts (via KRAB domain) with HDAC1 (By similarity).
Sequence-specific DNA binding transcriptional repressor. Represses target gene transcription by recruiting HDAC1 and HDAC2 histone deacetylases. Acts as a specific transcriptional repressor for PTCH1 during embryonic development. Required for osteoblast differentiation and sonic hedgehog/SHH signaling response. Binds to the consensus site 5'-GCGCCC-3' in the promoter of PTCH1 (By similarity).
The KRAB domain is necessary for its repressive activity.
A high level expression is seen in the heart, kidney and skeletal muscle while a lower level expression is seen in the brain and liver.
Mitochondrial aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of histidine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP).
The protein contains 2 transactivation domains (TAD). Each of these domains may be required for transcriptional activation of a subset of target genes.
Transcription regulator that syncronizes transcriptional and translational programs to promote macrophage invasion of tissues.
Expressed in the lung, in the ciliated cells of the airway epithelium (PubMed:25751668). Expression increased with differentiation of airway epithelial cells (PubMed:25751668). Not detected in the mucous cells (PubMed:25751668). Expressed in ciliated cells in the oviduct (PubMed:26170690). Also detected in stomach, colon, prostate and liver (PubMed:25751668). Expressed in breast, ovary, prostate and liver cancer (PubMed:26170690). Expression is associated with the level of differentiation of breast cancer (at protein level) (PubMed:26170690).
Interacts with LYPD3 and DAG1 (alphaDAG1).
Not induced as part of the cellular response to endoplasmic reticulum stress (PubMed:25751668). Up-regulated by androgens and by estrogens in prostate cancer cells (PubMed:23294566) Up-regulated by a hormone (estrogen-receptor alpha) independent mechanism in ovarian cancer (PubMed:22361111).
Required for calcium-mediated regulation of ciliary beat frequency and mucociliary clearance in the airway. Might be involved in the regulation of intracellular calcium in tracheal epithelial cells.
Zinc importer that regulates cytosolic zinc concentrations either via zinc influx from the extracellular compartment or efflux from intracellular organelles such as Golgi apparatus. May transport copper ions as well. The transport mechanism remains to be elucidated.
High expression levels in fetal and infant brains; much lower in adult brains.
In pancreatic acinar cells and, in lower levels, in brain. Enhanced expression of PSP-related transcripts and intraneuronal accumulation of PSP-like proteins is found in brain from Alzheimer disease and Down syndrome patients.
The composition of the O-linked carbohydrate on Thr-27 is complex and varied. In the crystallographic structure, the attached sugar appears to be N-acetylglucosamine, typical of an intracellular protein, rather than N-acetylgalactosamine.
Interacts with DNM1L/DLP1 through the TPR region; may form part of a larger protein complex at the endoplasmic reticulum-mitochondrial interface during mitochondrial fission (PubMed:12861026, PubMed:16118244, PubMed:24196833). Interacts with MARCHF5 (PubMed:16874301). Interacts with MIEF1 (PubMed:21701560). Interacts with PEX11A, PEX11B and PEX11G (PubMed:20826455).
Involved in the fragmentation of the mitochondrial network and its perinuclear clustering (PubMed:12783892, PubMed:12861026, PubMed:14996942, PubMed:23283981). Plays a minor role in the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface and mitochondrial fission (PubMed:12861026, PubMed:16118244, PubMed:23283981, PubMed:23530241, PubMed:24196833). May not be essential for the assembly of functional fission complexes and the subsequent membrane scission event (PubMed:23530241, PubMed:24196833). Also mediates peroxisomal fission (PubMed:16107562). May act when the products of fission are directed toward mitochondrial homeostasis, mitophagy, or apoptosis (PubMed:24196833). Can induce cytochrome c release from the mitochondrion to the cytosol, ultimately leading to apoptosis (PubMed:12783892).
The C-terminus is required for mitochondrial or peroxisomal localization, while the N-terminus is necessary for mitochondrial or peroxisomal fission, localization and regulation of the interaction with DNM1L.
Expressed exclusively in liver in both embryo and adult.
Strongly expressed in testis. Weakly expressed in spleen, brain, fetal brain and placenta. Detected in lung tumors.
EF-hand domains are paired. EF-hand 1 is paired with EF-hand 2 and EF-hand 3 is paired with EF-hand 4. The fifth EF-hand domain, left unpaired, does not bind the calcium but is responsible of the dimerization by EF-embrace. The first four EF-hand domains bind calcium, however it is not sure if the binding of EF-hand 4 to calcium is physiologically relevant.
Homodimer or heterodimer of a large (catalytic) and a small (regulatory) subunit. In presence of calcium, the heterodimer dissociates (By similarity).
Regulatory subunit of the calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Essential for embryonic development (By similarity).
The contact of the 5th EF-hand domain from each monomer allows the formation of the homodimer and also appears to mediate the contact between the large catalytic subunit and small regulatory subunit for the formation of the heterodimer.
Activated by phosphorylation on Thr-173.
Autophosphorylated. Phosphorylation on Thr-173 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39.
Expressed in hematopoietic progenitor cells and leukemic cell lines. Weakly expressed in the testis.
May play a role in hematopoietic cell proliferation or differentiation. Potential mediator of neuronal apoptosis.
Interacts with EIF2AK4/GCN2; this interaction stimulates the EIF2AK4/GCN2 kinase activity and is impaired by IMPACT upon a variety of stress conditions, such as amino acid depletion, UV-C irradiation, proteasome inhibitor treatment and glucose deprivation (PubMed:36638793). Interacts with IMPACT; this prevents the interaction of GCN1 with EIF2AK4/GCN2 and inhibits EIF2AK4/GCN2 kinase activity (By similarity). Interacts with RNF14; interaction takes place following ribosome stalling and promotes recruitment of RNF14 (PubMed:36638793).
Ribosome collision sensor that plays a key role in the RNF14-RNF25 translation quality control pathway, a pathway that takes place when a ribosome has stalled during translation, and which promotes ubiquitination and degradation of translation factors on stalled ribosomes (PubMed:32610081, PubMed:36638793). Directly binds to the ribosome and acts as a sentinel for colliding ribosomes: activated following ribosome stalling and promotes recruitment of RNF14, which directly ubiquitinates EEF1A1/eEF1A, leading to its degradation (PubMed:36638793). In addition to EEF1A1/eEF1A, the RNF14-RNF25 translation quality control pathway mediates degradation of ETF1/eRF1 and ubiquitination of ribosomal protein (PubMed:36638793). GCN1 also acts as a positive activator of the integrated stress response (ISR) by mediating activation of EIF2AK4/GCN2 in response to amino acid starvation (By similarity). Interaction with EIF2AK4/GCN2 on translating ribosomes stimulates EIF2AK4/GCN2 kinase activity, leading to phosphorylation of eukaryotic translation initiation factor 2 (eIF-2-alpha/EIF2S1) (By similarity). EIF2S1/eIF-2-alpha phosphorylation converts EIF2S1/eIF-2-alpha into a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, and thus to a reduced overall utilization of amino acids, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion (By similarity).
The RWDBD (RWD-binding domain) region mediates binding to RWD domain-containing proteins, such as EIF2AK4/GCN2, IMPACT and RNF14.
Ubiquitously expressed (PubMed:9039502). Expressed in skeletal muscules, ovary and testis (PubMed:9234705).
Prostate. Not expressed in placenta, decidua or ovary.
Relaxin is an ovarian hormone that acts with estrogen to produce dilatation of the birth canal in many mammals. May be involved in remodeling of connective tissues during pregnancy, promoting growth of pubic ligaments and ripening of the cervix.
Belongs to the phenylalanyl-tRNA synthetase beta subunit family. Type 2 subfamily.
Forms a regulatory protein-RNA complex, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mt-rRNA.
Minor enzyme contributing to the isomerization of uridine to pseudouridine (pseudouridylation) of specific mitochondrial mRNAs (mt-mRNAs) such as COXI and COXIII mt-mRNAs (PubMed:27974379, PubMed:31477916). As a component of a functional protein-RNA module, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mitochondrial ribosomal RNA (16S mt-rRNA), controls 16S mt-rRNA abundance and is required for intra-mitochondrial translation (PubMed:27667664). Also catalyzes pseudouridylation of some tRNAs, including synthesis of pseudouridine(55) from uracil-55, in the psi GC loop of a subset of tRNAs (PubMed:33023933).
Involved in mitochondrial tRNA methylation (PubMed:26189817). Specifically methylates the N1 position of guanosine-37 in various tRNAs. Methylation is not dependent on the nature of the nucleoside 5' of the target nucleoside. This is the first step in the biosynthesis of wybutosine (yW), a modified base adjacent to the anticodon of tRNAs and required for accurate decoding.
Associates primarily with cyclin-H (CCNH) and MAT1 to form the CAK complex. CAK can further associate with the core-TFIIH to form the TFIIH basal transcription factor; this complex is sensitive to UV light. The CAK complex binds to p53/TP53 in response to DNA damage. Interacts with CDK2, SF1/NR5A1, PUF60 and PRKCI. Interacts with HINT1 (PubMed:10958787).
Inactivated by phosphorylation. Repressed by roscovitine (seliciclib, CYC202), R547 (Ro-4584820) and SNS-032 (BMS-387032). The association of p53/TP53 to the CAK complex in response to DNA damage reduces kinase activity toward CDK2 and RNA polymerase II repetitive C-terminal domain (CTD), thus stopping cell cycle progression. The inactivation by roscovitine promotes caspase-mediated apoptosis in leukemic cells.
Phosphorylation of Ser-164 during mitosis inactivates the enzyme. Phosphorylation of Thr-170 is required for activity. Phosphorylated at Ser-164 and Thr-170 by CDK2.
Serine/threonine kinase involved in cell cycle control and in RNA polymerase II-mediated RNA transcription. Cyclin-dependent kinases (CDKs) are activated by the binding to a cyclin and mediate the progression through the cell cycle. Each different complex controls a specific transition between 2 subsequent phases in the cell cycle. Required for both activation and complex formation of CDK1/cyclin-B during G2-M transition, and for activation of CDK2/cyclins during G1-S transition (but not complex formation). CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Phosphorylates SPT5/SUPT5H, SF1/NR5A1, POLR2A, p53/TP53, CDK1, CDK2, CDK4, CDK6 and CDK11B/CDK11. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation, thus regulating cell cycle progression. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts (PubMed:9852112). Phosphorylation of POLR2A in complex with DNA promotes transcription initiation by triggering dissociation from DNA. Its expression and activity are constant throughout the cell cycle. Upon DNA damage, triggers p53/TP53 activation by phosphorylation, but is inactivated in turn by p53/TP53; this feedback loop may lead to an arrest of the cell cycle and of the transcription, helping in cell recovery, or to apoptosis. Required for DNA-bound peptides-mediated transcription and cellular growth inhibition.
(Microbial infection) Interacts with Epstein-Barr virus EBNA3 (PubMed:12372828). Interacts with Epstein-Barr virus EBNA6; this interaction leads to gene repression, but also seems to interfere with the repressive function of CtBP pre-bound to DNA, leading to EBNA6 mediated up-regulation of many cellular genes (PubMed:11462050).
(Microbial infection) Interacts with adenovirus E1A protein (via its C-terminus); the interaction disrupts the interaction of CTBP1 with RBBP8.
ADP-ribosylated; when cells are exposed to brefeldin A.
Corepressor targeting diverse transcription regulators such as GLIS2 or BCL6. Has dehydrogenase activity. Involved in controlling the equilibrium between tubular and stacked structures in the Golgi complex. Functions in brown adipose tissue (BAT) differentiation.
Homo- or heterodimer. Heterodimer with CTBP2. Interacts with PRDM16; the interaction represses white adipose tissue (WAT)-specific genes expression. Interacts with GLIS2, FOXP2, HDAC4, HDAC5, HDAC9 and ZNF217. Interacts with ELK3 (via its PXDLS motif). Interacts with RBBP8 (via its PXDLS motif); the interaction is disrupted by binding to adenovirus E1A. Interacts with FOXP1, HIPK2, PNN, NRIP1, MECOM, ZFHX1B and WIZ. Interacts with ZNF366 (via PXDLS motif) (PubMed:16393996, PubMed:17085477). Interaction with SATB1 (non-acetylated form); the interaction stabilizes its attachment to DNA and promotes transcription repression. Interacts with BCL6; the interaction is required for BCL6 transcriptional autoinhibition and inhibition of some BCL6 target genes. Interacts with IKZF4 (By similarity). Interacts with MCRIP1 (unphosphorylated form, via the PXDLS motif); competitively inhibiting CTBP-ZEB1 interaction (PubMed:25728771). Interacts with Bassoon/BSN; this interaction targets and anchors CTBP1 to presynapses (By similarity). Interacts with SIMC1 (PubMed:23707407).
NAD is required for efficient interaction with E1A. Cofactor binding induces a conformation change.
Sumoylation on Lys-428 is promoted by the E3 SUMO-protein ligase CBX4.
The level of phosphorylation appears to be regulated during the cell cycle. Phosphorylation by HIPK2 on Ser-422 induces proteasomal degradation.
Interacts with NUP214/CAN (PubMed:9049309, PubMed:30543681). Interacts with NUP62 and NUP98 (PubMed:30543681).
The disease is caused by variants affecting the gene represented in this entry. Disease mechanism likely includes impaired formation of the neuromuscular junction. NUP88 silencing in vitro results in reduced levels of rapsyn, a key player in clustering of nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction. Decreased rapsyn levels have also been observed in a patient muscle biopsy.
Activated by chelators like citrate, malate, and oxalate specially at alkaline pH.
Genetic variations in CYBRD1 may act as modifier of iron overload expression and account for the variance observed in serum ferritin levels in patients with hereditary hemochromatosis.
Plasma membrane reductase that uses cytoplasmic ascorbate as an electron donor to reduce extracellular Fe(3+) into Fe(2+) (PubMed:30272000). Probably functions in dietary iron absorption at the brush border of duodenal enterocytes by producing Fe(2+), the divalent form of iron that can be transported into enterocytes (PubMed:30272000). It is also able to reduce extracellular monodehydro-L-ascorbate and may be involved in extracellular ascorbate regeneration by erythrocytes in blood (PubMed:17068337). May also act as a ferrireductase in airway epithelial cells (Probable). May also function as a cupric transmembrane reductase (By similarity).
Present in erythrocyte membranes (at protein level). Also expressed in respiratory epithelium.
Associated with cisplatin (DDP)-resistance and radioresistance in the treatment of lung cancer as well as oral squamous cell carcinoma and poor clinical outcome in patients.
In cancer context, protects cells from induced-DNA damage and apoptosis. Acts, at least in part, through PI3K/AKT/NFKB signaling pathway and by preventing POLB degradation. Decreases POLB ubiquitation and stabilizes its protein levels.
Interacts with POLB (PubMed:25260657). Interacts with AKT1 and MT1X (PubMed:23251525). May interact with FAM168B (PubMed:22771904).
Inhibits urokinase-type plasminogen activator. The monocyte derived PAI-2 is distinct from the endothelial cell-derived PAI-1.
Nonselective, high-affinity receptor for both orexin-A and orexin-B neuropeptides (PubMed:9491897, PubMed:26950369). Triggers an increase in cytoplasmic Ca(2+) levels in response to orexin-A binding (PubMed:9491897, PubMed:26950369).
Homodimer or heterodimer (Potential). Interacts with HOXC8.
May function as a transcriptional regulator.
Ubiquitous. Strongly expressed in adult testis and kidney as well as fetal lung and kidney.
(Microbial infection) May interact with non-structural protein 4A/NS4A from Zika virus strains Mr-766 or French Polynesia 10087PF/2013; the interaction may inhibit ANKLE2 function and contribute to defects in brain development, such as microcephaly.
Interacts with BAF/BANF1. Interacts with protein phosphatase 2A (PP2A) components PPP2C (PPP2CA or PPP2CB) and PPP2R1A.
Involved in mitotic nuclear envelope reassembly by promoting dephosphorylation of BAF/BANF1 during mitotic exit (PubMed:22770216). Coordinates the control of BAF/BANF1 dephosphorylation by inhibiting VRK1 kinase and promoting dephosphorylation of BAF/BANF1 by protein phosphatase 2A (PP2A), thereby facilitating nuclear envelope assembly (PubMed:22770216). May regulate nuclear localization of VRK1 in non-dividing cells (PubMed:31735666). It is unclear whether it acts as a real PP2A regulatory subunit or whether it is involved in recruitment of the PP2A complex (PubMed:22770216). Involved in brain development (PubMed:25259927).
Expressed at highest levels in ascending colon and at moderate levels in adult kidney. Expressed at low levels in adult pancreas and at very low levels in adult liver. Expression is down-regulated in several primary tumors, such as kidney, colon and rectal tumors.
Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission. May act by mediating trimethylation of 'Lys-36' of histone H3 (H3K36me3), which is essential to allow on-time RNA elongation dynamics. Also monomethylates 'Lys-9' of histone H3 (H3K9me1) in vitro. The relevance of histone methyltransferase activity is however subject to discussion.
Interacts with components of the PAF1 complex (PAF1C) such as LEO1, CTR9 and CDC73. Interacts with NCOR1. Interacts with HDAC3.
Induces HBG1 expression (PubMed:16131492, PubMed:11162141). May have a role in spermatogenesis where it promotes autophagy in response to serum starvation, via the NF-kappaB pathway (By similarity).
Widely expressed in fetus, at a high level in fetal liver, brain and lung.
Chemotactic activity for lymphocytes but not for monocytes or neutrophils.
Belongs to the DEAD box helicase family. DDX20 subfamily.
Part of the core SMN complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP (PubMed:10601333, PubMed:17178713). Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG (PubMed:18984161, PubMed:12095920). Interacts with SMN1; the interaction is direct (PubMed:17178713). Interacts with GEMIN4; the interaction is direct (PubMed:17178713). Interacts with GEMIN5 (PubMed:33963192). Interacts with SNUPN; the interaction is direct (PubMed:12095920). Interacts with PPP4R2 (PubMed:12668731). Interacts with FOXL2 (PubMed:16153597). Interacts with EBV EBNA2 and EBNA3C (PubMed:10383418). Interacts with NANOS1 and PUM2 (PubMed:21800163).
The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs. Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (Sm core). In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP. To assemble core snRNPs, the SMN complex accepts the trapped 5Sm proteins from CLNS1A forming an intermediate. Binding of snRNA inside 5Sm triggers eviction of the SMN complex, thereby allowing binding of SNRPD3 and SNRPB to complete assembly of the core snRNP. May also play a role in the metabolism of small nucleolar ribonucleoprotein (snoRNPs).
(Microbial infection) Interacts with PI4KA/PI4KIIIalpha; CHKA bridges PI4KA/PI4KIIIalpha and hepatitis C virus (HCV) non-structural protein 5A (NS5A) and potentiates NS5A-stimulated PI4KA activity, which then facilitates the targeting of the ternary complex to the ER for viral replication.
Acetylated by KAT5 at Lys-247 following phosphorylation by AMPK, leading to monomerization and conversion into a tyrosine-protein kinase.
Homodimer (PubMed:34077757, PubMed:17007874, PubMed:20299452). Heterodimer with CHKB (By similarity).
Homodimerization or heterodimerization is required for the choline and ethanolamine kinase activities.
Monomer; acetylation by KAT5 promotes dissociation of the homodimer and monomerization.
Phosphorylated at Ser-279 by AMPK in response to glucose deprivation, leading to localization to lipid droplets.
Plays a key role in phospholipid biosynthesis by catalyzing the phosphorylation of free choline to phosphocholine, the first step in phosphatidylcholine biosynthesis (PubMed:19915674, PubMed:34077757, PubMed:17007874). Also phosphorylates ethanolamine, thereby contributing to phosphatidylethanolamine biosynthesis (PubMed:19915674, PubMed:17007874). Has higher activity with choline (PubMed:19915674, PubMed:17007874). May contribute to tumor cell growth (PubMed:19915674).
This isoform plays a key role in lipolysis of lipid droplets following glucose deprivation (PubMed:34077757). In response to glucose deprivation, phosphorylated by AMPK, promoting localization to lipid droplets (PubMed:34077757). Phosphorylation is followed by acetylation by KAT5, leading to dissociation of the homodimer into a monomer (PubMed:34077757). Monomeric CHKA isoform 1 is converted into a tyrosine-protein kinase, which phosphorylates lipid droplet structural proteins PLIN2 and PLIN3, leading to lipolysis of lipid droplets (PubMed:34077757).
Down-regulated following embryonic stem cells differentiation.
Expressed in undifferentiated embryonic stem cells. Expressed in airway epithelial cells (PubMed:36191189).
Interacts with MYH9 (PubMed:28345668). Interacts with MYH10 (PubMed:28345668).
Homodimer, and homooligomer. Heterodimer with SNX18. Interacts with ITCH. Interacts (via SH3 domain) with TNK2, WASL and ACTR3. Identified in a complex with TNK2 and clathrin heavy chains. Identified in a complex with the AP-2 complex, clathrin and DNM2. Interacts (via SH3 domain) with DNM1 and DNM2. Identified in an oligomeric complex containing DNM1 and SNX9. Interacts with FCHSD1 (By similarity). Interacts with ADAM9 and ADAM15 cytoplasmic tails.
Involved in endocytosis and intracellular vesicle trafficking, both during interphase and at the end of mitosis. Required for efficient progress through mitosis and cytokinesis. Required for normal formation of the cleavage furrow at the end of mitosis. Plays a role in endocytosis via clathrin-coated pits, but also clathrin-independent, actin-dependent fluid-phase endocytosis. Plays a role in macropinocytosis. Promotes internalization of TNFR. Promotes degradation of EGFR after EGF signaling. Stimulates the GTPase activity of DNM1. Promotes DNM1 oligomerization. Promotes activation of the Arp2/3 complex by WASL, and thereby plays a role in the reorganization of the F-actin cytoskeleton. Binds to membranes enriched in phosphatidylinositol 4,5-bisphosphate and promotes membrane tubulation. Has lower affinity for membranes enriched in phosphatidylinositol 3-phosphate.
Phosphorylated on tyrosine residues by TNK2. Phosphorylation promotes its activity in the degradation of EGFR.
The PX domain mediates interaction with membranes enriched in phosphatidylinositol phosphate. Has high affinity for phosphatidylinositol 4,5-bisphosphate, but can also bind to membranes enriched in other phosphatidylinositol phosphates.
Widely expressed, with highest levels in heart and placenta, and lowest levels in thymus and peripheral blood leukocytes.
Guanine nucleotide exchange factor (GEF) activating RAB10. Promotes the exchange of GDP to GTP, converting inactive GDP-bound RAB10 into its active GTP-bound form. Thereby, stimulates SLC2A4/GLUT4 glucose transporter-enriched vesicles delivery to the plasma membrane in response to insulin.
mRNA splicing factor that regulates the formation of epithelial cell-specific isoforms. Specifically regulates the expression of FGFR2-IIIb, an epithelial cell-specific isoform of FGFR2. Also regulates the splicing of CD44, CTNND1, ENAH, 3 transcripts that undergo changes in splicing during the epithelial-to-mesenchymal transition (EMT). Acts by directly binding specific sequences in mRNAs. Binds the GU-rich sequence motifs in the ISE/ISS-3, a cis-element regulatory region present in the mRNA of FGFR2.
Plays a critical role in the phospholipid salvage pathway from lysosomes to the cytosol (PubMed:36161949, PubMed:37075117). Mediates the rate-limiting, proton-dependent, lysosomal efflux of lysophospholipids, which can then be reacylated by acyltransferases in the endoplasmic reticulum to form phospholipids (PubMed:36161949, PubMed:37075117). Selective for zwitterionic headgroups such as lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), can also transport lysophosphatidylglycerol (LPG), but not other anionic lysophospholipids, sphingosine, nor sphingomyelin (PubMed:36161949). Transports lysophospholipids with saturated, monounsaturated, and polyunsaturated fatty acids, such as 1-hexadecanoyl-sn-glycero-3-phosphocholine, 1-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine and 1-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphocholine, respectively (PubMed:36161949, PubMed:37075117). Can also transport lysoplasmalogen (LPC with a fatty alcohol) such as 1-(1Z-hexadecenyl)-sn-glycero-3-phosphocholine (PubMed:36161949). Lysosomal LPC could function as intracellular signaling messenger (PubMed:37075117). Essential player in lysosomal homeostasis (PubMed:36161949). Crucial for cell survival under conditions of nutrient limitation (PubMed:37075117). May be involved in necrotic or autophagic cell death (PubMed:12815463).
By the anticancer drug fluorouracil (5FU).
Enforced expression in IMR-90 cells leads to increased levels of ROS and induces premature cell senescence and nuclear DNA damage.
Expression increases in senescent cells.
Has antibacterial activity against a variety of bacteria including S.aureus, P.aeruginosa and M.tuberculosis. Acts by inducing bacterial membrane breakage.
Induces production of reactive oxygen species (ROS) which are necessary for cell proliferation. May play a role in inducing oxidative DNA damage and replicative senescence. May play a role in the coordination of mitochondrial morphology and cell proliferation.
Up-regulated in a number of cancer cell lines when compared to a normal lung fibroblast cell line. Highly expressed in brain tumors.
Endopeptidase that degrades various components of the extracellular matrix such as collagen. Activates progelatinase A. Essential for pericellular collagenolysis and modeling of skeletal and extraskeletal connective tissues during development (By similarity). May be involved in actin cytoskeleton reorganization by cleaving PTK7 (PubMed:20837484). Acts as a positive regulator of cell growth and migration via activation of MMP15. Involved in the formation of the fibrovascular tissues in association with pro-MMP2 (PubMed:12714657). Cleaves ADGRB1 to release vasculostatin-40 which inhibits angiogenesis (PubMed:22330140).
Expressed in stromal cells of colon, breast, and head and neck. Expressed in lung tumors.
Interacts (via C-terminal cytoplasmic tail) with BST2. Interacts with DLL1; inhibits DLL1-induced Notch signaling (PubMed:21572390).
Part of the SNAPc complex composed of 5 subunits: SNAPC1, SNAPC2, SNAPC3, SNAPC4 and SNAPC5. SNAPC2 interacts with TBP and SNAPC4.
Probable transmembrane reductase that may use ascorbate as an electron donor and transfer electrons across membranes to reduce monodehydro-L-ascorbate radical and iron cations Fe(3+) in another cellular compartment.
Potentially plays a role in the Ras signal transduction pathway. Capable of suppressing v-Ras transformation in vitro.
E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6. Acts on both canonical and non-canonical Wnt signaling pathway. Acts as a tumor suppressor in the intestinal stem cell zone by inhibiting the Wnt signaling pathway, thereby restricting the size of the intestinal stem cell zone (PubMed:22575959). Along with RSPO2 and RNF43, constitutes a master switch that governs limb specification (By similarity).
Interacts with LRP6, FZD4, FZD5, FZD6 and FZD8 (PubMed:22575959). Interacts with RSPO1; interaction promotes indirect interaction with LGR4 and membrane clearance of ZNRF3 (PubMed:22575959). Also interacts with RSPO2 (PubMed:29769720). Interacts with LMBR1L (PubMed:31073040).
Negatively regulated by R-spondin proteins such as RSPO1: interaction with RSPO1 induces the indirect association between ZNRF3 and LGR4, promoting membrane clearance of ZNRF3.
C-type lectin domains 3 to 8 are not required for calcium-dependent binding of mannose, fucose and N-acetylglucosamine. C-type lectin domain 2 is responsible for sugar-binding in a calcium-dependent manner.
Fibronectin type-II domain mediates collagen-binding.
Interacts with C-terminal region of type I collagen/COL1A1 (By similarity). Interacts directly with PLAUR/UPAR and PLAU/pro-UPA to form a tri-molecular complex. Interacts with collagen V.
May play a role as endocytotic lectin receptor displaying calcium-dependent lectin activity. Internalizes glycosylated ligands from the extracellular space for release in an endosomal compartment via clathrin-mediated endocytosis. May be involved in plasminogen activation system controlling the extracellular level of PLAUR/PLAU, and thus may regulate protease activity at the cell surface. May contribute to cellular uptake, remodeling and degradation of extracellular collagen matrices. May play a role during cancer progression as well as in other chronic tissue destructive diseases acting on collagen turnover. May participate in remodeling of extracellular matrix cooperating with the matrix metalloproteinases (MMPs).
Ricin B-type lectin domain contacts with the second C-type lectin domain.
Ubiquitous with low expression in brain, placenta, lung, kidney, pancreas, spleen, thymus and colon. Expressed in endothelial cells, fibroblasts and macrophages. Highly expressed in fetal lung and kidney.
Almost exclusively expressed in immune cells, including dendritic cells, B-lymphocytes and natural killer cells.
Despite its name, does not contain a C-type lectin domain.
Disease susceptibility may be associated with variants affecting the gene represented in this entry. Three common non-coding variants of CLEC16A in strong linkage disequilibrium reach genome-wide significance for association with the disease (PubMed:17632545). The non-coding variant rs12708716 is associated with reduced expression of CLEC16A in beta cells and reduced beta cell function (PubMed:24949970).
Regulator of mitophagy through the upstream regulation of the RNF41/NRDP1-PRKN pathway. Mitophagy is a selective form of autophagy necessary for mitochondrial quality control. The RNF41/NRDP1-PRKN pathway regulates autophagosome-lysosome fusion during late mitophagy. May protect RNF41/NRDP1 from proteasomal degradation, RNF41/NRDP1 which regulates proteasomal degradation of PRKN. Plays a key role in beta cells functions by regulating mitophagy/autophagy and mitochondrial health.
Interacts with topoisomerase 1 and with TRIM5 isoform Delta.
Expressed in breast, colon and brain. In all 3 tissues, expressed in the microvasculature (at protein level). In addition, in the breast, found in the contractile myoepithelial cell layer which surrounds the breast ducts (at protein level). In the colon, expressed in the mucous membrane and colonic crypts and in the smooth muscle cell layer which provide movement of the colon (at protein level). In the cerebellum, localized around the Purkinje neurons and the granule cells of the granular layer, but not inside cell bodies (at protein level). Outside of the cerebellar cortex, expressed in glial cells (at protein level). Highly expressed away from the cell bodies within the dentate nucleus (at protein level).
May be involved in podosome and invadosome formation.
Efficient suppressor of aggregation and toxicity of disease-associated polyglutamine proteins.
The antiaggregation activity resides in the serine-rich region and the C-terminus.
Isoform 2 was reported to be located in the nucleus and to interact with HDAC1 and HDAC2 (PubMed:21285511). However, this work was later retracted (PubMed:30882370).
Sorting receptor that directs prohormones to the regulated secretory pathway. Acts also as a prohormone processing enzyme in neuro/endocrine cells, removing dibasic residues from the C-terminal end of peptide hormone precursors after initial endoprotease cleavage.
Regulates insulin-dependent IRS1 tyrosine phosphorylation in adipocytes by modulating the availability of IRS1 to IR tyrosine kinase. Its association with IRS1 is required for insulin-induced translocation of SLC2A4 to the cell membrane. Involved in TNF-induced impairment of insulin-dependent IRS1 tyrosine phosphorylation.
At alkaline pH BPGM favors the synthase reaction; however, at lower pH the phosphatase reaction is dominant. Inhibited by citrate.
Expressed in red blood cells. Expressed in non-erythroid cells of the placenta; present in the syncytiotrophoblast layer of the placental villi at the feto-maternal interface (at protein level).
Glycation of Lys-159 in diabetic patients inactivates the enzyme.
Plays a major role in regulating hemoglobin oxygen affinity by controlling the levels of its allosteric effector 2,3-bisphosphoglycerate (2,3-BPG). Also exhibits mutase (EC 5.4.2.11) activity.
Interacts with PAFAH1B1 (By similarity). Interacts with KATNA1 (PubMed:10751153, PubMed:26929214). This interaction enhances the microtubule binding and severing activity of KATNA1 and also targets this activity to the centrosome (PubMed:10751153). This interaction is weakly competed by KATNBL1 which has a lower affinity for it (PubMed:26929214). Interacts with ASPM; the katanin complex formation KATNA1:KATNB1 is required for the association of ASPM (By similarity). Interacts with dynein, microtubules and NDEL1 (PubMed:16203747). Interacts with KATNAL1; this interaction is weakly competed by KATNBL1 which has a lower affinity for it (PubMed:26929214). Interacts with CAMSAP2 and CAMSAP3; leading to regulate the length of CAMSAP-decorated microtubule stretches (PubMed:24486153).
Participates in a complex which severs microtubules in an ATP-dependent manner. May act to target the enzymatic subunit of this complex to sites of action such as the centrosome. Microtubule severing may promote rapid reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. Microtubule release from the mitotic spindle poles may allow depolymerization of the microtubule end proximal to the spindle pole, leading to poleward microtubule flux and poleward motion of chromosome. Microtubule release within the cell body of neurons may be required for their transport into neuronal processes by microtubule-dependent motor proteins. This transport is required for axonal growth.
Heterodimer with IL20RA and heterodimer with IL22RA1.
The IL20RA/IL20RB dimer is a receptor for IL19, IL20 and IL24. The IL22RA1/IL20RB dimer is a receptor for IL20 and IL24.
Widely expressed with highest levels in skin and testis. Highly expressed in psoriatic skin.
Expressed in all tissues tested, with the strongest expression in ovary.
Transcriptional activator. Activates the gene for selenocysteine tRNA (tRNAsec). Binds to the SPH motif of small nuclear RNA (snRNA) gene promoters. Participates in efficient U6 RNA polymerase III transcription via its interaction with CHD8.
Belongs to the eukaryotic ribosomal protein eS24 family.
Component of the small ribosomal subunit (PubMed:23636399). Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797).
Component of the small ribosomal subunit (PubMed:23636399). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399). Required for processing of pre-rRNA and maturation of 40S ribosomal subunits (PubMed:18230666). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Mature tissues, such as adult brain, skeletal muscle, heart, and kidney, express low levels, whereas tissues and organs with significant populations of proliferating cells, such as fetal brain, placenta, bone marrow, and various glandular organs, contain significantly higher levels.
Belongs to the eukaryotic ribosomal protein eL43 family.
Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM. The complex is not found in FA patients.
DNA repair protein required for FANCD2 ubiquitination.
ATP-dependent chromatin-remodeling factor which functions as substrate recognition component of the transcription regulatory histone acetylation (HAT) complex SAGA. Regulates polymerase II transcription. Also required for efficient transcription by RNA polymerase I, and more specifically the polymerase I transcription termination step. Regulates negatively DNA replication. Not only involved in transcription-related chromatin-remodeling, but also required to maintain a specific chromatin configuration across the genome. Is also associated with histone deacetylase (HDAC) activity (By similarity). Required for the bridging of SNF2, the FACT complex, the PAF complex as well as the U2 snRNP complex to H3K4me3. Functions to modulate the efficiency of pre-mRNA splicing in part through physical bridging of spliceosomal components to H3K4me3 (PubMed:18042460, PubMed:28866611). Required for maintaining open chromatin and pluripotency in embryonic stem cells (By similarity).
Component of the SAGA complex (By similarity). Interacts with BCLAF1, NCoR, SRP20 and SAFB (By similarity). Specifically interacts with methylated H3K4me2 and H3K4me3. Interacts with the FACT complex, the PAF complex and the U2 snRNP. Interacts directly with PAF1, SFA3A1, SFA3A2, SFA3A3, SNF2 and SSRP1.
Expressed in many tissues including in the brain, where the highest level of expression is found in the cerebellum and basal ganglia.
The 2 chromodomains are involved in the binding to the histone H3 methyllysine at position 4 (H3K4me3).
The CHD1 helical C-terminal domain (CHCT) binds DNA and nucleosomes.
Component of the large ribosomal subunit (PubMed:23636399, PubMed:32669547). Interacts with CRY1 (By similarity).
Hydroxylated on His-216 by RIOX1. The modification is impaired by hypoxia.
This protein can be partially incorporated into E.coli polysomes in vivo, indicating it can replace the endogenous protein.
Has an essential role in the formation of sperm flagella and flagellar structure maintainance. It acts as a suppressor of ubiquitination and degradation of proteins involved in flagellar development and motility.
Expressed in epidermis; in the spinous and granular layers and in placenta. Also found in the epithelia of the small intestine, macrophages of the lung and endothelial cells of the lung. Isoform 15 is expressed in epidermis and placenta. Isoform 1 is expressed in epidermis.
Homooligomer. Seems to be able to homodimerize and homotrimerize.
May act as a soluble regulator of keratinocyte differentiation.
Acts as component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. Core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built (PubMed:32453425, PubMed:34694004, PubMed:34700328, PubMed:35585232). The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity (PubMed:32453425). Required for the entry in S phase and for cell division (PubMed:8175912). Plays a role in terminally differentiated hair cells development of the cochlea and induces cells apoptosis (PubMed:26196677).
Component of the MCM2-7 complex (PubMed:9305914, PubMed:16899510, PubMed:17296731). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (PubMed:9305914, PubMed:16899510, PubMed:17296731, PubMed:34700328, PubMed:34694004, PubMed:32453425). Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex (PubMed:34700328, PubMed:34694004, PubMed:32453425). Interacts with DBF4 (By similarity). Interacts with KAT7 (PubMed:16387653). May interact with MCM10 (PubMed:11095689). Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR (PubMed:28191891). Forms a co-chaperone complex with DNAJC9 and histone H3.3-H4 heterodimers (PubMed:33857403). Within the complex, interacts (via N-terminus) with DNAJC9 (via C-terminus); the interaction is histone-dependent (PubMed:33857403). Interacts with histones H3.1 and H3.3 (PubMed:33857403).
Phosphorylated on Ser-108 by ATR in proliferating cells. Ser-108 proliferation is increased by genotoxic agents. Ser-40 is mediated by the CDC7-DBF4 and CDC7-DBF4B complexes, while Ser-53 phosphorylation is only mediated by the CDC7-DBF4 complex. Phosphorylation by the CDC7-DBF4 complex during G1/S phase is required for the initiation of DNA replication.
According to PubMed:11056053, widely expressed with highest levels in skeletal muscle and heart, moderate levels in pancreas, brain (dopaminergic neurons of adult and fetal substantia nigra) and kidney, and lower levels in lung and liver. According to PubMed:12351678 widely expressed with highest levels in brain, kidney and adrenal gland. Expressed in cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle. According to PubMed:12788921; expressed in adult and fetal heart, brain, liver, lung, skeletal muscle and kidney. Also expressed in placenta. Highest levels in adult heart, brain, lung and liver and fetal brain, heart spleen and skeletal muscle.
Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif.
Following exposure to hypoxia, activated in HeLa cells but not in cardiovascular cells.
It was previously reported that this protein was the ortholog of rat SM-20. However, EGLN3 is now considered the true ortholog of rat SM-20 since it shows substantially greater similarity.
Monomer. Interacts with ING4; the interaction inhibits the hydroxylation of HIF alpha proteins. Interacts with PTGES3 (via PXLE motif); thereby recruiting EGLN1 to the HSP90 pathway to facilitate HIF alpha proteins hydroxylation. Interacts with LIMD1. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with EPAS1. Interacts with CBFA2T3 (PubMed:25974097). Interacts with HIF1A (PubMed:25974097).
S-nitrosylation inhibits the enzyme activity up to 60% under aerobic conditions. Chelation of Fe(2+) has no effect on the S-nitrosylation. It is uncertain whether nitrosylation occurs on Cys-323 or Cys-326.
Variations in EGLN1 are associated with adaptation to high altitude (PubMed:20838600, PubMed:20466884, PubMed:24711448, PubMed:25129147). High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body and leads to an elevation of hematocrit levels and an increased number of erythrocytes (polycythemia) in non-adapted individuals. Genetic variations in EGLN1 contribute to adaptation to high altitute by maintaining hematocrit levels comparable to those for populations living at sea level and are present in two high-altitude regions where humans have lived for millennia, the Andean Altiplano and the Tibetan Plateau (PubMed:20838600, PubMed:20466884). Variants Glu-4 and Ser-127, which are frequently associated together and are present in the majority of Tibetan populations, participate in adaptation to high altitude (PubMed:24711448, PubMed:25129147). Molecular mechanisms explaining this adaptation are however unclear. According to a report, variants Glu-4 and Ser-127 lead to decreased interaction with PTGES3 and subsequent decrease of HIF alpha proteins degradation (PubMed:24711448). According to a second report, Glu-4 and Ser-127 haplotype enhances the catalytic activity under hypoxic conditions, promoting increased HIF alpha proteins degradation, thereby abrogating hypoxia-induced and HIF alpha-mediated augmentation of erythropoiesis and protecting Tibetans from polycythemia at high altitude (PubMed:25129147).
Aberrant MPST activity is found in a few cases of mercaptolactate-cysteine disulfiduria (MCDU) characterized by the appearance of large quantaties of the sulfur-containing amino acid, beta-mercaptolactate-cysteine disulfide, in the urine (PubMed:4973015, PubMed:4690911, PubMed:6945862). Some cases have associated intellectual disability (PubMed:4973015, PubMed:6945862).
By oxidative stress, and thioredoxin. Under oxidative stress conditions, the catalytic cysteine site is converted to a sulfenate which inhibits the MPST enzyme activity. Reduced thioredoxin cleaves an intersubunit disulfide bond to turn on the redox switch and reactivate the enzyme.
Monomer (active form). Homodimer; disulfide-linked (inactive form).
Thioredoxin (Trx) or dihydrolipoic acid (DHLA) are required to release hydrogen sulfide from the persulfide intermediate.
Transfer of a sulfur ion to cyanide or to other thiol compounds. Also has weak rhodanese activity. Detoxifies cyanide and is required for thiosulfate biosynthesis. Acts as an antioxidant. In combination with cysteine aminotransferase (CAT), contributes to the catabolism of cysteine and is an important producer of hydrogen sulfide in the brain, retina and vascular endothelial cells. Hydrogen sulfide H(2)S is an important synaptic modulator, signaling molecule, smooth muscle contractor and neuroprotectant. Its production by the 3MST/CAT pathway is regulated by calcium ions.
Expressed in all tissues examined. Isoforms are differentially expressed. Isoform 3 and isoform 5 were highly expressed, isoform 4 moderately expressed, isoform 2 lower expression, the lowest expression level was seem with isoform 1.
Involved in transcriptional regulation. Transcriptional activity differed among the various isoforms. All isoforms except isoform 3 seem to suppresses the transcriptional activities of AP-1 and p53/TP53.
Takes part in the salvage pathway for reutilization of fucose from the degradation of oligosaccharides.
Could be involved with bystin and tastin in a cell adhesion molecule complex that mediates an initial attachment of the blastocyst to uterine epithelial cells at the time of the embryo implantation. Directly responsible for homophilic cell adhesion.
Directly binds bystin, and indirectly tastin.
Strong expression at implantation sites. Found in the placenta from the sixth week of pregnancy. Was localized in the cytoplasm of the syncytiotrophoblast in the chorionic villi and in endometrial decidual cells at the uteroplacental interface. After week 10, the level decreased and then disappeared from placental villi. Also found in macrophages.
Heterodimer of an alpha and a beta subunit. Beta-4 associates with alpha-6. Interacts (via cytoplasmic region) with COL17A1 (via cytoplasmic region). Interacts (via cytoplasmic region) with DST isoform 3 (via N-terminus). Isoform beta-4a interacts (via cytoplasmic domain) with DST (via N-terminus). Interacts with RAC1. ITGA6:ITGB4 is found in a ternary complex with NRG1 and ERBB3 (PubMed:20682778). ITGA6:ITGB4 is found in a ternary complex with IGF1 and IGF1R (PubMed:22351760). ITGA6:ITGB4 interacts with IGF2 (PubMed:28873464).
Integrin alpha-6/beta-4 is a receptor for laminin. Plays a critical structural role in the hemidesmosome of epithelial cells. Is required for the regulation of keratinocyte polarity and motility. ITGA6:ITGB4 binds to NRG1 (via EGF domain) and this binding is essential for NRG1-ERBB signaling (PubMed:20682778). ITGA6:ITGB4 binds to IGF1 and this binding is essential for IGF1 signaling (PubMed:22351760). ITGA6:ITGB4 binds to IGF2 and this binding is essential for IGF2 signaling (PubMed:28873464).
Integrin alpha-6/beta-4 is predominantly expressed by epithelia. Isoform beta-4D is also expressed in colon and placenta. Isoform beta-4E is also expressed in epidermis, lung, duodenum, heart, spleen and stomach.
Palmitoylated by DHHC3 at several cysteines of the membrane-proximal region, enhancing stability and cell surface expression. Palmitoylation also promotes secondary association with tertaspanins.
The fibronectin type-III-like domains bind BPAG1 and plectin and probably also recruit BP230.
Involved in the retrieval of endoplasmic reticulum membrane proteins from the early Golgi compartment.
Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27', H3 'Lys-36' nor H4 'Lys-20'. Demethylates both di- and trimethylated H3 'Lys-9' residue, while it has no activity on monomethylated residues. Demethylation of Lys residue generates formaldehyde and succinate.
Component of the oligosaccharyltransferase (OST) complex (PubMed:31831667). OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits (PubMed:23606741, PubMed:25135935, PubMed:31831667). STT3A complex assembly occurs through the formation of 3 subcomplexes. Subcomplex 1 contains RPN1 and TMEM258, subcomplex 2 contains the STT3A-specific subunits STT3A, DC2/OSTC, and KCP2 as well as the core subunit OST4, and subcomplex 3 contains RPN2, DAD1, and OST48. The STT3A complex can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes (By similarity). Interacts with TMEM35A/NACHO (By similarity).
Can form heteromeric complexes with LRFN1, LRFN2, LRFN4 and LRFN5. Able to form homomeric complexes across cell junctions, between adjacent cells. Does not interact with DLG4 (By similarity).
Cell adhesion molecule that mediates homophilic cell-cell adhesion in a Ca(2+)-independent manner. Promotes neurite outgrowth in hippocampal neurons (By similarity).
Lacks a cytoplasmic PDZ-binding domain, which has been implicated in function of related Lrfn proteins.
(Microbial infection) Interacts with the HIV-1 protein Vpr.
Although related to the peptidase M67A family, it lacks the JAMM motif that probably constitutes the catalytic center and therefore it probably does not have a protease activity.
Belongs to the peptidase M67A family. CSN6 subfamily.
Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. Has some glucocorticoid receptor-responsive activity. Stabilizes COP1 through reducing COP1 auto-ubiquitination and decelerating COP1 turnover rate, hence regulates the ubiquitination of COP1 targets.
Component of the CSN complex, composed of COPS1/GPS1, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7 (COPS7A or COPS7B), COPS8 and COPS9 isoform 1 (PubMed:18850735, PubMed:26456823). In the complex, it probably interacts directly with COPS2, COPS4, COPS5, COPS7 (COPS7A or COPS7B) and COPS9 isoform 1 (PubMed:11337588, PubMed:26456823). Interacts with the translation initiation factor EIF3S6 (PubMed:12220626). Interacts weakly with RBX1 (PubMed:11337588). Directly interacts with COP1 and 14-3-3 protein sigma/SFN (PubMed:21625211). Interacts with ERCC6 (PubMed:26030138).
Contributes to the lung's defense against inhaled microorganisms, organic antigens and toxins. Interacts with compounds such as bacterial lipopolysaccharides, oligosaccharides and fatty acids and modulates leukocyte action in immune response. May participate in the extracellular reorganization or turnover of pulmonary surfactant. Binds strongly maltose residues and to a lesser extent other alpha-glucosyl moieties.
Expressed in lung, brain, pancreas and adipose tissue (mainly mature adipocytes).
Oligomeric complex of 4 set of homotrimers.
S-nitrosylation at Cys-35 and Cys-40 alters the quaternary structure which results in a pro-inflammatory chemoattractive signaling activity with macrophages.
As part of the DISP complex, may regulate the association of septins with actin and thereby regulate the actin cytoskeleton.
Component of the DOCK7-induced septin displacement/DISP complex, at least composed of DOCK7, LRCH3 and MYO6.
Predicted to contain a signal peptide and to be secreted. However, this is not consistent with an interaction with DOCK7 and MYO6 and the suggested function in cytoskeleton organization.
Protein glucosyltransferase that catalyzes the transfer of glucose from UDP-glucose to a serine residue within the consensus sequence peptide C-X-N-T-X-G-S-F-X-C (PubMed:30127001). Can also catalyze the transfer of xylose from UDP-xylose but less efficiently (PubMed:30127001). Specifically targets extracellular EGF repeats of proteins such as NOTCH1, NOTCH3, FBN1, FBN2 and LTBP1 (PubMed:30127001, PubMed:34411563). May regulate the transport of NOTCH1 and NOTCH3 to the plasma membrane and thereby the Notch signaling pathway (PubMed:30127001).
Regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content (PubMed:24531328, PubMed:24927523). May function as sterol isomerase (PubMed:25566323).
Substantial expression in liver and intestine, whereas all other tissues analyzed show low levels.
Odorant receptor involved in the detection of the flavor compound cis-3-hexen-1-ol (C3HEX), a compound typically described as 'green grassy' or the smell of 'cut grass'.
Variants Ala-113 and Gln-226 exhibit a reduced ability to smell C3HEX [MIM:615082]. When both variants are present in the same haplotype (allele 6M1-3*02), the response to C3HEX is abolished. African populations have a higher proportion of the C3HEX-nonresponsive haplotype than other populations. All haplotypes containing Gln-226 show low levels of surface expression.
Catalyzes the reduction of all-trans-retinal to all-trans-retinol in the presence of NADPH.
Located in a region of chromosome 1 which is often deleted in aggressive neuroblastoma tumors.
Widely expressed with highest levels found in heart, placenta, lung, liver, kidney, pancreas, thyroid, testis, stomach, trachea and spinal cord. Lower levels found in skeletal muscle, intestine and lymph node. No expression detected in brain. In the retina, expressed in cone but not rod outer segments.
(Microbial infection) Glycosylated at Arg-250 by enteropathogenic E.coli protein NleB1: arginine GlcNAcylation prevents homotypic/heterotypic death domain interactions.
Binds DAXX. Interacts with HIPK3 (By similarity). Part of a complex containing HIPK3 and FADD (By similarity). Binds RIPK1 and FAIM2 (PubMed:7538908, PubMed:10535980). Interacts with BABAM2 and FEM1B (PubMed:10542291, PubMed:15465831). Interacts with FADD (PubMed:21109225, PubMed:19118384). Interacts directly (via DED domain) with NOL3 (via CARD domain); inhibits death-inducing signaling complex (DISC) assembly by inhibiting the increase in FAS-FADD binding induced by FAS activation (By similarity). Interacts with CALM (PubMed:24914971). In the absence of stimulation, interacts with BIRC2, DDX3X and GSK3B. The interaction with BIRC2 and DDX3X is further enhanced upon receptor stimulation and accompanied by DDX3X and BIRC2 cleavage (PubMed:18846110).
Contains a death domain involved in the binding of FADD, and maybe to other cytosolic adapter proteins.
Dominant negative isoform, resistant to Fas-mediated apoptosis.
Isoform 1 and isoform 6 are expressed at equal levels in resting peripheral blood mononuclear cells. After activation there is an increase in isoform 1 and decrease in the levels of isoform 6.
Palmitoylated (PubMed:25301068). Palmitoylation by ZDHHC7 prevents the lysosomal degradation of FAS regulating its expression at the plasma membrane (PubMed:25301068).
Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T-cells, or both. The secreted isoforms 2 to 6 block apoptosis (in vitro).
Binds to GRB2. Isoform 2A binds to SYNJ2BP/OMP25. Isoform 2B2 C-terminal proline-rich region binds to a variety of SH3 domain-containing proteins including SH3GL1, SH3GL2, SH3GL3 and GRB2.
Inositol 5-phosphatase which may be involved in distinct membrane trafficking and signal transduction pathways. May mediate the inhibitory effect of Rac1 on endocytosis.
Expressed mainly on mature peripherical B cells. Detected in spleen, lymph node and appendix. Not detected in pre-B and -T cells.
May cooperate with MD-1 and TLR4 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) in B-cells. Leads to NF-kappa-B activation. Also involved in the life/death decision of B-cells (By similarity).
(Microbial infection) Interacts with Staphylococcus aureus proteins SSL5 and SSL11; these interactions prevent SELPLG-mediated neutrophil rolling.
(Microbial infection) Interacts with enterovirus 71 capsid proteins.
A SLe(x)-type proteoglycan, which through high affinity, calcium-dependent interactions with E-, P- and L-selectins, mediates rapid rolling of leukocytes over vascular surfaces during the initial steps in inflammation. Critical for the initial leukocyte capture.
Displays complex, core-2, sialylated and fucosylated O-linked oligosaccharides, at least some of which appear to contain poly-N-acetyllactosamine with varying degrees of substitution. Mainly disialylated or neutral forms of the core-2 tetrasaccharide, Galbeta1-->4GlcNAcbeta1-->6(Galbeta1-->3)GalNAcOH. The GlcN:GalN ratio is approximately 2:1 and the Man:Fuc ratio 3:5. Contains about 14% fucose with alpha-1,3 linkage present in two forms: One species is a disialylated, monofucosylated glycan, and the other, a monosialylated, trifucosylated glycan with a polylactosamine backbone. The fucosylated forms carry the Lewis antigen and are important for interaction with selectins and for functioning in leukocyte rolling. The modification containing the sialyl Lewis X glycan is on Thr-57. No sulfated O-glycans. Some N-glycosylation.
Expressed on neutrophils, monocytes and most lymphocytes.
Homodimer; disulfide-linked. Interaction with P-, E- and L-selectins, through their lectin/EGF domains, is required for promoting recruitment and rolling of leukocytes. These interactions require sialyl Lewis X glycan modification but there is a differing dependence for tyrosine sulfations. Sulfation on Tyr-51 of PSGL1 is most important for high affinity L-selectin/SELL binding while P-selectin/SELP requires sulfation on Tyr-48. E-selectin/SELE binds with much lower affinity and requires the sLe(x) epitope, but apparently not tyrosine sulfation. Dimerization appears not to be required for P-selectin/SELP binding. Interacts with SNX20. Interacts with MSN and SYK; mediates the activation of SYK by SELPLG. Interacts with HAVCR1 (PubMed:24703780).
Sulfation, in conjunction with the SLe(x)-containing glycan, is necessary for P- and L-selectin binding. High affinity P-selectin binding has a preferred requirement for the isomer sulfated on both Tyr-48 and Tyr-51, whereas L-selectin binding requires predominantly sulfation on Tyr-51 with sulfation on Tyr-48 playing only a minor role. These sulfations play an important role in L- and P-selectin-mediated neutrophil recruitment, and leukocyte rolling.
Highly expressed in the cerebral cortex, including frontal, parietal and occipital lobes. Putamen, amygdala, hippocampus and medulla oblongata show moderate expression. Caudate nucleus and thalamus express small amounts, whereas other brain regions show very weak or no expression.
May promote neurite outgrowth of developing thalamic neurons.
The LRR region is both necessary and sufficient for the interaction with NTNG1.
Interacts with STX6 (By similarity). Interacts with ZFYVE20.
May play a role in vesicle-mediated protein trafficking from the Golgi stack through the trans-Golgi network.
Ubiquitous. Expression was highest in testis, heart and brain, intermediate in kidney, spleen, prostate, ovary, small intestine and thymus and low in lung, skeletal muscle, placenta, colon, pancreas, peripheral blood leukocytes and liver.
Probably inhibits protein phosphatase 1 (PP1) in sperm via binding to catalytic subunit PPP1CC.
This protein is not related to the claudin family.
Expressed at high levels in lymphoid and hematopoietic tissues.
Septins polymerize into heterooligomeric protein complexes that form filaments, and can associate with cellular membranes, actin filaments and microtubules. GTPase activity is required for filament formation (By similarity). Interacts with AURKB.
Interacts with LETM1 (PubMed:36321428). Interacts with AFG3L2 (PubMed:35912435).
Plays an important role in maintenance of mitochondrial morphology and in mediating either calcium or potassium/proton antiport (PubMed:18417609, PubMed:36321428, PubMed:32977469, PubMed:35912435). Mediates proton-dependent calcium efflux from mitochondrion (PubMed:36321428, PubMed:35912435). Functions also as an electroneutral mitochondrial proton/potassium exchanger (PubMed:36321428). Required for the mitochondrial tubular network and cristae organization (PubMed:18417609, PubMed:36321428, PubMed:32977469). Involved in apoptotic release of cytochrome c (PubMed:18417609). Inhibits the proteolytic activity of AFG3L2, stimulating respiration and stabilizing respiratory enzymes in actively respiring mitochondria (PubMed:36321428). However, when mitochondria become hyperpolarized, GHITM loses its inhibitory activity toward AFG3L2 and the now the active AFG3L2 turns first on GHITM and, if hyperpolarization persists, on other proteins of the mitochondria, leading to a broad remodeling of the mitochondrial proteome (PubMed:36321428).
Undergoes AFG3L2-mediated proteolytic degradation, upon hyperpolarization of mitochondria.
Defects in TCF4 may cause autosomal dominant symmetrical acral keratoderma (SAK)syndrome. Symmetrical acral keratodermadefines is characterized by brown/black hyperkeratotic patches symmetrically distributed on the acral regions, especially the wrists, ankles, dorsa of hands, fingers and feet affects young and middle aged men. Patients have epidermis thickened by acanthosis and compact stratum corneum(PubMed:28921696).
Efficient DNA binding requires dimerization with another bHLH protein. Forms homo- or heterooligomers with myogenin. Interacts with HIVEP2. Interacts with NEUROD2 (By similarity). Interacts with AGBL1. Interacts with BHLHA9.
Expressed in adult heart, brain, placenta, skeletal muscle and to a lesser extent in the lung. In developing embryonic tissues, expression mostly occurs in the brain.
Incomplete and probable erroneous sequence.
The disease is caused by variants affecting the gene represented in this entry. Causative mutations are heterozygous TCF4 intronic trinucleotide repeat expansions (CTG)n.
Transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5-motif. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3'). Binds to the E-box present in the somatostatin receptor 2 initiator element (SSTR2-INR) to activate transcription (By similarity). Preferentially binds to either 5'-ACANNTGT-3' or 5'-CCANNTGG-3'.
Engineered fusion proteins consisting of the extracellular domain of CTLA4 and the IgG Fc region (Ctla4-Ig), inhibit T-cell-dependent antibody responses, and are used as immunosuppressive agents. They are soluble, have an enhanced affinity for B7 ligands and act as a competitive inhibitor of CD28.
Genetic variations in CTLA4 are associated with susceptibility to several autoimmune disorders (PubMed:18595775, PubMed:12724780, PubMed:10189842, PubMed:10924276, PubMed:15138458, PubMed:15657618, PubMed:15688186, PubMed:25329329, PubMed:25213377). They influence responsiveness to hepatitis B virus (HBV) infection [MIM:610424] (PubMed:15452244).
Genetic variations in CTLA4 may influence susceptibility to Graves disease, an autoimmune disorder associated with overactivity of the thyroid gland and hyperthyroidism.
Homodimer; disulfide-linked (PubMed:11279501, PubMed:11279502, Ref.23, PubMed:21156796, PubMed:28484017). Binds to CD80/B7-1 and CD86/B7.2 (PubMed:11279501, PubMed:11279502, PubMed:28484017). Interacts with ICOSLG (PubMed:28484017).
Inhibitory receptor acting as a major negative regulator of T-cell responses. The affinity of CTLA4 for its natural B7 family ligands, CD80 and CD86, is considerably stronger than the affinity of their cognate stimulatory coreceptor CD28.
N-glycosylation is important for dimerization.
Phosphorylation at Tyr-201 prevents binding to the AP-2 adapter complex, blocks endocytosis, and leads to retention of CTLA4 on the cell surface.
The therapeutic antibody Ipilimumab competes for the binding site of the endogenous ligands CD80/B7-1, CD86/B7-2 and ICOSLG.
Widely expressed with highest levels in lymphoid tissues. Detected in activated T-cells where expression levels are 30- to 50-fold less than CD28, the stimulatory coreceptor, on the cell surface following activation.
Component of nuclear RNase P and RNase MRP ribonucleoproteins (PubMed:8918471, PubMed:16723659). RNase P consists of a catalytic RNA moiety and 10 different protein chains; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40 (PubMed:16723659, PubMed:30454648). Within the RNase P complex, POP1, POP7 and RPP25 form the 'finger' subcomplex, POP5, RPP14, RPP40 and homodimeric RPP30 form the 'palm' subcomplex, and RPP21, POP4 and RPP38 form the 'wrist' subcomplex. All subunits of the RNase P complex interact with the catalytic RNA (PubMed:30454648). Several subunits of RNase P are also part of the RNase MRP complex. RNase MRP consists of a catalytic RNA moiety and about 8 protein subunits; POP1, POP7, RPP25, RPP30, RPP38, RPP40 and possibly also POP4 and POP5 (PubMed:16723659, PubMed:28115465).
Component of ribonuclease P, a ribonucleoprotein complex that generates mature tRNA molecules by cleaving their 5'-ends (PubMed:8918471, PubMed:30454648). Also a component of the MRP ribonuclease complex, which cleaves pre-rRNA sequences (PubMed:28115465).
Catalyzes the degradation of compounds such as putrescine, histamine, spermine, and spermidine, substances involved in allergic and immune responses, cell proliferation, tissue differentiation, tumor formation, and possibly apoptosis. Placental DAO is thought to play a role in the regulation of the female reproductive function.
Inhibited by amiloride in a competitive manner.
Inhibited by isoniazid, cimetidine, clonidine, pentamidine, berenil and pentamidine.
Part of a large chaperone multiprotein complex comprising CABP1, DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX.
Ubiquitously expressed with high expression in testis, moderate expression in the pancreas, spleen, prostate, small intestine and colon. Very low expression is seen in brain and skeletal muscle.
Disordered region at the N-terminus undergoes liquid-liquid phase separation (LLPS) for the formation of MARDO (mitochondria-associated ribonucleoprotein domain), a membraneless compartment that stores maternal mRNAs in oocytes.
Ubiquitinated and degradaded by the proteasome during oocyte meiotic maturation, leading to MARDO (mitochondria-associated ribonucleoprotein domain) membraneless compartment dissolution.
mRNA-binding protein that mediates formation of MARDO (mitochondria-associated ribonucleoprotein domain), a membraneless compartment that stores maternal mRNAs in oocytes. MARDO assembly around mitochondria is directed by an increase in mitochondrial membrane potential during oocyte growth. Promotes formation of MARDO phase-separated membraneless compartment by undergoing liquid-liquid phase separation upon binding to maternal mRNAs. Binds to the 3'-UTR of maternal mRNAs. Maternal mRNAs stored in the MARDO are translationally repressed. Essential for female fertility and oocyte-to-embryo transition by coordinating maternal mRNA storage, translation and degradation.
Belongs to the DEAD box helicase family. DEAH subfamily. DDX16/PRP8 sub-subfamily.
Component of pre-catalytic spliceosome complexes (PubMed:20423332, PubMed:20841358, PubMed:25296192, PubMed:29360106). Component of the minor spliceosome, which splices U12-type introns (PubMed:33509932). Interacts with GPKOW. Interacts with TRIM6 (PubMed:35263596). Interacts with RIGI (PubMed:35263596).
Expressed in the spleen, thyroid and testis. Also expressed in the brain and cerebellum.
Required for pre-mRNA splicing as component of the spliceosome (PubMed:20423332, PubMed:20841358, PubMed:25296192, PubMed:29360106). Contributes to pre-mRNA splicing after spliceosome formation and prior to the first transesterification reaction. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). Plays also a role in innate antiviral response by acting as a pattern recognition receptor sensing splicing signals in viral RNA (PubMed:35263596). Mechanistically, TRIM6 promotes the interaction between unanchored 'Lys-48'-polyubiquitin chains and DHX16, leading to DHX16 interaction with RIGI and ssRNA to amplify RIGI-dependent innate antiviral immune responses (PubMed:35263596).
Helicase activity toward DNA substrate is inhibited by micromolar concentrations of 5,6-dichloro-1-(beta-D-ribofuranosyl)benzotriazole (DRBT) and 4,5,6,7-tetrabromobenzotriazole (TBBT). Helicase activity toward RNA substrate is inhibited by elevated concentrations of TBBT. Inhibited by some ring-expanded nucleoside analogs.
Homodimer; in free form (PubMed:19509288). Component of the mitochondrial degradosome (mtEXO) complex which is a heteropentamer containing 2 copies of SUPV3L1 and 3 copies of PNPT1 (PubMed:19509288, PubMed:29967381). As part of mitochondrial degradosome complex, interacts with GRSF1 in a RNA-dependent manner; the interaction enhances the activity of the complex (PubMed:29967381). Interacts with LAMTOR5/HBXIP, WRN and BLM (PubMed:16176273, PubMed:17961633).
Major helicase player in mitochondrial RNA metabolism. Component of the mitochondrial degradosome (mtEXO) complex, that degrades 3' overhang double-stranded RNA with a 3'-to-5' directionality in an ATP-dependent manner. Involved in the degradation of non-coding mitochondrial transcripts (MT-ncRNA) and tRNA-like molecules (PubMed:29967381). ATPase and ATP-dependent multisubstrate helicase, able to unwind double-stranded (ds) DNA and RNA, and RNA/DNA heteroduplexes in the 5'-to-3' direction. Plays a role in the RNA surveillance system in mitochondria; regulates the stability of mature mRNAs, the removal of aberrantly formed mRNAs and the rapid degradation of non coding processing intermediates. Also implicated in recombination and chromatin maintenance pathways. May protect cells from apoptosis. Associates with mitochondrial DNA.
Despite its name, it does not contain a zinc-finger domain.
Probable S-adenosyl-L-methionine-dependent methyltransferase that acts as a component of the wybutosine biosynthesis pathway. Wybutosine is a hyper modified guanosine with a tricyclic base found at the 3'-position adjacent to the anticodon of eukaryotic phenylalanine tRNA (By similarity). May methylate the carboxyl group of leucine residues to form alpha-leucine ester residues.
Belongs to the sodium channel auxiliary subunit SCN3B (TC 8.A.17) family.
Modulates channel gating kinetics. Causes unique persistent sodium currents. Inactivates the sodium channel opening more slowly than the subunit beta-1. Its association with NFASC may target the sodium channels to the nodes of Ranvier of developing axons and retain these channels at the nodes in mature myelinated axons (By similarity).
The voltage-sensitive sodium channel consists of an ion conducting pore forming alpha-subunit regulated by one or more beta-1, beta-2, beta-3 and/or beta-4 subunits. Beta-1 and beta-3 are non-covalently associated with alpha, while beta-2 and beta-4 are covalently linked by disulfide bonds (By similarity).
Asymmetrically dimethylated. Probably methylated by PRMT1.
Expressed at high levels in thymus, lymph node, spleen, fetal kidney and adult testis. Constitutively associated with MPL and EPOR in hematopoietic cells.
Interacts with MPL/TPOR and EPOR and dissociates after ligand stimulation (PubMed:11784712). Interacts with DDX6, G3BP1, and ATXN2 (PubMed:23209657). Interacts with PRMT1 (PubMed:25748791). Interacts with CIC and ATXN1 (By similarity).
Involved in the regulation of stress granule and P-body formation.
Thrombopoietin triggers the phosphorylation on tyrosine residues in a way that is dependent on MPL C-terminal domain.
Autoproteolytically cleaved into 2 subunits, an extracellular subunit and a seven-transmembrane subunit. This proteolytic processing takes place early in the biosynthetic pathway, either in the endoplasmic reticulum or in the early compartment of the Golgi apparatus (By similarity).
Calcium-independent receptor of high affinity for alpha-latrotoxin, an excitatory neurotoxin present in black widow spider venom which triggers massive exocytosis from neurons and neuroendocrine cells (PubMed:35907405). Receptor for TENM2 that mediates heterophilic synaptic cell-cell contact and postsynaptic specialization. Receptor probably implicated in the regulation of exocytosis (By similarity).
Forms a heterodimer, consisting of a large extracellular region (p120) non-covalently linked to a seven-transmembrane moiety (p85). Interacts with syntaxin and with proteins of the SHANK family via the PDZ domain. Interacts (via extracellular domain) with FLRT1, FLRT2 and FLRT3 (via extracellular domain) (By similarity).
The extracellular domain coupled to the a single transmembrane region are sufficient for full responsiveness to alpha-latrotoxin.
Acts as an anion channel mediating the transport of chloride, sulfate and oxalate ions (PubMed:11834742). Mediates the transport of bromide, iodide, nitrate, gluconate, thiocyanate and bicarbonate ions (By similarity). Its permeability towards bicarbonate is weak and increases when pH is above 7 (By similarity). Mediates thiocyanate transport in retinal pigment epithelium cells (By similarity). Mediates iodide transport in the thyroid gland, playing an important role in the synthesis of thyroid hormones and the maintenance of thyroid function (PubMed:31372509). Although it is an anion channel, according to PubMed:12736153 and PubMed:32119864 it has been shown to exhibit chloride-bicarbonate exchanger activity.
Although it is an anion channel, according to PubMed:12736153 and PubMed:32119864 it has been shown to exhibit chloride-bicarbonate exchanger activity.
Disease-causing variants in SLC26A7 have been found in patients with thyroid dyshormonogenesis and congenital goitrous hypothyroidism.
Expressed in the thyroid gland (at protein level). Expressed in tonsillar high endothelial venule endothelial cells (HEVEC), placenta and in testis, expressed in a subgroup of basal cells in the epididymal ducts.
Is active at both alkaline and acidic pH. Activity is inhibited by 4,4'-Di-isothiocyanatostilbene-2,2'-disulfonic acid (DIDS - an inhibitor of several anion channels and transporters).
Up-regulated by hyperosmolarity and down-regulated by acidic pH.
Activates transcription. Required for nuclear translocation of FLOT1. Promotes cell proliferation.
Belongs to the Mediator complex subunit 25 family. PTOV1 subfamily.
Despite sequence similarity to MED25, to date this protein has not been identified as a component of the Mediator complex.
Expressed at low levels in quiescent cells. Expression rises upon entry into S-phase.
Expressed in brain, heart, kidney, liver, placenta, skeletal muscle and small intestine.
May activate transcription. Required for nuclear translocation of FLOT1. Promotes cell proliferation.
May interact with CREBBP. Interacts with FLOT1.
Ubiquitinated by the CRL2(KLHDC2) complex, which recognizes the diglycine (Gly-Gly) at the C-terminus, leading to its degradation (PubMed:29779948). Ubiquitinated by the CRL2(APPBP2) complex, which recognizes the Arg-Xaa-Xaa-Gly sequence at the C-terminus, leading to its degradation (PubMed:29779948).
May determine the distinct specification program of class A neurons in the dorsal part of the spinal cord and suppress specification of class B neurons.
Forms homodimers and heterodimers (PubMed:21462929).
The N-terminal coiled coil regions mediate homodimerization preferentially and heterodimerization type beta/beta. The C-terminal, non-coiled coil regions mediate heterodimerization type beta/alpha (By similarity).
Cytoplasmic protein that plays a role in the proper assembly of dynein arm complexes in motile cilia in both respiratory cells and sperm flagella.
Expressed in testis and in epithelial cells of trachea and bronchial tube.
Interacts (via SH3 domains) with CACNA1S (PubMed:29078335). Interacts with CACNA1H. Interacts with CACNA1C (By similarity).
Promotes expression of the ion channel CACNA1H at the cell membrane, and thereby contributes to the regulation of channel activity. Plays a minor and redundant role in promoting the expression of calcium channel CACNA1S at the cell membrane, and thereby contributes to increased channel activity. Slows down the inactivation rate of the calcium channel CACNA1C.
Interacts with HORMAD1 (PubMed:27723721). Interacts with REC114 (PubMed:31704776). Part of the MCD recombinosome complex, at least composed of IHO1, REC114 and MEI4 (By similarity). Interacts with ANKRD31 (By similarity).
Required for DNA double-strand breaks (DSBs) formation in unsynapsed regions during meiotic recombination. Probably acts by forming a complex with MEI4 and REC114, which activates DSBs formation in unsynapsed regions, an essential step to ensure completion of synapsis. Not required for HORMAD1 functions in pairing-independent synaptonemal complex formation, ATR recruitment to unsynapsed axes, meiotic silencing of unsynapsed chromatin (MSUC) or meiotic surveillance.
Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. May also promote the heterodimerization with the EGF receptor.
Extensive glycosylation precedes the proteolytic cleavage.
Restricted to the cerebellum in the adult.
Expressed in photoreceptor cells (at protein level).
Identified in a complex with RILP and DCTN1; interacts directly with RILP, but does not interact directly with DCTN1. Interacts with PRPH2.
Palmitoylated. Palmitoylation is required to maintain the protein at the melanosome membrane.
Probably functions as cargo-recognition protein that couples cytoplasmic vesicles to the transport machinery. Plays a role in hair pigmentation, a process that involves shedding of melanosome-containing vesicles from melanocytes, followed by phagocytosis of the melanosome-containing vesicles by keratinocytes. Functions on melanosomes as receptor for RILP and the complex formed by RILP and DCTN1, and thereby contributes to retrograde melanosome transport from the cell periphery to the center. Overexpression causes accumulation of late endosomes and/or lysosomes at the microtubule organising center (MTOC) at the center of the cell. Probably binds cholesterol and requires the presence of cholesterol in membranes to function in microtubule-mediated retrograde organelle transport. Binds phosphatidylinositol 3-phosphate, phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate and phosphatidylinositol 3,5-bisphosphate, but not phosphatidylinositol 3,4-bisphosphate or phosphatidylinositol 4,5-bisphosphate (By similarity). Required for normal phagosome clearing and normal activation of lysosomal enzymes in lysosomes from retinal pigment epithelium cells (PubMed:19240024). Required for normal degradation of the lipofuscin component N-retinylidene-N-retinylethanolamine (A2E) in the eye. May function in membrane fusion and regulate the biogenesis of disk membranes of photoreceptor rod cells (By similarity).
(Microbial infection) In case of infection by influenza A virus; required for viral replication in tracheal cells.
Involved in the cell surface expression of neuronal nicotinic receptors (By similarity). Binds RNA (By similarity).
Present in periodontal ligament fibroblasts (at protein level).
Guanine nucleotide exchange factor (GEF) regulating homeostasis of late endocytic pathway, including endosomal positioning, maturation and secretion, possibly through activating Rab proteins such as RAB27A and RAB27B. Seems to promote the exchange of GDP to GTP, converting inactive GDP-bound RAB27A and RAB27B into their active GTP-bound form.
Interacts with RAB27A and RAB27B (GDP-bound forms preferentially).
(Microbial infection) Phosphorylates herpes simplex virus 1/HHV-1 protein ICP0 and thus activates its SUMO-targeted ubiquitin ligase activity.
Activated through phosphorylation at Thr-68 by ATM in response to DNA double-strand breaks. Activation is modulated by several mediators including MDC1 and TP53BP1. Induces homodimerization with exchange of the T-loop/activation segment between protomers and transphosphorylation of the protomers. The autophosphorylated kinase dimer is fully active. Negatively regulated by PPM1D through dephosphorylation of Thr-68.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CHK2 subfamily.
High expression is found in testis, spleen, colon and peripheral blood leukocytes. Low expression is found in other tissues.
Homodimer. Homodimerization is part of the activation process but the dimer may dissociate following activation. Interacts with PML. Interacts with TP53. Interacts with RB1; phosphorylates RB1. Interacts with BRCA1. Interacts (phosphorylated at Thr-68) with MDC1; requires ATM-mediated phosphorylation of CHEK2. Interacts with TP53BP1; modulates CHEK2 phosphorylation at Thr-68 in response to ionizing radiation. Interacts with CDC25A; phosphorylates CDC25A and mediates its degradation in response to ionizing radiation. Interacts with CUL1; mediates CHEK2 ubiquitination and regulation. Interacts with CDKN2AIP. Interacts (via protein kinase domain) with CCAR2 (via N-terminus). Interacts with SIRT1.
Phosphorylated. Phosphorylated at Ser-73 by PLK3 in response to DNA damage, promoting phosphorylation at Thr-68 by ATM and the G2/M transition checkpoint. Phosphorylation at Thr-68 induces homodimerization. Autophosphorylates at Thr-383 and Thr-387 in the T-loop/activation segment upon dimerization to become fully active and phosphorylate its substrates like for instance CDC25C. DNA damage-induced autophosphorylation at Ser-379 induces CUL1-mediated ubiquitination and regulates the pro-apoptotic function. Phosphorylation at Ser-456 also regulates ubiquitination. Phosphorylated by PLK4.
Retains low level of catalytic activity.
Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells. Promotes the CCAR2-SIRT1 association and is required for CCAR2-mediated SIRT1 inhibition (PubMed:25361978).
Ubiquitinated. CUL1-mediated ubiquitination regulates the pro-apoptotic function. Ubiquitination may also regulate protein stability. Ubiquitinated by RNF8 via 'Lys-48'-linked ubiquitination.
(Microbial infection) Deamidated on 'Asn-210' by herpes simplex virus 1 protein UL37. This modification significantly reduces CGAS-dependent cGAMP production and innate immune signaling induced by dsDNA.
(Microbial infection) Degraded by an autophagy-mediated mechanism in presence of Chikungunya virus capsid protein.
(Microbial infection) Interacts with cytomegalovirus protein UL31; this interaction promotes dissociation of DNA from CGAS, thereby inhibiting the enzymatic activity of CGAS.
(Microbial infection) Interacts with herpes simplex virus 1 protein UL37; this interaction deaminates CGAS and inhibits its activation.
(Microbial infection) Interacts with herpes simplex virus 1 tegument protein VP22 (UL49); this interaction inhibits cGAS enzymatic activity by preventing the formation of liquid-like droplets by CGAS.
(Microbial infection) Interacts with herpes virus 8/HHV-8 protein ORF52; this interaction inhibits cGAS enzymatic activity by preventing the formation of liquid-like droplets by CGAS.
(Microbial infection) Interacts with herpesvirus 3 tegument protein VP22 (ORF9); this interaction inhibits cGAS enzymatic activity by preventing the formation of liquid-like droplets by CGAS.
(Microbial infection) Interacts with human cytomegalovirus proteins UL42 and UL83; these interactions result in the inhibition of cGAS-STING signaling.
(Microbial infection) Interacts with vaccinia virus protein OPG067; this interaction promotes CGAS proteasomal degradation.
(Microbial infection) Nucleotidyltransferase activity is inhibited by different herpesvirus tegument proteins (Herpes simplex virus 1 tegument protein VP22, herpes virus 8 protein ORF52 and herpesvirus 3 tegument protein VP22/ORF9) (PubMed:34015248, PubMed:34387695). Viral tegument proteins act by disrupting liquid-like droplets in which CGAS is activated, thereby preventing CGAS activity (PubMed:34015248, PubMed:34387695).
Acetylation at Lys-384, Lys-394 and Lys-414 inhibits the cyclic GMP-AMP synthase activity (PubMed:30799039). Deacetylated upon cytosolic DNA challenge such as viral infections (PubMed:30799039). Acetylation can be mediated by aspirin (acetylsalicylate) drug, which directly acetylates CGAS (PubMed:30799039). Acetylation by aspirin efficiently inhibits CGAS-mediated immune responses and is able to suppress self-DNA-induced autoimmunity (PubMed:30799039). Acetylation at Lys-47, Lys-56, Lys-62 and Lys-83 by KAT5 increases the cyclic GMP-AMP synthase activity by promoting DNA-binding and subsequent activation (PubMed:32817552).
Binds 1 Mg(2+) ion per subunit (PubMed:30007416). Is also active with Mn(2+) (PubMed:32814054). Mn(2+)-activated enzyme forms an inverted pppGp(2'-5')A intermediate, suggesting a non-canonical but accelerated 2',3'-cGAMP cyclization without substrate flip-over (By similarity). Mn(2+) ions are coordinated by triphosphate moiety of the inverted substrate, independent of the catalytic triad residues (By similarity).
Degraded via selective autophagy following interaction with IRGM (PubMed:32715615). IRGM promotes CGAS recruitment to autophagosome membranes, promoting its SQSTM1/p62-dependent autophagic degradation (PubMed:32715615).
Expressed in the monocytic cell line THP1.
Lys-187 and Leu-195 residues are specific to human and destabilize the interactions with short DNA, shifting the specificity toward the detection of curved long DNAs (PubMed:30007416). Lys-187 and Leu-195 also restrain cGAMP production and, therefore, immune activation, allowing a more fine-tuned response to pathogens (PubMed:30007416).
Monomer in the absence of DNA (PubMed:28363908). Homodimer in presence of dsDNA: forms a 2:2 dimer with two enzymes binding to two DNA molecules (PubMed:33273464, PubMed:30007416, PubMed:30799039, PubMed:31142647). Interacts with nucleosomes; interaction is mainly mediated via histones H2A and H2B and inactivates the nucleotidyltransferase activity by blocking DNA-binding and subsequent activation (PubMed:32911481, PubMed:32911480, PubMed:33051594, PubMed:32911482, PubMed:32912999). Interacts with PQBP1 (via WW domain) (PubMed:26046437). Interacts with TRIM14; this interaction recruits USP14, leading to deubiquitinate and stabilize CGAS and promote type I interferon production (PubMed:27666593, PubMed:32404352). Interacts with ZCCHC3; promoting sensing of dsDNA by CGAS (PubMed:30135424). Interacts (when not monomethylated) with (poly-ADP-ribosylated) PARP1; interaction takes place in the nucleus and prevents the formation of the PARP1-TIMELESS complex (PubMed:30356214). Interacts (when monomethylated) with SGF29; interaction with SGF29 prevents interaction with PARP1 (By similarity). Interacts with PCBP2; preventing the formation of liquid-like droplets in which CGAS is activated (PubMed:35322803). Interacts with IRGM; promoting CGAS degradation (PubMed:32715615).
Monomethylated at Lys-506 by SETD7 (PubMed:35210392). Monomethylation promotes interaction with SGF29, preventing interaction between PARP1 nad SGF29 (By similarity). Demethylation by RIOX1 promotes interaction with PARP1, followed by PARP1 inactivation (By similarity).
Nucleotidyltransferase that catalyzes the formation of cyclic GMP-AMP (2',3'-cGAMP) from ATP and GTP and plays a key role in innate immunity (PubMed:23258413, PubMed:24077100, PubMed:25131990, PubMed:23707061, PubMed:23722159, PubMed:29976794, PubMed:30799039, PubMed:21478870, PubMed:23707065, PubMed:24116191, PubMed:24462292, PubMed:32814054, PubMed:33273464, PubMed:26300263, PubMed:33542149, PubMed:31142647, PubMed:37217469). Catalysis involves both the formation of a 2',5' phosphodiester linkage at the GpA step and the formation of a 3',5' phosphodiester linkage at the ApG step, producing c[G(2',5')pA(3',5')p] (PubMed:28214358, PubMed:28363908). Acts as a key DNA sensor: directly binds double-stranded DNA (dsDNA), inducing the formation of liquid-like droplets in which CGAS is activated, leading to synthesis of 2',3'-cGAMP, a second messenger that binds to and activates STING1, thereby triggering type-I interferon production (PubMed:28314590, PubMed:28363908, PubMed:29976794, PubMed:33230297, PubMed:32817552, PubMed:33606975, PubMed:35438208, PubMed:35460603, PubMed:35322803, PubMed:35503863). Preferentially recognizes and binds curved long dsDNAs of a minimal length of 40 bp (PubMed:30007416). Acts as a key foreign DNA sensor, the presence of double-stranded DNA (dsDNA) in the cytoplasm being a danger signal that triggers the immune responses (PubMed:28363908). Has antiviral activity by sensing the presence of dsDNA from DNA viruses in the cytoplasm (PubMed:28363908). Also acts as an innate immune sensor of infection by retroviruses, such as HIV-2, by detecting the presence of reverse-transcribed DNA in the cytosol (PubMed:23929945, PubMed:24269171, PubMed:30270045, PubMed:32852081). In contrast, HIV-1 is poorly sensed by CGAS, due to its capsid that cloaks viral DNA from CGAS detection (PubMed:24269171, PubMed:30270045, PubMed:32852081). Detection of retroviral reverse-transcribed DNA in the cytosol may be indirect and be mediated via interaction with PQBP1, which directly binds reverse-transcribed retroviral DNA (PubMed:26046437). Also detects the presence of DNA from bacteria, such as M.tuberculosis (PubMed:26048138). 2',3'-cGAMP can be transferred from producing cells to neighboring cells through gap junctions, leading to promote STING1 activation and convey immune response to connecting cells (PubMed:24077100). 2',3'-cGAMP can also be transferred between cells by virtue of packaging within viral particles contributing to IFN-induction in newly infected cells in a cGAS-independent but STING1-dependent manner (PubMed:26229115). Also senses the presence of neutrophil extracellular traps (NETs) that are translocated to the cytosol following phagocytosis, leading to synthesis of 2',3'-cGAMP (PubMed:33688080). In addition to foreign DNA, can also be activated by endogenous nuclear or mitochondrial DNA (PubMed:31299200, PubMed:28738408, PubMed:28759889, PubMed:33230297, PubMed:33031745). When self-DNA leaks into the cytosol during cellular stress (such as mitochondrial stress, SARS-CoV-2 infection causing severe COVID-19 disease, DNA damage, mitotic arrest or senescence), or is present in form of cytosolic micronuclei, CGAS is activated leading to a state of sterile inflammation (PubMed:31299200, PubMed:28738408, PubMed:28759889, PubMed:33230297, PubMed:33031745, PubMed:35045565). Acts as a regulator of cellular senescence by binding to cytosolic chromatin fragments that are present in senescent cells, leading to trigger type-I interferon production via STING1 and promote cellular senescence (By similarity). Also involved in the inflammatory response to genome instability and double-stranded DNA breaks: acts by localizing to micronuclei arising from genome instability (PubMed:28738408, PubMed:28759889). Micronuclei, which are frequently found in cancer cells, consist of chromatin surrounded by their own nuclear membrane: following breakdown of the micronuclear envelope, a process associated with chromothripsis, CGAS binds self-DNA exposed to the cytosol, leading to 2',3'-cGAMP synthesis and subsequent activation of STING1 and type-I interferon production (PubMed:28738408, PubMed:28759889). Activated in response to prolonged mitotic arrest, promoting mitotic cell death (PubMed:31299200). In a healthy cell, CGAS is however kept inactive even in cellular events that directly expose it to self-DNA, such as mitosis, when cGAS associates with chromatin directly after nuclear envelope breakdown or remains in the form of postmitotic persistent nuclear cGAS pools bound to chromatin (PubMed:31299200, PubMed:33542149). Nuclear CGAS is inactivated by chromatin via direct interaction with nucleosomes, which block CGAS from DNA binding and thus prevent CGAS-induced autoimmunity (PubMed:31299200, PubMed:33542149, PubMed:33051594, PubMed:32911482, PubMed:32912999). Also acts as a suppressor of DNA repair in response to DNA damage: inhibits homologous recombination repair by interacting with PARP1, the CGAS-PARP1 interaction leading to impede the formation of the PARP1-TIMELESS complex (PubMed:30356214, PubMed:31544964). In addition to DNA, also sense translation stress: in response to translation stress, translocates to the cytosol and associates with collided ribosomes, promoting its activation and triggering type-I interferon production (PubMed:34111399). In contrast to other mammals, human CGAS displays species-specific mechanisms of DNA recognition and produces less 2',3'-cGAMP, allowing a more fine-tuned response to pathogens (PubMed:30007416).
Palmitoylation at Cys-474 by ZDHHC18 impairs DNA-binding, thereby preventing the cyclic GMP-AMP synthase activity.
Poly-ADP-ribosylation at Asp-191 by PARP1 impairs DNA-binding, thereby preventing the cyclic GMP-AMP synthase activity.
Polyglutamylated by TTLL6 at Glu-286, leading to impair DNA-binding activity. Monoglutamylated at Glu-314 by TTLL4, leading to impair the nucleotidyltransferase activity. Deglutamylated by AGBL5/CCP5 and AGBL6/CCP6.
Proteolytically cleaved by apoptotic caspases during apoptosis, leading to its inactivation (PubMed:30878284). The damage of the nucleus and the mitochondria during apoptosis leads to leakage of nuclear and mitochondrial DNA, which activate CGAS: cleavage and inactivation during apoptosis in required to prevent cytokine overproduction (By similarity). Cleaved by CASP3 at Asp-319 during virus-induced apoptosis, thereby inactivating it and preventing cytokine overproduction (PubMed:30878284). Cleaved by CASP1 at Asp-140 and Asp-157 upon DNA virus infection; the cleavage impairs cGAMP production (PubMed:28314590). Also cleaved by the pyroptotic CASP4 and CASP5 during non-canonical inflammasome activation; they don't cut at the same sites than CASP1 (PubMed:28314590).
Sumoylated at Lys-231 and Lys-479 by TRIM38 in uninfected cells and during the early phase of viral infection, promoting its stability by preventing ubiquitination at Lys-285 and Lys-479, and subsequent degradation (By similarity). Desumoylated by SENP2 during the late phase of viral infection (By similarity). Sumoylation at Lys-347, Lys-384 and Lys-394 prevents DNA-binding, oligomerization and nucleotidyltransferase activity (By similarity). Desumoylation at Lys-347, Lys-384 and Lys-394 by SENP7 relieves inhibition and activates CGAS (By similarity).
The N-terminal disordered part (1-160) binds unspecifically dsDNA and expands the binding and moving range of CGAS on dsDNA (PubMed:28214358, PubMed:28363908). The disordered and positively charged residues enhance CGAS-DNA phase separation by increasing the valencies of DNA-binding (PubMed:29976794). The N-terminus is required to sense chromatin and its phosphorylation blocks its activation by chromatin DNA (PubMed:33542149). When the N-terminal part (1-160) is missing the protein bound to dsDNA homodimerizes (By similarity).
The N-terminal disordered part (1-160) is phosphorylated by AURKB during the G2-M transition, blocking CGAS liquid phase separation and preventing activation (PubMed:33542149). Phosphorylation at Tyr-215 by BLK promotes cytosolic retention (PubMed:30356214). Localizes into the nucleus following dephosphorylation at Tyr-215 (PubMed:30356214). Phosphorylation at Ser-435 activates the nucleotidyltransferase activity (PubMed:32474700). Dephosphorylation at Ser-435 by PPP6C impairs its ability to bind GTP, thereby inactivating it (PubMed:32474700). Phosphorylation at Thr-68 and Ser-213 by PRKDC inhibits its cyclic GMP-AMP synthase activity by impairing homodimerization and activation (PubMed:33273464). Phosphorylation at Ser-305 by AKT (AKT1, AKT2 or AKT3) suppresses the nucleotidyltransferase activity (PubMed:26440888). Phosphorylation at Ser-305 by CDK1 during mitosis leads to its inhibition, thereby preventing CGAS activation by self-DNA during mitosis (PubMed:32351706). Dephosphorylated at Ser-305 by protein phosphatase PP1 upon mitotic exit (PubMed:32351706).
The arginine-anchor tightly binds to the canonical H2A acidic-patch residues.
The enzyme activity is strongly increased by double-stranded DNA (dsDNA), but not by single-stranded DNA or RNA (PubMed:23258413, PubMed:23707061, PubMed:26300263). DNA-binding induces the formation of liquid-like droplets in which CGAS is activated (PubMed:29976794, PubMed:33606975). Liquid-like droplets also create a selective environment that restricts entry of negative regulators, such as TREX1 or BANF1/BAF, allowing sensing of DNA (PubMed:33606975). A number of mechanisms exist to restrict its activity toward self-DNA (PubMed:31299200, PubMed:33051594, PubMed:32911482, PubMed:32912999, PubMed:33542149, PubMed:32792394). The nucleotidyltransferase activity is inhibited in the nucleus via its association with nucleosomes: interacts with the acidic patch of histones H2A and H2B, thereby blocking DNA-binding and subsequent activation (PubMed:31299200, PubMed:33051594, PubMed:32911482, PubMed:32912999). CGAS is also inactive when associated with mitotic chromatin (PubMed:33542149). Chromatin-bound CGAS cannot be activated by exogenous DNA in mitotic cells: phosphorylation of the N-terminal disordered part by AURKB during the G2-M transition blocks CGAS liquid phase separation and activation (PubMed:33542149). Activity toward self-DNA is inhibited by BANF1/BAF upon acute loss of nuclear membrane integrity: BANF1/BAF acts by outcompeting CGAS for DNA-binding, thereby preventing CGAS activation (PubMed:32792394). DNA-induced activation at micronuclei is also limited by TREX1, which degrades micronuclear DNA upon nuclear envelope rupture, thereby preventing CGAS activation (PubMed:33476576). Acetylation at Lys-384, Lys-394 and Lys-414 inhibits the cyclic GMP-AMP synthase activity (PubMed:30799039). Inhibited by aspirin (acetylsalicylate) drug, which acetylates CGAS (PubMed:30799039). Acetylation by KAT5 increases the cyclic GMP-AMP synthase activity by promoting DNA-binding and subsequent activation (PubMed:32817552). Phosphorylation at Ser-305 suppresses the nucleotidyltransferase activity (PubMed:26440888). Phosphorylation at Ser-435 promotes the cyclic GMP-AMP synthase activity (PubMed:32474700). Phosphorylation at Thr-68 and Ser-213 inhibits its cyclic GMP-AMP synthase activity (PubMed:33273464). Ubiquitination at Lys-173 and Lys-384 via 'Lys-27'-linked polyubiquitination enhances the cyclic GMP-AMP synthase activity (PubMed:28273161). Monoubiquitination at Lys-347 promotes oligomerization and subsequent activation (PubMed:29426904). Sumoylation at Lys-347, Lys-384 and Lys-394 prevents DNA-binding, oligomerization and nucleotidyltransferase activity (By similarity). The enzyme activity is impaired by the cleavage at Asp-140 and Asp-157 produced by CASP1 (PubMed:28314590). In addition to DNA, also activated by collided ribosomes upon translation stress: specifically binds collided ribosomes, promoting its activation and triggering type-I interferon production (PubMed:34111399). Strongly inhibited by compound PF-06928215, which is specific for human protein (PubMed:28934246, PubMed:30007416, PubMed:32459092). Inhibited by small-molecule inhibitors with a pyridoindole tricyclic core G108, G140 and G150 (PubMed:31113940).
Ubiquitinated at Lys-414 via 'Lys-48'-linked polyubiquitin chains, leading to its SQSTM1-mediated autophagic degradation (PubMed:27666593). Interaction with TRIM14 promotes recruitment of USP14, leading to deubiquitinate Lys-414 and stabilize CGAS (PubMed:27666593). Ubiquitinated at Lys-173 and Lys-384 by RNF185 via 'Lys-27'-linked polyubiquitination, promoting CGAS cyclic GMP-AMP synthase activity (PubMed:28273161). Monoubiquitination at Lys-347 by TRIM56 promotes oligomerization and subsequent activation (PubMed:29426904). Monoubiquitination by TRIM41 promotes CGAS activation (PubMed:29760876). Ubiquitination at Lys-285 and Lys-479 via 'Lys-48'-linked polyubiquitination promotes its degradation (By similarity). Deubiquitination at Lys-285 by USP29 promotes its stabilization (By similarity). Deubiquitinated by USP27X, promoting its stabilization (PubMed:31534008). Ubiquitinated at Lys-411 via 'Lys-63'-linked polyubiquitin chains by MARCHF8, leading to the inhibition of its DNA binding ability (PubMed:35503863).
Undergoes a liquid-like phase transition after binding to DNA, which is dependent on zinc.
Nucleolar protein that acts as a modulator of rRNA synthesis. Plays a central role during organogenesis (By similarity).
Interacts with VCP through the PUB domain (via C-terminus) and VIM motif (via N-terminus); the interaction is direct (PubMed:18656546, PubMed:19174149, PubMed:21896481, PubMed:21822278, PubMed:26475856). Forms a ternary complex with CAV1 and VCP (PubMed:21822278). Interacts with SYVN1 (PubMed:18656546). Interacts with HERPUD1 (PubMed:18656546). Interacts with VCPKMT (PubMed:23349634). May interact with DERL1 (PubMed:19275885). Interacts with PLAA, VCP and YOD1; may form a complex involved in macroautophagy (PubMed:27753622). Interacts with LMAN1 (PubMed:22337587).
May negatively regulate the ATPase activity of VCP, an ATP-driven segregase that associates with different cofactors to control a wide variety of cellular processes (PubMed:26475856). As a cofactor of VCP, it may play a role in the transport of CAV1 to lysosomes for degradation (PubMed:21822278, PubMed:23335559). It may also play a role in endoplasmic reticulum-associated degradation (ERAD) of misfolded proteins (PubMed:19275885). Together with VCP and other cofactors, it may play a role in macroautophagy, regulating for instance the clearance of damaged lysosomes (PubMed:27753622).
The UBX domain lacks key residues critical for VCP binding.
Was reported to interact with MDM2 and USP7 and to act in a complex with VCP in cooperation with USP7 to promote MDM2 deubiquitination and stabilization. However, the corresponding article has been retracted.
Interacts with NRBP1 (PubMed:22510880). Interacts with PKM isoform M2; the interaction results in reduced nuclear levels of PKM isoform M2, leading to repression of cyclin CCND1 transcription and reduced cell growth (PubMed:27573352). Interacts with WDR77 (PubMed:27337956).
May be involved in the loss of cell cycle regulation in colorectal tumors, expression is shown to be decreased in the majority of tumors.
Reduces the level of nuclear PKM isoform M2 which results in repression of cyclin CCND1 transcription and reduced cell growth.
A chromosomal aberration involving NHEJ1 is found in a patient with polymicrogyria. Translocation t(2;7)(q35;p22).
Belongs to the XRCC4-XLF family. XLF subfamily.
DNA repair protein involved in DNA non-homologous end joining (NHEJ); required for double-strand break (DSB) repair and V(D)J recombination (PubMed:16439204, PubMed:16439205, PubMed:17717001, PubMed:17317666, PubMed:17470781, PubMed:18644470, PubMed:20558749, PubMed:26100018, PubMed:18158905). Plays a key role in NHEJ by promoting the ligation of various mismatched and non-cohesive ends (PubMed:17717001, PubMed:17470781, PubMed:19056826). Together with PAXX, collaborates with DNA polymerase lambda (POLL) to promote joining of non-cohesive DNA ends (PubMed:30250067, PubMed:25670504). May act in concert with XRCC5-XRCC6 (Ku) to stimulate XRCC4-mediated joining of blunt ends and several types of mismatched ends that are non-complementary or partially complementary (PubMed:16439204, PubMed:16439205, PubMed:17317666, PubMed:17470781). Associates with XRCC4 to form alternating helical filaments that bridge DNA and act like a bandage, holding together the broken DNA until it is repaired (PubMed:22228831, PubMed:26100018, PubMed:28500754, PubMed:27437582, PubMed:21775435, PubMed:22287571, PubMed:21768349). The XRCC4-NHEJ1/XLF subcomplex binds to the DNA fragments of a DSB in a highly diffusive manner and robustly bridges two independent DNA molecules, holding the broken DNA fragments in close proximity to one other (PubMed:28500754, PubMed:27437582). The mobility of the bridges ensures that the ends remain accessible for further processing by other repair factors (PubMed:27437582). Binds DNA in a length-dependent manner (PubMed:17317666, PubMed:18158905).
Homodimer; mainly exists as a homodimer when not associated with XRCC4 (PubMed:18046455, PubMed:25574025, PubMed:25670504, PubMed:25941166, PubMed:18158905). Interacts with XRCC4; the interaction is direct and is mediated via a head-to-head interaction between N-terminal head regions (PubMed:16439205, PubMed:20558749, PubMed:22228831, PubMed:26100018, PubMed:18158905, PubMed:21936820, PubMed:21775435, PubMed:22287571, PubMed:21768349, PubMed:27437582). Component of the core long-range non-homologous end joining (NHEJ) complex (also named DNA-PK complex) composed of PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF (PubMed:16571728, PubMed:17317666, PubMed:33854234). Additional component of the NHEJ complex includes PAXX (PubMed:25574025, PubMed:25941166). Following autophosphorylation, PRKDC dissociates from DNA, leading to formation of the short-range NHEJ complex, composed of LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF (PubMed:33854234). Interacts with POLL (DNA polymerase lambda); promoting POLL recruitment to double-strand breaks (DSBs) and stimulation of the end-filling activity of POLL (PubMed:30250067).
Phosphorylated by PRKDC at the C-terminus in response to DNA damage (PubMed:18644470, PubMed:22228831, PubMed:28500754). Phosphorylations by PRKDC at the C-terminus of XRCC4 and NHEJ1/XLF are highly redundant and regulate ability of the XRCC4-NHEJ1/XLF subcomplex to bridge DNA (PubMed:22228831, PubMed:28500754). Phosphorylation does not prevent interaction with XRCC4 but disrupts ability to bridge DNA and promotes detachment from DNA (PubMed:22228831, PubMed:28500754).
The Leu-lock (Leu-115) site inserts into a hydrophobic pocket in XRCC4.
The coiled-coil region mediates homodimerization.
Was named 'Cernunnos' after the enigmatic Celtic god of hunting, the underworld and fertility.
Expressed in kidney, in proximal tubule epithelial cells. Expressed in colon cell lines.
The carbohydrate antigen disialyl Lewis a, which is at least partly synthesized by ST6GALNAC6, is a normal counterpart of sialyl Lewis a, better known as CA19-9, an antigen widely used as a serum marker for diagnosis of cancers in the digestive track. Disialyl Lewis a is predominantly expressed in non-malignant epithelial cells of the digestive organs, while sialyl Lewis a is preferentially expressed in cancers. Disialyl Lewis a in normal epithelial cells serves as a ligand for immunosuppressive receptors, such as SIGLEC7 and SIGLEC9, expressed on resident monocytes/macrophages and maintains immunological homeostasis of mucosal membranes in digestive organs. Sialyl Lewis a, as well as its positional isomer sialyl Lewis x, serves as a ligand for vascular cell adhesion molecule E-selectin and facilitates hematogenous metastasis through mediating adhesion of circulating cancer cells to vascular endothelium (PubMed:17760270).
Transfers the sialyl group (N-acetyl-alpha-neuraminyl or NeuAc) from CMP-NeuAc onto glycoproteins and glycolipids, forming an alpha-2,6-linkage. Produces branched type disialyl structures by transfer of a sialyl group onto the GalNAc or GlcNAc residue inside backbone core chains having a terminal sialic acid with an alpha-2,3-linkage on Gal. ST6GalNAcVI prefers glycolipids to glycoproteins, predominantly catalyzing the biosynthesis of ganglioside GD1alpha from GM1b (PubMed:12668675, PubMed:17123352). Besides GMb1, MSGG and other glycolipids, it shows activity towards sialyl Lc4Cer generating disialyl Lc4Cer, which can lead to the synthesis of disialyl Lewis a (Le(a)), suggested to be a cancer-associated antigen (PubMed:12668675). Also has activity toward GD1a and GT1b, and can generate DSGG (disialylgalactosylgloboside) from MSGG (monosialylgalactosylgloboside) (By similarity).
ATP functions as antagonist and inhibits ADP-induced mobilization of Ca(2+) (PubMed:9038354). The P2Y1 receptor-specific antagonists A3P5PS, A3P5P and A2P5P inhibit downstream signaling mediated by mobilization of Ca(2+) from intracellular stores, and platelet shape changes in response to extracellular ADP (PubMed:9442040).
Receptor for extracellular adenine nucleotides such as ADP (PubMed:9442040, PubMed:9038354, PubMed:25822790). In platelets, binding to ADP leads to mobilization of intracellular calcium ions via activation of phospholipase C, a change in platelet shape, and ultimately platelet aggregation (PubMed:9442040).
Apolipoprotein B is a major protein constituent of chylomicrons (apo B-48), LDL (apo B-100) and VLDL (apo B-100). Apo B-100 functions as a recognition signal for the cellular binding and internalization of LDL particles by the apoB/E receptor.
Defects in APOB associated with defects in other genes (polygenic) can contribute to hypocholesterolemia.
Genetic variations in APOB define the low density lipoprotein cholesterol level quantitative trait locus 4 (LDLCQ4) [MIM:615558].
Interacts with PCSK9 (PubMed:22580899). Interacts with MTTP (PubMed:26224785, PubMed:27206948). Interacts with AUP1 (PubMed:28183703). Interacts with CIDEB (By similarity).
Palmitoylated; structural requirement for proper assembly of the hydrophobic core of the lipoprotein particle.
The disease is caused by variants affecting the gene represented in this entry. Most cases of FHBL1 result from nonsense mutations in the APOB gene that lead to a premature stop codon, which generate prematurely truncated apo B protein products (PubMed:21981844).
The stop codon (UAA) at position 2180 is created by an APOBEC1-containing mRNA editing complex. Apo B-48, derived from the fully edited RNA, is produced only in the intestine and is found in chylomicrons. Apo B-48 is a shortened form of apo B-100 which lacks the LDL-receptor region. The unedited version (apo B-100) is produced by the liver and is found in the VLDL and LDL.
Ca(2+) and ATP binding cause major rearrangements of the cytoplasmic and transmembrane domains. According to the E1-E2 model, Ca(2+) binding to the cytosolic domain of the pump in the high-affinity E1 conformation is followed by the ATP-dependent phosphorylation of the active site Asp, giving rise to E1P. A conformational change of the phosphoenzyme gives rise to the low-affinity E2P state that exposes the Ca(2+) ions to the lumenal side and promotes Ca(2+) release. Dephosphorylation of the active site Asp mediates the subsequent return to the E1 conformation.
Cardiac/slow twitch, muscle specific isoform. Has a lower affinity for calcium and a higher catalytic turnover rate.
Has different conformational states with differential Ca2+ affinity. The E1 conformational state (active form) shows high Ca(2+) affinity, while the E2 state exhibits low Ca(2+) affinity. Reversibly inhibited by phospholamban (PLN) at low calcium concentrations. Inhibited by sarcolipin (SLN) and myoregulin (MRLN). The inhibition is blocked by VMP1 (PubMed:28890335). Enhanced by DWORF; DWORF increases activity by displacing sarcolipin (SLN), phospholamban (PLN) and myoregulin (MRLN) (By similarity). Stabilizes SERCA2 in its E2 state (PubMed:28890335).
Interacts with sarcolipin (SLN); the interaction inhibits ATP2A2 Ca(2+) affinity (PubMed:28890335). Interacts with phospholamban (PLN); the interaction inhibits ATP2A2 Ca(2+) affinity (PubMed:28890335). Interacts with myoregulin (MRLN) (By similarity). Interacts with DWORF (By similarity). Interacts with HAX1 (PubMed:18971376). Interacts with S100A8 and S100A9 (By similarity). Interacts with SLC35G1 and STIM1 (PubMed:22084111). Interacts with TMEM203 (PubMed:25996873). Interacts with TMEM64 and PDIA3 (By similarity). Interacts with TMX2 (PubMed:31735293). Interacts with VMP1; VMP1 competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2 (PubMed:28890335). Interacts with ULK1 (PubMed:28890335). Interacts with S100A1 in a Ca(2+)-dependent manner (PubMed:12804600). Interacts with TUNAR (By similarity). Interacts with FLVCR2; this interaction occurs in the absence of heme and promotes ATP2A2 proteasomal degradation; this complex is dissociated upon heme binding (By similarity). Interacts with FNIP1 (By similarity).
Involved in the regulation of the contraction/relaxation cycle. Acts as a regulator of TNFSF11-mediated Ca(2+) signaling pathways via its interaction with TMEM64 which is critical for the TNFSF11-induced CREB1 activation and mitochondrial ROS generation necessary for proper osteoclast generation. Association between TMEM64 and SERCA2 in the ER leads to cytosolic Ca(2+) spiking for activation of NFATC1 and production of mitochondrial ROS, thereby triggering Ca(2+) signaling cascades that promote osteoclast differentiation and activation.
Isoform 1 is widely expressed in smooth muscle and nonmuscle tissues such as in adult skin epidermis, with highest expression in liver, pancreas and lung, and intermediate expression in brain, kidney and placenta. Also expressed at lower levels in heart and skeletal muscle. Isoforms 2 and 3 are highly expressed in the heart and slow twitch skeletal muscle. Expression of isoform 3 is predominantly restricted to cardiomyocytes and in close proximity to the sarcolemma. Both isoforms are mildly expressed in lung, kidney, liver, pancreas and placenta. Expression of isoform 3 is amplified during monocytic differentiation and also observed in the fetal heart.
May be due to intron retention. Shows a lower apparent affinity for cytosolic calcium than isoform 2 and a catalytic turnover rate similar to isoform 1.
Nitrated under oxidative stress. Nitration on the two tyrosine residues inhibits catalytic activity.
PLN and SLN both have a single transmembrane helix; both occupy a similar binding site that is situated between the ATP2A2 transmembrane helices.
Serotonylated on Gln residues by TGM2 in response to hypoxia, leading to its inactivation.
This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen (PubMed:16402920, PubMed:12542527). Involved in autophagy in response to starvation. Upon interaction with VMP1 and activation, controls ER-isolation membrane contacts for autophagosome formation (PubMed:28890335). Also modulates ER contacts with lipid droplets, mitochondria and endosomes (PubMed:28890335). In coordination with FLVCR2 mediates heme-stimulated switching from mitochondrial ATP synthesis to thermogenesis (By similarity).
Detected in retina, kidney, liver, small intestine, placenta, lung, heart and skeletal muscle.
Retinol dehydrogenase with a clear preference for NADP. Converts all-trans-retinol to all-trans-retinal. Has no detectable activity towards 11-cis-retinol, 9-cis-retinol and 13-cis-retinol.
(Microbial infection) Interacts with EIAV p9; the interaction has been shown in vitro.
(Microbial infection) Interacts with Ebola virus VP40.
(Microbial infection) Interacts with HIV-1 p6.
(Microbial infection) Interacts with HTLV-1 Gag.
(Microbial infection) Interacts with Lassa virus protein Z.
(Microbial infection) Interacts with hepatitis E virus protein ORF3.
(Microbial infection) Interacts with human spumavirus Gag.
Belongs to the ubiquitin-conjugating enzyme family. UEV subfamily.
Component of the ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, a VPS37 protein (VPS37A to -D) and MVB12A or MVB12B in a 1:1:1:1 stoichiometry (PubMed:18005716). Interacts with VPS37A, VPS37B and VPS37C (PubMed:15218037, PubMed:15509564). Interacts with DMAP1 (PubMed:10888872). Interacts with ubiquitin (PubMed:11595185). Interacts with stathmin, GMCL and AATF (By similarity). Component of an ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, VPS37A and UBAP1 in a 1:1:1:1 stoichiometry (PubMed:21757351). Interacts with HGS; the interaction mediates the association with the ESCRT-0 complex. Interacts with GGA1 and GGA3 (PubMed:15143060, PubMed:15039775). Interacts (via UEV domain) with PDCD6IP/AIP1 (PubMed:14505570, PubMed:14519844). Interacts with VPS28, SNF8 and VPS36 (PubMed:14505570). Self-associates (PubMed:14505570, PubMed:14519844). Interacts with MVB12A; the association appears to be mediated by the TSG101-VPS37 binary subcomplex. Interacts with VPS37D. Interacts with LRSAM1. Interacts with CEP55; the interaction is required for cytokinesis but not for viral budding (PubMed:17853893). Interacts with PDCD6 (PubMed:18256029). Interacts with LITAF (PubMed:23166352). Interacts with MGRN1 (PubMed:17229889). Interacts with ARRDC1; recruits TSG101 to the plasma membrane (PubMed:21191027, PubMed:22315426).
Component of the ESCRT-I complex, a regulator of vesicular trafficking process. Binds to ubiquitinated cargo proteins and is required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies (MVBs). Mediates the association between the ESCRT-0 and ESCRT-I complex. Required for completion of cytokinesis; the function requires CEP55. May be involved in cell growth and differentiation. Acts as a negative growth regulator. Involved in the budding of many viruses through an interaction with viral proteins that contain a late-budding motif P-[ST]-A-P. This interaction is essential for viral particle budding of numerous retroviruses. Required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413). It may also play a role in the extracellular release of microvesicles that differ from the exosomes (PubMed:22315426).
Detected in normal as well as cancer tissues.
Heart, brain, placenta, lung, liver, skeletal, kidney and pancreas.
Monoubiquitinated at multiple sites by LRSAM1 and by MGRN1. Ubiquitination inactivates it, possibly by regulating its shuttling between an active membrane-bound protein and an inactive soluble form. Ubiquitination by MGRN1 requires the presence of UBE2D1.
The UEV domain binds ubiquitin and P-[ST]-A-P peptide motif independently.
The UEV domain is required for the interaction of the complex with ubiquitin. It also mediates the interaction with PTAP/PSAP motifs of HIV-1 P6 protein and human spumaretrovirus Gag protein.
The coiled coil domain may interact with stathmin.
May play a synaptic role at the postsynaptic lipid rafts possibly through interaction with CAMK2A.
Palmitoylation and myristoylation target the protein to the lipid rafts.
Predominantly expressed in neuroectoderm-derived tissues. Expressed in the brain and spinal cord, and at low levels, in the adrenal gland. In the bone marrow, confined to the CD34+ progenitor cells. Not found in peripheral blood mononuclear cells, nor lymph nodes. Tends to be expressed at high levels in acute myeloid leukemia and glioblastoma cells.
Expressed in the adult lung, and in fetal liver, lung, kidney, brain and spleen.
Arginine methylation by PRMT1, which is recruited by BMPR2, initiates BMP-Induced signaling and induces dissociation from the BMPR1B receptor at the cell surface leading to derepress downstream Smad1/Smad5 signaling.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Rare heterozygous SMAD6 variants are strongly associated with non-syndromic midline craniosynostosis and confer a very high risk for disease development, in the presence of a common risk allele (rs1884302) near the BMP2 locus.
Expressed in the brain, heart, ovary, peripheral blood leukocytes, small intestine, spleen, thymus, bone marrow, fetal liver and lymph nodes.
Interacts with NEDD4L (By similarity). Interacts with WWP1 (By similarity). Interacts with STAMBP and PRKX. Interacts with RNF111 and AXIN1. Interacts with TGF-beta type I receptor superfamily members, including ACVR1B, BMPR1B and TGFBR1. In response to BMP2, but not to TGFB treatment, interacts with SMAD1, but not with SMAD2, nor with SMAD4; this interaction may inhibit SMAD1 binding to SMAD4. Interacts with HOXC8 and HOXC9. Interacts with PELI1; this interaction interferes with PELI1 complex formation with TRAF6, IRAK1, IRAK4 and MYD88 in response to IL1B and hence negatively regulates IL1R-TLR signaling. Interacts with TSC22D1/TSC-22 (PubMed:21791611).
Monoubiquitinated at Lys-173 by the E2/E3 hybrid ubiquitin-protein ligase UBE2O, leading to reduced binding affinity for the activated BMP type I receptor ACVR1/ALK2, thereby enhancing BMP7 and regulating adipocyte differentiation (PubMed:23455153). Ubiquitinated by WWP1 (By similarity). Ubiquitinated by ARK2C, promoting proteasomal degradation, leading to enhance the BMP-Smad signaling (By similarity).
Phosphorylated by BMP type 1 receptor kinase and by PRKX.
The disease is caused by variants affecting the gene represented in this entry. SMAD6 variants may contribute to increased risk of congenital cardiovascular malformations (CVM). CVM is a major cause of mortality and morbidity in childhood. In most sporadic cases that cannot be attributed to particular malformation syndromes or teratogenic exposures, there remains a substantial excess familial risk, indicating a significant genetic contribution to disease susceptibility (PubMed:22275001).
Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators. SMAD6 is an inhibitory Smad (i-Smad) that negatively regulates signaling downstream of type I transforming growth factor-beta (PubMed:9436979, PubMed:16951688, PubMed:22275001, PubMed:9759503, PubMed:10647776, PubMed:10708948, PubMed:10708949, PubMed:30848080). Acts as a mediator of TGF-beta and BMP anti-inflammatory activities. Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear transport and NF-kappa-B-mediated expression of pro-inflammatory genes (PubMed:16951688). Blocks the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding (PubMed:9436979, PubMed:30848080). Binds to regulatory elements in target promoter regions (PubMed:16491121).
Activated by phosphorylation at Thr-288; this brings about a change in the conformation of the activation segment. Phosphorylation at Thr-288 varies during the cell cycle and is highest during M phase. Autophosphorylated at Thr-288 upon TPX2 binding. Thr-288 can be phosphorylated by several kinases, including PAK and PKA. Protein phosphatase type 1 (PP1) binds AURKA and inhibits its activity by dephosphorylating Thr-288 during mitosis. Phosphorylation at Ser-342 decreases the kinase activity. PPP2CA controls degradation by dephosphorylating Ser-51 at the end of mitosis.
Activation of CDK1, appears to be an upstream event of AURKA activation. Phosphatase inhibitor-2 (PPP1R2) and TPX2 act also as activators. Inactivated by the G2 checkpoint. Inhibited by GADD45A and p53/TP53, and through dephosphorylation by protein phosphatase type 1 (PP1). MLN8054 is also a potent and selective inhibitor. Activated during the early phase of cilia disassembly in the presence of CIMAP3. Inhibited by the small molecule inhibitor VX-680 (PubMed:28218735).
An article that concluded that AURKA-mediated phosphorylation of BRCA1 'Ser-308' plays a role in the normal cell cycle G2/M transition was withdrawn due to data manipulation of flow cytometry data.
Authors initially considered AURKA/STK6 and STK15 as 2 different proteins (PubMed:9771714). It is clear that they are the same protein.
Centrosome amplification can occur when the cycles are uncoupled, and this amplification is associated with cancer and with an increase in the levels of chromosomal instability.
Expression is cell-cycle regulated, low in G1/S, accumulates during G2/M, and decreases rapidly after.
Highly expressed in testis and weakly in skeletal muscle, thymus and spleen. Also highly expressed in colon, ovarian, prostate, neuroblastoma, breast and cervical cancer cell lines.
Mitotic serine/threonine kinase that contributes to the regulation of cell cycle progression (PubMed:26246606, PubMed:12390251, PubMed:18615013, PubMed:11039908, PubMed:17125279, PubMed:17360485). Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis (PubMed:26246606, PubMed:14523000). Required for normal spindle positioning during mitosis and for the localization of NUMA1 and DCTN1 to the cell cortex during metaphase (PubMed:27335426). Required for initial activation of CDK1 at centrosomes (PubMed:13678582, PubMed:15128871). Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2 (PubMed:18056443, PubMed:15128871, PubMed:14702041, PubMed:11551964, PubMed:15147269, PubMed:15987997, PubMed:17604723, PubMed:18615013). Regulates KIF2A tubulin depolymerase activity (PubMed:19351716). Important for microtubule formation and/or stabilization (PubMed:18056443). Required for normal axon formation (PubMed:19812038). Plays a role in microtubule remodeling during neurite extension (PubMed:19668197). Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and destabilizing p53/TP53 (PubMed:14702041). Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity (PubMed:11551964). Inhibits cilia outgrowth (By similarity). Required for cilia disassembly via phosphorylation of HDAC6 and subsequent deacetylation of alpha-tubulin (PubMed:17604723, PubMed:20643351). Regulates protein levels of the anti-apoptosis protein BIRC5 by suppressing the expression of the SCF(FBXL7) E3 ubiquitin-protein ligase substrate adapter FBXL7 through the phosphorylation of the transcription factor FOXP1 (PubMed:28218735).
Part of a complex composed of NEDD9, AURKA and CTTN; within the complex NEDD9 acts as a scaffold protein and is required for complex formation (PubMed:24574519). Identified in a complex with AUNIP and NIN (PubMed:20596670). Interacts with FBXL7 (By similarity). Interacts with CPEB1, JTB, TACC1, TPX2, PPP2CA, as well as with the protein phosphatase type 1 (PP1) isoforms PPP1CA, PPP1CB and PPP1CC (PubMed:15966895, PubMed:21225229, PubMed:14603251, PubMed:19668197, PubMed:19357306, PubMed:14580337, PubMed:18662907, PubMed:19801554, PubMed:27837025, PubMed:17229885, PubMed:11551964). Interacts also with its substrates ARHGEF2, BORA, KIF2A, PARD3, and p53/TP53 (PubMed:17488622, PubMed:16890155, PubMed:19351716, PubMed:19812038, PubMed:14702041). Interaction with BORA promotes phosphorylation of PLK1 (By similarity). Interacts with CIMAP3 (PubMed:20643351). Interacts with GADD45A, competing with its oligomerization (PubMed:20460379). Interacts (via C-terminus) with AUNIP (via C-terminus) (PubMed:20596670). Interacts with FRY; this interaction facilitates AURKA-mediated PLK1 phosphorylation (PubMed:22753416). Interacts with SIRT2 (PubMed:17726514, PubMed:22014574). Interacts with MYCN; interaction is phospho-independent and triggers AURKA activation; AURKA competes with FBXW7 for binding to unphosphorylated MYCN but not for binding to phosphorylated MYCN (PubMed:27837025). Interacts with HNRNPU (PubMed:21242313, PubMed:25986610). Interacts with AAAS (PubMed:26246606). Interacts with KLHL18 and CUL3 (PubMed:23213400). Interacts with FOXP1 (PubMed:28218735). Interacts with HDAC6; AURKA-mediated phosphorylation of HDAC6 promotes deacetylation of alpha-tubulin (PubMed:17604723).
Ubiquitinated by the E3 ubiquitin-protein ligase complex SCF(FBXL7) during mitosis, leading to its degradation by the proteasome (By similarity). Ubiquitinated by CHFR, leading to its degradation by the proteasome (By similarity). Ubiquitinated by the anaphase-promoting complex (APC), leading to its degradation by the proteasome (PubMed:10851084, PubMed:11039908). Ubiquitinated by the CUL3-KLHL18 ligase leading to its activation at the centrosome which is required for initiating mitotic entry (PubMed:23213400). Ubiquitination mediated by CUL3-KLHL18 ligase does not lead to its degradation by the proteasome (PubMed:23213400).
Chimeric cDNA. The N-terminus part of this cDNA matches at different locus on chromosome 1.
May be involved in the regulation of the proteolytic processing of the amyloid precursor protein (APP) possibly also implicating APOE.
May form homodimers and heterodimers with TMCC2 or TMCC3 via the coiled-coil domains (PubMed:24454821). Interacts with ribosomal proteins RPL4 and RPS6 (PubMed:24454821). Interacts with APOE and proteolytic processed C-terminal fragment C99 of the amyloid precursor protein (APP C99) (PubMed:21593558).
Component of the ribosomal small subunit (SSU) processome.
Involved in nucleolar processing of pre-18S ribosomal RNA. Has a role in the nuclear export of 40S pre-ribosomal subunit to the cytoplasm (By similarity).
Involved in nucleolar processing of pre-18S ribosomal RNA. Has a role in the nuclear export of 40S pre-ribosomal subunit to the cytoplasm.
Myosin is a hexamer of 2 heavy chains and 4 light chains. Interacts with SPATA6.
Homodimer (PubMed:17088322, PubMed:18455394). Interacts with DAOA (PubMed:12364586).
Regulates the level of the neuromodulator D-serine in the brain. Has high activity towards D-DOPA and contributes to dopamine synthesis. Could act as a detoxifying agent which removes D-amino acids accumulated during aging. Acts on a variety of D-amino acids with a preference for those having small hydrophobic side chains followed by those bearing polar, aromatic, and basic groups. Does not act on acidic amino acids.
Highly expressed in fetal and adult brain tissue.
Homodimer. Can also form heterodimers (By similarity).
May be involved in the trafficking and exocytosis of secretory vesicles in non-neuronal tissues. Is Ca(2+)-independent.
ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L/beta-2). ICAM2 may play a role in lymphocyte recirculation by blocking LFA-1-dependent cell adhesion. It mediates adhesive interactions important for antigen-specific immune response, NK-cell mediated clearance, lymphocyte recirculation, and other cellular interactions important for immune response and surveillance.
Can transfer its iron-sulfur clusters to the apoferrodoxins FDX1 and FDX2. Contributes to mitochondrial iron homeostasis and in maintaining normal levels of free iron and reactive oxygen species, and thereby contributes to normal mitochondrial function.
Activated by reversible S-nitrosylation (By similarity). Repeated very high-level exercise increases S-nitrosylation (PubMed:18268335).
Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR1 subfamily.
Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2843 may increase channel activity. Repeated very high-level exercise increases phosphorylation at Ser-2843.
Coexpression of normal and mutant Thr-4898 RYR1 in a 1:1 ratio produces RYR1 channels with normal halothane and caffeine sensitivities, but maximal levels of Ca(2+) release are reduced by 67%. Binding of [3H]ryanodine indicates that the heterozygous channel is activated by Ca(2+) concentrations 4-fold lower than normal. Single-cell analysis of cotransfected cells shows a significantly increased resting cytoplasmic Ca(2+) level and a significantly reduced luminal Ca(2+) level. These data indicated a leaky channel, possibly caused by a reduction in the Ca(2+) concentration required for channel activation. Comparison with 2 other coexpressed mutant/normal channels suggests that the Thr-4898 mutation produces one of the most abnormal RYR1 channels that has been investigated, and this level of abnormality is reflected in the severe and penetrant phenotype of affected CCD individuals.
Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules (PubMed:18650434, PubMed:18268335, PubMed:11741831, PubMed:16163667, PubMed:26115329). Repeated very high-level exercise increases the open probability of the channel and leads to Ca(2+) leaking into the cytoplasm (PubMed:18268335). Can also mediate the release of Ca(2+) from intracellular stores in neurons, and may thereby promote prolonged Ca(2+) signaling in the brain. Required for normal embryonic development of muscle fibers and skeletal muscle. Required for normal heart morphogenesis, skin development and ossification during embryogenesis (By similarity).
Defects in RYR1 may be a cause of Samaritan myopathy, a congenital myopathy with benign course. Patients display severe hypotonia and respiratory distress at birth. Unlike other congenital myopathies, the health status constantly improves and patients are minimally affected at adulthood.
Homotetramer. Can also form heterotetramers with RYR2 (By similarity). Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1) (PubMed:18268335). Repeated very high-level exercise decreases interaction with PDE4D and protein phosphatase 1 (PP1) (PubMed:18268335). Interacts with CALM; CALM with bound calcium inhibits the RYR1 channel activity (PubMed:18650434). Interacts with S100A1 (PubMed:18650434). Interacts with FKBP1A; this stabilizes the closed conformation of the channel. Interacts with CACNA1S; interaction with CACNA1S is important for activation of the RYR1 channel. Interacts with CACNB1. Interacts with TRDN and ASPH; these interactions stimulate RYR1 channel activity. Interacts with SELENON (By similarity). Interacts with scorpion calcins (AC P0DPT1; AC P0DM30; AC A0A1L4BJ42; AC P59868; AC P60254; AC B8QG00; AC L0GBR1; AC P60252; AC P60253) (By similarity).
Skeletal muscle and brain (cerebellum and hippocampus).
The calcium release channel activity resides in the C-terminal region while the remaining part of the protein constitutes the 'foot' structure spanning the junctional gap between the sarcoplasmic reticulum (SR) and the T-tubule. Pore opening is mediated via the cytoplasmic calcium-binding domains that mediate a small rotation of the channel-forming transmembrane regions that then leads to channel opening.
The calcium release is activated by increased cytosolic calcium levels, by nitric oxyde (NO), caffeine and ATP (PubMed:18268335, PubMed:16163667). Channel activity is modulated by the alkaloid ryanodine that binds to the open Ca-release channel with high affinity. At low concentrations, ryanodine maintains the channel in an open conformation. High ryanodine concentrations inhibit channel activity (By similarity). Channel activity is regulated by calmodulin (CALM) (PubMed:18650434). Channel activity is inhibited by magnesium ions, possibly by competition for calcium binding sites (By similarity).
Component of a ribonucleoprotein (RNP) complex (By similarity). Interacts with DDX6 (PubMed:31422817, PubMed:29510985, PubMed:31439631). Interacts with EIF4ENIF1/4E-T; promoting EIF4ENIF1/4E-T localization to P-bodies (PubMed:26027925, PubMed:32354837, PubMed:29510985). Interacts (via FFD box) with EDC4 (PubMed:29510985).
Essential for formation of P-bodies, cytoplasmic structures that provide storage sites for translationally inactive mRNAs and protect them from degradation (PubMed:16484376, PubMed:17074753, PubMed:29510985). Acts as a repressor of mRNA translation (PubMed:29510985). May play a role in mitotic spindle assembly (PubMed:26339800).
The LSM14 domain and the RGG repeats are required for accumulation in P-bodies, and the region containing the FDF motif is responsible for cytoplasmic retention.
Associates with PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex II (PI3KC3-C2) in which the core composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 is associated with UVRAG; in the complex interacts directly with PI3KC3 and UVRAG (PubMed:19270696, PubMed:21062745). Interacts with Rab7 (RAB7A or RAB7B) (GTP-bound form); Rab7 and UVRAG compete for RUBCN binding; can interact simultaneously with Rab7 and the PI3K complex (PubMed:20943950, PubMed:20974968, PubMed:21062745). Interacts with CYBA and CYBB; indicative for the association with the CYBA:CYBB NADPH oxidase heterodimer. Interacts with NOX4 and probably associates with the CYBA:NOX4 complex (PubMed:22423966). Interacts with YWHAB and CARD9 in a competitive and stimulation-dependent manner; RUBCN exchanges interaction from YWHAB to CARD9 upon stimulation with beta-1,3-glucan (PubMed:22423967).
Inhibits PIK3C3 activity; under basal conditions negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy. Negatively regulates endosome maturation and degradative endocytic trafficking and impairs autophagosome maturation process. Can sequester UVRAG from association with a class C Vps complex (possibly the HOPS complex) and negatively regulates Rab7 activation (PubMed:20974968, PubMed:21062745).
Involved in regulation of pathogen-specific host defense of activated macrophages. Following bacterial infection promotes NADH oxidase activity by association with CYBA thereby affecting TLR2 signaling and probably other TLR-NOX pathways. Stabilizes the CYBA:CYBB NADPH oxidase heterodimer, increases its association with TLR2 and its phagosome trafficking to induce antimicrobial burst of ROS and production of inflammatory cytokines (PubMed:22423966). Following fungal or viral infection (implicating CLEC7A (dectin-1)-mediated myeloid cell activation or RIGI-dependent sensing of RNA viruses) negatively regulates pro-inflammatory cytokine production by association with CARD9 and sequestering it from signaling complexes (PubMed:22423967).
Expressed in skeletal muscle, skin and scalp, but not in any other tissues or organs examined.
Autoacetylated at Lys-136 which stimulates its catalytic activity.
Catalytic subunit of N-terminal acetyltransferase complexes which display alpha (N-terminal) acetyltransferase activity (PubMed:15496142, PubMed:19826488, PubMed:19420222, PubMed:20145209, PubMed:27708256, PubMed:25489052, PubMed:29754825, PubMed:20154145, PubMed:32042062). Acetylates amino termini that are devoid of initiator methionine (PubMed:19420222). The alpha (N-terminal) acetyltransferase activity may be important for vascular, hematopoietic and neuronal growth and development. Without NAA15, displays epsilon (internal) acetyltransferase activity towards HIF1A, thereby promoting its degradation (PubMed:12464182). Represses MYLK kinase activity by acetylation, and thus represses tumor cell migration (PubMed:19826488). Acetylates, and stabilizes TSC2, thereby repressing mTOR activity and suppressing cancer development (PubMed:20145209). Acetylates HSPA1A and HSPA1B at 'Lys-77' which enhances its chaperone activity and leads to preferential binding to co-chaperone HOPX (PubMed:27708256). Acetylates HIST1H4A (PubMed:29754825). Acts as a negative regulator of sister chromatid cohesion during mitosis (PubMed:27422821).
Component of the N-terminal acetyltransferase A complex (also called the NatA complex) composed of NAA10 and NAA15 (PubMed:20154145, PubMed:15496142, PubMed:32042062). Within the complex interacts with NAA15 (PubMed:15496142, PubMed:20154145, PubMed:29754825, PubMed:32042062). Component of the N-terminal acetyltransferase A (NatA)/HYPK complex at least composed of NAA10, NAA15 and HYPK, which has N-terminal acetyltransferase activity (PubMed:20154145, PubMed:29754825, PubMed:32042062). In complex with NAA15, interacts with HYPK (PubMed:20154145, PubMed:29754825, PubMed:32042062). Component of the N-terminal acetyltransferase E (NatE) complex at least composed of NAA10, NAA15 and NAA50 (PubMed:29754825, PubMed:32042062). Within the complex interacts with NAA15; the interaction is required for binding to NAAT50 (PubMed:29754825, PubMed:32042062). Interacts with NAAT50 (PubMed:16507339, PubMed:32042062). The interaction of the NatA complex with NAA50 reduces the acetylation activity of the NatA complex (PubMed:32042062). Component of the N-terminal acetyltransferase E (NatE)/HYPK complex at least composed of NAA10, NAA15, NAA50 and HYPK (PubMed:32042062). In complex with NAA15, interacts with HYPK; the interaction with HYPK reduces the capacity of the NatA complex to interact with NAA50 (PubMed:29754825, PubMed:32042062). Interacts with HIF1A (via its ODD domain); the interaction increases HIF1A protein stability during normoxia, an down-regulates it when induced by hypoxia (PubMed:12464182). Interacts with the ribosome (PubMed:16507339). Binds to MYLK (PubMed:19826488). Interacts with NAA16 (PubMed:19480662). Interacts (via its C-terminal domain) with TSC2, leading to its acetylation (PubMed:20145209). Interacts with IKBKB (PubMed:19716809). Interacts with HSPA1A and HSPA1B leading to its acetylation (PubMed:27708256).
Phosphorylation by IKBKB/IKKB at Ser-209 promotes its proteasome-mediated degradation.
Binds to the plus end of microtubules and regulates microtubule dynamics and microtubule organization. Acts as processive microtubule polymerase. Promotes cytoplasmic microtubule nucleation and elongation. Plays a major role in organizing spindle poles. In spindle formation protects kinetochore microtubules from depolymerization by KIF2C and has an essential role in centrosomal microtubule assembly independently of KIF2C activity. Contributes to centrosome integrity. Acts as component of the TACC3/ch-TOG/clathrin complex proposed to contribute to stabilization of kinetochore fibers of the mitotic spindle by acting as inter-microtubule bridge. The TACC3/ch-TOG/clathrin complex is required for the maintenance of kinetochore fiber tension (PubMed:23532825). Enhances the strength of NDC80 complex-mediated kinetochore-tip microtubule attachments (PubMed:27156448).
Interacts with TACC1 (PubMed:11903063). Interacts with SLAIN2 and SLAIN1 (PubMed:21646404). Interacts with HNRNPA2B1 (PubMed:15703215). Interacts with TACC3 independently of clathrin (PubMed:25596274). Interacts with TACC3 and clathrin forming the TACC3/ch-TOG/clathrin complex located at spindle inter-microtubules bridges (PubMed:21297582, PubMed:23532825). Interacts with NDC80; indicative for an association with the NDC80 complex (PubMed:27156448).
Overexpressed in hepatomas and colonic tumors. Also expressed in skeletal muscle, brain, heart, placenta, lung, liver, kidney and pancreas. Expression is elevated in the brain; highly expressed in the Purkinje cell bodies of the cerebellum.
The TOG (tumor overexpressed gene) domains are arranged in a N-terminal pentameric array with each domain composed of six (for the most part non-canonical) HEAT repeats forming a oblong paddle-like structure. Intra-HEAT loops are positioned along a face of the TOG domain and bind to a single alpha/beta-tubulin heterodimer. The TOG domains in the array seem to be structurally and functionally polarized. Differential functions may range from microtubule (MT) lattice binding and/or free tubulin heterodimer binding to potentiating stable incorporation of tubulin into the MT lattice.
Constitutively phosphorylated on Ser-352; phosphorylation increases cell internalization and desensitizes the receptor.
Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and bone homeostasis.
In macrophages, down-regulated by endocannabinoid anandamide/AEA.
Preferentially expressed in cells of the immune system with higher expression in B-cells and NK cells (at protein level). Expressed in skin in suprabasal layers and hair follicles (at protein level). Highly expressed in tonsil and to a lower extent in spleen, peripheral blood mononuclear cells, and thymus. PubMed:14657172 could not detect expression in normal brain. Expressed in brain by perivascular microglial cells and dorsal root ganglion sensory neurons (at protein level). Two isoforms are produced by alternative promoter usage and differ only in the 5' UTR: isoform CB2A is observed predominantly in testis with some expression in brain, while isoform CB2B is predominant in spleen and leukocytes.
Based on current literature, utilization of para-aminobenzoic acid (pABA) involving C4-deamination is still unclear, and seems not to occur in bacteria, plants and mammals where only C5 hydroxylation of HHB has been shown, even if human COQ6 is able to support C4-deamination in yeast cells lacking COQ9.
Component of a multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9 (By similarity). Interacts with COQ8B and COQ7 (PubMed:24270420).
FAD-dependent monooxygenase required for the C5-ring hydroxylation during ubiquinone biosynthesis. Catalyzes the hydroxylation of 3-hexaprenyl-4-hydroxybenzoic acid (HHB) to 3-hexaprenyl-4,5-dihydroxybenzoic acid (DHHB). The electrons required for the hydroxylation reaction may be funneled indirectly from NADPH via a ferredoxin/ferredoxin reductase system to COQ6 (By similarity). Is able to perform the deamination reaction at C4 of 3-hexaprenyl-4-amino-5-hydroxybenzoic acid (HHAB) to produce DHHB when expressed in yeast cells lacking COQ9, even if utilization of para-aminobenzoic acid (pABA) involving C4-deamination seems not to occur in bacteria, plants and mammals, where only C5 hydroxylation of HHB has been shown (PubMed:26260787).
Mutations in COQ6 may play a role in susceptibility to Schwannomatosis, a cancer predisposition syndrome in which patients develop multiple non-vestibular schwannomas, benign neoplasms that arise from Schwann cells of the cranial, peripheral, and autonomic nerves.
Belongs to the chloride channel (TC 2.A.49) family. ClC-5/CLCN5 subfamily.
Kidney. Moderately expressed in aortic vascular smooth muscle and endothelial cells, and at a slightly higher level in the coronary vascular smooth muscle.
Proton-coupled chloride transporter. Functions as antiport system and exchanges chloride ions against protons (PubMed:20466723). Important for normal acidification of the endosome lumen. May play an important role in renal tubular function. The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The absence of conserved gating glutamate residues is typical for family members that function as channels (Probable).
Ubiquitinated by NEDD4L in the presence of albumin; which promotes endocytosis and proteasomal degradation.
Expression is detected in fetal cochlea.
Binds 1 [2Fe-2S] cluster per subunit. The [2Fe-2S] cluster is redox-active and pH labile and is significantly less stable at pH 4.5 as compared with pH 7.0.
Binds pioglitazone, an anti-diabetes drug. Binding increases the stability of the 2Fe-2S cluster.
Expression is down-regulated by glibenclamide and 5-[(4-carboxyphenyl)methylene]-2-thioxo-3-(3-trifluoromethyl)phenyl-4-thiazolidinone (CFTR(inh)172), and up-regulated by cAMP/isoproterenol/IBMX, components that inhibit and stimulate chloride transport activity respectively.
Expression is reduced in cells derived from cystic fibrosis patients.
L-cysteine transaminase that catalyzes the reversible transfer of the amino group from L-cysteine to the alpha-keto acid 2-oxoglutarate to respectively form 2-oxo-3-sulfanylpropanoate and L-glutamate (PubMed:36194135). The catalytic cycle occurs in the presence of pyridoxal 5'-phosphate (PLP) cofactor that facilitates transamination by initially forming an internal aldimine with the epsilon-amino group of active site Lys-55 residue on the enzyme (PLP-enzyme aldimine), subsequently displaced by formation of an external aldimine with the substrate amino group (PLP-L-cysteine aldimine). The external aldimine is further deprotonated to form a carbanion intermediate, which in the presence of 2-oxoglutarate regenerates PLP yielding final products 2-oxo-3-sulfanylpropanoate and L-glutamate. The proton transfer in carbanion intermediate is suggested to be controlled by the active site lysine residue, whereas PLP stabilizes carbanion structure through electron delocalization, also known as the electron sink effect (PubMed:36194135). Plays a key role in regulating maximal capacity for electron transport and oxidative phosphorylation (By similarity). May be involved in iron-sulfur cluster shuttling and/or in redox reactions. Can transfer the [2Fe-2S] cluster to an apo-acceptor protein only when in the oxidation state, likely serving as a redox sensor that regulates mitochondrial iron-sulfur cluster assembly and iron trafficking upon oxidative stress (PubMed:21788481, PubMed:23758282, PubMed:17584744).
As cells progress into S phase, a fraction of CUX1 molecules is proteolytically processed into N-terminally truncated proteins of 110 kDa by CTSL. Cell cycle-dependent processing of CUX1 serves to generate a CDP/Cux p110 with distinct DNA binding and transcriptional properties.
Asn-1290 may participate in regulating DNA-binding activity by promoting homo- and heterodimerization.
Homodimer; disulfide-linked. Interacts with GOLGA5.
Interacts with BANP. Interacts with SATB1 (via DNA-binding domains); the interaction inhibits the attachment of both proteins to DNA (By similarity).
May be involved in intra-Golgi retrograde transport.
Plays a role in cell cycle progression, in particular at the G1/S transition. As cells progress into S phase, a fraction of CUX1 molecules is proteolytically processed into N-terminally truncated proteins of 110 kDa. While CUX1 only transiently binds to DNA and carries the CCAAT-displacement activity, CDP/Cux p110 makes a stable interaction with DNA and stimulates expression of genes such as POLA1.
Transcription factor involved in the control of neuronal differentiation in the brain. Regulates dendrite development and branching, and dendritic spine formation in cortical layers II-III. Also involved in the control of synaptogenesis. In addition, it has probably a broad role in mammalian development as a repressor of developmentally regulated gene expression. May act by preventing binding of positively-activing CCAAT factors to promoters. Component of nf-munr repressor; binds to the matrix attachment regions (MARs) (5' and 3') of the immunoglobulin heavy chain enhancer. Represses T-cell receptor (TCR) beta enhancer function by binding to MARbeta, an ATC-rich DNA sequence located upstream of the TCR beta enhancer. Binds to the TH enhancer; may require the basic helix-loop-helix protein TCF4 as a coactivator.
Expressed at the highest levels in heart and placenta and at a lesser extent in lung, liver, skeletal muscle, kidney and pancreas.
Interacts with LEPR. Interacts with RAB13 (By similarity).
Negatively regulates leptin receptor (LEPR) cell surface expression, and thus decreases response to leptin. Negatively regulates growth hormone (GH) receptor cell surface expression in liver. May play a role in liver resistance to GH during periods of reduced nutrient availability.
This protein is encoded by LEPR gene, but shares with LEPR only the first two 5'-UTR exons. It therefore does not share any sequence similarity with LEPR.
Expressed in red blood cells (at protein level).
Interacts with PLCE1. Interacts with SGSM1, SGSM2 and SGSM3. The GTP-bound form of RAP2B interacts with RUNDC3A (By similarity).
Palmitoylated. Unlike RAP2A and RAP2C, palmitoylation of RAP2B is not required for association with recycling endosome membranes and activation of TNIK.
Small GTP-binding protein which cycles between a GDP-bound inactive and a GTP-bound active form. Involved in EGFR and CHRM3 signaling pathways through stimulation of PLCE1. May play a role in cytoskeletal rearrangements and regulate cell spreading through activation of the effector TNIK. May regulate membrane vesiculation in red blood cells.
The effector domain mediates the interaction with RUNDC3A.
A missense variant of ANKH cosegregates with a complex phenotype according to an autosomal recessive pattern. Affected homozygous individuals from a large consanguinous family show sensorineural and conductive hearing loss, intellectual disability, spinal ankylosis, and periarticular calcification of small joints. Only a mild arthropathy is observed in heterozygous individuals.
Found in osteoblasts from mandibular bone and from iliac bone; not detected in osteoclastic cells.
Transports adenosine triphosphate (ATP) and possibly other nucleoside triphosphates (NTPs) from cytosol to the extracellular space. Mainly regulates their levels locally in peripheral tissues while playing a minor systemic role. Prevents abnormal ectopic mineralization of the joints by regulating the extracellular levels of the calcification inhibitor inorganic pyrophosphate (PPi), which originates from the conversion of extracellular NTPs to NMPs and PPis by ENPP1 (PubMed:32639996, PubMed:35147247, PubMed:20943778). Regulates the release of the TCA cycle intermediates to the extracellular space, in particular citrate, succinate and malate. Extracellular citrate mostly present in bone tissue is required for osteogenic differentiation of mesenchymal stem cells, stabilization of hydroxyapatite structure and overall bone strength (PubMed:32639996). The transport mechanism remains to be elucidated (Probable).
(Microbial infection) Plays a role in modulating the adaptive immune response to yellow fever virus infection; promotes dendritic cells to initiate autophagy and antigene presentation to both CD4(+) and CD8(+) T-cells under amino acid starvation (PubMed:24310610).
Autophosphorylated; autophosphorylation on Thr-899 is increased upon amino acid starvation and in UV irradiation cells and inhibited in presence of IMPACT.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.
Homodimer; homodimerization is important for kinase activation by uncharged tRNAs (By similarity). Interacts with GCN1; this interaction stimulates EIF2AK4/GCN2 kinase activity and is impaired by IMPACT upon a variety of stress conditions, such as amino acid depletion, UV-C irradiation, proteasome inhibitor treatment and glucose deprivation (By similarity). Interacts with DNAJC3; this interaction inhibits EIF2AK4/GCN2 kinase activity during endoplasmic reticulum (ER), hypothermic and amino acid-starving stress conditions (By similarity). Interacts with MAP3K20; activates EIF2AK4/GCN2 kinase activity in response to moderate ribotoxic stress (PubMed:32610081).
Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to low amino acid availability (PubMed:25329545, PubMed:32610081). Plays a role as an activator of the integrated stress response (ISR) required for adaptation to amino acid starvation (By similarity). EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha into a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, and thus to a reduced overall utilization of amino acids, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion (PubMed:32610081). Binds uncharged tRNAs (By similarity). Required for the translational induction of protein kinase PRKCH following amino acid starvation (By similarity). Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation (PubMed:26102367). Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory (By similarity). Plays a role in neurite outgrowth inhibition (By similarity). Plays a proapoptotic role in response to glucose deprivation (By similarity). Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways (By similarity). Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication (By similarity).
The histidyl-tRNA synthetase-like region and protein kinase domains are necessary for eIF-2-alpha kinase activity and eIF-2-alpha-mediated translational control. The histidyl-tRNA synthetase-like domain is necessary for binding to uncharged tRNAs. Kinase domain 1 is a degenerate kinase domain.
Widely expressed (PubMed:10504407). Expressed in lung, smooth muscle cells and macrophages (PubMed:24292273).
Binds anionic lipids and gangliosides at acidic pH.
N-glycosylated; the glycan contains mannose-6-phosphate moieties.
Ubiquitous. Detected in brain, heart, skeletal muscle, kidney, testis, ovary and prostate.
By bacterial lipopolysaccharides (LPS) in the monocytic leukemia cell line THP-1.
Expressed predominantly in hematopoietic tissues. High levels detected in the bone marrow and lower levels in the peripheral leukocytes and lung. Also expressed in brain, heart, muscle, colon, thymus, spleen, kidney, liver, placenta and intestine. Within the leukocyte population expression is higher in neutrophils and eosinophils relative to T- or B-lymphocytes.
Receptor for medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. Capric acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) are the most potent agonists. Not activated by short-chain and long-chain saturated and unsaturated FFAs. Activation by medium-chain free fatty acid is coupled to a pertussis toxin sensitive G(i/o) protein pathway. May have important roles in processes from fatty acid metabolism to regulation of the immune system.
Possible morphogenetic cytoskeletal element in spermiogenic differentiation.
Testis. Not detectable or shows a drastically altered pattern of arrangement in the heads of malformed spermatozoa.
Contains a 30 bp insertion which does not match the genome.
Expressed predominantly in lung and testis (PubMed:19666007). Expressed in astrocytes (PubMed:24014093).
Homotrimer (PubMed:19666007). Forms heteromeric complexes with C1QL1 (PubMed:19666007). Interacts with RXFP1 (PubMed:24014093).
Activated by calcium-binding in the mitochondrial intermembrane space (PubMed:11566871). Inhibited by pyridoxal 5'-phosphate, bathophenathroline, mercurials, diethyl pyrocarbonate and N-ethylmaleimide (PubMed:11566871).
Expressed predominantly in the heart and skeletal muscle, weakly in brain and kidney.
Mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle (PubMed:11566871, PubMed:19641205, PubMed:24515575). Also mediates the uptake of L-cysteinesulfinate by mitochondria in exchange of L-glutamate and proton. Can also exchange L-cysteinesulfinate with aspartate in their anionic form without any proton translocation (PubMed:11566871).
The EF-hand 2 domain within the regulatory N-terminal domain binds one calcium in the mitochondrial intermembrane space. Calcium triggers the binding of the regulatory N-terminal domain to the C-terminal domain, opening a vestibule which allows the substrates to be translocated through the carrier domain. In the absence of calcium, the linker loop domain may close the vestibule and prevent substrates from entering the carrier domain.
Highly expressed in whole brain and spinal cord. Predominant expression in central tissues of the nervous system not only in neurons but also in Schwann cells.
Regulates the mitochondrial network by promoting mitochondrial fission.
While belonging to the GST superfamily, it lacks glutathione transferase activity.
Expressed in various embryonic organs at 6 to 12 embryonic weeks. Detected in vessels from 20-week embryonic organs as well as in endothelial cells from large vessels in neonate.
Interacts with SVBP; interaction enhances VASH2 tyrosine carboxypeptidase activity.
Tyrosine carboxypeptidase that removes the C-terminal tyrosine residue of alpha-tubulin, thereby regulating microtubule dynamics and function (PubMed:29146869). Critical for spindle function and accurate chromosome segregation during mitosis since microtubule detyronisation regulates mitotic spindle length and postioning (PubMed:31171830). Acts as an activator of angiogenesis: expressed in infiltrating mononuclear cells in the sprouting front to promote angiogenesis (PubMed:19204325). Plays a role in axon formation (PubMed:31235911).
Interferon (IFN)-inducible GTPase that plays important roles in innate immunity against a diverse range of bacterial, viral and protozoan pathogens (By similarity). Hydrolyzes GTP to GMP in two consecutive cleavage reactions and predominantly uses GTP and not GDP or GMP as the substrate (By similarity). Following infection, recruited to the pathogen-containing vacuoles or vacuole-escaped bacteria and acts as a positive regulator of inflammasome assembly by promoting the release of inflammasome ligands from bacteria (By similarity). Acts by promoting lysis of pathogen-containing vacuoles, releasing pathogens into the cytosol (By similarity). Following pathogen release in the cytosol, promotes recruitment of proteins that mediate bacterial cytolysis: this liberates ligands that are detected by inflammasomes, such as lipopolysaccharide (LPS) that activates the non-canonical CASP4/CASP11 inflammasome or double-stranded DNA (dsDNA) that activates the AIM2 inflammasome (By similarity). Also promotes IFN-gamma-mediated host defense against bacterial infections by regulating oxidative responses and bacteriolytic peptide generation (By similarity). May help to assemble NADPH oxidase on phagosomal membranes by acting as a bridging protein between NADPH oxidase cytosolic subunits NCF2-NCF4 and the membrane subunits CYBA-CYBB (By similarity). Participates along with GBP1 in trafficking monoubiquinated protein cargo to autolysosomes for generating ubiquitin-derived antimicrobial peptides (By similarity). Facilitates influenza A virus replication by inhibiting the activation of NF-kappaB and JAK-STAT signaling pathways and the expression of type I, type III interferons and pro-inflammatory cytokines (PubMed:33408175). Confers protection to several pathogens, including the bacterial pathogens Listeria monocytogenes and Mycobacterium bovis BCG as well as the protozoan pathogen Toxoplasma gondii (By similarity). Required for disruption of the parasitophorous vacuole formed following T.gondii infection and subsequent killing of the parasite (By similarity).
Monomer and dimer (By similarity). Interacts with CYBA, CYBA-CYBB complex and ATG4B (By similarity). Interacts (via GB1/RHD3-type G domain) with NCF2 and NCF2-NCF4 complex (By similarity).
Up-regulated in response to influenza virus A infection.
Can form homodimers and heterodimers with DACT1 or DACT3. Interacts with CSNK1D, PKA catalytic subunit, PKC-type kinase, DVL1, DVL3, VANGL1, VANGL2 and CTNND1 (By similarity). Interacts with DVL2.
May be involved in regulation of intracellular signaling pathways during development. Specifically thought to play a role in canonical and/or non-canonical Wnt signaling pathways through interaction with DSH (Dishevelled) family proteins.
Activity is not sensitive to inhibition by tetrodotoxin.
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.9/SCN11A subfamily.
Expressed in the dorsal root ganglia and trigeminal ganglia, olfactory bulb, hippocampus, cerebellar cortex, spinal cord, spleen, small intestine and placenta.
Sodium channel mediating the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which sodium ions may pass in accordance with their electrochemical gradient (PubMed:10580103, PubMed:12384689, PubMed:24036948, PubMed:24776970, PubMed:26645915, PubMed:25791876). Involved in membrane depolarization during action potential in nociceptors which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system (PubMed:24036948, PubMed:24776970, PubMed:26645915, PubMed:25791876). Also involved in rapid BDNF-evoked neuronal depolarization (PubMed:12384689).
The voltage-resistant sodium channel consists of an ion conducting pore forming alpha-subunit regulated by one or more auxiliary subunits SCN1B, SCN2B and SCN3B.
It is uncertain whether palmitoylation is on Cys-561 and/or Cys-562 and/or Cys-565.
Specifically phosphorylates the activated forms of G protein-coupled receptors. Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their desensitization. Seems to be involved in the desensitization of D2-like dopamine receptors in striatum and chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis (By similarity). Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor: LRP6 during Wnt signaling (in vitro).
Interacts with DEGS1; the interaction increases synthesis of chromophore-precursors by DEGS1.
Retina and pineal gland. Not present in photoreceptor cells but is expressed abundantly in the adjacent retinal pigment epithelium (RPE) and in the Mueller glial cells of the retina.
Soluble retinoid carrier essential the proper function of both rod and cone photoreceptors. Participates in the regeneration of active 11-cis-retinol and 11-cis-retinaldehyde, from the inactive 11-trans products of the rhodopsin photocycle and in the de novo synthesis of these retinoids from 11-trans metabolic precursors. The cycling of retinoids between photoreceptor and adjacent pigment epithelium cells is known as the 'visual cycle'.
E3 ubiquitin-protein ligase which binds polysumoylated chains covalently attached to proteins and mediates 'Lys-6'-, 'Lys-11'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination of those substrates and their subsequent targeting to the proteasome for degradation (PubMed:18408734, PubMed:19307308, PubMed:35013556). Regulates the degradation of several proteins including PML and the transcriptional activator PEA3 (PubMed:18408734, PubMed:19307308, PubMed:20943951). Involved in chromosome alignment and spindle assembly, it regulates the kinetochore CENPH-CENPI-CENPK complex by targeting polysumoylated CENPI to proteasomal degradation (PubMed:20212317). Regulates the cellular responses to hypoxia and heat shock through degradation of respectively EPAS1 and PARP1 (PubMed:19779455, PubMed:20026589). Alternatively, it may also bind DNA/nucleosomes and have a more direct role in the regulation of transcription for instance enhancing basal transcription and steroid receptor-mediated transcriptional activation (PubMed:12885770). Catalyzes ubiquitination of sumoylated PARP1 in response to PARP1 trapping to chromatin, leading to PARP1 removal from chromatin by VCP/p97 (PubMed:35013556).
Homodimer (via RING-type zinc finger domain) (By similarity). Interacts with GSC2 (By similarity). Interacts with AR/the androgen receptor and TBP (By similarity). Interacts with TCF20 (By similarity). Interacts with PATZ1 (PubMed:10713105). Interacts with TRPS1; negatively regulates TRPS1 transcriptional repressor activity (PubMed:12885770). Interacts with PML (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4, isoform PML-5 and isoform PML-6) (PubMed:15707587, PubMed:20943951, PubMed:23028697). Interacts with PRDM1/Blimp-1 (PubMed:28842558).
Sumoylated; conjugated by one or two SUMO1 moieties.
The RING-type zinc finger domain is required for the ubiquitination of polysumoylated substrates.
Widely expressed at low levels in many tissues; highly expressed in testis.
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. That Rab is involved in transcytosis, the directed movement of endocytosed material through the cell and its exocytosis from the plasma membrane at the opposite side. Mainly observed in epithelial cells, transcytosis mediates for instance, the transcellular transport of immunoglobulins from the basolateral surface to the apical surface. Most probably controls membrane trafficking through apical recycling endosomes in a post-endocytic step of transcytosis. Required for melanosome transport and release from melanocytes, it also regulates dendrite and dendritic spine development (By similarity). May also play a role in cell migration.
Up-regulated by forskolin probably through the transcription factor MITF.
Despite its name, it does not contain any EF-hand domains.
(Microbial infection) Involved in the interaction between HIV-1 virus and dendritic cells. Enhances HIV-1 binding/entry and virus infection. Requires ITIM motif-associated signal transduction pathway involving phosphatases PTPN6 and PTPN11, SYK, Src kinases and MAP kinases.
C-type lectin receptor that binds carbohydrates mannose and fucose but also weakly interacts with N-acetylglucosamine (GlcNAc) in a Ca(2+)-dependent manner (PubMed:27015765). Involved in regulating immune reactivity (PubMed:18258799, PubMed:10438934). Once triggered by antigen, it is internalized by clathrin-dependent endocytosis and delivers its antigenic cargo into the antigen presentation pathway resulting in cross-priming of CD8(+) T cells. This cross-presentation and cross-priming are enhanced by TLR7 and TLR8 agonists with increased expansion of the CD8(+) T cells, high production of IFNG and TNF with reduced levels of IL4, IL5 and IL13 (PubMed:18258799, PubMed:20530286). In plasmacytoid dendritic cells, inhibits TLR9-mediated IFNA and TNF production (PubMed:18258799). May be involved via its ITIM motif (immunoreceptor tyrosine-based inhibitory motifs) in the inhibition of B-cell-receptor-mediated calcium mobilization and protein tyrosine phosphorylation (PubMed:10438934).
Contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases (PubMed:20530286). Involved in the interaction between HIV-1 virus and dendritic cells. Enhances HIV-1 binding/entry and virus infection. Requires ITIM motif-associated signal transduction pathway involving phosphatases PTPN6 and PTPN11, SYK, Src kinases and MAP kinases (PubMed:20530286). ITIM motif-associated signal transduction pathway involving phosphatases PTPN6 and PTPN11, SYK, Src kinases and MAP kinases is required for HIV-1 binding/entry and virus infection (PubMed:20530286).
Expressed preferentially in hematopoietic tissues. Expressed in all circulating Ag-presenting cells such as dendritic cells, myeloid cells, monocytes, macrophages, B-cells and epidermal Langerhans cells (at protein level). Expressed in peripheral blood leukocytes, neutrophils, moderate quantities in spleen, lymph node, and bone marrow, and at very low levels in thymus.
May interact with PTPN6 via its ITIM motif.
TNF alpha, IL-1 alpha, and LPS, down-regulated expression at the surface of neutrophils (at protein level) (PubMed:11994513). Expression is decreased in dendritic cells by signals inducing their maturation (e.g. CD40 ligand, TLR9 ligands, LPS, and TNF alpha) (PubMed:10438934, PubMed:18258799). Isoform 2: mRNA expression is up-regulated by agonists of neutrophils CSF2/GM-CSF, IL3/interleukin-3, IL4/interleukin-4 and IL13/interleukin-13 (PubMed:11994513).
Binds the CaM kinase domain of CASK. Forms a ternary complex with CASK and LIN7A, LIN7B or LIN7C. Competes with APBA1 that forms a similar complex with CASK and LIN7 proteins. The tripartite complex CASKIN1/CASK/LIN7(A/B/C) binds the cytoplasmic tail of NRXN1 (By similarity). Polymerizes, via the tandem SAM domains, to form long, 8 nM wide fibers, upon which other proteins can assemble.
May link the scaffolding protein CASK to downstream intracellular effectors.
By estradiol in estrogen-responsive breast cancer cells.
Component of the HBO1 complex composed at least of ING4 or ING5, KAT7/HBO1, MEAF6, and one of JADE1, JADE2 and JADE3.
Scaffold subunit of some HBO1 complexes, which have a histone H4 acetyltransferase activity.
Ubiquitously expressed, with highest levels in placenta and uterus.
A chromosomal aberration involving MAF is found in some forms of multiple myeloma (MM). Translocation t(14;16)(q32.3;q23) with an IgH locus.
Acts as a transcriptional activator or repressor. Involved in embryonic lens fiber cell development. Recruits the transcriptional coactivators CREBBP and/or EP300 to crystallin promoters leading to up-regulation of crystallin gene during lens fiber cell differentiation. Activates the expression of IL4 in T helper 2 (Th2) cells. Increases T-cell susceptibility to apoptosis by interacting with MYB and decreasing BCL2 expression. Together with PAX6, transactivates strongly the glucagon gene promoter through the G1 element. Activates transcription of the CD13 proximal promoter in endothelial cells. Represses transcription of the CD13 promoter in early stages of myelopoiesis by affecting the ETS1 and MYB cooperative interaction. Involved in the initial chondrocyte terminal differentiation and the disappearance of hypertrophic chondrocytes during endochondral bone development. Binds to the sequence 5'-[GT]G[GC]N[GT]NCTCAGNN-3' in the L7 promoter. Binds to the T-MARE (Maf response element) sites of lens-specific alpha- and beta-crystallin gene promoters. Binds element G1 on the glucagon promoter. Binds an AT-rich region adjacent to the TGC motif (atypical Maf response element) in the CD13 proximal promoter in endothelial cells (By similarity). When overexpressed, represses anti-oxidant response element (ARE)-mediated transcription. Involved either as an oncogene or as a tumor suppressor, depending on the cell context. Binds to the ARE sites of detoxifying enzyme gene promoters.
Homodimer or heterodimer with other bHLH-Zip transcription factors. Binds DNA as a homodimer or as a heterodimer. Heterotetramer of two MAF and two USF2. Interacts with PAX6; the interaction is direct. Interacts with MYB; interaction takes place weakly in normal T-cells and increases in T-cells following stimulation through the TCR engagement. Interacts with MYB; the ternary complex formed with MYB and the CD13 promoter is regulated in response to differentiating signals. Interacts with USF2; the interaction inhibits its DNA-binding activity on the L7 promoter. Interacts with CREBBP, EP300 and ETS1 (By similarity).
Phosphorylated by GSK3 and MAPK13 on serine and threonine residues (Probable). The phosphorylation status can serve to either stimulate or inhibit transcription.
Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is triggered by glucocorticoids.
Up-regulated with tert-butyl hydroquinone (t-BHQ).
Expressed exclusively in tissues with a high content of epithelial cells. Highly expressed in salivary gland, mammary gland, kidney and prostate. Weakly expressed in placenta and lung. Isoform 1 and isoform 2 are differentially expressed in different tissues. In the kidney, only isoform 1 was expressed, while prostate expressed both isoforms, with levels of isoform 2 being higher. Expression is up-regulated during keratinocyte differentiation. Several epithelial carcinoma cell lines showed lack of expression.
Isoform 2 binds to DNA sequences containing the consensus nucleotide core sequence GGA[AT]. Transcriptionally activates SPRR2A and the parotid gland-specific PSP promoters.
Transcriptionally activator that may play a role in regulating the later stages of keratinocytes terminal differentiation.
Binds acetylated lysine residues in histone H1.4, H2A, H2B, H3 and H4 (in vitro).
Interacts with SYNRG and ITSN1 (By similarity). Interacts with SLC9A7.
Required for male fertility and normal male germ cell differentiation (By similarity). Plays a role in spermatogenesis (By similarity). Binds to RNA but not to DNA (By similarity).
May be involved in the assembly of microtubule arrays during cell elongation.
Belongs to the eukaryotic/archaeal RNase P protein component 1 family.
Component of nuclear RNase P and RNase MRP ribonucleoproteins (PubMed:10024167, PubMed:10352175, PubMed:30454648). RNase P consists of a catalytic RNA moiety and 10 different protein chains; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40 (PubMed:16723659, PubMed:30454648). Within the RNase P complex, POP1, POP7 and RPP25 form the 'finger' subcomplex, POP5, RPP14, RPP40 and homodimeric RPP30 form the 'palm' subcomplex, and RPP21, POP4 and RPP38 form the 'wrist' subcomplex. All subunits of the RNase P complex interact with the catalytic RNA (PubMed:30454648). Several subunits of RNase P are also part of the RNase MRP complex. RNase MRP consists of a catalytic RNA moiety and about 8 protein subunits; POP1, POP7, RPP25, RPP30, RPP38, RPP40 and possibly also POP4 and POP5 (PubMed:15096576).
Variable expression in some B-cell, myelomonocytic, and erythroleukemia cell lines.
The intracellular region is dispensable for its function.
Weakly expressed in most tissues, except in brain. Expressed at intermediate level in brain, including cerebellum, substantia nigra, thalamus, spinal cord, hippocampus and fetal brain. Also expressed in testis.
Transcriptional regulator. Activates E box-dependent transcription in collaboration with TCF3/E47, but the activity is completely antagonized by the negative regulator of neurogenesis HES1. Plays a role in the differentiation of subsets of neural cells by activating E box-dependent transcription (By similarity).
Expressed in cerebellum, brain stem, hippocampus, and frontal cortex.
Functions to regulate alternative splicing in neurons by binding pre-mRNA in a sequence-specific manner to activate exon inclusion or exclusion. It binds specifically to the sequences 5'-YCAY-3' and regulates splicing in only a subset of regulated exons (PubMed:10811881). Binding to an exonic 5'-YCAY-3' cluster changes the protein complexes assembled on pre-mRNA, blocking U1 snRNP binding and exon inclusion, whereas binding to an intronic 5'-YCAY-3' cluster enhances spliceosome assembly and exon inclusion. Binding to 5'-YCAY-3' clusters results in a local and asymmetric action to regulate spliceosome assembly and alternative splicing in neurons. Binding to an exonic 5'-YCAY-3' cluster changed the protein complexes assembled on pre-mRNA, blocking U1 snRNP (small nuclear ribonucleoprotein) binding and exon inclusion, whereas binding to an intronic 5'-YCAY-3' cluster enhanced spliceosome assembly and exon inclusion. With NOVA1, they perform unique biological functions in different brain areas and cell types. Autoregulates its own expression by acting as a splicing repressor. Acts to activate the inclusion of exon E3A in the glycine receptor alpha-2 chain and of exon E9 in gamma-aminobutyric-acid receptor gamma-2 subunit via a distal downstream UCAU-rich intronic splicing enhancer. Acts to regulate a novel glycine receptor alpha-2 chain splice variant (alpha-2N) in developing spinal cord (By similarity).
Probable cloning artifact leading to an insertion into the sequence.
Target antigen in a human paraneoplastic motor disorder, paraneoplastic opsoclonus-myoclonus ataxia (POMA). POMA antibodies block NOVAl RNA binding.
The KH domain consists of approximately 70 amino acids and includes a conserved hydrophobic core, an invariant Gly-X-X-Gly motif, and an additional variable segment (PubMed:10811881). The third KH domain (KH3) binds a hairpin RNA loop containing the 5'-UCAY-3' motif on targeted molecules (PubMed:10811881). RNA binding by KH3 requires residues C-terminal to the KH domain (PubMed:10811881).
Gp-Ib, a surface membrane protein of platelets, participates in the formation of platelet plugs by binding to von Willebrand factor, which is already bound to the subendothelium.
Two GP-Ib beta are disulfide-linked to one GP-Ib alpha. GP-IX is complexed with the GP-Ib heterodimer via a non covalent linkage. Interacts with TRAF4 (PubMed:20946164).
Expressed in adult fibroblasts and in a range of fetal tissues including tongue, palate, and mandible.
Depletion by RNAi inhibits growth and survival signaling cascades and induces cell death. The antagonist rimcazole produces the same effect.
Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. Involved in the regulation of different receptors it plays a role in BDNF signaling and EGF signaling. Also regulates ion channels like the potassium channel and could modulate neurotransmitter release. Plays a role in calcium signaling through modulation together with ANK2 of the ITP3R-dependent calcium efflux at the endoplasmic reticulum. Plays a role in several other cell functions including proliferation, survival and death. Originally identified for its ability to bind various psychoactive drugs it is involved in learning processes, memory and mood alteration (PubMed:16472803, PubMed:9341151). Necessary for proper mitochondrial axonal transport in motor neurons, in particular the retrograde movement of mitochondria. Plays a role in protecting cells against oxidative stress-induced cell death via its interaction with RNF112 (By similarity).
Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. Regulates calcium efflux at the endoplasmic reticulum.
Homotrimer (PubMed:27042935). Forms a ternary complex with ANK2 and ITPR3. The complex is disrupted by agonists. Interacts with KCNA4. Interacts with KCNA2; cocaine consumption leads to increased interaction. Interacts with RNF112 in an oxidative stress-regulated manner (By similarity).
Sigma receptors are classified into two subtypes (Sigma-1 and Sigma-2) based on their different pharmacological profile.
The C-terminal helices form a flat, hydrophobic surface that is probably tightly associated with the cytosolic surface of the endoplasmic reticulum membrane.
The NMR solution structure identifies a second transmembrane helix starting with Gly-91 (PubMed:25647032). The X-ray structure clearly shows that this region is not helical and not in the membrane; instead it is part of two beta-strands (PubMed:27042935).
Widely expressed with higher expression in liver, colon, prostate, placenta, small intestine, heart and pancreas. Expressed in the retina by retinal pigment epithelial cells. Expressed in alpha-motor neurons (PubMed:23314020).
Centriole-enriched microtubule-binding protein involved in centriole biogenesis. In collaboration with CEP295 and POC1B, is required for the centriole-to-centrosome conversion by ensuring the formation of bona fide centriole wall (PubMed:32060285). Functions as a linker component that maintains centrosome cohesion. Associates with CROCC and regulates its stability and localization to the centrosome (PubMed:31974111).
Interacts with CROCC (PubMed:31974111). Interacts with POC1B; the interaction is direct and recruits POC1B to centriolar microtubules (PubMed:32060285). Binds to centriolar microtubules (PubMed:32060285).
Moderate expression in G0 and G1, increasing in S and G2, and dropping in prophase, metaphase and anaphase (at protein level).
Interacts with GDI1, GDI2, CHM and CHML; phosphorylation at Thr-82 disrupts these interactions.
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. The low intrinsic GTPase activity of RAB43 is activated by USP6NL. Involved in retrograde transport from the endocytic pathway to the Golgi apparatus. Involved in the transport of Shiga toxin from early and recycling endosomes to the trans-Golgi network. Required for the structural integrity of the Golgi complex. Plays a role in the maturation of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis.
Widely expressed in brain, testis, lung, heart, ovary, colon, kidney, uterus and spleen but not in liver.
Transcriptional regulator. Binds to the 5'-flanking critical region of the SCARF1 promoter.
Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta. Expression is observed in the heart.
Component of the BCR(KLHL25) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL25 and RBX1.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex involved in various processes, such as translation homeostasis and lipid synthesis (PubMed:22578813, PubMed:27664236, PubMed:34491895). The BCR(KLHL25) ubiquitin ligase complex acts by mediating ubiquitination of hypophosphorylated EIF4EBP1 (4E-BP1): ubiquitination and subsequent degradation of hypophosphorylated EIF4EBP1 (4E-BP1) probably serves as a homeostatic mechanism to maintain translation and prevent eIF4E inhibition when eIF4E levels are low (PubMed:22578813). The BCR(KLHL25) complex does not target EIF4EBP1 (4E-BP1) when it is hyperphosphorylated or associated with eIF4E (PubMed:22578813). The BCR(KLHL25) complex also acts as a regulator of lipid synthesis by mediating ubiquitination and degradation of ACLY, thereby inhibiting lipid synthesis (PubMed:27664236, PubMed:34491895). BCR(KLHL25)-mediated degradation of ACLY promotes fatty acid oxidation and is required for differentiation of inducible regulatory T (iTreg) cells (PubMed:34491895).
Mainly expressed in hepatocytes and some weak expression in germinal center cells of lymph nodes.
May be involved in induction of apoptosis in CD4(+) T-cells, but not CD8(+) T-cells or hepatocytes.
Heterodimer of a regulatory subunit PIK3R2 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD) (PubMed:23604317). Interacts with AXL (PubMed:9178760). Interacts with FLT1 (tyrosine-phosphorylated) and FLT4 (tyrosine-phosphorylated) (PubMed:9600074, PubMed:15102829). Interacts with NYAP1, NYAP2 and MYO16 (By similarity). Interacts with FBXL2; PIK3R2 is a substrate of the SCF(FBXL2) complex (PubMed:23604317). Interacts with PTPN13; dephosphorylates PIK3R2 (PubMed:23604317). Interacts with XBP1 isoform 2; the interaction is direct and induces translocation of XBP1 isoform 2 into the nucleus in a ER stress- and/or insulin-dependent but PI3K-independent manner (By similarity). Interacts with PIK3R1; the interaction is dissociated in an insulin-dependent manner (By similarity). Interacts with SRC (PubMed:28903391).
Phosphorylated in response to signaling from activated receptor-type protein kinases (PubMed:19690332, PubMed:20068231). Dephosphorylated by PTPRJ (PubMed:18348712). Dephosphorylated at Tyr-655 by PTPN13. Phosphorylation of Tyr-655 impairs while its dephosphorylation promotes interaction with FBXL2 and SCF(FBXL2)-mediated polyubiquitination (PubMed:23604317).
Regulatory subunit of phosphoinositide-3-kinase (PI3K), a kinase that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Binds to activated (phosphorylated) protein-tyrosine kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Indirectly regulates autophagy (PubMed:23604317). Promotes nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement (By similarity).
The SH2 2 domain is required for interaction with FBXL2 and PTPN13.
Ubiquitinated. Polyubiquitination by the SCF(FBXL2) complex probably promotes proteasomal degradation of PIK3R2.
Chloride channel activity is allosterically activated by lumenal H(+) and Cl(-) leading to synaptic vesicles acidification. The L-glutamate transport activity is allosterically activated by lumenal H(+) and Cl(-). The allosteric activation by H(+) efficiently prevents non-vesicular efflux across the plasma membrane, thereby restricting L-glutamate transport activity to acidic membranes such as synaptic vesicles.
Expressed in several regions of the brain including amygdala, cerebellum, cerebral cortex, hippocampus, frontal lobe, medulla, occipital lobe, putamen and temporal lobe.
Martineau M. et al. show that may function as a L-glutamate/H(+) antiporter (By similarity). However, according to Eriksen J. et al., H(+) is an allosteric activator (By similarity).
Multifunctional transporter that transports L-glutamate as well as multiple ions such as chloride, proton, potassium, sodium and phosphate (PubMed:10820226). At the synaptic vesicle membrane, mainly functions as an uniporter which transports preferentially L-glutamate but also phosphate from the cytoplasm into synaptic vesicles at presynaptic nerve terminals of excitatory neural cells (By similarity). The L-glutamate or phosphate uniporter activity is electrogenic and is driven by the proton electrochemical gradient, mainly by the electrical gradient established by the vacuolar H(+)-ATPase across the synaptic vesicle membrane (By similarity). In addition, functions as a chloride channel that allows a chloride permeation through the synaptic vesicle membrane that affects the proton electrochemical gradient and promotes synaptic vesicles acidification (By similarity). Moreover, may function as a K(+)/H(+) antiport allowing to maintain the electrical gradient and to decrease chemical gradient and therefore sustain vesicular glutamate uptake (By similarity). The vesicular K(+)/H(+) antiport activity is electroneutral (By similarity). At the plasma membrane, following exocytosis, functions as a symporter of Na(+) and phosphate from the extracellular space to the cytoplasm allowing synaptic phosphate homeostasis regulation (PubMed:10820226). The symporter activity is driven by an inside negative membrane potential and is electrogenic (By similarity). Is necessary for synaptic signaling of visual-evoked responses from photoreceptors (By similarity).
Association, via its PDZ-recognition domain, with LIN7A, LIN7B, LIN7C, DLG1, CASK and APBA1 plays a key role in its localization and trafficking (By similarity). Homotetramer. Forms heteromer with KCNJ4.
Inward rectifying potassium channel that is activated by phosphatidylinositol 4,5-bisphosphate and that probably participates in controlling the resting membrane potential in electrically excitable cells. Probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium.
Phosphatidylinositol 4,5-bisphosphate binding to the cytoplasmic side of the channel triggers a conformation change leading to channel opening.
Acetylated at Lys-247. May be deacetylated by HDAC6, HDAC10 or SIRT1.
E3 SUMO-protein ligase helping SUMO1 conjugation to its coregulators NAB1 and NAB2, whose sumoylation down-regulates EGR2 transcriptional activity.
Interacts with HCFC1 (PubMed:14532282). Interacts with WWP2 (PubMed:19651900). Interacts with UBC9 (PubMed:21836637). Interacts with CITED1 (By similarity). Interacts (via phosphorylated form) with SFN (By similarity).
Sequence-specific DNA-binding transcription factor (PubMed:17717711). Plays a role in hindbrain segmentation by regulating the expression of a subset of homeobox containing genes and in Schwann cell myelination by regulating the expression of genes involved in the formation and maintenance of myelin (By similarity). Binds to two EGR2-consensus sites EGR2A (5'-CTGTAGGAG-3') and EGR2B (5'-ATGTAGGTG-3') in the HOXB3 enhancer and promotes HOXB3 transcriptional activation (By similarity). Binds to specific DNA sites located in the promoter region of HOXA4, HOXB2 and ERBB2 (By similarity). Regulates hindbrain segmentation by controlling the expression of Hox genes, such as HOXA4, HOXB3 and HOXB2, and thereby specifying odd and even rhombomeres (By similarity). Promotes the expression of HOXB3 in the rhombomere r5 in the hindbrain (By similarity). Regulates myelination in the peripheral nervous system after birth, possibly by regulating the expression of myelin proteins, such as MPZ, and by promoting the differentiation of Schwann cells (By similarity). Involved in the development of the jaw openener musculature, probably by playing a role in its innervation through trigeminal motor neurons (By similarity). May play a role in adipogenesis, possibly by regulating the expression of CEBPB (By similarity).
The disease is caused by variants affecting the gene represented in this entry. Patients affected by the amyelinating form carry a causative, homozygous deletion encompassing a myelin-specific enhancer of EGR2 (PubMed:22522483).
Ubiquitinated by WWP2 leading to proteasomal degradation.
(Microbial infection) In case of infection by retroviruses, acts as a cell receptor to retroviral envelopes similar to the porcine endogenous retrovirus (PERV-A).
Belongs to the riboflavin transporter family.
Highly expressed in brain, fetal brain and salivary gland. Weakly expressed in other tissues.
Plasma membrane transporter mediating the uptake by cells of the water soluble vitamin B2/riboflavin that plays a key role in biochemical oxidation-reduction reactions of the carbohydrate, lipid, and amino acid metabolism (PubMed:20463145, PubMed:22864630, PubMed:23243084, PubMed:24253200, PubMed:27702554). Humans are unable to synthesize vitamin B2/riboflavin and must obtain it via intestinal absorption (PubMed:20463145). May also act as a receptor for 4-hydroxybutyrate (Probable).
Plasma membrane transporter mediating the uptake by cells of the water soluble vitamin B2/riboflavin that plays a key role in biochemical oxidation-reduction reactions of the carbohydrate, lipid, and amino acid metabolism.
Riboflavin transport is Na(+)-independent but moderately pH-sensitive (PubMed:20463145). Activity is strongly inhibited by riboflavin analogs, such as lumiflavin (PubMed:20463145). Weakly inhibited by flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) (PubMed:20463145).
Expressed predominantly in leukocytes, lung and spleen. Expressed also in colon carcinoma, astrocytoma and glioblastomas.
Activity is strongly promoted by Co(2+), Ni(2+), Mg(2+) and Mn(2+) (PubMed:27322068). Activity is inhibited by EDTA (PubMed:27322068).
Despite belonging to the type II pantothenate kinase family, the pantothenate kinase domain contains a Val residue at position 147 and a Trp residue at position 211 instead of the two conserved active site residues, Glu and Arg. Lacks pantothenate kinase activity.
In the C-terminal section; belongs to the damage-control phosphatase family. Phosphopantetheine phosphatase II subfamily.
In the N-terminal section; belongs to the type II pantothenate kinase family.
Phosphatase activity is strongly promoted by several divalent cation ions but it is suggested s that Mn(2+) and possibly Ni(2+) represent biologically relevant metal ion cofactors for damage-control phosphatases.
Phosphatase which shows a preference for 4'-phosphopantetheine and its oxidatively damaged forms (sulfonate or S-sulfonate), providing strong indirect evidence that the phosphatase activity pre-empts damage in the coenzyme A (CoA) pathway (PubMed:27322068). Hydrolyzing excess 4'-phosphopantetheine could constitute a directed overflow mechanism to prevent its oxidation to the S-sulfonate, sulfonate, or other forms (PubMed:27322068). Hydrolyzing 4'-phosphopantetheine sulfonate or S-sulfonate would forestall their conversion to inactive forms of CoA and acyl carrier protein (PubMed:27322068). May play a role in the physiological regulation of CoA intracellular levels (Probable).
Subfamily II proteins have an EGMGR motif about 50 residues from the C-terminus (Probable). This motif lies near the metal-binding residues in the putative substrate-binding cleft 2 (Probable). Subfamily II proteins occur only in eukaryotes, in two forms: as a stand-alone unit in plants, and as a C-terminal domain of pantothenate kinases in plants, animals, and chytrid fungi (Probable).
Widely expressed with high expression in the muscle (PubMed:11479594). Expressed in the retina and lens epithelium, mainly in ganglion cell layer, outer plexiform layer and retinal pigment layer (at protein level) (PubMed:30585370).
Associates with TRAF1 and TRAF2, and probably also with TRAF3.
Highly expressed in heart, placenta and kidney. Intermediate expression in lung, skeletal muscle and pancreas.
Receptor for TNFSF12/TWEAK. Weak inducer of apoptosis in some cell types. Promotes angiogenesis and the proliferation of endothelial cells. May modulate cellular adhesion to matrix proteins.
Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975). Interacts with EP300, NPM1 and CDCA8 (PubMed:19015314, PubMed:18946085, PubMed:18259216, PubMed:19680224). Component of the 5FMC complex, at least composed of PELP1, LAS1L, TEX10, WDR18 and SENP3; the complex interacts with methylated CHTOP and ZNF148 (PubMed:22872859). Interacts with NOL9 (By similarity). Interacts with CCAR2 (PubMed:25406032).
On oxidative stress, SENP3 degradation is blocked by inhibition of its ubiquitination, which stabilizes it as it accumulates in the nucleoplasm.
Protease that releases SUMO2 and SUMO3 monomers from sumoylated substrates, but has only weak activity against SUMO1 conjugates (PubMed:16608850, PubMed:32832608). Deconjugates SUMO2 from MEF2D, which increases its transcriptional activation capability (PubMed:15743823). Deconjugates SUMO2 and SUMO3 from CDCA8 (PubMed:18946085). Redox sensor that, when redistributed into nucleoplasm, can act as an effector to enhance HIF1A transcriptional activity by desumoylating EP300 (PubMed:19680224). Required for rRNA processing through deconjugation of SUMO2 and SUMO3 from nucleophosmin, NPM1 (PubMed:19015314). Plays a role in the regulation of sumoylation status of ZNF148 (PubMed:18259216). Functions as a component of the Five Friends of Methylated CHTOP (5FMC) complex; the 5FMC complex is recruited to ZNF148 by methylated CHTOP, leading to desumoylation of ZNF148 and subsequent transactivation of ZNF148 target genes (PubMed:22872859). Deconjugates SUMO2 from KAT5 (PubMed:32832608).
Binding to chondroitin sulfate is mediated by the fourth EGF domain.
Broadly expressed, found on most hematopoietic cells, including activated lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. Expressed also abundantly by smooth muscle cells. Expressed in thyroid, colorectal, gastric, esophageal and pancreatic carcinomas too. Expression are increased under inflammatory conditions in the CNS of multiple sclerosis and in synovial tissue of patients with rheumatoid arthritis. Increased expression of CD97 in the synovium is accompanied by detectable levels of soluble CD97 in the synovial fluid.
Forms a heterodimer, consisting of a large extracellular region (alpha subunit) non-covalently linked to a seven-transmembrane moiety (beta subunit). Interacts with complement decay-accelerating factor (DAF). The largest isoform (isoform 1) interacts with chondroitin sulfate.
Proteolytically cleaved into 2 subunits, an extracellular alpha subunit and a seven-transmembrane subunit.
Rapid up-regulation during lymphocyte activation.
Receptor potentially involved in both adhesion and signaling processes early after leukocyte activation. Plays an essential role in leukocyte migration.
The first two EGF domains mediate the interaction with DAF. A third tandemly arranged EGF domain is necessary for the structural integrity of the binding region.
Autophosphorylated, leading to regulate its activity. Leptin promotes phosphorylation on tyrosine residues, including phosphorylation on Tyr-813 (By similarity). Autophosphorylation on Tyr-119 in response to EPO down-regulates its kinase activity (By similarity). Autophosphorylation on Tyr-868, Tyr-966 and Tyr-972 in response to growth hormone (GH) are required for maximal kinase activity (By similarity). Also phosphorylated by TEC (By similarity). Phosphorylated on tyrosine residues in response to interferon gamma signaling (PubMed:7615558, PubMed:7673114). Phosphorylated on tyrosine residues in response to a signaling cascade that is activated by increased cellular retinol (PubMed:21368206).
Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6.
Interacts with EPOR, LYN, SIRPA, SH2B1 and TEC (By similarity). Interacts with IL23R (PubMed:12023369). Interacts with SKB1 (PubMed:10531356). Interacts with STAM2 (PubMed:10899310). Interacts with IFNGR2 (via intracellular domain) (PubMed:7673114, PubMed:7615558). Interacts with LEPR (Isoform B) (By similarity). Interacts with HSP90AB1; promotes functional activation in a heat shock-dependent manner (PubMed:20353823). Interacts with STRA6 (PubMed:21368206). Interacts with RHEX; this interaction occurs in a erythropoietin (EPO)-dependent manner (PubMed:25092874). Interacts with ASB2; the interaction targets JAK2 for Notch-induced proteasomal degradation (PubMed:21119685).
Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins (PubMed:7615558). Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins (PubMed:9618263). Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. Part of a signaling cascade that is activated by increased cellular retinol and that leads to the activation of STAT5 (STAT5A or STAT5B) (PubMed:21368206). In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation (PubMed:20098430). Plays a role in cell cycle by phosphorylating CDKN1B (PubMed:21423214). Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin (PubMed:19783980).
Possesses 2 protein kinase domains. The second one probably contains the catalytic domain, while the presence of slight differences suggest a different role for protein kinase 1 (By similarity).
Regulated by autophosphorylation, can both activate or decrease activity (By similarity). Heme regulates its activity by enhancing the phosphorylation on Tyr-1007 and Tyr-1008 (PubMed:21036157).
Ubiquitously expressed throughout most tissues.
May act as a morphogenetic regulator of cell adhesion.
Acts as an activator of the protein-kinase ILK, thereby regulating cell motility (PubMed:24590809).
May play a role in tumor progression via its ability to activate the ILK protein-kinase activity.
Over-expressed in breast, bladder, melanoma and thyroid cancer cell lines and tumors (at protein level).
Expressed in heart, placenta, skeletal muscle, testis, brain and lung.
May act as a tumor suppressor. Inhibits tumor cell growth, when overexpressed.
Up-regulated by genotoxic stresses of adriamycin and/or UV irradiation in a p53/TP53-dependent manner.
N- and O-glycosylated. In head and neck cancer patients, O-glycosylated with glucosylgalactosyl carbohydrate moiety. This modification would require prior hydroxylation on the lysine residue.
Peptides IB-9 and P-E are the same peptide.
Proteolytically cleaved at the tripeptide Xaa-Pro-Gln, where Xaa in the P(3) position is mostly lysine. The endoprotease may be of microbial origin.
Pyroglutamate formation occurs on terminal Gln residues of cleaved peptides. Pyroglutamate formation found on at least Gln-398 and Gln-400.
The number of repeats is polymorphic and varies among different alleles (PubMed:2851479).
Belongs to the TDD superfamily. DTWD2 family.
Catalyzes the formation of 3-(3-amino-3-carboxypropyl)uridine (acp3U) at position 20a in the D-loop of several cytoplasmic tRNAs (acp3U(20a)) (PubMed:31804502). Also has a weak activity to form acp3U at position 20 in the D-loop of tRNAs (acp3U(20)) (PubMed:31804502).
Hereditary alpha tryptasemia is caused by an increase in the copy number (usually between two and three copies) of the alpha allele. Affected individuals have elevated basal serum tryptase levels that are associated with cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities. It is not clear if the associated multisystem complaints might be due to the coinheritance of a second functional genetic variant.
Homotetramer. The active tetramer is converted to inactive monomers at neutral and acidic pH in the absence of heparin. Low concentrations of inactive monomers become active monomers at pH 6.0 in the presence of heparin. When the concentration of active monomers is higher, they convert to active monomers and then to active tetramers. These monomers are active and functionally distinct from the tetrameric enzyme. In contrast to the hidden active sites in the tetrameric form, the active site of the monomeric form is accessible for macromolecular proteins and inhibitors eg: fibrinogen which is a substrate for the monomeric but not for the tetrameric form. The monomeric form forms a complex with SERPINB6.
Isoform 1 and isoform 2 are expressed in lung, stomach, spleen, heart and skin; in these tissues, isoform 1 is predominant. Isoform 2 is expressed in aorta, spleen, and breast tumor, with highest levels in the endothelial cells of some blood vessels surrounding the aorta, as well as those surrounding the tumor and low levels, if any, in mast cells (at protein level).
There are two alleles alpha and beta-I. The sequence shown is that of allele beta-I.
Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type. May play a role in innate immunity. Isoform 2 cleaves large substrates, such as fibronectin, more efficiently than isoform 1, but seems less efficient toward small substrates (PubMed:18854315).
Member of the machinery of polarized transport. Required for the indirect transcytotic route at the step of the egress of the transcytosing cargo from perinuclear endosomes in order for it to travel to the apical surface via a raft-dependent pathway.
Predominantly expressed in kidney, lung, and liver. Also found in thyroid gland, stomach and, at lower levels in testis and small intestine.
Belongs to the DNA glycosylase MPG family.
Binding to SSBP1 in mitochondria inhibits glycosylase activity in the context of a single-stranded DNA (ssDNA), but not a double-stranded DNA (dsDNA) substrates.
Hydrolysis of the deoxyribose N-glycosidic bond to excise 3-methyladenine, and 7-methylguanine from the damaged DNA polymer formed by alkylation lesions.
Interacts with CACNA1C. Identified in a complex with the L-type calcium channel subunits CACNA1C, CACNA2D1 and either CACNB1 or CACNB2. Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CNIH2, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5 and CACNG7. Interacts with CNIH2.
Palmitoylated. Probably palmitoylated by ZDHHC3 and ZDHHC7.
Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit (By similarity). Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization and by mediating their resensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits.
Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol.
May be involved in transcriptional regulation. May play a role in spermatogenesis.
Lysophospholipase which preferentially deacylates unsaturated lysophosphatidylcholine (C18:1), generating glycerophosphocholine. Also can deacylate, to a lesser extent, lysophosphatidylethanolamine (C18:1), lysophosphatidyl-L-serine (C18:1) and lysophosphatidic acid (C16:0).
The 3 cNMP binding domains are required for localization to the endoplasmic reticulum. The cNMP binding domain 3 is involved in the binding to lipid droplets.
Testis-specific. Expressed in melanoma, sarcoma, lung, breast, bladder, esophageal and ovarian cancers.
Alternative acceptor site favored by mutation in an exonic splicing enhancer (ESE). Causes cystic fibrosis (CF).
Belongs to the ABC transporter superfamily. ABCC family. CFTR transporter (TC 3.A.1.202) subfamily.
Binds and hydrolyzes ATP via the two cytoplasmic ABC transporter nucleotide-binding domains (PubMed:15284228). The two ATP-binding domains interact with each other, forming a head-to-tail dimer (PubMed:17036051). Normal ATPase activity requires interaction between the two domains (PubMed:15284228). The first ABC transporter nucleotide-binding domain has no ATPase activity by itself (By similarity).
Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis (PubMed:26823428). Mediates the transport of chloride ions across the cell membrane (PubMed:10792060, PubMed:11524016, PubMed:11707463, PubMed:12519745, PubMed:15010471, PubMed:12588899, PubMed:17036051, PubMed:19398555, PubMed:19621064, PubMed:22178883, PubMed:25330774, PubMed:1712898, PubMed:8910473, PubMed:9804160, PubMed:12529365, PubMed:17182731, PubMed:26846474, PubMed:28087700). Channel activity is coupled to ATP hydrolysis (PubMed:8910473). The ion channel is also permeable to HCO(3)(-); selectivity depends on the extracellular chloride concentration (PubMed:15010471, PubMed:19019741). Exerts its function also by modulating the activity of other ion channels and transporters (PubMed:12403779, PubMed:22178883, PubMed:22121115, PubMed:27941075). Plays an important role in airway fluid homeostasis (PubMed:16645176, PubMed:19621064, PubMed:26823428). Contributes to the regulation of the pH and the ion content of the airway surface fluid layer and thereby plays an important role in defense against pathogens (PubMed:14668433, PubMed:16645176, PubMed:26823428). Modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating the cell surface expression of the ENaC complex (PubMed:17434346, PubMed:27941075, PubMed:17182731). Inhibits the activity of the ENaC channel containing subunits SCNN1A, SCNN1B and SCNN1G (PubMed:17182731). Inhibits the activity of the ENaC channel containing subunits SCNN1D, SCNN1B and SCNN1G, but not of the ENaC channel containing subunits SCNN1A, SCNN1B and SCNN1G (PubMed:17182731, PubMed:27941075). May regulate bicarbonate secretion and salvage in epithelial cells by regulating the transporter SLC4A7 (PubMed:12403779). Can inhibit the chloride channel activity of ANO1 (PubMed:22178883). Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation (PubMed:19923167, PubMed:27714810).
Exon 9 splicing depends upon 2 polymorphic tracts within intron 8, a T(n) tract and TG(n) tract, where the number of T and/or TG repeats affect the extent of correct splicing of exon 9. Low numbers of T residues and high numbers of TG repeats give rise to less efficient splicing. Transcripts that lack exon 9 sequences fail to mature. Causes congenital bilateral absence of the vas deferens (CBAVD).
Expressed in the respiratory airway, including bronchial epithelium, and in the female reproductive tract, including oviduct (at protein level) (PubMed:22207244, PubMed:15716351). Detected in pancreatic intercalated ducts in the exocrine tissue, on epithelial cells in intralobular striated ducts in sublingual salivary glands, on apical membranes of crypt cells throughout the small and large intestine, and on the reabsorptive duct in eccrine sweat glands (PubMed:1284548, PubMed:28130590). Detected on the equatorial segment of the sperm head (at protein level) (PubMed:19923167). Detected in nasal and bronchial superficial epithelium (PubMed:15716351). Expressed by the central cells on the sebaceous glands, dermal adipocytes and, at lower levels, by epithelial cells (PubMed:28130590).
Monomer; does not require oligomerization for channel activity (PubMed:11524016). May form oligomers in the membrane (PubMed:11524016). Interacts with SLC26A3, SLC26A6 and SHANK2 (By similarity). Interacts with NHERF1 and MYO6 (PubMed:12403779, PubMed:15247260, PubMed:11304524). Interacts (via C-terminus) with GOPC (via PDZ domain); this promotes CFTR internalization and thereby decreases channel activity (PubMed:11707463, PubMed:16331976). Interacts with SLC4A7 through NHERF1 (PubMed:12403779). Found in a complex with MYO5B and RAB11A (PubMed:17462998). Interacts with ANO1 (PubMed:22178883). Interacts with SLC26A8 (PubMed:22121115). Interacts with AHCYL1; the interaction increases CFTR activity (By similarity). Interacts with CSE1L (PubMed:20933420). The core-glycosylated form interacts with GORASP2 (via PDZ GRASP-type 1 domain) in respone to ER stress (PubMed:21884936). Interacts with MARCHF2; the interaction leads to CFTR ubiqtuitination and degradation (PubMed:23818989).
Phosphorylated; cAMP treatment promotes phosphorylation and activates the channel (PubMed:12588899, PubMed:17036051, PubMed:8910473). Dephosphorylation decreases the ATPase activity (in vitro) (PubMed:8910473). Phosphorylation at PKA sites activates the channel (PubMed:10792060, PubMed:12519745, PubMed:12588899, PubMed:25330774). Phosphorylation at PKC sites enhances the response to phosphorylation by PKA (PubMed:12588899). Phosphorylated by AMPK; this inhibits channel activity (PubMed:12519745).
The PDZ-binding motif mediates interactions with GOPC and with the SLC4A7, NHERF1/EBP50 complex.
The R region is intrinsically disordered (PubMed:10792060, PubMed:17660831). It mediates channel activation when it is phosphorylated, but not in the absence of phosphorylation (PubMed:10792060).
The disease is caused by variants affecting the gene represented in this entry. There is some evidence that the functional defect caused by the most common variant Phe-508 DEL can be corrected by the binding to the snake phospholipase A2 crotoxin basic subunit CB. This toxin both disrupts the Phe-508 DEL-cytokeratin 8 complex, allowing for the escape from degradation, and increases the chloride channel current (PubMed:27241308).
Ubiquitinated, leading to its degradation in the lysosome (PubMed:19398555, PubMed:23818989). Deubiquitination by USP10 in early endosomes enhances its endocytic recycling to the cell membrane (PubMed:19398555). Ubiquitinated by RNF185 during ER stress (PubMed:24019521). Ubiquitinated by MARCHF2 (PubMed:23818989).
Cytotoxin and helminthotoxin. Also induces non-cytolytic histamine release from human basophils. Involved in antiparasitic defense mechanisms and immune hypersensitivity reactions. The proform acts as a proteinase inhibitor, reducing the activity of PAPPA.
Detected in plasma and urine (at protein level) (PubMed:25326458, PubMed:36213313). Detected in placenta (at protein level) (PubMed:32337544). High levels of the proform in placenta and pregnancy serum; in placenta, localized to X cells of septa and anchoring villi. Lower levels in a variety of other tissues including kidney, myometrium, endometrium, ovaries, breast, prostate, bone marrow and colon.
In pregnancy serum, the proform exists as a disulfide-linked 2:2 heterotetramer with PAPPA, as a disulfide-linked 2:2 heterotetramer with AGT, and as a complex (probably a 2:2:2 heterohexamer) with AGT and C3dg.
Levels of the proform increase in serum and placenta during pregnancy.
Autoregulated by feedback control of mRNA degradation (PubMed:31727855). In excess of soluble tubulin, nascent beta-tubulin chain binds TTC5/STRAP cofactor through the MREI motif which triggers cotranslation degradation of tubulin mRNA (PubMed:31727855).
Heterodimer of alpha and beta chains (PubMed:26637975). A typical microtubule is a hollow water-filled tube with an outer diameter of 25 nm and an inner diameter of 15 nM. Alpha-beta heterodimers associate head-to-tail to form protofilaments running lengthwise along the microtubule wall with the beta-tubulin subunit facing the microtubule plus end conferring a structural polarity. Microtubules usually have 13 protofilaments but different protofilament numbers can be found in some organisms and specialized cells. Interacts with CIMAP3 (PubMed:20643351). Interacts with DIAPH1 (PubMed:23325789). Interacts with MX1 (By similarity). May interact with RNABP10 (By similarity). Interacts with CFAP157 (By similarity). Nascent tubulin polypeptide interacts (via beta-tubulin MREI motif) with TTC5/STRAP; this interaction results in tubulin mRNA-targeted degradation (PubMed:31727855).
Some glutamate residues at the C-terminus are monoglycylated but not polyglycylated due to the absence of functional TTLL10 in human. Monoglycylation is mainly limited to tubulin incorporated into cilia and flagella axonemes, which is required for their stability and maintenance. Flagella glycylation controls sperm motility (Probable) (PubMed:28576883). Both polyglutamylation and monoglycylation can coexist on the same protein on adjacent residues, and lowering glycylation levels increases polyglutamylation, and reciprocally (Probable) (PubMed:28576883).
Some glutamate residues at the C-terminus are polyglutamylated, resulting in polyglutamate chains on the gamma-carboxyl group (PubMed:26875866, PubMed:28576883). Polyglutamylation plays a key role in microtubule severing by spastin (SPAST). SPAST preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity by SPAST increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold (PubMed:26875866). Glutamylation is also involved in cilia motility (By similarity).
Ubiquitously expressed with highest levels in spleen, thymus and immature brain.
Highest levels in heart, skeletal muscle and brain. Lower levels in pancreas, kidney, lung and placenta. Very low levels in liver.
Isoform Gamma-3 is phosphorylated on serine residues. Isoform Gamma-1 phosphorylation by ERK2 is IER3-dependent and inhibits ERK dephosphorylation by PP2A-PPP2R5C.
PP2A consists of a common heterodimeric core enzyme, composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with PPP2CA and PPP2R1A; the interaction is direct. Interacts with SGO1; the interaction is direct. Isoform 1 and isoform 2 interact with TP53 (phosphorylated at Ser-15 by ATM); increased upon DNA damage it drives PP2A-mediated dephosphorylation of TP53 at Thr-55. Interacts with IER3 and/or ERK kinases; regulates ERK dephosphorylation. Interacts with CIP2A; this interaction stabilizes CIP2A (PubMed:28174209).
The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment. The PP2A-PPP2R5C holoenzyme may specifically dephosphorylate and activate TP53 and play a role in DNA damage-induced inhibition of cell proliferation. PP2A-PPP2R5C may also regulate the ERK signaling pathway through ERK dephosphorylation.
May be involved in transcriptional regulation (Probable). In the central nervous system, may play a role in glial cell differentiation (By similarity).
Acts as E3 ubiquitin-protein ligase and regulates the degradation of target proteins. Polyubiquitinates MYD88. Negatively regulates MYD88-dependent production of pro-inflammatory cytokines. Can promote TRIF-dependent production of type I interferon and inhibits infection with vesicular stomatitis virus (By similarity). Promotes also activation of TBK1 and IRF3. Involved in the ubiquitination of erythropoietin (EPO) and interleukin-3 (IL-3) receptors. Thus, through maintaining basal levels of cytokine receptors, RNF41 is involved in the control of hematopoietic progenitor cell differentiation into myeloerythroid lineages (By similarity). Contributes to the maintenance of steady-state ERBB3 levels by mediating its growth factor-independent degradation. Involved in the degradation of the inhibitor of apoptosis BIRC6 and thus is an important regulator of cell death by promoting apoptosis. Acts also as a PRKN modifier that accelerates its degradation, resulting in a reduction of PRKN activity, influencing the balance of intracellular redox state. The RNF41-PRKN pathway regulates autophagosome-lysosome fusion during late mitophagy. Mitophagy is a selective form of autophagy necessary for mitochondrial quality control (PubMed:24949970).
Autoubiquitinated. Autoubiquitination leads to proteasomal degradation. Deubiquitinated by USP8 to get stabilized which induces apoptosis.
Interacts with USP8, ERBB3, PRKN and BIRC6. Interacts with CSF2RB, EPOR, IL3RA, MYD88 and TBK1. Interacts with CLEC16A (By similarity).
Endonuclease that cleaves polypeptidyl-tRNAs downstream of the ribosome-associated quality control (RQC) pathway to release incompletely synthesized polypeptides for degradation (PubMed:30244831, PubMed:29632312, PubMed:31011209). The RQC pathway disassembles aberrantly stalled translation complexes to recycle or degrade the constituent parts (PubMed:30244831, PubMed:29632312, PubMed:31011209). ANKZF1 acts downstream disassembly of stalled ribosomes and specifically cleaves off the terminal 3'-CCA nucleotides universal to all tRNAs from polypeptidyl-tRNAs, releasing (1) ubiquitinated polypeptides from 60S ribosomal subunit for degradation and (2) cleaved tRNAs (PubMed:31011209). ANKZF1-cleaved tRNAs are then repaired and recycled by ELAC1 and TRNT1 (PubMed:31011209, PubMed:32075755). Also plays a role in the cellular response to hydrogen peroxide and in the maintenance of mitochondrial integrity under conditions of cellular stress (PubMed:28302725).
The VLRF1 domain mediates binding to the 60S ribosomal subunit.
Belongs to the G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily. CHRM2 sub-subfamily.
Genetic variations in CHRM2 can influence susceptibility to alcoholism [MIM:103780].
Interacts with ARRB1 and ARRB2. Interacts with RACK1; the interaction regulates CHRM2 internalization.
Phosphorylated in response to agonist treatment.
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins.
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. Signaling promotes phospholipase C activity, leading to the release of inositol trisphosphate (IP3); this then triggers calcium ion release into the cytosol.
Interacts with PTPN22 (By similarity). Interacts with unphosphorylated ITGA4. Interacts with PTK2B/PYK2, PTPN12, AR and SRF. Interacts (via LD motif 3) with LYN and the interaction is induced upon B-cell antigen receptor (BCR) activation. Interacts (via LD motif 3) with PTK2/FAK.
Macrophages, monocytes and osteoclasts (at protein level). Strongly expressed in cells and tissues of hematopoietic origin. Highest expression in lymphoid tissues such as spleen, lymph node, thymus and appendix and in the vascular smooth muscle. Lower levels in bone marrow and fetal liver. Also expressed in peripheral blood lymphocytes and a number of hematopoietic cell lines. Very low levels found in epithelial cell lines. Expressed in prostate cancer (PCa) cells and its expression intensity is directly linked to PCa progression.
Phosphorylated on tyrosine residues. Phosphorylation on Tyr-72 is important for its inhibitory function. Bombesin stimulates phosphorylation on Tyr-22, Tyr-62 and Tyr-72.
The LIM domain 3 is critical for focal adhesion targeting and the suppression of paxillin (PXN) tyrosine phosphorylation. The LIM domain 3 alone or both LIM domains 3 and 4 can mediate interaction with AR.
Transcriptional coactivator for androgen receptor (AR) and serum response factor (SRF). Contributes to the regulation of cell adhesion, spreading and cell migration and acts as a negative regulator in integrin-mediated cell adhesion events. Suppresses the integrin-induced tyrosine phosphorylation of paxillin (PXN).
Transcriptional coactivator for androgen receptor (AR) and serum response factor (SRF). Contributes to the regulation of cell adhesion, spreading and cell migration and acts as a negative regulator in integrin-mediated cell adhesion events. Suppresses the integrin-induced tyrosine phosphorylation of paxillin (PXN). May play a critical role as an adapter protein in the formation of the adhesion zone in osteoclasts. Negatively regulates B-cell antigen receptor (BCR) signaling.
The sequence of 1-41 of PubMed:12359730 has not been submitted.
Weak expression seen in the late matrix and entire cortex area of the hair follicle.
Interacts with TRIM23 and CYTIP (PubMed:10748148, PubMed:11867758). Interacts (via coiled-coil domain) with FRMD4A (via coiled-coil domain) (By similarity). Interacts with FRMD4B (By similarity). Found in a complex with PARD3, CYTH1 and FRMD4A (By similarity). Interacts (via N-terminal domain) with INAVA (via N-terminal domain) (PubMed:29420262).
Promotes guanine-nucleotide exchange on ARF1, ARF5 and ARF6. Promotes the activation of ARF factors through replacement of GDP with GTP. Plays an important role in membrane trafficking, during junctional remodeling and epithelial polarization, through regulation of ARF6 activity.
Ubiquitinated by SCF(FBXW11) E3 ubiquitin-protein ligase complex. Ubiquitination induces proteasomal degradation.
Interacts with EVL and VASP and targets them to the leading edge (PubMed:15469845). Interacts (via Ras associating and PH domains) with RAC1 (PubMed:18499456).
Isoform RMO1-RAPH1 is ubiquitously expressed with highest levels in brain, heart, ovary and developing embryo. Isoform RMO1 is widely expressed with highest levels in liver. Low expression in B-cells.
Mediator of localized membrane signals. Implicated in the regulation of lamellipodial dynamics. Negatively regulates cell adhesion.
Reduced expression in metastatic osteosarcomas compared to primary osteosarcoma tumors. Down-regulated in both breast (43% of tissue samples) and ovarian (25% of tissue samples) cancers.
The chimpanzee and gorilla orthologous proteins do not exist, their genes are pseudogenes.
Various VN1R4 alleles are known. The sequence shown is that of allele VN1R4*1.
May regulate apoptosis of neural progenitor cells during their differentiation.
Acts as a GTPase-activating protein for Rab family protein(s) (PubMed:28067790, PubMed:19077034). Essential for the establishment of male fertility, and is required for both the production of normal sperm number and sperm function (By similarity). Plays an important role in the formation of intact mitochondria, outer dense fibers and axoneme within the sperm tail (By similarity). Essential for sperm mitochondrial sheath formation and for the interactions of ARMC12 with VDAC2 and VDAC3 (By similarity). May be involved in acrosome formation and cytoskeletal reorganization during spermiogenesis, possibly by regulating RAB3A activity (PubMed:21128978).
Expressed in round and elongated spermatids (at protein level). Expressed specifically in adult testis and very weakly in fetal brain.
Interacts with ACTB (By similarity). Interacts with ARMC12, TOMM20, DNAH7 and RAP1A (By similarity). Interacts with RAB10 (PubMed:28067790).
Interacts with CAMLG (PubMed:16243292). Interacts with PKD2 (PubMed:18235088). Interacts (via CST) with ARF4; this interaction allows an efficient PKHD1 trafficking to the cilium. Interacts (via CST) with RAB8A; this interaction controls trafficking through the endomembrane systeme and the cilium. Interacts (via CST) with TULP3; this interaction allows PKHD1 trafficking to the cilium (By similarity).
Loss-of-function PKHD1 variations may cause autosomal dominant polycystic liver disease (PCLD) in patients that lack variations in known causative genes, such as PRKCSH and SEC63.
Palmitoylated. Palmitoylation facilitates membrane targeting and the trafficking to the cilia.
Predominantly expressed in fetal and adult kidney. In the kidney, it is found in the cortical and medullary collecting ducts. Also present in the adult pancreas, but at much lower levels. Detectable in fetal and adult liver. Rather indistinct signal in fetal brain.
Promotes ciliogenesis in renal epithelial cells and therefore participates in the tubules formation and/ or ensures the maintenance of the architecture of the lumen of the kidney (By similarity). Has an impact on cellular symmetry by ensuring correct bipolar cell division through the regulation of centrosome duplication and mitotic spindle assembly and by maintaining oriented cell division (OCD) during tubular elongation through planar cell polarity (PCP) pathway (PubMed:20554582). During epithelial cell morphogenesis regulates also cell-cell and cell-matrix adhesion and participates in cell motility (By similarity). Promotes cell-cell contact through the positive regulation of PTK2 kinase activity leading to either positive regulation of epithelial cell proliferation through the HRAS/RAF1 pathways, or negative regulation of apoptosis through the PDK1/AKT1 pathway (By similarity). May act in collecting-duct and biliary differentiation (PubMed:11919560). May participate in the regulation of the cholangiocytes proliferation and the CCN2 production in an CXCL8-dependent manner (PubMed:30898581).
Several proteolytic cleavages occur within the extracellular domain, whereas at least one cleavage occurs within the cytoplasmic domain (PubMed:16956880). Cleaved by a probable proprotein convertase which produces an extracellular domain (polyductin extracellular domain, (PECD)) and a C-terminal fragment (polyductin transmembrane fragment (PTM)) which are tethered together by disulfide bonds (PubMed:17470460). This extracellular domain (PECD) is then shed from the primary cilium by activation of a member of the ADAM metalloproteinase disintegrins family, resulting in concomitant release of an intra-cellular C-terminal fragment (ICD) via a gamma-secretase-dependent process (PubMed:17470460). The proteolytic cleavage of the C-terminal intracellular fragment (ICD) is controlled by cytosolic calcium concentration and activation of PKC (PubMed:16956880).
Catalyzes the second step in the formation of the mannose 6-phosphate targeting signal on lysosomal enzyme oligosaccharides by removing GlcNAc residues from GlcNAc-alpha-P-mannose moieties, which are formed in the first step. Also hydrolyzes UDP-GlcNAc, a sugar donor for Golgi N-acetylglucosaminyltransferases.
Defects in NAGPA have been suggested to play a role in susceptibility to persistent stuttering. Stuttering is a common speech disorder characterized by repetitions, prolongations, and interruptions in the flow of speech.
Homotetramer arranged as two disulfide-linked homodimers. Interacts with AP4M1.
The C-terminal NPFKD sequence is an attractive candidate for either an endocytosis signal acting at the plasma membrane or a retrieval signal acting at the TGN to return the enzyme to the cis/medial-Golgi.
The precursor is cleaved and activated in the trans-Golgi network by a furin endopeptidase.
The tyrosine-based internalization signal may be essential for its retrieval from the plasma membrane to the TGN.
Expressed in brain, prostate, brain, kidney and some other organs.
Involved in the cell-cell adhesion. Has calcium- and magnesium-independent cell-cell adhesion activity. May have tumor-suppressor activity.
Homodimer; disulfide-linked (PubMed:17158226). Interacts (via extracellular domain) with ADAM10 (via extracellular domain) (PubMed:26686862, PubMed:30463011). Interacts (via cytoplasmic domain) with PLEKHA7 (via WW domains); the interaction is dependent on PDZD11 being bound to PLEKHA7 and facilitates the docking of ADAM10 to zonula adherens (PubMed:30463011).
Plays an important role in normal erythropoiesis (By similarity). It has a role in the differentiation of erythroid progenitors (By similarity). Regulates maturation and trafficking of the transmembrane metalloprotease ADAM10 (PubMed:26686862, PubMed:30463011). Negatively regulates ligand-induced Notch activity probably by regulating ADAM10 activity (PubMed:26686862). Mediates docking of ADAM10 to zonula adherens by interacting with ADAM10 and, in a PDZD11-dependent manner, with the zonula adherens protein PLEKHA7 (PubMed:30463011).
Predominantly expressed in erythroblasts.
Transcriptional regulator that acts as repressor or activator, depending on the context. Binds to NF-E2 DNA binding sites. Plays important roles in coordinating transcription activation and repression by MAFK (By similarity). Together with MAF, represses the transcription of genes under the control of the NFE2L2 oxidative stress pathway (PubMed:24035498).
Ubiquitinated by the SCF(FBXL17) complex, leading to its degradation by the proteasome.
Homotetramer; probably composed of anti-parallel linkage of two parallel dimers. Interacts with Ras. Interacts with RAB5B, with a much higher affinity for GTP-bound activated RAB5B. Does not interact with other members of the Rab family.
Ras effector protein. May function as an upstream activator and/or downstream effector for RAB5B in endocytic pathway. May function as a guanine nucleotide exchange (GEF) of RAB5B, required for activating the RAB5 proteins by exchanging bound GDP for free GTP.
Widely expressed. Expressed in heart, kidney, lung placenta. Expressed at low level in skeletal muscle, spleen and peripheral blood.
Belongs to the ROX family. NO66 subfamily.
Interacts with SP7/OSX; the interaction is direct (By similarity). Interacts with MYC (PubMed:17308053). Interacts with PHF19; leading to its recruitment to H3K36me3 sites (PubMed:23160351).
Oxygenase that can act as both a histone lysine demethylase and a ribosomal histidine hydroxylase (PubMed:23103944). Specifically demethylates 'Lys-4' (H3K4me) and 'Lys-36' (H3K36me) of histone H3, thereby playing a central role in histone code (By similarity). Preferentially demethylates trimethylated H3 'Lys-4' (H3K4me3) and monomethylated H3 'Lys-4' (H3K4me1) residues, while it has weaker activity for dimethylated H3 'Lys-36' (H3K36me2) (By similarity). Acts as a regulator of osteoblast differentiation via its interaction with SP7/OSX by demethylating H3K4me and H3K36me, thereby inhibiting SP7/OSX-mediated promoter activation (By similarity). Also catalyzes demethylation of non-histone proteins, such as CGAS: demethylation of monomethylated CGAS promotes interaction between CGAS and PARP1, followed by PARP1 inactivation (By similarity). Also catalyzes the hydroxylation of 60S ribosomal protein L8 on 'His-216', thereby playing a role in ribosome biogenesis (PubMed:23103944). Participates in MYC-induced transcriptional activation (PubMed:17308053).
Widely expressed. Overexpressed in lung carcinomas.
May play a role in neuronal migration during embryonic development.
Heterogeneous proteolytic processing generates N-terminal and C-terminal fragments.
Interacts with DOCK3 (By similarity). Homodimer. Component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity, although other components may exist. Interacts with HERPUD1, FLNA, FLNB and PARL.
Isoform 1 is seen in the placenta, skeletal muscle and heart while isoform 2 is seen in the heart, brain, placenta, liver, skeletal muscle and kidney.
Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. May function in the cytoplasmic partitioning of proteins. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is involved in calcium homeostasis (PubMed:16959576). Is a regulator of mitochondrion-endoplasmic reticulum membrane tethering and modulates calcium ions shuttling between ER and mitochondria (PubMed:21285369).
The PAL motif is required for normal active site conformation.
Associates with the mTORC2 complex that regulates cellular processes including survival and organization of the cytoskeleton (PubMed:17461779). Regulates the activity of the mTORC2 complex in a substrate-specific manner preventing for instance the specific phosphorylation of PKCs and thereby controlling cell migration (PubMed:22609986). Plays a role in the stimulation of ZFP36-mediated mRNA decay of several ZFP36-associated mRNAs, such as TNF-alpha and GM-CSF, in response to stress (PubMed:21964062). Required for ZFP36 localization to cytoplasmic stress granule (SG) and P-body (PB) in response to stress (PubMed:21964062).
Interacts with the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR (PubMed:17461779). Interacts with RFFL (PubMed:22609986). Interacts (via C-terminus) with ZFP36 (via C-terminus); this interaction may accelerate ZFP36-mediated mRNA decay during stress (PubMed:21964062). Interacts with RICTOR (PubMed:21964062).
Ubiquitinated. Ubiquitination by RFFL promotes proteasomal degradation of PRR5L thereby modifying the substrate-specific activity of the mTORC2 complex. Ubiquitination by RFFL is stimulated by LPA/lysophosphatidic acid.
(Microbial infection) Interacts with hepatitis delta virus NES (HDAg-L).
(Microbial infection) May play a role in the assembly of hepatitis delta virus (HDV).
Belongs to the LIMR family. LMBRD1 subfamily.
Interacts with ABCD4; this interaction induces the translocation of ABCD4 from the endoplasmic reticulum to the lysosome (PubMed:27456980, PubMed:28572511, PubMed:33845046). Interacts with ABCD4 and MMACHC; this interaction ensures the transport of cobalamin from the lysosome to the cytoplasm (PubMed:25535791). Interacts with INSR, adapter protein complex 2 and clathrin heavy chain (By similarity).
Lysosomal membrane chaperone required to export cobalamin (vitamin B12) from the lysosome to the cytosol, allowing its conversion to cofactors (PubMed:19136951). Targets ABCD4 transporter from the endoplasmic reticulum to the lysosome (PubMed:27456980). Then forms a complex with lysosomal ABCD4 and cytoplasmic MMACHC to transport cobalamin across the lysosomal membrane (PubMed:25535791). Acts as an adapter protein which plays an important role in mediating and regulating the internalization of the insulin receptor (INSR) (By similarity). Involved in clathrin-mediated endocytosis of INSR via its interaction with adapter protein complex 2 (By similarity). Essential for the initiation of gastrulation and early formation of mesoderm structures during embryogenesis (By similarity).
(Microbial infection) In CMV-infected cells, interacts with the viral glycoprotein UL16; this interaction causes RAET1G retention in the endoplasmic reticulum and cis-Golgi and prevents binding to and activation of KLRK1/NKG2D, providing CMV with an immune evasion mechanism.
Down-regulates the expression of KLRK1 and stimulates natural killer cells to secrete IFNG.
Isoform 1 is highly expressed in colon and in a number of tumor cell lines and highly restricted in normal tissues. Both isoforms are frequently expressed in cell lines derived from epithelial cancers, and in primary breast cancers.
Stimulates natural killer cells to secrete IFNG.
The functional form is cleaved C-terminally of the GPI-anchor and yields a 28 kDa protein.
Fetal ear, skin, and tongue and human cell lines. Highly up-regulated in psoriatic epidermis. Also highly expressed in the urine of bladder squamous cell carcinoma (SCC) bearing patients.
Ubiquitous expression in normal tissues. Expression is more elevated in adult liver, lung, spleen, and heart than in their fetal counterparts, and is higher in normal tissues than in the cancerous tissue or cell lines. Low levels of expression were detected in the promonocytic stage, whereas high levels of expression were detected in mature monocytes.
RNA-binding protein that plays an essential role in spermatogenesis. May act by binding to the 3'-UTR of mRNAs and regulating their translation. Promotes germ-cell progression to meiosis and formation of haploid germ cells.
Extracellular matrix protein that seems to be a ligand for ITGA8:ITGB1, ITGAV:ITGB1 and ITGA4:ITGB1 (By similarity) (PubMed:17909022). Involved in neurite outgrowth and cell migration in hippocampal explants (By similarity). During endochondral bone formation, inhibits proliferation and differentiation of proteoblasts mediated by canonical WNT signaling (By similarity). In tumors, stimulates angiogenesis by elongation, migration and sprouting of endothelial cells (PubMed:19884327). Expressed in most mammary tumors, may facilitate tumorigenesis by supporting the migratory behavior of breast cancer cells (PubMed:17909022).
Not detected in normal adult mammary tissues or brain but expressed in most breast tumors and brain tumors, such as glioblastomas, astrocytomas and oligodendrogliomas, tested (PubMed:17909022, PubMed:19884327). In brain tumors, detected around the endothelial cell layer of the clood vessels (PubMed:19884327).
Expressed in brain, heart, skeletal muscle, kidney and pancreas. Weakly expressed in aorta, liver and lung.
Putative C to U editing enzyme whose physiological substrate is not yet known.
Interacts (via N-terminus) with FAM161A (via central region); the interaction is direct.
May be involved in photoreceptor outer segment disk morphogenesis (By similarity).
Widely expressed, with highest levels in heart and brain. Also expressed in the retina (at protein level).
Belongs to the SMC family. RAD50 subfamily.
Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (PubMed:8756642, PubMed:9590181, PubMed:9705271, PubMed:10839544, PubMed:26215093). As part of the MRN complex, interacts with MCM8 and MCM9; the interaction recruits the complex to DNA repair sites (PubMed:26215093). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (PubMed:10783165). Found in a complex with TERF2 (PubMed:10888888). Interacts with RINT1 (PubMed:11096100). Interacts with BRCA1 via its N-terminal domain (PubMed:10426999). Interacts with DCLRE1C/Artemis (PubMed:15456891, PubMed:15723659). Interacts with MRNIP (PubMed:27568553). Interacts with CYREN (via XLF motif) (By similarity).
Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11 to prevent nucleolytic degradation past a given point (PubMed:11741547, PubMed:9590181, PubMed:9705271, PubMed:9651580). The complex may also be required for DNA damage signaling via activation of the ATM kinase (PubMed:15064416). In telomeres the MRN complex may modulate t-loop formation (PubMed:10888888).
Expressed at very low level in most tissues, except in testis where it is expressed at higher level. Expressed in fibroblasts.
The zinc-hook, which separates the large intramolecular coiled coil regions, contains 2 Cys residues that coordinate one molecule of zinc with the help of the 2 Cys residues of the zinc-hook of another RAD50 molecule, thereby forming a V-shaped homodimer. The two heads of the homodimer, which constitute the ATP-binding domain, interact with the MRE11 homodimer (By similarity).
Component of the HUSH complex, a multiprotein complex that mediates epigenetic repression. The HUSH complex is recruited to genomic loci rich in H3K9me3 and is probably required to maintain transcriptional silencing by promoting recruitment of SETDB1, a histone methyltransferase that mediates further deposition of H3K9me3. In the HUSH complex, contributes to the maintenance of the complex at chromatin (PubMed:26022416). Acts as a transcriptional corepressor and regulates the cell cycle, probably via the HUSH complex (PubMed:15474462, PubMed:17963697). The HUSH complex is also involved in the silencing of unintegrated retroviral DNA: some part of the retroviral DNA formed immediately after infection remains unintegrated in the host genome and is transcriptionally repressed (PubMed:30487602). May be involved in epithelial differentiation by contributing to epidermal integrity and barrier formation (PubMed:12853457).
Homodimer (PubMed:12853457). Component of the HUSH complex; at least composed of TASOR, PPHLN1 and MPHOSPH8 (PubMed:26022416). Interacts with SIN3A and HDAC1 (PubMed:17963697). May interact with PPL (PubMed:12853457).
Substrate of transglutaminase (in vitro).
Binds F-actin through its N-terminus. Interacts with MYZAP (By similarity). Binds RHOA, PPP1R12A/MBS and PPP1R12C/MBS85 through adjacent coiled coil domains.
Targets myosin phosphatase to the actin cytoskeleton. Required for the regulation of the actin cytoskeleton by RhoA and ROCK1. Depletion leads to an increased number of stress fibers in smooth muscle cells through stabilization of actin fibers by phosphorylated myosin. Overexpression of MRIP as well as its F-actin-binding region leads to disassembly of stress fibers in neuronal cells.
Expressed in lung, liver and lymphoid cells.
GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state. Has activity toward RAC1. Overexpression results in an increase in actin stress fibers and cell contraction.
The PH domain is required for localization to the membrane.
Directs RNA polymerase II nuclear import.
When transfected to S.cerevisiae cells, able to partially restore polymerase II mislocalization and cellular shape in IWR1 mutant cells.
Highly expressed in testis. Expressed at lower levels in colon, small intestine, ovary, prostate, thymus, spleen and peripheral blood leukocytes.
Interacts with HSP90; this interaction stabilizes and activates TSSK6 (By similarity). Interacts with the heat shock proteins HSPCB, HSPA8 and HSPA1A. These interactions appear to be required for TSSK6 kinase activity. Interacts with TSACC; this interaction is direct and recruits TSACC to HSP90, which is essential for kinase activity.
Required for sperm production and function. Plays a role in DNA condensation during postmeiotic chromatin remodeling (By similarity).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type B (BoNT/B, botB) which hydrolyzes the 76-Gln-|-Phe-77 bond and probably inhibits neurotransmitter release (PubMed:7803399).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type D (BoNT/D, botD) which probably hydrolyzes the 59-Lys-|-Leu-60 bond and inhibits neurotransmitter release (PubMed:22289120). Note that humans are not known to be infected by C.botulinum type D.
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type F (BoNT/F, botF) which hydrolyzes the 58-Gln-|-Lys-59 bond and probably inhibits neurotransmitter release (PubMed:19543288).
(Microbial infection) Targeted and hydrolyzed by C.tetani tetanus toxin (tetX) which hydrolyzes the 76-Gln-|-Phe-77 bond and probably inhibits neurotransmitter release (PubMed:7803399).
A structure of a fragment of this protein in complex with the catalytic domain of C.botulinum neurotoxin type B (BoNT/B, botB) was reported; because of the lack of clear and continuous electron density for the VAMP2 peptide in the complex structure, the paper was retracted (PubMed:10932255, PubMed:19578378). However this protein is a substrate for BoNT/B (PubMed:7803399, PubMed:22289120).
Involved in the targeting and/or fusion of transport vesicles to their target membrane (By similarity). Major SNARE protein of synaptic vesicles which mediates fusion of synaptic vesicles to release neurotransmitters. Essential for fast vesicular exocytosis and activity-dependent neurotransmitter release as well as fast endocytosis that mediates rapid reuse of synaptic vesicles (By similarity) (PubMed:30929742). Modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1.
Part of the SNARE core complex containing SNAP25, VAMP2 and STX1A; this complex constitutes the basic catalytic machinery of the complex neurotransmitter release apparatus (By similarity). Recruited to the SNARE complex following binding of the SNARE complex component STX1A to STXBP1 (By similarity). This complex binds to CPLX1. Interacts with BVES and STX4 (By similarity). Interacts with VAPA and VAPB. Interacts with WDFY2, PRKCZ and PRKCI (PubMed:17313651). Forms a complex with WDFY2 and PRKCZ (PubMed:17313651). Interacts (via N-terminus) with KCNB1 (via N-terminus and C-terminus); stimulates the channel inactivation rate of KCNB1 (By similarity). Interacts with SEPT8; the interaction inhibits interaction of VAMP2 with SYP. Interacts with SYP; the interaction is inhibited by interaction with SEPT8 (By similarity). Interacts with PICALM (PubMed:22118466, PubMed:21808019). Interacts with alpha-synuclein/SNCA (PubMed:20798282). Interacts with STX3 (By similarity).
Phosphorylated by PRKCZ in vitro and this phosphorylation is increased in the presence of WDFY2.
May play a role in fertility regulation.
Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids. Liver specific enzyme that acts as NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductase on the steroid nucleus and side chain (PubMed:14672942, PubMed:10998348, PubMed:7650035, PubMed:1530633, PubMed:11158055, PubMed:10634139, PubMed:19218247). Displays the ability to catalyze both oxidation and reduction in vitro, but most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentration of NADPH (PubMed:14672942). Acts preferentially as a 3-alpha-hydroxysteroid dehydrogenase (HSD) with a subsidiary 3-beta-HSD activity (PubMed:14672942). Catalyzes efficiently the transformation of the potent androgen 5-alpha-dihydrotestosterone (5alpha-DHT or 17beta-hydroxy-5alpha-androstan-3-one) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol) (PubMed:11158055, PubMed:10998348, PubMed:14672942). Catalyzes the reduction of estrone into 17beta-estradiol but with low efficiency (PubMed:14672942). Metabolizes a broad spectrum of natural and synthetic therapeutic steroid and plays an important role in metabolism of androgens, estrogens, progestereone and conjugated steroids (PubMed:10998348, PubMed:14672942, PubMed:19218247). Catalyzes the biotransformation of the pesticide chlordecone (kepone) to its corresponding alcohol leading to increased biliary excretion of the pesticide and concomitant reduction of its neurotoxicity since bile is the major excretory route (PubMed:2427522).
Inhibited by nonsteroidal the anti-inflammatory drugs (NSAID) flufenamic (PubMed:14672942). The oxidation reaction is inhibited by low micromolar concentrations of NADPH (PubMed:14672942).
The allele with Cys-145/Val-311 shows a three- to five-fold decrease in catalytic efficiency for xenobiotic and steroidal substrates compared to the Ser-145/Leu-311 allele.
The gene represented in this entry may act as a disease modifier. A splicing mutation resulting in loss of AKR1C4 exon 2 has been found in affected individuals carrying a causative mutation in AKR1C2 (PubMed:21802064). These patients manifest a more severe disease phenotype than individuals only carrying mutations in AKR1C2.
Component of a complex comprised of SH2D3C, BCAR1/CAS, and CRK (PubMed:12432078). Within the complex, interacts with SH2D3C (via C-terminus), and BCAR1/CAS (PubMed:12432078). Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases (PubMed:19381274). Interacts with ABL1, C3G, DOCK3, DOCK5, MAP4K1, MAPK8 and SOS via its first SH3 domain. Interacts (via SH2 domain) with BCAR1, CBL, CBLB, PXN, IRS4 and GAB1 upon stimulus-induced tyrosine phosphorylation. Interacts (via SH2 domain) with several tyrosine-phosphorylated growth factor receptors such as EGFR and INSR. Interacts with FLT1 (tyrosine-phosphorylated). Interacts with DOCK1 and DOCK4. Interacts with SHB. Interacts with PEAK1. Interacts with FASLG. Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and p130cas/BCAR1. Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1. Interacts with CBLC.
Interacts (via SH2 domain) with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated) (PubMed:10733900). Interacts with EPHA3 (phosphorylated); upon activation of EPHA3 by the ligand EFNA5 and EPHA3 tyrosine kinase activity-dependent and mediates EFNA5-EPHA3 signaling through RHOA GTPase activation (PubMed:11870224). Interacts with KIT (PubMed:12878163). Interacts with PEAK3; the interaction requires PEAK3 homodimerization (PubMed:31311869).
Involved in cell branching and adhesion mediated by BCAR1-CRK-RAPGEF1 signaling and activation of RAP1.
Phosphorylated on Tyr-221 upon cell adhesion. Results in the negative regulation of the association with SH2- and SH3-binding partners, possibly by the formation of an intramolecular interaction of phosphorylated Tyr-221 with the SH2 domain. This leads finally to the down-regulation of the Crk signaling pathway (PubMed:17515907). Isoform Crk-II: Phosphorylated by KIT (By similarity).
Proline isomerization at Pro-237 by PPIA acts as a switch between two conformations: an autoinhibitory conformation in the cis form, where the tandem SH3 domains interact intramolecularly, and an activated conformation in the trans form.
Regulates cell adhesion, spreading and migration (PubMed:31311869). Mediates attachment-induced MAPK8 activation, membrane ruffling and cell motility in a Rac-dependent manner. Involved in phagocytosis of apoptotic cells and cell motility via its interaction with DOCK1 and DOCK4 (PubMed:19004829). May regulate the EFNA5-EPHA3 signaling (By similarity).
The C-terminal SH3 domain function as a negative modulator for transformation and the N-terminal SH3 domain appears to function as a positive regulator for transformation.
The SH2 domain mediates interaction with tyrosine phosphorylated proteins. Mediates interaction with SHB.
(Microbial infection) Interacts with Salmonella typhimurium spiC.
(Microbial infection) May serve as a target for the spiC protein from Salmonella typhimurium, which inactivates it, leading to a strong alteration in cellular trafficking.
Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin. Facilitates the interaction between dynein and dynactin and activates dynein processivity (the ability to move along a microtubule for a long distance without falling off the track). Predominantly recruits 2 dyneins, which increases both the force and speed of the microtubule motor (PubMed:25035494, PubMed:33734450). Component of the FTS/Hook/FHIP complex (FHF complex). The FHF complex may function to promote vesicle trafficking and/or fusion via the homotypic vesicular protein sorting complex (the HOPS complex). May regulate clearance of endocytosed receptors such as MSR1. Participates in defining the architecture and localization of the Golgi complex. FHF complex promotes the distribution of AP-4 complex to the perinuclear area of the cell (PubMed:32073997).
Self-associates. Component of the FTS/Hook/FHIP complex (FHF complex), composed of AKTIP/FTS, FHIP1B, and one or more members of the Hook family of proteins HOOK1, HOOK2, and HOOK3. May interact directly with AKTIP/FTS, HOOK1 and HOOK2 (PubMed:32073997). Associates with several subunits of the homotypic vesicular sorting complex (the HOPS complex) including VPS16 and VPS41; these interactions may be indirect (PubMed:18799622). Interacts with MSR1, and this association is stimulated by ligand binding to MSR1 (PubMed:17237231). Interacts with microtubules (PubMed:11238449). Part of a tripartite complex with dynein and dynactin, acts an adapter linking the dynein motor complex and dynactin (PubMed:33734450). Interacts with dynein intermediate chain and dynactin (DCTN1) (PubMed:25035494). Interacts with CCDC181 (By similarity). Interacts with LRGUK (By similarity).
ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell (By similarity). Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane (By similarity). In addition to its ADP:ATP antiporter activity, also involved in mitochondrial uncoupling and mitochondrial permeability transition pore (mPTP) activity (By similarity). Plays a role in mitochondrial uncoupling by acting as a proton transporter: proton transport uncouples the proton flows via the electron transport chain and ATP synthase to reduce the efficiency of ATP production and cause mitochondrial thermogenesis (By similarity). Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A5/ANT2 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity) (By similarity). Proton transporter activity requires free fatty acids as cofactor, but does not transport it (By similarity). Probably mediates mitochondrial uncoupling in tissues that do not express UCP1 (By similarity). Also plays a key role in mPTP opening, a non-specific pore that enables free passage of the mitochondrial membranes to solutes of up to 1.5 kDa, and which contributes to cell death (PubMed:31883789). It is however unclear if SLC25A5/ANT2 constitutes a pore-forming component of mPTP or regulates it (By similarity). Acts as a regulator of mitophagy independently of ADP:ATP antiporter activity: promotes mitophagy via interaction with TIMM44, leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (By similarity). As part of the mitotic spindle-associated MMXD complex it may play a role in chromosome segregation (PubMed:20797633).
Monomer (By similarity). Component of the MMXD complex, which includes CIAO1, ERCC2, CIAO2B, MMS19 and SLC25A5/ANT2 (PubMed:20797633). Interacts with AK4 (PubMed:19130895). Interacts with ARHGAP11B, thereby inhibiting the mitochondrial permeability transition pore (mPTP) (PubMed:31883789). Interacts with TIMM44; leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (By similarity).
Interacts with SYTL2, SYTL4, MYRIP and MLPH. Interacts with RPH3A and RPH3A (By similarity). Interacts (GDP-bound form preferentially) with DENND10 (PubMed:30771381).
Small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate homeostasis of late endocytic pathway, including endosomal positioning, maturation and secretion (PubMed:30771381). Plays a role in NTRK2/TRKB axonal anterograde transport by facilitating the association of NTRK2/TRKB with KLC1 (PubMed:21775604). May be involved in targeting uroplakins to urothelial apical membranes (By similarity).
Probable adenosyl-L-methionine (AdoMet)-dependent tRNA (uracil-O(2)-)-methyltransferase.
Plus end-directed microtubule-dependent motor protein that regulates the length of motile cilia by mediating depolymerization of microtubules at ciliary tips.
May negatively affect PAX8-induced thyroglobulin/TG transcription.
By IFNG/IFN-gamma. A diverse population of cell types rapidly increases transcription of mRNA encoding this protein. This suggests that gamma-induced protein may be a key mediator of the IFNG/IFN-gamma response.
Mainly secreted by monocytes, endothelial cells as well as fibroblasts. Expressed by epithelial cells in thymus (PubMed:11157474). Microglial cells produce CXCL10 in response to viral stimulation (PubMed:12663757).
Monomer, dimer, and tetramer (PubMed:12737818). Interacts with CXCR3 (via N-terminus) (PubMed:19151743).
Pro-inflammatory cytokine that is involved in a wide variety of processes such as chemotaxis, differentiation, and activation of peripheral immune cells, regulation of cell growth, apoptosis and modulation of angiostatic effects (PubMed:7540647, PubMed:11157474, PubMed:22652417). Plays thereby an important role during viral infections by stimulating the activation and migration of immune cells to the infected sites (By similarity). Mechanistically, binding of CXCL10 to the CXCR3 receptor activates G protein-mediated signaling and results in downstream activation of phospholipase C-dependent pathway, an increase in intracellular calcium production and actin reorganization (PubMed:12750173, PubMed:19151743). In turn, recruitment of activated Th1 lymphocytes occurs at sites of inflammation (PubMed:12750173, PubMed:12663757). Activation of the CXCL10/CXCR3 axis also plays an important role in neurons in response to brain injury for activating microglia, the resident macrophage population of the central nervous system, and directing them to the lesion site. This recruitment is an essential element for neuronal reorganization (By similarity).
Several proteases can mediate post-secretion cleavages. DPP4 cleaves CXCL10 on its N-terminal 2 amino acids leading to an antagonist form of CXCL10. This dominant negative form is capable of binding CXCR3 but does not induce signaling. MMP9 cleaves 9 amino acids instead.
Potent stimulator of insulin secretion and relatively poor inhibitor of gastric acid secretion.
Binds 3 Ca(2+) ions per subunit. The calcium ions probably have a structural role.
Cleaved into a large and a small subunit.
Heterodimer of the large and small subunits; disulfide-linked.
Removes the secondary (acyloxyacyl-linked) fatty acyl chains from the lipid A region of bacterial lipopolysaccharides (PubMed:1883828, PubMed:8089145, PubMed:29343645). By breaking down LPS, terminates the host response to bacterial infection and prevents prolonged and damaging inflammatory responses (By similarity). In peritoneal macrophages, seems to be important for recovery from a state of immune tolerance following infection by Gram-negative bacteria (By similarity).
Homodimer. But, in contrast to other members of this family, cannot be disulfide-linked.
May be involved in follicular development. Oocyte-specific growth/differentiation factor that stimulates folliculogenesis and granulosa cell (GC) growth.
The mature protein migrates in two distinct mature proteins, P16 (16KDa) and P17 (17KDa).
Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. Involved in nucleolar processing of pre-18S ribosomal RNA.
Binds DNA and activates transcription of CYP11A1. Interaction with CREBBP and EP300 results in a synergistic transcriptional activation of CYP11A1.
Highest expression was seen in thymus, testis and adrenal cortex, expressed also in the adrenal medulla, thyroid, and stomach. Highly expressed in steroidogenic JEG-3 and MCF-7 cells, low expression was seen in non-steroidogenic Hep-G2 and HEK293 cells.
Interacts with CREBBP and EP300 (PubMed:11349124). Interacts with DNTTIP1 (PubMed:16371131, PubMed:21573134). Interacts with DNTT (PubMed:16371131).
A chromosomal aberration involving ARHGAP20 may be a cause of B-cell chronic lymphocytic leukemia (B-CLL) (PubMed:15543602). Translocation t(X;11)(q21;q23) with BRWD3 does not result in fusion transcripts but disrupts both genes (PubMed:15543602).
Expressed predominantly in the brain. Lower expression is found in lymph nodes.
(Microbial infection) Interacts with chikungunya virus nsP1 and nsP4; these interactions lead to viral RNA replication inhibition.
(Microbial infection) Interacts with sindbis virus nsP1 and nsP4; these interactions lead to viral RNA replication inhibition.
Plays a role in innate immunity (PubMed:35938871). Mechanistically, promotes alphaviruses RNA degradation by interacting with the viral polymerase nsP4 and the mRNA-capping enzyme nsP1 and thereby interfering with the interaction between viral RNA and nsP1.(PubMed:35938871).
Acyltransferase which catalyzes the transfer of an acyl group from an acyl-CoA to a lysophosphatidylinositol (1-acylglycerophosphatidylinositol or LPI) leading to the production of a phosphatidylinositol (1,2-diacyl-sn-glycero-3-phosphoinositol or PI) and participates in the reacylation step of the phospholipid remodeling pathway also known as the Lands cycle (PubMed:18772128, PubMed:18094042). Prefers arachidonoyl-CoA as the acyl donor, thus contributing to the regulation of free levels arachidonic acid in cell (PubMed:18772128, PubMed:18094042). In liver, participates in the regulation of triglyceride metabolism through the phosphatidylinositol acyl-chain remodeling regulation (PubMed:32253259).
Interacts with SPTSSA; the interaction facilitates MBOAT7 location to mitochondria-associated membranes (MAMs).
Overexpressed in metastatic breast and bladder carcinomas relative to normal breast epithelium and urothelium.
May have a role in the excitatory ribbon synapse junctions between hair cells and cochlear ganglion cells and presumably also in analogous synapses within the retina.
Expressed in liver and testis. Expressed in the seminiferous tubules (at protein level).
May be involved in transcriptional regulation. Has in vitro transcription inhibition activity. Acts as a tumor suppressor in hepatocellular carcinoma (HCC) cells.
Self-associates (via leucine zipper). Interacts (via leucine zipper) with ZIPK/DAPK3 (via leucine zipper). Interacts with MAD4.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A2 subfamily.
Inhibited by mazindol, desipramine, nomifensine and nortriptyline.
Mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline) (PubMed:2008212, PubMed:8125921). Can also mediate sodium- and chloride-dependent transport of dopamine (PubMed:8125921, PubMed:11093780).
Binds to both DNA and RNA in vitro, with a stronger binding capacity for RNA. May represent a nucleolar constitutive protein involved in ribosomal biosynthesis or assembly (By similarity).
Activated following phosphorylation at Thr-182 by p38-alpha/MAPK14, p38-beta/MAPK11, ERK2/MAPK1, ERK3/MAPK6, and ERK4/MAPK4. Activated by stress-related extracellular stimuli; such as H(2)O(2), arsenite, anisomycin TNF alpha and also PMA and the calcium ionophore A23187; but to a lesser extent. In vitro, activated by SQSTM1. Inhibited by diterpenoid alkaloid noroxoaconitine.
Directly regulated by MYC: expression is activated by MYC, suggesting the existence of a feedback regulatory loop.
Interacts with ERK3/MAPK6 and ERK4/MAPK4 (via FRIEDE motif); the interaction is direct (By similarity). Interacts with YWHAE; the interaction prevents phosphorylation of HSP27/HSPB1 leading to disrupt F-actin polymerization. Interacts with SQSTM1.
Phosphorylated on Thr-182 ERK3/MAPK6 or ERK4/MAPK4; which is the regulatory phosphorylation site and is located on the T-loop/loop 12, leading to activation. Phosphorylation at Thr-182 by p38-alpha/MAPK14, p38-beta/MAPK11 is subject to debate. Phosphorylated at Ser-115 by PKA/PRKACA, leading to localization to the cytoplasm. Autophosphorylated (By similarity).
The role of p38 MAPK kinases is unclear in phosphorylation and activation of MAPKAPK5. According to some reports, it interacts and is phosphorylated by p38-alpha/MAPK14 and p38-beta/MAPK11 (PubMed:9628874, PubMed:12808055). According to other reports, it is not activated by p38-alpha/MAPK14 and p38-beta/MAPK11. An explanation for these discrepancies, might be that the interaction with p38 MAPK kinases is weak and occurs only under specific conditions.
Tumor suppressor serine/threonine-protein kinase involved in mTORC1 signaling and post-transcriptional regulation. Phosphorylates FOXO3, ERK3/MAPK6, ERK4/MAPK4, HSP27/HSPB1, p53/TP53 and RHEB. Acts as a tumor suppressor by mediating Ras-induced senescence and phosphorylating p53/TP53. Involved in post-transcriptional regulation of MYC by mediating phosphorylation of FOXO3: phosphorylation of FOXO3 leads to promote nuclear localization of FOXO3, enabling expression of miR-34b and miR-34c, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent MYC translation. Acts as a negative regulator of mTORC1 signaling by mediating phosphorylation and inhibition of RHEB. Part of the atypical MAPK signaling via its interaction with ERK3/MAPK6 or ERK4/MAPK4: the precise role of the complex formed with ERK3/MAPK6 or ERK4/MAPK4 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPK (ERK3/MAPK6 or ERK4/MAPK4), ERK3/MAPK6 (or ERK4/MAPK4) is phosphorylated and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6 (or ERK4/MAPK4). Mediates phosphorylation of HSP27/HSPB1 in response to PKA/PRKACA stimulation, inducing F-actin rearrangement.
Domain-swapped homodimer. Component of an interferon-dependent multiprotein complex, at least composed of IFIT1, IFIT2 and IFIT3. Interacts with IFIT1 and IFIT3. Interacts with STING1/MITA and disrupts its interaction with MAVS or TBK1. Interacts with EIF3E and EIF3C.
IFN-induced antiviral protein which inhibits expression of viral messenger RNAs lacking 2'-O-methylation of the 5' cap. The ribose 2'-O-methylation would provide a molecular signature to distinguish between self and non-self mRNAs by the host during viral infection. Viruses evolved several ways to evade this restriction system such as encoding their own 2'-O-methylase for their mRNAs or by stealing host cap containing the 2'-O-methylation (cap snatching mechanism). Binds AU-rich viral RNAs, with or without 5' triphosphorylation, RNA-binding is required for antiviral activity. Can promote apoptosis.
The C-terminal part folds into a super-helical structure and has an extensively positively-charged nucleotide-binding channel on its inner surface.
Isoform 1 and isoform 2 are mainly expressed in heart, kidney, liver and skeletal muscle. Isoform 1 is also expressed in placenta. Isoform 2 is expressed in endothelial cells. Expressed in T-cells (at protein level).
Receptor for the C-X-C chemokine CXCL4 and also mediates the inhibitory activities of CXCL9, CXCL10 and CXCL11 on the proliferation, survival and angiogenic activity of human microvascular endothelial cells (HMVEC) through a cAMP-mediated signaling pathway (PubMed:12782716). Does not promote cell chemotaxis respons. Interaction with CXCL4 or CXCL10 leads to activation of the p38MAPK pathway and contributes to inhibition of angiogenesis. Overexpression in renal cancer cells down-regulates expression of the anti-apoptotic protein HMOX1 and promotes apoptosis.
Receptor for the C-X-C chemokine CXCL9, CXCL10 and CXCL11 and mediates the proliferation, survival and angiogenic activity of human mesangial cells (HMC) through a heterotrimeric G-protein signaling pathway (PubMed:12782716). Binds to CCL21. Probably promotes cell chemotaxis response.
Sulfation on Tyr-27 and Tyr-29 is essential for CXCL10 binding and subsequent signal transduction induction.
Expressed abundantly in brain (frontal and temporal lobes, hippocampus, hypothalamus, amygdala, substantia nigra, and pituitary), kidney, and prostate. Expressed in fetal brain, kidney and lung (PubMed:16672768). Expressed in melanocytes (PubMed:23999003).
Plays a role in dendrite formation by melanocytes (PubMed:23999003).
(Microbial infection) Also acts as a 5'-tyrosyl-RNA phosphodiesterase following picornavirus infection: its activity is hijacked by picornavirus and acts by specifically cleaving the protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection, without impairing the integrity of viral RNA.
DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DNA double-strand breaks/DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation (PubMed:27099339, PubMed:27060144). Thereby, protects the transcription of many genes involved in neurological development and maintenance from the abortive activity of TOP2. Hydrolyzes 5'-phosphoglycolates on protruding 5' ends on DSBs due to DNA damage by radiation and free radicals. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Acts as a regulator of ribosome biogenesis following stress. Has also 3'-tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'-tyrosyl-DNA phosphodiesterase in cells. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF-beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non-canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation.
Interacts with TRAF2, TRAF3, TRAF5, TRAF6, TNFRSF8/CD30, TNFRSF5/CD40, TNFRSF1B/TNF-R75, ETS1, ETS2, FLI1, SMAD3 and ACVR1B/ALK4.
Widely expressed (PubMed:10764746). Highly expressed in various brain regions, including the frontal and occipital lobes, the hippocampus, the striatum and the cerebellum (PubMed:24658003).
Belongs to the trans-sulfuration enzymes family.
Catalyzes the last step in the trans-sulfuration pathway from L-methionine to L-cysteine in a pyridoxal-5'-phosphate (PLP)-dependent manner, which consists on cleaving the L,L-cystathionine molecule into L-cysteine, ammonia and 2-oxobutanoate (PubMed:10212249, PubMed:19261609, PubMed:19961860, PubMed:18476726). Part of the L-cysteine derived from the trans-sulfuration pathway is utilized for biosynthesis of the ubiquitous antioxidant glutathione (PubMed:18476726). Besides its role in the conversion of L-cystathionine into L-cysteine, it utilizes L-cysteine and L-homocysteine as substrates (at much lower rates than L,L-cystathionine) to produce the endogenous gaseous signaling molecule hydrogen sulfide (H2S) (PubMed:10212249, PubMed:19261609, PubMed:19961860, PubMed:19019829). In vitro, it converts two L-cysteine molecules into lanthionine and H2S, also two L-homocysteine molecules to homolanthionine and H2S, which can be particularly relevant under conditions of severe hyperhomocysteinemia (which is a risk factor for cardiovascular disease, diabetes, and Alzheimer's disease) (PubMed:19261609). Lanthionine and homolanthionine are structural homologs of L,L-cystathionine that differ by the absence or presence of an extra methylene group, respectively (PubMed:19261609). Acts as a cysteine-protein sulfhydrase by mediating sulfhydration of target proteins: sulfhydration consists of converting -SH groups into -SSH on specific cysteine residues of target proteins such as GAPDH, PTPN1 and NF-kappa-B subunit RELA, thereby regulating their function (PubMed:22169477). By generating the gasotransmitter H2S, it participates in a number of physiological processes such as vasodilation, bone protection, and inflammation (Probable) (PubMed:29254196). Plays an essential role in myogenesis by contributing to the biogenesis of H2S in skeletal muscle tissue (By similarity). Can also accept homoserine as substrate (By similarity). Catalyzes the elimination of selenocystathionine (which can be derived from the diet) to yield selenocysteine, ammonia and 2-oxobutanoate (By similarity).
Estrogen receptor alpha (ESR1) regulates CSE promoter activity and induces protein expression in human osteoblasts.
Highly expressed in liver (PubMed:10727430, PubMed:20305127). Also in muscle and lower expression in most tissues except heart, pituitary gland, spleen, thymus, and vascular tissue, where it is hardly detected (PubMed:20305127).
Homotetramer (PubMed:19019829). Interacts with CALM in a calcium-dependent manner (By similarity).
Inhibited by propargylglycine, trifluoroalanine and aminoethoxyvinylglycine.
mRNA is detected from the 19th gestational week onwards at levels comparable with those of adult liver.
By interferons alpha and beta, and by Vaccinia virus infection.
S-adenosyl-L-methionine-dependent methyltransferase that mediates mRNA cap1 2'-O-ribose methylation to the 5'-cap structure of mRNAs. Methylates the ribose of the first nucleotide of a m(7)GpppG-capped mRNA and small nuclear RNA (snRNA) to produce m(7)GpppRm (cap1). Displays a preference for cap0 transcripts. Cap1 modification is linked to higher levels of translation. May be involved in the interferon response pathway.
Although related to peptidase M14 family, lacks the active site residues and zinc-binding sites, suggesting that it has no carboxypeptidase activity.
E3 ubiquitin ligase. Mediates the ubiquitination and subsequent proteasomal degradation of CKM, GMEB1 and HIBADH. Regulates the proteasomal degradation of muscle proteins under amino acid starvation, where muscle protein is catabolized to provide other organs with amino acids. Inhibits de novo skeletal muscle protein synthesis under amino acid starvation. Regulates proteasomal degradation of cardiac troponin I/TNNI3 and probably of other sarcomeric-associated proteins. May play a role in striated muscle atrophy and hypertrophy by regulating an anti-hypertrophic PKC-mediated signaling pathway. May regulate the organization of myofibrils through TTN in muscle cells.
Expressed throughout all developmental stages.
Homodimer. Homooligomer and heterooligomer. Interacts with SUMO2, titin/TTN and GMEB1. Interacts with TRIM54 and probably with TRIM55 and TNNI3. Forms a ternary complex with RACK1 and PRKCE (By similarity). Interacts with CKM.
Muscle specific. Selectively expressed in heart and skeletal muscle. Also expressed in the iris.
The B box-type zinc finger mediates homodimerization.
The RING-type zinc finger mediates interaction with SUMO2 and localization to the nucleus. Also required for the E3 ubiquitin ligase activity (By similarity).
Could play a role in regulating gene activity in the proliferative and/or differentiative pathways induced by NGF. May be an autocrine factor that attenuates or amplifies the initial ligand-induced signal (By similarity).
Belongs to the metallo-dependent hydrolases superfamily. Phosphotriesterase family.
Binds 1 heme b group per subunit, that coordinates a highly solvent-exposed Fe(III) atom.
Heme-binding protein able to scavenge peroxynitrite and to protect free L-tyrosine against peroxynitrite-mediated nitration, by acting as a peroxynitrite isomerase that converts peroxynitrite to nitrate. Therefore, this protein likely plays a role in peroxynitrite sensing and in the detoxification of reactive nitrogen and oxygen species (RNS and ROS, respectively). Is able to bind nitric oxide (NO) in vitro, but may act as a sensor of peroxynitrite levels in vivo, possibly modulating the transcriptional activity residing in the N-terminal region.
In the C-terminal section; belongs to the nitrobindin family.
The C-terminal nitrobindin region coordinates a heme and bears the isomerase activity. The N-terminal zinc finger domain likely binds DNA and may be involved in transcriptional regulation.
Expressed in red blood cells (at protein level) (PubMed:31086825). Widely expressed, with high expression in brain, heart, skeletal muscle and kidney (PubMed:15498460).
Interacts (via FFAT motif) with VAPA and VAPB (PubMed:30741634). Interacts with RAB7A (PubMed:30709847). Interacts with XK (PubMed:31086825, PubMed:32845802).
Mediates the transfer of lipids between membranes at organelle contact sites (By similarity). Binds phospholipids (PubMed:34830155). Required for the formation or stabilization of ER-mitochondria contact sites which enable transfer of lipids between the ER and mitochondria (PubMed:30741634). Negatively regulates lipid droplet size and motility (PubMed:30741634). Required for efficient lysosomal protein degradation (PubMed:30709847).
The C-terminal part (3058-3174) is involved in phospholipid binding, including phosphatidylinositol 4,5-bisphosphate.
The FFAT motif is required for interaction with VAPA and VAPB and its localization to the endoplasmic reticulum.
Belongs to the mitochondrion-specific ribosomal protein mS38 family.
Component of the mitochondrial small ribosomal subunit (mt-SSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (PubMed:23908630, PubMed:25838379). Interacts with Aurora-A (PubMed:12244051).
May act as a negative regulator of Aurora-A kinase, by down-regulation through proteasome-dependent degradation.
Ubiquitously expressed and especially highly expressed in heart, skeletal muscle and testis.
Belongs to the mitochondrion-specific ribosomal protein mS29 family.
Component of the mitochondrial small ribosomal subunit (mt-SSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (PubMed:25838379). Interacts with DELE1 (PubMed:20563667). Interacts with NOA1 (PubMed:19103604).
Involved in mediating interferon-gamma-induced cell death.
Codon in position 67 corresponds to a stop codon in genome.
May be involved in the development and regeneration of the musculoskeletal system.
Associates with splicing factor SF3B complex, involved in branch-site recognition.
May play a role pre-mRNA splicing through the association with the splicing factor SF3B complex which is involved in branch-site recognition.
Belongs to the proteasome subunit S5A family.
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD4 (PubMed:27428775, PubMed:27342858). Interacts with NUB1 (PubMed:11585840). Interacts with SQSTM1 (PubMed:15340068). Interacts with UBQLN4 (PubMed:15280365). Interacts with UBE3A (PubMed:22645313). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with DDI2 (PubMed:29290612).
Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMD4 acts as an ubiquitin receptor subunit through ubiquitin-interacting motifs and selects ubiquitin-conjugates for destruction. Displays a preferred selectivity for longer polyubiquitin chains.
The 2 UIM motifs are involved in the binding to a multi-ubiquitin chain in a cooperative way.
EBF4 expression was not detected in mouse NK cells and CD8(+) T-cells and there were no differences in the NK, CD8(+), and CD4(+) precursor and mature cell subsets in the thymus, spleen, or liver from a mouse EBF4 knockout (PubMed:35939714). It has been suggested, therefore, that the functions of EBF4 differ between humans and mice (PubMed:35939714).
Forms either a homodimer or a heterodimer with a related family member (By similarity). Interacts with MAPK3/ERK1 (PubMed:35939714). Interacts with STAT5A (PubMed:35939714).
In CD8(+) T-cells mRNA levels are down-regulated following T-cell receptor (TCR) stimulation (PubMed:35939714). In NK cells mRNA levels are down-regulated following KLRK1/NKG2D receptor stimulation (PubMed:35939714).
Most highly expressed in cytotoxic NK cells, especially CD16(+) NK cells, followed by CD8(+) T-cells.
Transcription factor (PubMed:35939714). Binds to specific sequence motif 5'-CCCNNG[GA]G-3' in regulatory elements of putative target immunoregulatory genes such as NKG7, GZMA, and TBX21 (PubMed:35939714). Positively modulates transcription of NKG7 (PubMed:35939714). May play a role in regulating FAS/CD95-mediated apoptosis in cytotoxic NK cells and T-cells, probably downstream of interleukin IL2 signaling (PubMed:35939714).
Chromatin-binding protein that acts as an adapter between distinct nucleosome components (H3K36me3 or H2A.Z) and chromatin-modifying complexes, contributing to the regulation of the levels of histone acetylation at actively transcribed genes (PubMed:30228260). Competes with CHD4 and MBD3 for interaction with MTA1 to form a NuRD subcomplex, preventing the formation of full NuRD complex (containing CHD4 and MBD3), leading to recruitment of HDACs to gene promoters resulting in turn in the deacetylation of nearby H3K27 and H2A.Z (PubMed:30228260). Plays a role in facilitating transcriptional elongation through regulation of histone acetylation (By similarity). Negatively regulates brown adipocyte thermogenesis by interacting with and stabilizing HDAC1 at the UCP1 gene promoter, thereby promoting histone deacetylation at the promoter leading to the repression of UCP1 expression (By similarity).
Component of a MTA1-specific subcomplex of the NuRD complex composed of PWWP2B, MTA1 and HDAC1 but does not contain CHD4 and MBD3 (PubMed:30228260). Interacts with MTA1 and HDAC1 (PubMed:30228260). Interacts with MTA2, MTA3, HDAC2, RBBP4, RBBP7, BRCC3 and ZNF516 (By similarity). Does not interact with CHD4 and MBD3 (PubMed:30228260).
Deubiquitinated by BRCC3; leading to its stabilization.
Expressed in tumor endothelial cells but absent or barely detectable in normal endothelial cells. Expressed in metastatic lesions of the liver and during angiogenesis of corpus luteum formation and wound healing. Expressed in vascular endothelial cells of malignant tumors but not in normal blood vessels. Expressed in stromal fibroblasts.
There are 3 copies of the NOMO gene on chromosome 16p12-p13: NOMO1 (AC Q5JPE7), NOMO2 (AC Q5JPE7) and NOMO3. All 3 are extremely similar, which makes their individual characterization difficult. Thus, most experiments probably do not discriminate between the different members. The results reported in other entries may therefore apply for this protein.
Expressed in epidermal keratinocytes, infant brain, cerebellum, and also in a variety of tumors, such as pancreatic cancer, diffuse type gastric cancer, ovarian cancer, esophageal cancer, skin squamous cell carcinoma, head and neck cancer. Not expressed in melanoma cell line A375 cells, normal epidermal melanocytes or normal dermal fibroblasts. Expressed in epidermal keratinocytes and squamous cell carcinoma (at protein level).
Involved in the regulation of cell migration (PubMed:18534823). May be involved in mediating the organization of the parallel fibers of granule cells during cerebellar development (By similarity).
As a component of the hypothalamic-pituitary-thyroid axis, it controls the secretion of thyroid-stimulating hormone (TSH) and is involved in thyroid hormone synthesis regulation. It also operates as modulator of hair growth. It promotes hair-shaft elongation, prolongs the hair cycle growth phase (anagen) and antagonizes its termination (catagen) by TGFB2. It stimulates proliferation and inhibits apoptosis of hair matrix keratinocytes.
Hypothalamus. Expressed in the hair follicle epithelium (at protein level).
Expressed in gastric tissues. Down-regulated in gastric cancer.
May play a role in acrosome formation in spermatogenesis and in fertilization.
Restriction fragment length polymorphisms (RFLPs) in gastric cancer showed loss of 5 kb fragment in comparison with the corresponding normal tissue.
The C-terminal lobe folds into an immunoglobulin-like domain and may mediate cell adhesion properties.
The sodium/potassium-transporting ATPase is composed of a catalytic alpha subunit, an auxiliary non-catalytic beta subunit and an additional regulatory subunit. Interacts with catalytic alpha subunit ATP12A.
This is the non-catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of Na(+) and K(+) ions across the plasma membrane. The exact function of the beta-3 subunit is not known.
Highly expressed in brain and, at much lower levels, in heart and pancreas.
May form heterooligomers with other PACSINs. Interacts with MAPT. Interacts with TRPV4 (By similarity). Interacts (via SH3 domain) with SYNJ1 and WASL. Interacts with DNM2 and DNM3. Interacts with both COBL and DBNL. Identified in a complex composed of COBL, PACSIN1 and WASL. Interacts with EHD1 and EHD3 (By similarity). Homodimer. Interacts (via SH3 domain) with DNM1; the interaction is reduced by DNM1 phosphorylation.
Plays a role in the reorganization of the microtubule cytoskeleton via its interaction with MAPT; this decreases microtubule stability and inhibits MAPT-induced microtubule polymerization. Plays a role in cellular transport processes by recruiting DNM1, DNM2 and DNM3 to membranes. Plays a role in the reorganization of the actin cytoskeleton and in neuron morphogenesis via its interaction with COBL and WASL, and by recruiting COBL to the cell cortex. Plays a role in the regulation of neurite formation, neurite branching and the regulation of neurite length. Required for normal synaptic vesicle endocytosis; this process retrieves previously released neurotransmitters to accommodate multiple cycles of neurotransmission. Required for normal excitatory and inhibitory synaptic transmission (By similarity). Binds to membranes via its F-BAR domain and mediates membrane tubulation.
The F-BAR domain forms a coiled coil and mediates membrane-binding and membrane tubulation. In the autoinhibited conformation, interaction with the SH3 domain inhibits membrane tubulation mediated by the F-BAR domain. DNM1 binding abolishes autoinhibition (By similarity).
Expressed in fetal and adult brain, prostate and testis.
Homodimer. Interacts with NRXN1 in a calcium-dependent manner. Interaction with neurexins is mediated by heparan sulfate glycan modification on neurexin. Interacts through its C-terminus with DLG4/PSD-95 third PDZ domain.
Expressed in brain, pancreas and kidney.
May be involved in transport vesicle docking to the plasma membrane.
The second C2 domain/C2B domain binds phospholipids regardless of whether calcium is present.
Exhibits carboxy-monopeptidase as well as carboxy-dipeptidase activity (PubMed:10504234). Capable of producing kinin potentiating peptides (By similarity).
The disulfide bridge formed between Cys-33 in the propeptide and the active site residue Cys-92 may prevent activation of the zymogen through formation of a reversible covalent bond with the active site residue.
Required for normal inner ear hair cell function and hearing.
TMEM132E is located in a region involved in a heterozygous deletion of approximately 4.7 Mb; this deletion, involving the NF1 gene and contiguous genes lying in its flanking regions, is observed in a patient with 17q11.2 microdeletion syndrome, a syndrome characterized by variable facial dysmorphism, intellectual disability, developmental delay, and an excessive number of neurofibromas.
Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins (PubMed:11336703, PubMed:11448771, PubMed:15778503, PubMed:11719191, PubMed:15908424, PubMed:16252235). Activates the canonical Wnt signaling pathway that controls cell fate determination and self-renewal during embryonic development and adult tissue regeneration (PubMed:11336703, PubMed:11719191). In particular, may play an important role in the development of the posterior patterning of the epiblast during gastrulation (By similarity). During bone development, regulates osteoblast proliferation and differentiation thus determining bone mass (PubMed:11719191). Mechanistically, the formation of the signaling complex between Wnt ligand, frizzled receptor and LRP5 coreceptor promotes the recruitment of AXIN1 to LRP5, stabilizing beta-catenin/CTNNB1 and activating TCF/LEF-mediated transcriptional programs (PubMed:11336703, PubMed:25920554, PubMed:24706814, PubMed:14731402). Acts as a coreceptor for non-Wnt proteins, such as norrin/NDP. Binding of norrin/NDP to frizzled 4/FZD4-LRP5 receptor complex triggers beta-catenin/CTNNB1-dependent signaling known to be required for retinal vascular development (PubMed:27228167, PubMed:16252235). Plays a role in controlling postnatal vascular regression in retina via macrophage-induced endothelial cell apoptosis (By similarity).
Genetic variations in LRP5 define the bone mineral density quantitative trait locus 1 (BMND1) [MIM:601884]. Variance in bone mineral density influences bone mass and contributes to size determination in the general population.
Homodimer; disulfide-linked. Forms phosphorylated oligomer aggregates on Wnt-signaling (By similarity). Component of a Wnt-signaling complex that contains a WNT protein, a FZD protein and LRP5 or LRP6. Interacts with FZD8; the interaction is formed on WNT-binding and signaling (PubMed:11448771). Interacts (via the phosphorylated PPPSP motif domains) with AXIN1; the interaction prevents inhibition of beta-catenin phosphorylation and signaling and is enhanced in the presence of GSK3B and WNT1 or WNT3A (PubMed:11336703, PubMed:14731402). Interacts (via beta-propeller regions 3 and 4) with DKK1; the interaction, enhanced by MESD and/or KREMEN, inhibits beta-catenin signaling by preventing GSK3-mediated phosphorylation of the PPPSP motifs and subsequent, AXIN1 binding (PubMed:11448771, PubMed:15778503, PubMed:19746449). Interacts with MESD; the interaction prevents the formation of LRP5 aggregates, targets LRP5 to the plasma membrane and, when complexed with KREMEN2, increases DKK1 binding (PubMed:17488095, PubMed:19746449, PubMed:15143163). Interacts with CSNK1E (PubMed:16513652). Interacts with SOST; the interaction antagonizes canonical Wnt signaling (PubMed:15778503, PubMed:15908424). Interacts with APCDD1 (PubMed:20393562). Interacts with CAPRIN2 (PubMed:18762581).
LRP5 variations may act as a disease modifier in autosomal dominant polycystic kidney disease (ADPKD) in patients who have causative mutations in PKD1. May contribute to the disease phenotype heterogeneity and hepatic cystogenesis.
Phosphorylation of cytoplasmic PPPSP motifs regulates the signal transduction of the Wnt signaling pathway through acting as a docking site for AXIN1.
Widely expressed, with the highest level of expression in the liver and in aorta.
Associates with the 26S proteasome; this association occurs upon exposure to arsenite and is reduced in the presence of ATP (PubMed:29804830). Interacts (via AN1-type 1 and 2 zinc fingers) with PSMD1; this interaction is increased upon arsenite treatment and occurs in an ATP-independent manner (PubMed:29804830). Interacts with PSMC4 (PubMed:29804830). Interacts with PSMA1 (PubMed:29804830). Interacts (via its ubiquitin-like region) with VCP; this interaction occurs in an arsenite-dependent manner and is necessary for the recruitment of the ubiquitin-selective ATPase VCP to stress granules (SGs) (PubMed:29804830).
Plays a role in the regulation of cytoplasmic stress granules (SGs) turnover. SGs are dynamic and transient cytoplasmic ribonucleoprotein assemblies important for cellular protein homeostasis when protein production is suspended after acute exogenous stress (PubMed:29804830). Associates with SGs and is involved in the efficient and specific arsenite-induced clearance process of SGs through the recruitment of the ubiquitin-selective ATPase VCP and the 26S proteasome (PubMed:29804830). This process requires both complexes for efficient degradation of damaged ubiquitinated SG proteins during recovery from arsenite stress, and hence avoiding aberrant cytoplasmic SGs degradation via autophagy (PubMed:29804830).
The ubiquitin-like region is necessary for its localization to stress granules (SGs) in a VCP-independent manner (PubMed:29804830). The AN1-type 1 and 2 zinc finger domains are necessary for the recruitment of the 26S proteasome to SGs (PubMed:29804830). Both the AN1-type 1 and 2 zinc finger domains and the ubiquitin-like region are necessary for efficient SGs clearance upon specific arsenite-induced responses (PubMed:29804830).
Expressed in megakaryocytes and platelets (at protein level).
Contains a phosphoserine at position 10 (alternate). Contains a O-linked (GlcNAc) serine at position 10 (alternate). O-GlcNAcylation at Ser-10 inhibits DNA binding and negatively regulates DeltaLf transcriptional activity, whereas phosphorylation activates it. Phosphorylation at Ser-10 also promotes proteasomal degradation.
Has antimicrobial activity and is able to permeabilize different ions through liposomal membranes.
Has opioid antagonist activity (PubMed:1369293). Shows higher degrees of preference for kappa-receptors than for mu-receptors (PubMed:1369293).
Has opioid antagonist activity (PubMed:1369293). Shows preference for mu-receptor (PubMed:1369293).
High levels are found in saliva and tears, intermediate levels in serum and plasma, and low levels in urine. In kidney, detected in the distal collecting tubules in the medulla but not in the cortical region or in blood vessels. Detected in peripheral blood neutrophils (at protein level). Isoform 1 and isoform DeltaLf are expressed in breast, prostate, spleen, pancreas, kidney, small intestine, lung, skeletal muscle, uterus, thymus and fetal liver. Isoform 1 is expressed in brain, testis and peripheral blood leukocytes; isoform DeltaLf is barely detectable in these tissues. Isoform DeltaLf is expressed in placenta, liver and ovary; isoform 1 is barely detectable in these tissues. In kidney, isoform 1 is expressed at high levels in the collecting tubules of the medulla but at very low levels in the cortex.
Lactoferricin binds to the bacterial surface and is crucial for the bactericidal functions. Has some antiviral activity against papillomavirus infection (PubMed:17481742). N-terminal region shows strong antifungal activity against C.albicans (PubMed:11083624). Contains two BBXB heparin-binding consensus sequences that appear to form the predominate functional GAG-binding site.
Major iron-binding and multifunctional protein found in exocrine fluids such as breast milk and mucosal secretions (PubMed:14573629, PubMed:1599934, PubMed:6802759, PubMed:3169987, PubMed:11179314, PubMed:12693969). Has antimicrobial activity, which depends on the extracellular cation concentration (PubMed:6802759). Antimicrobial properties include bacteriostasis, which is related to its ability to sequester free iron and thus inhibit microbial growth, as well as direct bactericidal properties leading to the release of lipopolysaccharides from the bacterial outer membrane (PubMed:14573629, PubMed:1599934, PubMed:6802759, PubMed:3169987, PubMed:11179314, PubMed:12693969). Can also prevent bacterial biofilm development in P.aeruginosa infection (PubMed:12037568). Has weak antifungal activity against C.albicans (PubMed:11083624). Has anabolic, differentiating and anti-apoptotic effects on osteoblasts and can also inhibit osteoclastogenesis, possibly playing a role in the regulation of bone growth (PubMed:15166119). Promotes binding of species C adenoviruses to epithelial cells, promoting adenovirus infection (PubMed:17079302). Can inhibit papillomavirus infections (PubMed:17481742). Stimulates the TLR4 signaling pathway leading to NF-kappa-B activation and subsequent pro-inflammatory cytokine production while also interfering with the lipopolysaccharide (LPS)-stimulated TLR4 signaling (PubMed:20345905). Inhibits neutrophil granulocyte migration to sites of apoptosis, when secreted by apoptotic cells (PubMed:19033648). Stimulates VEGFA-mediated endothelial cell migration and proliferation (PubMed:16842782). Binds heparin, chondroitin sulfate and possibly other glycosaminoglycans (GAGs) (PubMed:9359845). Also binds specifically to pneumococcal surface protein A (PspA), the lipid A portion of bacterial lipopolysaccharide (LPS), lysozyme and DNA (PubMed:9359845).
Monomer. Found in a complex with LTF, CLU, EPPIN and SEMG1.
O-GlcNAcylation at Ser-10 inhibits DNA binding and negatively regulates the transcriptional activity (PubMed:20404350). Alternatively can undergo phosphorylation at Ser-10 (PubMed:20404350).
Phosphorylation at Ser-10 activates the transcriptional activity (PubMed:20404350). Phosphorylation at Ser-10 also promotes proteasomal degradation (PubMed:20404350). Alternatively can undergo O-GlcNAcylation at Ser-10 (PubMed:20404350).
Poly-N-acetyllactosaminic carbohydrate moiety seems to be needed for TLR4 activation.
The lactotransferrin transferrin-like domain 1 functions as a serine protease of the peptidase S60 family that cuts arginine rich regions (PubMed:12535064). This function contributes to the antimicrobial activity (PubMed:12535064). Shows a preferential cleavage at -Arg-Ser-Arg-Arg-|- and -Arg-Arg-Ser-Arg-|-, and of Z-Phe-Arg-|-aminomethylcoumarin sites (PubMed:12535064).
The sequence shown corresponds to the reference genome sequence and is likely to represent the minor allele, whereas most publications refer to the longer sequence containing variant Arg-22 ins. Insertion of the additional arginine in variant Arg-22 ins creates an N-terminal basic cluster of four arginines, all of which appear to be important for the full functionality of the protein, including bactericidal and antifungal activities as well as binding to glycosaminoglycans, pspA, LPS, lysozyme and DNA.
Transcription factor with antiproliferative properties and ability to induce cell cycle arrest (PubMed:15222485). Binds to the DeltaLf response element found in the SKP1, BAX, DCPS, and SELENOH promoters (PubMed:22320386).
Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate.
Detected in all tissues including red cells, lymphocytes and cultured fibroblasts (at protein level). The highest activities occur in skeletal muscle and cardiac muscle.
Glycerol-3-phosphate phosphatase hydrolyzing glycerol-3-phosphate into glycerol. Thereby, regulates the cellular levels of glycerol-3-phosphate a metabolic intermediate of glucose, lipid and energy metabolism. Was also shown to have a 2-phosphoglycolate phosphatase activity and a tyrosine-protein phosphatase activity. However, their physiological relevance is unclear (PubMed:26755581). In vitro, has also a phosphatase activity toward ADP, ATP, GDP and GTP (By similarity).
Activity is enhanced by nerve growth factor (in superior cervical ganglia and adrenal medulla). Trans-synaptic stimulation with reserpine, acetylcholine and glucocorticoids.
Catalyzes the hydroxylation of dopamine to noradrenaline (also known as norepinephrine), and is thus vital for regulation of these neurotransmitters.
Homotetramer; composed of two disulfide-linked dimers.
Proteolytic cleavage after the membrane-anchor leads to the release of the soluble form.
There are two main alleles of DBH: DBH-A with Ala-318 and DBH-B with Ser-318 (PubMed:10490716, PubMed:10391209, PubMed:10391210).
Expressed in brain; strongly reduced in post-mortem elderly subjects with Alzheimer disease (PubMed:18776146, PubMed:19343227). Expressed in the fetal neocortex (PubMed:27668656).
Expressed in peri-urothelial cells of the proximal ureter and renal pelvis at 9 weeks of gestation.
Interacts (via homeobox domain) with APBB1 (via PID domain 1). Interacts (via N-terminus) with HDAC1 and HDAC2; the interaction is direct. Found in a trimeric complex with APBB1 and HDAC1; the interaction between HDAC1 and APBB1 is mediated by TSHZ3.
TSHZ3 haploinsufficiency due to proximal chromosome 19q13.11 deletions causes a neurodevelopmental disorder characterized by developmental delay, absent or delayed speech, intellectual disability, and autistic features. Some patients may have reanal tract abnormalities.
Transcriptional regulator involved in developmental processes. Functions in association with APBB1, SET and HDAC factors as a transcriptional repressor, that inhibits the expression of CASP4. TSHZ3-mediated transcription repression involves the recruitment of histone deacetylases HDAC1 and HDAC2. Associates with chromatin in a region surrounding the CASP4 transcriptional start site(s) (PubMed:19343227). Regulates the development of neurons involved in both respiratory rhythm and airflow control. Promotes maintenance of nucleus ambiguus (nA) motoneurons, which govern upper airway function, and establishes a respiratory rhythm generator (RRG) activity compatible with survival at birth. Involved in the differentiation of the proximal uretic smooth muscle cells during developmental processes. Involved in the up-regulation of myocardin, that directs the expression of smooth muscle cells in the proximal ureter (By similarity). Involved in the modulation of glutamatergic synaptic transmission and long-term synaptic potentiation (By similarity).
Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber. May additionally cooperate with the neuronal intermediate filament proteins PRPH and INA to form neuronal filamentous networks (By similarity).
There are a number of repeats of the tripeptide K-S-P, NFM is phosphorylated on a number of the serines in this motif. It is thought that phosphorylation of NFM results in the formation of interfilament cross bridges that are important in the maintenance of axonal caliber.
Catalyzes the amidation of bile acids (BAs) with the amino acids taurine and glycine (PubMed:12810727, PubMed:8034703, PubMed:2037576, PubMed:12239217). More than 95% of the BAs are N-acyl amidates with glycine and taurine (PubMed:8034703). Amidation of BAs in the liver with glycine or taurine prior to their excretion into bile is an important biochemical event in bile acid metabolism (PubMed:12810727). This conjugation (or amidation) plays several important biological roles in that it promotes the secretion of BAs and cholesterol into bile and increases the detergent properties of BAs in the intestine, which facilitates lipid and vitamin absorption (PubMed:12810727). May also act as an acyl-CoA thioesterase that regulates intracellular levels of free fatty acids (PubMed:12810727, PubMed:8034703, PubMed:12239217). In vitro, catalyzes the hydrolysis of long- and very long-chain saturated acyl-CoAs to the free fatty acid and coenzyme A (CoASH), and conjugates glycine to these acyl-CoAs (PubMed:12810727).
Expressed in the gallbladder mucosa and pancreas (PubMed:2037576, PubMed:12810727). Expressed in hepatocytes (at protein level) (PubMed:2037576, PubMed:12810727, PubMed:23415802).
Acts as an adapter for the phosphatase MTMR2 to regulate MTMR2 catalytic activity and subcellular location (PubMed:12668758). May function as a guanine nucleotide exchange factor (GEF) activating RAB28 (PubMed:20937701). Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form (PubMed:20937701). Inhibits myoblast differentiation in vitro and induces oncogenic transformation in fibroblasts (PubMed:9537414).
Although it belongs to the non-receptor class myotubularin subfamily, lacks the conserved active site cysteine residue at position 1422 in the dsPTPase catalytic loop and does not have phosphatase activity (PubMed:9537414). The pocket is however sufficiently preserved to bind phosphorylated substrates, and maybe protect them from phosphatases.
Heterodimer with lipid phosphatase MTMR2 (PubMed:12668758). Interacts with KMT2A/MLL1 (via SET domain) (PubMed:9537414). Interacts with SUV39H1 (PubMed:10848615).
The C-terminal domain mediates interaction with MTMR2.
Although strongly related to USP22, which deubiquitinates histones, lacks the N-terminal UBP-type zinc finger, suggesting it does not have the ability to deubiquitinate histones.
Deubiquitinase involved in innate antiviral immunity by mediating deubiquitination of CGAS and RIGI (PubMed:31534008, PubMed:32027733). Negatively regulates RIGI by mediating 'Lys-63'-linked deubiquitination of RIGI, inhibiting type I interferon signaling (PubMed:32027733). Also regulates 'Lys-63'-linked ubiquitination level of MDA5/IFIH1 (PubMed:32027733). Acts as a positive regulator of the cGAS-STING pathway by catalyzing 'Lys-48'-linked deubiquitination of CGAS, thereby promoting its stabilization (PubMed:31534008). Can reduce the levels of BCL2L11/BIM ubiquitination and stabilize BCL2L11 in response to the RAF-MAPK-degradation signal (By similarity). By acting on BCL2L11 levels, may counteract the anti-apoptotic effects of MAPK activity (By similarity).
Interacts with phosphorylated BCL2L11 isoform BIMEL; this interaction leads to BCL2L11 deubiquitination and stabilization.
A chromosomal aberration involving ASPSCR1 has been found in two patients with of papillary renal cell carcinoma. Translocation t(X;17)(p11.2;q25).
A chromosomal aberration involving ASPSCR1 is found in patients with alveolar soft part sarcoma. Translocation t(X;17)(p11;q25) with TFE3 forms a ASPSCR1-TFE3 fusion protein.
Interacts with GLUT4 (By similarity). Interacts with VCPKMT. Interacts with VCP.
Tethering protein that sequesters GLUT4-containing vesicles in the cytoplasm in the absence of insulin. Modulates the amount of GLUT4 that is available at the cell surface (By similarity). Enhances VCP methylation catalyzed by VCPKMT.
Ubiquitous. Highly expressed in testis, heart, skeletal muscle and pancreas.
DAZL and PUM2 bind its 3'-UTR mRNA, suggesting that these proteins may regulate its translation.
Highly expressed in testis, kidney, spleen, brain and fetal tissues. Also expressed at lower level in heart, lung, liver, small intestine, ovary, uterus, mammary gland and placenta.
Required for 60S pre-ribosomal subunits export to the cytoplasm.
Variations in SDAD1 may be a cause of susceptibility to seasonal allergic rhinitis (SAR). SAR is a common allergic disorder characterized by episodes of sneezing, rhinorrhea, and swelling of the nasal mucosa.
Has nucleotide phosphatase activity towards ATP, GTP, CTP, TTP and UTP. Hydrolyzes nucleoside diphosphates with lower efficiency.
At least two different alleles are known.
The N-terminus was initially (PubMed:2758468) thought to be fused with glucose-6-phosphate-dehydrogenase (G6PD) protein in vivo. However, PubMed:2570640 showed that it encodes a GMP reductase, and PubMed:1694726 showed that the chimeric protein is an artifact.
Mitochondrial amino-acid transporter (By similarity). Does not act as a serine transporter: not able to mediate transport of serine into mitochondria (PubMed:30442778).
A chromosomal aberration involving KIAA1549 is found in pilocytic astrocytoma. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation.
Abundantly expressed in the retina, compared with only minimal expression in brain and other tissues.
Expression is low to moderate in retina and tissues, such as heart and kidney, and is predominantly expressed in brain.
May play a role in photoreceptor function.
Essential component of the nuclear pore complex (NPC). The repeat-containing domain may be involved in anchoring components of the pore complex to the pore membrane. When overexpressed in cells induces the formation of cytoplasmic annulate lamellae (AL).
Strongly expressed in adult brain; especially in hippocampus, frontal lobe and temporal lobe.
Suppresses oncogenic transformation in neural and non-neural cells and down-regulates neural cell proliferation. Might be involved in transcriptional regulation (By similarity).
Defects in this gene may be a cause of male infertility.
Highly expressed in testis. Highly expressed in the round and late spermatids.
May be essential for spermiogenesis and male fertility probably by regulating the manchette dynamics, spermatid head shaping and sperm flagellum assembly.
Belongs to the TRAPP small subunits family. BET5 subfamily.
Part of the multisubunit transport protein particle (TRAPP) complex (PubMed:11805826). The heterodimer TRAPPC6B-TRAPPC3 interacts with TRAPPC1 likely providing a core for TRAPP complex formation (PubMed:16828797).
E3 ubiquitin-protein ligase involved in postreplication repair of UV-damaged DNA. Postreplication repair functions in gap-filling of a daughter strand on replication of damaged DNA. Associates to the E2 ubiquitin conjugating enzyme UBE2B to form the UBE2B-RAD18 ubiquitin ligase complex involved in mono-ubiquitination of DNA-associated PCNA on 'Lys-164'. Has ssDNA binding activity.
Homodimer (PubMed:21549715). Interacts with UBE2A and UBE2B, one homodimer binding one molecule of UBE2B. Interacts with SHPRH (PubMed:17130289, PubMed:17108083). Interacts with HLTF (PubMed:18316726, PubMed:18719106). Interacts with SPRTN; leading to enhance chromatin association of RAD18 and RAD18-mediated PCNA ubiquitination and translesion DNA synthesis (PubMed:22681887). Interacts (via C-terminus and phosphorylated form) with SLF1 (via BRCT domains); this interaction is required for efficient repair of UV-induced DNA damage (PubMed:15632077, PubMed:22036607, PubMed:25931565). Interacts with SLF2 (PubMed:25931565). Interacts with SMC5; this interaction is increased in a SLF1 or SLF2-dependent manner (PubMed:25931565).
Competes with SMC1 for binding to SMC3. May affect the availability of SMC3 to engage in the formation of multimeric protein complexes.
Interacts (via N- and C-terminal domains) with SMC3 (via central hinge region).
Expressed in embryonic stem cells (PubMed:16546155). Expressed in brain (PubMed:21646404).
Interacts with MAPRE1, MAPRE2, MAPRE3 and CKAP5 (PubMed:21646404). Interacts with ZDHHC17 (via ANK repeats) (PubMed:28882895).
Microtubule plus-end tracking protein that might be involved in the regulation of cytoplasmic microtubule dynamics, microtubule organization and microtubule elongation.
Cleaved by plasma kallikrein to yield 100 kDa and 35 kDa fragments, and the resulting 100 kDa fragment is further converted to a 70 kDa fragment.
Interacts (via C-terminus) with DNAJC1 (via SANT 2 domain); this interaction protects ITIH4 against cleavage by kallikrein in vitro.
Levels increase from 1.4 to 3-fold in acute-phase processes such as in acute ischemia stroke (AIS), unstable angina and programmed surgery. In hepatocytes, induced by IL6 but not by other cytokines such as IL1B.
N- and O-glycosylated. In urine, O-linked glycosylation on threonine residues in the region from Thr-719 to Thr-725 consists of core 1 or possibly core 8 glycans. Mainly Hex(HexNAc)(2), but also some Hex(3)(HexNAc)(3). N-glycosylated but not O-glycosylated in plasma.
Possible biomarker for acute ischemic stroke (PubMed:19263524). Peptides derived from the proline-rich potentially active peptide (PRO_0000016542) may be biomarkers for a variety of disease states including breast cancer (PubMed:21137033).
Type II acute-phase protein (APP) involved in inflammatory responses to trauma. May also play a role in liver development or regeneration.
Highly expressed in macrophages and hematopoietic tissues rich in lymphocytes, like spleen and thymus. Weakly expressed in heart and lung. In atherosclerotic plaques, expression is observed around the lipid core and at the shoulder region.
May be a receptor for oxidized free fatty acids derived from linoleic and arachidonic acids such as 9-hydroxyoctadecadienoic acid (9-HODE). Activates a G alpha protein, most likely G alpha(q). May be involved in apoptosis. Functions at the G2/M checkpoint to delay mitosis. May function as a sensor that monitors the oxidative states and mediates appropriate cellular responses such as secretion of paracrine signals and attenuation of proliferation. May mediate ths accumulation of intracellular inositol phosphates at acidic pH through proton-sensing activity.
More abundant than isoform 1 in leukocytes by approximately 3-fold.
Was originally thought to be a receptor for lysophosphatidylcholine (LPC) and sphingosylphosphorylcholine (SPC), However, this work has been retracted.
Encoded by an autosomal retrotransposed copy of the X-linked gene UTP14A. Evolution of autosomal retrogenes from X-linked progenitors compensates for X-chromosome silencing during male meiosis.
Essential for spermatogenesis. May be required specifically for ribosome biogenesis and hence protein synthesis during male meiosis (By similarity).
Putative transcription factor, which may be involved in patterning of central nervous system and pancreas.
Found in a complex with XPO6, Ran, ACTB and PFN1. Interacts with ACTB (PubMed:14592989). Interacts with ACTB in a RanGTP-dependent manner (PubMed:14592989).
Mediates the nuclear export of actin and profilin-actin complexes in somatic cells.
Appears to be essential for maintaining mitochondrial cristae formation and mitochondrial function by acting via YME1L1 in a kinase-independent manner to regulate essential mitochondrial structural proteins OPA1 and IMMT (PubMed:31125351). The action of this enzyme is not yet clear (Probable). It is not known if it has protein kinase activity and what type of substrate it would phosphorylate (Ser, Thr or Tyr) (Probable).
Belongs to the cyclic nucleotide-gated cation channel (TC 1.A.1.5) family. CNGB3 subfamily.
Tetramer formed of three CNGA3 and one CNGB3 modulatory subunits.
Visual signal transduction is mediated by a G-protein coupled cascade using cGMP as second messenger. This protein can be activated by cGMP which leads to an opening of the cation channel and thereby causing a depolarization of rod photoreceptors. Induced a flickering channel gating, weakened the outward rectification in the presence of extracellular calcium, increased sensitivity for L-cis diltiazem and enhanced the cAMP efficiency of the channel when coexpressed with CNGA3 (By similarity). Essential for the generation of light-evoked electrical responses in the red-, green- and blue sensitive cones.
Activity stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2).
Homodimer. Interacts with SRC and CRK. Interacts with RAB11FIP3. Interacts with PTK2B/PYK2 (By similarity). Interacts with CTTN. Interacts (via SH3 domain) with APC. Interacts with REPS2; the interaction is direct (PubMed:12149250). Forms a complex containing RAB11A, ASAP1, RAB3IP, RAP11FIP3 and ARF4; the complex promotes preciliary trafficking; the complex binds to RHO in photoreceptor cells and promotes RHO ciliary transport (PubMed:25673879).
Possesses phosphatidylinositol 4,5-bisphosphate-dependent GTPase-activating protein activity for ARF1 (ADP ribosylation factor 1) and ARF5 and a lesser activity towards ARF6. May coordinate membrane trafficking with cell growth or actin cytoskeleton remodeling by binding to both SRC and PIP2. May function as a signal transduction protein involved in the differentiation of fibroblasts into adipocytes and possibly other cell types. Part of the ciliary targeting complex containing Rab11, ASAP1, Rabin8/RAB3IP, RAB11FIP3 and ARF4, which direct preciliary vesicle trafficking to mother centriole and ciliogenesis initiation (PubMed:25673879).
The PH domain most probably contributes to the phosphoinositide-dependent regulation of ADP ribosylation factors.
Homodimer; disulfide-linked (By similarity). Forms trimer, hexamers and higher molecular weight oligomers (By similarity). May form heteromeric complexes with C1QTNF2 and C1QTNF12 and, to a lesser extent, with C1QTNF5 and C1QTNF10 (By similarity). Interacts with BMP5 and BMP7; the interaction inhibits BMP-induced transcription of HAMP (PubMed:30097509). Interacts with BMP6; the interaction inhibits BMP-induced transcription of HAMP (PubMed:31800957, PubMed:30097509). Interacts with BMP2 (PubMed:31800957). Interacts with heterodimers composed of BMP2 and BMP6 in vitro, the interaction inhibits the heterodimer binding to its receptor BMPR1A /ALK3 and thereby suppresses expression of HAMP (PubMed:31800957).
Iron-regulatory hormone that acts as an erythroid regulator after hemorrhage: produced by erythroblasts following blood loss and mediates suppression of hepcidin (HAMP) expression in the liver, thereby promoting increased iron absorption and mobilization from stores (PubMed:24880340, PubMed:30097509, PubMed:31800957). Promotes lipid uptake into adipocytes and hepatocytes via transcriptional up-regulation of genes involved in fatty acid uptake (By similarity). Inhibits apoptosis and inflammatory response in cardiomyocytes via promotion of sphingosine-1-phosphate (S1P) and cAMP-dependent activation of AKT signaling (By similarity). Inhibits autophagy induced by nutrient deficiency in hepatocytes via promoting the phosphorylation of IRS1, AKT, and MTOR, and thereby subsequent activation of the AKT-MTOR signaling pathway (By similarity). Negatively regulates the differentiation of osteoblasts, potentially via sequestering BMP2, and thereby inhibits the activation of SMAD signaling (By similarity). The reduction in BMP2 signaling in osteoblasts also results in an increase in expression of the osteoclastogenesis-promoting factors TNFSF11/RANKL and SOST, thereby indirectly promotes bone resorption (By similarity).
N-glycosylated; required for secretion of the mature protein.
Detected in adipocytes from white adipose tissue (at protein level) (PubMed:27832861). Detected in visceral adipose tissue and mammary gland (PubMed:9521880).
Interacts with ABHD5 (By similarity). Interacts with CIDEC (PubMed:23399566). Interacts with AQP7 (PubMed:27832861).
Major cAMP-dependent protein kinase-substrate in adipocytes, also dephosphorylated by PP1. When phosphorylated, may be maximally sensitive to HSL and when unphosphorylated, may play a role in the inhibition of lipolysis, by acting as a barrier in lipid droplet (By similarity).
Modulator of adipocyte lipid metabolism. Coats lipid storage droplets to protect them from breakdown by hormone-sensitive lipase (HSL). Its absence may result in leanness. Plays a role in unilocular lipid droplet formation by activating CIDEC. Their interaction promotes lipid droplet enlargement and directional net neutral lipid transfer. May modulate lipolysis and triglyceride levels.
Highly expressed in the nervous system including spinal cord, thalamus, hippocampus, hypothalamus and cerebellum.
Interacts with both alpha- and beta-tubulin (via C-terminal tubulin tails).
Polyglutamylase which modifies tubulin, generating polyglutamate side chains of variable lengths on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of tubulin (PubMed:16901895, PubMed:25959773). Mediates both ATP-dependent initiation and elongation steps of the polyglutamylation reaction (PubMed:16901895, PubMed:25959773). Preferentially modifies the beta-tubulin tail over an alpha-tail (PubMed:16901895, PubMed:25959773). Competes with monoglycylase TTLL3 for modification site on beta-tubulin substrate, thereby creating an anticorrelation between glycylation and glutamylation reactions (By similarity). Required for neurite growth; responsible for the strong increase in tubulin polyglutamylation during postnatal neuronal maturation (By similarity).
The enzyme uses its core to engage the disordered anionic tails of alpha- and beta-tubulin and the flexible c-MTBD (cationic microtubule binding domain) region to bind the microtubule and position itself for beta-tail modification. The c-MTBD region is positively charged and becomes ordered when bound to microtubules: it interacts with a negatively charged patch on alpha-tubulin. The presence of positive charges in the c-MTBD region is essential for proper binding.
Two forms exist; alpha-4a (shown here) and alpha-4b (PubMed:9335434). They seem to be equally abundant (PubMed:9335434).
Abundant in testis, brain, and kidney with lower levels detectable in other tissues.
Interacts with CADM1 (By similarity). Interacts with the LIN7 proteins.
Sodium- and proton-independent thyroid hormones and aromatic acids transporter (PubMed:11827462, PubMed:18337592, PubMed:28754537). Mediates both uptake and efflux of 3,5,3'-triiodothyronine (T3) and 3,5,3',5'-tetraiodothyronine (T4) with high affinity, suggesting a role in the homeostasis of thyroid hormone levels (PubMed:18337592). Responsible for low affinity bidirectional transport of the aromatic amino acids, such as phenylalanine, tyrosine, tryptophan and L-3,4-dihydroxyphenylalanine (L-dopa) (PubMed:11827462, PubMed:28754537). Plays an important role in homeostasis of aromatic amino acids (By similarity).
Strongly expressed in kidney and skeletal muscle and at lower level in placenta and heart.
Expressed in spermatozoa (PubMed:36708031). Expressed in airway epithelial cells (PubMed:36191189).
Interacts with TEKT1, TEKT2, TEKT4 and TEKT5.
May be proteolytically processed during the epididymal transit of spermatozoa.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia and flagellar axoneme (PubMed:36191189). Forms filamentous polymers in the walls of ciliary and flagellar microtubules (By similarity). Required for normal sperm mobility (By similarity).
May be involved in transcriptional regulation. May have a role in embryonic development.
Component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3.(PubMed:18984158). Interacts with HSD17B10/MRPP2; forming the MRPP1-MRPP2 subcomplex of the mitochondrial ribonuclease P complex (PubMed:23042678, PubMed:29040705). Interacts with GRSF1 (PubMed:23473034).
Mitochondrial tRNA N(1)-methyltransferase involved in mitochondrial tRNA maturation (PubMed:18984158, PubMed:21593607, PubMed:23042678, PubMed:27132592). Component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3, which cleaves tRNA molecules in their 5'-ends (PubMed:18984158). Together with HSD17B10/MRPP2, forms a subcomplex of the mitochondrial ribonuclease P, named MRPP1-MRPP2 subcomplex, which displays functions that are independent of the ribonuclease P activity (PubMed:23042678, PubMed:29040705). The MRPP1-MRPP2 subcomplex catalyzes the formation of N(1)-methylguanine and N(1)-methyladenine at position 9 (m1G9 and m1A9, respectively) in tRNAs; TRMT10C/MRPP1 acting as the catalytic N(1)-methyltransferase subunit (PubMed:23042678). The MRPP1-MRPP2 subcomplex also acts as a tRNA maturation platform: following 5'-end cleavage by the mitochondrial ribonuclease P complex, the MRPP1-MRPP2 subcomplex enhances the efficiency of 3'-processing catalyzed by ELAC2, retains the tRNA product after ELAC2 processing and presents the nascent tRNA to the mitochondrial CCA tRNA nucleotidyltransferase TRNT1 enzyme (PubMed:29040705). In addition to tRNA N(1)-methyltransferase activity, TRMT10C/MRPP1 also acts as a mRNA N(1)-methyltransferase by mediating methylation of adenosine residues at the N(1) position of MT-ND5 mRNA (PubMed:29072297). Associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly.
The identity of the enzyme catalyzing mitochondrial mRNA N(1)-methyltransferase is unclear. According to a report, mitochondrial mRNA N(1)-methyltransferase activity is catalyzed by TRMT61B (AC Q9BVS5) (PubMed:29107537). According to a second report, it is mediated by TRMT10C (PubMed:29072297). As both reports only tested one protein (either TRMT61B or TRMT10C), it is possible that both proteins have this activity.
Essential component of glycosylphosphatidylinositol-mannosyltransferase 1 which transfers the first of the 4 mannoses in the GPI-anchor precursors during GPI-anchor biosynthesis. Probably acts by stabilizing the mannosyltransferase PIGM (By similarity).
Homohexamer. Associates with CALHM3 as a pore-forming subunit in an hetero-hexameric channel complex (By similarity).
Inhibited by Gd(3+), Ruthenium Red, and Zn(2+) and partially inhibited by 2-aminoethoxydiphenyl borate.
Leu-86 causes a dysregulation of Ca(2+) homeostasis and amyloid precursor protein (APP) metabolism and has been suggested to be a risk factor for the development of Alzheimer disease (PubMed:18585350, PubMed:20061624, PubMed:20164592). However, this association with Alzheimer disease could not be confirmed in a number of studies performed in different populations (PubMed:19472444, PubMed:19070563, PubMed:19191331, PubMed:19191332, PubMed:19545933, PubMed:19655363, PubMed:21378601). According to a meta-analysis study, Leu-86 is likely not a genetic determinant of Alzheimer disease but may modulate age of onset by interacting with the effect of the APOE*4 allele of the APOE gene (PubMed:20847397).
Pore-forming subunit of a voltage-gated ion channel required for sensory perception of sweet, bitter and umami tastes (By similarity). Specifically present in type II taste bud cells, where it plays a central role in sweet, bitter and umami taste perception by inducing ATP release from the cell, ATP acting as a neurotransmitter to activate afferent neural gustatory pathways (By similarity). Together with CALHM3, forms a fast-activating voltage-gated ATP-release channel in type II taste bud cells (TBCs) (By similarity). Acts both as a voltage-gated and calcium-activated ion channel: mediates neuronal excitability in response to changes in extracellular Ca(2+) concentration (PubMed:22711817, PubMed:23300080). Has poor ion selectivity and forms a wide pore (around 14 Angstroms) that mediates permeation of Ca(2+), Na(+) and K(+), as well as permeation of monovalent anions (PubMed:22711817). Acts as an activator of the ERK1 and ERK2 cascade (PubMed:23345406). Triggers endoplasmic reticulum stress by reducing the calcium content of the endoplasmic reticulum (PubMed:21574960). May indirectly control amyloid precursor protein (APP) proteolysis and aggregated amyloid-beta (Abeta) peptides levels in a Ca(2+) dependent manner (PubMed:18585350).
Predominantly expressed in adult brain. Detected also in retinoic acid-differentiated SH-SY5Y cells. Specifically expressed in circumvallate taste bud cells.
Expression is highest in skeletal muscle, heart, kidney, and pancreas, whereas there is very little expression in brain and thymus.
Interacts with EIF4E (PubMed:9593750). Interacts with RPA2 (in unphosphorylated form via N-terminus); the interaction enhances EIF4EBP3-mediated inhibition of EIF4E-mediated mRNA nuclear export (PubMed:22684010).
Repressor of translation initiation that regulates EIF4E activity by preventing its assembly into the eIF4F complex: the hypophosphorylated form competes with EIF4G1/EIF4G3 and strongly binds to EIF4E, leading to repression of translation. In contrast, the hyperphosphorylated form dissociates from EIF4E, allowing interaction between EIF4G1/EIF4G3 and EIF4E, leading to initiation of translation (By similarity). Inhibits EIF4E-mediated mRNA nuclear export (PubMed:22684010).
Interacts with GNAZ, GNAI1 and GNAI3 (PubMed:8774883, PubMed:11443111, PubMed:18434541). Associates specifically with the activated, GTP-bound forms of GNAZ and GNAI3 (PubMed:8774883).
Regulates G protein-coupled receptor signaling cascades, including signaling downstream of the muscarinic acetylcholine receptor CHRM2. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form (PubMed:8774883, PubMed:10608901, PubMed:9353196, PubMed:11443111, PubMed:18434541). Modulates the activity of potassium channels that are activated in response to CHRM2 signaling (PubMed:11443111). Activity on GNAZ is inhibited by palmitoylation of the G-protein (PubMed:9353196).
Interacts strongly with LDBS. Interacts with LDB2 and LDB1. Interaction with complexes consisting of at least LDB1 and LHX3, acts to disassemble the complex; may preferentially disassemble LDB1-LHX3 complexes rather than complexes consisting of LDB1, LHX3 and ISL1. Interacts (via the LIM zinc-binding domain 1) with RBBP8 (PubMed:23353824). Interacts with both RPPB8 and LDB1 through the same face and cannot bind to both proteins simultaneously (By similarity). Interacts with BRCA1 (via the BRCT domains); the interaction represses BRCA1 transcriptional activity. Interacts with DEAF1; LMO4 blocks export from nucleus.
Transcription cofactor. Plays a role in establishing motor neuron identity, in concert with MNX1, acting, at least in part, to disrupt LDB1-LHX3 complexes thereby negatively modulating interneuron genes in motor neurons.
High-affinity transporter for the intake of thiamine (PubMed:10542220, PubMed:10391222, PubMed:33008889, PubMed:35512554, PubMed:35724964). Mediates H(+)-dependent pyridoxine transport (PubMed:33008889, PubMed:35512554, PubMed:35724964).
Pyridoxine transport is inhibited by carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and carbonyl cyanide m-chlorophenylhydrazone (CCCP).
Ubiquitous; most abundant in skeletal and cardiac muscle. Medium expression in placenta, heart, liver and kidney, low in lung.
Functions as a transcriptional repressor for PRDM1.
Sumoylated. Desumoylation by DESI1 reverses transcriptional repression activity (By similarity).
Expressed abundantly in lung, kidney and adrenal gland, but not in adult brain.
Homodimer, and heterodimer with other HLH proteins. Interacts with COPS5 and COPS7A. Interacts with IFI204. Interacts with GATA4 and NKX2-5. Interacts with ANKRD2; both proteins cooperate in myoblast differentiation (By similarity). Interacts with CLOCK and BMAL1.
Transcriptional regulator (lacking a basic DNA binding domain) which negatively regulates the basic helix-loop-helix (bHLH) transcription factors by forming heterodimers and inhibiting their DNA binding and transcriptional activity. Implicated in regulating a variety of cellular processes, including cellular growth, senescence, differentiation, apoptosis, angiogenesis, and neoplastic transformation. Involved in myogenesis by inhibiting skeletal muscle and cardiac myocyte differentiation and promoting muscle precursor cells proliferation. Inhibits the binding of E2A-containing protein complexes to muscle creatine kinase E-box enhancer. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer.
(Microbial infection) Interacts with Hantaan hantavirus glycoprotein N; this interaction contributes to the virus-induced degradation of mitochondria by autophagy, which leads to degradation of host MAVS and inhibition of type I interferon (IFN) responses.
(Microbial infection) The Legionella effector RavZ is a deconjugating enzyme that hydrolyzes the amide bond between the C-terminal glycine residue and an adjacent aromatic residue in ATG8 proteins conjugated to phosphatidylethanolamine (PE), producing an ATG8 protein that is resistant to reconjugation by the host machinery due to the cleavage of the reactive C-terminal glycine (PubMed:23112293, PubMed:28395732, PubMed:31722778). RavZ is also able to mediate delipidation of ATG8 proteins conjugated to phosphatidylserine (PS) (PubMed:33909989).
3 different light chains, LC1, LC2 and LC3, can associate with MAP1A and MAP1B proteins (By similarity). Interacts at microtubules with CABP1 (via EF-hands 1 and 2) but not with calmodulin (PubMed:15095872). Interacts with FYCO1 (via C-terminus) (PubMed:20100911, PubMed:24089205). Interacts with TP53INP1 and TP53INP2 (PubMed:22470510). Interacts with TBC1D25 (PubMed:21383079). Directly interacts with SQSTM1; this interaction leads to MAP1LC3B recruitment to inclusion bodies containing polyubiquitinated protein aggregates and to inclusion body degradation by autophagy (PubMed:17580304, PubMed:24089205, PubMed:24668264, PubMed:18524774). Interacts with ATG4B, MAPK15 and BNIP3 (PubMed:22948227, PubMed:23209295). Interacts with MAPB1, KEAP1, PCM1, OFD1, CEP131, and TECPR2 (PubMed:20562859, PubMed:24089205). Interacts with TBC1D5 (PubMed:22354992). Found in a complex with UBQLN1 and UBQLN2 (PubMed:20529957). Interacts with UBQLN4 (via STI1 1 and 2 domains). Interacts with UBQLN1 in the presence of UBQLN4 (PubMed:23459205). Interacts with ATG13 (PubMed:24290141). Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3 (PubMed:26040720, PubMed:34338405). No interaction, or very weak, with WDFY3 (PubMed:24668264). Interacts with PLCL1; the interaction inhibits autophagosome formation (By similarity). Interacts with TRIM16 (PubMed:30143514). Interacts with CRY1 and PER2 (By similarity). Interacts with the reticulophagy receptor TEX264 (PubMed:31006538, PubMed:31006537). Membrane-bound form LC3-II interacts with PHB and PHB2; the interaction takes place upon Parkin-mediated mitochondrial damage (PubMed:28017329). Interacts with PJVK; the interaction is direct (By similarity). Interacts with KBTBD6 and KBTBD7; the interaction is direct (PubMed:25684205). Interacts with AMBRA1 (via LIR motif) (PubMed:25215947). Interacts with JMY; the interaction results in the activation of JYM's nucleation activity in the cytoplasm (PubMed:30420355). Interacts with MOAP1 (via LIR motif) (PubMed:33783314). Interacts with TAX1BP1 (PubMed:26451915). Interacts with IRGM (PubMed:29420192). Interacts with STX17 (PubMed:29420192).
Most abundant in heart, brain, skeletal muscle and testis. Little expression observed in liver.
Phosphorylation by PKA inhibits conjugation of phosphatidylethanolamine (PE) (PubMed:22948227). Interaction with MAPK15 reduces the inhibitory phosphorylation and increases autophagy activity (PubMed:22948227).
PubMed:12740394 has shown that the protein is cleaved at Lys-122 but PubMed:15355958 has shown that the cleavage site is at Gly-120 as in other mammalian orthologs.
The precursor molecule is cleaved by ATG4 (ATG4A, ATG4B, ATG4C or ATG4D) to expose the glycine at the C-terminus and form the cytosolic form, LC3-I (PubMed:15187094, PubMed:15355958, PubMed:20818167, PubMed:29458288, PubMed:30661429, PubMed:31315929). The processed form is then activated by APG7L/ATG7, transferred to ATG3 and conjugated to phosphatidylethanolamine (PE) phospholipid to form the membrane-bound form, LC3-II (PubMed:15187094). During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid (PubMed:33909989). ATG4 proteins also mediate the delipidation of PE-conjugated forms (PubMed:29458288, PubMed:33909989). In addition, ATG4B and ATG4D mediate delipidation of ATG8 proteins conjugated to PS during non-canonical autophagy (PubMed:33909989). ATG4B constitutes the major protein for proteolytic activation (PubMed:30661429). ATG4D is the main enzyme for delipidation activity (By similarity).
Ubiquitin-like modifier involved in formation of autophagosomal vacuoles (autophagosomes) (PubMed:20418806, PubMed:23209295, PubMed:28017329). Plays a role in mitophagy which contributes to regulate mitochondrial quantity and quality by eliminating the mitochondria to a basal level to fulfill cellular energy requirements and preventing excess ROS production (PubMed:23209295, PubMed:28017329). In response to cellular stress and upon mitochondria fission, binds C-18 ceramides and anchors autophagolysosomes to outer mitochondrial membranes to eliminate damaged mitochondria (PubMed:22922758). While LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation (PubMed:20418806, PubMed:23209295, PubMed:28017329). Promotes primary ciliogenesis by removing OFD1 from centriolar satellites via the autophagic pathway (PubMed:24089205). Through its interaction with the reticulophagy receptor TEX264, participates in the remodeling of subdomains of the endoplasmic reticulum into autophagosomes upon nutrient stress, which then fuse with lysosomes for endoplasmic reticulum turnover (PubMed:31006537, PubMed:31006538). Upon nutrient stress, directly recruits cofactor JMY to the phagophore membrane surfaces and promotes JMY's actin nucleation activity and autophagosome biogenesis during autophagy (PubMed:30420355).
GTPase-activating protein (GAP) for RAC1 and RHOA, but not for CDC42.
Interacts with RHOU in a GTP-independent manner.
Interacts with SMAD1 (via MH1 and MH2 domains) (By similarity). Interacts with SMAD5 (PubMed:12370310). Interacts weakly with SMAD2 (By similarity). Interacts weakly with SMAD3 and SMAD4 (PubMed:12370310).
Transcriptional repressor. May modulate BMP and TGF-beta signal transduction, through its interaction with SMAD proteins.
May participate in diverse steps of neurogenesis. Inhibits the processing of pro-matrix metalloproteinase 2 (MMP-2) by MT1-MMP and MT3-MMP. May interfere with tumor invasion.
Highly expressed in brain, moderately expressed in thymus, spleen and lung, and weakly expressed in kidney, liver and peripheral blood lymphocytes. Also expressed in adrenal and pituitary glands, as well as testis.
Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition.
Expressed in brain particularly in the amygdala, hippocampus, substantia nigra and thalamus. Isoform 2 seems to be expressed ubiquitously.
May homomultimerize via its SAM domain (By similarity). Interacts with the C-terminus of SSTR2 via the PDZ domain. Interacts with IGSF9, SHARPIN, SPTAN1, HOMER1 and DLGAP1/GKAP isoforms 1 and 2 (By similarity). Part of a complex with DLG4/PSD-95 and DLGAP1/GKAP (By similarity). Interacts with BAIAP2. Interacts with HOMER1 and HOMER3 (By similarity).
Seems to be an adapter protein in the postsynaptic density (PSD) of excitatory synapses that interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and Homer, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction.
Antibodies against PNMA3 are present in sera from patients suffering of paraneoplastic neurological disorders.
Expressed at high levels in the brain and testis. Expressed at lower levels in the heart, trachea and kidney.
According to PubMed:9858585, highest levels of expression in adult testis, thymus and brain. Lower levels in placenta, spleen and colon. Consistently elevated levels in tumor-derived cells compared to non-transformed proliferating cells. According to PubMed:9840927: low levels in thymus, prostate, brain, skeletal muscle, and kidney. Elevated levels in lung. According to PubMed:9840943 highly expressed in testis, placenta, thymus and brain. In a lesser extent in small intestine and colon.
Activated by papilloma viral oncoproteins E6 and E7 which bind to and inactivate p53 and Rb, respectively.
Belongs to the cyclin family. Cyclin E subfamily.
Essential for the control of the cell cycle at the late G1 and early S phase.
Interacts with the CDK2 (in vivo) and CDK3 (in vitro) protein kinases to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex.
Phosphorylation by CDK2 triggers its release from CDK2 and degradation via the ubiquitin proteasome pathway.
Expressed in normal endometrium but overexpressed in endometroid tumors.
Interacts with HSPA5; may regulate the function of HSPA5 in apoptosis and cell proliferation.
May protect cells from cell death by inducing cytosolic vacuolization and up-regulating the autophagy pathway (PubMed:21072319). May play a role in apoptosis and cell proliferation through its interaction with HSPA5 (PubMed:26045166).
Arg-211 acts as a selectivity gate, preventing misactivation of ubiquitin by this NEDD8-specific E1 complex.
Belongs to the ubiquitin-activating E1 family. UBA3 subfamily.
Binding of TP53BP2 to the regulatory subunit NAE1 decreases activity.
Catalytic subunit of the dimeric UBA3-NAE1 E1 enzyme. E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Down-regulates steroid receptor activity. Necessary for cell cycle progression.
Heterodimer of UBA3 and NAE1. Interacts with NEDD8, UBE2F and UBE2M. Binds ESR1 and ESR2 with bound steroid ligand (By similarity). Interacts with TBATA (By similarity).
Componement of the CCZ1-MON1 RAB7A guanine exchange factor (GEF). Acts as a positive regulator of CCZ1-MON1A/B function necessary for endosomal/autophagic flux and efficient RAB7A localization (PubMed:29038162).
Found in a complex with RMC1, CCZ1 MON1A and MON1B.
Expressed in adult heart, brain, muscle and kidney, with very strong expression in brain. Also expressed in fetal brain, kidney and lung.
Proton-associated glucose transporter in the brain.
Rod-specific cGMP phosphodiesterase that catalyzes the hydrolysis of 3',5'-cyclic GMP (PubMed:20940301). This protein participates in processes of transmission and amplification of the visual signal.
Consists of at least two heavy chains and a number of intermediate and light chains. Interacts with BICD2 (PubMed:23664119). Interacts with CFAP45 and CFAP52 (PubMed:33139725).
Expressed in respiratory ciliated cells (at protein level).
Part of the dynein complex of respiratory cilia.
Binds DNA as dimer; homodimer and probable heterodimer with NR2F6 (PubMed:11682620). Interacts with GTF2B; this interaction is direct (PubMed:1517211). Interacts with COPS2 (PubMed:10207062).
Coup (chicken ovalbumin upstream promoter) transcription factor binds to the ovalbumin promoter and, in conjunction with another protein (S300-II) stimulates initiation of transcription. Binds to both direct repeats and palindromes of the 5'-AGGTCA-3' motif. Represses transcriptional activity of LHCG.
Inhibited by gonadotropin in granulosa cells.
Sequence-specific RNA-binding protein which plays an important role in the establishment and maintenance of the early morphology of cortical neurons during embryonic development. Acts as a translation repressor and controls a translationally regulated cell morphology program to ensure proper structuring of the nervous system. Translational control depends on recognition of its binding element within target mRNAs which consists of a mandatory UAG trimer upstream of a U/A-rich motif. Associated with polysomes (PubMed:25737280).
(Microbial infection) Interacts with human adenovirus early E1A protein; this interaction interferes with polysumoylation.
(Microbial infection) Interacts with human cytomegalovirus protein UL44.
(Microbial infection) Interacts with human herpesvirus 6 IE2.
Accepts the ubiquitin-like proteins SUMO1, SUMO2, SUMO3, SUMO4 and SUMO1P1/SUMO5 from the UBLE1A-UBLE1B E1 complex and catalyzes their covalent attachment to other proteins with the help of an E3 ligase such as RANBP2, CBX4 and ZNF451. Can catalyze the formation of poly-SUMO chains. Necessary for sumoylation of FOXL2 and KAT5. Essential for nuclear architecture and chromosome segregation. Sumoylates p53/TP53 at 'Lys-386'. Mediates sumoylation of ERCC6 which is essential for its transcription-coupled nucleotide excision repair activity (PubMed:26620705).
Expressed in heart, skeletal muscle, pancreas, kidney, liver, lung, placenta and brain. Also expressed in testis and thymus.
Forms a complex with SENP6 and UBE2I in response to UV irradiation (PubMed:17704809). Forms a tight complex with RANGAP1 and RANBP2 (PubMed:15378033, PubMed:15608651, PubMed:11853669, PubMed:15931224, PubMed:16732283). Identified in a complex with SUMO2 and UBE2I, where one ZNF451 interacts with one UBE2I and two SUMO2 chains, one bound to the UBE2I active site and the other to another region of the same UBE2I molecule (PubMed:12924945, PubMed:26524494). Interacts with SETX (PubMed:24105744). Interacts with HIPK1 and HIPK2 (By similarity). Interacts with PPM1J (By similarity). Interacts with RASD2 (By similarity). Interacts with TCF3 (By similarity). Interacts with NR2C1; the interaction promotes its sumoylation (By similarity). Interacts with SIAH1 (PubMed:9334332). Interacts with PARP (PubMed:9197546). Interacts with various transcription factors such as TFAP2A, TFAP2B, and TFAP2C (PubMed:12072434). Interacts with AR (PubMed:10383460). Interacts with ETS1 (PubMed:9333025). Interacts with SOX4 (PubMed:16631117). Interacts with RWDD3; the interaction enhances the sumoylation of a number of proteins such as HIF1A and I-kappa-B (PubMed:17956732, PubMed:23469069). Interacts with FOXL2 (PubMed:19744555). Interacts with DNM1l (via its GTPase and B domains); the interaction promotes sumoylation of DNM1L, mainly in its B domain (PubMed:19638400). Interacts with NFATC2IP; this inhibits formation of poly-SUMO chains (PubMed:20077568). Interacts with FHIT (PubMed:11085938). Interacts with PRKRA and p53/TP53 (By similarity). Interacts with UHRF2 (PubMed:23404503). Interacts with NR3C1 and this interaction is enhanced in the presence of RWDD3 (PubMed:23508108, PubMed:25918163). Interacts with MTA1 (PubMed:21965678). Interacts with ZNF451 (PubMed:26524494). Interacts with CPEB3 (By similarity). Interacts with SUMO1, SUMO2 and SUMO3 (PubMed:17466333). Interacts with IPO13 (PubMed:21139563). Interacts with DNMT1 (PubMed:19450230). Interacts with SUMO1P1/SUMO5 (PubMed:27211601). Interacts with PML-RARA oncoprotein (via the coiled-colied domain); the interaction is required for sumoylation of the PML-RARA oncoprotein (PubMed:15809060). Interacts with ZBED1/hDREF (PubMed:27068747).
Phosphorylation at Ser-71 significantly enhances SUMOylation activity.
Belongs to the queuine tRNA-ribosyltransferase family. QTRT2 subfamily.
Non-catalytic subunit of the queuine tRNA-ribosyltransferase (TGT) that catalyzes the base-exchange of a guanine (G) residue with queuine (Q) at position 34 (anticodon wobble position) in tRNAs with GU(N) anticodons (tRNA-Asp, -Asn, -His and -Tyr), resulting in the hypermodified nucleoside queuosine (7-(((4,5-cis-dihydroxy-2-cyclopenten-1-yl)amino)methyl)-7-deazaguanosine).
Autoinhibited by the ariadne domain, which masks the second RING-type zinc finger that contains the active site and inhibits the E3 activity (By similarity). Inhibition is relieved upon binding to neddylated cullin-RING ubiquitin ligase complexes, which activate the E3 ligase activity of ARIH1 (PubMed:24076655).
E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3 (PubMed:16118314, PubMed:17646546, PubMed:19340006, PubMed:24076655). Acts as an atypical E3 ubiquitin-protein ligase by working together with cullin-5-RING ubiquitin ligase complex (ECS complex, also named CRL5 complex) and initiating ubiquitination of ECS substrates: associates with ECS complex and specifically mediates addition of the first ubiquitin on ECS targets (By similarity). The initial ubiquitin is then elongated (By similarity). E3 ubiquitin-protein ligase activity is activated upon binding to neddylated form of the ECS complex (PubMed:24076655). Mediates 'Lys-6', 'Lys-48'- and 'Lys-63'-linked polyubiquitination (PubMed:16118314, PubMed:17646546, PubMed:19340006). May play a role in myelopoiesis (PubMed:19340006).
Interacts (via RING-type zinc finger 1) with UBE2L3 (PubMed:16118314, PubMed:19340006, PubMed:24076655). Interacts (via RING-type zinc finger 2) with UBE2N (PubMed:19340006). Interacts with neddylated CUL5 (PubMed:24076655). Interacts (via RING-type 2) with GFI1B (PubMed:17646546). Interacts with GFI1; prevents its ubiquitination and proteasomal degradation (PubMed:17646546). Interacts with DCUN1D1 (via UBA-like domain); promotes DCUN1D1 ubiquitination (PubMed:30587576).
Members of the RBR family are atypical E3 ligases. They interact with the E2 conjugating enzyme UBE2L3 and function like HECT-type E3 enzymes: they bind E2s via the first RING-type zinc finger, but require an obligate trans-thiolation step during the ubiquitin transfer, requiring a conserved active site Cys residue in the second RING-type zinc finger. The active site probably forms a thioester intermediate with ubiquitin taken from the active-site cysteine of the E2 before ultimately transferring it to a Lys residue on the substrate.
The Ariadne domain inhibits activity by masking the second RING-type zinc finger that contains the active site.
Ubiquitinated. Ubiquitination promotes proteasomal degradation.
Up-regulated by all-trans retinoic acid (ATRA). Up-regulated during differentiation of immature blood cells toward monocytes and granulocytes.
Widely expressed with higher expression in granulocytes.
Heterodimer with SNX9 (PubMed:20427313). Interacts with ITCH (PubMed:20491914). Interacts with dynamin-2 (DNM2), SYNJ1 and WASL (PubMed:20427313, PubMed:29437695). Interacts with the AP-1 complex (PubMed:18411244). Interacts with FCHSD1 (via the F-BAR domain) (By similarity).
Involved in endocytosis and intracellular vesicle trafficking, both during interphase and at the end of mitosis (PubMed:20427313, PubMed:18411244, PubMed:21048941, PubMed:22718350). Required for efficient progress through mitosis and cytokinesis (PubMed:22718350). Required for normal formation of the cleavage furrow at the end of mitosis (PubMed:22718350). Plays a role in endocytosis via clathrin-coated pits, but also clathrin-independent, actin-dependent fluid-phase endocytosis (PubMed:20427313). Plays a role in macropinocytosis (PubMed:21048941). Binds to membranes enriched in phosphatidylinositol 4,5-bisphosphate and promotes membrane tubulation (PubMed:18411244). Stimulates the GTPase activity of DNM2 (PubMed:20427313). Promotes DNM2 location at the plasma membrane (PubMed:20427313). Together with DNM2, involved in autophagosome assembly by regulating trafficking from recycling endosomes of phospholipid scramblase ATG9A (PubMed:29437695).
The PX domain mediates interaction with membranes enriched in phosphatidylinositol 4,5-bisphosphate.
Interacts with CEP63; the interaction is required for their location to proximal end of centrioles (PubMed:32402286). Interacts with microtubules (PubMed:32402286).
Pleiotropic regulator of centriole duplication, mitosis, and ciliogenesis. Critical interface between centrosome and microtubule-mediated cellular processes. Centriole duplication protein required for recruitment of CEP63, CEP152, and PLK4 to the centrosome. Independent of its centrosomal targeting, localizes to and interacts with microtubules and regulates microtubule nucleation, stability, and mitotic progression.
Can mediate aggregation most likely through a homophilic molecular interaction.
A polymorphism in IL10 promoter region is associated with resistance to graft-versus-host disease (GVHDS) [MIM:614395]. GVHDS is a major complication of allogeneic bone marrow transplantation, in which mature donor T-cells that contaminate the allogeneic bone marrow recognize the tissues of the recipient as foreign, causing a severe inflammatory disease.
Homodimer (PubMed:11485736, PubMed:15837194). Interacts with IL10RA and IL10RB (PubMed:16982608).
Major immune regulatory cytokine that acts on many cells of the immune system where it has profound anti-inflammatory functions, limiting excessive tissue disruption caused by inflammation. Mechanistically, IL10 binds to its heterotetrameric receptor comprising IL10RA and IL10RB leading to JAK1 and STAT2-mediated phosphorylation of STAT3 (PubMed:16982608). In turn, STAT3 translocates to the nucleus where it drives expression of anti-inflammatory mediators (PubMed:18025162). Targets antigen-presenting cells (APCs) such as macrophages and monocytes and inhibits their release of pro-inflammatory cytokines including granulocyte-macrophage colony-stimulating factor /GM-CSF, granulocyte colony-stimulating factor/G-CSF, IL-1 alpha, IL-1 beta, IL-6, IL-8 and TNF-alpha (PubMed:1940799, PubMed:7512027, PubMed:11564774). Interferes also with antigen presentation by reducing the expression of MHC-class II and co-stimulatory molecules, thereby inhibiting their ability to induce T cell activation (PubMed:8144879). In addition, controls the inflammatory response of macrophages by reprogramming essential metabolic pathways including mTOR signaling (By similarity).
Produced by a variety of cell lines, including T-cells, macrophages, mast cells and other cell types.
E3 Ubiquitin ligase proteins mediate ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Able to specifically bind RNA.
Widely expressed at low level. Highly expressed in skeletal muscle, kidney and heart. Expressed at low level in placenta, lung, brain, liver and pancreas.
Binding to misfolded proteins is mediated by a hydrophobic patch forming a large groove within the first two TPR repeats.
Interacts with EIF2AK4/GCN2; this interaction occurs under endoplasmic reticulum (ER) stress, hypothermic and amino acid starving stress conditions and inhibits EIF2AK4/GCN2 kinase activity. Interacts with EIF2AK3 (By similarity). Interacts with EIF2AK2 (PubMed:8576172). Forms a trimeric complex with DNAJB1 and HSPA8 (PubMed:9920933). Interacts with THAP12 (PubMed:9447982).
Involved in the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Acts as a negative regulator of the EIF2AK4/GCN2 kinase activity by preventing the phosphorylation of eIF-2-alpha at 'Ser-52' and hence attenuating general protein synthesis under ER stress, hypothermic and amino acid starving stress conditions (By similarity). Co-chaperone of HSPA8/HSC70, it stimulates its ATPase activity. May inhibit both the autophosphorylation of EIF2AK2/PKR and the ability of EIF2AK2 to catalyze phosphorylation of the EIF2A. May inhibit EIF2AK3/PERK activity.
The J domain mediates interaction with HSPA8.
Up-regulated during an endoplasmic reticulum stress via ATF6. Activated in response to infection by influenza virus through the dissociation of DNAJB1. Down-regulated by DNAJB1 and THAP12.
Widely expressed with high level in the pancreas and testis. Also expressed in cell lines with different levels.
Glycosylated. Glycosylation is essential for its activity.
Interferon-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response (PubMed:10464285, PubMed:9880569). Activated by detection of double stranded RNA (dsRNA): polymerizes higher oligomers of 2'-5'-oligoadenylates (2-5A) from ATP which then bind to the inactive monomeric form of ribonuclease L (RNASEL) leading to its dimerization and subsequent activation (PubMed:10464285, PubMed:9880569, PubMed:11682059). Activation of RNASEL leads to degradation of cellular as well as viral RNA, resulting in the inhibition of protein synthesis, thus terminating viral replication (PubMed:10464285, PubMed:9880569). Can mediate the antiviral effect via the classical RNASEL-dependent pathway or an alternative antiviral pathway independent of RNASEL (PubMed:21142819). In addition, it may also play a role in other cellular processes such as apoptosis, cell growth, differentiation and gene regulation (PubMed:21142819). May act as a negative regulator of lactation, stopping lactation in virally infected mammary gland lobules, thereby preventing transmission of viruses to neonates (By similarity). Non-infected lobules would not be affected, allowing efficient pup feeding during infection (By similarity).
Myristoylation is not essential for its activity.
Produced as a latent enzyme which is activated by double stranded RNA (dsRNA) generated during the course of viral infection(PubMed:9880569). The dsRNA activator must be at least 15 nucleotides long, and no modification of the 2'-hydroxyl group is tolerated (PubMed:9880569). ssRNA or dsDNA do not act as activators (PubMed:9880569). Strongly inhibited by copper, iron and zinc ions (PubMed:11682059). Partially inhibited by cobalt and nickel ions (PubMed:11682059).
ATP-dependent specificity component of the Clp protease complex. Hydrolyzes ATP (PubMed:28874591). Targets specific substrates for degradation by the Clp complex (PubMed:11923310, PubMed:22710082). Can perform chaperone functions in the absence of CLPP. Enhances the DNA-binding activity of TFAM and is required for maintaining a normal mitochondrial nucleoid structure (PubMed:22841477). ATP-dependent unfoldase that stimulates the incorporation of the pyridoxal phosphate cofactor into 5-aminolevulinate synthase, thereby activating 5-aminolevulinate (ALA) synthesis, the first step in heme biosynthesis (PubMed:28874591). Important for efficient erythropoiesis through up-regulation of heme biosynthesis (PubMed:25957689, PubMed:28874591).
Higher expression in skeletal muscle and heart and to a lesser extent in liver, brain, placenta, lung, kidney and pancreas.
Homohexamer that forms a ring structure; this hexamerization requires ATP binding. Component of the Clp complex formed by the assembly of two CLPP heptameric rings with two CLPX hexameric rings, giving rise to a symmetrical structure with two central CLPP rings flanked by a CLPX ring at either end of the complex. Interacts with TFAM.
A chromosomal aberration involving ARHGEF12 may be a cause of acute leukemia. Translocation t(11;11)(q23;23) with KMT2A/MLL1.
Interacts with GNA12 and GNA13, probably through the RGS-like domain. Interacts with RHOA, PLXNB1 and PLXNB2. Interacts through its PDZ domain with IGF1R beta subunit. Interacts with GCSAM.
May play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase and may act as GTPase-activating protein (GAP) for GNA12 and GNA13.
Ubiquitously expressed. Isoform 2 is found in jejunum and testis.
In the immune system, expression is restricted to activated class-I MHC-restricted cells, including NKT and CD8 T-cells (PubMed:10811014, PubMed:15811952, PubMed:16300832). Strongly expressed in spleen, thymus, small intestine, peripheral blood leukocyte, and in Purkinje neurons in cerebellum. Expressed at much lower levels in testis, ovary, colon, lung and lymphoid tissues (PubMed:16300832).
Mediates heterophilic cell-cell adhesion which regulates the activation, differentiation and tissue retention of various T-cell subsets (By similarity). Interaction with CADM1 promotes natural killer (NK) cell cytotoxicity and IFNG/interferon-gamma secretion by CD8+ T-cells in vitro as well as NK cell-mediated rejection of tumors expressing CADM1 in vivo (PubMed:15811952). Regulates CD8+ T-cell proliferation in response to T-cell receptor (TCR) activation (By similarity). Appears to be dispensable for CD8+ T-cell-mediated cytotoxicity (By similarity). Interaction with SCRIB promotes the late phase of cellular polarization of a subset of CD4+ T-cells, which in turn regulates TCR-mediated proliferation and IFNG, IL17 and IL22 production (By similarity). By interacting with CADM1 on CD8+ dendritic cells, regulates the retention of activated CD8+ T-cells within the draining lymph node (By similarity). Required for the intestinal retention of intraepithelial CD4+ CD8+ T-cells and, to a lesser extent, intraepithelial and lamina propria CD8+ T-cells and CD4+ T-cells (By similarity). Interaction with CADM1 promotes the adhesion to gut-associated CD103+ dendritic cells, which may facilitate the expression of gut-homing and adhesion molecules on T-cells and the conversion of CD4+ T-cells into CD4+ CD8+ T-cells (By similarity).
Monomer (PubMed:23583034). May form homodimer (via Ig-like V-type domain) (PubMed:23583034, PubMed:23871486). Interacts (via Ig-like V-type domain) with CADM1 (via Ig-like V-type domain); the interaction competes with CRTAM homodimerization and CADM1 homodimerization (PubMed:15781451, PubMed:15811952, PubMed:23871486). Interacts (via PDZ-binding motif) with SCRIB (via PDZ domain 3); the interaction promotes CRTAM and SCRIB polarization in a subset of CD4+ T-cells (By similarity).
The extracellular domain is required for the regulation of IFNG and IL22 production, but is dispensable for late T-cell polarization.
Core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (PubMed:11991638, PubMed:19325628, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Most spliceosomal snRNPs contain a common set of Sm proteins, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (PubMed:10025403, PubMed:19325628, PubMed:21113136, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Component of the U1 snRNP (PubMed:19325628, PubMed:21113136, PubMed:25555158). The U1 snRNP is composed of the U1 snRNA and the 7 core Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG, and at least three U1 snRNP-specific proteins SNRNP70/U1-70K, SNRPA/U1-A and SNRPC/U1-C (PubMed:19325628, PubMed:21113136, PubMed:25555158). Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39, plus LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8 (PubMed:26912367). Component of the minor spliceosome, which splices U12-type introns (PubMed:15146077, PubMed:33509932). Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG; catalyzes core snRNPs assembly (PubMed:16314521). Forms a 6S pICln-Sm complex composed of CLNS1A/pICln, SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG; ring-like structure where CLNS1A/pICln mimics additional Sm proteins and which is unable to assemble into the core snRNP. Interacts (via C-terminus) with SMN1 (via Tudor domain); the interaction is direct (PubMed:10500148, PubMed:11135666). Interacts with GEMIN2; the interaction is direct (PubMed:21816274). Interacts with SNRPD2; the interaction is direct (PubMed:21816274, PubMed:31799625).
Methylated on arginine residues by PRMT5 and PRMT7; probable asymmetric dimethylation which is required for assembly and biogenesis of snRNPs.
Plays a role in pre-mRNA splicing as a core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (PubMed:11991638, PubMed:18984161, PubMed:19325628, PubMed:23333303, PubMed:25555158, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). Component of both the pre-catalytic spliceosome B complex and activated spliceosome C complexes (PubMed:11991638, PubMed:26912367, PubMed:28502770, PubMed:28781166, PubMed:28076346). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (PubMed:15146077). May act as a charged protein scaffold to promote snRNP assembly or strengthen snRNP-snRNP interactions through non-specific electrostatic contacts with RNA (Probable).
Interacts with DCLK2 (By similarity). Possibly exists as a homodimer, homotrimer or a homotetramer. Interacts with F-actin, PPP1CA, neurabin-1, TGN38 and D(2) dopamine receptor. Interacts with RGS1, RGS2, RGS4, RGS19 and ADRA1B, ADRA2A, ADRA2B, ADRA2C, CDKN2A, PPP1R2, RASGFR1 and TIAM1. Interacts (via C-terminus) with SPATA13 (via C-terminal tail). Interacts with ADRA2B.
Seems to act as a scaffold protein in multiple signaling pathways. Modulates excitatory synaptic transmission and dendritic spine morphology. Binds to actin filaments (F-actin) and shows cross-linking activity. Binds along the sides of the F-actin. May play an important role in linking the actin cytoskeleton to the plasma membrane at the synaptic junction. Believed to target protein phosphatase 1/PP1 to dendritic spines, which are rich in F-actin, and regulates its specificity toward ion channels and other substrates, such as AMPA-type and NMDA-type glutamate receptors. Plays a role in regulation of G-protein coupled receptor signaling, including dopamine D2 receptors and alpha-adrenergic receptors. May establish a signaling complex for dopaminergic neurotransmission through D2 receptors by linking receptors downstream signaling molecules and the actin cytoskeleton. Binds to ADRA1B and RGS2 and mediates regulation of ADRA1B signaling. May confer to Rac signaling specificity by binding to both, RacGEFs and Rac effector proteins. Probably regulates p70 S6 kinase activity by forming a complex with TIAM1 (By similarity). Required for hepatocyte growth factor (HGF)-induced cell migration.
Stimulation of D1 (but not D2) dopamine receptors induces Ser-94 phosphorylation. Dephosphorylation of Ser-94 is mediated mainly by PP1 and to a lesser extent by PP2A. Phosphorylation of spinophilin disrupts its association with F-actin, but does not affect its binding to PP1 (By similarity).
Interacts with CDC42 and RHOQ, in a GTP-dependent manner.
Not detected in any of the adult tissues tested. May be expressed only in fetal or embryonic tissues.
Probably involved in the organization of the actin cytoskeleton. May act downstream of CDC42 to induce actin filament assembly leading to cell shape changes. Induces pseudopodia formation, when overexpressed in fibroblasts.
Binds to membranes enriched in phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Modifies membrane curvature and facilitates the formation of clathrin-coated invaginations (By similarity). Regulates receptor-mediated endocytosis (PubMed:10557078, PubMed:10393179).
Monomer. Binds clathrin, ZBTB16/ZNF145 and ITSN1 (By similarity). Binds ubiquitinated proteins (By similarity). Binds AP2A1 and AP2A2. Interacts with RALBP1 in a complex also containing NUMB and TFAP2A during interphase and mitosis. Interacts with AP2B1. Interacts with UBQLN2. Interacts with REPS2; the interaction is direct (PubMed:10557078, PubMed:10764745, PubMed:10393179). Interacts with EPS15; the interaction is direct (PubMed:10764745, PubMed:10393179). Interacts with ENTREP1 (PubMed:34927784).
Phosphorylated on serine and/or threonine residues in mitotic cells. Phosphorylation reduces interaction with REPS2, AP-2 and the membrane fraction. Depolarization of synaptosomes results in dephosphorylation.
The DPW repeat domain is involved in AP2A2 and clathrin binding.
The NPF repeat domain is involved in EPS15 binding.
The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction with the AP-2 complex subunit AP2B1.
RNA binding protein, may be involved in post-transcriptional regulatory mechanisms.
Ubiquitously expressed in all the cell lines and tissues tested.
Interacts with SLC39A6; which triggers cells to undergo EMT and mitosis (PubMed:27274087, PubMed:32797246). Found in a complex with SLC39A6, SLC39A10 and with the 'Ser-727' phosphorylated form of STAT3 throughout mitosis (PubMed:32797246). Found in a complex with SLC39A6, SLC39A10 and with NCAM1; this complex controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-tomesenchymal transition. Found in a complex with SLC39A6, SLC39A10 and with GSK3B that controls NCAM1 phosphorylation (By similarity).
Undergoes N-terminal ectodomain shedding.
Up-regulated in several breast cancer lines, and correlated to cancer progression as a marker of metastatic breast cancer.
Zinc-influx transporter (PubMed:30520657, PubMed:17359283, PubMed:27274087). When associated with SLC39A6, the heterodimer formed by SLC39A10 and SLC39A6 mediates cellular zinc uptake to trigger cells to undergo epithelial-to-mesenchymal transition (EMT) (PubMed:23186163). SLC39A10-SLC39A6 heterodimers play also an essentiel role in initiating mitosis by importing zinc into cells to initiate a pathway resulting in the onset of mitosis (PubMed:32797246). Plays an important for both mature B-cell maintenance and humoral immune responses (By similarity). When associated with SLC39A10, the heterodimer controls NCAM1 phosphorylation and integration into focal adhesion complexes during EMT (By similarity).
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase (PubMed:21645528). Positively regulates postnatal regression of retinal hyaloid vessels via suppression of VEGFR2/KDR activity, downstream of OPN5 (By similarity).
Expressed in the anterior pituitary gland.
Forms homo- and heterooligomers with DRD4 (PubMed:21184734). The interaction with DRD4 may modulate agonist-induced downstream signaling (PubMed:21184734). Interacts with CADPS and CADPS2 (PubMed:15857609). Interacts with GPRASP1, PPP1R9B and CLIC6 (By similarity). Interacts with ARRB2 (By similarity). Interacts with HTR2A (PubMed:21645528). Interacts with GNAI2 isoform sGi2, the interaction allows the creation of an intracellular pool of DRD2 that can be released to cell surface upon agonist stimulation (PubMed:17550964). Interacts with DRD1 (By similarity). Interacts with KCNA2 (By similarity).
Genetic variations in DRD2 may determine the genetic susceptibility to alcoholism [MIM:103780]. Genetic variations in DRD2 might be a protective factor against the development of withdrawal symptoms but might also be a risk factor in a highly burdened subgroup of alcoholics with a paternal and grandpaternal history of alcoholism and might contribute to suicide risk in alcoholics.
Palmitoylated. Palmitoylation which is required for proper localization to the plasma membrane and stability of the receptor could be carried on by ZDHHC4, ZDHHC3 and ZDHHC8.
Belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM1 sub-subfamily.
Expressed in the retina where it localizes to the outer plexiform layer. Specifically, it is expressed in retinal bipolar cells (BPCs) of the ON subtype (PubMed:30027108). Highly expressed in benign melanocytic nevi and diffusely expressed in various in situ melanomas, but not detected in melanoma metastases. Also expressed in melanocytes and pigmented metastatic melanoma cell lines. In melanocytes expression appears to be regulated at the level of transcription and mRNA processing.
Forms nonselective divalent cation-conducting channels which mediate the influx of Na(2+), Ca(2+), Mg(2+), Mn(2+), Ba(2+), and Ni(2+) into the cytoplasm, leading to membrane depolarization (PubMed:19436059, PubMed:21278253). Impermeable to zinc ions (PubMed:21278253). In addition, forms heteromultimeric ion channels with TRPM3 which are permeable for calcium and zinc ions (PubMed:21278253). Essential for the depolarizing photoresponse of retinal ON bipolar cells. It is part of the GRM6 signaling cascade. May play a role in metastasis suppression (By similarity). May act as a spontaneously active, calcium-permeable plasma membrane channel.
Interacts with TRPM3; the interaction results in the formation of a heteromultimeric cation channel complex (PubMed:21278253). Interacts with GPR179 (By similarity).
Up-regulated by hexamethylene bisacetamide (HBMA).
Expressed in salivary gland tissues and only in those that contain mucous acinar cells (e.g. sublingual and submandibular glands) and not in salivary glands containing only serous acinar cells (e.g. parotid gland).
May function in a protective capacity by promoting the clearance of bacteria in the oral cavity and aiding in mastication, speech, and swallowing. Binds P.aeruginosa pili.
N- and O-glycosylated. Contains fucose, mannose, galactose, N-acetylglucosamine and N-acetylgalactosamine.
The most common allele, MUC7*6, contains a tandem repeat domain comprising 6 repeats (shown here) each composed of 23 amino acids. These repeats are very similar but not identical. In a large cohort of 375 individuals from a variety of ethnic backgrounds, three different alleles were detected, MUC7*6 being the most common, in all populations studied, followed by MUC7*5 (5 repeats), with frequency varying from 0.05 in Africans to 0.22 in East Asians. The MUC7*5 allele is less prevalent in patients with asthma than in controls, and seems to have a protective role in respiratory function. MUC7*8 (8 repeats), a novel rare allele, was identified in 1 Northern European individual.
Distributive alpha-N-methyltransferase that methylates the N-terminus of target proteins containing the N-terminal motif [Ala/Gly/Pro/Ser]-Pro-Lys when the initiator Met is cleaved. Specifically catalyzes mono-, di- or tri-methylation of the exposed alpha-amino group of the Ala, Gly or Ser residue in the [Ala/Gly/Ser]-Pro-Lys motif and mono- or di-methylation of Pro in the Pro-Pro-Lys motif. Some of the substrates may be primed by NTMT2-mediated monomethylation (PubMed:24090352). Catalyzes the trimethylation of the N-terminal Gly in CENPA (after removal of Met-1). Responsible for the N-terminal methylation of KLHL31, MYL2, MYL3, RB1, RCC1, RPL23A and SET. Required during mitosis for normal bipolar spindle formation and chromosome segregation via its action on RCC1.
Calcium-binding protein involved in exocytosis of vesicles filled with neurotransmitters and neuropeptides. Probably acts upstream of fusion in the biogenesis or maintenance of mature secretory vesicles. Regulates neurotrophin release from granule cells leading to regulate cell differentiation and survival during cerebellar development. May specifically mediate the Ca(2+)-dependent exocytosis of large dense-core vesicles (DCVs) and other dense-core vesicles (By similarity).
Homodimer (By similarity). Interacts with the dopamine receptor DRD2.
The PH domain is essential for regulated exocytosis and binds phospholipids.
Widely expressed. Expressed in all adult and fetal tissues examined, with the strongest expression in kidney and pancreas. In brain, it is expressed at high levels in cerebellum, to a lesser degree in cerebral cortex, occipital pole, and frontal and temporal lobes. Only weakly expressed in medulla, spinal cord and putamen.
LA-PF4 stimulates DNA synthesis, mitosis, glycolysis, intracellular cAMP accumulation, prostaglandin E2 secretion, and synthesis of hyaluronic acid and sulfated glycosaminoglycan. It also stimulates the formation and secretion of plasminogen activator by human synovial cells. NAP-2 is a ligand for CXCR1 and CXCR2, and NAP-2, NAP-2(73), NAP-2(74), NAP-2(1-66), and most potent NAP-2(1-63) are chemoattractants and activators for neutrophils. TC-1 and TC-2 are antibacterial proteins, in vitro released from activated platelet alpha-granules. CTAP-III(1-81) is more potent than CTAP-III desensitize chemokine-induced neutrophil activation.
NAP-2(1-66) is produced by proteolytical processing, probably after secretion by leukocytes other than neutrophils.
NAP-2(73) and NAP-2(74) seem not be produced by proteolytical processing of secreted precursors but are released in an active form from platelets.
Proteolytic removal of residues 1-13 produces the active peptide beta-thromboglobulin, which is released from platelets along with platelet factor 4 and platelet-derived growth factor.
Proteolytic removal of residues 1-9 produces the active peptide connective tissue-activating peptide III (CTAP-III) (low-affinity platelet factor IV (LA-PF4)).
Component of the EvC complex composed of EFCAB7, IQCE, EVC2 and EVC; built from two subcomplexes, EVC2:EVC and EFCAB7:IQCE. Interacts with EVC2. Interacts with EFCAB7. Interacts with IQCE.
Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling. Involved in endochondral growth and skeletal development.
Found in the developing vertebral bodies, ribs, upper and lower limbs, heart, kidney, lung.
Transmembrane reductase that uses ascorbate as an electron donor in the cytoplasm and transfers electrons across membranes to reduce iron cations Fe(3+) into Fe(2+) in the lumen of the late endosome and lysosome. Reduced iron can then be extruded from the late endosome and lysosome to the cytoplasm by divalent metal-specific transporters. It is therefore most probably involved in endosomal and lysosomal cellular iron homeostasis.
(Microbial infection) In case of infection by polyomavirus, involved in the virus endoplasmic reticulum membrane penetration and infection (PubMed:21673190, PubMed:24675744).
Acts as a co-chaperone with HSPA8/Hsc70; required to promote protein folding and trafficking, prevent aggregation of client proteins, and promote unfolded proteins to endoplasmic reticulum-associated degradation (ERAD) pathway (PubMed:24732912). Acts by determining HSPA8/Hsc70's ATPase and polypeptide-binding activities (PubMed:24732912). Can also act independently of HSPA8/Hsc70: together with DNAJB12, acts as a chaperone that promotes maturation of potassium channels KCND2 and KCNH2 by stabilizing nascent channel subunits and assembling them into tetramers (PubMed:27916661). While stabilization of nascent channel proteins is dependent on HSPA8/Hsc70, the process of oligomerization of channel subunits is independent of HSPA8/Hsc70 (PubMed:27916661). When overexpressed, forms membranous structures together with DNAJB12 and HSPA8/Hsc70 within the nucleus; the role of these structures, named DJANGOs, is still unclear (PubMed:24732912).
Belongs to the DnaJ family. DNAJB12/DNAJB14 subfamily.
Interacts (via J domain) with HSPA8/Hsc70 (PubMed:23018488, PubMed:24732912, PubMed:27916661). Forms a multiprotein complex, at least composed of DNAJB12, DNAJB14, HSPA8/Hsc70 and SGTA; interaction with DNAJB14 and HSPA8/Hsc70 is direct (PubMed:24675744).
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Kinesin II subfamily.
Heterodimer of KIF3A and KIF3B (By similarity). KIF3A/KIF3B heterodimer interacts with KIFAP3 forming a heterotrimeric (KIF3A/KIF3B/KIFAP3) complex (By similarity). Interacts directly with IFT20 (By similarity). Interacts with the SMC3 subunit of the cohesin complex (PubMed:9506951). Interacts with FLCN (PubMed:27072130).
Microtubule-based molecular motor that transport intracellular cargos, such as vesicles, organelles and protein complexes. Uses ATP hydrolysis to generate force to bind and move along the microtubule (By similarity). Plays a role in cilia formation (PubMed:32386558). Involved in photoreceptor integrity and opsin trafficking in rod photoreceptors (PubMed:32386558). Transports vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit GRIN2A into neuronal dendrites (By similarity).
Acts as a mitochondrial iron-sulfur (Fe-S) cluster assembly factor that facilitates (Fe-S) cluster insertion into a subset of mitochondrial proteins. Probably acts together with NFU1 (PubMed:27532772).
Expressed in placenta, brain, heart, lung, liver, kidney and endothelial tissues.
Interacts with CPEB1. Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif (By similarity). Interacts (via cytoplasmic domain) with APBB2/FE65L (PubMed:8855266). Interacts (via intracellular domain) with APBB3/FE65L2 (PubMed:10081969).
May play a role in the regulation of hemostasis. The soluble form may have inhibitory properties towards coagulation factors. May interact with cellular G-protein signaling pathways. May bind to the DNA 5'-GTCACATG-3'(CDEI box). Inhibits trypsin, chymotrypsin, plasmin, factor XIA and plasma and glandular kallikrein. Modulates the Cu/Zn nitric oxide-catalyzed autodegradation of GPC1 heparan sulfate side chains in fibroblasts (By similarity).
The BPTI/Kunitz inhibitor domain is O-glycosylated.
Actin-based motor molecule with ATPase activity (PubMed:11940582, PubMed:36316095). Unconventional myosins serve in intracellular movements. Their highly divergent tails bind to membranous compartments, which are then moved relative to actin filaments. Binds to membranes containing anionic phospholipids via its tail domain. Involved in clathrin-mediated endocytosis and intracellular movement of clathrin-coated vesicles (PubMed:36316095). Required for normal morphology of the glomerular basement membrane, normal development of foot processes by kidney podocytes and normal kidney function. In dendritic cells, may control the movement of class II-containing cytoplasmic vesicles along the actin cytoskeleton by connecting them with the actin network via ARL14EP and ARL14.
Expressed in the immune system. In the kidney, predominantly expressed in the glomerulus, including podocytes.
Interacts with CALM and F-actin (PubMed:11940582). Interacts (via SH3 domain) with SYNJ1, DNM1 and DNM2 (PubMed:17257598). Interacts with ARL14EP (PubMed:21458045). Interacts with CARMIL1 (PubMed:19846667).
ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity.
Forms dimers with HSPA5/BIP in resting cells (By similarity). Oligomerizes in ER-stressed cells (By similarity). Interacts with DNAJC3 and MFN2 (By similarity). Interacts with TMEM33 (PubMed:26268696). Interacts with PDIA6 (PubMed:24508390). Interacts with LACC1 (PubMed:31875558).
Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions. Key activator of the integrated stress response (ISR) required for adaptation to various stress, such as unfolded protein response (UPR) and low amino acid availability (By similarity). EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activators ATF4 and QRICH1, and hence allowing ATF4- and QRICH1-mediated reprogramming (PubMed:33384352). Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1). Involved in control of mitochondrial morphology and function (By similarity).
Oligomerization of the N-terminal ER luminal domain by ER stress promotes PERK trans-autophosphorylation of the C-terminal cytoplasmic kinase domain at multiple residues including Thr-982 on the kinase activation loop (By similarity). Autophosphorylated. Phosphorylated at Tyr-619 following endoplasmic reticulum stress, leading to activate its tyrosine-protein kinase activity. Dephosphorylated by PTPN1/TP1B, leading to inactivate its enzyme activity.
Perturbation in protein folding in the endoplasmic reticulum (ER) promotes reversible dissociation from HSPA5/BIP and oligomerization, resulting in transautophosphorylation and kinase activity induction.
The lumenal domain senses perturbations in protein folding in the ER, probably through reversible interaction with HSPA5/BIP.
Ubiquitous. A high level expression is seen in secretory tissues.
A chromosomal aberration involving CCDC6 is found in papillary thyroid carcinomas (PTCs). Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene.
The protein has mostly an alpha helical conformation similar to myosin heavy-chain tail that might adopt a coiled-coil conformation.
Highly expressed in brain, cerebellum, and kidney. Lung, pancreas, and gastric mucosa show a weak expression. Also expressed in certain liver and kidney carcinomas.
Component of splicing factor SF3A which is composed of three subunits; SF3A3/SAP61, SF3A2/SAP62 and SF3A1/SAP114 (PubMed:8022796, PubMed:10882114, PubMed:11533230, PubMed:21349847). SF3A1 functions as scaffold that interacts directly with both SF3A2 and SF3A3 (PubMed:11533230, PubMed:21349847, PubMed:17098193). SF3A associates with the splicing factor SF3B and a 12S RNA unit to form the mature 17S U2 small nuclear ribonucleoprotein complex (17S U2 snRNP) (PubMed:10882114, PubMed:11533230, PubMed:17098193). Identified in the spliceosome 'E' complex, a precursor of the spliceosome 'A' complex (PubMed:10882114). Identified in the spliceosome 'A' and 'B' complexes (PubMed:8022796, PubMed:10882114, PubMed:29360106, PubMed:30315277). Identified in the spliceosome 'C' complex (PubMed:11991638).
Involved in pre-mRNA splicing as a component of the splicing factor SF3A complex that contributes to the assembly of the 17S U2 snRNP, and the subsequent assembly of the pre-spliceosome 'E' complex and the pre-catalytic spliceosome 'A' complex (PubMed:8022796, PubMed:10882114, PubMed:11533230). Involved in pre-mRNA splicing as a component of pre-catalytic spliceosome 'B' complexes (PubMed:29360106, PubMed:30315277).
Belongs to the AAA ATPase family. Katanin p60 subunit A1 subfamily. A-like 2 sub-subfamily.
Severs microtubules in vitro in an ATP-dependent manner. This activity may promote rapid reorganization of cellular microtubule arrays.
As a positive regulator of collagen fibrillogenesis, it is probably involved in the organization and remodeling of the extracellular matrix.
Expressed in osteoblast and visceral fat.
Isoform 1: Interacts with different types of collagen, including collagens I, III, and V (PubMed:29606302). Isoform 2: Interacts with GNG5, NFKBIA, MAPK1, MAPK3 and PTEN. Interaction with MAPK1 may stimulate DNA-binding. May interact with calmodulin. Binds to DNA in vitro.
May positively regulate MAP-kinase activity in adipocytes, leading to enhanced adipocyte proliferation and reduced adipocyte differentiation. May also positively regulate NF-kappa-B activity in macrophages by promoting the phosphorylation and subsequent degradation of I-kappa-B-alpha (NFKBIA), leading to enhanced macrophage inflammatory responsiveness. Can act as a transcriptional repressor.
The F5/8 type C domain binds to different types of collagen, including collagens I, III, and V.
High levels in peripheral blood lymphocytes, testis and ovary, lower levels in spleen, thymus, prostate, small intestine and colon.
Parallel homodimers formed between the membrane-bound and the cytosolic form, and also between 2 cytosolic forms.
Receptor for kinesin thus involved in kinesin-driven vesicle motility. Accumulates in integrin-based adhesion complexes (IAC) upon integrin aggregation by fibronectin.
Interacts with CD320 (via LDL-receptor class A domains).
Primary vitamin B12-binding and transport protein. Delivers cobalamin to cells.
Pro/Arg-259 polymorphism affects TCN2 plasma concentration and may interfere in vitamin B(12) cellular availability and homocysteine metabolism (PubMed:11159542).
Interacts with KNTC1 and ZW10. These interactions appear weak and may be transient or indirect (PubMed:19468067). Interacts with dynein intermediate chain and dynactin (DCTN1) (PubMed:25035494). Interacts with the catalytically active form of USP45 (PubMed:30258100).
Monoubiquitinated with'Lys-48' linkage (PubMed:30258100). Deubiquitinated by USP45 (PubMed:30258100).
Required for the localization of dynein and dynactin to the mitotic kintochore. Dynein is believed to control the initial lateral interaction between the kinetochore and spindle microtubules and to facilitate the subsequent formation of end-on kinetochore-microtubule attachments mediated by the NDC80 complex. Also required for correct spindle orientation. Does not appear to be required for the removal of spindle assembly checkpoint (SAC) proteins from the kinetochore upon bipolar spindle attachment (PubMed:17576797, PubMed:19468067). Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin. Facilitates the interaction between dynein and dynactin and activates dynein processivity (the ability to move along a microtubule for a long distance without falling off the track) (PubMed:25035494). Plays a role in cell migration (PubMed:30258100).
Belongs to the Rab3-GAP catalytic subunit family.
Catalytic subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which has GTPase-activating protein (GAP) activity towards various Rab3 subfamily members (RAB3A, RAB3B, RAB3C and RAB3D), RAB5A and RAB43, and guanine nucleotide exchange factor (GEF) activity towards RAB18 (PubMed:9030515, PubMed:10859313, PubMed:24891604). As part of the Rab3GAP complex, acts as a GAP for Rab3 proteins by converting active RAB3-GTP to the inactive form RAB3-GDP (PubMed:10859313). Rab3 proteins are involved in regulated exocytosis of neurotransmitters and hormones (PubMed:15696165). The Rab3GAP complex, acts as a GEF for RAB18 by promoting the conversion of inactive RAB18-GDP to the active form RAB18-GTP (PubMed:24891604). Required for recruiting and activating RAB18 at the endoplasmic reticulum (ER) membrane where it maintains proper ER structure (PubMed:24891604). Required for normal eye and brain development (PubMed:15696165, PubMed:23420520). May participate in neurodevelopmental processes such as proliferation, migration and differentiation before synapse formation, and non-synaptic vesicular release of neurotransmitters (PubMed:9030515, PubMed:9852129).
Acts as a replication initiation factor that brings together the MCM2-7 helicase and the DNA polymerase alpha/primase complex in order to initiate DNA replication. Additionally, plays a role in preventing DNA damage during replication. Key effector of the RBBP6 and ZBTB38-mediated regulation of DNA-replication and common fragile sites stability; acts as a direct target of transcriptional repression by ZBTB38 (PubMed:24726359).
Each zinc finger-like domain binds a zinc ion and is involved in both ssDNA and dsDNA binding, as is the OB-fold domain.
Expression is cell cycle regulated. Expression increases at the G1/S-boundary. Expression decreases in late M phase, remains low during G(1) phase, and starts to accumulate at the onset of S phase.
Self-associates (By similarity). Interacts with ORC2. May interact with MCM2 and MCM6. Interacts with the DNA polymerase alpha subunit POLA1. Interacts with RECQL4; this interaction regulates RECQL4 unwinding activity. Interacts with WDHD1.
The N-terminal domain mediates homodimerization.
By 17-beta-estradiol but also by a group of natural and synthetic estrogens as well as by estrogenic environmental compounds. Repressed by the antiestrogen 4-hydroxy-tamoxifen.
Key component of TNFSF11/RANKL- and TNF-induced osteoclastogenesis pathways, thereby mediates bone resorption in pathological bone loss conditions (By similarity). Required for TNFSF11/RANKL-induced osteoclastogenesis via its interaction with TNFRSF11A/RANK, thereby facilitates the downsteam transcription of NFATC1 and activation of PLCG2 (By similarity). Facilitates recruitment of the transcriptional repressor PRDM1/BLIMP1 to the promoter of the anti-osteoclastogenesis gene IRF8, thereby resulting in transcription of osteoclast differentiation factors (By similarity). May play a role in estrogen action (PubMed:14605097).
Part of a complex composed of EEIG1, TNFRSF11A/RANK, PLCG2, GAB2, TEC and BTK; complex formation increases in the presence of TNFSF11/RANKL (By similarity). Interacts with PRDM1/BLIMP1; following TNFSF11/RANKL stimulation in bone marrow-derived macrophages, the interaction promotes the binding of PRDM1/BLIMP1 to the gene promoter of IRF8 (By similarity).
Autophosphorylated, affecting interaction with TAF7.
Essential for transcriptional activity of the HLA class II promoter; activation is via the proximal promoter (PubMed:8402893, PubMed:7749984, PubMed:17493635, PubMed:16600381). Does not bind DNA (PubMed:8402893, PubMed:7749984, PubMed:17493635, PubMed:16600381). May act in a coactivator-like fashion through protein-protein interactions by contacting factors binding to the proximal MHC class II promoter, to elements of the transcription machinery, or both PubMed:8402893, PubMed:7749984, (PubMed:17493635, PubMed:16600381). Alternatively it may activate HLA class II transcription by modifying proteins that bind to the MHC class II promoter (PubMed:8402893, PubMed:7749984, PubMed:17493635, PubMed:16600381). Also mediates enhanced MHC class I transcription; the promoter element requirements for CIITA-mediated transcription are distinct from those of constitutive MHC class I transcription, and CIITA can functionally replace TAF1 at these genes. Activates CD74 transcription (PubMed:32855215). Exhibits intrinsic GTP-stimulated acetyltransferase activity (PubMed:11172716). Exhibits serine/threonine protein kinase activity: can phosphorylate the TFIID component TAF7, the RAP74 subunit of the general transcription factor TFIIF, histone H2B at 'Ser-37' and other histones (in vitro) (PubMed:24036077). Has antiviral activity against Ebola virus and coronaviruses, including SARS-CoV-2 (PubMed:32855215). Induces resistance by up-regulation of the p41 isoform of CD74, which blocks cathepsin-mediated cleavage of viral glycoproteins, thereby preventing viral fusion (PubMed:32855215).
Exhibits dominant-negative suppression of MHC class II gene expression.
Interacts with ZXDA and ZXDC (PubMed:17493635). Interacts with PML (isoform PML-2) (PubMed:23007646). Interacts with TAF7; interaction inhibits CIITA acetyltransferase activity, thereby repressing transcription (PubMed:20937824).
The GTP-binding motif doesn't confer GTPase activity but promotes nuclear localization.
The acetyltransferase domain is necessary for activation of both class I and class II transcription.
Belongs to the potassium channel family. B (Shab) (TC 1.A.1.2) subfamily. Kv2.2/KCNB2 sub-subfamily.
Homotetramer or heterotetramer with KCNB1. Heterotetramer with KCNS1 and KCNS2. Interacts (via phosphorylated FFAT motif) with VAPA and VAPB (PubMed:33124732).
Inhibited by quinine at micromolar levels. Modestly sensitive to millimolar levels of tetraethylammonium (TEA) and 4-aminopyridine (4-AP).
Phosphorylated. Phosphorylation at Ser-608 of the FFAT motif activates interaction with MOSPD2, VAPA and VAPB (PubMed:33124732).
The FFAT motif is involved in the interaction with VAPA and VAPB and its phosphorylation regulates these interactions.
Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and smooth muscle cells. Channels open or close in response to the voltage difference across the membrane, letting potassium ions pass in accordance with their electrochemical gradient. Homotetrameric channels mediate a delayed-rectifier voltage-dependent outward potassium current that display rapid activation and slow inactivation in response to membrane depolarization. Can form functional homotetrameric and heterotetrameric channels that contain variable proportions of KCNB1; channel properties depend on the type of alpha subunits that are part of the channel. Can also form functional heterotetrameric channels with other alpha subunits that are non-conducting when expressed alone, such as KCNS1 and KCNS2, creating a functionally diverse range of channel complexes. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Contributes to the delayed-rectifier voltage-gated potassium current in cortical pyramidal neurons and smooth muscle cells.
Component of a nucleolar TRAMP-like complex, an ATP-dependent exosome regulatory complex consisting of a helicase (MTREX), an oligadenylate polymerase (TENT4B or TENT4A), and a substrate specific RNA-binding factor (ZCCHC7 or ZCCHC8). Several TRAMP-like complexes exist with specific compositions and are associated with nuclear, or nucleolar RNA exosomes (PubMed:21855801). Interacts with CPEB1; the interaction is required for TENT4B-mediated translational control (PubMed:28383716).
Terminal nucleotidyltransferase that catalyzes preferentially the transfer of ATP and GTP on RNA 3' poly(A) tail creating a heterogeneous 3' poly(A) tail leading to mRNAs stabilization by protecting mRNAs from active deadenylation (PubMed:21788334, PubMed:30026317). Also functions as a catalytic subunit of a TRAMP-like complex which has a poly(A) RNA polymerase activity and is involved in a post-transcriptional quality control mechanism. Polyadenylation with short oligo(A) tails is required for the degradative activity of the exosome on several of its nuclear RNA substrates. Doesn't need a cofactor for polyadenylation activity (in vitro) (PubMed:21788334, PubMed:21855801). Required for cytoplasmic polyadenylation of mRNAs involved in carbohydrate metabolism, including the glucose transporter SLC2A1/GLUT1 (PubMed:28383716). Plays a role in replication-dependent histone mRNA degradation, probably through terminal uridylation of mature histone mRNAs. May play a role in sister chromatid cohesion (PubMed:18172165). Mediates 3' adenylation of the microRNA MIR21 followed by its 3'-to-5' trimming by the exoribonuclease PARN leading to degradation (PubMed:25049417). Mediates 3' adenylation of H/ACA box snoRNAs (small nucleolar RNAs) followed by its 3'-to-5' trimming by the exoribonuclease PARN which enhances snoRNA stability and maturation (PubMed:22442037).
Growth factor that binds to EGFR, ERBB4 and other EGF receptor family members. Potent mitogen for retinal pigment epithelial cells and vascular smooth muscle cells.
Synthesized in several tissues and tumor cells. Predominantly expressed in pancreas and small intestine.
Heart. The fetal heart shows a greater expression in the atrium than in the ventricle, while the adult heart shows a greater expression in the ventricle than in the atrium. Isoform 6 predominates in normal adult heart. Isoforms 1, 7 and 8 are expressed in fetal heart. Isoform 7 is also expressed in failing adult heart.
Phosphorylation at Thr-213 by PRKCA induces significant reduction in myofilament calcium sensitivity and actomyosin ATPase activity.
Belongs to the CWC16 family. YJU2 subfamily.
Component of the spliceosome (PubMed:29301961). Present in the activated B complex, the catalytically activated B* complex which catalyzes the branching, the catalytic step 1 C complex catalyzing the exon ligation, and the postcatalytic P complex containing the ligated exons (mRNA) and the excised lariat intron (By similarity). Identified in the spliceosome C complex; in the complex interacts directly with PRP16 (PubMed:29301961).
Part of the spliceosome which catalyzes two sequential transesterification reactions, first the excision of the non-coding intron from pre-mRNA and then the ligation of the coding exons to form the mature mRNA (PubMed:29301961). Plays a role in stabilizing the structure of the spliceosome catalytic core and docking of the branch helix into the active site, producing 5'-exon and lariat intron-3'-intermediates (By similarity). May protect cells from TP53-dependent apoptosis upon dsDNA break damage through association with PRP19-CD5L complex (PubMed:22952453).
Interacts with CCNB1/cyclin B1. Interacts with YWHAE/14-3-3 epsilon when phosphorylated. Interacts with CUL1 specifically when CUL1 is neddylated and active. Interacts with BTRC/BTRCP1 and FBXW11/BTRCP2. Interactions with CUL1, BTRC and FBXW11 are enhanced upon DNA damage. Interacts with PIM1. Interacts with CHEK2; mediates CDC25A phosphorylation and degradation in response to infrared-induced DNA damages. Interacts with HSP90AB1; prevents heat shock-mediated CDC25A degradation and contributes to cell cycle progression (PubMed:22843495).
Phosphorylated by CHEK1 on Ser-76, Ser-124, Ser-178, Ser-279, Ser-293 and Thr-507 during checkpoint mediated cell cycle arrest. Also phosphorylated by CHEK2 on Ser-124, Ser-279, and Ser-293 during checkpoint mediated cell cycle arrest. Phosphorylation on Ser-178 and Thr-507 creates binding sites for YWHAE/14-3-3 epsilon which inhibits CDC25A. Phosphorylation on Ser-76, Ser-124, Ser-178, Ser-279 and Ser-293 may also promote ubiquitin-dependent proteolysis of CDC25A by the SCF complex. Phosphorylation of CDC25A at Ser-76 by CHEK1 primes it for subsequent phosphorylation at Ser-79, Ser-82 and Ser-88 by NEK11. Phosphorylation by NEK11 is required for BTRC-mediated polyubiquitination and degradation. Phosphorylation by PIM1 leads to an increase in phosphatase activity. Phosphorylated by PLK3 following DNA damage, leading to promote its ubiquitination and degradation.
Stimulated by B-type cyclins. Stimulated by PIM1-mediated phosphorylation.
The phosphodegron motif mediates interaction with specific F-box proteins when phosphorylated. Putative phosphorylation sites at Ser-79 and Ser-82 appear to be essential for this interaction.
Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Directly dephosphorylates CDK1 and stimulates its kinase activity. Also dephosphorylates CDK2 in complex with cyclin E, in vitro.
Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex that contains FZR1/CDH1 during G1 phase leading to its degradation by the proteasome. Ubiquitinated by a SCF complex containing BTRC and FBXW11 during S phase leading to its degradation by the proteasome. Deubiquitination by USP17L2/DUB3 leads to its stabilization.
Epidermis, buccal mucosa, esophagus and cervix.
Plays a role in the regulation of retinal ganglion cell (RGC) neurite outgrowth, and hence in the development of the inner retina and optic nerve. Appears to be a potent inhibitor of regeneration following spinal cord injury.
Widely expressed in mitochondria-enriched tissues. Found in heart, muscle, kidney, liver, brain and placenta.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A1 subfamily.
Interacts (via PDZ domain-binding motif) with PALS1; interaction increases SLC6A1-mediated GABA uptake.
Mediates transport of gamma-aminobutyric acid (GABA) together with sodium and chloride and is responsible for the reuptake of GABA from the synapse (PubMed:30132828). The translocation of GABA, however, may also occur in the reverse direction leading to the release of GABA (By similarity). The direction and magnitude of GABA transport is a consequence of the prevailing thermodynamic conditions, determined by membrane potential and the intracellular and extracellular concentrations of Na(+), Cl(-) and GABA (By similarity). Can also mediate sodium- and chloride-dependent transport of hypotaurine but to a much lower extent as compared to GABA (By similarity).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRR3 sub-subfamily.
Generally pentameric. There are five types of GABA(A) receptor chains: alpha, beta, gamma, delta, and rho. Forms a ternary complex with SQSTM1 and PRKCZ (By similarity).
The sequence shown in this entry differs from the translation of the reference genome assembly (GRCh38/hg38) due to a nonsense variant creating stop codon at position 205 in the reference genome.
The sequence shown in this entry differs from the translation of the reference genome assembly (GRCh38/hg38) due to a nonsense variant creating stop codon at position 205 in the reference genome. The sequence shown in this entry is that of variant p.Ter205Tyr, which has a frequency of about 79% in the human population according to the Genome Aggregation Database (gnomAD v3.1.2).
Associates with the intermediate 315 kDa subcomplex of incompletely assembled complex I. Interacts with TMEM70 (PubMed:33753518).
Chaperone protein involved in the assembly of the mitochondrial NADH:ubiquinone oxidoreductase complex (complex I). Participates in constructing the membrane arm of complex I.
Generalized expression enhanced in heart and skeletal muscle.
Colocalizes with ZEB1 in E-cadherin-negative cells from established lines, and stroma of normal colon as well as in de-differentiated epithelial cells at the invasion front of colorectal carcinomas (at protein level).
Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B) and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible developmental- and tissue-specific combinations (PubMed:22952240, PubMed:26601204). Component of the BAF complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C. In muscle cells, the BAF complex also contains DPF3 (PubMed:18765789). Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin. Component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin (PubMed:26601204). Component of SWI/SNF (GBAF) subcomplex, which includes at least BICRA or BICRAL (mutually exclusive), BRD9, SS18, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, SMARCC1/BAF155, and SMARCD1/BAF60A (PubMed:29374058). Component of the BAF53 complex, at least composed of BAF53A, RUVBL1, SMARCA4/BRG1/BAF190A, and TRRAP, which preferentially acetylates histone H4 (and H2A) within nucleosomes (PubMed:11839798). Component of the CREST-BRG1 complex, at least composed of SMARCA4/BRG1/BAF190A, SS18L1/CREST, HDAC1, RB1 and SP1 (By similarity). Interacts with PHF10/BAF45A (By similarity). Interacts with MYOG (By similarity). Interacts directly with IKFZ1; the interaction associates IKFZ1 with the BAF complex (PubMed:10204490). Interacts with ZEB1 (via N-terminus) (PubMed:20418909). Interacts with NR3C1, PGR, SMARD1, TOPBP1 and ZMIM2/ZIMP7 (PubMed:9590696, PubMed:12917342, PubMed:15075294, PubMed:16051670). Interacts with (via the bromodomain) with TERT; the interaction regulates Wnt-mediated signaling (PubMed:19571879). Interacts with TBX21 in a KDM6B-dependent manner (By similarity). Interacts with KDM6A and KDM6B (By similarity). Interacts with HNRNPU; this interaction occurs in embryonic stem cells and stimulates global Pol II-mediated transcription (By similarity). Interacts with ACTL6A (PubMed:28649782). Interacts with DLX1 (By similarity). Interacts with DPF2 (PubMed:20460684). Interacts with DPF3a (isoform 2 of DPF3/BAF45C) and with HDGFL2 in a DPF3a-dependent manner (PubMed:32459350). May interact with ADNP2 (PubMed:23071114). Interacts with LETMD1 (via C-terminal); the interaction regulates transcriptional expression of thermogenic genes in brown adipose tissue (By similarity).
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Component of the CREST-BRG1 complex, a multiprotein complex that regulates promoter activation by orchestrating the calcium-dependent release of a repressor complex and the recruitment of an activator complex. In resting neurons, transcription of the c-FOS promoter is inhibited by SMARCA4-dependent recruitment of a phospho-RB1-HDAC repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex. At the same time, there is increased recruitment of CREBBP to the promoter by a CREST-dependent mechanism, which leads to transcriptional activation. The CREST-BRG1 complex also binds to the NR2B promoter, and activity-dependent induction of NR2B expression involves the release of HDAC1 and recruitment of CREBBP. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development, a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth. SMARCA4/BAF190A may promote neural stem cell self-renewal/proliferation by enhancing Notch-dependent proliferative signals, while concurrently making the neural stem cell insensitive to SHH-dependent differentiating cues (By similarity). Acts as a corepressor of ZEB1 to regulate E-cadherin transcription and is required for induction of epithelial-mesenchymal transition (EMT) by ZEB1. Binds via DLX1 to enhancers located in the intergenic region between DLX5 and DLX6 and this binding is stabilized by the long non-coding RNA (lncRNA) Evf2 (By similarity). Binds to RNA in a promiscuous manner (By similarity). Binding to RNAs including lncRNA Evf2 leads to inhibition of SMARCA4 ATPase and chromatin remodeling activities (By similarity). In brown adipose tissue, involved in the regulation of thermogenic genes expression (By similarity).
According to PubMed:8973356, it is ubiquitously expressed with high levels in lung and kidney and low levels in heart and liver. Highly expressed in cell lines derived from nervous system tumors arising from glia, low or absent in non-glial-derived nervous system tumor cell lines. Also found in fetal kidney. According to PubMed:7607567 it is expressed only in brain tumor glioblastoma multiforme/astrocytoma and not in other nervous system tumors or normal fetal or adult tissues.
Directly interacts with GOLGA1 and GOLGA4 (PubMed:29084197). Interacts with FAM91A1, C17ORF75 and WDR11; the interaction recruits TBC1D23 to AP-1-derived vesicles (PubMed:29084197, PubMed:29426865). Directly interacts with WASHC1 and WASHC2A/FAM21A (PubMed:29084197). Interacts with FKBP15 (PubMed:29084197).
Isoform 1: Widely expressed, including in fetal adult brain (corpus callosum, pons, cerebellum), spinal cord, heart, skeletal muscle, thymus and bone marrow, and at lower levels in spleen. Hardly detected in liver, kidney, colon and testis. Isoform 2: Expressed at high levels in liver, kidney, colon and testis. Hardly detected in tissues expressing high levels of isoform 1. Expressed at low levels in spleen.
Putative Rab GTPase-activating protein which plays a role in vesicular trafficking (PubMed:28823707). Involved in endosome-to-Golgi trafficking. Acts as a bridging protein by binding simultaneously to golgins, including GOLGA1 and GOLGA4, located at the trans-Golgi, and to the WASH complex, located on endosome-derived vesicles (PubMed:29084197, PubMed:29426865). Together with WDR11 complex facilitates the golgin-mediated capture of vesicles generated using AP-1 (PubMed:29426865). Plays a role in brain development, including in cortical neuron positioning (By similarity). May also be important for neurite outgrowth, possibly through its involvement in membrane trafficking and cargo delivery, 2 processes that are essential for axonal and dendritic growth (By similarity). May act as a general inhibitor of innate immunity signaling, strongly inhibiting multiple TLR and dectin/CLEC7A-signaling pathways. Does not alter initial activation events, but instead affects maintenance of inflammatory gene expression several hours after bacterial lipopolysaccharide (LPS) challenge (By similarity).
Belongs to the TFIIE alpha subunit family.
Tetramer of two alpha and two beta chains (PubMed:1956398). Interacts with TAF6/TAFII80 (PubMed:7667268). Interacts with ATF7IP (PubMed:19106100). Interacts with SND1 (PubMed:7651391).
Belongs to the mitochondrion-specific ribosomal protein mL51 family.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379, PubMed:25278503). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins (PubMed:25278503, PubMed:25838379). Interacts with OXA1L (By similarity).
Phosphorylated. Phosphorylation on Thr-562 occurs specifically during mitosis.
The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5. Interacts with FBXO43; the interaction is direct.
Belongs to the Schlafen family. Subgroup II subfamily.
Homodimer (PubMed:34272366). Interacts with PDE3A; direct low affinity interaction which is stimulated by binding of 17beta-estradiol/E2 to PDE3A and that positively regulates the ribonuclease activity of SLFN12 (PubMed:31420216, PubMed:35104454, PubMed:34272366, PubMed:34707099). Interacts with SERPINB12; as part of a pathway regulating cell differentiation (PubMed:30045019).
Phosphorylation at Ser-368 and Ser-573 negatively regulates the ribonuclease activity (PubMed:35104454). Dephosphorylation is induced by the interaction with PDE3A and stimulates the rRNA ribonuclease activity (PubMed:35104454).
Ribonuclease which is part of an E2/17beta-estradiol-induced pro-apoptotic signaling pathway. E2 stabilizes the PDE3A/SLFN12 complex in the cytosol, promoting the dephosphorylation of SLFN12 and activating its pro-apoptotic ribosomal RNA/rRNA ribonuclease activity. This apoptotic pathway might be relevant in tissues with high concentration of E2 and be for instance involved in placenta remodeling (PubMed:31420216, PubMed:35104454, PubMed:34272366, PubMed:34707099). May play a role in cell differentiation (PubMed:30045019).
Component of the microprocessor complex, or pri-miRNA processing protein complex, which is composed of DROSHA and DGCR8 (PubMed:15589161, PubMed:15574589, PubMed:15531877, PubMed:16751099, PubMed:26027739, PubMed:26748718). The microprocessor complex is a heterotrimer; each of the two DROSHA RNase III domains binds one DGCR8 (via C-terminal region) (PubMed:26027739, PubMed:26748718). Interacts with SP1 and SNIP1 (PubMed:10976766, PubMed:18632581). Interacts with SRRT/ARS2 (By similarity). Interacts with CPSF3 and ISY1; this interaction is in an RNA dependent manner (By similarity). Interacts with PUS10; interaction promotes pri-miRNAs processing (PubMed:31819270).
Each RNase III domain binds at least one Mg(2+) or Mn(2+) ion.
Ribonuclease III double-stranded (ds) RNA-specific endoribonuclease that is involved in the initial step of microRNA (miRNA) biogenesis. Component of the microprocessor complex that is required to process primary miRNA transcripts (pri-miRNAs) to release precursor miRNA (pre-miRNA) in the nucleus. Within the microprocessor complex, DROSHA cleaves the 3' and 5' strands of a stem-loop in pri-miRNAs (processing center 11 bp from the dsRNA-ssRNA junction) to release hairpin-shaped pre-miRNAs that are subsequently cut by the cytoplasmic DICER to generate mature miRNAs. Involved also in pre-rRNA processing. Cleaves double-strand RNA and does not cleave single-strand RNA. Involved in the formation of GW bodies.
The 2 RNase III domains form an intramolecular dimer where the domain 1 cuts the 3'strand while the domain 2 cleaves the 5'strand of pri-miRNAs, independently of each other.
Expressed in the outer root sheath and medulla region of hair follicle specifically from eyebrow and beard, digital pulp, nail matrix and nail bed epithelium, mucosal stratified squamous epithelia and in basal cells of oral epithelium, palmoplantar epidermis and sweat and mammary glands. Also expressed in myoepithelium of prostate, basal layer of urinary bladder, cambial cells of sebaceous gland and in exocervix (at protein level).
Heterodimer of a type I and a type II keratin. KRT17 associates with KRT6 isomers (KRT6A or KRT6B). Interacts with TRADD and SFN (By similarity).
Induced in damaged or stressed epidermis. Induced by the cytokines interferon-gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha) and transforming growth factor-alpha (TGF-alpha), and by the potent NF-kappa B inhibitor compounds Bay 11-7082 and Bay 11-7085. Down-regulated by the drug Imatinib.
Phosphorylation at Ser-44 occurs in a growth- and stress-dependent fashion in skin keratinocytes, it has no effect on filament organization.
Type I keratin involved in the formation and maintenance of various skin appendages, specifically in determining shape and orientation of hair (By similarity). Required for the correct growth of hair follicles, in particular for the persistence of the anagen (growth) state (By similarity). Modulates the function of TNF-alpha in the specific context of hair cycling. Regulates protein synthesis and epithelial cell growth through binding to the adapter protein SFN and by stimulating Akt/mTOR pathway (By similarity). Involved in tissue repair. May be a marker of basal cell differentiation in complex epithelia and therefore indicative of a certain type of epithelial 'stem cells'. Acts as a promoter of epithelial proliferation by acting a regulator of immune response in skin: promotes Th1/Th17-dominated immune environment contributing to the development of basaloid skin tumors (By similarity). May act as an autoantigen in the immunopathogenesis of psoriasis, with certain peptide regions being a major target for autoreactive T-cells and hence causing their proliferation.
May play a role in epithelioid conversion of fibroblasts.
Heterodimer with NSUN4; this interaction may be required for NSUN4 recruitment to the mitochondrial large ribosomal subunit.
Regulator of mitochondrial ribosome biogenesis and translation. Binds to mitochondrial ribosomal RNAs 16S, 12S and 7S and targets NSUN4 RNA methyltransferase to the mitochondrial large ribosomal subunit (39S).
The MTERF repeats form a half-donut shaped, right-handed superhelix, where the concave side displays a positively charged path for nucleic acid interaction.
The mature mitochondrial protein exists in 2 forms differing at the level of their N-terminus, one is starting at residue 43 and the other at residue 48.
Defects in FBXO32 are associated with susceptibility to dilated cardiomyopathy (DCM). A disorder characterized by ventricular and impaired systolic function, resulting in heart failure and arrhythmia. Patient are at risk of premature death.
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO32) formed of CUL1, SKP1, RBX1 and FBXO32.
Specifically expressed in cardiac and skeletal muscle.
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Probably recognizes and binds to phosphorylated target proteins during skeletal muscle atrophy. Recognizes TERF1.
Belongs to the methyltransferase superfamily. Trimethylguanosine synthase family.
Catalyzes the 2 serial methylation steps for the conversion of the 7-monomethylguanosine (m(7)G) caps of snRNAs and snoRNAs to a 2,2,7-trimethylguanosine (m(2,2,7)G) cap structure. The enzyme is specific for guanine, and N7 methylation must precede N2 methylation. Hypermethylation of the m7G cap of U snRNAs leads to their concentration in nuclear foci, their colocalization with coilin and the formation of canonical Cajal bodies (CBs). Plays a role in transcriptional regulation.
May form homooligomers. Interacts with CREBBP/CBP, EED/WAIT1, EP300/P300, NCOA6/PRIP, PPARBP/PBP and SMN.
Ubiquitously expressed. High expression in heart, skeletal muscle, kidney, liver and placenta.
Forms homooligomers, but does not form complexes with the other coronins. Interacts with Arp2/3 complex components, including ACTR2, ARPC1B and ARPC2. Binds actin (By similarity).
Phosphorylation by PKC on Ser-2 regulates the interaction with the Arp2/3 complex and cell motility in fibroblasts. Phosphorylation does not seem to affect subcellular location.
Regulates leading edge dynamics and cell motility in fibroblasts. May be involved in cytokinesis and signal transduction (By similarity).
Associates with IL12RB1 to form the interleukin-23 receptor. Binds IL23 and mediates T-cells, NK cells and possibly certain macrophage/myeloid cells stimulation probably through activation of the Jak-Stat signaling cascade. IL23 functions in innate and adaptive immunity and may participate in acute response to infection in peripheral tissues. IL23 may be responsible for autoimmune inflammatory diseases and be important for tumorigenesis.
Expressed by monocytes, Th1, Th0, NK and dendritic cells. Isoform 1 is specifically expressed in NK cells.
Heterodimer with IL12RB1. In presence of IL23, the heterodimer forms the IL23 receptor. Interacts with JAK2 and in presence of IL23 with STAT3.
Produced by translation in an alternate frame of the cDNA encoding isoform 2.
Produced by translation in an alternate frame of the cDNA encoding isoform 3.
Produced by translation in an alternate frame of the cDNA encoding isoform 4.
Produced by translation in an alternate frame of the cDNA encoding isoform 5.
Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B) and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific (Probable). Component of the BAF complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C. In muscle cells, the BAF complex also contains DPF3 (PubMed:18765789). Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin (By similarity). May be a component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin (PubMed:22952240, PubMed:26601204). Interacts with SMARCA4/BRG1/BAF190A (PubMed:14701856). Component of SWI/SNF (GBAF) subcomplex, which includes at least BICRA or BICRAL (mutually exclusive), BRD9, SS18, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, SMARCC1/BAF155, and SMARCD1/BAF60A (PubMed:29374058). The precise distribution of the related SMARCD1, SMARCD2 and SMARCD3 proteins among these and other SWI/SNF nucleosome-remodeling complexes is not fully known. May allow recruitment of SWI/SNF containing complexes specifically to promoters where these factors are located. Also interacts with several nuclear receptors including PPARG/NR1C3, RXRA/NR1F1, ESR1, NR5A1, NR5A2/LRH1 and other transcriptional activators including the HLH protein SREBF1/SREBP1 and the homeobox protein PBX1 (PubMed:14701856). Interacts with PRDM1/BLIMP1 (PubMed:32417234).
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Stimulates nuclear receptor mediated transcription. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity).
Isoform 2 and isoform 1 are expressed in brain, heart, kidney, placenta, prostate, salivary gland, spleen, testis, thyroid, trachea and uterus. Isoform 1 is also expressed in skeletal muscle and adipose tissue.
Interacts (via COMM domain) with COMMD1 (via COMM domain). Interacts with RELA, RELB, NFKB1/p105, NFKB2/p100. Interacts with CCDC22, CCDC93, SCNN1B, CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL7.
NADH-dependent oxidoreductase which catalyzes the oxidation of all-trans-retinol to all-trans-retinal. Plays a role in the regulation of cardiac and skeletal muscle metabolic functions. Maintains Ca(2+) intracellular homeostasis by repressing Ca(2+) release from the sarcoplasmic reticulum (SR) in myotubes, possibly through local alternations in NAD/NADH or retinol/retinal. Also plays a role in Ca(2+) homeostasis by controlling Ca(2+) overload in the cytosol and the SR in myotubes. Involved in glucose uptake into skeletal muscles and muscle performance by activating PI3K and mTORC2-mediated AKT1 phosphorylation signaling pathways, possibly through the action of its downstream catalytic product all-trans-retinoic acid.
The N-terminus region encompasses a short hydrophobic sequence bound to the sarcoplasmic reticulum membrane, whereas the C-terminus catalytic domain faces the myoplasm.
Associates with a SMAD7-transcriptional complex. Interacts with SNW1 and TOR1AIP1 (By similarity). According to PubMed:17592128, does not associate with known Na,K-ATPase alpha-subunits.
Highly expressed in skeletal muscle and at a lower level in heart.
May act as a transcriptional coregulator during muscle development through its interaction with SNW1. Has lost its ancestral function as a Na,K-ATPase beta-subunit.
Fructosamine-3-kinase involved in protein deglycation by mediating phosphorylation of fructoselysine residues on glycated proteins, to generate fructoselysine-3 phosphate (PubMed:11016445, PubMed:11522682, PubMed:11975663). Fructoselysine-3 phosphate adducts are unstable and decompose under physiological conditions (PubMed:11522682, PubMed:11975663). Involved in intracellular deglycation in erythrocytes (PubMed:11975663). Involved in the response to oxidative stress by mediating deglycation of NFE2L2/NRF2, glycation impairing NFE2L2/NRF2 function (By similarity). Also able to phosphorylate psicosamines and ribulosamines (PubMed:14633848).
Widely expressed (PubMed:11522682). Expressed in erythrocytes (PubMed:11016445).
Essential for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase (PubMed:23125284). Acts as a chaperone in the early steps of cytochrome c oxidase subunit II (MT-CO2/COX2) maturation, stabilizing the newly synthesized protein and presenting it to metallochaperones SCO1/2 which in turn facilitates the incorporation of the mature MT-CO2/COX2 into the assembling CIV holoenzyme (PubMed:24403053).
Found in a complex with TMEM177, COA6, MT-CO2/COX2, COX18, SCO1 and SCO2. Interacts with SCO1, SCO2 and COA6 in a MT-CO2/COX2- and COX18-dependent manner (PubMed:29154948, PubMed:24403053, PubMed:28330871). Interacts with COX18 in a MT-CO2/COX2-dependent manner (PubMed:28330871). Interacts with MT-CO2/COX2 (PubMed:29154948, PubMed:24403053, PubMed:23125284, PubMed:28330871). Interacts with TMEM177 (PubMed:29154948).
Part of a ternary complex containing STX5A, NSFL1C and VCP. NSFL1C forms a homotrimer that binds to one end of a VCP homohexamer. The complex binds to membranes enriched in phosphatidylethanolamine-containing lipids and promotes Golgi membrane fusion. Interaction with VCIP135 leads to dissociation of the complex via ATP hydrolysis by VCP. Binds ubiquitin and mono-ubiquitinated proteins via its N-terminal UBA-like domain when bound to VCP (By similarity).
Part of a ternary complex containing STX5A, NSFL1C and VCP. NSFL1C forms a homotrimer that binds to one end of a VCP homohexamer. The complex binds to membranes enriched in phosphatidylethanolamine-containing lipids and promotes Golgi membrane fusion. Interaction with VCIP135 leads to dissociation of the complex via ATP hydrolysis by VCP. Binds ubiquitin and mono-ubiquitinated proteins via its N-terminal UBA-like domain when bound to VCP.
Phosphorylated during mitosis. Phosphorylation inhibits interaction with Golgi membranes and is required for the fragmentation of the Golgi stacks during mitosis (By similarity).
Reduces the ATPase activity of VCP (By similarity). Necessary for the fragmentation of Golgi stacks during mitosis and for VCP-mediated reassembly of Golgi stacks after mitosis (By similarity). May play a role in VCP-mediated formation of transitional endoplasmic reticulum (tER) (By similarity). Inhibits the activity of CTSL (in vitro) (PubMed:15498563). Together with UBXN2B/p37, regulates the centrosomal levels of kinase AURKA/Aurora A during mitotic progression by promoting AURKA removal from centrosomes in prophase (PubMed:23649807). Also, regulates spindle orientation during mitosis (PubMed:23649807).
Phosphorylated and activated by MTOR. Phosphorylation by PKC within the NLS in response to mitogenic stimuli causes cytoplasmic retention.
Phosphorylates specifically ribosomal protein S6 (PubMed:29750193). Seems to act downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression in an alternative pathway regulated by MEAK7 (PubMed:29750193).
A chromosomal aberration involving GOPC is found in a glioblastoma multiforme sample. An intra-chromosomal deletion del(6)(q21q21) is responsible for the formation of GOPC-ROS1 chimeric protein which has a constitutive receptor tyrosine kinase activity.
Homooligomer (By similarity). Interacts with FZD5 (By similarity). Interacts with FZD8 (PubMed:16882988). Interacts with GRID2 and BECN1 (By similarity). Interacts with CSPG5 (By similarity). Interacts with CLCN3 (By similarity). Interacts with STX6 (PubMed:11384996). Interacts with CFTR (PubMed:11707463). Interacts with ASIC3 (PubMed:15317815). Interacts with GOLGA3 (PubMed:15951434). Interacts with NLGN1 (PubMed:16882988). Interacts with RHOQ (PubMed:15546864). Interacts with MARCHF2; the interaction leads to CFTR ubiquitination and degradation (PubMed:23818989). Interacts with ADRB1 (PubMed:15358775). May interact with CACNG2 (By similarity). Interacts with CCDC62 (By similarity).
Plays a role in intracellular protein trafficking and degradation (PubMed:11707463, PubMed:14570915, PubMed:15358775). May regulate CFTR chloride currents and acid-induced ASIC3 currents by modulating cell surface expression of both channels (By similarity). May also regulate the intracellular trafficking of the ADR1B receptor (PubMed:15358775). May play a role in autophagy (By similarity). Together with MARCHF2 mediates the ubiquitination and lysosomal degradation of CFTR (PubMed:23818989). Overexpression results in CFTR intracellular retention and lysosomaldegradation in the lysosomes (PubMed:11707463, PubMed:14570915).
The PDZ domain mediates interactions with FZD5, FZD8, ASIC3, GRID2, CLCN3 (By similarity). Mediates also interaction with CFTR and ADRB1.
The coiled-coil region probably mediates association to membranes, targeting to the Golgi, and interactions with GOLGA3, and STX6. May also mediate interaction with RHOQ (By similarity).
Acts as a regulator of the tubular endoplasmic reticulum (ER) network by modulating intracellular calcium homeostasis. Mechanistically, stimulates PKD2 calcium-dependent activity (By similarity). Suppresses the RTN3/4-induced formation of the ER tubules (PubMed:25612671). Positively regulates PERK-mediated and IRE1-mediated unfolded protein response signaling (PubMed:26268696). Plays an essential role in VEGF-mediated release of Ca(2+) from ER stores during angiogenesis (PubMed:30760708). Also plays a role in the modulation of innate immune signaling through the cGAS-STING pathway by interacting with RNF26 (PubMed:32614325). Participates in lipid metabolism by acting as a downstream effector of the pyruvate kinase/PKM. Forms a complex with RNF5 to facilitate polyubiquitination and subsequent degradation of SCAP on the ER membrane (PubMed:34487377).
Interacts with EIF2AK3 (PubMed:26268696). Interacts with ARL6IP1, isoform RTN1-A of RTN1, isoform RTN2-B of RTN2, isoform 3 of RTN3 and isoform 3 of RTN4 (PubMed:25612671). Interacts with RNF5 (PubMed:34487377). Interacts with RNF26 (PubMed:32614325). Interacts with PKD2 (By similarity).
Prostate cancer and several cancer cell lines (at protein level). Widely expressed. Expressed at higher levels in endocrine-resistant breast cancer cells as compared to endocrine-sensitive breast cancer cells. Expressed at higher levels in early recurrence breast cancer tissues as compared to non-recurrent breast tumors.
Interacts with DDB1, DDX5, DDX6, DHX30, DHX36, DDX47, DICER1, AGO2, ELAVL1, HNRNPF, IGF2BP1, ILF3, IMP8, MATR3, MOV10, PABPC1, PRMT5, RBM4, SART3, TNRC6B, UPF1 and YBX1. Associates with polysomes and messenger ribonucleoproteins (mNRPs). Interacts with LIMD1, WTIP and AJUBA. Interacts with APOBEC3F, APOBEC3G and APOBEC3H.
Lacks RNA cleavage activity due to the absence of the conserved His at position 805, but also because it binds the RNA in a subtly different manner that precludes efficient cleavage.
Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) or short interfering RNAs (siRNAs), and represses the translation of mRNAs which are complementary to them. Lacks endonuclease activity and does not appear to cleave target mRNAs. Also required for transcriptional gene silencing (TGS) of promoter regions which are complementary to bound short antigene RNAs (agRNAs).
Ubiquitinated on surface-exposed lysines by a SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 during target-directed microRNA degradation (TDMD), a process that mediates degradation of microRNAs (miRNAs). Ubiquitination by the SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 leads to its subsequent degradation, thereby exposing miRNAs for degradation. ZSWIM8 recognizes and binds AGO1 when it is engaged with a TDMD target.
Involved in the packaging of pre-mRNA into hnRNP particles, transport of poly(A) mRNA from the nucleus to the cytoplasm and may modulate splice site selection.
Belongs to the methyltransferase superfamily. PrmA family.
Catalytic subunit of a heterodimer with TRMT112, which specifically methylates the 6th position of adenine in position 1832 of 18S rRNA (PubMed:31328227, PubMed:32217665, PubMed:33357433, PubMed:33428944, PubMed:35033535). N6-methylation of adenine(1832) in 18S rRNA resides in the decoding center of 18S rRNA and is required for translation and embryonic stem cells (ESCs) pluripotency and differentiation (PubMed:33357433).
Expressed from very early development (8 post-conceptual weeks) and expression persists through adulthood in multiple substructures of the brain, including the cerebellar cortex, hippocampus, and striatum.
Heterodimer; heterodimerizes with TRMT112.
rRNA N6-adenosine-methyltransferase activity is inhibited by zinc.
Facilitates DNA repair, cell cycle progression, and cell proliferation through its interaction with CIAO2B.
Interacts with CIAO2B; the interaction is direct (PubMed:30742009). Interacts with MMS19; the interaction is indirect (PubMed:30742009).
Binds fibroblast growth factor and E-selectin (cell-adhesion lectin on endothelial cells mediating the binding of neutrophils).
Expressed both in adult and fetal tissues.
Fucosylation is essential for binding to E-selectin.
Widely expressed. Highest levels in pancreas, skeletal muscle, placenta, heart, testis and ovary. Also found in the kidney, liver, lung and brain.
Inhibited by 1,2,3-triazole urea covalent inhibitors KT172, DH376 and DO34 (PubMed:26668358). Inhibited by p-hydroxy-mercuri-benzoate and HgCl(2), but not to PMSF. Also inhibited by RHC80267 (PubMed:14610053). Diacylglycerol lipase activity is inhibited by the phosphorylation of Ser-782 and Ser-808 by CAMK2A (PubMed:23502535).
Interacts (via C-terminal) with CAMK2A; leading to the phosphorylation and inhibition of DAGLA enzymatic activity (PubMed:23502535). Interacts (via PPXXF motif) with HOMER1 and HOMER2; this interaction is required for DAGLA membrane localization (By similarity).
Phosphorylated at Ser-782 and Ser-808 by CAMK2A; phosphorylation by CAMK2A inhibits diacylglycerol lipase activity.
Serine hydrolase that hydrolyzes arachidonic acid-esterified diacylglycerols (DAGs) to produce the principal endocannabinoid, 2-arachidonoylglycerol (2-AG) (PubMed:14610053, PubMed:26668358, PubMed:23502535). Preferentially hydrolyzes sn-1 fatty acids from diacylglycerols (DAG) that contain arachidonic acid (AA) esterified at the sn-2 position to biosynthesize 2-AG (PubMed:14610053, PubMed:26668358, PubMed:23502535). Has negligible activity against other lipids including monoacylglycerols and phospholipids (PubMed:14610053). Plays a key role in regulating 2-AG signaling in the central nervous system (CNS). Regulates 2-AG involved in retrograde suppression at central synapses. Supports axonal growth during development and adult neurogenesis. Plays a role for eCB signaling in the physiological regulation of anxiety and depressive behaviors. Regulates also neuroinflammatory responses in the brain, in particular, LPS-induced microglial activation (By similarity).
The disease may be caused by variants affecting the gene represented in this entry. A copy number variation consisting of a 260-kb duplication at chromosome 11q12.2-12.3 is responsible for SCA20. The critical gene within the duplicated segment may be DAGLA.
Belongs to the potassium channel KCNN family. KCa2.3/KCNN3 subfamily.
Do not produce functional channels, but selectively suppresses endogenous SK3 currents, in a dominant-negative fashion. This dominant inhibitory effect extends to other members of the SK subfamily. Widely distributed in human tissues and is present at 20-60% of SK3 in the brain.
Forms a voltage-independent potassium channel activated by intracellular calcium (PubMed:31155282, PubMed:20562108). Activation is followed by membrane hyperpolarization (By similarity). Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization (By similarity).
Heterooligomer. The complex is composed of 4 channel subunits each of which binds to a calmodulin subunit which regulates the channel activity through calcium-binding (By similarity). Interacts with CALM1 (PubMed:31155282).
Inhibited by bee venom neurotoxin apamin.
The second poly-Gln region of KCNN3 is highly polymorphic and the number of Gln varies from 12 to 28 in the population.
Seems to promote the survival of visceral and proprioceptive sensory neurons.
Variant Glu-76 (frequently reported as Glu-63) was thought to be associated with severe forms of schizophrenia. This does not seem to be the case.
Belongs to the Dus family. Dus3 subfamily.
Catalyzes the synthesis of dihydrouridine, a modified base, in various RNAs, such as tRNAs, mRNAs and some long non-coding RNAs (lncRNAs) (PubMed:34556860). Mainly modifies the uridine in position 47 (U47) in the D-loop of most cytoplasmic tRNAs (PubMed:34556860). Also able to mediate the formation of dihydrouridine in some mRNAs, thereby regulating their translation (PubMed:34556860).
Component of the RNA exosome complex. The catalytically inactive RNA exosome core (Exo-9) complex is believed to associate with catalytic subunits EXOSC10, and DIS3 or DIS3L in cytoplasmic- and nuclear-specific RNA exosome complex forms.
Putative cytoplasm-specific catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA.
May be involved in protection from oxidative damage.
E3 ubiquitin-protein ligase that may mediate ubiquitination of MHC-I and CD4, and promote their subsequent endocytosis and sorting to lysosomes via multivesicular bodies. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates.
Ubiquitously expressed at low levels. Highest levels are found in pancreas and liver.
Binds 2 divalent metal cations per subunit (PubMed:17727341). Site 2 has a preference for magnesium and/or manganese ions (By similarity).
Expressed in various tissues but not in cells of the immune system.
Part of a complex containing AKAP5, ADCY5, ADCY6 and PKD2.
Expressed abundantly in ovary and testis, and weakly in all other tissues tested.
Involved in endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins, possibly by tethering VCP to the endoplasmic reticulum membrane. May play a role in reproduction.
Forms homodimers and elongated homopolymers (By similarity). Interacts with RPGR (PubMed:10958648, PubMed:10958647, PubMed:24981858). Interacts with NPHP4 (PubMed:16339905, PubMed:21224891). Interacts with NEK4 (PubMed:21685204). Interacts with SPATA7 (PubMed:25398945). Interacts with CEP290/NPHP6; mediating the association between RPGR and CEP290/NPHP6 (PubMed:20200501).
Heterozygous non-synonymous variants of RPGRIP1 may cause or increase the susceptibility to various forms of glaucoma, a genetically heterogeneous disorder. It is the second cause of blindness worldwide owing to the progressive degeneration of retinal ganglion neurons (PubMed:21224891).
May function as scaffolding protein. Required for normal location of RPGR at the connecting cilium of photoreceptor cells. Required for normal disk morphogenesis and disk organization in the outer segment of photoreceptor cells and for survival of photoreceptor cells.
Strong expression in retina, with weaker expression in testis. Expressed in other neurons such as amacrine cells. Colocalizes with RGPR in the outer segment of rod photoreceptors and cone outer segments.
The C2 domain does not bind calcium ions, and does not bind phosphoinositides.
Heterotetramer of two PDHA1 and two PDHB subunits (PubMed:12651851, PubMed:17474719, PubMed:19081061). The heterotetramer interacts with DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules (PubMed:14638692). Interacts with DLAT (PubMed:20160912).
The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2.
Detected in fetal cochlea, and at low levels in placenta and testis.
Interacts with TOMT (By similarity). The interaction of TMC1 and TMC2 with TOMT is required for the transportation of TMC1/2 into the stereocilia of hair cells. Interacts (via N-terminus) with both isoforms CD1 and CD3 of PCDH15 (By similarity). Interacts with CIB2 (PubMed:34089643). Interacts with CIB3 (By similarity).
Probable ion channel required for the normal function of cochlear hair cells.
(Microbial infection) May play a role in limiting virus spread by inhibiting proliferation of virus-infected cells. Upon infection with diverse DNA and RNA viruses, inhibits cell-cycle progression by binding to promoters and activating transcription of genes encoding cell-cycle inhibitors, such as p21/CDKN1A (PubMed:21767813).
Expressed in several tissues, with highest levels in pancreas and prostate. Expressed at relatively lower levels in brain.
Interacts with SMAD4, the interaction takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator to induce the expression of genes involved in assembly of collagen extracellular matrix.
Precursor of the transcription factor form (Processed cyclic AMP-responsive element-binding protein 3-like protein 1), which is embedded in the endoplasmic reticulum membrane with N-terminal DNA-binding and transcription activation domains oriented toward the cytosolic face of the membrane (PubMed:12054625, PubMed:16417584, PubMed:25310401). In response to ER stress or DNA damage, transported to the Golgi, where it is cleaved in a site-specific manner by resident proteases S1P/MBTPS1 and S2P/MBTPS2. The released N-terminal cytosolic domain is translocated to the nucleus where it activates transcription of specific target genes involved in the cell-cycle progression inhibition (PubMed:12054625, PubMed:21767813, PubMed:25310401).
The disease may be caused by variants affecting the gene represented in this entry. OI16 affected patients show a genomic deletion encompassing CREB3L1 and the first exon of DGKZ. The absence of this exon does not affect all DGKZ isoforms, some are still produced at normal level. It cannot be ruled out that DGKZ could contribute to the phenotype, but in view of its role in bone formation, CREB3L1 is a strong OI16-causing candidate (PubMed:24079343). This hypothesis is corroborated by the observation of CREB3L1 knockout mice which exhibit features reminiscent of severe human osteogenesis imperfecta.
Transcription factor involved in cell type specific DNA damage and unfolded protein response (UPR). Binds the DNA consensus sequence 5'-GTGXGCXGC-3' (PubMed:21767813). Plays a critical role in bone formation through the transcription of COL1A1, and possibly COL1A2, and the secretion of bone matrix proteins. Directly binds to the UPR element (UPRE)-like sequence in an osteoblast-specific COL1A1 promoter region and induces its transcription. Does not regulate COL1A1 in other tissues, such as skin (By similarity). Required to protect astrocytes from ER stress-induced cell death. In astrocytes, binds to the cAMP response element (CRE) of the BiP/HSPA5 promoter and participate in its transcriptional activation (By similarity). In astrocytes and osteoblasts, upon DNA damage, inhibits cell-cycle progression after G2/M phase by binding to promoters and activating transcription of genes encoding cell-cycle inhibitors, such as p21/CDKN1A (By similarity). Required for TGFB1 to activate genes involved in the assembly of collagen extracellular matrix (PubMed:25310401).
Ubiquitinated by HRD1/SYVN1; undergoes 'Lys-48'-linked ubiquitination, followed by rapid proteasomal degradation under normal conditions. Upon ER stress, SYVN1 E3 ubiquitin-protein ligase dissociates from its substrate, ubiquitination does not occur and CREB3L1 is stabilized.
Upon ER stress or DNA damage, translocated to the Golgi apparatus, where it is processed by regulated intramembrane proteolysis (RIP) to release the cytosol-facing N-terminal transcription factor domain. The cleavage is performed sequentially by site-1 and site-2 proteases (S1P/MBTPS1 and S2P/MBTPS2) (PubMed:16417584, PubMed:21767813, PubMed:25310401, PubMed:27499293). RIP is induced by TGFB1 and ceramide (PubMed:25310401, PubMed:27499293).
E3 ubiquitin-protein ligase involved in regulation of the Notch pathway through influencing the stability and activity of several Notch ligands.
Highest expression in brain, prostate and small intestine. In the brain the levels are higher in fetal than in adult stage. In the adult brain the highest levels are detected in the olfactory system, cerebellar cortex, optic nerve and the frontal lobe.
COPII is composed of at least five proteins: the Sec23/24 complex, the Sec13/31 complex and SAR1 (PubMed:10075675, PubMed:17499046). Interacts with STING1; promoting STING1 translocation to COPII vesicles in a STEEP1-dependent manner (PubMed:32690950). Interacts with RNF139 (PubMed:19706601). Interacts with TMED2 and TMED10 (PubMed:20427317). Interacts with CNIH4 (PubMed:24405750).
Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules for their transport to the Golgi complex (PubMed:17499046, PubMed:20427317, PubMed:18843296). Plays a central role in cargo selection within the COPII complex and together with SEC24A may have a different specificity compared to SEC24C and SEC24D. May package preferentially cargos with cytoplasmic DxE or LxxLE motifs and may also recognize conformational epitopes (PubMed:17499046, PubMed:18843296).
Required for the assembly of F-actin structures, such as stress fibers. Depends on the Rho-ROCK cascade for its activity. Contributes to the coordination of microtubules with actin fibers and plays a role in cell elongation. Acts synergistically with ROCK1 to promote SRC-dependent non-apoptotic plasma membrane blebbing.
Self-associates via the FH2 domain. Binds to F-actin via its N-terminus. Binds to the cytoplasmic domain of CD21 via its C-terminus. Interacts with ROCK1 in a Src-dependent manner.
Component of the NF-E2 complex essential for regulating erythroid and megakaryocytic maturation and differentiation. Binds to the hypersensitive site 2 (HS2) of the beta-globin control region (LCR). This subunit (NFE2) recognizes the TCAT/C sequence of the AP-1-like core palindrome present in a number of erythroid and megakaryocytic gene promoters. Requires MAFK or other small MAF proteins for binding to the NF-E2 motif. May play a role in all aspects of hemoglobin production from globin and heme synthesis to procurement of iron.
Expressed in hematopoietic cells and also in colon and testis.
Homodimer; can bind DNA as a homodimer. Erythroid transcription activator nuclear factor erythroid-derived 2 (NF-E2), composed of a heterodimer of NFE2 and MAFK, possesses transactivation activity on beta-globin. Also forms high affinity heterodimer with MAFG; the interaction promotes erythropoiesis. Interacts (via the PXY motif 1) with ITCH (via the WW 1 domain); the interaction promotes 'Lys63'-linked ubiquitination of NFE2, translocates it to the cytoplasm and inhibits its transactivation activity. Interacts with KMT2D/MLL2; the interaction promotes transactivation of the beta-globin locus (By similarity). Interacts with MAPK8 (phosphorylated form); the interaction leads to phosphorylation of NFE2 in undifferentiated cells (By similarity).
Phosphorylated on serine residues. In undifferentiated erythrocytes, phosphorylated by MAPK8 which then leads to ubiquitination and protein degradation.
Sumoylated. Sumoylation is required for translocation to nuclear bodies PODs, anchoring to the gene loci, and transactivation of the beta-globin gene.
The PXY motifs are required for binding WW domains. PXY1 is required to promote transactivation of beta-globin and for hyperacetylation of histone H3, but not for binding to the HS2 promoter site (By similarity).
Ubiquitinated mainly by 'Lys63'-linked ubiquitin. Polyubiquitination with 'Lys63'-linked ubiquitin by ITCH retains NFE2 in the cytoplasm preventing its transactivation activity. In undifferentiated erythrocyte, ubiquitinated after MAPK8-mediatd phosphorylation leading to protein degradation (By similarity).
Interacts with NTSR1 (PubMed:23140271). Interacts with SORT1 (PubMed:19122660). Interacts with SORL1 (PubMed:11294867).
Neurotensin is cleaved and degraded by Angiotensin-converting enzyme (ACE) and neprilysin (MME).
Neurotensin may play an endocrine or paracrine role in the regulation of fat metabolism. It causes contraction of smooth muscle.
Interacts with MBD1, SETDB1 and SP1. Probably forms a complex with SETDB1 and MBD1.
Recruiter that couples transcriptional factors to general transcription apparatus and thereby modulates transcription regulation and chromatin formation. Can both act as an activator or a repressor depending on the context. Mediates MBD1-dependent transcriptional repression, probably by recruiting complexes containing SETDB1. The complex formed with MBD1 and SETDB1 represses transcription and probably couples DNA methylation and histone H3 'Lys-9' trimethylation (H3K9me3) activity (Probable).
Constitutively expressed in distinct types of epithelia such as those in oral mucosa, esophagus, papillae of tongue and hair follicle outer root sheath.
Heterodimer of a type I and a type II keratin. KRT6 isomers associate with KRT16 and/or KRT17.
There are at least six isoforms of human type II keratin-6 (K6).
Appears to be expressed in a wide range of tissues.
Binds to PIM1 (By similarity). Binds to ZNHIT4.
Is thought to be a target protein for the PIM1 kinase. May play some roles in B-cell proliferation in association with PIM1 (By similarity).
Acts as an assembly platform for Rho protein signaling complexes. Limits guanine nucleotide exchange activity of MCF2L toward RHOA, which results in an inhibition of both its transcriptional activation ability and its transforming activity. Does not inhibit activity of MCF2L toward CDC42, or activity of MCF2 toward either RHOA or CDC42 (By similarity). May be involved in cell cycle regulation.
Interacts with MCF2L. May interact with MCF2, ARHGEF1, BCR, VAV1 and FGD1, but not with TIAM1. Interacts with GTP-bound CDC42 and SRC (By similarity).
Heterodimer of an alpha and a beta subunit. The alpha subunit is composed of a heavy and a light chain linked by a disulfide bond. Alpha-IIb associates with beta-3. Directly interacts with RNF181. Interacts (via C-terminus cytoplasmic tail region) with CIB1; the interaction is direct and calcium-dependent. Interacts (via C-terminus cytoplasmic tail region) with CIB2, CIB3 and CIB4; the interactions are stabilized/increased in a calcium and magnesium-dependent manner. ITGA2B:ITGB3 interacts with PPIA/CYPA; the interaction is ROS and PPIase activity-dependent and is increased in the presence of thrombin (By similarity).
Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. It recognizes the sequence R-G-D in a wide array of ligands. It recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha-IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial cell surface.
Isoform 1 and isoform 2 are expressed in platelets and megakaryocytes, but not in reticulocytes. Not detected in Jurkat, nor in U937 cell lines (PubMed:2351656). Isoform 3 is expressed in prostate adenocarcinoma, as well as in several erythroleukemia, prostate adenocarcinoma and melanoma cell lines, including PC-3, DU-145, HEL, WM983A, WM983B and WM35. Not detected in platelets, nor in normal prostate (at protein level) (PubMed:9809974).
Position 874 is associated with platelet-specific alloantigen HPA-3/BAK/LEK. HPA-3A/BAK(A)/LEK(A) has Ile-874 and HPA-3B/BAK(B)/LEK(B) has Ser-874. HPA-3B is involved in neonatal alloimmune thrombocytopenia (NAIT or NATP).
(Microbial infection) Interacts with HIV-1 Envelope polyprotein gp160 and protein Vpu (PubMed:2214026, PubMed:16331979, PubMed:9641677, PubMed:7604010).
(Microbial infection) Interacts with Human Herpes virus 7 surface proteins.
(Microbial infection) Primary receptor for human immunodeficiency virus-1 (HIV-1) (PubMed:2214026, PubMed:16331979, PubMed:9641677, PubMed:12089508). Down-regulated by HIV-1 Vpu (PubMed:17346169). Acts as a receptor for Human Herpes virus 7/HHV-7 (PubMed:7909607).
Forms disulfide-linked homodimers at the cell surface. Interacts with LCK (PubMed:16888650). Interacts with PTK2/FAK1 (PubMed:18078954). Binds to P4HB/PDI. Interacts with IL16; this interaction induces a CD4-dependent signaling in lymphocytes (PubMed:1673145). Interacts (via Ig-like V-type domain) with MHCII alpha chain (via alpha-2 domain) and beta chain (via beta-2 domain); this interaction increases the affinity of TCR for peptide-MHCII. CD4 oligomerization via Ig-like C2-type 2 and 3 domains appears to be required for stable binding to MHCII and adhesion between T cells and APCs (PubMed:27114505, PubMed:21900604, PubMed:7604010).
Highly expressed in T-helper cells. The presence of CD4 is a hallmark of T-helper cells which are specialized in the activation and growth of cytotoxic T-cells, regulation of B cells, or activation of phagocytes. CD4 is also present in other immune cells such as macrophages, dendritic cells or NK cells.
Integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses against both external and internal offenses. In T-cells, functions primarily as a coreceptor for MHC class II molecule:peptide complex. The antigens presented by class II peptides are derived from extracellular proteins while class I peptides are derived from cytosolic proteins. Interacts simultaneously with the T-cell receptor (TCR) and the MHC class II presented by antigen presenting cells (APCs). In turn, recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. LCK then initiates different intracellular signaling pathways by phosphorylating various substrates ultimately leading to lymphokine production, motility, adhesion and activation of T-helper cells. In other cells such as macrophages or NK cells, plays a role in differentiation/activation, cytokine expression and cell migration in a TCR/LCK-independent pathway. Participates in the development of T-helper cells in the thymus and triggers the differentiation of monocytes into functional mature macrophages.
Palmitoylation and association with LCK contribute to the enrichment of CD4 in lipid rafts.
Phosphorylated by PKC; phosphorylation at Ser-433 plays an important role for CD4 internalization.
The Ig-like V-type domain mediates the interaction with MHCII.
The OKT monoclonal antibodies are widely used for the analysis of human peripheral blood T-lymphocytes. OKT4 reacts with T-helper/inducer lymphocytes. The OKT4 epitope of the CD4 cell-surface protein is polymorphic in white, black, and Japanese populations. The variable phenotypic expression is due a CD4 polymorphism. OKT4 positive individuals carry Arg-265 and OKT4 negative individuals carry Trp-265 [MIM:613949].
Metalloprotease with an atypical HExxxH zinc-binding motif instead of HExxH, which interrupts the active site-containing helix without affecting the integrity of the catalytic site arrangement.
The N-terminal disordered region enhances its anchoring on microtubules, while dampening processivity on the polymerized substrate.
Tyrosine carboxypeptidase that removes the C-terminal tyrosine residue of alpha-tubulin, thereby regulating microtubule dynamics and function (PubMed:35482892). Also able to remove the C-terminal phenylalanine residue of alpha-tubulin TUBA8 (PubMed:35482892). Recognizes adjacent tubulin dimers along the same protofilament (PubMed:35482892).
Adenylyl cyclase that catalyzes the formation of the signaling molecule cAMP in response to activation of G protein-coupled receptors (PubMed:9628827, PubMed:12972952, PubMed:15879435, PubMed:10987815). Contributes to signaling cascades activated by CRH (corticotropin-releasing factor), corticosteroids and beta-adrenergic receptors (PubMed:9628827).
Detected in skeletal muscle, pancreas, lung, heart, kidney, liver, brain and placenta (PubMed:9628827, PubMed:10987815). Expressed in multiple cells of the lung, with expression highest in airway smooth muscle (PubMed:12972952).
Insensitive to calcium/calmodulin, forskolin and somatostatin. Stimulated by beta-adrenergic receptor activation (PubMed:9628827). Activity is down-regulated by calcium/calcineurin (PubMed:10987815).
By androgens and, in the LNCaP cell line, by estrogens. Androgenic control may be lost in prostate cancer cells during tumor progression from an androgen-dependent to an androgen-independent phase.
Highly expressed in the prostate and, at a lower level, in the testis.
Interacts with serum response factor (SRF) (By similarity). Interacts with SPDEF (PubMed:11809674). Interacts with WDR77 (PubMed:12972618). Interacts with TOPORS which polyubiquitinates NKX3-1 and induces its proteasomal degradation (PubMed:18077445). Interacts with FEM1B (By similarity).
Transcription factor, which binds preferentially the consensus sequence 5'-TAAGT[AG]-3' and can behave as a transcriptional repressor. Plays an important role in normal prostate development, regulating proliferation of glandular epithelium and in the formation of ducts in prostate. Acts as a tumor suppressor controlling prostate carcinogenesis, as shown by the ability to inhibit proliferation and invasion activities of PC-3 prostate cancer cells.
Ubiquitinated by TOPORS; monoubiquitinated at several residues and also polyubiquitinated on single residues.
Acts as a coactivator of transcriptional activity. Required to increase TGFB1/Smad-mediated transactivation. Acts through SMAD2, SMAD3 and SMAD4 to increase transcriptional activity. Increases phosphorylation of SMAD2 and SMAD3 on their C-terminal SSXS motif, possibly through recruitment of TGFBR1. Promotes the nuclear accumulation of SMAD2, SMAD3 and SMAD4 proteins (PubMed:26347403). Binds to poly(A) RNA (PubMed:17099224, PubMed:26347403).
Homodimer; each protein chain binds one RNA molecule via the external surface of the homodimer (PubMed:26347403). Interacts with SMAD2, SMAD3 and SMAD4; the interactions are direct (PubMed:17099224).
The RRM domain is necessary for interaction with SMAD4. Both the RRM domain and the C-terminus are required for TGFB1/Smad-mediated transactivation activity.
Ubiquitously expressed, at various levels depending on the isoform and the tissue.
Expressed in ocular tissues including retinal pigment epithelium, cornea, ciliary muscle and non-pigmented ciliary epithelium. Also expressed in optic nerve, cartilage, skin and lymph node.
GPATCH3 variants may be involved in the pathogenesis of congenital glaucoma, an ocular disease characterized by marked increase of intraocular pressure at birth or early childhood, large ocular globes (buphthalmos) and corneal edema. It results from developmental defects of the trabecular meshwork and anterior chamber angle of the eye that prevent adequate drainage of aqueous humor.
Interacts with mitochondrial MAVS; the interaction is markedly increased upon viral infection.
Involved in transcriptional regulation. It is able to activate transcription from the CXCR4 promoter and therefore it might control neural crest cell migration involved in ocular and craniofacial development (PubMed:28397860). Is a negative regulator of immune antiviral response, acting via down-regulation of RIG-I-like receptors signaling and inhibition of type I interferon production. The control mechanism involves interaction with mitochondrial MAVS and inhibition of MAVS assembly with downstream proteins implicated in antiviral response, such as TBK1 and TRAF6 (PubMed:28414768).
DNA-binding protein that accumulates at DNA double-strand breaks (DSBs) following DNA damage and promotes DNA resection and homologous recombination (PubMed:29042561). Serves as a sensor of DNA damage: binds DNA with a strong preference for DNA substrates that mimic structures generated at stalled replication forks, and anchors RBBP8/CtIP to DSB sites to promote DNA end resection and ensuing homologous recombination repair (PubMed:29042561). Inhibits non-homologous end joining (NHEJ) (PubMed:29042561). Required for the dynamic movement of AURKA at the centrosomes and spindle apparatus during the cell cycle (PubMed:20596670).
Expressed in heart, skeletal muscles, placenta and testis.
Interacts (via C-terminus) with AURKA (via C-terminus) (PubMed:20596670). Interacts (via N-terminus) with NIN; this interaction blocks NIN phosphorylation by both AURKA and GSK3B (PubMed:20596670). Identified in a complex with NIN and AURKA (PubMed:20596670). Interacts with RBBP8/CtIP (PubMed:29042561).
Constructs encoding portions of SNCA and SNCAIP co-transfected in mammalian cells promote cytosolic inclusions resembling the Lewy bodies of Parkinson disease. Coexpression of SNCA, SNCAIP, and PRKN result in the formation of Lewy body-like. ubiquitin-positive cytosolic inclusions. SNCAIP isoform 2 is particularly aggregation-prone. Familial mutations in PRKN disrupt the ubiquitination of SNCAIP and the formation of the ubiquitin-positive inclusions. These results provide a molecular basis for the ubiquitination of Lewy body-associated proteins and link PRKN and SNCA in a common pathogenic mechanism through their interaction with SNCAIP.
Detected in brain (at protein level). Widely expressed, with highest levels in brain, heart and placenta.
Homodimer (Probable). Heterodimer of isoform 1 and isoform 2 (Probable). Interacts with SIAH1, SIAH2, SNCA, RNF19A and PRKN. Isoform 2 has a strong tendency to form aggregates and can sequester isoform 1.
Isoform 2 inhibits the ubiquitin ligase activity of SIAH1 and inhibits proteasomal degradation of target proteins. Isoform 2 inhibits autoubiquitination and proteasomal degradation of SIAH1, and thereby increases cellular levels of SIAH. Isoform 2 modulates SNCA monoubiquitination by SIAH1.
Ubiquitinated; mediated by SIAH1, SIAH2 or RNF19A and leading to its subsequent proteasomal degradation. In the absence of proteasomal degradation, ubiquitinated SNCAIP accumulates in cytoplasmic inclusion bodies. Isoform 2 is subject to limited ubiquitination that does not lead to proteasomal degradation.
Transcriptional activator. Able to bind to two different type of DNA binding sites. More effective than isoform FOXJ2.S in transcriptional activation (PubMed:10777590, PubMed:10966786). Plays an important role in spermatogenesis, especially in spermatocyte meiosis (By similarity).
Belongs to the peptidase S26 family. IMP1 subfamily.
The BTB domain might play a role in targeting to acrosomal vesicles.
Malonate and methylmalonate semialdehyde dehydrogenase involved in the catabolism of valine, thymine, and compounds catabolized by way of beta-alanine, including uracil and cytidine.
Plays a role in valine and pyrimidine metabolism. Binds fatty acyl-CoA.
Expressed in liver, placenta, retina and retinal pigment epithelium.
Deubiquitinase that mediates deubiquitination of target proteins such as BECN1, MITF, SKP2 and USP10 and is involved in various processes such as autophagy, endoplasmic reticulum-associated degradation (ERAD), cell cycle progression or DNA damage response (PubMed:21571647, PubMed:32772043, PubMed:33592542). Component of a regulatory loop that controls autophagy and p53/TP53 levels: mediates deubiquitination of BECN1, a key regulator of autophagy, leading to stabilize the PIK3C3/VPS34-containing complexes. Alternatively, forms with NEDD4 a deubiquitination complex, which subsequently stabilizes VPS34 to promote autophagy (PubMed:32101753). Also deubiquitinates USP10, an essential regulator of p53/TP53 stability. In turn, PIK3C3/VPS34-containing complexes regulate USP13 stability, suggesting the existence of a regulatory system by which PIK3C3/VPS34-containing complexes regulate p53/TP53 protein levels via USP10 and USP13. Recruited by nuclear UFD1 and mediates deubiquitination of SKP2, thereby regulating endoplasmic reticulum-associated degradation (ERAD). Also regulates ERAD through the deubiquitination of UBL4A a component of the BAG6/BAT3 complex. Mediates stabilization of SIAH2 independently of deubiquitinase activity: binds ubiquitinated SIAH2 and acts by impairing SIAH2 autoubiquitination. Regulates the cell cycle progression by stabilizing cell cycle proteins such as SKP2 and AURKB (PubMed:32772043). In addition, plays an important role in maintaining genomic stability and in DNA replication checkpoint activation via regulation of RAP80 and TOPBP1 (PubMed:33592542). Deubiquitinates the multifunctional protein HMGB1 and subsequently drives its nucleocytoplasmic localization and its secretion (PubMed:36585612). Positively regulates type I and type II interferon signalings by deubiquitinating STAT1 but negatively regulates antiviral response by deubiquitinating STING1 (PubMed:23940278, PubMed:28534493).
Interacts with UFD1. Interacts (via UBA domains) with SIAH2 (when ubiquitinated). Interacts with BAG6; the interaction is direct and may mediate UBL4A deubiquitination (PubMed:24424410). Interacts (via UBA 2 domain) with AMFR; the interaction is direct (PubMed:24424410). Interacts with UBL4A; may be indirect via BAG6 (PubMed:24424410). Interacts with NEDD4 (PubMed:32101753).
Phosphorylated by AURKB at Ser-114; leading to stabilization of cell cycle proteins such as SKP2 and AURKB, but not MCL1.
Specifically inhibited by spautin-1 (specific and potent autophagy inhibitor-1), a derivative of MBCQ that binds to USP13 and inhibits deubiquitinase activity. Regulated by PIK3C3/VPS34-containing complexes. The weak deubiquitinase activity in vitro suggests the existence of some mechanism that activates the enzyme.
The UBA domains mediate binding to ubiquitin.
The UBP-type zinc finger has lost its ability to bind ubiquitin and USP13 is not activated by unanchored ubiquitin. Swapping with the UBP-type zinc finger from USP5 restores ability to bind unanchored ubiquitin and subsequent activation of the protein (PubMed:22216260).
Belongs to the G-protein coupled receptor 1 family. Neurotensin receptor subfamily. NTSR1 sub-subfamily.
Expressed in prostate (at protein level). Detected in colon and peripheral blood mononuclear cells. Detected at very low levels in brain.
G-protein coupled receptor for the tridecapeptide neurotensin (NTS) (PubMed:8381365, PubMed:21725197, PubMed:23140271). Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system. Signaling leads to the activation of downstream MAP kinases and protects cells against apoptosis (PubMed:21725197).
Interacts (palmitoylated form) with GNA11.
Palmitoylated; this is required for normal localization at membrane rafts and normal GNA11-mediated activation of down-stream signaling cascades. The palmitoylation level increases in response to neurotensin treatment.
The ligand binding pocket consists mainly of extracellular loops ECL2 and ECL3, as well as transmembrane regions TM6 and TM7.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A3 subfamily.
Highly expressed in substantia nigra (PubMed:7637582). Expressed in axonal varicosities in dopaminergic nerve terminals (at protein level) (PubMed:17296554). Expressed in the striatum (at protein level) (PubMed:17296554).
Homooligomer; disulfide-linked (Ref.16). Interacts with PRKCABP and TGFB1I1 (PubMed:11343649, PubMed:12177201). Interacts (via N-terminus) with SYNGR3 (via N-terminus) (By similarity). Interacts with SLC18A2 (By similarity). Interacts with TOR1A (ATP-bound); TOR1A regulates SLC6A3 subcellular location (PubMed:15505207). Interacts with alpha-synuclein/SNCA (PubMed:26442590). Interacts with SEPTIN4 (By similarity).
Inhibited by mazindol, GBR 12783 dihydrochloride, GBR 12909 dihydrochloride, nomifensine, diclofensine, amfonelic acid, Lu 19005, Win-35428, amphetamine, bupropion, cocaine and ritalin.
Mediates sodium- and chloride-dependent transport of dopamine (PubMed:1406597, PubMed:8302271, PubMed:10375632, PubMed:11093780, PubMed:15505207, PubMed:19478460). Also mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline) (By similarity). Regulator of light-dependent retinal hyaloid vessel regression, downstream of OPN5 signaling (By similarity).
Expressed on neurons in the most rostral segment of the mammalian brain, the telencephalon.
Glycosylation at Asn-54 is critical for functional folding.
ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L/beta-2).
Genetic variations in ABO define the ABO blood group system [MIM:616093]. The ABO blood group system is the most important blood group system in blood transfusion. The sequence shown here is that of the A transferase. The B form differs by a few residues substitution. Residues 266 and 268 are important for specificity. The reference genome assembly (GRCh38/hg38) describes a non-functional O-type ABO allele. The O-type ABO allele results in a guanine deletion (NM_020469.2: c.286delG). This deletion induces a frameshift and creates a premature stop codon resulting in a truncated (117 amino acids) protein deprived of any glycosyltransferase activity (PubMed:2333095).
The conserved DXD motif is involved in cofactor binding. The manganese ion interacts with the beta-phosphate group of UDP and may also have a role in catalysis.
This protein is the basis of the ABO blood group system. The histo-blood group ABO involves three carbohydrate antigens: A, B, and H. A, B, and AB individuals express a glycosyltransferase activity that converts the H antigen to the A antigen (by addition of UDP-GalNAc) or to the B antigen (by addition of UDP-Gal), whereas O individuals lack such activity.
Microtubule-based anterograde translocator for membranous organelles.
Required for formation of the sperm connecting piece during spermiogenesis. Sperm connecting piece is essential for linking the developing flagellum to the head during late spermiogenesis. May be involved in myosin-based microfilament transport through interaction with myosin subunits.
E3 ubiquitin and SUMO-protein ligase that plays a role in different biological processes such as innate immunity, inflammation or apoptosis (PubMed:15001576, PubMed:37086853). Potentiates MAP3K3-mediated activation of JUN/AP1 and DDIT3 transcriptional regulators (PubMed:14743216). Negatively regulates MYB transcriptional activity by sequestering it to the cytosol via SUMOylation (By similarity). Plays a role in the phosphorylation of MAPK1 and/or MAPK3, probably via its interaction with MAP3K3. Negatively regulates RLR-mediated innate immunity by promoting 'Lys-48'-linked ubiquitination of TBK1 through its RING domain to inhibit the cellular antiviral response (PubMed:37086853). Promotes 'Lys-29'-linked polyubiquitination of NEMO/IKBKG and RELA leading to targeting these two proteins to lysosomal degradative pathways, reducing the transcriptional activity of NF-kappa-B (PubMed:21518757).
Homodimer. Interacts with MAP3K3 and promotes the kinase activity of this enzyme.
Ubiquitinates itself upon phosphorylation.
Ubiquitously expressed with high levels in skeletal muscle, heart, colon, spleen, kidney, liver and placenta.
A chromosomal aberration involving SEPTIN9/MSF is found in therapy-related acute myeloid leukemia (t-AML). Translocation t(11;17)(q23;q25) with KMT2A/MLL1.
Filament-forming cytoskeletal GTPase (By similarity). May play a role in cytokinesis (Potential). May play a role in the internalization of 2 intracellular microbial pathogens, Listeria monocytogenes and Shigella flexneri.
Septins polymerize into heterooligomeric protein complexes that form filaments, and associate with cellular membranes, actin filaments, and microtubules. GTPase activity is required for filament formation. Interacts with SEPTIN2, SEPTIN6, SEPTIN7, SEPTIN11 and SEPTIN14. Interacts with RTKN and ARHGEF18. In a mesenchymal cell line, Rho/RTKN signals cause disruption of wild-type septin filaments, but not of those containing isoform 2 variants HNA Trp-106 and Phe-111. In a mesenchymal cell line, isoform 2 variants HNA Trp-106 and Phe-111, but not wild type, form filaments with SEPTIN4.
Widely expressed. Isoforms are differentially expressed in testes, kidney, liver heart, spleen, brain, peripheral blood leukocytes, skeletal muscle and kidney. Specific isoforms appear to demonstrate tissue specificity. Isoform 5 is the most highly expressed in fetal tissue. Isoform 1 is detected in all tissues except the brain and thymus, while isoform 2, isoform 3, and isoform 4 are detected at low levels in approximately half of the fetal tissues.
Interacts with the retinal-specific guanylyl cyclase GC1.
May be involved in the trafficking of signaling proteins to the cilia.
Interacts with CACNA1C. Identified in a complex with the L-type calcium channel subunits CACNA1C, CACNA2D1 and either CACNB1 or CACNB2.
Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit.
Found in a complex with CFAP410, NEK1 and SPATA7 (PubMed:26167768). Interacts with NEK1 (PubMed:26290490, PubMed:26167768).
Plays a role in cilia formation and/or maintenance (By similarity). Plays a role in the regulation of cell morphology and cytoskeletal organization (PubMed:21834987). Involved in DNA damage repair (PubMed:26290490).
Widely expressed (PubMed:26974433, PubMed:9325172). Expressed in the retina (PubMed:26294103).
Associates with pre-60S ribosomes in the nucleoplasm. Interacts (via its hexameric AAA ATPase ring) with the PELP1 complex (via PELP1); the interaction is regulated by SUMO conjugation of PELP1 and is crucial for recruitment of MDN1 to the pre-ribosomal particle (PubMed:27814492). Interacts (via VWFA/MIDAS domain) with WDR12 (via UBL domain) (PubMed:26601951). Interacts (via VWFA/MIDAS domain) with NLE1 (via UBL domain) (PubMed:26601951).
Nuclear chaperone required for maturation and nuclear export of pre-60S ribosome subunits (PubMed:27814492). Functions at successive maturation steps to remove ribosomal factors at critical transition points, first driving the exit of early pre-60S particles from the nucleolus and then driving late pre-60S particles from the nucleus (By similarity). At an early stage in 60S maturation, mediates the dissociation of the PeBoW complex (PES1-BOP1-WDR12) from early pre-60S particles, rendering them competent for export from the nucleolus to the nucleoplasm (By similarity). Subsequently recruited to the nucleoplasmic particles through interaction with SUMO-conjugated PELP1 complex (PubMed:27814492). This binding is only possible if the 5S RNP at the central protuberance has undergone the rotation to complete its maturation (By similarity).
Plays an essential role in autophagy. TMEM74-induced autophagy may involve PI3K signal transduction.
3'-5' exonuclease activity is activated by sodium and manganese (PubMed:16687656). 3'-5' exonuclease and 3'-phosphodiesterase activities are stimulated in presence of PCNA (PubMed:19443450).
Functions as a weak apurinic/apyrimidinic (AP) endodeoxyribonuclease in the DNA base excision repair (BER) pathway of DNA lesions induced by oxidative and alkylating agents (PubMed:16687656). Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends. Also displays double-stranded DNA 3'-5' exonuclease, 3'-phosphodiesterase activities (PubMed:16687656, PubMed:19443450, PubMed:32516598). Shows robust 3'-5' exonuclease activity on 3'-recessed heteroduplex DNA and is able to remove mismatched nucleotides preferentially (PubMed:16687656, PubMed:19443450). Also exhibits 3'-5' exonuclease activity on a single nucleotide gap containing heteroduplex DNA and on blunt-ended substrates (PubMed:16687656). Shows fairly strong 3'-phosphodiesterase activity involved in the removal of 3'-damaged termini formed in DNA by oxidative agents (PubMed:16687656, PubMed:19443450). In the nucleus functions in the PCNA-dependent BER pathway (PubMed:11376153). Plays a role in reversing blocked 3' DNA ends, problematic lesions that preclude DNA synthesis (PubMed:32516598). Required for somatic hypermutation (SHM) and DNA cleavage step of class switch recombination (CSR) of immunoglobulin genes (By similarity). Required for proper cell cycle progression during proliferation of peripheral lymphocytes (By similarity).
Highly expressed in brain and kidney. Weakly expressed in the fetal brain.
Interacts with PCNA; this interaction is triggered by reactive oxygen species and increased by misincorporation of uracil in nuclear DNA.
The PCNA interacting protein (PIP) box mediates interaction with PCNA and recruitment to DNA single-strand breaks.
A stop codon in the gene coding for this protein at position Gln-19 is responsible for functional diversity thus producing a pseudogene.
Forms functional homodimers and homooligomers (PubMed:18215144). Can also form heterooligomers with PLPP1 and PLPP3 (PubMed:18215144).
Found mainly in brain, pancreas and placenta.
Magnesium-independent phospholipid phosphatase (PubMed:9705349). Insensitive to N-ethylmaleimide (PubMed:9705349). Inhibited by sphingosine, zinc ions and modestly by propanolol (PubMed:9705349, PubMed:9607309).
Magnesium-independent phospholipid phosphatase that catalyzes the dephosphorylation of a variety of glycerolipid and sphingolipid phosphate esters including phosphatidate/PA, lysophosphatidate/LPA, sphingosine 1-phosphate/S1P and ceramide 1-phosphate/C1P (PubMed:9705349, PubMed:9607309, PubMed:16467304). Has no apparent extracellular phosphatase activity and therefore most probably acts intracellularly (PubMed:16467304). Also acts on N-oleoyl ethanolamine phosphate/N-(9Z-octadecenoyl)-ethanolamine phosphate, a potential physiological compound (PubMed:9607309). Through dephosphorylation of these bioactive lipid mediators produces new bioactive compounds and may regulate signal transduction in different cellular processes (Probable). Indirectly regulates, for instance, cell cycle G1/S phase transition through its phospholipid phosphatase activity (By similarity).
Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. May be involved in spermatogenesis during sexual maturation (By similarity).
Ubiquitous. Expressed in fetal and adult tissues.
Behaves as a myelinotrophic and neurotrophic factor, these effects are mediated by its G-protein-coupled receptors, GPR37 and GPR37L1, undergoing ligand-mediated internalization followed by ERK phosphorylation signaling.
Defects in PSAP saposin-D region are found in a variant of Tay-Sachs disease (GM2-gangliosidosis).
N-linked glycans show a high degree of microheterogeneity.
Saposin-A and saposin-C stimulate the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46). Saposin-C apparently acts by combining with the enzyme and acidic lipid to form an activated complex, rather than by solubilizing the substrate.
Saposin-B co-purifies with 1 molecule of phosphatidylethanolamine.
Saposin-B is a homodimer. Prosaposin exists as a roughly half-half mixture of monomers and disulfide-linked dimers (PubMed:10406958, PubMed:12510003, PubMed:7730378, PubMed:21835174). Monomeric prosaposin interacts (via C-terminus) with sortilin/SORT1, the interaction is required for targeting to lysosomes (PubMed:14657016, PubMed:22431521). Interacts with GRN; facilitates lysosomal delivery of progranulin from the extracellular space and the biosynthetic pathway (PubMed:26370502).
Saposin-B stimulates the hydrolysis of galacto-cerebroside sulfate by arylsulfatase A (EC 3.1.6.8), GM1 gangliosides by beta-galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha-galactosidase A (EC 3.2.1.22). Saposin-B forms a solubilizing complex with the substrates of the sphingolipid hydrolases.
Saposin-D is a specific sphingomyelin phosphodiesterase activator (EC 3.1.4.12).
Saposins are specific low-molecular mass non-enzymic proteins, they participate in the lysosomal degradation of sphingolipids, which takes place by the sequential action of specific hydrolases.
The lysosomal precursor is proteolytically processed to 4 small peptides, which are similar to each other and are sphingolipid hydrolase activator proteins.
The one residue extended Saposin-B-Val is only found in 5% of the chains.
Activated by an increase in cytosolic calcium levels that induce a conformational change of the N-terminal regulatory domain, uncapping the channel and allowing transport (By similarity). Inhibited by bathophenanthroline, mersalyl, p-hydroxymercuribenzoate, bromcresol purple, tannic acid, pyridoxal 5'-phosphate and p-hydroxymercuribenzoate (PubMed:15123600).
Electroneutral antiporter that mediates the transport of adenine nucleotides through the inner mitochondrial membrane. Originally identified as an ATP-magnesium/inorganic phosphate antiporter, it also acts as a broad specificity adenyl nucleotide antiporter. By regulating the mitochondrial matrix adenine nucleotide pool could adapt to changing cellular energetic demands and indirectly regulate adenine nucleotide-dependent metabolic pathways (PubMed:15123600). Also acts as a regulator of mitochondrial calcium uptake and can probably transport trace amounts of other divalent metal cations in complex with ATP (PubMed:24430870, PubMed:28695448). In vitro, a low activity is also observed with guanyl and pyrimidine nucleotides (PubMed:15123600).
Expressed at low levels in most tissues examined, with highest expression in brain, skeletal muscle and pancreas.
Interacts with MCU (PubMed:24430870). Interacts with MICU1 (PubMed:24430870).
Activation of the C1 complex is under control of the C1-inhibitor. It forms a proteolytically inactive stoichiometric complex with the C1r or C1s proteases. May play a potentially crucial role in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins. Very efficient inhibitor of FXIIa. Inhibits chymotrypsin and kallikrein.
Binds to E.coli stcE which allows localization of SERPING1 to cell membranes thus protecting the bacteria against complement-mediated lysis. Interacts with MASP1.
Can be proteolytically cleaved by E.coli stcE.
Chymotrypsin uses Ala-465 as its reactive site in normal plasma protease C1 inhibitor, and His-466 as its reactive site in the variant His-466.
Highly glycosylated (49%) with N- and O-glycosylation. O-glycosylated with core 1 or possibly core 8 glycans. N-glycan heterogeneity at Asn-25: Hex5HexNAc4 (minor), dHex1Hex5HexNAc4 (minor), Hex6HexNAc5 (major) and dHex1Hex6HexNAc5 (minor).
Expressed in small intestine, colon, testis, spleen, and leukocyte.
Expressed in liver, kidney, pancreas and at low levels in brain and heart. Expressed in embryonic brain and developing neural retina.
In 37 day post-ovulation (dpo) embryos, expression is found in the mid- and hindbrain, regions known to be involved in motor control of eye movement, and in the ventricular zone of the forebrain. In 56 dpo embryos, expressed in the ventricular layer of the forebrain, midbrain, cerebellar primordium, spinal cord and the developing neural retina. In later development, highly expressed in postmitotic cells within the developing subplate and cortical plate.
May play a role during neuronal differentiation and development. Shares a similar tissue distribution, co-localize with, and interact with isoform 1 in NT2 cells.
Plays a role in neurite development, may be through the activation of the GTPase RAC1. Plays a role in the control of eye movement and gaze stability.
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:2175712, PubMed:15544348). Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes (PubMed:2175712, PubMed:15544348). Also plays an important role in the biosynthesis of complex lipids (Probable). Can also phosphorylate 1-alkyl-2-acylglycerol in vitro as efficiently as diacylglycerol provided it contains an arachidonoyl group (PubMed:15544348). Also involved in the production of alkyl-lysophosphatidic acid, another bioactive lipid, through the phosphorylation of 1-alkyl-2-acetyl glycerol (PubMed:22627129).
Stimulated by calcium and phosphatidylserine.
Highly expressed in testis. Detected in prostate, kidney, bladder, lung and bone marrow.
May be a homodimer, which associates with multiple calmodulin or myosin light chains (By similarity). Interacts with RIPL2, the interaction is required for its role in dendrite formation (By similarity). Interacts with MLPH (PubMed:12062444). Interacts with SYTL4 (By similarity). Interacts with MYRIP (By similarity). Interacts with RAB10; mediates the transport to the plasma membrane of SLC2A4/GLUT4 storage vesicles (PubMed:22908308). Interacts with FMR1; this interaction occurs in association with polyribosome (By similarity).
Processive actin-based motor that can move in large steps approximating the 36-nm pseudo-repeat of the actin filament. Involved in melanosome transport. Also mediates the transport of vesicles to the plasma membrane. May also be required for some polarization process involved in dendrite formation.
The disease is caused by variants affecting the gene represented in this entry. Some patients who have MYO5A pathogenic variants and originally diagnosed with Griscelli syndrome 1 may rather have Elejalde syndrome.
Down-regulates the expression of several chemokine receptors. Interferes with HIV-1 replication by suppressing Tat-induced viral LTR promoter activity.
Expressed in fetal lung, but not in any adult tissues examined. Expression was detected in an osteosarcoma cDNA library.
(Microbial infection) Interacts with human adenovirus type 9 E4-ORF1 protein.
(Microbial infection) Interacts with human papillomavirus 18/HPV18 protein E6.
Expressed in heart, brain, placenta, liver, skeletal muscle, kidney and pancreas.
Interacts with CLDN5, DLG4, GRIN1, F11R/JAM, CLDN1, NG2, CRB1, MPP4 and PALS1 (By similarity). Interacts with HTR2A, HTR2B, HTR2C, PLEKHA1/TAPP1, PLEKHA2/TAPP2, CXADR, SYNGAP1, CAMK2A and CAMK2B. Interacts with FAT4 (via cytoplasmic domain) (By similarity). Interacts with DLL1 (By similarity).
Member of the NMDAR signaling complex that may play a role in control of AMPAR potentiation and synaptic plasticity in excitatory synapses (PubMed:11150294, PubMed:15312654). Promotes clustering of HT2RC at the cell surface (By similarity).
The PDZ domain 1 binds NG2. The PDZ domains 7 and 10 bind the Ad9 E4-ORF1 oncoprotein. The PDZ domain 9 binds F11R. The PDZ domain 10 binds the C-terminus of CLDN1 and KIT and the C-terminal PDZ-binding motif of HTR2C. The PDZ domain 13 binds CXADR (By similarity). The PDZ domain 2 binds CAMK2A and CAMK2B. The PDZ domains 10 and 13 bind PLEKHA1 and PLEKHA2. The PDZ domain 13 binds SYNGAP1.
Binds GTP saturably and exhibits a low intrinsic rate of GTP hydrolysis.
Belongs to the PIGG/PIGN/PIGO family. PIGN subfamily.
Ethanolamine phosphate transferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers ethanolamine phosphate to the first alpha-1,4-linked mannose of the glycosylphosphatidylinositol precursor of GPI-anchor (By similarity). May act as suppressor of replication stress and chromosome missegregation.
Ethanolamine phosphate transferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers ethanolamine phosphate to the first alpha-1,4-linked mannose of the glycosylphosphatidylinositol precursor of GPI-anchor.
Highly expressed in testis, cerebellum, temporal lobe, hippocampus and the adrenal gland. Moderately expressed in spleen, uterus, thymus, pancreas, kidney, stomach and rectum.
Transcriptional repressor. May repress NR5A1, PPARG, NR1H3, NR4A2, ESR1 and NR3C1 transcriptional activity.
Binds to the central extracellular domain of APP and inhibits beta-secretase cleavage of APP.
Cell adhesion protein that promotes the attachment of spinal cord and sensory neuron cells and the outgrowth of neurites in vitro. May contribute to the growth and guidance of axons in both the spinal cord and the PNS (By similarity). Major factor for vascular smooth muscle cell.
Highest expression in lung, lower expression in brain, heart, kidney, liver and testis, and lowest expression in pancreas, skeletal muscle and ovary. Not expressed in spleen.
Contributes to histone modification (PubMed:19131338, PubMed:19556245, PubMed:19103755, PubMed:20018852, PubMed:16600877, PubMed:16829960). May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4' (PubMed:16829960). As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3 (PubMed:19556245). H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation (PubMed:18840606). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:19103755, PubMed:20018852). May regulate osteoblasts differentiation (By similarity). In association with RBBP5 and ASH2L, stimulates the histone methyltransferase activities of KMT2A, KMT2B, KMT2C, KMT2D, SETD1A and SETD1B (PubMed:21220120, PubMed:22266653).
Interacts with PAXBP1; the interaction is direct and links a WDR5-containing histone methyltransferase complex to PAX7 and PAX3 (By similarity). Interacts with HCFC1 (PubMed:12670868). Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4 (PubMed:19103755). Component of the SET1 complex, at least composed of the catalytic subunit (SETD1A or SETD1B), WDR5, WDR82, RBBP5, ASH2L/ASH2, CXXC1/CFP1, HCFC1 and DPY30 (PubMed:16253997, PubMed:17355966, PubMed:17998332, PubMed:18838538). Core component of several methyltransferase-containing complexes including MLL1/MLL, MLL2/3 (also named ASCOM complex) and MLL4/WBP7 (PubMed:15199122, PubMed:15960975, PubMed:17021013, PubMed:17500065). Each complex is at least composed of ASH2L, RBBP5, WDR5, DPY30, one or more specific histone methyltransferases (KMT2A/MLL1, KMT2D/MLL2, KMT2C/MLL3 and KMT2B/MLL4), and the facultative components PAGR1, BAP18, CHD8, E2F6, HCFC1, HCFC2, HSP70, INO80C, KDM6A, KANSL1, LAS1L, MAX, MCRS1, MEN1, MGA, MYST1/MOF, NCOA6, PAXIP1/PTIP, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9, TEX10 and alpha- and beta-tubulin (PubMed:14992727, PubMed:18378692). Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1 (PubMed:20018852). Interacts with KMT2A/MLL1 (via WIN motif) and RBBP5; the interaction is direct (PubMed:19556245, PubMed:21220120, PubMed:22665483, PubMed:22266653, PubMed:18840606, PubMed:18829459). Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1 (PubMed:19103755). In the complex, it probably interacts directly with KAT2A, MBIP and KAT14 (PubMed:19103755). Interacts with histone H3 (PubMed:16946699, PubMed:16600877, PubMed:16829960, PubMed:16829959). Interacts with SETD1A (via WIN motif) (PubMed:17998332, PubMed:22665483, PubMed:22266653). Component of a histone methylation complex composed of at least ZNF335, RBBP5, ASH2L and WDR5; the complex may have histone H3-specific methyltransferase activity, however does not have specificity for 'Lys-4' of histone H3 (PubMed:19131338). Interacts with ZNF335 (PubMed:19131338, PubMed:23178126). Components of this complex may associate with components of the ZNF335-CCAR2-EMSY nuclear receptor-mediated transcription complex to form a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY, MKI67, RBBP5, ASH2L and WDR5 (PubMed:19131338). Interacts with PER1 (By similarity). Interacts with KMT2B (via WIN motif), KMT2C (via WIN motif), KMT2D (via WIN motif) and SETD1B (via WIN motif) (PubMed:22665483, PubMed:22266653, PubMed:18840606).
Homooligomer (via coiled coil domain) (PubMed:10669747). Interacts with NF2; the interaction is direct (PubMed:10669747). Interacts with ANK3 (PubMed:25950943).
Preferentially expressed in brain, skeletal muscles and heart. Also expressed in detected in pancreas, kidney, liver, lung, and placenta.
Interacts with MAGI1 at tight junctions, forms a tripartite complex with NPHS1. Interacts with LNX1 isoform 2 via its PDZ 2 domain, it may also interact with other isoforms containing this domain.
Provides, together with MAGI1, an adhesion machinery at tight junctions, which may regulate the permeability of kidney glomerulus and small intestinal epithelial cells. Mediates calcium-independent homophilic cell adhesion. In testis, it may function as a cell adhesion molecule rather than a tight-junction protein. It may participate in the adhesion between spermatogonia-spermatogonia, spermatogonia-Sertoli cells, and Sertoli cells-Sertoli cells (By similarity).
Deiminated by PADI1, PADI2 or PADI3 in vitro. The deiminated form is degraded by calpain-1/CAPN1 more quickly and into shorter peptides than the intact protein.
Essential for normal cell-cell adhesion in the cornified cell layers (PubMed:29758285). Important for proper integrity and mechanical strength of the stratum corneum of the epidermis (PubMed:29505760).
Expressed in skin, thymus, stomach and placenta, but not detected in heart, brain, liver, lung, bone marrow, small intestine, spleen, prostate, colon, adrenal gland, kidney, pancreas, mammary gland, bladder, thyroid, salivary gland and trachea. Weakly expressed in esophagus, tonsils and testis (at protein level). In the skin, strongly expressed in the upper stratum granulosum and lower stratum corneum, but not detected in the upper stratum corneum (at protein level) (PubMed:19384417) (PubMed:21531719). In scalp hair follicles, mainly restricted within the granular and cornified cells surrounding the infundibular outer root sheath, with weak expression in central and proximal outer root sheath (at protein level). Tends to be down-regulated in sporiatic lesions compared to non-lesional skin inthe same patients (PubMed:19384417).
In cultured foreskin fibroblasts, up-regulated in response to Ca(2+) stimulation.
May be processed by calpain-1/CAPN1 in the uppermost epidermal layers.
(Microbial infection) Interacts with human cytomegalovirus protein UL148.
Homodimer and homooligomer (By similarity). May form a complex with ERLEC1, HSPA5, OS9, and SYVN1 (PubMed:18502753, PubMed:18264092). Interacts with FOXRED2 and EDEM1 (PubMed:19524542, PubMed:19706418). Interacts with LPL (PubMed:25066055). Interacts with LMF1; may stabilize the complex formed by LPL and LMF1 and thereby promote the export of LPL dimers (By similarity). Component of the HRD1 complex, which comprises at least SYNV1/HRD1, DERL1/2, FAM8A1, HERPUD1/HERP, OS9, SEL1L and UBE2J1 (PubMed:16186509, PubMed:28827405). SYNV1 assembles with SEL1L and FAM8A1 through its transmembrane domains, but interaction with its cytoplasmic domain is required to confer stability to FAM8A1 and enhance recruitment of HERPUD1 (PubMed:28827405). The interaction with SYNV1/HRD1 is direct (PubMed:26471130).
Plays a role in the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins (PubMed:16186509, PubMed:29997207). Enhances SYVN1 stability. Plays a role in LPL maturation and secretion. Required for normal differentiation of the pancreas epithelium, and for normal exocrine function and survival of pancreatic cells. May play a role in Notch signaling.
Most highly expressed in heart tissue, with lower levels in the skeletal muscle, kidney, lung and other organs.
Plays a role in regulating cardiac sodium current; decreased enzymatic activity with resulting increased levels of glycerol 3-phosphate activating the DPD1L-dependent SCN5A phosphorylation pathway, may ultimately lead to decreased sodium current; cardiac sodium current may also be reduced due to alterations of NAD(H) balance induced by DPD1L.
Interacts with GNAO1, GNAI2 and GNAI3 (By similarity). Interacts with GNAI1 (PubMed:18434541, PubMed:21115486). Interacts (via RGS and GoLoco domains) with GNAI1; the interaction occurs in the centrosomes. Interaction with GNAI1 or GNAI3 (via active GTP- or inactive GDP-bound forms) prevents association of RGS14 with centrosomes or nuclear localization (By similarity). Interacts with RABGEF1; the interactions is GTP-dependent. Interacts with RAP2A; the interactions is GTP-dependent and does not alter its function on G(i) alpha subunits either as GAP or as GDI (By similarity). Associates with microtubules (PubMed:15917656). Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3 and RGS14. Interacts with RIC8A (via C-terminus). Interacts (via RBD 1 domain) with HRAS (active GTP-bound form preferentially). Interacts (via RBD domains) with BRAF (via N-terminus); the interaction mediates the formation of a ternary complex with RAF1. Interacts (via RBD domains) with RAF1 (via N-terminus); the interaction mediates the formation of a ternary complex with BRAF. Interacts with KRAS (active GTP-bound form preferentially), MRAS (active GTP-bound form preferentially), NRAS (active GTP-bound form preferentially) and RRAS (active GTP-bound form preferentially).
Phosphorylated by PKC. Phosphorylation is increased in presence of forskolin and may enhance the GDI activity on G(i) alpha subunit GNAI1 (By similarity).
Regulates G protein-coupled receptor signaling cascades. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form. Besides, modulates signal transduction via G protein alpha subunits by functioning as a GDP-dissociation inhibitor (GDI). Has GDI activity on G(i) alpha subunits GNAI1 and GNAI3, but not on GNAI2 and G(o)-alpha subunit GNAO1. Has GAP activity on GNAI0, GNAI2 and GNAI3. May act as a scaffold integrating G protein and Ras/Raf MAPkinase signaling pathways. Inhibits platelet-derived growth factor (PDGF)-stimulated ERK1/ERK2 phosphorylation; a process depending on its interaction with HRAS and that is reversed by G(i) alpha subunit GNAI1. Acts as a positive modulator of microtubule polymerisation and spindle organization through a G(i)-alpha-dependent mechanism. Plays a role in cell division. Required for the nerve growth factor (NGF)-mediated neurite outgrowth. Involved in stress resistance. May be involved in visual memory processing capacity and hippocampal-based learning and memory.
The GoLoco domain is necessary for GDP-dissociation inhibitor (GDI) activity, translocation out of the nucleus and interaction with G(i) alpha subunits GNAI1, GNAI2 and GNAI3.
The RBD domains are necessary for localization to the nucleus and centrosomes.
The RGS domain is necessary for GTPase-activating protein (GAP) activity for G subunits and localization to the nucleus and centrosomes.
Postsynaptic protein that regulates circuit dynamics in the central nervous system by modulating the temporal dynamics of interneuron recruitment. Specifically present in excitatory synapses onto oriens-lacunosum molecular (OLM) interneurons and acts as a regulator of presynaptic release probability to direct the formation of highly facilitating pyramidal-OLM synapses (By similarity). Inhibits phosphatase activity of protein phosphatase 1 (PP1) complexes.
Belongs to the thiamine pyrophosphokinase family.
Catalyzes the phosphorylation of thiamine to thiamine pyrophosphate. Can also catalyze the phosphorylation of pyrithiamine to pyrithiamine pyrophosphate.
Detected in heart, kidney, testis, small intestine and peripheral blood leukocytes, and at very low levels in a variety of tissues.
Interacts with CD81; the interaction prevents nuclear translocation of HHEX (By similarity). Interacts (via N-terminus) with SOX13; abolishes the SOX13-mediated inhibition of WNT-mediated transcriptional activity via competitive inhibition of the SOX13-TCF7 complex (PubMed:20028982). Interacts with EIF4E; the interaction inhibits EIF4E-mediated mRNA nuclear export (PubMed:12554669).
Liver and promyelocytic leukemia cell line HL-60.
Recognizes the DNA sequence 5'-ATTAA-3' (By similarity). Transcriptional repressor (By similarity). Activator of WNT-mediated transcription in conjunction with CTNNB1 (PubMed:20028982). Establishes anterior identity at two levels; acts early to enhance canonical WNT-signaling by repressing expression of TLE4, and acts later to inhibit NODAL-signaling by directly targeting NODAL (By similarity). Inhibits EIF4E-mediated mRNA nuclear export (PubMed:12554669). May play a role in hematopoietic differentiation (PubMed:8096636).
Promotes neurite outgrowth and especially branching of neuritic processes in primary hippocampal and cortical cells.
(Microbial infection) In case of filoviruses Ebola/EBOV and Marburg/MARV infection, the complex formed by viral matrix protein VP40 and SMURF2 facilitates virus budding.
(Microbial infection) Interacts (via WW domains) with EBOV and MARV VP40 (via PPXY motif); the interaction facilitates VP40 virus-like particle budding.
(Microbial infection) The WW domains mediate binding with matrix protein VP40.
Auto-ubiquitinated and ubiquitinated in the presence of RNF11 and UBE2D1 (PubMed:19343052, PubMed:30696809). Ubiquitinated by the SCF(FBXL15) complex and TTC3, leading to its degradation by the proteasome (PubMed:21572392, PubMed:30696809). 'Lys-48'-linked polyubiquitination mediated by TRAF4 at Lys-119 leads to SMURF2 proteasomal degradation (PubMed:31076633).
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:11016919). Interacts with SMAD7 to trigger SMAD7-mediated transforming growth factor beta/TGF-beta receptor ubiquitin-dependent degradation, thereby down-regulating TGF-beta signaling (PubMed:11163210, PubMed:12717440, PubMed:21791611). In addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with AIMP1 (PubMed:18448069). Also forms a stable complex with TGF-beta receptor-mediated phosphorylated SMAD1, SMAD2 and SMAD3, and targets SMAD1 and SMAD2 for ubiquitination and proteasome-mediated degradation (PubMed:11016919, PubMed:11158580, PubMed:11389444). SMAD2 may recruit substrates, such as SNON, for ubiquitin-dependent degradation (PubMed:11389444). Negatively regulates TGFB1-induced epithelial-mesenchymal transition and myofibroblast differentiation (PubMed:30696809).
Interacts (via WW domains) with SMAD1 (PubMed:11158580). Interacts (via WW domains) with SMAD2 (via PY-motif) (PubMed:11158580, PubMed:11389444). Interacts (via WW domains) with SMAD3 (via PY-motif) (PubMed:11158580, PubMed:11389444). Interacts with SMAD6 (PubMed:11158580). Interacts with SMAD7 (via PY-motif) and TGFBR1; SMAD7 recruits SMURF2 to the TGF-beta receptor and regulates its degradation (PubMed:11163210, PubMed:11158580, PubMed:33673144, PubMed:16061177, PubMed:16641086). Does not interact with SMAD4; SMAD4 lacks a PY-motif (PubMed:11158580). Interacts with AIMP1 (PubMed:18448069). Interacts with SNON (PubMed:11389444). Interacts with STAMBP and RNF11 (PubMed:14562029, PubMed:14755250). May interact with NDFIP1 and NDFIP2; this interaction induces the E3 ubiquitin-protein ligase activity. Interacts with TTC3 (Probable).
The second and third WW domains are responsible for interaction with the PY-motif of R-SMAD (SMAD1, SMAD2 and SMAD3).
Belongs to the protein kinase superfamily. Tyr protein kinase family. ROR subfamily.
Expressed at high levels during early embryonic development. The expression levels drop strongly around day 16 and there are only very low levels in adult tissues.
Expressed strongly in human heart, lung and kidney, but weakly in the CNS. Isoform Short is strongly expressed in fetal and adult CNS and in a variety of human cancers, including those originating from CNS or PNS neuroectoderm.
Has very low kinase activity in vitro and is unlikely to function as a tyrosine kinase in vivo (PubMed:25029443). Receptor for ligand WNT5A which activate downstream NFkB signaling pathway and may result in the inhibition of WNT3A-mediated signaling (PubMed:25029443, PubMed:27162350). In inner ear, crucial for spiral ganglion neurons to innervate auditory hair cells (PubMed:27162350).
The kinase domain has very low catalytic activity in vitro.
Almost ubiquitous. Detected in fetal brain, lung, liver and kidney; in adult heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine and colon. Not detected in peripheral blood leukocytes. In brain, restricted to post-mitotic neurons.
Binds to the transactivation domains of E2F1 and p53. Binds also SV40 large T antigen and adenovirus E1A. Interacts with nucleobindin 1 and 2 (By similarity).
Growth suppressor that facilitates the entry of the cell into cell cycle arrest. Functionally similar to the retinoblastoma protein it binds to and represses the activity of cell-cycle-promoting proteins such as SV40 large T antigen, adenovirus E1A, and the transcription factor E2F. Necdin also interacts with p53 and works in an additive manner to inhibit cell growth. Also functions as a transcription factor and directly binds to specific guanosine-rich DNA sequences (By similarity).
Located in the Prader-Willi syndrome (PWS) chromosome region. Prader-Willi syndrome is a contiguous gene syndrome resulting from deletion of the paternal copies of the imprinted SNRPN gene, the necdin gene, and possibly other genes within the chromosome region 15q11-q13.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues. Preferentially acts on mannose-linked GlcNAc. Also able to catalyze the transfer of sulfate to position 6 of the N-acetylgalactosamine (GalNAc) residue of chondroitin. Also acts on core 2 mucin-type oligosaccharide and N-acetyllactosamine oligomer with a lower efficiency. Has weak or no activity toward keratan sulfate and oligosaccharides containing the Galbeta1-4GlcNAc. Catalyzes 6-O-sulfation of beta-benzyl GlcNAc but not alpha- or beta-benzyl GalNAc.
Widely expressed. Highly expressed in heart, spleen, liver and ovary. Expressed at lower level in brain, placenta, thyroid, spinal cord and peripheral blood leukocytes. Not expressed in adult skin.
(Microbial infection) In infection processes acts as an attachment site for microbial proteins, including Listeria monocytogenes internalin B (InlB) and Staphylococcus aureus protein A.
(Microbial infection) Interacts with Epstein-Barr virus EBNA1.
(Microbial infection) Interacts with HIV-1 Tat and HCV core protein.
(Microbial infection) Interacts with L.monocytogenes internalin B.
(Microbial infection) Interacts with Rubella virus capsid protein; the interaction occurs in mitochondria (PubMed:10823864, PubMed:12034482). Interacts with Rubella virus protease/methyltransferase p150 (PubMed:22238231).
(Microbial infection) Interacts with Staphylococcus aureus protein A/spa, HIV-1 Tat and HCV core protein.
(Microbial infection) Interacts with Staphylococcus aureus protein A/spa.
(Microbial infection) Involved in HIV-1 replication, presumably by contributing to splicing of viral RNA.
(Microbial infection) Involved in replication of Rubella virus.
Enhanced cell surface expression upon platelet and monocyte activation.
Expressed on cell surface of peripheral blood cells (at protein level); Surface expression is reported for macrophages and monocyte-derived dendritic cells.
Homotrimer; three monomers form a donut-shaped structure with an unusually asymmetric charge distribution on the surface. Interacts with CDK13, HRK, VTN, NFYB, ADRA1B, FOXC1, DDX21, DDX50, NCL, SRSF1, SRSF9 and CDKN2A isoform smARF. Interacts with CD93; the association may represent a cell surface C1q receptor. Interacts with KRT1; the association represents a cell surface kininogen receptor. Interacts with CD209; the interaction is indicative for a C1q:C1QBP:CD209 signaling complex. Interacts with FBL and RRP1; the respective interactions with C1QBP are competitive. Probably associates with the mitoribosome. Interacts with MAVS; the interaction occurs upon viral transfection. Interacts with PPIF. Interacts with U2AF1L4. Interacts with PLEKHN1 (PubMed:18191643). Interacts with VGF-derived peptide TLQP-21 (By similarity). Interacts with POLGARF which is produced from an alternative reading frame of the POLG gene; the interaction results in nucleolar localization of C1QBP, probably due to prevention of C1QBP maturation and redirection from mitochondria to nucleoli (PubMed:32958672).
Is believed to be a multifunctional and multicompartmental protein involved in inflammation and infection processes, ribosome biogenesis, protein synthesis in mitochondria, regulation of apoptosis, transcriptional regulation and pre-mRNA splicing. At the cell surface is thought to act as an endothelial receptor for plasma proteins of the complement and kallikrein-kinin cascades. Putative receptor for C1q; specifically binds to the globular 'heads' of C1q thus inhibiting C1; may perform the receptor function through a complex with C1qR/CD93. In complex with cytokeratin-1/KRT1 is a high affinity receptor for kininogen-1/HMWK. Can also bind other plasma proteins, such as coagulation factor XII leading to its autoactivation. May function to bind initially fluid kininogen-1 to the cell membrane. The secreted form may enhance both extrinsic and intrinsic coagulation pathways. It is postulated that the cell surface form requires docking with transmembrane proteins for downstream signaling which might be specific for a cell-type or response. By acting as C1q receptor is involved in chemotaxis of immature dendritic cells and neutrophils and is proposed to signal through CD209/DC-SIGN on immature dendritic cells, through integrin alpha-4/beta-1 during trophoblast invasion of the decidua, and through integrin beta-1 during endothelial cell adhesion and spreading. Signaling involved in inhibition of innate immune response is implicating the PI3K-AKT/PKB pathway. Required for protein synthesis in mitochondria (PubMed:28942965). In mitochondrial translation may be involved in formation of functional 55S mitoribosomes; the function seems to involve its RNA-binding activity. May be involved in the nucleolar ribosome maturation process; the function may involve the exchange of FBL for RRP1 in the association with pre-ribosome particles. Involved in regulation of RNA splicing by inhibiting the RNA-binding capacity of SRSF1 and its phosphorylation. Is required for the nuclear translocation of splicing factor U2AF1L4. Involved in regulation of CDKN2A- and HRK-mediated apoptosis. Stabilizes mitochondrial CDKN2A isoform smARF. May be involved in regulation of FOXC1 transcriptional activity and NFY/CCAAT-binding factor complex-mediated transcription. May play a role in antibacterial defense as it can bind to cell surface hyaluronan and inhibit Streptococcus pneumoniae hyaluronate lyase. May be involved in modulation of the immune response; ligation by HCV core protein is resulting in suppression of interleukin-12 production in monocyte-derived dendritic cells. Involved in regulation of antiviral response by inhibiting RIGI- and IFIH1-mediated signaling pathways probably involving its association with MAVS after viral infection.
The subcellular location has been matter of debate. After being reported to be exclusively localized to mitochondria, demonstrations of promiscuous associations and locations were considered as artifactual due to the extremely acidic character and the use of different tagged versions of the protein (PubMed:9305894, PubMed:11493647). However, its location to multiple compartments linked to diverse functions is now accepted. The N-termini of the surface and secreted forms are identical to the reported processed mitochondrial form.
Binds 1 heme b (iron(II)-protoporphyrin IX) group non-covalently per subunit.
Catalyzes the oxidation of sulfite to sulfate, the terminal reaction in the oxidative degradation of sulfur-containing amino acids.
Thyroid receptor interacting proteins (TRIPs) specifically interact with the ligand binding domain of the thyroid receptor (TR) (PubMed:7776974). Requires the presence of thyroid hormone for its interaction (PubMed:7776974). Interacts with NUFIP1 (PubMed:28335020). Interacts (via HIT-type zinc finger) with the RUVBL1/RUVBL2 complex in the presence of ADP (PubMed:28561026).
Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity (PubMed:2558109, PubMed:4322742, PubMed:7683654, PubMed:7523412, PubMed:15615692, PubMed:20826823). Composed of two similar catalytic domains, each possessing a functional active site, with different selectivity for substrates (PubMed:1851160, PubMed:1320019, PubMed:7683654, PubMed:7876104, PubMed:10913258, PubMed:19773553). Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin (PubMed:4322742, PubMed:1851160, PubMed:11432860, PubMed:19773553, PubMed:23056909). Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response (PubMed:2558109, PubMed:6055465, PubMed:4322742, PubMed:6270633, PubMed:7683654, PubMed:15615692). Acts as a regulator of synaptic transmission by mediating cleavage of neuropeptide hormones, such as substance P, neurotensin or enkephalins (PubMed:656131, PubMed:6270633, PubMed:6208535, PubMed:15615692). Catalyzes degradation of different enkephalin neuropeptides (Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Phe and possibly Met-enkephalin-Arg-Gly-Leu) (PubMed:656131, PubMed:6270633, PubMed:2982830). Acts as a regulator of synaptic plasticity in the nucleus accumbens of the brain by mediating cleavage of Met-enkephalin-Arg-Phe, a strong ligand of Mu-type opioid receptor OPRM1, into Met-enkephalin (By similarity). Met-enkephalin-Arg-Phe cleavage by ACE decreases activation of OPRM1, leading to long-term synaptic potentiation of glutamate release (By similarity). Also acts as a regulator of hematopoietic stem cell differentiation by mediating degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) (PubMed:8257427, PubMed:7876104, PubMed:8609242, PubMed:26403559). Acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin, an antagonist peptide of the cannabinoid receptor CNR1 (PubMed:18077343). Involved in amyloid-beta metabolism by catalyzing degradation of Amyloid-beta protein 40 and Amyloid-beta protein 42 peptides, thereby preventing plaque formation (PubMed:11604391, PubMed:16154999, PubMed:19773553). Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones (PubMed:2983326, PubMed:7683654, PubMed:9371719, PubMed:10336644). Degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) and amyloid-beta proteins is mediated by the N-terminal catalytic domain, while angiotensin I and cholecystokinin cleavage is mediated by the C-terminal catalytic region (PubMed:7876104, PubMed:10336644, PubMed:19773553).
Inhibitors of ACE are commonly used to treat hypertension and some types of renal and cardiac dysfunction.
Isoform Testis-specific only binds 1 Zn(2+) ion per subunit.
Isoform produced by alternative promoter usage that is specifically expressed in spermatocytes and adult testis, and which is required for male fertility (PubMed:1651327, PubMed:1668266). In contrast to somatic isoforms, only contains one catalytic domain (PubMed:1651327, PubMed:1668266). Acts as a dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of substrates (PubMed:1668266, PubMed:24297181). The identity of substrates that are needed for male fertility is unknown (By similarity). May also have a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety. The GPIase activity was reported to be essential for the egg-binding ability of the sperm (By similarity). This activity is however unclear and has been challenged by other groups, suggesting that it may be indirect (By similarity).
Monomer and homodimer; homodimerizes following binding to an inhibitor (PubMed:16476786). Interacts with calmodulin (CALM1, CALM2 or CALM3); interaction takes place in the cytoplasmic region and regulates phosphorylation and proteolytic cleavage (By similarity).
Phosphorylated by CK2 on Ser-1299; which allows membrane retention (PubMed:12386153). Phosphorylated on tyrosine residues on its extracellular part, promoting cleavage by secretase enzymes and formation of the soluble form (Angiotensin-converting enzyme, soluble form) (By similarity).
Produced following proteolytic cleavage by secretase enzymes that cleave the transmembrane form in the juxtamembrane stalk region upstream of the transmembrane region (PubMed:8253769, PubMed:7499427, PubMed:10769174, PubMed:11274151). Cleavage can take place at different sites of the juxtamembrane stalk region (PubMed:8253769, PubMed:7499427, PubMed:10769174, PubMed:11274151).
Soluble form that is released in blood plasma and other body fluids following proteolytic cleavage in the juxtamembrane stalk region.
Specifically expressed in spermatocytes and adult testis.
Strongly inhibited by lisinopril and captopril.
The dipeptidyl carboxypeptidase activity is strongly activated by chloride (PubMed:7683654, PubMed:11432860, PubMed:15615692, PubMed:12540854, PubMed:16476442). The dipeptidyl carboxypeptidase activity is specifically inhibited by lisinopril, captopril and enalaprilat (PubMed:6270633, PubMed:6208535, PubMed:1320019, PubMed:7876104, PubMed:8609242, PubMed:12540854, PubMed:16476442).
Ubiquitously expressed, with highest levels in lung, kidney, heart, gastrointestinal system and prostate.
Expressed in brain, kidney, pancreas, placenta, liver, thymus and prostate.
Golgi serine/threonine protein kinase that phosphorylates secretory pathway proteins within Ser-x-Glu/pSer motifs and plays a key role in biomineralization of bones and teeth (PubMed:22582013, PubMed:23754375, PubMed:25789606). Constitutes the main protein kinase for extracellular proteins, generating the majority of the extracellular phosphoproteome (PubMed:26091039). Mainly phosphorylates proteins within the Ser-x-Glu/pSer motif, but also displays a broader substrate specificity (PubMed:26091039). Phosphorylates ERO1A, enhancing its activity which is required to maintain endoplasmic reticulum redox homeostasis and for oxidative protein folding (PubMed:29858230, PubMed:34349020). During endoplasmic reticulum stress, phosphorylates P4HB/PDIA1 which induces a functional switch, causing P4HB to change from an oxidoreductase to a molecular chaperone (PubMed:32149426). This is critical to maintain ER proteostasis and reduce cell death under ER stress (PubMed:32149426). Phosphorylation of P4HB also promotes its interaction with ERN1, leading to reduced activity of ERN1, a key sensor for the endoplasmic reticulum unfolded protein response (PubMed:32149426). Required for osteoblast differentiation and mineralization (PubMed:34349020). Phosphorylates casein as well as a number of proteins involved in biomineralization such as AMELX, AMTN, ENAM and SPP1/OPN (PubMed:22582013, PubMed:25789606, PubMed:34349020). In addition to its role in biomineralization, also plays a role in lipid homeostasis, wound healing and cell migration and adhesion (PubMed:26091039).
Homodimer; disulfide-linked (PubMed:34349020). Interacts with FAM20A; probably forming a heterotetramer of 2 subunits of FAM20A and 2 subunits of FAM20C (PubMed:25789606). Interacts with protease MBTPS1/S1P; the interaction results in FAM20C cleavage and secretion (PubMed:34349020). Interacts with COPII components SEC23A and SEC24A; transport of FAM20C from the endoplasmic reticulum to the Golgi is likely to be mediated by COPII vesicles (PubMed:34349020).
N-glycosylation is required for folding.
Propeptide cleavage by MBTPS1/S1P promotes FAM20C secretion and maximal kinase activity which is essential for efficient osteoblast differentiation and biomineralization.
Serine/threonine protein kinase activity is increased upon interaction with FAM20A.
Catalyzes the asymmetric hydrolysis of diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A) to yield AMP and ATP (By similarity). Exhibits decapping activity towards FAD-capped RNAs and dpCoA-capped RNAs in vitro (By similarity).
(Microbial infection) Interacts with Staphylococcus aureus protein SdrE; this interaction inhibits complement-mediated bacterial opsonization.
Controls the classical pathway of complement activation. It binds as a cofactor to C3b/C4b inactivator (C3bINA), which then hydrolyzes the complement fragment C4b. It also accelerates the degradation of the C4bC2a complex (C3 convertase) by dissociating the complement fragment C2a. Alpha chain binds C4b. It interacts also with anticoagulant protein S and with serum amyloid P component.
Contributes to the neddylation of all cullins by transferring NEDD8 from N-terminally acetylated NEDD8-conjugating E2s enzyme to different cullin C-terminal domain-RBX complexes which is necessary for the activation of cullin-RING E3 ubiquitin ligases (CRLs) (PubMed:26906416, PubMed:23201271, PubMed:19617556). May play a role in DNA damage response and may participate in cell proliferation and anchorage-independent cell growth (PubMed:23098533, PubMed:24192928).
Expression is decreased in a time-dependent manner after UVC exposure.
Part of a complex that contains DCUN1D5, CUL1 and RBX1; this interaction is bridged by CUL1 (PubMed:24192928, PubMed:26906416). Interacts (via the DCUN1 domain) with the unneddylated cullins: interacts with CUL1, CUL2, CUL3, CUL4A, CUL4B and CUL5; these interactions promote the cullin neddylation and the identity of the cullin dictates the affinity of the interaction (PubMed:24192928, PubMed:26906416, PubMed:23201271). Interacts (via DCUN1 domain) with UBE2M (N-terminally acetylated form) and probably with UBE2F (N-terminally acetylated form) (PubMed:24192928, PubMed:23201271). May also interact with regulators or subunits of cullin-RING ligases such as RBX1, RNF7, ELOB and DDB1; these interactions are bridged by cullins (PubMed:26906416). Interacts with CAND1; this interaction is bridged by cullins and strongly inhibits the neddylation of cullins. These CAND-cullin-DCNL complexes can only be neddylated in the presence of a substrate adapter (PubMed:24192928, PubMed:26906416).
Phosphorylation at Ser-41 is independent of cullin's interaction. Phosphorylated in response to both TICAM1 and MYD88 dependent Toll-like receptor (TLR) pathway activation (By similarity). Phosphorylated in response to IL1B stimulation (PubMed:29958295).
The DCUN1 domain, also known as PONY domain, mediates the interaction with different cullins (PubMed:23201271, PubMed:24192928). The DCUN1 domain mediates the interaction with the N-terminally acetylated NEDD8-conjugating E2s enzyme leading to the NEDD8 transfer from N-terminally acetylated NEDD8-conjugating E2s enzyme to different cullin C-terminal domain-RBX complexes; the neddylation efficiency correlates with the DCUN1D5-cullin and DCUN1D5-E2 interaction affinities (PubMed:23201271).
Weakly expressed in testis, skin and immune tissues (thymus, spleen and lymph nodes).
Belongs to the actin family. ARP5 subfamily.
Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the helicase ATP-binding and the helicase C-terminal domain of INO80. Interacts with DDB1. Interacts with ACTR8; the interaction is observed in asynchronous (interphase) cells but not in metaphase-arrested cells indicative for a possible dissociation of the INO80 complex in mitotic cells.
Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair. Involved in DNA double-strand break repair and UV-damage excision repair.
Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.
Like erythrocyte spectrin, the spectrin-like proteins are capable of forming dimers which can further associate to tetramers. Interacts (via C-terminal spectrin repeats) with TRPC4. Interacts with CALM and EMD. Interacts with isoform 1 of ACP1. Identified in a complex with ACTN4, CASK, IQGAP1, MAGI2, NPHS1 and SPTBN1. Interacts with SHANK3 (via ANK repeats). Interacts with CLN3; this interaction regulates the fodrin localization at the plasma membrane (Probable).
Phosphorylation of Tyr-1176 decreases sensitivity to cleavage by calpain in vitro.
Homooligomer (PubMed:31652072). F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). CF(0) has three main subunits: a, b and c. Component of an ATP synthase complex composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5PD, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and ATP5MJ (By similarity). Interacts with TMEM70 (homooligomer form); this interaction facilitates the oligomer formation of subunit c/ATP5MC1 (c-ring) and the c-ring membrane insertion and also protects ATP5MC1 against intramitochondrial proteolysis (PubMed:31652072).
Trimethylated by ATPSCKMT at Lys-104. Methylation is required for proper incorporation of the C subunit into the ATP synthase complex and mitochondrial respiration.
Expressed in lung and in primary lung squamous cell carcinoma (LSCC).
Plays a role as a mediator of E2F1-induced apoptosis in the absence of p53/TP53 (PubMed:15565177). Plays a role as a mediator of E2F1-induced apoptosis in the absence of p53/TP53. Inhibits TLR9 response to nucelic acids and regulates TLR9-mediated innate immune response (By similarity).
Up-regulated in the mitochondria by E2F1 after addition of 4-hydroxytamoxifen (at protein level).
Component of the p62 complex, a complex at least composed of NUP62, NUP54, and NUP58 (By similarity). Interacts with NUP88 (PubMed:30543681). Interacts with NUTF2 (By similarity). Interacts with HIKESHI (PubMed:22541429). Interacts with OSBPL8 (PubMed:21698267). Interacts with CAPG (PubMed:18266911). Interacts with SAS6 and TUBG1 at the centrosome (PubMed:24107630). Interacts with MCM3AP isoform GANP (PubMed:23652018).
Essential component of the nuclear pore complex (PubMed:1915414). The N-terminal is probably involved in nucleocytoplasmic transport (PubMed:1915414). The C-terminal is involved in protein-protein interaction probably via coiled-coil formation, promotes its association with centrosomes and may function in anchorage of p62 to the pore complex (PubMed:1915414, PubMed:24107630). Plays a role in mitotic cell cycle progression by regulating centrosome segregation, centriole maturation and spindle orientation (PubMed:24107630). It might be involved in protein recruitment to the centrosome after nuclear breakdown (PubMed:24107630).
O-glycosylated. Contains about 10 N-acetylglucosamine side chain sites predicted for the entire protein, among which only one in the C-terminal.
Catalyzes a salvage reaction resulting in the formation of AMP, that is energically less costly than de novo synthesis.
PubMed:15764369 initially suggested a role in targeting SLC4A1 (kidney anion exchanger 1) to the plasma membrane; it does not seem to do so as it does not interact with SLC4A1 and has no effect on SLC4A1 trafficking.
(Microbial infection) Stearoylated By S.flexneri N-epsilon-fatty acyltransferase IcsB, promoting S.flexneri evasion of autophagy.
ISGylated. Isgylation inhibits its interaction with VTA1.
Probable peripherally associated component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses) (PubMed:14519844). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. Involved in HIV-1 p6- and p9-dependent virus release (PubMed:14519844).
Probable peripherally associated component of the endosomal sorting required for transport complex III (ESCRT-III). ESCRT-III components are thought to multimerize to form a flat lattice on the perimeter membrane of the endosome. Several assembly forms of ESCRT-III may exist that interact and act sequentially. Interacts with VTA1; the interaction involves soluble CHMP5 (PubMed:15644320, PubMed:17261583, PubMed:21543490). Interacts with CHMP2A (PubMed:14519844). Interacts with NOD2 (PubMed:27812135). Interacts with BROX (PubMed:22484091).
Allelic variants in IL4RA are associated with a susceptibility to atopy, an immunological condition that can lead to clinical symptoms such as allergic rhinitis, sinusitis, asthma and eczema.
Allelic variants in IL4RA are associated with cedar pollen sensitization. Individuals develop Japanese cedar pollinosis with increased exposure to cedar pollen. Japanese cedar pollinosis is a type I allergic disease with ocular and nasal symptoms that develop paroxysmally on contact with Japanese cedar pollen. These symptoms, which occur seasonally each year, are typical features of allergic rhinitis, such as sneezing, excessive nasal secretion, nasal congestion, and conjunctival itching.
Isoform 1 and isoform 2 are highly expressed in activated T-cells.
On IL4 binding, phosphorylated on C-terminal tyrosine residues. Phosphorylation on any one of tyrosine residues, Tyr-575, Tyr-603 or Tyr-631, is required for STAT6-induced gene induction.
Receptor for both interleukin 4 and interleukin 13. Couples to the JAK1/2/3-STAT6 pathway. The IL4 response is involved in promoting Th2 differentiation. The IL4/IL13 responses are involved in regulating IgE production and, chemokine and mucus production at sites of allergic inflammation. In certain cell types, can signal through activation of insulin receptor substrates, IRS1/IRS2.
Soluble IL4R (sIL4R) inhibits IL4-mediated cell proliferation and IL5 up-regulation by T-cells.
The extracellular domain represents the IL4 binding protein (IL4BP).
The functional IL4 receptor is formed by initial binding of IL4 to IL4R. Subsequent recruitment to the complex of the common gamma chain, in immune cells, creates a type I receptor and, in non-immune cells, of IL13RA1 forms a type II receptor. IL4R can also interact with the IL13/IL13RA1 complex to form a similar type II receptor (PubMed:7775445, PubMed:8804422). Interacts with PIK3C3 (By similarity). Interacts with the SH2-containing phosphatases, PTPN6/SHIP1, PTPN11/SHIP2 and INPP5D/SHIP (PubMed:11714803). Interacts with JAK1 through a Box 1-containing region; inhibited by SOCS5. Interacts with SOCS5; inhibits IL4 signaling (By similarity). Interacts with JAK3 (PubMed:7538655). Interacts with CLM1 (By similarity).
The soluble form (sIL4R/IL4BP) can also be produced by proteolytic cleavage at the cell surface (shedding) by a metalloproteinase.
Belongs to the Mediator complex subunit 23 family.
Interacts with ELK1 (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with CEBPB (when not methylated), CTNNB1, and GLI3. Interacts with the adenovirus E1A protein.
Required for transcriptional activation subsequent to the assembly of the pre-initiation complex (By similarity). Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors. Required for transcriptional activation by adenovirus E1A protein. Required for ELK1-dependent transcriptional activation in response to activated Ras signaling.
Specifically dephosphorylates sphingosine 1-phosphate (S1P), dihydro-S1P, and phyto-S1P. Does not act on ceramide 1-phosphate, lysophosphatidic acid or phosphatidic acid (PubMed:16782891). Sphingosine-1-phosphate phosphatase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway (PubMed:12815058, PubMed:11756451, PubMed:16782891). Regulates the intracellular levels of the bioactive sphingolipid metabolite S1P that regulates diverse biological processes acting both as an extracellular receptor ligand or as an intracellular second messenger (PubMed:11756451, PubMed:12815058, PubMed:16782891). Involved in efficient ceramide synthesis from exogenous sphingoid bases. Converts S1P to sphingosine, which is readily metabolized to ceramide via ceramide synthase. In concert with sphingosine kinase 2 (SphK2), recycles sphingosine into ceramide through a phosphorylation/dephosphorylation cycle (By similarity). Regulates endoplasmic-to-Golgi trafficking of ceramides, resulting in the regulation of ceramide levels in the endoplasmic reticulum, preferentially long-chain ceramide species, and influences the anterograde membrane transport of both ceramide and proteins from the endoplasmic reticulum to the Golgi apparatus (PubMed:16782891). The modulation of intracellular ceramide levels in turn regulates apoptosis (By similarity). Via S1P levels, modulates resting tone, intracellular Ca(2+) and myogenic vasoconstriction in resistance arteries (PubMed:18583713). Also involved in unfolded protein response (UPR) and ER stress-induced autophagy via regulation of intracellular S1P levels (PubMed:20798685, PubMed:18583713). Involved in the regulation of epidermal homeostasis and keratinocyte differentiation (By similarity).
Ubiquitous, with the strongest level in placenta and kidney.
Binds HCLS1. Interacts with the SH3 domain of HCLS1 in vitro (By similarity).
NPY is implicated in the control of feeding and in secretion of gonadotrophin-release hormone.
One of the most abundant peptides in the nervous system. Also found in some chromaffin cells of the adrenal medulla.
The neuropeptide Y form is cleaved at Pro-30 by the prolyl endopeptidase FAP (seprase) activity (in vitro).
Homodimer (PubMed:34711951). Interacts with IPO9; the interaction is direct (PubMed:34711951). Associates (via SYVS motif) with 20S and 26S proteasomes (PubMed:34711951). Interacts with SMARCD1; promoting SWI/SNF complex recruitment (By similarity). Interacts with NFKBIZ (By similarity). Interacts with YWHAB (By similarity).
Molecular adapter that acts as a bridge between a variety of multiprotein complexes, and which is involved in embryonic development, immunity, myogenesis and brain development (PubMed:34711951). Plays a key role in nuclear protein degradation by promoting import of proteasomes into the nucleus: directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end, bridging them together and mediating the import of pre-assembled proteasome complexes through the nuclear pore (PubMed:34711951). Involved in innate immunity by regulating the production of interleukin-6 (IL6) downstream of Toll-like receptor (TLR): acts by bridging the NF-kappa-B inhibitor NFKBIZ and the SWI/SNF complex, leading to promote induction of IL6 (By similarity). Also involved in adaptive immunity by promoting B-cell activation (By similarity). Involved in brain development: required for the survival and proliferation of cerebral cortical progenitor cells (By similarity). Involved in myogenesis: required for skeletal muscle formation and skeletal development, possibly by regulating expression of muscle differentiation factors (By similarity). Also plays a role in facilitating interdigital tissue regression during limb development (By similarity).
Widely expressed with the highest expression in peripheral blood leukocytes.
Binds HA-I and HA-II plasma membrane adapters (By similarity). Interacts with DPP4; the interaction is direct. Binds GGA1, GGA2 and GGA3. Interacts with the heterotrimeric retromer cargo-selective complex (CSC), formed by VPS26 (VPS26A or VPS26B), VPS29 and VPS35; which is involved in retrograde trafficking of the receptor from endosomes to the Golgi apparatus (Probable).
Contains 15 repeating units of approximately 147 AA harboring four disulfide bonds each. The most highly conserved region within the repeat consists of a stretch of 13 AA that contains cysteines at both ends.
Mediates the transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes (PubMed:2963003, PubMed:18817523). Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate receptors in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelysosomal compartment where the low pH mediates the dissociation of the complex (PubMed:2963003, PubMed:18817523). The receptor is then recycled back to the Golgi for another round of trafficking through its binding to the retromer (PubMed:18817523). This receptor also binds IGF2 (PubMed:18046459). Acts as a positive regulator of T-cell coactivation by binding DPP4 (PubMed:10900005).
Palmitoylated (PubMed:18817523). Undergoes cysteine S-palmitoylation which promotes interaction with the retromer cargo-selective complex which mediates its retrograde trafficking to the Golgi apparatus (PubMed:18817523).
GTPase activator component of the RGS7-GNB5 complex that regulates G protein-coupled receptor signaling cascades (PubMed:10521509, PubMed:10862767, PubMed:31189666). The RGS7-GNB5 complex acts as an inhibitor signal transduction by promoting the GTPase activity of G protein alpha subunits, such as GNAO1, thereby driving them into their inactive GDP-bound form (PubMed:10521509, PubMed:10862767). May play a role in synaptic vesicle exocytosis (PubMed:12659861) (Probable). Glycine-dependent regulation of the RGS7-GNB5 complex by GPR158 affects mood and cognition via its ability to regulate neuronal excitability in L2/L3 pyramidal neurons of the prefrontal cortex (By similarity). Modulates the activity of potassium channels that are activated by GNAO1 in response to muscarinic acetylcholine receptor M2/CHRM2 signaling (PubMed:15897264).
Interacts with GNB5, forming the RGS7-GNB5 complex (PubMed:10521509, PubMed:10339615). Interacts with GPR158; promotes the GTPase activator activity of the RGS7-GNB5 complex in absence of glycine, in contrast GTPase activator activity of the RGS7-GNB5 complex is inhibited in presence of glycine (PubMed:31189666, PubMed:34815401, PubMed:34793198). Interacts with GPR179 (By similarity). Interacts with PKD1; this prevents rapid proteasomal degradation (PubMed:10339594). Interacts with RGS7BP, leading to regulate the subcellular location of the heterodimer formed with GNB5 (PubMed:15897264). Interacts (phosphorylated form) with 14-3-3 protein YWHAQ (PubMed:10862767). Interacts with SNAPIN (PubMed:12659861). Interacts with GNAI1 (PubMed:18434541). Interacts with GNAO1, GNAI3 and GNAZ (By similarity).
Phosphorylation and subsequent interaction with 14-3-3 proteins inhibits GAP activity.
Ubiquitinated, leading to rapid proteasomal degradation.
Associates with core 1 beta-3-galactosyltransferase (C1GALT1), probably not with the soluble active form.
Defects in C1GALT1C1 in Ag104A cell line create a tumor-specific glycopeptidic neo-epitope. This epitope induces a high-affinity, highly specific, syngeneic monoclonal antibody. This is caused by the abolition of function of a glycosyltransferase, disrupting O-glycan Core 1 synthesis.
Probable chaperone required for the generation of 1 O-glycan Gal-beta1-3GalNAc-alpha1-Ser/Thr (T antigen), which is a precursor for many extended O-glycans in glycoproteins. Probably acts as a specific molecular chaperone assisting the folding/stability of core 1 beta-3-galactosyltransferase (C1GALT1).
Ubiquitously expressed. Abundantly expressed in salivary gland, stomach, small intestine, kidney, and testis and at intermediate levels in whole brain, cerebellum, spinal cord, thymus, spleen, trachea, lung, pancreas, ovary, and uterus.
Was originally (PubMed:12361956) assigned to be a glycosyltransferase. However, it was later shown (Ref.2 and PubMed:12464682) that it has no transferase activity and rather acts as a chaperone.
Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, activation of proteolysis of misfolded proteins and the formation and dissociation of protein complexes. Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation. This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. The affinity for polypeptides is regulated by its nucleotide bound state. In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. It goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release (PubMed:26865365).
Only at higher temperatures, and no basal expression.
Homodimer; disulfide-linked. May form heterodimers with FEZ2. Interacts with the NH2-terminal variable region (V1) of PKC zeta and weakly with that of PKC epsilon (By similarity). Interacts with UBE4B. Interacts with SAP30L. Interacts with SCOC and ULK1; SCOC interferes with ULK1-binding to FEZ1. Directly interacts with SCOC and UVRAG. Stabilizes the interaction between SCOC and UVRAG during amino acid starvation.
May be involved in axonal outgrowth as component of the network of molecules that regulate cellular morphology and axon guidance machinery. Able to restore partial locomotion and axonal fasciculation to C.elegans unc-76 mutants in germline transformation experiments. May participate in the transport of mitochondria and other cargos along microtubules.
Phosphorylated by protein kinase C zeta; which enhances interaction with UBE4B and polyubiquitination.
Polyubiquitinated in a UBE4B-dependent manner; which does not lead to proteasomal degradation and may be important for neurogenic activity. Polyubiquitin linkage seems to be mainly through Lys-26.
Homodimer (PubMed:25596185). Monomer (PubMed:23144459). Interacts with TST (PubMed:19136963). May interact with RELA (PubMed:12398897).
Sulfur dioxygenase that plays an essential role in hydrogen sulfide catabolism in the mitochondrial matrix. Hydrogen sulfide (H(2)S) is first oxidized by SQRDL, giving rise to cysteine persulfide residues. ETHE1 consumes molecular oxygen to catalyze the oxidation of the persulfide, once it has been transferred to a thiophilic acceptor, such as glutathione (R-SSH). Plays an important role in metabolic homeostasis in mitochondria by metabolizing hydrogen sulfide and preventing the accumulation of supraphysiological H(2)S levels that have toxic effects, due to the inhibition of cytochrome c oxidase. First described as a protein that can shuttle between the nucleus and the cytoplasm and suppress p53-induced apoptosis by sequestering the transcription factor RELA/NFKB3 in the cytoplasm and preventing its accumulation in the nucleus (PubMed:12398897).
Dephosphorylates proteins phosphorylated on Ser, Thr, and Tyr residues and low molecular weight phosphatase substrate para-nitrophenylphosphate. Phosphorylates phosphatidylinositol 3,4,5-trisphosphate (PIP3).
Expressed in brain, heart, kidney, spleen, liver, colon, testis, muscle, placenta, thyroid gland, pancreas, ovary, prostate, skin, peripheral blood, and bone marrow.
Expressed in fetal brain and fetal liver.
The metalloprotease domain is constituted by the two C-terminal nuclear regions.
Transmembrane metalloprotease whose catalytic activity is critical for processing lamin A/LMNA on the inner nuclear membrane and clearing clogged translocons on the endoplasmic reticulum (PubMed:33315887, PubMed:33293369). Proteolytically removes the C-terminal three residues of farnesylated proteins (PubMed:33315887, PubMed:33293369). Plays also an antiviral role independently of its protease activity by restricting enveloped RNA and DNA viruses, including influenza A, Zika, Ebola, Sindbis, vesicular stomatitis, cowpox, and vaccinia (PubMed:28246125, PubMed:28169297). Mechanistically, controls IFITM antiviral pathway to hinder viruses from breaching the endosomal barrier by modulating membrane fluidity (PubMed:35283811).
Widely expressed. High levels in kidney, prostate, testis and ovary.
Cartilage matrix protein is a major component of the extracellular matrix of non-articular cartilage. It binds to collagen.
A conserved histidine residue in the third TMD (His-115) may play an essential role in the pH sensitivity of SLCO1B1/OATP1B1-mediated substrate transport.
Highly expressed in liver, at the basolateral membranes of centrilobular hepatocytes (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:12196548, PubMed:22232210). Expressed in liver (at protein level) (PubMed:15159445). Expressed in fetal liver (PubMed:10873595). Not detected in heart, brain, placenta, lung, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocyte (PubMed:10358072, PubMed:10873595). In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed in Leydig cells and within the tubules (PubMed:35307651).
Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:12196548, PubMed:11159893, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15970799, PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16627748, PubMed:16624871). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463).
Expressed in the brain, with expression in the epithelial cell layer of the choroid plexus (at protein level).
Probable hormone that may attenuate cell proliferation and induce senescence of oligodendrocyte and neural precursor cells in the central nervous system (By similarity). ECRG4-induced senescence is characterized by G1 arrest, RB1 dephosphorylation and accelerated CCND1 and CCND3 proteasomal degradation (By similarity).
Forms homotrimers which can further assemble to form higher-order oligomeric complexes. Interacts with ADGRB3. May interact with ERFE. Forms heterooligomers with C1QL3 and C1QL4, when proteins are coexpressed; this interaction does not occur after secretion.
May regulate the number of excitatory synapses that are formed on hippocampus neurons. Has no effect on inhibitory synapses (By similarity).
Possesses 3'-5' exoribonuclease activity. Required for 3'-end trimming of AGO1-bound miRNAs (By similarity).
Catalyzes the conjugation of long-chain fatty acyl-CoA thioester and glycine to produce long-chain N-(fatty acyl)glycine, an intermediate in the primary fatty acid amide biosynthetic pathway.
Homodimer. Can form trans-heterodimers with NECTIN3. Interacts with EPB41L1, DLG3, PALS2 and CASK (By similarity).
Involved in the cell-cell adhesion. Has both calcium-independent homophilic cell-cell adhesion activity and calcium-independent heterophilic cell-cell adhesion activity with IGSF4, NECTIN1 and NECTIN3. Interaction with EPB41L1 may regulate structure or function of cell-cell junctions (By similarity).
Isoform 1 is expressed mainly in adult and fetal brain. Isoform 2 is highly expressed in adult brain and weakly expressed in placenta. In brain, Isoform 2 is highly expressed in cerebellum.
Markedly in glioma cell lines and prostate cancer cell lines.
The cytoplasmic region mediates interaction with EPB41L1, DLG3, PALS2 and CASK.
By acting through a filamin-A/F-actin axis, it controls the start of neocortical cell migration from the ventricular zone. May be able to induce the degradation of filamin-A.
Interacts with FLNA. Interacts with RHOD (in GTP-bound form).
Moderately expressed in adult heart and brain. Weakly expressed in lung, skeletal muscle, ovary, testis, kidney, and fetal brain, and hardly detectable in liver, pancreas, spleen, and fetal liver. Within brain, moderate expression is found in amygdala and caudate nucleus.
Isoform 1 is expressed in testis and glioblastoma. Isoform 2 is expressed in fetal lung.
(Microbial infection) Interacts with HTLV-1 protein p13(II).
Inactivated by interferon-induced RSAD2. This inactivation may result of disruption of lipid rafts at the plasma membrane, and thus have an antiviral effect since many enveloped viruses need lipid rafts to bud efficiently out of the cell.
Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones. FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate.
Interacts with MCM3AP/GANP. Interacts with PPP5C, and the phosphatase 2A core enzyme composed of the PPP2CA catalytic subunit and the constant regulatory subunit PPP2R1A. Finds in a complex with ABCB1, TFPI2 and PPP2R3C; leading to the dephosphorylation of ABCB1.
May regulate MCM3AP phosphorylation through phosphatase recruitment (By similarity). May act as a negative regulator of ABCB1 expression and function through the dephosphorylation of ABCB1 by TFPI2/PPP2R3C complex (PubMed:24333728). May play a role in the activation-induced cell death of B-cells (By similarity).
Ubiquitously expressed in brain and other tissues.
Acts as both a repressor and activator of transcription (PubMed:21654807). Binds to the consensus sequence 5'-GACCACCCAC-3' (By similarity). By controlling the expression of genes involved in cell differentiation inhibits the lineage commitment of multipotent cells (PubMed:21654807). Prevents, for instance, the differentiation of multipotent mesenchymal cells into adipocyte and osteoblast (By similarity).
Interacts with KLF4 (PubMed:21654807). Interacts with POU5F1 and/or POU5F1B (PubMed:21654807). Interacts with SOX2 (PubMed:21654807).
The combined transgenic expression of the OSK transcription factors POU5F1/OCT4, SOX2 and KLF4, reprograms differentiated cells into induced pluripotent stem cells/iSPCs. iPSCs exhibit the morphology and properties of embryonic stem/ES cells. The coexpression of GLIS1 can increase the efficiency of OSK-induced pluripotent stem cells/iPSCs production.
A synthetic analog known as octreotide or SMS 201-995 is available under the name Sandostatin (Novartis). It is used for the treatment of a variety of disorders including acromegaly and the symptomatic treatment of carcinoid tumors and vasoactive intestinal peptide tumors.
C-terminal amidation of the neuronostatin peptide is required for its biological activity, including for the regulation of mean arterial pressure.
Inhibits the secretion of pituitary hormones, including that of growth hormone/somatotropin (GH1), PRL, ACTH, luteinizing hormone (LH) and TSH. Also impairs ghrelin- and GnRH-stimulated secretion of GH1 and LH; the inhibition of ghrelin-stimulated secretion of GH1 can be further increased by neuronostatin.
May enhance low-glucose-induced glucagon release by pancreatic alpha cells (By similarity). This effect may be mediated by binding to GPR107 and PKA activation (By similarity). May regulate cardiac contractile function (By similarity). May compromise cardiomyocyte viability (By similarity). In the central nervous system, may impair memory retention and may affect hippocampal excitability (By similarity). May also have anxiolytic and anorexigenic effects (By similarity). May play a role in arterial pressure regulation (By similarity). May inhibit basal, but not ghrelin- or GnRH-stimulated secretion of GH1 or LH, but does not affect the release of other pituitary hormones, including PRL, ACTH, FSH or TSH. Potentiates inhibitory action of somatostatin on ghrelin-stimulated secretion of GH1, but not that on GnRH-stimulated secretion of LH (PubMed:29615476).
Interacts with POU1F1 (PubMed:26612202). At neuronal promoters, interacts with LDB1, in motor neurons LDB1 is displaced by ISL1 and a ternary complex is formed in which ISL1 contacts both LHX3 and LDB1; allosteric structural changes in the DNA binding domain of LHX3, induced by the ISL1-LHX3 interaction, may explain differences in sequence specificity of the different complexes. Interacts with LDB2. May interact with CITED2/MRG1 (By similarity).
The LIM domain specifically interacts with the Pit-1 POU domain and is required for synergistic interactions with Pit-1, but not for basal transcriptional activation events.
Transcription factor. Recognizes and binds to the consensus sequence motif 5'-AATTAATTA-3' in the regulatory elements of target genes, such as glycoprotein hormones alpha chain CGA and visual system homeobox CHX10, positively modulating transcription; transcription can be co-activated by LDB2. Synergistically enhances transcription from the prolactin promoter in cooperation with POU1F1/Pit-1 (By similarity). Required for the establishment of the specialized cells of the pituitary gland and the nervous system (PubMed:21149718). Involved in the development of interneurons and motor neurons in cooperation with LDB1 and ISL1 (By similarity).
Essential sperm cell-surface protein required for sperm-egg fusion and fertilization.
Expressed in fibroblasts (at protein level).
GMPPA is a close homolog of GMPPB, that has been shown to catalyze the formation of GDP-mannose, an essential precursor of glycan moieties of glycoproteins and glycolipids. However, lymphocytes from AAMR patients, that exhibit very low GMPPA protein levels, have unchanged GDP-mannose pyrophosphorylase activity and higher GDP-mannose levels than those from healthy controls. Affected individuals and control subjects show similar N-glycosylation profiles, both for transferrin glycosylation and for N-glycans derived from either total serum protein or immunoglobulin G. These observations led to the hypothesis that GMPPA might serve as a regulatory subunit and allow allosteric feedback inhibition of GMPPB by GDP-mannose. Alignment of GMPPAs and GMPPBs from various species shows that GMPPAs are characterized by a 2 amino acid-insertion (residues 11-12) in a highly conserved motif that borders the catalytic pocket and binds the nucleotide substrate in homologous enzymes. This insertion might inactivate the ancestral catalytic site, converting it to an allosteric site (PubMed:24035193).
May serve as a regulatory subunit and allow allosteric feedback inhibition of GMPPB by GDP-mannose.
Can convert androstan-3-alpha,17-beta-diol (3-alpha-diol) to androsterone in vitro, suggesting that it may participate in androgen metabolism during steroidogenesis. May act by metabolizing compounds that stimulate steroid synthesis and/or by generating metabolites that inhibit it. Has no activity toward DHEA (dehydroepiandrosterone), or A-dione (4-androste-3,17-dione), and only a slight activity toward testosterone to A-dione. Tumor-associated antigen in cutaneous T-cell lymphoma.
Present at high level in steroidogenic cells such as syncytiotrophoblasts, sebaceous gland, Leydig cells, and granulosa cells of the dominant follicle and corpus luteum. In lung, it is detected in the ciliated epithelium and in acini of adult trachea, in bronchioles, but not in alveoli. In the eye, it is detected in the nonpigmented epithelium of the ciliary body and, at lower level, in the inner nuclear layer of the retina (at protein level). Widely expressed. Highly expressed in retina, pancreas, kidney, liver, lung, adrenal, small intestine, ovary and heart.
Has a wider tissue distribution than isoform 1, and acts as dominant-negative antagonist.
Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May also regulate the TOR signaling cascade. Phosphorylates PFKFB2 (PubMed:36402789).
Serves as a positive regulator of myogenic differentiation by inducing cell cycle arrest, the expression of myogenin and other muscle-specific proteins, and myotube formation.
Binds SUMO1 and UBE2I. Interacts with AXIN1, JUN, MDM2, PARK7, TP53 and TP73 isoform alpha, but not TP73 isoform beta. Interacts with STAT4 following IL12 and IFN-alpha stimulation of T-cells. Interacts also with GTF2I, GTF2IRD1, IKFZ1, DAB2 and MSX2, as well as with several steroid receptors, including ESR1, ESR2, NR3C1, PGR, AR, and with NCOA2 (By similarity). Sumoylation of a target protein seems to enhance the interaction. Binds to sumoylated ELK1. Binds DNA, such as CDKN1A promoter, in a sequence-specific manner. Interacts with PLAG1. Interacts with KLF8; the interaction results in SUMO ligation and repression of KLF8 transcriptional activity and of its cell cycle progression into G(1) phase. PIAS2-beta interacts with IFIH1/MDA5. Isoform PIAS2-alpha interacts with PML (isoform PML-12). Interacts with PRDM1/Blimp-1 (PubMed:28842558).
Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. Plays a crucial role as a transcriptional coregulator in various cellular pathways, including the STAT pathway, the p53 pathway and the steroid hormone signaling pathway. The effects of this transcriptional coregulation, transactivation or silencing may vary depending upon the biological context and the PIAS2 isoform studied. However, it seems to be mostly involved in gene silencing. Binds to sumoylated ELK1 and enhances its transcriptional activity by preventing recruitment of HDAC2 by ELK1, thus reversing SUMO-mediated repression of ELK1 transactivation activity. Isoform PIAS2-beta, but not isoform PIAS2-alpha, promotes MDM2 sumoylation. Isoform PIAS2-alpha promotes PARK7 sumoylation. Isoform PIAS2-beta promotes NCOA2 sumoylation more efficiently than isoform PIAS2-alpha. Isoform PIAS2-alpha sumoylates PML at'Lys-65' and 'Lys-160'.
Isoform 3 expression in adult testis is 14.2-fold stronger than in embryonic testis.
Mainly expressed in testis. Isoform 3 is expressed predominantly in adult testis, weakly in pancreas, embryonic testis and sperm, and at very low levels in other organs.
Up-regulated transiently during myeloid differentiation in various cells lines, such as HL-60, U-937, K-562, induced by either phorbol ester (TPA) or retinoic acid.
Exists both as a covalent disulfide-linked homohexamer, and a complex of three disulfide-linked dimers non-covalently kept together. Interacts with MCFD2. May interact with TMEM115. Interacts with RAB3GAP1 and RAB3GAP2 (PubMed:22337587). Interacts with UBXN6 (PubMed:22337587). Interacts with SERPINA1/alpha1-antitrypsin (PubMed:31142615).
Mannose-specific lectin. May recognize sugar residues of glycoproteins, glycolipids, or glycosylphosphatidyl inositol anchors and may be involved in the sorting or recycling of proteins, lipids, or both. The LMAN1-MCFD2 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.
The FF ER export motif at the C-terminus is not sufficient to support endoplasmic reticulum exit, and needs assistance of Gln-501 for proper recognition of COPII coat components.
(Microbial infection) Interacts with SV40 Large T antigen; this interactions allows viral DNA replication.
A chromosomal aberration involving TOP1 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with NUP98.
Monomer. Interacts with ERCC6 (PubMed:26030138).
Phosphorylation at Ser-506 by CK2 increases binding to supercoiled DNA and sensitivity to camptothecin.
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then rotates around the intact phosphodiester bond on the opposing strand, thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Involved in the circadian transcription of the core circadian clock component BMAL1 by altering the chromatin structure around the ROR response elements (ROREs) on the BMAL1 promoter.
Specifically inhibited by camptothecin (CPT), a plant alkaloid with antitumor activity.
Sumoylated. Lys-117 is the main site of sumoylation. Sumoylation plays a role in partitioning TOP1 between nucleoli and nucleoplasm. Levels are dramatically increased on camptothecin (CPT) treatment.
Binds to GC boxes promoters elements. Probable transcriptional activator that has a role in the coordination of changes in transcription required to generate pattern in the developing embryo (By similarity).
(Microbial infection) A number of viral and bacterial pathogens seem to bind MCP in order to exploit its immune regulation property and directly induce an immunosuppressive phenotype in T-cells.
(Microbial infection) Acts as a receptor for Adenovirus subgroup B2 and Ad3.
(Microbial infection) Acts as a receptor for Herpesvirus 6/HHV-6.
(Microbial infection) Acts as a receptor for cultured Measles virus.
(Microbial infection) Binds to Streptococcus pyogenes M protein and to type IV pili from Neisseria (PubMed:7708671, PubMed:9379894, PubMed:11260136, PubMed:11971006).
(Microbial infection) Interacts with human adenovirus B/D fiber protein (PubMed:12915534, PubMed:14566335, PubMed:15047806, PubMed:15078926, PubMed:15919905, PubMed:16254377).
(Microbial infection) Interacts with human herpesvirus 6 GH protein (PubMed:12663806, PubMed:12724329).
(Microbial infection) Interacts with measles virus H protein.
(Microbial infection) May act as a receptor for pathogenic bacteria Neisseria and Streptococcus pyogenes (PubMed:7708671, PubMed:9379894, PubMed:11260136, PubMed:11971006).
Acts as a cofactor for complement factor I, a serine protease which protects autologous cells against complement-mediated injury by cleaving C3b and C4b deposited on host tissue. May be involved in the fusion of the spermatozoa with the oocyte during fertilization. Also acts as a costimulatory factor for T-cells which induces the differentiation of CD4+ into T-regulatory 1 cells. T-regulatory 1 cells suppress immune responses by secreting interleukin-10, and therefore are thought to prevent autoimmunity.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Other genes may play a role in modifying the phenotype. Patients with CD46 mutations seem to have an overall better prognosis compared to patients carrying CFH mutations.
Expressed by all cells except erythrocytes.
Extensively O-glycosylated in the Ser/Thr-rich domain. O-glycosylation is required for Neisseria binding but not for Measles virus or human adenovirus binding.
In epithelial cells, isoforms B/D/F/H/J/L/3 are phosphorylated by YES1 in response to infection by Neisseria gonorrhoeae; which promotes infectivity. In T-cells, these isoforms may be phosphorylated by LCK.
Interacts with C3b (PubMed:3260937, PubMed:1717583). Interacts with C4b (PubMed:1717583). Interacts with moesin/MSN (PubMed:7884872).
N-glycosylated on Asn-83; Asn-114 and Asn-273 in most tissues, but probably less N-glycosylated in testis. N-glycosylation on Asn-114 and Asn-273 is required for cytoprotective function. N-glycosylation on Asn-114 is required for Measles virus binding. N-glycosylation on Asn-273 is required for Neisseria binding. N-glycosylation is not required for human adenovirus binding.
Sushi domains 1 and 2 are required for interaction with human adenovirus B PIV/FIBER protein and with Measles virus H protein. Sushi domains 2 and 3 are required for Herpesvirus 6 binding. Sushi domain 3 is required for Neisseria binding. Sushi domains 3 and 4 are required for interaction with Streptococcus pyogenes M protein and are the most important for interaction with C3b and C4b.
Detected in the epithelium and lumen of the epididymis, and in sperm (at protein level).
Has antibacterial activity against the Gram-negative bacteria E.coli. May play a role in sperm maturation and fertilization.
Forms a homodimer or heterodimer with other members of the family (By similarity). Interacts with MAL2.
Binds TRAF2, TRAF5 and TRAF6. Binds the NH2-terminal domain of CAMLG with its C-terminus.
Highly expressed in spleen, thymus, small intestine and peripheral blood leukocytes. Expressed in resting B-cells and activated T-cells, but not in resting T-cells.
Receptor for TNFSF13/APRIL and TNFSF13B/TALL1/BAFF/BLYS that binds both ligands with similar high affinity. Mediates calcineurin-dependent activation of NF-AT, as well as activation of NF-kappa-B and AP-1. Involved in the stimulation of B- and T-cell function and the regulation of humoral immunity.
Part of the nascent polypeptide-associated complex (NAC), which is a heterodimer of NACA and BTF3 (via NAC-A/B domains). NAC associates with ribosomes through the BTF3/NACB subunit. Both subunits can contact nascent polypeptide chains.
When associated with NACA, prevents inappropriate targeting of non-secretory polypeptides to the endoplasmic reticulum (ER). Binds to nascent polypeptide chains as they emerge from the ribosome and blocks their interaction with the signal recognition particle (SRP), which normally targets nascent secretory peptides to the ER. BTF3 is also a general transcription factor that can form a stable complex with RNA polymerase II. Required for the initiation of transcription.
Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses (By similarity).
Phosphorylated. Autophosphorylates upon ligand-binding. Autophosphorylation on Tyr-614 is required for interaction with SH2 domain-containing proteins.
Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Generally has an overlapping and redundant function with EPHB2. Like EPHB2, functions in axon guidance during development regulating for instance the neurons forming the corpus callosum and the anterior commissure, 2 major interhemispheric connections between the temporal lobes of the cerebral cortex. In addition to its role in axon guidance also plays an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and the formation of excitatory synapses. Controls other aspects of development through regulation of cell migration and positioning. This includes angiogenesis, palate development and thymic epithelium development for instance. Forward and reverse signaling through the EFNB2/EPHB3 complex also regulate migration and adhesion of cells that tubularize the urethra and septate the cloaca. Finally, plays an important role in intestinal epithelium differentiation segregating progenitor from differentiated cells in the crypt.
Ubiquitinated by RNF186, mainly through 'Lys-48' and 'Lys-63'-linked polyubiquitin chains.
(Microbial infection) Acts as a receptor for Dengue virus by binding exposed phosphatidyl-serine at the surface of virion membrane (PubMed:23084921). TIM1 and Dengue virus are co-internalized during virus entry (PubMed:29742433).
(Microbial infection) Acts as a receptor for Ebolavirus and Marburg virus by binding exposed phosphatidyl-serine at the surface of virion membrane (PubMed:21536871). Serves as a dual receptor for Ebolavirus by also interacting with envelope glycoprotein GP (PubMed:26487564).
(Microbial infection) Acts as a receptor for Hepatitis A virus.
(Microbial infection) Acts as a receptor for Zika virus by binding to envelope protein E.
(Microbial infection) Interacts with Ebolavirus envelope glycoprotein GP.
(Microbial infection) Interacts with hepatitis A virus capsid proteins.
(Microbial infection) Plays a positive role in Chikungunya virus cell entry.
(Microbial infection) Ubiquitination is required for Dengue virus endocytosis.
Interacts with STAM (PubMed:29742433). Interacts with SELPLG (PubMed:24703780).
Phosphatidylserine receptor that plays an important functional role in regulatory B-cells homeostasis including generation, expansion and suppressor functions (By similarity). As P-selectin/SELPLG ligand, plays a specialized role in activated but not naive T-cell trafficking during inflammatory responses (PubMed:24703780). Controls thereby T-cell accumulation in the inflamed central nervous system (CNS) and the induction of autoimmune disease (PubMed:24703780). Regulates also expression of various anti-inflammatory cytokines and co-inhibitory ligands including IL10 (By similarity). Acts as regulator of T-cell proliferation (By similarity). May play a role in kidney injury and repair (PubMed:17471468).
The extracellular part of the protein can be cleaved and detected in urine and is in correlation with the expression in the kidney.
The region containing tandem repeats is polymorphic and the sequence shown here corresponds to the most common allele (PubMed:14534576). An association between hepatitis A virus (HAV) infection and atopic diseases has been observed in individuals with that allele (PubMed:14534576). Allelic variation does not affect HAV-infection rates in Caucasians, Asians and African Americans (PubMed:14534576).
Ubiquitinated at two lysine residues Lys-338 and Lys-346 on its cytoplasmic domain. Ubiquitination promotes receptor endocytosis and target receptors for lysosomal degradation and termination of receptor signaling.
Up-regulated in the kidney in renal diseases (at protein level).
Widely expressed, with highest levels in kidney and testis. Expressed by activated CD4+ T-cells during the development of helper T-cells responses.
Beta-galactoside-binding lectin that acts as a sensor of membrane damage caused by infection and restricts the proliferation of infecting pathogens by targeting them for autophagy (PubMed:22246324, PubMed:28077878). Detects membrane rupture by binding beta-galactoside ligands located on the lumenal side of the endosome membrane; these ligands becoming exposed to the cytoplasm following rupture (PubMed:22246324, PubMed:28077878). Restricts infection by initiating autophagy via interaction with CALCOCO2/NDP52 (PubMed:22246324, PubMed:28077878). Required to restrict infection of bacterial invasion such as S.typhimurium (PubMed:22246324). Also required to restrict infection of Picornaviridae viruses (PubMed:28077878). Has a marked preference for 3'-O-sialylated and 3'-O-sulfated glycans (PubMed:21288902).
Homodimer (PubMed:21288902, Ref.15). Interacts with CALCOCO2/NDP52 (PubMed:22246324). Interacts with PDPN; the interaction is glycosylation-dependent; may participate in connection of the lymphatic endothelium to the surrounding extracellular matrix.
Ubiquitous. Selective expression by prostate carcinomas versus normal prostate and benign prostatic hypertrophy.
Ancillary protein that assembles as a beta subunit with a voltage-gated potassium channel complex of pore-forming alpha subunits. Modulates the gating kinetics and enhances stability of the channel complex. Assembled with KCNB1 modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1 (PubMed:12954870). Associated with KCNC4/Kv3.4 is proposed to form the subthreshold voltage-gated potassium channel in skeletal muscle and to establish the resting membrane potential (RMP) in muscle cells. Associated with KCNQ1/KCLQT1 may form the intestinal cAMP-stimulated potassium channel involved in chloride secretion that produces a current with nearly instantaneous activation with a linear current-voltage relationship.
Expressed in hippocampal neurons (at protein level) (PubMed:12954870). Widely expressed with highest levels in kidney and moderate levels in small intestine.
Interacts with KCNB1. Interacts with KCNC2 (By similarity). Associates with KCNC4/Kv3.4 (PubMed:11207363). Interacts with KCNQ1; produces a current with nearly instantaneous activation with a linear current-voltage relationship and alters membrane raft localization (By similarity) (PubMed:20533308).
Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. When overexpressed, membrane-assembled circular arrays of CHMP4A filaments can promote or stabilize negative curvature and outward budding. Via its interaction with PDCD6IP involved in HIV-1 p6- and p9-dependent virus release. CHMP4A/B/C are required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413).
Probable core component of the endosomal sorting required for transport complex III (ESCRT-III). ESCRT-III components are thought to multimerize to form a flat lattice on the perimeter membrane of the endosome. Several assembly forms of ESCRT-III may exist that interact and act sequentially. Self-associates; overexpression leads to the assembly of filaments that curve and associate to create circular rings. Interacts with CHMP2A. Interacts with CHMP3; the interaction requires the release of CHMP4A autoinhibition. Interacts with CHMP4B. Interacts with CHMP4C. Interacts with CHMP6. Interacts with VPS4A. Interacts with PDCD6IP; the interaction is direct.
Widely expressed. Expressed at higher level in heart, kidney, liver and skeletal muscle. Also expressed in brain, placenta, lung and pancreas.
Catalyzes the first and rate-limiting step of polyamine biosynthesis that converts ornithine into putrescine, which is the precursor for the polyamines, spermidine and spermine. Polyamines are essential for cell proliferation and are implicated in cellular processes, ranging from DNA replication to apoptosis.
Homodimer. Only the dimer is catalytically active, as the active sites are constructed of residues from both monomers (Probable). Does not form a heterodimer with AZIN2 (By similarity).
Inhibited by S-nitrosylation (PubMed:10462479, PubMed:11461922). Inhibited by antizymes (AZs) OAZ1, OAZ2 and OAZ3 in response to polyamine levels. AZs inhibit the assembly of the functional homodimer by binding to ODC monomers. Additionally, OAZ1 targets ODC monomers for ubiquitin-independent proteolytic destruction by the 26S proteasome (PubMed:17900240). Inhibited by 1-amino-oxy-3-aminopropane (APA, an isosteric analog of putrescine) (PubMed:17407445). Irreversibly inhibited by alpha-difluoromethylornithine (DFMO) (PubMed:17407445).
S-Nitrosylation inhibits the enzyme. S-Nitrosylated in vitro on 4 cysteine residues.
The disease is caused by variants affecting the gene represented in this entry. BABS is due to truncating variants that lead to a gain of function. This phenomenon apparently results from truncation proximal to or involving the C-terminal region of ODC1 protein, distal enough to allow escape from nonsense-mediated decay. A gain of function is corroborated by elevated plasma levels of N-acetylputrescine, with otherwise normal polyamine levels, in affected individuals.
Each ZP domain consists of an N-terminal (ZP-N) and C-terminal (ZP-C) region connected by a flexible linker; the linker allows the ZP domain to wrap around the ZP-C subdomain of the preceding subunit.
Expressed in pancreas (at protein level) (PubMed:8666297, PubMed:10760606). Specifically expressed by M (microfold) cells which are atypical epithelial cells of the intestine (at protein level) (PubMed:19907495).
Functions as an intestinal M-cell transcytotic receptor specific for type-I-piliated bacteria that participates in the mucosal immune response toward these bacteria. At the apical membrane of M-cells it binds fimH, a protein of the bacteria type I pilus tip. Internalizes bound bacteria, like E.coli and S.typhimurium, from the lumen of the intestine and delivers them, through M-cells, to the underlying organized lymphoid follicles where they are captured by antigen-presenting dendritic cells to elicit a mucosal immune response.
Interacts with SYCN (By similarity). Interacts with bacterial adhesin fimH (PubMed:19907495, PubMed:35273390).
N-glycosylated. Glycosylated Asn-65 may be required for interaction with bacterial adhesin fimH.
May play some role in mitochondrial processes.
Ubiquitous. Most prominent expression in skeletal muscle and kidney.
Detected in heart, brain, placenta, lung, skeletal muscle, liver, kidney and pancreas.
Forms a complex with EDC3, DCP2, DDX6 and EDC4/HEDLS, within this complex directly interacts with EDC3 (PubMed:16364915). Part of a cytoplasmic complex containing proteins involved in mRNA decay, including XRN1 and LSM1 (PubMed:12515382). Interacts with DCP1B (PubMed:12417715). Interacts with DCP2 (PubMed:12417715). Interacts with DDX17 in an RNA-independent manner (PubMed:21876179). Interacts with PNRC2 (PubMed:19150429). Interacts with SMAD4 (PubMed:11836524). Interacts with UPF1 (PubMed:12417715). Interacts with ZC3HAV1 (PubMed:21876179). Interacts with ZFP36L1 (PubMed:15687258). Interacts with NBDY (PubMed:27918561). Interacts with DHX34; the interaction is RNA-independent (PubMed:25220460).
Necessary for the degradation of mRNAs, both in normal mRNA turnover and in nonsense-mediated mRNA decay (PubMed:12417715). Removes the 7-methyl guanine cap structure from mRNA molecules, yielding a 5'-phosphorylated mRNA fragment and 7m-GDP (PubMed:12417715). Contributes to the transactivation of target genes after stimulation by TGFB1 (PubMed:11836524). Essential for embryonic development (PubMed:33813271).
Essential for sperm motility and is involved in the regulation of the beating frequency of motile cilia on the epithelial cells of the respiratory tract (By similarity). Required for the establishment of radial spokes in sperm flagella (By similarity).
Interacts with ASTN2; the interaction is not calcium-dependent.
Neuronal adhesion molecule that is required for normal migration of young postmitotic neuroblasts along glial fibers, especially in the cerebellum. Required for normal rate of migration of granule cells during brain development and for normal cerebellum development.
Glucose 1,6-bisphosphate synthase using 1,3-bisphosphoglycerate as a phosphate donor and a series of 1-phosphate sugars, including glucose 1-phosphate, mannose 1-phosphate, ribose 1-phosphate and deoxyribose 1-phosphate, as acceptors (PubMed:17804405). In vitro, also exhibits very low phosphopentomutase and phosphoglucomutase activity which are most probably not physiologically relevant (PubMed:17804405).
Autoacetylation strongly increases tubulin acetylation.
Belongs to the acetyltransferase ATAT1 family.
Component of the BBSome complex. Interacts with AP2 alpha-adaptins, including AP2A2, but not with AP1 gamma-adaptin (AP1G1/AP1G2); this interaction is required for efficient alpha-tubulin acetylation, hence clathrin-coated pits are sites of microtubule acetylation.
Specifically acetylates 'Lys-40' in alpha-tubulin on the lumenal side of microtubules. Promotes microtubule destabilization and accelerates microtubule dynamics; this activity may be independent of acetylation activity. Acetylates alpha-tubulin with a slow enzymatic rate, due to a catalytic site that is not optimized for acetyl transfer. Enters the microtubule through each end and diffuses quickly throughout the lumen of microtubules. Acetylates only long/old microtubules because of its slow acetylation rate since it does not have time to act on dynamically unstable microtubules before the enzyme is released. Required for normal sperm flagellar function. Promotes directional cell locomotion and chemotaxis, through AP2A2-dependent acetylation of alpha-tubulin at clathrin-coated pits that are concentrated at the leading edge of migrating cells. May facilitate primary cilium assembly.
Could play a role in cell proliferation during neuronal differentiation and in protection against cell death.
Interacts with CLN5 (By similarity). Interacts with CLN3 (PubMed:17237713).
Binds DNA through the consensus sequence 5'-CAATG-3'. May be involved in transcriptional regulation and may play a role in tooth formation (By similarity).
In the embryo, expressed in developing craniofacial structures including dental epithelium of maxillary molar tooth organs, tongue epithelium and muscle, and craniofacial bone osteoblasts. In the adult, expressed in mesoderm-derived tissues such as skeletal muscle, heart, kidney and liver. Intermediate expression in spleen, thymus and brain. Low levels in endoderm-derived tissues such as intestine and colon.
Homodimer. Heterodimer with either PEX11A or PEX11B. Interacts with FIS1.
Promotes membrane protrusion and elongation on the peroxisomal surface.
Expressed in plasmacytoid dendritic cells (PDCs). Constitutively expressed in immature monocyte-derived dendritic cells (iMDDC) and is significantly down-regulated upon maturation with LPS but not with TNF-alpha.
Lectin-type cell surface receptor which may play a role in antigen capturing by dendritic cells (PubMed:11748283, PubMed:21880719, PubMed:25995448). Specifically recognizes non-sialylated galactose-terminated biantennary glycans containing the trisaccharide epitope Gal(beta1-3/4)GlcNAc(beta1-2)Man (PubMed:21880719, PubMed:25995448). Binds to serum IgG (PubMed:25995448). Efficiently targets ligand into antigen-processing and peptide-loading compartments for presentation to T-cells (PubMed:11748283). May mediate potent inhibition of induction of IFN-alpha/beta expression in plasmacytoid dendritic cells (PubMed:11748283, PubMed:21880719). May act as a signaling receptor that activates protein-tyrosine kinases and mobilizes intracellular calcium (PubMed:11748283).
Component of the NF-kappa-B p65-c-Rel complex. Component of the NF-kappa-B p50-c-Rel complex. Component of the NF-kappa-B p52-c-Rel complex. Homodimer; component of the NF-kappa-B c-Rel-c-Rel complex (By similarity). Interacts with NKIRAS1. Interacts with NFKBIB (By similarity). Interacts with NFKBIE.
Proto-oncogene that may play a role in differentiation and lymphopoiesis. NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. The NF-kappa-B heterodimer RELA/p65-c-Rel is a transcriptional activator.
Citrate synthase is found in nearly all cells capable of oxidative metabolism.
Methylated (PubMed:28391595, PubMed:28887308). Trimethylation at Lys-395 by CSKMT decreases citrate synthase activity (PubMed:28887308).
May function in the secretion of milk-fat droplets. May act as a specific membrane-associated receptor for the association of cytoplasmic droplets with the apical plasma membrane (By similarity). Inhibits the proliferation of CD4 and CD8 T-cells activated by anti-CD3 antibodies, T-cell metabolism and IL2 and IFNG secretion (By similarity).
Seems to associate with xanthine dehydrogenase/oxidase.
Contains an ion transport-like region is related to the membrane segments of voltage-gated ion channels.
Isoform 1 mediates the transport of synaptic vesicles in neuronal cells.
Isoform 3 is abundant in the skeletal muscle. It is also expressed in fetal brain, lung and kidney, and adult heart, placenta, testis, ovary and small intestine. Isoform 2 is abundant in the brain and also expressed in fetal heart, lung, liver and kidney, and adult skeletal muscle, placenta, liver, kidney, heart, spleen, thymus, prostate, testis, ovary, small intestine, colon and pancreas.
Monomer (By similarity). Interacts (via C-terminus end of the kinesin-motor domain) with CHP1; the interaction occurs in a calcium-dependent manner (By similarity). Interacts with KIFBP (PubMed:16225668). Interacts with MADD (via death domain) (By similarity).
Motor for anterograde transport of mitochondria. Has a microtubule plus end-directed motility. Isoform 2 is required for induction of neuronal apoptosis.
RTL5 is one of at least 11 genes called Mar or Mart related to long terminal repeat retrotransposons. They do not correspond to functional retrotransposons, but rather to neofunctionalized retrotransposons genes.
Part of the neuronal tubulin polyglutamylase complex which contains TPGS1, TPGS2, TTLL1, LRRC49 and NICN1 (Probable). Interacts with PCM1; TTLL1, TPGS1, TPGS2 and LRRC49 (PubMed:34782749).
Alcohol dehydrogenase. Exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism.
Dimer of identical or non-identical chains of class I alcohol dehydrogenase: ADH1A, ADH1B, and ADH1C.
Two main alleles are known, ADH3*1 or gamma-1 has Arg-272/Ile-350 while ADH3*2 or gamma-2 has Gln-272/Val-350. ADH3*1 is associated with a fast rate of ethanol oxidation and ADH3*2 with a slow rate.
Expressed in the brain, mainly in postmitotic neurons, including GABAergic neurons, but not in astrocytes (at protein level).
May be involved in the remodeling of cytoskeletal components, such as alpha-tubulin, and in this way regulates neurite branching and elongation, as well as cell motility.
Up-regulated during neuronal differentiation of neuroblastoma cells treated with all-trans or 9-cis retinoic acid.
Various anomalies in ULK4 gene have been reported for several cases of schizophrenia, schizophrenia plus bipolar disorder and autism. ULK4 gene has been proposed to be a rare susceptibility risk factor for a range of psychiatric diseases including schizophrenia.
CLOCK-BMAL1 double mutations within the PAS domains result in synergistic desensitization to high levels of CRY on repression of CLOCK-BMAL1 transcriptional activity of PER1 and disrupt circadian rhythmicity.
Component of the circadian clock oscillator which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins (By similarity). Interacts with KMT2A; in a circadian manner (By similarity). Forms a heterodimer with BMAL1 (PubMed:21613214, PubMed:23229515). The CLOCK-BMAL1 heterodimer is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and for phosphorylation of both CLOCK and BMAL1 (By similarity). Interacts with NR3C1 in a ligand-dependent fashion (PubMed:21980503). Interacts with ESR1 and estrogen stimulates this interaction (PubMed:23160374). Interacts with the complex p35/CDK5 (PubMed:24235147). Interacts with RELA/p65 (By similarity). Interacts with KAT2B, CREBBP, EP300 (PubMed:14645221). Interacts with ID1 and ID3 (By similarity). Interacts with ID2 (PubMed:20861012). Interacts with MTA1 (By similarity). Interacts with OGA (By similarity). Interacts with SIRT1 (By similarity). Interacts with CIPC (By similarity). Interacts with EZH2 (By similarity). Interacts with EIF4E, PIWIL1 and DDX4 (By similarity). Interacts with PER2 and CRY1 and the interaction with PER and CRY proteins requires translocation to the nucleus. Interacts with PER1 and CRY2 (By similarity). Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits transcription activation (PubMed:21613214). Interaction of the CLOCK-BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (PubMed:21613214). The CLOCK-BMAL1 heterodimer interacts with GSK3B. Interacts with KDM5A (PubMed:21960634). Interacts with MYBBP1A (By similarity). Interacts with THRAP3 (By similarity). Interacts with MED1; this interaction requires the presence of THRAP3 (By similarity). Interacts with NCOA2 (By similarity). The CLOCK-BMAL1 heterodimer interacts with PASD1 (PubMed:25936801). Interacts with ASS1 and IMPDH2; in a circadian manner (PubMed:28985504). Interacts with NDUFA9 (PubMed:28985504). Interacts with PIWIL2 (via PIWI domain) (PubMed:28903391). Interacts with HNF4A (PubMed:30530698).
Hair follicles (at protein level). Expressed in all tissues examined including spleen, thymus, prostate, testis, ovary, small intestine, colon, leukocytes, heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Highest levels in testis and skeletal muscle. Low levels in thymus, lung and liver. Expressed in all brain regions with highest levels in cerebellum. Highly expressed in the suprachiasmatic nucleus (SCN).
O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents protein degradation by inhibiting ubiquitination. It also stabilizes the CLOCK-BMAL1 heterodimer thereby increasing CLOCK-BMAL1-mediated transcriptional activation of PER1/2/3 and CRY1/2.
Phosphorylation is dependent on the CLOCK-BMAL1 heterodimer formation. Phosphorylation enhances the transcriptional activity, alters the subcellular localization and decreases the stability of the heterodimer by promoting its degradation. Phosphorylation shows circadian variations in the liver. May be phosphorylated by CSNK1D and CKSN1E.
Sumoylation enhances its transcriptional activity and interaction with ESR1, resulting in up-regulation of ESR1 activity. Estrogen stimulates sumoylation. Desumoylation by SENP1 negatively regulates its transcriptional activity. Sumoylation stimulates cell proliferation and increases the proportion of S phase cells in breast cancer cell lines.
Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. Regulates the circadian expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an enhancer of the transactivation potential of NF-kappaB. Plays an important role in the homeostatic regulation of sleep. The CLOCK-BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. The CLOCK-BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking adenine nucleotide at the 3-prime end of the canonical 6-nucleotide E-box sequence (PubMed:23229515). CLOCK specifically binds to the half-site 5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3' (PubMed:23229515). The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (PubMed:23229515). CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner BMAL1. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation of multiple lysine residues located in its hinge region (PubMed:21980503). The acetyltransferase activity of CLOCK is as important as its transcription activity in circadian control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian manner. Facilitated by BMAL1, rhythmically interacts and acetylates argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian oscillation of arginine biosynthesis and subsequent ureagenesis (PubMed:28985504). Drives the circadian rhythm of blood pressure through transcriptional activation of ATP1B1 (By similarity).
Down-regulates transcriptional activation by nuclear receptors such as NR1F2.
Interacts with NR1F2, RARA and THRB in a ligand-dependent manner.
Cell surface proteoglycan that bears heparan sulfate.
In adult, primarily expressed in the brain. Also detected in fetal brain, lung and liver.
May function as a sodium-dependent glucose transporter. Potential channels for urea in the inner medulla of kidney.
Expressed at high levels in the lymph nodes, thymus and appendix. Intermediate levels seen in colon and trachea, while low levels found in spleen, small intestine, lung, kidney and stomach.
Interacts with TNFAIP6 (via Link domain).
May play a role not only in inflammatory and immunological responses but also in normal lymphocyte recirculation and homing. May play an important role in trafficking of T-cells in thymus, and T-cell and B-cell migration to secondary lymphoid organs. Binds to chemokine receptor CCR7. Recombinant CCL19 shows potent chemotactic activity for T-cells and B-cells but not for granulocytes and monocytes. Binds to atypical chemokine receptor ACKR4 and mediates the recruitment of beta-arrestin (ARRB1/2) to ACKR4.
Conflicting results are reported regarding the interaction with PABPC1. Some studies found that the interaction depends on the presence of mRNA (PubMed:23711370, PubMed:28650797). Others found that the interaction is direct and does not depend on the presence of mRNA (PubMed:20430826, PubMed:24532714, PubMed:25940091).
Interacts with PABPC1/PABP (PubMed:20430826, PubMed:24532714, PubMed:25940091, PubMed:23711370, PubMed:28650797). Interacts with EIF4A1 (PubMed:24532714). Interacts with RPTOR (PubMed:24532714, PubMed:25940091, PubMed:28650797). Recruited to the active mTORC1 complex via interaction with RPTOR (PubMed:25940091, PubMed:28650797). Inhibition of mTORC1 activity strongly reduces interaction with RPTOR and the mTORC1 complex (PubMed:25940091, PubMed:28650797). Identified in a complex with mRNA, PABPC1, EIF4E and EIF4G1 (PubMed:20430826, PubMed:28650797). Found in a complex with PABPC1 and SHFL (PubMed:26735137).
Phosphorylated on multiple Ser and Thr residues in response to active mTORC1. Phosphorylation is important for interaction with RPTOR and the mTORC1 complex. Phosphorylation promotes dissociation from the 5'UTR of mRNA molecules with a 5'TOP motif.
RNA-binding protein that regulates the translation of specific target mRNA species downstream of the mTORC1 complex, in function of growth signals and nutrient availability (PubMed:20430826, PubMed:23711370, PubMed:24532714, PubMed:25940091, PubMed:28650797, PubMed:28673543, PubMed:29244122). Interacts on the one hand with the 3' poly-A tails that are present in all mRNA molecules, and on the other hand with the 7-methylguanosine cap structure of mRNAs containing a 5' terminal oligopyrimidine (5'TOP) motif, which is present in mRNAs encoding ribosomal proteins and several components of the translation machinery (PubMed:23711370, PubMed:25940091, PubMed:28650797, PubMed:29244122, PubMed:26206669, PubMed:28379136). The interaction with the 5' end of mRNAs containing a 5'TOP motif leads to translational repression by preventing the binding of EIF4G1 (PubMed:25940091, PubMed:28650797, PubMed:29244122, PubMed:28379136). When mTORC1 is activated, LARP1 is phosphorylated and dissociates from the 5' untranslated region (UTR) of mRNA (PubMed:25940091, PubMed:28650797). Does not prevent binding of EIF4G1 to mRNAs that lack a 5'TOP motif (PubMed:28379136). Interacts with the free 40S ribosome subunit and with ribosomes, both monosomes and polysomes (PubMed:20430826, PubMed:24532714, PubMed:25940091, PubMed:28673543). Under normal nutrient availability, interacts primarily with the 3' untranslated region (UTR) of mRNAs encoding ribosomal proteins and increases protein synthesis (PubMed:23711370, PubMed:28650797). Associates with actively translating ribosomes and stimulates translation of mRNAs containing a 5'TOP motif, thereby regulating protein synthesis, and as a consequence, cell growth and proliferation (PubMed:20430826, PubMed:24532714). Stabilizes mRNAs species with a 5'TOP motif, which is required to prevent apoptosis (PubMed:20430826, PubMed:23711370, PubMed:25940091, PubMed:28673543).
The C-terminal region mediates interaction with the mRNA and polysomes (PubMed:24532714, PubMed:26206669, PubMed:28379136). It is required for translational repression of mRNAs with a 5'TOP motif (PubMed:29244122).
The N-terminal region mediates interaction with PABPC1.
Up-regulated in a number of hepatocellular carcinoma cell lines and liver cancer lesions, as well as in patients with hepatocellular carcinoma with a lower survival rate (at protein level).
It is uncertain whether Met-1 or Met-79 is the initiator.
Receptor for cysteinyl leukotrienes mediating bronchoconstriction of individuals with and without asthma. Stimulation by LTD4 results in the contraction and proliferation of smooth muscle, edema, eosinophil migration and damage to the mucus layer in the lung. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. The rank order of affinities for the leukotrienes is LTD4 >> LTE4 = LTC4 >> LTB4.
Selective antagonists, such as montelukast (Singulair), zafirlukast (Accolate) and pranlukast (Onon), are used in the treatment of the asthma crisis.
Widely expressed, with highest levels in spleen and peripheral blood leukocytes. Lower expression in several tissues, such as lung (mostly in smooth muscle bundles and alveolar macrophages), placenta, small intestine, pancreas, colon and heart.
Ethanolamine-phosphate cytidylyltransferase that catalyzes the second step in the synthesis of phosphatidylethanolamine (PE) from ethanolamine via the CDP-ethanolamine pathway (PubMed:9083101, PubMed:31637422). Phosphatidylethanolamine is a dominant inner-leaflet phospholipid in cell membranes, where it plays a role in membrane function by structurally stabilizing membrane-anchored proteins, and participates in important cellular processes such as cell division, cell fusion, blood coagulation, and apoptosis (PubMed:9083101).
Strongest expression in liver, heart, and skeletal muscle.
Expressed in bone; present in osteoblasts and osteocytes. No expression is observed in osteoclast. Expressed in several regions of the brain.
Homooligomer. Interacts with MUSK; the heterodimer forms an AGRIN receptor complex that binds AGRIN resulting in activation of MUSK (By similarity). Interacts (via the extracellular domain) with SOST; the interaction facilitates the inhibition of Wnt signaling (PubMed:21471202). Interacts with MESD; the interaction promotes glycosylation of LRP4 and its cell-surface expression (By similarity).
Mediates SOST-dependent inhibition of bone formation. Functions as a specific facilitator of SOST-mediated inhibition of Wnt signaling. Plays a key role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between motor neuron and skeletal muscle. Directly binds AGRIN and recruits it to the MUSK signaling complex. Mediates the AGRIN-induced phosphorylation of MUSK, the kinase of the complex. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Alternatively, may be involved in the negative regulation of the canonical Wnt signaling pathway, being able to antagonize the LRP6-mediated activation of this pathway. More generally, has been proposed to function as a cell surface endocytic receptor binding and internalizing extracellular ligands for degradation by lysosomes. May play an essential role in the process of digit differentiation (By similarity).
Expressed on limbic neurons and fiber tracts as well as in single layers of the superior colliculus, spinal cord and cerebellum.
Mediates selective neuronal growth and axon targeting. Contributes to the guidance of developing axons and remodeling of mature circuits in the limbic system. Essential for normal growth of the hippocampal mossy fiber projection (By similarity).
(Microbial infection) Required for poxvirus protein synthesis by mediating ubiquitination of RPS10/eS10 and RPS20/uS10 (PubMed:29719242). Poxvirus encoding mRNAs contain unusual 5' poly(A) leaders and ZNF598 is required for their translational efficiency, possibly via its ability to suppress readthrough or sliding on shorter poly(A) tracts (PubMed:29719242).
E3 ubiquitin-protein ligase that plays a key role in the ribosome quality control (RQC), a pathway that takes place when a ribosome has stalled during translation, leading to degradation of nascent peptide chains (PubMed:28065601, PubMed:28132843, PubMed:28685749, PubMed:32579943, PubMed:32099016, PubMed:33581075). ZNF598 is activated when ribosomes are stalled within an mRNA following translation of prematurely polyadenylated mRNAs (PubMed:28065601, PubMed:28132843, PubMed:28685749). Acts as a ribosome collision sensor: specifically recognizes and binds collided di-ribosome, which arises when a trailing ribosome encounters a slower leading ribosome, leading to terminally arrest translation (PubMed:28065601, PubMed:28132843, PubMed:28685749, PubMed:30293783). Following binding to colliding ribosomes, mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS3/uS3, and 'Lys-63'-linked polyubiquitination of RPS20/uS10 (PubMed:28065601, PubMed:28132843, PubMed:28685749). Polyubiquitination of RPS20/uS10 promotes recruitment of the RQT (ribosome quality control trigger) complex, which drives the disassembly of stalled ribosomes, followed by degradation of nascent peptides (PubMed:32579943, PubMed:32099016, PubMed:36302773). E3 ubiquitin-protein ligase activity is dependent on the E2 ubiquitin-conjugating enzyme UBE2D3 (PubMed:28685749). Also acts as an adapter that recruits the 4EHP-GYF2 complex to mRNAs (PubMed:22751931, PubMed:32726578). Independently of its role in RQC, may also act as a negative regulator of interferon-stimulated gene (ISG) expression (PubMed:29719242).
Interacts with the E2 ubiquitin-conjugating enzyme UBE2D3 (PubMed:28685749). Component of the 4EHP-GYF2 complex, at least composed of EIF4E2, GIGYF2 and ZNF598 (PubMed:22751931, PubMed:32726578).
N-alpha-acetyltransferase that specifically mediates the acetylation of the acidic amino terminus of processed forms of beta- and gamma-actin (ACTB and ACTG, respectively) (PubMed:30028079, PubMed:29581253). N-terminal acetylation of processed beta- and gamma-actin regulates actin filament depolymerization and elongation (PubMed:29581253). In vivo, preferentially displays N-terminal acetyltransferase activity towards acid N-terminal sequences starting with Asp-Asp-Asp and Glu-Glu-Glu (PubMed:30028079, PubMed:29581253). In vitro, shows high activity towards Met-Asp-Glu-Leu and Met-Asp-Asp-Asp (PubMed:10644992, PubMed:29581307). May act as a tumor suppressor (PubMed:10644992).
Strongly expressed in heart and skeletal muscle, followed by brain and pancreas, with weak expression in kidney, liver, and lung and no expression in placenta.
(Microbial infection) Dephosphorylated at Tyr-279 by M.tuberculosis PtpA, which leads to prevention of apoptosis during early stages of microbial infection.
Activated by phosphorylation at Tyr-279. In response to insulin, inhibited by phosphorylation at Ser-21 by PKB/AKT1; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by lithium.
Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1 (PubMed:11749387, PubMed:17478001, PubMed:19366350). Requires primed phosphorylation of the majority of its substrates (PubMed:11749387, PubMed:17478001, PubMed:19366350). Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:11749387, PubMed:17478001, PubMed:19366350). Regulates glycogen metabolism in liver, but not in muscle (By similarity). May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:10868943, PubMed:17478001). In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin (PubMed:17229088). Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease (PubMed:12761548). May be involved in the regulation of replication in pancreatic beta-cells (By similarity). Is necessary for the establishment of neuronal polarity and axon outgrowth (By similarity). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions which activates KAT5/TIP60 acetyltransferase activity and promotes acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (By similarity). Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075).
Higher expression and activity of GSK3A are found in the skeletal muscle (vastus lateralis) of patients with type 2 diabetes (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes (PubMed:19366350).
Monomer. Interacts with ARRB2 (By similarity). Interacts with AXIN1 and CTNNB1/beta-catenin (PubMed:17229088). Interacts with CTNND2 (PubMed:19706605). Interacts with LMBR1L (PubMed:31073040). Interacts with DDX3X (PubMed:18846110). Interacts with TNFRSF10B (PubMed:18846110). Interacts with RICTOR; the interaction results in phosphorylation of RICTOR at 'Thr-1695' by GSK3A which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075).
Phosphorylated by AKT1 at Ser-21: upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and deactivates GSK3A, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-279.
Composed of 4 alpha helices: 2 hydrophobic transmembrane regions (alpha3 and alpha4) and 2 alpha helices (alpha1 and alpha2) (By similarity). Alpha1 and alpha2 feature one hydrophobic side and a hydrophilic side (By similarity). In normal conditions, NINJ2 is inactivated and alpha1 and alpha2 helices are not inserted into the membrane (By similarity). Following NINJ2 activation, alpha1 and alpha2 helices insert into the membrane and drive NINJ2 oligomerization via interactions between alpha3 and alpha4 and the hydrophobic face of alpha1 from an adjacent subunit (By similarity). Such structures disrupt membrane integrity and form a lesion through the introduction of the hydrophilic faces of alpha1 and alpha2 into the hydrophobic membrane (By similarity).
Effector of necroptotic and pyroptotic programmed cell death that mediates plasma membrane rupture (cytolysis) (By similarity). Acts downstream of Gasdermin (GSDMA, GSDMB, GSDMC, GSDMD, or GSDME) or MLKL during pyroptosis or necroptosis, respectively: oligomerizes in response to death stimuli and promotes plasma membrane rupture by introducing hydrophilic faces of 2 alpha helices into the hydrophobic membrane, leading to release intracellular molecules named damage-associated molecular patterns (DAMPs) that propagate the inflammatory response (By similarity). Also acts as a homophilic transmembrane adhesion molecule involved in nerve regeneration (PubMed:10627596). Promotes axonal growth (PubMed:10627596).
In normal conditions, NINJ2 is inactivated (By similarity). In response to death stimuli, homooligomerizes and disrupts membrane integrity by introducing the hydrophilic faces of alpha1 and alpha2 helices into the hydrophobic membrane (By similarity).
Widely expressed. In adult, higher expression in the bone marrow and peripheral blood lymphocytes, medium in the lung, lymph node, thyroid, uterus, thymus, spleen, prostate and skeletal muscle, lower in the liver, placenta, brain, heart and kidney. In embryo, higher expression in the thymus, heart and liver, lower in the spleen, lung, brain and kidney.
Receptor for ATP and UTP coupled to G-proteins that activate a phosphatidylinositol-calcium second messenger system. The affinity range is UTP = ATP > ATP-gamma-S >> 2-methylthio-ATP = ADP.
Spleen, testis, kidney, liver, lung, heart and brain.
Acts as a transcriptional repressor through interaction with histone deacetylases (HDACs). May be important for spermiogenesis.
Interacts with HDAC1, HDAC3, HDAC6 and, to a lesser extent, with HDAC7.
Calcium sensor that participates in triggering neurotransmitter release at the synapse (By similarity). May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse (By similarity). It binds acidic phospholipids with a specificity that requires the presence of both an acidic head group and a diacyl backbone. A Ca(2+)-dependent interaction between synaptotagmin and putative receptors for activated protein kinase C has also been reported. It can bind to at least three additional proteins in a Ca(2+)-independent manner; these are neurexins, syntaxin and AP2. Plays a role in dendrite formation by melanocytes (PubMed:23999003).
Homotetramer (Probable). Heterodimer; heterodimerizes with SYT2 in presence of calcium (By similarity). Interacts with SCAMP5 (PubMed:19234194). Interacts with STON2 (PubMed:11381094). Forms a complex with SV2B, syntaxin 1 and SNAP25 (By similarity). Interacts with SV2A, SV2B and SV2C (By similarity). Interacts with RIMS1 (By similarity). Interacts with PRRT2 (By similarity). Interacts with DNAJC5 in a phosphorylation-dependent manner (By similarity). Interacts (via N-terminus) with RAB3A (By similarity). Interacts with SYT12 (By similarity). Interacts with calmodulin (By similarity).
May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse. It binds acidic phospholipids with a specificity that requires the presence of both an acidic head group and a diacyl backbone.
The second C2 domain mediates interaction with SV2A and probably with STN2.
Low affinity ligand for the ERBB4 tyrosine kinase receptor. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. Does not bind to the ERBB1, ERBB2 and ERBB3 receptors (By similarity).
Forms a SNARE complex with VTI1B, STX8 and VAMP8 which functions in the homotypic fusion of late endosomes. Component of the SNARE complex composed of STX7, STX8, VAMP7 and VTI1B that is required for heterotypic fusion of late endosomes with lysosomes (By similarity). Interacts with VPS11, VPS16 and VPS18. Interacts with VPS33A. Interacts with TPC1 (By similarity).
Highest expression is found in placenta followed by heart, skeletal muscle, kidney and brain. Low expression is found in pancreas, lung and liver.
May be involved in protein trafficking from the plasma membrane to the early endosome (EE) as well as in homotypic fusion of endocytic organelles. Mediates the endocytic trafficking from early endosomes to late endosomes and lysosomes.
Can form homooligomers. Interacts with KCNA1 (via cytoplasmic N-terminal domain) and KCNA4.
Inhibits potassium fluxes in cells. May regulate Kv1 family channel proteins by retaining a fraction of channels in endomembranes.
Ubiquitous in normal tissues and expressed in some tumor tissues.
Preferentially incorporated into the newly assembled daughter centriole during centriole assembly at the late G1 or early S phase. Remains in the daughter centrioles throughout the cell cycle. At the next cycle of centriole duplication, its amount on the original daughter centriole eventually decreases.
Required for centriole duplication. Inhibition of centriole duplication leading to defects in cytokinesis.
Widely expressed (at protein level). Highly expressed in testis. Also expressed in spleen, thymus, prostate, small intestine, colon and peripheral blood leukocytes.
Depending on the authors, the form called histatin-2 is alternatively a proteolytic product, or the non-phosphorylated form of histatin-1.
Histatins are salivary proteins that are considered to be major precursors of the protective proteinaceous structure on tooth surfaces (enamel pellicle). In addition, histatins exhibit antibacterial and antifungal activities.
(Microbial infection) Interacts with Epstein-Barr virus protein BILF1; this interaction mediates MAVS UFMylation and subsequent routing from mitochondria to lysosomes.
E3 protein ligase that mediates ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to lysine residues on target proteins, and which plays a key role in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress (PubMed:20018847, PubMed:20164180, PubMed:20228063, PubMed:25219498, PubMed:32160526, PubMed:37311461). In response to endoplasmic reticulum stress, recruited to the endoplasmic reticulum membrane by DDRGK1, and mediates ufmylation of proteins such as RPN1 and RPL26/uL24, thereby promoting reticulophagy of endoplasmic reticulum sheets (PubMed:32160526). Ufmylation-dependent reticulophagy inhibits the unfolded protein response (UPR) via ERN1/IRE1-alpha (PubMed:23152784, PubMed:32160526). Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis, blood vessel morphogenesis or inflammatory response (PubMed:32050156). Regulates inflammation in response to endoplasmic reticulum stress by promoting reticulophagy, leading to inhibit the activity of the NF-kappa-B transcription factor (By similarity). Mediates ufmylation of DDRGK1 and CDK5RAP3; the role of these modifications is however unclear: as both DDRGK1 and CDK5RAP3 act as substrate adapters for ufmylation, it is uncertain whether ufmylation of these proteins is a collateral effect or is required for ufmylation (PubMed:20531390, PubMed:20018847). Catalyzes ufmylation of various subunits of the ribosomal complex or associated components, such as RPS3/uS3, RPS20/uS10, RPL10/uL16, RPL26/uL24 and EIF6 (By similarity). Anchors CDK5RAP3 in the cytoplasm, preventing its translocation to the nucleus which allows expression of the CCND1 cyclin and progression of cells through the G1/S transition (PubMed:20531390). Also involved in the response to DNA damage: recruited to double-strand break sites following DNA damage and mediates monoufmylation of histone H4 (PubMed:30886146). Catalyzes ufmylation of TRIP4, thereby playing a role in nuclear receptor-mediated transcription (PubMed:25219498). Required for hematopoietic stem cell function and hematopoiesis (By similarity). Required for cardiac homeostasis (By similarity).
Interacts with DDRGK1 (via PCI domain) (PubMed:20018847, PubMed:20164180, PubMed:25219498, PubMed:32160526). Interacts with UFC1 (PubMed:20018847, PubMed:30886146). Interacts with RELA (PubMed:20164180). Interacts with TRIP4 (PubMed:25219498). Interacts with CDK5RAP3; the interaction is direct (PubMed:20164180, PubMed:20228063). Interacts with NBN; promoting recruitment to double-strand breaks following DNA damage (PubMed:30886146).
Phosphorylated at Ser-462 by ATM, enhancing protein ligase activity and promoting ATM activation in a positive feedback loop.
Ubiquitinated, leading to its degradation by the proteasome (PubMed:20164180). Interaction with CDK5RAP3 protects both proteins against ubiquitination and degradation via the proteasome (PubMed:20164180).
Ubiquitously expressed, with a high expression in liver (at protein level) (PubMed:20018847). Low expression in several invasive hepatocellular carcinomas, such Hep-G2, Hep 3B2.1-7, HLE and PLC (PubMed:20018847).
Up-regulated by thapsigargin (PubMed:23152784). Down-regulated in the failing hearts of patients with dilated cardiomyopathy (PubMed:23152784).
Belongs to the PTH2 family. PTRHD1 subfamily.
Binds double-stranded DNA. Binds preferentially to supercoiled DNA and cruciform DNA structures. Seems to be involved in transcriptional regulation. May function as a transcriptional repressor. Could have a role in the regulation of hematopoietic differentiation through activation of unknown target genes. Controls cellular proliferation by modulating the functions of cell cycle regulatory factors including p53/TP53 and the retinoblastoma protein. May be involved in TP53-mediated transcriptional activation by enhancing TP53 sequence-specific DNA binding and modulating TP53 phosphorylation status. Seems to be involved in energy-level-dependent activation of the ATM/ AMPK/TP53 pathway coupled to regulation of autophagy. May be involved in regulation of TP53-mediated cell death also involving BRCA1. May be involved in the senescence of prostate epithelial cells. Involved in innate immune response by recognizing viral dsDNA in the cytosol and probably in the nucleus. After binding to viral DNA in the cytoplasm recruits TMEM173/STING and mediates the induction of IFN-beta. Has anti-inflammatory activity and inhibits the activation of the AIM2 inflammasome, probably via association with AIM2. Proposed to bind viral DNA in the nucleus, such as of Kaposi's sarcoma-associated herpesvirus, and to induce the formation of nuclear caspase-1-activating inflammasome formation via association with PYCARD. Inhibits replication of herpesviruses such as human cytomegalovirus (HCMV) probably by interfering with promoter recruitment of members of the Sp1 family of transcription factors. Necessary to activate the IRF3 signaling cascade during human herpes simplex virus 1 (HHV-1) infection and promotes the assembly of heterochromatin on herpesviral DNA and inhibition of viral immediate-early gene expression and replication. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer.
Expressed in peripheral blood leukocytes, fibroblasts and lymphoid cells. Present in myeloid precursors (CD34+) and throughout monocyte development, but its expression is down-regulated in erythroid and polymorphonuclear precursor cells. Present in prostate, ovary and breast (at protein level).
Forms homooligomers; isoform 2 can self-associate or associate with isoform 1 or isoform 3. Interacts with TMEM173, AIM2, PYCARD and CASP1. Interacts with BRCA1, TP53, E2F1, RB1 and SP1. Interacts with MTA1. Interacts with PYDC5 (PubMed:24531343).
Interacts with AIM2; preventing the interaction between AIM2 and PYCARD/ASC (PubMed:30104205). Interacts with STING1 (PubMed:30104205).
Isoform 3 seems to show a minor degree of complex carbohydrate addition.
Isoform that specifically inhibits the AIM2 inflammasome (PubMed:30104205). Binds double-stranded DNA (dsDNA) in the cytoplasm, impeding its detection by AIM2 (PubMed:30104205). Also prevents the interaction between AIM2 and PYCARD/ASC via its interaction with AIM2, thereby inhibiting assembly of the AIM2 inflammasome (PubMed:30104205). This isoform also weakly induce production of type I interferon-beta (IFNB1) via its interaction with STING1 (PubMed:30104205).
Lysine acetylation in the multipartite nuclear localization signal (NLS) regulates the subcellular location. In vitro can be acetylated by p300/EP300 coupled to cytoplasmic localization.
Strongly induced by IFNG/IFN-gamma and, to a lesser extent, by alpha interferon. In HL-60 cells, maximum induction by IFNG/IFN-gamma occurs within 12 hours whereas, for IFN-alpha, only 10-fold induction was observed after 36 hours. Induced in vitro by dimethylsulfoxide, retinoic acid and 1,25 dihydroxyvitamin D3. Induced in monocytes by IFN-alpha and viral dsDNA. Induced by glucose restriction.
The HIN-200 domains mediates dsDNA binding via electrostatic interactions.
Ubiquitinated by human herpes simplex virus 1 (HHV-1) ICP0 protein; leading to degradation by the proteasome.
Interacts with IL8 (PubMed:1840701). Interacts with GNAI2 (PubMed:8662698).
Receptor to interleukin-8, which is a powerful neutrophils chemotactic factor (PubMed:1840701). Binding of IL-8 to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system (PubMed:8662698).
Alpha-1,3-xylosyltransferase, which elongates the O-linked xylose-glucose disaccharide attached to EGF-like repeats in the extracellular domain of target proteins by catalyzing the addition of the second xylose (PubMed:22117070, PubMed:8982869). Known targets include Notch proteins and coagulation factors, such as F9 (PubMed:22117070, PubMed:8982869).
Has the highest in vitro activity with 20 mM Mn(2+), a concentration entirely out of the physiological range. Can also utilize Mg(2+), suggesting this may be the physiological cofactor.
Homodimer (PubMed:22117070). Dimer formation may be essential for the retention in endoplasmic reticulum (Probable).
Genetic variations in ZBTB38 define the stature quantitative trait locus 10 (STQTL10) [MIM:612221]. Adult height is an easily observable and highly heritable complex continuous trait. Because of this, it is a model trait for studying genetic influence on quantitative traits.
Interacts with CBFA2T3. Interacts with ZBTB4. Interacts with RBBP6.
The BTB domain is not required for activation of transcription or self-association.
Transcriptional regulator with bimodal DNA-binding specificity. Binds with a higher affinity to methylated CpG dinucleotides in the consensus sequence 5'-CGCG-3' but can also bind to E-box elements (5'-CACGTG-3'). Can also bind specifically to a single methyl-CpG pair. Represses transcription in a methyl-CpG-dependent manner (PubMed:16354688). Plays an important role in regulating DNA replication and common fragile sites (CFS) stability in a RBBP6- and MCM10-dependent manner; represses expression of MCM10 which plays an important role in DNA-replication (PubMed:24726359). Acts as a transcriptional activator. May be involved in the differentiation and/or survival of late postmitotic neurons (By similarity).
Ubiquitinated by RBBP6; leading to its degradation by the proteasome.
(Microbial infection) Deubiquitinated by porcine reproductive and respiratory syndrome virus Nsp2 protein, which thereby interferes with NFKBIA degradation and impairs subsequent NF-kappa-B activation.
Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL (RELA/p65 and NFKB1/p50) dimers in the cytoplasm by masking their nuclear localization signals (PubMed:1493333, PubMed:7479976, PubMed:36651806). On cellular stimulation by immune and pro-inflammatory responses, becomes phosphorylated promoting ubiquitination and degradation, enabling the dimeric RELA to translocate to the nucleus and activate transcription (PubMed:7796813, PubMed:7628694, PubMed:7878466, PubMed:7479976).
Interacts with RELA; the interaction requires the nuclear import signal (PubMed:1493333). Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Interacts with NKIRAS1 and NKIRAS2 (PubMed:10657303). Interacts with isoform 1 and isoform 2 of RWDD3; the interaction enhances sumoylation (PubMed:17956732, PubMed:23469069). Interacts with PRMT2 (PubMed:16648481). Interacts with PRKACA in platelets; this interaction is disrupted by thrombin and collagen (PubMed:20356841). Interacts with MEFV (PubMed:18577712). Interacts with DDRGK1; positively regulates NFKBIA phosphorylation and degradation (PubMed:23675531).
Phosphorylated at Ser-32 and Ser-36 by IKKA/CHUK and IKKB/IKBKB; disables inhibition of NF-kappa-B DNA-binding activity (PubMed:7796813, PubMed:7628694, PubMed:7878466, PubMed:8631829, PubMed:9701247, PubMed:10329681, PubMed:10882136). Phosphorylation at positions 32 and 36 is prerequisite to recognition by the SCF(FBXW11) and SCF(BTRC) complexes, leading to polyubiquitination and subsequent degradation (PubMed:7628694, PubMed:8631829, PubMed:9701247, PubMed:10329681). Phosphorylated at Ser-32 in response to FK506 treatment: phosphorylation is independent of IKKA/CHUK and IKKB/IKBKB and promotes NFKBIA degradation, followed by NF-kappa-B activation (PubMed:10574930). Phosphorylated at Tyr-42: its effect is however unclear (PubMed:8797825, PubMed:8940099). According to a report, phosphorylation at Tyr-42 activates NF-kappa-B without triggering proteolytic degradation of NFKBIA (PubMed:8797825). According to another publication, phosphorylation at Tyr-42 inhibits NF-kappa-B activity by preventing phosphorylation at Ser-32 and Ser-36 and subsequent ubiquitination and degradation (PubMed:8940099).
Polyubiquitinated at Lys-21 and/or Lys-22 following phosphorylation at Ser-32 and Ser-36 (PubMed:7479976, PubMed:8631829, PubMed:9701247, PubMed:10329681, PubMed:20347421). Monoubiquitinated at Lys-21 and/or Lys-22 by UBE2D3 (PubMed:7479976, PubMed:10329681, PubMed:20347421). Ubiquitin chain elongation is then performed by CDC34 in cooperation with the SCF(FBXW11) E3 ligase complex, building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin (PubMed:10437795, PubMed:20347421). The resulting polyubiquitination leads to protein degradation (PubMed:7628694, PubMed:7479976, PubMed:20347421). Also ubiquitinated by the SCF(BTRC) complex following stimulus-dependent phosphorylation at Ser-32 and Ser-36 (PubMed:10644755). Deubiquitinated by USP38, leading to NF-kappa-B inhibition (PubMed:36651806).
Sumoylated; sumoylation requires the presence of the nuclear import signal. Sumoylation blocks ubiquitination and proteasome-mediated degradation of the protein thereby increasing the protein stability.
Binds via its C-terminal region to the N-terminal region of MYC. Associates with AKAP1/S-AKAP84. Interacts with MYCBPAP. Interacts with CFAP91 (PubMed:12223483).
Highly expressed in heart, placenta, pancreas, skeletal muscle and kidney. Also present at low levels in lung.
May control the transcriptional activity of MYC. Stimulates the activation of E box-dependent transcription by MYC.
Binds to the C-terminal propeptide of types I and II procollagens and may enhance the cleavage of that propeptide by BMP1.
Highly expressed in the heart, trabecular meshwork, pituitary gland, bladder, mammary gland, trachea and placenta and weakly expressed in the brain. Expressed in cartilage.
Interacts with heparin with high affinity, and type I or II collagen.
Interacts with TEFs (By similarity). Interacts with IRF2BP2.
Probable target of nonsense-mediated mRNA decay.
Expressed in trophoblasts and placental stem villi vessels, but not in cultured placental smooth muscle cells.
Belongs to the glutamate--cysteine ligase type 3 family.
Catalyzes the ATP-dependent ligation of L-glutamate and L-cysteine and participates in the first and rate-limiting step in glutathione biosynthesis.
May act as an adapter that regulates LRP2 function.
Acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins (PubMed:9187108, PubMed:9256433). Also acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-diphosphate, phosphatidylinositol 3-phosphate and inositol 1,3,4,5-tetrakisphosphate with order of substrate preference in vitro PtdIns(3,4,5)P3 > PtdIns(3,4)P2 > PtdIns3P > Ins(1,3,4,5)P4 (PubMed:16824732, PubMed:26504226, PubMed:9593664). Tumor suppressor, the lipid phosphatase activity is critical for its tumor suppressor function (PubMed:9187108, PubMed:9616126, PubMed:9811831). Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival (PubMed:31492966, PubMed:37279284). The unphosphorylated form cooperates with MAGI2 to suppress AKT1 activation (PubMed:11707428). In motile cells, suppresses the formation of lateral pseudopods and thereby promotes cell polarization and directed movement (PubMed:22279049). Dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion formation (PubMed:22279049). Required for growth factor-induced epithelial cell migration; growth factor stimulation induces PTEN phosphorylation which changes its binding preference from the p85 regulatory subunit of the PI3K kinase complex to DLC1 and results in translocation of the PTEN-DLC1 complex to the posterior of migrating cells to promote RHOA activation (PubMed:26166433). Meanwhile, TNS3 switches binding preference from DLC1 to p85 and the TNS3-p85 complex translocates to the leading edge of migrating cells to activate RAC1 activation (PubMed:26166433). Plays a role as a key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Involved in the regulation of synaptic function in excitatory hippocampal synapses. Recruited to the postsynaptic membrane upon NMDA receptor activation, is required for the modulation of synaptic activity during plasticity. Enhancement of lipid phosphatase activity is able to drive depression of AMPA receptor-mediated synaptic responses, activity required for NMDA receptor-dependent long-term depression (LTD) (By similarity). May be a negative regulator of insulin signaling and glucose metabolism in adipose tissue. The nuclear monoubiquitinated form possesses greater apoptotic potential, whereas the cytoplasmic nonubiquitinated form induces less tumor suppressive ability (PubMed:10468583, PubMed:18716620).
Acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins. Also acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-diphosphate, phosphatidylinositol 3-phosphate and inositol 1,3,4,5-tetrakisphosphate with order of substrate preference in vitro PtdIns(3,4,5)P3 > PtdIns(3,4)P2 > PtdIns3P > Ins(1,3,4,5)P4.
Constitutively phosphorylated by CK2 under normal conditions. Phosphorylated in vitro by MAST1, MAST2, MAST3 and STK11. Phosphorylation results in an inhibited activity towards PIP3. Phosphorylation can both inhibit or promote PDZ-binding. Phosphorylation at Tyr-336 by FRK/PTK5 protects this protein from ubiquitin-mediated degradation probably by inhibiting its binding to NEDD4. Phosphorylation by ROCK1 is essential for its stability and activity. Phosphorylation by PLK3 promotes its stability and prevents its degradation by the proteasome. Phosphorylated on Thr-319 and Thr-321 in the C2-type tensin domain following EGF stimulation which changes its binding preference from the p85 regulatory subunit of the PI3K kinase complex to DLC1 (PubMed:26166433).
Enzymatic activity is enhanced in the presence of phosphatidylserine.
Expressed at a relatively high level in all adult tissues, including heart, brain, placenta, lung, liver, muscle, kidney and pancreas.
Functional kinase, like isoform 1 it antagonizes the PI3K-AKT/PKB signaling pathway. Plays a role in mitochondrial energetic metabolism by promoting COX activity and ATP production, via collaboration with isoform 1 in increasing protein levels of PINK1.
ISGylated. ISGylation promotes PTEN degradation.
Monomer. The unphosphorylated form interacts with the second PDZ domain of MAGI2 and with DLG1 and MAST2 in vitro (PubMed:10646847, PubMed:10760291, PubMed:11707428). Interacts with MAGI2, MAGI3, MAST1 and MAST3, but neither with MAST4 nor with DLG5; interaction with MAGI2 increases protein stability (PubMed:10748157, PubMed:15951562). Interacts with NEDD4 (PubMed:17218260). Interacts with NDFIP1 and NDFIP2; in the presence of NEDD4 or ITCH, this interaction promotes PTEN ubiquitination (PubMed:25801959, PubMed:20534535). Interacts (via C2 domain) with FRK (PubMed:19345329). Interacts with USP7; the interaction is direct (PubMed:18716620). Interacts with ROCK1 (By similarity). Interacts with XIAP/BIRC4 (PubMed:19473982). Interacts with STK11; the interaction phosphorylates PTEN (PubMed:15987703). Interacts with PPP1R16B (PubMed:25007873). Interacts with NOP53; regulates PTEN phosphorylation and increases its stability (PubMed:15355975). Interacts (via PDZ domain-binding motif) with DLG4; the interaction is induced by NMDA and is required for PTEN location at postsynaptic density (By similarity). Interacts with the regulatory p85 subunit of the PI3K kinase complex and with Rho GTPase-activating protein DLC1; in resting cells, interacts (via C2 tensin-type domain) with p85 but, following growth factor stimulation, PTEN is phosphorylated which leads to weakened interaction with p85 and enhanced interaction (via C2 tensin-type domain) with DLC1 while p85 interaction with TNS3 increases (PubMed:26166433).
Monoubiquitinated; monoubiquitination is increased in presence of retinoic acid. Deubiquitinated by USP7; leading to its nuclear exclusion. Monoubiquitination of one of either Lys-13 and Lys-289 amino acid is sufficient to modulate PTEN compartmentalization. Ubiquitinated by XIAP/BIRC4.
PTEN mutations are found in a subset of patients with Proteus syndrome, a genetically heterogeneous condition. The molecular diagnosis of PTEN mutation positive cases classifies Proteus syndrome patients as part of the PTEN hamartoma syndrome spectrum. As such, patients surviving the early years of Proteus syndrome are likely at a greater risk of developing malignancies.
Produced by alternative initiation at a CTG start codon of isoform 1. May contain a signal peptide at positions 1-21.
The C2 domain binds phospholipid membranes in vitro in a Ca(2+)-independent manner; this binding is important for its tumor suppressor function.
Interacts with GNAI1 and GNAQ (PubMed:18434541). Interacts with GNAZ and GNAI2. Interacts with OPRM1. Forms a complex with mu-opioid receptors and G(alpha)z/i2 subunits, including GNAZ and GNAI2; the formation of this complex results in mu-opioid receptor desensitization (By similarity). Interacts with HINT1 (By similarity).
Predominantly expressed in the cerebellum. Also expressed in the cortex and medulla. Weakly expressed in a number of peripheral tissues notably spleen, lung and leukocytes.
Regulates G protein-coupled receptor signaling cascades, including signaling via muscarinic acetylcholine receptor CHRM2 and dopamine receptor DRD2. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form (PubMed:15096504). Binds selectively to GNAZ and GNAI2 subunits, accelerates their GTPase activity and regulates their signaling activities. Negatively regulates mu-opioid receptor-mediated activation of the G-proteins (By similarity).
Sumoylated with SUMO1 and SUM02 in synaptosomes. The sumoylated forms act as a scaffold for sequestering mu-opioid receptor-activated G(alpha) subunits (By similarity). Desumoylated by HINT1 (By similarity).
Co-chaperone that binds directly to HSC70 and HSP70 and regulates their ATPase activity.
Highly expressed in kidney; not detectable in the other tissues tested.
Inhibited by thiosulfate, selenate, molybdate, tungstate, citrate and succinate.
Sodium:sulfate symporter that mediates sulfate reabsorption in the kidney and small intestine (PubMed:11161786). Can also mediate the transport of selenate and thiosulfate (By similarity).
May play a role in preadipocyte differentiation and adipogenesis.
A chromosomal aberration involving CHST11 is found in B-cell chronic lymphocytic leukemias. Translocation t(12;14)(q23;q32) with IgH.
Catalyzes the transfer of sulfate to position 4 of the N-acetylgalactosamine (GalNAc) residue of chondroitin. Chondroitin sulfate constitutes the predominant proteoglycan present in cartilage and is distributed on the surfaces of many cells and extracellular matrices. Can also sulfate Gal residues in desulfated dermatan sulfate. Preferentially sulfates in GlcA->GalNAc unit than in IdoA->GalNAc unit. Does not form 4, 6-di-O-sulfated GalNAc when chondroitin sulfate C is used as an acceptor.
N-glycosylated; required for activity and stability.
Widely expressed. Highly expressed in spleen, thymus, bone marrow, peripheral blood leukocytes, lymph node, heart, brain, lung and placenta.
Transcription repressor that plays a role in regulation of embryonic stem cells (ESCs) differentiation. Required for ESCs differentiation and acts by mediating autorepression of NANOG in ESCs: binds to the NANOG promoter and promotes association of NANOG protein to its own promoter and recruits the NuRD complex, which deacetylates histones. Not required for establishement and maintenance of ESCs (By similarity). Represses the transcription of a number of genes including GAST, ODC1 and VIM. Binds to the G-rich box in the enhancer region of these genes.
May be a positive regulator of adipogenesis.
Predominantly expressed in white adipose tissue (WAT) especially in the stromal vascular cells. Expressed in adipocyte differentiable 3T3-L1 cells but not in the non-adipogenic cell line NIH-3T3. Expression increased in the early stage of adipogenesis.
A chromosomal aberration disrupting PDZD7 has been found in patients with non-syndromic sensorineural deafness. Translocation t(10;11),t(10;11).
Homodimerizes (via PDZ2 domain). Component of USH2 complex, composed of ADGRV1, PDZD7, USH2A and WHRN. Interacts (via PDZ domains) with WHRN; the interaction is direct (By similarity). Interacts with USH1G (PubMed:19028668). Interacts with ADGRV1 (via the cytoplasmic region) (PubMed:20440071). Interacts with USH2A (via the cytoplasmic region) (PubMed:20440071). Interacts with MYO7A (via MyTH4-FERM domains) (By similarity).
In cochlear developing hair cells, essential in organizing the USH2 complex at stereocilia ankle links. Blocks inhibition of adenylate cyclase activity mediated by ADGRV1.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. A PDZD7 mutation has been found in combination with a mutation in ADGRV1 in a patient affected by Usher syndrome, suggesting PDZD7 mutations contribute to digenic Usher syndrome.
Weakly expressed in the inner ear. Expressed in the retinal pigment epithelium.
Receptor for the heterotrimeric lymphotoxin containing LTA and LTB, and for TNFS14/LIGHT. Promotes apoptosis via TRAF3 and TRAF5. May play a role in the development of lymphoid organs.
Self-associates. Associates with TRAF3, TRAF4 and TRAF5.
(Microbial infection) Interacts with Mopeia virus protein Z.
(Microbial infection) Interacts with Respiratory syncytial virus protein N; this interaction may promote viral growth by inhibiting the innate immune response.
(Microbial infection) Interacts with the HTLV-1 protein Tax.
Homooligomer. Interacts with TNFAIP3. Interacts with STARD13. Interacts with MYO6 (PubMed:31371777). Interacts with TOM1; the interaction is indirect and is mediated by MYO6, which acts as a bridge between TOM1 and TAX1BP1 (PubMed:31371777). Interacts with MAVS; this interaction induces MAVS polyubiquitination (PubMed:27736772). Interacts with TNIP1 (PubMed:21885437). Interacts with TRAF6; this interaction mediates deubiquitination of TRAF6 and inhibition of NF-kappa-B activation (PubMed:17703191). Interacts with RIPK1; this interaction negatively regulates RIPK1 ubiquitination (PubMed:17703191). Interacts with NBR1 (PubMed:33226137, PubMed:34471133). Interacts with TBK1 (PubMed:33226137). Interacts with RB1CC1 (PubMed:33226137, PubMed:34471133). Interacts with SQSTM1 (PubMed:34471133). Interacts with AZI2 (PubMed:30459273).
Phosphorylated in the C-terminal region by CHUK/IKKA leading to NF-kappa-B signaling down-regulation.
The C-terminal UBZ-type zinc fingers function as ubiquitin-binding domains.
Ubiquitin-binding adapter that participates in inflammatory, antiviral and innate immune processes as well as selective autophagy regulation (PubMed:30459273, PubMed:29940186, PubMed:30909570). Plays a key role in the negative regulation of NF-kappa-B and IRF3 signalings by acting as an adapter for the ubiquitin-editing enzyme A20/TNFAIP3 to bind and inactivate its substrates (PubMed:17703191). Disrupts the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKBKE to attenuate 'Lys63'-linked polyubiquitination of TBK1 and thereby IFN-beta production (PubMed:21885437). Recruits also A20/TNFAIP3 to ubiquitinated signaling proteins TRAF6 and RIPK1, leading to their deubiquitination and disruption of IL-1 and TNF-induced NF-kappa-B signaling pathways (PubMed:17703191). Inhibits virus-induced apoptosis by inducing the 'Lys-48'-linked polyubiquitination and degradation of MAVS via recruitment of the E3 ligase ITCH, thereby attenuating MAVS-mediated apoptosis signaling (PubMed:27736772). As a macroautophagy/autophagy receptor, facilitates the xenophagic clearance of pathogenic bacteria such as Salmonella typhimurium and Mycobacterium tuberculosis (PubMed:26451915). Upon NBR1 recruitment to the SQSTM1-ubiquitin condensates, acts as the major recruiter of RB1CC1 to these ubiquitin condensates to promote their autophagic degradation (PubMed:33226137, PubMed:34471133).
Binds to the myc promoter and acts as a transcriptional repressor. May be a tumor suppressor.
Binds two Mg(2+) per subunit. Required for catalysis and for stabilizing the dimer.
Glycolytic enzyme the catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate (PubMed:29775581, PubMed:1369209). In addition to glycolysis, involved in various processes such as growth control, hypoxia tolerance and allergic responses (PubMed:2005901, PubMed:10802057, PubMed:12666133, PubMed:29775581). May also function in the intravascular and pericellular fibrinolytic system due to its ability to serve as a receptor and activator of plasminogen on the cell surface of several cell-types such as leukocytes and neurons (PubMed:12666133). Stimulates immunoglobulin production (PubMed:1369209).
Induced in diffuse large cell lymphoma (DLCL) after treatment with the natural biological agent, Bryo1. Up-regulated in response to enterovirus 71 (EV71) infection (at protein level).
It is uncertain whether the alternative initiation site is at Met-94 or at Met-97.
Lysine 2-hydroxyisobutyrylation (Khib) by p300/EP300 activates the phosphopyruvate hydratase activity.
Mammalian enolase is composed of 3 isozyme subunits, alpha, beta and gamma, which can form homodimers or heterodimers which are cell-type and development-specific (PubMed:18560153). ENO1 interacts with PLG in the neuronal plasma membrane and promotes its activation. The C-terminal lysine is required for this binding (PubMed:9308760). Isoform MBP-1 interacts with TRAPPC2B (PubMed:11134351). Interacts with ENO4 and PGAM2 (By similarity). Interacts with CMTM6 (PubMed:28813417).
Used as a diagnostic marker for many tumors and, in the heterodimeric form, alpha/gamma, as a marker for hypoxic brain injury after cardiac arrest. Also marker for endometriosis. Antibodies against alpha-enolase are present in sera from patients with cancer-associated retinopathy syndrome (CAR), a progressive blinding disease which occurs in the presence of systemic tumor growth, primarily small-cell carcinoma of the lung and other malignancies. Is identified as an autoantigen in Hashimoto encephalopathy (HE) a rare autoimmune disease associated with Hashimoto thyroiditis (HT). HT is a disorder in which destructive processes overcome the potential capacity of thyroid replacement leading to hypothyroidism.
Coiled-coil-mediated oligomerization enhances the catalytic activity. Proteolytic processing of the C-terminus may release the protein from membranes and constitute a mean to regulate the enzyme. May be regulated by HSPB2, RAC1, RAF1 and G-protein second messengers.
Homodimer; homodimerization stimulates the kinase activity. Interacts with HSPB2; may enhance DMPK kinase activity. Interacts with PLN; phosphorylates PLN. May interact with RAC1; may regulate DMPK kinase activity. Interacts with LMNA; may regulate nuclear envelope stability.
Most isoforms are expressed in many tissues including heart, skeletal muscle, liver and brain, except for isoform 2 which is only found in the heart and skeletal muscle, and isoform 14 which is only found in the brain, with high levels in the striatum, cerebellar cortex and pons.
Non-receptor serine/threonine protein kinase which is necessary for the maintenance of skeletal muscle structure and function. May play a role in myocyte differentiation and survival by regulating the integrity of the nuclear envelope and the expression of muscle-specific genes. May also phosphorylate PPP1R12A and inhibit the myosin phosphatase activity to regulate myosin phosphorylation. Also critical to the modulation of cardiac contractility and to the maintenance of proper cardiac conduction activity probably through the regulation of cellular calcium homeostasis. Phosphorylates PLN, a regulator of calcium pumps and may regulate sarcoplasmic reticulum calcium uptake in myocytes. May also phosphorylate FXYD1/PLM which is able to induce chloride currents. May also play a role in synaptic plasticity.
Phosphorylated. Autophosphorylates. Phosphorylation by RAF1 may result in activation of DMPK.
Proteolytic processing of the C-terminus may remove the transmembrane domain and release the kinase from membranes stimulating its activity.
The coiled coil domain is required for homodimerization and regulates the enzymatic activity.
The disease is caused by variants affecting the gene represented in this entry. The causative mutation is a CTG expansion in the 3'-UTR of the DMPK gene. A length exceeding 50 CTG repeats is pathogenic, while normal individuals have 5 to 37 repeats. Intermediate alleles with 35-49 triplets are not disease-causing but show instability in intergenerational transmissions. Disease severity varies with the number of repeats: mildly affected persons have 50 to 150 repeats, patients with classic DM have 100 to 1,000 repeats, and those with congenital onset can have more than 2,000 repeats.
(Microbial infection) Interacts with JC virus agnoprotein; this interaction induces the dissociation of CBX5 from LBR, resulting in destabilization of the nuclear envelope.
Component of heterochromatin that recognizes and binds histone H3 tails methylated at 'Lys-9' (H3K9me), leading to epigenetic repression. In contrast, it is excluded from chromatin when 'Tyr-41' of histone H3 is phosphorylated (H3Y41ph). Can interact with lamin-B receptor (LBR). This interaction can contribute to the association of the heterochromatin with the inner nuclear membrane. Involved in the formation of functional kinetochore through interaction with MIS12 complex proteins.
Interacts directly with ATRX, CHAF1A, LBR, NIPBL, SP100, STAM2 and TRIM28 via the chromoshadow domain (PubMed:15882967, PubMed:9169472). Can interact directly with CBX3 via the chromoshadow domain (PubMed:9169472). Interacts with KMT5B and KMT5C (By similarity). Interacts with HP1BP3 (PubMed:20042602). Interacts with histone H3 methylated at 'Lys-9' (PubMed:11242053, PubMed:21047797). Interacts with BAHD1, MIS12 and DSN1 (PubMed:15502821, PubMed:19666599). Interacts with POGZ; POGZ and PXVXL motif-containing proteins such as INCENP and TRIM28 compete for interaction with CBX5 (PubMed:20562864, PubMed:20850016, PubMed:21346195). Interacts with INCENP and TRIM24 (PubMed:11313457). Interacts with CHAMP1 (PubMed:20850016). Interacts with PRR14 (via N-terminus) (PubMed:25906157). Interacts with RRP1B (PubMed:19710015). Interacts with HNRNPU (via C-terminus); this interaction is, at least in part, RNA-dependent (PubMed:19617346). Interacts with LRIF1 (via PxVxL motif) (PubMed:23542155). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (PubMed:32051553). May form homodimers (By similarity). Interacts with SMYD5 (By similarity). Interacts with CHD3 (PubMed:28977666). Interacts with CHD4 (PubMed:28977666).
Phosphorylation of HP1 and LBR may be responsible for some of the alterations in chromatin organization and nuclear structure which occur at various times during the cell cycle (By similarity). Phosphorylated during interphase and possibly hyper-phosphorylated during mitosis.
(Microbial infection) Interacts with HIV-2 viral protein Vpx; promoting interaction with a E3 ubiquitin-protein ligase complex containing DCAF1, leading to subsequent ubiquitination and degradation of SAMHD1.
(Microbial infection) Phosphorylation at Thr-592 by Epstein-Barr virus kinase BGLF4 and human cytomegalovirus/HCMV UL97 leads to a reduced level of dCTPase and dTTPase activity and the loss of viral restriction.
(Microbial infection) Ubiquitinated following interaction with HIV-2 viral protein Vpx; Vpx promotes interaction and with a DCX (DDB1-CUL4-X-box) E3 ubiquitin ligase, leading to proteasomal degradation.
Allosterically activated and regulated via the combined actions of GTP and dNTPs (dATP, dGTP, dTTP and dCTP): Allosteric site 1 binds GTP, while allosteric site 2 binds dNTP (PubMed:25288794, PubMed:25267621, PubMed:25760601). Allosteric activation promotes the formation of highly active homotetramers (PubMed:22056990, PubMed:24141705, PubMed:24217394, PubMed:25288794, PubMed:25267621, PubMed:25760601). Phosphorylation at Thr-592 impairs homotetramerization, thereby inhibiting dNTPase activity, leading to reduced ability to restrict infection by viruses (PubMed:23602554, PubMed:23601106, PubMed:26294762, PubMed:26431200, PubMed:29610582, PubMed:29670289).
By IFNG/IFN-gamma. Up-regulated in TNF treated lung fibroblasts.
Expressed in heart, skeletal muscle, spleen, liver, small intestine, placenta, lung and peripheral blood leukocytes (PubMed:11064105). No expression is seen in brain and thymus (PubMed:11064105).
Homodimer; in absence of GTP and dNTP (PubMed:24141705, PubMed:24217394, PubMed:28229507, PubMed:25760601). Homotetramer; in GTP- and dNTP-bound form (PubMed:23601106, PubMed:26101257, PubMed:24141705, PubMed:24217394, PubMed:28229507, PubMed:26294762, PubMed:26431200, PubMed:25288794, PubMed:25267621, PubMed:25760601). Interacts with MRE11; leading to stimulate the exonuclease activity of MRE11 (PubMed:28834754, PubMed:29670289). Interacts with RBBP8/CtIP (PubMed:28834754). Interacts (via its C-terminus) with CD81.
In human, and in contrast to mouse protein, the SAM domain is not required for deoxynucleoside triphosphate (dNTPase) activity and ability to restrict infection by viruses.
Phosphorylation at Thr-592 by CDK1 acts as a switch to control deoxynucleoside triphosphate (dNTPase)-dependent and -independent functions (PubMed:29670289). Phosphorylation at Thr-592 takes place in cycling cells: it reduces the stability of the homotetramer, impairing the dNTPase activity and subsequent ability to restrict infection by viruses (PubMed:23602554, PubMed:23601106, PubMed:26294762, PubMed:26431200, PubMed:31291580). It also inhibits ability to suppress LINE-1 retrotransposon activity (PubMed:29610582). In contrast, phosphorylation at Thr-592 promotes DNA end resection at stalled replication forks in response to DNA damage (PubMed:29670289).
Phosphorylation at Thr-592 was initially thought to impair ability to restrict infection by viruses without affecting the deoxynucleoside triphosphate (dNTPase) activity (PubMed:23601106). However, it was later shown that phosphorylation reduces the stability of the homotetramer, leading to impair the dNTPase activity (PubMed:26294762, PubMed:26431200).
Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks (PubMed:19525956, PubMed:21613998, PubMed:21720370, PubMed:23602554, PubMed:23601106, PubMed:22056990, PubMed:24336198, PubMed:26294762, PubMed:26431200, PubMed:28229507, PubMed:28834754, PubMed:29670289). Has deoxynucleoside triphosphate (dNTPase) activity, which is required to restrict infection by viruses, such as HIV-1: dNTPase activity reduces cellular dNTP levels to levels too low for retroviral reverse transcription to occur, blocking early-stage virus replication in dendritic and other myeloid cells (PubMed:19525956, PubMed:21613998, PubMed:21720370, PubMed:23602554, PubMed:23601106, PubMed:23364794, PubMed:25038827, PubMed:26101257, PubMed:22056990, PubMed:24336198, PubMed:28229507, PubMed:26294762, PubMed:26431200). Likewise, suppresses LINE-1 retrotransposon activity (PubMed:24035396, PubMed:29610582, PubMed:24217394). Not able to restrict infection by HIV-2 virus; because restriction activity is counteracted by HIV-2 viral protein Vpx (PubMed:21613998, PubMed:21720370). In addition to virus restriction, dNTPase activity acts as a regulator of DNA precursor pools by regulating dNTP pools (PubMed:23858451). Phosphorylation at Thr-592 acts as a switch to control dNTPase-dependent and -independent functions: it inhibits dNTPase activity and ability to restrict infection by viruses, while it promotes DNA end resection at stalled replication forks (PubMed:23602554, PubMed:23601106, PubMed:29610582, PubMed:29670289). Functions during S phase at stalled DNA replication forks to promote the resection of gapped or reversed forks: acts by stimulating the exonuclease activity of MRE11, activating the ATR-CHK1 pathway and allowing the forks to restart replication (PubMed:29670289). Its ability to promote degradation of nascent DNA at stalled replication forks is required to prevent induction of type I interferons, thereby preventing chronic inflammation (PubMed:27477283, PubMed:29670289). Ability to promote DNA end resection at stalled replication forks is independent of dNTPase activity (PubMed:29670289). Enhances immunoglobulin hypermutation in B-lymphocytes by promoting transversion mutation (By similarity).
Was initially thought to have 3'-5' exonuclease activity, acting on single-stranded RNA (PubMed:23364794, PubMed:25038827). A publication also reported some DNA 3'-5' exonuclease activity (PubMed:23364794). However, it was later shown that SAMHD1 does not possess DNA and/or RNA exonuclease activities and that these activities are due to contamination during the purification process that can be removed after chromatography steps (PubMed:26101257). The exonuclease activity observed was maybe due to the presence of MRE11 during the purification steps (PubMed:29670289).
Was intially thought to be allosterically stimulated by dGTP (PubMed:22056990, PubMed:24141705, PubMed:24217394). However, it was later shown that it is allosterically activated and regulated via the combined actions of GTP and dNTPs (dATP, dGTP, dTTP and dCTP), which bind two separate binding sites (PubMed:25288794, PubMed:25267621, PubMed:25760601).
Expression increases in early G1 phase and reaches highest levels during the S and G2/M phases.
Interacts with the CDK2 and the CDC2 protein kinases to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex. Does not bind CDK4 and CDK5 (in vitro). The cyclin A1-CDK2 complex interacts with transcription factor E2F-1 and RB proteins. Found in a complex with CDK2, CABLES1 and CCNE1 (By similarity). Interacts with INCA1 (PubMed:15159402, PubMed:21540187). Interacts with KLHDC9 (PubMed:15159402).
May be involved in the control of the cell cycle at the G1/S (start) and G2/M (mitosis) transitions. May primarily function in the control of the germline meiotic cell cycle and additionally in the control of mitotic cell cycle in some somatic cells.
Very high levels in testis and very low levels in brain. Also found in myeloid leukemia cell lines.
DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA. The resultant detrimental levels of mutations in the proviral genome, along with a deamination-independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells. Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single- or double-stranded RNA. Exhibits antiviral activity against simian immunodeficiency virus (SIV), hepatitis B virus (HBV) and human T-cell leukemia virus type 1 (HTLV-1) and may inhibit the mobility of LTR and non-LTR retrotransposons.
Expressed at high and moderate levels in peripheral blood leukocytes, spleen, testes, heart, thymus, prostate and ovary. Also expressed at low levels in several other tissues.
Homodimer. Interacts with APOBEC3G. Does not interact with APOBEC1.
Phorbol 12-myristate 13-acetate (PMA) induces overexpression in keratinocytes. Up-regulated by IFN-alpha.
Interacts with CEP152; the interaction is mutually exclusive with CEP63.
Key structural component of the deuterosome, a structure that promotes de novo centriole amplification in multiciliated cells. Deuterosome-mediated centriole amplification occurs in terminally differentiated multiciliated cells and can generate more than 100 centrioles. Probably sufficient for the specification and formation of the deuterosome inner core. Interacts with CEP152 and recruits PLK4 to activate centriole biogenesis (By similarity).
Component of the RNA polymerase I (Pol I) complex consisting of at least 13 subunits.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase I which synthesizes ribosomal RNA precursors.
Interacts with RTN1; regulates the ceramide glucosyltransferase activity of UGCG.
Participates in the initial step of the glucosylceramide-based glycosphingolipid/GSL synthetic pathway at the cytosolic surface of the Golgi (PubMed:8643456, PubMed:1532799). Catalyzes the transfer of glucose from UDP-glucose to ceramide to produce glucosylceramide/GlcCer (such as beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine) (PubMed:1532799, PubMed:8643456). GlcCer is the core component of glycosphingolipids/GSLs, amphipathic molecules consisting of a ceramide lipid moiety embedded in the outer leaflet of the membrane, linked to one of hundreds of different externally oriented oligosaccharide structures (PubMed:8643456). Glycosphingolipids are essential components of membrane microdomains that mediate membrane trafficking and signal transduction, implicated in many fundamental cellular processes, including growth, differentiation, migration, morphogenesis, cell-to-cell and cell-to-matrix interactions (By similarity). They are required for instance in the proper development and functioning of the nervous system (By similarity). As an example of their role in signal transduction, they regulate the leptin receptor/LEPR in the leptin-mediated signaling pathway (By similarity). They also play an important role in the establishment of the skin barrier regulating keratinocyte differentiation and the proper assembly of the cornified envelope (By similarity). The biosynthesis of GSLs is also required for the proper intestinal endocytic uptake of nutritional lipids (By similarity). Catalyzes the synthesis of xylosylceramide/XylCer (such as beta-D-xylosyl-(1<->1')-N-acylsphing-4-enine) using UDP-Xyl as xylose donor (PubMed:33361282).
The D1, D2, D3, (Q/R)XXRW motif is a critical part of the GCS active site, involved in catalysis and UDP-sugar binding.
Interacts with BLOC1S4, BLOC1S5 and BLOC1S6 (By similarity). Component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) composed of BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. Octamer composed of one copy each BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. The BLOC-1 complex associates with the AP-3 protein complex and membrane protein cargos. Interacts directly with BLOC1S2.
Interacts with DOCK2, which may activate it. Interacts with S100A8 and calprotectin (S100A8/9) (PubMed:10559471, PubMed:15642721). Found in a complex with SH3RF1, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (By similarity). Interacts with PAK1 (PubMed:30723080, PubMed:30654050).
Plasma membrane-associated small GTPase which cycles between an active GTP-bound and inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses, such as secretory processes, phagocytose of apoptotic cells and epithelial cell polarization. Augments the production of reactive oxygen species (ROS) by NADPH oxidase.
(Microbial infection) Interacts with M.bovis FbpB via the collagen-binding region.
(Microbial infection) Interacts with S.aureus FnbA.
(Microbial infection) Interacts with fibronectin-binding proteins from other Mycobacteria.
(Microbial infection) Interacts with recombinant S.pneumoniae PavA (rqcH).
(Microbial infection) Interacts with recombinant S.suis FbpS (rqcH) via fibronectin's N-terminal 30 kDa region.
Binds fibronectin and induces fibril formation. This fibronectin polymer, named superfibronectin, exhibits enhanced adhesive properties. Both anastellin and superfibronectin inhibit tumor growth, angiogenesis and metastasis. Anastellin activates p38 MAPK and inhibits lysophospholipid signaling.
Expressed between 12 and 19 weeks post-conception (WPC) in Bruch's membrane, with expression in the choroid evident from 14 WPC onwards (at protein level) (PubMed:29777959). Expressed in the inner limiting membrane at 17 WPC (at protein level) (PubMed:29777959). Ugl-Y1, Ugl-Y2 and Ugl-Y3 are present in the urine from 0 to 17 years of age (PubMed:17614963, PubMed:3584091).
Expressed by fetal and tumor-associated cells.
Expressed in the inner limiting membrane and around blood vessels in the retina (at protein level) (PubMed:29777959). Plasma FN (soluble dimeric form) is secreted by hepatocytes. Cellular FN (dimeric or cross-linked multimeric forms), made by fibroblasts, epithelial and other cell types, is deposited as fibrils in the extracellular matrix. Ugl-Y1, Ugl-Y2 and Ugl-Y3 are found in urine (PubMed:17614963).
Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin (PubMed:3024962, PubMed:3900070, PubMed:3593230, PubMed:7989369). Fibronectins are involved in cell adhesion, cell motility, opsonization, wound healing, and maintenance of cell shape (PubMed:3024962, PubMed:3900070, PubMed:3593230, PubMed:7989369). Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization (By similarity). Participates in the regulation of type I collagen deposition by osteoblasts (By similarity). Acts as a ligand for the LILRB4 receptor, inhibiting FCGR1A/CD64-mediated monocyte activation (PubMed:34089617).
Forms covalent cross-links mediated by a transglutaminase, such as F13A or TGM2, between a glutamine and the epsilon-amino group of a lysine residue, forming homopolymers and heteropolymers (e.g. fibrinogen-fibronectin, collagen-fibronectin heteropolymers).
It is not known whether both or only one of Thr-2155 and Thr-2156 are/is glycosylated.
Mostly heterodimers or multimers of alternatively spliced variants, connected by 2 disulfide bonds near the carboxyl ends; to a lesser extent homodimers. Interacts with FBLN1, AMBP, TNR, LGALS3BP and COL13A1. Interacts with FBLN7 (By similarity). Interacts with COMP (PubMed:12225811). Interacts (via type III repeats 9-14) with TNFAIP6 (via CUB domain); this interaction enhances fibronectin fibril assembly. TNFAIP6 may act as a bridging molecule between FN1 and THBS1 (PubMed:18042364). Interacts with TNR; the interaction inhibits cell adhesion and neurite outgrowth (By similarity). Interacts with FST3 and MYOC.
Proteolytic processing produces the C-terminal NC1 peptide, anastellin.
Secreted by contracting muscle, induces liver autophagy, a degradative pathway for nutrient mobilization and damage removal, and systemic insulin sensitization via hepatic ITGA5:ITGB1 integrin receptor signaling.
Serotonylated on Gln residues by TGM2 in response to hypoxia.
Some lysine residues are oxidized to allysine by LOXL3, promoting fibronectin activation and matrix formation.
Numerous size polymorphism are present in KRTAP4 gene family, which are mainly due to variations in the sequence encoding cysteine-rich repeat segments (PubMed:15955084). Allele shown is KAP4.5-v1 (PubMed:15955084).
Autocatalytically cleaved in response to mitochondrial depolarization both at the N-terminus and C-terminus to generate the short active form (S-OMA1) (By similarity). Autocatalytic processing at the C-terminus takes place at residues 447-456 (By similarity). The S-OMA1 form is unstable (By similarity). Degradaded by YMEL1 in response to membrane depolarization (PubMed:26923599). Protein turnover is regulated by prohibitin (PHB and PHB2), which promotes degradation of OMA1 in a cardiolipin-binding manner (By similarity).
May form a redox-dependent disulfide bond (By similarity). Exists in a semi-oxidized state and is activated by prolonged hypoxia (PubMed:31044600).
Metalloprotease that is part of the quality control system in the inner membrane of mitochondria (PubMed:20038677, PubMed:25605331, PubMed:32132706, PubMed:32132707). Activated in response to various mitochondrial stress, leading to the proteolytic cleavage of target proteins, such as OPA1, UQCC3 and DELE1 (PubMed:20038677, PubMed:25275009, PubMed:32132706, PubMed:32132707). Following stress conditions that induce loss of mitochondrial membrane potential, mediates cleavage of OPA1 at S1 position, leading to OPA1 inactivation and negative regulation of mitochondrial fusion (PubMed:20038677, PubMed:25275009). Also acts as a regulator of apoptosis: upon BAK and BAX aggregation, mediates cleavage of OPA1, leading to the remodeling of mitochondrial cristae and allowing the release of cytochrome c from mitochondrial cristae (PubMed:25275009). In depolarized mitochondria, may also act as a backup protease for PINK1 by mediating PINK1 cleavage and promoting its subsequent degradation by the proteasome (PubMed:30733118). May also cleave UQCC3 in response to mitochondrial depolarization (PubMed:25605331). Also acts as an activator of the integrated stress response (ISR): in response to mitochondrial stress, mediates cleavage of DELE1 to generate the processed form of DELE1 (S-DELE1), which translocates to the cytosol and activates EIF2AK1/HRI to trigger the ISR (PubMed:32132706, PubMed:32132707). Its role in mitochondrial quality control is essential for regulating lipid metabolism as well as to maintain body temperature and energy expenditure under cold-stress conditions (By similarity). Binds cardiolipin, possibly regulating its protein turnover (By similarity). Required for the stability of the respiratory supercomplexes (By similarity).
Protease activity is activated upon autocatalytic cleavage in response to mitochondrial depolarization.
The stress-sensor region regulates proteolysis and activation.
Was initially reported to localize in the endoplasmic reticulum (PubMed:12886954). However, it was later shown that it localizes to mitochondrion (PubMed:20038677).
Widely expressed, with strong expression in the heart, skeletal muscle, kidney and liver.
Acts in an adapter protein-like fashion to mediate the interaction between the kinase PRKCZ and its substrate VAMP2 and increases the PRKCZ-dependent phosphorylation of VAMP2 (PubMed:17313651). Positively regulates adipocyte differentiation, by facilitating the phosphorylation and thus inactivation of the anti-adipogenetic transcription factor FOXO1 by the kinase AKT1 (PubMed:18388859). Plays a role in endosomal control of AKT2 signaling; required for insulin-stimulated AKT2 phosphorylation and glucose uptake and insulin-stimulated phosphorylation of AKT2 substrates (By similarity). Participates in transferrin receptor endocytosis (PubMed:16873553).
Homodimer (PubMed:16792529). Interacts (via WD repeats 1-3) with AKT1, AKT2, PRKCZ and PRKCI (PubMed:16792529). Interacts with VAMP2 (PubMed:17313651). Forms a complex with VAMP2 and PRKCZ (PubMed:17313651). Interacts with FOXO1 (By similarity). Forms a complex with AKT1 and FOXO1 (By similarity).
The FYVE-type zinc finger is essential for its vesicular localization.
Homodimer (PubMed:26238318). Interacts with PCNA; interaction is disrupted in response to UV irradiation (PubMed:19419956).
Magnesium may be the real cofactor in vivo.
May catalyze the hydrolysis of nucleoside triphosphates including dGTP, dTTP, dCTP, their oxidized forms like 8-oxo-dGTP and the prodrug thiopurine derivatives 6-thio-dGTP and 6-thio-GTP (PubMed:26238318). Could also catalyze the hydrolysis of some nucleoside diphosphate derivatives (PubMed:22556419, PubMed:26238318). Hydrolyzes oxidized nucleosides triphosphates like 8-oxo-dGTP in vitro, but the specificity and efficiency towards these substrates are low. Therefore, the potential in vivo sanitizing role of this enzyme, that would consist in removing oxidatively damaged forms of nucleosides to prevent their incorporation into DNA, is unclear (PubMed:26238318, PubMed:22556419). Through the hydrolysis of thioguanosine triphosphates may participate in the catabolism of thiopurine drugs (PubMed:26238318, PubMed:25108385). May also have a role in DNA synthesis and cell cycle progression by stabilizing PCNA (PubMed:19419956). Exhibits decapping activity towards dpCoA-capped RNAs in vitro (By similarity).
Polymorphic NUDT15 variants define the poor metabolism of thiopurines 2 genetic locus (THPM2) [MIM:616903]. Thiopurines are used as immunosuppressants or cytotoxic drugs and are prescribed for a variety of clinical conditions including leukemia, autoimmune disease and organ transplantation. Patients with low NUDT15 activities have an increased risk for toxic effects after receiving standard doses of thiopurine drugs.
(Microbial infection) Identified in a complex with SMU1 and influenza A virus RNA polymerase subunits PB1 and PB2. Directly interacts with SMU1 and with influenza A virus RNA polymerase subunits PB1 and PB2.
(Microbial infection) Required, together with SMU1, for normal splicing of influenza A virus NS1 pre-mRNA, which is required for the production of the exportin NS2 and for the production of influenza A virus particles. Not required for the production of VSV virus particles.
Component of the spliceosome B complex (PubMed:22365833, PubMed:28781166). Interacts with SMU1 (PubMed:22365833, PubMed:24945353). Interacts with MAD1L1 (PubMed:22351768). May interact with DHX15 (PubMed:24252166).
Expressed at similar levels in fetal and adult tissues.
Involved in pre-mRNA splicing as a component of the spliceosome (PubMed:28781166). Auxiliary spliceosomal protein that regulates selection of alternative splice sites in a small set of target pre-mRNA species (Probable). Required for normal mitotic cell cycle progression (PubMed:22351768, PubMed:24252166). Recruits MAD1L1 and MAD2L1 to kinetochores, and is required to trigger the spindle assembly checkpoint (PubMed:22351768). Required for normal accumulation of SMU1 (PubMed:24945353).
Up-regulated during mitosis (at protein level).
Was originally thought to be the IK factor, a cytokine involved in the negative regulatory pathway of constitutive MHC class II antigens expression.
Component of the nexin-dynein regulatory complex (N-DRC) a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes.
Component of the nexin-dynein regulatory complex (N-DRC). Interacts with DRC1 (PubMed:34169321). Interacts with TCTE1/DRC5 (By similarity). Interacts with DRC7 (By similarity).
Expressed in trophoblast cells of placental villi.
GTPase activator for the Rho-type GTPases. As a GCM1 downstream effector, it is involved in placental development and positively regulates trophoblast cells migration. It regulates cytoskeletal remodeling by controlling the activity of Rho GTPases including RHOA, CDC42 and RAC1 (PubMed:27917469).
Belongs to the glycosyl hydrolase 85 family.
Endoglycosidase that releases N-glycans from glycoproteins by cleaving the beta-1,4-glycosidic bond in the N,N'-diacetylchitobiose core. Involved in the processing of free oligosaccharides in the cytosol.
Widely expressed. Expressed at higher level in thymus and spleen.
Ligand for CXCR2 (By similarity). Has chemotactic activity for neutrophils. May play a role in inflammation and exert its effects on endothelial cells in an autocrine fashion. In vitro, the processed form GRO-gamma(5-73) shows a fivefold higher chemotactic activity for neutrophilic granulocytes.
N-terminal processed form GRO-gamma(5-73) is produced by proteolytic cleavage after secretion from peripheral blood monocytes.
By IFNG during macrophage activation, and by TNF and IL1B.
Homodimer; homodimerization occurs upon GTP-binding and is required for the second hydrolysis step from GDP to GMP (PubMed:10970849, PubMed:16511497). Undergoes conformational changes and oligomerization upon GTP-binding and hydrolysis (PubMed:28645896). Heterodimer with other family members, including GBP2, GBP3, GBP4 and GBP5 (PubMed:10970849, PubMed:16511497). Dimerization regulates subcellular location to membranous structures (PubMed:21151871). Interacts with SQSTM1 (By similarity).
Interferon (IFN)-inducible GTPase that plays important roles in innate immunity against a diverse range of bacterial, viral and protozoan pathogens (PubMed:22106366, PubMed:29144452, PubMed:16511497, PubMed:31268602). Hydrolyzes GTP to GMP in two consecutive cleavage reactions: GTP is first hydrolyzed to GDP and then to GMP in a processive manner (PubMed:7512561, PubMed:16511497). Following infection, recruited to the pathogen-containing vacuoles or vacuole-escaped bacteria and promotes both autophagy and inflammasome assembly (PubMed:29144452, PubMed:31268602). Promotes host defense against bacterial infections by regulating bacteriolytic peptide generation via its interaction with ubiquitin-binding protein SQSTM1, which delivers monoubiquitinated proteins to autolysosomes for the generation of bacteriolytic peptides (By similarity). Also acts as a positive regulator of inflammasome assembly by promoting the release of inflammasome ligands from bacteria (PubMed:31268602). Acts by promoting lysis of pathogen-containing vacuoles, releasing pathogens into the cytosol (By similarity). Following pathogen release in the cytosol, promotes recruitment of proteins that mediate bacterial cytolysis: this liberates ligands that are detected by inflammasomes, such as lipopolysaccharide (LPS) that activates the non-canonical CASP4/CASP11 inflammasome or double-stranded DNA (dsDNA) that activates the AIM2 inflammasome (PubMed:31268602). Confers protection to several pathogens, including the bacterial pathogens L.monocytogenes and M.bovis BCG as well as the protozoan pathogen T.gondii (PubMed:31268602). Exhibits antiviral activity against influenza virus (PubMed:22106366).
Belongs to the flagellar radial spoke RSP3 family.
Component of the axonemal radial spoke 1 (RS1) and 2 (RS2) complexes, at least composed of spoke head proteins RSPH1, RSPH3, RSPH9 and the cilia-specific component RSPH4A or sperm-specific component RSPH6A, spoke stalk proteins RSPH14, DNAJB13, DYDC1, ROPN1L and NME5, and the RS1 complex-specific anchor protein IQUB (By similarity). Interacts with IQUB (PubMed:36355624). Interacts with phosphorylated MAPK1 (PubMed:19684019). Interacts with MEK1 (PubMed:19684019). Interacts with PKA regulatory subunits PRKAR1A and PRKAR1B (PubMed:19684019). Interacts with RSPH1 (By similarity). Interacts with RSPH4A (By similarity). Interacts with RSPH6A (By similarity). Interacts with RSPH9 (By similarity).
Functions as part of axonemal radial spoke complexes that play an important part in the motility of sperm and cilia (By similarity). Functions as a protein kinase A-anchoring protein that scaffolds the cAMP-dependent protein kinase holoenzyme. May serve as a point of convergence for MAPK and PKA signaling in cilia (PubMed:19684019).
Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797). May be a component of the proposed t-UTP subcomplex of the ribosomal small subunit (SSU) processome containing at least UTP4, WDR43, HEATR1, UTP15, WDR75 (PubMed:17699751, PubMed:22916032). Interacts directly with UTP4 and WDR43 (PubMed:24219289).
Catalyzes the conversion of the 17-keto group of estrone, 4- and 5-androstenes and 5-alpha-androstanes into their 17-beta-hydroxyl metabolites and the conversion of the 3-keto group of 3-, 3,17- and 3,20- diketosteroids into their 3-hydroxyl metabolites. Exhibits reductive 3-beta-hydroxysteroid dehydrogenase activity toward 5-beta-androstanes, 5-beta-pregnanes, 4-pregnenes and bile acids. May also reduce endogenous and exogenous alpha-dicarbonyl compounds and xenobiotic alicyclic ketones.
Inhibited by flavonoids including apigenin, luteolin, genistein, kaempferol and quercetin and also by carbenoxolone, zearalenone, glycyrrhetinic, curcumin and flufenamic acid.
Isoform 1: Ubiquitously expressed, with highest levels in testis, small intestine, colon, kidney, brain and heart. Isoform 3: Expressed in brain, heart and skeletal muscle.
Caspase inhibitor. Acts as a regulator of procaspase-1/CASP1 activation implicated in the regulation of the proteolytic maturation of pro-interleukin-1 beta (IL1B) and its release during inflammation. Inhibits the release of IL1B in response to LPS in monocytes. Also induces NF-kappa-B activation during the pro-inflammatory cytokine response. Also able to inhibit CASP1-mediated neuronal cell death, TNF-alpha, hypoxia-, UV-, and staurosporine-mediated cell death but not ER stress-mediated cell death. Acts by preventing activation of caspases CASP1 and CASP4, possibly by preventing the interaction between CASP1 and RIPK2.
Down-regulated in patients suffering of Huntington disease.
Homooligomer. Interacts with CASP1, CASP4, CARD8 and RIPK2.
Widely expressed. Expressed at higher level in placenta, spleen, lymph node and bone marrow. Weakly or not expressed in thymus.
Interacts (via PQIIIT motif) with PPP3R1, PPP3R2, PPP3CA, PPP3CB and PPP3CC (PubMed:34446558). Interacts with VDAC2 (By similarity). Interacts with ATG16L1 (via WD repeats) (By similarity).
Plays an important role in sperm motility and male fertility (By similarity). Required for sperm midpiece flexibility and for the localization of sperm calcineurin to the mitochondria (By similarity). Promotes mitophagy as well as acts as an autophagy mediator in male germline cells (By similarity). Links damaged mitochondria to autophagosomes via its binding to the outer mitochondrial membrane protein VDAC2, as well as to key autophagy machinery component ATG16L1 (By similarity).
Hormone that acts as a blood lipid regulator by regulating serum triglyceride levels (PubMed:22569073, PubMed:22809513, PubMed:23150577). May be involved in the metabolic transition between fasting and refeeding: required to direct fatty acids to adipose tissue for storage in the fed state (By similarity).
In response to food intake. Stimulated by insulin.
Initially reported to specifically promote pancreatic beta cell proliferation without insulin resistance and to promote beta cell mass expansion, thereby improving glucose tolerance (PubMed:23623304). However, this result could not be confirmed by further studies and the original paper was later retracted (PubMed:28038792). The lack of a role in beta cell proliferation was also confirmed in another study (PubMed:25417115).
Predominantly expressed in liver. Also expressed in adipose tissues.
Proteolytically cleaved at the N-terminus.
The gene represented in this entry may be involved in disease pathogenesis. Increased protein levels are observed in the serum of patients and are associated with insulin resistance (PubMed:25024395, PubMed:25303484, PubMed:24963292, PubMed:24852694). According to another report, protein levels are decreased in the serum of patients (PubMed:25050901). Discrepancies between increased and decreased levels of proteins levels in T2D patients may be explained by the use of different kits developed on the market that either use antibodies recognizing the N-terminal or the C-terminal part of the protein (PubMed:25099942). These results should however be reinvestigated in light of recent advances that suggest that this protein is not promoting pancreatic beta cell proliferation.
The gene represented in this entry may be involved in disease pathogenesis. Increased protein levels are observed in the serum of patients. This result should however be reinvestigated in light of recent advances that suggest that this protein is not promoting pancreatic beta cell proliferation.
Transcripts are up-regulated by 100 fold during adipogenesis.
Hydrolyzes the phosphatidylinositol 4,5-bisphosphate (PIP2) to generate 2 second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG mediates the activation of protein kinase C (PKC), while IP3 releases Ca(2+) from intracellular stores. Essential for trophoblast and placental development. May participate in cytokinesis by hydrolyzing PIP2 at the cleavage furrow (PubMed:10336610). Regulates neurite outgrowth through the inhibition of RhoA/Rho kinase signaling (By similarity).
Present in corneal epithelial cells (at protein level).
Strongly activated by phosphatidic acid. Inhibited by phosphatidylethanolamine (PtdEtn), phosphatidylcholine (PtdCho), sphingomyelin and phosphatidylserine (PtdSer).
The C2 domain is a Ca(2+)-dependent membrane-targeting module.
The PH domain mediates interaction with the surface membrane by binding to PIP2.
Autoinhibited by the C-terminal PH domain which folds back and binds to the surface of the DH domain, blocking binding of RHOA to the catalytic center of the DH domain (PubMed:31888991). The 2nd BRCT domain is also involved in inhibition, probably by helping to impede RHOA binding (PubMed:31888991). Allosterically activated by binding of activated GTP-bound RHOA to the PH domain which stimulates the release of PH inhibition and promotes the binding of substrate RHOA to the catalytic center (PubMed:31888991). Binding of phosphorylated RACGAP1 to the N-terminal BRCT domain-containing region also releases autoinhibition (PubMed:25068414).
Expressed in lung epithelial cells (at protein level). Expressed in squamous cell carcinoma, primary non-small cell lung cancer tumors and lung adenocarcinoma.
Guanine nucleotide exchange factor (GEF) that catalyzes the exchange of GDP for GTP. Promotes guanine nucleotide exchange on the Rho family members of small GTPases, like RHOA, RHOC, RAC1 and CDC42. Required for signal transduction pathways involved in the regulation of cytokinesis. Component of the centralspindlin complex that serves as a microtubule-dependent and Rho-mediated signaling required for the myosin contractile ring formation during the cell cycle cytokinesis. Regulates the translocation of RHOA from the central spindle to the equatorial region. Plays a role in the control of mitotic spindle assembly; regulates the activation of CDC42 in metaphase for the process of spindle fibers attachment to kinetochores before chromosome congression. Involved in the regulation of epithelial cell polarity; participates in the formation of epithelial tight junctions in a polarity complex PARD3-PARD6-protein kinase PRKCQ-dependent manner. Plays a role in the regulation of neurite outgrowth. Inhibits phenobarbital (PB)-induced NR1I3 nuclear translocation. Stimulates the activity of RAC1 through its association with the oncogenic PARD6A-PRKCI complex in cancer cells, thereby acting to coordinately drive tumor cell proliferation and invasion. Also stimulates genotoxic stress-induced RHOB activity in breast cancer cells leading to their cell death.
Homodimer (PubMed:15545273, PubMed:14645260, PubMed:16170345). Homooligomer (PubMed:15545273). Found in the centralspindlin complex (PubMed:16236794). Interacts with NR1I3 (By similarity). Interacts (Thr-359 phosphorylated form) with PARD6A; the interaction is observed in cancer cells (PubMed:15254234, PubMed:19617897). Interacts (Thr-359 phosphorylated form) with PRKCI; the interaction is observed in cancer cells (PubMed:19617897). Interacts with PKP4; the interaction is observed at the midbody (PubMed:22814378). Interacts with RACGAP1/CYK4; the interaction is direct, occurs in a microtubule-dependent manner, occurs at anaphase and during cytokinesis, is inhibited in metaphase by phosphorylation of ECT2 on Thr-373 and is stimulated in early anaphase by dephosphorylation of ECT2 probably on Thr-373 through CDK1 activity (PubMed:16103226, PubMed:16129829, PubMed:16236794, PubMed:19468300, PubMed:19468302, PubMed:25068414). Interacts with PLK1; the interaction is stimulated upon its phosphorylation on Thr-444 (PubMed:16247472). Interacts with RHOA; the interaction results in allosteric activation of ECT2 (PubMed:31888991). Interacts with KIF23, PARD3, PARD6B and PRKCQ (PubMed:15254234, PubMed:16236794). Interacts with NEDD9/HEF1 (PubMed:16394104).
Phosphorylated by PLK1 in vitro. Hyperphosphorylated during the G2 phase of the cell cycle. Phosphorylation at Thr-373 occurs during the G2/M phase, relieves its auto-inhibition status and stimulates its GEF activity. Phosphorylation at Thr-444 in G2/M phase is required for subsequent binding with PLK1 and Rho exchange activation. Dephosphorylated at the time of cytokinesis. Phosphorylation at Thr-359 is required for its transformation activity in cancer cells.
The BRCT domains 1 and 2 are required for intramolecular interaction, but not for intermolecular oligomerization (PubMed:15545273). The BRCT domains negatively inhibit its GEF activity in interphase cells (PubMed:15545273, PubMed:31888991). The same BRCT domains may act as a positive regulatory motif for the completion of cytokinesis after the breakdown of nuclear membrane during mitosis (PubMed:15545273).
Up-regulated by calcium in cells forming cell-cell contact sites. Up-regulated by DNA damaging agents like H(2)O(2) or ionizing radiation (IR).
Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P) (PubMed:10617617). S1P is a bioactive lysophospholipid that elicits diverse physiological effects on most types of cells and tissues (PubMed:10617617). When expressed in rat HTC4 hepatoma cells, is capable of mediating S1P-induced cell proliferation and suppression of apoptosis (PubMed:10617617). Receptor for the chemokine-like protein FAM19A5 (PubMed:29453251). Mediates the inhibitory effect of FAM19A5 on vascular smooth muscle cell proliferation and migration (By similarity).
E3 ubiquitin-protein ligase that mediates ubiquitination oF target proteins (PubMed:23277564, PubMed:24275455, PubMed:24981174). Depending on the associated E2 ligase, mediates 'Lys-48'- and 'Lys-63'-linked polyubiquitination of substrates (By similarity). Part of a BAG6-dependent quality control process ensuring that proteins of the secretory pathway that are mislocalized to the cytosol are degraded by the proteasome. Probably acts by providing the ubiquitin ligase activity associated with the BAG6 complex and be responsible for ubiquitination of the hydrophobic mislocalized proteins and their targeting to the proteasome (PubMed:24981174, PubMed:29042515). May also play a role in the endosomal recycling of IGF2R, the cation-independent mannose-6-phosphate receptor (PubMed:24275455). May play a role in the endosomal sorting and degradation of several membrane receptors including EGFR, FLT3, MET and CXCR4, by mediating their ubiquitination (PubMed:23418353). By ubiquitinating CDKN1A/p21 and targeting it for degradation, may also promote cell proliferation (PubMed:23026136). May monoubiquitinate AICDA (PubMed:23277564).
Interacts with CCDC50, EGFR, FLT3 and SCAMP3 (PubMed:23418353). Interacts with BAG6 (via ubiquitin-like domain); required for BAG6-dependent ubiquitination of proteins mislocalized to the cytosol (PubMed:24981174, PubMed:27193484). Interacts with CDKN1A (PubMed:23026136). Interacts with AICDA (PubMed:23277564).
The C4-type zinc finger is required for interaction with BAG6.
Ubiquitinated. May undergo autoubiquitination.
It is uncertain whether Met-1, Met-171 or Met-172 is the initiator.
Dimer of alpha and beta chains (PubMed:34996871, PubMed:35482892). A typical microtubule is a hollow water-filled tube with an outer diameter of 25 nm and an inner diameter of 15 nM (PubMed:34996871, PubMed:35482892). Alpha-beta heterodimers associate head-to-tail to form protofilaments running lengthwise along the microtubule wall with the beta-tubulin subunit facing the microtubule plus end conferring a structural polarity (PubMed:34996871, PubMed:35482892). Microtubules usually have 13 protofilaments but different protofilament numbers can be found in some organisms and specialized cells (PubMed:34996871, PubMed:35482892). Interacts with UNC5C (via cytoplasmic domain); this interaction is decreased by NTN1/Netrin-1 (PubMed:28483977). Interacts with NLRP5/MATER at cytoskeleton microtubules (PubMed:24374158). Interacts with DPYSL5 (PubMed:33894126).
Expression is primarily restricted to central and peripheral nervous system. Greatly increased expression in most cancerous tissues.
Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers (PubMed:34996871). Microtubules grow by the addition of GTP-tubulin dimers to the microtubule end, where a stabilizing cap forms (PubMed:34996871). Below the cap, tubulin dimers are in GDP-bound state, owing to GTPase activity of alpha-tubulin (PubMed:34996871). TUBB3 plays a critical role in proper axon guidance and maintenance (PubMed:20074521). Binding of NTN1/Netrin-1 to its receptor UNC5C might cause dissociation of UNC5C from polymerized TUBB3 in microtubules and thereby lead to increased microtubule dynamics and axon repulsion (PubMed:28483977). Plays a role in dorsal root ganglion axon projection towards the spinal cord (PubMed:28483977).
Contains one covalently linked retinal chromophore. Upon light absorption, the covalently bound 11-cis-retinal is converted to all-trans-retinal. After hydrolysis of the Schiff base and release of the covalently bound all-trans-retinal, active rhodopsin is regenerated by binding of a fresh molecule of 11-cis-retinal(PubMed:12566452).
Homodimer (By similarity). May form a complex composed of RHO, GRK1 and RCVRN in a Ca(2+)-dependent manner; RCVRN prevents the interaction between GRK1 and RHO (By similarity). Interacts with GRK1 (PubMed:28524165). Interacts (phosphorylated form) with SAG (PubMed:28524165, PubMed:26200343, PubMed:28753425). Interacts with GNAT1 (PubMed:26200343). Interacts with GNAT3. SAG and G-proteins compete for a common binding site (PubMed:26200343). Interacts with PRCD; the interaction promotes PRCD stability (By similarity). Forms a complex with ASAP1 and ARF4. Forms a complex with ASAP1, RAB11A, Rabin8/RAB3IP, ARF4 and RAB11FIP3; the complex regulates Golgi-to-cilia rhodopsin/RHO transport in photoreceptors (By similarity).
Phosphorylated on some or all of the serine and threonine residues present in the C-terminal region (By similarity). After activation by light, phosphorylated by GRK1 (in vitro) (PubMed:28524165).
Photoreceptor required for image-forming vision at low light intensity (PubMed:8107847, PubMed:7846071). Required for photoreceptor cell viability after birth (PubMed:2215617, PubMed:12566452). Light-induced isomerization of the chromophore 11-cis-retinal to all-trans-retinal triggers a conformational change that activates signaling via G-proteins (PubMed:8107847, PubMed:28524165, PubMed:26200343, PubMed:28753425). Subsequent receptor phosphorylation mediates displacement of the bound G-protein alpha subunit by the arrestin SAG and terminates signaling (PubMed:28524165, PubMed:26200343).
Rod shaped photoreceptor cells which mediate vision in dim light.
Involved in modulation of cell growth and cellular response to gamma radiation probably via regulation of the Akt signaling pathway. Involved in regulation of p53/TP53. Suppresses p53/TP53 protein levels and promotes its ubiquitination; the function is dependent on USP7 and independent on MDM2. Proposed to displace p53/TP53 from interaction with USP7.
Binds opioids in the presence of acidic lipids; probably involved in cell contact.
Acts as a molecular chaperone for G protein-coupled receptors, regulating their biogenesis and exit from the ER.
Belongs to the glutaredoxin family. YDR286C subfamily.
Belongs to the lambda interferon family.
By viral infections or double-stranded RNA.
Cytokine with antiviral, antitumour and immunomodulatory activities. Plays a critical role in the antiviral host defense, predominantly in the epithelial tissues. Acts as a ligand for the heterodimeric class II cytokine receptor composed of IL10RB and IFNLR1, and receptor engagement leads to the activation of the JAK/STAT signaling pathway resulting in the expression of IFN-stimulated genes (ISG), which mediate the antiviral state. Has a restricted receptor distribution and therefore restricted targets: is primarily active in epithelial cells and this cell type-selective action is because of the epithelial cell-specific expression of its receptor IFNLR1. Seems not to be essential for early virus-activated host defense in vaginal infection, but plays an important role in Toll-like receptor (TLR)-induced antiviral defense. Plays a significant role in the antiviral immune defense in the intestinal epithelium. Exerts an immunomodulatory effect by up-regulating MHC class I antigen expression.
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIB subfamily.
Calcium/calmodulin-regulated and magnesium-dependent enzyme that catalyzes the hydrolysis of ATP coupled with the transport of calcium out of the cell (PubMed:8530416). By regulating sperm cell calcium homeostasis, may play a role in sperm motility (By similarity).
Interacts with PDZD11 (PubMed:12763866). Interacts with SLC35G1 and STIM1 (PubMed:22084111). Interacts with calmodulin (PubMed:2963820, PubMed:10493800).
Isoform XB is the most abundant isoform and is expressed ubiquitously. Isoforms containing segment Z have only been detected in heart, while isoforms containing segment a have been found in heart, stomach and brain cortex.
Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase. May be involved in activation of the SAPK/JNK pathway Stimulates genotoxic stress-induced RHOB activity in breast cancer cells leading to their cell death.
By TGFB1. Up-regulated by DNA damaging agents like H(2)O(2) or ionizing radiation (IR).
Interacts with RHOA in its GTP- and GDP-bound states, and with CDC42 in its GTP-bound state. Interacts with the PDZ 1 domain of BAIAP1 (By similarity).
Heterotrimer of an alpha 1(IX), an alpha 2(IX) and an alpha 3(IX) chain (By similarity). The chains are linked to each other by interchain disulfide bonds (By similarity). Trimers are also cross-linked via hydroxylysines (By similarity).
Belongs to the NADP-dependent oxidoreductase L4BD family.
Functions as 15-oxo-prostaglandin 13-reductase and acts on 15-keto-PGE1, 15-keto-PGE2, 15-keto-PGE1-alpha and 15-keto-PGE2-alpha with highest activity towards 15-keto-PGE2 (PubMed:19000823). Overexpression represses transcriptional activity of PPARG and inhibits adipocyte differentiation (By similarity).
Expressed specifically in testis and fetal ovaries.
Expression detected in fetal ovaries between wpf (weeks post-fertilization) 11 and 27; expression peaks at wpf 14.5 and is decreasing afterwards.
Interacts with XPO1. Interacts with MEIOSIN (By similarity).
Meiosis-inducer required for the transition into meiosis for both female and male germ cells. In female germ cells, acts downstream of ZGLP1 as a key effector of the meiotic program: required for premeiotic DNA replication and subsequent events in meiotic prophase. During spermatogenesis, next to its role in meiotic initiation, promotes (but is not required for) spermatogonial differentiation. In complex with MEIOSIN, directly activates the transcription of a subset of critical meiotic genes playing a central role in cell-cycle switching from mitosis to meiosis.
Aggregates keratin intermediate filaments and promotes disulfide-bond formation among the intermediate filaments during terminal differentiation of mammalian epidermis.
Expressed in skin, thymus, stomach, tonsils, testis, placenta, kidney, pancreas, mammary gland, bladder, thyroid, salivary gland and trachea, but not detected in heart, brain, liver, lung, bone marrow, small intestine, spleen, prostate, colon, or adrenal gland (PubMed:19384417). In the skin, mainly expressed in stratum granulosum of the epidermis (PubMed:1429717) (PubMed:19384417).
Filaggrin is initially synthesized as a large, insoluble, highly phosphorylated precursor containing many tandem copies of 324 AA, which are not separated by large linker sequences. During terminal differentiation it is dephosphorylated and proteolytically cleaved. The N-terminal of the mature protein is heterogeneous, and is blocked by the formation of pyroglutamate.
Undergoes deimination of some arginine residues (citrullination).
A beta-galactoside alpha2-3 sialyltransferase involved in terminal sialylation of glycoproteins and glycolipids (PubMed:8288606, PubMed:8611500). Catalyzes the transfer of sialic acid (N-acetyl-neuraminic acid; Neu5Ac) from the nucleotide sugar donor CMP-Neu5Ac onto acceptor Galbeta-(1->3)-GalNAc- and Galbeta-(1->4)-GlcNAc-terminated glycoconjugates through an alpha2-3 linkage (PubMed:8288606, PubMed:8611500). Plays a major role in hemostasis. Responsible for sialylation of plasma VWF/von Willebrand factor, preventing its recognition by asialoglycoprotein receptors (ASGPR) and subsequent clearance. Regulates ASGPR-mediated clearance of platelets (By similarity). Participates in the biosynthesis of the sialyl Lewis X epitopes, both on O- and N-glycans, which are recognized by SELE/E-selectin, SELP/P-selectin and SELL/L-selectin. Essential for selectin-mediated rolling and adhesion of leukocytes during extravasation (PubMed:25498912). Contributes to adhesion and transendothelial migration of neutrophils likely through terminal sialylation of CXCR2 (By similarity). In glycosphingolipid biosynthesis, sialylates GM1 and GA1 gangliosides to form GD1a and GM1b, respectively (PubMed:8288606). Metabolizes brain c-series ganglioside GT1c forming GQ1c (By similarity). Synthesizes ganglioside LM1 (IV3Neu5Ac-nLc4Cer), a major structural component of peripheral nerve myelin (PubMed:8611500).
Expressed in fetal tissues, with highest levels in heart, lung, and kidney.
Highly expressed in adult placenta, heart and kidney.
Forms a homodimer or heterodimer with other members of the family. All isoforms interact with several 14-3-3 proteins.
Interacts only with YWHAB and YWHAQ among 14-3-3 proteins.
Isoform 2 is expressed at lower levels in fetal brain and kidney than in adult brain and kidney.
Isoform 2 is expressed in colon, breast, prostate, pancreas and kidney tumor cell lines. Isoform 2 is expressed at high levels in kidney, prostate, brain, small intestine and pancreas, at moderate levels in placenta and colon, at low levels in lung, liver and heart, and at very low levels in spleen, thymus, peripheral mononuclear blood cells, testis and ovary.
Client-loading PAQosome/R2TP complex cofactor that selects NOP58 to promote box C/D small nucleolar ribonucleoprotein (snoRNP) assembly. Acts as a bridge between NOP58 and the R2TP complex via RUVBL1:RUVBL2.
Interacts with NOP58, RUVBL1 and RUVBL2; the interactions are direct and NOPCHAP1 bridges the association of NOP58 with RUVBL1:RUVBL2 even in absence of snoRNAs. The interactions with RUVBL1 and RUVBL2 are disrupted upon ATP binding.
(Microbial infection) Phosphorylation by vaccinia virus protein E3 and rotavirus A stabilizes the eIF-2/GDP/eIF-2B complex and prevents GDP/GTP exchange reaction, thus impairing the recycling of eIF2 between successive rounds of initiation and leading to global inhibition of translation.
Activity is regulated by phosphorylation at Ser-49 and Ser-52, which stabilizes the eIF2/GDP/eIF-2B complex and prevents the eIF-2B-mediated exchange of GDP for GTP, thereby preventing the formation of the 43S pre-initiation complex (43S PIC) (PubMed:15207627, PubMed:18032499). This results in the global attenuation of 5' cap-dependent protein synthesis and concomitant translation of ISR-specific mRNAs that contain a short upstream open reading frame (uORF) in their 5' UTR, such as ATF4, ATF5, DDIT3/CHOP and PPP1R15A/GADD34 (PubMed:19131336).
Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA (PubMed:16289705). This complex binds to a 40S ribosomal subunit, followed by mRNA binding to form a 43S pre-initiation complex (43S PIC) (PubMed:16289705). Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF2 and release of an eIF2-GDP binary complex (PubMed:16289705). In order for eIF2 to recycle and catalyze another round of initiation, the GDP bound to eIF2 must exchange with GTP by way of a reaction catalyzed by eIF-2B (PubMed:16289705). EIF2S1/eIF2-alpha is a key component of the integrated stress response (ISR), required for adaptation to various stress: phosphorylation by metabolic-stress sensing protein kinases (EIF2AK1/HRI, EIF2AK2/PKR, EIF2AK3/PERK and EIF2AK4/GCN2) in response to stress converts EIF2S1/eIF2-alpha in a global protein synthesis inhibitor, leading to an attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activators ATF4 and QRICH1, and hence allowing ATF4- and QRICH1-mediated reprogramming (PubMed:19131336, PubMed:33384352).
Phosphorylation at Ser-49 and Ser-52 stabilizes the eIF-2/GDP/eIF-2B complex and prevents GDP/GTP exchange reaction, thus impairing the recycling of eIF2 between successive rounds of initiation and leading to global inhibition of translation, while concomitantly initiating the preferential translation of integrated stress response (ISR)-specific mRNAs (PubMed:15207627, PubMed:18032499, PubMed:19131336). Substrate for at least 4 kinases: EIF2AK1/HRI, EIF2AK2/PKR, EIF2AK3/PERK and EIF2AK4/GCN2 (By similarity). Phosphorylated; phosphorylation on Ser-52 by the EIF2AK4/GCN2 protein kinase occurs in response to amino acid starvation and UV irradiation (By similarity).
This gene should not be confused with EIF2A, with which it shares the alias EIF2A. Although both of these proteins function in binding initiator tRNA to the 40S ribosomal subunit, the eIF2 complex requires GTP, whereas the EIF2A protein does so in a codon-dependent manner.
Up-regulated upon endoplasmic reticulum stress.
eIF2 is an heterotrimer composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain (PubMed:23063529). eIF2 is member of the 43S pre-initiation complex (43S PIC). eIF2 forms a complex with at least CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5 (By similarity). Interaction with METAP2 protects EIF2S1 from inhibitory phosphorylation (By similarity). Interacts with ABCF1 isoform 2 (PubMed:17894550). Associates with ribosomes (PubMed:17894550). Interacts with DDX3X in an RNA-independent manner (PubMed:18596238).
Antibodies against PNMA2 are present in sera from patients suffering of paraneoplastic neurological disorders.
Brain-specific. In some cancer patients, specifically expressed by testicular tumor cells.
(Microbial infection) Interacts with hepatitis B virus HBX; this interaction inhibits formation of the HBX-DDB1 complex, thus inhibiting viral replication.
By interferons alpha and gamma in a STAT1-dependent way.
Highest expression in liver; undetectable in skeletal muscle.
Interacts with MAVS (PubMed:24379373). Interacts with WRNIP1 and PPP6C; these interactions positively regulate the RIGI signaling pathway (PubMed:29053956). Interacts with CGAS; this interaction stabilizes CGAS and promotes type I interferon production (PubMed:27666593, PubMed:32404352). Interacts with USP14; this interaction mediates the cleavage of 'Lys-48'-linked ubiquitination of CGAS (PubMed:27666593). Interacts with TBK1 (PubMed:32404352). Interacts with SPI1 (By similarity).
Plays an essential role in the innate immune defense against viruses and bacteria (PubMed:30150992, PubMed:32404352). Facilitates the type I IFN response by interacting with MAVS at the outer mitochondria membrane and thereby recruiting NF-kappa-B essential modulator IKBKG/NEMO to the MAVS signalosome, leading to the activation of both the IFN regulatory factor 3/IRF3 and NF-kappa-B pathways (PubMed:24379373). Positively regulates the CGAS-induced type I interferon signaling pathway by stabilizing CGAS and inhibiting its autophagic degradation (PubMed:27666593). Acts as a scaffold between TBK1 and STAT3 to promote phosphorylation of STAT3 and resolve interferon-stimulated gene (ISG) expression (PubMed:32404352). Inhibits the transcriptional activity of SPI1 in a dose-dependent manner (By similarity).
The B-box zinc finger is responsible for inhibition of SPI1-mediated transcriptional activation.
Ubiquitinated (PubMed:24379373). Undergoes 'Lys-63'-linked polyubiquitination; this modification allows IKBKG/NEMO recruitment to MAVS. Undergoes 'Lys-48'-linked polyubiquitination by RNF125; this modification mediates its degradation via the ubiquitin-proteasome pathway (PubMed:28476934).
Detected in testis (at protein level). Detected in testis.
Functions during spermatogenesis as a chaperone for a range of client proteins that are important for sperm adhesion onto the egg zona pellucida and for subsequent penetration of the zona pellucida. Required for normal sperm migration from the uterus into the oviduct. Required for normal male fertility. Binds calcium ions (By similarity).
Interacts with PPIB. Interacts with ADAM2 (By similarity). Interacts with PDILT.
Expressed primarily in the brain and heart, with low expression in the kidney, pancreas and muscle.
Expressed primarily in the fetal brain, with low expression in the lung, and kidney at 6-7 weeks dpc (PubMed:8666406, PubMed:24886874). Weak expression in the fetal heart and muscle (PubMed:24886874).
Transcription factor that acts as a transcriptional activator (PubMed:24886874, PubMed:26543203). Binds cooperatively with POU3F2/BRN2 or POU3F1/OCT6 to gene promoters, which enhances transcriptional activation (By similarity). Acts as a transcriptional activator of TEAD2 by binding to its gene promoter and first intron (By similarity). Plays a redundant role with SOX4 and SOX12 in cell survival of developing tissues such as the neural tube, branchial arches and somites, thereby contributing to organogenesis (By similarity).
Catalyzes the last step of tRNA splicing, the transfer of the splice junction 2'-phosphate from ligated tRNA to NAD to produce ADP-ribose 1''-2'' cyclic phosphate.
Widely expressed. Weakly or not expressed in lung, spleen, small intestine and peripheral blood leukocytes.
Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A2 subfamily.
Homotrimer (PubMed:15265858, PubMed:15483603, PubMed:26483543). Isoform 3 can oligomerize with isoform 1 (PubMed:20688910). Interacts with AJUBA (By similarity).
Palmitoylation at Cys-38 is not required for correct subcellular localization, but is important for glutamate uptake activity.
Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:7521911, PubMed:14506254, PubMed:15265858, PubMed:26690923). Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion (PubMed:14506254). Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport (PubMed:14506254). Essential for the rapid removal of released glutamate from the synaptic cleft, and for terminating the postsynaptic action of glutamate (By similarity).
A residue in the 7th transmembrane region (Thr-355 in human, 'Asn-351' in mouse and rat) is important for species-specific sensitivity to various agonists.
Detected in cerebral artery smooth muscle cells (at protein level). Detected in brain cortex, striatum, amygdala, medulla, hippocampus, caudate nucleus and putamen.
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances, such as lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Regulates the release of 5-hydroxytryptamine, dopamine and acetylcholine in the brain, and thereby affects neural activity, nociceptive processing, pain perception, mood and behavior. Besides, plays a role in vasoconstriction of cerebral arteries.
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various alkaloids and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Regulates the release of 5-hydroxytryptamine, dopamine and acetylcholine in the brain, and thereby affects neural activity, nociceptive processing, pain perception, mood and behavior. Besides, plays a role in vasoconstriction of cerebral arteries.
Ligands are bound in a hydrophobic pocket formed by the transmembrane helices.
Phosphorylated. Desensitization of the receptor may be mediated by its phosphorylation.
Component of a THAP1/THAP3-HCFC1-OGT complex that contains at least, either THAP1 or THAP3, HCFC1 and OGT. Interacts directly with OGT and HCFC1 (via its HBM).
Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1.
Highly expressed in heart, skeletal muscle and placenta. Weaker expression in brain, kidney and liver.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. KLP2 subfamily.
Expressed in testis, colon, thymus and in breast cancer.
Plus-end directed kinesin-like motor enzyme involved in mitotic spindle assembly.
Electroneutral antiporter that exchanges sodium for protons or ammonium ions at the basolateral membrane of epithelia to regulate cell volume and intracellular pH upon hypertonic conditions (By similarity). As part of transcellular ammonia transport in renal tubules, mediates basolateral ammonium extrusion in the medullary thick ascending limb, regulating the corticopapillary ammonium gradient and overall renal acid excretion (By similarity). Mediates sodium:proton exchange in gastric parietal cells secondary to cAMP-dependent acid secretion and hyperosmolarity. Possibly coupled to chloride:bicarbonate antiporter, enables loading of parietal cells with sodium and chloride ions to maintain cell volume and normal gastric acid secretion (By similarity). Functions as a sodium sensor in neurons of organum vasculosum of the lamina terminalis where it regulates water intake in response to increased sodium concentration in body fluids (By similarity).
Homodimer; each protomer has one site for sodium and one site for proton binding (By similarity). Interacts with CHP1 and CHP2 (By similarity).
Belongs to the glycosyltransferase 8 family. Glycogenin subfamily.
Divalent metal ions. Required for self-glucosylation. Manganese is the most effective.
Highly expressed in skeletal muscle and heart, with lower levels in brain, lung, kidney and pancreas.
Homodimer (PubMed:22160680). Interacts (via C-terminus) with glycogen synthase GYS1 (PubMed:17055998). Interacts (via C-terminus) with glycogen synthase GYS2 (By similarity). This interaction is required for GYS2-mediated glycogen synthesis (By similarity).
Self-glucosylates, via an inter-subunit mechanism, to form an oligosaccharide primer that serves as substrate for glycogen synthase.
Self-glycosylated by the transfer of glucose residues from UDP-glucose to itself, forming an alpha-1,4-glycan of around 10 residues attached to Tyr-195.
IP3K is activated by calcium and calmodulin. Form B is much more sensitive to calcium/calmodulin than form A.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv12.1/KCNH8 sub-subfamily.
Pore-forming (alpha) subunit of voltage-gated potassium channel. Elicits a slowly activating, outward rectifying current. Channel properties may be modulated by cAMP and subunit assembly.
Primarily expressed in the nervous system.
Higher expression in adult kidney and liver and to a lesser extent in adult and fetal spleen, adult lymph nodes and appendix, and fetal liver and kidney. Strongly decreased in hepatocellular carcinoma tissues (at protein level).
Proton-coupled transporter that delivers pathogen-associated or danger-associated molecular patterns to cytosolic pattern recognition receptors as part of the innate immune response to microbes or tissue injury (PubMed:28539433, PubMed:34235268). Has selectivity toward muropeptides that contain the amino acid diaminopimelic acid (DAP-type peptidoglycan muropeptides) including Tri-DAP and tracheal toxin (TCT), common in Gram-negative bacteria and Gram-positive bacilli. In the context of immune recognition of skin microbiota, shuttles bacterial muropeptides across the endolysosomal membranes into the cytosol for recognition by NOD1, triggering MYD88-dependent secretion of IL1A and neutrophil recruitment in a pyroptosis-type inflammatory process (PubMed:28539433). To a lesser extent and redundantly, transports muramyl dipeptides derived from most bacterial proteoglycans, eliciting NOD2 receptor activation and downstream inflammatory responses (PubMed:28539433). Postulated to function as a dominant importer of cyclic GMP-AMP dinucleotides (cGAMPs) in monocyte and macrophage cell lineages. Selectively imports cGAMPs derived from pathogenic bacteria such as 3'3'-cGAMP thus providing for differential immune recognition of pathogenic versus commensal bacteria. During tumorigenesis may transport extracellular tumor-derived 2'3'-cGAMP across the plasma membrane of M1-polarized macrophages to activate the anti-tumoral stimulator of interferon genes (STING) pathway (PubMed:34235268). The transport mechanism, its electrogenicity and stoichiometry remain to be elucidated (Probable).
Strongly expressed in the adult thymus. Expressed in spleen, lymph nodes, thymus, PBL, bone marrow and fetal liver. Expressed in monocytes and pre-dendridic cells.
Up-regulated in keratinocytes upon differentiation.
Expressed in bone marrow stromal cells from both multiple myeloma patients and healthy donors. Seems to be ubiquitously expressed.
Interacts with DLX5, DLX7 and MSX2 and forms homomultimers. Interacts with UNC5A. Interacts with TRIM28 and PJA1. Interacts with NGFR/p75NTR and RORA.
Involved in the apoptotic response after nerve growth factor (NGF) binding in neuronal cells. Inhibits cell cycle progression, and facilitates NGFR-mediated apoptosis. May act as a regulator of the function of DLX family members. May enhance ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex. Plays a role in the circadian rhythm regulation. May act as RORA co-regulator, modulating the expression of core clock genes such as BMAL1 and NFIL3, induced, or NR1D1, repressed.
Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC) (PubMed:17360435). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13 (PubMed:17360435). The SEH1 subunit appears to be only weakly associated with the Nup107-160 subcomplex (PubMed:17360435). Component of the GATOR2 subcomplex, composed of MIOS, SEC13, SEH1L, WDR24 and WDR59 (PubMed:23723238). The GATOR2 complex interacts with CASTOR1 and CASTOR2; the interaction is negatively regulated by arginine (PubMed:26972053, PubMed:36528027, PubMed:35831510). The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612). SESN1, SESN2 and SESN3 convey leucine availability via direct interaction with SEH1L and WDR24 (PubMed:35831510).
Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC (PubMed:15146057, PubMed:17363900). The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation. This subunit plays a role in recruitment of the Nup107-160 subcomplex to the kinetochore (PubMed:15146057, PubMed:17363900).
The GATOR2 complex is negatively regulated by the upstream amino acid sensors CASTOR1 and SESN2, which sequester the GATOR2 complex in absence of amino acids (PubMed:26972053, PubMed:25457612, PubMed:27487210, PubMed:35831510). In the presence of abundant amino acids, GATOR2 is released from CASTOR1 and SESN2 and activated (PubMed:26972053, PubMed:25457612, PubMed:27487210, PubMed:35831510).
Binds HTATIP2/TIP30. Interacts with YLPM1. Forms a complex with ILF2, ILF3, YLPM1, KHDRBS1, RBMX and PPP1CA.
Contains one Leu-Xaa-Xaa-Leu-Leu (LxxLL) motif that is essential for the association with nuclear receptors.
Nuclear receptor coregulator that can have both coactivator and corepressor functions. Interacts with nuclear receptors for steroids (ESR1 and ESR2) independently of the steroid binding domain (AF-2) of the ESR receptors, and with the orphan nuclear receptor NR1D2. Involved in the coactivation of nuclear steroid receptors (ER) as well as the corepression of MYC in response to 17-beta-estradiol (E2).
Aminopeptidase with specificity towards an acidic amino acid at the N-terminus. Likely to play an important role in intracellular protein and peptide metabolism.
One of the zinc ions is readily exchangeable with other divalent cations such as manganese, which strongly stimulates the enzymatic activity.
Tetrahedron-shaped homododecamer built from six homodimers.
Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter PRAMEF6.
Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex, which mediates ubiquitination of target proteins, leading to their degradation (PubMed:26138980). The CRL2(PRAMEF6) complex mediates ubiquitination and degradation of truncated MSRB1/SEPX1 selenoproteins produced by failed UGA/Sec decoding (PubMed:26138980).
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.6/SCN8A subfamily.
Expressed in the hippocampus with increased expression in epileptic tissue compared to normal adjacent tissue (at protein level) (PubMed:28842554). Isoform 5: Expressed in non-neuronal tissues, such as monocytes/macrophages.
In macrophages and melanoma cells, may participate in the control of podosome and invadopodia formation.
Inhibited by tetrodotoxin and, more weakly, by its metabolite 4,9-ah-tetrodotoxin.
Mediates the voltage-dependent sodium ion permeability of excitable membranes (PubMed:29726066). Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient.
Phosphorylation at Ser-1497 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents.
The voltage-sensitive sodium channel consists of an ion-conducting pore-forming alpha subunit regulated by one or more beta-1 (SCN1B), beta-2 (SCN2B), beta-3 (SCN3B) and/or beta-4 (SCN4B) subunits. Beta-1 (SCN1B) and beta-3 (SCN3B) are non-covalently associated with alpha, while beta-2 (SCN2B) and beta-4 (SCN4B) are covalently linked by disulfide bonds. Interacts with NEDD4 and NEDD4L (By similarity). Interacts with FGF13 (PubMed:33245860). Interacts with FGF14, GBG3, GBB2 and SCN1B (PubMed:26900580). Interacts with the conotoxin GVIIJ (PubMed:24497506). Interacts with the conotoxin GVIIJ (PubMed:24497506). Interacts with the spider beta/delta-theraphotoxin-Pre1a (PubMed:28428547). Interacts with CALM1; the interaction modulates the inactivation rate of SCN8A (By similarity).
Up-regulated in the hippocampus after epilepsy.
During periods of oxidative stress, Sec-49 may react with a superoxide radical, irreversibly lose hydroselenide and be converted to dehydroalanine.
Protects the hemoglobin in erythrocytes from oxidative breakdown. In platelets, plays a crucial role of glutathione peroxidase in the arachidonic acid metabolism (PubMed:11115402).
Catalyzes ATP-dependent phosphorylation of D-ribulose at C-5 to form D-ribulose 5-phosphate. Postulated to function in a metabolite repair mechanism by preventing toxic accumulation of free D-ribulose formed by non-specific phosphatase activities. Alternatively, may play a role in regulating D-ribulose 5-phosphate recycling in the pentose phosphate pathway. Can phosphorylate ribitol with low efficiency.
Expressed in fetal brain (at protein level).
Expressed in kidney, lung and small intestine and to a lower extent in liver and detected in cerebrospinal fluid (at protein level).
Highly expressed in retinal pigment epithelium. Also expressed in kidney, testis, liver, brain, small intestine and colon.
Symmetrically cleaves beta-carotene into two molecules of retinal using a dioxygenase mechanism.
(Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1; leading to inhibition of the recruitment of MAP1LC3A/LC3 to SQSTM1-positive structures.
A chromosomal aberration involving SQSTM1 is found in a form of acute lymphoblastic leukemia. Translocation t(5;9)(q35;q34) with NUP214.
Autophagy receptor required for selective macroautophagy (aggrephagy) (PubMed:34471133, PubMed:16286508, PubMed:20168092, PubMed:24128730, PubMed:28404643, PubMed:22622177, PubMed:33509017). Functions as a bridge between polyubiquitinated cargo and autophagosomes (PubMed:34471133). Interacts directly with both the cargo to become degraded and an autophagy modifier of the MAP1 LC3 family (PubMed:16286508, PubMed:20168092, PubMed:24128730, PubMed:28404643, PubMed:22622177). Along with WDFY3, involved in the formation and autophagic degradation of cytoplasmic ubiquitin-containing inclusions (p62 bodies, ALIS/aggresome-like induced structures). Along with WDFY3, required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed:24128730, PubMed:20168092). Also involved in autophagy of peroxisomes (pexophagy) in response to reactive oxygen species (ROS) by acting as a bridge between ubiquitinated PEX5 receptor and autophagosomes (PubMed:26344566). May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. Adapter that mediates the interaction between TRAF6 and CYLD (By similarity). May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102). Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed:29496741). Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: interaction inactivates the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes (PubMed:20452972, PubMed:28380357, PubMed:33393215). Sequesters tensin TNS2 into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal degradation (PubMed:25101860).
By proteasomal inhibitor PSI and prostaglandin J2 (PGJ2) (at protein level). By phorbol 12-myristate 13-acetate (PMA). Expression is directly activated by NFE2L2/NRF2; creating a positive feeback loop (PubMed:20452972).
During myogenesis, there is a marked increase in levels in fully differentiated myotubes compared to undifferentiated myoblasts.
Homooligomer or heterooligomer; may form homotypic arrays. Dimerization interferes with ubiquitin binding. Interacts directly with PRKCI and PRKCZ (Probable). Forms ternary complexes with PRKCZ and KCNAB2 or PRKCZ and GABBR3. Also interacts with KCNAB1, GABRR1, GABRR2 and GABRR3. Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6 (By similarity). Interacts with EBI3, LCK, RASA1, PRKCZ, PRKCI, NR2F2, NTRK1, NTRK2, NTRK3, NBR1, MAP2K5, TRIM13, TRIM55 and MAPKAPK5. Interacts with the proteasome subunits PSMD4 and PSMC2. Interacts with K63-polyubiquitinated MAPT/TAU. Interacts with IKBKB through PRKCZ and PRKCI. Interacts with NGFR through TRAF6 and bridges that complex to NTRK1. Forms a complex with MAP2K5 and PRKCZ or PRKCI. Component of a ternary complex with PAWR and PRKCZ. Upon TNF-alpha stimulation, interacts with RIPK1 probably bridging IKBKB to the TNF-R1 complex composed of TNF-R1/TNFRSF1A, TRADD and RIPK1. Forms a complex with JUB/Ajuba, PRKCZ and TRAF6. Interacts with TRAF6 (By similarity). Interacts with CYLD (PubMed:32185393). Identified in a complex with TRAF6 and CYLD (By similarity). Identified in a heterotrimeric complex with ubiquitin and ZFAND5, where ZFAND5 and SQSTM1 both interact with the same ubiquitin molecule. Directly interacts with MAP1LC3A and MAP1LC3B, as well as with other MAP1 LC3 family members, including GABARAP, GABARAPL1 and GABARAPL2; these interactions are necessary for the recruitment MAP1 LC3 family members to inclusion bodies containing polyubiquitinated protein aggregates and for their degradation by autophagy. Interacts with FHOD3. Interacts with TRMI5. Interacts with SESN1 (PubMed:23274085). Interacts with SESN2 (PubMed:23274085, PubMed:25040165). Interacts with ULK1 (PubMed:25040165). Interacts with UBD (PubMed:25422469). Interacts with WDR81; the interaction is direct and regulates the interaction of SQSTM1 with ubiquitinated proteins (PubMed:28404643). Interacts with WDFY3; this interaction is required to recruit WDFY3 to cytoplasmic bodies and to PML bodies (PubMed:20168092). Interacts with TRIM23 (PubMed:28871090). Interacts with LRRC25 (PubMed:29288164). Interacts with TRIM50 (PubMed:22792322). Interacts with TRIM16 (PubMed:30143514). Interacts with STING1; leading to relocalization of STING1 to autophagosomes. Interacts (when phosphorylated at Ser-349) with KEAP1; the interaction is direct and inactivates the BCR(KEAP1) complex by sequestering KEAP1 in inclusion bodies, promoting its degradation (PubMed:20495340, PubMed:20452972). Interacts with GBP1 (By similarity). Interacts with MOAP1; promoting dissociation of SQSTM1 inclusion bodies that sequester KEAP1 (PubMed:33393215). Interacts with TAX1BP1 (PubMed:34471133). Interacts with (ubiquitinated) PEX5; specifically binds PEX5 ubiquitinated at 'Lys-209' in response to reactive oxygen species (ROS) (PubMed:26344566). Interacts (via PB1 domain) with TNS2; the interaction leads to sequestration of TNS2 in cytoplasmic aggregates with SQSTM1 and promotes TNS2 ubiquitination and proteasomal degradation (PubMed:25101860). Interacts with IRS1; the interaction is disrupted by the presence of tensin TNS2 (PubMed:25101860). Interacts with TRIM11 (when ubiquitinated); promoting AIM2 recruitment to autophagosomes and autophagy-dependent degradation of AIM2 (PubMed:27498865). Interacts with ECSIT; this interaction inhibits TLR4 signaling via functional regulation of the TRAF6-ECSIT complex (PubMed:31281713).
In a cell model for Huntington disease (HD), appears to form a shell surrounding aggregates of mutant HTT that may protect cells from apoptosis, possibly by recruiting autophagosomal components to the polyubiquitinated protein aggregates.
Phosphorylated. May be phosphorylated by PRKCZ (By similarity). Phosphorylated in vitro by TTN (PubMed:15802564). Phosphorylation at Ser-403 by ULK1 is stimulated by SESN2 (PubMed:25040165). Phosphorylated at Ser-403 by TBK1, leading to promote relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed:29496741). Phosphorylation at Ser-349 by MTOR promotes interaction with KEAP1 and inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (By similarity).
The PB1 domain mediates homooligomerization and interactions with FHOD3, MAP2K5, NBR1, PRKCI, PRKCZ and WDR81. Both the PB1 and UBA domains are necessary and sufficient for the localization into the ubiquitin-containing inclusion bodies.
The UBA domain binds specifically 'Lys-63'-linked polyubiquitin chains of polyubiquitinated substrates. Mediates the interaction with TRIM55. Both the UBA and PB1 domains are necessary and sufficient for the localization into the ubiquitin-containing inclusion bodies.
The ZZ-type zinc finger mediates the interaction with RIPK1.
Ubiquitinated by UBE2J1 and RNF26 at Lys-435: ubiquitinated SQSTM1 attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102, PubMed:33472082). Deubiquitination by USP15 releases target vesicles for fast transport into the cell periphery (PubMed:27368102). Ubiquitinated by the BCR(KEAP1) complex at Lys-420, increasing SQSTM1 sequestering activity and promoting its degradation (PubMed:28380357). Ubiquitinated via 'Lys-29' and 'Lys-33'-linked polyubiquitination leading to xenophagic targeting of bacteria and inhibition of their replication (PubMed:27880896).
Acts as a neurotrophic factor in postnatal mature neurons enhancing neuronal survival (PubMed:31536960). Promotes cell proliferation and neurogenesis in undifferentiated neural progenitor cells at the embryonic stage and inhibits differentiation of astrocytes (By similarity). Its neurotrophic activity is exerted via MAPK1/ERK2, MAPK3/ERK1 and AKT1/AKT pathways (By similarity). Neurotrophic activity is enhanced by binding to heme (By similarity). Acts also as an anorexigenic neurotrophic factor that contributes to energy balance (By similarity).
The cytochrome b5 heme-binding domain was proven to bind heme, although it lacks the conserved iron-binding His residue at position 82.
Ubiquitously expressed with high expression in heart. Over-expressed in various tumors including carcinomas of the uterine cervix, lymphoma, colon, lung, skin and leukemia, as well as carcinoma of the breast.
Up-regulated in immortal cells. Induced in estrogen receptor positive breast cancer expressing progesterone receptor.
Binds FMN1. Interacts with the Arg/Gly-rich-flanked Pro-rich of KHDRBS1/SAM68. Arginine methylation in these regions has no effect on this binding.
These WW domains interact with Arg/Gly-rich-flanked Pro-rich domains found in several WW domain-binding proteins (WBPs). The N-terminal WW domain has the greater ligand-binding ability (By similarity).
Expressed specifically in embryonic pituitary.
Possibly involved in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.
Homodimer. Interacts with E2F1 and with histone H4 acetylated at 'Lys-13'.
May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.
One bromodomain is sufficient for a partial interaction with histone H4 acetylated at 'Lys-13'.
Able to activate MAPK/ERK and TGFB signaling pathways (PubMed:22971576). May regulate the activity of genes involved in intestinal barrier function and immunoprotective inflammation (By similarity). May play a role in cell proliferation (PubMed:22971576).
A frameshift mutation disrupting ZFP36L2 have been found in a patient with acute myeloid leukemia, suggesting that defective ZFP36L2 might be involved in the pathogenesis of certain types of hematological cancers (PubMed:21109922).
Associates with the cytoplasmic CCR4-NOT deadenylase to trigger ARE-containing mRNA deadenylation and decay processes (PubMed:25106868). Interacts with CNOT7; this interaction is inhibited in response to phorbol 12-myristate 13-acetate (PMA) treatment in a p38 MAPK-dependent manner (PubMed:25106868). Interacts with CNOT6L.
Expressed mainly in the basal epidermal layer, weakly in the suprabasal epidermal layers (PubMed:27182009). Expressed in epidermal keratinocytes (at protein level) (PubMed:27182009). Expressed in oocytes (PubMed:34611029).
Phosphorylated by RPS6KA1 at Ser-490 and Ser-492 upon phorbol 12-myristate 13-acetate (PMA) treatment; this phosphorylation results in dissociation of the CCR4-NOT-deadenylase complex and induces p38 MAPK-mediated stabilization of the low-density lipoprotein (LDL) receptor (LDLR) mRNA (PubMed:25106868). Phosphorylation occurs during early preadipocyte differentiation (By similarity).
Up-regulated by butyrate in colorectal cancer cells (PubMed:10367403). Up-regulated in keratinocytes after wounding (PubMed:20166898, PubMed:27182009). Up-regulated strongly by granulocyte macrophage colony-stimulating factor (GM-CSF) in keratinocytes (PubMed:20166898). Up-regulated moderately by transforming growth factor (TGF-beta), epidermal growth factor (EGF), tumor necrosis factor (TNF-alpha) and fibroblast growth factor (FGF1) in keratinocytes (PubMed:20166898). Up-regulated also by glucocorticoid dexamethasone in keratinocytes (PubMed:20166898).
Zinc-finger RNA-binding protein that destabilizes several cytoplasmic AU-rich element (ARE)-containing mRNA transcripts by promoting their poly(A) tail removal or deadenylation, and hence provide a mechanism for attenuating protein synthesis (PubMed:25106868, PubMed:14981510, PubMed:34611029). Acts as a 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery (PubMed:25106868). Functions by recruiting the CCR4-NOT deadenylase complex and probably other components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs, and hence promotes ARE-mediated mRNA deadenylation and decay processes (PubMed:25106868). Binds to 3'-UTR ARE of numerous mRNAs (PubMed:20506496, PubMed:25106868, PubMed:14981510). Promotes ARE-containing mRNA decay of the low-density lipoprotein (LDL) receptor (LDLR) mRNA in response to phorbol 12-myristate 13-acetate (PMA) treatment in a p38 MAPK-dependent manner (PubMed:25106868). Positively regulates early adipogenesis by promoting ARE-mediated mRNA decay of immediate early genes (IEGs). Plays a role in mature peripheral neuron integrity by promoting ARE-containing mRNA decay of the transcriptional repressor REST mRNA. Plays a role in ovulation and oocyte meiotic maturation by promoting ARE-mediated mRNA decay of the luteinizing hormone receptor LHCGR mRNA. Acts as a negative regulator of erythroid cell differentiation: promotes glucocorticoid-induced self-renewal of erythroid cells by binding mRNAs that are induced or highly expressed during terminal erythroid differentiation and promotes their degradation, preventing erythroid cell differentiation. In association with ZFP36L1 maintains quiescence on developing B lymphocytes by promoting ARE-mediated decay of several mRNAs encoding cell cycle regulators that help B cells progress through the cell cycle, and hence ensuring accurate variable-diversity-joining (VDJ) recombination process and functional immune cell formation. Together with ZFP36L1 is also necessary for thymocyte development and prevention of T-cell acute lymphoblastic leukemia (T-ALL) transformation by promoting ARE-mediated mRNA decay of the oncogenic transcription factor NOTCH1 mRNA.
Belongs to the DNA polymerase type-B-like family. GLD2 subfamily.
Cytoplasmic poly(A) RNA polymerase that adds successive AMP monomers to the 3'-end of specific RNAs, forming a poly(A) tail (PubMed:15070731, PubMed:31792053). In contrast to the canonical nuclear poly(A) RNA polymerase, it only adds poly(A) to selected cytoplasmic mRNAs (PubMed:15070731). Does not play a role in replication-dependent histone mRNA degradation (PubMed:18172165). Adds a single nucleotide to the 3' end of specific miRNAs, monoadenylation stabilizes and prolongs the activity of some but not all miRNAs (PubMed:23200856, PubMed:31792053).
Expressed in brain. Within brain, it is expressed in cerebellum, hippocampus and medulla.
Interacts with CPEB1, CPEB2, CPSF1 and PABPC1 (By similarity). Interacts with QKI isoform QKI7; promoting recruitment to miRNA miR-122 and miR-122 stabilization (PubMed:31792053).
Granulocytes. Expressed in skin. Predominantly expressed in the granular layer of skin, notably the acrosyringium. Identified in several biological fluids such as sweat, saliva, tears, plasma and urine.
Has an antitumor activity (PubMed:8742060). Was found to be a marker of late differentiation of the skin. Implicated in maintaining the physiological and structural integrity of the keratinocyte layers of the skin (PubMed:14721776, PubMed:17008884). In vitro down-regulates keratinocyte proliferation; the function may involve the proposed role as modulator of nicotinic acetylcholine receptors (nAChRs) activity. In vitro inhibits alpha-7-dependent nAChR currents in an allosteric manner (PubMed:14506129, PubMed:26905431). In T cells may be involved in regulation of intracellular Ca(2+) signaling (PubMed:17286989). Seems to have an immunomodulatory function in the cornea (By similarity). The function may implicate a possible role as a scavenger receptor for PLAU thereby blocking PLAU-dependent functions of PLAUR such as in cell migration and proliferation (PubMed:25168896).
Homodimer. Interacts with PLAU (PubMed:25168896). Interacts with CHRNA7 (PubMed:26905431).
It is not certain that ARS and ANUP are identical proteins.
Regulated by retinoic acid, EGF and IFNG/IFN-gamma (PubMed:14721776). Down-regulated by IL-13 in cultured human bronchial epithelial cells (related to asthmatic condition) (PubMed:20621062).
Belongs to the UTP23/FCF1 family. UTP23 subfamily.
Involved in rRNA-processing and ribosome biogenesis.
Expressed in lachrymal gland, thymus, kidney, testis, ovary and salivary gland.
Heterodimer of a lipophilin A and a lipophilin C (mammaglobin B) monomer associated head to head.
Component of a CRL5 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL5, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter KLHDC1.
Substrate-recognition component of a Cul5-RING (CRL5) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:32200094). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (PubMed:32200094). The CRL5(KLHDC1) complex mediates ubiquitination and degradation of truncated SELENOS selenoprotein produced by failed UGA/Sec decoding, which ends with a glycine (PubMed:32200094).
Widely expressed, with high levels in skeletal muscle, pancreas and liver. Undetectable in peripheral blood leukocytes.
Acetylation, which is up-regulated by glucose and insulin and down-regulated by glucagon, inhibits the glycogen phosphorylase activity by promoting PPP1R3B-mediated recruitment of phosphatase PP1 and Ser-15 dephosphorylation.
Allosterically regulated through the non-covalent binding of metabolites, being activated by AMP and inhibited by ATP, ADP, and glucose-6-phosphate. The activity is also controlled by post-translational modifications including phosphorylation and acetylation.
Homodimer; enzymatically active (PubMed:10980448, PubMed:10949035). Interacts with PPP1R3B; recruits the phosphatase PP1 which dephosphorylates and inactivates PYGL/glycogen phosphorylase (PubMed:22225877).
Phosphorylation at Ser-15 converts inactive phosphorylase b into active phosphorylase a (PubMed:10949035). Dephosphorylation of Ser-15 by phosphatase PP1 inactivates the enzyme (PubMed:22225877).
Chaperone protein which promotes assembly of the 20S proteasome as part of a heterodimer with PSMG2. The PSMG1-PSMG2 heterodimer binds to the PSMA5 and PSMA7 proteasome subunits, promotes assembly of the proteasome alpha subunits into the heteroheptameric alpha ring and prevents alpha ring dimerization.
Forms a heterodimer with PSMG2. The PSMG1-PSMG2 heterodimer interacts directly with the PSMA5 and PSMA7 proteasome alpha subunits.
In the adult, detected in brain, colon, leukocytes, breast and testis. Widely expressed in the fetus. Also expressed in a variety of proliferating cell lines.
May play a role in mediating neutrophil activation and chemotaxis.
Phosphorylated by casein kinase II, protein kinase C and MAPKAPK2. Phosphorylation by PKC induces translocation from membrane to cytoplasm. Phosphorylation by MAPKAPK2 may regulate neutrophil chemotaxis (By similarity).
Component of an NADPH oxidase complex composed of a heterodimer formed by the membrane proteins CYBA and CYBB and the cytosolic subunits NCF1, NCF2 and NCF4 (PubMed:8280052). Interacts with NCF2 and NCF1 (PubMed:12887891, PubMed:15657040). The NCF2-NCF4 complex interacts with GBP7 (via GB1/RHD3-type G domain) (By similarity).
Component of the NADPH-oxidase, a multicomponent enzyme system responsible for the oxidative burst in which electrons are transported from NADPH to molecular oxygen, generating reactive oxidant intermediates. It may be important for the assembly and/or activation of the NADPH-oxidase complex.
Expression is restricted to hematopoietic cells.
The PB1 domain mediates the association with NCF2/p67-PHOX.
The PX domain mediates interaction with membranes enriched in phosphatidylnositol 3-phosphate.
Interacts with peptide-free HLA-F open conformer.
Receptor on natural killer (NK) cells and T cells for MHC class I molecules (PubMed:24018270, PubMed:28636952). Upon binding of peptide-free HLA-F open conformer, negatively regulates NK and T cell effector functions (PubMed:24018270). Acts as a receptor on astrocytes for HLA-F. Through interaction with HLA-F, may protect motor neurons from astrocyte-induced toxicity (PubMed:26928464).
Centrosomal protein that plays a key role in cell delamination by regulating microtubule organization (By similarity). Required for the delamination and retention of neural stem cells from the subventricular zone during neurogenesis (By similarity). Also regulates the epithelial-to-mesenchymal transition in other epithelial cells (By similarity). Acts by increasing centrosomal microtubule nucleation and recruiting nucleation factors and minus-end stabilizers, thereby destabilizing microtubules at the adherens junctions and mediating constriction of the apical endfoot (By similarity). In addition, may also act as a transcription factor that specifically activates the expression of the CD40 receptor and its ligand CD40L/CD154, two cell surface molecules on lymphocytes that are critical for antigen-dependent-B-cell development (PubMed:11268217). Binds to A/T-rich promoters (PubMed:11268217). It is unclear how it can both act as a microtubule organizer and as a transcription factor; additional evidences are required to reconcile these two apparently contradictory functions (Probable).
Interacts with DCTN1. Interacts with MAPRE1/EB1. Interacts with ODF2. Interacts with CAMSAP3.
Phosphorylated; phosphorylation regulates dissociation from and reassembly at the centrosome.
Predominantly expressed by lymphoid tissues. Highly expressed in the spleen, lymph nodes and peripheral blood leukocytes, expressed at lower level in the thymus. Mainly expressed by germinal center B-lymphocytes, a stage in which receptor and ligand interactions are crucial for B-lymphocyte maturation. Expressed by B- and T-lymphocytes, Natural killer cells and CD1a(+)CD14(-) but not CD1a(-)CD14(+) dendritic cells. Weakly or not expressed in fetal liver and in adult bone marrow.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. NR1/GRIN1 subfamily.
Component of NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:7685113, PubMed:28126851, PubMed:26919761, PubMed:26875626, PubMed:28105280). Sensitivity to glutamate and channel kinetics depend on the subunit composition (PubMed:26919761).
Heterotetramer. Forms heterotetrameric channels composed of two zeta subunits (GRIN1), and two epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) (in vitro) (PubMed:7685113, PubMed:28126851, PubMed:26919761, PubMed:26875626, PubMed:28105280). Can also form heterotetrameric channels that contain at least one zeta subunit (GRIN1), an epsilon subunit, plus GRIN3A or GRIN3B (in vitro). In vivo, the subunit composition may vary in function of the expression levels of the different subunits. Found in a complex with GRIN2A or GRIN2B, GRIN3A and PPP2CB (By similarity). Found in a complex with GRIN2A or GRIN2B and GRIN3B (By similarity). Interacts with SNX27 (via PDZ domain); the interaction is required for recycling to the plasma membrane when endocytosed and prevent degradation in lysosomes (By similarity). Interacts with DLG4 and MPDZ. Interacts with LRFN1 and LRFN2 (By similarity). Interacts with MYZAP (PubMed:18849881). Found in a complex with DLG4 and PRR7 (By similarity). Found in a complex with GRIN2B and PRR7 (PubMed:27458189). Interacts with PRR7; the interaction is reduced following NMDA receptor activity (PubMed:27458189).
NMDA is probably regulated by C-terminal phosphorylation of an isoform of NR1 by PKC. Dephosphorylated on Ser-897 probably by protein phosphatase 2A (PPP2CB). Its phosphorylated state is influenced by the formation of the NMDAR-PPP2CB complex and the NMDAR channel activity.
Highly expressed in liver; lower expression in testis and skin.
Transcriptional activator. Binds the consensus sequence 5'-DHWATTGAYTWWD-3' on a variety of gene promoters such as those of HNF3B and TTR. Important for liver genes transcription.
G protein-coupled receptor which associates with the patched protein (PTCH) to transduce hedgehog protein signaling. Binding of sonic hedgehog (SHH) to its receptor patched prevents inhibition of smoothened (SMO) by patched. When active, SMO binds to and sequesters protein kinase A catalytic subunit PRKACA at the cell membrane, preventing PRKACA-mediated phosphorylation of GLI transcription factors which releases the GLI proteins from PRKACA-mediated inhibition and allows for transcriptional activation of hedgehog pathway target genes (By similarity). Required for the accumulation of KIF7, GLI2 and GLI3 in the cilia (PubMed:19592253). Interacts with DLG5 at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation (By similarity).
Homodimer (PubMed:23636324). Interacts (via C-terminus) with protein kinase A catalytic subunit PRKACA; interacts with free PRKACA subunits and the interaction leads to sequestration of PRKACA at the membrane, preventing PRKACA-mediated phosphorylation of GLI transcription factors (By similarity). Interacts with ARRB2 (By similarity). Interacts with KIF7 (PubMed:19592253). Interacts with BBS5 and BBS7; the interactions are indicative for the association of SMO with the BBsome complex to facilitate ciliary localization of SMO (PubMed:22072986). Interacts with DLG5 and SDCBP (By similarity). Interacts with GAS8/DRC4 (PubMed:21659505).
Phosphorylation by GRK kinases is required for interaction with protein kinase A catalytic subunit PRKACA.
The N-terminal extracellular domain mediates sterol-binding which is required for maximal activation of signaling (PubMed:24859340). Contains a second sterol-binding site within the seven-transmembrane pocket which is also required for activation (By similarity). The activating sterol is likely to be cholesterol (PubMed:35658032). The extracellular site is required for SHH-induced activity while the site within the transmembrane pocket regulates basal signaling in the absence of SHH (PubMed:35658032).
The disease is caused by variants affecting the gene represented in this entry. 8 individuals have been identified with the disease-causing mutation Phe-412 and all were mosaic. The mutation could not be reliably detected in blood, greatest success rates were obtained with affected tissues obtained by invasive procedures. It is thought that the mutation has arisen postzygotically early during embryonic development (PubMed:27236920). This mutation has also been identified in ameloblastoma, medulloblastoma, meningioma, and basal cell carcinoma, and has been reported as the oncogenic driver in some of these tumors (PubMed:24859340).
Calcium-independent lectin displaying mannose-binding specificity and able to maintain carbohydrate recognition activity in an acidic environment. May be involved in inflammatory and metaplastic responses of the gastrointestinal epithelium.
Highly expressed in the gastrointestinal tract including the duodenum, jejunum, ileum, ileocecum, appendix, descending colon, pancreas and small intestine. Weakly expressed in normal colon and stomach. Strongly expressed in most colorectal tumors than in normal colon. Preferentially expressed in mucinous tumors and in some cases neuro-endocrine tumors. Expressed in mucus-secreting cells and enterocyte-like cells. In small intestine expressed at the basal perinuclear zone of goblet cells.
Up-regulated by mucosal injury from active Crohn's disease or ulcerative colitis. Up-regulated in colorectal tumors. Up-regulated in epithelial cells at regenerating margins of peptic ulcers in the stomach and duodenum.
Acts as a regulator of endoplasmic reticulum (ER) and nuclear envelope (NE) morphogenesis. Affects the ratio between tubular ER and ER sheets by promoting sheet formation at the expense of tubules. Influences NE expansion, nuclear pore complex formation and proper localization of inner nuclear membrane proteins (PubMed:26906412).
May be proteolytically processed into subunits alpha-2-3 and delta-3 that are disulfide-linked. It is however unclear whether such cleavage really takes place in vivo and has a functional role (By similarity).
Only detected in brain. Not present in lung, testis, aorta, spleen, jejunum, ventricular muscle and kidney (at protein level). According to PubMed:11687876, it is brain-specific, while according to PubMed:11245980, it is widely expressed.
The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-type calcium channel (CACNA1A), N-type (CACNA1B), L-type (CACNA1C OR CACNA1D) but not T-type (CACNA1G) (By similarity).
(Microbial infection) Down-regulation upon calcium-induced keratinocyte differentiation is prevented in the presence of human papillomavirus (HPV), independently of HPV E5 protein (at protein level). The physiological relevance of this observation is unclear.
(Microbial infection) Interacts with human papillomavirus (HPV) E5 proteins.
In primary foreskin keratinocytes, down-regulated during calcium-induced differentiation (at protein level). The physiological relevance of this observation is unclear as YIPF4 protein is expressed throughout the epithelial layers in organotypic raft cultures, a cell-culture model of stratified epithelium.
Involved in the maintenance of the Golgi structure.
(Microbial infection) Interacts with enterovirus 71/EV71 non-structural protein precursor 3CD; this interaction promotes EV71 replication.
(Microbial infection) Promotes enterovirus 71 replication by mediating the internal ribosome entry site (IRES) activity of viral 5'-UTR.
Interacts with PPP1CA (PubMed:15705855, PubMed:26095357). Interacts with EIF2S1 (PubMed:26095357). Interacts with PCNA (By similarity). Interacts with LYN and KMT2A/MLL1 (PubMed:11517336). Interacts with PPP1R1A and SMARCB1 (PubMed:12016208). Interacts with SMAD7 (PubMed:14718519). Interacts with BAG1 (PubMed:12724406). Interacts with NOX4 (PubMed:26742780).
Phosphorylated at multiple Ser/Thr residues. Phosphorylated on tyrosine by LYN; which impairs its antiproliferative activity. Phosphorylation at Tyr-262 enhances proteasomal degradation, this position is dephosphorylated by PTPN2.
Polyubiquitinated. Exhibits a rapid proteasomal degradation with a half-life under 1 hour, ubiquitination depends on endoplasmic reticulum association.
Recruits the serine/threonine-protein phosphatase PPP1CA to prevents excessive phosphorylation of the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from stress (PubMed:26742780, PubMed:26095357). Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1 (PubMed:14718519). May promote apoptosis by inducing p53/TP53 phosphorylation on 'Ser-15' (PubMed:14635196). Plays an essential role in autophagy by tuning translation during starvation, thus enabling lysosomal biogenesis and a sustained autophagic flux (PubMed:32978159). Acts also a viral restriction factor by attenuating HIV-1 replication (PubMed:31778897). Mechanistically, mediates the inhibition of HIV-1 TAR RNA-mediated translation (PubMed:31778897).
Specifically produced in response to stress: in absence of stress, some upstream open reading frame (uORF) of this transcript is translated, thereby preventing its translation (PubMed:19131336). By methyl methanesulfonate and ionizing irradiation (PubMed:9153226). By IL24/interleukin-24 in melanoma cells; which induces apoptosis (PubMed:10490642, PubMed:12114539). By viral infection including enterovirus 71/EV71 or HIV-1 (PubMed:34985336, PubMed:31778897).
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CDC7 subfamily.
Forms a complex with either DBF4/DBF4A or DBF4B, leading to the activation of the kinase activity (PubMed:10373557, PubMed:12065429, PubMed:15668232, PubMed:17062569). Interacts with CLASPIN (via the acidic patch); the interaction is required for phosphorylation of MCM proteins and CLASPIN (PubMed:27401717).
Kinase involved in initiation of DNA replication. Phosphorylates critical substrates that regulate the G1/S phase transition and initiation of DNA replication, such as MCM proteins and CLASPIN.
(Microbial infection) May act as a proviral factor. In association with ATG5, negatively regulates the innate antiviral immune response by impairing the type I IFN production pathway upon vesicular stomatitis virus (VSV) infection (PubMed:17709747). Required for the translation of incoming hepatitis C virus (HCV) RNA and, thereby, for the initiation of HCV replication, but not required once infection is established (PubMed:19666601).
Expression is induced by mitochondrial DNA deletions, chloramphenicol and nicotinamide.
Forms a conjugate with ATG5 (PubMed:11096062, PubMed:12207896, PubMed:11825910, PubMed:17709747, PubMed:26812546, PubMed:23202584). The ATG12-ATG5 conjugate forms a complex with several units of ATG16L1 (PubMed:23202584). Forms an 800-kDa complex composed of ATG12-ATG5 and ATG16L2 (By similarity). Interacts with DHX58/RIG-1, IFIH1/MDA5 and MAVS/IPS-1 in monomeric form as well as in ATG12-ATG5 conjugate. The interaction with MAVS is further enhanced upon vesicular stomatitis virus (VSV) infection (PubMed:17709747). Interacts with ATG3 and ATG7 (PubMed:11096062, PubMed:12207896, PubMed:11825910, PubMed:23202584). Interacts with ATG10 (By similarity). Interacts with TECPR1 (PubMed:22342342). Interacts with SH3BGRL (PubMed:34870550).
Shares weak sequence similarity with ubiquitin family, but contains an 'ubiquitin superfold' and the C-terminal Gly is required for isopeptide linkage.
Small amount of ATG5-ATG12 conjugate is enough to perform normal autophagy.
Ubiquitin-like protein involved in autophagy vesicles formation. Conjugation with ATG5 through a ubiquitin-like conjugating system involving also ATG7 as an E1-like activating enzyme and ATG10 as an E2-like conjugating enzyme, is essential for its function. The ATG12-ATG5 conjugate acts as an E3-like enzyme which is required for lipidation of ATG8 family proteins and their association to the vesicle membranes.
Receptor for the glial cell line-derived neurotrophic factor, ARTN (artemin). Mediates the artemin-induced autophosphorylation and activation of the RET receptor tyrosine kinase.
Widely expressed in adult and fetus which exhibit a similar pattern. Essentially not expressed in the central nervous system, but highly expressed in several sensory and sympathetic ganglia of the peripheral nervous system. Moderate expression in many non-neuronal tissues, particularly those of the digestive and urogenital systems, but high expression in stomach and appendix. Several types of glandular tissues show low expression. Very low or no expression detected in the hematopoietic system.
Was originally thought to interact with CCNA1 and found in a complex with CCNA1 and CDK2 (PubMed:15159402). However the amino acid sequence described in this paper contains several frameshifts and a wrong choice of frame, so results from this paper need to be validated.
Induced by the DNA-damaging agents etoposide and neocarzinostatin.
Interacts with H3K4me3 and to a lesser extent with H3K4me2. Component of a mSin3A-like complex at least consisting of SIN3A, HDAC1, HDAC2, RBBP4/RbAp48, RBBP7/RbAp46, SAP30 and ING2.
Low expression except in testis, where it reaches half of ING2a levels.
Seems to be involved in p53/TP53 activation and p53/TP53-dependent apoptotic pathways, probably by enhancing acetylation of p53/TP53. Component of a mSin3A-like corepressor complex, which is probably involved in deacetylation of nucleosomal histones. ING2 activity seems to be modulated by binding to phosphoinositides (PtdInsPs).
Sumoylation enhances its association with SIN3A and is required for binding to some target gene promoters, this is the case for TMEM71.
Widely expressed. Higher expressed in colon-cancer tumor than in normal colon tissues.
Homo and heterooligomer. Interacts with MTOR; controls MTOR-dependent IGF2 expression during myoblast differentiation (By similarity).
Plays a role as negative regulator of myoblast differentiation, in part through effects on MTOR signaling. Has no detectable enzymatic activity (By similarity).
Found in all tissues examined, most abundant in placenta and least abundant in brain and heart. Expressed in a variety of cancer cell lines (PubMed:25893292).
Homodimer; in the endoplasmic reticulum but also at the cell membrane. Heterohexamer; TGFB1, TGFB2 and TGFB3 homodimeric ligands assemble a functional receptor composed of two TGFBR1 and TGFBR2 heterodimers to form a ligand-receptor heterohexamer. The respective affinity of TGBRB1 and TGFBR2 for the ligands may modulate the kinetics of assembly of the receptor and may explain the different biological activities of TGFB1, TGFB2 and TGFB3. Component of a complex composed of TSC22D1 (via N-terminus), TGFBR1 and TGFBR2; the interaction between TSC22D1 and TGFBR1 is inhibited by SMAD7 and promoted by TGFB1 (PubMed:21791611). Interacts with CD109; inhibits TGF-beta receptor activation in keratinocytes. Interacts with RBPMS. Interacts (unphosphorylated) with FKBP1A; prevents TGFBR1 phosphorylation by TGFBR2 and stabilizes it in the inactive conformation. Interacts with SMAD2, SMAD3 and ZFYVE9; ZFYVE9 recruits SMAD2 and SMAD3 to the TGF-beta receptor. Interacts with TRAF6 and MAP3K7; induces MAP3K7 activation by TRAF6. Interacts with PARD6A; involved in TGF-beta induced epithelial to mesenchymal transition. Interacts with NEDD4L (PubMed:15496141). Interacts with SMAD7, SMURF1 and SMURF2; SMAD7 recruits NEDD4L, SMURF1 and SMURF2 to the TGF-beta receptor (PubMed:11163210, PubMed:11278251). Interacts with USP15 and VPS39. Interacts with SDCBP (via C-terminus) (PubMed:25893292). Interacts with CAV1 and this interaction is impaired in the presence of SDCBP (PubMed:25893292). Interacts with APPL1; interaction is TGF beta dependent; mediates trafficking of the TGFBR1 from the endosomes to the nucleus via microtubules in a TRAF6-dependent manner (PubMed:26583432).
Kept in an inactive conformation by FKBP1A preventing receptor activation in absence of ligand. CD109 is another inhibitor of the receptor.
Phosphorylated at basal levels in the absence of ligand. Activated upon phosphorylation by TGFBR2, mainly in the GS domain. Phosphorylation in the GS domain abrogates FKBP1A-binding.
The disease is caused by variants affecting the gene represented in this entry. TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS1 by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS1 by the OMIM resource.
Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.
Ubiquitinated; undergoes ubiquitination catalyzed by several E3 ubiquitin ligases including SMURF1, SMURF2 and NEDD4L2. Results in the proteasomal and/or lysosomal degradation of the receptor thereby negatively regulating its activity. Deubiquitinated by USP15, leading to stabilization of the protein and enhanced TGF-beta signal. Its ubiquitination and proteasome-mediated degradation is negatively regulated by SDCBP (PubMed:25893292).
By phosphorylation of various serine residues.
Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I. The beta chain acts as a regulatory unit and modulates the activity of the holoenzyme in response to phosphorylation.
Ser-701 is probably phosphorylated by PKA.
As a member of the subcortical maternal complex (SCMC), plays an essential role for zygotes to progress beyond the first embryonic cell divisions via regulation of actin dynamics (PubMed:26537248). Required for the formation of F-actin cytoplasmic lattices in oocytes which in turn are responsible for symmetric division of zygotes via the regulation of mitotic spindle formation and positioning (By similarity).
Component of the subcortical maternal complex (SCMC), at least composed of NLRP5, KHDC3L, OOEP, and TLE6 isoform 1 (PubMed:26537248, PubMed:25542835). Within the complex, interacts with NLRP5, KHDC3L and OOEP (PubMed:26537248, PubMed:25542835). The SCMC may facilitate translocation of its components between the nuclear and cytoplasmic compartments (PubMed:25542835). As part of the SCMC interacts with the SCMC-associated protein ZBED3 (By similarity). As part of the SCMC interacts with the SCMC-associated protein NLRP4F (By similarity). As part of the SCMC interacts with the SCMC-associated protein CFL1/Cofilin-1 (By similarity).
Contrary to other WD repeat Groucho/TLE family members, does not contain any identifiable Q, GP, CcN or SP domains. Only the C-terminal WD-repeat domain is conserved.
Homodimers (By similarity). Interacts with FOXG1/BF-1; the interaction inhibits TLE1 interaction with FOXG1/BF-1 (By similarity). Interacts with NFATC1 (By similarity). Interacts with PAX6 (By similarity).
Regulates spermatogonia proliferation and cell cycle progression, potentially via regulation of cell cycle regulatory genes such as; CEBPB, CEBPA, CSF3, PCNA, and CDK4 (By similarity). Suppresses FOXG1/BF-1-mediated transcriptional repression by inhibiting interaction of the transcriptional corepressor TLE1 with FOXG1 which promotes cortical neuron differentiation (By similarity). Acts as a transcriptional corepressor of NFATC1-mediated gene expression by contributing to PAX6-mediated repression (By similarity).
CD2 interacts with lymphocyte function-associated antigen CD58 (LFA-3) and CD48/BCM1 to mediate adhesion between T-cells and other cell types. CD2 is implicated in the triggering of T-cells, the cytoplasmic domain is implicated in the signaling function.
Expressed in natural killer cells (at protein level).
Interacts with CD48 (By similarity). Interacts with CD58 (LFA-3) (PubMed:10380930). Interacts with CD2AP (By similarity). Interacts with PSTPIP1 (PubMed:9857189). Interacts with FCGR3A; this interaction modulates NK cell activation and cytotoxicity.
Detected in erythrocytes (at protein level) (PubMed:23219802). Expressed in spleen erythroblasts and tumoral kidney (PubMed:7989337).
Homotrimer; each subunit contains a pore through which urea permeates (By similarity). Identified in a complex with STOM (PubMed:23219802).
Inhibited by phloretin and para-chloromercuribenzene sulfonate.
Mediates the transport of urea driven by a concentration gradient across the cell membrane of erythrocytes (PubMed:7989337, PubMed:10514515, PubMed:7797558, PubMed:8997401). Also mediates the transport of urea across the cell membrane of the renal inner medullary collecting duct which is critical to the urinary concentrating mechanism (By similarity). Facilitates water transport in erythrocytes (By similarity).
SLC14A1 is responsible for the Kidd blood group system (JK) [MIM:111000]. JK is defined by 2 alleles, JK*01 and JK*02 that give rise to Jk(a) and Jk(b) antigens respectively. The molecular basis of the Jk(a)/Jk(b) antigens is a single variation in position 280; Asp-280 corresponds to Jk(a) and Asn-280 to Jk(b). Some individuals carry silenced JK*01 and JK*02 alleles, designated JK*01N or JK*02N. They results in a Jk(null) phenotype associated with reduced urea permeability of red blood cells. Jk(null) is not associated with any obvious clinical syndrome except for a urine concentration defect.
Expressed in many tissues except in heart.
Transcription factor required for myelination of differentiated oligodendrocytes. Required for the conversion of oligodendrocytes from the premyelinating to the myelinating state. In the developing central nervous system (CNS), involved in the maintenance in the progenitor stage by promoting the cell cycle. Specifically binds to the 5'-TCAT-3' DNA sequence (By similarity). Has transcription repressor activity in vitro.
Autoubiquitinated; promoting its own degradation.
E3 ubiquitin-protein ligase that specifically catalyzes 'Lys-29'- and 'Lys-48'-linked polyubiquitin chains (PubMed:11278995, PubMed:12692129, PubMed:16341092, PubMed:16601690, PubMed:24811749, PubMed:24158444, PubMed:25752573, PubMed:25752577, PubMed:34239127, PubMed:33637724, PubMed:32039437). Accepts ubiquitin from the E2 ubiquitin-conjugating enzyme UBE2D1 in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:9575161, PubMed:32039437). Associates with the proteasome and promotes elongation of ubiquitin chains on substrates bound to the 26S proteasome (PubMed:24158444, PubMed:28396413, PubMed:31375563). Also catalyzes 'Lys-29'- and 'Lys-48'-linked ubiquitination of 26S proteasome subunit ADRM1/RPN13 in response to proteotoxic stress, impairing the ability of the proteasome to bind and degrade ubiquitin-conjugated proteins (PubMed:24811749, PubMed:31375563). Acts as a negative regulator of autophagy by mediating 'Lys-29'- and 'Lys-48'-linked ubiquitination of PIK3C3/VPS34, promoting its degradation (PubMed:33637724). Can assemble unanchored poly-ubiquitin chains in either 'Lys-29'- or 'Lys-48'-linked polyubiquitin chains; with some preference for 'Lys-48' linkages (PubMed:11278995, PubMed:16601690, PubMed:25752577). Acts as a negative regulator of type I interferon by mediating 'Lys-48'-linked ubiquitination of IRF3 and IRF7, leading to their degradation by the proteasome (PubMed:21167755). Catalyzes ubiquitination and degradation of CAND2 (PubMed:12692129).
Highly expressed in skeletal muscle. Detected at much lower levels in kidney and pancreas.
Interacts with 26S proteasomes (PubMed:12692129, PubMed:24158444). Interacts (via the HECT domain) with UBE2D1 and, less efficiently, with UBE2L3 (PubMed:11278995, PubMed:9575161).
Homodimer and heterodimer of MIP-1-alpha(4-69) and MIP-1-beta(3-69).
Monokine with inflammatory and chemokinetic properties. Binds to CCR5. One of the major HIV-suppressive factors produced by CD8+ T-cells. Recombinant MIP-1-beta induces a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). The processed form MIP-1-beta(3-69) retains the abilities to induce down-modulation of surface expression of the chemokine receptor CCR5 and to inhibit the CCR5-mediated entry of HIV-1 in T-cells. MIP-1-beta(3-69) is also a ligand for CCR1 and CCR2 isoform B.
N-terminal processed form MIP-1-beta(3-69) is produced by proteolytic cleavage after secretion from peripheral blood lymphocytes.
Associated with Fc receptor gamma chain. The GPVI:FcRgamma complex is associated with the Src kinase family FYN and LYN (PubMed:10961879, PubMed:9295288). Interacts with TRAF4 (PubMed:20946164). Interacts with COL1A1, but not with COL4A4 (By similarity).
Collagen receptor involved in collagen-induced platelet adhesion and activation. Plays a key role in platelet procoagulant activity and subsequent thrombin and fibrin formation. This procoagulant function may contribute to arterial and venous thrombus formation. The signaling pathway involves the FcR gamma-chain, the Src kinases (likely FYN or LYN) and SYK, the adapter protein LAT and leads to the activation of PLCG2.
Has no transmembrane domain. Does not interact with Fc receptor gamma chain. Does not bind to collagen-like peptides.
N-linked glycosylation at Asn-92 is not required for the cell surface expression, but contributes to maximal adhesion to type I collagen, collagen-related peptide (CRP), and, to a lesser extent, to the snake venom C-type lectin convulxin (CVX).
Interferon-induced RNA-binding protein involved in the human innate immune response. Has a broad and adaptable RNA structure recognition important for RNA recognition specificity in antiviral defense. Binds precursor and processed tRNAs as well as poly-U-tailed tRNA fragments (PubMed:25092312, PubMed:23317505, PubMed:23774268). Specifically binds single-stranded RNA bearing a 5'-triphosphate group (PPP-RNA), thereby acting as a sensor of viral single-stranded RNAs. Single-stranded PPP-RNAs, which lack 2'-O-methylation of the 5' cap and bear a 5'-triphosphate group instead, are specific from viruses, providing a molecular signature to distinguish between self and non-self mRNAs by the host during viral infection. Directly binds PPP-RNA in a non-sequence-specific manner (PubMed:23334420). Also recognizes and selectively binds AT-rich dsDNA (PubMed:23774268). Additionally, as a mediator in innate immunity, regulates positively IKK-NFKB signaling by sinergizing the recruitment of IKK to MAP3K7 (PubMed:26334375).
Monomer (PubMed:23317505, PubMed:23334420, PubMed:23774268). Interacts with MAP3K7 and the components of the IKK core complex CHUK, IKBKB and IKBKG; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375).
RNA recognition is mediated by a convoluted intramolecular fold of the TPR repeats (TPR eddy), which scaffolds unique additional helices that form an RNA binding cleft (PubMed:23317505, PubMed:23334420). Undergoes a conformational change upon RNA-binding: unliganded exists in a more open conformation, facilitating RNA entry (PubMed:23334420).
Expressed in all areas of the brain tested.
In contrast to other members of the family, lacks the regions that come into close contact with the mRNA in the ribosomal A-site and determine the STOP codon specificity, suggesting a loss of codon specificity for translation release factor activity.
Interacts (via C-terminus) with MTRES1 (via S4 domain) (PubMed:33243891). Associates with mitoribosomal S39 large subunit, peptidyl tRNA and nascent chain (PubMed:33243891).
Methylation of glutamine in the GGQ triplet by HEMK1.
Part of a mitoribosome-associated quality control pathway that prevents aberrant translation by responding to interruptions during elongation (PubMed:33243891). As heterodimer with MTRES1, ejects the unfinished nascent chain and peptidyl transfer RNA (tRNA), respectively, from stalled ribosomes. Recruitment of mitoribosome biogenesis factors to these quality control intermediates suggests additional roles for MTRES1 and MTRF during mitoribosome rescue (PubMed:33243891).
Belongs to the DPH1/DPH2 family. DPH2 subfamily.
Binds 1 [4Fe-4S] cluster per subunit. The cluster facilitates the reduction of the catalytic iron-sulfur cluster in the DPH1 subunit.
Component of the 2-(3-amino-3-carboxypropyl)histidine synthase complex composed of DPH1, DPH2, DPH3 and a NADH-dependent reductase (By similarity). Interacts with DPH1 (By similarity).
Required for the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2 (PubMed:32576952). DPH1 and DPH2 transfer a 3-amino-3-carboxypropyl (ACP) group from S-adenosyl-L-methionine (SAM) to a histidine residue, the reaction is assisted by a reduction system comprising DPH3 and a NADH-dependent reductase (By similarity). Facilitates the reduction of the catalytic iron-sulfur cluster found in the DPH1 subunit (By similarity).
Required for the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2. DPH1 and DPH2 transfer a 3-amino-3-carboxypropyl (ACP) group from S-adenosyl-L-methionine (SAM) to a histidine residue, the reaction is assisted by a reduction system comprising DPH3 and a NADH-dependent reductase. Facilitates the reduction of the catalytic iron-sulfur cluster found in the DPH1 subunit.
Strongly expressed in skeletal muscle. Moderately expressed in heart, small intestine, liver, pancreas, testis and colon. Weakly expressed in brain, placenta, kidney, spleen, thymus, prostate, ovary and lymphocytes.
Binds to but does not cross-link actin. Required for the formation and maintenance of inner ear hair cell stereocilia and staircase formation. Essential for normal hearing.
Interacts with MYO3A (via C-terminus). Interacts with MYO3B (via C-terminus).
Component of the IFT complex B, at least composed of IFT20, IFT22, IFT25, IFT27, IFT46, IFT52, TRAF3IP1/IFT54, IFT57, IFT74, IFT80, IFT81, and IFT88. Interacts directly with IFT57 and KIF3B/Kinesin II subunit (By similarity). Interacts with IFT88 (By similarity). Interacts with CEP83 (PubMed:23530209). Interacts with SPEF2 (via C-terminus) (PubMed:19889948). Interacts with CBL and CBLB (PubMed:29237719). Interacts with TRIP11 (PubMed:19112494). Interacts with TTC21A (PubMed:30929735). Interacts with SPATA1 (By similarity). Interacts with USH1G (PubMed:31637240).
Part of intraflagellar transport (IFT) particles involved in ciliary process assembly (PubMed:17604723). May play a role in the trafficking of ciliary membrane proteins from the Golgi complex to the cilium (PubMed:16775004). Regulates the platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway. Required for protein stability of E3 ubiquitin ligases CBL and CBLB that mediate ubiquitination and internalization of PDGFRA for proper feedback inhibition of PDGFRA signaling (PubMed:29237719). Essential for male fertility. Plays an important role in spermatogenesis, particularly spermiogenesis, when germ cells form flagella. May play a role in the transport of flagellar proteins ODF2 and SPAG16 to build sperm flagella and in the removal of redundant sperm cytoplasm (By similarity). Also involved in autophagy since it is required for trafficking of ATG16L and the expansion of the autophagic compartment (By similarity).
Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds specifically and cooperatively to the SPH and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription in vivo in a cell-specific manner. The activation function appears to be mediated by a limiting cell-specific transcriptional intermediary factor (TIF). Involved in cardiac development. Binds to the M-CAT motif.
Unusual initiator. The initiator methionine is coded by a non-canonical ATT isoleucine codon.
At 4-10 weeks pc, strong expression in the developing central nervous system, kidneys, testis and lung. Differentially expressed within renal tubules.
Component of the VCB (VHL-Elongin BC-CUL2) complex; this complex acts as a ubiquitin-ligase E3 and directs proteasome-dependent degradation of targeted proteins. Interacts with CUL2; this interaction is dependent on the integrity of the trimeric VCB complex. Interacts (via the beta domain) with HIF1A (via the NTAD domain); this interaction mediates degradation of HIF1A in normoxia and, in hypoxia, prevents ubiquitination and degradation of HIF1A by mediating hypoxia-induced translocation to the nucleus, a process which requires a hypoxia-dependent regulatory signal. Interacts with ADRB2; the interaction, in normoxia, is dependent on hydroxylation of ADRB2 and the subsequent VCB-mediated ubiquitination and degradation of ADRB2. Under hypoxia, hydroxylation, interaction with VHL, ubiquitination and subsequent degradation of ADRB2 are dramatically decreased. Interacts with RNF139, USP33 and JADE1. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Isoform 1 and isoform 3 interact with LIMD1 (via LIM zinc-binding 2), AJUBA (via LIM domains) and WTIP (via LIM domains). Interacts with EPAS1. Interacts with CARD9. Interacts with DCUN1D1 independently of CUL2; this interaction engages DCUN1D1 in the VCB complex and triggers CUL2 neddylation and consequently cullin ring ligase (CRL) substrates polyubiquitylation (PubMed:23401859). Interacts with ALAS1 (hydroxylated form) (PubMed:16234850).
Expressed in the adult and fetal brain and kidney.
Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex (PubMed:10944113, PubMed:17981124, PubMed:19584355). Seems to act as a target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions (PubMed:10944113, PubMed:17981124). Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases (PubMed:10944113, PubMed:17981124). Ubiquitinates, in an oxygen-responsive manner, ADRB2 (PubMed:19584355). Acts as a negative regulator of mTORC1 by promoting ubiquitination and degradation of RPTOR (PubMed:34290272).
Produced by alternative initiation at Met-54 of isoform 1.
Highly expressed in granulocytes while expression is very low in fibroblasts, chondrocytes, monocytes, and T- as well as B-cell lines.
This enzyme scavenges exogenous and endogenous cytidine and 2'-deoxycytidine for UMP synthesis.
Binds RAB27A that has been activated by GTP-binding via its N-terminus. Binds MYO5A via its C-terminal coiled coil domain.
Rab effector protein involved in melanosome transport. Serves as link between melanosome-bound RAB27A and the motor protein MYO5A.
Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the cortical actin filament dynamics.
(Microbial infection) Required for cell entry of coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus EMC (HCoV-EMC), by endocytosis.
Each of the two internal repeats contains five hydrophobic transmembrane segments (S1, S2, S3, S5, S6) and one positively charged transmembrane segment (S4). S4 segments probably represent the voltage-sensor and are characterized by a series of positively charged amino acids at every third position (By similarity).
Genetic variants in TPCN2 define the skin/hair/eye pigmentation variation locus 10 (SHEP10) [MIM:612267]. Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair.
Homodimer (PubMed:30860481). Interacts with LRRK2 (PubMed:22012985). Interacts with HAX1 (PubMed:24188827). Interacts with MTOR; the interaction is required for TPCN2 ATP sensitivity (PubMed:23394946). Found in a complex with LSM12, TPCN1 and TPCN2 (PubMed:34362892). Interacts with LSM12 (PubMed:34362892).
Intracellular channel initially characterized as a non-selective Ca(2+)-permeable channel activated by NAADP (nicotinic acid adenine dinucleotide phosphate), it is also a highly-selective Na(+) channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate) (PubMed:19387438, PubMed:19620632, PubMed:20880839, PubMed:30860481, PubMed:32167471, PubMed:31825310, PubMed:23063126, PubMed:24776928, PubMed:23394946, PubMed:24502975). Localizes to the lysosomal and late endosome membranes where it regulates organellar membrane excitability, membrane trafficking, and pH homeostasis. Is associated with a plethora of physiological processes, including mTOR-dependent nutrient sensing, skin pigmentation and autophagy (PubMed:32167471, PubMed:23394946, PubMed:18488028). Ion selectivity is not fixed but rather agonist-dependent and under defined ionic conditions, can be readily activated by both NAADP and PI(3,5)P2 (PubMed:31825310, PubMed:32167471, PubMed:24502975). As calcium channel, it increases the pH in the lysosomal lumen, as sodium channel, it promotes lysosomal exocytosis (PubMed:31825310, PubMed:32167471). Plays a crucial role in endolysosomal trafficking in the endolysosomal degradation pathway and is potentially involved in the homeostatic control of many macromolecules and cell metabolites (By similarity) (PubMed:18488028, PubMed:19387438, PubMed:19620632, PubMed:20880839, PubMed:23063126, PubMed:23394946, PubMed:24502975, PubMed:24776928, PubMed:31825310, PubMed:32167471, PubMed:32679067). Also expressed in melanosomes of pigmented cells where mediates a Ca(2+) channel and/or PI(3,5)P2-activated melanosomal Na(+) channel to acidify pH and inhibit tyrosinase activity required for melanogenesis and pigmentation (PubMed:27140606). Unlike the voltage-dependent TPCN1, TPCN2 is voltage independent and can be activated solely by PI(3,5)P2 binding. In contrast, PI(4,5)P2, PI(3,4)P2, PI(3)P and PI(5)P have no obvious effect on channel activation (PubMed:30860481).
Regulated by Mg(2+) ions, cytosolic Mg(2+) selectively inhibits outward current while lysosomal Mg(2+) modestly inhibits both the outward and inward currents. In the absence of Mg(2+), NAADP readily activates TPCN2, with properties similar to PI(3,5)P2 (PubMed:24502975). Na(+) current is inhibited by ATP in a MTORC-dependent manner. ATP sensitivity is independent of PI(3,5)P2 (PubMed:23394946). Both current elicited by PI(3,5)P2 as well as NAADP are inhibited by tetrandrine.
Widely expressed. Expressed at high level in liver and kidney.
Has been found in brain, heart, skeletal muscle and kidney. Found to be overexpressed in tumor tissues.
Interacts heterophilically through its MAM domain with proteins in axon-rich regions and through its Ig-like domains with proteins in differentiating muscle (By similarity). Interacts (through the Ig-like domains) with NLGN2.
Required for radial migration of cortical neurons in the superficial layer of the neocortex (By similarity). Plays a role in the formation or maintenance of inhibitory synapses. May function by inhibiting the activity of NLGN2.
Alpha2 catalytic subunit of the cytosolic type I platelet-activating factor (PAF) acetylhydrolase (PAF-AH (I)) heterotetrameric enzyme that catalyzes the hydrolyze of the acetyl group at the sn-2 position of PAF and its analogs and modulates the action of PAF. The activity and substrate specificity of PAF-AH (I) are affected by its subunit composition. The alpha2/alpha2 homodimer (PAFAH1B2/PAFAH1B2 homodimer) hydrolyzes PAF and 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylethanolamine (AAGPE) more efficiently than 1-O-alkyl-2-acetyl-sn-glycero-3-phosphoric acid (AAGPA). In contrast, the alpha1/alpha2 heterodimer(PAFAH1B3/PAFAH1B3 heterodimer) hydrolyzes AAGPA more efficiently than PAF, but has little hydrolytic activity towards AAGPE (By similarity). May play a role in male germ cell meiosis during the late pachytenestage and meiotic divisions as well as early spermiogenesis (By similarity).
Beta subunit (PAFAH1B1) stimulates the acetylhydrolase activity of the alpha2/alpha2 catalytic homodimer.
Forms a catalytic dimer which is either homodimer (alpha2/alpha2 homodimer) or heterodimer with PAFAH1B3 (alpha2/alpha1 heterodimer). Component of the cytosolic (PAF-AH (I)) heterotetrameric enzyme, which is composed of PAFAH1B1 (beta), PAFAH1B2 (alpha2) and PAFAH1B3 (alpha1) subunits. The catalytic activity of the enzyme resides in the alpha1 (PAFAH1B3) and alpha2 (PAFAH1B2) subunits, whereas the beta subunit (PAFAH1B1) has regulatory activity. Trimer formation is not essential for the catalytic activity (By similarity). Interacts (homodimer form) with PAFAH1B1 (homodimer form); PAFAH1B2 competes with NDEL1 for PAFAH1B1 binding (PubMed:15572112). Interacts with VLDLR; this interaction may modulate the Reelin pathway (By similarity).
Originally the subunits of the type I platelet-activating factor (PAF) acetylhydrolase was named alpha (PAFAH1B1), beta (PAFAH1B2) and gamma (PAFAH1B3) (PubMed:9144386) (By similarity). Now these subunits have been renamed beta (PAFAH1B1), alpha2 (PAFAH1B2) and alpha1 (PAFAH1B3) respectively (By similarity).
Hydrolyzes fatty acids from S-acylated cysteine residues in proteins (PubMed:26701913). Has depalmitoylating activity towards DLG4/PSD95 (PubMed:26701913). Has depalmitoylating activity towards GAP43 (By similarity). Has depalmitoylating activity towards MAP6 (By similarity). Has depalmitoylating activity towards NRAS (PubMed:26701913).
Palmitoylated on cysteine residues located in a cysteine cluster at the N-terminus which promotes membrane localization. Palmitoylation is required for post-synaptic localization and for depalmitoylating activity towards DLG4/PSD95.
Although ATG16L2 is structurally similar to ATG16L1 and is likewise able to form a complex with the autophagy proteins ATG5 and ATG12, overexpression and knockdown studies in mouse suggest that ATG16L2 is not essential for canonical autophagy.
Homooligomer. Heterooligomer with ATG16L1. Interacts with ATG5. Self-oligomerizes to form a 800-kDa complex composed of ATG12-ATG5 and ATG16L2. Interacts with RAB33B.
May play a role in regulating epithelial homeostasis in an ATG16L1-dependent manner.
(Microbial infection) Can synergize with DHX9 to activate the CTE-mediated gene expression of type D retroviruses.
(Microbial infection) In case of EBV infection, may target PRKACA to EBNA-LP-containing nuclear sites to modulate transcription from specific promoters.
(Microbial infection) In case of HIV-1 infection, involved in the DHX9-promoted annealing of host tRNA(Lys3) to viral genomic RNA as a primer in reverse transcription; in vitro negatively regulates DHX9 annealing activity.
Could play a role in constitutive transport element (CTE)-mediated gene expression by association with DHX9. Increases CTE-dependent nuclear unspliced mRNA export (PubMed:10748171, PubMed:11402034). Proposed to target PRKACA to the nucleus but does not seem to be implicated in the binding of regulatory subunit II of PKA (PubMed:10761695, PubMed:11884601). May be involved in nuclear envelope breakdown and chromatin condensation. May be involved in anchoring nuclear membranes to chromatin in interphase and in releasing membranes from chromating at mitosis (PubMed:11034899). May regulate the initiation phase of DNA replication when associated with TMPO isoform Beta (PubMed:12538639). Required for cell cycle G2/M transition and histone deacetylation during mitosis. In mitotic cells recruits HDAC3 to the vicinity of chromatin leading to deacetylation and subsequent phosphorylation at 'Ser-10' of histone H3; in this function seems to act redundantly with AKAP8 (PubMed:16980585). May be involved in regulation of pre-mRNA splicing (PubMed:17594903).
Interacts (via N-terminus) with DHX9 (via RGG region) (PubMed:10748171, PubMed:11402034). Interacts with TMPO isoform Beta, PRPF40A, RNF43, lamin-B (PubMed:11034899, PubMed:12538639, PubMed:16391387, PubMed:18313049). Interacts with HDAC3; increased during mitosis (PubMed:16980585). Interacts with EBV EBNA-LP (PubMed:11160753). Interacts with HIV-1 reverse transcriptase/ribonuclease H (PubMed:25034436).
Phosphorylated on serine or threonine residues possibly by PKA; probably modulating the interaction with TMPO isoform Beta.
Ubiquitously expressed. Expressed in the brain cortex (at protein level).
During early embryo development, its expression is restricted to the 4-cell to 8-cell stage of the preimplantation embryo.
Paired-like homeobox transcription factor involved in embryogenesis (PubMed:27578796, PubMed:30479355). May act as a regulator of embryo genome activation (PubMed:27578796). Binds to a 36 bp DNA elements containing a 5'-TAATCC-3' sequence motif, referred to as EEA motif (EGA-enriched Alu-motif), present in the promoters of target genes activated in early embryos (PubMed:27578796, PubMed:30479355).
The 9aaTAD motif is a conserved putative nine amino acid transactivation motifs in C-terminus of the LEUTX region.
The homeobox contain essential residues (Ile-54, Lys-57, Ala-61) for binding to the 5'-TAATCC-3' motif of the targe gene promoters.
The homeobox is incomplete and cannot bind to the 36 bp motif found in the promoters of the target genes.
Acyl-CoA diphosphatase that mediates the hydrolysis of a wide range of CoA and CoA esters yielding 3',5'-ADP and the corresponding 4'-phosphopantetheine derivative as products (By similarity). Hydrolyzes short- and medium-chain acyl-CoAs, exhibiting the highest activity toward free CoA, hexanoyl-CoA, and octanoyl-CoA and the lowest activity against acetyl-CoA (By similarity). Exhibits decapping activity towards dpCoA-capped RNAs in vitro (By similarity).
Catalyzes both phosphatidylcholine and phosphatidylethanolamine biosynthesis from CDP-choline and CDP-ethanolamine, respectively. Involved in protein-dependent process of phospholipid transport to distribute phosphatidyl choline to the lumenal surface. Has a higher cholinephosphotransferase activity than ethanolaminephosphotransferase activity.
Calcium-binding protein that may play a role in the adhesion of neutrophils to fibronectin. May play a role in the formation of focal adhesions.
Detected in neutrophils and macrophages (at protein level). Highly expressed in bone marrow.
Acetylated (PubMed:32789493). Deacetylation by SIRT6 in response to UV stress facilitates nucleotide excision repair pathway (the NER pathway) transduction (PubMed:32789493).
Component of the UV-DDB complex which includes DDB1 and DDB2. The UV-DDB complex interacts with monoubiquitinated histone H2A and binds to XPC via the DDB2 subunit. Component of the DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex DDB1-CUL4-ROC1 (also known as CUL4-DDB-ROC1 and CUL4-DDB-RBX1), which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1. DDB2 may function as the substrate recognition module within this complex. The DDB1-CUL4-ROC1 complex may associate with the COP9 signalosome, and this inhibits the E3 ubiquitin-protein ligase activity of the complex. A large number of other DCX complexes may also exist in which an alternate substrate targeting subunit replaces DDB2. These targeting subunits are generally known as DCAF (DDB1- and CUL4-associated factor) or CDW (CUL4-DDB1-associated WD40-repeat) proteins. Isoform D1 and isoform D2 do not interact with DDB1.
Expression is induced in response to treatment with IR or UV and this requires p53/TP53 activity.
Interblade loops of the WD repeat region mediate most of the interaction with DNA. A hairpin between blades 5 and 6 inserts into DNA minor groove and mediates recognition of lesions and separation of the damaged and undamaged strands.
Phosphorylation by ABL1 negatively regulate UV-DDB activity.
Protein, which is both involved in DNA repair and protein ubiquitination, as part of the UV-DDB complex and DCX (DDB1-CUL4-X-box) complexes, respectively (PubMed:10882109, PubMed:11278856, PubMed:11705987, PubMed:9892649, PubMed:12732143, PubMed:15882621, PubMed:16473935, PubMed:18593899, PubMed:32789493). Core component of the UV-DDB complex (UV-damaged DNA-binding protein complex), a complex that recognizes UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair (PubMed:10882109, PubMed:11278856, PubMed:11705987, PubMed:16260596, PubMed:12944386, PubMed:14751237, PubMed:32789493). The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches (PubMed:10882109, PubMed:11278856, PubMed:11705987, PubMed:16260596, PubMed:12944386). Also functions as the substrate recognition module for the DCX (DDB2-CUL4-X-box) E3 ubiquitin-protein ligase complex DDB2-CUL4-ROC1 (also known as CUL4-DDB-ROC1 and CUL4-DDB-RBX1) (PubMed:12732143, PubMed:15882621, PubMed:16473935, PubMed:18593899, PubMed:26572825). The DDB2-CUL4-ROC1 complex may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage (PubMed:16678110, PubMed:16473935). The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair (PubMed:16678110, PubMed:16473935). The DDB2-CUL4-ROC1 complex also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER (PubMed:15882621). The DDB2-CUL4-ROC1 complex also ubiquitinates KAT7/HBO1 in response to DNA damage, leading to its degradation: recognizes KAT7/HBO1 following phosphorylation by ATR (PubMed:26572825).
The DWD box is required for interaction with DDB1.
Ubiquitinated by CUL4A in response to UV irradiation. Ubiquitination appears to both impair DNA-binding and promotes ubiquitin-dependent proteolysis. Degradation of DDB2 at sites of DNA damage may be a prerequisite for their recognition by XPC and subsequent repair. CUL4A-mediated degradation appears to be promoted by ABL1.
Ubiquitinated, leading to proteasomal degradation, and deubiquitinated by USP24. Deubiquitinated by USP44; leading to its stabilization on DNA lesions (By similarity).
Ubiquitously expressed; with highest levels in corneal endothelium and lowest levels in brain. Isoform D1 is highly expressed in brain and heart. Isoform D2, isoform D3 and isoform D4 are weakly expressed.
Interacts with CTNNB1 (when unphosphorylated), perhaps preventing interaction of CTNNB1 with TCF4, and thereby regulating transcription activation; phosphorylation of CTNNB1 may inhibit the interaction.
Transcription cofactor (PubMed:30097457). Negatively regulates transcription activation by catenin beta-1 CTNNB1, perhaps acting by competing with TCF4 for CTNNB1 binding (PubMed:30097457). May play a role in DNA-damage response signaling (PubMed:33924684). Binds specifically to DNA sequences at peri-centromeric chromatin loci.
Up-regulated by ultraviolet (UV) light (at protein level).
Bifunctional glycosyltransferase with both alpha-1,3-xylosyltransferase and beta-1,3-glucuronyltransferase activities involved in the maturation of alpha-dystroglycan (DAG1) by glycosylation leading to DAG1 binding to laminin G-like domain-containing extracellular proteins with high affinity and in a phosphorylated-O-mannosyl trisaccharide dependent manner (PubMed:15661757, PubMed:15752776, PubMed:25138275). Elongates the glucuronyl-beta-1,4-xylose-beta disaccharide primer structure by adding repeating units [-3-Xylose-alpha-1,3-GlcA-beta-1-] to produce a heteropolysaccharide (By similarity). Supports the maturation of DAG1 more effectively than LARGE1 (PubMed:15752776). In addition, can modify both heparan sulfate (HS)- and chondroitin/dermatan sulfate (CS/DS)-proteoglycans (PGs), namely GPC4, with a glycosaminoglycan (GAG)-like polysaccharide composed of xylose and glucuronic acid to confer laminin binding (By similarity).
Widely expressed. Expressed at high level in placenta, pancreas and kidney compared to LARGE. Not expressed in brain.
Adapter protein that plays a key role in innate immune response against fungi by forming signaling complexes downstream of C-type lectin receptors (PubMed:26961233, PubMed:33558980). CARD9-mediated signals are essential for antifungal immunity against a subset of fungi from the phylum Ascomycota (PubMed:24231284, PubMed:25702837, PubMed:25057046, PubMed:26679537, PubMed:26961233, PubMed:26521038, PubMed:27777981, PubMed:29080677, PubMed:33558980). Transduces signals in myeloid cells downstream of C-type lectin receptors CLEC7A (dectin-1), CLEC6A (dectin-2) and CLEC4E (Mincle), which detect pathogen-associated molecular pattern metabolites (PAMPs), such as fungal carbohydrates, and trigger CARD9 activation (By similarity). Upon activation, CARD9 homooligomerizes to form a nucleating helical template that recruits BCL10 via CARD-CARD interaction, thereby promoting polymerization of BCL10 and subsequent recruitment of MALT1: this leads to activation of NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:11053425, PubMed:26488816, PubMed:31296852, PubMed:26961233, PubMed:33558980). CARD9 signaling in antigen-presenting cells links innate sensing of fungi to the activation of adaptive immunity and provides a cytokine milieu that induces the development and subsequent of interleukin 17-producing T helper (Th17) cells (PubMed:24231284). Also involved in activation of myeloid cells via classical ITAM-associated receptors and TLR: required for TLR-mediated activation of MAPK, while it is not required for TLR-induced activation of NF-kappa-B (By similarity). CARD9 can also be engaged independently of BCL10: forms a complex with RASGRF1 downstream of C-type lectin receptors, which recruits and activates HRAS, leading to ERK activation and the production of cytokines (By similarity). Acts as an important regulator of the intestinal commensal fungi (mycobiota) component of the gut microbiota (PubMed:33548172). Plays an essential role in antifungal immunity against dissemination of gut fungi: acts by promoting induction of antifungal IgG antibodies response in CX3CR1(+) macrophages to confer protection against disseminated C.albicans or C.auris infection (PubMed:33548172). Also mediates immunity against other pathogens, such as certain bacteria, viruses and parasites; CARD9 signaling is however redundant with other innate immune responses (By similarity). In response to L.monocytogenes infection, required for the production of inflammatory cytokines activated by intracellular peptidoglycan: acts by connecting NOD2 recognition of peptidoglycan to downstream activation of MAP kinases (MAPK) without activating NF-kappa-B (By similarity).
Expression is restricted to several populations of phagocytes, such as macrophages, monocytes, and dendritic cells (PubMed:33548172). Highly expressed in spleen (PubMed:11053425). Also detected in liver, placenta, lung, peripheral blood leukocytes and in brain (PubMed:11053425).
Maintained in an autoinhibited state via homodimerization in which the CARD domain forms an extensive interaction with the adjacent linker and coiled-coil regions (PubMed:31296852). Activation downstream of C-type lectin receptors, by phosphorylation by PRKCD and/or ubiquitination by TRIM62, triggers disruption of the CARD domain-coiled coil interface, CARD9 homooligomerization and BCL10 recruitment, followed by activation of NF-kappa-B and MAP kinase p38 pathways (PubMed:26488816, PubMed:31296852). Zinc-binding inhibits activation by stabilizing the CARD ground-state conformation and restricting its capacity to form BCL10-nucleating filaments (PubMed:30206119).
Monomer (PubMed:30206119). Homodimer; homodimerization is mediated by the CARD domain which forms an extensive interaction with the adjacent linker and coiled-coil regions; leads to an autoinhibited state (PubMed:30206119, PubMed:31296852). Homomultimer; polymerizes following activation, forming a nucleating helical template that seeds BCL10-filament formation via a CARD-CARD interaction (PubMed:31296852). Interacts (via CARD domain) with BCL10 (via CARD domain); interaction takes place following CARD9 activation and polymerization, leading to the formation of a filamentous CBM complex assembly (PubMed:11053425, PubMed:26488816, PubMed:31296852, PubMed:26521038). Component of a CBM complex (CARD9-BCL10, MALT1), composed of CARD9, BCL10 and MALT1 (PubMed:26521038). Interacts with RASGRF1 (PubMed:26521038). Interacts with NOD2 (via NACHT domain); interaction is direct (PubMed:24960071). Interacts with RIPK2 (By similarity). Interacts with VHL; without leading to protein degradation (By similarity).
Phosphorylated at Thr-231 by PRKCD downstream of C-type lectin receptors activation: phosphorylation promotes interaction with BCL10, followed by activation of NF-kappa-B and MAP kinase p38 pathways (By similarity). Phosphorylated at Thr-531 and Thr-533 by CK2 following interaction with VHL, leading to inhibit the ability to activate NF-kappa-B (By similarity).
The disease is caused by variants affecting the gene represented in this entry. Defects induce reduced numbers of CD4(+) Th17 lymphocytes as well as a lack of monocyte-derived cytokines in response to Candida strains (PubMed:23335372). Neutrophils show a selective Candida albicans killing defect with abnormal ultrastructural phagolysosomes and outgrowth of hyphae (PubMed:23335372).
The linker region, also named autoinhibitory interface, is required to prevent constitutive activation and maintain CARD9 in an autoinhibitory state (PubMed:31296852). Disruption of this region triggers polymerization and activation, leading to formation of BCL10-nucleating filaments (PubMed:31296852).
Ubiquitinated at Lys-125 via 'Lys-27'-linked ubiquitin by TRIM62 downstream of C-type lectin receptors activation; leading to CARD9 activation, followed by activation of NF-kappa-B and MAP kinase p38 pathways (PubMed:26488816, PubMed:31296852). Deubiquitinated at Lys-125 by USP15, inhibiting CARD9 (PubMed:33093067).
Up-regulated in asthenozoospermic sperm.
Both isoforms are expressed ubiquitously (at transcript level), isoform 1 being the most predominant (PubMed:28626029). Expressed in the fetal brain and different regions of the adult brain and spinal cord (PubMed:28626029).
Component of a transport protein particle (TRAPP) complex that may function in specific stages of inter-organelle traffic (PubMed:16025134, PubMed:16828797). Specifically involved in the early development of neural circuitry, likely by controlling the frequency and amplitude of intracellular calcium transients implicated in the regulation of neuron differentiation and survival (Probable).
Homodimer (PubMed:16025134, PubMed:16828797). Part of a TRAPP complex. Heterodimer with TRAPPC3 (PubMed:16025134, PubMed:16828797). The heterodimer TRAPPC6B-TRAPPC3 interacts with TRAPPC1 likely providing a core for TRAPP complex formation (PubMed:16828797).
May not be essential for endoplasmic reticulum-to-Golgi transport.
Belongs to the eukaryotic ribosomal protein eS28 family.
Component of the 40S small ribosomal subunit (PubMed:23636399, PubMed:25901680, PubMed:25957688). Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3 (PubMed:34516797).
Component of the small ribosomal subunit (PubMed:23636399, PubMed:25901680, PubMed:25957688). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399, PubMed:25901680, PubMed:25957688). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797).
Interacts with STX1A, STX2 and STX3 (By similarity). Interacts with STX11.
Involved in intracellular vesicle trafficking and vesicle fusion with membranes. Contributes to the granule exocytosis machinery through interaction with soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins that regulate membrane fusion. Regulates cytotoxic granule exocytosis in natural killer (NK) cells.
Placenta, lung, liver, kidney and pancreas, as well as in peripheral blood lymphocytes.
Lysyl hydroxylase activity is strongly inhibited by imidazole.
Multifunctional enzyme that catalyzes a series of essential post-translational modifications on Lys residues in procollagen (PubMed:11956192, PubMed:12475640, PubMed:18298658, PubMed:30089812, PubMed:18834968). Plays a redundant role in catalyzing the formation of hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens (PubMed:9582318, PubMed:9724729, PubMed:11956192, PubMed:12475640, PubMed:18298658, PubMed:30089812, PubMed:18834968). Plays a redundant role in catalyzing the transfer of galactose onto hydroxylysine groups, giving rise to galactosyl 5-hydroxylysine (PubMed:12475640, PubMed:18298658, PubMed:30089812, PubMed:18834968). Has an essential role by catalyzing the subsequent transfer of glucose moieties, giving rise to 1,2-glucosylgalactosyl-5-hydroxylysine residues (PubMed:10934207, PubMed:11896059, PubMed:11956192, PubMed:12475640, PubMed:18298658, PubMed:30089812, PubMed:18834968). Catalyzes hydroxylation and glycosylation of Lys residues in the MBL1 collagen-like domain, giving rise to hydroxylysine and 1,2-glucosylgalactosyl-5-hydroxylysine residues (PubMed:25419660). Essential for normal biosynthesis and secretion of type IV collagens (PubMed:18834968) (Probable). Essential for normal formation of basement membranes (By similarity).
The C-terminal domain that mediates lysyl hydroxylase activity is also important for homodimerization.
The N-terminal domain mediates glycosyltransferase activity.
Ubiquitous (PubMed:9724729). Detected in heart, placenta and pancreas and at lower levels in lung, liver and skeletal muscle (PubMed:9582318, PubMed:9724729).
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). CF(0) has three main subunits: a, b and c. Component of an ATP synthase complex composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5PD, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and ATP5MJ. Interacts with PPIF. Interacts with BCL2L1 isoform BCL-X(L); the interaction mediates the association of BCL2L1 isoform BCL-X(L) with the mitochondrial membrane F(1)F(0) ATP synthase and enhances neurons metabolic efficiency. Interacts with CLN5 and PPT1. Interacts with S100A1; this interaction increases F1-ATPase activity (By similarity). Interacts with MTLN (PubMed:32243843). Interacts with TTC5/STRAP; the interaction results in decreased mitochondrial ATP production (PubMed:25168243).
Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Subunits alpha and beta form the catalytic core in F(1). Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits.
Down-regulated by gemcitabine/GMZ (at protein level) (PubMed:19345744). Down-regulated upon serum starvation (PubMed:19345744).
Inhibited by dithiothreitol (DTT) and 2-mercaptoethanol (PubMed:16229686). Activity is mildly stimulated by Ca(2+) and Mg(2+), but is not inhibited by EDTA (PubMed:10781606, PubMed:16229686). Activity is inhibited by millimolar levels of Fe(2+), Zn(2+) and Cu(2+) (PubMed:16229686, PubMed:17475390). Inhibited by cholesterol (PubMed:17475390).
N-glycosylated. Required for enzyme activity.
O-glycosylated. Required to retain it as a type II membrane protein at the cell surface.
Phosphorylated. May prevent ubiquitination and subsequent degradation.
Plasma membrane ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at neutral pH (PubMed:10781606, PubMed:16229686, PubMed:26190575). Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation (PubMed:15946935, PubMed:19345744, PubMed:24798654). Also catalyzes the reverse reaction allowing the synthesis of ceramides from fatty acids and sphingosine (PubMed:11278489, PubMed:17475390). Together with sphingomyelinase, participates in the production of sphingosine and sphingosine-1-phosphate from the degradation of sphingomyelin, a sphingolipid enriched in the plasma membrane of cells (PubMed:16061940). Also participates in the hydrolysis of ceramides from the extracellular milieu allowing the production of sphingosine-1-phosphate inside and outside cells (By similarity). This is the case for instance with the digestion of dietary sphingolipids in the intestinal tract (By similarity).
Primarily expressed in intestine (PubMed:17334805). Ubiquitously expressed with higher levels in kidney, skeletal muscle and heart (PubMed:10781606). The ubiquitous expression observed for ASAH2 might be an experimental artifact due to the paralog ASAH2B (PubMed:17334805).
Proteolytic cleavage of the N-terminus removes the signal-anchor and produces a soluble form of the protein.
Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is triggered by nitric oxide.
Was proposed to be mitochondrial, based on experiments with an N-terminal GFP-tag (PubMed:10781606). The in vivo localization to the mitochondrion could not be confirmed (PubMed:15845354). However, it has been observed for the mouse (AC Q9JHE3) and rat (AC Q91XT9) orthologs.
Along with COA3, core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex.
Core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. Requires for coordination of the early steps of cytochrome c oxidase assembly with the synthesis of MT-CO1.
Detected in liver and prostate (at protein level). Detected in adult liver, lung, brain, placenta, prostate, adrenal gland, testis, mammary gland, spleen, spinal cord and uterus. Detected in caudate nucleus, and at lower levels in amygdala, corpus callosum, hippocampus, substantia nigra and thalamus. Detected in fetal lung, liver and brain.
NAD-dependent oxidoreductase with broad substrate specificity that shows both oxidative and reductive activity (in vitro). Has 17-beta-hydroxysteroid dehydrogenase activity towards various steroids (in vitro). Converts 5-alpha-androstan-3-alpha,17-beta-diol to androsterone and estradiol to estrone (in vitro). Has 3-alpha-hydroxysteroid dehydrogenase activity towards androsterone (in vitro). Has retinol dehydrogenase activity towards all-trans-retinol (in vitro). Can convert androsterone to epi-androsterone. Androsterone is first oxidized to 5-alpha-androstane-3,17-dione and then reduced to epi-andosterone. Can act on both C-19 and C-21 3-alpha-hydroxysteroids.
Interacts with TOGARAM1, CCDC66, CEP104, CSPP1 and CEP290.
Involved in ciliogenesis (PubMed:32453716). It is required for appropriate acetylation and polyglutamylation of ciliary microtubules, and regulation of cilium length (PubMed:32453716). Acts as a positive regulator of hedgehog (Hh)signaling (By similarity). May participate in the trafficking and/or retention of GLI2 and GLI3 proteins at the ciliary tip (By similarity).
Strongly expressed in most melanomas and melanocytes. Weakly expressed in the testis.
Up-regulated in response to serum starvation in fibroblasts.
A chromosomal aberration involving SEC31A is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;4)(p23;q21) with ALK.
COPII is composed of at least 5 proteins: the SEC23/24 complex, the SEC13/31 complex and SAR1. SEC13 and SEC31 make a 2:2 tetramer that forms the edge element of the COPII outer coat. The tetramer self-assembles in multiple copies to form the complete polyhedral cage. Interacts (via WD 8) with SEC13 (By similarity). Interacts with PDCD6; interaction takes place in response to cytosolic calcium increase and leads to bridge together the BCR(KLHL12) complex and SEC31A, leading to monoubiquitination (PubMed:27716508) (PubMed:16957052, PubMed:17196169, PubMed:27716508, PubMed:25667979). Interacts with KLHL12.
Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER) (PubMed:10788476). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules (By similarity).
The ALG-2-binding site motif-2 (ABS-2) contains a PXPGF sequence that binds hydrophobic pocket 3 of PDCD6.
Exhibits both phospholipase A1/2 and acyltransferase activities (PubMed:19615464, PubMed:22825852, PubMed:22605381, PubMed:26503625). Shows phospholipase A1 (PLA1) and A2 (PLA2) activity, catalyzing the calcium-independent release of fatty acids from the sn-1 or sn-2 position of glycerophospholipids (PubMed:19615464, PubMed:22825852, PubMed:22605381). For most substrates, PLA1 activity is much higher than PLA2 activity (PubMed:19615464). Shows O-acyltransferase activity, catalyzing the transfer of a fatty acyl group from glycerophospholipid to the hydroxyl group of lysophospholipid (PubMed:19615464). Shows N-acyltransferase activity, catalyzing the calcium-independent transfer of a fatty acyl group at the sn-1 position of phosphatidylcholine (PC) and other glycerophospholipids to the primary amine of phosphatidylethanolamine (PE), forming N-acylphosphatidylethanolamine (NAPE), which serves as precursor for N-acylethanolamines (NAEs) (PubMed:19615464, PubMed:22825852, PubMed:22605381). Catalyzes N-acylation of PE using both sn-1 and sn-2 palmitoyl groups of PC as acyl donor (PubMed:22605381). Exhibits high phospholipase A1/2 activity and low N-acyltransferase activity (PubMed:22825852).
Expressed in liver, kidney, small intestine testis and colon (PubMed:19615464). Undetectable in testis, placenta, salivary gland and fetal brain (PubMed:18163183).
Acts as an endocytic receptor to direct captured antigens from the extracellular space to a specialized antigen-processing compartment (By similarity). Causes reduced proliferation of B-lymphocytes.
Expressed in spleen, thymus, colon and peripheral blood lymphocytes. Detected in myeloid and B-lymphoid cell lines. Isoform 2 and isoform 3 are expressed in malignant Hodgkin lymphoma cells called Hodgkin and Reed-Sternberg (HRS) cells.
Interacts with FMNL2; this interaction promotes muscle-derived satellite cell (MDSC) migration and differentiation.
Promotes the migration of muscle-derived satellite cells (MDSCs) during differentiation throught interaction with FMNL2 and therefore may participate in microfilament assembly.
Restricted to progenitors and secondary lymph tissues. In normal hematopoiesis, it is restricted to immature B- and T-lymphoid cells. Present in differentiating embryonic stem cells (at protein level).
Transcription factor that play a central role in proper axial mesendoderm morphogenesis and endoderm formation. Required for efficient differentiation of cells from the primitive streak stage to blood, by acting early in the recruitment and/or expansion of mesodermal progenitors to the hemangioblastic and hematopoietic lineages. Also involved in the morphogenesis of the heart and the gut during embryogenesis. Acts as a negative regulator of brachyury expression (By similarity).
Component of striatin-interacting phosphatase and kinase (STRIPAK) complex (By similarity). Interacts with CTTNBP2NL.
A chromosomal aberration disrupting NAV3 has been found in patients with Sezary syndrome (PubMed:16166283). Translocation t(12;18)(q21;q21.2) (PubMed:16166283).
Highly expressed in brain. Expressed at low levels in heart and placenta. Present in activated T-cells but not in resting T-cells (at protein level). Down-regulated in primary neuroblastoma.
Plays a role in cell migration (PubMed:21471154). May be involved in neuron regeneration. May regulate IL2 production by T-cells.
Belongs to the calmodulin family. Calglandulin subfamily.
Expressed in prostate, thymus, heart, skeleton muscle, bone marrow and ovary.
Belongs to the aldolase class II family. MtnB subfamily.
Catalyzes the dehydration of methylthioribulose-1-phosphate (MTRu-1-P) into 2,3-diketo-5-methylthiopentyl-1-phosphate (DK-MTP-1-P). Functions in the methionine salvage pathway, which plays a key role in cancer, apoptosis, microbial proliferation and inflammation. May inhibit the CASP1-related inflammatory response (pyroptosis), the CASP9-dependent apoptotic pathway and the cytochrome c-dependent and APAF1-mediated cell death.
Homotetramer (PubMed:24367089). Interacts with APAF1 (PubMed:15262985). May interact with CASP1 (PubMed:22837397).
Isoform 1 is ubiquitously expressed. Isoform 2 is expressed at lower levels and detected in heart, brain, pancreas, liver, placenta, skeletal muscle and kidney.
May play a role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons. Directly binds piRNAs, a class of 24 to 30 nucleotide RNAs that are generated by a Dicer-independent mechanism and are primarily derived from transposons and other repeated sequence elements. Besides their function in transposable elements repression, piRNAs are probably involved in other processes during meiosis such as translation regulation (By similarity).
Component of the serine palmitoyltransferase (SPT) complex, which is also composed of SPTLC2 or SPTLC3 and SPTSSA or SPTSSB (PubMed:19416851, PubMed:33558761, PubMed:33558762, PubMed:37308477, PubMed:19132419). The heterodimer consisting of SPTLC1 and SPTLC2/SPTLC3 forms the catalytic core of the enzyme, while SPTSSA or SPTSSB subunits determine substrate specificity (PubMed:33558762, PubMed:37308477). SPT also interacts with ORMDL proteins, especially ORMDL3, which negatively regulate SPT activity in the presence of ceramides (PubMed:20182505, PubMed:30700557, PubMed:33558762, PubMed:37308477, PubMed:34059824). Forms dimers of heterodimers with SPTLC2 (PubMed:33558761, PubMed:33558762). Interacts with RTN4 (isoform B) (By similarity).
Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-chain bases. The SPT complex is also composed of SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this complex, the heterodimer with SPTLC2 or SPTLC3 forms the catalytic core (PubMed:19416851, PubMed:33558762). The composition of the serine palmitoyltransferase (SPT) complex determines the substrate preference (PubMed:19416851, PubMed:33558762). The SPTLC1-SPTLC2-SPTSSA complex shows a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as substrates, with a slight preference for C14-CoA (PubMed:19648650, PubMed:19416851). The SPTLC1-SPTLC2-SPTSSB complex shows a strong preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB isozyme displays an ability to use a broader range of acyl-CoAs, without apparent preference (PubMed:19648650, PubMed:19416851, PubMed:33558761, PubMed:33558762). Required for adipocyte cell viability and metabolic homeostasis (By similarity).
Expression at protein level is highly increased in brains of patients with Alzheimer disease. No changes are observed at mRNA level.
Phosphorylation at Tyr-164 inhibits activity and promotes cell survival.
SPT complex catalytic activity is negatively regulated by ORMDL proteins, including ORMDL3, in the presence of ceramides (PubMed:37308477). This mechanism allows to maintain ceramide levels at sufficient concentrations for the production of complex sphingolipids, but which prevents the accumulation of ceramides to levels that trigger apoptosis (Probable).
The disease is caused by variants affecting the gene represented in this entry. Variants associated with ALS27 tend to disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in up-regulated SPT activity and elevated levels of canonical SPT products.
The disease is caused by variants affecting the gene represented in this entry. Variants associated with HSAN1A tend to increase serine palmitoyltransferase (SPT) usage of alanine or glycine rather than serine, resulting in deoxysphingolipid synthesis. Deoxysphingolipids cannot be efficiently degraded by the cell machinery and cause cell toxicity.
The transmembrane domain is involved in the interaction with ORMDL3.
Widely expressed. Not detected in small intestine.
May form homomeric filament after self-association or heteromeric filament after association with beta-tectorin (Probable). Interacts with CEACAM16.
One of the major non-collagenous components of the tectorial membrane (By similarity). The tectorial membrane is an extracellular matrix of the inner ear that covers the neuroepithelium of the cochlea and contacts the stereocilia bundles of specialized sensory hair cells. Sound induces movement of these hair cells relative to the tectorial membrane, deflects the stereocilia and leads to fluctuations in hair-cell membrane potential, transducing sound into electrical signals.
The presence of a hydrophobic C-terminus preceded by a potential cleavage site strongly suggests that tectorins are synthesized as glycosylphosphatidylinositol-linked, membrane-bound precursors. Tectorins are targeted to the apical surface of the inner ear epithelia by the lipid and proteolytically released into the extracellular compartment.
Zona pellucida domain may enable to form filaments.
Expressed primarily in kidney. Expressed in specific nephron segments and in the stria vascularis of the inner ear.
Functions as a beta-subunit for CLCNKA and CLCNKB chloride channels. In the kidney CLCNK/BSND heteromers mediate chloride reabsorption by facilitating its basolateral efflux. In the stria, CLCNK/BSND channels drive potassium secretion by recycling chloride for the basolateral SLC12A2 cotransporter.
Interacts with CLCNK channels. Forms heteromers with CLCNKA in the thin ascending limb of Henle and with CLCNKB in the thick ascending limb and more distal segments (By similarity).
Palmitoylation is necessary for activation of plasma membrane-inserted CLC-K/barttin channels.
Highly expressed in adult salivary gland and at much lower levels in mammary gland, kidney and placenta.
Transcription factor. Binds optimally to the DNA consensus sequence 5'-YYTAATGRTTTTY-3'. May control the expression of neural adhesion molecules such as L1 or Ng-CAM during embryonic development of both the central and peripherical nervous system. May be involved in controlling adhesive processes in keratinizing epithelia (By similarity).
Binds EPS15 (By similarity). Interacts with ITSN1 (By similarity). Binds AP-2 and clathrin. Interacts with UBQLN2.
Highest expression is found in brain. Detected at lower levels in lung and liver.
Plays a role in the formation of clathrin-coated invaginations and endocytosis.
The DPW repeat domain is involved in AP-2 and clathrin binding.
Belongs to the syndecan proteoglycan family.
Cell surface proteoglycan that contains both heparan sulfate and chondroitin sulfate and that links the cytoskeleton to the interstitial matrix (By similarity). Regulates exosome biogenesis in concert with SDCBP and PDCD6IP (PubMed:22660413). Able to induce its own expression in dental mesenchymal cells and also in the neighboring dental epithelial cells via an MSX1-mediated pathway (By similarity).
Detected in placenta (at protein level) (PubMed:32337544). Detected in fibroblasts (at protein level) (PubMed:36213313).
Interacts with CDCP1. Interacts (via C-terminus) with TIAM1 (via PDZ domain). Interacts with MDK (By similarity).
Shedding is enhanced by a number of factors such as heparanase, thrombin or EGF. Also by stress and wound healing. PMA-mediated shedding is inhibited by TIMP3.
Acts as a front-end fatty acyl-coenzyme A (CoA) desaturase that introduces a cis double bond at carbon 5 located between a preexisting double bond and the carboxyl end of the fatty acyl chain. Involved in biosynthesis of highly unsaturated fatty acids (HUFA) from the essential polyunsaturated fatty acids (PUFA) linoleic acid (LA) (18:2n-6) and alpha-linolenic acid (ALA) (18:3n-3) precursors. Specifically, desaturates dihomo-gamma-linoleoate (DGLA) (20:3n-6) and eicosatetraenoate (ETA) (20:4n-3) to generate arachidonate (AA) (20:4n-6) and eicosapentaenoate (EPA) (20:5n-3), respectively (PubMed:10601301, PubMed:10769175). As a rate limiting enzyme for DGLA (20:3n-6) and AA (20:4n-6)-derived eicosanoid biosynthesis, controls the metabolism of inflammatory lipids like prostaglandin E2, critical for efficient acute inflammatory response and maintenance of epithelium homeostasis. Contributes to membrane phospholipid biosynthesis by providing AA (20:4n-6) as a major acyl chain esterified into phospholipids. In particular, regulates phosphatidylinositol-4,5-bisphosphate levels, modulating inflammatory cytokine production in T-cells (By similarity). Also desaturates (11E)-octadecenoate (trans-vaccenoate)(18:1n-9), a metabolite in the biohydrogenation pathway of LA (18:2n-6) (By similarity).
Does not exhibit any catalytic activity toward 20:3n-6, but it may enhance FADS2 activity.
Strongly down-regulated upon differentiation in a neuroblastoma cell line (at protein level).
Widely expressed, with highest levels in liver, brain, adrenal gland and heart. Highly expressed in fetal liver and brain.
(Microbial infection) Plays a positive role in viral cDNA synthesis.
A chromosomal aberration involving PATZ1 is associated with small round cell sarcoma. Translocation t(1;22)(p36.1;q12) with EWSR1.
Homodimer (By similarity). Interacts with RNF4 (PubMed:10713105). Interacts (via C-terminus) with TP53; this interaction inhibits TP53 ability to activate transcription (PubMed:25755280).
Transcriptional regulator that plays a role in many biological processes such as embryogenesis, senescence, T-cell development or neurogenesis (PubMed:10713105, PubMed:25755280, PubMed:31875552). Interacts with the TP53 protein to control genes that are important in proliferation and in the DNA-damage response. Mechanistically, the interaction inhibits the DNA binding and transcriptional activity of TP53/p53 (PubMed:25755280). Part of the transcriptional network modulating regulatory T-cell development and controls the generation of the regulatory T-cell pool under homeostatic conditions (PubMed:31875552).
Expressed in brain, testis, pituitary gland, pancreas and bone marrow. Also poorly expressed in malignant astrocytomas and several neuroectodermal tumor cell lines. Weakly expressed in medulloblastoma (MB) compared with normal cerebellar tissues.
Interacts with CPEB3 (via N-terminal domain); the interaction increases CPEB3 ubiquitination. Interacts with DLL1.
Plays a role in hippocampal-dependent synaptic plasticity, learning and memory. Involved in the formation of spines and functional synaptic contacts by modulating the translational activity of the cytoplasmic polyadenylation element-binding protein CPEB3. Promotes ubiquitination of CPEB3, and hence induces CPEB3-dependent mRNA translation activation of glutamate receptor GRIA1 and GRIA2. Can function as an E3 ubiquitin-protein ligase to activate monoubiquitination of JAG1 (in vitro), thereby regulating the Notch pathway. Acts as a tumor suppressor; inhibits malignant cell transformation of medulloblastoma (MB) cells by inhibiting the Notch signaling pathway.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins (PubMed:22496338). In vitro catalyzes 'Lys-48'-linked polyubiquitination (PubMed:20061386). Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates ubiquitination of PEX5 and auto-ubiquitination of STUB1, TRAF6 and TRIM63/MURF1 (PubMed:18042044, PubMed:18359941). Ubiquitinates STUB1-associated HSP90AB1 in vitro (PubMed:18042044). Lacks inherent specificity for any particular lysine residue of ubiquitin (PubMed:18042044). Essential for viral activation of IRF3 (PubMed:19854139). Mediates polyubiquitination of CYP3A4 (PubMed:19103148).
Component of a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Interacts with RNF11.
PubMed:9362508 cloned and sequenced SFT which consisted of UBE2D1 last coding exon along with intronic sequences on the 5'-end of this exon. A function in iron transport has been described.
Ubiquitous. Up-regulated in livers of iron-overloaded patients with hereditary hemochromatosis.
Brain (at protein level) (PubMed:18953672). Ubiquitous. Highly expressed throughout the brain; detected in neurons and in neuropathological lesions, such as neurofibrillary tangles and Lewy bodies. Highly expressed in heart, placenta, pancreas, lung, liver, skeletal muscle and kidney.
Degraded during both macroautophagy and during chaperone-mediated autophagy (CMA).
Dimerization is dependent upon the central region of the protein containing the STI1 domains and is independent of its ubiquitin-like and UBA domains.
May be a prognostic marker for lung adenocarcinoma patient clinical outcome.
Monomer and homodimer (PubMed:16813565). Heterodimer with UBQLN2 (PubMed:16813565). Binds CD47, NBL1, GABRA1, GABRA2, GABRA3, GABRA6, GABRB1, GABRB2 and GABRB3 (By similarity). Binds UBE3A, BTRC, P4HB and MTOR. Interacts with the proteasome 19S subunit. Interacts (via ubiquitin-like domain) with TREX1; the interaction is direct and may control TREX1 subcellular location. Forms a complex with UBXN4 and VCP. Interacts (via UBA domain) with UBQLN4 (via ubiquitin-like domain). Found in a complex with UBQLN2 and MAP1LC3A/B/C. The monomeric form interacts with PSEN2. The monomeric form interacts with PSEN1 (PubMed:11076969, PubMed:21143716). Interacts with ORAI1. Interacts (via UBA domain) with TICAM1. Interacts with EPS15. Interacts (via UBA domain) with UBA52 and (via ubiquitin-like domain) with PSMD3 and PSMD4. Interacts with HERPUD1. Interacts with MAP1LC3A/B/C in the presence of UBQLN4. Interacts (via ubiquitin-like domain) with EPS15 (via UIM domains) and both the ubiquitinated and non-ubiquitinated forms can interact with EPS15. Interacts (via ubiquitin-like domain) with EPS15L1, HGS (via UIM domain) and STAM2 (via UIM domain). Interacts with BCL2L10/BCL-B; in the cytoplasm (PubMed:22233804).
Plays a role in unfolded protein response (UPR) by attenuating the induction of UPR-inducible genes, DDTI3/CHOP, HSPA5 and PDIA2 during ER stress (PubMed:18953672). Plays a key role in the regulation of the levels of PSEN1 by targeting its accumulation to aggresomes which may then be removed from cells by autophagocytosis (PubMed:21143716).
Plays a role in unfolded protein response (UPR) by attenuating the induction of UPR-inducible genes, DDTI3/CHOP, HSPA5 and PDIA2 during ER stress.
Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and endoplasmic reticulum-associated protein degradation (ERAD) pathway. Mediates the proteasomal targeting of misfolded or accumulated proteins for degradation by binding (via UBA domain) to their polyubiquitin chains and by interacting (via ubiquitin-like domain) with the subunits of the proteasome (PubMed:15147878). Plays a role in the ERAD pathway via its interaction with ER-localized proteins UBXN4, VCP and HERPUD1 and may form a link between the polyubiquitinated ERAD substrates and the proteasome (PubMed:19822669, PubMed:18307982). Involved in the regulation of macroautophagy and autophagosome formation; required for maturation of autophagy-related protein LC3 from the cytosolic form LC3-I to the membrane-bound form LC3-II and may assist in the maturation of autophagosomes to autolysosomes by mediating autophagosome-lysosome fusion (PubMed:19148225, PubMed:20529957, PubMed:23459205). Negatively regulates the TICAM1/TRIF-dependent toll-like receptor signaling pathway by decreasing the abundance of TICAM1 via the autophagic pathway (PubMed:21695056). Promotes the ubiquitination and lysosomal degradation of ORAI1, consequently down-regulating the ORAI1-mediated Ca2+ mobilization (PubMed:23307288). Suppresses the maturation and proteasomal degradation of amyloid beta A4 protein (A4) by stimulating the lysine 63 (K63)-linked polyubiquitination. Delays the maturation of A4 by sequestering it in the Golgi apparatus and preventing its transport to the cell surface for subsequent processing (By similarity). Ubiquitinates BCL2L10 and thereby stabilizes protein abundance (PubMed:22233804).
The UBA domain mediates binding to PSEN1 and PSEN2. It also binds ubiquitin with micromolar affinity, independently of polyubiquitin linkage type. Essential for its association with microtubule-associated protein 1 light chain 3 (MAP1LC3).
The ubiquitin-like domain mediates its association with the subunits of the proteasome.
Guanine nucleotide exchange factor (GEF), which can activate some, but not all, G-alpha proteins. Able to activate GNAI1, GNAO1 and GNAQ, but not GNAS by exchanging bound GDP for free GTP. Involved in regulation of microtubule pulling forces during mitotic movement of chromosomes by stimulating G(i)-alpha protein, possibly leading to release G(i)-alpha-GTP and NuMA proteins from the NuMA-GPSM2-G(i)-alpha-GDP complex (By similarity). Also acts as an activator for G(q)-alpha (GNAQ) protein by enhancing the G(q)-coupled receptor-mediated ERK activation.
Interacts with GDP-bound G alpha proteins GNAI1, GNAO1 and GNAQ, and with GNA13 with lower affinity. Does not interact with G-alpha proteins when they are in complex with subunits beta and gamma. Interacts (via C-terminus) with RGS14; the interaction stimulates the dissociation of the complex between RGS14 and the active GTP-bound form of GNAI1 (By similarity). Interacts with NCS1; interaction is favored in the absence of Ca(2+) and myristoylation of NCS1 is not required (PubMed:25074811, PubMed:28119500, PubMed:29966094).
Contactins mediate cell surface interactions during nervous system development. Has some neurite outgrowth-promoting activity (By similarity).
In brain, it is expressed in frontal lobe, occipital lobe, cerebellum and amygdala.
First thought to play a role in the regulation of apoptosis, mediating mitochondria-induced cell death in vascular smooth muscle cells through the release of cytochrome c (COX) from mitochondria and the activation of the caspase cascade (By similarity). However, recent studies show that it is not directly involved in apoptosis regulation but in the protection of COX from oxidatively induced degradation (PubMed:30552096, PubMed:25175347).
In conditions of increased oxidative stress, the protein is stabilized, increasing its mature intramitochondrial form and thereby protecting COX from oxidatively induced degradation.
In normal conditions, the cytoplasmic precursor protein is rapidly degraded by the ubiquitination-proteasome system (UPS). Oxidative stress induces protein stabilization and import into mitochondria where it protects COX from degradation.
It is uncertain whether Met-1 or Met-14 is the initiator. However, according to some experiments, Met-14 seems to be the initiator.
N-terminal mitochondrial targeting sequence is cleaved from the mature protein once in the mitochondrion.
Protein may not fold correctly and may be rapidly degraded.
Required for cytochrome c complex (COX) IV assembly and function Protects COX assembly from oxidation-induced degradation, COX being the terminal component of the mitochondrial respiratory chain.
Expressed in myeloma and epidermoid carcinoma cell lines.
Interacts with IRS1 and IRS2 (By similarity). Interacts (via bromo domain) with acetylated lysine residues on histone H1.4, histone H3 and H4 (in vitro).
Probable regulator of the insulin and insulin-like growth factor signaling pathways. Stimulates cell proliferation through regulation of cyclin transcription and has an anti-apoptotic activity through AKT1 phosphorylation and activation. Plays a role in the regulation of cell morphology and cytoskeletal organization.
(Microbial infection) Interacts with Epstein-Barr virus (EBV) protein EBNA1; this interaction facilitates transcriptional activation by EBNA1.
(Microbial infection) Interacts with bovine papillomavirus type 1 regulatory protein E2. This interactions may serve for the tethering of viral genomes to host mitotic chromosomes allowing successful partitioning of the viral genome during cell division.
(Microbial infection) Interacts with human herpes virus-8 (HHV-8) protein LANA.
A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUTM1 which produces a BRD4-NUTM1 fusion protein.
Acts as a chromatin insulator in the DNA damage response pathway. Inhibits DNA damage response signaling by recruiting the condensin-2 complex to acetylated histones, leading to chromatin structure remodeling, insulating the region from DNA damage response by limiting spreading of histone H2AX/H2A.x phosphorylation.
Binds acetylated histone H4 (PubMed:29176719). Interacts with p53/TP53; the interaction is direct (PubMed:23317504). Interacts (via CTD region) with CDK9 and CCNT1, acting as an associated component of P-TEFb complex (PubMed:16109376, PubMed:16109377, PubMed:23317504, PubMed:24360279). Interacts with RELA (when acetylated at 'Lys-310')(PubMed:19103749). Interacts (via NET domain) with NSD3, CHD4, BICRA and ATAD5 (PubMed:21555454, PubMed:29176719). The interaction with BICRA bridges BRD4 to the GBAF complex (PubMed:29374058, PubMed:16109376, PubMed:16109377, PubMed:19103749, PubMed:21555454, PubMed:23317504). Interacts (via NET domain) with JMJD6 (via JmjC and N-terminal domains); the interaction is stronger in presence of ssRNA and recruits JMJD6 on distal enhancers (PubMed:24360279, PubMed:21555454, PubMed:29176719). Interacts with NSD3 (PubMed:29176719). Isoform B: interacts with NCAPD3 and SMC2 (PubMed:23728299).
Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. Remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure (PubMed:23589332, PubMed:23317504, PubMed:22334664). During interphase, plays a key role in regulating the transcription of signal-inducible genes by associating with the P-TEFb complex and recruiting it to promoters. Also recruits P-TEFb complex to distal enhancers, so called anti-pause enhancers in collaboration with JMJD6. BRD4 and JMJD6 are required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P-TEFb, thereby transforming it into an active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II (PubMed:23589332, PubMed:19596240, PubMed:16109377, PubMed:16109376, PubMed:24360279). Promotes phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II (PubMed:23086925). According to a report, directly acts as an atypical protein kinase and mediates phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II; these data however need additional evidences in vivo (PubMed:22509028). In addition to acetylated histones, also recognizes and binds acetylated RELA, leading to further recruitment of the P-TEFb complex and subsequent activation of NF-kappa-B (PubMed:19103749). Also acts as a regulator of p53/TP53-mediated transcription: following phosphorylation by CK2, recruited to p53/TP53 specific target promoters (PubMed:23317504).
Does not contain the C-terminal (CTD) region required to recruit the P-TEFb complex.
Phosphorylation by CK2 disrupt the intramolecular binding between the bromo domain 2 and the NPS region and promotes binding between the NPS and the BID regions, leading to activate the protein and promote binding to acetylated histones. In absence of phosphorylation, BRD4 does not localize to p53/TP53 target gene promoters, phosphorylation promoting recruitment to p53/TP53 target promoters.
Some specific inhibitors of BRD4 that prevent binding to acetylated histones by binding Asn-140 and Asn-433 are promising therapeutic molecules for the treatment of leukemias. JQ1, a thieno-triazolo-1,4-diazepine derivative, and I-BET, a benzodiazepine derivative, have been tested on tumors with success (PubMed:20871596, PubMed:21068722, PubMed:21964340). Treatment with GSK1210151A (I-BET151, a I-BET derivative) has strong effets on mixed lineage leukemia and promotes myeloid differentiation and leukemia stem-cell depletion (PubMed:21964340).
The 2 bromo domains mediate specific binding to acetylated histones via Asn-140 and Asn-433, respectively (PubMed:20871596). The exact combination of modified histone tails required to recruit BRD4 to target genes is still unclear. The first bromo domain has high affinity for acetylated histone H4 tail, whereas the second bromo domain recognizes multiply acetylated marks in histone H3 (PubMed:22464331). A number of specific inhibitors bind competitively to acetyl-lysine-binding residues Asn-140 and Asn-433, promoting removal from acetylated histones. Many of these inhibitors are benzodiazepine derivatives (PubMed:22137933, PubMed:22136404, PubMed:23517011, PubMed:23530754).
The C-terminal (CTD) region mediates interaction and recruitment of CDK9 and CCNT1 subunits of the P-TEFb complex (PubMed:16109376, PubMed:16109377). It is also required for maintenance of higher-order chromatin structure (PubMed:22334664).
The NET domain mediates interaction with a number of chromatin proteins involved in transcription regulation (NSD3, JMJD6, CHD4, GLTSCR1 and ATAD5).
Composed of a heavy chain (beta) and a light chain (alpha). Component of an NADPH oxidase complex composed of a heterodimer formed by the membrane proteins CYBA and CYBB and the cytosolic subunits NCF1, NCF2 and NCF4. Interacts with NCF1 (via SH3 domain). Interacts with SH3PXD2A (By similarity). Interacts with DUOX1, DUOX2 and TPO. Interacts with NOX3 and NOX4. Interacts with calprotectin (S100A8/9) (PubMed:22808130). Interacts with GBP7 (By similarity).
Critical component of the membrane-bound oxidase of phagocytes that generates superoxide. Associates with NOX3 to form a functional NADPH oxidase constitutively generating superoxide.
Phosphorylation at Thr-147 enhances NADPH oxidase activity by promoting p47phox binding.
The heme prosthetic group could be coordinated with residues of the light chain, the heavy chain, or both, and it is possible that more than one heme is present per cytochrome b-245.
Ubiquitinated at Lys-149 likely by RNF145.
Core component of multiple cullin-RING-based ECS (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of target proteins (PubMed:10205047, PubMed:12004076, PubMed:12050673, PubMed:15590694, PubMed:26138980, PubMed:29779948, PubMed:29775578). This includes the von Hippel-Lindau ubiquitination complex CBC(VHL) (PubMed:10205047, PubMed:12004076, PubMed:12050673, PubMed:15590694). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes (PubMed:10205047, PubMed:12004076, PubMed:12050673, PubMed:15590694). As part of a multisubunit ubiquitin ligase complex composed of elongin BC complex (ELOB and ELOC), elongin A/ELOA, RBX1 and CUL5; polyubiquitinates monoubiquitinated POLR2A (PubMed:19920177). A number of ECS complexes (containing either KLHDC2, KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B or FEM1C as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:26138980, PubMed:29779948, PubMed:29775578). ECS(LRR1) ubiquitinates MCM7 and promotes CMG replisome disassembly by VCP and chromatin extraction during S-phase (By similarity).
Heterotrimer of an A (ELOA, ELOA2 or ELOA3P), ELOB and ELOC subunit (PubMed:10205047, PubMed:17997974). The elongin BC complex interacts with EPOP; leading to recruit the elongin BC complex to Polycomb group (PcG) target genes, thereby restricting excessive activity of the PRC2/EED-EZH2 complex (By similarity). Part of E3 ubiquitin ligase complexes with CUL5 or CUL2, RBX1 and a substrate adapter protein that can be either ASB2, KLHDC2, KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B, FEM1C, LRR1, SOCS1, SOCS5, ELOA, VHL or WSB1 (PubMed:15590694, PubMed:19413330, PubMed:22286099, PubMed:26138980, PubMed:29779948, PubMed:29775578, PubMed:34700328, PubMed:19920177). Interacts with VHL (PubMed:10205047, PubMed:11006129). Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with SPSB1 (PubMed:17189197). Interacts with KLHDC10; which may be an E3 ubiquitin ligase complex substrate recognition component (PubMed:23102700). May also interact with DCUN1D1, DCUN1D2, DCUN1D3 and DCUN1D5 (PubMed:26906416). As part of the Elongin BC E3 ubiquitin ligase complex; interacts with NRBP1 (PubMed:22510880, PubMed:11006129, PubMed:15590694, PubMed:17189197, PubMed:19920177, PubMed:22286099, PubMed:23102700, PubMed:26138980, PubMed:26906416, PubMed:29775578, PubMed:29779948, PubMed:10205047, PubMed:17997974, PubMed:34700328) (By similarity). Component of the ECS(PCMTD1) complex with the substrate recognition subunit PCMTD1 (PubMed:35486881). Interacts with PCMTD1 (via the BC-box); the interaction is direct and stabilizes PCMTD1 (PubMed:35486881).
SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex) (PubMed:7638163). In embryonic stem cells, the elongin BC complex is recruited by EPOP to Polycomb group (PcG) target genes in order generate genomic region that display both active and repressive chromatin properties, an important feature of pluripotent stem cells (By similarity).
Has a low cysteine content when compared to the majority of known KAP family members. Possesses several C-terminal tyrosine-containing tandem decameric repeat structures.
Specific expression in the middle/upper hair cuticle.
Deletion of the TJP1/ZO1 interaction motif (ZIM) decreases but does not abolish colocalization with TJP1/ZO1.
Homodimer (PubMed:11042084). Interacts with TJP1/ZO1 (PubMed:12023291). Interacts with SPEF1 (PubMed:31473225).
Localized on the cytoplasmic face of tight junctions of polarized epithelia and some endothelia. Expressed in pancreas, kidney, liver and lung, but not in skeletal muscle, placenta, brain or heart.
Probably plays a role in the formation and regulation of the tight junction (TJ) paracellular permeability barrier.
Chromosomal recombination involving RPL7A activates the receptor kinase domain of the TRK oncogene.
Component of the large ribosomal subunit (PubMed:23636399, PubMed:32669547). Interacts with CRY1 (By similarity). Interacts with DICER1, AGO2, TARBP2, MOV10 and EIF6; they form a large RNA-induced silencing complex (RISC) (PubMed:17507929).
Auto-ubiquitinated; which leads to proteasomal degradation.
E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. These substrates include FILIP1, p53/TP53, CDKN1A and TERT. Keeps cells alive by suppressing p53/TP53 under normal conditions, but stimulates apoptosis by repressing CDKN1A under stress conditions. Acts as a negative regulator of telomerase. Has negative and positive effects on RNA polymerase II-dependent transcription.
Frequently induced in esophageal squamous cell carcinoma (SCC) tissues.
Interacts with p53/TP53 and CDKN1A. Interacts with TERT, modulating telomere length homeostasis.
Belongs to the apolipoprotein C3 family.
Component of triglyceride-rich very low density lipoproteins (VLDL) and high density lipoproteins (HDL) in plasma (PubMed:18201179, PubMed:22510806). Plays a multifaceted role in triglyceride homeostasis (PubMed:18201179, PubMed:22510806). Intracellularly, promotes hepatic very low density lipoprotein 1 (VLDL1) assembly and secretion; extracellularly, attenuates hydrolysis and clearance of triglyceride-rich lipoproteins (TRLs) (PubMed:18201179, PubMed:22510806). Impairs the lipolysis of TRLs by inhibiting lipoprotein lipase and the hepatic uptake of TRLs by remnant receptors (PubMed:18201179, PubMed:22510806). Formed of several curved helices connected via semiflexible hinges, so that it can wrap tightly around the curved micelle surface and easily adapt to the different diameters of its natural binding partners (PubMed:18408013).
The most abundant glycoforms are characterized by an O-linked disaccharide galactose linked to N-acetylgalactosamine (Gal-GalNAc), further modified with up to 3 sialic acid residues. Less abundant glycoforms are characterized by more complex and fucosylated glycan moieties. O-glycosylated on Thr-94 with a core 1 or possibly core 8 glycan.
Belongs to the cyclic nucleotide phosphodiesterase family. PDE9 subfamily.
Expressed in all tissues examined (testis, brain, small intestine, skeletal muscle, heart, lung, thymus, spleen, placenta, kidney, liver, pancreas, ovary and prostate) except blood (PubMed:9624146). Highest levels in brain, heart, kidney, spleen, prostate and colon. Isoform PDE9A12 is found in prostate (PubMed:12565835). In brain, present in the cortex, cerebellum, and subiculum (at protein level) (PubMed:22328573). In heart, primarily localizes to myocytes (PubMed:25799991).
Inhibited by zaprinast; inhibitor is however not specific to PDE9A (PubMed:9624146). Specifically inhibited by BAY-73-6691 (1-(2-chlorophenyl)-6-((2R)-3,3,3- trifluoro-2-methylpropyl)-1,5-dihydro-4H-pyrazolo(3,4-d)pyrimidine-4-one) (PubMed:16150925). BAY-73-9961 has two enantiomers, (R) and (S), due to the presence of a chiral center, and both forms vary in their pattern of interaction (PubMed:20121115, PubMed:21483814). Specifically inhibited by PF-4181366 (4H-Pyrazolo[3,4-d]pyrimidin-4-one, 1- cyclopentyl-1,5-dihydro-6-[(3S,4S)-4-methyl- 1-(6-quinoxalinylmethyl)-3-pyrrolidinyl]-one) (PubMed:19919087). Specifically inhibited by PF-4449613 ((R)-6-(1-(3-phenoxyazetidin-1-yl)ethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin- 4(5H)-one) (PubMed:25799991). Specifically inhibited by inhibitor 28 (2-((1-(2-Chlorophenyl)-4-hydroxy-1Hpyrazolo[ 3,4-d]pyrimidin-6-yl)amino)-N-(4- methoxyphenyl)propanamide): inhibitor forms a hydrogen bond with Tyr-484 and Gln-513 (PubMed:22985069). Specifically inhibited by 1-Cyclopentyl-6-[(1r)-1-(3-phenoxyazetidin- 1-Yl)ethyl]-1,5-dihydro-4h-pyrazolo[3,4-D] pyrimidin-4-one: inhibitor forms a hydrogen bond with Tyr-484 and Gln-513 (PubMed:23025719).
N-(4-methoxyphenyl)-N~2~-[1-(2-methylphenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-L-alaninamide correspond to compound 28.
PDE9A is a potential target for treatment of diseases such as stress-induced heart disease or long-term memory defects. Specific inhibitors, such as BAY-73-6691 or PF-4449613 are promising candidates for clinical tests.
Specifically hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes. Highly specific: compared to other members of the cyclic nucleotide phosphodiesterase family, has the highest affinity and selectivity for cGMP (PubMed:9624146, PubMed:18757755, PubMed:21483814). Specifically regulates natriuretic-peptide-dependent cGMP signaling in heart, acting as a regulator of cardiac hypertrophy in myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in heart (PubMed:25799991). Additional experiments are required to confirm whether its ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to heart or is a general feature of the protein (Probable). In brain, involved in cognitive function, such as learning and long-term memory (By similarity).
Up-regulated in left ventricular hypertrophy from aortic stenosis and following heart failure with preserved ejection fraction (at protein level).
Autophosphorylated and phosphorylated during M-phase of the cell cycle (PubMed:9988268, PubMed:10518011, PubMed:15122335). Phosphorylated by STK3/MST2 at Ser-909 and Thr-1079, which results in its activation (PubMed:15688006). Phosphorylation at Ser-464 by NUAK1 and NUAK2 leads to decreased protein level and is required to regulate cellular senescence and cellular ploidy (PubMed:19927127).
Complexes with CDK1 in early mitosis (PubMed:9988268). LATS1-associated CDK1 has no mitotic cyclin partner and no apparent kinase activity (PubMed:9988268). Binds phosphorylated ZYX, locating this protein to the mitotic spindle and suggesting a role for actin regulatory proteins during mitosis (PubMed:10831611). Binds to and colocalizes with LIMK1 at the actomyosin contractile ring during cytokinesis (PubMed:15220930). Interacts (via PPxY motif 2) with YAP1 (via WW domains) (PubMed:18158288). Interacts with MOB1A and MOB1B (PubMed:19739119). Interacts with LIMD1, WTIP and AJUBA (PubMed:20303269). Interacts with ESR1, DCAF1 and DCAF13; probably recruits DCAF1 and DCAF13 to ESR1 to promote ESR1 ubiquitination and ubiquitin-mediated proteasomal degradation (PubMed:28068668). Interacts with STK3/MST2; this interaction is inhibited in the presence of DLG5 (PubMed:28087714). Interacts with SCRIB in the presence of DLG5 (PubMed:28169360). Interacts with WWTR1/TAZ (By similarity).
Expressed in all adult tissues examined except for lung and kidney.
Negative regulator of YAP1 in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS1 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. Acts as a tumor suppressor which plays a critical role in maintenance of ploidy through its actions in both mitotic progression and the G1 tetraploidy checkpoint. Negatively regulates G2/M transition by down-regulating CDK1 kinase activity. Involved in the control of p53 expression. Affects cytokinesis by regulating actin polymerization through negative modulation of LIMK1. May also play a role in endocrine function. Plays a role in mammary gland epithelial cell differentiation, both through the Hippo signaling pathway and the intracellular estrogen receptor signaling pathway by promoting the degradation of ESR1 (PubMed:28068668).
Prevents the interaction between CTNNB1 and TCF family members, and acts as negative regulator of the Wnt signaling pathway.
Adapter protein that links SCN10A to clathrin. Regulates SCN10A channel activity, possibly by promoting channel internalization (By similarity).
Interacts with SCN10A and clathrin. Identified in a complex containing SCN10A, clathrin and SCLT1 (By similarity).
May be involved in transcriptional regulation as a weak repressor when alone, or a potent one when fused with a heterologous protein containing a KRAB B-domain.
AMP and XMP inhibit AICAR formyltransferase activity (PubMed:10985775). AICAR formyltransferase activity is inhibited by N-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5- [(3R)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide (LSN 3213128), which acts as a tumor suppression in cancer cell lines (PubMed:29072452).
Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis (PubMed:11948179, PubMed:14756554). Acts as a transformylase that incorporates a formyl group to the AMP analog AICAR (5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide) to produce the intermediate formyl-AICAR (FAICAR) (PubMed:9378707, PubMed:11948179, PubMed:10985775). Can use both 10-formyldihydrofolate and 10-formyltetrahydrofolate as the formyl donor in this reaction (PubMed:10985775). Also catalyzes the cyclization of FAICAR to IMP (PubMed:11948179, PubMed:14756554). Is able to convert thio-AICAR to 6-mercaptopurine ribonucleotide, an inhibitor of purine biosynthesis used in the treatment of human leukemias (PubMed:10985775). Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571).
Homodimer (PubMed:14756553, PubMed:14966129). Associates with internalized INSR complexes on Golgi/endosomal membranes (PubMed:25687571). Interacts with INSR; ATIC together with PRKAA2/AMPK2 and HACD3/PTPLAD1 is proposed to be part of a signaling network regulating INSR autophosphorylation and endocytosis (PubMed:25687571).
Present in the heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas.
The IMP cyclohydrolase activity resides in the N-terminal region.
The de novo purine synthesis pathway includes 10 sequential steps, beginning with phosphoribosyl pyrophosphate and ending with inositol monophosphate (IMP), the first purin compound of the pathway.
(Microbial infection) Interacts with C.albicans GPD2; the interaction is direct and leads to the degradation of C3.
Head-to-tail homodimer and heterodimer with CFHR2 or CFHR5.
Involved in complement regulation. The dimerized forms have avidity for tissue-bound complement fragments and efficiently compete with the physiological complement inhibitor CFH. Can associate with lipoproteins and may play a role in lipid metabolism.
N-glycosylated. Two forms are observed; one with a single side chain and the other with two.
Appears in S phase, peaks in G2 phase, decreases in mitosis, lowest in early G1 phase and then accumulates again in late G1 and S phase (at protein level).
Component of the SCF(CCNF) complex consisting of CUL1, RBX1, SKP1 and CCNF (PubMed:20596027). Interacts with SKP1 (PubMed:8706131, PubMed:12122006). Interacts with CUL1 (PubMed:26818844). Interacts with CCNB1; interaction is required for nuclear localization of CCNB1 (PubMed:10716937, PubMed:20596027). Interacts with CCP110; this interaction leads to CCP110 ubiquitination and degradation via the proteasome pathway (PubMed:22441691). Interacts (via the Cyclin N-terminal domain) with MYBL2/BMYB (PubMed:25557911). Interacts with FZR1/CDH1 (via N-terminus) (PubMed:27653696). Interacts with RRM2 (via Cy motif and when phosphorylated at 'Thr-33'); the interaction occurs exclusively in G2 and early M (PubMed:22632967). Interacts with CDC6 (via Cy motif); the interaction takes place during G2 and M phase (PubMed:26818844).
Degraded when the spindle assembly checkpoint is activated during the G2-M transition. Degradation depends on the C-terminal PEST sequence.
Down-regulated in an ATR-dependent manner in response to DNA damage induced by doxorubicin, camptothecin, UV-C, methyl methanesulfonate, nocodazole, or gamma-irradiation. Down-regulation in response to DNA damage is required to allow RRM2 accumulation within the nucleus and for efficient DNA repair.
Founding member of the F-box domain protein family, which obtained its name from cyclin-F.
Member of the cyclin family, however, unlike most members of the cyclin family, it does not bind or activate a cyclin-dependent kinase.
Phosphorylated just before cells enter into mitosis.
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:20596027, PubMed:22632967, PubMed:27653696, PubMed:26818844, PubMed:27080313, PubMed:28852778). The SCF(CCNF) E3 ubiquitin-protein ligase complex is an integral component of the ubiquitin proteasome system (UPS) and links proteasome degradation to the cell cycle (PubMed:8706131, PubMed:20596027, PubMed:27653696, PubMed:26818844). Mediates the substrate recognition and the proteasomal degradation of various target proteins involved in the regulation of cell cycle progression and in the maintenance of genome stability (PubMed:20596027, PubMed:22632967, PubMed:27653696, PubMed:26818844). Mediates the ubiquitination and proteasomal degradation of CP110 during G2 phase, thereby acting as an inhibitor of centrosome reduplication (PubMed:20596027). In G2, mediates the ubiquitination and subsequent degradation of ribonucleotide reductase RRM2, thereby maintaining a balanced pool of dNTPs and genome integrity (PubMed:22632967). In G2, mediates the ubiquitination and proteasomal degradation of CDC6, thereby suppressing DNA re-replication and preventing genome instability (PubMed:26818844). Involved in the ubiquitination and degradation of the substrate adapter CDH1 of the anaphase-promoting complex (APC/C), thereby acting as an antagonist of APC/C in regulating G1 progression and S phase entry (PubMed:27653696). May play a role in the G2 cell cycle checkpoint control after DNA damage, possibly by promoting the ubiquitination of MYBL2/BMYB (PubMed:25557911).
The D box motifs 1-5 (amino acid sequence RxxL) are involved in substrate binding, such as FZR1/CDH1, and may be ubiquitinated.
The nuclear localization signals mediate the localization to the nucleus and are required for CCNB1 localization to the nucleus.
Ubiquitinated by the anaphase-promoting complex (APC/C); leading to its degradation by the proteasome.
Widely expressed, with expression detected in the heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
May regulate the dynamics and distribution of mitochondria in neural cells.
A cytochrome P450 monooxygenase involved in the metabolism of endogenous polyunsaturated fatty acids (PUFAs) and their oxygenated derivatives (oxylipins). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase). Catalyzes the hydroxylation of carbon hydrogen bonds, with preference for omega-1 and omega-2 positions (PubMed:10791960, PubMed:16112640, PubMed:15789615). Hydroxylates (5Z,8Z,11Z,14Z)-eicosatetraenoic acid (arachidonate) predominantly at omega-2 position to form (18R)-hydroxyeicosatetraenoic acid (18R-HETE) (PubMed:10791960). Exhibits omega-1 hydroxylase activity toward prostaglandin (PG) H1, PGH2 and PGI2 (PubMed:10791960, PubMed:15789615). Catalyzes the epoxidation of double bonds of PUFAs, including docosahexaenoic and docosapentaenoic acids (PubMed:16112640). Shows little activity against PGD2, PGE1, PGE2, PGF2alpha, and leukotriene B4.
Expressed in the epithelium of seminal vesicles, in renal cortex, in adult and fetal liver, in epidermis, in corneal epithelium, in sweat glands, hair follicles, epithelial linings of the ampulla of vas deferens and of the stomach and small intestine, as well as in the transitional epithelium of the bladder and ureter (at protein level). In the epidermis, expressed from the basal cell to the granular cell layers. In the corneal epithelium, expressed in all cell layers. Also detected in prostate. Up-regulated in the epidermis of psoriatic lesions.
May be involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors.
Associates with components of the mitochondrial respiratory chain complex I.
Required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) (PubMed:20858599, PubMed:25678554). Involved in mid-late stages of complex I assembly (PubMed:25678554).
Component of a complex which is at least composed of HTATSF1/Tat-SF1, the P-TEFb complex components CDK9 and CCNT1, RNA polymerase II, SUPT5H, and NCL/nucleolin. Interacts with GTF2F2/RAP30 and POLR2A. Interacts with TCERG1/CA150. Interacts with SF3A2/SAP62 and the spliceosomal U small nuclear ribonucleoproteins (snRNPs).
Functions as a general transcription factor playing a role in the process of transcriptional elongation. May mediate the reciprocal stimulatory effect of splicing on transcriptional elongation. In case of infection by HIV-1, it is up-regulated by the HIV-1 proteins NEF and gp120, acts as a cofactor required for the Tat-enhanced transcription of the virus.
The RRM domains mediate interaction with U snRNPs.
Defects in GALNTL5 have been found in a patient with primary infertility due to asthenozoospermia.
In contrast to other members of the family, lacks the C-terminal ricin B-type lectin domain, which contributes to the glycopeptide specificity. No glycosyltransferase activity has been detected in an in vitro assay (PubMed:24398516).
Mainly expressed in testis. Weakly or not expressed in other tissues.
Probable inactive glycosyltransferase required during spermatid development. May participate in protein loading into the acrosomes and accumulation of ubiquitin-proteasome systems around the head-tail coupling apparatus region.
At least 5 different SAA1 alleles have been described: SAA1.1 (SAA1alpha), SAA1.2 (SAA1beta), SAA1.3 (SAA1gamma), SAA1.4 (SAA1delta), SAA1.5 (also named SAA1beta but which differs from SAA1.2). We use here the revised nomenclature described in PubMed:10211414. The sequence shown is that of SAA1.1.
Elevated serum SAA1 protein levels may be associated with lung cancer.
Expressed by the liver; secreted in plasma (at protein level).
Homohexamer; dimer of trimers. Can form amyloid fibrils after partial proteolysis; the native, undenatured protein does not form amyloid fibrils (in vitro). Apolipoprotein of the HDL complex. Binds to heparin.
Reactive, secondary amyloidosis is characterized by the extracellular accumulation in various tissues of the SAA1 protein. These deposits are highly insoluble and resistant to proteolysis; they disrupt tissue structure and compromise function.
This protein is the precursor of amyloid protein A, which is formed by the removal of approximately 24 residues from the C-terminal end.
Does not bind to cimetidine and tripolidine. Shows modest affinity for thioperamide, imetit, N-alpha-methylhistamine and R(-)-alpha-methylhistamine. Isoform 4 is unable to bind to iodoproxyfan while isoforms 1 and 3 bind it with high affinity.
Expressed predominantly in the CNS, with the greatest expression in the thalamus and caudate nucleus. The various isoforms are mainly coexpressed in brain, but their relative expression level varies in a region-specific manner. Isoform 3 and isoform 7 are highly expressed in the thalamus, caudate nucleus and cerebellum while isoform 5 and isoform 6 show a poor expression. Isoform 5 and isoform 6 show a high expression in the amygdala, substantia nigra, cerebral cortex and hypothalamus. Isoform 7 is not found in hypothalamus or substantia nigra.
The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist). Agonist stimulation of isoform 3 neither modified adenylate cyclase activity nor induced intracellular calcium mobilization.
Binds Ca(2+) via the C2 domains in absence of phospholipids.
Calcium sensor which is essential for the stabilization of normal baseline neurotransmitter release and for the induction and long-term maintenance of presynaptic homeostatic plasticity.
Heterooligomer with MCU; this reduces MCU channel activity. Homooligomer (By similarity). Component of the uniplex complex, composed of MCU, MCUB, MICU1, MICU2 and EMRE/SMDT1.
Negatively regulates the activity of MCU, the mitochondrial inner membrane calcium uniporter, and thereby modulates calcium uptake into the mitochondrion. Does not form functional calcium channels by itself. Mitochondrial calcium homeostasis plays key roles in cellular physiology and regulates cell bioenergetics, cytoplasmic calcium signals and activation of cell death pathways.
NODAL coreceptor involved in the correct establishment of the left-right axis. May play a role in mesoderm and/or neural patterning during gastrulation.
This gene differs from CFC1B by only one residue at position 78:R -> W. R78W is also thought to be a CFC1 polymorphism which has been shown to lead to a different cell surface distribution and activity (PubMed:11799476, PubMed:11062482).
Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols. Displays enzymatic activity towards endogenous metabolites such as aromatic and aliphatic aldehydes, ketones, monosacharides, bile acids and xenobiotics substrates. Key enzyme in the polyol pathway, catalyzes reduction of glucose to sorbitol during hyperglycemia (PubMed:1936586). Reduces steroids and their derivatives and prostaglandins. Displays low enzymatic activity toward all-trans-retinal, 9-cis-retinal, and 13-cis-retinal (PubMed:12732097, PubMed:19010934, PubMed:8343525). Catalyzes the reduction of diverse phospholipid aldehydes such as 1-palmitoyl-2-(5-oxovaleroyl)-sn -glycero-3-phosphoethanolamin (POVPC) and related phospholipid aldehydes that are generated from the oxydation of phosphotidylcholine and phosphatdyleethanolamides (PubMed:17381426). Plays a role in detoxifying dietary and lipid-derived unsaturated carbonyls, such as crotonaldehyde, 4-hydroxynonenal, trans-2-hexenal, trans-2,4-hexadienal and their glutathione-conjugates carbonyls (GS-carbonyls) (PubMed:21329684).
Cys-299 may regulate the kinetic and inhibition properties of the enzyme, but does not participate in catalysis (PubMed:8343525). Tolrestat inhibits retinal reduction (PubMed:12732097).
Highly expressed in embryonic epithelial cells (EUE) in response to osmotic stress.
Abundant in the cervix. Moderately abundant in the uterus and fetal skin. Expression is markedly increased in psoriatic skin (18.5 fold increase in comparison with normal skin) and its overexpression alters the protein composition of cornified cell envelope (CE), but does not affect keratinocyte differentiation. Expressed in the granular cell layer of epidermis in uninvolved psoriatic skin and in the psoriatic lesions it is found in the upper-spinous layer. Increased expression also seen in atopic dermatitis (14.3 fold increase in comparison with normal skin) and mycosis fungoides (4.6 fold increase in comparison with normal skin) and in both conditions expressed in the granular cell layer of epidermis.
Directly or indirectly cross-linked to CE proteins loricin and involucrin (IVL).
Belongs to the peptidase M24A family. Methionine aminopeptidase eukaryotic type 2 subfamily.
Binds 2 divalent metal cations per subunit. Has a high-affinity and a low affinity metal-binding site. The true nature of the physiological cofactor is under debate. The enzyme is active with cobalt, zinc, manganese or divalent iron ions. Most likely, methionine aminopeptidases function as mononuclear Fe(2+)-metalloproteases under physiological conditions, and the catalytically relevant metal-binding site has been assigned to the histidine-containing high-affinity site. Also manganese has been proposed to be the physiological cofactor for human METAP2.
Binds EIF2S1 at low magnesium concentrations. Interacts strongly with the eIF-2 gamma-subunit EIF2S3.
Contains approximately 12 O-linked N-acetylglucosamine (GlcNAc) residues. O-glycosylation is required for EIF2S1 binding.
Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val).
Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). The catalytic activity of human METAP2 toward Met-Val peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N-terminal Met-Val and Met-Thr sequences in vivo.
Interacts strongly with the eIF-2 gamma-subunit EIF2S3 (By similarity). Binds EIF2S1 at low magnesium concentrations.
Protects eukaryotic initiation factor EIF2S1 from translation-inhibiting phosphorylation by inhibitory kinases such as EIF2AK2/PKR and EIF2AK1/HCR. Plays a critical role in the regulation of protein synthesis.
Expressed primarily in the subendothelium of large blood vessels. Also expressed in arterioles and venules in muscle, heart, kidney, spleen, umbilical cord, liver and lung and is also found in connective tissue layers around hair follicles, around nerve bundles in muscle, in the dura of the optic nerve, in cornea and sclera, and in the perichondrium of cartilaginous tissues. In the kidney, expressed in mesangial cells, glomerular endothelial cells, and tubular epithelial cells. Also expressed in mast cells, and in astrocytes during the repair process. Expressed in Descemet's membrane. Specifically expressed in peritoneal fibroblasts and mesothelial cells.
Four consecutive Gly-Pro-Pro triplets are present at the C-terminus of the triple-helical region. These may provide the high thermal stability of this region.
Homotrimers, or heterotrimers in association with alpha 2(VIII) type collagens. Four homotrimers can form a tetrahedron stabilized by central interacting C-terminal NC1 trimers.
Macromolecular component of the subendothelium. Major component of the Descemet's membrane (basement membrane) of corneal endothelial cells. Also a component of the endothelia of blood vessels. Necessary for migration and proliferation of vascular smooth muscle cells and thus, has a potential role in the maintenance of vessel wall integrity and structure, in particular in atherogenesis.
Proteolytically cleaved by neutrophil elastase, in vitro. Proteolytic processing produces the C-terminal NC1 domain fragment, vastatin.
Up-regulated during vascular injury, in atherosclerosis and in diabetes.
Vastatin, the C-terminal fragment comprising the NC1 domain, inhibits aortic endothelial cell proliferation and causes cell apoptosis.
Part of the TFIIIC subcomplex TFIIIC2, consisting of six subunits, GTF3C1, GTF3C2, GTF3C3, GTF3C4, GTF3C5 and GTF3C6. Interacts with BRF1, GTF3C6 and TBP.
Highly expressed in spleen, lymph nodes, lung and placenta. Expressed at moderate level in thymus, kidney, heart and digestive tract. Weakly expressed in other lymphoid tissues. Detected in T-cells.
By cytokines (TNF-alpha and interleukin-1) in acute monocytic leukemia cell line THP-1 cells.
Cell cycle-regulated with highest level in G2 phase.
HeLa cells with a reduced level of PDS5A show a mild defect in sister chromatid cohesion. HeLa cells with a reduced level of RAD21 show reduced association of PDS5A with chromatin.
Highest level in colon. Low levels in lung, ovary, breast and kidney. Reduced level in renal tumor tissue. Isoform 2 is expressed in kidney.
Interacts with the cohesin complex. Interacts with WAPL (via FGF motifs) or CDCA5 (via the FGF motif); the interaction is direct, cohesin-dependent and competitive. Interacts with SMC3. Interacts with TP63.
Probable regulator of sister chromatid cohesion in mitosis which may stabilize cohesin complex association with chromatin. May couple sister chromatid cohesion during mitosis to DNA replication. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair.
Barely detectable in differentiated tissues. Expressed in embryonic stem cells and in other dividing cells, such as some tumor cell lines.
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits (By similarity). RPC3/POLR3C, RPC6/POLR3F and RPC7/POLR3G form a Pol III subcomplex. Directly interacts with POLR3C/RPC62 (PubMed:21358628, PubMed:24107381, PubMed:26394183). Also found a trimeric complex with POLR3C and POLR3GL (PubMed:24107381).
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Specific peripheric component of RNA polymerase III which synthesizes small RNAs, such as 5S rRNA and tRNAs (PubMed:20154270). May direct with other members of the RPC3/POLR3C-RPC6/POLR3F-RPC7/POLR3G subcomplex RNA Pol III binding to the TFIIIB-DNA complex via the interactions between TFIIIB and POLR3F. May be involved either in the recruitment and stabilization of the subcomplex within RNA polymerase III, or in stimulating catalytic functions of other subunits during initiation. Plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs), induce type I interferon and NF- Kappa-B through the RIG-I pathway (PubMed:19609254, PubMed:19631370).
Down-regulated in embryonic stem cells upon differentiation into embroid bodies (at protein level) (PubMed:20154270, PubMed:21898682, PubMed:28494942). An analogous down-regulation is observed during differentiation of induced pluripotent stem cells (PubMed:21898682).
Induced by NANOG and POU5F1/OCT4 (PubMed:21898682). Negatively regulated by the interaction of microRNA MIR1305 with 3 miRNA responsive elements (miREs) in its 3'-UTR (PubMed:27339422).
Component of the STAGA transcription coactivator-HAT complex, at least composed of SUPT3H, GCN5L2, TAF5L, TAF6L, SUPT7L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9.
Probably involved in transcriptional regulation.
Expressed in skeletal muscle, lower levels in thymus and brain.
Putative tumor suppressor gene that may be implicated in the origin and progression of lung cancer.
(Microbial infection) In case of infection by Herpesvirus saimiri, may play a role in vesicular transport or membrane fusion events necessary for transport to lysosomes. Induces lysosomal vesicle formation via interaction with Herpesvirus saimiri tyrosine kinase-interacting protein (TIP). Subsequently, TIP recruits tyrosine-protein kinase LCK, resulting in down-regulation of T-cell antigen receptor TCR. May play a role in generation of enlarged endosomal vesicles via interaction with TIP (PubMed:12196293). In case of infection by papillomavirus HPV11, promotes the maintenance of the viral genome via its interaction with HPV11 helicase E1 (PubMed:18032488).
(Microbial infection) Interacts with Saimiriine herpesvirus TIP protein.
(Microbial infection) Interacts with human cytomegalovirus protein UL138.
(Microbial infection) Interacts with papillomavirus HPV11 E1 protein.
Interacts with USP46 (PubMed:19075014, PubMed:26388029). Interacts with USP1 (PubMed:18082604, PubMed:26388029). Interacts with USP12 (PubMed:19075014, PubMed:27650958, PubMed:27373336). Component of the USP12-WDR20-WDR48 deubiquitinating complex (PubMed:27373336). Interacts with PHLPP1 (PubMed:24145035). Interacts with RAD51AP1; the interaction is direct and promotes formation of a trimeric complex with RAD51 via RAD51AP1 (PubMed:27463890, PubMed:27239033). Interacts with ATAD5; the interaction regulates USP1-mediated PCNA deubiquitination (PubMed:20147293). Interacts with RAD51; the interaction is enhanced under replication stress (PubMed:31844045).
Knockdown of WDR48 increases Akt activation.
N-terminal WD region interacts with TIP and C-terminal region mediates lysosomal localization (Probable). The WD repeats are required for the interaction with deubiquitinating enzymes USP1, USP12 and USP46.
Regulator of deubiquitinating complexes, which acts as a strong activator of USP1, USP12 and USP46 (PubMed:18082604, PubMed:19075014, PubMed:31253762, PubMed:26388029). Enhances the USP1-mediated deubiquitination of FANCD2; USP1 being almost inactive by itself (PubMed:18082604, PubMed:31253762). Activates deubiquitination by increasing the catalytic turnover without increasing the affinity of deubiquitinating enzymes for the substrate (PubMed:19075014, PubMed:27373336). Also activates deubiquitinating activity of complexes containing USP12 (PubMed:19075014, PubMed:27650958, PubMed:27373336). In complex with USP12, acts as a potential tumor suppressor by positively regulating PHLPP1 stability (PubMed:24145035). Docks at the distal end of the USP12 fingers domain and induces a cascade of structural changes leading to the activation of the enzyme (PubMed:27650958, PubMed:27373336). Together with RAD51AP1, promotes DNA repair by stimulating RAD51-mediated homologous recombination (PubMed:27463890, PubMed:27239033, PubMed:32350107). Binds single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) (PubMed:27239033, PubMed:31253762, PubMed:32350107). DNA-binding is required both for USP1-mediated deubiquitination of FANCD2 and stimulation of RAD51-mediated homologous recombination: both WDR48/UAF1 and RAD51AP1 have coordinated role in DNA-binding during these processes (PubMed:31253762, PubMed:32350107). Together with ATAD5 and by regulating USP1 activity, has a role in PCNA-mediated translesion synthesis (TLS) by deubiquitinating monoubiquitinated PCNA (PubMed:20147293). Together with ATAD5, has a role in recruiting RAD51 to stalled forks during replication stress (PubMed:31844045).
Interacts with spectrin via SPTBN1; the interaction is direct (PubMed:24117850). Interacts with calmodulin; calcium-dependent it prevents interaction with spectrin (PubMed:24117850).
Key microtubule-organizing protein that specifically binds the minus-end of non-centrosomal microtubules and regulates their dynamics and organization (PubMed:19508979, PubMed:21834987, PubMed:24486153, PubMed:24706919, PubMed:24117850). Specifically recognizes growing microtubule minus-ends and stabilizes microtubules (PubMed:24486153, PubMed:24706919). Acts on free microtubule minus-ends that are not capped by microtubule-nucleating proteins or other factors and protects microtubule minus-ends from depolymerization (PubMed:24486153, PubMed:24706919). In contrast to CAMSAP2 and CAMSAP3, tracks along the growing tips of minus-end microtubules without significantly affecting the polymerization rate: binds at the very tip of the microtubules minus-end and acts as a minus-end tracking protein (-TIP) that dissociates from microtubules after allowing tubulin incorporation (PubMed:24486153, PubMed:24706919). Through interaction with spectrin may regulate neurite outgrowth (PubMed:24117850).
Detected in cerebrospinal fluid (at protein level) (PubMed:25326458). Brain.
May modulate neuronal adhesion and neurite growth during development by binding to neural cell adhesion molecules (NG-CAM and N-CAM). Chondroitin sulfate proteoglycan; binds to hyaluronic acid.
O-glycosylated; contains chondroitin sulfate.
May function in cell specification, particularly in the CNS.
Constitutively phosphorylated at Ser-412 in the cytoplasm. At the plasma membrane, is rapidly dephosphorylated, a process that is required for clathrin binding and ADRB2 endocytosis but not for ADRB2 binding and desensitization. Once internalized, is rephosphorylated.
Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Involved in internalization of P2RY4 and UTP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 ands subsequent recycling. Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). ERK1/2 activated by the beta-arrestin scaffold is largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Recruits c-Src/SRC to ADRB2 resulting in ERK activation. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Inhibits ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Is required for SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to internalized NK1R resulting in ERK1/2 activation, which is required for the antiapoptotic effects of SP. Is involved in proteinase-activated F2RL1-mediated ERK activity. Acts as signaling scaffold for the AKT1 pathway. Is involved in alpha-thrombin-stimulated AKT1 signaling. Is involved in IGF1-stimulated AKT1 signaling leading to increased protection from apoptosis. Involved in activation of the p38 MAPK signaling pathway and in actin bundle formation. Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. May serve as nuclear messenger for GPCRs. Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. Involved in regulation of LEF1 transcriptional activity via interaction with DVL1 and/or DVL2 Also involved in regulation of receptors other than GPCRs. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) (By similarity). Involved in IL8-mediated granule release in neutrophils. Required for atypical chemokine receptor ACKR2-induced RAC1-LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. Involved in the internalization of the atypical chemokine receptor ACKR3. Negatively regulates the NOTCH signaling pathway by mediating the ubiquitination and degradation of NOTCH1 by ITCH. Participates in the recruitment of the ubiquitin-protein ligase to the receptor (PubMed:23886940).
Monomer. Homodimer. Homooligomer; the self-association is mediated by InsP6-binding. Heterooligomer with ARRB2; the association is mediated by InsP6-binding. Interacts with GPR143. Interacts with ADRB2 (phosphorylated). Interacts with CHRM2 (phosphorylated). Interacts with LHCGR. Interacts with CYTH2 and CASR. Interacts with AP2B1 (dephosphorylated at 'Tyr-737'); phosphorylation of AP2B1 at 'Tyr-737' disrupts the interaction. Interacts (dephosphorylated at Ser-412) with CLTC. Interacts with CCR2 and GRK2. Interacts with CRR5. Interacts with PTAFR (phosphorylated on serine residues). Interacts with CLTC and MAP2K3. Interacts with CREB1. Interacts with TRAF6. Interacts with IGF1R and MDM2. Interacts with C5AR1. Interacts with PDE4D. Interacts with SRC (via the SH3 domain and the protein kinase domain); the interaction is independent of the phosphorylation state of SRC C-terminus. Interacts with TACR1. Interacts with RAF1. Interacts with CHUK, IKBKB and MAP3K14. Interacts with DVL1; the interaction is enhanced by phosphorylation of DVL1. Interacts with DVL2; the interaction is enhanced by phosphorylation of DVL2. Interacts with IGF1R. Associates with MAP kinase p38. Part of a MAPK signaling complex consisting of TACR1, ARRB1, SRC, MAPK1 (activated) and MAPK3 (activated). Part of a MAPK signaling complex consisting of F2RL1, ARRB1, RAF1, MAPK1 (activated) and MAPK3 (activated) (By similarity). Interacts with MAP2K4/MKK4. Interacts with HCK and CXCR1 (phosphorylated). Interacts with ACKR3 and ACKR4. Interacts with ARRDC1; the interaction is direct (PubMed:23886940). Interacts with GPR61, GPR62 and GPR135 (PubMed:28827538).
The C-terminus binds InsP6 with high affinity.
The N-terminus binds InsP6 with low affinity.
The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1 (By similarity). Binding to phosphorylated GPCRs induces a conformationanl change that exposes the motif to the surface.
The ubiquitination status appears to regulate the formation and trafficking of beta-arrestin-GPCR complexes and signaling. Ubiquitination appears to occur GPCR-specific. Ubiquitinated by MDM2; the ubiquitination is required for rapid internalization of ADRB2. Deubiquitinated by USP33; the deubiquitination leads to a dissociation of the beta-arrestin-GPCR complex. Stimulation of a class A GPCR, such as ADRB2, induces transient ubiquitination and subsequently promotes association with USP33.
Interacts (GTP-bound form) with MICALL1; regulates RAB8A association with recycling endosomes (By similarity). Interacts with MICALL2; competes with RAB13 and is involved in E-cadherin endocytic recycling (By similarity). Interacts (GTP-bound form) with MICAL1, MICALCL, MICAL3, EHBP1 and EHBP1L1; at least in case of MICAL1, MICALCL, MICAL3 and EHBP1L1 two molecules of RAB8A can bind to one molecule of the effector protein; ternary complexes of RAB8A, RAB13 and either MICAL1 or EHBP1L1 are possible (PubMed:27552051). Interacts with EHD1 (PubMed:19864458). Interacts with MAP4K2 and SYTL4 (By similarity). Interacts with SGSM1 and SGSM3 (By similarity). Interacts with RABIF, RIMS2, RPH3A and RPH3A (By similarity). Interacts with OPTN (PubMed:15837803). Interacts with RAB3IP (PubMed:12221131). Interacts with MYO5B (PubMed:21282656). Interacts with CIMAP3 (PubMed:20643351). Interacts with BIRC6/bruce (PubMed:18329369). Interacts with OCRL (PubMed:22543976, PubMed:21378754). Interacts with AHI1 (By similarity). Interacts with DCDC1 (PubMed:22159412). Interacts with LRRK2; interaction facilitates phosphorylation of Thr-72 (PubMed:26824392). Interacts with RAB31P, GDI1, GDI2, CHM, CHML, RABGGTA, RABGGTB, TBC1D15 and INPP5B; these interactions are dependent on Thr-72 not being phosphorylated (PubMed:26824392, PubMed:29125462). Interacts with RILPL1 and RILPL2; these interactions are dependent on the phosphorylation of Thr-72 by LRRK2 (PubMed:29125462, PubMed:30398148). Interacts with DZIP1; prevents inhibition by the GDP-dissociation inhibitor GDI2 (PubMed:25860027).
Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase (Probable). Activated in response to insulin (By similarity).
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. That Rab is involved in polarized vesicular trafficking and neurotransmitter release. Together with RAB11A, RAB3IP, the exocyst complex, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis (PubMed:20890297). Regulates the compacted morphology of the Golgi (PubMed:26209634). Together with MYO5B and RAB11A participates in epithelial cell polarization (PubMed:21282656). Also involved in membrane trafficking to the cilium and ciliogenesis (PubMed:21844891, PubMed:30398148). Together with MICALL2, may also regulate adherens junction assembly (By similarity). May play a role in insulin-induced transport to the plasma membrane of the glucose transporter GLUT4 and therefore play a role in glucose homeostasis (By similarity). Involved in autophagy (PubMed:27103069).
Belongs to the glycosyltransferase 17 family.
Expression is up-regulated by CDH1/E-cadherin-mediated cell-cell interaction.
It is involved in the regulation of the biosynthesis and biological function of glycoprotein oligosaccharides. Catalyzes the addition of N-acetylglucosamine in beta 1-4 linkage to the beta-linked mannose of the trimannosyl core of N-linked sugar chains, called bisecting N-acetylglucosamine (GlcNAc). It is one of the most important enzymes involved in the regulation of the biosynthesis of glycoprotein oligosaccharides. The addition of this bisecting GlcNAc residue alters not only the composition, but also the conformation of the N-glycan. The introduction of the bisecting GlcNAc residue results in the suppression of further processing and elongation of N-glycans, precluding the formation of beta-1,6 GlcNAc branching, catalyzed by MGAT5 since it is unable to use the bisected oligosaccharide as a substrate (PubMed:19403558). Addition of bisecting N-acetylglucosamine to CDH1/E-cadherin modulates CDH1 cell membrane location (PubMed:19403558). Inhibits NeuAc-alpha-2,3-Gal-beta-1,4-GlcNAc- formation which modulates sialylation levels and plays a role in cell migration regulation (PubMed:26801611). In brain, addition of bisecting N-acetylglucosamine to BACE1 blocks its lysosomal targeting in response to oxidative stress and further degradation which increases its location to early endosome and the APP cleavage (By similarity).
Functions as a negative regulator of TGF-beta signaling and thereby probably plays a role in cell proliferation, differentiation, apoptosis, motility, extracellular matrix production and immunosuppression. In the canonical TGF-beta pathway, ZFYVE9/SARA recruits the intracellular signal transducer and transcriptional modulators SMAD2 and SMAD3 to the TGF-beta receptor. Phosphorylated by the receptor, SMAD2 and SMAD3 then form a heteromeric complex with SMAD4 that translocates to the nucleus to regulate transcription. Through interaction with SMAD2 and SMAD3, LDLRAD4 may compete with ZFYVE9 and SMAD4 and prevent propagation of the intracellular signal.
Interacts with PMEPA1. Interacts (via the SMAD interaction motif) with SMAD2 and SMAD3.
The SMAD interaction motif is required for interaction with SMAD2 and SMAD3 and the negative regulation of TGF-beta signaling.
Expressed most abundantly in the brain at protein level. Present in cortex, cerebellum and midbrain. Found in neurons. Elevated expressions detected in Alzheimer brain samples. Also expressed in testis.
Originated from non-coding DNA sequences (insertion of repeat elements especially Alu). Seems to exist only in human.
Forms homodimers and heterodimers with liprins-alpha and liprins-beta (PubMed:9624153). Interacts with the second PTPase domain of PTPRD, PTPRF and PTPRS (PubMed:9624153). Binds RIMS1, RIMS2, RIMS3 and RIMS4 (By similarity).
Predominantly expressed in brain (PubMed:9624153). Also detected in sperm (at protein level) (PubMed:23124857).
EF-1 binds magnesium constitutively under physiological conditions, EF-3 and EF-4 bind calcium cooperatively and EF-2 binds neither calcium nor magnesium.
Homodimer; when bound to calcium or magnesium. Interacts (via C-terminus) with ITPR1, ITPR2 and ITPR3. This binding is calcium dependent and the interaction correlates with calcium concentration. An additional calcium-independent interaction with the N-terminus of ITPR1 results in a decreased InsP(3) binding to the receptor. Interacts with CACNA1A (via C-terminal CDB motif) in the pre- and postsynaptic membranes. Interacts with CACNA1C (via C-terminal C and IQ motifs). The binding to the C motif is calcium independent whereas the binding to IQ requires the presence of calcium and is mutually exclusive with calmodulin binding. Interacts with CACNA1D (By similarity). Interacts with TRPC5 (via C-terminus). Interacts (via EF-hands 1 and 2) at microtubules with MAP1LC3B. Interacts with MYO1C (By similarity). Interacts (via EF-hands 1 and 2) with NSMF (via the central NLS-containing motif region), the interaction occurs in a calcium dependent manner after synaptic NMDA receptor stimulation and prevents nuclear import of NSMF. Interacts with SPACA9 (By similarity).
It is currently uncertain whether calbrain represent a spliced isoform.
Modulates calcium-dependent activity of inositol 1,4,5-triphosphate receptors (ITPRs)(PubMed:14570872). Inhibits agonist-induced intracellular calcium signaling (PubMed:15980432). Enhances inactivation and does not support calcium-dependent facilitation of voltage-dependent P/Q-type calcium channels (PubMed:11865310). Causes calcium-dependent facilitation and inhibits inactivation of L-type calcium channels by binding to the same sites as calmodulin in the C-terminal domain of CACNA1C, but has an opposite effect on channel function (PubMed:15140941). Suppresses the calcium-dependent inactivation of CACNA1D (By similarity). Inhibits TRPC5 channels (PubMed:15895247). Prevents NMDA receptor-induced cellular degeneration. Required for the normal transfer of light signals through the retina (By similarity).
Phosphorylated. The phosphorylation regulates the activity.
Retina and brain. Somatodendritic compartment of neurons. Calbrain was found exclusively in brain where it is abundant in the hippocampus, habenular area in the epithalamus and in the cerebellum.
The interaction with CACNA1A is described as calcium independent in PubMed:11865310 while it is shown to be acutely calcium dependent in PubMed:14570872. PubMed:12032348 describes a stimulatory effect of CABP1 during agonist-induced intracellular calcium signaling while PubMed:14570872 and PubMed:11865310 show an inhibitory effect.
Genetic variations in NRTN may contribute to Hirschsprung disease, in association with mutations of RET gene, and possibly mutations in other loci. Hirschsprung disease is a disorder of neural crest development is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.
Supports the survival of sympathetic neurons in culture. May regulate the development and maintenance of the CNS. Might control the size of non-neuronal cell population such as haemopoietic cells.
Catalyzes the three-step monooxygenation required for the demethylation of 4,4-dimethyl and 4alpha-methylsterols, which can be subsequently metabolized to cholesterol (PubMed:21285510, PubMed:28673550, PubMed:23583456, PubMed:26114596). Also involved in drug metabolism, as it can metabolize eldecalcitol (ED-71 or 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)-cholecalciferol), a second-generation vitamin D analog, into 1alpha,2beta,25-trihydroxy vitamin D3; this reaction occurs via enzymatic hydroxylation and spontaneous O-dehydroxypropylation (PubMed:26038696).
Acts as component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. Core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built (PubMed:32453425, PubMed:34694004, PubMed:34700328, PubMed:35585232, PubMed:16899510, PubMed:9305914). The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity (PubMed:32453425).
Component of the MCM2-7 complex (PubMed:16899510, PubMed:17296731, PubMed:9305914). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (PubMed:16899510, PubMed:17296731, PubMed:9305914, PubMed:32453425, PubMed:34700328, PubMed:34694004). Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex (PubMed:34700328, PubMed:34694004, PubMed:32453425). May interact with MCM10 (PubMed:11095689). Interacts with TIPIN (PubMed:17116885). Interacts with CDT1 (PubMed:20202939). Interacts with MCMBP (PubMed:17296731). Interacts with DDI2 (PubMed:29290612).
Intronic variations in MCM6 upstream from the LCT gene are associated with adult-type hypolactasia [MIM:223100] leading to lactose intolerance, or with lactase persistance. Lactose intolerance is a normal physiological phenomenon caused by developmental down-regulation of lactase activity during childhood or early adulthood. A non-coding variation in MCM6 affects the transcriptional regulation of the LCT gene resulting in down-regulation of lactase activity. However, the majority of Northern Europeans and some African populations have the ability to maintain lactase activity and digest lactose throughout life (lactase persistence).
(Microbial infection) Interacts with vaccinia virus protein A36 (PubMed:27670116).
Adapter protein that provides a link between the endocytic membrane traffic and the actin assembly machinery (PubMed:11584276, PubMed:29887380). Acts as guanine nucleotide exchange factor (GEF) for CDC42, and thereby stimulates actin nucleation mediated by WASL and the ARP2/3 complex (PubMed:11584276). Plays a role in the assembly and maturation of clathrin-coated vesicles (By similarity). Recruits FCHSD2 to clathrin-coated pits (PubMed:29887380). Involved in endocytosis of activated EGFR, and probably also other growth factor receptors (By similarity). Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR); internalization of ITGB1 as DAB2-dependent cargo but not TFR may involve association with DAB2 (PubMed:22648170). Promotes ubiquitination and subsequent degradation of EGFR, and thereby contributes to the down-regulation of EGFR-dependent signaling pathways. In chromaffin cells, required for normal exocytosis of catecholamines. Required for rapid replenishment of release-ready synaptic vesicles at presynaptic active zones (By similarity). Inhibits ARHGAP31 activity toward RAC1 (PubMed:11744688).
Contains a premature stop codon, potentially subjected to NMD.
In an autoinhibited form the SH3 domain 5 may bind intramolecularly to the DH domain, thus blocking the CDC42-binding site.
Interacts (via DH domain) with CDC42 (PubMed:11584276, PubMed:12006984). Interacts (via SH3 domain 1) with WASL (PubMed:11584276). Interacts with dynamin, SNAP25 and SNAP23 (By similarity). Interacts with clathrin-associated proteins and other components of the endocytic machinery, such as SPIN90, EPS15, EPN1, EPN2, STON2, FCHO1, FCHO2 and DAB2 (PubMed:20448150, PubMed:22484487, PubMed:22648170). Interacts (via SH3 domains) with REPS1 and SGIP1 (PubMed:20946875). Interacts with ARHGAP31 (PubMed:11744688). Interacts with ADAM15 (PubMed:19718658). Interacts with PRRT2 (By similarity). Interacts (via SH3 domain 4) with FCHSD2 (via SH3 domain 2) (PubMed:29887380). Interacts (via SH3 domain 1) with DENND2B (PubMed:29030480). Interacts (via SH3 domains) with CBL (By similarity). Isoform 2: Interacts with CBL and DNM1 (PubMed:21712076). Isoform 2: Interacts with LMNA (PubMed:29599122). Isoform 2: Interacts with importin subunit KPNA1; this is likely to mediate its import into the nucleus (PubMed:29599122).
Isoform 1 is expressed almost exclusively in the brain. Isoform 2 is detected in brain, spleen, lung, liver, heart, skeletal muscle and kidney. Isoform 5 is primarily expressed in brain, spleen, lung and kidney (at protein level) (PubMed:21712076). Isoform 1 and isoform 2 are detected in brain (PubMed:10482960). Isoform 2 is ubiquitous in adult and fetal tissues with high expression in skeletal muscle, heart, spleen, ovary, testis and all fetal tissues tested and low expression in thymus, blood, lung, liver and pancreas. Isoform 1 is expressed almost exclusively in the brain, in all brain regions. Not expressed in the spinal cord (PubMed:9799604, PubMed:21712076, PubMed:11690630).
Plays a role in synaptic vesicle endocytosis in brain neurons.
SH3-3, SH3-4 and SH3-5, but not SH3-1 and SH3-2 domains, bind to dynamin (By similarity). SH3-1 and SH3-4 bind to ARHGAP31.
Studies in clathrin-mediated endocytosis of ITGB1 and TFR used a siRNA mixture of ISTN1 and ISTN2, and a Dab2 mutant with impaired binding to EH domain-containing proteins EPS15 and ITSN1 suggesting a partially overlapping role of the EH domain-containing proteins.
The KLERQ domain binds to SNAP-25 and SNAP-23.
Catalyzes the activation of fatty acids by CoA to produce an acyl-CoA, the first step in fatty acid metabolism (PubMed:11772874). Capable of activating medium-chain fatty acids with a preference for isobutyrate among fatty acids with 2-6 carbon atoms (By similarity).
A paper describing ATG4B tissue expression has been retracted, due to concerns of image duplication in some of the figures.
Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins (PubMed:15169837, PubMed:15187094, PubMed:17347651, PubMed:19322194, PubMed:21177865, PubMed:26378241, PubMed:29232556, PubMed:28821708, PubMed:30443548, PubMed:30661429, PubMed:22302004, PubMed:27527864, PubMed:28633005, PubMed:30076329). Required for canonical autophagy (macroautophagy), non-canonical autophagy as well as for mitophagy (PubMed:33773106, PubMed:33909989). The protease activity is required for proteolytic activation of ATG8 family proteins: cleaves the C-terminal amino acid of ATG8 proteins MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAPL1, GABARAPL2 and GABARAP, to reveal a C-terminal glycine (PubMed:15169837, PubMed:15187094, PubMed:17347651, PubMed:20818167, PubMed:19322194, PubMed:21177865, PubMed:22302004, PubMed:27527864, PubMed:28633005, PubMed:29458288, PubMed:30661429, PubMed:28287329). Exposure of the glycine at the C-terminus is essential for ATG8 proteins conjugation to phosphatidylethanolamine (PE) and insertion to membranes, which is necessary for autophagy (PubMed:15169837, PubMed:15187094, PubMed:17347651, PubMed:19322194, PubMed:21177865, PubMed:22302004). Protease activity is also required to counteract formation of high-molecular weight conjugates of ATG8 proteins (ATG8ylation): acts as a deubiquitinating-like enzyme that removes ATG8 conjugated to other proteins, such as ATG3 (PubMed:31315929, PubMed:33773106). In addition to the protease activity, also mediates delipidation of ATG8 family proteins (PubMed:15187094, PubMed:28633005, PubMed:29458288, PubMed:32686895, PubMed:33909989, PubMed:19322194). Catalyzes delipidation of PE-conjugated forms of ATG8 proteins during macroautophagy (PubMed:15187094, PubMed:29458288, PubMed:32686895, PubMed:33909989, PubMed:19322194). Also involved in non-canonical autophagy, a parallel pathway involving conjugation of ATG8 proteins to single membranes at endolysosomal compartments, by catalyzing delipidation of ATG8 proteins conjugated to phosphatidylserine (PS) (PubMed:33909989). Compared to other members of the family (ATG4A, ATG4C or ATG4C), constitutes the major protein for proteolytic activation of ATG8 proteins, while it displays weaker delipidation activity than other ATG4 paralogs (PubMed:29458288, PubMed:30661429). Involved in phagophore growth during mitophagy independently of its protease activity and of ATG8 proteins: acts by regulating ATG9A trafficking to mitochondria and promoting phagophore-endoplasmic reticulum contacts during the lipid transfer phase of mitophagy (PubMed:33773106).
Forms reversible intrachain disulfide bonds in response to oxidative stress (PubMed:31880198). Forms interchain disulfide bonds, leading to formation of homooligomers in response to oxidation (PubMed:31880198).
Inhibited by N-ethylmaleimide (PubMed:21177865). Redox-regulated during autophagy since reducing conditions activate ATG4A whereas an oxidizing environment such as the presence of H(2)O(2) inhibits its activity (PubMed:17347651). The cysteine protease activity compounds is inhibited by styrylquinoline compounds 4-28 and LV-320 (PubMed:30076329).
Interacts with PFKP; promoting phosphorylation of ATG4B at Ser-34 (PubMed:33607258). Interacts with GBP7 (By similarity).
O-glycosylated by OGT, leading to increase protease activity, thereby promoting the proteolytic activation of ATG8 family proteins.
Phosphorylation at Ser-383 and Ser-392 promotes autophagy by increasing protein delipidation activity without affecting proteolytic activation of ATG8 proteins (PubMed:26378241). Phosphorylation at Ser-316 by ULK1 inhibits autophagy by decreasing both proteolytic activation and delipidation activities (PubMed:28821708). Phosphorylation at Ser-316 is dephosphorylated by protein phosphatase 2A (PP2A) (PubMed:28821708). Phosphorylation at Ser-34 by AKT2 promotes its hydrolase activity, leading to increased proteolytic activation and delipidation of ATG8 family proteins (PubMed:30443548). Phosphorylation at Ser-34 by AKT1 promotes mitochondrial localization and inhibition of the F1F0-ATP synthase activity, leading to elevation of mitochondrial reactive oxygen species (ROS) (PubMed:29165041).
S-nitrosylation at Cys-189 and Cys-292 in response to high glucose decreases both proteolytic activation and delipidation activities.
The LIR motif (LC3-interacting region) is required for the interaction with ATG8 family proteins MAP1LC3A, MAP1LC3B, MAP1LC3C and GABARAPL1 (PubMed:28287329). Required for proteolytic activation and delipidation of ATG8 proteins (PubMed:29458288, PubMed:28287329).
Ubiquitinated by RNF5, leading to its degradation by the proteasome.
Belongs to the peroxiredoxin-like PRXL2 family. PRXL2A subfamily.
Expressed in CSF1 and TNFSF11-stimulated CD14(+) peripheral blood mononuclear cells (PBMCs).
Involved in redox regulation of the cell (PubMed:26438880, PubMed:19951071). Acts as an antioxidant (PubMed:19951071, PubMed:26438880). Inhibits TNFSF11-induced NFKB1 and JUN activation and osteoclast differentiation (PubMed:19951071). May affect bone resorption and help to maintain bone mass (PubMed:19951071). Acts as a negative regulator of macrophage-mediated inflammation by inhibiting macrophage production of inflammatory cytokines, probably through suppression of the MAPK signaling pathway (PubMed:26438880).
The active site cysteines correspond to the redox-active cysteines of peroxiredoxins.
Up-regulated by CSF1 in peripheral blood mononuclear cells (PBMCs). This induction is reduced in the presence of TNFSF11.
Belongs to the AAA ATPase family. PCH2 subfamily.
Plays a key role in chromosome recombination and chromosome structure development during meiosis. Required at early steps in meiotic recombination that leads to non-crossovers pathways. Also needed for efficient completion of homologous synapsis by influencing crossover distribution along the chromosomes affecting both crossovers and non-crossovers pathways. Also required for development of higher-order chromosome structures and is needed for synaptonemal-complex formation. In males, required for efficient synapsis of the sex chromosomes and for sex body formation. Promotes early steps of the DNA double-strand breaks (DSBs) repair process upstream of the assembly of RAD51 complexes. Required for depletion of HORMAD1 and HORMAD2 from synapsed chromosomes (By similarity). Plays a role in mitotic spindle assembly checkpoint (SAC) activation (PubMed:28553959).
Specifically interacts with the ligand binding domain of the thyroid receptor (TR). This interaction does not require the presence of thyroid hormone for its interaction. Interacts with HPV16 E1. Interacts with proteasome subunit PSMA8; to participate in meiosis progression during spermatogenesis (By similarity).
The disease is caused by variants affecting the gene represented in this entry. MVA3 is caused by biallelic mutations in the TRIP13 gene.
Binds laminin-1 and laminin-5. Interacts with LGALS3 (By similarity). Interacts with AGR2 and AGR3.
Expressed in placenta, skin and urothelium. Found in suprabasal keratinocytes of chronic wounds. Weak expression is found in esophagus and peripheral blood mononuclear cells. Found in the majority of primary and metastatic transitional cell carcinomas (TCCs) and as well in breast cancer tissues, but not in adjacent normal tissues. High expression is found in the tumor component of some noninvasive superficial lesions and in invasive and metastatic urothelial cancers.
Supports cell migration. May be involved in urothelial cell-matrix interactions. May be involved in tumor progression.
Up-regulated in migrating keratinocytes during epithelization of incisional skin wounds.
Interacts with SDHA in its FAD-bound form.
Plays an essential role in the assembly of succinate dehydrogenase (SDH), an enzyme complex (also referred to as respiratory complex II) that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain, and which couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol (PubMed:24954416). Binds to the flavoprotein subunit SDHA in its FAD-bound form, blocking the generation of excess reactive oxygen species (ROS) and facilitating its assembly with the iron-sulfur protein subunit SDHB into the SDH catalytic dimer (By similarity).
Apo(a) is known to be proteolytically cleaved, leading to the formation of the so-called mini-Lp(a). Apo(a) fragments accumulate in atherosclerotic lesions, where they may promote thrombogenesis. O-glycosylation may limit the extent of proteolytic fragmentation. Homology with plasminogen kringles IV and V is thought to underlie the atherogenicity of the protein, because the fragments are competing with plasminogen for fibrin(ogen) binding.
Apo(a) is the main constituent of lipoprotein(a) (Lp(a)). It has serine proteinase activity and is able of autoproteolysis. Inhibits tissue-type plasminogen activator 1. Lp(a) may be a ligand for megalin/Gp 330.
Disulfide-linked to apo-B100. Binds to fibronectin and decorin.
LPA genetic variants, including variations in the number of Kringle domains, define the lipoprotein(a) quantitative trait locus (LPAQTL) and influence lipoprotein(a) levels in plasma [MIM:618807]. Depending on the individual, the encoded protein contains 2-43 copies of kringle IV-2 repeats. Often the assignement of amino acids in lipoprotein(a) is based on a long allele that contains 37 copies of the kringle-type repeats (PubMed:3670400). The reference allele represented here contains 15 copies of the kringle-type repeats.
N- and O-glycosylated. The N-glycans are complex biantennary structures present in either a mono- or disialylated state. The O-glycans are mostly (80%) represented by the monosialylated core type I structure, NeuNAcalpha2-3Galbeta1-3GalNAc, with smaller amounts of disialylated and non-sialylated O-glycans also detected.
Belongs to the archaeal Rpo3/eukaryotic RPB3 RNA polymerase subunit family.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I and III which synthesize ribosomal RNA precursors and small RNAs, such as 5S rRNA and tRNAs, respectively. RPAC1 is part of the Pol core element with the central large cleft and probably a clamp element that moves to open and close the cleft (By similarity).
Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+) (PubMed:26631410). Critical component of the visual transduction cascade, controlling the calcium concentration of outer segments during light and darkness (PubMed:20850105). Light causes a rapid lowering of cytosolic free calcium in the outer segment of both retinal rod and cone photoreceptors and the light-induced lowering of calcium is caused by extrusion via this protein which plays a key role in the process of light adaptation (PubMed:20850105).
Expressed in the retina, particularly in the inner segment, outer and inner nuclear layers, and ganglion cell layer.
The uncleaved signal sequence is required for efficient membrane targeting and proper membrane integration.
(Microbial infection) Activated upon human coronavirus SARS-CoV-2 infection, leading to lung epithelial cell death (PubMed:35594856). Activation takes place in response to (1) activation of NLRP1 and (2) inactivation of GSDMD following NLRP1 and GSDMD cleavage by the SARS-CoV-2 3C-like proteinase nsp5 (PubMed:35594856).
(Microbial infection) Pore-forming protein, which promotes maternal placental pyroptosis in response to Zika virus infection, contributing to adverse fetal outcomes.
Cleavage at Asp-270 by CASP3 (mature and uncleaved precursor forms) or granzyme B (GZMB) relieves autoinhibition and is sufficient to initiate pyroptosis.
Expressed in cochlea (PubMed:9771715). Low level of expression in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas, with highest expression in placenta (PubMed:9771715).
Intramolecular interactions between N- and C-terminal domains may be important for autoinhibition in the absence of activation signal. The intrinsic pyroptosis-inducing activity is carried by the N-terminal domain, that is released upon cleavage by CASP3 or granzyme B (GZMB).
Is a tumor suppressor gene with an important role in colorectal cancer (CRC).
Pore-forming protein produced by cleavage by CASP3 or granzyme B (GZMB), which converts non-inflammatory apoptosis to pyroptosis or promotes granzyme-mediated pyroptosis, respectively (PubMed:27281216, PubMed:28459430, PubMed:32188940, PubMed:33852854, PubMed:35594856). After cleavage, moves to the plasma membrane, homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the release of mature interleukins (IL1B and IL16) and triggering pyroptosis (PubMed:28459430, PubMed:32188940, PubMed:33852854, PubMed:35594856). Binds to inner leaflet lipids, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate (PubMed:28459430). Cleavage by CASP3 switches CASP3-mediated apoptosis induced by TNF or danger signals, such as chemotherapy drugs, to pyroptosis (PubMed:27281216, PubMed:28459430, PubMed:32188940). Mediates secondary necrosis downstream of the mitochondrial apoptotic pathway and CASP3 activation as well as in response to viral agents (PubMed:28045099). Exhibits bactericidal activity (PubMed:27281216). Cleavage by GZMB promotes tumor suppressor activity by triggering robust anti-tumor immunity (PubMed:21522185, PubMed:32188940). Suppresses tumors by mediating granzyme-mediated pyroptosis in target cells of natural killer (NK) cells: cleavage by granzyme B (GZMB), delivered to target cells from NK-cells, triggers pyroptosis of tumor cells and tumor suppression (PubMed:32188940, PubMed:31953257). May play a role in the p53/TP53-regulated cellular response to DNA damage (PubMed:16897187).
Precursor of a pore-forming protein that converts non-inflammatory apoptosis to pyroptosis (PubMed:27281216, PubMed:28459430, PubMed:33852854, PubMed:35594856). This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-E, N-terminal) binds to membranes and forms pores, triggering pyroptosis (PubMed:28459430).
Succination by the Krebs cycle intermediate fumarate, which leads to S-(2-succinyl)cysteine residues, inhibits processing by caspases, and ability to initiate pyroptosis (PubMed:32820063). Succination modification is catalyzed by a non-enzymatic reaction caused by an accumulation of fumarate (PubMed:32820063).
The full-length protein before cleavage is inactive: intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of activation signal (PubMed:28045099, PubMed:28459430). The intrinsic pyroptosis-inducing activity is carried by the released N-terminal moiety (Gasdermin-E, N-terminal) following cleavage by CASP3 or granzyme B (GZMB) (PubMed:28459430, PubMed:32188940, PubMed:31953257, PubMed:35594856). Activated by NLRP1 in the absence of GSDMD expression: NLRP1 cleaves and activates CASP8, promoting downstream activation of CASP3 and subsequent activation of GSDME (PubMed:33852854, PubMed:35594856).
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 Nucleoprotein and Spike protein homotrimer.
Homooctamer; disulfide-linked (PubMed:18223257). Binds to C1q (By similarity).
Plays a role in the regulation of innate resistance to pathogens, inflammatory reactions, possibly clearance of self-components and female fertility.
Aquaporins contain two tandem repeats each containing two membrane-spanning helices and a pore-forming loop with the signature motif Asn-Pro-Ala (NPA). Each tandem repeat contains a loop and a short helix that enter and leave the lipid bilayer on the same side (By similarity).
Expressed in the cortex and nucleus of the retina lens (at protein level) (PubMed:30790544). Major component of lens fiber gap junctions (PubMed:24120416).
Fatty acylated at Met-1 and Lys-238. The acyl modifications, in decreasing order of ion abundance, are: oleoyl (C18:1) > palmitoyl (C16:0) > stearoyl (C18:0) > eicosenoyl (C20:1) > dihomo-gamma-linolenoyl (C20:3) > palmitoleoyl (C16:1) > eicosadienoyl (C20:2).
Homotetramer (PubMed:24120416). Homooctamer formed by head-to-head interaction between homotetramers from adjoining membranes. Interacts with CALM; one CALM molecule interacts with the cytoplasmic domains of two aquaporins, leading to channel closure (By similarity). Interacts (via C-terminus) with BFSP1 (via C-terminus) in aged lens fiber cells (By similarity).
Subject to partial proteolytic cleavage in the eye lens core. Partial proteolysis promotes interactions between tetramers from adjoining membranes (By similarity).
Water channel (PubMed:24120416). Channel activity is down-regulated by CALM when cytoplasmic Ca(2+) levels are increased. May be responsible for regulating the osmolarity of the lens. Interactions between homotetramers from adjoining membranes may stabilize cell junctions in the eye lens core (By similarity). Plays a role in cell-to-cell adhesion and facilitates gap junction coupling (PubMed:24120416).
Expressed in serum, peripheral leukocytes and cytotoxic T-lymphocytes, but not in granulocytes and monocytes (at protein level).
Mitochondrial carrier mediating the transport of coenzyme A (CoA) in mitochondria in exchange for intramitochondrial (deoxy)adenine nucleotides and adenosine 3',5'-diphosphate.
Endonuclease that probably plays a role in the DNA damage response and DNA repair.
Expressed in fetal spleen, liver and thymus.
Expression is predominant in adult bone marrow.
Interacts (via LEM domain) with BANF1; the interaction may favor BANF1 dimerization.
The LEM domain is required for GIY-YIG domain-mediated DNA cleavage and induction of DNA damage response.
Atypical PKCs (PRKCI and PRKCZ) exhibit an elevated basal enzymatic activity (that may be due to the interaction with SMG1 or SQSTM1) and are not regulated by diacylglycerol, phosphatidylserine, phorbol esters or calcium ions. Two specific sites, Thr-410 (activation loop of the kinase domain) and Thr-560 (turn motif), need to be phosphorylated for its full activation. Phosphatidylinositol 3,4,5-trisphosphate might be a physiological activator (By similarity). Isoform 2: Constitutively active (By similarity).
CDH5 is required for its phosphorylation at Thr-410. Phosphorylated by protein kinase PDPK1; phosphorylation is inhibited by the apoptotic C-terminal cleavage product of PKN2. Phosphorylation at Thr-410 by PI3K activates the kinase.
Calcium- and diacylglycerol-independent serine/threonine-protein kinase that functions in phosphatidylinositol 3-kinase (PI3K) pathway and mitogen-activated protein (MAP) kinase cascade, and is involved in NF-kappa-B activation, mitogenic signaling, cell proliferation, cell polarity, inflammatory response and maintenance of long-term potentiation (LTP). Upon lipopolysaccharide (LPS) treatment in macrophages, or following mitogenic stimuli, functions downstream of PI3K to activate MAP2K1/MEK1-MAPK1/ERK2 signaling cascade independently of RAF1 activation. Required for insulin-dependent activation of AKT3, but may function as an adapter rather than a direct activator. Upon insulin treatment may act as a downstream effector of PI3K and contribute to the activation of translocation of the glucose transporter SLC2A4/GLUT4 and subsequent glucose transport in adipocytes. In EGF-induced cells, binds and activates MAP2K5/MEK5-MAPK7/ERK5 independently of its kinase activity and can activate JUN promoter through MEF2C. Through binding with SQSTM1/p62, functions in interleukin-1 signaling and activation of NF-kappa-B with the specific adapters RIPK1 and TRAF6. Participates in TNF-dependent transactivation of NF-kappa-B by phosphorylating and activating IKBKB kinase, which in turn leads to the degradation of NF-kappa-B inhibitors. In migrating astrocytes, forms a cytoplasmic complex with PARD6A and is recruited by CDC42 to function in the establishment of cell polarity along with the microtubule motor and dynein. In association with FEZ1, stimulates neuronal differentiation in PC12 cells. In the inflammatory response, is required for the T-helper 2 (Th2) differentiation process, including interleukin production, efficient activation of JAK1 and the subsequent phosphorylation and nuclear translocation of STAT6. May be involved in development of allergic airway inflammation (asthma), a process dependent on Th2 immune response. In the NF-kappa-B-mediated inflammatory response, can relieve SETD6-dependent repression of NF-kappa-B target genes by phosphorylating the RELA subunit at 'Ser-311'. Phosphorylates VAMP2 in vitro (PubMed:17313651).
Expressed in brain, and to a lesser extent in lung, kidney and testis.
Forms a ternary complex with SQSTM1 and KCNAB2. Forms another ternary complex with SQSTM1 and GABRR3. Forms a complex with SQSTM1 and MAP2K5 (By similarity). Interacts with PARD6A, PARD6B, PARD6G and SQSTM1. Part of a complex with PARD3, PARD6A or PARD6B or PARD6G and CDC42 or RAC1. Interacts with ADAP1/CENTA1. Forms a ternary complex composed of SQSTM1 and PAWR. Interacts directly with SQSTM1 (Probable). Interacts with IKBKB. Interacts (via the protein kinase domain) with WWC1. Forms a tripartite complex with WWC1 and DDR1, but predominantly in the absence of collagen. Component of the Par polarity complex, composed of at least phosphorylated PRKCZ, PARD3 and TIAM1. Interacts with PDPK1 (via N-terminal region). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529). Interacts with VAMP2 (PubMed:17313651). Forms a complex with WDFY2 and VAMP2 (PubMed:17313651). Interacts with APPL1 (PubMed:26583432).
Involved in late synaptic long term potention phase in CA1 hippocampal cells and long term memory maintenance.
Reported to phosphorylate STK11 leading to nuclear export of STK11, subsequent inhibition of PI3K/Akt signaling, and increased apoptosis in vein endothelial cells treated with the oxidant peroxynitrite (PubMed:18321849). However this paper was withdrawn by the authors due to concerns of image duplication in the figures. Its role in protein phosphorylation has been confirmed in other studies (PubMed:15084291, PubMed:15324659).
The PB1 domain mediate mutually exclusive interactions with SQSTM1 and PARD6B.
Acid-stable proteinase inhibitor with strong affinities for trypsin, chymotrypsin, elastase, and cathepsin G (PubMed:3533531, PubMed:3462719, PubMed:2039600, PubMed:2110563, PubMed:10702419, PubMed:24121345). Modulates the inflammatory and immune responses after bacterial infection, and after infection by the intracellular parasite L.major. Down-regulates responses to bacterial lipopolysaccharide (LPS) (By similarity). Plays a role in regulating the activation of NF-kappa-B and inflammatory responses (PubMed:10702419, PubMed:24352879). Has antimicrobial activity against mycobacteria, but not against salmonella. Contributes to normal resistance against infection by M.tuberculosis. Required for normal resistance to infection by L.major. Required for normal wound healing, probably by preventing tissue damage by limiting protease activity (By similarity). Together with ELANE, required for normal differentiation and proliferation of bone marrow myeloid cells (PubMed:24352879).
Detected in blood plasma (PubMed:24352879). Detected in bone marrow myeloid cells (PubMed:24352879). Detected in airway sputum (PubMed:2039600). Detected in parotid gland secretions (PubMed:3462719). Detected in seminal plasma (at protein level) (PubMed:3485543). Detected in uterus cervix (PubMed:3533531).
Down-regulated in response to low ELANE activity. Up-regulated by ELANE treatment in bone marrow cells.
Interacts with GRN; interaction protects progranulin from proteolysis.
The pathologies of several chronic and acute diseases of the respiratory tract involve an imbalance between the proteases of cells involved in inflammatory responses and the inhibitors of these proteases. The inflammation-mediated release of neutrophil elastase in the lungs of patients whose levels of active alpha-1-antiprotease are compromised by genetic background, cigarette smoking, air pollutants, or a combination of all three can result in severe lung damage and a decreased lifespan. The relatively small size of this protein, its lack of glycosylation and its stability make this protein a candidate for use as a therapeutic agent in diseases mediated by leukocyte elastase-antielastase imbalances.
Component of the multisubunit TRAPP (transport protein particle) complex, which includes at least TRAPPC2, TRAPPC2L, TRAPPC3, TRAPPC3L, TRAPPC4, TRAPPC5, TRAPPC8, TRAPPC9, TRAPPC10, TRAPPC11 and TRAPPC12. Interacts with the heterodimer TRAPPC3-TRAPPC6A. Interacts with TRAPPC6A.
Expressed in testis, liver, bladder, lung, spleen and brain, several cell lines and primary chondrocytes cell line.
Plays a role in vesicular transport from endoplasmic reticulum to Golgi.
Component of the IFT complex B, at least composed of IFT20, IFT22, IFT25, IFT27, IFT46, IFT52, TRAF3IP1/IFT54, IFT57, IFT74, IFT80, IFT81, and IFT88 (By similarity). Interacts with IFT20 (By similarity). Interacts with IFT88 (By similarity). Interacts with IFT80, IFT-81, IFT74, IFT172, IFT70B and KIF17 (By similarity). Interacts with BLOC1S2 (By similarity). Interacts with RYBP (By similarity). Interacts with HOMER1; the interaction possibly prevents the pro-apoptotic effects of IFT57 (By similarity). Interacts with HIP1 (PubMed:11788820). In normal conditions, it poorly interacts with HIP1, HIP1 being strongly associated with HTT (PubMed:11788820). However, in mutant HTT proteins with a long poly-Gln region, interaction between HTT and HIP1 is inhibited, promoting the interaction between HIP1 and IFT57, leading to apoptosis (PubMed:11788820). Interacts with BFAR (PubMed:14502241). Interacts with TTC25 (PubMed:25860617). Interacts with USH1G (PubMed:31637240). Interacts with chicken anemia virus protein apoptin (PubMed:12745083).
Present in many tissues such as brain, thymus, lymph node, lung, liver, skin and kidney (at protein level).
Required for the formation of cilia. Plays an indirect role in sonic hedgehog signaling, cilia being required for all activity of the hedgehog pathway (By similarity). Has pro-apoptotic function via its interaction with HIP1, leading to recruit caspase-8 (CASP8) and trigger apoptosis. Has the ability to bind DNA sequence motif 5'-AAAGACATG-3' present in the promoter of caspase genes such as CASP1, CASP8 and CASP10, suggesting that it may act as a transcription regulator; however the relevance of such function remains unclear.
The pseudo DED region (pDED) mediates the interaction with HIP1.
Essential for the control of the cell cycle at the G1/S (start) transition.
Highly expressed in testis and placenta. Low levels in bronchial epithelial cells.
Interacts with CDK2 protein kinase to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex (PubMed:15660127). Found in a complex with CDK2, CABLES1 and CCNA1 (By similarity). Part of a complex consisting of UHRF2, CDK2 and CCNE1 (PubMed:15178429). Interacts directly with UHRF2; the interaction ubiquitinates CCNE1 and appears to occur independently of CCNE1 phosphorylation (PubMed:21952639). Interacts with INCA1 (PubMed:21540187).
Lacks 49 residues within the cyclin box and cannot complex with CDK2.
Phosphorylation of both Thr-395 by GSK3 and Ser-399 by CDK2 creates a high affinity degron recognized by FBXW7, and accelerates degradation via the ubiquitin proteasome pathway. Phosphorylation at Thr-77 creates a low affinity degron also recognized by FBXW7.
Ubiquitinated by UHRF2; appears to occur independently of phosphorylation.
Interacts with FAF2 (PubMed:23297223). Interacts with LMBR1L (PubMed:31073040). Interacts with AMFR and VCP (By similarity).
Restricts trafficking of FAF2 from the endoplasmic reticulum to lipid droplets (PubMed:23297223). In association with LMBR1L and E3 ubiquitin-protein ligase AMFR, negatively regulates the canonical Wnt signaling pathway in the lymphocytes by promoting the ubiquitin-mediated degradation of CTNNB1 and Wnt receptors FZD6 and LRP6 (PubMed:31073040).
Homotrimer (PubMed:8610159, PubMed:23776208). Interacts with CXCR2 extracellular domain (By similarity). Interacts with the CD74 extracellular domain, USO1, COPS5 and BNIPL (PubMed:11089976, PubMed:12681488, PubMed:12782713, PubMed:19454686, PubMed:23776208).
Pro-inflammatory cytokine involved in the innate immune response to bacterial pathogens (PubMed:15908412, PubMed:17443469, PubMed:23776208). The expression of MIF at sites of inflammation suggests a role as mediator in regulating the function of macrophages in host defense (PubMed:15908412, PubMed:17443469, PubMed:23776208). Counteracts the anti-inflammatory activity of glucocorticoids (PubMed:15908412, PubMed:17443469, PubMed:23776208). Has phenylpyruvate tautomerase and dopachrome tautomerase activity (in vitro), but the physiological substrate is not known (PubMed:11439086, PubMed:17526494). It is not clear whether the tautomerase activity has any physiological relevance, and whether it is important for cytokine activity (PubMed:11439086, PubMed:17526494).
Serum levels of MIF are elevated in patients with severe sepsis or septic shock. High levels of MIF are correlated with low survival. Drugs that inhibit tautomerase activity protect against death due to sepsis.
Up-regulated in concanavalin-A-treated lymphocytes. Up-regulated in macrophages upon exposure to M.tuberculosis antigens.
Has fucosyltransferase activity toward biantennary N-glycan acceptors. Does not fucosylate GlcNAc residue within type 2 lactosamine unit.
Has minor fucosyltransferase activity toward biantennary N-glycan acceptors. Does not fucosylate GlcNAc residue within type 2 lactosamine unit.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-6/CHRNA6 sub-subfamily.
Neuronal AChR seems to be composed of two different types of subunits: alpha and non-alpha (beta). Interacts with LYPD6 (PubMed:27344019).
(Microbial infection) Interacts (via N-terminus) with varicella-zoster virus (VZV) envelope glycoprotein E (via N-terminus); the membrane-associated isoform may function as an entry receptor for this virus (PubMed:17055432, PubMed:17553876).
(Microbial infection) The membrane-associated isoform acts as an entry receptor for varicella-zoster virus (VZV).
ATP-binding induces a conformation change.
Activated by small peptides (By similarity). Activated by ATP and GTP, and to a lesser extent by CTP, TTP and PPPi (PubMed:17613531). Inhibited by bacitracin (PubMed:17055432, PubMed:17613531). In vitro modification of Cys residues impairs enzyme activity (PubMed:18986166).
Detected in brain and in cerebrospinal fluid (at protein level).
Homodimer (PubMed:17051221, PubMed:19321446, PubMed:23922390, PubMed:26394692, PubMed:29596046) (Probable). Can also form homotetramers (By similarity).
Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, natriuretic peptides, glucagon, bradykinin, kallidin, and other peptides, and thereby plays a role in intercellular peptide signaling (PubMed:2293021, PubMed:10684867, PubMed:26968463, PubMed:17051221, PubMed:17613531, PubMed:18986166, PubMed:19321446, PubMed:23922390, PubMed:24847884, PubMed:26394692, PubMed:29596046, PubMed:21098034). Substrate binding induces important conformation changes, making it possible to bind and degrade larger substrates, such as insulin (PubMed:23922390, PubMed:26394692, PubMed:29596046). Contributes to the regulation of peptide hormone signaling cascades and regulation of blood glucose homeostasis via its role in the degradation of insulin, glucagon and IAPP (By similarity). Plays a role in the degradation and clearance of APP-derived amyloidogenic peptides that are secreted by neurons and microglia (PubMed:9830016, PubMed:26394692) (Probable). Degrades the natriuretic peptides ANP, BNP and CNP, inactivating their ability to raise intracellular cGMP (PubMed:21098034). Also degrades an aberrant frameshifted 40-residue form of NPPA (fsNPPA) which is associated with familial atrial fibrillation in heterozygous patients (PubMed:21098034). Involved in antigen processing. Produces both the N terminus and the C terminus of MAGEA3-derived antigenic peptide (EVDPIGHLY) that is presented to cytotoxic T lymphocytes by MHC class I.
The SlyX motif may be involved in the non-conventional secretion of the protein.
Phosphorylation at Tyr-34 is essential for its ability to promote megakaryocyte differentiation.
Promotes megakaryocyte differentiation by enhancing ERK and JNK signaling as well as up-regulating RUNX1 and FLI1 expression (PubMed:24681962). Represses NF-kappa-B transcriptional activity by inhibiting phosphorylation of RELA at 'Ser-536' (PubMed:24681962). May be involved in early neuronal development (By similarity).
Up-regulated by NF-kappa-B RELA/p65 (PubMed:24681962). Up-regulated during 12-O-tetradecanoyl phorbol-acetate (TPA)-induced megakaryocytic differentiation of K562 and HEL cells (PubMed:24681962).
Cell surface receptor that may play a role in the innate and adaptive immune response. Acts as a counter-receptor for CD276 and interaction with CD276 on T-cells enhances T-cell activation.
Detected in cultured B-cells, T-cell leukemia and monocyte leukemia. Expressed constitutively on CD8 T-cells and induced on CD4 T-cells after activation.
Induced in CD4 T-cells by concanavalin-A.
Interacts with CD276 and this interaction enhances T-cell activation.
RAB2B effector protein required for accurate acrosome formation and normal male fertility.
GTPase-activating protein for RhoA, and perhaps for Cdc42. May be involved in regulation of cytoskeletal reorganization, cell proliferation and cell motility. Acts a tumor suppressor in hepatocellular carcinoma cells.
Ubiquitously expressed. Underexpressed in hepatocellular carcinoma cells and some breast cancer cell lines.
NADH-cytochrome b5 reductases are involved in desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction.
Has been shown to act as a sodium/bicarbonate cotransporter in exchange for intracellular chloride (By similarity). Has also been shown to act as a sodium/biocarbonate cotransporter which is not responsible for net efflux of chloride, with the observed chloride efflux being due to chloride self-exchange (PubMed:18319254).
Sodium/bicarbonate cotransporter which plays an important role in regulating intracellular pH (PubMed:18319254). Has been shown to act as a sodium/bicarbonate cotransporter in exchange for intracellular chloride (By similarity). Has also been shown to act as a sodium/biocarbonate cotransporter which does not couple net influx of bicarbonate to net efflux of chloride, with the observed chloride efflux being due to chloride self-exchange (PubMed:18319254). Controls neuronal pH and may contribute to the secretion of cerebrospinal fluid (By similarity). Reduces the excitability of CA1 pyramidal neurons and modulates short-term synaptic plasticity (By similarity). Required in retinal cells to maintain normal pH which is necessary for normal vision (By similarity). In the kidney, likely to mediate bicarbonate reclamation in the apical membrane of the proximal tubules (By similarity).
The N-terminal cytoplasmic domain is likely to have a high level of intrinsic disorder.
Isoform 1 is only expressed in the brain. Isoform 2 is ubiquitously detected with highest expression in skeletal muscle and detected in myocardial myofibrils. Variant Val-7 and Val-9 are detected in the brain only.
Isoform 2 interacts with the sarcomeric proteins, MRLC2, MYOM1 and ENO3.
Probable hydrolase that plays an aggravative role in the development of cardiac hypertrophy via activation of the NF-kappa-B signaling pathway.
Highly expressed in fetal lung, liver, kidney, adult heart, brain and skeletal muscle. Weakly expressed in placenta, fetal brain, and adult lung, liver, kidney and pancreas.
Protein disulfide isomerase (By similarity). Promotes the localization of acetylcholine receptors (AChRs) to the plasma membrane (By similarity).
Component of the 43S pre-initiation complex (43S PIC), which binds to the mRNA cap-proximal region, scans mRNA 5'-untranslated region, and locates the initiation codon (PubMed:9732867, PubMed:12435632, PubMed:14600024). Together with eIF1A (EIF1AX), EIF1 facilitates scanning and is essential for start codon recognition on the basis of AUG nucleotide context and location relative to the 5'-cap (PubMed:9732867, PubMed:12435632, PubMed:14600024). Participates to initiation codon selection by influencing the conformation of the 40S ribosomal subunit and the positions of bound mRNA and initiator tRNA; this is possible after its binding to the interface surface of the platform of the 40S ribosomal subunit close to the P-site (PubMed:14600024). Together with eIF1A (EIF1AX), also regulates the opening and closing of the mRNA binding channel, which ensures mRNA recruitment, scanning and the fidelity of initiation codon selection (PubMed:9732867). Continuously monitors and protects against premature and partial base-pairing of codons in the 5'-UTR with the anticodon of initiator tRNA (PubMed:9732867, PubMed:12435632). Together with eIF1A (EIF1AX), acts for ribosomal scanning, promotion of the assembly of 48S complex at the initiation codon (43S PIC becomes 48S PIC after the start codon is reached), and dissociation of aberrant complexes (PubMed:9732867). Interacts with EIF4G1, which in a mutual exclusive interaction associates either with EIF1 or with EIF4E on a common binding site (PubMed:29987188). EIF4G1-EIF1 complex promotes ribosome scanning (on both short and long 5'UTR), leaky scanning (on short 5'UTR) which is the bypass of the initial start codon, and discrimination against cap-proximal AUG (PubMed:29987188). Is probably maintained within the 43S PIC in open conformation thanks to eIF1A-EIF5 interaction (PubMed:24319994). Once the correct start codon is reached, EIF1 is physically excluded from the decoding site, shifting the PIC into the closed conformation and arresting it at the start codon (PubMed:22813744).
Component of the 43S pre-initiation complex (43S PIC), which is composed of the 40S ribosomal subunit, EIF1, eIF1A (EIF1AX), eIF3 complex, EIF5 and eIF2-GTP-initiator tRNA complex (eIF2 ternary complex). Interacts with EIF4G1; in specific 5'-UTR length and AUG context (PubMed:29987188). Interacts with EIF5; which in a mutual exclusive interaction associates either with EIF1 or with EIF2S2 on a common binding site (PubMed:22813744). Interacts with RENT2 (PubMed:11073994).
Associates with PYCARD/ASC and modulates its ability to collaborate with MEFV/pyrin and NLRP3/cryopyrin in NF-kappa-B and pro-caspase-1 activation. Suppresses kinase activity of NF-kappa-B inhibitor kinase (IKK) complex, expression of NF-kappa-B inducible genes and inhibits NF-kappa-B activation by cytokines and LPS.
Interacts with PYCARD/ASC (via pyrin domain).
Predominantly expressed in monocytes, macrophages and granulocytes.
Forms a multiprotein complex with MMACHC, MMADHC and MTR.
Found in all tissues tested, particularly abundant in skeletal muscle.
It is debated whether the reduction of free aquacob(II)alamin occurs spontaneously or is enzyme catalyzed.
Key enzyme in methionine and folate homeostasis responsible for the reactivation of methionine synthase (MTR/MS) activity by catalyzing the reductive methylation of MTR-bound cob(II)alamin (PubMed:17892308). Cobalamin (vitamin B12) forms a complex with MTR to serve as an intermediary in methyl transfer reactions that cycles between MTR-bound methylcob(III)alamin and MTR bound-cob(I)alamin forms, and occasional oxidative escape of the cob(I)alamin intermediate during the catalytic cycle leads to the inactive cob(II)alamin species (Probable). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (PubMed:27771510). Also necessary for the utilization of methyl groups from the folate cycle, thereby affecting transgenerational epigenetic inheritance (By similarity). Also acts as a molecular chaperone for methionine synthase by stabilizing apoMTR and incorporating methylcob(III)alamin into apoMTR to form the holoenzyme (PubMed:16769880). Also serves as an aquacob(III)alamin reductase by reducing aquacob(III)alamin to cob(II)alamin; this reduction leads to stimulation of the conversion of apoMTR and aquacob(III)alamin to MTR holoenzyme (PubMed:16769880).
Detected in the majority of epithelial cells in tumor and normal tissues. Expressed also in human umbilical vein endothelial cells.
Endothelial orphan receptor that acts as a key regulator of angiogenesis.
The transmembrane domain is not required for cleavage, but it is required for dimer formation.
Up-regulated in tumor endothelial cells. Up-regulated by DLL4.
Belongs to the steroid 5-alpha reductase family. Polyprenol reductase subfamily.
Expressed in preadipocytes (at protein level) (PubMed:26855069). Overexpressed in hormone-refractory prostate cancers (HRPC). Almost no or little expression in normal adult organs.
Plays a key role in early steps of protein N-linked glycosylation by being required for the conversion of polyprenol into dolichol (PubMed:20637498). Dolichols are required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-glycosylation (PubMed:20637498). Acts as a polyprenol reductase that promotes the reduction of the alpha-isoprene unit of polyprenols into dolichols in a NADP-dependent mechanism (PubMed:20637498). Also able to convert testosterone (T) into 5-alpha-dihydrotestosterone (DHT) (PubMed:17986282, PubMed:26855069).
E3 ubiquitin ligase that plays important roles in the regulation of neuronal apoptosis, selective autophagy or cell proliferation (PubMed:22023800, PubMed:19358823, PubMed:27562068). Stimulates the degradation of kinetochore ZW10 interacting protein ZWINT in a proteasome-dependent manner, leading to negative regulation of cell proliferation (PubMed:22023800). Inhibits autophagic degradation of diverse known targets while contributing to autophagy of midbodies. Autophagy-inhibitory activity involves MCL1, which TRIM17 assembles into complexes with the key autophagy regulator BECN1 (PubMed:27562068). Controls neuronal apoptosis by mediating ubiquitination and degradation of MCL1 to initiate neuronal death. In addition, regulates NFAT transcription factors NFATC3 and NFATC4 activities by preventing their nuclear localization, thus inhibiting their transcriptional activities. Decreases TRIM41-mediated degradation of ZSCAN2 thereby stimulating alpha-synuclein/SNCA transcription in neuronal cells (By similarity). Prevents the E3 ubiquitin-ligase activity of TRIM28 and its interaction with anti-apoptotic BCL2A1, blocking TRIM28 from ubiquitinating BCL2A1 (PubMed:19358823).
Interacts (via coiled coil) with TRIM44 (via coiled coil) (PubMed:19358823). Interacts with TRIM28; this interaction prevents TRIM28 activity on BCL2A1 (PubMed:30042493). Interacts with TRIM41; this interaction prevents TRIM41 activity on ZSCAN2 (By similarity). Interacts with BECN1 (PubMed:27562068). Interacts with NFATC3 and NFATC4; these interactions prevent NFATC3 and NFATC4 nuclear localization (By similarity).
Acetylation at Lys-19 drastically decreases the production of N-oleoyl and N-arachidonoyl glycines.
Expressed at highest levels in salivary gland and trachea. Also detected in thyroid gland, spinal cord, prostate, lung and fetal brain.
Mitochondrial acyltransferase which transfers the acyl group to the N-terminus of glycine (PubMed:22475485, PubMed:20305126). Conjugates numerous substrates, such as arachidonoyl-CoA and saturated medium and long-chain acyl-CoAs ranging from chain-length C8:0-CoA to C18:0-CoA, to form a variety of N-acylglycines. Shows a preference for monounsaturated fatty acid oleoyl-CoA (C18:1-CoA) as an acyl donor. Does not exhibit any activity toward C22:6-CoA and chenodeoxycholoyl-CoA, nor toward serine or alanine (PubMed:20305126).
Expressed in numerous tissues. Particularly prevalent in the adrenal gland, thyroid gland, heart and skeletal muscle.
Expression is decreased in Caco-2 cells upon PPARD activation.
Genetic variations in NPC1L1 influence low density lipoprotein cholesterol (LDL-C) content defining the low density lipoprotein cholesterol level quantitative trait locus 7 (LDLCQ7) [MIM:617966]. Inactivating variants may confer a lower risk of coronary heart disease (PubMed:25390462). Rare NPC1L1 variants also influence response to ezetimibe, a drug that reduces plasma LDL-C by blocking sterol absorption in enterocytes (PubMed:15679830).
Interacts with RAB11A, MYO5B and RAB11FIP2. Interaction with RAB11A, MYO5B and RAB11FIP2 is required for proper transport to the plasma membrane upon cholesterol depletion. Interacts with NPC2. Interacts with LIMA1 (PubMed:29880681).
Plays a major role in cholesterol homeostasis (PubMed:22095670). Critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte (PubMed:22095670). Involved in plant sterol absorption, it transports sitosterol, although at lower rates than cholesterol (By similarity). Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorption and is approved for the treatment of hypercholesterolemia (PubMed:15928087). May have a function in the transport of multiple lipids and their homeostasis, thereby influencing lipid metabolism regulation (PubMed:15671032). May be involved in caveolin trafficking from the plasma membrane (By similarity). In addition, acts as a negative regulator of NPC2 and down-regulates its expression and secretion by inhibiting its maturation and accelerating its degradation (PubMed:22095670).
Widely expressed. Expressed in liver. Also expressed in small intestine, pancreas, kidney, lung, pancreas, spleen, heart, gall bladder, brain, testis, stomach and muscle.
Isoform 3 and isoform 4 are phosphorylated on Ser-62 and Ser-64.
Binding protein for dimer of the RII-beta regulatory subunit of cAMP-dependent protein kinase (PKA) and also for the protein kinase C (PKC) and the phosphatase calcineurin (PP2B). Each enzyme is inhibited when bound to the anchoring protein. Also binds the beta2-adrenergic receptor. Part of a complex containing AKAP5, ADCY5, ADCY6 and PDE4C (By similarity). Interacts with ADCY8, and enhances its phosphorylation at lipid rafts.
Multivalent scaffold protein that anchors the cAMP-dependent protein kinase/PKA to cytoskeletal and/or organelle-associated proteins, targeting the signal carried by cAMP to specific intracellular effectors (PubMed:1512224). Association with the beta2-adrenergic receptor (beta2-AR) not only regulates beta2-AR signaling pathway, but also the activation by PKA by switching off the beta2-AR signaling cascade. Plays a role in long term synaptic potentiation by regulating protein trafficking from the dendritic recycling endosomes to the plasma membrane and controlling both structural and functional plasticity at excitatory synapses (PubMed:25589740).
Palmitoylated (PubMed:21771783, PubMed:25589740). Palmitoylation at Cys-36 and Cys-129 play a key role in the targeting of AKAP5 to lipid rafts (PubMed:21771783). Palmitoylation by ZDHHC2 is required for AKAP5 function in LTP-stimulated recycling endosome exocytosis (PubMed:25589740).
Postsynaptic recycling endosome membrane
Predominantly in the cerebral cortex and the postsynaptic densities of the forebrain, and to a lesser extent in adrenal medulla, lung and anterior pituitary.
The N-terminal region, which is highly basic, is required for interaction with calmodulin.
Activity is chloride-dependent (PubMed:18375752). Inhibited by AMP-PNP, gammaS-ATP, diadenosine triphosphate, 4,4'- diisothiocyanatostilbene-2,2'-disulfonate (DIDS) and Evans blue (PubMed:18375752).
Voltage-gated ATP nucleotide uniporter that can also transport the purine nucleotides ADP and GTP. Uses the membrane potential as the driving force to control ATP accumulation in lysosomes and secretory vesicles (PubMed:18375752, PubMed:23467297). By controlling ATP storage in lysosomes, regulates ATP-dependent proteins of these organelles (PubMed:35269509). Also indirectly regulates the exocytosis of ATP through its import into lysosomes in astrocytes and secretory vesicles such as adrenal chromaffin granules, mucin granules and synaptic vesicles (PubMed:18375752, PubMed:23467297).
Widely expressed, but more predominantly in adrenal gland, brain and thyroid.
High affinity receptor for the C-C type chemokines CCL17/TARC, CCL22/MDC and CKLF isoform 1/CKLF1. The activity of this receptor is mediated by G(i) proteins which activate a phosphatidylinositol-calcium second messenger system. Can function as a chemoattractant homing receptor on circulating memory lymphocytes and as a coreceptor for some primary HIV-2 isolates. In the CNS, could mediate hippocampal-neuron survival.
In natural killer cells, CCL22 binding induces phosphorylation on yet undefined Ser/Thr residues, most probably by beta-adrenergic receptor kinases 1 and 2.
Predominantly expressed in the thymus, in peripheral blood leukocytes, including T-cells, mostly CD4+ cells, and basophils, and in platelets; at lower levels, in the spleen and in monocytes (PubMed:10754297, PubMed:9169480). Detected also in macrophages, IL-2-activated natural killer cells and skin-homing memory T-cells, mostly the ones expressing the cutaneous lymphocyte antigen (CLA). Expressed in brain microvascular and coronary artery endothelial cells (PubMed:10754297).
Displays arylsulfatase activity at neutral pH, when co-expressed with SUMF1; arylsulfatase activity is measured in the secretion medium of retinal cell line, but no activity is recorded when measured in cell extracts (PubMed:19262745). Lacks arylsulfatase activity (PubMed:16500042).
Expressed in placenta, in embryonic stem cells, fetal eyes and lens.
The oxidation of Cys-93 residue to 3-oxoalanine (also known as C(alpha)-formylglycine) by SUMF1/Sulfatase-modifying factor 1, seems critical for catalytic activity.
A polymorphism in LTA accounts, in part, for susceptibility to leprosy linked to chromosome 6p21.3 (LPRS4) [MIM:610988].
Cytokine that in its homotrimeric form binds to TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM (PubMed:9462508). In its heterotrimeric form with LTB binds to TNFRSF3/LTBR. Lymphotoxin is produced by lymphocytes and is cytotoxic for a wide range of tumor cells in vitro and in vivo.
Cytokine that in its homotrimeric form binds to TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM. In its heterotrimeric form with LTB binds to TNFRSF3/LTBR. Lymphotoxin is produced by lymphocytes and is cytotoxic for a wide range of tumor cells in vitro and in vivo.
Homotrimer, and heterotrimer of either two LTB and one LTA subunits or (less prevalent) two LTA and one LTB subunits. Interacts with TNFRSF14 (PubMed:9462508).
Homotrimer, and heterotrimer of either two LTB and one LTA subunits or (less prevalent) two LTA and one LTB subunits. Interacts with TNFRSF14.
(Microbial infection) Interacts with Mason-Pfizer monkey virus protein Gag.
(Microbial infection) Interacts with human papillomavirus 16 L2 protein; this interaction is essential for virus intracellular transport during entry.
(Microbial infection) Is involved in intracellular targeting of D-type retrovirus gag polyproteins to the cytoplasmic assembly site.
Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. Binds to transport cargos and is involved in apical cargo transport such as rhodopsin-bearing vesicles in polarized epithelia. May also be a accessory component of axonemal dynein.
Expressed in heart, placenta, skeletal muscle kidney, pancreas, spleen, prostate, testis, ovary, ileum and colon. Expressed in lung endothelial and smooth muscle cells (at protein level).
Homodimer (Probable). The cytoplasmic dynein 1 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs); the composition seems to vary in respect to the IC, LIC and LC composition. The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits. The ICs and LICs bind directly to the HC dimer and the LCs assemble on the IC dimer. DYNLT1 and DYNLT3 compete for association with dynein IC (DYNC1I1 or DYNC1I2). Self-associates. Interacts with DYNC1I1 and DYNC1I2. Interacts with RHO. Interacts with DOC2A, DOC2B and SCN10A. Interacts with PVR. Interacts with SVIL isoform 2. Interacts with BMPR2. Interacts with GNB1; the interaction occurs in presence of guanine nucleotide-binding protein G(T) subunit gamma; the interaction diminishes the association of DYNLT1 with dynein IC (DYNC1I1 or DYNC1I2). Interacts with GNB2, GNB3 and GNB5; the interactions occur in presence of guanine nucleotide-binding protein G(T) subunit gamma (By similarity). Interacts with ACVR2B and ARHGEF2. Interacts with DNAI4 (By similarity).
Phosphorylated by BMPR2; the phosphorylation is abolished by BMPR2 mutations in exon 12 which lead to truncated forms of BMPR2 and which are linked to primary pulmonary hypertension (PPH1) [MIM:178600]. The phosphorylation status is proposed to regulate the association with the cytoplasmic dynein complex and may have role in cytoplasmic dynein cargo release (By similarity).
Plays a role in neuronal morphogenesis; the function is independent of cytoplasmic dynein and seems to be coupled to regulation of the actin cytoskeleton by enhancing Rac1 activity. The function in neurogenesis may be regulated by association with a G-protein beta-gamma dimer. May function as a receptor-independent activator of heterotrimeric G-protein signaling; the activation appears to be independent of a nucleotide exchange. Plays a role in regulating neurogenesis; inhibits the genesis of neurons from precursor cells during cortical development presumably by antagonizing ARHGEF2. Involved in the regulation of mitotic spindle orientation (By similarity). Unrelated to the role in retrograde microtubule-associated movement may play a role in the dimerization of cytoplasmic proteins/domains such as for ACVR2B. Binds to the cytoplasmic domain of ACVR2B and, in vitro, inhibits ACVR2B signaling (PubMed:27502274).
Highly expressed in heart, skeletal muscle, immune system, adrenal gland and liver.
Was originally thought to be a receptor for adrenomedullin.
Detected in heart and in blood lymphocytes and monocytes (at protein level) (PubMed:15505343). High expression in testis, moderate to low in spleen, heart, kidney, pancreas, skeletal muscle, brain and leukocyte (PubMed:9786900). Restricted expression in normal tissues, but widely expressed in cancer cells.
Homodimer (PubMed:32415067). Interacts with GRID2IP (By similarity). Interacts with EMB; interaction mediates SLC16A7 targeting to the plasma membrane (By similarity). Interacts with isoform 2 of BSG (By similarity).
Proton-coupled monocarboxylate symporter. Catalyzes the rapid transport across the plasma membrane of monocarboxylates such as L-lactate, pyruvate and ketone bodies, acetoacetate, beta-hydroxybutyrate and acetate (PubMed:9786900, PubMed:32415067). Dimerization is functionally required and both subunits work cooperatively in transporting substrate (PubMed:32415067).
Transport activity exhibits steep dependence on substrate concentration (PubMed:32415067). Substrate concentration sensitivity of SLC16A7 arises from the strong inter-subunit cooperativity of the SLC16A7 dimer during transport (PubMed:32415067). Inhibited by AR-C155858 (PubMed:32415067).
Defects in HYLS1 may be involved in ciliopathies other than hydrolethalus syndrome 1. A homozygous mutation resulting in a C-terminal extension of 11 residues has been found in patients diagnosed as Joubert syndrome, a ciliopathy presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease.
Belongs to the PNRC family. PNRC1 subfamily.
Expressed in liver, lung, fat and NK/T cells.
Interacts with many nuclear receptors including AR, ESR1, ESRRA, ESRRG, NR3C1/GR, NR5A1, PGR, TR, RAR and RXR. Interacts with GRB2.
Nuclear receptor coactivator. May play a role in signal transduction.
The interaction between PNRC1 and nuclear receptors is dependent on the SH3 binding motif.
Belongs to the eukaryotic ATPase B chain family.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(0) has three main subunits: a, b and c.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). CF(0) has three main subunits: a, b and c. Component of an ATP synthase complex composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5PD, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and ATP5MJ (By similarity).
Cleaves substrates with C-terminal arginine residues. Probably modulates the Wnt signaling pathway, by cleaving some undefined protein. May play a role in cleavage during prohormone processing.
In placenta, it is present within invasive trophoblasts and in the surrounding extracellular space. Also present in amnion cells, but is not readily apparent in the extracellular matrix of this cell type. Present in normal pituitary gland and neoplastic pituitary gland (especially POMC-, GH- and PRL-producing adenomas) (at protein level). Widely expressed.
Inhibited by 2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGTA) and guanidinoethylmercaptosuccinic acid (GEMSA). Inhibited by chelating agents such as EDTA and EGTA.
Homodimer (PubMed:20521842). Interacts with PRPF19; required for SETMAR recruitment to damaged DNA sites (PubMed:18263876). Interacts with PCNA (PubMed:20457750). Interacts with TOP2A; stimulates TOP2A topoisomerase activity (PubMed:18790802, PubMed:20457750). May interact with RAD9A and/or RAD9B (PubMed:20457750).
In the C-terminal section; belongs to the mariner transposase family.
In the N-terminal section; belongs to the class V-like SAM-binding methyltransferase superfamily.
Methylated. Methylation regulates activity in DNA decatenation.
Phosphorylated at Ser-508 by CHEK1 and dephosphorylated by protein phosphatase 2A/PP2A. Phosphorylation at Ser-508 is enhanced by DNA damage and promotes recruitment to damaged DNA. It stimulates DNA repair and impairs replication fork restart.
Protein derived from the fusion of a methylase with the transposase of an Hsmar1 transposon that plays a role in DNA double-strand break repair, stalled replication fork restart and DNA integration. DNA-binding protein, it is indirectly recruited to sites of DNA damage through protein-protein interactions. Has also kept a sequence-specific DNA-binding activity recognizing the 19-mer core of the 5'-terminal inverted repeats (TIRs) of the Hsmar1 element and displays a DNA nicking and end joining activity (PubMed:16332963, PubMed:16672366, PubMed:17877369, PubMed:17403897, PubMed:18263876, PubMed:22231448, PubMed:24573677, PubMed:20521842). In parallel, has a histone methyltransferase activity and methylates 'Lys-4' and 'Lys-36' of histone H3. Specifically mediates dimethylation of H3 'Lys-36' at sites of DNA double-strand break and may recruit proteins required for efficient DSB repair through non-homologous end-joining (PubMed:16332963, PubMed:21187428, PubMed:22231448). Also regulates replication fork processing, promoting replication fork restart and regulating DNA decatenation through stimulation of the topoisomerase activity of TOP2A (PubMed:18790802, PubMed:20457750).
The mariner transposase Hsmar1 region mediates DNA-binding. It has retained some of the nucleases activity but has lost its transposase activity because the active site contains an Asn in position 610 instead of an Asp residue.
The mariner transposase region in only present in primates and appeared 40-58 million years ago, after the insertion of a transposon downstream of a preexisting SET gene, followed by the de novo exonization of previously non-coding sequence and the creation of a new intron.
Widely expressed, with highest expression in placenta and ovary and lowest expression in skeletal muscle.
Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Functionally coupled with the E2 ubiquitin-protein ligases UB2D1, UB2D2 and UB2D3. Regulator of EGFR mediated signal transduction; upon EGF activation, ubiquitinates EGFR. Isoform 1, but not isoform 2, inhibits EGF stimulated MAPK1 activation. Promotes ubiquitination of SRC phosphorylated at 'Tyr-419'. In collaboration with CD2AP may act as regulatory checkpoint for Ret signaling by modulating the rate of RET degradation after ligand activation; CD2AP converts it from an inhibitor to a promoter of RET degradation; the function limits the potency of GDNF on neuronal survival.
Autoubiquitinated when phosphorylated at Tyr-341, enhanced by SRC; suggesting proteasomal degradation.
EF-hand-like and Sh2-like domains are required for N-terminal inhibition of E3 activity.
Interacts with ubiquitin-conjugating enzyme E2 UBE2D2 and UBE2D3. Isoform 1 interacts with EGFR (tyrosine phosphorylated). Interacts with the SH3 domain proteins LYN and CRK. Interacts (via RING-type zinc finger) with TGFB1I1 (via LIM zinc-binding domain 2); the interaction is direct and enhances the E3 activity. Interacts directly with RET (inactive) and CD2AP; dissociates from RET upon RET activation by GDNF which also increases the interaction with CD2AP suggesting dissociation as CBLC:CD2AP complex. Interacts with SRC; the interaction is enhanced when SRC is phosphorylated at 'Tyr-419'.
Phosphorylated on multiple tyrosine residues by SRC. Isoform 1, but not isoform 2, is phosphorylated on tyrosines by EGFR.
Phosphorylation at Tyr-341 is necessary and sufficient for the activation of E3 activity.
Contains two Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. Only motif 1 is essential for the association with nuclear receptors, while adjacent Ser-884 displays selectivity for nuclear receptors.
Frequently amplified or overexpressed in colon, breast and lung cancers.
Monomer and homodimer. Interacts with RBM39 (By similarity). Interacts in vitro with the basal transcription factors GTF2A and TBP, suggesting an autonomous transactivation function. Interacts with NCOA1, CRSP3, RBM14, the histone acetyltransferases EP300 and CREBBP, and with the methyltransferases NCOA6IP and PRMT2/HRMT1L1. Component of the MLL2/3 complex (also named ASCOM complex), at least composed of KMT2D/MLL2 or KMT2C/MLL3, ASH2L, RBBP5, WDR5, NCOA6, DPY30, KDM6A, PAXIP1/PTIP, PAGR1 and alpha- and beta-tubulin. Interacts with ZNF335; may enhance ligand-dependent transcriptional activation by nuclear hormone receptors.
Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Coactivates expression in an agonist- and AF2-dependent manner. Involved in the coactivation of different nuclear receptors, such as for steroids (GR and ERs), retinoids (RARs and RXRs), thyroid hormone (TRs), vitamin D3 (VDR) and prostanoids (PPARs). Probably functions as a general coactivator, rather than just a nuclear receptor coactivator. May also be involved in the coactivation of the NF-kappa-B pathway. May coactivate expression via a remodeling of chromatin and its interaction with histone acetyltransferase proteins.
Phosphorylation on Ser-884 leads to a strong decrease in binding to ESR1 and ESR2.
Ubiquitous. Highly expressed in brain, prostate, testis and ovary; weakly expressed in lung, thymus and small intestine.
Blood plasma, seminal plasma, urine, saliva, sweat, epithelial cells of various human glands, liver.
N-glycosylated. N-glycan at Asn-128: Hex5HexNAc4.
Stimulates lipid degradation in adipocytes and causes the extensive fat losses associated with some advanced cancers. May bind polyunsaturated fatty acids.
In absence of activation signal, PARP16 is autoinhibited by the PARP alpha-helical domain (also named HD region), which prevents effective NAD(+)-binding (By similarity). Activity is highly stimulated by signals, which unfold the PARP alpha-helical domain, relieving autoinhibition (By similarity).
Intracellular mono-ADP-ribosyltransferase that plays a role in different processes, such as protein translation and unfolded protein response (UPR), through the mono-ADP-ribosylation of proteins involved in those processes (PubMed:22701565, PubMed:23103912, PubMed:25043379, PubMed:34314702). Acts as an inhibitor of protein translation by catalyzing mono-ADP-ribosylation of ribosomal subunits, such as RPL14 and RPS6, thereby inhibiting polysome assembly and mRNA loading (PubMed:34314702). Mono-ADP-ribosylation of ribosomal subunits is promoted by NMNAT2 (PubMed:34314702). Involved in the unfolded protein response (UPR) by ADP-ribosylating and activating EIF2AK3 and ERN1, two important UPR effectors (PubMed:23103912). May also mediate mono-ADP-ribosylation of karyopherin KPNB1 a nuclear import factor (PubMed:22701565). May not modify proteins on arginine or cysteine residues compared to other mono-ADP-ribosyltransferases (PubMed:22701565).
The PARP alpha-helical domain (also named HD region) is regulatory, it packs against the catalytic domain.
Component of the back of Sec61 (BOS) complex, composed of NCLN/Nicalin, NOMO (NOMO1, NOMO2 or NOMO3) and TMEM147 (PubMed:15257293, PubMed:20538592, PubMed:36261522). The BOS complex is part of the multi-pass translocon (MPT) complex, composed of three subcomplexes, the GEL complex (composed of RAB5IF/OPTI and TMCO1), the BOS complex (composed of NCLN/Nicalin, NOMO and TMEM147) and the PAT complex (composed of WDR83OS/Asterix and CCDC47) (PubMed:36261522, PubMed:32820719). The MPT complex associates with the SEC61 complex (PubMed:36261522, PubMed:32820719).
Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes (PubMed:36261522, PubMed:32820719). The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions (PubMed:36261522). May antagonize Nodal signaling and subsequent organization of axial structures during mesodermal patterning, via its interaction with NOMO (By similarity).
Acetylated during myogenic differentiation.
Acts as an inhibitor of the small GTPase RHOA (PubMed:25588844). Plays a role in fetal mononuclear myoblast differentiation by promoting filopodia and myotube formation (PubMed:17150207). Maintains naive T lymphocytes in a quiescent state (PubMed:27556504).
Acts as an inhibitor of the small GTPase RHOA and plays several roles in the regulation of myoblast and hair cell differentiation, lymphocyte T proliferation and neutrophil polarization (PubMed:17150207, PubMed:24687993, PubMed:23241886, PubMed:24958875, PubMed:25588844, PubMed:27556504). Inhibits chemokine-induced T lymphocyte responses, such as cell adhesion, polarization and migration (PubMed:23241886). Involved also in the regulation of neutrophil polarization, chemotaxis and adhesion (By similarity). Required for normal development of inner and outer hair cell stereocilia within the cochlea of the inner ear (By similarity). Plays a role for maintaining the structural organization of the basal domain of stereocilia (By similarity). Involved in mechanosensory hair cell function (By similarity). Required for normal hearing (PubMed:24958875).
Cells lacking isoform 2 exhibit a severe reduction of myotube formation. In contrast, isoform 2 overexpression induces formation of filopodia.
Expressed in primary fetal mononuclear myoblast (PubMed:17150207). Expressed strongly in naive T lymphocytes (PubMed:27556504). Expressed weakly in activated T lymphocytes (at protein level) (PubMed:27556504). Expressed in blood cells and adult tissues of hematopoietic origin, such as the secondary lymphoid organs (PubMed:23241886). Expressed in cytotrophoblast (PubMed:9055809).
Homooligomer; homooligomerization is regulated by RHOC and leads to the formation of concatemers through the association of N- and C-termini (By similarity). Interacts with 14-3-3 proteins; these interactions occur during myogenic cell differentiation (PubMed:24687993). Interacts with HDAC6; this interaction occurs during early myogenic differentiation and prevents HDAC6 to deacetylate tubulin (PubMed:24687993). Interacts with DYSF; this interaction occurs during early myogenic differentiation (PubMed:24687993). Interacts with MYOF (PubMed:24687993). Interacts with RHOC (By similarity). Isoform 1 and isoform 2 interact (via active GTP- or inactive GDP-bound forms) with RHOA; these interactions are direct, block the loading of GTP to RHOA and decrease upon chemokine CCL19 stimulation in primary T lymphocytes (PubMed:23241886, PubMed:25588844). Isoform 2 interacts (phosphorylated form) with HDAC6; this interaction induces T cell proliferation arrest (PubMed:27556504). Isoform 2 interacts (phosphorylated form) with 14-3-3 proteins; these interactions induces T cell proliferation arrest (PubMed:27556504). Isoform 2 interacts with 14-3-3 proteins (PubMed:25588844). Isoform 2 interacts (via phosphorylated form) with YWHAB; this interaction occurs in a chemokine-dependent manner and does not compete for binding of RIPOR2 with RHOA nor blocks inhibition of RIPOR2-mediated RHOA activity (PubMed:25588844). Isoform 2 interacts with YWHAE (PubMed:25588844). Isoform 2 interacts with YWHAQ (PubMed:25588844).
Phosphorylated. Isoform 2 is phosphorylated in T cells (PubMed:27556504). Chemokine-induced phosphorylation of isoform 2 in neutrophils occurs in a PKC- and AKT-dependent manner, resulting in RIPOR2 interaction with YWHAB and stabilization (PubMed:25588844). Isoform 2 is phosphorylated by PKCA, AKT1 and MAPKAPK1A; in vitro (PubMed:25588844).
Up-regulated during fetal mononuclear myoblast differentiation (PubMed:17150207, PubMed:24687993). Up-regulated during cytotrophoblast differentiation (PubMed:9055809). Up-regulated during granulocyte differentiation (PubMed:9055809). Isoform 1 and isoform 2 are down-regulated in T lymphocytes upon T-cell antigen receptor (TCR) stimulation (PubMed:27556504). Isoform 1 and isoform 2 are up-regulated by FOXO1 (PubMed:23241886).
Acts as a sulfur carrier required for 2-thiolation of mcm(5)S(2)U at tRNA wobble positions of cytosolic tRNA(Lys), tRNA(Glu) and tRNA(Gln). Serves as sulfur donor in tRNA 2-thiolation reaction by being thiocarboxylated (-COSH) at its C-terminus by MOCS3. The sulfur is then transferred to tRNA to form 2-thiolation of mcm(5)S(2)U. Also acts as a ubiquitin-like protein (UBL) that is covalently conjugated via an isopeptide bond to lysine residues of target proteins such as MOCS3, ATPBD3, CTU2, USP15 and CAS. The thiocarboxylated form serves as substrate for conjugation and oxidative stress specifically induces the formation of UBL-protein conjugates.
(Microbial infection) Facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via two independent mechanisms, proteolytic cleavage of ACE2 receptor which promotes viral uptake, and cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry (PubMed:24227843, PubMed:32142651, PubMed:32404436, PubMed:34159616, PubMed:33051876). The cleavage of SARS-COV2 spike glycoprotein occurs between the S2 and S2' site (PubMed:32703818). Upon SARS-CoV-2 infection, increases syncytia formation by accelerating the fusion process (PubMed:34159616, PubMed:33051876). Proteolytically cleaves and activates the spike glycoproteins of human coronavirus 229E (HCoV-229E) and human coronavirus EMC (HCoV-EMC) and the fusion glycoproteins F0 of Sendai virus (SeV), human metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses (HPIV). Essential for spread and pathogenesis of influenza A virus (strains H1N1, H3N2 and H7N9); involved in proteolytic cleavage and activation of hemagglutinin (HA) protein which is essential for viral infectivity.
Expressed in several tissues that comprise large populations of epithelial cells with the highest level of transcripts measured in the prostate gland. Expressed in type II pneumocytes in the lung (at protein level). Expressed strongly in small intestine. Also expressed in colon, stomach and salivary gland. Coexpressed with ACE2 within lung type II pneumocytes, ileal absorptive enterocytes, intestinal epithelial cells, cornea, gallbladder and nasal goblet secretory cells (Ref.21).
Plasma membrane-anchored serine protease that cleaves at arginine residues (PubMed:32703818). Participates in proteolytic cascades of relevance for the normal physiologic function of the prostate (PubMed:25122198). Androgen-induced TMPRSS2 activates several substrates that include pro-hepatocyte growth factor/HGF, the protease activated receptor-2/F2RL1 or matriptase/ST14 leading to extracellular matrix disruption and metastasis of prostate cancer cells (PubMed:15537383, PubMed:26018085, PubMed:25122198). In addition, activates trigeminal neurons and contribute to both spontaneous pain and mechanical allodynia (By similarity).
Proteolytically processed; by an autocatalytic mechanism.
The catalytically active form interacts with ACE2.
Active complex is found in G1, S and G2 phases.
Complex that is thought to mediate chromatin assembly in DNA replication and DNA repair. Assembles histone octamers onto replicating DNA in vitro. CAF-1 performs the first step of the nucleosome assembly process, bringing newly synthesized histones H3 and H4 to replicating DNA; histones H2A/H2B can bind to this chromatin precursor subsequent to DNA replication to complete the histone octamer.
Differentially phosphorylated during cell cycle. During mitosis the p60 subunit of inactive CAF-1 is hyperphosphorylated and displaced into the cytosol. Progressivly dephosphorylated from G1 to S and G2 phase. Phosphorylated p60 is recruited to chromatin undergoing DNA repair after UV irradiation in G1, S or G2 phases.
Subunit of the CAF-1 complex that contains RBBP4, CHAF1B and CHAF1A. CHAF1A binds directly to CHAF1B. Only minor amounts of RBBP4 are complexed with CHAF1A and CHAF1B in G1 phase. In G2 and S phase also monomeric CHAF1B is detected. Interacts with histones H3.1, H3.2 and H3.1t (PubMed:33857403).
Belongs to the apolipoprotein C2 family.
Component of chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) in plasma. Plays an important role in lipoprotein metabolism as an activator of lipoprotein lipase.
Component of chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) in plasma. Plays an important role in lipoprotein metabolism as an activator of lipoprotein lipase. Both proapolipoprotein C-II and apolipoprotein C-II can activate lipoprotein lipase. In normolipidemic individuals, it is mainly distributed in the HDL, whereas in hypertriglyceridemic individuals, predominantly found in the VLDL and LDL.
Proapolipoprotein C-II is synthesized as a sialic acid containing glycoprotein which is subsequently desialylated prior to its proteolytic processing.
Proapolipoprotein C-II, the major form found in plasma undergoes proteolytic cleavage of its N-terminal hexapeptide to generate apolipoprotein C-II, which occurs as the minor form in plasma.
(Microbial infection) Cleaved and degraded by hepatitis A virus (HAV) protein 3CD allowing the virus to disrupt host TLR3 signaling.
(Microbial infection) Cleaved by CVB3 protease 3C allowing the virus to disrupt host TLR3 signaling.
(Microbial infection) Cleaved by HCV protease NS3/4A, thereby disrupting TLR3 signaling and preventing the establishment of an antiviral state.
(Microbial infection) Cleaved by Seneca Valley virus protease 3C allowing the virus to disrupt host TLR3 signaling.
(Microbial infection) Cleaved by protease 3C of human enterovirus D68 (EV68) allowing the virus to disrupt host TLR3 signaling.
(Microbial infection) Interacts (via C-terminus) with coxsackievirus B3 (CVB3) protease 3C.
(Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction allows the cleavage of TICAM1/TRIF and subsequent suppression of host innate immunity.
(Microbial infection) Interacts with hepatitis C virus (HCV) NS3/4A protease; this interaction leads to TICAM1 cleavage, thereby disrupting TLR3 signaling and preventing the establishment of an antiviral state.
Homodimer (PubMed:12539043). Found in a multi-helicase-TICAM1 complex at least composed of DHX36, DDX1, DDX21 and TICAM1; this complex exists in resting cells with or without poly(I:C) RNA ligand stimulation. Interacts (via TIR domain) with DDX21 (via C-terminus). Interacts (via TIR domain) with DHX36 (via C-terminus) (By similarity). Interacts with AZI2 and IRF7 (PubMed:12471095, PubMed:15611223). Interacts with TICAM2 in TLR4 recruitment (PubMed:12721283, PubMed:25736436). Interaction with PIAS4 inhibits the TICAM1-induced NF-kappa-B, IRF and IFNB1 activation (PubMed:15251447). Interacts with IKBKB and IKBKE. Interaction with SARM1 blocks TICAM1-dependent transcription factor activation (PubMed:16964262). Interacts with TRAF3 (By similarity). Interacts (when phosphorylated) with IRF3; following activation and phosphorylation on the pLxIS motif by TBK1, recruits IRF3 (PubMed:12471095, PubMed:14739303, PubMed:25636800, PubMed:27302953). Interacts with TBK1, TRAF6 and RIPK1 and these interactions are enhanced in the presence of WDFY1 (PubMed:14982987, PubMed:25736436). Interacts with TRAFD1 (By similarity). Interacts with UBQLN1 (via UBA domain) (PubMed:21695056). Interacts with TLR4 in response to LPS in a WDFY1-dependent manner (By similarity). Interacts with WDFY1 in response to poly(I:C) (By similarity). Interacts (via the TIR domain) with TLR3 in response to poly(I:C) and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with TRIM56 (PubMed:22948160). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines (By similarity). Interacts (via the TIR domain) with TLR5 (PubMed:20855887). Interacts with TRIM8 (PubMed:28747347).
Involved in innate immunity against invading pathogens. Adapter used by TLR3, TLR4 (through TICAM2) and TLR5 to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis (PubMed:12471095, PubMed:12539043, PubMed:14739303, PubMed:28747347). Ligand binding to these receptors results in TRIF recruitment through its TIR domain (PubMed:12471095, PubMed:12539043, PubMed:14739303). Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively (PubMed:12471095, PubMed:12539043, PubMed:14739303). Phosphorylation by TBK1 on the pLxIS motif leads to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent immunity against invading pathogens (PubMed:25636800). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines (By similarity).
Phosphorylated by TBK1 (PubMed:14530355, PubMed:25636800). Following activation, phosphorylated by TBK1 at Ser-210 in the pLxIS motif (PubMed:25636800). The phosphorylated pLxIS motif constitutes an IRF3-binding motif, leading to recruitment of the transcription factor IRF3 to induce type-I interferons and other cytokines (PubMed:25636800, PubMed:27302953).
Polyubiquitinated at Lys-229 by TRIM38 with 'Lys-48'-linked chains, leading to proteasomal degradation (PubMed:23056470). Polyubiquitinated with 'Lys-6'- and 'Lys-33'-linked chains in a TRIM8-dependent manner; ubiquitination disrupts the interaction with TBK1 and subsequent interferon production (PubMed:28747347).
The N-terminal domain (TRIF-NTD) is globular and consists of two alpha-helical subdomains connected by a 14-residue linker. It shares structural similarity with IFIT family members N-terminal regions.
The N-terminal region is essential for activation of the IFNB promoter activity.
The pLxIS motif constitutes an IRF3-binding motif: following phosphorylation by TBK1, the phosphorylated pLxIS motif of TICAM1 recruits IRF3 (PubMed:25636800). IRF3 is then phosphorylated and activated by TBK1 to induce type-I interferons and other cytokines (PubMed:25636800).
Ubiquitously expressed but with higher levels in liver.
Involved in the positive regulation of histone H3-K9 dimethylation.
Not found in adult tissues except in dorsal root ganglia.
The poly-alanine tract is polymorphic in the general population and contains a maximum of 14 alanines.
Expressed in the brain, heart, kidney, testis, pancreas, muscle and peripheral blood leukocytes.
Highest expression observed in liver, spleen and testis; moderate expression in the choroid plexus, hippocampus, cerebrum and cerebellum of brain, and in kidney cortex and kidney medulla. Also observed in heart, pancreas, muscle, lung, placenta, stomach and small intestine. Weakest expression seen in peripheral blood lymphocytes, colon, duodenum, jejunum, ileum and skeletal muscle.
Mediates sodium- and bicarbonate-dependent electrogenic sodium bicarbonate cotransport, with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3.
Allosterically activated by phosphatidylserine and/or phosphatidylinositol 4-phosphate (PtdIns(4)P), and phosphatidylinositol 5-phosphate (PtdIns(5)P) (PubMed:19038970). Interaction with MTMR9 increases catalytic activity towards phosphatidylinositol 3,5-bisphosphate (PubMed:19038970).
Homodimer (PubMed:19038970). Heterodimer (via C-terminus) with MTMR9 (via C-terminus) (PubMed:12890864, PubMed:16787938, PubMed:19038970, PubMed:23188820). Interacts with ALKBH4 (PubMed:23145062). Interacts with KCNN4 (PubMed:15831468). Interacts (via GRAM domain) with RAB1B (in GDP-bound form); the interaction regulates MTMR6 recruitment to the endoplasmic reticulum-Golgi intermediate compartment (PubMed:23188820).
Phosphatase that acts on lipids with a phosphoinositol headgroup (PubMed:19038970, PubMed:22647598). Dephosphorylates phosphatidylinositol 3-phosphate (PtdIns(3)P) and phosphatidylinositol 3,5-bisphosphate (PubMed:19038970, PubMed:22647598) (Probable). Binds with high affinity to phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) but also to phosphatidylinositol 3-phosphate (PtdIns(3)P), phosphatidylinositol 4-phosphate (PtdIns(4)P), and phosphatidylinositol 5-phosphate (PtdIns(5)P), phosphatidic acid and phosphatidylserine (PubMed:19038970). Negatively regulates ER-Golgi protein transport (By similarity). Probably in association with MTMR9, plays a role in the late stages of macropinocytosis by dephosphorylating phosphatidylinositol 3-phosphate in membrane ruffles (PubMed:24591580). Acts as a negative regulator of KCNN4/KCa3.1 channel activity in CD4(+) T-cells possibly by decreasing intracellular levels of phosphatidylinositol 3-phosphate (PubMed:15831468). Negatively regulates proliferation of reactivated CD4(+) T-cells (PubMed:16847315). In complex with MTMR9, negatively regulates DNA damage-induced apoptosis (PubMed:19038970, PubMed:22647598). The formation of the MTMR6-MTMR9 complex stabilizes both MTMR6 and MTMR9 protein levels (PubMed:19038970).
The C-terminus domain (aa 502-621) mediates interaction with MTMR9.
Expressed abundantly but differentially in a variety of neural and nonneural tissues. There is high expression in mammary gland, kidney, fetal brain, and lung and lower expression in heart and liver.
May play a role in cell motility and cell adhesion.
Activated by phosphatidylserine and tumor necrosis factor (TNF). Inhibited by scyphostatin.
Catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide (PubMed:16517606, PubMed:25180167). It has a relevant role in the homeostasis of membrane sphingolipids, thereby influencing membrane integrity, and endoplasmic reticulum organization and function (PubMed:31495489). May sensitize cells to DNA damage-induced apoptosis (PubMed:18505924). In skeletal muscle, mediates TNF-stimulated oxidant production (By similarity).
Expressed in skeletal muscle but a lower levels than isoform 1 (at protein level).
Expression is induced by DNA-damage and TNF.
Oligomer of 24 subunits. There are two types of subunits: L (light) chain and H (heavy) chain. The major chain can be light or heavy, depending on the species and tissue type. The functional molecule forms a roughly spherical shell with a diameter of 12 nm and contains a central cavity into which the insoluble mineral iron core is deposited. Iron enters the spherical protein shell through pores that are formed between subunits. Mutations leading to truncation or the addition of extra residues at the C-terminus interfere with normal pore formation and with iron accumulation.
Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation. Also plays a role in delivery of iron to cells. Mediates iron uptake in capsule cells of the developing kidney (By similarity).
Arginine transport is strongly inhibited by lysine, glutamate, leucine, glutamine, methionine and histidine, in the presence of Na(+) (PubMed:10903140). Also inhibited by protein kinase C (PKC) and treatment with phorbol-12-myristate-13-acetate (PMA) (PubMed:17329401).
Expressed in normal fibroblasts and those from LPI patients (PubMed:11078698). Also expressed in HUVECs, monocytes, RPE cells, and various carcinoma cell lines (PubMed:11742806, PubMed:14603368, PubMed:15280038, PubMed:17197568, PubMed:17329401). Expressed in brain, heart, testis, kidney, small intestine and parotis (PubMed:10903140). Highly expressed in T lymphocytes (PubMed:31705628).
Heterodimer with SLC3A2, that functions as an antiporter which operates as an efflux route by exporting cationic amino acids such as L-arginine from inside the cells in exchange with neutral amino acids like L-leucine, L-glutamine and isoleucine, plus sodium ions and may participate in nitric oxide synthesis (PubMed:9829974, PubMed:10903140, PubMed:16785209, PubMed:31705628, PubMed:15756301, PubMed:11311135, PubMed:17329401, PubMed:14603368, PubMed:19562367). Also exchanges L-arginine with L-lysine in a sodium-independent manner (PubMed:10903140). The transport mechanism is electroneutral and operates with a stoichiometry of 1:1 (PubMed:10903140). Contributes to ammonia-induced increase of L-arginine uptake in cerebral cortical astrocytes leading to ammonia-dependent increase of nitric oxide (NO) production via inducible nitric oxide synthase (iNOS) induction, and protein nitration (By similarity). May mediate transport of ornithine in retinal pigment epithelial (RPE) cells (PubMed:17197568). May also transport glycine betaine in a sodium dependent manner from the cumulus granulosa into the enclosed oocyte (By similarity).
(Microbial infection) Interacts with Streptococcus gordonii hsa protein.
Along with GYPB, GYPA is responsible for the MNS blood group system [MIM:111300]. The molecular basis of the GPA M/N bloodgroup antigen is a variation at positions 20 and 24. Ser-20 and Gly-24 correspond to M (shown); 'Leu-20' and 'Glu-24' correspond to N.
Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane (PubMed:35835865). Glycophorin A is the major intrinsic membrane protein of the erythrocyte. The N-terminal glycosylated segment, which lies outside the erythrocyte membrane, has MN blood group receptors. Appears to be important for the function of SLC4A1 and is required for high activity of SLC4A1. May be involved in translocation of SLC4A1 to the plasma membrane. Is a receptor for influenza virus. Is a receptor for Plasmodium falciparum erythrocyte-binding antigen 175 (EBA-175); binding of EBA-175 is dependent on sialic acid residues of the O-linked glycans. Appears to be a receptor for Hepatitis A virus (HAV).
GYPA polymorphisms are involved in resistance to malaria [MIM:611162].
Homodimer (PubMed:11313283, PubMed:1463744, PubMed:35835865). Component of the ankyrin-1 complex in the erythrocyte, composed of ANK1, RHCE, RHAG, SLC4A1, EPB42, GYPA, GYPB and AQP1 (PubMed:35835865). Interacts with SLC4A1; a GYPA monomer is bound at each end of the SLC4A1 dimer forming an heterotetramer (PubMed:35835865).
Involved in several unequal homologous recombinations or gene conversion events, predominantly with GYPB and more rarely with GYPE. The resulting fusion proteins are observed in different phenotypes and encode low incidence bloodgroup antigens.
The major O-linked glycan are NeuAc-alpha-(2-3)-Gal-beta-(1-3)-[NeuAc-alpha-(2-6)]-GalNAcOH (about 78 %) and NeuAc-alpha-(2-3)-Gal-beta-(1-3)-GalNAcOH (17 %). Minor O-glycans (5 %) include NeuAc-alpha-(2-3)-Gal-beta-(1-3)-[NeuAc-alpha-(2-6)]-GalNAcOH NeuAc-alpha-(2-8)-NeuAc-alpha-(2-3)-Gal-beta-(1-3)-GalNAcOH. About 1% of all O-linked glycans carry blood group A, B and H determinants. They derive from a type-2 precursor core structure, Gal-beta-(1,3)-GlcNAc-beta-1-R, and the antigens are synthesized by addition of fucose (H antigen-specific) and then N-acetylgalactosamine (A antigen-specific) or galactose (B antigen-specific). Specifically O-linked-glycans are NeuAc-alpha-(2-3)-Gal-beta-(1-3)-GalNAcOH-(6-1)-GlcNAc-beta-(4-1)-[Fuc-alpha-(1-2)]-Gal-beta-(3-1)-GalNAc-alpha (about 1%, B antigen-specific) and NeuAc-alpha-(2-3)-Gal-beta-(1-3)-GalNAcOH-(6-1)-GlcNAc-beta-(4-1)-[Fuc-alpha-(1-2)]-Gal-beta (1 %, O antigen-, A antigen- and B antigen-specific).
By DNA damage. Increases after UV irradiation, X-ray irradiation, oxidative stress (H(2)O(2)) or addition of the chemotherapeutic DNA-damaging agents etoposide, adriamycin, cisplatin or fluorouracil.
Component of some SCF (SKP1-cullin-F-box) protein ligase complex that plays a central role in G1 arrest following DNA damage. Specifically recognizes phosphorylated cyclin-D1 (CCND1), promoting its ubiquitination and degradation by the proteasome, resulting in G1 arrest. May act as a tumor suppressor.
Expression is cell-cycle regulated, and peaks at late G2 to early G1 phase (at protein level).
Highly expressed in brain. Expressed at moderate levels in most tissues, except bone marrow.
Phosphorylation at Ser-278 by ATM following gamma-irradiation results in its stabilization.
E3 ubiquitin-protein ligase that acts as a regulator of antiviral immune response and inflammation by mediating ubiquitination of substrates (PubMed:18773414, PubMed:27929086, PubMed:27992402). Acts as a regulator of innate immune defense against viruses by mediating 'Lys-63'-linked ubiquitination of MAVS, promoting MAVS polymerization and formation of three-stranded helical filaments on mitochondria (PubMed:27992402). Acts as a negative regulator of the NLRP3 inflammasome by catalyzing 'Lys-48'-linked ubiquitination of NLRP3, leading to its degradation (PubMed:27929086). Regulator of Src-induced anchorage independent cell growth (By similarity).
May form oligomers (PubMed:18773414). Interacts with isoform p52shc of SHC1 (By similarity).
Up-regulated in gastric adenocarcinomas.
By methyl-beta-cyclodextrin (By similarity). Up-regulated upon induced differentiation and in heat stress.
Homodimer. Heterodimer with ARL6IP1. Forms multimers. Interacts with ARL6. Interacts with prenylated RAB1A and RAB3A. Interacts with SLC1A1/EAAC1. Interacts with RTN2 (via first transmembrane domain). Does not interact with VAMP1, VAMP2 or VAMP3.
Regulates intracellular concentrations of taurine and glutamate. Negatively modulates SLC1A1/EAAC1 glutamate transport activity by decreasing its affinity for glutamate in a PKC activity-dependent manner. Plays a role in the retention of SLC1A1/EAAC1 in the endoplasmic reticulum.
Cytokine with antiviral, antitumour and immunomodulatory activities. Plays a critical role in the antiviral host defense, predominantly in the epithelial tissues. Acts as a ligand for the heterodimeric class II cytokine receptor composed of IL10RB and IFNLR1, and receptor engagement leads to the activation of the JAK/STAT signaling pathway resulting in the expression of IFN-stimulated genes (ISG), which mediate the antiviral state. Has a restricted receptor distribution and therefore restricted targets: is primarily active in epithelial cells and this cell type-selective action is because of the epithelial cell-specific expression of its receptor IFNLR1. Exerts an immunomodulatory effect by up-regulating MHC class I antigen expression.
(Microbial infection) Glucosylated at Thr-35 by C.difficile toxin TcdA in the colonic epithelium, and by P.sordellii toxin TcsL in the vascular endothelium.
Activated by the guanine nucleotide-exchange factors RAPGEF3 and RAPGEF4 in a cAMP-dependent manner. Nucleotide exchange is also specifically stimulated by RAPGEF5, RASGEF1A and RASGEF1B.
Interacts (GTP-bound form) with RUNDC3A. Interacts with RGS14; the interaction is GTP-dependent (By similarity). Interacts with PLCE1. Interacts with ARHGAP29, SGSM1, SGSM2 and SGSM3. Interacts (GTP-bound form preferentially) with TNIK (via the CNH domain); the interaction is direct and recruits RAP2A to the E3 ubiquitin ligase NEDD4. Interacts with MINK1. Interacts (GTP-bound form preferentially) with MAP4K4. Interacts with cytoskeletal actin.
Small GTP-binding protein which cycles between a GDP-bound inactive and a GTP-bound active form. In its active form interacts with and regulates several effectors including MAP4K4, MINK1 and TNIK. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. More generally, it is part of several signaling cascades and may regulate cytoskeletal rearrangements, cell migration, cell adhesion and cell spreading.
Ubiquitinated; undergoes 'Lys-63' monoubiquitination and diubiquitination by NEDD4. Multiple lysine residues are probably modified. Ubiquitination requires TNIK, prevents interaction with effectors and inactivates RAP2A.
Belongs to the Mediator complex subunit 25 family.
Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Required for RARA/RXRA-mediated transcription.
Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with CREBBP. Interacts with ESR1, GR, RARA, RXRA and THRB in a ligand-dependent fashion. Binds the Herpes simplex virus activator VP16.
Ubiquitously expressed. Highest levels in brain, heart, kidney, peripheral leukocytes, placenta, skeletal muscle and spleen.
Has an important role in epithelial desmosome-mediated cell-cell adhesion.
Although the active site residues are conserved, it lacks the conserved His residue which is normally found 9 residues before the catalytic His.
Binds DNA as a monomer. Binds TLE1 (By similarity). Interacts with FOXA1 and FOXA3 (PubMed:19919681). Interacts with PRKDC (PubMed:19478084). Interacts with AKT1 (By similarity). Interacts with TET1; this interaction may recruit TET1 to specific genomic loci to mediate their demethylation (PubMed:35798741).
Phosphorylation on Thr-156 abolishes binding to target promoters and subsequent transcription activation upon insulin stimulation.
Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues. Is thought to act as a 'pioneer' factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites. Binds DNA with the consensus sequence 5'-[AC]A[AT]T[AG]TT[GT][AG][CT]T[CT]-3' (By similarity). In embryonic development is required for notochord formation. Involved in the development of multiple endoderm-derived organ systems such as the liver, pancreas and lungs; FOXA1 and FOXA2 seem to have at least in part redundant roles. Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis; regulates the expression of genes important for glucose sensing in pancreatic beta-cells and glucose homeostasis. Involved in regulation of fat metabolism. Binds to fibrinogen beta promoter and is involved in IL6-induced fibrinogen beta transcriptional activation.
Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions and is involved in various processes including cellular proliferation, migration, adhesion and attachment, inflammatory response to CNS injury, regulation of vascular inflammation and adaptive responses of the heart to pressure overload and in myocardial function and remodeling. Binds to structural extracellular matrix (ECM) proteins and modulates the ECM in response to tissue damage, contributing to cardioprotective and adaptive ECM remodeling. Plays a role in ER stress response, via its interaction with the activating transcription factor 6 alpha (ATF6) which produces adaptive ER stress response factors and protects myocardium from pressure overload. May contribute to spinal presynaptic hypersensitivity and neuropathic pain states after peripheral nerve injury. May play a role in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury in a NOTCH1-dependent manner (By similarity).
Homopentamer; disulfide-linked. Interacts with PTBP3. Interacts with NOTCH1 (By similarity). Interacts (via EGF-like 3; calcium-binding domain) with ATF6 and facilitates its processing, activation and nuclear translocation.
Activity seems to be attenuated by autophosphorylation. Binding to the SL1 region of U3 small nucleolar RNA promotes auto-phosphorylation activity (PubMed:32103174). Inhibited by wortmannin (PubMed:9766667).
Autophosphorylated at two clusters, the T2609 cluster and the S2056 cluster (PubMed:33854234). Autophosphorylated on Ser-2056, Thr-2609, Thr-2638 and Thr-2647 (PubMed:14734805, PubMed:12186630, PubMed:12231622, PubMed:33854234). Ser-2056 and Thr-2609 are DNA damage-inducible phosphorylation sites (inducible with ionizing radiation, IR) dephosphorylated by PPP5C (PubMed:14734805, PubMed:12186630, PubMed:12231622). Autophosphorylation induces a conformational change that leads to remodeling of the DNA-PK complex, requisite for efficient end processing and DNA repair (PubMed:14734805, PubMed:12186630, PubMed:12231622). Autophosphorylation in trans within DNA-PK complexes loaded on DNA ends leads to the dissociation of PRKDC from DNA and the transition into the short-range NHEJ complex (PubMed:33854234). Autophosphorylation of the T2609 cluster is required for hematopoietic development and protein synthesis in erythrocytes precursors (By similarity).
DNA-PK is a heterotrimer of PRKDC and the Ku dimer (composed of XRCC6/Ku70 and XRCC5/Ku86) (PubMed:15758953, PubMed:25670504). Formation of this complex may be promoted by interaction with ILF3 (PubMed:9442054). Component of the core long-range non-homologous end joining (NHEJ) complex (also named DNA-PK complex) composed of PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF (PubMed:15758953, PubMed:25670504, PubMed:33854234). Additional component of the NHEJ complex includes PAXX (PubMed:25574025, PubMed:25941166). Following autophosphorylation, PRKDC dissociates from DNA (PubMed:33854234). Interacts with DNA-PKcs-interacting protein (KIP) with the region upstream the kinase domain (PubMed:9372844). PRKDC alone also interacts with and phosphorylates DCLRE1C, thereby activating the latent endonuclease activity of this protein (PubMed:11955432, PubMed:15071507, PubMed:14744996, PubMed:15456891, PubMed:15574326, PubMed:15811628, PubMed:15936993). Interacts with C1D (PubMed:9679063). Interacts with TTI1 and TELO2 (PubMed:20801936, PubMed:20427287, PubMed:20810650). Interacts with CIB1 (PubMed:9372844). Interacts with SETX (PubMed:23149945). Interacts with NR4A3; the DNA-dependent protein kinase complex DNA-PK phosphorylates and activates NR4A3 and prevents NR4A3 ubiquitination and degradation (PubMed:25852083). Interacts with BRAT1 (PubMed:22977523). Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA (PubMed:28712728). Interacts with KAT5 (PubMed:32832608).
Polyubiquitinated by RNF144A, leading to proteasomal degradation.
Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage (PubMed:11955432, PubMed:12649176, PubMed:14734805, PubMed:33854234). Involved in DNA non-homologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination (PubMed:11955432, PubMed:12649176, PubMed:14734805, PubMed:33854234). Must be bound to DNA to express its catalytic properties (PubMed:11955432). Promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C) (PubMed:11955432). Recruited by XRCC5 and XRCC6 to DNA ends and is required to (1) protect and align broken ends of DNA, thereby preventing their degradation, (2) and sequester the DSB for repair by NHEJ (PubMed:15574326, PubMed:11955432, PubMed:12649176, PubMed:14734805, PubMed:33854234). Act as a scaffold protein to aid the localization of DNA repair proteins to the site of damage (PubMed:15574326, PubMed:11955432, PubMed:12649176, PubMed:14734805). The assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step (PubMed:15574326, PubMed:11955432, PubMed:12649176, PubMed:14734805). Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion (By similarity). Also involved in modulation of transcription (PubMed:15574326, PubMed:11955432, PubMed:12649176, PubMed:14734805). As part of the DNA-PK complex, involved in the early steps of ribosome assembly by promoting the processing of precursor rRNA into mature 18S rRNA in the small-subunit processome (PubMed:32103174). Binding to U3 small nucleolar RNA, recruits PRKDC and XRCC5/Ku86 to the small-subunit processome (PubMed:32103174). Recognizes the substrate consensus sequence [ST]-Q (PubMed:15574326, PubMed:11955432, PubMed:12649176, PubMed:14734805). Phosphorylates 'Ser-139' of histone variant H2AX, thereby regulating DNA damage response mechanism (PubMed:14627815, PubMed:16046194). Phosphorylates ASF1A, DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, FH, SRF, NHEJ1/XLF, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC and RFA2 (PubMed:2507541, PubMed:2247066, PubMed:1597196, PubMed:8407951, PubMed:8464713, PubMed:9362500, PubMed:9139719, PubMed:10026262, PubMed:10467406, PubMed:12509254, PubMed:11889123, PubMed:14612514, PubMed:14599745, PubMed:15177042, PubMed:18644470, PubMed:26666690, PubMed:30247612, PubMed:14704337, PubMed:16397295, PubMed:26237645, PubMed:28712728, PubMed:29478807). Can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA (PubMed:9679063). Ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D (PubMed:9363941). Contributes to the determination of the circadian period length by antagonizing phosphorylation of CRY1 'Ser-588' and increasing CRY1 protein stability, most likely through an indirect mechanism (By similarity). Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728). Also regulates the cGAS-STING pathway by catalyzing phosphorylation of CGAS, thereby impairing CGAS oligomerization and activation (PubMed:33273464). Also regulates the cGAS-STING pathway by mediating phosphorylation of PARP1 (PubMed:35460603).
Highly expressed in skeletal muscle. Expressed in fetal cochlea. Also expressed in infant brain, fetal heart, pancreatic islet, melanocyte, pineal gland, placenta, corneal stroma, and parathyroid tumor. Weakly expressed or undetectable in adult brain, heart, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung and peripheral blood leukocytes. Expressed in rhabdomyosarcoma RD cells (at protein level).
Interacts with ubiquitin and polyubiquitinated proteins. Identified in a heterotrimeric complex with ubiquitin and SQSTM1, where ZFAND5 and SQSTM1 both interact with the same ubiquitin molecule (By similarity). Homooligomer and/or heterooligomer. Interacts (via A20-type domain) with IKBKG and RIPK1 and with TRAF6 (via AN1-type domain).
Involved in protein degradation via the ubiquitin-proteasome system. May act by anchoring ubiquitinated proteins to the proteasome. Plays a role in ubiquitin-mediated protein degradation during muscle atrophy. Plays a role in the regulation of NF-kappa-B activation and apoptosis. Inhibits NF-kappa-B activation triggered by overexpression of RIPK1 and TRAF6 but not of RELA. Inhibits also tumor necrosis factor (TNF), IL-1 and TLR4-induced NF-kappa-B activation in a dose-dependent manner. Overexpression sensitizes cells to TNF-induced apoptosis. Is a potent inhibitory factor for osteoclast differentiation.
The A20-type zinc finger directly binds polyubiquitin chains and associates with the 26S proteasome. The zinc-finger A20-type domain is essential for inhibition of NF-kappa-B activation (By similarity).
Highest levels in the placenta and fetal kidney, followed by fetal lung and brain. In adult brain, abundantly expressed in the cerebellum, followed by cerebral cortex, medulla and spinal cord; very low levels in total brain, frontal lobe, temporal lobe and putamen. Weak expression detected in adult brain, heart, lung, skeletal muscle, pancreas, spleen and prostate.
Interacts with WNT7B (By similarity). Interacts with MYOC (PubMed:19188438).
Receptor for Wnt proteins. Functions in the canonical Wnt/beta-catenin signaling pathway (By similarity). The canonical Wnt/beta-catenin signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues (Probable).
Adapter protein, which is found in various multiprotein chromatin complexes with histone acetyltransferase activity (HAT), which gives a specific tag for epigenetic transcription activation. Component of the NuA4 histone acetyltransferase complex which is responsible for acetylation of nucleosomal histones H4 and H2A. Plays a central role in MYC transcription activation, and also participates in cell transformation by MYC. Required for p53/TP53-, E2F1- and E2F4-mediated transcription activation. Also involved in transcription activation mediated by the adenovirus E1A, a viral oncoprotein that deregulates transcription of key genes. Probably acts by linking transcription factors such as E1A, MYC or E2F1 to HAT complexes such as STAGA thereby allowing transcription activation. Probably not required in the steps following histone acetylation in processes of transcription activation. May be required for the mitotic checkpoint and normal cell cycle progression. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome. May play a role in the formation and maintenance of the auditory system (By similarity).
Belongs to the PI3/PI4-kinase family. TRA1 subfamily.
Interacts with MYC, E2F1 and E2F4 transcription factors. Interacts directly with p53/TP53. Interacts with GCN5L2. Component of various HAT complexes. Component of the PCAF complex, at least composed of TADA2L/ADA2, SUPT3H, TADA3L/ADA3, TAF5L/PAF65-beta, TAF6L/PAF65-alpha, TAF10/TAFII30, TAF12/TAFII20, TAF9/TAFII31 and TRRAP. Component of the TFTC-HAT complex, at least composed of TAF5L, TAF6L, TADA3L, SUPT3H/SPT3, TAF2/TAFII150, TAF4/TAFII135, TAF5/TAFII100, GCN5L2/GCN5, TAF10 and TRRAP. Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6. Component of the STAGA complex, at least composed of SUPT3H, GCN5L2, SUPT7L, TAF5L, TAF6L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9. The STAGA core complex is associated with a subcomplex required for histone deubiquitination composed of ATXN7L3, ENY2 and USP22. Component of the BAF53 complex, at least composed of BAF53A, RUVBL1, SMARCA4/BRG1, and TRRAP, which preferentially acetylates histone H4 (and H2A) within nucleosomes. Interacts with NPAT. Interaction with TELO2 and TTI1. Component of a SWR1-like complex.
TRRAP mutation Phe-722 has been frequently found in cutaneous malignant melanoma, suggesting that TRRAP may play a role in the pathogenesis of melanoma.
The PI3K/PI4K domain is required for the recruitment of HAT complexes, and the MYC-dependent transactivation. Although it is strongly related to the PI3/PI4-kinase family, it lacks the typical motifs that constitute the catalytic site of PI3/PI4-kinase proteins, and lacks such activity.
Belongs to the selenoprotein M/F family.
May function as a thiol-disulfide oxidoreductase that participates in disulfide bond formation.
Atypical sulfotransferase family member with very low affinity for 3'-phospho-5'-adenylyl sulfate (PAPS) and very low catalytic activity towards L-triiodothyronine, thyroxine, estrone, p-nitrophenol, 2-naphthylamine, and 2-beta-naphthol. May have a role in the metabolism of drugs and neurotransmitters in the CNS.
Highly expressed in the cerebral cortex and frontal lobe, slightly less in the cerebellum, occipital and temporal lobes, relatively low in the medulla and putamen, and lowest in the spinal cord. No expression detected in the pancreas (PubMed:10698717). Highly expressed in fetal brain and occipital lobe, slightly less in the whole brain, frontal lobe, hippocampus, and lung, very low expression in cerebellum, medulla oblongata, temporal lobe, testis, kidney and appendix (PubMed:12039030).
Highly expressed in the liver, kidney and testis. Isoform 2 and isoform 3 are expressed specifically in testis and fetal liver, but not in the adult liver.
Key enzyme in the regulation of glycerol uptake and metabolism.
Acts as a transcriptional activator (By similarity). Activates transcription of CGA/alpha-GSU, via binding to the downstream activin regulatory element (DARE) in the gene promoter (By similarity). Plays a role in terminal differentiation of interneurons, such as amacrine and bipolar cells in the developing retina. Likely to play a regulatory role in the development of the ventral forebrain (By similarity). May play a role in craniofacial patterning and morphogenesis (By similarity).
Interacts (via homeobox DNA-binding domain) with POU4F2; this interaction enhances retinal ganglion cell (RGC) differentiation.
Expressed in germ cells as well as in somatic cells of the testis (at protein level).
Activation of this receptor requires concentrations that exceed the chloroquine concentrations observed in plasma of patients undergoing chloroquine treatment. However, chloroquine accumulates at much higher level in the skin where the receptor is located. Chloroquine-induced itch is very common among black Africans (up to 70%) but less common in other populations.
Orphan receptor. Probably involved in the function of nociceptive neurons. May regulate nociceptor function and/or development, including the sensation or modulation of pain. Potently activated by enkephalins including BAM22 (bovine adrenal medulla peptide 22) and BAM (8-22)(PubMed:26582731). BAM22 is the most potent compound and evoked a large and dose-dependent release of intracellular calcium in stably transfected cells. G(alpha)q proteins are involved in the calcium-signaling pathway. Activated by the antimalarial drug, chloroquine. May mediate chloroquine-induced itch, in a histamine-independent manner.
Homodimer (By similarity). Heterodimer; with a RXR molecule (By similarity). Binds DNA preferentially as a RAR/RXR heterodimer (By similarity). Heterodimerizes (via NR LBD) with RXRA (PubMed:29021580). Interacts weakly with NCOR2 (PubMed:12554770).
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence or presence of hormone ligand, acts mainly as an activator of gene expression due to weak binding to corepressors (PubMed:12554770). The RXRA/RARB heterodimer can act as a repressor on the DR1 element and as an activator on the DR5 element (PubMed:29021580). In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity).
The DNA-binding nuclear receptor domain and the NR LBD domain are required for binding of the RARB/RXRA heterodimer to both DR1 and DR5 DNA elements.
Can form oligomers through the transmembrane domains. Interacts with EMD; the interaction retains EMD at the inner nuclear membrane. Interacts with LMNA and LMNB2 (By similarity). Interacts with SUN2. Interacts with RNF26; this interaction is important to modulate innate immune signaling through the cGAS-STING pathway (PubMed:32614325). Interacts with CARD10 (PubMed:27991920). Interacts with gap junctions proteins GJB2/Cx26 and GJB4/Cx30 (PubMed:34050020).
Highest expression in placenta. Also found at lower levels in heart, ovary, spleen, small intestine, thymus, prostate and testis.
May have an important role in maintaining nuclear envelope structure by organizing protein complexes at the inner nuclear membrane. Required for retaining emerin at the inner nuclear membrane (By similarity). Plays a role in the modulation of innate immune signaling through the cGAS-STING pathway by interacting with RNF26 (PubMed:32614325). In addition, functions as a critical signaling component in mediating NF-kappa-B activation by acting downstream of EGFR and upstream of CARD10 (PubMed:27991920). Contributes to passive conductance current in cochlear glia-like supporting cells, mediated by gap junctions and necessary for hearing and speech discrimination (PubMed:34050020).
(Microbial infection) Interacts with S.typhimurium protein SseK3; SseK3 does not glycosylate TRIM32.
(Microbial infection) May play a significant role in mediating the biological activity of the HIV-1 Tat protein in vivo (PubMed:7778269). Binds specifically to the activation domain of HIV-1 Tat and can also interact with the HIV-2 and EIAV Tat proteins in vivo (PubMed:7778269).
Has an E3 ubiquitin ligase activity (PubMed:19349376, PubMed:31123703). Ubiquitinates DTNBP1 (dysbindin) and promotes its degradation (PubMed:19349376). May ubiquitinate BBS2 (PubMed:22500027). Ubiquitinates PIAS4/PIASY and promotes its degradation in keratinocytes treated with UVB and TNF-alpha (By similarity). Also acts as a regulator of autophagy by mediating formation of unanchored 'Lys-63'-linked polyubiquitin chains that activate ULK1: interaction with AMBRA1 is required for ULK1 activation (PubMed:31123703).
It self-associates (PubMed:19349376). Interacts with DTNBP1 (PubMed:19349376). Interacts with PIAS4/PIASY upon treatment with UVB and TNF-alpha (By similarity). Interacts with AMBRA1; promoting activation of ULK1 through unanchored 'Lys-63'-linked polyubiquitin chains (PubMed:31123703).
Spleen, thymus, prostate, testis, ovary, intestine, colon and skeletal muscle.
The disease is caused by variants affecting the gene represented in this entry. It has been suggested that TRIM32 might be the E3 ubiquitin ligase for BBS2, a component of the BBSome complex involved in ciliogenesis, that is ubiquitinated and degraded by the proteasome (PubMed:22500027).
Homodimer (PubMed:20691902). Interacts with the C-terminal Rho-GAP domain and the basic region of RACGAP1 (PubMed:14744859). The interaction with RACGAP1 inhibits its GAP activity towards CDC42 in vitro, which may be required for maintaining normal spindle morphology (PubMed:14744859). Interacts (via N-terminus) with the C-terminus of CENPE (via C-terminus); the interaction occurs during late mitosis (PubMed:15297875). Interacts (via N-terminus) with KIF4A (via C-terminus); the interaction is required for the progression of mitosis (PubMed:15297875, PubMed:16431929, PubMed:29848660). Interacts (via N-terminus) with KIF23 (via C-terminus); the interaction occurs during late mitosis (PubMed:15297875). Interacts with KIF14 and KIF20A (PubMed:15625105, PubMed:16431929). Interacts with PLK1 (PubMed:19468300). Interacts with KIF20B (PubMed:17409436).
Key regulator of cytokinesis that cross-links antiparrallel microtubules at an average distance of 35 nM. Essential for controlling the spatiotemporal formation of the midzone and successful cytokinesis. Required for KIF14 localization to the central spindle and midbody. Required to recruit PLK1 to the spindle. Stimulates PLK1 phosphorylation of RACGAP1 to allow recruitment of ECT2 to the central spindle. Acts as an oncogene for promoting bladder cancer cells proliferation, apoptosis inhibition and carcinogenic progression (PubMed:17409436).
Microtubule binding occurs via a basic patch in the central spectrin-like domain and requires also the unstructured C-terminal domain.
Overexpressed in bladder cancer cells (PubMed:17409436).
Phosphorylation by CDK1 in early mitosis holds PRC1 in an inactive monomeric state, during the metaphase to anaphase transition, PRC1 is dephosphorylated, promoting interaction with KIF4A, which then translocates PRC1 along mitotic spindles to the plus ends of antiparallel interdigitating microtubules. Dephosphorylation also promotes MT-bundling activity by allowing dimerization. Phosphorylation by CDK1 prevents PLK1-binding: upon degradation of CDK1 at anaphase and dephosphorylation, it is then phosphorylated by PLK1, leading to cytokinesis.
Predominantly expressed in testis and heart.
SPDYE1 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region (PubMed:12073013).
AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis (PubMed:15861136, PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781, PubMed:31204173). This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781, PubMed:31204173). Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface (By similarity). Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling (By similarity). Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport (PubMed:11994271). AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity (By similarity). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (By similarity). AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase) (PubMed:11154276). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis (PubMed:11154276). AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating the mTORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1 (PubMed:12150915, PubMed:12172553). Also regulates the mTORC1 signaling pathway by catalyzing phosphorylation of CASTOR1 and DEPDC5 (PubMed:31548394, PubMed:33594058). AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization (PubMed:10358075). In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319' (PubMed:10358075). FOXO3 and FOXO4 are phosphorylated on equivalent sites (PubMed:10358075). AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein) (PubMed:9829964). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1 (PubMed:9829964). AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (By similarity). Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis (By similarity). Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity (By similarity). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth (By similarity). AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) (PubMed:12176338, PubMed:12964941). AKT mediates the antiapoptotic effects of IGF-I (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). May be involved in the regulation of the placental development (By similarity). Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3 (PubMed:17726016). Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation (PubMed:20086174, PubMed:20231902). Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation (PubMed:19592491). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity (PubMed:10576742). Phosphorylation of BAD stimulates its pro-apoptotic activity (PubMed:10926925). Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 (PubMed:23431171). Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility (PubMed:20471940). Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation (PubMed:18507042). Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization (PubMed:16982699). These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation (PubMed:16139227). Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation (PubMed:20682768). Phosphorylates PCK1 at 'Ser-90', reducing the binding affinity of PCK1 to oxaloacetate and changing PCK1 into an atypical protein kinase activity using GTP as donor (PubMed:32322062). Also acts as an activator of TMEM175 potassium channel activity in response to growth factors: forms the lysoK(GF) complex together with TMEM175 and acts by promoting TMEM175 channel activation, independently of its protein kinase activity (PubMed:32228865). Acts as an inhibitor of tRNA methylation by mediating phosphorylation of the N-terminus of METTL1, thereby inhibiting METTL1 methyltransferase activity (PubMed:15861136). In response to LPAR1 receptor pathway activation, phosphorylates Rabin8/RAB3IP which alters its activity and phosphorylates WDR44 which induces WDR44 binding to Rab11, thereby switching Rab11 vesicular function from preciliary trafficking to endocytic recycling (PubMed:31204173).
Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B. Acetylation results in reduced phosphorylation and inhibition of activity. Deacetylated at Lys-14 and Lys-20 by SIRT1. SIRT1-mediated deacetylation relieves the inhibition.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.
Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction.
Cleavage by caspase-3/CASP3 (By similarity). Cleaved at the caspase-3 consensus site Asp-462 during apoptosis, resulting in down-regulation of the AKT signaling pathway and decreased cell survival (PubMed:23152800).
Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages.
Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.
In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain.
Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts (via the C-terminus) with CCDC88A (via its C-terminus). Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE-binding (By similarity). Interacts with AGAP2 (isoform 2/PIKE-A); the interaction occurs in the presence of guanine nucleotides. Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A and TCL1B. Interacts with CDKN1B; the interaction phosphorylates CDKN1B promoting 14-3-3 binding and cell-cycle progression. Interacts with MAP3K5 and TRAF6. Interacts with BAD, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with RAF1. Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with TNK2 and CLK2. Interacts (via the C-terminus) with THEM4 (via its C-terminus). Interacts with and phosphorylated by PDPK1. Interacts with PA2G4 (By similarity). Interacts with KIF14; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation (PubMed:24784001). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529). Forms a complex with WDFY2 and FOXO1 (By similarity). Interacts with FAM168A (PubMed:23251525). Interacts with SYAP1 (via phosphorylated form and BSD domain); this interaction is enhanced in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation and activates AKT1 (PubMed:23300339). Interacts with PKHM3 (By similarity). Interacts with FKBP5/FKBP51; promoting interaction between Akt/AKT1 and PHLPP1, thereby enhancing dephosphorylation and subsequent activation of Akt/AKT1 (PubMed:28147277). Interacts with TMEM175; leading to formation of the lysoK(GF) complex (PubMed:32228865). Acts as a negative regulator of the cGAS-STING pathway by mediating phosphorylation of CGAS during mitosis, leading to its inhibition (PubMed:26440888).
O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1. O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site.
PUBMED:19940129 has been retracted because the same data were used to represent different experimental conditions.
Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity (PubMed:12149249, PubMed:14761976, PubMed:15047712, PubMed:16266983, PubMed:17013611, PubMed:20978158, PubMed:9736715, PubMed:23799035, PubMed:8978681, PubMed:28147277). Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA (PubMed:20333297). This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation (PubMed:9512493). Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1 (PubMed:21464307, PubMed:8978681). Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1 (PubMed:15718470, PubMed:18456494, PubMed:20481595, PubMed:8978681). Ser-473 phosphorylation is enhanced by interaction with AGAP2 isoform 2 (PIKE-A) (PubMed:14761976). Ser-473 phosphorylation is enhanced in focal cortical dysplasias with Taylor-type balloon cells (PubMed:17013611). Ser-473 phosphorylation is enhanced by signaling through activated FLT3 (By similarity). Ser-473 is dephosphorylated by PHLPP (PubMed:28147277). Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase (PubMed:21329884). The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase (PubMed:21329884). Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (PubMed:9512493). AIM2 acts as an inhibitor of AKT1 by inhibiting phosphorylation Ser-473: AIM2 acts both by inhibiting the activity of PRKDC/DNA-PK kinase and promoting dephosphorylation by PP2A phosphatase (By similarity).
The AGC-kinase C-terminal mediates interaction with THEM4.
Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation (PubMed:20481595, PubMed:21392984, PubMed:9512493, PubMed:9736715). Inhibited by pyrrolopyrimidine inhibitors like aniline triazole and spiroindoline (PubMed:18456494, PubMed:20810279).
Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation (PubMed:19713527). When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated (PubMed:20059950). When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome (PubMed:20059950). Also ubiquitinated by TRIM13 leading to its proteasomal degradation (PubMed:21333377). Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation (PubMed:22410793). Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome (By similarity).
Component of the multisubunit TRAPP (transport protein particle) complex, which includes at least TRAPPC2, TRAPPC2L, TRAPPC3, TRAPPC3L, TRAPPC4, TRAPPC5, TRAPPC8, TRAPPC9, TRAPPC10, TRAPPC11 and TRAPPC12. Directly interacts with IKBKB and MAP3K14.
Expressed at high levels in muscle and kidney and to a lower extent in brain, heart and placenta.
Functions as an activator of NF-kappa-B through increased phosphorylation of the IKK complex. May function in neuronal cells differentiation. May play a role in vesicular transport from endoplasmic reticulum to Golgi.
Belongs to the WD repeat LIS1/nudF family.
Can self-associate. Interacts with DCX, dynein, dynactin, IQGAP1, KATNB1, NDE1, NDEL1, NUDC and RSN. Interacts with DISC1, and this interaction is enhanced by NDEL1. Interacts with DAB1 when DAB1 is phosphorylated in response to RELN/reelin signaling. Component of cytosolic PAF-AH IB, which is composed of PAFAH1B1 (alpha), PAFAH1B2 (beta) and PAFAH1B3 (gamma) subunits. Trimer formation is not essential for the catalytic activity of the enzyme which is contributed solely by the PAFAH1B2 (beta) and PAFAH1B3 (gamma) subunits.
Component of the cytosolic PAF-AH (I) heterotetrameric enzyme, which is composed of PAFAH1B1 (beta), PAFAH1B2 (alpha2) and PAFAH1B3 (alpha1) subunits. The catalytic activity of the enzyme resides in the alpha1 (PAFAH1B3) and alpha2 (PAFAH1B2) subunits, whereas the beta subunit (PAFAH1B1) has regulatory activity. Trimer formation is not essential for the catalytic activity. Interacts with the catalytic dimer of PAF-AH (I) heterotetrameric enzyme: interacts with PAFAH1B2 homodimer (alpha2/alpha2 homodimer), PAFAH1B3 homodimer (alpha1/alpha1 homodimer) and PAFAH1B2-PAFAH1B3 heterodimer (alpha2/alpha1 heterodimer) (By similarity). Interacts with IQGAP1, KATNB1 and NUDC. Interacts with DAB1 when DAB1 is phosphorylated in response to RELN/reelin signaling (By similarity). Can self-associate. Interacts with DCX, dynein, dynactin, NDE1, NDEL1 and RSN. Interacts with DISC1, and this interaction is enhanced by NDEL1. Interacts with INTS13. Interacts with DCDC1 (PubMed:22159412).
Dimerization mediated by the LisH domain may be required to activate dynein.
Fairly ubiquitous expression in both the frontal and occipital areas of the brain.
Originally the subunits of the type I platelet-activating factor (PAF) acetylhydrolase was named alpha (PAFAH1B1), beta (PAFAH1B2) and gamma (PAFAH1B3) (By similarity) (Ref.4). Now these subunits have been renamed beta (PAFAH1B1), alpha2 (PAFAH1B2) and alpha1 (PAFAH1B3) respectively (By similarity).
Positively regulates the activity of the minus-end directed microtubule motor protein dynein. May enhance dynein-mediated microtubule sliding by targeting dynein to the microtubule plus end. Required for several dynein- and microtubule-dependent processes such as the maintenance of Golgi integrity, the peripheral transport of microtubule fragments and the coupling of the nucleus and centrosome. Required during brain development for the proliferation of neuronal precursors and the migration of newly formed neurons from the ventricular/subventricular zone toward the cortical plate. Neuronal migration involves a process called nucleokinesis, whereby migrating cells extend an anterior process into which the nucleus subsequently translocates. During nucleokinesis dynein at the nuclear surface may translocate the nucleus towards the centrosome by exerting force on centrosomal microtubules. Also required for proper activation of Rho GTPases and actin polymerization at the leading edge of locomoting cerebellar neurons and postmigratory hippocampal neurons in response to calcium influx triggered via NMDA receptors. May also play a role in other forms of cell locomotion including the migration of fibroblasts during wound healing. Non-catalytic subunit of an acetylhydrolase complex which inactivates platelet-activating factor (PAF) by removing the acetyl group at the SN-2 position.
Regulatory subunit (beta subunit) of the cytosolic type I platelet-activating factor (PAF) acetylhydrolase (PAF-AH (I)), an enzyme that catalyzes the hydrolyze of the acetyl group at the sn-2 position of PAF and its analogs and participates in PAF inactivation. Regulates the PAF-AH (I) activity in a catalytic dimer composition-dependent manner (By similarity). Required for proper activation of Rho GTPases and actin polymerization at the leading edge of locomoting cerebellar neurons and postmigratory hippocampal neurons in response to calcium influx triggered via NMDA receptors (By similarity). Positively regulates the activity of the minus-end directed microtubule motor protein dynein. May enhance dynein-mediated microtubule sliding by targeting dynein to the microtubule plus end. Required for several dynein- and microtubule-dependent processes such as the maintenance of Golgi integrity, the peripheral transport of microtubule fragments and the coupling of the nucleus and centrosome. Required during brain development for the proliferation of neuronal precursors and the migration of newly formed neurons from the ventricular/subventricular zone toward the cortical plate. Neuronal migration involves a process called nucleokinesis, whereby migrating cells extend an anterior process into which the nucleus subsequently translocates. During nucleokinesis dynein at the nuclear surface may translocate the nucleus towards the centrosome by exerting force on centrosomal microtubules. May also play a role in other forms of cell locomotion including the migration of fibroblasts during wound healing. Required for dynein recruitment to microtubule plus ends and BICD2-bound cargos (PubMed:22956769). May modulate the Reelin pathway through interaction of the PAF-AH (I) catalytic dimer with VLDLR (By similarity).
In placental villi, detected only in the trophoblast layer (cytotrophoblast and syncytiotrophoblast). Not detected in stromal, endothelial or Hofbauer cells (at protein level).
Inhibitory regulator of the Ras-cyclic AMP pathway. Stimulates the GTPase of normal but not oncogenic Ras p21; this stimulation may be further increased in the presence of NCK1.
Interacts with SQSTM1. Interacts with SPSB1; the interaction does not promote degradation. Interacts with CAV2 (tyrosine phosphorylated form). Directly interacts with NCK1. Interacts with PDGFRB (tyrosine phosphorylated). Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1. Interacts with tyrosine-phosphorylated EPHB4 (PubMed:8955277).
Mutations in the SH2 domain of RASA seem to be oncogenic and cause basal cell carcinomas.
Phosphorylated by SRC and LCK. The phosphorylation SRC inhibits its ability to stimulate the Ras-GTPase activity, whereas phosphorylation by LCK does not display any effect on stimulation activity.
Expression is restricted to placenta, kidney, testis, uterus, fetal lung, and fetal and adult brain.
Forms a soluble 1:1 complex with AFM; this prevents oligomerization and is required for prolonged biological activity (PubMed:26902720). The complex with AFM may represent the physiological form in body fluids (PubMed:26902720). Interacts with FZD5 (By similarity). Interacts with PORCN (By similarity). Interacts (via intrinsically disordered linker region) with RECK; interaction with RECK confers ligand selectivity for Wnt7 in brain endothelial cells and allows these cells to selectively respond to Wnt7 (PubMed:30026314).
Ligand for members of the frizzled family of seven transmembrane receptors that functions in the canonical Wnt/beta-catenin signaling pathway (By similarity). Plays an important role in embryonic development, including dorsal versus ventral patterning during limb development, skeleton development and urogenital tract development (PubMed:16826533). Required for central nervous system (CNS) angiogenesis and blood-brain barrier regulation (PubMed:30026314). Required for normal, sexually dimorphic development of the Mullerian ducts, and for normal fertility in both sexes (By similarity). Required for normal neural stem cell proliferation in the hippocampus dentate gyrus (By similarity). Required for normal progress through the cell cycle in neural progenitor cells, for self-renewal of neural stem cells, and for normal neuronal differentiation and maturation (By similarity). Promotes formation of synapses via its interaction with FZD5 (By similarity).
Expressed in heart, brain, placenta, lung, muscle and kidney.
PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules.
The gene encoding this protein appears to have arisen by SVA-mediated retrotransposition of the SLC35G6 gene in the primate lineage.
Hydrolyzes fatty acids from S-acylated cysteine residues in proteins. Has depalmitoylating activity towards NRAS and DLG4/PSD95.
Belongs to the ornithine cyclodeaminase/mu-crystallin family.
Expressed in neural tissue, muscle and kidney.
Specifically catalyzes the reduction of imine bonds in brain substrates that may include cystathionine ketimine (CysK) and lanthionine ketimine (LK). Binds thyroid hormone which is a strong reversible inhibitor. Presumably involved in the regulation of the free intracellular concentration of triiodothyronine and access to its nuclear receptors.
Activated by factor XIIa (or XII), which cleaves each polypeptide after Arg-387 into the light chain, which contains the active site, and the heavy chain, which associates with high molecular weight (HMW) kininogen.
Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
Homodimer; disulfide-linked. Forms a heterodimer with SERPINA5. After activation the heavy and light chains are also linked by a disulfide bond.
Isoform 2 is produced by platelets and megakaryocytes but absent from other blood cells.
N-glycosylated on both chains. N-glycosylated sites mainly consist of nonfucosylated sialylated biantennary (in high abundance) and/or triantennary (in low abundance) complex structures. Glycosylation at Asn-163 uses a rare non-canonical Asn-X-Cys glycosite.
Belongs to the phosphatidylserine decarboxylase family. PSD-B subfamily. Eukaryotic type I sub-subfamily.
Catalyzes the formation of phosphatidylethanolamine (PtdEtn) from phosphatidylserine (PtdSer) (PubMed:30488656, PubMed:30858161). Plays a central role in phospholipid metabolism and in the interorganelle trafficking of phosphatidylserine. May be involved in lipid droplet biogenesis at the endoplasmic reticulum membrane (By similarity).
Heterodimer of a large membrane-associated beta subunit and a small pyruvoyl-containing alpha subunit.
Is synthesized initially as an inactive proenzyme. Formation of the active enzyme involves a self-maturation process in which the active site pyruvoyl group is generated from an internal serine residue via an autocatalytic post-translational modification. Two non-identical subunits are generated from the proenzyme in this reaction, and the pyruvate is formed at the N-terminus of the alpha chain, which is derived from the carboxyl end of the proenzyme. The autoendoproteolytic cleavage occurs by a canonical serine protease mechanism, in which the side chain hydroxyl group of the serine supplies its oxygen atom to form the C-terminus of the beta chain, while the remainder of the serine residue undergoes an oxidative deamination to produce ammonia and the pyruvoyl prosthetic group on the alpha chain. During this reaction, the Ser that is part of the protease active site of the proenzyme becomes the pyruvoyl prosthetic group, which constitutes an essential element of the active site of the mature decarboxylase.
(Microbial infection) Isoform 3/ZIN binds RIPK1 and HIV Vif.
4 different alternatively spliced mRNAs code for this protein isoform.
Allosterically activated by 'Lys-63'-linked di-ubiquitin.
E3 ubiquitin ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their ubiquitination (PubMed:34998453). Plays a role in the regulation of antiviral responses by promoting the degradation of TRAF3, TLR4 and TLR9 (PubMed:15107846, PubMed:19893624). In turn, down-regulates NF-kappa-B and IRF3 activation as well as beta interferon production. Participates also in the regulation of autophagy by ubiquitinating BECN1 leading to its degradation and autophagy inhibition (PubMed:25484083). Plays a role in ARC-dependent synaptic plasticity by mediating ARC ubiquitination resulting in its rapid proteasomal degradation (PubMed:24945773). Plays aso an essential role in spermatogenesis and male fertility (By similarity). Mechanistically, regulates meiosis by promoting the degradation of PRKACB through the ubiquitin-mediated lysosome pathway (By similarity). Modulates the gonadotropin-releasing hormone signal pathway by affecting the stability of STAU2 that is required for the microtubule-dependent transport of neuronal RNA from the cell body to the dendrite (By similarity).
Inhibits TNF and IL-1 mediated activation of NF-kappa-B. Promotes TNF and RIP mediated apoptosis.
Interacts with UBE2L3 and to some extent with UBE2L6. Interacts with TRAF3, TLR3, TLR4, TLR5 and TLR9. Isoform 3/ZIN binds RIPK1.
Phosphorylation at Ser-719 enhances acceptor ubiquitin binding and chain-type specificity towards 'Lys-63' di-ubiquitin but not di-ubiquitin with other linkage types.
Ubiquitous, with the highest levels of expression in testis and peripheral blood leukocytes.
Auxiliary subunit of GABA-B receptors that determine the pharmacology and kinetics of the receptor response. Increases agonist potency and markedly alter the G-protein signaling of the receptors by accelerating onset and promoting desensitization (By similarity).
Interacts as a tetramer with GABRB1 and GABRB2.
Present in a variety of fetal organs, with highest expression levels in the cochlea and brain and, in stark contrast, is detected only at extremely low levels in adult organs, such as brain and lung.
A chromosomal aberration involving FSTL3 is found in a case of B-cell chronic lymphocytic leukemia. Translocation t(11;19)(q13;p13) with CCDN1.
Interacts with INHBA and INHBB. Interacts with FN1. Interacts with ADAM12. Isoform 2 interacts with MLLT10; the interaction enhances MLLT10 in vitro transcriptional activity and self-association. Interacts with MSTN.
Isoform 1 or the secreted form is a binding and antagonizing protein for members of the TGF-beta family, such us activin, BMP2 and MSTN. Inhibits activin A-, activin B-, BMP2- and MSDT-induced cellular signaling; more effective on activin A than on activin B. Involved in bone formation; inhibits osteoclast differentiationc. Involved in hematopoiesis; involved in differentiation of hemopoietic progenitor cells, increases hematopoietic cell adhesion to fibronectin and seems to contribute to the adhesion of hematopoietic precursor cells to the bone marrow stroma. Isoform 2 or the nuclear form is probably involved in transcriptional regulation via interaction with MLLT10.
Extracellular lectin functioning as a pattern-recognition receptor in innate immunity. Binds the sugar moieties of pathogen-associated molecular patterns (PAMPs) displayed on microbes and activates the lectin pathway of the complement system. May also activate monocytes through a G protein-coupled receptor, FFAR2, inducing the secretion of interleukin-8/IL-8 (PubMed:21037097). Binds preferentially to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in a 2-3 linkage.
Homotrimer (PubMed:17897951). Interacts with elastin/ELN. Interacts (via Fibrinogen C-terminal domain) with FFAR2. Interacts with CRP; may regulate monocyte activation by FCN1.
Peripheral blood leukocytes, monocytes and granulocytes. Also detected in spleen, lung, and thymus, may be due to the presence of tissue macrophages or trapped blood in these tissues. Not detected on lymphocytes.
The fibrinogen C-terminal domain mediates calcium-dependent binding to carbohydrates and tethering to the cell surface in monocytes and granulocytes. The domain undergoes a conformational switch at pH under 6.2, and looses its carbohydrate-binding ability.